PMID- 27115053 TI - Mass-forming Intrahepatic Cholangiocarcinoma: Diffusion-weighted Imaging as a Preoperative Prognostic Marker. AB - Purpose To assess the value of diffusion-weighted (DW) imaging as a prognostic marker in preoperative evaluation of patients with mass-forming intrahepatic cholangiocarcinoma (ICC). Materials and Methods This retrospective study was approved by the institutional review board, and the informed consent requirement was waived. A total of 91 patients who underwent hepatic resection and DW imaging for mass-forming ICC were included. Two radiologists evaluated the degree of diffusion restriction of the tumors by using qualitative (visual) interpretation combined with quantitative analysis by volumetric evaluation of the whole tumor on DW images. Patients were classified into two groups: those in whom less than one-third of the tumor showed diffusion restriction (group 1) and those in whom more than one-third of the tumor showed diffusion restriction (group 2). Imaging findings in tumors were compared with pathology findings. Disease-free and overall survival rates were compared between the two groups by using the Kaplan Meier method with the log-rank test. Results There were 43 patients in group 1 and 48 patients in group 2. The 1- and 3-year disease-free survival rates were 30% and 16%, respectively, in group 1 and 75% and 64%, respectively, in group 2 (P < .001). The 1- and 3-year overall survival rates were 77% and 26%, respectively, in group 1 and 92% and 67%, respectively, in group 2 (P = .001). Multivariate analysis revealed that diffusion restriction (P = .024), differentiation (P = .030), and intrahepatic metastasis (P = .001) were independent prognostic factors for overall survival. Conclusion The degree of diffusion restriction on DW images may be a prognostic marker in preoperative evaluation of patients with mass-forming ICC. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 27115052 TI - Accuracy of fundus autofluorescence imaging for the diagnosis and monitoring of retinal conditions: a systematic review. AB - BACKGROUND: Natural fluorescence in the eye may be increased or decreased by diseases that affect the retina. Imaging methods based on confocal scanning laser ophthalmoscopy (cSLO) can detect this 'fundus autofluorescence' (FAF) by illuminating the retina using a specific light 'excitation wavelength'. FAF imaging could assist the diagnosis or monitoring of retinal conditions. However, the accuracy of the method for diagnosis or monitoring is unclear. OBJECTIVE: To conduct a systematic review to determine the accuracy of FAF imaging using cSLO for the diagnosis or monitoring of retinal conditions, including monitoring of response to therapy. DATA SOURCES: Electronic bibliographic databases; scrutiny of reference lists of included studies and relevant systematic reviews; and searches of internet pages of relevant organisations, meetings and trial registries. Databases included MEDLINE, EMBASE, The Cochrane Library, Web of Science and the Medion database of diagnostic accuracy studies. Searches covered 1990 to November 2014 and were limited to the English language. REVIEW METHODS: References were screened for relevance using prespecified inclusion criteria to capture a broad range of retinal conditions. Two reviewers assessed titles and abstracts independently. Full-text versions of relevant records were retrieved and screened by one reviewer and checked by a second. Data were extracted and critically appraised using the Quality Assessment of Diagnostic Accuracy Studies criteria (QUADAS) for assessing risk of bias in test accuracy studies by one reviewer and checked by a second. At all stages any reviewer disagreement was resolved through discussion or arbitration by a third reviewer. RESULTS: Eight primary research studies have investigated the diagnostic accuracy of FAF imaging in retinal conditions: choroidal neovascularisation (one study), reticular pseudodrusen (three studies), cystoid macular oedema (two studies) and diabetic macular oedema (two studies). Sensitivity of FAF imaging using an excitation wavelength of 488 nm was generally high (range 81-100%), but was lower (55% and 32%) in two studies using longer excitation wavelengths (514 nm and 790 nm, respectively). Specificity ranged from 34% to 100%. However, owing to limitations of the data, none of the studies provide conclusive evidence of the diagnostic accuracy of FAF imaging. LIMITATIONS: No studies on the accuracy of FAF imaging for monitoring the progression of retinal conditions or response to therapy were identified. Owing to study heterogeneity, pooling of diagnostic outcomes in meta analysis was not conducted. All included studies had high risk of bias. In most studies the patient spectrum was not reflective of those who would present in clinical practice and no studies adequately reported how FAF images were interpreted. CONCLUSIONS: Although already in use in clinical practice, it is unclear whether or not FAF imaging is accurate, and whether or not it is applied and interpreted consistently for the diagnosis and/or monitoring of retinal conditions. Well-designed prospective primary research studies, which conform to the paradigm of diagnostic test accuracy assessment, are required to investigate the accuracy of FAF imaging in diagnosis and monitoring of inherited retinal dystrophies, early age-related macular degeneration, geographic atrophy and central serous chorioretinopathy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014997. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27115054 TI - Imaging Outcomes of Liver Imaging Reporting and Data System Version 2014 Category 2, 3, and 4 Observations Detected at CT and MR Imaging. AB - Purpose To determine the proportion of untreated Liver Imaging Reporting and Data System (LI-RADS) version 2014 category 2, 3, and 4 observations that progress, remain stable, or decrease in category and to compare the cumulative incidence of progression in category. Materials and Methods In this retrospective, longitudinal, single-center, HIPAA-compliant, institutional review board-approved study, 157 patients (86 men and 71 women; mean age +/- standard deviation, 59.0 years +/- 9.7) underwent two or more multiphasic computed tomographic (CT) or magnetic resonance (MR) imaging examinations for hepatocellular carcinoma surveillance, with the first examination in 2011 or 2012. One radiologist reviewed baseline and follow-up CT and MR images (mean follow-up, 614 days). LI RADS categories issued in the clinical reports by using version 1.0 or version 2013 were converted to version 2014 retrospectively; category modifications were verified with another radiologist. For index category LR-2, LR-3, and LR-4 observations, the proportions that progressed, remained stable, or decreased in category were calculated. Cumulative incidence curves for progression were compared according to baseline LI-RADS category (by using log-rank tests). Results All 63 index LR-2 observations remained stable or decreased in category. Among 166 index LR-3 observations, seven (4%) progressed to LR-5, and eight (5%) progressed to LR-4. Among 52 index LR-4 observations, 20 (38%) progressed to a malignant category. The cumulative incidence of progression to a malignant category was higher for index LR-4 observations than for index LR-3 or LR-2 observations (each P < .001) but was not different between LR-3 and LR-2 observations (P = .155). The cumulative incidence of progression to at least category LR-4 was trend-level higher for index LR-3 observations than for LR-2 observations (P = .0502). Conclusion Observations classified according to LI-RADS version 2014 categories are associated with different imaging outcomes. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 27115055 TI - Cu(I)-Catalyzed Tandem Reaction of Carbene Coupling and Horner-Wadsworth-Emmons Type Olefination: Access toward Enynes. AB - A novel strategy to synthesize 1,3-enynes has been successfully developed based on Cu(I)-catalyzed cross-coupling of alpha-diazo phosphonates and alkynes with a subsequent Horner-Wadsworth-Emmons (HWE) type reaction. This method provides straightforward access to conjugated enynes with high efficiency, good stereoselectivity and excellent functional group compatibility. Copper(I) carbene migratory insertion plays a crucial role in this transformation. PMID- 27115056 TI - Tuning Complexity by Lithiation: A Family of Intergrowth Structures Using Condensed hypho-Icosahedra in the Li-Doped Ca-Zn System. AB - Cluster chemistry of intermetallics with valence electron counts (VECs) in the range of 2.0-3.0 is intriguing. Lithiation of polar intermetallics in this VEC region is found to be an effective chemical route to produce new complex structures with different stability mechanisms. In this work, two new complex intermetallic structures have been discovered in the Ca-Li-Zn system: Ca12LixZn59 x and Ca15LixZn75-x. Ca12LixZn59-x, x ~ 5.65(3)-14.95(3), forms in the trigonal space group R3m, with a = 9.074(1)-9.1699(2) A, c = 53.353(1)-53.602(1) A, and Z = 3. In comparison, Ca15LixZn75-x, x ~ 19.07(2), crystallizes in the space group P63/mmc, with a ~ 9.183(1) A, c ~ 45.191(5) A), and Z = 2. Both structures are members of a large intergrowth family featuring slabs of dimers (D) and trimers (T) stacking along [001], with the sequences DTDDTDDTD for Ca12LixZn59-x and TDDDTDDD for Ca15LixZn75-x. Each dimer consists of two face-sharing Zn-centered hypho-icosahedra, and each trimer comprises a Li-centered icosahedron sandwiched by two hypho-icosahedra. This intergrowth family includes several known intermetallic structure types involving very electropositive metals, e.g., SrMg5.2, Ba2Li4.21Al4.79, and Sr9Li17.5Al25.5. Because of cluster defects and condensation, both Ca12LixZn59-x and Ca15LixZn75-x are electronically akin to close-packed metals, and their structural stabilities can be interpreted by a Hume-Rothery mechanism rather than the Zintl-Klemm concept. PMID- 27115057 TI - Synthesis and Comprehensive Structural and Chiroptical Characterization of Enones Derived from (-)-alpha-Santonin by Experiment and Theory. AB - The aim of the present work is to explain the causes of the observed deviations from sector and helicity rules to determine the absolute configuration of optically active alpha,beta-unsaturated ketones by means of electronic circular dichroism (ECD). To this end, a series of model compounds with a common decahydronaphthalene skeleton representing both cisoid and transoid enones were synthesized. In the framework of this work, detailed dichroic studies supported by single crystal X-ray analysis were performed where possible. To assist the achievement of the desired objectives the conformational flexibility of the selected cis-enones through the dependence of solvent and temperature on the ECD spectra were examined. All experimental studies were supplemented by detailed DFT calculations. A notable result of the study is assessing the applicability of the enone sector and helicity rules in dichroic studies and potential restrictions. To this end, a number of factors that could determine the signs of the individual Cotton effects has been considered. Among these nonminimum structure effects, i.e., twisting of the enone chromophore and nonplanarity of the enone double bond can be mentioned. PMID- 27115058 TI - Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression. AB - CONTEXT: Prostate cancer metastases preferentially target bone, and the calcium sensing receptor (CaSR) may play a role in promoting this metastatic progression. OBJECTIVE: We evaluated the association of prostate tumor CaSR expression with lethal prostate cancer. DESIGN: A validated CaSR immunohistochemistry assay was performed on tumor tissue microarrays. Vitamin D receptor (VDR) expression and phosphatase and tensin homolog tumor status were previously assessed in a subset of cases by immunohistochemistry. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and pathological tumor node metastasis stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of CaSR expression with lethal prostate cancer. SETTING: The investigation was conducted in the Health Professionals Follow-up Study and Physicians' Health Study. PARTICIPANTS: We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009. MAIN OUTCOME: Participants were followed up or cancer-specific mortality or development of metastatic disease. RESULTS: On average, men were followed up 13.6 years, during which there were 83 lethal events. High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables (HR 2.0; 95% CI 1.2-3.3). Additionally, there was evidence of effect modification by VDR expression; CaSR was associated with lethal progression among men with low tumor VDR expression (HR 3.2; 95% CI 1.4-7.3) but not in cases with high tumor VDR expression (HR 0.8; 95% CI 0.2-3.0). CONCLUSIONS: Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases. PMID- 27115059 TI - Dynamics and Predictors of Serum TSH and fT4 Reference Limits in Early Pregnancy: A Study Within the Danish National Birth Cohort. AB - CONTEXT: Thyroid hormones are important developmental factors and levels should be adequate both in the pregnant woman and in the fetus. However, there is no consensus on maternal thyroid test reference limits in early pregnancy. OBJECTIVE: Estimation of week-to-week changes in and predictors of TSH and free T4 (fT4) reference limits in the first trimester of pregnancy. DESIGN: Measurement of TSH and fT4 in biobank sera collected in pregnancy weeks 5-19 from a random sample of the Danish National Birth Cohort that enrolled 101 032 pregnant in 1996-2002. SETTING: National cohort of pregnant women. PARTICIPANTS: Healthy participants (n = 6671) were identified and individual characteristics retrieved using interview data and data from Danish national health registers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reference limits for TSH and fT4 in each first trimester pregnancy week and predictors of these reference limits. RESULTS: TSH reference limits were very variable. Up to and including week 6, nonpregnancy reference limits could be used. In weeks 9-12, TSH upper reference limit was approximately 0.4 mU/L lower than the nonpregnancy upper limit. The TSH lower reference limit was approximately 0.1 mU/L. fT4 variations were reverse to those of TSH, but changes were small with approximately 4% higher reference limits during the weeks 9-12. TSH upper reference limit was lower in multiparous women and women with lower iodine intake but higher in obese women. fT4 was lower in smokers. CONCLUSIONS: TSH reference limits differ widely in the first trimester of pregnancy. The use of a uniform set of reference limits is an inordinate simplification that will lead to frequent misclassification and possibly to incorrect choice of therapy. PMID- 27115060 TI - Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes. AB - CONTEXT: Skeletal deterioration, leading to an increased risk of fracture, is a known complication of type 2 diabetes mellitus (T2D). Yet plausible mechanisms to account for skeletal fragility in T2D have not been clearly established. OBJECTIVE: The objective of the study was to determine whether bone material properties, as measured by reference point indentation, and advanced glycation endproducts (AGEs), as determined by skin autofluorescence (SAF), are related in patients with T2D. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a tertiary medical center. PATIENTS: Sixteen postmenopausal women with T2D and 19 matched controls participated in the study. MAIN OUTCOME MEASURES: Bone material strength index (BMSi) by in vivo reference point indentation, AGE accumulation by SAF, and circulating bone turnover markers were measured. RESULTS: BMSi was reduced by 9.2% in T2D (P = .02) and was inversely associated with the duration of T2D (r = -0.68, P = .004). Increased SAF was associated with reduced BMSi (r = -0.65, P = .006) and lower bone formation marker procollagen type 1 amino-terminal propeptide (r = -0.63, P = .01) in T2D, whereas no associations were seen in controls. SAF accounted for 26% of the age adjusted variance in BMSi in T2D (P = .03). CONCLUSIONS: Bone material properties are impaired in postmenopausal women with T2D as determined by reference point indentation. The results suggest a role for the accumulation of AGEs to account for inferior BMSi in T2D. PMID- 27115061 TI - Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes. AB - CONTEXT: In type 1 diabetes mellitus, low levels of insulin-like growth factor -1 (IGF-1) and IGF binding protein-3 (IGFBP-3) and high levels of GH and IGFBP-1 are present, probably due to portal vein insulinopenia. OBJECTIVE: To test the hypothesis that continuous ip insulin infusion (CIPII) has a more pronounced effect than sc insulin therapy on regulation of the GH-IGF-1 axis. DESIGN: This was a prospective, observational case-control study. Measurements were performed twice at a 26-week interval. SETTING: Two secondary care hospitals in the Netherlands participated in the study. PATIENTS: There were a total of 184 patients, age- and gender-matched, of which 39 used CIPII and 145 sc insulin therapy for the past 4 years. OUTCOMES: Primary endpoint included differences in IGF-1. Secondary outcomes were differences in GH, IGFBP-1, and IGFBP-3. RESULTS: IGF-1 was higher with CIPII as compared to SC insulin therapy: 124 MUg/liter (95% confidence interval [CI], 111-138) vs 108 MUg/liter (95% CI 102-115) (P = .035). Additionally, IGFBP-3 concentrations were higher and IGFBP-1 and GH concentrations were lower with CIPII as compared to SC insulin therapy: 3.78 mg/liter (95% CI, 3.49-4.10) vs 3.31 mg/liter (95% CI, 3.17-3.47) for IGFBP-3, 50.9 MUg/liter (95% CI, 37.9-68.2) vs 102.6 MUg/liter (95% CI, 87.8-119.8) for IGFBP-1 and 0.68 MUg/liter (95% CI, 0.44-1.06) vs 1.21 MUg/liter (95% CI, 0.95 1.54) for GH, respectively. In multivariate analysis, IGF-1 had no significant association with HbA1c. CONCLUSIONS: The GH-IGF-1 axis may be affected by the route of insulin administration with CIPII counteracting dysregulation of the GH IGF1 axis present during sc insulin therapy. PMID- 27115062 TI - Secular Changes in Postfracture Outcomes Over 2 Decades in Australia: A Time Trend Comparison of Excess Postfracture Mortality in Two Birth Controls Over Two Decades. AB - CONTEXT: Hip fracture incidence has been declining and life expectancy improving. However, trends of postfracture outcomes are unknown. OBJECTIVES: The objective of the study was to compare the refracture risk and excess mortality after osteoporotic fracture between two birth cohorts, over 2 decades. DESIGN: Prospective birth cohorts were followed up over 2 decades (1989-2004 and 2000 2014). SETTING: The study was conducted in community-dwelling participants in Dubbo, Australia. PARTICIPANTS: Women and men aged 60-80 years, participating in Dubbo Osteoporosis Epidemiology Study 1 (DOES 1; born before 1930) and Dubbo Osteoporosis Epidemiology Study 2 (DOES 2; born after 1930) participated in the study. MAIN OUTCOME MEASURE: Age-standardized fracture and mortality over two time intervals: (1989-2004 [DOES 1] and 2000-2014 [DOES 2]) were measured. RESULTS: The DOES 2 cohort had higher body mass index and bone mineral density and lower initial fracture rate than DOES 1, but similar refracture rates [age standardized refracture rates per 1000 person-years: women: 53 (95% confidence interval [CI] 42-63) and 51 (95% CI 41-60) and men: 53 (95% CI 38-69) and 55 (95% CI 40-71) for DOES 2 and DOES 1, respectively). Absolute postfracture mortality rates declined in DOES 2 compared with DOES 1, mirroring the improvement in general-population life expectancy. However, when compared with period-specific general-population mortality, there was a similar 2.1- to 2.6-fold increased mortality risk after a fracture in both cohorts (age-adjusted standardized mortality ratio, women: 2.05 [95% CI 1.43-2.83] and 2.43 [95% CI 1.95-2.99] and men: 2.56 [95% CI 1.78-3.58] and 2.48 [95% CI 1.87-3.22] for DOES 2 and DOES 1, respectively). CONCLUSION: Over the 2 decades, despite the decline in the prevalence of fracture risk factors, general-population mortality, and initial fracture incidence, there was no improvement in postfracture outcomes. Refracture rates were similar and fracture-associated mortality was 2-fold higher than expected. These data indicate that the low postfracture treatment rates are still a major problem. PMID- 27115063 TI - Vitamin D-Fortified Bread Is as Effective as Supplement in Improving Vitamin D Status: A Randomized Clinical Trial. AB - CONTEXT: Bread can potentially be a suitable vehicle for fortification with vitamin D. OBJECTIVE: This study was undertaken to evaluate the following: 1) the bioavailability of vitamin D from the fortified Iranian bread and 2) the possible effects of daily consumption of the fortified bread on certain health aspects. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, double-blind, placebo controlled trial conducted over 8 weeks in 90 healthy subjects aged 20-60 years. INTERVENTION: Subjects were randomly allocated to one of three groups: 1) fortified bread (FP; 50 g bread fortified with 25 MUg vitamin D3 plus placebo daily; n = 30); 2) supplement (SP; 50 g plain bread plus 25 MUg vitamin D supplement daily; n = 30); and 3) control (CP; 50 g plain bread plus placebo daily; n = 30). OUTCOME MEASURES: Initial and final anthropometric and biochemical assessments were performed. RESULTS: The within-group changes of serum 25-hydroxyvitamin D concentrations were 39.0 +/- 22.6 (P < .001), 28.9 +/- 31.2 (P < .001), and -9.2 +/- 12.3 nmol/L in the FP, SP, and CP groups, respectively. Only in FP and SP groups, serum intact PTH concentrations decreased approximately 13.5% and 14.5%, respectively. Visceral fat also showed a significant decrement in FP (-1.05% +/- 1.4%; P <= .001) and SP (-0.96% +/- 1.7%; P = .006). Serum low-density lipoprotein cholesterol concentration showed a within-group reduction in FP (-10.4 +/- 11.2 mg/dL; P < .001) and an insignificant decrement in SP (-6.6 +/- 20.2 mg/dL; P = .083). Serum high-density lipoprotein increased in both vitamin D-supplemented groups (FP: 9.7 +/- 7.6 vs SP: 5.7 +/- 6.7 mg/dL; P < .001). CONCLUSION: Vitamin D-fortified bread could be potentially effective in raising circulating 25-hydroxyvitamin D levels of the population to nearly adequate levels. PMID- 27115064 TI - Enantioselective Total Syntheses of Various Amphilectane and Serrulatane Diterpenoids via Cope Rearrangements. AB - Ampilectane and serrulatane natural products are structurally and stereochemically complex compounds that display various potent pharmacological activities ranging from anti-inflammatory to antituberculosis. A general synthetic route toward this family of natural products has been developed, which accomplished a number of amphilectane and serrulatane natural products. The key step employed a stereoselective Cope rearrangement either promoted by gold catalysis or thermal conditions, while a regioselective gold-catalyzed 6-endo-dig cyclization was optimized to afford a precursor. The preparation of the chiral beta-ketoester as a starting material was established via an optimized asymmetric 1,4-addition followed by trapping with Mander's reagent, and this initially installed stereogenic center provided good control in the subsequent introduction of all the other stereocenters. A rarely investigated one-pot conversion of alpha pyrone into phenol was also examined to enable the syntheses. DFT calculations explain the high stereoselectivity of the Cope rearrangement of the intermediate that eventually led to amphilectolide and caribenol A. PMID- 27115065 TI - Radiation dose of 18F-FDG to lactating breasts, its effect on the effective dose and a more accurate effective dose from 18F-FDG. AB - INTRODUCTION: Lactating breasts have greater uptake of fluorine-18 fluorodeoxyglucose (F-FDG) than nonlactating breasts; however, there are no published data on the radiation dose from F-FDG to lactating breasts or this effect on the effective dose (ED). In addition, the International Commission on Radiological Protection's (ICRP) most recently published ED of 1.9*10 mSv/MBq from F-FDG was calculated using weighting factors that have since been superseded. We therefore calculated the F-FDG radiation dose to the lactating breast, its effect on the ED and calculated more up-to-date EDs from F-FDG for nonlactating patients. METHODS: Breast uptake of F-FDG and volume were determined from PET/CT images of a lactating patient. These data, together with previously published biokinetic data on F-FDG, were used to calculate a radiation dose to the lactating breasts and its effect on the ED. In addition, tissue weighting factors and organ doses from the ICRP publications 103 and 106 were used to calculate more up-to-date EDs from F-FDG in nonlactating patients. RESULTS: The absorbed dose to the lactating breast from F-FDG is 1.75*10 mGy/MBq, which results in an increase in the ED of 6%. In nonlactating patients, a more up-to date ED from F-FDG is 1.77*10 mSv/MBq for women and 1.64*10 mSv/MBq for men. CONCLUSION: This is the first reported dosimetry of F-FDG in lactating breasts, data that are required when justifying the radiation dose from an F-FDG PET scan in lactating patients. In addition, we calculated more up-to-date EDs from F-FDG that are lower than the current widely reported ED and should be used in future publications on F-FDG. PMID- 27115066 TI - Variability in the amount of fluorine-18 fluorodeoxyglucose excreted in urine measured from oncology patients during PET/computed tomography imaging. AB - The objectives of this work were to estimate the amount of fluorine-18 fluorodeoxyglucose (F-FDG) excreted (AFE) in the patient urine during the uptake phase as percentage of the injected activity and to examine the effect of blood glucose levels (BGL) on the excreted amount and whether it varies among men and women using statistical analysis methods. Radiation dose rates were measured at 1 m from 50 patients, 24 men and 26 women, before and after the first void using a calibrated ionization chamber. The F-FDG was injected in the patients using a calibrated automatic dose injection system. Statistical analysis using hypothesis testing was carried out. Patients with BGL above 5 mmol/l had a higher AFE of 12.3% in comparison with 8.3% of the patients with BGL below 5 mmol/l. A statistically nonsignificant correlation (r=0.183, P<0.249) between AFE and BGL was found; a nonsignificant difference was found in the AFE measured among the male and female patients. The AFE measured was 12+/-6%, with a range of (2-30%). There was a wide variation in the first void time of 39+/-8 min, with a range of (17-68) min. A simple noninvasive measurement method is presented that enabled the estimation of the amount of F-FDG excreted from the patient during voiding. Statistical analysis concluded that the amount of F-FDG excreted does not depend on sex, but is perhaps influenced by BGL. PMID- 27115070 TI - A prospective-longitudinal study on the association of anxiety disorders prior to pregnancy and pregnancy- and child-related fears. AB - This study aimed to investigate the relation between anxiety disorders prior to pregnancy and specific pregnancy- and child-related fears during pregnancy and after delivery. 306 expectant mothers were interviewed regarding anxiety (and depressive) disorders prior to pregnancy and pregnancy- and child-related fears (e.g. fear of labor pain, fear of infant injury) using the Composite International Diagnostic Interview for Women (CIDI-V). Pregnancy- and child related fears were particularly pronounced in women with multiple anxiety disorders and women with comorbid anxiety and depressive disorders prior to pregnancy. Further analyses revealed associations between particular anxiety disorders and specific pregnancy- and child-related fears. Results remained stable when considering potential confounders such as maternal age, education, marital status, parity, prior abortion and preterm delivery or low birth weight. Our study suggests that especially women with multiple anxiety and/or comorbid depressive disorders may benefit from early targeted interventions to prevent an escalation of anxiety and fears over the peripartum period. PMID- 27115071 TI - Different relationships between central dopamine system and sub-processes of inhibition: Spontaneous eye blink rate relates with N2 but not P3 in a Go/Nogo task. AB - Clinical studies show that dysfunction of the dopamine (DA) system could differently modulate N2 and P3 components in a Go/Nogo task, a classical inhibition task. However, results of previous clinical studies cannot be arbitrarily generalized to healthy adults. Thus, the present exploratory study aimed to investigate whether there are significant and variable relationships between individual differences of the DA system in normal healthy persons and N2- and P3-related sub-processes of inhibition in a Go/Nogo task. DA function was measured by spontaneous eye blink rate (EBR), which is an effective clinical and non-invasive measure and strongly related to the activity of the central dopaminergic system. A total of 28 young adults participated in this experiment. Results showed that Nogo-N2 and Nogo-P3 of all participants were larger than Go N2 and Go-P3, while Nogo-N2 and Nogo-P3 were significantly related with Nogo accuracy. Moreover, it was shown that higher EBRs were significantly correlated with larger and more negative N2 amplitudes under Go- and Nogo-conditions; however, there were no significant correlations between participants' EBRs and N2 latencies, and between EBRs and average amplitudes of P3 under the two conditions. Based on these results, we concluded that the central DA system was associated with the N2-related conflict monitoring rather than P3-related sub process of inhibition. PMID- 27115073 TI - MRI in the evaluation of localization-related epilepsy. AB - This article covers the MRI evaluation of patients with epilepsy, with a focus on neuroimaging in those with localization-related epilepsy who may be potential epilepsy surgery candidates. The article includes structural MRI to identify a lesion, functional MRI to identify the eloquent cortex and diffusion tensor imaging to identify the eloquent white matter tracts. We consider the equipment, protocol or procedures, and reporting of MRI in patients with epilepsy. Recommendations for both adult and pediatric patients are described for protocols and procedures. The authors hope that this article will provide a standardized approach for clinical imaging of patients with suspected localization-related epilepsy who may be evaluated for epilepsy surgery. J. Magn. Reson. Imaging 2016. PMID- 27115074 TI - Factors Associated With Utilization of Cardiac Rehabilitation Among Patients With Ischemic Heart Disease in the Veterans Health Administration: A QUALITATIVE STUDY. AB - BACKGROUND: Cardiac rehabilitation (CR) programs reduce morbidity and mortality in patients with ischemic heart disease but are vastly underutilized in the United States, including the Veterans Health Administration (VA) Healthcare System. Numerous barriers affecting utilization have been identified in other health care systems, but the specific factors affecting Veterans are unknown. We sought to identify barriers and facilitators associated with utilization of CR in VA facilities. METHODS: We performed a qualitative study of 56 VA patients, providers, and CR program managers at 30 VA facilities across the United States. We conducted semistructured interviews with key informants to explore their attitudes and knowledge toward CR. Interviews were conducted until thematic saturation occurred. Analyses using grounded theory to identify key themes were conducted using the qualitative data analysis package ATLAS.ti. RESULTS: We identified 6 themes as barriers and 5 as facilitators. The most common barriers to participation in CR were patient transportation issues (68%), lack of patient willingness to participate (41%), and no access to a nearby VA hospital with a CR program (30%). The most common facilitators were involvement of a dedicated provider or "clinical champion" (50%), provider knowledge of or experience with CR (48%), and patient desire for additional medical support (32%). CONCLUSIONS: Our findings suggest that addressing access issues and educating and activating providers on CR may increase utilization of CR programs. Targeting these specific factors may improve utilization of CR programs. PMID- 27115072 TI - The effects of graded levels of calorie restriction: VII. Topological rearrangement of hypothalamic aging networks. AB - Connectivity in a gene-gene network declines with age, typically within gene clusters. We explored the effect of short-term (3 months) graded calorie restriction (CR) (up to 40 %) on network structure of aging-associated genes in the murine hypothalamus by using conditional mutual information. The networks showed a topological rearrangement when exposed to graded CR with a higher relative within cluster connectivity at 40CR. We observed changes in gene centrality concordant with changes in CR level, with Ppargc1a, and Ppt1 having increased centrality and Etfdh, Traf3 and Abcc1 decreased centrality as CR increased. This change in gene centrality in a graded manner with CR, occurred in the absence of parallel changes in gene expression levels. This study emphasizes the importance of augmenting traditional differential gene expression analyses to better understand structural changes in the transcriptome. Overall our results suggested that CR induced changes in centrality of biological relevant genes that play an important role in preventing the age-associated loss of network integrity irrespective of their gene expression levels. PMID- 27115075 TI - Delayed Anaerobic Threshold in Heart Failure Patients With Atrial Fibrillation. AB - PURPOSE: To assess whether atrial fibrillation (AF) in heart failure (HF) affects oxygen uptake at anaerobic threshold ((Equation is included in full-text article.)O2 AT) and heart rate (HR) kinetics. METHODS: A total of 15 patients with HF and AF and 18 with HF and sinus rhythm (SR) performed a maximal incremental and 2 constant workload cycle ergometer cardiopulmonary exercise tests (below and above AT, at 25% and 75% of maximal workload, respectively). At constant workload tests, kinetics of (Equation is included in full-text article.)O2 and HR were assessed by calculating time constant (tau). RESULTS: HF patients with AF showed a similar peak (Equation is included in full-text article.)O2 to those with SR (16.7 +/- 4.5 mL/kg/min vs 16.6 +/- 3.9 mL/kg/min). However, (Equation is included in full-text article.)O2 AT (11.3 +/- 2.9 mL/kg/min vs 9.3 +/- 2.8 mL/kg/min; P < .05), peak HR (149 +/- 18.8 bpm vs 116.4 +/- 20.4 bpm; P < .001), HR AT (125.3 +/- 19.1 bpm vs 90.3 +/- 15.5 bpm; P < .001), and HR increase during exercise were greater in HF patients with AF. Finally, tauHR and tau(Equation is included in full-text article.)O2 below and above AT were not significantly different. CONCLUSIONS: In HF patients with AF, despite a similar peak (Equation is included in full-text article.)O2 compared with patients with HF and SR, (Equation is included in full-text article.)O2 AT is higher because of a higher HR and a greater HR increase during exercise. One postulated mechanism would be a greater cardiac output increase at the beginning of exercise in HF patients with AF. The delayed AT generates uncertainty about the meaning of a (Equation is included in full-text article.)O2 value at AT in HF patients with AF, because a higher AT is usually associated with better performance and a better prognosis. PMID- 27115076 TI - Prescribing Cycle Exercise Intensity Using Moderate Symptom Levels in Chronic Obstructive Pulmonary Disease. AB - PURPOSE: Laboratory-based cardiopulmonary exercise testing from which to prescribe cycle training intensity in pulmonary rehabilitation for people with chronic obstructive pulmonary disease (COPD) is not readily available in clinical practice. Alternative methods of prescribing cycle exercise intensity, such as patient symptoms of dyspnea or rating of perceived exertion (RPE), have been used, but it is unknown whether cycle intensity based on such symptoms elicits an exercise intensity appropriate for achieving physiological training responses. The aim of the study was to determine the exercise intensity elicited when continuous cycle exercise was prescribed at symptoms of moderate dyspnea or RPE in people with COPD. METHODS: Participants with diagnosed COPD performed lung function tests and an incremental cycle test to peak work capacity. On a subsequent day, participants performed 10 minutes of cycle exercise based on moderate symptoms (CycleSYMP) of either dyspnea or RPE, depending on which symptom limited the incremental cycle test. Oxygen uptake ((Equation is included in full-text article.)O2) was measured during all exercise using a portable metabolic system (Cosmed K4b). RESULTS: Thirty participants, mean age of 70 +/- 9 years and FEV1 60 +/- 12% predicted, completed the study. The mean intensity achieved during CycleSYMP was 78 +/- 12%(Equation is included in full-text article.)O2peak and 71 +/- 18 % (Equation is included in full-text article.)O2Reserve. Steady-state (Equation is included in full-text article.)O2 was achieved by the sixth minute of CycleSYMP. CONCLUSIONS: Using symptoms of moderate dyspnea or RPE as a method of prescribing cycle exercise elicited a high training intensity at which steady-state was achieved in people with mild to moderate COPD. PMID- 27115078 TI - Simultaneous fluorescence imaging of selenol and hydrogen peroxide under normoxia and hypoxia in HepG2 cells and in vivo. AB - Based on the rapid substitution reaction of the Au-S bond by selenol, we designed and synthesized a nanoprobe 5-FAM-peptide-AuNPs for selenol. Real-time imaging shows that this probe together with the molecular probe QCy7-H2O2 is able to simultaneously and differentially monitor the concentrations of selenol and H2O2 in living cells and in vivo. PMID- 27115079 TI - Catalytic Conversion of Alcohols into Carboxylic Acid Salts in Water: Scope, Recycling, and Mechanistic Insights. AB - The catalytic conversion of alcohols into carboxylic acid salts in water was performed in the presence of ruthenium complexes supported by aliphatic PNP pincer ligands preformed or formed in situ. High activity toward a wide substrate scope was achieved with turnover number values of up to 4000. The air-stable catalytic system can be recycled by using toluene as a catalyst-immobilizing phase; the activity is maintained after five consecutive runs. Finally, mechanistic studies allowed some fundamental aspects related to water activation to be unveiled and to the mechanism postulated. PMID- 27115096 TI - Reevaluation of the Amsterdam Inventory for Auditory Disability and Handicap Using Item Response Theory. AB - PURPOSE: We reevaluated the psychometric properties of the Amsterdam Inventory for Auditory Disability and Handicap (AIADH; Kramer, Kapteyn, Festen, & Tobi, 1995) using item response theory. Item response theory describes item functioning along an ability continuum. METHOD: Cross-sectional data from 2,352 adults with and without hearing impairment, ages 18-70 years, were analyzed. They completed the AIADH in the web-based prospective cohort study "Netherlands Longitudinal Study on Hearing." A graded response model was fitted to the AIADH data. Category response curves, item information curves, and the standard error as a function of self-reported hearing ability were plotted. RESULTS: The graded response model showed a good fit. Item information curves were most reliable for adults who reported having hearing disability and less reliable for adults with normal hearing. The standard error plot showed that self-reported hearing ability is most reliably measured for adults reporting mild up to moderate hearing disability. CONCLUSIONS: This is one of the few item response theory studies on audiological self-reports. All AIADH items could be hierarchically placed on the self-reported hearing ability continuum, meaning they measure the same construct. This provides a promising basis for developing a clinically useful computerized adaptive test, where item selection adapts to the hearing ability of individuals, resulting in efficient assessment of hearing disability. PMID- 27115098 TI - On the Quantum Spin Hall Gap of Monolayer 1T'-WTe2. AB - Positive quantum spin Hall gap in mono-layer 1T'-WTe2 is consistently supported by density-functional theory calculations, ultrafast pump-probe, and electrical transport measurements. It is argued that monolayer 1T'-WTe2 , which was predicted to be a semimetallic quantum spin Hall material, is likely a truly 2D quantum spin Hall insulator with a positive quantum spin Hall gap. PMID- 27115100 TI - Correlates of Sex Frequency and Sexual Satisfaction Among Partnered Older Adults. AB - This study examines behaviors associated with sex frequency and sexual satisfaction in a national sample of partnered older adults, age 50 to 85 (N = 9,164), together for over one year. The results indicate that older adults with active and satisfying sex lives engage more frequently in open sexual communication and setting the mood for sexual activity. Additionally, synchronicity in sexual desire and activities is related to a high-frequency and highly satisfying sex life in older adulthood. An expansive sexual repertoire, as measured by the number of sexual activities used during the last sexual encounter and the incorporation of sexual variety, is also associated with greater sex frequency and sexual satisfaction. PMID- 27115099 TI - Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management. AB - Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Liver cancer occurrence in infancy, 1.5 for million children per year, falls far below the threshold of interest for dedicated drug development programs, and this disease is so rare that it is very difficult to gather enough children into a phase II clinical trial. Here, we present the establishment of an unprecedented preclinical platform of 24 pediatric liver cancer patient-derived xenografts (PLC-PDXs) from 20 hepatoblastomas (HBs), 1 transitional liver cell tumor (TCLT), 1 hepatocellular carcinoma, and 2 malignant rhabdoid tumors. Cytogenetic array and mutational analysis of the parental tumors and the corresponding PLC-PDXs show high conservation of the molecular features of the parental tumors. The histology of PLC-PDXs is strikingly similar to that observed in primary tumors and recapitulates the heterogeneity of recurrent disease observed in the clinic. Tumor growth in the mouse is strongly associated with elevated circulating alpha fetoprotein (AFP), low rate of necrosis/fibrosis after treatment, and gain of chromosome 20, all indicators of resistance to chemotherapy and poor outcome. Accordingly, the ability of a tumor to generate PLC-PDX is predictive of poor prognosis. Exposure of PLC-PDXs to standards of care or therapeutic options already in use for other pediatric malignancies revealed unique response profiles in these models. Among these, the irinotecan/temozolomide combination induced strong tumor regression in the TCLT and in a model derived from an AFP-negative relapsing HB. CONCLUSION: These results provide evidence that PLC-PDX preclinical platform can strongly contribute to accelerate the identification and diversification of anticancer treatment for aggressive subtypes of pediatric liver cancer. (Hepatology 2016;64:1121-1135). PMID- 27115101 TI - Normalization to Maximal Voluntary Contraction is Influenced by Subacromial Pain. AB - In this study, we aimed to determine if electromyography (EMG) normalization to maximal voluntary isometric contractions (MVIC) was influenced by subacromial pain in patients with subacromial impingement syndrome. Patients performed MVICs in unique testing positions for each shoulder muscle tested before and after subacromial injection of local anesthetic. In addition to collection of MVIC data, EMG data during an arm elevation task were recorded before and after injection. From a visual analog pain scale, patients had a 64% decrease in pain following the injection. Significant increases in MVICs were noted in 4 of the 7 shoulder muscles tested: anterior, middle and posterior deltoid, and lower trapezius. No significant differences were noticed for the upper trapezius, latissimus dorsi, or serratus anterior. MVIC condition (pre and post injection) had a significant influence on EMG normalization for the anterior deltoid and lower trapezius muscle. Results indicate that subacromial pain can influence shoulder muscle activity, especially for the deltoid muscles and lower trapezius. In addition, normalization to MVIC in the presence of pain can have unpredictable results. Caution should be taken when normalizing EMG data to MVIC in the presence of pain. PMID- 27115102 TI - Systemic Sclerosis: know more, hope more. PMID- 27115103 TI - Capillaroscopy 2016: new perspectives in systemic sclerosis. AB - Systemic sclerosis (SSc) is an autoimmune disorder of unknown aetiology characterized by early impairment of the microvascular system. Nailfold microangiopathy and decreased peripheral blood perfusion are typical clinical aspects of SSc. The best method to evaluate vascular injury is nailfold videocapillaroscopy, which detects peripheral capillary morphology, and classifies and scores the abnormalities into different patterns of microangiopathy. Microangiopathy appears to be the best evaluable predictor of the disease development and has been observed to precede the other symptoms by many years. Peripheral blood perfusion is also impaired in SSc, and there are different methods to assess it: laser Doppler and laser speckle techniques, thermography and other emerging techniques. PMID- 27115104 TI - Systemic sclerosis: markers and targeted treatments. AB -

Systemic sclerosis (SSc) is characterized by autoantibody production, progressive microvasculopathy, and aberrant extracellular matrix protein (ECM) synthesis in tissues. The disease presents two major clinical hallmarks: Raynaud's phenomenon (RP) and skin involvement, followed by varying prevalences of internal organ involvement. Despite significant advances in the management of certain organ-specific involvements and symptoms, the research for efficient markers and targets, to be used for an optimized treatment, is still ongoing. Therapies targeting the vasculature (i.e. ET-1 receptor antagonists, phosphodiesterase-5 (PDE-5) inhi bitor, agiotensin-converting enzyme inhibition, prostacyclins), the immune system and/or the fibrotic process (i.e. traditional disease modifying anti-rheu - matic drugs DMARDs such as methotrexate, cyclospo - rine or mycophenolate mofetil, biologicals like rituxi - mab, tocilizumab or abatacept) have been or are being eva luated in SSc. Advanced approaches, reserved to unres ponsive SSc patients, include autologous haema - topoietic stem cell transplantation (HSTC) and intravenous immunoglobulins (IVIG). Interestingly, it is expected that new and future possible diagnostic and therapeutical approaches in SSc will come from epigenetic studies (MicroRNAs). Ideally, combination therapy in SSc seems the best approach, together with the early intervention on the major hallmarks of the disease in "at risk" patients, that consists of the microvascular damage/altered function and the autoimmune reaction, followed by the progressive and systemic fibrotic process.

. PMID- 27115105 TI - Cardiovascular profiles of scleroderma patients with arrhythmias and conduction disorders. AB - Introduction Arrhythmias and conduction disorders are common among patients with scleroderma. Their early identification is important, since scleroderma patients with arrhythmias have a higher mortality risk compared with scleroderma patients without arrhythmias. The aim of this study was to characterize the cardiovascular profiles of scleroderma patients with different types of arrhythmias and conduction disorders. Methods One hundred and ten consecutive patients with a diagnosis of systemic sclerosis according to the ACR criteria were included in the study. Patients underwent a 12-lead ECG and a 24-hour Holter ECG monitoring for arrhythmias and conduction disorders identification. Blood sample testing, echocardiography, spirometry, chest X-ray and, when considered appropriate, high resolution chest CT were also performed. A subgroup of 21 patients underwent NT pro BNP level measurements. Patients' clinical and para-clinical characteristics were compared according to the presence or absence of arrhythmias and conduction disorders. Results The prevalence of arrhythmia and conduction disturbances was 60.9%. Patients with such disorders were older (54.4 +/- 13.3 vs. 49.7 +/- 10.1 years, p=0.05), had a higher prevalence of pulmonary hypertension (p=0.008), valve disease (p < 0.001), especially mitral and tricuspid regurgitation, chamber enlargement on echocardiography (left atrial and right ventricular, p = 0.012 and 0.005, respectively) as well as higher NT-pro BNP levels: 265.5 +/- 399.7 vs. 163 +/- 264.3 pg/ml, p=0.04. Conclusion Arrhythmias and conduction disorders are common in patients with scleroderma. Patients with such disorders are older, have a higher prevalence of pulmonary hypertension, more severe mitral and tricuspid regurgitation, left atrial and right ventricular dilation on echocardiography. PMID- 27115106 TI - Sonographic Measurements Can Be Misleading for Diagnosing Carpal Tunnel Syndrome in Patients with Rheumatoid Arthritis. AB - OBJECTIVES: To compare the nerve cross sectional areas (CSA) of patients with RA without any sign of peripheral neuropathy to healthy controls. METHODS: Clinical, electrophysiological and sonographic assessments were done by three blinded researchers. The patients who had an electrodiagnostic or clinical of peripheral neuropathy were excluded from the study. Nerve CSA were measured in various levels; hamatum hook, pisiform bone, radio-ulnar joint, distal 1/3 of forearm, and elbow for median nerve; radio-ulnar joint, pisiform bone, distal 1/3 of forearm, and medial epicondyle for ulnar nerve. RESULTS: The study was completed with 30 women with RA and 30 healthy women. Despite both groups had neither clinical nor electrophysiological neuropathy, the sonographic measurements showed that median nerve CSA at radioulnar joint, pisiform and hamatum levels of patients with RA were larger in rheumatoid arthritis patients than healthy controls. Ulnar nerve CSA at radioulnar joint, pisiform and distal 1/3 forearm and medial epicondyle levels of patients with RA were also increased (p<0.05). If the pisiform level median nerve CSA>10 mm2 was used as sonographic carpal tunnel syndrome (CTS) criterion, 23/60 hands of 30 patients with RA and 5/60 hands of 30 healthy controls could be diagnosed as CTS. CONCLUSION: Median and ulnar nerve CSA were larger than healthy control in patients with rheumatoid arthritis without clinical and electrophysiological peripheral neuropathy. The rheumatologists should be careful to diagnose CTS in patients with RA while using US. PMID- 27115107 TI - Anti CD20 (Rituximab) therapy in refractory pediatric rheumatic diseases. AB - OBJECTIVES: We aim to report the efficacy and safety of rituximab (RTX) in patients diagnosed with juvenile systemic lupus erythematosus (JSLE) or juvenile idiopathic arthritis (JIA) refractory to conventional treatment. METHODS: A retrospective review was made of all medical records of patients with JSLE or JIA treated with RTX between January 2009 and January 2015 in the Pediatric Rheumatology Unit of a central hospital. RESULTS: Five patients, 4 with JSLE and 1 with extended oligoarticular JIA, received 10 cycles of RTX (23 infusions). The scheme of RTX frequently used was 750 mg/m2 two weeks apart. The median follow-up time after receiving the first cycle of RTX was 24 months (12 - 70). The four patients with JSLE were female (three caucasian and one black). The patient with JIA was a caucasian male. The median age at diagnosis was 10 years (16 months - 17years). The median evolution time until receiving RTX was 6 years (5 months - 15 years). Refractory class IV lupus nephritis was the most common indication for receiving RTX. Previous treatment to RTX included nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, immunosuppressive drugs and corticosteroids in all patients and anti-TNFalpha (etanercept) in the patient with JIA. It was possible to reduce the mean oral corticosteroid dose after RTX, ranging from 23 mg/day (20-25mg/day) before RTX to 11 mg/day (0-20 mg/day) at the last evaluation. Disease activity before RTX and at last evaluation also improved. The SLEDAI score, for JSLE, decreased from a median of 15, 5 (11 - 18) to 3 (0 - 6), and the JADAS-27 score, for JIA, also diminished from 40.4 to 3.5. Adverse events occurred in 2 patients, including delayed second dose after the diagnosis of cryptococcosis and respiratory tract infection with concomitant hypogammaglobulinemia needing of immunoglobulin replacement and antibiotic therapy. CONCLUSIONS: Rituximab might have a role in the treatment of JSLE and JIA. However controlled studies and long term follow-up are needed to evaluate its safety and efficacy. PMID- 27115108 TI - Sexual Dysfunction in Male Patients With Behcet's Disease. AB - INTRODUCTION: The purpose of this study was to evaluate sexual dysfunction in male patients with Behcet's Disease in comparison to healthy control subjects. MATERIAL AND METHODS: Seventy-two sexually active male patients with Behcet's Disease and 62 healthy control subjects were included in this study. Patients' demographic and clinical characteristics were noted. Sexual function was assessed by means of the International Index of Erectile Function scoring system. In addition, disease-related quality of life was measured by means of the Nottingham Health Profile, and anxiety and depression levels were assessed by means of the Hospital Anxiety and Depression Scale. RESULTS: Patients with Behcet's Disease scored significantly lower in each of the 5 parameters of International Index of Erectile Function (p < 0.001) and significantly higher in Hospital Anxiety and Depression Scale compared to healthy control subjects (p < 0.001). International Index of Erectile Function scores correlated with age, duration of disease and Hospital Anxiety and Depression Scale and Nottingham Health Profile scores in patients with Behcet's Disease (p < 0.05). CONCLUSION: Sexual function is impaired in male patients with Behcet's Disease, which might be associated by age, duration of disease, psychological status and quality of life. PMID- 27115109 TI - Melatonin receptor 1b polymorphisms in women with Systemic Lupus Erythematosus. AB - AIM: The pineal hormone melatonin could exert an important influence on the immune system and autoimmunity. Its effect on the immunocompetent cells might be mediated at least partially through specific melatonin receptors. However, the role of melatonin - melatonin receptor 1B (MTNR1B) interrelations in human autoimmune diseases is still unknown. Therefore, the present study aimed to investigate the possible influence of the MTNR1B gene polymorphisms for the development and clinical expression of systemic lupus erythematosus (SLE). METHODS: 109 female SLE patients and 101 healthy women were genotyped for the MTNR1B rs1562444, rs10830962 and rs10830963 polymorphisms. RESULTS: No genotype distribution differences were found between patients and controls. The presence of MTNR1B rs10830963 C/C genotype was related to increased prevalence of leucopenia compared to genotypes C/G and G/G after Bonferroni correction for multiple comparisons [36.5% vs. 14.5%, p=0.014]. Moreover, the rs10830963 G/G carriers had lower number of lupus criteria in comparison to patients with C/C genotype. CONCLUSIONS: The present data suggested that MTNR1B polymorphisms could influence the clinical features in lupus patients, and especially the susceptibility to leucopenia. PMID- 27115111 TI - Good response to rituximab in a patient with granulomatosis with polyangiitis and pulmonary, renal manifestations and ophthalmoplegia. AB - Cyclophosphamide (CYC) is a classical drug for the treatment of severe granulomatosis with polyangiitis (GPA). However, a considerable number of patients are resistant to standard treatment and it can show substantial toxicity. Therefore, alternative agents should be considered in refractory cases. We report the successful use of rituximab (RTX) in a 70-year-old patient diagnosed of GPA who developed ophthalmoplegia, an uncommon complication of GPA. The patient also had upper and lower respiratory tract involvement and kidney manifestations with good prognosis. We review the causes of ophtalmoparesis and the treatment with RTX in GPA. PMID- 27115110 TI - Association Study of an AFF1 Gene Polymorphism (rs340630) with Iranian Systemic Lupus Erythematosus Patients. AB - AIM: To investigate whether an AFF1 polymorphism was associated with susceptibility and clinical features of SLE in Iranian patients. METHODS: A total of 320 patients with SLE and 330 age, sex and ethnically matched healthy control subjects were enrolled in the present study. Both cases and healthy controls were genotyped for rs340630 polymorphism located inside the AFF1using Amplification Refractory Mutation System-PCR (ARMS-PCR). In order to investigation of SNP association and clinical features of SLE, clinical manifestations of patients were recorded. The distributions of rs340630 genotypes were tested for deviation from Hardy-Weinberg in controls. Genotypic and allelic distribution between patients and controls were assessed by chi-squares test. The Odds Ratio (OR) and 95 % Confidence Intervals were calculated from multiple logistic regression analysis. MAJOR RESULTS: Both A and G alleles of rs340630were seen among the Iranian samples. All three genotypes of rs340630 were found, i.e., homozygous A/A (OR=1/01, 95%CI=%72 - 1/42, P= %99), homozygous G/G (OR=%92, 95%CI= %63 - 1/35, P=%77) and heterozygous A/G (OR=1/03, 95%CI= %76 - 1/41, P=%87). In the SLE group, the number of patients with renal disorder was significantly higher for the AG genotype compared to other genotypes of AFF1 polymorphism (P= 0.05). CONCLUSION: There was no association between AFF1 polymorphism (rs340630) and SLE. However, our findings indicated that AFF1 polymorphism (rs340630) was significantly (P=0.0045) correlated with renal disorder in Iranian population. PMID- 27115112 TI - [Dermatomyositis-like syndrome in x-linked agammaglobulinemia]. AB - Primary immunodeficiencies (PIDs) encompass more than 250 different pathological conditions. X-linked agammaglobulinemia (XLA) has been occasionally associated with cutaneous and muscular manifestations resembling dermatomyositis, often termed dermatomyositis-like syndrome (DLS). This syndrome has been associated with cutaneous, muscular and central nervous system manifestations, accompanying a persistent infection by an Echovirus. According to sixteen previously reported cases, this syndrome has a poor prognosis. We report the case of a 27-years old male, with XLA and DLS, successfully treated with 6 cycles of human immunoglobulin and methotrexate. Clinical symptoms improved dramatically with a complete resolution of the musculoskeletal manifestations. Despite this clinical response, prognosis should remain reserved. The evolution of this syndrome remains unpredictable and therapeutic options are limited. To the best of our knowledge, there are only a few reports of similar cases which have survived so many months after the diagnosis. PMID- 27115113 TI - Idiopathic Hypoparathyroidism Mimicking Ankylosing Spondylitis: A Case Report. AB - Idiopathic hypoparathyroidism, inadequate secretion of parathyroid hormone of unknown etiology, may mimic ankylosing spondylitis both clinically and radiologically. Spinal complaints may be the first sign of any endocrinological disorder. PMID- 27115114 TI - Lipoma Arborescens: a rare cause of recurrent synovial hydrathrosis at paediatric age. PMID- 27115115 TI - Hypogeusia as a side effect of leflunomide. PMID- 27115116 TI - A case of chronic lymphocytic leukemia still taking etanercept for ankylosing spondylitis. AB - The possible risk of hematologic malignancies in anti TNF users is a matter of debate. Whether associated with the drug or not, how to behave when a hematologic malignancy is discovered in the course of anti TNF treatment remains unanswered. Here we present a 66 year old male patient who had AS for 30 years and had been on etanercept for the last two years and who is diagnosed with B cell chronic lymphocytic leukemia (CLL) stage 1. The patient is still on etanercept for 5 years after the diagnosis without any progression in CLL. PMID- 27115117 TI - Direct Growth of MoS2 Microspheres on Ni Foam as a Hybrid Nanocomposite Efficient for Oxygen Evolution Reaction. AB - MoS2 microspheres are directly grown on the conductive Ni foam and the as obtained MoS2 -Ni electrodes exhibit highly efficient electrocatalytic performances for oxygen evolution in 1.0 m NaOH, displaying a rather low overpotential of 0.310 V at 20.0 mA cm(-2) , a high current density, good cyclic stability, and excellent flexibility. PMID- 27115118 TI - Temperature (de)activated patchy colloidal particles. AB - We present a new model of patchy particles in which the interaction sites can be activated or deactivated by varying the temperature of the system. We study the thermodynamics of the system by means of Wertheim's first order perturbation theory, and use Flory-Stockmayer theory of polymerization to analyse the percolation threshold. We find a very rich phase behaviour including lower critical points and reentrant percolation. PMID- 27115119 TI - Mechanism for the stabilization of protein clusters above the solubility curve: the role of non-ideal chemical reactions. AB - Dense protein clusters are known to play an important role in nucleation of protein crystals from dilute solutions. While these have generally been thought to be formed from a metastable phase, the observation of similar, if not identical, clusters above the critical point for the dilute-solution/strong solution phase transition has thrown this into doubt. Furthermore, the observed clusters are stable for relatively long times. Because protein aggregation plays a central role in some pathologies, understanding the nature of such clusters is an important problem. One mechanism for the stabilization of such structures was proposed by Pan, Vekilov and Lubchenko and was investigated using a dynamical density functional theory model which confirmed the viability of the model. Here, we revisit that model and incorporate additional physics in the form of state dependent reaction rates. We show by a combination of numerical results and general arguments that the state-dependent rates disrupt the stability mechanism. Finally, we argue that the state-dependent reactions correct unphysical aspects of the model with ideal (state-independent) reactions and that this necessarily leads to the failure of the proposed mechanism. PMID- 27115120 TI - Subgenual cingulate cortical activity predicts the efficacy of electroconvulsive therapy. AB - Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its mechanism of action is unknown. Our goal was to investigate the neurobiological underpinnings of ECT response using longitudinally collected resting-state functional magnetic resonance imaging (rs-fMRI) in 16 patients with treatment-resistant depression and 10 healthy controls. Patients received bifrontal ECT 3 times a week under general anesthesia. We acquired rs-fMRI at three time points: at baseline, after the 1st ECT administration and after the course of the ECT treatment; depression was assessed with the Hamilton Depression Rating Scale (HAM-D). The primary measure derived from rs-fMRI was fractional amplitude of low frequency fluctuation (fALFF), which provides an unbiased voxel wise estimation of brain activity. We also conducted seed-based functional connectivity analysis based on our primary findings. We compared treatment related changes in HAM-D scores with pre- and post-treatment fALFF and connectivity measures. Subcallosal cingulate cortex (SCC) demonstrated higher BOLD signal fluctuations (fALFF) at baseline in depressed patients, and SCC fALFF decreased over the course of treatment. The baseline level of fALFF of SCC predicted response to ECT. In addition, connectivity of SCC with bilateral hippocampus, bilateral temporal pole, and ventromedial prefrontal cortex was significantly reduced over the course of treatment. These results suggest that the antidepressant effect of ECT may be mediated by downregulation of SCC activity and connectivity. SCC function may serve as an important biomarker of target engagement in the development of novel therapies for depression that is resistant to treatment with standard medications. PMID- 27115121 TI - Resting-state abnormalities in amnestic mild cognitive impairment: a meta analysis. AB - Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer's disease (AD). As no effective drug can cure AD, early diagnosis and intervention for aMCI are urgently needed. The standard diagnostic procedure for aMCI primarily relies on subjective neuropsychological examinations that require the judgment of experienced clinicians. The development of other objective and reliable aMCI markers, such as neural markers, is therefore required. Previous neuroimaging findings revealed various abnormalities in resting-state activity in MCI patients, but the findings have been inconsistent. The current study provides an updated activation likelihood estimation meta-analysis of resting-state functional magnetic resonance imaging (fMRI) data on aMCI. The authors searched on the MEDLINE/PubMed databases for whole-brain resting-state fMRI studies on aMCI published until March 2015. We included 21 whole-brain resting-state fMRI studies that reported a total of 156 distinct foci. Significant regional resting state differences were consistently found in aMCI patients relative to controls, including the posterior cingulate cortex, right angular gyrus, right parahippocampal gyrus, left fusiform gyrus, left supramarginal gyrus and bilateral middle temporal gyri. Our findings support that abnormalities in resting-state activities of these regions may serve as neuroimaging markers for aMCI. PMID- 27115122 TI - Pleiotropy between neuroticism and physical and mental health: findings from 108 038 men and women in UK Biobank. AB - People with higher levels of neuroticism have an increased risk of several types of mental disorder. Higher neuroticism has also been associated, less consistently, with increased risk of various physical health outcomes. We hypothesised that these associations may, in part, be due to shared genetic influences. We tested for pleiotropy between neuroticism and 17 mental and physical diseases or health traits using linkage disequilibrium regression and polygenic profile scoring. Genetic correlations were derived between neuroticism scores in 108 038 people in the UK Biobank and health-related measures from 14 large genome-wide association studies (GWASs). Summary information for the 17 GWASs was used to create polygenic risk scores for the health-related measures in the UK Biobank participants. Associations between the health-related polygenic scores and neuroticism were examined using regression, adjusting for age, sex, genotyping batch, genotyping array, assessment centre and population stratification. Genetic correlations were identified between neuroticism and anorexia nervosa (rg=0.17), major depressive disorder (rg=0.66) and schizophrenia (rg=0.21). Polygenic risk for several health-related measures were associated with neuroticism, in a positive direction in the case of bipolar disorder, borderline personality, major depressive disorder, negative affect, neuroticism (Genetics of Personality Consortium), schizophrenia, coronary artery disease, and smoking (beta between 0.009-0.043), and in a negative direction in the case of body mass index (beta=-0.0095). A high level of pleiotropy exists between neuroticism and some measures of mental and physical health, particularly major depressive disorder and schizophrenia. PMID- 27115123 TI - Exercise during early, but not late abstinence, attenuates subsequent relapse vulnerability in a rat model. AB - Exercise has shown promise as a nonpharmacological intervention for addiction, with evidence suggesting a potential utility for relapse prevention. In humans, exercise as an intervention is typically introduced well after the initiation of abstinence, yet neurobiological data from preclinical studies suggest that it may be more effective if initiated during early abstinence. Here, using rat models, we determined whether the beneficial effects of exercise on relapse vulnerability depends on when exercise is first initiated, during early versus late abstinence. Once rats (n=47) acquired cocaine self-administration, they were given 24-h access to cocaine (1.5 mg/kg per infusion) under a discrete trial procedure (four infusions per hour) for 10 days. The rats then began a 14-day abstinence period in which they had access (2 h per day) to a locked wheel throughout abstinence (sedentary) or an unlocked wheel during early (days 1-7), late (days 8-14) or throughout (days 1-14) abstinence (n=10-14 per group). Cocaine seeking, as assessed under an extinction/cued-induced reinstatement procedure, was examined on day 15 of abstinence. Exercise beginning during early abstinence robustly attenuated subsequent cocaine seeking, and this effect persisted even when exercise ended on the seventh day of abstinence. In contrast, exercise during late abstinence was not effective and these animals displayed high levels of cocaine seeking similar to those observed in sedentary animals. These results indicate that the timing of exercise availability differentially impacts cocaine seeking with results suggesting that exercise during early, but not late, abstinence may provide long-term protection against cocaine relapse. PMID- 27115124 TI - A reply to 'Metabolic effects of sapropterin treatment in autism spectrum disorder: a preliminary study'. PMID- 27115129 TI - Sexuality and meaning in Freud and Merleau-Ponty. AB - This article analyzes the links between the conception of the body and of sexuality found in Freud and Merleau-Ponty. The French philosopher refers to Freud in various of his works, and performs a reading of Freud through which he rescues the meaning that the latter gives to sexuality as he integrates it into the totality of the person, without making it into a blind or merely instinctive force. As a consequence of this integration, the notions of the unconscious and of instinct or drive are interpreted in the light of the meaning or signification that they have in the person's behavior. Merleau-Ponty's notion of pre-reflective knowledge plays a decisive role in this understanding of meaning. In the same way, it allows important contemporary analysts to use these studies in their therapeutic work and also in psychological studies. PMID- 27115126 TI - The effect of nutritional supplementation on quality of life in people living with HIV: a randomised controlled trial. AB - OBJECTIVE: To determine the effects of lipid-based nutrient supplements (LNS) on the quality of life of people living with HIV (PLHIV) during the first 3 months of antiretroviral treatment (ART) and to investigate the effects of timing of supplementation by comparing with supplementation during the subsequent 3 months. METHODS: A randomised controlled trial was conducted in three ART clinics within public health facilities in Jimma, Ethiopia. Participants were PLHIV eligible to start ART with body mass index >17 kg/m(2) and given daily supplements of 200 g of LNS containing whey or soya either during the first 3 months or the subsequent months of ART. The outcome was measured in terms of total quality-of-life scores on the adapted version of the WHOQOL-HIV-BREF assessed at baseline, three and six months. RESULTS: Of the 282 participants, 186 (66.0%) were women. The mean age (SD) was 32.8 (+/-9.0) years, and the mean (SD) total quality-of-life score was 82.0 (+/-14.8) at baseline assessment. At 3 months, participants who received LNS showed better quality of life than those who only received ART without LNS (beta = 6.2, 95% CI: 2.9: 9.6). At 6 months, there was no difference in total quality of-life score between the early and delayed supplementation groups (beta = 3.0, 95% CI: -0.4: 6.4). However, the early supplementation group showed higher scores on the social and spirituality domains than the delayed group. CONCLUSIONS: LNS given during the first three months of ART improves the quality of life of PLHIV. PMID- 27115125 TI - Dissociating the therapeutic effects of environmental enrichment and exercise in a mouse model of anxiety with cognitive impairment. AB - Clinical evidence indicates that serotonin-1A receptor (5-HT1AR) gene polymorphisms are associated with anxiety disorders and deficits in cognition. In animal models, exercise (Ex) and environmental enrichment (EE) can change emotionality-related behaviours, as well as enhance some aspects of cognition and hippocampal neurogenesis. We investigated the effects of Ex and EE (which does not include running wheels) on cognition and anxiety-like behaviours in wild-type (WT) and 5-HT1AR knock-out (KO) mice. Using an algorithm-based classification of search strategies in the Morris water maze, we report for we believe the first time that Ex increased the odds for mice to select more hippocampal-dependent strategies. In the retention probe test, Ex (but not EE) corrected long-term spatial memory deficits displayed by KO mice. In agreement with these findings, only Ex increased hippocampal cell survival and BDNF protein levels. However, only EE (but not Ex) modified anxiety-like behaviours, demonstrating dissociation between improvements in cognition and innate anxiety. EE enhanced hippocampal cell proliferation in WT mice only, suggesting a crucial role for intact serotonergic signalling in mediating this effect. Together, these results demonstrate differential effects of Ex vs EE in a mouse model of anxiety with cognitive impairment. Overall, the 5-HT1AR does not seem to be critical for those behavioural effects to occur. These findings will have implications for our understanding of how Ex and EE enhance experience-dependent plasticity, as well as their differential impacts on anxiety and cognition. PMID- 27115130 TI - Online role-play simulations with emotionally responsive avatars for the early detection of Native youth psychological distress, including depression and suicidal ideation. AB - Gatekeeper training is a widely used prevention method for training local community members to recognize the signs and symptoms of suicide and to support appropriate referrals for mental health. Training community "gatekeepers" is critical for increasing access to care for those youth who are in need, as youth often turn first to family and friends for help. This study examines the outcomes at pre-training, post-training, and 3-month follow-up for American Indian and Alaska Native (AI/AN) students, teachers, and faculty completing online role-play gatekeeper training simulations. The simulations use emotionally responsive avatars that have memory and personality, and respond like real students experiencing psychological distress in realistic situations. Data from 86 matched pairs showed significant increases in self-identified gatekeeper attitudes of preparedness, likelihood (behavioral intent) and self-efficacy to engage in helping behaviors (i.e., identifying those in psychological distress, talking to them, and supporting a referral for services) 3 months after training. This study provides promising evidence for use of online avatar-based training with AI/AN communities and has the potential to address many of the current challenges with gatekeeper training in Indian Country. PMID- 27115131 TI - At the Bedside: Traditional Navajo practitioners in a patient-centered health care model. AB - The growing national racial and ethnic diversity has created a greater need for health care delivery systems and health care providers to be more responsive to unique patient needs, that goes beyond meeting the immediate health problems to include attention to other critical component of patient care that take into account cultural competency such as health literacy, health beliefs and behaviors, cultural practices, etc. PMID- 27115132 TI - A collaborative case study: The Office of Native Medicine. AB - National concerns about reducing the persistent health disparities found among varying racial and ethnic populations have led to initiatives to improve health care delivery systems. Many of these initiatives also promote the cultural competence of health care providers as a way to meet unique patient needs that go beyond immediate health problems, and to account for other critical components of patient care, such as health literacy, health beliefs and behaviors, and cultural practices. This case study describes a patient-centered care model developed by the Chinle Comprehensive Health Care Facility on the Navajo Reservation in Arizona, a model that has added a cadre of traditional tribal practitioners as part of its hospital and other clinical service resources. PMID- 27115133 TI - American Indian veterans and VA services in three tribes. AB - The purpose of this project was to describe experiences of reservation-based American Indian (AI) veterans with the Department of Veterans Affairs (VA), and to identify opportunities for improving care and services. Focus group discussions and individual interviews were conducted with AI veterans, family members, and community members in three diverse tribes. Results showed that many veterans in tribal communities experienced challenges receiving services and benefits from the VA, including lack of culturally competent care, transportation problems, and difficulties navigating the system. Family members, often main caregivers for AI veterans, lacked necessary resources, including sources for information, support services, and financial means to procure adequate care. A number of strengths also were identified, including local leadership and a strong community commitment to improve care for veterans. PMID- 27115134 TI - Establishing the reliability and validity of the sources of strength in one American Indian community. AB - Strength-based approaches that explore resilience and health among Native communities are needed. This report highlights the results from a sources of strength inventory reported over a 2-year period by participants (N = 48) from a Montana tribe who attended cultural camps. The authors found the sources of strength scale to be a reliable and valid measure for the population (N = 11 items, alpha = .945). The community plans to use the results of this study to inform and promote strength-based measures grounded in the resilience of youth, families, and culture. PMID- 27115136 TI - Cardiac Troponin Rapid Rule-Out Protocols in Suspected Acute Coronary Syndrome: The Faster the Better or a Loss of Information regarding Outcome and Adjunctive Therapy. PMID- 27115137 TI - Twelve Weeks of Sprint Interval Training Improves Indices of Cardiometabolic Health Similar to Traditional Endurance Training despite a Five-Fold Lower Exercise Volume and Time Commitment. AB - AIMS: We investigated whether sprint interval training (SIT) was a time-efficient exercise strategy to improve insulin sensitivity and other indices of cardiometabolic health to the same extent as traditional moderate-intensity continuous training (MICT). SIT involved 1 minute of intense exercise within a 10 minute time commitment, whereas MICT involved 50 minutes of continuous exercise per session. METHODS: Sedentary men (27+/-8y; BMI = 26+/-6kg/m2) performed three weekly sessions of SIT (n = 9) or MICT (n = 10) for 12 weeks or served as non training controls (n = 6). SIT involved 3x20-second 'all-out' cycle sprints (~500W) interspersed with 2 minutes of cycling at 50W, whereas MICT involved 45 minutes of continuous cycling at ~70% maximal heart rate (~110W). Both protocols involved a 2-minute warm-up and 3-minute cool-down at 50W. RESULTS: Peak oxygen uptake increased after training by 19% in both groups (SIT: 32+/-7 to 38+/-8; MICT: 34+/-6 to 40+/-8ml/kg/min; p<0.001 for both). Insulin sensitivity index (CSI), determined by intravenous glucose tolerance tests performed before and 72 hours after training, increased similarly after SIT (4.9+/-2.5 to 7.5+/-4.7, p = 0.002) and MICT (5.0+/-3.3 to 6.7+/-5.0 x 10-4 min-1 [MUU/mL]-1, p = 0.013) (p<0.05). Skeletal muscle mitochondrial content also increased similarly after SIT and MICT, as primarily reflected by the maximal activity of citrate synthase (CS; P<0.001). The corresponding changes in the control group were small for VO2peak (p = 0.99), CSI (p = 0.63) and CS (p = 0.97). CONCLUSIONS: Twelve weeks of brief intense interval exercise improved indices of cardiometabolic health to the same extent as traditional endurance training in sedentary men, despite a five-fold lower exercise volume and time commitment. PMID- 27115138 TI - Dermatomyositis and Polymyositis in the Intensive Care Unit: A Single-Center Retrospective Cohort Study of 102 Patients. AB - INTRODUCTION: Patients with idiopathic inflammatory myopathies (IIMs) are sometimes complicated with life-threatening conditions requiring intensive care unit (ICU) admission. In the past, owing to the low incidence of IIM, little was known about such patients. Our aim was to investigate the clinical features and outcomes of these patients and identify their risk factors for mortality. METHODS: A retrospective study was performed of IIM patients admitted over an 8 year period to the medical ICU of a tertiary referral center in China. We collected data regarding demographic features, IIM-related clinical characteristics, reasons for admission, organ dysfunction, and outcomes. Independent predictors of ICU mortality were identified through multivariate logistic regression analysis. RESULTS: Of the 102 patients in our cohort, polymyositis (PM), dermatomyositis (DM), and clinically amyopathic dermatomyositis (CADM) accounted for 23.5%, 64.7%, and 11.7% respectively. The median duration from the onset of IIM to ICU admission was 4.3 months (interquartile range [IQR], 2.6-9.4 months). Reasons for ICU admission were infection alone (39.2%), acute exacerbation of IIM alone (27.5%), the coexistence of both (27.5%), or other reasons (5.8%). Pneumonia accounted for 97% of the infections; 63.2% of infections with documented pathogens were caused by opportunistic agents. Rapid progressive interstitial lung disease (RP-ILD) was responsible for 87.5% of acute exacerbation of IIM. The median Acute Physiology and Chronic Health Evaluation II (APACHE II) score on ICU day 1 was 17 (IQR 14 20). On ICU admission, acute respiratory failure (ARF) was the most common type (80.4%) of organ failure. The mortality rate in the ICU was 79.4%. Factors associated with increased ICU mortality included a diagnosis of DM (including CADM), a high APACHE II score, the presence of ARF, a decreased PaO2/FiO2 ratio, and a low lymphocyte count at the time of ICU admission. CONCLUSIONS: The outcome of IIM patients admitted to the ICU was extremely poor. A diagnosis of DM/CADM, the presence and severity of ARF, and the lymphocyte counts at ICU admission were shown to be valuable for predicting outcome. Opportunistic infections and rapidly progressive interstitial lung disease warrant concern in treating these patients. PMID- 27115139 TI - Long-Term Health-Related Quality of Life in German Patients with Juvenile Idiopathic Arthritis in Comparison to German General Population. AB - OBJECTIVE: Aims of the study were to investigate health-related quality of life (HRQOL) in adult patients with former diagnosis of Juvenile Idiopathic Arthritis (JIA), to compare their HRQOL with the general population and to identify factors related to a poor outcome. METHODS: In 2012, a cross-sectional survey was performed by mailing a questionnaire to a large cohort of former and current patients of the German Centre for Rheumatology in Children and Adolescents. Only adult patients (>=18 years) with a diagnosis compatible with JIA were included (n = 2592; response 66%). The questionnaire included information about HRQOL (EQ5D), disease-related questions and socio-demographics. Prevalence and 95% confidence intervals (CI) of problems with mobility, self-care, usual activities, pain and anxiety/depression were standardized to the German general population. Factors associated with low HRQOL in JIA patients were identified using logistic regression models. RESULTS: Sixty-two percent of the study population was female; age range was 18-73 years. In all dimensions, JIA patients reported statistically significantly more problems than the general population with largest differences in the pain dimension (JIA patients 56%; 95%CI 55-58%; general population 28%; 26 29%) and the anxiety/depression dimension (28%; 27-29% vs. 4%; 4-5%). Lower HRQOL in JIA patients was associated with female sex, older age, lower level of education, still being under rheumatic treatment and disability. CONCLUSIONS: HRQOL in adult JIA patients is considerably lower than in the general population. As this cohort includes historic patients the new therapeutic schemes available today are expected to improve HRQOL in future. PMID- 27115141 TI - [Medicolegal aspects of child abuse]. AB - CLINICAL ISSUE: The prevention and clinical diagnostics of maltreatment of children and adolescents represents a great challenge to all medical disciplines concerned; therefore, an interdisciplinary collaboration is indispensable. DIAGNOSTICS: Medicolegal experts require specific radiological examination methods for the differentiation between accidental and non-accidental injuries, depending on the corresponding point in question. In addition, a clear and structured radiological appraisal of the findings is necessary. On the other hand, radiologists require an appropriate succinctly phrased question from the medicolegal expert. PRACTICAL RECOMMENDATIONS: A close collaboration between radiologists and medicolegal experts is mandatory for a better recognition of cases of child abuse; therefore, the joint establishment of diagnostic standards and a comprehensive implementation is necessary. PMID- 27115143 TI - Myocardial Viability and Revascularization: Current Understanding and Future Directions. AB - The initial observation of functional recovery in dysfunctional myocardium following revascularization led to the introduction of the concept of hibernating myocardium. Since then, the pathophysiologic basis of hibernating myocardium has been well described. Multiple imaging modalities have been utilized to prospectively detect viable myocardium and thus predict its functional recovery following revascularization. It has been hypothesized that viability imaging will be instrumental in the selection of patients with ischemic cardiomyopathy likely to benefit from revascularization. Multiple observational studies built a large body of evidence supporting this concept. However, data from prospective studies failed to substantiate utility of viability testing. This review aims to summarize the current literature and describe the role of viability imaging in current clinical practice as well as future directions. PMID- 27115142 TI - Sphingosine-1-Phosphate Signaling in Endothelial Disorders. AB - Numerous preclinical studies indicate that sustained endothelial activation significantly contributes to tissue edema, perpetuates the inflammatory response, and exacerbates tissue injury ultimately resulting in organ failure. However, no specific therapies aimed at restoring endothelial function are available as yet. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of endothelial function and endothelial responses to injury. Recent studies indicate that S1PR are attractive targets to treat not only disorders of the arterial endothelium but also microvascular dysfunction caused by ischemic or inflammatory injury. In this article, we will review the current knowledge of the role of S1P and its receptors in endothelial function in health and disease, and we will discuss the therapeutic potential of targeting S1PR not only for disorders of the arterial endothelium but also the microvasculature. The therapeutic targeting of S1PR in the endothelium could help to bridge the gap between biomedical research in vascular biology and clinical practice. PMID- 27115145 TI - Decrease of Tocilizumab Dose in Patients with Rheumatoid Arthritis: A Pilot Study. AB - BACKGROUND: The efficacy and safety of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) are well demonstrated. Doses of 4 and 8 mg/kg are used intravenously. The objective of our study was to report the efficacy and safety for a set of patients who had an 8 mg/kg doze of TCZ and for another set who had this treatment first at a dose of 8 followed by 4 mg/kg. METHODS: All RA patients treated with TCZ in a University Hospital Centre Department of Rheumatology between January 2010 and December 2014 were included. Sixty-three patients received TCZ at a dose of 8 mg/kg and 19 patients received this treatment first receiving a dose of 8 mg/kg decreased to 4 mg/kg. The demographic characteristics, the clinical response and adverse events were reported. RESULTS: At the end of follow-up, 48% of patients were in clinical remission defined by disease activity score based on 28 joints with an erythrocyte sedimentation rate <2.6 in the 8 mg/kg group and 74% of patients in the 8-4 mg/kg. The rates of severe infections were 4.8 per 100 patients-years (PY) in the 8 mg/kg group and 2.9 per 100 PY in the 8 then 4 mg/kg. The infections were mainly pulmonary, ENT and skin infections. CONCLUSION: Our study reported the efficacy and safety of the TCZ in patients with RA in 'real life' with the dose of 8 mg/kg or 8 then 4 mg/kg. PMID- 27115144 TI - Dynamic Contrast-Enhanced MRI to Study Atherosclerotic Plaque Microvasculature. AB - Rupture of a vulnerable atherosclerotic plaque of the carotid artery is an important underlying cause of clinical ischemic events, such as stroke. Abundant microvasculature has been identified as an important aspect contributing to plaque vulnerability. Plaque microvasculature can be studied non-invasively with dynamic contrast-enhanced (DCE-)MRI in animals and patients. In recent years, several DCE-MRI studies have been published evaluating the association between microvasculature and other key features of plaque vulnerability (e.g., inflammation and intraplaque hemorrhage), as well as the effects of novel therapeutic interventions. The present paper reviews this literature, focusing on DCE-MRI methods of acquisition and analysis of atherosclerotic plaques, the current state and future potential of DCE-MRI in the evaluation of plaque microvasculature in clinical and preclinical settings. PMID- 27115146 TI - Decellularized aortic conduits: could their cryopreservation affect post implantation outcomes? A morpho-functional study on porcine homografts. AB - Decellularized porcine aortic valve conduits (AVCs) implanted in a Vietnamese Pig (VP) experimental animal model were matched against decellularized and then cryopreserved AVCs to assess the effect of cryopreservation on graft hemodynamic performance and propensity to in vivo repopulation by host's cells. VPs (n = 12) underwent right ventricular outflow tract substitution using AVC allografts and were studied for 15-month follow-up. VPs were randomized into two groups, receiving AVCs treated with decellularization alone (D; n = 6) or decellularization/cryopreservation (DC; n = 6), respectively. Serial echocardiography was carried out to follow up hemodynamic function. All explanted AVCs were processed for light and electron microscopy. No signs of dilatation, progressive stenosis, regurgitation, and macroscopic calcification were echocardiographically observed in both D and DC groups. Explanted D grafts exhibited near-normal features, whereas the presence of calcification, inflammatory infiltrates, and disarray of elastic lamellae occurred in some DC grafts. In the unaltered regions of AVCs from both groups, almost complete re endothelialization was observed for both valve cusps and aorta walls. In addition, side-by-side repopulation by recipient's fibroblasts, myofibroblasts, and smooth muscle cells was paralleled by ongoing tissue remodeling, as revealed by the ultrastructural identification of typical canals of collagen fibrillogenesis and elastogenesis-related features. Incipient neo-vascularization and re-innervation of medial and adventitial tunicae of grafted aortic walls were also detected for both D and DC groups. Cryopreservation did not affect post implantation AVC hemodynamic behavior and was topically propensive to cell repopulation and tissue renewal, although graft deterioration including calcification was present in several areas. Thus, these preliminary data provide essential information on feasibility of decellularization and cryopreservation coupling in the perspective of treatment optimization and subsequent clinical trials using similarly treated human allografts as innovative heart valve substitutes. PMID- 27115148 TI - Experimental Assessment of the Effects of Temperature and Food Availability on Particle Mixing by the Bivalve Abra alba Using New Image Analysis Techniques. AB - The effects of temperature and food addition on particle mixing in the deposit feeding bivalve Abra alba were assessed using an experimental approach allowing for the tracking of individual fluorescent particle (luminophore) displacements. This allowed for the computations of vertical profiles of a set of parameters describing particle mixing. The frequency of luminophore displacements (jumps) was assessed through the measurement of both waiting times (i.e., the time lapses between two consecutive jumps of the same luminophore) and normalized numbers of jumps (i.e., the numbers of jumps detected in a given area divided by the number of luminophores in this area). Jump characteristics included the direction, duration and length of each jump. Particle tracking biodiffusion coefficients (Db) were also computed. Data originated from 32 experiments carried out under 4 combinations of 2 temperature (Te) and 2 food addition (Fo) levels. For each of these treatments, parameters were computed for 5 experimental durations (Ed). The effects of Se, Fo and Ed were assessed using PERmutational Multivariate ANalyses Of VAriance (PERMANOVAs) carried out on vertical depth profiles of each particle mixing parameter. Inversed waiting times significantly decreased with Ed whereas the normalized number of jumps did not, thereby suggesting that it constitutes a better proxy of jump frequency when assessing particle mixing based on the measure of individual particle displacements. Particle mixing was low during autumn temperature experiments and not affected by Fo, which was attributed to the dominant effect of low temperature. Conversely, particle mixing was high during summer temperature experiments and transitory inhibited by food addition. This last result is coherent with the functional responses (both in terms of activity and particle mixing) already measured for individual of the closely related clam A. ovata originating from temperate populations. It also partly resulted from a transitory switch between deposit- and suspension-feeding caused by the high concentration of suspended particulate organic matter immediately following food addition. PMID- 27115147 TI - Prognostic value of diastolic wall strain in patients with chronic heart failure with reduced ejection fraction. AB - Left ventricular (LV) diastolic dysfunction plays a crucial role in heart failure with reduced ejection fraction (HFrEF). LV stiffness is a main component of diastolic function, but its role and prognostic value in HFrEF patients remains unclear. This study aimed to determine whether diastolic wall strain (DWS) as a noninvasive and simple marker of LV stiffness can predict the prognosis of HFrEF patients who were administrated chronic beta blockade enough. We enrolled 75 HFrEF patients who were administrated chronic beta blockade. We evaluated the echocardiographic parameters and plasma brain natriuretic peptide (BNP) before the induction of beta blockade and also obtained pulmonary artery wedge pressure (PAWP) from the right heart catheterization. DWS was obtained from standard M mode echocardiography as follows: DWS = [(LV posterior wall thickness (LVPWT) at end-systole - LVPWT at end-diastole)/LVPWT] at end-systole. DWS did not correlate with other echocardiographic parameters and PAWP. We defined primary outcome as HF hospitalization or cardiovascular death and followed for 7 years. The incidence rate was higher in low DWS than high DWS patients (p = 0.04). Other echocardiographic parameters could not be significant predictors of HFrEF outcome under the condition of enough beta blocker therapy. In multivariate analysis, DWS was the independent contributor to the event-free time. Impaired LV stiffness evaluated with DWS was associated with worse outcome and DWS might be an independent prognostic factor in HFrEF patients with chronic beta blockade. PMID- 27115149 TI - Polyphenols: a Promising Nutritional Approach to Prevent or Reduce the Progression of Prehypertension. AB - Diet plays a crucial role in maintaining healthy blood pressure. Functional foods are increasingly popular among health-conscious consumers to reduce cardiovascular risk factors and improve vascular health. In particular, dietary polyphenols represent an extraordinary inventory of structurally different compounds that may represent promising candidate chemical entities to prevent or delay the onset of hypertension. In recent years, it has been recognized that prehypertension may be a predictor of clinical hypertension and consequently of cardiovascular risk. Moreover, prehypertension status is associated with increased levels of several inflammatory markers and it is also characterized by structural changes, including endothelial dysfunction and arteriolar hypertrophy. Despite the low bioavailability of polyphenols and the lack of clinical data from nutritional intervention studies, the antihypertensive role of polyphenols to control blood pressure and reduce inflammation and endothelial dysfunction has been subject of recent debate. The purpose of this article is to discuss the potential benefits of dietary polyphenols as a promising and effective nutritional strategy for the management of prehypertension. PMID- 27115150 TI - Correction: A Comparison of Microbial Water Quality and Diversity for Ballast and Tropical Harbor Waters. AB - [This corrects the article DOI: 10.1371/journal.pone.0143123.]. PMID- 27115151 TI - UK Renal Registry 18th Annual Report: Chapter 4 Demography of Patients Receiving Renal Replacement Therapy in Paediatric Centres in the UK in 2014. AB - A total of 917 children and young people under 18 years with established renal failure (ERF) were receiving treatment at paediatric nephrology centres in 2014.At the census date (31st December 2014), 79.3% of prevalent paediatric patients aged ,18 years had a functioning kidney transplant, 11.2% were receiving haemodialysis (HD) and 9.5% were receiving peritoneal dialysis (PD). In patients aged ,16 years, prevalence of ERF was 60.4 per million age related population (pmarp) and the incidence 9.4 pmarp. The most common primary renal diagnosis was renal dysplasia+reflux, present in 32.6% of prevalent paediatric patients aged ,16 years. About a third of patients had one or more reported comorbidity at onset of renal replacement therapy (RRT). The improvement in rates of pre-emptive transplantation for those referred early has been maintained over the last 10 years at 37.5%, compared to 27.4% in 2000-2004. At transfer to adult services, 90.3% of patients had a functioning kidney transplant. Survival during childhood amongst children commencing RRT was the lowest in those aged less than two years compared to those aged 12 to less than 16 years with a hazard ratio of 4.1 (confidence interval 2.2-8.0), and in those receiving dialysis compared to having a functioning transplant with a hazard ratio of 6.3 (confidence interval 3.9 10.2). PMID- 27115152 TI - Early Detection of Epidemic GII-4 Norovirus Strains in UK and Malawi: Role of Surveillance of Sporadic Acute Gastroenteritis in Anticipating Global Epidemics. AB - Noroviruses are endemic in the human population, and are recognised as a leading cause of acute gastroenteritis worldwide. Although they are a highly diverse group of viruses, genogroup-II genotype-4 (GII-4) noroviruses are the most frequently identified strains worldwide. The predominance of GII-4 norovirus strains is driven by the periodic emergence of antigenic variants capable of evading herd protection. The global molecular epidemiology of emerging GII-4 strains is largely based on data from outbreak surveillance programmes, but the epidemiology of GII-4 strains among sporadic or community cases is far less well studied. To understand the distribution of GII-4 norovirus strains associated with gastroenteritis in the wider population, we characterised the GII-4 norovirus strains detected during studies of sporadic cases of infectious gastroenteritis collected in the UK and Malawi between 1993 and 2009. Our data shows that GII-4 norovirus strains that have emerged as strains of global epidemic importance have circulated in the community up to 18 years before their recognition as pandemic strains associated with increases in outbreaks. These data may suggest that more comprehensive surveillance programmes that incorporate strains associated with sporadic cases may provide a way for early detection of emerging strains with pandemic potential. This may be of particular relevance as vaccines become available. PMID- 27115153 TI - A Clinical Study of Maxillary Sinus Squamous Cell Carcinoma. AB - We report a retrospective study of 26 patients with maxillary sinus squamous cell carcinoma who were treated at the Sapporo Medical University between January 2002 and December 2008. The 5-year local control rate was 85.7% in patients with stage T2-3 disease and 61.0% in patients with stage T4a disease. The overall 5-year survival rate was 71.3% and the 5-year disease-specific survival rate was 79.9%. The 5-year disease-specific survival rate was 100% in patients with T2-3 disease and 44.4% in patients with T4 disease. The 5-year disease-specific survival rate was 76.3% in patients with N0 disease and 87.5% in patients with N+ disease. Five patients died of stage T4a disease. Two died of uncontrolled tumors at the primary site and 3 patients died of lung metastasis. We should consider another approach for the treatment of patients with advanced maxillary sinus carcinoma in the future. PMID- 27115154 TI - Encapsulation of Bacteriophage in Liposome Accentuates Its Entry in to Macrophage and Shields It from Neutralizing Antibodies. AB - Phage therapy has been a centre of attraction for biomedical scientists to treat infections caused by drug resistant strains. However, ability of phage to act only on extracellular bacteria and probability of interference by anti-phage antibodies in vivo is considered as a important limitation of bacteriophage therapy. To overcome these hurdles, liposome were used as delivery vehicle for phage in this study. Anti-phage antibodies were raised in mice and pooled serum was evaluated for its ability to neutralize free and liposome entrapped phage. Further, ability of phage and liposome-entrapped phage to enter mouse peritoneal macrophages and kill intracellular Klebsiella pneumoniae was compared. Also, an attempt to compare the efficacy of free phage and liposome entrapped phage, alone or in conjunction with amikacin in eradicating mature biofilm was made. The entrapment of phage in liposome provided 100% protection to phage from neutralizing antibody. On the contrary un-entrapped phage got neutralized within 3 h of its interaction with antibody. Compared to the inability of free phage to enter macrophages, the liposome were able to deliver entrapped phage inside macrophages and cause 94.6% killing of intracellular K. pneumoniae. Liposome entrapped phage showed synergistic activity along with amikacin to eradicate mature biofilm of K. pneumoniae. Our study reinforces the growing interest in using phage therapy as a means of targeting multidrug resistant bacterial infections as liposome entrapment of phage makes them highly effective in vitro as well as in vivo by overcoming the majority of the hurdles related to clinical use of phage. PMID- 27115155 TI - An Innovative Field-Applicable Molecular Test to Diagnose Cutaneous Leishmania Viannia spp. Infections. AB - Cutaneous and mucosal leishmaniasis is widely distributed in Central and South America. Leishmania of the Viannia subgenus are the most frequent species infecting humans. L. (V.) braziliensis, L. (V.) panamensis are also responsible for metastatic mucosal leishmaniasis. Conventional or real time PCR is a more sensitive diagnostic test than microscopy, but the cost and requirement for infrastructure and trained personnel makes it impractical in most endemic regions. Primary health systems need a sensitive and specific point of care (POC) diagnostic tool. We developed a novel POC molecular diagnostic test for cutaneous leishmaniasis caused by Leishmania (Viannia) spp. Parasite DNA was amplified using isothermal Recombinase Polymerase Amplification (RPA) with primers and probes that targeted the kinetoplast DNA. The amplification product was detected by naked eye with a lateral flow (LF) immunochromatographic strip. The RPA-LF had an analytical sensitivity equivalent to 0.1 parasites per reaction. The test amplified the principal L. Viannia species from multiple countries: L. (V.) braziliensis (n = 33), L. (V.) guyanensis (n = 17), L. (V.) panamensis (n = 9). The less common L. (V.) lainsoni, L. (V.) shawi, and L. (V.) naiffi were also amplified. No amplification was observed in parasites of the L. (Leishmania) subgenus. In a small number of clinical samples (n = 13) we found 100% agreement between PCR and RPA-LF. The high analytical sensitivity and clinical validation indicate the test could improve the efficiency of diagnosis, especially in chronic lesions with submicroscopic parasite burdens. Field implementation of the RPA-LF test could contribute to management and control of cutaneous and mucosal leishmaniasis. PMID- 27115156 TI - Cochlear Implantation in Children with Cochlear Malformation. AB - Cochlear implantation (CI) has proven to be an effective treatment for severe bilateral sensorineural hearing loss (SNHL). Inner ear malformation is a rare anomaly and occurs in approximately 20% of cases with congenital SNHL. In cases with cochlear malformation, CI can be successfully performed in nearly all patients, the exceptions being those with complete labyrinthine and cochlear aplasia. It is important to evaluate the severity of inner ear deformity and other associated anomalies during the preimplantation radiological assessment in order to identify any complication that may potentially occur during the surgery and subsequent patient management. PMID- 27115157 TI - Effect of flaxseed oil on serum systemic and vascular inflammation markers and oxidative stress in hemodialysis patients: a randomized controlled trial. AB - PURPOSE: The aim of this study was to investigate the effects of flaxseed oil consumption on serum systemic and vascular inflammation markers, and oxidative stress in hemodialysis (HD) patients. METHODS: In this randomized, double-blind, clinical trial, 34 HD patients were randomly assigned to either the flaxseed oil or the control group. The patients in the flaxseed oil group received 6 g/day flaxseed oil for 8 week, whereas the control group received 6 g/day medium-chain triglycerides (MCT) oil. At baseline and the end of week 8, serum concentrations of high-sensitive C-reactive protein (hs-CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM 1), sE-selectin, and malondialdehyde (MDA) were measured after a 12- to 14-h fast. RESULTS: Serum hs-CRP, a systemic inflammation marker, and sVCAM-1, a vascular inflammation marker, reduced significantly in the flaxseed oil group at the end of week 8 compared to baseline (P < 0.05), and the reductions were significant in comparison with the MCT oil group (P < 0.05). There were no significant differences between the two groups in mean changes in serum sICAM-1, sE-selectin, and MDA. CONCLUSION: This study indicates that daily consumption of 6 g flaxseed oil reduces serum hs-CRP and sVCAM-1, which are two risk factors for CVD. Therefore, the inclusion of flaxseed oil in the usual diet of HD patients can be considered as a strategy for reducing CVD risk factors. PMID- 27115158 TI - Laparoscopic onlay lingual mucosal graft ureteroplasty for proximal ureteral stricture: initial experience and 9-month follow-up. AB - PURPOSE: We present our initial experience and 9-month outcomes of the novel technique of laparoscopic onlay lingual mucosal graft ureteroplasty for proximal ureteral stricture. MATERIALS AND METHODS: In June 2015, transperitoneal laparoscopic onlay lingual mucosal graft ureteroplasty was performed on a male patient with proximal stricture of the left ureter. The patient complained with left frank pain. Severe hydronephrosis and proximal ureteral dilatation were noted through ultrasonography and CT scan. The length of upper ureteral stricture was 30 mm including 10-mm occlusion. A 46 mm in length and 15 mm in width lingual mucosa graft was harvested from the ventral of the tongue and placed in the strictured ureter as a ventral onlay for laparoscopic ureteroplasty. Operative time, intraoperative, and postoperative complications were well recorded. Follow up was performed with renal ultrasound, CT scan, and nuclear scan renography as well as clinical assessment of symptoms. RESULTS: The new technique was performed successful without intraoperative and postoperative complications. Neither hydronephrosis nor proximal ureteral dilatation in the left side was found through ultrasonography 3, 6, 9 months and CT scan 6 month postoperatively. The left renal function, glomerular filtration rate, had a recovery from 9.6 ml/min preoperatively to 14.0 ml/min at 6-month follow-up, and the patient has no complaints about the donor site and flank pain. CONCLUSIONS: To our knowledge, we present the initial experience with laparoscopic onlay lingual mucosal graft ureteroplasty for proximal ureteral stricture. With 9-month outcomes, the new technique appears to be an excellent option for proximal ureteral stricture. PMID- 27115159 TI - Analysis of technique and patient survival over time in patients undergoing peritoneal dialysis. AB - PURPOSE: This study used national claims data to investigate the technique and patient survival over time in incident peritoneal dialysis (PD) patients. METHODS: Incident end-stage renal disease patients undergoing PD and older than 18 years were selected from Taiwan health insurance databases. These patients were grouped into three study periods according to year of dialysis initiation: 1997-2001, 2002-2006, and 2007-2011. The study end-points included technique failure and mortality. RESULTS: The patients in the most recent era were older and more likely to have higher levels of comorbidity. Compared with the 1997-2001 group, the risks of technique failure were similar in the in the 2002-2006 (hazard ratio [HR] 1.10, 95 % confidence interval [CI] 0.98-1.24) and 2007-2011 groups (HR 1.11, 95 % CI 0.98-1.26), respectively. Relative to the 1997-2001 group, the risks of mortality were higher in the 2002-2006 group (HR 1.59, 95 % CI 1.26-2.02) and similar in the 2007-2011 group (HR 1.20, 95 % CI 0.93-1.55). Using icodextrin and automated peritoneal dialysis (APD) were associated with lower risks of technique failure (HR 0.62 and 0.86, 95 % CI 0.56-0.68 and 0.77 0.95, respectively) and mortality (HR 0.55 and 0.81, 95 % CI 0.45-0.66 and 0.67 0.99, respectively). CONCLUSIONS: Despite increase in disease burden in the most recent era, the outcomes remained relatively stable. The use of APD and icodextrin appears to have significantly ameliorated the impact of the increase in comorbidity burden. PMID- 27115160 TI - D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice. AB - D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice. PMID- 27115162 TI - Erratum to: Monte Carlo dosimetry of the IRAsource high dose rate 192Ir brachytherapy source. PMID- 27115163 TI - Review of 3D image data calibration for heterogeneity correction in proton therapy treatment planning. AB - Correct modelling of the interaction parameters of patient tissues is of vital importance in proton therapy treatment planning because of the large dose gradients associated with the Bragg peak. Different 3D imaging techniques yield different information regarding these interaction parameters. Given the rapidly expanding interest in proton therapy, this review is written to make readers aware of the current challenges in accounting for tissue heterogeneities and the imaging systems that are proposed to tackle these challenges. A summary of the interaction parameters of interest in proton therapy and the current and developmental 3D imaging techniques used in proton therapy treatment planning is given. The different methods to translate the imaging data to the interaction parameters of interest are reviewed and a summary of the implementations in several commercial treatment planning systems is presented. PMID- 27115164 TI - Clinic in Crisis Response: Imagined Immunities. PMID- 27115165 TI - Detecting Abeta deposition and RPE cell senescence in the retinas of SAMP8 mice. AB - AIM: Our previous study indicated that Abeta-induced Retinal Pigment Epithelial (RPE) cell senescence may be associated with chronic inflammation in age-related macular degeneration (AMD). The present study was designed to explore whether Abeta deposition and RPE senescence could be found in the senescence-prone mouse strain 8 (SAMP8), which is an animal model for AMD. METHODS: Eyes of both SAMP8 and age-matched SAMR1 (SAM resistant) mice were examined in vivo by fundus photography and electroretinography (ERG). Retinal morphological features were assessed using light and electron microscopy. Abeta deposition and p16-positive senescent RPE cells were traced using immunofluorescence labeling. P16 expression was detected using western blot. Expressions of IL-6 and IL-8 in RPE/choroid were analyzed using RT-PCR. RESULTS: In fundus of SAMP8, age-dependent increase of drusen-like lesions and the increase of granular autofluorescent spots were respectively detected using IR (near-infrared) and AF (autofluorescence) imaging of confocal scanning laser ophthalmoscope. The amplitude of the ERGs declined with age in SAMP8 and these changes were paralleled with the significant changes in retinal morphological features examined by funduscopy. Histopathological analysis found significant loss of photoreceptor outer segments (OS) and abnormal localization of RPE cells in aged SAMP8 mice. Degenerative changes in RPE cells of aged SAMP8 mice, including massive vacuoles, thickened Bruch's membrane (BrM), and loss of basal infoldings were further confirmed by electron microscopy. Increased Abeta deposits in OS layer and p16-positive senescent RPE cells were observed using immunofluorescence microscopy. Western blot confirmed that P16 expression was significantly increased in RPE cells of aged SAMP8 mice. Expressions of proinflammatory IL-6 and IL-8 were significantly upregulated in RPE/choroid of aged SAMP8 mice. CONCLUSIONS: Our results showed that aged SAMP8 mice developed ocular pathology similar to some features of human AMD. In this AMD mouse model, Abeta deposition and RPE senescence may be associated with AMD development, and RPE senescence is likely a mechanistic link between Abeta deposition and inflammation. PMID- 27115166 TI - Systematic study of novel lncRNAs in different gastrointestinal cancer cells. AB - BACKGROUND: Recently, many lncRNAs were found to be deregulated in various human cancers and play important roles in carcinogenesis. MATERIAL AND METHODS: To investigate the association of lncRNAs to gastrointestinal cancers, 12 cases of esophageal cancer and hepatic cancer, 16 cases of gastric cancer and colorectal cancer and their matched adjacent tissue samples, 12 esophageal cancer cell lines, 7 gastric cancer cell lines, 10 colorectal cancer cell lines, and 11 hepatic cancer cell lines were examined. RNA-seq, bioinformatics pipeline, co expression network, and gene ontology enrichment analysis were performed. RESULTS: We have identified 23,169 candidate novel lncRNA transcripts. Comparing with protein coding genes the lncRNAs tend to be shorter and have less exons. Remarkably, we found 15 lncRNAs that were down-regulated in all cancer cell lines among all four types of cancers. In addition, we analyzed the differentially expressed lncRNAs in gastrointestinal cancer cells before and after treatment with 5-Aza. Many lncRNAs were up-regulated after 5-Aza treatment, which suggested that the expression of these lncRNAs may be regulated by DNA methylation. Finally, based on the co-expression network and GO enrichment analysis, we predicted that many novel lncRNAs were involved in pathways like apoptosis, cell cycle, cell adhesion, EMT, epigenetic regulation, DNA damage response signaling, and immune response. CONCLUSION: Based on RNA-Seq and bioinformatics analysis, we have identified a significant number of novel lncRNAs, which could be involved in important pathways related to gastrointestinal cancer development. Overall, we provide a rich resource for identifying new biomarkers and studying novel lncRNA regulation pathways in gastrointestinal cancer. PMID- 27115167 TI - Rockets, radiosensitizers, and RRx-001: an origin story part I. AB - From Adam and Eve, to Darwinism, origin stories attempt to fill in the blanks, connect the dots, and define the turning points that are fundamental to subsequent developments. The purpose of this review is to present the origin story of a one-of-a-kind anticancer agent, RRx-001, which emerged from the aerospace industry as a putative radiosensitizer; not since the dynamite-to dilator transformation of nitroglycerin in 1878 or the post-World War II explosive-to-elixir conversion of hydralazine, an ingredient in rocket fuel, to an antihypertensive, an antidepressant and an antituberculant, has energetic chemistry been harnessed for therapeutic purposes. This is Part 1 of the radiosensitization story; Parts 2 and 3, which detail the crossover activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews. PMID- 27115168 TI - Integrating understanding of epidemiology and genomics in B-cell non-Hodgkin lymphoma as a pathway to novel management strategies. AB - Non-Hodgkin lymphomas include a biologically and clinically heterogeneous group of cancers distinguished by genetics, histology, and treatment outcomes. New discoveries regarding the genomic alterations and epidemiological exposures associated with these lymphomas have enhanced our understanding of factors that contribute to lymphomagenesis for specific subtypes. We explore the impact of normal B-cell biology engineered for recognizing a wide variety of antigens on the development of specific lymphoma subtypes, review lymphoma genetics, and examine the epidemiology of B-cell NHLs including recent investigations of risk factors for particular lymphoma subtypes based on large pooled analyses. Burkitt lymphoma, an aggressive form of B-cell NHL involving translocation of the MYC gene and an immunoglobulin gene has been associated with a history of eczema, hepatitis C, and occupation as a cleaner. Increased risk of diffuse large B-cell lymphoma has been associated with increased young adult body mass index, history of B-cell-activating autoimmune diseases, hepatitis C, and several single nucleotide variants involving the human leukocyte antigen (HLA) region of chromosome 6 and non-HLA loci near EXOC2, PVT1, MYC, and NCOA1. Tumor sequencing studies suggest that multiple pathways are involved in the development of DLBCL. Additional studies of epidemiological exposures, genome wide associations, and tumor sequencing in follicular, lymphoplasmacytic, marginal zone, and mantle cell lymphoma demonstrate overlapping areas of increased risk factors and unique factors for specific subtypes. Integrating these findings is important for constructing comprehensive models of NHL pathogenesis, which could yield novel targets for therapy and strategies for lymphoma prevention in certain populations. PMID- 27115169 TI - Notch -- a goldilocks signaling pathway in disease and cancer therapy. AB - The Notch signaling pathway is a fundamental signaling mechanism operating in most, if not all, multicellular organisms and in most cell types in the body. Like other "ivy league" pathways such as Wnt, PI3K, Sonic Hedgehog, Receptor Tyrosine Kinases (RTKs), and JAK/STAT signaling, the Notch pathway is a linear signaling mechanism, i.e., an extracellular ligand activates a receptor, which ultimately leads to transcriptional alterations in the cell nucleus, but Notch signaling is a strict cell-cell communication mechanism and lacks built-in amplification steps in the signaling pathway. Dysregulated Notch signaling, either by direct mutations in the pathway or by altered signaling output, is increasingly linked to disease, and Notch can act as an oncogene or tumor suppressor depending on the cellular context. This underscores that appropriate level of Notch signaling is important for differentiation and tissue homeostasis, a notion supported also by genetic data indicating that Notch signaling is very gene dosage-sensitive. Thus, too much or too little signaling can lead to disease and Notch can therefore be considered a Goldilocks signaling pathway. Given the emerging role of dysregulated Notch signaling in disease, there is increasing interest in developing therapeutic approaches to modulate Notch signaling. In this review we discuss recent findings on how signal transduction is tuned in the Notch pathway and how Notch signaling is dysregulated in disease. We also discuss different strategies to modulate Notch signaling for clinical use, for example by novel antibody-based tools and by taking advantage of the cross-talk between Notch and other signaling mechanisms. PMID- 27115170 TI - NK cell-based immunotherapies: awakening the innate anti-cancer response. AB - Metastasis is the leading cause of cancer-related death, as effective therapies remain an unsolved challenge in the clinical management of disseminated disease. Despite studies over the last decade reinforcing the role of the immune system in controlling cancer progression, our knowledge of immune control of cancer metastasis is still quite poor. Natural killer (NK) cells are a critical component of innate immunity and are able to recognize and trigger cell death in tumors by detecting receptor expression abnormalities in transformed cells. Recent studies and clinical trials have highlighted that manipulation of NK cell activation can be used as an immunotherapy in cancer. In this review, I provide an overview of potential immunotherapies that modulate NK cell responses against tumor metastases. PMID- 27115171 TI - Leukocyte trafficking: Can we bring the fight to the tumor? AB - Control of leukocyte trafficking plays a critical role in the establishment of effective immune responses. It is now well established that the number or ratio of effector to suppressor immune cells within the tumor microenvironment can significantly impact tumor growth and clinical outcomes. Recently approved immunotherapies by the FDA, and those in development, aim to stimulate effector immune cell function. For example, many checkpoint inhibitors seek to stimulate an immune response to tumors by reversing T-cell exhaustion. However, activation of the immune response outside the tumor microenvironment can lead to sometimes fatal immune-mediated adverse events -- the result of "on-target, off-tumor" effects. Thus, control of localization of these activated effector cells remains a critical component of optimizing tumor response while minimizing immune mediated adverse events. Chemokines and chemoattractants, along with their receptors on immune cells, govern leukocyte trafficking; thus, understanding their expression pattern in the context of the tumor microenvironment and developing approaches to favorably alter those should lead to improved efficacy of current immunotherapeutics. This review highlights the background of cancer immunotherapy, leukocyte trafficking, and some novel approaches being utilized to optimize recruitment of effector immune cells into the tumor microenvironment. Future combinatorial immunotherapy should incorporate therapeutics aimed at 1) favorably altering the tumor microenvironment, 2) activating effector immune cells, and 3) optimizing effector cell trafficking into tumors. PMID- 27115172 TI - B cell-targeted immunotherapy for type 1 diabetes: What can make it work? AB - Immunotherapy has revolutionized treatment of cancers and autoimmune diseases. Bucking the trend, however, is type 1 diabetes (T1D), although it is one of best understood autoimmune diseases and individuals at genetic risk are identifiable with high certainty. Here we review the major obstacles associated with pan-B cell-depletion using rituximab (RTX) and discuss the notion that B cell-directed therapy may be most effective as a preventive measure. We suggest that it will be more productive to aim at identifying and targeting autoreactive B cells rather than making adjustments to pan-B cell depletion and that non-conventional alternative therapies such as antibody blockade of FasL to bolster IL-10 producing Breg cells, which work successfully in mice, should be considered. PMID- 27115173 TI - Stabilization of HfB12 in Y1-xHfxB12 under Ambient Pressure. AB - Alloys of metal dodecaborides-YB12 with HfB12-were prepared via arc-melting in order to stabilize the metastable HfB12 high-pressure phase under ambient pressure. Previously, HfB12 had been synthesized only under high-pressure (6.5 GPa). Powder X-ray diffraction (PXRD) and energy-dispersive X-ray spectroscopy (EDS) were used to confirm the purity and phase composition of the prepared samples. The solubility limit for HfB12 in Y1-xHfxB12 (cubic UB12 structure type) was determined to be ~35 at. % Hf by PXRD and EDS analysis. The value of the cubic unit cell parameter (a) changed from 7.505 A (pure YB12) to 7.454 A across the solid solution range. Vickers hardness increased from 40.9 +/- 1.6 GPa for pure YB12 to 45.0 +/- 1.9 GPa under an applied load of 0.49 N for the Y1-xHfxB12 solid solution composition with ~28 at. % Hf, suggesting both solid solution hardening and extrinsic hardening due to the formation of secondary phases of hafnium. PMID- 27115174 TI - Magnetically Responsive Nanostructures with Tunable Optical Properties. AB - Stimuli-responsive materials can sense specific environmental changes and adjust their physical properties in a predictable manner, making them highly desired components for designing novel sensors, intelligent systems, and adaptive structures. Magnetically responsive structures have unique advantages in applications, as external magnetic stimuli can be applied in a contactless manner and cause rapid and reversible responses. In this Perspective, we discuss our recent progress in the design and fabrication of nanostructured materials with various optical responses to externally applied magnetic fields. We demonstrate tuning of the optical properties by taking advantage of the magnetic fields' abilities to induce magnetic dipole-dipole interactions or control the orientation of the colloidal magnetic nanostructures. The design strategies are expected to be extendable to the fabrication of novel responsive materials with new optical effects and many other physical properties. PMID- 27115175 TI - Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting. AB - G-quadruplex structures (G4) are promising anticancerous targets. A great number of small molecules targeting these structures have already been identified through biophysical methods. In cellulo, some of them are able to target either telomeric DNA and/or some sequences involved in oncogene promotors, both resulting in cancer cell death. However, only a few of them are able to bind to these structures G4 irreversibly. Here we combine within the same molecule the G4 binding agent PDC (pyridodicarboxamide) with a N-heterocyclic carbene-platinum complex NHC-Pt already identified for its antitumor properties. The resulting conjugate platinum complex NHC-Pt-PDC stabilizes strongly G-quadruplex structures in vitro, with affinity slightly affected as compared to PDC. In addition, we show that the new conjugate binds preferentially and irreversibly the quadruplex form of the human telomeric sequence with a profile in a way different from that of NHC-Pt thereby indicating that the platination reaction is oriented by stacking of the PDC moiety onto the G4-structure. In cellulo, NHC-Pt-PDC induces a significant loss of TRF2 from telomeres that is considerably more important than the effect of its two components alone, PDC and NHC-Pt, respectively. PMID- 27115176 TI - Synthesis and Characterization of a Promising Novel FFAR1/GPR40 Targeting Fluorescent Probe for beta-Cell Imaging. AB - Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of beta-cells bears the potential to contribute to an improved understanding, diagnosis, and development of new treatment options for diabetes. Here, we describe the first small molecule fluorescent probe targeting the free fatty acid receptor 1 (FFAR1/GPR40). This receptor is highly expressed on beta-cells, and was up to now unexplored for imaging purposes. We designed a novel probe by facile modification of the selective and potent FFAR1 agonist TAK-875. Effective and specific binding of the probe was demonstrated using FFAR1 overexpressing cells. We also successfully labeled FFAR1 on MIN6 and INS1E cells, two widely used beta-cell models, by applying an effective amplification protocol. Finally, we showed that the probe is capable of inducing insulin secretion in a glucose-dependent manner, thus demonstrating that functional activity of the probe was maintained. These results suggest that our probe represents a first important step to successful beta-cell imaging by targeting FFAR1. The developed probe may prove to be particularly useful for in vitro and ex vivo studies of diabetic cellular and animal models to gain new insights into disease pathogenesis. PMID- 27115177 TI - Gut microbial metabolites in health and disease. PMID- 27115178 TI - MMP-9 overexpression is associated with intragenic hypermethylation of MMP9 gene in melanoma. AB - Tumor spreading is associated with the degradation of extracellular matrix proteins, mediated by the overexpression of matrix metalloproteinase 9 (MMP-9). Although, such overexpression was linked to epigenetic promoter methylation, the role of intragenic methylation was not clarified yet. Melanoma was used as tumor model to investigate the relationship between the DNA intragenic methylation ofMMP9 gene and MMP-9 overexpression at transcriptional and protein levels. Computational analysis revealed DNA hypermethylation within the intragenic CpG-2 region of MMP9 gene in melanoma samples with high MMP-9 transcript levels. In vitro validation showed that CpG-2 hotspot region was hypermethylated in the A375 melanoma cell line with highest mRNA and protein levels of MMP-9, while low methylation levels were observed in the MEWO cell line where MMP-9 was undetectable. Concordant results were demonstrated in both A2058 and M14 cell lines. This correlation may give further insights on the role of MMP-9 upregulation in melanoma. PMID- 27115179 TI - A Smoking Cessation Campaign on Twitter: Understanding the Use of Twitter and Identifying Major Players in a Health Campaign. AB - The current study examined the use of online social media for a health campaign. Collecting tweets (N = 1,790) about the recent smoking cessation campaign by the Centers for Disease Control and Prevention, the current study investigated the dissemination of health campaign messages on Twitter and answered questions from the process evaluation of health campaigns: who tweeted about the campaign, who played central roles in disseminating health campaign messages, and how various features of Twitter were used for sharing of campaign messages. Results showed that individuals and nonprofit organizations posted frequently about the campaign: Individuals and nonprofit organizations posted about 40% and 30% of campaign-related tweets, respectively. Although the campaign under investigation was steered by a government agency, nonprofit organizations played a vital role as mediators who disseminated campaign messages. The culture of retweeting demonstrated its particular usefulness for the dissemination of campaign messages. Despite the expectation that the use of social media would expand opportunities for engagement, actual two-way interactions were few or minimal. Drawn from the results, practical suggestions on how to strategize the use of Twitter for future health campaigns are discussed. PMID- 27115196 TI - Development of a patient decision aid on inhaled corticosteroids use for adults with asthma. AB - BACKGROUND: Patient decision aids (PDAs) are used in shared decision making to improve practitioner-patient communication and help patients decide about treatment options. To develop a PDA for adults with asthma considering inhaled corticosteroids, with or without long-acting beta2-agonists, to optimize asthma control. METHODS: The PDA was developed based on the International Patient Decision Aid Standards. Step 1: PDA was drafted. Step 2: PDA acceptability was assessed among target users, certified asthma educators (CAEs) and adults with asthma, following an iterative process. a) Participants read the PDA, b) rated its presentation, length, balance, and perceived usefulness, indicated what they liked/disliked about it, and made suggestions for improvement. c) Based on results from (b), PDA was refined. This process was repeated with new participants until no suggestions were made. Step 3: The PDA was field tested with target users. Interviews with CAEs were conducted to identify areas of improvement. Step 4: Final PDA version was written. RESULTS: A color-printed, 4 page, letter-sized PDA was drafted. Acceptability testing involved 11 CAEs (women, n = 10) and 20 adults with asthma (women, n = 13; age 22-61 years). Five successive refined versions were produced. Major changes were made to PDA terminology, instructions, paper size, and visual presentation. Two CAEs (women, n = 2) and 26 adults with asthma (women, n = 19; age 20-65 years) field tested PDA. Minor changes were made to language and instructions to ensure usability. The final version was a color-printed, 12-page, A3-sized booklet. CONCLUSION: Our newly developed PDA was found acceptable and usable in target users. PMID- 27115197 TI - The Topical Application of Rosuvastatin in Preventing Knee Intra-Articular Adhesion in Rats. AB - BACKGROUND Intra-articular adhesion is one of the common complications of post knee surgery and injury. The formation of joint adhesion can lead to serious dysfunction. Rosuvastatin (ROS) is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, with multiple biological effects. In our study, the object was to evaluate the effectiveness of ROS in the prevention of post operative knee adhesion in rats. MATERIAL AND METHODS Femoral condyle exposing surgery was performed on 45 healthy Sprague Dawley rats. Gelatin sponges soaked with 20 mg/kg of ROS, 10 mg/kg of ROS, or saline were used to cover the surgical site. The post-operative knee joints were fixed in a flexed position with micro Kirschner wires for four weeks. ROS effectiveness for treating intra-articular adhesion was determined with visual score evaluation, hydroxyproline content, histological analyses, immunohistochemistry, and inflammatory and vascular endothelial growth factors expression. RESULTS The animals' recovery was stable after surgery. The hydroxyproline content, visual score, and inflammatory vascular growth factors expression levels suggested that, compared with the control group, the ROS treatment groups showed better outcomes. ROS prevented joint adhesion formation, collagen deposition, and vascularization at the surgical site, and also inhibited inflammatory activity post-operatively. Compared with the 10 mg/kg ROS group, the 20 mg/kg ROS group showed significantly better outcomes. CONCLUSIONS The local application of ROS reduced intra-articular adhesion formation, collagen deposition, and vascularization at the surgical site, and inhibited inflammatory activity post-operatively. These results suggested optimal concentration of ROS to be 20 mg/kg. PMID- 27115198 TI - Access to Thiophene and 1H-Pyrrole via Amine-Initiated (3 + 2) Annulation and Aromatization Cascade Reaction of beta'-Acetoxy Allenoate and 1,2-Bisnucleophile. AB - The amine-catalyzed cascade (3 + 2) annulation and aromatization sequence between beta'-acetoxy allenoates and 1,2-bisnucleophiles has been developed. When 1,4 dithane-2,5-diol is used as the bisnucleophile partner, the corresponding reaction affords fully substituted thiophene-2-carbaldehyde, which might proceed via the amine-catalyzed (3 + 2) annulation and subsequent oxidative aromatization. The reaction protocol is also applicable to a 2-tosylamino carbonyl bisnucleophile, wherein the (3 + 2) annulation is followed by 1,2 elimination of a tosyl group and isomerization to give a 1H-pyrrole product. PMID- 27115199 TI - Developing an Ethical and Legal Interoperability Assessment Process for Retrospective Studies. AB - The past decade has witnessed the creation of major international research consortia, aiming to facilitate the sharing of data from different studies to maximize health benefits. However, combining heterogeneous data across existing studies requires addressing issues related to both data harmonization and ethical and legal interoperability. This article proposes a rigorous interoperability assessment process to assess whether different data sets are sufficiently ethically and legally interoperable to allow for a given proposed research use. The methodology used to develop this process is based on a comprehensive analysis of the international ethical and legal framework governing the use of retrospective data in research, and includes the following steps: (I) finding existing processes; (II) comparing processes to identify similarities and differences and determining the limits of the "consistent whole"; (III) establishing common principles and procedures; and, (IV) changing or removing processes that do not contribute to the consistent whole. Each of these four steps were examined using step-specific methodologies, including (a) literature and policy reviews; (b) consultations with international ethical, legal and social implications (ELSI) experts; and (c) a case study piloting the proposed framework in an actual international research consortium. This assessment process takes into account key legal and ethical components such as consent, recontact, and waiver of consent. As a result, this analysis allows the development of a comprehensive filter used to verify the legal and ethical restrictions pertaining to a data set. This in turns helps in determining whether the given data set can to be used for a proposed research project, or is ethically and legally interoperable for use in research collaborations. By integrating this filter to the regular data access processes used by cohorts, not only will researchers be able to create virtual "mega-cohorts" of research participants, but it will also ensure that these cohorts respect basic legal and ethical precepts. PMID- 27115200 TI - Renal outcomes in mixed proliferative and membranous lupus nephritis (Class III/IV + V): A long-term observational study. AB - OBJECTIVES: In this study, we aimed to assess the effect of combination of proliferative and membranous lesions (Class III + V or IV + V) on renal outcomes as an independent category distinct from Class III and IV. METHODS: We retrospectively analyzed 103 Japanese patients (14 male and 89 female) with Class III/IV LN, with or without Class V, who underwent renal biopsy and were treated at our institution. Renal endpoint was defined as doubling of serum creatinine or end-stage renal disease (ESRD). RESULTS: The number of patients in each group was as follows: pure Class III/IV, 81 patients and mixed Class III/IV + V, 22 patients. During a median follow-up period of 125.0 months, 10 patients developed renal endpoint: five had Class III/IV LN and five had a combination of Class III/IV + V. Kaplan-Meier analyses demonstrated that patients with mixed Class III/IV + V LN had significantly poorer renal outcomes than patients with Class III/IV LN. Multivariate Cox regression analyses identified serum creatinine, active and chronic lesions (A/C), and mixed Class III/IV + V) as independent risk factors for poor renal outcomes. CONCLUSIONS: This study demonstrated a combination of proliferative and membranous LN (ISN/RPS Class III/IV + V) predicts poor renal outcomes. PMID- 27115201 TI - An Exploratory Microdialysis Study to Assess the Ocular Pharmacokinetics of Ciprofloxacin Eye Drops in Rabbits. AB - PURPOSE: Despite the high frequency of use, data regarding the ocular in vivo pharmacokinetics (PK) of topically applied antibiotics are sparse. This study seeks to investigate the PK of the widely used fluoroquinolone ciprofloxacin by means of in vivo microdialysis. METHODS: Twelve New Zealand white rabbits were included in the experiments. Under general anesthesia, microdialysis probes were implanted in the anterior chamber and the posterior segment of the same eye. After a period of 90 min after implantation, one drop of ciprofloxacin was administered onto the ocular surface. Microdialysis samples of the anterior chamber and the vitreous were collected every 30 min for 6 h. Relative recovery was assessed by retrodialysis to calculate absolute concentration values. Samples were analyzed using HPLC. RESULTS: In the anterior chamber, the maximum total drug concentration (Cmax) amounted to 0.373 +/- 0.281 MUg/mL and was reached (Tmax) after 116 +/- 36 min. Calculated area under the concentration-time curve AUC(0-n) for ciprofloxacin in the anterior chamber was 78.8 +/- 47.1 MUg min/mL. For the vitreous, Cmax was 0.02 +/- 0.03 MUg/mL and maximum drug concentration was reached 107 +/- 60 min after topical administration. AUC(0-n) for ciprofloxacin in the vitreous was 0.269 +/- 0.370 MUg min/mL. CONCLUSION: Microdialysis is a suitable method to assess in vivo pharmacokinetic profiles in the anterior chamber and in the vitreous. In the anterior chamber, maximum drug concentration was reached ~2 h after single drug administration. Although the drug concentration in the vitreous was considerably lower, time course of drug concentration was comparable. PMID- 27115202 TI - Disclosure of sexual assault experiences among undergraduate women at historically black colleges and universities (HBCUs). AB - OBJECTIVE: To document the sexual assault disclosure experiences of historically black college or university (HBCU) students. PARTICIPANTS: A total of 3,951 female, undergraduate students at 4 HBCUs. METHODS: All women at the participating schools were recruited in November 2008 to participate in a Web based survey including both closed- and open-ended questions. Survey data were weighted for nonresponse bias. RESULTS: The majority of sexual assault survivors disclosed their experience to someone close to them, but disclosure to formal supports, particularly law enforcement agencies, was extremely rare. Nonreporters had concerns about the seriousness of the incident and their privacy. On the basis of qualitative data, strategies identified by students to increase reporting included more education and awareness about sexual assault, more survivor services and alternative mechanisms for reporting, and better strategies for protecting the confidentiality of survivors. CONCLUSIONS: Official sexual assault victimization data are of limited utility in conveying the extent of sexual assault among HBCU students, and efforts to increase reporting, such as peer education and enhanced confidentiality procedures, are needed. PMID- 27115203 TI - Inhibitory Effects of Tranilast on Cytokine, Chemokine, Adhesion Molecule, and Matrix Metalloproteinase Expression in Human Corneal Fibroblasts Exposed to Poly(I:C). AB - : Purpose/Aim: Viral infection of the cornea can result in inflammation and scarring and eventually cause blindness. Polyinosinic-polycytidylic acid [poly(I:C)], an analog of viral double-stranded RNA, induces the synthesis of various cytokines, chemokines, adhesion molecules, and matrix metalloproteinases (MMPs) in corneal fibroblasts. The effects of tranilast on the expression of these molecules in human corneal fibroblasts were examined. MATERIALS AND METHODS: Human corneal fibroblasts were cultured with or without poly(I:C) or tranilast. The release of the proinflammatory cytokine interleukin (IL)-6 and of the chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) was measured with enzyme-linked immunosorbent assays. The expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), MMP-1, and MMP-3 was evaluated by immunoblot or immunofluorescence analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs), c-Jun (a component of the transcription factor AP-1), and IkappaB-alpha (an endogenous inhibitor of the transcription factor NF-kappaB) was examined by immunoblot analysis. RESULTS: Tranilast inhibited in a concentration- and time-dependent manner the production of IL-6, IL-8, MCP-1, ICAM-1, VCAM-1, MMP-1, and MMP-3 by corneal fibroblasts exposed to poly(I:C). It also inhibited the poly(I:C)-induced phosphorylation of c-Jun and the MAPK JNK without affecting that of IkappaB-alpha or the MAPKs ERK and p38. CONCLUSIONS: Tranilast inhibited proinflammatory cytokine, chemokine, adhesion molecule, and MMP expression in human corneal fibroblasts exposed to poly(I:C), with these effects likely being mediated by attenuation of JNK-AP-1 signaling. Tranilast might therefore be expected to limit immune cell infiltration and stromal degradation associated with viral infection of the cornea. PMID- 27115204 TI - Transcription-induced DNA supercoiling: New roles of intranucleosomal DNA loops in DNA repair and transcription. AB - RNA polymerase II (Pol II) transcription through chromatin is accompanied by formation of small intranucleosomal DNA loops. Pol II captured within a small loop drives accumulation of DNA supercoiling, facilitating further transcription. DNA breaks relieve supercoiling and induce Pol II arrest, allowing detection of DNA damage hidden in chromatin structure. PMID- 27115205 TI - Usability Testing of Guided Internet-based Parent Training for Challenging Behavior in Children with Fetal Alcohol Spectrum Disorder (Strongest Families FASD). AB - BACKGROUND: In order to meet the need for accessible interventions and support for families affected by fetal alcohol spectrum disorder (FASD), we have developed an Internet-based, distance intervention for caregivers of children with FASD between the ages of four and twelve, called Strongest FamiliesTM FASD. OBJECTIVES: To evaluate the usability of the Strongest Families FASD program content and website in terms of learnability, efficiency and acceptability. METHODS: A remote usability testing approach was conducted in two iterative cycles of participants. Synchronous online usability testing sessions were conducted, followed by asynchronous testing. A total of 18 participants were included, comprised of both health care professionals with expertise in FASD and caregivers of children with FASD. The data collected in each cycle was examined for commonalities and results were used to inform changes to the website and content after each cycle. RESULTS: Participants rated the website as appealing and relatively easy and fast to use. Nevertheless, several usability problems were identified such as difficulty navigating between sections of content on the website, displaying too much content per page, and the relevance and appropriateness of the content as it related to FASD. CONCLUSIONS: The identification of usability problems was an important step in refining the Strongest Families FASD program before its effectiveness is evaluated in a randomized controlled trial. PMID- 27115206 TI - Fabrication and characterization of Mg-doped chitosan-gelatin nanocompound coatings for titanium surface functionalization. AB - Titanium and its alloys have been widely used in clinic and achieved great success. Due to the bio-inertness of titanium surface, challenges still exit in some compromised conditions. The present study aimed to functionalize titanium surface with magnesium (Mg)-doped chitosan/gelatin (CS/G) nanocompound coatings via electrophoretic deposition (EPD). CS/G coatings loaded with different amount of magnesium were successfully prepared on titanium substrate via EPD. Physicochemical characterization of the coatings confirmed that magnesium ions were loaded into the coatings in a dose-dependent manner. XRD results demonstrated that co-deposition of magnesium influenced the crystallinity of the coatings, and a new crystalline substance presented, namely hydrated basic magnesium carbonate. Mechanical tests showed improved tensile and shear bond strength of the magnesium-doped coatings, while the excessively high magnesium concentration could eventually decrease the bonding strength. Sustained release of magnesium ion was detected by ICP-OES within 28 days. TEM images also displayed that nanoparticles could be released from the coatings. In vitro cellular response assays demonstrated that the Mg-doped nanocompound coatings could enhance the proliferation and osteogenic differentiation of MC3T3-E1 cells compared to CS/G coatings. Therefore, it could be concluded that Mg-doped CS/G nanocompound coatings were successfully fabricated on titanium substrates via EPD. It would be a promising candidate to functionalize titanium surface with such organic-inorganic nanocompound coatings. PMID- 27115207 TI - Production of truncated MBD4 protein by frameshift mutation in DNA mismatch repair-deficient cells enhances 5-fluorouracil sensitivity that is independent of hMLH1 status. AB - Methyl-CpG binding domain protein 4 (MBD4) is a DNA glycosylase that can remove 5 fluorodeoxyuracil from DNA as well as repair T:G or U:G mismatches. MBD4 is a target for frameshift mutation with DNA mismatch repair (MMR) deficiency, creating a truncated MBD4 protein (TruMBD4) that lacks its glycosylase domain. Here we show that TruMBD4 plays an important role for enhancing 5-fluorouracil (5FU) sensitivity in MMR-deficient colorectal cancer cells. We found biochemically that TruMBD4 binds to 5FU incorporated into DNA with higher affinity than MBD4. TruMBD4 reduced the 5FU affinity of the MMR recognition complexes that determined 5FU sensitivity by previous reports, suggesting other mechanisms might be operative to trigger cytotoxicity. To analyze overall 5FU sensitivity with TruMBD4, we established TruMBD4 overexpression in hMLH1 proficient or -deficient colorectal cancer cells followed by treatment with 5FU. 5FU-treated TruMBD4 cells demonstrated diminished growth characteristics compared to controls, independently of hMLH1 status. Flow cytometry revealed more 5FU treated TruMBD4 cells in S phase than controls. We conclude that patients with MMR-deficient cancers, which show characteristic resistance to 5FU therapy, may be increased for 5FU sensitivity via secondary frameshift mutation of the base excision repair gene MBD4. PMID- 27115208 TI - Laboratory Investigations for Diagnosis of Autoimmune and Inflammatory Periocular Disease: Part II. AB - PURPOSE: To review the important laboratory serological investigations routinely performed for the diagnosis of autoimmune and inflammatory diseases of the orbit and ocular adnexa. METHODS: Review of the literature as well as personal clinical experience of the authors. Due to the extensive nature of the topic, the review has been split into 2 parts. Part I covers thyroid eye disease, IgG4-related disease, and myasthenia gravis. In part II of the review, sarcoidosis, vasculitis, Sjogren syndrome, and giant cell arteritis will be discussed. RESULTS: Several relatively specific serologic tests are available for the diagnosis of a variety of inflammatory and serologic diseases of the orbit. CONCLUSION: In cases of limited orbital or sino-orbital disease, serologic testing may be negative in a significant number of patients. Specifically, the clinician should be wary of ruling out limited orbital sarcoid or sinoorbital granulomatosis with polyangiitis based on serologic testing alone. Part I of this review has covered serologic testing for thyroid eye disease, IgG4-related disease, and myasthenia gravis. In part II, the authors discuss serologic testing for sarcoidosis, vasculitis, Sjogren syndrome (SS), and giant cell arteritis (GCA). PMID- 27115209 TI - Blepharophimosis Ptosis Epicanthus Inversus Syndrome With Congenital Hypothyroidism and Brachydactyly in a 7-Year-Old Girl. AB - A 7-year-old female presented with blepharophimosis ptosis epicanthus inversus syndrome with congenital hypothyroidism and brachydactyly. She displayed typical manifestations of type II blepharophimosis ptosis epicanthus inversus syndrome (normal uterus position, ovarian volume, and normal serum hormone levels). She takes levothyroxine sodium daily due to her congenital hypothyroidism. Karyotype analysis and genetic analysis of FOXL2 coding sequence was found to be normal. mtDNA A3243G, A8344G, 8993, and 13513 genes were also normal. The absence of mutations excluded mitochondrial encephalomyopathies. To the best of our knowledge, this is the first reported case of blepharophimosis ptosis epicanthus inversus syndrome with congenital hypothyroidism and brachydactyly. PMID- 27115210 TI - Use of Computed Tomography-Derived Prosthetics for Intraoperative Guidance of Tumor Resection. AB - Preoperative computed tomography (CT)-derived design and modeling provides a useful guide for a more accurate reconstruction of a variety of complex maxillofacial deformities. While the use of three-dimensional CT imaging has focused mainly on bony reconstruction, the use of this technique to facilitate soft tissue reconstruction represents an important innovation that can assist surgeons with preoperative planning and intraoperative decision-making. In this study, the authors report the novel use of three-dimensional CT scan modeling to facilitate the resection of a large maxillofacial neurofibroma in a patient with neurofibromatosis. In conjunction with an anaplastologist, the combined use of tangible models and aesthetic judgments significantly optimizes the quality of the initial resection and subsequent reconstruction. By utilizing an interdisciplinary approach, it is possible to achieve optimal symmetry in the setting of complex maxillofacial deformities. PMID- 27115211 TI - Anterior Cranial Vault Distraction for the Treatment of Normocephalic Pancraniosynostosis. AB - Normocephalic pancraniosynostosis is a rare form of craniosynostosis that usually presents later in life secondary to a delayed onset of symptoms and the presence of a normal head shape. Since its initial description in the literature in 2010, normocephalic pancraniosynostosis remains a rare clinical entity that has only been reported in 6 patients. Surgical treatment in the 2 published reports has been by staged total calvarial reconstruction or anterior cranial vault remodeling with bilateral frontoorbital advancement. In this case report, the authors present 1 patient with normocephalic pancraniosynostosis and propose surgical treatment by anterior cranial vault expansion with distraction osteogenesis. PMID- 27115213 TI - The Benefit of a Complete Cephalic Trim and the Importance of the Scroll Area. AB - Cephalic trimming of the lower lateral cartilage (LLC) of the nose is often performed to refine a broad nasal tip in the horizontal dimension. The focus of cephalic trimming remains the preservation of the width of the lateral crura and the cartilage remnant at the cephalic end of the LLC is usually left intact, which leads to inadequate cephalic trimming.The authors suggest that cephalic trimming should continue all the way to the cephalic end of the LLC and no remnant cartilage should be left in the scroll area. This would make it possible to reduce the bulk of the nasal tip in an acceptable manner. Trimming of the whole cephalic side of the LLC would disrupt the scroll area, allowing authors to assess rhinoplasty as a 2-stage surgical procedure: that is, nasal tip and middle vault.In conclusion, complete cephalic trimming without leaving any remnant cartilage in the scroll area is necessary for adequate nasal tip refinement, and disruption of the scroll area allows the rhinoplasty to be compartmentalized to achieve more desirable results in the middle vault and the nasal tip. PMID- 27115214 TI - Short-course oral steroids as an adjunct therapy for chronic rhinosinusitis. AB - BACKGROUND: This review is one of a suite of six Cochrane reviews looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is a common condition involving inflammation of the lining of the nose and paranasal sinuses. It is characterised by nasal blockage and nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Oral corticosteroids are used to control the inflammatory response and improve symptoms. OBJECTIVES: To assess the effects of a short course of oral corticosteroids as an adjunct ('add-on') therapy in people with chronic rhinosinusitis who are already on standard treatments. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 7); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a short course (up to 21 days) of oral corticosteroids to placebo or no treatment, where all patients were also receiving pharmacological treatment for chronic rhinosinusitis. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease specific health-related quality of life (HRQL), patient-reported disease severity, and the adverse event of mood or behavioural disturbances. Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score, and the adverse events of insomnia, gastrointestinal disturbances and osteoporosis. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: Two trials with a total of 78 participants met the inclusion criteria. Both the populations and the 'standard' treatments differed in the two studies. Oral steroids as an adjunct to intranasal corticosteroids One trial in adults with nasal polyps included 30 participants. All participants used intranasal corticosteroids and were randomised to either short-course oral steroids (oral methylprednisolone, 1 mg/kg and reduced progressively over a 21-day treatment course) or no additional treatment. None of the primary outcome measures of interest in this review were reported by the study. There may have been an important reduction in the size of the polyps (measured by the nasal polyps score, a secondary outcome measure) in patients receiving oral steroids and intranasal corticosteroids, compared to intranasal corticosteroids alone (mean difference (MD) -0.46, 95% confidence interval (CI) -0.87 to -0.05; 30 participants; scale 1 to 4) at the end of treatment (21 days). This corresponds to a large effect size, but we are very uncertain about this estimate as we judged the study to be at high risk of bias. Moreover, longer-term data were not available and the other outcomes of interest were not reported. Oral steroids as an adjunct to antibiotics One trial in children (mean age of eight years) without nasal polyps included 48 participants. The trial compared oral corticosteroids (oral methylprednisolone, 1 mg/kg and reduced progressively over a 15-day treatment course) with placebo in participants who also received a 30-day course of antibiotics. This study addressed one of the primary outcome measures (disease severity) and one secondary outcome (CT score). For disease severity the four key symptoms used to define chronic rhinosinusitis in children (nasal blockage, nasal discharge, facial pressure, cough) were combined into one score. There was a greater improvement in symptom severity 30 days after the start of treatment in patients who received oral steroids and antibiotics compared with placebo and antibiotics (MD -7.10, 95% CI -9.59 to -4.61; 45 participants; scale 0 to 40). The observed mean difference corresponds to a large effect size. At the same time point there was a difference in CT scan score (MD -2.90, 95% CI -4.91 to -0.89; 45 participants; scale 0 to 24). We assessed the quality of the evidence to be low.There were no data available for the longer term (three months). AUTHORS' CONCLUSIONS: There might be an improvement in symptom severity, polyps size and condition of the sinuses when assessed using CT scans in patients taking oral corticosteroids when these are used as an adjunct therapy to antibiotics or intranasal corticosteroids, but the quality of the evidence supporting this is low or very low (we are uncertain about the effect estimate; the true effect may be substantially different from the estimate of the effect). It is unclear whether the benefits of oral corticosteroids as an adjunct therapy are sustained beyond the short follow-up period reported (up to 30 days), as no longer-term data were available.There were no data in this review about the adverse effects associated with short courses of oral corticosteroids as an adjunct therapy.More research in this area, particularly research evaluating longer-term outcomes and adverse effects, is required. PMID- 27115215 TI - Different types of intranasal steroids for chronic rhinosinusitis. AB - BACKGROUND: This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Topical (intranasal) corticosteroids are used with the aim of reducing inflammation in the sinonasal mucosa in order to improve patient symptoms. OBJECTIVES: To assess the effects of different types of intranasal steroids in people with chronic rhinosinusitis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 7); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing first-generation intranasal corticosteroids (e.g. beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide) with second-generation intranasal corticosteroids (e.g. ciclesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, betamethasone sodium phosphate), or sprays versus drops, or low-dose versus high-dose intranasal corticosteroids. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis (nosebleed). Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse event of local irritation. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included nine RCTs (911 participants), including four different comparisons. None of the studies evaluated our first primary outcome measure, disease-specific HRQL. Fluticasone propionate versus beclomethasone dipropionate We identified two small studies (56 participants with polyps) that evaluated disease severity and looked at the primary adverse effect: epistaxis , but no other outcomes. We cannot report any numerical data but the study authors reported no difference between the two steroids. The evidence was of very low quality. Fluticasone propionate versus mometasone furoate We identified only one study (100 participants with polyps) that evaluated disease severity (nasal symptoms scores), which reported no difference (no numerical data available). The evidence was of very low quality. High-dose versus low-dose steroidsWe included five studies (663 participants with nasal polyps), three using mometasone furoate (400 ug versus 200 ug in adults and older children, 200 ug versus 100 ug in younger children) and two using fluticasone propionate drops (800 ug versus 400 ug). We found low quality evidence relating to disease severity and nasal polyps size, with results from the high-dose and low-dose groups being similar. Although all studies reported more improvement in polyp score in the high-dose group, the significance of this is unclear due to the small size of the improvements.The primary adverse effect, epistaxis , was more common when higher doses were used (risk ratio (RR) 2.06, 95% confidence interval (CI) 1.20 to 3.54, 637 participants, moderate quality evidence). Most of the studies that contributed data to this outcome used a broad definition of epistaxis, which ranged from frank bleeding to bloody nasal discharge to flecks of blood in the mucus. Aqueous nasal spray versus aerosol spray We identified only one poorly reported study (unclear number of participants for comparison of interest, 91 between three treatment arms), in which there were significant baseline differences between the participants in the two groups. We were unable to draw meaningful conclusions from the data. AUTHORS' CONCLUSIONS: We found insufficient evidence to suggest that one type of intranasal steroid is more effective than another in patients with chronic rhinosinusitis, nor that the effectiveness of a spray differs from an aerosol. We identified no studies that compared drops with spray.It is unclear if higher doses result in better symptom improvements (low quality evidence), but there was moderate quality evidence of an increased risk of epistaxis as an adverse effect of treatment when higher doses were used. This included all levels of severity of epistaxis and it is likely that the proportion of events that required patients to discontinue usage is low due to the low numbers of withdrawals attributed to it. If epistaxis is limited to streaks of blood in the mucus it may be tolerated by the patient and it may be safe to continue treatment. However, it may be a factor that affects compliance.There is insufficient evidence to suggest that the different types of corticosteroid molecule or spray versus aerosol have different effects. Lower doses have similar effectiveness but fewer side effects.Clearly more research in this area is needed, with specific attention given to trial design, disease-specific health related quality of life outcomes and evaluation of longer-term outcomes and adverse effects. PMID- 27115216 TI - Saline irrigation for chronic rhinosinusitis. AB - BACKGROUND: This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Nasal saline irrigation is commonly used to improve patient symptoms. OBJECTIVES: To evaluate the effects of saline irrigation in patients with chronic rhinosinusitis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 9); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 30 October 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing saline delivered to the nose by any means (douche, irrigation, drops, spray or nebuliser) with (a) placebo, (b) no treatment or (c) other pharmacological interventions. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis. Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse events of local irritation and discomfort. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included two RCTs (116 adult participants). One compared large-volume (150 ml) hypertonic (2%) saline irrigation with usual treatment over a six-month period; the other compared 5 ml nebulised saline twice a day with intranasal corticosteroids, treating participants for three months and evaluating them on completion of treatment and three months later. Large-volume, hypertonic nasal saline versus usual care One trial included 76 adult participants (52 intervention, 24 control) with or without polyps.Disease-specific HRQL was reported using the Rhinosinusitis Disability Index (RSDI; 0 to 100, 100 = best quality of life). At the end of three months of treatment, patients in the saline group were better than those in the placebo group (mean difference (MD) 6.3 points, 95% confidence interval (CI) 0.89 to 11.71) and at six months there was a greater effect (MD 13.5 points, 95% CI 9.63 to 17.37). We assessed the evidence to be of low quality for the three months follow-up and very low quality for the six months follow-up. Patient-reported disease severity was evaluated using a "single-item sinus symptom severity assessment" but the range of scores is not stated, making it impossible for us to determine the meaning of the data presented.No adverse effects data were collected in the control group but 23% of participants in the saline group experienced side effects including epistaxis. General HRQL was measured using SF-12 (0 to 100, 100 = best quality of life). No difference was found after three months of treatment (low quality evidence) but at six months there was a small difference favouring the saline group, which may not be of clinical significance and has high uncertainty (MD 10.5 points, 95% CI 0.66 to 20.34) (very low quality evidence). Low-volume, nebulised saline versus intranasal corticosteroids One trial included 40 adult participants with polyps. Our primary outcome of disease-specific HRQL was not reported. At the end of treatment (three months) the patients who had intranasal corticosteroids had less severe symptoms (MD -13.50, 95% CI -14.44 to -12.56); this corresponds to a large effect size. We assessed the evidence to be of very low quality. AUTHORS' CONCLUSIONS: The two studies were very different in terms of included populations, interventions and comparisons and so it is therefore difficult to draw conclusions for practice. The evidence suggests that there is no benefit of a low-volume (5 ml) nebulised saline spray over intranasal steroids. There is some benefit of daily, large-volume (150 ml) saline irrigation with a hypertonic solution when compared with placebo, but the quality of the evidence is low for three months and very low for six months of treatment. PMID- 27115217 TI - Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis. AB - BACKGROUND: This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. The use of topical (intranasal) corticosteroids has been widely advocated for the treatment of chronic rhinosinusitis given the belief that inflammation is a major component of this condition. OBJECTIVES: To assess the effects of intranasal corticosteroids in people with chronic rhinosinusitis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 8); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing intranasal corticosteroids (e.g. beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide) against placebo or no treatment in patients with chronic rhinosinusitis. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis. Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse events of local irritation or other systemic adverse events. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 18 RCTs with a total of 2738 participants. Fourteen studies had participants with nasal polyps and four studies had participants without nasal polyps. Only one study was conducted in children. Intranasal corticosteroids versus placebo or no intervention Only one study (20 adult participants without polyps) measured our primary outcome disease specific HRQL using the Rhinosinusitis Outcome Measures-31 (RSOM-31). They reported no significant difference (numerical data not available) (very low quality evidence).Our second primary outcome, disease severity , was measured using the Chronic Sinusitis Survey in a second study (134 participants without polyps), which found no important difference (mean difference (MD) 2.84, 95% confidence interval (CI) -5.02 to 10.70; scale 0 to 100). Another study (chronic rhinosinusitis with nasal polyps) reported an increased chance of improvement in the intranasal corticosteroids group (RR 2.78, 95% CI 1.76 to 4.40; 109 participants). The quality of the evidence was low.Six studies provided data on at least two of the individual symptoms used in the EPOS 2012 criteria to define chronic rhinosinusitis (nasal blockage, rhinorrhoea, loss of sense of smell and facial pain/pressure). When all four symptoms in the EPOS criteria were available on a scale of 0 to 3 (higher = more severe symptoms), the average MD in change from baseline was -0.26 (95% CI -0.37 to -0.15; 243 participants; two studies; low quality evidence). Although there were more studies and participants when only nasal blockage and rhinorrhoea were considered (MD -0.31, 95% CI -0.38 to 0.24; 1702 participants; six studies), the MD was almost identical to when loss of sense of smell was also considered (1345 participants, four studies; moderate quality evidence).When considering the results for the individual symptoms, benefit was shown in the intranasal corticosteroids group. The effect size was larger for nasal blockage (MD -0.40, 95% CI -0.52 to -0.29; 1702 participants; six studies) than for rhinorrhoea (MD -0.25, 95% CI -0.33 to -0.17; 1702 participants; six studies) or loss of sense of smell (MD -0.19, 95% CI -0.28 to 0.11; 1345 participants; four studies). There was heterogeneity in the analysis for facial pain/pressure (MD -0.27, 95% CI -0.56 to 0.02; 243 participants; two studies). The quality of the evidence was moderate for nasal blockage, rhinorrhoea and loss of sense of smell, but low for facial pain/pressure.There was an increased risk of epistaxis with intranasal corticosteroids (risk ratio (RR) 2.74, 95% CI 1.88 to 4.00; 2508 participants; 13 studies; high quality evidence).Considering our secondary outcome, general HRQL, one study (134 participants without polyps) measured this using the SF-36 and reported a statistically significant benefit only on the general health subscale. The quality of the evidence was very low.It is unclear whether there is a difference in the risk of local irritation (RR 0.94, 95% CI 0.53 to 1.64; 2124 participants; 11 studies) (low quality evidence).None of the studies treated or followed up patients long enough to provide meaningful data on the risk of osteoporosis or stunted growth (children). Other comparisons We identified no other studies that compared intranasal corticosteroids plus co-intervention A versus placebo plus co intervention A. AUTHORS' CONCLUSIONS: Most of the evidence available was from studies in patients with chronic rhinosinusitis with nasal polyps. There is little information about quality of life (very low quality evidence). For disease severity, there seems to be improvement for all symptoms (low quality evidence), a moderate-sized benefit for nasal blockage and a small benefit for rhinorrhoea (moderate quality evidence). The risk of epistaxis is increased (high quality evidence), but these data included all levels of severity; small streaks of blood may not be a major concern for patients. It is unclear whether there is a difference in the risk of local irritation (low quality evidence). PMID- 27115218 TI - The mesentery in Crohn's disease: friend or foe? AB - PURPOSE OF REVIEW: This article assesses the role of the mesentery in Crohn's disease. RECENT FINDINGS: The mesentery is centrally positioned both anatomically and physiologically. Overlapping mesenteric and submucosal mesenchymal contributions are important in the pathobiology of Crohn's disease. Mesenteric contributions explain the topographic distribution of Crohn's disease in general and mucosal disease in particular. Operative strategies that are mesenteric based (i.e. mesocolic excision) may reduce rates of postoperative recurrence. SUMMARY: The net effect of mesenteric events in Crohn's disease is pathologic. This can be targeted by operative means. VIDEO ABSTRACT: http://links.lww.com/COG/A18. PMID- 27115219 TI - From bench to bedside: molecular imaging in inflammatory bowel diseases. AB - PURPOSE OF REVIEW: Standard structural imaging procedures such as endoscopy, ultrasonography, or MRI are an integral part of the rational management of patients with inflammatory bowel diseases (IBDs). There is nevertheless the need for further refined imaging approaches that are able to overcome the limitations of currently used formats. The advent of molecular imaging modalities that allow real-time visualization of cellular processes not only in the preclinical setting but also in clinical trials has demonstrated its ability to improve current therapeutic strategies. The purpose of this review is to present and discuss advancements in the field of molecular imaging approaches in the IBD field. RECENT FINDINGS: Recent preclinical and clinical studies have addressed the applicability of molecular imaging for improving the differentiation between benign and malignant mucosal alterations, increasing the detection of dysplastic intestinal lesions, and predicting individual responses to biological therapies. SUMMARY: Molecular imaging in IBD represents an exciting and evolving field that has the potential to impact on current diagnostic and therapeutic algorithms in the treatment of IBD patients by analyzing and visualizing the molecular mechanisms that drive mucosal inflammation. It might enable us to base individualized therapeutic decisions on preceded molecular level analysis by suitable imaging modalities. PMID- 27115220 TI - Does everyone with inflammatory bowel disease need to be treated with combination therapy? AB - PURPOSE OF REVIEW: This article describes the evolution of combination therapy in inflammatory bowel disease and how to determine when combination may not be necessary. RECENT FINDINGS: The combination of an immunosuppressive agent with an antibody to tumor necrosis factor has proven to be more effective than monotherapy with either an immunosuppressive agent or an antibody to tumor necrosis factor alone. The emergence of therapeutic drug monitoring has identified the importance of maintaining adequate circulating drug levels and suppressing antibody formation to the biological agent. The concomitant use of an immunosuppressive agent can help effect this. Although this may be optimal therapy in moderately ill patients. I review why there still remains a role for using monotherapy with immunosuppressive agents, as well as consideration of therapy withdrawal. SUMMARY: Although combination therapy is the treatment of choice in persons with moderate to severe disease or who have lost response to biological monotherapy, there remains a role for monotherapy with immunosuppressive agents. Though the newer biological therapies are mostly not used in combination, this may be a future approach considering their response rates are also correlated with higher drug levels. Many persons with inflammatory bowel disease can remain well on an immunosuppressive agent alone and some can even maintain a longstanding remission off all therapy. PMID- 27115221 TI - Influence of DTPA Treatment on Internal Dose Estimates. AB - In case of internal contamination with plutonium materials, a treatment with diethylene triamine pentaacetic acid (DTPA) can be administered in order to reduce plutonium body burden and consequently avoid some radiation dose. DTPA intravenous injections or inhalation can start almost immediately after intake, in parallel with urinary and fecal bioassay sampling for dosimetric follow-up. However, urine and feces excretion will be significantly enhanced by the DTPA treatment. As internal dose is calculated from bioassay results, the DTPA effect on excretion has to be taken into account. A common method to correct bioassay data is to divide it by a factor representing the excretion enhancement under DTPA treatment by intravenous injection. Its value may be based on a nominal reference or observed after a break in the treatment. The aim of this study was to estimate the influence of this factor on internal dose by comparing the dose estimated using default or upper and lower values of the enhancement factor for 11 contamination cases. The observed upper and lower values of the enhancement factor were 18.7 and 63.0 for plutonium and 24.9 and 28.8 for americium. For americium, a default factor of 25 is proposed. This work demonstrates that the use of a default DTPA enhancement factor allows the determination of the magnitude of the contamination because dose estimated could vary by a factor of 2 depending on the value of the individual DTPA enhancement factor. In case of significant intake, an individual enhancement factor should be determined to obtain a more reliable dose assessment. PMID- 27115222 TI - Perception of Radiation Risk by Japanese Radiation Specialists Evaluated as a Safe Dose Before the Fukushima Nuclear Accident. AB - From October to December 2010, just before the radiological accident at the Fukushima Daiichi nuclear power plant, 71 radiation professionals from radiation facilities in Japan were asked what they considered as a "safe dose" of radiation for themselves, their partners, parents, children, siblings, and friends. Although the 'safe dose' they noted varied widely, from less than 1 mSv y to more than 100 mSv y, the average dose was 35.6 mSv y, which is around the middle point between the legal exposure dose limits for the annual average and for any single year. Similar results were obtained from other surveys of members of the Japan Radioisotope Association (36.9 mSv y) and of the Oita Prefectural Hospital (36.8 mSv y). Among family members and friends, the minimum average "safe" dose was 8.5 mSv y for children, for whom 50% of the responders claimed a "safe dose" of less than 1 mSv. Gender, age and specialty of the radiation professional also affected their notion of a "safe dose." These findings suggest that the perception of radiation risk varies widely even for radiation professionals and that the legal exposure dose limits derived from regulatory science may act as an anchor of safety. The different levels of risk perception for different target groups among radiation professionals appear similar to those in the general population. The gap between these characteristics of radiation professionals and the generally accepted picture of radiation professionals might have played a role in the state of confusion after the radiological accident. PMID- 27115223 TI - Modeling Study of a Proposed Field Calibration Source Using K-40 and High-Z Targets for Sodium Iodide Detectors. AB - Calibration sources based on the primordial isotope potassium-40 (K) have reduced controls on the source's activity due to its terrestrial ubiquity and very low specific activity. Potassium-40's beta emissions and 1,460.8 keV gamma ray can be used to induce K-shell fluorescence x rays in high-Z metals between 60 and 80 keV. A gamma ray calibration source that uses potassium chloride salt and a high Z metal to create a two-point calibration for a sodium iodide field gamma spectroscopy instrument is thus proposed. The calibration source was designed in collaboration with the Sandia National Laboratory using the Monte Carlo N Particle eXtended (MCNPX) transport code. Two methods of x-ray production were explored. First, a thin high-Z layer (HZL) was interposed between the detector and the potassium chloride-urethane source matrix. Second, bismuth metal powder was homogeneously mixed with a urethane binding agent to form a potassium chloride-bismuth matrix (KBM). The bismuth-based source was selected as the development model because it is inexpensive, nontoxic, and outperforms the high-Z layer method in simulation. Based on the MCNPX studies, sealing a mixture of bismuth powder and potassium chloride into a thin plastic case could provide a light, inexpensive field calibration source. PMID- 27115224 TI - Implementation of a Portable HPGe for Field Contamination Assay. AB - Using MCNP to construct a detector model based initially on x-ray images of a portable high purity germanium (HPGe) detector followed by normalizing covering material values to also agree with check source responses, a validation of the model was attained. By calibrating the detector parameters using large count spectra, rigorous reproducibility is attained for high activity measurements but does not prevent deviations from normality in error distributions at the very low count events where spectral peaks are not always identifiable. The resulting model was created to allow operational assay of contamination over large areal distributions that could not otherwise be measured, such as the exhaust shaft at the Waste Isolation Pilot Plant (WIPP). Results indicate that contamination levels of activity in the exhaust shaft can be assayed to within a factor of 2. Detection limits are evaluated to be well below the contamination levels, which would constitute a legal environmental release if unfiltered ventilation of the underground facility were used. PMID- 27115225 TI - Biokinetics of 90Sr in Male Nonhuman Primates. AB - The current study tests the hypothesis that the biokinetics of Sr can be represented by simplification of the ICRP publication 78 Sr model. Default and proposed models were evaluated by their ability to predict injected activity and more thoroughly define the activity residing in the skeleton of rhesus monkeys. The data obtained from studies done by Patricia Durbin and her colleagues at the Lawrence Berkley National Laboratory were used to create a profile of the activity residing in the skeleton at the time of sacrifice. Post mortem data along with periodic whole body count data were used to optimize the biokinetic parameters using the Integrated Modules for Bioassay Analysis (IMBA), Weighted Likelihood Monte-Carlo Sampling (WeLMoS) program to better predict the intake and fit of the bioassay data. Analysis of the default ICRP 78 parameters resulted in an overprediction of activity in the skeleton for a male cohort by as much as 180%. Using Monte Carlo sampling methods, three models were developed and optimized for a composite cohort of male monkeys. Of the three developed models, one model proved to have the best predictive capabilities. The optimized model C obtained for the male cohort was then tested on a validation cohort to test predictive capabilities. Using the optimized model C parameters, the ability to predict activity in the skeleton was improved in comparison to ICRP 78. Prediction of the intake from bioassay data was also improved by a factor of 2 in comparison to ICRP 78. The results suggest that the modified transfer rates of model C could be used as default parameters for biokinetic nonhuman primate modeling and potentially extrapolated to humans. PMID- 27115226 TI - Efficiency Calibration for Environmental Gamma Spectrometry Using GATE. AB - This work investigated the utility of performing efficiency calibration for environmental gamma spectrometry using the Monte Carlo based, free of charge GATE toolbox. The validity of this approach was tested by comparing output efficiency values of an in-house developed GATE-based program with experimental measurements covering various geometries and primary photon energies. The results of this comparison revealed relative deviations within +/-20%, thus validating the employed computational approach. Moreover, the GATE-based method was able to predict quantities that are generally difficult to measure experimentally, such as the number of interactions preceding full energy absorption. These computationally obtained predictions were found to be in agreement with theory. PMID- 27115227 TI - Soluble Vascular Endothelial Cadherin as a New Biomarker of Irradiation in Highly Irradiated Baboons with Bone Marrow Protection. AB - Vascular endothelial cadherin is the main component of adherens junctions enabling cohesion of the endothelial monolayer in vessels. The extracellular part of vascular endothelial cadherin (VE-cadherin) can be cleaved, releasing soluble fragments in blood (sVE-cadherin). In some diseases with endothelial dysfunction, a correlation between increased blood sVE-cadherin levels and disease state has been proposed. Irradiation is known to induce endothelial damage, but new serum biomarkers are needed to evaluate endothelial damage after irradiation. Here, the authors investigated whether sVE-cadherin may be an interesting biomarker of irradiation in highly irradiated baboons with bone marrow protection. sVE cadherin was detected in the plasma of young as well as old baboons. Plasma sVE cadherin levels significantly decrease a few days after irradiation but recover in the late time after irradiation. Kinetic analysis of plasma sVE-cadherin levels suggests a correlation with white blood cell counts in both the acute phase of irradiation and during hematopoietic recovery, suggesting that plasma sVE-cadherin levels may be partly linked to the disappearance and recovery of white blood cells. Interestingly, after hematopoietic recovery was completed, sVE cadherin levels were found to exceed control values, suggesting that plasma sVE cadherin may represent a new biomarker of endothelial damage or neovascularization in the late time after irradiation. PMID- 27115228 TI - Primary Beam Air Kerma Dependence on Distance from Cargo and People Scanners. AB - The distance dependence of air kerma or dose rate of the primary radiation beam is not obvious for security scanners of cargo and people in which there is relative motion between a collimated source and the person or object being imaged. To study this problem, one fixed line source and three moving-source scan geometry cases are considered, each characterized by radiation emanating perpendicular to an axis. The cases are 1) a stationary line source of radioactive material, e.g., contaminated solution in a pipe; 2) a moving, uncollimated point source of radiation that is shuttered or off when it is stationary; 3) a moving, collimated point source of radiation that is shuttered or off when it is stationary; and 4) a translating, narrow "pencil" beam emanating in a flying-spot, raster pattern. Each case is considered for short and long distances compared to the line source length or path traversed by a moving source. The short distance model pertains mostly to dose to objects being scanned and personnel associated with the screening operation. The long distance model pertains mostly to potential dose to bystanders. For radionuclide sources, the number of nuclear transitions that occur a) per unit length of a line source or b) during the traversal of a point source is a unifying concept. The "universal source strength" of air kerma rate at 1 m from the source can be used to describe x-ray machine or radionuclide sources. For many cargo and people scanners with highly collimated fan or pencil beams, dose varies as the inverse of the distance from the source in the near field and with the inverse square of the distance beyond a critical radius. Ignoring the inverse square dependence and using inverse distance dependence is conservative in the sense of tending to overestimate dose. PMID- 27115229 TI - Use of Transportable Radiation Detection Instruments to Assess Internal Contamination From Intakes of Radionuclides Part I: Field Tests and Monte Carlo Simulations. AB - The detonation of a radiological dispersion device or other radiological incidents could result in the dispersion of radioactive materials and intakes of radionuclides by affected individuals. Transportable radiation monitoring instruments could be used to measure photon radiation from radionuclides in the body for triaging individuals and assigning priorities to their bioassay samples for further assessments. Computer simulations and experimental measurements are required for these instruments to be used for assessing intakes of radionuclides. Count rates from calibrated sources of Co, Cs, and Am were measured on three instruments: a survey meter containing a 2.54 * 2.54-cm NaI(Tl) crystal, a thyroid probe using a 5.08 * 5.08-cm NaI(Tl) crystal, and a portal monitor incorporating two 3.81 * 7.62 * 182.9-cm polyvinyltoluene plastic scintillators. Computer models of the instruments and of the calibration sources were constructed, using engineering drawings and other data provided by the manufacturers. Count rates on the instruments were simulated using the Monte Carlo radiation transport code MCNPX. The computer simulations were within 16% of the measured count rates for all 20 measurements without using empirical radionuclide-dependent scaling factors, as reported by others. The weighted root mean-square deviations (differences between measured and simulated count rates, added in quadrature and weighted by the variance of the difference) were 10.9% for the survey meter, 4.2% for the thyroid probe, and 0.9% for the portal monitor. These results validate earlier MCNPX models of these instruments that were used to develop calibration factors that enable these instruments to be used for assessing intakes and committed doses from several gamma-emitting radionuclides. PMID- 27115230 TI - Outdoor Exposure to Solar Ultraviolet Radiation and Legislation in Brazil. AB - The total ozone column of 265 +/- 11 Dobson Units in the tropical-equatorial zones and 283 +/- 16 Dobson Units in the subtropics of Brazil are among the lowest on Earth, and as a result, the prevalence of skin cancer due to solar ultraviolet radiation is among the highest. Daily erythemal doses in Brazil can be over 7,500 J m. Erythemal dose rates on cloudless days of winter and summer are typically about 0.147 W m and 0.332 W m, respectively. However, radiation enhancement events yielded by clouds have been reported with erythemal dose rates of 0.486 W m. Daily doses of the diffuse component of erythemal radiation have been determined with values of 5,053 J m and diffuse erythemal dose rates of 0.312 W m. Unfortunately, Brazilians still behave in ways that lead to overexposure to the sun. The annual personal ultraviolet radiation ambient dose among Brazilian youths can be about 5.3%. Skin cancer in Brazil is prevalent, with annual rates of 31.6% (non-melanoma) and 1.0% (melanoma). Governmental and non-governmental initiatives have been taken to increase public awareness of photoprotection behaviors. Resolution #56 by the Agencia Nacional de Vigilancia Sanitaria has banned tanning devices in Brazil. In addition, Projects of Law (PL), like PL 3730/2004, propose that the Sistema Unico de Saude should distribute sunscreen to members of the public, while PL 4027/2012 proposes that employers should provide outdoor workers with sunscreen during professional outdoor activities. Similar laws have already been passed in some municipalities. These are presented and discussed in this study. PMID- 27115231 TI - The Higher a Detector, the Larger Its Circle of Investigation. PMID- 27115235 TI - Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions: C-H activation of unprotected tetrazoles. AB - The first examples of selective ortho-directed C-H activation with unprotected 2 aryltetrazoles are described. A new base-assisted protocol for iridium(i) hydrogen isotope exchange catalysis allows access to ortho-deuterated and tritiated tetrazoles, including the tetrazole-containing pharmaceutical, Valsartan. Preliminary mechanistic studies are also presented. PMID- 27115236 TI - A dynamic DFT approach to generalized diffusion equations in a system with long ranged and hydrodynamic interactions. AB - We build on an existing approximation scheme to the Smoluchowski equation in order to derive a dynamic density functional theory (DDFT) including two-body hydrodynamic interactions. A generalized diffusion equation and a wavenumber dependent diffusion coefficient D(k) are derived by linearization in the density fluctuations. The result is applied to a colloidal monolayer at a fluid interface, having bulk-like hydrodynamic interactions and/or interacting via long ranged capillary forces. In these cases, D(k) shows characteristic singularities as [Formula: see text]. The consequences of these singularities are studied by means of analytical perturbation theory, numerical solution of DDFT and simulations for an explicit example: the capillary collapse of a finite, disk like distribution of particles. There is in general a good agreement between DDFT and simulations if the initial density distributions for the theoretical prediction correspond to the actual initial configurations of simulations, rather than to an average over them. Otherwise, discrepancies arise that are discussed in detail. PMID- 27115237 TI - A density functional theory for colloids with two multiple bonding associating sites. AB - Wertheim's multi-density formalism is extended for patchy colloidal fluids with two multiple bonding patches. The theory is developed as a density functional theory to predict the properties of an associating inhomogeneous fluid. The equation of state developed for this fluid depends on the size of the patch, and includes formation of cyclic, branched and linear clusters of associated species. The theory predicts the density profile and the fractions of colloids in different bonding states versus the distance from one wall as a function of bulk density and temperature. The predictions from our theory are compared with previous results for a confined fluid with four single bonding association sites. Also, comparison between the present theory and Monte Carlo simulation indicates a good agreement. PMID- 27115238 TI - A Study I Kind of Wish I Had Done. PMID- 27115239 TI - Development of a Pitch Discrimination Screening Test for Preschool Children. AB - BACKGROUND: There is a critical need for tests of auditory discrimination for young children as this skill plays a fundamental role in the development of speaking, prereading, reading, language, and more complex auditory processes. Frequency discrimination is important with regard to basic sensory processing affecting phonological processing, dyslexia, measurements of intelligence, auditory memory, Asperger syndrome, and specific language impairment. PURPOSE: This study was performed to determine the clinical feasibility of the Pitch Discrimination Test (PDT) to screen the preschool child's ability to discriminate some of the acoustic demands of speech perception, primarily pitch discrimination, without linguistic content. The PDT used brief speech frequency tones to gather normative data from preschool children aged 3 to 5 yrs. RESEARCH DESIGN: A cross-sectional study was used to gather data regarding the pitch discrimination abilities of a sample of typically developing preschool children, between 3 and 5 yrs of age. The PDT consists of ten trials using two pure tones of 100-msec duration each, and was administered in an AA or AB forced-choice response format. STUDY SAMPLE: Data from 90 typically developing preschool children between the ages of 3 and 5 yrs were used to provide normative data. DATA ANALYSIS: Nonparametric Mann-Whitney U-testing was used to examine the effects of age as a continuous variable on pitch discrimination. The Kruskal Wallis test was used to determine the significance of age on performance on the PDT. Spearman rank was used to determine the correlation of age and performance on the PDT. RESULTS: Pitch discrimination of brief tones improved significantly from age 3 yrs to age 4 yrs, as well as from age 3 yrs to the age 4- and 5-yrs group. Results indicated that between ages 3 and 4 yrs, children's auditory discrimination of pitch improved on the PDT. The data showed that children can be screened for auditory discrimination of pitch beginning with age 4 yrs. CONCLUSIONS: The PDT proved to be a time efficient, feasible tool for a simple form of frequency discrimination screening in the preschool population before the age where other diagnostic tests of auditory processing disorders can be used. PMID- 27115240 TI - Hearing Aid Benefit in Patients with Mild Sensorineural Hearing Loss: A Systematic Review. AB - BACKGROUND: Untreated sensorineural hearing loss (SNHL) is associated with chronic health-care conditions, isolation, loneliness, and reduced quality of life. Although hearing aids can minimize the negative effects of SNHL, only about one in five persons with SNHL seeks help for communication problems. Many persons wait 10 yr or more from the time they first notice a problem before pursuing amplification. Further, little information about the benefits of amplification is available for persons with mild SNHL (MSNHL), who likely defer treatment even longer. PURPOSE: To conduct a systematic review to weigh the evidence regarding benefits derived from the use of amplification by adults with MSNHL. RESEARCH DESIGN: Systematic review with meta-analysis. STUDY SAMPLE: Adult hearing aid wearers with bilateral average pure-tone thresholds <=45 dB HL at 500, 1000, 2000, and 4000 Hz. DATA COLLECTION AND ANALYSIS: PubMed, Cumulative Index to Nursing and Allied-Health Literature, Cochrane Collaboration, and Google Scholar were searched independently by the authors during September 2013. The authors used a consensus approach to assess the quality and extract data for the meta analysis. RESULTS: Of 106 articles recovered for full-text review, only 10 met inclusion criteria (at least Level IV of evidence and involved and reported separate pre-/postfitting hearing aid outcomes for patients with MSNHL). Included studies involved mainly middle-aged to elderly patients using hearing aids of various styles and circuitry. Results from all of the studies indicated positive benefits from amplification for patients with MSNHL. Data from five studies were suitable for a meta-analysis, which produced a small-to-medium effect size of 0.85 (95% confidence intervals = 0.44-1.25) after adjusting for a small publication bias. This evidence confirmed benefits from the use of amplification in adults with MSNHL. CONCLUSIONS: Evidence exists supporting the notion that adults with MSNHL benefit from hearing aids. This information is important and useful to audiologists, patients, and third-party payers, even considering that most of the studies in this systematic review were limited, somewhat dated, and used analog and early digital technology available when the studies were conducted. Clinical recommendations may be even stronger as future studies become available for patients fit with modern styles and high-technology hearing aids. PMID- 27115241 TI - The Effect of Decreased Audibility on MMSE Performance: A Measure Commonly Used for Diagnosing Dementia. AB - BACKGROUND: Hearing loss and dementia are both prevalent in late adulthood. The most common test used to determine cognitive status in late adulthood, the Mini Mental State Examination (MMSE), is presented face to face, usually in the context of the physician's office in the presence of background noise. Despite the problems of hearing loss and cognitive problems in late life, there is an absence of evidence linking hearing-related deficits to performance on the MMSE and dementia diagnoses. PURPOSE: This study examined the effect of decreased audibility on performance on the MMSE. RESEARCH DESIGN: A between-subjects design was implemented. Participants were randomly assigned to one of five degrees of simulated hearing loss conditions and were blinded to condition assignment. STUDY SAMPLE: One hundred and twenty-five young normal-hearing participants were randomized into five conditions of varying degrees of simulated hearing loss. DATA COLLECTION AND ANALYSIS: Performance on the MMSE was scored and cognitive status was categorized based on the scores. Analysis of variance with conditions as a between-subjects factor was conducted with post hoc multiple comparisons to determine the effect of audibility on performance. RESULTS: Reduced audibility significantly affected performance on the MMSE in a sample of young adults, resulting in greater apparent cognitive deficits as audibility decreased. CONCLUSIONS: Apparent cognitive deficits based on MMSE scores obtained in test conditions in which audibility is reduced could result in incorrectly identified cognitive loss if clinicians are not alert to hearing loss when patients are evaluated. Furthermore, health care providers should be cautious when using family report of cognitive impairment to diagnose dementia without accounting for hearing loss because the impression of family members may be based on misinterpretation of the effects of hearing loss. PMID- 27115242 TI - Audiologist Practices: Parent Hearing Aid Education and Support. AB - BACKGROUND: Early identification of hearing loss has led to routine fitting of hearing aids in infants and young children. Amplification provides opportunities to optimize child development, although it also introduces challenges for parents to navigate. Audiologists have a central role in providing parents with support to achieve effective management strategies and habits. PURPOSE: The purpose of this study was to explore current practices of pediatric audiologists who work with children birth to 5 yr of age, regarding their support of parent learning in achieving effective hearing aid management, identify existing gaps in service delivery, and to determine if audiologists were receptive to receiving training related to effective approaches to provide counseling and support to parents. RESEARCH DESIGN: A cross-sectional, population-based survey was used. STUDY SAMPLE: Three hundred and forty-nine surveys were analyzed from pediatric audiologists who provided services to children birth to 5 yr of age. Responses were received from 22 states in the United States. DATA COLLECTION AND ANALYSIS: Responses were collected through the mail and online. Descriptive statistics were used to analyze the information. RESULTS: More than half (61%) of the audiologists in the study had been providing pediatric hearing aid services to children birth to 5 yr of age for >10 yr. Of the audiologists who reported monitoring hours of hearing aid use, the majority reported that they used data logging (90%). More than half of the audiologists (57%) who shared data logging with parents reported that they encountered defensiveness from parents when addressing hearing aid use. Information and skills that were not routinely provided by one-third to one-half of the audiologists included the following: how to get access to loaner hearing aids (30%), available hearing aid options/accessories (33%), available financial assistance (36%), how to teach hearing aid management to other caregivers (38%), how to do hearing aid maintenance (44%), and how to do a Ling 6 sound check (52%). Many audiologists reported they did not frequently collaborate with speech-language pathologists (48%), early interventionists (47%), or physicians (68%). More than half of the audiologists indicated a desire for more training in counseling skills, for all 14 items queried, to support parents with hearing aid management (53-79%), regardless of their previous training experience. CONCLUSIONS: For young children with hearing loss to achieve optimal benefit from auditory experiences for speech and language development, they need evidence-based, comprehensive, and coordinated hearing aid management. Audiologists have an important role for teaching information and skills related to hearing aids, supporting parent learning, and collaborating with other providers. Pediatric audiologists in this study recognized and desired the need for further training in counseling skills that can better prepare them to meet the emotional needs of parents in the hearing aid management process. PMID- 27115243 TI - On the Relationship Between Musicianship and Contralateral Suppression of Transient-Evoked Otoacoustic Emissions. AB - BACKGROUND: The medial olivocochlear (MOC) efferent reflex that modulates outer hair cell function has been shown to be more robust in musicians versus nonmusicians as evidenced in greater contralateral suppression of transient evoked otoacoustic emissions (TEOAEs). All previous research comparing musical ability and MOC efferent strength has defined musicianship dichotomously (i.e., high-level music students or professional classical musicians versus nonmusicians). PURPOSE: The objective of the study was to further explore contralateral suppression of TEOAEs among adults with a full spectrum of musicianship ranging from no history of musicianship to professional musicians. Musicianship was defined by both self-report and with an objective test to quantify individual differences in perceptual music skills. RESEARCH DESIGN: A single-factor between-subjects and correlational research designs were employed. STUDY SAMPLE: Forty-five normal-hearing young adults participated. DATA COLLECTION AND ANALYSIS: Participants completed a questionnaire concerning their music experience and completed the Brief Profile of Music Perception Skills (PROMS) to quantify perceptual musical skills across multiple musical domains (i.e., accent, melody, tempo, and tuning). TEOAEs were evaluated with 60 dB peak equivalent sound pressure level click stimuli with and without a contralateral 65 dB sound pressure level white noise suppressor. TEOAE suppression was expressed in two ways, absolute TEOAE suppression in dB and a normalized index of TEOAE suppression (i.e., percentage of suppression). RESULTS: Participants who considered themselves musicians scored significantly higher on all subscales and total Brief PROMS score (p < 0.05). There was no statistically significant difference between musicians and nonmusicians in absolute TEOAE suppression or percentage of TEOAE suppression (p > 0.05). There were no statistically significant correlations or linear predictive relationships between subscale or total Brief PROMS scores with absolute and percentage of TEOAE suppression (p > 0.05). CONCLUSIONS: The findings do not support the notion of a graded enhancement of MOC efferent suppression among adults with varied degrees of musicianship from nonmusicians to professional musicians. PMID- 27115244 TI - Cochlear Spiral Ganglion Neuron Apoptosis in Neonatal Mice with Murine Cytomegalovirus-Induced Sensorineural Hearing Loss. AB - BACKGROUND: Sensorineural hearing loss (SNHL) is the most common consequence of congenital cytomegalovirus (CMV) infection, and could result in neurological abnormalities and intellectual and developmental disabilities. PURPOSE: To explore the mechanism of murine CMV (MCMV)-induced SNHL in neonatal mice model. RESEARCH DESIGN: A repeated measures design was used. STUDY SAMPLE: Total 72 neonatal BALB/C mice (36 males and 36 females) were randomly divided into two groups. DATA COLLECTION AND ANALYSIS: MCMV suspension (50% tissue culture infective dose = 10(4.15) IU/0.1 ml, 15 MUl) or physiological saline was intracranially injected into neonatal mice in the experimental or control group, respectively. Auditory brainstem response (ABR) was measured at three weeks postinjection. At 1, 3, 5, 7, 14, and 21 days postinjection, MCMV-DNA polymerase chain reaction analysis was performed to detect MCMV infection in cochlea, followed by terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis and immunohistochemistry staining. RESULTS: Extended latency, decreased amplitude, and increased threshold of ABR wave I were observed in the experimental group. Polymerase chain reaction test was positive from 3 to 21 days postinjection in the experimental group and negative at each time point in the control group. The average apoptosis index was higher in the experimental group than that in the control group from 3 to 21 days postinjection (p < 0.01). In addition, compared with the control group, B-cell lymphoma 2 and B-cell lymphoma 2-associated protein ratio was decreased in the experimental group (p < 0.01). CONCLUSION: Spiral ganglion neuron apoptosis was an important component of the mechanism of SNHL in MCMV-infected mice. PMID- 27115245 TI - Hearing Aid Patient Education Materials: Is There Room for Improvement? AB - PURPOSE: The purpose of this study was to analyze and compare the readability of patient education materials (PEMs) from leading manufacturers of behind-the-ear style hearing aids and popular hearing aid information Web sites to determine if they meet guidelines recommended by public health agencies. RESEARCH DESIGN: Analysis of hearing aid PEMs. METHODS: Printed user guides from six of the leading manufacturers of BTE hearing aids and 15 of the most popular hearing aid information Web sites were accessed online and analyzed for readability using the Gunning-Fog Index, New Fog Count, Raygor Estimate Graph, Simple Measure of Gobbledygook, and Flesch Reading Ease score. RESULTS: Overall average grade-level readability for all six printed manufacturer user manuals was calculated to be written at a 10th grade reading level. Overall average grade-level readabilities for all 15 popular online hearing aid-information Web sites representing professional organizations, suppliers, and health information services were calculated to be written at 10th, 10th, and 11th grade reading levels, respectively. Average Flesch Reading Ease scores for all printed guides and online patient information Web sites were calculated to fall within the fairly difficult category for readability. CONCLUSIONS: PEMs provided by top hearing aid manufactures and popular hearing aid Web sites are written well above the reading level recommended by the National Institutes of Health. Consideration should be given toward simplifying these materials in order to enhance user experience and increase compliance among behind-the-ear hearing aid users. PMID- 27115247 TI - Structural and Spectroscopic Characterization of Rhenium Complexes Containing Neutral, Monoanionic, and Dianionic Ligands of 2,2'-Bipyridines and 2,2':6,2" Terpyridines: An Experimental and Density Functional Theory (DFT)-Computational Study. AB - The molecular and electronic structures of the members of the following electron transfer series have been determined by single crystal X-ray crystallography, temperature dependent magnetic susceptibility measurements, and UV-vis-NIR and electron paramagnetic resonance spectroscopy and verified by density functional theory calculations (DFT B3LYP): [Re((Me)bpy)3](n), [Re(tpy)2](n), [Re(Tp)(bpy)Cl](n) (n = 2+, 1+, 0, 1-), and [Re(bpy)(CO)3](1+,0,1-) ((Me)bpy = 4, 4'-dimethyl-2,2'-bipyridine; Tp(-) = tris-pyrazolylborate, tpy = 2, 2':6, 2" terpyridine). For each series we show that the average Cpy-Cpy bond length and the average C-Nchel bond distance vary in a linear fashion with the charge n of the N,N'-coordinated (bpy)(n) and N,N',N"-coordinated (tpy)(n) ligand. Consequently, the difference Delta between these two bond lengths varies also linearly with n. Delta is shown to be a useful single marker for the oxidation level of these two heterocyclic ligands (neutral, pi-radical anion, and dianion). In addition, we have synthesized and structurally as well as spectroscopically characterized the following complexes: [((cy)DAB(*))Re(IV)Cl3(PPh3)](0) 1, [Re(III)(tpy(*))Cl(PPh3)2]Cl 2, [Re(III)(tpy(0))2Cl](OTf)2.2Et2O 8. There are no structurally significant (experimentally detectable) pi-back-bond effects of the neutral bpy(0) or tpy(0) ligands irrespective of the d(N) configuration (N = 0-7) of the central Re atom. PMID- 27115248 TI - Near-IR Electrochromism in Electrodeposited Thin Films of Cyclometalated Complexes. AB - Homogeneous thin films of controlled thickness obtained from cyclometalated complexes of general formula [(C(?)N)M(O(?)N)], where M = Pd(II) or Pt(II), H(C(?)N) = 2-phenylpyridine and, respectively, 2-thienylpyridine and H(O(?)N) = a triphenylamine functionalized Schiff base, have been deposited by oxidative electropolymerization. The films have been electrochemically and morphologically characterized. The metallopolymeric thin films present stable reversible redox behavior and typical cauliflower-like textures in agreement with a nucleation growth electropolymerization mechanism. However, the film growth is greatly influenced by the nature of the metal center, with a higher tendency of the Pt complexes to promote the 3D growth. Furthermore, a complete spectroelectrochemical study has been performed on electrodeposited films showing near-IR absorption in the oxidized state, high contrast ratios (up to 65%) and low response times. PMID- 27115250 TI - Editor's Column: A Reflection on Studies Using Retrospective Record Review. AB - PURPOSE: In this column, the Editor of the American Journal of Speech-Language Pathology reflects on the value of retrospective record review and considers the design elements that contribute to sound methodology in this format. PMID- 27115254 TI - Pueblo Series, Acoma: Raymond Jonson. PMID- 27115249 TI - Chemical Tools To Monitor and Manipulate Adaptive Immune Responses. AB - Methods to monitor and manipulate the immune system are of enormous clinical interest. For example, the development of vaccines represents one of the earliest and greatest accomplishments of the biomedical research enterprise. More recently, drugs capable of "reawakening" the immune system to cancer have generated enormous excitement. But, much remains to be done. All drugs available today that manipulate the immune system cannot distinguish between "good" and "bad" immune responses and thus drive general and systemic immune suppression or activation. Indeed, with the notable exception of vaccines, our ability to monitor and manipulate antigen-specific immune responses is in its infancy. Achieving this finer level of control would be highly desirable. For example, it might allow the pharmacological editing of pathogenic immune responses without restricting the ability of the immune system to defend against infection. On the diagnostic side, a method to comprehensively monitor the circulating, antigen specific antibody population could provide a treasure trove of clinically useful biomarkers, since many diseases expose the immune system to characteristic molecules that are deemed foreign and elicit the production of antibodies against them. This Perspective will discuss the state-of-the-art of this area with a focus on what we consider seminal opportunities for the chemistry community to contribute to this important field. PMID- 27115255 TI - Consensus Plans Emerge to Tackle Long-term Care Costs. PMID- 27115262 TI - A Patient-Designed Do-It-Yourself Mobile Technology System for Diabetes: Promise and Challenges for a New Era in Medicine. PMID- 27115263 TI - A PIECE OF MY MIND. Mentorship Malpractice. PMID- 27115265 TI - Association of Changes in Air Quality With Bronchitic Symptoms in Children in California, 1993-2012. AB - IMPORTANCE: Childhood bronchitic symptoms are significant public and clinical health problems that produce a substantial burden of disease. Ambient air pollutants are important determinants of bronchitis occurrence. OBJECTIVE: To determine whether improvements in ambient air quality in Southern California were associated with reductions in bronchitic symptoms in children. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study involving 4602 children (age range, 5-18 years) from 3 cohorts was conducted during the 1993-2001, 1996-2004, and 2003 2012 years in 8 Southern California communities. A multilevel logistic model was used to estimate the association of changes in pollution levels with bronchitic symptoms. EXPOSURES: Average concentrations of nitrogen dioxide, ozone, particulate matter with an aerodynamic diameter of less than 10 um (PM10) and less than 2.5 um (PM2.5). MAIN OUTCOMES AND MEASURES: Annual age-specific prevalence of bronchitic symptoms during the previous 12 months based on the parent's or child's report of a daily cough for 3 months in a row, congestion or phlegm other than when accompanied by a cold, or bronchitis. RESULTS: The 3 cohorts included a total of 4602 children (mean age at baseline, 8.0 years; 2268 girls [49.3%]; 2081 Hispanic white [45.2%]) who had data from 2 or more annual questionnaires. Among these children, 892 (19.4%) had asthma at age 10 years. For nitrogen dioxide, the odds ratio (OR) for bronchitic symptoms among children with asthma at age 10 years was 0.79 (95% CI, 0.67-0.94) for a median reduction of 4.9 ppb, with absolute decrease in prevalence of 10.1%. For ozone, the OR was 0.66 (95% CI, 0.50-0.86) for a median reduction of 3.6 ppb, with an absolute decrease in prevalence of 16.3%. For PM10, the OR was 0.61 (95% CI, 0.48-0.78) for a median reduction of 5.8 ug/m3, with an absolute decrease in prevalence of 18.7%. For PM2.5, the OR was 0.68 (95% CI, 0.53-0.86) for a median reduction of 6.8 ug/m3, with absolute decrease in prevalence of 15.4%. Among children without asthma (n = 3710), the ORs were 0.84 (95% CI, 0.76-0.92) for nitrogen dioxide; 0.85 (95% CI, 0.74-0.97) for ozone, 0.80 (95% CI, 0.70-0.92) for PM10, and 0.79 (95% CI, 0.69-0.91) for PM2.5; with absolute decrease in prevalence of 1.8% for nitrogen dioxide, 1.7% for ozone, 2.2% for PM10, and 2.3% for PM2.5. The associations were similar or slightly stronger at age 15 years. CONCLUSIONS AND RELEVANCE: Decreases in ambient pollution levels were associated with statistically significant decreases in bronchitic symptoms in children. Although the study design does not establish causality, the findings support potential benefit of air pollution reduction on asthma control. PMID- 27115266 TI - Does This Patient Have Infectious Mononucleosis?: The Rational Clinical Examination Systematic Review. AB - IMPORTANCE: Early, accurate diagnosis of infectious mononucleosis can help clinicians target treatment, avoid antibiotics, and provide an accurate prognosis. OBJECTIVE: To systematically review the literature regarding the value of the clinical examination and white blood cell count for the diagnosis of mononucleosis. DATA SOURCES: The databases of PubMed (from 1966-2016) and EMBASE (from 1947-2015) were searched and a total of 670 articles and abstracts were reviewed for eligibility. STUDY SELECTION: Eleven studies were included that reported data sufficient to calculate sensitivity, specificity, or both for clinical examination findings and white blood cell count parameters compared with a valid reference standard. DATA EXTRACTION AND SYNTHESIS: Data were abstracted from each article by at least 2 reviewers, with discrepancies reconciled by consensus. Clinical findings evaluated in only 1 study are reported with sensitivity, specificity, likelihood ratio (LR), and 95% confidence interval, which were calculated from the available data. Findings evaluated in only 2 studies were summarized with their range, findings evaluated in 3 studies were summarized with a univariate random-effects summary, and findings evaluated in 4 or more studies were summarized with a bivariate random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, and LRs for the diagnosis of mononucleosis. RESULTS: Mononucleosis is most commonly present among patients aged 5 to 25 years (especially those aged 16-20 years, among whom approximately 1 in 13 patients presenting with sore throat has mononucleosis). The likelihood of mononucleosis is reduced with the absence of any lymphadenopathy (summary sensitivity, 0.91; positive LR range, 0.23-0.44), whereas the likelihood increases with the presence of posterior cervical adenopathy (summary specificity, 0.87; positive LR, 3.1 [95% CI, 1.6-5.9]), inguinal or axillary adenopathy (specificity range, 0.82-0.91; positive LR range, 3.0-3.1), palatine petechiae (specificity, 0.95; positive LR, 5.3 [95% CI, 2.1-13]), and splenomegaly (specificity range, 0.71-0.99; positive LR range, 1.9-6.6). Symptoms are of limited value for the diagnosis of mononucleosis; sore throat and fatigue are sensitive (range, 0.81-0.83) but nonspecific. The presence of atypical lymphocytosis significantly increases the likelihood of mononucleosis (summary LR, 11.4 [95% CI, 2.7-35] for atypical lymphocytes >=10%, 26 [95% CI, 9.6-68] for those with 20%, and 50 [95% CI, 38-64] for those with 40%). The combination of a patient having greater than 50% lymphocytes and greater than 10% atypical lymphocytes also is useful (specificity, 0.99; positive LR, 54 [95% CI, 8.4 189]). CONCLUSIONS AND RELEVANCE: In adolescent and adult patients presenting with sore throat, the presence of posterior cervical, inguinal or axillary adenopathy, palatine petechiae, splenomegaly, or atypical lymphocytosis is associated with an increased likelihood of mononucleosis. PMID- 27115267 TI - Management of Atopic Dermatitis. PMID- 27115268 TI - Safety of Testosterone Replacement Therapy. PMID- 27115269 TI - Physicians' Knowledge About FDA Approval Standards and Perceptions of the "Breakthrough Therapy" Designation. PMID- 27115264 TI - Effect of a Quality Improvement Intervention With Daily Round Checklists, Goal Setting, and Clinician Prompting on Mortality of Critically Ill Patients: A Randomized Clinical Trial. AB - IMPORTANCE: The effectiveness of checklists, daily goal assessments, and clinician prompts as quality improvement interventions in intensive care units (ICUs) is uncertain. OBJECTIVE: To determine whether a multifaceted quality improvement intervention reduces the mortality of critically ill adults. DESIGN, SETTING, AND PARTICIPANTS: This study had 2 phases. Phase 1 was an observational study to assess baseline data on work climate, care processes, and clinical outcomes, conducted between August 2013 and March 2014 in 118 Brazilian ICUs. Phase 2 was a cluster randomized trial conducted between April and November 2014 with the same ICUs. The first 60 admissions of longer than 48 hours per ICU were enrolled in each phase. INTERVENTIONS: Intensive care units were randomized to a quality improvement intervention, including a daily checklist and goal setting during multidisciplinary rounds with follow-up clinician prompting for 11 care processes, or to routine care. MAIN OUTCOMES AND MEASURES: In-hospital mortality truncated at 60 days (primary outcome) was analyzed using a random-effects logistic regression model, adjusted for patients' severity and the ICU's baseline standardized mortality ratio. Exploratory secondary outcomes included adherence to care processes, safety climate, and clinical events. RESULTS: A total of 6877 patients (mean age, 59.7 years; 3218 [46.8%] women) were enrolled in the baseline (observational) phase and 6761 (mean age, 59.6 years; 3098 [45.8%] women) in the randomized phase, with 3327 patients enrolled in ICUs (n = 59) assigned to the intervention group and 3434 patients in ICUs (n = 59) assigned to routine care. There was no significant difference in in-hospital mortality between the intervention group and the usual care group, with 1096 deaths (32.9%) and 1196 deaths (34.8%), respectively (odds ratio, 1.02; 95% CI, 0.82-1.26; P = .88). Among 20 prespecified secondary outcomes not adjusted for multiple comparisons, 6 were significantly improved in the intervention group (use of low tidal volumes, avoidance of heavy sedation, use of central venous catheters, use of urinary catheters, perception of team work, and perception of patient safety climate), whereas there were no significant differences between the intervention group and the control group for 14 outcomes (ICU mortality, central line-associated bloodstream infection, ventilator-associated pneumonia, urinary tract infection, mean ventilator-free days, mean ICU length of stay, mean hospital length of stay, bed elevation to >=30 degrees , venous thromboembolism prophylaxis, diet administration, job satisfaction, stress reduction, perception of management, and perception of working conditions). CONCLUSIONS AND RELEVANCE: Among critically ill patients treated in ICUs in Brazil, implementation of a multifaceted quality improvement intervention with daily checklists, goal setting, and clinician prompting did not reduce in-hospital mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01785966. PMID- 27115270 TI - Acute Kidney Injury With Buffered Crystalloids vs Saline Among ICU Patients. PMID- 27115271 TI - Acute Kidney Injury With Buffered Crystalloids vs Saline Among ICU Patients. PMID- 27115272 TI - Acute Kidney Injury With Buffered Crystalloids vs Saline Among ICU Patients. PMID- 27115273 TI - Acute Kidney Injury With Buffered Crystalloids vs Saline Among ICU Patients. PMID- 27115274 TI - Acute Kidney Injury With Buffered Crystalloids vs Saline Among ICU Patients. PMID- 27115275 TI - Covariate Adjustment and Propensity Score. PMID- 27115277 TI - Affiliation Preference for 2 Authors. PMID- 27115276 TI - Acute Kidney Injury With Buffered Crystalloids vs Saline Among ICU Patients- Reply. PMID- 27115278 TI - Incorrect Effect Estimate. PMID- 27115279 TI - Covariate Adjustment and Propensity Score--Reply. PMID- 27115281 TI - A Harvey Anniversary: 1616-1916. PMID- 27115282 TI - JAMA PATIENT PAGE. Infectious Mononucleosis. PMID- 27115285 TI - The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-beta1 biliary secretion in mice. AB - The secretin/secretin receptor (SR) axis is up-regulated by proliferating cholangiocytes during cholestasis. Secretin stimulates biliary proliferation by down-regulation of let-7a and subsequent up-regulation of the growth-promoting factor, nerve growth factor (NGF). It is not known whether the secretin/SR axis plays a role in subepithelial fibrosis observed during cholestasis. Our aim was to determine the role of the secretin/SR axis in activation of biliary fibrosis in animal models and human primary sclerosing cholangitis (PSC). Studies were performed in wild-type (WT) mice with bile duct ligation (BDL), BDL SR(-/-) mice, or Mdr2(-/-) mouse models of cholestatic liver injury. In selected studies, the SR antagonist (Sec 5-27) was used to block the secretin/SR axis. Biliary proliferation and fibrosis were evaluated as well as secretion of secretin (by cholangiocytes and S cells), expression of markers of fibrosis, transforming growth factor-beta1 (TGF-beta1), transforming growth factor-beta1 receptor (TGF beta1R), let-7a, and downstream expression of NGF. Correlative studies were performed in human control and PSC liver tissue biopsies, serum, and bile. SR antagonist reduced biliary proliferation and hepatic fibrosis in BDL WT and Mdr2( /-) mice. There was decreased expression of let-7a in BDL and Mdr2(-/-) cholangiocytes that was associated with increased NGF expression. Inhibition of let-7a accelerated liver fibrosis was attributed to cholestasis. There was increased expression of TGF-beta1 and TGF-beta1R. Significantly higher expression of secretin, SR, and TGF-beta1 was observed in PSC patient liver samples compared to healthy controls. In addition, there was higher expression of fibrosis genes and remarkably decreased expression of let-7a and increased expression of NGF compared to the control. CONCLUSION: The secretin/SR axis plays a key role in regulating the biliary contribution to cholestasis-induced hepatic fibrosis. (Hepatology 2016;64:865-879). PMID- 27115286 TI - Improving Appropriate Neurologic Prognostication after Cardiac Arrest. A Stepped Wedge Cluster Randomized Controlled Trial. AB - RATIONALE: Predictions about neurologic prognosis that are based on early clinical findings after out-of-hospital cardiac arrest (OHCA) are often inaccurate and may lead to premature decisions to withdraw life-sustaining treatments (LST) in patients who might otherwise survive with good neurologic outcomes. OBJECTIVES: To improve adherence to recommendations for appropriate neurologic prognostication after OHCA and reduce deaths from premature decisions to withdraw LST. METHODS: This was a pragmatic stepped wedge cluster randomized controlled trial evaluating a multifaceted quality intervention (education, pathways, local champions, audit-feedback). The primary outcome was appropriate neurologic prognostication, defined as (1a) no early withdrawal of LST (WLST) (within 72 h) based on estimates of poor neurologic prognosis and (1b) no WLST between 72 hours and 7 days in absence of clinical predictors of poor neurologic prognosis or (2) surviving beyond 7 days. Secondary outcomes were deaths from early WLST and survival with good neurologic outcome. MEASUREMENTS AND MAIN RESULTS: Between June 1, 2011, and June 30, 2014, a total of 905 patients with OHCA were enrolled from ICUs of 18 Ontario hospitals. Rates of appropriate neurologic prognostication increased after the intervention (68% vs. 74% patients; odds ratio [OR], 1.79; 95% confidence interval [CI], 1.01-3.19; P = 0.05). However, rates of survival to hospital discharge (46% vs. 50%; OR, 1.71; 95% CI, 0.97-3.01; P = 0.06) and survival with good neurologic outcome remained similar (38% vs. 43%; OR, 1.43; 95% CI, 0.84-2.86; P = 0.19). CONCLUSIONS: A multicenter quality intervention improved rates of appropriate neurologic prognostication after OHCA but did not increase survival with good neurologic outcome. Clinical trial registered with www.clinicaltrials.gov (NCT 01472458). PMID- 27115287 TI - A Geometrically-Constrained Mathematical Model of Mammary Gland Ductal Elongation Reveals Novel Cellular Dynamics within the Terminal End Bud. AB - Mathematics is often used to model biological systems. In mammary gland development, mathematical modeling has been limited to acinar and branching morphogenesis and breast cancer, without reference to normal duct formation. We present a model of ductal elongation that exploits the geometrically-constrained shape of the terminal end bud (TEB), the growing tip of the duct, and incorporates morphometrics, region-specific proliferation and apoptosis rates. Iterative model refinement and behavior analysis, compared with biological data, indicated that the traditional metric of nipple to the ductal front distance, or percent fat pad filled to evaluate ductal elongation rate can be misleading, as it disregards branching events that can reduce its magnitude. Further, model driven investigations of the fates of specific TEB cell types confirmed migration of cap cells into the body cell layer, but showed their subsequent preferential elimination by apoptosis, thus minimizing their contribution to the luminal lineage and the mature duct. PMID- 27115288 TI - Air Oxidation of Activated Carbon to Synthesize a Biomimetic Catalyst for Hydrolysis of Cellulose. AB - Oxygenated carbon catalyzes the hydrolysis of cellulose present in lignocellulosic biomass by utilizing the weakly acidic functional groups on its surface. Here we report the synthesis of a biomimetic carbon catalyst by simple and economical air-oxidation of a commercially available activated carbon. Air- oxidation at 450-500 degrees C introduced 2000-2400 MUmol g(-1) of oxygenated functional groups on the material with minor changes in the textural properties. Selectivity towards the formation of carboxylic groups on the catalyst surface increased with the increase in oxidation temperature. The degree of oxidation on carbon catalyst was found to be proportional to its activity for hydrolysis of cellulose. The hydrolysis of eucalyptus in the presence of carbon oxidized at 475 degrees C afforded glucose yield of 77 % and xylose yield of 67 %. PMID- 27115289 TI - Electrostatic Interaction-Directed Growth of Nickel Phosphate Single-Walled Nanotubes for High Performance Oxygen Evolution Reaction Catalysts. AB - A series of nickel phosphate single-walled nanotubes with controllable structure parameters are fabricated by utilizing alkali metal ions with the same charge number but different ion radii. Different electrostatic interactions between the cations and related growing intermediates are demonstrated to play a crucial role in controlling the growing process of nanotubes. PMID- 27115291 TI - Pharmacological management of breathlessness in COPD: recent advances and hopes for the future. AB - INTRODUCTION: Activity-related breathlessness is often the dominant symptom in patients with chronic obstructive pulmonary disease (COPD) and usually persists despite optimal medical therapy. Currently, our inability to meaningfully alter the pathophysiology of the underlying disease means that we must focus our attention on relieving this distressing symptom so as to improve exercise tolerance and quality of life. AREAS COVERED: The current review examines the neurobiology of breathlessness and constructs a solid physiological rationale for amelioration of this distressing symptom. We will examine the efficacy of interventions which: 1) reduce the increased central drive to breathe (opioids); 2) improve the respiratory system's ability to appropriately respond to this increased demand (bronchodilators); and 3) address the important affective dimension of breathlessness (anxiolytics). Expert commentary: Advances in our understanding of the mechanisms of activity-related breathlessness in COPD, and its measurement in the clinical domain, now set the stage for the development of effective management strategies on an individual patient basis. PMID- 27115290 TI - Bacterial beta-Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2). AB - Human glucosylcerebrosidase 2 (GBA2) of the CAZy family GH116 is responsible for the breakdown of glycosphingolipids on the cytoplasmic face of the endoplasmic reticulum and Golgi apparatus. Genetic defects in GBA2 result in spastic paraplegia and cerebellar ataxia, while cross-talk between GBA2 and GBA1 glucosylceramidases may affect Gaucher disease. Here, we report the first three dimensional structure for any GH116 enzyme, Thermoanaerobacterium xylanolyticum TxGH116 beta-glucosidase, alone and in complex with diverse ligands. These structures allow identification of the glucoside binding and active site residues, which are shown to be conserved with GBA2. Mutagenic analysis of TxGH116 and structural modeling of GBA2 provide a detailed structural and functional rationale for pathogenic missense mutations of GBA2. PMID- 27115292 TI - pHAST (pH-Driven Aptamer Switch for Thrombin) Catch-and-Release of Target Protein. AB - A pH-driven DNA nanomachine based on the human alpha-thrombin binding aptamer was designed for the specific catch-and-release of human alpha-thrombin at neutral and acidic pH, respectively. In neutral conditions, the thrombin aptamer component of the nanomachine is exposed and exists in the G-quadruplex conformation required to bind to the target protein. At slightly acidic pH, the polyadenine tail of the nanomachine becomes partially protonated and A+(anti)*G(syn) mispairing results in a conformational change, causing the target protein to be released. Forster resonance energy transfer (FRET) was used to monitor conformational switching over multiple pH cycles. Electrophoretic mobility shift assay (EMSA) and fluorescence anisotropy were used to show pH dependent protein binding and release by the nanomachine. This approach could be applied generally to existing G-rich aptamers to develop novel biosensors, theranostics, and nanoswitches. PMID- 27115293 TI - The Non-Conventional Effects of Glucocorticoids in Cancer. AB - Synthetic corticosteroids are widely used for the treatment of a variety of diseases, including pre-malignant and malignant conditions. In striking contrast, recent evidence suggests that corticosteroids can bear tumor-promoting effects in solid tumors of epithelial origin. We have recently shown that epithelial tissues, including the mucosa of the oral cavity and the skin, are able to modulate the local concentration of active corticosteroids and to produce steroids de novo. This has important clinical and physiopathological implications, because tissue-specific regulation of glucocorticoids plays a key role in the overall effect of these molecules. In the present review of the current English literature, performed using MEDLINE/PubMed/Ovid databases, we collected published evidence to demonstrate that corticosteroids induce effects that are more complex and controversial than previously acknowledged. Published studies clearly demonstrate that this class of molecules influences pathophysiological processes that are strictly related to malignancy, providing the rationale for further investigation. J. Cell. Physiol. 231: 2368-2373, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27115294 TI - Advancing the framework for considering the effects of climate change on worker safety and health. AB - In 2009, a preliminary framework for how climate change could affect worker safety and health was described. That framework was based on a literature search from 1988-2008 that supported seven categories of climate-related occupational hazards: (1) increased ambient temperature; (2) air pollution; (3) ultraviolet radiation exposure; (4) extreme weather; (5) vector-borne diseases and expanded habitats; (6) industrial transitions and emerging industries; and (7) changes in the built environment. This article reviews the published literature from 2008 2014 in each of the seven categories. Additionally, three new topics related to occupational safety and health are considered: mental health effects, economic burden, and potential worker safety and health impacts associated with the nascent field of climate intervention (geoengineering). Beyond updating the literature, this article also identifies key priorities for action to better characterize and understand how occupational safety and health may be associated with climate change events and ensure that worker health and safety issues are anticipated, recognized, evaluated, and mitigated. These key priorities include research, surveillance, risk assessment, risk management, and policy development. Strong evidence indicates that climate change will continue to present occupational safety and health hazards, and this framework may be a useful tool for preventing adverse effects to workers. PMID- 27115295 TI - Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice. AB - Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke. PMID- 27115311 TI - Validation of PI-RADS v.2 for prostate cancer diagnosis with MRI at 3T using an external phased-array coil. AB - PURPOSE: To date, few studies have validated the Prostate Imaging Reporting and Data System Version 2 (PI-RADS v. 2) for the diagnosis of prostate cancer. Our aim was to validate PI-RADS v.2 using 3 Tesla (T) MRI. MATERIALS AND METHODS: This is a retrospective study of 54 consecutive patients who underwent 3T MRI with a body-array coil for diagnostic confirmation of prostate cancer or cancer staging between June 2013 and June 2015. Sensitivity, specificity, and agreement were calculated based on a criterion of PI-RADS score = 3. Inter-examiner agreement was determined by the weighted kappa statistic. RESULTS: Histological findings were positive for cancer in 33 patients and negative in 21 patients. Considering a PI-RADS score of 3 as positive for cancer, the accuracy of each reader was 85.20% and 70.40%, respectively, and agreement coefficients were kappa = 0.69 and kappa = 0.35. Considering PI-RADS 3 as absence of cancer, the accuracy of each reader was 77.80% and 77.80%, respectively, and agreement was kappa = 0.55 and kappa = 0.54. Inter-reader agreement was moderate/good (weighted kappa = 0.53; 95% confidence interval: 0.39-0.66; P = 0.038). CONCLUSION: High accuracy was obtained for the diagnosis of prostate cancer using 3T MRI with a body coil and the PI-RADS v.2 score. J. Magn. Reson. Imaging 2016;44:1354-1359. PMID- 27115312 TI - Triple Dipole Effect from Self-Assembled Small-Molecules for High Performance Organic Photovoltaics. AB - A novel triple dipole effect has been observed for Cl-assisted self-assembled small-molecules on ITO substrate, and a highest polymer solar cell performance of 9.2% is obtained. PMID- 27115313 TI - Asthma, COPD and comorbidities in elderly people. AB - Co-morbidities are a significant problem in the elderly population but are rarely presented and analyzed for interdependencies among the various coexisting chronic diseases. OBJECTIVE: The aim of this study was to present a profile of comorbidities in elderly patients with and without asthma and COPD. METHODS: Respondents were recruited at 20 sites in Poland. Stratified random sampling from patient databases resulted in 15,973 patients older than 60 years of age. A retrospective analysis of medical history and ICD-10 codes was performed. In addition, patients underwent a spirometry test with a bronchial reversibility test and were administered questionnaires on the prevalence of chronic diseases by doctors. RESULTS: The study population consisted of 1023 asthmatic patients, 1084 patients with COPD and 1076 control subjects without any signs of bronchoconstriction and with correct spirometry. Patients with asthma exhibited a similar distribution of cardiovascular and metabolic co-morbidities as the control group. However, asthmatic patients had a higher prevalence of arterial hypertension and depression with an odds ratio (OR) = 1.48 (95% CI: 1.38-1.62) and OR = 1.52 (95% CI: 1.44-1.68), respectively. Coronary disease (OR = 2.12; 95% CI: 1.97-2.33), cor pulmonale (OR = 3.1; 95% CI: 2.87-3.22) and heart failure (OR = 2.71; 95% CI: 2.64-3.11) were predominantly observed in patients with COPD. Patients with severe asthma exhibited a greater predisposition to cardiovascular and neuropsychiatric diseases. CONCLUSION: Asthma coexisted frequently with arterial hypertension and depression in elderly patients. Patients with COPD have a more exaggerated profile of coexisting diseases, specifically cardiovascular problems. PMID- 27115314 TI - "Don't Try to Cover the Sky with Your Hands": Parents' Experiences with Prognosis Communication About Their Children with Advanced Cancer. AB - BACKGROUND: Physicians worry that disclosure of prognostic information can be distressing and deprive families of hope. Retrospective studies have shown that prognostic disclosure does not abrogate hope, but prospective data are lacking. OBJECTIVE: The study objective was to prospectively evaluate responses to prognosis communication among parents of children with advanced cancer. DESIGN: For this qualitative study we audiotaped conversations between clinicians and parents of children with newly relapsed or refractory cancer, and then interviewed parents about experiences with prognosis communication. Parents were asked to reflect on physician statements about prognosis. SETTING/SUBJECTS: Subjects were 32 pairs of parents and clinicians of children with relapsed or refractory cancer treated at Dana-Farber/Boston Children's Center for Cancer and Blood Disorders, Boston, Massachusetts. RESULTS: Prognosis was discussed in 28/32 conversations (88%). Although most parents (N = 22, 69%) found prognostic information upsetting, most also valued honest communication about prognosis (N = 22, 69%.) Parents noted that frank disclosure fostered hope by relieving uncertainty and allowing them to make the best possible decisions for their children. Excessive optimism or a lack of information, in contrast, was sometimes experienced as a threat to hope and the parent-clinician relationship. A minority of parents were upset by clinician communication about prognosis (N = 4, 12%), but most did not consider the clinician responsible for their distress. Rather, parents attributed distress to the difficult situation. CONCLUSIONS: Many parents consider prognosis communication to be both difficult and necessary. While upsetting, prognostic information engenders hope by helping parents feel prepared to do their best for their children in the difficult days to come. PMID- 27115315 TI - A Three-Step Synthesis of Tetrasubstituted NH-Pyrroles. AB - Buta-1,3-dienes appended with electron-withdrawing groups (EWGs), derived from the [2 + 2] cycloaddition-retroelectrocyclization (CA-RE) cascade, react with (predominately) nitrogen-based nucleophiles affording tetrasubstituted 2-amino-NH pyrroles in moderate to excellent yields with complete regioselectivity. Penta 2,4-dien-1-ones also undergo a similar transformation, providing analogous products and greatly enhancing the substitution of the pyrrole available. Oxidation from pyrrole to pyrrolidinone affords highly colored compounds that experience a strong bathochromic shift of the longest-wavelength absorption band in the UV/vis spectrum upon protonation, with return to the original spectra following neutralization. PMID- 27115316 TI - Differences in the Vibrational Dynamics of H(2)O and D(2)O: Observation of Symmetric and Antisymmetric Stretching Vibrations in Heavy Water. AB - Water's ability to donate and accept hydrogen bonds leads to unique and complex collective dynamical phenomena associated with its hydrogen-bond network. It is appreciated that the vibrations governing liquid water's molecular dynamics are delocalized, with nuclear motion evolving coherently over the span of several molecules. Using two-dimensional infrared spectroscopy, we have found that the nuclear motions of heavy water, D2O, are qualitatively different than those of H2O. The nonlinear spectrum of liquid D2O reveals distinct O-D stretching resonances, in contrast to H2O. Furthermore, our data indicates that condensed phase O-D vibrations have a different character than those in the gas phase, which we understand in terms of weakly delocalized symmetric and antisymmetric stretching vibrations. This difference in molecular dynamics reflects the shift in the balance between intra- and intermolecular couplings upon deuteration, an effect which can be understood in terms of the anharmonicity of the nuclear potential energy surface. PMID- 27115317 TI - Positive Sides of the Disease: Posttraumatic Growth in Adults with Type 2 Diabetes. AB - Type 2 diabetes is a chronic disease that can causes positive changes, as well as psychological distress. The aim of the this study is to investigate the posttraumatic growth level of adults with type 2 diabetes and to identify the relationship among perceived social support, coping, diabetes management self efficacy, perceived expressed emotions, and PTG in diabetes patients from non western, developing country. The findings revealed that patients experience a moderate level of posttraumatic growth. Regression analyses showed that the severity of the disease, educational level, perceived social support, problem focused coping, optimistic coping and the criticism/hostility dimension of expressed emotions were associated significantly with posttraumatic growth. In the conclusion part, these findings were consistent with the posttraumatic growth theory. The study reveals that professionals aiming to increase the posttraumatic growth of diabetes patients may need to focus on and facilitate perceived social support, adaptive coping strategies, and perceived expressed emotions to facilitate growth experiences. PMID- 27115318 TI - Vascular assessment of liver disease-towards a new frontier in MRI. AB - Complex haemodynamic phenomena underpin the pathophysiology of chronic liver disease. Non-invasive MRI-based assessment of hepatic vascular parameters therefore has the potential to yield meaningful biomarkers for chronic liver disease. In this review, we provide an overview of vascular sequelae of chronic liver disease amenable to imaging evaluation and describe the current supportive evidence, strengths and the limitations of MRI methodologies, including dynamic contrast-enhanced, dynamic hepatocyte-specific contrast-enhanced, phase-contrast, arterial spin labelling and MR elastography in the assessment of hepatic vascular parameters. We review the broader challenges of quantitative hepatic vascular MRI, including the difficulties of motion artefact, complex post-processing, long acquisition times, validation and limitations of pharmacokinetic models, alongside the potential solutions that will shape the future of MRI and deliver this new frontier to the patient bedside. PMID- 27115319 TI - Efficacy of Bimatoprost Plus Timolol Fixed Combination in Open Angle Glaucoma Patients Previously Treated with Dorzolamide Plus Timolol Fixed Combination. AB - PURPOSE: To evaluate the efficacy and safety of bimatoprost plus timolol fixed combination (BTFC) in patients with primary open angle glaucoma (POAG) previously treated with dorzolamide plus timolol fixed combination (DTFC). MATERIALS AND METHODS: Retrospective, medical records review study. Medical records of patients with POAG previously treated with DTFC and then switched to BTFC for poor intraocular pressure (IOP) control or ocular discomfort were included in the analysis. One baseline IOP diurnal curve, and one diurnal curve under each treatment were required to be eligible for this study. The primary outcome was to compare the mean diurnal IOP between DTFC and BTFC. Secondary outcomes were to compare the IOP diurnal fluctuation, and the percentage of patients achieving a target IOP <14, <16, and <18 mmHg between the two treatments. RESULTS: Medical records of 96 patients were analyzed (mean age 65.8 years +/- 7.2, range 39-89 years). The mean diurnal IOP was 23.7 +/- 3.8 mmHg at baseline, 16.9 +/- 3.4 mmHg with DTFC and 15.1 +/- 2.9 mmHg after therapy was switched to BTFC (p < 0.0001 each treatment vs baseline; p < 0.0001 DTFC vs BTFC). The proportion of patients achieving a mean diurnal IOP <18, <16, and <14 mmHg was 76%, 35.4%, and 12.5% with DTFC and 81.2%, 68.8%, and 37.5% with BTFC (p = 0.20, p < 0.01, and p < 0.0001 between the two treatments, respectively). IOP fluctuation did not differ significantly between the treatments. CONCLUSION: BTFC can provide additional lowering in the mean diurnal IOP in patients previously treated with DTFC with no significant differences in the safety and tolerability profile. PMID- 27115320 TI - Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab. AB - Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing. PMID- 27115321 TI - Positive reporting? Is there a bias is reporting of patient and public involvement and engagement? PMID- 27115322 TI - Type 1 diabetes and GAD65 limbic encephalitis: a case report of a 10-year-old girl. AB - Limbic encephalitis is a rare neurological disorder that may be difficult to recognize. Clinical features include memory impairment, temporal lobe seizures and affective disturbance. We report the case of a 10-year-old girl with type 1 diabetes mellitus that presented with seizures, depressed mood and memory changes. The diagnosis of glutamic acid decarboxylase 65 (GAD65) mediated limbic encephalitis relied on cerebral magnetic resonance imaging lesions and high serological and cerebrospinal fluid GAD65-antibodies titers. High-dose steroidal therapy was started with clinical improvement. Relapse led to a second high-dose steroid treatment followed by rituximab with remission. A correlation between serum GAD65-antibodies levels and symptoms was found, demonstrating GAD65 antibodies titers may be useful for clinical follow-up and immunotherapy guidance. This report raises awareness of this serious neurological condition that may be associated with type 1 diabetes, underlining the importance of an early diagnosis and prompt treatment for a better prognosis. PMID- 27115323 TI - Cannabinoids in Health and Disease. PMID- 27115324 TI - Immunoproteomics technologies in the discovery of autoantigens in autoimmune diseases. AB - Proteomics technologies are often used for the identification of protein targets of the immune system. Here, we discuss the immunoproteomics technologies used for the discovery of autoantigens in autoimmune diseases where immune system dysregulation plays a central role in disease onset and progression. These autoantigens and associated autoantibodies can be used as potential biomarkers for disease diagnostics, prognostics and predicting/monitoring drug responsiveness (theranostics). Here, we compare a variety of methods such as mass spectrometry (MS)-based [serological proteome analysis (SERPA), antibody mediated identification of antigens (AMIDA), circulating immune complexome (CIC) analysis, surface enhanced laser desorption/ionization-time of flight (SELDI-TOF)], nucleic acid based serological analysis of antigens by recombinant cDNA expression cloning (SEREX), phage immunoprecipitation sequencing (PhIP-seq) and array-based immunoscreening (proteomic microarrays), luciferase immunoprecipitation systems (LIPS), nucleic acid programmable protein array (NAPPA) methods. We also review the relevance of immunoproteomic data generated in the last 10 years, with a focus on the aforementioned MS based methods. PMID- 27115325 TI - Phytochemical screening, safety evaluation, anti-inflammatory and analgesic studies of the leaf extracts of Sterculia tragacantha. AB - BACKGROUND: Sterculia tragacantha (Sterculiaceae) is used in the treatment of boils, diarrhea, dyspepsia, fever, gonorrhea, snake bite, syphilis, and tapeworm in some West African nations. This study is to investigate its anti-inflammatory and analgesic activities since the plant is being used to treat fever. METHODS: Fresh leaves of the plant were collected and dried at room temperature and pulverized into powder form and 200 g of this powder was dissolved first in hexane for 72 h and the extract was filtered and the filtrate was concentrated while the substrate was further dissolved in chloroform, ethyl acetate and methanol at different times and similar procedure adopted as for the hexane. The organic solvents were used based on order of increasing polarity. Graded concentrations of the solvent extracts were prepared and used for the study. Pilot toxicity test was carried out to determine safety dose using hematology and serum chemistry as indices of toxicity. Thereafter anti-inflammatory and analgesic studies were conducted using standard tests such as carrageenan, histamine-induced-edema, tail flick test and acetic writhing test. Phytochemical screening of the plant was also conducted. RESULTS: Phytochemical screening of the powdered material showed that alkaloid, flavonoid and reducing sugar were present while tannin, cardiac glycosides, saponins and anthraquinones were absent. Pilot toxicity test using aqueous extract at 100 mg/mL concentration showed that no mortality was recorded although the animals that received 3,000 mg/kg dose exhibited slight dullness after 48 h. No significant changes were also observed for the packed cell volume, hemoglobin, white blood cell counts, platelet counts, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, albumin, globulin except for the 200 and 3,000 mg/kg doses that caused significant increase in the level of total protein. The n hexane, chloroform, ethyl acetate, and methanol extracts of S. tragacantha and indomethacin produced significant (p<0.05) inhibition of paw edema compared with the control using histamine and carrageenan methods of paw edema induction. There was significant (p<0.05) reduction in writhing movements at 100 mg/kg and 200 mg/kg of n-hexane, chloroform, and ethyl acetate leaf extracts of S. tragacantha and indomethacin (10 mg/kg) when compared to the control. This effect using tail flick test was not as effective when compared to the writhing test. CONCLUSIONS: The different leaf extracts of S. tragacantha exhibited anti-inflammatory and analgesic properties and they are also safe for medicinal use. PMID- 27115326 TI - Disposable surgical face masks for preventing surgical wound infection in clean surgery. AB - BACKGROUND: Surgical face masks were originally developed to contain and filter droplets containing microorganisms expelled from the mouth and nasopharynx of healthcare workers during surgery, thereby providing protection for the patient. However, there are several ways in which surgical face masks could potentially contribute to contamination of the surgical wound, e.g. by incorrect wear or by leaking air from the side of the mask due to poor string tension. OBJECTIVES: To determine whether the wearing of disposable surgical face masks by the surgical team during clean surgery reduces postoperative surgical wound infection. SEARCH METHODS: In December 2015, for this seventh update, we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL. We also searched the bibliographies of all retrieved and relevant publications. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised controlled trials comparing the use of disposable surgical masks with the use of no mask. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. MAIN RESULTS: We included three trials, involving a total of 2106 participants. There was no statistically significant difference in infection rates between the masked and unmasked group in any of the trials. We identified no new trials for this latest update. AUTHORS' CONCLUSIONS: From the limited results it is unclear whether the wearing of surgical face masks by members of the surgical team has any impact on surgical wound infection rates for patients undergoing clean surgery. PMID- 27115327 TI - Diquafosol for Soft Contact Lens Dryness: Clinical Evaluation and Tear Analysis. AB - PURPOSE: To evaluate the efficacy of topical application of 3% diquafosol tetrasodium solution for the treatment of soft contact lens (SCL) wearers with dryness. In addition to clinical tests and subjective symptoms, we assessed the fluorescence intensity of wheat germ agglutinin conjugate of fluorescein (F-WGA) used as a marker of membrane-associated mucins and sialic acid concentration in tear fluids as a marker of secreted mucins. METHODS: Twelve SCL wearers with dryness symptoms were treated with diquafosol for 4 weeks. Clinical tests included the tear film break-up time (BUT), corneal and conjunctival fluorescein staining scores, and Schirmer values. Subjective symptoms were evaluated by the Dry Eye-Related Quality-of-Life Score (DEQS). Fluorescence intensities in the central cornea were measured by fluorophotometry at 5 minutes after a 5% F-WGA solution was applied to the eye. The tears collected by the Schirmer test strips were analyzed by high-performance liquid chromatography (HPLC), and the concentrations of sialic acid; total protein; and the four major tear proteins secretory IgA, lactoferrin, lipocalin-1, and lysozyme proteins were measured. RESULTS: Comparing the results before and after diquafosol treatment, BUT (p < 0.01), kerato-conjunctival staining score (p < 0.05), corneal staining score (p < 0.05), and DEQS score (p < 0.01) showed statistically significant improvements. The F-WGA fluorescence intensities (p < 0.0001) significantly increased after treatment, whereas the concentrations of sialic acid and tear proteins remained unchanged. CONCLUSIONS: Topical application of diquafosol solution to the SCL wearers with dryness improved biomarker of membrane-associated mucins, BUT, staining of cornea and conjunctiva, and subjective symptoms. PMID- 27115329 TI - Laparoscopic Pancreatoduodenectomy in 50 Consecutive Patients with No Mortality: A Single-Center Experience. AB - BACKGROUND: Laparoscopic pancreatic surgery has gradually expanded to include pancreatoduodenectomy (PD). This study presents data regarding the efficacy of laparoscopic PD in a single center. METHODS: This was a single-cohort, prospective observational study. From March 2012 to September 2015, 50 consecutive patients underwent laparoscopic PD using a five-trocar technique. Reconstruction of the digestive tract was performed with double jejunal loop technique whenever feasible. Patients with radiological signs of portal vein invasion were operated by open approach. RESULTS: Twenty-seven women and 23 men with a median age of 63 years (range 23-76) underwent laparoscopic PD. Five patients underwent total pancreatectomy. All, but 1 patient (previous bariatric operation), underwent pylorus-preserving resection. Reconstruction was performed with double jejunal loop in all cases except in 5 cases of total pancreatectomy. Conversion was required in 3 patients (6%) as a result of difficult dissection (two cases) and unsuspected portal vein invasion (1 patient). Median operative time was 420 minutes (range 360-660), and the 90-day mortality was nil. Pancreatic fistula occurred in 13 patients (26%). There was one grade C (reoperated), one grade B (percutaneous drainage), and all remaining were grade A (conservative treatment). Other complications included port site bleeding (n = 1), biliary fistula (n = 2), and delayed gastric emptying (n = 2). Mean hospital stay was 8.4 days (range 5-31). CONCLUSIONS: Laparoscopic PD is feasible and safe, but is technically demanding and may be reserved to highly skilled laparoscopic surgeons with proper training in high-volume centers. Isolated pancreatic anastomosis may be useful to decrease the severity of postoperative pancreatic fistulas. Therefore, it could be a good option in patients with a high risk for developing postoperative pancreatic, as well as by less-experienced surgeons. PMID- 27115328 TI - The ADAMs family of proteases as targets for the treatment of cancer. AB - The ADAMs (a disintegrin and metalloproteases) are transmembrane multidomain proteins implicated in multiple biological processes including proteolysis, cell adhesion, cell fusion, cell proliferation and cell migration. Of these varied activities, the best studied is their role in proteolysis. However, of the 22 ADAMs believed to be functional in humans, only approximately a half possess matrix metalloproteinase (MMP)-like protease activity. In contrast to MMPs which are mostly implicated in the degradation of extracellular matrix proteins, the main ADAM substrates are the ectodomains of type I and type II transmembrane proteins. These include growth factor/cytokine precursors, growth factor/cytokine receptors and adhesion proteins. Recently, several different ADAMs, especially ADAM17, have been shown to play a role in the development and progression of multiple cancer types. Consistent with this role in cancer, targeting ADAM17 with either low molecular weight inhibitors or monoclonal antibodies was shown to have anti-cancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents is unknown. Furthermore, efficacy in clinical trials remains to be shown. PMID- 27115330 TI - Hydrosoluble 50% N-acetylation-thiolated chitosan complex with cobalt as a pH responsive renal fibrosis targeting drugs. AB - About 50% N-acetylation-thiolated chitosan possessing good water solubility was modified from commercial low-molecular-weight chitosan. Chitosan performed obvious target toward renal tubular epithelial cells, and bivalent cobalt ions improved the renal fibrosis inflammation significantly. There were many complexation sites on chitosan after being modified with sulfydryl. So sulfydryl played a role of connecting bridge between chitosan and cobalt ions. Then, this N acetylation-thiolated chitosan cobalt (NTCC) nanocomplex was designed. The nanocomplex showed excellent stability under normal physiological conditions, and cobalt would be released from the biomaterials in acidic environment. As it was affected by inflammation, the pH in renal fibrosis lesion region was acidic. So there was a specific drug release process happening in lesion region. And drug release efficiency was determined by acidity, which demonstrated that lower the acidity, the faster and more the cobalt ion release. When this nanocomplex was intraperitoneally injected into ureter-obstructed mice, obvious attenuation of fibrotic progression was shown. It was demonstrated that NTCC exhibited special renal-targeting capacity and could be chosen as drug for treating renal fibrosis. PMID- 27115332 TI - Facile synthesis of monodisperse of hollow mesoporous SiO2 nanoparticles and in situ growth of Ag nanoparticles for antibacterial. AB - Monodispersed hollow mesoporous silica nanoparticles (HMSNs) are successfully synthesized via a facile dual template method, in which poly(styrene-co-methyl methacrylate-co-methacrylic acid) (PS-PMMA-PMAA) particles are used as hard template for producing the hollow structure and cetyltrimethylammonium bromide (CTAB) used for introducing the mesopores in the silica shells. The obtained HMSNs possess uniform diameter and morphology, and the shell of which could be adjusted by changing the addition of silicon precursor. The synthesized HMSNs have been characterized by transmission electron microscopy (TEM) and nitrogen physisorption. Furthermore, the HMSNs are used as support for in-situ deposition of silver nanoparticles (Ag NPs) using n-butylamine as reducing agent for AgNO3 in ethanol. Significantly, Ag NPs were successfully supported in the HMSNs without any aggregation. The Ag-deposited HMSNs showed excellent dispersibility in ethanol and water, and their antibacterial activity against Escherichia coli (E. coli) ATCC 25922 and Staphylococcus aureus (S. aureus) ATCC 6538 have been demonstrated. Therefore, the unique nanostructure based on the HMSNs provided a useful platform for the fabrication of antibacterial agent with superior activity and accessibility. And also, it is expected to be a significant template for the synthesis of other novel nanostructures. PMID- 27115331 TI - Replication timing and transcriptional control: beyond cause and effect-part III. AB - DNA replication is essential for faithful transmission of genetic information and is intimately tied to chromosome structure and function. Genome duplication occurs in a defined temporal order known as the replication-timing (RT) program, which is regulated during the cell cycle and development in discrete units referred to as replication domains (RDs). RDs correspond to topologically associating domains (TADs) and are spatio-temporally compartmentalized in the nucleus. While improvements in experimental tools have begun to reveal glimpses of causality, they have also unveiled complex context-dependent relationships that challenge long recognized correlations of RT to chromatin organization and gene regulation. In particular, RDs/TADs that switch RT during development march to the beat of a different drummer. PMID- 27115333 TI - Nanoscaled zero valent iron/graphene composite as an efficient adsorbent for Co(II) removal from aqueous solution. AB - A magnetic graphene, i.e., nanoscaled zero valent iron/graphene (0FG) composite, was prepared, characterized and applied for the removal of Co(II) from aqueous solution. The magnetic graphene (0FG) was synthesized through reduction of graphene oxide (GO) and ferrous ions by potassium borohydride. The kinetics and isotherms of Co(II) adsorption onto 0FG were investigated. The mechanism for Co(II) removal was proposed based on the Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS) and the X-ray absorption fine structure (XAFS) analysis. The results showed that pseudo second-order models and the Freundlich isotherm model fitted well with the data obtained. The adsorption capacity of 0FG was calculated from the Langmuir isotherm, which was 65.58, 101.60 and 134.27mg/g at 10, 20 and 30 degrees C, respectively. Thermodynamic parameters suggested that the adsorption process was endothermic and spontaneous. Co(2+) was stabilized by gamma-FeOOH/gamma-Fe2O3/Fe3O4 on the surface of graphene sheets, forming CoFe2O4-like nanocrystals. The coordination numbers and interatomic distances indicated that Co(2+) mainly occupied the octahedral site, while pseudo-tetrahedral coordination may occur by dehydroxylation of Co(O,OH)6. Magnetic graphene is a potential adsorbent for Co(2+) removal. PMID- 27115334 TI - The impact of precarious employment on mental health: The case of Italy. AB - Although there has been a sizeable empirical literature measuring the effect of job precariousness on the mental health of workers the debate is still open, and understanding the true nature of such relationship has important policy implications. In this paper, we investigate the impact of precarious employment on mental health using a unique, very large data set that matches information on job contracts for over 2.7 million employees in Italy followed over the years 2007-2011, with their psychotropic medication prescription. We examine the causal effects of temporary contracts, their duration and the number of contract changes during the year on the probability of having one or more prescriptions for medication to treat mental health problems. To this end, we estimate a dynamic Probit model, and deal with the potential endogeneity of regressors by adopting an instrumental variables approach. As instruments, we use firm-level probabilities of being a temporary worker as well as other firm-level variables that do not depend on the mental illness status of the workers. Our results show that the probability of psychotropic medication prescription is higher for workers under temporary job contracts. More days of work under temporary contract as well as frequent changes in temporary contract significantly increase the probability of developing mental health problems that need to be medically treated. We also find that moving from permanent to temporary employment increases mental illness; symmetrically, although with a smaller effect in absolute value, moving from temporary to permanent employment tends to reduce it. Policy interventions aimed at increasing the flexibility of the labour market through an increase of temporary contracts should also take into account the social and economic cost of these reforms, in terms of psychological wellbeing of employees. PMID- 27115335 TI - Brunei epidemiological stroke study: patterns of hypertension and stroke risk. AB - OBJECTIVES: Hypertension is the most important known risk factor for cardiovascular diseases. A cross-sectional study was conducted in Brunei Darussalam to estimate the prevalence of hypertension and its association with socioeconomic and life-style factors and impact on stroke incidence. METHODS: Five thousand and sixty-three participants aged above 18 years from 2103 randomly selected households in the Brunei-Muara district of Brunei Darussalam were surveyed. Hypertension was defined as mean SBP at least 140 mmHg, DBP at least 90 mmHg, or taking antihypertensive medication and blood pressure was measured twice. Logistic regression models are used to analyze the association between hypertension/medication for hypertension and sex, age, overweight, education, smoking, family history of hypertension, and employment. RESULTS: A total of 48.3% [95% confidence interval (CI): 46.9-49.7%] of all respondents were identified as hypertensive. Prevalence of hypertension was higher in men (52.8%; 95% CI: 50.7-54.9%) compared to women (45.0%; 95% CI: 43.2-46.8%) and women seek treatment more often than men. Age, overweight, lower levels of education, and a family history of high blood pressure are positively associated with the prevalence of hypertension. The prevalence of overweight (57.3%) and obesity (23.7%) is high and the attributable risk of hypertension for stroke is large. CONCLUSION: The prevalence of hypertension in Brunei is high in both women and men. Information campaigns and prevention programs are needed to be able to cope with the increasing problem of hypertension and resulting diseases like stroke in Brunei in the near future. PMID- 27115336 TI - Endoplasmic reticulum stress inhibition reduces hypertension through the preservation of resistance blood vessel structure and function. AB - OBJECTIVE: Our purpose was to determine if endoplasmic reticulum stress inhibition lowers blood pressure (BP) in hypertension by correcting vascular dysfunction. METHODS: The spontaneously hypertensive rat (SHR) was used as a model of human essential hypertension with its normotensive control, the Wistar Kyoto rat. Animals were subjected to endoplasmic reticulum stress inhibition with 4-phenylbutyric acid (4-PBA; 1 g/kg per day, orally) for 5 weeks from 12 weeks of age. BP was measured weekly noninvasively and at endpoint with carotid arterial cannulation. Small mesenteric arteries were removed for vascular studies. Function was assessed with a Mulvany-Halpern style myograph, and structure was assessed by measurement of medial-to-lumen ratio in perfusion fixed vessels as well as three-dimensional confocal reconstruction of vessel wall components. Endoplasmic reticulum stress was assessed by quantitative real time-PCR and western blotting; oxidative stress was assessed by 3-nitrotyrosine and dihydroethidium staining. RESULTS: 4-PBA significantly lowered BP in SHR (vehicle 206.1 +/- 4.3 vs. 4-PBA 178.9 +/- 3.1, systolic) but not Wistar Kyoto. 4-PBA diminished contractility and augmented endothelial-dependent vasodilation in SHR small mesenteric arteries, as well as reducing media-to-lumen ratio. 4-PBA significantly reduced endoplasmic reticulum stress in SHR resistance vessels. Normotensive resistance vessels, treated with the endoplasmic reticulum stress inducing agent, tunicamycin, show decreased endothelial-dependent vasodilation; this was improved with 4-PBA treatment. 3-Nitrotyrosine and dihydroethidium staining indicated that endoplasmic reticulum stress leads to reactive oxygen species generation resolvable by 4-PBA treatment. CONCLUSION: Endoplasmic reticulum stress caused endothelial-mediated vascular dysfunction contributing to elevated BP in the SHR model of human essential hypertension. PMID- 27115337 TI - Increased epoxyeicosatrienoic acids and reduced soluble epoxide hydrolase expression in the preeclamptic placenta. AB - BACKGROUND: Epoxyeicosatrienoic acids (EETs) derived from cytochrome P450 (CYP) dependent metabolism of arachidonic acid are increased in the plasma of women with preeclampsia as compared with normal pregnancy and are significantly higher in fetal than in maternal plasma and erythrocytes. We hypothesized that differences in EET synthesis or metabolism in the feto-placental unit contributed to the observed differences in circulating EETs. METHOD: To evaluate EETs, formation as well as the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), biopsies of placenta were collected from 19 normal pregnancy and 10 preeclampsia at the time of cesarean section delivery. EETs were extracted from tissue homogenates and analyzed by liquid chromatography coupled with tandem mass spectrometry. RESULTS: Both cis-EETs and trans-EETs were detected in the placenta. Concentration of total EETs was higher in the placenta from preeclampsia compared with normal pregnancy (2.37 +/- 1.42 ng/mg vs. 1.20 +/ 0.72 ng/mg, mean +/- SD, P < 0.01), especially the 5,6-, 8,9- and 11,12-EETs, measured in a subgroup of tissue samples (normal pregnancy = 10, preeclampsia = 5). By immunohistochemistry, sEH, CYP2J2, CYP4A11 were present in placental villi with different pattern distribution, whereas CYP2C8 was not detectable. Neither were CYP2J2, CYP4A11, and CYP2C8 detected in the umbilical cord. Western blot analysis of placenta homogenates showed reduced expression of sEH in preeclampsia as compared with normal pregnancy. CONCLUSION: Increased EETs in the placenta and umbilical cord are associated with the presence of CYP2J2, whereas reduced expression of sEH in preeclampsia may be the key factor of increased EETs in the placenta. PMID- 27115338 TI - Longitudinal growth during fetal life and infancy and cardiovascular outcomes at school-age. AB - OBJECTIVE: Low birth weight is associated with cardiovascular disease. We examined the effects of fetal and infant growth patterns on cardiovascular outcomes in children. METHODS: In a population-based prospective cohort study among 6239 children, we estimated fetal-femur length and weight by 20 and 30 weeks ultrasound, and child length and weight at birth, 0.5, 1, 2 and 6 years. We measured blood pressure (BP), carotid-femoral pulse wave velocity, aortic root diameter, left ventricular mass and fractional shortening at 6 years. We used regression analyses to identify longitudinal growth patterns associated with height-standardized vascular outcomes and body-surface-area-standardized cardiac outcomes. RESULTS: Younger gestational age and lower birth weight were associated with higher BP, smaller aortic root diameter and lower left ventricular mass in childhood (all P values <0.05). Children with decelerated or normal fetal growth followed by accelerated infant growth had higher BP, whereas those with decelerated growth during both fetal life and infancy had a relatively larger left ventricular mass. Longitudinal growth analyses showed that children with increased BP tended to be smaller during third trimester of fetal life, but of normal size during infancy, than children with normal BP. Children with increased aortic root diameter or left ventricular mass tended to be larger during fetal life, but of similar size during infancy. CONCLUSION: Specific fetal and infant growth patterns are associated with different cardiovascular outcomes in children. Further studies are needed to identify the underlying mechanisms and the long-term cardiovascular consequences. PMID- 27115340 TI - 'Waterloo': when normal blood cells meet leukemia. AB - PURPOSE OF REVIEW: Mortality and morbidity associated with leukemia are largely due to frequently occurring cytopenias or the dysfunction of normal blood cells in patients. Our knowledge of how normal blood cells degenerate in response to leukemic cell infiltration has been quite limited. This review summarizes recent findings and discusses both extrinsic and intrinsic mechanisms underlying the suppression of normal hematopoiesis in leukemia. RECENT FINDINGS: Recent studies have shown that leukemic cells are able to remodel the bone marrow niche by secreting specific cytokines or dampening its hematopoietic-supporting functions. In turn, a suitable microenvironment for leukemic cell proliferation but not for normal hematopoietic cell growth is created. Intrinsically, the leukemic condition impairs the normalcy of hematopoietic stem and progenitor cells and alters their signaling networks; consequently, it exhausts hematopoietic progenitor cells and forces stem cells into a more quiescent state, which would allow a reversible suppression of hematopoietic regeneration. The deepened quiescence of hematopoietic stem cells in leukemic marrow was achieved in part via transcription factor Egr3. SUMMARY: These findings provide new insights into the mechanisms underlying hematopoietic suppression in response to leukemic cell outgrowth and offer new strategies to further improve current therapies for leukemias, placing more emphasis on the augmentation of normal hematopoietic regeneration when targeting leukemic cells. PMID- 27115339 TI - Upregulation of P53 promoted G1 arrest and apoptosis in human umbilical cord vein endothelial cells from preeclampsia. AB - OBJECTIVE: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. Current research has focused on endothelial dysfunction regarding pathogenesis of preeclampsia. However, very limited or no studies so far have been performed to assess possible damaged endothelial cell growth/development in the placenta-umbilical cord circulation system in human preeclampsia. METHODS: We isolated and cultured human umbilical cord vein endothelial cells (HUVECs) from normal and preeclampsia pregnancies in vitro. We used 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay to measure cell growth and flow cytometric analysis to determine cell-cycle distribution. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was employed for cell apoptosis experiments. RESULTS: The study showed that the cell growth was significantly suppressed, accompanied by the increased G1 arrest and apoptosis in cultured HUVECs from preeclampsia pregnancies comparing with normotensive controls. Protein P53 was upregulated in the cultured HUVECs from preeclampsia pregnancies, which induced G1 arrest, followed by upregulating P21 expression, and downregulating cyclin E expression and CDK2-cyclin E complexes. On the other hand, upregulation of P53 also activated Bax gene and repressed Bcl-2 and BIRC5 genes, resulting in an increase of the Bax/Bcl-2 ratio and subsequently activating caspase cascade, ultimately led to an initiation of the apoptotic machinery. CONCLUSION: These results indicated that in preeclampsia, vascular endothelial cells could be damaged and cellular proliferation was depressed in human placenta-umbilical cord circulation, adding new information on endothelial cell injury for better understanding the pathogenesis of preeclampsia. PMID- 27115341 TI - Construction of 3D nanostructure hierarchical porous graphitic carbons by charge induced self-assembly and nanocrystal-assisted catalytic graphitization for supercapacitors. AB - A smart and sustainable strategy based on charge-induced self-assembly and nanocrystal-assisted catalytic graphitization is explored for the efficient construction of 3D nanostructure hierarchical porous graphitic carbons from the pectin biopolymer. The electrostatic interaction between the negatively charged pectin chains and magnesium ions plays a crucial role in the formation of 3D architectures. The 3D HPGCs possess a three-dimensional carbon framework with a hierarchical porous structure, flake-like graphitic carbon walls and high surface area (1320 m(2) g(-1)). The 3D HPGCs show an outstanding specific capacitance of 274 F g(-1) and excellent rate capability with a high capacitance retention of 85% at a high current density of 50 A g(-1) for supercapacitor electrodes. This strategy provided a novel approach to effectively construct 3D porous carbon nanostructures from biopolymers. PMID- 27115342 TI - Binary mixtures of rod-like colloids under shear: microscopically-based equilibrium theory and order-parameter dynamics. AB - This paper is concerned with the dynamics of a binary mixture of rod-like, repulsive colloidal particles driven out of equilibrium by means of a steady shear flow (Couette geometry). To this end we first derive, starting from a microscopic density functional in Parsons-Lee approximation, a mesoscopic free energy functional whose main variables are the orientational order parameter tensors. Based on this mesoscopic functional we then explore the stability of isotropic and nematic equilibrium phases in terms of composition and rod lengths. Second, by combining the equilibrium theory with the Doi-Hess approach for the order parameter dynamics under shear, we investigate the orientational dynamics of binary mixtures for a range of shear rates and coupling parameters. We find a variety of dynamical states, including synchronized oscillatory states of the two components, but also symmetry breaking behavior where the components display different in-plane oscillatory states. PMID- 27115343 TI - Density functional theory for polymeric systems in 2D. AB - We propose density functional theory for polymeric fluids in two dimensions. The approach is based on Wertheim's first order thermodynamic perturbation theory (TPT) and closely follows density functional theory for polymers proposed by Yu and Wu (2002 J. Chem. Phys. 117 2368). As a simple application we evaluate the density profiles of tangent hard-disk polymers at hard walls. The theoretical predictions are compared against the results of the Monte Carlo simulations. We find that for short chain lengths the theoretical density profiles are in an excellent agreement with the Monte Carlo data. The agreement is less satisfactory for longer chains. The performance of the theory can be improved by recasting the approach using the self-consistent field theory formalism. When the self-avoiding chain statistics is used, the theory yields a marked improvement in the low density limit. Further improvements for long chains could be reached by going beyond the first order of TPT. PMID- 27115344 TI - Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors. AB - The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17beta-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics. PMID- 27115345 TI - ESCRT-III drives the final stages of CUPS maturation for unconventional protein secretion. AB - The unconventional secretory pathway exports proteins that bypass the endoplasmic reticulum. In Saccharomyces cerevisiae, conditions that trigger Acb1 secretion via this pathway generate a Grh1 containing compartment composed of vesicles and tubules surrounded by a cup-shaped membrane and collectively called CUPS. Here we report a quantitative assay for Acb1 secretion that reveals requirements for ESCRT-I, -II, and -III but, surprisingly, without the involvement of the Vps4 AAA ATPase. The major ESCRT-III subunit Snf7 localizes transiently to CUPS and this was accelerated in vps4Delta cells, correlating with increased Acb1 secretion. Microscopic analysis suggests that, instead of forming intraluminal vesicles with the help of Vps4, ESCRT-III/Snf7 promotes direct engulfment of preexisting Grh1 containing vesicles and tubules into a saccule to generate a mature Acb1 containing compartment. This novel multivesicular / multilamellar compartment, we suggest represents the stable secretory form of CUPS that is competent for the release of Acb1 to cells exterior. PMID- 27115346 TI - Analysis of protein phosphorylation in nerve terminal reveals extensive changes in active zone proteins upon exocytosis. AB - Neurotransmitter release is mediated by the fast, calcium-triggered fusion of synaptic vesicles with the presynaptic plasma membrane, followed by endocytosis and recycling of the membrane of synaptic vesicles. While many of the proteins governing these processes are known, their regulation is only beginning to be understood. Here we have applied quantitative phosphoproteomics to identify changes in phosphorylation status of presynaptic proteins in resting and stimulated nerve terminals isolated from the brains of Wistar rats. Using rigorous quantification, we identified 252 phosphosites that are either up- or downregulated upon triggering calcium-dependent exocytosis. Particularly pronounced were regulated changes of phosphosites within protein constituents of the presynaptic active zone, including bassoon, piccolo, and RIM1. Additionally, we have mapped kinases and phosphatases that are activated upon stimulation. Overall, our study provides a snapshot of phosphorylation changes associated with presynaptic activity and provides a foundation for further functional analysis of key phosphosites involved in presynaptic plasticity. PMID- 27115348 TI - Fluorescent Chemosensors for Selective and Sensitive Detection of Phosmet/Chlorpyrifos with Octahedral Ni(2+) Complexes. AB - The hexadentate ligands H2L1-L3 with mixed S, N, O donor sites and possessing substituents having either "no" or electron-releasing/withdrawing nature at terminal ends are synthesized. The ligands H2L1-L3 were tested for binding with library of metal ions, wherein maximum efficiency was observed with Ni(2+), and it motivated us to prepare the Ni(2+) complexes. The ligand H2L1 underwent deprotonation and formed binuclear complex when interacted with Ni(2+) as evident from its crystal structure. The H2L2 and H2L3 having electron withdrawing/electron releasing groups, respectively, were also deprotonated; however, they afforded mononuclear complexes with Ni(2+) ion. This signifies the importance of steric parameters instead of electronic factors in these particular cases. Impressed by differential behavior of complexes of H2L1 and H2L2/H2L3 with Ni(2+) and their photophysical and electrochemical properties, all the metal complexes were studied for their chemosensing ability. Nowadays with increased use of organophosphate, there is alarming increase of these agents in the environment, and thus we require efficient technique to estimate the level of these agents with high sensitivity and selectivity in aqueous medium. The Ni(2+) complexes with hydrophobic nature were suspended into aqueous medium for testing them as sensor for organophosphate. The (L1)2.(Ni(2+))2 could sense phosmet with detection limit of 44 nM, whereas L2.Ni(2+) and L3.Ni(2+) exhibited the detection limits of 62 and 71 nM, respectively, for chlorpyrifos. PMID- 27115347 TI - The target of the DEAH-box NTP triphosphatase Prp43 in Saccharomyces cerevisiae spliceosomes is the U2 snRNP-intron interaction. AB - The DEAH-box NTPase Prp43 and its cofactors Ntr1 and Ntr2 form the NTR complex and are required for disassembling intron-lariat spliceosomes (ILS) and defective earlier spliceosomes. However, the Prp43 binding site in the spliceosome and its target(s) are unknown. We show that Prp43 fused to Ntr1's G-patch motif (Prp43_Ntr1GP) is as efficient as the NTR in ILS disassembly, yielding identical dissociation products and recognizing its natural ILS target even in the absence of Ntr1's C-terminal-domain (CTD) and Ntr2. Unlike the NTR, Prp43_Ntr1GP disassembles earlier spliceosomal complexes (A, B, B(act)), indicating that Ntr2/Ntr1-CTD prevents NTR from disrupting properly assembled spliceosomes other than the ILS. The U2 snRNP-intron interaction is disrupted in all complexes by Prp43_Ntr1GP, and in the spliceosome contacts U2 proteins and the pre-mRNA, indicating that the U2 snRNP-intron interaction is Prp43's major target. PMID- 27115349 TI - Effect of Different Bearing Ratios on the Friction between Ultrahigh Molecular Weight Polyethylene Ski Bases and Snow. AB - The purpose of this study was to analyze the effect of surfaces with different bearing ratios, but similar roughness heights, on the friction between ultrahigh molecular weight polyethylene (UHMWPE) and snow. On a linear tribometer positioned inside a cold chamber, the different samples were tested over a wide range of velocities and snow temperatures. The surface roughness was measured with a focus variation microscope and analyzed using the bearing ratio curve and its parameters. The surface energy was investigated by measuring the contact angles of a polar (water) and nonpolar (diiodmethane) liquid. The friction tests showed that the bearing ratio had a major effect on the friction between UHMWPE and snow. For temperatures close to the melting point a surface with wide grooves and narrow plateaus (nonbearing surface) performed well. For cold conditions, the friction was less for a surface with narrow grooves and wide plateaus (bearing surface). Interpretations of the results are given on the basis of mixed friction, with lubricated friction being dominant at higher snow temperatures and solid-solid interaction at lower ones. PMID- 27115350 TI - Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study. AB - Cervical cancer (CC) is caused by high-risk human papillomavirus persistence due to the immunosuppressive tumor microenvironment mediated by cytokines. Vaginal microbiota determines the presence of certain cytokines locally. We assessed the association between cervical microbiota diversity and the histopathological diagnosis of each stage of CC, and we evaluated mRNA cervical expression levels of IL-4, IL-6, IL-10, TGF-beta1, TNF-alpha and IFN-gamma across the histopathological diagnosis and specific bacterial clusters. We determined the cervical microbiota by high throughput sequencing of 16S rDNA amplicons and classified it in community state types (CST). Mean difference analyses between alpha-diversity and histopathological diagnosis were carried out, as well as a beta-diversity analysis within the histological diagnosis. Cervical cytokine mRNA expression was analyzed across the CSTs and the histopathological diagnoses. We found a significant difference in microbiota's diversity in NCL-HPV negative women vs those with squamous intraepithelial lesions (SIL) and CC(p = 0.006, p = 0.036).When beta-diversity was evaluated, the CC samples showed the highest variation within groups (p<0.0006) and the largest distance compared to NCL-HPV negative ones (p<0.00001). The predominant bacteria in women with normal cytology were L. crispatus and L. iners, whereas for SIL, it was Sneathia spp. and for CC, Fusobacterium spp. We found higher median cervical levels of IL-4 and TGF-beta1 mRNA in the CST dominated by Fusobacterium spp. These results suggest that the cervical microbiota may be implicated in cervical cancer pathology. Further cohort studies are needed to validate these findings. PMID- 27115351 TI - A Survey of Dog Owners in Remote Northern Australian Indigenous Communities to Inform Rabies Incursion Planning. AB - Australia is underprepared for a rabies incursion due to a lack of information about how a rabies outbreak would spread within the susceptible canine populations and which control strategies would be best to control it. The aim of this study was to collect information to parameterize a recently developed dog rabies spread model as well as use this information to gauge how the community would accept potential control strategies. Such information-together with model outputs-would be used to inform decision makers on the best control strategies and improve Australia's preparedness against a canine rabies incursion. The parameters this study focussed on were detection time, vaccination rates and dog culling and dog movement restriction compliance. A cross-sectional survey of 31 dog-owners, using a questionnaire, was undertaken in the five communities of the Northern Peninsular Area (NPA) in northern Australia regarding community dog movements, veterinary visits, reporting systems, perceptions of sick dogs and potential human behaviours during hypothetical rabies outbreaks. It highlighted the significant shortfalls in veterinary care that would need to be vastly improved during an outbreak, who educational programs should be targeted towards and which dog movements should be restricted. The results indicate that men were significantly more likely than women to allow their dogs to roam and to move their dogs. The current low vaccination rate of 12% highlighted the limited veterinary services that would need to be substantially increased to achieve effective rabies control. Participation in mass vaccination was accepted by 100% of the respondents. There was lower acceptance for other possible rabies control strategies with 10-20% of the respondents stating a resistance to both a mass culling program and a ban on dog movements. Consequently, movement bans and mass dog culling would have limited effectiveness as a control strategy in the NPA community. More than half of the respondents said that they would report their sick dogs within a week. This would lead to a much more optimistic rabies detection time than observed in other regions with recent dog rabies outbreaks. Findings from this study can be used to parameterize a recently developed dog rabies spread model as well as to develop informed policies for managing a future rabies incursion, thus improving Australia's preparedness against a canine rabies incursion. PMID- 27115353 TI - Clinical Utility of an Enzyme-Linked Immunosorbent Assay for Detecting Anti Melanoma Differentiation-Associated Gene 5 Autoantibodies. AB - OBJECTIVE: Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. METHODS: Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients' serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. RESULTS: In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P <= 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006). CONCLUSION: Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM. PMID- 27115354 TI - Musculoskeletal Geometry, Muscle Architecture and Functional Specialisations of the Mouse Hindlimb. AB - Mice are one of the most commonly used laboratory animals, with an extensive array of disease models in existence, including for many neuromuscular diseases. The hindlimb is of particular interest due to several close muscle analogues/homologues to humans and other species. A detailed anatomical study describing the adult morphology is lacking, however. This study describes in detail the musculoskeletal geometry and skeletal muscle architecture of the mouse hindlimb and pelvis, determining the extent to which the muscles are adapted for their function, as inferred from their architecture. Using I2KI enhanced microCT scanning and digital segmentation, it was possible to identify 39 distinct muscles of the hindlimb and pelvis belonging to nine functional groups. The architecture of each of these muscles was determined through microdissections, revealing strong architectural specialisations between the functional groups. The hip extensors and hip adductors showed significantly stronger adaptations towards high contraction velocities and joint control relative to the distal functional groups, which exhibited larger physiological cross sectional areas and longer tendons, adaptations for high force output and elastic energy savings. These results suggest that a proximo-distal gradient in muscle architecture exists in the mouse hindlimb. Such a gradient has been purported to function in aiding locomotor stability and efficiency. The data presented here will be especially valuable to any research with a focus on the architecture or gross anatomy of the mouse hindlimb and pelvis musculature, but also of use to anyone interested in the functional significance of muscle design in relation to quadrupedal locomotion. PMID- 27115355 TI - Detection and Identification of Hematologic Malignancies and Solid Tumors by an Electrochemical Technique. AB - PURPOSE: Develop and evaluate an electrochemical method to identify healthy individuals, malignant hematopathic patients and solid tumor patients by detecting the leukocytes in whole-blood. METHODS: A total of 114 individual blood samples obtained from our affiliated hospital in China (June 2015- August 2015) were divided into three groups: healthy individuals (n = 35), hematologic malignancies (n = 41) and solid tumors (n = 38). An electrochemical workstation system was used to measure differential pulse voltammetry due to the different electrochemical behaviors of leukocytes in blood samples. Then, one-way analysis of variance (ANOVA) was applied to analyze the scanning curves and to compare the peak potential and peak current. RESULTS: The scanning curve demonstrated the specific electrochemical behaviors of the blank potassium ferricyanide solution and that mixed with blood samples in different groups. Significant differences in mean peak potentials of mixture and shifts (DeltaEp (mV)) were observed of the three groups (P< = 0.001). 106.00+/-9.00 and 3.14+/-7.48 for Group healthy individuals, 120.90+/-11.18 and 18.10+/-8.81 for Group hematologic malignancies, 136.84+/-11.53 and 32.89+/-10.50 for Group solid tumors, respectively. In contrast, there were no significant differences in the peak currents and shifts. CONCLUSIONS: The newly developed method to apply the electrochemical workstation system to identify hematologic malignancies and solid tumors with good sensitivity and specificity might be effective, suggesting a potential utility in clinical application. PMID- 27115356 TI - Relating the Surface Properties of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) to Their Bactericidal Effect towards a Biofilm of Streptococcus mutans. AB - This study was designed to determine the effects of superparamagnetic iron oxide nanoparticles (SPIONs) on the biological activity of a bacterial biofilm (Streptococcus mutans). Our hypothesis was that the diffusion of the SPIONs into biofilms would depend on their surface properties, which in turn would largely be determined by their surface functionality. Bare, positively charged and negatively charged SPIONs, with hydrodynamic diameters of 14.6 +/- 1.4 nm, 20.4 +/- 1.3 nm and 21.2 +/- 1.6 nm were evaluated. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) and electrophoretic mobility (EPM) measurements were used to confirm that carboxylic functional groups predominated on the negatively charged SPIONS, whereas amine functional groups predominated on the positively charged particles. Transmission electron microscopy (TEM) showed the morphology and sizes of SPIONs. Scanning electron microscopy (SEM) and EPM measurements indicated that the surfaces of the SPIONs were covered with biomolecules following their incubation with the biofilm. Bare SPIONs killed bacteria less than the positively charged SPIONs at the highest exposure concentrations, but the toxicity of the bare and positively charged SPIONs was the same for lower SPION concentrations. The positively charged SPIONs were more effective in killing bacteria than the negatively charged ones. Nonetheless, electrophoretic mobilities of all three SPIONs (negative, bare and positively charged) became more negative following incubation with the (negatively-charged) biofilm. Therefore, while the surface charge of SPIONS was important in determining their biological activity, the initial surface charge was not constant in the presence of the biofilm, leading eventually to SPIONS with fairly similar surface charges in situ. The study nonetheless suggests that the surface characteristics of the SPIONS is an important parameter controlling the efficiency of antimicrobial agents. The analysis of the CFU/mL values shows that the SPIONs have the same toxicity on bacteria in solution in comparison with that on the biofilm. PMID- 27115357 TI - Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies. AB - AIM: We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta analysis of genome-wide association studies (GWAS) in 2014. METHODS: We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. RESULTS: Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019-1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026-1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. CONCLUSIONS: Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population. PMID- 27115358 TI - Correlates of Protection against Norovirus Infection and Disease-Where Are We Now, Where Do We Go? PMID- 27115359 TI - Pretreatment Acoustic Predictors of Gender, Femininity, and Naturalness Ratings in Individuals With Male-to-Female Gender Identity. AB - PURPOSE: The purpose of this study was to describe the pretreatment acoustic characteristics of individuals with male-to-female gender identity (IMtFGI) and investigate the ability of the acoustic measures to predict ratings of gender, femininity, and vocal naturalness. METHOD: This retrospective descriptive study included 2 groups of participants. Speakers were IMtFGI who had not previously received communication feminization treatment (N = 25). Listeners were members of the lay community (N = 30). Acoustic data were retrospectively obtained from pretreatment recordings, and pretreatment recordings also served as stimuli for 3 perceptual rating tasks (completed by listeners). RESULTS: Acoustic data generally were within normal limits for male speakers. All but 2 speakers were perceived to be male, limiting information about the relationship between acoustic measures and gender perception. Fundamental frequency (reading) significantly predicted femininity ratings (p = .000). A total of 3 stepwise regression models indicated that minimum frequency (range task), second vowel formant (sustained vowel), and shimmer percentage (sustained vowel) together significantly predicted naturalness ratings (p = .005, p = .003, and p = .002, respectively). CONCLUSIONS: Study aims were achieved with the exception of acoustic predictors of gender perception, which could be described for only 2 speakers. Future research should investigate measures of prosody, voice quality, and other aspects of communication as predictors of gender, femininity, and naturalness. PMID- 27115363 TI - Truncated View of the Broekzijder Mill on the Gein, Wings Facing West: Piet Mondrian. PMID- 27115372 TI - Digital Health and Patient Safety. PMID- 27115373 TI - A PIECE OF MY MIND. The Patient You Least Want to See. PMID- 27115374 TI - New Horizons in Allergen Immunotherapy. PMID- 27115375 TI - Moving From Clinical Trials to Precision Medicine: The Role for Predictive Modeling. PMID- 27115376 TI - Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial. AB - IMPORTANCE: The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma. OBJECTIVES: To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period. DESIGN, SETTINGS, AND PARTICIPANTS: Double-blind, randomized, placebo controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis. Key exclusion criteria were FEV1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months. INTERVENTIONS: 1:1:1 randomization to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [n = 275] or 12 SQ-HDM [n = 282]) in addition to ICS and the short-acting beta2-agonist salbutamol. MAIN OUTCOMES AND MEASURES: Primary outcome was time to first moderate or severe asthma exacerbation during the ICS reduction period. Secondary outcomes were deterioration in asthma symptoms, change in allergen-specific immunoglobulin G4 (IgG4), change in asthma control or asthma quality-of-life questionnaires, and adverse events. RESULTS: Among 834 randomized patients (mean age, 33 years [range, 17-83]; women, 48%), 693 completed the study. The 6 SQ-HDM and 12 SQ-HDM doses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR]: 0.72 [95% CI, 0.52-0.99] for the 6 SQ-HDM group, P = .045, and 0.69 [95% CI, 0.50-0.96] for the 12 SQ-HDM group, P = .03). The absolute risk differences based on the observed data (full analysis set) in the active groups vs the placebo group were 0.09 (95% CI, 0.01-0.15) for the 6 SQ-HDM group and 0.10 (95% CI, 0.02-0.16) for the 12 SQ-HDM group. There was no significant difference between the 2 active groups. Compared with placebo, there was a reduced risk of an exacerbation with deterioration in asthma symptoms (HR, 0.72 [95% CI, 0.49-1.02] for the 6 SQ-HDM group, P = .11, and 0.64 [95% CI, 0.42-0.96] for the 12 SQ-HDM group, P = .03) and a significant increase in allergen-specific IgG4. However, there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions. The most frequent adverse events were mild to moderate oral pruritus (13% for the 6 SQ-HDM group, 20% for the 12 SQ-HDM group, and 3% for the placebo group), mouth edema, and throat irritation. CONCLUSIONS AND RELEVANCE: Among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points; the reduction was primarily due to an effect on moderate exacerbations. Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2010-018621-19. PMID- 27115377 TI - Association Between Rotating Night Shift Work and Risk of Coronary Heart Disease Among Women. AB - IMPORTANCE: Prospective studies linking shift work to coronary heart disease (CHD) have been inconsistent and limited by short follow-up. OBJECTIVE: To determine whether rotating night shift work is associated with CHD risk. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 189,158 initially healthy women followed up over 24 years in the Nurses' Health Studies (NHS [1988-2012]: N = 73,623 and NHS2 [1989-2013]: N = 115,535). EXPOSURES: Lifetime history of rotating night shift work (>=3 night shifts per month in addition to day and evening shifts) at baseline (updated every 2 to 4 years in the NHS2). MAIN OUTCOMES AND MEASURES: Incident CHD; ie, nonfatal myocardial infarction, CHD death, angiogram-confirmed angina pectoris, coronary artery bypass graft surgery, stents, and angioplasty. RESULTS: During follow-up, 7303 incident CHD cases occurred in the NHS (mean age at baseline, 54.5 years) and 3519 in the NHS2 (mean age, 34.8 years). In multivariable-adjusted Cox proportional hazards models, increasing years of baseline rotating night shift work was associated with significantly higher CHD risk in both cohorts. In the NHS, the association between duration of shift work and CHD was stronger in the first half of follow up than in the second half (P=.02 for interaction), suggesting waning risk after cessation of shift work. Longer time since quitting shift work was associated with decreased CHD risk among ever shift workers in the NHS2 (P<.001 for trend). [table: see text] CONCLUSIONS AND RELEVANCE: Among women who worked as registered nurses, longer duration of rotating night shift work was associated with a statistically significant but small absolute increase in CHD risk. Further research is needed to explore whether the association is related to specific work hours and individual characteristics. PMID- 27115378 TI - Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: A Review. AB - IMPORTANCE: Lyme disease, human granulocytic anaplasmosis (HGA), and babesiosis are emerging tick-borne infections. OBJECTIVE: To provide an update on diagnosis, treatment, and prevention of tick-borne infections. EVIDENCE REVIEW: Search of PubMed and Scopus for articles on diagnosis, treatment, and prevention of tick borne infections published in English from January 2005 through December 2015. FINDINGS: The search yielded 3550 articles for diagnosis and treatment and 752 articles for prevention. Of these articles, 361 were reviewed in depth. Evidence supports the use of US Food and Drug Administration-approved serologic tests, such as an enzyme immunoassay (EIA), followed by Western blot testing, to diagnose extracutaneous manifestations of Lyme disease. Microscopy and polymerase chain reaction assay of blood specimens are used to diagnose active HGA and babesiosis. The efficacy of oral doxycycline, amoxicillin, and cefuroxime axetil for treating Lyme disease has been established in multiple trials. Ceftriaxone is recommended when parenteral antibiotic therapy is recommended. Multiple trials have shown efficacy for a 10-day course of oral doxycycline for treatment of erythema migrans and for a 14-day course for treatment of early neurologic Lyme disease in ambulatory patients. Evidence indicates that a 10-day course of oral doxycycline is effective for HGA and that a 7- to 10-day course of azithromycin plus atovaquone is effective for mild babesiosis. Based on multiple case reports, a 7- to 10-day course of clindamycin plus quinine is often used to treat severe babesiosis. A recent study supports a minimum of 6 weeks of antibiotics for highly immunocompromised patients with babesiosis, with no parasites detected on blood smear for at least the final 2 weeks of treatment. CONCLUSIONS AND RELEVANCE: Evidence is evolving regarding the diagnosis, treatment, and prevention of Lyme disease, HGA, and babesiosis. Recent evidence supports treating patients with erythema migrans for no longer than 10 days when doxycycline is used and prescription of a 14-day course of oral doxycycline for early neurologic Lyme disease in ambulatory patients. The duration of antimicrobial therapy for babesiosis in severely immunocompromised patients should be extended to 6 weeks or longer. PMID- 27115379 TI - Body Fat Distribution and Diabetic Retinopathy in People With Type 2 Diabetes. PMID- 27115380 TI - Lyme Disease Serology. PMID- 27115381 TI - Breast Cancer Screening Using Tomosynthesis and Digital Mammography in Dense and Nondense Breasts. PMID- 27115382 TI - Content, Readability, and Understandability of Dense Breast Notifications by State. PMID- 27115383 TI - TP53 Gene and Cancer Resistance in Elephants. PMID- 27115384 TI - TP53 Gene and Cancer Resistance in Elephants. PMID- 27115385 TI - TP53 Gene and Cancer Resistance in Elephants. PMID- 27115386 TI - TP53 Gene and Cancer Resistance in Elephants--Reply. PMID- 27115387 TI - Mechanical Thrombectomy and Functional Outcomes After Stroke. PMID- 27115388 TI - Mechanical Thrombectomy and Functional Outcomes After Stroke. PMID- 27115389 TI - Mechanical Thrombectomy and Functional Outcomes After Stroke--Reply. PMID- 27115390 TI - Conflict or Confluence of Interest? PMID- 27115391 TI - Conflict or Confluence of Interest?--Reply. PMID- 27115392 TI - Incorrect Compound. PMID- 27115394 TI - Public Health Laboratories. PMID- 27115395 TI - JAMA PATIENT PAGE. The US Preventive Services Task Force. PMID- 27115396 TI - Aquaporin gene therapy for disorders of cholestasis? PMID- 27115397 TI - Post-fledging movements of white-tailed eagles: Conservation implications for wind-energy development. AB - The presence of poorly sited wind farms raises concerns for wildlife, including birds of prey. Therefore, there is a need to extend the knowledge of the potential human-wildlife conflicts associated with wind energy. Here, we report on the movements and habitat use of post-fledging satellite-tagged white-tailed eagles in Finland, where wind-energy development is expected to increase in the near future. In particular, we examine the probability of a fledgling approaching a hypothetical turbine that is placed at different distances from the nest. We found that this probability is high at short distances but considerably decreases with increasing distances to the nest. A utilisation-availability analysis showed that the coast was the preferred habitat. We argue that avoiding construction between active nests and the shoreline, as well as adopting the currently 2-km buffer zone for turbine deployment, can avoid or minimise potential impacts on post-fledging white-tailed eagles. PMID- 27115398 TI - Verapamil Inhibits the Pelvic Pressure Increase Corresponding to Flow Perfusion in the Porcine Percutaneous Renal Puncture Model. AB - PURPOSE: To estimate the effects of verapamil on pelvic pressure and investigate the possible systemic side effects in the porcine model during the procedure of increasing perfusion rates. MATERIALS AND METHODS: In the experimental group, the pelvic pressure was recorded with increasing perfusion rates of the renal pelvis (0, 2, 4, 6, 8, 10, 14 and 20 ml/min) in response to intraluminal administration of increasing concentrations of verapamil (0, 0.1, 1, 10 and 100 ug/ml) in isotonic saline. In the isotonic saline group, the pressure flow study was also done by increasing perfusion rates of the renal pelvis per animal using isotonic saline without verapamil. RESULTS: Perfusion with 1, 10 and 100 ug/ml verapamil caused a decrease in pelvic pressure as a response to increasing flow rates, whereas perfusion with 0.1 ug/ml verapamil did not obviously inhibit the increase of pelvic pressure at all perfusion rates compared with other concentrations. Importantly, the mean systolic blood pressure and mean heart rate were stable despite the increase of flow rates and verapamil concentrations. In the isotonic saline group, perfusion with isotonic saline resulted in an increase in the pelvic pressure with an increase in flow rates each time. CONCLUSIONS: Endoluminal administration of verapamil reduces pelvic pressure significantly without any untoward systemic cardiovascular side effects. PMID- 27115399 TI - Attitudes Toward HIV Pre-Exposure Prophylaxis in a United States Urban Clinic Population. AB - A majority of US studies on attitudes toward PrEP focus on men who have sex with men with little representation of African Americans. This cross-sectional study seeks to determine openness to PrEP, and examine motivations for openness among Philadelphia residents. Patients undergoing HIV rapid testing between May 2012 and December 2014 in a public setting were administered a survey. Questions included openness to PrEP and reasons for openness to PrEP. Multivariate logistic regression models were used to investigate associations between openness and potential predictors. Analyses were conducted using R version 3.2.4 and the epitools and car packages. Of 5606 respondents, over 90 % were African American. Men were more likely to express openness (61.4 % of men, 54.8 % of women, p < 0.0001). Predictors of openness were younger age, black race, higher perceived risk for HIV by patient or as assessed by Tester, intermittent /no condom use, greater number of partners in 12 months and previous HIV testing. The main reason for openness was fear of HIV, and for disinterest was lack of recognition of risk. Understanding openness to PrEP, and reasons for openness to or disinterest in PrEP are critical to determining the best approaches to facilitate engagement in PrEP care by communities and persons at elevated risk for HIV acquisition. Further study is needed on how best to manage disinterest in PrEP by those at high risk for HIV, and how openness to PrEP translates into concrete steps to take PrEP. PMID- 27115400 TI - Pilot Randomized Trial of Collaborative Behavioral Treatment for Chronic Pain and Depression in Persons Living with HIV/AIDS. AB - In this pilot study, we assessed feasibility and acceptability of a behavior therapy intervention for pain and depressive symptoms in persons living with HIV/AIDS (PLWH). We randomly assigned 23 participants to HIV-PASS (HIV-Pain and Sadness Study) or a health education control arm for 3 months. On average, participants attended more than 5 sessions (of 7 possible) in both arms. Qualitative data suggest HIV-PASS participants understood key messages and made concrete behavioral changes. HIV-PASS was associated with effects in the expected direction for three of four outcomes, including the primary outcome (pain-related interference with functioning). Findings suggest that HIV-PASS is promising. PMID- 27115402 TI - Congenital Microtia Treated at Sapporo Medical University Hospital: Clinical Characteristics and Associated Anomalies. AB - Seventy-three children who underwent plastic surgery for their external ear malformations between December 2010 and May 2013 at the Sapporo Medical University Hospital were evaluated. The predominance of right-sided malformation (62%) in males (71%) was similar to that reported previously, but the number of bilateral cases (9.3%) was lower than that in previous reports. We classified patients' ears using Marx's classification. The pure-tone average (average air conduction thresholds measured at 500, 1,000 and 2,000 Hz) was used as the representative value for the hearing level, which was compared with a patient's Marx classification. We evaluated the facial nerve position using high-resolution computed tomography scans. A thorough understanding of anatomical variations and complications, as well as performing appropriate treatments, is required for otolaryngologists to effectively manage congenital microtia. PMID- 27115401 TI - The Impact of Discrimination on the Mental Health of Trans*Female Youth and the Protective Effect of Parental Support. AB - Significant health disparities exist for transgender female (trans*female) youth. We assessed differences in mental health outcomes based on exposure to discrimination among transgender female youth in the San Francisco Bay Area aged 16-24 years. Youth were recruited using a combination of respondent driven sampling with online and social media methods. Logistic regression models were used to estimate odds ratios for the mental health outcomes, comparing levels of discrimination and levels of resiliency promoting protective factors among sexually active youth in the sample (N = 216). High transgender-based discrimination was significantly associated with greater odds of PTSD (AOR, 2.6; 95 % CI 1.4-5.0), depression (AOR, 2.6; 95 % CI 1.2-5.9), and stress related to suicidal thoughts (AOR 7.7, 95 % CI 2.3-35.2). High racial discrimination was significantly associated with greater odds of psychological stress (AOR 3.6; 95 % CI 1.2-10.8), PTSD (AOR 2.1; 95 % CI 1.1-4.2) and stress related to suicidal thoughts (AOR 4.3, 95 % CI 1.5-13.3). Parental closeness was related to significantly lower odds of all four mental health outcomes measured, and intrinsic resiliency positively reduced risk for psychological stress, PTSD, and stress related to suicidal thoughts. Transgender and racial discrimination may have deleterious effects on the mental health of trans*female youth. Interventions that address individual and intersectional discrimination and build resources for resiliency and parental closeness may have success in preventing mental health disorders in this underserved population. PMID- 27115403 TI - UK Renal Registry 18th Annual Report (December 2015) Chapter 5: Survival and Causes of Death in UK Adult Patients on Renal Replacement Therapy in 2014: National and Centre-specific Analyses. AB - Survival of incident patients on RRT continued to improve over the last 14 years for both short and long term survival up to 10 years post RRT start. One year after 90 day age adjusted survival for incident RRT patients in the 2013 cohort increased to 91.4% from the previous year (91.0%); survival increased in incident patients aged ,65 years and in older patients (565 years). There was a difference in one year after 90 day incident survival by age group and diabetic status: diabetic patients aged ,65 years have slightly worse survival than non-diabetic patients, but survival for older diabetic patients (565 years) was significantly better than for non-diabetic patients. One year age adjusted survival for prevalent dialysis patients was 88.6% in the 2013 cohort, a slight decrease from the 2012 cohort (89.3%). Age adjusted one year survival for prevalent dialysis patients with diabetic primary renal disease has been declining slightly since 2012. Centre and UK country variability was evident in incident and prevalent patient survival after adjusting to age 60 and this finding would benefit from further investigation. The relative one year risk of death on RRT decreased with age from about 19 times that of the general population at age 35-39 years to 2.6 times at age 85 and over. In the prevalent RRT population, cardiovascular disease was the most common cause of death, accounting for 23% of deaths. Infection accounted for 20% of deaths and treatment withdrawal for 16% of deaths. PMID- 27115404 TI - Does the ethical appropriateness of paying donors depend on what body parts they donate? AB - The idea of paying donors in order to make more human bodily material available for therapy, assisted reproduction, and biomedical research is notoriously controversial. However, while national and international donation policies largely oppose financial incentives they do not treat all parts of the body equally: incentives are allowed in connection to the provision of some parts but not others. Taking off from this observation, I discuss whether body parts differ as regards the ethical legitimacy of incentives and, if so, why. I distinguish two approaches to this issue. On a "principled" approach, some but not all body parts are inherently special in a way that proscribes payment. On a "pragmatic" approach, the appropriateness of payment in relation to a specific part must be determined through an overall assessment of e.g. the implications of payment for the health and welfare of providers, recipients, and third parties, and the quality of providers' consent. I argue that the first approach raises deep and potentially divisive questions about the good life, whereas the second approach invokes currently unsupported empirical assumptions and requires difficult balancing between different values and the interests of different people. This does not mean that any attempt to distinguish between body parts in regard to the appropriateness of payment necessarily fails. However, I conclude, any plausible such attempt should either articulate and defend a specific view of the good life, or gather relevant empirical evidence and apply defensible principles for weighing goods and interests. PMID- 27115405 TI - Evidence for a distinct gut microbiome in kidney stone formers compared to non stone formers. AB - The trillions of microbes that colonize our adult intestine are referred to as the gut microbiome (GMB). Functionally it behaves as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. While the relationship between the GMB and kidney stone disease (KSD) has not been investigated, dysbiosis of the GMB has been associated with diabetes, obesity and cardiovascular disease. In this pilot study we sought to identify unique changes in the GMB of kidney stone patients compared to patients without KSD. With an IRB approved protocol we enrolled 29 patients into our pilot study. 23 patients were kidney stone formers and six were non-stone forming controls. Specimens were collected after a 6h fast and were flash frozen in dry ice and then stored at -80 degrees C. Microbiome: determination of bacterial abundance was by analysis of 16 s rRNA marker gene sequences using next generation sequencing. Sequencing of the GMB identified 178 bacterial genera. The five most abundant enterotypes within each group made up to greater than 50 % of the bacterial abundance identified. Bacteroides was 3.4 times more abundant in the KSD group as compared to control (34.9 vs 10.2 %; p = 0.001). Prevotella was 2.8 times more abundant in the control group as compared to the KSD group (34.7 vs 12.3 %; p = 0.005). In a multivariate analysis including age, gender, BMI, and DM, kidney stone disease remained an increased risk for high prevalence for Bacteroides (OR = 3.26, p = 0.033), whereas there was an inverse association with Prevotella (OR = 0.37, p = 0.043). There were no statistically significant differences in bacterial abundance levels for Bacteroides or Prevotella when comparing patients with and without DM, obesity (BMI >30), HTN or HLD. 11 kidney stone patients completed 24 h urine analysis at the time of this writing. Looking at the bacterial genuses with at least 4 % abundance in the kidney stone group, Eubacterium was inversely correlated with oxalate levels (r = -0.60, p < 0.06) and Escherichia trended to an inverse correlation with citrate (r = -0.56, p < 0.08). We also compared bacterial abundance between uric acid (UA) stone formers (n = 5) and non UA stone formers (n = 18) and found no significant difference between them. We identified two genus of bacteria in the GMB that had significant association with KSD. Interestingly, components of the 24-h urine appear to be correlated to bacterial abundance. These preliminary studies for the first time associate differences in the GMB with kidney stone formation. Further studies are warranted to evaluate the potential causative role of preexisting dysbiosis in kidney stone disease. PMID- 27115407 TI - A Clinical Review of Thyroid Cancer at Sapporo Medical University Hospital. AB - Thyroid cancer is a disease that affects 8,000 new individuals a year, a number that has increased approximately 3-fold in the past 30 years. The increase in the incidence of thyroid cancer can be related to various factors. The evolution of diagnostic technology has distinctly occurred in the fields of diagnostic imaging, cytology and immunochemistry. For example, liquid-based cytology, developed to assess gynecological lesions, has improved diagnostic accuracy over conventional smear cytology. This technique can also be positively applied to cytological analyses of thyroid cancer. In the field of tumor biomarkers, thyroglobulin and trefoil factor-1 are well known and useful. On the other hand, a new specific biomarker of thyroid cancer has been developed. Furthermore, definitive diagnosis of follicular thyroid tumors is extremely difficult or impossible with current tumor biomarkers and cytological methods. Although the standard treatment for thyroid cancer is a basic surgical resection, iodine adjuvant therapy after surgery is a well-known treatment. Here we present a treatment strategy for thyroid cancer according to the statistics obtained at our facility. PMID- 27115408 TI - Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection. AB - RATIONALE: Mucosal-associated invariant T (MAIT) cells are a recently described abundant, proinflammatory T-cell subset with unknown roles in pulmonary immunity. Nontypeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during chronic obstructive pulmonary disease (COPD) exacerbations and is a plausible target for MAIT cells. OBJECTIVES: To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids (ICS) on their frequency and function in COPD. METHODS: Eleven subjects with COPD receiving ICS, 8 steroid-naive subjects with COPD, and 21 healthy control subjects underwent phlebotomy, sputum induction, bronchoalveolar lavage, and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi. MEASUREMENTS AND MAIN RESULTS: Frequencies of Valpha7.2+CD161+ MAIT cells, surface expression of the major histocompatibility complex-related protein 1 (MR1), and intracellular IFN-gamma expression were measured by flow cytometry. MAIT-cell frequencies were reduced in peripheral blood of ICS-treated subjects with COPD (median 0.38%; interquartile range [IQR], 0.25-0.96) compared with healthy control subjects (1.8%; IQR, 1.4-2.5; P = 0.001) or steroid-naive patients with COPD (1.8%; IQR, 1.2-2.3; P = 0.04). MAIT cells were reduced in bronchial biopsies from subjects with COPD treated with steroids (0.73%; IQR, 0.46-1.3) compared with healthy control subjects (4.0%; IQR, 1.6-5.0; P = 0.02). Coculture of live NTHi increased macrophage surface expression of MR1 and induced IFN-gamma from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-gamma-positive frequencies, 2.9, 8.6, and 27.6%, respectively). In vitro fluticasone and budesonide reduced MR1 surface expression twofold and decreased NTHi-induced IFN-gamma secretion eightfold. CONCLUSIONS: MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naive, COPD. NTHi constitutes a target for pulmonary MAIT-cell immune responses, which are significantly impaired by corticosteroids. PMID- 27115409 TI - Surface heat shock protein 90 serves as a potential receptor for calcium oxalate crystal on apical membrane of renal tubular epithelial cells. AB - Adhesion of calcium oxalate monohydrate (COM) crystals on renal tubular epithelial cells is a crucial step in kidney stone formation. Finding potential crystal receptors on the apical membrane of the cells may lead to a novel approach to prevent kidney stone disease. Our previous study identified a large number of crystal-binding proteins on the apical membrane of MDCK cells. However, their functional role as potential crystal receptors had not been validated. The present study aimed to address the potential role of heat shock protein 90 (HSP90) as a COM crystal receptor. The apical membrane was isolated from polarized MDCK cells by the peeling method and recovered proteins were incubated with COM crystals. Western blot analysis confirmed the presence of HSP90 in the apical membrane and the crystal-bound fraction. Immunofluorescence staining without permeabilization and laser-scanning confocal microscopy confirmed the surface HSP90 expression on the apical membrane of the intact cells. Crystal adhesion assay showed that blocking surface HSP90 by specific anti-HSP90 antibody and knockdown of HSP90 by small interfering RNA (siRNA) dramatically reduced crystal binding on the apical surface of MDCK cells (by approximately 1/2 and 2/3, respectively). Additionally, crystal internalization assay revealed the presence of HSP90 on the membrane of endocytic vesicle containing the internalized COM crystal. Moreover, pretreatment of MDCK cells with anti-HSP90 antibody significantly reduced crystal internalization (by approximately 1/3). Taken together, our data indicate that HSP90 serves as a potential receptor for COM crystals on the apical membrane of renal tubular epithelial cells and is involved in endocytosis/internalization of the crystals into the cells. PMID- 27115410 TI - Natural Sources as Innovative Solutions Against Fungal Biofilms. AB - Fungal cells are capable of adhering to biotic and abiotic surfaces and form biofilms containing one or more microbial species that are microbial reservoirs. These biofilms may cause chronic and acute infections. Fungal biofilms related to medical devices are particularly responsible for serious infections such as candidemia. Nowadays, only a few therapeutic agents have demonstrated activities against fungal biofilms in vitro and/or in vivo. So the discovery of new anti biofilm molecules is definitely needed. In this context, biodiversity is a large source of original active compounds including some that have already proven effective in therapies such as antimicrobial compounds (antibacterial or antifungal agents). Bioactive metabolites from natural sources, useful for developing new anti-biofilm drugs, are of interest. In this chapter, the role of molecules isolated from plants, lichens, algae, microorganisms, or from animal or human origin in inhibition and/or dispersion of fungal biofilms (especially Candida and Aspergillus biofilms) is discussed. Some essential oils, phenolic compounds, saponins, peptides and proteins and alkaloids could be of particular interest in fighting fungal biofilms. PMID- 27115411 TI - Fungal Biofilms: Update on Resistance. AB - Over the past decade, the emergence of biofilm-related invasive fungal diseases has been the subject of numerous studies focused on antifungal resistance and its impact on antifungal therapy in severely ill patients. The majority of the studies investigated the molecular mechanisms involved in antifungal resistance and pathogenicity of biofilm production by Candida albicans and Aspergillus fumigatus, the most common etiologic agents of yeast and mold invasive infections. The main mechanism characterizing biofilm-related antifungal resistance is the production of extracellular matrix, a physical barrier preventing the drugs from entering and expressing their activity. However, over expression of efflux pumps, genetic changes of drug targets, persister cells, biofilm-host immune system interaction, proteins leading to filamentation, all together contribute to the onset of biofilm antifungal resistance. Some of these mechanisms are shared with planktonic cells and are often related to developmental phases of biofilm formation. All physical and genetic factors leading to biofilm-related antifungal resistance have been briefly discussed. PMID- 27115412 TI - Glucagon is the key factor in the development of diabetes. AB - Glucagon plays important roles in normal glucose homeostasis and in metabolic abnormalities, particularly diabetes. Glucagon excess, rather than insulin deficiency, is essential for the development of diabetes for several reasons. Glucagon increases hepatic glucose and ketone production, the catabolic features of insulin deficiency. Hyperglucagonaemia is present in every form of diabetes. Beta cell destruction in glucagon receptor null mice does not cause diabetes unless mice are administered adenovirus encoding the glucagon receptor. In rodent studies the glucagon suppressors leptin and glucagon receptor antibody suppressed all catabolic manifestations of diabetes during insulin deficiency. Insulin prevents hyperglycaemia; however, insulin monotherapy cannot cure diabetes such that non-diabetic glucose homeostasis is achieved. Glucose-responsive beta cells normally regulate alpha cells, and diminished insulin action on alpha cells will favour hypersecretion of glucagon by the alpha cells, thus altering the insulin:glucagon ratio. Treating diabetes by suppression of glucagon, with leptin or antibody against the glucagon receptor, normalised glucose level (without glycaemic volatility) and HbA1c. Glucagon suppression also improved insulin sensitivity and glucose tolerance. If these results can be translated to humans, suppression of glucagon action will represent a step forward in the treatment of diabetes. This review summarises a presentation given at the 'Novel data on glucagon' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Mona Abraham and Tony Lam, DOI: 10.1007/s00125-016-3950-3 , and by Russell Miller and Morris Birnbaum, DOI: 10.1007/s00125-016-3955-y ) and an overview by the Session Chair, Isabel Valverde (DOI: 10.1007/s00125-016-3946-z ). PMID- 27115413 TI - The power of numbers. PMID- 27115414 TI - An overview of glucagon research. PMID- 27115415 TI - Glucagon: acute actions on hepatic metabolism. AB - Type 2 diabetes mellitus is the result of impaired systemic control of glucose homeostasis, in part through the dysregulation of the hormone glucagon. Glucagon acts on the liver to increase glucose production through alterations in hepatic metabolism, and reducing the elevated glucagon signalling in diabetic patients is an attractive strategy for the treatment of hyperglycaemia. Here we review the actions of the hormone in the liver, focusing on the acute alterations of metabolic pathways. This review summarises a presentation given at the 'Novel data on glucagon' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Mona Abraham and Tony Lam, DOI: 10.1007/s00125-016-3950-3 , and by Young Lee and colleagues, DOI: 10.1007/s00125-016-3965-9 ) and an overview by the Session Chair, Isabel Valverde (DOI: 10.1007/s00125-016-3946-z ). PMID- 27115416 TI - Glucagon action in the brain. AB - In recent years, novel discoveries have reshaped our understanding of the biology of brain glucagon in the regulation of peripheral homeostasis. Here we compare and contrast brain glucagon action in feeding vs glucose regulation and depict the physiological relevance of brain glucagon by reviewing their actions in two key regions of the central nervous system: the mediobasal hypothalamus and the dorsal vagal complex. These novel findings pave the way to future therapeutic strategies aimed at enhancing brain glucagon action for the treatment of diabetes and obesity. This review summarises a presentation given at the 'Novel data on glucagon' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Young Lee and colleagues, DOI: 10.1007/s00125-016-3965-9 ), and by Russell Miller and Morris Birnbaum, DOI: 10.1007/s00125-016-3955-y ) and an overview by the Session Chair, Isabel Valverde (DOI: 10.1007/s00125-016-3946-z ). PMID- 27115417 TI - C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21. AB - AIMS/HYPOTHESIS: Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy. METHODS: Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2) like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2 knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]). RESULTS: Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis. CONCLUSIONS/INTERPRETATION: The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21. PMID- 27115418 TI - To Revascularise or Not To Revascularise, That Is the Question: the Diagnostic and Management Conundrum of Ischaemic Cardiomyopathy. AB - Ischaemic cardiomyopathy is an important cardiovascular condition that has differing pathophysiological substrates and clinical manifestations. Contemporary management involves the administration of heart failure pharmacotherapy and device therapy where indicated, which has good prognostic data to support it. Whilst the role of revascularisation is clear in those patients presenting with an acute coronary syndrome or angina, the role in those patients presenting either incidentally, with predominant heart failure symptoms, or in those presenting with acute heart failure with an associated elevated troponin is less well defined and lacks randomised outcome data to support its adoption. The aim of this review is therefore to discuss the challenges in the diagnosis of ischaemic cardiomyopathy with a review of the existing imaging modalities that can facilitate, and to revisit the variety of clinical presentations that can occur, with particular emphasis on the contemporary role of revascularisation in these cohorts of patients. PMID- 27115419 TI - Effects of Erosion Protocol Design on Erosion/Abrasion Study Outcome and on Active Agent (NaF and SnF2) Efficacy. AB - There is no standard for testing anti-erosive/anti-abrasive agents, making the assessment and comparison of study results difficult. Factors which are varied in study designs are amongst others the erosive medium regarding concentration and pH or movement type of acid. The present study therefore investigated the impact of these factors on dimension of tissue loss and on efficacy of active agents used as anti-erosive/anti-abrasive therapeutics. In 8 experiments, consisting of 8 groups each (n = 20 each), resulting in a total of 64 groups, enamel specimens were demineralised (10 days, 6 * 2 min/day) using different acids (1, 0.5 and 0.3% citric acid at native pH 2.3, 2.5 and 2.8, respectively, and 0.3% citric acid adjusted to pH 3.6) with two different movement types (jerky or smooth). Specimens were immersed (2 * 2 min/day) in slurries of 1,450 ppm F- toothpaste (NaF), 1,450 ppm F- and 3,436 ppm Sn2+ toothpaste (NaF/SnF2), 970 ppm F- and 3,000 ppm Sn2+ gel (SnF2) or placebo, or were additionally brushed during immersion (15 s, 200 g). All groups were in between stored in a mineral salt solution. Tissue loss was determined profilometrically. Movement type, pH and concentration of acid had a substantial impact on study outcome. The combination of jerky movement and concentrated acid masked, to some extent, differences between erosive and erosive-abrasive tissue loss. The acid at low concentration (0.3%), independent of pH, was too mild to produce any tissue loss. The model with the best ability to demonstrate effects of abrasive impacts and active agents used the 1% acid concentration combined with smooth acid movements. PMID- 27115420 TI - Gdf-15 deficiency does not alter vulnerability of nigrostriatal dopaminergic system in MPTP-intoxicated mice. AB - Growth/differentiation factor-15 (Gdf-15) is a member of the transforming growth factor-beta (Tgf-beta) superfamily and has been shown to be a potent neurotrophic factor for midbrain dopaminergic (DAergic) neurons both in vitro and in vivo. Gdf 15 has also been shown to be involved in inflammatory processes. The aim of this study was to identify the role of endogenous Gdf-15 in the MPTP (1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease (PD) by comparing Gdf-15 (+/+) and Gdf-15 (-/-) mice. At 4 days and 14 days post-MPTP administration, both Gdf-15 (+/+) and Gdf-15 (-/-) mice showed a similar decline in DAergic neuron numbers and in striatal dopamine (DA) levels. This was followed by a comparable restorative phase at 90 days and 120 days, indicating that the absence of Gdf-15 does not affect the susceptibility or the recovery capacity of the nigrostriatal system after MPTP administration. The MPTP-induced microglial and astrocytic response was not significantly altered between the two genotypes. However, pro-inflammatory and anti-inflammatory cytokine profiling revealed the differential expression of markers in Gdf-15 (+/+) and Gdf-15 (-/-) mice after MPTP administration. Thus, the MPTP mouse model fails to uncover a major role of endogenous Gdf-15 in the protection of MPTP-lesioned nigrostriatal DAergic neurons, in contrast to its capacity to protect the 6-hydroxydopamine-intoxicated nigrostriatal system. PMID- 27115421 TI - Discovery and complete genome sequence of a novel circovirus-like virus in the endangered rowi kiwi, Apteryx rowi. AB - Circoviruses are circular, non-enveloped, single-stranded DNA viruses around 2000 nucleotides (nt) in length and include the pathogenic species, Porcine circovirus 1 and Beak and feather disease virus, capable of causing significant morbidity and mortality. This group of viruses may be robust to degradation by external environments, and avian circoviruses are known to move between closely related hosts. Using a de novo metagenomic approach, followed by confirmatory PCR, we identify for the first time a circular Rep-encoding single-stranded (CRESS) DNA virus in New Zealand kiwi, Apteryx spp., derived from faecal matter of the rowi kiwi (A. rowi) showing signs of verminous dermatitis. The entire 2085 nt genome was cloned and sequenced and contains both capsid and replicase genes, as well as a conserved 9 nt motif. Phylogenetic analyses place it within Circoviridae, adjacent to other environmental CRESS-DNA viruses, and most closely related to badger circovirus-like virus (Meles meles circovirus-like virus). As the rowi is the most critically endangered kiwi, it is vital to understand the role of rowi kiwi circovirus-like virus as a possible pathogen and also any potential cross species transmission. PMID- 27115422 TI - Distribution and source apportionment studies of heavy metals in soil of cotton/wheat fields. AB - Heavy metals enriched agricultural soils have been the subject of great concern because these metals have potential to be transferred to the soil solution and afterward accumulated in food chain. To study the trace metal persistence in crop soil, 90 representative soil samples were collected and analyzed for heavy metal (As, Cd, Cu, Fe, Mn, Ni, Pb, and Zn) and anions (chloride, nitrates, phosphates and sulfates). Cluster and factor analysis techniques were used for the source identification of these excessive heavy metal levels and ecological risk was determined with potential ecological risk assessment. The degree of enrichment of eight studied heavy metals in comparison with the corresponding background levels decreased in order: Cd > Pb > Fe > Ni > Mn > As > Cu ~ Zn. Arsenic and cadmium exhibited 1.30- and 1.64-fold exceeded levels than threshold limits set by National environment quality standards, respectively. Cd in cotton field's soil may lead to higher potential risk than other heavy metals. On overall basis, the cumulative mean potential ecological risk for the district (207.75) corresponded to moderate risk level with higher contributions from As and Pb especially from Cd. Cadmium formed strong positive correlation with phosphate content of soil at p < 0.01. Cluster analysis indicated that Cluster 1 (extremely polluted) probably originated from anthropogenic inputs of phosphate fertilizer and past usage of arsenical pesticides. PMID- 27115423 TI - Clinical significance of atypical glandular cells in Pap tests: An analysis of more than 3000 cases at a large academic women's center. AB - BACKGROUND: The interpretation of atypical glandular cells (AGC) in Papanicolaou (Pap) tests and screening for glandular neoplasia remain challenging. METHODS: Pap tests with an AGC interpretation from January 2008 to December 2013 were retrieved from a pathology database, and cases with histologic follow-up within 1 year were included in the study. RESULTS: There were 589,830 Pap tests during the study period, and 3709 cases (0.6%) were reported as AGC, which included the following: AGC, not otherwise specified (52.0%); atypical endocervical cells (28.0%); and other categories. There were 3007 cases (81.1%) with histologic follow-up results within 1 year. Cervical intraepithelial neoplasia 2/3 (CIN2/3), cervical adenocarcinoma in situ (AIS)/adenocarcinoma, and endometrial carcinoma were identified in 5.6%, 1.9%, and 5.5% of cases, respectively. Glandular neoplasia was more likely to be identified in cases with pure AGC subcategories than cases with AGC and squamous abnormalities. Endometrial neoplasia was more likely to be identified in cases with atypical endometrial cells than other categories. Overall, the most common severe abnormality on histologic follow-up was CIN2/3. Although CIN2/3 was the most common severe lesion in patients younger than 30 years (10.0%) and in patients aged 30 to 49 years (6.4%), endometrial carcinoma was the most common lesion in women who were 50 years old or older (13.7%). Endocervical glandular lesions (AIS and adenocarcinoma) occurred in only 1.9% of women. CONCLUSIONS: AGC subtypes and ages significantly affect histological follow-up results; 90.5% of cases with carcinoma on histologic follow-up were either endometrial or metastatic carcinoma. This study supports the recommendation that women with AGC Pap test results should be followed up with both endocervical and endometrial sampling. Cancer Cytopathol 2016;124:589 95. (c) 2016 American Cancer Society. PMID- 27115424 TI - Comparison between two different parameters of argon plasma coagulation in the treatment of chronic radiation proctopathy. PMID- 27115425 TI - Radiation target volume definition after induction chemotherapy in locally advanced rectal cancer. PMID- 27115426 TI - Solution-Processable High-Purity Semiconducting SWCNTs for Large-Area Fabrication of High-Performance Thin-Film Transistors. AB - For the large-area fabrication of thin-film transistors (TFTs), a new conjugated polymer poly[9-(1-octylonoyl)-9H-carbazole-2,7-diyl] is developed to harvest ultrahigh-purity semiconducting single-walled carbon nanotubes. Combined with spectral and nanodevice characterization, the purity is estimated up to 99.9%. High density and uniform network formed by dip-coating process is liable to fabricate high-performance TFTs on a wafer-scale and the as-fabricated TFTs exhibit a high degree of uniformity. PMID- 27115427 TI - Clickable Photoaffinity Ligands for Metabotropic Glutamate Receptor 5 Based on Select Acetylenic Negative Allosteric Modulators. AB - G protein-coupled receptors (GPCRs) represent the largest class of current drug targets. In particular, small-molecule allosteric modulators offer substantial potential for selectively "tuning" GPCR activity. However, there remains a critical need for experimental strategies that unambiguously determine direct allosteric ligand-GPCR interactions, to facilitate both chemical biology studies and rational structure-based drug design. We now report the development and use of first-in-class clickable allosteric photoprobes for a GPCR based on metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulator (NAM) chemotypes. Select acetylenic mGlu5 NAM lead compounds were rationally modified to contain either a benzophenone or an aryl azide as a photoreactive functional group, enabling irreversible covalent attachment to mGlu5 via photoactivation. Additionally, a terminal alkyne or an aliphatic azide was incorporated as a click chemistry handle, allowing chemoselective attachment of fluorescent moieties to the irreversibly mGlu5-bound probe via tandem photoaffinity labeling bioorthogonal conjugation. These clickable photoprobes retained submicromolar affinity for mGlu5 and negative cooperativity with glutamate, interacted with the "common allosteric-binding site," displayed slow binding kinetics, and could irreversibly label mGlu5 following UV exposure. We depleted the number of functional mGlu5 receptors using an irreversibly bound NAM to elucidate and delineate orthosteric agonist affinity and efficacy. Finally, successful conjugation of fluorescent dyes via click chemistry was demonstrated for each photoprobe. In the future, these clickable photoprobes are expected to aid our understanding of the structural basis of mGlu5 allosteric modulation. Furthermore, tandem photoaffinity labeling-bioorthogonal conjugation is expected to be a broadly applicable experimental strategy across the entire GPCR superfamily. PMID- 27115428 TI - The safety and efficacy of olaparib therapy in patients with relapsed ovarian cancer. AB - INTRODUCTION: PARP inhibition is an exciting new anticancer strategy. Olaparib has recently obtained a first in class license in Europe and the USA for the treatment of relapsed BRCA-mutant ovarian cancer. AREAS COVERED: We review the key preclinical and clinical data surrounding its use in the maintenance setting. Expert commentary: We also consider the market profile, regulatory issues surrounding the agent and offer a five year speculative viewpoint of its future development in ovarian cancer. PMID- 27115429 TI - Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants. AB - Patterns of disease co-occurrence that deviate from statistical independence may represent important constraints on biological mechanism, which sometimes can be explained by shared genetics. In this work we study the relationship between disease co-occurrence and commonly shared genetic architecture of disease. Records of pairs of diseases were combined from two different electronic medical systems (Columbia, Stanford), and compared to a large database of published disease-associated genetic variants (VARIMED); data on 35 disorders were available across all three sources, which include medical records for over 1.2 million patients and variants from over 17,000 publications. Based on the sources in which they appeared, disease pairs were categorized as having predominant clinical, genetic, or both kinds of manifestations. Confounding effects of age on disease incidence were controlled for by only comparing diseases when they fall in the same cluster of similarly shaped incidence patterns. We find that disease pairs that are overrepresented in both electronic medical record systems and in VARIMED come from two main disease classes, autoimmune and neuropsychiatric. We furthermore identify specific genes that are shared within these disease groups. PMID- 27115430 TI - Predictors of Treatment Attrition Among Adult Outpatients With Clinically Significant Suicidal Ideation. AB - OBJECTIVE: To identify demographic, diagnostic, and personality factors that predict treatment dropout in a sample of outpatients with clinically significant suicidal ideation. METHOD: A total of 287 adult outpatients at elevated risk for suicide completed self-report measures of demographics, suicidal and depression symptoms, and personality characteristics at treatment intake. Clinician-assessed psychiatric diagnoses and ratings of overall functioning also were collected. RESULTS: Lower overall functioning (odds ratio [OR] = .947; 95% confidence interval [CI] [.909, .987]) and the presence of a substance use disorder (OR = 4.543; 95% CI [1.058, 19.499]) were the most robust predictors of attrition. Dropouts also were more likely to have a depressive disorder, more comorbid diagnoses, and more severe depression and suicidal symptoms. CONCLUSIONS: Findings suggest that clinician-assessed poorer overall functioning and a substance use disorder diagnosis are risk factors for attrition among suicidal individuals, above and beyond other symptom measures. Further research is warranted to investigate attrition in additional outpatient samples. PMID- 27115431 TI - Clinical utility of HCV core antigen detection and quantification in the diagnosis and management of patients with chronic hepatitis C receiving an all oral, interferon-free regimen. AB - BACKGROUND: The introduction of highly potent direct-acting combination therapies for HCV have negated the role of response-guided therapy and reduced the role of treatment monitoring. However, there remains a need to identify patients who are actively infected with HCV and discriminate those who have achieved sustained virological response (SVR) from those who fail to achieve SVR. METHODS: A total of 1,678 plasma samples from the 631 subjects enrolled in AbbVie's SAPPHIRE I trial (NCT01716585) were tested in a blinded fashion with Abbott HCV core antigen (cAg) assay and results were compared with Roche High-Pure system/COBAS(r) TaqMan HCV RNA 2.0 assay. RESULTS: Using 10 fmol/l as the clinical cutoff for cAg, the HCV RNA and cAg tests were in 100% agreement for true negative samples and 99.6% agreement for truly positive samples. One discordant (screening) sample was identified. This sample was target not detected by HCV RNA method but positive by anti-HCV and highly positive by ARCHITECT core antigen (7,912 fmol/l). Seventeen samples had cAg levels in the 'grey zone' >3 but <10 fmol/l at initial testing and were re-tested per package insert. All of these samples gave a result of <3 fmol/l upon retest. These results were in alignment with target not detected HCV RNA result. One sample had a cAg >3 but <10 fmol/l when tested on three consecutive occasions (5.8, 5.5 and 4.4) but had a target not detected RNA result. CONCLUSIONS: In this study cAg, with a 10 fmol/l cutoff, accurately identified 99.6% of patients with active viraemia and discriminated all subjects who achieved SVR from those who failed therapy. PMID- 27115446 TI - Condensation in Nanoporous Packed Beds. AB - In materials with tiny, nanometer-scale pores, liquid condensation is shifted from the bulk saturation pressure observed at larger scales. This effect is called capillary condensation and can block pores, which has major consequences in hydrocarbon production, as well as in fuel cells, catalysis, and powder adhesion. In this study, high pressure nanofluidic condensation studies are performed using propane and carbon dioxide in a colloidal crystal packed bed. Direct visualization allows the extent of condensation to be observed, as well as inference of the pore geometry from Bragg diffraction. We show experimentally that capillary condensation depends on pore geometry and wettability because these factors determine the shape of the menisci that coalesce when pore filling occurs, contrary to the typical assumption that all pore structures can be modeled as cylindrical and perfectly wetting. We also observe capillary condensation at higher pressures than has been done previously, which is important because many applications involving this phenomenon occur well above atmospheric pressure, and there is little, if any, experimental validation of capillary condensation at such pressures, particularly with direct visualization. PMID- 27115447 TI - Dynamic Chiral Nanoparticle Assemblies and Specific Chiroplasmonic Analysis of Cancer Cells. AB - Fabricated Ag@Au core-shell nanoparticle (CS NP) assemblies exhibit pronounced and reverse chiral bisignate plasmonic signals spanning 400 to 580 nm, in comparison to Ag NP assemblies. The time-dependent chiro-optical response of assemblies that shift with shell deposition is systematically recorded. Chiral Ag@Au CS NP assemblies first achieve the special discrimination of circulating tumor cells with HER2 overexpression. PMID- 27115448 TI - CT-assessed large airway involvement and lung function decline in eosinophilic asthma: The association between induced sputum eosinophil differential counts and airway remodeling. AB - OBJECTIVES: Eosinophilic asthma (EA) is a distinct clinical phenotype characterized by eosinophilic airway inflammation and airway remodeling. Few studies have used computed tomography (CT) scanning to assess the association between sputum eosinophil differential counts and airway involvement. We aimed to investigate the clinical characteristics and airway involvement of EA, and to examine the correlation between induced sputum eosinophil differential counts and CT-assessed airway remodeling. METHODS: We retrospectively divided 63 patients with stable asthma receiving inhaled corticosteroids into 2 groups: 26 patients with EA (sputum eosinophil >3%) and 37 patients with non-eosinophilic asthma (NEA). Clinical measurements such as spirometry, fractional exhaled nitric oxide levels (FeNO), and CT-assessed indices of airway involvement were compared between the groups. Multivariate analysis was performed to identify determinants of the percentage of wall area (WA%). RESULTS: The EA group had significantly longer asthma duration, lower pulmonary function, and higher FeNO than the NEA group. Also, the EA group had higher WA% and smaller airway luminal area than the NEA group. Sputum eosinophil differential counts and WA% were positively correlated. The multivariate linear regression analysis showed that the factors associated with WA% included sputum eosinophil differential counts, age, and body mass index. However, asthma duration was not associated with WA%. Our CT-assessed findings demonstrated large airway involvement in EA, and we observed a positive association between induced sputum eosinophil differential counts and WA%. CONCLUSIONS: The findings indicate that induced sputum eosinophil differential counts may be associated with airway remodeling in patients with stable asthma. PMID- 27115449 TI - Former Military Nurse Officers: One Answer to the Faculty Shortage? PMID- 27115450 TI - Work Factors of Importance to Adjunct Nursing Faculty. AB - BACKGROUND: The use of adjunct faculty has increased exponentially in the past decade. It is essential that resources to retain adjuncts are identified and made available to adjunct faculty. To identify the appropriate factors, it is essential to discover what nursing adjunct instructors perceive to be the factors of importance to their work role. The purpose of the article was to determine the perceived factors of importance and availability of work role needs of adjunct faculty. METHOD: A quantitative, exploratory design was developed, using an anonymous online Adjunct Instructor Likert Scale Survey. The sample included participating adjunct instructors from a possible total of 91 midsized, midwestern baccalaureate nursing programs. RESULTS: Fourteen of 18 pairs were significantly different (p < .05) in adjunct perception. CONCLUSION: Using these data, colleges of nursing may be able to identify adjunct work factors in that can be improved to increase adjunct faculty recruitment, satisfaction, and retention. [J Nurs Educ. 2016;55(5):245-251.]. PMID- 27115451 TI - The Flipped Learning Approach in Nursing Education: A Literature Review. AB - BACKGROUND: This integrative review examines the application of the pedagogical methodology-the flipped classroom-in nursing education. METHOD: A literature search of the CINAHL, ERIC, and the National Library of Medicine (PubMed and MEDLINE) databases was conducted, using the following key words: flipped classroom, inverted classroom, and nursing education. RESULTS: Results of a literature search yielded 94 articles, with 13 meeting the criteria of the flipped classroom approach in nursing education. Themes identified include the theoretical underpinning, strategies for implementation of a flipped classroom, and student satisfaction with and outcomes of the flipped classroom approach. CONCLUSION: Syntheses of the findings indicate that the flipped classroom approach can yield positive outcomes, but further study of this methodology is needed to guide future implementation. [J Nurs Educ. 2016;55(5):252-257.]. PMID- 27115452 TI - Effects of Associate Degree Nursing Students' Characteristics on Perceptions and Experiences of Mentoring. AB - BACKGROUND: Mentoring has been identified as a key education program support structure to facilitate student success. METHOD: A cross-sectional study was conducted to investigate how associate degree nursing program students experience mentoring and persistence. Mentoring perceptions were evaluated using the College Student Mentoring Scale. Associate degree nursing students throughout the state of Michigan were recruited for an online survey. RESULTS: Sample characteristics (N = 283) resembled those compiled by the National League for Nursing. The study found that men met with a mentor more frequently and perceived greater psychological, emotional, and academic support than women. Part-time students and students who had never failed a nursing course also reported they met more frequently with a mentor than full-time students and those who had failed a nursing course. CONCLUSION: The findings contribute to an evidence base to support the further development and evaluation of mentoring programs for nursing students. [J Nurs Educ. 2016;55(5):258-265.]. PMID- 27115453 TI - Improving Pressure Ulcer Staging Accuracy Through a Nursing Student Experiential Intervention. AB - BACKGROUND: Staging of pressure ulcers (PUs) is often inaccurate. The purpose of this study was to evaluate the effectiveness of a student-focused intervention to improve PU staging accuracy in nursing students. METHOD: Nursing students from two universities were included. The control group (n = 103) received a standard lecture about PUs; the intervention group (n = 55) completed a PU module, participated in Skin Day at a local hospital, and received the standard lecture. All students completed a PU staging tool to determine their staging accuracy. Scores were compared using analysis of variance. RESULTS: Students in the intervention group were significantly more accurate in PU staging, especially stage II PUs and suspected deep tissue injury. Stage III PUs were the most difficult to stage for all students. CONCLUSION: Skin Day provided students with hands-on clinical experience, which assisted them in becoming better at staging PUs. This type of experiential opportunity should be considered for all students, as accurate staging is necessary for best practice adherence. [J Nurs Educ. 2016;55(5):266-270.]. PMID- 27115454 TI - Stakeholder Perceptions, Learning Opportunities, and Student Outcomes in Three Clinical Learning Models. AB - BACKGROUND: Understanding the strengths and challenges of various clinical models is important for nursing education. METHOD: Three long-standing clinical models (preceptored, hybrid, and traditional) were compared on several outcome measures related to satisfaction, learning opportunities, and student outcomes. Students, faculty, and preceptors participated in this study. RESULTS: Although no differences were noted in satisfaction or standardized examination scores, students in the preceptored clinical model were able to practice more psychomotor skills. Although participants in the preceptored model reported spending more time communicating with staff nurses than did those in the other models, students in the traditional model spent more time with faculty. No differences were noted among groups in student clinical observation time. CONCLUSION: All clinical learning models were focused on how clinical time was structured, without an emphasis on how faculty and preceptors work with students to develop nursing clinical reasoning skills. Identifying methodology to impact thinking in the clinical environment is a key next step. [J Nurs Educ. 2016;55(5):271-277.]. PMID- 27115455 TI - Senior Nursing Students' Perceptions of Caring for Patients at the End of Life. AB - BACKGROUND: Nursing students often feel unprepared to provide end-of-life care. Studies have examined students' learning outcomes and attitudes regarding end-of life care, but it is unclear how students perceived their nursing program prepared them in both knowledge and confidence. Such research could help inform curricula revisions. METHOD: This pilot study used a primarily qualitative approach with narrative questions and quantitative survey questions to a lesser degree. Seventy-one students from three baccalaureate nursing cohorts were participants. RESULTS: Five themes became apparent: Students Have Confidence in Provision of Physical Care, Students Lack Confidence in Provision of Emotional Care, Students Experience Stress and Lack of Knowledge When Caring for Families, Students Have Concern They Will Be Too Emotionally Involved, and Students Feel Personal Experiences Enhance Their Confidence. CONCLUSION: Student perceptions are important to consider when revising curricula to enhance learning and promote confidence in addressing emotional care at the end of life. [J Nurs Educ. 2016;55(5):279-283.]. PMID- 27115456 TI - Building Graduate Student Capacity as Future Researchers Through a Research and Training Award Program. AB - BACKGROUND: With the global shortage of doctor of philosophy-prepared nursing faculty and an aging nursing professorate, the nursing profession is at risk of having fewer nurses doing research and fewer faculty to supervise the next generation of nurse researchers. METHOD: A research training award for graduate nursing students was piloted with the intent of providing a research-intensive experiential learning opportunity that would contribute to graduate students' future roles as nurse researchers. This article describes the program design, implementation, and evaluation. FINDINGS: The Graduate Student Research Training Awards afforded students an opportunity to develop research and methodologic skills and achieve student-centered outcomes. These awards build their capacity as future researchers by both empowering them and increasing their confidence in research. The input and evaluation from graduate students was integral to the success of the program. CONCLUSION: Graduate student research training awards can be a valuable experiential learning opportunity in research intensive graduate programs. [J Nurs Educ. 2016;55(5):284-287.]. PMID- 27115457 TI - Teaching Nursing Students the Importance of Treatment Fidelity in Intervention Research: Students as Interventionists. AB - BACKGROUND: Treatment fidelity is the extent to which a study team adheres to the dictates of a study protocol. It ensures that the intervention has been implemented as intended. Including and monitoring treatment fidelity reduces threats to validity and is vital to providing reputable, sound research. METHOD: This article describes specific measures taken to teach nursing students the key concepts and methodologic issues associated with treatment fidelity in intervention research studies through active learning. Twelve senior-level nursing students participated as interventionists in a study that spanned 4 months. RESULTS: Treatment fidelity strategies included development of a manual, proper training and supervision of interventionists, a follow-up meeting with the interventionists, checklists, and a controller. CONCLUSION: The treatment fidelity strategies implemented throughout the study provided an opportunity for students to learn firsthand how such strategies are implemented and how they strengthened the confidence that study findings are indeed related to the intervention. [J Nurs Educ. 2016;55(5):288-291.]. PMID- 27115458 TI - A Case-Based Curriculum With the Nurse as Coach. AB - BACKGROUND: Nurses need new skill sets that emphasize health outcomes and cost reduction. A bachelor of science in nursing (BSN) program partnered with community agencies to design a curriculum to address these skills. METHOD: Two focus groups were conducted with 24 participants employed as care coordinators, nurse coaches, or health navigators. RESULTS: Three themes and subgroups emerged that guided a curriculum design that emphasized case-based rather than place based client focus, coaching as a curriculum thread, and new and varied community experiences. Community health concepts were introduced early and reinforced throughout. Health coaching was identified as a powerful framework and tool to address client needs. Further study is needed to measure outcomes of the new curriculum. CONCLUSION: Changing paradigms in nursing education is challenging. Care coordination and coaching skills can broaden the competency base of RNs and can be included in a BSN curriculum. More study is needed to measure outcomes. [J Nurs Educ. 2016;55(5):292-295.]. PMID- 27115459 TI - Using Interactive Video-Based Teaching to Improve Nursing Students' Ability to Provide Patient-Centered Discharge Teaching. AB - BACKGROUND: Nursing students rarely are afforded the opportunity to provide discharge teaching in the acute care environment, especially at the sophomore level. METHOD: Three video modules were developed that presented examples of effective and ineffective education for patients with complex chronic conditions. Students viewed modules during postconference using portable technology. A training manual that included objectives, lesson plans, evidence-based teaching points, and a discussion model guided presentation. RESULTS: The modules were presented to 216 sophomore nursing students. Following course completion, 20 students and 10 faculty were randomly selected to participate in two focus groups. Students commented positively on the format and illustration of effective teaching. Faculty rated the teaching strategy positively and the format as easy to use. CONCLUSION: Interactive video modules can be used to foster patient teaching skills early in the nursing curriculum. Future studies are needed to evaluate the ability to transfer skills learned to the clinical setting. [J Nurs Educ. 2016;55(5):296-299.]. PMID- 27115460 TI - Building Genetic Competence Through Partnerships and Interactive Models. AB - BACKGROUND: Nurses are increasingly using genetic-directed therapies in routine care, but evidence indicates that nurse educators lack knowledge about basic genetic concepts and related clinical implications. Educators are the key to preparing future nurses for effective practice in the genomic era, and creative approaches are needed for faculty development. METHOD: Nurse educators in academic and clinical settings partnered with science educators who use sophisticated DNA, RNA, and protein models to explore ways to teach abstract genetic concepts. RESULTS: Hands-on learning enabled the workshop participants to understand how transcription of gene mutations leads to the translation of defective proteins responsible for specific diseases. Participants found using the models helped clarified complex concepts that occur at the cellular level. CONCLUSION: Partnerships with science educators can address gaps in nurse educators' knowledge about genetics and introduce creative teaching strategies. [J Nurs Educ. 2016;55(5):300-303.]. PMID- 27115461 TI - Learning Argentine Tango to Develop Nursing Student Empathy for Patients. PMID- 27115462 TI - The Effects of a Single Session of Music Therapy on the Agitated Behaviors of Patients Receiving Hospice Care. AB - BACKGROUND: Research suggests that agitation is a common symptom for hospice patients, but while studies have examined the outcomes of music therapy on the agitated behaviors of patients in other settings, none have addressed this symptom in patients with terminal illnesses. OBJECTIVE: The study objective was to determine whether a single session of music therapy provided by a board certified music therapist and using the entrainment principle would decrease agitation in hospice patients. DESIGN: This pilot study was a single-blind, pretest/posttest design. Music therapists used the principle of entrainment with live music during the treatment session. SETTING/SUBJECTS: Subjects included in the study were 77 patients at a large hospice in south Florida with documented agitation. MEASUREMENTS: Agitation was measured using the Overt Agitation Severity Scale (OASS) for 5 minutes prior to and 5 minutes following a 20 minute music therapy intervention. RESULTS: Results from 73 participants were analyzed with a mean difference of -5.77 points from pretest to posttest. Results indicating a decrease in agitation were statistically significant (p < 0.001) for the entire sample. Age, gender, location, and diagnosis were found to have no significant effects on the results. CONCLUSIONS: Results indicate that a single session of music therapy using the entrainment principle may be an effective treatment for hospice patients experiencing agitation. PMID- 27115463 TI - Development and Applications of Transesterification Reactions Catalyzed by N Heterocyclic Olefins. AB - A novel method to utilize N-heterocyclic olefins (NHOs), the alkylidene derivatives of N-heterocycic carbenes, as organocatalysts to promote transesterification reactions has been developed. Because of their strong Bronsted/Lewis basicity, NHOs can enhance the nucleophilicity of alcohols for their acylation reactions with carboxylic esters. This transformation can be employed in industrially relevant processes such as the production of biodiesel, the depolymerization of polyethylene terephthalate (PET) from plastic bottles for recycling purposes, and the ring-opening polymerization of cyclic esters to form biodegradable polymers such as polylactide (PLA) and polycaprolactone (PCL). PMID- 27115464 TI - Nanoscale View of Dewetting and Coating on Partially Wetted Solids. AB - There remain significant gaps in our ability to predict dewetting and wetting despite the extensive study over the past century. An important reason is the absence of nanoscopic knowledge about the processes near the moving contact line. This experimental study for the first time obtained the liquid morphology within 10 nm of the contact line, which was receding at low speed (U < 50 nm/s). The results put an end to long-standing debate about the microscopic contact angle, which turned out to be varying with the speed as opposed to the constant-angle assumption that has been frequently employed in modeling. Moreover, a residual film of nanometer thickness ubiquitously remained on the solid after the receding contact line passed. This microscopic residual film modified the solid surface and thus made dewetting far from a simple reverse of wetting. A complete scenario for dewetting and coating is provided. PMID- 27115465 TI - Expression of the chemokine CXCL14 in the tumour stroma is an independent marker of survival in breast cancer. AB - BACKGROUND: Expression of the chemokine CXCL14 has previously been shown to be elevated in the tumour stroma of, for example, prostate and breast cancer. Cancer associated fibroblast-derived CXCL14 enhances tumour growth in mouse models of prostate and breast cancer. However, the prognostic significance of compartment specific expression of CXCL14 has not been studied. METHODS: CXCL14 mRNA expression was analysed in a breast cancer tissue microarray (TMA) of formalin fixed, paraffin-embedded tumours by the RNAscope 2.0 Assay. Epithelial and stromal expression was analysed separately and correlated with clinicopathological characteristics and survival. RESULTS: CXCL14 was variably and independently expressed in malignant and stromal cells of breast cancer. Total and stromal expression of CXCL14 did not associate with clinicopathological parameters. Epithelial CXCL14 expression was significantly associated with oestrogen receptor alpha (ERalpha)-positive tumours and lower proliferation status. Total CXCL14 expression correlated significantly with shorter breast cancer-specific and recurrence-free survival. High stromal, but not epithelial, CXCL14 expression was significantly associated with shorter survival in univariable and multivariable analyses. Moreover, the correlation between stromal CXCL14 expression and survival was more prominent in ER negative, triple negative and basal-like breast cancers. CONCLUSIONS: The identification of prognostic significance of stromal CXCL14 in breast cancer demonstrates novel clinical relevance of a stroma-derived secreted factor and illustrates the importance of tumour compartment-specific analyses. On the basis of the prognostic signals from difficult-to-treat subgroups, CXCL14 should also be considered as a candidate drug target. PMID- 27115466 TI - Use of tricyclic antidepressants and risk of glioma: a nationwide case-control study. AB - BACKGROUND: A protective effect of tricyclic antidepressants (TCAs) against gliomas has been suggested by a small number of studies. We investigated this putative association in a nationwide setting. METHODS: Using a case-control design, we identified all patients with histologically verified glioma (cases) in Denmark between 2000 and 2012 and matched these 1 : 20 to population controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) for glioma associated with long-term (?3 years) use of TCAs. Similar analyses were performed for selective serotonin reuptake inhibitors (SSRIs). RESULTS: We identified 3767 glioma cases and 75 340 population controls. Long-term use of TCAs was inversely associated with risk of glioma (OR 0.72, 95% CI: 0.41-1.25). Long-term SSRI use was not associated with glioma risk (OR 0.93, 95% CI: 0.75 1.16). CONCLUSIONS: Our study indicated that long-term use of TCAs may be associated with a reduced risk of glioma, however, the statistical precision was limited. A similar pattern was not observed for use of SSRIs. PMID- 27115467 TI - Impact of partial bivalent HPV vaccination on vaccine-type infection: a population-based analysis. AB - BACKGROUND: Data on the effectiveness of one dose of HPV vaccine are lacking, particularly in population-based settings. Data from a national HPV immunisation catch-up programme of 14-18-year-old girls were used to assess the effectiveness of<3 doses of the bivalent vaccine on vaccine-type and cross-reactive-type HPV infection. METHODS: Cervical samples from women attending for their first cervical smear, which had been genotyped for HPV as part of a longitudinal HPV surveillance programme were linked to immunisation records to establish the number of vaccine doses (0, 1, 2 and 3) administered. Vaccine effectiveness (VE) adjusted for deprivation and age at first dose, was assessed for prevalent HPV 16/18 and HPV 31/33/45 infection. RESULTS: VE for prevalent HPV 16/18 infection associated with 1, 2 and 3 doses was 48.2% (95% CI 16.8, 68.9), 54.8% (95% CI 30.7, 70.8) and 72.8% (95% CI 62.8, 80.3). Equivalent VE for prevalent HPV 31/33/45 infection was -1.62% (95% CI -85.1, 45.3), 48.3% (95% CI 7.6, 71.8) and 55.2% (95% CI 32.6, 70.2). CONCLUSIONS: Consistent with recent aggregated trial data, we demonstrate the potential effectiveness of even one dose of HPV vaccine on vaccine-type infection. Given that these women were immunised as part of a catch-up campaign, the VE observed in this study is likely to be an underestimate of what will occur in girls vaccinated at younger ages. Further population-based studies which look at the clinical efficacy of one-dose schedules are warranted. PMID- 27115468 TI - Health service use and costs in the last 6 months of life in elderly decedents with a history of cancer: a comprehensive analysis from a health payer perspective. AB - BACKGROUND: There is growing interest in end-of-life care in cancer patients. We aim to characterise health service use and costs in decedents with cancer history and examine factors associated with resource use and costs at life's end. METHODS: We used routinely collected claims data to quantify health service use and associated costs in two cohorts of elderly Australians diagnosed with cancer: one cohort died from cancer (n=4271) and the other from non-cancer causes (n=3072). We used negative binomial regression to examine the factors associated with these outcomes. RESULTS: Those who died from cancer had significantly higher rates of hospitalisations and medicine use but lower rates of emergency department use than those who died from non-cancer causes. Overall health care costs were significantly higher in those who died from cancer than those dying from other causes; and 40% of costs were expended in the last month of life. CONCLUSIONS: We analysed health services use and costs from a payer perspective, and highlight important differences in patterns of care by cause of death in patients with a cancer history. In particular, there are growing numbers of highly complex patients approaching the end of life and the heterogeneity of these populations may present challenges for effective health service delivery. PMID- 27115469 TI - Expression of breast cancer stem cell markers as predictors of prognosis and response to trastuzumab in HER2-positive breast cancer. AB - BACKGROUND: Breast cancer stem cells (BCSCs) have been suggested to have clinical implications for cancer therapeutics because of their proposed role in chemoresistance. The aim of this study was to investigate the impact of BCSC marker expression on clinical outcome and trastuzumab response in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: We analysed the expression of BCSC markers, CD44+/CD24- and aldehyde dehydrogenase 1 (ALDH1), and clinical outcomes in three sets of breast cancer cases: Set 1, 242 HER2-positive primary breast cancers treated by various modalities; Set 2, 447 HER2-positive primary breast cancers treated with surgery and chemotherapy plus adjuvant trastuzumab; Set 3, 112 metastatic HER2-positive breast cancers treated with trastuzumab. RESULTS: Expression of CD44+/CD24- and ALDH1 was detected in 30.7% and 10.0%, respectively, of the Set 1 cases, and was associated with hormone receptor negativity. In survival analyses, expression of CD44+/CD24-, but not ALDH1, was found to be an independent prognostic factor for poor disease-free and overall survival in whole patients and also in the subgroup not receiving adjuvant trastuzumab. In Set 2 cases treated with adjuvant trastuzumab, CD44+/CD24- expression was an independent prognostic factor for poor disease-free survival, but not for overall survival; expression of ALDH1 had no impact on disease-free or overall survival. In metastatic disease treated with trastuzumab (Set 3 cases), CD44+/CD24- and ALDH1 expression had no effect on trastuzumab response or survival. CONCLUSIONS: These results suggest that the CD44+/CD24- phenotype can be used as a prognostic factor for clinical outcome and a predictive factor of trastuzumab response in patients with HER2-positive primary breast cancer. PMID- 27115470 TI - Expression of two WFDC1/ps20 isoforms in prostate stromal cells induces paracrine apoptosis through regulation of PTGS2/COX-2. AB - BACKGROUND: WFDC1/Prostate stromal 20 (ps20) is a small secreted protein highly expressed within the prostate stroma. WFDC1/ps20 expression is frequently downregulated or lost in prostate cancer (PCa) and ps20 has demonstrated growth suppressive functions in numerous tumour model systems, although the mechanisms of this phenomenon are not understood. METHODS: Ps20 was cloned and overexpressed in DU145, PC3, LNCaP and WPMY-1 cells. Cellular growth, cell cycle and apoptosis were characterised. WPMY-1 stromal cells expressing ps20 were characterised by transcriptome microarray and the function of WPMY-1 conditioned media on growth of PCa cell lines was assessed. RESULTS: Prostrate stromal 20 expression enhanced the proliferation of LNCaP cells, whereas stromal WPMY-1 cells were inhibited and underwent increased apoptosis. Prostrate stromal 20-expressing WPMY-1 cells secrete a potently proapoptotic conditioned media. Prostrate stromal 20 overexpression upregulates expression of cyclooxygenase-2 (COX-2) in LNCaP and WPMY-1 cells, and induces expression of a growth-suppressive phenotype, which inhibits proliferation of PCa cells by ps20-expressing WPMY-1 conditioned media. This growth suppression was subsequently shown to be dependent on COX-2 function. CONCLUSIONS: This work posits that expression of ps20 in the prostate stroma can regulate growth of epithelial and other tissues through the prostaglandin synthase pathway, and thereby restricts development and progression of neoplasms. This provides a rational for selective pressure against ps20 expression in tumour associated stroma. PMID- 27115471 TI - Mitochondrial dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African-American men with prostate cancer. AB - BACKGROUND: African-American (AA) patients with prostate cancer (PCa) respond poorly to current therapy compared with Caucasian American (CA) PCa patients. Although underlying mechanisms are not defined, mitochondrial dysfunction is a key reason for this disparity. METHODS: Cell death, cell cycle, and mitochondrial function/stress were analysed by flow cytometry or by Seahorse XF24 analyzer. Expression of cellular proteins was determined using immunoblotting and real-time PCR analyses. Cell survival/motility was evaluated by clonogenic, cell migration, and gelatin zymography assays. RESULTS: Glycolytic pathway inhibitor dichloroacetate (DCA) inhibited cell proliferation in both AA PCa cells (AA cells) and CA PCa cells (CA cells). AA cells possess reduced endogenous reactive oxygen species, mitochondrial membrane potential (mtMP), and mitochondrial mass compared with CA cells. DCA upregulated mtMP in both cell types, whereas mitochondrial mass was significantly increased in CA cells. DCA enhanced taxol induced cell death in CA cells while sensitising AA cells to doxorubicin. Reduced expression of heat shock proteins (HSPs) was observed in AA cells, whereas DCA induced expression of CHOP, C/EBP, HSP60, and HSP90 in CA cells. AA cells are more aggressive and metastatic than CA cells. CONCLUSIONS: Restoration of mitochondrial function may provide new option for reducing PCa health disparity among American men. PMID- 27115472 TI - Comment on 'Wild-type APC prediction of poor prognosis in microsatellite-stable proximal colorectal cancer differs according to the age of onset'. PMID- 27115473 TI - European Portuguese Adaptation of Glasgow Content of Thoughts Inventory (GCTI): Psychometric Characterization in Higher Education Students. AB - Persistent cognitive activity is an important factor in disturbing sleep-onset both during bedtime and when attempting to get back to sleep after nocturnal awakenings. One of the most specific self-report measures designed to assess this feature is the Glasgow Content of Thoughts Inventory (GCTI). In this study, we investigated the preliminary psychometric properties of GCTI in a large sample of higher education European Portuguese students (N = 2995). Our results suggest that there is evidence of good internal consistency (alpha = 0.93) and validity indicators. Moreover, we found an interpretable factorial structure comprising 5 correlated factors that needs to be confirmed in future studies. The European Portuguese version of the GCTI appears to be a reliable and valid instrument for measurement of sleep-onset disturbing cognitions. PMID- 27115474 TI - The interrater reliability of an objective structured practical examination in measuring the clinical reasoning ability of chiropractic students. AB - OBJECTIVE: The objective structured practical examination (OSPE) is a case-based assessment that can be used to assess the clinical reasoning ability of students. The reliability of using an OSPE for this purpose has not been reported in the literature. The objective of this study was to determine the interrater reliability of the OSPE in measuring the clinical reasoning ability of chiropractic students. METHODS: Two examiners tested each student simultaneously when enough were available as a check for interrater reliability. The scores for students over 4 exam administrations were compiled, and we calculated an intraclass correlation coefficient (ICC) using 1-way random single measures. RESULTS: Paired scores were available for 133 students. The ICC was .685, showing a fair-to-good level of agreement for faculty in assessing the clinical reasoning ability of chiropractic students using an OSPE. CONCLUSION: The OSPE can be a valuable tool for testing clinical reasoning abilities because it can simulate the decision-making process that needs to be implemented in clinical practice. Faculty members at our chiropractic college were able to achieve an acceptable level of reliability in measuring the clinical reasoning abilities of students using an OSPE. Other health professional programs may consider using this tool for assessing the clinical reasoning skills of their students. PMID- 27115475 TI - Real-world glycemic, blood pressure, and weight control in patients with type 2 diabetes mellitus treated with canagliflozin-an electronic health-record-based study. AB - BACKGROUND: Canagliflozin (CANA) has been shown to improve HbA1c, blood pressure (BP), and weight in patients with type 2 diabetes mellitus (T2DM) in clinical trials. This study describes HbA1c, BP, and weight in T2DM patients treated with CANA in a real-world setting. METHODS: Adults with >=1 diagnosis for T2DM and >=12 months of clinical activity before the first CANA prescription (index) were identified in the IMS Health Real-World Data Electronic Medical Records - US database. Patient quality measures were described at baseline and 3, 6, 9, and 12 months post-index. Selected goals were HbA1c <7% (<53 mmol/mol), <8% (<64 mmol/mol), and >9% (>75 mmol/mol, poor control), BP <140/90 mmHg, and weight loss >=5%. RESULTS: In total, 16,163 patients were identified (mean age = 58.5 years; 47.9% female; 75.8% white). At baseline, 90.4% of patients used >=1 anti hyperglycemic agent. Among patients with baseline HbA1c >=7% (n = 10,478; 64.8%; mean HbA1c = 8.8%), 21.2%, 59.5%, and 17.6% had an HbA1c <7%, <8%, and >9% after 3 months, respectively; these proportions remained stable through 12 months. Among patients with baseline BP >=140/90, 60.0% and 75.6% attained systolic BP <140 mmHg and diastolic BP <90 mmHg after 3 months, respectively; proportions remained stable through 12 months. Weight loss >=5% was observed in 13.3% of patients at 3 months and the proportion increased to 25.8% at 12 months. LIMITATIONS: This study relied on prescription data, which does not necessarily indicate that the medication was taken as prescribed. Some patients were also treated with other anti-hyperglycemics, anti-hypertensives, and weight loss medications during the follow-up, which may have contributed to the effects reported. CONCLUSIONS: Most patients with inadequate HbA1c and BP levels at baseline achieved respective goals after 3 months of CANA, and the proportions of responders remained stable through 12 months. Weight loss >=5% was increasingly observed over time. PMID- 27115476 TI - Framework for enhancing clinical practice guidelines through continuous patient engagement. AB - BACKGROUND: Patient engagement in clinical practice guideline (CPG) development is recommended by multiple institutions and instruments measuring guideline quality. Approaches to engaging patients, however, vary between oversight organizations, quality tools and guideline developers. OBJECTIVE: We propose a ten-step framework outlining steps and options for patient engagement in guideline development with the goal of highlighting steps for patient engagement and methods by which this can be achieved. DISCUSSION: This framework provides a model for continuous patient engagement in CPGs by outlining ten steps of guideline development occurring at the levels of the developer/committee and the individual guideline project. At the developer level, patients can assist in topic nomination (step 1), topic prioritization (step 2) and guideline development group selection (step 3). Within specific guideline projects, patients' opinions may be incorporated when framing the question (step 4), creating an analytic framework and research plan (step 5), conducting the systematic review and conclusion formation (step 6), development of recommendations (step 7) and dissemination and implementation (step 8). At the end of process, patients can again be engaged at the developer level by helping determine when guidelines need updating (step 9) and evaluating the developer's approach to patient engagement (step 10). CONCLUSIONS: Patient engagement at each CPG development step has different purposes, mechanisms, advantages and disadvantages, and implications for resource utilization. This framework can serve as a resource for guideline developers desiring to increase patient engagement and reference for researchers investigating engagement methodology at different steps of the CPG lifecycle. PMID- 27115477 TI - Yoga for asthma. AB - BACKGROUND: Asthma is a common chronic inflammatory disorder affecting about 300 million people worldwide. As a holistic therapy, yoga has the potential to relieve both the physical and psychological suffering of people with asthma, and its popularity has expanded globally. A number of clinical trials have been carried out to evaluate the effects of yoga practice, with inconsistent results. OBJECTIVES: To assess the effects of yoga in people with asthma. SEARCH METHODS: We systematically searched the Cochrane Airways Group Register of Trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched PEDro. We searched ClinicalTrials.gov and the WHO ICTRP search portal. We searched all databases from their inception to 22 July 2015, and used no restriction on language of publication. We checked the reference lists of eligible studies and relevant review articles for additional studies. We attempted to contact investigators of eligible studies and experts in the field to learn of other published and unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared yoga with usual care (or no intervention) or sham intervention in people with asthma and reported at least one of the following outcomes: quality of life, asthma symptom score, asthma control, lung function measures, asthma medication usage, and adverse events. DATA COLLECTION AND ANALYSIS: We extracted bibliographic information, characteristics of participants, characteristics of interventions and controls, characteristics of methodology, and results for the outcomes of our interest from eligible studies. For continuous outcomes, we used mean difference (MD) with 95% confidence interval (CI) to denote the treatment effects, if the outcomes were measured by the same scale across studies. Alternatively, if the outcomes were measured by different scales across studies, we used standardised mean difference (SMD) with 95% CI. For dichotomous outcomes, we used risk ratio (RR) with 95% CI to measure the treatment effects. We performed meta-analysis with Review Manager 5.3. We used the fixed-effect model to pool the data, unless there was substantial heterogeneity among studies, in which case we used the random-effects model instead. For outcomes inappropriate or impossible to pool quantitatively, we conducted a descriptive analysis and summarised the findings narratively. MAIN RESULTS: We included 15 RCTs with a total of 1048 participants. Most of the trials were conducted in India, followed by Europe and the United States. The majority of participants were adults of both sexes with mild to moderate asthma for six months to more than 23 years. Five studies included yoga breathing alone, while the other studies assessed yoga interventions that included breathing, posture, and meditation. Interventions lasted from two weeks to 54 months, for no more than six months in the majority of studies. The risk of bias was low across all domains in one study and unclear or high in at least one domain for the remainder.There was some evidence that yoga may improve quality of life (MD in Asthma Quality of Life Questionnaire (AQLQ) score per item 0.57 units on a 7-point scale, 95% CI 0.37 to 0.77; 5 studies; 375 participants), improve symptoms (SMD 0.37, 95% CI 0.09 to 0.65; 3 studies; 243 participants), and reduce medication usage (RR 5.35, 95% CI 1.29 to 22.11; 2 studies) in people with asthma. The MD for AQLQ score exceeded the minimal clinically important difference (MCID) of 0.5, but whether the mean changes exceeded the MCID for asthma symptoms is uncertain due to the lack of an established MCID in the severity scores used in the included studies. The effects of yoga on change from baseline forced expiratory volume in one second (MD 0.04 litres, 95% CI -0.10 to 0.19; 7 studies; 340 participants; I(2) = 68%) were not statistically significant. Two studies indicated improved asthma control, but due to very significant heterogeneity (I(2) = 98%) we did not pool data. No serious adverse events associated with yoga were reported, but the data on this outcome was limited. AUTHORS' CONCLUSIONS: We found moderate-quality evidence that yoga probably leads to small improvements in quality of life and symptoms in people with asthma. There is more uncertainty about potential adverse effects of yoga and its impact on lung function and medication usage. RCTs with a large sample size and high methodological and reporting quality are needed to confirm the effects of yoga for asthma. PMID- 27115478 TI - Emergency Department Management of Febrile Respiratory Illness in Children. AB - BACKGROUND: There are limited data regarding testing and treatment patterns for children presenting to the emergency department (ED) with a febrile respiratory illness. OBJECTIVES: The aims of the study were to evaluate the rates of diagnostic testing, antibiotic use, and pneumonia diagnosis among children presenting to an ED with a febrile respiratory illness and to evaluate whether differences exist on the basis of care at a pediatric versus a general ED. METHODS: Cross-sectional study of children presenting to an ED with a febrile respiratory illness from 2001 to 2010 used the National Hospital Ambulatory Medical Care Survey. Using extrapolated estimates from the weighted population sample, rates of laboratory and radiographic testing, antibiotic use, and pneumonia diagnosis were ascertained. Comparisons were made between children treated at a general versus pediatric ED. A subpopulation of children undergoing chest radiograph was identified to target those with concern for radiographic pneumonia. RESULTS: Fifteen percent of the 12 million visits for febrile respiratory illness occurred in a pediatric ED. Thirteen percent (95% confidence interval [CI], 11-15) of patients had a complete blood count, 4% (95% CI, 3-5) had a blood culture, and 33% (95% CI, 30-35) had a chest radiograph obtained; no differences were observed on the basis of ED type. Despite similar rates of pneumonia diagnosis, antibiotics were prescribed less often for children cared for in a pediatric (35% [95% CI, 30-41]) versus general ED (50% [95% CI, 47-53]). Similar findings were observed among the subgroup of children with febrile respiratory illness undergoing chest radiograph. CONCLUSIONS: High rates of diagnostic testing were observed among children with febrile respiratory illnesses, despite low rates of pneumonia diagnosis. Antibiotic use was higher among children cared for at a general ED compared with pediatric ED. PMID- 27115479 TI - Methylphenidate Overdose Causing Secondary Polydipsia and Severe Hyponatremia in an 8-Year-Old Boy. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is an increasingly common diagnosis of childhood that manifests with symptoms that affect cognitive, academic, behavioral, emotional, and social functioning. There are a multitude of pharmaceutical therapies to choose from when managing this condition, and though many studies on the safety and efficacy of these medications have been published, adverse effects still occur. CASE: This case discusses a previously healthy 8 year-old boy who had been prescribed 20-mg lisdexamfetamine dimesylate for ADHD however mistakenly took his brother's 36-mg methylphenidate extended-release tablets, resulting in hyperhidrosis, excessive thirst, polydipsia, and combative behavior that began within 3 hours of ingestion. He was evaluated at a community hospital emergency department and given lorazepam due to agitation and combativeness before discharge. However, he returned with hypothermia, hyponatremia, and status epilepticus resulting in intubation. Patient was transferred to our facility where a computer tomography of his head was negative and hyponatremia was corrected with 3% NaCl saline solution. A lumbar puncture was performed due to temperature instability before starting broad-spectrum antibiotics. Cerebrospinal fluid findings were normal, and he was extubated at 18 hours postingestion. Patient was discharged home after 3 days with no residual symptoms. DISCUSSION/CONCLUSIONS: Though both lisdexamfetamine dimesylate and methylphenidate are widely used among pediatricians today for treatment of ADHD, reports of life-threatening water intoxication as a result of overdose is rare. Studies have reported that severe 3,4-methylenedioxymethamphtamine toxicity in adults is associated with syndrome of inappropriate diuretic hormone (SIADH) secretion, hyponatremia, and seizures, along with serotonin-induced transient elevation in antidiuretic hormone. Adult schizophrenics who receive psychostimulants have also been shown to develop polydipsia with hyponatremia. Although the use of psychostimulants in adult schizophrenic patients has been studied, literature on toxicity and effects in the pediatric psychiatric population is scarce. We would suggest that this patient's polydipsia and hyponatremia are most likely a result of his ingestion of a toxic dose of a long acting agent known to cause secondary psychosis. PMID- 27115480 TI - Mitochondrial autophagy promotes healthy aging. PMID- 27115481 TI - Anticlastogenicity and Anticarcinogenicity of Purple Rice Extract in Rats. AB - Oryza sativa L. var. indica cv. Kum Doi Saket is a pigmented rice variety grown in northern Thailand. Our previous study found that the methanol extract of purple rice seed had the highest level of antimutagenicity in a Salmonella mutation assay. The present study was designed to evaluate its in vivo anticlastogenic and anticarcinogenic potentials. The purple rice extract had no acute toxicity on rats. The oral administration of 1,000 mg/kg body weight (bw) of the extract for 28 days did not increase the number of micronucleated hepatocytes. Interestingly, it significantly reduced the amount of micronucleus formation in the liver of diethylnitrosamine (DEN)-treated rats. The inhibitory mechanism involved the induction of hepatic glutathione S-transferase (GST) activity. In addition, oral administration of 500 mg/kg bw extract for 10 weeks significantly decreased the number of hepatic GST placental form positive foci, but did not modulate the number of colonic aberrant crypt foci in DEN- and dimethylhydrazine-initiated rats. In conclusion, the methanol extract of purple rice seed showed no toxicity, clastogenicity, or carcinogenicity in laboratory rats. It did display chemopreventive activity against the early stages of rat hepatocarcinogenesis. PMID- 27115482 TI - Textile dye degradation using nano zero valent iron: A review. AB - Water soluble unfixed dyes and inorganic salts are the major pollutants in textile dyeing industry wastewater. Existing treatment methods fail to degrade textile dyes and have limitations too. The inadequate treatment of textile dyeing wastewater is a major concern when effluent is directly discharged into the nearby environment. Long term disposal threatens the environment, which needs reclamation. This article reviews the current knowledge of nano zero valent iron (nZVI) technique in the degradation of textile dyes. The application of nZVI on textile dye degradation is receiving great attention in the recent years because nZVI particles are highly reactive towards the pollutant, less toxic, and economical. The nZVI particles aggregate quickly with respect to time and the addition of supports such as resin, nickel, zinc, bentonite, biopolymer, kaolin, rectorite, nickel-montmorillonite, bamboo, cellulose, biochar, graphene, and clinoptilolite enhanced the stability of iron nanoparticles. Inclusion of supports may in turn introduce additional toxic pollutants, hence green supports are recommended. The majority of investigations concluded dye color removal as textile dye compound removal, which is not factual. Very few studies monitored the removal of total organic carbon and observed the products formed. The results revealed that partial mineralization of the textile dye compound was achieved. Instead of stand alone technique, nZVI can be integrated with other suitable technique to achieve complete degradation of textile dye and also to treat multiple pollutants in the real textile dyeing wastewater. It is highly recommended to perform more bench-scale and pilot-scale studies to apply this technique to the textile effluent contaminated sites. PMID- 27115483 TI - Furosemide's one little hydrogen atom: NMR crystallography structure verification of powdered molecular organics. AB - The potential of NMR crystallography to verify molecular crystal structures deposited in structural databases is evaluated, with two structures of the pharmaceutical furosemide serving as examples. While the structures differ in the placement of one H atom, using this approach, we verify one of the structures in the Cambridge Structural Database using quantitative tools, while establishing that the other structure does not meet the verification criteria. PMID- 27115484 TI - Innate Resistance and Susceptibility to Norovirus Infection. PMID- 27115485 TI - Incidence of Norovirus and Other Viral Pathogens That Cause Acute Gastroenteritis (AGE) among Kaiser Permanente Member Populations in the United States, 2012-2013. AB - Noroviruses and other viral pathogens are increasingly recognized as frequent causes of acute gastroenteritis (AGE). However, few laboratory-based data are available on the incidence of AGE caused by viral pathogens in the U.S. This study examined stool specimens submitted for routine clinical diagnostics from patients enrolled in Kaiser Permanente (KP) health plans in metro Portland, OR, and the Maryland, District of Columbia, and northern Virginia geographic areas to estimate the incidence of viral enteropathogens in these populations. Over a one year study period, participating laboratories randomly selected stools submitted for routine clinical diagnostics for inclusion in the study along with accompanying demographic and clinical data. Selected stools were tested for norovirus, rotavirus, sapovirus, and astrovirus using standardized real-time RT PCR protocols. Each KP site provided administrative data which were used in conjunction with previously published data on healthcare utilization to extrapolate pathogen detection rates into population-based incidence rates. A total of 1,099 specimens collected during August 2012 to September 2013 were included. Mean age of patients providing stool specimens was 46 years (range: 0 98 years). Noroviruses were the most common viral pathogen identified among patients with AGE (n = 63 specimens, 6% of specimens tested). In addition, 22 (2%) of specimens were positive for rotavirus; 19 (2%) were positive for sapovirus; and 7 (1%) were positive for astrovirus. Incidence of norovirus associated outpatient visits was 5.6 per 1,000 person-years; incidence of norovirus disease in the community was estimated to be 69.5 per 1,000 person years. Norovirus incidence was highest among children <5 years of age (outpatient incidence = 25.6 per 1,000 person-years; community incidence = 152.2 per 1,000 person-years), followed by older adults aged >65 years (outpatient incidence = 7.8 per 1,000 person-years; community incidence = 75.8 per 1,000 person-years). Outpatient incidence rates of rotavirus, sapovirus, and astrovirus were 2.0, 1.6, 0.6 per 1,000 person-years, respectively; community incidence rates for these viruses were 23.4, 22.5, and 8.5 per 1,000 person-years, respectively. This study provides the first age-group specific laboratory-based community and outpatient incidence rates for norovirus AGE in the U.S. Norovirus was the most frequently detected viral enteropathogen across the age spectrum with the highest rates of norovirus disease observed among young children and, to a lesser extent, the elderly. These data provide a better understanding of the norovirus disease burden in the United States, including variations within different age groups, which can help inform the development, targeting, and future impacts of interventions, including vaccines. PMID- 27115486 TI - Diseases Neglected by the Media in Espirito Santo, Brazil in 2011-2012. AB - BACKGROUND: The aims of the present study were to identify and analyse the Diseases Neglected by the Media (DNMs) via a comparison between the most important health issues to the population of Espirito Santo, Brazil, from the epidemiological perspective (health value) and their effective coverage by the print media, and to analyse the DNMs considering the perspective of key journalists involved in the dissemination of health topics in the state media. METHODOLOGY: Morbidity and mortality data were collected from official documents and from Health Information Systems. In parallel, the diseases reported in the two major newspapers of Espirito Santo in 2011-2012 were identified from 10,771 news articles. Concomitantly, eight interviews were conducted with reporters from the two newspapers to understand the journalists' reasons for the coverage or neglect of certain health/disease topics. PRINCIPAL FINDINGS: Quantitatively, the DNMs identified diseases associated with poverty, including tuberculosis, leprosy, schistosomiasis, leishmaniasis, and trachoma. Apart from these, diseases with outbreaks in the period evaluated, including whooping cough and meningitis, some cancers, respiratory diseases, ischaemic heart disease, and stroke, were also seldom addressed by the media. In contrast, dengue fever, acquired immune deficiency syndrome (AIDS), diabetes, breast cancer, prostate cancer, tracheal cancer, and bronchial and lung cancers were broadly covered in the period analysed, corroborating the tradition of media disclosure of these diseases. Qualitatively, the DNMs included rare diseases, such as amyotrophic lateral sclerosis (ALS), leishmaniasis, Down syndrome, and verminoses. The reasons for the neglect of these topics by the media included the political and economic interests of the newspapers, their editorial line, and the organizational routine of the newsrooms. CONCLUSIONS: Media visibility acts as a strategy for legitimising priorities and contextualizing various realities. Therefore, we propose that the health problems identified should enter the public agenda and begin to be recognized as legitimate demands. PMID- 27115487 TI - Association between Cognition and Serum Insulin-Like Growth Factor-1 in Middle Aged & Older Men: An 8 Year Follow-Up Study. AB - Low levels of insulin-like growth factor-1 (IGF-1), an essential neurotrophic factor, have been associated with worse cognitive function in older adults. However, few studies have assessed the prospective association of serum IGF-1 with cognitive function. We aimed to determine the association between serum IGF 1 on concurrent and prospective cognitive function in a population sample of men aged 40-80 years. Blood samples were assessed for IGF-1 levels at baseline and neuropsychological assessments were performed at baseline (n = 400) and at follow up after a mean duration of 8.3 years (n = 286). Linear regression analyses were carried out to determine the associations between quintiles of IGF-1 and cognitive function at the baseline and follow-up visits. Results showed that those in the top quintile of IGF-1 had lower processing capacity and global cognition scores at follow-up after controlling for cognitive function at baseline and other confounding factors. Additional analyses exploring associations with IGF-1 separately in middle-aged and older participants, and with quartiles of IGF-1 produced similar results. In those older than 60 years, high IGF-1 levels were also associated with lower baseline processing capacity. These results suggest that high IGF-1 levels are associated with worse long-term cognition in men. Together with past studies, we suggest that both, high and low levels of IGF-1 may be associated with poor cognitive function and that optimum levels of IGF-1 (quintile 2 and 3 in current study) may be associated with better cognitive function. PMID- 27115488 TI - Predictive Blood Chemistry Parameters for Pansteatitis-Affected Mozambique Tilapia (Oreochromis mossambicus). AB - One of the largest river systems in South Africa, the Olifants River, has experienced significant changes in water quality due to anthropogenic activities. Since 2005, there have been various "outbreaks" of the inflammatory disease pansteatitis in several vertebrate species. Large-scale pansteatitis-related mortality events have decimated the crocodile population at Lake Loskop and decreased the population at Kruger National Park. Most pansteatitis-related diagnoses within the region are conducted post-mortem by either gross pathology or histology. The application of a non-lethal approach to assess the prevalence and pervasiveness of pansteatitis in the Olifants River region would be of great importance for the development of a management plan for this disease. In this study, several plasma-based biomarkers accurately classified pansteatitis in Mozambique tilapia (Oreochromis mossambicus) collected from Lake Loskop using a commercially available benchtop blood chemistry analyzer combined with data interpretation via artificial neural network analysis. According to the model, four blood chemistry parameters (calcium, sodium, total protein and albumin), in combination with total length, diagnose pansteatitis to a predictive accuracy of 92 percent. In addition, several morphometric traits (total length, age, weight) were also associated with pansteatitis. On-going research will focus on further evaluating the use of blood chemistry to classify pansteatitis across different species, trophic levels, and within different sites along the Olifants River. PMID- 27115489 TI - Not All Diabetes in Infants is Type 1: A Case Report. AB - Neonatal diabetes mellitus (NDM), defined as persistent hyperglycemia occurring in the first months of life, is a rare cause of hyperglycemia and is often misdiagnosed as type 1 diabetes mellitus (T1DM). Numerous reports have shown that the successful transition from insulin to sulfonylurea agents can be achieved in up to 90% of patients with NDM. However, most of the reports pertain to infants; the literature is limited regarding treatment of adults with NDM. We present our experience with a patient with permanent NDM, initially misdiagnosed as T1DM, who subsequently was successfully transitioned to oral sulfonylurea therapy after 37 years of insulin dependence. PMID- 27115490 TI - Maternal Dietary Supplementation with Oligofructose-Enriched Inulin in Gestating/Lactating Rats Preserves Maternal Bone and Improves Bone Microarchitecture in Their Offspring. AB - Nutrition during pregnancy and lactation could exert a key role not only on maternal bone, but also could influence the skeletal development of the offspring. This study was performed in rats to assess the relationship between maternal dietary intake of prebiotic oligofructose-enriched inulin and its role in bone turnover during gestation and lactation, as well as its effect on offspring peak bone mass/architecture during early adulthood. Rat dams were fed either with standard rodent diet (CC group), calcium-fortified diet (Ca group), or prebiotic oligofructose-enriched inulin supplemented diet (Pre group), during the second half of gestation and lactation. Bone mineral density (BMD) and content (BMC), as well as micro-structure of dams and offspring at different stages were analysed. Dams in the Pre group had significantly higher trabecular thickness (Tb.Th), trabecular bone volume fraction (BV/TV) and smaller specific bone surface (BS/BV) of the tibia in comparison with CC dams. The Pre group offspring during early adulthood had an increase of the lumbar vertebra BMD when compared with offspring of CC and Ca groups. The Pre group offspring also showed significant increase versus CC in cancellous and cortical structural parameters of the lumbar vertebra 4 such as Tb.Th, cortical BMD and decreased BS/BV. The results indicate that oligofructose-enriched inulin supplementation can be considered as a plausible nutritional option for protecting against maternal bone loss during gestation and lactation preventing bone fragility and for optimizing peak bone mass and architecture of the offspring in order to increase bone strength. PMID- 27115491 TI - Mindfulness Enhances Episodic Memory Performance: Evidence from a Multimethod Investigation. AB - Training in mindfulness, classically described as a receptive attentiveness to present events and experiences, has been shown to improve attention and working memory. Both are key to long-term memory formation, and the present three-study series used multiple methods to examine whether mindfulness would enhance episodic memory, a key form of long-term memory. In Study 1 (N = 143), a self reported state of mindful attention predicted better recognition performance in the Remember-Know (R-K) paradigm. In Study 2 (N = 93), very brief training in a focused attention form of mindfulness also produced better recognition memory performance on the R-K task relative to a randomized, well-matched active control condition. Study 3 (N = 57) extended these findings by showing that relative to randomized active and inactive control conditions the effect of very brief mindfulness training generalized to free-recall memory performance. This study also found evidence for mediation of the mindfulness training-episodic memory relation by intrinsic motivation. These findings indicate that mindful attention can beneficially impact motivation and episodic memory, with potential implications for educational and occupational performance. PMID- 27115492 TI - Immunogenicity of Outer Membrane Proteins VirB9-1 and VirB9-2, a Novel Nanovaccine against Anaplasma marginale. AB - Anaplasma marginale is the most prevalent tick-borne livestock pathogen and poses a significant threat to cattle industry. In contrast to currently available live blood-derived vaccines against A. marginale, alternative safer and better-defined subunit vaccines will be of great significance. Two proteins (VirB9-1 and VirB9 2) from the Type IV secretion system of A. marginale have been shown to induce humoral and cellular immunity. In this study, Escherichia coli were used to express VirB9-1 and VirB9-2 proteins. Silica vesicles having a thin wall of 6 nm and pore size of 5.8 nm were used as the carrier and adjuvant to deliver these two antigens both as individual or mixed nano-formulations. High loading capacity was achieved for both proteins, and the mouse immunisation trial with individual as well as mixed nano-formulations showed high levels of antibody titres over 107 and strong T-cell responses. The mixed nano-formulation also stimulated high level recall responses in bovine T-cell proliferation assays. These results open a promising path towards the development of efficient A. marginale vaccines and provide better understanding on the role of silica vesicles to deliver multivalent vaccines as mixed nano-formulations able to activate both B-cell and T-cell immunity, for improved animal health. PMID- 27115493 TI - Influence of Age on Caloric Response. AB - In an aging society, the number of patients suffering from vertigo and dizziness is increasing. Vertigo is mostly thought to occur owing to otorhinolaryngologic disease. In contrast, it is difficult to diagnose dizziness, because of its varied causes, and we believe that the number of elderly patients suffering from dizziness is increasing. Here, we evaluated the relationship between canal paralysis and symptoms at the first medical examination and age-related changes in caloric response, and obtained the following 3 main findings: (a) 41.3% of the patients with canal paralysis complained of dizziness at the first medical examination, with an increased tendency in patients aged >70 years; (b) the slow phase eye velocity (SPEV) of patients aged >70 years was lower than that of patients aged <=69 years, and the SPEV of patients complaining of vertigo was higher than that of patients who complained of dizziness during a caloric test, and (c) the percentage of patients complaining of dizziness and those not complaining of symptoms during a caloric test increased with age. In conclusion, patients with canal paralysis tend to complain of dizziness at the first medical examination, and the percentage of patients without vertigo during a caloric test increased with age. PMID- 27115495 TI - Network-based approaches for analysis of complex biological systems. AB - Cells function and respond to changes in their environment by the coordinated activity of their molecular components, including mRNAs, proteins and metabolites. At the heart of proper cellular function are molecular networks connecting these components to process extra-cellular environmental signals and drive dynamic, context-specific cellular responses. Network-based computational approaches aim to systematically integrate measurements from high-throughput experiments to gain a global understanding of cellular function under changing environmental conditions. We provide an overview of recent methodological developments toward solving two major computational problems within this field in the past two years (2013-2015): network reconstruction and network-based interpretation. Looking forward, we envision development of methods that can predict phenotypes with high accuracy as well as provide biologically plausible mechanistic hypotheses. PMID- 27115494 TI - Demyelination induces transport of ribosome-containing vesicles from glia to axons: evidence from animal models and MS patient brains. AB - Glial cells were previously proven capable of trafficking polyribosomes to injured axons. However, the occurrence of such transfer in the general pathological context, such as demyelination-related diseases, needs further evidence. Since this may be a yet unidentified universal contributor to axonal survival, we study putative glia-axonal ribosome transport in response to demyelination in animal models and patients in both peripheral and central nervous system. In the PNS we investigate whether demyelination in a rodent model has the potential to induce ribosome transfer. We also probe the glia-axonal ribosome supply by implantation of transgenic Schwann cells engineered to produce fluorescent ribosomes in the same demyelination model. We furthermore examine the presence of axonal ribosomes in mouse experimental autoimmune encephalomyelitis (EAE), a well-established model for multiple sclerosis (MS), and in human MS autopsy brain material. We provide evidence for increased axonal ribosome content in a pharmacologically demyelinated sciatic nerve, and demonstrate that at least part of these ribosomes originate in the transgenic Schwann cells. In the CNS one of the hallmarks of MS is demyelination, which is associated with severe disruption of oligodendrocyte-axon interaction. Here, we provide evidence that axons from spinal cords of EAE mice, and in the MS human brain contain an elevated amount of axonal ribosomes compared to controls. Our data provide evidence that increased axonal ribosome content in pathological axons is at least partly due to glia-to-axon transfer of ribosomes, and that demyelination in the PNS and in the CNS is one of the triggers capable to initiate this process. PMID- 27115496 TI - Multi-class and multi-scale models of complex biological phenomena. AB - Computational modeling has significantly impacted our ability to analyze vast (and exponentially increasing) quantities of experimental data for a variety of applications, such as drug discovery and disease forecasting. Single-scale, single-class models persist as the most common group of models, but biological complexity often demands more sophisticated approaches. This review surveys modeling approaches that are multi-class (incorporating multiple model types) and/or multi-scale (accounting for multiple spatial or temporal scales) and describes how these models, and combinations thereof, should be used within the context of the problem statement. We end by highlighting agent-based models as an intuitive, modular, and flexible framework within which multi-scale and multi class models can be implemented. PMID- 27115497 TI - High definition for systems biology of microbial communities: metagenomics gets genome-centric and strain-resolved. AB - The systems biology of microbial communities, organismal communities inhabiting all ecological niches on earth, has in recent years been strongly facilitated by the rapid development of experimental, sequencing and data analysis methods. Novel experimental approaches and binning methods in metagenomics render the semi automatic reconstructions of near-complete genomes of uncultivable bacteria possible, while advances in high-resolution amplicon analysis allow for efficient and less biased taxonomic community characterization. This will also facilitate predictive modeling approaches, hitherto limited by the low resolution of metagenomic data. In this review, we pinpoint the most promising current developments in metagenomics. They facilitate microbial systems biology towards a systemic understanding of mechanisms in microbial communities with scopes of application in many areas of our daily life. PMID- 27115499 TI - Water Sources in a Zoological Park Harbor Genetically Diverse Strains of Clostridium Perfringens Type A with Decreased Susceptibility to Metronidazole. AB - The presence of Clostridium perfringens in water is generally regarded as an indicator of fecal contamination, and exposure to waterborne spores is considered a possible source of infection for animals. We assessed the presence and genetic diversity of C. perfringens in water sources in a zoological park located in Madrid (Spain). A total of 48 water samples from 24 different sources were analyzed, and recovered isolates were toxinotyped, genotyped by fluorophore enhanced repetitive polymerase chain reaction (rep-PCR) fingerprinting and tested for antimicrobial susceptibility. C. perfringens was recovered from 43.8 % of water samples and 50 % of water sources analyzed. All isolates (n = 70) were type A and 42.9 % were beta2-toxigenic (i.e., cpb2+), but none contained the enterotoxin-encoding gene (cpe). Isolates belonged to 15 rep-PCR genotypes and most genetic diversity (88 %) was distributed among isolates obtained from the same sample. Most isolates displayed intermediate susceptibility (57.1 %; MIC = 16 MUg ml-1) or resistance (5.7 %; MIC >= 32 MUg ml-1) to metronidazole. No resistance to other antimicrobials was detected, although some isolates showed elevated MICs to erythromycin and/or linezolid. Finally, a marginally significant association between absence of cpb2 and decreased susceptibility to metronidazole (MIC >= 16 MUg ml-1) was detected. In conclusion, our results reveal a high prevalence of C. perfringens type A in the studied water reservoirs, which constitutes a health risk for zoo animals. The elevated MICs to metronidazole observed for genetically diverse isolates is a cause of additional concern, but more work is required to clarify the significance of reduced metronidazole susceptibility in environmental strains. PMID- 27115500 TI - Number of hummingbird visits determines flower mite abundance on hummingbird feeders. AB - Members of several genera of mites from the family Melicharidae (Mesostigmata) use hummingbirds as transport host to move from flower to flower, where they feed on pollen and nectar. The factors that influence hummingbird flower mite abundance on host plant flowers are not currently known. Here we tested whether hummingbird flower mite abundance on an artificial nectar source is determined by number of hummingbird visits, nectar energy content or species richness of visiting hummingbirds. We conducted experiments employing hummingbird feeders with sucrose solutions of low, medium, and high energy concentrations, placed in a xeric shrubland. In the first experiment, we recorded the number of visiting hummingbirds and the number of visiting hummingbird species, as well as the abundance of hummingbird flower mites on each feeder. Feeders with the highest sucrose concentration had the most hummingbird visits and the highest flower mite abundances; however, there was no significant effect of hummingbird species richness on mite abundance. In the second experiment, we recorded flower mite abundance on feeders after we standardized the number of hummingbird visits to them. Abundance of flower mites did not differ significantly between feeders when we controlled for hummingbird visits. Our results suggest that nectar energy concentration determines hummingbird visits, which in turn determines flower mite abundance in our feeders. Our results do not support the hypothesis that mites descend from hummingbird nostrils more on richer nectar sources; however, it does not preclude the possibility that flower mites select for nectar concentration at other spatial and temporal scales. PMID- 27115501 TI - Potential of astigmatid mites (Acari: Astigmatina) as prey for rearing edaphic predatory mites of the families Laelapidae and Rhodacaridae (Acari: Mesostigmata). AB - Laelapidae and Rhodacaridae are important families of edaphic predatory mites and species of these families have been considered for use in biological control programs of soil pests. Mites of Cohort Astigmatina (Acari: Sarcoptiformes) have been largely used as factitious prey in the mass rearing of various edaphic or plant-inhabiting predatory mites. Stratiolaelaps scimitus (Womersley) (Mesostigmata: Laelapidae) (widely commercialized for the control of fungus gnats and thrips) and Protogamasellopsis zaheri Abo-Shnaf, Castilho and Moraes (Mesostigmata: Rhodacaridae) (not available commercially but promising for the control of thrips and nematodes) are known to be reared on Tyrophagus putrescentiae (Schrank) (Astigmatina: Acaridae), but the possibility to find a perhaps more efficient prey has not been evaluated. The objective of this paper was to evaluate different astigmatid species as prey for these predators. S. scimitus and P. zaheri oviposited on all evaluated astigmatids and the acarid mites T. putrescentiae and Aleuroglyphus ovatus (Tropeau) were the most suitable prey; to confirm the effect of prey on oviposition rates, pregnant females of the predators were kept under starvation conditions and oviposition was negligible or null. Survivorship was always higher than 78 % and was not influenced by prey species or starvation. PMID- 27115502 TI - The Effect of Testicular Torsion Duration on Testicular Steroidogenesis in the Rat Model. AB - BACKGROUND: Testicular torsion is an emergency condition in which spermatogenesis may be irreversibly damaged. There have been controversial results about the effect of testicular torsion on steroidogenesis. We aimed at investigating the effect of testicular torsion on steroidogenesis. MATERIAL AND METHODS: A total of 40 adult male rats were divided into 4 groups. Left testicles were removed in all groups. Right testicles were torsioned and remained in the torsion position for 1, 3 and 5 h in study groups, whereas no torsion was performed in control. Serum luteinizing hormone (LH) and total testosterone (TT) levels were measured on the 3rd and 30th days of surgery and orchiectomy was performed on the 30th day of testicular torsion for histopathological evaluation. RESULTS: TT levels of study groups were significantly lower than that of the control group on the 3rd day of torsion. LH of study groups was higher than that of the control group, but the difference was significant only in the 5 h-torsion group. The total number of Leydig cells increased in 1- and 3-h groups, whereas it decreased in the 5-hour group. CONCLUSION: Testosterone production and Leydig cell functions significantly decreased after 5 h torsion in the rat model. The duration of torsion less than 5 h yielded partial dysfunction on steroidogenesis. PMID- 27115503 TI - UK Renal Registry 18th Annual Report: Chapter 6 Comorbidities and Current Smoking Status amongst Patients starting Renal Replacement Therapy in England, Wales and Northern Ireland from 2013 to 2014. AB - Data on comorbidity at the time of start of renal replacement therapy (RRT) were submitted to the UK Renal Registry (UKRR) for 7,786 (58.1%) incident patients between 2013 and 2014. In 2014, 11 centres provided data on 100% of new patients and eight provided data for less than 5% of new patients, highlighting the continued wide variation in the completeness of data returns. In 2014, comorbidity data completeness in Wales and Northern Ireland was around 90% compared with 53% in England. In patients with comorbidity data, about half (49.8%) had one or more comorbidities and in the subgroup of patients aged 565 years, this increased to 63.1%. Diabetes mellitus (listed as primary renal disease or comorbidity) and ischaemic heart disease were the most common comorbid conditions, observed in 36% and 20% of patients respectively. Most comorbid conditions were more prevalent in patients aged 565 years, but the prevalence rates for ischaemic heart disease and malignancy were substantially higher than the rest. In 2013-2014, 12.5% of incident RRT patients were recorded as being smokers at initiation of dialysis; this is a decrease from 14% in the previous two years (2011-2012). Amongst incident RRT patients of White origin, the prevalence of having at least one comorbid condition was approximately 14% and 7% higher than in incident patients of Black and South Asian origin, respectively. There was a higher prevalence of ischaemic heart disease and peripheral vascular disease in patients referred early to a nephrologist than amongst patients referred late. Malignancy was much more common in patients who were referred late. PMID- 27115504 TI - Bioengineered Models of Solid Human Tumors for Cancer Research. AB - The lack of controllable in vitro models that can recapitulate the features of solid tumors such as Ewing's sarcoma limits our understanding of the tumor initiation and progression and impedes the development of new therapies. Cancer research still relies of the use of simple cell culture, tumor spheroids, and small animals. Tissue-engineered tumor models are now being grown in vitro to mimic the actual tumors in patients. Recently, we have established a new protocol for bioengineering the Ewing's sarcoma, by infusing tumor cell aggregates into the human bone engineered from the patient's mesenchymal stem cells. The bone niche allows crosstalk between the tumor cells, osteoblasts and supporting cells of the bone, extracellular matrix, and the tissue microenvironment. The bioreactor platform used in these experiments also allows the implementation of physiologically relevant mechanical signals. Here, we describe a method to build an in vitro model of Ewing's sarcoma that mimics the key properties of the native tumor and provides the tissue context and physical regulatory signals. PMID- 27115505 TI - Uniform Embryoid Body Production and Enhanced Mesendoderm Differentiation with Murine Embryonic Stem Cells in a Rotary Suspension Bioreactor. AB - Embryonic stem cells (ESCs) are capable of differentiating into almost all cell types in vitro and hold great promise for drug screening, developmental studies and have a huge potential in many therapeutic areas. ESCs can aggregate to form embryoid body (EB) in static suspension culture by spontaneous differentiation, which resembles an intact embryo; while static suspension culture cannot prevent agglomeration of cells and offers little control over the size and shape of EBs, it results in aggregation of EBs into large, irregular masses, which prejudice the efficiency of differentiation of cells. Recently, bioreactor-based platforms have been shown to not only offer a beneficial effect on increasing diffusion of nutrients and oxygen which promotes cell viability and proliferation but also display local biomechanical properties (e.g., low fluid shear stresses and hydrodynamic force) in tissue development and organogenesis. This chapter describes a protocol for using a rotary suspension bioreactor to produce embryoid bodies and process the differentiation of mouse embryonic stem cells (mESCs), and to assess the efficiency of EB differentiation in the bioreactor by real-time PCR and immunostaining. PMID- 27115506 TI - Bioreactor Expansion of Skin-Derived Precursor Schwann Cells. AB - Scaling up the production of cells in a culture process is a critical step when trying to develop cell-based regenerative therapies. Static cultures often cannot be easily scaled up to clinically relevant cell numbers. Alternatively, bioreactors offer a highly valuable means to develop a clinical-ready process. To culture adherent cells in suspension, such as skin-derived precursor Schwann cells (SKP-SCs), microcarriers need to be used. Microcarriers are small spherical beads suspended within the vessel that allow for higher growth surface area to volume ratio. Here we describe the procedure of combining microcarriers with the controllability of bioreactors to generate higher cell densities in smaller reactor volumes leading to a more efficient and cost-effective cell production for applications in regenerative medicine. PMID- 27115507 TI - Cardiac dilatation index as an indicator of terminal central congestion evaluated using postmortem CT and forensic autopsy data. AB - Previous studies demonstrated possible application of postmortem quantitative CT data analysis of the heart and lung in situ to investigate terminal cardiopulmonary pathophysiology. The present study analyzed virtual CT morphometric and autopsy data of the heart to investigate terminal central congestion in forensic autopsy cases (n=113, within 3 days postmortem); the virtual total heart weight in situ was estimated using CT morphometry, and the difference from and ratio to the measured weight at autopsy were calculated as indicators of heart blood pooling and the cardiac dilatation index (CDI) before dissection, respectively. There were substantial differences between the estimated heart blood pooling in situ and volume recovered at autopsy, including a characteristic decrease in drowning, alcohol/sedative-hypnotic intoxication and sudden cardiac death (SCD), possibly due to blood redistribution after thoracic dissection. The estimated in situ heart blood pool and CDI values were higher in SCD but lower in fatal hemorrhage and hemopericardium, as well as in acute mechanical asphyxiation and hyperthermia (heatstroke). In addition, there was a significant difference in heart blood pooling between mechanical asphyxiation or drowning and SCD. The CDI was significantly lower in fatal hyperthermia (heatstroke) than in drowning, fatal methamphetamine abuse, alcohol/sedative hypnotic intoxication and SCD. These findings suggest the usefulness of applying the CDI and postmortem heart blood volume in situ as supplementary indicators of terminal central congestion, especially for investigating deaths from hemorrhage, hemopericardium, hyperthermia (heatstroke) and SCD. PMID- 27115508 TI - Transcranial direct current stimulation of the frontal-parietal-temporal area attenuates cue-induced craving for heroin. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is an effective approach to modulate brain region functions. We assessed if a single tDCS session over the bilateral frontal-parietal-temporal (FPT) areas would reduce cue induced craving in heroin addicts. METHODS: Twenty non-treated, long-term heroin-addicted subjects were randomly assigned to receive either real tDCS (1.5 mA, cathodal over bilateral FPT for 20 min) or control tDCS stimulation (turning off the stimulation after 30 s). The participants received heroin cue exposure (containing both injection and inhalation procedures) before and after stimulation and rated their craving after each block of cue presentation. RESULTS: Stimulation of the bilateral FPT with real tDCS for 20 min reduced craving scores significantly (68 +/- 8.4 pre-stimulation vs. 43 +/- 7.6 post stimulation, p = 0.003), while the control stimulation group showed no significant changes. No side effects of tDCS were reported. CONCLUSIONS: One session of tDCS over bilateral FPT area significantly reduced subjective craving score induced by heroin cues in heroin addicted subjects. PMID- 27115509 TI - Principal components analysis of agitation outcomes in Alzheimer's disease. AB - BACKGROUND: We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory. METHODS: We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects. RESULTS: The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22 0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62). CONCLUSIONS: Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure. PMID- 27115511 TI - Junctional Adhesion Molecule-A in Head and Neck Squamous Cell Carcinoma. AB - Junctional adhesion molecule-A (JAM-A), which belongs to the IgG superfamily, is one of the tight junction molecules. JAM-A is dysregulated in various cancers and is closely associated with the invasion and metastasis of cancers such as breast cancer, lung cancer and pancreatic cancer. In the present study, we found a high expression of JAM-A in head and neck squamous cell carcinoma (HNSCC) as well as beta-catenin in immunohistochemistry. The expression of JAM-A and beta-catenin was of a low level in differentiation-induced cancer pearl regions of HNSCC. Real time PCR showed the high expression of JAM-A mRNA through all differentiated stages (well, moderate, poor) of HNSCC. When we performed ELISA using the serum of HNSCC patients to measure plasma-soluble JAM-A, it was found to be higher in HNSCC patients than healthy subjects. These results indicate that JAM-A is one of the malignancy markers of HNSCC as well as beta-catenin in histopathology, and the plasma-soluble JAM-A may contribute to a serum diagnosis of HNSCC. JAM-A is a promising molecular target for diagnosis and therapy in HNSCC. PMID- 27115512 TI - A Quantitative Exposure Planning Tool for Surgical Approaches to the Sacroiliac Joint. AB - OBJECTIVES: To aid in surgical planning by quantifying and comparing the osseous exposure between the anterior and posterior approaches to the sacroiliac joint. METHODS: Anterior and posterior approaches were performed on 12 sacroiliac joints in 6 fresh-frozen torsos. Visual and palpable access to relevant surgical landmarks was recorded. Calibrated digital photographs were taken of each approach and analyzed using Image J. RESULTS: The average surface areas of exposed bone were 44 and 33 cm for the anterior and posterior approaches, respectively. The anterior iliolumbar ligament footprint could be visualized in all anterior approaches, whereas the posterior aspect could be visualized in all but one posterior approach. The anterior approach provided visual and palpable access to the anterior superior edge of the sacroiliac joint in all specimens, the posterior superior edge in 75% of specimens, and the inferior margin in 25% and 50% of specimens, respectively. The inferior sacroiliac joint was easily visualized and palpated in all posterior approaches, although access to the anterior and posterior superior edges was more limited. The anterior S1 neuroforamen was not visualized with either approach and was more consistently palpated when going posterior (33% vs. 92%). CONCLUSIONS: Both anterior and posterior approaches can be used for open reduction of pure sacroiliac dislocations, each with specific areas for assessing reduction. In light of current plate dimensions, fractures more than 2.5 cm lateral to the anterior iliolumbar ligament footprint are amenable to anterior plate fixation, whereas those more medial may be better addressed through a posterior approach. PMID- 27115513 TI - Immunomodulatory effects of mesenchymal stromal cells-derived exosome. AB - The mechanisms underlying immunomodulatory ability of mesenchymal stromal cells (MSCs) remain unknown. Recently, studies suggested that the immunomodulatory activity of MSCs is largely mediated by paracrine factors. Among which, exosome is considered to play a major role in the communication between MSCs and target tissue. The aim of our study is to investigate the effect of MSCs-derived exosome on peripheral blood mononuclear cells (PBMCs), especially T cells. We find that the MSCs-derived exosome extracted from healthy donors' bone marrow suppressed the secretion of pro-inflammatory factor TNF-alpha and IL-1beta, but increased the concentration of anti-inflammatory factor TGF-beta during in vitro culture. In addition, exosome may induce conversion of T helper type 1 (Th1) into T helper type 2 (Th2) cells and reduced potential of T cells to differentiate into interleukin 17-producing effector T cells (Th17). Moreover, the level of regulatory T cells (Treg) and cytotoxic T lymphocyte-associated protein 4 were also increased. These results suggested that MSC-derived exosome possesses the immunomodulatory properties. However, it showed no effects on the proliferation of PBMCs or CD3+ T cells, but increases the apoptosis of them. In addition, indoleamine 2, 3-dioxygenase (IDO) was previously shown to mediate the immunoregulation of MSCs, which was increased in PBMCs co-cultured with MSCs. In our study, IDO showed no significant changes in PBMCs exposed to MSCs-derived exosome. We conclude that exosome and MSCs might differ in their immune modulating activities and mechanisms. PMID- 27115516 TI - Management of Persistent Cognitive Symptoms After Sport-Related Concussion. AB - PURPOSE: This case review examines treatments speech-language pathologists at our clinic delivered to middle school, high school, and college students for the management of persistent cognitive symptoms after sport-related concussion. The goal is to examine a range of treatment options, describe clinical rationale for selecting those treatments, and report outcomes in order to identify feasible interventions for systematic evaluation through efficacy research. METHOD: Review of clinic intake data identified 63 cases referred for cognitive rehabilitation over a 36-month period. Twenty-four cases (14 women and 10 men) met selection criteria, including documented sport-related concussion, postconcussion symptoms persisting at least 2 months with deleterious effect on school performance, and enrollment in secondary or postsecondary education. The authors independently coded demographics, treatment approaches, functional goal domains, and outcomes. RESULTS: Treatment approaches fell into 4 broad categories: direct attention training, metacognitive strategy training, training assistive technology for cognition, and psychoeducational supports. Eighty-three percent of clients achieved self-selected functional goals. CONCLUSIONS: Research has focused primarily on return to play and provision of academic accommodations in the initial weeks following concussion. Findings from this case series suggest that speech-language pathologists can deliver individualized interventions that lead to positive clinical outcomes. The authors hope findings encourage efficacy research. PMID- 27115517 TI - Locating structures and evolution pathways of reconstructed rutile TiO2(011) using genetic algorithm aided density functional theory calculations. AB - Titanium dioxide (TiO2) is an important metal oxide that has been used in many different applications. TiO2 has also been widely employed as a model system to study basic processes and reactions in surface chemistry and heterogeneous catalysis. In this work, we investigated the (011) surface of rutile TiO2 by focusing on its reconstruction. Density functional theory calculations aided by a genetic algorithm based optimization scheme were performed to extensively sample the potential energy surfaces of reconstructed rutile TiO2 structures that obey (2 * 1) periodicity. A lot of stable surface configurations were located, including the global-minimum configuration that was proposed previously. The wide variety of surface structures determined through the calculations performed in this work provide insight into the relationship between the atomic configuration of a surface and its stability. More importantly, several analytical schemes were proposed and tested to gauge the differences and similarities among various surface structures, aiding the construction of the complete pathway for the reconstruction process. PMID- 27115515 TI - A Selective Transforming Growth Factor-beta Ligand Trap Attenuates Pulmonary Hypertension. AB - RATIONALE: Transforming growth factor-beta (TGF-beta) ligands signal via type I and type II serine-threonine kinase receptors to regulate broad transcriptional programs. Excessive TGF-beta-mediated signaling is implicated in the pathogenesis of pulmonary arterial hypertension, based in part on the ability of broad inhibition of activin-like kinase (ALK) receptors 4/5/7 recognizing TGF-beta, activin, growth and differentiation factor, and nodal ligands to attenuate experimental pulmonary hypertension (PH). These broad inhibition strategies do not delineate the specific contribution of TGF-beta versus a multitude of other ligands, and their translation is limited by cardiovascular and systemic toxicity. OBJECTIVES: We tested the impact of a soluble TGF-beta type II receptor extracellular domain expressed as an immunoglobulin-Fc fusion protein (TGFBRII Fc), serving as a selective TGF-beta1/3 ligand trap, in several experimental PH models. METHODS: Signaling studies used cultured human pulmonary artery smooth muscle cells. PH was studied in monocrotaline-treated Sprague-Dawley rats, SU5416/hypoxia-treated Sprague-Dawley rats, and SU5416/hypoxia-treated C57BL/6 mice. PH, cardiac function, vascular remodeling, and valve structure were assessed by ultrasound, invasive hemodynamic measurements, and histomorphometry. MEASUREMENTS AND MAIN RESULTS: TGFBRII-Fc is an inhibitor of TGF-beta1 and TGF beta3, but not TGF-beta2, signaling. In vivo treatment with TGFBRII-Fc attenuated Smad2 phosphorylation, normalized expression of plasminogen activator inhibitor 1, and mitigated PH and pulmonary vascular remodeling in monocrotaline-treated rats, SU5416/hypoxia-treated rats, and SU5416/hypoxia-treated mice. Administration of TGFBRII-Fc to monocrotaline-treated or SU5416/hypoxia-treated rats with established PH improved right ventricular systolic pressures, right ventricular function, and survival. No cardiac structural or valvular abnormalities were observed after treatment with TGFBRII-Fc. CONCLUSIONS: Our findings are consistent with a pathogenetic role of TGF-beta1/3, demonstrating the efficacy and tolerability of selective TGF-beta ligand blockade for improving hemodynamics, remodeling, and survival in multiple experimental PH models. PMID- 27115518 TI - Density functional theory of equilibrium random copolymers: application to surface adsorption of aggregating peptides. AB - We generalize a recently developed polymer density functional theory (PDFT) for polydisperse polymer fluids to the case of equilibrium random copolymers. We show that the generalization of the PDFT to these systems allows us to obtain a remarkable simplification compared to the monodispersed polymers. The theory is used to treat a model for protein aggregation into linear filaments in the presence of surfaces. Here we show that, for attractive surfaces, there is evidence of significant enhancement of protein aggregation. This behaviour is a consequence of a surface phase transition, which has been shown to occur with ideal equilibrium polymers in the presence of sufficiently attractive surfaces. For excluding monomers, this transition is suppressed, though an echo of the underlying ideal transition is present in the sudden change in the excess adsorption. PMID- 27115519 TI - Meiotic recombination analysis in female ducks (Anas platyrhynchos). AB - Meiotic recombination in female ducks was directly studied by immunolocalization of MLH1 protein, a mismatch repair protein of mature recombination nodules. In total, 6820 crossovers were scored along the autosomal synaptonemal complexes in 122 meiotic nuclei. From this analysis we predict that the female map length of the duck is 2845 cM, with a genome wide recombination rate of 2 cM/Mb. MLH1-focus mapping along the six largest bivalents shows regional variations of recombination frequencies that can be linked to differences in chromosome morphology. From this MLH1 mapping it can be inferred that distally located markers will appear more separated in genetic maps than physically equidistant markers located near the centromeres on bivalents 1 and 2. Instead, markers at interstitial positions on the acrocentric bivalents 3-6 will appear more tightly linked than expected on the basis of their physical distance because recombination is comparatively lower at the mid region of these chromosomes. The present results provide useful information to complement linkage mapping in ducks and extend previous knowledge about the variation of recombination rates among domestic Galloanserae. PMID- 27115521 TI - Driven colloidal fluids: construction of dynamical density functional theories from exactly solvable limits. AB - The classical dynamical density functional theory (DDFT) provides an approximate extension of equilibrium DFT to treat nonequilibrium systems subject to Brownian dynamics. However, the method fails when applied to driven systems, such as sheared colloidal dispersions. The breakdown of DDFT can be traced back to an inadequate treatment of the flow-induced distortion of the pair correlation functions. By considering the distortion of the pair correlations to second order in the flow-rate we show how to systematically correct the DDFT for driven systems. As an application of our approach we consider Poiseuille flow. The theory predicts that the particles will accumulate in spatial regions where the local shear rate is small, an effect known as shear-induced migration. We compare these predictions to Brownian dynamics simulations with generally good agreement. PMID- 27115522 TI - Blur and the perception of depth at occlusions. AB - The depth ordering of two surfaces, one occluding the other, can in principle be determined from the correlation between the occlusion border's blur and the blur of the two surfaces. If the border is blurred, the blurrier surface is nearer; if the border is sharp, the sharper surface is nearer. Previous research has found that observers do not use this informative cue. We reexamined this finding. Using a multiplane display, we confirmed the previous finding: Our observers did not accurately judge depth order when the blur was rendered and the stimulus presented on one plane. We then presented the same simulated scenes on multiple planes, each at a different focal distance, so the blur was created by the optics of the eye. Performance was now much better, which shows that depth order can be reliably determined from blur information but only when the optical effects are similar to those in natural viewing. We asked what the critical differences were in the single- and multiplane cases. We found that chromatic aberration provides useful information but accommodative microfluctuations do not. In addition, we examined how image formation is affected by occlusions and observed some interesting phenomena that allow the eye to see around and through occluding objects and may allow observers to estimate depth in da Vinci stereopsis, where one eye's view is blocked. Finally, we evaluated how accurately different rendering and displaying techniques reproduce the retinal images that occur in real occlusions. We discuss implications for computer graphics. PMID- 27115523 TI - Real-world effectiveness of ledipasvir/sofosbuvir in 4,365 treatment-naive, genotype 1 hepatitis C-infected patients. AB - Real-world effectiveness data are needed to inform hepatitis C virus (HCV) treatment decisions. The uptake of ledipasvir/sofosbuvir (LDV/SOF) regimens across health care settings has been rapid, but variations often occur in clinical practice. The aim of this study was to assess sustained virologic response (SVR) of LDV/SOF+/-ribavirin (RBV) in routine medical practice. This observational, intent-to-treat cohort was comprised of 4,365 genotype 1, treatment-naive, HCV-infected veterans treated with LDV/SOF+/-RBV. SVR rates were 91.3% (3,191/3,495) for LDV/SOF and 92.0% (527/573) for LDV/SOF+RBV (P = 0.65). African American race (odds ratio 0.70, 95% confidence interval 0.54-0.90, P = 0.004) and FIB-4 >3.25 (odds ratio 0.56, 95% confidence interval 0.43-0.71, P < 0.001) were independently associated with decreased likelihood of SVR; age, sex, body mass index, decompensated liver disease, diabetes, genotype 1 subtype, and regimen did not predict SVR. In models limited to those who completed 12 weeks of treatment, African American race was no longer a significant predictor of SVR but FIB-4 >3.25 (odds ratio 0.35, 95% confidence interval 0.24-0.50, P < 0.001) remained. Among those without cirrhosis (defined by FIB-4 <=3.25) and with baseline HCV RNA<6,000,000 IU/mL, SVR rates were 93.2% (1,020/1,094) for those who completed 8 weeks of therapy and 96.6% (875/906) for those who completed 12 weeks of therapy (P = 0.001). CONCLUSIONS: In this real-world cohort, SVR rates with LDV/SOF+/-RBV nearly matched the rates reported in clinical trials and were consistently high across all subgroups; those without cirrhosis but with HCV RNA<6,000,000 IU/mL were less likely to achieve SVR with 8 weeks compared to 12 weeks of therapy, although the numeric difference in SVR rates was small. (Hepatology 2016;64:405-414). PMID- 27115524 TI - Erythrocyte rheological properties but not whole blood and plasma viscosity are associated with severity of hypertension in older people. AB - OBJECTIVE: This study was carried out to determine whether changes in hemorheological parameters parallel the severity of essential hypertension. METHODS: A total of 198 older hypertensive patients were recruited and classified into 3 stages of hypertension according to the grading standard of hypertension. The whole blood viscosity (WBV) at various shear rates, plasma viscosity and erythrocyte rheology (including erythrocyte rigidity index, erythrocyte aggregation index and erythrocyte deformation index) were examined. RESULTS: Erythrocyte rheology paralleled the severity of essential hypertension and was significantly correlated to the average 24 h systolic blood pressure and diastolic blood pressure. Logistic analysis revealed that erythrocyte rigidity and the erythrocyte aggregation index were positively correlated with the severity of hypertension, while the erythrocyte deformation index was negatively correlated. No association was found between WBV, plasma viscosity and the severity of hypertension. CONCLUSION: The rheological properties of erythrocyte viscosity were correlated with the severity of hypertension in older people but the WBV and plasma viscosity were not. PMID- 27115526 TI - Deficiency of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Intestinal Epithelial Cells Has No Appreciable Impact on Dextran Sulphate Sodium Colitis Severity But Promotes Wound Healing. AB - BACKGROUND/AIMS: The protein tyrosine phosphatase non-receptor type 2 (PTPN2) is known to mediate susceptibility to inflammatory bowel diseases. Cell culture experiments suggest that PTPN2 influences barrier function, autophagy and secretion of pro-inflammatory cytokines. PTPN2 knockout mice die a few weeks after birth due to systemic inflammation, emphasizing the importance of this phosphatase in inflammatory processes. The aim of this study was to investigate the role of PTPN2 in colon epithelial cells by performing dextran sulphate sodium (DSS)-induced colitis in PTPN2xVilCre mice. METHODS: Acute colitis was induced by administering 2.5 or 2% DSS for 7 days and chronic colitis by 4 cycles of treatment using 1% DSS. Body weight of mice was measured regularly and colonoscopy was done at the end of the experiments. Mice were sacrificed afterwards and colon specimens were obtained for H&E staining. For analysis of wound healing, mechanical wounds were introduced during endoscopy and wound closure assessed by daily colonoscopy. RESULTS: Although colonoscopy and weight development suggested changes in colitis severity, the lack of any influence of PTPN2 deficiency on histological scoring for inflammation severity after acute or chronic DSS colitis indicates that colitis severity is not influenced by epithelial-specific loss of PTPN2. Chronic colitis induced the development of aberrant crypt foci more frequently in PTPN2xVilCre mice compared to their wild type littermates. On the other hand, loss of PTPN2-induced enhanced epithelial cell proliferation and promoted wound closure. CONCLUSIONS: Loss of PTPN2 in intestinal epithelial cells (IECs) has no significant influence on inflammation in DSS colitis. Obviously, loss of PTPN2 in IECs can be compensated in vivo, thereby suppressing a phenotype. This lack of a colitis-phenotype might be due to enhanced epithelial cell proliferation and subsequent increased wound-healing capacity of the epithelial layer. PMID- 27115525 TI - Finerenone: a New Mineralocorticoid Receptor Antagonist Without Hyperkalemia: an Opportunity in Patients with CKD? AB - Aldosterone binds to the mineralocorticoid receptor and has an important regulatory role in body fluid and electrolyte balance. It also influences a variety of different cell functions such as oxidative stress, inflammation and organ fibrosis. The important role of the tissue-specific mineralocorticoid receptors in cardiovascular and renal injury has been shown in knockout animals and in clinical studies Mineralocorticoid receptor antagonists seem to exert their beneficial effects via anti-oxidative, anti-inflammatory and anti-fibrotic effects. Spironolactone and eplerenone were the first steroidal mineralocorticoid receptor antagonist. The established steroidal mineralocorticoid receptor antagonists show important therapeutic effects but are hampered by a variety of side effects, most importantly clinically significant hyperkaliemia. Selective non-steroidal mineralocorticoid receptor antagonists have been recently developed and demonstrate effectiveness in early clinical trials. Finereroneholds promise for the future application of this new mineralocorticoid receptor antagonist class in patients with chronic kidney disease since it has shown a significant reduction in UACR combined with a safety profile similar to that in the placebo group. However, further long-term studies investigating relevant clinical end points like reduction in cardiovascular or renal event rate are warranted. PMID- 27115527 TI - Recyclable Magnetic Mesoporous Nanocomposite with Improved Sensing Performance toward Nitrite. AB - A magnetic nanomaterial for nitrite ion detection was demonstrated in the present study. This nanomaterial was prepared by grafting a rhodamine 6G derivative (denoted as Rh 6G-OH) into the channels of core-shell magnetic mesoporous silica nanospheres. The nanocomposite (denoted as Fe3O4@Rh 6G) showed large surface area and improved fluorescent performance to accumulate and recognize NO2(-), and its superparamagnetic behavior played an important role in reusability. The fluorescent intensity decreased linearly along with the NO2(-) concentration in the range of 1-50 MUM, and the detection limit was estimated to be 0.8 MUM, which was much lower than the maximum limit of nitrite ion in drinking water (65 MUM) recommended by World Health Organization. Importantly, Fe3O4@Rh 6G could be magnetically collected and effectively reutilized after six test cycles. PMID- 27115528 TI - Reliability and validity of the Hungarian version of the Pittsburgh Sleep Quality Index (PSQI-HUN): comparing psychiatric patients with control subjects. AB - PURPOSE: The Pittsburgh Sleep Quality Index is used to evaluate subjective sleep quality, and it is commonly used in clinical research. Subjective sleep quality is also an important clinical measure in patients with psychiatric disorders. The aim of the present study was to evaluate the reliability and validity of the Hungarian version of the Pittsburgh Sleep Quality Index (PSQI-HUN) in both clinical and non-clinical samples. METHODS: The original version of PSQI was translated into Hungarian according to standard guidelines. The PSQI-HUN and the Athens Insomnia Scale (AIS) were subsequently administered to 53 psychiatric patients (schizophrenia, recurrent depressive disorder, mixed anxiety, and depressive disorder) and 178 healthy controls. RESULTS: Internal consistency as measured by Cronbach's alpha in the whole sample was 0.79. Pearson's product moment correlations between component scores and the global scores were high (0.59-0.88) in the PSQI-HUN indicating the homogeneity of the scale. PSQI-HUN global and component scores differed significantly between psychiatric patients and control subjects. In the psychiatric patient subsample, schizophrenics had lower global scores compared to the other two patient groups. The analysis of convergent validity showed significant correlations between the AIS and the global as well as the component scores of the PSQI-HUN (except the component of sleep latency). CONCLUSIONS: The present study concludes that the PSQI-HUN is a reliable, valid, and standardized measure for assessment of the subjective sleep quality in clinical and research settings. PMID- 27115529 TI - Structural and functional retinal abnormalities in type 2 diabetes with obstructive sleep apnea. PMID- 27115531 TI - The Evolution of Modern Cardiac Surgery and the Necessity to Change. AB - This article depicts the Kit V. Arom Lecture, which was held at the 15th Annual Congress of the International Society for Minimally Invasive Cardiothoracic Surgery in Berlin, Germany. It describes the evolution of modern cardiac surgery and the necessity for cardiac surgeons to change. The article is dedicated to a pioneer in minimally invasive cardiac surgery and a good friend, Kit V. Arom, MD. PMID- 27115532 TI - Transaortic Aortic Valve Implantation in 100 Patients: Follow-up to 3 Years. AB - OBJECTIVE: Transaortic aortic valve implantation (TAo-AVI) through the ascending aorta is a novel technique and is used as an alternative in patients with poor femoral access. Although early results have been promising, no midterm data have been published yet. To determine whether this approach is an acceptable treatment option, we analyzed the first 100 cases performed at our institution with a follow-up to 3 years. METHODS: Between July 2011 and January 2015, a total of 100 patients with high-risk or inoperable aortic valve stenosis were treated with TAo AVI. Preoperative patient data were collected and analyzed retrospectively. All surviving patients were seen for clinical and echocardiographic examination for follow-up. RESULTS: Median follow-up was 15 months. Device success was accomplished in 94 patients (94%). There were no access site complications. The 30-day mortality rate was 9%. Stroke occurred in a total of six patients (6%). Survival at 1-, 2-, and 3 years was 75%, 62%, and 58%, respectively. CONCLUSIONS: Our results show that TAo-AVI is a promising alternative to transapical implantation for treating severe inoperable aortic valve stenosis. PMID- 27115533 TI - Health-Related Quality of Life After Minimally Invasive Cardiac Surgery. AB - OBJECTIVE: Factors influencing health-related quality of life (HRQL) after minimally invasive cardiac surgery have not been well described. We examined the trajectory of HRQL after minimally invasive cardiac surgery and the role of perioperative factors and rhythm on HRQL changes. METHODS: Patients underwent minimally invasive surgical ablation for atrial fibrillation and/or valve surgery (n = 235). Health-related quality of life (SF-12) and clinical status were assessed preoperatively and postoperatively. RESULTS: Physical summary HRQL (F = 36.2, P < 0.001) and mental summary HRQL (F = 3.2, P = 0.047) improved significantly by 12 months after surgery. Improvement on HRQL peaked at 6 months and plateaued between 6 and 12 months. Physical HRQL was similar to age-based normal values before surgery (P = 0.66) and surpassed norms by 6 months after surgery (P < 0.001). Younger age (r = -0.15, P = 0.02) and lower EuroSCORE II (r = -0.19, P = 0.003) correlated with greater HRQL improvements by 6 months. Only lower EuroSCORE II (r = -0.14, P = 0.04) correlated with greater HRQL improvement by 12 months. Length of stay and major morbidity were not related to HRQL improvement. In surgical ablation patients, restoration of stable sinus rhythm throughout the first 12 months was associated with greater physical HRQL improvement by 6 months compared with patients who had atrial arrhythmia recurrences (change, 5.0 vs. -1.0, P = 0.02). CONCLUSIONS: Health-related quality of life improved significantly after minimally invasive cardiac surgery. These improvements were influenced by age, operative risk, symptoms, and rhythm status. Even patients with HRQL in a normal range before surgery can experience improved HRQL after surgery. Minimally invasive cardiac surgery can offer decreased postoperative complications and also improved HRQL. PMID- 27115534 TI - Robotic Septal Myectomy and Mitral Valve Repair for Idiopathic Hypertrophic Subaortic Stenosis With Systolic Anterior Motion. AB - Combined therapeutic approach with performing mitral valve repair may be necessitated for the treatment of idiopathic hypertrophic subaortic stenosis (IHSS) with systolic anterior motion. This report includes operative technique for combined robotic septal myectomy and mitral valve repair. A 45-year-old man with IHSS was admitted to our center for surgical intervention. The transthoracic echocardiography showed typical asymmetric ventricular hypertrophy. Left ventricle posterior wall thickness was 11 mm, and interventricular septum thickness was 21 mm. Mitral valve leaflets were found to be elongated. Mild-to severe mitral regurgitation was detected with eccentric mitral jet. Aortic peak gradient was 128 mm Hg. Robotic mitral repair and septal myectomy through left atrial exposure was performed. The anterior leaflet was detached, and the septal muscle in a mass of 1 * 0.7 * 0.5 cm was resected. Next, the anterior leaflet was reattached with continuous suture. The plication of the posterior leaflet with transverse incision was performed to diminish the length of posterior leaflet. After the magic suture for posteromedial commissure was performed, a 34 Medtronic Future ring was implanted for mitral annuloplasty. Postoperative course was uneventful. The patient was discharged on the sixth postoperative day. Combined robotic septal myectomy and mitral valve repair for IHSS with systolic anterior motion may be feasible. PMID- 27115536 TI - Exposure of a Dengue Vector to Tea and Its Waste: Survival, Developmental Consequences, and Significance for Pest Management. AB - Dengue mosquitoes are evolving into a broader global public health menace, with relentless outbreaks and the rise in number of Zika virus disease cases as reminders of the continued hazard associated with Aedes vectors. The use of chemical insecticides-the principal strategy against mosquito vectors-has been greatly impeded due to the development of insecticide resistance and the shrinking spectrum of effective agents. Therefore, there is a pressing need for new chemistries for vector control. Tea contains hundreds of chemicals, and its waste, which has become a growing global environmental problem, is almost as rich in toxicants as green leaves. This paper presents the toxic and sublethal effects of different crude extracts of tea on Aedes albopictus. The survival rates of larvae exposed to tea extracts, especially fresh tea extract (FTE), were markedly lower than those in the control treatment group. In addition to this immediate toxicity against different developmental stages, the extracts tested caused a broad range of sublethal effects. The developmental time was clearly longer in containers with tea, especially in those with young larvae (YL) and FTE. Among the survivors, pupation success was reduced in containers with tea, which also produced low adult emergence rates with increasing tea concentration. The production of eggs tended to be reduced in females derived from the tea treatment groups. These indirect effects of tea extracts on Ae. albopictus exhibited different patterns according to the exposed larval stage. Taken together, these findings indicate that tea and its waste affect most key components of Ae. albopictus vectorial capacity and may be useful for dengue control. Reusing tea waste in vector control could also be a practical solution to the problems associated with its pollution. PMID- 27115535 TI - Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery. AB - Intra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Chatelier's principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery. PMID- 27115538 TI - Divergent transcription and epigenetic directionality of human promoters. AB - Genome-wide datasets measuring nascent RNA have revealed that active human promoters frequently display divergent transcription, generating a stable mRNA in the forward direction toward the gene and a typically unstable one in the reverse direction away from the gene. Recent work has shown that these transcripts originate from two distinct core promoters within a single nucleosome-free region (NFR). Different levels of forward and reverse activity lead to a wide range of directionality for promoter NFRs. Importantly, directionality is also reflected in the epigenetic modifications of nucleosomes immediately adjacent to the NFR. Here, we review the current literature pertaining to divergent transcription from promoter NFRs and its association with combinatorial histone post-translational modifications, or chromatin states, on upstream and downstream nucleosomes. Finally, we discuss several models to interpret the directionality of promoter chromatin states. PMID- 27115539 TI - A Global Scale Scenario for Prebiotic Chemistry: Silica-Based Self-Assembled Mineral Structures and Formamide. AB - The pathway from simple abiotically made organic compounds to the molecular bricks of life, as we know it, is unknown. The most efficient geological abiotic route to organic compounds results from the aqueous dissolution of olivine, a reaction known as serpentinization (Sleep, N.H., et al. (2004) Proc. Natl. Acad. Sci. USA 101, 12818-12822). In addition to molecular hydrogen and a reducing environment, serpentinization reactions lead to high-pH alkaline brines that can become easily enriched in silica. Under these chemical conditions, the formation of self-assembled nanocrystalline mineral composites, namely silica/carbonate biomorphs and metal silicate hydrate (MSH) tubular membranes (silica gardens), is unavoidable (Kellermeier, M., et al. In Methods in Enzymology, Research Methods in Biomineralization Science (De Yoreo, J., Ed.) Vol. 532, pp 225-256, Academic Press, Burlington, MA). The osmotically driven membranous structures have remarkable catalytic properties that could be operating in the reducing organic rich chemical pot in which they form. Among one-carbon compounds, formamide (NH2CHO) has been shown to trigger the formation of complex prebiotic molecules under mineral-driven catalytic conditions (Saladino, R., et al. (2001) Biorganic & Medicinal Chemistry, 9, 1249-1253), proton irradiation (Saladino, R., et al. (2015) Proc. Natl. Acad. Sci. USA, 112, 2746-2755), and laser-induced dielectric breakdown (Ferus, M., et al. (2015) Proc Natl Acad Sci USA, 112, 657-662). Here, we show that MSH membranes are catalysts for the condensation of NH2CHO, yielding prebiotically relevant compounds, including carboxylic acids, amino acids, and nucleobases. Membranes formed by the reaction of alkaline (pH 12) sodium silicate solutions with MgSO4 and Fe2(SO4)3.9H2O show the highest efficiency, while reactions with CuCl2.2H2O, ZnCl2, FeCl2.4H2O, and MnCl2.4H2O showed lower reactivities. The collections of compounds forming inside and outside the tubular membrane are clearly specific, demonstrating that the mineral self-assembled membranes at the same time create space compartmentalization and selective catalysis of the synthesis of relevant compounds. Rather than requiring odd local conditions, the prebiotic organic chemistry scenario for the origin of life appears to be common at a universal scale and, most probably, earlier than ever thought for our planet. PMID- 27115540 TI - Influence of Subtropical Region Strawberry Cultivars on Jelly Characteristics. AB - At the end of the production period of strawberries grown in subtropical regions, postharvest durability is severely diminished due to rising temperatures which compromises the commercialization of fresh fruit. An ideal option would be to process strawberries in the form of preserves, jams, and jellies. Along this line it becomes extremely important to conduct a survey of which cultivars grown in subtropical regions are more suitable for processing in the form of jelly, as well as to understand what the consumer profile is for this product. The objective of this study was to evaluate the influence of different strawberry cultivars grown in subtropical regions of Brazil (Camarosa, Festival, San Andreas, Oso Grande, Camino Real, and Albion) on the physicochemical characteristics, rheological properties and sensory acceptance of the resulting jelly in order to identify cultivars with the greatest potential for industrial use. The strawberry cultivars presented different physicochemical characteristics which resulted in jellies with different physicochemical and rheological characteristics. In this study, however, we verified that all cultivars have potential to be processed in the form of jelly due to good acceptance of all formulations prepared. In general consumers prefer a lighter-colored strawberry jelly, with a less intense red color, more acidic, and less consistent/firm. PMID- 27115541 TI - The several elements of intestinal innate immune system at the beginning of the life of broiler chicks. AB - Functional capacity of digestive system and intestinal adaptive immunity are immature at hatching of broiler chicks. Therefore, intestinal innate immunity after hatching is vital to young chicks. The purpose of this study was to investigate expression and tissue distributions of several elements of the innate immune system (i.e., TLR2, TLR4, CD83, and MHC class II expressing cells) in the intestine of one-day-old chicks. For this purpose, ileum and cecum were examined the under different conditions, which included the control and 1, 3, 6, 12, or 24 h after injection of lipopolysaccharide (LPS) and phosphate buffered saline. The findings indicated that regardless of the antigenic stimulation, Toll-like receptor (TLR) 2 and TLR4 expressing cells were present in the intestinal tissues of one-day-old chicks. We noticed that the intestinal segments have different TLR expression levels after LPS stimulation. Dendritic cells were identified, and they left the intestinal tissue after LPS treatment. MHC class II molecules were diffusely present in both the ileum and cecum. This study demonstrates that the intestinal tissue of one-day-old chicks has remarkable defensive material, including histological properties and several elements of the innate immune system. Microsc. Res. Tech. 79:604-614, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27115554 TI - Pi Band Dispersion along Conjugated Organic Nanowires Synthesized on a Metal Oxide Semiconductor. AB - Surface-confined dehalogenation reactions are versatile bottom-up approaches for the synthesis of carbon-based nanostructures with predefined chemical properties. However, for devices generally requiring low-conductivity substrates, potential applications are so far severely hampered by the necessity of a metallic surface to catalyze the reactions. In this work we report the synthesis of ordered arrays of poly(p-phenylene) chains on the surface of semiconducting TiO2(110) via a dehalogenative homocoupling of 4,4"-dibromoterphenyl precursors. The supramolecular phase is clearly distinguished from the polymeric one using low energy electron diffraction and scanning tunneling microscopy as the substrate temperature used for deposition is varied. X-ray photoelectron spectroscopy of C 1s and Br 3d core levels traces the temperature of the onset of dehalogenation to around 475 K. Moreover, angle-resolved photoemission spectroscopy and tight binding calculations identify a highly dispersive band characteristic of a substantial overlap between the precursor's pi states along the polymer, considered as the fingerprint of a successful polymerization. Thus, these results establish the first spectroscopic evidence that atomically precise carbon-based nanostructures can readily be synthesized on top of a transition-metal oxide surface, opening the prospect for the bottom-up production of novel molecule semiconductor devices. PMID- 27115556 TI - Interactions of Polyethylenimines with Zwitterionic and Anionic Lipid Membranes. AB - Interactions between polyethylenimines (PEIs) and phospholipid membranes are of fundamental importance for various biophysical applications of these polymers such as gene delivery. Despite investigations into the nature of these interactions, their molecular basis remains poorly understood. In this article, we combined experimental methods and atomistic molecular dynamics (MD) simulations to obtain comprehensive insight into the effect of linear and branched PEIs on zwitterionic and anionic bilayers used as simple models of mammalian cellular membranes. Our results show that PEIs adsorb only partially on the surface of zwitterionic membranes by forming hydrogen bonds to the lipid headgroups, whereas a large part of the polymer chains dangles freely in the aqueous phase. In contrast, PEIs readily adhere to and insert into the anionic membrane. The attraction of the polymer chains to the membrane is due to electrostatic interactions as well as hydrogen bonding between the amine groups of PEI and the phosphate groups of lipids. These interactions were found to induce a substantial reorganization of the bilayer in the polymer vicinity due to the reorientation of lipid molecules. The lipid headgroups were pulled toward the center of the membrane, which can facilitate transmembrane translocations of anionic lipids. Furthermore, the PEI-lipid interactions affect the stability of liposomal dispersions, but we did not see any evidence of disruption of the vesicular structures into small fragments at polymer concentrations typically used in gene therapy. Our results provide a detailed molecular-level description of the lipid organization in the membrane in the presence of polycations that can be useful in understanding their mechanisms of in vitro and in vivo cytotoxicity. PMID- 27115555 TI - Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit. AB - The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays. PMID- 27115559 TI - The Oregon Experience: What Do We Really Know? PMID- 27115558 TI - Acculturation and quality of life in urban, African American caregivers of children with asthma. AB - OBJECTIVE: Racial/ethnic minority caregivers of children with asthma are at risk for low levels of quality of life (QOL). Limited research has identified factors that contribute to lower QOL among African American caregivers. This study examined associations between acculturation (e.g., engaging in values/beliefs traditional of one's culture versus adopting mainstream cultural views) and caregiver QOL in low-income, urban African American families of children (7-12 years) with persistent asthma. We also investigated the association between caregiver QOL and child emergency department (ED) use. METHODS: Fifty-five caregivers and their children completed interview-based questionnaires in a single research session. Caregivers completed the Pediatric Asthma Caregiver Quality of Life Questionnaire (PACQLQ), the African American Acculturation Scale Revised (AAAS-R), and reported on child asthma variables. Children completed items assessing asthma control. RESULTS: Higher overall QOL and emotional function subscale scores were associated with more traditional African American religious beliefs/practices (r = .288, p = .033; r = .333, p = .013). Higher emotional function subscale scores were associated with more traditional values of African American families (r = .306, p = .023). Lower QOL was found among caregivers of children who had visited the ED three or more times in the last year. CONCLUSIONS: Less acculturation tied to religious beliefs/practices and family values (as measured by the AAAS-R) may serve a protective role in reducing the burden low-income, urban African American caregivers experience in managing child asthma. This study is the first of its kind to study acculturation in African American caregivers of children with asthma. PMID- 27115557 TI - Tunable Thermal-Sensitive Polymer-Graphene Oxide Composite for Efficient Capture and Release of Viable Circulating Tumor Cells. AB - A highly sensitive microfluidic system to capture circulating tumor cells from whole blood of cancer patients is presented. The device incorporates graphene oxide into a thermoresponsive polymer film to serve as the first step of an antibody functionalization chemistry. By decreasing the temperature, captured cells may be released for subsequent analysis. PMID- 27115560 TI - One-Step Synthesis of Diverse Pyridine-Containing Heterocycles with 3 Ethoxycyclobutanones at Room Temperature. AB - An efficient and convenient approach toward a diversity-oriented synthesis of bioactive pyridine-containing fused heterocycles is described. Through a Lewis acid catalyzed union of 3-ethoxycyclobutanones with various heterocyclic amines, a broad range of heterocyclic compounds were prepared readily at ambient temperature with excellent regioselectivity. PMID- 27115561 TI - Maxillary Anterior Segmental Distraction Osteogenesis to Correct Maxillary Deficiencies in a Patient With Cleft Lip and Palate. AB - This report describes a case of successful orthodontic treatment using maxillary anterior segmental distraction osteogenesis with an internal maxillary distractor and bilateral sagittal split ramus osteotomy in a girl with cleft lip and palate. A 16-year-old girl with unilateral cleft lip and palate exhibited midface retrusion because of growth inhibition of the maxillary complex and mandibular excess. After the presurgical orthodontic treatment, 6.0-mm advancement of the maxillary anterior segment and 4.0-mm set back of the mandible were performed. After a retention period, the patient's midface convexity was greatly improved and the velopharyngeal competence was preserved without relapse. PMID- 27115562 TI - Interferon Regulatory Factor 6 Controls Proliferation of Keratinocytes From Children With Van der Woude Syndrome. AB - OBJECTIVE: Interferon Regulatory Factor 6 (IRF6) is critical for craniofacial development, epidermal differentiation, and tissue repair. IRF6 mutations cause Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome. Individuals with VWS exhibit craniofacial anomalies, including cleft lip and palate and lip pits. Furthermore, they have an increased risk for wound-healing complications following surgical repair when compared with patients with nonsyndromic cleft lip and palate (NSCLP). However, nothing is known about the skin of these patients. The objective was to characterize the skin of patients with VWS. We hypothesize that IRF6 is required for proper skin homeostasis in humans. DESIGN: Discarded tissue from a hip was collected during surgical alveolar bone graft. Samples from children with VWS harboring IRF6 mutations (n = 2) were compared with samples from children with NSCLP (n = 7). Histology was assessed following hematoxylin and eosin staining. The expressions of Proliferating Cell Nuclear Antigen, IRF6, P63, and Keratin 10 were determined by immunofluorescence. Keratinocytes were isolated and their proliferation potential was assessed by colony-forming efficiency assay. RESULTS: Hip skin from children with VWS showed a thicker epidermis when compared with that from children with NSCLP. Proliferating Cell Nuclear Antigen staining revealed an increase in proliferation in syndromic tissues when compared with controls. However, P63 and Keratin 10 expression were similar between groups. Finally, keratinocytes from VWS showed increased long term proliferation when compared with NSCLP. CONCLUSIONS: These results support, in vivo and in vitro, a previously described role for IRF6 in epidermal proliferation in humans. They further demonstrate a critical function for IRF6 in cutaneous homeostasis. PMID- 27115563 TI - Response to "Older Adults' Experiences of Living With Cleft Lip and Palate: A Qualitative Study Exploring Ageing and Appearance". PMID- 27115564 TI - New developments in classical density functional theory. PMID- 27115565 TI - Tele-Interpersonal Psychotherapy Acutely Reduces Depressive Symptoms in Depressed HIV-Infected Rural Persons: A Randomized Clinical Trial. AB - Human immunodeficiency virus (HIV)-positive rural individuals carry a 1.3-times greater risk of a depressive diagnosis than their urban counterparts. This randomized clinical trial tested whether telephone-administered interpersonal psychotherapy (tele-IPT) acutely relieved depressive symptoms in 132 HIV-infected rural persons from 28 states diagnosed with Diagnostic and Statistical Manual of Mental Disorders-IV major depressive disorder (MDD), partially remitted MDD, or dysthymic disorder. Patients were randomized to either 9 sessions of one-on-one tele-IPT (n = 70) or standard care (SC; n = 62). A series of intent-to-treat (ITT), therapy completer, and sensitivity analyses assessed changes in depressive symptoms, interpersonal problems, and social support from pre- to postintervention. Across all analyses, tele-IPT patients reported significantly lower depressive symptoms and interpersonal problems than SC controls; 22% of tele-IPT patients were categorized as a priori "responders" who reported 50% or higher reductions in depressive symptoms compared to only 4% of SC controls in ITT analyses. Brief tele-IPT acutely decreased depressive symptoms and interpersonal problems in depressed rural people living with HIV. PMID- 27115566 TI - Understanding the impact of breast cancer adjuvant endocrine therapy on cognitive function: a work in progress. PMID- 27115567 TI - Quality of life, long-term survivors and long-term outcome from the ABC-02 study. AB - BACKGROUND: The ABC-02 (Advanced Biliary Tract Cancer) study established cisplatin and gemcitabine (CisGem) as the standard first-line chemotherapy for patients with locally advanced or metastatic biliary tract cancer (BTC). We examine quality of life (QoL), describe the long-term survivors and provide a long-term outcome. METHODS: A total of 410 BTC patients were randomised to receive either CisGem or gemcitabine alone (Gem); 324 patients consented to complete EORTC QLQ-C30 and EORTC QLQ-PAN26 QoL questionnaires; 268 (83%) patients returned at least one QoL questionnaire (134 in each arm). Long-term survivors were defined as those surviving over 2 years and we performed a final analysis of the primary outcome; overall survival (OS). RESULTS: Most QoL scales showed a trend favouring the combined CisGem arm, including functional and symptomatic scales, although the differences were not statistically significant. Forty-five (11%)) patients survived at least 2 years (34 received CisGem and 11 Gem) and 21 (5%) 3 years or more (14 received CisGem and 7 Gem). After a median follow-up of 9.2 months and 398 deaths, the median OS was 11.7 months for CisGem and 8.1 months for Gem (hazard ratio (HR)=0.65, 95% CI: 0.53-0.79, P<0.001). CONCLUSIONS: The survival advantage of CisGem compared to Gem was not associated with an improvement or deterioration of QoL. Long-term survivors were more likely to have received CisGem and the long-term OS is identical to that previously described. PMID- 27115568 TI - Mipsagargin, a novel thapsigargin-based PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with refractory, advanced or metastatic solid tumours. AB - BACKGROUND: Mipsagargin (G-202; (8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin)-Asp-gamma-Glu-gamma-Glu-gamma-GluGluOH)) is a novel thapsigargin based targeted prodrug that is activated by PSMA-mediated cleavage of an inert masking peptide. The active moiety is an inhibitor of the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump protein that is necessary for cellular viability. We evaluated the safety of mipsagargin in patients with advanced solid tumours and established a recommended phase II dosing (RP2D) regimen. METHODS: Patients with advanced solid tumours received mipsagargin by intravenous infusion on days 1, 2 and 3 of 28-day cycles and were allowed to continue participation in the absence of disease progression or unacceptable toxicity. The dosing began at 1.2 mg m(-2) and was escalated using a modified Fibonacci schema to determine maximally tolerated dose (MTD) with an expansion cohort at the RP2D. Plasma was analysed for mipsagargin pharmacokinetics and response was assessed using RECIST criteria. RESULTS: A total of 44 patients were treated at doses ranging from 1.2 to 88 mg m(-2), including 28 patients in the dose escalation phase and 16 patients in an expansion cohort. One dose-limiting toxicity (DLT; Grade 3 rash) was observed in the dose escalation portion of the study. At 88 mg m(-2), observations of Grade 2 infusion-related reaction (IRR, 2 patients) and Grade 2 creatinine elevation (1 patient) led to declaration of 66.8 mg m(-2) as the recommended phase II dose (RP2D). Across the study, the most common treatment-related adverse events (AEs) were fatigue, rash, nausea, pyrexia and IRR. Two patients developed treatment related Grade 3 acute renal failure that was reversible during the treatment-free portion of the cycle. To help ameliorate the IRR and creatinine elevations, a RP2D of 40 mg m(-2) on day 1 and 66.8 mg m(-2) on days 2 and 3 with prophylactic premedications and hydration on each day of infusion was established. Clinical response was not observed, but prolonged disease stabilisation was observed in a subset of patients. CONCLUSIONS: Mipsagargin demonstrated an acceptable tolerability and favourable pharmacokinetic profile in patients with solid tumours. PMID- 27115569 TI - Tubal ligation and incidence of 26 site-specific cancers in the Million Women Study. AB - BACKGROUND: Tubal ligation is known to be associated with a reduction in ovarian cancer risk. Associations with breast, endometrial and cervical cancers have been suggested. We investigated associations for 26 site-specific cancers in a large UK cohort. METHODS: Study participants completed a questionnaire on reproductive and lifestyle factors in 1996-2001, and were followed for cancer and death via national registries. Using Cox regression models, we estimated adjusted relative risks (RRs) for 26 site-specific cancers among women with vs without tubal ligation. RESULTS: In 1 278 783 women without previous cancer, 167 430 incident cancers accrued during 13.8 years' follow-up. Significantly reduced risks were found in women with tubal ligation for cancers of the ovary (RR=0.80, 95% CI: 0.76-0.85; P<0.001; n=8035), peritoneum (RR=0.81, 0.66-0.98; P=0.03; n=730), and fallopian tube (RR=0.60, 0.37-0.96; P=0.04; n=168). No significant associations were found for endometrial, breast, or cervical cancers. CONCLUSIONS: The reduced risks of ovarian, peritoneal and fallopian tube cancers are consistent with hypotheses of a common origin for many tumours at these sites, and with the suggestion that tubal ligation blocks cells, carcinogens or other agents from reaching the ovary, fallopian tubes and peritoneal cavity. PMID- 27115570 TI - The effect of aspirin and nonsteroidal anti-inflammatory drug use after diagnosis on survival of oesophageal cancer patients. AB - BACKGROUND: Aspirin use has been shown to lower incidence and mortality in cancer patients. The aim of this population-based study was to determine the effect of postdiagnosis low-dose aspirin use on survival of patients with oesophageal cancer. METHODS: Patients with oesophageal cancer (1998-2010) were selected from the Eindhoven Cancer Registry and linked with outpatient pharmacy data regarding aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Users were subdivided into both prediagnosis and postdiagnosis or only postdiagnosis users. Parametric survival models with an exponential (Poisson) distribution were used with non specific death as endpoint. RESULTS: In this study 560 patients were included. Overall, 157 patients (28.0%) were non-users, 293 patients (52.3%) pre- and postdiagnosis (89 aspirin and 204 NSAID users) and 110 patients (19.6%) only postdiagnosis users (16 aspirin and 94 NSAID users). Postdiagnosis aspirin use was associated with overall survival (RR 0.45 (95% CI 0.34-0.60; P<0.001); adjusted rate ratio was 0.42 (95% CI: 0.30-0.57; P<0.001). Postdiagnosis use of NSAIDs was associated with overall survival (RR 0.61 (95% CI 0.49-0.76; <0.001); however, adjusted analyses did not show a significant association with a rate ratio of 0.84 (95% CI 0.66-1.07; P=0.2). CONCLUSIONS: Our study shows that postdiagnosis aspirin use might be associated with a higher survival rate in oesophageal cancer patients. A randomised clinical trial is needed to verify our observations of possible postdiagnosis aspirin use benefit. PMID- 27115572 TI - Does the Term "Deflators" Reflect More Accurately the Beneficial Effects of Long acting Bronchodilators in COPD? PMID- 27115571 TI - Educational and occupational outcomes of childhood cancer survivors 30 years after diagnosis: a French cohort study. AB - BACKGROUND: Although survival from childhood cancer has increased, little is known on the long-term impact of treatment late effects on occupational attainment or work ability. METHODS: A total of 3512 five-year survivors treated before the age of 19 years in 10 French cancer centres between 1948 and 2000 were identified. Educational level, employment status and occupational class of survivors were assessed by a self-reported questionnaire. These outcome measures were compared with sex-age rates recorded in the French population, using indirect standardisation. Paternal occupational class was also considered to control for the role of survivors' socioeconomic background on their achievement. Multivariable analyses were conducted to explore clinical characteristics associated with the outcomes. RESULTS: A total of 2406 survivors responded to the questionnaire and survivors aged below 25 years were included in the current analysis. Compared with national statistics adjusted on age and sex, male survivors were more likely to be college graduates (39.2% vs 30.9% expected; P<0.001). This higher achievement was not observed either for leukaemia or central nervous system (CNS) tumour survivors. Health-related unemployment was higher for survivors of CNS tumour (28.1% vs 4.3%; P<0.001) but not for survivors of other diagnoses. Survivors of non-CNS childhood cancer had a similar or a higher occupational class than expected. CONCLUSIONS: Survivors treated for CNS tumour or leukaemia, especially when treatment included cranial irradiation, might need support throughout their lifespan. PMID- 27115573 TI - Late Preterm and Term Birth: Neonatal Hyperbilirubinemia and Birth Model. AB - AIM: To evaluate the mode of delivery's influence on development of neonatal hyperbilirubinemia in term or near term infants. METHODS: The hyperbilirubinemic neonates were divided into two groups according to their mode of delivery (i.e., vaginal or cesarean). The birth weight and gestational age at the time of birth, the age of the neonates in days, and the serum levels of bilirubin of the neonates at the time of hyperbilirubinemia were compared from the date of hospitalization until treatment, based on the birth model. RESULTS: 288 were fulfilled the inclusion criteria during the neonatal period. The vaginal delivery group consisted of 157 infants (16.8%) with hyperbilirubinemia, whereas the cesarean group included 131 (22.6%) infants with hyperbilirubinemia. Neonates in the cesarean group had a significantly higher rate of hyperbilirubinemia (p = 0.01). CONCLUSION: This study revealed that compared with vaginal births, cesarean births led to higher rates of neonatal hyperbilirubinemia. PMID- 27115574 TI - Intrahepatic angiogenesis increases portal hypertension in hepatitis B patients with cirrhosis. AB - AIM: It remains unclear whether intrahepatic angiogenesis increases portal hypertension (PH) in hepatitis B with cirrhosis. We aim to investigate the relationship between intrahepatic angiogenesis and PH in hepatitis B patients with cirrhosis. METHODS: Sixty hepatitis B patients with cirrhosis and 40 healthy subjects were included in this study. Angiogenesis markers vascular endothelial growth factor receptor-2 (VEGFR2), von Willebrand factor (vWF), and fibrosis marker alpha-smooth muscle actin (alpha-SMA) were observed by immunohistochemistry. Sirius Red staining was also used to determine liver fibrosis. Correlations between levels of intrahepatic angiogenesis and Child-Pugh classes, liver fibrosis degree, and portal vein pressure were examined. We also analyzed the relationship between levels of intrahepatic angiogenesis and complications of PH, including esophageal varices (EV), ascites, and hypersplenism. RESULTS: Correlation was observed between the levels of VEGFR2 (r = 0.590, P < 0.01), vWF (r = 0.524, P < 0.01) in tissue, and Child-Pugh classes. Significant correlations were observed between levels of VEGFR2 and alpha-SMA (r = 0.710, P < 0.01), VEGFR2 and Sirius Red (r = 0.841, P < 0.01), vWF and alpha SMA (r = 0.768, P < 0.01), and vWF and Sirius Red (r = 0.825, P < 0.01). Patients with hepatic venous pressure gradient (HVPG) >=12 mmHg showed higher levels of VEGFR2 and vWF expression compared to those with (HVPG) <12 mmHg (2.60 +/- 1.28% vs. 1.09 +/- 0.73%; 5.85 +/- 2.45% vs. 2.31 +/- 1.34%, P < 0.01), respectively. Moreover, complications of PH, including size of esophageal varices (P < 0.01), presence of ascites (P < 0.01), and spleen volume (P < 0.01) were significantly affected by the levels of intrahepatic angiogenesis. CONCLUSION: Intrahepatic angiogenesis increases PH in hepatitis B patients with cirrhosis. The study provides the potential ways to intervene in the progresses for therapeutic benefits in cirrhosis and PH. PMID- 27115575 TI - A hybrid method based upon nonlinear Lamb wave response for locating a delamination in composite laminates. AB - A new hybrid method based upon nonlinear Lamb wave response in time and frequency domains is introduced to locate a delamination in composite laminates. In Lamb wave based nonlinear method, the presence of damage is shown by the appearance of higher harmonics in the Lamb wave response. The proposed method not only uses this spectral information but also the corresponding temporal response data, for locating the delamination. Thus, the method is termed as a hybrid method. The paper includes formulation of the method and its application to locate a Barely Visible Impact Damage (BVID) induced delamination in a Carbon Fiber Reinforced Polymer (CFRP) laminate. The method gives the damage location fairly well. It is a baseline free method, as it does not need data from the pristine specimen. PMID- 27115576 TI - Translational research in the BJD: communicating science to a larger audience. PMID- 27115577 TI - Buschke-Ollendorff syndrome. PMID- 27115578 TI - The eyelash comes to the fore. PMID- 27115579 TI - Panniculitis associated with alpha-1 antitrypsin deficiency: from early descriptions to current targeted therapy. PMID- 27115580 TI - Photodynamic therapy for acne: are we there yet? PMID- 27115581 TI - Quantifying the mortality burden for skin cancers other than melanoma. PMID- 27115582 TI - Sweating the small stuff. PMID- 27115583 TI - Serological biomarkers for determining prognosis in Merkel cell carcinoma. PMID- 27115584 TI - Serum lactate dehydrogenase is a more useful biomarker of prognosis than serum S100B in patients with BRAF-mutant melanoma. PMID- 27115585 TI - Human papillomavirus is a risk factor for asymptomatic bacterial sexually transmitted infections in HIV-infected men who have sex with men. PMID- 27115586 TI - Ustekinumab, another biologic with potential to help patients with hidradenitis suppurativa? PMID- 27115587 TI - Indications for micrographic surgery. PMID- 27115588 TI - Measuring the impact of skin disease on children's quality of life. PMID- 27115589 TI - In vivo model for postinflammatory hyperpigmentation: a step forward. PMID- 27115590 TI - Conflicts of interest among academic dermatologists: freedom or constraint? AB - Intangible and institutional conflicts of interest can particularly affect academia. Academic scientists have peculiar social responsibilities with respect to education and research. These responsibilities may conflict with the increased presence of industry in academia and commercialization of academic research through patents and royalties. Drug approval is almost entirely dependent worldwide on data produced in studies led by pharmaceutical industries. A reflection of the increasing role of the market in academic research is given by exaggerated claims in press releases by academic institutions. In consideration of the extensive presence of industry in academia, there is a need for a move from individual to institutional conflicts of interest disclosure, defining institutional policies for regulating conflicts of interest and developing an 'ethically credible partnership'. PMID- 27115591 TI - A case of paraneoplastic pemphigus associated with Castleman disease reacting with multiple autoantigens, including the p200 protein. PMID- 27115592 TI - Cover Image: Unique presentation of a subungual malignant melanoma in situ. PMID- 27115594 TI - Image Gallery: Dermatologic and retinal manifestations of pseudoxanthoma elasticum. PMID- 27115595 TI - Image Gallery: Exuberant tufted folliculitis affecting the scalp. PMID- 27115596 TI - Image Gallery: Flagellate dermatitis. PMID- 27115600 TI - Similar molecular determinants on Rem mediate two distinct modes of inhibition of CaV1.2 channels. AB - Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like GTPases that potently inhibit all high-voltage-gated calcium (CaV1/CaV2) channels and are, thus, well-positioned to tune diverse physiological processes. Understanding how RGK proteins inhibit CaV channels is important for perspectives on their (patho)physiological roles and could advance their development and use as genetically-encoded CaV channel blockers. We previously reported that Rem can block surface CaV1.2 channels in 2 independent ways that engage distinct components of the channel complex: (1) by binding auxiliary beta subunits (beta-binding-dependent inhibition, or BBD); and (2) by binding the pore-forming alpha1C subunit N-terminus (alpha1C-binding dependent inhibition, or ABD). By contrast, Gem uses only the BBD mechanism to block CaV1.2. Rem molecular determinants required for BBD CaV1.2 inhibition are the distal C-terminus and the guanine nucleotide binding G-domain which interact with the plasma membrane and CaVbeta, respectively. However, Rem determinants for ABD CaV1.2 inhibition are unknown. Here, combining fluorescence resonance energy transfer, electrophysiology, systematic truncations, and Rem/Gem chimeras we found that the same Rem distal C-terminus and G-domain also mediate ABD CaV1.2 inhibition, but with different interaction partners. Rem distal C-terminus interacts with alpha1C N-terminus to anchor the G-domain which likely interacts with an as-yet-unidentified site. In contrast to some previous studies, neither the C-terminus of Rem nor Gem was sufficient to inhibit CaV1/CaV2 channels. The results reveal that similar molecular determinants on Rem are repurposed to initiate 2 independent mechanisms of CaV1.2 inhibition. PMID- 27115601 TI - Fruit Extract from Pyropolyporus fomentarius (L. ex Fr.) Teng Induces Mitochondria-Dependent Apoptosis in Leukemia Cells but Enhances Immunomodulatory Activities of Splenic Lymphocytes. AB - Pyropolyporus fomentarius (L. ex Fr.) Teng is a unique woody mushroom due to its medicinal value with numerous pharmacological activities. This study presented the potential antitumor and immunomodulatory properties of ethanol extract of P. fomentarius. The results showed that P. fomentarius extract inhibited the viability of murine leukemia L1210 cells in a dose-dependent manner with IC50 value of 69.35 MUg/ml. Flow cytometry analysis demonstrated that the extract induced apoptosis in L1210 cells. Additionally, the decline of mitochondrial membrane potential was observed as well as the changes of caspase-3, caspase-9, Bcl-2, and Bax, suggesting that proapoptosis effect of the extract involved mitochondria-related pathway. Simultaneously, the P. fomentarius extract significantly enhanced the proliferation and activation of splenic lymphocytes in a dose-dependent manner. This P. fomentarius extract has potential applications as a natural antitumor agent with immunomodulatory activity. PMID- 27115602 TI - Incidence of Norovirus-Associated Medical Encounters among Active Duty United States Military Personnel and Their Dependents. AB - BACKGROUND: Norovirus is a leading cause of gastroenteritis episodes and outbreaks in US military deployments, but estimates of endemic disease burden among military personnel in garrison are lacking. METHODS: Diagnostic codes from gastroenteritis-associated medical encounters of active duty military personnel and their beneficiaries from July 1998-June 2011 were obtained from the Armed Forces Health Surveillance Center. Using time-series regression models, cause unspecified encounters were modeled as a function of encounters for specific enteropathogens. Model residuals (representing unexplained encounters) were used to estimate norovirus-attributable medical encounters. Incidence rates were calculated using population data for both active duty and beneficiary populations. RESULTS: The estimated annual mean rate of norovirus-associated medically-attended visits among active duty personnel and their beneficiaries was 292 (95% CI: 258 to 326) and 93 (95% CI: 80 to 105) encounters per 10,000 persons, respectively. Rates were highest among beneficiaries <5 years of age with a median annual rate of 435 (range: 318 to 646) encounters per 10,000 children. Norovirus was estimated to cause 31% and 27% of all-cause gastroenteritis encounters in the active duty and beneficiary populations, respectively, with over 60% occurring between November and April. There was no evidence of any lag effect where norovirus disease occurred in one population before the other, or in one beneficiary age group before the others. CONCLUSIONS: Norovirus is a major cause of medically-attended gastroenteritis among non deployed US military active duty members as well as in their beneficiaries. PMID- 27115603 TI - Impact of Helminth Infection on the Clinical and Microbiological Presentation of Chagas Diseases in Chronically Infected Patients. AB - BACKGROUND: Helminth infections are highly prevalent in tropical and subtropical countries, coexisting in Chagas disease endemic areas. Helminth infections in humans may modulate the host immune system, changing the Th1/Th2 polarization. This immunological disturbance could modify the immune response to other infections. The aim of this study is to evaluate the relationship between clinical, microbiological and epidemiological characteristics of Chagas disease patients, with the presence of helminth infection. METHODS: A prospective observational study was conducted at Vall d'Hebron University Hospital (Barcelona, Spain). Inclusion criteria were: age over 18 years, diagnosis of Chagas disease, and not having received specific treatment for Chagas disease previously to the inclusion. The study protocol included Chagas disease assessment (cardiac and digestive evaluation, detection of T. cruzi DNA measured by PCR in peripheral blood), and helminth infection diagnosis (detection of IgG anti-Strongyloides stercoralis by ELISA, microscopic examination of stool samples from three different days, and specific faecal culture for S. stercoralis larvae). RESULTS: Overall, 65 patients were included, median age was 38 years, 75.4% were women and most of them came from Bolivia. Cardiac and digestive involvement was present in 18.5% and 27.7% of patients respectively. T. cruzi PCR was positive in 28 (43.1%) patients. Helminth infection was diagnosed in 12 (18.5%) patients. No differences were observed in clinical and epidemiological characteristics between patients with and without helminth infection. Nevertheless, the proportion of patients with positive T. cruzi PCR was higher among patients with helminth infection compared with patients without helminth infection (75% vs 35.8%, p = 0.021). CONCLUSIONS: We observed a high prevalence of S. stercoralis infection among chronic Chagas disease patients attended in our tropical medicine unit. Strongyloidiasis was associated with significantly higher proportion of positive T. cruzi RT-PCR determined in peripheral blood. PMID- 27115604 TI - Condomless Vaginal Intercourse and Its Associates among Men Who Have Sex with Men in China. AB - BACKGROUND: HIV prevalence has increased rapidly among men who have sex with men (MSM) in China reaching alarmingly high levels in some cities. Bisexual MSM have potential to transmit HIV and syphilis to their female partners through condomless vaginal intercourse (CVI). Thus, estimation of the burden of CVI and identification of its associates seemed necessary to control this cross-gender transmission. METHOD: In a cross-sectional study, using respondent-driven sampling and snowball sampling, 2958 MSM were recruited from seven Chinese cities, interviewed and tested for HIV and syphilis. Descriptive analysis of the socio-demographic and behaviors followed by simple and multiple logistic regressions [adjusted for income, city, race and social network size to determine adjusted odds ratio (aOR)] were performed using SAS-9.1. RESULTS: Among participating MSM, 19.03% were engaged in CVI. Prevalence of HIV and syphilis among participants involved in CVI were 5.86% and 14.74% respectively. MSM who were older [aOR for aged 40-49 = 2.60 (95% CI: 1.54-4.37)], married [aOR = 6.13 (4.95-7.58)], attended primary school or below [aOR = 3.86 (2.26-6.69)], met male partners at spa/bathhouse/sauna/massage parlor [aOR = 3.52 (2.62-4.72)] and had heterosexual orientation [aOR = 13.81 (7.14-26.70)] were more likely to have CVI. Furthermore, correct knowledge regarding HIV [aOR = 0.70 (0.55, 0.88)] and exposure to HIV prevention interventions [aOR = 0.67 (0.54, 0.82)] were negatively associated with CVI. CONCLUSIONS: CVI was found to be common among MSM in China. To minimize the transmission of HIV and syphilis from bisexual MSM to their relatively female partners, targeted interventions should specifically focus on bisexual MSM especially the older and married subgroups. PMID- 27115605 TI - A Presence-Only Model of Suitable Roosting Habitat for the Endangered Indiana Bat in the Southern Appalachians. AB - We know little about how forest bats, which are cryptic and mobile, use roosts on a landscape scale. For widely distributed species like the endangered Indiana bat Myotis sodalis, identifying landscape-scale roost habitat associations will be important for managing the species in different regions where it occurs. For example, in the southern Appalachian Mountains, USA, M. sodalis roosts are scattered across a heavily forested landscape, which makes protecting individual roosts impractical during large-scale management activities. We created a predictive spatial model of summer roosting habitat to identify important predictors using the presence-only modeling program MaxEnt and an information theoretic approach for model comparison. Two of 26 candidate models together accounted for >0.93 of AICc weights. Elevation and forest type were top predictors of presence; aspect north/south and distance-to-ridge were also important. The final average best model indicated that 5% of the study area was suitable habitat and 0.5% was optimal. This model matched our field observations that, in the southern Appalachian Mountains, optimal roosting habitat for M. sodalis is near the ridge top in south-facing mixed pine-hardwood forests at elevations from 260-575 m. Our findings, coupled with data from other studies, suggest M. sodalis is flexible in roost habitat selection across different ecoregions with varying topography and land use patterns. We caution that, while mature pine-hardwood forests are important now, specific areas of suitable and optimal habitat will change over time. Combining the information theoretic approach with presence-only models makes it possible to develop landscape-scale habitat suitability maps for forest bats. PMID- 27115607 TI - Pneumolabyrinth with Labyrinthitis as the Suspected Cause. AB - Pneumolabyrinth is a rare condition with air bubbles existing in the vestibule and/or cochlea. We report a case of pneumolabyrinth without trauma that was suspected to be caused by labyrinthitis. A 65-year-old man presented with vertigo and hearing loss in the left ear after catching a cold. Computed tomography performed after there had been no improvement in the patient's symptoms showed the presence of air bubbles in the vestibule, semicircular canals and cochlea. The patient was transferred to our hospital with suspected perilymphatic fistula. Bacterial infection was suspected after the laboratory tests had indicated a severe inflammatory response, and the patient was treated with antibiotics. However, no bacteria were detected in a bacterial culture of the otorrhea. An exploratory tympanotomy was performed to improve the patient's staggering gait and to examine the middle ear, with no obvious fistula being observed. Subsequent fenestration of the round window revealed a white mass that appeared to contain bacteria which was collected from the cochlea and submitted for analysis and bacterial culture. However, no bacteria were detected and the mass contained white blood cells. We suspected pneumolabyrinth following labyrinth infection. However, the cause of air bubble formation remains unclear and needs to be validated with further research. PMID- 27115606 TI - Hepatitis C Virus Protein Interaction Network Analysis Based on Hepatocellular Carcinoma. AB - Epidemiological studies have validated the association between hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC). An increasing number of studies show that protein-protein interactions (PPIs) between HCV proteins and host proteins play a vital role in infection and mediate HCC progression. In this work, we collected all published interaction between HCV and human proteins, which include 455 unique human proteins participating in 524 HCV-human interactions. Then, we construct the HCV-human and HCV-HCC protein interaction networks, which display the biological knowledge regarding the mechanism of HCV pathogenesis, particularly with respect to pathogenesis of HCC. Through in-depth analysis of the HCV-HCC interaction network, we found that interactors are enriched in the JAK/STAT, p53, MAPK, TNF, Wnt, and cell cycle pathways. Using a random walk with restart algorithm, we predicted the importance of each protein in the HCV-HCC network and found that AKT1 may play a key role in the HCC progression. Moreover, we found that NS5A promotes HCC cells proliferation and metastasis by activating AKT/GSK3beta/beta-catenin pathway. This work provides a basis for a detailed map tracking new cellular interactions of HCV and identifying potential targets for HCV-related hepatocellular carcinoma treatment. PMID- 27115608 TI - Blocking as a friend of induction in verbal category learning. AB - We conducted an experiment to investigate the influences of interleaved versus blocked presentation of disparate verbal exemplars on the induction of category concepts. The practice schedules of four experimental groups were juxtaposed such that sets of exemplar-category associations were either solved in succession (i.e., blocked), systematically intermixed (i.e., interleaved), or presented with an incremental transition from blocked to interleaved practice. Counter to current trends in the literature, in which interleaving alone has been facilitative of induction in some tasks, we found that participants whose initial exposure to the category exemplars involved blocked presentation performed better in both implicit and explicit tests of concept learning. The results are discussed with respect to the impacts of task type, task difficulty, and exemplar relatedness on induction. PMID- 27115609 TI - Analytic and heuristic processes in the detection and resolution of conflict. AB - Previous research with the ratio-bias task found larger response latencies for conflict trials where the heuristic- and analytic-based responses are assumed to be in opposition (e.g., choosing between 1/10 and 9/100 ratios of success) when compared to no-conflict trials where both processes converge on the same response (e.g., choosing between 1/10 and 11/100). This pattern is consistent with parallel dual-process models, which assume that there is effective, rather than lax, monitoring of the output of heuristic processing. It is, however, unclear why conflict resolution sometimes fails. Ratio-biased choices may increase because of a decline in analytical reasoning (leaving heuristic-based responses unopposed) or to a rise in heuristic processing (making it more difficult for analytic processes to override the heuristic preferences). Using the process dissociation procedure, we found that instructions to respond logically and response speed affected analytic (controlled) processing (C), leaving heuristic processing (H) unchanged, whereas the intuitive preference for large nominators (as assessed by responses to equal ratio trials) affected H but not C. These findings create new challenges to the debate between dual-process and single process accounts, which are discussed. PMID- 27115610 TI - Lichtheimia Infection in a Lymphoma Patient: Case Report and a Brief Review of the Available Diagnostic Tools. AB - We describe the case of a patient with a T-lymphoblastic lymphoma whose disseminated mucormycosis was diagnosed with delay, and we address the diagnostic and therapeutic decision-making process and review the diagnostic workup of patients with potential IFD. The diagnosis was delayed despite a suggestive radiological presentation of the patient's pulmonary lesion. The uncommon risk profile (T-lymphoblastic lymphoma, short neutropenic phases) wrongly led to a low level of suspicion. The diagnosis was also hampered by the lack of indirect markers for infections caused by Mucorales, the low sensitivity of both fungal culture and panfungal PCR, and the limited availability of species-specific PCR. A high level of suspicion of IFD is needed, and aggressive diagnostic procedures should be promptly initiated even in apparently low-risk patients with uncommon presentations. The extent of the analytical workup should be decided on a case-by case base. Diagnostic tests such as the galactomannan and beta-D-glucan test and/or PCR on biological material followed by sequencing should be chosen according to their availability and after evaluation of their specificity and sensitivity. In high-risk patients, preemptive therapy with a broad-spectrum mould-active antifungal agent should be started before definitive diagnostic findings become available. PMID- 27115611 TI - Kerion and Tinea Corporis Caused by Rabbit-Derived Trichophyton interdigitale in Three Siblings and One Consulting Doctor Using beta-Tubulin Gene to Identify the Pathogen. AB - Trichophyton interdigitale is generally deemed as an anamorph of Arthroderma vanbreuseghemii based on internal transcribed spacer (ITS) sequencing, but recently their anamorph/teleomorph connection should be cautioned based on beta tubulin phylogeny. We report three siblings and one consulting doctor who developed kerion and tinea corporis after contact with domestic rabbits. Seven same strains were isolated from four patients and three regions of a sick rabbit. The ITS and D1/D2 sequences of our isolate were 99 % homologous to A. Vanbreuseghemii, while beta-tubulin sequence was 100 % identical to T. interdigitale. Our isolate was identified as T. interdigitale based on maximum likelihood analysis of beta-tubulin. Random amplified polymorphic DNA revealed that the band patterns of five isolated strains and another rabbit-derived strain WCH023 were identical for OPF-03 and OPF-12. Skin lesions of all patients resolved completely for 2- to 6-week therapy of oral terbinafine and topical 1 % bifonazole or 1 % terbinafine cream. This study demonstrates that T. interdigitale of rabbit origin can cause various types of human dermatophytosis by mild scratch. Terbinafine may be the first choice for dermatophytosis caused by T. interdigitale. PMID- 27115613 TI - In vivo protein allylation to capture protein methylation candidates. AB - An approach combining in vivo protein allylation, chemical tagging and affinity enrichment was devised to capture protein methylation candidates in yeast S. cerevisiae. The study identified 167 hits, covering many proteins with known methylation events on different types of amino acid residues. PMID- 27115612 TI - A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression. AB - BACKGROUND: While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. METHODS: We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310). RESULTS: Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. INTERPRETATION: Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes. PMID- 27115615 TI - Bioethanol fermentation as alternative valorization route of agricultural digestate according to a biorefinery approach. AB - This study investigates the feasibility of producing bioethanol from solid digestate after a mechanical fractionation (i.e. centrifugal milling), in order to improve the energy recovery from agricultural wastes and the sustainability of anaerobic digestion plants. A bioethanol yield of 37gkg(-1)TS was evaluated for the solid digestate fraction. Mass and energetic balances were performed and compared between two scenarios: (A) one-stage bioethanol fermentation and (B) two stage anaerobic digestion-bioethanol fermentation, in order to evaluate the feasibility and the advantages of the two-stage process. Results revealed that, compared to the one-stage process, the dual anaerobic digestion-bioethanol process permitted: (i) to diversify biofuels production; (ii) to provide the thermal energy sufficient for drying digestate (13,351kWhthday(-1)), for the subsequent milling step; (iii) to reduce the electric energy requirement for the milling step (from 23,880 to 3580kWhelday(-1)); (iv) to produce extra electrical energy of 8483kWhelday(-1); (v) to improve the reduction of waste streams generated (from 13% to 54% of organic matter removal). PMID- 27115614 TI - Genome-Scale Transcriptome Analysis of the Desert Shrub Artemisia sphaerocephala. AB - BACKGROUND: Artemisia sphaerocephala, a semi-shrub belonging to the Artemisia genus of the Compositae family, is an important pioneer plant that inhabits moving and semi-stable sand dunes in the deserts and steppes of northwest and north-central China. It is very resilient in extreme environments. Additionally, its seeds have excellent nutritional value, and the abundant lipids and polysaccharides in the seeds make this plant a potential valuable source of bio energy. However, partly due to the scarcity of genetic information, the genetic mechanisms controlling the traits and environmental adaptation capacity of A. sphaerocephala are unknown. RESULTS: Here, we present the first in-depth transcriptomic analysis of A. sphaerocephala. To maximize the representation of conditional transcripts, mRNA was obtained from 17 samples, including living tissues of desert-growing A. sphaerocephala, seeds germinated in the laboratory, and calli subjected to no stress (control) and high and low temperature, high and low osmotic, and salt stresses. De novo transcriptome assembly performed using an Illumina HiSeq 2500 platform resulted in the generation of 68,373 unigenes. We analyzed the key genes involved in the unsaturated fatty acid synthesis pathway and identified 26 A. sphaerocephala fad2 genes, which is the largest fad2 gene family reported to date. Furthermore, a set of genes responsible for resistance to extreme temperatures, salt, drought and a combination of stresses was identified. CONCLUSION: The present work provides abundant genomic information for functional dissection of the important traits of A. sphaerocephala and contributes to the current understanding of molecular adaptive mechanisms of A. sphaerocephala in the desert environment. Identification of the key genes in the unsaturated fatty acid synthesis pathway could increase understanding of the biological regulatory mechanisms of fatty acid composition traits in plants and facilitate genetic manipulation of the fatty acid composition of oil crops. PMID- 27115616 TI - A robust and cost-effective integrated process for nitrogen and bio-refractory organics removal from landfill leachate via short-cut nitrification, anaerobic ammonium oxidation in tandem with electrochemical oxidation. AB - A cost-effective process, consisting of a denitrifying upflow anaerobic sludge blanket (UASB), an oxygen-limited anoxic/aerobic (A/O) process for short-cut nitrification, and an anaerobic reactor (ANR) for anaerobic ammonia oxidation (anammox), followed by an electrochemical oxidation process with a Ti-based SnO2 Sb2O5 anode, was developed to remove organics and nitrogen in a sewage diluted leachate. The final chemical oxygen demand (COD), ammonia nitrogen (NH4(+)-N) and total nitrogen (TN) of 70, 11.3 and 39 (all in mg/L), respectively, were obtained. TN removal in UASB, A/O and ANR were 24.6%, 49.6% and 16.1%, respectively. According to the water quality and molecular biology analysis, a high degree of anammox besides short-cut nitrification and denitrification occurred in A/O. Counting for 16.1% of TN removal in ANR, at least 43.2-49% of TN was removed via anammox. The anammox bacteria in A/O and ANR, were in respective titers of (2.5-5.9)*10(9) and 2.01*10(10)copy numbers/(gSS). PMID- 27115617 TI - Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation. AB - Activation of CD4+ T cells through interactions with peptides bound to Major Histocompatibility Complex Class II (MHC-II) molecules is a crucial step in clearance of most pathogens. Consequently, many viruses have evolved ways of blocking this aspect of adaptive immunity, from specific targeting of processing and presentation components to modulation of signaling pathways that regulate peptide presentation in addition to many other host defense mechanisms. Such cases of interference are far less common compared to what has been elucidated in MHC-I processing and presentation. This may be attributable in part to the complexity of MHC-II antigen processing, the scope of which is only now coming to light. PMID- 27115619 TI - Nutritionally Deprived Black-Horned Tree Cricket (Oecanthus nigricornis) Consumes Own Spermatophore After Failed Mating. PMID- 27115618 TI - Racial Pride and Condom Use in Post-Incarcerated African-American Men Who Have Sex With Men and Women: Test of a Conceptual Model for the Men in Life Environments Intervention. AB - African-American men who have sex with men and women (MSMW) are among those most heavily impacted by HIV in the United States, and those who have histories of incarceration are at further risk of infection. The Men in Life Environments (MILE) HIV prevention intervention was developed to provide culturally appropriate skills-based education and support for African-American MSMW with recent histories of incarceration. The MILE's conceptual framework was informed by three theories: Theory of Reasoned Action and Planned Behavior, Critical Thinking and Cultural Affirmation Model, and Empowerment Theory. The theory-based framework posits that improving racial pride is crucial in building self-efficacy and intentions that in turn promote health-protective behaviors. Therefore, our study aimed to assess whether baseline associations between racial pride and condom use self-efficacy, intentions, and behaviors among African-American MSMW with histories of incarceration align with our conceptual model. We report data on 212 participants recruited from Los Angeles County Sheriff's Department Men's Central Jail and the local community. Using structural equation modeling, we tested two separate models: one with female sexual partners and one with male sexual partners, while stratifying by participant's HIV status. Only among HIV negative participants was greater racial pride associated with less condomless intercourse with men. In this group, greater self-efficacy and intentions-but not racial pride-predicted less condomless intercourse with women. Our findings suggest that racial pride is an important factor to address in HIV prevention interventions for post-incarcerated African-American MSMW. PMID- 27115620 TI - Scrutinizing microwave effects on glucose uptake in yeast cells. AB - Taking into account different literature reports on microwave (MW) effects on living organisms, we thoroughly investigated the influence of constant 2.45 GHz MW irradiation on glucose uptake in yeast cells. A Saccharomyces cerevisiae suspension of 2.9 * 108 cells/ml was used in all experiments. A large specific absorption rate of 0.55 W/g of suspension is compensated by efficient external cooling of the reaction vessel, which established a strong non-equilibrium flow of energy through the solution and enabled a constant bulk temperature of 30 degrees C to within 1 degrees C during glucose uptake. Comparison of MW effects with control experiments revealed insignificant changes of glucose uptake during the initial stages of the experiment (up to the 10th min). Statistically "notable" differences during the next 20 min of the irradiation were detected corresponding to thermal overheating of 2 degrees C. Possible specific thermal MW effects may be related to local temperature increase and a large flow of energy throughout the system. The obtained effects show that environmental MW pollution (fortunately) is of too low intensity to provoke metabolic changes in living cells. At the same time, a longer exposure of cells to electromagnetic irradiation may have impacts on biochemical applications and production of valuable biotechnological products. PMID- 27115621 TI - Inorganic and organic fertilizers impact the abundance and proportion of antibiotic resistance and integron-integrase genes in agricultural grassland soil. AB - Soil fertilization with animal manure or its digestate may facilitate an important antibiotic resistance dissemination route from anthropogenic sources to the environment. This study examines the effect of mineral fertilizer (NH4NO3), cattle slurry and cattle slurry digestate amendment on the abundance and proportion dynamics of five antibiotic resistance genes (ARGs) and two classes of integron-integrase genes (intI1 and intI2) in agricultural grassland soil. Fertilization was performed thrice throughout one vegetation period. The targeted ARGs (sul1, tetA, blaCTX-M, blaOXA2 and qnrS) encode resistance to several major antibiotic classes used in veterinary medicine such as sulfonamides, tetracycline, cephalosporins, penicillin and fluoroquinolones, respectively. The non-fertilized grassland soil contained a stable background of tetA, blaCTX-M and sul1 genes. The type of applied fertilizer significantly affected ARGs and integron-integrase genes abundances and proportions in the bacterial community (p<0.001 in both cases), explaining 67.04% of the abundance and 42.95% of the proportion variations in the grassland soil. Both cattle slurry and cattle slurry digestate proved to be considerable sources of ARGs, especially sul1, as well as integron-integrases. Sul1, intI1 and intI2 levels in grassland soil were elevated in response to each organic fertilizer's application event, but this increase was followed by a stage of decrease, suggesting that microbes possessing these genes were predominantly entrained into soil via cattle slurry or its digestate application and had somewhat limited survival potential in a soil environment. However, the abundance of these three target genes did not decrease to a background level by the end of the study period. TetA was most abundant in mineral fertilizer treated soil and blaCTX-M in cattle slurry digestate amended soil. Despite significantly different abundances, the abundance dynamics of bacteria possessing these genes were similar (p<0.05 in all cases) in different treatments and resembled the dynamics of the whole bacterial community abundance in each soil treatment. PMID- 27115622 TI - Smartphone-based noise mapping: Integrating sound level meter app data into the strategic noise mapping process. AB - The strategic noise mapping process of the EU has now been ongoing for more than ten years. However, despite the fact that a significant volume of research has been conducted on the process and related issues there has been little change or innovation in how relevant authorities and policymakers are conducting the process since its inception. This paper reports on research undertaken to assess the possibility for smartphone-based noise mapping data to be integrated into the traditional strategic noise mapping process. We compare maps generated using the traditional approach with those generated using smartphone-based measurement data. The advantage of the latter approach is that it has the potential to remove the need for exhaustive input data into the source calculation model for noise prediction. In addition, the study also tests the accuracy of smartphone-based measurements against simultaneous measurements taken using traditional sound level meters in the field. PMID- 27115623 TI - Occurrence of microcystins in water, bloom, sediment and fish from a public water supply. AB - Microcystin (MC) accumulation was determined in the liver and muscle of two omnivorous fish species which are consumed and are economically important, and in a planktivorous-carnivorous fish from Lake Egirdir, Turkey. Free extractable MCs in fish tissue samples were detected by enzyme-linked immunosorbent assay (ELISA) with confirmation by high performance liquid chromatography with photodiode array detection (HPLC-PDA). MC-LA and -YR, were detected in both liver and muscle, followed by MCs -LY, -LF, -RR and -LR respectively. The MC concentrations varied between 0.043 and 1.72MUg/g dry weight in liver and muscle tissues. MCs were also determined in samples of water, sediment and a bloom sample of Microcystis aeruginosa from the lake by HPLC-PDA. MC-LY and -YR were most commonly identified in water samples, with total MC concentrations ranging from 2.9+/-0.05 to 13.5+/ 2.3MUg/L. Sediment analyses, showed that MC-YR was present in samples between 7.0 and 17.6MUg/g dw, especially in October, November and December when no MC-YR was recorded in water, followed by MC-LW. The findings indicate that water and sediment contained MCs, and more importantly that fish were contaminated with MCs that may pose an MC-associated human health risk. PMID- 27115624 TI - The MARINA model (Model to Assess River Inputs of Nutrients to seAs): Model description and results for China. AB - Chinese agriculture has been developing fast towards industrial food production systems that discharge nutrient-rich wastewater into rivers. As a result, nutrient export by rivers has been increasing, resulting in coastal water pollution. We developed a Model to Assess River Inputs of Nutrients to seAs (MARINA) for China. The MARINA Nutrient Model quantifies river export of nutrients by source at the sub-basin scale as a function of human activities on land. MARINA is a downscaled version for China of the Global NEWS-2 (Nutrient Export from WaterSheds) model with an improved approach for nutrient losses from animal production and population. We use the model to quantify dissolved inorganic and organic nitrogen (N) and phosphorus (P) export by six large rivers draining into the Bohai Gulf (Yellow, Hai, Liao), Yellow Sea (Yangtze, Huai) and South China Sea (Pearl) in 1970, 2000 and 2050. We addressed uncertainties in the MARINA Nutrient model. Between 1970 and 2000 river export of dissolved N and P increased by a factor of 2-8 depending on sea and nutrient form. Thus, the risk for coastal eutrophication increased. Direct losses of manure to rivers contribute to 60-78% of nutrient inputs to the Bohai Gulf and 20-74% of nutrient inputs to the other seas in 2000. Sewage is an important source of dissolved inorganic P, and synthetic fertilizers of dissolved inorganic N. Over half of the nutrients exported by the Yangtze and Pearl rivers originated from human activities in downstream and middlestream sub-basins. The Yellow River exported up to 70% of dissolved inorganic N and P from downstream sub-basins and of dissolved organic N and P from middlestream sub-basins. Rivers draining into the Bohai Gulf are drier, and thus transport fewer nutrients. For the future we calculate further increases in river export of nutrients. The MARINA Nutrient model quantifies the main sources of coastal water pollution for sub-basins. This information can contribute to formulation of effective management options to reduce nutrient pollution of Chinese seas in the future. PMID- 27115625 TI - Update on Genomic Databases and Resources at the National Center for Biotechnology Information. AB - The National Center for Biotechnology Information (NCBI), as a primary public repository of genomic sequence data, collects and maintains enormous amounts of heterogeneous data. Data for genomes, genes, gene expressions, gene variation, gene families, proteins, and protein domains are integrated with the analytical, search, and retrieval resources through the NCBI website, text-based search and retrieval system, provides a fast and easy way to navigate across diverse biological databases.Comparative genome analysis tools lead to further understanding of evolution processes quickening the pace of discovery. Recent technological innovations have ignited an explosion in genome sequencing that has fundamentally changed our understanding of the biology of living organisms. This huge increase in DNA sequence data presents new challenges for the information management system and the visualization tools. New strategies have been designed to bring an order to this genome sequence shockwave and improve the usability of associated data. PMID- 27115626 TI - Protein Structure Databases. AB - Web-based protein structure databases come in a wide variety of types and levels of information content. Those having the most general interest are the various atlases that describe each experimentally determined protein structure and provide useful links, analyses, and schematic diagrams relating to its 3D structure and biological function. Also of great interest are the databases that classify 3D structures by their folds as these can reveal evolutionary relationships which may be hard to detect from sequence comparison alone. Related to these are the numerous servers that compare folds-particularly useful for newly solved structures, and especially those of unknown function. Beyond these are a vast number of databases for the more specialized user, dealing with specific families, diseases, structural features, and so on. PMID- 27115627 TI - The MIntAct Project and Molecular Interaction Databases. AB - Molecular interaction databases collect, organize, and enable the analysis of the increasing amounts of molecular interaction data being produced and published as we move towards a more complete understanding of the interactomes of key model organisms. The organization of these data in a structured format supports analyses such as the modeling of pairwise relationships between interactors into interaction networks and is a powerful tool for understanding the complex molecular machinery of the cell. This chapter gives an overview of the principal molecular interaction databases, in particular the IMEx databases, and their curation policies, use of standardized data formats and quality control rules. Special attention is given to the MIntAct project, in which IntAct and MINT joined forces to create a single resource to improve curation and software development efforts. This is exemplified as a model for the future of molecular interaction data collation and dissemination. PMID- 27115628 TI - Applications of Protein Thermodynamic Database for Understanding Protein Mutant Stability and Designing Stable Mutants. AB - Protein stability is the free energy difference between unfolded and folded states of a protein, which lies in the range of 5-25 kcal/mol. Experimentally, protein stability is measured with circular dichroism, differential scanning calorimetry, and fluorescence spectroscopy using thermal and denaturant denaturation methods. These experimental data have been accumulated in the form of a database, ProTherm, thermodynamic database for proteins and mutants. It also contains sequence and structure information of a protein, experimental methods and conditions, and literature information. Different features such as search, display, and sorting options and visualization tools have been incorporated in the database. ProTherm is a valuable resource for understanding/predicting the stability of proteins and it can be accessed at http://www.abren.net/protherm/ . ProTherm has been effectively used to examine the relationship among thermodynamics, structure, and function of proteins. We describe the recent progress on the development of methods for understanding/predicting protein stability, such as (1) general trends on mutational effects on stability, (2) relationship between the stability of protein mutants and amino acid properties, (3) applications of protein three-dimensional structures for predicting their stability upon point mutations, (4) prediction of protein stability upon single mutations from amino acid sequence, and (5) prediction methods for addressing double mutants. A list of online resources for predicting has also been provided. PMID- 27115629 TI - Classification and Exploration of 3D Protein Domain Interactions Using Kbdock. AB - Comparing and classifying protein domain interactions according to their three dimensional (3D) structures can help to understand protein structure-function and evolutionary relationships. Additionally, structural knowledge of existing domain domain interactions can provide a useful way to find structural templates with which to model the 3D structures of unsolved protein complexes. Here we present a straightforward guide to using the "Kbdock" protein domain structure database and its associated web site for exploring and comparing protein domain-domain interactions (DDIs) and domain-peptide interactions (DPIs) at the Pfam domain family level. We also briefly explain how the Kbdock web site works, and we provide some notes and suggestions which should help to avoid some common pitfalls when working with 3D protein domain structures. PMID- 27115630 TI - Data Mining of Macromolecular Structures. AB - The use of macromolecular structures is widespread for a variety of applications, from teaching protein structure principles all the way to ligand optimization in drug development. Applying data mining techniques on these experimentally determined structures requires a highly uniform, standardized structural data source. The Protein Data Bank (PDB) has evolved over the years toward becoming the standard resource for macromolecular structures. However, the process selecting the data most suitable for specific applications is still very much based on personal preferences and understanding of the experimental techniques used to obtain these models. In this chapter, we will first explain the challenges with data standardization, annotation, and uniformity in the PDB entries determined by X-ray crystallography. We then discuss the specific effect that crystallographic data quality and model optimization methods have on structural models and how validation tools can be used to make informed choices. We also discuss specific advantages of using the PDB_REDO databank as a resource for structural data. Finally, we will provide guidelines on how to select the most suitable protein structure models for detailed analysis and how to select a set of structure models suitable for data mining. PMID- 27115631 TI - Criteria to Extract High-Quality Protein Data Bank Subsets for Structure Users. AB - It is often necessary to build subsets of the Protein Data Bank to extract structural trends and average values. For this purpose it is mandatory that the subsets are non-redundant and of high quality. The first problem can be solved relatively easily at the sequence level or at the structural level. The second, on the contrary, needs special attention. It is not sufficient, in fact, to consider the crystallographic resolution and other feature must be taken into account: the absence of strings of residues from the electron density maps and from the files deposited in the Protein Data Bank; the B-factor values; the appropriate validation of the structural models; the quality of the electron density maps, which is not uniform; and the temperature of the diffraction experiments. More stringent criteria produce smaller subsets, which can be enlarged with more tolerant selection criteria. The incessant growth of the Protein Data Bank and especially of the number of high-resolution structures is allowing the use of more stringent selection criteria, with a consequent improvement of the quality of the subsets of the Protein Data Bank. PMID- 27115632 TI - Homology-Based Annotation of Large Protein Datasets. AB - Advances in DNA sequencing technologies have led to an increasing amount of protein sequence data being generated. Only a small fraction of this protein sequence data will have experimental annotation associated with them. Here, we describe a protocol for in silico homology-based annotation of large protein datasets that makes extensive use of manually curated collections of protein families. We focus on annotations provided by the Pfam database and suggest ways to identify family outliers and family variations. This protocol may be useful to people who are new to protein data analysis, or who are unfamiliar with the current computational tools that are available. PMID- 27115633 TI - Identification and Correction of Erroneous Protein Sequences in Public Databases. AB - Correct prediction of the structure of protein-coding genes of higher eukaryotes is a difficult task therefore public sequence databases incorporating predicted sequences are increasingly contaminated with erroneous sequences. The high rate of misprediction has serious consequences since it significantly affects the conclusions that may be drawn from genome-scale sequence analyses.Here we describe the MisPred and FixPred approaches that may help the identification and correction of erroneous sequences. The rationale of these approaches is that a protein sequence is likely to be erroneous if some of its features conflict with our current knowledge about proteins. PMID- 27115634 TI - Improving the Accuracy of Fitted Atomic Models in Cryo-EM Density Maps of Protein Assemblies Using Evolutionary Information from Aligned Homologous Proteins. AB - Cryo-Electron Microscopy (cryo-EM) has become an important technique to obtain structural insights into large macromolecular assemblies. However the resolution of the density maps do not allow for its interpretation at atomic level. Hence they are combined with high resolution structures along with information from other experimental or bioinformatics techniques to obtain pseudo-atomic models. Here, we describe the use of evolutionary conservation of residues as obtained from protein structures and alignments of homologous proteins to detect errors in the fitting of atomic structures as well as improve accuracy of the protein protein interfacial regions in the cryo-EM density maps. PMID- 27115635 TI - Systematic Exploration of an Efficient Amino Acid Substitution Matrix: MIQS. AB - Amino acid sequence comparisons to find similarities between proteins are fundamental sequence information analyses for inferring protein structure and function. In this study, we improve amino acid substitution matrices to identify distantly related proteins. We systematically sampled and benchmarked substitution matrices generated from the principal component analysis (PCA) subspace based on a set of typical existing matrices. Based on the benchmark results, we identified a region of highly sensitive matrices in the PCA subspace using kernel density estimation (KDE). Using the PCA subspace, we were able to deduce a novel sensitive matrix, called MIQS, which shows better detection performance for detecting distantly related proteins than those of existing matrices. This approach to derive an efficient amino acid substitution matrix might influence many fields of protein sequence analysis. MIQS is available at http://csas.cbrc.jp/Ssearch/ . PMID- 27115636 TI - Promises and Pitfalls of High-Throughput Biological Assays. AB - This chapter discusses some of the pitfalls encountered when performing biomedical research involving high-throughput "omics" data and presents some strategies and guidelines that researchers should follow when undertaking such studies. We discuss common errors in experimental design and data analysis that lead to irreproducible and non-replicable research and provide some guidelines to avoid these common mistakes so that researchers may have confidence in study outcomes, even if the results are negative. We discuss the importance of ranking and prespecifying hypotheses, performing power analysis, careful experimental design, and preplanning of statistical analyses in order to avoid the "fishing expedition" data analysis strategy, which is doomed to fail. The impact of multiple testing on false-positive rates is discussed, particularly in the context of the analysis of high-throughput data, and methods to correct for it are presented, as well as approaches to detect and correct for experimental biases and batch effects, which often plague high-throughput assays. We highlight the importance of sharing data and analysis code to facilitate reproducibility and present tools and software that are appropriate for this purpose. PMID- 27115637 TI - Optimizing RNA-Seq Mapping with STAR. AB - Recent advances in high-throughput sequencing technology made it possible to probe the cell transcriptomes by generating hundreds of millions of short reads which represent the fragments of the transcribed RNA molecules. The first and the most crucial task in the RNA-seq data analysis is mapping of the reads to the reference genome. STAR (Spliced Transcripts Alignment to a Reference) is an RNA seq mapper that performs highly accurate spliced sequence alignment at an ultrafast speed. STAR alignment algorithm can be controlled by many user-defined parameters. Here, we describe the most important STAR options and parameters, as well as best practices for achieving the maximum mapping accuracy and speed. PMID- 27115638 TI - Predicting Conformational Disorder. AB - In the last two decades, it has become increasingly evident that a large number of proteins are either fully or partially disordered. Intrinsically disordered proteins are ubiquitous proteins that fulfill essential biological functions while lacking a stable 3D structure. Their conformational heterogeneity is encoded at the amino acid sequence level, thereby allowing intrinsically disordered proteins or regions to be recognized based on their sequence properties. The identification of disordered regions facilitates the functional annotation of proteins and is instrumental for delineating boundaries of protein domains amenable to crystallization. This chapter focuses on the methods currently employed for predicting disorder and identifying regions involved in induced folding. PMID- 27115639 TI - Classification of Protein Kinases Influenced by Conservation of Substrate Binding Residues. AB - With the advent of genome sequencing projects in the recent past, several kinases have come to light as regulating different signaling pathways. These kinases are generally classified into different subfamilies based on their sequence similarity with members of known subfamilies of kinases. A functional association is then defined to the kinase based on the subfamily to which it has been characterized. However, one of the key factors that give identity to a kinase in a subfamily is its ability to phosphorylate a given set of substrates. Substrate specificity of a kinase is largely determined by the residues at the substrate binding site. Though in general the sequence similarity based measure for classification more or less gives the preliminary idea on subfamily, understanding the molecular basis of kinase substrate recognition could further refine the classification scheme for kinases and render a better understanding of their functional role. In this analysis we emphasize on the possibility of using putative substrate binding information in the classification of a given kinase into a particular subfamily. PMID- 27115640 TI - Spectral-Statistical Approach for Revealing Latent Regular Structures in DNA Sequence. AB - Methods of the spectral-statistical approach (2S-approach) for revealing latent periodicity in DNA sequences are described. The results of data analysis in the HeteroGenome database which collects the sequences similar to approximate tandem repeats in the genomes of model organisms are adduced. In consequence of further developing of the spectral-statistical approach, the techniques for recognizing latent profile periodicity are considered. These techniques are basing on extension of the notion of approximate tandem repeat. Examples of correlation of latent profile periodicity revealed in the CDSs with structural-functional properties in the proteins are given. PMID- 27115641 TI - Protein Crystallizability. AB - Obtaining diffracting quality crystals remains a major challenge in protein structure research. We summarize and compare methods for selecting the best protein targets for crystallization, construct optimization and crystallization condition design. Target selection methods are divided into algorithms predicting the chance of successful progression through all stages of structural determination (from cloning to solving the structure) and those focusing only on the crystallization step. We tried to highlight pros and cons of different approaches examining the following aspects: data size, redundancy and representativeness, overfitting during model construction, and results evaluation. In summary, although in recent years progress was made and several sequence properties were reported to be relevant for crystallization, the successful prediction of protein crystallization behavior and selection of corresponding crystallization conditions continue to challenge structural researchers. PMID- 27115642 TI - Analysis and Visualization of ChIP-Seq and RNA-Seq Sequence Alignments Using ngs.plot. AB - The continual maturation and increasing applications of next-generation sequencing technology in scientific research have yielded ever-increasing amounts of data that need to be effectively and efficiently analyzed and innovatively mined for new biological insights. We have developed ngs.plot-a quick and easy-to use bioinformatics tool that performs visualizations of the spatial relationships between sequencing alignment enrichment and specific genomic features or regions. More importantly, ngs.plot is customizable beyond the use of standard genomic feature databases to allow the analysis and visualization of user-specified regions of interest generated by the user's own hypotheses. In this protocol, we demonstrate and explain the use of ngs.plot using command line executions, as well as a web-based workflow on the Galaxy framework. We replicate the underlying commands used in the analysis of a true biological dataset that we had reported and published earlier and demonstrate how ngs.plot can easily generate publication-ready figures. With ngs.plot, users would be able to efficiently and innovatively mine their own datasets without having to be involved in the technical aspects of sequence coverage calculations and genomic databases. PMID- 27115643 TI - Datamining with Ontologies. AB - The use of ontologies has increased rapidly over the past decade and they now provide a key component of most major databases in biology and biomedicine. Consequently, datamining over these databases benefits from considering the specific structure and content of ontologies, and several methods have been developed to use ontologies in datamining applications. Here, we discuss the principles of ontology structure, and datamining methods that rely on ontologies. The impact of these methods in the biological and biomedical sciences has been profound and is likely to increase as more datasets are becoming available using common, shared ontologies. PMID- 27115644 TI - Functional Analysis of Metabolomics Data. AB - Metabolomics aims at characterizing the repertory of small chemical compounds in a biological sample. As it becomes more massive and larger sets of compounds are detected, a functional analysis is required to convert these raw lists of compounds into biological knowledge. The most common way of performing such analysis is "annotation enrichment analysis," also used in transcriptomics and proteomics. This approach extracts the annotations overrepresented in the set of chemical compounds arisen in a given experiment. Here, we describe the protocols for performing such analysis as well as for visualizing a set of compounds in different representations of the metabolic networks, in both cases using free accessible web tools. PMID- 27115645 TI - Bacterial Genomic Data Analysis in the Next-Generation Sequencing Era. AB - Bacterial genome sequencing is now an affordable choice for many laboratories for applications in research, diagnostic, and clinical microbiology. Nowadays, an overabundance of tools is available for genomic data analysis. However, tools differ for algorithms, languages, hardware requirements, and user interface, and combining them as it is necessary for sequence data interpretation often requires (bio)informatics skills which can be difficult to find in many laboratories. In addition, multiple data sources, as well as exceedingly large dataset sizes, and increasingly computational complexity further challenge the accessibility, reproducibility, and transparency of the entire process. In this chapter we will cover the main bioinformatics steps required for a complete bacterial genome analysis using next-generation sequencing data, from the raw sequence data to assembled and annotated genomes. All the tools described are available in the Orione framework ( http://orione.crs4.it ), which uniquely combines in a transparent way the most used open source bioinformatics tools for microbiology, allowing microbiologist without any specific hardware or informatics skill to conduct data-intensive computational analyses from quality control to microbial gene annotation. PMID- 27115646 TI - A Broad Overview of Computational Methods for Predicting the Pathophysiological Effects of Non-synonymous Variants. AB - Next-generation sequencing has provided extraordinary opportunities to investigate the massive human genetic variability. It helped identifying several kinds of genomic mismatches from the wild-type reference genome sequences and to explain the onset of several pathogenic phenotypes and diseases susceptibility. In this context, distinguishing pathogenic from functionally neutral amino acid changes turns out to be a task as useful as complex, expensive, and time consuming.Here, we present an exhaustive and up-to-dated survey of the algorithms and software packages conceived for the estimation of the putative pathogenicity of mutations, along with a description of the most popular mutation datasets that these tools used as training sets. Finally, we present and describe software for the prediction of cancer-related mutations. PMID- 27115647 TI - Recommendation Techniques for Drug-Target Interaction Prediction and Drug Repositioning. AB - The usage of computational methods in drug discovery is a common practice. More recently, by exploiting the wealth of biological knowledge bases, a novel approach called drug repositioning has raised. Several computational methods are available, and these try to make a high-level integration of all the knowledge in order to discover unknown mechanisms. In this chapter, we review drug-target interaction prediction methods based on a recommendation system. We also give some extensions which go beyond the bipartite network case. PMID- 27115648 TI - Protein Residue Contacts and Prediction Methods. AB - In the field of computational structural proteomics, contact predictions have shown new prospects of solving the longstanding problem of ab initio protein structure prediction. In the last few years, application of deep learning algorithms and availability of large protein sequence databases, combined with improvement in methods that derive contacts from multiple sequence alignments, have shown a huge increase in the precision of contact prediction. In addition, these predicted contacts have also been used to build three-dimensional models from scratch.In this chapter, we briefly discuss many elements of protein residue residue contacts and the methods available for prediction, focusing on a state-of the-art contact prediction tool, DNcon. Illustrating with a case study, we describe how DNcon can be used to make ab initio contact predictions for a given protein sequence and discuss how the predicted contacts may be analyzed and evaluated. PMID- 27115649 TI - The Recipe for Protein Sequence-Based Function Prediction and Its Implementation in the ANNOTATOR Software Environment. AB - As biomolecular sequencing is becoming the main technique in life sciences, functional interpretation of sequences in terms of biomolecular mechanisms with in silico approaches is getting increasingly significant. Function prediction tools are most powerful for protein-coding sequences; yet, the concepts and technologies used for this purpose are not well reflected in bioinformatics textbooks. Notably, protein sequences typically consist of globular domains and non-globular segments. The two types of regions require cardinally different approaches for function prediction. Whereas the former are classic targets for homology-inspired function transfer based on remnant, yet statistically significant sequence similarity to other, characterized sequences, the latter type of regions are characterized by compositional bias or simple, repetitive patterns and require lexical analysis and/or empirical sequence pattern-function correlations. The recipe for function prediction recommends first to find all types of non-globular segments and, then, to subject the remaining query sequence to sequence similarity searches. We provide an updated description of the ANNOTATOR software environment as an advanced example of a software platform that facilitates protein sequence-based function prediction. PMID- 27115650 TI - Big Data, Evolution, and Metagenomes: Predicting Disease from Gut Microbiota Codon Usage Profiles. AB - Metagenomics projects use next-generation sequencing to unravel genetic potential in microbial communities from a wealth of environmental niches, including those associated with human body and relevant to human health. In order to understand large datasets collected in metagenomics surveys and interpret them in context of how a community metabolism as a whole adapts and interacts with the environment, it is necessary to extend beyond the conventional approaches of decomposing metagenomes into microbial species' constituents and performing analysis on separate components. By applying concepts of translational optimization through codon usage adaptation on entire metagenomic datasets, we demonstrate that a bias in codon usage present throughout the entire microbial community can be used as a powerful analytical tool to predict for community lifestyle-specific metabolism. Here we demonstrate this approach combined with machine learning, to classify human gut microbiome samples according to the pathological condition diagnosed in the human host. PMID- 27115651 TI - Big Data in Plant Science: Resources and Data Mining Tools for Plant Genomics and Proteomics. AB - In modern plant biology, progress is increasingly defined by the scientists' ability to gather and analyze data sets of high volume and complexity, otherwise known as "big data". Arguably, the largest increase in the volume of plant data sets over the last decade is a consequence of the application of the next generation sequencing and mass-spectrometry technologies to the study of experimental model and crop plants. The increase in quantity and complexity of biological data brings challenges, mostly associated with data acquisition, processing, and sharing within the scientific community. Nonetheless, big data in plant science create unique opportunities in advancing our understanding of complex biological processes at a level of accuracy without precedence, and establish a base for the plant systems biology. In this chapter, we summarize the major drivers of big data in plant science and big data initiatives in life sciences with a focus on the scope and impact of iPlant, a representative cyberinfrastructure platform for plant science. PMID- 27115652 TI - Global Health Education in a Changing World: The Next New Conversations Topic. PMID- 27115653 TI - Addressing Comparisons, Connections, and Collaborations in Medical Education to Enhance Health Across the World Through New Conversations: A Guest Editorial. PMID- 27115654 TI - More on How USMLE Step 1 Scores Are Challenging Academic Medicine. PMID- 27115655 TI - More on How USMLE Step 1 Scores Are Challenging Academic Medicine. PMID- 27115656 TI - In Reply to Mehta et al and to London et al. PMID- 27115657 TI - Social Media and Storytelling in Medicine: Probing Deeper. PMID- 27115658 TI - Social Media and Storytelling in Medicine: Probing Deeper. PMID- 27115659 TI - Postgraduate Clinical Observerships for International Medical School Graduates: Time for Regulation. PMID- 27115660 TI - Medical Schools Based on Principles of Community Responsibility in Argentina. PMID- 27115661 TI - Meeting at the Table. PMID- 27115662 TI - Artist's Statement: The Girl in Blue and Her Dying Newborn. PMID- 27115663 TI - Hannah Arendt. PMID- 27115664 TI - Commentary on Hannah Arendt. PMID- 27115665 TI - Rule of Thumb. PMID- 27115668 TI - UK Renal Registry 18th Annual Report: Chapter 7 Adequacy of Haemodialysis in UK Adult Patients in 2014: National and Centre-specific Analyses. AB - Data suitable for urea reduction ratio (URR) analyses were available for 14,761 (71.9%) of the 20,539 patients receiving haemodialysis (HD) in the UK on the 30/9/2014. In 2014, 88.6% of prevalent HD patients achieved a URR .65%. The between centre range of prevalent patients achieving this target was wide (74.9 97.0%). The median URR in 2014 was 75%. URR was greater in those with longer dialysis vintage, with 91.2% of patients who had survived on renal replacement therapy (RRT) for more than two years achieving a URR .65% compared with only 73.4% of those on RRT for less than six months. Large variation between centres in the percentage of patients achieving the UK Renal Association's (RA) URR guideline persists. PMID- 27115669 TI - Expression of Inflammasome-Associated Proteins in Human Oropharyngeal Squamous Cell Carcinoma. AB - Inflammasomes, large protein complexes typically consisting of a Nod-like receptor (NLR), adapter protein apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1, are postulated to be activated in response to danger signals arising from tumors. Inflammasomes are thought to have critical but contrasting roles through facilitating antitumor immunity and inducing oncogenic factors. However, the role and function of inflammasomes in oropharyngeal carcinoma remain unclear. We analyzed nine specimens of oropharyngeal squamous cell carcinoma (SCC) and determined the expression of NLRP3, ASC, interleukin (IL)-1beta, IL-18 and caspase-1 in the specimens with and without human papilloma virus (HPV) infection using immunohistochemistry, and analyzed the correlations between the altered expression of these proteins and clinicopathological factors of oropharyngeal SCC. We found strong expression of NLRP3, ASC, IL-1beta, IL-18 and caspase-1 in human oropharyngeal SCC and weak or no expression of these proteins in normal tonsils. Furthermore, the distribution of mindbomb E3 ubiquitin protein ligase 1 and inflammasome-associated proteins in oropharyngeal SCC was not significantly different; there was no correlation between the expression of inflammasome-associated proteins and HPV infection. These findings suggest that inflammasomes in oropharyngeal SCC play a key role through facilitating antitumor immunity and the possibility of new roles for inflammasomes in the oropharynx. PMID- 27115670 TI - Neuropathic pain: an updated grading system for research and clinical practice. AB - The redefinition of neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system," which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the "definite" level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research. PMID- 27115673 TI - Particle conservation in dynamical density functional theory. AB - We present the exact adiabatic theory for the dynamics of the inhomogeneous density distribution of a classical fluid. Erroneous particle number fluctuations of dynamical density functional theory are absent, both for canonical and grand canonical initial conditions. We obtain the canonical free energy functional, which yields the adiabatic interparticle forces of overdamped Brownian motion. Using an exact and one of the most advanced approximate hard core free energy functionals, we obtain excellent agreement with simulations. The theory applies to finite systems in and out of equilibrium. PMID- 27115671 TI - Modulation of Corpus Striatal Neurochemistry by Astrocytes and Vasoactive Intestinal Peptide (VIP) in Parkinsonian Rats. AB - The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used in animal models of Parkinson's disease. In various neurodegenerative diseases, astrocytes play direct, active, and critical roles in mediating neuronal survival and functions. Vasoactive intestinal peptide (VIP) has neurotrophic actions and modulates a number of astrocytic activities. In this study, the effects of VIP on the striatal neurochemistry were investigated in parkinsonian rats. Adult Sprague Dawley rats were divided into sham-operated, unilaterally 6-OHDA-lesioned, and lesioned + VIP-administered (25 ng/kg i.p.) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection and then every 2 days throughout 15 days. Extracellular striatal concentration of glutathione (GSH), gamma aminobutyric acid (GABA), glutamate (GLU), and lactate were measured in microdialysates by high-performance liquid chromatography (HPLC). Quantification of GABA and activity dependent neuroprotective protein (ADNP)-expressing cells were determined by glutamic acid decarboxylase (GAD)/ADNP + glial fibrillary acidic protein (GFAP) double immunohistochemistry. Our results demonstrated that a 6-OHDA lesion significantly increased the density of astrocytes in the striatum and VIP treatment slightly reduced the gliosis. Extracellular concentration of GABA, GLU, and lactate levels did not change, but GSH level significantly increased in the striatum of parkinsonian rats. VIP treatment reduced GSH level comparable to sham-operated groups, but enhanced GABA and GLU levels. Our double labeling results showed that VIP primarily acts on neurons to increase ADNP and GAD expression for protection. These results suggest that, in the 6-OHDA-induced neurodegeneration model, astrocytes were possibly activated for forefront defensiveness by modulating striatal neurochemistry. PMID- 27115672 TI - SEPT14 Is Associated with a Reduced Risk for Parkinson's Disease and Expressed in Human Brain. AB - Genes involved in cytoskeletal stability and trafficking, such as MAPT and SNCA, are important risk factors for Parkinson's disease (PD). Two members of the cytoskeletal Septin family, SEPT4 and SEPT5, were implicated in PD pathobiology. We aimed to determine whether Septin genes are associated with Parkinson's disease. To this end, six SNPs located in four different Septin loci were analyzed in 720 PD patients and 740 controls, all of Ashkenazi-Jewish origin. In addition, SEPT14 was sequenced and its expression was determined in different human tissues. Our results revealed that two SNPs in the SEPT14 locus, rs11981883 and rs10241628, were associated with a reduced risk for PD (p = 0.02 and p = 0.005). A third SNP, rs77231105, was localized in the putative promoter of SEPT14 and was predicted to affect the binding of the transcription factor Nkx2.5. This SNP was also associated with a reduced risk for PD (OR = 0.28, p < 0.0007). The three SEPT14 SNPs defined a protective haplotype which significantly reduced the risk for PD by 4-fold (p = 0.002). SEPT14 was found to be expressed in the brain and in the Substantia Nigra. These results suggest that SEPT14 may have a protective role in Parkinson's disease pathogenesis, yet more studies are necessary to validate these results. PMID- 27115674 TI - Arsenic Induction of Metallothionein and Metallothionein Induction Against Arsenic Cytotoxicity. AB - Human exposure to arsenic (As) can lead to oxidative stress that can become evident in organs such as the skin, liver, kidneys and lungs. Several intracellular antioxidant defense mechanisms including glutathione (GSH) and metallothionein (MT) have been shown to minimize As cytotoxicity. The current review summarizes the involvement of MT as an intracellular defense mechanism against As cytotoxicity, mostly in blood. Zinc (Zn) and selenium (Se) supplements are also proposed as a possible remediation of As cytotoxicity. In vivo and in vitro studies on As toxicity were reviewed to summarize cytotoxic mechanisms of As. Intracellular antioxidant defense mechanisms of MT are linked in relation to As cytotoxicity. Arsenic uses a different route, compared to major metal MT inducers such as Zn, to enter/exit blood cells. A number of in vivo and in vitro studies showed that upregulated MT biosynthesis in blood components are related to toxic levels of As. Despite the cysteine residues in MT that aid to bind As, MT is not the preferred binding protein for As. Nonetheless, intracellular oxidative stress due to As toxicity can be minimized, if not eliminated, by MT. Thus MT induction by essential metals such as Zn and Se supplementation could be beneficial to fight against As toxicity. PMID- 27115675 TI - Disposal of Unused Drugs: Knowledge and Behavior Among People Around the World. AB - The purpose of this systematic review was to determine the practice of medication disposal around the world and get insight into possible association between environmental awareness and people's behavior regarding this issue. A literature search (2005-2015) was performed to identify reports with quantitative data on disposal practices published in peer-reviewed literature. The most common method for disposal of unused medications in households is disposal in the garbage (Kuwait, United Kingdom, Lithuania, Qatar, Serbia, Ghana, Bangladesh, Malta and Saudi Arabia). The practice of flushing drugs into the sewage system still takes place in New Zealand, USA and Bangladesh. Only in Sweden and Germany, practice of returning drugs to pharmacy was practiced to a larger extent. The environmental impact of improper medication disposal is expected in countries with poorly functioning waste management schemes (Middle Eastern, Asian and African countries). Lack of the adequate information and clear instructions on proper manners of drug disposal was reported in many surveyed countries (USA, New Zealand, Bangladesh, Malta and Ireland). Clear and definite connection between knowledge about environmental detrimental effects of improper drug disposal and the preference towards disposal methods could not be established. Many respondents were generally concerned with issues of inadequate medicines discarding but the behavior regarding disposal of unused drugs often did not equate the awareness (Serbia, USA, Kuwait, Malta and UK). The current data emphasizes the global issue of improper medicine disposal, prevalent in environmentally-aware people. PMID- 27115676 TI - Density functional theory of gas-liquid phase separation in dilute binary mixtures. AB - We examine statics and dynamics of phase-separated states of dilute binary mixtures using density functional theory. In our systems, the difference of the solvation chemical potential between liquid and gas [Formula: see text] (the Gibbs energy of transfer) is considerably larger than the thermal energy [Formula: see text] for each solute particle and the attractive interaction among the solute particles is weaker than that among the solvent particles. In these conditions, the saturated vapor pressure increases by [Formula: see text], where [Formula: see text] is the solute density added in liquid. For [Formula: see text], phase separation is induced at low solute densities in liquid and the new phase remains in gaseous states, even when the liquid pressure is outside the coexistence curve of the solvent. This explains the widely observed formation of stable nanobubbles in ambient water with a dissolved gas. We calculate the density and stress profiles across planar and spherical interfaces, where the surface tension decreases with increasing interfacial solute adsorption. We realize stable solute-rich bubbles with radius about 30 nm, which minimize the free energy functional. We then study dynamics around such a bubble after a decompression of the surrounding liquid, where the bubble undergoes a damped oscillation. In addition, we present some exact and approximate expressions for the surface tension and the interfacial stress tensor. PMID- 27115677 TI - Peroxisome proliferator-activated receptors in cardiac energy metabolism and cardiovascular disease. AB - Cardiomyocytes mainly depend on energy produced from the oxidation of fatty acids and mitochondrial oxidative phosphorylation. Shortage of energy or excessive fat accumulation can lead to cardiac disorders. High saturated fat intake and a sedentary life style have a major influence in the development of cardiovascular disease (CVD). Peroxisome proliferator-activated receptors (PPARs), one of the nuclear receptor super family members, play critical role in the metabolism of lipids by regulating their oxidation and storage. Furthermore, they are involved in glucose homeostasis as well. PPARs, mainly alpha (alpha) and beta/delta (beta/delta), have a significant effect on the lipid metabolism and anti inflammation in endothelial cells (ECs), vascular smooth muscle cells, and also in cardiomyocytes. Pro-inflammatory cytokines, mainly tumour necrosis factor alpha, released at the site of inflammation in the sub-ECs of coronary arteries can inactivate the PPARs which can eventually lead to decreased energy production in the myocardium. Various synthetic ligands of PPAR-alpha and beta/delta have many favourable effects in modulating the vascular diseases and heart failure. Despite the adverse effects from therapy using PPAR- gamma ligands, several laboratories are now focused on synthesizing partial activators which may combine their beneficial effects with lowering of undesirable side effects. This review discusses the role of isoforms of PPAR in the cardiomyocytes energy balance and CVD. The knowledge will help in the synthesis of ligands for their partial activation in order to render energy balance and protection from CVD. PMID- 27115678 TI - [Endoprosthetic tumor replacement : Reconstruction of the extensor mechanism and complications]. AB - BACKGROUND: The reconstruction of the extensor mechanism around the knee is an essential part of tumorresection and tumor arthroplasty in orthopaedic oncology for functional rehabilitation of quality of life and daily activities. OBJECTIVES: Operative procedures, treatment options and management of complications with reconstruction of the extensor mechanism after tumor resection around the knee depend on the type of arthroplasty. MATERIALS AND METHODS: Description of the different treatment option for extensor deficiency divided into infra- and suprapatellar modalities. RESULTS: The operative procedure is always an individual decision depending on the size of the tumor and its localisation. The extensor mechanism is reconstructed with autogenic, allogenic or synthetic material in combination with tumor arthroplasty. CONCLUSIONS: Extensor reconstruction (supra-/infrapatellar) is an essential part of tumor resection and tumor arthroplasty around the knee. Often, low functional results and high levels of complications (arthrofibrosis, rerupture extensor mechanism, periprosthetic joint infection) are seen in these highly demanding cases in orthopaedic oncology. PMID- 27115679 TI - Postextubation Dysphagia in Critical Patients: A First Report From the Largest Step-Down Intensive Care Unit in Greece. AB - PURPOSE: This study provided preliminary data on the occurrence and impact of postextubation dysphagia in the largest Greek step-down intensive care unit (ICU) over 2 years. METHOD: A retrospective observational cohort study of patients referred for swallowing assessment postextubation was conducted from November, 2011, to August, 2013. RESULTS: Of the 357 patients admitted to the unit during this period, 87, aged 55.8 +/- 18.1 years (61 male, 26 female), were referred and evaluated. Of these, 2.3% were found to have no dysphagia, and 21.8% and 75.9% were diagnosed with mild and moderate/severe dysphagia, respectively. Across severity levels, 23% of patients in the unit were found to have dysphagia. Patients with moderate/severe dysphagia were more likely to have had prolonged intubation (> 48 hr; p = .02) and exhibit signs of aspiration (p = .002) than those with no or mild dysphagia. Prolonged intubation was associated with increased likelihood of moderate/severe dysphagia by a factor of 12 (p = .042, odds ratio = 12.355) compared to short intubation. Moderate/severe dysphagia was correlated with pneumonia (p = .02), feeding tube placement (p = .004) and in hospital mortality (p = .034). CONCLUSION: In this sample, moderate/severe dysphagia was correlated with prolonged intubation, and was found to increase the risk for pneumonia and in-hospital mortality. Our results suggest the importance of early dysphagia management in critical patients in Greece and globally. PMID- 27115680 TI - Neuroscience: Suppressing One Drive for a Chance to Satisfy Another. PMID- 27115681 TI - A CCaMK-CYCLOPS-DELLA Complex Activates Transcription of RAM1 to Regulate Arbuscule Branching. PMID- 27115682 TI - Developmental prosopagnosia. AB - A Quick guide to developmental prosopagnosia, a condition definied by problems in recognising faces that, in contrast with acquired prosopagnosia, develop in the absence of manifest brain injury. PMID- 27115683 TI - Bioluminescence. AB - Kahle and Umbers introduce the ways by which organisms emit light though chemical reactions. PMID- 27115684 TI - Mountain-climbing bears protect cherry species from global warming through vertical seed dispersal. AB - In a warming climate, temperature-sensitive plants must move toward colder areas, that is, higher latitude or altitude, by seed dispersal [1]. Considering that the temperature drop with increasing altitude (-0.65 degrees C per 100 m altitude) is one hundred to a thousand times larger than that of the equivalent latitudinal distance [2], vertical seed dispersal is probably a key process for plant escape from warming temperatures. In fact, plant geographical distributions are tracking global warming altitudinally rather than latitudinally, and the extent of tracking is considered to be large in plants with better-dispersed traits (e.g., lighter seeds in wind-dispersed plants) [1]. However, no study has evaluated vertical seed dispersal itself due to technical difficulty or high cost. Here, we show using a stable oxygen isotope that black bears disperse seeds of wild cherry over several hundred meters vertically, and that the dispersal direction is heavily biased towards the mountain tops. Mountain climbing by bears following spring-to-summer plant phenology is likely the cause of this biased seed dispersal. These results suggest that spring- and summer-fruiting plants dispersed by animals may have high potential to escape global warming. Our results also indicate that the direction of vertical seed dispersal can be unexpectedly biased, and highlight the importance of considering seed dispersal direction to understand plant responses to past and future climate change. PMID- 27115685 TI - Severity of seabed spatial competition decreases towards the poles. AB - For more than a century ecologists have considered that competitive interactions between species are more intense at low latitudes [1,2]. This is frequently invoked as either an explanation or a consequence of higher species richness in the tropics, also suggesting that competition shifts from intra- to inter specific towards the tropics [1]. Another common assumption is that within a community, intraspecific competition needs to be relatively strong, compared to inter-specific competition, in order to enable stable coexistence of species [3]. However, many analyses have found no consistent large scale geographic patterns in the intensity of intra- or interspecific competition [4]. Here, we show a clear latitudinal trend in contest competition for space in nearshore marine environments, for bryozoans (sessile, colonial, suspension feeding animals). Bryozoans form species-rich assemblages with other encrusting fauna and flora (corraline algae), and are highly abundant across the globe [5]. We find that whilst the intensity of competition (percentage of bryozoan colonies involved in direct physical spatial interactions with bryozoan or other encrusters) differed little with latitude, its severity (percentage of bryozoan colonies involved in contests with a win/loss outcome, leading to death of the loser) was three times lower at the poles than in the tropics. The cause of this change in severity was a strong shift in taxonomic relatedness of competitors, from interactions between species of different families dominating at lower latitudes, to mainly intraspecific competition at the poles. PMID- 27115686 TI - Nutrient Acquisition: The Generation of Bioactive Vitamin B12 by Microalgae. AB - Many microalgae acquire vitamin B12 from marine prokaryotes. A new study demonstrates that vitamin B12 is synthesized by planktonic cyanobacteria as pseudocobalamin, a form not bioactive in microalgae. However, some microalgae can remodel pseudocobalamin to the active cobalamin form, adding complexity to our assessment of active vitamin B12 in the environment. PMID- 27115687 TI - Plant Reproduction: AMOR Enables Males to Respond to Female Signals. AB - The pollen tube of flowering plants undertakes a long journey to transport two sperm cells for double fertilization. New work on pollen tube guidance has identified an arabinogalactan-derived ovular factor that primes tubes to respond to female gametophyte-secreted attraction signals. PMID- 27115688 TI - Spatial Cognition: Finding the Boundary in the Occipital Place Area. AB - A new study using transcranial magnetic stimulation and a virtual reality navigation task has shown that we need the brain's occipital place area to accurately remember where objects are located in relation to boundaries, but not in relation to landmarks. PMID- 27115689 TI - Evolution: On the Origin of Symmetry, Synapsis, and Species. AB - As two species diverge from one another, they become increasingly isolated by reproductive incompatibilities. New findings, however, undermine this evolutionary orthodoxy, showing that the first identified mammal speciation gene causes only transient incompatibility between diverging species. PMID- 27115690 TI - Plant Signaling: HY5 Synchronizes Resource Supply. AB - A new report shows that the HY5 transcription factor moves from shoots to roots in plants, mediating light regulation of root growth and nitrate uptake. This finding offers not only a mechanistic insight into shoot-root communication, but also scope for increasing crop yields. PMID- 27115691 TI - Oogenesis: Ageing Oocyte Chromosomes Rely on Amazing Protein Stability. AB - Meiotic chromosome segregation in mouse oocytes seems to rely on highly stable cohesins and CENP-A produced in the fetus and not replenished during postnatal life. Hence, demise of these proteins may underpin declining oocyte quality in ageing mammals and thus marks a major problem of reproductive health in humans. PMID- 27115692 TI - Parkinson's Disease: A Traffic Jam? AB - Recent large-scale proteomic analyses of two protein kinases that are linked to Parkinson's disease have identified a remarkable convergence between their respective impacts on the phosphoproteome: activation of both LRRK2 and PINK1 leads to phosphorylation of several members of the Rab family of small GTPases, which regulate membrane trafficking. PMID- 27115693 TI - Zoology: War of the Worms. AB - The phylogenetic affinities of Xenacoelomorpha - the phylum comprising Xenoturbella bocki and acoelomorph worms - are debated. Two recent studies conclude they represent the earliest branching bilaterally symmetrical animals, but additional tests may be needed to confirm this notion. PMID- 27115694 TI - New Xist-Interacting Proteins in X-Chromosome Inactivation. AB - To achieve dosage compensation of X-linked gene expression, female mammalian cells inactivate one X chromosome through a process called X-chromosome inactivation (XCI). A central component of this process is the X-encoded long non coding RNA Xist. Following upregulation from one X chromosome, Xist spreads in cis, kicking off a plethora of events that ultimately results in stable X-linked gene repression, which is then faithfully transmitted to all daughter cells. In the last decades, intensive work has been undertaken to understand each of the steps in XCI, namely Xist transcription control, Xist spreading and localization, and silencing of gene expression. Recently, several groups have spearheaded the research of Xist's interactome and the factors involved in silencing. Several novel proteins have now been shown to be required for the transcriptional silencing of the X chromosome and/or Xist spreading and localization to the inactive X chromosome. Here, we review these new findings in the context of existing knowledge about Xist-interacting factors. PMID- 27115695 TI - Enhancing community based health programs in Iran: a multi-objective location allocation model. AB - Community Based Organizations (CBOs) are important health system stakeholders with the mission of addressing the social and economic needs of individuals and groups in a defined geographic area, usually no larger than a county. The access and success efforts of CBOs vary, depending on the integration between health care providers and CBOs but also in relation to the community participation level. To achieve widespread results, it is important to carefully design an efficient network which can serve as a bridge between the community and the health care system. This study addresses this challenge through a location allocation model that deals with the hierarchical nature of the system explicitly. To reflect social welfare concerns of equity, local accessibility, and efficiency, we develop the model in a multi-objective framework, capturing the ambiguity in the decision makers' aspiration levels through a fuzzy goal programming approach. This study reports the findings for the real case of Shiraz city, Fars province, Iran, obtained by a thorough analysis of the results. PMID- 27115696 TI - [Laboratory diagnostics in rheumatology]. PMID- 27115697 TI - [Role of non-coding regulatory ribonucleic acids in chronic inflammatory diseases]. AB - Non-coding regulatory ribonucleic acids (RNA), including microRNA, long non coding RNA and circular RNA, can influence the expression of genes mediating inflammatory processes and therefore affect the course and progression of chronic inflammatory diseases. Recent studies using antisense oligonucleotides suggest that such non-coding regulatory RNAs are suitable as novel therapeutic target molecules for the treatment of inflammatory rheumatic diseases. PMID- 27115699 TI - Vicinity of FLAIR Hyperintensities and SWI Microbleeds in Cerebral Amyloid Angiopathy-Related Inflammation. PMID- 27115698 TI - Smart Macroporous IPN Hydrogels Responsive to pH, Temperature, and Ionic Strength: Synthesis, Characterization, and Evaluation of Controlled Release of Drugs. AB - Fast responsive macroporous interpenetrating polymer network (IPN) hydrogels were fabricated in this work by a sequential strategy, as follows: the first network, consisting of poly(N,N-dimethylaminoethyl methacrylate) (PDMAEM) cross-linked with N,N'-methylenebisacrylamide (BAAm), was prepared at -18 degrees C, the second network consisting of poly(acrylamide) (PAAm) cross-linked with BAAm, being also generated by cryogelation technique. Both single network cryogels (SNC) and IPN cryogels were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, and water uptake. The presence of weak polycation PDMAEM endows the SNCs and the IPNs cryogels with sensitivity at numerous external stimuli such as pH, temperature, ionic strength, electric field, among which the first three were investigated in this work. It was found that the initial concentration of monomers in both networks was the key factor in tailoring the properties of IPN cryogels such as swelling kinetics, equilibrium water content (EWC), phase transition temperature and the response at ionic strength. The pore size increased after the formation of the second network, the swelling kinetics in pure water being comparable with that of the SNC, phase transition temperature being situated in the range 35-36 degrees C for IPN cryogels. The water uptake at equilibrium (WUeq) abruptly increased at pH < 3.0 in the case of SNCs, whereas the response of IPN cryogels at the decrease of pH from 6.0 to 1.0 was strongly dependent on the gel structure, the values of WUeq being lower at a higher concentration of DMAEM in the first network, the monomer concentration in the second network being about 10 wt %. The pH response was very much diminished when the monomer concentration was high in both networks (15 wt % in the first network, and 21 wt % in the second network). The increase of the ionic strength from 0 up to 0.3 M NaCl led to the decrease of the WUeq, for all cryogels, the level of dehydration being higher and faster for the SNC than for the corresponding IPN cryogel. The release of diclofenac sodium (DS), as a model acidic drug, triggered by pH, temperature, and ionic strength from the IPN cryogels was evaluated. A pulsatile release of DS from the IPN cryogels was presented, with a slower release at 34 degrees C (below VPTT) and a faster release at 37 and 40 degrees C (above the VPTT). PMID- 27115701 TI - Multidrug-Resistant Bacterial Donor-Derived Infections in Solid Organ Transplantation. AB - Although rare, donor-derived infections (DDIs) caused by multidrug-resistant (MDR) bacteria can have devastating consequences for organ transplant recipients. Recognition of MDR bacterial DDIs can be challenging, as MDR bacteria are prevalent in most hospitals and distinguishing their transmission through transplantation from other, more typical routes of acquisition are difficult. New technologies such as whole genome sequencing have recently proven to be a powerful advance in the investigation of MDR bacterial DDIs. Once recognized, the optimal treatment of MDR bacterial DDIs is not clear. Herein, we review the clinical manifestations, outcomes, and management of MDR bacterial DDIs, and identify areas of uncertainty toward which the transplant community should direct further research efforts. PMID- 27115700 TI - Norovirus in Transplantation. AB - Noroviruses are among the most common cause of diarrhea in transplant recipients. The clinical spectrum of norovirus infection after transplant is increasingly being recognized. As substantial morbidity is now associated with norovirus infections in this population; the quest for rapid diagnostic modalities and newer therapies has expanded. Transplant recipients with norovirus infection are at risk for several complications, including protracted illness with malnutrition, organ failure, and chronic viral shedding. This review summarizes the current knowledge on the epidemiology, complications, diagnosis, and treatment of norovirus infection in the transplant setting. PMID- 27115702 TI - A Proposed Computed Tomography Contrast Agent Using Carboxybetaine Zwitterionic Tantalum Oxide Nanoparticles: Imaging, Biological, and Physicochemical Performance. AB - OBJECTIVES: The aim of this study was to produce and evaluate a proposed computed tomography (CT) contrast agent based on carboxybetaine zwitterionic (CZ)-coated soluble tantalum oxide (TaO) nanoparticles (NPs). We chose tantalum to provide superior imaging performance compared with current iodine-based clinical CT contrast agents. We developed the CZ coating to provide biological and physical performance similar to that of current iodinated contrast agents. In addition, the aim of this study was to evaluate the imaging, biological, and physicochemical performance of this proposed contrast agent compared with clinically used iodinated agents. MATERIALS AND METHODS: We evaluated CT imaging performance of our CZ-TaO NPs compared with that of an iodinated agent in live rats, imaged centrally located within a tissue-equivalent plastic phantom that simulated a large patient. To evaluate vascular contrast enhancement, we scanned the rats' great vessels at high temporal resolution during and after contrast agent injection. We performed several in vivo CZ-TaO NP studies in healthy rats to evaluate tolerability. These studies included injecting the agent at the anticipated clinical dose (ACD) and at 3 times and 6 times the ACD, followed by longitudinal hematology to assess impact to blood cells and organ function (from 4 hours to 1 week). Kidney histological analysis was performed 48 hours after injection at 3 times the ACD. We measured the elimination half-life of CZ-TaO NPs from blood, and we monitored acute kidney injury biomarkers with a kidney injury assay using urine collected from 4 hours to 1 week. We measured tantalum retention in individual organs and in the whole carcass 48 hours after injection at ACD. Carboxybetaine zwitterionic TaO NPs were synthesized and analyzed in detail. We used multidimensional nuclear magnetic resonance to determine surface functionality of the NPs. We measured NP size and solution properties (osmolality and viscosity) of the agent over a range of tantalum concentrations, including the high concentrations required for standard clinical CT imaging. RESULTS: Computed tomography imaging studies demonstrated image contrast improvement of approximately 40% to 50% using CZ-TaO NPs compared with an iodinated agent injected at the same mass concentration. Blood and organ analyses showed no adverse effects after injection in healthy naive rats at 3 times the ACD. Retention of tantalum at 48 hours after injection was less than 2% of the injected dose in the whole carcass, which very closely matched the reported retention of existing commercial iodine-based contrast agents. Urine analysis of sensitive markers for acute kidney injury showed no responses at 1 week after injection at 3 times the ACD; however, a moderate response in the neutrophil gelatinase-associated lipocalin biomarker was measured at 24 and 48 hours. Compared with other TaO NPs reported in the literature, CZ-TaO NPs had relatively low osmolality and viscosity at concentrations greater than 200 mg Ta/mL and were similar in these physical properties to dimeric iodine-based contrast agents. CONCLUSIONS: We found that a CZ-TaO NP-based contrast agent is potentially viable for general-purpose clinical CT imaging. Our results suggest that such an agent can be formulated with clinically viable physicochemical properties, can be biologically safe and cleared rapidly in urine, and can provide substantially improved image contrast at CT compared with current iodinated agents. PMID- 27115704 TI - Efficacy of forming biofilms by Pseudomonas migulae AN-1 toward in situ bioremediation of aniline-contaminated aquifer by groundwater circulation wells. AB - The formation and activity of aniline-degrading biofilms developed by the psychrotrophic Pseudomonas migulae AN-1 were studied for the in situ remediation of contaminated aquifer using in-well bioreactor of groundwater circulating wells (GCWs). Biofilms grown in mineral salt medium with aniline exhibited tolerance to high concentrations of aniline. In aniline degradation rate, AN-1 biofilms exhibited slight differences compared with planktonic cells. The effectiveness and bio-implication of AN-1 biofilms in GCWs were investigated to treat aniline contaminated aquifer. The results demonstrate that AN-1 biofilms survived the GCWs treatment process with high aniline-degrading efficiency. This system provides a novel environmentally friendly technology for the in situ bioremediation of low-volatile contaminants. PMID- 27115703 TI - Acid-adaptive mechanisms of Streptococcus mutans-the more we know, the more we don't. PMID- 27115705 TI - Quantifying the impact of PM2.5 and associated heavy metals on respiratory health of children near metallurgical facilities. AB - The aim of this study was to link the concentrations of particulate matter with an aerodynamic diameter below 2.5 MUm (PM2.5) and associated heavy metals with occurrence of wheezing and hospitalizations due to wheezing in 111 children who live near metallurgical plants in Targoviste City, Romania. A group of 72 children with high levels of immunoglobulin E (IgE) and eosinophils, as well as frequent wheezing episodes, was geolocated on digital thematic maps. Monitoring campaigns and medical assessments were performed over two consecutive years (2013 2014). The multiannual average concentrations of PM2.5 ranged from 4.6 to 22.5 MUg m(-3), up to a maximum value of 102 MUg m(-3). Significant correlations (p < 0.01) were observed between the locations of the children with respiratory issues and the PM2.5 multiannual average (r = 0.985) and PM2.5 maximum (r = 0.813). Fe, Ni, Cd, and Cr were the main marker elements of the emissions from steel production and metal-working facilities in the Targoviste area. The results support the hypothesis that increased PM2.5 levels directly influence wheezing symptom and asthma attacks in the analyzed group. IgE, eosinophils, and wheezing episodes may be considered key indicators with which to evaluate the adverse effects of PM2.5 air pollution on children's health. PMID- 27115707 TI - Unique Length-Dependent Biophysical Properties of Repetitive DNA. AB - Expansion of a trinucleotide repeat (TNR) sequence is the molecular signature of several neurological disorders. The formation of noncanonical structures by the TNR sequence is proposed to contribute to the expansion mechanism. Furthermore, it is known that the propensity for expansion increases with repeat length. In this work, we use calorimetry to describe the thermodynamic parameters (DeltaH, TDeltaS, and DeltaG) of the noncanonical stem-loop hairpins formed by the TNR sequences (CAG)n and (CTG)n, as well as the canonical (CAG)n/(CTG)n duplexes, for n = 6-14. Using a thermodynamic cycle, we calculated the same thermodynamic parameters describing the process of converting from noncanonical stem-loop hairpins to a canonical duplex. In addition to these thermodynamic analyses, we used spectroscopic techniques to determine the rate at which the noncanonical structures convert to duplex and the activation enthalpy DeltaH(?) describing this process. We report that the thermodynamic parameters of unfolding the stem loop (CTG)n and (CAG)n hairpins, along with the thermodynamic and kinetic properties of hairpin to duplex conversion, do not proportionally correspond to the increase in length, but rather show a unique pattern that depends on whether the sequence has an even or odd number of repeats. PMID- 27115708 TI - Allosteric modulators of MEK1: drug design and discovery. AB - Mitogen-activated protein kinase kinase (MAPKK, MEK) mediates signal transduction, controlling cell proliferation and survival. MEK occupies a key downstream position in the Ras-Raf-MEK-ERK signaling pathway, implying that inhibition of MEK will potently suppress tumor cell growth, with potential applications in cancer therapy. Based on the promising therapeutic effects of MEK modulators, continued efforts have been made in this class. Here, we review the discovery and development of MEK1 allosteric modulators, classifying them into four structural groups. The allosteric mechanisms and recent clinical progress involving these modulators are also reviewed. PMID- 27115709 TI - The Vast and Varied Global Burden of Norovirus: Prospects for Prevention and Control. AB - Globally, norovirus is associated with approximately one-fifth of all diarrhea cases, with similar prevalence in both children and adults, and is estimated to cause over 200,000 deaths annually in developing countries. Norovirus is an important pathogen in a number of high-priority domains: it is the most common cause of diarrheal episodes globally, the principal cause of foodborne disease outbreaks in the United States, a key health care-acquired infection, a common cause of travel-associated diarrhea, and a bane for deployed military troops. Partly as a result of this ubiquity and burden across a range of different populations, identifying target groups and strategies for intervention has been challenging. And, on top of the breadth of this public health problem, there remain important gaps in scientific knowledge regarding norovirus, especially with respect to disease in low-income settings. Many pathogens can cause acute gastroenteritis. Historically, rotavirus was the most common cause of severe disease in young children globally. Now, vaccines are available for rotavirus and are universally recommended by the World Health Organization. In countries with effective rotavirus vaccination programs, disease due to that pathogen has decreased markedly, but norovirus persists and is now the most common cause of pediatric gastroenteritis requiring medical attention. However, the data supporting the precise role of norovirus in low- and middle-income settings are sparse. With vaccines in the pipeline, addressing these and other important knowledge gaps is increasingly pressing. We assembled an expert group to assess the evidence for the global burden of norovirus and to consider the prospects for norovirus vaccine development. The group assessed the evidence in the areas of burden of disease, epidemiology, diagnostics, disease attribution, acquired immunity, and innate susceptibility, and the group considered how to bring norovirus vaccines from their current state of development to a viable product that will benefit global health. PMID- 27115710 TI - Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases. AB - INTRODUCTION: Asparagine endopeptidase (AEP) is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Our most recent study identifies that it possesses the delta-secretase activity, and that it is implicated in numerous neurological diseases such as Alzheimer's disease (AD) and stroke. Accumulating evidence supports that the inhibition of AEP exhibits beneficial effects for treating these devastating diseases. AREAS COVERED: Based on recent evidence, it is clear that AEP cleaves its substrate, such as amyloid precursor protein (APP), tau and SET, and plays a critical role in neuronal cell death in various neurodegenerative diseases and stroke. In this article, the basic biology of AEP, its knockout phenotypes in mouse models, its substrates in neurodegenerative diseases, and its small peptidyl inhibitors and prodrugs are discussed. In addition, we discuss the potential of AEP as a novel therapeutic target for neurodegenerative diseases. EXPERT OPINION: AEP plays a unique role in numerous biological processes, depending on both pH and context. Most striking is our most recent finding; that AEP is activated in an age dependent manner and simultaneously cleaves both APP and tau, thereby unifying both major pathological events in AD. Thus, AEP acts as an innovative trigger for neurodegenerative diseases. Inhibition of AEP will provide a disease-modifying treatment for neurodegenerative diseases including AD. PMID- 27115711 TI - Assay and Inhibition of the Purified Catalytic Domain of Diacylglycerol Lipase Beta. AB - The diacylglycerol lipases (DAGLalpha and DAGLbeta) hydrolyze DAG to generate 2 arachidonoylglycerol (2-AG), the principal endocannabinoid and main precursor of arachidonic acid (AA). The DAGLs make distinct tissue specific contributions toward 2-AG and AA levels, and therefore, selective modulators for these enzymes could play crucial roles toward harnessing their therapeutic potential. Relatively high-throughput assays have recently been reported for DAGLalpha and have proven useful toward the characterization of inhibitors of this enzyme. Similar assays are also warranted for DAGLbeta which was the aim of this study. We first adapted previously reported DAGLalpha membrane assays (using PNPB and DiFMUO as substrates) to measure recombinant DAGLbeta activity in membranes. In contrast to results with DAGLalpha, both substrates provided a relatively limited signal window for measuring DAGLbeta activity, however, an improved window was obtained when employing a third commercially available substrate, EnzChek. In order to further improve on the assay parameters, we successfully purified the glutathione S-transferase (GST) tagged catalytic domain of DAGLbeta. Activity of the enzyme was confirmed using EnzChek as well as two DAGL inhibitors (THL and OMDM-188). The purified DAGLbeta catalytic domain assay described here provides the basis for a relatively clean and convenient assay with the potential to be adapted for high-throughput drug discovery efforts. PMID- 27115712 TI - Probing amyloid-beta pathology in transgenic Alzheimer's disease (tgArcSwe) mice using MALDI imaging mass spectrometry. AB - The pathological mechanisms underlying Alzheimer's disease (AD) are still not understood. The disease pathology is characterized by the accumulation and aggregation of amyloid-beta (Abeta) peptides into extracellular plaques, however the factors that promote neurotoxic Abeta aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used to study Abeta deposition in transgenic mouse brain tissue and to elucidate the plaque-associated chemical microenvironment. The imaging experiments were performed in brain sections of transgenic Alzheimer's disease mice carrying the Arctic and Swedish mutation of amyloid-beta precursor protein (tgArcSwe). Multivariate image analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their chemical identity. This include cortical and hippocampal Abeta deposits, whose amyloid peptide content was further verified using immunohistochemistry and laser microdissection followed by MALDI MS analysis. Subsequent statistical analysis on spectral data of regions of interest revealed brain region-specific differences in Abeta peptide aggregation. Moreover, other plaque-associated protein species were identified including macrophage migration inhibitory factor suggesting neuroinflammatory processes and glial cell reactivity to be involved in AD pathology. The presented data further highlight the potential of IMS as a powerful approach in neuropathology. Hanrieder et al. described an imaging mass spectrometry based study on comprehensive spatial profiling of C-terminally truncated Abeta species within individual plaques in tgArcSwe mice. Here, brain region-dependent differences in Abeta truncation and other plaque-associated proteins, such as macrophage migration inhibitory factor, were observed. The data shed further light on plaque-associated molecular mechanisms implicated in Alzheimer's pathogenesis. Cover image for this issue: doi: 10.1111/jnc.13328. PMID- 27115713 TI - Tetrahymena australis (Protozoa, Ciliophora): A Well-Known But "Non-Existing" Taxon - Consideration of Its Identification, Definition and Systematic Position. AB - A cryptic species of the Tetrahymena pyriformis complex, Tetrahymena australis, has been known for a long time but never properly diagnosed based on taxonomic methods. The species name is thus invalid according to the International Code of Zoological Nomenclature. Recently, a population isolated from a freshwater lake in Wuhan, China was investigated using live observations, silver staining methods and gene sequence data. This organism can be separated from other described species of the T. pyriformis complex by its relatively small body size, the number of somatic kineties and differences in sequences of two genes, namely the small subunit ribosomal RNA (SSU rRNA) and the mitochondrial cytochrome c oxidase subunit I (cox1). We compared the SSU rRNA gene sequences of all available Tetrahymena species to reveal the nucleotide differences within this genus. The sequence of the Wuhan population is identical to two sequences of a previously isolated strain of T. australis (ATCC #30831). Phylogenetic analyses indicate that these three sequences (X56167, M98015, KT334373) cluster with Tetrahymena shanghaiensis (EF070256) in a polytomy. However, sequence divergence of the cox1 gene between the Wuhan population and another strain of T. australis (ATCC #30271) is 1.4%, suggesting that these may represent different subspecies. PMID- 27115714 TI - Microfluidic Chip for the Photocatalytic Production of Active Chlorine. AB - Active chlorine is the most powerful microbicidal reagent in swimming pools, potable water, hospitals, and medical surgeries. Its production mainly relies on reactive inorganic intermediates and electrochemical methods that involve undesired waste products and high energy as well as material costs. In this study, we fabricated a low-cost chip based on sputter-coated thin films of silver (Ag) that acted as recyclable and effective photoelectrode for the photocatalytic production of active chlorine (HOCl) from aqueous media and artificial sunlight. The photoelectrode was electrochemically activated to AgCl at low overpotentials between 0.2 and 0.4 V vs Ag|AgCl (3 M KCl) and photocatalytically reduced to Ag(0) for 15 consecutive cycles, showing the electrode still being active. However, because of poor adhesion properties on the selected substrates, degradation effects were observed over time. Furthermore, the Ag@AgCl photoelectrode was integrated into a microfluidic chip, and we showed for the first time a light-driven microfluidic chip generating a constant stream of active chlorine. PMID- 27115715 TI - Chemical Functionalisation and Photoluminescence of Graphene Quantum Dots. AB - Chemical modification of graphene quantum dots (GQDs) can influence their physical and chemical properties; hence, the investigation of the effect of organic functional groups on GQDs is of importance for developing GQD-organic hybrid materials. Three peripherally functionalised GQDs having a third generation dendritic wedge (GQD-2), long alkyl chains (GQD-3) and a polyhedral oligomeric silsesquioxane group (GQD-4) were prepared by the Cu(I) -catalysed Huisgen cycloaddition reaction of GQD-1 with organic azides. Cyclic voltammetry indicated that reduction occurred on the surfaces of GQD-1-4 and on the five membered imide rings at the periphery, and this suggested that the functional groups distort the periphery by steric interactions between neighbouring functional groups. The HOMO-LUMO bandgaps of GQD-1-4 were estimated to be approximately 2 eV, and their low-lying LUMO levels (<-3.9 eV) were lower than that of phenyl-C61 -butyric acid methyl ester, an n-type organic semiconductor. The solubility of GQD-1-4 in organic solvents depends on the functional groups present. The functional groups likely cover the surfaces and periphery of the GQDs, and thus increase their affinity for solvent and avoid precipitation. Similar to GQD-2, both GQD-3 and GQD-4 emitted white light upon excitation at 360 nm. Size-exclusion chromatography demonstrated that white-light emission originates from the coexistence of differently sized GQDs that have different photoluminescence emission wavelengths. PMID- 27115716 TI - Efficacy of Training Interprofessional Spiritual Care Generalists. AB - BACKGROUND: Provision of spiritual/religious (S/R) care has been associated with improvements in patient care, patient-provider relationships, and resource utilization. Clinicians identify a lack of training in S/R care as the primary impediment. The purpose of the study was to evaluate the effectiveness of one day, simulation-based workshops to prepare interprofessional clinicians to function as capable, confident, and ethical spiritual care generalists. METHODS: Interprofessional practitioners (physicians, nurses, social workers, psychologists, child life specialists) in a quaternary care academic pediatric hospital participated in daylong Spiritual Generalist workshops utilizing professional actors to learn requisite spiritual generalist skills. Participants completed pre- and postworkshop questionnaires on the day of the workshop, and three-month follow-up self-report questionnaires that included 1-5-point Likert scale items focused on 15 spiritual generalist skills. RESULTS: One hundred fifteen interprofessional staff members completed pre- and postquestionnaires and three-month follow-up surveys. Analysis revealed significant mean improvement in all 15 spiritual generalist skills targeted for developing mastery within each of three broad domains: Spiritual Screen and Care Plan, Provision of Spiritual Care, and Professional Development. Although the initial degree of improvement tended to be greater immediately postworkshop, 14 of the 15 spiritual generalist skills remained significantly higher at three months compared to preworkshop. CONCLUSIONS: This daylong workshop of concentrated instruction, including didactics, visual slideshow, simulation of clinical scenarios, and debriefing/discussion components, was efficient and effective in training clinicians from varied disciplines to learn basic generalist-level spiritual care skills and to collaborate more effectively with chaplains, the spiritual specialists. PMID- 27115717 TI - Novel 3-Aminothiazolquinolones: Design, Synthesis, Bioactive Evaluation, SARs, and Preliminary Antibacterial Mechanism. AB - A series of novel 3-aminothiazolquinolones as analogues of quinolone antibacterial agents were designed and synthesized in an effort to circumvent quinolone resistance. Among these 3-aminothiazolquinolones, 3-(2-aminothiazol-4 yl)-7-chloro-6-(pyrrolidin-1-yl) quinolone 12b exhibited potent antibacterial activity, low cytotoxicity to hepatocyte cells, strong inhibitory potency to DNA gyrase, and a broad antimicrobial spectrum including against multidrug-resistant strains. This active molecule 12b also induced bacterial resistance more slowly than norfloxacin. Analysis of structure-activity relationships (SARs) disclosed that the 2-aminothiazole fragment at the 3-position of quinolone plays an important role in exerting antibacterial activity. Molecular modeling and experimental investigation of aminothiazolquinolone 12b with DNA from a sensitive methicillin-resistant Staphylococcus aureus (MRSA) strain revealed that the possible antibacterial mechanism might be related to the formation of a compound 12b-Cu(2+)-DNA ternary complex in which the Cu(2+) ion acts as a bridge between the backbone of 3-aminothiazolquinolone and the phosphate group of the nucleic acid. PMID- 27115718 TI - Templated Oligosaccharide Synthesis: The Linker Effect on the Stereoselectivity of Glycosylation. AB - A new method for intramolecular oligosaccharide synthesis that is conceptually related to the general molecular clamp approach is introduced. Exceptional alpha selectivity has been achieved in a majority of applications. Unlike other related concepts, this approach is based on the bisphenol A template, which allows one to connect multiple building blocks to perform templated oligosaccharide synthesis with complete stereoselectivity. This principle was demonstrated by the synthesis of an alpha,alpha-linked trisaccharide. PMID- 27115719 TI - Outcomes of follow-up care after an emergency department visit among pediatric asthmatics in the military health system. AB - BACKGROUND AND OBJECTIVES: Asthma exacerbations frequently trigger emergency department (ED) visits. Guidelines recommend timely follow-up after an ED visit for asthma, however, other studies have questioned the quality of follow-up care and their effect on subsequent ED utilization. We evaluated follow-up care on asthma outcomes in pediatric asthmatics enrolled in the Military Health System (MHS) after an ED visit for asthma. METHODS: This retrospective study utilized MHS data to evaluate 2-17-year-old persistent asthmatics with an ED visit for asthma between 2010-2012. Demographics, medication dispensing, and subsequent asthma related ED and hospital utilization were compared between those with or without a 28-day follow-up appointment. RESULTS: 10,460 of 88,837 persistent asthmatics met inclusion criteria for an asthma ED visit. 4,964 (47.5%) had >= 1 follow-up visit. In the 29-365 days after their ED visit, 21.1% of the follow-up cohort required an ED re-visit compared to 24.0% of the patients without follow up. Follow-up care was associated with a reduction in ED re-visits (adjusted hazard ratio 0.86; 95% confidence interval 0.79, 0.93). Controller medications were dispensed to 76.0% of the follow-up cohort within 90 days of their ED visit compared to 49.7% in the group without follow-up. CONCLUSIONS: Despite universal access to healthcare, less than half of pediatric MHS asthma patients had follow up within 28 days of an ED visit. Those with follow-up were more likely to fill a controller medication within 90 days post-ED visit, and less likely to have an asthma ED re-visit in the subsequent year. PMID- 27115720 TI - Odisolane, a Novel Oxolane Derivative, and Antiangiogenic Constituents from the Fruits of Mulberry (Morus alba L.). AB - Mulberry, the fruit of Morus alba L., is known as an edible fruit and commonly used in Chinese medicines as a warming agent and as a sedative, tonic, laxative, odontalgic, expectorant, anthelmintic, and emetic. Systemic investigation of the chemical constituents of M. alba fruits led to the identification of a novel oxolane derivative, (R*)-2-((2S*,3R*)-tetrahydro-2-hydroxy-2-methylfuran-3 yl)propanoic acid (1), namely, odisolane, along with five known heterocyclic compounds (2-6). The structure of the new compound was elucidated on the basis of HR-MS, 1D and 2D NMR ((1)H-(1)H COSY, HSQC, HMBC, and NOESY) data analysis. Compound 1 has a novel skeleton that consists of 8 carbon units with an oxolane ring, which until now has never been identified in natural products. The isolated compounds were subjected to several activity tests to verify their biological function. Among them, compounds 1, 3, and 5 significantly inhibited cord formation in HUVECs. The action mechanism of compound 3, which had the strongest antiangiogenic activity, was mediated by decreasing VEGF, p-Akt, and p-ERK protein expression. These results suggest that compounds isolated from M. alba fruits might be beneficial in antiangiogenesis therapy for cancer treatment. PMID- 27115721 TI - Long-range weight functions in fundamental measure theory of the non-uniform hard sphere fluid. AB - We introduce long-range weight functions to the framework of fundamental measure theory (FMT) of the non-uniform, single-component hard-sphere fluid. While the range of the usual weight functions is equal to the hard-sphere radius R, the modified weight functions have range 3R. Based on the augmented FMT, we calculate the radial distribution function g(r) up to second order in the density within Percus' test particle theory. Consistency of the compressibility and virial routes on this level allows us to determine the free parameter gamma of the theory. As a side result, we obtain a value for the fourth virial coefficient B 4 which deviates by only 0.01% from the exact result. The augmented FMT is tested for the dense fluid by comparing results for g(r) calculated via the test particle route to existing results from molecular dynamics simulations. The agreement at large distances (r > 6R) is significantly improved when the FMT with long-range weight functions is used. In order to improve agreement close to contact (r = 2R) we construct a free energy which is based on the accurate Carnahan-Starling equation of state, rather than the Percus-Yevick compressibility equation underlying standard FMT. PMID- 27115722 TI - Detection of simulated periodontal defects using cone-beam CT and digital intraoral radiography. AB - OBJECTIVES: This study sought to assess the diagnostic value of CBCT and digital intraoral radiography for the detection of periodontal defects in the sheep mandible. METHODS: In this in vitro study, 80 periodontal defects including Grades I, II and III furcation involvements, one-, two-, three-wall and trough like infrabony defects, fenestration and dehiscence were artificially created in the sheep mandible by burr. Intraoral digital radiographs using photostimulable phosphor plates and CBCT scans were obtained. Three periodontists evaluated the images for the presence and type of defects. The results were compared with the gold standard (photographs of the created defects). RESULTS: CBCT scans were significantly superior to digital radiographs for the detection of Grade I furcation involvements, three-wall defects, fenestrations and dehiscence (p < 0.05). No significant difference was noted between CBCT and digital radiography for the detection of Grades II and III furcation involvements, one-wall, two-wall and trough-like defects (p-value > 0.05). CONCLUSIONS: CBCT was superior to digital intraoral radiography for the detection of Grade I furcation involvements, three-wall defects, dehiscence and fenestrations. PMID- 27115723 TI - Fetal Cleft Lip/Palate Surgery: End of a Dream? AB - Recognition that a fetus can scarlessly heal in intrauterine life led to various animal studies in the mid 1980s exploring the possibility of fetal cleft lip/palate surgery. The idea of scarless cleft repair seemed like a possible dream after the promising results from the early animal studies. In this review, we analyze the progress made in the 30 years since our first experience with animal models. PMID- 27115724 TI - Racial and ethnic disparities in substance use disorders and outcomes in elderly prostate cancer patients. AB - Substance use among cancer patients is an important psychosocial comorbidity. Currently, there is a paucity of information regarding racial disparity in substance use among cancer patients. The objective of this study was to analyze racial and ethnic disparity in prevalence of substance use and its effects on outcomes in Medicare elderly with advanced prostate cancer using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. We used ICD-9 diagnosis codes to identify substance use disorder. Outcomes were health service use, cost, and mortality. Prevalence of substance use varied among White, African American, and Hispanic patients with advanced-stage prostate cancer. Racial and ethnic disparity existed in the association between substance use and outcomes. A multidisciplinary coordinated care approach is essential to address racial and ethnic disparities in substance use among prostate cancer patients and to achieve optimal clinical management and improved outcomes of care. PMID- 27115725 TI - Tissue transglutaminase is involved in mechanical load-induced osteogenic differentiation of human ligamentum flavum cells. AB - Mechanical load-induced osteogenic differentiation might be the key cellular event in the calcification and ossification of ligamentum flavum. The aim of this study was to investigate the influence of tissue transglutaminase (TGM2) on mechanical load-induced osteogenesis of ligamentum flavum cells. Human ligamentum flavum cells were obtained from 12 patients undergoing lumbar spine surgery. Osteogenic phenotypes of ligamentum flavum cells, such as alkaline phosphatase (ALP), Alizarin red-S stain, and gene expression of osteogenic makers were evaluated following the administration of mechanical load and BMP-2 treatment. The expression of TGM2 was evaluated by real-time PCR, Western blotting, and enzyme-linked immunosorbent assay (ELISA) analysis. Our results showed that mechanical load in combination with BMP-2 enhanced calcium deposition and ALP activity. Mechanical load significantly increased ALP and OC gene expression on day 3, whereas BMP-2 significantly increased ALP, OPN, and Runx2 on day 7. Mechanical load significantly induced TGM2 gene expression and enzyme activity in human ligamentum flavum cells. Exogenous TGM2 increased ALP and OC gene expression; while, inhibited TG activity significantly attenuated mechanical load induced and TGM2-induced ALP activity. In summary, mechanical load-induced TGM2 expression and enzyme activity is involved in the progression of the calcification of ligamentum flavum. PMID- 27115726 TI - Insights into the removal of terbuthylazine from aqueous solution by several treatment methods. AB - This paper reports the removal of the s-triazine herbicide terbuthylazine (TBA) from aqueous solution by various treatment methods including adsorption onto activated carbon (AC) and multiwalled carbon nanotubes (MWCNT), UV254 photolysis, UV254/H2O2, single ozonation, O3/H2O2, catalytic ozonation (AC, MWCNT and TiO2 as catalysts) and some solar driven processes such as TiO2 photocatalytic oxidation and photo-ozonation. TBA was adsorbed onto AC and MWCNT following a pseudo-second order kinetics and Freundlich isotherm. Rapid small scale column tests showed that TBA could be removed from solution by adsorption onto AC better than atrazine. The UV254/H2O2 treatment resulted in excellent removal of TBA primarily due to the oxidation capability of hydroxyl radicals (kHO = 3.310(9) M(-1) s(-1)) generated from H2O2 photolysis. As the H2O2 initial concentration was increased from 5 to 50 mg L(-1) the HO exposure per UV fluence (RHO,UV) increased, making the process more efficient. Single ozonation also allowed complete removal of the herbicide though the process was slow (kO3=15.4 M(-1) s(-1) at pH > 4). The ozonation process could be greatly accelerated by the enhanced generation of HO through O3/H2O2 and O3/AC processes, which also led to more efficient processes in terms of ozone utilization. Commercial TiO2 (TiO2-P25) and lab prepared anatase TiO2 (TiO2-cat) nanoparticles catalyzed the removal of TBA by solar photocatalysis. In contrast, a lab prepared MWCNT-TiO2 composite was not useful as catalyst in solar photo-oxidation processes because of the HO scavenging nature of the MWCNT used as support. A mechanism for TBA degradation by O3 and HO has been suggested after TBA degradation intermediates identification. PMID- 27115727 TI - AAV-mediated transduction and targeting of retinal bipolar cells with improved mGluR6 promoters in rodents and primates. AB - Adeno-associated virus (AAV) vectors have been a powerful gene delivery vehicle to the retina for basic research and gene therapy. For many of these applications, achieving cell type-specific targeting and high transduction efficiency is desired. Recently, there has been increasing interest in AAV mediated gene targeting to specific retinal bipolar cell types. A 200-bp enhancer in combination with a basal SV40 promoter has been commonly used to target transgenes into ON-type bipolar cells. In the current study, we searched for additional cis-regulatory elements in the mGluR6 gene for improving AAV-mediated transduction efficiency into retinal bipolar cells. Our results showed that the combination of the endogenous mGluR6 promoter with additional enhancers in the introns of the mGluR6 gene markedly enhanced AAV transduction efficiency as well as made the targeting more selective for rod bipolar cells in mice. Furthermore, the AAV vectors with the improved promoter could target to ON bipolar cells with robust transduction efficiency in the parafovea and the far peripheral retina of marmoset monkeys. The improved mGluR6 promoter constructs could provide a valuable tool for genetic manipulation in rod bipolar cells in mice and facilitate clinical applications for ON bipolar cell-based gene therapies. PMID- 27115728 TI - Hydrogen peroxide affects ion channels in lily pollen grain protoplasts. AB - Ion homeostasis plays a central role in polarisation and polar growth. In several cell types ion channels are controlled by reactive oxygen species (ROS). One of the most important cells in the plant life cycle is the male gametophyte, which grows under the tight control of both ion fluxes and ROS balance. The precise relationship between these two factors in pollen tubes has not been completely elucidated, and in pollen grains it has never been studied to date. In the present study we used a simple model - protoplasts obtained from lily pollen grains at the early germination stage - to reveal the effect of H2 O2 on cation fluxes crucial for pollen germination. Here we present direct evidence for two ROS-sensitive currents on the pollen grain plasma membrane: the hyperpolarisation activated calcium current, which is strongly enhanced by H2 O2 , and the outward potassium current, which is modestly enhanced by H2 O2 . We used low concentrations of H2 O2 that do not cause an intracellular oxidative burst and do not damage cells, as demonstrated with fluorescent staining. PMID- 27115729 TI - Identification of novel and diverse rotaviruses in rodents and insectivores, and evidence of cross-species transmission into humans. AB - Rotaviruses are an important cause of severe diarrheal illness in children globally. We characterized rotaviruses sampled in humans, insectivores (shrews) and rodents from urban and rural regions of Zhejiang province, China. Phylogenetic analyses revealed seven genotypic constellations of human rotaviruses with six different combinations of G and P genotypes - G3P[8] (50.06%), G9P[8] (36.16%), G1P[8] (8.92%), G2P[4] (4.63%), G3P[3] (0.12%), and G3P[9] (0.12%). In rodents and shrews sampled from the same locality we identified a novel genotype constellation (G32-P[46]-I24-R18-C17-M17-A28-N17-T19 E24-H19), a novel P genotype (P[45]), and two different AU-1-like rotaviruses associated with a G3P[3] genotype combination. Of particular note was a novel rotavirus from a human patient that was closely related to viruses sampled from rodents in the same region, indicative of a local species jump. In sum, these data are suggestive of the cross-species transmission of rodent rotaviruses into humans and for reassortment among human and animal rotaviruses. PMID- 27115730 TI - Time Course of Molecular and Metabolic Events in the Development of Insulin Resistance in Fructose-Fed Rats. AB - We aimed to determine the time-course of metabolic changes related to the early onset of insulin resistance (IR), trying to evidence breaking points preceding the appearance of the clinical IR phenotype. The model chosen was the fructose (FRU)-fed rat compared to controls fed with starch. We focused on the hepatic metabolism after 0, 5, 12, 30, or 45 days of FRU intake. The hepatic molecular metabolic changes followed indeed a multistep trajectory rather than a continuous progression. After 5 d of FRU feeding, we observed deep modifications in the hepatic metabolism, driven by the induction of lipogenic genes and important glycogen depletion. Thereafter, a steady-state period between days 12 and 30 was observed, characterized by a switch from carbohydrate to lipid utilization at the hepatic level and increased insulin levels aiming at alleviating lipid accumulation and hyperglycemia, respectively. The FRU-fed animals were only clinically IR at day 45 (altered homeostasis model assessment-estimated insulin resistance and muscle glucose transport). Furthermore, the urine metabolome revealed even earlier metabolic trajectory changes that precede the hepatic alterations. We identified several candidate metabolites linked to the tryptophan nicotinamide metabolism and the installation of fasting hyperglycemia that suggest a role of this metabolic pathway on the development of the IR phenotype in the FRU-fed rats. PMID- 27115731 TI - Prediction of survival in patients with oesophageal or junctional cancer receiving neoadjuvant chemoradiotherapy and surgery. AB - BACKGROUND: The value of conventional prognostic factors is unclear in the era of multimodal treatment for oesophageal cancer. This study aimed to quantify the impact of neoadjuvant chemoradiotherapy (nCRT) and surgery on well established prognostic factors, and to develop and validate a prognostic model. METHODS: Patients treated with nCRT plus surgery were included. Multivariable Cox modelling was used to identify prognostic factors for overall survival. A prediction model for individual survival was developed using stepwise backward selection. The model was internally validated leading to a nomogram for use in clinical practice. RESULTS: Some 626 patients who underwent nCRT plus surgery were included. In the multivariable model, only pretreatment cN category and ypN category were independent prognostic factors. The final prognostic model included cN, ypT and ypN categories, and had moderate discrimination (c-index at internal validation 0.63). CONCLUSION: In patients with oesophageal or oesophagogastric cancer treated with nCRT plus surgery, overall survival can best be estimated using a prediction model based on cN, ypT and ypN categories. Predicted survival according to this model showed only moderate correlation with observed survival, emphasizing the need for new prognostic factors to improve survival prediction. PMID- 27115732 TI - Characterization of Plasmid-Mediated Quinolone Resistance Determinants in High Level Quinolone-Resistant Enterobacteriaceae Isolates from the Community: First Report of qnrD Gene in Algeria. AB - OBJECTIVE: The objective was to assess the prevalence of plasmid-mediated quinolone resistance (PMQR)-producing isolates in a collection of quinolone resistant Enterobacteriaceae of community origin isolated in Bejaia, Algeria. METHODS: A total of 141 nalidixic acid-resistant Enterobacteriaceae community isolates were collected in Bejaia (Northern Algeria) and screened for PMQR genes using polymerase chain reaction (PCR). For PMQR-positive strains, antimicrobial susceptibility testing was performed by broth microdilution and disk diffusion. Mutations in the quinolone resistance-determining regions of the target genes, gyrA and parC, were detected with a PCR-based method and sequencing. Southern blotting, conjugation and transformation assays and molecular typing by pulsed field gel electrophoresis (PFGE), and multilocus sequence typing were also performed. RESULTS: The prevalence of PMQR-producing Enterobacteriaceae isolates was 13.5% (19/141); 11 of these isolates produced Aac(6')-Ib-cr and 8 were qnr positive (4 qnrB1-like, 2 qnrS1-like, and 2 qnrD1-like), including the association with aac(6')-Ib-cr gene in three cases. PMQR gene transfer by conjugation was successful in 6 of 19 isolates tested. PFGE revealed that most of the PMQR-positive Escherichia coli isolates were unrelated, except for two groups comprising two and four isolates, respectively, including the virulent multidrug resistant clone E. coli ST131 that were clonally related. CONCLUSION: Our findings indicate that PMQR determinants are prevalent in Enterobacteriaceae isolates from the community studied. We describe the first report of the qnrD gene in Algeria. PMID- 27115733 TI - Introspective responses to cues and motivation to reduce cigarette smoking influence state and behavioral responses to cue exposure. AB - In the current study, we aimed to extend smoking cue-reactivity research by evaluating delay discounting as an outcome of cigarette cue exposure. We also separated introspection in response to cues (e.g., self-reporting craving and affect) from cue exposure alone, to determine if introspection changes behavioral responses to cigarette cues. Finally, we included measures of quit motivation and resistance to smoking to assess motivational influences on cue exposure. Smokers were invited to participate in an online cue-reactivity study. Participants were randomly assigned to view smoking images or neutral images, and were randomized to respond to cues with either craving and affect questions (e.g., introspection) or filler questions. Following cue exposure, participants completed a delay discounting task and then reported state affect, craving, and resistance to smoking, as well as an assessment of quit motivation. We found that after controlling for trait impulsivity, participants who introspected on craving and affect showed higher delay discounting, irrespective of cue type, but we found no effect of response condition on subsequent craving (e.g., craving reactivity). We also found that motivation to quit interacted with experimental conditions to predict state craving and state resistance to smoking. Although asking about craving during cue exposure did not increase later craving, it resulted in greater delaying of discounted rewards. Overall, our findings suggest the need to further assess the implications of introspection and motivation on behavioral outcomes of cue exposure. PMID- 27115734 TI - Perioperative omega-3 Polyunsaturated Fatty Acid Nutritional Support in Gastrointestinal Cancer Surgical Patients: A Systematic Evaluation. AB - This study was a systematic evaluation of the beneficial effects of n-3 polyunsaturated fatty acid (PUFA) in abdominal cancer surgical patients. A literature search of the databases PubMed, Medline, Cochrane, and EMBASE was conducted for studies published up to November 2014 in English language journals. Randomized controlled trials (RCTs) examining the effects of n-3 PUFA intake relative to conventional nutrition in surgical patients were included. The main outcomes were the duration of systemic inflammatory response syndrome (SIRS), length of hospital stay (LOS), serum C-reactive protein (CRP) levels, and postoperative complications. We identified 15 RCTs among 158 relevant trials. The results indicated the associations between n-3 PUFA intake and reduced LOS [mean differences (MDs), -2.47 d; 95% confidence intervals (CIs), -3.25 to -1.69], duration of SIRS (MD, -0.57 d; 95% CI, -0.92 to -0.22), and serum CRP levels (MD, -3.97 mg/l; 95% CI, -7.88 to -0.07) compared with consumption of conventional nutrition, as well as reduced incidence of postoperative infectious complications (risk ratio, 0.66; 95% CI, 0.49-0.87). This systematic evaluation suggests that n 3 PUFA significantly reduces the postoperative infectious complication rate, and shortens hospitalization and SIRS duration, particularly in malnourished gastrointestinal cancer patients. PMID- 27115735 TI - Effects of oxytetracycline on archaeal community, and tetracycline resistance genes in anaerobic co-digestion of pig manure and wheat straw. AB - In this study, the effects of different concentrations of oxytetracycline (OTC) on biogas production, archaeal community structure, and the levels of tetracycline resistance genes (TRGs) were investigated in the anaerobic co digestion products of pig manure and wheat straw. PCR denaturing gradient gel electrophoresis analysis and real-time quantitative polymerase chain reaction (RT qPCR) (PCR) were used to detect the archaeal community structure and the levels of four TRGs: tet(M), tet(Q), tet(W), and tet(C). The results showed that anaerobic co-digestion with OTC at concentrations of 60, 100, and 140 mg/kg (dry weight of pig manure) reduced the cumulative biogas production levels by 9.9%, 10.4%, and 14.1%, respectively, compared with that produced by the control, which lacked the antibiotic. The addition of OTC substantially modified the structure of the archaeal community. Two orders were identified by phylogenetic analysis, that is, Pseudomonadales and Methanomicrobiales, and the methanogen present during anaerobic co-digestion with OTC may have been resistant to OTC. The abundances of tet(Q) and tet(W) genes increased as the OTC concentration increased, whereas the abundances of tet(M) and tet(C) genes decreased as the OTC concentration increased. PMID- 27115736 TI - Global Economic Burden of Norovirus Gastroenteritis. AB - BACKGROUND: Despite accounting for approximately one fifth of all acute gastroenteritis illnesses, norovirus has received comparatively less attention than other infectious pathogens. With several candidate vaccines under development, characterizing the global economic burden of norovirus could help funders, policy makers, public health officials, and product developers determine how much attention and resources to allocate to advancing these technologies to prevent and control norovirus. METHODS: We developed a computational simulation model to estimate the economic burden of norovirus in every country/area (233 total) stratified by WHO region and globally, from the health system and societal perspectives. We considered direct costs of illness (e.g., clinic visits and hospitalization) and productivity losses. RESULTS: Globally, norovirus resulted in a total of $4.2 billion (95% UI: $3.2-5.7 billion) in direct health system costs and $60.3 billion (95% UI: $44.4-83.4 billion) in societal costs per year. Disease amongst children <5 years cost society $39.8 billion, compared to $20.4 billion for all other age groups combined. Costs per norovirus illness varied by both region and age and was highest among adults >=55 years. Productivity losses represented 84-99% of total costs varying by region. While low and middle income countries and high income countries had similar disease incidence (10,148 vs. 9,935 illness per 100,000 persons), high income countries generated 62% of global health system costs. In sensitivity analysis, the probability of hospitalization had the largest impact on health system cost estimates ($2.8 billion globally, assuming no hospitalization costs), while the probability of missing productive days had the largest impact on societal cost estimates ($35.9 billion globally, with a 25% probability of missing productive days). CONCLUSIONS: The total economic burden is greatest in young children but the highest cost per illness is among older age groups in some regions. These large costs overwhelmingly are from productivity losses resulting from acute illness. Low, middle, and high income countries all have a considerable economic burden, suggesting that norovirus gastroenteritis is a truly global economic problem. Our findings can help identify which age group(s) and/or geographic regions may benefit the most from interventions. PMID- 27115737 TI - Spread of the Invasive Mosquitoes Aedes aegypti and Aedes albopictus in the Black Sea Region Increases Risk of Chikungunya, Dengue, and Zika Outbreaks in Europe. PMID- 27115738 TI - Protective Effects of Hydrogen Gas on Experimental Acute Pancreatitis. AB - Acute pancreatitis (AP) is an inflammatory disease mediated by damage to acinar cells and pancreatic inflammation. In patients with AP, subsequent systemic inflammatory responses and multiple organs dysfunction commonly occur. Interactions between cytokines and oxidative stress greatly contribute to the amplification of uncontrolled inflammatory responses. Molecular hydrogen (H2) is a potent free radical scavenger that not only ameliorates oxidative stress but also lowers cytokine levels. The aim of the present study was to investigate the protective effects of H2 gas on AP both in vitro and in vivo. For the in vitro assessment, AR42J cells were treated with cerulein and then incubated in H2-rich or normal medium for 24 h, and for the in vivo experiment, AP was induced through a retrograde infusion of 5% sodium taurocholate into the pancreatobiliary duct (0.1 mL/100 g body weight). Wistar rats were treated with inhaled air or 2% H2 gas and sacrificed 12 h following the induction of pancreatitis. Specimens were collected and processed to measure the amylase and lipase activity levels; the myeloperoxidase activity and production levels; the cytokine mRNA expression levels; the 8-hydroxydeoxyguanosine, malondialdehyde, and glutathione levels; and the cell survival rate. Histological examinations and immunohistochemical analyses were then conducted. The results revealed significant reductions in inflammation and oxidative stress both in vitro and in vivo. Furthermore, the beneficial effects of H2 gas were associated with reductions in AR42J cell and pancreatic tissue damage. In conclusion, our results suggest that H2 gas is capable of ameliorating damage to the pancreas and AR42J cells and that H2 exerts protective effects both in vitro and in vivo on subjects with AP. Thus, the results obtained indicate that this gas may represent a novel therapy agent in the management of AP. PMID- 27115739 TI - New Miocene Fossils and the History of Penguins in Australia. AB - Australia has a fossil record of penguins reaching back to the Eocene, yet today is inhabited by just one breeding species, the little penguin Eudyptula minor. The description of recently collected penguin fossils from the re-dated upper Miocene Port Campbell Limestone of Portland (Victoria), in addition to reanalysis of previously described material, has allowed the Cenozoic history of penguins in Australia to be placed into a global context for the first time. Australian pre Quaternary fossil penguins represent stem taxa phylogenetically disparate from each other and E. minor, implying multiple dispersals and extinctions. Late Eocene penguins from Australia are closest to contemporaneous taxa in Antarctica, New Zealand and South America. Given current material, the Miocene Australian fossil penguin fauna is apparently unique in harbouring 'giant penguins' after they went extinct elsewhere; and including stem taxa until at least 6 Ma, by which time crown penguins dominated elsewhere in the southern hemisphere. Separation of Australia from Antarctica during the Palaeogene, and its subsequent drift north, appears to have been a major event in Australian penguin biogeography. Increasing isolation through the Cenozoic may have limited penguin dispersal to Australia from outside the Australasian region, until intensification of the eastwards-flowing Antarctic Circumpolar Current in the mid Miocene established a potential new dispersal vector to Australia. PMID- 27115740 TI - Decoding the Attentional Demands of Gait through EEG Gamma Band Features. AB - Rehabilitation techniques are evolving focused on improving their performance in terms of duration and level of recovery. Current studies encourage the patient's involvement in their rehabilitation. Brain-Computer Interfaces are capable of decoding the cognitive state of users to provide feedback to an external device. On this paper, cortical information obtained from the scalp is acquired with the goal of studying the cognitive mechanisms related to the users' attention to the gait. Data from 10 healthy users and 3 incomplete Spinal Cord Injury patients are acquired during treadmill walking. During gait, users are asked to perform 4 attentional tasks. Data obtained are treated to reduce movement artifacts. Features from delta(1 - 4Hz), theta(4 - 8Hz), alpha(8 - 12Hz), beta(12 - 30Hz), gammalow(30 - 50Hz), gammahigh(50 - 90Hz) frequency bands are extracted and analyzed to find which ones provide more information related to attention. The selected bands are tested with 5 classifiers to distinguish between tasks. Classification results are also compared with chance levels to evaluate performance. Results show success rates of ~67% for healthy users and ~59% for patients. These values are obtained using features from gamma band suggesting that the attention mechanisms are related to selective attention mechanisms, meaning that, while the attention on gait decreases the level of attention on the environment and external visual information increases. Linear Discriminant Analysis, K-Nearest Neighbors and Support Vector Machine classifiers provide the best results for all users. Results from patients are slightly lower, but significantly different, than those obtained from healthy users supporting the idea that the patients pay more attention to gait during non-attentional tasks due to the inherent difficulties they have during normal gait. This study provides evidence of the existence of classifiable cortical information related to the attention level on the gait. This fact could allow the development of a real-time system that obtains the attention level during lower limb rehabilitation. This information could be used as feedback to adapt the rehabilitation strategy. PMID- 27115741 TI - Sweet supramolecular elastomers from alpha,omega-(beta-cyclodextrin terminated) PDMS. AB - Azido beta-cyclodextrins were attached to propiolate-functionalized polydimethylsiloxanes by metal-free click chemistry. The obtained telechelic copolymers spontaneously produced elastomeric gums. Demixing and supramolecular associations are the driving forces for the construction of these strongly associated (but reversible) physical networks. PMID- 27115742 TI - Behavior of Primary Cilia and Tricellular Tight Junction Proteins during Differentiation in Temperature-Sensitive Mouse Cochlear Precursor Hair Cells. AB - In the sensory hair cells of the mammalian cochlea, the primary cilia in the planar cell polarity as well as the tight junctions in the epithelial cell polarity and the barrier are important to maintain normal hearing. Temperature sensitive mouse cochlear precursor hair cells were used to investigate the behavior of primary cilia and tricellular tight junction proteins during the differentiation of sensory hair cells. In undifferentiated cells (incubated at 33 degrees C), many acetylated tubulin-positive primary cilia were observed, and each was accompanied with an x03B3;-tubulin-positive basal body. The primary cilia had a '9 + 0' architecture with nine outer microtubule doublets but lacking a central pair of microtubules. In differentiated cells (incubated at 39 degrees C), acetylated tubulin-positive primary cilia as well as acetylated tubulin positive cilia-like structures were partially observed on the cell surface. In differentiated cells, the number of primary cilia was markedly reduced compared with undifferentiated cells, and innumerable cilia-like structures with no ciliary pockets were partially observed on the cell surface. In undifferentiated cells, few tricellulin molecules and lipolysis-stimulated lipoprotein receptors (LSRs) were observed in the cytoplasm. In differentiated cells, many tricellulin molecules and LSRs were observed on the membranes and within the cytoplasm. Conditional immortalized mouse cochlear precursor hair cells may be useful to investigate the roles of primary cilia and tricellular tight junctions during cellular differentiation and degeneration such as apoptosis. PMID- 27115743 TI - Use of endocrinological and neurological medication among 5-year survivors of young onset brain tumors. AB - The burden of late-effects for young onset brain tumor (BT) survivors needs more careful evaluation. Our aim was to assess the need for endocrinological and neurological medication among this specific group. We identified 5-year survivors diagnosed at the age of 0-24 years between 1988 and 2004 from the Finnish Cancer Registry (N = 602). Data on endocrinological and neurological drug purchases were collected from the Social Insurance Institution of Finland. Five years after diagnosis the most commonly purchased drugs had been: antiepileptics (44.8 %), systemic hydrocortisone (18.3 %), female sex hormones (17.6 %), thyroid hormones (11.2 %), and growth hormone (10.0 %). The survivors showed an increased hazard ratio (HR) for a need for new types of drugs still 5 years after diagnosis. Thyroid hormones (HR 10.6, 95 % CI 5.1-21.4), estrogens (HR 8.0, 95 % CI 2.1 25.7), and antiepileptics (HR 6.3, 95 % CI 3.4-11.2) were bought with high frequencies. Irradiation increased the hazard for drug-purchases other than antiepileptics. Cumulative incidence of purchases of estrogens or androgens increased still 15 years after diagnosis. The cumulative incidence of purchasing thyroid hormones and antiepileptics showed continuous increase for the youngest group, whereas survivors diagnosed at 15-24 years of age reached stable level before 15 years from diagnosis. The need for new medication continued more than a decade after BT diagnosis. Especially the need for new thyroid or sex hormone medication among childhood BT survivors may emerge long after diagnosis. PMID- 27115744 TI - Fluorescence imaging of in vivo miR-124a-induced neurogenesis of neuronal progenitor cells using neuron-specific reporters. AB - BACKGROUND: Facilitation of the differentiation of the stem cells toward neuronal lineage is crucial for enhancing the differentiation efficacy of grafted stem cells for the possible treatment of neurodegenerative disorders. MicroRNA124a (miR-124a) has been considered as a neuronal lineage regulator, possessing the capability to activate neuronal differentiation. In this study, using a neuronal promoter-based reporter and live-cell fluorescence imaging, we visualized in vitro and in vivo the enhanced neuronal differentiation of neuronal progenitor cells with miR-124a overproduction. METHODS: The neuron specific alpha1 tubulin promoter-driven RFP reporter (pTa1-RFP) was used to trace the miR-124a-induced neuronal differentiation in live cell condition. MiR-124a or miR-scramble in 10 % glucose buffer was mixed with in vivo-jetPEITM and in vivo fluorescence images were obtained daily using Maestro spectral fluorescent imager. RESULTS: Neurite outgrowth was clearly seen in F11 cells after miR-124a transfection, and immunofluorescence staining showed increase of Tuj1 and NF at 48 hours. When pTa1 RFP-transfected F11 cells were implanted simultaneously with miR-124a into the nude mice, gradually increasing reporter signals and morphological changes indicated neuronal differentiation for 48 hours in live cells in vitro. The miR 124a-treated F11 cells showed higher reporter signals on in vivo fluorescence imaging than miR-scramble-treated cells, which were verified by ex vivo confirmation of Tuj1 and NF expression. CONCLUSIONS: These results indicated that neuronal reporter-based neurogenesis imaging can be used for monitoring miR-124a acting as neuronal activator when miRNA was injected in in vivo PEI-coated form for miRNA-mediated regenerative therapy. PMID- 27115745 TI - Microbial population dynamics during sludge granulation in an A/O/A sequencing batch reactor. AB - The evolution of the bacterial population during formation of denitrifying phosphorus removal granular sludge was investigated using high-throughput pyrosequencing. As a result, mature granules with a compact structure were obtained in an anaerobic/aerobic/anoxic (A/O/A) sequencing batch reactor under an organic loading rate as low as 0.3kg COD/(m(3).d). Rod-shaped microbes were observed to cover with the outer surface of granules. Besides, reliable COD and simultaneous nitrogen and phosphorus removal efficiencies were achieved over the whole operation period. MiSeq pyrosequencing analysis illustrated that both the microbial diversity and richness increased sharply during the granulation process, whereas they stayed stable after the presence of granules. Some microorganisms seemed to contribute to the formation of granules, and some were identified as functional bacterial groups responsible for constructing the biological reactor. PMID- 27115746 TI - Organosolv liquefaction of sugarcane bagasse catalyzed by acidic ionic liquids. AB - An efficient and eco-friendly process is proposed for sugarcane bagasse liquefaction under mild condition using IL catalyst and environmental friendly solvent of ethanol/H2O. The relationship between IL acidic strength and its catalytic performance is investigated. The effects of reaction condition parameters such as catalyst dosage, temperature, time and solvent are also intensively studied. The results show that ethanol/H2O has a significant promotion effect on the simultaneous liquefaction of sugarcane bagasse carbohydrate and lignin. 97.5% of the bagasse can be liquefied with 66.46% of volatile product yield at 200 degrees C for 30min. Furthermore, the IL catalyst shows good recyclability where no significant loss of the catalytic activity is exhibited even after five runs. PMID- 27115747 TI - Response of a three dimensional bioelectrochemical denitrification system to the long-term presence of graphene oxide. AB - In this study, a three dimensional bioelectrochemical denitrification system (3D BEDS) was operated under long-term graphene oxide (GO) condition to treat high nitrate polluted water. When GO concentration increased from 0 to 100mgL(-1), nitrate removal efficiency slightly decreased from 99.52% to 94.81%. However, when GO concentration was further increased to 150mgL(-1), the denitrification efficiency dramatically decreased to 74.95%. Increasing GO concentration in this BEDS resulted in decreased community richness, and the abundances of the dominant bacterial communities presented obvious shift. The abundances of denitrifying genes napA, nirS, and nirK showed no obvious changes with GO concentration lower than 50mgL(-1). However, the abundances of the three genes decreased when GO concentration was further increased to higher than 100mgL(-1). The increased lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) production demonstrated that long-term presence of GO caused chronic impacts onto microorganisms in this BEDS. PMID- 27115748 TI - Cellulosic bioethanol production from Jerusalem artichoke (Helianthus tuberosus L.) using hydrogen peroxide-acetic acid (HPAC) pretreatment. AB - Jerusalem artichoke (JA) is recognized as a suitable candidate biomass crop for bioethanol production because it has a rapid growth rate and high biomass productivity. In this study, hydrogen peroxide-acetic acid (HPAC) pretreatment was used to enhance the enzymatic hydrolysis and to effectively remove the lignin of JA. With optimized enzyme doses, synergy was observed from the combination of three different enzymes (RUT-C30, pectinase, and xylanase) which provided a conversion rate was approximately 30% higher than the rate with from treatment with RUT-C30 alone. Fermentation of the JA hydrolyzates by Saccharomyces cerevisiae produced a fermentation yield of approximately 84%. Therefore, Jerusalem artichoke has potential as a bioenergy crop for bioethanol production. PMID- 27115749 TI - Self-Reported Periodontitis and Incident Type 2 Diabetes among Male Workers from a 5-Year Follow-Up to MY Health Up Study. AB - AIMS: The purpose of this study was to examine whether periodontitis is associated with incident type 2 diabetes in a Japanese male worker cohort. METHODS: The study participants were Japanese men, aged 36-55 years, without diabetes. Data were extracted from the MY Health Up study, consisting of self administered questionnaire surveys at baseline and following annual health examinations for an insurance company in Japan. The oral health status of the participants was classified by two self-reported indicators: (1) gingival hemorrhage and (2) tooth loosening. Type 2 diabetes incidence was determined by self-reporting or blood test data. Modified Poisson regression approach was used to estimate the relative risks and the 95% confidence intervals of incident diabetes with periodontitis. Covariates included age, body mass index, family history of diabetes, hypertension, current smoking habits, alcohol use, dyslipidemia, and exercise habits. RESULTS: Of the 2895 candidates identified at baseline in 2004, 2469 men were eligible for follow-up analysis, 133 of whom were diagnosed with diabetes during the 5-year follow-up period. Tooth loosening was associated with incident diabetes [adjusted relative risk = 1.73, 95% confidence interval = 1.14-2.64] after adjusting for other confounding factors. Gingival hemorrhage displayed a similar trend but was not significantly associated with incident diabetes [adjusted relative risk = 1.32, 95% confidence interval = 0.95 1.85]. CONCLUSIONS: Tooth loosening is an independent predictor of incident type 2 diabetes in Japanese men. PMID- 27115750 TI - Mitochondrial DNA supplementation as an enhancer of female reproductive capacity. AB - PURPOSE OF REVIEW: There has been increasing interest in developing assisted reproductive technologies to overcome failure at fertilization and early embryonic arrest. Some of the affected patients harbor too few copies of mitochondrial DNA (mtDNA) in their eggs at the time of fertilization, which results in developmental failure. RECENT FINDINGS: In the last 3-5 years, there has been a drive to overcome mtDNA deficiency through mitochondrial supplementation protocols using autologous populations of mitochondrial DNA so as not to perturb the offspring's genetic identity or mediate a series of side effects because of the mixing of two distinct populations of mitochondrial DNA. It is evident that there is strict regulation of mitochondrial DNA copy number from the primordial germ cell through to the time when tissues are specified during organogenesis. Supplementation of oocytes can give rise to better quality embryos, enhanced blastocyst rates, and ongoing pregnancies. It utilizes a key mitochondrial DNA replication event that takes place shortly after fertilization to stabilize the embryonic genome. SUMMARY: These findings provide a rationale for undertaking mitochondrial supplementation and propose a mechanism to explain why the process can enhance embryo development. They also take the approach a step closer to clinical practice. PMID- 27115752 TI - Improve the Efficiency of Surgery for Femoral Shaft Fractures with A Novel Instrument: A Randomized Controlled Trial. AB - OBJECTIVE: To improve the efficacy of closed reduction and wire guiding during intramedullary nail internal fixation in femoral shaft fractures. METHODS: A novel instrument was designed and manufactured. Sixty-eight patients were enrolled from February 2011 to December 2013. The instrument designed was used during the operation in the experimental group, but not in the control group. RESULTS: All patients exhibited fracture union, excluding 1 patient in the experimental group and 2 in the control group who had non-union; all of whom achieved fracture union with reoperation. There were no statistically significant differences in operative blood loss or duration of hospital stay between the groups (P > 0.05). The operative time, frequency of wire drilling, and number of open reduction cases, were significantly smaller in the experimental group than in the control group (P < 0.05). CONCLUSION: Femoral shaft fractures are difficult to reduce using general methods; the novel instrument showed high clinical value and proved effective and safe in assisting with closed reduction and intramedullary nail fixation for femoral shaft fractures. TRIAL REGISTRATION: ChiCTR ChiCTR-ICR-15007335. PMID- 27115753 TI - Erratum to: Genetic and Environmental Contributions to the Relationships Between Brain Structure and Average Lifetime Cigarette Use. PMID- 27115754 TI - Erratum to: rtfA, a putative RNA-Pol II transcription elongation factor gene, is necessary for normal morphological and chemical development in Aspergillus flavus. PMID- 27115755 TI - Expression and bioactivity of recombinant human serum albumin and dTMP fusion proteins in CHO cells. AB - The 14-amino acid (IEGPTLRQWLAARA) thrombopoietin mimetic peptide (TMP) shares no sequence homology with native thrombopoietin (TPO). When dimerized, it displays a high-binding affinity for the TPO receptor and has equipotent bioactivity with recombinant human TPO (rhTPO) in stimulating proliferation and maturation of megakaryocytes in vitro. However, TMP is limited for clinical usage because of its short half-life in vivo. In this study, fusion proteins that composed of tandem dimer of TMP (dTMP) genetically fused at the C- or N-terminus of human serum albumin (HSA) were separately expressed in Chinese hamster ovary (CHO) cells. In vitro bioactivity assays showed that purified fusion proteins promoted the proliferation of megakaryocytes in a dose-dependent manner and activated signal transducer and activator of transcription (STAT) pathway in TPO receptor dependent manner. Following subcutaneous administration, both HSA-dTMP and dTMP HSA significantly elevated peripheral platelet counts in normal mice in a dose dependent manner. In addition, fusion with HSA successfully prolonged dTMP half life in mice. However, when HSA was fused at the C-terminus of dTMP, the bioactivity of dTMP-HSA was about half of that of HSA-dTMP. In conclusion, these results suggested that HSA/dTMP fusion proteins might be potential drugs for thrombocytopenia and, when HSA was fused at the N-terminus of dTMP, the fusion protein had a higher activity. PMID- 27115756 TI - Burkholderia: an update on taxonomy and biotechnological potential as antibiotic producers. AB - Burkholderia is an incredibly diverse and versatile Gram-negative genus, within which over 80 species have been formally named and multiple other genotypic groups likely represent new species. Phylogenetic analysis based on the 16S rRNA gene sequence and core genome ribosomal multilocus sequence typing analysis indicates the presence of at least three major clades within the genus. Biotechnologically, Burkholderia are well-known for their bioremediation and biopesticidal properties. Within this review, we explore the ability of Burkholderia to synthesise a wide range of antimicrobial compounds ranging from historically characterised antifungals to recently described antibacterial antibiotics with activity against multiresistant clinical pathogens. The production of multiple Burkholderia antibiotics is controlled by quorum sensing and examples of quorum sensing pathways found across the genus are discussed. The capacity for antibiotic biosynthesis and secondary metabolism encoded within Burkholderia genomes is also evaluated. Overall, Burkholderia demonstrate significant biotechnological potential as a source of novel antibiotics and bioactive secondary metabolites. PMID- 27115757 TI - Applying theories of microbial metabolism for induction of targeted enzyme activity in a methanogenic microbial community at a metabolic steady state. AB - Novel enzymes that are stable in diverse conditions are intensively sought because they offer major potential advantages in industrial biotechnology, and microorganisms in extreme environments are key sources of such enzymes. However, most potentially valuable enzymes are currently inaccessible due to the pure culturing problem of microorganisms. Novel metagenomic and metaproteomic techniques that circumvent the need for pure cultures have theoretically provided possibilities to identify all genes and all proteins in microbial communities, but these techniques have not been widely used to directly identify specific enzymes because they generate vast amounts of extraneous data.In a first step towards developing a metaproteomic approach to pinpoint targeted extracellular hydrolytic enzymes of choice in microbial communities, we have generated and analyzed the necessary conditions for such an approach by the use of a methanogenic microbial community maintained on a chemically defined medium. The results show that a metabolic steady state of the microbial community could be reached, at which the expression of the targeted hydrolytic enzymes were suppressed, and that upon enzyme induction a distinct increase in the targeted enzyme expression was obtained. Furthermore, no cross talk in expression was detected between the two focal types of enzyme activities under their respective inductive conditions. Thus, the described approach should be useful to generate ideal samples, collected before and after selective induction, in controlled microbial communities to clearly discriminate between constituently expressed proteins and extracellular hydrolytic enzymes that are specifically induced, thereby reducing the analysis to only those proteins that are distinctively up regulated. PMID- 27115758 TI - Harnessing the potential of ligninolytic enzymes for lignocellulosic biomass pretreatment. AB - Abundant lignocellulosic biomass from various industries provides a great potential feedstock for the production of value-added products such as biofuel, animal feed, and paper pulping. However, low yield of sugar obtained from lignocellulosic hydrolysate is usually due to the presence of lignin that acts as a protective barrier for cellulose and thus restricts the accessibility of the enzyme to work on the cellulosic component. This review focuses on the significance of biological pretreatment specifically using ligninolytic enzymes as an alternative method apart from the conventional physical and chemical pretreatment. Different modes of biological pretreatment are discussed in this paper which is based on (i) fungal pretreatment where fungi mycelia colonise and directly attack the substrate by releasing ligninolytic enzymes and (ii) enzymatic pretreatment using ligninolytic enzymes to counter the drawbacks of fungal pretreatment. This review also discusses the important factors of biological pretreatment using ligninolytic enzymes such as nature of the lignocellulosic biomass, pH, temperature, presence of mediator, oxygen, and surfactant during the biodelignification process. PMID- 27115759 TI - Analysis of Clinicians' Perceptual Cough Evaluation. AB - This study examined the relationships between subjective descriptors and objective airflow measures of cough. We hypothesized that coughs with specific airflow characteristics would share common subjective perceptual descriptions. Thirty clinicians (speech-language pathologists, otolaryngologists, and neurologists) perceptually evaluated ten cough audio samples with specific airflow characteristics determined by peak expiratory flow rate, cough expired volume, cough duration, and number of coughs in the cough epoch. Participants rated coughs by strength, duration, quality, quantity, and overall potential effectiveness for airway protection. Perception of cough strength and effectiveness was determined by the combination of presence of pre-expulsive compression phase, short peak expiratory airflow rate rise time, high peak expiratory flow rates, and high cough volume acceleration. Perception of cough abnormality was defined predominantly by descriptors of breathiness and strain. Breathiness was characteristic for coughs with either absent compression phases and relatively high expiratory airflow rates or coughs with significantly low expired volumes and reduced peak flow rates. In contrast, excessive strain was associated with prolonged compression phases and low expiratory airflow rates or the absence of compression phase with high peak expiratory rates. The study participants reached greatest agreement in distinguishing between single and multiple coughs. Their assessment of cough strength and effectiveness was less consistent. Finally, the least agreement was shown in determining the quality categories. Modifications of cough airflow can influence perceptual cough evaluation outcomes. However, the inconsistency of cough ratings among our participants suggests that a uniform cough rating system is required. PMID- 27115760 TI - Number of Gastrointestinal Symptoms is a Useful Means of Identifying Patients with Cancer for Dysphagia. AB - Dysphagia is a symptom suggestive of severe underlying pathology, although its causes include organic and non-organic disorders. The epidemiology of dysphagia is, however, poorly understood. We evaluated the prevalence of dysphagia in outpatients in Japan, measured the proportion ultimately found to have an organic cause, and recorded the nature of their symptoms and the underlying disorder. Of 5362 consecutive outpatients attending the Digestive Center at our hospital between June 1, 2010 and December 31, 2012, 186 patients (3.5 %) had dysphagia with a frequency score of >=5 out of 6. The most common diagnosis was cancer (34 patients, 18.3 %), followed by gastroesophageal reflux disease (24 patients, 12.9 %). An esophageal motility disorder was diagnosed in 21 patients (11.3 %); the causes in the remaining 107 patients (57.5 %) were miscellaneous. Multivariable analysis identified the following predictors of cancer: age >= 54 years, weight loss, being a drinker of alcohol, and <=2 gastrointestinal symptoms. Our findings can be used to inform the prioritization of referrals from primary care for investigation and treatment for patients with cancer for dysphagia. PMID- 27115761 TI - An improved strategy to detect the epithelial-mesenchymal transition process in circulating tumor cells in hepatocellular carcinoma patients. AB - PURPOSE: We adopted a new strategy to explore the relationship between the EMT process of CTCs and hepatocellular carcinoma (HCC). Furthermore, we intend to illustrate the potential diagnostic value of CTCs of distinct phenotypes in HCC. METHODS: The clinical data of 33 HCC patients and 10 healthy volunteers were collected retrospectively. By using the optimized CanPatrol CTC enrichment technique, patient blood samples of about 5 ml were collected, and CTCs were identified and characterized. The first step of this detection process was to isolate CTCs via a filter-based method; then, an RNA in situ hybridization (RNA ISH) technique based on the branched DNA signal amplification technology was used to classify the CTCs according to EMT markers. The relationships between HCC CTCs and clinical characteristics were analyzed. RESULTS: The number of epithelial CTCs was related to tumor size (r = 0.456, p = 0.008), epithelial-mesenchymal mixed CTCs were related to tumor number (r = 0.421, p = 0.015), and mesenchymal CTC was associated with metastasis (r = 0.375, p = 0.032). There was no significant correlation between CTC number and other clinicopathological factors, such as age, serum AFP level or cirrhosis. CONCLUSIONS: Epithelial-mesenchymal mixed CTCs seem to play an important role in EMT transition in HCC, mixed CTCs might be a vital factor for intrahepatic metastasis, and mesenchymal CTCs had the potential to be a predictor of extrahepatic metastasis. PMID- 27115763 TI - UK Renal Registry 18th Annual Report: Chapter 8 Haemoglobin, Ferritin and Erythropoietin amongst UK Adult Dialysis Patients in 2014: National and Centre specific Analyses. AB - In the UK in 2014: The median haemoglobin (Hb) of patients at the time of starting dialysis was 100 g/L with 50% of patients having a Hb 5100 g/L. The median Hb in patients starting haemodialysis (HD) was 97 g/L (IQR 87-106) and in patients starting peritoneal dialysis (PD) was 108 g/L (IQR 100-117). At start of dialysis, 54% of patients presenting early had Hb 5100 g/L whilst only 33% of patients presenting late had Hb 5100 g/L. The median Hb of prevalent patients on HD was 111 g/L with an IQR of 103-120 g/L. The median Hb of prevalent patients on PD was 112 g/L with an IQR of 103-121 g/L. 81% of HD patients and 83% of PD patients had Hb 5100 g/L. 58% of HD patients and 56% of PD patients had Hb 5100 and 4120 g/L. The median ferritin in HD patients was 432 mg/L (IQR 274-631) and 95% of HD patients had a ferritin 5100 mg/L. The median ferritin in PD patients was 292 mg/L (IQR 168-479) with 88% of PD patients having a ferritin 5100 mg/L. In England, Wales and Northern Ireland in 2014: The median erythropoietin stimulating agent (ESA) dose was higher for HD than PD patients (7,333 vs. 4,148 IU/week). PMID- 27115764 TI - Diagnosis and Treatment of Obstructive Sleep Apnea Syndrome in Children. AB - Sleep is important for children pertaining to their physical and mental growth. Obstructive sleep apnea syndrome (OSAS) in children has been shown to have different effects as compared to OSAS in adults, including deficits in cognition and neuropsychological functions, hyperactivity, ADHD, behavior problems, aggressive behavior, learning problems and nocturnal enuresis. Hypertrophy of the adenoids and tonsils is a major cause of OSAS in children; therefore, adenotonsillectomy may decrease the effects of OSAS pertaining to physical and mental growth. It is important to accurately diagnose and appropriately treat OSAS in children to prevent OSAS in their adulthood. PMID- 27115765 TI - Surface Electromyography Reliably Records Electrophysiologically Evoked Internal Anal Sphincter Activity: A More Minimally Invasive Approach for Monitoring Extrinsic Innervation. AB - BACKGROUND: Even in the case of minimally invasive pelvic surgery, sparing of the autonomic nerve supply is a prerequisite for maintaining anal sphincter function. Internal anal sphincter (IAS) innervation could be electrophysiologically identified based on processed electromyographic (EMG) recordings with conventional bipolar needle electrodes (NE). This experimental study aimed for the development of a minimally invasive approach via intra-anal surface EMG for recordings of evoked IAS activity. METHODS: Six male pigs underwent nerve-sparing low anterior rectal resection. Electric autonomic nerve stimulations were performed under online-processed EMG of the IAS. EMG recordings were simultaneously carried out with conventional bipolar NE as the reference method and newly developed intra-anal surface electrodes (SE) in different designs. RESULTS: In all experiments, the IAS activity could be continuously visualized via EMG recordings based on NE and SE. The median number of bipolar electric stimulations per animal was 27 (range 5-52). The neurostimulations resulted in significant EMG amplitude increases for both recording types [NE: median 3.0 uV (interquartile range, IQR 2.8-3.5) before stimulation vs. 7.1 uV (IQR 3.9-13.8) during stimulation, p < 0.001; SE: median 3.6 uV (IQR 3.1-4.3) before stimulation vs. 6.8 uV (IQR 4.8-10.3) during stimulation, p < 0.001]. CONCLUSIONS: Intra-anal SE enabled reliable EMG of electrophysiologically evoked IAS activity similar to the conventional recording via NE. The transfer of the method to access platforms for transanal total mesorectal excision or robotics may offer a practical more minimally invasive approach for monitoring extrinsic innervation. PMID- 27115766 TI - The surgical anatomy of the lateral femoral cutaneous nerve in the inguinal region: a meta-analysis. AB - PURPOSE: Several variations in the anatomy and injury of the lateral femoral cutaneous nerve (LFCN) have been studied since 1885. The aim of our study was to analyze the available data on the LFCN and find a true prevalence to help in the planning and execution of surgical procedures in the area of the pelvis, namely inguinal hernia repair. METHODS: A search of the major medical databases was performed for LFCN anatomy. The anatomical data were collected and analyzed. RESULTS: Twenty-four studies (n = 1,720) were included. The most common pattern of the LFCN exiting the pelvis was medial to the Sartorius as a single branch. When it exited in this pattern, it did so on average 1.90 cm medial to the anterior superior iliac spine (ASIS). CONCLUSIONS: The LFCN and its variations are important to consider especially during inguinal hernia repair, abdominoplasty, and iliac bone grafting. We suggest maintaining a distance of 3 cm or more from the ASIS when operating to prevent injury to the LFCN. PMID- 27115767 TI - Whole-exome sequencing identifies a potential TTN mutation in a multiplex family with inguinal hernia. AB - PURPOSE: Inguinal hernia repair is one of the most common procedures in general surgery. Males are seven times more likely than females to develop a hernia and have a 27 % lifetime 'risk' of inguinal hernia repair. Several studies have demonstrated that a positive family history is an important risk factor for the development of primary inguinal hernia, which indicates that genetic factors may play important roles in the etiology of the disease. So far, the contribution of genetic factors and underlying mechanisms for inguinal hernia remain largely unknown. The aim of this study was to investigate a multiplex Estonian family with inguinal hernia across four generations. METHODS: The whole-exome sequencing was carried out in three affected family members and subsequent mutation screening using Sanger sequencing was performed in ten family members (six affected and four unaffected). RESULTS: Whole-exome sequencing in three affected family members revealed a heterozygous missense mutation c.88880A>C (p.Lys29627Thr; RefSeq NM_001256850.1) in the highly conserved myosin-binding A band of the TTN gene. Sanger sequencing demonstrated that this mutation cosegregated with the disease in this family and was not present in ethnically matched control subjects. CONCLUSION: We report that missense variant in the A band of TTN is the strongest candidate mutation for autosomal-dominant inguinal hernia with incomplete penetrance. PMID- 27115768 TI - Tissue thyroid hormones and thyronamines. AB - It has been known for a long time that changes in cardiac function are a major component of the clinical presentation of thyroid disease. Increased heart rate and hyperdynamic circulation are hallmarks of hyperthyroidism, while bradycardia and decreased contractility characterize hypothyroidism. Recent findings have provided novel insights in the physiology and pathophysiology of heart regulation by thyroid hormones. In this review, we summarize the present knowledge on thyroxine (T4) transport and metabolism and on the biochemical pathways leading to genomic and non-genomic effects produced by 3,5,3'-triiodothyronine (T3) and by its active metabolites, particularly 3,5-diiodothyronine (T2) and 3 iodothyronamine (T1AM). On this basis, specific issues of special interest for cardiology are discussed, namely (1) relevance of the regulation of proteins involved in the control of calcium homeostasis and in pacemaker cell activity, due to non-genomic as well as to classical genomic effects; (2) stimulation of fatty acid oxidation by T2 and T1AM, the latter also causing a negative inotropic and chronotropic action at micromolar concentrations; (3) induction of D3 deiodinase in heart failure, potentially causing selective cardiac hypothyroidism, whose clinical implications are still controversial; and (4) cardioprotective effect of T1AM, possibly occurring at physiological concentrations, and relevance of T3 and of thyroid hormone receptor alpha1 in post-infarction repair. PMID- 27115769 TI - Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci. AB - To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within +/ 100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3' region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci. PMID- 27115770 TI - The Role of Resilience in the Clinical Management of Chronic Pain. AB - Chronic pain affects more individuals than does cancer, heart disease, and diabetes combined. Yet, our treatment options remain remarkably limited. Often, highly effective psychotherapeutic approaches are limited by many barriers such as access, reimbursement, and acceptability; however, resilience-based positive activity interventions could offer a promising alternative. These interventions are engaging, non-stigmatizing, and do not require a mental health professional for their provision. This article reviews the new, but limited, research exploring the use of positive activity interventions for the treatment of patients with chronic pain. The related psychological and biological mechanisms are addressed, as are suggestions for more systematically evaluating the potential for positive activity interventions to become an adjunct to or stand alone intervention strategy for patients with chronic pain. PMID- 27115771 TI - Gender Differences in Homicide of Neonates, Infants, and Children under 5 y in South Africa: Results from the Cross-Sectional 2009 National Child Homicide Study. AB - BACKGROUND: Homicide of children is a global problem. The under-5-y age group is the second largest homicide age group after 15-19 y olds, but has received little research attention. Understanding age and gender patterns is important for assisting with developing prevention interventions. Here we present an age and gender analysis of homicides among children under 5 y in South Africa from a national study that included a focus on neonaticide and infanticide. METHODS AND FINDINGS: A retrospective national cross-sectional study was conducted using a random sample of 38 medico-legal laboratories operating in 2009 to identify homicides of children under 5 y. Child data were abstracted from the mortuary files and autopsy reports, and both child and perpetrator data data were collected from police interviews. We erred towards applying a conservative definition of homicide and excluded sudden infant death syndrome cases. We estimated that 454 (95% CI 366, 541) children under the age of 5 y were killed in South Africa in 2009. More than half (53.2%; 95% CI 46.7%, 59.5%) were neonates (0-28 d), and 74.4% (95% CI 69.3%, 78.9%) were infants (under 1 y), giving a neonaticide rate of 19.6 per 100,000 live births and an infanticide rate of 28.4 per 100,000 live births. The majority of the neonates died in the early neonatal period (0-6 d), and abandonment accounted for 84.9% (95% CI 81.5%, 87.8%) of all the neonates killed. Distinct age and gender patterns were found, with significantly fewer boy children killed in rural settings compared to urban settings (odds ratio 0.6; 95% CI 0.4, 0.9; p = 0.015). Abuse-related killings and evidence of sexual assault were more common among older girls than in all other age and gender groups. Mothers were identified as the perpetrators in all of the neonaticides and were the most common perpetrators overall (71.0%; 95% CI 63.9%, 77.2%). Abandoned neonates were mainly term babies, with a mean gestational age of 38 wk. We did not have information on abandonment motives for all newborns and did not know if babies were abandoned with the intention that they would die or with the hope that they would be found alive. We therefore considered all abandoned babies as homicides. CONCLUSIONS: Homicide of children is an extreme form or consequence of violence against children. This national study provides one of the first analyses of neonaticide and infanticide by age and gender and shows the failure of reproductive and mental health and social services to identify and help vulnerable mothers. Multi-sectoral prevention strategies are needed. PMID- 27115772 TI - The Comparative Double-Blind Clinical Study in Antihelmintic Efficacy Between Thai Traditional Herbal Formulae and Mebendazole. AB - This study was carried out in Mahasarakham Primary Healthcare Centre, Mahasarakham province in the area of Northeastern of Thailand. The experiment was randomized controlled trial in the clinical study to examine the efficacy of Thai Traditional Herbal Formula (TTHF) in the treatment of antihelmintic activity of mixed worm infections in human. The 2 experimental groups consisted of 10 patients, and 5 patients for control group with inclusion and exclusion criteria, who were screened by the selection of mixed worm infection symptom samples. The investigation and extraction of worm eggs per gram (EPG) of patient feces method were performed with Ether-Formalin Sedimentation test. The percentage of reduction of EPG of patient feces were collected, counted, and confirmed by parasitologist, and the clinical efficacy was investigated by the physician and the pharmacist. The percent EPG data were collected before and after the treatment with TTHF and with mebendazole. The result showed that TTHF had higher efficacy in antihelmintic activity than mebendazole and placebo, which had the percent reduction of EPG of feces as 93.69 in TTHF and percent reduction of EPG of feces as 87.50 in mebendazole. The suggestion of this study should increase the number of samples of worm-infected patients, which the samples can be identified with the specific helminths genus and species to obtain the efficacy by the treatment using TTHF and mebendazole comparatively. PMID- 27115773 TI - Efficient Flame Retardant Thin Films Synthesized by Atmospheric Pressure PECVD through the High Co-deposition Rate of Hexamethyldisiloxane and Triethylphosphate on Polycarbonate and Polyamide-6 Substrates. AB - An innovative approach to produce high-performance and halogen-free flame retardant thin films at atmospheric pressure is reported. PDMS-based coatings with embedded dopant-rich polyphosphates are elaborated thanks to a straightforward approach, using an atmospheric pressure dielectric barrier discharge (AP-DBD). Deposition conditions have been tailored to elaborate various thin films that can match the fire performance requirements. Morphology, chemical composition, and structure are investigated, and results show that the coatings performances are increased by taking advantage of the synergistic effect of P and Si flame retardant compounds. More specifically, this study relates the possibility to obtain flame retardant properties on PolyCarbonate and PolyAmide-6 thanks to their covering by a 5 MUm thick coating, i.e. very thin films for this field of application, yet quite substantial for plasma processes. Hence, this approach enables deposition of flame retardant coatings onto different polymer substrates, providing a versatile fireproofing solution for different natures of polymer substrates. The presence of an expanded charred layer at the surface acts as a protective barrier limiting heat and mass transfer. This latter retains and consumes a part of the PC or PA-6 degradation byproducts and then minimizes the released flammable gases. It may also insulate the substrate from the flame and limit mass transfers of remaining volatile gases. Moreover, reactions in the condensed phase have also been highlighted despite the relatively thin thickness of the deposited layers. As a result of these phenomena, excellent performances are obtained, illustrated by a decrease of the peak of the heat release rate (pHRR) and an increase of the time to ignition (TTI). PMID- 27115774 TI - The local structure factor near an interface; beyond extended capillary-wave models. AB - We investigate the local structure factor S (z;q) at a free liquid-gas interface in systems with short-ranged intermolecular forces and determine the corrections to the leading-order, capillary-wave-like, Goldstone mode divergence of S (z;q) known to occur for parallel (i.e. measured along the interface) wavevectors [Formula: see text]. We show from explicit solution of the inhomogeneous Ornstein Zernike equation that for distances z far from the interface, where the profile decays exponentially, S (z;q) splits unambiguously into bulk and interfacial contributions. On each side of the interface, the interfacial contributions can be characterised by distinct liquid and gas wavevector dependent surface tensions, [Formula: see text] and [Formula: see text], which are determined solely by the bulk two-body and three-body direct correlation functions. At high temperatures, the wavevector dependence simplifies and is determined almost entirely by the appropriate bulk structure factor, leading to positive rigidity coefficients. Our predictions are confirmed by explicit calculation of S (z;q) within square-gradient theory and the Sullivan model. The results for the latter predict a striking temperature dependence for [Formula: see text] and [Formula: see text], and have implications for fluctuation effects. Our results account quantitatively for the findings of a recent very extensive simulation study by Hofling and Dietrich of the total structure factor in the interfacial region, in a system with a cut-off Lennard-Jones potential, in sharp contrast to extended capillary-wave models which failed completely to describe the simulation results. PMID- 27115776 TI - Information Functional Theory: Electronic Properties as Functionals of Information for Atoms and Molecules. AB - How to accurately predict electronic properties of a Columbic system with the electron density obtained from experiments such as X-ray crystallography is still an unresolved problem. The information-theoretic approach recently developed in the framework of density functional reactivity theory is one of the efforts to address the issue. In this work, using 27 atoms and 41 molecules as illustrative examples, we present a study to demonstrate that one is able to satisfactorily describe such electronic properties as the total energy and its components with information-theoretic quantities like Shannon entropy, Fisher information, Ghosh Berkowitz-Parr entropy, and Onicescu information energy. Closely related to the earlier attempt of expanding density functionals using simple homogeneous functionals, this work not only confirms Nagy's proof that Shannon entropy alone should contain all the information needed to adequately describe an electronic system but also provides a feasible pathway to map the relationship between the experimentally available electron density and various electronic properties for Columbic systems such as atoms and molecules. Extensions to other electronic properties are straightforward. PMID- 27115777 TI - [Not Available]. AB - The objective of this study was to overview high-qualitative systematic reviews to synthesize the evidence for associations between sedentary behavior and health outcomes in adults. There is evidence for a cross-sectional association between accelerometer measured sedentary time and poorer insulin sensitivity, and an association between sedentary breaks and BMI/waist circumference and triglycerides. Based on intervention studies (only randomized cross-over), there is evidence for an association between prolonged sitting and some markers for poorer cardiovascular health, but it is unclear whether this may be generalized to adults in general. There is also evidence to support an association between self-reported sedentary behavior (e.g., screen-time and total sitting time) and cardiovascular disease incidence and death, cancer incidence and death, and all cause mortality. The inconsistent use of sedentary measures suggests, however, that caution is required when interpreting the results. PMID- 27115778 TI - [Not Available]. AB - Two studies have examined safety regarding drug treatment of pediatric inpatients (including both children in pediatric clinics and in adult clinics) within the Sahlgrenska University Hospital, Gothenburg. 20% of pediatric inpatients are treated outside of pediatric clinics. The highest risks are seen during prescription followed by administration and preparation of drugs (greatest risk: wrong dose). The staff perceives risks related to drug prescription, the IT system for medication management and the work environment. Improved support systems for drug prescription and administration, coordination of procedures and development of IT systems adapted to the specific needs associated with drug treatment of children as well as improved working environment is needed. PMID- 27115780 TI - [Not Available]. PMID- 27115779 TI - [Not Available]. AB - In 2003 the Council of Europe published a resolution on food and nutritional care in hospitals. The resolution suggests screening of nutritional status for all patients and a care plan should be established for malnourished patients or patients at risk of malnutrition. In 2004 a survey amongst Swedish physicians, nurses and dieticians focusing on education, knowledge in clinical nutrition, division of responsibilities and guidelines was made. The results showed that Swedish hospitals did not meet the standards set by the Council. This study is a ten year follow-up of the original study from 2004. Data from 2014 show only minor improvements. Screening of nutritional status was still performed in less than fifty percent of all hospitalisations. The level of knowledge is still seen as a barrier against optimal treatment of malnutrition. Lack of guidelines was mentioned as another barrier, and a majority of physicians and nurses were not aware of the existing guidelines. PMID- 27115781 TI - [Not Available]. PMID- 27115782 TI - [Not Available]. PMID- 27115783 TI - [Not Available]. PMID- 27115784 TI - [Not Available]. PMID- 27115785 TI - [Not Available]. PMID- 27115786 TI - [Not Available]. PMID- 27115787 TI - [Not Available]. PMID- 27115789 TI - [Not Available]. PMID- 27115788 TI - [Not Available]. PMID- 27115790 TI - Brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive haematologic malignancies and hepatic or renal impairment. AB - AIMS: Brentuximab vedotin, an antibody-drug conjugate (ADC), selectively delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) into CD30 expressing cells. The pharmacokinetics of brentuximab vedotin have been characterized in patients with CD30-positive haematologic malignancies. The primary objective of this phase 1 open label evaluation was to assess the pharmacokinetics of brentuximab vedotin in patients with hepatic or renal impairment. METHODS: Systemic exposures were evaluated following intravenous administration of 1.2 mg kg(-1) brentuximab vedotin in patients with CD30 positive haematologic malignancies and hepatic (n = 7) or renal (n = 10) impairment and compared with those of unimpaired patients (n = 8) who received 1.2 mg kg(-1) brentuximab vedotin in another arm of the study. RESULTS: For any hepatic impairment, the ratios of geometric means (90% confidence interval) for AUC(0,infinity) were 0.67 (0.48, 0.93) for ADC and 2.29 (1.27, 4.12) for MMAE. Mild or moderate renal impairment caused no apparent change in ADC or MMAE exposures. Severe renal impairment (creatinine clearance <30 ml min(-1) ; n = 3) decreased ADC exposures (0.71 [0.54, 0.94]) and increased MMAE exposures (1.90 [0.85, 4.21]). No consistent pattern of specific adverse events was evident, but analysis of the safety data was confounded by the patients' poor baseline conditions. Five patients died due to adverse events considered unrelated to brentuximab vedotin. All had substantial comorbidities and most had poor baseline performance status. CONCLUSIONS: Hepatic impairment and severe renal impairment may cause decreases in brentuximab vedotin ADC exposures and increases in MMAE exposures. PMID- 27115791 TI - Abnormal Origin of one Pulmonary Artery from the Ascending Aorta-Embryologic Considerations. AB - Anomalous origin of one of the pulmonary arteries from the aorta is unusual. The reported morbidity and mortality is mostly due to early onset vascular disease. Early surgical intervention has significantly improved outcomes. The diagnosis of this abnormality is challenging. The nomenclature used is inconsistent. Familiarity with this abnormality and consistent use of definitions and classifications is mandatory. An attempt is made to clarify misleading inconsistencies. An older ontogenetic theory is revisited. PMID- 27115792 TI - Findings of the margin around lesions by magnifying endoscopy with narrow-band imaging in early gastric carcinoma and intestinal metaplasia. AB - OBJECTIVE: Many endoscopists have reported their own classifications of early gastric carcinoma (EGC) using magnifying narrow-band imaging (M-NBI). However, few reports on classifying the margin around lesions by M-NBI have been published. The aim of this study was to advocate the usefulness of the demarcation area classification for the diagnosis of EGC. METHODS: Altogether 197 lesions that could be investigated by M-NBI were included in this study, consisting of 115 EGC and 82 intestinal metaplasias (IM). We hypothesized that the changes in white zone (fusion and erasure signs) and blood vessel (extend and draw sign) were the indications of EGC and we retrospectively investigated this hypothesis. RESULTS: For the investigation of the white zone in the demarcation area, both fusion (P < 0.0001) and erasure signs (P < 0.0001) were observed more often in EGC than in IM, with an accuracy of 80.7%. For the investigation of blood vessel in the demarcation area, both the extend (P < 0.001) and the draw sign (P < 0.0001) were observed more often in EGC than in IM, with an accuracy of 59.9%. CONCLUSION: Estimations of the white zone and blood vessels in the demarcation area are useful for the diagnosis of EGC. PMID- 27115793 TI - Musculoskeletal Injuries in Iraq and Afghanistan: Epidemiology and Outcomes Following a Decade of War. AB - The combined wars in Afghanistan and Iraq represent the longest ongoing conflicts in American military history, with a combined casualty estimate of >59,000 service members. The nature of combat over the last decade has led to precipitous increases in severe orthopaedic injuries, including traumatic amputations and injuries to the spine. Nearly 75% of all injuries sustained in combat now are caused by explosive mechanisms, and fractures comprise 40% of all musculoskeletal injuries. Injuries to the axial skeleton are more frequent among personnel exposed to combat, and spinal trauma is identified in nearly 40% of those killed. Musculoskeletal injuries are expensive and generate some of the highest rates of long-term disability. Noncombat musculoskeletal injuries are endemic within deployed military service members and occur at a greater than threefold rate compared with combat musculoskeletal injuries. Service members with musculoskeletal injuries or behavioral health conditions, such as posttraumatic stress disorder, depression, and psychosis, and those occupying a low socioeconomic status, have an increased risk of inferior outcomes. PMID- 27115794 TI - Subtotal Scapulectomy With Scapulothoracic Fusion and Local Tendon Transfer for Management of Chondrosarcoma. AB - Scapulectomy can dramatically alter glenohumeral function and the ability of patients to conduct activities of daily living. In oncologic cases, treatment of the tumor can compromise local musculature, making successful reconstruction difficult to achieve. Depending on the resection level, local musculature may be inadequate to restore shoulder range of motion and/or glenohumeral stability. Surgeons have attempted to address these issues via soft-tissue repairs, allograft replacement, and prosthetic replacement, with variable success. Outcomes are better when a greater portion of the scapula is preserved, thus saving functional rotator cuff muscle bellies. However, preservation of significant rotator cuff musculature is not routinely possible. To our knowledge, no authors in the English-language orthopaedic literature have reported on local tendon transfers as a technique to augment and reconstruct the rotator cuff in a patient with previous scapulectomy. PMID- 27115795 TI - Selective Role of Vinculin in Contractile Mechanisms of Endothelial Permeability. AB - Increased vascular endothelial cell (EC) permeability is a result of intercellular gap formation that may be induced by contraction-dependent and contraction-independent mechanisms. This study investigated a role of the adaptor protein vinculin in EC permeability induced by contractile (thrombin) and noncontractile (IL-6) agonists. Although thrombin and IL-6 caused a similar permeability increase in human pulmonary ECs and disrupted the association between vinculin and vascular endothelial-cadherin, they induced different patterns of focal adhesion (FA) arrangement. Thrombin, but not IL-6, caused formation of large, vinculin-positive FAs, phosphorylation of FA proteins, FA kinase and Crk-associated substrate, and increased vinculin-talin association. Thrombin-induced formation of talin-positive FA and intercellular gaps were suppressed in ECs with small interfering RNA-induced vinculin knockdown. Vinculin knockdown and inhibitors of Rho kinase and myosin-II motor activity also attenuated thrombin-induced EC permeability. Importantly, ectopic expression of the vinculin mutant lacking the F-actin-binding domain decreased thrombin-induced Rho pathway activation and EC permeability. In contrast, IL-6-induced EC permeability did not involve RhoA- or myosin-dependent mechanisms but engaged Janus kinase/signal transducer and activator of transcription-mediated phosphorylation and internalization of vascular endothelial-cadherin. This process was vinculin independent but Janus kinase/tyrosine kinase Src-dependent. These data suggest that vinculin participates in a contractile-dependent mechanism of permeability by integrating FA with stress fibers, leading to maximal RhoA activation and EC permeability response. Vinculin inhibition does not affect contractile-independent mechanisms of EC barrier failure. This study provides, for the first time, a comparative analysis of two alternative mechanisms of vascular endothelial barrier dysfunction and defines a specific role for vinculin in the contractile type of permeability response. PMID- 27115796 TI - Reforming international drug policy. PMID- 27115797 TI - Yellow fever: a global reckoning. PMID- 27115798 TI - The perfect storm: climate change and its health consequences. PMID- 27115799 TI - A fatter, healthier but more unequal world. PMID- 27115800 TI - Lean economies and innovation in mental health systems. PMID- 27115801 TI - Expression of concern--Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. PMID- 27115803 TI - US election: what are the candidate's health-care pledges? PMID- 27115804 TI - Libya's health crisis looks set to worsen. PMID- 27115805 TI - Stronger rules needed for medical device cybersecurity. PMID- 27115806 TI - Kazuo Ishiguro's uncanny science. PMID- 27115808 TI - My mother's tongue. PMID- 27115809 TI - John Kurtzke. PMID- 27115810 TI - PATHWAY-2: spironolactone for resistant hypertension. PMID- 27115811 TI - A call to reprioritise metrics to evaluate illicit drug policy. PMID- 27115812 TI - PATHWAY-2: spironolactone for resistant hypertension. PMID- 27115813 TI - PATHWAY-2: spironolactone for resistant hypertension. PMID- 27115814 TI - PATHWAY-2: spironolactone for resistant hypertension - Authors' reply. PMID- 27115815 TI - A step forward for data protection and biomedical research. PMID- 27115816 TI - Tobacco control in China: still a long way to go. PMID- 27115818 TI - Department of Error. PMID- 27115817 TI - Health equity for LGBTQ people through education. PMID- 27115819 TI - CNS infection safety signal of RTS,S/AS01 and possible association with rabies vaccine. PMID- 27115820 TI - Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. AB - BACKGROUND: Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. METHODS: We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18.5 kg/m(2) [underweight], 18.5 kg/m(2) to <20 kg/m(2), 20 kg/m(2) to <25 kg/m(2), 25 kg/m(2) to <30 kg/m(2), 30 kg/m(2) to <35 kg/m(2), 35 kg/m(2) to <40 kg/m(2), >=40 kg/m(2) [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. FINDINGS: We used 1698 population-based data sources, with more than 19.2 million adult participants (9.9 million men and 9.3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21.7 kg/m(2) (95% credible interval 21.3-22.1) in 1975 to 24.2 kg/m(2) (24.0-24.4) in 2014 in men, and from 22.1 kg/m(2) (21.7-22.5) in 1975 to 24.4 kg/m(2) (24.2-24.6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21.4 kg/m(2) in central Africa and south Asia to 29.2 kg/m(2) (28.6 29.8) in Polynesia and Micronesia; for women the range was from 21.8 kg/m(2) (21.4-22.3) in south Asia to 32.2 kg/m(2) (31.5-32.8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13.8% (10.5-17.4) to 8.8% (7.4-10.3) in men and from 14.6% (11.6-17.9) to 9.7% (8.3-11.1) in women. South Asia had the highest prevalence of underweight in 2014, 23.4% (17.8-29.2) in men and 24.0% (18.9-29.3) in women. Age-standardised prevalence of obesity increased from 3.2% (2.4-4.1) in 1975 to 10.8% (9.7-12.0) in 2014 in men, and from 6.4% (5.1-7.8) to 14.9% (13.6 16.1) in women. 2.3% (2.0-2.7) of the world's men and 5.0% (4.4-5.6) of women were severely obese (ie, have BMI >=35 kg/m(2)). Globally, prevalence of morbid obesity was 0.64% (0.46-0.86) in men and 1.6% (1.3-1.9) in women. INTERPRETATION: If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia. FUNDING: Wellcome Trust, Grand Challenges Canada. PMID- 27115821 TI - Guillain-Barre syndrome associated with Zika virus infection. PMID- 27115822 TI - Department of Error. PMID- 27115825 TI - Cellular correlates of selfish spermatogonial selection. PMID- 27115826 TI - Asthma-specific health-related quality of life of people in Great Britain: A national survey. AB - BACKGROUND: Although the ultimate goal of asthma treatment is to improve asthma specific Health-Related Quality-Of-Life (HRQOL), in the UK population this is insufficiently studied. National asthma-specific HRQOL data is needed to inform strategies to address this condition. AIMS AND OBJECTIVES: To benchmark asthma specific HRQOL in a national survey of adults with asthma, and explore differences in this measure within subsections of the population. METHODS: We analysed answers to the Marks Asthma Quality-of-Life Questionnaire (AQLQ-M) from a representative sample of 658 adults with asthma. Respondents answered asthma specific questions to assess control, previous hospital admissions, asthma attacks and an indicator of severity. Higher scores indicate poorer HRQOL (maximum = 60). The highest quintile formed a subgroup 'Poor HRQOL'. Data were weighted to correct for any biases caused by differential non-response. Chi square analyses were used to determine differences between good and poor quality of life and regression analyses performed to determine what factors are associated with poor HRQOL. RESULTS: The response rate was 49%. AQLQ-M median (IQR) scores were 5 (2-13) for the total sample (poor HRQOL = 21, good HRQOL = 3). Significant differences between good and poor HRQOL were observed in smoking status, SES, employment status and co-morbidities, but no differences were found between age groups. Those with poorly controlled asthma were significantly more likely to have poor HRQOL, >=1 breathing related hospital admission or >=1 asthma attack. CONCLUSIONS: This article provides benchmarking data on asthma-specific HRQOL. Improved strategies are needed to target interventions towards people experiencing poor HRQOL. PMID- 27115827 TI - Modified step-cut osteotomy for correction of post-traumatic cubitus varus deformity: a report of 19 cases. AB - We reviewed the outcomes of post-traumatic varus deformity treated with modified step-cut osteotomy in 19 patients (average age, 7.4 years; range, 4.3-16.8 years at time of surgery). The average follow-up period was 29.6 months. The mean range of motion was 15.0 degrees /124.7 degrees (extension/flexion) before surgery and 6.8 degrees /132.6 degrees at final follow-up. The humerus-elbow-wrist angle was -21.1 degrees before surgery and 4.2 degrees at final follow-up, with a loss of 4.4 degrees from the value of the humerus-elbow-wrist angle after the surgery. Osteotomy was fixed with Kirschner wires, and, in five cases, chips of excised bone could be inserted to avoid elbow extension. However, in eight cases, usually concerning younger patients, the elbow was fixed in hyperextension higher than 5 degrees . No patient developed postoperative infections or later complications. Only one patient had transient nerve palsy. The modified step-cut osteotomy can precisely and stably correct the varus deformity in the coronal plane, especially in patients under 10 years of age. To avoid radial nerve palsy, we recommend that the retractors be removed sometimes during the operation. PMID- 27115828 TI - Alcohol abuse recovery through the lens of Manitoban First Nations and Aboriginal women: A qualitative study. AB - We describe a phenomenological study that explored the experiences of First Nations and Aboriginal women during their journey of recovery from alcohol abuse. Seven women participated in individual, tape-recorded interviews, during which they described their experiences, yielding written protocols that were thematically analyzed. Results from this study revealed seven predominant themes that included the following: (a) guilt and shame, (b) unresolved core issues, (c) resilience, (d) tenacity, (e) recovery process, (f) family and friends, and (g) tradition and spirituality. Findings and implications for clinicians, administrators, educators, and future research are included. PMID- 27115830 TI - Polymers as Reference Partitioning Phase: Polymer Calibration for an Analytically Operational Approach To Quantify Multimedia Phase Partitioning. AB - Polymers are increasingly applied for the enrichment of hydrophobic organic chemicals (HOCs) from various types of samples and media in many analytical partitioning-based measuring techniques. We propose using polymers as a reference partitioning phase and introduce polymer-polymer partitioning as the basis for a deeper insight into partitioning differences of HOCs between polymers, calibrating analytical methods, and consistency checking of existing and calculation of new partition coefficients. Polymer-polymer partition coefficients were determined for polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and organochlorine pesticides (OCPs) by equilibrating 13 silicones, including polydimethylsiloxane (PDMS) and low-density polyethylene (LDPE) in methanol-water solutions. Methanol as cosolvent ensured that all polymers reached equilibrium while its effect on the polymers' properties did not significantly affect silicone-silicone partition coefficients. However, we noticed minor cosolvent effects on determined polymer-polymer partition coefficients. Polymer-polymer partition coefficients near unity confirmed identical absorption capacities of several PDMS materials, whereas larger deviations from unity were indicated within the group of silicones and between silicones and LDPE. Uncertainty in polymer volume due to imprecise coating thickness or the presence of fillers was identified as the source of error for partition coefficients. New polymer-based (LDPE-lipid, PDMS-air) and multimedia partition coefficients (lipid-water, air-water) were calculated by applying the new concept of a polymer as reference partitioning phase and by using polymer polymer partition coefficients as conversion factors. The present study encourages the use of polymer-polymer partition coefficients, recognizing that polymers can serve as a linking third phase for a quantitative understanding of equilibrium partitioning of HOCs between any two phases. PMID- 27115831 TI - In Situ Proteome Profiling and Bioimaging Applications of Small-Molecule Affinity Based Probes Derived From DOT1L Inhibitors. AB - DOT1L is the sole protein methyltransferase that methylates histone H3 on lysine 79 (H3K79), and is a promising drug target against cancers. Small-molecule inhibitors of DOT1L such as FED1 are potential anti-cancer agents and useful tools to investigate the biological roles of DOT1L in human diseases. FED1 showed excellent in vitro inhibitory activity against DOT1L, but its cellular effect was relatively poor. In this study, we designed and synthesized photo-reactive and "clickable" affinity-based probes (AfBPs), P1 and P2, which were cell-permeable and structural mimics of FED1. The binding and inhibitory effects of these two probes against DOT1L protein were extensively investigated in vitro and in live mammalian cells (in situ). The cellular uptake and sub-cellular localization properties of the probes were subsequently studied in live-cell imaging experiments, and our results revealed that, whereas both P1 and P2 readily entered mammalian cells, most of them were not able to reach the cell nucleus where functional DOT1L resides. This offers a plausible explanation for the poor cellular activity of FED1. Finally with P1/P2, large-scale cell-based proteome profiling, followed by quantitative LC-MS/MS, was carried out to identify potential cellular off-targets of FED1. Amongst the more than 100 candidate off targets identified, NOP2 (a putative ribosomal RNA methyltransferase) was further confirmed to be likely a genuine off-target of FED1 by preliminary validation experiments including pull-down/Western blotting (PD/WB) and cellular thermal shift assay (CETSA). PMID- 27115832 TI - Phase behaviour and correlations of parallel hard squares: from highly confined to bulk systems. AB - We study a fluid of two-dimensional parallel hard squares in bulk and under confinement in channels, with the aim of evaluating the performance of fundamental-measure theory (FMT). To this purpose, we first analyse the phase behaviour of the bulk system using FMT and Percus-Yevick (PY) theory, and compare the results with molecular dynamics and Monte Carlo simulations. In a second step, we study the confined system and check the results against those obtained from the transfer matrix method and from our own Monte Carlo simulations. Squares are confined to channels with parallel walls at angles of 0 degrees or 45 degrees relative to the diagonals of the parallel hard squares, respectively, which allows for an assessment of the effect of the external-potential symmetry on the fluid structural properties. In general FMT overestimates bulk correlations, predicting the existence of a columnar phase (absent in simulations) prior to crystallization. The equation of state predicted by FMT compares well with simulations, although the PY approach with the virial route is better in some range of packing fractions. The FMT is highly accurate for the structure and correlations of the confined fluid due to the dimensional crossover property fulfilled by the theory. Both density profiles and equations of state of the confined system are accurately predicted by the theory. The highly non uniform pair correlations inside the channel are also very well described by FMT. PMID- 27115833 TI - Using assistive robots to promote inclusive education. AB - PURPOSE: This paper describes the development and test of physical and virtual integrated augmentative manipulation and communication assistive technologies (IAMCATs) that enable children with motor and speech impairments to manipulate educational items by controlling a robot with a gripper, while communicating through a speech generating device. METHOD: Nine children with disabilities, nine regular and nine special education teachers participated in the study. Teachers adapted academic activities so they could also be performed by the children with disabilities using the IAMCAT. An inductive content analysis of the teachers' interviews before and after the intervention was performed. RESULTS: Teachers considered the IAMCAT to be a useful resource that can be integrated into the regular class dynamics respecting their curricular planning. It had a positive impact on children with disabilities and on the educational community. However, teachers pointed out the difficulties in managing the class, even with another adult present, due to the extra time required by children with disabilities to complete the activities. CONCLUSIONS: The developed assistive technologies enable children with disabilities to participate in academic activities but full inclusion would require another adult in class and strategies to deal with the additional time required by children to complete the activities. Implications for Rehabilitation Integrated augmentative manipulation and communication assistive technologies are useful resources to promote the participation of children with motor and speech impairments in classroom activities. Virtual tools, running on a computer screen, may be easier to use but further research is needed in order to evaluate its effectiveness when compared to physical tools. Full participation of children with motor and speech impairments in academic activities using these technologies requires another adult in class and adequate strategies to manage the extra time the child with disabilities may require to complete the activities. PMID- 27115834 TI - UV Light Induced Direct Synthesis of Phenanthrene Derivatives from a Linear 3 Aryl-N-(arylsulfonyl) Propiolamides. AB - A novel photochemical approach for the synthesis of phenanthrene derivatives from linear 3-aryl-N-(arylsulfonyl) propiolamides via a tandem radical Smiles rearrangement/C-S bonding/Mallory reaction is disclosed. The control experiment results and isolation of the key intermediates give further insight into the reaction mechanism. Gram scale reaction using a flow reactor demonstrated the synthetic potential applications of our protocol. PMID- 27115836 TI - The value of FDG-PET in the staging of gastric adenocarcinoma: A single institution retrospective review. AB - BACKGROUND: The value of FDG-PET in the staging of gastric adenocarcinoma (GA) has been subject to debate. METHODS: We performed a retrospective review of GA patients between 2006 and 2014 and identified those who had a CT and FDG-PET before initiating treatment. CT and FDG-PET images were analyzed by a blinded body radiologist and nuclear physician, respectively. Disease stage was assessed, looking at primary tumor (PT), locoregional (LLN) and distant lymph node disease (DLN), and metastasis (M). RESULTS: We identified 608 patients who had biopsy proven GA and 207 (34.0%) had a CT and FDG-PET as part of their staging work-up. Of these, imaging from 166 (27.3%) patients was available for review. CT identified PT, LLN, DLN, and M in 120 (72.3%), 84 (50.6%), 25 (15.1%), and 32 (19.3%) patients, respectively; while FDG-PET identified PT, LLN, DLN, and M in 125 (75.3%), 78 (47.0%), 41 (24.7%), and 27 (16.3%) of patients, respectively. FDG-PET up-staged 31 (18.7%) patients while it down-staged 17 (10.2%) patients. Of patients who were up-staged, 20 (64.5%) developed progressive disease. CONCLUSIONS: Our findings support the use of FDG-PET as a valuable adjunct to CT in the staging of GA, as it changed the stage in 48 (28.9%) patients. J. Surg. Oncol. 2016;113:640-646. (c) 2016 Wiley Periodicals, Inc. PMID- 27115835 TI - Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase. AB - Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC50 for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC associated neuromast migration in zebrafish embryos without inducing life threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice. PMID- 27115837 TI - Comment on stereotactic body radiation therapy for small primary or recurrent hepatocellular carcinoma. PMID- 27115838 TI - Fluid shear stress promotes osteoblast proliferation via the Galphaq-ERK5 signaling pathway. AB - Fluid shear stress (FSS) is a ubiquitous mechanical stimulus that potently promotes osteoblast proliferation. Previously, we reported that extracellular signal-regulated kinase 5 (ERK5) is essential for FSS-induced osteoblast proliferation. However, the precise mechanism by which FSS promotes osteoblast proliferation via ERK5 activation is poorly understood. The aim of this study was to determine the critical role of Galphaq in FSS-induced ERK5 phosphorylation and osteoblast proliferation, as well as the downstream targets of the Galphaq-ERK5 pathway. MC3T3-E1 cells were transfected with 50 nM Galphaq siRNA, treated with 5 mM XMD8-92 (a highly selective inhibitor of ERK5 activity), and/or exposed to FSS (12 dyn/cm(2)). Cell proliferation was evaluated using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression levels of Galphaq, P-ERK5, ERK5, Cyclin B1, and CDK1 were analyzed by Western blot. Physiological FSS exposure for 60 min remarkably promoted MC3T3-E1 cell proliferation, however, this effect was suppressed by siRNA-mediated Galphaq knockdown or inhibition of ERK5 activity by XMD8-92 treatment, suggesting that Galphaq and ERK5 might modulate FSS-increased osteoblast proliferation. Furthermore, ERK5 phosphorylation was dramatically inhibited by Galphaq siRNA. In addition, our study further revealed that FSS treatment of MC3T3-E1 cells for 60 min markedly upregulated the protein expression levels of Cyclin B1 and CDK1, and this increased expression was predominantly blocked by Galphaq siRNA or XMD8-92 treatment. We propose that FSS acts on the Galphaq-ERK5 signaling pathway to upregulate Cyclin B1 and CDK1 expression, thereby resulting in MC3T3-E1 cell proliferation. Thus, the Galphaq-ERK5 signaling pathway may provide useful information regarding the treatment of bone metabolic disease. PMID- 27115839 TI - Application of Peptide Nucleic Acid-based Assays Toward Detection of Somatic Mosaicism. AB - Peptide nucleic acids (PNAs) are synthetic oligonucleotides with many applications. Compared with DNA, PNAs bind their complementary DNA strand with higher specificity and strength, an attribute that can make it an effective polymerase chain reaction clamp. A growing body of work has demonstrated the utility of PNAs in detecting low levels of mutant DNA, particularly in the detection of circulating mutated tumor cells in the peripheral blood. The PNA based assay has greater sensitivity than direct sequencing and is significantly more affordable and rapid than next-generation deep sequencing. We have previously demonstrated that PNAs can successfully detect somatic mosaicism in patients with suspected disease phenotypes. In this report, we detail our methodology behind PNA design and application. We describe our protocol for optimizing the PNA for sequencing use and for determining the sensitivity of the PNA-based assay. Lastly, we discuss the potential applications of our assay for future laboratory and clinical purposes and highlight the role of PNAs in the detection of somatic mosaicism. PMID- 27115840 TI - In Vivo Selection Against Human Colorectal Cancer Xenografts Identifies an Aptamer That Targets RNA Helicase Protein DHX9. AB - The ability to selectively target disease-related tissues with molecules is critical to the design of effective therapeutic and diagnostic reagents. Recognizing the differences between the in vivo environment and in vitro conditions, we employed an in vivo selection strategy to identify RNA aptamers (targeting motifs) that could localize to tumor in situ. One of the selected molecules is an aptamer that binds to the protein DHX9, an RNA helicase that is known to be upregulated in colorectal cancer. Upon systemic administration, the aptamer preferentially localized to the nucleus of cancer cells in vivo and thus has the potential to be used for targeted delivery. PMID- 27115841 TI - Effects of Confinement on the Dielectric Response of Water Extends up to Mesoscale Dimensions. AB - The extent of confinement effects on water is not clear in the literature. While some properties are affected only within a few nanometers from the wall surface, others are affected over long length scales, but the range is not clear. In this work, we have examined the dielectric response of confined water under the influence of external electric fields along with the dipolar fluctuations at equilibrium. The confinement induces a strong anisotropic effect which is evident up to 100 nm channel width, and may extend to macroscopic dimensions. The root mean-square fluctuations of the total orientational dipole moment in the direction perpendicular to the surfaces is 1 order of magnitude smaller than the value attained in the parallel direction and is independent of the channel width. Consequently, the isotropic condition is unlikely to be recovered until the channel width reaches macroscopic dimensions. Consistent with dipole moment fluctuations, the effect of confinement on the dielectric response also persists up to channel widths considerably beyond 100 nm. When an electric field is applied in the perpendicular direction, the orientational relaxation is 3 orders of magnitude faster than the dipolar relaxation in the parallel direction and independent of temperature. PMID- 27115842 TI - Extending the market exclusivity of therapeutic antibodies through dosage patents. AB - Dosage patents are one way to extend the market exclusivity of an approved drug beyond the lifetime of the patent that protects the drug as such. Dosage patents may help to compensate the applicant for the long period where the active pharmaceutical ingredient as such is already under patent prosecution, but not on the market yet, due to lengthy development and approval procedures. This situation erodes part of the time the drug is marketed under patent protection. Dosage patents filed at a later date can provide remedy for this problem. Examples of successful and unsuccesful attempts, and the reasons for the respective outcomes, are provided in this article. PMID- 27115843 TI - Long-term drug survival of biological agents in patients with rheumatoid arthritis in clinical practice. AB - OBJECTIVES: To assess and compare the long-term drug survival (time to drug discontinuation) of biological agents (BA) in patients with rheumatoid arthritis (RA) in clinical practice. Factors associated with discontinuation of BAs were also investigated. METHOD: We conducted an observational longitudinal study of RA patients taking BAs from 1999 to 2013. The primary endpoint was BA discontinuation due to: adverse drug reactions (ADRs), inefficacy, and other causes. Incidence rates of discontinuation (IRs) per 100 patient-years were estimated using survival techniques. Comparisons between BA discontinuation rates and other associated factors were made using Cox regression models. RESULTS: We included 851 courses of BA therapy (1869 patient-years). Adalimumab (33%) was the BA most frequently used, followed by etanercept (24.4%), infliximab, and rituximab. Treatment was suspended in 558 cases [IR 29.8, 95% confidence interval (CI) 27-32]. In the first year of therapy 68% continued on BAs, and after 10 years the retention rate did not exceed 10%. The IR due to inefficacy was 12.1 (95% CI 10.6-13.8) and the IR of ADRs was 13.6 (95% CI 12-15). The unadjusted IR was higher for rituximab than for tumour necrosis factor (TNF) antagonists. In multivariate analysis, infliximab was the BA with the highest risk of discontinuation, compared to adalimumab. Calendar period, taking subsequent courses of BAs, concomitant therapy, and specific comorbidities were also independent factors associated with discontinuation. CONCLUSIONS: After several years of BA treatment in clinical practice, the survival rate was low, mainly as a result of ADRs and inefficacy. We also found differences between the discontinuation rates of BAs and other clinical factors that modify their survival. PMID- 27115844 TI - Sex-specific responses of Populus deltoides to Glomus intraradices colonization and Cd pollution. AB - The positive effects of arbuscular mycorrhizal fungi (AM) on the survival, growth and physiology of plants under various stress conditions have been widely recognized. However, whether sex-dependent susceptibility to AM colonization exists, which can induce a differential tolerance between the sexes to stress conditions, is still unclear. In this study, we investigated the effects of Glomus intraradices on Cd-stressed males and females of Populus deltoides (spiked with 10 mg Cd per kg dry substrate) in terms of morphology, physiology, biochemistry, ultrastructure, and toxin storage and translocation. Exposure to Cd promoted the colonization by G. intraradices in males, but not in females. Generally, females suffered more impairments than males in response to Cd stress, reflected by leaf symptoms, the extent of lipid peroxidation, and integrity of the cellular ultrastructure, whether they were inoculated or not. Inoculation with G. intraradices alleviated the phytotoxic effects of Cd in females by stimulating antioxidant enzymes, decreasing levels of reactive oxygen species (ROS) and restricting Cd transfer to the shoots. In contrast, these beneficial effects induced by AM were not detected in mycorrhizal males compared to non mycorrhizal males, based on thiobarbituric acid-reactive substances (TBARS) and cellular ultrastructure. Inoculation with AM promoted Cd accumulation in males but not in females, and caused the sequestration of more toxic Cd in the root systems in both sexes. Therefore, our results suggest that inoculated males of P. deltoides are suitable candidates for phytostabilization in Cd-polluted soils, due to their higher accumulation ability and greater tolerance relative to inoculated females. PMID- 27115845 TI - Combined effects of short-term exposure to elevated CO2 and decreased O2 on the physiology and energy budget of the thick shell mussel Mytilus coruscus. AB - Hypoxia and ocean acidification are two consequences of anthropogenic activities. These global trends occur on top of natural variability. In environments such as estuarine areas, short-term acute pH and O2 fluctuations are occurring simultaneously. The present study tested the combined effects of short-term seawater acidification and hypoxia on the physiology and energy budget of the thick shell mussel Mytilus coruscus. Mussels were exposed for 72 h to six combined treatments with three pH levels (8.1, 7.7 and 7.3) and two dissolved oxygen (DO) levels (2 mg L(-1), 6 mg L(-1)). Clearance rate (CR), food absorption efficiency (AE), respiration rate (RR), ammonium excretion rate (ER), O:N ratio and scope for growth (SFG) were significantly reduced, and faecal organic dry weight ratio (E) was significantly increased at low DO. Low pH did not lead to a reduced SFG. Interactive effects of pH and DO were observed for CR, E and RR. Principal component analysis (PCA) revealed positive relationships among most physiological indicators, especially between SFG and CR under normal DO conditions. These results demonstrate that Mytilus coruscus was sensitive to short-term (72 h) exposure to decreased O2 especially if combined with decreased pH levels. In conclusion, the short-term oxygen and pH variation significantly induced physiological changes of mussels with some interactive effects. PMID- 27115846 TI - Oxidation of AOX and organic compounds in pharmaceutical wastewater in RSM optimized-Fenton system. AB - Adsorbable organic halogens (AOX) and total organic carbon (TOC) removal efficiencies in pharmaceutical wastewater treated by Fenton process under response surface methodology (RSM) optimized conditions were studied. High regression coefficient value R(2) (R(2) = 0.9680, 0.9040 for AOX and TOC removal efficiency, respectively) and low value coefficient of variation (2.21%, 2.04% for AOX and TOC, respectively) of the quadratic model indicated that the model was accurate in predicting the experimental results. The desirability function was used to optimize AOX and TOC removal efficiencies simultaneously. The optimal pH, Fe(2+) concentration, molar ratio of H2O2/Fe(2+) and reaction time were found to be 3.3, 19.05 mM, 20.16 and 2.2 h, respectively, and 91.78% AOX and 75.01% TOC were removed under these conditions, which was validated. Furthermore, gas chromatography-mass spectrometer (GC-MS) results revealed that 28 out of 33 kinds of organic compounds, including 11 kinds of AOX were completely removed by the Fenton process while one new AOX compound, 4,5,6,7-tetrachlorophthalide, was produced which was the result of the carbonyl of 4,5,6,7-tetrachloro-1,3 isobenzofurandione being attacked in the Fenton reaction. These results indicated that analysis of organics was important since new AOX compounds could be produced in Fenton process despite the value of AOX decreasing. PMID- 27115847 TI - Roxarsone binding to soil-derived dissolved organic matter: Insights from multi spectroscopic techniques. AB - The fate and transport of roxarsone (ROX), a widely used organoarsenic feed additive, in soil is significantly influenced by the ubiquitous presence of soil derived dissolved organic matter (DOM). In this study, fluorescence quenching titration and two-dimensional correlation spectroscopy (2D-COS) were employed to study ROX binding to DOM. Binding mechanisms were revealed by fluorescence lifetime measurement and Fourier transform infrared spectroscopy (FTIR). Humic- and protein-like fluorophores were identified in the excitation-emission matrix and synchronous fluorescence spectra of DOM. The conditional stability constant (log KC) for ROX binding to DOM was found to be 5.06, indicating that ROX was strongly bound to DOM. The binding order of ROX to DOM fluorophores revealed by 2D-COS followed the sequence of protein-like fluorophore ~ the longer wavelength excited humic-like (L-humic-like) fluorophore > the shorter wavelength excited humic-like (S-humic-like) fluorophore. 2D-COS resolved issues with peak overlapping and allowed further exploration of the interaction between ROX and DOM. Results of fluorescence lifetime and FTIR spectra demonstrated that ROX interacted with DOM through the hydroxyl, amide II, carboxyl, aliphatic CH, and NO2 groups, yielding stable DOM-ROX complexes. The strong interaction between ROX and DOM implies that DOM plays an important role in the environmental fate of ROX in soil. PMID- 27115848 TI - Evaluation of impact factors on PM2.5 based on long-term chemical components analyses in the megacity Beijing, China. AB - Nine years of sampling and analyses of fine particles (PM2.5) were performed in Beijing from 2005 to 2013. Twenty-seven chemical elements and black carbon (BC) in PM2.5 were analyzed in order to study chemical characteristics and temporal distribution of Beijing aerosols. Principle component analysis defined different types of elemental sources, based on which, the influences of a variety of anthropogenic activities including governmental intervention measures and natural sources on air quality were evaluated. For the first time, Ga is used as a tracer element for heating activities mainly using coal in Beijing, due to its correlation with BC and coal combustion, as well as its concentration variation between the heating- and non-heating periods. The traffic restrictions effectively reduced emissions of relevant heavy metals such as As, Cd, Sn and Sb. The expected long-term effectiveness of the steel smelters relocation was not observed due to the nearby relocation with increased capacity. Firework display during every Chinese spring festival season and special events such as the Olympic Games resulted in several times higher concentrations of K, Sr and Ba than other days and thus they were proposed as tracers for firework display. The impacts of all these factors were quantified and evaluated. Sand dust or dust storms induced higher concentrations of geogenic elements in PM2.5 compared to non-dust days. Sustainable mitigation measures, such as traffic restrictions, are necessary to be continued and improved to obtain more "blue sky" days in the future. PMID- 27115849 TI - Hypoglycemic Constituents Isolated from Trapa natans L. Pericarps. AB - Trapa natans L., called water chestnut or water caltrop, is a floating aquarium plant. Its fruits are widely used as food. Two new tannins, 1 and 2, one new neolignan, 14, one new norlignan, 17, and 20 known compounds, 3-13, 15, 16, and 18-24 were isolated from T. natans pericarps in this study. The 1, 2, 14, and 17 structures were elucidated using a chemical method and extensive spectral evidence. A series of hydrolyzable tannins, 1-8, a lignin, 13, a flavonoid, 16, a norlignan, 17, and phenolic compounds, 18, 20, 21, and 24 resulted in the enhanced glucose uptake activity in C2C12 myotubes. Compounds 4 and 5 significantly increased GLUT4 protein expression in C2C12 myotubes. In addition, 4 and 5 improved the phosphorylation of AMPK, AKT(S473), and AKT(T308). The involvement of AMPK and PI3K in the mechanism of action of compounds 4 and 5 was confirmed by use of AMPK and PI3K inhibitors, which completely suppressed the 4- and 5-mediated activities of glucose uptake in C2C12 myotubes. We also demonstrated that 4 and 5 could increase GLUT4 protein levels in plasma membranes. PMID- 27115850 TI - Dual Unnatural Amino Acid Incorporation and Click-Chemistry Labeling to Enable Single-Molecule FRET Studies of p97 Folding. AB - Many cellular functions are critically dependent on the folding of complex multimeric proteins, such as p97, a hexameric multidomain AAA+ chaperone. Given the complex architecture of p97, single-molecule (sm) FRET would be a powerful tool for studying folding while avoiding ensemble averaging. However, dual site specific labeling of such a large protein for smFRET is a significant challenge. Here, we address this issue by using bioorthogonal azide-alkyne chemistry to attach an smFRET dye pair to site-specifically incorporated unnatural amino acids, allowing us to generate p97 variants reporting on inter- or intradomain structural features. An initial proof-of-principle set of smFRET results demonstrated the strengths of this labeling method. Our results highlight this as a powerful tool for structural studies of p97 and other large protein machines. PMID- 27115851 TI - BRILLIANT BLUE G-ASSISTED INTERNAL LIMITING MEMBRANE PEELING FOR MACULAR HOLE: A Systematic Review of Literature and Meta-Analysis. AB - PURPOSE: To evaluate the effect of internal limiting membrane peeling with brilliant blue G (BBG) for the treatment of macular hole compared with peeling procedures with other dyes or without dye. METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically reviewed. Outcome measures were the primary closure rate and postoperative best-corrected visual acuity. RESULTS: Nine studies that included 846 eyes were selected. There was no significant difference in preoperative best-corrected visual acuity between the BBG and no BBG (i.e., other dyes or no dye) groups (mean difference 0.02 logMAR [equivalent to 1 Early Treatment Diabetic Retinopathy Study (ETDRS) letter]; 95% confidence interval -0.09 to 0.04 [-2-4.5 ETDRS letters]; P = 0.45). The macular hole closure rate using BBG was not significantly different from that using indocyanine green (odds ratio 1.98; 95% confidence interval 0.71-5.48; P = 0.19). The postoperative best-corrected visual acuity was more favorable with BBG than with indocyanine green (mean difference -0.10 logMAR [5 ETDRS letters]; 95% confidence interval -0.16 to -0.03 [1.5-8 ETDRS letters]; P = 0.004) or with no BBG (mean difference -0.11 [5.5 ETDRS letters]; 95% confidence interval -0.18 to 0.04 [2-9 ETDRS letters]; P = 0.003). CONCLUSION: BBG could contribute to better visual acuity outcome than other dyes for internal limiting membrane peeling in patients with macular hole; however, it does not significantly influence the closure rate. PMID- 27115852 TI - PIGMENT EPITHELIAL DETACHMENT RESPONSE TO AFLIBERCEPT IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION REFRACTORY TO RANIBIZUMAB: Time Course and Drug Effects. AB - PURPOSE: To investigate the time course of pigment epithelium detachment (PED) height and its change after anti-vascular endothelial growth factor switch from ranibizumab to aflibercept in neovascular age-related macular degeneration. METHODS: This retrospective study included 60 eyes of 50 consecutive patients with neovascular age-related macular degeneration who showed refractory intraretinal or subretinal fluid (>=9 months) despite monthly ranibizumab treatment and an associated PED (height >=150 MUm). The treatment was switched to aflibercept, and patients were followed-up for at least 9 months. Data on the height and type of PED, exudative fluid, and best-corrected visual acuity were collected at four different time points (two before and two after the drug switch). RESULTS: The maximal PED height was significantly decreased over time, both under ranibizumab and aflibercept treatment. However, the reduction was significantly greater during the 3 months after the switch to aflibercept, due to two outliers. Visual acuity remained stable. Complete resolution of intraretinal or subretinal fluid was observed in 9 cases (15%) at 3 months after switch, allowing for treatment interval extension. CONCLUSION: Maximal PED height continuously decreased over time. Switching the intravitreal anti-vascular endothelial growth factor medication from ranibizumab to aflibercept had a significantly stronger short-term effect on PED height reduction, without changes in visual acuity. PMID- 27115853 TI - ONE-YEAR RESULTS OF ADJUNCTIVE PHOTODYNAMIC THERAPY FOR TYPE 1 NEOVASCULARIZATION ASSOCIATED WITH THICKENED CHOROID. AB - PURPOSE: To evaluate the 1-year results of adjunctive photodynamic therapy in patients with Type 1 neovascularization associated with thickened choroid who were refractory to anti-vascular endothelial growth factor monotherapy. METHODS: Data on 28 eyes of 28 patients with Type 1 neovascularization with a minimum subfoveal choroidal thickness of 300 MUm were reviewed. All showed persistent subretinal and/or intraretinal fluid after at least 4 anti-vascular endothelial growth factor injections in the 6 months before adjunctive photodynamic therapy. No eyes had certain polypoidal lesions on indocyanine green angiography. RESULTS: At 3 months, complete fluid absorption was observed in 24 eyes (85.7%). The mean best-corrected visual acuity significantly improved (20/53-20/44, P = 0.040) and mean subfoveal choroidal thickness reduced (386 to 350 MUm, P < 0.001) compared with baseline. Over a 1-year follow-up period, 17 eyes (60.7%) were free from recurrent fluid accumulation. Anti-vascular endothelial growth factor injection was mainly used in retreatment (mean: 1.5). At 12 months, best-corrected visual acuity improved by >=0.3 logMAR or maintained compared with baseline in 27 eyes (96.4%). CONCLUSION: Adjunctive photodynamic therapy in eyes with Type 1 neovascularization with thickened choroid that were refractory to anti-vascular endothelial growth factor monotherapy resulted in complete fluid absorption in most eyes, which translated to visual improvement until 1 year. PMID- 27115854 TI - THE ASSOCIATION BETWEEN CUTICULAR DRUSEN AND KIDNEY FUNCTION: A Population-Based Case-Control Study. AB - PURPOSE: To determine the association between cuticular drusen (CD) and kidney function. DESIGN: observational case-control study. METHODS: SETTING: Population based. Patients or Study Population: 53 participants with (CD) and 53 age- and sex-matched controls, selected from the Danish Rural Eye Study. Cuticular drusen participants were diagnosed using fluorescein angiography and controls were excluded if the patients were suspected of having CD on fundus photography or did not have an available estimated glomerular filtration rate. MAIN OUTCOME MEASURES: creatinine and estimated glomerular filtration rate. RESULTS: The mean estimated glomerular filtration rate of those with CD was 73.3 mL.min.1.73 m (95% confidence interval [CI]: 70.0-76.6) and 73.4 mL.minute.1.73 m (95% CI: 69.5 77.3) in controls. The difference was not significant (P: 0.970). The mean creatinine among those with CD was 72.8 MUmol/L (69.3-76.4) and 73.5 MUmol/L (95% CI: 69.3-77.6) among controls. The difference was not significant (P = 0.820). CONCLUSION: The authors did not find an association between a (CD) diagnosis and decreased kidney function at a population level. PMID- 27115855 TI - ANTIANGIOGENICS IN CHOROIDAL NEOVASCULARIZATION ASSOCIATED WITH LASER IN CENTRAL SEROUS CHORIORETINOPATHY. AB - BACKGROUND/PURPOSE: To report characteristics and treatment outcome of choroidal neovascularization (CNV) secondary to laser photocoagulation and photodynamic therapy (PDT) in central serous chorioretinopathy. METHODS: Retrospective analysis of 12 eyes of 12 patients, who were diagnosed to have CNV secondary to laser photocoagulation or PDT for central serous chorioretinopathy. Collected data included demographic details, history of presenting illness, clinical examination details including visual acuity at presentation, and follow-up with imaging and treatment details. Main outcome measures were resolution of CNV activity at the last follow-up. Secondary outcomes included change in visual acuity at final follow-up from baseline, number of injections, treatment-free interval, and adverse events. RESULTS: This study included 12 eyes of CNV secondary to laser photocoagulation (8 eyes) and PDT (4 eyes). Mean age of study subjects was 47.6 +/- 15.4 years (range 33-82) with 8 men and 4 women. Mean interval between laser photocoagulation/PDT and diagnosis of CNV was 23.9 +/- 54.5 months. All subjects had unilateral CNV with classic CNV on fluorescein angiography. Eight eyes had extrafoveal CNV, and four eyes had juxtafoveal CNV. Baseline best-corrected visual acuity was 0.56 +/- 0.51 (Snellen equivalent 20/60) logMAR, and final best-corrected visual acuity was 0.53 +/- 0.51 (Snellen equivalent 20/60) logMAR with no significant difference (P = 0.84). All four eyes that presented with the CNV secondary to PDT group required additional PDT treatment because of poor response to antivascular endothelial growth factor therapy. At the last follow-up, only one patient in the laser group had active CNV; the remaining patients of both groups had scarred CNV. Mean follow-up duration was 22.4 +/- 23.1 months. Mean number of injections was 3.16 +/- 2.62. Longest treatment-free interval was 8.29 +/- 11.4 months. CONCLUSION: Antivascular endothelial growth factor therapy appears to be safe and efficacious in CNVs secondary to laser photocoagulation and PDT. Choroidal neovascularizations secondary to PDT appear to be more resistant to antivascular endothelial growth factor therapy than those because of laser photocoagulation and required additional PDT. PMID- 27115856 TI - NONINFECTIOUS VITRITIS AFTER INTRAVITREAL INJECTION OF ANTI-VEGF AGENTS: Variations in Rates and Presentation by Medication. AB - PURPOSE: The purpose of this study was to describe and compare the rates and characteristics of noninfectious vitritis after intravitreal injection of bevacizumab (Avastin, Genentech, South San Francisco, CA), ranibizumab (Lucentis, Genentech), and aflibercept (Eylea, Regeneron, Tarrytown, NY). METHODS: A retrospective case series evaluated intravitreal injections from 2006 to 2013. Cases of inflammatory response were separated into culture-positive endophthalmitis, noninfectious vitritis (not treated with intravitreal antibiotics), and indeterminate. Noninfectious cases were analyzed for rate, presentation, and clinical course. RESULTS: A total of 66,356 bevacizumab, 26,161 ranibizumab, and 8071 aflibercept injections were screened. The rates of noninfectious vitritis were 0.10% (67 cases) for bevacizumab, 0.02% (6 cases) for ranibizumab, and 0.16% (13 cases) for aflibercept. The differences were statistically significant based on Chi-square analysis (P < 0.001). Mean differences in visual decline were not significant by Kruskal-Wallis analysis (P = 0.12), but the percentage of patients with any visual decline did vary by medication according to Fisher exact test (P < 0.05). The percentage of patients with complaints of pain, blurred vision, and subjective floaters was not significantly different by medication based on Fisher exact testing (P = 0.2, P = 0.18, P = 0.16, respectively). Bevacizumab and aflibercept cases tended to present in separate chronological clusters. CONCLUSION: The results suggest a difference in rates of noninfectious vitritis for antivascular endothelial growth factor medications. Many cases tended to cluster instead of occurring at a consistent rate each year. PMID- 27115857 TI - INCIDENCE AND RELATION WITH ANATOMICAL AND FUNCTIONAL VARIABLES OF POSTOPERATIVE MACULAR DISPLACEMENT IN RHEGMATOGENOUS RETINAL DETACHMENT. AB - PURPOSE: To investigate the incidence of postsurgical retinal displacement in patients treated with pars plana vitrectomy for rhegmatogenous retinal detachment and to assess the influence of displacement on macular function. METHODS: Observational prospective study of 20 consecutive cases of rhegmatogenous retinal detachment who underwent 23-G pars plana vitrectomy with gas (C3F8 or SF6) tamponade, and prone resting. Three months after surgery, retinal displacement was evaluated by fundus autofluorescence. Macular function was evaluated with optical coherence tomography, multifocal electroretinogram, best-corrected visual acuity, and stereopsis. RESULTS: Postoperative retinal displacement was observed in 60% of cases. No correlation between the type of tamponade used and retinal displacement was observed. Similarly, no association between retinal displacement and postoperative stereopsis or visual acuity was found. A lower amplitude in P1 wave on the multifocal electroretinogram was observed in eyes with rhegmatogenous retinal detachment compared with the contralateral eye. However, no statistically significant differences between groups with or without retinal displacement were found. CONCLUSION: Retinal displacement in patients who undergo pars plana vitrectomy to treat rhegmatogenous retinal detachment is common. However, this displacement does not seem to affect macular function. PMID- 27115858 TI - LASER PROPHYLACTIC TREATMENT OF THE FELLOW EYE IN GIANT RETINAL TEARS: Long-Term Follow-up. AB - PURPOSE: To report the results of a retrospective study on prophylactic laser treatment versus observation of giant retinal tears (GRTs) fellow eyes. METHODS: One hundred and sixty consecutive charts of patients operated for GRT were included in this retroprospective study. Standard office visit included manifest and corrected refraction, intraocular pressure measurement, slit-lamp examination of the anterior and posterior segment with +90 diopter lens, and indirect ophthalmoscopy were performed at baseline and during follow-up period. RESULTS: Observation group included 62 and prophylactic laser treatment group 98 eyes. The incidence of retinal tears with localized preequatorial retinal detachment, GRTs with macula-ON retinal detachment, and GRTs with Macula-OFF retinal detachment were 3.2, 0, and 14.5%, respectively, during 43.5 +/- 19.8 months of follow-up period in observation group and 11.2, 2, and 0%, respectively, in prophylactic laser treatment group during 37.2 +/- 16.3 months of follow-up period. CONCLUSION: Prophylactic laser treatment of GRTs fellow eyes decreased the incidence of GRTs and limited the consequences of newly developed tears, lowering the occurrence of a macula-off retinal detachment with a consequent better final visual outcome respect to observation group. PMID- 27115859 TI - A PILOT STUDY OF CHOROIDAL THICKNESS IN LONG-TERM SMOKERS. AB - PURPOSE: To compare the choroidal thicknesses in long-term smokers with those of nonsmoking healthy individuals using spectral domain optical coherence tomography. PARTICIPANTS: Forty-six individuals who had been smoking at least for 20 years, but otherwise without systemic problems, participated in this prospective pilot study. The control group comprised 42 nonsmoking individuals. METHODS: The ages, refractions, and axial length measurements of the cases were recorded. Central macular thickness and choroidal thickness at the fovea and at 500 MUm intervals from the foveal center in both temporal and nasal directions were measured using spectral domain optical coherence tomography. RESULTS: Although the smoking period of the smokers was mean 32.4 +/- 9 years (range: 20 60), the mean pack-years of cigarettes was 35.1 +/- 23.8 (range: 10-120). No significant difference was observed regarding refraction value and axial length between smokers and nonsmokers group. In addition, no significant difference was observed for central macular thickness and choroidal thickness values at 500, 1,000, 1,500, and 2,000 MUm nasal and temporal part of the fovea, between 2 groups. CONCLUSION: Macular and choroidal thicknesses in long-term smokers were observed to be similar to those of healthy individuals. PMID- 27115860 TI - Clinical and laboratory predictors of deep vein thrombosis after acute stroke. AB - BACKGROUND: Deep vein thrombosis (DVT) is a common complication of acute stroke, but the new incidence in the era of improved specialist input in stroke care is yet unknown. The models for VTE diagnosis is well established, but prediction models to target at-risk patients for pharmacological prophylaxis is lacking and requires further research, particularly in the aftermath of acute stroke. OBJECTIVES: To predict DVT after acute stroke using markers of haemostatic activation and stroke severity scores. METHODS: We examined the clinical utility of laboratory factors such as thrombin generation, D-dimer, fibrinogen alongside clinical factors (National Institute of Health Stroke Scale and Barthel Index) in the prediction of asymptomatic DVT, among 92 consecutively admitted patients. RESULTS: One in five patients (19.6%) had objectively confirmed DVT (6 proximal, 12 distal). Thrombolytic therapy did not protect against DVT, with 21% (6/29) of patients treated with r-tPA went on to develop DVT. Thrombin generation and fibrinogen had no clinical utility, but D-dimer at baseline and week 2 had high clinical potential in the prediction of asymptomatic DVT (2425ng/mL versus 1010ng/mL; p=0.001) and (2240 Vs 970ng/mL; p<0.001) respectively. Patients with DVT had worse stroke severity, and are functionally less able, with lower Barthel index (p=0.05), and high National Institute of Health Stroke Score (p=0.07). CONCLUSION: Thrombolytic therapy and specialist stroke intervention does not protect against DVT risk. D-dimer concentration within 48h of acute stroke is independently associated with development of DVT. This observation would require confirmation in a large study. PMID- 27115861 TI - Aminoacetylation Reaction Catalyzed by Leucyl-tRNA Synthetase Operates via a Self Assisted Mechanism Using a Conserved Residue and the Aminoacyl Substrate. AB - Leucyl-tRNA synthetase catalyzes attachment of leucine amino acid to its cognate tRNA. During the second, aminoacetylation, step of the reaction, the leucyl moiety is transferred from leucyl-adenylate to the terminal A76 adenosine of tRNA. In this work, we have investigated the aminoacetylation step catalyzed by leucyl-tRNA synthase, using ab initio quantum chemical/molecular mechanical hybrid potentials in conjunction with reaction-path-location algorithms and molecular dynamics free energy simulations. We have modeled reaction mechanisms arising from both crystallographic studies and computational work. We invoke various groups as potential proton acceptors-namely, the phosphate and leucyl amino groups of leucyl-adenylate, the A76 base of tRNA, and the Asp80 and Glu532 residues of the protein-and consider both metal-assisted and metal-free reactions. Free energy calculations indicate that both the phosphate group of leucyl adenylate and Glu532 are not strong bases. This agrees with the results of the quantum chemical/molecular mechanical reaction path calculations which give high free energy barriers for the studied pathways involving these groups. A self assisted mechanism with the leucyl amino group and Asp80 as proton acceptors is the most likely. Furthermore, in this mechanism the presence of a metal ion coordinated by the phosphate group and Glu532 strongly activates the reaction. PMID- 27115862 TI - Population-based analysis of colorectal cancer risk after oophorectomy. AB - BACKGROUND: The development of colorectal cancer is influenced by hormonal factors. Oophorectomy alters endogenous levels of sex hormones, but the effect on colorectal cancer risk is unclear. The aim of this cohort study was to examine colorectal cancer risk after oophorectomy for benign indications. METHODS: Women who had undergone oophorectomy between 1965 and 2011 were identified from the Swedish Patient Registry. Standard incidence ratios (SIRs) and 95 per cent confidence intervals for colorectal cancer risk were calculated compared with those in the general population. Stratification was carried out for unilateral and bilateral oophorectomy, and hysterectomy without specification of whether the ovaries were removed or not. Associations between the three oophorectomy options and colorectal cancer risk in different locations were assessed by means of hazard ratios (HRs) and 95 per cent confidence intervals calculated by Cox proportional hazards regression modelling. RESULTS: Of 195 973 women who had undergone oophorectomy, 3150 (1.6 per cent) were diagnosed with colorectal cancer at a later date (median follow-up 18 years). Colorectal cancer risk was increased after oophorectomy compared with that in the general population (SIR 1.30, 95 per cent c.i. 1.26 to 1.35). The risk was lower for younger age at oophorectomy (15 39 years: SIR 1.10, 0.97 to 1.23; 40-49 years: SIR 1.26, 1.19 to 1.33; P for trend < 0.001). The risk was highest 1-4 years after oophorectomy (SIR 1.66, 1.51 to 1.81; P < 0.001). In the multivariable analysis, women who underwent bilateral oophorectomy had a higher risk of rectal cancer than those who had only unilateral oophorectomy (HR 2.28, 95 per cent c.i. 1.33 to 3.91). CONCLUSION: Colorectal cancer risk is increased after oophorectomy for benign indications. PMID- 27115863 TI - Parasitic zoonoses present some risks with low-temperature cooking of pork. AB - A recent article in this journal documents enhanced sensory qualities of pork cooked to low temperatures. The aim of this letter is to point out that the incidence of Trichinella spiralis in many countries and the more widespread incidence of Toxoplasma gondii present a concern for the adoption of low temperature cooking of pork unless extended cooking times are used. PMID- 27115864 TI - Chemical compositions, free amino acid contents and antioxidant activities of Hanwoo (Bos taurus coreanae) beef by cut. AB - The objective of this study was to evaluate chemical compositions, free amino acid contents, and antioxidant activities of different cuts of Hanwoo (Bos taurus coreanae) beef. Beef preferences and prices in the Korean market depend on cut. Therefore, comparisons were made between high-preference cuts (group 1 [G1], including loin, tenderloin, and rib) and low-preference cuts (group 2 [G2], including brisket, topside, and shank). Meat samples were collected from 10 fattened cows. Crude fat content was significantly higher in G1 than in G2 (p<0.05). The amounts of crude protein and total free amino acid were negatively correlated with crude fat content (p<0.05). Overall G2 contained higher levels of free amino acids with antioxidant activity than G1. Antioxidant activities were also significantly higher in G2 compared with G1 (p<0.05). In conclusion, providing consumers with positive information about G2 as found in this study could help health-conscious consumers choosing among beef products and further promote increased consumption of low-preference beef cuts. PMID- 27115865 TI - Consumer facial expression in relation to smoked ham with the use of face reading technology. The methodological aspects and informative value of research results. AB - The study determined the emotional reactions of consumers in relation to hams using face visualization method, which was recorded by FaceReader (FR). The aims of the research were to determine the effect of the ham samples on the type of emotion, to examine more deeply the individual emotional reactions of consumers and to analyse the emotional variability with regard to the temporal measurement of impressions. The research involved testing the effectiveness of measuring emotions in response to the ongoing flavour impression after consumption of smoked hams. It was found that for all of the assessed samples, neutral and negative emotions prevailed as the overall emotions recorded during the assessment of the taste/flavour impression. The range of variability of the overall emotions depended more on the consumer reactions and less on the properties of the assessed product. Consumers expressed various emotions in time and the ham samples evoked different emotional reactions as an effect of duration of the impression. PMID- 27115866 TI - Aqueous Extracts of Toona sinensis Leaves Inhibit Renal Carcinoma Cell Growth and Migration Through JAK2/stat3, Akt, MEK/ERK, and mTOR/HIF-2alpha Pathways. AB - Toona sinensis (TS) is a type of deciduous tree, which is distributed widely in Asia and used as a traditional herb medicine. Previously, we demonstrated that aqueous extracts of TS leaves (TSL-1) induce apoptosis in two clear types of human renal carcinoma cells (ccRCC) via mitochondria-dependent pathway. In this study, we further investigated the more detailed mechanism of TSL-1-induced antitumor effects on ccRCCs. TSL-1 treatment arrested ccRCC cells in G0/G1 phase through the decrease of cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 as well as induction of p53 and FOXO3a protein expressions. On the other hand, the inhibitory effects of TSL-1 on migration were also observed in 786-O and A-498 cells. Mechanically, we presented that TSL-1 could suppress cell cycle progression and motility via inhibiting the phosphorylation of JAK2/stat3, Akt, MEK/ERK, and mTOR in a concentration- and time-dependent manner. Moreover, we found that TSL-1 inhibited p21, HIF-2alpha, c-Myc, VEGF, and MMP9 protein expressions in both cell lines. In conclusion, these findings suggested that TS induced apoptosis and its antimigration activity in ccRCC cells were accompanied by inactivation of several oncogenic pathways. PMID- 27115867 TI - A comparison of the burden and resultant risk associated with occupational falls from a height and on the same level in Australia. AB - Occupational falls are one of the leading causes of occupational injury and death internationally. This study described the nature of occupational falls following an analysis of workers compensation data in Western Australia. Frequencies, proportions and incidence rates were calculated following mechanism, gender, age and industry stratification. The natures of injury and bodily locations affected were compared between mechanisms of fall. Industry incidence rates were ranked and their corresponding proportions reported. Cost and lost time were described and risk scores for each burden type (incapacity, cost and lost time) were calculated and compared between fall mechanisms. Of all occupational falls, the proportion, incidence rates and risk scores of falls on same level were consistently greater compared to falls from a height. Gender, age and industry groups that appear to be at highest risk vary with the measure used and mechanism of incident. This study translates epidemiological information into a risk score that can aid in prioritisation. Practitioner Summary: This paper presents an in depth analysis of Worker's Compensation claims for falls in Western Australia. Calculated proportion, incidence rates and formulated risk scores for falls on the level were consistently greater compared to falls from a height. Limitations associated with the analysis of large-scale data-sets are described. PMID- 27115868 TI - Effects of Shift Work on the Postural and Psychomotor Performance of Night Workers. AB - The purpose of the study was to investigate the effects of shift work on the psychomotor and postural performance of night workers. The study included 20 polysomnography technicians working schedule of 12-h night shift by 36-h off. On the first day of protocol, the body mass and height were measured, and an actigraph was placed on the wrist of each participant. On the second day of protocol, sleepiness by Karolinska Sleepiness Scale, postural control by force platform (30 seconds) and psychomotor performance by Psychomotor Vigilance Task (10 minutes) were measured before and after 12-h night work. Results showed that after 12-h night work, sleepiness increased by 59% (p<0.001), postural control variables increased by 9% (p = 0.048), and 14% (p = 0.006). Mean reaction time, and the number of lapses of attention increased by 13% (p = 0.006) and 425% (p = 0.015), respectively, but the mean reciprocal reaction time decreased by 7%. In addition, there were correlations between sleepiness and postural control variables with opened eyes (r = 0.616, 95% confidence interval [CI] = 0.361 0.815; r = 0.538; 95% CI = 0.280-0.748) and closed eyes (r = 0.557; 95% CI = 0.304-0.764, r = 0497; 95% CI = 0.325-0.715) and a pronounced effect of sleepiness on postural sway (R2 = 0.393; 95% CI = 0.001-0.03). Therefore, 12-h night work system and sleepiness showed a negative impact in postural and psychomotor vigilance performance of night workers. As unexpected, the force platform was feasibility to detect sleepiness in this population, underscoring the possibility of using this method in the workplace to prevent occupational injuries and accidents. PMID- 27115870 TI - Synthesis, characterization of new copper (ii) Schiff base and 1,10 phenanthroline complexes and study of their bioproperties. AB - Three mononuclear Cu(II) complexes [Cu(naph-phe)phen] (1), [Cu(naph-tyr)(phen)] (2) and [Cu(naph-trp)(phen)] (3) were synthesized, characterized and their biological properties were studied. Complexes 1, 2, 3 exhibit square pyramidal geometry where Schiff base acts as a binegative tridentate ONO donor ligand and phen acts as NN donor ligand. CT-DNA binding studies revealed that the complexes bind through intercalative mode and show good binding propensity. The hydrolytic DNA cleavage activity of these complexes has been studied using gel electrophoresis. The DNA binding and cleavage affinities decrease in the order of 3>2>1. The in-vitro antimicrobial activities of the complexes were also studied. PMID- 27115869 TI - Inflammation Enhances the Risks of Stroke and Death in Chronic Chagas Disease Patients. AB - Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by real-time PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lower mRNA expression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL-22 but exhibited higher expression of IFN-gamma and TNF-alpha compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF alpha compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-gamma, TNF-alpha and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-alpha and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease. PMID- 27115871 TI - Tooth color change caused by photosensitizers after photodynamic therapy: An in vitro study. AB - This study aimed to perform an in vitro evaluation of the effect of photosensitizers used in photodynamic therapy (PDT) on tooth color change when used in combination with conventional endodontic treatment. Forty extracted human mandibular premolars were accessed and underwent root canal therapy and PDT. Photosensitizers were used in accordance with the experimental groups: MB (n=10) PDT with Methylene Blue at 0.01%; TB (n=10) - PDT with Toluidine Blue at 0.01%; MG (n=10) - PDT with Malachite Green at 0.01%, at the concentration of 0.1mg/mL; and PC (n=10) - positive control, PDT with Endo-PTC cream stained with Methylene Blue at 25%. The samples were irradiated with 660-nm diode laser by means of a 330-MUm-diameter optical fiber cable at a power density of 40mW for 120s. After light curing, the photosensitizers were removed from the specimens with 10mL sodium hypochlorite at 1%. A reflectance spectrometer was used for evaluation of color prior to and 60days after the experimental procedure based on the CIE L*a*b* system. According to ANOVA test, there were statistically significant differences between the experimental groups (p=0.003). Tukey's test showed a significant difference between PC and TB (p=0.008), as well as between MG and TB (p=0.009). However, there was no statistically significant difference between PC, MG (p=0.957) and MB (p=0.103). It was concluded that the use of PDT as an adjuvant to root canal therapy, using different photosensitizers, led to color change in tooth structure. PMID- 27115872 TI - Island-Model Genomic Selection for Long-Term Genetic Improvement of Autogamous Crops. AB - Acceleration of genetic improvement of autogamous crops such as wheat and rice is necessary to increase cereal production in response to the global food crisis. Population and pedigree methods of breeding, which are based on inbred line selection, are used commonly in the genetic improvement of autogamous crops. These methods, however, produce a few novel combinations of genes in a breeding population. Recurrent selection promotes recombination among genes and produces novel combinations of genes in a breeding population, but it requires inaccurate single-plant evaluation for selection. Genomic selection (GS), which can predict genetic potential of individuals based on their marker genotype, might have high reliability of single-plant evaluation and might be effective in recurrent selection. To evaluate the efficiency of recurrent selection with GS, we conducted simulations using real marker genotype data of rice cultivars. Additionally, we introduced the concept of an "island model" inspired by evolutionary algorithms that might be useful to maintain genetic variation through the breeding process. We conducted GS simulations using real marker genotype data of rice cultivars to evaluate the efficiency of recurrent selection and the island model in an autogamous species. Results demonstrated the importance of producing novel combinations of genes through recurrent selection. An initial population derived from admixture of multiple bi-parental crosses showed larger genetic gains than a population derived from a single bi-parental cross in whole cycles, suggesting the importance of genetic variation in an initial population. The island-model GS better maintained genetic improvement in later generations than the other GS methods, suggesting that the island-model GS can utilize genetic variation in breeding and can retain alleles with small effects in the breeding population. The island-model GS will become a new breeding method that enhances the potential of genomic selection in autogamous crops, especially bringing long-term improvement. PMID- 27115873 TI - Alirocumab, a Therapeutic Human Antibody to PCSK9, Does Not Affect CD81 Levels or Hepatitis C Virus Entry and Replication into Hepatocytes. AB - BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PSCK9) is secreted mainly from the liver and binds to the low-density lipoprotein receptor (LDLR), reducing LDLR availability and thus resulting in an increase in LDL-cholesterol. While the LDLR has been implicated in the cell entry process of the hepatitis C virus (HCV), overexpression of an artificial non-secreted, cell membrane-bound form of PCSK9 has also been shown to reduce surface expression of CD81, a major component of the HCV entry complex, leading to concerns that pharmacological inhibition of PCSK9 may increase susceptibility to HCV infection by increasing either CD81 or LDLR availability. Here, we evaluated effects of PCSK9 and PCSK9 blockade on CD81 levels and HCV entry with a physiologically relevant model using native secreted PCSK9 and a monoclonal antibody to PCSK9, alirocumab. METHODS AND RESULTS: Flow cytometry and Western blotting of human hepatocyte Huh-7 cells showed that, although LDLR levels were reduced when cells were exposed to increasing PCSK9 concentrations, there was no correlation between total or surface CD81 levels and the presence and amount of soluble PCSK9. Moreover, inhibiting PCSK9 with the monoclonal antibody alirocumab did not affect expression levels of CD81. In an in vitro model of HCV entry, addition of soluble PCSK9 or treatment with alirocumab had no effect on the ability of either lentiviral particles bearing the HCV glycoproteins or JFH-1 based cell culture virus to enter hepatocytes. Consistent with these in vitro findings, no differences were observed in hepatic CD81 levels using in vivo mouse models, including Pcsk9-/- mice compared with wild-type controls and hyperlipidemic mice homozygous for human Pcsk9 and heterozygous for Ldlr deletion, treated with either alirocumab or isotype control antibody. CONCLUSION: These results suggest that inhibition of PCSK9 with alirocumab has no effect on CD81 and does not result in increased susceptibility to HCV entry. PMID- 27115874 TI - Remotely Sensed Environmental Conditions and Malaria Mortality in Three Malaria Endemic Regions in Western Kenya. AB - BACKGROUND: Malaria is an important cause of morbidity and mortality in malaria endemic countries. The malaria mosquito vectors depend on environmental conditions, such as temperature and rainfall, for reproduction and survival. To investigate the potential for weather driven early warning systems to prevent disease occurrence, the disease relationship to weather conditions need to be carefully investigated. Where meteorological observations are scarce, satellite derived products provide new opportunities to study the disease patterns depending on remotely sensed variables. In this study, we explored the lagged association of Normalized Difference Vegetation Index (NVDI), day Land Surface Temperature (LST) and precipitation on malaria mortality in three areas in Western Kenya. METHODOLOGY AND FINDINGS: The lagged effect of each environmental variable on weekly malaria mortality was modeled using a Distributed Lag Non Linear Modeling approach. For each variable we constructed a natural spline basis with 3 degrees of freedom for both the lag dimension and the variable. Lag periods up to 12 weeks were considered. The effect of day LST varied between the areas with longer lags. In all the three areas, malaria mortality was associated with precipitation. The risk increased with increasing weekly total precipitation above 20 mm and peaking at 80 mm. The NDVI threshold for increased mortality risk was between 0.3 and 0.4 at shorter lags. CONCLUSION: This study identified lag patterns and association of remote- sensing environmental factors and malaria mortality in three malaria endemic regions in Western Kenya. Our results show that rainfall has the most consistent predictive pattern to malaria transmission in the endemic study area. Results highlight a potential for development of locally based early warning forecasts that could potentially reduce the disease burden by enabling timely control actions. PMID- 27115875 TI - "You're on ten, where can you go from there?" Tufnel problems in repeated experiential judgments. AB - We describe a set of Tufnel problems that arise when repeated use of a fixed point scale precipitates failures to assess a full range of subjective experiences. As empirical evidence, participants in Study 1 periodically reported their depth of mind wandering on either 5- or 7-point Likert scales during a sustained attention task. The proportion of participants providing maximum scale ratings increased quickly over time-on-task and did so more quickly for the 5 point than for the 7-point group. Participants in Study 2 completed the same task using a 10-point scale before indicating whether and where they could have used a scale extended to "11" during the task. Slightly more than 20% of participants reported needing a scale extension. This Need for 11 was associated with differences in both reports of mind wandering depth and task performance. We conclude that Tufnel problems warrant methodological consideration and reflect interesting constraints on human judgment. PMID- 27115876 TI - Relationship between Otitis Media and Epithelial Function in the Lymphoepithelium of Pediatric Adenoids. AB - Nose- or nasopharynx-associated lymphoid tissue (NALT) has a unique role that is distinct from that of other lymphoid tissues. During upper airway mucosal immune response, NALT induces a variety of responses, including cytokine and chemokine production and innate immune response, to establish acquired immunity. NALT consists of epithelial cells, epithelium-associated lymphoid tissues such as IgA committed B cells, innate lymphocytes, T helper cells and dendritic cells. Intranasal immunization has recently been shown to effectively induce a proactive immune response in the local mucosa in addition to a systemic immune response. A variety of factors can cause otitis media, including Eustachian tube dysfunction, inflammation, allergy and viral and bacterial infections. However, the detailed pathogenesis of otitis media is not yet completely understood. In this report, we provide evidence suggesting that adenoid tissue as a component of NALT in children may play an important role in inducing innate immunity following viral infection. PMID- 27115878 TI - Pharmacological Development of Target-Specific Delocalized Lipophilic Cation Functionalized Carboranes for Cancer Therapy. AB - PURPOSE: Tumor cell heterogeneity and microenvironment represent major hindering factors in the clinical setting toward achieving the desired selectivity and specificity to malignant tissues for molecularly targeted cancer therapeutics. In this study, the cellular and molecular evaluation of several delocalized lipophilic cation (DLC)-functionalized carborane compounds as innovative anticancer agents is presented. METHODS: The anticancer potential assessment of the DLC-carboranes was performed in established normal (MRC-5, Vero), cancer (U 87 MG, HSC-3) and primary glioblastoma cancer stem (EGFR(pos), EGFR(neg)) cultures. Moreover, the molecular mechanism of action underlying their pharmacological response is also analyzed. RESULTS: The pharmacological anticancer profile of DLC-functionalized carboranes is characterized by: a) a marked in vitro selectivity, due to lower concentration range needed (ca. 10 fold) to exert their cell growth-arrest effect on U-87 MG and HSC-3, as compared with that on MRC-5 and Vero; b) a similar selective growth inhibition behavior towards EGFR(pos) and EGFR(neg) cultures (>10 fold difference in potency) without, however, the activation of apoptosis in cultures; c) notably, in marked contrast to cancer cells, normal cells are capable of recapitulating their full proliferation potential following exposure to DLC-carboranes; and, d) such pharmacological effects of DLC-carboranes has been unveiled to be elicited at the molecular level through activation of the p53/p21 axis. CONCLUSIONS: Overall, the data presented in this work indicates the potential of the DLC-functionalized carboranes to act as new selective anticancer therapeutics that may be used autonomously or in therapies involving radiation with thermal neutrons. Importantly, such bifunctional capacity may be beneficial in cancer therapy. PMID- 27115879 TI - Endoscopic Devices for Obesity. AB - The obesity epidemic, recognized by the World Health Organization in 1997, refers to the rising incidence of obesity worldwide. Lifestyle modification and pharmacotherapy are often ineffective long-term solutions; bariatric surgery remains the gold standard for long-term obesity weight loss. Despite the reported benefits, it has been estimated that only 1% of obese patients will undergo surgery. Endoscopic treatment for obesity represents a potential cost-effective, accessible, minimally invasive procedure that can function as a bridge or alternative intervention to bariatric surgery. We review the current endoscopic bariatric devices including space occupying devices, endoscopic gastroplasty, aspiration technology, post-bariatric surgery endoscopic revision, and obesity related NOTES procedures. Given the diverse devices already FDA approved and in development, we discuss the future directions of endoscopic therapies for obesity. PMID- 27115880 TI - The Role of Cognitive Factors in Predicting Balance and Fall Risk in a Neuro Rehabilitation Setting. AB - INTRODUCTION: There is a consistent body of evidence supporting the role of cognitive functions, particularly executive function, in the elderly and in neurological conditions which become more frequent with ageing. The aim of our study was to assess the role of different domains of cognitive functions to predict balance and fall risk in a sample of adults with various neurological conditions in a rehabilitation setting. METHODS: This was a prospective, cohort study conducted in a single centre in the UK. 114 participants consecutively admitted to a Neuro-Rehabilitation Unit were prospectively assessed for fall accidents. Baseline assessment included a measure of balance (Berg Balance Scale) and a battery of standard cognitive tests measuring executive function, speed of information processing, verbal and visual memory, visual perception and intellectual function. The outcomes of interest were the risk of becoming a faller, balance and fall rate. RESULTS: Two tests of executive function were significantly associated with fall risk, the Stroop Colour Word Test (IRR 1.01, 95% CI 1.00-1.03) and the number of errors on part B of the Trail Making Test (IRR 1.23, 95% CI 1.03-1.49). Composite scores of executive function, speed of information processing and visual memory domains resulted in 2 to 3 times increased likelihood of having better balance (OR 2.74 95% CI 1.08 to 6.94, OR 2.72 95% CI 1.16 to 6.36 and OR 2.44 95% CI 1.11 to 5.35 respectively). CONCLUSIONS: Our results show that specific subcomponents of executive functions are able to predict fall risk, while a more global cognitive dysfunction is associated with poorer balance. PMID- 27115881 TI - Influence of Reproductive Status: Home Range Size in Water Voles (Arvicola amphibius). AB - The relationship between home range and reproductive status of water voles (Arvicola amphibius) was studied by radio-tracking on an island off the coast of northern Norway in 2006-2009. The aim was to test assumptions about the species' social structure relative to other microtines. Juveniles used fairly small ranges (about 400 m2), with no difference between males and females. Subadults, overwintered voles in April, had ranges similar to juveniles. Reproductively active males (mean 2774.0 m2) increased their range seven-fold relative to juvenile males, with ranges on average 3.3 times larger than adult females (mean 848.3 m2), which also expanded their range. Most litters were born in May and June, and as reproduction ceased in July adult males reduced their range whilst females did not. Body mass or year did not influence home range size. Overlap of home ranges varied, but could be extensive in both adult males and females. The water vole had a social structure similar to some Microtus species, but females appeared to be non-territorial and males perhaps conditioned territorial and non territorial. PMID- 27115882 TI - Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn's Disease Patients. AB - Tumor necrosis factor alpha inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn's disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients. PMID- 27115883 TI - Musculoskeletal imaging insight 2015: Kenya. AB - Over the past 6 years the International Skeletal Society (ISS) outreach programs have become popular amongst the various radiology organizations in sub-Saharan Africa. So much so that that the ISS outreach is now routinely expected to participate in many of the international radiology conferences in that part of the world. The organizational planning for an outreach visit to Kenya took place over a 3-year period. Eventually a double-headed event; the seventh and eighth sub-Saharan outreach efforts were organized in Nairobi and in Mombasa, Kenya. The Nairobi outreach was an educational course on musculoskeletal imaging at the University of Nairobi and the Aga Khan University in Nairobi from 26 to 28 May 2015. The Mombasa outreach was organized in collaboration with the African Society of Radiology (ASR) at their annual meeting in Mombasa from 30 May to 2 June 2015. PMID- 27115884 TI - Evaluation of (18)F-FDG PET and MRI in differentiating benign and malignant peripheral nerve sheath tumors. AB - OBJECTIVE: To compare 18F-FDG PET/CT and MRI for differentiating benign and malignant peripheral nerve sheath tumors (BPNSTs and MPNSTs) and correlate imaging characteristics with histopathology. MATERIALS AND METHODS: Patients with pathologically proven PNSTs undergoing 18F-FDG PET/CT were retrospectively reviewed. PET/CTs and, if available, MRIs were analyzed, noting multiple imaging characteristics and likely pathology (benign or malignant). RESULTS: Thirty-eight patients with 23 BPNSTs and 20 MPNSTs were analyzed. MPNSTs had higher SUVmax (10.1 +/- 1.0, 4.2 +/- 0.4, p < 0.0001), metabolic tumor volume (146.5 +/- 39.4, 21.7 +/- 6.6 cm(3), p = 0.01), total lesion glycolysis (640.7 +/- 177.5, 89.9 +/- 23.2 cm(3)*g/ml, p = 0.01), and SUVmax/LiverSUVmean (5.3 +/- 0.5, 2.0 +/- 0.2, p < 0.0001). All lesions with SUVmax < 4.3 were benign. All lesions with SUVmax > 8.1 were malignant. SUVmax cutoff of 6.1 yielded 90.0 % sensitivity and 78.3 % specificity for MPNSTs. SUVmax/LiverSUVmean cutoff of 3.0 yielded 90.0 % sensitivity and 82.6 % specificity. MPNSTs more commonly had heterogeneous FDG activity (p < 0.0001), perilesional edema (p = 0.004), cystic degeneration/necrosis (p = 0.015), and irregular margins (p = 0.004). There was no difference in lesion size, MRI signal characteristics, or enhancement. Expertly interpreted MRI had 62.5-81.3 % sensitivity and 94.1-100.0 % specificity while PET had 90.0-100.0 % sensitivity and 52.2-82.6 % specificity for diagnosing MPNSTs. CONCLUSIONS: FDG PET and MRI play a complementary role in PNST evaluation. Multiple metabolic parameters and MRI imaging characteristics are useful in differentiating BPNSTs from MPNSTs. This underscores the potential critical role of PET/MRI in these patients. PMID- 27115885 TI - T2 mapping of articular cartilage of the glenohumeral joint at 3.0 T in healthy volunteers: a feasibility study. AB - OBJECTIVE: The purpose of this study was to assess the T2 values of the glenohumeral joint cartilage in healthy asymptomatic individuals at 3.0 T and to analyze the T2 profile of the humeral cartilage. MATERIALS AND METHODS: This prospective study was approved by our institutional review board and written informed consent was obtained. Thirteen subjects (mean age, 28.6 years; age range, 24-33 years) were included and underwent multiecho spin-echo T2-weighted MR imaging and T2 mapping was acquired. Regions of interest were placed on the humeral cartilage and glenoid cartilage on oblique coronal images. T2 profiles of humeral cartilage were measured from the bone-cartilage interface to the articular surface. Intra-observer agreement was analyzed using intraclass correlation coefficient (ICC). RESULTS: All 13 joints showed normal appearance on conventional T2-weighted images. The mean T2 values of humeral and glenoid cartilage were 50.5 +/- 12.1 and 49.0 +/- 9.9 ms, respectively. Intra-observer agreement was good, as determined by ICC (0.736). Longer T2 values were observed at the articular surface with a tendency to decrease toward the bone-cartilage interface. The mean cartilage T2 value was 69.03 +/- 21.2 ms at the articular surface and 46.99 +/- 19.6 ms at the bone-cartilage interface. CONCLUSION: T2 values of the glenohumeral joint cartilage were similar to reported values of cartilage in the knee. The T2 profile of normal humeral cartilage showed a spatial variation with an increase in T2 values from the subchondral bone to the articular surface. PMID- 27115886 TI - Role of renal urothelium in the development and progression of kidney disease. AB - The clinical and financial impact of chronic kidney disease (CKD) is significant, while its progression and prognosis is variable and often poor. Studies using the megabladder (mgb -/- ) model of CKD show that renal urothelium plays a key role in modulating early injury responses following the development of congenital obstruction. The aim of this review is to examine the role that urothelium has in normal urinary tract development and pathogenesis. We discuss normal morphology of renal urothelium and then examine the role that uroplakins (Upks) play in its development. Histologic, biochemical, and molecular characterization of Upk1b RFP/RFP mice indicated Upk1b expression is essential for normal urinary tract development, apical plaque/asymmetric membrane unit (AUM) formation, and differentiation and functional integrity of the renal urothelium. Our studies provide the first evidence that Upk1b is directly associated with the development of congenital anomalies of the urinary tract (CAKUT), spontaneous age-dependent hydronephrosis, and dysplastic urothelia. These observations demonstrate the importance of proper urothelial differentiation in normal development and pathogenesis of the urinary tract and provide a unique working model to test the hypothesis that the complex etiology associated with CKD is dependent upon predetermined genetic susceptibilities that establish pathogenic thresholds for disease initiation and progression. PMID- 27115887 TI - Measuring and estimating glomerular filtration rate in children. AB - Glomerular filtration rate (GFR) is the best index for kidney function in health and disease. Knowledge of the GFR is essential for the detection (diagnosis) and monitoring of renal function during disease progression and for ensuring correct medication doses. Inulin clearance (plasma or urine) is currently considered to be the gold standard for measuring GFR, but in clinical practice the measurement of other exogenous filtration markers from the plasma often replaces that of inulin clearance. Different protocols can be used to determine the area under the plasma disappearance curve, and an understanding of these methods is important. GFR can also be estimated by GFR equations (eGFR), which are most often used in clinical practice because they only require a knowledge of the serum creatinine or cystatin C level and demographic information. eGFR equations are easy to use but they do have their limitations, and it is important to know how these equations were derived and in which circumstances they can be used most accurately. The aim of this review is to explain how GFR can be measured using the renal clearance and the plasma clearance method and which eGFR equations can be applied to children, as well as how and when these equations can be used in clinical practice. PMID- 27115888 TI - Life expectancy with chronic kidney disease: an educational review. AB - Can renal prognosis and life expectancy be accurately predicted? Increasingly, the answer is yes. The natural history of different forms of renal disease is becoming clearer; the degree of reduction in glomerular filtration rate (GFR) and the magnitude of proteinuria are strong predictors of renal outcome. Actuarial data on life expectancy from the start of renal replacement therapy are available from renal registries such as the U.S. Renal Data System (USRDS), and the UK Renal Registry. Recently, similar data have become available for patients with chronic kidney disease. Data collected from a large population-based registry in Alberta, Canada and stratified for different levels of estimated GFR (eGFR) have shown that the reduction in life expectancy with kidney failure is not a uremic event associated with starting dialysis but a continuous process that is evident from an eGFR of <=60 ml/min. Nevertheless, despite the poor prognosis of the last stages of renal failure, progress in the treatment and management of these patients and, in particular, of their cardiovascular risk factors continues to improve long-term outcome. PMID- 27115890 TI - UK Renal Registry 18th Annual Report: Chapter 9 Biochemical Variables amongst UK Adult Dialysis Patients in 2014: National and Centre-specific Analyses. AB - In 2014 57.5% of HD patients and 62.7% of PD patients achieved the audit measure for phosphate. 29.0% of HD and 30.3% of PD patients had a serum phosphate above the audit standard range. 79.1% of HD and 79.7% of PD patients had adjusted calcium between 2.2-2.5 mmol/L. 57.4% of HD and 65.0% of PD patients had a serum PTH between 16-72 pmol/L. 16.4% of HD and 12.0% of PD patients had a serum PTH .72 pmol/L. Simultaneous control of all three parameters within current audit standards was achieved by 50.3% of HD and 52.5% of PD patients. 60.4% of HD and 81.8% of PD patients achieved the audit measure for bicarbonate. PMID- 27115891 TI - The Heidelberg Appendicitis Score Simplifies Identification of Pediatric Appendicitis. AB - OBJECTIVE: To identify the factors that facilitate the diagnosis of pediatric appendicitis. METHODS: Institutionally approved retrospective, single center analysis of all patients with acute abdominal pain was done. Medical history, symptoms, laboratory and radiologic findings of all children presenting with abdominal pain were evaluated. To identify the best predictors, uni- and multi variate analysis were used. RESULTS: In 2 years, 431 patients fulfilled the inclusion criteria. Data was complete in all subjects. Of these, 156 (36.2 %) suffered from appendicitis. The best discriminators for appendicitis were clinical and ultrasound features. The four best factors were identified by CART analysis (continuous abdominal pain, tenderness on the right lower quadrant, rebound tenderness and conspicuous ultrasound) and combined to the Heidelberg Appendicitis score. A positive score (>3 features) is highly predictive for acute appendicitis (PPV 89.3 %, NPV 94.9 %) and includes all cases of perforated appendicitis. CONCLUSIONS: It is possible to predict acute appendicitis in children. The decision making process can be simplified by the proposed Heidelberg Appendicitis score, which is comprised of four factors. It has great potential to facilitate and accelerate the diagnosis of pediatric appendicitis. PMID- 27115892 TI - Expression and Localization of Human Defensins in Palatine Tonsils. AB - Defensins are small antimicrobial peptides and effector components of innate immune responses. Recent studies have shed light on their beneficial functions for the prevention of infection and potential for development of new drugs. Here, we showed the expression profiles of human defensins in palatine tonsils with 3 different diseases: tonsillar hypertrophy, recurrent tonsillitis and focal infection of the tonsil. RT-PCR analysis and immunofluorescence revealed that the expression of human alpha-defensin 4 and beta-defensin 3 (beta3) in palatine tonsils with tonsillar hypertrophy was lower than that in recurrent tonsillitis and focal infection of the tonsil, suggesting that chronic inflammation induces defensin expression. Interestingly, beta2 and beta3 mRNAs were specifically expressed by palatine tonsil tissues but not in human peripheral blood mononuclear cells and mucosa of the small intestine. Additionally, we observed that exposure to a Toll-like receptor 4 ligand, lipopolysaccharide, which is used as a bacterial infection model, increases the production of beta2 in culture supernatants from tonsillar epithelial cells in a dose-dependent manner. Taken together, these results indicate that beta2 produced by tonsillar epithelial cells plays an important role in the innate immune response for bacterial infections. PMID- 27115893 TI - Detection of Fetal Sex, Aneuploidy and a Microdeletion from Single Placental Syncytial Nuclear Aggregates. AB - OBJECTIVES: A key problem in prenatal screening using extra-embryonic cells is the feasibility of extracting usable DNA from a small number of cells. Syncytial nuclear aggregates (SNAs) are multinucleated structures shed from the placenta. This study assesses the potential of SNAs as a source of fetal DNA for the detection of genetic abnormalities. METHODS: SNAs were collected in vitro. Whole genome amplification was used to amplify DNA from single SNAs, and DNA quality and quantity was assessed by spectrophotometry and PCR. Confocal microscopy was used to count nuclei within SNAs, determine metabolic activity and investigate DNA damage. Fetal sex and chromosomal/genetic abnormalities were investigated with array-comparative genomic hybridization (aCGH). RESULTS: DNA was amplified from 81% of the individual SNAs. A mean of 61 +/- 43 nuclei were found per SNA. DNA strand breaks were found in 76% of the SNAs. Seventy-five percent of SNAs yielded whole-genome-amplified DNA of sufficient quality for aCGH after storage and shipping. Individual SNAs from the same pregnancy reliably gave the same chromosomal profile, and fetal sex and trisomies could be detected. A microdeletion was detected in one pregnancy. CONCLUSION: SNAs could provide a source of extra-embryonic DNA for the prenatal screening/diagnosis of fetal sex and chromosomal and sub-chromosomal genetic abnormalities. PMID- 27115894 TI - New concept of the pathogenesis and therapeutic orientation of acquired communicating hydrocephalus. AB - Hydrocephalus is a common medical condition characterized by abnormalities in the secretion, circulation and absorption of cerebrospinal fluid (CSF), resulting in ventricle dilatation. For the communicating hydrocephalus, without etiological treatment, its pathogenesis has been considered as a research emphasis. Many factors can damage the CSF system and trigger communicating hydrocephalus, including tumor surgery and hydrocephalus neurological diseases, such as brain trauma, infection, ICH and SAH. But according to our clinical experience, a big proportion of patients do not develop hydrocephalus. That is because the absorbing ability of CSF can compensate within a certain range. If the damage exceeds that range, hydrocephalus will occur. Once it occurs, it is not likely to be reversed, so a shunt surgery is always needed. Therefore, we believe that our orientation could transform the treatment of patient who has already showed hydrocephalus symptoms to the prevention of the occurrence in the patient with high risk of hydrocephalus. Based on the hypothesis above, we first divide the process of hydrocephalus into three stages and we believe that hydrocephalus are possible be reversed or halted in stage 1 and 2. The new concept of the pathogenesis in hydrocephalus will enrich our understanding and provide new insights to the therapeutic orientation. In conclusion, the future research direction should be the prevention of hydrocephalus, which should take a long period from the immediate occurrence of brain injury to several months or even years after the injury. PMID- 27115895 TI - Effect of associated aneurysms on the management of intracranial arteriovenous malformations. PMID- 27115896 TI - Elevated serum IL-11, TNF alpha, and VEGF expressions contribute to the pathophysiology of hypertensive intracerebral hemorrhage (HICH). AB - To study the changes in serum interleukin-11 (IL-11), tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) expressions following hypertensive intracerebral hemorrhage (HICH), and explore their associations with disease severity and prognosis. Serum IL-11, TNF-alpha, and VEGF levels after 1, 3, 7, and 14 days after HICH were assayed using enzyme-linked immunosorbent assay (ELISA), and neurological deficit score (NDS) were recorded at admission and discharge for 99 HICH cases. Then 45 healthy controls were included and assayed for serum IL-11, TNF-alpha, and VEGF levels. Serum IL-11, TNF-alpha, and VEGF levels were higher in HICH patients than healthy controls (all P < 0.05). TNF alpha was higher at the 3rd day following disease onset than other time points (all P < 0.05), while IL-11 and VEGF peaked at the 7th day and dropped below baseline values at the 14th day (all P < 0.05). Serum IL-11 was positively correlated with TNF-alpha (r = 0.70, P < 0.05) and VEGF (r = 0.72, P < 0.05). Serum TNF-alpha was positively correlated with VEGF (r = 0.46, P < 0.05). Serum IL-11, TNF-alpha, and VEGF were associated with disease severity in HICH patients. Patients with more severe disease tended to have higher NDS at admission, and higher IL-11, TNF-alpha, and VEGF during treatment were associated with higher NDS at discharge. Serum IL-11, TNF-alpha, and VEGF may involve in the pathophysiology of HICH, thus IL-11, TNF-alpha, and VEGF may be prognostic factors for post HICH neurologic damage. PMID- 27115897 TI - Expression of CysLTR1 and 2 in Maturating Lymphocytes of Hyperplasic Tonsils Compared to Peripheral Cells in Children. AB - Cysteinyl-leukotriene receptors 1 and 2 (CysLTR1 and 2) are related to allergic inflammatory responses. Recent studies demonstrated their role in lymphocyte division and maturation in the bone marrow. Few data are available about CysLTRs function in lymphocyte maturation in tonsils. The objectives of this study are to compare CysLTRs expression in peripheral blood lymphocytes with expression in maturating lymphocytes of hyperplasic tonsil and to check the influence of respiratory allergies in this process. Leukocytes of peripheral blood (PL) and hyperplasic tonsils of children were immunostained for CysLTR1, CysLTR2, CD3 (T cells), and CD19 (B cells) and read in flow cytometer. Lymphocyte of tonsils were divided in differentiating small cells (SC) and mitotic large cells (LC); percentage of B and T cells expressing CysLTRs was determined, and comparison was done using ANOVA and Tukey's tests. Data were analyzed as a whole and categorizing patients according the presence of allergies. Sixty children were enrolled in this study. There was a large expression of CysLTR1 and 2 in CD3+ LC, and such expression decreased progressively in SC and PL. In B cells, the highest expression of CysLTR1 and 2 was found in PL while SC showed the lowest and LC showed the intermediate expression. This pattern kept unchanged in groups of allergic and non-allergic individuals. CysLTRs seem to be involved in lymphocyte maturation that occurs in tonsils, without influence of allergies. New studies aiming the clinic treatment of tonsil hyperplasia must be targeted to the development of drugs capable of blocking both CysLTR1 and 2. PMID- 27115899 TI - Long-term Outcomes of Laparoscopic Versus Open Surgery for Clinical Stage I Gastric Cancer: The LOC-1 Study. AB - BACKGROUND: Clinical trials comparing laparoscopic gastrectomy (LG) versus traditional open gastrectomy (OG) have been planned, their surgical outcomes reported but their oncologic outcomes are still pending. Consequently, we have conducted this large-scale historical cohort study to provide relevant information rapidly to guide our current practice. METHODS: Through a consensus meeting involving surgeons, biostatisticians, and epidemiologists, 30 variables of preoperative information possibly influencing surgeons' choice between LG versus OG and potentially associating with outcomes were identified to enable rigorous estimation of propensity scores. A total of 4235 consecutive patients who underwent gastrectomy for gastric adenocarcinoma were identified and their relevant data were gathered from the participating hospitals. After propensity score matching, 1848 patients (924 each for LG and OG) were selected for comparison of long-term outcomes. RESULTS: In the propensity-matched population, the 5-year overall survival was 96.3% [95% confidence interval (CI) 95.0-97.6] in the OG as compared with 97.1% (95% CI, 95.9-98.3) in LG. The number of all-cause death was 33/924 in the OG and 24/924 in the LG through the entire period, and the hazard ratio (LG/OG) for overall death was 0.75 (95% CI, 0.44-1.27; P = 0.290). The 3-year recurrence-free survival was 97.4% (95% CI, 96.4-98.5) in the OG and 97.7% (95% CI, 96.5-98.8) in the LG. The number of recurrence was 22/924 in the OG and 21/924 in the LG through the entire period, and the hazard ratio was 1.01 (95% CI, 0.55-1.84; P = 0.981). CONCLUSIONS: This observational study adjusted for all-known confounding factors seems to provide strong enough evidence to suggest that LG is oncologically comparable to OG for gastric cancer. PMID- 27115903 TI - On-demand Reporting of Risk-adjusted and Smoothed Rates for Quality Profiling in ACS NSQIP. AB - BACKGROUND: Surgical quality improvement depends on hospitals having accurate and timely information about comparative performance. Profiling accuracy is improved by risk adjustment and shrinkage adjustment to stabilize estimates. These adjustments are included in ACS NSQIP reports, where hospital odds ratios (OR) are estimated using hierarchical models built on contemporaneous data. However, the timeliness of feedback remains an issue. STUDY DESIGN: We describe an alternative, nonhierarchical approach, which yields risk- and shrinkage-adjusted rates. In contrast to our "Traditional" NSQIP method, this approach uses preexisting equations, built on historical data, which permits hospitals to have near immediate access to profiling results. We compared our traditional method to this new "on-demand" approach with respect to outlier determinations, kappa statistics, and correlations between logged OR and standardized rates, for 12 models (4 surgical groups by 3 outcomes). RESULTS: When both methods used the same contemporaneous data, there were similar numbers of hospital outliers and correlations between logged OR and standardized rates were high. However, larger differences were observed when the effect of contemporaneous versus historical data was added to differences in statistical methodology. CONCLUSIONS: The on demand, nonhierarchical approach provides results similar to the traditional hierarchical method and offers immediacy, an "over-time" perspective, application to a broader range of models and data subsets, and reporting of more easily understood rates. Although the nonhierarchical method results are now available "on-demand" in a web-based application, the hierarchical approach has advantages, which support its continued periodic publication as the gold standard for hospital profiling in the program. PMID- 27115907 TI - The possible mechanisms of the human microbiome in allergic diseases. AB - In the present paper, we discuss the importance of the microbiome in allergic disease. In this review paper, the data from the Medline (PubMed) and search engine of Kirikkale University were systematically searched for all relevant articles in June 15th, 2015 for the past 30 years. The keywords of "microbiome", "dysbiosis", "allergy", "allergic rhinitis", "allergic disease", "mechanisms" and "treatment" were used alone or together. In this paper, microbiomes were presented in terms of "Definition", "Influence of ?the human microbiome on health", "The microbiome and allergic diseases", and "Modulation of the gut microbiota in terms of treatment and prevention". Microbiological dysbiosis is also reviewed. The microbiome is the genetic material of all microbes (bacteria, fungi, protozoa, and viruses) that live on or in the human body. Microbes outnumber human cells in a 10:1 ratio. Most microbes live in the gut, particularly the large intestine. Changes in the immune function of the respiratory tract are (at least in theory) linked to the immunomodulatory activity of the gut microbiota via the concept of a "common mucosal response". The gut microbiota shapes systemic immunity, thus affecting the lung mucosa. Alternatively, changes in the gut microbiota may reflect alterations in the oropharyngeal microbiota, which may in turn directly affect the lung microbiota and host immune responses via microaspiration. Dysbiosis is defined as qualitative and quantitative changes in the intestinal flora; and modern diet and lifestyle, antibiotics, psychological and physical stress result in alterations in bacterial metabolism, as well as the overgrowth of potentially pathogenic microorganisms. All immune system components are directly or indirectly regulated by the microbiota. The nature of microbial exposure early in life appears to be important for the development of robust immune regulation; disruption of either the microbiota or the host response can trigger chronic inflammation. Dysbiosis is also an important clinical entity. Antibiotics, psychological and physical stress, and dietary factors contribute to intestinal dysbiosis. PMID- 27115908 TI - "Dry", "moist", and "wet" status of the middle ear in the regeneration of the eardrum. PMID- 27115909 TI - A study of the anterior ethmoidal artery and a new classification of the ethmoid roof (Yenigun classification). AB - Aims of this study are to analyze the association of the anterior ethmoidal artery's (AEA) visualization with variations in its adjacent structures in coronal, axial, and sagittal CT images, to assess its relation with the ethmoid roof, and, based on this relation, to introduce a new classification for the ethmoid roof. A retrospective, cross-sectional study was performed in a tertiary referral center. In this retrospective, cross-sectional study, the coronal, axial, and sagittal CTs of 184 patients have been surveyed and the AEA canal, the ethmoid roof, and their relations with surrounding structures have been assessed. The Keros classification used to measure the depth of the lateral lamella of the cribriform plate (LLCP) in the ethmoid roof has been modified to include anterior posterior length of the LLCP. It was shown that the visualization of the AEA canal increases in a statistically significant manner with an increase in the superior-inferior depth and the anterior-posterior length of the LLCP bilaterally. In the presence of supraorbital pneumatization, AEA visualization was shown to increase bilaterally significantly. This study demonstrated a positive correlation between the AEA canal, the LLCP superior-inferior depth, and the anterior-posterior length. It was shown that with the increased depth and length of the LLCP and in the presence of supraorbital pneumatization, the visualization of the artery and hence the injury risks are increased. The LLCP anterior-posterior length is as clinically relevant as is its depth, and a radiologic classification has been defined according to the anterior-posterior length of the LLCP. PMID- 27115912 TI - Capillary wave Hamiltonian for the Landau-Ginzburg-Wilson density functional. AB - We study the link between the density functional (DF) formalism and the capillary wave theory (CWT) for liquid surfaces, focused on the Landau-Ginzburg-Wilson (LGW) model, or square gradient DF expansion, with a symmetric double parabola free energy, which has been extensively used in theoretical studies of this problem. We show the equivalence between the non-local DF results of Parry and coworkers and the direct evaluation of the mean square fluctuations of the intrinsic surface, as is done in the intrinsic sampling method for computer simulations. The definition of effective wave-vector dependent surface tensions is reviewed and we obtain new proposals for the LGW model. The surface weight proposed by Blokhuis and the surface mode analysis proposed by Stecki provide consistent and optimal effective definitions for the extended CWT Hamiltonian associated to the DF model. A non-local, or coarse-grained, definition of the intrinsic surface provides the missing element to get the mesoscopic surface Hamiltonian from the molecular DF description, as had been proposed a long time ago by Dietrich and coworkers. PMID- 27115910 TI - Persistent Microstructural Deficits of Internal Capsule in One-Year Abstinent Male Methamphetamine Users: a Longitudinal Diffusion Tensor Imaging Study. AB - White matter (WM) alterations have been reported in methamphetamine (MA) users. However, knowledge about longitudinal changes in WM during abstinence from MA remains unknown. The present study aimed to examine how WM changes in long-term MA abstinent, in particular, whether the WM deficits would recover as the duration of abstinence extended. Twenty male MA dependent individuals and 19 healthy controls (HCs) were recruited and participated in both clinical assessments and diffusion tensor imaging (DTI) scans. The MA group underwent two DTI scans, a baseline scan with a duration of abstinence of 6.4 months and and a follow-up scan with a duration of abstinence of 13.0 months. Tract-Based Spatial Statistics was utilized to conduct baseline DTI analysis of MA group compared with HCs. The clusters with significant group differences of factional anisotropy (FA) were extracted as region of interests (ROIs). Mean values of DTI measurements (FA, mean diffusivity, axial diffusivity and radial diffusivity) were calculated within the ROIs in each subject's native space at baseline and follow-up. The MA group showed significant lower FA in the right internal capsule and superior corona radiate than HCs. The deficits did not recover when the duration of abstinence from MA reached 13 months. No significant correlations were found between FA and clinical measurements. Our results suggested persistent microstructure deficits of WM tracts surrounding the basal ganglia in MA dependent individuals. PMID- 27115911 TI - Child Homicide: A Global Public Health Concern. AB - In this perspective, Delan Devakumar and David Osrin discuss Abrahams and colleagues' findings in the context of evidence about child homicide in different countries, and consider etiology along with implications for child protection and prevention. PMID- 27115913 TI - Superwettability-Induced Confined Reaction toward High-Performance Flexible Electrodes. AB - To find a general strategy to realize confinement of the conductive layer for high-performance flexible electrodes, with improved interfacial adhesion and high conductivity, is of important scientific significance. In this work, superwettability-induced confined reaction is used to fabricate high-performance flexible Ag/polymer electrodes, showing significantly improved silver conversion efficiency and interfacial adhesion. The as-prepared flexible electrodes by superhydrophilic polymeric surface under oil are highly conductive with an order of magnitude higher than the Ag/polymer electrodes obtained from original polymeric surface. The high conductivity achieved via superhydrophilic confinement is ascribed to the fact that the superhydrophilic polymeric surface can enhance the reaction rate of silver deposition and reduce the size of silver nanoparticles to achieve the densest packing. This new approach will provide a simple method to fabricate flexible and highly conductive Ag/polymer electrodes with excellent adhesion between the conductive layer and the substrate, and can be extended to other metal/polymeric electrodes or alloy/polymeric electrodes. PMID- 27115914 TI - Effectiveness of Emergency Department Based Palliative Care for Adults with Advanced Disease: A Systematic Review. AB - BACKGROUND: Emergency departments (EDs) are seeing more patients with palliative care (PC) needs, but evidence on best practice is scarce. OBJECTIVES: To examine the effectiveness of ED-based PC interventions on hospital admissions (primary outcome), length of stay (LOS), symptoms, quality of life, use of other health care services, and PC referrals for adults with advanced disease. METHODS: We searched five databases until August 2014, checked reference lists/conference abstracts, and contacted experts. Eligible studies were controlled trials, pre post studies, cohort studies, and case series reporting outcomes of ED-based PC. RESULTS: Five studies with 4374 participants were included: three case series and two cohort studies. Interventions included a screening tool, traditional ED-PC, and integrated ED-PC. Two studies reported on hospital admissions: in one study there was no statistically significant difference in 90-day readmission rates between patients who initiated integrated PC at the ED (11/50 patients, 22%) compared to those who initiated PC after hospital admission (179/1385, 13%); another study showed a high admission rate (90%) in 14 months following ED-PC, but without comparison. One study showed an LOS reduction (mean 4.32 days in ED initiated PC group versus 8.29 days in postadmission-initiated group; p < 0.01). There was scarce evidence on other outcomes except for conflicting findings on survival: in one study, ED-PC patients were more likely to experience an interval between ED presentation and death >9 hours (OR 2.75, 95% CI 2.21-3.41); another study showed increased mortality risk in the intervention group; and a case series described a higher in-hospital death rate when PC was ED-initiated (62%), compared to ward (16%) or ICU (50%) (unknown p-value). CONCLUSIONS: There is yet no evidence that ED-based PC affects patient outcomes except for indication from one study of no association with 90-day hospital readmission but a possible reduction in LOS if integrated PC is introduced early at ED rather than after hospital admission. There is an urgent need for trials to confirm these findings alongside other potential benefits and survival effects. PMID- 27115918 TI - Acidity of Strong Acids in Water and Dimethyl Sulfoxide. AB - Careful analysis and comparison of the available acidity data of HCl, HBr, HI, HClO4, and CF3SO3H in water, dimethyl sulfoxide (DMSO), and gas-phase has been carried out. The data include experimental and computational pKa and gas-phase acidity data from the literature, as well as high-level computations using different approaches (including the W1 theory) carried out in this work. As a result of the analysis, for every acid in every medium, a recommended acidity value is presented. In some cases, the currently accepted pKa values were revised by more than 10 orders of magnitude. PMID- 27115915 TI - Racial isolation and exposure to airborne particulate matter and ozone in understudied US populations: Environmental justice applications of downscaled numerical model output. AB - BACKGROUND: Researchers and policymakers are increasingly focused on combined exposures to social and environmental stressors, especially given how often these stressors tend to co-locate. Such exposures are equally relevant in urban and rural areas and may accrue disproportionately to particular communities or specific subpopulations. OBJECTIVES: To estimate relationships between racial isolation (RI), a measure of the extent to which minority racial/ethnic group members are exposed to only one another, and long-term particulate matter with an aerodynamic diameter of <2.5MU (PM2.5) and ozone (O3) levels in urban and nonurban areas of the eastern two-thirds of the US. METHODS: Long-term (5year average) census tract-level PM2.5 and O3 concentrations were calculated using output from a downscaler model (2002-2006). The downscaler uses a linear regression with additive and multiplicative bias coefficients to relate ambient monitoring data with gridded output from the Community Multi-scale Air Quality (CMAQ) model. A local, spatial measure of RI was calculated at the tract level, and tracts were classified by urbanicity, RI, and geographic region. We examined differences in estimated pollutant exposures by RI, urbanicity, and demographic subgroup (e.g., race/ethnicity, education, socioeconomic status, age), and used linear models to estimate associations between RI and air pollution levels in urban, suburban, and rural tracts. RESULTS: High RI tracts (>=80th percentile) had higher average PM2.5 levels in each category of urbanicity compared to low RI tracts (<20th percentile), with the exception of the rural West. Patterns in O3 levels by urbanicity and RI differed by region. Linear models indicated that PM2.5 concentrations were significantly and positively associated with RI. The largest association between PM2.5 and RI was observed in the rural Midwest, where a one quintile increase in RI was associated with a 0.90MUg/m(3) (95% confidence interval: 0.83, 0.99MUg/m(3)) increase in PM2.5 concentration. Associations between O3 and RI in the Northeast, Midwest and West were positive and highest in suburban and rural tracts, even after controlling for potential confounders such as percentage in poverty. CONCLUSION: RI is associated with higher 5year estimated PM2.5 concentrations in urban, suburban, and rural census tracts, adding to evidence that segregation is broadly associated with disparate air pollution exposures. Disproportionate burdens to adverse exposures such as air pollution may be a pathway to racial/ethnic disparities in health. PMID- 27115917 TI - Plasmonic gold nanodiscs fabricated into a photonic-crystal nanocavity. AB - We fabricate and characterise an optical structure consisting of a photonic crystal L3 nanocavity containing two gold nanodisks placed close to a field antinode. We use finite difference time domain (FDTD) modelling to show that the optical properties of the nanocavity are sensitive to the physical separation between the gold nanodisks, and that at reduced separation, the q-factor of a cavity mode polarised parallel to the dimer long-axis is reduced, indicating coupling between the cavity mode and a localised plasmon. Preliminary experimental measurements indeed indicate a damping of the cavity mode in the presence of the dimer; a result consistent with the FDTD modelling. Such a scheme may be used to integrate plasmonic systems into all-optical photonic circuits. PMID- 27115916 TI - Mechanistic polychlorinated biphenyl exposure modeling of mothers in the Canadian Arctic: the challenge of reliably establishing dietary composition. AB - BACKGROUND: Traditional food (TF) consumption represents the main route of persistent organic pollutant (POP) exposure for indigenous Arctic Canadians. Ongoing dietary transitions away from TFs and toward imported foods (IFs) may contribute to decreasing POP exposures observed in these groups. METHODS: To explore this issue, we combined the global fate and transport model GloboPOP and the human food chain bioaccumulation model ACC-Human Arctic to simulate polychlorinated biphenyl (PCB) exposure in two indigenous Arctic Canadian communities from the Inuvik region, Northwest Territories and Baffin region, Nunavut. Using dietary survey information from initial (1996-98) and follow-up (2005-07) biomonitoring campaigns in Inuvik and Baffin, we simulated PCB exposures (PCB-118, -138, -153, and -180) for each individual study participant and also whole study populations. RESULTS: TF intake rates, particularly of marine mammals (MMs), were the most important predictors of modeled PCB exposure, while TF consumption did not associate consistently with measured PCB exposures. Further, reported mean TF intake increased from baseline to follow-up in both Inuvik (from 8 to 183gd(-1)) and Baffin (from 60 to 134gd(-1)), opposing both the expected dietary transition direction and the observed decrease in human PCB exposures in these communities (SigmaPCB Inuvik: from 43 to 29ngglipid(-1), SigmaPCB Baffin: from 213 to 82ngglipid(-1)). However dietary questionnaire data are frequently subject to numerous biases (e.g., recall, recency, confirmation), and thus casts doubt on the usefulness of these data. CONCLUSIONS: Ultimately, our model's capability to reproduce historic PCB exposure data in these two groups was highly sensitive to TF intake, further underscoring the importance of accurate TF consumption reporting, and clarification of the role of dietary transitions in future POP biomonitoring of indigenous Arctic populations. PMID- 27115920 TI - A new clinical sign or just fancy apparel? Determining the significance of a skirt. PMID- 27115919 TI - Diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: finding a needle in a haystack. PMID- 27115926 TI - French comment on article: Prospective evaluation of bacteremia rates and infectious complications among patients undergoing single-operator choledochoscopy during ERCP. PMID- 27115922 TI - Use of the patency capsule in daily practice. PMID- 27115923 TI - Reply to Cebrian et al. PMID- 27115921 TI - Laterally spreading tumor through the magnifying glass: we only see what we know. PMID- 27115933 TI - Video Comment on Forde et al. PMID- 27115930 TI - French comment on article: Endoscopic predictors of deep submucosal invasion in colorectal laterally spreading tumors. PMID- 27115932 TI - Video Comment on Osera et al. PMID- 27115929 TI - French comment on article: Clinicopathological, endoscopic, and molecular characteristics of the "skirt" - a new entity of lesions at the margin of laterally spreading tumors. PMID- 27115934 TI - Video Comment on Gourcerol et al. PMID- 27115931 TI - French comment on article: Endoscopic resection of subtotal or completely circumferential laterally spreading colonic adenomas: technique, caveats, and outcomes. PMID- 27115927 TI - French comment on article: Screening primary sclerosing cholangitis and biliary dysplasia with endoscopic retrograde cholangiography and brush cytology: risk factors for biliary neoplasia. PMID- 27115936 TI - Laryngeal Tube Practice in a Metropolitan Ambulance Service: A Five-year Retrospective Observational Study (2009-2013). AB - BACKGROUND: The endotracheal tube (ETT) is considered the gold standard in emergency airway management, although supraglottic airway devices, especially the laryngeal tube (LT), have recently gained in importance. Although regarded as an emergency device in case of failure of endotracheal intubation in most systems, we investigated the dynamics of the use of the LT in a metropolitan ambulance service without any regulations on the choice of airway device. METHODS: A retrospective, observational study on all patients from the Municipal Ambulance Service, Vienna in need of advanced airway management over a 5-year period. Differences between years were compared; influencing factors for the use of the LT were analyzed using multivariable logistic regression. RESULTS: In total 5,175 patients (mean age 62 +/- 20 years, 36.6% female) underwent advanced airway management. Of these, 15.6% received the LT. LT use increased from 20 out of 1,001 (2.0%) in 2009 to 292 of 1,085 (26.9%) in 2013 (p < 0.001). The increase between each consecutive year was also significant. Paramedics more frequently inserted the LT than physicians (RR 1.80 (95%CI 1.48-2.16); p < 0.001). Female patients received a LT less frequently (RR 0.84 (95%CI 0.72-0.97), p = 0.013). There was no difference regarding airway device due to underlying causes requiring airway management and no relationship to the NACA-score. CONCLUSION: In a European EMS system of physician and paramedic response, the proportion of airway managed by LT over ETT rose considerably over five years. Although the ET is still the gold standard, the LT is gaining in importance for EMS physicians and paramedics. PMID- 27115937 TI - Benefits and perspectives on the use of biofuels. PMID- 27115938 TI - Increasing uranium exposure durations to the aquatic snail Amerianna cumingi does not result in lower toxicity estimates. AB - Reproductive inhibition (egg production) of the aquatic snail Amerianna cumingi over 4 d has been used to derive toxicity estimates for toxicants of concern in tropical Australia. Toxicity estimates from this test have been used as chronic data points in species sensitivity distributions (SSDs) for deriving site specific guideline values. However, revised guidance for the Australian and New Zealand Water Quality Guidelines advises that test durations for adult macroinvertebrates should be >=14 d to be considered chronic. Hence, to strengthen the data set underpinning the site-specific guideline value for uranium (U) in Magela Creek, which receives water from the Ranger Uranium Mine in northern Australia, the toxicity of U to A. cumingi was compared after 4 d, 9 d, and 14 d. Daily U concentrations were measured because of expected U loss during testing, providing extensive chemical analyses of the U exposure during the toxicity tests. Comparison of the U concentrations causing 50% reproductive inhibition (IC50) after 4 d, 9 d, and 14 d showed no difference in toxicity (4 d IC50 = 161 MUg L-1 , confidence interval = 133-195; 9-d IC50 = 151 MUg L-1 , confidence interval = 127-180; 14-d IC50 = 153 MUg L-1 , confidence interval = 29 180). The present study provides evidence that test durations of <14 d are suitable for assessing chronic toxicity to U for this species and supports the use of the 4-d toxicity estimate in the SSD for U. Environ Toxicol Chem 2016;35:2851-2858. (c) 2016 Commonwealth of Australia. PMID- 27115940 TI - PSYCHOLOGIES OF SMALL DIFFERENCES. PMID- 27115928 TI - French comment on article: Long-term outcomes of covered self-expandable metal stents for treating benign biliary strictures. PMID- 27115939 TI - COMMENTARY ON DE JONGH ET AL. (2016) CRITIQUE OF ISTSS COMPLEX PTSD GUIDELINES: FINDING THE WAY FORWARD. PMID- 27115941 TI - Determination of Organic Partitioning Coefficients in Water-Supercritical CO2 Systems by Simultaneous in Situ UV and Near-Infrared Spectroscopies. AB - CO2 injected into depleted oil or gas reservoirs for long-term storage has the potential to mobilize organic compounds and distribute them between sediments and reservoir brines. Understanding this process is important when considering health and environmental risks, but little quantitative data currently exists on the partitioning of organics between supercritical CO2 and water. In this work, a high-pressure, in situ measurement capability was developed to assess the distribution of organics between CO2 and water at conditions relevant to deep underground storage of CO2. The apparatus consists of a titanium reactor with quartz windows, near-infrared and UV spectroscopic detectors, and switching valves that facilitate quantitative injection of organic reagents into the pressurized reactor. To demonstrate the utility of the system, partitioning coefficients were determined for benzene in water/supercritical CO2 over the range 35-65 degrees C and approximately 25-150 bar. Density changes in the CO2 phase with increasing pressure were shown to have dramatic impacts on benzene's partitioning behavior. Our partitioning coefficients were approximately 5-15 times lower than values previously determined by ex situ techniques that are prone to sampling losses. The in situ methodology reported here could be applied to quantify the distribution behavior of a wide range of organic compounds that may be present in geologic CO2 storage scenarios. PMID- 27115942 TI - A Word from the Scientific Committee. 14th Gordon L. Snider Critical Issues Workshop. PMID- 27115943 TI - Chairman's Summary: Can Cystic Fibrosis and Alpha-1 Antitrypsin Deficiency Inform Chronic Obstructive Pulmonary Disease? PMID- 27115944 TI - Computed Tomography-based Subclassification of Chronic Obstructive Pulmonary Disease. AB - Computed tomography (CT) is an obvious modality for subclassification of COPD. Traditionally, the pulmonary involvement of chronic obstructive pulmonary disease (COPD) in smokers is understood as a combination of deleterious effects of smoking on small airways (chronic bronchitis and small airways disease) and distal to the airways with destruction and loss of lung parenchyma (emphysema). However, segmentation of airways is still experimental; with contemporary high resolution CT (HRCT) we can just see the "entrance" of small airways, and until now changes in airway morphology that have been observed in COPD are subtle. Furthermore, recent results indicate that emphysema may also be the essential pathophysiologic mechanism behind the airflow limitation of COPD. The definition of COPD excludes bronchiectasis as a symptomatic subtype of COPD, and CT findings in chronic bronchitis and exacerbations of COPD are rather unspecific. This leaves emphysema as the most obvious candidate for subclassification of COPD. Both chest radiologists and pulmonary physicians are quite familiar with the appearance of various patterns of emphysema on HRCT, such as centrilobular, panlobular, and paraseptal emphysema. However, it has not yet been possible to develop operational definitions of these patterns that can be used by computer software to automatically classify CT scans into distinct patterns. In conclusion, even though various emphysema patterns can be recognized visually, CT has not yet demonstrated a great potential for automated subclassification of COPD, and it is an open question whether it will ever be possible to achieve success equivalent to that obtained by HRCT in the area of interstitial lung diseases. PMID- 27115945 TI - Pulmonary Physiology of Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Alpha-1 Antitrypsin Deficiency. AB - Cystic fibrosis is predominantly an airway disease with marked bronchiectatic changes associated with inflammation, chronic colonization, and progressive airflow obstruction. The condition can be identified in childhood and monitored with detectable airway changes early in life while conventional spirometry remains in the normal range. Alpha-1 antitrypsin deficiency can also be detected early in life through blood spot and genetic testing and leads (in some) to the development of airflow obstruction and a predominant emphysema phenotype with bronchiectatic changes in about 30%. Early detection also allows the natural history of the pulmonary physiological changes to be determined. Chronic obstructive pulmonary disease is usually detected late in the disease process when significant damage has occurred. The condition consists of varying combinations of airway disease, bronchiectasis, colonization, and emphysema. Lessons learned from the physiological evolution of airway disease in cystic fibrosis and the emphysema of alpha-1 antitrypsin deficiency provide strategies to enable early detection of chronic obstructive pulmonary disease in general and its phenotypes. PMID- 27115946 TI - Neutrophil Fates in Bronchiectasis and Alpha-1 Antitrypsin Deficiency. AB - The neutrophil is a powerful cellular defender of the vulnerable interface between the environment and pulmonary tissues. This cell's potent weapons are carefully calibrated in the healthy state to maximize effectiveness in fighting pathogens while minimizing tissue damage and allowing for repair of what damage does occur. The three related chronic airway disorders of cystic fibrosis, non cystic fibrosis bronchiectasis, and alpha-1 antitrypsin deficiency all demonstrate significant derangements of this homeostatic system that result in their respective pathologies. An important shared feature among them is the inefficient resolution of chronic inflammation that serves as a central means for neutrophil-driven lung damage resulting in disease progression. Examining the commonalities and divergences between these diseases in the light of their immunopathology is informative and may help guide us toward future therapeutics designed to modulate the neutrophil's interplay with the pulmonary environment. PMID- 27115947 TI - Does Protease-Antiprotease Imbalance Explain Chronic Obstructive Pulmonary Disease? AB - Chronic obstructive pulmonary disease (COPD) is defined as airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with the inhalation of noxious gases, typically cigarette smoke. The protease-antiprotease paradigm suggests that the pathogenesis of COPD and emphysema is the result of an imbalance between enzymes that degrade the extracellular matrix within the lung and proteins that oppose this proteolytic activity. This review assesses the genetic evidence in support of protease antiprotease imbalance in the pathogenesis of COPD. It also articulates why suppression of protease activity in alpha-1 antitrypsin deficiency may be insufficient to prevent the progression of COPD. Rather, alpha-1 antitrypsin deficiency may be better treated by small-molecules so reads molecules, RNA silencing, and other strategies that target the protein misfolding and polymerization that cause the disease. PMID- 27115948 TI - The Unfolded Protein Response in Chronic Obstructive Pulmonary Disease. AB - Accumulation of nonfunctional and potentially cytotoxic, misfolded proteins in chronic obstructive pulmonary disease (COPD) is believed to contribute to lung cell apoptosis, inflammation, and autophagy. Because of its fundamental role as a quality control system in protein metabolism, the "unfolded protein response" (UPR) is of potential importance in the pathogenesis of COPD. The UPR comprises a series of transcriptional, translational, and post-translational processes that decrease protein synthesis while enhancing protein folding capacity and protein degradation. Several studies have suggested that the UPR contributes to lung cell apoptosis and lung inflammation in at least some subjects with human COPD. However, information on the prevalence of the UPR in subjects with COPD, the lung cells that manifest a UPR, and the role of the UPR in the pathogenesis of COPD is extremely limited and requires additional study. PMID- 27115949 TI - Alpha-1 Antitrypsin and Lung Cell Apoptosis. AB - Discovery of alpha-1 antitrypsin (A1AT) as the principal circulating inhibitor of neutrophil elastase was critical to the appreciation of protease/antiprotease imbalance involvement in the pathogenesis of emphysema. Additional targets of A1AT have been uncovered, along with their contribution to alveolar wall destruction induced by cigarette smoke exposure. We highlight in this report mechanisms of A1AT antiapoptotic effects on structural lung endothelial cells. This function was largely dependent on uptake of the protein from the circulation via clathrin- and, in part, caveolae-mediated endocytosis and on specific interactions with cysteine proteases such as capsase-3, -6, and -7. Exposures to cigarette smoke diminished A1AT intracellular uptake and its anticaspase action, suggesting that even in A1AT-suficient individuals, cigarette smoke may weaken the serpin's endothelial prosurvival effect. In addition, cigarette smoke exposure or genetic mutations known to induce posttranslational modifications such as oxidation or polymerization may alter A1AT bidirectional intracellular traffic in endothelial cells and thus determine its functional bioavailability in certain lung compartments. Uncovering and harnessing the A1AT canonical and noncanonical mechanisms will advance our understanding of the pathogenesis of emphysema and may provide means to improve the effectiveness of therapies in both A1AT-sufficient and A1AT-deficient individuals. PMID- 27115950 TI - Cystic Fibrosis Transmembrane Conductance Regulator. Implications in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease. AB - Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) have traditionally been viewed as two distinct entities of unrelated origins. However, molecular, cellular, and clinical studies have revealed that cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction is common to both conditions, one (CF) being defined genetically and the other (COPD) as an acquired CFTR deficiency. Multiple molecular mechanisms of cigarette smoke induced CFTR dysfunction have been reported. More importantly, considerable evidence of cigarette smoke-induced CFTR dysfunction in several respiratory and nonrespiratory tissues have been confirmed, making CFTR a target that cannot be overlooked in our quest to understand COPD and improve therapies for individuals affected by this disease. This review summarizes the molecular, cellular, and clinical evidence that CFTR dysfunction is induced by cigarette smoke exposure both in vitro and in vivo, and explores how this may contribute to the development of COPD. PMID- 27115951 TI - Mucus Hyperconcentration as a Unifying Aspect of the Chronic Bronchitic Phenotype. AB - Abnormalities in mucus production and qualitative properties such as mucus hydration are central to the pathophysiology of airway disease including cystic fibrosis, asthma, and chronic bronchitis. In vitro air-liquid interface epithelial cell cultures demonstrate direct relationships between mucociliary transport, periciliary liquid (PCL) height, and mucus concentration (expressed as percent solids or partial osmotic pressure). In health, the osmotic modulus/pressure of the PCL exceeds that of the mucus layer, resulting in efficient, low-friction movement of mucus. In disease, through multiple mechanisms, the osmotic pressure of the mucus begins to exceed basal PCL values, resulting in compression of the cilia and slowing of mucus transport. The in vivo data in both cystic fibrosis and chronic bronchitis parallel in vitro data demonstrating that when mucus osmotic pressure is increased, mucociliary clearance is decreased. In chronic bronchitis, there is a direct correlation between FEV1 and percent solids of mucus, demonstrating a strong relationship between disease progression and mucus abnormalities. Animal models, based mechanistically on raised sodium absorption (and therefore water absorption) from airway surfaces, mimic the pathophysiology of chronic obstructive pulmonary disease. Collectively, these data suggest the importance of mucus concentration in the pathogenesis of airway disease. It is important to understand the precise mechanisms that result in mucus hyperconcentration, for example, mucin overproduction versus abnormal regulation of ion/water transport, which may be unique to and characteristic of each disease phenotype. The measurement of mucus concentration may be a simple method to diagnose chronic bronchitis, monitor its progression, and serve as a biomarker for development of new therapies. PMID- 27115952 TI - Airway Hydration, Apical K(+) Secretion, and the Large-Conductance, Ca(2+) activated and Voltage-dependent Potassium (BK) Channel. AB - Large-conductance, calcium-activated, and voltage-gated K(+) (BK) channels are expressed in many tissues of the human body, where they play important roles in signaling not only in excitable but also in nonexcitable cells. Because BK channel properties are rendered in part by their association with four beta and four gamma subunits, their channel function can differ drastically, depending on in which cellular system they are expressed. Recent studies verify the importance of apically expressed BK channels for airway surface liquid homeostasis and therefore of their significant role in mucociliary clearance. Here, we review evidence that inflammatory cytokines, which contribute to airway diseases, can lead to reduced BK activity via a functional down-regulation of the gamma regulatory subunit LRRC26. Therefore, manipulation of LRRC26 and pharmacological opening of BK channels represent two novel concepts of targeting epithelial dysfunction in inflammatory airway diseases. PMID- 27115954 TI - Unplugging Mucus in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease. AB - Airway mucus obstruction is a key feature of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The thin layer of mucus that covers healthy airway surfaces has important protective functions in lung defense. However, excess mucus produces airflow obstruction and provides a nidus for bacterial infection and inflammation. Despite its importance in pathogenesis, understanding of the mechanisms underlying airway mucus obstruction, as well as therapeutic options, remain limited. Studies in the rare genetic disease CF identified airway surface dehydration due to cystic fibrosis transmembrane conductance regulator (CFTR) gene dysfunction as an important disease mechanism that may explain mucus stasis and plugging in a spectrum of muco-obstructive lung diseases, including COPD. This concept is supported by the phenotype of the beta-epithelial Na(+) channel-transgenic mouse that exhibits airway surface dehydration and develops a spontaneous lung disease that shares key features with CF and COPD, such as airway mucus plugging, chronic neutrophilic inflammation, and structural lung damage. Furthermore, preclinical testing demonstrated that hydration strategies, including osmotically active hypertonic saline and preventive inhibition of the amiloride-sensitive epithelial Na(+) channel are effective in unplugging airways in this mouse model of chronic obstructive lung disease. On the other hand, genetic deletion of neutrophil elastase, a potent stimulus for mucus hypersecretion, reduced goblet cell metaplasia and mucin expression but had no effect on mucus obstruction in vivo. Collectively, these studies demonstrate that airway surface dehydration is sufficient to produce mucus obstruction even in the absence of mucus hypersecretion and support further clinical testing of hydrating agents as a promising therapeutic strategy to unplug mucus in CF and COPD. PMID- 27115953 TI - Therapeutic Approaches to Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Chronic Bronchitis. AB - Chronic obstructive pulmonary disease is a common cause of morbidity and a rising cause of mortality worldwide. Its rising impact indicates the ongoing unmet need for novel and effective therapies. Previous work has established a pathophysiological link between the chronic bronchitis phenotype of chronic obstructive pulmonary disease and cystic fibrosis as well as phenotypic similarities between these two airways diseases. An extensive body of evidence has established that cigarette smoke and its constituents contribute to acquired dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways, pointing to a mechanistic link with smoking-related and chronic bronchitis. Recent interest surrounding new drugs that target both mutant and wild-type CFTR channels has paved the way for a new treatment opportunity addressing the mucus defect in chronic bronchitis. We review the clinical and pathologic evidence for modulating CFTR to address acquired CFTR dysfunction and pragmatic issues surrounding clinical trials as well as a discussion of other ion channels that may represent alternative therapeutic targets. PMID- 27115955 TI - Hydrator Therapies for Chronic Bronchitis. Lessons from Cystic Fibrosis. AB - Patients with the chronic bronchitis form of chronic obstructive pulmonary disease and cystic fibrosis share similar clinical features, including mucus obstruction of airways and the development of chronic/recurrent airways infections that often manifest as disease exacerbations. There is growing evidence that these diseases may have parallels in disease pathogenesis as well, including cystic fibrosis transmembrane conductance regulator dysfunction, mucus dehydration, and defective mucociliary clearance. As progress is made in the development of therapies that target the basic defects that lead to cystic fibrosis lung disease, it is possible that similar approaches could also benefit patients with chronic bronchitis. A deeper understanding of how tobacco smoke and other triggers of chronic bronchitis actually lead to disease, and exploration of the concept that therapies that restore cystic fibrosis transmembrane conductance regulator function, mucus hydration, and/or mucociliary clearance may benefit patients with chronic bronchitis, hold the prospect of significant progress in treating this prevalent disease. PMID- 27115956 TI - Alpha-1 Antitrypsin Therapy in Cystic Fibrosis and the Lung Disease Associated with Alpha-1 Antitrypsin Deficiency. AB - Cystic fibrosis and alpha-1 antitrypsin (AAT) deficiency are two of the commonest lethal hereditary lung diseases affecting white individuals. Although having quite different phenotypic extrapulmonary presentations, the lung disease associated with these conditions is exemplified by a neutrophil-dominated inflammation in which neutrophil elastase plays a major role. In AAT deficiency the diminution of the anti-neutrophil elastase protection, due to diminished AAT levels in the lung, predisposes the lung to an unopposed neutrophil elastase attack, whereas, in cystic fibrosis, the levels of AAT and other antiproteases are normal, but the neutrophil elastase burden is so large that it overwhelms the normal anti-neutrophil elastase protection. With this as background, it seems logical to augment the anti-neutrophil elastase defenses of the lung in both conditions using exogenous AAT. The type of AAT, the route of administration, and the physiologic, radiologic, and clinical readouts for this type of therapy are discussed, along with the similarities and differences between the two conditions and their responses to AAT therapy. PMID- 27115957 TI - Beat diabetes: an urgent call for global action. PMID- 27115958 TI - Bangladesh's rural water scandal. PMID- 27115959 TI - UK PrEP decision re-ignites HIV activism. PMID- 27115960 TI - Bipolar disorders: key clinical considerations. PMID- 27115961 TI - The Notes: encounters with medicine. PMID- 27115963 TI - Recovery efforts in Flint slowly begin to take form. PMID- 27115964 TI - Medical education and regulation in the spotlight in India. PMID- 27115965 TI - Profile: Liverpool School of Tropical Medicine, UK. PMID- 27115966 TI - Applause. PMID- 27115968 TI - Majid Ezzati: a positive enthusiasm for global health. PMID- 27115969 TI - Willard Cates, Jr. PMID- 27115970 TI - HIV moments and pre-exposure prophylaxis. PMID- 27115971 TI - HIV moments and pre-exposure prophylaxis--Authors' reply. PMID- 27115972 TI - Refusal to provide health care to people with HIV in France. PMID- 27115973 TI - Changes in the primary outcome in Ebola vaccine trial. PMID- 27115974 TI - Changes in the primary outcome in Ebola vaccine trial--Authors' reply. PMID- 27115975 TI - REGULATE-PCI trial--Author's reply. PMID- 27115976 TI - REGULATE-PCI trial. PMID- 27115977 TI - Organ donation during the financial crisis in Greece. PMID- 27115978 TI - Are doctors in training being trained? PMID- 27115979 TI - Autologous dermal graft combined with a modified degloving procedure for penile augmentation in young adults: a preliminary study. AB - In order to evaluate the effect of penile enhancement, we retrospectively reviewed the data of the patients operated with autologous dermal graft implantation combined with a modified penile degloving procedure. The patients with the complaints of small penis, asking for penile augmentation, and normal erectile function were psychologically screened and enrolled. Data of follow-up visit including patient demographics, medical history, surgical procedure, patient-reported outcomes were analysed. In all, 30 eligible persons were operated. After degloving of the penis, the suspensory ligament was incised and the tunica albuginea was fixed to the proximal tunica dartos at the penile base. Then, the dermis graft was implanted on the dorsal surface of the tunica albuginea. The file of follow-up visit was available in 17 (57%) patients. The mean age was 23.7 years (19-35 years) and the mean follow-up was 13 months (range, 4-24 months). During the follow-up period, the average gain in the penis length was 2.7 cm in flaccid and 0.8 cm in erection, respectively. And the average gain in the penis circumference was 1.5 cm in flaccid and 1.2 cm in erection, respectively. Also, psychosexual sexual self-esteem and confidence of the patients were significantly improved (p < 0.001). Overall, 13 (76%) patients reported satisfaction with the penile appearance. We believe that the surgery is both safe and effective in the enhancement of the penis, however, further clinical studies with a larger patient population are necessary. PMID- 27115980 TI - Severe neck scarring: A consequence of fractional CO2 laser resurfacing. AB - Fractional CO2 laser resurfacing using aggressive treatment parameters may result in adverse effects comparable to those of fully ablative CO2 laser resurfacing. A 45-year-old female underwent fractional CO2 laser treatment of the neck. She contacted the author for treatment of the marked erythema, swelling, and perceived skin tightness that resulted from the resurfacing procedure. This case report describes how the author treated these complications, provides a plausible explanation for why they occurred, and recommends treatment modifications to minimize the risk of their occurrence. PMID- 27115981 TI - Delays in Seeking Health Care: Comparison of Veterans and the General Population. AB - OBJECTIVES: Recent reports of delays in receiving care among U.S. Veterans have received national attention. Such delays may have an effect on veterans' propensity to seek healthcare as well, which could be detrimental to their health. There exists no evidence at the national level of the magnitude of perceived care delay in the Veterans Affairs (VA) system and how it compares to populations with other types of insurance coverage in the U.S. STUDY DESIGN AND METHODS: This cross-sectional study analyzed a recent nationally representative survey database (n = 10,907). Descriptive and multivariate regression analyses were performed to determine how care delay for veterans compares with the general population. RESULTS: We found that 17.2% of Americans delayed seeking needed healthcare in 2010-2011, but the figure was 29% for veterans. Also, there was a significant association of care delay with VA health care coverage after adjusting for other personal factors and region of the country. CONCLUSIONS: Study results suggest a possible link between VA access problems and veterans' behavior in seeking needed healthcare, which may be creating disparities in the effectiveness of care for this vulnerable and deserving population. Our study provides evidence of self-reported care delay among veterans. More studies are necessary to further understand factors in relation to delaying seeking care among veterans. PMID- 27115984 TI - Characterization of Cysteinylation and Trisulfide Bonds in a Recombinant Monoclonal Antibody. AB - A recombinant monoclonal antibody with trisulfide bonds and cysteinylation was thoroughly characterized in the current study. Trisulfide bonds and cysteinylation were first detected when the recombinant monoclonal antibody was analyzed by LC-MS to determine the molecular weights of the intact antibody and its F(ab')2 fragment generated from IdeS digestion. LC-MS analysis of nonreduced tryptic peptides indicated trisulfide bonds are associated with the interchain disulfide bonds of both A isoform and A/B isoform and cysteinylation is associated only with the A isoform. A low percentage of trisulfide bonds was detected in between the light chain and heavy chain disulfide bond of the A and A/B forms. While the majority of trisulfide bonds and cysteinylation is associated with the hinge region peptide that involves the four closely spaced cysteine residues of the heavy chain. The locations of trisulfide bond and cysteinylation were determined using a combination of Edman sequencing and LC-MS. In the A isoform, the major site of the trisulfide bond and cysteinylation is between the first disulfide bond in the hinge region. In the A/B isoform, the trisulfide was also located in between the disulfide bond that is formed by the second pair of cysteine residues. PMID- 27115985 TI - Singly Bonded Monoadduct rather than Methanofullerene: Manipulating the Addition Pattern of Trimetallic Nitride Clusterfullerene through One Endohedral Metal Atom Substitution. AB - Bingel-Hirsch reactions of trimetallic nitride clusterfullerenes (NCFs) generally yield methanofullerene (cyclopropane) adducts instead of singly bonded derivatives, which have been reported for monometallofullerenes. Herein, we report the synthesis and characterization of the Bingel-Hirsch derivative of a mixed metal nitride clusterfullerene (MMNCF) TiY2 N@Ih -C80 . Surprisingly, in contrast to the reported Bingel-Hirsch cyclopropane adducts of the analogous NCF Y3 N@Ih -C80 , the Bingel-Hirsch derivative of TiY2 N@Ih -C80 is the first singly bonded monoadduct (labeled as TiY2 N@C80 -Mono) to be reported, which was determined unambiguously by single-crystal X-ray crystallography. Besides, the reactivity of TiY2 N@Ih -C80 was found to be significantly improved relative to that of Y3 N@Ih -C80 . Upon substituting one endohedral yttrium (Y) atom of Y3 N@Ih -C80 with titanium (Ti), the Bingel-Hirsch derivative changes from the cyclopropane to the singly bonded monoadduct, revealing that not only the reactivity but also the addition pattern of NCFs can be manipulated simultaneously through one endohedral metal atom substitution. PMID- 27115986 TI - Collectivism and individualism in Latino recovery homes. AB - Research indicates that Latinos underutilize substance abuse interventions; cultural variables may contribute to difficulties accessing and completing treatment for this group. As a result, there is a need to understand the role of cultural constructs in treatment outcomes. The purpose of this study was to investigate how levels of collectivism (COL) and individualism (IND) relate to length of stay and relapse outcomes in self-run recovery homes. We compared Latinos in several culturally modified recovery Oxford Houses to Latinos in traditional recovery Oxford Houses. By examining COL and IND in the OH model, we explored whether aspects of COL and IND led to longer lengths of stay and better substance use outcomes. We hypothesized that higher levels of COL would predict longer stays in an Oxford House and less relapse. COL did not have a main effect on length of stay. However, COL had a significant interaction effect with house type such that COL was positively correlated with length of stay in traditional houses and negatively correlated with length of stay in the culturally modified condition; that is, those with higher collectivism tended to stay longer in traditional houses. When we investigated COL, length of stay, and substance use, COL was negatively correlated with relapse in the culturally modified houses and positively correlated with relapse in the traditional houses. In other words, those with higher COL spent less time and had less relapse in the culturally modified compared to the traditional Oxford Houses. The implications of these findings are discussed. PMID- 27115987 TI - Fundamental measure theory for non-spherical hard particles: predicting liquid crystal properties from the particle shape. AB - Density functional theory (DFT) for hard bodies provides a theoretical description of the effect of particle shape on inhomogeneous fluids. We present improvements of the DFT framework fundamental measure theory (FMT) for hard bodies and validate these improvements for hard spherocylinders. To keep the paper self-contained, we first discuss the recent advances in FMT for hard bodies that lead to the introduction of fundamental mixed measure theory (FMMT) in our previous paper (2015 Europhys. Lett. 109 26003). Subsequently, we provide an efficient semi-empirical alternative to FMMT and show that the phase diagram for spherocylinders is described with similar accuracy in both versions of the theory. Finally, we present a semi-empirical modification of FMMT whose predictions for the phase diagram for spherocylinders are in excellent quantitative agreement with computer simulation results. PMID- 27115988 TI - An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. AB - Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders. PMID- 27115989 TI - A Basal Lithostrotian Titanosaur (Dinosauria: Sauropoda) with a Complete Skull: Implications for the Evolution and Paleobiology of Titanosauria. AB - We describe Sarmientosaurus musacchioi gen. et sp. nov., a titanosaurian sauropod dinosaur from the Upper Cretaceous (Cenomanian-Turonian) Lower Member of the Bajo Barreal Formation of southern Chubut Province in central Patagonia, Argentina. The holotypic and only known specimen consists of an articulated, virtually complete skull and part of the cranial and middle cervical series. Sarmientosaurus exhibits the following distinctive features that we interpret as autapomorphies: (1) maximum diameter of orbit nearly 40% rostrocaudal length of cranium; (2) complex maxilla-lacrimal articulation, in which the lacrimal clasps the ascending ramus of the maxilla; (3) medial edge of caudal sector of maxillary ascending ramus bordering bony nasal aperture with low but distinct ridge; (4) 'tongue-like' ventral process of quadratojugal that overlaps quadrate caudally; (5) separate foramina for all three branches of the trigeminal nerve; (6) absence of median venous canal connecting infundibular region to ventral part of brainstem; (7) subvertical premaxillary, procumbent maxillary, and recumbent dentary teeth; (8) cervical vertebrae with 'strut-like' centroprezygapophyseal laminae; (9) extremely elongate and slender ossified tendon positioned ventrolateral to cervical vertebrae and ribs. The cranial endocast of Sarmientosaurus preserves some of the most complete information obtained to date regarding the brain and sensory systems of sauropods. Phylogenetic analysis recovers the new taxon as a basal member of Lithostrotia, as the most plesiomorphic titanosaurian to be preserved with a complete skull. Sarmientosaurus provides a wealth of new cranial evidence that reaffirms the close relationship of titanosaurs to Brachiosauridae. Moreover, the presence of the relatively derived lithostrotian Tapuiasaurus in Aptian deposits indicates that the new Patagonian genus represents a 'ghost lineage' with a comparatively plesiomorphic craniodental form, the evolutionary history of which is missing for at least 13 million years of the Cretaceous. The skull anatomy of Sarmientosaurus suggests that multiple titanosaurian species with dissimilar cranial structures coexisted in the early Late Cretaceous of southern South America. Furthermore, the new taxon possesses a number of distinctive morphologies-such as the ossified cervical tendon, extremely pneumatized cervical vertebrae, and a habitually downward-facing snout-that have rarely, if ever, been documented in other titanosaurs, thus broadening our understanding of the anatomical diversity of this remarkable sauropod clade. The latter two features were convergently acquired by at least one penecontemporaneous diplodocoid, and may represent mutual specializations for consuming low-growing vegetation. PMID- 27115990 TI - Correction: Dengue in Java, Indonesia: Relevance of Mosquito Indices as Risk Predictors. PMID- 27115992 TI - VITREORETINAL COMPLICATIONS AFTER PENETRATING KERATOPLASTY. AB - PURPOSE: To evaluate the time, incidence, and visual outcome of vitreoretinal complications after penetrating keratoplasty (PK). METHODS: A retrospective chart review of 1,594 eyes that underwent PK was conducted. Preoperative characteristics, visual significance, and postoperative vitreoretinal complications were analyzed. RESULTS: The incidence of vitreoretinal complications after PK was 3.3% (52/1,594). The mean follow-up period was 38.5 +/ 29.8 months. The mean time for vitreoretinal complications to occur was 4.8 months. The most common vitreoretinal complication was vitreous hemorrhage (0.75%), and others included choroidal detachment (0.7%), endophthalmitis (0.6%), and retinal detachment (0.5%). Majority of vitreous hemorrhage, endophthalmitis, and choroidal detachment occurred within 1 month postoperatively, but most cases of cystoid macular edema and epiretinal membrane occurred after 3 months. At follow-up after PK, the mean corrected distance visual acuity was worse among eyes that experienced vitreoretinal complications compared with eyes that did not (P = 0.013). CONCLUSION: Vitreoretinal complications after PK occurred in a significant percentage, resulting in persistent reduction of corrected distance visual acuity. Given this, it is of particular importance to control intraoperative and postoperative intraocular pressure, infection, and inflammation which will contribute to decrease in the incidence of vitreoretinal complications after PK. PMID- 27115991 TI - Motor Adaptations to Pain during a Bilateral Plantarflexion Task: Does the Cost of Using the Non-Painful Limb Matter? AB - During a force-matched bilateral task, when pain is induced in one limb, a shift of load to the non-painful leg is classically observed. This study aimed to test the hypothesis that this adaptation to pain depends on the mechanical efficiency of the non-painful leg. We studied a bilateral plantarflexion task that allowed flexibility in the relative force produced with each leg, but constrained the sum of forces from both legs to match a target. We manipulated the mechanical efficiency of the non-painful leg by imposing scaling factors: 1, 0.75, or 0.25 to decrease mechanical efficiency (Decreased efficiency experiment: 18 participants); and 1, 1.33 or 4 to increase mechanical efficiency (Increased efficiency experiment: 17 participants). Participants performed multiple sets of three submaximal bilateral isometric plantarflexions with each scaling factor during two conditions (Baseline and Pain). Pain was induced by injection of hypertonic saline into the soleus. Force was equally distributed between legs during the Baseline contractions (laterality index was close to 1; Decreased efficiency experiment: 1.16+/-0.33; Increased efficiency experiment: 1.11+/ 0.32), with no significant effect of Scaling factor. The laterality index was affected by Pain such that the painful leg contributed less than the non-painful leg to the total force (Decreased efficiency experiment: 0.90+/-0.41, P<0.001; Increased efficiency experiment: 0.75+/-0.32, P<0.001), regardless of the efficiency (scaling factor) of the non-painful leg. When compared to the force produced during Baseline of the corresponding scaling condition, a decrease in force produced by the painful leg was observed for all conditions, except for scaling 0.25. This decrease in force was correlated with a decrease in drive to the soleus muscle. These data highlight that regardless of the overall mechanical cost, the nervous system appears to prefer to alter force sharing between limbs such that force produced by the painful leg is reduced relative to the non painful leg. PMID- 27115993 TI - POOR PROGNOSTIC FACTORS IN PATIENTS WITH BIRDSHOT RETINOCHOROIDOPATHY. AB - PURPOSE: To identify prognostic factors for poor visual outcome in patients with birdshot retinochoroidopathy. METHODS: A case-control study of 98 patients with birdshot retinochoroidopathy (196 eyes) was evaluated with a follow-up period of at least 12 months. After exclusion of glaucoma, optic atrophy, and macular scar, the remaining eligible patients were categorized into two groups: poor visual outcomes and good visual outcomes. Poor visual outcome was defined as less than 6 mean deviation score on Swedish interactive threshold algorithm (SITA) short wavelength automated perimetry (SWAP) test and abnormality (amplitude or implicit time) of 30 Hz flicker electroretinogram at 4-year follow-up and at the most recent visit for separate analysis. Potential factors between both groups were statistically analyzed by Chi-square test and logistic regression model. RESULTS: After the aforementioned exclusion, the remaining 77 patients with an average follow-up period of 52 +/- 29 months (335 person-years, 36% with follow-up of more than 5 years) were divided into two groups. Sixteen patients were categorized as having poor visual outcome. Univariate analysis identified significant association of abnormal 30 Hz flicker electroretinogram amplitude (P = 0.004), implicit time (P = 0.002), and SITA SWAP mean deviation at the initial visit (P < 0.001) in the poor visual outcome group. Multivariate logistic regression analysis identified only SITA SWAP mean deviation to be associated with poor visual outcome (adjusted odds ratio, 32.50; 95% confidence interval [3.84-275.32]; P = 0.001) at the initial visit. To verify the model validity, an analysis of 42 patients at 4-year follow-up was performed and the outcome was confirmed (adjusted odds ratio, 8.80; 95% confidence interval [1.58-49.16]; P = 0.013). CONCLUSION: Worse SITA SWAP mean deviation at the initial visit is a predictor of poor visual outcome in patients with birdshot retinochoroidopathy, and may serve as a proxy marker for delayed effective steroid sparing therapy in patients with birdshot retinochoroidopathy. PMID- 27115994 TI - ONE-YEAR OUTCOMES OF A NOVEL TECHNIQUE FOR RESCUING AND SCLERAL FIXATING A POSTERIOR DISLOCATED INTRAOCULAR LENS-BAG COMPLEX WITHOUT CONJUNCTIVAL OPENING (HOFFMAN POCKETS). AB - PURPOSE: To present the 1-year follow-up of a novel surgical technique that allows for suture fixation of a posteriorly dislocated lens-bag complex without the need for conjunctival incision. METHODS: A retrospective chart review of 19 patients who underwent posterior chamber intraocular lens rescue using the novel surgical technique was performed. Data were collected 1 year after surgery for all patients. RESULTS: Average preoperative vision was 20/500, whereas 3 months and 12 months postoperatively, the vision was 20/65 and 20/54, respectively. Three of 15 eyes had decentration of the sutured intraocular lens, 2 of which required additional surgical repair. CONCLUSION: Outcome data at 1 year support this novel technique as a viable option for the surgical repair of a dislocated lens-capsular bag complex. PMID- 27115995 TI - Cataract Surgery Using Vitreous Cutter. PMID- 27115997 TI - Role of Cysteinyl Leukotrienes in Allergic Rhinitis. AB - Cysteinyl leukotrienes (CysLTs) are lipid mediators that have been implicated in the pathogenesis of allergic rhinitis. Pharmacological studies using CysLTs indicate that two classes of receptor exist: CysLT1 receptor (CysLT1R) and CysLT2 receptor (CysLT2R). The CysLT1R is a high-affinity leukotriene D4 receptor with lower affinity for leukotriene C4 that is sensitive to the CysLT1R antagonist currently used to treat asthma and allergic rhinitis. Our previous immunohistochemical and autoradiographic studies have demonstrated the presence of anti-CysLT1R antibodies labeled in eosinophils, mast cells, macrophages, neutrophils and vascular endothelial cells in human nasal mucosa. Furthermore, we have revealed that the novel radioactive CysLT1R antagonist [3H]-pranlukast bound specifically to CysLT1R in human inferior turbinates and its binding sites were localized to vascular endothelium and the interstitial cells. These data suggest that the major targets of CysLT1R antagonists in allergic rhinitis are the vascular bed and infiltrated leukocytes such as mast cells, eosinophils and macrophages. Clinical trials have demonstrated that CysLT1R antagonists are as effective as antihistamines for the treatment of allergic rhinitis; however, they are less effective than intranasal steroids. The use of CysLT1R antagonists in combination with antihistamines has generally resulted in greater efficacy than when these agents were used alone. PMID- 27115996 TI - Evidence for a Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome. AB - eIF5A is the only protein known to contain the essential and unique amino acid residue hypusine. eIF5A functions in both translation initiation due to its stimulation of methionyl-puromycin synthesis and translation elongation, being highly required for peptide-bound formation of specific ribosome stalling sequences such as poly-proline. The functional interaction between eIF5A, tRNA, and eEF2 on the surface of the ribosome is further clarified herein. Fluorescence anisotropy assays were performed to determine the affinity of eIF5A to different ribosomal complexes and reveal its interaction exclusively and directly with the 60S ribosomal subunit in a hypusine-dependent manner (Ki60S-eIF5A-Hyp = 16 nM, Ki60S-eIF5A-Lys = 385 nM). A 3-fold increase in eIF5A affinity to the 80S is observed upon charged-tRNAiMet binding, indicating positive cooperativity between P-site tRNA binding and eIF5A binding to the ribosome. Previously identified conditional mutants of yeast eIF5A, eIF5AQ22H/L93F and eIF5AK56A, display a significant decrease in ribosome binding affinity. Binding affinity between ribosome and eIF5A-wild type or mutants eIF5AK56A, but not eIF5AQ22H/L93F, is impaired in the presence of eEF2 by 4-fold, consistent with negative cooperativity between eEF2 and eIF5A binding to the ribosome. Interestingly, high copy eEF2 is toxic only to eIF5AQ22H/L93F and causes translation elongation defects in this mutant. These results suggest that binding of eEF2 to the ribosome alters its conformation, resulting in a weakened affinity of eIF5A and impairment of this interplay compromises cell growth due to translation elongation defects. PMID- 27115998 TI - Monocyte Trafficking, Engraftment, and Delivery of Nanoparticles and an Exogenous Gene into the Acutely Inflamed Brain Tissue - Evaluations on Monocyte-Based Delivery System for the Central Nervous System. AB - The ability of monocytes and monocyte-derived macrophages (MDM) to travel towards chemotactic gradient, traverse tissue barriers, and accumulate precisely at diseased sites makes them attractive candidates as drug carriers and therapeutic gene delivery vehicles targeting the brain, where treatments are often hampered by the blockade of the blood brain barrier (BBB). This study was designed to fully establish an optimized cell-based delivery system using monocytes and MDM, by evaluating their homing efficiency, engraftment potential, as well as carriage and delivery ability to transport nano-scaled particles and exogenous genes into the brain, following the non-invasive intravenous (IV) cell adoptive transfer in an acute neuroinflammation mouse model induced by intracranial injection of Escherichia coli lipopolysaccharides. We demonstrated that freshly isolated monocytes had superior inflamed-brain homing ability over MDM cultured in the presence of macrophage colony stimulating factor. In addition, brain trafficking of IV infused monocytes was positively correlated with the number of adoptive transferred cells, and could be further enhanced by transient disruption of the BBB with IV administration of Mannitol, Bradykinin or Serotonin right before cell infusion. A small portion of transmigrated cells was detected to differentiate into IBA-1 positive cells with microglia morphology in the brain. Finally, with the use of superparamagnetic iron oxide nanoparticles SHP30, the ability of nanoscale agent-carriage monocytes to enter the inflamed brain region was validated. In addition, lentiviral vector DHIV-101 was used to introduce green fluorescent protein (GFP) gene into monocytes, and the exogenous GFP gene was detected in the brain at 48 hours following IV infusion of the transduced monocytes. All together, our study has set up the optimized conditions for the more-in-depth tests and development of monocyte-mediated delivery, and our data supported the notion to use monocytes as a non-invasive cell-based delivery system for the brain. PMID- 27115999 TI - Association between Triglyceride to HDL-C Ratio (TG/HDL-C) and Insulin Resistance in Chinese Patients with Newly Diagnosed Type 2 Diabetes Mellitus. AB - OBJECTIVES: To explore the association between the triglyceride to HDL-C ratio (TG/HDL-C) and insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus. METHODS: Patients with newly diagnosed type 2 diabetes mellitus (272 men and 288 women) were enrolled and divided into three groups according to TG/HDL-C tertiles. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR). Demographic information and clinical characteristics were obtained. Spearman's correlation was used to estimate the association between TG/HDL-C and other variables. Multiple logistic regression analyses were adopted to obtain probabilities of insulin resistance. A receiver operating characteristic analysis was conducted to evaluate the ability of TG/HDL-C to discriminate insulin resistance. RESULTS: TG/HDL-C was associated with insulin resistance in Chinese patients with newly diagnosed T2DM (Spearman's correlation coefficient = 0.21, P < 0.01). Patients in the higher tertiles of TG/HDL-C had significantly higher HOMA-IR values than patients in the lower tertiles [T1: 2.68(1.74-3.70); T2: 2.96(2.29-4.56); T3: 3.09(2.30-4.99)]. Multiple logistic regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR, and patients in the higher TG/HDL-C tertile had a higher OR than those in the lower TG/HDL-C tertile, after adjusting for multiple covariates including indices for central obesity [T1: 1; T2: 4.02(1.86-8.71); T3: 4.30(1.99-9.29)]. Following stratification of waist circumference into quartiles, the effect of TG/HDL-C on insulin resistance remained significant irrespective of waist circumference. CONCLUSIONS: TG/HDL-C was associated with insulin resistance independent of waist circumference. Whether it could be a surrogate marker for insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus still needs to be confirmed by more researches. PMID- 27116000 TI - Multiple Oxidative Modifications in the Ophiobolin Biosynthesis: P450 Oxidations Found in Genome Mining. AB - Heterologous expression of four candidate genes found in ophiobolin gene clusters from three fungal strains was employed to elucidate the late-stage biosynthetic pathway of phytotoxin ophiobolin. Expression of oblBAc (cytochrome P450) from the cryptic gene cluster gave unexpected products, and that of oblBBm/oblBEv from the gene cluster of ophiobolin producers, with oblDBm as the transporter, yielded intermediate ophiobolin C through an unusual four-step oxidation process. The observation made in this study may provide a useful guideline for the elucidation of genuine biosynthetic pathways of natural products. PMID- 27116002 TI - Molecular Profile of the Brazilian Weaver Ant Camponotus textor Forel (Hymenoptera, Formicidae). AB - Camponotus textor Forel is, to date, the only weaver ant recorded from Brazil, and all existing studies on the species are restricted to describing its weaving and nesting behaviors. The aim of this work is to establish the molecular profile of the species. We sampled eight different colonies by sequencing mitochondrial genes (COI, transfer DNA (tRNA), and an intergenic spacer) and the nuclear gene 28S ribosomal DNA (rDNA). We then assessed haplotype diversity and also analyzed distribution patterns of this species based on the correlation between genetic and geographic distances. Our results provide an additional tool for species identification by identifying new regions that can be used as molecular markers for barcoding (such as the intergenic spacer (IGS) and tRNA-Leu). In addition, the phylogenetic analysis revealed that C. textor has features that could be associated with deep population divergences. We identified a wide range of mitotypes and three distinct groups, suggesting a possible reduction of gene flow between colonies. PMID- 27116001 TI - Production of dengue virus envelope protein domain III-based antigens in tobacco chloroplasts using inducible and constitutive expression systems. AB - Dengue fever is a disease in many parts of the tropics and subtropics and about half the world's population is at risk of infection according to the World Health Organization. Dengue is caused by any of the four related dengue virus serotypes DEN-1, -2, -3 and -4, which are transmitted to people by Aedes aegypti mosquitoes. Currently there is only one vaccine (Dengvaxia((r))) available (limited to a few countries) on the market since 2015 after half a century's intensive efforts. Affordable and accessible vaccines against dengue are hence still urgently needed. The dengue envelop protein domain III (EDIII), which is capable of eliciting serotype-specific neutralizing antibodies, has become the focus for subunit vaccine development. To contribute to the development of an accessible and affordable dengue vaccine, in the current study we have used plant based vaccine production systems to generate a dengue subunit vaccine candidate in tobacco. Chloroplast genome engineering was applied to express serotype specific recombinant EDIII proteins in tobacco chloroplasts using both constitutive and ethanol-inducible expression systems. Expression of a tetravalent antigen fusion construct combining EDIII polypeptides from all four serotypes was also attempted. Transplastomic EDIII-expressing tobacco lines were obtained and homoplasmy was verified by Southern blot analysis. Northern blot analyses showed expression of EDIII antigen-encoding genes. EDIII protein accumulation levels varied for the different recombinant EDIII proteins and the different expression systems, and reached between 0.8 and 1.6 % of total cellular protein. Our study demonstrates the suitability of the chloroplast compartment as a production site for an EDIII-based vaccine candidate against dengue fever and presents a Gateway((r)) plastid transformation vector for inducible transgene expression. PMID- 27116004 TI - Functional Single Nucleotide Polymorphisms (SNPs) in the Genes Encoding the Human Deoxyribonuclease (DNase) Family Potentially Relevant to Autoimmunity. AB - OBJECTIVE: To continue our previous investigations, we have extensively investigated the function of the 61, 41, and 35 non-synonymous single nucleotide polymorphisms (SNPs) in the human genes encoding DNASE1, DNASE1L3, and DNASE2, respectively, potentially relevant to autoimmune diseases. METHODS: The site directed mutagenesis was employed to amino acid-substituted constructs corresponding to each SNP. The COS-7 cells were transfected with each vector and DNase activity was assayed by the single radial enzyme diffusion method. By using PolyPhen-2, changes in the DNase function of each non-synonymous SNP were predicted. Genotyping of all the non-synonymous SNPs was performed in 14 different populations including 3 ethnic groups using the polymerase chain reaction followed by the restriction fragment length polymorphism method. RESULTS: Expression analysis demonstrated these SNPs to be classified into four categories with regard to the effect on DNase activity: SNPs not affecting the activity level, ones reducing it, ones abolishing it, and ones elevating it. In particular, 9, 5, and 4 SNPs producing a loss-of-function variant of the enzymes in DNASE1, DNASE1L3, and DNASE2, respectively, were confirmed. SNPs producing DNase loss of function can be estimated by PolyPhen-2 to be "probably damaging" with a high accuracy of prediction. Almost all of these functional SNPs producing a loss of function or substantially low activity-harboring forms exhibited a mono allelic distribution in all of the populations. CONCLUSION: A minor allele of functional SNPs, despite the remarkably low genetic heterogeneity of the SNPs, might be a genetic risk factor for autoimmune diseases. PMID- 27116003 TI - Appropriateness of newborn screening for classic galactosaemia: a systematic review. AB - Currently, there is no universal agreement on galactosaemia screening, fundamentally because of the risk-benefit uncertainties. We conducted two exhaustive systematic searches in the main electronic databases (PubMed, Embase, Cochrane, etc.) to recover relevant information about the disease and screening test/s in order to support decision making in Spain. All of the 45 studies identified that covered disease issues were retrospective case series or cross sectional analysis (level-4 evidence). Studies consistently found that the majority of patients presented characteristic symptomatology before diagnosis. Long term disabilities were not significantly correlated with age of diagnosis, onset of dietary restriction or strict diet compliance. The five studies that provided accuracy data used different cut-off points and verification tests, and thus differed in their definitions of a positive case (level-3b evidence). The estimated sensitivity was 100 % and the specificity 99.9 %. The false-positive rate ranged from 0.0005 % to 0.25 %, and the PPV from 0 % to 64.3 %. The comparative clinical effectiveness in relation to not screening or implementation of other programs is unknown. In summary, existing evidence remains insufficient to establish the appropriateness of newborn screening for galactosaemia screening, although health benefits could be expected if early diagnosis and treatment is achieved. If screening is implemented in Spain, it would be important that a pilot programme be implemented to assess false positive rate and ensure that early diagnosis is not delayed. PMID- 27116006 TI - Embryo Transfer with Controlled Injection Speed to Increase Pregnancy Rates: A Randomized Controlled Trial. AB - BACKGROUND/AIMS: Catheter injection speed affects depth and placement of the embryo into the uterine cavity and is shown to be highly variable in, and between, subjects in a manually performed embryo transfer. In an effort to standardize the injection speed during embryo transfer, we developed an automated transfer pump: the pump-regulated embryo transfer (PRET) device. In this randomized controlled trial, we aimed to investigate if standardization of the injection speed and pressure with this PRET results in a better controlled positioning of the transferred embryo(s). METHODS: Five hundred ninety-nine in vitro fertilization/intracytoplasmic sperm injection/frozen-thawed embryo transfer cycles were randomly assigned to the PRET or manual transfer. Positioning of the embryo(s) into the uterine cavity was measured with ultrasound. RESULTS: The PRET device generates a significantly smaller variance of the positioning of the embryo(s) into the uterine cavity. This resulted in an ongoing pregnancy rate of 21% in the PRET versus 17% in the manual (p = 0.22) transfer group; frozen-thawed embryo transfers resulted in 17.5 versus 10.9% (p = 0.097), respectively. CONCLUSION: The PRET results in better controlled positioning of the embryo(s), and it also gives the opportunity to standardize embryo transfer. Whether the PRET may positively influence pregnancy rates, needs to be investigated in a multicenter trial. PMID- 27116005 TI - A First Tetraplex Assay for the Simultaneous Quantification of Total alpha Synuclein, Tau, beta-Amyloid42 and DJ-1 in Human Cerebrospinal Fluid. AB - The quantification of four distinct proteins (alpha-synuclein, beta-amyloid1-42, DJ-1, and total tau) in cerebrospinal fluid (CSF) has been proposed as a laboratory-based platform for the diagnosis of Parkinson's disease (PD) and Alzheimer's disease (AD). While there is some clinical utility in measuring these markers individually, their usage in routine clinical testing remains challenging, in part due to substantial overlap of concentrations between healthy controls and diseased subjects. In contrast, measurement of different analytes in a single sample from individual patients in parallel appears to considerably improve the accuracy of AD or PD diagnosis. Here, we report the development and initial characterization of a first, electrochemiluminescence-based multiplex immunoassay for the simultaneous quantification of all four proteins ('tetraplex') in as little as 50 MUl of CSF. In analytical performance experiments, we assessed its sensitivity, spike-recovery rate, parallelism and dilution linearity as well as the intra- and inter-assay variability. Using our in-house calibrators, we recorded a lower limit of detection for alpha-synuclein, beta-amyloid42, DJ-1, and t-tau of 1.95, 1.24, 5.63, and 4.05 pg/ml, respectively. The corresponding, linear concentration range covered >3 orders of magnitude. In diluted CSF samples (up to 1:4), spike-recovery rates ranged from a low of 55% for beta-amyloid42 to a high of 98% for DJ-1. Hillslopes ranged from 1.03 to 1.30, and inter-assay variability demonstrated very high reproducibility. Our newly established tetraplex assay represents a significant technical advance for fluid-based biomarker studies in neurodegenerative disorders allowing the simultaneous measurement of four pivotal makers in single CSF specimens. It provides exceptional sensitivity, accuracy and speed. PMID- 27116007 TI - Evaporation-Induced Pattern Formation of Decanol Droplets. AB - Pattern formation in far-from-equilibrium systems is observed in several disciplines including biology, geophysics, and reaction-diffusion chemistry, comprising both living and nonliving systems. We aim to study such nonequilibrium dynamics on the laboratory scale with materials of simple composition. We present a novel system based on a 1-decanol droplet placed in a solution of alkaline decanoate. Previously, we showed the short time scale behavior of this system, which included chemotaxis and maze solving. Here we explore long time scale dynamics of the system (several hours) when open to the environment. We observe dramatic morphological changes in the droplet including long tentacular structures, and we analyze the morphology of these structures at both the macroscopic and microscopic scales across a large range of initial conditions. Such reproducible morphological changes in simple droplets open a path to the exploration of shape-based effects in larger-scale pattern-formation studies. PMID- 27116008 TI - Evaluation of the Bio-Rad Dx CT/NG/MG(r) assay for simultaneous detection of Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium in urine. AB - We evaluated the performance of the Bio-Rad real-time Dx CT/NG/MG(r) assay for detection of C. trachomatis, N. gonorrhoeae and M. genitalium on a collection of 441 urine samples from sexually transmitted infections, or travellers consultations and from anonymous sperm donors that were previously analysed with the Abbott RealTime CT/NG assay. Samples positive for C. trachomatis or N. gonorrhoeae with the Abbott assay had all previously been confirmed with an in house real-time PCR assay. Samples positive for M. genitalium with the Bio-Rad assay were subsequently analysed by an in-house real-time PCR. On a total of 441 urines, 104 samples were positive for C. trachomatis, 12 were positive for N. gonorrhoeae and seven were positive for M. genitalium. After retesting of discrepant results, the test results were completely concordant, resulting in a calculated sensitivity and specificity of the Bio-Rad assay of 98.1 % and 100 % for C. trachomatis and of 91.7 % and 100 % for N. gonorrhoeae. Results for M. genitalium with the Bio-Rad assay were also concordant with the results of an in house PCR. We also evaluated the performance of automated nucleic acid extractions of urine samples with the NucliSENS easyMAG (bioMerieux) compared to the manual DNA extraction prescribed by the insert of the kit. The easyMAG extraction gave lower Ct values, relieved inhibition and had a lower hands-on time. PMID- 27116010 TI - Obstetric outcome and incidence of congenital anomalies in 2351 IVF/ICSI babies. AB - PURPOSE: The aim of this study was to provide a comprehensive follow-up of fetal and perinatal outcome and the incidence of congenital anomalies in babies born after fresh embryo transfers compared to those conceived spontaneously in infertile couples. METHODS: Retrospective comparative analysis of all clinical pregnancies from fresh cleavage-stage embryo transfer cycles (IVF and ICSI) compared with infertile patients who conceived spontaneously in the same time period (control). Congenital anomalies were classified following the European Surveillance of Congenital Anomalies (EUROCAT) classification. RESULTS: A total of 2414 assisted reproductive technology (ART) pregnancies were compared to 582 spontaneous conceptions in the control infertile group representing 2306 deliveries. No significant differences were found in pregnancy outcome between the two groups (delivery rate, abortion rate, ectopic pregnancies, medical abortions for fetal anomalies, single and twins mean gestational age, and weight at delivery). A significant difference (p < 0.001) was found in the twin (21.3 vs 2.3 %) and triplet rates (2.3 vs 0 %). A total of 2351 babies were delivered in the ART group and 449 in the control group. A total of 90 babies (3.8 %) were diagnosed with a major congenital anomaly in the ART group and 15 (3.3 %) in the control group (p = ns). The overall rate of major congenital anomalies (105/2800) in ART and spontaneous pregnancies in infertile couples was significantly higher when compared to the EUROCAT 2.0 versus 3.75 % (p = 0.0002). DISCUSSION: Babies born after ART treatments and from spontaneous conception in infertile couples had rates of congenital anomalies higher than those recorded by the EUROCAT. However, the rates of anomalies were not different within the infertile population whether conceived by ART or spontaneously. These data suggest that the diagnosis of infertility in itself is the common denominator for the increase in the rates of anomalies seen in both ART and spontaneous conceptions. PMID- 27116011 TI - MR imaging features of focal liver lesions in Wilson disease. AB - Hepatic involvement in Wilson disease (WD) manifests as a diffuse chronic disease in the majority of patients. However, in a subset of patients focal liver lesions may develop, presenting with a wide range of imaging features. The majority of focal liver lesions in patients with WD are benign nodules, but there are reports that have described malignant liver tumors or dysplastic nodules in these patients. Because of the possibility of malignant transformation of liver nodules, major concerns have been raised with respect to the management and follow-up of patients with WD in whom focal liver lesions have been identified. The assessment of liver involvement in patients with WD is generally performed with ultrasonography. However, ultrasonography conveys limited specificity so that magnetic resonance (MR) imaging is often performed to improve lesion characterization. This review was performed to illustrate the spectrum of MR imaging features of focal liver lesions that develop in patients with WD. It is assumed that familiarity with the MR imaging presentation of focal liver lesions in WD may help clarify the actual nature of hepatic nodules in patients with this condition. PMID- 27116009 TI - Impact of selective digestive decontamination on respiratory tract Candida among patients with suspected ventilator-associated pneumonia. A meta-analysis. AB - The purpose here is to establish the incidence of respiratory tract colonization with Candida (RT Candida) among ICU patients receiving mechanical ventilation within studies in the literature. Also of interest is its relationship with candidemia and the relative importance of topical antibiotic (TA) use as within studies of selective digestive decontamination (SDD) versus other candidate risk factors towards it. The incidence of RT Candida was extracted from component (control and intervention) groups decanted from studies of various TA and non-TA ICU infection prevention methods with summary estimates derived using random effects. A benchmark RT Candida incidence to provide overarching calibration was derived using (observational) groups from studies without any prevention method under study. A multi-level regression model of group level data was undertaken using generalized estimating equation (GEE) methods. RT Candida data were sourced from 113 studies. The benchmark RT Candida incidence is 1.3; 0.9-1.8 % (mean and 95 % confidence intervals). Membership of a concurrent control group of a study of SDD (p = 0.02), the group-wide presence of candidemia risk factors (p < 0.001), and proportion of trauma admissions (p = 0.004), but neither the year of study publication, nor membership of any other component group, nor the mode of respiratory sampling are predictive of the RT Candida incidence. RT Candida and candidemia incidences are correlated. RT Candida incidence can serve as a basis for benchmarking. Several relationships have been identified. The increased incidence among concurrent control groups of SDD studies cannot be appreciated in any single study examined in isolation. PMID- 27116012 TI - Prediction of tumor response after neoadjuvant chemoradiotherapy in rectal cancer using (18)fluorine-2-deoxy-D-glucose positron emission tomography-computed tomography and serum carcinoembryonic antigen: a prospective study. AB - PURPOSE: To investigate the association between (18)fluorine-2-deoxy-D-glucose positron emission tomography-computed tomography ((18)F-FDG PET/CT) parameters, serum carcinoembryonic antigen (CEA), and tumor response in patients with rectal cancer receiving neoadjuvant chemoradiotherapy (nCRT). METHODS: Sixty-four patients with T3-4 and/or node-positive rectal cancer receiving nCRT followed by surgery were prospectively studied. PET/CT was performed before, and in 28 patients, both before and after nCRT. The pre-/post-nCRT maximum standardized uptake (SUVmax) values, differences between pre-/post-nCRT SUVmax (?SUVmax), response index of SUVmax (RI-SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and CEA were measured. The ability of PET/CT parameters and CEA to predict Mandard's tumor regression grade (TRG) and pathological complete remission (pCR) were evaluated. RESULTS: 31 patients were identified as responders (TRG 1-2), and 19 exhibited pCR. For responders, significant differences were found for DeltaSUVmax (24.88 vs. 15.39 g/ml, p = 0.037), RI-SUVmax (0.76 vs. 0.63, p = 0.025), DeltaSUVmean (14.43 vs. 8.65 g/ml, p = 0.029), RI-SUVmean (0.77 vs. 0.63, p = 0.011), CEA-pre (6.30 vs. 27.86 MUg/L, p < 0.001), CEA-post (2.22 vs. 5.49 MUg/L, p = 0.002), DeltaCEA (4.08 vs. 23.13 MUg/L, p < 0.001), and RI-CEA (0.25 vs. 0.55, p = 0.002). Differences between pCR and non-pCR patients were noted as RI-SUVmean (0.77 vs. 0.65, p = 0.043), MTV-pre (9.87 vs. 14.62 cm(3), p = 0.045), CEA-pre (5.62 vs. 22.27 MUg/L, p = 0.002), CEA-post (1.95 vs. 4.72 MUg/L, p = 0.001), and DeltaCEA (3.68 vs. 17.99 MUg/L, p = 0.013). Receiver operating characteristic analysis revealed that RI-SUVmean exhibited the greatest accuracy in predicting responders, whereas CEA-post and DeltaCEA exhibited the greatest accuracy in predicting pCR. CONCLUSIONS: (18)F-FDG PET/CT parameters and CEA are accurate tools for predicting tumor response to nCRT in rectal cancer. PMID- 27116013 TI - Photobiomodulation for the management of radiation dermatitis: the DERMIS trial, a pilot study of MLS((r)) laser therapy in breast cancer patients. AB - PURPOSE: The aim of this study was to assess the effectiveness and acceptability of photobiomodulation using MLS((r)) laser therapy (LT) in the management of acute radiation dermatitis (RD). METHODS: We compared two successive groups of breast cancer patients undergoing identical radiotherapy regimens post lumpectomy. Both groups received our standard skin care but the second group received six additional LT sessions (beam area 19.635 cm(2), 0.168 W/cm(2), 4 J/cm(2)), starting at fraction 20 of radiotherapy (control and LT group, N = 41 and 38, respectively). The clinical outcomes were the severity of RD (using the Radiation Therapy Oncology Group [RTOG] criteria and the Radiotherapy-Induced Skin Reaction Assessment Scale [RISRAS]) and dermatology-specific quality of life (Skindex-16) before the start of LT and at the end of radiotherapy. Secondary outcomes were patients' ratings of skin care or LT (pleasantness, soothing effect, and global satisfaction). RESULTS: Skin toxicity was equivalent between the groups before the start of LT but significantly differed at the end of radiotherapy, with an aggravation in the control but not in the LT group (e.g., 29 versus 3 % of RTOG grade 2 RD, respectively, P < 0.005). We found no significant group differences with respect to quality of life. However, the RISRAS subjective score decreased in the LT group only, implying a decreased impact of RD on patients' quality of life. Finally, patients' ratings were significantly higher for LT than for standard care. CONCLUSIONS: These findings suggest that LT might be effective to manage acute RD and warrant further research. TRIAL REGISTRATION: CLINICAL TRIAL NUMBER: NCT01932073. https://clinicaltrials.gov/ct2/show/NCT01932073 . PMID- 27116014 TI - Cancer-related fatigue: appraising evidence-based guidelines for screening, assessment and management. AB - PURPOSE: There is inconsistent management of cancer-related fatigue (CRF) by health professionals worldwide. This research aims to identify the most appropriate guidelines for the management of cancer-related fatigue. METHODS: A systematic search of international literature identified evidence-based clinical practice guidelines for CRF. Four reviewers independently appraised the highest quality guidelines using the AGREE-II instrument and National Heath and Medical Research Council (NHMRC) guideline standards. RESULTS: Five guidelines met the inclusion criteria. Of these, the 2015 Canadian Association of Psychosocial Oncology (CAPO) CRF guidelines and the 2014 American Society of Clinical Oncology (ASCO) fatigue guidelines for cancer survivors were selected for in-depth appraisal. The CAPO guideline scored higher than the ASCO for five domains of the AGREE-II. For one domain, the differences were statistically significant (p <= 0.05). The CAPO guideline met 37 of 47 NHMRC mandatory guideline standards and the ASCO guideline met 20. The difference in the proportion of standards met was statistically significant for one domain (p <= 0.05). Both guidelines had low scores for applicability and implementation. CONCLUSIONS: Currently, the CAPO guideline for cancer-related fatigue has the strongest evidence for use. To enhance implementation, further strategies for guideline dissemination and application are needed. PMID- 27116015 TI - Confluence-dependent resistance to cisplatin in lung cancer cells is regulated by transforming growth factor-beta. AB - PURPOSE OF THE STUDY: Confluence-dependent resistance (CDR) is a phenomenon in which the efficacy of anti-cancer agents decreases when cell density increases. CDR in lung cancer has never been reported. The purpose of this study is to investigate if CDR can occur in NSCLC cells and to find a role for transforming growth factor (TGF)-beta as a mechanism of CDR. MATERIALS AND METHODS: Non-small cell lung cancer (NSCLC) cell lines A549 and H2228 were exposed to cisplatin in a variety of cell density conditions. RNA interference targeting TGF-beta receptor I was performed to silence the TGF-beta pathway. RESULTS: CDR to cisplatin was induced in NSCLC cells, whereas CDR to crizotinib, an inhibitor of activin receptor-like kinase, was not observed. During confluent conditions, the TGF beta1 concentration in the culture medium was the highest. Exogenous TGF-beta1 inhibited cell proliferation and reduced sensitivity to cisplatin. Inhibition of the TGF-beta pathway increased in terms of sensitivity to cisplatin at confluency. CONCLUSIONS: CDR to cisplatin can occur in NSCLC cells, and the TGF beta pathway is associated with the regulation of CDR. PMID- 27116016 TI - Survey of Clinical Extended-Spectrum Beta-Lactamase-Producing Enterobacter cloacae Isolates in a Chinese Tertiary Hospital, 2012-2014. AB - A total of 72 consecutive and nonduplicate clinical extended-spectrum beta lactamase (ESBL)-producing Enterobacter cloacae isolates were collected from our hospital from 2012 to 2014 for analyzing the prevalence of plasmid-mediated quinolone resistance (PMQR) genes, 16S rRNA methyltransferase (16S-RMTase) encoding genes, and carbapenem-hydrolyzing beta-lactamase (CHbetaL) genes, as well as integrons. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were carried out to characterize the genetic relatedness. The isolates mainly harbored blaCTX-M (n = 51, 70.8%) and blaSHV (n = 46, 63.9%) genes. High prevalence of PMQR genes qnrA1 (n = 24, 33.3%), qnrB (n = 4, 5.6%), qnrS1 (n = 2, 2.8%), and aac(6')-Ib-cr (n = 21, 29.2%) was observed. Furthermore, CHbetaLs IMP-4 (n = 6, 8.3%) and IMP-8 (n = 4, 5.6%), as well as class I integrons (n = 29, 40.3%), were found in the ESBL-producing E. cloacae isolates. PFGE revealed 69 pulsotypes. MLST distinguished 44 sequence types (STs) with ST124 (n = 7, 9.7%), ST50 (n = 3, 4.2%), ST45 (n = 3, 4.2%), and ST93 (n = 3, 4.2%) being the predominant STs. The results indicate a possible clonal transmission of ST124 isolates in the hospital that needs further surveillance. The genetic diversity of the other numerous distinctive STs indicates that most of the ESBL-producing E. cloacae in our hospital might arise through stepwise accumulations of multiple drug-resistance determinants in different clones. PMID- 27116017 TI - Quantitative Interpretation of the Low-Bias Conductance of Au-Mesitylene-Au Molecular Junctions Formed from Mesitylene Monolayers. AB - The atomic structure and electronic transport properties of Au-mesitylene-Au molecular junctions formed from a mesitylene monolayer without any anchoring groups are investigated by employing the non-equilibrium Green's function formalism combined with density functional theory. The intermolecular and adsorbate-substrate interactions are described by the non-local optB88 van der Waals functional. Two types of Au-mesitylene-Au molecular junctions are constructed, in which either an isolated mesitylene molecule or a mesitylene molecule embedded into a monolayer lying flat on one electrode surface is in contact with an atomic protrusion of the other electrode surface. The calculated low-bias conductance values of these two junctions are both in quantitative agreement with the reported experimental values [S. Afsari, Z. Li, and E. Borguet, Angew. Chem. Int. Ed. 2014, 53, 9771; Angew. Chem. 2014, 126, 9929]. This indicates that the measured conductance is intrinsic at the single-molecule Au-mesitylene-Au junction and that the intermolecular interactions in the mesitylene monolayer have little effect. PMID- 27116019 TI - UK Renal Registry 18th Annual Report: Chapter 10 Clinical, Haematological and Biochemical Parameters in Patients Receiving Renal Replacement Therapy in Paediatric Centres in the UK in 2014: National and Centre-specific Analyses. AB - The median height z-score for paediatric patients on dialysis was -2.1 and for those with a functioning transplant -1.3. Children transplanted before the age of 12 years improved their height z-score over the subsequent five years, whereas those older than 12 maintained their height z-score, with all transplanted patients having a similar median height z-score after five years of starting renal replacement therapy (RRT). The median weight z-score for children on dialysis was -1.4 whereas children with a functioning transplant had a near normal weight for age and sex with a median z-score of -0.3. Of those with data, 75% of the prevalent paediatric RRT population had one or more 'traditional' risk factors for cardiovascular disease, with 1 in 10 having all three risk factors present. For the 10 centres reporting quarterly laboratory data, the average creatinine in transplant patients was 79 mmol/L; dialysis patients had normal average anaemia and acidosis markers and evidence of secondary hyperparathyroidism with an average PTH of 17.3 pmol/L. For transplant patients, 80% achieved the systolic blood pressure (SBP) standard and 93% achieved the haemoglobin standard. For haemodialysis patients, 57% achieved the SBP standard, 62% achieved the haemoglobin standard, 82% achieved the calcium standard, 51% achieved the phosphate standard and 39% achieved the parathyroid hormone (PTH) standard. For peritoneal dialysis patients, 70% achieved the SBP standard, 77% achieved the haemoglobin standard, 72% achieved the calcium standard, 54% achieved the phosphate standard and 33% achieved the PTH standard. PMID- 27116020 TI - Implementing the Biopharmaceutics Classification System in Drug Development: Reconciling Similarities, Differences, and Shared Challenges in the EMA and US FDA-Recommended Approaches. AB - The US-FDA recently posted a draft guideline for industry recommending procedures necessary to obtain a biowaiver for immediate-release oral dosage forms based on the Biopharmaceutics Classification System (BCS). This review compares the present FDA BCS biowaiver approach, with the existing European Medicines Agency (EMA) approach, with an emphasis on similarities, difficulties, and shared challenges. Some specifics of the current EMA BCS guideline are compared with those in the recently published draft US-FDA BCS guideline. In particular, similarities and differences in the EMA versus US-FDA approaches to establishing drug solubility, permeability, dissolution, and formulation suitability for BCS biowaiver are critically reviewed. Several case studies are presented to illustrate the (i) challenges of applying for BCS biowaivers for global registration in the face of differences in the EMA and US-FDA BCS biowaiver criteria, as well as (ii) challenges inherent in applying for BCS class I or III designation and common to both jurisdictions. PMID- 27116021 TI - Development and Validation of Electrochemiluminescence Assays to Measure Free and Total sSLAMF7 in Human Serum in the Absence and Presence of Elotuzumab. AB - Elotuzumab is a first in class humanized IgG1 monoclonal antibody for the treatment of multiple myeloma (MM). Elotuzumab targets the glycoprotein signaling lymphocyte activation molecule family 7 (SLAMF7, also described as CS1 or CRACC) which is expressed on the surface of myeloma cells and a subset of immune cells, including natural killer cells. A soluble version of SLAMF7 (sSLAMF7) has also been reported in MM patients but has not been evaluated as a potential biomarker following therapeutic intervention. In order to measure serum levels of sSLAMF7, two immunoassays were developed to monitor changes in circulating sSLAMF7 before and after elotuzumab treatment. Free (drug-unbound) and total (drug-bound and unbound) electrochemiluminescence (ECL) ELISA assays were developed and validated following a fit for purpose (FFP) methodology. Both assays met analytical acceptance criteria for precision, drug interference, dilution linearity, spike recovery, parallelism, and stability. Both exhibited the range and sensitivity necessary to measure clinical samples with an LLOQ of 51.2 pg/mL and ULOQs of 160 (free) and 800 ng/mL (total). Previously described assays were unable to detect sSLAMF7 in healthy individuals. However, due to the increased sensitivity of these new assays, low but measurable sSLAMF7 levels were detected in all normal healthy sera evaluated and were significantly elevated in MM patients. Cohort statistics revealed a significant increase of circulating sSLAMF7 in MM patients versus normal controls and both significant decreases in free and increases in total levels of protein post-elotuzumab treatment. PMID- 27116022 TI - The FDA's Experience with Emerging Genomics Technologies-Past, Present, and Future. AB - The rapid advancement of emerging genomics technologies and their application for assessing safety and efficacy of FDA-regulated products require a high standard of reliability and robustness supporting regulatory decision-making in the FDA. To facilitate the regulatory application, the FDA implemented a novel data submission program, Voluntary Genomics Data Submission (VGDS), and also to engage the stakeholders. As part of the endeavor, for the past 10 years, the FDA has led an international consortium of regulatory agencies, academia, pharmaceutical companies, and genomics platform providers, which was named MicroArray Quality Control Consortium (MAQC), to address issues such as reproducibility, precision, specificity/sensitivity, and data interpretation. Three projects have been completed so far assessing these genomics technologies: gene expression microarrays, whole genome genotyping arrays, and whole transcriptome sequencing (i.e., RNA-seq). The resultant studies provide the basic parameters for fit-for purpose application of these new data streams in regulatory environments, and the solutions have been made available to the public through peer-reviewed publications. The latest MAQC project is also called the SEquencing Quality Control (SEQC) project focused on next-generation sequencing. Using reference samples with built-in controls, SEQC studies have demonstrated that relative gene expression can be measured accurately and reliably across laboratories and RNA seq platforms. Besides prediction performance comparable to microarrays in clinical settings and safety assessments, RNA-seq is shown to have better sensitivity for low expression and reveal novel transcriptomic features. Future effort of MAQC will be focused on quality control of whole genome sequencing and targeted sequencing. PMID- 27116023 TI - A Model-Based Approach for Joint Analysis of Pain Intensity and Opioid Consumption in Postoperative Pain. AB - Joint analysis of pain intensity and opioid consumption is encouraged in trials of postoperative pain. However, previous approaches have not appropriately addressed the complexity of their interrelation in time. In this study, we applied a non-linear mixed effects model to simultaneously study pain intensity and opioid consumption in a 4-h postoperative period for 44 patients undergoing percutaneous kidney stone surgery. Analysis was based on 748 Numerical Rating Scale (NRS) scores of pain intensity and 51 observed morphine and oxycodone dosing events. A joint model was developed to describe the recurrent pattern of four key phases determining the development of pain intensity and opioid consumption in time; (A) Distribution of pain intensity scores which followed a truncated Poisson distribution with time-dependent mean score ranging from 0.93 to 2.45; (B) Probability of transition to threshold pain levels (NRS >= 3) which was strongly dependent on previous pain levels ranging from 2.8-15.2% after NRS of 0-2; (C) Probability of requesting opioid when allowed (NRS >= 3) which was strongly correlated with the number of previous doses, ranging from 89.8% for requesting the first dose to 26.1% after three previous doses; (D) Reduction in pain scores after opioid dosing which was significantly related to the pain intensity at time of opioid request (P < 0.001). This study highlights the importance of analyzing pain intensity and opioid consumption in an integrated manner. Non-linear mixed effects modeling proved a valuable tool for analysis of interventions that affect pain intensity, probability of rescue dosing or the effect of opioids in the postoperative pain period. PMID- 27116024 TI - Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin. AB - This study explored the utility of mechanistic absorption models to describe the in vivo performance of a low solubility/low permeability compound in normal healthy subjects. Sixteen healthy human volunteers received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by HPLC. In vitro ciprofloxacin release from the oral tablets was tested under a variety of conditions. A mechanistic model was used to explore in vivo dissolution and intestinal absorption. Although dissolution rate influenced the location of drug release, absorption challenges appeared to be associated with permeability limitations in the lower small intestine and colon. The apparent relationship between drug solubilization within the upper small intestinal and formulation overall bioavailability suggested the presence of an intestinal absorption window in many individuals. Failure to absorb drug within this window appeared to be linked with the likelihood of in vivo drug precipitation. Challenges encountered during this modeling exercise included large intersubject variability in product in vivo dissolution and the apparent limitations in ciprofloxacin absorption. Although transporter activity was not included as a model parameter, this evaluation demonstrated how identifying the location of drug absorption across several formulations provided an opportunity to identify factors to consider when formulating similar low solubility/low permeability compounds. The use of mechanistic models was invaluable for our understanding of in vivo product performance and for the assessment of individual profiles rather than means. The latter was essential for understanding the potential challenges that may be encountered when introducing a formulation into a patient population. PMID- 27116025 TI - PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans. AB - Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended. PMID- 27116026 TI - Studies of Tonsils in Basic and Clinical Perspectives: From the Past to the Future. AB - The tonsils are located at the entrance of the pharynx as a cardinal constituent of Waldeyer's ring, taking part not only in local immune responses, but also in systemic immunity. Functional deficits of tonsils primarily underlie the pathogenesis of various characteristic disorders, including tonsillar focal infections such as palmoplantar pustulosis and IgA nephropathy, in addition to the highly prevalent sleep disorder called obstructive sleep apnea syndrome. Although the mechanisms underlying these disorders remain unknown, the tonsils have long been postulated as a unique and enigmatic immune organ. Lymphoid cells and tissues from surgically resected tonsils are often employed to analyze the human immune response from a retrospective view. This approach has provided much new fundamental evidence for understanding innate and acquired immune responses, thereby facilitating further studies in the fields of mucosal immunity and specific humoral immunity originating in the germinal center. Future studies of the tonsils in basic and clinical research are expected to reveal the mechanisms of tonsil-related disorders as well as the nature of human immunity. In this review, which is primarily based on our original research over the past 3 decades, we summarize our findings and discuss the future prospects of studies focusing on the tonsils. PMID- 27116027 TI - A new implementation of digital X-ray radiogrammetry and reference curves of four indices of cortical bone for healthy European adults. AB - Digital X-ray radiogrammetry performs measurements on a hand radiograph in digital form. We present an improved implementation of the method and provide reference curves for four indices for the amount of bone. We collected 1662 hand radiographs of healthy subjects of age 9-100 years. PURPOSE: The digital X-ray radiogrammetry (DXR) method has been shown to be efficient for diagnosis of osteoporosis and for assessment of progression of rheumatoid arthritis. The aim of this work is to present a new DXR implementation and reference curves of four indices of cortical bone and to compare their relative SDs in healthy subjects at fixed age and gender. MATERIALS AND METHODS: A total of 1662 hand radiographs of healthy subjects of age 9-100 years were collected in Jena in 2001-2005. We also used a longitudinal study of 116 Danish children born in 1952 with on average 11 images taken over the age range 7 to 40 years. The new DXR method reconstructs the whole metacarpal contour so that the metacarpal lengths can be measured and used in two of the indices. The new DXR method automatically validates 97 % of the images and is implemented as a local server for PACS users. RESULTS: The Danish bone health index (BHI) data are consistent with the Jena data and also with the published BHI reference for healthy children. BHI is found to have smaller relative SD than the other three indices in the Jena cohort over the age range 20-80 years. CONCLUSION: The new DXR method is an extension of the existing BoneXpert method for children, which allows patients to be followed from childhood into adulthood with the same method. By making all four indices of cortical bone available within the same medical device, it becomes possible to decide which index has the best relation to fracture risk in future studies. PMID- 27116028 TI - The ITA.LI.CA Staging System: A Novel Staging System for Hepatocellular Carcinoma. AB - In this Perspective, Neehar Parikh and Amit Singal discuss the advantages of the ITA.LI.CA staging system for prognoses of liver cancer developed by Alessandro Vitale and colleagues. PMID- 27116029 TI - Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure-Activity Relationships. AB - Simulated screening of DNA encoded libraries indicates that the presence of truncated byproducts complicates the relationship between library member enrichment and equilibrium association constant (these truncates result from incomplete chemical reactions during library synthesis). Further, simulations indicate that some patterns observed in reported experimental data may result from the presence of truncated byproducts in the library mixture and not structure-activity relationships. Potential experimental methods of minimizing the presence of truncates are assessed via simulation; the relationship between enrichment and equilibrium association constant for libraries of differing purities is investigated. Data aggregation techniques are demonstrated that allow for more accurate analysis of screening results, in particular when the screened library contains significant quantities of truncates. PMID- 27116030 TI - Ranibizumab (Lucentis) versus Bevacizumab (Avastin) for the Treatment of Age Related Macular Degeneration: An Economic Disparity of Eye Health. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the advent of anti-vascular endothelial growth factor agents (VEGF) has revolutionized treatment for neovascular AMD. Two of the most popular anti VEGF agents, ranibizumab (Lucentis; Genentech/Roche) and bevacizumab (Avastin; Genentech/Roche), effectively treat neovascular AMD but have a substantial difference in price. Multiple level 1 trials have demonstrated that bevacizumab is noninferior to ranibizumab in the treatment of neovascular AMD and that both have similar safety profiles. The decision to use one drug over the other is multifactorial with influences from industry as well as individual physician biases. However, the additional billions spent on ranibizumab result in a large economic disparity that is not rationalized by cost effectiveness models. PMID- 27116031 TI - Metabolic response of lung cancer cells to radiation in a paper-based 3D cell culture system. AB - This work demonstrates the application of a 3D culture system-Cells-in-Gels-in Paper (CiGiP)-in evaluating the metabolic response of lung cancer cells to ionizing radiation. The 3D tissue-like construct-prepared by stacking multiple sheets of paper containing cell-embedded hydrogels-generates a gradient of oxygen and nutrients that decreases monotonically in the stack. Separating the layers of the stack after exposure enabled analysis of the cellular response to radiation as a function of oxygen and nutrient availability; this availability is dictated by the distance between the cells and the source of oxygenated medium. As the distance between the cells and source of oxygenated media increased, cells show increased levels of hypoxia-inducible factor 1-alpha, decreased proliferation, and reduced sensitivity to ionizing radiation. Each of these cellular responses are characteristic of cancer cells observed in solid tumors. With this setup we were able to differentiate three isogenic variants of A549 cells based on their metabolic radiosensitivity; these three variants have known differences in their metastatic behavior in vivo. This system can, therefore, capture some aspects of radiosensitivity of populations of cancer cells related to mass-transport phenomenon, carry out systematic studies of radiation response in vitro that decouple effects from migration and proliferation of cells, and regulate the exposure of oxygen to subpopulations of cells in a tissue-like construct either before or after irradiation. PMID- 27116032 TI - Bub1 targeting to centromeres is sufficient for Sgo1 recruitment in the absence of kinetochores. AB - Centromeric chromatin containing the histone H3 variant centromere protein A (CENP-A) directs kinetochore assembly through a hierarchical binding of CENPs, starting with CENP-C and CENP-T. Centromeres are also the chromosomal regions where cohesion, mediated by cohesin, is most prominently maintained in mitosis. While most cohesin dissociates from chromosome arms in prophase, Shugoshin 1 (Sgo1) prevents this process at centromeres. Centromeric localization of Sgo1 depends on histone H2A phosphorylation by the kinase Bub1, but whether additional interactions with kinetochore components are required for Sgo1 recruitment is unclear. Using the Xenopus egg cell-free system, we here show that both CENP-C and CENP-T can independently drive centromeric accumulation of Sgo1 through recruitment of Bub1 to the KNL1, MIS12, NDC80 (KMN) network. The spindle assembly checkpoint (SAC) kinase Mps1 is also required for this pathway even in the absence of checkpoint signaling. Sgo1 recruitment is abolished in chromosomes lacking kinetochore components other than CENP-A. However, forced targeting of Bub1 to centromeres is sufficient to restore Sgo1 localization under this condition. PMID- 27116034 TI - (+/-)-Japonicols A-D, Acylphloroglucinol-Based Meroterpenoid Enantiomers with Anti-KSHV Activities from Hypericum japonicum. AB - (+/-)-Japonicols A-D (1a/1b-4a/4b), four pairs of new phloroglucinol-based terpenoid enantiomers, were isolated from Hypericum japonicum. Their absolute configurations were confirmed through comparison of their experimental and calculated electronic circular dichroism spectra and single-crystal X-ray diffraction analyses. Compounds 1a/1b, 2a/2b, and 3a/3b possess 2 oxabicyclo[3.3.1]nonane, pyrano[3,2-b]pyran, and benzo[b]cyclopenta[e]oxepine ring systems, respectively. The effects of the phloroglucinols on anti-Kaposi's sarcoma-associated herpesvirus were assessed, and 2a exhibited a moderate inhibitory effect, with an EC50 value of 8.75 MUM and a selectivity index of 16.06. PMID- 27116033 TI - Transformation-associated recombination (TAR) cloning for genomics studies and synthetic biology. AB - Transformation-associated recombination (TAR) cloning represents a unique tool for isolation and manipulation of large DNA molecules. The technique exploits a high level of homologous recombination in the yeast Sacharomyces cerevisiae. So far, TAR cloning is the only method available to selectively recover chromosomal segments up to 300 kb in length from complex and simple genomes. In addition, TAR cloning allows the assembly and cloning of entire microbe genomes up to several Mb as well as engineering of large metabolic pathways. In this review, we summarize applications of TAR cloning for functional/structural genomics and synthetic biology. PMID- 27116035 TI - Protein-SIP in environmental studies. AB - Metaproteomics coupled to stable isotope probing (SIP) was established to detect metabolically active key players in microbial communities. Here, we discuss the current state of protein-based stable isotope probing (protein-SIP) and the perspectives of using different stable isotope atoms (i.e. 13C, 15N, 18O, 34/36S), multiple isotope labelling, the utilisation of substrates of major abundance and micro-pollutants [pesticides, herbicides and pharmaceuticals present in the environment at very low concentrations (ngMUg/L)], and applications in complex model systems and in situ studies in the environment. PMID- 27116036 TI - Highly Crystalline Films of Organic Small Molecules with Alkyl Chains Fabricated by Weak Epitaxy Growth. AB - Because side-chain engineering of organic conjugated molecules has been widely utilized to tune organic solid-state optoelectronic properties, the achievement of their high-quality films is important for realizing high-performance devices. Here, highly crystalline films of an organic molecule with short alkyl chains, 5,8,15,18-tetrabutyl-5,8,15,18-tetrahydroindolo[3,2 a]indole[30,20:5,6]quinacridone (C4-IDQA), are fabricated by weak epitaxy growth, and highly oriented, large-area, and continuous films are obtained. Because of the soft matter properties, the C4-IDQA molecules can adjust themselves to realize commensurate epitaxy growth on the inducing layers and exhibited good lattice matching in the thin film phase. The crystalline phase is also observed in thicker C4-IDQA films. The growth behavior of C4-IDQA on the inducing layer is further investigated, including the strong dependence of film morphologies on substrate temperatures and deposition rates due to the poor diffusion ability of C4-IDQA molecules. Moreover, highly crystalline films and high electron field effect mobility are also obtained for the small molecule N,N'-dioctyl-3,4:9,10 perylene tetracarboxylic diimide (C8-PTCDI), which demonstrate that the weak epitaxy growth method could be an effective way to fabricate highly crystalline films of organic small molecules with flexible side chains. PMID- 27116037 TI - Principles of Public Reason in the UNFCCC: Rethinking the Equity Framework. AB - Since 2011, the focus of international negotiations under the UNFCCC has been on producing a new climate agreement to be adopted in 2015. This phase of negotiations is known as the Durban Platform for Enhanced Action. The goal has been to update the global effort on climate for long-term cooperation. In this period, various changes have been contemplated on the design of the architecture of the global climate effort. Whereas previously, the negotiation process consisted of setting mandated targets exclusively for developed countries, the current setting requests of each country to pledge its contribution to the climate effort in the form of Intended Nationally Determined Contributions (INDCs). The shift away from establishing negotiated targets for rich countries alone towards a universal system of participation through intended contributions raised persistent questions on how exactly the new agreement can ensure equitable terms. How to conceptualize equity within the 2015 climate agreement, and beyond, is the focus of this paper. The paper advances a framework on equity, which moves away from substantive moral conceptions of burden allocation toward refining principles of public reason specially designed for the negotiation process under the UNFCCC. The paper outlines the framework's main features and discusses how it can serve a facilitating role for multilateral discussion on equity on a long term basis capable of adapting to changing circumstances. PMID- 27116038 TI - How the Invisible Hand is Supposed to Adjust the Natural Thermostat: A Guide for the Perplexed. AB - Mainstream climate economics takes global warming seriously, but perplexingly concludes that the optimal economic policy is to almost do nothing about it. This conclusion can be traced to just a few "normative" assumptions, over which there exists fundamental disagreement amongst economists. This paper explores two axes of this disagreement. The first axis ("market vs. regulation") measures faith in the invisible hand to adjust the natural thermostat. The second axis expresses differences in views on the efficiency and equity implications of climate action. The two axes combined lead to a classification of conflicting approaches in climate economics. The variety of approaches does not imply a post-modern "anything goes", as the contradictions between climate and capitalism cannot be wished away. PMID- 27116039 TI - This "Ethical Trap" Is for Roboticists, Not Robots: On the Issue of Artificial Agent Ethical Decision-Making. AB - In this paper we address the question of when a researcher is justified in describing his or her artificial agent as demonstrating ethical decision-making. The paper is motivated by the amount of research being done that attempts to imbue artificial agents with expertise in ethical decision-making. It seems clear that computing systems make decisions, in that they make choices between different options; and there is scholarship in philosophy that addresses the distinction between ethical decision-making and general decision-making. Essentially, the qualitative difference between ethical decisions and general decisions is that ethical decisions must be part of the process of developing ethical expertise within an agent. We use this distinction in examining publicity surrounding a particular experiment in which a simulated robot attempted to safeguard simulated humans from falling into a hole. We conclude that any suggestions that this simulated robot was making ethical decisions were misleading. PMID- 27116040 TI - Zoledronate and Molecular Iodine Cause Synergistic Cell Death in Triple Negative Breast Cancer through Endoplasmic Reticulum Stress. AB - Women consuming molecular iodine (I2) through seaweeds suffer the least from breast cancers. Zoledronate (Zol) is in clinical use for alleviation of bone pain in cancer patients. Triple negative breast cancers exhibit high mortality due to lack of neoadjuvant chemotherapy. I2 and Zol independently cause weak antiproliferative and apoptotic effect. So far, their combined effects have not been tested. We analyzed the effect of combination of I2 with Zol as a potent adjuvant therapeutic agent for triple negative breast cancer cells (MDA-MBA-231) and in the mice model of breast cancer. Cell viability, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, Western blotting, real-time PCR, flow cytometry, and other assays were performed for assessing cell death, calcium levels, and migration potential, respectively, in treated cells. The increased caspase 8, increased [Ca(2+)]c levels, and endoplasmic reticulum (ER) stress resulted in apoptosis. Real time and fluorescence-based analysis demonstrated that the combination treatment targets ER Ca(2+) homeostasis chaperons leading to apoptosis. Combination therapy reduces metalloproteinases 2 and 9, inhibits invasion/migration of cells, and prevents growth of tumor in mice. I2 + Zol combination treatment induces synergistic increase in ER-mediated apoptosis, reduces invasion/migration potential of MDA-MB-231 cells, and exhibits antiproliferative property in vivo demonstrating its potential as combination therapy. PMID- 27116041 TI - Nucleocytoplasmic transport in C9orf72-mediated ALS/FTD. AB - A GGGGCC hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies indicate that disruption of nucleocytoplasmic transport pathways play a critical role in the pathogenesis of C9orf72-mediated ALS/FTD (C9 ALS). Here, we discuss mechanisms by which C9orf72 mutations cause nucleocytoplasmic transport deficits and contribute to disease pathogenesis. We review the current literature regarding nucleocytoplasmic transport disruption in C9-ALS, and discuss implications and directions for future research. PMID- 27116042 TI - Recent developments in biochar as an effective tool for agricultural soil management: a review. AB - In recent years biochar has been demonstrated to be a useful amendment to sequester carbon and reduce greenhouse gas emission from the soil to the atmosphere. Hence it can help to mitigate global environment change. Some studies have shown that biochar addition to agricultural soils increases crop production. The mechanisms involved are: increased soil aeration and water-holding capacity, enhanced microbial activity and plant nutrient status in soil, and alteration of some important soil chemical properties. This review provides an in-depth consideration of the production, characterization and agricultural use of different biochars. Biochar is a complex organic material and its characteristics vary with production conditions and the feedstock used. The agronomic benefits of biochar solely depend upon the use of particular types of biochar with proper field application rate under appropriate soil types and conditions. (c) 2016 Society of Chemical Industry. PMID- 27116043 TI - Substituent effects and chemoselectivity of the intramolecular Buchner reaction of diazoacetamide derivatives catalyzed by the di-Rh(ii)-complex. AB - A density functional theory (DFT) study was performed to reveal that the substituent effects in the alpha-site have an effect on the chemoselectivity of the intramolecular Buchner reaction of diazoacetamide catalyzed by Rh2(OAc)4. The substituent effect is investigated considering five different groups (Z = -Me, OMe, -H, -CN and -C(O)Me) in the substrates. The substituent group in the alpha site changes the electronegativity of the C-atom in carbene and affects the chemoselectivity. The basis of chemoselectivity is the distribution of products that was analyzed by DFT calculations. The barrier energy of the favorable pathway is clearly lower than that of the other pathways. Nucleophilic substituent groups, such as -H, -OMe and -Me, are regarded as electron-donating groups, which increase the electropositivity of the C-atom in carbene compounds and improve the reactivity of the aromatic addition reaction. Electrophilic substituent groups, such as -CN and -C(O)Me, are regarded as electron-withdrawing groups, which decrease the electropositivity of the C-atom in carbene compounds and favor the C-H activation step. The computational results showed that the main product is cycloheptatriene when Z = -H/-OMe. The main product is beta-lactam when the substituent group is -CN/-C(O)Me. When the substituent group is -Me, the products are a mixture of gamma-lactams, beta-lactams and cycloheptatriene. PMID- 27116045 TI - Limiting Cumulative HIV Viremia Copy-Years by Early Treatment Reduces Risk of AIDS and Death. AB - BACKGROUND: Viremia copy-years (VCY), a time-updated measure of cumulative HIV exposure, predicts AIDS/death; although its utility in deciding when to start combination antiretroviral therapy (cART) remains unclear. We aimed to assess the impact of initiating versus deferring cART on risk of AIDS/death by levels of VCY both independent of and within CD4 cell count strata >=500 cells per cubic millimeter. METHODS: Using Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) data, we created a series of nested "trials" corresponding to consecutive months for individuals >=16 years at seroconversion after 1995 who were cART-naive and AIDS-free. Pooling across all trials, time to AIDS/death by CD4, and VCY strata was compared in those initiating vs. deferring cART using Cox models adjusted for: country, sex, risk group, seroconversion year, age, time since last HIV-RNA, and current CD4, VCY, HIV-RNA, and mean number of previous CD4/HIV-RNA measurements/year. RESULTS: Of 9353 individuals, 5312 (57%) initiated cART and 486 (5%) acquired AIDS/died. Pooling CD4 strata, risk of AIDS/death associated with initiating vs. deferring cART reduced as VCY increased. In patients with high CD4 cell counts, >=500 cells per cubic millimeter, there was a trend for a greater reduction for those initiating vs. deferring with increasing VCY (P = 0.09), with the largest benefit in the VCY >=100,000 copy-years/mL group [hazard ratio (95% CI) = 0.41 (0.19 to 0.87)]. CONCLUSIONS: For individuals with CD4 >=500 cells per cubic millimeter, limiting the cumulative HIV burden to <100,000 copy-years/mL through cART may reduce the risk of AIDS/death. PMID- 27116046 TI - Linear Growth Faltering Among HIV-Exposed Uninfected Children. AB - BACKGROUND: HIV-exposed uninfected (HEU) children experience increased mortality compared with their HIV-unexposed uninfected (HUU) peers. It is unclear whether HEU children are also at increased risk for undernutrition, a modifiable risk factor for mortality. METHODS: We conducted a cross-sectional, population-based survey of children <5 years of age in 5 health districts in Botswana. Linear mixed-effects models were used to assess continuous outcomes, and generalized estimating equations were used to estimate relative risks of stunting, wasting, and underweight between HEU (n = 396) and HUU (n = 1109) children. Secondary analyses examined potential mediation by low birth weight. RESULTS: The association between maternal HIV exposure and child stunting varied significantly by child age (P < 0.01). HEU children <1 and >=2 years of age had 1.85 [95% confidence interval (CI): 1.03 to 3.31; P = 0.04] and 1.41 (95% CI: 1.06 to 1.88; P = 0.02) times the risk of stunting compared with HUU children after multivariate adjustment, respectively. During the period of 1-2 years of age, when breastfeeding cessation occurred among HUU children, HUU children had increased risk of stunting compared with HEU children who were predominantly formula fed (relative risk: 1.56; 95% CI: 1.05 to 2.32; P = 0.03). A mediation analysis estimated that 67% of the excess risk of stunting among HEU children >=2 years was attributable to low birth weight (P = 0.02). There was no difference in risk of wasting or underweight. CONCLUSION: HEU children are at increased risk of stunting compared with their HUU peers; however, interventions to increase birth weight may significantly ameliorate this excess risk. Interventions to support optimal growth during weaning are needed for all breast-fed children. PMID- 27116044 TI - Higher Time-Updated Body Mass Index: Association With Improved CD4+ Cell Recovery on HIV Treatment. AB - BACKGROUND: Prior studies found overweight or obese HIV-infected individuals had greater early CD4 cell recovery on antiretroviral therapy (ART), but the results have been inconsistent. We assessed the longitudinal relationship between body mass index (BMI) and CD4 cell recovery on ART in a large, multisite cohort to identify potential physiologic links between adiposity and CD4 cell expansion. METHODS: We modeled the relationship of time-updated BMI with CD4 count in patients starting ART from 17 North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohorts. The primary analysis used a linear mixed effects model incorporating up to 13 years of data per patient and adjusted for age, sex, race, ART regimen, baseline CD4 count and other covariates. Sensitivity analyses limited the cohort to patients with sustained viral suppression or censored at virologic failure. RESULTS: Fourteen thousand eighty-four HIV infected individuals initiating ART contributed data between 1998 and 2010. Time updated BMI was significantly associated with CD4 cell recovery over time (P < 0.001). After 5 years of ART, the mean CD4 count at a BMI of 30 kg/m was 22% higher than at a BMI of 22 kg/m (606 vs. 498 cells per microliter) and 34% higher at a BMI of 40 kg/m (665 vs. 498 cells per microliter). Results were similar in the sensitivity analyses. DISCUSSION: Higher BMI is associated with long-term advantages in immune recovery on ART. Although it is unclear if this impacts health outcomes, including balancing the negative health effects of obesity, elucidating the underlying mechanism could identify therapies for patients with suboptimal immune reconstitution. PMID- 27116047 TI - Plasma Efavirenz Exposure, Sex, and Age Predict Virological Response in HIV Infected African Children. AB - BACKGROUND: Owing to insufficient evidence in children, target plasma concentrations of efavirenz are based on studies in adults. Our analysis aimed to evaluate the pediatric therapeutic thresholds and characterize the determinants of virological suppression in African children. METHODS: We analyzed data from 128 African children (aged 1.7-13.5 years) treated with efavirenz, lamivudine, and one among abacavir, stavudine, or zidovudine, and followed up to 36 months. Individual pharmacokinetic (PK) measures [plasma concentration 12 hours after dose (C12h), plasma concentration 24 hours after dose (C24h), and area under the curve (AUC0-24)] were estimated using population PK modeling. Cox multiple failure regression and multivariable fractional polynomials were used to investigate the risks of unsuppressed viral load associated with efavirenz exposure and other factors among 106 initially treatment-naive children, and likelihood profiling was used to identify the most predictive PK thresholds. RESULTS: The risk of viral load >100 copies per milliliter decreased by 42% for every 2-fold increase in efavirenz mid-dose concentration [95% confidence interval (CI): 23% to 57%; P < 0.001]. The most predictive PK thresholds for increased risk of unsuppressed viral load were C12h 1.12 mg/L [hazard ratio (HR): 6.14; 95% CI: 2.64 to 14.27], C24h 0.65 mg/L (HR: 6.57; 95% CI: 2.86 to 15.10), and AUC0-24 28 mg.h/L (HR: 5.77; 95% CI: 2.28 to 14.58). Children older than 8 years had a more than 10-fold increased risk of virological nonsuppression (P = 0.005); among children younger than 8 years, boys had a 5.31 times higher risk than girls (P = 0.007). Central nervous system adverse events were infrequently reported. CONCLUSIONS: Our analysis suggests that the minimum target C24h and AUC0-24 could be lowered in children. Our findings should be confirmed in a prospective pediatric trial. PMID- 27116048 TI - Non-AIDS-Defining Cancer Mortality: Emerging Patterns in the Late HAART Era. AB - BACKGROUND: Non-AIDS-defining cancers (non-ADCs) have become the leading non-AIDS related cause of death among people with HIV/AIDS. We aimed to quantify the excess risk of cancer-related deaths among Italian people with AIDS (PWA), as compared with people without AIDS (non-PWA). METHODS: A nationwide, population based, retrospective cohort study was carried out among 5285 Italian PWA, aged 15 74 years, diagnosed between 2006 and 2011. Date of death and multiple-cause-of death data were retrieved up to December 2011. Excess mortality, as compared with non-PWA, was estimated using sex- and age-standardized mortality ratios (SMRs) and the corresponding 95% confidence intervals (CIs). RESULTS: Among 1229 deceased PWA, 10.3% reported non-ADCs in the death certificate, including lung (3.1%), and liver (1.4%), cancers. A 7.3-fold (95% CI: 6.1 to 8.7) excess mortality was observed for all non-ADCs combined. Statistically significant SMRs emerged for specific non-ADCs, ie, anus (5 deaths, SMR = 227.6, 95% CI: 73.9 to 531.0), Hodgkin lymphoma (12 deaths, SMR = 122.0, 95% CI: 63.0 to 213.0), unspecified uterus (4 deaths, SMR = 52.5, 95% CI: 14.3 to 134.5), liver (17 deaths, SMR = 13.2, 95% CI: 7.7 to 21.1), skin melanoma (4 deaths, SMR = 10.9, 95% CI: 3.0 to 27.8), lung (38 deaths, SMR = 8.0, 95% CI: 5.7 to 11.0), head and neck (9 deaths, SMR = 7.8, 95% CI: 3.6 to 14.9), leukemia (5 deaths, SMR = 7.6, 95% CI: 2.4 to 17.7), and colon-rectum (10 deaths, SMR = 5.4, 95% CI: 2.6 to 10.0). SMRs for non-ADCs were particularly elevated among PWA infected through injecting drug use. CONCLUSION: This population-based study documented extremely elevated risks of death for non-ADCs among PWA. These findings stress the need of preventive interventions for both virus-related and non-virus-related cancers among HIV-infected individuals. PMID- 27116050 TI - Three-phase contact line and line tension of electrolyte solutions in contact with charged substrates. AB - The three-phase contact line formed by the intersection of a liquid-vapor interface of an electrolyte solution with a charged planar substrate is studied in terms of classical density functional theory applied to a lattice model. The influence of the substrate charge density and of the ionic strength of the solution on the intrinsic structure of the three-phase contact line and on the corresponding line tension is analyzed. We find a negative line tension for all values of the surface charge density and of the ionic strength considered. The strength of the line tension decreases upon decreasing the contact angle via varying either the temperature or the substrate charge density. PMID- 27116049 TI - Benefits to Speech Perception in Noise From the Binaural Integration of Electric and Acoustic Signals in Simulated Unilateral Deafness. AB - OBJECTIVES: This study used vocoder simulations with normal-hearing (NH) listeners to (1) measure their ability to integrate speech information from an NH ear and a simulated cochlear implant (CI), and (2) investigate whether binaural integration is disrupted by a mismatch in the delivery of spectral information between the ears arising from a misalignment in the mapping of frequency to place. DESIGN: Eight NH volunteers participated in the study and listened to sentences embedded in background noise via headphones. Stimuli presented to the left ear were unprocessed. Stimuli presented to the right ear (referred to as the CI-simulation ear) were processed using an eight-channel noise vocoder with one of the three processing strategies. An Ideal strategy simulated a frequency-to place map across all channels that matched the delivery of spectral information between the ears. A Realistic strategy created a misalignment in the mapping of frequency to place in the CI-simulation ear where the size of the mismatch between the ears varied across channels. Finally, a Shifted strategy imposed a similar degree of misalignment in all channels, resulting in consistent mismatch between the ears across frequency. The ability to report key words in sentences was assessed under monaural and binaural listening conditions and at signal to noise ratios (SNRs) established by estimating speech-reception thresholds in each ear alone. The SNRs ensured that the monaural performance of the left ear never exceeded that of the CI-simulation ear. The advantages of binaural integration were calculated by comparing binaural performance with monaural performance using the CI-simulation ear alone. Thus, these advantages reflected the additional use of the experimentally constrained left ear and were not attributable to better ear listening. RESULTS: Binaural performance was as accurate as, or more accurate than, monaural performance with the CI-simulation ear alone. When both ears supported a similar level of monaural performance (50%), binaural integration advantages were found regardless of whether a mismatch was simulated or not. When the CI-simulation ear supported a superior level of monaural performance (71%), evidence of binaural integration was absent when a mismatch was simulated using both the Realistic and the Ideal processing strategies. This absence of integration could not be accounted for by ceiling effects or by changes in SNR. CONCLUSIONS: If generalizable to unilaterally deaf CI users, the results of the current simulation study would suggest that benefits to speech perception in noise can be obtained by integrating information from an implanted ear and an NH ear. A mismatch in the delivery of spectral information between the ears due to a misalignment in the mapping of frequency to place may disrupt binaural integration in situations where both ears cannot support a similar level of monaural speech understanding. Previous studies that have measured the speech perception of unilaterally deaf individuals after CI but with nonindividualized frequency-to-electrode allocations may therefore have underestimated the potential benefits of providing binaural hearing. However, it remains unclear whether the size and nature of the potential incremental benefits from individualized allocations are sufficient to justify the time and resources required to derive them based on cochlear imaging or pitch-matching tasks. PMID- 27116051 TI - Human resources for health--investing in action. PMID- 27116052 TI - Mental health care in French prisons. PMID- 27116053 TI - Fixing emergency general surgery in England. PMID- 27116054 TI - Yellow fever vaccine supply: a possible solution. PMID- 27116055 TI - Increasing value and reducing waste in biomedical research: librarians are listening and are part of the answer. PMID- 27116057 TI - Brazil's health system woes worsen in economic crisis. PMID- 27116058 TI - Cryptococcal meningitis: a blind spot in curbing AIDS. PMID- 27116059 TI - The straitjacket. PMID- 27116062 TI - War's carnage: wounds and weapons. PMID- 27116063 TI - Andrew Herxheimer. PMID- 27116064 TI - Human resources in protracted crises: Syrian medical workers. PMID- 27116065 TI - The GAS trial. PMID- 27116066 TI - The GAS trial. PMID- 27116067 TI - The GAS trial. PMID- 27116068 TI - The GAS trial - Authors' reply. PMID- 27116069 TI - Questioning the outcome of the Building Blocks trial. PMID- 27116070 TI - Questioning the outcome of the Building Blocks trial - Authors' reply. PMID- 27116071 TI - Challenges faced by young Chinese doctors. PMID- 27116072 TI - The benefits of screening programmes. PMID- 27116073 TI - Department of Error. PMID- 27116074 TI - Suicide rates in children and young people increase. PMID- 27116075 TI - Department of Error. PMID- 27116076 TI - Department of Error. PMID- 27116077 TI - An efficient indenyl-derived phosphine ligand for the Suzuki-Miyaura coupling of sterically hindered aryl halides. AB - An air-stable aryl substituted indenyl phosphine used in combination with Pd(OAc)2 provides a highly efficient catalyst for the Suzuki-Miyaura cross coupling reaction of sterically hindered aryl halides with aryl boronic acids. PMID- 27116078 TI - Economic Impact of an Advanced Illness Consultation Program within a Medicare Advantage Plan Population. AB - BACKGROUND: In the United States the quality and cost associated with medical treatment for individuals experiencing an advanced illness is highly variable and is often misaligned with the patient's and family's quality of life values and priorities. Many of the obstacles that stand in the way of aligning the care that an individual receives with their priorities are well understood in the context of behavioral science. Through employing behavioral based approaches to improve the quality of communication and shared decision making processes among patients, providers and families it is possible to enhance the efficiency of delivering care which is also more highly aligned with the individual's preferences. OBJECTIVES: The study objectives were to measure the economic impact of a proprietary advanced illness behavioral consultation program, the Vital Decisions Living Well Consultation Program (LWCP), on the cost of care delivered during the last six and three months of life for enrolled members in a Medicare Advantage plan. STUDY DESIGN: Retrospective matched case control analysis examined medical, pharmaceutical, and capitation expenses after an offset by premium revenue. METHODS: The treatment population consisted of participating members of the LWCP who died between October 1, 2011 and March 31, 2013 (N = 1755). The control population consisted of plan members who died between July 1, 2008 and June 1, 2011, prior to the introduction of the LWCP (N = 5560). Criteria used to match treatment subjects with one or more control subjects were diagnosis, age at death, and health care costs incurred prior to the time under examination. A paired t-test evaluated the significance of differences between the matched treatment and control members. RESULTS: The mean cost reduction during the last six months of life for treatment members compared to matched control group members was $13,956 (p < 0.001) during the last six months of life and $9,285 (p < 0.001) during the last three months of life. CONCLUSION: Members with advanced illness who participated in LWCP had significantly lower end-of-life (EOL) spending compared to matched members who did not participate in the program. PMID- 27116079 TI - A Data Mining Approach to Predict In Situ Detoxification Potential of Chlorinated Ethenes. AB - Despite advances in physicochemical remediation technologies, in situ bioremediation treatment based on Dehalococcoides mccartyi (Dhc) reductive dechlorination activity remains a cornerstone approach to remedy sites impacted with chlorinated ethenes. Selecting the best remedial strategy is challenging due to uncertainties and complexity associated with biological and geochemical factors influencing Dhc activity. Guidelines based on measurable biogeochemical parameters have been proposed, but contemporary efforts fall short of meaningfully integrating the available information. Extensive groundwater monitoring data sets have been collected for decades, but have not been systematically analyzed and used for developing tools to guide decision-making. In the present study, geochemical and microbial data sets collected from 35 wells at five contaminated sites were used to demonstrate that a data mining prediction model using the classification and regression tree (CART) algorithm can provide improved predictive understanding of a site's reductive dechlorination potential. The CART model successfully predicted the 3-month-ahead reductive dechlorination potential with 75.8% and 69.5% true positive rate (i.e., sensitivity) for the training set and the test set, respectively. The machine learning algorithm ranked parameters by relative importance for assessing in situ reductive dechlorination potential. The abundance of Dhc 16S rRNA genes, CH4, Fe(2+), NO3( ), NO2(-), and SO4(2-) concentrations, total organic carbon (TOC) amounts, and oxidation-reduction potential (ORP) displayed significant correlations (p < 0.01) with dechlorination potential, with NO3(-), NO2(-), and Fe(2+) concentrations exhibiting precedence over other parameters. Contrary to prior efforts, the power of data mining approaches lies in the ability to discern synergetic effects between multiple parameters that affect reductive dechlorination activity. Overall, these findings demonstrate that data mining techniques (e.g., machine learning algorithms) effectively utilize groundwater monitoring data to derive predictive understanding of contaminant degradation, and thus have great potential for improving decision-making tools. A major need for realizing the predictive capabilities of data mining approaches is a curated, open-access, up to-date and comprehensive collection of biogeochemical groundwater monitoring data. PMID- 27116081 TI - Physical activity in individuals with haemophilia and experience with recombinant factor VIII Fc fusion protein and recombinant factor IX Fc fusion protein for the treatment of active patients: a literature review and case reports. AB - The World Federation of Hemophilia and the National Hemophilia Foundation encourage people with haemophilia (PWH) to participate in routine physical activity. The benefits of physical activity for PWH include improvements in joint, bone, and muscle health. Accordingly, a number of studies suggest that levels of physical activity among PWH are similar to those of their healthy peers, especially among individuals who began prophylaxis at an early age (<=3 years). Importantly, several studies found either no increased risk or only a transient increase in risk of bleeding with more intensive physical activity compared with less intensive physical activity. Data on optimal prophylaxis regimens for PWH who participate in physical/sporting activities; however, remain sparse. Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor IX Fc fusion protein (rFIXFc) demonstrated efficacy for the prevention and treatment of bleeding episodes in Phase 3 clinical trials of participants with haemophilia A and B, respectively, with most individuals able to maintain or increase their physical activities. This manuscript reviews the current literature that describes physical activity in PWH. Additionally, case studies are presented to provide supplemental information to clinicians illustrating the use of rFVIIIFc and rFIXFc in physically active patients with haemophilia A and B, respectively. These case reports demonstrate that it is possible for patients to be physically active and maintain good control of their haemophilia with extended interval prophylactic dosing using rFVIIIFc or rFIXFc. PMID- 27116082 TI - Blue emitting organic semiconductors under high pressure: status and outlook. AB - This review describes essential optical and emerging structural experiments that use high GPa range hydrostatic pressure to probe physical phenomena in blue emitting organic semiconductors including pi-conjugated polyfluorene and related compounds. The work emphasizes molecular structure and intermolecular self organization that typically determine transport and optical emission in pi conjugated oligomers and polymers. In this context, hydrostatic pressure through diamond anvil cells has proven to be an elegant tool to control structure and interactions without chemical intervention. This has been highlighted by high pressure optical spectroscopy whilst analogous x-ray diffraction experiments remain less frequent. By focusing on a class of blue-emitting pi-conjugated polymers, polyfluorenes, this article reviews optical spectroscopic studies under hydrostatic pressure, addressing the impact of molecular and intermolecular interactions on optical excitations, electron-phonon interaction, and changes in backbone conformations. This picture is connected to the optical high pressure studies of other pi-conjugated systems and emerging x-ray scattering experiments from polyfluorenes which provides a structure-property map of pressure-driven intra- and interchain interactions. Key obstacles to obtain further advances are identified and experimental methods to resolve them are suggested. PMID- 27116084 TI - The effect of audiovisual distraction on the tolerability of flexible bronchoscopy: a randomized trial. AB - OBJECTIVE: It is important to minimize patient discomfort during invasive diagnostic and therapeutic procedures such as bronchoscopy. The aim of this study was to investigate the effect of audiovisual distraction on the tolerability of flexible bronchoscopy (FB). MATERIALS AND METHODS: We conducted a prospective, randomized, controlled trial on patients undergoing FB at a hospital in Zahedan, Iran, in 2015. The patients were equally and randomly divided into a control group and an experimental group. Patients in the control group received standard care during FB While patients in the experimental group selected familiar folk music that was played during the procedure along with the screening of images of nature. The duration of the FB was recorded and cough, dyspnea, choking, nausea and pain were evaluated using a visual analogue scale before and after the procedure. Statistical analysis was carried out using paired and independent t tests, chi2 -tests and analysis of covariance. RESULTS: Sixty patients met the inclusion criteria and were randomized. The duration of the FB procedure was significantly shorter in the experimental group compared with the control group (mean +/- standard deviation 7.87 +/- 2.12 min and 10.27 +/- 1.72 min, respectively; P < 0.05). Dyspnea, cough and pain were significantly less severe in the experimental group compared with the control group (P < 0.05), but choking and nausea were not significantly different between the two groups (P > 0.1). CONCLUSIONS: Our findings showed that audiovisual distraction had a positive effect on the tolerability of FB. This method has important potential as a simple and practical approach in reducing discomfort during invasive diagnostic and treatment procedures. PMID- 27116085 TI - Novel in vivo mouse model of implant related spine infection. AB - Post-operative spine infections are a challenge, as hardware must often be retained to prevent destabilization of the spine, and bacteria form biofilm on implants, rendering them inaccessible to antibiotic therapy, and immune cells. A model of posterior-approach spinal surgery was created in which a stainless steel k-wire was transfixed into the L4 spinous process of 12-week-old C57BL/six mice. Mice were then randomized to receive either one of three concentrations (1 * 102 , 1 * 103 , and 1 * 104 colony forming units (CFU)) of a bioluminescent strain of Staphylococcus aureus or normal saline at surgery. The mice were then longitudinally imaged for bacterial bioluminescence to quantify infection. The 1 * 102 CFU group had a decrease in signal down to control levels by POD 25, while the 1 * 103 and 1 * 104 CFU groups maintained a 10-fold higher signal through POD 35. Bacteria were then harvested from the pin and surrounding tissue for confirmatory CFU counts. All mice in the 1 * 104 CFU group experienced wound breakdown, while no mice in the other groups had this complication. Once an optimal bacterial concentration was determined, mice expressing enhanced green fluorescent protein in their myeloid cells (Lys-EGFP) were utilized to contemporaneously quantify bacterial burden, and immune response. Neutrophil fluorescence peaked for both groups on POD 3, and then declined. The infected group continued to have a response above the control group through POD 35. This study, establishes a noninvasive in vivo mouse model of spine implant infection that can quantify bacterial burden and host inflammation longitudinally in real time without requiring animal sacrifice. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:193-199, 2017. PMID- 27116086 TI - Cellulose Tailored Anatase TiO2 Nanospindles in Three-Dimensional Graphene Composites for High-Performance Supercapacitors. AB - The morphologies of transition metal oxides have decisive impact on the performance of their applications. Here, we report a new and facile strategy for in situ preparation of anatase TiO2 nanospindles in three-dimensional reduced graphene oxide (RGO) structure (3D TiO2@RGO) using cellulose as both an intermediate agent eliminating the negative effect of graphene oxide (GO) on the growth of TiO2 crystals and as a structure-directing agent for the shape controlled synthesis of TiO2 crystals. High-resolution transmission electron microscopy and X-ray diffractometer analysis indicated that the spindle shape of TiO2 crystals was formed through the restriction of the growth of high energy {010} facets due to preferential adsorption of cellulose on these facets. Because of the 3D structure of the composite, the large aspect ratio of the TiO2 nanospindles, and the exposed high-energy {010} facets of the TiO2 crystals, the 3D TiO2@RGO(Ce 1.7) exhibited excellent capacitive performance as an electrode material for supercapacitors, with a high specific capacitance (ca. 397 F g(-1)), a high energy density (55.7 Wh kg(-1)), and a high power density (1327 W kg(-1)) on the basis of the masses of RGO and TiO2. These levels of capacitive performance far exceed those of previously reported TiO2-based composites. PMID- 27116087 TI - Educational Value of Digital Whole Slides Accompanying Published Online Pathology Journal Articles: A Multi-Institutional Study. AB - CONTEXT: -Despite great interest in using whole slide imaging (WSI) in pathology practice and education, few pathology journals have published WSI pertinent to articles within their pages or as supplemental materials. OBJECTIVE: -To evaluate whether there is measurable added educational value of including WSI in publications. DESIGN: -Thirty-seven participants, 16 (43.3%), 15 (40.5%), and 6 (16.2%) junior pathology residents (postgraduate year 1-2), senior pathology residents (postgraduate year 3-4), and board-certified pathologists, respectively, read a sequence of 10 journal articles on a wide range of pathology topics. A randomized subgroup also reviewed the WSI published with the articles. Both groups completed a survey tool assessing recall of text-based content and of image-based material pertinent to the diseases but not present in the fixed published images. RESULTS: -The group examining WSI had higher performance scores in 72% of image-based questions (36 of 50 questions) as compared with the non-WSI group. As an internal study control, the WSI group had higher performance scores in only 40% of text-based questions (6 of 15 questions). The WSI group had significantly better performance than the non-WSI group for image-based questions compared with text-based questions (P < .05, Fisher exact test). CONCLUSION: -Our study provides supporting evidence that WSI offers enhanced value to the learner beyond the text and fixed images selected by the author. We strongly encourage more journals to incorporate WSI into their publications. PMID- 27116088 TI - Estrogen Receptor and Cytokeratin 5 Are Reliable Markers to Separate Usual Ductal Hyperplasia From Atypical Ductal Hyperplasia and Low-Grade Ductal Carcinoma In Situ. AB - CONTEXT: -High-molecular weight cytokeratins, such as cytokeratin 5 (CK5), are helpful to distinguish usual ductal hyperplasia (UDH) from atypical ductal hyperplasia (ADH) or low-grade ductal carcinoma in situ (DCIS). Few studies have looked at combining CK5 with estrogen receptor (ER) to differentiate UDH from ADH. OBJECTIVE: -To evaluate the expression pattern of CK5 and ER as single or combined markers to separate UDH from ADH and low-grade DCIS. DESIGN: -A total of 23 ADH, 10 low-grade DCIS, and 32 UDH whole-tissue slides were stained for ER, CK5, progesterone receptor (PR), and Bcl-2. Nuclear staining of ER and PR was scored as diffuse (>80%), focal (10%-80%), or negative (<10%). Cytoplasmic staining of CK5 and Bcl-2 was scored as diffuse (>60%), focal (10%-60%), or negative (<10%). Differences in staining patterns were evaluated. RESULTS: -For ER staining: 94% of ADH/DCIS cases showed a diffuse staining pattern, whereas none of the 32 UDH cases showed diffuse staining. For CK5 staining: 96% of ADH/DCIS cases were negative or focally positive, whereas all 32 UDH cases had diffuse staining. The combination of ER and CK5 increased the sensitivity (94% to 97%). For PR staining: 11 of 23 ADH cases (48%), 6 of 10 DCIS cases (60%), and 4 of 32 UDH cases (13%) showed diffuse staining. Bcl-2 staining showed no statistical significance (P = .73). CONCLUSIONS: -Although morphology remains the gold standard, ER and CK5 are useful makers to differentiate UDH from ADH. Progesterone receptor staining may have limited value, and Bcl-2 staining is not useful. PMID- 27116089 TI - Margin Status in Shave Biopsies of Nonmelanoma Skin Cancers: Is It Worth Reporting? AB - CONTEXT: -The practice of reporting margin status in biopsies is relatively unique to biopsies of the skin and highly variable among pathologists. OBJECTIVE: -To address the accuracy of margin evaluation in shave biopsies of nonmelanoma skin cancers. DESIGN: -We collected shave biopsies of squamous and basal cell carcinomas that appeared to have uninvolved margins on routine sign out. We obtained deeper levels on corresponding tissue blocks until blocks were exhausted and examined them for tumor at biopsy margins. RESULTS: -Forty-seven consecutive cases were collected, including 20 squamous cell (43%) and 27 basal cell (57%) carcinomas. Eleven of 47 cases (23%) with negative margins at initial diagnosis demonstrated positive margins upon deeper-level examination. Margins of 8 of 27 basal cell carcinomas (30%) and 3 of 20 squamous cell carcinomas (15%) were erroneously classified as "negative" on routine examination. CONCLUSIONS: -No guidelines exist regarding the reporting of margins in nonmelanoma skin cancer biopsies, and reporting practices vary extensively among pathologists. We found that nearly one-quarter of positive margins in shave biopsies for cutaneous carcinomas are missed on standard histologic examination. Moreover, reporting of a positive margin may also be misleading if the clinician has definitively treated the skin cancer at the time of biopsy. For these reasons, and as routine exhaustion of all tissue blocks is impractical, the decision to include or exclude a comment regarding the margin status should be given conscious consideration, accounting for the clinical intent of the biopsy and any known information regarding postbiopsy treatment. PMID- 27116090 TI - Infrared Spectrum of Toluene: Comparison of Anharmonic Isolated-Molecule Calculations and Experiments in Liquid Phase and in a Ne Matrix. AB - First-principles anharmonic calculations are carried out for the CH stretching vibrations of isolated toluene and compared with the experimental infrared spectra of isotopologues of toluene in a Ne matrix at 3 K and of liquid toluene at room temperature. The calculations use the vibrational self-consistent field method and the B3LYP potential surface. In general, good agreement is found between the calculations and experiments. However, the spectrum of toluene in a Ne matrix is more complicated than that predicted theoretically. This distinction is discussed in terms of matrix-site and resonance effects. Interestingly, the strongest peak in the CH stretching spectrum has similar widths in the liquid phase and in a Ne matrix, despite the very different temperatures. Implications of this observation to the broadening mechanism are discussed. Finally, our results show that the B3LYP potential offers a good description of the anharmonic CH stretching band in toluene, but a proper description of matrix-site and resonance effects remains a challenge. PMID- 27116091 TI - Peroral transhepatic cholangioscopy-guided electrohydraulic lithotripsy via an endoscopic ultrasonography-guided hepaticogastrostomy route for bile duct stones in a patient with Roux-en-Y anatomy. PMID- 27116092 TI - Transgastric endoscopic vacuum therapy with a new open-pore film drainage device in a case of infective pancreatic necrosis. PMID- 27116093 TI - Biliary tract intraductal papillary mucinous neoplasm: single-operator cholangioscopy and clearance of mucin obstruction. PMID- 27116094 TI - Peroral video cholangioscopic findings in a biliary intraductal mucinous cystic neoplasm. PMID- 27116095 TI - Spontaneous perforation of an intramural esophageal pseudodiverticulosis treated with intraluminal endoscopic vacuum therapy using a double-lumen vacuum drainage with intestinal feeding tube. PMID- 27116096 TI - A very rare postcholecystectomy complication. PMID- 27116097 TI - Endoscopic mucosal resection of duodenal carcinoid. PMID- 27116098 TI - Endoscopic treatment of colonic diverticular bleeding using an over-the-scope clip. PMID- 27116099 TI - Complete resection of a 225-mm circumferential rectosigmoid intramucosal carcinoma by endoscopic submucosal dissection. PMID- 27116100 TI - Endoscopic cholecystogastrostomy in a patient with gallbladder empyema secondary to cholangiocarcinoma. PMID- 27116101 TI - Usefulness of confocal laser endomicroscopy for the diagnosis of ileocecal lymphoma. PMID- 27116102 TI - Neural substrates of cognitive biases during probabilistic inference. AB - Decision making often requires simultaneously learning about and combining evidence from various sources of information. However, when making inferences from these sources, humans show systematic biases that are often attributed to heuristics or limitations in cognitive processes. Here we use a combination of experimental and modelling approaches to reveal neural substrates of probabilistic inference and corresponding biases. We find systematic deviations from normative accounts of inference when alternative options are not equally rewarding; subjects' choice behaviour is biased towards the more rewarding option, whereas their inferences about individual cues show the opposite bias. Moreover, inference bias about combinations of cues depends on the number of cues. Using a biophysically plausible model, we link these biases to synaptic plasticity mechanisms modulated by reward expectation and attention. We demonstrate that inference relies on direct estimation of posteriors, not on combination of likelihoods and prior. Our work reveals novel mechanisms underlying cognitive biases and contributions of interactions between reward dependent learning, decision making and attention to high-level reasoning. PMID- 27116103 TI - Droplet Characterization and Penetration of an Ultra-Low Volume Mosquito Adulticide Spray Targeting the Asian Tiger Mosquito, Aedes albopictus, within Urban and Suburban Environments of Northeastern USA. AB - Adult control of Aedes albopictus via ultra-low volume is difficult because this species occurs primarily in peridomestic habitats where obstacles such as buildings and vegetation can disrupt spray plumes and droplet dispersion. We determined droplet penetration and characterization of a pyrethroid adulticide applied from the ground at mid (46.77 ml/ha) and maximum (93.53 ml/ha) label rates within cryptic habitats of urban and suburban environments. Droplets were collected from all habitats, with no significant differences detected between locations within the same application rate or collection method. No differences were detected in droplet densities (drops per mm2) between rates within urban environments, but more droplets were collected in urban (149.93 +/- 11.07 SE) than suburban sites (114.37 +/- 11.32) at the maximum label rate (P = 0.003). The excellent penetration of aerosols into cryptic habitats of an urban site was likely due to the shorter spray paths afforded by our network of roads and alleys. Mid label rates displayed similar droplet density values as maximum label rates in urban areas, indicating that lower rates may be used effectively to reduce costs, lessen non-target effects, and increase environmental stewardship. Advances in formulations and technology are driving changes in adulticide applications, leading to use of the minimum effective dose for maximum efficacy, precision, and accountability. PMID- 27116104 TI - High-Throughput Blood- and Lymph-Capillaries with Open-Ended Pores Which Allow the Transport of Drugs and Cells. AB - High-throughput screening of drug diffusion and cell transports from the blood /lymph-capillary (BC/LC) networks to the peripheral cells in 3D engineered tissues using a microplate would make a powerful tool for in vitro pharmacokinetic assessments. Here, perfusable BC/LC networks embedded in 3D tissues inside a 24-microplate using a cell-coating technology are reported which allows location control of cell layers. Arrangement of an endothelial cell layer at the top, middle, and bottom of dermal fibroblast tissues provides an interconnected BC/LC networks possessing open pores on both surfaces. When fluorescently labeled dextran, microparticles, and red blood cells are applied to the top surfaces, diffusion and penetration through the networks are observed depending on the size of the substances. Moreover, BC networks mimick a series of in vivo processes of cancer metastasis, extravasation, growth, and growth suppression with drug treatment. The perfusable networks existing in 3D-tissues show great potential for in vitro pharmacokinetic studies. PMID- 27116105 TI - Vomiting as a Symptom and Transmission Risk in Norovirus Illness: Evidence from Human Challenge Studies. AB - BACKGROUND: In the US, noroviruses are estimated to cause 21 million cases annually with economic losses reaching $2 billion. Outbreak investigations frequently implicate vomiting as a major transmission risk. However, little is known about the characteristics of vomiting as a symptom or the amount of virus present in emesis. METHODOLOGY AND PRINCIPAL FINDINGS: Emesis samples and symptomology data were obtained from previous norovirus human challenge studies with GI.1 Norwalk virus, GII.2 Snow Mountain virus, and a pilot study with GII.1 Hawaii virus. Viral titers in emesis were determined using strain-specific quantitative RT-PCR. In all four studies, vomiting was common with 40-100% of infected subjects vomiting at least once. However, only 45% of subjects with vomiting also had diarrhea. Most of the emesis samples had detectable virus and the mean viral titers were 8.0 x 105 and 3.9 x 104 genomic equivalent copies (GEC)/ml for GI and GII viruses, respectively (p = 0.02). Sample pH was correlated with GII.2 Snow Mountain virus detection. CONCLUSIONS AND SIGNIFICANCE: Half of all subjects with symptomatic infection experienced vomiting and the average subject shed 1.7 x 108 GEC in emesis. Unlike shedding through stool, vomiting is more likely to result in significant environmental contamination, leading to transmission through fomites and airborne droplets. This quantitative data will be critical for risk assessment studies to further understand norovirus transmission and develop effective control measures. The correlation between sample pH and virus detection is consistent with a single site of virus replication in the small intestine and stomach contents becoming contaminated by intestinal reflux. Additionally, the frequency of vomiting without concurrent diarrhea suggests that epidemiology studies that enroll subjects based on the presence of diarrhea may be significantly underestimating the true burden of norovirus disease. PMID- 27116106 TI - Racial/Ethnic Disparities in Medicare Beneficiaries' Care Coordination Experiences. AB - BACKGROUND: Little is known about racial/ethnic differences in the experience of care coordination. To the extent that they exist, such differences may exacerbate health disparities given the higher prevalence of some chronic conditions among minorities. OBJECTIVE: To investigate the extent to which racial/ethnic disparities exist in the receipt of coordinated care by Medicare beneficiaries. SUBJECTS: A total of 260,974 beneficiaries who responded to the 2013 Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. METHODS: We fit a series of linear, case-mix adjusted models predicting Medicare CAHPS measures of care coordination from race/ethnicity. RESULTS: Hispanic, black, and Asian/Pacific Islander (API) beneficiaries reported that their personal doctor had medical records and other relevant information about their care significantly less often than did non-Hispanic white beneficiaries (-2 points for Hispanics, -1 point for blacks, and -4 points for APIs on a 100-point scale). These 3 groups also reported significantly greater difficulty getting timely follow-up on test results than non-Hispanic white beneficiaries (-9 points for Hispanics, -1 point for blacks, -5 points for APIs). Hispanic and black beneficiaries reported that help was provided in managing their care significantly less often than did non Hispanic white beneficiaries (-2 points for Hispanics, -3 points for blacks). API beneficiaries reported that their personal doctor discussed their medications and had up-to-date information on care from specialists significantly less often than did non-Hispanic white beneficiaries (-2 and -4 points, respectively). DISCUSSION: These results suggest a need for efforts to address racial/ethnic disparities in care coordination to help ensure high-quality care for all patients. Public reporting of plan-level performance data by race/ethnicity may also be helpful to Medicare beneficiaries and their advocates. PMID- 27116107 TI - Effect of a Pragmatic, Cluster-randomized Controlled Trial on Patient Experience With Care: The Transforming Outcomes for Patients Through Medical Home Evaluation and reDesign (TOPMED) Study. AB - BACKGROUND: Health reform programs like the patient-centered medical home are intended to improve the triple aim. Previous studies on patient-centered medical homes have shown mixed effects, but high value elements (HVEs) are expected to improve the triple aim. OBJECTIVE: The aim of this study is to understand whether focusing on HVEs would improve patient experience with care. METHODS: Eight clinics were cluster-randomized in a year-long trial. Both arms received practice facilitation, IT-based reporting, and financial incentives. Intervention practices were encouraged to choose HVEs for quality improvement goals. To assess patient experience, 1597 Consumer Assessment of Healthcare Providers and Systems surveys were sent pretrial and posttrial to a stratified random sample of patients. Difference-in-difference multivariate analysis was used to compare patient responses from intervention and control practices, adjusting for confounders. RESULTS: The response rate was 43% (n=686). Nonrespondent analysis showed no difference between arms, although differences were seen by risk status and age. The overall difference in difference was 2.8%, favoring the intervention. The intervention performed better in 9 of 11 composites. The intervention performed significantly better in follow-up on test results (P=0.091) and patients' rating of the provider (P=0.091), whereas the control performed better in access to care (P=0.093). Both arms also had decreases, including 4 of 11 composites for the intervention, and 8 of 11 for the control. DISCUSSION: Practices that targeted HVEs showed significantly more improvement in patient experience of care. However, contemporaneous trends may have affected results, leading to declines in patient experience in both arms. PMID- 27116108 TI - The Association of Gasoline Prices With Hospital Utilization and Costs for Motorcycle and Nonmotorcycle Motor Vehicle Injuries in the United States. AB - OBJECTIVES: This study examined the association between gasoline prices and hospitalizations for motorcycle and nonmotorcycle motor vehicle crash (MVC) injuries. METHODS: Data on inpatient hospitalizations were obtained from the 2001 to 2010 Nationwide Inpatient Sample. Panel feasible generalized least squares models were used to estimate the effects of monthly inflation-adjusted gasoline prices on hospitalization rates for MVC injuries and to predict the impact of increasing gasoline taxes. RESULTS: On the basis of the available data, a $1.00 increase in the gasoline tax was associated with an estimated 8348 fewer annual hospitalizations for nonmotorcycle MVC injuries, and reduced hospital costs by $143 million. However, the increase in the gasoline tax was also associated with an estimated 3574 more annual hospitalizations for motorcycle crash injuries, and extended hospital costs by $73 million. CONCLUSIONS: This analysis of some existing data suggest that the increased utilization and costs of hospitalization from motorcycle crash injuries associated with an increase in the price of gasoline are likely to substantially offset reductions in nonmotorcycle MVC injuries. A policy decision to increase the gasoline tax could improve traffic safety if the increased tax is paired with public health interventions to improve motorcycle safety. PMID- 27116109 TI - Who Were the Early Adopters of Dabigatran?: An Application of Group-based Trajectory Models. AB - BACKGROUND: Variation in physician adoption of new medications is poorly understood. Traditional approaches (eg, measuring time to first prescription) may mask substantial heterogeneity in technology adoption. OBJECTIVE: Apply group based trajectory models to examine the physician adoption of dabigratran, a novel anticoagulant. METHODS: A retrospective cohort study using prescribing data from IMS XponentTM on all Pennsylvania physicians regularly prescribing anticoagulants (n=3911) and data on their characteristics from the American Medical Association Masterfile. We examined time to first dabigatran prescription and group-based trajectory models to identify adoption trajectories in the first 15 months. Factors associated with rapid adoption were examined using multivariate logistic regressions. OUTCOMES: Trajectories of monthly share of oral anticoagulant prescriptions for dabigatran. RESULTS: We identified 5 distinct adoption trajectories: 3.7% rapidly and extensively adopted dabigatran (adopting in <=3 mo with 45% of prescriptions) and 13.4% were rapid and moderate adopters (<=3 mo with 20% share). Two groups accounting for 21.6% and 16.1% of physicians, respectively, were slower to adopt (6-10 mo post-introduction) and dabigatran accounted for <10% share. Nearly half (45.2%) of anticoagulant prescribers did not adopt dabigatran. Cardiologists were much more likely than primary care physicians to rapidly adopt [odds ratio (OR)=12.2; 95% confidence interval (CI), 9.27-16.1] as were younger prescribers (age 36-45 y: OR=1.49, 95% CI, 1.13-1.95; age 46-55: OR=1.34, 95% CI, 1.07-1.69 vs. >55 y). CONCLUSIONS: Trajectories of physician adoption of dabigatran were highly variable with significant differences across specialties. Heterogeneity in physician adoption has potential implications for the cost and effectiveness of treatment. PMID- 27116110 TI - Medicaid Health Home Reducing Costs and Reliance on Emergency Department: Evidence From Iowa. AB - BACKGROUND: The Affordable Care Act allowed an optional Medicaid State Plan benefit for states to establish Health Homes coordinating care for people who have chronic conditions. Differences in medical home program incentives and implementation styles are important to understand in evaluating effects on key outcomes such as cost and acute care. In Iowa, a Medicaid Health Home (MHH) program was developed targeting Medicaid members with multiple chronic conditions. Provider patient management payments were tied to the number of chronic conditions of MHH members. OBJECTIVES: To assess the effects of an Iowa MHH program on total spending, emergency department (ED) utilization, and ED spending. DATA: Claims data from January 2011 through December 2013; per member per month unit of analysis. RESEARCH DESIGN: We use a difference-in-difference regression design comparing pre/post outcomes for MHH members to pre/post outcomes for Medicaid members not participating in the MHH. We include individual fixed effects and matched controls to minimize the potential for confounding. In addition, we include a series of administrative covariates to control for individual demographic and geographic variation. RESULTS: Participation in the MHH program reduced spending by $132 per member per month. There is also evidence that the largest cost savings occur with a lag, as those in the program longer than a year showed the most savings. Members were less likely to visit the ED compared with traditional Medicaid recipients and ED spending was also lower for MHH members. CONCLUSIONS: Participation in a MHH program led to fewer ED visits and lower overall spending among Medicaid recipients in Iowa. PMID- 27116111 TI - Validity of the Agency for Health Care Research and Quality Patient Safety Indicators and the Centers for Medicare and Medicaid Hospital-acquired Conditions: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The Agency for Health Care Research and Quality Patient Safety Indicators (PSIs) and Centers for Medicare and Medicaid Services Hospital acquired Conditions (HACs) are increasingly being used for pay-for-performance and public reporting despite concerns over their validity. Given the potential for these measures to misinform patients, misclassify hospitals, and misapply financial and reputational harm to hospitals, these need to be rigorously evaluated. We performed a systematic review and meta-analysis to assess PSI and HAC measure validity. METHODS: We searched MEDLINE and the gray literature from January 1, 1990 through January 14, 2015 for studies that addressed the validity of the HAC measures and PSIs. Secondary outcomes included the effects of present on admission (POA) modifiers, and the most common reasons for discrepancies. We developed pooled results for measures evaluated by >=3 studies. We propose a threshold of 80% for positive predictive value or sensitivity for pay-for performance and public reporting suitability. RESULTS: Only 5 measures, Iatrogenic Pneumothorax (PSI 6/HAC 17), Central Line-associated Bloodstream Infections (PSI 7), Postoperative hemorrhage/hematoma (PSI 9), Postoperative deep vein thrombosis/pulmonary embolus (PSI 12), and Accidental Puncture/Laceration (PSI 15), had sufficient data for pooled meta-analysis. Only PSI 15 (Accidental Puncture and Laceration) met our proposed threshold for validity (positive predictive value only) but this result was weakened by considerable heterogeneity. Coding errors were the most common reasons for discrepancies between medical record review and administrative databases. POA modifiers may improve the validity of some measures. CONCLUSION: This systematic review finds that there is limited validity for the PSI and HAC measures when measured against the reference standard of a medical chart review. Their use, as they currently exist, for public reporting and pay-for-performance, should be publicly reevaluated in light of these findings. PMID- 27116113 TI - Variations in Occipitocervical and Cervicothoracic Alignment Parameters Based on Age: A Prospective Study of Asymptomatic Volunteers Using Full-Body Radiographs. AB - STUDY DESIGN: Cross-Sectional Cohort Study OBJECTIVE.: To describe age-stratified normative values of novel occipitocervical, cervical, and cervicothoracic alignment parameters. SUMMARY OF BACKGROUND DATA: Full-body radiographic images obtained without stitching or vertical distortion represent an ideal method to evaluate occipitocervical alignment and horizontal gaze. METHODS: One hundred twenty adults with no back or neck symptoms were recruited. Age, sex, body mass index, Neck Disability Index (NDI), and Oswestry Disability Index scores were recorded. Radiographic parameters measured included: center sacral vertebral line, chin brow vertical angle (CBVA), orbital tilt (OrT), orbital slope, occipital slope (OS), occipital incidence, occiput-C2 (O-C2) lordosis, cervical lordosis (C2-C7, CL), T1 slope (TS), neck tilt, thoracic inlet angle (TIA), cervicothoracic kyphosis (C6-T4), and C2-C7 sagittal vertical axis (C2-7 SVA). Interobserver reliability was calculated for all measurements (intraclass correlation coefficient, ICC). A Pearson correlation was used to determine relationships between variables. RESULTS: A total of 115 patients were analyzed; average age as 50.1 years (range 22-78). All measured variables had an ICC >0.6. CL (r = -0.33, P < 0.001), TS (r = 0.42, P < 0.001), TIA (r = 0.24, P = 0.010), and C7 SVA (r = 0.48, P < 0.001) all increased with age. OrT (r = -0.88, P < 0.001) and OS (r = 0.73, P < 0.001) were both strongly correlated with CBVA and each other (r = -0.83, P <= 0.001). Both measures were also correlated with the C2-C7 SVA (OrT, r = 0.41, P < 0.001; OS, r = -0.29, P = 0.002) and O-C2 angle (OrT, r = 0.46, P < 0.001; OS, r = -0.28, P = 0.003). C6-T4 angulations was negatively correlated with NDI scores in this population (r = -0.25, P = 0.007). CONCLUSION: We present age-based normative values for occipitocervical, cervicothoracic, and cervical alignment parameters using a novel biplanar radiographic imaging technique. We introduce measures of craniocervical alignment that might provide surgeons with an intuitive way to account for the position of the orbit when planning cervical deformity correction. LEVEL OF EVIDENCE: 4. PMID- 27116114 TI - Perioperative Complications in 155 Patients Who Underwent Oblique Lateral Interbody Fusion Surgery: Perspectives and Indications From a Retrospective, Multicenter Survey. AB - STUDY DESIGN: A retrospective multicenter survey. OBJECTIVE: To investigate the perioperative complications of oblique lateral interbody fusion (OLIF) surgery. SUMMARY OF BACKGROUND DATA: OLIF has been widely performed to achieve minimally invasive, rigid lumbar lateral interbody fusion. The associated perioperative complications are not yet well described. METHODS: The participants were patients who underwent OLIF surgery under the diagnosis of degenerative lumbar diseases between April 2013 and May 2015 at 11 affiliated medical institutions. The collected data were classified into intraoperative and early-stage postoperative (<=1 mo) complications. The intraoperative complications were then subcategorized into organ damage (neural, vertebral, vascular, and others) and other complications, mainly related to instrumental failure. The collected data were also divided and analyzed based on whether the surgeon was certified to perform the surgery and the incidence of complications in the early (April 2013-March 2014) and late stages (April 2014-May 2015) of OLIF introduction. RESULTS: In the 155 included patients, 75 complications were reported (incidence rate, 48.3%). The most common complication was endplate fracture/subsidence (18.7%), followed by transient psoas weakness and thigh numbness (13.5%) and segmental artery injury (2.6%). Almost all these complications were transient, except for three patients who had permanent damage: one had ureteral injury and two had neurological injury. Postoperative complications included surgical site infection (1.9%) and reoperation (1.9%). Whether the primary operator was experienced did not affect the incidence of complications. Regarding the introductory stage, the incidence of complications was 50% in the early stage and 38% in the late stage. CONCLUSION: The overall incidence of perioperative complications of OLIF surgery reached 48.3%, of which only 1.9% resulted in permanent damage. Our analysis based on surgeon experience indicated that the OLIF procedure could be performed without increasing incidence of complications, under the guidance of experienced supervisors. LEVEL OF EVIDENCE: 3. PMID- 27116115 TI - A Systematic Review of the Soft-Tissue Connections Between Neck Muscles and Dura Mater: The Myodural Bridge. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To elucidate the existence of soft tissue connections between the neck muscles and cervical dura mater. SUMMARY OF BACKGROUND DATA: Several studies discuss the existence of a cervical myodural bridge; however, conflicting data have been reported. METHODS: Searches were conducted in the PubMed, Web of Science, Cochrane Library, and PEDro databases. Studies reporting original data regarding the continuity of non-post-surgical soft tissue between the cervical muscles and dura mater were reviewed. Two reviewers independently selected articles, and a third one resolved disagreements. Another two researchers extracted the methodology of the study, the anatomical findings, and evaluated the quality of the studies using Quality Appraisal for Cadaveric Studies Scale. A different third researcher resolved disagreements. RESULTS: Twenty-six studies were included. A soft tissue connection between the rectus capitis posterior minor, the rectus capitis posterior major, and the obliquus capitis inferior muscles seems to be proved with a strong level of evidence for each one of them. Controversy exists about the possible communication between the dura mater and the upper trapezius, rhomboideus minor, serratus posterior superior, and splenius capitis by means of the ligamentum nuchae. Finally, there is limited evidence about the existence of a soft tissue connection between rectus capitis anterior muscle and the dura mater. CONCLUSION: There is a continuity of soft tissue between the cervical musculature and the cervical dura mater; this might have physiological, pathophysiological, and therapeutic implications, and going some way to explaining the effect of some therapies in craniocervical disorders. LEVEL OF EVIDENCE: N/A. PMID- 27116117 TI - Ionic Polymer Microspheres Bearing a Co(III) -Salen Moiety as a Bifunctional Heterogeneous Catalyst for the Efficient Cycloaddition of CO2 and Epoxides. AB - We report a unique strategy to obtain the bifunctional heterogeneous catalyst TBB Bpy@Salen-Co (TBB=1,2,4,5-tetrakis(bromomethyl)benzene, Bpy=4,4'-bipyridine, Salen-Co=N,N'-bis({4-dimethylamino}salicylidene)ethylenediamino cobalt(III) acetate) by combining a cross-linked ionic polymer with a Co(III) -salen Schiff base. The catalyst showed extra high activity for CO2 fixation under mild, solvent-free reaction conditions with no requirement for a co-catalyst. The synthesized catalyst possessed distinctive spherical structural features, abundant halogen Br(-) anions with good leaving group ability, and accessible Lewis acidic Co metal centers. These unique features, together with the synergistic role of the Co and Br(-) functional sites, allowed TBB-Bpy@Salen-Co to exhibit enhanced catalytic conversion of CO2 into cyclic carbonates relative to the corresponding monofunctional analogues. This catalyst can be easily recovered and recycled five times without significant leaching of Co or loss of activity. Moreover, based on our experimental results and previous work, a synergistic cycloaddition reaction mechanism was proposed. PMID- 27116118 TI - Multiwell Assay for the Analysis of Sugar Gut Permeability Markers: Discrimination of Sugar Alcohols with a Fluorescent Probe Array Based on Boronic Acid Appended Viologens. AB - With the aim of discerning between different sugar and sugar alcohols of biomedical relevance, such as gut permeability, arrays of 2-component probes were assembled with up to six boronic acid-appended viologens (BBVs): 4,4'-o-BBV, 3,3' o-BBV, 3,4'-o-BBV, 4,4'-o,m-BBV, 4,7'-o-PBBV, and pBoB, each coupled to the fluorophore 8-hydroxypyrene, 1,3,6-trisulfonic acid trisodium salt (HPTS). These probes were screened for their ability to discriminate between lactulose, l rhamnose, 3-O-methyl-d-glucose, and xylose. Binding studies of sugar alcohols mannitol, sorbitol, erythritol, adonitol, arabitol, galactitol, and xylitol revealed that diols containing threo-1,2-diol units have higher affinity for BBVs relative diols containing erythro-1,2 units. Those containing both threo-1,2- and 1,3-syn diol motifs showed high affinity for boronic acid binding. Fluorescence from the arrays were examined by principle component analysis (PCA) and linear discriminant analysis (LDA). Arrays with only three BBVs sufficed to discriminate between sugars (e.g., lactulose) and sugar alcohols (e.g., mannitol), establishing a differential probe. Compared with 4,4'-o-BBV, 2-fold reductions in lower limits of detection (LOD) and quantification (LOQ) were achieved for lactulose with 4,7-o-PBBV (LOD 41 MUM, LOQ 72 MUM). Using a combination of 4,4'-o BBV, 4,7-o-PBBV, and pBoB, LDA statistically segregated lactulose/mannitol (L/M) ratios from 0.1 to 0.5, consistent with values encountered in small intestinal permeability tests. Another triad containing 3,3'-o-BBV, 4,4'-o-BBV, and 4,7-o PBBV also discerned similar L/M ratios. This proof-of-concept demonstrates the potential for BBV arrays as an attractive alternate to HPLC to analyze mixtures of sugars and sugar alcohols in biomedical applications and sheds light on structural motifs that make this possible. PMID- 27116119 TI - 5-Hydroxy-7-Methoxyflavone Triggers Mitochondrial-Associated Cell Death via Reactive Oxygen Species Signaling in Human Colon Carcinoma Cells. AB - Plant-derived compounds are an important source of clinically useful anti-cancer agents. Chrysin, a biologically active flavone found in many plants, has limited usage for cancer chemotherapeutics due to its poor oral bioavailability. 5 Hydroxy-7-methoxyflavone (HMF), an active natural chrysin derivative found in various plant sources, is known to modulate several biological activities. However, the mechanism underlying HMF-induced apoptotic cell death in human colorectal carcinoma cells in vitro is still unknown. Herein, HMF was shown to be capable of inducing cytotoxicity in HCT-116 cells and induced cell death in a dose-dependent manner. Treatment of HCT-116 cells with HMF caused DNA damage and triggered mitochondrial membrane perturbation accompanied by Cyt c release, down regulation of Bcl-2, activation of BID and Bax, and caspase-3-mediated apoptosis. These results show that ROS generation by HMF was the crucial mediator behind ER stress induction, resulting in intracellular Ca2+ release, JNK phosphorylation, and activation of the mitochondrial apoptosis pathway. Furthermore, time course study also reveals that HMF treatment leads to increase in mitochondrial and cytosolic ROS generation and decrease in antioxidant enzymes expression. Temporal upregulation of IRE1-alpha expression and JNK phosphorylation was noticed after HMF treatment. These results were further confirmed by pre-treatment with the ROS scavenger N-acetyl-l-cysteine (NAC), which completely reversed the effects of HMF treatment by preventing lipid peroxidation, followed by abolishment of JNK phosphorylation and attenuation of apoptogenic marker proteins. These results emphasize that ROS generation by HMF treatment regulates the mitochondrial mediated apoptotic signaling pathway in HCT-116 cells, demonstrating HMF as a promising pro-oxidant therapeutic candidate for targeting colorectal cancer. PMID- 27116120 TI - Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells. AB - Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non-small-cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3-deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co-treatment with 3-deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co-treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co-treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co-treatment strongly suppressed EGFR signaling, not only in EGFR-wild-type NSCLC cells, but also in EGFR-mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co-treatment suppressed the in vivo tumor growth of EGFR-mutant, EGFR-tyrosine kinase-resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC. PMID- 27116121 TI - Density functional theory for systems with mesoscopic inhomogeneities. AB - We study the effects of fluctuations on the mesoscopic length scale on systems with mesoscopic inhomogeneities. Equations for the correlation function and for the average volume fraction are derived in the self-consistent Gaussian approximation. The equations are further simplified by postulating the expression for the structure factor consistent with scattering experiments for self assembling systems. Predictions of the approximate theory are verified by a comparison with the exact results obtained earlier for the one-dimensional lattice model with first-neighbor attraction and third-neighbor repulsion. We find qualitative agreement for the correlation function, the equation of state and the dependence of the chemical potential MU on the volume fraction zeta. Our results confirm also that strong inhomogeneities in the disordered phase are found only in the case of strong repulsion. The inhomogeneities are reflected in an oscillatory decay of the correlation function with a very large correlation length, three inflection points in the [Formula: see text] curve and a compressibility that for increasing zeta takes very large, very small and again very large values. PMID- 27116122 TI - Enhanced Rice Blast Resistance by CRISPR/Cas9-Targeted Mutagenesis of the ERF Transcription Factor Gene OsERF922. AB - Rice blast is one of the most destructive diseases affecting rice worldwide. The adoption of host resistance has proven to be the most economical and effective approach to control rice blast. In recent years, sequence-specific nucleases (SSNs) have been demonstrated to be powerful tools for the improvement of crops via gene-specific genome editing, and CRISPR/Cas9 is thought to be the most effective SSN. Here, we report the improvement of rice blast resistance by engineering a CRISPR/Cas9 SSN (C-ERF922) targeting the OsERF922 gene in rice. Twenty-one C-ERF922-induced mutant plants (42.0%) were identified from 50 T0 transgenic plants. Sanger sequencing revealed that these plants harbored various insertion or deletion (InDel) mutations at the target site. We showed that all of the C-ERF922-induced allele mutations were transmitted to subsequent generations. Mutant plants harboring the desired gene modification but not containing the transferred DNA were obtained by segregation in the T1 and T2 generations. Six T2 homozygous mutant lines were further examined for a blast resistance phenotype and agronomic traits, such as plant height, flag leaf length and width, number of productive panicles, panicle length, number of grains per panicle, seed setting percentage and thousand seed weight. The results revealed that the number of blast lesions formed following pathogen infection was significantly decreased in all 6 mutant lines compared with wild-type plants at both the seedling and tillering stages. Furthermore, there were no significant differences between any of the 6 T2 mutant lines and the wild-type plants with regard to the agronomic traits tested. We also simultaneously targeted multiple sites within OsERF922 by using Cas9/Multi-target-sgRNAs (C-ERF922S1S2 and C-ERF922S1S2S3) to obtain plants harboring mutations at two or three sites. Our results indicate that gene modification via CRISPR/Cas9 is a useful approach for enhancing blast resistance in rice. PMID- 27116124 TI - Radiological Assessment of the Anatomy of Frontal Recess Cells and the Anterior Ethmoidal Artery. AB - It is necessary for the surgeon to be familiar with frontal recess anatomy during an endoscopic approach to the frontal sinuses. The aim of this study was to evaluate the prevalence of frontal recess cells in Japanese adults as well as the association between the frontal recess and the location of the anterior ethmoidal artery (AEA). The frontal recess cells and the AEAs were retrospectively evaluated in CT scans of the nasal and paranasal sinuses for 89 patients. The prevalence of agger nasi cells was 90.7%. The frequency of frontal cell types 1, 2, 3 and 4 was 28.8, 0.6, 2.6 and 0%, respectively. Suprabullar cells (SBCs) and frontal bullar cells (FBCs) were identified in 78/96 sides (81.3%) and 24/96 sides (24%), respectively. The prevalence of the medial group of frontal recess cells (interfrontal sinus septal cells) was 12.4%. In 42/61 sides (68.9%), the AEAs were located within the posterior margin of the SBCs or the FBCs. Therefore, SBCs, FBCs and the vertical portion of the middle turbinate are reliable landmarks for the identification of AEAs. PMID- 27116123 TI - Expression Stabilities of Candidate Reference Genes for RT-qPCR in Chinese Jujube (Ziziphus jujuba Mill.) under a Variety of Conditions. AB - Reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) is a powerful method for evaluating patterns of gene expression. Jujube whole genome sequencing has been completed, and analysis of gene function, an important part of any follow-up study, requires the appropriate selection of reference genes. Indeed, suitable reference gene selection for RT-qPCR is critical for accurate normalization of target gene expression. In this study, the software packages geNorm and NormFinder were employed to examine the expression stabilities of nine candidate reference genes under a variety of conditions. Actin-depolymerizing factor 1 (ACT1), Histone-H3 (His3), and Polyadenylate binding protein-interacting protein (PAIP) were determined to be the most stably expressed genes during five stages of fruit development and ACT1, SiR-Fd, BTF3, and Tubulin alpha chain (TUA) across different tissues/organs. Whereas ACT1, Basic Transcription factor 3 (BTF3), Glyceraldehyde-3-phosphate dehydrogenase (GADPH), and PAIP were the most stable under dark conditions. ACT1, PAIP, BTF3, and Elongation factor 1- gamma (EF1gamma) were the most stably expressed genes under phytoplasma infection. Among these genes, SiR-Fd and PAIP are here first reported as stable reference genes. When normalized using these most stable reference genes, the expression patterns of four target genes were found to be in accordance with physiological data, indicating that the reference genes selected in our study are suitable for use in such analyses. This study provides appropriate reference genes and corresponding primers for further RT-qPCR studies in Chinese jujube and emphasizes the importance of validating reference genes for gene expression analysis under variable experimental conditions. PMID- 27116125 TI - Molecular studies on structural changes and oligomerisation of violaxanthin de epoxidase associated with the pH-dependent activation. AB - Violaxanthin de-epoxidase (VDE) is a conditionally soluble enzyme located in the thylakoid lumen and catalyses the conversion of violaxanthin to antheraxanthin and zeaxanthin, which are located in the thylakoid membrane. These reactions occur when the plant or algae are exposed to saturating light and the zeaxanthin formed is involved in the process of non-photochemical quenching that protects the photosynthetic machinery during stress. Oversaturation by light results in a reduction of the pH inside the thylakoids, which in turn activates VDE and the de epoxidation of violaxanthin. To elucidate the structural events responsible for the pH-dependent activation of VDE, full length and truncated forms of VDE were studied at different pH using circular dichroism (CD) spectroscopy, crosslinking and small angle X-ray scattering (SAXS). CD spectroscopy showed the formation of alpha-helical coiled-coil structure, localised in the C-terminal domain. Chemical crosslinking of VDE showed that oligomers were formed at low pH, and suggested that the position of the N-terminal domain is located near the opening of lipocalin-like barrel, where violaxanthin has been predicted to bind. SAXS was used to generate models of monomeric VDE at high pH and also a presumably dimeric structure of VDE at low pH. For the dimer, the best fit suggests that the interaction is dominated by one of the domains, preferably the C-terminal domain due to the lost ability to oligomerise at low pH, shown in earlier studies, and the predicted formation of coiled-coil structure. PMID- 27116127 TI - [The first page]. PMID- 27116126 TI - Photorespiration provides the chance of cyclic electron flow to operate for the redox-regulation of P700 in photosynthetic electron transport system of sunflower leaves. AB - To elucidate the molecular mechanism to oxidize the reaction center chlorophyll, P700, in PSI, we researched the effects of partial pressure of O2 (pO2) on photosynthetic characteristic parameters in sunflower (Helianthus annuus L.) leaves. Under low CO2 conditions, the oxidation of P700 was stimulated; however the decrease in pO2 suppressed its oxidation. Electron fluxes in PSII [Y(II)] and PSI [Y(I)] showed pO2-dependence at low CO2 conditions. H(+)-consumption rate, estimated from Y(II) and CO2-fixation/photorespiration rates (JgH(+)), showed the positive curvature relationship with the dissipation rate of electrochromic shift signal (V H (+) ), which indicates H(+)-efflux rate from lumen to stroma in chloroplasts. Therefore, these electron fluxes contained, besides CO2 fixation/photorespiration-dependent electron fluxes, non-H(+)-consumption electron fluxes including Mehler-ascorbate peroxidase (MAP)-pathway. Y(I) that was larger than Y(II) surely implies the functioning of cyclic electron flow (CEF). Both MAP-pathway and CEF were suppressed at lower pO2, with plastoquinone pool reduced. That is, photorespiration prepares the redox-poise of photosynthetic electron transport system for CEF activity as an electron sink. Excess Y(II), [DeltaY(II)] giving the curvature relationship with V H (+) , and excess Y(I) [DeltaCEF] giving the difference between Y(I) and Y(II) were used as an indicator of MAP-pathway and CEF activity, respectively. Although DeltaY(II) was negligible and did not show positive relationship to the oxidation-state of P700, DeltaCEF showed positive linear relationship to the oxidation-state of P700. These facts indicate that CEF cooperatively with photorespiration regulates the redox-state of P700 to suppress the over-reduction in PSI under environmental stress conditions. PMID- 27116128 TI - [No. 15 GOA - for many practices a "forgotten cypher"]. PMID- 27116129 TI - [The left hand appears completely cramped]. PMID- 27116130 TI - [Painless new nodules on the thumb]. PMID- 27116131 TI - ["The patient can be reassured that henceforth she will no longer have to shave "]. PMID- 27116132 TI - [Long-term antibiotics are senseless]. PMID- 27116133 TI - [Author of MMW is honored]. PMID- 27116134 TI - [For physicians everything will be improved]. PMID- 27116135 TI - [The liver and saving the liver]. PMID- 27116136 TI - [Dangerous mushroom poisonings in migrants!]. PMID- 27116137 TI - [Tremendous progress but still also problems]. PMID- 27116138 TI - [The family physician as vaccination manager]. PMID- 27116139 TI - [Medicinal teas and phytotherapeutic drugs for the stomach]. PMID- 27116140 TI - [20 kg weight loss - that can also be dangerous without underweight]. PMID- 27116141 TI - [Aspiration pneumonia in elderly patients: treacherous and often fatal]. PMID- 27116142 TI - [Should even more patients be treated with statins?]. PMID- 27116143 TI - [Aortic stenosis: a new impetus for transcatheter heart valves]. PMID- 27116144 TI - [Can antidiabetic drugs trigger an allergy?]. PMID- 27116145 TI - [Among junior physicians depression is rampant]. PMID- 27116146 TI - [Asthma guideline for family practice]. PMID- 27116147 TI - [Private patients also advised by telephone]. PMID- 27116148 TI - [Unusual EBM definition of chronic patient care]. PMID- 27116149 TI - [Which pill helps in impotence?]. PMID- 27116150 TI - [Good thing there is an MDK report!]. PMID- 27116151 TI - [The general practitioner of European astronauts]. PMID- 27116152 TI - [The wrong partner, poor tax saving model]. PMID- 27116153 TI - [Non-physician practice assistant is worth more structurally than financially]. PMID- 27116155 TI - [Not Available]. PMID- 27116154 TI - [Alternative medicine practitioners live well off borreliosis]. PMID- 27116156 TI - [A physician treats immediately]. PMID- 27116157 TI - [Imbalance in life can promote burnout]. PMID- 27116158 TI - [Hypertension: vascular risk rapidly increases]. PMID- 27116159 TI - [Should diabetics have breakfast?]. PMID- 27116160 TI - [Redness and coating wander across the tongue]. PMID- 27116161 TI - [Also genetic tests change nothing in life style]. PMID- 27116162 TI - [Imaging reveals bone marrow hyperplasia signs of the skull]. PMID- 27116163 TI - [Did Martin Luther die of sequelae of an acute coronary syndrome?]. PMID- 27116164 TI - [Hemolytic treatment in apoplexy is successful]. PMID- 27116165 TI - [Minor head injuries under antiocoagulation-antiplatelet drugs distributed like lozenges]. PMID- 27116166 TI - [Emergency department management of mild traumatic brain injury in adults - an evidence-based algorithmic approach]. PMID- 27116167 TI - [Emergency department management of mild traumatic brain injury in children - an evidencebased algorithmic approach]. PMID- 27116168 TI - [Emergency checklist: Unliateral leg edema]. PMID- 27116169 TI - [Dental biocorrosions - etiology, diagnostic, prevention and treatment options]. PMID- 27116170 TI - [The skin: a mirrow reflecting internal diseases]. PMID- 27116171 TI - [Colitis ulcerosa - a diagnostic and therapeutic update]. PMID- 27116172 TI - [First biosimilar etanercept is available]. PMID- 27116173 TI - [Physical fitness improves quality of life]. PMID- 27116174 TI - [Combination drug improves adherence]. PMID- 27116175 TI - [Effective LDL cholesterol reduction for high risk patients]. PMID- 27116176 TI - [Containing bacteria naturally]. PMID- 27116177 TI - [Hawthorn slows blood vessel aging]. PMID- 27116178 TI - [This is a typical paw position sign]. PMID- 27116179 TI - [The nodule is exactly what it looks like]. PMID- 27116180 TI - Assessing DNA Barcodes for Species Identification in North American Reptiles and Amphibians in Natural History Collections. AB - BACKGROUND: High rates of species discovery and loss have led to the urgent need for more rapid assessment of species diversity in the herpetofauna. DNA barcoding allows for the preliminary identification of species based on sequence divergence. Prior DNA barcoding work on reptiles and amphibians has revealed higher biodiversity counts than previously estimated due to cases of cryptic and undiscovered species. Past studies have provided DNA barcodes for just 14% of the North American herpetofauna, revealing the need for expanded coverage. METHODOLOGY/PRINCIPAL FINDINGS: This study extends the DNA barcode reference library for North American herpetofauna, assesses the utility of this approach in aiding species delimitation, and examines the correspondence between current species boundaries and sequence clusters designated by the BIN system. Sequences were obtained from 730 specimens, representing 274 species (43%) from the North American herpetofauna. Mean intraspecific divergences were 1% and 3%, while average congeneric sequence divergences were 16% and 14% in amphibians and reptiles, respectively. BIN assignments corresponded with current species boundaries in 79% of amphibians, 100% of turtles, and 60% of squamates. Deep divergences (>2%) were noted in 35% of squamate and 16% of amphibian species, and low divergences (<2%) occurred in 12% of reptiles and 23% of amphibians, patterns reflected in BIN assignments. Sequence recovery declined with specimen age, and variation in recovery success was noted among collections. Within collections, barcodes effectively flagged seven mislabeled tissues, and barcode fragments were recovered from five formalin-fixed specimens. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that DNA barcodes can effectively flag errors in museum collections, while BIN splits and merges reveal taxa belonging to deeply diverged or hybridizing lineages. This study is the first effort to compile a reference library of DNA barcodes for herpetofauna on a continental scale. PMID- 27116181 TI - Remote Patient Monitoring via Non-Invasive Digital Technologies: A Systematic Review. AB - BACKGROUND: We conducted a systematic literature review to identify key trends associated with remote patient monitoring (RPM) via noninvasive digital technologies over the last decade. MATERIALS AND METHODS: A search was conducted in EMBASE and Ovid MEDLINE. Citations were screened for relevance against predefined selection criteria based on the PICOTS (Population, Intervention, Comparator, Outcomes, Timeframe, and Study Design) format. We included studies published between January 1, 2005 and September 15, 2015 that used RPM via noninvasive digital technology (smartphones/personal digital assistants [PDAs], wearables, biosensors, computerized systems, or multiple components of the formerly mentioned) in evaluating health outcomes compared to standard of care or another technology. Studies were quality appraised according to Critical Appraisal Skills Programme. RESULTS: Of 347 articles identified, 62 met the selection criteria. Most studies were randomized control trials with older adult populations, small sample sizes, and limited follow-up. There was a trend toward multicomponent interventions (n = 26), followed by smartphones/PDAs (n = 12), wearables (n = 11), biosensor devices (n = 7), and computerized systems (n = 6). Another key trend was the monitoring of chronic conditions, including respiratory (23%), weight management (17%), metabolic (18%), and cardiovascular diseases (16%). Although substantial diversity in health-related outcomes was noted, studies predominantly reported positive findings. CONCLUSIONS: This review will help decision makers develop a better understanding of the current landscape of peer-reviewed literature, demonstrating the utility of noninvasive RPM in various patient populations. Future research is needed to determine the effectiveness of RPM via noninvasive digital technologies in delivering patient healthcare benefits and the feasibility of large-scale implementation. PMID- 27116182 TI - Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14. AB - Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker's z-scores categorized: >=1.0 standard deviation (SD) below mean; <1.0 SD below mean; <=1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p <= 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18-0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z >= 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores <= -1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ >= 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology. PMID- 27116183 TI - Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer. AB - In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enumeration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7-5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3-9.7 m). The most common toxicities (all grades/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to foretinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484). PMID- 27116184 TI - Compliance with hormonal therapy. PMID- 27116185 TI - Nottingham prognostic index plus (NPI+) predicts risk of distant metastases in primary breast cancer. AB - The Nottingham prognostic index plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification for breast cancer superior to the traditional NPI. This study aimed to determine prognostic capability of the NPI+ in predicting risk of development of distant disease. A well-characterised series of 1073 primary early-stage BC cases treated in Nottingham and 251 cases from Budapest were immunohistochemically assessed for cytokeratin (Ck)5/6, Ck18, EGFR, oestrogen receptor (ER), progesterone receptor, HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class and prognostic scores were assigned using individual algorithms for each biological class incorporating clinicopathologic parameters and investigated in terms of prediction of distant metastases-free survival (MFS). The NPI+ identified distinct prognostic groups (PG) within each molecular class which were predictive of MFS providing improved patient outcome stratification superior to the traditional NPI. NPI+ PGs, between series, were comparable in predicting patient outcome between series in luminal A, basal p53 altered and HER2+/ER+ (p > 0.01) tumours. The low-risk groups were similarly validated in luminal B, luminal N, basal p53 normal tumours (p > 0.01). Due to small patient numbers the remaining PGs could not be validated. NPI+ was additionally able to predict a higher risk of metastases at certain distant sites. This study may indicate the NPI+ as a useful tool in predicting the risk of metastases. The NPI+ provides accurate risk stratification allowing improved individualised clinical decision making for breast cancer. PMID- 27116186 TI - Ethnic differences in the relationships between diabetes, early age adiposity and mortality among breast cancer survivors: the Breast Cancer Health Disparities Study. AB - The contribution of type 2 diabetes and obesity on mortality in breast cancer (BC) patients has not been well studied among Hispanic women, in whom these exposures are highly prevalent. In a multi-center population-based study, we examined the associations between diabetes, multiple obesity measures, and mortality in 1180 Hispanic and 1298 non-Hispanic white (NHW) women who were diagnosed with incident invasive BC from the San Francisco Bay Area, New Mexico, Utah, Colorado, and Arizona. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards regression models. The median follow-up time from BC diagnosis to death was 10.8 years. In ethnic stratified results, the association for BC-specific mortality among Hispanics was significantly increased (HR 1.85 95 % CI 1.11, 3.09), but the ethnic interaction was not statistically significant. In contrast, obesity at age 30 increased BC specific mortality risk in NHW women (HR 2.33 95 % CI 1.36, 3.97) but not Hispanics (p-interaction = 0.045). Although there were no ethnic differences for all-cause mortality, diabetes, obesity at age 30, and post-diagnostic waist-hip ratio were significantly associated with all-cause mortality in all women. This study provides evidence that diabetes and adiposity, both modifiable, are prognostic factors among Hispanic and NHW BC patients. PMID- 27116187 TI - Coordinated Parameter Identification Technique for the Inertial Parameters of Non Cooperative Target. AB - Space operations will be the main space missions in the future. This paper focuses on the precise operations for non-cooperative target, and researches of coordinated parameter identification (CPI) which allows the motion of multi joints. The contents of this paper are organized: (1) Summarize the inertial parameters identification techniques which have been conducted now, and the technique based on momentum conservation is selected for reliability and realizability; (2) Elaborate the basic principles and primary algorithm of coordinated parameter identification, and analyze some special problems in calculation (3) Numerical simulation of coordinated identification technique by an case study on non-cooperative target of spacecraft mounting dual-arm with six joints is done. The results show that the coordinated parameter identification technique could get all the inertial parameters of the target in 3D by one-time identification, and does not need special configuration or driven joints, moreover the results are highly precise and save much more time than traditional ones. PMID- 27116188 TI - Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms. AB - The third version of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine body neoplasms was published in 2013. The guidelines comprise nine chapters and nine algorithms. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. This revision was intended to collect up-to-date international evidence. The highlights of this revision are to (1) newly specify costs and conflicts of interest; (2) describe the clinical significance of pelvic lymph node dissection and para-aortic lymphadenectomy, including variant histologic types; (3) describe more clearly the indications for laparoscopic surgery as the standard treatment; (4) provide guidelines for post-treatment hormone replacement therapy; (5) clearly differentiate treatment of advanced or recurrent cancer between the initial treatment and the treatment carried out after the primary operation; (6) collectively describe fertility-sparing therapy for both atypical endometrial hyperplasia and endometrioid adenocarcinoma (corresponding to G1) and newly describe relapse therapy after fertility-preserving treatment; and (7) newly describe the treatment of trophoblastic disease. Overall, the objective of these guidelines is to clearly delineate the standard of care for uterine body neoplasms in Japan with the goal of ensuring a high standard of care for all Japanese women diagnosed with uterine body neoplasms. PMID- 27116189 TI - Toward the Total Synthesis of Amphidinolide N: Synthesis of the C8-C29 Fragment. AB - A synthesis of the C8-C29 fragment of amphidinolide N, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been achieved. The key features of the synthesis involve a convergent union of the C9 C15 and C16-C29 fragments by Steglich esterification and the construction of a pyran unit through a Tebbe methylenation/ring-closing metathesis sequence. PMID- 27116190 TI - Risk factors of kyphosis recurrence after implant removal in thoracolumbar burst fractures following posterior short-segment fixation. AB - PURPOSE: Our aim was to evaluate the results of short-segment pedicle instrumentation with screw insertion in the fracture level and find factors predicting kyphosis recurrence in thoracolumbar burst fractures. METHODS: We retrospectively analysed 122 patients with thoracolumbar burst fracture who were divided into two groups: kyphosis recurrence and no kyphosis recurrence. Pre operative radiographic data comprising Cobb angle (CA), regional angle, anterior vertebra height (AVH), upper intervertebral angle, vertebral wedge angle (VWA), pre-anteroposterior A/P approach, superior endplate fracture, load-sharing classification (LSC) score and clinical data including age, visual analogue scale (VAS) score, thoracolumbar injury classification and severity score were compared between groups. T test, Pearson's chi-square and multivariate logistic regression were calculated for variables. RESULTS: CA, VWA and AVH were significantly corrected after surgery. CA changed from 23.7 to 3.0 (p <0.001), VWA from 38.7 to 9.6 (p <0.001) and AVH from 48.8 % to 91.2 % (p <0.001). These parameters were well maintained during the follow-up period with a mild, tolerant loss of correction. Neurological function and pain were significantly improved without deterioration. Age, pre-A/P and pre-AVH < 50 % influenced kyphosis recurrence (p = 0.032, 0.026, 0.011, respectively). CONCLUSIONS: Short-segment pedicle instrumentation including the fractured vertebra was effective in treating thoracolumbar burst fractures. The loss of correction at follow-up after implant removal was associated with age, A/P ratio and anterior vertebral height < 50 %. PMID- 27116191 TI - Erratum to: Chronic and Invasive Fungal Infections in a Family with CARD9 Deficiency. PMID- 27116192 TI - Tackling multidrug resistance mediated by efflux transporters in tumor-initiating cells. AB - INTRODUCTION: Expression of the multifunctional ATP-binding cassette (ABC) efflux transporter gene family is a well-established mechanism for protecting cancer stem cells (CSCs) from damage or death due to toxins. The outcome of such protection makes CSCs innately multidrug resistant (MDR) to conventional chemotherapy. AREAS COVERED: While research has focused on gaining better insight into the role of ABC transporters in CSC drug resistance, various strategies to circumvent the function of these transporters have been proposed, including inhibition of transporter function through targeted tyrosine kinase inhibitors, competitive and allosteric modulators, shRNA-mediated inhibition, nanoparticle mediated delivery of inhibitors, and modulating the regulation of transcriptional and signaling pathways involving ABC transporters. This review highlights the role of MDR mediated by ABC transporters, particularly in CSCs, and the current progress and pitfalls of strategies to circumvent MDR in CSCs. EXPERT OPINION: Cancer stem cells are now a subject of intense research, as it is hypothesized that these progenitors predominantly beget tumorigenesis, chemoresistance, and metastasis. Consequently, the design and synthesis of more effective ABC transporter inhibitors, to increase cytotoxic drug concentrations in CSCs (thus increasing their eradication), is a promising approach for the field of oncology. PMID- 27116193 TI - Differential modulation of plant immune responses by diverse members of the Pseudomonas savastanoi pv. savastanoi HopAF type III effector family. AB - The Pseudomonas savastanoi pv. savastanoi NCPPB 3335 type III secretion system (T3SS) effector repertoire includes 33 candidates, seven of which translocate into host cells and interfere with plant defences. The present study was performed to investigate the co-existence of both plasmid- and chromosomal encoded members of the HopAF effector family, HopAF1-1 and HopAF1-2, respectively, in the genome of NCPPB 3335. Here, we show that the HopAF1 paralogues are widely distributed in the Pseudomonas syringae complex, where HopAF1-1 is most similar to the homologues encoded by other P. syringae pathovars infecting woody hosts that belong to phylogroups 1 and 3. We show that the expression of both HopAF1-1 and HopAF-2 is transcriptionally dependent on HrpL and demonstrate their delivery into Nicotiana tabacum leaves. Although the heterologous delivery of either HopAF1-1 or HopAF1-2 significantly suppressed the production of defence-associated reactive oxygen species levels, only HopAF1-2 reduced the levels of callose deposition. Moreover, the expression of HopAF1-2 by functionally effectorless P. syringae pv. tomato DC3000D28E completely inhibited the hypersensitive response in tobacco and significantly increased the competitiveness of the strain in Nicotiana benthamiana. Despite their functional differences, subcellular localization studies reveal that green fluorescent protein (GFP) fusions to either HopAF1-1 or HopAF1-2 are targeted to the plasma membrane when they are expressed in plant cells, a process that is completely dependent on the integrity of their N-myristoylation motif. Our results further support the notion that highly similar T3SS effectors might differentially interact with diverse plant targets, even when they co-localize in the same cell compartment. PMID- 27116194 TI - Bistable perception in normal aging: perceptual reversibility and its relation to cognition. AB - The effects of age on the ability to resolve perceptual ambiguity are unknown, though it depends on frontoparietal attentional networks known to change with age. We presented the bistable Necker cube to 24 middle-aged and OAs (older adults; 56-78 years) and 20 YAs (younger adults; 18-24 years) under passive viewing and volitional control conditions: Hold one cube percept and Switch between cube percepts. During passive viewing, OAs had longer dominance durations (time spent on each percept) than YAs. In the Hold condition, OAs were less able than YAs to increase dominance durations. In the Switch condition, OAs and YAs did not differ in performance. Dominance durations in either condition correlated with performance on tests of executive function mediated by the frontal lobes. Eye movements (fixation deviations) did not differ between groups. These results suggest that OAs' reduced ability to hold a percept may arise from reduced selective attention. The lack of correlation of performance between Hold and executive-function measures suggests at least a partial segregation of underlying mechanisms. PMID- 27116196 TI - Mindfulness-based stress reduction as a novel treatment for interstitial cystitis/bladder pain syndrome: a randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: Mindfulness-based stress reduction (MBSR) is a standardized meditation program that may be an effective therapy for interstitial cystitis/bladder pain syndrome (IC/BPS), a condition exacerbated by stress. The aims of this study were to explore whether MBSR improved IC/BPS symptoms and the feasibility/acceptability of MSBR among women with IC/BPS. METHODS: This randomized controlled trial included women with IC/BPS undergoing first- or second-line therapies. Women were randomized to continuation of usual care (UC) or an 8-week MBSR class + usual care (MBSR). Participants completed baseline and 8-week post-treatment questionnaires, including the O'Leary-Sant Symptom Problem Index (OSPI), the visual analog pain scale (VAS), the Short Form Health Survey (SF-12), the Female Sexual Function Index (FSFI), and the Pain Self-Efficacy Questionnaire (PSEQ). The Global Response Assessment (GRA) was completed post treatment. Analyses were performed using Student's t test, Chi-squared, and MANOVA where appropriate. RESULTS: Eleven women were randomized to UC and 9 to MBSR, without differences in group characteristics. More MBSR participants' symptoms were improved on the GRA (7 out of 8 [87.5 %] vs 4 out of 11 [36.4 %], p = 0.03). The MBSR group showed greater improvement in the OSPI total (p = 0.0498) and problem scores (p = 0.036); the OSPI symptom score change did not differ. PSEQ scores improved in MBSR compared with UC (p = 0.035). VAS, SF-12, and FSFI change did not differ between groups. Eighty-six percent of MBSR participants felt more empowered to control symptoms, and all participants planned to continue MBSR. CONCLUSIONS: This trial provides initial evidence that MBSR is a promising adjunctive therapy for IC/BPS. Its benefit may arise from patients' empowerment and ability to cope with symptoms. PMID- 27116197 TI - Knowledge of pelvic organ prolapse in patients and their information-seeking preferences: comparing Vienna and Moscow. AB - INTRODUCTION AND HYPOTHESIS: We hypothesized that knowledge of pelvic organ prolapse (POP) and patient information-seeking preferences are the same in the two capital cities. METHODS: First-visit patients were recruited at tertiary referral urogynaecological units in Vienna (137) and in Moscow (112). A 16-item scale was used to assess the patient knowledge of POP. The 16 items comprised 12 specific items taken from the Prolapse and Incontinence Knowledge Questionnaire (PIKQ) and four added items. The preliminary psychometric assessment of the knowledge scales in German and Russian was performed in the Vienna and in Moscow centres. RESULTS: The mean total knowledge scores in patients in Vienna and in Moscow were not significantly different: 9.7 +/- 3.5 vs. 9.8 +/- 2.9 (p = 0.92). Patients in Vienna were more likely to answer questions about the pathogenesis of POP correctly. Patients in Moscow achieved higher scores for items assessing knowledge about the diagnosis of POP. Women in the two study groups equally preferred to obtain information about POP from medical specialists (72 % and 82 %; p = 0.61), followed by friends and family for patients in Vienna (25 %), and the internet for patients in Moscow (23 %). Patients in Vienna were more likely to use printed sources (18 % and 7 %; p = 0.001) than patients in Moscow. CONCLUSIONS: The mean level of knowledge of POP did not differ between patients in Vienna and patients in Moscow. The differences between the specific knowledge domains might be explained by different cultural preferences for seeking health information and by the range of the information sources available. PMID- 27116198 TI - Radiofrequency in female external genital cosmetics and sexual function: a randomized clinical trial. AB - INTRODUCTION AND HYPOTHESIS: Female sexual behavior goes through cultural changes constantly, and recently, some women have shown the desire the ideal genitalia. In this study, we aimed to evaluate clinical responses to nonablative radiofrequency (RF) in terms of its cosmetic outcome in the female external genitalia and its effect on sexual function. METHODS: A single-masking randomized controlled trial was conducted in 43 women (29 sexually active) who were unsatisfied with the appearance of their external genitalia. The women were divided into an RF group (n = 21, 14 sexually active) and a control group (n = 22, 15 sexually active). Eight sessions of RF were performed once a week. Photographs (taken before the first session and 8 days after the last session) were evaluated by the women and three blinded health professionals by using two 3 point Likert scales (unsatisfied, unchanged, and satisfied; and worst, unchanged, and improved). Sexual function was evaluated using the Female Sexual Function Index (FSFI) and analyzed using the Student t test. Women's satisfaction and health professional evaluation were analyzed using the chi-square test and inter- and intragroup binomial comparisons. RESULTS: Satisfaction response rates were 76 and 27 % for the RF and control groups, respectively (p = 0.001). All professionals found a clinical improvement association in the treated group with RF in comparison with the control group (p < 0.01). The overall FSFI sexual function score increased by 3.51 points in the RF group vs 0.1 points in the control group (p = 0.003). CONCLUSIONS: RF is an alternative for attaining a cosmetic outcome for the female external genitalia, with positives changes in patients' satisfaction and FSFI scores. PMID- 27116199 TI - UK Renal Registry 18th Annual Report: Chapter 11 2014 Multisite Dialysis Access Audit in England, Northern Ireland and Wales and 2013 PD One Year Follow-up: National and Centre-specific Analyses. AB - Data are presented from the third combined vascular and peritoneal dialysis access audit. In 2014, 53 centres in England, Wales and Northern Ireland (out of 62) returned data on first access from 4,339 incident haemodialysis (HD) patients and 1,090 incident peritoneal dialysis (PD) patients. Of the 5,429 incident patients, 20.1% started dialysis on PD, 27.8% started with an arteriovenous fistula (AVF), 1.0% with an arteriovenous graft (AVG), 27.1% on a tunnelled line (TL) and 24.0% on a non-tunnelled line (NTL). Older patients (565 years) were more likely to start haemodialysis using AVF compared to their younger counterparts (36.2% vs. 32.8%). Thirteen of the nineteen centres (68%) using the physician led percutaneous insertion technique had over 20% of their incident patients starting on PD when compared to only seven out of fourteen centres (50%) which used single technique (open surgical or laparoscopic) for their PD catheter insertion. Wide variations were apparent between centres for use of AVF as the first haemodialysis access ranging from 10-54%. Eight of the 49 centres were achieving close to the 65% target for AV fistula in their incident patients. Length of time known to nephrology services and likelihood of commencing dialysis using either an AVF or a PD catheter are strongly associated. Patients who were known to a nephrologist for over one year were more likely to start dialysis with AVF, as compared to those who were referred between 90-365 days (39.2% vs. 24.6%). Similarly, patients who were known to a nephrologist between 90 days and one year were more likely to start on PD when compared to patients who were referred <90 days prior to dialysis start (26.9% vs. 9.1%). By comparison, amongst the late presenters, only 3.5% had first access documented as an AVF and 87.3% started dialysis on either a tunnelled line or a non-tunnelled line. Initial surgical assessment was a key determinant of the likelihood of AVF formation. Of the incident patients known to renal services for longer than three months and in those assessed by a surgeon at least three months prior to starting dialysis, 71.4% started dialysis with an AVF whereas of those who were not seen by a surgeon only 10.8% did. Thirty one of the 38 centres were 2 or 3 standard deviations below the 85% target for prevalent haemodialysis patients with an AV fistula. For centres returning data on one-year peritoneal dialysis outcomes, the majority of centres (28/32) maintained 550% of patients on PD at one year, having censored for transplantation. This report demonstrates wide variations in practice between centres across several domains in the provision of dialysis access and further work will be required to understand the underlying reasons. PMID- 27116200 TI - A Case Study of Anisakiasis in the Palatine Tonsils. AB - Anisakidosis is a nematode infection caused by the ingestion of larvae-infected raw or undercooked fish. Although gastric anisakiasis is a common disease in Japan due to the popularity of eating raw and undercooked fish, reports of anisakiasis in the tonsils are extremely rare. A 68-year-old man presenting with clinical features of peritonsillitis was admitted for examination. The right peritonsillar region exhibited slight edematous swelling and rash, and a white foreign body was observed. This foreign body was removed, and pathological examination revealed Anisakis. PMID- 27116201 TI - Study on Enhanced Dissolution of Azilsartan-Loaded Solid Dispersion, Prepared by Combining Wet Milling and Spray-Drying Technologies. AB - The purpose of this study was to develop a combination method of wet milling and spray-drying technologies to prepare the solid dispersion and improve the dissolution rate of poorly water-soluble drug candidates. Azilsartan (AZL) was selected as the model drug for its poor water solubility. In the study, AZL loaded solid dispersion was prepared with polyethylene glycol 6000 (PEG6000) and hydroxypropyl cellulose with super low viscosity (HPC-SL) as stabilizers by using combination of wet grinding and spray-drying methods. The high AZL loading solid dispersion was then characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Besides, dissolution test was carried out by the paddle method and stability investigation was also conducted. As a result, the dissolution rate of the solid dispersion tablets was found to be greater than conventional tablets, but in close agreement with market tablets. Furthermore, the formulation was shown to be stable at 40 +/- 2 degrees C and 75 +/- 5% for at least 6 months, owing to its decreased particle size, morphology, and its crystal form. It was concluded that the combination of wet milling and spray-drying approaches to prepare solid dispersion would be a prospective method to improve the dissolution rate of poorly water-soluble drugs. PMID- 27116202 TI - Using Supercritical Fluid Technology (SFT) in Preparation of Tacrolimus Solid Dispersions. AB - Tacrolimus is an immunosuppressant agent that suffers from poor and variable bioavailability. This can be related to limited solubility and dissolution. The main objective of this study is to use SFT to prepare solid dispersions of tacrolimus in order to enhance its dissolution. SFT was selected since it offers several advantages over conventional techniques such as efficiency and stability. Several solid dispersions of tacrolimus were prepared using SFT to enhance its dissolution. The selected polymers included soluplus, PVP, HPMC, and porous chitosan. TPGS was used as a surfactant additive with chitosan, HPMC, and PVP. Soluplus dispersions were used to study the effect of processing parameters (time, temperature, and pressure) on loading efficiency (LE) and dissolution of the preparation. Physicochemical characterization was performed using DSC, X-ray diffraction, FTIR analysis, SEM, and in vitro drug release. Stability testing was evaluated after 3 months for selected dispersions. Significant improvement for the release profile was achieved for the prepared dispersions. Better release achieved in the soluplus dispersions which reached maximum cumulative release equal to 98.76% after 24 h. Drug precipitated in its amorphous form in all prepared dispersions except those prepared from chitosan. All dispersions were physically stable except for PVP preparations that contained TPGS which started to re-crystallize after one month. Prepared dispersions were proved to be affected by supercritical processing parameters. In conclusion, SFT was successfully used to prepare dispersions of tacrolimus that exhibited higher dissolution than raw drug. Dissolution rate and stability are affected by the type of the polymer. PMID- 27116203 TI - Characterization of Antimicrobial Agent Loaded Eudragit RS Solvent Exchange Induced In Situ Forming Gels for Periodontitis Treatment. AB - Eudragit RS (ERS), a quaternary polyacrylate positively charged polymer, exhibits a very low permeability and swells in aqueous media independently of pH without dissolving. Owing to its high solubility in N-methyl pyrrolidone (NMP), it was interesting to apply as polymer matrix for solvent-exchanged in situ forming gel. The aim of this research was to prepare in situ forming gels from ERS to deliver the antimicrobial agents (doxycycline hyclate, metronidazole, and benzoyl peroxide) for periodontitis treatment. They were evaluated for viscosity and rheology, gel formation, syringeability, drug release, and antimicrobial activities. The solvent exchange between NMP and an external aqueous simulated gingival crevicular fluid stimulated the dissolved ERS transforming into the opaque rigid gel. Antimicrobial agent loaded ERS systems exhibited Newtonian flow with acceptable syringeability. The higher-loaded ERS promoted the more prolongation of drug release because of the retardation of water diffusion into the precipitated matrix. Antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans, and Porphyromonas gingivalis depended on type of drugs and test microorganisms. Doxycycline hyclate loaded ERS systems showed these activities greater than the others; however, all of them could inhibit all test microorganisms. Thus, the solvent exchange-induced in situ forming gels comprising ERS-antimicrobial drugs exhibited potential use as localized delivery systems for periodontitis treatment. PMID- 27116205 TI - Disparities in Adherence to Screening Guidelines for Diabetic Retinopathy in the United States: A Comprehensive Review and Guide for Future Directions. AB - Diabetic retinopathy (DR) is the leading cause of new-onset blindness in American adults aged 20-74 years old. The number of diabetics living with diagnosed DR increased by 89%, from 4.06 million to 7.69 million, between 2000 and 2010. Projected numbers from the Vision Health Initiative by the CDC predict that the rate of DR will triple by 2050, from 5.5 million people living with DR to 16 million. Screening guidelines aim to detect cases early because the treatments for DR can reduce severe vision loss by up to 94%. However, adherence to these guidelines is quite low. It is estimated that more than half of patients with diabetes may fail to receive necessary screening. Risk factors for non-screening discussed in this study include low health literacy, lack of access to care, pregnancy, physician adherence to guidelines, unique factors present in different minority populations, gender and age disparities, and living in rural regions. This paper also aims to address potential interventions that may improve adherence rates. PMID- 27116204 TI - Donor Conception Disclosure: Directive or Non-Directive Counselling? AB - It is widely agreed among health professionals that couples using donor insemination should be offered counselling on the topic of donor conception disclosure. However, it is clear from the literature that there has long been a lack of agreement about which counselling approach should be used in this case: a directive or a non-directive approach. In this paper we investigate which approach is ethically justifiable by balancing the two underlying principles of autonomy (non-directive approach) and beneficence (directive approach). To overrule one principle in favour of another, six conditions should be fulfilled. We analyse the arguments in favour of the beneficence principle, and consequently, a directive approach. This analysis shows that two conditions are not met; the principle of autonomy should not be overridden. Therefore, at this moment, a directive counselling approach on donor conception disclosure cannot be ethically justified. PMID- 27116207 TI - CORR Insights(r): LUMiC(r) Endoprosthetic Reconstruction After Periacetabular Tumor Resection: Short-term Results. PMID- 27116206 TI - Development and Validation of a New Prognostic System for Patients with Hepatocellular Carcinoma. AB - BACKGROUND: Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. METHODS AND FINDINGS: Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26-106 mo) and 39 mo for Taiwanese patients (interquartile range, 12-61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score <= 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2-3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4-5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score's prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. CONCLUSIONS: The ITA.LI.CA prognostic system includes both a tumor staging-stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)-and a prognostic score-integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations. PMID- 27116208 TI - Physicians' Attire Influences Patients' Perceptions in the Urban Outpatient Orthopaedic Surgery Setting. AB - BACKGROUND: Previous work has established that physician attire influences patients' perceptions of their physicians. However, research from different specialties has disagreed regarding what kinds of physician attire might result in increased trust and confidence on the part of patients. QUESTIONS/PURPOSES: The purpose of this study was to investigate how surgeon attire affects patients' perceptions of trust and confidence in an urban orthopaedic outpatient setting. METHODS: Eighty-five of 100 patients solicited completed a three-part questionnaire in the outpatient orthopaedic clinic at an urban teaching hospital. In the first section, participants viewed eight images, four of a male surgeon and four of a female surgeon wearing a white coat over formal attire, scrubs, business attire, and casual attire, and rated each image on a five-level Likert scale. Participants were asked how confident, trustworthy, safe, caring, and smart the surgeon appeared, how well the surgery would go, and how willing they would be to discuss personal information with the pictured surgeon. The participant ranked all images from most to least confident in the second part and the last section obtained demographic information from the patients. Surveys were scored using a five-level Likert scale and a Friedman test was used to detect statistical significance when comparing all attires. For multiple pairwise comparisons, a Bonferroni correction was applied. RESULTS: The white coat on the male surgeon elicited modestly higher ratings in confidence (mean difference [MD], 0.367 +/- 0.737; 95% CI, 0.202-0.532; p < 0.001), intelligence (MD, 0.216 +/- 0.603; 95% CI, 0.077-0.356; p = 0.027), surgical skill (MD, 0.325 +/- 0.658; 95% CI, 0.175-0.474; p < 0.001), trust (MD, 0.312 +/- 0.613; 95% CI, 0.173-0.451; p < 0.001), ability to discuss confidential information (MD, 0.253 +/- 0.742; 95% CI, 0.087-0.419; p = 0.023), caring (MD, 0.279 +/- 0.655; 95% CI, 0.124-0.432; p = 0.006), and safety (MD, 0.260 +/- 0.594; 95% CI, 0.125-0.395; p = 0.002) compared with business attire. Similarly, the white coat was preferred to casual attire in all categories (confidence: MD, 0.810 +/- 0.921; smart: MD, 0.493 +/- 0.801; surgical skill: MD, 0.640 +/- 0.880; ability to discuss: MD, 0.564 +/- 0.988; trust: MD, 0.545 +/- 0.836; safety: MD, 0.581 +/- 0.860; caring: MD, 0.479 +/- 0.852; p < 0.001 for all comparisons). For the female surgeon, white coat and scrubs were not different, however the white coat was preferred to business attire in four of seven categories. Casual clothing was widely disliked in all categories for surgeons (men and women). When attire was compared for confidence on a scale, the white coat ranked higher than business (MD, 0.439 +/- 1.491; p = 0.006) and casual attire (MD, 1.043 +/- 2.054; p < 0.001), but not scrubs (MD, 0.169 +/- 1.230; p = 1.000). CONCLUSIONS: In this urban outpatient orthopaedic practice, patients' preferences varied based on the sex of the pictured surgeon in the survey. Overall, however, modest preferences were observed for the white coat in terms of confidence, intelligence, trust, and safety. Furthermore patients are more willing to discuss personal information and believe that their surgery will go better if the surgeon wears a white coat or scrubs. These results are consistent with those of several studies in other settings and therefore may be generalizable in other locations and specialties. Given the increasing awareness and concern for physician-spread hospital infection, this study lends support to scrub attire over business or casual attire if physicians do not wear a white coat. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 27116209 TI - CORR Insights(r): The John Charnley Award: Redefining the Natural History of Osteoarthritis in Patients With Hip Dysplasia and Impingement. PMID- 27116210 TI - Scleral and choroidal volume in relation to axial length in infants with retinoblastoma versus adults with malignant melanomas or end-stage glaucoma. AB - PURPOSE: To measure scleral and choroidal volume in eyes of Chinese, and to assess associations with age and axial length. METHODS: We histomorphometrically examined globes from infants and adults which had been enucleated due to retinoblastoma, uveal melanoma, or absolute painful glaucoma. Thickness of sclera and choroid were measured, and volumes were calculated. RESULTS: The study included 225 globes (mean axial length: 24.6 +/- 4.2 mm; range:17.0-35.7 mm; mean age: 30.4 +/- 22.6 years; range: 1-83 years). Mean computed scleral volume was 648 +/- 136 mm(3). Scleral volume in children aged <5 years significantly increased with longer axial length (P = 0.001; correlation coefficient r: 0.42) and older age (P = 0.003; r: 0.39) in univariate analysis. In multivariate analysis within the group of children aged <=2 years, larger scleral volume increased with longer axial length (P = 0.04; standardized correlation coefficient beta: 0.32; correlation coefficient B: 21.6; 95 % confidence interval (CI): 0.52, 42.7) and showed a statistically non-significant tendency to increase with older age (P = 0.06;b eta: 0.30; B: 56.9; 95% CI: -1.5,115). In individuals aged >= 5 years, scleral volume was not significantly associated with axial length (P = 0.75) or age (P = 0.13). Mean choroidal volume as measured and calculated in 95 individuals (age: 16-81 years) was 44.1 +/- 14.1 mm(3), and was not significantly associated with age (P = 0.47; r: -0.08) or axial length (P = 0.83; r: -0.02). CONCLUSIONS: This study on children eyes with retinoblastoma and adult eyes with malignant melanomas or end-stage glaucoma suggests that primary eye growth up to an age of 2 years is associated with an increase in scleral volume. After the age of 2 years, scleral volume and choroidal volume remain unchanged, leading to scleral and choroidal thinning with longer axial length, in particular at the posterior pole. PMID- 27116211 TI - Cataract development in patients treated with proton beam therapy for uveal melanoma. AB - PURPOSE: To evaluate the incidence, risk factors, and dosages of proton beam therapy associated with cataract development, and long-term visual outcomes after treatment of uveal melanoma. METHODS: All patients receiving primary proton beam therapy for uveal melanoma between 1998 and 2008 with no signs of cataract before irradiation were included. A minimum follow-up of 12 months was determined. Exclusion criteria included all applied adjuvant therapies such as intravitreal injections, laser photocoagulation, tumor resections, or re-irradiation. For subgroup analysis, we included all patients who underwent brachytherapy between 1998 and 2008 for uveal melanoma, considering the above mentioned inclusion and exclusion criteria. RESULTS: Two hundred and fifty-eight patients matched our inclusion criteria. Median follow-up was 72.6 months (12.0-167.4 months). Of these 258 patients, 71 patients (66.3 %) presented with cataract after 31.3 months (0.7-142.4 months), of whom 35 (20.4 %) required surgery after 24.2 (0.7 111.1 months) to ensure funduscopic tumor control. Kaplan-Meier estimates calculated a risk for cataract of 74.3 % after 5 years. There was no increase in metastasis or local recurrence in these patients. Patient's age was the sole independent statistically significant risk factor for cataract development. The probability of cataract occurrence significantly increased with doses to lens exceeding 15-20 CGE. Neither the appearance of cataract nor cataract surgery influenced long-term visual outcome. CONCLUSION: Cataract formation is the most frequent complication after irradiation. There is no benefit vis-a-vis brachytherapy with regard to cataract development. Data indicate a dose-effect threshold of 0.5 CGE for cataractogenesis, with significantly increasing risk above a dose of 15 CGE. Furthermore, cataract surgery can be performed without an increased risk for metastasis. PMID- 27116212 TI - Quantitative comparison of disc rim color in optic nerve atrophy of compressive optic neuropathy and glaucomatous optic neuropathy. AB - PURPOSE: The purpose was to investigate an objective and quantitative method to estimate the redness of the optic disc neuroretinal rim, and to determine the usefulness of this method to differentiate compressive optic neuropathy (CON) from glaucomatous optic neuropathy (GON). METHODS: In our study there were 126 eyes: 40 with CON, 40 with normal tension glaucoma (NTG), and 46 normal eyes (NOR). Digital color fundus photographs were assessed for the redness of disc rim color using ImageJ software. We separately measured the intensity of red, green, and blue pixels from RGB images. Three disc color indices (DCIs), which indicate the redness intensity, were calculated through existing formulas. RESULTS: All three DCIs of CON were significantly smaller than those of NOR (P < 0.001). In addition, when compared with NTG, DCIs were also significantly smaller in CON (P < 0.05). A comparison of mild CON and mild NTG (mean deviation (MD) > -6 dB), in which the extent of retinal nerve fiber layer thinning is comparable, the DCIs of mild CON were significantly smaller than those of mild NTG (P < 0.05). In contrast, DCIs did not differ between moderate-to-severe stages of CON and NTG (MD <= -6 dB), though the retinal nerve fibers of CON were more severely damaged than those of NTG. To differentiate between mild CON and mild NTG, all AUROCs for the three DCIs were above 0.700. CONCLUSIONS: A quantitative and objective assessment of optic disc color was useful in differentiating early-stage CON from GON and NOR. PMID- 27116213 TI - Is the change of oxygen extraction from retinal vessels upon flicker light stimulation dependent on the nerve fiber layer thickness in glaucoma patients? PMID- 27116214 TI - Reply to letter to the editor: Subfoveal Choroidal Thickness as a Predictor of Treatment Response to Anti-Vascular Endothelial Growth Factor Therapy for Polypoidal Choroidal Vasculopathy. PMID- 27116215 TI - IVIM perfusion fraction is prognostic for survival in brain glioma. AB - INTRODUCTION: The interest in measuring brain perfusion with intravoxel incoherent motion (IVIM) MRI has significantly increased in the last 3 years. Our aim was to evaluate the prognostic value for survival of intravoxel incoherent motion perfusion fraction in patients with gliomas, and compare it to dynamic susceptibility contrast relative cerebral blood volume and apparent diffusion coefficient. METHODS: Images were acquired in 27 patients with brain gliomas (16 high grades, 11 low grades), before any relevant treatment. Region of maximal perfusion fraction, maximal relative cerebral blood volume, and minimal apparent diffusion coefficient were obtained. The accuracy of all three methods for 2-year survival prognosis was compared using the area under the receiver operating characteristic curve and Kaplan-Meier survival curves. RESULTS: Death or survival for at least 2 years after imaging could be documented in 22/27 patients. The cutoff values of 0.112 for the perfusion fraction, of 3.01 for the relative cerebral blood volume, and 1033 * 10-6 mm2/s for apparent diffusion coefficient led to an identical sensitivity of 0.889, and a specificity of 0.833, 0.517, and 0.750, respectively for 2 year survival prognosis. The corresponding areas under the receiver operating characteristic curves were 0.84, 076, and 0.86, respectively. All three methods had a significant log rank test considering overall survival (p = 0.001, p = 0.028, and p = 0.002). CONCLUSION: In this relatively small cohort, maximal IVIM perfusion fraction, similarly to maximal relative cerebral blood volume and minimal apparent diffusion coefficient, was prognostic for survival in patients with gliomas. Maximal IVIM perfusion fraction and minimal apparent diffusion coefficient performed similarly in predicting survival, and both slightly outperformed maximal relative cerebral blood volume. PMID- 27116216 TI - Treatment of a Giant Fusiform Basilar Aneurysm with Partial Intra-Aneurysmal Embolization Combined with Mid-Basilar Artery Occlusion in a Child. PMID- 27116217 TI - Evolving medicinal chemistry strategies in antibiotic discovery. AB - Chemical modification of synthetic or natural product antibiotic scaffolds to expand potency and spectrum and to bypass mechanisms of resistance has dominated antibiotic drug discovery and proven immensely successful. However, the inexorable evolution of drug resistance coupled with a drought in innovation in antibiotic discovery contribute to a dearth of new drugs entering to market. Better understanding of the physicochemical properties of antibiotic chemical space is required to inform new antibiotic discovery. Innovations such as the development of antibiotic adjuvants to preserve efficacy of existing drugs together with expanding antibiotic chemical diversity through synthetic biology or new techniques to mine antibiotic producing organisms, are required to bridge the growing gap between the need for new drugs and their discovery. PMID- 27116218 TI - Self-Assembly Dynamics of Linear Virus-Like Particles: Theory and Experiment. AB - We experimentally and theoretically studied the self-assembly kinetics of linear virus-like particles (VLPs) consisting of double-stranded DNA and virus-like coat proteins. The polynucleotide acts as a self-assembly template for our proteins with engineered attractive protein-DNA and protein-protein interactions that imitate the physicochemical functionality of virus coat proteins. Inspired by our experimental observations, where we found that VLPs grow from one point onward, our model presumes a nucleation step before subsequent sequential cooperative binding from one of the ends of the polynucleotide. By numerically solving the pertinent reaction rate equations, we investigated the assembly dynamics as a function of the ratio between the number of available binding sites and proteins in the solution, i.e., the stoichiometry of the molecular building blocks. Depending on the stoichiometry, we found monotonic or nonmonotonic assembly kinetics. If the proteins in the solution vastly outnumber the binding sites on all of the polynucleotides, then the assembly kinetics were strictly monotonic and the assembled fraction increases steadily with time. However, if the concentration of proteins and binding sites is equal, then we found an overshoot in the concentration of fully covered polynucleotides. We compared our model with length distributions of two types of VLPs measured by atomic force microscopy imaging and found satisfactory agreement, suggesting that a relatively simple model may be useful in describing the assembly kinetics of chemically complex systems. We furthermore re-evaluated data by Hernandez-Garcia et al. (Nat. Nanotechnol. 2014, 9, 698-702) to include the effect of a finite protein concentration previously ignored. By fitting our model to the experimental data, we were able to pinpoint the sum of the protein-protein and protein-DNA interaction free energies, the binding rate of a protein to the DNA, and the nucleation free energy associated with switching a protein from the solution to the bound conformation. The values that we found for the VLPs are comparable to virus capsid binding energies of linear and spherical viruses. PMID- 27116219 TI - A C60-aryne building block: synthesis of a hybrid all-carbon nanostructure. AB - The synthesis of a [60]fullerene-benzyne building block and its further chemical cycloaddition reaction with graphene has resulted in a new all-carbon hybrid material which has been characterized by TGA, FTIR and Raman spectroscopies, XPS as well as AFM and TEM. Based on computational studies, the formation of both [2+2] and [4+2] cycloadducts on the graphene surface is feasible. PMID- 27116220 TI - Tracking Se Assimilation and Speciation through the Rice Plant - Nutrient Competition, Toxicity and Distribution. AB - Up to 1 billion people are affected by low intakes of the essential nutrient selenium (Se) due to low concentrations in crops. Biofortification of this micronutrient in plants is an attractive way of increasing dietary Se levels. We investigated a promising method of Se biofortification of rice seedlings, as rice is the primary staple for 3 billion people, but naturally contains low Se concentrations. We studied hydroponic Se uptake for 0-2500 ppb Se, potential phyto-toxicological effects of Se and the speciation of Se along the shoots and roots as a function of added Se species, concentrations and other nutrients supplied. We found that rice germinating directly in a Se environment increased plant-Se by factor 2-16, but that nutrient supplementation is required to prevent phyto-toxicity. XANES data showed that selenite uptake mainly resulted in the accumulation of organic Se in roots, but that selenate uptake resulted in accumulation of selenate in the higher part of the shoot, which is an essential requirement for Se to be transported to the grain. The amount of organic Se in the plant was positively correlated with applied Se concentration. Our results indicate that biofortification of seedlings with selenate is a successful method to increase Se levels in rice. PMID- 27116221 TI - A Multi-Site Study of Norovirus Molecular Epidemiology in Australia and New Zealand, 2013-2014. AB - BACKGROUND: Norovirus (NoV) is the major cause of acute gastroenteritis across all age groups. In particular, variants of genogroup II, genotype 4 (GII.4) have been associated with epidemics globally, occurring approximately every three years. The pandemic GII.4 variant, Sydney 2012, was first reported in early 2012 and soon became the predominant circulating NoV strain globally. Despite its broad impact, both clinically and economically, our understanding of the fundamental diversity and mechanisms by which new NoV strains emerge remains limited. In this study, we describe the molecular epidemiological trends of NoV associated acute gastroenteritis in Australia and New Zealand between January 2013 and June 2014. METHODOLOGY: Overall, 647 NoV-positive clinical faecal samples from 409 outbreaks and 238 unlinked cases of acute gastroenteritis were examined by RT-PCR and sequencing. Phylogenetic analysis was then performed to identify NoV capsid genotypes and to establish the temporal dominance of circulating pandemic GII.4 variants. Recombinant viruses were also identified based on analysis of the ORF1/2 overlapping region. FINDINGS: Peaks in NoV activity were observed, however the timing of these epidemics varied between different regions. Overall, GII.4 NoVs were the dominant cause of both outbreaks and cases of NoV-associated acute gastroenteritis (63.1%, n = 408/647), with Sydney 2012 being the most common GII.4 variant identified (98.8%, n = 403/408). Of the 409 reported NoV outbreaks, aged-care facilities were the most common setting in both Western Australia (87%, n = 20/23) and New Zealand (58.1%, n = 200/344) while most of the NoV outbreaks were reported from hospitals (38%, n = 16/42) in New South Wales, Australia. An analysis of a subset of non-GII.4 viruses from all locations (125/239) showed the majority (56.8%, n = 71/125) were inter-genotype recombinants. These recombinants were surprisingly diverse and could be classified into 18 distinct recombinant types, with GII.P16/GII.13 (24% of recombinants) the most common. CONCLUSION: This study revealed that following its emergence in 2012, GII.4 Sydney 2012 variant continued to be the predominant cause of NoV-associated acute gastroenteritis in Australia and New Zealand between 2013 and 2014. PMID- 27116222 TI - Multigenerational Effects of Heavy Metals on Feeding, Growth, Initial Reproduction and Antioxidants in Caenorhabditis elegans. AB - Earlier studies showed that toxicities of excessive metals lasted over generations. Yet, these studies mainly employed one-generation exposure, and the effects of multigenerational challenges need further studies. Presently, Caenorhabditis elegans were exposed to cadmium, copper, lead and zinc for four consecutive generations (G1 to G4) at environmental concentrations. The feeding, growth, initial reproduction, superoxide dismutase (SOD) and catalase (CAT) were determined. All data were represented in the percentage of that in control (POC), and POC in the control was normalized to 100%. In G1 and G2, the POC values in feeding, growth and initial reproduction were generally within 10% of the control (100%), indicating non-significant effects. The POC values in SOD and CAT were significantly higher than 100%, showing stimulatory effects. In G3 and G4, the POC values in feeding, growth and initial reproduction were significantly lower than 100%, showing inhibitory effects which were more severe in G4 than in G3. Meanwhile, SOD and CAT continuously showed stimulatory effects, and the stimulatory effects on SOD increased from G1 to G4. The effects with multigenerational challenges were different from those in one-generation exposure. The effects in later generations demonstrated the importance of multigenerational challenges in judging long-term influences of metals. PMID- 27116223 TI - The lognormal and gamma distribution models for estimating molecular weight distributions of polymers using PGSE NMR. AB - We present comprehensive derivations for the statistical models and methods for the use of pulsed gradient spin echo (PGSE) NMR to characterize the molecular weight distribution of polymers via the well-known scaling law relating diffusion coefficients and molecular weights. We cover the lognormal and gamma distribution models and linear combinations of these distributions. Although the focus is on methodology, we illustrate the use experimentally with three polystyrene samples, comparing the NMR results to gel permeation chromatography (GPC) measurements, test the accuracy and noise-sensitivity on simulated data, and provide code for implementation. PMID- 27116224 TI - Dangerous Pressurization and Inappropriate Alarms during Water Occlusion of the Expiratory Circuit of Commonly Used Infant Ventilators. AB - BACKGROUND: Non-invasive continuous positive airways pressure is commonly a primary respiratory therapy delivered via multi-purpose ventilators in premature newborns. Expiratory limb occlusion due to water accumulation or 'rainout' from gas humidification is a frequent issue. A case of expiratory limb occlusion due to rainout causing unexpected and excessive repetitive airway pressurisation in a Draeger VN500 prompted a systematic bench test examination of currently available ventilators. OBJECTIVE: To assess neonatal ventilator response to partial or complete expiratory limb occlusion when set to non-invasive continuous positive airway pressure mode. DESIGN: Seven commercially available neonatal ventilators connected to a test lung using a standard infant humidifier circuit with partial and/or complete expiratory limb occlusion were examined in a bench test study. Each ventilator was set to deliver 6 cmH2O in non-invasive mode and respiratory mechanics data for 75%, 80% and 100% occlusion were collected. RESULTS: Several ventilators responded inappropriately with complete occlusion by cyclical pressurisation/depressurisation to peak pressures of between 19.4 and 64.6 cm H2O at rates varying between 2 to 77 inflations per minute. Tidal volumes varied between 10.1 and 24.3mL. Alarm responses varied from 'specific' (tube occluded) to 'ambiguous' (Safety valve open). Carefusion Avea responded by continuing to provide the set distending pressure and displaying an appropriate alarm message. Draeger Babylog 8000 did not alarm with partial occlusions and incorrectly displayed airways pressure at 6.1cmH2O compared to the measured values of 13cmH2O. CONCLUSIONS: This study found a potential for significant adverse ventilator response due to complete or near complete expiratory limb occlusion in CPAP mode. PMID- 27116225 TI - Growing tumors induce a local STING dependent Type I IFN response in dendritic cells. AB - The importance of endogenous Type I IFNs in cancer immune surveillance is well established by now. Their role in polarization of tumor-associated neutrophilic granulocytes into anti-tumor effector cells has been recently demonstrated. Yet, the cellular source of Type I IFNs as well as the mode of induction is not clearly defined. Here, we demonstrate that IFN-beta is induced by growing murine tumors. Induction is mainly mediated via STING-dependent signaling pathways, suggesting tumor derived DNA as trigger. Transcription factors IRF3 and IRF5 were activated under these conditions which is consistent with tumor infiltrating dendritic cells (DCs) being the major cellular source of IFN-beta at the tumor site. Besides DCs, tumor cells themselves are induced to contribute to the production of IFN-beta. Taken together, our data provide further information on immune surveillance by Type I IFNs and suggest novel potent cellular targets for future cancer therapy. PMID- 27116226 TI - A novel blue luminescent material Na2[Co(C2O4)2(H2O)2].6H2O: synthesis, structure, luminescence and magnetic properties. AB - The synthesis, crystal structure and physical properties of new disodium trans diaquabis(oxalato)cobaltate(ii)hexahydrate {Na2[Co(C2O4)2(H2O)2].6H2O} crystals have been investigated. Single crystal X-ray analysis reveals that this compound crystallizes in the triclinic system with the space group P1[combining macron]. The structure of this complex consists of [Co(C2O4)2(H2O)2](2-) anionic units with a slightly distorted octahedral geometry of cobalt surrounded by four oxygen atoms of two oxalate groups. The anionic units are interlinked by two Na(+) ions with different octahedral and distorted octahedral environments. The electronic absorption spectra of the compound exhibit bands at 208, 246 and 526 nm in the UV and visible regions. A strong blue luminescence was observed at room temperature when excited at 355 nm. The M(H) curve at 2 K shows a significant nonlinear behaviour with almost zero coercivity which clearly indicates an extremely weak antiferromagnetic/ferromagnetic state of the complex. PMID- 27116228 TI - Enantiorecognition of planar "metallocenic" chirality by a nitrile hydratase/amidase bienzymatic system. AB - For the first time, a bacterial strain expressing a nitrile hydratase/amidase activity was able to recognize a planar element of chirality: Rhodococcus rhodochrous PA-34 whole cells catalysed with a high level of enantioselectivity the biotransformation of a novel nitrile ferrocene derivative into its corresponding amide and/or acid. An important parameter in the enzymatic recognition is the choice of the inducer selected for the bacterial growth phase. PMID- 27116227 TI - Effect of Vitamin D3 Supplementation on Inflammatory Markers and Glycemic Measures among Overweight or Obese Adults: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Obesity induced low-grade chronic inflammation disrupts proper immune and metabolic function. Vitamin D deficiency increases inflammation, which is associated with cardiometabolic risk. This systematic review examines the association between oral vitamin D (VD) supplementation and circulating inflammatory biomarkers and glycemic outcomes from randomized controlled trials (RCTs) of overweight and/or obese adults. METHODS: MEDLINE OVID, EMBASE and the Cochrane Central Register of Controlled Trials were searched according to a predefined protocol. Eligible RCTs included adults randomized to receive either oral VD or placebo. Two reviewers independently assessed RCTs for inclusion. Bias was assessed using the Cochrane Collaboration risk of bias tool. Mean differences were calculated comparing end-of-study sample means between the independent VD and placebo groups. RESULTS: Eleven unique RCTs met inclusion criteria from a total of 3,383 identified citations, including 79 screened articles and 14 full text data extractions. Inflammatory and glycemic measures were reported in 7 and 10 RCTs, respectively. Most trial findings were non-significant with considerable heterogeneity in design, participants and outcomes. All but one trial was rated as either high or unclear risk of bias. Two RCTs reported significant changes in inflammatory biomarkers; however, the mean difference between groups was not statistically significant: C-reactive protein 0.19 mg/L (p = 0.88); Tumor Necrosis Factor -0.54 pg/ml (p = 0.20). Two other trials found significant mean differences in fasting plasma glucose -0.32 mmol/L (p = 0.03), Hemoglobin A1c 0.13% (p = 0.04), and Homeostatic Model Assessment -0.86 (p = 0.02) following VD supplementation. CONCLUSIONS: Overall, there is no clear established benefit of VD supplementation on inflammatory biomarkers among overweight/obese adults. Baseline serum VD possibly influences the effect of VD repletion on inflammatory markers. Risk of bias was present in most studies, thus supporting the need for higher quality studies in this area to more conclusively understand the role VD supplementation has on inflammatory pathways. PMID- 27116229 TI - Nasal Mucosal Expression of the Receptors for Inflammatory Chemical Mediators. AB - The nasal allergic response is a complex process involving interactions between many chemical mediators such as histamine, bradykinin, cysteinyl leukotrienes, platelet-activating factor, prostaglandin D2 and thromboxane A2. The actions of these chemical mediators are facilitated by specific cell surface receptors that are coupled to G-proteins. Current therapeutic strategies against nasal allergic responses are mainly based on drugs that target these chemical mediators. To understand the role of these chemical mediators in allergic rhinitis, determining the identity and distribution of their receptors is of considerable interest. We have examined the expression and localization of the receptors for these chemical mediators in human nasal mucosa. Here, we review our data on the expression and localization of these receptors in allergic rhinitis, and we discuss the roles of chemical mediators in allergic rhinitis. PMID- 27116230 TI - Testing the measurement invariance of the University of Washington Self-Efficacy Scale short form across four diagnostic subgroups. AB - PURPOSE: The University of Washington Self-Efficacy Scale (UW-SES) was originally developed for people with multiple sclerosis (MS) and spinal cord injury (SCI). This study evaluates the measurement invariance of the 6-item short form of the UW-SES across four disability subgroups. Evidence of measurement invariance would extend the UW-SES for use in two additional diagnostic groups: muscular dystrophy (MD) and post-polio syndrome (PPS). METHODS: Multi-group confirmatory factor analysis was used to evaluate successive levels of measurement invariance of the 6-item short form, the UW-SES: (a) configural invariance, i.e., equivalent item factor structures between groups; (b) metric invariance, i.e., equivalent unstandardized factor loadings between groups; and (c) scalar invariance, i.e., equivalent item intercepts between groups. Responses from the four groups with different diagnostic disorders were compared: MD (n = 172), MS (n = 868), PPS (n = 225), and SCI (n = 242). RESULTS: The results of this study support that the most rigorous form of invariance (i.e., scalar) holds for the 6-item short form of the UW-SES across the four diagnostic subgroups. CONCLUSIONS: The current study suggests that the 6-item short form of the UW-SES has the same meaning across the four diagnostic subgroups. Thus, the 6-item short form is validated for people with MD, MS, PPS, and SCI. PMID- 27116231 TI - Case Series Investigating the Efficacy and Safety of Bilateral Fluocinolone Acetonide (ILUVIEN((r))) in Patients with Diabetic Macular Edema: 10 Eyes with 12 Months Follow-up. AB - INTRODUCTION: This short case series presents the results from 5 patients with bilateral chronic diabetic macular edema (DME), 12 months after they were initially treated with ILUVIEN ((r)) [0.2 MUg/day fluocinolone acetonide (FAc)]. METHODS: Ten eyes from five patients with pseudophakic lenses were investigated. Patients had bilateral, chronic DME and had received prior laser and anti-VEGF therapy. Visual and anatomic outcomes were investigated 12 months post-FAc implant in both eyes. RESULTS: At baseline, central retinal thickness (CRT) was 645.3 +/- 176.1 microns (mean +/- standard deviation), intraocular pressure (IOP) was 13.7 +/- 3.6 mmHg and visual acuity (VA) was 44.5 +/- 18.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Mean CRT improved at 6 months (341.7 +/- 169.7 microns) and 12 months (287.4 +/- 103.1 microns) and there were concurrent improvements in VA (ETDRS letters were 56 +/- 16 and 55 +/- 16 at 6 and 12 months, respectively). Mean IOP was stable throughout and <=21 mmHg. Left and right eyes were compared in the 5 patients by plotting changes in CFT, IOP and VA at 12 months, from baseline levels. CONCLUSION: This bilateral case series demonstrates the effectiveness of a sustained, controlled low dose of FAc in the management of bilateral DME over a 12-month period. The FAc implant has shown to work well in treatment of bilateral DME, although longer follow-up of these patients is still needed. FUNDING: Publication charges were funded by Alimera Sciences Ltd. PMID- 27116232 TI - Gambling Harm and Crime Careers. AB - Incarcerated populations across the world have been found to be consistently and significantly more vulnerable to problem gambling than general populations in the same countries. In an effort to gain a more specific understanding of this vulnerability the present study applied latent class analysis and criminal career theory to gambling data collected from a sample of English and Scottish, male and female prisoners (N = 1057). Theoretical links between gambling and crime were tested through three hypotheses: (1) that prisoners in the UK would have higher rates of problem gambling behaviour than the national population; (2) that if the link between gambling and crime is coincidental, gambling behaviour would be highly prevalent in an offending population, and (3) if connections between gambling behaviour and offending are co-symptomatic a mediating factor would show a strong association. The first of these was supported, the second was not supported and the third was partially supported. Latent class analysis found six gambling behaviour clusters measured by responses to the Problem Gambling Severity Index, primarily distinguished by loss chasing behaviour. Longitudinal offending data drawn from the Police National Computer database found four criminal career types, distinguished by frequency and persistence over time. A significant association was found between higher level loss chasing and high rate offending in criminal careers suggesting that impulse control may be a mediating factor for both gambling harm and criminal careers. PMID- 27116233 TI - Sudden unexpected cardiac death as the first symptom in young people: some useful clinical information from a systematic standardized anatomical study. PMID- 27116234 TI - The conflicting regulations on the use of magnetic resonance-conditional devices in Italy: is there room to solve this conflict? PMID- 27116235 TI - Risk of sudden death in subjects with Brugada type 1 electrocardiographic pattern and no previous cardiac arrest: is it high enough to justify an extensive use of prophylactic ICD? PMID- 27116236 TI - Antiviral Role of IFITM Proteins in African Swine Fever Virus Infection. AB - The interferon-induced transmembrane (IFITM) protein family is a group of antiviral restriction factors that impair flexibility and inhibit membrane fusion at the plasma or the endosomal membrane, restricting viral progression at entry. While IFITMs are widely known to inhibit several single-stranded RNA viruses, there are limited reports available regarding their effect in double-stranded DNA viruses. In this work, we have analyzed a possible antiviral function of IFITMs against a double stranded DNA virus, the African swine fever virus (ASFV). Infection with cell-adapted ASFV isolate Ba71V is IFN sensitive and it induces IFITMs expression. Interestingly, high levels of IFITMs caused a collapse of the endosomal pathway to the perinuclear area. Given that ASFV entry is strongly dependent on endocytosis, we investigated whether IFITM expression could impair viral infection. Expression of IFITM1, 2 and 3 reduced virus infectivity in Vero cells, with IFITM2 and IFITM3 having an impact on viral entry/uncoating. The role of IFITM2 in the inhibition of ASFV in Vero cells could be related to impaired endocytosis-mediated viral entry and alterations in the cholesterol efflux, suggesting that IFITM2 is acting at the late endosome, preventing the decapsidation stage of ASFV. PMID- 27116237 TI - Periprocedural 3D imaging of the left atrium and esophagus: comparison of different protocols of 3D rotational angiography of the left atrium and esophagus in group of 547 consecutive patients undergoing catheter ablation of the complex atrial arrhythmias. AB - A new method in creating 3D models of the left atrium (LA) and esophagus before catheter ablation of atrial arrhythmias is 3D rotational angiography (3DRA) of the LA. The purpose of this retrospective study was to test various acquisition protocols of the 3DRA and attempt to define the parameters influencing the success of the protocols. From August 2010 to November 2014, 3DRA of the LA using the Philips Allura FD 10 X-ray system was performed in 547 consecutive patients using right atrial and left atrial protocols. Visualization of the esophagus was performed after oral administration of a contrast agent. Patients were monitored for success (creation of a useful 3D models) and evaluated for a number of parameters affecting the success of 3DRA. The success of the RA protocol was 88.89 % with and 91.91 % without esophagus imaging. The success of the LA protocol was 97.42 % with and 94.54 % without esophagus imaging. The only factor reducing the success of the RA protocol was BMI; the LA protocol was not influenced by any factor. Ventricular fibrillation induced in two patients was successfully treated with defibrillation. 3DRA of the LA is a reliable method that supports catheter ablation of complex atrial arrhythmias. The LA protocol with esophagus imaging was significantly more reliable than the RA protocol; the other protocols were comparable. The RA protocol may be negatively affected by high BMI. Simultaneous imaging of the esophagus is safe and feasible, and the LA protocol can be recommended. PMID- 27116238 TI - Reproducibility and observer variability of tissue phase mapping for the quantification of regional myocardial velocities. AB - To systematically investigate the reproducibility of global and segmental left ventricular (LV) velocities derived from tissue phase mapping (TPM). Breath held and ECG synchronized TPM data (spatial/temporal resolution = 2 * 2 mm(2)/20.8 ms) were acquired in 18 healthy volunteers. To analyze scan-rescan variability, TPM was repeated in all subjects during a second visit separated by 16 +/- 5 days. Data analysis included LV segmentation, and quantification of global and regional (AHA 16-segment modal) metrics of LV function [velocity-time curves, systolic and diastolic peak and time-to-peak (TTP) velocities] for radial (Vr), long-axis (Vz) and circumferential (VPhi) LV velocities. Mean velocity time curves in basal, mid ventricular, and apical locations showed highly similar LV motion patterns for all three velocity components (Vr, VPhi, Vz) for scan and rescan. No significant differences for both systolic and diastolic peak and TTP myocardial velocities were observed. Segmental analysis revealed similar regional peak Vr and Vz during both systole and diastole except for three LV segments (p = 0.045, p = 0.033, and p = 0.009). Excellent (p < 0.001) correlations between scans and rescan for peak Vr (R(2) = 0.92), peak Vz (R(2) = 0.90), radial TTP (R(2) = 0.91) and long-axis TTP (R(2) = 0.88) confirmed good agreement. Bland-Altman analysis demonstrated excellent intra-observer and good inter-observer analysis agreement but increased variability for long axis peak velocities. TPM based analysis of global and regional myocardial velocities can be performed with good reproducibility. Robustness of regional quantification of long-axis velocities was limited but spatial velocity distributions across the LV could reliably be replicated. PMID- 27116239 TI - Nutrition and risk of dementia: overview and methodological issues. AB - After two decades of research on nutrition and dementia there is strong evidence for preventive effects of vitamin E, B vitamins, and n-3 fatty acids and deleterious effects of saturated fat on dementia. Among specific foods with evidence of neuroprotection are green leafy vegetables, other vegetables, berries, and seafood. A number of studies have examined dietary patterns, particularly the Mediterranean diet and DASH (Dietary Approaches to Stop Hypertension), neither of which is tailored to the specific foods and nutrients that have been identified as neuroprotective. A new diet called MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) incorporates many elements of the Mediterranean diet and DASH but with modifications that reflect current evidence for brain neuroprotection. The evidence in support of the relation of various nutrients and the Mediterranean diet to dementia has been inconsistent. The inconsistencies may be explained by inattention to nutrient/food intake levels in the interpretation of study findings and trial design, including a shifting metric among studies for scoring adherence to the Mediterranean diet. Future studies should pay particular attention to levels of intake in the design and analyses of nutritional studies. PMID- 27116240 TI - Nutrient intake, nutritional status, and cognitive function with aging. AB - With the demographic aging of populations worldwide, diseases associated with aging are becoming more prevalent and costly to individuals, families, and healthcare systems. Among aging-related impairments, a decline in cognitive function is of particular concern, as it erodes memory and processing abilities and eventually leads to the need for institutionalized care. Accumulating evidence suggests that nutritional status is a key factor in the loss of cognitive abilities with aging. This is of tremendous importance, as dietary intake is a modifiable risk factor that can be improved to help reduce the burden of cognitive impairment. With respect to nutrients, there is evidence to support the critical role of several B vitamins in particular, but also of vitamin D, antioxidant vitamins (including vitamin E), and omega-3 fatty acids, which are preferentially taken up by brain tissue. On the other hand, high intakes of nutrients that contribute to hypertension, atherosclerosis, and poor glycemic control may have negative effects on cognition through these conditions. Collectively, the evidence suggests that considerable slowing and reduction of cognitive decline may be achieved by following a healthy dietary pattern, which limits intake of added sugars, while maximizing intakes of fish, fruits, vegetables, nuts, and seeds. PMID- 27116242 TI - Vitamin D in dementia prevention. AB - Beyond effects on bone health, vitamin D exerts effects on a variety of target organs, including the brain. The discussion herein presents the state of the art in research on the neurological role of vitamin D and clinical implications among older adults, including implications for dementia onset and progression. Some of the neurosteroid actions of vitamin D include regulation of calcium homeostasis, clearance of amyloid-beta peptide, antioxidant and anti-inflammatory effects, and possible protection against the neurodegenerative mechanisms associated with Alzheimer's disease (AD). The correction of age-related hypovitaminosis D and cognitive decline has been reported by various cross-sectional and longitudinal studies reporting associations of lower vitamin D concentrations with brain changes and poorer cognition, specifically with respect to executive dysfunction. Epidemiological studies have consistently shown an association between inadequate dietary intake of vitamin D and cognitive disorders, including greater AD risk. Although there have not been any randomized placebo-controlled trials conducted to examine the effectiveness of vitamin D supplementation to prevent AD, several nonrandomized controlled studies have found that older adults experienced cognitive improvements after 1-15 months of vitamin D supplementation. Therefore, it appears crucial to maintain vitamin D concentrations at sufficiently high levels in order to slow, prevent, or improve neurocognitive decline. PMID- 27116241 TI - Nutritional interventions for Alzheimer's prevention: a clinical precision medicine approach. AB - Alzheimer's disease (AD) is a major source of morbidity and mortality, with the disease burden expected to rise as the population ages. No disease-modifying agent is currently available, but recent research suggests that nutritional and lifestyle modifications can delay or prevent the onset of AD. However, preventive nutritional interventions are not universally applicable and depend on the clinical profile of the individual patient. This article reviews existing nutritional modalities for AD prevention that act through improvement of insulin resistance, correction of dyslipidemia, and reduction of oxidative stress, and discusses how they may be modified on the basis of individual biomarkers, genetics, and behavior. In addition, we report preliminary results of clinical application of these personalized interventions at the first AD prevention clinic in the United States. The use of these personalized interventions represents an important application of precision medicine techniques for the prevention of AD that can be adopted by clinicians across disciplines. PMID- 27116243 TI - Utility of human epididymis protein 4 serum marker for the detection of adnexal malignancy: a multicentric prospective study. AB - The aim of this study was to assess the usefulness of the human epididymis protein 4 (HE4) serum biomarker in predicting malignant disease in a clinical setting in comparison with other diagnostic tools, such as serum CA125 and ROMA score. A multicentric prospective observational study was carried out between January 2010 and December 2011 in four European centres (Italy, Portugal, Latvia and Spain). Data from 981 healthy controls and patients diagnosed with adnexal pathology were collected. Data on the ROMA index, CA124 and HE4 tumour markers were analysed. The receiver-operator characteristics curve and the area under the curve were analysed to discriminate between malignant and nonmalignant disease. Predictive values were also calculated. In total, 642 (65.4%) patients presented with a pelvic mass, with 324 (33%) of them being diagnosed with malignant disease. Sensitivity for HE4 was 64.1%; specificity was 95.7%; and positive predictive value was 88.1%, with a 4.3% false-positive rate. On comparing malignant disease versus nonmalignant/healthy patients, there was a significant difference (P<0.001) in the area under the curve. The receiver-operator characteristic for CA125 was 0.79 [95% confidence interval (CI): 0.76-0.83], for HE4 was 0.89 (95% CI: 0.87-0.91) and for ROMA was 0.71 (95% CI: 0.68-0.75). The HE4 serum marker showed similar sensitivity, but better specificity, than CA125 and can improve the detection of malignant pathology in women diagnosed with adnexal pathology. PMID- 27116244 TI - Evaluating the Impact of AAC Interventions in Reducing Hospitalization-related Stress: Challenges and Possibilities. AB - Hospitalization is a stressful context for all children and their families, but especially for children with communication difficulties. Effective communication using augmentative and alternative communication (AAC) strategies can play a critical role in preparing and supporting everyone involved in such situations to have discussions that minimize insecurity, allow children to express their concerns, and so decrease negative stress and anxiety. However, there is a critical need to identify robust and reliable ways of evaluating the effectiveness of interventions that seek to achieve this aim. This research note illustrates some of the challenges and problems that require attention and suggests possible new research tools, for example, the use of physiological measures. The evaluation of an AAC intervention on a day surgery ward is described and used to illustrate one potential physiological measure for evaluating the impact of an intervention. PMID- 27116245 TI - The Origin of a Paradigm. PMID- 27116247 TI - Surprises in astrophysical gasdynamics. AB - Much of astrophysics consists of the study of ionized gas under the influence of gravitational and magnetic fields. Thus, it is not possible to understand the astrophysical universe without a detailed knowledge of the dynamics of magnetized fluids. Fluid dynamics is, however, a notoriously tricky subject, in which it is all too easy for one's a priori intuition to go astray. In this review, we seek to guide the reader through a series of illuminating yet deceptive problems, all with an enlightening twist. We cover a broad range of topics including the instabilities acting in accretion discs, the hydrodynamics governing the convective zone of the Sun, the magnetic shielding of a cooling galaxy cluster, and the behaviour of thermal instabilities and evaporating clouds. The aim of this review is to surprise and intrigue even veteran astrophysical theorists with an idiosyncratic choice of problems and counterintuitive results. At the same time, we endeavour to bring forth the fundamental ideas, to set out important assumptions, and to describe carefully whatever novel techniques may be appropriate to the problem at hand. By beginning at the beginning, and analysing a wide variety of astrophysical settings, we seek not only to make this review suitable for fluid dynamic veterans, but to engage novice recruits as well with what we hope will be an unusual and instructive introduction to the subject. PMID- 27116246 TI - Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides. AB - Recently, catalytic peptides were introduced that mimicked protease activities and showed promising selectivity of products even in organic solvents where protease cannot perform well. However, their catalytic efficiency was extremely low compared to natural enzyme counterparts presumably due to the lack of stable tertiary fold. We hypothesized that assembling these peptides along with simple hydrophobic pockets, mimicking enzyme active sites, could enhance the catalytic activity. Here we fused the sequence of catalytic peptide CP4, capable of protease and esterase-like activities, into a short amyloidogenic peptide fragment of Abeta. When the fused CP4-Abeta construct assembled into antiparallel beta-sheets and amyloid fibrils, a 4.0-fold increase in the hydrolysis rate of p nitrophenyl acetate (p-NPA) compared to neat CP4 peptide was observed. The enhanced catalytic activity of CP4-Abeta assembly could be explained both by pre organization of a catalytically competent Ser-His-acid triad and hydrophobic stabilization of a bound substrate between the triad and p-NPA, indicating that a design strategy for self-assembled peptides is important to accomplish the desired functionality. PMID- 27116249 TI - Author's reply to the letter to the editor regarding "Hemoglobin level is a more predictive diagnostic marker for acute pyelonephritis than mean platelet volume". PMID- 27116248 TI - Long-term prognosis of AL and AA renal amyloidosis: a Japanese single-center experience. AB - BACKGROUND: Few studies have been conducted on the long-term prognosis of patients with amyloid light chain (AL) and amyloid A (AA) renal amyloidosis in the same cohort. METHODS: We retrospectively examined 68 patients with biopsy proven renal amyloidosis (38 AL and 30 AA). Clinicopathological findings at the diagnosis and follow-up data were evaluated in each patient. We analyzed the relationship between clinicopathological parameters and survival data. RESULTS: Significant differences were observed in several clinicopathological features, such as proteinuria levels, between the AL and AA groups. Among all patients, 84.2 % of the AL group and 93.3 % of the AA group received treatments for the underlying diseases of amyloidosis. During the follow-up period (median 18 months in AL and 61 months in AA), 36.8 % of the AL group and 36.7 % of the AA group developed end-stage renal failure requiring dialysis, while 71.1 % of the AL group and 56.7 % of the AA group died. Patient and renal survivals were significantly longer in the AA group than in the AL group. eGFR of >60 mL/min/1.73 m2 at biopsy and an early histological stage of glomerular amyloid deposition were identified as low-risk factors. A multivariate analysis showed that cardiac amyloidosis and steroid therapy significantly influenced patient and renal survivals. CONCLUSIONS: Our results showed that heart involvement was the major predictor of poor outcomes in renal amyloidosis, and that the prognosis of AA renal amyloidosis was markedly better than that in previously reported cohorts. Therapeutic advances in inflammatory diseases are expected to improve the prognosis of AA amyloidosis. PMID- 27116250 TI - Molecular density functional theory of water including density-polarization coupling. AB - We present a three-dimensional molecular density functional theory of water derived from first-principles that relies on the particle's density and multipolar polarization density and includes the density-polarization coupling. This brings two main benefits: (i) scalar density and vectorial multipolar polarization density fields are much more tractable and give more physical insight than the full position and orientation densities, and (ii) it includes the full density-polarization coupling of water, that is known to be non vanishing but has never been taken into account. Furthermore, the theory requires only the partial charge distribution of a water molecule and three measurable bulk properties, namely the structure factor and the Fourier components of the longitudinal and transverse dielectric susceptibilities. PMID- 27116252 TI - Amputation Versus Limb-Salvage Surgery in Patients with Osteosarcoma: A Meta analysis. AB - BACKGROUND: This meta-analysis compared survival and function in patients with limb osteosarcoma treated with limb-salvage surgery (LSS) versus amputation or rotationplasty. METHODS: Medline, Cochrane, EMBASE, and Google Scholar were searched until November 30, 2015 for studies reporting Musculoskeletal Tumor Society (MSTS) scores and survival rates in osteosarcoma patients. Differences between patients undergoing LSS versus ablative surgery were analyzed based on MSTS scores and postoperative survival rates. RESULTS: Of 1330 patients in the studies analyzed, 934 underwent LSS, and 662 were treated with amputation. A random-effects model was applied due to heterogeneity among studies (Q statistic = 1.829, I (2) = 0 %, p = 0.767). No difference was found in post-operative local recurrence rate between amputees and patients receiving LSS. The 5-year survival rate was significantly lower with amputation compared with LSS (OR 0.628; 95 % CI 0.431-0.913, p = 0.015). The 2-year survival rate was not different between amputation and LSS. In addition, amputees had lower MSTS scores than those undergoing LSS (difference in means = -4.46 %, 95 % CI 6.49-2.45 %, p < 0.001). CONCLUSIONS: LSS results in higher 5-year survival rates and better functional outcomes as indicated by MSTS scores in patients with limb osteosarcomas. PMID- 27116253 TI - Tissue communication in a systemic immune response of Drosophila. AB - Several signaling pathways, including the JAK/STAT and Toll pathways, are known to activate blood cells (hemocytes) in Drosophila melanogaster larvae. They are believed to regulate the immune response against infections by parasitoid wasps, such as Leptopilina boulardi, but how these pathways control the hemocytes is not well understood. Here, we discuss the recent discovery that both muscles and fat body take an active part in this response. Parasitoid wasp infection induces Upd2 and Upd3 secretion from hemocytes, leading to JAK/STAT activation mainly in hemocytes and in skeletal muscles. JAK/STAT activation in muscles, but not in hemocytes, is required for an efficient encapsulation of wasp eggs. This suggests that Upd2 and Upd3 are important cytokines, coordinating different tissues for the cellular immune response in Drosophila. In the fat body, Toll signaling initiates a systemic response in which hemocytes are mobilized and activated hemocytes (lamellocytes) are generated. However, the contribution of Toll signaling to the defense against wasps is limited, probably because the wasps inject inhibitors that prevent the activation of the Toll pathway. In conclusion, parasite infection induces a systemic response in Drosophila larvae involving major organ systems and probably the physiology of the entire organism. PMID- 27116254 TI - Factors regulating bone remodeling processes in aseptic implant loosening. AB - This study was undertaken to screen periprosthetic tissues (PPTs) under specified conditions for a series of molecular components and describe them in bone remodeling processes within aseptic loosening. PPT samples were obtained from patients undergoing revision surgery of endoprostheses (n = 24) and synovial tissues from patients with OA (control) (n = 18), patients with any form of inflammatory arthritides were excluded. Tissue samples were examined via microbiology, histology (H&E, TRAP), immunohistochemistry (CD68/anti-S100a4), quantitative real-time PCR (ALP, COL1A1, cathepsin K, M-CSF, MMP13, OPG, RANK, RANKL, TNF-alpha, and TRAP) and an endotoxin-assay. PPT samples contained a variety of cellular components and stained positive for TRAP (56%), CD68 (100%), and S100a4 (100%). Wear debris were found in cells staining positive for CD68 and S100a4. In PPTs significantly higher ALP, COL1A1, MMP-13, RANK, RANKL, and TRAP expression were found along with a significantly higher RANKL/OPG ratio and a significantly lower OPG expression. No significant difference was observed for M CSF, TNF-alpha, cathepsin K, and endotoxin levels. In conclusion we found osteogenic proteins (ALP, COL1A1), a proteolytic enzyme (MMP-13), markers for osteoclast differentiation (RANK, RANKL), and osteoclast activity (TRAP) to be increased in PPT, whereas OPG expression decreased significantly in comparison to control. We present data about a large series of molecular components in PPT and describe novel and key findings about their expression levels in regards to aseptic implant loosening. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:248-257, 2017. PMID- 27116251 TI - miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. AB - MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy. PMID- 27116255 TI - Nanocapillary Atmospheric Pressure Plasma Jet: A Tool for Ultrafine Maskless Surface Modification at Atmospheric Pressure. AB - With respect to microsized surface functionalization techniques we proposed the use of a maskless, versatile, simple tool, represented by a nano- or microcapillary atmospheric pressure plasma jet for producing microsized controlled etching, chemical vapor deposition, and chemical modification patterns on polymeric surfaces. In this work we show the possibility of size-controlled surface amination, and we discuss it as a function of different processing parameters. Moreover, we prove the successful connection of labeled sugar chains on the functionalized microscale patterns, indicating the possibility to use ultrafine capillary atmospheric pressure plasma jets as versatile tools for biosensing, tissue engineering, and related biomedical applications. PMID- 27116256 TI - Study of the Reaction Cl + Ethyl Formate at 700-950 Torr and 297 to 435 K: Product Distribution and the Kinetics of the Reaction C2H5OC(?O) -> CO2 + C2H5. AB - The kinetics and mechanism of the reaction of atomic chlorine with ethyl formate [Cl + CH3CH2O(C?O)H, reaction 1] have been examined. These experiments were performed at pressures of 760-950 Torr and temperatures from 297 to 435 K. Reactants and products were quantified by gas chromatography-flame ionization detector (GC/FID) analysis. The initial mixture contained ethyl formate, Cl2, and N2. Cl atoms were generated by UV photolysis of this initial mixture at 360 nm, which dissociates Cl2. The rate constant of reaction 1 was measured at 297 K relative to that of the reaction Cl + C2H5Cl (reaction 2), yielding the rate constant ratio k1/k2 = 1.09 +/- 0.05. The final products formed from reaction 1 are ethyl chloroformate, 1-chloroethyl formate, and 2-chloroethyl formate. These products result from the reactions with Cl2 of the three free radicals formed by H atom abstraction from ethylformate in reaction 1. Based on the molar yields of these three chlorinated products, the yields of the three radicals formed from reaction 1 at 297 K are (25 +/- 3) mole percent of CH3CH2O(C?O); (67 +/- 5) mole percent of CH3CHO(C?O)H; and (8 +/- 2) mole percent of CH2CH2O(C?O)H. A second phase of this experiment measured the rate constant of the decarboxylation of the ethoxy carbonyl radical [CH3CH2O(C?O) -> CO2 + C2H5, reaction 4] relative to the rate constant of its reaction with Cl2 [CH3CH2O(C?O) + Cl2 -> CH3CH2O(C?O)Cl + Cl, reaction 3a]. Over the temperature range 297 to 404 K at 1 atm total pressure, this ratio can be expressed by k4/k3a = 10(23.56+/-0.22) e(-(12700+/ 375)/RT) molecules cm(-3). Estimating the value of k3a (which has not been measured) based on similar reactions, the expression k4 = 5.8 * 10(12) e( (12700)/RT) s(-1) is obtained. The estimated error of this rate constant is +/- a factor of 2 over the experimental temperature range. This rate expression is compared with recent ab initio calculations of the decarboxylation of the analogous methoxy carbonyl radical. PMID- 27116257 TI - Letter to the Editor concerning "Virtually bloodless posterior midline exposure of the lumbar spine using the 'paramidline' fatty plane" by Moghimi MH, Leonard DA, Cho CH, et al. (Eur Spine J (2016) 25;956-962). PMID- 27116259 TI - Shakespeare: the bard at the bedside. PMID- 27116258 TI - A model of acute central cervical spinal cord injury syndrome combined with chronic injury in goats. AB - PURPOSE: To develop a large animal model for acute central cervical spinal cord injury syndrome (ACCSCIS. METHODS: Twenty-four adult male goats were randomized into four groups including group A with acute compression injury, group B with anterior chronic compression, group C as the test group that received anterior chronic compression by screw and acute compression by posterior balloon insertion, and group D as normal controls that received sham surgery. Neurological function (modified Tarlov motor function), CT, MRI, cortical somatosensory evoked potentials (CSEP), and pathological analysis were evaluated. The data were analyzed statistically. RESULTS: The motor function of the goats in group C was significantly lower than other groups. CSEP before spinal cord compression showed a stable pattern. Spinal cord compression resulted in a gradual decrement in the peak latency and significant increment in the peak amplitude. Cervical spinal canal occupying ratio was significantly lower in group C than the other groups. MRI revealed focal low signal in T1 weighted images and focal high signal in T2 weighted images in group C. Pathological analysis showed more severe lesions in the gray matter than that in the white matter in group C. CONCLUSIONS: The model well simulated the pathogenesis and resembled the clinical characteristics of ACCSCIS. This model seems to have the potential to contribute to the development of effective therapies for ACCSCIS. PMID- 27116260 TI - Securing a fairer deal for children. PMID- 27116261 TI - Strong stewardship to fight antimicrobial resistance. PMID- 27116262 TI - Transfusion-transmitted malaria: is hope around the corner? PMID- 27116263 TI - No more excuses: viral hepatitis can be eliminated. PMID- 27116264 TI - Improving access to NCD medicines through collaboration. PMID- 27116266 TI - Chernobyl disaster 30 years on: lessons not learned. PMID- 27116267 TI - Nepal's slow road to recovery, 1 year after the earthquakes. PMID- 27116268 TI - Systemic lupus erythematosus. PMID- 27116269 TI - Tolullah Oni: public health specialist with a global ambition. PMID- 27116271 TI - "The infirmity of his age": Shakespeare's 400th anniversary. PMID- 27116272 TI - Partial breast irradiation and the GEC-ESTRO trial. PMID- 27116273 TI - Partial breast irradiation and the GEC-ESTRO trial. PMID- 27116274 TI - Partial breast irradiation and the GEC-ESTRO trial - Authors' reply. PMID- 27116275 TI - Objection to chronic disease based restrictions during the Hajj. PMID- 27116276 TI - Mephedrone use is increasing in London. PMID- 27116277 TI - The language of biomedical sciences. PMID- 27116278 TI - Frailty in emergency departments. PMID- 27116279 TI - Iran and science publishing in the post-sanctions era. PMID- 27116280 TI - Department of Error. PMID- 27116281 TI - Tu Youyou's Nobel Prize and the academic evaluation system in China. PMID- 27116282 TI - Effect of Plasmodium inactivation in whole blood on the incidence of blood transfusion-transmitted malaria in endemic regions: the African Investigation of the Mirasol System (AIMS) randomised controlled trial. AB - BACKGROUND: Transfusion-transmitted malaria is a frequent but neglected adverse event in Ghana. We did a randomised controlled clinical trial to assess the efficacy and safety of a whole blood pathogen reduction technology at preventing transfusion transmission of Plasmodium spp parasites. METHODS: For this randomised, double-blind, parallel-group clinical trial, eligible adult patients (aged >= 18 years) with blood group O+, who required up to two whole blood unit transfusions within 3 days of randomisation and were anticipated to remain in hospital for at least 3 consecutive days after initial transfusion, were enrolled from Komfo Anokye Teaching Hospital in Kumasi, Ghana. The main exclusion criteria were symptoms of clinical malaria, antimalaria treatment within 7 days before randomisation, fever, and haemorrhage expected to require transfusion with up to two units of whole blood during the 3 days following study entry. Eligible patients were randomly assigned 1:1 by computer-generated permuted block randomisation (block size four) list to receive transfusion with either pathogen reduced whole blood (treated) or whole blood prepared and transfused by standard local practice (untreated). Patients, health-care providers, and data collectors were masked to treatment allocation. Patients in both groups received up to two whole blood unit transfusions that were retrospectively tested for parasitaemia. Pre-transfusion and post-transfusion blood samples (taken on days 0, 1, 3, 7, and 28) were tested for presence and amount of parasite genome, and assessed for haematological and biochemical parameters. The primary endpoint was the incidence of transfusion-transmitted malaria in non-parasitaemic recipients exposed to parasitaemic whole blood, defined as two consecutive parasitaemic post transfusion samples with parasite allelic matching, assessed at 1-7 days after transfusion. Secondary endpoints included haematological parameters and a safety analysis of adverse events in patients. This study is registered with ClinicalTrials.gov, number NCT02118428, and with the Pan African Clinical Trials Registry, number PACTR201406000777310. FINDINGS: Between March 12, 2014, and Nov 7, 2014, 227 patients were enrolled into the study, one of whom was subsequently excluded because she did not meet the inclusion criteria. Of the 226 randomised patients, 113 were allocated to receive treated whole blood and 113 to receive standard untreated whole blood. 223 patients (111 treated and 112 untreated) received study-related transfusions, whereas three patients (two treated and one untreated) did not. 214 patients (107 treated and 107 untreated) completed the protocol as planned and comprised the per-protocol population. Overall, 65 non parasitaemic patients (28 treated and 37 untreated) were exposed to parasitaemic blood. The incidence of transfusion-transmitted malaria was significantly lower for the pathogen-reduced (treated) patients (1 [4%] of 28 patients) than the untreated group (8 [22%] of 37 patients) in this population (p=0.039). Overall, 92 (41%) of 223 patients reported 145 treatment-related emergent adverse events during the conduct of the study, with a similar incidence of adverse events between groups receiving untreated or treated whole blood. No transfusion-related deaths occurred in the trial. INTERPRETATION: Treatment of whole blood with the Mirasol pathogen reduction system for whole blood reduced the incidence of transfusion-transmitted malaria. The primary endpoint of the study was achieved in the population of non-parasitaemic patients receiving parasitaemic whole blood. The safety profile and clinical outcomes were similar across the two treatment groups. FUNDING: Terumo BCT Inc. PMID- 27116283 TI - The path to eradication: a progress report on the malaria-eliminating countries. AB - In the past several years, as worldwide morbidity and mortality due to malaria have continued to decrease, the global malaria community has grown increasingly supportive of the idea of malaria eradication. In 2015, three noteworthy global documents were released-the WHO's Global Technical Strategy for Malaria 2016 2030, the Roll Back Malaria Partnership's Action and Investment to defeat Malaria 2016-2030, and From Aspiration to Action: What Will It Take to End Malaria?-that collectively advocate for malaria elimination and eradication and outline key operational, technical, and financial strategies to achieve progress toward malaria eradication. In light of this remarkable change in global attitudes toward malaria elimination and eradication, and as the malaria community debates how and when to embark on this ambitious goal, it is important to assess current progress along the path to eradication. Although low-income, high-burden countries are often the focus when discussing the substantial challenges of eradication, the progress toward elimination in middle-income, low-burden countries is a major driver of global progress and deserves better recognition. Additionally, although global support and guidance is essential for success, malaria elimination and eradication efforts will ultimately be driven at the country level and achieved in a collaborative manner, region by region. In this Review, we examine the present status of the 35 malaria-eliminating countries, summarise existing national and regional elimination goals and the regional frameworks that support them, and identify the most crucial enabling factors and potential barriers to achieving eradication by a theoretical end date of 2040. PMID- 27116287 TI - Endocan: a novel predictor of endothelial dysfunction in obstructive sleep apnea syndrome. AB - BACKGROUND AND AIMS: Obstructive sleep apnea syndrome (OSA) is an independent risk factor for endothelial dysfunction and cardiometabolic diseases. Plasma endocan levels are elevated in a large number of diseases, and is a novel surrogate endothelial cell dysfunction marker. We aimed to assess the role of serum endocan level as a potential mechanism of endothelial dysfunction in OSA patients. MATERIALS AND METHODS: This was a cohort study in which patients who had undergone a sleep study for diagnosis of OSA were recruited. Included patients were grouped according to apnea-hypopnea index (AHI) as mild, moderate and severe OSA. Patients with AHI < 5 served as control group. Endothelial function was evaluated with flow-mediated dilatation (FMD). Plasma endocan level was measured for all patients. RESULTS: One hundred twenty eight OSA patients included (15 controls, 22 with mild, 22 with moderate and 69 with severe OSA). The mean age was 51.6 +/- 11.9 years and 43.8% (56/128) of the study population was female. As expected, the prevalence of hypertension, diabetes and cardiovascular disease increased as the severity of OSA increased. Endocan levels were significantly higher and FMD measurements were lower in patients with OSA compared to healthy controls. There was a positive correlation between AHI and serum endocan levels (rho = 0.826, P < 0.0001) and there was a negative correlation between AHI and FMD (rho = -0.686, P < 0.0001) In addition, we observed a strong negative correlation between serum endocan level and FMD (rho = -0.613, P < 0.0001). In linear regression analysis AHI was independently related both with endocan (P < 0.0001) and FMD (P = 0.011). CONCLUSION: Serum endocan level is strongly associated with the severity of OSA and endothelial dysfunction. Endocan might be a useful early novel marker for premature vascular endothelial system damage in OSA patients. PMID- 27116288 TI - Assessment of relationship between galectin-3 and ambulatory ECG-based microvolt T-wave alternans in sustained systolic-diastolic hypertension patients. AB - OBJECTIVES: Galectin-3 is a marker associated with myocardial fibrosis and left ventricular myocardial index (LVMI). Myocardial fibrosis and LVMI have been reported in many studies to be associated with microvolt T-wave alternans (MTWA) positivity. In this study, galectin-3 levels of normotensive individuals and sustained systolic-diastolic hypertensive patients were compared and the association between galectin-3 levels and ambulatory ECG-based MTWA was investigated. METHODS: A total of 184 individuals were included in the study, among whom, 43 were normotensive and 141 had sustained systolic-diastolic hypertension without cardiovascular or chronic renal failure. Galectin-3, MTWA, and LVMI were evaluated in all participants. Galectin-3 levels of hypertensive and normotensive participants were compared. The association between galectin-3, MTWA, LVMI, and estimated glomerular filtration rate (eGFR) was investigated in hypertensive patients. RESULTS: LVMI and galectin-3 levels were higher among hypertensive patients compared with normotensives (94.9+/-26.8 vs. 76.4+/-22.9 g/m, 7.325+/-2.123 vs. 5.233+/-1.506 ng/ml; P<0.001, P<0.001). Correlation analysis carried out among the hypertensive patients showed that the galectin-3 level was correlated positively to LVMI, age, and MTWA positivity (r=0.396, P<0.001; r=0.358, P<0.001; r=0.361, P<0.001, respectively), whereas it was correlated negatively to eGFR and male sex (r=-0.364, P<0.001; r=-0.280, P=0.001, respectively). Multiple logistic regression analysis indicated that LVMI and galectin-3 showed an independent association with MTWA positivity in hypertensive patients (P=0.003 and 0.005, respectively). CONCLUSION: Increased galectin-3 levels are associated with ambulatory ECG-based MTWA positivity, decreased eGFR, and increased LVMI in hypertensive patients. This association may be used for risk classification in this patient group. PMID- 27116291 TI - UK Renal Registry 18th Annual Report: Chapter 12 Epidemiology of Reported Infections amongst Patients Receiving Dialysis for Established Renal Failure in England 2013 to 2014: a Joint Report from Public Health England and the UK Renal Registry. AB - From 1st May 2013 to 30th April 2014 there were 35 episodes of Methicillin resistant Staphylococcus aureus (MRSA) bacteraemia in established renal failure patients on dialysis. This is now fairly stable year-on-year equating to a rate of 0.15 episodes per 100 dialysis patient years, following an initial decline in rates from 4.0 episodes per 100 dialysis patient years in 2005 when reporting began. Methicillin sensitive Staphylococcus aureus (MSSA) bacteraemia rates were slightly higher this year at 2.23 per 100 dialysis patient years (compared with 1.59 episodes per 100 dialysis patient years last year) with 526 episodes of blood stream infection reported. In 2005, the first year this was reported, there were 1,114 MSSA bacteraemias in 54 centres. There were 247 Clostridium difficile infection episodes with a rate of 1.05 per 100 dialysis patient years, slightly higher than last year at 0.55 episodes per 100 dialysis patient years. Escherichia coli infections occurred at a rate of 1.49 per 100 dialysis patient years, very similar to the rate reported last year (1.32 episodes per 100 dialysis patient years). This report has utilised a new methodology to identify cases, linking all established renal failure cases known to the UK Renal Registry (UKRR) with all infections reported to Public Health England and avoids the need for the local microbiology team to flag the patient as a renal patient. This may have increased the reliability of diagnosis at the UKRR level. In each infection for which access data were collected, the presence of a central venous catheter appeared to correlate with increased risk. PMID- 27116292 TI - Readability of Educational Materials to Support Parent Sexual Communication With Their Children and Adolescents. AB - Sexual communication is a principal means of transmitting sexual values, expectations, and knowledge from parents to their children and adolescents. Many parents seek information and guidance to support talking with their children about sex and sexuality. Parent education materials can deliver this guidance but must use appropriate readability levels to facilitate comprehension and motivation. This study appraised the readability of educational materials to support parent sexual communication with their children. Fifty brochures, pamphlets, and booklets were analyzed using the Flesch-Kincaid, Gunning Fog, and Simple Measure of Gobbledygook (SMOG) index methods. Mean readability grade-level scores were 8.3 (range = 4.5-12.8), 9.7 (range = 5.5-14.9), and 10.1 (range = 6.7 13.9), respectively. Informed by National Institutes of Health-recommended 6th to 7th grade levels and American Medical Association-recommended 5th to 6th grade levels, percentages falling at or below the 7.0 grade level were calculated as 38%, 12%, and 2% and those falling at or below the 6.0 grade level were calculated as 12%, 2%, and 0% based on the Flesch-Kincaid, Gunning Fog, and SMOG methods, respectively. These analyses indicate that the majority of educational materials available online to support parents' communication with their children about sex and sexuality do not meet the needs of many or most parents. Efforts to improve the accessibility of these materials are warranted. PMID- 27116293 TI - Metabolism and urinary excretion kinetics of di(2-ethylhexyl) terephthalate (DEHTP) in three male volunteers after oral dosage. AB - Di(2-ethylhexyl) terephthalate (DEHTP) is used as a substitute for di(2 ethylhexyl) phthalate (DEHP), an ortho-phthalate-based plasticizer that is classified and labeled due to its toxicity to reproduction. In this study the metabolism and urinary excretion kinetics of DEHTP were investigated by single oral dosage of 50 mg DEHTP to three male volunteers (resulting in individual dosages between 0.55 and 0.59 mg/kg body weight). Separate urine samples were consecutively collected for 48 h. In analogy to DEHP, we quantified specific side chain-oxidized monoester metabolites of DEHTP (5OH-MEHTP, 5oxo-MEHTP, 5cx-MEPTP and 2cx-MMHTP) by HPLC-MS/MS with online sample clean-up and isotope dilution. All postulated metabolites were detectable in all samples after dosage. The predominant, specific urinary metabolite was 5cx-MEPTP representing about 13.0 % of the applied dose as mean of the three volunteers (range 7.0-20.4 %) in urine, followed by 5OH-MEHTP (mean: 1.8 %; range 1.3-2.4 %) and 5oxo MEHTP (mean: 1.0 %; range 0.6-1.6 %). 2cx-MMHTP was a minor metabolite representing only 0.3 % (range 0.2-0.4 %). In total, about 16.1 % of the dose was recovered in urine as the above investigated specific metabolites within 48 h with the major share (95 %) being excreted within the first 24 h. Investigation of the glucuronidation patterns revealed that the carboxy-metabolites are excreted almost completely in their free form (>90 %), whereas for 5OH-MEHTP and 5oxo-MEHTP, glucuronidation is preferred (>70 %). With this study we provide reliable urinary excretion factors to calculate DEHTP intakes based on metabolite concentrations in environmental and occupational studies. PMID- 27116294 TI - Epigallocatechin gallate (EGCG) inhibits adhesion and migration of neural progenitor cells in vitro. AB - Food supplements based on herbal products are widely used during pregnancy as part of a self-care approach. The idea that such supplements are safe and healthy is deeply seated in the general population, although they do not underlie the same strict safety regulations than medical drugs. We aimed to characterize the neurodevelopmental effects of the green tea catechin epigallocatechin gallate (EGCG), which is now commercialized as high-dose food supplement. We used the "Neurosphere Assay" to study the effects and unravel underlying molecular mechanisms of EGCG treatment on human and rat neural progenitor cells (NPCs) development in vitro. EGCG alters human and rat NPC development in vitro. It disturbs migration distance, migration pattern, and nuclear density of NPCs growing as neurospheres. These functional impairments are initiated by EGCG binding to the extracellular matrix glycoprotein laminin, preventing its binding to beta1-integrin subunits, thereby prohibiting cell adhesion and resulting in altered glia alignment and decreased number of migrating young neurons. Our data raise a concern on the intake of high-dose EGCG food supplements during pregnancy and highlight the need of an in vivo characterization of the effects of high-dose EGCG exposure during neurodevelopment. PMID- 27116296 TI - Erratum to: Mervyn Deitel-Biography. PMID- 27116295 TI - Serum Bioavailable Vitamin D Concentrations and Bone Mineral Density in Women After Obesity Surgery. AB - INTRODUCTION: Low bone mass after obesity surgery may arise as a consequence of chronic malabsorption of calcium and vitamin D. However, we have not found any role of serum 25-hydroxyvitamin D or of polymorphisms in the vitamin D receptor gene in previous studies. PURPOSE: To investigate the circulating bioavailable 25 hydroxyvitamin D in women after bariatric procedures and its association with bone mass. PATIENTS AND METHODS: The study consisted of 91 women on follow-up for 7 +/- 2 years after bariatric surgery. We measured bone mineral density (BMD), serum parathormone (PTH), 25-hydroxyvitamin D, and vitamin D binding protein (VDBP). All patients were genotyped for two variants in the coding region of VDBP (rs4588 and rs7041). Bioavailable 25-hydroxyvitamin D was calculated in double homozygotes. RESULTS: We found a negative correlation between bioavailable 25 hydroxyvitamin D and PTH (r = -0.373, P = 0.018), but not with BMD at lumbar spine (r = -0.065, P = 0.682) or hip (r = -0.029, P = 0.857). When adjusting by age, similar results were found for PTH (r = -0.441, P = 0.005), BMD at lumbar spine (r = -0.026, P = 0.874) and hip (r = -0.096, P = 0.561). After multivariate linear regression, forcing bioavailable 25-hydroxyvitamin D into the model resulted in a weak significant association with BMD at the lumbar spine (beta = - 0.247, P = 0.025). CONCLUSIONS: Serum bioavailable 25-hydroxyvitamin D concentrations are not associated with bone mass loss after bariatric surgery in women. The negative association with serum PTH levels suggests that vitamin D supplementation partly improves secondary hyperparathyroidism, yet other mechanisms may contribute to low bone mass after bariatric surgery. PMID- 27116298 TI - Patient dissatisfaction and institutional betrayal in the Canadian medical system: A qualitative study. AB - Individuals who struggle with chronic medical conditions frequently use medical services and may depend on the medical system to ensure their overall well-being. As a result, they may be at a greater risk of feeling betrayed by the medical system when their needs are not being met. The current study aimed to qualitatively assess patients' negative experiences with the medical system that may lead to feelings of institutional betrayal. A total of 14 Canadian adults struggling with various chronic conditions completed an online open-ended questionnaire. Results indicated that institutional betrayal is composed of doctor-level betrayal (inadequate medical care and lack of psychological support) as well as system-level betrayal. The findings are discussed in the context of betrayal trauma theory; specifically, patients' appraisals of their negative health care experiences may play a vital role when one is considering the impact of institutional betrayal on an individual's overall well-being. PMID- 27116299 TI - Determining Multiple Responses of Pseudomonas aeruginosa PAO1 to an Antimicrobial Agent, Free Nitrous Acid. AB - Free nitrous acid (FNA) has recently been demonstrated as an antimicrobial agent on a range of micro-organisms, especially in wastewater-treatment systems. However, the antimicrobial mechanism of FNA is largely unknown. Here, we report that the antimicrobial effects of FNA are multitargeted. The response of a model denitrifier, Pseudomnas aeruginosa PAO1 (PAO1), common in wastewater treatment, was investigated in the absence and presence of inhibitory level of FNA (0.1 mg N/L) under anaerobic denitrifying conditions. This was achieved through coupling gene expression analysis, by RNA sequencing, and with a suite of physiological analyses. Various transcripts exhibited significant changes in abundance in the presence of FNA. Respiration was likely inhibited because denitrification activity was severely depleted, and decreased transcript levels of most denitrification genes occurred. As a consequence, the tricarboxylic acid (TCA) cycle was inhibited due to the lowered cellular redox state in the FNA-exposed cultures. Meanwhile, during FNA exposure, PAO1 rerouted its carbon metabolic pathway from the TCA cycle to pyruvate fermentation with acetate as the end product as a possible survival mechanism. Additionally, protein synthesis was significantly decreased, and ribosome preservation was evident. These findings improve our understanding of PAO1 in response to FNA and contribute toward the potential application for use of FNA as an antimicrobial agent. PMID- 27116300 TI - Insights of the Crystallization Process of Molecular Sieve AlPO4-5 Prepared by Solvent-Free Synthesis. AB - Crystallization of AlPO4-5 with AFI structure under solvent-free conditions has been investigated. Attention was mainly focused on the characterization of the intermediate phases formed at the early stages during the crystallization. The development in the long-range ordering of the solid phases as a function of crystallization time was monitored by XRD, SEM, IR, UV-Raman, and MAS NMR techniques. Particularly, the UV-Raman spectroscopy was employed to obtain the information on the formation process of the framework. J-HMQC (27)Al/(31)P double resonance NMR experiments were used to identify the P-O-Al bonded species in the intermediate phases. For the first time the P-O-Al bonded species in the intermediate phases can be correctly described through using this advanced NMR technique. The crystallization under solvent-free conditions appears to follow the pathway: The initial amorphous raw material is converted to an intermediate phase which has four-/six-membered ring species, then gradually transformed into crystalline AlPO4-5. This observation is not consistent with the common idea that the intermediate phase is the semicrystalline intermediates with a three dimensional structure. PMID- 27116301 TI - Phenylacylphenol derivatives with anti-melanogenic activity from Stewartia pseudocamellia. AB - Three new phenylacylphenol derivatives, stewartianol (1), deoxystewartianol-4'-O arabinoglucoside (2), and stewartianol-3-O-glucoside (3), along with nine known compounds, methylesculin (4), fraxoside (5), fraxetin (6), scopletin (7), (+) dihydromyricetin (8), (+)-taxifolin-7-O-beta-D-glucose (9), (+)-taxifolin (10), (+)-dihydrokaempferol-7-O-beta-D-glucose (11), and 3-acetyl-ursolic acid (12), were isolated from the twigs of Stewartia pseudocamellia; commonly used as folk medicine in Korea. The structures of the isolated compounds were identified using spectroscopic analysis, including 1D, 2D NMR, MS and compared with published data. The compounds were tested for their anti-melanogenic activity in cultured murine B16 melanoma cells. Stewartianol (1) and stewartianol-3-O-glucoside (3) showed an inhibitory effect significantly on melanogenesis in a concentration dependent manner. PMID- 27116302 TI - Comparison of the Effective Fragment Potential Method with Symmetry-Adapted Perturbation Theory in the Calculation of Intermolecular Energies for Ionic Liquids. AB - The effective fragment potential (EFP) method that decomposes the interaction energy as a sum of the five fundamental forces-electrostatic, exchange-repulsion, polarization, dispersion, and charge transfer-was applied to a large test set of ionic liquid ion pairs and compared against the state-of-the-art method, Symmetry Adapted Perturbation Theory (SAPT). The ion pairs include imidazolium and pyrrolidinium cations combined with anions that are routinely used in the field of ionic liquids. The aug-cc-pVDZ, aug-cc-pVTZ, and 6-311++G(d,p) basis sets were used for EFP, while SAPT2+3/aug-cc-pVDZ provided the benchmark energies. Differences between the two methods were found to be large, and strongly dependent on the anion type. For the aug-cc-pVTZ basis set, which produced the least errors, average relative errors were between 2.3% and 18.4% for pyrrolidinium ion pairs and between 2.1% and 27.7% for imidazolium ion pairs for each individual energetic component (excluding charge transfer), as well as the total interaction energy. Charge transfer gave the largest relative errors: 56% and 63% on average for pyrrolidinium- and imidazolium-based ion pairs, respectively. Scaling of the EFP components against SAPT2+3 showed improvement for polarization (induction) and dispersion terms, thus indicating potential for the development of cost-effective alternatives for intermolecular induction and dispersion potentials for ionic liquids. PMID- 27116303 TI - Guardians' Perceptions of Cats' Welfare and Behavior Regarding Visiting Veterinary Clinics. AB - To assess the welfare of cats at the veterinary clinic and how caregivers and veterinarians affect it, a survey of Italian cat guardians (n = 1,111) was conducted using a 28-item multichoice questionnaire. Most cats showed impaired welfare during all stages of a clinic visit: before entering, in the waiting room, moving to the examination room, on the examination table, and after returning home. A relationship was found between welfare states in each stage. Stress worsened with further experience and had negative effects on traveling and handling in other situations. Restraint, pain, and anxiety led to aggression toward vets and guardians. Guardians showed a positive attitude toward their cats' health and welfare, and the veterinarians' behavior toward the cats was a reason for changing the veterinarian. One in 10 veterinarians examined the cat immediately, without stroking, talking, or offering food. However, the use of food was effective only if cats were not already stressed. Educating guardians and veterinarians to minimize stress during every stage of a clinic visit is the best approach to improving welfare for cats visiting the clinic. PMID- 27116318 TI - Enantioselective Total Synthesis of (+)-Amphirionin-4. AB - An enantioselective total synthesis of (+)-amphirionin-4 has been accomplished in a convergent manner. The synthesis features an efficient enzymatic lipase resolution to access the tetrahydrofuranol core in optically active form. The functionalized tetrahydrofuran derivative was synthesized via an oxocarbenium ion mediated highly diastereoselective syn-allylation reaction. The polyene side chain was synthesized using Stille coupling reactions. Nozaki-Hiyama-Kishi coupling was utilized to construct the C-8 stereocenter and complete the synthesis of (+)-amphirionin-4. PMID- 27116319 TI - Neonatal hyperoxia increases airway reactivity and inflammation in adult mice. AB - BACKGROUND: Supplemental O2 to treat bronchopulmonary dysplasia (BPD) in premature infants, is a major risk factor producing alteration in lung function, airway reactivity, and predisposition to respiratory infections. This study explores inflammatory and airway responses following neonatal hyperoxia in adult mice. METHODS: Newborn mouse litters were randomized to 85% O2 or room air (RA) on P3 for 12 days; mice were sacrificed either on P15 or at 15 weeks following recovery in RA. Airway hyper reactivity (AHR) was assessed in vivo (8 and 12 weeks) and in vitro (15 weeks) with methacholine; Lung and BAL were assayed for inflammatory mediators, cell counts, CD3 immunohistochemistry, and histopathology. RESULTS: Hyperoxic mice had increased airway reactivity at baseline and following methacholine challenge in vivo (8 and 12 weeks); isolated tracheal rings had a significantly higher constriction response to methacholine in vitro compared to RA group. Inflammatory markers were higher at 2 weeks (MCP 1, IL-12, INF-gamma) and at 15 weeks (LTB4 , VEGF); Lipoxin-A4 was lower in the hyperoxia group at both time points. Increased airway smooth muscle thickness and angiogenesis in the lung was seen at 15 weeks. Hyperoxic lungs exhibited alveolar simplification at 2 and 15 weeks. Absolute lymphocyte count was higher in lavage fluid with an increased CD3 cell count at 15 weeks suggesting persistent inflammation in adult mice following neonatal hyperoxia. CONCLUSIONS: Exposure to hyperoxia in newborn mice increases long-term airway reactivity with persistent lung inflammation associated with a marked increase in lymphocytes, suggesting long-term consequences in adults. Pediatr Pulmonol. 2016;51:1131-1141. (c) 2016 Wiley Periodicals, Inc. PMID- 27116320 TI - Erratum to: Calculation of total energy expenditure in publications on physical activity energy by Yamada et al. in 2009 and 2013. PMID- 27116321 TI - Characterization and Optimization of Amylase Production in WangLB, a High Amylase Producing Strain of Bacillus. AB - The costs of amylase represent ca. 24 % of the expenditures in the starch industry and an increase in amylase production and/or activity will greatly cut down on production costs. In the present study, we obtained a high amylase producing strain of bacteria, WangLB, and identified it as a member of the Bacillus genus based on 16S rDNA analysis. The fermentation conditions for amylase production in the strain were optimized, and the maximum amylase activity we obtained was 26,670 +/- 1390 U/mL, under the optimized conditions of 48-h incubation in liquid starch medium, 35 degrees C, pH 10, 1 % v/v inoculum concentration, 20 g/L starch concentration, and 0.1 % w/v peptone. The influences of 16 small organic inducers on amylase production were tested, and the results showed that 20 mmol/L alanine greatly enhanced amylase production to 290 % of the baseline level. We also conducted an amylase enzymology analysis. The molecular weight of the amylase was 55 kD, determined by SDS-PAGE. The optimum temperature and pH for the amylase were 55 degrees C and pH 9, respectively. The enzyme also showed high activity over a wide range of temperatures (50-85 degrees C) and pH values (3-10), and the activity of the amylase was Ca(2+) independent. The kinetic parameters K m and V max were 0.37 +/- 0.02 mg/mL and 233 U/mg, respectively. Finally, the amylase was applied to the hydrolysis of five different brands of starch. It was found that the hydrolyzability of the substrate by amylase increased along with starch solubility. PMID- 27116322 TI - Disentangling the Association between Statins, Cholesterol, and Colorectal Cancer: A Nested Case-Control Study. AB - BACKGROUND: Several prior studies have found an association between statin use and reduced risk of colorectal cancer. We hypothesized that these findings may be due to systematic bias and examined the independent association of colorectal cancer risk with statin use, serum cholesterol, and change in cholesterol concentration. METHODS AND FINDINGS: 22,163 colorectal cancer cases and 86,538 matched controls between 1995 and 2013 were identified within The Health Improvement Network (THIN) a population-representative database. Conditional logistic regression models estimated colorectal cancer risk with statin use, serum total cholesterol (mmol/L), and change in total cholesterol level. We confirmed a decreased risk of colorectal cancer with statin use (long-term: odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; short-term: OR, 0.92; 95% CI, 0.85-0.99). However, to assess whether the observed association may result from indication bias, a subgroup analysis was conducted among patients prescribed a statin. In this subgroup (n = 5,102 cases, n = 19,032 controls), 3.1% of case subjects and 3.1% of controls discontinued therapy. The risk of colorectal cancer was not significantly different among those who continued statin therapy and those who discontinued (OR, 0.98; 95% CI, 0.79-1.22). Increased serum cholesterol was independently associated with decreased risk of colorectal cancer (OR, 0.89 per mmol/L increase; 95% CI, 0.87-0.91); the association was only present if serum cholesterol was measured near the cancer diagnosis (<6 mo: OR, 0.76; 95% CI, 0.47-0.61; >24 mo: OR, 0.98; 95% CI, 0.93 1.03). Decreases in serum total cholesterol >1 mmol/L >=1 year prior to cancer diagnosis were associated with subsequent colorectal cancer (statin users: OR, 1.25; 95 CI%, 1.03-1.53; nonusers: OR, 2.36; 95 CI%, 1.78-3.12). As an observational study, limitations included incomplete data and residual confounding. CONCLUSIONS: Although the risk of colorectal cancer was lower in statin users versus nonusers, no difference was observed among those who continued versus discontinued statin therapy, suggesting the potential for indication bias. The association between decreased serum cholesterol and colorectal cancer risk suggests a cholesterol-lowering effect of undiagnosed malignancy. Clinical judgment should be used when considering causes of cholesterol reduction in patients, including those on statin therapy. PMID- 27116323 TI - Eye Care Disparities and Health-Related Consequences in Elderly Patients with Age Related Eye Disease. AB - The elderly population in the United States (age 65 and older) is growing rapidly, estimated by the U.S. Census Department to reach 83.7 million by 2050.(1) Visual impairment increases with age among all racial and ethnic groups.(2) In the elderly, the most common culprits for vision loss are cataract, glaucoma, and age-related macular degeneration (AMD).(2) In the developed world, vision loss from cataract has been dramatically reduced by increased access to cataract surgery. However, AMD and glaucoma lead to irreversible vision loss without early diagnosis and intervention. In the U.S., cases of AMD are expected to double by 2050, reaching 17.8 million among patients age 50 or older.(3) Similarly, cases of glaucoma are expected to reach 5.5 million by 2050, an increase of over 90% from 2014.(3) The visually impaired elderly face disparities in access to eye care, and subsequent general medical and psychosocial complications. PMID- 27116324 TI - The Stillbirth Classification System for the Safe Passage Study: Incorporating Mechanism, Etiology, and Recurrence. AB - OBJECTIVE: Describe the classification system for assigning the cause of stillbirth in the Safe Passage Study, an international, multi-institutional, prospective analysis conducted by the NIAAA/NICHD-funded Prenatal Alcohol in SIDS and Stillbirth (PASS) Research Network. The study mission is to determine the role of prenatal alcohol and/or cigarette smoke exposure in adverse pregnancy outcomes, including stillbirth, in a high-risk cohort of 12,000 maternal/fetal dyads. METHODS: The PASS Network classification system is based upon 5 'sites of origin' for cause of stillbirth, further subdivided into mechanism subcategories; both are employed to assign an ultimate cause of death. Each PASS stillbirth was assigned a cause of death, and status of sporadic versus recurrent. Adjudication involved review of maternal and obstetrical records; fetal autopsy and placental findings; and required complete consensus in each case. Two published classification systems, i.e., INCODE and ReCoDe, were used for comparison. RESULTS: Causes of stillbirth classified were: fetal (26%), placental (53%), external (5%), and undetermined (16%). Nine cases (47%) had placental causes of death due to maternal disorders that carry recurrence risks. There was full agreement for cause of death across the three classification systems in 26% of cases, and partial agreement among them in 42% of cases. CONCLUSIONS: The proposed PASS schema employs a user-friendly classification that provides comparable information to previously published systems. Advantages include its simplicity, mechanistic formulations, tight clinicopathologic integration, provision for an undetermined category, and its wide applicability to perinatal mortality review boards with access to information routinely collected during clinicopathologic evaluations. PMID- 27116325 TI - OCT-guided management of a pregnant woman with ST-elevation myocardial infarction. PMID- 27116326 TI - Duration of dual antiplatelet therapy after various drug-eluting stent implantation. AB - OBJECTIVE: To evaluate efficacy and safety of long duration dual anti-platelet therapy i.e., >12months (L-DAPT) and short duration DAPT i.e., <=12months (S DAPT) after various drug-eluting stent (DES) implantation. METHODS: We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) assessing the effect of L-DAPT versus S-DAPT after sirolimus-eluting (Cypher(r)); paclitaxel-eluting stents (Taxus(r)); zotarolimus-eluting (Endeavor(r)) and everolimus-eluting stents (Xience V(r)) implantation. Odds ratio (OR) and 95% confidence intervals (CI) were calculated using random-effects models. Subgroup analyses were performed comparing two second generation DES and for RCTs comparing S-DAPT and L-DAPT. RESULTS: We included six RCTs that randomized 19,012 patients to S-DAPT versus L DAPT (4638 in first generation DES; 14,374 in second generation DES; 8099 EES; 4876 in ZES). Compared with L-DAPT, S-DAPT was associated with a higher rate of myocardial infarction (MI) and stent thrombosis (ST) after first [2.65 (1.88, 3.73) and 3.85 (2.14-6.93) respectively] and a higher rate of MI after second generation DES [1.33 (1.06, 1.67)]. There were no significant differences in the rates of all cause mortality, cardiovascular (CV) mortality and stroke with L DAPT and S-DAPT after implantation of first [0.97 (0.52, 1.81); 1.19 (0.52-2.70); and 1.12 (0.36-3.52) respectively] and second generation DES [0.93 (0.69, 1.25); 0.93 (0.63, 1.36); and 0.58 (0.19, 1.75), respectively]. On further analysis of type of second generation DES, S-DAPT continues to show a higher rate of MI and ST after EES implantation [1.54 (1.11, 2.13) and 2.68 (1.20-5.94) respectively]; however there was no significant difference in the rate of MI and ST with S-DAPT and L-DAPT after ZES implantation [1.07 (0.44, 2.61) and 1.11(0.39, 3.13), respectively]. CONCLUSION: 1) Compared with L-DAPT, S-DAPT was associated with a higher rate of MI without any significant difference in the rate of all cause mortality, CV mortality and stroke after first and second generation DES. 2) Rate of ST was also higher with S-DAPT compared to L-DAPT after first generation DES implantation; however, it was not significantly different after second generation DES. 3) On further subgroup analysis of second-generation stent there was no significant difference in the rate of all cause mortality, CV mortality, MI, ST and stroke with S-DAPT and L-DAPT after ZES implantation. S-DAPT may be optimal for newer generation stents particularly ZES. PMID- 27116327 TI - Symptomatic exercise-induced complete atrioventricular block due to severe superior vena cava stenosis. PMID- 27116328 TI - Acute anterior myocardial infarction after heavy exercise in a young sportsman: Importance of intravascular ultrasonography on differential diagnosis. PMID- 27116329 TI - The effectiveness of bilirubin for the treatment of ischemia-reperfusion injury in an experimental model: Can it be extrapolated to humans? PMID- 27116330 TI - Is 10-second electrocardiogram recording enough for accurately estimating heart rate in atrial fibrillation. AB - BACKGROUND: At present, the estimation of rest heart rate (HR) in atrial fibrillation (AF) is obtained by apical auscultation for 1min or on the surface electrocardiogram (ECG) by multiplying the number of RR intervals on the 10second recording by six. But the reasonability of 10second ECG recording is controversial. METHODS: ECG was continuously recorded at rest for 60s to calculate the real rest HR (HR60s). Meanwhile, the first 10s and 30s ECG recordings were used for calculating HR10s (sixfold) and HR30s (twofold). The differences of HR10s or HR30s with the HR60s were compared. The patients were divided into three sub-groups on the HR60s <80, 80-100 and >100bpm. RESULTS: No significant difference among the mean HR10s, HR30s and HR60s was found. A positive correlation existed between HR10s and HR60s or HR30s and HR60s. Bland Altman plot showed that the 95% reference limits were high as -11.0 to 16.0bpm for HR10s, but for HR30s these values were only -4.5 to 5.2bpm. Among the three subgroups with HR60s <80, 80-100 and >100bpm, the 95% reference limits with HR60s were -8.9 to 10.6, -10.5 to 14.0 and -11.3 to 21.7bpm for HR10s, but these values were -3.9 to 4.3, -4.1 to 4.6 and -5.3 to 6.7bpm for HR30s. CONCLUSION: As 10s ECG recording could not provide clinically accepted estimation HR, ECG should be recorded at least for 30s in the patients with AF. It is better to record ECG for 60s when the HR is rapid. PMID- 27116331 TI - Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction. AB - INTRODUCTION: Cardiac phenotypes should be pronounced in hereditary hemorrhagic telangiectasia (HHT) due to frequent systemic arteriovenous malformations (AVMs), iron deficiency anemia, hypoxemia, hyperdynamic circulations, venous thromboemboli, and paradoxical emboli through pulmonary AVMs. METHODS/RESULTS: In an international survey, 1025 respondents (median age 55years) met HHT diagnostic criteria: 942 (91.9%) reported nosebleeds, 452 (44.1%) at least daily. AVMs were commonly reported in pulmonary (544, 53%), hepatic (194, 18.9%) and/or cerebral (92, 9.0%) circulations. 770/1025 (75%) had used iron tablets, 256 (25.0%) intravenous iron, and 374 (36.5%) received blood transfusions. Arrhythmias were reported by 113/1025 (11%, including 44 (4.3%) with atrial fibrillation), angina by 36 (3.5%), and cardiac failure by 26 (2.5%). In multivariate logistic regression, these phenotypes were associated with hepatic AVMs/pulmonary hypertension (relatively interchangeable variables), blood transfusions, and intravenous iron. Cardiac insufficiency/failure often provokes intensive anemia treatments, but associations with arrhythmias, particularly with a greater transfusion burden, were less easy to explain. Myocardial infarction (23/1025; 2.2%), and abnormal coronary angiogram (<=31/76, <=54%) rates appeared low. Provocative preliminary data were obtained including HHT-affected respondents' parents and grandparents in whom HHT could be confidently assigned, or excluded based on autosomal dominant inheritance patterns: in crude and survival analyses, myocardial infarctions were reported less frequently for individuals with HHT, particularly for males (p=0.001). CONCLUSION: Arrhythmias are the most common cardiac phenotype in HHT, and likely to be aggravated by iron deficiency anemia, its treatments, and/or high output states due to AVMs. Myocardial infarction rates may be reduced in this apparently high risk population. PMID- 27116332 TI - High-Responsivity, High-Detectivity, Ultrafast Topological Insulator Bi2Se3/Silicon Heterostructure Broadband Photodetectors. AB - As an exotic state of quantum matter, topological insulators have promising applications in new-generation electronic and optoelectronic devices. The realization of these applications relies critically on the preparation and properties understanding of high-quality topological insulators, which however are mainly fabricated by high-cost methods like molecular beam epitaxy. We here report the successful preparation of high-quality topological insulator Bi2Se3/Si heterostructure having an atomically abrupt interface by van der Waals epitaxy growth of Bi2Se3 films on Si wafer. A simple, low-cost physical vapor deposition (PVD) method was employed to achieve the growth of the Bi2Se3 films. The Bi2Se3/Si heterostructure exhibited excellent diode characteristics with a pronounced photoresponse under light illumination. The built-in potential at the Bi2Se3/Si interface greatly facilitated the separation and transport of photogenerated carriers, enabling the photodetector to have a high light responsivity of 24.28 A W(-1), a high detectivity of 4.39 * 10(12) Jones (Jones = cm Hz(1/2) W(-1)), and a fast response speed of aproximately microseconds. These device parameters represent the highest values for topological insulator-based photodetectors. Additionally, the photodetector possessed broadband detection ranging from ultraviolet to optical telecommunication wavelengths. Given the simple device architecture and compatibility with silicon technology, the topological insulator Bi2Se3/Si heterostructure holds great promise for high performance electronic and optoelectronic applications. PMID- 27116334 TI - Safety of immune checkpoint inhibitors in Chinese patients with melanoma. AB - This study aimed to determine the tolerability of Chinese melanoma patients, particularly those with hepatitis B virus (HBV) infection, to immune checkpoint inhibitor therapy. Patients with metastatic melanoma who received anti-cytotoxic T lymphocyte-associated antigen-4 antibody (ipilimumab) or anti-programmed death 1 antibody (pembrolizumab) therapy at our hospital between August 2012 and July 2015 were retrospectively reviewed. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Twenty-three patients with advanced melanoma were included; nine and 10 patients received infusions of ipilimumab and pembrolizumab, respectively, whereas four patients received concurrent ipilimumab and pembrolizumab therapy. There was no cessation of treatment because of agent-related adverse events in any patient. Immune-related adverse events were observed in 44% (4/9), 60% (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab, pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment, respectively. The most frequent immune-related adverse events were endocrine disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and dermatological events (17%, 4/23). There were no gastrointestinal reactions. Toxicities were usually mild and easily managed; only 13% (3/23) of patients had grade 3 adverse events and none experienced grade 4 events or treatment-related death. No additional toxicity nor severe hepatotoxicity was observed in 11 patients who had previous HBV infection. The recommended anti-cytotoxic T lymphocyte-associated antigen-4 and anti-programmed death 1 antibody doses were well tolerated by Chinese patients. Thus, immune checkpoint inhibitors appear to be effective and safe in metastatic melanoma patients, including those with pre existing HBV infection. PMID- 27116333 TI - To wake up cancer stem cells, or to let them sleep, that is the question. AB - Cancer stem cells (CSCs) generate transient-amplifying cells and thereby contribute to cancer propagation. A fuller understanding of the biological features of CSCs is expected to lead to the development of new anticancer therapies capable of eradicating this life-threatening disease. Cancer stem cells are known to maintain a non-proliferative state and to enter the cell cycle only infrequently. Given that conventional anticancer therapies preferentially target dividing cells, CSCs are resistant to such treatments, with those remaining after elimination of bulk cancer cells potentially giving rise to disease relapse and metastasis as they re-enter the cell cycle after a period of latency. Targeting of the switch between quiescence and proliferation in CSCs is therefore a potential strategy for preventing the reinitiation of malignancy, underscoring the importance of elucidation of the mechanisms by which these cells are maintained in the quiescent state. The fundamental properties of CSCs are thought to be governed cooperatively by internal molecules and cues from the external microenvironment (stem cell niche). Several such intrinsic and extrinsic regulators are responsible for the control of cell cycle progression in CSCs. In this review, we address two opposite approaches to the therapeutic targeting of CSCs - wake-up and hibernation therapies - that either promote or prevent the entry of CSCs into the cell cycle, respectively, and we discuss the potential advantages and risks of each strategy. PMID- 27116335 TI - Pyogenic granuloma in patients treated with selective BRAF inhibitors: another manifestation of paradoxical pathway activation. AB - Cutaneous toxicities under therapy with selective BRAF inhibitors such as vemurafenib or encorafenib (LGX818) are frequent, including plantar hyperkeratosis, squamous cell carcinoma, and second primary melanoma. Pyogenic granuloma is a benign, rapidly growing, eruptive hemangioma that often bleeds and ulcerates. Common causes are mechanical trauma and cast immobilization, as well as multiple drugs such as retinoids and antineoplastic agents. However, the development of pyogenic granuloma under treatment with encorafenib (LGX818) has not yet been reported. These three cases might be further examples for paradoxical activation of the mitogen-activated protein kinase pathway. We report three male patients with metastatic BRAFV600E-mutated melanoma who developed pyogenic granulomas 16, 10, and 12 weeks after treatment initiation with the selective BRAF inhibitors vemurafenib or encorafenib (LGX818). Except for one patient receiving retinoids, the clinical history for other frequent causes of pyogenic granuloma was negative. Pyogenic granulomas are not listed in the drugs investigator brochure but seem to be associated with selective BRAF inhibitors and might be a cutaneous phenomenon of paradoxical mitogen-activated protein kinase pathway activation. This correlation has to be confirmed by further observations. PMID- 27116336 TI - Cross-Cultural Validation of the High Blood Pressure Health Literacy Scale in a Chinese Community. AB - BACKGROUND: Considering the importance of health literacy (HL) for the maximum yield from the hypertension control programs, development of a reliable and valid instrument of hypertension-related HL is critical. This study aimed to translate and validate the High Blood Pressure-Health Literacy Scale (HBP-HLS) into Chinese (C-HBP-HLS) and evaluate its psychometric properties in Chinese context. METHOD: Between June 2013 and January 2014, a cross-sectional study was conducted among recruited hypertensive patients belonging to the Han and Kazakh-Chinese communities in Urumqi, Xinjiang, China. RESULTS: A pilot sample (n = 242) was selected for the exploratory factor analysis of the translated and modified instrument. Another sample (n = 308) was recruited for the confirmatory factor analysis. C-HBP-HLS consisted of five dimensions (Print Health Literacy, Medication Label, Understanding Ability, Newest Vital Sign Test, and Avoiding Food Allergy) containing 15 items, accounting for 77.7% of the total variance. The 5-factor model demonstrated a good overall fit. The scale-level content validity index was 0.85. Cronbach's alpha of the overall scale was 0.78 and test retest reliability was 0.96. Education level had a strong positive correlation with the scores for items Q1, Q2, and Q3(r = 0.481, 0.492, 0.475, respectively). Health Literacy scores among Kazakh patients were significantly lower than Han (7.13+/-7.90 vs. 30.10+/-13.42, Z = -14.573, P<0.001). CONCLUSION: C-HBP-HLS demonstrated suitable factor structure and robust psychometric properties for measuring health literacy level among hypertensive patients in China. PMID- 27116337 TI - Organic Chemical Attribution Signatures for the Sourcing of a Mustard Agent and Its Starting Materials. AB - Chemical attribution signatures (CAS) are being investigated for the sourcing of chemical warfare (CW) agents and their starting materials that may be implicated in chemical attacks or CW proliferation. The work reported here demonstrates for the first time trace impurities from the synthesis of tris(2-chloroethyl)amine (HN3) that point to the reagent and the specific reagent stocks used in the synthesis of this CW agent. Thirty batches of HN3 were synthesized using different combinations of commercial stocks of triethanolamine (TEA), thionyl chloride, chloroform, and acetone. The HN3 batches and reagent stocks were then analyzed for impurities by gas chromatography/mass spectrometry. All the reagent stocks had impurity profiles that differentiated them from one another. This was demonstrated by building classification models with partial least-squares discriminant analysis (PLSDA) and obtaining average stock classification errors of 2.4, 2.8, 2.8, and 11% by cross-validation for chloroform (7 stocks), thionyl chloride (3 stocks), acetone (7 stocks), and TEA (3 stocks), respectively, and 0% for a validation set of chloroform samples. In addition, some reagent impurities indicative of reagent type were found in the HN3 batches that were originally present in the reagent stocks and presumably not altered during synthesis. More intriguing, impurities in HN3 batches that were apparently produced by side reactions of impurities unique to specific TEA and chloroform stocks, and thus indicative of their use, were observed. PMID- 27116339 TI - Alphacute Exercise Alters the Levels of Human Saliva miRNAs Involved in Lipid Metabolism. AB - The response of micro-ribonucleic acid (miRNA) expression to exercise has not been studied in saliva, although saliva combines non-invasive collection with the largest number of miRNA species among biological fluids and tissues. Thus, the purpose of this study was to investigate the effect of acute exercise on the expression of 8 human saliva miRNAs involved in lipid metabolism. 19 healthy, physically active men (VO2max, 40.9+/-1.6 mL.kg(-1).min(-1), mean+/-se) performed a 50-min interval exercise program on stationary bicycle (spinning). Saliva samples were collected before and after exercise for miRNA expression analysis by real-time polymerase chain reaction. Statistically significant (p<0.05) changes after exercise were found in 2 of the 8 miRNAs, namely, hsa-miR-33a (fold change, 7.66+/-2.94; p=0.012), which regulates cholesterol homeostasis and fatty acid metabolism in the liver, and hsa-miR-378a (fold change 0.79+/-0.11, p=0.048), which regulates energy homeostasis and affects lipogenesis and adipogenesis. These alterations may contribute to our understanding of physiological responses to exercise and the therapeutic potential of exercise against cardiovascular disease, obesity, and the metabolic syndrome. Moreover, our findings open the possibility of noninvasively studying miRNAs that regulate the function of specific organs. PMID- 27116340 TI - Injury and Illness Rates During Ultratrail Running. AB - This study aimed to describe injury/illness rates in ultratrail runners competing in a 65-km race to build a foundation for injury prevention and help race organizers to plan medical provision for these events. Prospectively transcribed medical records were analysed for 77 athletes at the end of the race. Number of injuries/illnesses per 1 000 runners and per 1 000-h run, overall injury/illness rate and 90% confidence intervals and rates for major and minor illnesses, musculoskeletal injuries, and skin disorders were analysed. A total of 132 injuries/illnesses were encountered during the race. The overall injuries/illnesses were 1.9 per runner and 13.1 per 1 000-h run. Medical illnesses were the most prominent medical diagnoses encountered (50.3%), followed by musculoskeletal injuries (32.8%), and skin-related disorders (16.9%). Despite the ultra-long nature of the race, the majority of injuries/illnesses were minor in nature. Medical staff and runners should prepare to treat all types of injuries and illnesses, especially the fatigue arising throughout the course of an ultratrail run and injuries to the lower limbs. Future studies should attempt to systematically identify injury locations and mechanisms in order to better direct injury prevention strategies and plan more accurate medical care. PMID- 27116338 TI - A spectrum of CodY activities drives metabolic reorganization and virulence gene expression in Staphylococcus aureus. AB - The global regulator CodY controls the expression of dozens of metabolism and virulence genes in the opportunistic pathogen Staphylococcus aureus in response to the availability of isoleucine, leucine and valine (ILV), and GTP. Using RNA Seq transcriptional profiling and partial activity variants, we reveal that S. aureus CodY activity grades metabolic and virulence gene expression as a function of ILV availability, mediating metabolic reorganization and controlling virulence factor production in vitro. Strains lacking CodY regulatory activity produce a PIA-dependent biofilm, but development is restricted under conditions that confer partial CodY activity. CodY regulates the expression of thermonuclease (nuc) via the Sae two-component system, revealing cascading virulence regulation and factor production as CodY activity is reduced. Proteins that mediate the host-pathogen interaction and subvert the immune response are shut off at intermediate levels of CodY activity, while genes coding for enzymes and proteins that extract nutrients from tissue, that kill host cells, and that synthesize amino acids are among the last genes to be derepressed. We conclude that S. aureus uses CodY to limit host damage to only the most severe starvation conditions, providing insight into one potential mechanism by which S. aureus transitions from a commensal bacterium to an invasive pathogen. PMID- 27116341 TI - Muscular Oxygen Uptake Kinetics in Aged Adults. AB - Pulmonary oxygen uptake (VO2) kinetics and heart rate kinetics are influenced by age and fitness. Muscular VO2 kinetics can be estimated from heart rate and pulmonary VO2. In this study the applicability of a test using pseudo-random binary sequences in combination with a model to estimate muscular VO2 kinetics was tested. Muscular VO2 kinetics were expected to be faster than pulmonary VO2 kinetics, slowed in aged subjects and correlated with maximum VO2 and heart rate kinetics. 27 elderly subjects (73+/-3 years; 81.1+/-8.2 kg; 175+/-4.7 cm) participated. Cardiorespiratory kinetics were assessed using the maximum of cross correlation functions, higher maxima implying faster kinetics. Muscular VO2 kinetics were faster than pulmonary VO2 kinetics (0.31+/-0.1 vs. 0.29+/-0.1 s; p=0.004). Heart rate kinetics were not correlated with muscular or pulmonary VO2 kinetics or maximum VO2. Muscular VO2 kinetics correlated with maximum VO2 (r=0.35; p=0.033). This suggests, that muscular VO2 kinetics are faster than estimates from pulmonary VO2 and related to maximum VO2 in aged subjects. In the future this experimental approach may help to characterize alterations in muscular VO2 under various conditions independent of motivation and maximal effort. PMID- 27116342 TI - Lipolytic Markers, Insulin and Resting Fat Oxidation are Associated with Maximal Fat Oxidation. AB - The maximal capacity to oxidize fat during exercise (MFO) is associated with 24-h fat balance and insulin sensitivity. Understanding factors that influence MFO could have implications for metabolic health. We investigated relationships between selected plasma metabolites, hormones and overnight-fasted resting fat oxidation rates (Resting), with MFO. Resting fat oxidation and MFO was measured in 57 men with blood collected at rest and during exercise. Plasma glycerol (R=0.39, P=0.033), non-esterified fatty acids (NEFA: R=0.27, P=0.030) and insulin (R=- 0.36, P=0.007) measured at MFO correlated with MFO; only glycerol remained correlated when controlled for resting concentrations (R=0.36, P=0.008). The change in glycerol from rest to MFO correlated with exercise-induced fat oxidation (R=0.32, P=0.012). VO 2max correlated with resting fat oxidation (R=0.44, P=0.001) and MFO (R=0.52, P<0.001). Resting fat oxidation correlated with MFO (R=0.55, P<0.001); this remained when controlled for VO 2max (R=0.41, P=0.001). This study reports weak-to-moderate, albeit significant, relationships between plasma lipolytic markers, insulin and resting overnight-fasted fat oxidation with MFO and shows the plasma glycerol response to uniquely reflect exercise-induced fat oxidation. VO 2max correlates with fat oxidation but the relationship can be dissociated. Interventions to increase fat oxidation for optimal metabolic health would benefit from, but are not reliant on, increases in VO 2max. PMID- 27116343 TI - Effects of Cold Stimulation on Mitochondrial Activity and VEGF Expression in vitro. AB - We aimed to clarify the effects of cold stimulation at various temperatures on mitochondrial activity and vascular endothelial growth factor (VEGF) expression in vitro. Human fibroblast, human mesenchymal stem cell, and rat skeletal muscle myoblast cell lines were used. For each cell type, cells were divided into 4 groups and stimulated in various cold temperatures (0, 4, 17 and 25 degrees C) 3 times for 15 min each by placement on crushed ice or floating on cold water set at each temperature. Control cells were subjected to warm water at 37 degrees C. Factors related to mitochondrial activity, mitochondrial DNA copy numbers, and VEGF expression were analyzed 24 h after the last cold stimulation. In all cell types, significant increases of factors related to mitochondrial activity and mitochondrial DNA copy numbers were seen in the 4 degrees C and 17 degrees C stimulated cells compared with control cells. In rat skeletal muscle cells stimulated at 4 degrees C, VEGF expression significantly increased compared to the control cells. Our data suggest that cold stimulation at certain temperatures promotes mitochondrial activity, biogenesis and VEGF expression. PMID- 27116344 TI - The Case for Increased Physical Activity in Chronic Inflammatory Bowel Disease: A Brief Review. AB - Regular physical activity reduces the risk of colon cancer, but there is little information on the merits of such activity in the prevention and management of chronic inflammatory bowel disease (CIBD). The present systematic review thus documents current levels of habitual physical activity and aerobic and muscular function in CIBD, and examines the safety, practicality and efficacy of exercise programmes in countering the disease process, correcting functional deficits and enhancing quality of life. A systematic search of the Ovid/Medline database from January 1996 to May 2015 linked the terms physical activity/motor activity/physical fitness/physical training/physical education/training/exercise/exercise therapy with Crohn's disease/colitis/ulcerative colitis/inflammatory bowel disease, supplementing this information by a scanning of reference lists and personal files.12 of 16 published studies show a low level of habitual physical activity in CIBD, with sub-normal values for aerobic power, lean tissue mass and muscular strength. 3 of 4 studies suggest physical activity may reduce the risk of developing IBD, and 11 interventions all note that exercise programmes are well tolerated with some decreases of disease activity, and functional gains leading to an increased health-related quality of life. Moreover, programme compliance rates compare favourably with those seen in the treatment of other chronic conditions. More information on mechanisms is needed, but regular moderate aerobic and/or resistance exercise improves the health status of patients with CIBD both by modulating immune function and by improving physical function. A regular exercise programme should thus become an important component in the management of CIBD. PMID- 27116345 TI - Energetic and Metabolic Power Demands of National Rugby League Match-Play. AB - The purpose of this study was to apply a time-motion model to estimate and describe the energy expenditure and metabolic power demands of playing positions in elite rugby league match-play, utilizing Global Positioning System (GPS) devices. 18 elite rugby league players participated in this study. Players' positional groups included: outside backs (n=59 files, n=4 players), adjustables (n=74 files, n=4 players), wide-running (n=104 files, n=7 players) and hit-up forwards (n=36 files, n=3 players). Outside backs expended the greatest total energy (40.1+/-5.0 kJ.kg(-1)) per match, equivalent to 8.1%, 26.6% and 61.9% greater energy than adjustables, wide-running and hit-up forwards, respectively. Adjustables attained an anaerobic index 7.3% higher than wide-running forwards, 19.7% higher than hit-up forwards (p=0.001) and 43.2% higher than outside backs (p<0.001). Wide-running forwards achieved an anaerobic index (0.34+/-0.04) 11% and 32.8% higher than hit-up forwards (p=0.001) and outside backs (p<0.001), respectively. Mean power of adjustables (10.0+/-0.9 W.kg(-1)) was significantly higher than all other groups (outside backs: 28.8%, 7.8+/-1.0; hit-up: 12.4%, 8.9+/-0.6; and wide-running: 8.7%, 9.2+/-0.7 forwards) (p<0.001). Energetics indices indicated differing metabolic demands for all positional groups, suggesting position-specific conditioning drills are required to replicate the energetic demands of match-play. PMID- 27116346 TI - Susceptibility to Exercise-Induced Muscle Damage: a Cluster Analysis with a Large Sample. AB - We investigated the responses of indirect markers of exercise-induced muscle damage (EIMD) among a large number of young men (N=286) stratified in clusters based on the largest decrease in maximal voluntary contraction torque (MVC) after an unaccustomed maximal eccentric exercise bout of the elbow flexors. Changes in MVC, muscle soreness (SOR), creatine kinase (CK) activity, range of motion (ROM) and upper-arm circumference (CIR) before and for several days after exercise were compared between 3 clusters established based on MVC decrease (low, moderate, and high responders; LR, MR and HR). Participants were allocated to LR (n=61), MR (n=152) and HR (n=73) clusters, which depicted significantly different cluster centers of 82%, 61% and 42% of baseline MVC, respectively. Once stratified by MVC decrease, all muscle damage markers were significantly different between clusters following the same pattern: small changes for LR, larger changes for MR, and the largest changes for HR. Stratification of individuals based on the magnitude of MVC decrease post-exercise greatly increases the precision in estimating changes in EIMD by proxy markers such as SOR, CK activity, ROM and CIR. This indicates that the most commonly used markers are valid and MVC orchestrates their responses, consolidating the role of MVC as the best EIMD indirect marker. PMID- 27116347 TI - Individual Muscle use in Hamstring Exercises by Soccer Players Assessed using Functional MRI. AB - This study used functional magnetic resonance imaging (fMRI) to compare individual muscle use in exercises aimed at preventing hamstring injuries. Thirty six professional soccer players were randomized into 4 groups, each performing either Nordic hamstring, flywheel leg curl, Russian belt or conic-pulley exercise. MRIs were performed before and immediately after a bout of 4 sets of 8 repetitions. Pre-post exercise differences in contrast shift (T2) were analyzed for the long (BFLh) and short head (BFSh) of biceps femoris, semitendinosus (ST), semimembranosus (SM) and gracilis (GR) muscles. Flywheel leg curl increased (P<0.001) T2 of GR (95%), ST (65%), BFSh (51%) and BFLh (14%). After the Nordic hamstring, GR (39%), ST (16%) and BFSh (14%) showed increased T2 (P<0.001). Russian belt and conic-pulley exercise produced subtle (P<0.02) T2 increases of ST (9 and 6%, respectively) and BFLh (7 and 6%, respectively). Russian belt increased T2 of SM (7%). Among exercises examined, flywheel leg curl showed the most substantial hamstring and GR muscle use. However, no single exercise executed was able to increase T2 of all hamstring and synergist muscles analyzed. It is therefore suggested that multiple exercises must be carried out to bring in, and fully activate all knee flexors and hip extensors. PMID- 27116348 TI - Estimation of the Maximal Lactate Steady State in Endurance Runners. AB - This study aimed to predict the velocity corresponding to the maximal lactate steady state (MLSSV) from non-invasive variables obtained during a maximal multistage running field test (modified University of Montreal Track Test, UMTT), and to determine whether a single constant velocity test (CVT), performed several days after the UMTT, could estimate the MLSSV. Within 4-5 weeks, 20 male runners performed: 1) a modified UMTT, and 2) several 30 min CVTs to determine MLSSV to a precision of 0.25 km.h(-1). Maximal aerobic velocity (MAV) was the best predictor of MLSSV. A regression equation was obtained: MLSSV=1.425+(0.756.MAV); R(2)=0.63. Running velocity during the CVT (VCVT) and blood lactate at 6 (La6) and 30 (La30) min further improved the MLSSV prediction: MLSSV=VCVT+0.503 - (0.266.DeltaLa30 6); R(2)=0.66. MLSSV can be estimated from MAV during a single maximal multistage running field test among a homogeneous group of trained runners. This estimation can be further improved by performing an additional CVT. In terms of accuracy, simplicity and cost-effectiveness, the reported regression equations can be used for the assessment and training prescription of endurance runners. PMID- 27116349 TI - Cardiovascular Benefits of Endurance Training in Seniors: 40 is not too Late to Start. AB - It is unknown whether commencing structured endurance training after 40 years of age is powerful enough to induce beneficial cardiovascular adaptations in later life. 34 men between the ages of 55 and 75 were included: 10 life-long sedentary seniors (SED), 13 endurance master athletes who commenced training<=30 years of age (ET30), and 11 endurance master athletes who commenced training>=40 years of age with no prior physical training (ET40). All performed resting 5-min spectral heart rate (HR) variability analysis, resting and submaximal-exercise echocardiography, and a maximal exercise test. Maximal oxygen uptake was higher and resting HR was lower in both trained groups vs. SED, without difference between ET30 and ET40. Atrial and left ventricle dimensions were greater in ET30 and ET40 vs. SED, without difference between both athletes groups. At rest, total arterial compliance was improved in both ET30 and ET40 compared to SED. During submaximal exercise, improvement in global LV afterload was only observed in ET30 vs. SED. Two powerful markers of health, maximal oxygen uptake and resting HR, did not differ between athletes who commenced training before 30 or after 40 years of age, but were significantly improved compared to their life-long sedentary counterparts. PMID- 27116350 TI - Anthropometry, Physical Fitness and Coordination of Young Figure Skaters of Different Levels. AB - The aim of the present study was to identify anthropometric, physical, coordinative and ice-skating specific characteristics that discriminate young elite ice skaters from non-elite skaters and their non-skating peers. 32 skaters aged 9-12 years old (11 elites and 21 non-elites) voluntarily participated in the study. They were submitted to 5 anthropometric, 7 physical, 3 coordination and 5 ice-skating specific tests. Reference values of a representative healthy non skating sample were taken from the Flemish Sports Compass dataset. Figure skaters appeared to be predominantly average mature (93.8%), were lighter and leaner than the reference sample, and demonstrated better physical characteristics and motor coordination. There was no difference between the elite and non-elite group regarding maturity status and anthropometric or physical parameters. Still, elite skaters scored better than non-elites on the coordination tests jumping sideways and tended to do so on the moving sideways test. Profiles of figure skaters differ clearly from a reference population, while non-sport-specific motor coordination tests allow discrimination between elite and non-elite skaters. The relevance of these findings with respect to talent detection and identification in young ice skaters are discussed. PMID- 27116351 TI - Density functional models of the interfacial tensions near the critical endpoints and tricritical point of three-phase equilibria. AB - We treat two different density-functional models of the structures and tensions of the interfaces between phases on approach to the tricritical point of three phase equilibrium. The major objective is to account for some of the results of earlier experimental measurements of these tensions. The thermodynamic background is first reviewed, including representations of the properties near the critical endpoints and tricritical point and of the wetting transitions that may occur on approach to those critical points. The first of the models treated is analytically soluble. Its properties are illuminating but at the price of some artificiality paid for its analytical solubility. The second model, called model T, is in a class of those treated in the past and analyzed numerically. Some of its properties are obtained with sufficient precision to allow one to conclude with near certainty what the analytically exact results would be. This model, too, illuminates the experimental measurements. It is noted where its properties are in accord with those of the analytically soluble model and where the two differ. PMID- 27116352 TI - Correction: Mapping and Characterizing Selected Canopy Tree Species at the Angkor World Heritage Site in Cambodia Using Aerial Data. AB - [This corrects the article DOI: 10.1371/journal.pone.0121558.]. PMID- 27116353 TI - Norovirus Recombinant Strains Isolated from Gastroenteritis Outbreaks in Southern Brazil, 2004-2011. AB - Noroviruses are recognized as one of the leading causes of viral acute gastroenteritis, responsible for almost 50% of acute gastroenteritis outbreaks worldwide. The positive single-strand RNA genome of noroviruses presents a high mutation rate and these viruses are constantly evolving by nucleotide mutation and genome recombination. Norovirus recombinant strains have been detected as causing acute gastroenteritis outbreaks in several countries. However, in Brazil, only one report of a norovirus recombinant strain (GII.P7/GII.20) has been described in the northern region so far. For this study, 38 norovirus strains representative of outbreaks, 11 GII.4 and 27 non-GII.4, were randomly selected and amplified at the ORF1/ORF2 junction. Genetic recombination was identified by constructing phylogenetic trees of the polymerase and capsid genes, and further SimPlot and Bootscan analysis of the ORF1/ORF2 overlap. Sequence analysis revealed that 23 out of 27 (85%) non-GII.4 noroviruses were recombinant strains, characterized as: GII.P7/GII.6 (n = 9); GIIP.g/GII.12 (n = 4); GII.P16/GII.3 (n = 4); GII.Pe/GII.17 (n = 2); GII.P7/GII.14 (n = 1); GII.P13/GII.17 (n = 1); GII.P21/GII.3 (n = 1); and GII.P21/GII.13 (n = 1). On the other hand, among the GII.4 variants analyzed (Den Haag_2006b and New Orleans_2009) no recombination was observed. These data revealed the great diversity of norovirus recombinant strains associated with outbreaks, and describe for the first time these recombinant types circulating in Brazil. Our results obtained in southern Brazil corroborate the previous report for the northern region, demonstrating that norovirus recombinant strains are circulating more frequently than we expected. In addition, these results emphasize the relevance of including ORF1/ORF2-based analysis in surveillance studies as well as the importance of characterizing strains from other Brazilian regions to obtain epidemiological data for norovirus recombinant strains circulating in the country. PMID- 27116354 TI - A Cold-Inducible DEAD-Box RNA Helicase from Arabidopsis thaliana Regulates Plant Growth and Development under Low Temperature. AB - DEAD-box RNA helicases comprise a large family and are involved in a range of RNA processing events. Here, we identified one of the Arabidopsis thaliana DEAD-box RNA helicases, AtRH7, as an interactor of Arabidopsis COLD SHOCK DOMAIN PROTEIN 3 (AtCSP3), which is an RNA chaperone involved in cold adaptation. Promoter:GUS transgenic plants revealed that AtRH7 is expressed ubiquitously and that its levels of the expression are higher in rapidly growing tissues. Knockout mutant lines displayed several morphological alterations such as disturbed vein pattern, pointed first true leaves, and short roots, which resemble ribosome-related mutants of Arabidopsis. In addition, aberrant floral development was also observed in rh7 mutants. When the mutants were germinated at low temperature (12 degrees C), both radicle and first leaf emergence were severely delayed; after exposure of seedlings to a long period of cold, the mutants developed aberrant, fewer, and smaller leaves. RNA blots and circular RT-PCR revealed that 35S and 18S rRNA precursors accumulated to higher levels in the mutants than in WT under both normal and cold conditions, suggesting the mutants are partially impaired in pre-rRNA processing. Taken together, the results suggest that AtRH7 affects rRNA biogenesis and plays an important role in plant growth under cold. PMID- 27116355 TI - Initial Effects of Differently Treated Biogas Residues from Municipal and Industrial Wastes on Spring Barley Yield Formation. AB - Soil application of biogas residues (BGRs) is important for closing nutrient cycles. This study examined the efficiency and impact on yields and yield formation of solid-liquid separated residues from biodegradable municipal and industrial wastes (bio-waste) in comparison to complete BGRs, nitrification inhibitor, agricultural BGRs, mineral fertilizer and unfertilized plots as control. The experiment was set up as a randomized block design on silt loam Cambisol. Biogas residues from four biogas plants were evaluated. Plants per m2, ears per plant, grains per ear and thousand grain weight (TGW) were measured at harvest. Fertilization with BGRs resulted in similar biomass yields compared with mineral fertilizer. Mineral fertilizer (71 dt/ha) and plots fertilized with liquid fraction (59-62 dt/ha) indicated a trend to higher yields than solid fraction or complete BGR due to its high ammonia content. Liquid fractions and fraction with nitrification inhibitor induced fewer plants per m2 than corresponding solid and complete variants due to a potential phytotoxicity of high NH4-N concentration during germination. However, barley on plots fertilized with liquid fraction compensated the disadvantages at the beginning during the vegetation period and induced higher grain yields than solid fraction. This was attributable to a higher number of ears per plant and grains per ear. In conclusion, BGRs from biodegradable municipal and industrial wastes can be used for soil fertilization and replace considerable amounts of mineral fertilizer. Our study showed that direct application of the liquid fraction of BGR is the most suitable strategy to achieve highest grain yields. Nevertheless potential phytotoxicity of the high NH4-N concentration in the liquid fraction should be considered. PMID- 27116356 TI - Determination of rivaroxaban, apixaban and edoxaban in rat plasma by UPLC-MS/MS method. AB - To establish a rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of rivaroxaban, apixaban and edoxaban in rat plasma. The analytes and the internal standard (diazepam) were separated on an Acquity UPLC BEH C18 chromatography column (2.1 mm * 50 mm, 1.7 MUm) using gradient elution with a mobile phase of acetonitrile and 0.1 % formic acid in water at a flow rate of 0.4 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 436.1 > 145.1 for rivaroxaban, m/z 460.0 -> 443.1 for apixaban, m/z 548.2 -> 366.1 for edoxaban and m/z 285.2 -> 193.1 for diazepam (IS) using a positive electrospray ionization interface. The method was validated over a concentration range of 1.0 200 ng/mL for rivaroxaban, 1.0-100 ng/mL for apixaban and 1.0-500 ng/mL for edoxaban. Total time for each chromatograph was 3.5 min. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations <10.5 % and the accuracy values ranged from -9.9 to 11.3 %. The method was successfully applied to a pharmacokinetic study of rivaroxaban, apixaban and edoxaban in rats. PMID- 27116357 TI - Coronary sinus thrombus without spontaneous contrast. PMID- 27116358 TI - Parafricta Bootees and Undergarments to Reduce Skin Breakdown in People with or at Risk of Pressure Ulcers: A NICE Medical Technologies Guidance. AB - As part of the development of the National Institute for Health and Care Excellence (NICE) Medical Technologies Guidance on Parafricta Bootees and Undergarments to reduce skin breakdown in people with, or at risk of, pressure ulcers, the manufacturer (APA Parafricta Ltd) submitted clinical and economic evidence, which was critically appraised by an External Assessment Centre (EAC) and subsequently used by the Medical Technologies Advisory Committee (MTAC) to develop recommendations for further research. The University of Birmingham and Brunel University, acting as a consortium, were commissioned to act as the EAC, independently appraising the submission. This article is an overview of the original evidence submitted, the EAC's findings and the final NICE guidance. Very little comparative evidence was submitted to demonstrate the effectiveness of Parafricta Bootees or Undergarments. The sponsor submitted a simple cost analysis to estimate the costs of using Parafricta in addition to current practice-in comparison with current practice alone-in hospital and community settings separately. The analysis took a National Health Service (NHS) perspective. The basis of the analysis was a previously published comparative study, which showed no statistical difference in average lengths of stay between patients who wore Parafricta Undergarments and Bootees, and those who did not. The economic model incorporated the costs of Parafricta but assumed shorter lengths of stay with Parafricta. The sponsor concluded that Parafricta was cost saving relative to the comparators. The EAC made amendments to the sponsor's analysis to correct for errors and to reflect alternative assumptions. Parafricta remained cost saving in most analyses, and the savings per prevalent case ranged from L757 in the hospital model to L3455 in the community model. All analyses were severely limited by the available data on effectiveness-in particular, a lack of good quality comparative studies. PMID- 27116359 TI - The Efficiency of Increasing the Capacity of Physiotherapy Screening Clinics or Traditional Medical Services to Address Unmet Demand in Orthopaedic Outpatients: A Practical Application of Discrete Event Simulation with Dynamic Queuing. AB - BACKGROUND: Hospital outpatient orthopaedic services traditionally rely on medical specialists to assess all new patients to determine appropriate care. This has resulted in significant delays in service provision. In response, Orthopaedic Physiotherapy Screening Clinics and Multidisciplinary Services (OPSC) have been introduced to assess and co-ordinate care for semi- and non-urgent patients. OBJECTIVES: To compare the efficiency of delivering increased semi- and non-urgent orthopaedic outpatient services through: (1) additional OPSC services; (2) additional traditional orthopaedic medical services with added surgical resources (TOMS + Surg); or (3) additional TOMS without added surgical resources (TOMS - Surg). METHODS: A cost-utility analysis using discrete event simulation (DES) with dynamic queuing (DQ) was used to predict the cost effectiveness, throughput, queuing times, and resource utilisation, associated with introducing additional OPSC or TOMS +/- Surg versus usual care. RESULTS: The introduction of additional OPSC or TOMS (+/-surgery) would be considered cost effective in Australia. However, OPSC was the most cost-effective option. Increasing the capacity of current OPSC services is an efficient way to improve patient throughput and waiting times without exceeding current surgical resources. An OPSC capacity increase of ~100 patients per month appears cost effective (A$8546 per quality-adjusted life-year) and results in a high level of OPSC utilisation (98 %). CONCLUSION: Increasing OPSC capacity to manage semi- and non-urgent patients would be cost effective, improve throughput, and reduce waiting times without exceeding current surgical resources. Unlike Markov cohort modelling, microsimulation, or DES without DQ, employing DES-DQ in situations where capacity constraints predominate provides valuable additional information beyond cost effectiveness to guide resource allocation decisions. PMID- 27116360 TI - Adenovirus-Mediated ICOSIg Gene Therapy in a Presensitized Murine Model of Allergic Rhinitis. AB - Allergic rhinitis is a chronic inflammatory disease of the upper airways caused by Th2 cell-type cytokines in response to allergen exposure. The inducible costimulator (ICOS), the third member of the CD28/CTLA4 family, plays an important role in immune response. In this study, adenovirus vectors containing ICOSIg (Adex1CAICOSIg) were administered to effectively inhibit the ICOS/ICOSL interaction, and the effects of Adex1CAICOSIg on allergic rhinitis were examined. Intranasal administration of Adex1CAICOSIg attenuated airway inflammation, as demonstrated by a decrease in nasal symptoms and infiltration of eosinophils into the nasal mucosa, as well as by a decrease in local IL-5 expression. Therefore, the ICOS/ICOSL pathway significantly contributes to the progression of allergic rhinitis. PMID- 27116361 TI - Measuring the Developing Therapeutic Relationship Between Pregnant Women and Community Health Workers Over the Course of the Pregnancy in a Study Intervention. AB - The Scale to Assess the Therapeutic Relationship in Community Mental Health Care (STAR) is a frequently-administered tool for measuring therapeutic relationships between clinicians and patients. This manuscript tested the STAR's psychometric properties within a community health worker (CHW)-led intervention study involving pregnant and postpartum women. Women (n = 141) enrolled in the study completed the 12-item participant STAR survey (STAR-P) at two time points over the course of pregnancy and at two time points after delivery. The factor structure of the STAR-P proved to be unstable with this population. However, a revised 9-item STAR-P revealed a two-factor model of positive and negative interactions, and demonstrated strong internal consistency at postpartum time points. The revised STAR-P shows strong psychometric properties, and is suitable for use to evaluate the relationship developed between CHWs and pregnant and postpartum women in an intervention program. PMID- 27116362 TI - Pediatric acute asthma exacerbations: Evaluation and management from emergency department to intensive care unit. AB - OBJECTIVE: The goal of this report is to review available modalities for assessing and managing acute asthma exacerbations in pediatric patients, including some that are not included in current expert panel guidelines. While it is not our purpose to provide a comprehensive review of the National Asthma Education and Prevention Program (NAEPP) guidelines, we review NAEPP-recommended treatments to provide the full range of treatments available for managing exacerbations with an emphasis on the continuum of care between the ER and ICU. DATA SOURCES: We searched PubMed using the following search terms in different combinations: asthma, children, pediatric, exacerbation, epidemiology, pathophysiology, guidelines, treatment, management, oxygen, albuterol, beta2 agonist, anticholinergic, theophylline, corticosteroid, magnesium, heliox, BiPAP, ventilation, mechanical ventilation, non-invasive mechanical ventilation and respiratory failure. We attempted to weigh the evidence using the hierarchy in which meta-analyses of randomized controlled trials (RCTs) provide the strongest evidence, followed by individual RCTs, followed by observational studies. We also reviewed the NAEPP and Global Initiative for Asthma expert panel guidelines. RESULTS AND CONCLUSIONS: Asthma is the most common chronic disease of childhood, and acute exacerbations are a significant burden to patients and to public health. Optimal assessment and management of exacerbations, including appropriate escalation of interventions, are essential to minimize morbidity and prevent mortality. While inhaled albuterol and systemic corticosteroids are the mainstay of exacerbation management, escalation may include interventions discussed in this review. PMID- 27116363 TI - Time Resolved EPR Study on the Photoinduced Long-Range Charge-Separated State in Protein: Electron Tunneling Mediated by Arginine Residue in Human Serum Albumin. AB - To elucidate how local molecular conformations play a role on electronic couplings for the long-range photoinduced charge-separated (CS) states in protein systems, we have analyzed time-resolved electron paramagnetic resonance (TREPR) spectra by polarized laser irradiations of 9,10-anthraquinone-1-sulfonate (AQ1S( )) bound to human serum albumin (HSA). Analyses of the magnetophotoselection effects on the EPR spectra and a docking simulation clarified the molecular geometry and the electronic coupling of the long-range CS states of AQ1S(*2-) tryptophan214 radical cation (W214(*+)) separated by 1.2 nm. The ligand of AQ1S( ) has been demonstrated to be bound to the drug site I in HSA. Molecular conformations of the binding region were estimated by the docking simulations, indicating that an arginine218 (R218(+)) residue bound to AQ1S(*2-) mediates the long-range electron-transfer. The energetics of triad states of AQ1S(*2-)-R218(+) W214(*+) and AQ1S(-)-R218(*)-W214(*+) have been computed on the basis of the density functional molecular orbital calculations, providing the clear evidence for the long-range electronic couplings of the CS states in terms of the superexchange tunneling model through the arginine residue. PMID- 27116364 TI - Brief group psychoeducation for caregivers of individuals with bipolar disorder: A randomized controlled trial. AB - BACKGROUND: Bipolar disorder is associated with significant impairment in personal and social functioning for the individual and their caregivers. Psychoeducation for caregivers is beneficial, but interventions have typically required a significant time commitment and have not assessed changes in self efficacy. This study evaluated the effectiveness of a brief, two-session psychoeducational intervention for caregivers. It was hypothesized that the intervention would reduce caregiver burden and distress, and increase bipolar disorder knowledge and bipolar disorder self-efficacy. METHODS: Participants (N=32) were randomized to immediate or waitlist control conditions. The intervention involved two, 150-minute group sessions spaced one-week apart. At pre-, post-, and one-month follow-up participants completed the Depression, Anxiety, Stress Scale (DASS-21), Burden Assessment Scale, Knowledge of Bipolar Disorder Scale, and a Bipolar Disorder Self-efficacy Scale. RESULTS: Compared to the waitlist control group, the immediate treatment group demonstrated large and significant reductions in caregiver burden, and increases in bipolar disorder knowledge and bipolar disorder self-efficacy. These improvements maintained or increased to follow-up. No significant change was observed on the DASS-21. LIMITATIONS: Reliance on self-report and the sample comprised mostly of parents and partners, so it unclear if results generalize to other carer groups. CONCLUSIONS: Large and enduring improvements in carer burden, knowledge, and bipolar disorder self-efficacy can be achieved from a very brief, two-session intervention. PMID- 27116365 TI - Oxidative potential of size-fractionated atmospheric aerosol in urban and rural sites across Europe. AB - In this study we applied several assays, an in vitro rat alveolar macrophage model, a chemical ROS probe (DTT, dithiothreitol), and cytokine induction (TNFalpha) to examine relationships between PM-induced generation of reactive oxygen species (ROS) and PM composition, using a unique set of size-resolved PM samples obtained from urban and rural environments across Europe. From April-July 2012, we collected PM from roadside canyon, roadside motorway, and background urban sites in each of six European cities and from three rural sites spanning the continent. A Hi-Vol sampler was used to collect PM in three size classes (PM>7, PM7-3, PM3) and PM was characterized for total elements, and oxidative activity quantified in unfiltered and filtered PM extracts. We measured a remarkable uniformity in air concentrations of ROS and especially DTT activity across the continent. Only a 4-fold difference was documented for DTT across the urban sites and a similar variance was documented for ROS, implying that chemical drivers of oxidative activity are relatively similar between sites. The ROS and DTT specific activity was greater at urban background sites (and also rural sites) than at urban canyon locations. PM3 dominated the size distribution of both ROS activity (86% of total) and DTT activity (76% of total), reflecting both the large contribution of PM3 to total PM mass levels and importantly the higher specific oxidative activity of the PM3 in comparison with the larger particles. The soluble fraction of total activity was very high for DTT (94%) as well as for ROS (64%) in the PM3. However in the larger PM size fractions the contributions of the insoluble components became increasingly significant. The dominance of the insoluble PM drivers of activity was particularly evident in the TNFalpha data, where the insoluble contribution to cytokine production could be 100-fold greater than that from soluble components. ROS and DTT activity were strongly correlated in the PM3 (r = 0.93), however oxidative activity was not correlated with any measured inorganic element in this size cut. In contrast, significant correlations of both ROS and DTT oxidative activity with specific groups of chemical elements were documented in the larger PM size fractions. PMID- 27116366 TI - Confocal fluorescence microscopy to evaluate changes in adipocytes in the tumor microenvironment associated with invasive ductal carcinoma and ductal carcinoma in situ. AB - Adipose tissue is a dynamic organ that provides endocrine, inflammatory and angiogenic factors, which can assist breast carcinoma cells with invasion and metastasis. Previous studies have shown that adipocytes adjacent to carcinoma, known as cancer-associated adipocytes, undergo extensive changes that correspond to an "activated phenotype," such as reduced size relative to adipocytes in non neoplastic breast tissue. Optical imaging provides a tool that can be used to characterize adipocyte morphology and other features of the tumor microenvironment. In this study, we used confocal fluorescence microscopy to acquire images of freshly excised breast tissue stained topically with proflavine. We developed a computerized algorithm to identify and quantitatively measure phenotypic properties of adipocytes located adjacent to and far from normal collagen, ductal carcinoma in situ and invasive ductal carcinoma. Adipocytes were measured in confocal fluorescence images of fresh breast tissue collected from 22 patients. Results show that adipocytes adjacent to neoplastic tissue margins have significantly smaller area compared to adipocytes far from the margins of neoplastic lesions and compared to adipocytes adjacent to non neoplastic collagenous stroma. These findings suggest that confocal microscopic images can be utilized to evaluate phenotypic properties of adipocytes in breast stroma which may be useful in defining alterations in microenvironment that may aid in the development and progression of neoplastic lesions. PMID- 27116367 TI - Interspecific hybridization impacts host range and pathogenicity of filamentous microbes. AB - Interspecific hybridization is widely observed within diverse eukaryotic taxa, and is considered an important driver for genome evolution. As hybridization fuels genomic and transcriptional alterations, hybrids are adept to respond to environmental changes or to invade novel niches. This may be particularly relevant for organisms that establish symbiotic relationships with host organisms, such as mutualistic symbionts, endophytes and pathogens. The latter group is especially well-known for engaging in everlasting arms races with their hosts. Illustrated by the increased identification of hybrid pathogens with altered virulence or host ranges when compared with their parental lineages, it appears that hybridization is a strong driver for pathogen evolution, and may thus significantly impact agriculture and natural ecosystems. PMID- 27116368 TI - Macrobiota - helminths as active participants and partners of the microbiota in host intestinal homeostasis. AB - Important insights have recently been gained in our understanding of the intricate relationship in the intestinal milieu between the vertebrate host mucosal immune response, commensal bacteria, and helminths. Helminths are metazoan worms (macrobiota) and trigger immune responses that include potent regulatory components capable of controlling harmful inflammation, protecting barrier function and mitigating tissue damage. They can secrete a variety of products that directly affect immune regulatory function but they also have the capacity to influence the composition of microbiota, which can also then impact immune function. Conversely, changes in microbiota can affect susceptibility to helminth infection, indicating that crosstalk between these two disparate groups of endobiota can play an essential role in host intestinal immune function and homeostasis. PMID- 27116369 TI - Long-term effects of abscisic acid (ABA) on the grape berry phenylpropanoid pathway: Gene expression and metabolite content. AB - ABA has been proposed as the main signal triggering the onset of the ripening process in grapes, and modulating the secondary metabolism in grape berry skins. To determine the effect of ABA on secondary metabolism in berries, clusters of Carmenere were sprayed with 0 MULL(-1) ABA; 50 MULL(-1) ABA and 100 MULL(-1) ABA during pre-veraison, and the gene expression of the transcription factors and enzymes of the phenylpropanoid pathway were assessed from veraison to 70 days after veraison (DAV). Additionally, flavonols, tannins and anthocyanins were assessed from veraison until harvest (110 DAV). ABA accelerated sugar and anthocyanin accumulation at veraison. The grape transcript abundance of VvDFR, VvANS, VvUFGT and VvMybA1, all peaking around veraison mimicked the concentration of ABA throughout the season. The highest anthocyanin concentration occurred 35 DAV for all treatments, but higher pigment concentrations were observed in ABA treated berries at veraison and from 60 to 70 DAV to harvest. VvPAL was also increased by treatment at the higher concentration of ABA from veraison to 40 DAV. Regarding flavanol synthesis, VvLAR2 and VvMyb4A decreased from veraison until 40 DAV and then increased again until 70 DAV. Compared to the control, both ABA treatments resulted in a less-than-proportional reduction of the expression of both genes compared to the control and, after 40 DAV, in a more-than proportional increase compared to the control, suggesting a long-term effect of the pre-veraison ABA spray on the berries. A concomitant increase in flavanols was observed in berries after 40 DAV, and this occurred at a higher extent in berries treated with the highest ABA concentration. PMID- 27116370 TI - Transcriptome de novo assembly and analysis of differentially expressed genes related to cytoplasmic male sterility in cabbage. AB - Cytoplasmic male sterility (CMS) is a maternally inherited trait producing abnormal pollen during anther development. To identify the critical genes and pathways that are involved in the sterility and to better understand the underlying mechanisms, cabbage anthers at different developmental stages were cytologically examined and the transcriptomes were analyzed in CMS line and its maintainer line using the next-generation sequencing (NGS) technology. Microscopy showed that anther development in the CMS line was abnormal in the tetrad stage and failed to produce fertile pollen. We obtained 55,663,594 and 54,801,384 raw transcriptome reads from the sterile and maintainer lines, respectively, and assembled these reads into 68,851 unigenes with an average size of 1028 bp. By using the fragments assigned per kilobase of target per million mapped reads (FPKM) method, 5592 differentially expressed genes were identified, consisting of 3403 up- and 2089 down-regulated genes. Furthermore, there were 1011 and 45 genes specifically expressed in the maintainer or sterile line, respectively. Gene Ontology (GO) functional annotation and enrichment analysis of metabolic pathways were performed to map and analyze the candidate genes that may be involved in male sterility. Expression of eighteen genes was examined using qRT-PCR and their expression patterns were found to be same as the sequencing data. A clear cytological difference exists between the sterile and maintainer lines. The differentially expressed genes are associated with carbohydrate and energy metabolisms, or encode transcription factors, heat shock proteins and other stress proteins. Identification of these candidate genes provides a comprehensive understanding of the mechanism underlying CMS in cabbage. PMID- 27116371 TI - A novel formaldehyde metabolic pathway plays an important role during formaldehyde metabolism and detoxification in tobacco leaves under liquid formaldehyde stress. AB - Tobacco and Arabidopsis are two model plants often used in botany research. Our previous study indicated that the formaldehyde (HCHO) uptake and assimilation capacities of tobacco leaves were weaker than those of Arabidopsis leaves. After treatment with a 2, 4 or 6 mM HCHO solution for 24 h, detached tobacco leaves absorbed approximately 40% of the HCHO from the treatment solution. (13)C-NMR analysis detected a novel HCHO metabolic pathway in 2 mM H(13)CHO-treated tobacco leaves. [4-(13)C]Asn, [3-(13)C]Gln and [U-(13)C]oxalic acid (OA) were produced from this pathway after H(13)COOH generation during H(13)CHO metabolism in tobacco leaves. Pretreatments of cyclosporin A (CSA) and dark almost completely inhibited the generation of [4-(13)C]Asn, [3-(13)C]Gln and [U-(13)C]OA from this pathway but did not suppressed the production of H(13)COOH in 2 mM H(13)CHO treated tobacco leaves. The evidence suggests that this novel pathway has an important role during the metabolic detoxification of HCHO in tobacco leaves. The analysis of the chlorophyll and Rubisco contents indicated that CSA and dark pretreatments did not severely affect the survival of leaf cells but significantly inhibited the HCHO uptake by tobacco leaves. Based on the effects of CSA and dark pretreatments on HCHO uptake and metabolism, it is estimated that the contribution of this novel metabolic pathway to HCHO uptake is approximately 60%. The data obtained from the (13)C-NMR analysis revealed the mechanism underlying the weaker HCHO uptake and assimilation of tobacco leaves compared to Arabidopsis leaves. PMID- 27116372 TI - Water stress induces changes in polyphenol profile and antioxidant capacity in poplar plants (Populus spp.). AB - This paper is aimed to characterize young poplar plants under the influence of water stress provoked by polyethileneglycol 6000 (PEG 6000). Three polar genotypes (M1, B229, and PE19/66) were grown in hydroponics and subjected to 100 and 200 mOsm PEG 6000 during six days. Polyphenol characterization, two enzymatic markers and antioxidant capacity in leaves and roots were investigated in stressed plants. Total phenol content, ferric reducing antioxidant capacity (FRAP) and DPPH antiradical power (DPPH ARP) were determined for estimating total antioxidant capacity. Polyphenol oxidase (PPO) and phenylalanine ammonia lyase (PAL) were determined as enzymatic markers. Polyphenol characterization of poplar samples was performed by HPLC-PDA analysis. All results were subjected to correlation analysis and principal component analysis (PCA). Inspite of the decrease of total phenol content in investigated genotypes, as well as total antioxidant capacity, some of polyphenols were affected by stress like flavonoids chrysin, myricetine, kaempferol and isoferulic acid in roots of B229 genotype (Populus deltoides). Genotype B229 also showed the increase of antioxidant capacity and PAL activity in root and leaves under stress what could be the indicator of the adaptability of poplar plants to water stress. Significant positive correlations were obtained between PAL, antioxidant capacity as well as phenolic acids among themselves. Chemometric evaluation showed close interdependence between flavonoids, FRAP, DPPH antiradical power and both investigated enzymes of polyphenol metabolism, PAL and PPO. PMID- 27116373 TI - Association mapping of caffeine content with TCS1 in tea plant and its related species. AB - Caffeine is the most abundant purine alkaloid in majority of tea plant and its related species. This purine alkaloid contributes to the important flavor and health attributes of tea. Tea caffeine synthase 1 (TCS1, EC 2.1.1.159/2.1.1.160) gene plays a crucial role in caffeine biosynthesis. The objective of this study was to investigate the genetic relationship between the TCS1 and caffeine content of tea plant and its related species using association mapping. We identified 87 single-nucleotide polymorphisms (SNPs, pi = 0.00447) by resequencing the TCS1 locus of 44 tea accessions. Linkage disequilibrium (LD) analysis showed that LD did not extend over the entire gene (r(2) < 0.1, within 1000 bp). Two cleaved amplified polymorphism sequence (CAPS) markers were developed from sequence variations (SNP4318 and SNP6252). By association mapping, we identified SNP4318 associated with caffeine content in four environments, explaining 4.0%-7.7% of the phenotypic variance. We also validated the significant marker-trait associations in site-directed mutagenesis experiments. Examination of allelic variation and linkage disequilibrium by a candidate-gene-based approach can help to decipher the genetic basis of caffeine biosynthesis. Moreover, the SNP marker identified in this study can potentially be applied for future marker-assisted selection to improve tea quality. PMID- 27116374 TI - Protonation of nitriles: isolation and characterization of alkyl- and arylnitrilium ions. AB - The reactions of acetonitrile, propionitrile, butyronitrile, N,N dimethylaminoacetonitrile, benzonitrile, o-tolunitrile and 1,4-dicyanobenzene with HF/AsF5 or HF/SbF5 in anhydrous HF result in protonation of the nitrile. The obtained nitrilium ions were isolated as [AsF6](-), [SbF6](-) and [Sb2F11](-) salts and characterized by multinuclear NMR and vibrational spectroscopy, and their X-ray crystal structures. PMID- 27116375 TI - Statistical Analysis of Categorical Time Series of Atmospheric Elementary Circulation Mechanisms - Dzerdzeevski Classification for the Northern Hemisphere. AB - Northern hemisphere elementary circulation mechanisms, defined with the Dzerdzeevski classification and published on a daily basis from 1899-2012, are analysed with statistical methods as continuous categorical time series. Classification consists of 41 elementary circulation mechanisms (ECM), which are assigned to calendar days. Empirical marginal probabilities of each ECM were determined. Seasonality and the periodicity effect were investigated with moving dispersion filters and randomisation procedure on the ECM categories as well as with the time analyses of the ECM mode. The time series were determined as being non-stationary with strong time-dependent trends. During the investigated period, periodicity interchanges with periods when no seasonality is present. In the time series structure, the strongest division is visible at the milestone of 1986, showing that the atmospheric circulation pattern reflected in the ECM has significantly changed. This change is result of the change in the frequency of ECM categories; before 1986, the appearance of ECM was more diverse, and afterwards fewer ECMs appear. The statistical approach applied to the categorical climatic time series opens up new potential insight into climate variability and change studies that have to be performed in the future. PMID- 27116376 TI - Efficient access to cis-decalinol frameworks: copper(i)-catalyzed borylative cyclization of allene cyclohexanediones. AB - Cu-catalyzed borylative cyclization of allene cyclohexanediones has been described through a tandem beta-borylation and intramolecular allylic addition process, affording borylated cis-decalinols with excellent yields and diastereoselectivities. A good enantioselectivity is also achieved in the asymmetric version. The hemiboronate group in the cyclization products could be subjected to several useful transformations. PMID- 27116377 TI - Left ventricular rotational dyssynchrony before cardiac resynchronization therapy: a step forward into ventricular mechanics. AB - AIMS: Heart failure patients show impaired left ventricular rotation and twist. In patients undergoing cardiac resynchronization therapy (CRT) significance of preimplant left ventricular rotational timing between different ventricular regions is unknown. We thoroughly evaluated, in patients eligible for CRT, baseline left ventricular rotational mechanics, also assessing segmental rotational timing, and investigated whether the presence of rotational dyssynchrony may be associated with echocardiographic response. METHODS: By two dimensional speckle-tracking echocardiography, baseline peak apical and basal rotation, peak twist, and time-related parameters, such as delays between opposite segments at base and apex, were assessed in 55 CRT patients and 11 healthy participants. RESULTS: At 6 months, 30 (54%) patients were echocardiographic responders. Left ventricular rotation and twist had no association with response. All time-related parameters were significantly altered in CRT patients. Maximum basal and apical segments delay, and anteroseptal posterior delays at base and apex, were longer in responders than in nonresponders (P < 0.05 for all), regardless of the presence of left bundle branch block (LBBB) and QRS duration. At multivariable analysis, apical anteroseptal-posterior delay resulted as independently associated with response [odds ratio (OR): 1.022 (1.007-1.038); P = 0.004]. A cut-off value of 97.5 ms for apical anteroseptal-posterior delay predicted response with 96% specificity and 57% sensitivity (AUC = 0.83). Magnitude of left ventricular reverse remodeling was significantly related to apical anteroseptal-posterior delay (P = 0.001). CONCLUSION: In heart failure patients eligible for CRT, left ventricular rotational timing is altered. Dyssynchrony in rotational mechanics shows a specific pattern in responders regardless of the presence of LBBB. Apical anteroseptal-posterior rotational delay is independently associated with left ventricular reverse remodeling. PMID- 27116378 TI - The beta-cyanoalanine synthase pathway: beyond cyanide detoxification. AB - Production of cyanide through biological and environmental processes requires the detoxification of this metabolic poison. In the 1960s, discovery of the beta cyanoalanine synthase (beta-CAS) pathway in cyanogenic plants provided the first insight on cyanide detoxification in nature. Fifty years of investigations firmly established the protective role of the beta-CAS pathway in cyanogenic plants and its role in the removal of cyanide produced from ethylene synthesis in plants, but also revealed the importance of this pathway for plant growth and development and the integration of nitrogen and sulfur metabolism. This review describes the beta-CAS pathway, its distribution across and within higher plants, and the diverse biological functions of the pathway in cyanide assimilation, plant growth and development, stress tolerance, regulation of cyanide and sulfide signalling, and nitrogen and sulfur metabolism. The collective roles of the beta-CAS pathway highlight its potential evolutionary and ecological importance in plants. PMID- 27116379 TI - The Icatibant Outcome Survey: treatment of laryngeal angioedema attacks. AB - OBJECTIVE: To characterize the management and outcomes of life-threatening laryngeal attacks of hereditary angioedema (HAE) treated with icatibant in the observational Icatibant Outcome Survey (NCT01034969) registry. METHODS: This retrospective analysis was based on data from patients with HAE type I/II who received healthcare professional-administered or self-administered icatibant to treat laryngeal attacks between September 2008 and May 2013. RESULTS: Twenty centers in seven countries contributed data. Overall, 42 patients with HAE experienced 67 icatibant-treated laryngeal attacks. Icatibant was self administered for 62.3% of attacks (healthcare professional-administered, 37.7%). One icatibant injection was used for 87.9% of attacks, with rescue or concomitant medication used for 9.0%. The median time to treatment was 2.0 h (n=31 attacks) and the median time to resolution was 6.0 h (n=35 attacks). CONCLUSIONS: This analysis describes successful use of icatibant for the treatment of laryngeal HAE attacks in a real-world setting. PMID- 27116380 TI - Correlation of Aqueous Humor Lysyl Oxidase Activity with TGF-beta Levels and LOXL1 Genotype in Pseudoexfoliation. AB - PURPOSE: Pseudoexfoliation (PXF) is a microfibrillopathy involving disordered elastogenesis. Abnormal extracellular matrix (ECM) production underlies the pathophysiology of PXF. The enzyme Lysyl oxidase (LOX) and its isoforms are known to cross-link the elastin and collagen. Though the etiopathogensis of PXF is not well understood, studies report on the genetic risk involving LOXL1 gene. This study aims to screen LOXL1 coding variants rs1048661 and rs3825942 in the South Indian population and the implication of the single nucleotide polymorphism (SNP) with LOX activity. The levels of transforming growth factor beta (TGF-beta) in aqueous humor and its correlation with the LOX activity were also examined. METHODS: Blood, plasma, and aqueous aspirates were prospectively collected from PXF cases with and without glaucoma and cataract cases as controls. DNA was extracted from 48 PXF cases without glaucoma, 12 PXF cases with glaucoma, and 40 age-matched cataract-alone controls without PXF/glaucoma for analyzing LOX SNPs. LOX activity was measured in aqueous humor and plasma of 30 PXF cases without glaucoma, 24 age-matched cataract-alone controls without PXF/glaucoma, and 14 PXF cases with glaucoma. Protein levels of LOX, LOXL1, LOXL2, and total TGF-beta were estimated in plasma and aqueous humor by ELISA. RESULTS: The specific activity of LOX in aqueous humor was found to be significantly lowered in PXF cases compared with cataract-alone controls (p = 0.014). This decrease in LOX activity in PXF cases was associated with high-risk GG haplotype. However, this was not statistically significant and a larger sample size is warranted. TGF-beta1 and TGF-beta2 negatively correlated with LOX activity in aqueous humor (p = 0.028; p = 0.046, respectively). CONCLUSIONS: The LOXL1 SNPs, rs1048661 and rs3825942, are associated with PXF in the South Indian population correlating with lowered LOX activity in the aqueous humor. The increased level of total TGF-beta in the aqueous humor of PXF cases is possibly associated with LOX regulation which needs further investigation. PMID- 27116381 TI - Cytomegalovirus-Infected Primary Endothelial Cells Trigger NKG2C+ Natural Killer Cells. AB - Among innate cells, natural killer (NK) cells play a crucial role in the defense against cytomegalovirus (CMV). In some individuals, CMV infection induces the expansion of NKG2C+ NK cells that persist after control of the infection. We have previously shown that KIR2DL+ NK cells, in contrast to NKG2C+ NK cells, contribute to controlling CMV infection using a CMV-infected monocyte-derived dendritic cell (MDDC) model. However, the nature of CMV-infected cells contributing to the expansion of the NKG2C+ NK cell subset remains unclear. To gain more insight into this question, we investigated the contribution of NKG2C+ NK cell activation by CMV-infected primary human aortic endothelial cells (EC) isolated from kidney transplant donors, which constitutively express the human leukocyte antigen (HLA)-E molecule. Here, we show that, although classic HLA class I expression was drastically downregulated, nonclassic HLA-E expression was maintained in CMV-infected EC. By comparing HLA expression patterns in CMV infected EC, fibroblasts and MDDC, we demonstrate a cell-dependent modulation of HLA-E expression by CMV infection. NKG2C+ NK cell degranulation was significantly triggered by CMV-infected EC regardless of the nature of the HLA-E allele product. EC, predominantly present in vessels, may constitute a privileged site for CMV infection that drives a 'memory' NKG2C+ NK cell subset. PMID- 27116383 TI - Stability analysis of a continuum-based constrained mixture model for vascular growth and remodeling. AB - A stabilizing criterion is derived for equations governing vascular growth and remodeling. We start from the integral state equations of the continuum-based constrained mixture theory of vascular growth and remodeling and obtain a system of time-delayed differential equations describing vascular growth. By employing an exponential form of the constituent survival function, the delayed differential equations can be reduced to a nonlinear ODE system. We demonstrate the degeneracy of the linearized system about the homeostatic state, which is a fundamental cause of the neutral stability observations reported in prior studies. Due to this degeneracy, stability conclusions for the original nonlinear system cannot be directly inferred. To resolve this problem, a sub-system is constructed by recognizing a linear relation between two states. Subsequently, Lyapunov's indirect method is used to connect stability properties between the linearized system and the original nonlinear system, to rigorously establish the neutral stability properties of the original system. In particular, this analysis leads to a stability criterion for vascular expansion in terms of growth and remodeling kinetic parameters, geometric quantities and material properties. Numerical simulations were conducted to evaluate the theoretical stability criterion under broader conditions, as well as study the influence of key parameters and physical factors on growth properties. The theoretical results are also compared with prior numerical and experimental findings in the literature. PMID- 27116382 TI - Protective Effects of Edaravone in Adult Rats with Surgery and Lipopolysaccharide Administration-Induced Cognitive Function Impairment. AB - Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterized by cognitive declines in patients after surgery. Previous studies have suggested that surgery contributed to such impairment. It has been proven that neuroinflammation may exacerbate surgery-induced cognitive impairment in aged rats. The free radical scavenger edaravone has high blood brain barrier permeability, and was demonstrated to effectively remove free radicals from the brain and alleviate the development of POCD in patients undergoing carotid endarterectomy, suggesting its potential role in preventing POCD. For this reason, this study was designed to determine whether edaravone is protective against POCD through its inhibitory effects on inflammatory cytokines and oxidative stress. First, Sprague Dawley adult male rats were administered 3 mg/kg edaravone intraperitoneally after undergoing a unilateral nephrectomy combined with lipopolysaccharide injection. Second, behavioral parameters related to cognitive function were recorded by fear conditioning and Morris Water Maze tests. Last, superoxide dismutase activities and malondialdehyde levels were measured in the hippocampi and prefrontal cortex on postoperative days 3 and 7, and microglial (Iba1) activation, p-Akt and p-mTOR protein expression, and synaptic function (synapsin 1) were also examined 3 and 7 days after surgery. Rats that underwent surgery plus lipopolysaccharide administration showed significant impairments in spatial and working memory, accompanied by significant reductions in hippocampal-dependent and independent fear responses. All impairments were attenuated by treatment with edaravone. Moreover, an abnormal decrease in superoxide dismutase activation, abnormal increase in malondialdehyde levels, significant increase in microglial reactivity, downregulation of p-Akt and p-mTOR protein expression, and a statistically significant decrease in synapsin-1 were observed in the hippocampi and prefrontal cortices of rats at different time points after surgery. All mentioned abnormal changes were totally or partially reversed by edaravone. To our knowledge, few reports have shown greater protective effects of edaravone on POCD induced by surgery plus lipopolysaccharide administration from its anti-oxidative stress and anti inflammatory effects, as well as maintenance of Akt/mTOR signal pathway activation; these might be closely related to the therapeutic effects of edaravone. Our research demonstrates the potential use of edaravone in the treatment of POCD. PMID- 27116384 TI - Low-dose decitabine plus all-trans retinoic acid in patients with myeloid neoplasms ineligible for intensive chemotherapy. AB - In our previous in vitro trials, decitabine and all-trans retinoic acid (ATRA) demonstrated synergistic effects on growth inhibition, differentiation, and apoptosis in SHI-1 cells; in K562 cells, ATRA enhanced the effect of decitabine on p16 demethylation, and the combination of the two drugs was found to activate RAR-beta expression (p16 and RAR-beta are two tumor suppressor genes). On the rationale of our in vitro trials, we used low-dose decitabine and ATRA to treat 31 myeloid neoplasms deemed ineligible for intensive chemotherapy. The regimen consisted of decitabine at the dose of 15 mg/m(2) intravenously over 1 h daily for consecutive 5 days and ATRA at the dose of 20 mg/m(2) orally from day 1 to 28 except day 4 to 28 in the first cycle, and the regimen was repeated every 28 days. After 6 cycles, decitabine treatment was stopped, and ATRA treatment was continued for maintenance treatment. Treated with a median of 2 cycles (range 1 6), 7 patients (22.6 %) achieved complete remission (CR), 7 (22.6 %) marrow CR (mCR), and 4 (12.9 %) partial remission (PR). The overall remission (CR, mCR, and PR) rate was 58.1 %, and the best response (CR and mCR) rate was 45.2 %. The median overall survival (OS) was 11.0 months, the 1-year OS rate was 41.9 %, and the 2-year OS rate was 26.6 %. In univariate analyses, age, performance status, comorbidities, white blood cell counts and platelets at diagnosis, percentage of bone marrow blasts, karyotype, and treatment efficacy demonstrated no impacts on OS (P > 0.05, each). Main side effects were tolerable hematologic toxicities. In conclusion, low-dose decitabine plus ATRA is a promising treatment for patients with myeloid neoplasms judged ineligible for intensive chemotherapy. PMID- 27116385 TI - Shells of charge: a density functional theory for charged hard spheres. AB - A functional for the electrostatic excess free-energy for charged, hard sphere fluids is proposed. The functional is derived from two complementary, but equivalent, interpretations of the mean spherical approximation (MSA). The first combines fundamental measure theory (FMT) from hard-core interactions with the idea that MSA can be interpreted in terms of the interaction spherical shells of charge. This formulation gives the free-energy density as a function of weighted densities. When all the ions have the same size, the functional adopts an FMT like form. The second in effect 'functionalizes' the derivation of MSA; that is, it generalizes the MSA as a functional-based version of MSA (fMSA). This formulation defines the free-energy density as a function of a position-dependent MSA screening parameter and the weighted densities of the FMT approach. This FMT/fMSA functional is shown to give accurate density profiles, as compared to Monte Carlo simulations, under a wide range of ion concentrations, size asymmetries, and valences. PMID- 27116386 TI - A Novel Homozygous SLC2A9 Mutation Associated with Renal-Induced Hypouricemia. AB - BACKGROUND: Hereditary renal hypouricemia (RHUC) is a genetically heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA; acute kidney injury (AKI) and nephrolithiasis are recognized complications. Type 1 (RHUC1) is caused by mutations in the SLC22A12 gene, whereas RHUC2 is caused by mutations in the SLC2A9 gene. Patient ethnicity is diverse but only few Caucasian families with an SLC2A9 mutation have been reported. METHODS: The current report describes the clinical history, biochemical and molecular genetics findings of a native Austrian family with RHUC2. The propositus presented with 2 episodes of exercise induced AKI and exhibited profound hypouricemia. Mutational screening of the SLC22A12 and SLC2A9 genes was performed. RESULTS: The molecular analyses revealed the homozygous c.512G>A transition that leads to the p.Arg171His missense substitution in SLC2A9, confirming the diagnosis of RHUC2. Segregation study of the causal mutation revealed that the mother and elder sister were heterozygous carriers, whereas the younger sister was found to be homozygous. CONCLUSION: We report the identification of a novel mutation in SLC2A9 as the cause of RHUC2 in a native Austrian family. We show that glucose transporter 9 mutations cause severe hypouricemia in homozygous individuals and confirm the high risk of AKI in male individuals harbouring these mutations. In our literature review, we provide an overview of the putative underlying pathophysiology, potential renal complications, findings on kidney biopsy as well as potential long-time renal sequelae. PMID- 27116387 TI - Neocortex: a lean mean memory storage machine. PMID- 27116388 TI - Foraging and flight trump defense and fight. PMID- 27116391 TI - Ubiquitination and filamentous structure of cytidine triphosphate synthase. AB - Living organisms respond to nutrient availability by regulating the activity of metabolic enzymes. Therefore, the reversible post-translational modification of an enzyme is a common regulatory mechanism for energy conservation. Recently, cytidine-5'-triphosphate (CTP) synthase was discovered to form a filamentous structure that is evolutionarily conserved from flies to humans. Interestingly, induction of the formation of CTP synthase filament is responsive to starvation or glutamine depletion. However, the biological roles of this structure remain elusive. We have recently shown that ubiquitination regulates CTP synthase activity by promoting filament formation in Drosophila ovaries during endocycles. Intriguingly, although the ubiquitination process was required for filament formation induced by glutamine depletion, CTP synthase ubiquitination was found to be inversely correlated with filament formation in Drosophila and human cell lines. In this article, we discuss the putative dual roles of ubiquitination, as well as its physiological implications, in the regulation of CTP synthase structure. PMID- 27116392 TI - Variation in Pregnancy Options Counseling and Referrals, And Reported Proximity to Abortion Services, Among Publicly Funded Family Planning Facilities. AB - CONTEXT: As frontline providers, publicly funded family planning clinics represent a critical link in the health system for women seeking information about pregnancy options, yet scant information exists on their provision of relevant services. Understanding their practices is important for gauging how well these facilities serve patients' needs. METHODS: A 2012 survey of 567 publicly funded family planning facilities in 16 states gathered information on referral-making for adoption and abortion services, and perceived proximity to abortion services. Chi-square, multivariable logistic regression and multinomial logistic regression analyses were performed to assess differences among facilities in referral-making and reported proximity to abortion services. RESULTS: Abortion referrals were provided by a significantly smaller proportion of providers than were adoption referrals (84% vs. 97%). Health departments and community health centers were significantly less likely than comprehensive reproductive health centers to refer for abortion services and to have a list of abortion providers available (odds ratios, 0.1-0.2). Rural facilities were more likely than urban ones to report a distance of more than 100 miles to the closest first-trimester abortion provider (relative risk ratio, 11.4), second-trimester abortion provider (8.7) and medication abortion provider (8.0). Health departments were more likely than comprehensive reproductive health centers not to know the location of the closest first-trimester, second-trimester or medication abortion provider (2.5-3.5). CONCLUSION: A better understanding of disparities in provision of pregnancy options counseling and referrals at publicly funded family planning clinics is needed to ensure that women get timely care. PMID- 27116393 TI - Activated PI3Kdelta syndrome type 2: Two patients, a novel mutation, and review of the literature. AB - BACKGROUND: Autosomal dominant gain-of-function mutations in PIK3R1 encoding for the regulatory subunit (p85alpha, p55alpha, and p50alpha) of Class IA phosphoinositide 3-kinase (PI3K) result in the activated PI3Kdelta syndrome (APDS) type 2 characterized by childhood-onset combined immunodeficiency, lymphoproliferation, and immune dysregulation. To improve clinical awareness and understanding of these rare diseases, we reviewed all hitherto published cases with APDS type 1 and type 2 for their clinical and immunologic symptoms and added novel clinical, immunologic, and genetic findings of two patients with APDS type 2. METHODS: Clinical, immunologic, and genetic evaluation of two new patients with APDS2 was performed followed by the systematic collection of all available previously published data of patients with APDS1 and APDS2. RESULTS: Patients with APDS type 1 (n = 49) and type 2 (n = 15) showed an indistinguishable immunologic phenotype. Overlapping clinical features shared by APDS type 1 and type 2 were observed, but our review also revealed previously unnoticed clinical differences such as remarkably high incidence of microcephaly, poor growth/short stature in patients with APDS2. Clinical management and outcome were variable and included prophylactic antibiotics, immunosuppression, immunoglobulin substitution, and hematopoietic stem cell transplantation. CONCLUSIONS: A disease specific registry collecting prospective and long-term follow-up data of patients with APDS, as currently set up by the European Society for Immunodeficiencies, are needed to better understand the natural history and to optimize treatment concepts and thereby improving the outcome of this heterogenous patient group. PMID- 27116394 TI - NIR-Triggered Rapid Shape Memory PAM-GO-Gelatin Hydrogels with High Mechanical Strength. AB - Shape memory hydrogels containing over 76 wt % of water were synthesized in a one pot method, and interpenetrating double network was formed by physically cross linked gelatin network and chemically cross-linked polyacrylamide (PAM) network with graphene oxide (GO). The temporary shape was quickly fixed by cooling in ice water for 30 s after deformation at 80 degrees C for 10 s. Shape recovery started in 10 s under near-infrared (NIR) irradiation and almost completed within 60 s depending on the curling angle. A small amount of GO in the hydrogels (<=1.5 mg/mL) played a key role in NIR energy absorption and transformation into thermal energy. The hydrogel without GO showed no response to the NIR irradiation and cannot recover to its permanent shape by NIR irradiation. Temperature sweep was conducted in the cycle of 20 degrees C -> 80 degrees C -> 20 degrees C, and the structure change in the hydrogels with temperature was investigated according to the storage modulus G' and tangent of the loss angle tan delta as a function of the hydrogel composition. The shape-memory capability was confirmed as the contribution from the triple-helix cross-linking network of gelatin. High mechanical toughness (strength > 400 kPa and broken strain > 500%) was achieved by the double-network with the sacrificial gelatin network and GO bridging to dissipate deformation energy. The optimized composition of the hydrogel was found to be a key point to realize stable temporary shape and rapid recovery to the permanent shape controlled by NIR irradiation with reasonable strength. The facile preparation and noncontact gentle stimulus of the present hydrogel hold great potential to be used in soft actuator materials. PMID- 27116395 TI - On magnitudes in memory: An internal clock account of space-time interaction. AB - Traditionally, research on time perception has diverged into a representational approach that focuses on the interaction between time and non-temporal magnitude information like spatial distance, and a mechanistic approach that emphasizes the workings and timecourse of components within an internal clock. We combined these approaches in order to identify the locus of space-time interaction effects in the mechanistic framework of the internal clock model. In three experiments, we contrasted the effects of spatial distance (a long- vs. short-distance line) on time perception with those of visual flicker (a flickering vs. static stimulus) in a duration reproduction paradigm. We found that both a flickering stimulus and a long-distance line lengthened reproduced time when presented during time encoding. However, when presented during time reproduction, a flickering stimulus shortened reproduced time but a long-distance line had no effect. The results thus show that, while visual flickers affects duration accumulation itself, spatial distance instead biases the memory of the accumulated duration. These findings are consistent with a clock-magnitude account of space-time interaction whereby both temporal duration and spatial distance are represented as mental magnitudes that can interfere with each other while being kept in memory, and places the locus of interaction between temporal and non-temporal magnitude dimensions at the memory maintenance stage of the internal clock model. PMID- 27116396 TI - Evidence for Inhibition of Lysozyme Amyloid Fibrillization by Peptide Fragments from Human Lysozyme: A Combined Spectroscopy, Microscopy, and Docking Study. AB - Degenerative diseases, such as Alzheimer's and prion diseases, as well as type II diabetes, have a pathogenesis associated with protein misfolding, which routes with amyloid formation. Recent strategies for designing small-molecule and polypeptide antiamyloid inhibitors are mainly based on mature fibril structures containing cross beta-sheet structures. In the present study, we have tackled the hypothesis that the rational design of antiamyloid agents that can target native proteins might offer advantageous prospect to design effective therapeutics. Lysozyme amyloid fibrillization was treated with three different peptide fragments derived from lysozyme protein sequence R(107)-R(115). Using low resolution spectroscopic, high-resolution NMR, and STD NMR-restrained docking methods such as HADDOCK, we have found that these peptide fragments have the capability to affect lysozyme fibril formation. The present study implicates the prospect that these peptides can also be tested against other amyloid-prone proteins to develop novel therapeutic agents. PMID- 27116397 TI - Ionization and Fragmentation of DCOOD Induced by Synchrotron Radiation at the Oxygen 1s Edge: The Role of Dimer Formation. AB - The ionization and photofragmentation of molecules in the core region has been widely investigated for monomers and dimers of organic molecules in the gas phase. In this study, we used synchrotron radiation to excite electrons of the oxygen K-edge in an effusive molecular beam of doubly deuterated formic acid. We used time-of-flight mass spectrometry and employed the spectroscopic techniques photoelectron-photoion coincidence and photoelectron photoion-photoion coincidence to obtain spectra of single and double coincidences at different pressures. Our results indicate the presence of ions and ion pairs that have charge-to-mass ratio higher than the monomer DCOOD, as the (DCOOD).D(+), and pairs (DCO(+), DCO(+)) and (CO(+), DCO(+)). Comparing the spectra obtained for different pressures we can ascertain that these ions are formed by the fragmentation of DCOOD dimers. PMID- 27116398 TI - Simultaneous saccharification and fermentation of corncobs with genetically modified Saccharomyces cerevisiae and characterization of their microstructure during hydrolysis. AB - Cellulose is an abundant natural polysaccharide that is universally distributed. It can be extracted from corncobs, which are inexpensive, easily accessible, renewable, and environmentally friendly. A common strategy for effectively utilizing cellulose is efficient heterogeneous expression of cellulase genes in Saccharomyces cerevisiae. However, the improvement of cellulose utilization is a relevant issue. Based on our previous findings, we constructed an integrated secretion expression vector, pHBM368-pgk, containing a constitutive promoter sequence. Three genetically modified S. cerevisiae strains containing heterologous beta-glucosidase, exoglucanase, and endoglucanase genes were constructed. The results of a 1-L bioreactor fermentation process revealed that the mixed recombinant S. cerevisiae could efficiently carry out simultaneous saccharification and fermentation (SSF) by using corncobs as the sole carbon source. The ethanol concentration reached 6.37 g/L after 96 hours of fermentation, which was about 3 times higher than that produced by genetically modified S. cerevisiae with the inducible promoter sequence. To investigate the microstructure characteristics of hydrolyzed corncobs during the fermentation process, corncob residues were detected by using a scanning electron microscope. This study provides a feasible method to improve the effect of SSF using corncobs as the sole carbon source. PMID- 27116399 TI - Sinus surgery postpones chronic Gram-negative lung infection: cohort study of 106 patients with cystic fibrosis. AB - BACKGROUND: In patients with cystic fibrosis (CF) the sinuses are a bacterial reservoir for Gram-negative bacteria (GNB). From the sinuses the GNB can repeatedly migrate to the lungs. In a one-year follow-up study, endoscopic sinus surgery (ESS) with adjuvant therapy reduced the frequency of pulmonary samples positive for GNB. We investigated whether the effect is sustained. METHODOLOGY: We report the effect of ESS and adjuvant therapy three years postoperatively in a CF cohort participating in this prospective clinical follow-up study. The primary endpoint was the lung infection status defined by Leeds criteria. RESULTS: One hundred and six CF patients underwent ESS; 27 had improved lung infection status after three years. The prevalence of patients free of lung colonization with GNB significantly increased from 16/106 patients (15%) preoperatively to 35/106 patients (33%) after three years. The total cohort had decreasing lung function during follow-up; however, in 27 patients with improved lung infection status lung function was stable. Revision surgery was performed in 31 patients (28%). CONCLUSION: ESS with adjuvant therapy significantly improves the lung infection status for at least three years in our cohort of patients with CF and may postpone chronic lung infection with GNB and thus stabilize lung function. PMID- 27116401 TI - Evaluation of radiocesium concentrations in new leaves of wild plants two years after the Fukushima Dai-ichi Nuclear Power Plant accident. AB - Radiocesium ((137)Cs) transfer to plants immediately after the Fukushima Dai-ichi Nuclear Power Plant accident was investigated by collecting newly emerged leaf and soil samples between May 2011 and November 2012 from 20 sites in the Fukushima prefecture. Radiocesium concentrations in leaf and soil samples were measured to calculate concentration ratios (CR). Woody plants exhibited high CR values because (137)Cs deposited on stems and/or leaves were transferred to newly emerging tissues. The CR values in 2012 declined as compared to that in 2011. Exchangeable (137)Cs rates in soil (extraction rate) samples were measured at five sites. These rates decreased at four sites in 2012 and depended on environmental conditions and soil type. Both CR values and extraction rates decreased in 2012. However, CR values reflected the changes in extraction rates and characteristics of each species. Amaranthaceae, Chenopodiaceae, and Polygonaceae, which had been identified as Cs accumulators, presented no clear (137)Cs accumulation ability. In 2012, the perennial plant Houttuynia cordata and deciduous trees Chengiopanax sciadophylloides and Acer crataegifolium displayed high CR values, indicating that these species are (137)Cs accumulators and may be considered as potential species for phytoremediation. PMID- 27116402 TI - Determination of (226)Ra in produced water by liquid scintillation counting. AB - It is proposed a method for the determination of (226)Ra in offshore platform liquid effluent samples (produced water). The method is based on a two-phase liquid scintillation counting system and allows for the direct and simple determination of (226)Ra content. Samples with high barium content may also have high (226)Ra concentration. Therefore, the sample volume is based on the barium concentration and ranges from 10 mL to 100 mL. Our new method was tested using multiple real samples and was compared with the BaSO4 precipitation method. The results based on the LSC were 30% higher than the precipitation method, which is attributed to the self-absorption of alpha particles in the BaSO4 precipitate. The determination of both (226)Ra and (228)Ra in the liquid effluent of offshore oil platforms is mandatory in Brazil. Thus, a second method of accurately assessing (228)Ra content remains necessary. PMID- 27116407 TI - American Association for the Surgery of Trauma statement on firearm injuries. PMID- 27116408 TI - Admissions for isolated nonoperative mild head injuries: Sharing the burden among trauma surgery, neurosurgery, and neurology. AB - BACKGROUND: Isolated nonoperative mild head injuries (INOMHI) occur with increasing frequency in an aging population. These patients often have multiple social, discharge, and rehabilitation issues, which far exceed the acute component of their care. This study was aimed to compare the outcomes of patients with INOMHI admitted to three services: trauma surgery, neurosurgery, and neurology. METHODS: Retrospective case series (January 1, 2009 to August 31, 2013) at an academic Level I trauma center. According to an institutional protocol, INOMHI patients with Glasgow Coma Scale (GCS) of 13 to 15 were admitted on a weekly rotational basis to trauma surgery, neurosurgery, and neurology. The three populations were compared, and the primary outcomes were survival rate to discharge, neurological status at hospital discharge as measured by the Glasgow Outcome Score (GOS), and discharge disposition. RESULTS: Four hundred eighty eight INOMHI patients were admitted (trauma surgery, 172; neurosurgery, 131; neurology, 185). The mean age of the study population was 65.3 years, and 58.8% of patients were male. Seventy-seven percent of patients has a GCS score of 15. Age, sex, mechanism of injury, Charlson Comorbidity Index, Injury Severity Score, Abbreviated Injury Scale in head and neck, and GCS were similar among the three groups. Patients who were admitted to trauma surgery, neurosurgery and neurology services had similar proportions of survivors (98.8% vs 95.7% vs 94.7%), and discharge disposition (home, 57.0% vs 61.6% vs 55.7%). The proportion of patients with GOS of 4 or 5 on discharge was slightly higher among patients admitted to trauma (97.7% vs 93.0% vs 92.4%). In a logistic regression model adjusting for Charlson Comorbidity Index CCI and Abbreviated Injury Scale head and neck scores, patients who were admitted to neurology or neurosurgery had significantly lower odds being discharged with GOS 4 or 5. While the trauma group had the lowest proportion of repeats of brain computed tomography (61.6%), the neurosurgery group had the highest proportion of intensive care unit admission (29.8%), and the neurology group had the longest emergency department stay (7.5 hours), there were no significant differences in duration of hospital stay, in-hospital complications, and readmission within 30 days. CONCLUSIONS: Although there were differences in use of health care resources, and the proportion of patients with GOS of 4 or 5 on discharge was slightly higher among patients admitted to trauma, most clinical outcomes were similar in INOMHI patients admitted to trauma surgery, neurosurgery, or neurology in our institution. A rotational policy of admitting INOMHI patients is feasible among services with expertise in and commitment to the care of these patients. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 27116409 TI - Role of computed tomography angiography in the management of Zone II penetrating neck trauma in patients with clinical hard signs. PMID- 27116410 TI - Prehospital lactate improves accuracy of prehospital criteria for designating trauma activation level. AB - BACKGROUND: Trauma activation level is determined by prehospital criteria. The American College of Surgeons (ACS) recommends trauma activation criteria; however, their accuracy may be limited. Prehospital lactate has shown promise in predicting trauma center resource requirements. Our objective was to investigate the added value of incorporating prehospital lactate in an algorithm to designate trauma activation level. METHODS: Air medical trauma patients undergoing prehospital lactate measurement were included. Algorithms using ACS activation criteria (ACS) and ACS activation criteria plus prehospital lactate (ACS+LAC) to designate trauma activation level were compared. Test characteristics and net reclassification improvement (NRI), which evaluates reclassification of patients among risk categories with additional predictive variables, were calculated. Algorithms were compared to predict trauma center need defined as more than 1 unit of blood in the emergency department; spinal cord injury; advanced airway; thoracotomy or pericardiocentesis; ICP monitoring; emergent operative or interventional radiology procedure; or death. RESULTS: There were 6,347 patients included. Twenty-eight percent had trauma center need. The ACS+LAC algorithm upgraded 256 patients and downgraded 548 patients compared to the ACS algorithm. The ACS+LAC algorithm versus ACS algorithm had an NRI of 0.058 (95% confidence interval [CI], 0.044-0.071; p < 0.01), with an event NRI of -0.5% and nonevent NRI of 6.2%. When weighted to favor changes in undertriage, the ACS+LAC still had a favorable overall reclassification (weighted NRI, 0.041; 95% CI, 0.028-0.054; p = 0.01). The ACS+LAC algorithm increased positive predictive value, negative predictive value, and accuracy. Over-triage was reduced 7.2%, while undertriage only increased 0.7%. The area under the curve was significantly higher for the ACS+LAC algorithm (0.79 vs. 0.76; p < 0.01). CONCLUSIONS: The ACS+LAC algorithm reclassified patients to more appropriate levels of trauma activation compared to the ACS algorithm. This overall benefit is achieved by significant reduction in overtriage relative to very small increase in undertriage. In the context of trauma team activation, this trade-off may be acceptable, especially in the current health care environment. LEVEL OF EVIDENCE: Therapeutic/care management study, level III; prognostic/epidemiologic study, level III. PMID- 27116411 TI - Re: Role of computed tomography angiography in the management of Zone II penetrating neck trauma in patients with clinical hard signs. PMID- 27116412 TI - Early feeds not force feeds: Enteral nutrition in traumatic brain injury. AB - BACKGROUND: Brain Trauma Foundation guidelines recommend the early use of enteral nutrition to optimize recovery following traumatic brain injury (TBI). Our aim was to examine the effect of early feeds (<=24 hours) on clinical outcomes after TBI. METHODS: We performed a 3-year retrospective study of patients with severe TBI (Glasgow Coma Scale score <8) who were intubated, admitted to the intensive care unit (ICU), and received tube feeds. Early tube feeds (early TF) were defined as initiation of tube feeds within 24 hours, whereas late tube feeds (late TF) were defined as initiation of tube feeds after 24 hours. Outcome measures included pneumonia rates, days on ventilator, hospital and ICU stay, and mortality rates. RESULTS: A total of 90 patients (early TF: 58, late TF: 32) were included, of which 73.3% were male, mean age was 42 (SD, 20) years, and median head Abbreviated Injury Scale score was 4 (range, 3-5). There was no difference in age (p = 0.1), head Abbreviated Injury Scale score (p = 0.5), or admission Glasgow Coma Scale score (p = 0.9) between the two groups. Patients with early TF were associated with higher number of ICU days (p = 0.03) and higher pneumonia rates (p = 0.04), but there was no significant difference in mortality (p = 0.44) as compared with those who underwent late TF. CONCLUSIONS: Although early tube feeds are known to improve outcomes in TBI patients, our data suggest that early feeds in TBI patients are associated with higher rates of pneumonia and greater hospital resource utilization. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 27116413 TI - Dexmedetomidine as an adjunct for sedation in patients with traumatic brain injury. AB - BACKGROUND: In patients with traumatic brain injury (TBI), optimizing sedation is challenging because maintaining a clinical examination is important in being able to detect neurological deterioration. Propofol (PROP) is frequently used as a sedative in TBI since it has been shown to reduce the cerebral metabolic rate, but it may lead to PROP-related infusion syndrome and hemodynamic compromise. Dexmedetomidine (DEX) is a sedative that produces minimal respiratory depression with opioid-sparing effects. The purpose of this study was to determine whether sedation with DEX would be safe in patients with severe TBI. METHODS: This prospective observational single-center study was conducted from 2011 to 2013. Patients with severe TBI were treated according to standard of care per the Brain Trauma Foundation guidelines. Sedative agents were titrated using the Richmond Agitation Sedation Scale (RASS) while maintaining intracranial pressure of less than 20 mm Hg and cerebral perfusion pressure of greater than 60 mm Hg. The primary outcome measure was the mean time in target RASS (0 = alert and calm to 2 = light sedation). RESULTS: A total of 198 patients were enrolled in the study. Patient-days (1,028 in total) were stratified into four groups: DEX only (n = 222), DEX + PROP (n = 148), PROP only (n = 599), and NEITHER (n = 59). Regression analyses indicated a significant difference in target RASS between sedative agents (p = 0.001). The DEX-only group had the highest adjusted mean daily estimate of 16.0 hours in target RASS. Hypotension was significantly higher in both the DEX only (p = 0.01) and DEX + PROP (p = 0.01) groups than in the PROP only group. CONCLUSIONS: Dexmedetomidine was found to be associated with significantly more hypotension. Therefore, larger studies are needed to identify the role of DEX in TBI. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 27116414 TI - Usability and Acceptability of a Web-Based Program for Chemotherapy-Induced Peripheral Neuropathy. AB - Chemotherapy-induced neuropathy is a painful and debilitating adverse effect of certain chemotherapy drugs. There have not been any patient-centered, easily accessible Web-based interventions to assist with self-management of chemotherapy induced neuropathy. The aims of this study were to evaluate usability and acceptability and to estimate an effect size of a Web-based intervention for assessing and managing chemotherapy-induced neuropathy. Participants (N = 14) were instructed to complete the Creativity, Optimism, Planning, and Expert Information for Chemotherapy-Induced Peripheral Neuropathy program and provide verbal responses to the program. Participants completed the Chemotherapy Induced Peripheral Neuropathy Assessment Tool and Post-Study System Usability Questionnaire. Iterative changes were made to the COPE-CIPN. Participants were asked to provide feedback on the revised COPE-CIPN, repeat the Chemotherapy Induced Peripheral Neuropathy Assessment Tool, and evaluate acceptability using the Acceptability e-Scale. The COPE-CIPN demonstrated high usability (mean, 1.98 [SD, 1.12]) and acceptability (mean, 4.40 [SD, 0.52]). Comments indicated that the interface was easy to use, and the information was helpful. While neuropathy symptoms continued to increase in this group of patients receiving neurotoxic chemotherapy, there was a decrease in mean level of interference with activities from 53.71 to 39.29 over 3 to 4 months, which indicated a moderate effect (d = 0.39) size. The COPE-CIPN may be a useful intervention to support self-management of chemotherapy-induced neuropathy. PMID- 27116415 TI - Teens' Reactance to Anti-Smoking Public Service Announcements: How Norms Set the Stage. AB - Data from a study of the effects of anti-smoking ads were analyzed. This study measured the accessibility of peer and parent norms for smoking, exposed teens to three anti-smoking ads that either emphasized personal narratives of the dangers of smoking or had a surprise ending, and measured reactance to the messages. Readiness to smoke was assessed via a phone survey 3 months later. The accessibility of pro-smoking peer norms increased readiness to engage in smoking behavior through reactance toward anti-smoking messages. The accessibility of parent norms was unrelated to reactance. Reactance was particularly strong when the ads included a surprise ending. Peer norms that oppose smoking, particularly if they can be brought to mind quickly, are an important protective factor in that they may reduce reactance to anti-smoking messages. PMID- 27116417 TI - Improving interprofessional collaboration: The effect of training in nonviolent communication. AB - This article examines the effects of nonviolent communication (NVC) training on the interprofessional collaboration (IPC) of two health and social services sector care teams. The study was conducted in 2013 with two interprofessional teams (N = 9) using a mixed method research design to measure the effects of the training. Individual IPC competency was measured using the Team Observed Structured Clinical Encounter tool, and group competency using the Observed Interprofessional Collaboration tool. A focus group was held to collect participant perceptions of what they learned in the training. Results revealed improvements in individual competency in client/family-centered collaboration and role clarification. Improvements in group competency were also found with respect to teams' ability to develop a shared plan of action. Data suggests that participants accepted and adopted training content. After the training, they appeared better able to identify the effects of spontaneous communication, more understanding of the mechanisms of empathy, and in a better position to foster collective leadership. PMID- 27116418 TI - Development and validation of an automated liquid-liquid extraction GC/MS method for the determination of THC, 11-OH-THC, and free THC-carboxylic acid (THC-COOH) from blood serum. AB - The analysis of Delta(9)-tetrahydrocannabinol (THC) and its metabolites 11 hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Delta(9) tetrahydrocannabinol (THC-COOH) from blood serum is a routine task in forensic toxicology laboratories. For examination of consumption habits, the concentration of the phase I metabolite THC-COOH is used. Recommendations for interpretation of analysis values in medical-psychological assessments (regranting of driver's licenses, Germany) include threshold values for the free, unconjugated THC-COOH. Using a fully automated two-step liquid-liquid extraction, THC, 11-OH-THC, and free, unconjugated THC-COOH were extracted from blood serum, silylated with N methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA), and analyzed by GC/MS. The automation was carried out by an x-y-z sample robot equipped with modules for shaking, centrifugation, and solvent evaporation. This method was based on a previously developed manual sample preparation method. Validation guidelines of the Society of Toxicological and Forensic Chemistry (GTFCh) were fulfilled for both methods, at which the focus of this article is the automated one. Limits of detection and quantification for THC were 0.3 and 0.6 MUg/L, for 11-OH-THC were 0.1 and 0.8 MUg/L, and for THC-COOH were 0.3 and 1.1 MUg/L, when extracting only 0.5 mL of blood serum. Therefore, the required limit of quantification for THC of 1 MUg/L in driving under the influence of cannabis cases in Germany (and other countries) can be reached and the method can be employed in that context. Real and external control samples were analyzed, and a round robin test was passed successfully. To date, the method is employed in the Institute of Legal Medicine in Giessen, Germany, in daily routine. Automation helps in avoiding errors during sample preparation and reduces the workload of the laboratory personnel. Due to its flexibility, the analysis system can be employed for other liquid-liquid extractions as well. To the best of our knowledge, this is the first publication on a comprehensively automated classical liquid-liquid extraction workflow in the field of forensic toxicological analysis. Graphical abstract GC/MS with MPS Dual Head at the Institute of Legal Medicine, Giessen, Germany. Modules from left to right: (quick) Mix (for LLE), wash station, tray 1 (vials for extracts), solvent reservoir, (m) VAP (for extract evaporation), Solvent Filling Station (solvent supply), cooled tray 2 (vials for serum samples), and centrifuge (for phase separation). PMID- 27116419 TI - Application of a NMR-based untargeted quantitative metabonomic approach to screen for illicit salbutamol administration in cattle. AB - The use of metabonomic methodologies to identify illicit salbutamol administration in cattle has not been previously investigated. In this study, a nuclear magnetic resonance (NMR)-based untargeted quantitative metabonomic approach was applied to discriminate biofluid samples (plasma and urine) obtained from cattle before and after salbutamol treatment. Six male cattle (265.7 +/- 3.9 kg) were fed salbutamol (0.15 mg/kg body weight) for 21 consecutive days. Plasma and urine samples were collected before and after treatment. By the use of targeted profiling, 46 and 43 metabolites in plasma and urine, respectively, were quantified, of which 9 and 11 metabolites were significantly affected (P < 0.05) by salbutamol treatment. Partial least squares discriminant analysis showed that both plasma and urine samples collected after treatment were well separated from those before treatment, with Q (2) values of 0.56 and 0.573 for plasma and urine samples, respectively. The variable importance plot (VIP) scores of glucose and lactate in plasma, and urine, hippurate, acetate, glycine, formate, n phenylacetyl, benzoate, and phenylacetate in urine were >1.0, which implies that these metabolites may serve as potential biomarkers for salbutamol treatment. These findings suggest the potential value of NMR-based untargeted quantitative metabonomic methodologies for plasma and urine analyses as a screening technique for detection of illicit salbutamol usage in cattle. PMID- 27116420 TI - Erratum to: LC-MS/MS determination of potential endocrine disruptors of cortico signalling in rivers and wastewaters. PMID- 27116421 TI - Mitigation of microtiter plate positioning effects using a block randomization scheme. AB - Microtiter plate-based assays are a common tool in biochemical and analytical labs. Despite widespread use, results generated in microtiter plate-based assays are often impacted by positional bias, in which variability in raw signal measurements are not uniform in all regions of the plate. Since small positional effects can disproportionately affect assay results and the reliability of the data, an effective mitigation strategy is critical. Commonly used mitigation strategies include avoiding the use of outer regions of the plate, replicating treatments within and between plates, and randomizing placement of treatments within and between plates. These strategies often introduce complexity while only partially mitigating positional effects and significantly reducing assay throughput. To reduce positional bias more effectively, we developed a novel block-randomized plate layout. Unlike a completely randomized layout, the block randomization scheme coordinates placement of specific curve regions into pre defined blocks on the plate based on key experimental findings and assumptions about the distribution of assay bias and variability. Using the block-randomized plate layout, we demonstrated a mean bias reduction of relative potency estimates from 6.3 to 1.1 % in a sandwich enzyme-linked immunosorbent assay (ELISA) used for vaccine release. In addition, imprecision in relative potency estimates decreased from 10.2 to 4.5 % CV. Using simulations, we also demonstrated the impact of assay bias on measurement confidence and its relation to replication strategies. We outlined the underlying concepts of the block randomization scheme to potentially apply to other microtiter-based assays. PMID- 27116422 TI - Cytogenetic Behavior of Trigeneric Hybrid Progeny Involving Wheat, Rye and Psathyrostachys huashanica. AB - Trigeneric hybrids are commonly used as bridges to transfer genes from some wild species to cultivated wheat and to measure the genomic interaction between donor species. We previously reported that trigeneric germplasms were produced by crossing wheat-Psathyrostachys huashanica amphiploids (PHW-SA, 2n = 8x = 56, AABBDDNsNs) with hexaploid triticale (Zhongsi 828, 2n = 6x = 42, AABBRR). In the present study, chromosome pairing behavior and the genome constitution of the F4 progenies of wheat-rye-P. huashanica trigeneric hybrids were studied. Cytological analysis showed that the chromosome number of F4 progenies ranged from 39 to 46, and 57.5% of them had 42 chromosomes. The mean meiotic configuration of F4 lines was 1.71 univalents, 20.26 bivalents, 0.04 trivalents, and 0.001 quadrivalents per pollen mother cell. Among the lines with 2n = 42, the average pairing configuration was 1.21 univalents, 16.22 ring bivalents, 4.16 rod bivalents, and 0.01 trivalents. This result indicated that these lines were cytologically stable. Other lines with 2n = 39, 40, 41, 43, 44, 45, and 46, bearing a high number of univalents or multivalents, showed abnormal meiotic behavior. Genomic in situ hybridization (GISH) revealed that all F4 lines had 11-14 rye chromosomes, but no P. huashanica chromosomes. The complete set of 14 rye chromosomes was found in 19 lines. At meiosis, GISH detected 1-6 univalents with hybridization signals of rye in 13 lines. Bivalents with fluorescence signals were identified in each line, ranging from 3 to 7. A quadrivalent with hybridization signals was observed in only 1 line, K13-714-8. Lagging chromosomes, chromosome bridges, micronuclei, and chromosome fragments hybridizing with the probe were not discovered in any of the lines. These results inferred that the behavior of rye chromosomes was normal during meiosis. In addition, 21 lines of 2n = 42 (91.3%) with 12 or 14 rye chromosomes, always contained 6 or 7 bivalents bearing fluorescence signals. This suggested that the rye chromosomes exhibiting complete pairing in these lines were cytologically stable during meiosis and may therefore be considered as new hexaploid triticales. Thus, these lines might be potential materials for further hexaploid triticale improvement. PMID- 27116424 TI - Solid-State Redox Switching of Magnetic Exchange and Electronic Conductivity in a Benzoquinoid-Bridged Mn(II) Chain Compound. AB - We demonstrate that incorporation of a redox-active benzoquinoid ligand into a one-dimensional chain compound can give rise to a material that exhibits simultaneous solid-state redox switching of optical, magnetic, and electronic properties. Metalation of the ligand 4,5-bis(pyridine-2-carboxamido)-1,2-catechol ((N,O)LH4) with Mn(III) affords the chain compound Mn((N,O)L)(DMSO). Structural and spectroscopic analysis of this compound show the presence of Mn(II) centers bridged by (N,O)L(2-) ligands, resulting partially from a spontaneous ligand-to metal electron transfer. Upon soaking in a solution of the reductant Cp2Co, Mn((N,O)L)(DMSO) undergoes a ligand-centered solid-state reduction to [Mn((N,O)L)](-), as revealed by a suite of techniques, including Raman and X-ray absorption spectroscopy. The ligand-based reduction engenders a dramatic modulation of the physical properties of the chain compound. An electrochromic response, evidenced by a color change from dark green to dark purple is accompanied by a nearly 40-fold increase in magnetic coupling strength, from J = 0.38(1) to -15.6(2) cm(-1), and a 10,000-fold increase in electronic conductivity, from sigma = 2.33(1) * 10(-12) S/cm (Ea = 0.64(1) eV) to 8.61(1) * 10(-8) S/cm (Ea = 0.39(1) eV). Importantly, the chemical reduction is reversible: treatment of the reduced compound with [Cp2Fe](+) regenerates the oxidized chain. Taken together, these results highlight the ability of benzoquinoid ligands to facilitate solid-state ligand-based redox reactions in nonporous coordination solids, giving rise to reversible switching of optical properties, magnetic exchange interactions, and electronic conductivity. PMID- 27116423 TI - Guidelines for the Management of Wet Age-Related Macular Degeneration: Recommendations from a Panel of Greek Experts. AB - PURPOSE: To propose guidelines for the management of patients with wet age related macular degeneration (wAMD), taking into account the results of large multicenter studies and clinical experience of retina experts. METHOD: A team of retina experts developed a consensus paper after three consecutive meetings. The group was focused on guidelines to help clinical decision-making around the definition of successful treatment and the definition of non-response to therapy. RESULTS: Parameters suggestive of a successful response to treatments included: any gain in best corrected visual acuity (BCVA) or vision loss that is less than 5-10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, reduction of central retinal thickness, partial or complete absorption of subretinal fluid (SRF), reduction of intraretinal fluid, reduction of pigment epithelial detachment or restoration of the anatomy of outer retinal layers. Non-response to current treatment was considered in the case of loss of BCVA greater than 10 ETDRS letters, increased retinal edema or increase of SRF as evidenced by optical coherence tomography or new bleeding in biomicroscopy. CONCLUSION: The introduction of anti-VEGF agents revolutionized the treatment of wAMD. Given the complexity of the disease, the emerging new agents and the difference of cases recruited in clinical trials compared to those appearing in every-day practice, it is essential to individualize treatment options taking into account the results of clinical trials. PMID- 27116426 TI - Curtius-like Rearrangement of an Iron-Nitrenoid Complex and Application in Biomimetic Synthesis of Bisindolylmethanes. AB - A Curtius-like rearrangement of hydroxamates to isocyanates was discovered. This reaction was initiated from an iron(II)-nitrenoid complex, which was generated by the iron(II)-catalyzed cleavage of N-O bonds of functionalized hydroxamates. To demonstrate the efficiency of this new Curtius-like rearrangement in synthetic chemistry, a biomimetic strategy for the one-pot preparation of bisindolylmethanes was developed. PMID- 27116425 TI - Sulfation of Lower Chlorinated Polychlorinated Biphenyls Increases Their Affinity for the Major Drug-Binding Sites of Human Serum Albumin. AB - The disposition of toxicants is often affected by their binding to serum proteins, of which the most abundant in humans is serum albumin (HSA). There is increasing interest in the toxicities of environmentally persistent polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms (LC-PCBs) due to their presence in both indoor and outdoor air. PCB sulfates derived from metabolic hydroxylation and sulfation of LC-PCBs have been implicated in endocrine disruption due to high affinity-binding to the thyroxine-carrying protein, transthyretin. Interactions of these sulfated metabolites of LC-PCBs with HSA, however, have not been previously explored. We have now determined the relative HSA-binding affinities for a group of LC-PCBs and their hydroxylated and sulfated derivatives by selective displacement of the fluorescent probes 5 dimethylamino-1-naphthalenesulfonamide and dansyl-l-proline from the two major drug-binding sites on HSA (previously designated as Site I and Site II). Values for half-maximal displacement of the probes indicated that the relative binding affinities were generally PCB sulfate >= OH-PCB > PCB, although this affinity was site- and congener-selective. Moreover, specificity for Site II increased as the numbers of chlorine atoms increased. Thus, hydroxylation and sulfation of LC-PCBs result in selective interactions with HSA which may affect their overall retention and toxicity. PMID- 27116427 TI - Exchange-Correlation Functionals via Local Interpolation along the Adiabatic Connection. AB - The construction of density-functional approximations is explored by modeling the adiabatic connection locally, using energy densities defined in terms of the electrostatic potential of the exchange-correlation hole. These local models are more amenable to the construction of size-consistent approximations than their global counterparts. In this work we use accurate input local ingredients to assess the accuracy of a range of local interpolation models against accurate exchange-correlation energy densities. The importance of the strictly correlated electrons (SCE) functional describing the strong coupling limit is emphasized, enabling the corresponding interpolated functionals to treat strong correlation effects. In addition to exploring the performance of such models numerically for the helium and beryllium isoelectronic series and the dissociation of the hydrogen molecule, an approximate analytic model is presented for the initial slope of the local adiabatic connection. Comparisons are made with approaches based on global models, and prospects for future approximations based on the local adiabatic connection are discussed. PMID- 27116428 TI - The role of nitric oxide signalling in response to salt stress in Chlamydomonas reinhardtii. AB - MAIN CONCLUSION: Nitric oxide signal and GSNOR activity play an essential role for Chlamydomonas reinhardtii response to salt stress. The unicellular alga Chlamydomonas reinhardtii is one of the most important model organisms phylogenetically situated between higher plants and animals. In the present study, we used comparative proteomics and physiological approaches to study the mechanisms underlying the response to salt stress in C. reinhardtii. We identified 74 proteins that accumulated differentially after salt stress, including oxidative enzymes and enzymes associated with nitric oxide (NO) metabolism, cell damage, and cell autophagy processes. A set of antioxidant enzymes, as well as S-nitrosoglutathione reductase (GSNOR) activity, were induced to balance the cellular redox status during short-term salt stress. Enzymes involved in DNA repair and cell autophagy also contribute to adaptation to short term salt stress. However, under long-term salt stress, antioxidant enzymes and GSNOR were gradually inactivated through protein S-nitrosylation, leading to oxidative damage and a reduction in cell viability. Modulating the protein S nitrosylation levels by suppressing GSNOR activity or adding thioredoxin affected the plant's adaptation to salt stress, through altering the redox status and DNA damage and autophagy levels. Based on these data, we propose that unicellular algae use multiple strategies to adapt to salt stress, and that, during this process, GSNOR activity and protein S-nitrosylation levels play important roles. PMID- 27116429 TI - Heat-induced accumulation of protein synthesis elongation factor 1A implies an important role in heat tolerance in potato. AB - MAIN CONCLUSION: Potato eukaryotic elongation factor 1A comprises multiple isoforms, some of which are heat-inducible or heat-upregulated and might be important in alleviating adverse effects of heat stress on plant productivity. Heat stress substantially reduces crop productivity worldwide, and will become more severe due to global warming. Identification of proteins involved in heat stress response may help develop varieties for heat tolerance. Eukaryotic elongation factor 1A (eEF1A) is a cytosolic, multifunctional protein that plays a central role in the elongation phase of translation. Some of the non-canonical eEF1A activities might be important in developing plant heat-stress tolerance. In this study, we investigated effects of heat stress (HS) on eEF1A expression at the protein level in potato, a highly heat vulnerable crop. Our results from both the controlled environment and the field have shown that potato eEF1A is a heat inducible protein of 49.2-kDa with multiple isoforms (5-8). Increase in eEF1A abundance under HS can be mainly attributed to 2-3 basic polypeptides/isoforms. A significant correlation between eEF1A abundance and the potato productivity in the field was observed in two extremely hot years 2011 and 2012. Genomic Southern blot analysis indicated the existence of multiple genes encoding eEF1A in potato. Identification, isolation and utilization of heat-inducible eEF1A genes might be helpful for the development of the heat-tolerant varieties. PMID- 27116430 TI - Determination of Glutathione, Selenium, and Malondialdehyde in Different Edible Mushroom Species. AB - In this study, the amount of reduced glutathione (GSH), oxidized glutathione (GSSG), and malondialdehyde (MDA) were determined by high performance liquid chromatography (HPLC), and selenium was determined by using the fluorescence spectrophotometer in eight different species of edible mushrooms. Brittlegill mushroom (Russula delica), meadow mushroom (Agaricus campestris), dryad's saddle mushroom (Polyporus squamosus), white button mushroom (Agaricus bisporus), Pleurotus spp., ink mushroom (Coprinus atramentarius), ebekari mushroom (slimy) (Elazig local) and casir mushroom (Pleurotus eryngii) (Tunceli local) were used for analysis. The amounts of GSH, GSSG, Se, and MDA with GSH/GSSG ratio in the eight different species of edible mushrooms were observed in between 269.10 +/- 16.94-1554.83 +/- 58.12 MUg/g; 23.55 +/- 1.89-841.90 +/- 20.03 MUg/g; 15.06 +/- 1.56-82.10 +/- 3.84 MUg/g; 5.46 +/- 0.50-27.45 +/- 2.58 MUg/g wet weight and 0.32 41.35, respectively. There is a weak correlation (R 2 = 0.389) between MDA and Se, on the other hand, the correlation (R 2 = 0.831) between GSH/GSSG ratio and selenium in mushrooms are reasonable well. In a similar manner, there is a weak correlation (R 2 = 0551) between GSH/GSSG and MDA ratios in mushrooms. It was found that these edible mushroom species are good source of glutathione (GSH, GSSG), and selenium (Se) in terms of quantities obtained; therefore, it can be said that mushrooms are a rich source of antioxidants. PMID- 27116431 TI - Cognitive flexibility and changes in hopelessness across time: A moderation hypothesis. AB - Prior literature has suggested that cognitive flexibility is implicated in the feeling of hopelessness. However, studies on the nature of their relationship have been scarce. This study posits a moderation hypothesis on the relationship between cognitive flexibility and hopelessness. A total of 78 elderly participants (Mage = 70, SD = 6.1) were administered a self-report measure of hopelessness across two time points approximately 10 months apart and a measure of cognitive flexibility. We hypothesized that baseline hopelessness scores would moderate the relationship between cognitive flexibility and hopelessness scores 10 months later. Specifically, among the high baseline hopelessness group, we predicted that cognitively flexible participants would report lower hopelessness scores 10 months later. However, for the low baseline hopelessness group, cognitive flexibility would be unrelated to hopelessness scores 10 months later. The results of a bootstrapped moderation analysis controlling for age, sex, education, and general cognitive status supported our moderation hypothesis and predictions. These findings reveal the complex nature of the relationship between cognitive flexibility and hopelessness. The implications of these findings in the wider clinical context were discussed. PMID- 27116432 TI - Clinical Implications of Cancer Genomics: A Call for Papers. AB - In this month's editorial, the PLOS Medicine Editors announce an upcoming Special Issue, with Guest Editors Elaine Mardis and Marc Ladanyi, on actionable advances in research on the cancer genome. PMID- 27116433 TI - High-Capacity Molecular Scale Conversion Anode Enabled by Hybridizing Cluster Type Framework of High Loading with Amino-Functionalized Graphene. AB - Exploring high-capacity anodes with multielectron reaction, sufficient charge/mass transfer, and suppressed volume expansion is highly desired. The open frameworks consisting of independent structure units, which possess conversion reaction potentiality, can meet these demands and show advantages over routine insertion-type open frameworks with at most one-electron transfer or conversion materials with compact ligand linkage. Here, we report a class of electrochemically stable cluster-like polyoxometalates (POMs) as such open framework anodes. Their high loading and low solubility are enabled by Al- or Si driven polymerization and hybridization with positively charged graphene, which immobilizes polyanions of POMs and improves their electric contact. Al-based POM composite (NAM-EDAG) for Li-storage achieves a high reversible capacity above 1000 mAh g(-1) and tolerates a long-term cycling with more than 1100 cycles and a current density up to 20 A g(-1). A six-electron conversion reaction occurring at molecular scale and the consequent optimized distribution of products benefiting from original open framework are also responsible for the high electroactivity. POM-based open frameworks give inspiration for exploring advanced, less soluble (or insoluble) framework materials made up of electroactive molecule or cluster moieties for Li- and Na-storage. PMID- 27116434 TI - [Adverse reactions to metal orthopedic implants after knee arthroplasty]. AB - Based on several clinical examples, the range of adverse or hypersensitive reactions to metal implants especially after total knee replacement are presented. In general, we found the patients to generally be women who present with pain, swelling, and local or generalized eczema. Some also present with early aseptic loosening mainly in the first 4 years after implantation. For these patients, a detailed allergy-specific history should be taken and a patch test should be performed; if necessary, blood ion levels should be evaluated to exclude cobaltism. Before revision surgery and exchange of the implant we always perform arthroscopic inspection to obtain biopsies for microbiology and histopathology. Using the Consensus Classification a good evaluation for planning revision with the different implant options is possible. PMID- 27116454 TI - Correction: Centering the Organizing Center in the Arabidopsis thaliana Shoot Apical Meristem by a Combination of Cytokinin Signaling and Self-Organization. AB - [This corrects the article DOI: 10.1371/journal.pone.0147830.]. PMID- 27116455 TI - Is There Any Evidence for Rapid, Genetically-Based, Climatic Niche Expansion in the Invasive Common Ragweed? AB - Climatic niche shifts have been documented in a number of invasive species by comparing the native and adventive climatic ranges in which they occur. However, these shifts likely represent changes in the realized climatic niches of invasive species, and may not necessarily be driven by genetic changes in climatic affinities. Until now the role of rapid niche evolution in the spread of invasive species remains a challenging issue with conflicting results. Here, we document a likely genetically-based climatic niche expansion of an annual plant invader, the common ragweed (Ambrosia artemisiifolia L.), a highly allergenic invasive species causing substantial public health issues. To do so, we looked for recent evolutionary change at the upward migration front of its adventive range in the French Alps. Based on species climatic niche models estimated at both global and regional scales we stratified our sampling design to adequately capture the species niche, and localized populations suspected of niche expansion. Using a combination of species niche modeling, landscape genetics models and common garden measurements, we then related the species genetic structure and its phenotypic architecture across the climatic niche. Our results strongly suggest that the common ragweed is rapidly adapting to local climatic conditions at its invasion front and that it currently expands its niche toward colder and formerly unsuitable climates in the French Alps (i.e. in sites where niche models would not predict its occurrence). Such results, showing that species climatic niches can evolve on very short time scales, have important implications for predictive models of biological invasions that do not account for evolutionary processes. PMID- 27116456 TI - Human Leukocyte Antigen and Systemic Sclerosis in Japanese: The Sign of the Four Independent Protective Alleles, DRB1*13:02, DRB1*14:06, DQB1*03:01, and DPB1*02:01. AB - OBJECTIVE: Several studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic sclerosis (SSc) have been reported. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are found in SSc patients. Here, we sought to identify HLA alleles associated with SSc in Japanese, and explored their associations with SSc phenotypes including the presence of autoantibodies. METHODS: Associations of HLA DRB1, DQB1, and DPB1 were analyzed in 463 Japanese SSc patients and 413 controls. RESULTS: We found that DRB1*13:02 (P = 0.0011, Pc = 0.0319, odds ratio [OR] 0.46, 95% confidence interval [CI] 0.29-0.73), DRB1*14:06 (P = 6.60X10-5, Pc = 0.0020, OR 0.05, 95%CI 0.01-0.41), DQB1*03:01 (P = 0.0009, Pc = 0.0150, OR 0.56, 95%CI 0.40-0.79), and DPB1*02:01 (P = 5.16X10-6, Pc = 8.77X10-5, OR 0.52, 95%CI 0.39 0.69) were protectively associated with SSc. In addition, these four alleles seemed to be independently associated with the protection against the susceptibility of SSc. On the other hand, we could not find predisposing alleles for overall SSc. With respect to SSc subsets, a tendency for these four alleles to be protectively associated was observed. However, there was a significant association between DRB1*01:01, DRB1*10:01, DQB1*05:01, and DPB1*04:02 and the susceptibility to SSc with ACA. On the other hand, the presence of DRB1*15:02, DQB1*06:01, DPB1*03:01, and DPB1*09:01 was associated with SSc with ATA. CONCLUSION: Thus, the present study has identified protective associations of the four HLA class II alleles with overall Japanese SSc and predisposing associations of HLA class II alleles with Japanese SSc subsets. PMID- 27116457 TI - Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients. AB - BACKGROUND AND OBJECTIVES: Nuclear receptors PXR (pregnane X receptor, NR1I2) and CAR (constitutive androstane receptor, NR1I3) are key regulators of irinotecan metabolism, and ligand-dependent modulation of their activity leads to significant drug-drug interactions. Because genetic polymorphisms can also affect the activity of these xenobiotic-sensing receptors, we hypothesized that they could contribute to the interpatient variability of irinotecan pharmacokinetics and to the toxicity of irinotecan-based regimens. PATIENTS AND METHODS: In a cohort of 109 metastatic colorectal cancer patients treated with irinotecan (180 mg/m(2)) in combination with other drugs, associations were assessed between 21 selected single nucleotide polymorphisms of NR1I2 or NR1I3 and pharmacokinetic parameters or toxicity of irinotecan and its metabolites. RESULTS: After adjustment of the tests by the UGT1A1*28 genotype and correction for multiple testing, the A allele of NR1I2-rs10934498 was associated with a decreased exposition and an increased degradation of SN-38, the active metabolite (p = 0.009 and p = 0.017, respectively). The risk of hematological toxicity was associated with NR1I2-rs10934498 and NR1I2-rs2472677 (p = 0.009 and p = 0.003, respectively). CONCLUSION: Our results reveal for the first time the involvement of NR1I2 in the pharmacogenetics of irinotecan and suggest that it may help to predict the toxicity of low-dose irinotecan. PMID- 27116458 TI - Population-Based Incidence Rates of Diarrheal Disease Associated with Norovirus, Sapovirus, and Astrovirus in Kenya. AB - BACKGROUND: Diarrheal diseases remain a major cause of mortality in Africa and worldwide. While the burden of rotavirus is well described, population-based rates of disease caused by norovirus, sapovirus, and astrovirus are lacking, particularly in developing countries. METHODS: Data on diarrhea cases were collected through a population-based surveillance platform including healthcare encounters and household visits in Kenya. We analyzed data from June 2007 to October 2008 in Lwak, a rural site in western Kenya, and from October 2006 to February 2009 in Kibera, an urban slum. Stool specimens from diarrhea cases of all ages who visited study clinics were tested for norovirus, sapovirus, and astrovirus by RT-PCR. RESULTS: Of 334 stool specimens from Lwak and 524 from Kibera, 85 (25%) and 159 (30%) were positive for norovirus, 13 (4%) and 31 (6%) for sapovirus, and 28 (8%) and 18 (3%) for astrovirus, respectively. Among norovirus-positive specimens, genogroup II predominated in both sites, detected in 74 (87%) in Lwak and 140 (88%) in Kibera. The adjusted community incidence per 100,000 person-years was the highest for norovirus (Lwak: 9,635; Kibera: 4,116), followed by astrovirus (Lwak: 3,051; Kibera: 440) and sapovirus (Lwak: 1,445; Kibera: 879). For all viruses, the adjusted incidence was higher among children aged <5 years (norovirus: 22,225 in Lwak and 17,511 in Kibera; sapovirus: 5,556 in Lwak and 4,378 in Kibera; astrovirus: 11,113 in Lwak and 2,814 in Kibera) compared to cases aged >=5 years. CONCLUSION: Although limited by a lack of controls, this is the first study to estimate the outpatient and community incidence rates of norovirus, sapovirus, and astrovirus across the age spectrum in Kenya, suggesting a substantial disease burden imposed by these viruses. By applying adjusted rates, we estimate approximately 2.8-3.3 million, 0.45-0.54 million, and 0.77-0.95 million people become ill with norovirus, sapovirus, and astrovirus, respectively, every year in Kenya. PMID- 27116459 TI - Metabolomics Revealed an Association of Metabolite Changes and Defective Growth in Methylobacterium extorquens AM1 Overexpressing ecm during Growth on Methanol. AB - Methylobacterium extorquens AM1 is a facultative methylotroph capable of growth on both single-carbon and multi-carbon compounds. The ethylmalonyl-CoA (EMC) pathway is one of the central assimilatory pathways in M. extorquens during growth on C1 and C2 substrates. Previous studies had shown that ethylmalonyl-CoA mutase functioned as a control point during the transition from growth on succinate to growth on ethylamine. In this study we overexpressed ecm, phaA, mcmAB and found that upregulating ecm by expressing it from the strong constitutive mxaF promoter caused a 27% decrease in growth rate on methanol compared to the strain with an empty vector. Targeted metabolomics demonstrated that most of the central intermediates in the ecm over-expressing strain did not change significantly compared to the control strain; However, poly-beta hydroxybutyrate (PHB) was 4.5-fold lower and 3-hydroxybutyryl-CoA was 1.6-fold higher. Moreover, glyoxylate, a toxic and highly regulated essential intermediate, was determined to be 2.6-fold higher when ecm was overexpressed. These results demonstrated that overexpressing ecm can manipulate carbon flux through the EMC pathway and divert it from the carbon and energy storage product PHB, leading to an accumulation of glyoxylate. Furthermore, untargeted metabolomics discovered two unusual metabolites, alanine (Ala)-meso diaminopimelic acid (mDAP) and Ala-mDAP-Ala, each over 45-fold higher in the ecm over-expressing strain. These two peptides were also found to be highly produced in a dose-dependent manner when glyoxylate was added to the control strain. Overall, this work has explained a direct association of ecm overexpression with glyoxylate accumulation up to a toxic level, which inhibits cell growth on methanol. This research provides useful insight for manipulating the EMC pathway for efficiently producing high-value chemicals in M. extorquens. PMID- 27116461 TI - A Novel Drug Delivery System for the Human Nasal Epithelium. AB - The epithelium of upper respiratory tissues such as the human nasal mucosa forms a continuous barrier via tight junctions (TJs). The development of a drug delivery system for use across the nasal mucosa is being reconsidered. In intranasal administration across the nasal mucosa, the paracellular pathway regulated by TJs is extremely important. It is known that the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds the TJ protein claudin and disrupts the tight junctional barrier without inducing a cytotoxic effect. We investigated the effects of C-CPE mutants on the function of TJs of human nasal epithelial cells (HNECs) and on the permeability of human recombinant insulin across HNECs treated with C-CPE 194 and C-CPE m19. We recently reported that C CPE mutants 194 and m19 can regulate the permeability of insulin across HNECs via the MAPK pathway and may play a crucial role in therapy for various diseases via direct intranasal insulin administration. On the other hand, microRNAs (miRNAs) are known to regulate the expression of TJs as direct or indirect targets in genes to maintain barrier function. We investigated the effects of miRNAs on the epithelial barrier of HNECs and found that miRNA-146a plays crucial roles in the maintenance of the TJ barrier and innate immune response against invading pathogens. This chapter reviews a novel drug delivery system across the nasal mucosa from the point of view of the epithelial barrier function. PMID- 27116460 TI - Synonymous mutation gene design to overexpress ACCase in creeping bentgrass to obtain resistance to ACCase-inhibiting herbicides. AB - Overexpression of a native gene can cause expression of both introduced and native genes to be silenced by posttranscriptional gene silencing (PTGS) mechanisms. PTGS mechanisms rely on sequence identity between the transgene and native genes; therefore, designing genes with mutations that do not cause amino acid changes, known as synonymous mutations, may avoid PTGS. For proof of concept, the sequence of acetyl-coA carboxylase (ACCase) from creeping bentgrass (Agrostis stolonifera L.) was altered with synonymous mutations. A native bentgrass ACCase was cloned and used as a template for the modified gene. Wild type (WT) and modified genes were further modified with a non-synonymous mutation, coding for an isoleucine to leucine substitution at position 1781, known to confer resistance to ACCase-inhibiting herbicides. Five-hundred calli of creeping bentgrass 'Penn A-4' were inoculated with Agrobacterium containing either the WT or modified genes, with or without the herbicide-resistance mutation. Six herbicide-resistant-transgenic events containing the modified gene with the 1781 mutation were obtained. Transcription of the modified ACCase was confirmed in transgenic plants, showing that gene-silencing mechanisms were avoided. Transgenic plants were confirmed to be resistant to the ACCase inhibiting herbicide, sethoxydim, providing evidence that the modified gene was functional. The result is a novel herbicide-resistance trait and shows that overexpression of a native enzyme with a gene designed with synonymous mutations is possible. PMID- 27116462 TI - Efficacy of vaginally applied estrogen, testosterone, or polyacrylic acid on vaginal atrophy: a randomized controlled trial. AB - OBJECTIVE: Vaginal atrophy is a common chronic condition among postmenopausal women that can affect their quality of life. Recent studies have evaluated new treatment alternatives for vaginal atrophy; however, few therapeutic options have been thoroughly evaluated. This study aimed to compare the effectiveness and adverse effects of estrogen, testosterone, polyacrylic acid, and placebo lubricant for the treatment of postmenopausal women with vaginal atrophy. METHODS: We conducted a randomized clinical trial with 80 postmenopausal women aged between 40 and 70 years who were being followed up at the Menopause Clinic of CAISM UNICAMP between November 2011 and January 2013. Women were randomly assigned to topical vaginal treatment with estrogen, testosterone, polyacrylic acid, and placebo lubricant, three times a week for 12 weeks. We used the vaginal maturation index, pH, vaginal health score, vaginal flora, laboratory tests, and ultrasound to evaluate changes of vaginal atrophy at baseline and after 6 and 12 weeks of treatment. RESULTS: After a 12-week treatment with topical estrogen and testosterone compared with the lubricant, an increased percentage of participants had vaginal pH less than 5, increased vaginal score, and an increase in the number of lactobacilli. Treatment with topical estrogen improved the vaginal maturation index and showed increased levels of estradiol in three women. No changes were observed in the endometrial evaluation of all treatment groups. CONCLUSIONS: After a 12-week treatment with testosterone and estrogen compared with placebo lubrication, there was a significant improvement in vaginal trophism in postmenopausal women with vaginal atrophy. PMID- 27116463 TI - Oral versus transdermal estrogens and venous thromboembolism in postmenopausal women: what is new since 2003? PMID- 27116464 TI - Efficacy and tolerability of bazedoxifene in Mexican women with osteoporosis: a subgroup analysis of a randomized phase 3 trial. AB - OBJECTIVE: Bazedoxifene (BZA) is a selective estrogen receptor modulator that reduces fracture risk and bone turnover in postmenopausal women with osteoporosis. This analysis evaluated BZA's effects on bone mineral density (BMD) and bone turnover in Mexican women with osteoporosis from the global pivotal trial (Study Evaluating Bazedoxifene Acetate in Osteoporosis in Postmenopausal Women). METHODS: In this 3-year, phase 3, randomized, double-blind trial, healthy postmenopausal women with osteoporosis (N = 7,492) received BZA 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The subanalyses of Mexican women assessed serum concentrations of osteocalcin and collagen type 1 C-telopeptide, BMD, and tolerability with BZA 20 mg/d versus placebo. RESULTS: In the Mexican subgroup (BZA, n = 39; placebo, n = 37) at month 12, BZA 20 mg/d produced significant (P < 0.001) percentage decreases from baseline in osteocalcin (-40.5 vs -18.5) and C telopeptide (-45.7 vs -29.4). For BZA versus placebo, percentage change in BMD from baseline to month 36 was 3.3 versus 0.64 for lumbar spine, -0.18 versus -1.8 for total hip, 0.21 versus -2.6 for femoral neck, and -0.55 versus -1.4 for femoral trochanter; differences were not statistically significant. Results were comparable to the overall study population in which differences were statistically significant. Common adverse events (>=20%) included arthralgia, back pain, gastritis, headache, influenza, and pain; none led to study withdrawal. CONCLUSIONS: In Mexican women with osteoporosis, BZA was well tolerated and seems to produce BMD changes comparable to the global phase 3 population, although differences versus placebo were not statistically significant in this smaller subgroup. PMID- 27116465 TI - Metabolic syndrome as a predictor of endometrial polyps in postmenopausal women. AB - OBJECTIVE: The aim of the study was to evaluate clinical predictive factors for endometrial polyps in postmenopausal women compared with postmenopausal women without polyps. METHODS: In this cross-sectional study, 132 Brazilian women with a histopathological diagnosis of endometrial polyps were compared with 264 women without endometrial alterations (control). The study group included women aged at least 45 years with amenorrhea for at least 12 months, who underwent hysteroscopic polypectomy. The control group consisted of women aged at least 45 years with amenorrhea for at least 12 months, without postmenopausal bleeding and endometrial thickness less than 5 mm by transvaginal ultrasonography. Clinical, anthropometric (body mass index and waist circumference), laboratory, and ultrasonographic data were collected to evaluate predictive factors for endometrial polyps. The Student's t test, chi test, and logistic regression (odds ratio [OR]) were used for statistical analysis. RESULTS: A higher percentage of women with polyps were obese (72%) when compared with control (39%) (P < 0.0001). Waist circumference was greater among women with polyps (P = 0.0001). The incidence of diabetes, hypertension, and dyslipidemia was higher among women with endometrial polyps (P < 0.0001). According to the diagnostic criteria of the US National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III), 48.5% of the women with polyps and 33.3% of the controls were classified as having metabolic syndrome (MetS) (P = 0.004). The risk of endometrial polyps was higher in women with body mass index at least 25 kg/m (OR = 4.66; 95% CI 2.16 10.05); glucose at least 100 mg/dL (OR = 2.83; 95% CI 1.36-5.90); dyslipidemia (OR = 7.02; 95% CI 3.70-13.32); diabetes (OR = 2.58; 95% CI 1.05-6.32); and MetS (OR = 2.76; 95% CI 1.18-6.46) when compared with control, adjusted for age, and time since menopause. CONCLUSIONS: In postmenopausal women, obesity, dyslipidemia, hyperglycemia, and the presence of MetS were predictive factors for endometrial polyps. PMID- 27116466 TI - Critical analysis of carcinogenicity study outcomes. Relationship with pharmacological properties. AB - Predicting the outcome of life-time carcinogenicity studies in rats based on chronic (6-month) toxicity studies in this species is possible in some instances. This should reduce the number of such studies and hence have a significant impact on the total number of animals used in safety assessment of new medicines. From a regulatory perspective, this should be sufficient to grant a waiver for a carcinogenicity study in those cases where there is confidence in the outcome of the prediction. Pharmacological properties are a frequent key factor for the carcinogenic mode of action of some pharmaceuticals, but data-analysis on a large dataset has never been formally conducted. We have conducted an analysis of a dataset based on the perspective of the pharmacology of 255 compounds from industrial and regulatory sources. It is proposed that a pharmacological, class specific, model may consist of an overall causal relationship between the pharmacological class and the histopathology findings in rats after 6 months treatment, leading to carcinogenicity outcome after 2 years. Knowledge of the intended drug target and pathway pharmacology should enhance the prediction of either positive or negative outcomes of rat carcinogenicity studies. The goal of this analysis is to review the pharmacological properties of compounds together with the histopathology findings from the chronic toxicity study in rodents in order to introduce an integrated approach to estimate the risk of human carcinogenicity of pharmaceuticals. This approach would allow scientists to define conditions under which 2-year rat carcinogenicity studies will or will not add value to such an assessment. We have demonstrated the possibility of a regulatory waiver for a carcinogenicity study in rats, as currently discussed in the International Council for Harmonization (ICH) - formerly known as the International Conference on Harmonization (ICH), by applying the proposed prediction approach in a number of case studies. PMID- 27116467 TI - Erratum to: A Comparative Study on the In Vitro Effects of the DNA Methyltransferase Inhibitor 5-Azacytidine (5-AzaC) in Breast/Mammary Cancer of Different Mammalian Species. PMID- 27116468 TI - Cyclic diguanylate regulation of Bacillus cereus group biofilm formation. AB - Biofilm formation can be considered a bacterial virulence mechanism. In a range of Gram-negatives, increased levels of the second messenger cyclic diguanylate (c di-GMP) promotes biofilm formation and reduces motility. Other bacterial processes known to be regulated by c-di-GMP include cell division, differentiation and virulence. Among Gram-positive bacteria, where the function of c-di-GMP signalling is less well characterized, c-di-GMP was reported to regulate swarming motility in Bacillus subtilis while having very limited or no effect on biofilm formation. In contrast, we show that in the Bacillus cereus group c-di-GMP signalling is linked to biofilm formation, and to several other phenotypes important to the lifestyle of these bacteria. The Bacillus thuringiensis 407 genome encodes eleven predicted proteins containing domains (GGDEF/EAL) related to c-di-GMP synthesis or breakdown, ten of which are conserved through the majority of clades of the B. cereus group, including Bacillus anthracis. Several of the genes were shown to affect biofilm formation, motility, enterotoxin synthesis and/or sporulation. Among these, cdgF appeared to encode a master diguanylate cyclase essential for biofilm formation in an oxygenated environment. Only two cdg genes (cdgA, cdgJ) had orthologs in B. subtilis, highlighting differences in c-di-GMP signalling between B. subtilis and B. cereus group bacteria. PMID- 27116469 TI - Congenital Extrahepatic Portosystemic Shunt (Abernethy Malformation Type Ib) with Associated Hepatocellular Carcinoma: Case report and Literature Review. AB - Abernethy malformation, also termed congenital portosystemic shunt and congenital absence of portal vein (CAPV) is the result of malformation of the splanchnic venous system. Congenital portosystemic shunts are divided into extra-and intrahepatic shunts. Two shunts have been defined: type I is characterized by the complete diversion of portal blood into the vena cava with an associated congenital absence of the portal vein. Type II is defined by an intact but diverted portal vein through a side-to-side, extrahepatic connection to the vena cava. The clinical manifestations of Abernethy malformation are diverse with a typical presentation consisting of hypoxia and hepto-pulmonary syndrome. Histologically, focal nodular hyperplasia, nodular regenerative hyperplasia, liver adenoma, hepatoblastoma, and hepatocellular carcinoma have all been reported. Herein we report a case of Abernethy malformation, type Ib, in a 12 month old male who was found to have a small hepatocellular carcinoma at the time of explant. The immunohistochemical characteristics in relation to the genetic aspects are discussed. To our knowledge, this is the first reported case of hepatocellular carcinoma developing in a patient who is under the age of 5 years old with Abernethy Malformation. PMID- 27116470 TI - Prognostic Significance of Tag SNP rs1045411 in HMGB1 of the Aggressive Gastric Cancer in a Chinese Population. AB - Compelling evidences have suggested that high mobility group box-1 (HMGB1) gene plays a crucial role in cancer development and progression. This study aimed to evaluate the effects of single nucleotide polymorphisms (SNPs) in HMGB1 gene on the survival of gastric cancer (GC) patients. Three tag SNPs from HMGB1 gene were selected and genotyped using Sequenom iPEX genotyping system in a cohort of 1030 GC patients (704 in training set, 326 in validation set). Multivariate Cox proportional hazard model and Kaplan-Meier Curve were used for prognosis analysis. AG/AA genotypes of SNP rs1045411 in HMGB1 gene were significantly associated with better overall survival (OS) in a set of 704 GC patients when compared with GG genotypes (HR = 0.77, 95% CI: 0.60-0.97, P = 0.032). This prognostic effect was verified in an independent validation set and pooled analysis (HR = 0.80, 95% CI: 0.62-0.99, P = 0.046; HR = 0.78, 95% CI: 0.55-0.98, P = 0.043, respectively). In stratified analysis, the protective effect of rs1045411 AG/AA genotypes was more prominent in patients with adverse strata, compared with patients with favorable strata. Furthermore, strong joint predictive effects on OS of GC patients were noted between rs1045411 genotypes and Lauren classification, differentiation, stage or adjuvant chemotherapy. Additionally, functional assay indicated a significant effect of rs1045411 on HMGB1 expression. Our results suggest that rs1045411 in HMGB1 is significantly associated with clinical outcomes of Chinese GC patients after surgery, especially in those with aggressive status, which warrants further validation in other ethnic populations. PMID- 27116471 TI - Development of a Rapid Microbore Metabolic Profiling Ultraperformance Liquid Chromatography-Mass Spectrometry Approach for High-Throughput Phenotyping Studies. AB - A rapid gradient microbore ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) method has been developed to provide a high-throughput analytical platform for the metabolic phenotyping of urine from large sample cohorts. The rapid microbore metabolic profiling (RAMMP) approach was based on scaling a conventional reversed-phase UPLC-MS method for urinary profiling from 2.1 mm * 100 mm columns to 1 mm * 50 mm columns, increasing the linear velocity of the solvent, and decreasing the gradient time to provide an analysis time of 2.5 min/sample. Comparison showed that conventional UPLC-MS and rapid gradient approaches provided peak capacities of 150 and 50, respectively, with the conventional method detecting approximately 19 000 features compared to the ~6 000 found using the rapid gradient method. Similar levels of repeatability were seen for both methods. Despite the reduced peak capacity and the reduction in ions detected, the RAMMP method was able to achieve similar levels of group discrimination as conventional UPLC-MS when applied to rat urine samples obtained from investigative studies on the effects of acute 2-bromophenol and chronic acetaminophen administration. When compared to a direct infusion MS method of similar analysis time the RAMMP method provided superior selectivity. The RAMMP approach provides a robust and sensitive method that is well suited to high throughput metabonomic analysis of complex mixtures such as urine combined with a 5-fold reduction in analysis time compared with the conventional UPLC-MS method. PMID- 27116472 TI - Improved activity and thermo-stability of the horse radish peroxidase with graphene quantum dots and its application in fluorometric detection of hydrogen peroxide. AB - Graphene quantum dots (GQDs) have received extensive concern in many fields such as optical probe, bioimaging and biosensor. However, few reports refer on the influence of GQDs on enzyme performance. The paper reports two kinds of graphene quantum dots (termed as GO-GQDs and N,S-GQDs) that were prepared by cutting of graphene oxide and pyrolysis of citric acid and l-cysteine, and their use for the horse radish peroxidase (HRP) modification. The study reveals that GO-GQDs and N,S-GQDs exhibit an opposite effect on the HRP performance. Only HRP modified with GO-GQDs offers an enhanced activity (more than 1.9 times of pristine enzyme) and thermo-stability. This is because GO-GQDs offer a larger conjugate rigid plane and fewer hydrophilic groups compared to N,S-GQDs. The characteristics can make GO-GQDs induce a proper conformational change in the HRP for the catalytic performance, improving the enzyme activity and thermo-stability. The HRP modified with green luminescent GO-GQDs was also employed as a biocatalyst for sensing of H2O2 by a fluorometric sensor. The colorless tetramethylbenzidine (TMB) is oxidized into blue oxidized TMB in the presence of H2O2 by the assistance of HRP/GO-GQDs, leading to an obvious fluorescence quenching. The fluorescence intensity linearly decreases with the increase of H2O2 concentration in the range from 2*10-9 to 2*10-4M with the detection limit of 6.8*10-10M. The analytical method provides the advantage of sensitivity, stability and accuracy compared with present H2O2 sensors based on the pristine HRP. It has been successfully applied in the determination of H2O2 in real water samples. The study also opens a new avenue for modification of enzyme activity and stability that offers great promise in applications such as biological catalysis, biosensing and enzyme engineering. PMID- 27116473 TI - IR and py/GC/MS examination of amber relics excavated from 6th century royal tomb in Korean Peninsula. AB - Relics of amber were excavated from King Muryeong's tomb constructed in the 6th century on the Korean peninsula. To estimate the provenance, FTIR (Fourier transform infrared spectroscopy) and py/GC/MS (pyrolysis/gas chromatography/mass spectrometry) analysis were utilized. The reference Baltic amber sample was also analyzed with the same method for comparison. The relics were confirmed to be amber from the FTIR analysis where an absorption band near 1150cm(-1), characteristic one in Baltic amber, was also observed. In py/GC/MS analysis, pyrolyzed products like butanedioic acid and dehydroabietic acid, known constituents of amber, were observed. In addition, d-fenchyl alcohol, camphor, borneol and butanedioic acid, typical constituents of Baltic amber, were observed in some samples. From this, it appears that some of relics were made from Baltic amber and that Baltic amber was transported to the Korean peninsula in the time of tomb construction. PMID- 27116475 TI - Separation and purification of an anti-tumor peptide from rapeseed (Brassica campestris L.) and the effect on cell apoptosis. AB - Rapeseed peptides were prepared by means of the combined methods of the laboratory bacteria enzyme synergy and the solid-state fermentation of rapeseed meal. The rapeseed peptides were separated and purified with the tumor cell in vitro anti-proliferative activity as an index. Moreover, a kind of rapeseed peptide component RSP-4-3-3 (rapeseed anti-tumor peptide RSP-4-3-3) with high activity was selected. Furthermore, by using reversed-phase high performance liquid chromatography (RP-HPLC) coupled with electrospray ionization mass spectrometry (ESI-MS/MS), the analysis result of its possible amino acid sequence showed that it was Trp-Thr-Pro (408.2 Da). Inverted microscope observation technology and western blot experiments were applied to explore the antitumor impact of the rapeseed peptide RSP-4-3-3 on tumor cells. The results showed that the rapeseed antitumor peptide RSP-4-3-3 could significantly change the morphological features of the HepG2 cells in vitro and cause apoptosis, thus inhibiting the proliferation of the HepG2 cells. PMID- 27116474 TI - Utility of KRAS mutation detection using circulating cell-free DNA from patients with colorectal cancer. AB - In this study, we evaluated the clinical utility of detecting KRAS mutations in circulating cell-free (ccf)DNA of metastatic colorectal cancer patients. We prospectively recruited 94 metastatic colorectal cancer patients. Circulating cell-free DNA was extracted from plasma samples and analyzed for the presence of seven KRAS point mutations. Using the Invader Plus assay with peptide nucleic acid clamping method and digital PCR, KRAS mutations were detected in the ccfDNA in 35 of 39 patients previously determined to have primary tumors containing KRAS mutations using the Luminex method, and in 5 of 55 patients with tumors containing wild-type KRAS. Curative resection was undertaken in 7 of 34 patients with primary and ccfDNA KRAS mutations, resulting in the disappearance of the mutation from the cell-free DNA in five of seven patients. Three of these patients had tumor recurrence and KRAS mutations in their ccfDNA reappeared. Epidermal growth factor receptor blockade was administered to 24 of the KRAS tumor wild-type patients. Of the 24 patients with wild-type KRAS in their primary tumors, three patients had KRAS mutations in their ccfDNA and did not respond to treatment with epidermal growth factor receptor (EGFR) blockade. We also detected a new KRAS mutation in five patients during chemotherapy with EGFR blockade, before disease progression was detectable with imaging. The detection of KRAS mutations in ccfDNA is an attractive approach for predicting both treatment response and acquired resistance to EGFR blockade, and for detecting disease recurrence. PMID- 27116476 TI - Crystallization of soft matter under confinement at interfaces and in wedges. AB - The surface freezing and surface melting transitions that are exhibited by a model two-dimensional soft matter system are studied. The behaviour when confined within a wedge is also considered. The system consists of particles interacting via a soft purely repulsive pair potential. Density functional theory (DFT) is used to calculate density profiles and thermodynamic quantities. The external potential due to the confining walls is modelled via a hard wall with an additional repulsive Yukawa potential. The surface phase behaviour depends on the range and strength of this repulsion: when the repulsion is weak, the wall promotes freezing at the surface of the wall. The thickness of this frozen layer grows logarithmically as the bulk liquid-solid phase coexistence is approached. Our mean-field DFT predicts that this crystalline layer at the wall must be nucleated (i.e. there is a free energy barrier) and its formation is necessarily a first-order transition, referred to as 'prefreezing', by analogy with the prewetting transition. However, in contrast to the latter, prefreezing cannot terminate in a critical point, since the phase transition involves a change in symmetry. If the wall-fluid interaction is sufficiently long ranged and the repulsion is strong enough, surface melting can occur instead. Then the interface between the wall and the bulk crystalline solid is wetted by the liquid phase as the chemical potential is decreased towards the value at liquid-solid coexistence. It is observed that the finite thickness fluid film at the wall has a broken translational symmetry due to its proximity to the bulk crystal, and so the nucleation of the wetting film can be either first order or continuous. Our mean-field theory predicts that for certain wall potentials there is a premelting critical point analogous to the surface critical point for the prewetting transition. When the fluid is confined within a linear wedge, this can strongly promote freezing when the opening angle of the wedge is commensurate with the crystal lattice. PMID- 27116477 TI - Effect of Solvation on Electron Detachment and Excitation Energies of a Green Fluorescent Protein Chromophore Variant. AB - Hybrid quantum mechanics/molecular mechanics (QM/MM) is applied to the fluorinated green fluorescent protein (GFP) chromophore (DFHBDI) in its deprotonated form to understand the solvatochromic shifts in its vertical detachment energy (VDE) and vertical excitation energy (VEE). This variant of the GFP chromophore becomes fluorescent in an RNA environment and has a wide range of applications in biomedical and biochemical fields. From microsolvation studies, we benchmark (with respect to full QM) the accuracy of our QM/MM calculations with effective fragment potential (EFP) as the MM method of choice. We show that while the solvatochromic shift in the VEE is minimal (0.1 eV blue shift) and its polarization component is only 0.03 eV, the effect of the solvent on the VDE is quite large (3.85 eV). We also show by accurate calculations on the solvatochromic shift of the VDE that polarization accounts for ~0.23 eV and therefore cannot be neglected. The effect of the counterions on the VDE of the deprotonated chromophore in solvation is studied in detail, and a charge-smearing scheme is suggested for charged chromophores. PMID- 27116478 TI - Self-organization of hydrophobic-capped triblock copolymers with a polyelectrolyte midblock: a coarse-grained molecular dynamics simulation study. AB - We present the results of a Langevin dynamics simulation study of micellar organization and hydrogel formation in the solutions of coarse-grained ABA copolymer chains. Polymer chains are modeled as bead-spring chains of Lennard Jones particles by explicit treatment of ionic species in implicit solvent. The studied copolymer is composed of a polyelectrolyte midblock flanked by two hydrophobic endblocks. We explore the self-assembly of copolymer solutions at a fixed polymer concentration and temperature upon systematic variation of the midblock charge fraction, valency of neutralizing counterions, and the stiffness and length of hydrophobic endblocks. Minimization of the surface energy, conformational entropy of the midblock chains, electrostatic repulsion of midblock charges, and the translational entropy of counterions are found to play central roles in controlling the self-organization features of copolymer solutions. Flower-like micelles with A-blocks forming the core of spherical aggregates and B-blocks constituting the micelle corona are established for the neutral midblocks. Increasing the charge content of B chains lowers the fraction of loop conformations and yields a spanning hydrogel network with midblocks bridging the hydrophobic clusters. Counterion valence is shown to exert a strong effect on the micelle size and network structure. The increase in the rigidity of terminal A-blocks increases the fraction of bridging chains and results in the formation of a hydrogel network with bundle-like hydrophobic domains. Longer endblocks are shown to increase the hydrophobic cluster size and enhance the bridged midblock fraction. The qualitative agreement between the experimental and theoretical studies is also discussed. The comprehensive molecular picture provides a framework for the future studies of stimuli-responsive copolymer systems. PMID- 27116480 TI - Medial Synovial Fold of the Posterior Cruciate Ligament on Knee Magnetic Resonance Imaging and Arthroscopy: Retrospective Investigation of Impingement. AB - OBJECTIVE: The purpose of this study was to classify the types of medial synovial fold of the posterior cruciate ligament (PCL) on magnetic resonance imaging (MRI) and to identify the relationships between fold type and impingement of the PCL on arthroscopy. SUBJECTS AND METHODS: Ninety-nine patients who underwent knee MRI and arthroscopy were included. All MRIs were retrospectively and independently assessed by 2 radiologists. Medial synovial folds of the PCL on MRI were categorized into 3 types. Type A showed no medial synovial fold. Type B showed a small synovial protrusion that did not extend beyond an imaginary line drawn from the medial tibial spine to the lateral aspect of the medial femoral condyle. Type C had a long enough fold to extend beyond the imaginary line. The presence of a tear in the anterior cruciate ligament, PCL, or menisci and impingement of the PCL were obtained from arthroscopic records. RESULTS: Intraobserver agreement in the classification of medial synovial folds was nearly perfect (kappa = 0.850). Interobserver agreement was substantial (kappa = 0.759). Of 99 cases, 34 were type A, 41 were type B, and 24 were type C folds on MRI. Thirty-nine impingements of the PCL (39.4%) were identified on arthroscopy. Multivariable analysis revealed that type C folds were 40.60 times more likely to have impingement than type A folds (odds ratio, 40.60; 95% confidence interval, 8.73-188.93; P < 0.001). CONCLUSIONS: Of the 3 types of medial synovial folds, type C was significantly associated with impingement of the PCL on arthroscopy. Therefore, type C folds may be a cause of internal derangement of the knee. PMID- 27116479 TI - Short- and Long-Term Reproducibility of Intrahepatic Lipid Quantification by 1H MR Spectroscopy and CT in Obesity. AB - OBJECTIVE: This study aimed to assess short- and long-term reproducibility of intrahepatic lipid (IHL) quantification by proton magnetic resonance spectroscopy (H-MRS) and computed tomography (CT). METHODS: Sixteen obese subjects underwent H MRS using a single-voxel point-resolved single-voxel spectroscopy sequence at 3 T and noncontrast single-slice CT of the liver. Measurements were repeated after 6 weeks and 6 months. Clinical parameters (weight, activity, serum lipids) were collected. Short-term (baseline to 6 weeks) and long-term (baseline to 6 months) reproducibility of IHL was assessed by coefficient of variance (CV), SD, and intraclass correlation coefficient (ICC). RESULTS: Short-term reproducibility and long-term reproducibility of H-MRS were as follows: CV, 5.9% to 18.8%; SD, 0.7 to 1.9; and ICC, 0.998 to 0.995 (95% confidence interval, 0.942-0.999). Short-term reproducibility and long-term reproducibility of CT were as follows: CV, 4.4% to 14.2%; SD, 2.4 to 8.7; and ICC, 0.766 to 0.982 (95% confidence interval, 0.271 0.994). There was no significant change in clinical parameters (P > 0.3). CONCLUSIONS: Proton magnetic resonance spectroscopy and CT are reproducible methods for short- and long-term quantification of IHL content. Our results can guide sample size calculations for interventional and longitudinal studies. PMID- 27116481 TI - Do Naranjo Criteria Still Apply to Ipilimumab-induced Uveitis? PMID- 27116482 TI - [Is it still Necessary to Discontinue Using Daily Wear Soft Contact Lenses for a Period before LASIK?]. AB - PURPOSE: The aim of this study was to verify whether soft contact lenses (SCL) can have a clinically significant impact on refraction before LASIK. METHODS: Retrospective analysis of 113 eyes for which the refraction was measured initially and after discontinuing soft contact lenses for at least 7 days. Both spherical and cylindrical measurements were performed. In addition, the difference between postoperative refraction and the target refraction for these eyes was calculated for both spherical and cylindrical refraction. RESULTS: In 8 % (18 %) of the eyes, the spherical or cylindrical refraction changed by 0.5 dioptre or more after a week of not wearing soft contact lenses. Total spherical refraction changed by an average of 0.15 dioptre (p = 0.58) and cylindrical refraction by 0.18 dioptre (p = 0.006). After LASIK, the difference between postoperative and target refraction was significantly different for both spherical refraction (0.3 dioptre) and for cylindrical refraction (0.21 dioptre). DISCUSSION: The differences in the measurements during this study suggest that a modern soft contact lenses should still be discontinued before LASIK. The optimal duration of the discontinuation remains to be determined. PMID- 27116483 TI - AcuFocus Corneal Inlay to Correct Presbyopia Using Femto-LASIK. One Year Results of a Prospective Cohort Study. AB - PURPOSE: To evaluate the safety and efficacy of the AcuFocus small aperture corneal inlay (KAMRA) for the correction of presbyopia using femto-LASIK. PATIENTS AND METHODS: This is a prospective, non-randomised cohort study including 50 presbyopic patients with hyperopia, emmetropia or mild myopia. The intracorneal inlay was implanted in the non-dominant eye using a VisuMax femtosecond laser (Zeiss 500 kHz) to create a superior-hinged flap. The inlay was centred over the visual axis. Minimum postoperative follow-up was performed for a period of 12 months. RESULTS: Fifty intracorneal inlays were implanted. At one year follow-up, the median uncorrected near visual acuity significantly improved from Jaeger (J)8 to J2 (p < 0.001). 94 % of patients could read J3 or better. The median uncorrected distance visual acuity also improved from 20/32 to 20/22 (p < 0.001). 92 % of patients could see 20/32 or better. One implant had to be recentred at four weeks follow-up. One implant was removed six months after implantation due to insufficient uncorrected near and distance visual acuity as well as slight corneal haze, which resolved four weeks later under topical treatment with fluorometholone eye drops, without any loss of best corrected distance visual acuity. No other complications occurred during the postoperative follow-up period. CONCLUSION: AutoFocus Corneal Inlay (ACI), also known as KAMRA, can provide a safe, effective and, most importantly, reversible treatment for presbyopia in hyperopic, myopic and emmetropic patients. PMID- 27116484 TI - [Implantation of an Artificial Iris in 11 Patients]. AB - Background. Iris defects are mostly acquired after injury, or may be iatrogenic after surgical excision of iris tumours or the result of collateral trauma after anterior segment surgery. They cause severe visual disability, e.g. glare, loss of contrast sensitivity, and loss of best corrected visual acuity. The foldable Koch iris prosthesis has a customised iris design and may be used to reconstruct the anterior segment in patients with partial or complete aniridia. History and Signs. We present the surgical management and clinical course of 6 patients with traumatic iris defects, together with 3 patients with partial aniridia after cataract surgery. Cataract surgery and implantation of an artificial iris were performed in 2 female patients (3 eyes) with congenital aniridia syndrome. Therapy and Outcome. No patient exhibited complications in the postoperative course, with the exception of various intraocular pressure peaks due to secondary glaucoma, that were all corrected by medication to lower topical pressure. Conclusions. In patients with major iris defects, the artificial iris allows functionally and aesthetically satisfactory reconstruction of the anterior segment. PMID- 27116485 TI - Repeated Intrastromal Injections of Voriconazole in Combination with Corneal Debridement for Recalcitrant Fungal Keratitis - a Case Series. AB - BACKGROUND: To report the use of intrastromal voriconazole injections combined with corneal debridement to treat deep recalcitrant fungal keratitis. HISTORY AND SIGNS: Three patients (2 female and 1 male) with culture proven fungal keratitis (1 Fusarium, 1 Candida, 1 Pseudallescheria boydii) were included in this study. The patients were treated with repeated intrastromal voriconazole (100 mg/1 ml) in combination with corneal debridement. THERAPY AND OUTCOME: The mean age of the patients was 65 years. The mean number of injections was 5. The patients were injected every 2-3 days. This technique required repeated corneal debridement to achieve complete resolution in these three cases. CONCLUSIONS: Repeated intrastromal injection of voriconazole in combination with corneal debridement appears to be an effective and safe way to treat recalcitrant fungal keratitis, even in Fusarium keratitis. PMID- 27116486 TI - Urrets-Zavalia Syndrome after Iris-Claw-Lens Implantation, Inadequate Iridectomy and Acute Glaucoma. PMID- 27116487 TI - [Therapeutic Use of Botulinum Toxin to Correct Misalignment of the Eyes]. AB - BACKGROUND/PURPOSE: There are no concrete guidelines for the therapeutic use of botulinum toxin in strabismus. The 2012 Cochrane Analysis concluded that it was controversial, but included only 4 prospective randomized controlled trials. However, many retrospective studies suggest that botulinum toxin treatment is a viable alternative to surgical treatment. We have now retrospectively evaluated the outcomes of our patients treated with botulinum toxin. PATIENTS AND METHODS: We retrospectively reviewed the charts of the patients treated with Botox(r) for strabismus. The period covered was between 2003 and 2015, with a follow-up of at least 6 months. Successful outcome was defined as alignment within <= 10 prism dioptres, with stereopsis at the final follow-up. RESULTS: 16 patients were included, including 11 children. The mean follow-up was 19 months. All 11 children were initially esotropic; 9 exhibited lasting angle reduction (mean 25.5 prism dioptres) at the final follow-up, and 6 of these (54.5 %) achieved a successful outcome. Only one adult patient achieved a lasting angle reduction. Other benefits were: Psychological relief due to reduced nystagmus (n = 1), relief of headaches from decompensating exophoria (n = 1), and renewed ability to read, due to less adduction of the dominant eye in a patient with bilateral sixth nerve palsy. Transient ptosis without obstruction of the visual axis was seen in 4 (36 %) of the children, but in none of the adults. CONCLUSIONS: Botulinum toxin has a lasting effect, especially in children with esotropia. It is minimally invasive and can prevent surgery. If there is subsequent surgery, the dosage may be reduced. Ptosis rates were comparable to those in the literature. PMID- 27116488 TI - Eyeglasses for Children - a Survey of Daily Practice. AB - BACKGROUND: Glasses for children are recommended and prescribed by different groups of professionals. We set out to compare the prescription practices of ophthalmologists, orthoptists and optometrists/opticians in Switzerland. METHODS: Online questionnaire on the prescription and recommendation of glasses in fictitious cases of children of different ages, refractive values and symptoms. The questionnaire was sent out to members of the Swiss Ophthalmological Society, Swiss Orthoptics and Schweizerischer Berufsverband fur Augenoptik und Optometrie. RESULTS: 307 questionnaires were analysed. Optometrists/opticians recommended glasses with a significantly smaller cycloplegic refraction value (p < 0.005) than did orthoptists and ophthalmologists. In the example of a 14-year-old asymptomatic child, ophthalmologists recommended glasses at + 2.64 [Dpt], orthoptists at + 2.44 [Dpt] and optometrists/opticians at + 1.32 [Dpt]. Optometrists/opticians tended to recommend slightly higher correction values in glasses than did ophthalmologists and orthoptists. CONCLUSION: In Switzerland, optometrists/opticians recommend glasses with significantly smaller cycloplegic refraction values than do orthoptists and ophthalmologists, regardless of age or symptoms described in these fictitious cases. PMID- 27116489 TI - Unexpected Effect of Calcium Channel Blockers on the Optic Nerve Compartment Syndrome. AB - BACKGROUND: The optic nerve compartment syndrome is a pathological condition in which cerebrospinal fluid of the subarachnoid space surrounding the optic nerve is partly or totally segregated from the cerebrospinal fluid of the intracranial subarachnoid space, leading - inter alia - to an increase in the diameter of the optic nerve sheath. The pathogenesis of this condition remains unclear. We have observed clinically that optic nerve compartment syndrome often occurs in normal tension glaucoma patients with Flammer syndrome. To treat Flammer syndrome, some glaucoma patients received a low dose of a calcium channel blocker and we analysed whether this treatment also had an effect on the optic nerve compartment syndrome. PATIENTS AND METHODS: We retrospectively analysed the data of 10 eyes of seven patients suffering from a combination of primary open angle glaucoma, optic nerve compartment syndrome, and Flammer syndrome. We included subjects who had eye socket echography before and after a few months of therapy with a calcium channel blocker. THERAPY AND RESULTS: All patients received a low dose of a calcium channel blocker (nifedipine or amlodipine) to treat Flammer syndrome. As expected, the symptoms of Flammer syndrome were mitigated. To our surprise, the optic nerve compartment syndrome also improved in eight of the 10 eyes (80 %), but remained unchanged in the remainder. CONCLUSIONS: To some extent, the optic nerve compartment syndrome is related to the combination of primary open angle glaucoma and Flammer syndrome. On the basis of our results, we hypothesise that treatment of Flammer syndrome may also improve the optic nerve compartment syndrome. PMID- 27116490 TI - [Vision Screening in Zurich]. AB - BACKGROUND: In the city of Zurich, vision screening is performed by school medical services as part of the legally compulsory preventive medical examinations. We retrospectively evaluated the results of the 2011-2012 school year. PATIENTS AND METHODS: Preventive medical examinations by the school medical services were performed in all kindergartens. The examinations were mandatory for first, second and eighth grade children, whilst those for the fourth grade were voluntary. The basic diagnostic testing consisted of monocular visual acuity (Snellen E chart) for all age groups and the stereopsis test (TNO test) in kindergartens. RESULTS: Vision screening was performed on 7499 children. 1471 first graders (55 %), 201 fourth graders (11 %) and 211 eighth graders (12.3 %) did not pass the examinations. In 33.7 % of the children who underwent the follow up examination from an ophthalmologist, amblyogenic potential was found. CONCLUSIONS: Vision screening by the school medical services enrols most of the children from a single age group. The Snellen E charts used for the monocular distance acuity, together with the TNO stereo test, appear to constitute an effective testing combination. Ophthalmological follow-up examinations of the affected children revealed that one third were afflicted by amblyogenic factors. PMID- 27116491 TI - Transsynaptic Retrograde Degeneration: Clinical Evidence with Homonymous RGCL Loss on OCT. AB - BACKGROUND: Retinal thinning after a retrogeniculate lesion (transsynaptic retrograde degeneration) was first described 50 years ago, but has long been a controversial issue. It is now possible to use OCT for the in vivo measurement of retinal thickness. MATERIAL AND METHODS: This was a retrospective study of patients with homonymous visual field loss, with SD-OCT assessment (RNFL and RGCL measurements) in isolated retrogeniculate lesions, subsequently confirmed by a neuroradiologist. RESULTS: Nine patients with vascular, inflammatory or tumour brain lesions were included in the study. Homonymous RGCL thinning was found in all patients, and correlated with the visual field defect. No correlation was found with RNFL. CONCLUSIONS: The homonymous defect of RGCL in patients with retrogeniculate lesions demonstrates the presence of transsynaptic retrograde degeneration. RGCL is a better predictor of visual field defects than RNFL measurement. PMID- 27116492 TI - Sequential Bilateral Non-Arteritic Anterior Ischaemic Optic Neuropathy in Superficial Intracranial Siderosis. PMID- 27116493 TI - Acute Lid Swelling: a Series of Unusual Cases, Treatment and Follow-up. AB - BACKGROUND: There are many different aetiologies for acute lid swelling, including infection, inflammation, degeneration, tumours and trauma. We present five uncommon cases of acute lid swelling and give an overview of differential diagnoses for rapidly evolving eyelid swelling. HISTORY AND SIGNS: We reviewed the charts of five patients with initial presentation of acute lid swelling. For the five patients, there were diagnoses of Churg Strauss syndrome, an allergic reaction to hyaluronic acid, lymphangioma, a ruptured dermoid cyst and a co infected pre-existing orbital lesion that was only evident in the follow-up. THERAPY AND OUTCOME: Individual patients required totally different treatments. A ruptured dermoid is a dramatic problem that demands immediate surgical attention. Swelling in sinusitis in a child is just as important, but requires antibiotic treatment, careful follow-up and subsequent treatment of any secondarily infected pre-existing lesion. The less dramatic first presentations were more difficult to diagnose and required protracted observation and immunosuppressive treatment. CONCLUSIONS: The key to success often lies in the assessment of the patient's history and correctly timed surgery. Dramatic first manifestations were often easier to treat than initially low grade lid swelling. Unclear results, such as a low grade eosinophilia, should not be ignored. PMID- 27116494 TI - Temporary Medial Upper Eyelid Lagophthalmos after External Dacryocystorhinostomy. AB - Background. Report of three cases of medial upper eyelid lagophthalmos as complication of external dacryocystorhinostomy. History and Signs. Shortly after dacryocystorhinostomy (skin incision on the side of the nose), three of ten consecutive patients (28 +/- 4 years; mean +/- standard deviation), presented with an ipsilateral lagophthalmos of 4 +/- 1 mm in voluntary eyelid closure and 6 +/- 1 mm in spontaneous blink. The lagophthalmos was due to a selective paresis of the medial part of the orbicularis oculi muscle of the upper eyelid. Patient 1 complained bitterly of dry eye symptoms and of her lagophthalmos. Patient 2 had mild symptoms but became very concerned after peers made her aware of her asymmetric blink. Patient 3 was asymptomatic and did not notice anything particular. Therapy and Outcome. Lagophthalmos resolved spontaneously within three months after surgery, first by improvement of voluntary eyelid closure and then of spontaneous blinking. Conclusions. Temporary lagophthalmos can occur as a complication of external dacryocystorhinostomy, most likely due to damage of the (only recently described) superficial buccal and/or zygomatic branches of the facial nerve that run upward to cross over the medial ligament and innervate the medial part of the orbicularis oculi muscle. PMID- 27116495 TI - Subkutanes Granuloma anulare am Orbitarand kann eine Dermoidzyste imitieren. PMID- 27116496 TI - [Endonasal Dacryocystorhinostomy (DCR) with Transcanalicular Endoillumination (TCE) of the Saccus Lacrimalis]. AB - Endonasal dacryocystorhinostomy (DCR) has been established as a standard procedure of lacrimal surgery, since it causes much less tissue damage than ab externo procedures. Diffiulties in visualization of the target area has been a limitation to the transnasal approach. An improvement of the classical endonasal DCR was achieved by the introduction of a transcanalicular endoillumination (TCE) of the lacrimal sac using a 23-Gauge vitreoretinal light probe, which can easily be intubated into the cannaliculi and advanced into the the lacrimal sac. Illumination of the lacrimal sac guides the endonasal approach and facilitates the creation of a lacrimal bypass. In our standard procedure a bicanalicular silicone intubation through the osteotomy is finally placed. Due to the introduction of TCE of the lacrimal sac, the surgical procedure of endonasal DCR became less traumatic and needed a significantly reduced operating time. PMID- 27116497 TI - A Novel Technique of Plastic Evisceration for Larger Implants. PMID- 27116498 TI - Improvement in Visual Function in Patients with Inherited Diseases of the Retina Following Acupuncture Treatment. AB - BACKGROUND: The aim of this pilot study was to examine the short-term effect on visual function of acupuncture treatment in a cohort of patients with inherited diseases of the retina. PATIENTS AND METHODS: A prospective pilot study was performed on 14 patients (10 ?, 4 ?; mean age: 43.43 y (+/- 19.72 y)), with the clinically and electrophysiologically confirmed diagnosis of inherited disease of the retina. Acupuncture treatment consisted of needle application to the body and ears and was performed following a standardized protocol. The treatment was scheduled for 10 half-hour sessions over five weeks. Visual function was measured before acupuncture, between acupuncture treatments and after the end of treatment. Objective measurements included best corrected visual acuity (ETDRS charts), contrast vision (CSV-1000, Vector Vision) and Goldmann perimetry (isopters 3IIIe; Haag-Streit). Subjective evaluation was based on evaluation questionnaires. To exclude the effect of variability on the psychophysical tests, a non-acupuncture control group (Nr: 8; 5 ?, 3 ?; mean age: 38.56 y (+/- 9.08 y)) was taken for comparison. RESULTS: All patients with inherited diseases of the retina showed general improvement in objective visual functions, with post-/pre- acupuncture improvement in: visual acuity (p = 0.031, left eyes), contrast vision (p = 0.015 and p = 0.041; both eyes) and widening of the temporal radius of the visual field (0.013; left eyes). Subjectively, all patients reported better daytime, color and contrast vision, better visual focus and less visual tiredness. In addition, some general symptoms, such as longer sleep-onset time, feeling cold, and migraine/headache attacks were significantly reduced. CONCLUSIONS: The acupuncture protocol improved visual function in our patients with inherited diseases of the retina and was well tolerated. Nevertheless, the long-term effect of this complementary therapy remains to be evaluated. PMID- 27116499 TI - Malposition of Teeth and Jaws in Patients with Congenital Superior Oblique Palsy. AB - BACKGROUND: Patients with congenital superior oblique palsy tend to adopt a head tilt to the contralateral side to maintain binocular single vision. It has long been recognised that facial asymmetries may be caused by a head tilt. The aim of this study was to describe the effect of habitual head tilt due to congenital superior oblique palsy on dental occlusion. PATIENTS AND METHODS: The study was designed as a descriptive cohort study. Ten patients with congenital superior oblique palsy (3 female, 7 male; mean age 51.7 (y) +/- 15.8 SD, ranging from 19 to 69 (y)) underwent orthodontic examination. Orthodontic findings and values for vertical, torsional and horizontal deviation measured with the Harms tangent screen and stereopsis using a random dot test were compared. RESULTS: Three orthodontic parameters were found to correlate significantly or at least as trend with orthoptic parameters. Midline deviation of the upper jaw to the face (rho = 0.623; p = 0.054) and anterior positioning of upper first molar in the sagittal plane (rho = 0.594; p = 0.07) correlate with the vertical deviation; overbite correlates with horizontal deviation measured in the primary position (rho = 0.768; p = 0.016). CONCLUSIONS: In this small study, three orthodontic parameters correlated with orthoptic findings in patients with congenital superior oblique palsy. Further studies are needed to establish whether congenital superior oblique palsy is more frequent in patients exhibiting abnormal values of these orthodontic parameters. PMID- 27116500 TI - Unilateral Loss of Vision after Spinal Surgery in a Patient with Flammer Syndrome. PMID- 27116501 TI - [Calcified Phthisis Bulbi: Development and Pathology in a Case History]. PMID- 27116502 TI - SLO Fundus Imaging Is the Most Sensitive Modality of Multimodal Imaging for Macular Microembolisms with Subtle Signs. AB - Background. Microemboli of fat or other material into the terminal macular retinal circulation can be difficult to diagnose. We report 2 cases that showed subtle signs where SLO fundus imaging was most sensitive to precisely outline the limits of the inner retina infarction. Patients and Methods. Multimodal imaging analysis was performed including fundus photography, fluorescein angiography, indocyanine green angiography, Optical Coherence Tomography and SLO fundus imaging of 2 cases with suspected infarction of the inner retina. Cases. A 30 year-old man reported a grey central spot OD a few days after being squeezed between two cars with a sacrum fracture. Vision was 0.2 OD, and 1.0 OS. Examination was unremarkable and fluorescein angiography was normal. Octopus visual field showed a tiny central scotoma OD. Microperimetry showed decreased central sensitivity OD > OS. The only sign was a dark area on the SLO fundus picture indicating a subtle infarction of the inner retina (OD > OS) with nothing visible on the OCT. Resolution of lesions on the SLO picture ODS occurred in parallel with improvement of microperimetry and visual acuity. A 32-year-old woman suspected to take IV drugs had a sudden drop of vision to 0.4 OD and count fingers at 6 feet OS. Signs included macular hemorrhages and non perfusion on FA. The striking sign was a large dark area on the SLO picture precisely delineating the more extensive infarcted area of internal retina corresponding to OCT hyperreflectivity, visible in this case. Conclusions. Macular ischemia due to microemboli can show obvious fundus signs as hemorrhages, cotton wool spots and non perfusion or can present in a subclinical fashion. The SLO picture has a higher image contrast and higher resolution compared to conventional fundus photography and so can precisely delineate ischemic changes of the inner retina causing the unexplained visual loss. PMID- 27116503 TI - Peripheral Bilateral Telangiectasiae in Multiple Sclerosis Patients Treated with Interferon B1a. PMID- 27116504 TI - Anatomical and Functional Results of Lamellar Macular Holes Surgery. AB - PURPOSE: To determine the long-term surgical findings and outcomes after vitrectomy for symptomatic lamellar macular holes. METHODS: We studied 28 patients with lamellar macular holes and central visual loss or distortion. All interventions were standard 25 G vitrectomy with membranectomy of the internal limiting membrane (ILM), peeling and gas tamponade with SF6 20 %. Operations were performed by a single experienced surgeon within the last 3 years. Best corrected visual acuity and optical coherence tomography appearance were determined preoperatively and postoperatively. RESULTS: Following the surgical procedure, all macular holes were closed; however, in 3 eyes, significant foveal thinning was associated with changes in the retinal pigment epithelium changes. The mean best-corrected visual acuity improved postoperatively in the majority of the patients (n: 21, mean 0.3 logMAR), stabilised in 4 patients and decreased in 3 patients (mean 0.4 logMAR). Spectral Domain-Optical coherence tomography (SD-OCT) showed resolution of the lamellar lesion and improved macular contour in all cases. CONCLUSION: We demonstrated improvement in postoperative vision and the anatomical reconstruction of the anatomical contour of the fovea in most eyes with symptomatic lamellar holes. These findings indicate that vitrectomy, membranectomy and ILM peeling with gas tamponade is a beneficial treatment of symptomatic lamellar macular holes. PMID- 27116505 TI - Long-Term Functional and Anatomical Outcome of Radial Optic Neurotomy for Central Retinal Vein Occlusion. AB - BACKGROUND: Without treatment, the natural history of central retinal vein occlusion (CRVO) can result in severe loss of vision. MATERIAL AND METHODS: This was a retrospective study of 10 eyes with CRVO treated with pars plana vitrectomy (PPV), combined with radial optic neurotomy. The patients completed a minimum of 5 years follow-up. RESULTS: Median age at the time of surgery was 67 +/- 14 years. Median follow-up was 79 +/- 9 months. Ischaemic changes were present in 4 patients pre-operatively. Baseline median logMAR BCVA was 2.00 +/- 0.76 and improved significantly to a median of 0.35 +/- 0.54 (p < 0.0001, two tailed t test) at 5 years follow-up. The baseline median central macular thickness (CMT) was 645 +/- 108 um and improved significantly, to a median of 203 +/- 72 um (p < 0.0001, two tailed t test). One of the patients developed neovascular complications during the follow-up period. CONCLUSIONS: Our results compare very favorably with the natural history of CRVO. All patients demonstrated a trend to improved visual acuity, while only one of the patients developed neovascular complications. These results provide information on the potential long-term effect of PPV in patients with CRVO and may help to reassess the place of the surgical management of CRVO in patients who do not respond to medical treatment. PMID- 27116506 TI - Increased Prevalence of Flammer Syndrome in Patients with Retinitis Pigmentosa. AB - BACKGROUND: "Retinitis pigmentosa" refers to a group of degenerative eye diseases with a genetic background. Flammer syndrome encompasses a set of symptoms and signs, mainly but not exclusively related to dysregulation of blood vessels. The purpose of the present study was to determine, with the help of a questionnaire, whether symptoms of Flammer syndrome occur more often in patients with retinitis pigmentosa than in controls. METHODS: 76 patients with retinitis pigmentosa (members of the Swiss patient organization for retinitis pigmentosa) and 274 control subjects answered a questionnaire (Flammer Syndrome Questionnaire) on 15 symptoms and signs of Flammer syndrome. RESULTS: Seven of 15 symptoms and signs of Flammer syndrome were significantly more often positive in retinitis pigmentosa patients than in controls. Six additional symptoms and signs occurred non-significantly more often and 2 non-significantly less often in patients with retinitis pigmentosa. CONCLUSION: Retinitis pigmentosa patients suffer significantly more often from symptoms and signs of the Flammer syndrome than control subjects. This includes low body mass index, low blood pressure, feeling cold, migraine, increased smell perception and perfectionism. The reason for this association between retinitis pigmentosa and Flammer syndrome and the potential implications need to be determined. PMID- 27116507 TI - Transient Subfoveal Fluid and Visual Loss after Ocriplasmin. AB - BACKGROUND: Intravitreal injection of ocriplasmin for the enzymatic resolution of vitreomacular traction was approved for the EU in 2013. We wish to report our clinical findings and adverse effects that were not observed in the registration trial. THERAPY AND OUTCOME: In 5 of our first 12 consecutive cases, resolution of the vitreomacular traction occurred after injecting ocriplasmin. 9 of the 12 patients developed subfoveal fluid, manifest at day 3 post-intervention; this was completely re-absorbed by 6 weeks in 8 of 9 eyes. All 9 cases with subretinal fluid exhibited a significant reduction in mean visual acuity at the first visit, of 0.33 LogMAR (p = 0.008, Wilcoxon signed rank test). After regression of the subretinal fluid, visual acuity returned to the baseline value. CONCLUSIONS: In the light of the documented adverse effects of the registration trial, the relatively high rate of subfoveal fluid after injecting ocriplasmin was surprising. Possible causes include enzymatic lysis of the matrix between the outer segments of the photoreceptors and the microvilli of the RPE-cells, or barrier disturbances in the RPE through lysis of the zonulae occludentes. PMID- 27116508 TI - A Novel Recessive RPGRIP1 Mutation Causing Leber Congenital Amaurosis. AB - BACKGROUND: Leber congenital amaurosis is an early-onset childhood severe retinal dystrophy, of significant genetic heterogeneity. RPGRIP1 is ubiquitously expressed, but mutations in RPGRIP1 lead to a retina-restricted phenotype, such as Leber congenital amaurosis and cone-rod dystrophy. PATIENT AND METHODS: We analysed a consanguineous family from Egypt in which one individual, a four-year old girl, was affected with Leber congenital amaurosis. IROme, a proprietary enrichment system for retinal dystrophy genes, was applied and high throughput sequencing was performed. RESULTS: Severe visual impairment was reported during infancy. The fundus of the affected patient exhibited disc pallor and attenuated vessels. Neurodevelopmental delay and brain atrophy in the CT scan were reported. Genomic sequencing identified a novel homozygous deletion, c.[420delG], in RPGRIP1. This mutation was not detected in 80 ethnically matched controls and has not been reported elsewhere. CONCLUSIONS: Identifying new mutations in Leber congenital amaurosis-related genes and their clinical manifestations can improve our understanding of the disease and could help to stratify the population for potential therapies. PMID- 27116509 TI - Acid Violet 17: a New Dye for Chromovitrectomy? AB - BACKGROUND: Acid violet 17 (AV17) has recently received CE certification as a dye for intraocular use during vitreoretinal interventions. This publication reviews the available preclinical and clinical data on the use of this new dye. MATERIAL AND METHODS: A systematic MEDLINE literature search was conducted on preclinical testing, clinical testing, and application of AV17 in ocular cell cultures, organ cultures, or ex vivo and in vivo ocular surgical procedures. RESULTS: Of the 59 primary hits, 5 publications (4 preclinical, 1 clinical) were identified as reporting relevant data. All available results on preclinical testing referred to concentrations of AV17 much lower (0.005 to 1.0 mg/ml) than the presently marketed dye (1.5 mg/ml, ala purple, ala(r)medics, Dornstadt/Germany). Toxic or undesired effects of AV17 on different ocular structures or cells were observed under the following conditions: retinal pigment epithelium: 0.25 mg/ml, 180 seconds, 0.05 mg/ml, 1800 seconds; ganglion cell viability: 0.25 mg/ml, 30 seconds; Muller cell activation: 0.25 mg/ml, 30 seconds; astrocyte activation 0.5 mg/ml, 30 seconds; microglia activation: 0.5 mg/ml, 300 seconds. No adverse effects were observed in a clinical case series of macular hole surgery (Peel et al. 2015). In this series, the dye was not applied as described in the label. In our own clinical experience, two different undesired effects were observed: transient discolouration of hydrophilic intraocular lenses and degeneration of the RPE in cases of macular hole surgery. CONCLUSIONS: Preclinical tests indicate that AV17 has toxic and undesired effects at concentrations much lower than claimed by suppliers. Against the background of these data and the first observations of adverse clinical effects, it seems advisable to be cautious when using AV17. PMID- 27116510 TI - Effect of Risk Alleles in CFH, C3, and VEGFA on the Response to Intravitreal Bevacizumab in Tunisian Patients with Neovascular Age-related Macular Degeneration. AB - Purpose. The aim of this pharmacogenetic study was to evaluate the impact of high risk alleles in factor H, factor C3 and vascular endothelial growth factor (VEGF) on the response to intravitreal bevacizumab in patients with neovascular age related macular degeneration (AMD) in a Tunisian population. Methods. Ninety patients with active neovascular AMD treated with intravitreal bevacizumab injections were enrolled in the study. Treatment response was evaluated by comparing BCVA at baseline and at 12 months. Patients were classified into either "poor responders" (PR) or "good responders" (GR). Single nucleotide polymorphism (SNP) genotyping was performed for rs1061170 in FH, rs2230199 in C3 andrs699947, rs2010963 and rs3025039 in VEGF. The association between genotype and visual response at 12 months was assessed. Results. Seventy-seven participants were assigned to the GR group and 13 to the PR group. No correlation was found between FH, C3 and VEGF variant alleles and treatment response. However, haplotype analysis of rs699947 ((- 2578) C/A), rs2010963 ((+ 405) C/G) and rs3025039 ((+ 936) C/T) SNPs revealed that the AGT haplotype was associated with a poor response at 12months (p = 0.048). No association was found between treatment response and the cumulative effect of all high-risk alleles of C3, FH and VEGF. All three types of CNV were found in both groups at a comparable frequency. Conclusions. The VEGF haplotype TGA could be used as a marker for poor visual prognosis in Tunisian patients with neovascular AMD treated with bevacizumab. PMID- 27116511 TI - Long-term Results of Intravitreal Anti-VEGF Injections in Wet AMD: A Meta Analysis. AB - BACKGROUND: Although intravitreal anti-VEGF medications are widely used in age related macular degeneration, no systematic data analysis is available on the long-term prognosis of this relatively new therapeutic approach. MATERIAL AND METHODS: A meta-analysis was performed on available Medline literature. 13 relevant clinical studies (14 case series) could be identified, covering 10 247 treated eyes. The majority of available reports originate from single centre retrospective real-life environments. RESULTS: The mean improvement in average visual gain was 0.9 +/- 0.5 (mean +/- 1 standard deviation, median; 0.8 lines) at year 1, 1.2 +/- 1.1 (median: 1.1) letters at year 2, 0.7 +/- 1.0 (median: 0.7) letters at year 3, and 0.2 +/- 0.8 (median: 0.5), 0.4 +/- 0.4 (median: 0.5) at years 4 and 5. The drop-out rates in these studies was relatively high. At the end of year 3, the average percentage of observed eyes was 44.3 +/- 18.4 % (mean +/- 1 standard deviation), at the end of year 4 23.5 +/- 23.9 % and after years 6 and 7 below 10 % (8.2 and 7.9 %). The mean treatment frequency of injections in all available studies was highest in year 1 (6.4 +/- 1.2, 6.1 - mean +/- SD; median), followed by relatively consistent mean values of 4.1 and 5.1 (year (Y)2: 4.4, Y3: 4.3, Y4: 4.7, Y5: 4.1, Y6: 5.1, Y7: 4.7) injections per year. CONCLUSIONS: The results of this meta-analysis clearly indicate that intravitreal anti-VEGF injection therapy is capable of maintaining visual acuity on a long term basis of at least 4-5 years. PMID- 27116512 TI - Swiss Family with Dominant Stargardt Disease Caused by a Recurrent Mutation in the ELOVL4 Gene. PMID- 27116514 TI - Angioid Streaks in Types I and II Congenital Dyserythropoietic Anaemia (CDA). AB - Background. Angioid streaks (AS) are visible irregular breaks in Bruch's membrane, extending radially from the optic nerve head and with overlaying atrophic retinal pigment epithelium. In 50 % of patients, AS are associated with Pseudoxanthoma elasticum, Ehlers-Danlos syndrome, sickle cell anaemia or Paget's disease. In 50 % of patients, AS are idiopathic. Congenital Dyserythropoietic Anaemia (CDA) is a rare, inherited disorder of ineffective erythropoiesis with morphologically abnormal erythroblasts. CDA was first recognised as a separate entity in 1968 and classified into three main groups. CDA demographics have identified 614 known families and > 700 cases worldwide. A few case reports of AS in CDA I and III have been published, but there is no report of AS in CDA II, the most frequent of the CDAs, as well no follow-up. History and Signs. 8 eyes of 4 CDA patients were examined. The CDA I patients were a 46 year old man and a 52 year old woman. They were first seen in 2009 and followed up for 9 and 11 months, respectively. The 2 female CDA II patients were seen in 2010 and were aged 35 and 42 years at first presentation. Vision, Amsler grid, optical coherence tomography (OCT), fundus pictures and fluorescent angiography were performed. Blood was drawn for neutrophil elastase determination (ELA2). Therapy and Outcome. All patients showed bilateral AS. Mean best corrected visual acuity was 20/20 without metamorphopsia and with normal OCT. During the follow-up period, no progression occurred. No choroidal neovascularisation (CNV) was detected. ELA2 serum levels were normal. Conclusions. This is the first report of AS in CDA II and the first follow-up in CDA I. No evidence of progression was seen within this period of time. Longer follow-up is needed to detect whether AS progresses. All patients with AS should be seen by an ophthalmologist on a regular basis. The risk of CNV is given. Therapy is possible and the outcome is best if the CNV is recognised and treated early. PMID- 27116513 TI - Incidence and Surgical Management of Simultaneous Bilateral Retinal Detachment. AB - BACKGROUND: Simultaneous bilateral retinal detachment (RD) is very rare and its incidence has not been very well characterised. MATERIAL AND METHODS: Retrospective review of RD cases treated at the Jules Gonin Eye Hospital between 1999 and 2010. RESULTS: Over the 11 year period, 10 patients (20 eyes) with simultaneous bilateral RD were identified (average incidence among RD= 0.9 %). Mean age: 46.4 +/- 17.6 years, with a M : F Ratio of 6 : 4. Pseudophakia was present in 10 eyes and myopia >=-5.0 dioptres in 11 eyes. Visual symptoms were unilateral in 7 patients, bilateral in 2 patients and absent in one patient. RD was macula-on in 15 eyes and macula-off in 5 eyes. Atrophic holes were present in 11 eyes, U-tears in 6 eyes and a combination in 3 eyes. Primary surgery consisted of buckle surgery (11 eyes), vitrectomy (6 eyes) and combines technique (3 eyes). The final anatomical success rate was 100 %. Mean follow-up time was 22.7 +/- 4.95 months. CONCLUSION: The incidence of bilateral simultaneous RD appears to be very low and surgical success rates are excellent. Bilateral pre-operative dilated fundoscopy is mandatory, as the majority of patients have unilateral symptoms. PMID- 27116515 TI - Recurrent Central Serous Chorioretinopathy Under Combined Vemurafenib and Cobimetinib Treatment. PMID- 27116516 TI - Pattern-Dystrophie ahnliche subretinale Pigmentdispersion nach Identations Chirurgie bei Amotio retinae. PMID- 27116517 TI - Relation Between Implant Position and Perceptual Threshold in a Patient with Epiretinal Prosthesis System. PMID- 27116518 TI - Ocular Manifestation of Non-Parenchymal Neuro-Behcet Syndrome. PMID- 27116519 TI - Vitrectomy with Gas Tamponade and anti-VEGF Injections for the Management of Submacular Hemorrhage. PMID- 27116520 TI - Unexpected Intraocular Migration of a Cilium During Pars Plana Vitrectomy. PMID- 27116521 TI - [Spectral Domain Optical Coherence Tomography (SD-OCT) in Surgery for Optic Disc Pit Maculopathy]. PMID- 27116522 TI - Radiation Retinopathy 15 Years after Orbital Irradiation for Thyroid Orbitopathy. PMID- 27116523 TI - Retinopathy after 30 Gray Whole Brain Radiation. PMID- 27116524 TI - Hydroxychloroquine-Induced Retinal Toxicity. PMID- 27116526 TI - Prevention of Silicone Oil Migration and Baerveldt Tube Blockage in Retinal Detachment Surgery with Partial Aniridia. PMID- 27116525 TI - [Unusual Occlusion of the Central Retinal Vein in a 28-Year-Old Patient]. PMID- 27116527 TI - Cyclical Spontaneous Resorption of Serous Macular Detachment Associated with Optic Disc Coloboma. PMID- 27116528 TI - Can Low Dose Radiation Therapy (2 * 2 Gy) be Used in Primary Bilateral Conjunctival Follicular Lymphoma? PMID- 27116529 TI - [Optical Coherence Tomography (OCT) in Diffuse Choroidal Haemangioma in Sturge Weber Syndrome Treated with Low Dose Ocular Irradiation]. PMID- 27116530 TI - Multimodal Imaging of Retinal Astrocytic Hamartoma Associated with Congenital Hypertrophy of Retinal Pigment Epithelium. PMID- 27116531 TI - Ocular Toxoplasmosis: an Update. AB - INTRODUCTION: Although the seroprevalence of toxoplasmosis has undergone a progressive 50 % decline during the past 20 years, the disease remains an economically important health hazard in many countries. Ocular toxoplasmosis (OT) is the most frequent cause of infectious posterior uveitis, and new insights into its pathophysiology have paved the way for new therapeutic strategies. METHODS: This review summarises recent insights into the disease, its clinical manifestations and therapeutic options. The data have been gleaned from a PubMed search, which was conducted in August 2015 using the key term "ocular toxoplasmosis". RESULTS: A laboratory confirmation of the diagnosis serves as the basis for estimating the clinical burden of OT. This is more severe in South America than in Europe, due to the higher incidence of the more virulent New World parasitic strains. It is not yet possible to differentiate between acquired and congenital cases in most patients. However, in elderly individuals, clinical manifestations of acquired OT are more frequently encountered and in atypical forms. Although inflammation may initially be more pronounced in acquired than in congenital cases of OT, the final visual acuity is usually better and the risk of recurrence lower. Amongst the numerous therapeutic options, none is clearly superior. In immunocompromised individuals and in those with frequent recurrences, prophylactic measures should be considered. CONCLUSION: OT is still a potentially vision-threatening affection, namely in elderly individuals with acquired disease and in those patients harbouring the more aggressive New World strains of the parasite. Owing to the limitations in diagnostic sensitivity and therapeutic efficacy, treatment strategies have to be tailored to the individual needs. PMID- 27116532 TI - Intraocular Inflammation Associated with New Therapies for Cutaneous Melanoma - Case Series and Review. AB - Background. In advanced cutaneous melanoma, new systemic therapies include immunotherapy by checkpoint inhibition and targeted inhibition of the mitogen activated protein kinase pathway; these are becoming increasingly well established. We describe the clinical presentation of uveitis in three patients with concomitant systemic melanoma treatment. History and Signs. Three patients with metastatic melanoma receiving systemic therapy (ipilimumab, vemurafenib) presented at our institution with a short history of ocular symptoms. Clinical findings included anterior uveitis, intermediate uveitis, disc swelling, inflammatory choroidal lesions and retinal vasculitis. Therapy and Outcome. All three patients responded well to local and/or systemic steroid treatment. In one case, the systemic anti-cancer drug was discontinued after the onset of uveitis. Conclusions. Ocular inflammation may occur in the setting of systemic melanoma therapy. Presentations of uveitis include Vogt-Koyanagi-Harada-like syndromes. Ocular inflammation can usually be controlled by topical and sometimes systemic corticosteroid therapy. However, treatment guidelines are not established and management of these patients demands close cooperation with the oncologist. PMID- 27116533 TI - Spectral Domain Optical Coherence Tomography for the Characterization of Kyrieleis Exudates Involving Both the Fovea and Retinal Vessels. PMID- 27116534 TI - Epilepsy in children and adolescents: Disease concepts, practical knowledge, and coping. AB - PROBLEM: Children suffering from epilepsy face severe difficulties in daily life. However, data about the self-assessment of children are scarce. METHODS: From October 2013 to February 2014, patients aged 6-18years suffering from epilepsy were consecutively invited (i) to take part in a structured interview and (ii) to draw a picture about their self-assessment of epilepsy. RESULTS: Eighty-four children and their parents agreed to participate: (i) 63/84 (75%) of the children named their disease correctly; contagiousness was assumed by 8/84 (10%); 81/84 (96%) knew whether they have to take medication; 36/69 (52%) of the children taking long-term medication reported the name(s) of their medication; 8/69 (12%) believed that their medication will cure their disease; 45/84 (54%) named specific precautions to prevent harm from seizures; 6/84 (7%) believed that nonadherence to safety precautions would cause new seizures; and 23/84 (27%) believed that they are worse off than healthy children. (ii) 67/84 (80%) drew a picture titled "This is how I feel when I have a seizure". Specific symptoms [17/67 (25%)] and the interaction between child and environment [12/67 (18%)] were the most common subjects. CONCLUSION: Most children with epilepsy had rather good knowledge about medication; half of the children knew specific safety precautions. The children were often able to describe their seizures well. Pictures drawn by patients can give an insight into their experiences. Teaching programs should, among others, address the fear of contagiousness of epilepsy in some children and the fact that children with epilepsy might feel disadvantaged. PMID- 27116535 TI - Seizure clusters: A common, understudied and undertreated phenomenon in refractory epilepsy. AB - Epilepsy is widely prevalent globally and has emerged as a well-studied neurological condition in the recent past. Seizure clusters, a type of seizures, and several aspects pertaining to the etiopathogenesis and management of clusters are yet to be elucidated. This review is an attempt to recapitulate the current understanding of seizure clusters based on the research that has been performed on seizure clusters. This article will provide a comprehensive review of various aspects of clusters, and discusses definitions, prevalence, risk factors, impact on quality of life, approved treatment modalities, and recent advances in management. PMID- 27116536 TI - Anxiety disorders in people with epilepsy. AB - Anxiety disorders are frequent, though probably underdiagnosed, comorbidities in epilepsy. Epilepsy and anxiety may share common neurobiological correlates as shown in animal models and suggested by studies demonstrating anxiety disorders before the manifestation of epilepsy. Comorbid anxiety disorders have a major impact on the affected patients' quality of life and may increase the risk for suicidality. Successful treatment of the epilepsy may alleviate anxiety symptoms. Treatment of anxiety is based on selective serotonin reuptake inhibitors, benzodiazepines (although only as second-line choices), and psychotherapy. Specific AEDs (especially pregabalin) have been shown to have anxiolytic properties. This paper is aimed at reviewing anxiety disorders in patients with epilepsy discussing current scientific evidence about pathophysiology, clinical aspects, and treatment strategies. PMID- 27116537 TI - Status epilepticus associated with pregnancy: A cohort study. AB - BACKGROUND: Status epilepticus (SE) is a neurological emergency associated with a high mortality rate and long-term cognitive sequelae. Status epilepticus in pregnancy poses a tremendous threat to both mother and fetus, making a correct diagnosis and treatment a challenging task for clinicians. The prevalence, underlying etiology, and outcomes of pregnancy-related SE remain largely unknown. METHODS: We retrospectively studied all SE episodes (n=366) in patients admitted to our neurological ICU over a period of 8.5years. The patients who developed SE during pregnancy and within 6months after delivery were considered to have pregnancy-related SE. Patients with eclampsia were not included as they were usually cared for in our obstetric unit. RESULTS: Seven patients with pregnancy related SE were identified (2.1% of all cases of SE), with the majority (85%) occurring de novo except for one patient who had a previous history of epilepsy related SE due to withdrawal of antiepileptic medication. In terms of etiology, limbic encephalitis and cerebral venous sinus thrombosis were the two main etiologies of de novo SE associated with pregnancy. The overall mortality rate was 28.5% at discharge, and poor outcomes were especially noted in the patients with limbic encephalitis compared to other etiologies. CONCLUSIONS: Pregnancy associated SE is rare and predominantly occurs in patients without a history of epilepsy. An autoimmune etiology should be considered in pregnant patients with de novo SE, which was associated with poor outcomes. Thorough investigations and prompt treatment according to the etiology may be required to improve the final outcomes of both mother and fetus. PMID- 27116538 TI - The Effect of Everolimus on Scar Formation in Glaucoma Filtering Surgery in a Rabbit Model. AB - PURPOSE: To investigate the efficiency of everolimus on the prevention of postoperative scar in a rabbit model of glaucoma filtering surgery in comparison with mitomycin-C (MMC). MATERIALS AND METHODS: Thirty New Zealand albino rabbits were randomly assigned into 3 groups, each including ten rabbits: an everolimus group (Group 1), a MMC group (Group 2), and a sham group (Group 3). A limbal based trabeculectomy was performed on the right eyes of all the rabbits. For 28 days following surgery, the eyes were evaluated in terms of intraocular pressure (IOP), morphological and biomicroscopic changes, and complications in the bleb. On the 28th day, four eyes randomized from each group were enucleated and histologically and immunohistochemically analyzed. Transforming growth factor beta1 (TGF-beta1), metalloproteinase (MMP-2, MMP-9), and proliferative cell nuclear antigen (PCNA) expressions in each group were evaluated. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method was used for apoptosis. RESULTS: Bleb survival was statistically significantly longer for a period in Group 1 compared to Group 2. When postoperative IOPs of three groups were measured, it was seen that there is significant IOP reduction in all three groups. However, there were increases in the mean IOP values beginning from the 5th day in Group 2 and from the 3rd day in Group 3 while in Group 1 mean IOP values began to increase beginning from 10th day and the mean IOP values in Group 1 remained at a lower level in comparison to the other groups for 28 days (p < 0.05). The expressions of TGF-beta1, MMP-2, MMP-9, and PCNA were reduced in Group 1 compared to other groups. TUNEL positive apoptotic cells were significantly increased in Group 1 compared to other groups (p < 0.05). CONCLUSION: Everolimus appears to suppress the proliferation of fibroblast and thus may provide an effective treatment strategy in glaucoma filtering surgery. PMID- 27116539 TI - Genotype 3b of human parvovirus B19 detected from hospitalized children with solid malignancies in a North Indian tertiary care hospital. AB - Human parvovirus B19 (B19V) infection is known to cause serious consequences in immuno-compromized individuals. The present cross sectional study was designed to estimate the prevalence and genotype distribution of B19V in children receiving chemotherapy for solid malignancies at a tertiary care hospital in North India during October 2013 to May 2015. Serum samples from all the patients were tested for anti-B19V IgM and IgG antibodies and for B19V-DNA as soon as received. Samples testing positive for B19V-DNA were subjected to viral load estimation and to genotype determination by sequencing. Total 96 children were enrolled of which 9 (9.3%), 32 (33.3%), and 25 (26%) tested positive for anti-B19V IgM, anti-B19V IgG, and B19V-DNA, respectively. The viral load of B19V-DNA positive children ranged from 5.5 * 10(2) to 3.5 * 10(12) copies/ml. Accordingly children were divided into three groups: group I, with acute infection (n = 25); group II, previously exposed (n = 27), and group III, negative for B19V infection or with inappropriate antibody response (n = 44). B19V positivity was significantly associated (P-value < 0.0001) with a history of blood transfusion in the past 6 months, severe anemia (hemoglobin levels <6 gm%) and thrombocytopenia (platelets <150,000/cu.mm.). Sequence analysis of 21 of 25 DNA positive samples showed that all of them were Genotype 3b that clustered into three groups. All the sequences within each cluster were identical. The nucleotide identity of the sequences suggests a nosocomial outbreak of B19V during the study period. Children on chemotherapy for solid tumors should be routinely screened for B19V infection by both serology and PCR. J. Med. Virol. 88:1922-1929, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27116541 TI - Mechanistic Studies on Garratt-Braverman Cyclization: The Diradical-Cycloaddition Puzzle. AB - In this work, we present the results of extensive multiprong studies involving the fate of deuterium-labeled substrates, EPR, trapping experiments, and LA-LDI mass spectrometry to sort out the controversies relating to the mechanism of Garratt-Braverman cyclization in two systems, namely bis-propargyl sulfones and ethers. The results are in conformity with a diradical mechamism for the sulfone, while for the ether, the anionic [4 + 2] appears to be the preferred pathway. This shows that the mechanistic pathway toward GB cyclization is dependent upon the nature of heteroatom (O or S in sulfone) bridging the propargyl arms. PMID- 27116540 TI - Adolescent, caregiver, and friend preferences for integrating social support and communication features into an asthma self-management app. AB - OBJECTIVES: This study examines: 1) adolescent preferences for using asthma self management mobile applications (apps) to interact with their friends, caregivers, medical providers, and other adolescents with asthma and 2) how caregivers and friends would use mobile apps to communicate with the adolescent and serve as sources of support for asthma management. METHODS: We recruited 20 adolescents aged 12-16 years with persistent asthma, their caregivers (n = 20), and friends (n = 3) from two suburban pediatric practices in North Carolina. We gave participants iPods with two preloaded asthma apps and asked them to use the apps for 1 week. Adolescents and caregivers provided app feedback during a semi structured interview at a regularly-scheduled clinic appointment and during a telephone interview one week later. Friends completed one telephone interview. Interviews were audio-recorded and transcribed verbatim. An inductive, theory driven analysis was used to identify themes and preferences. RESULTS: Adolescents preferred to use apps for instrumental support from caregivers, informational support from friends, and belonging and informational support from others with asthma. The majority of adolescents believed apps could enhance communication with their caregivers and medical providers, and the theme of self-reliance emerged in which caregivers and adolescents believed apps could enable adolescents to better self-manage their asthma. Friends preferred to use apps to provide instrumental and informational support. CONCLUSIONS: Given preferences expressed in this study, apps may help adolescents obtain social support to better self-manage their asthma. Future app-based interventions should include features enabling adolescents with asthma to communicate and interact with their caregivers, medical providers, and friends. PMID- 27116543 TI - Direct oral anticoagulants: a practical guide for the emergency physician. AB - The direct oral anticoagulants (DOACs) are the mainstay for stroke prophylaxis in nonvalvular atrial fibrillation and treatment of acute venous thrombosis. They are attractive alternatives to warfarin because of their efficacy, ease of prescription and safety profile. The emergency department has gained expertise in the management of DOAC bleeding complications, but has been slower to adopt prescription decisions. Emergency clinicians are in a unique position to identify patients who are prescribed DOACs and are at high risk of impending bleeding. This is a practical guide for the emergency clinician on how to prescribe DOACs, the red flags for DOAC patients in the emergency department and advances in the treatment of bleeding. PMID- 27116542 TI - Tobacco carcinogen induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation. AB - Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-kappaB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of alpha7 nicotinic acetylcholine receptor in the lung and NF-kappaB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury. PMID- 27116544 TI - Overexpression of Cathepsin E Interferes with Neuronal Differentiation of P19 Embryonal Teratocarcinoma Cells by Degradation of N-cadherin. AB - Cathepsin E (CatE), an aspartic protease, has a limited distribution in certain cell types such as gastric cells. CatE is not detectable in the normal brain, whereas it is increasingly expressed in damaged neurons and activated microglia of the pathological brain. Neurons expressing high levels of CatE showed apparent morphological changes, including a marked shrinkage of the cytoplasmic region and beading of neurites, suggesting neuronal damage. The intracellular level of CatE in neurons is strictly regulated at both transcriptional and translational levels. Although the up-regulation of CatE may cause pathological changes in neurons, little information is available about the precise outcome of the increased expression of CatE in neurons. In this study, we have attempted to clarify the outcome of up-regulated CatE gene expression in neurons using the P19 cell neuronal differentiation after the overexpression of CatE. We unexpectedly found that the overexpression of CatE interfered with neuronal differentiation of P19 cells through an impairment of cell aggregate formation. Pepstatin A, an aspartic protease inhibitor, restored the impaired cell aggregation of P19/CatE cells. The small number of P19 cells differentiated into neurons had abnormal morphology characterized by their fusiform cell bodies with short processes. Furthermore, CatE proteolytically cleaved the extracellular domain of N-cadherin. These observations suggest that the overexpression of CatE interferes with neuronal differentiation of P19 cells through an impairment of cell aggregate formation, possibly through proteolytic degradation of N-cadherin. PMID- 27116545 TI - miR-183 Inhibits UV-Induced DNA Damage Repair in Human Trabecular Meshwork Cells by Targeting of KIAA0101. AB - PURPOSE: The purpose of this study was to investigate the mechanisms by which miR 183 may contribute to the phenotypic alterations associated with stress-induced senescence of human trabecular meshwork (HTM) cells. METHODS: Changes in gene expression induced by miR-183 in HTM cells were evaluated by gene array analysis, confirmed by quantitative-PCR (Q-PCR), and analyzed by MetaCore pathway analysis. Effects of miR-183 on cell proliferation were assessed by incorporation of bromodeoxyuridine incorporation, and DNA damage by CometAssay after ultraviolet (UV) irradiation in primary HTM cells, and confirmed in human diploid fibroblasts (HDF) and HeLa cells. A plasmid expressing KIAA0101 without its 3'-untranslated region (3'-UTR) was cotransfected with miR-183 to evaluate the role of KIAA0101 on the effects induced by miR-183. RESULTS: miR-183 affected the expression of multiple genes involved in cell cycle regulation and DNA damage response in HTM cells. Forced expression of miR-183 in HTM and HDF resulted in a significant decrease in proliferation in primary HTM and HDF cells but not in HeLa cells. In all cell types tested, overexpression of miR-183 resulted in increased DNA damage under UV irradiation. Expression of KIAA0101 lacking the 3'-UTR region partially prevented the effects of miR-183 on cell proliferation and completely reversed the effects on UV-induced DNA damage. CONCLUSIONS: Our results suggest that the observed up-regulation of miR-183 after stress-induced senescence in HTM cells may contribute to reinforce cellular senescence by inhibiting cell cycle progression through multiple gene targets and limiting the DNA repair mechanisms through inhibition of KIAA0101. PMID- 27116546 TI - NorLeu3A(1-7) Accelerates Clear Corneal Full Thickness Wound Healing. AB - PURPOSE: We evaluated the effect of the renin angiotensin system (RAS) peptide NorLeu3-Angiotensin (1-7) (NLE) formulated in a viscoelastic gel (USB004) on the healing of full-thickness corneal injuries. METHODS: Dutch pigmented rabbits received conjunctival administration of 0.3% USB004, 0.03% USB004, or vehicle control to healthy and full-thickness injured eyes administered once daily for 28 consecutive days. Safety was evaluated using IOP measurement, slit-lamp examination, and confocal microscopy. Evaluations for both efficacy studies included an oblique light examination, modified Seidel test (Seidel test with gentle ocular pressure) as well as during elevated IOP test, confocal microscopy imaging, and histologic analysis. RESULTS: Application of 0.3% USB004, 0.03% USB004, and vehicle-control was safe in healthy and incised eyes. Further, application of 0.3% and 0.03% USB004 following full-thickness corneal incision resulted in a 2-fold acceleration of resolution of edema and inflammation, reduction in duration of wound leakage on a modified Seidel test (Seidel test with gentle ocular pressure) as well as during elevated IOP test, and healing with near normal architecture without evidence of fibrosis and angiogenesis when compared to vehicle-control animals. CONCLUSIONS: Topical ocular application of 0.3% and 0.03% USB004 promotes full-thickness cornea wound healing without the evidence of fibrosis and angiogenesis. Further studies are warranted to determine the cornea-specific mechanism of action(s) that promotes regeneration leading to clear corneal healing. PMID- 27116547 TI - Engineering a Light-Attenuating Artificial Iris. AB - PURPOSE: Discomfort from light exposure leads to photophobia, glare, and poor vision in patients with congenital or trauma-induced iris damage. Commercial artificial iris lenses are static in nature to provide aesthetics without restoring the natural iris's dynamic response to light. A new photo-responsive artificial iris was therefore developed using a photochromic material with self adaptive light transmission properties and encased in a transparent biocompatible polymer matrix. METHODS: The implantable artificial iris was designed and engineered using Photopia, a class of photo-responsive materials (termed naphthopyrans) embedded in polyethylene. Photopia was reshaped into annular disks that were spin-coated with polydimethylsiloxane (PDMS) to form our artificial iris lens of controlled thickness. RESULTS: Activated by UV and blue light in approximately 5 seconds with complete reversal in less than 1 minute, the artificial iris demonstrates graded attenuation of up to 40% of visible and 60% of UV light. There optical characteristics are suitable to reversibly regulate the incident light intensity. In vitro cell culture experiments showed up to 60% cell death within 10 days of exposure to Photopia, but no significant cell death observed when cultured with the artificial iris with protective encapsulation. Nuclear magnetic resonance spectroscopy confirmed these results as there was no apparent leakage of potentially toxic photochromic material from the ophthalmic device. CONCLUSIONS: Our artificial iris lens mimics the functionality of the natural iris by attenuating light intensity entering the eye with its rapid reversible change in opacity and thus potentially providing an improved treatment option for patients with iris damage. PMID- 27116548 TI - Longitudinal Development of Refractive Error in Children With Accommodative Esotropia: Onset, Amblyopia, and Anisometropia. AB - PURPOSE: We investigated longitudinal changes of refractive error in children with accommodative esotropia (ET) throughout the first 12 years of life, its dependence on age at onset of ET, and whether amblyopia or anisometropia are associated with defective emmetropization. METHODS: Longitudinal refractive errors in children with accommodative ET were analyzed retrospectively. Eligibility criteria included: initial hyperopia >= +4.00 diopters (D), initial cycloplegic refraction before 4 years, at least 3 visits, and at least one visit between 7 and 12 years. Children were classified as having infantile (N = 30; onset <= 12 months) or late-onset (N = 78; onset at 18-48 months) accommodative ET. Cycloplegic refractions culled from medical records were converted into spherical equivalent (SEQ). RESULTS: Although the initial visit right eye SEQ was similar for the infantile and late-onset groups (+5.86 +/- 1.28 and +5.67 +/- 1.26 D, respectively), there were different developmental changes in refractive error. Neither group had a significant decrease in hyperopia before age 7 years, but after 7 years, the infantile group experienced a myopic shift of -0.43 D/y. The late-onset group did not experience a myopic shift at 7 to 12 years. Among amblyopic children, a slower myopic shift was observed for the amblyopic eye. Among anisometropic children, the more hyperopic eye experienced more myopic shift than the less hyperopic eye. CONCLUSIONS: Children with infantile accommodative ET experienced prolonged hyperopia followed by a myopic shift after 7 years of age, consistent with dissociation between infantile emmetropization and school age myopic shift. In contrast, children with late-onset accommodative ET had little myopic shift before or after 7 years. PMID- 27116549 TI - Albumen Transport to Bruch's Membrane and RPE by Choriocapillaris Caveolae. AB - PURPOSE: The choriocapillaris (CC), the capillary network of the choroid, is positioned adjacent to Bruch's membrane (BM) and the RPE. The aim of this study was to clarify the mechanism(s) for transport of serum albumen from CC lumen to RPE. METHODS: Alexa647 conjugated to BSA (BSA-A647) or PBS was administrated via the femoral vein to young and aged wild-type (WT; C57BL/6J) mice and Caveolin-1 knockout mice (Cav1(-/-)). Mice were perfused with PBS and killed at 30 minutes, 1 hour, and 4 hours after injection. Eyecups were cryopreserved, and cryosections were analyzed on a Zeiss 710 confocal microscope. Bovine serum albumin conjugated to gold nanoparticles (BSA-GNP) was administrated through the left common carotid artery. Mice were perfused with PBS and killed at 30 minutes after injection. Eyecups were embedded after fixation, and 70-nm-thick sections were analyzed on a Hitachi H7600 transmission electron microscope. RESULTS: In eyes of WT young mice, BSA-A647 was transported to the RPE at 30 minutes and diffused to the photoreceptor layer by 1 hour. In contrast, most BSA-A647 was found in the CC in Cav1(-/-) eyes. The majority of BSA-GNP found in the CC of young WT mice was on the luminal side in caveolae at 30 minutes after injection. In aged WT mice, BSA GNPs were found in defective tight junctions between endothelial cells and appeared trapped at the diaphragm of fenestrations. CONCLUSIONS: Normally, CC carefully regulates transport system of BSA from lumen to BM by caveolae-mediated transcytosis; however, endothelium cells of aged control WT mice have leaky tight junctions and lacked regulated BSA transport. PMID- 27116552 TI - Dense ionic fluids confined in planar capacitors: in- and out-of-plane structure from classical density functional theory. AB - The ongoing scientific interest in the properties and structure of electric double layers (EDLs) stems from their pivotal role in (super)capacitive energy storage, energy harvesting, and water treatment technologies. Classical density functional theory (DFT) is a promising framework for the study of the in- and out of-plane structural properties of double layers. Supported by molecular dynamics simulations, we demonstrate the adequate performance of DFT for analyzing charge layering in the EDL perpendicular to the electrodes. We discuss charge storage and capacitance of the EDL and the impact of screening due to dielectric solvents. We further calculate, for the first time, the in-plane structure of the EDL within the framework of DFT. While our out-of-plane results already hint at structural in-plane transitions inside the EDL, which have been observed recently in simulations and experiments, our DFT approach performs poorly in predicting in plane structure in comparison to simulations. However, our findings isolate fundamental issues in the theoretical description of the EDL within the primitive model and point towards limitations in the performance of DFT in describing the out-of-plane structure of the EDL at high concentrations and potentials. PMID- 27116551 TI - Metastatic Disease in Polyploid Uveal Melanoma Patients Is Associated With BAP1 Mutations. AB - PURPOSE: Most of the uvea melanoma (UM) display a near-diploid (normal, -2N) karyotype with only a few chromosomal changes. In contrast to these simple aberrations 18% of the UM samples show a polyploid character (>2N) and this was associated with an unfavorable prognosis. This study attempts to gain insight in the prognostic value of polyploidy in UM. METHODS: In 202 patients the ploidy status of the UM was determined using cytogenetic analysis, fluorescence-in-situ hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and/or single nucleotide polymorphism (SNP) array analysis. Immunohistochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) and the mutation hotspots for the SF3B1, EIF1AX, GNAQ, and GNA11 genes was carried out using Sanger sequencing or whole-exome sequencing. RESULTS: Twenty-three patients had a polyploid UM karyotype (11.4%). Patients with a polyploid tumor had larger tumors (15.61 vs. 13.13 mm, P = 0.004), and more often loss of heterozygosity of chromosome 3 (P = 0.003). No difference in occurrence of mutations between polyploid and diploid tumors was observed for BAP1, SF3B1, EIF1AX, GNAQ, and GNA11. Polyploidy did not affect survival (P = 0.143). BAP1 deficiency was the only significant independent prognostic predictor for patients with polyploid tumors, with a 16-fold increased hazard ratio (HR 15.90, P = 0.009). CONCLUSIONS: The prevalence of mutations in the UM related genes is not different in polyploid UM compared with diploid UM. Moreover, similar to patients with diploid UM, BAP1 mutation is the most significant prognostic predictor of metastasis in patients with polyploid UM. PMID- 27116550 TI - Genetic Association Analysis of Drusen Progression. AB - PURPOSE: Age-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis. METHODS: Exome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure. RESULTS: We observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (rho = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02). CONCLUSIONS: In this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk. PMID- 27116553 TI - UK Renal Registry 18th Annual Report: Chapter 2 UK Renal Replacement Therapy Prevalence in 2014: National and Centre-specific Analyses. AB - There were 58,968 adult patients receiving renal replacement therapy (RRT) in the UK on 31st December 2014, an absolute increase of 4.0% from 2013.The actual number of patients increased 2.0% for haemodialysis (HD), 5.3% for those with a functioning transplant but decreased 0.7% for peritoneal dialysis (PD).The UK adult prevalence of RRT was 913 per million population (pmp). The reported prevalence in 2000 was 523 pmp.The number of patients receiving home HD increased by 6.7% from 1,113 patients in 2013 to 1,188 patients in 2014.The median age of prevalent patients was 59 years(HD 67 years, PD 64 years, transplant 53 years).In 2000, the median age was 55 years (HD 63 years, PD 58 years, transplant 48 years). In 2014,the percentage of RRT patients aged greater than 75 years was 16.0%.For all ages, the prevalence rate in men exceeded that in women, peaking in age group 75-79 years at 3,100 pmp in men and for women at 1,600 pmp in age group 70-74 years.The most common identifiable renal diagnosis was glomerulonephritis (19%), followed by diabetes(16%) and aetiology uncertain (16%).Transplantation continued as the most common treatment modality (53%), HD was used in 41%and PD in 6% of RRT patients.Prevalence rates in patients aged 585 years continued to increase between 2013 and 2014 (1,021 per million age related population (pmarp) to 1,060 pmarp). PMID- 27116555 TI - Sexual Synchronicity and Communication Among Partnered Older Adults. AB - Based on secondary analysis of respondent narratives (N = 2,049), this study examined attitudes and behaviors associated with sex frequency and sexual satisfaction in a national sample of partnered older adults, age 50 to 85. In contrast to conventional assumptions about diminished sexuality in older adulthood, the results of this study indicate that sex frequency and sexual satisfaction continue to play an important part in the lives of many partnered older adults. Open communication and sexual synchronicity, including open communication about sexual synchronicity, encourage active and satisfying sex lives in older adulthood. Implications for therapists helping older adults maintain an active and satisfying sex life are discussed. PMID- 27116554 TI - Topical HPMC/S-Nitrosoglutathione Solution Decreases Inflammation and Bone Resorption in Experimental Periodontal Disease in Rats. AB - S-nitrosoglutathione (GSNO) is a nitric oxide (NO) donor, which exerts antioxidant, anti-inflammatory, and microbicidal actions. Intragingival application of GSNO was already shown to decrease alveolar bone loss, inflammation and oxidative stress in an experimental periodontal disease (EPD) model. In the present study, we evaluated the potential therapeutic effect of topical applications of hydroxypropylmethylcellulose (HPMC)/GSNO solutions on EPD in Wistar rats. EPD was induced by placing a sterilized nylon (3.0) thread ligature around the cervix of the second left upper molar of the animals, which received topical applications of a HPMC solutions containing GSNO 2 or 10 mM or vehicle (HPMC solution), 1 h prior to the placement of the ligature and then twice daily until sacrifice on day 11. Treatment with HPMC/GSNO 10 mM solution significantly reduced alveolar bone loss, oxidative stress and TNF-alpha e IL 1beta levels in the surrounding gingival tissue, and led to a decreased transcription of RANK and TNF-alpha genes and elevated bone alkaline phosphatase, compared to the HPMC group. In conclusion, topical application of HPMC/GSNO solution is a potential treatment to reduce inflammation and bone loss in periodontal disease. PMID- 27116556 TI - Enhanced isopropanol and n-butanol production by supplying exogenous acetic acid via co-culturing two clostridium strains from cassava bagasse hydrolysate. AB - The focus of this study was to produce isopropanol and butanol (IB) from dilute sulfuric acid treated cassava bagasse hydrolysate (SACBH), and improve IB production by co-culturing Clostridium beijerinckii (C. beijerinckii) with Clostridium tyrobutyricum (C. tyrobutyricum) in an immobilized-cell fermentation system. Concentrated SACBH could be converted to solvents efficiently by immobilized pure culture of C. beijerinckii. Considerable solvent concentrations of 6.19 g/L isopropanol and 12.32 g/L butanol were obtained from batch fermentation, and the total solvent yield and volumetric productivity were 0.42 g/g and 0.30 g/L/h, respectively. Furthermore, the concentrations of isopropanol and butanol increased to 7.63 and 13.26 g/L, respectively, under the immobilized co-culture conditions when concentrated SACBH was used as the carbon source. The concentrations of isopropanol and butanol from the immobilized co-culture fermentation were, respectively, 42.62 and 25.45 % higher than the production resulting from pure culture fermentation. The total solvent yield and volumetric productivity increased to 0.51 g/g and 0.44 g/L/h when co-culture conditions were utilized. Our results indicated that SACBH could be used as an economically favorable carbon source or substrate for IB production using immobilized fermentation. Additionally, IB production could be significantly improved by co culture immobilization, which provides extracellular acetic acid to C. beijerinckii from C. tyrobutyricum. This study provided a technically feasible and cost-efficient way for IB production using cassava bagasse, which may be suitable for industrial solvent production. PMID- 27116557 TI - Role of basophils in protective immunity to parasitic infections. AB - Basophils have been recognized as important players for protective immunity against a variety of different endo- and ectoparasites. Although basophils represent a relatively rare and short-lived cell type, they produce large quantities of effector molecules including histamine, cytokines, chemokines, and lipid mediators which promote type 2 immune responses. Basophils can be activated either directly by parasite-derived factors or indirectly by recognition of parasite-derived antigens via IgE bound to its high-affinity receptor FcepsilonRI on the cell surface. Many parasitic infections cause expansion and tissue recruitment of basophils, but the role of basophils for protective immunity remains poorly understood. The development of basophil-deficient mouse models over the past few years makes it possible to study their contributions in various infections. We review here the current knowledge regarding the role of basophils for protective or immunomodulatory functions of basophils mainly during infections of mice with protozoan parasites, helminths, and ectoparasites. PMID- 27116559 TI - Clinical Review of Cochlear Implantation Performed at Sapporo Medical University Hospital. AB - More than 20 years have passed since cochlear implantation (CI) was first introduced in Japan. We began CI at the Sapporo Medical University Hospital in 1988; since then, up to the first half of 2015, we have performed CI on 280 ears. In patients aged less than and those aged over 18 years, 121 and 159 ears, respectively, have undergone surgery. This report presents typical cases of CI, such as an adult case, a bilateral case, a case where both hearing and vision were impaired, a pediatric case, a case with multiple handicaps, a case with a genetic mutation leading to severe hearing loss, and a complicated case. In addition, complications with CI cases experienced during extended follow-up periods are also summarized. PMID- 27116560 TI - Impact of elective termination on the occurrence of severe birth defects identified in a hospital-based active malformations surveillance program (1999 to 2002). AB - BACKGROUND: The number of affected infants and the types of malformations identified by a malformation surveillance programs can be impacted if elective terminations for malformations are not included. METHODS: The occurrence of malformations in all newborn infants was determined in a daily review of the findings in the pediatricians' examinations and those of all consultants. In addition, the findings in autopsies of all elective terminations were reviewed to identify all fetuses with structural abnormalities. A severity scale was used to subdivide the malformations. To establish the impact of elective termination, the malformed infants identified in the Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston were analyzed for the 2 years before and after the hospital decreased significantly the number of elective terminations temporarily (1999-2000 vs. 2001-2002). The effect on the number of malformations identified at birth, as well as malformations of greater severity, was determined. RESULTS: The number of terminated fetuses with malformations decreased dramatically after termination services were interrupted (p < 0.0001). There were no differences in the prevalence rates of all malformations in the 2 years before and after the change in access to elective terminations. However, there were significant decreases in the number of infants identified with lethal/life-limiting and severe/handicapping malformations. CONCLUSION: In the surveillance for malformations among newborn infants, the inclusion of malformed fetuses from elective terminations had a significant effect on the number of infants with the more severe malformations identified. Birth Defects Research (Part A) 106:659-666, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27116558 TI - Mammalian telomeres and their partnership with lamins. AB - Chromosome ends are complex structures, which require a panel of factors for their elongation, replication, and protection. We describe here the mechanics of mammalian telomeres, dynamics and maintainance in relation to lamins. Multiple biochemical connections, including association of telomeres to the nuclear envelope and matrix, of telomeric proteins to lamins, and of lamin-associated proteins to chromosome ends, underline the interplay between lamins and telomeres. Paths toward senescence, such as defective telomere replication, altered heterochromatin organization, and impaired DNA repair, are common to lamins' and telomeres' dysfunction. The convergence of phenotypes can be interpreted through a model of dynamic, lamin-controlled functional platforms dedicated to the function of telomeres as fragile sites. The features of telomeropathies and laminopathies, and of animal models underline further overlapping aspects, including the alteration of stem cell compartments. We expect that future studies of basic biology and on aging will benefit from the analysis of this telomere-lamina interplay. PMID- 27116561 TI - Partial-surface-passivation strategy for transition-metal-based copper-gold nanocage. AB - An effective strategy involving the corrosion of partial-surface-passivated Cu nanoparticles is proposed for synthesizing transition-metal-based Cu-Au alloy nanocages. Time-dependent X-ray absorption spectroscopy demonstrates that the hollow-cage Cu-Au alloy nanostructure is formed by sequential erosion of the partial surface and interior Cu and by the alloying of Au and Cu. PMID- 27116562 TI - Relationship between neck acceleration and muscle activation in people with chronic neck pain: Implications for functional disability. AB - BACKGROUND: Previous study has found that people with chronic neck pain moved with a consistently compromised acceleration/deceleration at their cervical and thoracic spines. This study examined the strength of the association between the electromyographic activities and the acceleration/deceleration of the cervical and thoracic spine, and its correlation with the functional disabilities in individuals with neck pain. METHODS: Time history of the cervical and thoracic acceleration/deceleration and EMG activity was acquired in thirty-four subjects with chronic neck pain and thirty-four age- and gender-matched asymptomatic subjects during active neck movements. The strength of the association between the electromyographic activity of spinal muscles and the cervical and thoracic acceleration/deceleration was determined using cross-correlation method. Relationship between the strength of this association and the severity of the functional disabilities in neck pain group was examined using correlation analysis. FINDINGS: The strength of the association between cervical and thoracic acceleration/deceleration and electromyographic activities was significantly lower in neck pain group. Significant negative correlations were found between the functional disability level and the strength of this defined association in the symptomatic group. INTERPRETATION: The compromised capability of the spinal muscles to produce acceleration/deceleration in the neck pain group may imply an impaired electromechanical coupling of these spinal muscles when performing neck movements. Significant negative correlation of the degree of functional disabilities suggests that the present approach can be used as an objective and specific evaluation of the dynamic performance of the spinal muscles and its relationship with the functional disabilities in neck pain subjects. PMID- 27116563 TI - Flexible Electrode Design: Fabrication of Freestanding Polyaniline-Based Composite Films for High-Performance Supercapacitors. AB - Polyaniline (PANI) is a promising pseudocapacitance electrode material. However, its structural instability leads to low cyclic stability and limited rate capability which hinders its practical applications. In view of the limitations, flexible PANI-based composite films are developed to improve the electrochemical performance of electrode materials. We report in the research a facile and cost effective approach for fabrication of a high-performance supercapacitor (SC) with excellent cyclic stability and tunable energy and power densities. SC electrode containing a very high mass loading of active materials is a flexible film of PANI, tissue wiper-based cellulose, graphite-based exfoliated graphite (ExG), and silver nanoparticles with potential applications in wearable electronics. The optimum preparation weight ratios of silver nitrate/aniline and ExG/aniline used in the research are estimated to be 0.18 and 0.65 (or higher), respectively. Our results show that an ultrahigh capacitance of 3.84 F/cm(2) (240.10 F/g) at a discharge rate of 5 mA can be achieved. In addition, our study shows that the power density can be increased from 1531.3 to 3000 W/kg by selecting the weight ratio of ExG/aniline to be more than 0.65, with a sacrifice in the energy density. The obtained promising electrochemical properties are found to be mainly attributed to an effective combination of PANI, ExG, cushiony cellulose scaffold, and silver as well as the porosity of the composite. PMID- 27116565 TI - SCSPOD14, a South China Sea physical oceanographic dataset derived from in situ measurements during 1919-2014. AB - In addition to the oceanographic data available for the South China Sea (SCS) from the World Ocean Database (WOD) and Array for Real-time Geostrophic Oceanography (Argo) floats, a suite of observations has been made by the South China Sea Institute of Oceanology (SCSIO) starting from the 1970s. Here, we assemble a SCS Physical Oceanographic Dataset (SCSPOD14) based on 51,392 validated temperature and salinity profiles collected from these three datasets for the period 1919-2014. A gridded dataset of climatological monthly mean temperature, salinity, and mixed and isothermal layer depth derived from an objective analysis of profiles is also presented. Comparisons with the World Ocean Atlas (WOA) and IFREMER/LOS Mixed Layer Depth Climatology confirm the reliability of the new dataset. This unique dataset offers an invaluable baseline perspective on the thermodynamic processes, spatial and temporal variability of water masses, and basin-scale and mesoscale oceanic structures in the SCS. We anticipate improvements and regular updates to this product as more observations become available from existing and future in situ networks. PMID- 27116566 TI - Spectral Quasi-Equilibrium Manifold for Chemical Kinetics. AB - The Spectral Quasi-Equilibrium Manifold (SQEM) method is a model reduction technique for chemical kinetics based on entropy maximization under constraints built by the slowest eigenvectors at equilibrium. The method is revisited here and discussed and validated through the Michaelis-Menten kinetic scheme, and the quality of the reduction is related to the temporal evolution and the gap between eigenvalues. SQEM is then applied to detailed reaction mechanisms for the homogeneous combustion of hydrogen, syngas, and methane mixtures with air in adiabatic constant pressure reactors. The system states computed using SQEM are compared with those obtained by direct integration of the detailed mechanism, and good agreement between the reduced and the detailed descriptions is demonstrated. The SQEM reduced model of hydrogen/air combustion is also compared with another similar technique, the Rate-Controlled Constrained-Equilibrium (RCCE). For the same number of representative variables, SQEM is found to provide a more accurate description. PMID- 27116570 TI - Rab6 functions in polarized transport in Drosophila photoreceptors. AB - Selective membrane transport pathways are essential for cells in situ to construct and maintain a polarized structure comprising multiple plasma membrane domains, which is essential for their specific cellular functions. Genetic screening in Drosophila photoreceptors harboring multiple plasma membrane domains enables the identification of genes involved in polarized transport pathways. Our genome-wide high-throughput screening identified a Rab6-null mutant with a rare phenotype characterized by a loss of 2 apical transport pathways with an intact basolateral transport. Although the functions of Rab6 in the Golgi apparatus are well known, its function in polarized transport is unexpected. The mutant phenotype and localization of Rab6 strongly indicate that Rab6 regulates transport between the trans-Golgi network (TGN) and recycling endosomes (REs): basolateral cargos are segregated at the TGN before Rab6 functions, but cargos going to multiple apical domains are sorted at REs. Both the medial-Golgi resident protein Metallophosphoesterase (MPPE) and the TGN marker GalT::CFP exhibit diffused co-localized distributions in Rab6-deficient cells, suggesting they are trapped in the retrograde transport vesicles returning to trans-Golgi cisternae. Hence, we propose that Rab6 regulates the fusion of retrograde transport vesicles containing medial, trans-Golgi resident proteins to the Golgi cisternae, which causes Golgi maturation to REs. PMID- 27116571 TI - Effect of Defects on Decay of Voltage and Capacity for Li[Li0.15Ni0.2Mn0.6]O2 Cathode Material. AB - Lithium-rich manganese metal layered oxides are very promising cathode materials for high-energy-density lithium-ion batteries, but improvement in voltage decay and capacity fade is a great challenge, which is mainly related to the structural instability or reconstruction of material's surface. Defects, such as part lattice distortions, local cation disordering and atomic ununiformity, often aggravate the further structural changes upon cycling. In this paper, we found that PEG contributed to form better layered structure, well crystallinity, uniform composition and polyhedral nanoparticles for Li[Li0.15Ni0.2Mn0.6]O2 (LNMO). On the basis of the comparative trial, a mechanism of electronegativity difference is proposed to elucidate cation nonuniform distribution. Higher electronegativity of Ni (1.91) than Mn (1.55) show a stronger ability of attraction between Ni and O atoms, and then led to Ni atoms show stronger diffusion driving force toward particle surface to contact the rich O atoms during sintering in air. However, PEG polymer can form a better barrier for more O atoms to attract Ni and Mn atoms on particle surface so that facilitated a uniform distribution. The electrochemical test indicated that the decay of discharge capacity and working voltage was mitigated, which was identified by the result of HRTEM analysis that the initial less defect structure obviously retarded the phase transformation from the layered to spinel after 50 cycles. Therefore, defects are crucial for understanding the voltage fade and capacity decay, and the improvement of performance also demonstrates that designing optimum compositions and ordering atomic arrangements will contribute to stabilize the surface structure and restrain inherent phase transitions. PMID- 27116572 TI - Enhanced recombinant factor VII expression in Chinese hamster ovary cells by optimizing signal peptides and fed-batch medium. AB - Signal peptides play an important role in directing and efficiently transporting secretory proteins to their proper locations in the endoplasmic reticulum of mammalian cells. The aim of this study was to enhance the expression of recombinant coagulation factor VII (rFVII) in CHO cells by optimizing the signal peptides and type of fed-batch culture medium used. Five sub-clones (O2, I3, H3, G2 and M3) with different signal peptide were selected by western blot (WB) analysis and used for suspension culture. We compared rFVII expression levels of 5 sub-clones and found that the highest rFVII expression level was obtained with the IgK signal peptide instead of Ori, the native signal peptide of rFVII. The high protein expression of rFVII with signal peptide IgK was mirrored by a high transcription level during suspension culture. After analyzing culture and feed media, the combination of M4 and F4 media yielded the highest rFVII expression of 20 mg/L during a 10-day suspension culture. After analyzing cell density and cell cycle, CHO cells feeding by F4 had a similar percentage of cells in G0/G1 and a higher cell density compared to F2 and F3. This may be the reason for high rFVII expression in M4+F4. In summary, rFVII expression was successfully enhanced by optimizing the signal peptide and fed-batch medium used in CHO suspension culture. Our data may be used to improve the production of other therapeutic proteins in fed-batch culture. PMID- 27116573 TI - Transplantation in the UK. PMID- 27116575 TI - Connecting the Dots: Will a Better Understanding of Liver Cell Homeostasis Lead to Improved Therapies for Recovery After Transplantation? PMID- 27116576 TI - Commercialization of Transplantation Research. PMID- 27116577 TI - Professor J. Richard Batchelor (1931-2015). PMID- 27116578 TI - Paul Ichiro Terasaki September 10, 1929 to January 25, 2016: Transplant Pioneer. PMID- 27116579 TI - Brain Death in the Media. PMID- 27116580 TI - A simple intervention to improve antibiotic treatment times for neutropenic sepsis. AB - OBJECTIVES: Patients with suspected Neutropenic sepsis require rapid antibiotic administration, but despite extensive education, only 67% of patients received antibiotics within 60 minutes . METHODS: A Neutropenic Sepsis Alert Card was created, as a Patient Specific Directive - this allows nurses to administer antibiotics to specific patients without prior medical review. RESULTS: Since the intervention, 301 patients presented with suspected neutropenic sepsis. 277 patients (92%) received their first dose of intravenous antibiotics within 1 hour of arrival into hospital, compared to 95 out of 143 patients (67%) presenting between January and June of 2014 (p=0.036). CONCLUSION: The Neutropenic Sepsis Alert Card can significantly improve door to antibiotic needle time for chemotherapy patients with suspected neutropenic sepsis. This intervention is inexpensive and easily replicable in other health care organisations. PMID- 27116581 TI - The Relationship between Resource Utilization, Clinical Risk and Hospital Costs for Emergency Medical Admissions. AB - There has been little study of the relationship between resource utilisation, clinical risks and hospital costs in acute medicine with the question remaining as to whether current funding models reflect patient acuity. We examined the relationship between resource use for investigations/allied professional and patient episode costs in all emergency medical admissions admitted to our institution during 2008-2013. Univariate estimates were compared with a multivariate model adjusted for major cost predictors. Interestingly, the model adjusted cost estimates changed considerably when compared with univariate analysis. We used both linear and non-linear (quantile regression) methods due to the highly skewed nature of hospital costs. The data suggested that hospital episode costs were predictable and driven by objective measures of clinical complexity. The use of expensive investigations and healthcare professional time was secondary to the clinical acuity. Thus, cost was heavily weighted towards higher complexity, and lower resource utilisation associated with lower risk patient groups. However, the non-linear nature of the costings would caution against simple predictor models and non-linear techniques such as quantile regression may, as we have demonstrated, prove superior in defining the underlying relationships. PMID- 27116582 TI - Measurement of generic patient reported outcome measures (PROMs) in an acute admission unit: A feasibility study. AB - OBJECTIVE: Measuring patient-reported outcome measures (PROMs) is a challenge in Acute Admission Units (AAUs), where patients present with a variety of pathologies. Generic PROMs may be used to measure the quality of care in this population. The main objective of this study was to assess the feasibility of measuring generic PROMs in a Dutch AAU. DESIGN: Longitudinal cohort study Setting: An AAU of a tertiary hospital in Amsterdam, the Netherlands Participants: 123 patients admitted to the AAU during 5 weeks in May and June 2015 METHODS: Patients admitted to the AAU were asked to fill out a questionnaire relating to three time points: 7 days before, during, and within 2 weeks after admission. Additionally, patients were asked to report on their experienced level of safety on the AAU and the contribution of the AAU to their recovery. RESULTS: There were significant trends in generic PROMs for all three domains. Physical functioning decreased during hospital admission and almost fully returned to the previous level after discharge. Satisfaction with social role and anxiety significantly decreased over time. CONCLUSIONS: Measuring generic PROMs in the AAU is feasible. The analysis of the PROMs took little effort and results could be reported back to the healthcare workers on the AAU quickly. Patients appreciated being asked about their own perceived health and the quality of care. Given that this is the first study focusing on PROMs in AAU patients in the Netherlands, future studies with larger sample sizes, and from other nations are needed to further investigate PROMs in this patient group to establish International reference values. PMID- 27116583 TI - A simple intervention to improve patient safety, save time and improve staff experience in the AMU procedure room. AB - Over the last decade, operating theatres and Intensive Care Units (ICUs) have established systematic methods for performing procedures on patients that have been shown to reduce complications and improve patient safety. Whilst the use of procedure rooms on Acute Medicine Units (AMUs) is highly recommended by patient safety groups and Royal College publications, they are not universally available or appropriately utilised. In this article we discuss a quality improvement project that was undertaken on an AMU at a large university teaching hospital in the United Kingdom, highlighting its successes and challenges. PMID- 27116584 TI - Implementation of NICE recommendations on abdomino-pelvic CT, following unprovoked venous thromboembolism, in a UK teaching hospital: no additional detection of occult malignancy and high numbers of incidental findings. AB - INTRODUCTION: NICE Clinical Guideline 144 recommends that patients with an unprovoked VTE, who do not have signs or symptoms of cancer on initial investigation, be considered for further investigation with an abdomino-pelvic CT to exclude occult malignancy. This study aimed to evaluate numbers of scans performed in a UK teaching hospital and outcomes, following this recommendation. METHODS: Retrospective review of CT scans performed before and after publication of the NICE guidance in 2012. CT reports and case notes were analysed. Type and stage of malignancy, treatment and other relevant findings were documented. For the 2014 data set, all incidental radiological findings and follow-up recommendations were reviewed. RESULTS: The annual number of CT scans requested for "unprovoked VTE", rose by 142% following publication of NICE Clinical Guideline 144. In the 2011 - 2012 data set, 21 patients were included, one of which was found to have a malignancy, which was clinically overt at the time of diagnosis i.e. not occult. Five patients (23.8%) had incidental findings requiring further investigation. In the 2014 - 2015 data set, 51 patients were included, five (9.8%) of which were found to have malignancy. In retrospect, all showed signs/symptoms of potential malignancy on initial investigation. No occult malignancies were detected in the patients correctly referred. Incidental findings warranting further investigation were reported in ten cases (19.6%). On review, follow-up advice was deemed incorrect in four of these. CONCLUSION: Addition of an abdomino-pelvic CT scan in patients with a first unprovoked VTE and no signs or symptoms of cancer on initial investigation, significantly increased the number of scans and incidental findings, but did not pick up any additional occult malignancies. PMID- 27116585 TI - Acute Mitral Regurgitation: an important cause of respiratory distress. AB - Acute mitral regurgitation (acute MR) is a rare cause of acute respiratory distress, which can present diagnostic challenges. We present the case of a 57 year old man who developed acute shortness of breath subsequently associated with fever, raised white cells and elevated CRP. Chest x-ray revealed unilateral shadowing and he was treated for pneumonia, despite the finding of severe mitral regurgitation on echo. Failure to respond to antibiotic treatment following 3 weeks on ITU led to the consideration of acute MR as the cause of his symptoms and he responded well to diuretics. He subsequently underwent mitral valve repair. The causes and clinical presentations of this condition are discussed. PMID- 27116586 TI - When is a stroke not a stroke? An unusual mimic presenting to AMU. AB - INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a rare prion disease classically manifesting with rapidly progressive dementia, abnormal movements and typical electroencephalographic (EEG) changes. CASE REPORT: A 74 year-old Caucasian man was recently discharged from another centre diagnosed with a stroke. He re presented to our acute medical unit with worsening symptoms, and stroke remained the working diagnosis. Collateral history revealed a progressive cognitive decline and unilateral myoclonus. Further investigations supported the diagnosis of probable CJD, confirmed by the national CJD surveillance centre. DISCUSSION: Signs and symptoms atypical of stroke should raise the possibility of alternative diagnoses, including prion disease. CJD can present with unilateral symptoms, EEG and MRI changes. Early diagnosis prevents unnecessary investigations and treatments, allowing early palliative care input, where appropriate. PMID- 27116587 TI - Evaluating early-life asthma definitions as a marker for subsequent asthma in an electronic medical record setting. AB - BACKGROUND: Case definitions for asthma incidence in early life vary between studies using medical records to define disease. This study assessed the impact of different approaches to using medical records on estimates of asthma incidence by age 3 and determined the validity of early-life asthma case definitions in predicting school-age asthma. METHODS: Asthma diagnoses and medications by age 3 were used to classify 7103 children enrolled in Kaiser Permanente Georgia according to 14 definitions of asthma. School-age asthma was defined as an asthma diagnosis between ages 5 and 8. Sensitivity (probability of asthma by age 3 given school-age asthma), specificity (probability of no asthma by age 3 given no school-age asthma), positive and negative predictive values (probability of (no) school-age asthma given (no) asthma by age 3), and likelihood ratios (combining sensitivity and specificity) were used to determine predictive ability. RESULTS: 9.0-35.2% of children were classified as asthmatic by age 3 depending on asthma case definition. Early-life asthma classifications were more specific than sensitive and were better at identifying children who would not have school-age asthma (negative predictive values: 80.7-86.6%) than at predicting children who would have school-age asthma (positive predictive values: 43.5-71.5%). CONCLUSIONS: Choice of case definition had a large impact on the estimate of asthma incidence. While ability to predict school-age asthma was limited, several case definitions performed similarly to clinical asthma prediction tools used in previous asthma research (e.g., the Asthma Predictive Index). PMID- 27116588 TI - Sustainable Process for the Preparation of High-Performance Thin-Film Composite Membranes using Ionic Liquids as the Reaction Medium. AB - A new form of interfacial polymerization to synthesize thin-film composite membranes realizes a more sustainable membrane preparation and improved nanofiltration performance. By introducing an ionic liquid (IL) as the organic reaction phase, the extremely different physicochemical properties to those of commonly used organic solvents influenced the top-layer formation in several beneficial ways. In addition to the elimination of hazardous solvents in the preparation, the m-phenylenediamine (MPD) concentration could be reduced 20-fold, and the use of surfactants and catalysts became redundant. Together with the more complete recycling of the organic phase in the water/IL system, these factors resulted in a 50 % decrease in the mass intensity of the top-layer formation. Moreover, a much thinner top layer with a high ethanol permeance of 0.61 L m(-2) h(-1) bar(-1) [99 % Rose Bengal (RB, 1017 Da) retention; 1 bar=0.1 MPa] was formed without the use of any additives. This EtOH permeance is 555 and 161 % higher than that for the conventional interfacial polymerization (without and with additives, respectively). In reverse osmosis, high NaCl retentions of 97 % could be obtained. Finally, the remarkable decrease in the membrane surface roughness indicates the potential for reduced fouling with this new type of membrane. PMID- 27116589 TI - Tunable Aggregation and Gelation of Thermoresponsive Suspensions of Polymer Grafted Cellulose Nanocrystals. AB - The colloidal stability together with the tunable aggregation and viscoelastic properties of thermoresponsive polymer-grafted cellulose nanocrystals (CNCs) were investigated. TEMPO oxidation of CNCs followed by peptidic coupling in water were used to covalently graft thermosensitive Jeffamine polyetheramine M2005 chains onto the surface of CNCs. The resulting polymer-decorated particles (M2005-g CNCs) exhibited new colloidal properties, by their ability to perfectly redisperse in water and organic solvents such as toluene, dichloromethane or DMF after freeze-drying. In addition, they presented an enhanced thermal stability when compared to that of sulfated or TEMPO-oxidized CNCs. Dynamic light scattering experiments were used to demonstrate that the thermally induced aggregation of M2005-g-CNCs was fully reversible and reproducible over many temperature cycles and that, most interestingly, the aggregation number could be tuned by varying the ionic strength and/or the pH of the medium, making the suspension multiresponsive. This property arises from the variations of the sign (attractive or repulsive) and the range of the different types (entropic, electrostatic, hydrophobic) of interaction forces between the thermosensitive polymer-decorated nanoparticles. The variation of the viscoelastic properties of M2005-g-CNCs suspensions as a function of temperature, probed by oscillatory rheology measurements of more concentrated suspensions, revealed a reversible temperature-triggered liquid-to-gel transition. Such enhanced functionalities pave the way to the design of advanced CNC-based materials benefiting both from the intrinsic characteristics of these biosourced particles and the new properties imparted by the stimuli-sensitive grafted chains. PMID- 27116590 TI - Physicochemical Requirements Inferred for Chemical Self-Organization Hardly Support an Emergence of Life in the Deep Oceans of Icy Moons. AB - An approach to the origin of life, focused on the property of entities capable of reproducing themselves far from equilibrium, has been developed recently. Independently, the possibility of the emergence of life in the hydrothermal systems possibly present in the deep oceans below the frozen crust of some of the moons of Jupiter and Saturn has been raised. The present report is aimed at investigating the mutual compatibility of these alternative views. In this approach, the habitability concept deduced from the limits of life on Earth is considered to be inappropriate with regard to emerging life due to the requirement for an energy source of sufficient potential (equivalent to the potential of visible light). For these icy moons, no driving force would have been present to assist the process of emergence, which would then have had to rely exclusively on highly improbable events, thereby making the presence of life unlikely on these Solar System bodies, that is, unless additional processes are introduced for feeding chemical systems undergoing a transition toward life and the early living organisms. KEY WORDS: Icy moon-Bioenergetics-Chemical evolution Habitability-Origin of life. Astrobiology 16, 328-334. PMID- 27116592 TI - Use of Head Guards in AIBA Boxing Tournaments-A Cross-Sectional Observational Study. AB - OBJECTIVE: This study looks at the changes in injuries after the implementation of a new rule by the International Boxing Association (AIBA) to remove head guards from its competitions. DESIGN: A cross-sectional observational study performed prospectively. This brief report examines the removal of head guards in 2 different ways. The first was to examine the stoppages due to blows to the head by comparing World Series Boxing (WSB), without head guards, to other AIBA competitions with head guards. Secondly, we examined the last 3 world championships: 2009 and 2011 (with head guards) and 2013 (without head guards). SETTING: World Series Boxing and AIBA world championship boxing. PARTICIPANTS: Boxers from WSB and AIBA world championships. INTERVENTIONS: The information was recorded by ringside medical physicians. MAIN OUTCOME MEASURES: Stoppages per 10 000 rounds; stoppages per 1000 hours. RESULTS: Both studies show that the number of stoppages due to head blows was significantly decreased without head guards. The studies also showed that there was a notable increase in cuts. CONCLUSIONS: Removing head guards may reduce the already small risk of acute brain injury in amateur boxing. PMID- 27116591 TI - Communication Barriers and the Clinical Recognition of Diabetic Peripheral Neuropathy in a Diverse Cohort of Adults: The DISTANCE Study. AB - The purpose of this study was to explore communication barriers as independent predictors and potential mediators of variation in clinical recognition of diabetic peripheral neuropathy (DPN). In this cross-sectional analysis, we estimated the likelihood of having a DPN diagnosis among 4,436 patients with DPN symptoms. We controlled for symptom frequency, demographic and clinical characteristics, and visit frequency using a modified Poisson regression model. We then evaluated 4 communication barriers as independent predictors of clinical documentation and as possible mediators of racial/ethnic differences: difficulty speaking English, not talking to one's doctor about pain, limited health literacy, and reports of suboptimal patient-provider communication. Difficulty speaking English and not talking with one's doctor about pain were independently associated with not having a diagnosis, though limited health literacy and suboptimal patient-provider communication were not. Limited English proficiency partially attenuated, but did not fully explain, racial/ethnic differences in clinical documentation among Chinese, Latino, and Filipino patients. Providers should be encouraged to talk with their patients about DPN symptoms, and health systems should consider enhancing strategies to improve timely clinical recognition of DPN among patients who have difficult speaking English. More work is needed to understand persistent racial/ethnic differences in diagnosis. PMID- 27116595 TI - Single Atom (Pd/Pt) Supported on Graphitic Carbon Nitride as an Efficient Photocatalyst for Visible-Light Reduction of Carbon Dioxide. AB - Reducing carbon dioxide to hydrocarbon fuel with solar energy is significant for high-density solar energy storage and carbon balance. In this work, single atoms of palladium and platinum supported on graphitic carbon nitride (g-C3N4), i.e., Pd/g-C3N4 and Pt/g-C3N4, respectively, acting as photocatalysts for CO2 reduction were investigated by density functional theory calculations for the first time. During CO2 reduction, the individual metal atoms function as the active sites, while g-C3N4 provides the source of hydrogen (H*) from the hydrogen evolution reaction. The complete, as-designed photocatalysts exhibit excellent activity in CO2 reduction. HCOOH is the preferred product of CO2 reduction on the Pd/g-C3N4 catalyst with a rate-determining barrier of 0.66 eV, while the Pt/g-C3N4 catalyst prefers to reduce CO2 to CH4 with a rate-determining barrier of 1.16 eV. In addition, deposition of atom catalysts on g-C3N4 significantly enhances the visible-light absorption, rendering them ideal for visible-light reduction of CO2. Our findings open a new avenue of CO2 reduction for renewable energy supply. PMID- 27116593 TI - Invasive Lobular Carcinoma Mimicking Papillary Carcinoma: A Report of Three Cases. AB - Encapsulated and solid papillary carcinomas (EPCs and SPCs) are considered historically as a special form of ductal carcinoma in situ. Invasive lobular carcinoma (ILC) is characterised by a discohesive growth pattern. There are several variants of ILC, but, as yet, no papillary subtype has been identified. Here we report 3 cases of ILC presenting as papillary carcinoma (PC) with a typical solid papillary growth pattern. One case was reported on core biopsy as EPC (B5a). The 3 ensuing resection specimens showed features typical of SPC with a circumscribed malignant epithelial proliferation containing fibrovascular cores and surrounded, at least focally, by a thick fibrous capsule. The lobular nature of these tumours was confirmed on the resection specimens by the absence of E cadherin and beta-catenin membrane expression. The invasive nature was confirmed by the presence of entrapped fat cells, the absence of myoepithelial cells and focal merging of the solid papillary areas with classic ILC at the periphery. Of note, 1 case was a recurrent carcinoma without an in situ component. CONCLUSION: This study provides further evidence that EPC and SPC represent a unique growth pattern of breast carcinomas rather than reflecting the in situ or invasive nature of the tumour, and that ILC can acquire a papillary growth pattern. PMID- 27116596 TI - Bottom-Up Self-Assembly of the Sphere-Shaped Icosametallic Oxo Clusters {Cu20} and {Cu12Zn8}. AB - A discrete nanospheric icosametallic cluster comprised of 20 Cu ions (1) was self assembled from facile synthesis. Adjustment of the synthesis by the choice of ligands gave rise to another cluster (2) with an intact icosacupric core and improved stability. Referring to the synthesis of 1 and 2, a heterometallic cluster (3), which contains 12 Cu(II) and 8 Zn(II), was designed and characterized by single-crystal X-ray diffraction, combined with elemental analysis, energy-dispersive X-ray, X-ray photoelectron spectroscopy, thermogravimetric analysis, and element mapping. The magnetic measurements of 2 and 3 and the scanning electron microscopy images and UV-visible diffuse reflectance measurements of metal oxides from 2 and 3 indicate that isolation of {Cu12M8} is a new synthetic route to materials with engineered properties. PMID- 27116597 TI - Filicinic Acid Based Meroterpenoids with Anti-Epstein-Barr Virus Activities from Hypericum japonicum. AB - Seven filicinic acid-based meroterpenoids (1-7), possessing 6/6/11, 6/6/7/5, or 6/6/10 ring systems, were isolated from Hypericum japonicum. All of them have novel skeletons with the incorporation of sesquiterpenoid moieties to an acylated filicinic acid. Compounds 2a and 4 exhibited significant efficacy on anti-Epstein Barr virus, with EC50 values of 0.57 and 0.49 MUM, respectively. Furthermore, compounds 2a and 4 were well accommodated to the binding pocket of 2GV9 predicted by the molecular docking. PMID- 27116600 TI - Biventricular Rupture with Extracardiac Left-to-Right Shunt Complicating Acute Myocardial Infarction. AB - BACKGROUND: Simultaneous rupture of the left and right ventricles is an extremely rare mechanical complication of acute myocardial infarction (MI). When associated with the formation of a false aneurysm, an extracardiac left-to-right shunt may occur. METHODS: We summarized all published data describing this unique condition. We searched the PubMed and Google Scholar databases for case reports in peer-reviewed journals from 1 January 1980 to 1 May 2015. We identified 16 articles describing 17 cases. RESULTS: In all but 1 case, biventricular wall rupture (BVWR) resulted from an inferior MI. The clinical presentations of BVWR were variable and included cardiogenic shock, congestive heart failure and an absence of any cardiac symptoms. In most cases, there was a hemodynamically significant left-to-right shunt, with pulmonary to systemic blood flow (Qp/Qs) >2. Diagnostic difficulties were reported in most cases, and some patients were initially misdiagnosed as having ventricular septal rupture (VSR). Surgical closure of the defect was successful in most cases, and some asymptomatic patients were managed conservatively. CONCLUSION: BVWR with an intact interventricular septum and extracardiac left-to-right shunt is a rare mechanical complication of acute MI, often misdiagnosed as VSR. It has a variable clinical course, probably related to the magnitude of the shunt. PMID- 27116601 TI - Postoperative residua and sequelae in adults with repaired tetralogy of Fallot. AB - Postoperative residua and sequelae after repair of tetralogy of Fallot in adults became one of the major concerns in the field of adult congenital heart disease. Right heart failure and arrhythmia can result fatal, and are considered to be related dilated right ventricle due to pulmonary valve regurgitation. Although precise indication of pulmonary valve replacement (PVR) is still not established, right ventricular end-diastolic volume index less than 150-170 ml/m(2) and right ventricular end systolic volume index less than 82-90 ml/m(2) may be border line for RV remodeling after PVR. Biological prosthetic valve is generally used at the pulmonary position. PMID- 27116602 TI - Genetics of Hereditary Angioedema Revisited. AB - Contemporary genetic research has provided evidences that angioedema represents a diverse family of disorders related to kinin metabolism, with a much greater genetic complexity than was initially considered. Convincing data have also recently been published indicating that the clinical heterogeneity of hereditary angioedema due to C1 inhibitor deficiency (classified as C1-INH-HAE) could be attributed at least in part, either to the type of SERPING1 mutations or to mutations in genes encoding for enzymes involved in the metabolism and function of bradykinin. Alterations detected in at least one more gene (F12) are nowadays considered responsible for 25 % of cases of hereditary angioedema with normal C1 INH (type III hereditary angioedema (HAE), nlC1-INH-HAE). Interesting data derived from genetic approaches of non-hereditary angioedemas indicate that other immune pathways might be implicated in the pathogenesis of HAE. More than 125 years after the recognition of the hereditary nature of HAE by Osler, the heterogeneity of clinical expressions, the genetics of this disorder, and the genotype-phenotype relationships, still presents a challenge that will be discussed in this review. Large scale, in-depth genetic studies are expected not only to answer these emerging questions but also to further elucidate many of the unmet aspects of angioedema pathogenesis. Uncovering genetic biomarkers affecting the severity of the disease and/or the effectiveness of the various treatment modalities might lead to the prevention of attacks and the optimization of C1-INH HAE management that is expected to provide a valuable benefit to the sufferers of angioedema. PMID- 27116604 TI - Size relationships of different body parts in the three dipteran species Drosophila melanogaster, Ceratitis capitata and Musca domestica. AB - Body size is an integral feature of an organism that influences many aspects of life such as fecundity, life span and mating success. Size of individual organs and the entire body size represent quantitative traits with a large reaction norm, which are influenced by various environmental factors. In the model system Drosophila melanogaster, pupal size and adult traits, such as tibia and thorax length or wing size, accurately estimate the overall body size. However, it is unclear whether these traits can be used in other flies. Therefore, we studied changes in size of pupae and adult organs in response to different rearing temperatures and densities for D. melanogaster, Ceratitis capitata and Musca domestica. We confirm a clear sexual size dimorphism (SSD) for Drosophila and show that the SSD is less uniform in the other species. Moreover, the size response to changing growth conditions is sex dependent. Comparison of static and evolutionary allometries of the studied traits revealed that response to the same environmental variable is genotype specific but has similarities between species of the same order. We conclude that the value of adult traits as estimators of the absolute body size may differ among species and the use of a single trait may result in wrong assumptions. Therefore, we suggest using a body size coefficient computed from several individual measurements. Our data is of special importance for monitoring activities of natural populations of the three dipteran flies, since they are harmful species causing economical damage (Drosophila, Ceratitis) or transferring diseases (Musca). PMID- 27116603 TI - From vestigial to vestigial-like: the Drosophila gene that has taken wing. AB - The members of the vestigial-like gene family have been identified as homologs of the Drosophila vestigial, which is essential to wing formation. All members of the family are characterized by the presence of the TONDU domain, a highly conserved sequence that mediates their interaction with the transcription factors of the TEAD family. Mammals possess four vestigial-like genes that can be subdivided into two classes, depending on the number of Tondu domains present. While vestigial proteins have been studied in great depth in Drosophila, we still have sketchy knowledge of the functions of vestigial-like proteins in vertebrates. Recent studies have unveiled unexpected functions for some of these members and reveal the role they play in the Hippo pathway. Here, we present the current knowledge about vestigial-like family gene members and their functions, together with their identification in different taxa. PMID- 27116605 TI - Short Report: Serological Evidence of Under-Reported Dengue Circulation in Sierra Leone. AB - Dengue virus (DENV) is thought to have emerged from a sylvatic cycle in Africa but has since become adapted to an urban-centric transmission cycle. These urban areas include villages in West Africa where DENV is not often routinely considered for patients presenting with febrile illnesses, as other endemic diseases (malaria, Lassa fever, e.g.) present with similar non-specific symptoms. Thus, dengue is likely under diagnosed in the region. These plaque reduction neutralization test-50 (PRNT50) screening results of patients presenting with fevers of unknown origin (FUO) at a clinic in Kenema, Sierra Leone indicate that all four serotypes of DENV likely circulate in areas surrounding Kenema. Using a more conservative PRNT80 cut-off value, our results still indicate the presence of antibody to all four serotypes in the region. Identifying alternate etiologies of FUOs in this region will assist clinicians in plan-of-care decisions as well as follow-up priorities. This is particularly relevant given the Ebola outbreak in the region, where diagnosis has a range of downstream effects ranging from correct allocation of medical resources, appropriate isolation of patients, and ultimately, a better informed public health sector. PMID- 27116606 TI - Correction: Nitro-Arachidonic Acid Prevents Angiotensin II Induced Mitochondrial Dysfunction in Kidney Proximal Tubular Cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0150459.]. PMID- 27116607 TI - Biochar, Bentonite and Zeolite Supplemented Feeding of Layer Chickens Alters Intestinal Microbiota and Reduces Campylobacter Load. AB - A range of feed supplements, including antibiotics, have been commonly used in poultry production to improve health and productivity. Alternative methods are needed to suppress pathogen loads and maintain productivity. As an alternative to antibiotics use, we investigated the ability of biochar, bentonite and zeolite as separate 4% feed additives, to selectively remove pathogens without reducing microbial richness and diversity in the gut. Neither biochar, bentonite nor zeolite made any significant alterations to the overall richness and diversity of intestinal bacterial community. However, reduction of some bacterial species, including some potential pathogens was detected. The microbiota of bentonite fed animals were lacking all members of the order Campylobacterales. Specifically, the following operational taxonomic units (OTUs) were absent: an OTU 100% identical to Campylobacter jejuni; an OTU 99% identical to Helicobacter pullorum; multiple Gallibacterium anatis (>97%) related OTUs; Bacteroides dorei (99%) and Clostridium aldenense (95%) related OTUs. Biochar and zeolite treatments had similar but milder effects compared to bentonite. Zeolite amended feed was also associated with significant reduction in the phylum Proteobacteria. All three additives showed potential for the control of major poultry zoonotic pathogens. PMID- 27116609 TI - Role of Crosstalk between Epithelial and Immune Cells, the Epimmunome, in Allergic Rhinitis Pathogenesis. AB - Recently, the prevalence of allergic rhinitis has been dramatically increasing worldwide. As conventional therapies for allergic rhinitis, such as antihistamines, leukotriene receptor antagonists, nasal sprays and allergen immunotherapy, have limitations, the development of new drugs is required. Recent studies have revealed that epithelial cell-derived cytokines, including thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33, are able to control immune cells, such as dendritic cells and T cells, thereby acting as 'master switches' in allergic disease. In addition, new roles have been identified for follicular helper T cells and regulatory B cells in allergic disease, and they are considered to be promising targets for new therapies. Thus, crosstalk between epithelial and immune cells, the epimmunome, underlies the pathogenesis of allergic rhinitis. Greater understanding of the epimmunome may lead to breakthroughs in the development of new treatments for allergic rhinitis and will help us cure many patients suffering from its severe symptoms in the future. PMID- 27116608 TI - Feeding soywaste or pellet on performance and carcass characteristics of post weaning kids. AB - Twelve Jermasia kids were individually housed in pens to study the effects of soywaste on growth performance and carcass characteristics and to compare such effects with commercial pellet. Kids were divided into a pellet group and a soywaste group, including six kids (3 males and 3 females) in each group. Pellet or soywaste was offered to kids at a rate of 2.0 % dry matter (DM) of body weight/day in addition to Napier grass ad libitum. In last 10 days of experiment, kids were housed in metabolism crates for faeces collection. At the end of the experiment, three males from each group were slaughtered. Kids fed soywaste diet consumed more grass and neutral detergent fibre (NDF) than those fed pellet. The same trend was found for the digestibilities of DM, organic matter (OM) and NDF. Conversely, kids fed soywaste diet consumed less soywaste supplement than kids fed pellet. No treatment effects were observed on total intakes of DM, OM and crude protein (CP) including CP digestibility. Similarly, no effects were found on carcass and non-carcass components, except for lean, lean to fat ratio and kidney weight which were higher for kids fed soywaste diet. Results indicate that soywaste is effective as a feed for growing kids. PMID- 27116610 TI - Temporal Changes in Local Functional Connectivity Density Reflect the Temporal Variability of the Amplitude of Low Frequency Fluctuations in Gray Matter. AB - Data-driven functional connectivity density (FCD) mapping is being increasingly utilized to assess brain connectomics at rest in the healthy brain and its disruption in neuropsychiatric diseases with the underlying assumption that the spatiotemporal hub distribution is stationary. However, recent studies show that functional connectivity is highly dynamic. Here we study the temporal variability of the local FCD (lFCD) at high spatiotemporal resolution (2-mm isotropic; 0.72s) using a sliding-window approach and 'resting-state' datasets from 40 healthy subjects collected under the Human Connectome Project. Prominent functional connectivity hubs in visual and posterior parietal cortices had pronounced temporal changes in local FCD. These dynamic patterns in the strength of the lFCD hubs occurred in cortical gray matter with high sensitivity (up to 85%) and specificity (> 85%) and showed high reproducibility (up to 72%) across sessions and high test-retest reliability (ICC(3,1) > 0.5). The temporal changes in lFCD predominantly occurred in medial occipitoparietal regions and were proportional to the strength of the connectivity hubs. The temporal variability of the lFCD was associated with the amplitude of the low frequency fluctuations (ALFF). Pure randomness did not account for the probability distribution of lFCD. Shannon entropy increased in proportion to the strength of the lFCD hubs suggesting high average flow of information per unit of time in the lFCD hubs, particularly in medial occipitoparietal regions. Thus, the higher dynamic range of the lFCD hubs is consistent with their role in the complex orchestration of interacting brain networks. PMID- 27116611 TI - An insect with a delta-12 desaturase, the jewel wasp Nasonia vitripennis, benefits from nutritional supply with linoleic acid. AB - The availability of linoleic acid (LA; C18:2(?9,12)) is pivotal for animals. While vertebrates depend on a nutritional supply, some invertebrates, including the parasitic wasp Nasonia vitripennis, are able to synthesize LA from oleic acid (OA; C18:1(?9)). This raises the question as to whether these animals nevertheless benefit from the additional uptake of LA with the diet. LA plays an important role in the sexual communication of N. vitripennis because males use it as a precursor for the synthesis of an abdominal sex pheromone attracting virgin females. We reared hosts of N. vitripennis that were fed diets enriched in the availability of stearic acid (SA: C18:0), OA or LA. N. vitripennis males developing on the different host types clearly differed in both the fatty acid composition of their body fat and sex pheromone titres. Males from LA-enriched hosts had an almost fourfold higher proportion of LA and produced significantly more sex pheromone than males from SA (2.2-fold) and OA (1.4-fold) enriched hosts, respectively. Our study demonstrates that animals being able to synthesize important nutrients de novo may still benefit from an additional supply with their diet. PMID- 27116612 TI - Variation in Care for Patients with Irritable Bowel Syndrome in the United States. AB - OBJECTIVES: Irritable bowel syndrome (IBS) affects nearly one in seven Americans. Significant national variations in care may exist, due to a current lack of standardized diagnosis and treatment algorithms; this can translate into a substantial additional economic burden. The study examines healthcare resource utilization in patients with IBS and in the subset of IBS patients with constipation (IBS-C) and analyzes the variation of IBS care for these patients across the United States (US). METHODS: Healthcare resource use (HRU), including gastrointestinal (GI) procedures and tests, all-cause and intestinal-related medical visits, GI specialist visits, and constipation or diarrhea pharmacy prescriptions for IBS patients enrolled in a large US administrative claims database (2001-2012) were analyzed for the 24-month period surrounding first diagnosis. Multivariate regression models, adjusting for age, gender, year of first diagnosis, insurance type, and Charlson comorbidity index, compared HRU across states (each state vs. the average of all other states). RESULTS: Of 201,322 IBS patients included, 77.2% were female. Mean age was 49.4 years. One in three patients had >=3 distinct GI medical procedures or diagnostic tests; 50.1% visited a GI specialist. Significant HRU differences were observed in individual states compared to the national average. IBS-C patients had more medical visits, procedures, and pharmacy prescriptions for constipation/diarrhea than IBS patients without constipation. CONCLUSIONS: This study is the first to identify considerable regional variations in IBS healthcare across the US and to note a markedly higher HRU by IBS-C patients than by IBS patients without constipation. Identifying the reasons for these variations may improve quality of care and reduce the economic burden of IBS. PMID- 27116613 TI - Using Linear Equating to Map PROMIS((r)) Global Health Items and the PROMIS-29 V2.0 Profile Measure to the Health Utilities Index Mark 3. AB - BACKGROUND: Preference-based health-related quality of life (HR-QOL) scores are useful as outcome measures in clinical studies, for monitoring the health of populations, and for estimating quality-adjusted life-years. METHODS: This was a secondary analysis of data collected in an internet survey as part of the Patient Reported Outcomes Measurement Information System (PROMIS((r))) project. To estimate Health Utilities Index Mark 3 (HUI-3) preference scores, we used the ten PROMIS((r)) global health items, the PROMIS-29 V2.0 single pain intensity item and seven multi-item scales (physical functioning, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, sleep disturbance), and the PROMIS-29 V2.0 items. Linear regression analyses were used to identify significant predictors, followed by simple linear equating to avoid regression to the mean. RESULTS: The regression models explained 48 % (global health items), 61 % (PROMIS-29 V2.0 scales), and 64 % (PROMIS-29 V2.0 items) of the variance in the HUI-3 preference score. Linear equated scores were similar to observed scores, although differences tended to be larger for older study participants. CONCLUSIONS: HUI-3 preference scores can be estimated from the PROMIS((r)) global health items or PROMIS-29 V2.0. The estimated HUI-3 scores from the PROMIS((r)) health measures can be used for economic applications and as a measure of overall HR-QOL in research. PMID- 27116614 TI - Examination of Reticulocytosis among Chronically Transfused Children with Sickle Cell Anemia. AB - Sickle cell anemia (SCA) is an inherited hemolytic anemia with compensatory reticulocytosis. Recent studies have shown that increased levels of reticulocytosis during infancy are associated with increased hospitalizations for SCA sequelae as well as cerebrovascular pathologies. In this study, absolute reticulocyte counts (ARC) measured prior to transfusion were analysed among a cohort of 29 pediatric SCA patients receiving chronic transfusion therapy (CTT) for primary and secondary stroke prevention. A cross-sectional flow cytometric analysis of the reticulocyte phenotype was also performed. Mean duration of CTT was 3.1 +/- 2.6 years. Fifteen subjects with magnetic resonance angiography (MRA) -vasculopathy had significantly higher mean ARC prior to initiating CTT compared to 14 subjects without MRA-vasculopathy (427.6 +/- 109.0 K/MUl vs. 324.8 +/- 109.2 K/MUl, p<0.05). No significant differences in hemoglobin or percentage sickle hemoglobin (HbS) were noted between the two groups at baseline. Reticulocyte phenotyping further demonstrated that the percentages of circulating immature [CD36(+), CD71(+)] reticulocytes positively correlated with ARC in both groups. During the first year of CTT, neither group had significant reductions in ARC. Among this group of children with SCA, cerebrovasculopathy on MRA at initiation of CTT was associated with increased reticulocytosis, which was not reduced after 12 months of transfusions. PMID- 27116615 TI - Norovirus Epidemiology in Africa: A Review. AB - Norovirus (NoV) is recognised as a leading cause of gastroenteritis worldwide across all age groups. The prevalence and diversity of NoVs in many African countries is still unknown, although early sero-prevalence studies indicated widespread early infection. Reports on NoVs in Africa vary widely in terms of study duration, population groups and size, inclusion of asymptomatic controls, as well as genotyping information. This review provides an estimate of NoV prevalence and distribution of genotypes of NoVs in Africa. Inclusion criteria for the review were study duration of at least 6 months, population size of >50 and diagnosis by RT-PCR. As regions used for genotyping varied, or genotyping was not always performed, this was not considered as an inclusion criteria. A literature search containing the terms norovirus+Africa yielded 74 publications. Of these 19 studies from 14 out of the 54 countries in Africa met the inclusion criteria. Data from studies not meeting the inclusion criteria, based on sample size or short duration, were included as discussion points. The majority of studies published focused on children, under five years of age, hospitalised with acute gastroenteritis. The mean overall prevalence was 13.5% (range 0.8-25.5%) in children with gastroenteritis and 9.7% (range 7-31%) in asymptomatic controls, where tested. NoV GII.4 was the predominant genotype identified in most of the studies that presented genotyping data. Other prevalent genotypes detected included GII.3 and GII.6. In conclusion, NoV is a common pathogen in children with diarrhoea in Africa, with considerable carriage in asymptomatic children. There is however, a paucity of data on NoV infection in adults. PMID- 27116617 TI - Associations of Subjective Sleep Quality and Daytime Sleepiness With Cognitive Impairment in Adults and Elders With Heart Failure. AB - This study examined the association of subjective nighttime sleep quality and daytime sleepiness with cognitive impairment in 105 adults (< 60 years old) and 167 elders (>= 60 years old) with heart failure. Nighttime sleep quality and daytime sleepiness were measured by the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. Cognitive impairment was assessed using a neuropsychological battery measuring attention, memory, and processing speed. Multivariate logistic regression was used. In adults, daytime sleepiness was associated with cognitive impairment, whereas poor nighttime sleep quality was associated with cognitive impairment in elders. Age may play an important role in how sleep impacts cognition in persons with heart failure. Improving nighttime sleep quality and daytime sleepiness in this population may improve cognition. PMID- 27116618 TI - Effect of electrical field strength applied by PEF processing and storage temperature on the outgrowth of yeasts and moulds naturally present in a fresh fruit smoothie. AB - Pulsed electrical field (PEF) technology offers an alternative to thermal pasteurisation of high-acid fruit juices, by extending the shelf life of food products, while retaining its fresh taste and nutritional value. Substantial research has been performed on the effect of electrical field strength on the inactivation kinetics of spoilage and pathogenic micro-organisms and on the outgrowth of spoilage micro-organisms during shelf life. However, studies on the effect of electrical field strength on the inactivation and outgrowth of surviving populations during shelf life are missing. In this study, we assessed the influence of electrical field strength applied by PEF processing and storage temperature on the outgrowth of surviving yeast and mould populations naturally present in fresh fruit smoothie in time. Therefore, an apple-strawberry-banana smoothie was treated in a continuous-flow PEF system (130L/h), using similar inlet and outlet conditions (preheating temperature 41 degrees C, maximum temperature 58 degrees C) to assure that the amount of energy across the different conditions was kept constant. Smoothies treated with variable electrical field strengths (13.5, 17.0, 20.0 and 24.0kV/cm) were compared to smoothies without treatment for outgrowth of yeasts and moulds. Outgrowth of yeasts and moulds stored at 4 degrees C and 7 degrees C was analysed by plating and visual observation and yeast growth was modelled using the modified logistic growth model (Zwietering model). Results showed that the intensity of the electrical field strength had an influence on the degree of inactivation of yeast cells, resulting in a faster outgrowth over time at lower electrical field strength. Outgrowth of moulds over time was not affected by the intensity of the electrical field strength used. Application of PEF introduces a trade-off between type of spoilage: in untreated smoothie yeasts lead to spoilage after 8days when stored at 4 or 7 degrees C, whereas in PEF treated smoothie yeasts were (partly) inactivated and provided outgrowth opportunities for moulds, which led to spoilage by moulds after 14days (7 degrees C) or 18days (4 degrees C). PMID- 27116616 TI - Chemopreventive effect of 18beta-glycyrrhetinic acid via modulation of inflammatory markers and induction of apoptosis in human hepatoma cell line (HepG2). AB - Hepatocellular carcinoma is one of the most common lethal diseases worldwide and there is no effective treatment till date. Natural products derived from the plants play an important role in chemoprevention and act as therapeutic antitumor agents. Licorice is a plant that has been used in food and medicine for the treatment of various diseases. 18beta-Glycyrrhetinic acid (18beta-GA), a pentacyclic triterpenoid obtained from the roots of licorice plant, is reported to possess various pharmacological properties such as antitumor and antiinflammatory activities. The present study was designed to elucidate the chemopreventive effect of 18beta-GA through antiinflammation, antiproliferation, and induction of apoptosis in human hepatoma cell line HepG2. 18beta-GA significantly inhibits the proliferation of HepG2 cell without affecting the normal liver cell line (Chang's). In the present study, 18beta-GA increased the formation of reactive oxygen species, nitric oxide production, and loss of mitochondrial membrane potential, suggesting the involvement of 18beta-GA in apoptosis which was also confirmed by assessing the markers involved in apoptosis like caspase-3, caspase-9, Bax:Bcl-2 ratio, and cleaved PARP. 18beta-GA also downregulated the expression of inflammatory proteins such as NF-kappaB, iNOS, and COX-2. Keeping these data into consideration, our results suggest that 18beta GA may be used as a chemopreventive agent in liver cancer. PMID- 27116619 TI - The microbiological quality of pasteurized milk sold by automatic vending machines. AB - The microbiological quality of pasteurized milk samples (n = 39) collected during 13 weekly intervals from three automatic vending machines (AVM) in Greece was investigated. Microbiological counts (total aerobic (TAC), total psychrotrophic (TPC), Enterobacteriaceae (EC), and psychrotrophic aerobic bacterial spore counts (PABSC)) were obtained at the time of sampling and at the end of shelf-life (3 days) after storage of the samples at 4 or 8 degrees C. TAC were found to be below the 10(7 ) CFU ml(-1) limit of pasteurized milk spoilage both during sampling as well as when milk samples were stored at either storage temperature for 3 days. Enterobacteriaceae populations were below 1 CFU ml(-1) in 69.2% of the samples tested at the time of sampling, whereas the remaining samples contained low numbers, typically less than 10 CFU ml(-1) . All samples tested negative for the presence of Listeria monocytogenes. Analogous microbiological data were also obtained by sampling and testing prepackaged, retail samples of pasteurized milk from two dairy companies in Greece (n = 26). From a microbiological standpoint, the data indicate that the AVM milk samples meet the quality standards of pasteurized milk. However, the prepackaged, retail milk samples yielded better results in terms of TAC, TPC and EC, compared to the AVM samples at the end of shelf-life. SIGNIFICANCE AND IMPACT OF THE STUDY: Recently, Greek dairy farmers organized in cooperatives launched the sale of pasteurized milk via AVM and this study reports on the microbiological quality of this product. The data show that AVM milk is sold at proper refrigeration temperatures and meets the quality standards of pasteurized milk throughout the manufacturer's specified shelf-life. However, based on the microbiological indicators tested, the keeping quality of the tested prepackaged, retail samples of pasteurized milk at the end of shelf-life upon storage under suboptimal refrigeration temperature (8 degrees C) was better. PMID- 27116620 TI - Matched elastic constants for a perfect helical planar state and a fast switching time in chiral nematic liquid crystals. AB - Chiral nematic liquid crystals possess a self-assembled helical structure and exhibit unique selective reflection in visible and infrared light regions. Their optical properties can be electrically tuned. The tuning involves the unwinding and restoring of the helical structure. We carried out an experimental study on the mechanism of the restoration of the helical structure. We constructed chiral nematic liquid crystals with variable elastic constants by doping bent-dimers and studied their impact on the restoration. With matched twist and bend elastic constants, the helical structure can be restored dramatically fast from the field induced homeotropic state. Furthermore, defects can be eliminated to produce a perfect planar state which exhibits high selective reflection. PMID- 27116634 TI - The University of Michigan Sarcoma Survivorship Clinic: Preventing, Diagnosing, and Treating Chronic Illness for Improved Survival and Long-Term Health. AB - The Children's Cancer Survivorship Study reports more chronic illnesses in sarcoma survivors than other pediatric cancers. Chemotherapy and radiation put survivors at risk for developing chronic illnesses, including heart disease, diabetes, hypertension, and kidney failure. Sarcoma survivors may have a reduced life expectancy and signs of heart disease in their 30s and 40s. Since these medical problems occur much later in the general population, they often go undetected or misdiagnosed in sarcoma survivors, creating delays in intervention and treatment. The good news is that these chronic illnesses can often be prevented or minimized. The most common adverse effect of chemotherapy and radiation is coronary artery disease (CAD). CAD has a number of risk factors, including hypertension, diabetes, obesity, and dyslipidemia. These risk factors are modifiable with lifestyle changes, including diet and exercise, and/or pharmacological intervention. By identifying and managing risk factors like hypertension early, we in turn reduce the risk for CAD and prolong survival. This is well established in the general population; there is no reason a priori not to apply it to sarcoma survivors. Sarcoma survivors should be followed by physicians who understand the late effects and outcomes of sarcoma treatment. The University of Michigan Sarcoma Survivorship Clinic provides long-term care for sarcoma survivors by preventing, diagnosing, and treating the adverse long-term physical and psychological effects associated with sarcoma survivorship. PMID- 27116636 TI - Planar Vacancies in Sn1-xBixTe Nanoribbons. AB - Vacancy engineering is a crucial approach to manipulate physical properties of semiconductors. Here, we demonstrate that planar vacancies are formed in Sn1 xBixTe nanoribbons by using Bi dopants via a facile chemical vapor deposition. Through combination of sub-angstrom-resolution imaging and density functional theory calculations, these planar vacancies are found to be associated with Bi segregations, which significantly lower their formation energies. The planar vacancies exhibit polymorphic structures with local variations in the lattice relaxation level, determined by their proximity to the nanoribbon surface. Such polymorphic planar vacancies, in conjunction with Bi dopants, trigger distinct localized electronic states, offering platforms for device applications of ternary chalcogenide materials. PMID- 27116635 TI - Development of polymeric micelles for targeting intractable cancers. AB - In relation to recent advances in nanobiotechnologies, cancer-targeted therapy using nano-scaled drug carriers (nanocarriers) has been attracting enormous attention with success in clinical studies. Polymeric micelles, core-shell-type nanoparticles formed through the self-assembly of block copolymers, are one of the most promising nanocarrier, because their critical features such as size, stability, and drug incorporation efficiency and release rate can be modulated by designing the constituent block copolymers. The utilities of polymeric micelles have been reported not only in experimental tumor models in mice but also in clinical studies. In this article, we aim to explain the rationale of designing polymeric micelles for targeting intractable cancers such as pancreatic cancer, glioblastoma, and metastases. Also, we review recent progress in clinical studies on polymeric micelles incorporating anticancer drugs. In addition, we introduce the next generation of polymeric micelles as the platform integrated with smart functionalities such as targetability, environmental sensitivity, and imaging properties. Thus, polymeric micelles can realize safe and effective cancer therapy, and offer tailor-made medicines for individual patients. PMID- 27116637 TI - Power Analysis and Sample Size Determination in Metabolic Phenotyping. AB - Estimation of statistical power and sample size is a key aspect of experimental design. However, in metabolic phenotyping, there is currently no accepted approach for these tasks, in large part due to the unknown nature of the expected effect. In such hypothesis free science, neither the number or class of important analytes nor the effect size are known a priori. We introduce a new approach, based on multivariate simulation, which deals effectively with the highly correlated structure and high-dimensionality of metabolic phenotyping data. First, a large data set is simulated based on the characteristics of a pilot study investigating a given biomedical issue. An effect of a given size, corresponding either to a discrete (classification) or continuous (regression) outcome is then added. Different sample sizes are modeled by randomly selecting data sets of various sizes from the simulated data. We investigate different methods for effect detection, including univariate and multivariate techniques. Our framework allows us to investigate the complex relationship between sample size, power, and effect size for real multivariate data sets. For instance, we demonstrate for an example pilot data set that certain features achieve a power of 0.8 for a sample size of 20 samples or that a cross-validated predictivity QY(2) of 0.8 is reached with an effect size of 0.2 and 200 samples. We exemplify the approach for both nuclear magnetic resonance and liquid chromatography-mass spectrometry data from humans and the model organism C. elegans. PMID- 27116638 TI - Niacin and olive oil promote skewing to the M2 phenotype in bone marrow-derived macrophages of mice with metabolic syndrome. AB - Metabolic syndrome (MetS) is associated with obesity, dyslipemia, type 2 diabetes and chronic low-grade inflammation. The aim of this study was to determine the role of high-fat low-cholesterol diets (HFLCDs) rich in SFAs (HFLCD-SFAs), MUFAs (HFLCD-MUFAs) or MUFAs plus omega-3 long-chain PUFAs (HFLCD-PUFAs) on polarisation and inflammatory potential in bone marrow-derived macrophages (BMDMs) from niacin (NA)-treated Lep(ob/ob)LDLR(-/-) mice. Animals fed with HFLCD SFAs had increased weight and serum triglycerides, and their BMDMs accumulated triglycerides over the animals fed with HFLCD-MUFAs or -PUFAs. Furthermore, BMDMs from animals fed with HFLCD-SFAs were polarised towards the M1 phenotype with functional competence to produce pro-inflammatory cytokines, whereas BMDMs from animals fed with HFLCD-MUFAs or -PUFAs were skewed to the anti-inflammatory M2 phenotype. These findings open opportunities for developing novel nutritional strategies with olive oil as the most important dietary source of MUFAs (notably oleic acid) to prevent development and progression of metabolic complications in the NA-treated MetS. PMID- 27116639 TI - Role of the source to building lateral separation distance in petroleum vapor intrusion. AB - The adoption of source to building separation distances to screen sites that need further field investigation is becoming a common practice for the evaluation of the vapor intrusion pathway at sites contaminated by petroleum hydrocarbons. Namely, for the source to building vertical distance, the screening criteria for petroleum vapor intrusion have been deeply investigated in the recent literature and fully addressed in the recent guidelines issued by ITRC and U.S.EPA. Conversely, due to the lack of field and modeling studies, the source to building lateral distance received relatively low attention. To address this issue, in this work we present a steady-state vapor intrusion analytical model incorporating a piecewise first-order aerobic biodegradation limited by oxygen availability that accounts for lateral source to building separation. The developed model can be used to evaluate the role and relevance of lateral vapor attenuation as well as to provide a site-specific assessment of the lateral screening distances needed to attenuate vapor concentrations to risk-based values. The simulation outcomes showed to be consistent with field data and 3-D numerical modeling results reported in previous studies and, for shallow sources, with the screening criteria recommended by U.S.EPA for the vertical separation distance. Indeed, although petroleum vapors can cover maximum lateral distances up to 25-30m, as highlighted by the comparison of model outputs with field evidences of vapor migration in the subsurface, simulation results by this new model indicated that, regardless of the source concentration and depth, 6m and 7m lateral distances are sufficient to attenuate petroleum vapors below risk-based values for groundwater and soil sources, respectively. However, for deep sources (>5m) and for low to moderate source concentrations (benzene concentrations lower than 5mg/L in groundwater and 0.5mg/kg in soil) the above criteria were found extremely conservative as the model results indicated that for such scenarios the lateral screening distance may be set equal to zero. PMID- 27116641 TI - Sequence Dependence of Viral RNA Encapsidation. AB - We develop a Flory mean-field theory for viral RNA (vRNA) molecules that extends the current RNA folding algorithms to include interactions between different sections of the secondary structure. The theory is applied to sequence-selective vRNA encapsidation. The dependence on sequence enters through a single parameter: the largest eigenvalue of the Kramers matrix of the branched polymer obtained by coarse graining the secondary structure. Differences between the work of encapsidation of vRNA molecules and of randomized isomers are found to be in the range of 20 kBT, more than sufficient to provide a strong bias in favor of vRNA encapsidation. The method is applied to a packaging competition experiment where large vRNA molecules compete for encapsidation with two smaller RNA species that together have the same nucleotide sequence as the large molecule. We encounter a substantial, generic free energy bias, that also is of the order of 20 kBT, in favor of encapsidating the single large RNA molecule. The bias is mainly the consequence of the fact that dividing up a large vRNA molecule involves the release of stored elastic energy. This provides an important, nonspecific mechanism for preferential encapsidation of single larger vRNA molecules over multiple smaller mRNA molecules with the same total number of nucleotides. The result is also consistent with recent RNA packaging competition experiments by Comas-Garcia et al.1 Finally, the Flory method leads to the result that when two RNA molecules are copackaged, they are expected to remain segregated inside the capsid. PMID- 27116640 TI - Characterization of chlorinated solvent contamination in limestone using innovative FLUTe(r) technologies in combination with other methods in a line of evidence approach. AB - Characterization of dense non-aqueous phase liquid (DNAPL) source zones in limestone aquifers/bedrock is essential to develop accurate site-specific conceptual models and perform risk assessment. Here innovative field methods were combined to improve determination of source zone architecture, hydrogeology and contaminant distribution. The FACTTM is a new technology and it was applied and tested at a contaminated site with a limestone aquifer, together with a number of existing methods including wire-line coring with core subsampling, FLUTe(r) transmissivity profiling and multilevel water sampling. Laboratory sorption studies were combined with a model of contaminant uptake on the FACTTM for data interpretation. Limestone aquifers were found particularly difficult to sample with existing methods because of core loss, particularly from soft zones in contact with chert beds. Water FLUTeTM multilevel groundwater sampling (under two flow conditions) and FACTTM sampling and analysis combined with FLUTe(r) transmissivity profiling and modeling were used to provide a line of evidence for the presence of DNAPL, dissolved and sorbed phase contamination in the limestone fractures and matrix. The combined methods were able to provide detailed vertical profiles of DNAPL and contaminant distributions, water flows and fracture zones in the aquifer and are therefore a powerful tool for site investigation. For the limestone aquifer the results indicate horizontal spreading in the upper crushed zone, vertical migration through fractures in the bryozoan limestone down to about 16-18m depth with some horizontal migrations along horizontal fractures within the limestone. Documentation of the DNAPL source in the limestone aquifer was significantly improved by the use of FACTTM and Water FLUTeTM data. PMID- 27116642 TI - "Professional Helper" or "Helping Professional?" The Patient-Physician Relationship in the Chronic Pain Setting, With Special Reference to the Current Opioid Debate. AB - There seems to be a strong cultural expectation among patients for effective pain relief. As a result, physicians often find themselves trying to bridge the gap between the chronic pain patient's expectations and harsh biomedical reality. The typology of Emanuel and Emanuel of four models for the patient-physician relationship is used in this article as a conceptual tool to examine the possible roles of physicians in the context of chronic noncancer pain. Their typology is reconceptualized as a "pathway" along which the physician is able to walk more or less far, starting from the "information" end of the path. The other end of the pathway is "caring deliberation." I then propose that, in pain medicine today, consumerism is a powerful incentive for physicians to stay at the information end of the spectrum. Against this background, I discuss the current opioid epidemic in the United States and the need for what has been called a new medical professionalism. I conclude by challenging educators involved in pain medicine continuing professional development to not only design adequate biomedical educational programs, but also consider issues like professionalism, personal development, critical self-reflection, and the ethics of engaging in caring deliberation with chronic pain patients. PMID- 27116643 TI - Running Energy Cost and Spring-Mass Behavior in Young versus Older Trained Athletes. AB - PURPOSE: The aim of this study was to compare energy cost of running and lower limb spring-mass characteristics and maximal power between young and older highly trained runners. METHODS: Twenty highly trained male endurance runners were divided into two groups: young and master athletes. Two testing sessions were used to measure and compare (i) lower limb power during three jumping tests (squat jump (SJ), countermovement jump (CMJ), and rebound jump (RJ)) as well as stiffness during the RJ test and running trials (using an OptoJump system (Microgate, Bolzano, Italy) placed on the floor for jumping and on each side of the treadmill belt for running), and (ii) the energy cost of running and oxygen consumption (VO2) kinetics (using an Oxycon Pro breath-by-breath gas analyzer (Jaeger, Hochberg, Germany)) at three speeds: 10 km.h, self-selected speed, and speed corresponding to 90% of the second ventilatory threshold (VT2). RESULTS: Energy cost of running was higher in masters than in young athletes at all speeds (10 km.h, 13.0%; self-selected, 10.8%; 90% VT2, 7.7% on average). Jumping power was lower in masters (SJ, -28.0%; CMJ, -30.5%; RJ, -27.9%) and significantly correlated with energy cost at 10 km.h and at self-selected speed (10 km.h: r = 0.71, -0.70, -0.47; self-selected speed: r = -0.76, -0.74, -0.58, respectively). RJ stiffness was also lower in masters (-27.8%), although stiffness during running showed no difference between groups. CONCLUSIONS: A long-lasting running practice seemed to preserve the bouncing mechanism of master athletes, yet their energy cost was higher when compared with younger runners, which might have been associated with a lower muscle power. PMID- 27116644 TI - Optimizing QT Interval Measurement for the Preparticipation Screening of Young Athletes. AB - PURPOSE: Sudden cardiac death is the leading cause of death in athletes. Long QT syndrome (LQTS) is one of the most common cardiogenetic diseases that can lead to sudden cardiac death and is identified by QT interval prolongation on an ECG. Recommendations for QT monitoring in athletes are adopted from nonathlete populations. To improve screening, ECG data of athletes are assessed to determine a more appropriate method for QT interval estimation. METHODS: ECG (CardeaScreen) data were collected from June 2010 to March 2015. ECG data with HR greater than 100 bpm were excluded. Fiducial points of outliers were manually corrected if the QRS onset or the T wave offset was misidentified. A model of best fit was determined and compared across four QT correction factors. Classification analysis was used to compare the Bazett's corrected QT interval to the 99th percentile of uncorrected QT interval. RESULTS: High school (n = 597), college (n = 1207), and professional athletes (n = 273) (N = 2077) were analyzed. Mean age was 19 +/- 3.5 yr. QT interval varied by cohort (HS = 388 +/- 30, Col = 410 +/- 33, Pro = 407 +/- 27, p < 0.0001). A nonlinear power function with a cubic exponent of -0.349 fit the data the best (R = 0.64). Of the four common correction factors, Fridericia had the lowest residual dependence to HR (m = 0.10). With standard screening, 75% of athletes within the top 1% for QT interval were not identified for further investigation for LQTS. CONCLUSION: Up to 75% of athletes possessing an uncorrected QT interval greater than 99% of the population are not identified for investigation for LQTS using the recommended criteria. We propose a new method of risk stratification that replaces QT interval correction. Further study is needed to establish QT interval distributions and risk thresholds in athletes. PMID- 27116645 TI - Graded versus Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome. AB - PURPOSE: There is increasing evidence of immune system dysfunction in chronic fatigue syndrome (CFS), but little is known of the regular exercise effects on immune cell parameters. This pilot study investigated the effects of graded and intermittent exercise on CD4 lymphocyte subset counts and activation compared with usual care. METHODS: Twenty-four CFS patients (50.2 +/- 10 yr) were randomized to graded exercise (GE), intermittent exercise (IE), or usual care (UC) groups; 18 sedentary non-CFS participants (50.6 +/- 10 yr) were controls (CTL) for blood and immunological comparisons. Outcome measures were pre- and postintervention flow cytometric analyses of circulating lymphocyte subset cell counts; expression of CD3, CD4, CD25, and CD134; full blood counts; and VO2peak. RESULTS: Preintervention, CD3 cell counts, and expression of CD4, CD25, CD134, and CD4CD25CD134 were significantly lower in GE, IE, and UC compared with CTL (P < 0.05). Total lymphocyte concentration was significantly lower in GE and IE groups compared with CTL. There were significant postintervention increases in i) expression of CD4 and CD4CD25CD134 for GE and IE, but CD25 and CD134 for IE only; ii) circulating counts of CD3 and CD4 for GE, and CD3, CD4, CD8, CD3CD4CD8, CD3CD16CD56, CD19, and CD45 for IE; iii) neutrophil concentration for GE; and iv) VO2peak and elapsed test time for IE and GE, VEpeak for IE. CONCLUSIONS: Twelve weeks of GE and IE training significantly improved CD4 lymphocyte activation and aerobic capacity without exacerbating CFS symptoms. IE may be a more effective exercise modality with regard to enhanced CD4 activation in CFS patients. PMID- 27116646 TI - Exploring the Relationship between Adiposity and Fitness in Young Children. AB - PURPOSE: High levels of cardiorespiratory fitness (CRF) may attenuate the association between the excessive adiposity and the risks of cardiovascular and metabolic disease. The purpose of this study was to stratify children according to their body mass index (BMI) and adiposity (body fat percentage [BF%]) and to compare levels of CRF across subgroups. METHODS: This prospective cohort study comprises a cross-sectional and longitudinal analyses of data collected at baseline (n = 641) and 2 yr later (n = 579) on children (7.4-11.6 yr) attending public school in Denmark. Levels of CRF were measured using the Andersen test, whereas BF% was measured by dual-energy x-ray absorptiometry. RESULTS: There were 560 children (87.4%) classified as normal weight according to BMI at baseline, of which 46 (7.4%) were identified as having excessive BF%. These children had significantly lower CRF (mean [95% confidence interval]: -63.1 m [-100.2 to 25.9]) than children with normal BMI and normal BF%, and the effect of BF% on CRF was significantly worse in boys than girls. Overweight children with high BF% had significantly lower prospective (2 yr) CRF levels (-34.4 m [-58.0 to -10.7]) than children with normal BMI and BF%. However, children who improved their BMI and/or BF% classification during the 2-yr period achieved CRF levels (8.9 m [-30.2 to 47.9]), which were comparable with children with normal BMI and BF% at both measurement time points. CONCLUSION: The CRF levels in children are affected by BMI and BF%, although BF% appears to play a greater role. This association between BF% and CRF is sex dependent, with CRF levels in boys being affected to a greater extent by BF%. Children identified as "normal weight" by BMI but presenting with excessive BF% had significantly lower CRF than "normal weight" children with low BF%. PMID- 27116648 TI - Strength Training Biases Goal-Directed Aiming. AB - PURPOSE: Goal-directed movements tend to resemble the characteristics of previously executed actions. Here we investigated whether a single bout of strength training, which typically involves stereotyped actions requiring strong neural drive, can bias subsequent aiming behavior toward the direction of trained forces. METHODS: In experiment 1 (n = 10), we tested the direction of force exerted in an isometric aiming task before and after 40 repetitions of 2-s maximal-force ballistic contractions toward a single directional target. In experiment 2 (n = 12), each participant completed three training conditions in a counterbalanced crossover design. In two conditions, both the aiming task and the training were conducted in the same (neutral) forearm posture. In one of these conditions, the training involved weak forces to determine whether the level of neural drive during training influences the degree of bias. In the third condition, high-force training contractions were performed in a 90 degrees pronated forearm posture, whereas the low-force aiming task was performed in a neutral forearm posture. This dissociated the extrinsic training direction from the pulling direction of the trained muscles during the aiming task. RESULTS: In experiment 1, we found that aiming direction was biased toward the training direction across a large area of the work space (approximately +/-135 degrees ; tested for 16 targets spaced 22.5 degrees apart), whereas in experiment 2, we found systematic bias in aiming toward the training direction defined in extrinsic space, but only immediately after high-force contractions. CONCLUSION: Our findings suggest that bias effects of training involving strong neural drive generalize broadly to untrained movement directions and are expressed according to extrinsic rather than muscle-based coordinates. PMID- 27116647 TI - Exercise following Mental Work Prevented Overeating. AB - Mental work may promote caloric intake, whereas exercise may offset positive energy balance by decreasing energy intake and increasing energy expenditure. PURPOSE: This study aimed to replicate previous findings that mental work increases caloric intake compared with a rest condition and assess whether exercise after mental work can offset this effect. METHODS: Thirty-eight male and female university students were randomly assigned to mental work + rest (MW + R) or mental work + exercise (MW + E). Participants also completed a baseline rest (BR) visit consisting of no mental work or exercise. Visit order was counterbalanced. During the MW + R or MW + E visit, participants completed a 20 min mental task and either a 15-min rest (MW + R) or a 15-min interval exercise (MW + E). Each visit ended with an ad libitum pizza lunch. A two-way repeated measures ANOVA was used to compare eating behavior between groups. RESULTS: Participants in the MW + R condition consumed an average of 100 more kilocalories compared with BR (633.3 +/- 72.9 and 533.9 +/- 67.7, respectively, P = 0.02), and participants in MW + E consumed an average of 25 kcal less compared with BR (432.3 +/- 69.2 and 456.5 +/- 64.2, respectively, P > 0.05). When including the estimated energy expenditure of exercise in the MW + E conditions, participants were in negative energy balance by an average of 98.5 +/- 41.5 kcal, resulting in a significant difference in energy balance between the two groups (P = 0.001). CONCLUSION: An acute bout of interval exercise after mental work resulted in significantly decreased food consumption compared with a nonexercise condition. These results suggest that an acute bout of exercise may be used to offset positive energy balance induced by mental tasks. PMID- 27116649 TI - Cost of severe asthma in Brazil-systematic review. AB - INTRODUCTION: Severe asthma is characterized by frequent exacerbations, symptoms limiting daily activities and nocturnal symptoms. It requires the continuous use of medications, at high doses, and, sometimes, continuous use of oral corticosteroids, representing a significant burden to health system and society. This systematic review sought to address economic data related to severe asthma in Brazil. METHOD: In June 2014, electronic searches were conducted to identify relevant publications. Quality criteria were developed and applied to each selected study. In order to compare results across the selected studies, costs were refined to an annual basis, grouped according to the study perspective, inflated and converted to 2014 USD. RESULTS: Cost analyses from the Brazilian public health system perspective were derived from two studies and showed an average annual hospital cost per patient of 135 USD and 733 USD, respectively. From the family perspective, average annual direct costs per patient varied from 764 USD to 929 USD. CONCLUSION: Hospitalizations and medications seem to be the most important resources funded by the Brazilian public health system and by patients and their families. Although further studies are necessary, as information on cost of this disease is scarce in Brazil, these findings suggest that there is a potential room for improving severe asthma care among Brazilian patients. PMID- 27116650 TI - A fundamental measure density functional for fluid and crystal phases of the Asakura-Oosawa model. AB - We investigate a density functional for the Asakura-Oosawa model of colloid polymer mixtures, describing both fluid and crystal phases. It is derived by linearizing the two-component fundamental-measure hard sphere tensor functional in the second (polymer) component. We discuss the formulation of an effective density functional for colloids only. For small polymer-colloid size ratios the effective, polymer-induced potential between colloids is short-range attractive and of two-body form but we show that the effective density functional is not equivalent to standard mean-field approaches where attractions are taken into account by terms second order in the colloid density. We calculate numerically free energies and phase diagrams in good agreement with available simulations, furthermore we discuss the colloid and polymer distributions in the crystal and determine equilibrium vacancy concentrations. Numerical results reveal a fairly strong sensitivity to the specific type of underlying fundamental measure hard sphere functional which could aid further development of fundamental measure theory. PMID- 27116651 TI - Mapping the Photoresponse of CH3NH3PbI3 Hybrid Perovskite Thin Films at the Nanoscale. AB - Perovskite solar cells (PSCs) based on thin films of organolead trihalide perovskites (OTPs) hold unprecedented promise for low-cost, high-efficiency photovoltaics (PVs) of the future. While PV performance parameters of PSCs, such as short circuit current, open circuit voltage, and maximum power, are always measured at the macroscopic scale, it is necessary to probe such photoresponses at the nanoscale to gain key insights into the fundamental PV mechanisms and their localized dependence on the OTP thin-film microstructure. Here we use photoconductive atomic force microscopy spectroscopy to map for the first time variations of PV performance at the nanoscale for planar PSCs based on hole transport-layer free methylammonium lead triiodide (CH3NH3PbI3 or MAPbI3) thin films. These results reveal substantial variations in the photoresponse that correlate with thin-film microstructural features such as intragrain planar defects, grains, grain boundaries, and notably also grain-aggregates. The insights gained into such microstructure-localized PV mechanisms are essential for guiding microstructural tailoring of OTP films for improved PV performance in future PSCs. PMID- 27116652 TI - [The Marketing of Healthcare Services in ENT-Clinics]. AB - OBJECTIVE: The provision of healthcare services in Germany is based on fundamental principles of solidarity and is highly regulated. The question arises which conditions exist for marketing for healthcare services in ENT-clinics in Germany. MATERIAL AND METHODS: The marketing options will be elicited using environmentally analytical considerations. RESULTS: The objectives can be achieved using measures derived from external instruments (service policy, pricing policy, distribution policy or communications policy) or from an internal instrument (human resources policy). The policy environment is particularly influenced by the regulatory framework, which particularly restricts the scope for both the pricing and communications policies. All measures must, however, reflect ethical frameworks, which are regarded as the fundamental premise underlying healthcare services and may be at odds with economic factors. Scope for flexibility in pricing exists only within the secondary healthcare market, and even there only to a limited extent. The significance of price in the marketing of healthcare services is thus very low. If marketing activities are to succeed, a market analysis must be carried out exploring the relevant factors for each individual provider. However, the essential precondition for the marketing of healthcare services is trust. CONCLUSIONS: The marketing of healthcare services differs from that of business management-oriented enterprises in other branches of economy. In the future the importance of marketing activities will increase. PMID- 27116653 TI - Development of Causative Treatment Strategies for Lacrimal Gland Insufficiency by Tissue Engineering and Cell Therapy. Part 1: Regeneration of Lacrimal Gland Tissue: Can We Stimulate Lacrimal Gland Renewal In Vivo? AB - Severe dry eye syndrome (DES) is a complex disease that is commonly caused by inflammatory and degenerative changes in the lacrimal gland, and can result in severe pain and disruption to visual acuity. In healthy subjects, the ocular surface is continually lubricated by the tear film that ensures that the ocular surface remains moist and free of debris, enabling normal vision. The lacrimal fluid, mid-layer of the tear film, is mainly produced by the lacrimal gland and if this is dysfunctional for any reason, severe DES can develop. Currently, only palliative treatments for DES exist that aim to either replace or retain tears and/or minimize inflammation. A curative approach that aims to trigger the regeneration of existing lacrimal gland tissue in situ may, therefore, be very beneficial to DES patients. This article reviews the different approaches that have been explored toward lacrimal gland regeneration. Progress to date in vitro, in vivo, and in man is described with a focus on clinical feasibility and efficacy. Promising candidates for drug-dependent treatment of DES are growth factors and cytokines, such as hepatocyte growth factor (HGF) and tumor necrosis factor alpha-stimulated gene 6 protein (TSG-6). Only a few studies have evaluated gene therapy for lacrimal gland deficiencies, but with promising results. However gene therapy carries a variety of risks regarding carcinogenesis and therefore a treatment in the near future using this approach seems to be unlikely. Cell therapies utilizing mesenchymal stem cells (MSCs) seem to be more applicable than those using human amniotic membrane (hAM) epithelial cells or induced pluripotent stem (iPS) cells, since MSCs combine the favorable traits of both (multipotency, capability to stimulate regeneration immunomodulatory and non-immunogenic properties). PMID- 27116654 TI - Separation of collagen-bound and porous bone water transverse relaxation in mice: proposal of a multi-step approach. AB - The separation and quantification of collagen-bound water (CBW) and pore water (PW) components of the cortical bone signal are important because of their different contribution to bone mechanical properties. Ultrashort TE (UTE) imaging can be used to exploit the transverse relaxation from CBW and PW, allowing their quantification. We tested, for the first time, the feasibility of UTE measurements in mice for the separation and quantification of the transverse relaxation of CBW and PW in vivo using three different approaches for T2 * determination. UTE sequences were acquired at 4.7 T in six mice with 10 different TEs (50-5000 MUs). The transverse relaxation time T2 * of CBW (T2 *cbw ) and PW (T2 *pw ) and the CBW fraction (bwf) were computed using a mono-exponential (i), a standard bi-exponential (ii) and a new multi-step bi-exponential (iii) approach. Regions of interest were drawn at multiple levels of the femur and vertebral body cortical bone for each mouse. The sum of the normalized squared residuals (Res) and the homogeneity of variance were tested to compare the different methods. In the femur, approach (i) yielded mean T2 * +/- standard deviation (SD) of 657 +/- 234 MUs. With approach (ii), T2 *cbw , T2 *pw and bwf were 464 +/- 153 MUs, 15 777 +/- 10 864 MUs and 57.6 +/- 9.9%, respectively. For approach (iii), T2 *cbw , T2 *pw and bwf were 387 +/- 108 MUs, 7534 +/- 2765 MUs and 42.5 +/- 6.2%, respectively. Similar values were obtained from vertebral bodies. Res with approach (ii) was lower than with the two other approaches (p < 0.007), but T2 *pw and bwf variance was lower with approach (iii) than with approach (ii) (p < 0.048). We demonstrated that the separation and quantification of cortical bone water components with UTE sequences is feasible in vivo in mouse models. The direct bi-exponential approach exhibited the best approximation to the measured signal curve with the lowest residuals; however, the newly proposed multi-step algorithm resulted in substantially lower variability of the computed parameters. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27116655 TI - Synthesis of Enantiomeric Polyhydroxyalkylpyrrolidines from 1,3-Dipolar Cycloadducts. Evaluation as Inhibitors of a beta-Galactofuranosidase. AB - Enantiomeric 2,3,4-tris(hydroxyalkyl)-5-phenylpyrrolidines have been synthesized from the major cycloadducts obtained by the 1,3-dipolar cycloaddition of sugar enones with azomethine ylides derived from natural amino acids. Reduction of the ketone carbonyl group of the cycloadducts, which possess a basic structure of bicyclic 6-(menthyloxy)hexahydropyrano[4,3-c]pyrrol-7(6H)one, afforded a number of pyrrolidine-based bicyclic systems. A sequence of reactions, which involved hydrolysis of the menthyloxy substituent, reduction, N-protection, and degradative oxidation, afforded varied pyrrolidine structures having diverse configurations and patterns of substitution; in particular, polyhydroxylated derivatives have been obtained. The unprotected products were isolated as pyrrolidinium trifluoroacetates. Because of the furanose-like nature of the target trihydroxyalkyl pyrrolidines, these molecules have been evaluated as inhibitors of the beta-galactofuranosidase from Penicillium fellutanum. The compounds showed practically no inhibitory activity for concentration of pyrrolidines in the range of 0.1-1.6 mM. PMID- 27116657 TI - Short article: Management of ruptured hepatocellular carcinoma in a European tertiary care center. AB - GOALS AND BACKGROUND: Spontaneous rupture is a rare complication of hepatocellular carcinoma (HCC). Treatment options consist of transcatheter arterial embolization (TAE), hepatic resection, and conservative therapy. The best approach is under debate. STUDY: This study presents a review of clinical data of patients with a ruptured HCC admitted to a European tertiary care center. RESULTS: Eleven patients were included; six (55%) had underlying cirrhosis. The majority of patients (73%) had no previous history of HCC. Spontaneous HCC rupture was diagnosed using abdominal computed tomography with or without a diagnostic paracentesis. Computed tomography showed one or two tumors in eight (73%) patients; the other patients had multiple tumors or diffuse infiltrative HCC. Seven (64%) patients were initially treated by TAE and one (9%) patient underwent hepatic resection. The remaining three (27%) patients, all of whom had liver cirrhosis, received conservative therapy. Two patients initially treated by TAE underwent a delayed resection and ultimately received systemic therapy. Overall, at the end of the follow-up period, three patients were still alive at 84, 991, and 1026 days after the initial presentation. Eight (73%) patients had died after a median of 88 days (range 7-417). One year after presentation, none of the conservatively treated patients was alive compared with three out of seven (43%) patients treated with TAE with or without delayed resection. CONCLUSION: Patients with a spontaneously ruptured HCC have a poor prognosis. In selected patients, however, prolonged survival is possible using TAE as initial therapy with or without a delayed resection and systemic therapy. PMID- 27116656 TI - Isolated limb perfusion with biochemotherapy and oncolytic virotherapy combines with radiotherapy and surgery to overcome treatment resistance in an animal model of extremity soft tissue sarcoma. AB - The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP-delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV-1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology. PMID- 27116658 TI - Preface: Sight Restoration Through Stem Cell Therapy. AB - This publication presents chapters based on a meeting entitled "Sight Restoration Through Stem Cell Therapy" held on June 13, 2015, in Santa Monica, CA, sponsored by the Ocular Research Symposia Foundation (ORSF). It was chaired by Michael Young, PhD, Harvard Medical School, and Gerald Chader, PhD, University of Southern California. The mission of this publication and of the ORSF in general is to focus attention on unmet medical needs and current research opportunities in eye research with the objective of accelerating translation of research findings to effective clinical care. In the meeting, new research advances on stem cells and opportunities for their clinical application were highlighted and are recounted in the following chapters of this publication. By identifying "low hanging fruit" (i.e., the best opportunities for successful transition of laboratory research to prevention and new treatments and cures for ocular diseases), we seek to spur funding at both the basic research and clinical levels, resulting in sight-saving and sight-restoration measures in the near future. PMID- 27116659 TI - Stemming the Tide of Age-Related Macular Degeneration: New Therapies for Old Retinas. PMID- 27116660 TI - Subretinal Transplantation of Embryonic Stem Cell-Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years. AB - Advanced macular degeneration is an important cause of vision loss in the United States with over 2 million people affected by the disease. Despite substantial progress in the development of new therapies for wet AMD, the severe visual impairment associated with geographic atrophy in dry AMD or Stargardt disease remains untreatable. Recently, two phase I/II studies involving 18 patients with these diseases have demonstrated that it is possible to safely implant human embryonic stem cell-derived RPE (hESC-RPE) in an attempt to rescue photoreceptors and visual function. The anatomical and functional results are encouraging, with more than half of treated patients experiencing sustained improvements in visual acuity and demonstrating evidence of possible cellular engraftment. However, any conclusions remain tempered by the relatively short follow-up time, lack of a formal control group, poor initial visual acuity, and small number of patients. Aside from an instance of postoperative infectious endophthalmitis, no adverse events related to the cell therapy, such as hyperproliferation, tumorigenicity, or rejection-related inflammation were noted in this initial cohort of 18 patients. These first-in-human safety studies have opened the door to future studies enrolling patients with less advanced disease, treating other diseases that result in RPE loss, employing shorter immunosuppressive regimens, and using alternative strategies for RPE transplantation such as sheets of cells with or without scaffolding to mimic Bruch's membrane. The ultimate goal of these initial safety studies is to promote continued translation of complex biological therapies into meaningful treatment strategies that may address unmet medical needs. PMID- 27116661 TI - Stem Cell Sources and Their Potential for the Treatment of Retinal Degenerations. AB - Stem cells offer unprecedented opportunities for the development of strategies geared toward the treatment of retinal degenerative diseases. A variety of cellular sources have been investigated for various potential clinical applications, including tissue regeneration, disease modeling, and screening for non-cell-based therapeutic agents. As the field transitions from more than a decade of preclinical research to the first phase I/II clinical trials, we provide a concise overview of the stem cell sources most commonly used, weighing their therapeutic potential on the basis of their technical strengths/limitations, their ethical implications, and the extent of the progress achieved to date. This article serves as a framework for further in-depth analyses presented in the following chapters of this Special Issue. PMID- 27116663 TI - Mimicking Retinal Development and Disease With Human Pluripotent Stem Cells. AB - As applications of human pluripotent stem cells (hPSCs) continue to be refined and pursued, it is important to keep in mind that the strengths and weaknesses of this technology lie with its developmental origins. The remarkable capacity of differentiating hPSCs to recapitulate cell and tissue genesis has provided a model system to study stages of human development that were not previously amenable to investigation and experimentation. Furthermore, demonstration of developmentally appropriate, stepwise differentiation of hPSCs to specific cell types offers support for their authenticity and their suitability for use in disease modeling and cell replacement therapies. However, limitations to farming cells and tissues in an artificial culture environment, as well as the length of time required for most cells to mature, are some of the many issues to consider before using hPSCs to study or treat a particular disease. Given the overarching need to understand and modulate the dynamics of lineage-specific differentiation in stem cell cultures, this review will first examine the capacity of hPSCs to serve as models of retinal development. Thereafter, we will discuss efforts to model retinal disorders with hPSCs and present challenges that face investigators who aspire to use such systems to study disease pathophysiology and/or screen for therapeutics. We also refer readers to recent publications that provide additional insight and details on these rapidly evolving topics. PMID- 27116662 TI - Photoreceptor Fate Determination in the Vertebrate Retina. AB - Photoreceptors are highly specialized primary sensory neurons that sense light and initiate vision. This critical role is well demonstrated by the fact that visual impairment accompanies photoreceptor loss or dysfunction in many human diseases. With the remarkable advances in stem cell research, one therapeutic approach is to use stem cells to generate photoreceptors and then engraft them into diseased eyes. Knowledge of the molecular mechanisms that control photoreceptor genesis during normal development can greatly aid in the production of photoreceptor cells for this approach. This article will discuss advances in our understanding of the molecular mechanisms that regulate photoreceptor fate determination during development. Recent lineage studies have shown that there are distinct retinal progenitor cells (RPCs) that produce specific combinations of daughter cell types, including photoreceptors and other types of retinal cells. Gene regulatory networks, in which transcription factors interact via cis regulatory DNA elements, have been discovered that operate within distinct RPCs, and/or newly postmitotic cells, to direct the choice of photoreceptor fate. PMID- 27116664 TI - Photoreceptor Transplantation in Late Stage Retinal Degeneration. AB - The recent advances in cell-based therapies for the repair of the pigmented epithelium is providing additional impetus for the translation of photoreceptor transplantation to eventual clinical trials. The prospects for transplantation of photoreceptors as a potential therapy for the treatment of photoreceptor degeneration will depend on successfully addressing many critical issues in preclinical studies. Although most of the studies that have carried out transplants of photoreceptors have primarily used normal mice, there have been recent reports that have also shown some success following transplantation to mouse models of retinitis pigmentosa. However, while these results are promising, there are several key issues that require further investigation in order to better understand the optimum timing for transplantation, given the extensive remodeling of the retina that occurs in late stage disease. PMID- 27116667 TI - Cell Therapy Applications for Retinal Vascular Diseases: Diabetic Retinopathy and Retinal Vein Occlusion. AB - Retinal vascular conditions, such as diabetic retinopathy and retinal vein occlusion, remain leading causes of vision loss. No therapy exists to restore vision loss resulting from retinal ischemia and associated retinal degeneration. Tissue regeneration is possible with cell therapy. The goal would be to restore or replace the damaged retinal vasculature and the retinal neurons that are damaged and/or degenerating from the hypoxic insult. Currently, various adult cell therapies have been explored as potential treatment. They include mesenchymal stem cells, vascular precursor cells (i.e., CD34+ cells, hematopoietic cells or endothelial progenitor cells), and adipose stromal cells. Preclinical studies show that all these cells have a paracrine trophic effect on damaged ischemic tissue, leading to tissue preservation. Endothelial progenitor cells and adipose stromal cells integrate into the damaged retinal vascular wall in preclinical models of diabetic retinopathy and ischemia-reperfusion injury. Mesenchymal stem cells do not integrate as readily but appear to have a primary paracrine trophic effect. Early phase clinical trials have been initiated and ongoing using mesenchymal stem cells or autologous bone marrow CD34+ cells injected intravitreally as potential therapy for diabetic retinopathy or retinal vein occlusion. Adipose stromal cells or pluripotent stem cells differentiated into endothelial colony-forming cells have been explored in preclinical studies and show promise as possible therapies for retinal vascular disorders. The relative safety or efficacy of these various cell therapies for treating retinal vascular disorders have yet to be determined. PMID- 27116665 TI - HC-HA/PTX3 Purified From Amniotic Membrane as Novel Regenerative Matrix: Insight Into Relationship Between Inflammation and Regeneration. AB - PURPOSE: Human limbal palisade of Vogt is an ideal model for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation is a common manifestation of limbal stem cell deficiency, which is the major cause of corneal blindness, and presents as a threat to the success of transplanted limbal epithelial stem cells. Clinical studies have shown that the efficacy of transplantation of limbal epithelial stem cells can be augmented by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti inflammatory, antiscarring, and antiangiogenic action to promote wound healing. METHODS: Review of published data to determine the molecular action mechanism explaining how AM exerts the aforementioned therapeutic actions. RESULTS: From the water-soluble extract of cryopreserved AM, we have biochemically purified one novel matrix component termed heavy chain (HC)-hyaluronan (HA)/pentraxin 3 (PTX3) as the key relevant tissue characteristic responsible for the aforementioned AM's efficacy. Heavy chain-HA is a complex formed by a covalent linkage between HA and HC1 of inter-alpha-trypsin inhibitor (IalphaI) by tumor necrosis factor stimulated gene-6 (TSG-6). This complex may then be tightly associated with PTX3 to form HC-HA/PTX3 complex. Besides exerting an anti-inflammatory, antiscarring, and antiangiogenic effects, HC-HA/PTX3 complex also uniquely maintains limbal niche cells to support the quiescence of limbal epithelial stem cells. CONCLUSIONS: We envision that HC-HA/PTX3 purified from AM can be used as a unique substrate to refine ex vivo expansion of limbal epithelial stem cells by maintaining stem cell quiescence, self-renewal and fate decision. Furthermore, it can also be deployed as a platform to launch new therapeutics in regenerative medicine by mitigating nonresolving inflammation and reinforcing the well-being of stem cell niche. PMID- 27116666 TI - The Potential of Human Stem Cells for the Study and Treatment of Glaucoma. AB - PURPOSE: Currently, the only available and approved treatments for glaucoma are various pharmacologic, laser-based, and surgical procedures that lower IOP. Although these treatments can be effective, they are not always sufficient, and they cannot restore vision that has already been lost. The goal of this review is to briefly assess current developments in the application of stem cell biology to the study and treatment of glaucoma and other forms of optic neuropathy. METHODS: A combined literature review and summary of the glaucoma-related discussion at the 2015 "Sight Restoration Through Stem Cell Therapy" meeting that was sponsored by the Ocular Research Symposia Foundation (ORSF). RESULTS: Ongoing advancements in basic and eye-related developmental biology have enabled researchers to direct murine and human stem cells along specific developmental paths and to differentiate them into a variety of ocular cell types of interest. The most advanced of these efforts involve the differentiation of stem cells into retinal pigment epithelial cells, work that has led to the initiation of several human trials. More related to the glaucoma field, there have been recent advances in developing protocols for differentiation of stem cells into trabecular meshwork and retinal ganglion cells. Additionally, efforts are being made to generate stem cell-derived cells that can be used to secrete neuroprotective factors. CONCLUSIONS: Advancing stem cell technology provides opportunities to improve our understanding of glaucoma-related biology and develop models for drug development, and offers the possibility of cell-based therapies to restore sight to patients who have already lost vision. PMID- 27116669 TI - Stem Cell Therapy in Nonneovascular Age-Related Macular Degeneration. AB - Age-related macular degeneration (ARMD) is the leading cause of blindness in subjects older than 50 years of age in the developed world. There are two types of ARMD, neovascular (NV) and nonneovascular (NN). While anti-VEGF-based therapies have significantly decreased the visual morbidity associated with NV ARMD, there are no effective treatments for NN-ARMD. A detailed discussion of NV ARMD and related therapies is the topic of another section of this special supplement. This review will focus mainly on NN-ARMD. Vision loss in nonneovascular ARMD is highly correlated with the loss of RPE cells and areas of geographic atrophy (GA). Pilot studies using subretinal transplantation of autologous or allogeneic RPE during the past 20 to 30 years have demonstrated that stem cell-derived RPE have the potential to rescue photoreceptor function and restore vision. New methods of differentiating RPE from human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) have created a potentially unlimited supply of RPE cells to meet the demands of future commercially viable stem cell products. Thanks to fundamental advances in stem cell biology, vitreoretinal surgery, and noninvasive retinal imaging, stem cell-based therapies for NN-ARMD are emerging and several clinical trials are in progress. However, there are major regulatory, safety, and technical challenges that remain. This review will focus on summarizing the most promising aspects of stem cell-based therapy for NN-ARMD and highlighting areas that require further research. PMID- 27116670 TI - Retinal Structure Measurements as Inclusion Criteria for Stem Cell-Based Therapies of Retinal Degenerations. AB - PURPOSE: We reviewed and illustrated the most optimal retinal structural measurements to make in stem cell clinical trials. METHODS: Optical coherence tomography (OCT) and autofluorescence (AF) imaging were used to evaluate patients with severe visual loss from nonsyndromic and syndromic retinitis pigmentosa (RP), ABCA4-Stargardt disease, and nonneovascular age-related macular degeneration (AMD). Outer nuclear layer (ONL), rod outer segment (ROS) layer, inner retina, ganglion cell layer (GCL), and nerve fiber layer (NFL) thicknesses were quantified. RESULTS: All patients had severely reduced visual acuities. Retinitis pigmentosa patients had limited visual fields; maculopathy patients had central scotomas with retained peripheral function. For the forms of RP illustrated, there was detectable albeit severely reduced ONL across the scanned retina, and normal or hyperthick GCL and NFL. Maculopathy patients had no measurable ONL centrally; it became detectable with eccentricity. Some maculopathy patients showed unexpected GCL losses. Autofluorescence imaging illustrated central losses of RPE integrity. A hypothetical scheme to relate patient data with different phases of retinal remodeling in animal models of retinal degeneration was presented. CONCLUSIONS: Stem cell science is advancing, but it is not too early to open the discussion of criteria for patient selection and monitoring. Available clinical tools, such as OCT and AF imaging, can provide inclusion/exclusion criteria and robust objective outcomes. Accepting that early trials may not lead to miraculous cures, we should be prepared to know why scientifically and clinically-so we can improve subsequent trials. We also must determine if retinal remodeling is an impediment to efficacy. PMID- 27116668 TI - Treatment Paradigms for Retinal and Macular Diseases Using 3-D Retina Cultures Derived From Human Reporter Pluripotent Stem Cell Lines. AB - We discuss the use of pluripotent stem cell lines carrying fluorescent reporters driven by retinal promoters to derive three-dimensional (3-D) retina in culture and how this system can be exploited for elucidating human retinal biology, creating disease models in a dish, and designing targeted drug screens for retinal and macular degeneration. Furthermore, we realize that stem cell investigations are labor-intensive and require extensive resources. To expedite scientific discovery by sharing of resources and to avoid duplication of efforts, we propose the formation of a Retinal Stem Cell Consortium. In the field of vision, such collaborative approaches have been enormously successful in elucidating genetic susceptibility associated with age-related macular degeneration. PMID- 27116671 TI - Cross-View Action Recognition via Transferable Dictionary Learning. AB - Discriminative appearance features are effective for recognizing actions in a fixed view, but may not generalize well to a new view. In this paper, we present two effective approaches to learn dictionaries for robust action recognition across views. In the first approach, we learn a set of view-specific dictionaries where each dictionary corresponds to one camera view. These dictionaries are learned simultaneously from the sets of correspondence videos taken at different views with the aim of encouraging each video in the set to have the same sparse representation. In the second approach, we additionally learn a common dictionary shared by different views to model view-shared features. This approach represents the videos in each view using a view-specific dictionary and the common dictionary. More importantly, it encourages the set of videos taken from the different views of the same action to have the similar sparse representations. The learned common dictionary not only has the capability to represent actions from unseen views, but also makes our approach effective in a semi-supervised setting where no correspondence videos exist and only a few labeled videos exist in the target view. The extensive experiments using three public datasets demonstrate that the proposed approach outperforms recently developed approaches for cross-view action recognition. PMID- 27116672 TI - Toner Savings Based on Quasi-Random Sequences and a Perceptual Study for Green Printing. AB - Toner savings in monochromatic printing are an important target for improving green computing performance and more specifically green printing. In order to extend the lifetime of the printer cartridge, some options are available for laser printers, usually reducing the number of dots with respect to the normal print quality. However available algorithms and patents do not provide a method for dynamically adapting the percentage of toner savings to the required printing quality. In this paper, we introduce a new quasi-random sequence-based algorithm for reducing the number of dots in the printing process, able to achieve optimal discrepancy and low computational complexity, for all print quality levels. In order to reduce patterns in the removed dots, blue noise dithering is applied when the desired percentage of toner savings is moderate. The proposed solution can be easily implemented in the printer firmware, given its low computational complexity. In order to verify the results from a perceptual point of view, an extended test with 135 volunteers and more than 5000 comparisons has been performed, besides checking that toner is effectively saved. Results show that the proposed approach can produce a reduction of the perceived quality almost directly proportional to the number of monochromatic dots skipped, with only a reduced influence from the font used. The perceptual results are better in the proposal than in the previous approaches. The proposed algorithm appears to be a promising technique for improving green printing in monochromatic laser printers without using custom fonts. PMID- 27116674 TI - UK Renal Registry 18th Annual Report: Chapter 3 Demographic and Biochemistry Profile of Kidney Transplant Recipients in the UK in 2014: National and Centre specific Analyses. AB - There was a 2% fall in overall renal transplant numbers in 2014, with a significant fall in kidney donation from donors after circulatory death (10%). In 2014, death-censored renal transplant failure rates in prevalent patients were similar to previous years at 2.4% per annum. Transplant patient death rates remained stable at 2.3 per 100 patient years. The median age of incident and prevalent renal transplant patients in the UK was 50.6 and 53.3 years respectively. The median eGFR of prevalent renal transplant recipients was 52.5 ml/min/1.73 m2. The median eGFR of patients one year after transplantation was 57.4 ml/min/1.73 m2 post live transplant, 53.6 ml/min/1.73 m2 post brainstem death transplant and 50.1 ml/min/1.73 m2 post circulatory death transplant. In 2014, 13% of prevalent transplant patients had eGFR ,30 ml/min/1.73 m2. The median decline in eGFR slope beyond the first year after transplantation was 0.48 ml/min/1.73 m2/year.In 2014, malignancy (26%) and infection (24%) remained the commonest causes of death in patients with a functioning renal transplant. PMID- 27116673 TI - LINE-related component of mouse heterochromatin and complex chromocenters' composition. AB - Chromocenters are interphase nuclear landmark structures of constitutive heterochromatin. The tandem repeat (TR)-enriched parts of different chromosomes cluster together in chromocenters. There has been progress in recent years in determining the protein content of chromocenters, although it is not clear which DNA sequences underly constitutive heterochromatin apart from the TRs. The aim of the current work was to find out which DNA sequences besides TRs are involved in chromocenters' formation. Biochemically isolated chromocenters and microdissected centromeric regions were amplified by DOP-PCR, then cloned and sequenced. Alignment to Repbase, the mouse reference genome and WGS databases separated the sequences from both libraries into three groups: (1) sequences with similarity to pericentromere mouse major satellite; (2) sequences without similarity to any repetitive sequences; (3) sequences with similarity to long interspersed nuclear elements (LINEs). LINE-related sequences have a disperse pattern distribution on chromosomes predicted in silico. Selected clones were used for fluorescent in situ hybridization (FISH). The 10 clones tested hybridized to chromocenters and centromeric regions of metaphase chromosomes. These clones were used for double FISH with four known cloned TRs (satDNA, satellite DNA) and a probe specific for the sex chromosomes. The probes bind various chromocenters' regions without overlapping; so, FISH results reveal a complex chromocenter composition. We mapped 18 LINE-derived clones to the RepBase L1 records. Most of them grouped in a ~2-kb region at the end of the second ORF and 3' untranslated region (UTR). So, even the limited number of the clones allows us to determine the region of the L1 element that is specific for heterochromatic regions. Although the L1 full-length probe did not hybridize at detectable levels to the heterochromatic region on any chromosome, the 2-kb fragment found is definitely a part of these regions. The precise LINE ~2-kb fragment is the component of mouse and human constitutive heterochromatin enriched with TRs. The method used for amplification of the probes from two sources of the heterochromatic material uncovered the enrichment of a precise fragment of LINE within chromocenters. PMID- 27116675 TI - MR Image Reconstruction Using Block Matching and Adaptive Kernel Methods. AB - An approach to Magnetic Resonance (MR) image reconstruction from undersampled data is proposed. Undersampling artifacts are removed using an iterative thresholding algorithm applied to nonlinearly transformed image block arrays. Each block array is transformed using kernel principal component analysis where the contribution of each image block to the transform depends in a nonlinear fashion on the distance to other image blocks. Elimination of undersampling artifacts is achieved by conventional principal component analysis in the nonlinear transform domain, projection onto the main components and back-mapping into the image domain. Iterative image reconstruction is performed by interleaving the proposed undersampling artifact removal step and gradient updates enforcing consistency with acquired k-space data. The algorithm is evaluated using retrospectively undersampled MR cardiac cine data and compared to k-t SPARSE-SENSE, block matching with spatial Fourier filtering and k-t l1-SPIRiT reconstruction. Evaluation of image quality and root-mean-squared-error (RMSE) reveal improved image reconstruction for up to 8-fold undersampled data with the proposed approach relative to k-t SPARSE-SENSE, block matching with spatial Fourier filtering and k-t l1-SPIRiT. In conclusion, block matching and kernel methods can be used for effective removal of undersampling artifacts in MR image reconstruction and outperform methods using standard compressed sensing and l1 regularized parallel imaging methods. PMID- 27116677 TI - 3D Interdigital Au/MnO2 /Au Stacked Hybrid Electrodes for On-Chip Microsupercapacitors. AB - On-chip microsupercapacitors (MSCs) have application in powering microelectronic devices. Most of previous MSCs are made from carbon materials, which have high power but low energy density. In this work, 3D interdigital Au/MnO2 /Au stacked MSCs have been fabricated based on laser printed flexible templates. This vertical-stacked electrode configuration can effectively increase the contact area between MnO2 active layer and Au conductive layer, and thus improve the electron transport and electrolyte ion diffusion, resulting in enhanced pseudocapacitive performance of MnO2 . The stacked electrode can achieve an areal capacitance up to 11.9 mF cm(-2) . Flexible and all-solid-state MSCs are assembled based on the sandwich hybrid electrodes and PVA/LiClO4 gel electrolyte and show outstanding high-rate capacity and mechanical flexibility. The laser printing technique in this work combined with the physical sputtering and electrodeposition allows fabrication of MSC array with random sizes and patterns, making them promising power sources for small-scale flexible microelectronic energy storage systems (e.g., next-generation smart phones). PMID- 27116678 TI - Copper catalyzed aerobic oxidative cyclization and ketonization: one pot synthesis of benzoimidazo[1,2-a]imidazolones. AB - A highly efficient synthesis of benzoimidazo[1,2-a]imidazolone through a novel oxidative 5-exo-dig cyclization-ketonization cascade of 2-aminobenzimidazole, aldehyde and terminal alkyne has been explored under aerobic conditions. The reaction proceeds through copper-catalyzed addition of terminal alkynes to imines derived from 2-aminobenzimidazole with aldehyde followed by intramolecular cyclization. The atmospheric molecular oxygen acts as an oxygen source for the newly formed carbonyl group in the final product. PMID- 27116676 TI - Membrane channel gene expression in human costal and articular chondrocytes. AB - Chondrocytes are the uniquely resident cells found in all types of cartilage and key to their function is the ability to respond to mechanical loads with changes of metabolic activity. This mechanotransduction property is, in part, mediated through the activity of a range of expressed transmembrane channels; ion channels, gap junction proteins, and porins. Appropriate expression of ion channels has been shown essential for production of extracellular matrix and differential expression of transmembrane channels is correlated to musculoskeletal diseases such as osteoarthritis and Albers-Schonberg. In this study we analyzed the consistency of gene expression between channelomes of chondrocytes from human articular and costal (teenage and fetal origin) cartilages. Notably, we found 14 ion channel genes commonly expressed between articular and both types of costal cartilage chondrocytes. There were several other ion channel genes expressed only in articular (6 genes) or costal chondrocytes (5 genes). Significant differences in expression of BEST1 and KCNJ2 (Kir2.1) were observed between fetal and teenage costal cartilage. Interestingly, the large Ca(2+) activated potassium channel (BKalpha, or KCNMA1) was very highly expressed in all chondrocytes examined. Expression of the gap junction genes for Panx1, GJA1 (Cx43) and GJC1 (Cx45) was also observed in chondrocytes from all cartilage samples. Together, this data highlights similarities between chondrocyte membrane channel gene expressions in cells derived from different anatomical sites, and may imply that common electrophysiological signaling pathways underlie cellular control. The high expression of a range of mechanically and metabolically sensitive membrane channels suggest that chondrocyte mechanotransduction may be more complex than previously thought. PMID- 27116679 TI - The effect of site-to-site variability in ultrasensitive dose responses. AB - In this paper we study the ultrasensitive behavior of multisite phosphorylation or ligand binding systems, under site-to-site variations in the modification rates. Using computational methods and mathematical analysis, we prove that the Hill coefficient reaches its maximum value when all sites are identical to each other. This is shown for a non-cooperative multisite system with arbitrary activation function as well as for the well known MWC model. We also show that the Hill coefficient of the dose response is locally robust to variations in individual modification rates. The results suggest that maximal ultrasensitivity is reached when sites are similar to each other but not necessarily identical, a conformation found in unstructured modification domains present in many experimental systems. PMID- 27116680 TI - Quality of Care for Cervical and Endometrial Cancer Patients: The Impact of Different Techniques of Sentinel Lymph Node Mapping on Patient Satisfaction. AB - OBJECTIVES: The purpose of this study was to assess the quality of care in patients who underwent sentinel lymph node (SLN) mapping for endometrial and cervical cancer staging, and evaluate the impact of different techniques on patient satisfaction, i.e. radiotracer Tc99m versus indocyanine green (ICG) or methylene blue injection. METHOD: Women with preoperative stage I endometrial cancer or stage I (1A2-1B1) cervical cancer who underwent surgical staging, including SLN mapping, were considered for this study. Patient satisfaction was assessed using the European Organisation for Research and Treatment of Cancer IN PATSAT32 questionnaire. Women were classified into two groups according to the different nodal mapping techniques: intracervical preoperative injection of Tc99m nanocolloid + intraoperative blue dye (Group 1) versus intraoperative cervical injection of ICG or blue dye (Group 2). Differences in patient satisfaction scores between the groups were analyzed. RESULTS: Of the 178 eligible women, 143 were included in the study (endometrial cancer n = 106, cervical cancer n = 37): 57 underwent SLN mapping with Tc99m and blue dye (Group 1), and 86 women were mapped intraoperatively with blue dye alone or ICG (Group 2). Analysis of IN PATSAT32 questionnaire scores showed a higher patient satisfaction score for patients in Group 2 (p = 0.001), which was independent of the physician and surgical outcomes evaluated. The scores were statistically better for Group 2, and also in rating doctors (p = 0.0001), nurses (p = 0.006), and care and services organizations (p = 0.001). CONCLUSIONS: Cervical and endometrial cancer patients who underwent SLN mapping by ICG or blue dye perceived a better quality of care when compared with those patients who underwent the combined radiocolloid and blue dye technique. PMID- 27116681 TI - Intraoperative Fluid Resuscitation Strategies in Pancreatectomy: Results from 38 Hospitals in Michigan. AB - BACKGROUND: Fluid administration practices may affect complication rates in some abdominal surgeries, but effects in patients undergoing pancreatectomy are not understood well. We sought to determine whether amount of intraoperative fluid administered to patients undergoing pancreatectomy is associated with postoperative complication rates and to determine whether hospitals vary in their fluid administration practices. METHODS: Data for 504 patients undergoing pancreatectomy at 38 hospitals between 2012 and 2015 were evaluated. The main exposure was intraoperative fluid administration (<=10, 10-15, >15 mL/kg/h). Mortality, complications, and length of stay were the main outcomes of interest. Patient-level associations between exposure and outcome were tested, with adjustment for potentially confounding patient and surgical factors, using random intercept, mixed-effects linear or logistic regression models. Hospitals were then categorized as having a restrictive, intermediate, or liberal resuscitation practice, and adjusted outcomes were compared. RESULTS: A total of 167 (33.1 %), 185 (36.7 %) and 152 (30.2 %) patients received restrictive, intermediate, or liberal fluid administration, respectively. Hospitals with more restrictive practices had significantly lower adjusted 30-day mortality than those with more liberal practices (2.7 vs. 6.6 %; P < 0.001). Hospitals with more restrictive practices had the lowest rates of severe (Grade 2 and 3) complications (15.4 % restrictive vs. 25.3 % intermediate vs. 44.3 % liberal; P < 0.001). More restrictive hospitals had decreased adjusted mean length of stay (9.5 days vs. 12.7 days intermediate vs. 11.6 days liberal; P < 0.001). CONCLUSIONS: More restrictive intraoperative resuscitation practices in pancreatectomy are associated with decreased hospital-level mortality, severe complications, and length of stay. PMID- 27116682 TI - Preliminary investigation of the effects of gamma-tACS on working memory in schizophrenia. AB - Working memory impairment in schizophrenia has been strongly associated with abnormalities in gamma oscillations within the dorsolateral prefrontal cortex (DLFPC). We recently published the first ever study showing that anodal transcranial direct current stimulation (tDCS) to the left DLPFC was able to significantly improve working memory in schizophrenia and did so seemingly via restoring normal gamma oscillatory function. Transcranial alternating current stimulation (tACS) is a form of electrical brain stimulation that delivers stimulation at a specific frequency and has been shown to entrain endogenous cortical oscillations. Therefore, gamma (gamma) tACS may be even more effective than tDCS in improving working memory in schizophrenia. In a randomized repeated measures study we compared the effects of gamma-tACS, tDCS and sham stimulation on the performance of the two back working memory tasks in ten patients with schizophrenia. There was a significant time by stimulation interaction, with tDCS and sham showing trend-level improvements in working memory, while gamma-tACS, contrary to our hypothesis, showed no change. The results are discussed in light of posited divergent effects of tACS and tDCS on the pathophysiology of working memory impairment in schizophrenia. PMID- 27116683 TI - Developmental exposure to acetaminophen does not induce hyperactivity in zebrafish larvae. AB - First line pain relief medication during pregnancy relies nearly entirely on the over-the-counter analgesic acetaminophen, which is generally considered safe to use during gestation. However, recent epidemiological studies suggest a risk of developing attention-deficit/hyperactivity disorder (ADHD)-like symptoms in children if mothers use acetaminophen during pregnancy. Currently, there are no experimental proofs that prenatal acetaminophen exposure causes developmental brain alterations of progeny. Exposure to high acetaminophen concentrations causes liver toxicity, which is well investigated in different model organisms. However, sub-liver-toxic concentrations have not been experimentally investigated with respect to ADHD endophenotypes such as hyperactivity. We used zebrafish to investigate the potential impact of acetaminophen exposure on locomotor activity levels, and compared it to the established zebrafish Latrophilin 3 (Lphn3) ADHD model. We determined the sub-liver-toxic concentration of acetaminophen in zebrafish larvae and treated wild-type and lphn3.1 knockdown larvae with increasing concentrations of acetaminophen. We were able to confirm that lphn3.1 knockdown alone causes hyperactivity, strengthening the implication of Lphn3 dysfunction as an ADHD risk factor. Neither acute nor chronic exposure to acetaminophen at sub-liver-toxic concentrations in wild-type or lphn3.1 knock downs increases locomotor activity levels. Together our findings show that embryonic to larval exposure to acetaminophen does not cause hyperactivity in zebrafish larvae. Furthermore, there are no additive and/or synergistic effects of acetaminophen exposure in a susceptible background induced by knock-down of lphn3.1. Our experimental study suggests that there is, at least in zebrafish larvae, no direct link between embryonic acetaminophen exposure and hyperactivity. Further work is necessary to clarify this issue in humans. PMID- 27116685 TI - Chitotriosidase: A New Inflammatory Marker in Diabetic Complications. AB - Chitotriosidase (CHIT1) belongs to chitinase family. So far this enzyme has been the best investigated human chitinase regarding its biological activity and association with various disorders. In a healthy population, CHIT1 activity is very low and originates in the circulating polymorphonuclear cells. Conversely, during the development of acute/chronic inflammatory disorders, the enzymatic activity of CHIT1 increases significantly. Recently, CHIT1 has also been involved in the pathogenesis of diabetes mellitus (DM). Mounting evidence from experimental studies revealing the increase of CHIT1 levels in pathological conditions, such as atherosclerosis, coronary artery disease, acute ischemic stroke, cerebrovascular dementia, nonalcoholic fatty liver disease, and osteolytic processes suggest its critical role in the evolutions and complications of DM. This review is addressed to provide mechanistic insights by highlighting the relationship between CHIT1 and diabetes, and their contribution in the exacerbation of this disease. PMID- 27116688 TI - Different Prognostic Significance of Cardiac Troponin at Presentation and Peak Cardiac Troponin in Patients with Non-ST Segment Elevation Myocardial Infarction. AB - OBJECTIVES: Non-ST elevation myocardial infarction (NSTEMI) is one of the most common manifestations of acute coronary syndromes (ACS). We evaluated the prognostic role of cardiac troponin I (cTnI) at presentation and peak cardiac troponin I in patients with NSTEMI. METHODS: We consecutively enrolled 215 subjects presenting with NSTEMI. Subjects were followed up for 1 year. cTnI at presentation and the peak value of cTnI were measured. The primary end point was defined as cardiovascular death, readmission to hospital with heart failure and new ACS. RESULTS: The subjects who presented the primary end point (49 subjects) had significantly increased values of peak cTnI compared to subjects free of cardiovascular events [7.19 (2.97-21.32) vs. 4.09 (1.18-11.85) ng/l; p = 0.002]. Nevertheless, cTnI at presentation did not differ between subjects who presented the primary end point and those free of events (p = 0.39). Multivariate Cox regression analysis after adjustment for confounders revealed by the univariate analysis showed that for an increase in peak cTnI from 1 to 10 ng/l, there is a 60% anticipated increase in the relative risk to present the primary end point (p = 0.04). CONCLUSION: These findings documented the different prognostic significance of cTnI at presentation and peak cTnI in patients presenting with NSTEMI, and highlighted the importance of monitoring the levels of cTnI in this high-risk population. PMID- 27116687 TI - Heterogeneous Inhibition in Macroscopic Current Responses of Four Nicotinic Acetylcholine Receptor Subtypes by Cholesterol Enrichment. AB - The nicotinic acetylcholine receptor (nAChR), located in the cell membranes of neurons and muscle cells, mediates the transmission of nerve impulses across cholinergic synapses. In addition, the nAChR is also found in the electric organs of electric rays (e.g., the genus Torpedo). Cholesterol, which is a key lipid for maintaining the correct functionality of membrane proteins, has been found to alter the nAChR function. We were thus interested to probe the changes in the functionality of different nAChRs expressed in a model membrane with modified cholesterol to phospholipid ratios (C/P). In this study, we examined the effect of increasing the C/P ratio in Xenopus laevis oocytes expressing the neuronal alpha7, alpha4beta2, muscle-type, and Torpedo californica nAChRs in their macroscopic current responses. Using the two-electrode voltage clamp technique, it was found that the neuronal alpha7 and Torpedo nAChRs are significantly more sensitive to small increases in C/P than the muscle-type nAChR. The peak current versus C/P profiles during enrichment display different behaviors; alpha7 and Torpedo nAChRs display a hyperbolic decay with two clear components, whereas muscle-type and alpha4beta2 nAChRs display simple monophasic decays with different slopes. This study clearly illustrates that a physiologically relevant increase in membrane cholesterol concentration produces a remarkable reduction in the macroscopic current responses of the neuronal alpha7 and Torpedo nAChRs functionality, whereas the muscle nAChR appears to be the most resistant to cholesterol inhibition among all four nAChR subtypes. Overall, the present study demonstrates differential profiles for cholesterol inhibition among the different types of nAChR to physiological cholesterol increments in the plasmatic membrane. This is the first study to report a cross-correlation analysis of cholesterol sensitivity among different nAChR subtypes in a model membrane. PMID- 27116689 TI - Evaluation of the muscle morphology of the obturator externus and piriformis as the predictors of avascular necrosis of the femoral head in acetabular fractures. AB - Avascular necrosis (AVN) of femoral head is a recognised complication of fracture dislocation of the hip joint but is not studied frequently in relation to acetabulum fractures. The aim was to establish the relationship between obturator externus and piriformis muscle morphology in acetabulum fractures and potenital development of AVN of the femoral head. Twenty-five fractures were included in this prospective study and were subjected to radiological assessment and computed tomography of the pelvis. Magnetic resonance imaging (MRI) of the hip was performed to assess the morphology of obturator externus and piriformis, and findings were compared intraoperatively (in 15 cases). Serial radiographs were taken at monthly intervals to assess the development of avascular necrosis. The patients with no evidence of AVN on radiographs at 6 months had additional MRI scans to look for such changes. Three patients developed AVN of femoral head and two had complete tears of piriformis and/or obturator externus muscles on the pre operative MRI with the findings confirmed intraoperatively (p = 0.013). None of the patients without changes of AVN at 6-month follow-up had complete tears of either or both muscles. Of these patients, there was one case each of T-type fracture, isolated posterior wall fracture with hip dislocation, and posterior wall with transverse fracture of the acetabulum. Complete tears of obturator externus and/or piriformis muscles are a strong predictor of future development of AVN of the femoral head. PMID- 27116690 TI - Congenital pyloric atresia: Early and delayed presentations-A single centre experience of a rare anomaly. AB - Pyloric atresia may occur as an isolated or pure atresia or may be associated with other anomalies like those involving skin, renal or gastrointestinal systems etc. The most frequent association is with junctional epidermolysis bullosa, a rare autosomal recessive disorder affecting the skin and mucosa. We present a prospective evaluation of three patients of pyloric atresia at our institute over last 2 years (2012-2014)-one of them presenting at 5th day of life and the other two at 5 and 6 years of age, respectively. Two of them did not have any other associated anomaly whereas one patient had incidental finding of Meckel's diverticulum at the time of surgery for pyloric atresia plus he had been operated upon for right-sided pelvioureteric junction obstruction at 1 year of age. All patients underwent laparotomy after stabilization. The two patients presenting late had type 1 pyloric atresia with a pyloric membrane having a central hole in both the patients. So, excision of the membrane with Heineke Mikulicz pyloroplasty was done in both of them. The neonate who presented early had type 2 pyloric atresia and underwent Finney's pyloroplasty. PMID- 27116691 TI - Testicular seminoma clinical stage 1: treatment outcome on a routine care level. AB - PURPOSE: Clinical stage 1 (CS1) testicular seminoma involves an almost 100 % disease-specific survival in controlled clinical trials. We aimed to find out whether these results can be matched in patients managed on the routine care level. PATIENTS, METHODS: In total, 725 patients with seminoma CS1 were prospectively enrolled from 130 institutions. Adjuvant management as decided by local physicians involved surveillance (n = 256), radiotherapy (41), 1* Carboplatin (362), and 2* Carboplatin (66). We registered type of management, age, duration of follow-up (F/U), relapse, rete testis invasion (RTI), and tumor size. Actuarial relapse-free survival curves were calculated for treatment modalities and stratified for tumor sizes and RTI. A Cox regression model was calculated to explore for factors influencing relapses. RESULTS: Disease-specific survival was 100 %. Crude relapse rates were 8.2, 2.4, 5.0, and 1.5 % for surveillance, radiotherapy, 1* Carboplatin, and 2* Carboplatin after a median F/U of 30 months. RTI and tumor size were not associated with progression in surveillance patients. One course Carboplatin caused relapses in 6.8 % in tumor sizes >4 cm and 9.3 % (actuarial 13 %) in sizes >5 cm. The Cox model revealed the association of tumor size with recurrence in the entire seminoma population (Hazard ratio 1.17; 95 % confidence intervals 1.03-1.33). CONCLUSIONS: The overall outcome of CS1 seminoma managed on the routine care level mirrors that of controlled trials. Unexpectedly, the risk factors in surveillance patients were not confirmed, but tumor size proved to be a risk indicator in the entire group of seminoma. Importantly, one course Carboplatin involved low efficacy to control the disease in large tumors. PMID- 27116695 TI - Synthesis and Properties of Novel Silver-Containing DNA Molecules. AB - Migration of silver atoms from silver nano-particles selectively to a double stranded poly(dG)-poly(dC) polymer leads to metallization of the DNA. As a result the DNA molecules become shorter and thicker (higher), as evident from the atomic force microscopy imaging analysis. The metalized molecules can be detected by transmission and scanning electron microscopy in contrast to the initial non metalized ones. PMID- 27116693 TI - Cross-fostering reduces obesity induced by early exposure to monosodium glutamate in male rats. AB - Maternal obesity programmes a range of metabolic disturbances for the offspring later in life. Moreover, environmental changes during the suckling period can influence offspring development. Because both periods significantly affect long term metabolism, we aimed to study whether cross-fostering during the lactation period was sufficient to rescue a programmed obese phenotype in offspring induced by maternal obesity following monosodium L-glutamate (MSG) treatment. Obesity was induced in female Wistar rats by administering subcutaneous MSG (4 mg/g body weight) for the first 5 days of postnatal life. Control and obese female rats were mated in adulthood. The resultant pups were divided into control second generation (F2) (CTLF2), MSG-treated second generation (F2) (MSGF2), which suckled from their CTL and MSG biological dams, respectively, or CTLF2-CR, control offspring suckled by MSG dams and MSGF2-CR, MSG offspring suckled by CTL dams. At 120 days of age, fat tissue accumulation, lipid profile, hypothalamic leptin signalling, glucose tolerance, glucose-induced, and adrenergic inhibition of insulin secretion in isolated pancreatic islets were analysed. Maternal MSG induced obesity led to an obese phenotype in male offspring, characterized by hyperinsulinaemia, hyperglycaemia, hyperleptinaemia, dyslipidaemia, and impaired leptin signalling, suggesting central leptin resistance, glucose intolerance, impaired glucose-stimulated, and adrenergic inhibition of insulin secretion. Cross-fostering normalized body weight, food intake, leptin signalling, lipid profiles, and insulinaemia, but not glucose homeostasis or insulin secretion from isolated pancreatic islets. Our findings suggest that alterations during the lactation period can mitigate the development of obesity and prevent the programming of adult diseases. PMID- 27116692 TI - Hurdles in selection process of nanodelivery systems for multidrug-resistant cancer. AB - PURPOSE: Most of the nanomedicines for treatment of multidrug-resistant cancer do not reach Phase III trials and many are terminated or withdrawn or are in an indeterminate state since long without any study results being presented. Extensive perusal of nanomedicine development research revealed that one of the critical aspects influencing clinical outcomes and which requires diligent scrutiny is selection process of nanodelivery system. METHODS: Research papers and articles published on development of nanodelivery systems for treatment of multidrug-resistant cancer were analyzed. Observations and conclusions noted by these researchers which might shed some light on poor clinical performance of nanocarriers were collated and summarized under observation section. Further research articles were studied to find possible solutions which may be applied to these particular problems for resolving them. The inferences of these findings were composed in Result section. RESULT: Plausible solutions for the observed obstacles were noted as examples of novel formulations that can yield the following: better in vivo imaging, precise targeting and dosing of a specific site and specific cell type in a particular cancer, modulation of tumor surroundings, intonation of systemic effects and high reproducibility. CONCLUSION: The angle of approach to the development of best nanosystem for a specific type of tumor needs to be spun around. Some of these changes can be brought about by individual scientists, some need to be established by collated efforts of scientists globally and some await advent of better technologies. Regardless of the stratagem, it can be said decisively that the schematics of development phase need rethinking. PMID- 27116696 TI - Elucidating Structural Characteristics of Biomass using Solution-State 2 D NMR with a Mixture of Deuterated Dimethylsulfoxide and Hexamethylphosphoramide. AB - Recent developments of NMR methods for characterization of lignocellulosic biomass allow improved understanding of plant cell-wall structures with minimal deconstruction and modification of biomass. This study introduces a new NMR solvent system composed of dimethylsulfoxide (DMSO-d6 ) and hexamethylphosphoramide (HMPA-d18 ). HMPA as a co-solvent enhanced swelling and mobility of the biomass samples; thereby it allowed enhancing signals of NMR spectra. The structural information of biomass was successfully analyzed by the proposed NMR solvent system (DMSO-d6 /HMPA-d18 ; 4:1, v/v) with different biomass. The proposed bi-solvent system does not require derivatization or isolation of biomass, facilitating a facile sample preparation and involving with no signals overlapping with biomass peaks. It also allows analyzing biomass with a room-temperature NMR probe instead of cryo-probes, which are traditionally used for enhancing signal intensities. PMID- 27116697 TI - Global income and production impacts of using GM crop technology 1996-2014. AB - This paper provides an economic assessment of the value of using genetically modified (GM) crop technology in agriculture at the farm level. It follows and updates earlier annual studies which examined economic impacts on yields, key costs of production, direct farm income and effects, and impacts on the production base of the 4 main crops of soybeans, corn, cotton and canola. The commercialisation of GM crops has continued to occur at a rapid rate since the mid 1990s, with important changes in both the overall level of adoption and impact occurring in 2014. This annual updated analysis shows that there continues to be very significant net economic benefits at the farm level amounting to $17.7 billion in 2014 and $150.3 billion for the 19-year period 1996-2014 (in nominal terms). These economic gains have been divided roughly 50% each to farmers in developed and developing countries. About 65% of the gains have derived from yield and production gains with the remaining 35% coming from cost savings. The technology has also made important contributions to increasing global production levels of the 4 main crops, having, for example, added 158 million tonnes and 322 million tonnes respectively, to the global production of soybeans and maize since the introduction of the technology in the mid 1990s. PMID- 27116698 TI - Follicular thyroid carcinoma in a male adolescent with Williams-Beuren syndrome. PMID- 27116699 TI - Influence of caffeine on the protective activity of gabapentin and topiramate in a mouse model of generalized tonic-clonic seizures. AB - BACKGROUND: Caffeine may interact with classical antiepileptic drugs (AEDs), reducing their anticonvulsant effects in basic seizure models. The aim of the present study was to ascertain whether intraperitoneal caffeine (acute or chronic for 15 days) could attenuate the anticonvulsant effect of some newer AEDs: gabapentin (GBP) and topiramate (TPM) against electroconvulsions in mice. METHODS: Maximal electroshock (MES)-induced mouse seizure model was used for the estimation of the anticonvulsant activity of TPM whilst the protective activity of GBP was evaluated in the threshold test for maximal (tonic) convulsions. Adverse effects were evaluated by measurement of long-term memory (the step through passive avoidance task) and motor coordination (chimney test). Plasma AED concentrations were also measured to determinate any pharmacokinetic contribution to the observed effects. RESULTS: Caffeine (both acute and chronic at 23.1 and 46.2mg/kg) significantly reduced the protective effects of TPM against MES. As regards GBP, caffeine (acutely at 46.2mg/kg and chronically at 23.1 or 46.2mg/kg) significantly diminished the GBP-induced increases in the electroconvulsive threshold. In addition, caffeine did not affect the free plasma concentrations of TPM or GBP. Acute and chronic caffeine (23.1 and 46.2mg/kg) enhanced the impairment of motor coordination in mice pretreated with GBP whilst an opposite effect was observed in TPM injected mice and pretreated with chronic caffeine at 46.2mg/kg. CONCLUSION: The results indicate that newer AEDs, GBP or TPM behave in the exactly same way as classical antiepileptics in mice challenged with caffeine. This hazardous effect of caffeine is not subject to tolerance. PMID- 27116700 TI - Opioid-induced redistribution of 6TM and 7TM MU opioid receptors: A hypothesized mechanistic facilitator model of opioid-induced hyperalgesia. AB - Opioids are still the most popular form of pain treatment, but many unavoidable side effects make opioids a big challenge in effective pain management. Opioid induced hyperalgesia (OIH), a paradoxical phenomenon, portrays an increased sensitivity to harmful stimuli caused by opioid exposure. Changes in the neural modulation are considered a major contributor to the development of OIH. Activation of opioid receptors (ORs) and corresponding downstream molecules are the vital composition of functional performance of opioids. Increasing interests were proposed of the interaction between ORs and other neural transmitter systems such as glutamatergic, GABAergic and adrenergic ones to the genesis of OIH. G protein coupled MU-opioid receptor (MOR) was studied comprehensively on its role in the development of OIH. In addition to the relationship between MOR and other neurotransmitter receptors, a new intracellular MOR that has six transmembrane (6TM) domains was identified, and found to perform a pro-nociceptive task in contrast to the counterpart 7TM isoform. A mechanistic model of OIH in which both 6TM and 7TM MORs undergoing membrane redistribution upon opioid exposure is proposed which eventually facilitates the neurons more sensitive to nociceptive stimulation than that of the preceding opioid exposure. PMID- 27116701 TI - C-terminal Src kinase-mediated EPIYA phosphorylation of Pragmin creates a feed forward C-terminal Src kinase activation loop that promotes cell motility. AB - Pragmin is one of the few mammalian proteins containing the Glu-Pro-Ile-Tyr-Ala (EPIYA) tyrosine-phosphorylation motif that was originally discovered in the Helicobacter pylori CagA oncoprotein. Following delivery into gastric epithelial cells by type IV secretion and subsequent tyrosine phosphorylation at the EPIYA motifs, CagA serves as an oncogenic scaffold/adaptor that promiscuously interacts with SH2 domain-containing mammalian proteins such as the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) and the C-terminal Src kinase (Csk), a negative regulator of Src family kinases. Like CagA, Pragmin also forms a physical complex with Csk. In the present study, we found that Pragmin directly binds to Csk by the tyrosine-phosphorylated EPIYA motif. The complex formation potentiates kinase activity of Csk, which in turn phosphorylates Pragmin on tyrosine-238 (Y238), Y343, and Y391. As Y391 of Pragmin comprises the EPIYA motif, Pragmin-Csk interaction creates a feed-forward regulatory loop of Csk activation. Together with the finding that Pragmin and Csk are colocalized to focal adhesions, these observations indicate that the Pragmin-Csk interaction, triggered by Pragmin EPIYA phosphorylation, robustly stimulates the kinase activity of Csk at focal adhesions, which direct cell-matrix adhesion that regulates cell morphology and cell motility. As a consequence, expression of Pragmin and/or Csk in epithelial cells induces an elongated cell shape with elevated cell scattering in a manner that is mutually dependent on Pragmin and Csk. Deregulation of the Pragmin-Csk axis may therefore induce aberrant cell migration that contributes to tumor invasion and metastasis. PMID- 27116702 TI - More sensitivity of cortical GABAergic neurons than glutamatergic neurons in response to acidosis. AB - Acidosis impairs brain functions. Neuron-specific mechanisms underlying acidosis induced brain dysfunction remain elusive. We studied the sensitivity of cortical GABAergic neurons and glutamatergic neurons to acidosis by whole-cell recording in brain slices. The acidification to the neurons was induced by perfusing artificial cerebral spinal fluid with lower pH. This acidification impairs excitability and synaptic transmission in the glutamatergic and GABAergic neurons. Acidosis impairs spiking capacity in the GABAergic neurons more than in the glutamatergic neurons. Acidosis also strengthens glutamatergic synaptic transmission and attenuates GABAergic synaptic transmission on the GABAergic neurons more than the glutamatergic neurons, which results in the functional impairment of these GABAergic neurons. This acidosis-induced dysfunction predominantly in the cortical GABAergic neurons drives the homeostasis of neuronal networks toward overexcitation and exacerbates neuronal impairment. PMID- 27116703 TI - State dependency of inhibitory control performance: an electrical neuroimaging study. AB - Behavioral and brain responses to stimuli not only depend on their physical features but also on the individuals' neurocognitive states before stimuli onsets. While the influence of pre-stimulus fluctuations in brain activity on low level perceptive processes is well established, the state dependency of high order executive processes remains unclear. Using a classical inhibitory control Go/NoGo task, we examined whether and how fluctuations in the brain activity during the period preceding the stimuli triggering inhibition influenced inhibitory control performance. Seventeen participants completed the Go/NoGo task while 64-channel electroencephalogram was recorded. We compared the event-related potentials preceding the onset of the NoGo stimuli associated with inhibition failures false alarms (FA) vs. successful inhibition correct rejections (CR) with data-driven statistical analyses of global measures of the topography and strength of the scalp electric field. Distributed electrical source estimations were used to localize the origin of the event-related potentials modulations. We observed differences in the global field power of the event-related potentials (FA > CR) without concomitant topographic modulations over the 40 ms period immediately preceding NoGo stimuli. This result indicates that the same brain networks were engaged in the two conditions, but more strongly before FA than CR. Source estimations revealed that this effect followed from a higher activity before FA than CR within bilateral inferior frontal gyri and the right inferior parietal lobule. These findings suggest that uncontrolled quantitative variations in pre-stimulus activity within attentional and control brain networks influence inhibition performance. The present data thereby demonstrate the state dependency of cognitive processes of up to high-order executive levels. PMID- 27116704 TI - An open trial evaluating an attention bias modification program for overweight adults who binge eat. AB - BACKGROUND AND OBJECTIVES: Binge eating is prevalent and is associated with significant psychiatric and medical comorbidities. To date, the most effective psychological treatments for individuals who binge eat are not effective for all patients and they do not result in significant weight loss. Dual process theories suggest that implicit factors, such as attention bias, may influence behavior, even when the behavior is in opposition to long-term goals. Attention bias modification programs have been tested in other areas of psychopathology, and could be utilized to improve outcomes for people who binge eat. Thus, the aim of this open trial was to conduct a preliminary evaluation of an attention bias modification program (ABM-Food) designed to train attention away from food cues. METHODS: Adults who binge eat and were overweight or obese enrolled in an 8-week ABM-Food program, which consisted of one session in the lab each week and two training sessions at home. Nine participants completed the ABM-Food training program and the post-treatment assessment, and 8 completed the 3-month post treatment assessment. RESULTS: Results showed that the ABM-Food program is a feasible and acceptable treatment for adults who binge eat. Initial effectiveness data showed decreases in weight, eating disorder symptoms, binge eating, loss of control and responsivity to food in the environment, as well as changes in attention bias. The majority of these effects remained at the 3-month follow-up time point. LIMITATIONS: This study is limited by the single-group open label trial, and the small sample size. CONCLUSIONS: This open trial provides initial evidence for the feasibility, acceptability and effectiveness of ABM-Food for individuals who binge eat and are overweight or obese. PMID- 27116705 TI - Control of electrochemical signals from quantum dots conjugated to organic materials by using DNA structure in an analog logic gate. AB - Various bio-logic gates have been studied intensively to overcome the rigidity of single-function silicon-based logic devices arising from combinations of various gates. Here, a simple control tool using electrochemical signals from quantum dots (QDs) was constructed using DNA and organic materials for multiple logic functions. The electrochemical redox current generated from QDs was controlled by the DNA structure. DNA structure, in turn, was dependent on the components (organic materials) and the input signal (pH). Independent electrochemical signals from two different logic units containing QDs were merged into a single analog-type logic gate, which was controlled by two inputs. We applied this electrochemical biodevice to a simple logic system and achieved various logic functions from the controlled pH input sets. This could be further improved by choosing QDs, ionic conditions, or DNA sequences. This research provides a feasible method for fabricating an artificial intelligence system. PMID- 27116706 TI - Flow of colloidal solids and fluids through constrictions: dynamical density functional theory versus simulation. AB - Using both dynamical density functional theory and particle-resolved Brownian dynamics simulations, we explore the flow of two-dimensional colloidal solids and fluids driven through a linear channel with a constriction. The flow is generated by a constant external force acting on all colloids. The initial configuration is equilibrated in the absence of flow and then the external force is switched on instantaneously. Upon starting the flow, we observe four different scenarios: a complete blockade, a monotonic decay to a constant particle flux (typical for a fluid), a damped oscillatory behaviour in the particle flux, and a long-lived stop-and-go behaviour in the flow (typical for a solid). The dynamical density functional theory describes all four situations but predicts infinitely long undamped oscillations in the flow which are always damped in the simulations. We attribute the mechanisms of the underlying stop-and-go flow to symmetry conditions on the flowing solid. Our predictions are verifiable in real-space experiments on magnetic colloidal monolayers which are driven through structured microchannels and can be exploited to steer the flow throughput in microfluidics. PMID- 27116707 TI - Antioxidant and Anti-quorum Sensing Potential of Acer monspessulanum subsp. monspessulanum Extracts. AB - In this study, anti-quorum sensing, and antioxidant activities, and chemical composition of Acer monspessulanum subsp. monspessulanum extracts were evaluated. Determination of the antioxidant activity was revealed by DPPH radical scavenging activity, the total phenolic content assay, and the beta-carotene/linoleic acid assay. The detection of phenolic compounds was determined using RP-HPLC. Anti quorum sensing activity and violacein inhibition activity were determined using Chromobacterium violaceum CV026 and C. violaceum ATCC 112 472, respectively. The determination of anti-swarming activity was carried out with Pseudomonas aeruginosa PA01. In DPPH and total phenolic content assays, the water extract exhibited good antioxidant activity. In the beta-carotene-linoleic acid assay, ethyl acetate and ethanol extracts exhibited good lipid peroxidation inhibition activity, demonstrating 96.95 +/- 0.03 % and 95.35 +/- 0.00 % at 2.5 mg/mL concentrations, respectively. The predominant phenolic compounds of the extracts were determined as rutin, naringin, catechin hydrate, quercetin, and protocatechuic acid. Ethyl acetate and ethanol extracts were found to contain a high level of violacein inhibition and anti-quorum sensing activity. The ethanol extract also showed weak anti-swarming activity. In this first study that used Acer monspessulanum subsp. monspessulanum extracts, it was revealed that the water extract has antioxidant activity and the ethanol and ethyl acetate extracts have anti-quorum sensing activity depending on the phenolic compounds that it contained. PMID- 27116708 TI - Determination of itraconazole and its photodegradation products with kinetic evaluation by ultra-performance liquid chromatography/tandem mass spectrometry. AB - A simple and reproducible UPLC-MS/MS method for the determination of itraconazole (ITZ) and its photodegradation products formed during exposure to UV-A radiation was developed. Chromatographic separations were carried out using an Acquity UPLC BEH C18 column (2.1 * 100 mm, 1.7 MUm particle size). The column was maintained at 40 degrees C, and eluted under gradient conditions from 100% to 50% of eluent A over 13 min, at a flow rate of 0.3 mL min-1 . Eluent A was 0.1% (v/v) formic acid in water; eluent B was 0.1% (v/v) formic acid in acetonitrile. The linear regression analysis for the calibration curve showed a good linear correlation over the concentration range 0.0066-0.15 mg mL-1 with determination coefficient > 0.99. The activities of some photocatalysts during degradation process of ITZ were compared. It was found that indirect photodegradation of ITZ was more effective than direct photolysis. Under our experimental conditions the photodegradation rate constant depended on the applied catalysts with catalytic activity decreasing in the following pattern: FeCl3 > TiO2 /FeCl3 > TiO2 . The kinetic analysis of the photodegradation data revealed that the degradation of the ITZ follows first-order kinetics. The photodegradation products of ITZ were identified, and their fragmentation pathways, derived from MS/MS data, were proposed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27116709 TI - Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5. AB - MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC50 = 0.3 MUM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC50 = 104 nM) was the most potent small molecular, and about 3 times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds. PMID- 27116710 TI - Combretastatin A-4 derived 5-(1-methyl-4-phenyl-imidazol-5-yl)indoles with superior cytotoxic and anti-vascular effects on chemoresistant cancer cells and tumors. AB - 5-(1-Methyl-4-phenyl-imidazol-5-yl)indoles 5 were prepared and tested as analogs of the natural vascular-disrupting agent combretastatin A-4 (CA-4). The 3-bromo 4,5-dimethoxyphenyl derivative 5c was far more active than CA-4 with low nanomolar IC50 concentrations against multidrug-resistant KB-V1/Vbl cervix and MCF-7/Topo mamma carcinoma cells, and also against CA-4-resistant HT-29 colon carcinoma cells. While not interfering markedly with the polymerization of tubulin in vitro, indole 5c completely disrupted the microtubule cytoskeleton of cancer cells at low concentrations. It also destroyed real blood vessels, both in the chorioallantoic membrane (CAM) of fertilized chicken eggs and within tumor xenografts in mice, without harming embryo or mouse, respectively. Indole 5c was less toxic than CA-4 to endothelial cells, fibroblasts, and cardiomyocytes. In highly vascularized xenograft tumors 5c induced distinct discolorations and histological features typical of vascular-disrupting agents, such as disrupted vessel structures, hemorrhages, and extensive necrosis. In a first preliminary therapy trial, indole 5c retarded the growth of resistant xenograft tumors in mice. (c) 2016 Elsevier Science Ltd. All rights reserved. PMID- 27116711 TI - Synthesis and preliminary evaluation of 3-thiocyanato-1H-indoles as potential anticancer agents. AB - A novel series of twenty 3-thiocyanato-1H-indoles, carrying diversification at positions N-1, C-2 and C-5 of the heterocyclic core, were synthesized; their antiproliferative activity against four human cancer cell lines (HL60, HEP-2, NCI H292 and MCF-7) was evaluated, employing doxorubicin as positive control. Indole, N-methylindole and 2-(4-chlorophenyl)-N-methylindole demonstrated to be essentially inactive, whereas several of their congener 3-thiocyanato-1H-indoles displayed good to excellent levels of potency (IC50 <= 6 MUM), while being non hemolytic. N-Phenyl-3-thiocyanato-1H-indole and 1-methyl-2-(4-chlorophenyl)-3 thiocyanato-1H-indole showed good to high potency against all the cell lines. On the other side, the N-(4-chlorophenyl)-, 2-(4-chlorophenyl)- and 2-phenyl- 3 thiocyanato-1H-indole derivatives were slightly less active against the test cell lines. Overall, these results suggest that the indole-3-thiocyanate motif can be suitably decorated to afford highly cytotoxic compounds and that the substituted indole can be employed as a useful scaffold toward more potent compounds. PMID- 27116712 TI - A dielectric barrier discharge ionization based interface for online coupling surface plasmon resonance with mass spectrometry. AB - The online combination of surface plasmon resonance (SPR) with mass spectrometry (MS) could be beneficial for accurately acquiring molecular interaction data simultaneously with their structural information at high throughputs. In this work, a novel SPR-MS interface was developed using a dielectric barrier discharge ionization (DBDI) source. The DBDI source was placed in front of the MS inlet, generating an ionization plasma jet. A spray tip was set between the DBDI source outlet and the MS inlet, nebulizing the SPR sample solution. Using this interface, samples could first be studied by SPR, then sprayed and ionized, finally analyzed by MS. By analyzing model samples containing small-molecule drugs dissolved in salt containing solutions, the practicability of this SPR-DBDI MS interface was proved, observing the consistent change of SPR and MS signals. Compared with our previously developed direct analysis in real time (DART) based SPR-MS interface, this new interface exhibited a higher and better tolerance to non-volatile salts, and different ionization capabilities for various samples. These results indicated that the interface could find further utilization in SPR MS studies especially when physiological conditions were needed. PMID- 27116713 TI - Epigenetic mechanisms involved in modulation of inflammatory diseases. AB - PURPOSE OF REVIEW: The activation of inflammatory response is dependent upon genetic factors and epigenetic control mechanisms. This overview will highlight recent advances in the understanding of epigenetic dynamics during cellular inflammation. RECENT FINDINGS: There is a growing body of evidence indicating that alterations of the chromatin state associate with an increased risk of chronic disease development and inflammation. Epigenetic alterations respond rapidly to environmental changes and have a profound effect on gene regulatory cross-wirings and transcriptional regulation. SUMMARY: Systematic dissection of the mechanisms underlying epigenetic effects during inflammatory response is a critical step toward elucidation of the cell's molecular processes and holds potential for the development of novel therapies for the treatment of chronic diseases. PMID- 27116714 TI - Cognitive biases to appearance-related stimuli in body dissatisfaction: A systematic review. AB - Emerging literature has documented the presence of cognitive biases toward body image related stimuli among individuals with high levels of body image concerns compared to those with low levels of body image concerns. However, the robustness and nature of these cognitive biases are unclear. The aims of this study were to conduct a systematic literature search and perform a critical synthesis of studies examining the relationship between cognitive biases toward body image related stimuli and body image concerns. Our review identified 32 studies meeting inclusion criteria. Dot-probe, Stroop, free recall, and eye-tracking were among the most frequently used paradigms. The extant literature provides robust support for the presence of attention biases toward body image-related stimuli among individuals with high levels of body dissatisfaction compared to those with lower levels of concerns. Evidence was also found for the existence of judgment biases and memory biases. Furthermore, results suggest that body image-related cognitive biases, and levels of body dissatisfaction can be manipulated. Initial evidence was also found for differential patterns of biases toward "fat" and "thin" stimuli. These findings confirm the importance of considering cognitive biases within etiological models of body image concerns and suggest that these processes might provide novel treatment targets. PMID- 27116715 TI - Misha Pless, MD, BAS. PMID- 27116716 TI - Multiple Sclerosis. PMID- 27116717 TI - Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An Update. AB - Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, obesity in early life, infection with the Epstein-Barr virus, and cigarette smoking are the most consistent environmental predictors of MS risk. The authors review the epidemiological data, critically discuss the evidence for causality of these and other associations, and briefly review the possibility of interventions to reduce MS risk. PMID- 27116718 TI - Immunology of Multiple Sclerosis. AB - Multiple sclerosis (MS) is considered a prototypic autoimmune disease of the central nervous system (CNS). A complex genetic background with the HLA-DR15 haplotype as the main genetic risk factor and over 100 mostly immune-related minor risk alleles as well as several environmental factors contribute to the etiology of MS. With respect to pathomechanisms, autoimmune inflammation in early MS is primarily mediated by adaptive immune responses and involves autoreactive T cells, B cells, and antibodies, while the later, chronic stages of MS are characterized by a compartmentalized immune response in the CNS with activated microglia and macrophages. A host of immune cells and mediators can contribute to the autoimmune process, but CNS-related factors such as localization of lesions, vulnerability of oligodendrocytes, neurons/axons, and secondary metabolic changes all play a role in the heterogeneous expression of the disease, including different pathologic lesion patterns, neuroimaging findings, disease courses, and severity and response to treatment. PMID- 27116719 TI - Promising Oral Compounds for the Treatment of Multiple Sclerosis: A Glance into the Future. AB - Recently, there have been major advances in the development of disease-modifying treatments for multiple sclerosis (MS) and new promising treatment compounds are on the horizon. The available drugs mainly target inflammatory components of MS; hence, there is an urgent need for new treatment approaches that focus on the neurodegenerative aspects of the disease. Innovative study designs and biomarkers such as neurofilament light chain and brain atrophy measurement could help to identify neuroprotective treatments for the progressive phase of MS.Furthermore, there is increasing knowledge on the impact of dietary factors on MS (e.g., vitamin D). Although their exact role in the pathophysiology of MS is unclear, there are first hints that they might modulate the disease course. Randomized studies are necessary to evaluate the value of substitution therapies for these dietary factors. In this review, the authors focus on promising oral compounds and dietary factors that are in the early development stages for the treatment of MS. PMID- 27116720 TI - Parenteral Treatment of Multiple Sclerosis: The Advent of Monoclonal Antibodies. AB - Improved disease control is critical for enhancing the lives of those living with multiple sclerosis. With specific immunologic targets, monoclonal antibody (mAb) treatments are highly effective options for relapsing forms of multiple sclerosis. The mechanism, efficacy, and current safety profiles are detailed for the two mAb therapies, natalizumab and alemtuzumab, with regulatory approval in multiple countries. Daclizumab, which targets the interleukin-2 receptor, and ocrelizumab, which depletes B cells, have convincing phase 3 clinical trial data and may very well provide new options in the near future. Trial results of other B-cell-directed therapies, ofatumumab and rituximab, are reviewed. Less-frequent dosing of glatiramer acetate and interferon beta-1a highlight developments in the first generation of parenteral immunomodulatory therapy. Remyelination using mAbs has moved into clinical trials with the first agents, anti-LINGO-1, rHIgM22, and anti-SEMA 4D. PMID- 27116721 TI - Pediatric Multiple Sclerosis. AB - Pediatric multiple sclerosis (MS) is a chronic inflammatory neurologic disease that is challenging to diagnose and treat. Although there are many clinical parallels between pediatric-onset MS and adult-onset MS, there is also accumulating evidence of distinguishing clinical features that may, in part, arise from development-specific, neuroimmune processes governing MS pathogenesis in children. Here the authors describe the clinical features, diagnosis, and treatment of pediatric MS, with a particular focus on describing clinical features and highlighting new developments that promise a better understanding of pediatric MS pathogenesis. An important task that lies ahead for pediatric neurologists is better understanding the early gene-environment interaction that precipitates the first demyelinating event in pediatric MS. This area is of particular importance for understanding the MS etiology and the natural history of pediatric MS. Such understanding should in turn inform new developments in diagnostic tools, long-term therapies, and much-needed biomarkers. Such biomarkers are not only valuable for defining the disease onset, but also for monitoring both the treatment response and a disease evolution that spans multiple decades in children with MS. PMID- 27116722 TI - Women's Issues in Multiple Sclerosis. AB - Multiple sclerosis (MS) typically affects 3 times more women than men during the reproductive years. The author describes what is known about the effects of various reproductive exposures on MS course, including menarche, childbearing, and menopause. Then, the management of childbearing is reviewed. Topics include preconception counseling, prenatal care, discontinuation of MS therapies, and management of postpartum relapses. Overall, most women with MS can be encouraged to become pregnant and breastfeed their children, should they choose to do so. PMID- 27116723 TI - Advanced Structural and Functional Brain MRI in Multiple Sclerosis. AB - Conventional magnetic resonance imaging (MRI) of the central nervous system is crucial for an early and reliable diagnosis and monitoring of patients with multiple sclerosis (MS). Focal white matter (WM) lesions, as detected by MRI, are the pathological hallmark of the disease and show some relation to clinical disability, especially in the long run. Gray matter (GM) involvement is evident from disease onset and includes focal (i.e., cortical lesions) and diffuse pathology (i.e., atrophy). Both accumulate over time and show close relation to physical disability and cognitive impairment. Using advanced quantitative MRI techniques such as magnetization transfer imaging (MTI), diffusion tensor imaging (DTI), proton MR spectroscopy ((1)H-MRS), and iron imaging, subtle MS pathology has been demonstrated from early stages outside focal WM lesions in the form of widespread abnormalities of the normal appearing WM and GM. In addition, studies using functional MRI have demonstrated that brain plasticity is driven by MS pathology, playing adaptive or maladaptive roles to neurologic and cognitive status and explaining, at least in part, the clinicoradiological paradox of MS. PMID- 27116724 TI - Optical Coherence Tomography in Multiple Sclerosis. AB - Retinal optical coherence tomography (OCT) has recently become a vital tool for clinicians and researchers in ophthalmology and, increasingly, in neurology. Optical coherence tomography is quickly and easily performed, well-tolerated by patients, and allows high-resolution viewing of unmyelinated axons and other retinal structures in vivo. These factors have led OCT to find favor as a method of quantifying neuroaxonal loss in multiple sclerosis (MS), and the increasing acceptance of the anterior visual pathway as a model to investigate MS in humans.In this short review, the authors discuss OCT findings in MS research, and the relationships of these structural findings with established functional outcome measures such as visual acuity and electrophysiological examinations. The utility of OCT in patients with acute optic neuritis is emphasized. Optical coherence tomography is a particularly powerful tool when the individual retinal layers are visualized and quantified following the segmentation of scans; this technique shows promise as a method for defining novel MS phenotypes. PMID- 27116725 TI - Vision Disturbances in Multiple Sclerosis. AB - Visual disturbances are frequently encountered in multiple sclerosis (MS), and include problems with how affected individuals see the world (afferent visual pathway symptoms) and how their eyes move together (efferent visual pathway disorders). Optic neuritis is the most common afferent visual pathway manifestation of MS, from which visual recovery is often incomplete. Visual field defects caused by lesions in the retrochiasmal or retrogeniculate regions of the afferent visual pathway also occur, albeit less frequently. Efferent visual pathway lesions causing ocular misalignment and nystagmus may lead to diplopia and oscillopsia, respectively. Vision loss has a major impact on perceptions regarding quality of life in MS. Therefore, it is important for clinicians to be able to identify and localize the underlying basis of visual disturbances to provide the best care possible for their patients. PMID- 27116726 TI - Neurorehabilitation Topics in Patients with Multiple Sclerosis: From Outcome Measurements to Rehabilitation Interventions. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and the most common cause of nontraumatic disability in young adults. It is a heterogeneous disease associated with long-term disability, negatively influencing quality of life. Disease-modifying pharmacological therapies may decrease activity and progression of the disease, and symptomatic pharmacological treatments may reduce complaints to a certain extent; however, MS patients mostly still suffer from several neurologic deficits in the course of their disease. Consequently, specific comprehensive nonpharmacological rehabilitation interventions are needed to reduce disability to obtain better independence in activities of daily living, resulting in an optimal quality of life. Here the authors give an overview of the main sensorimotor symptoms in MS. Some of the most commonly used standardized outcome assessments are presented, and existing evidence-based motor rehabilitation strategies are described. PMID- 27116728 TI - Voiding Dysfunction in Multiple Sclerosis. PMID- 27116727 TI - Cognitive Impairment in Multiple Sclerosis: Clinical Manifestation, Neuroimaging Correlates, and Treatment. AB - Cognitive impairment is found in up to 70% of patients with multiple sclerosis (MS). Once thought of as a variant of subcortical dementia with a characteristic set of deficits, we now know that MS-related cognitive impairment can have many faces. This conceptual change in neuropsychology is embedded in a paradigm shift in the neuroscientific understanding of MS over the past 25 years: Partly based on modern neuroimaging techniques, the classical view of MS as an inflammatory demyelinating disease affecting the white matter of the central nervous system has been extended. In particular, many studies have shown that the MS pathology also includes neurodegeneration, and that gray matter structures such as the cerebral cortex can also show focal lesions, atrophy, or both. The authors present an updated summary of the clinical manifestation and neuroimaging correlates of cognitive impairment in MS, and discuss the relatively few treatment options available to date. PMID- 27116730 TI - Overcoming Long-Term Variability in Local Field Potentials Using an Adaptive Decoder. AB - Long-term variability remains one of the major hurdles in using intracortical recordings like local field potentials for brain computer interfaces (BCI). Practical neural decoders need to overcome time instability of neural signals to estimate subject behavior accurately and faithfully over the long term. This paper presents a novel decoder that 1) characterizes each behavioral task (i.e., different movement directions under different force conditions) with multiple neural patterns and 2) adapts to the long-term variations in neural features by identifying the stable neural patterns. This adaptation can be performed in both an unsupervised and a semisupervised learning framework requiring minimal feedback from the user. To achieve generalization over time, the proposed decoder uses redundant sparse regression models that adapt to day-to-day variations in neural patterns. While this update requires no explicit feedback from the BCI user, any feedback (explicit or derived) to the BCI improves its performance. With this adaptive decoder, we investigated the effects of long-term neural modulation especially when subjects encountered new external forces against movement. The proposed decoder predicted eight hand-movement directions with an accuracy of 95% over two weeks (when there was no external forces); and 85% in later acquisition sessions spanning up to 42 days (when the monkeys countered external field forces). Since the decoder can operate with or without manual intervention, it could alleviate user frustration associated with BCI. PMID- 27116731 TI - MARCOnI-ConvNet-Based MARker-Less Motion Capture in Outdoor and Indoor Scenes. AB - Marker-less motion capture has seen great progress, but most state-of-the-art approaches fail to reliably track articulated human body motion with a very low number of cameras, let alone when applied in outdoor scenes with general background. In this paper, we propose a method for accurate marker-less capture of articulated skeleton motion of several subjects in general scenes, indoors and outdoors, even from input filmed with as few as two cameras. The new algorithm combines the strengths of a discriminative image-based joint detection method with a model-based generative motion tracking algorithm through an unified pose optimization energy. The discriminative part-based pose detection method is implemented using Convolutional Networks (ConvNet) and estimates unary potentials for each joint of a kinematic skeleton model. These unary potentials serve as the basis of a probabilistic extraction of pose constraints for tracking by using weighted sampling from a pose posterior that is guided by the model. In the final energy, we combine these constraints with an appearance-based model-to-image similarity term. Poses can be computed very efficiently using iterative local optimization, since joint detection with a trained ConvNet is fast, and since our formulation yields a combined pose estimation energy with analytic derivatives. In combination, this enables to track full articulated joint angles at state-of the-art accuracy and temporal stability with a very low number of cameras. Our method is efficient and lends itself to implementation on parallel computing hardware, such as GPUs. We test our method extensively and show its advantages over related work on many indoor and outdoor data sets captured by ourselves, as well as data sets made available to the community by other research labs. The availability of good evaluation data sets is paramount for scientific progress, and many existing test data sets focus on controlled indoor settings, do not feature much variety in the scenes, and often lack a large corpus of data with ground truth annotation. We therefore further contribute with a new extensive test data set called MPI-MARCOnI for indoor and outdoor marker-less motion capture that features 12 scenes of varying complexity and varying camera count, and that features ground truth reference data from different modalities, ranging from manual joint annotations to marker-based motion capture results. Our new method is tested on these data, and the data set will be made available to the community. PMID- 27116732 TI - Real-Time Simultaneous Pose and Shape Estimation for Articulated Objects Using a Single Depth Camera. AB - In this paper we present a novel real-time algorithm for simultaneous pose and shape estimation for articulated objects, such as human beings and animals. The key of our pose estimation component is to embed the articulated deformation model with exponential-maps-based parametrization into a Gaussian Mixture Model. Benefiting from this probabilistic measurement model, our algorithm requires no explicit point correspondences as opposed to most existing methods. Consequently, our approach is less sensitive to local minimum and handles fast and complex motions well. Moreover, our novel shape adaptation algorithm based on the same probabilistic model automatically captures the shape of the subjects during the dynamic pose estimation process. The personalized shape model in turn improves the tracking accuracy. Furthermore, we propose novel approaches to use either a mesh model or a sphere-set model as the template for both pose and shape estimation under this unified framework. Extensive evaluations on publicly available data sets demonstrate that our method outperforms most state-of-the-art pose estimation algorithms with large margin, especially in the case of challenging motions. Furthermore, our shape estimation method achieves comparable accuracy with state of the arts, yet requires neither statistical shape model nor extra calibration procedure. Our algorithm is not only accurate but also fast, we have implemented the entire processing pipeline on GPU. It can achieve up to 60 frames per second on a middle-range graphics card. PMID- 27116733 TI - Bayesian Modeling of Temporal Coherence in Videos for Entity Discovery and Summarization. AB - A video is understood by users in terms of entities present in it. Entity Discovery is the task of building appearance model for each entity (e.g., a person), and finding all its occurrences in the video. We represent a video as a sequence of tracklets, each spanning 10-20 frames, and associated with one entity. We pose Entity Discovery as tracklet clustering, and approach it by leveraging Temporal Coherence (TC): the property that temporally neighboring tracklets are likely to be associated with the same entity. Our major contributions are the first Bayesian nonparametric models for TC at tracklet level. We extend Chinese Restaurant Process (CRP) to TC-CRP, and further to Temporally Coherent Chinese Restaurant Franchise (TC-CRF) to jointly model entities and temporal segments using mixture components and sparse distributions. For discovering persons in TV serial videos without meta-data like scripts, these methods show considerable improvement over state-of-the-art approaches to tracklet clustering in terms of clustering accuracy, cluster purity and entity coverage. The proposed methods can perform online tracklet clustering on streaming videos unlike existing approaches, and can automatically reject false tracklets. Finally we discuss entity-driven video summarization- where temporal segments of the video are selected based on the discovered entities, to create a semantically meaningful summary. PMID- 27116734 TI - Speckle Reduction in 3D Optical Coherence Tomography of Retina by A-Scan Reconstruction. AB - Optical coherence tomography (OCT) is a micrometer-scale, cross-sectional imaging modality for biological tissue. It has been widely used for retinal imaging in ophthalmology. Speckle noise is problematic in OCT. A raw OCT image/volume usually has very poor image quality due to speckle noise, which often obscures the retinal structures. Overlapping scan is often used for speckle reduction in a 2D line-scan. However, it leads to an increase of the data acquisition time. Therefore, it is unpractical in 3D scan as it requires a much longer data acquisition time. In this paper, we propose a new method for speckle reduction in 3D OCT. The proposed method models each A -scan as the sum of underlying clean A scan and noise. Based on the assumption that neighboring A -scans are highly similar in the retina, the method reconstructs each A -scan from its neighboring scans. In the method, the neighboring A -scans are aligned/registered to the A scan to be reconstructed and form a matrix together. Then low rank matrix completion using bilateral random projection is utilized to iteratively estimate the noise and recover the underlying clean A -scan. The proposed method is evaluated through the mean square error, peak signal to noise ratio and the mean structure similarity index using high quality line-scan images as reference. Experimental results show that the proposed method performs better than other methods. In addition, the subsequent retinal layer segmentation also shows that the proposed method makes the automatic retinal layer segmentation more accurate. The technology can be embedded into current OCT machines to enhance the image quality for visualization and subsequent analysis such as retinal layer segmentation. PMID- 27116736 TI - Ultrasonic Defect Characterization in Heavy Rotor Forgings by Means of the Synthetic Aperture Focusing Technique and Optimization Methods. AB - Ultrasonic nondestructive testing of steel forgings aims at the detection and classification of material inhomogeneities to ensure the components fitness for use. Due to the high price and safety critical nature of large forgings for turbomachinery, there is great interest in the application of imaging algorithms to inspection data. However, small flaw indications that cannot be sufficiently resolved have to be characterized using amplitude-based quantification. One such method is the distance gain size method, which converts the maximum echo amplitudes into the diameters of penny-shaped equivalent size reflectors. The approach presented in this contribution combines the synthetic aperture focusing technique (SAFT) with an iterative inversion scheme to locate and quantify small flaws in a more reliable way. Ultrasonic inspection data obtained in a pulse-echo configuration are reconstructed by means of an Synthetic Focusing Technique (SAFT). From the reconstructed data, the amount and approximate location of small flaws are extracted. These predetermined positions, along with the constrained defect model of a penny-shaped crack, provide the initial parametrization for an elastodynamic simulation based on the Kirchhoff approximation. The identification of the optimal parameter set is achieved through an iteratively regularized Gauss Newton method. By testing the characterization method on a series of flat-bottom holes under laboratory conditions, we demonstrate that the procedure is applicable over a wide range of defect sizes. To show suitability for large forging inspection, we additionally evaluate the inspection data of a large generator shaft forging of 0.6-m diameter. PMID- 27116735 TI - Multi-Objective Memetic Search for Robust Motion and Distortion Correction in Diffusion MRI. AB - Effective image-based artifact correction is an essential step in the analysis of diffusion MR images. Many current approaches are based on retrospective registration, which becomes challenging in the realm of high b -values and low signal-to-noise ratio, rendering the corresponding correction schemes more and more ineffective. We propose a novel registration scheme based on memetic search optimization that allows for simultaneous exploitation of different signal intensity relationships between the images, leading to more robust registration results. We demonstrate the increased robustness and efficacy of our method on simulated as well as in vivo datasets. In contrast to the state-of-art methods, the median target registration error (TRE) stayed below the voxel size even for high b -values (3000 s .mm-2 and higher) and low SNR conditions. We also demonstrate the increased precision in diffusion-derived quantities by evaluating Neurite Orientation Dispersion and Density Imaging (NODDI) derived measures on a in vivo dataset with severe motion artifacts. These promising results will potentially inspire further studies on metaheuristic optimization in diffusion MRI artifact correction and image registration in general. PMID- 27116737 TI - Phase and Amplitude Modulation Methods for Nonlinear Ultrasound Imaging With CMUTs. AB - Conventional amplitude and phase modulated pulse sequences for selective imaging of nonlinear tissue and ultrasound contrast agents are designed for piezoelectric transducers that behave linearly. Inherent nonlinearity of capacitive micromachined ultrasonic transducers (CMUTs), especially during large-signal operation, renders these methods inapplicable. In this paper, we present different pulse sequences for nonlinear imaging that are valid for small- and large-signal CMUT operations. For small-signal operation, two-pulse amplitude and phase modulation methods for microbubble and tissue harmonic imaging are presented, where CMUT nonlinearity is compensated via subharmonic excitation. In the large-signal regime, using a nonlinear model, we first show that there is a simple linear relationship between the phases of each harmonic distortion component generated and the input drive signal. Based on this observation, we demonstrate a pulse sequence using N+1 consecutive phase modulated transmit events to extract N harmonics of the nonlinear contrast agent echo content uncorrupted by CMUT nonlinearity. The proposed methods assume no apriori information about the transducer and, therefore, are applicable to any CMUT. The phase modulation method is also valid for piezoelectric transducers and systems with nonlinearities described by Taylor series where the same phase relationship between the input signal and the harmonic content is valid. The proof of principle experiments using a commercial contrast agent validates the phase modulated pulse sequences for CMUTs, operating in a highly nonlinear collapse snapback mode and for piezoelectric transducers. PMID- 27116738 TI - Direct Digital Demultiplexing of Analog TDM Signals for Cable Reduction in Ultrasound Imaging Catheters. AB - In real-time catheter-based 3-D ultrasound imaging applications, gathering data from the transducer arrays is difficult, as there is a restriction on cable count due to the diameter of the catheter. Although area and power hungry multiplexing circuits integrated at the catheter tip are used in some applications, these are unsuitable for use in small sized catheters for applications, such as intracardiac imaging. Furthermore, the length requirement for catheters and limited power available to on-chip cable drivers leads to limited signal strength at the receiver end. In this paper, an alternative approach using analog time division multiplexing (TDM) is presented, which addresses the cable restrictions of ultrasound catheters. A novel digital demultiplexing technique is also described, which allows for a reduction in the number of analog signal processing stages required. The TDM and digital demultiplexing schemes are demonstrated for an intracardiac imaging system that would operate in the 4- to 11-MHz range. A TDM integrated circuit (IC) with an 8:1 multiplexer is interfaced with a fast analog-to-digital converter (ADC) through a microcoaxial catheter cable bundle, and processed with a field-programmable gate array register-transfer level simulation. Input signals to the TDM IC are recovered with -40-dB crosstalk between the channels on the same microcoax, showing the feasibility of this system for ultrasound imaging applications. PMID- 27116742 TI - Adaptive Quantization Parameter Cascading in HEVC Hierarchical Coding. AB - The state-of-the-art High Efficiency Video Coding (HEVC) standard adopts a hierarchical coding structure to improve its coding efficiency. This allows for the quantization parameter cascading (QPC) scheme that assigns quantization parameters (Qps) to different hierarchical layers in order to further improve the rate-distortion (RD) performance. However, only static QPC schemes have been suggested in HEVC test model, which are unable to fully explore the potentials of QPC. In this paper, we propose an adaptive QPC scheme for an HEVC hierarchical structure to code natural video sequences characterized by diversified textures, motions, and encoder configurations. We formulate the adaptive QPC scheme as a non-linear programming problem and solve it in a scientifically sound way with a manageable low computational overhead. The proposed model addresses a generic Qp assignment problem of video coding. Therefore, it also applies to group-of picture-level, frame-level and coding unit-level Qp assignments. Comprehensive experiments have demonstrated that the proposed QPC scheme is able to adapt quickly to different video contents and coding configurations while achieving noticeable RD performance enhancement over all static and adaptive QPC schemes under comparison as well as HEVC default frame-level rate control. We have also made valuable observations on the distributions of adaptive QPC sets in the videos of different types of contents, which provide useful insights on how to further improve static QPC schemes. PMID- 27116747 TI - Ion Channel Based Bio-Synthetic Modulator for Diffusive Molecular Communication. AB - In diffusion-based molecular communication (DMC), a transmitter nanomachine is responsible for signal modulation. Thereby, the transmitter has to be able to control the release of the signaling molecules employed for representing the transmitted information. In nature, an important class of control mechanisms for releasing molecules from cells utilizes ion channels which are pore-forming proteins across the cell membrane. The opening and closing of the ion channels is controlled by a gating parameter. In this paper, an ion channel based modulator for DMC is proposed which controls the rate of molecule release from the transmitter by modulating a gating parameter signal. Exploiting the capabilities of the proposed modulator, an on-off keying modulation technique is introduced and the corresponding average modulated signal, i.e., the average release rate of the molecules from the transmitter, is analyzed. However, since the modulated signal is random in nature, it may deviate from its average. Therefore, the concept of modulator noise is introduced and the statistics of the modulated signal are investigated. Finally, by assuming a simple transparent receiver, the performance of the proposed on-off keying modulation format is studied. The derived analytical expressions for the average modulated signal are confirmed with particle based simulations. Our numerical results reveal that performance estimates of DMC systems obtained based on the assumption of instantaneous molecule release at the transmitter may substantially deviate from the performance achieved with practical modulators. PMID- 27116750 TI - Low-Power, 8-Channel EEG Recorder and Seizure Detector ASIC for a Subdermal Implantable System. AB - EEG remains the mainstay test for the diagnosis and treatment of patients with epilepsy. Unfortunately, ambulatory EEG systems are far from ideal for patients who have infrequent seizures. These systems only last up to 3 days and if a seizure is not captured during the recordings, a definite diagnosis of the patient's condition cannot be given. This work aims to address this need by proposing a subdermal implantable, eight-channel EEG recorder and seizure detector that has two modes of operation: diagnosis and seizure counting. In the diagnosis mode, EEG is continuously recorded until a number of seizures are recorded. In the seizure counting mode, the system uses a low-power algorithm to track the number of seizures a patient has, providing doctors with a reliable count to help determine medication efficacy or other clinical endpoint. An ASIC that implements the EEG recording and seizure detection algorithm was designed and fabricated in a 0.18 MUm CMOS process. The ASIC includes eight EEG channels and is designed to minimize the system's power and size. The result is a power efficient analog front end that requires 2.75 MUW per channel in diagnosis mode and 0.84 MUW per channel in seizure counting mode. Both modes have an input referred noise of approximately 1.1 MUVrms. PMID- 27116751 TI - A Multi-User Surface Visuo-Haptic Display Using Electrostatic Friction Modulation and Capacitive-Type Position Sensing. AB - This paper proposes a visuo-haptic feedback system that can provide haptic feedback to multiple users on an LCD monitor using electrostatic adhesion and built-in capacitive sensors. The prototype system consists of a 40-inch LCD monitor, an ITO electrode sheet arranged on the monitor, and multiple contact pads for electrostatic adhesion. By applying low-frequency haptic voltage and high-frequency sensing voltage to each pad, the system realizes passive haptic feedback, as well as position sensing using the same components. The passive haptic feedback force exceeds 1 N at 300 V rms. The performance of the sensing system is investigated in terms of interference, which shows the haptic voltage and existence of multiple pads can affect the sensing and can shift the output by a few millimeters. A pilot application, virtual hockey game, successfully demonstrates the sensing and haptic rendering capability of the proposed system. The effect of the interference on the demonstration is discussed. PMID- 27116752 TI - Pseudo-Haptic Feedback in Teleoperation. AB - In this paper, we develop possible realizations of pseudo-haptic feedback in teleoperation systems based on existing works for pseudo-haptic feedback in virtual reality and the intended applications. We derive four potential factors affecting the performance of haptic feedback (calculation operator, maximum displacement, offset force, and scaling factor), which are analyzed in three compliance identification experiments. First, we analyze the principle usability of pseudo-haptic feedback by comparing information transfer measures for teleoperation and direct interaction. Pseudo-haptic interaction yields well above chance performance, while direct interaction performs almost perfectly. In order to optimize pseudo-haptic feedback, in the second study we perform a full factorial experimental design with 36 subjects performing 6,480 trials with 36 different treatments. Information transfer ranges from 0.68 bit to 1.72 bit in a task with a theoretical maximum of 2.6 bit, with a predominant effect of the calculation operator and a minor effect of the maximum displacement. In a third study, short- and long-term learning effects are analyzed. Learning effects regarding the performance of pseudo-haptic feedback cannot be observed for single day experiments. Tests over 10 days show a maximum increase in information transfer of 0.8 bit. The results show the feasibility of pseudo-haptic feedback for teleoperation and can be used as design basis for task-specific systems. PMID- 27116755 TI - Railway Track Circuit Fault Diagnosis Using Recurrent Neural Networks. AB - Timely detection and identification of faults in railway track circuits are crucial for the safety and availability of railway networks. In this paper, the use of the long-short-term memory (LSTM) recurrent neural network is proposed to accomplish these tasks based on the commonly available measurement signals. By considering the signals from multiple track circuits in a geographic area, faults are diagnosed from their spatial and temporal dependences. A generative model is used to show that the LSTM network can learn these dependences directly from the data. The network correctly classifies 99.7% of the test input sequences, with no false positive fault detections. In addition, the t-Distributed Stochastic Neighbor Embedding (t-SNE) method is used to examine the resulting network, further showing that it has learned the relevant dependences in the data. Finally, we compare our LSTM network with a convolutional network trained on the same task. From this comparison, we conclude that the LSTM network architecture is better suited for the railway track circuit fault detection and identification tasks than the convolutional network. PMID- 27116756 TI - Perceptually Guided Photo Retargeting. AB - We propose perceptually guided photo retargeting, which shrinks a photo by simulating a human's process of sequentially perceiving visually/semantically important regions in a photo. In particular, we first project the local features (graphlets in this paper) onto a semantic space, wherein visual cues such as global spatial layout and rough geometric context are exploited. Thereafter, a sparsity-constrained learning algorithm is derived to select semantically representative graphlets of a photo, and the selecting process can be interpreted by a path which simulates how a human actively perceives semantics in a photo. Furthermore, we learn the prior distribution of such active graphlet paths (AGPs) from training photos that are marked as esthetically pleasing by multiple users. The learned priors enforce the corresponding AGP of a retargeted photo to be maximally similar to those from the training photos. On top of the retargeting model, we further design an online learning scheme to incrementally update the model with new photos that are esthetically pleasing. The online update module makes the algorithm less dependent on the number and contents of the initial training data. Experimental results show that: 1) the proposed AGP is over 90% consistent with human gaze shifting path, as verified by the eye-tracking data, and 2) the retargeting algorithm outperforms its competitors significantly, as AGP is more indicative of photo esthetics than conventional saliency maps. PMID- 27116758 TI - Data-Driven Tracking Control With Adaptive Dynamic Programming for a Class of Continuous-Time Nonlinear Systems. AB - A data-driven adaptive tracking control approach is proposed for a class of continuous-time nonlinear systems using a recent developed goal representation heuristic dynamic programming (GrHDP) architecture. The major focus of this paper is on designing a multivariable tracking scheme, including the filter-based action network (FAN) architecture, and the stability analysis in continuous-time fashion. In this design, the FAN is used to observe the system function, and then generates the corresponding control action together with the reference signals. The goal network will provide an internal reward signal adaptively based on the current system states and the control action. This internal reward signal is assigned as the input for the critic network, which approximates the cost function over time. We demonstrate its improved tracking performance in comparison with the existing heuristic dynamic programming (HDP) approach under the same parameter and environment settings. The simulation results of the multivariable tracking control on two examples have been presented to show that the proposed scheme can achieve better control in terms of learning speed and overall performance. PMID- 27116759 TI - Adaptive Leader-Following Consensus for Second-Order Time-Varying Nonlinear Multiagent Systems. AB - The leader-following consensus problem is investigated for second-order time varying nonlinear multiagent systems with unmodeled dynamics and unknown parameters over directed communication topology. Under the assumption that the unknown nonlinearities satisfy Lipschitz conditions with time-varying gains, a local adaptive law is introduced for the design of consensus protocol that enable all followers' state variables to consensus with that of leader asymptotically. The proposed protocols are independent of system parameters and only require the relative state information of its neighbors, and hence they are fully distributed. Simulation examples are given to illustrate the effectiveness of the theoretical results. PMID- 27116760 TI - Maximum Margin of Twin Spheres Support Vector Machine for Imbalanced Data Classification. AB - Twin support vector machine (TSVM) finds two nonparallel planes by solving a pair of smaller-sized quadratic programming problems (QPPs) rather than a single large one as in the conventional support vector machine (SVM); this makes the learning speed of TSVM approximately four times faster than that of the standard SVM. One major limitation of TSVM is that it involves an expensive matrix inverse operation when solving the dual problem. In addition, TSVM is less effective when dealing with the imbalanced data. In this paper, we propose a maximum margin of twin spheres support vector machine (MMTSSVM) for imbalanced data classification. MMTSSVM only needs to find two homocentric spheres. On one hand, the small sphere captures as many samples in the majority class as possible; on the other hand, the large sphere pushes out most samples in the minority class by increasing the margin between two homocentric spheres. MMTSSVM involves a QPP and a linear programming problem as opposed to a pair of QPPs as in classical TSVM or a larger sized QPP in SVM, thus it greatly increases the computational speed. More importantly, MMTSSVM avoids the matrix inverse operation. The property of parameters in MMTSSVM is discussed and testified by one artificial experiment. Experimental results on nine benchmark datasets demonstrate the effectiveness of the proposed MMTSSVM in comparison with state-of-the-art algorithms. Finally, we apply MMTSSVM into Alzheimer's disease medical experiment and also obtain a better experimental result. PMID- 27116762 TI - Child and Adult Care Food Program: Meal Pattern Revisions Related to the Healthy, Hunger-Free Kids Act of 2010. Final rule. AB - This final rule updates the meal pattern requirements for the Child and Adult Care Food Program to better align them with the Dietary Guidelines for Americans, as required by the Healthy, Hunger-Free Kids Act of 2010. This rule requires centers and day care homes participating in the Child and Adult Care Food Program to serve more whole grains and a greater variety of vegetables and fruit, and reduces the amount of added sugars and solid fats in meals. In addition, this final rule supports mothers who breastfeed and improves consistency with the Special Supplemental Nutrition Program for Women, Infants, and Children and with other Child Nutrition Programs. Several of the changes are extended to the National School Lunch Program, School Breakfast Program, and Special Milk Program. These changes are based on the Dietary Guidelines for Americans, science based recommendations made by the National Academy of Medicine (formerly the Institute of Medicine of the National Academies), cost and practical considerations, and stakeholder's input. This is the first major revision of the Child and Adult Care Food Program meal patterns since the Program's inception in 1968. These improvements to the meals served in the Child and Adult Care Food Program are expected to safeguard the health of young children by ensuring healthy eating habits are developed early, and improve the wellness of adult participants. PMID- 27116761 TI - Contrast-ing opinions: biparametric versus multiparametric prostate MRI. PMID- 27116763 TI - Access to Health Insurance. PMID- 27116764 TI - Access to Health Insurance: State Children's Health Insurance Program. PMID- 27116765 TI - Business of Health: Business of Health Insurance. PMID- 27116766 TI - Business of Health: Business of Healthcare. PMID- 27116767 TI - Emergency Care. PMID- 27116768 TI - Healthcare Facilities. PMID- 27116769 TI - Healthcare Workforce. PMID- 27116770 TI - Healthcare Information Technology. PMID- 27116771 TI - Medical Errors and Patient Safety: Reducing Medical Errors and Improving Patient Safety. PMID- 27116772 TI - Medical Malpractice and Tort Reform. PMID- 27116774 TI - Healthcare Reform: Enforcement and Compliance. PMID- 27116773 TI - Quality of Healthcare. PMID- 27116775 TI - Healthcare Reform: Administrative Rulemaking. PMID- 27116776 TI - Healthcare Reform: Delivery Reform. PMID- 27116777 TI - Healthcare Reform: Insurance Market Reform. PMID- 27116778 TI - Healthcare Reform: Payment Reform. PMID- 27116779 TI - Healthcare Reform: State Specific Responses. PMID- 27116780 TI - Managed Care. PMID- 27116781 TI - Mandated Benefits. PMID- 27116782 TI - Long-Term Care: End-Of-Life Issues. PMID- 27116783 TI - Long-Term Care: Funding of Long-Term Care. PMID- 27116784 TI - Long-Term Care: Facility Quality and Safety. PMID- 27116785 TI - Long-Term Care: Home and Community-Based Services Year-End Report--2015. PMID- 27116786 TI - Medicaid Copayments. PMID- 27116787 TI - Medicaid Provider Tax. PMID- 27116788 TI - Benefits and Services. PMID- 27116789 TI - [2015 Medicaid Eligibility 50-State Survey Findings]. PMID- 27116790 TI - Federal Medicaid Policy. PMID- 27116791 TI - Medicaid Reimbursement. PMID- 27116792 TI - Medicaid Restructuring. PMID- 27116793 TI - Medicaid Waivers. PMID- 27116794 TI - Pharmaceuticals and Medical Devices: Cost Savings. PMID- 27116795 TI - Pharmaceuticals and Medical Devices: Medicare Part D. PMID- 27116796 TI - Pharmaceuticals and Medical Devices: Business Practices. PMID- 27116797 TI - Pharmaceutical and Medical Devices: FDA Oversight. PMID- 27116798 TI - Pharmaceuticals and Medical Devices: Medical Devices. PMID- 27116799 TI - Trinity Health Offers Patient Payment Options and Reduces A/R Days. PMID- 27116800 TI - Make Your Patient Statements Work Harder. PMID- 27116801 TI - Millennials Set Pace for Healthcare and Revenue Cycle Management. PMID- 27116802 TI - Predictors of severe sepsis among patients hospitalized for community-acquired pneumonia. PMID- 27116804 TI - Increasing evidence supports the need for multiplex testing of sexually transmitted infections. PMID- 27116805 TI - Point-of-care testing and its implications for STIs. PMID- 27116803 TI - Hepatitis C: challenges and opportunities in the laboratory diagnosis of infection. PMID- 27116806 TI - Molecular diagnostics, automation, and enhancing lab workflow. PMID- 27116807 TI - The case for RFID in blood banking. PMID- 27116808 TI - Emerging education program assists cytotechnologists in a changing landscape. PMID- 27116810 TI - Lab sales compensation: contexts and considerations. PMID- 27116809 TI - MLO exclusive report: The 2016 laboratory professional annual salary survey. PMID- 27116812 TI - President's Perspective. PMID- 27116813 TI - Case of the Month. Cleidocranial Dysplasia. PMID- 27116814 TI - Preoperative Continuation of Aspirin with Appropriate Hemostatic Measure is Currently Recommended (UT CAT #2850). PMID- 27116815 TI - A Guiding Star in My Dental Journey. PMID- 27116816 TI - One Person Can Make a Difference. PMID- 27116817 TI - His Gold Texas Pin. PMID- 27116818 TI - His Immeasurable Guidance. PMID- 27116819 TI - It's Not What You Know, but Who You Know. PMID- 27116820 TI - A Father's Influence. PMID- 27116821 TI - A Life of Giving: A Life of Paying It Forward. PMID- 27116822 TI - Working With Professionals. PMID- 27116823 TI - When You Learn, Teach. PMID- 27116824 TI - If You're Lucky, Your Answer is Yes. PMID- 27116825 TI - A Genuine Love for Students. PMID- 27116826 TI - HOW TO DEAL WITH BAD REVIEWS, SPOT A SCAM, and Which Revew Sites Matter Most to Your Online Reputation. PMID- 27116827 TI - The Pediatric Dental Patient. PMID- 27116828 TI - [THE PERSPECTIVES OF DEVELOPMENT OF HEALTH CARE OF THE RUSSIAN FEDERATION]. AB - The article considers actual conditions and characteristics of reformation of health care of Russia. The comparison is applied to such sectoral aspects as decentralization, medical care accessibility, public sector of health care, health of healthy population, resources distribution, medical insurance, paid medical services, etc. The comprehensive approach is proposed to resolving problems of national health care and alternatives of main direction of sectoral development. PMID- 27116829 TI - [THE MORBIDITY OF POPULATION OF THE RUSSIAN FEDERATION: GEOGRAPHIC CHARACTERISTICS]. AB - The article considers the results of analysis of characteristics of morbidity of population residing in various geographic conditions of the Russian Federation. The comparison was applied to morbidity of residents of subjects of the Russian Federation residing approximately at the levels of 50 and 60 of northern longitude according data of 2008-2013. The average annual size of population of the Northern territories amounted to 8,994,112 and in the southern territories 32,600,569. The maximal differences are noted in relation to diseases of respiratory organs and congenital abnormalities of blood circulation system. Actually, indicators of morbidity of diseases of cardiovascular system and ischemic heart diseases had no differences. The rest of analyzed indicators differed on 10-40% towards higher values in the Northern regions. The exception included cerebrovascular diseases with morbidity higher in southern territories up to 11% than in northern territories. PMID- 27116830 TI - [THE CRISIS PHENOMENA AND HEALTH]. AB - The analysis was carried out concerning impact of cyclicity of social economic development on population health of the Russian Federation. The conclusions are made related to necessity of determining priorities of development of national system of population health care. PMID- 27116831 TI - [THE SOCIAL HYGIENE AS A PHENOMENON OF SCIENTIFIC REVOLUTION IN MEDICINE OF LATE XIX--FIRST HALF XX CENTURIES]. AB - The article presents results of analysis of works of late XIX--first quarter of XY centuries devoted to problems of social hygiene. It is established that origin of social hygiene was directly related to crucial revision of conceptions of causes and essence of diseases that created necessary conditions for transfer into medicine ideas and methods of political economy, sociology and eugenics. It is proved that origin of social hygiene was appropriate consequence of those crucial alterations in mass physician's consciousness that characterize scientific revolution in medicine of late XIX--first half XX centuries. PMID- 27116832 TI - [THE STATE OF TRAFFIC TRAUMATISM ACCORDING DATA OF OFFICIAL MEDICAL STATISTICS]. AB - The article presents situation with traffic accident traumatism and medical care support of victims of traffic accidents at pre-hospital and hospital stages. The recommendations are proposed concerning insertion of additions into reporting forms of federal (sectoral) monitoring to guarantee fullness of information. PMID- 27116833 TI - [THE HEALTH OF PARAMEDICAL PERSONNEL AND IMPACTING FACTORS]. AB - The article presents results of sociological survey of 650 paramedical personnel. It is established that 37% out ofthem suffer from chronic diseases. The given indicator is reliably higher in patients of elder age having three and more children and low income. The relationship is established between health level and opinions ofparamedicalpersonnel about public significance ofprofession availability of conflicts with physicians and labor loads. The signs of emotional burnout syndrome have 77.8-83.3% of respondents according different techniques. PMID- 27116834 TI - [THE RESULTS OF ANALYSIS OF MORBIDITY OF URBAN FEMALE POPULATION ACCORDING DATA OF APPEALABILITY TO MEDICAL ORGANIZATION]. AB - The article presents analysis of primary morbidity according data of appealability to polyclinic in 2009-2013. It is established that indicator increased up to 7.7% mainly at the expense of neoplasms, diseases of blood circulation system, musculo-skeletal system and nervous system. The first rank positions in primarily morbidity among women were placed by diseases of respiratory organs, urogenital system and blood circulation system. In age groups of less than 30 years, 30-39 years and 40-49 years diseases of respiratory system, urogenital system registered more frequently. In age groups of 50-59 years, 60-69 years and 70 years and older diseases of blood circulation system, musculo-skeletal system and digestive system registered more frequently. The visits of women to polyclinic because of diseases were the least during summer period The number of visits were approximately the same during autumn and spring time. Besides, number of visits because of diseases was the least in December and January. PMID- 27116835 TI - [THE ANALYSIS OF LIFE SPAN AND MORTALITY OF PATIENTS WITH SPINOCEREBELLAR ATAXIA TYPE I]. AB - The article presents results of investigation of certain unclear aspects of mortality of patients with spinocerebellar ataxia type I including patients with the same number of CAG-repetitions. The analysis of mortality of patients observed from 1993 to nowadays was implemented. Sampling included 112 patients during that period 53 patients died. The comparative analysis was implemented concerning received data and results of analysis of mortality of patients died prior to 1980. According received data, average value of CAG-repetitions of normal allele was equal to 30.2, and ofpathologic allele--48.7. The average life span made up to 52.8 years, average age of disease onset--38 years and natural duration of disease--14.8 years. The analysis of life span of patients with equal length of repetitions demonstrated that range of life span of patients makes up to from 8 to 23 years. It is established that life of patients becomes shorter because of accidents, cancer and concomitant diseases of cardiovascular system. The presence of such concomitant disease as tuberculosis of lungs results in no shortening of life of patients. The comparative analysis of mortality during the period over 34 years demonstrated that age of disease onset turned out to be more conservative and stable indicator of morbidity. Despite of lacking of effective methods of treatment of disease, the natural duration of disease increased statistically reliable up to 1.8 times during period of observation. The analysis of life span ofpatients with spinocerebellar ataxia type I demonstrated that their life span except length of CAG-expansion depends on a number of factors accelerating and retarding development of disease. At that, life span of patients with the same number of CAG-repetitions can significantly differ The malignant neoplasms, diseases of cardiovascular system and external causes are to be referred to factors accelerating and retarding development of main disease. The addition oftuberculosis in our case resulted in no alteration of natural course of disease. The other factors exist prolonging life of patients, including factors of social economic and medical character They require additional specification and thorough investigation with the purpose of developing methods ofpreventive correction of neuro-degeneration processes. PMID- 27116836 TI - [THE SELF-ASSESSMENT OF PHYSICIANS THEIR QUALIFICATION AND SOCIAL STATUS]. AB - The 103 medical organizations of the Tverskaia oblast were involved as study base to carry out questionnaire survey of physicians of different specialties concerning issues of self-assessment of qualification and social status. The most of the respondents (66.8 +/- 1.98%) assessed themselves as good specialists, 20.8 +/- 1.71% as fair specialists and 11.9 +/- 1.36%--as perfect specialists. The own social status respondents assessed in general as not too high. So, 53.1 +/- 2.10% of physicians refer themselves to middle class of society and 30 +/- 1.93%--to below middle class of society. Among respondents, 3 +/- 0.71% referred themselves to high class of society and 3.2 +/- 0.74%--to the lowest class of society. The low incomes and overwork were noted by respondents as main problems of their life. The study results testify the necessity of correction of programs of medical education at all levels, actuality of activities of increasing social status of physician and development of benevolent conditions of work and rest. PMID- 27116837 TI - [THE MEDICAL GENETIC COUNSELING AND PREVENTION OF INBORN AND CONGENITAL PATHOLOGY IN THE RUSSIAN FEDERATION]. AB - The review presents main causes and tasks of organization of medical genetic counseling targeted to preventing occurrence of patients with inherent and inborn pathology in families. It is demonstrated that improvement of methods of prenatal diagnostic increased effectiveness of medical genetic counseling. The resolution of problems of medical genetic counseling depends on population education and organization of preventive activities at the level of district physicians, family physicians and gynecologists. PMID- 27116838 TI - [THE PROBLEMS OF GOAL-ORIENTED PLANNING OF MUNICIPALITY HEALTH CARE]. AB - The administration of city of Serpukhov of the Moscow oblast, 142203 Serpukhov, Russia The article presents results of special study carried out with the purpose to determine effectiveness of the Program "Development of health care system of the city of Serpukhov in 2011-2013". The comparative analysis was applied to indicators planned by the Program as achievements and actually achieved indicators. The critical remarks concerning listing of regulate indicators are presented and argued. PMID- 27116839 TI - [THE DEVELOPMENT OF MOBILE APPLICATION OF PATIENT FOR IMPLEMENTATION OF REMOTE MONITORING]. AB - The article considers issues of necessity of development and implementation of mobile application of patient within the framework of automated system of remote monitoring of human health indicators as a mean of increasing quality of medical care of patients. PMID- 27116840 TI - [THE PROFESSIONAL MEDICAL SELF-APPRAISAL OF GRADUATES OF COMPREHENSIVE SCHOOLS OF THE REPUBLIC OF KAZAKHSTAN]. AB - The human resources play a decisive role in support of effective functioning of any health care system. The study was carried out to analyze characteristics offormation ofprofessional self-appraisal of graduates of comprehensive schools of the Republic of Kazakhstan choosing medical specialties. The study was organized in city of Pavlodar and the Pavlodarskaia oblast of the Republic of Kazakhstan. The sample included 447 schoolchildren of 9-10 classes, 25 workers of 3 urban and 1 rural schools, 12 lecturers of medical university. The questionnaire survey was applied. The statistical processing of data was implemented using SPSS v.20 software. It is established that medicine became a popular profession because it was chosen by 22% of schoolchildren. Out of them, only 37.4% belonged among personality type "human-human" corresponding to medical specialties. The childhood dream became main cause of choosing medicine among 55.6% of schoolchildren. The second place took perspective of employment and third place--insistent advice of parents (13.1% and 7.1% correspondingly). Only 31.3% of schoolchildren were aware of specificity of medical specialties and 52.5% had independent experience of initial medical care provision. The additional training is considered by 72.7% of schoolchildren as necessary for entering medical university. The workers of schools and medical university 65.5% and 66.7% limit themselves by once-only activities. The vocational guidance activities implemented in comprehensive schools of the Republic of Kazakhstan can be significantly ameliorated. The possibility of implementing personality type test is to be considered. The application of innovative methods of vocational guidance is to be considered too. PMID- 27116841 TI - [THE INDIVIDUAL AND SOCIAL FACTORS EFFECTING REFUSAL FROM VACCINATION OF CHILDREN IN THE TOWN OF SEMEII OF THE REPUBLIC OF KAZAKHSTAN]. AB - The number of cases of refusal from vaccination increases all over the world. In the Republic of Kazakhstan many studies are devoted to epidemiology of propagation of vaccine-controllable infections, medical aspects ofimmunization, analysis of immunological status and complications of immunization. The issues of awareness of population of the Republic of Kazakhstan about vaccination and refusal of it are investigated insufficiently. This occurrence became a cause of studying the given problem. The study was carried out to investigate attitude ofpopulation to vaccination and main factors of risk of refusal from vaccination of children residing in the city of Semeii and rural districts of the Eastern Kazakhstan oblast. The single-stage longitudinal study was carried out in the Centers of primary medical social care ofpopulation ofcity of Semeii and in polyclinic of the Abaiiskii district of the Eastern Kazakhstan oblast. The period of study continued from April 7 2015 to May 31 2015. The criteria of inclusion were conditionally healthy children. The questionnaire survey included 1184 respondents (mothers) with average age of 27.2 years. The sampling predominantly consisted ofKazakhs (805), Russians (307), representatives ofother nationalities (72). Among mothers, most of them had specialized secondary education (43.7%), the higher education had 30.5%, undergraduate higher education - 1.4%, secondary education - 21.6% and basic school education --2.8%. The results of study demonstrated that families refused from vaccination have negative attitude to vaccination in general though they are satisfied with functioning of vaccination room. The refusal of vaccination is more characterized to urban full families with satisfied income and having girls as children. The respondents consider that information about vaccination received by themfrom medical personnel contains surplus data concerning complications. They are not enouzh for activities in case of deterioration of health of child after vaccination. PMID- 27116842 TI - [SANTORIO AND THE FIRST SCIENTIFIC REVOLUTION OF XVII CENTURY]. AB - The national publications about Santorio and his works factually provide no information to medical society of Russia. The article presents discussion about significance of his works for the first scientific revolution in XVII century. The conception of this significance is expanded. The personal position is substantiated concerning evaluation of ratio of inputs by Santorio and Galileo into initiation of scientific revolution. PMID- 27116843 TI - Jens Sandahl Christiansen, DMSci, FRCPI (1948-2015). PMID- 27116844 TI - Contingent Screening for Small by Weight for Gestational Age Neonates. AB - Effective screening for small for gestational age neonates (SGA), in the absence of preeclampsia, can be accomplished using a contingent screening method. The basis for the contingent model is a combined assessment at 19-24 weeks gestation to stratify patients according to their risk. We can then identify prenatally over 90% of SGA neonates for a false positive rate of 10%. PMID- 27116845 TI - Changing and Unchanging Perspectives regarding Intersex in the Last Half Century: Topics Presented in the Lawson Wilkins Lecture* at the 2015 Pediatric Endocrine Society Meeting. AB - The understanding, care and treatment of patients born with intersex or disorders of sex development conditions has evolved considerably over the last five decades. Regarding those who require evaluation before gender assignment is made, each "generation" of approach has been based upon and reflects the contemporary biological, social and psychological understanding. The most recent generation needs to consider the dramatically changed societal viewpoints regarding the acceptance and expansion beyond a binary perception of sexuality. This together with advances in genetic etiologies, surgical refinements and psychological support should result in better care and quality of life (QoL) outcomes for patients with these conditions. This paper reviews the successive generations of approach and discusses the multiple challenges facing the multidisciplinary teams caring for these patients today. PMID- 27116846 TI - Evidence-Based Management of Patients with 45,X/46,XY Gonadal Dysgenesis and Male Sex Assignment: from Infancy to Adulthood. AB - 45,X/46,XY gonadal dysgenesis is a disorder of sexual differentiation with a wide clinical presentation, ranging from Turner-like females to individuals with genital ambiguity to azoospermic but otherwise normal-appearing males. Hence, patients can be assigned female or male sex. Female patients are managed according to the Turner Syndrome Guidelines, whereas males are managed on a case by-case basis. Male patients present with multiple medical challenges: undervirilization, hypogonadism, gonadoblastoma risk, and short stature. Many require surgeries and hormonal treatments that are time-sensitive and irreversible. Nonetheless, these therapeutic decisions are made without evidence based guidelines. This review describes the medical concerns and possible interventions in male patients with 45,X/46,XY dysgenesis for each stage of development. Interventions should be addressed within a patient-centered framework by a multidisciplinary team and after thorough discussion with the family. We use the GRADE system to appraise the existing evidence and provide recommendations based on the available evidence. PMID- 27116847 TI - Salivary Biomarkers in Pediatric Metabolic Disease Research. AB - The increasing prevalence of childhood obesity and obesity-related metabolic disorders is now considered a global pandemic. The main goal of the pediatric obesity research community is to identify children who are at risk of becoming obese before their body mass index rises above age norms. To do so, we must identify biomarkers of metabolic health and immunometabolism that can be used for large-scale screening and diagnosis initiatives among at-risk children. Because blood sampling is often unacceptable to both parents and children when there is no direct benefit to the child, as in a community-based research study, there is a clear need for a low-risk, non-invasive sampling strategy. Salivary analysis is now well recognized as a likely candidate for this purpose. In this review, we discuss the physiologic role of saliva and its strengths and limitations as a fluid for biomarker discovery, obesity screening, metabolic disease diagnosis, and response monitoring after interventions. We also describe the current state of the salivary biomarker field as it pertains to metabolic research, with a special emphasis on studies conducted in children and adolescents. Finally, we look forward to technological developments, such as salivary "omics" and point of service diagnostic devices, which have the potential to accelerate the pace of research and discovery in this vitally important field. PMID- 27116848 TI - Thyroid Hemiagenesis from Childhood to Adulthood: Review of Literature and Personal Experience. AB - Thyroid hemiagenesis (TH) is a rare congenital abnormality of the thyroid gland, characterised by the absence of one lobe. The true prevalence of this congenital abnormality is not known because the absence of one thyroid lobe usually does not cause clinical symptoms by itself. Between 1970 and 2010, 329 cases of TH have been reported. It is interesting to note that most cases have an agenesis of the left lobe (80% of cases) followed by the isthmus (44-50% of cases). Although the female to male ratio was 1:1.4 in 24,032 unselected 11-to 14-yr-old schoolchildren from South-eastern Sicily, several other reports have documented a higher prevalence in women, which may indicate a possible gender association. Most cases of TH are diagnosed when patients present a lesion in the functioning lobe. The functioning lobe of the thyroid gland can be a site of pathological changes similar to a normally developed gland and may present a spectrum of diseases like multinodular goiter, colloid goiter, follicular adenoma, thyroiditis, hypothyroidism and hyperthyroidism. In three of our patients, TH was associated with Hashimoto thyroiditis (n = 1) and with subclinical hypothyroidism (n = 2). The frequency of thyroid abnormalities in patients with TH varies with age, due to the longer exposure of the hemi-agenetic gland to TSH overstimulation in older patients. This could explain the controversy about the benign character of this anomaly. Other extrathyroidal lesions, such as parathyroid adenoma or hyperplasia, cervical thymic cysts, ectopic sublingual thyroid gland and thyroglossal duct cyst have been reported with TH. Therefore, systematic follow up of all identified cases is recommended. PMID- 27116849 TI - [Address by the rector of the Pomeranian Medical University in Szczecin inaugurating the acadefnic year of 2014/2015]. PMID- 27116850 TI - Leucocytosis as a specific risk predictor after abdominal aortic aneurysm open repair. AB - INTRODUCTION: Prediction of early death in abdominal aortic aneurysm - open repair is widely described. There is no superiority of any risk stratification tool. Some of the risk calculators are quite accurate, but very complicated (e.g. P-POSSUM, V-POSSUM). Some are simpler but never used in vascular surgery (e.g. ECOG). Therefore, only leucocytosis itself appears to be an independent and highly specific factor in prediction of early death prior to surgery. This might be used as an early warning factor raising surgeons' attention, especially in centers not using any risk calculators on a regular basis. The aim of this study was to comparison of commonly used early death prediction calculators for abdominal aortic aneurysm - open repair. We took into account the following scales: Glasgow Aneurysm Score (GAS), V-POSSUM, Eagle score, American Society of Anesthesia Score, ECOG, Goldman/Detsky. However, we also have been looking for independent risk factors of early postoperative death. MATERIAL AND METHODS: Retrospective analysis of 79 patients who underwent elective open repair of abdominal aortic aneurysm over 3 years (2011-2013 Szczecin, Poland). We have excluded patients treated due to ruptured aneurysms and with the use of a stentgraft. Receiver operating curve analysis was used to asses all prediction abilities. RESULTS: We noted 6 deaths (7.59%). Receiver operating curve analysis confirms good prediction force for V-POSSUM (p = 0.0001, criterion over 1.9%) and GAS (p = 0.0109, criterion over 73 pt.). Areas under curve are respectively 0.806 and 0.743. However, leucocytosis itself over 10 T/L was the most specific (over 88%) risk factor in early death prediction (p < 0.0001). CONCLUSION: V-POSSUM and GAS are suitable risk calculators for abdominal aortic aneurysm - open repair. Leucocytosis discovered prior to the surgery is a highly specific early death predictor. PMID- 27116851 TI - Clinical and radiological characteristics of the cyst of the septum pellucidum in endoscopically treated patients. AB - INTRODUCTION: The cavum of the septum pellucidum occurs in up to 15% of adults and is considered as an anatomical variant. How- ever, some patients reveal symptoms which are associated with the evolution from the cavum in the form of a cyst of the septum pelludum. Cyst incidence is much lower. The pathomechanism and risk factors of such changes are not fully understood. Among the theories for the formation of the cyst, most attention is given to the hypothesis of the mechanism of the valve in the flow of cerebrospinal fluid. However, this statement can be validated only on the basis of direct observation, which can be made in vivo only with the help of the endoscopic method. The aim of this study was to describe the clinical and radiological features coexisting with the expanding cysts of the septum pellucidum. The research also included considerations on the pathogenesis of the expanding cysts of the septum pellucidum, as well as the evaluation of the intraoperative endoscopic image. MATERIAL AND METHODS: The study included 27 patients of the Department of Neurosurgery Pomeranian Medical University in Szczecin, diagnosed with an expanding cyst of the septum pellucidum, who underwent neurosurgery treatment. The patients' clinical and radiological symptoms were evaluated before and after surgical intervention. Analysis of the intraoperative endoscopic images was also performed. RESULTS: The most common clinical symptoms in patients before surgery were similar: headache, dizziness, nausea and vomiting, advanced nervous functions disorders, and visual defects. In most cases the symptoms resolved after surgical treatment, which proves their association with the occurrence of cysts. Significant differences in radiographic measurements before and after surgery where also noted, which allowed the determination of clinical and radiological criteria for the diagnosis of expanding cysts of the septum pellucidum, and intravital intraoperative findings allowed direct proof of the cyst's filling mechanism. The obtained results allowed us to prove the hypothesis of the valve mechanism as the main factor causing the symptoms in patients with expanding cysts of the septum pellucidum, and to determine the components of the syndrome of the septum pellucidum cyst. They confirmed the validity of the selection of surgical treatment using an endoscope. Furthermore, changes in the geometry of the structures of the central nervous system observed in the analysis of radiological images before and after surgery made further research on the dynamics of this anatomical area in patients with expanding cysts of the septum pellucidum reasonable. PMID- 27116852 TI - Promising results from cyclophosphamide based immunosuppression therapy of thrombotic thrombocytopenic purpura. AB - PURPOSE: Thrombotic thrombocytopenic purpura is a rare disease. Therefore, the small numbers of patients in trials results in statistically weak evidence supporting treatment guidelines. The aetiology of this disease is based on a deficiency of metalloproteinase 13 (ADAMTS-13), which leads to the creation of von Willebrand factor polymers and platelet microthrombosis in small vessels. Treatment relies on plasma exchange. Immunosuppression based on cyclophosphamide is not recommended in current guidelines. The aim of this study was to assess the early and long-term effects of treatment, and to evaluate therapy prognostic factors. MATERIAL AND METHODS: This was a retrospective study of 10 patients hospitalized 14 times due to new or recurrent onset of TTP. Currently recommended treatment was used in all cases, including total plasma exchange (range 0.5-2 plasma volume). The volume of exchange plasma was 24.6 L (mean) over 20 days (median). All patients received glucocorticosteroids. Immuno-uppression (based on cyclophosphamide in 7 cases) was utilized in 70% of patients (9 patients). RESULTS: Of all 11 patients 9 (70%) survived and achieved remission. Fifty percent of patients stayed in long-lasting remission. Average follow-up time was 36 months (median 14.5 months, range 10 days to 108 months). Factors improving the chance of remission were: age below 55 years (p < 0.05), no tachycardia on admission to hospital (p < 0.001), and immunosuppression based on cyclophosphamide (p = 0.032). CONCLUSIONS: Presence of tachycardia on TTP onset and age above 55 years reduce the survival and remission rate. Remission from TTP is suggested to be caused by immunosuppression based on cyclophosphamide. PMID- 27116853 TI - [Hydronephrosis of unclear etiology with symptoms of acute abdomen - case report]. AB - We report a case of a patient whose clinical status and results of a plain chest X-ray showed digestive tract perforation, but in whom the true cause of the disease appeared to be hydronephrosis, probably caused by a tumour of the pyelo ureteral junction. The course of the diagnostic process and causes of the false diagnosis and unnecessary laparotomy are discussed. The usefulness of computed tomography scanning with contrast in the detection of clinically unlcear abdominal disorders (i.e. radiologically "silent" perforation) is emphasised. PMID- 27116854 TI - [Iatrogenic pseudoaneurysm of the brachial artery in a 4-month-old child - a case report]. AB - We present a rare case of an iatrogenic pseudoaneurysm of the brachial artery in a 4-month-old child. As there are reports of such lesions in children that undergo invasive treatment such as sophisticated cardiovascular or radiological interventions and have preexisting risk factors, our patients had no history of vessel caniulation in hospital conditions and no systemic problems. A simple ambulatory blood draw caused a tear in the brachial artery wall, that later formed a pseudoaneurysm, a month before parents suddenly noticed mass on their child's arm. A microsurgical repair was performed. A significant increase in endovascular treatment options has been observed over last decades. Successful treatment was a result of fast radiological diagnostic and effective co-operation between paediatric and general vascular surgeons. Our case should raise awareness of paediatric practitioners about iatrogenic trauma of vessels in the differential diagnosis of tumours and vascular lesions. PMID- 27116855 TI - [Distal ventriculoatrial shunt catheter implantation under fluoroscopy guidance throught the left internal jugular vein as a rescue technique - a case report]. AB - Revision of the distal ventriculoatrial shunt catheter is a rare challenge for the neurosurgeon. Its dysfunction associated with inflammation also binds to systemic complications. The paper presents a case report of a patient with bacterial colonisation of distal ventriculoatrial shunt catheter caused by separation of the layers of a old surgical wound. Catheter was removed by revision of the right internal jugular vein. Out of necessity, the distal catheter has been implanted back into the right atrium through.the left internal jugular vein under fluoroscopy guidance. The paper consist of course of treatment, data from the literature and own description of the implantation way of the catheter through the veins on the left side of the neck. PMID- 27116856 TI - Elaidic acid and vaccenic acid in the plasma of pregnant women and umbilical blood plasma. AB - INTRODUCTION: The studies suggest that trans fatty acids are the most harmful type of fatty acids, and their ingestion leads to an increase in oxidative stress, changes in the plasma levels of LDL cholesterol, and a reduction in n-6 and n-3 fatty acids utilization. The objective of this study was to determine the concentration profiles of elaidic and vaccenic acids in maternal blood plasma in the perinatal period, and in the plasma of blood collected from the umbilical vein. The article deals with the issue of the correlation between the levels of trans-unsaturated fatty acids in maternal and neonatal blood, which could suggest the transplacental transport of these acids. The potential correlations between the levels of trans-unsaturated fatty acids in maternal and umbilical blood and birth weight and body length in neonates was also verified. MATERIAL AND METHODS: The study group comprised 53 pregnant patients of the Clinic of Obstetrics and Perinatology of the Pomeranian Medical University in Szczecin, aged 18-39 years, together with their newborn babies. Elaidic and vaccenic acid levels were determined in maternal and umbilical plasma. Fatty acid methyl esters were injected onto the capillary column of the Agilent 6890M gas chromatography system integrated with an autosampler. The content of individual fatty acids was determined from the reference curves and expressed in mg/mL. RESULTS: The lowest levels of both acids were observed in umbilical blood plasma. The level of elaidic acid was 0.0019 mg/mL +/- 0.0013 mg/mL, while the level of vaccenic acid was 0.0007 mg/mL +/- 0.0011 mg/mL. A statistically significant negative correlation was observed between maternal vaccenic acid levels and umbilical vaccenic acid levels. CONCLUSIONS: The presence of trans-unsaturated fatty acids (elaidic acid and vaccenic acid) in umbilical plasma is evidence of the transplacental transport of these acids. The significantly higher levels of elaidic acid compared to vaccenic acid in umbilical plasma suggests that vaccenic acid is more extensively metabolized in placenta. The levels of trans-unsaturated fatty acids had no effect on birth weight and body length in neonates. PMID- 27116857 TI - [Trans fatty acids (elaidic and vaccenic) in the human milk]. AB - INTRODUCTION: The structure of trans unsaturated fatty acids (TFAs) includes at least one double bond with a trans configuration. Numerous studies have shown that TFAs influence negative changes in blood lipid profile, may initiate or accelerate the course of many inflammatory diseases, and reduce n-6 and n-3 fatty acids' utilization. Their presence in tissues and systemic fluids is mainly the result of ingestion of TFA-containing foods. The objective of this study was to determine the concentration profiles of elaidic and vaccenic acids in human milk, and the existence of potential correlations between the levels of trans unsaturated fatty acids and long chain polyunsaturated fatty acids. MATERIALS AND METHODS: The study group consisted of 53 lactating women, aged 18-39 years, 5-6 weeks after delivery. Elaidic and vaccenic acid levels were determined in human milk. Fatty acid methyl esters were injected onto the capillary column of an Agilent 6890M gas chromatography system integrated with an autosampler. Geometrical and positional isomers of fatty acids were identified by comparing their retention times with those of the fatty acid standards from Sigma-Aldrich. The content of individual fatty acids was determined from the reference curves and expressed in mg/mL. RESULTS: The level of elaidic acid was 0.2572 +/- 0.1811 mg/mL, and the level of vaccenic acid was 0.2736 +/- 0.1852 mg/mL. No negative correlations between the levels of the analyzed TFAs and PUFAs were observed in human milk. CONCLUSIONS: The levels of elaidic and vaccenic acid were similar and had no negative influence on the levels of arachidonic acid and docosahexaenoic acid. PMID- 27116858 TI - Interdisciplinary index of prosthodontic/substitution orthodontic treatment need for patients with missing teeth. AB - The need for treatment in cases of missing teeth may result from aesthetic demands or functional impairment, although tooth loss itself does not necessarily constitute a need for prosthetic replacement. In selected cases, restorative treatment can be replaced by tooth autotransplantation or substitution orthodontic treatment. The authors have tried to make an index based not on missing particular teeth, but on the presence of spacing requiring restoration. An attempt has been made to categorize the restorative treatment need. Orthodontic treatment was considered, when it could completely eliminate the need for prosthetic treatment. The proposed classification could be used for assessing eligibility for public refund of restorative or substitution orthodontic treatment, as well as to motivate the patients to have restorations. It should be an individual approach-based decision, which treatment: orthodontic substitution tooth movement or prosthodontic is more cost-effective for the rest of the patient's life. PMID- 27116859 TI - [Remineralizing methods in early caries lesions - review of the literature]. AB - Early diagnosis and treatment of early caries lesions are the basic tenets of minimally invasive dentistry. One of the key elements of a biological approach is the usage of remineralizing agents, which are great alternative to surgical intervention. This article shows a review of the literature concering materials used for the treatment of early caries lesions. PMID- 27116860 TI - [Comparison of root canal system disinfection effectiveness with and without rubber dam use]. AB - INTRODUCTION: Endodontic treatment consists in necrotic pulp removal, proper root canal preparation, and sealed obliteration. The effectiveness of treatment depends on careful root canal disinfection of existing bacteria. Modern endodontics recommends the use of a rubber dam, not only to protect the patient from endodontic instrument aspiration, but also to protect root canals from bacteria existing in saliva. The aim of the study is a comparison of root canal disinfection among patients treated with and without rubber dam protection. MATERIAL AND METHODS: Endodontic treatient of 36 patients who came to the Department of Conservative Dentistry and Endodontics was performed. 36 teeth were qualified to the treatment. In 17 patients the whole treatment was done with rubber dam protection. In the other 19 (II group) the treated tooth was isolated only by cotton rolls. After chamber trepanation, and after chemo-mechanical root canal preparation, samples of root canal bacteria were taken. After 24h incubation, the density of bacterial suspension was checked using a spectrophotometer. RESULTS: In both groups of patients very similar results were obtained: a high density of bacterial suspension in samples taken before treatment, and a significantly lower density in samples taken after chemo mechanical root canal preparation. CONCLUSIONS: In our research the use or lack of use of a rubber dam does not change the effectiveness of root canal disinfection. PMID- 27116861 TI - [Spectrophotometric determination of protein content in THP-1 monocytes/macrophages - description of the method]. AB - Proteins are the basic building block of tissue, and are part of enzymes and hormones regulating many important life processes. Changes in their concentration control the metabolic processes of the cell. Quantitative determination of the protein content is divided into indirect methods (e.g. Kjeldahl method) and direct methods (buret method, Lowry, immunoenzymatic, formol method, based on incorporation of dye in the range of ultraviolet spectrophotometry, and based on the phenomenon of selective absorption of radiation in the infrared range). One of the methods for the determination of protein content is the spectrophotometric method described by Bradford. The protein concentration assay procedure utilizes the phenomenon of formation of the dye (Coomassie Brillant Blue G-250)-protein and colour intensity is proportional to the protein content in the solution. The aim of this study was to verify the usefulness of this method for determining the protein content in THP-1 cells cultured with extracts of nettle fruit stalks (Urtica dioica L.). Aqueous and alcohol extracts at two concentrations were used. It has been shown that the spectrophotometric determination of protein content by the Bradford method is an effective and accurate method for determining the concentration of protein in THP-1 macrophages. The results indicate that this method can be recommended for the determination of the protein content in other cell cultures. PMID- 27116862 TI - [Slow retinal degeneration in a mouse model: morphological and functional aspects]. AB - INTRODUCTION: Diseases causing sensory impairments are a major clinical and sociological problem, especially those that cause loss of vision, which can significantly decrease the quality of a patient's life. It is therefore necessary to comprehend the mechanisms of the disease and find a treatment which can eliminate its cause. To achieve it, researchers use genetically modified animals for examination, as models of human diseases. MATERIAL AND METHODS: In this paper, two animal models of slow retinal degeneration are compared to assess changes in their retinas - mice, homozygous for the PRPH2 gene, and heterozygotes which were obtained by crossing with BALB/c. The degeneration rate was determined by measuring the thickness of particular retinal layers at specific time points. The Flat Mount technique was used to evaluate pigment epithelium deteriora- tion, while electroretinography was used monthly to estimate electrophysiological changes of the retinal photoreceptors in dark and light adaptation. RESULTS: It was found that the most severe and rapid deterioration was present in homozygotes. It caused a total loss of photoreceptor outer and inner segments, outer nuclear layer and outer plexiform layer. ERG revealed absolute suppression of retinal electrophysiology from the 1st month. Heterozygous mice were less impaired and degeneration progressed more gradually. None of the layers were completely destroyed. Electroretinography revealed progressive loss of retinal activity for the duration of the experiment. In the group of mice manifesting homozygous mutation in the PRPH2 gene, the RPE65 protein expression was abnormal. The cells of these mice were characterized by a lack of cytoplasm continuity and the presence of numerous vacuoles, which may indicate degenerative changes in the pigment epithelium. There were no significant differences in RPE65 protein expression between the control and heterozygous individuals. This may indicate correct cell morphology. CONCLUSIONS: Each of the tested mouse models of retinal degeneration may find its application in the study of this disease. The differences between them allow the selection of the optimal model for a particular experiment. PMID- 27116863 TI - The content of linoleic and alpha-linolenic acid in different types of Yerba Mate, depending on country of origin and the conditions of the infusion. AB - INTRODUCTION: Yerba Mate (Ilexparaguariensis) is one of the most widely consumed teas in South America. It is becoming more and more popular in North America and Europe. The aim of the study was a qualitative and quantitative analysis of the fatty acids from the omega 6 and omega 3 families in Yerba Mate teas. METHODS: There were two types of infusions - cold and hot (three brews from the same leaves). Yerba Mate was incu bated for 10 min, then 2 mL of the brew was taken for isola tion. Fatty acids were extracted by the Folch method. The resulting fatty acid methyl esters were analyzed using gas chromatography. RESULTS: The analysis of fatty acids in the infusions of Yerba Mate showed a significant amount of linoleic acid (LA) and alpha linolenic acids (ALA). The concentrations of these acids present in fresh infusions were approx. 250 ug/mL for infusion of LA, and 600 ug/mL infusion for ALA. With the subsequent brew using the same leaves the amount of fatty acids decreased significantly (p < 0.01). CONCLUSIONS: Drinking Yerba Mate can supply ALA and LA, which are essential in a well-balanced diet. For individuals who regularly consume Yerba Mate, it can be an important source of polyunsaturated fatty acids (PUFA) supplementation. The most preferred way to brew the tea is cold infusion, which delivers the highest dose of unchanged PUFAs. This method of brewing also reduces the gastrointestinal exposure to high temperature, and thus reduces the risk of cancer incidence. PMID- 27116864 TI - [Early age at menarche - relationship with socioeconomic status and selected factors connected with health status]. AB - INTRODUCTION: Current research from around the world indicates a trend toward younger ages at the first menstruation. At the same time more and more studies point out the negative consequences of early puberty. Early age at menarche is significantly correlated with the risk of metabolic syndrome, breast cancer and female reproductive system cancer, as well as illnesses such asthma and bulimia. The aim of the study was to examine the relationship between age at menarche and socioeconomic status and selected factors connected with biological conditions. MATERIAL AND METHODS: The data were obtained from 671 female university students. Height, weight, waist and hip circumference were measured, and BMI, WHR, WHtR were calculated. A questionnaire form was used to assess the age at menarche, biological conditions and socioeconomic status of the surveyed students. RESULTS: There were no significant differences in the number of the early, average and late maturing students between the socioeconomic groups. The early maturing girls were characterized by higher values of waist circumference, BMI, WHR and WHtR. The prevalence of obesity and abdominal obesity was highest among the early maturing girls. The analysis did not show statistically significant relationships between age at menarche and selected factors connected with biological conditions. CONCLUSION: Early maturation increases the risk of obesity and central adiposity distribution. PMID- 27116865 TI - [Selected bacterial infections - unavoidable threats to the health and lives of the man]. AB - In the present study we wanted to show that bacterial infections are an important factor threatening both the health and life of humans. This problem concerns the global population, both in developed and developing countries, and is often the cause of a significant proportion of deaths due to the negative impact of exo- and endotoxins on the host. Numerous infectious diseases caused by biological factors are undoubtedly associated with various risk factors. Despite the continuous development of medicine and countless actions spreading knowledge about bacterial gastrointestinal infections and sepsis, these conditions are still not marginal in the everyday hospital environment. Particular attention in this work was put on hospital infections because they are a major public health concern. Although a significant increase in awareness of the problem has been observed in Poland in recent years, this is still an important problem for medicine, and is also an economic issue. In addition, bacteria and their toxins can be used as a biological weapon for terrorist attacks. PMID- 27116866 TI - [Demodex folliculorum and demodex brevis]. AB - Demodex are cosmopolitan mites occurring in many species of mammals. Two morphologically distinct Demodex species parasitize on humans: Demodexfolliculorum (Simon, 1842) and Demodex brevis (Akbulatova, 1963). Until recently, these species have been regarded as commensals; now they are considered as parasitic organisms. In people, Demodex spp. can be found mainly in the sebaceous glands of the skin (mainly in the area of the forehead, cheeks, nose, behind ears and neck), in hearing aids, and on the scalp, covered with hair. Infection with demodex happens through direct contact with infected bed linen, towels, creams and other cosmetics. Despite the high prevalence of Demodex spp. in the human population, symptoms of demodecosis are not common, and can be found mainly in people with weakened immune systems due to aging or a number of diseases. PMID- 27116867 TI - [The influence of kinesiotaping on lumbar spine pain]. AB - INTRODUCTION: Pain in the lumbosacral spine is currently one of the most common pain complaints among the elderly. About 72% of the Polish population younger than 40 years have at least once been treated by a doctor for back pain. Degenerative changes of intervertebral joints, overloads, intervertebral disc diseases, and dysfunction of spinal ligaments are very often responsible for the formation of back pain, which is basically a problem of the elderly, MATERIAL AND METHODS: The study was conducted among 60 residents of a Nursing Home in Szczecin with chronic lumbar pain. The age range was 56-85 years. Subjects were randomly divided into two groups of 30 (study group, where KinesioTaping was used, and a control group without KinesioTaping application). To assess the degree of pain experienced by the patient a visual analogue scale (VAS) in the horizontal format from 0-10 was used, on which subjects scored the severity of pain. Flexion, extension, tilt and rotation were measured with a tape to assess spinal and trunk mobility. RESULTS: In all patients, who had a KinesioTaping patch applied on the lumbosacral spine pain measured by VAS reduced (p <= 0.001). Considering respondents' sex, the spine mobility in the tilting position improved in men in the study group in terms of tilting to both sides. In all patients, the application of a KinesioTaping patch significantly improved the rotation to the right side (p <= 0.05), scores in the "finger-floor" flexion test (p <= 0.01), and the extension range (p <= 0.01). CONCLUSION: KinesioTaping is a beneficial method reducing pain and improving the mobility in the lumbosacral spine. The improvement was independent of the sex of the respondents. PMID- 27116868 TI - [Food hypersensitivity in the population of school children in Opole]. AB - INTRODUCTION: The prevalence of food allergy among children is high and constantly increasing, especially in urban environments. The aim of the study was to assess the prevalence of food hypersensitivity among children living in Opole. MATERIAL AND METHODS: The study included 450 children (224 girls and 216 boys), aged 7-10 years from elementary schools in Opole. A survey was conducted on the basis of the EuroPrevall international programme questionnaire and a self designed questionnaire for collecting information. Data were analyzed with the Statistica 8 software package. The level of significance for all analyses was p < 0.05. RESULTS: The questionnaire was completed by the parents of 440 (98%) children. 89% (n = 392) of the parents agreed to being contacted again. Adverse reactions following food consumption were reported in 205 children (46.05%), including 93 children (45.36%) with two to four reactions a month. The most common symptoms were as follows: rash (28.29%), diarrhoea (26.34%). The symptoms occurred after the consumption of cow's milk (35.12%), hen eggs (12.19%), strawberries (8.78%), dairy products (5.36%), nuts (5.36%), chocolate (4.87%), and cocoa (4.87%). CONCLUSION: The study revealed a high reporting of food hypersensitivity among children in Opole. PMID- 27116869 TI - [Not Available]. PMID- 27116870 TI - [Not Available]. PMID- 27116871 TI - [Early social isolation increases aggression and impairs a short-term habituation in acoustic startle reflex in rats]. AB - Prolonged social isolation in early ontogeny leads to various changes in behavior and cognitive dysfunction in adult rats; however, data on the disorders are contradictory. In the present work, we studied the effects of early social isolation in Wistar rats by indices of psychomotor activity, aggression, anxiety, depression-like behavior, sensorimotor reactivity and short-term habituation of acoustic startle reflex. On the 24th postnatal day, rats were weaned from the dams and housed in individual cages for nine consecutive weeks. Animal behavior was evaluated at the age of one, two and three months. Immediately after weaning from the dam rats in the experimental group did not differ from the control on any of the indices. After four weeks of social isolation, rats showed an increased aggression in the social contact test. In rats isolated for an 8-weeks period, the increase in active non-aggressive contacts with a slight increase in motor activity in the elevated plus maze (E PM) accompanied increased aggression. At any terms of examination, isolated rats did not differ from the control in the anxiety in EPM, in the anxiety-phobic score, which is evaluated in a battery of tests, and in the duration of immobility which characterizes depression in the forced swimming test. Rats isolated for an 8-weeks period increased daily liquid intake by increasing the consumption of sucrose. After nine weeks of isolation, basal startle amplitude and prepulse inhibition that is, the characteristics of sensorimotor gating did not differ from the control, but there was a lack of short-term habituation of the acoustic startle reflex. Based on the data obtained, Wistar rats subjected to prolonged social isolation can be seen as a model of increased aggression with signs of cognitive deficits by indices of non associative learning in the acoustic startle reflex. PMID- 27116872 TI - [Antiarrhythmic effect of oligonucleotides accompanied by activation of HSP70 protein in the heart of rats]. AB - The mechanisms of the protective effect of oligonucleotides (OGN) during pathological processes are poorlyunderstood. The goal of this work was to study the effect of OGN on arrhythmias induced by myocardial ischemia and reperfusion, and the HSP70 level in the heart. As a source of OGN was used the drug "Derinat" ("Technomedservis", Russia). In male Wistar rats were pre-treated the drug for 7 days (i/m, 7.5 mg/kg).The intensity of the arrhythmias was assessed by ECG during 10 min occlusion of the left coronary artery and subsequent 5 min of reperfusion. Protein HSP70 determined in the left ventricle of the heart by Western-blot analysis. During ischemia, this drug reduced duration of extrasystolia by 13 times and the incidence of ventricular tachycardia by 1.5 times. During reperfusion the drug reduced the incidence of ventricular fibrillation, a more than 2-fold, as compared with the control (respectively 23% vs 56%) and by 5 times its duration (8,4 +/- 2,3 48,1 +/- sec vs 18 7 sec). "Derinat" increased the HSP70 level in the heart by 65% compared with control. CONCLUSION: These data support the fact that the activation of HSP70 synthesis, induced by OGN is one of the mechanisms that increases the heart resistance to the ischemic and reperfusion damages. PMID- 27116873 TI - [The role of erythrocyte microvesiculation and hemoglobin glycation in hemorheological disordes during burn injury]. AB - INTRODUCTION: Hemorheological disorders play an important part in pathogenesis of acute period of burn injury. This mechanism remains practically unstudied. Thus, unknown is the role of hemoglobin glycation and erythrocyte microvesiculation in the decrease in erythrocyte deformability after thermal trauma. METHODS: Research was performed on 30 blood samples of burn patients in the acute period and 40 blood samples of healthy donors. The number of erythrocyte-derived microvesicles was determined by flow cytometry and then standardized in the samples; the microvesicles were preliminarily separated by ultracentrifugation at 100,000 g, for 60 minutes. Electrophoretic mobility of erythrocytes was measured in a processing chamber of the optical cuvette under the light microscope. Deformability of erythrocytes was assessed by the level of their extension in the artificial shear flow. RESULTS: It was found that the amount of HbA1c in red blood cells of burn patients demonstrated a 2-fold increase compared to healthy donors. In the experiments in vitro it was proved that deformability of erythrocytes correlates with the level of hemoglobin glycation. Hb glycation leads to the increased rigidity of erythrocytes also by increasing their microvesiculation. The number of microvesicles derived from red blood cells of burn patients demonstrated a 3.47-fold increase compared to healthy donors. An important reason for microvesiculation is the destabilization of lipid complex of erythrocyte membrane, which is accompanied by the increase in the erythrocyte negative charge. It can be concluded that Hb glycation and redistribution of erythrocyte membrane phospholipids are he important reasons for the increase erythrocyte microvesiculation and are accompanied by the decrease in erythrocyte deformability after thermal trauma. PMID- 27116874 TI - [The role of opioidergic and GABAergic systems in the mechanosensitivity regulation of the respiratory system in rats]. AB - In anaesthetized white outbred male rats we investigated the change of respiratory mechanoreceptors sensitivity to morphine and phenibut. Bilateral transection of the vagus nerves causes a severely slowdown of respiratory rate in 30 minutes after the systemic administration of morphine, however after administration of phenibut the respiratory rate and other respiration parameters have not changed significantly. It means that the activation of opioid receptors by morphine does not significantly affect the function of the respiratory mechanoreceptor control loop, and transection of the vagus nerves on this background increases the probability of respiratory rhythm disorders. Activation of GABAergic system by phenibut significantly weakened the impact of the regulating contour of the respiratory mechanoreceptor on breathing parameters, up to effect of "central vagotomy": that is, to no changes in respiratory parameters after cutting the vagus nerves. PMID- 27116875 TI - [New phytotherapeutic composition for restoring bone and cartilage. Experimental study]. AB - Presents a new import-substituting the composition of the powder mixture 60 medicinal plants and dead bees. In prednisolonbuy models of osteoporosis have shown dose-dependent regenerative effects bone and cartilage of the hip joints of mice. Unwanted side effects when taking composition was observed. It is assumed the possibility of effective application of the composition as a complementary treatment for osteoporosis. PMID- 27116876 TI - [Peripheral blood cells luminol-dependent chemiluminescence at the different stages of atopic dermatitis]. AB - Aim of this work was to record the luminol-dependent spontaneous and induced chemiluminescence at the different stages of atopic dermatitis. METHODS: Peripheral blood cells were obtained from adult patient with atopic dermatitis followed by the registration of luminol-dependent chemiluminescence on luminograph. Opsonized zymosan as well as yeasts Candida tropicalis have been used to induce the chemiluminescence. RESULTS: Spontaneous and induced chemiluminescence were slightly elevated at the mild atopic dermatitis but were decreased at the severe stage of disease. Statistically significant difference has been found between group with mild and severe atopic dermatitis, Skin contamination by yeasts Candida tropicalis causes the increased level of blood cells chemiluminescence at the first week of atopic relapse when the disease was mild. Severe stage of atopic dermatitis was coupled with statistically significant inhibition of both, spontaneous and induced chemiluminescence. CONCLUSIONS: Luminol-dependent chemiluminescence of peripheral blood cells from adult atopic dermatitis patients may be stimulated at the mild stage and suppressed at severe stage of atopic dermatitis. PMID- 27116877 TI - [Alteration of white rats brain tissue inducted by assessment of silver nanocomposite incapsulated in polymer matrix]. AB - The paper present experimental materials of intragastric administration of silver nanoparticles encapsulated in polymer matrix of arabinogalactan by white outbred male rats. Animals were injected "pure" arabinogalactan and colloid silver solution containing silver macroform separately for comparison. Research provided data about status of brain tissue at the impact of these substances on organism. Histological analysis revealed the presence of a pathological process, character and intensity of which varied depending on the type of injected material. Pathological process under the influence of silver-arabinogalactan characterized by appearance in brain tissue of perivascular edema and development of acute inflammation in formation of glial scars, swelling of vascular bundles in sum. PMID- 27116878 TI - [Vascular reactivity and receptor expression of endogenous vasoconstrictor in rats with alcoholic cardiomyopathy and insulation stress]. AB - On the model of alcohol cardiomyopathy studied the effect of chronic ethanol consumption and the insulation stress on the reactivity of isolated rat aorta and the expression of the endogenous vasoconstrictor receptors in the aorta. Pushing alcoholization outbred rats was carried out for 24-28 weeks, using as the sole source of liquid 10% ethanol solution. In assessing the results of the study took into account the age of the animals. It is found that the reactivity of isolated aortic rings dissected from the body of old (40-45 weeks) nonstressed rats in response to endothelin-1 (ET1), noradrenaline (NA), arginine vasopressin (AVP) or angiotensin II (ATII) is not different from such reactivity for young animals. However, with the increase in life expectancy increases the sensitivity of vessels to vasoconstrictor action of serotonin (5HT). Prolonged stress insulation and the consumption of high doses of ethanol the stress lead to increased ET1- and NA-induced contraction of the aortic rings and a significant decrease in contractile response of the aorta to the impact ATII and AVP. Stress and alco- hol in combination with stress causing reduction mRNA ETA-R, AT1A-R. and V1A-R and increased mRNA alpha1-AR in rat aorta. It is found that in the vessels of stressed and alcoholized animals reduced level of expression of cytosolic glucocorticoid receptors (GR), which is a transcription factor for genes ETA-R, AT1A-R V1A-R. It is propoused that the development of vascular hyporesponsiveness of stressed and alcoholized rats to action ATII and AVP is the result of reducing the expression of their receptors on the GR-dependent mechanism. It is shown that under the influence of ethanol vessels become hyporeactivity selectively with respect to the action of 5HT. The mechanism of this process is unclear. Importantly, the changes in the contractile properties vessels recovered from the rat at 1 month after the abolition of the reception of ethanol (step abstinence) were similar to changes found at the alcohohzed animals. Thus, the importance of breaking the neuroendocrine regulation of vascular tone during long-term consumption of ethanol has a stressor components. Furthermore, in this experimental model we not received data in favor ethanol direct impact on the development of hypertension. PMID- 27116879 TI - [Zinc homeostasis and indicators of muscle activity in experimental graduated exercise on the background of zinc asparaginate]. AB - The influence of a regular (for 7 and 14 days) 10-minute dosed exercise in isolation and on the background of intragastric administration of 5 and 15 mg/kg of zinc (II) asparaginate on the distribution of this metal in the organs and tissues of experimental animals and the indicators of muscle activity such as the level of lactate, creatinine and creatine kinase (EC 2.7.3.2.) serum were studied. It has been shown that exercise stress for 14 days causes a more pronounced change in homeostasis Zn, compared with 7 day, it is reflected in increased levels in the kidney, serum, liver, skeletal muscle and fur animals. It has been shown that graduated exercise for 14 days causes a more pronounced change in Zn homeostasis, compared with 7 day that expressed in increased its levels in the kidney, serum, liver, skeletal muscle and fur animals. Introduction zinc (II) asparaginate accompanied by an increase of its content in the liver, kidneys, hair and serum, but not skeletal and cardiac muscle. The combination of physical activity and the introduction of zinc positive effect on homeostasis of Zn, and the terms of muscle activity. The protective effect of zinc asparaginate with graduated exercise in the experiment was concluded. PMID- 27116880 TI - [Polymorphism of genes of interleukin-1 family as factor of pathogenesis of nozokomialny pneumonia]. AB - Despite the abundance of research devoted to nosocomial pneumonia, so far there are no clear diagnostic criteria for it and predict the outcome of nosocomial pneumonia is based on the individual clinical, instrumental, laboratory and other parameters that are not related to each other as links in a single pathogenesis. External factors contributing to the development of the pneumonia and determine its prognosis, adequately lit, and the problem lies in the fact that no comprehensive clinical and pathophysiological approach to assessing the outcome of nosocomial pneumonia considering its immunogenetic features. One aspect of learning is nosocomial pneumonia appraisal of immune system, in particular, -- cytokines that have both diagnostic and prognostic value. As is known, the level of immune reactivity of the organism is fixed genetically, therefore, determines the importance polymorphisms of genes coding for the expression of cytokines as key participants in the intercellular interactions. In the present article we found that one of the factors immunopathogenesis of nosocomial pneumonia is a gene polymorphism IL-1beta (-511) C-->T and IL-1RN. Genetic markers of risk of its development is the carrier of the allele C of gene IL-1beta (-511) C->T. The severity and clinical features of the pneumonia associated with the presence of the genotype of the patients T allele of the gene IL-1beta (-511) C-->T. Implementation of the pathogenetic action of this polymorphism is carried out due to overproduction of the cytokine IL-1beta. Exposure to nosocomial pneumonia associated with haplotypes IL-1RN * 4-IL-1beta (-511) C-->T gene of the same name cytokines having polar biological effects. PMID- 27116881 TI - [Effect of adaptation to hypoxia on expression of NO synthase isoforms in rat myocardium]. AB - Previously we have shown that adaptation to hypoxia (AH) is cardio- and vasoprotective in myocardial ischemic and reperfusion injury and this protection is associated with restriction of nitrosative stress. The present study was focused on further elucidation of NO-dependent mechanisms of AH by identifying specific NO synthases (NOS) that could play the major role in AH protection. AH was performed in a normobaric hypoxic chamber by breathing hypoxic gas mixture (9.5-10% O2) for 5-10 min with intervening 4 min normoxia (5-8 cycles daily for 21 days). Expression of neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) protein was measured in the left ventricular myocardium using Western blot analysis with respective antibodies. AH educed iNOS protein expression by 71% (p < 0.05) whereas eNOS protein expression tended to be reduced by 41% compared to control (p < 0.05). nNOS protein expression remained unchanged after AH. Selective iNOS inhibition can mimic the AH-induced protection. Therefore protective effects of AH could be at least partially due to restriction of iNOS and, probably, eNOS expression. PMID- 27116882 TI - [Microwave emission from water in bioanalytical systems]. AB - Mechanical stimulation of aqueous protein solution was found to be accompanied by electromagnetic radiation in the superhigh frequency range. This radiation was observed at solution temperatures near the phase transitions of water. This effect may occur in various bioanalytical systems, associated with injection of aqueous solutions in these systems, and may have impact on the results of bioalytical measurements. The discovered effect of generation of nonequilibrium microwave emission of water medium (which is the main component of the organism) in the 38-39 degrees C temperature range, i.e. in the range of elevated temperature of the organism (which accompanies pathological condition in humans upon inflammatory diseases, i.e., infactious etc.) may be used for development of new non-invasive methods of disease diagnostics. PMID- 27116883 TI - [The influence of extreme factors on homing multipotent mesenchymal stromal cells]. AB - In this study, we studied homing multipotent mesenchymal stromal cells under influence of extreme factors: after radiation exposure, acute blood loss. Absorbed dose ionizing radiation amounted to 4.0 C (causes acute radiation sickness in mice), acute blood loss was caused by bleeding from the tail vein of the mouse in the amount of 2% of the body weight of the animal. Label MMSC used fluorochrome DAPI, ready to use. The experiments were performed on 60 Mature mice (males) age 6-8 months, weighing 20-25 g. Experiments on the culture of multipotent mesenchymal stromal cells from the placenta (chorion) performed on laboratory mice female at the age of 3-4 months in the gestation period of 14 days. Introduction suspensions of MMSC was carried out at a dose of 6 million cells/mouse, suspended in 0.2 ml 0.9% NaCl solution. The control group of laboratory animals MMSC transplantation was carried out also in the amount of 6 million cells/mouse. The assessment was made of tissue chimerism in the peripheral blood, bone marrow, spleen, small intestine, liver, lung, kidney, heart after 1 and 24 hours after transplantation of labeled cells. It was found a significant decrease in the content of labeled MMSC in the peripheral blood at extreme impact, indicating a migration of the transplanted cells in the damaged tissue. Homing transplanted MMSC is realized mainly in those tissues that underwent the most damage. PMID- 27116884 TI - [Emotional stress as a clinical model to study the pathogenesis of the initial phase of the general adaptation syndrome]. AB - INTRODUCTION: General adaptation syndrome (GAS), the basis of the development of which is stress phenomenon, is an essential component of the pathogenesis of many diseases and syndromes. However, the patho genesis of GAS hitherto is considered exclusively from the endocrinological viewpoint. This relates primarily to the initial phase of the GAS, a clinical model for the study of which may be psycho emotional stress (PES), which we studied using three groups of volunteers. METHODS: The first one consists of 25 students who were waiting for unaccustomed physical activity (17 men) and play debut on the stage (8 women). The second group consists of 48 children (2-14 years) who expected for "planned" surgery. The third group of volunteers is made up of 80 students (41 women and 39 men) during the first exam. The concentration of cortisol, endotoxin (ET), the activity of antiendotoxin immunity (AEI) and the haemostatic system parameters were determined in the blood serum of volunteers in various combinations. RESULTS: We found laboratory evidence for PES at 92% of students of the first group, 58% of children of the second one and in 21% of students of the third group of volunteers (mostly women). The concentration of ET increased at 13 (52%) volunteers of the first group with a significant increase of average indicators in the whole group (from 0.84 +/- 0.06 to 1.19 +/- 0.04 EU/ml). At children of the second group, the average concentration of ET increased even more significantly (from 0.42 +/- 0.02 to 1.63 +/- 0.11 EU/ml), which was accompanied by the activation of the hemostasis system. A degree of the activation was directly dependent on the level of ET in the general circulation and on an activity of AEI. Examination stress in the third group of volunteers is accompanied by activation of plasma hemostasis (increased initial thrombosis rate and reduced the time it starts, lag-period) in 26% of female students and 15% of male students. CONCLUSION: We suggest that it is possible to use the PES as a clinical model for studying the initial phase of the GAS, examine the role of excess of intestinal ET in the general blood circulation (endotoxin aggression) in the induction of systemic inflammation, which is very likely participated in the initiation of the GAS. PMID- 27116885 TI - [Hypoxia as functional base of metabolic processes changes in erythrocytes and hepatocytes of rats after prolonged Simvastatin (Zokor) intake]. AB - Concentration of glycolysis metabolites, activity of enzymes of carbohydrate and energetic metabolism and antioxidant enzymes was investigated in hepatocytes and erythrocytes with the purpose of estimation of functional metabolic changes of cells rebuilding after prolonged Simvastatin intake (Zocor, 20 mg; on 1.5 mg once a day during 3 months). It was established that total metabolic reaction on prolonged Simvastatin intake at intact animals characterized by hypoxia formation, that manifested by increasing of 2.3-BPG concentration in erythrocytes, lactate accumulation in erythrocytes and hepatocytes. Different side changes of glutathione-dependent enzymes activity, activation of first line of antioxidant defense enzymes testify about tense defense mechanisms of erythrocytes and hepatocytes. Biochemical changes in blood plasma shows tendency to cytolysis syndrome formation and affection of biosynthetic liver function. Decreasing of ceruloplasmin concentration can be used as additional biochemical test in estimation of the state of liver affection at prolonged Simvastatin intake. PMID- 27116886 TI - [Adaptation to physical load and the state of the autonomic nervous system in young women with low blood pressure]. AB - OBJECTIVE: The purpose of research--the study of the relationship between adaptation of the cardiovascular system to physical activity and the autonomic newous system in young women with low blood pressure. METHODS: Evaluated test Ruffier index Kerdo women-university students aged 18-35 years, engaged in physical culture within the educational process. Compare the 69 women with low blood pressure (SBP 61-99 mmHg) and 35 women with normal blood pressure (SBP 120 129 mmHg). Index Ruffier groups did not differ in average and adequate "good result". In the group of women with low blood pressure showed a reduction in fitness (Ruffier-index of 10 or higher) when sympathetic activation. Reduced recorded in 14.5% (10 cases), which is significantly more than the parasympathetic activation--0 cases when p = 0.003. Analysis of the dynamics of SBP, DBP and heart rate during the Ruffier test showed that low blood pressure after 1 minute rest in SBP and DBP were higher than baseline. CONCLUSIONS: According to the test Ruffier in young women with low blood pressure and sympathicotonia in 14.5% of cases there is a lack of adaptation to physical stress. When low blood pressure with vagotonia --only good and average adaptation to physical stress. Screening test of physical activity in young women with low blood pressure are not quickens the pulse, but leads to a slight increase in SBP and DBP. PMID- 27116887 TI - [Pathogenetic mechanisms of phantom-pain syndrome]. AB - This review considers the literature data on the epidemiology of phantom-pain syndrome (PPS) presents the results of numerous clinical studies demonstrating the lack of effectiveness of the vast majority of modem non-pharmacological and pharmacological methods of treatment of PPS. Detail presents data on the patho genetic mechanisms underlying the PPS. According to most researchers, the major role in the patho genesis of the PPS has the reorganization of the somatosensory area of the cerebral cortex of the brain. At the same time discusses the views of researchers who believe that the main reason PPS is to strengthen nociceptive and nonnociceptive afferentation in the peripheral newous system. The comparison of these conflicting data it is concluded that in the genesis of the PPS plays the role of both primary and secondary sensitization. Leading important dysfunction of the central nervous system. Details the modern understanding of the mechanisms underlying the high efficiency of suppression of PPS during stimulation of motor cortex. PMID- 27116888 TI - [Age-related changes of the brain]. AB - The first morphological signs of aging of the brain are found in the white matter already at a young age (20-40 years), and later (40-50 years) in a gray matter. After the 40-50 years appear and in subsequently are becoming more pronounced functional manifestations of morphological changes: the weakening of sensory motor and cognitive abilities. While in principle this dynamic of age-related changes is inevitable, the rate of their development to a large extent determined by the genetic characteristics and lifestyle of the individual. According to modem concepts age-related changes in the number of nerve cells are different in different parts of the brain. However, these changes are not large and are not the main cause of senile decline brain. The main processes that contribute to the degradation of the brain develop as in the bodies of neurons and in neuropil. In the bodies of neurons--it is a damage (usually decrease) of the level of expression of many genes, and especially of the genes determining cell communication. In neuropil: reduction in the number of synapses and the strength of synaptic connections, reduction in the number of dendritic spines and axonal buttons, reduction in the number and thickness of the dendritic branches, demyelination of axons. As the result of these events, it becomes a violation of the rate of formation and rebuilding neuronal circuits. It is deplete associative ability, brain plasticity, and memory. PMID- 27116889 TI - A HISTORY OF MEDICAL RESIDENCY. PMID- 27116890 TI - IN THE NAME OF THE CHILD. PMID- 27116892 TI - Growing our knowledge about head circumference. PMID- 27116891 TI - Differentiation-Dependent Energy Production and Metabolite Utilization: A Comparative Study on Neural Stem Cells, Neurons, and Astrocytes. AB - While it is evident that the metabolic machinery of stem cells should be fairly different from that of differentiated neurons, the basic energy production pathways in neural stem cells (NSCs) or in neurons are far from clear. Using the model of in vitro neuron production by NE-4C NSCs, this study focused on the metabolic changes taking place during the in vitro neuronal differentiation. O2 consumption, H(+) production, and metabolic responses to single metabolites were measured in cultures of NSCs and in their neuronal derivatives, as well as in primary neuronal and astroglial cultures. In metabolite-free solutions, NSCs consumed little O2 and displayed a higher level of mitochondrial proton leak than neurons. In stem cells, glycolysis was the main source of energy for the survival of a 2.5-h period of metabolite deprivation. In contrast, stem cell-derived or primary neurons sustained a high-level oxidative phosphorylation during metabolite deprivation, indicating the consumption of own cellular material for energy production. The stem cells increased O2 consumption and mitochondrial ATP production in response to single metabolites (with the exception of glucose), showing rapid adaptation of the metabolic machinery to the available resources. In contrast, single metabolites did not increase the O2 consumption of neurons or astrocytes. In "starving" neurons, neither lactate nor pyruvate was utilized for mitochondrial ATP production. Gene expression studies also suggested that aerobic glycolysis and rapid metabolic adaptation characterize the NE-4C NSCs, while autophagy and alternative glucose utilization play important roles in the metabolism of stem cell-derived neurons. PMID- 27116893 TI - Barriers to improve neonatal care in Mexico. PMID- 27116894 TI - Canadian Nutrition Society: Scientific Abstracts from the 7th Annual Scientific Meeting / Societe canadienne de nutrition : Resumes scientifiques de la 7(e) reunion scientifique annuelle. PMID- 27116895 TI - Characteristics, diagnosis and therapeutic strategies for IgG4-related orbital disease. AB - Thanks to detailed studies conducted in recent years, a new disease syndrome was identified in 2001. It is known as a IgG4-related disease and its differentiation is based on the analysis of IgG4 levels in the affected tissues. The IgG4-related disease is considered to be a generalized pathological process involving a wide spectrum of various disorders that may affect distant organs. Orbital IgG4 related disease is a recently reported issue that may prove important for the elucidation of the etiology of idiopathic, lymphoplasmacytic or fibrotic disorders of various organs, including the orbits. In this article, we are describing epidemiology and differential diagnostics of IgG4-related orbital disease with particular focus on pseudotumors, MALT lymphomas and lymphocyte/plasma cell infiltrations of the orbit. We are also discussing therapeutic possibilities currently available in the management of the disease. PMID- 27116896 TI - Engraftment syndrome manifesting as acute brachial neuropathy following high-dose chemotherapy for management of plasma cell myeloma. PMID- 27116897 TI - Absence of a stable atomic structure in fluorinated graphene. AB - Based on the results of first-principles calculations we demonstrate that significant distortion of graphene sheets caused by adsorption of fluorine atoms leads to the formation of metastable patterns for which the next step of fluorination is considerably less energetically favorable. Existence of these stable patterns oriented along the armchair direction makes possible the synthesis of various CFx structures. The combination of strong distortion of the nonfluorinated graphene sheet with the doping caused by the polar nature of C-F bonds reduces the energy cost of migration and the energy of migration barriers, making possible the migration of fluorine atoms on the graphene surface as well as transformation of the shapes of fluorinated areas. The decreasing energy cost of migration with increasing fluorine content also leads to increasing numbers of single fluorine adatoms, which could be the source of magnetic moments. PMID- 27116898 TI - Emerging site-specific bioconjugation strategies for radioimmunotracer development. AB - INTRODUCTION: Radioimmunotracers are a promising class of companion diagnostics for precision medicine. They are composed of an antibody-based targeting agent and a radiolabeled imaging probe. Together with the tendency towards the use of small antibody-derived fragments, the employed conjugation method is gaining increasing attention. Conventional bioconjugation methods result in heterogeneous tracer populations of which the single elements can differ in immunoreactivity, pharmacokinetic behavior and stability. Site-specific conjugation strategies try to overcome these shortcomings and facilitate radioimmunotracer delivery, characterization and manufacturing. AREAS COVERED: An overview is provided of site-specific conjugation strategies for use in radioimmunotracer development. Currently applied strategies are discussed, together with other emerging site specific conjugation methods that are applicable to diabodies, single-chain variable fragments (scFvs) and camelid single-domain antibody-fragments (sdAbs or nanobodies). EXPERT OPINION: The ultimate goal of site-specific bioconjugation strategies is to allow precise control over the conjugation site, to result in homogenous tracer populations, and to be versatile in use with different imaging probes. Chemoenzymatic methods appear to be promising in this respect. PMID- 27116899 TI - Clinical Impact of the Cardio-Ankle Vascular Index for Predicting Cardiovascular Events After Acute Coronary Syndrome. AB - BACKGROUND: We hypothesized the cardio-ankle vascular stiffness index (CAVI) could predict future cardiovascular events. METHODS AND RESULTS: We enrolled 288 consecutive patients with acute coronary syndrome (ACS) who underwent CAVI measurement soon after the onset of ACS. Exclusion criteria were as follows: unable to detect significant stenosis by coronary angiography, severe aortic insufficiency, peripheral artery disease, atrial fibrillation (AF), informed consent was not given. We divided the patients into 2 groups according to the cutoff value of CAVI determined by receiver-operating characteristics curve for the prediction of cardiovascular events: low CAVI group, 135 patients with CAVI <=8.325; high CAVI group, 153 patients with CAVI >8.325. Patients were followed up for a median period of 15 months. The primary and secondary endpoints were the incidence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke), and nonfatal ischemic stroke. Of the 288 patients, cardiovascular events occurred in 19 patients (6.6%). The Kaplan Meier estimate of the event-free rate revealed cardiovascular events occurred more frequently in the high CAVI group than in the low CAVI group (log-rank, P<0.001). Multiple adjusted Cox proportional hazards analysis, including age, indicated the high CAVI group was an independent predictor of cardiovascular events (hazard ratio [HR] 18.00, P=0.005), and nonfatal ischemic stroke (HR 9.371, P=0.034). CONCLUSIONS: High CAVI is an independent predictor of cardiovascular events and nonfatal ischemic stroke in patients with ACS. (Circ J 2016; 80: 1420-1426). PMID- 27116900 TI - Dynamic endophenotypes and longitudinal trajectories: capturing changing aspects of development in early psychosis. PMID- 27116902 TI - Breakthrough symptoms after switching long-acting injectable paliperidone palmitate from the gluteal to the deltoid site of administration. PMID- 27116903 TI - Effectiveness of clinical alternatives to nerve conduction studies for screening for diabetic distal symmetrical polyneuropathy: A multi-center study. AB - AIM: This study explored the possibility of developing an alternative, simple and rapid test for the screening of distal symmetrical polyneuropathy (DSPN), for use in local primary care facilities. METHODS: 4023 patients with type 2 diabetes mellitus (T2DM), aged 18-80 years, from 21 hospitals in China were screened for inclusion in a prospective diagnostic assessment of DSPN, between April 2011 and March 2012. Patients underwent nerve conduction study (NCS; as the gold standard) and clinical assessments of ankle reflexes (AR) and thermal (T), vibration (V), pressure (P), and pinprick (PP) sensations. RESULTS: Results from various combinations of these clinical assessments were compared to determine the optimal screening regimens. The Toronto Consensus Panel definition was used to confirm clinical DSPN (symptoms or signs plus abnormal NCS). 3883 of the 4023 patients (M:F, 2162:1721; mean age, 56.79+/-13.16 years) were included. No significant differences were found between the two most efficient clinical assessment combinations, AR+PP+T+V and AR+T+V (P=0.9612). Compared to the diagnosis made using AR+T+V, the same diagnosis was reached using AR+PP+P+V+T in 100% of patients with probable clinical DSPN, 84.05% with possible clinical DSPN, and 96.84% with no DSPN. The AR+T+V assessment was also ~40% faster than the AR+PP+P+V+T assessment. CONCLUSIONS: Combined AR+T+V assessment is a valuable tool for screening diabetic patients for DSPN, potentially decreasing costs to local primary care facilities and making care more available to underserved populations. PMID- 27116904 TI - Outcomes of Women Treated for Popliteal Artery Aneurysms. AB - BACKGROUND: Popliteal artery aneurysms (PAAs) in women are rare and their outcomes compared with men with PAA are unknown. The purpose of this study was to compare the surgical outcomes of PAA of women with men. METHODS: All patients who underwent PAA repair at a single institution from 1985 to 2013 were reviewed. All women with degenerative PAA treated during that time frame were matched on year of repair to men. Presentation, mode of repair, and outcomes were reviewed. Survival and amputation-free survival were evaluated by life table analysis. RESULTS: During the study interval, 8 women with degenerative PAA underwent surgical treatment (1.6% of 485 total PAA repairs). The overall median follow-up was 5 years (range 1 month to 19 years), but the median follow-up was shorter for women than men (1.6 vs. 6 years, P = 0.04). At the time of repair, women were of similar age compared with men (73.5 vs. 71.7 years) and had similar aneurysm size (2.7 vs. 2.9 cm). Women had similar urgency (25 vs. 17.5% emergent) and symptomatic status (50% vs. 55% acute) even though 7 of the 8 women had a thrombosed PAA at the time of repair. Operative time, approach, graft type, and inflow and outflow sources were similar between genders. No women received endovascular repair (0% vs. 10%, P = 0.5). One patient of each gender underwent major amputation (one woman on post-operative day 158 and one man on post operative day 3). Overall, women had lower survival and amputation-free survival at 2 years (51% vs. 100% and 20% vs. 94%, P < 0.01 for both, standard error 0.2). CONCLUSIONS: PAA requiring intervention in women is a rare clinical occurrence. Although our series is limited, women requiring PAA repair had higher long-term mortality compared with men with a similar pathology and treatment strategy. PMID- 27116905 TI - A Novel Anesthetic Technique for PEVAR. AB - BACKGROUND: Percutaneous endovascular aneurysm repair (PEVAR) continues to evolve. Device profiles continue to decline, further reducing the physiological insult of the procedure. Anesthesia, however, has not evolved with a large proportion of patients continuing to receive general anesthesia for their increasingly less invasive procedures. We report on a novel anesthetic technique providing outstanding anesthesia in patients undergoing PEVAR in an outpatient setting. The total anesthesia used was remarkably cost effective. METHODS: Six patients underwent PEVAR in an outpatient setting. The patients received moderate intravenous (IV) access sedation using versed and fentanyl in combination with bilateral ilioinguinal nerve blocks. Patients received 25 mL bilaterally of 0.5% bupivicaine with epinephrine. All patients were American Society of Anesthesiologists class III. None received central venous access, arterial, or urinary catheters. Standard noninvasive monitoring was used. A board-certified anesthesiologist was present at all times during the procedures. RESULTS: All patients underwent successful repair. Average cost per case for anesthetic supplies averaged around $7.00. The fentanyl dose ranged from 100 to 200 MUg with an average dose of 130 MUg. Versed dose ranged from 2 to 3 mg with an average dose of 2.4 mg. No patient required conversion to general anesthesia. Postoperative pain relief was excellent. Two patients required pain medication before discharge. Two patients required oral narcotic analgesic the night of discharge. No patients required narcotics after that time. CONCLUSIONS: Bilateral ilioinguinal nerve block, when combined with moderate IV sedation allows outstanding anesthesia for patients undergoing PEVAR. This novel combination has not been reported previously. The technique provides safe, effective, care for of a subset of patients not requiring general anesthesia. It offers a greatly reduced cost when compared with general anesthesia. Additional benefits include prolonged pain relief perioperatively as well as potentially decreasing the physiologic and cognitive effects seen with general anesthesia. PMID- 27116906 TI - Anatomic Variation of Rami Communicantes in the Upper Thoracic Sympathetic Chain: A Human Cadaveric Study. AB - BACKGROUND: Hyperhidrosis is secondary to over activation of the sympathetic nervous system and surgical sympathectomy is the treatment of choice when other modalities have failed. This study investigated anatomic variation in the upper thoracic sympathetic chain and associated rami communicantes among cadaveric specimens. It considers the implications of these findings on surgical techniques to treat hyperhidrosis. METHODS: The upper 4 thoracic sympathetic ganglia, intercostal nerves, and connecting rami were dissected, measured and mapped in 40 sides of 20 adult human cadavers. Ganglia location was recorded. The incidence, orientation, and distance travelled by rami communicantes was compared across different ganglionic levels and between sides. RESULTS: The percentage of ganglia located below their associated intercostal space was 6.25% with stellate ganglions present in 70% of specimens and Kuntz fibers noted in 40%. There was a stepwise reduction in incidence of rami from superior to inferior placed ganglia. The number of rami identified across all levels was significantly greater on the right (P = 0.03). The horizontal distance between the sympathetic chain and union of the rami on the intercostal nerves was significantly greater on the right across all levels (P = 0.04). CONCLUSIONS: There was substantial variation in the rami communicantes across the upper 4 ganglia and between right and left sides. Consideration of this variation should be given when planning surgical sympathectomy for hyperhidrosis particularly to avoid symptom recurrence. PMID- 27116907 TI - Three-Dimensional Modeling Analysis of Visceral Arteries and Kidneys during Respiration. AB - BACKGROUND: Visceral arteries are commonly involved in endovascular repair of complex abdominal aortic aneurysms (AAAs). To improve repair techniques and reduce long-term complications involving visceral arteries, it is crucial to understand in vivo arterial geometry and the deformations due to visceral organ movement with respiration. This study quantifies deformation of the celiac, superior mesenteric (SMA), and renal arteries during respiration and correlates the deformations with diaphragmatic excursion. METHODS: Sixteen patients with small AAAs underwent magnetic resonance angiography during inspiratory and expiratory breathholds. From geometric models of the aorta and visceral arteries, vessel length, branch angle, curvature, and positions were computed, along with degree of diaphragmatic excursion as indicated by kidney translation. RESULTS: From inspiration to expiration, the celiac artery exhibited axial shortening of 4.8 +/- 6.4% (P < 0.001) and a mean curvature increase of 0.03 +/- 0.02 mm(-1), greater than other visceral arteries (P < 0.01). With expiration, the SMA, left and right renal arteries (LRA and RRA) angled upward by -9.8 +/- 6.4 degrees , 6.4 +/- 6.4 degrees , and -5.2 +/- 5.0 degrees , respectively (P < 0.005). All vessels translated superiorly (P < 0.0005) and posteriorly (P < 0.01), and the SMA translated rightward additionally (P < 0.005). The left and right kidneys translated by 22 +/- 9 mm and 21 +/- 9 mm, mostly superiorly (P < 0.001). Translations of all visceral arteries were moderately correlated to the right kidney (R > 0.50). Correlation of the LRA with the left kidney was greater than that of the RRA with the right kidney. CONCLUSIONS: The celiac artery exhibited less branch angle change, and greater axial and curvature deformations than the other visceral arteries, due to the vicinity to the liver and influence of the median arcuate ligament. Correlation between visceral arteries and kidney translations revealed that diaphragmatic excursion affects vessel mobility. Weaker correlation of the RRA to the right kidney indicates mechanical shielding from the inferior vena cava. PMID- 27116908 TI - Impaired sperm quality, delayed mating but no costs for offspring fitness in crickets winning a fight. AB - The outcome of male-male contest competition is known to affect male mating success and is believed to confer fitness benefits to females through preference for dominant males. However, by mating with contest winners, females can incur significant costs spanning from decreased fecundity to negative effects on offspring. Hence, identifying costs and benefits of male dominance on female fitness is crucial to unravel the potential for a conflict of interests between the sexes. Here, we investigated males' pre- and post-copulatory reproductive investment and its effect on female fitness after a single contest a using the field cricket Gryllus bimaculatus. We allowed males to fight and immediately measured their mating behaviour, sperm quality and offspring viability. We found that males experiencing a fight, independently of the outcome, delayed matings, but their courtship effort was not affected. However, winners produced sperm of lower quality (viability) compared to losers and to males that did not experience fighting. Results suggest a trade-off in resource allocation between pre- and post-mating episodes of sexual selection. Despite lower ejaculate quality, we found no fitness costs (fecundity and viability of offspring) for females mated to winners. Overall, our findings highlight the importance of considering fighting ability when assessing male reproductive success, as winners may be impaired in their competitiveness at a post-mating level. PMID- 27116909 TI - Quantitative Measure of Receptor Agonist and Modulator Equi-Response and Equi Occupancy Selectivity. AB - G protein-coupled receptors (GPCRs) are an important class of drug targets. Quantitative analysis by global curve fitting of properly designed dose-dependent GPCR agonism and allosterism data permits the determination of all affinity and efficacy parameters based on a general operational model. We report here a quantitative and panoramic measure of receptor agonist and modulator equi response and equi-occupancy selectivity calculated from these parameters. The selectivity values help to differentiate not only one agonist or modulator from another, but on-target from off-target receptor or functional pathway as well. Furthermore, in conjunction with target site free drug concentrations and endogenous agonist tones, the allosterism parameters and selectivity values may be used to predict in vivo efficacy and safety margins. PMID- 27116910 TI - Evaluation of lorcaserin on progression of prediabetes to type 2 diabetes and reversion to euglycemia. AB - OBJECTIVES: Lorcaserin is a selective 5-HT2C (5-hydroxytryptamine 2C) receptor agonist indicated for weight management. Here, we assess the impact of lorcaserin on progression from prediabetes to type 2 diabetes (T2D) and on reversion from prediabetes to euglycemia. METHODS: This is a post hoc analysis of pooled data from two Phase 3 studies, BLOOM and BLOSSOM (N = 6136), evaluating the impact of lorcaserin on weight and glycemic parameters over 52 weeks in the subpopulation of obese/overweight subjects with prediabetes, alternately defined by fasting plasma glucose (FPG) 100-125 mg/dl or glycated hemoglobin (HbA1c) 5.7-6.4% at baseline. RESULTS: At Week 52, in the subpopulation with prediabetes, nearly twice as many lorcaserin-treated subjects achieved >=5% weight loss versus placebo (HbA1c: 55.6% vs. 27.5%, p < 0.001; FPG: 52.8% vs. 28.8%, p < 0.001), and a significantly lower percentage of lorcaserin-treated subjects progressed to T2D versus placebo based on HbA1c (lorcaserin 3.2%, placebo 5.0%, p = 0.032) but not FPG (lorcaserin 1.6%, placebo 2.6%, p = 0.227). A significantly greater proportion of lorcaserin-treated subjects versus placebo also reverted to euglycemia based on both HbA1c (lorcaserin 40%, placebo 29.5%, p < 0.001) and FPG (lorcaserin 52.4%, placebo 46.5%, p = 0.047). CONCLUSION: In subjects with prediabetes, lorcaserin may contribute to weight loss and improve glycemic parameters, and thus may help with preventing progression to T2D and promoting reversion to euglycemia. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are NCT00395135 (BLOOM) and NCT00603902 (BLOSSOM). PMID- 27116911 TI - Diagnostic value of soluble triggering receptor expressed on myeloid cells in paediatric sepsis: a systematic review. AB - BACKGROUND: Differential diagnosis between sepsis and non-infectious inflammatory disorders demands improved biomarkers. Soluble Triggering Receptor Expression on Myeloid cells (sTREM-1) is an activating receptor whose role has been studied throughout the last decade. We performed a systematic review to evaluate the accuracy of plasma sTREM-1 levels in the diagnosis of sepsis in children with Systemic Inflammatory Response Syndrome (SIRS). METHODS: A literature search of PubMed, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and ISI Web of Knowledge databases was performed using specific search terms. Studies were included if they assessed the diagnostic accuracy of plasma sTREM-1 for sepsis in paediatric patients with SIRS. Data on sensitivity, specificity, positive predictive value, negative predictive value, area under receiver operating characteristic curve were extracted. The methodological quality of each study was assessed using a checklist based on the Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: Nine studies comprising 961 patients were included, four of which were in newborns, three in children and two in children with febrile neutropenia. Some data from single studies support a role of sTREM-1 as a diagnostic tool in pediatric sepsis, but cannot be considered conclusive, because a quantitative synthesis was not possible, due to heterogeneity in studies design. CONCLUSIONS: This systematic review suggests that available data are insufficient to support a role for sTREM in the diagnosis and follow-up of paediatric sepsis. PMID- 27116912 TI - Commentary on 'Cost-effectiveness of Screening for Abdominal Aortic Aneurysm in Combination with Medical Intervention in Patients with Small Aneurysms'. PMID- 27116913 TI - Acibenzolar-S-methyl may prevent vector-mediated flavescence doree phytoplasma transmission, but is ineffective in inducing recovery of infected grapevines. AB - BACKGROUND: Acibenzolar-S-methyl (BTH), a functional analogue of salicylic acid (SA), is known to elicit a systemic resistance across a broad range of plant pathogen interactions, but so far it has not been tested against flavescence doree (FDP), one of the most devastating grapevine diseases. The aim of this work was to evaluate the activity of BTH in preventing FDP transmission by the insect vector and in inducing recovery of infected grapevines. RESULTS: Repeated 2 mM applications of BTH to test grapevine cuttings (cv. Barbera) exposed to adults of the infectious vector Scaphoideus titanus Ball reduced the rate of infected plants. The effect was not recorded following similar BTH applications to highly susceptible young in vitro propagated vines. A high natural recovery rate (more than 70%) was observed over a 3 year period in field-infected grapevines of the same cultivar. Under these conditions, BTH repeated applications over the whole period clearly failed to increase recovery of field-infected grapevines. CONCLUSION: Following a 3 year experiment, it can be concluded that, although high doses and repeated applications of BTH reduced vector transmission of FDP, BTH was ineffective in inducing recovery of FDP-infected grapevines cv. Barbera under field conditions. (c) 2016 Society of Chemical Industry. PMID- 27116914 TI - Sulfurovum riftiae sp. nov., a mesophilic, thiosulfate-oxidizing, nitrate reducing chemolithoautotrophic epsilonproteobacterium isolated from the tube of the deep-sea hydrothermal vent polychaete Riftia pachyptila. AB - An anaerobic, nitrate-reducing, sulfur- and thiosulfate-oxidizing bacterium, designated strain 1812ET, was isolated from the vent polychaete Riftia pachyptila, which was collected from a deep-sea hydrothermal vent on the East Pacific Rise. Cells were Gram-stain-negative rods, measuring approximately 1.05+/ 0.11 um by 0.40+/-0.05 um. Strain 1812ET grew at 25 - -45 degrees C (optimum 35 degrees C), with 1.5-4.0 % (w/v) NaCl (optimum 3.0 %) and at pH 5.0-8.0 (optimum pH 6.0). The generation time under optimal conditions was 3 h. Strain 1812ET was an anaerobic chemolithotroph that grew with either sulfur or thiosulfate as the energy source and carbon dioxide as the sole carbon source. Nitrate was used as a sole terminal electron acceptor. The predominant fatty acids were C16 : 1omega7c, C18 : 1omega7c and C16 : 0. The major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The major respiratory quinone was menaquinone MK-6 and the G+C content of the genomic DNA was 47.4 mol%. Phylogenetic analysis of the 16S rRNA gene of strain 1812ET showed that the isolate belonged to the Epsilonproteobacteria, and its closest relatives were Sulfurovum lithotrophicum 42BKTT and Sulfurovum aggregans Monchim 33T (98.3 and 95.7 % sequence similarity, respectively). DNA-DNA relatedness between strain 1812ET and the type strain of S. lithotrophicum was 29.7 %, demonstrating that the two strains are not members of the same species. Based on the phylogenetic, molecular, chemotaxonomic and physiological evidence, strain 1812ET represents a novel species within the genus Sulfurovum, for which the name Sulfurovum riftiae sp. nov. is proposed. The type strain is 1812ET (=DSM 101780T=JCM 30810T). PMID- 27116915 TI - To what extent do site-based training, mentoring, and operational research improve district health system management and leadership in low- and middle income countries: a systematic review protocol. AB - BACKGROUND: District health managers play a key role in the effectiveness of decentralized health systems in low- and middle-income countries. Inadequate management and leadership skills often hamper their ability to improve quality of care and effectiveness of health service delivery. Nevertheless, significant investments have been made in capacity-building programmes based on site-based training, mentoring, and operational research. This systematic review aims to review the effectiveness of site-based training, mentoring, and operational research (or action research) on the improvement of district health system management and leadership. Our secondary objectives are to assess whether variations in composition or intensity of the intervention influence its effectiveness and to identify enabling and constraining contexts and underlying mechanisms. METHODS: We will search the following databases: MEDLINE, PsycInfo, Cochrane Library, CRD database (DARE), Cochrane Effective Practice and Organisation of Care (EPOC) group, ISI Web of Science, Health Evidence.org, PDQ Evidence, ERIC, EMBASE, and TRIP. Complementary search will be performed (hand searching journals and citation and reference tracking). Studies that meet the following PICO (Population, Intervention, Comparison, Outcome) criteria will be included: P: professionals working at district health management level; I: site based training with or without mentoring, or operational research; C: normal institutional arrangements; and O: district health management functions. We will include cluster randomized controlled trials, controlled before-and-after studies, interrupted time series analysis, quasi-experimental designs, and cohort and longitudinal studies. Qualitative research will be included to contextualize findings and identify barriers and facilitators. Primary outcomes that will be reported are district health management and leadership functions. We will assess risk of bias with the Cochrane Collaboration's tools for randomized controlled trials (RCT) and non RCT studies and Critical Appraisal Skills Programme checklists for qualitative studies. We will assess strength of recommendations with the GRADE tool for quantitative studies, and the CERQual approach for qualitative studies. Synthesis of quantitative studies will be performed through meta-analysis when appropriate. Best fit framework synthesis will be used to synthesize qualitative studies. DISCUSSION: This protocol paper describes a systematic review assessing the effectiveness of site-based training (with or without mentoring programmes or operational research) on the improvement of district health system management and leadership. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015032351. PMID- 27116916 TI - Metabolic responses of Beauveria bassiana to hydrogen peroxide-induced oxidative stress using an LC-MS-based metabolomics approach. AB - The entomopathogenic fungus, Beauveria bassiana, is commonly used as a biological agent for pest control. Environmental and biological factors expose the fungus to oxidative stress; as a result, B. bassiana has adopted a number of anti-oxidant mechanisms. In this study, we investigated metabolites of B. bassiana that are formed in response to oxidative stress from hydrogen peroxide (H2O2) by using a liquid chromatography mass spectrometry (LC-MS) approach. Partial least-squares discriminant analysis (PLS-DA) revealed differences between the control and the H2O2-treated groups. Hierarchical cluster analysis (HCA) showed 18 up-regulated metabolites and 25 down-regulated metabolites in the H2O2-treated fungus. Pathway analysis indicated that B. bassiana may be able to alleviate oxidative stress by enhancing lipid catabolism and glycometabolism, thus decreasing membrane polarity and preventing polar H2O2 or ROS from permeating into fungal cells and protecting cells against oxidative injury. Meanwhile, most of the unsaturated fatty acids that are derived from glycerophospholipids hydrolysis can convert into oxylipins through autoxidation, which can prevent the reactive oxygen of H2O2 from attacking important macromolecules of the fungus. Results showed also that H2O2 treatment can enhance mycotoxins production which implies that oxidative stress may be able to increase the virulence of the fungus. In comparison to the control group, citric acid and UDP-N-acetylglucosamine were down-regulated, which suggested that metabolic flux was occurring to the TCA cycle and enhancing carbohydrate metabolism. The findings from this study will contribute to the understanding of how the molecular mechanisms of fungus respond to environmental and biological stress factors as well as how the manipulation of such metabolisms may lead to selection of more effective fungal strains for pest control. PMID- 27116917 TI - Food insufficiency and food insecurity as risk factors for physical disability among Palestinian refugees in Lebanon: Evidence from an observational study. AB - BACKGROUND: Potential interactions between malnutrition and disability are increasingly recognized, and both are important global health issues. Causal effects working from nutrition to disability and from disability back to nutrition present an empirical challenge to measuring either of these effects. However, disability affects nutrition whatever the cause of disability, whereas nutrition is likelier to affect disease-related disability than war- or work related disability. OBJECTIVE: This paper investigates the association of food insufficiency with the risk of physical disability. Data on disability by cause allow us to address the difficulty of reverse causality. METHODS: Multinomial logit regressions of disability by cause on food insufficiency are run using survey data from 2010 on 2575 Palestinian refugee households in Lebanon. Controls include household sociodemographic, health and economic characteristics. Regressions of food insufficiency on disability by cause are also run. RESULTS: Disability has a significant coefficient in regressions of food insufficiency, whatever the cause of disability; but in regressions of disability on food insufficiency, food insufficiency is significant only for disease-related disability (log odds of disease-related disability .78 higher, p = .008). The difference in the results by cause of disability is evidence of a significant association between food insufficiency and disease-related disability, net of any reverse effect from disability to food access. CONCLUSIONS: The association between disease-related disability and food insufficiency is statistically significant suggesting that even taking into account feedback from disability to nutrition, nutrition is an effective level of intervention to avert the poverty disability trap resulting from the impoverishing effect of disability. PMID- 27116918 TI - Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. AB - BACKGROUND: Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. METHODS: We did a randomised, double-blind, triple dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. FINDINGS: 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1.3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2.2%) of 989 in the bupropion group, 25 (2.5%) of 1006 in the nicotine patch group, and 24 (2.4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1.28 (95% CI -2.40 to 0.15) and -0.08 (-1.37 to 1.21), respectively; the RDs for comparisons with nicotine patch were -1.07 (-2.21 to 0.08) and 0.13 (-1.19 to 1.45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6.5%) of 1026 participants in the varenicline group, 68 (6.7%) of 1017 in the bupropion group, 53 (5.2%) of 1016 in the nicotine patch group, and 50 (4.9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1.59 (95% CI -0.42 to 3.59) and 1.78 (-0.24 to 3.81), respectively; the RDs versus nicotine patch were 1.22 (-0.81 to 3.25) and 1.42 ( 0.63 to 3.46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3.61, 95% CI 3.07 to 4.24), nicotine patch (1.68, 1.46 to 1.93), and bupropion (1.75, 1.52 to 2.01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2.07 [1.75 to 2.45] and 2.15 [1.82 to 2.54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. INTERPRETATION: The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. FUNDING: Pfizer and GlaxoSmithKline. PMID- 27116919 TI - Safety of smoking cessation drugs for mentally ill patients. PMID- 27116920 TI - Avalanche Survival After Rescue With the RECCO Rescue System: A Case Report. AB - We report a case of survival of a completely buried avalanche victim after being located with the radar-based RECCO Rescue System. In the winter of 2015, 2 off piste skiers were completely buried in an avalanche near the secured ski area in Baqueira Beret, Spain. The first victim was located with the RECCO Rescue System in less than 35 minutes and was alive and conscious at extrication. This system emits radio waves and requires a specific reflector. It is a portable device that is used by more than 600 rescue organizations worldwide, especially in secured ski areas. The device should be brought to the avalanche site together with electronic avalanche transceivers, a probing team, and avalanche dogs. In the hands of experienced professionals, the device may allow rapid location of victims not carrying an electronic avalanche transceiver. Although it is not the first successful extrication of a victim with the RECCO Rescue System, it is the first case published in the medical literature and is intended to encourage data collection and to increase our understanding of the effectiveness of this device in avalanche rescue. PMID- 27116921 TI - Sildenafil and Exercise Capacity in the Elderly at Moderate Altitude. AB - OBJECTIVE: Hypobaric hypoxia decreases exercise capacity and causes hypoxic pulmonary vasoconstriction and pulmonary hypertension. The phosphodiesterase-5 inhibitor sildenafil is a pulmonary vasodilator that may improve exercise capacity at altitude. We aimed to determine whether sildenafil improves exercise capacity, measured as maximal oxygen consumption (peak Vo2), at moderate altitude in adults 60 years or older. METHODS: The design was a randomized, double-blind, placebo-controlled, crossover study. After baseline cardiopulmonary exercise testing at 1400 m, 12 healthy participants (4 women) aged 60 years or older, who reside permanently at approximately 1400 m and are regularly active in self propelled mountain recreation above 2000 m, performed maximal cardiopulmonary cycle exercise tests in a hypobaric chamber at a simulated altitude of 2750 m after ingesting sildenafil and after ingesting a placebo. RESULTS: After placebo, mean peak Vo2 was significantly lower at 2750 m than 1400 m: 37.0 mL . kg(-1) . min(-1) (95% CI, 32.7 to 41.3) vs 39.1 mL . kg(-1) . min(-1) (95% CI, 33.5 to 44.7; P = .020). After placebo, there was no difference in heart rate (HR) or maximal workload at either altitude (z = 0.182; P = .668, respectively). There was no difference between sildenafil and placebo at 2750 m in peak Vo2 (P = .668), O2 pulse (P = .476), cardiac index (P = .143), stroke volume index (z = 0.108), HR (z = 0.919), or maximal workload (P = .773). Transthoracic echocardiography immediately after peak exercise at 2750 m showed tricuspid annular plane systolic velocity was significantly higher after sildenafil than after placebo (P = .019), but showed no difference in tricuspid annular plane systolic excursion (P = .720). CONCLUSIONS: Sildenafil (50 mg) did not improve exercise capacity in adults 60 years or older at moderate altitude in our study. This might be explained by a "dosing effect" or insufficiently high altitude. PMID- 27116922 TI - Lightning Strike in Pregnancy With Fetal Injury. AB - Injuries from lightning strikes are an infrequent occurrence, and are only rarely noted to involve pregnant victims. Only 13 cases of lightning strike in pregnancy have been previously described in the medical literature, along with 7 additional cases discovered within news media reports. This case report presents a novel case of lightning-associated injury in a patient in the third trimester of pregnancy, resulting in fetal ischemic brain injury and long-term morbidity, and reviews the mechanics of lightning strikes along with common injury patterns of which emergency providers should be aware. PMID- 27116923 TI - Traumatic Amputation of Finger From an Alligator Snapping Turtle Bite. AB - Legend states that the alligator snapping turtle (Macrochelys temminckii) should be handled with extreme caution as it has jaw strength powerful enough to bite a wooden broomstick in half. Tales of bite injuries from what is the largest freshwater turtle in North America exist anecdotally, yet there are few descriptions of medical encounters for such. The risk of infection from reptilian bites to the hand in an aquatic environment warrants thorough antibiotic treatment in conjunction with hand surgery consultation. We present the first case report of a near total amputation of an index finger in an adolescent boy who had been bitten by a wild "gator snapper." PMID- 27116924 TI - Metacarpophalangeal joint stiffness. Still a challenge for the hand surgeon? AB - OBJECTIVES: The aim of this study is to analyse the outcomes of the surgical treatment of metacarpophalangeal stiffness by dorsal teno-arthrolysis in our centre, and present a review the literature. MATERIAL AND METHODS: This is a retrospective study of 21 cases of metacarpophalangeal stiffness treated surgically. Dorsal teno-arthrolysis was carried out on all patients. A rehabilitation programme was started ten days after surgery. An evaluation was performed on the aetiology, variation in pre- and post-operative active mobility, complications, DASH questionnaire, and a subjective satisfaction questionnaire. RESULTS: The mean age of the patients was 36.5 years and the mean follow-up was 6.5 years. Of the 21 cases, the most common cause was a metacarpal fracture (52.4%), followed by complex trauma of the forearm (19%). Improvement in active mobility was 30.5 degrees , despite obtaining an intra-operative mobility 0-90 degrees in 80% of cases. Mean DASH questionnaire score was 36.9 points. The outcome was described as excellent in 10% of our patients, good in 30%, poor in 40%, and bad in the remaining 20%. There was a complex regional pain syndrome in 9.5% of cases, and intrinsic muscle injury in 14.3%. CONCLUSION: Because of its difficult management and poor outcomes, surgical treatment of metacarpophalangeal stiffness in extension is highly complex, with dorsal teno-arthrolysis being a reproducible technique according to our results, and the results reported in the literature. PMID- 27116925 TI - Lordosis manoeuvre in the diagnosis of lumbar facet syndrome. AB - In lumbar pain patients an aetiopathogenic diagnosis leads to a better management. When there are alarm signs, they should be classified on an anatomical basis through anamnesis and physical examination. A significant group is of facet origin (lumbar facet syndrome [LFS]), but the precise clinical diagnosis remains cumbersome and time-consuming. In clinical practice it is observed that patients with an advanced degenerative disease do not perform extension or rotation of their lumbar spine when prompted to extend it, but rather knee flexion, making the manoeuvre meaningless. For this reason, a new simple and quick clinical test was developed for the diagnosis of lumbar facet syndrome, with a facet block-test as a confirmation. HYPOTHESIS: The new test is better than a classic one in the diagnosis of facet syndrome, and probably even better than imaging studies MATERIALS AND METHODS: A prospective study was conducted on a series of 68 patients (01/01/2012-30/06/2013). A comparison in between: classic manoeuvre (CM), imaging diagnostics (ID), and the new lordosis manoeuvre (LM) test. Examination and block test by one author, and evaluation of results by another one. EXCLUSION CRITERIA: Deformity and instability. using a physical. OBJECTIVE: To determine the effectiveness of a new clinical test (LM) for the diagnosis of LFS (as confirmed by a positive block-test of medial branch of dorsal ramus of the lumbar root, RMRDRL). STATISTICS: R package software. RESULTS: The LM was most effective (p<.0001; Kappa 0.524, p<.001). There was no correlation between either the CM or ID and the block-test results (Kappa, CM: 0.078; p=.487, and ID: 0.195; p=.105). There was a correlation between ID (CAT/MR) and LM (p=.024; Kappa 0.289 p=.014), although not with CM. There was no correlation between ID (plain X-rays) and CM or LM. CONCLUSIONS: A new test for diagnosis of LFS is presented that is reliable, quick, and simple. Clinical examination is more reliable than imaging test for the diagnosis of LFS. PMID- 27116926 TI - The rule of three. PMID- 27116928 TI - The Association Between Gait Characteristics and Ambulatory Physical Activity in Older People: A Cross-Sectional and Longitudinal Observational Study Using Generation 100 Data. AB - This study aimed to determine if temporal-spatial gait characteristics are associated with free-living ambulatory physical activity in relatively-healthy older people. A total of 630 women and 593 men had valid data from gait tests and activity monitoring. Gait speed alone was associated with daily step count. Gait speed along with cadence, walk ratio, step length, step time, and swing time were associated with measures of higher intensity activity and overall activity. Those who walked slower were less active. After controlling for gait speed, shorter step length, shorter step time, shorter swing time, and higher cadence were associated with less activity. This finding may be an indication of the functional consequences of a breakdown in the stride length-cadence relationship and/or compensations to increase stability. Asymmetry measures at preferred and fast walking speeds showed no association with physical activity levels. Gait speed was the only predictor of change in activity over the subsequent 12 months. PMID- 27116929 TI - Training needs assessment of health care professionals in a developing country: the example of Saint Lucia. AB - BACKGROUND: Continuing education (CE) is crucial for quality improvement in health care. The needs assessment of CE helps ensure effectiveness. However, such an assessment necessitates certain techniques that are unfamiliar to health care communities in developing countries. This study identifies the needs of providing CE to health care personnel in Saint Lucia. METHODS: This study was designed as a questionnaire survey to investigate the demographics, training needs, and preferred approaches to improve performance of the target population. The study population included the health care professionals of major public health care facilities in Saint Lucia. We used the World Health Organization-adopted Hennessy Hicks Training Needs Analysis Questionnaire, a self-reported close-ended structured questionnaire with a core set of 30 items. These items refer to tasks that are central to the role of health care professionals and are categorized into six superordinate categories: research/audit, communication/teamwork, clinical skills, administrative, managerial/supervisory, and continuing professional education. RESULTS: In total, 208 questionnaires were distributed; the response rate was 66.8%, and most respondents were nurses. The need for continuing professional education was rated the highest priority, followed by research/audit activities. The evidence suggests that most respondents required training in communication skills, management, clinical skills, and research methods. CONCLUSIONS: Providing training according to the needs is vital, particularly in developing countries. The present research methodology and findings offer perspectives on how to conduct needs assessment and offer reference points for developing countries whose background and health care environment are similar to those of Saint Lucia. PMID- 27116927 TI - VDAC2-specific cellular functions and the underlying structure. AB - Voltage Dependent Anion-selective Channel 2 (VDAC2) contributes to oxidative metabolism by sharing a role in solute transport across the outer mitochondrial membrane (OMM) with other isoforms of the VDAC family, VDAC1 and VDAC3. Recent studies revealed that VDAC2 also has a distinctive role in mediating sarcoplasmic reticulum to mitochondria local Ca(2+) transport at least in cardiomyocytes, which is unlikely to be explained simply by the expression level of VDAC2. Furthermore, a strictly isoform-dependent VDAC2 function was revealed in the mitochondrial import and OMM-permeabilizing function of pro-apoptotic Bcl-2 family proteins, primarily Bak in many cell types. In addition, emerging evidence indicates a variety of other isoform-specific engagements for VDAC2. Since VDAC isoforms display 75% sequence similarity, the distinctive structure underlying VDAC2-specific functions is an intriguing problem. In this paper we summarize studies of VDAC2 structure and functions, which suggest a fundamental and exclusive role for VDAC2 in health and disease. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID- 27116930 TI - Pre- and post-procedural quality indicators for colonoscopy: A nationwide survey. AB - BACKGROUND: The provision of high-quality colonoscopy can be assessed by evaluating technical aspects of the procedure and, at individual center level, by comparing structural indicators and institutional policies for managing peri procedural issues with guideline recommendations. AIM: To assess the colonoscopy quality (CQ) in Italy at center level. METHODS: Gastroenterologists participating in a nationwide colonoscopy education initiative provided information on structural indicators of their centers and on institutional policies by answering 10 multiple-choice clinical scenarios. Practice variation across centers and compliance with guidelines were analyzed. RESULTS: Data from 282 Italian centers were evaluated. Overall, a significant proportion of centers did not meet CQ standards as concerns endoscopy facilities and equipments (e.g., dedicated recovery room, dirty-to-clean path, reporting software). CQ assurance programs were implemented in only 25% of centers. Concerning peri-procedural issues, main discrepancies with guidelines were recorded in the underuse of split-dose preparation (routinely adopted by 18% of centers), the routine request of coagulation tests prior to colonoscopy (30%), the routine interruption of aspirin for polypectomy (18%), and the adoption of 3-year surveillance for low-risk adenoma (49%). CONCLUSIONS: Present survey shows a significant variation in the CQ of endoscopy centers in Italy on many items of colonoscopy practice that should be targeted for future interventions. PMID- 27116931 TI - A Multidisciplinary Evaluation of a Web-based eLearning Training Programme for SAFRON II (TROG 13.01): a Multicentre Randomised Study of Stereotactic Radiotherapy for Lung Metastases. AB - AIMS: In technically advanced multicentre clinical trials, participating centres can benefit from a credentialing programme before participating in the trial. Education of staff in participating centres is an important aspect of a successful clinical trial. In the multicentre study of fractionated versus single fraction stereotactic ablative body radiotherapy in lung oligometastases (TROG 13.01), knowledge transfer of stereotactic ablative body radiotherapy techniques to the local multidisciplinary team is intended as part of the credentialing process. In this study, a web-based learning platform was developed to provide education and training for the multidisciplinary trial teams at geographically distinct sites. MATERIALS AND METHODS: A web-based platform using eLearning software consisting of seven training modules was developed. These modules were based on extracranial stereotactic theory covering the following discrete modules: Clinical background; Planning technique and evaluation; Planning optimisation; Four-dimensional computed tomography simulation; Patient-specific quality assurance; Cone beam computed tomography and image guidance; Contouring organs at risk. Radiation oncologists, medical physicists and radiation therapists from hospitals in Australia and New Zealand were invited to participate in this study. Each discipline was enrolled into a subset of modules (core modules) and was evaluated before and after completing each module. The effectiveness of the eLearning training will be evaluated based on (i) knowledge retention after participation in the web-based training and (ii) confidence evaluation after participation in the training. Evaluation consisted of a knowledge test and confidence evaluation using a Likert scale. RESULTS: In total, 130 participants were enrolled into the eLearning programme: 81 radiation therapists (62.3%), 27 medical physicists (20.8%) and 22 radiation oncologists (16.9%). There was an average absolute improvement of 14% in test score (P < 0.001) after learning. This score improvement compared with initial testing was also observed in the long-term testing (>4 weeks) after completing the modules (P < 0.001). For most there was significant increase in confidence (P < 0.001) after completing all the modules. PMID- 27116932 TI - Long-term effects of cerebral hypoperfusion on neural density and function using misery perfusion animal model. AB - We investigated the chronic effects of cerebral hypoperfusion on neuronal density and functional hyperemia using our misery perfusion mouse model under unilateral common carotid artery occlusion (UCCAO). Neuronal density evaluated 28 days after UCCAO using [(11)C]flumazenil-PET and histology indicated no neurologic deficit in the hippocampus and neocortex. CBF response to sensory stimulation was assessed using laser-Doppler flowmetry. Percentage changes in CBF response of the ipsilateral hemisphere to UCCAO were 18.4 +/- 3.0%, 6.9 +/- 2.8%, 6.8 +/- 2.3% and 4.9 +/- 2.4% before, and 7, 14 and 28 days after UCCAO, respectively. Statistical significance was found at 7, 14 and 28 days after UCCAO (P < 0.01). Contrary to our previous finding (Tajima et al. 2014) showing recovered CBF response to hypercapnia on 28 days after UCCAO using the same model, functional hyperemia was sustained and became worse 28 days after UCCAO. PMID- 27116933 TI - Distinct genital tract HIV-specific antibody profiles associated with tenofovir gel. PMID- 27116934 TI - The effect of muscle endurance and fatigue on participation in adolescents with cerebral palsy. PMID- 27116936 TI - New amination strategies based on nitrogen-centered radical chemistry. AB - The interesting and diverse biological activities of nitrogen-containing compounds make the construction of the C-N bond of great importance. Despite the tremendous advances that have been made in this research field, C-N bond formation based on nitrogen-centered radicals remains a significant challenge due to the harsh conditions required for the generation of nitrogen-centered radicals and their propensity for hydrogen abstraction or engaging in other degradation pathways. In the past several years, novel methodologies for C-N bond constructions based on nitrogen centered-radical intermediates, coordinated with metal or generated in the presence of visible-light and a photocatalyst, have attracted considerable attention. This tutorial review will summarize the significant progress of these efficient and mild radical amination reactions, with an emphasis on approaches for the generation of nitrogen-centered radicals and their reaction patterns, related mechanisms and synthetic applications, as well as unmet challenges in this emerging and promising field. PMID- 27116935 TI - LIMK Regulates Tumor-Cell Invasion and Matrix Degradation Through Tyrosine Phosphorylation of MT1-MMP. AB - During their metastatic spread, cancer cells need to remodel the extracellular matrix in order to migrate through stromal compartments adjacent to the primary tumor. Dissemination of breast carcinoma cells is mediated by membrane type 1 matrix metalloproteinase (MT1-MMP/MMP14), the main invadopodial matrix degradative component. Here, we identify MT1-MMP as a novel interacting partner of dual-specificity LIM Kinase-1 and -2 (LIMK1/2), and provide several evidence for phosphorylation of tyrosine Y573 in the cytoplasmic domain of MT1-MMP by LIMK. Phosphorylation of Y573 influences association of F-actin binding protein cortactin to MT1-MMP-positive endosomes and invadopodia formation and matrix degradation. Moreover, we show that LIMK1 regulates cortactin association to MT1 MMP-positive endosomes, while LIMK2 controls invadopodia-associated cortactin. In turn, LIMK1 and LIMK2 are required for MT1-MMP-dependent matrix degradation and cell invasion in a three-dimensional type I collagen environment. This novel link between LIMK1/2 and MT1-MMP may have important consequences for therapeutic control of breast cancer cell invasion. PMID- 27116937 TI - Issues around childhood disclosure of HIV status - findings from a qualitative study in West Bengal, India. AB - INTRODUCTION: Informing the children living with HIV (CLH) about their disease (disclosure) is important from the perspective of disease treatment and overall psychosocial development. There are no published studies that qualitatively explored HIV disclosure-related issues among CLH in India. Our aim was to provide insights into the perceptions of informal caregivers of CLH regarding childhood disclosure. METHODS: Children were defined as those aged <16 years. In-depth interviews were conducted with 34 primary caregivers of CLH aged 8 to 15 years old who were residing in West Bengal, India. The participants were recruited with the help of a community-based organization that provides need-based services to people living with HIV. RESULTS: We obtained caregivers' perspectives on the motivators and barriers of childhood disclosure. Health benefits such as medication adherence emerged as an important motivator, while distress caused by disclosure and potential for stigma were identified as barriers. Health care providers were the preferred disclosers for most caregivers, followed by the caregivers themselves. Some caregivers wanted their child to learn about his/her HIV status by him/herself. There was no consensus among the caregivers about the ideal age for disclosure. Many preferred to wait until the child attained maturity or was of marriageable age. DISCUSSION: Disclosure of HIV status to children is an emotional issue, both for the caregiver and the child. Like most low-or middle-income countries, no standardized, age-appropriate disclosure guidelines exist in India. Our findings advocate adoption of a multi-faceted approach, including increased availability of social and familial support, for childhood HIV disclosure. PMID- 27116938 TI - Radiotherapy cannot prolong overall survival of young prostate cancer patients with bone metastases. AB - BACKGROUND: Patients with prostate cancer is commonly diagnosed with bone metastases. With the growing use of prostate-specific antigen testing, the frequency of prostate cancer has progressively increased in patients younger than 70 years. Radiotherapy is recognized for its effect on local control of bone metastases, but whether it could prolong overall survival is still controversial. METHODS: A total of 113 prostate cancer patients (<70y) with bone metastases were retrospectively analyzed. The Kaplan-Meier method was used for survival analysis with log-rank test. Multivariate analysis was performed to find the prognostic factors with the COX regression model. RESULTS: The 1-, 2-, 3-, 5-, 7- and 10 year survival rates were 97.14, 82.86, 62.61, 38.76, 25.83 and 13.84 % respectively in the radiotherapy group, and 92.75, 73.91, 54.66, 36.63, 26.03 and 17.85 % respectively in the non-radiotherapy group, which showed no significant difference. Multivariate COX regression showed the overall survival was associated with alkaline phosphatase when bone metastases occurred and the number of bone metastases. CONCLUSION: With the advances in life-prolonging treatment of metastatic prostate cancer, radiotherapy may not be the first choice for young bone metastatic prostate cancer patients in order to improve survival. PMID- 27116939 TI - Removal of methadone by extended dialysis using a high cut-off dialyzer: implications for the treatment of overdose and for pain management in patients undergoing light chain removal. AB - The synthetic opioid methadone hydrochloride has a low molecular weight of 346 D, a high volume of distribution (4 - 7 L/kg), and is lipophilic. It is used as an analgesic and for the maintenance treatment of opiate dependence. In drug addicts, methadone is frequently involved in mixed intoxications that can lead to death. Here we present the case of a drug addict in whom a high cut-off dialysis membrane together with extended dialysis was used in the setting of suspected overdose and acute kidney injury. Although the observed dialyzer plasma clearance (31.5 mL/min) and reduction ratio (38%) were higher than previously reported for standard hemodialysis, the total amount of methadone in the spent dialysate after 1 extended dialysis session was quite low. Hence, even extended dialysis with a high cut-off membrane does not seem to offer a clinically relevant benefit in the setting of overdose for enhanced methadone removal. On the other hand, in patients undergoing high cut-off dialysis for the removal of light chains, methadone could still be used as an analgesic without an additional dose after high cut-off hemodialysis. PMID- 27116940 TI - Radial versus femoral access for percutaneous coronary intervention in ST elevation myocardial infarction patients treated with fibrinolysis: Results from the randomized routine early invasive clinical trials. AB - BACKGROUND: To investigate the relationship between arterial access site choice (radial versus femoral) and clinical outcomes among STEMI patients undergoing routine PCI after fibrinolysis. METHODS: Patient-level data from trials of STEMI patients evaluating routine PCI after fibrinolysis were included. The primary endpoint was 30-day major bleeding; secondary endpoints included 30-day death and re-infarction. RESULTS: 1891 patients underwent PCI (trans-radial n=338, trans femoral n=1553). Trans-radial PCI patients were less likely to be >75years (2% vs. 8%, p=0.0001), heavier (median weight 82 [72-90] vs. 80 [70-90] kg, p=0.0013) and more likely in Killip class I at presentation (87% vs. 82%, p=0.03). At 30days, trans-radial PCI was associated with a similar unadjusted risk for major bleeding (3.7% vs. 1.2%, Odds Ratio [OR] 0.43 [95% CI 0.13-1.48], p=0.18), mortality (3.4% vs. 1.2%, OR 0.34 [0.09-1.28], p=0.11) and re-infarction (3.9% vs. 4.7%, OR 1.25 [0.60-2.58], p=0.56). In multivariable analysis, radial access was associated with similar estimates for bleeding and death/reinfarction risk. CONCLUSIONS: In STEMI patients treated with fibrinolysis and undergoing an early routine invasive strategy, radial compared to femoral PCI is chosen in younger, less ill patients and is independently associated with similar risk of bleeding, re-infarction, and mortality. SUMMARY: This study evaluated the relationship between arterial access choice (radial versus femoral) and in-hospital and 30-day outcomes in patients undergoing routine PCI after fibrinolysis for STEMI. We included patient-level data from trials evaluating a strategy of routine PCI after fibrinolysis for STEMI. Of 1891 patients undergoing PCI, trans-radial access (n=338) was chosen in younger, lower risk patients. At 30days, trans radial access was associated with a similar unadjusted and adjusted risk of major bleeding, re-infarction and mortality. PMID- 27116941 TI - Approaches towards molecular amplification for sensing. AB - Diagnostic assays that rely on molecular interactions have come a long way; from initial reversible detection systems towards irreversible reaction indicator based methods. More recently, the emergence of innovative molecular amplification methodologies has revolutionised sensing, allowing diagnostic assays to achieve ultra-low limits of detection. There have been a significant number of molecular amplification approaches developed over recent years to accommodate the wide variety of analytes that require sensitive detection. To celebrate this achievement, this comprehensive critical review has been compiled to give a broad overview of the many different approaches used to attain amplification in sensing with an aim to inspire the next generation of diagnostic assays looking to achieve the ultimate detection limit. This review has been created with the focus on how each conceptually unique molecular amplification methodology achieves amplification, not just its sensitivity, while highlighting any key processes. Excluded are any references that were not found to contain an obvious molecular amplifier or amplification component, or that did not use an appropriate signal readout that could be incorporated into a sensing application. Additionally, methodologies where amplification is achieved through advances in instrumentation are also excluded. Depending upon the type of approach employed, amplification strategies are divided into four categories: target, label, signal or receptor amplification. More recent, more complex protocols combine a number of approaches and are therefore categorised by which amplification component described within was considered as the biggest advancement. The advantages and disadvantages of each methodology are discussed along with any limits of detection, if stated in the original article. Any subsequent use of the methodology within sensing or any other application is also mentioned to draw attention to its practicality. The importance of amplification within sensing is wholly emphasised while perspectives on the future direction of the field are also shared. PMID- 27116942 TI - Multicomponent (Ce, Cu, Ni) oxides with cage and core-shell structures: tunable fabrication and enhanced CO oxidation activity. AB - Solvothermal synthesis of Cu2O cubes from Cu(OAc)2 in ethanol provided templates for tunable formation of novel multicomponent composites: hollow CeO2-Cu2O (), core-shell NiO@Cu2O () and hollow CeO2-NiO-Cu2O (). Composites catalyze the oxidation of CO at a lower temperature than the parent Cu2O cubes. PMID- 27116943 TI - A scoping review of indirect comparison methods and applications using individual patient data. AB - BACKGROUND: Several indirect comparison methods, including network meta-analyses (NMAs), using individual patient data (IPD) have been developed to synthesize evidence from a network of trials. Although IPD indirect comparisons are published with increasing frequency in health care literature, there is no guidance on selecting the appropriate methodology and on reporting the methods and results. METHODS: In this paper we examine the methods and reporting of indirect comparison methods using IPD. We searched MEDLINE, Embase, the Cochrane Library, and CINAHL from inception until October 2014. We included published and unpublished studies reporting a method, application, or review of indirect comparisons using IPD and at least three interventions. RESULTS: We identified 37 papers, including a total of 33 empirical networks. Of these, only 9 (27 %) IPD NMAs reported the existence of a study protocol, whereas 3 (9 %) studies mentioned that protocols existed without providing a reference. The 33 empirical networks included 24 (73 %) IPD-NMAs and 9 (27 %) matching adjusted indirect comparisons (MAICs). Of the 21 (64 %) networks with at least one closed loop, 19 (90 %) were IPD-NMAs, 13 (68 %) of which evaluated the prerequisite consistency assumption, and only 5 (38 %) of the 13 IPD-NMAs used statistical approaches. The median number of trials included per network was 10 (IQR 4-19) (IPD-NMA: 15 [IQR 8-20]; MAIC: 2 [IQR 3-5]), and the median number of IPD trials included in a network was 3 (IQR 1-9) (IPD-NMA: 6 [IQR 2-11]; MAIC: 2 [IQR 1-2]). Half of the networks (17; 52 %) applied Bayesian hierarchical models (14 one-stage, 1 two stage, 1 used IPD as an informative prior, 1 unclear-stage), including either IPD alone or with aggregated data (AD). Models for dichotomous and continuous outcomes were available (IPD alone or combined with AD), as were models for time to-event data (IPD combined with AD). CONCLUSIONS: One in three indirect comparison methods modeling IPD adjusted results from different trials to estimate effects as if they had come from the same, randomized, population. Key methodological and reporting elements (e.g., evaluation of consistency, existence of study protocol) were often missing from an indirect comparison paper. PMID- 27116945 TI - Optical coherence tomography angiography for longitudinal monitoring of vascular changes in human cutaneous burns. AB - Assessment of vasculature is an important aspect of monitoring healing of cutaneous burn injuries. Recent advances in optical coherence tomography (OCT) have enabled it to be used to perform high-resolution imaging of the cutaneous vasculature in vivo, with the potential to provide a superior alternative to the conventional assessment of scoring skin color. The goal of this study is to investigate the feasibility of OCT angiography for longitudinal monitoring of vasculature and identification of vascular features in human cutaneous burns. We integrate several OCT imaging protocols and image-processing techniques into a systematic method for longitudinal monitoring and automatic quantification. The demonstration of this method on a partial-thickness burn shows the accurate co location of longitudinal scans; characteristic vascular features in different healing phases; and eventual decrease of the elevated vasculature area density and vessel diameter to normal levels. Such a method holds promise for longitudinal monitoring of vasculature in burn injures as well as in other cutaneous vascular pathologies and responses to treatment. PMID- 27116946 TI - Occupational therapists' perceptions of occupation in practice: An exploratory study. AB - BACKGROUND/AIM: The World Federation of Occupational Therapists' minimum standards state occupation and its relationship with health must be concepts covered in occupational therapy education. Therefore, it is assumed that Australian graduates have sound knowledge of the principles of occupation-based practice. In some practice settings, the link to occupation may not be explicit and graduates could face challenges to being occupation-based. The aims of this pilot study were to explore graduates' perceptions of occupation in their practice and to investigate whether graduates felt sufficiently prepared for occupation-based practice. METHODS: Two focus groups with eight therapists in total were employed to uncover experiences and perceptions of occupation. Themes were synthesised using Braun and Clarke's method of thematic analysis, where line by line coding was employed to inductively build themes. RESULTS: Participants believed that occupation-based practice was important but did not necessarily need to be implemented as a means of intervention. From the participants' perspective, simply striving for occupation as the end goal of therapy was acceptable. A strong focus on impairment-based practice hindered some therapists from exploring the use of occupation-based practice. For recent graduates, workplace culture was pervasive and inhibited the use of occupation. In addition, participants felt university educators did not provide an integrated or consistent approach when teaching how to apply occupation in practice. CONCLUSION: Workplace expectations and limited power to influence practice are impeding graduates from authentically applying occupation in practice. Insights from recently graduated therapists about occupation have the potential to inform future directions of occupation-based practice. PMID- 27116944 TI - Key mechanisms governing resolution of lung inflammation. AB - Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the primary responses to injury, infection and irritation, largely mediated by granulocyte effector cells such as neutrophils and eosinophils. Failure to remove an inflammatory stimulus (often resulting in failed resolution of inflammation) can lead to chronic inflammation resulting in tissue injury caused by high numbers of infiltrating activated granulocytes. Successful resolution of inflammation is dependent upon the removal of these cells. Under normal physiological conditions, apoptosis (programmed cell death) precedes phagocytic recognition and clearance of these cells by, for example, macrophages, dendritic and epithelial cells (a process known as efferocytosis). Inflammation contributes to immune defence within the respiratory mucosa (responsible for gas exchange) because lung epithelia are continuously exposed to a multiplicity of airborne pathogens, allergens and foreign particles. Failure to resolve inflammation within the respiratory mucosa is a major contributor of numerous lung diseases. This review will summarise the major mechanisms regulating lung inflammation, including key cellular interplays such as apoptotic cell clearance by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions. The different acute and chronic inflammatory disease states caused by dysregulated/impaired resolution of lung inflammation will be discussed. Furthermore, the resolution of lung inflammation during neutrophil/eosinophil dominant lung injury or enhanced resolution driven via pharmacological manipulation will also be considered. PMID- 27116947 TI - Success rates of dacryoendoscopy-guided probing for recalcitrant congenital nasolacrimal duct obstruction. AB - PURPOSE: Our aim was to review the success rates of dacryoendoscopy-guided probing for recalcitrant congenital nasolacrimal duct obstruction (CNLDO). METHODS: We reviewed the medical records of 498 patients (521 eyes) diagnosed with CNLDO between January 2011 and November 2013. Of these, 54 eyes met the eligibility criteria and underwent probing with a dacryoendoscope. RESULTS: Of the 54 eyes, 21 were classified as failed cases at other hospitals, 13 as cases requiring conversion from blind to dacryoendoscopy-guided probing during surgery at our hospital, and 20 as cases requiring intervention under general anesthesia because of difficulty with topical anesthesia. The overall success rate with dacryoendoscopy was 98.1 % (53/54 eyes) at postoperative week 2 and 97.1 % (33/34 eyes) a year after surgery. Among the cases that failed at other hospitals, one showed the formation of five false passages in the middle area of the nasolacrimal duct. In 11 eyes, slit-like adhesion was confirmed as a blurred linear line at the distal end of the nasolacrimal duct. Patency could be smoothly achieved by releasing the adhesion. CONCLUSIONS: Our study showed a high success rate for dacryoendoscopy-guided probing in CNLDO patients. The use of a dacryoendoscope allows direct visualization of the lacrimal passage and is likely to become necessary for managing CNLDO. PMID- 27116948 TI - Sentinel Lymph Node Biopsy and Isolated Tumor Cells in Invasive Lobular Versus Ductal Breast Cancer. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy is the standard of care for axillary staging in invasive breast cancer. The introduction of SLN biopsy with an extensive pathology examination, in addition to the introduction of the 2002 TNM classification, led to different axillary classification outcomes. We evaluated the effect of axillary staging procedures and subsequent axillary nodal status in patients with invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC) from 1998 to 2013. MATERIALS AND METHODS: The use of SLN biopsy and the nodal status distribution were analyzed in patients with stage T1-T2 ILC and IDC. Logistic regression analysis was performed to determine the independent effect of histologic type on the probability of the presence of isolated tumor cells (ITCs), micrometastases, and macrometastases. RESULTS: A total of 89,971 women were diagnosed, 10,146 with ILC (11%) and 79,825 with IDC (89%). The patients who had undergone SLN biopsy were more frequently diagnosed with ITCs than were those who had undergone axillary lymph node dissection only (odds ratio, 8.8; 95% confidence interval, 7.0-11.2). In 2013, the proportion of patients with ITCs in the axillary nodes was 8% in those with ILC and 4.4% in those with IDC. Patients with ILC were significantly more likely to have ITCs in their axillary lymph nodes than were patients with IDC (odds ratio, 1.8; 95% confidence interval, 1.6 2.0). CONCLUSION: With the introduction of SLN biopsy and the renewed 2002 TNM classification, patients with ILC have been more frequently diagnosed with ITCs than have patients with IDC. The clinical consequence of this finding must be established from further research. PMID- 27116949 TI - l-Histidinium thiocyanurate: Experimental and theoretical studies of a new nonlinear optical material. AB - A new organic compound, l-histidinium thiocyanurate thiocyanuric acid dihydrate, has been synthesized and characterized by single crystal X-ray diffraction, infrared spectroscopy and nonlinear optical measurements. The efficiency of the second-harmonic generation was evaluated with the Kurtz and Perry powder method at a fundamental wavelength of 1064nm. By using the experimental structure, the molecular first hyperpolarizability tensor was determined with Hartree-Fock and density functional theory methods. The second-order susceptibility tensor of the crystal was evaluated using the oriented gas model with the Lorenz-Lorentz and the Wortmann-Bishop local-field corrections. PMID- 27116950 TI - Quantum chemical study of a derivative of 3-substituted dithiocarbamic flavanone. AB - The aim of this work is to characterize a quite novel 3-dithiocarbamic flavonoid by vibrational spectroscopy in conjunction with Density Functional Theory (DFT) calculations. Quantum mechanics calculations of energies, geometries and vibrational wavenumbers in the ground state were carried out by using hybrid functional B3LYP with 6-311G(d,p) as basis set. The results indicate a remarkable agreement between the calculated molecular geometries, as well as vibrational frequencies, and the corresponding experimental data. In addition, a complete assignment of all the absorption bands present in the vibrational spectrum has been performed. In order to assess its chemical potential, quantum molecular descriptors characterizing the interactions between the 3-dithiocarbamic flavonoid and its biological receptors have been computed. The frontier molecular orbitals and the HOMO-LUMO energy gap have been used in order to explain the way in which the new molecule can interact with other species and to characterize its molecular chemical stability/reactivity. The molecular electrostatic potential (MEP) map, computed in order to identify the sites of the studied flavonoid that are most likely to interact with electrophilic and nucleophilic species, is discussed. PMID- 27116951 TI - Health literacy and the use of healthcare services in Belgium. AB - BACKGROUND: Most of the existing studies demonstrating the relationships between health literacy and health service use have been conducted outside Europe and cannot be generalised to European healthcare systems. Moreover, the majority of studies measure healthcare use via self-reports. This study investigated whether health literacy is related to the use of health services measured objectively via patient records in a European country. METHODS: 9617 members of a Belgian health insurance fund (59% females, ages 18-88 years, mean age 55.8 years) completed an online questionnaire including the 16-item European Health Literacy Survey Questionnaire (HLS-EU-Q) and agreed to have their responses linked to the insurance fund's health service use records. A two-part model approach was used to assess the association between health literacy and the use of healthcare services and the costs related, adjusting for personal and behavioural characteristics. RESULTS: Low health literacy is associated with more admissions to 1-day clinics, general practitioner (GP) home consultations, psychiatrist consultations and ambulance transports, and with longer stays in general hospitals. Associations with psychiatric hospitalisations and specialist consultations are also found but are not significant when correction for multiple comparisons is applied. In contrast, health literacy is not significantly related to the number of GP consultations, admissions to 1-day surgical clinics or emergency consultations. The relationship between health literacy and medication use is inconsistent. CONCLUSION: The results partly confirm that low health literacy is associated with greater use of healthcare services, and especially of more specialised services. Improving the health literacy of the population can be an effective strategy to promote a more (cost)-effective use of the healthcare services and thus contribute to population health. PMID- 27116952 TI - Alleviation of Lead-Induced Apoptosis by Puerarin via Inhibiting Mitochondrial Permeability Transition Pore Opening in Primary Cultures of Rat Proximal Tubular Cells. AB - Previous study has demonstrated that mitochondrial-dependent apoptotic pathway is involved in the nephroprotective effect of puerarin (PU) against lead-induced cytotoxicity in primary cultures of rat proximal tubular (rPT) cells. To further clarify how PU exerts its antiapoptotic effects, this study was designed to investigate the role of mitochondrial permeability transition (MPT) and subsequent apoptotic events in the process of PU against Pb-induced cytotoxicity in rPT cells. The results showed that Pb-mediated mitochondrial permeability transition pore (MPTP) opening together with mitochondrial cytochrome c release, activations of caspase-9 and caspase-3, and subsequent poly-ADP-ribose polymerase (PARP) cleavage can be effectively blocked by the addition of PU. Simultaneously, upregulation and downregulation of Bcl-2 and Bax with increased Bcl-2/Bax ratio due to PU administration further alleviated Pb-induced mitochondrial apoptosis. Moreover, PU can reverse Pb-induced ATP depletion by restoring mitochondrial fragmentation to affect ATP production and by regulating expression levels of ANT 1 and ANT-2 to improve ATP transport. In summary, PU produced a significant protection against Pb-induced mitochondrial apoptosis in rPT cells by inhibiting MPTP opening to ameliorate the mitochondrial dysfunction. PMID- 27116953 TI - Fluoride Content of Bottled Drinking Waters in Qatar. AB - Fluoridation of drinking water has been recognized as one of the most effective ways of achieving community-wide exposure to the caries prevention effects of fluoride (F). A vast majority of people in Qatar use bottled water for drinking. Use of bottled water without knowing the F level may expose children to dental caries risk if the F level is lower than optimal or to dental fluorosis if the F level is too high. The aim of this study was to determine the F concentration of bottled water available in Qatar. A total of 32 brands of bottled water were evaluated. The F concentrations displayed on the labels were recorded. The F ion selective electrode method was used to measure the F concentration in water samples, and three measurements were taken for every sample to ensure reproducibility. The p value was set at 0.05. The F concentration ranged from 0.06 to 3.0 ppm with a mean value of 0.8 ppm (+/-0.88). The F levels were provided by the manufacturers on the labels of 60 % of the samples, but this was significantly lower than the measured F levels (p < 0.0001). Moreover, bottled water that was produced in Saudi Arabia had significantly higher levels of F when compared to those produced in other countries (p < 0.05). There was a wide variation in the F levels in the different brands of bottled water. Furthermore, there was a significant disparity between the F levels which were measured and those that were provided on the labels. PMID- 27116954 TI - Aluminium and Acrylamide Disrupt Cerebellum Redox States, Cholinergic Function and Membrane-Bound ATPase in Adult Rats and Their Offspring. AB - Accumulation of aluminium and acrylamide in food is a major source of human exposure. Their adverse effects are well documented, but there is no information about the health problems arising from their combined exposure. The aim of the present study was to examine the possible neurotoxic effects after co-exposure of pregnant and lactating rats to aluminium and acrylamide in order to evaluate redox state, cholinergic function and membrane-bound ATPases in the cerebellum of adult rats and their progeny. Pregnant female rats have received aluminium (50 mg/kg body weight) via drinking water and acrylamide (20 mg/kg body weight) by gavage, either individually or in combination from the 14th day of pregnancy until day 14 after delivery. Exposure to these toxicants provoked an increase in malondialdehyde (MDA) and advanced oxidation protein product (AOPP) levels and a decrease in SOD, CAT, GPx, Na+K+-ATPase, Mg2+-ATPase and AChE activities in the cerebellum of mothers and their suckling pups. A reduction in GSH, NPSH and vitamin C levels was also observed. These changes were confirmed by histological results. Interestingly, co-exposure to these toxicants exhibited synergism based on physical and biochemical variables in the cerebellum of mothers and their progeny. PMID- 27116955 TI - Nutrient depletion modifies cell wall adsorption activity of wine yeast. AB - Yeast cell wall is a structure that helps yeasts to manage and respond to many environmental stresses. The mannosylphosphorylation is a modification in response to stress that provides the cell wall with negative charges able to bind compounds present in the environment. Phenotypes related to the cell wall modification such as the filamentous growth in Saccharomyces cerevisiae are affected by nutrient depletion. The present work aimed at describing the effect of carbon and/or nitrogen limitation on the aptitude of S. cerevisiae strains to bind coloured polyphenols. Carbon- and nitrogen-rich or deficient media supplemented with grape polyphenols were used to simulate different grape juice conditions-early, mid, 'adjusted' for nitrogen, and late fermentations. In early fermentation condition, the R+G+B values range from 106 (high adsorption, strain Sc1128) to 192 (low adsorption, strain Sigma1278b), in mid-fermentation the values range from 111 (high adsorption, strain Sc1321) to 258 (low adsorption, strain Sc2306), in 'adjusted' for nitrogen conditions the values range from 105 (high adsorption, strain Sc1321) to 194 (low adsorption, strain Sc2306) while in late fermentation conditions the values range from 101 (high adsorption, strain Sc384) to 293 (low adsorption, strain Sc2306). The effect of nutrient availability is not univocal for all the strains and the different media tested modified the strains behaviour. In all the media the strains show significant differences. Results demonstrate that wine yeasts decrease/increase their parietal adsorption activity according to the nutrient availability. The wide range of strain variability observed could be useful in selecting wine starters. PMID- 27116956 TI - Diversity of Cronobacter spp. isolates from the vegetables in the middle-east coastline of China. AB - Cronobacter spp. has caused life-threatening neonatal infections mainly resulted from consumption of contaminated powdered infant formula. A total of 102 vegetable samples from retail markets were evaluated for the presence of Cronobacter spp. Thirty-five presumptive Cronobacter isolates were isolated and identified using API 20E and 16S rDNA sequencing analyses. All isolates and type strains were characterized using enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR), and genetic profiles of cluster analysis from this molecular typing test clearly showed that there were differences among isolates from different vegetables. A polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) based on the amplification of the gyrB gene (1258 bp) was developed to differentiate among Cronobacter species. A new PCR-RFLP assay based on the amplification of the gyrB gene using Alu I and Hinf I endonuclease combination is established and it has been confirmed an accurate and rapid subtyping method to differentiate Cronobacter species. Sequence analysis of the gyrB gene was proven to be suitable for the phylogenetic analysis of the Cronobacter strains, which has much better resolution based on SNPs in the identification of Cronobacter species specificity than PCR-RFLP and ERIC-PCR. Our study further confirmed that vegetables are one of the most common habitats or sources of Cronobacter spp. contamination in the middle-east coastline of China. PMID- 27116957 TI - Temperature-induced changes in treatment efficiency and microbial structure of aerobic granules treating landfill leachate. AB - This paper investigates the effect of temperature on nitrogen and carbon removal by aerobic granules from landfill leachate with a high ammonium concentration and low concentration of biodegradable organics. The study was conducted in three stages; firstly the operating temperature of the batch reactor with aerobic granules was maintained at 29 degrees C, then at 25 degrees C, and finally at 20 degrees C. It was found that a gradual decrease in operational temperature allowed the nitrogen-converting community in the granules to acclimate, ensuring efficient nitrification even at ambient temperature (20 degrees C). Ammonium was fully removed from leachate regardless of the temperature, but higher operational temperatures resulted in higher ammonium removal rates [up to 44.2 mg/(L h) at 29 degrees C]. Lowering the operational temperature from 29 to 20 degrees C decreased nitrite accumulation in the GSBR cycle. The highest efficiency of total nitrogen removal was achieved at 25 degrees C (36.8 +/- 10.9 %). The COD removal efficiency did not exceed 50 %. Granules constituted 77, 80 and 83 % of the biomass at 29, 25 and 20 degrees C, respectively. Ammonium was oxidized by both aerobic and anaerobic ammonium-oxidizing bacteria. Accumulibacter sp., Thauera sp., cultured Tetrasphaera PAO and Azoarcus-Thauera cluster occurred in granules independent of the temperature. Lower temperatures favored the occurrence of denitrifiers of Zooglea lineage (not Z. resiniphila), bacteria related to Comamonadaceae, Curvibacter sp., Azoarcus cluster, Rhodobacter sp., Roseobacter sp. and Acidovorax spp. At lower temperatures, the increased abundance of denitrifiers compensated for the lowered enzymatic activity of the biomass and ensured that nitrogen removal at 20 degrees C was similar to that at 25 degrees C and significantly higher than removal at 29 degrees C. PMID- 27116958 TI - Braf, Kras and Helicobacter pylori epigenetic changes-associated chronic gastritis in Egyptian patients with and without gastric cancer. AB - We aimed to study MLH1 and MGMT methylation status in Helicobacter pylori associated chronic gastritis in Egyptian patients with and without gastric cancer. 39 patients were included in our study. They were divided into 2 groups; patients without (group I) and with gastric adenocarcinoma (group II). Patients were subjected to clinical examination, abdominal ultrasound and upper endoscopy for gastric biopsy. Biopsies were subjected to urease test, histological examination, and DNA purification. H. pylori, Braf, Kras, MLH1 and MGMT methylation were assessed by quantitative PCR. DNA sequencing was performed to assess Braf and Kras genes mutation. qPCR of H. pylori was significantly higher in patients with adenocarcinoma (group II) than those without adenocarcinoma (group I); with a p < 0.001 as well as in patients with age above 50 years with a p value = 0.008. By applying logistic regression analysis it was reported that the H. pylori qPCR is a significant predictor to the adenocarcinoma with OR = 1.025 (95 % CI: 1. 002-1.048), with sensitivity of 90 % and specificity of 100 %. Adenocarcinoma patients had a significantly higher mean age and levels of H. Pylori, Braf, K-ras, methylated MGMT and methylated MLH1 than those of gastritis patients. DNA sequence analysis of Braf (codon 12) and Kras (codon 600) had genes mutation in gastric adenocarcinoma versus chronic gastritis. CONCLUSION: H. pylori may cause epigenetic changes predisposing the patients to cancer stomach. Estimation of H. pylori by qPCR can be a good predictor to adenocarcinoma. Braf and Kras genes mutation were reveled in gastritis and adenocarcinoma patients. PMID- 27116959 TI - Enumeration and rapid identification of yeasts during extraction processes of extra virgin olive oil in Tuscany. AB - The aim of this study was to evaluate the occurrence of yeast populations during different olive oil extraction processes, carried out in three consecutive years in Tuscany (Italy), by analysing crushed pastes, kneaded pastes, oil from decanter and pomaces. The results showed yeast concentrations ranging between 10(3) and 10(5) CFU/g or per mL. Seventeen dominant yeast species were identified by random amplified polymorphic DNA with primer M13 and their identification was confirmed by restriction fragments length polymorphism of ribosomal internal transcribed spacer and sequencing rRNA genes. The isolation frequencies of each species in the collected samples pointed out that the occurrence of the various yeast species in olive oil extraction process was dependent not only on the yeasts contaminating the olives but also on the yeasts colonizing the plant for oil extraction. In fact, eleven dominant yeast species were detected from the washed olives, but only three of them were also found in oil samples at significant isolation frequency. On the contrary, the most abundant species in oil samples, Yamadazyma terventina, did not occur in washed olive samples. These findings suggest a phenomenon of contamination of the plant for oil extraction that selects some yeast species that could affect the quality of olive oil. PMID- 27116960 TI - Mutual interactions of Pleurotus ostreatus with bacteria of activated sludge in solid-bed bioreactors. AB - White rot fungi are well known for their ability to degrade xenobiotics in pure cultures but few studies focus on their performance under bacterial stress in real wastewaters. This study investigated mutual interactions in co-cultures of Pleurotus ostreatus and activated sludge microbes in batch reactors and different culture media. Under the bacterial stress an increase in the dye decolorization efficiency (95 vs. 77.1 %) and a 2-fold elevated laccase activity (156.7 vs. 78.4 Ul(-1)) were observed in fungal-bacterial cultures compared to pure P. ostreatus despite a limited growth of bacteria in mixed cultures. According to 16S-rDNA analyses, P. ostreatus was able to alter the structure of bacterial communities. In malt extract-glucose medium the fungus inhibited growth of planktonic bacteria and prevented shifts in bacterial utilization of potential C-sources. A model bacterium, Rhodococcus erythropolis responded to fungal metabolites by down regulation of uridylate kinase and acetyl-CoA synthetase. PMID- 27116961 TI - Illumina-based analysis of the rhizosphere microbial communities associated with healthy and wilted Lanzhou lily (Lilium davidii var. unicolor) plants grown in the field. AB - Lanzhou lily (Liliumdavidii var. unicolor) is the best edible lily as well as a traditional medicinal plant in China. The microbes associated with plant roots play crucial roles in plant growth and health. However, little is known about the differences of rhizosphere microbes between healthy and wilted Lanzhou lily (Lilium davidii var. unicolor) plants. The objective of this study was to compare the rhizosphere microbial community and functional diversity of healthy and wilted plants, and to identify potential biocontrol agents with significant effect. Paired end Illumina Mi-Seq sequencing of 16S rRNA and ITS gene amplicons was employed to study the bacterial and fungal communities in the rhizosphere soil of Lanzhou lily plants. BIOLOG technology was adopted to investigate the microbial functional diversity. Our results indicated that there were major differences in the rhizosphere microbial composition and functional diversity of wilted samples compared with healthy samples. Healthy Lanzhou lily plants exhibited lower rhizosphere-associated bacterial diversity than diseased plants, whereas fungi exhibited the opposite trend. The dominant phyla in both the healthy and wilted samples were Proteobacteria and Ascomycota, i.e., 34.45 and 64.01 %, respectively. The microbial functional diversity was suppressed in wilted soil samples. Besides Fusarium, the higher relative abundances of Rhizoctonia, Verticillium, Penicillium, and Ilyonectria (Neonectria) in the wilted samples suggest they may pathogenetic root rot fungi. The high relative abundances of Bacillus in Firmicutes in healthy samples may have significant roles as biological control agents against soilborne pathogens. This is the first study to find evidence of major differences between the microbial communities in the rhizospheric soil of healthy and wilted Lanzhou lily, which may be linked to the health status of plants. PMID- 27116962 TI - Diversity, molecular phylogeny and fingerprint profiles of airborne Aspergillus species using random amplified polymorphic DNA. AB - In the present study, diversity and phylogenetic relationship of Aspergillus species isolated from Tehran air was studied using random amplified polymorphic DNA (RAPD)-polymerase chain reaction (RAPD-PCR). Thirty-eight Aspergillus isolates belonging to 12 species i.e. A. niger (28.94 %, 11 isolates), A. flavus (18.42 %, 7 isolates), A. tubingensis (13.15 %, 5 isolates), A. japonicus (10.52 %, 4 isolates), A. ochraceus (10.52 %, 4 isolates), and 2.63 %, 1 isolate from each A. nidulans, A. amstelodami, A. oryzae, A. terreus, A. versicolor, A. flavipes and A. fumigatus were obtained by settle plate method which they were distributed in 18 out of 22 sampling sites examined. Fungal DNA was extracted from cultured mycelia of all Aspergillus isolates on Sabouraud Dextrose Agar and used for amplification of gene fragments in RAPD-PCR using 11 primers. RAPD-PCR data was analyzed using UPGMA software. Resulting dendrogram of combined selected primers including PM1, OPW-04, OPW-05, P160, P54, P10 and OPA14 indicated the distribution of 12 Aspergillus species in 8 major clusters. The similarity coefficient of all 38 Aspergillus isolates ranged from 0.02 to 0.40 indicating a wide degree of similarities and differences within and between species. Taken together, our results showed that various Aspergillus species including some important human pathogenic ones exist in the outdoor air of Tehran by different extents in distribution and diversity and suggested inter- and intra-species genetic diversity among Aspergillus species by RAPD-PCR as a rapid, sensitive and reproducible method. PMID- 27116963 TI - Characterizing and handling different kinds of AM fungal spores in the rhizosphere. AB - Spores are important propagules as well as the most reliable species distinguishing traits of arbuscular mycorrhizal (AM) fungi. During surveys of AM fungal communities, spore enumeration and spore identification are frequently conducted, but generally little attention is given to the age and viability of the spores. In this study, AM fungal spores in the rhizosphere were characterized as live or dead by vital staining and by performing a germination assay. A considerable proportion of the spores in the rhizosphere were dead despite their intact appearance. Furthermore, morphological and molecular analyses of spores to determine species identity revealed that both viable spores and dead spores with contents were identified. The accurate identification of spores at different developmental stages on the basis of morphology requires considerable experience. Our findings suggest that surveys of AM fungal communities based on spore enumeration and morphological and molecular identification are likely to be inaccurate, primarily because of the large proportion of dead spores in the rhizosphere. A viability check is recommended prior to spore molecular identification, and the use of trap cultures would give more reliable morphological identification results. We show that the abundance and activity of AM fungi in the rhizosphere can be determined by calculating the density of viable spores and the density of spores that could germinate. The adoption of these methods should provide a more reliable basis for further AM fungal community analysis. PMID- 27116964 TI - Spatial dynamics of the bacterial community structure in the gastrointestinal tract of red kangaroo (Macropus rufus). AB - The quantification and community of bacteria in the gastrointestinal (GI) tract (stomach, jejunum, ileum, cecum, colon and rectum) of red kangaroos (Macropus rufus) were examined by using real-time PCR and paired-end Illumina sequencing. The quantification of bacteria showed that the number of bacteria in jejunum and rectum was significantly lower than that in colon and cecum (P < 0.05). A total of 1,872,590 sequences was remained after quality-filtering and 50,948 OTUs were identified at the 97 % similarity level. The dominant phyla in the GI tract of red kangaroos were identified as Actinobacteria, Bacteroidetes and Firmicutes. At the level of genus, the samples from different parts of GI tract clustered into three groups: stomach, small intestine (jejunum and ileum) and large intestine (cecum and rectum). Prevotella (29.81 %) was the most dominant genus in the stomach and significantly (P < 0.05) higher than that in other parts of GI tract. In the small intestine, Bifidobacterium (33.04, 12.14 %) and Streptococcus (22.90, 19.16 %) were dominant genera. Unclassified Ruminococcaceae was the most dominant family in large intestine and the total relative abundance of unclassified bacteria was above 50 %. In identified genera, Dorea was the most important variable to discriminate large intestine and it was significantly higher in cecum than in stomach, small intestine and colon (P < 0.05). Bifidobacterium (21.89 %) was the only dominant genus in colon. Future work on culture in vitro and genome sequencing of those unidentified bacteria might give us insight into the function of these microorganisms in the GI tract. In addition, the comparison of the bacterial community in the foregut of kangaroos and other herbivores and the rumen might give us insight into the mechanism of fiber degradation and help us exploit approaches to improve the feed efficiency and subsequently, reduce the methane emission from herbivores. PMID- 27116965 TI - Rapid method for DNA isolation from a tough cell wall green alga Tetraspora sp. CU2551. AB - Genetic studies are important to understand the complex biological system of various organisms. Some eukaryotic green organisms have tough cell wall which precludes the efficient extraction of the genetic materials. Here, we developed the method for simple and rapid isolation of high quality DNA from a green alga Tetraspora sp. CU2551. The cell homogenization procedures were combined with physical force plus heat treatment to disrupt the cell envelope of Tetraspora sp. CU2551. Without protease treatment, vortexing with glass bead for 30-105 s at 70 degrees C led to the isolation of a high purity DNA which was suitable for downstream process. The improved method was successfully developed and could be applied for the rapid isolation of DNA from other unicellular and filamentous green microalgal strains. PMID- 27116966 TI - Cloning, expression and antioxidant activity of a novel collagen from Pelodiscus sinensis. AB - Collagen is the main structural protein of various connective tissues in animals and naturally plays an important role within the body. It is increasingly used within certain areas, such as medicine, citology and cosmetology. The soft shelled turtle (Pelodiscus sinensis) is a commercially important aquatic species rich in collagen. In this study, a novel collagen gene fragment of 756 bp, which encodes 252 deduced amino acid residues, including 25 conserved Gly-X-Y motifs, was cloned from a soft-shelled turtle. Recombinant soft-shelled turtle collagen (rSTC) was stably expressed in Escherichia coli Rosetta and purified by His GraviTrap affinity columns. The antioxidant activities of rSTC were measured using hydroxyl and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. The results showed that rSTC quenched the free radicals in a dose-dependent manner. The hydroxyl radical scavenging activity (HRSA) of rSTC was 98.9 % at a concentration of 3 mg/mL. At a concentration of 5 mg/mL, rSTC exhibited a DPPH radical scavenging activity of 32.7 %. At the tested concentrations, rSTC exhibited higher HRSA and lower DPPH radical scavenging activity. PMID- 27116967 TI - Evaluation of microbial population dynamics in the co-composting of cow manure and rice straw using high throughput sequencing analysis. AB - Microbial population dynamics in co-composting of cow manure and rice straw were evaluated using 16S high throughput sequencing technology. Physicochemical factors, including temperature, pH, nitrogen contents, the ratio of carbon and nitrogen, and germination index, were also determined in this study. 16S high throughput sequencing results showed that bacterial community structure and composition significantly varied in each phase of composting. The major phyla included Bacteroidetes, Proteobacteria, Firmicutes, Actinobacteria and Planctomycetes, respectively. Bacteroidetes and Proteobacteria were the most abundant phyla in all phases, and Actinobacteria was just dominant in the mesophilic phase, while Firmicutes and Planctomycetes were ubiquitous. At the genus level, Simiduia, Flavobacterium, unclassified Chitinophagaceae and Flexibacter notably changed in each phase of composting. Bacterial community diversity in the mesophilic phase was higher than that in others based on the Shannon-Wiener index and Simpson diversity index. The ratio of carbon and nitrogen and germination index indicated that the co-composting of cow manure and rice straw reached maturation. The result of nitrogen contents showed that nitrogen loss mainly occurred in the thermophilic phase. In addition, the differences in the distributions of key OTUs between in the late thermophilic phase and the cooling and maturation phase were unobvious compared with other phase's base on the principal component analysis. Redundancy analysis revealed that the changes of nitrogen played a predominant role in the distributions of OTUs during the composting process. PMID- 27116968 TI - A novel process for obtaining pinosylvin using combinatorial bioengineering in Escherichia coli. AB - Pinosylvin as a bioactive stilbene is of great interest for food supplements and pharmaceuticals development. In comparison to conventional extraction of pinosylvin from plant sources, biosynthesis engineering of microbial cell factories is a sustainable and flexible alternative method. Current synthetic strategies often require expensive phenylpropanoic precursor and inducer, which are not available for large-scale fermentation process. In this study, three bioengineering strategies were described to the development of a simple and economical process for pinosylvin biosynthesis in Escherichia coli. Firstly, we evaluated different construct environments to give a highly efficient constitutive system for enzymes of pinosylvin pathway expression: 4-coumarate: coenzyme A ligase (4CL) and stilbene synthase (STS). Secondly, malonyl coenzyme A (malonyl-CoA) is a key precursor of pinosylvin bioproduction and at low level in E. coli cell. Thus clustered regularly interspaced short palindromic repeats interference (CRISPRi) was explored to inactivate malonyl-CoA consumption pathway to increase its availability. The resulting pinosylvin content in engineered E. coli was obtained a 1.9-fold increase depending on the repression of fabD (encoding malonyl-CoA-ACP transacylase) gene. Eventually, a phenylalanine over producing E. coli consisting phenylalanine ammonia lyase was introduced to produce the precursor of pinosylvin, trans-cinnamic acid, the crude extraction of cultural medium was used as supplementation for pinosylvin bioproduction. Using these combinatorial processes, 47.49 mg/L pinosylvin was produced from glycerol. PMID- 27116969 TI - Consolidating biofuel platforms through the fermentative bioconversion of crude glycerol to butanol. AB - Economic realities for the rising industrial biofuel production have changed substantially during the low oil price period starting in the mid 2010's. Increased competition requires the sector to increase productivity through the reduction of low-value by-products and full utilization of all value and energy stored in their respective feedstock. Biodiesel is produced commercially from substrates such as animal fat and vegetable oil, generating approximately 10 wt% crude glycerol as its main, currently underutilized, by-product. This crude glycerol is contaminated with catalyst, soap, free fatty acids, glycerides and methyl esters; hence only a small fraction enters the existing glycerol markets, while the purification costs for the majority of crude glycerol are simply too high. However, this presents a unique opportunity to generate additional value. One technical possibility is to use crude glycerol as a carbon source for butanol production, a compound of higher value and energy, a potential additive for gasoline and diesel fuels and bulk chemical commodity. Conversion facilities could be co-located with biodiesel plants, utilizing established infrastructure and adding significant value and productivity to the existing biodiesel industry. This review focuses on the current activities geared towards the bioconversion of crude glycerol to butanol. PMID- 27116970 TI - Application of anhydrobiosis and dehydration of yeasts for non-conventional biotechnological goals. AB - Dehydration of yeast cells causes them to enter a state of anhydrobiosis in which their metabolism is temporarily and reversibly suspended. This unique state among organisms is currently used in the production of active dry yeasts, mainly used in baking and winemaking. In recent decades non-conventional applications of yeast dehydration have been proposed for various modern biotechnologies. This mini-review briefly summarises current information on the application of dry yeasts in traditional and innovative fields. It has been shown that dry yeast preparations can be used for the efficient protection, purification and bioremediation of the environment from heavy metals. The high sorption activity of dehydrated yeasts can be used as an interesting tool in winemaking due to their effects on quality and taste. Dry yeasts are also used in agricultural animal feed. Another interesting application of yeast dehydration is as an additional stage in new methods for the stable immobilisation of microorganisms, especially in cases when biotechnologically important strains have no affinity with the carrier. Such immobilisation methods also provide a new approach for the successful conservation of yeast strains that are very sensitive to dehydration. In addition, the application of dehydration procedures opens up new possibilities for the use of yeast as a model system. Separate sections of this review also discuss possible uses of dry yeasts in biocontrol, bioprotection and biotransformations, in analytical methods as well as in some other areas. PMID- 27116971 TI - Updates on industrial production of amino acids using Corynebacterium glutamicum. AB - L-Amino acids find various applications in biotechnology. L-Glutamic acid and its salts are used as flavor enhancers. Other L-amino acids are used as food or feed additives, in parenteral nutrition or as building blocks for the chemical and pharmaceutical industries. L-amino acids are synthesized from precursors of central carbon metabolism. Based on the knowledge of the biochemical pathways microbial fermentation processes of food, feed and pharma amino acids have been developed. Production strains of Corynebacterium glutamicum, which has been used safely for more than 50 years in food biotechnology, and Escherichia coli are constantly improved using metabolic engineering approaches. Research towards new processes is ongoing. Fermentative production of L-amino acids in the million-ton scale has shaped modern biotechnology and its markets continue to grow steadily. This review focusses on recent achievements in strain development for amino acid production including the use of CRISPRi/dCas9, genome-reduced strains, biosensors and synthetic pathways to enable utilization of alternative carbon sources. PMID- 27116972 TI - Government abused power as sole employer of junior doctors, says BMA chair. PMID- 27116973 TI - Ocular syphilis: opportunities to address important unanswered questions. PMID- 27116974 TI - Comparative Effectiveness of Carotid Artery Stenting Versus Carotid Endarterectomy Among Medicare Beneficiaries. AB - BACKGROUND: Effectiveness of carotid artery stenting (CAS) relative to carotid endarterectomy (CEA) among Medicare patients has not been established. We compared effectiveness of CAS versus CEA among Medicare beneficiaries. METHODS AND RESULTS: We linked Medicare data (2000-2009) to the Society for Vascular Surgery's Vascular Registry (2005-2008) and the National Cardiovascular Data Registry's (NCDR) Carotid Artery Revascularization and Endarterectomy Registry (2006-2008/2009). Medicare patients were followed up from procedure date until death, stroke/transient ischemic attack, periprocedural myocardial infarction, or a composite end point for these outcomes. We derived high-dimensional propensity scores using registry and Medicare data to control for patient factors and adjusted for provider factors in a Cox regression model comparing CAS with CEA. Among 5254 Society for Vascular Surgery's Vascular Registry (1999 CAS; 3255 CEA) and 4055 Carotid Artery Revascularization and Endarterectomy Registry (2824 CAS; 1231 CEA) Medicare patients, CAS patients had a higher comorbidity burden and were more likely to be at high surgical risk (Society for Vascular Surgery's Vascular Registry: 96.7% versus 44.5%; Carotid Artery Revascularization and Endarterectomy Registry: 71.3% versus 44.7%). Unadjusted outcome risks were higher for CAS. Mortality risks remained elevated for CAS after adjusting for patient-level factors (hazard ratio, 1.24; 95% confidence interval, 1.06-1.46). After further adjustment for provider factors, differences between CAS and CEA were attenuated or no longer present (hazard ratio for mortality, 1.13; 95% confidence interval, 0.94-1.37). Performance was comparable across subgroups defined by sex and degree of carotid stenosis, but there was a nonsignificant trend suggesting a higher risk of adverse outcomes in older (>80) and symptomatic patients undergoing CAS. CONCLUSIONS: Outcomes after CAS and CEA among Medicare beneficiaries were comparable after adjusting for both patient- and provider level factors. PMID- 27116975 TI - Vancouver Transcatheter Aortic Valve Replacement Clinical Pathway: Minimalist Approach, Standardized Care, and Discharge Criteria to Reduce Length of Stay. AB - We describe the development, implementation, and evaluation of a standardized clinical pathway to facilitate safe discharge home at the earliest time after transfemoral transcatheter aortic valve replacement. Between May 2012 and October 2014, the Heart Team developed a clinical pathway suited to the unique requirements of transfemoral transcatheter aortic valve replacement in contemporary practice. The components included risk-stratified minimalist periprocedure approach, standardized postprocedure care with early mobilization and reconditioning, and criteria-driven discharge home. Our aim was to reduce variation in care, identify a subgroup of patients suitable for early discharge (<=48 hours), and decrease length of stay for all patients. We addressed barriers related to historical practices, complex multidisciplinary stakeholder engagement, and adoption of length of stay as a quality indicator. We retrospectively reviewed the experiences of 393 consecutive patients; 150 (38.2%) were discharged early. At baseline, early discharge patients had experienced less previous balloon aortic valvuloplasty, had higher left ventricular ejection fraction, better cognitive function, and were less frail than the standard discharge group (>48 hours). Early discharge was associated with the use of local anesthesia, implantation of balloon expandable device, avoidance of urinary catheter, and early removal of temporary pacemaker. Median length of stay was 1 day for early discharge and 3 days for other patients; 97.7% were discharged home. There were no differences in 30-day mortality (1.3%), disabling stroke (0.8%), or readmission (10.7%). The implementation of a transcatheter aortic valve replacement clinical pathway shifted the program's approach to combine standardized processes and individual risk stratification. The Vancouver transcatheter aortic valve replacement clinical pathway requires a rigorous assessment to determine its efficacy, safety, and reproducibility. PMID- 27116976 TI - Pioneer Axon Navigation Is Controlled by AEX-3, a Guanine Nucleotide Exchange Factor for RAB-3 in Caenorhabditis elegans. AB - Precise and accurate axon tract formation is an essential aspect of brain development. This is achieved by the migration of early outgrowing axons (pioneers) allowing later outgrowing axons (followers) to extend toward their targets in the embryo. In Caenorhabditis elegans the AVG neuron pioneers the right axon tract of the ventral nerve cord, the major longitudinal axon tract. AVG is essential for the guidance of follower axons and hence organization of the ventral nerve cord. In an enhancer screen for AVG axon guidance defects in a nid 1/Nidogen mutant background, we isolated an allele of aex-3 aex-3 mutant animals show highly penetrant AVG axon navigation defects. These defects are dependent on a mutation in nid-1/Nidogen, a basement membrane component. Our data suggest that AEX-3 activates RAB-3 in the context of AVG axon navigation. aex-3 genetically acts together with known players of vesicular exocytosis: unc-64/Syntaxin, unc 31/CAPS, and ida-1/IA-2. Furthermore our genetic interaction data suggest that AEX-3 and the UNC-6/Netrin receptor UNC-5 act in the same pathway, suggesting AEX 3 might regulate the trafficking and/or insertion of UNC-5 at the growth cone to mediate the proper guidance of the AVG axon. PMID- 27116977 TI - IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. AB - BACKGROUND: Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse gliomas is unknown. Gain-of function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. METHODS: We analyzed the database of The Cancer Genome Atlas for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligand expression levels and NK cell mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza-2'deoxycytodine (decitabine) as a potential NK cell sensitizing agent in IDH mutant cells. RESULTS: IDH mutant glioma stemlike cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes are resistant to NK cell-mediated lysis. Decitabine increases NKG2D ligand expression and restores NK-mediated lysis of IDH mutant cells in an NKG2D-dependent manner. CONCLUSIONS: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas. PMID- 27116979 TI - Facile Multiscale Patterning by Creep-Assisted Sequential Imprinting and Fuel Cell Application. AB - The capability of fabricating multiscale structures with desired morphology and incorporating them into engineering applications is key to realizing technological breakthroughs by employing the benefits from both microscale and nanoscale morphology simultaneously. Here, we developed a facile patterning method to fabricate multiscale hierarchical structures by a novel approach called creep-assisted sequential imprinting. In this work, nanopatterning was first carried out by thermal imprint lithography above the glass transition temperature (Tg) of a polymer film, and then followed by creep-assisted imprinting with micropatterns based on the mechanical deformation of the polymer film under the relatively long-term exposure to mechanical stress at temperatures below the Tg of the polymer. The fabricated multiscale arrays exhibited excellent pattern uniformity over large areas. To demonstrate the usage of multiscale architectures, we incorporated the multiscale Nafion films into polymer electrolyte membrane fuel cell, and this device showed more than 10% higher performance than the conventional one. The enhancement was attributed to the decrease in mass transport resistance because of unique cone-shape morphology by creep-recovery effects and the increase in interfacial surface area between Nafion film and electrocatalyst layer. PMID- 27116978 TI - Large-scale assessment of the gliomasphere model system. AB - BACKGROUND: Gliomasphere cultures are widely utilized for the study of glioblastoma (GBM). However, this model system is not well characterized, and the utility of current classification methods is not clear. METHODS: We used 71 gliomasphere cultures from 68 individuals. Using gene expression-based classification, we performed unsupervised clustering and associated gene expression with gliomasphere phenotypes and patient survival. RESULTS: Some aspects of the gene expression-based classification method were robust because the gliomasphere cultures retained their classification over many passages, and IDH1 mutant gliomaspheres were all proneural. While gene expression of a subset of gliomasphere cultures was more like the parent tumor than any other tumor, gliomaspheres did not always harbor the same classification as their parent tumor. Classification was not associated with whether a sphere culture was derived from primary or recurrent GBM or associated with the presence of EGFR amplification or rearrangement. Unsupervised clustering of gliomasphere gene expression distinguished 2 general categories (mesenchymal and nonmesenchymal), while multidimensional scaling distinguished 3 main groups and a fourth minor group. Unbiased approaches revealed that PI3Kinase, protein kinase A, mTOR, ERK, Integrin, and beta-catenin pathways were associated with in vitro measures of proliferation and sphere formation. Associating gene expression with gliomasphere phenotypes and patient outcome, we identified genes not previously associated with GBM: PTGR1, which suppresses proliferation, and EFEMP2 and LGALS8, which promote cell proliferation. CONCLUSIONS: This comprehensive assessment reveals advantages and limitations of using gliomaspheres to model GBM biology, and provides a novel strategy for selecting genes for future study. PMID- 27116980 TI - [Common opinion on the application of fluorescence in situ hybridization technique in prenatal diagnosis]. PMID- 27116981 TI - [Indications and pregnancy outcomes of intrapartum cesarean section after the new partogram applied]. AB - OBJECTIVE: To study the changes of intrapartum cesarean rate, cesarean indications and pregnancy outcomes after the new partogram applied. METHODS: Totally 3 290 pregnant women trying to vaginal delivery which were managed according to the new partogram in Beijing Obstetrics and Gynecology Hospital, Capital Medical University from August to October in 2014(new partogram group)were involved; 2 987 pregnancy women trying to vaginal delivery from May to July in 2014 which were managed according to the old partogram(old partogram group)were involved as control. The intrapartum cesarean rate, cesarean indications and the pregnancy outcomes between the two groups were analyzed. RESULTS: The rate of intrapartum cesarean delivery was 8.50%(254/2 987)in old partogram group, and was significantly higher than that in new partogram group(6.2%, 204/3 290; P<0.01). Cesarean indications in old partogram group included 18 labor protraction(7.1%, 18/254), 82 labor arrest(32.3%, 82/254), 44 relative cephalopelvic disproportion(17.3%, 44/254), 80 fetal distress(31.5%, 80/254), 23 intrauterine infection(9.1%, 23/254)and 7 cesarean delivery on maternal request(CDMR; 2.8%, 7/254). Cesarean indications in new partogram group included 33 labor arrest(16.2%, 33/204), 71 relative cephalopelvic disproportion(34.8%, 71/204), 73 fetal distress(35.8%, 73/204)and 22 intrauterine infection(10.8%, 22/204), 5 CDMR(2.5%, 5/204). There were no significant differences in incidence of asphyxia neonatorum and puerperal morbidity(P> 0.05), but the incidence of postpartum hemorrhage in new partogram group was higher than the old partogram group[6.9%(14/204)versus 1.6%(4/254), P<0.05]. CONCLUSION: After the new partogram applied, the rate of intrapartum cesarean delivery is significantly decreased, but the incidence of postpartum hemorrhage is increased. PMID- 27116982 TI - [Obstetrical complications of thyroid peroxidase antibody positive during pregnancy and effects of intervention: a meta-analysis]. AB - OBJECTIVE: To explore the correlation between thyroid peroxidase antibody(TPOAb)and outcomes during pregnancy and the effects of treatment on outcomes. METHODS: PubMed, Cochrane Library, Science Direct, Embase, Chinese Biomedicine, and Wanfangdata had been searched. Case-control and cohort studies about TPOAb and pregnancy outcomes were searched according to the inclusion and exclusion criteria. Fifty studies were finally recruited(all of cohort-studies, 10 for English and 5 for Chinese). Review Manager 5.3 were used to test the heterogeneity of the results among the different studies and amalgamate the effect size using fixed or random effect models. RESULTS: Meta-analysis showed TPOAb(+)with normal thyroid function increase the risks of miscarriage,and premature delivery, OR calculated were 2.02(95%CI: 1.13-3.62, P=0.001)and 1.39(95%CI: 1.11-1.76, P=0.005), while showed no relative risk to hypertensive disease, placental abruption in pregnancy and fetal growth restriction, OR calculated were 1.29(95%CI: 1.00-1.67, P=0.080), 0.42(95%CI: 0.12-1.43, P=0.210)and 1.61(95%CI: 0.23-11.12, P=0.100). TPOAb(+)with normal thyroid function increase miscarriage in in vitro fertilization and embryo transfer(IVF ET), OR calculated were 2.14(95%CI: 1.43-3.21, P=0.000). Levothyroxine(LT4)for patients of TPOAb(+)with normal thyroid dysfunction decrease adverse obstetric outcomes, OR calculated were 0.43(95%CI: 0.22-0.85, P=0.020). CONCLUSIONS: TPOAb(+)with normal thyroid function increase the risks of miscarriage,and premature delivery. TPOAb(+)with normal thyroid function increase miscarriage in IVF-ET. LT4 for patients of TPOAb(+)with normal thyroid dysfunction decrease adverse obstetric outcomes. PMID- 27116983 TI - [A randomized, single-blind, parallel-controlled and multicentre study: compare the efficacy and safety of domestic and imported human recombinant FSH in WHO group II anovulatory infertility]. AB - OBJECTIVE: To evaluate the efficacy and safety of domestic human recombinant FSH(rhFSH)in women with anovulation of WHO group II. METHODS: A randomized, blind, parallel-controlled, non-inferiority and multicenter study was performed. A total of 534 admitted to 13 hospitals from May 2008 to August 2009. There were 531 women with ovulatory disorder was included in the statistical analysis, were randomly divided into test group(domestic rhFSH, n=352)and control group(imported rhFSH, n=179). Percentage of cycle with mature follicle, ovulation rate, clinical pregnancy rate, multiple pregnancy rate, ovarian hyperstimulation syndrome(OHSS)and adverse events were observed. RESULTS: No statistical significant differences(P>0.05)were observed between the two groups in terms of the efficiency on mature follicle[91.8%(323/352)versus 88.8%(159/179)], ovulation rate[91.3%(295/323)verus 90.6%(144/159)], clinical pregnancy rate[19.2%(62/323)verus 18.2%(29/159)], the number of the follicles<14 mm, the level of serum LH and progesterone, the thickness of endometrium on the day of hCG administration. The number of follicle>=18 mm and 14 mm<=follicle<18 mm and the level of serum estradiol on the day of hCG in the test group were significantly higher than those in the control group(P<0.05). The number of days of rhFSH administration in the test group was significantly less than that in the control group[(9.8+/-2.2)versus(11.4+/- 0.6)days, P<0.05], the dosage of rhFSH was significantly lower than that in the control group[(879 +/- 419)versus(1 043+/-663)U, P<0.05]. The multiple pregnancy rate in the test group was significantly higher than that in the control group[21%(13/62)versu 10%(3/29), P<0.05]. The incidence of OHSS and adverse events were similar between the two groups(P>0.05), and no other adverse events were observed in test group during treatment. CONCLUSION: Ovarian stimulation with domestic rhFSH is effective, safe and economical in women with anovulation of WHO group II. PMID- 27116984 TI - [Analysis of 13 cases of rhabdomyosarcoma in the female genital tract]. AB - OBJECTIVE: To investigate the clinical features, treatments and prognostic factors of rhabdomyosarcoma(RMS)in the female genital tract. METHODS: A retrospective analysis was performed on 13 cases of RMS in the female genital tract. Clinical characteristics, treatments and prognosis were compared and analyzed statistically. RESULTS: The median age was 21.0 years(range, 6 to 54 years). There were 6 cases vaginal RMS and 7 cases cervical RMS, included 11 cases of embryonal RMS(ERMS)and 2 cases of alveolar RMS(ARMS). According to the Federation International of Gynecology and Obstetrics(FIGO)staging system, there were 6 cases of stage I , 3 cases of stage II, 1 case of stage III and 3 cases of stage IV, the median survival time were respectively 112.5, 153.0, 9.0 and 3.5 months. According to the Intergroup Rhabdomyosarcom Study Group(IRSG)staging system, there were 10 cases of stage I and 3 cases of the stage IV, and their median survival time were respectively 112.5 and 3.5 months. Nine patients received surgery and the median survival time was 108.0 months(range, 9 to 228 months), 6 of them received chemotherapy after surgery and the median survival time was 152.0 months(range, 9 to 228 months), the other 3 cases did not receive any therapy after surgery and the median survival time was 25.0 months(range, 9 to 108 months). Four patients did not receive surgery and the median survival time was 6.3 months(range, 1 to 117 months). There were 2 cases received combined treatment included radiotherapy and the survival time were respectively 4 and 198 months. There were 8 cases who was survival without disease and 5 cases died of cancer. The median survival time in 13 patients was 25.0 months(range, 1 to 228 months)and the 5-year overall survival rate was 58.6%. CONCLUSIONS: The prognosis of early stage of RMS in the female genital tract is good. While, the prognosis of advanced stage is poor. The standard treatment strategy is combination of surgery and chemotherapy, whether radiotherapy could improve the prognosis still need further study. PMID- 27116985 TI - [Variation of long-chain 3-hydroxyacyl CoA dehydrogenase DNA methylated modification and correlation with gene mRNA expression of early-onset preeclampsia, HELLP syndrome and antiphospholipid syndrome in trophoblast cells of placenta]. AB - OBJECTIVE: By detecting the DNA methylation and gene expression of long-chain 3 hydroxyacyl CoA dehydrogenase(LCHAD)in trophoblast cells, analyze the correlation of DNA methylation and gene expression in early-onset preeclampsia(EPE), hemolysis, elevated liver enzymes, and low platelets(HELLP)syndrome and antiphospholipid syndrome(APS), to investigate the molecular basis of long-chain fatty acid oxidation changes in different preeclampsia and pathological pregnancy. METHODS: Primary human cytotrophoblast cells and HTR8/Svneo cells were treated with serum from patients with EPE(14 cases), HELLP(12 cases), APS(14 cases), and normal pregnant women(NP, 14 cases). The methylation level of LCHAD gene promoter region through the MassARRAY platform and mRNA expression level by real-time fluorescent quantitative PCR technique were conducted. RESULTS: (1)Cytosine-phosphate-guanine(CpG)sites in human LCHAD DNA promoter region: CpG sites were detected in the range of 558 bp before LCHAD gene transcription start site, the detected CpG sites were 11 sites including 8 single sites and 3 complex sites. The position of these sites were at-984,-960,-899,-853,-811,-796,-774, 727,-615,-595,-579 respectively.(2)The sites of-899,-853,-615 and-595 showed increased methylation level in EPE and HELLP groups. The methylation level at 899,-853 and-615 sites in EPE and HELLP groups were significantly higher than those in NP group(P<0.01). The methylation level at-853 site was higher in EPE group than that in HELLP group(P<0.05). The-595 site showed the unmethylated in EPE, HELLP and APS groups. There were significantly difference between the 3 groups and EPE group(P<0.01).(3)The gene expression of LCHAD mRNA in EPE(0.048+/ 0.005), HELLP(0.045+/-0.006)and APS(0.044+/-0.004)groups were significantly lower than NP group(0.076+/-0.009; P<0.01).(4)The correlation of methylation level and gene expression in all groups: the methylation level at-899,-853,-727,-615 and 579 sites were negatively correlated with gene mRNA expression in EPE group(P<0.05). The methylation level at-899,-853 and-615 sites were negatively correlated with gene mRNA expression in HELLP group(P< 0.05). CONCLUSIONS: The variation of LCHAD DNA methylation of trophoblast cells are found among EPE, HELLP syndrome and APS. The different correlation of LCHAD DNA methylation and gene expression are different in pathological groups. LCHAD DNA methylation of EPE and HELLP syndrome were significantly increased and negatively correlated with LCHAD gene mRNA expression. These results further revealed the molecular basis of long-chain fatty acid oxidation in different preeclampsia and pathological pregnancy. PMID- 27116986 TI - [25S rDNA genotype and antifungal susceptibility of vaginal Candida albicans]. AB - OBJECTIVE: To investigate 25S rDNA genotype distribution of vaginal Candida albicans and its relationship with antifungal susceptibility. METHODS: A total of 954 isolates of Candida albicans were subjected to genotype analysis according to the presence and the size of transposable group I intron in 25S rDNA with PCR; 156 isolates were enrolled to detect their antifungal susceptibility of 5 antifungal agents with the M27-A3 broth microdilution method. RESULTS: Totally 876 isolates were determined to be intronless genotype A(91.8%, 876/954); 58(6.1%, 58/954)and 20 isolates(2.1%, 20/954)were introncontaining genotype B and genotype C, respectively. The minimal inhibitory concentrations(MIC)of itraconazole and fluconazole against the intron-containing group were significantly higher than those of the intronless group(0.25 versus 0.125 MUg/ml, P<0.05; 0.25 versus 0.125 MUg/ml, P<0.01), whereas the MIC of nystatin against the intron-containing group was lower than that of the intronless group(4 versus 8 MUg/ml, P< 0.01). The resistance rate of Candida albicans to itraconazole of the intron-containing group was significantly higher than that of the intronless group[24%(19/78)versus 3%(2/78), P<0.01]. Cross-resistance analysis revealed 5 of the 21(24%)itraconazole resistant isolates were cross-resistant to fluconazole , and 5 of the 6(5/6)fluconazole-resistant strains were cross-resistant to itraconazole. Besides, all the five strains simultaneously resistant to itraconazole and fluconazole belonged to the intron-containing group. CONCLUSION: The presence of the transposable group I intron in 25S rDNA of vaginal Candida albicans might be important in affecting itraconazole, fluconazole and nystatin susceptibility. PMID- 27116987 TI - [Effect of MTRR gene on apoptosis and autophagy pathways in multiresistant epithelial ovarian cancer]. AB - OBJECTIVE: To explore the effect of down-regulated methionine synthase reductase(MTRR)gene on the apoptosis and autophagy pathway, and offer a possible approach for the MTRR to reverse the multi-resistant ovarian cancer. METHODS: (1)The experiment was divided into 3 groups, SKOV3/DDP-MTRRi(down-regulated MTRR group), SKOV3/DDP-NC(negative control group), and SKOV3/DDP(blank control group). Different concentration of cisplatin(0, 1, 2, and 4 MUg/ml)treated on 3 groups cells. The apoptosis rate was measured by flow cytometry(FCM). Autophagy was detected by immunofluorescence. Autophagy microtubule associated protein light chain 3beta(LC3B)and p62 were detected by western blot. The formation of autophagosome of cells was observed by transmission electron microscope.(2)Detection of autophagy and apoptosis of SKOV3/DDP-MTRRi induced by rapamycin. The experiment was divided into 4 groups included rapamycin group(5 nmol/L rapamycin), rapamycin+cisplatin group(5 nmol/L rapamycin+ 4 MUg/ml cisplatin), cisplatin group(4 MUg/ml cisplatin)and blank control group. LC3B and p62 protein were detected by western blot. The survival rate cells were detected by methyl thiazolyl tetrazolium(MTT)method. The apoptosis rate was measured by FCM.(3)The 3 groups cells(SKOV3/DDP, SKOV3/DDP-NC and SKOV3/DDP-MTRRi)induced by a certain concentration of cisplatin(4 MUg/ml)after 48 hours, then detecting the protein expression of caspase, Bcl-2 family in apoptosis pathway and the key proteins in phosphatidylinositol-3 kinase(PI3K)/protein kinase B(Akt)autophagy pathways by western blot, getting the time when the proteins' expression changed. RESULTS: (1)The 3 groups cells(SKOV3/DDP, SKOV3/DDP-NC, and SKOV3/DDP MTRRi)induced by a certain concentration of cisplatin(4 MUg/ml)after 48 hours, apoptosis and autophagy of 3 groups of cells were gradually increased with the increased concentration of cisplatin. The apoptosis rate of SKOV3/DDP-MTRRi cells[(26.2 +/- 1.4)%]were significantly increased compared with the SKOV3/DDP-NC cells or SKOV3/DDP cells[(14.8+/-2.4)%,(14.2+/-2.4)%; all P<0.05]at 2 MUg/ml cisplatin. Immunofluorescence tests revealed that the aggregates of LC3B in SKOV3/DDP-MTRRi cells were more than that of SKOV3/DDP-NC cells and SKOV3/DDP cells. The expression of LC3B of SKOV3/DDP-MTRRi cells was lower than those of SKOV3/DDP-NC cells and SKOV3/DDP cells(P<0.05). The expression of p62 of SKOV3/DDP-MTRRi cells was higher than those of SKOV3/DDP-NC cells and SKOV3/DDP cells(P<0.05). The structure of chloroplast was integrity and autophagosome was dispersing in plastids of SKOV3/DDP-NC cells and SKOV3/DDP cells. Organelles disappear and vacuoles increased obviously in SKOV3/DDP-MTRRi cells, no autophagosome was observed.(2)The expression of LC3B of rapamycin + cisplatin group was higher than those of other 3 group cells(1.72+/-0.08, 1.43+/-0.04, 1.37+/-0.11, and 1.11+/-0.09; P<0.05). The expression of p62 of rapamycin + cisplatin group was significant decreased(0.58 +/- 0.10, 0.94 +/- 0.12, 1.21 +/- 0.11, and 1.57 +/- 0.10; P<0.05). The survival rate of rapamycin + cisplatin group was higher than that of cisplatin group[(0.78+/-0.03)% vs(0.62+/-0.03)%; P=0.018], the apoptosis rate was significant decreased in rapamycin+ cisplatin group[(59.0 +/- 3.9)% vs(40.4 +/- 3.0)%, P=0.019].(3)The 3 groups cells(SKOV3/DDP, SKOV3/DDP-NC, and SKOV3/DDP-MTRRi)induced by a certain concentration of cisplatin(4 MUg/ml)after 48 hours, the expression of Bax in 3 groups cell were not evidently changed(P= 0.661). The expression of Bcl-2 was significantly decreased in SKOV3/DDP-MTRRi cells(P=0.030). The expression of caspase-3, caspase-7, caspase-9, and poly(ADP-ribose)polymerase(PARP)were not evidently changed(P>0.05), but cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, and cleaved PARP were significantly increased in SKOV3/DDP-MTRRi cells(P<0.05). For the autophagy pathway, the expression of phosphorylated Akt(p Akt)and phosphorylated mammalian target of rapamycin(p-mTOR)were significantly increased(P <0.05), but Akt and mTOR had no significant variation. The expression of phosphatase and tensin homologue deleted on chromosome ten(PTEN)was significantly decreased(P <0.05). CONCLUSIONS: MTRR silencing significantly increase cisplatin-induced apoptosis and reduce the autophagy induced by cisplatin in SKOV3/DDP cells. Down-regulation of MTRR enhanced the chemosensitivity of cisplatinresistant ovarian cancer cells may be by activating caspase and Bcl-2 apoptosis family and inhibiting the PI3K/Akt autophagy pathway. PMID- 27116988 TI - Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications. AB - INTRODUCTION: Polyethylene glycol (PEG) is a polymer of choice in drug delivery systems. This USFDA-approved polymer is popular due to its tunable properties and well-established safety profile: prime requisites considered during the selection of any excipient in formulation development. AREAS COVERED: The unique properties and applications of PEG have been discussed at length in the existing literature. However, a proper guidance on selection of PEG grade to cater to one's purpose is lacking. This article provides preliminary guidelines to formulators on selection of appropriate PEG grade, typically based on its physico-chemical properties and role-based functional application in pharmaceuticals. It should be noted that the aim article is not to deep dive in each application area. EXPERT OPINION: Guidance on PEG application and grade of choice is lacking in the available literature. The authors have discussed and provided guidance to formulators on the appropriate PEG grade selection for particular application based on the available in vitro and in vivo literature data. In this review a State-of-the-art use of PEG in therapeutic applications, its clinical status and commercial use is also summarized. Nevertheless, toxicities related to different PEG grades and related impurities are discussed in this review. PMID- 27116989 TI - Effects of Selenizing Codonopsis pilosula Polysaccharide on Macrophage Modulatory Activities. AB - The purpose of the present study was to investigate the immune-enhancing activity of selenizing Codonopsis pilosula polysaccharide (sCPPS5) in nonspecific immune response. In in vitro experiment, the results showed that sCPPS5 could promote the phagocytic uptake, NO production, and TNF-alpha and IL-6 secretion of RAW264.7 cells. sCPPS5 could also strongly increase the IkappaB-alpha degradation in the cytosol and the translocation of NF-kappaB p65 subunit into the nucleus of RAW264.7 cells. In the vivo experiment, sCPPS5 at medium doses could significantly improve the phagocytic index of peritoneal macrophages and induce the secretion of TNF-alpha and IL-6. Moreover, the effect of sCPPS5 was significantly better than Codonopsis pilosula polysaccharide (CPPS). These results indicated that selenylation modification could significantly enhance the immune-enhancing activity of CPPS in the nonspecific immune response. PMID- 27116990 TI - A New Approach to Produce Resveratrol by Enzymatic Bioconversion. AB - An enzymatic reaction system was developed and optimized for bioconversion of resveratrol from glucose. Liquid enzyme extracts were prepared from Alternaria sp. MG1, an endophytic fungus from grape, and used directly or after immobilization with sodium alginate. When the enzyme solution was used, efficient production of resveratrol was found within 120 min in a manner that was pH-, reaction time-, enzyme amount-, substrate type-, and substrate concentration dependent. After the optimization experiments using the response surface methodology, the highest value of resveratrol production (224.40 ug/l) was found under the conditions of pH 6.84, 0.35 g/l glucose, 0.02 mg/l coenzyme A, and 0.02 mg/l ATP. Immobilized enzyme extracts could keep high production of resveratrol during recycling use for two to five times. The developed system indicated a potential approach to resveratrol biosynthesis independent of plants and fungal cell growth, and provided a possible way to produce resveratrol within 2 h, the shortest period needed for biosynthesis of resveratrol so far. PMID- 27116991 TI - A Modified Quantum Dot-Based Dot Blot Assay for Rapid Detection of Fish Pathogen Vibrio anguillarum. AB - Vibrio anguillarum, a devastating pathogen causing vibriosis among marine fish, is prevailing in worldwide fishery industries and accounts for grievous economic losses. Therefore, a rapid on-site detection and diagnostic technique for this pathogen is in urgent need. In this study, two mouse monoclonal antibodies (MAbs) against V. anguillarum, 6B3-C5 and 8G3-B5, were generated by using hybridoma technology and their isotypes were characterized. MAb 6B3-C5 was chosen as the detector antibody and conjugated with quantum dots. Based on MAb 6B3- C5 labeled with quantum dots, a modified dot blot assay was developed for the on-site determination of V. anguillarum. It was found that the method had no cross reactivity with other than V. anguillarum bacteria. The detection limit (LOD) for V. anguillarum was 1 * 10(3) CFU/ml in cultured bacterial suspension samples, which was a 100-fold higher sensitivity than the reported colloidal gold immunochromatographic test strip. When V. anguillarum was mixed with turbot tissue homogenates, the LOD was 1 * 10(3) CFU/ml, suggesting that tissue homogenates did not influence the detection capabilities. Preenrichment with the tissue homogenates for 12 h could raise the LOD up to 1 * 10(2) CFU/ml, confirming the reliability of the method. PMID- 27116992 TI - Analysis of the Fluoroquinolone Antibiotic Resistance Mechanism of Salmonella enterica Isolates. AB - Quinolone-resistant Salmonella strains were isolated from patient samples, and several quinolone-sensitive strains were used to analyze mutations in the quinolone resistance-determining region (QRDR) of gyrA, gyrB, parC, and parE and to screen for plasmid-mediated quinolone resistance. Among the 21 strains that showed resistance to nalidixic acid and ciprofloxacin (MIC 0.125-2.0 MUg/ml), 17 strains had a mutation in QRDR codon 87 of gyrA, and 3 strains had a single mutation (Ser83 -> Phe). Another cause of resistance, efflux pump regulation, was studied by examining the expression of acrB, ramA, marA, and soxS. Five strains, including Sal-KH1 and Sal-KH2, showed no increase in relative expression in an analysis using the qRT-PCR method (p < 0.05). In order to determine the genes involved in the resistance, the Sal-9 isolate that showed decreased susceptibility and did not contain a mutation in the gyrA QRDR was used to make the STM (MIC 8 MUg/ml) and STH (MIC 16 MUg/ml) ciprofloxacin-resistant mutants. The gyrA QRDR Asp87 -> Gly mutation was identified in both the STM and STH mutants by mutation analysis. qRT-PCR analysis of the efflux transporter acrB of the AcrAB-TolC efflux system showed increased expression levels in both the STM (1.79-fold) and STH (2.0-fold) mutants. In addition, the expression of the transcriptional regulator marA was increased in both the STM (6.35-fold) and STH (21.73-fold) mutants. Moreover, the expression of soxS was increased in the STM (3.41-fold) and STH (10.05-fold) mutants (p < 0.05). Therefore, these results indicate that AcrAB-TolC efflux pump activity and the target site mutation in gyrA are involved in quinolone resistance. PMID- 27116993 TI - A Strategy to Increase Microbial Hydrogen Production, Facilitating Intracellular Energy Reserves. AB - Overexpression of the genes encoding phosphoeneolpyruvate carboxykinase (pckA) and NAD-dependent malic enzyme (maeA) facilitates higher intracellular ATP and NAD(P)H concentrations, respectively, under aerobic conditions in Escherichia coli. To verify a hypothesis that higher intracellular energy reserves might contribute to H2 fermentation, wild-type E. coli strains overexpressing pckA and maeA were cultured under anaerobic conditions in a glucose minimal medium. Overexpression of pckA and maeA enabled E. coli to produce 3- times and 4-times greater H2 (193 and 284 nmol, respectively) than the wild type (66 nmol H2). The pckA and maeA genes were further overexpressed in a hydrogenase-3-enhanced E. coli strain. The hydrogenase-3-enhanced strain (W3110+fhlA) produced 322 nmol H2, whereas the ATP-enhanced strain (W3110+fhlA+pckA) produced 50% increased H2 (443 nmol). Total H2 in the NAD(P)H-enhanced strain (W3110+fhlA+maeA) was similar to that in the control strain at 319 nmol H2. Possible explanations for the contribution of the increased cellular energy reserves to the enhanced hydrogen fermentation observed are discussed based on the viewpoint of metabolic engineering strategy. PMID- 27116994 TI - NQO1-Knockout Mice Are Highly Sensitive to Clostridium Difficile Toxin A-Induced Enteritis. AB - Clostridium difficile toxin A causes acute gut inflammation in animals and humans. It is known to downregulate the tight junctions between colonic epithelial cells, allowing luminal contents to access body tissues and trigger acute immune responses. However, it is not yet known whether this loss of the barrier function is a critical factor in the progression of toxin A-induced pseudomembranous colitis. We previously showed that NADH:quinone oxidoreductase 1 (NQO1) KO (knockout) mice spontaneously display weak gut inflammation and a marked loss of colonic epithelial tight junctions. Moreover, NQO1 KO mice exhibited highly increased inflammatory responses compared with NQO1 WT (wild type) control mice when subjected to DSS-induced experimental colitis. Here, we tested whether toxin A could also trigger more severe inflammatory responses in NQO1 KO mice compared with NQO1 WT mice. Indeed, our results show that C. difficile toxin A-mediated enteritis is significantly enhanced in NQO1 KO mice compared with NQO1 WT mice. The levels of fluid secretion, villus disruption, and epithelial cell apoptosis were also higher in toxin A-treated NQO1 KO mice compared with WT mice. The previous and present results collectively show that NQO1 is involved in the formation of tight junctions in the small intestine, and that defects in NQO1 enhance C. difficile toxin A-induced acute inflammatory responses, presumably via the loss of epithelial cell tight junctions. PMID- 27116995 TI - Universal Indicators for Oil and Gas Prospecting Based on Bacterial Communities Shaped by Light-Hydrocarbon Microseepage in China. AB - Light hydrocarbons accumulated in subsurface soil by long-term microseepage could favor the anomalous growth of indigenous hydrocarbon-oxidizing microorganisms, which could be crucial indicators of underlying petroleum reservoirs. Here, Illumina MiSeq sequencing of the 16S rRNA gene was conducted to determine the bacterial community structures in soil samples collected from three typical oil and gas fields at different locations in China. Incubation with n-butane at the laboratory scale was performed to confirm the presence of "universal microbes" in light-hydrocarbon microseepage ecosystems. The results indicated significantly higher bacterial diversity in next-to-well samples compared with background samples at two of the three sites, which were notably different to oil contaminated environments. Variation partitioning analysis showed that the bacterial community structures above the oil and gas fields at the scale of the present study were shaped mainly by environmental parameters, and geographic location was able to explain only 7.05% of the variation independently. The linear discriminant analysis effect size method revealed that the oil and gas fields significantly favored the growth of Mycobacterium, Flavobacterium, and Pseudomonas, as well as other related bacteria. The relative abundance of Mycobacterium and Pseudomonas increased notably after n-butane cultivation, which highlighted their potential as biomarkers of underlying oil deposits. This work contributes to a broader perspective on the bacterial community structures shaped by long-term light-hydrocarbon microseepage and proposes relatively universal indicators, providing an additional resource for the improvement of microbial prospecting of oil and gas. PMID- 27116996 TI - Effect of linker length between variable domains of single chain variable fragment antibody against daidzin on its reactivity. AB - The peptide linker between variable domains of heavy (VH) and light (VL) chains is one of important factors that influence the characteristics of scFv, including binding activity and specificity against target antigen. The scFvs against daidzin (DZ-scFvs) with different linker lengths were constructed in the format of VH-(GGGGS)n-VL (n = 1, 3, 5, and 7). They were expressed in the hemolymph of silkworm larvae using the Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid DNA system, and their reactivity against daidzin and related compounds were evaluated using an indirect competitive enzyme-linked immunosorbent assay (icELISA), which is applicable for quantitative analysis of daidzin. The results showed that the reactivity of scFvs against daidzin was increased, whereas specificity slightly decreased when their peptide linker was lengthened. These results suggested that the linker length of DZ-scFvs contributes to its reactivity. In addition, the results emphasize that the linker length could control the reactivity of DZ scFvs. PMID- 27116997 TI - Response of relapsed central nervous system hairy cell leukemia to vemurafenib. PMID- 27116998 TI - Breast Cancer: A Molecular and Redox Snapshot. AB - SIGNIFICANCE: Breast cancer is a unique disease characterized by heterogeneous cell populations causing roadblocks in therapeutic medicine, owing to its complex etiology and primeval understanding of the biology behind its genesis, progression, and sustenance. Globocan statistics indicate over 1.7 million new breast cancer diagnoses in 2012, accounting for 25% of all cancer morbidities. RECENT ADVANCES: Despite these dismal statistics, the introduction of molecular gene signature platforms, progressive therapeutic approaches in diagnosis, and management of breast cancer has led to more effective treatment strategies and control measures concurrent with an equally reassuring decline in the mortality rate. CRITICAL ISSUES: However, an enormous body of research in this area is requisite as high mortality associated with metastatic and/or drug refractory tumors continues to present a therapeutic challenge. Despite advances in systemic chemotherapy, the median survival of patients harboring metastatic breast cancers continues to be below 2 years. FUTURE DIRECTIONS: Hence, a massive effort to scrutinize and evaluate chemotherapeutics on the basis of the molecular classification of these cancers is undertaken with the objective to devise more attractive and feasible approaches to treat breast cancers and improve patients' quality of life. This review aims to summarize the current understanding of the biology of breast cancer as well as challenges faced in combating breast cancer, with special emphasis on the current battery of treatment strategies. We will also try and gain perspective from recent encounters on novel findings responsible for the progression and metastatic transformation of breast cancer cells in an endeavor to develop more targeted treatment options. Antioxid. Redox Signal. 25, 337-370. PMID- 27116999 TI - Clinical and cognitive insight in patients with acute-phase psychosis: Association with treatment and neuropsychological functioning. AB - BACKGROUND: The severity of psychopathology cannot fully explain deficits in the multi-dimensional construct of insight. AIMS: The aim of this study was to evaluate the correlates and associations of clinical and cognitive insight in patients in an acute phase of psychosis and to analyse the impact of acute treatment on these variables. METHODS: This study examined 47 inpatients who were recently hospitalized with acute exacerbation of schizophrenia. All subjects were assessed at both admission and discharge with the Positive and Negative Syndrome Scale (PANSS), Schedule for the Assessment of Insight-Expanded Version (SAI-E), Beck Cognitive Insight Scale (BCIS), and a neurocognition battery. RESULTS: Patients with schizophrenia gained clinical insight after treatment. Cognitive insight did not change significantly after treatment. Insight showed significant negative correlations with positive symptoms and general psychopathology, but not with negative symptoms. Clinical insight was not associated with neuropsychological functioning in this cohort. CONCLUSION: Gaining clinical insight in the acute phase of illness was associated with the remission of positive symptoms, but not with neuropsychological functioning. Some significant correlations between clinical and cognitive insights were detected, which suggests that cognitive insight contributes to clinical insight but is not treatment-dependent. Long-term treatment may be required to understand the contribution of insight to the outcome of patients with schizophrenia. PMID- 27117000 TI - Proactive and Reactive Criminal Thinking and Self-Reported Offending: A Cross National Survey of Seventh- Through Ninth-Grade Boys and Girls. AB - The purpose of this study was to assess the cross-national generalizability of the moderately strong relationship between proactive criminal thinking (PCT) and reactive criminal thinking (RCT) and whether RCT correlates better with self reported offending than PCT across gender and international cluster. Correlations between PCT, RCT, and self-reported offending were calculated and compared in a cross-national sample of 59,992 (29,083 boys, 30,909 girls) seventh through ninth graders. These correlational analyses were conducted on the total sample as well as on six different international clusters. Consistent with predictions, the PCT and RCT correlated highly in all samples (.51-.62) and though the two scales achieved similar correlations with offending, the RCT correlated significantly better with offending after controlling for PCT than PCT correlated with offending after controlling for RCT. These results provide cross-national support for the supposition that RCT is a more important correlate of offending than PCT in early to mid-adolescence. PMID- 27117001 TI - Cognitive-Behavioral Therapy Efficacy for Reducing Recidivism Rates of Moderate- and High-Risk Sexual Offenders: A Scoping Systematic Literature Review. AB - This literature scoping review compared recidivism rates of moderate- and high risk sexual offenders who received cognitive-behavioral therapy (CBT) oriented treatments. Ten empirical studies from 2001 to 2014 were selected for review that met the following criteria: (a) Treatment program included a CBT-based intervention with a comparative intervention; (b) participants included adult, male, moderate- and high-risk sexual offenders only; and (c) follow-up data for up to 12 months. Data were analyzed using a summative metric for recidivism rate comparisons ( N = 3,073 for CBT and N = 3,588, for comparison approaches). Sexual offense recidivism rates varied from 0.6% to 21.8% (with CBT) and from 4.5% to 32.3% (with comparison intervention). The within-sample median rate of violent recidivism with a history of sexual offense was 21.1% (with CBT) versus 32.6% (comparison). Sexual offenders had a general felonies (within-sample) median recidivism rate of 27.05% (with CBT) versus 51.05% (comparison). The evidence supports the conclusion that CBT in its various forms is an efficacious treatment modality to prevent offense recidivism by sexual offenders. Suggestions for future research are considered. PMID- 27117002 TI - The Development of Self-Control in Late Adolescence: An Analysis of Trajectories and Predictors of Change Within Trajectories. AB - Gottfredson and Hirschi argue that parenting is the primary source of self control. Research on the etiology of self-control has provided partial support for this proposition. Studies have shown parenting is an important determinant of self-control; however, research has also shown that other social and biological/genetic factors also influence the development of self-control. The current study contributes to the literature by examining the possibility that sources of self-control may vary across subgroups, which exhibit different developmental patterns of self-control. Analyses are based on 6-year panel data from a sample of South Korean youths. The results indicate that youths are clustered into three subgroups showing stable, increasing, and decreasing levels of self-control over time. Similarities/differences in the relationships among family, school, peer, and community variables and self-control appeared across the subgroups. Theoretical and policy implications are discussed. PMID- 27117004 TI - Gut hormone secretion, gastric emptying, and glycemic responses to erythritol and xylitol in lean and obese subjects. AB - With the increasing prevalence of obesity and a possible association with increasing sucrose consumption, nonnutritive sweeteners are gaining popularity. Given that some studies indicate that artificial sweeteners might have adverse effects, alternative solutions are sought. Xylitol and erythritol have been known for a long time and their beneficial effects on caries prevention and potential health benefits in diabetic patients have been demonstrated in several studies. Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) are released from the gut in response to food intake, promote satiation, reduce gastric emptying (GE), and modulate glucose homeostasis. Although glucose ingestion stimulates sweet taste receptors in the gut and leads to incretin and gastrointestinal hormone release, the effects of xylitol and erythritol have not been well studied. Ten lean and 10 obese volunteers were given 75 g of glucose, 50 g of xylitol, or 75 g of erythritol in 300 ml of water or placebo (water) by a nasogastric tube. We examined plasma glucose, insulin, active GLP-1, CCK, and GE with a [(13)C]sodium acetate breath test and assessed subjective feelings of satiation. Xylitol and erythritol led to a marked increase in CCK and GLP-1, whereas insulin and plasma glucose were not (erythritol) or only slightly (xylitol) affected. Both xylitol and erythritol induced a significant retardation in GE. Subjective feelings of appetite were not significantly different after carbohydrate intake compared with placebo. In conclusion, acute ingestion of erythritol and xylitol stimulates gut hormone release and slows down gastric emptying, whereas there is no or only little effect on insulin release. PMID- 27117003 TI - The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. OBJECTIVE: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. METHOD: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid beta. RESULTS: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month old 3xTg mice. CONCLUSION: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation. PMID- 27117005 TI - Involvement of a proapoptotic gene (BBC3) in islet injury mediated by cold preservation and rewarming. AB - Long-term pancreatic cold ischemia contributes to decreased islet number and viability after isolation and culture, leading to poor islet transplantation outcome in patients with type 1 diabetes. In this study, we examined mechanisms of pancreatic cold preservation and rewarming-induced injury by interrogating the proapoptotic gene BBC3/Bbc3, also known as Puma (p53 upregulated modulator of apoptosis), using three experimental models: 1) bioluminescence imaging of isolated luciferase-transgenic ("Firefly") Lewis rat islets, 2) cold preservation of en bloc-harvested pancreata from Bbc3-knockout (KO) mice, and 3) cold preservation and rewarming of human pancreata and isolated islets. Cold preservation-mediated islet injury occurred during rewarming in "Firefly" islets. Silencing Bbc3 by transfecting Bbc3 siRNA into islets in vitro prior to cold preservation improved postpreservation mitochondrial viability. Cold preservation resulted in decreased postisolation islet yield in both wild-type and Bbc3 KO pancreata. However, after culture, the islet viability was significantly higher in Bbc3-KO islets, suggesting that different mechanisms are involved in islet damage/loss during isolation and culture. Furthermore, Bbc3-KO islets from cold preserved pancreata showed reduced HMGB1 (high-mobility group box 1 protein) expression and decreased levels of 4-hydroxynonenal (4-HNE) protein adducts, which was indicative of reduced oxidative stress. During human islet isolation, BBC3 protein was upregulated in digested tissue from cold-preserved pancreata. Hypoxia in cold preservation increased BBC3 mRNA and protein in isolated human islets after rewarming in culture and reduced islet viability. These results demonstrated the involvement of BBC3/Bbc3 in cold preservation/rewarming-mediated islet injury, possibly through modulating HMGB1- and oxidative stress-mediated injury to islets. PMID- 27117006 TI - Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice. AB - We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion-derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle. PMID- 27117008 TI - Electronic binding energy and thermal relaxation of Li and LiNa atomic alloying clusters. AB - We examined the effects of atomic hetero- and under-coordination on the relaxation of the interatomic bonding and electronic binding energy of Li and LiNa cluster alloying using a combination of the bond-order-length-strength correlation and density functional theory calculations. We found that bond nature alteration by heterocoordination, bond relaxation by thermal excitation and atomic coordination contribute intrinsically to the core-level energy shifts with resolution of the binding energy at the atomic sites of terrace edges, facets, and bulk of the LiNa alloy nanoclusters. Our strategies may simplify the complexity of core electron binding energies in analyzing the experimental data of the irregularly coordinating atoms. PMID- 27117007 TI - High-intensity exercise training increases the diversity and metabolic capacity of the mouse distal gut microbiota during diet-induced obesity. AB - Diet and exercise underpin the risk of obesity-related metabolic disease. Diet alters the gut microbiota, which contributes to aspects of metabolic disease during obesity. Repeated exercise provides metabolic benefits during obesity. We assessed whether exercise could oppose changes in the taxonomic and predicted metagenomic characteristics of the gut microbiota during diet-induced obesity. We hypothesized that high-intensity interval training (HIIT) would counteract high fat diet (HFD)-induced changes in the microbiota without altering obesity in mice. Compared with chow-fed mice, an obesity-causing HFD decreased the Bacteroidetes-to-Firmicutes ratio and decreased the genetic capacity in the fecal microbiota for metabolic pathways such as the tricarboxylic acid (TCA) cycle. After HFD-induced obesity was established, a subset of mice were HIIT for 6 wk, which increased host aerobic capacity but did not alter body or adipose tissue mass. The effects of exercise training on the microbiota were gut segment dependent and more extensive in the distal gut. HIIT increased the alpha diversity and Bacteroidetes/Firmicutes ratio of the distal gut and fecal microbiota during diet-induced obesity. Exercise training increased the predicted genetic capacity related to the TCA cycle among other aspects of metabolism. Strikingly, the same microbial metabolism indexes that were increased by exercise were all decreased in HFD-fed vs. chow diet-fed mice. Therefore, exercise training directly opposed some of the obesity-related changes in gut microbiota, including lower metagenomic indexes of metabolism. Some host and microbial pathways appeared similarly affected by exercise. These exercise- and diet induced microbiota interactions can be captured in feces. PMID- 27117009 TI - Long-Term High-Effort Endurance Exercise in Older Adults: Diminishing Returns for Cognitive and Brain Aging. AB - While there is evidence that age-related changes in cognitive performance and brain structure can be offset by increased exercise, little is known about the impact long-term high-effort endurance exercise has on these functions. In a cross-sectional design with 12-month follow-up, we recruited older adults engaging in high-effort endurance exercise over at least 20 years, and compared their cognitive performance and brain structure with a nonsedentary control group similar in age, sex, education, IQ, and lifestyle factors. Our findings showed no differences on measures of speed of processing, executive function, incidental memory, episodic memory, working memory, or visual search for older adults participating in long-term high-effort endurance exercise, when compared without confounds to nonsedentary peers. On tasks that engaged significant attentional control, subtle differences emerged. On indices of brain structure, long-term exercisers displayed higher white matter axial diffusivity than their age-matched peers, but this did not correlate with indices of cognitive performance. PMID- 27117010 TI - Shock absorption during transtibial amputee gait: Does longitudinal prosthetic stiffness play a role? AB - BACKGROUND: Reduced-stiffness components are often prescribed in lower-limb prostheses, but their efficacy in augmenting shock absorption has been inconclusive. OBJECTIVES: To perform a systematic variation of longitudinal prosthetic stiffness over a wide range of values and to evaluate its effect on shock absorption during gait. STUDY DESIGN: Repeated-measures crossover experiment. METHODS: Twelve subjects with a unilateral transtibial amputation walked at normal and fast self-selected speeds. Longitudinal prosthetic stiffness was modified by springs within a shock-absorbing pylon: normal (manufacturer recommended), 75% of normal (medium), 50% of normal (soft), and rigid (displacement blocked). The variables of interest were kinematic (stance-phase knee flexion and pelvic obliquity) and kinetic (prosthetic-side ground reaction force loading peak magnitude and timing). RESULTS: No changes were observed in kinematic measures during gait. A significant difference in peak ground reaction force magnitudes between medium and normal ( p = 0.001) during freely selected walking was attributed to modified walking speed ( p = 0.008). Ground reaction force peaks were found to be statistically different during fast walking, but only between isolated stiffness conditions. Thus, altering longitudinal prosthesis stiffness produced no appreciable change in gait biomechanics. CONCLUSION: Prosthesis stiffness does not appear to substantially influence shock absorption in transtibial prosthesis users. Clinical relevance Varying the level of longitudinal prosthesis stiffness did not meaningfully influence gait biomechanics at self-selected walking speeds. Thus, as currently prescribed within a transtibial prosthesis, adding longitudinal stiffness in isolation may not provide the anticipated shock absorption benefits. Further research into residual limb properties and compensatory mechanisms is needed. PMID- 27117011 TI - Clinical study on the unloading effect of hip bracing on gait in patients with hip osteoarthritis. AB - BACKGROUND: Internal hip abduction moment is a major indicator for hip loading. A new hip bracing concept was designed to unload the cartilaginous area in hip osteoarthritis via an abduction and external rotation force intended to alter the weight bearing area and reduce compression through the joint. OBJECTIVE: To assess the effect of a novel brace on hip rotation in the transverse and coronal planes and on the hip abduction moment. STUDY DESIGN: Repeated measures. METHODS: Gait analysis was performed on 14 subjects with unilateral symptomatic hip osteoarthritis. Pain, joint motion, moments and vertical ground reaction force were compared between the braced and the unbraced (control), randomly assigned, conditions. RESULTS: Nine participants felt an immediate reduction in pain while walking with the hip brace. Peak hip abduction moment significantly decreased on the osteoarthritis side ( p = 0.017). Peak hip adduction ( p = 0.004) and internal rotation ( p = 0.0007) angles significantly decreased at stance with the brace. CONCLUSION: Wearing the brace would appear to reduce the compressive joint reaction force at the femuroacetabular interface as indicated by a reduction in internal hip abduction moment along with immediate pain reduction in nine participants. Further long-term studies are warranted. Clinical relevance The brace rotates the hip in the transverse and coronal planes, possibly resulting in a decrease in load through the diseased area of cartilage. In some patients, an immediate decrease in pain was experienced. The brace offers an alternative solution for hip osteoarthritis patients not ready for a hip replacement. PMID- 27117012 TI - The effectiveness of braces and orthoses for patients with knee osteoarthritis: A systematic review of Japanese-language randomised controlled trials. AB - BACKGROUND: Knee osteoarthritis is common. The evidence regarding the effectiveness of braces and orthoses for patients with knee osteoarthritis is inconclusive according to English-language literature. English-language reviews to date have not included Japanese-language studies. OBJECTIVES: This study aimed to collect and synthesise Japanese-language randomised controlled trials investigating the effectiveness of braces and orthoses for patients with knee osteoarthritis. STUDY DESIGN: Systematic review. METHODS: Eight databases were systematically searched from inception to 29 July 2015. Only Japanese-language randomised controlled trials were included. Risk of bias was assessed using Physiotherapy Evidence Database scale. A meta-analysis was not appropriate due to the heterogeneity in the included studies. RESULTS: Seven randomised controlled trials with low to high risks of bias were included. Six of seven included studies were conducted by the same author group. Limited evidence supported the positive effects of short-lever elastic knee braces to improve pain and functional disability in specific outcomes. No evidence was found to support the use of foot orthoses, such as laterally wedged insoles, medial arch support and metatarsal arch pad. CONCLUSION: Our systematic review found no conclusive evidence about the effectiveness of any braces and orthoses for patients with medial knee osteoarthritis. Future Japanese-language studies should address methodological flaws exposed in this review and strengthen the international evidence base. Clinical relevance This is the first systematic review of Japanese language randomised controlled trials investigating orthoses for patients with knee osteoarthritis. Clinicians can consider the use of short-lever elastic knee braces to improve specifically pain on squat or walking. Evidence found in this review does not support the use of foot orthoses. PMID- 27117013 TI - The development of a low-cost three-dimensional printed shoulder, arm, and hand prostheses for children. AB - BACKGROUND AND AIM: The prosthetic options for higher level amputees are limited and costly. Advancements in computer-aided design programs and three-dimensional printing offer the possibility of designing and manufacturing transitional prostheses at very low cost. The aim of this project was to describe an inexpensive three-dimensional printed mechanical shoulder prosthesis to assist a pre-selected subject in performing bi-manual activities. TECHNIQUE: The main function of the body-powered, manually adjusted three-dimensional printed shoulder prosthesis is to provide a cost-effective, highly customized transitional device to individuals with congenital or acquired forequarter amputations. DISCUSSION: After testing the prototype on a young research participant, a partial correction of the patient's spinal deviation was noted due to the counterweight of the device. The patient's family also reported improved balance and performance of some bimanual activities after 2 weeks of using the device. Limitations of the design include low grip strength and low durability. Clinical relevance The prosthetic options for higher level amputees are limited and costly. The low-cost three-dimensional printed shoulder prosthesis described in this study can be used as a transitional device in preparation for a more sophisticated shoulder prosthesis. PMID- 27117014 TI - Static load bearing exercises of individuals with transfemoral amputation fitted with an osseointegrated implant: Loading compliance. AB - BACKGROUND: Load-bearing exercises are performed by transfemoral amputees fitted with an osseointegrated implant to facilitate bone remodelling. OBJECTIVE: This study presents the loading compliance comparing loads prescribed and applied on the three axes of the implant during static load-bearing exercises with a specific emphasis on axial and vectorial comparisons. STUDY DESIGN: Cohort study. METHODS: A total of 11 fully rehabilitated unilateral transfemoral amputees fitted with an osseointegrated implant performed five trials in four loading conditions using a static standing frame. The load prescribed was monitored using a vertical single-axis strain gauge connected to an electronic display. The tri axial forces applied on the implant were measured directly with an instrumented pylon including a six-channel transducer. The analysis included 'axial' and 'vectorial' comparisons corresponding to the difference between the force applied on the long axis of the implant and the load prescribed as well as the resultant of the three components of the load applied and the load prescribed, respectively. RESULTS: The results demonstrated that axial and vectorial differences were significant in all conditions ( p < 0.05), except for the vectorial difference for the 40 kg condition ( p = 0.182). CONCLUSION: The significant lack of axial compliance led to systematic underloading of the long axis of the implant. Clinical relevance This study contributes to a better understanding of the load applied on an osseointegrated implant during the static load-bearing exercises that could contribute to improve the design of apparatus to monitor loading exercises as well as clinical guidelines for the loading progression during rehabilitation. PMID- 27117015 TI - Twenty years of ambient observations of nitrogen oxides and specified hydrocarbons in air masses dominated by traffic emissions in Germany. AB - The analysis of the individual composition of hydrocarbon (VOC) mixtures enables us to transform observed VOC-concentrations into their respective total VOC reactivity versus OH radicals (RVOC = Sigma(kOH+VOCi * [VOCi])). This is particularly useful because local ozone production essentially depends on this single parameter rather than on the details of the underlying hydrocarbon mixture (Klemp et al., Schriften des Forschungszentrums Julich, Energy & Environment, 2012, 21). The VOC composition also enables us to pin down the major emission source of hydrocarbons in urban areas to be petrol cars with temporarily reduced catalyst efficiency (the so-called cold-start situation) whereas the source of nitrogen oxides (NOx = NO + NO2) is expected to be nowadays dominated by diesel cars. The observations in the vicinity of main roads in German cities show a decrease in the ratio of OH reactivities of VOC and NO2 (RVOC/RNO2) by a factor of 7.5 over the time period 1994-2014. This is larger than the expected decrease of a factor of 2.9 taking estimated trends of VOC and NOx traffic emissions in Germany (Umweltbundesamt Deutschland, National Trend Tables for the German Atmospheric Emission Reporting, 2015), during this time period. The observed reduction in the RVOC/RNO2 ratio leads to a drastic decrease in local ozone production driven by the reduction in hydrocarbons. The analysis reveals that the overall reduction of ozone production benefits from the low decrease of NOx emissions from road traffic which is a consequence of the eventual absence of catalytic converters for nitrogen oxide removal in diesel cars up to now. PMID- 27117016 TI - A new title and a new cover for our journal. PMID- 27117017 TI - Isolated or predominant capitolunate osteoarthritis is the consequence of lunotriquetral dissociation. X-ray analysis of 22 consecutive cases. AB - Secondary osteoarthritis due to a scapholunate malalignment is well known, but is debatable in cases of lunotriquetral malalignment. It has been shown that lunotriquetral malalignment can lead to midcarpal osteoarthritis. The hypothesis of this retrospective study was that a relationship exists between the presence of midcarpal osteoarthritis and the presence of lunotriquetral malalignment. All patients with midcarpal osteoarthritis, isolated or predominant, treated between 1981 and 2013 were reviewed. Intracarpal angles were measured and the relative position of the carpal bones was analyzed by two examiners. Osteoarthritis of the wrist's joints was quantified in three stages. Diagnosis of static dissociative ligament lesion was made and correlated with the location of osteoarthritis. Twenty-two wrists in 20 patients (13 men and 7 women; mean age of 59 years) were included. The lunocapitate osteoarthritis was moderate in 6 cases and severe in 16 cases. The radioscaphoid osteoarthritis was moderate in 5 cases and severe in 1 case. Lunotriquetral malalignment was present in all cases; it was isolated in 8 cases and associated with scapholunate malalignment in 14 cases. In isolated lunotriquetral malalignment cases, midcarpal osteoarthritis was isolated or associated with degenerative lesions of lunotriquetral interval. Cases of perilunate instability in which the osteoarthritis is more severe in the midcarpal joint than in the radioscaphoid joint likely resulted from an injurying mechanism with ulnar beginning (ulnar-sided perilunate instability). PMID- 27117018 TI - The role of extrinsic ligaments in maintaining carpal stability - A prospective statistical analysis of 85 arthroscopic cases. AB - Several biomechanical studies have shown that the scapholunate (SL) and lunotriquetral (LT) ligaments are not the only stabilizers of the proximal carpal row. However, no study has yet analyzed the range of ligament lesions leading to instability in vivo. Arthroscopy has been used to assess the condition of the wrist's extrinsic ligaments by palpating and tensioning the various ligament and capsule structures. In this prospective study, this arthroscopic method was used in 85 cases of wrist sprain without static instability to evaluate the correlation between lesions of the intrinsic and extrinsic carpal ligaments and carpal instability. In SL instability, a scapholunate interosseous ligament (SLIL) lesion was statistically correlated with lesions of the long radiolunate ligament (P<0.05). There also was a statistically significant correlation between lesions of the SLIL and the radioscaphocapitate, scaphotrapezial and dorsal intercarpal ligaments. There was a correlation between the stage of SL instability and the number of lax extrinsic ligaments (P<0.05) but not with the severity of the extrinsic ligament lesions. In LT instability, a LT interosseous ligament lesion was statistically correlated with lesions of the dorsal intercarpal ligament (P<0.05). There also was a correlation between the stage of LT instability and the number (P<0.005) and severity (P<0.001) of the extrinsic ligament lesions. Arthroscopy can reveal hidden radiographic instability and can also be used to define the number and severity of injured ligaments. In carpal instability, a lesion of one intrinsic carpal ligament was associated with a lesion of one or more extrinsic ligaments. PMID- 27117019 TI - No correlation between severity of preoperative degenerative changes in the trapeziometacarpal joint and short-term clinical outcome after total joint arthroplasty. AB - In this study, we wanted to investigate whether the severity of preoperative degenerative changes in the trapeziometacarpal (TM) joint seen on CT scans would influence the clinical outcomes after total TM joint arthroplasty, and particularly whether discrete degenerative changes in the scaphotrapezial (ST) joint would negatively affect the clinical outcome. Patients classified as Eaton Glickel stage 2 or 3, as well as patients with Eaton-Glickel stage 4 disease who had discrete degenerative changes in the ST joint (i.e., narrowing and sclerotic changes but no osteophytes) were included in the study; patients with more severe degenerative changes of the ST joint were excluded. Follow-up was done using the Disability of Arm, Shoulder and Hand (DASH) score at 3, 6 and 12 months after surgery together with grip strength and pain using a 100-mm visual analog scale. In all, 59 patients with 69 total joint arthroplasties were included in the study; there were 47 females and 12 males with a mean age of 59 years (range 41 77). We found no significant difference between the three patient groups in their improvement in grip strength from preoperative to 12 months. Also we found no statistically significant differences in the DASH score or pain level at rest or during activity between the preoperative and all the postoperative time points. Total TM joint arthroplasty can produce excellent short-term clinical results with a good restoration of grip strength and function. Discrete degenerative changes in the ST joint appear not to be a contraindication for treating TM joint osteoarthritis with total joint arthroplasty. PMID- 27117020 TI - Trapeziectomy and ligament reconstruction tendon interposition after failed trapeziometacarpal joint replacement. AB - Total trapeziometacarpal (TMC) joint replacement is increasingly being performed for the treatment of basal joint arthritis. However, complications such as instability or loosening are also frequent with TMC ball-and-socket joint replacement. Management of these complications lacks consensus. The purpose of this study was to report the results of 12 cases of failed TMC joint replacement that were treated by trapeziectomy with ligament reconstruction and tendon interposition (LRTI) arthroplasty. The follow-up consisted of functional (numerical scale, DASH score, satisfaction), physical (range of motion, strength) and radiological (Barron and Eaton ratio measurement) assessments. At a mean follow-up of 21 months, 11 patients were satisfied or very satisfied after surgery. The mean pain score was 2/10 and the mean DASH score 30/100. Mean thumb palmar and radial abduction was 40 degrees . Thumb opposition measured by the Kapandji technique was 9/10. The height ratio was slightly increased. Trapeziectomy with LRTI after TMC joint replacement appears to be an attractive salvage procedure. PMID- 27117021 TI - Foreign body reaction after trapeziectomy and Dacron interposition. AB - The purpose of this study was to evaluate patients who were treated with trapeziectomy and Dacron interposition in our hospital and to describe the incidence of foreign body reactions. Between 2004 and 2010, 10 women with trapeziometacarpal osteoarthritis underwent Dacron interpositional arthroplasty. One patient had surgery in both hands. Implants were removed in two patients, 5 and 8 years postoperatively. Histological analysis confirmed the presence of a foreign body reaction with giant cells in both cases. At a mean follow-up of 9 years, seven patients with the implant still in place were available for review and clinical examination. Mean DASH score was 32 and mean VAS for pain and satisfaction was 1.6 and 8.8, respectively. Mean grip strength was 11.4kg and mean key pinch strength was 1.5kg. Recent radiographs were available in nine hands. Seven out of nine hands had radiological signs of a foreign body reaction with bone erosion. A severe reaction occurred in three patients. We no longer use the Dacron implant and recommend careful monitoring of all patients in whom this implant has been used. PMID- 27117022 TI - Functional treatment of metacarpal diaphyseal fractures by buddy taping: A prospective single-center study. AB - Metacarpal diaphyseal fractures are classically treated using a non-removable glove for 4 to 6 weeks. Here, we report the results of treatment by immediate active protected mobilization (buddy taping for four weeks) of minimally displaced M2 to M5 fractures. Fifty-four fractures (15 transverse or short oblique and 39 spiral or long oblique) in 51 patients were included during a one year period; the average age of patients was 31 years. Clinical and radiographic assessments were carried out at day 15 and then months 1, 2 and 6 post-fracture. Thirty-one cases were reviewed at day 15, 27 at 1 month, and 22 at 2 months. The initial volar tilt was 26 degrees on average for the short oblique or transverse fractures, and 11.5 degrees for the long oblique or spiral fractures. Six fractures (11%) experienced 16.6 degrees of secondary displacement on average. The fracture was healed in 37% of cases at 1 month, and in 100% of cases at 2 months in the patients who were reviewed clinically. Reduction in the QuickDASH and VAS for pain was evidence of fast functional recovery. The range of motion was comparable to that of the contralateral side in 90% cases after 2 months. Grip and pinch strength was 33% less than the contralateral side at 2 months. Although secondary displacement occurs in some cases, the functional results of this simple and practical treatment method are good after 2 months, as there is little pain, stiffness, strength loss and no cases of nonunion. PMID- 27117023 TI - Acute felon and paronychia: Antibiotics not necessary after surgical treatment. Prospective study of 46 patients. AB - Paronychia and felon are the most common infections of the hand. Surgical treatment is required once an abscess develops, but systematic use of postoperative antibiotic therapy remains open for discussion. Antibiotics both favor the selection of resistant bacteria and increase the cost of treatment. To our knowledge, no study has demonstrated their benefit following excision, yet many practitioners prescribe them systematically and empirically. In our current practices, we do not use antibiotic coverage following excision of uncomplicated paronychia or felon (no signs of arthritis, osteitis, flexor tenosynovitis, lymphangitis), except in potentially at-risk patients (immunosuppressed, diabetic, cardiac valve prosthesis recipient). Since this approach seems to lead to good outcomes, our objective was to evaluate them clinically in this study. Our prospective study included 46 patients who were not considered at risk. There were 26 cases of paronychia, 3 cases of felon and 17 patients presenting both paronychia and felon. All cases were abscessed and uncomplicated. All patients underwent surgical excision, and none received postoperative antibiotics. Follow up took place on the day after surgery, at days 7, 14, 21 and 45. The main criterion for evaluation was healing of the infection and the wound. We recorded 45 cases of healing with no complications and a single case of recurrence. Surgical excision of paronychia or felon without antibiotic coverage gives excellent results with only rare recurrence. The single failure can be attributed to inadequate excision. Antibiotic therapy has no role in managing uncomplicated felon or paronychia in patients who are otherwise not at risk. Successful treatment depends above all on the completeness of the surgical excision. PMID- 27117025 TI - Injury mechanisms in supraclavicular stretch injuries of the brachial plexus. AB - The aim of this study was to describe the mechanisms involved in stretch injuries of the brachial plexus. One hundred and fifty consecutive patients with supraclavicular brachial plexus injuries (BPI) were asked about the mechanism of injury during the actual injury event, particularly about the type of trauma to their shoulder, shoulder girdle and head. Fifty-seven of the patients provided enough information about their accident to allow for analysis of the shoulder trauma. The injury mechanism for all patients having upper root or total palsy (n=46) was described as a direct vertical impact to the shoulder. In 44 of these patients, the trauma followed a motorcycle accident and, in most of them, the patient hit a fixed vertical structure before falling to the ground. The injury mechanism for the lower root palsy cases (n=11) was variable. The most frequent mechanism was forceful anterior shoulder compression by a car seat belt. We found that injury mechanisms differed significantly from the ones commonly discussed in published studies. PMID- 27117024 TI - Medial collateral ligament healing after posttraumatic radial head arthroplasty: A retrospective study of 33 cases with a mean follow-up of 73 months. AB - Comminuted radial head fractures are usually associated with destabilizing lesions of the elbow. The radial head prosthesis (RHP) is a therapeutic alternative when fracture fixation is impossible, as it restores one of the elbow's secondary stabilizers. The aim of this study was to assess healing of the medial collateral ligament (MCL) after implantation of a RHP. All patients implanted with a RHP during the 2003-2012 period were eligible for follow-up ultrasound evaluation of MCL healing. A clinical evaluation with standardized tests (DASH and MEPS) was performed and the patients asked to evaluate their elbow's stability during the same follow-up visit. Out of the 33 eligible patients, 20 were included with a mean follow-up of 73 months. The MCL had been torn in 15 of these 20 patients; the MCL appeared healed on the ultrasound images in 13 patients. The elbow was considered subjectively stable in 19 patients. The mean DASH score was 21.4 (+/-16.67) and the mean MEPS was 84.7 (+/-13.9); these scores were 17.19 (+/-14.0) and 88.3 (+/-10.9) for patients with a healed MCL, versus 32.5 (+/-10.6) and 70 (+/-0.0) for patients with a non-healed MCL. Our findings suggest that a torn MCL can heal after RHP implantation, even without surgical ligament repair or reattachment. PMID- 27117026 TI - Comparison of the effects of different vasoactive and antiplatelet drugs on perforator flap viability. An experimental study. AB - Perforator flaps are very popular in the reconstruction of soft tissue defects. As these flaps generally depend on a single perforator, drugs that increase the perfusion of the flap and/or prevent vascular complications may increase flap survival. In this study, we compared the effects of systemically administered hydralazine (arterial vasodilator via potassium channels), nifedipine (arterial vasodilator via calcium channels), piracetam (antiplatelet and regulator of microcirculation) and alprostadil (vasodilator, antiplatelet, rheological and cytoprotective) on flap survival in a rat epigastric artery perforator flap model. The percentage of necrosis was measured on each flap and evaluated using one-way analysis of variance (Anova). Histopathological analyses were also performed. Mean flap survival area was 3.85 cm(2) in the control group. Mean flap survival area was 4.88 cm(2) in the nifedipine group, 4.69 cm(2) in the hydralazine group, 10.55 cm(2) in the piracetam group and 11.3 cm(2) in the alprostadil group. When compared with the control group, all drugs except hydralazine improved flap survival; piracetam and alprostadil yielded significantly better results than nifedipine. Only the alprostadil group showed signs of improved vascularity in the histological analysis. As far as perforator flap survival is concerned, drugs that regulate the microcirculation by a combination of different antiaggregation mechanisms appear more beneficial than single action vasodilators. Alprostadil, a synthetic PGE-1 analogue, has combined antiplatelet and vasoactive effects that further increase flap survival. PMID- 27117027 TI - What are the ethical boundaries to innovation? PMID- 27117028 TI - Physiological role and clinical utility of inositols in polycystic ovary syndrome. AB - During the last decades, a substantial body of research has focused on the role of the two major inositol (Ins) stereoisomers, myoinositol (myoIns) and D chiroinositol (D-chiroIns), both second messengers of insulin, in insulin dependent processes, including polycystic ovary syndrome (PCOS). MyoIns has been shown to affect different pathways at both ovarian and non-ovarian level. On the contrary, D-chiroIns alone is unable to exert significant improvements in the ovarian cell functions, as its beneficial effects are mainly limited to the non ovarian tissue in which it may significantly inhibit the negative cellular consequences of hyperinsulinemia. However, both Ins isomers can be positively associated in the management of PCOS patients in a ratio corresponding to their physiological plasma ratio (40:1). This appears to exert a synergistic effect according to a multi-targeted design. In this respect, new fundamental insights into the biological mechanisms displayed by Ins, as well as clinical trials based on the myoIns + D-chiroIns formulations, have already provided encouraging results. PMID- 27117030 TI - Glutathione reductase gsr-1 is an essential gene required for Caenorhabditis elegans early embryonic development. AB - Glutathione is the most abundant thiol in the vast majority of organisms and is maintained in its reduced form by the flavoenzyme glutathione reductase. In this work, we describe the genetic and functional analysis of the Caenorhabditis elegans gsr-1 gene that encodes the only glutathione reductase protein in this model organism. By using green fluorescent protein reporters we demonstrate that gsr-1 produces two GSR-1 isoforms, one located in the cytoplasm and one in the mitochondria. gsr-1 loss of function mutants display a fully penetrant embryonic lethal phenotype characterized by a progressive and robust cell division delay accompanied by an aberrant distribution of interphasic chromatin in the periphery of the cell nucleus. Maternally expressed GSR-1 is sufficient to support embryonic development but these animals are short-lived, sensitized to chemical stress, have increased mitochondrial fragmentation and lower mitochondrial DNA content. Furthermore, the embryonic lethality of gsr-1 worms is prevented by restoring GSR-1 activity in the cytoplasm but not in mitochondria. Given the fact that the thioredoxin redox systems are dispensable in C. elegans, our data support a prominent role of the glutathione reductase/glutathione pathway in maintaining redox homeostasis in the nematode. PMID- 27117029 TI - Oncometabolites: Unconventional triggers of oncogenic signalling cascades. AB - Cancer is a complex and heterogeneous disease thought to be caused by multiple genetic lesions. The recent finding that enzymes of the tricarboxylic acid (TCA) cycle are mutated in cancer rekindled the hypothesis that altered metabolism might also have a role in cellular transformation. Attempts to link mitochondrial dysfunction to cancer uncovered the unexpected role of small molecule metabolites, now known as oncometabolites, in tumorigenesis. In this review, we describe how oncometabolites can contribute to tumorigenesis. We propose that lesions of oncogenes and tumour suppressors are only one of the possible routes to tumorigenesis, which include accumulation of oncometabolites triggered by environmental cues. PMID- 27117031 TI - Use of antidepressants in Parkinson's disease: A Swedish register-based study of over 1.5 million older people. AB - INTRODUCTION: It has been suggested that depression in Parkinson's Disease (PD) is often unrecognized and undertreated. However, few previous studies have studied the use of antidepressants in a large sample of both home-dwelling and institutionalized elderly persons with PD. We aimed to study the use of antidepressants in older persons using anti-parkinson drugs (APD, used as a proxy for PD), stratified by residential setting. METHODS: We analyzed individual data on age, sex, residential setting and drug use in over 1.5 million older persons in the Swedish Prescribed Drug Register on 31th of December 2013. RESULTS: Twenty two percent of the home-dwellers and 50% of the institutionalized elderly persons with APD used antidepressants. Persons with APD had a higher probability of use of any antidepressant compared to persons without APD. A selective serotonin reuptake inhibitor (SSRI) was the most commonly used antidepressants in both settings followed by mirtazapin. CONCLUSIONS: The high use of antidepressants among older persons with APD warrants further studies on the quality of treatment of depression in PD. PMID- 27117032 TI - Development of a web-based tool for automated processing and cataloging of a unique combinatorial drug screen. AB - Facing totally resistant bacteria, traditional drug discovery efforts have proven to be of limited use in replenishing our depleted arsenal of therapeutic antibiotics. Recently, the natural anti-bacterial properties of metal ions in synergy with metal-coordinating ligands have shown potential for generating new molecule candidates with potential therapeutic downstream applications. We recently developed a novel combinatorial screening approach to identify compounds with copper-dependent anti-bacterial properties. Through a parallel screening technique, the assay distinguishes between copper-dependent and independent activities against Mycobacterium tuberculosis with hits being defined as compounds with copper-dependent activities. These activities must then be linked to a compound master list to process and analyze the data and to identify the hit molecules, a labor intensive and mistake-prone analysis. Here, we describe a software program built to automate this analysis in order to streamline our workflow significantly. We conducted a small, 1440 compound screen against M. tuberculosis and used it as an example framework to build and optimize the software. Though specifically adapted to our own needs, it can be readily expanded for any small- to medium-throughput screening effort, parallel or conventional. Further, by virtue of the underlying Linux server, it can be easily adapted for chemoinformatic analysis of screens through packages such as OpenBabel. Overall, this setup represents an easy-to-use solution for streamlining processing and analysis of biological screening data, as well as offering a scaffold for ready functionality expansion. PMID- 27117033 TI - Hypermanganesemia with Dystonia, Polycythemia and Cirrhosis (HMDPC) due to mutation in the SLC30A10 gene. AB - Manganese (Mn) is an essential element for metabolic pathways but it can be toxic when present in excessive amounts in the body. Hypermanganesemia along with dystonia, polycythemia, characteristic MRI brain findings in the basal ganglia, and chronic liver disease are the hallmarks of an inherited Mn transporter defect due to mutations in the SLC30A10 gene. We are reporting three siblings who presented with features of dystonia, polycythemia, MRI brain showing basal ganglia hyperintensity on T1 weighted images and chronic liver disease. Blood Mn levels were markedly elevated in the affected patients. Mutation analysis of DNA samples of the affected children confirmed a homozygous missense mutation in SLC30A10. Chelation therapy with intravenous disodium calcium edetate was started in two siblings and led to a marked decrease in whole blood Mn. Oral Penicillamine was later added to the therapy which further improved blood Mn levels. This is a rare disorder and is one of the potentially treatable inherited metal storage disorders. It can be fatal if left untreated. Penicillamine may be an effective alternative to disodium calcium edetate. PMID- 27117034 TI - A compound heterozygous EARS2 mutation associated with mild leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). AB - Mitochondrial glutamyl-tRNA synthetase is a major component of protein biosynthesis that loads tRNAs with cognate amino acids. Mutations in the gene encoding this enzyme have been associated with a variety of disorders related to oxidative phosphorylation. Here, we present a case of leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) presenting a biphasic clinical course characterized by delayed psychomotor development and seizure. High-throughput sequencing revealed a novel compound heterozygous mutation in mitochondrial glutamyl-tRNA synthetase 2 (EARS2), which appears to be causative of disease symptoms. PMID- 27117035 TI - A case of succinic semialdehyde dehydrogenase deficiency with status epilepticus and rapid regression. AB - BACKGROUND: Clinical phenotypic expression of SSADH deficiency is highly heterogeneous, and some infants may develop refractory secondary generalized seizures. PATIENT: A 9-month-old boy manifested partial seizures, developing severe status epilepticus, and conventional antiepileptic drugs were ineffective. Use of ketamine contributed to the control of status epilepticus, achieving a reduction in frequency of partial seizures, and improving EEG findings without apparent complications. Diffusion-weighted images showed hyperintensities in the bilateral basal ganglia and fornix, and multiple T2 hyperintensity lesions were detected. (123)I-iomazenil (IMZ) SPECT revealed a decrease in binding of (123)I iomazenil predominantly in the left temporal region by the 18th day of hospitalization. However, repeated IMZ-SPECT on the 46th day of hospitalization demonstrated almost no accumulation across a broad region, sparing the left temporal region. The patient showed rapid regression, refractory myoclonus, and severe progressive brain atrophy. CONCLUSION: IMZ-SPECT findings demonstrated reduced benzodiazepine receptor binding and its dynamic changes in an SSADH deficient patient. Considering the down regulation of the GABAA receptor, ketamine should be included in pharmacotherapeutic strategies for treatment of refractory status epilepticus in SSADH-deficient patients. PMID- 27117036 TI - Warfarin dose requirements with different genotypes of CYP2C9 and VKORC1 for patients with atrial fibrillation and valve replacement. AB - AIMS: To investigate whether genetic variants of CYP2C9 and VKORC1 have different effects on the dose of warfarin in 180 Han Chinese patients who were recruited from the Fu Wai Hospital. All were on maintenance treatment with stable daily warfarin doses for a period of at least 3 months. METHODS: DNA was isolated and genotyped using a Warfarin dosage Prediction Kit for single nucleotide polymorphisms (SNPs) of CYP2C9 and VKORC1. RESULTS: The VKORC1 and CYP2C9*3 polymorphisms are significantly associated with warfarin maintenance dosages. Patients with AG&GG genotype in VKORC1 needed higher doses than those with AA genotypes (4.55 +/- 1.27 mg/ day vs. 2.90 +/- 0.97 mg/day, p < 0.001). Patients with *1/*3 genotype in CYP2C9 need doses lower than those with *1/*1 genotypes (1.73 +/- 0.95 mg/day vs. 3.23 +/- 1.13 mg/day, p < 0.001). There were no significant differences between the warfarin maintenance dosages in patients with atrial fibrillation (3.09 +/- 1.16 mg/day), patients with heart valve replacement (2.95 +/- 1.21 mg/day) and those with both atrial fibrillation and heart valve replacement (3.36 +/- 1.13 mg/day) (p > 0.05). The mean warfarin daily dose requirements in the genotypes of VKORC1 and CYP2C9 were not dependent on the medical indication(s) present. CONCLUSIONS: Genetic variants of CYP2C9, VKORC1, and age are significant determinants of the maintenance dose of warfarin. The medical indications atrial fibrillation, valve replacement, or a combination of both are not determinants of the warfarin dose requirements. PMID- 27117037 TI - Evolocumab and alirocumab: exploring original procurement models to manage the reimbursement of these innovative treatments. AB - BACKGROUND: PCSK9 inhibitors (evolocumab and alirocumab) pose a challenge of sustainability because the potential patients are extremely numerous and the budget impact at the drugs' full price would be prohibitive. We have studied the reimbursability of these agents by constructing a series of price-volume simulations that used a model previously employed for sofosbuvir. METHODS: Our price-volume model is based on the following parameters: I) total patients candidate to the treatment; II) patients actually treated; III) treatment full cost per patient; IV) estimated nationwide budget impact in the absence of any price-volume intervention; V) price-halving population (PHP), which is the main model parameter. Treated patients ranged from 30,000 to 100,000. The full nominal yearly cost per patient was set at 10,000 ?. RESULTS: In 9 price-volume simulations (testing three values of PHP at 25,000 or 50,0000 or 100,000 patients), the total national expenditure varied from 204 to 721 million ?. In the least expensive scenario (PHP = 25,000 patients), the expenditure ranged from 204 to 338 million ? while the average treatment cost per year was 3,382 ?. At more than 100,000 treated patients, the treatment cost reduced to 626 ?. On the other hand, the scenarios based on PHP = 50,000 and PHP = 100,000 patients were very unlikely to be acceptable for national health systems. CONCLUSIONS: Our study offered a pattern of different scenarios among which some national health systems in Europe could select the "true" decision on PCSK9 inhibitors. This decision is expected to be made over the next few months. PMID- 27117038 TI - Population pharmacokinetic characteristics of sirolimus in healthy Chinese subjects and renal transplant patients. AB - AIM: To identify the factors affecting the pharmacokinetics (PKs) of sirolimus in healthy Chinese subjects and renal transplant patients. METHODS: A population PK model of sirolimus was constructed using dense data from 22 healthy volunteers and sparse data from 105 renal transplant patients. RESULTS: The data were well described by a two-compartment model with first-order absorption. The estimates of absorption rate constant (Ka), clearance (CL/F), and central volume of distribution (V2/F) were 0.24 h(-1), 8.81 L/h, and 676 L, respectively. The CL/F in renal transplant patients was 45.5% lower than that in healthy subjects. Based on the final model, CL/F decreased significantly with increasing cyclosporine (CsA) daily dose and age. A decrease of 7.3% in CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in CL/F for every 20-year increase in age was observed. Moreover, V2/F increased significantly with increasing serum creatinine in our study. However, the range of serum creatinine concentration and the interindividual variability for V2/F are large. CONCLUSION: This is the first study to characterize the population PKs of sirolimus using a two-compartment model in healthy Chinese subjects and renal transplant patients. A decrease of 7.3% in the sirolimus CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in the sirolimus CL/F for every 20-year increase in age was observed, which allowed us to better optimize sirolimus dosing regimens in Chinese renal transplant patients. PMID- 27117039 TI - Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities. AB - OBJECTIVES: To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. MATERIALS: Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). METHOD: The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. RESULTS: Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database enables the user to sort and download targeted information as a Microsoft Excel spreadsheet. CONCLUSION: Because of the comprehensive and standardized nature of the clinical drug trial database and its ease of access it should serve as valuable information repository and research tool for accessing clinical trial information and making evidence-based decisions by regulatory professionals, clinical research investigators, and medical practitioners. PMID- 27117040 TI - Prolonged effects of miconazole oral gel on warfarin anticoagulation even after treatment withdrawal. AB - OBJECTIVE: We investigated the effect of terminating miconazole oral gel (MOG) treatment on the anticoagulant activity of warfarin by evaluating changes in international normalized ratio levels (INR). METHODS: Data were collected from the medical records of 6 patients treated with warfarin and MOG. RESULTS: Following cessation of MOG treatment, increased INR and INR/dose levels were observed for an average of 15 days, showing that the anticoagulant activity of warfarin was increased for ~ 2 weeks. CONCLUSIONS: Closer monitoring of INR levels for at least 2 weeks may be required upon withdrawal of MOG treatment in patients treated with warfarin. PMID- 27117041 TI - Detection of pulmonary and coronary artery anomalies in tetralogy of Fallot using non-ECG-gated CT angiography. AB - OBJECTIVES: To evaluate the use of non-ECG-gated computed tomography (CT) angiography to describe pulmonary and coronary defects in patients with tetralogy of Fallot (TOF). PATIENTS AND METHODS: This retrospective study was carried out on TOF patients having undergone pre-operative non-ECG-gated CT angiography between February 2007 and September 2012. The following clinical parameters were recorded: mean age at CT angiography, sex, the existence of genetic disease and the need to sedate the patient prior to CT angiography. CT data were analyzed retrospectively to determine the site(s) of pulmonary stenosis (infundibular, valvular or arterial), the size of pulmonary arteries and the presence of anomalous coronary artery courses. CT findings were then compared to the anatomy observed during surgery. RESULTS: Thirty-five patients were included in the study. The mean age was 4.30+/-1.91months (boys/girls=17/18). Two patients had associated chromosome disorders (one 22q11 microdeletion and one CHARGE syndrome). Sixteen patients (45.71%) were sedated prior to CT. Pulmonary artery assessment revealed 24 patients (68.57%) with infundibular stenosis, 5 (17.5%) with infundibular and/or valvular stenosis, and 6 (21%) with anomalous pulmonary arteries. CT angiography also evidenced anomalous coronary arteries in 8 patients (22.85%). CONCLUSION: Due to its reduced scanning time and high spatial resolution, non-ECG-gated CT angiography is a non-invasive imaging modality that provides accurate information on pulmonary and coronary artery anatomy in patients with TOF. PMID- 27117042 TI - [Self-esteem, resilience, locus of control and suicide risk in nursing students]. AB - AIM: Assuming that suicide is the result of a series of factors acting cumulatively, the aim of this paper was to study the association of self-esteem, resilience and locus of control with the risk of suicidal behavior in a sample of nursing students. METHOD: Observational, cross-sectional and correlational study with 186 nursing students who answered a questionnaire that contained, in addition to demographic data, the Spanish forms of Rosenberg self-esteem scale, the brief resilient coping scale, the Plutchik scale of suicide risk and the Rotter's internal-external locus of control scale. RESULTS: The scores of males and females are very similar on all scales except Locus of Control, where a significantly greater tendency of females attributed to external control. 6.4% of students have scores indicating suicide risk. Suicide risk scores correlated negatively and significantly with self-esteem and resilience and positively with locus of control. The multiple linear regression analysis identified self-esteem as the main variable related to suicide risk. CONCLUSIONS: The results suggest that students who have low self-esteem, have difficulty in adjusting to adverse situations and tend to the external attribution of the consequences of their actions may have an increased risk of suicidal behavior. Furthermore, the identification of self-esteem as the important factor involved in suicide risk can help in designing prevention programs. PMID- 27117043 TI - Total shoulder arthroplasty in patients with HIV infection: complications, comorbidities, and trends. AB - BACKGROUND: Patients with human immunodeficiency virus (HIV) infection were previously at substantial risk for immunosuppression-related complications. As a result of highly active antiretroviral therapy, HIV-infected patients are living longer and are presenting for elective surgery. Outcomes in HIV-infected patients are well described for hip and knee arthroplasty but not for total shoulder arthroplasty (TSA). The purpose of this study was to examine postoperative complications of TSA in HIV-positive patients. METHODS: We queried the entire 2005 to 2012 Medicare database. Current Procedural Terminology and International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify the procedure, demographics, comorbidities, and postoperative complications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: The query returned 2528 HIV-positive patients who underwent TSA or reverse TSA (RTSA). There was increased utilization of TSA and RTSA in this population from 2005 to 2012; 1353 patients had 2-year follow-up. These patients were slightly older and had higher prevalence of comorbidities, suggesting a sicker cohort. HIV-positive patients had alarmingly higher rates of 90-day cerebrovascular accident (OR, 35.98; CI, 30.34-42.67). HIV-positive patients had higher overall rates of broken prosthetic joints (OR, 1.72; CI, 1.20 2.47), periprosthetic infection (OR, 1.36; CI, 1.01-1.82), and TSA revision or repair (OR, 2.44; CI, 1.81-3.28). CONCLUSIONS: To our knowledge, this is the first study that directly examines the postoperative outcomes of HIV-positive patients after TSA or RTSA. As more of these patients present for surgery, surgeons should be aware that these patients might be at increased risk for certain postoperative surgical and medical complications. PMID- 27117044 TI - On-resin Diels-Alder reaction with inverse electron demand: an efficient ligation method for complex peptides with a varying spacer to optimize cell adhesion. AB - Solid phase peptide synthesis (SPPS) is the method of choice to produce peptides. Several protecting groups enable specific modifications. However, complex peptide conjugates usually require a rather demanding conjugation strategy, which is mostly performed in solution. Herein, an efficient strategy is described using an on-resin Diels-Alder reaction with inverse electron demand (DARinv). This method is compatible with the standard Fmoc/tBu strategy and is easy to monitor. As a proof of concept a titanium binding peptide was modified with a cyclic cell binding peptide (RGD) by DARinv on a solid support applying different tetrazines and alkenes. The generated bulky DARinv linkers were employed to act as the required spacer for RGD mediated cell adhesion on titanium. In vitro studies demonstrated improved cell spreading on DARinv-conjugated peptides and revealed, in combination with molecular dynamics-simulation, new insights into the design of spacers between the RGD peptide and the surface. Performing the DARinv on resin expands the toolbox of SPPS to produce complex peptide conjugates under mild, catalyst free conditions with reduced purification steps. The resulting conjugate can be effectively exploited to promote cell adhesion on biomaterials. PMID- 27117045 TI - An exploration of exercise-induced cognitive enhancement and transfer effects to dietary self-control. AB - The primary objective of this study was to examine the effects of aerobic exercise on executive function, specifically inhibitory control, and the transfer to self-control in the dietary domain. It was hypothesized that exercise would enhance inhibitory control, and that this enhancement would facilitate self control in a laboratory taste test paradigm. Using a crossover design, 51 participants completed counterbalanced sessions of both moderate exercise (experimental condition) and minimal effort walking (control condition) using a treadmill; the intersession interval was 7days. Prior to each exercise bout participants completed a Stroop task. Following each bout participants completed a second Stoop task, as well as a bogus taste test involving three appetitive calorie dense snack foods and two control foods; the amount of each food type consumed during the taste test was covertly measured. Results revealed that moderate exercise significantly improved performance on the Stroop task, and also reduced food consumption during the taste test for appetitive calorie dense snack foods; there was no exercise effect on control food consumption. Exercise-induced gains in Stroop performance mediated the effects of moderate exercise on appetitive snack food consumption. Together these findings provide evidence that a bout of a moderate aerobic exercise can enhance inhibitory control, and support for cross-domain transfer effects to dietary self-control. PMID- 27117046 TI - Corrigendum to "Comparison of transport methods for patients with ST-elevation myocardial infarction to a percutaneous coronary intervention center and determination of factors influencing long-term mortality" [Int. J. Cardiol. 202 (2016) 135-137]. PMID- 27117047 TI - Erratum to "Exploring potential mortality reductions in 9 European countries by improving diet and lifestyle: A modelling approach" [Int. J. Cardiol. 207 (2016) 286-291]. PMID- 27117048 TI - Right Place, Right Time: Focalization of Membrane Proteins in Gram-Positive Bacteria. AB - Membrane proteins represent a significant proportion of total bacterial proteins and perform vital cellular functions ranging from exchanging metabolites and genetic material, secretion and sorting, sensing signal molecules, and cell division. Many of these functions are carried out at distinct foci on the bacterial membrane, and this subcellular localization can be coordinated by a number of factors, including lipid microdomains, protein-protein interactions, and membrane curvature. Elucidating the mechanisms behind focal protein localization in bacteria informs not only protein structure-function correlation, but also how to disrupt the protein function to limit virulence. Here we review recent advances describing a functional role for subcellular localization of membrane proteins involved in genetic transfer, secretion and sorting, cell division and growth, and signaling. PMID- 27117049 TI - The Commonalities in Bacterial Effector Inhibition of Apoptosis. AB - Antiapoptotic pathways of the host cell play integral roles in bacterial pathogenesis, with inhibition of those pathways resulting in halted disease pathology. Certain pathogens have developed elegant mechanisms to modulate the fate of the host cell, many of which target novel pathways that are poorly understood in the context of the cell biology. Bacterial pathogenesis research not only promotes the understanding of the role of antiapoptotic pathways in bacterial infection, but has a broader context in understanding the epitome of human disease, that is, developing the understanding of tumorigenic or inflammatory pathways. Here we review host antiapoptotic signalling pathways manipulated by translocated bacterial effectors that propagate the disease state, drawing common parallels and showing the novel differences. PMID- 27117050 TI - Snbeta-zeolite catalyzed oxido-reduction cascade chemistry with biomass-derived molecules. AB - High activity of post-synthetically synthesized Sn-beta, producing novel caprolactone polymer building blocks, is demonstrated in Meerwein-Ponndorf-Verley (MPV), Oppenauer (OPO), Baeyer-Villiger (BV) and cascade reactions thereof with biomass-derived molecules. PMID- 27117051 TI - Characterization of TNF-alpha- and IL-17A-Mediated Synergistic Induction of DEFB4 Gene Expression in Human Keratinocytes through IkappaBzeta. AB - Human beta-defensin 2 (hBD2), encoded by the DEFB4 gene, is an antimicrobial peptide playing an essential role in inflammatory processes in the skin. hBD2 expression is regulated synergistically by tumor necrosis factor-alpha (TNF alpha) and IL-17A; however, the underlying regulatory mechanisms are unknown. The purpose of this study was to characterize the molecular mechanism by which TNF alpha and IL-17A synergistically induce hBD2 expression. In cultured human keratinocytes we show that a constitutive noninducible binding of the transcription factor organic cation transporter 1 (OCT1) to the DEFB4 promoter is crucial for IL-17A/TNF-alpha-mediated synergistic induction of hBD2 but not the synergistic induction of CCL20, IL8, IL17C and LCN2. Interestingly, stimulation with IL-17A results in a p38 mitogen-activated protein kinase-dependent accumulation of inhibitor of nuclear factor kappaB zeta (IkappaBzeta), which is a necessity for synergistic induction of hBD2. Finally, co-stimulation with TNF alpha induces DNA binding of NF-kappaB and activator protein 1 (AP-1) to two specific sites in the DEFB4 promoter region. Hence, our study shows how two inflammatory stimuli are integrated by three different signaling pathways into the regulation of one specific target gene involving the three specific transcription factors OCT1, NF-kappaB, and AP-1 as well as the transcriptional cofactor IkappaBzeta. These findings may be important in psoriasis, where TNF alpha and IL-17A have been identified as key pathogenic cytokines. PMID- 27117052 TI - Endoscopic treatment of grades IV and V vesicoureteral reflux with two bulking substances: Dextranomer hyaluronic acid copolymer versus polyacrylate polyalcohol copolymer in children. AB - PURPOSE: We aimed at evaluating the efficacy and complications of two bulking substances: dextranomer/hyaluronic acid copolymer(Dx/Ha;Dexell(r)) versus polyacrylate polyalcohol copolymer(PPC;Vantris(r)) in subureteric injection treatment of children with high grades (grades IV-V) vesicoureteral reflux(VUR). METHODS: Data of patients undergoing endoscopic treatment of high grade VUR (January 2009-August 2015) were retrospectively investigated. Patients with high grade VUR caused by posterior urethral valve, duplex system, paraureteral diverticula and neurogenic bladder were excluded. Classical subureteric injection method (STING) was used. Seventy-three children (45 girls and 28 boys) who had 88 refluxing renal units (RRUs) with grades IV-V VUR (n=64/n=24) underwent endoscopic treatment using Dx/Ha (n=63 RRUs) and PPC (n=25 RRUs). RESULTS: Mean age of patients in Dx/Ha and PPC groups were 6 (3) and 6 (3.75) year (p=0.81), and volumes of these substances given were 1.3 (1) and 1 (0.5) mL (p=0.003), respectively. Overall, for the first endoscopic injection, success rate of grades IV-V VUR per RRU was 53.9% with Dx/Ha, compared to 80% in PPC-injected group, (p=0.024). Late ureterovesical junction obstruction developed only in one patient in PPC-injected group. No ureteral obstruction was observed in Dx/Ha-injected group. CONCLUSIONS: Endoscopic injection of PPC resulted in significantly higher success rate, compared to Dx/Ha in subureteric injection treatment of children with high grade VUR. However, the development of late ureterovesical junction obstruction should also be taken into account in PPC injection. PMID- 27117053 TI - Once-daily fluticasone furoate and vilanterol for adolescents and adults with symptomatic asthma: A systematic review with meta-analysis. AB - BACKGROUND: Fluticasone furoate and vilanterol is a new inhaled corticosteroid (ICS) and long-acting beta2-agonist (LABA) combination developed for once-daily administration via a dry powder inhaler. OBJECTIVE: To assess the efficacy and safety of fluticasone furoate-vilanterol in adolescents and adults with symptomatic asthma compared with ICS monotherapy or twice-daily ICS-LABA formulations. METHODS: Randomized, placebo-controlled trials with longer than 8 weeks of treatment duration were included. Primary outcome was pulmonary function (forced expiratory volume in 1 second [FEV1] or peak expiratory flow rate [PEF]). RESULTS: Seven published randomized clinical trials were included (5,668 patients). Fluticasone furoate-vilanterol was associated with significant increases in trough FEV1 and morning and evening PEF compared with fluticasone furoate, 100 MUg, monotherapy (90 mL, 20.1 L/min, and 18.9 L/min respectively). Fluticasone furoate-vilanterol reduced significantly the rate of severe asthma exacerbations (number need to treat for benefit = 24). Fluticasone furoate vilanterol also produced significant increases in weighted FEV1 and morning and evening PEF (140 mL, 32.6 L/min, and 25.7 L/min, respectively) compared with fluticasone propionate, 500 MUg twice daily. Fluticasone furoate-vilanterol presented a nonsignificant increase in the frequency of cardiac events (6.4% vs 1.8%) compared with fluticasone propionate. No differences were found between both available doses of fluticasone furoate-vilanterol (200/25 MUg and 100/25 MUg) in terms of efficacy. However, patients receiving fluticasone furoate vilanterol, 200/25 MUg, had a trend toward an increased risk of cardiac events. CONCLUSION: Fluticasone furoate-vilanterol combination was associated with an increase in trough FEV1 compared with fluticasone furoate-fluticasone propionate; however, observed differences may not be clinically significant. Studies comparing fluticasone furoate-vilanterol with fixed twice-daily ICS-LABA combinations are required. PMID- 27117055 TI - Mechanical ventilation in idiopathic pulmonary fibrosis: Unresolved dilemma. PMID- 27117054 TI - Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression. AB - Covalent addition of a methyl group to adenosine N(6) (m(6)A) is an evolutionarily conserved and common RNA modification that is thought to modulate several aspects of RNA metabolism. While the presence of multiple m(6)A editing sites on diverse viral RNAs was reported starting almost 40 years ago, how m(6)A editing affects virus replication has remained unclear. Here, we used photo crosslinking-assisted m(6)A sequencing techniques to precisely map several m(6)A editing sites on the HIV-1 genome and report that they cluster in the HIV-1 3' untranslated region (3' UTR). Viral 3' UTR m(6)A sites or analogous cellular m(6)A sites strongly enhanced mRNA expression in cis by recruiting the cellular YTHDF m(6)A "reader" proteins. Reducing YTHDF expression inhibited, while YTHDF overexpression enhanced, HIV-1 protein and RNA expression, and virus replication in CD4+ T cells. These data identify m(6)A editing and the resultant recruitment of YTHDF proteins as major positive regulators of HIV-1 mRNA expression. PMID- 27117056 TI - Bevacizumab Continuation Versus Treatment Holidays After First-Line Chemotherapy With Bevacizumab in Patients With Metastatic Colorectal Cancer: A Health Economic Analysis of a Randomized Phase 3 Trial (SAKK 41/06). AB - BACKGROUND: Bevacizumab (BEV)-containing therapies are costly. We performed a health economic analysis of a randomized phase 3 study (SAKK 41/06) that compared BEV continuation as a single agent (BEV) with treatment holidays (no BEV) after completing 4 to 6 cycles of first-line chemotherapy plus BEV in metastatic colorectal cancer patients. PATIENTS AND METHODS: Costs for first-line chemotherapy with BEV, BEV continuation therapy, hospitalizations (length of stay), control visits, diagnostic tests, and second-line and later rounds of chemotherapy were collected. Mean costs per patient per treatment arm and an incremental cost-effectiveness ratio were calculated. Probabilistic sensitivity analysis was performed to account for uncertainty in the input parameters. RESULTS: The total incurred mean costs per patient were 126,631 Swiss francs (CHF) [95% confidence interval (CI), 116,521-136,740] for BEV versus CHF100,146 (95% CI, 92,811-107,481) for no BEV. The incremental cost effectiveness ratio was CHF108,991 per life-year gained (LYG; 95% CI from probabilistic sensitivity analysis, 62,890-248,515). Compared to a willingness-to-pay threshold of CHF100,000/LYG, there was 42% probability that BEV continuation was cost effective, which decreased to 20% at a threshold of CHF75,000/LYG. Economic equality was reached in only 0.07% of cases. CONCLUSION: The clinical conclusion that BEV continuation as a single agent after completion of first-line chemotherapy is of low therapeutic value is supported by this health economic analysis. Costs increase without significant clinical benefit in this setting. PMID- 27117057 TI - The relationship between persuasive technology principles, adherence and effect of web-Based interventions for mental health: A meta-analysis. AB - BACKGROUND: Research has shown that web-based interventions concerning mental health can be effective, although there is a broad range in effect sizes. Why some interventions are more effective than others is not clear. Persuasive technology is one of the aspects which has a positive influence on changing attitude and/or behavior, and can contribute to better outcomes. According to the Persuasive Systems Design Model there are various principles that can be deployed. It is unknown whether the number and combinations of principles used in a web-based intervention affect the effectiveness. Another issue in web-based interventions is adherence. Little is known about the relationship of adherence on the effectiveness of web-based interventions. OBJECTIVE: This study examines whether there is a relationship between the number and combinations of persuasive technology principles used in web-based interventions and the effectiveness. Also the influence of adherence on effectiveness of web-based interventions is investigated. METHODS: This study elaborates on the systematic review by [37] and therefore the articles were derived from that study. Only web-based interventions were included that were intended to be used on more than one occasion and studies were excluded when no information on adherence was provided. 48 interventions targeted at mental health were selected for the current study. A within-group (WG) and between-group (BG) meta-analysis were performed and subsequently subgroup analyses regarding the relationship between the number and combinations of persuasive technology principles and effectiveness. The influence of adherence on the effectiveness was examined through a meta-regression analysis. RESULTS: For the WG meta-analysis 40 treatment groups were included. The BG meta-analysis included 19 studies. The mean pooled effect size in the WG meta-analysis was large and significant (Hedges' g=0.94), while for the BG meta-analysis this was moderate to large and significant (Hedges' g=0.78) in favor of the web-based interventions. With regard to the number of persuasive technology principles, the differences between the effect sizes in the subgroups were significant in the WG subgroup analyses for the total number of principles and for the number of principles in the three categories Primary Task Support, Dialogue Support, and Social Support. In the BG subgroup analyses only the difference in Primary Task Support was significant. An increase in the total number of principles and Dialogue Support principles yielded larger effect sizes in the WG subgroup analysis, indicating that more principles lead to better outcomes. The number of principles in the Primary Task Support (WG and BG) and Social Support (WG) did not show an upward trend but had varying effect sizes. We identified a number of combinations of principles that were more effective, but only in the WG analyses. The association between adherence and effectiveness was not significant. CONCLUSIONS: There is a relationship between the number of persuasive technology principles and the effectiveness of web-based interventions concerning mental health, however this does not always mean that implementing more principles leads to better outcomes. Regarding the combinations of principles, specific principles seemed to work well together (e.g. tunneling and tailoring; reminders and similarity; social learning and comparison), but adding another principle can diminish the effectiveness (e.g. tunneling, tailoring and reduction). In this study, an increase in adherence was not associated with larger effect sizes. The findings of this study can help developers to decide which persuasive principles to include to make web-based interventions more persuasive. PMID- 27117058 TI - (5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S) HETE that retains key vasoconstrictive and antiproliferative activity. AB - 15(S)-Hydroxyeicosa-(5Z,8Z,11Z,13E)-tetraenoic acid (15(S)-HETE) is a metabolite of arachidonic acid that elicits a number of biological effects including vasoconstriction and angiogenesis. (5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13 ynoic acid (HETE analog 1) is a synthetic isomer of 15(S)-HETE that is much more stable to autoxidation. Using isometric recording of isolated pulmonary arteries from male and female rabbits, HETE analog 1 and 15(S)-HETE were found to elicit concentration-dependent contractions that were slightly greater in females compared to males. The maximal response in females was greater with 15(S)-HETE. HETE analog 1 and 15(S)-HETE increased [(3)H]-thymidine incorporation in vascular smooth muscle cells cultured from male rabbit pulmonary arteries; both the maximal response and potency were greater with 15(S)-HETE. In contrast, HETE analog 1 produced a concentration-dependent inhibition in proliferation and migration of human hormone-independent prostate carcinoma PC-3 cells. The protocol for synthesis of HETE analog 1 is reported. The stability of this substance and its similar biological profile to 15(S)-HETE support future studies in eicosanoid research. PMID- 27117059 TI - A non-viral gene therapy for treatment of recessive dystrophic epidermolysis bullosa. PMID- 27117060 TI - Patient-reported outcome measures in children with chronic health conditions: terminology and utility. PMID- 27117061 TI - Incidence of infants born small- and large-for-gestational-age in an Italian cohort over a 20-year period and associated risk factors. AB - BACKGROUND: We assessed the incidence of infants born small-for-gestational-age (SGA) and large-for-gestational-age (LGA) in an Italian cohort over 20 years (1993-2013). Furthermore, we investigated maternal factors associated with SGA and LGA births. METHODS: A retrospective review of obstetric records was performed on infants born in Chieti (Italy) covering every 5(th) year over a 20 year period, specifically examining data for 1993, 1998, 2003, 2008, and 2013. Infants with birthweight <10(th) percentile were defined as SGA, and those with birthweight >90(th) percentile as LGA. Data collected included newborn anthropometry, birth (multiple vs singleton), maternal anthropometry, previous miscarriage, gestational diabetes, hypertension, and smoking during pregnancy. RESULTS: There were a pooled total of 5896 live births recorded across the 5 selected years. The number of SGA (+60.6 %) and LGA (+90.2 %) births increased considerably between 1993 and 2013. However, there were no marked changes in the incidence of SGA or LGA births (8.3 % and 10.8 % in 1993 versus 7.6 % and 11.7 % in 2013, respectively). Maternal factors associated with increased risk of SGA infants included hypertension, smoking, and previous miscarriage (all p < 0.05), while greater pre-pregnancy BMI and gestational diabetes were risk factors for LGA births (all p < 0.05). CONCLUSIONS: There was an increase in the number of SGA and LGA births in Chieti over the last two decades, but there was little change in incidence over time. Most maternal factors associated with increased odds of SGA and LGA births were modifiable, thus incidence could be reduced by targeted interventions. PMID- 27117062 TI - Lack of parental rule-setting on eating is associated with a wide range of adolescent unhealthy eating behaviour both for boys and girls. AB - BACKGROUND: Unhealthy eating habits in adolescence lead to a wide variety of health problems and disorders. The aim of this study was to assess the prevalence of absence of parental rules on eating and unhealthy eating behaviour and to explore the relationships between parental rules on eating and a wide range of unhealthy eating habits of boys and girls. We also explored the association of sociodemographic characteristics such as gender, family affluence or parental education with eating related parental rules and eating habits of adolescents. METHODS: The data on 2765 adolescents aged 13-15 years (mean age: 14.4; 50.7 % boys) from the Slovak part of the Health Behaviour in School-Aged Children (HBSC) study 2014 were assessed. The associations between eating-related parental rules and unhealthy eating patterns using logistic regression were assessed using logistic regression. RESULTS: Unhealthy eating habits occurred frequently among adolescents (range: 18.0 % reported skipping breakfast during weekends vs. 75.8 % for low vegetables intake). Of all adolescents, 20.5 % reported a lack of any parental rules on eating (breakfast not mandatory, meal in front of TV allowed, no rules about sweets and soft drinks). These adolescents were more likely to eat unhealthily, i.e. to skip breakfast on weekdays (odds ratio/95 % confidence interval: 5.33/4.15-6.84) and on weekends (2.66/2.12-3.34), to report low consumption of fruits (1.63/1.30-2.04) and vegetables (1.32/1.04-1.68), and the frequent consumption of sweets (1.59/1.30-1.94), soft drinks (1.93/1.56-2.38) and energy drinks (2.15/1.72-2.70). CONCLUSIONS: Parental rule-setting on eating is associated with eating behaviours of adolescents. Further research is needed to disentangle causality in this relationship. If causal, parents may be targeted to modify the eating habits of adolescents. PMID- 27117063 TI - Altering workplace attitudes for resident education (A.W.A.R.E.): discovering solutions for medical resident bullying through literature review. AB - BACKGROUND: Physicians-in-training are challenged every day with grueling academic requirements, job strain, and patient safety concerns. Residency shapes the skills and values that will percolate to patient care and professional character. Unfortunately, impediments to the educational process due to medical resident mistreatment by bullying remain highly prevalent in training today. METHODS: A PubMed literature review was undertaken using key terms to help define resident mistreatment by bullying, determine its prevalence, identify its potential causes and sequelae, and find suggestions for changing this detrimental culture of medical training. RESULTS: We identified 62 relevant articles. The most frequently noted form of mistreatment was verbal abuse, with the most common perpetrators being fellow physicians of higher hierarchical power. Mistreatment exists due to its cyclical nature and the existing culture of medical training. These disruptive behaviors affect the wellbeing of both medical residents and patients. CONCLUSIONS: This article highlights the importance of creating systems that educate physicians-in-training about professional mistreatment by bullying and the imperative in recognizing and correcting these abuses. Resident bullying leads to increased resident stress, decreased resident wellbeing as well as risks to patient safety and increased healthcare costs. Solutions include education of healthcare team members, committee creation, regulation of feedback, and creation of a zero-tolerance policy focused on the health of both patients and residents. Altering workplace attitudes will diminish the detrimental effects that bullying has on resident training. PMID- 27117065 TI - Levels of C-reactive protein (CRP) in elderly patients with unipolar depression - case control analysis. AB - AIM: C-reactive protein (CRP) is the major acute-phase plasma protein. Studies show that patients with depression have elevated levels of CRP. The aim of the study was to determine differences in CRP serum level in elderly patients with unipolar depression (DEP) compared with non-depressed elderly patients (nonDEP) using case-control analysis. METHODS: Serum level of CRP was measured in 404 (DEP: n = 202, nonDEP: n = 202) Caucasian inpatients aged >=60 (350 women, 86.7%; mean age = 76.7 years). RESULTS: Mean CRP level in the study groups was: DEP 2.67 +/- 2.56 mg/dL, nonDEP 2.41 +/- 2.19 mg/dL, the difference was not significant (p = 0.96). The overall rate of being above the high level of CRP (set at 3.0 mg/L) was 33.2% for DEP and 29.2% for nonDEP groups (p = 0.39). It was also found that, in the whole study group, CRP level was not correlated with age (p = 0.10). CONCLUSIONS: Elderly patients with depression have no increased CRP levels. A high percentage (~30%) of all subjects had a CRP level >3 mg/L, which is the cut off point for increased cardiovascular risk. PMID- 27117067 TI - Burden of allergy diets in Finnish day care reduced by change in practices. AB - BACKGROUND: Nonessential allergy diets in children with mild symptoms may harm the development of immunological tolerance and impose a burden on families and day care. We aimed to reduce the high prevalence of allergy diets in day care by reforming the practices for inquiring about need of special diets from parents. METHODS: We developed a new special diet form and an information leaflet based on the new allergy guidelines. The new form was implemented into 40 Finnish day care centres in the capital region in 2013-2015. The questionnaires on practices concerning special diets in day care centres and allergy knowledge were collected from the personnel. RESULTS: After 2 years, the new special diet form was used by 64% of families with food-allergic children, and the prevalence of allergy diets in day care centres decreased by 43% to 4.3% (IQ range 3.05-5.96). A significant decrease was found in the prevalence of all basic (milk, grains, egg) and most other allergy diets (P for trend < 0.01). The new practice was well accepted by day care and kitchen personnel. Lack of updated allergy knowledge was noted among day care personnel. CONCLUSIONS: The burden of allergy diets in day care settings could be decreased by simple pragmatic changes based on current allergy guidelines. Old allergy attitudes persisted among day care personnel, indicating the need for continuous education. PMID- 27117064 TI - Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review. AB - Sleep abnormalities are associated with acute and chronic use of addictive substances. Although sleep complaints associated with use and abstinence from addictive substances are widely recognized, familiarity with the underlying sleep abnormalities is often lacking, despite evidence that these sleep abnormalities may be recalcitrant and impede good outcomes. Substantial research has now characterized the abnormalities associated with acute and chronic use of alcohol, cannabis, cocaine, and opiates. This review summarizes this research and discusses the clinical implications of sleep abnormalities in the treatment of substance use disorders. PMID- 27117066 TI - Methamphetamine alters microglial immune function through P2X7R signaling. AB - BACKGROUND: Purinoceptors have emerged as mediators of chronic inflammation and neurodegenerative processes. The ionotropic purinoceptor P2X7 (P2X7R) is known to modulate proinflammatory signaling and integrate neuronal-glial circuits. Evidence of P2X7R involvement in neurodegeneration, chronic pain, and chronic inflammation suggests that purinergic signaling plays a major role in microglial activation during neuroinflammation. In this study, we investigated the effects of methamphetamine (METH) on microglial P2X7R. METHODS: ESdMs were used to evaluate changes in METH-induced P2X7R gene expression via Taqman PCR and protein expression via western blot analysis. Migration and phagocytosis assays were used to evaluate functional changes in ESdMs in response to METH treatment. METH induced proinflammatory cytokine production following siRNA silencing of P2X7R in ESdMs measured P2X7R-dependent functional changes. In vivo expression of P2X7R and tyrosine hydroxylase (TH) was visualized in an escalating METH dose mouse model via immunohistochemical analysis. RESULTS: Stimulation of ESdMs with METH for 48 h significantly increased P2X7R mRNA (*p < 0.0336) and protein expression (*p < 0.022). Further analysis of P2X7R protein in cellular fractionations revealed increases in membrane P2X7R (*p < 0.05) but decreased cytoplasmic expression after 48 h METH treatment, suggesting protein mobilization from the cytoplasm to the membrane which occurs upon microglial stimulation with METH. Forty-eight hour METH treatment increased microglial migration towards Fractalkine (CX3CL1) compared to control (****p < 0.0001). Migration toward CX3CL1 was confirmed to be P2X7R-dependent through the use of A 438079, a P2X7R competitive antagonist, which reversed the METH effects (****p < 0.0001). Similarly, 48 h METH treatment increased microglial phagocytosis compared to control (****p < 0.0001), and pretreatment of P2X7R antagonist reduced METH induced phagocytosis (****p < 0.0001). Silencing the microglial P2X7R decreased TNF-alpha (*p < 0.0363) and IL-10 production after 48 h of METH treatment. Additionally, our studies demonstrate increased P2X7R and decreased TH expression in the striata of escalating dose METH animal model compared to controls. CONCLUSIONS: This study sheds new light on the functional role of P2X7R in the regulation of microglial effector functions during substance abuse. Our findings suggest that P2X7R plays an important role in METH-induced microglial activation responses. P2X7R antagonists may thus constitute a novel target of therapeutic utility in neuroinflammatory conditions by regulating pathologically activated glial cells in stimulant abuse. PMID- 27117069 TI - [Guidelines for the diagnosis and treatment of adult community acquired pneumonia in China (2016 Edition)]. PMID- 27117070 TI - [Implementation of a new guideline to minimize mistakes in the diagnosis and treatment of severe community acquired pneumonia]. PMID- 27117068 TI - Neuroprotection of ischemic preconditioning is mediated by thioredoxin 2 in the hippocampal CA1 region following a subsequent transient cerebral ischemia. AB - Preconditioning by brief ischemic episode induces tolerance to a subsequent lethal ischemic insult, and it has been suggested that reactive oxygen species are involved in this phenomenon. Thioredoxin 2 (Trx2), a small protein with redox regulating function, shows cytoprotective roles against oxidative stress. Here, we had focused on the role of Trx2 in ischemic preconditioning (IPC)-mediated neuroprotection against oxidative stress followed by a subsequent lethal transient cerebral ischemia. Animals used in this study were randomly assigned to six groups; sham-operated group, ischemia-operated group, IPC plus (+) sham operated group, IPC + ischemia-operated group, IPC + auranofin (a TrxR2 inhibitor) + sham-operated group and IPC + auranofin + ischemia-operated group. IPC was subjected to a 2 minutes of sublethal transient ischemia 1 day prior to a 5 minutes of lethal transient ischemia. A significant loss of neurons was found in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) in the ischemia-operated-group 5 days after ischemia-reperfusion; in the IPC + ischemia operated-group, pyramidal neurons in the SP were well protected. In the IPC + ischemia-operated-group, Trx2 and TrxR2 immunoreactivities in the SP and its protein level in the CA1 were not significantly changed compared with those in the sham-operated-group after ischemia-reperfusion. In addition, superoxide dismutase 2 (SOD2) expression, superoxide anion radical ( O2-) production, denatured cytochrome c expression and TUNEL-positive cells in the IPC + ischemia operated-group were similar to those in the sham-operated-group. Conversely, the treatment of auranofin to the IPC + ischemia-operated-group significantly increased cell damage/death and abolished the IPC-induced effect on Trx2 and TrxR2 expressions. Furthermore, the inhibition of Trx2R nearly cancelled the beneficial effects of IPC on SOD2 expression, O2- production, denatured cytochrome c expression and TUNEL-positive cells. In brief, this study shows that IPC conferred neuroprotection against ischemic injury by maintaining Trx2 and suggests that the maintenance or enhancement of Trx2 expression by IPC may be a legitimate strategy for therapeutic intervention of cerebral ischemia. PMID- 27117071 TI - [The effect of renal function change on the curative effect of antibiotics]. PMID- 27117072 TI - [Development and clinical application of new antibiotics for treatment of community aquired pneumonia]. PMID- 27117073 TI - [The indications for glucocorticoids in treating community-acquired pneumonia in adults: a meta-analysis]. AB - OBJECTIVE: Community acquired pneumonia (CAP) is a common pulmonary infectious disease. Glucocorticoids (GCS) as one of the most powerful anti-inflammation drugs, are still the most controversial adjuvant therapy in treating CAP. Which sub-groups of CAP patients would benefit from GCS is a debating topic. Our aim of this study is to find the indications for GCS in treating adult CAP patients by using meta-analysis. METHOD: "Steroids, glucocorticoids, corticosteroids, hydrocortisone, prednisone, cortisol, methylprednisolone, dexamethasone"and"community-acquired pneumonia"were used as key words both in Chinese and English to search all published literature in Pubmed, EMBASE MEDLINE, Cochrane, CNKI and Wanfang Database until March 2015. RESULTS: All 840 articles were reviewed, and 11 high quality randomized clinical trials involving 1942 adult CAP patients were included in this meta-analysis. Using GCS did not significantly reduce mortality in all CAP patients (OR=0.68, 95%CI 0.46-0.99, P=0.04). But in the subgroup analysis, patients with severe CAP benefited from GCS treatment (OR=0.35, 95%CI 0.17-0.75, P=0.007). GCS also increased the risk of hyperglycemia (OR=1.99, 95%CI 1.50-2.65, P<0.000 01). CONCLUSION: RESULTS from this meta-analysis suggested that GCS should only be rigorously used in severe CAP patients. PMID- 27117074 TI - [Gene typing and antibiotic resistance of methicillin-resistant Staphylococcus aureus isolated from lower respiratory tract at two hospitals in Shanghai]. AB - OBJECTIVE: To study the genotyping characteristics and antibiotic resistance of methicillin-resistant Staphylococcus aureus(MRSA) isolated from lower respiratory tract at 2 different level hospitals in Shanghai. METHODS: The subjects included 155 patients at Ruijin Hospital and Tongren Hospital between January 2013 and June 2014, including 108 males and 47 females, with a mean age of 67.8+/-16.5. The 155 MRSA strains were isolated from lower respiratory tract specimens and multilocus sequence typing (MLST) and spa typing were analyzed by the PCR method. The antimicrobial resistance of MRSA was tested by VITEK-32. Fisher's exact test was used for statistical analysis. RESULTS: Among the 155 strains, 28 MLST-spa molecular types were identified, of which ST764-t002(41.29%), ST239-t037(17.42%) and ST239-t030(10.32%) were the most predominant types. The MRSA strains were susceptible to linezolid, vancomycin and teicoplanin, and also had a lower resistance to trimethoprim-sulfamethoxazole and rifampin, with a susceptible rate of 83.9% and 83.2% respectively, but were highly resistant to other antibiotics. The resistance rate of ST239-t037 to trimethoprim-sulfamethoxazole was higher than that of other types, and the resistance rate of ST239-t030 to rifampin was higher than that of other types, the differences being significant(P<0.001). The mean length of hospital stay of the 155 patients was (97+/-84) days, and mechanical ventilation were used in 78(50.3%) patients, while 108(69.7%))patients received invasive procedures. Broad-spectrum antibiotics were used in 136 (87.1%) patients. There were differences in age, hospitalization days, smoking history, history of COPD, mechanical ventilation, and operation between the 2 hospitals(P<0.05). CONCLUSION: Most of the MRSA strains at Ruijin Hospital and Tongren Hospital between January 2013 and June 2014 were multi-drug resistant, and the susceptibility spectrum of different genotypes was different. PMID- 27117075 TI - [The clinical analysis of extracorporeal membrane oxygenation for adult severe acute respiratory distress syndrome]. AB - OBJECTIVE: To investigate the clinical experience and associated factors of extracorporeal membrane oxygenation(ECMO) for adult patients with severe acute respiratory distress syndrome (ARDS). METHODS: The clinical data of 58 adult patients with severe ARDS, which met the criteria for ECMO and treated in comprehensive intensive care unit of the Second Affiliated Hospital of Zhengzhou University from August 2012 to June 2015, were retrospectively collected and analyzed. The patients were divided into the ECMO group and the control group according to whether ECMO support was used. The ECMO group was further divided into the survival group and the non-survival group according to outcomes 3 months after the initiation of ECMO. The statistics software of SPSS 17.0 was used for data analysis. RESULTS: Of the 58 patients, 28 were treated with VV-ECMO. There were 22 males and 6 females, aged from 34 to 61 years, with a mean age of (49+/ 8) years. Mean time of mechanical ventilation before ECMO therapy was(71+/-25) h. The main factors(the lowest PaO2/FiO2 and pH, the highest PEEP, PaCO2 and serum lactate level, the grade of APACHEII, Murray and SOFA) between the ECMO group and the control group were not significantly different(all P>0.05). There were no significant differences in the factors before therapy(all P>0.05), except pH, heart rate (HR) and mean arterial pressure (MAP) between the ECMO survival group and the ECMO non-survival group. Compared with the factors at the same time point in the control group, those of the ECMO group were significantly improved after ECMO running 2 hours and 1 day (all P<0.05). Most factors of the ECMO group were also significantly improved after ECMO running 2 days (all P<0.05) except MAP; the MAP of the ECMO non-survival group being lower than the control group (t=2.433, P=0.019). After ECMO running 3 days, most factors of the ECMO survival group were better than those of the control group (all P<0.05) except MAP, but most factors between the ECMO non-survival group and the control group were not significantly different (all P>0.05), while the serum lactate level was higher (t=-3.156, P=0.003) and the MAP lower (t=3.578, P=0.001). Eighteen patients were successfully weaned from ECMO, and 15 patients survived to 3 months without severe disability. The survival rate between the ECMO group and the control group was not significantly different(53.57% and 43.33%, chi(2)=0.608, P=0.436). CONCLUSIONS: Our experience suggests that VV-ECMO may be an effective life support treatment for severe ARDS and should be used as early as possible when the ECMO criteria are met. Indexes such as age, time of mechanical ventilation before ECMO therapy, time between disease onset and ECMO therapy, HR, MAP, serum lactate level and serum procalcitonin level, may be the risk factors for prognosis. PMID- 27117078 TI - [The application of quick pathogen detection in community-acquired pneumonia]. PMID- 27117076 TI - [Risk factors for pulmonary embolism in acute exacerbation of chronic obstructive pulmonary disease]. AB - OBJECTIVE: To study the risk factors for acute pulmonary embolism (PE) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: From November of 2009 to May of 2014, 522 admitted patients [aged 42-93 years, mean(72+/-9)] with AECOPD received CT pulmonary angiography(CTPA) in the First Affiliated Hospital of Guangzhou Medical University. The patients were classified as PE positive (positive result on CTPA) or PE negative (negative results on CTPA), and related risk factors for PE were analyzed. RESULTS: The frequency of PE was 10.3% in this series of 522 patients with AECOPD. Single factor analysis showed that the following factors were significantly different (chi(2)=4.32-57.06, mean P<0.05)between PE positive and PE negative groups: age>=70 years, immobilization>=3 days, deep vein thrombosis(DVT) and a history of venous thromboembolism(VTE), cor pulmonale caused by COPD, pneumonia, stroke, artery embolization, atrial fibrillation, lower extremity edema, the levels of N-terminal pro-brain natriuretic peptide(NT proBNP) and D-dimmer. Multiple regression analysis showed that immobilization >=3 days(OR=25.36, 95%CI: 7.42-86.69, P<0.001), lower extremity edema(OR=7.34, 95%CI: 3.43-15.71, P<0.001) and D-dimmer>=2 000 MUg/L(OR=10.10, 95%CI: 2.25-45.42, P=0.003) were the risk factors. The ratio for purulent sputum was 48.1%(26/54) in the PE positive group, and 42.6% (23/54) of the patients showed concurrent purulent sputum and increase of blood markers of infection. The frequency of purulent sputum between PE positive and PE negative groups was not different. CONCLUSIONS: Patients with AECOPD admitted to hospital should be considered for the presence of PE if they had the risk factors of immobilization>=3 days, lower extremity edema and D-dimmer >=2 000 MUg/L. PMID- 27117077 TI - [Establishment and evaluation of a prognostic model for acute pulmonary embolism]. AB - OBJECTIVE: To identify the factors influencing the prognosis of patients with acute pulmonary embolism(PE) and to establish a prognostic model. METHODS: The clinical data of 331 patients (141 males and 190 females, aged 9 to 87 years ) with acute PE in Fujian Hospital from January 2007 to September 2013 were analyzed. Univariate analysis and logistic regression analysis were used for selecting the independent prognostic factors for acute PE. Based on logistic regression analysis, a prognostic model for PE was established. RESULTS: Univariate analysis showed that statistically significant (all P<0.05) factors influencing the prognosis of PE were diabetes, tricuspid systolic murmur, body temperature, respiratory rate, heart rate, aspartate aminotransferase, triglycerides, abnormal ECG, mechanical ventilation, circulatory failure during hospitalization, risk stratification of PE, types of treatment, and use of low molecular-weight heparin and Warfarin. Logistic regression analysis showed that recent (<1 month) operation or fracture, tricuspid systolic murmur, high triglyceride level, circulatory failure during hospitalization and mechanical ventilation were independent factors for poor prognosis of PE, while combined use of low-molecular-weight heparin and Warfarin was a protective factor for the prognosis of PE. The Fisher prognostic model equation was y=0.144+ 1.266x1+ 0.869x2+ 1.794x3-0.517x4+ 3.555x5+ 0.661x6. The accuracy of the Fisher discriminant function was 93.0%. CONCLUSION: Recent (<1 month) operation or fracture, tricuspid systolic murmur, high triglyceride level, shock during hospitalization and mechanical ventilation were signs of poor prognosis for PE, while combined use of low-molecular-weight heparin and Warfarin were beneficial for the prognosis. The discriminant function based on these data can be helpful for predicting the prognosis of patients with PE. PMID- 27117079 TI - [Research progress of the related genes of inflammatory response in obstructive sleep apnea syndrome]. PMID- 27117080 TI - Anisotropic effective interactions and stack formation in mixtures of semiflexible ring polymers. AB - By means of extensive computer simulations, we investigate the formation of columnar structures (stacks) in concentrated solutions of semiflexible ring polymers. To characterize the stacks we employ an algorithm that identifies tube like structures in the simulation cell. Stacks are found both in the real system and in the fluid of soft disks interacting through the effective anisotropic pair potential derived for the rings [P. Poier et al., Macromolecules, 2015, 48, 4983 4997]. Furthermore, we investigate binary mixtures of cluster-forming and non cluster-forming rings. We find that monodispersity is not a requirement for stack formation. The latter is found for a broad range of mixture compositions, though the columns in the mixtures exhibit important differences to those observed in the monodisperse case. We extend the anisotropic effective model to mixtures. We show that it correctly predicts stack formation and constitutes a significant improvement with respect to the usual isotropic effective description based only on macromolecular centers-of-mass. PMID- 27117081 TI - Identification of risk factors for hospital admission using multiple-failure survival models: a toolkit for researchers. AB - BACKGROUND: The UK population is ageing; improved understanding of risk factors for hospital admission is required. Linkage of the Hertfordshire Cohort Study (HCS) with Hospital Episode Statistics (HES) data has created a multiple-failure survival dataset detailing the characteristics of 2,997 individuals at baseline (1998-2004, average age 66 years) and their hospital admissions (regarded as 'failure events') over a 10 year follow-up. Analysis of risk factors using logistic regression or time to first event Cox modelling wastes information as an individual's admissions after their first are disregarded. Sophisticated analysis techniques are established to examine risk factors for admission in such datasets but are not commonly implemented. METHODS: We review analysis techniques for multiple-failure survival datasets (logistic regression; time to first event Cox modelling; and the Andersen and Gill [AG] and Prentice, Williams and Peterson Total Time [PWP-TT] multiple-failure models), outline their implementation in Stata, and compare their results in an analysis of housing tenure (a marker of socioeconomic position) as a risk factor for different types of hospital admission (any; emergency; elective; >7 days). The AG and PWP-TT models include full admissions histories in the analysis of risk factors for admission and account for within-subject correlation of failure times. The PWP-TT model is also stratified on the number of previous failure events, allowing an individual's baseline risk of admission to increase with their number of previous admissions. RESULTS: All models yielded broadly similar results: not owner-occupying one's home was associated with increased risk of hospital admission. Estimated effect sizes were smaller from the PWP-TT model in comparison with other models owing to it having accounted for an increase in risk of admission with number of previous admissions. For example, hazard ratios [HR] from time to first event Cox models were 1.67(95 % CI: 1.36,2.04) and 1.63(95 % CI:1.36,1.95) for not owner-occupying one's home in relation to risk of emergency admission or death among women and men respectively; corresponding HRs from the PWP-TT model were 1.34(95 % CI:1.15,1.56) for women and 1.23(95 % CI:1.07,1.41) for men. CONCLUSION: The PWP TT model may be implemented using routine statistical software and is recommended for the analysis of multiple-failure survival datasets which detail repeated hospital admissions among older people. PMID- 27117082 TI - Vkorc1 sequencing suggests anticoagulant resistance in rats in New Zealand. AB - BACKGROUND: Anticoagulant toxins are used globally to control rats. Resistance of Rattus species to these toxins now occurs in at least 18 countries in Europe, America and Asia. Resistance is often associated with single nucleotide polymorphisms (SNPs) in the Vkorc1 gene. This study gives a first overview of the distribution and frequency of Vkorc1 SNPs in rats in New Zealand. New Zealand is unusual in having no native rodents but three species of introduced Rattus - norvegicus Berk., rattus L. and exulans Peale. RESULTS: Sequence variants occurred in at least one species of rat at all 30 of the sites sampled. Three new SNPs were identified, one in kiore and two in ship rats. No SNPs previously associated with resistance were found in Norway rats or kiore, but seven ship rats were heterozygous and one homozygous for the A74T variant. Its resultant Tyr25Phe mutation has previously been associated with resistance to both first- and second-generation anticoagulants in ship rats in Spain. CONCLUSIONS: This is the first evidence of potential resistance to anticoagulant toxins in rats in New Zealand. Further testing using blood clotting response times in dosed rats is needed to confirm resistance potentially conferred by the Tyr25Phe mutation. Assessment is also needed of the potential of the other non-synonymous variants (Ala14Val, Ala26Val) recorded in this study to confer resistance to anticoagulant toxins. (c) 2016 Society of Chemical Industry. PMID- 27117085 TI - Parents' perceptions of the services provided to children with cerebral palsy in the transition from preschool rehabilitation to school-based services. AB - AIM: To describe the course of parents' perceptions of the family centredness of rehabilitation services provided to their children with cerebral palsy (CP) before and after the transition from preschool to school-based services. BACKGROUND: Parents of 59 children with CP aged 2.5 to 4.5 years filled in the 56 item Measure of Processes of Care (MPOC-56) on three occasions pre (2) and post (1) transition to school-based services. Friedman tests were used to describe changes in parents' perceptions over time. Mann-Whitney U tests were used to describe differences in course of parents' perceptions between regular school and special school or day care. RESULTS: Parents' perceptions of preschool services were stable between the ages of 2.5 and 3.5 years, with a decline after transition on four of the five domains of the MPOC (P < 0.05). The domain providing general information was scored lowest (median at baseline 3.56, IQR 2.39) compared with the four other MPOC domains, but remained stable over time. No differences in course of parental perceptions were found for school type. CONCLUSION: The transition from preschool to school-based services for children with CP is associated with a decrease in parents' perception of family centredness independent of the type of school. The transition in services has a negative impact on perceived family-centred practices. PMID- 27117086 TI - Cytoxicity, dynamic and thermal properties of bio-based rosin-epoxy resin/ castor oil polyurethane/ carbon nanotubes bio-nanocomposites. AB - In order to prepare bio-nanocomposites with no-cytotoxicity, the rosin-based epoxy resin (MPAER) and castor oil-based polyurethane (COPU) were synthesized and carbon nanotubes (CNTs) was used to enhance the properties of curing MPAER/COPU materials. The curing reaction, dynamic mechanical and thermal properties of this system were characterized by FTIR, NMR, DMA, TG et al. The cytotoxicity of materials is evaluated for HeLa cells using a MTT cell-viability assay. The results showed that COPU can cure MPAER and CNTs can increase effectively the properties of MPAER/COPU nanocomposites. The Tg of MPAER/COPU/CNTs has the highest value when CNTs content is 0.4 wt%, which is 52.4 degrees C higher than the pure MPAER/COPU. Thermal stability of the nanocomposites is enhanced by the addition of CNTs, the initial decomposition temperature Td5 of the sample No. 0.4 has increased from 284.5 to 305.2 degrees C, which is 20.7 degrees C higher than No. 0. The impact strength of the No. 0.4 film is 15 kg cm higher than the pure resin system. The survival rate of HeLa cells to the products is greater than 90% within 48 and 72 h, which demonstrate that this material has excellent biocompatibility and no obvious cytotoxicity for HeLa cells, which may be used in the medical treatment. PMID- 27117087 TI - Fingolimod modulates multiple neuroinflammatory markers in a mouse model of Alzheimer's disease. AB - Sphingosine 1-phosphate (SP1) receptors may be attractive targets for modulation of inflammatory processes in neurodegenerative diseases. Recently fingolimod, a functional S1P1 receptor antagonist, was introduced for treatment of multiple sclerosis. We postulated that anti-inflammatory mechanisms of fingolimod might also be protective in Alzheimer's disease (AD). Therefore, we treated a mouse model of AD, the 5xFAD model, with two doses of fingolimod (1 and 5 mg/kg/day) and measured the response of numerous markers of Abeta pathology as well as inflammatory markers and neurochemistry using biochemical, immunohistochemistry and high resolution magic angle spinning magnetic resonance spectroscopy (MRS). In mice at 3 months of age, we found that fingolimod decreased plaque density as well as soluble plus insoluble Abeta measured by ELISA. Fingolimod also decreased GFAP staining and the number of activated microglia. Taurine has been demonstrated to play a role as an endogenous anti-inflammatory molecule. Taurine levels, measured using MRS, showed a very strong inverse correlation with GFAP levels and ELISA measurements of Abeta, but not with plaque density or activated microglia levels. MRS also showed an effect of fingolimod on glutamate levels. Fingolimod at 1 mg/kg/day provided better neuroprotection than 5 mg/kg/day. Together, these data suggest a potential therapeutic role for fingolimod in AD. PMID- 27117088 TI - Semi-supervised clustering of fractionated electrograms for electroanatomical atrial mapping. AB - BACKGROUND: Electrogram-guided ablation procedures have been proposed as an alternative strategy consisting of either mapping and ablating focal sources or targeting complex fractionated electrograms in atrial fibrillation (AF). However, the incomplete understanding of the mechanism of AF makes difficult the decision of detecting the target sites. To date, feature extraction from electrograms is carried out mostly based on the time-domain morphology analysis and non-linear features. However, their combination has been reported to achieve better performance. Besides, most of the inferring approaches applied for identifying the levels of fractionation are supervised, which lack of an objective description of fractionation. This aspect complicates their application on EGM guided ablation procedures. METHODS: This work proposes a semi-supervised clustering method of four levels of fractionation. In particular, we make use of the spectral clustering that groups a set of widely used features extracted from atrial electrograms. We also introduce a new atrial-deflection-based feature to quantify the fractionated activity. Further, based on the sequential forward selection, we find the optimal subset that provides the highest performance in terms of the cluster validation. The method is tested on external validation of a labeled database. The generalization ability of the proposed training approach is tested to aid semi-supervised learning on unlabeled dataset associated with anatomical information recorded from three patients. RESULTS: A joint set of four extracted features, based on two time-domain morphology analysis and two non linear dynamics, are selected. To discriminate between four considered levels of fractionation, validation on a labeled database performs a suitable accuracy (77.6 %). Results show a congruence value of internal validation index among tested patients that is enough to reconstruct the patterns over the atria to located critical sites with the benefit of avoiding previous manual classification of AF types. CONCLUSIONS: To the best knowledge of the authors, this is the first work reporting semi-supervised clustering for distinguishing patterns in fractionated electrograms. The proposed methodology provides high performance for the detection of unknown patterns associated with critical EGM morphologies. Particularly, obtained results of semi-supervised training show the advantage of demanding fewer labeled data and less training time without significantly compromising accuracy. This paper introduces a new method, providing an objective scheme that enables electro-physiologist to recognize the diverse EGM morphologies reliably. PMID- 27117089 TI - FET proteins regulate lifespan and neuronal integrity. AB - The FET protein family includes FUS, EWS and TAF15 proteins, all of which have been linked to amyotrophic lateral sclerosis, a fatal neurodegenerative disease affecting motor neurons. Here, we show that a reduction of FET proteins in the nematode Caenorhabditis elegans causes synaptic dysfunction accompanied by impaired motor phenotypes. FET proteins are also involved in the regulation of lifespan and stress resistance, acting partially through the insulin/IGF signalling pathway. We propose that FET proteins are involved in the maintenance of lifespan, cellular stress resistance and neuronal integrity. PMID- 27117090 TI - Effects of germination season on life history traits and on transgenerational plasticity in seed dormancy in a cold desert annual. AB - The maternal environment can influence the intensity of seed dormancy and thus seasonal germination timing and post-germination life history traits. We tested the hypotheses that germination season influences phenotypic expression of post germination life history traits in the cold desert annual Isatis violascens and that plants from autumn- and spring-germinating seeds produce different proportions of seeds with nondeep and intermediate physiological dormancy (PD). Seeds were sown in summer and flexibility in various life history traits determined for plants that germinated in autumn and in spring. A higher percentage of spring- than of autumn-germinating plants survived the seedling stage, and all surviving plants reproduced. Number of silicles increased with plant size (autumn- > spring-germinating plants), whereas percent dry mass allocated to reproduction was higher in spring- than in autumn-germinating plants. Autumn-germinating plants produced proportionally more seeds with intermediate PD than spring-germinating plants, while spring-germinating plants produced proportionally more seeds with nondeep PD than autumn-germinating plants. Flexibility throughout the life history and transgenerational plasticity in seed dormancy are adaptations of I. violascens to its desert habitat. Our study is the first to demonstrate that autumn- and spring-germinating plants in a species population differ in proportion of seeds produced with different levels of PD. PMID- 27117083 TI - The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum. AB - Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer's disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non demented elderly. PMID- 27117093 TI - Energetics of nonpolar and polar compounds in cationic, anionic, and nonionic micelles studied by all-atom molecular dynamics simulation combined with a theory of solutions. AB - Energetic analysis was conducted for nonpolar and polar solutes bound in a cationic micelle of dodecyl trimethyl ammonium bromide (DTAB), an anionic micelle of sodium dodecyl sulfate (SDS), and a nonionic micelle of tetraethylene glycol monododecyl ether (Brij30). All-atom molecular dynamics simulation was performed, and the free energies of binding the solutes in the hydrophobic-core and headgroup regions of the micelles were computed using the energy-representation method. It was found in all the micelles examined that aromatic naphthalene is preferably located more outward than aliphatic propane and that the polar solutes are localized at the interface of the hydrophobic and hydrophilic regions. The roles of the surfactant and water were then elucidated by decomposing the free energy into the contributions from the respective species. Water was observed to play a decisive role in determining the binding location of the solute, while the surfactant was found to be more important for the overall stabilization of the solute within the micelle. The effects of attractive and repulsive interactions of the solute with the surfactant and water were further examined, and their competition was analyzed in connection with the preferable location of the solute in the micellar system. PMID- 27117091 TI - Intrinsic Connectivity Provides the Baseline Framework for Variability in Motor Performance: A Multivariate Fusion Analysis of Low- and High-Frequency Resting State Oscillations and Antisaccade Performance. AB - Intrinsic brain activity provides the functional framework for the brain's full repertoire of behavioral responses; that is, a common mechanism underlies intrinsic and extrinsic neural activity, with extrinsic activity building upon the underlying baseline intrinsic activity. The generation of a motor movement in response to sensory stimulation is one of the most fundamental functions of the central nervous system. Since saccadic eye movements are among our most stereotyped motor responses, we hypothesized that individual variability in the ability to inhibit a prepotent saccade and make a voluntary antisaccade would be related to individual variability in intrinsic connectivity. Twenty-three individuals completed the antisaccade task and resting-state functional magnetic resonance imaging (fMRI). A multivariate analysis of covariance identified relationships between fMRI oscillations (0.01-0.2 Hz) of resting-state networks determined using high-dimensional independent component analysis and antisaccade performance (latency, error rate). Significant multivariate relationships between antisaccade latency and directional error rate were obtained in independent components across the entire brain. Some of the relationships were obtained in components that overlapped substantially with the task; however, many were obtained in components that showed little overlap with the task. The current results demonstrate that even in the absence of a task, spectral power in regions showing little overlap with task activity predicts an individual's performance on a saccade task. PMID- 27117092 TI - Allosteric Control of Icosahedral Capsid Assembly. AB - During the life cycle of a virus, viral proteins and other components self assemble to form an ordered protein shell called a capsid. This assembly process is subject to multiple competing constraints, including the need to form a thermostable shell while avoiding kinetic traps. It has been proposed that viral assembly satisfies these constraints through allosteric regulation, including the interconversion of capsid proteins among conformations with different propensities for assembly. In this article, we use computational and theoretical modeling to explore how such allostery affects the assembly of icosahedral shells. We simulate assembly under a wide range of protein concentrations, protein binding affinities, and two different mechanisms of allosteric control. We find that above a threshold strength of allosteric control, assembly becomes robust over a broad range of subunit binding affinities and concentrations, allowing the formation of highly thermostable capsids. Our results suggest that allostery can significantly shift the range of protein binding affinities that lead to successful assembly and thus should be taken into account in models that are used to estimate interaction parameters from experimental data. PMID- 27117094 TI - [The role of IRA B cells in selected inflammatory processes]. AB - The first report about the discovery of new, previously unknown immune cells named IRA B cells (innate response activator B cells) appeared in 2012. So far, their presence has been verified in both mice and humans. However, IRA B cells belong to the family of B lymphocytes and have a number of characteristics unique to this group of cells. IRA B cells are formed from activated B1a lymphocytes after their contact with a pathogen. B1a lymphocytes mainly reside within body cavities. Activated by the pathogen, they move on into secondary lymphoid organs (spleen, lymph nodes) where they differentiate into IRA B cells. IRA B cells are a rich source of granulocyte-macrophage colony stimulating factor (GM-CSF). GM CSF can stimulate IRA B cells in an autocrine manner for the secretion of intracellular stocks of immunoglobulin M (IgM), which can facilitate pathogens' phagocytosis by neutrophils. GM-CSF also stimulates neutrophils into active phagocytosis. Rapid eradication of the pathogen can prevent the development of an excessive inflammatory response, which can be dangerous for the organism. Until now the involvement of IRA B lymphocytes in the pathogenesis of sepsis and pneumonia has been proven, as well as their role in the progression of atherosclerotic lesions in mice. There is research in progress on the possibility of increasing the number of IRA B cells, for example by intravenous supply of modified immunoglobulins. It is necessary to characterize human IRA B cells and to determine their role in the functioning of the immune system. PMID- 27117095 TI - [Liposomes as non-viral carriers for genetic drugs]. AB - Methods in cancer therapy particularly in recent years, are rapidly changing, due to the need of design of new, more effective therapeutic strategies. Very promising approach to treatment of the neoplastic diseases is antisense gene therapy. Due to the low toxicity of treatment and eliminating not only the symptoms but also the molecular causes of the disease it may represent a breakthrough in cancer therapies. Delivery of a therapeutic DNA or RNA oligonucleotides to the target cells in vivo requires suitable carrier system. Non-viral drug carriers are increasingly used in new systems of targeted gene therapy. This review presents new generation of non-viral carriers, and is focused on immunoliposomes finding potential application in targeted gene therapy. PMID- 27117096 TI - Wegener's granulomatosis and pyoderma gangrenosum--rare causes of facial ulcerations. AB - BACKGROUND: Pyoderma gangrenosum (PG) is caused by immune system dysfunction, and particularly improper functioning of neutrophils. At least half of all PG patients also suffer from autoimmunological diseases, one of which is Wegener granulomatosis (WG). The purpose of this article was to compare cases of patients with WG and PG in terms of their clinical course, histopathology, and applied treatment. In both, histopathological features are not fully distinct. Data from microbiological and immunological evaluation and clinical presentation are required to establish the diagnosis. We also present the case of a patient with WG and deep facial skin lesions not responding to standard treatment. METHODS: Systematic review of the literature in PubMed using the search terms "Wegener granulomatosis AND Pyoderma gangrenosum" and case report. RESULTS: The finding of 22 reports in the literature (PubMed) suggests that it is a rare phenomenon. This study revealed a similar rate of comorbidity of WG and PG in both genders and an increased incidence of both diseases after the age of 50. Among skin lesions there was a dominance of ulceration, most often deep and painful, covering a large area with the presence of advanced necrosis and destruction of the surrounding tissue. The most common location proved to be the cervical-cephalic area. The most popular treatment included steroids with cyclophosphamide. DISCUSSION: The rarity of the coexistence of these two diseases results in a lack of effective therapy. In such cases sulfone derivatives are still effective and provide an alternative to standard immunosuppression methods. Hyperbaric therapy and plasmapheresis can also play an important complementary role. PMID- 27117097 TI - [Aspartate aminotransferase--key enzyme in the human systemic metabolism]. AB - Aspartate aminotransferase is an organ-nonspecific enzyme located in many tissues of the human body where it catalyzes reversible reaction of transamination. There are two aspartate aminotransferase isoforms--cytoplasmic (AST1) and mitochondrial (AST2), that usually occur together and interact with each other metabolically. Both isoforms are homodimers containing highly conservative regions responsible for catalytic properties of enzyme. The common feature of all aspartate aminotransfeses is Lys - 259 residue covalent binding with prosthetic group - pyridoxal phosphate. The differences in the primary structure of AST isoforms determine their physico-chemical, kinetic and immunological properties. Because of the low concentration of L-aspartate (L-Asp) in the blood, AST is the only enzyme, which supply of this amino acid as a substrate for many metabolic processes, such as urea cycle or purine and pyrimidine nucleotides in the liver, synthesis of L-arginine in the kidney and purine nucleotide cycle in the brain and the skeletal muscle. AST is also involved in D-aspartate production that regulates the metabolic activity at the auto-, para- and endocrine level. Aspartate aminotransferase is a part of the malate-aspartate shuttle in the myocardium, is involved in gluconeogenesis in the liver and kidney, glyceroneogenesis in the adipose tissue, and synthesis of neurotransmitters and neuro-glial pathway in the brain. Recently, the significant role of AST in glutaminolysis - normal metabolic pathway in tumor cells, was demonstrated. The article is devoted the role of AST, known primarily as a diagnostic liver enzyme, in metabolism of various human tissues and organs. PMID- 27117098 TI - [Molecular bases of cellular senescence: Hayflick phenomenon 50 years later]. AB - Normal human somatic cells have strictly limited proliferative capacity and reach a state of senescence when it becomes exhausted. It is believed that senescence is a response to extensive and irreparable DNA injury, localized in telomeric and/or non-telomeric regions of the genome. Main cause of this damage is oxidative stress, increasing due to deteriorated function of mitochondria. Senescent cells accumulate in tissues during aging, which is causatively linked with the development of various pathologies in elderly individuals, including cancer. This paper, prepared exactly 50 years after Leonard Hayflick's discovery of the relationship between cellular senescence and organismal aging is aimed at presenting the current knowledge about molecular determinants of senescence, with particular emphasis paid to the role of oxidative stress, effectors of senescence at the level of cell cycle, markers of this phenomenon, and the effect of senescent cells on the development of certain age-related diseases. PMID- 27117099 TI - The role of endogenous cardiotonic steroids in pathogenesis of cardiovascular and renal complications of arterial hypertension. AB - Endogenous cardiotonic steroids (CTS), also called digitalis-like factors, are a group of steroid hormones linking high salt intake and elevated blood pressure and in part responsible for target organ damage in arterial hypertension. CTS act primarily through their ability to inhibit the ubiquitous transport enzyme sodium potassium adenosine triphosphatase (Na+/K+-ATPase). A portion of Na+/K+-ATPase does not seem to actively "pump" sodium and potassium but is closely associated with other key signaling proteins. Plasma concentration and urine excretion of CTS are increased in experimental models with volume expansion and on a high salt diet. Elevated plasma concentration of marinobufagenin has been shown in volume expanded states such as essential hypertension, primary aldosteronism, chronic renal failure, congestive heart failure and pregnancy. In experimental models marinobufagenin induces heart and kidney fibrosis to the same extent as observed in uremia. Neutralization of marinobufagenin with antibodies prevents such heart remodeling. Expanding our understanding of this new class of hormones may lead to development of novel and effective therapeutic strategies in hypertensive patients with renal and cardiovascular complications. PMID- 27117100 TI - [Immunological markers of rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is the most common connective tissue disease of autoimmune origin. The disease is characterized by chronic inflammation leading to bone erosions and organ involvement. RA is a progressive disease. It affects the quality of life, leading to disability and death mainly due to premature cardiovascular disease. Early diagnosis and appropriate treatment are essential for prognosis and quality of life improvement. In 2010 the American College of Rheumatology (ACR) and The European League Against Rheumatism (EULAR) established new RA classification criteria. Besides clinical symptoms it includes two immunologic criteria: rheumatoid factor (RF) and anti-citrullinated protein antibodies (anti-CCP antibodies). RF is the first well-known RA immunologic marker. It is observed in 80-85% of patients with RA. Elevated serum level of RF has been associated with increased disease activity, radiographic progression, and the presence of extraarticular manifestations. The sensitivity of RF is 50 90%, and specificity is 50-95%. Anti-CCP antibodies appear to be a more specific marker than RF. They are often present at the very beginning of the disease, or even years before the first symptoms. The prognostic value of anti-CCP antibodies is well established. High serum level of anti-CCP correlates with poor prognosis and early erosions of the joints. The sensitivity of anti-CCP2 is 48-80%, and specificity is 96-98%. New immunologic markers include anti-carbamylated protein antibodies (anti-CarP) and antibodies against heterogeneous nuclear ribonucleoproteins (anti-hnRNP A2/B1, RA33). Scientists aim to identify a highly sensitive and specific biomarker of the disease that not only has diagnostic and prognostic value but also may predict the response to treatment. PMID- 27117101 TI - EGFR and Bcl-2 in gastric mucosa of children infected with Helicobacter pylori. AB - The aim of the study was to evaluate the expression of EGFR and Bcl-2 proteins as inhibitory markers of apoptosis in surface epithelial cells and gland cells of antral gastric mucosa in children infected with Helicobacter pylori according to the severity and activity of antral gastritis and to assess the correlation between the number of cells expressing EGFR and the number of cells expressing Bcl-2 in H. pylori infected children. MATERIALS AND METHODS: The study included 44 children: 68.2% with chronic gastritis and positive IgG against H. pylori, and 31.8% with functional disorders of the gastrointestinal tract and with normal IgG against H. pylori. The evaluation of EGFR expression in gastric mucosa was performed immunohistochemically using monoclonal mouse anti-EGFR antibody. The polyclonal antibody was used to determine the expression of anti-Bcl-2. RESULTS: A significant increase in the number of cells expressing EGFR and Bcl-2 protein was found in the epithelial cells in severe as well as mild and moderate gastritis in the group of children infected with H. pylori. An increase in the number of cells expressing EGFR and Bcl-2 protein was also found in the epithelial cells in group I according to the activity of gastritis. There was a statistically significant positive correlation between the numbers of cells expressing EGFR and Bcl-2 in H. pylori infected children. CONCLUSION: Increased expression of EGFR and Bcl-2 proteins in the epithelial cells and a statistically significant positive correlation between the numbers of cells expressing EGFR and Bcl-2 in H. pylori infected children could suggest increased regeneration abilities of gastric mucosa. PMID- 27117102 TI - DNA damage and apoptosis in blood neutrophils of inflammatory bowel disease patients and in Caco-2 cells in vitro exposed to betanin. AB - Inflammatory bowel diseases (IBD) are chronic, relapsing, inflammatory disorders of the gastrointestinal tract, and continuing colonic inflammation is considered an important risk factor in the development of colorectal cancer. Our previous studies showed that beetroot (Beta vulgaris var. rubra) products and their major component betanin modulate the reactive oxygen species (ROS) production and DNA damage in 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated human polymorphonuclear neutrophils of healthy volunteers. The aim of the present study was to evaluate the effects of betanin on the oxidative DNA damage and apoptosis in neutrophils isolated from blood of patients with inflammatory bowel disease- ulcerative colitis (UC) and Crohn's disease (CD). The results were compared with those obtained in colon carcinoma-derived Caco-2 cells. Betanin treatment at the concentration of 100 MUM for 24 h increased DNA damage assessed by comet assay in IBD patients' neutrophils. A similar effect although less pronounced was observed in Caco-2 cells. Treatment of Caco-2 cells with H2O2 caused a 4-fold increase of DNA strand breaks in comparison to untreated cells, but pre-treatment with betanin reduced DNA damage in these cells. Betanin also induced procaspase-3 cleavage and caspase-3 activity accompanied by the loss of mitochondrial transmembrane potential, indicating its pro-apoptotic activity. These results suggest that betanin may support mechanisms that lead to the release of ROS and apoptotic cell death. In this way betanin may exert anti-inflammatory and potentially cancer preventive activity. PMID- 27117103 TI - Evaluation of serum chemokine RANTES concentration as a biomarker in the diagnosis of early-onset severe infections in neonates. AB - OBJECTIVE: Only a few studies on improving the early diagnosis of severe neonatal infections have focused on the role of serum RANTES concentration (sRC). The aim of the study was to establish sRC in neonates with early-onset infections, according to their gestational age, sex, birth asphyxia, mode of delivery and value of some biochemical and hematological parameters. MATERIAL/METHODS: The analysis comprised 129 neonates, including 89 infected (52 preterm, 37 full-term; 43 with sepsis, 39 with congenital pneumonia, 7 with severe urinary tract infection) and 40 healthy (control group, 25 full-term, 15 preterm). The sRC in peripheral vein blood was measured by the ELISA method using Quantikine Set (R & D systems, USA). RESULTS: The sRC in infected neonates ranged from 10.83 to 122.55 MUg/ml, in full-term neonates from 18.28 to 122.55 MUg/ml, and in preterm from 10.83 to 118.24 MUg/ml. The mean sRCs in full-term septic neonates (73.95+/ 25.99 MUg/ml) and with organ infections (58.43+/-29.24 MUg/ml) were significantly higher than healthy ones (28.25+/-14.06 MUg/ml). The mean sRCs in septic preterm neonates (59.17+/-28.29 MUg/ml) and those with organ infections (50.86+/-28.16) were significantly higher than in healthy preterm neonates (25.61+/-8.29 MUg/ml). Positive correlations between sRC and CRP value (r=0.3014, p=0.004) and between sRC and band cell count (r=0.2489, p=0.019) were found in all infected neonates. CONCLUSION: The significant increase of serum RANTES concentration in early-onset infections in neonates, regardless of their gestational age, sex and birth asphyxia, not only proves the presence of an active immunological process but also may be a useful biomarker for diagnosis of severe neonatal infections. PMID- 27117104 TI - [PARP1 inhibitors: contemporary attempts at their use in anticancer therapy and future perspective]. AB - Current cancer therapies are based mainly on the use of compounds that cause DNA damage. Unfortunately, even the combination therapies do not give rewarding effects, due to the high efficiency of DNA damage repair mechanisms in tumor cells. Therefore, the present studies should be focused on proteins that are involved in DNA repair systems. Poly(ADP-ribose) polymerase-1 is an example of a protein commonly known as an enzyme that plays a role in the detection of DNA damage and repair. Activation of PARP1 in response to DNA damage leads to poly ADP-ribosylation of proteins contributing to DNA repair systems, therefore facilitating the maintenance of genome stability. On the other hand, inhibition of PARP1 enzyme results in the accumulation of DNA damage, which in turn contributes to cell death. Studies on inhibitors of PARP1 are still ongoing, and some of them are currently in the third phase of clinical trials. To date, only one representative of the PARP1 inhibitors, called olaparib, has been approved for anti-cancer therapy in the EU and the USA. Moreover, a growing body of evidence indicates a role of this protein in various intracellular processes such as bioenergetics, proliferation, regulation of gene expression, cell death as well as immunoregulation. A number of different intracellular processes regulated by PARP1 give rise to potential wider use of PARP1 inhibitors in treatment of other diseases, including immune or autoimmune disorders. PMID- 27117105 TI - Explaining the Decrease in Deaths from Cardiovascular Disease in Poland. The Top Down Risk Assessment Approach, from Policy to Health Impact. AB - OBJECTIVE: The purpose of this paper was to assess the relations between policy and health outcome SETTING: The CVD mortality rate in Poland over the past two decades has decreased by about 40%. It was the highest decrease among Central and Eastern European countries and also exceptional on a global scale. DESIGN: Key determinants which can account for these phenomena include CVD-related life style factors, better environmental indicators, and better access to medical technologies and to pharmacological treatment. Health policy played a vital role. METHODS: The study was based on an extensive literature review, documentation analysis and questionnaire survey research. The top-down risk assessment approach model was implemented, which followed the logical pathway between the policy, health determinants, risk factors and health outcome. RESULTS: Several national public health programs have been implemented since the beginning of the 1990s. The National Health Fund has constantly increased the expenditures on cardiology treatment. The number of invasive cardiology units has increased, as has the number of coronarography and angioplasty procedures in the same period. CONCLUSIONS: The significant mortality decrease can indicate to policy makers that it is necessary to prioritize policies to manage effective, innovative medical interventions. Topdown policy risk assessment is a useful methodological tool to present the full chain of interactions. PMID- 27117106 TI - Markers of inflammation, activation of blood platelets and coagulation disorders in inflammatory bowel diseases. AB - Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease. It is a group of chronic disorders characterized by inflammation of the gastrointestinal track with unknown etiology. Currently applied biomarkers include CRP, ESR, pANCA, ASCA, and fecal calprotectin. The etiopathogenesis of IBD is multifactorial. In patients with IBD in inflamed alimentary tract mucosa the number of recruited monocytes and activated macrophages which are source of cytokines. In IBD, the exacerbation is accompanied by thrombocytosis. Platelets play a crucial role in the hemostasis and inflammatory response. Selectins, which regulates the hemostasis and inflammatory response, stimulates the secretion of many inflammatory mediators such as beta-thromboglobuline, CD40L, fibrinogen, IL 1beta, platelet factor-4. In the course of IBD the following changes are observed: an increase in the number of platelets (reactive thrombocytosis), PDW and PCT, reduction in MPV, increased production and excretion of granular content products (P-selectin, GP53, beta-TG, PF-4, vWF, fibrinolytic inhibitors). PMID- 27117107 TI - [Influenza surveillance]. AB - Influenza surveillance was established in 1947. From this moment WHO (World Health Organization) has been coordinating international cooperation, with a goal of monitoring influenza virus activity, effective diagnostic of the circulating viruses and informing society about epidemics or pandemics, as well as about emergence of new subtypes of influenza virus type A. Influenza surveillance is an important task, because it enables people to prepare themselves for battle with the virus that is constantly mutating, what leads to circulation of new and often more virulent strains of influenza in human population. As vaccination is the most effective method of fighting the virus, one of the major tasks of GISRS is developing an optimal antigenic composition of the vaccine for the current epidemic season. European Influenza Surveillance Network (EISN) has also developed over the years. EISN is running integrated epidemiological and virological influenza surveillance, to provide appropriate data to public health experts in member countries, to enable them undertaking relevant activities based on the current information about influenza activity. In close cooperation with GISRS and EISN are National Influenza Centres--national institutions designated by the Ministry of Health in each country. PMID- 27117108 TI - Intracellular glutathione level and efflux in human melanoma and cervical cancer cells differing in doxorubicin resistance. AB - INTRODUCTION: Drug resistance continues to be a major problem in cancer treatment. Occurrence of this phenomenon is often associated with altered levels of glutathione (GSH) and GSH-related enzymes. The aim of the study was to evaluate the possible involvement of GSH and GSH-related enzymes in doxorubicin (DOX) resistance in two types of cancer cells of different etiology, from both parental and DOX-resistant sublines. MATERIALS AND METHODS: The human melanoma (ME18 and ME18/R) and cervical cancer cells (HeLa and KB-V1) were tested in terms of their DOX sensitivity (EZ4U test), GSH level (HPLC) and its efflux (spectrofluorometrically). The effects of inhibition of the GSH-related enzymes gamma-glutamylcysteine synthetase (gamma-GCS) and glutathione S-transferase (GST) were also evaluated. RESULTS: Exposure to DOX caused an increase of GSH levels in all tested cells except for HeLa cells. However, depletion of GSH did not have a significant influence on the sensitivity of the cells to DOX. Inhibition of the activity of GST also did not have a major effect on DOX sensitivity, although it caused changes of the GSH content. Our attempts to use the spectrofluorometric method for measurements of GSH efflux were not successful. It could be suggested that in ME18 and HeLa cells treated with DOX, GSH efflux does occur. DISCUSSION: The obtained results seem to refute the hypothesis of a central role of GSH in DOX resistance of the tested cells. Despite observations of different effects related to GSH, they do not seem to be essential in terms of DOX resistance. The mechanisms underlying DOX resistance are highly cell-specific. PMID- 27117109 TI - [KIM-1 and NGAL as potential biomarkers for the diagnosis and cancer progression]. AB - On the basis of scientific literature, there is growing evidence that KIM-1 and NGAL are interesting and promising biomarkers not only in acute and chronic inflammatory processes but also in oncogenesis. There are a number of studies which investigate their possible use in diagnosis, treatment and monitoring of therapy effectiveness. The results of recent research suggests that they may play an important role in standard oncology practice. Simultaneous measurement of KIM 1 and NGAL in urine can play a crucial role in carcinogenesis assessment and cancer progression. In the future, they can become rapid diagnostic indicators, which allow one to determine cancer subtype leading to biopsy replacement and therapy improvement. In the present work, beside biochemical characteristics of KIM-1 and NGAL, we will also discuss their role in the diagnosis and assessment of development of cancer. PMID- 27117110 TI - [The cellular receptors of exogenous RNA]. AB - One of the key determinants of survival for organisms is proper recognition of exogenous and endogenous nucleic acids. Therefore, high eukaryotes developed a number of receptors that allow for discrimination between friend or foe DNA and RNA. Appearance of exogenous RNA in cytoplasm provides a signal of danger and triggers cellular responses that facilitate eradication of a pathogen. Recognition of exogenous RNA is additionally complicated by fact that large amount of endogenous RNA is present in cytoplasm Thus, number of different receptors, found in eukaryotic cells, is able to recognize that nucleic acid. First group of those receptors consist endosomal Toll like receptors, namely TLR3, TLR7, TLR8 and TLR13. Those receptors recognize RNA released from pathogens that enter the cell by endocytosis. The second group includes cytoplasmic sensors like PKR and the family of RLRs comprised of RIG-I, MDA5 and LGP2. Cytoplasmic receptors recognize RNA from pathogens invading the cell by non-endocytic pathway. In both cases binding of RNA by its receptors results in activation of the signalling cascades that lead to the production of interferon and other cytokines. PMID- 27117111 TI - [Consequences of extrahepatic manifestations of hepatitis C viral infection (HCV)]. AB - The hepatitis C virus (HCV) is a primarily hepatotropic virus. However, numerous extrahepatic symptoms are observed in patients chronically infected with HCV, e.g. cryoglobulinemia, lymphoproliferative disorders, kidney diseases, disturbances of the central and peripheral nervous system, thyroid gland, pancreas, lymph nodes and pituitary gland, that develop at various times after the infection. Complex mechanisms underlie these processes, both molecular, related to direct effects of the virus on cells or tissues and indirect mechanisms, resulting from the response of the immune system to infection (via cytokines or oxidative stress), and from the antiviral treatment used. Understanding these mechanisms may contribute to the definition of new prognostic factors, important for the early diagnosis of the infection, which in turn may improve treatment efficacy. This paper is a review of the incidence of selected extrahepatic manifestations of HCV infection and their underlying pathogenetic mechanisms and risk factors. PMID- 27117113 TI - [The development of methods for obtaining monoclonal antibody-producing cells]. AB - Monoclonal antibodies (mAbs) are biomolecules of great scientific and practical significance. In contrast to polyclonal antibodies from immune sera, they are homogeneous and monospecific, since they are produced by hybridoma cells representing a clone arising from a single cell. The successful technology was described for the first time in 1975; the inventors were later awarded the Nobel Prize. Currently, mAbs are broadly used as a research tool, in diagnostics and medicine in particular for the treatment of cancer or in transplantology. About 47 therapeutics based on monoclonal antibodies are now available in the US and Europe, and the number is still growing. Production of monoclonal antibodies is a multistage, time-consuming and costly process. Growing demand for these molecules creates space for research focused on improvements in hybridoma technology. Lower costs, human labor, and time are important goals of these attempts. In this article, a brief review of current methods and their advances is given. PMID- 27117112 TI - [The role of inflammation in colon cancer pathogenesis]. AB - The results of the latest research more and more bind development of neoplasms with the chronic inflammation. Inflammatory process creates microenvironment promoting development of neoplasms; as a result, malignant process start to develop in places, where chronic inflammation proceeds or regeneration of tissues takes place. Inflammatory cells not only create suitable microenvironment for development of neoplasms, but also excrete number of cytokines and growth factors promoting survival of a neoplasmatic cell and avoiding its apoptosis, promoting neoangiogenesis and metastases formation. Moreover, cytokines and other pro inflammatory factors modulate expression of genes important in cancerogenesis, they also activate NFkappaB-dependent signaling pathways, which favor neoplasmatic cells to avoid apoptosis. On the other hand, oxidative stress accompanying chronic inflammation may promote mutagenesis, enabling that way the neoplasm development. The same cells and metabolic pathways are engaged in inflammatory and neoplasmatic processes, and development of cancer may be a consequence of loss of control over tissue regeneration during resolution of chronic inflammation. The role of most important cells and metabolic pathways in inflammatory process, which may lead to colon cancer, was discussed in this paper. PMID- 27117114 TI - Frankincense--therapeutic properties. AB - Recently, increasing interest in natural dietary and therapeutic preparations used as dietary supplements has been observed. One of them is frankincense. This traditional medicine of the East is believed to have anti-inflammatory, expectorant, antiseptic, and even anxiolytic and anti-neurotic effects. The present study aims to verify the reported therapeutic properties of Boswellia resin and describe its chemical composition based on available scientific studies. The main component of frankincense is oil (60%). It contains mono- (13%) and diterpenes (40%) as well as ethyl acetate (21.4%), octyl acetate (13.4%) and methylanisole (7.6%). The highest biological activity among terpenes is characteristic of 11-keto-beta-acetyl-beta-boswellic acid, acetyl-11-keto-beta boswellic acid and acetyl-alpha-boswellic acid. Contemporary studies have shown that resin indeed has an analgesic, tranquilising and anti-bacterial effects. From the point of view of therapeutic properties, extracts from Boswellia serrata and Boswellia carterii are reported to be particularly useful. They reduce inflammatory conditions in the course of rheumatism by inhibiting leukocyte elastase and degrading glycosaminoglycans. Boswellia preparations inhibit 5 lipoxygenase and prevent the release of leukotrienes, thus having an anti inflammatory effect in ulcerative colitis, irritable bowel syndrome, bronchitis and sinusitis. Inhalation and consumption of Boswellia olibanum reduces the risk of asthma. In addition, boswellic acids have an antiproliferative effect on tumours. They inhibit proliferation of tumour cells of the leukaemia and glioblastoma subset. They have an anti-tumour effect since they inhibit topoisomerase I and II-alpha and stimulate programmed cell death (apoptosis). PMID- 27117115 TI - Deregulation of Apoptosis - Is it Still an Important Issue in Pathogenesis of Chronic Lymphocytic Leukemia? AB - Chronic lymphocytic leukemia (CLL), a clonal expansion of B CD5+ cells, is the most common type of adult leukemia in western countries. The accumulation of neoplastic B-cells is primarily caused by prolonged life-span of these cells due to deregulation of apoptosis, and only marginally due to a higher proliferation rate. In spite of numerous reports characterizing particular mechanisms of B-CLL cell apoptosis, still relatively little is known about the complex regulation of this process. Therefore, more detailed research is required to understand the complicated mechanisms and regulatory processes of apoptosis in neoplastic B lymphocytes. PMID- 27117116 TI - Giant unilamellar vesicles containing Rhodamine 6G as a marker for immunoassay of bovine serum albumin and lipocalin-2. AB - Functionalized giant unilamellar vesicles (GUVs) containing a fluorescence dye Rhodamine 6G is proposed as a marker in sandwich-type immunoassay for bovine serum albumin (BSA) and lipocalin-2 (LCN2). The GUVs were prepared by the electroformation method and functionalized with anti-BSA antibody and anti-LCN2 antibody, respectively. The purification of antibody-modified GUVs was achieved by conventional centrifugation and a washing step in a flow system. To antigen on an antibody slip, antibody-modified GUVs were added as a marker and incubated. After wash-out of excess reagents and lysis of the bound GUVs with Triton X-100, the fluorescence image was captured. The fluorometric immunoassays for BSA and LCN2 exhibited lower detection limits of 4 and 80 fg ml(-)(1), respectively. PMID- 27117117 TI - Verifiable emission reductions in European urban areas with air-quality models. AB - The first and second AutoOil programmes were conducted since 1992 as a partnership between the European Commission and the automobile and oil industries. These have introduced emission reductions in Europe based on numerical modelling for a target year. They aimed to identify the most cost effective way to meet desired future air quality over the whole European Union. In their time, these regulatory efforts were considered an important step towards a new approach for establishing European emission limits. With this work, we review the effectiveness of forecasts carried out with numerical modelling and compare these with the actual measurements at the target year, which was the year 2010. Based on these comparisons and new technological innovations these methodologies can incorporate new sectorial assessments for improving the accuracy of the modelling forecasts and for examining the representativeness of emissions reductions, as well as for the simultaneous assessment of population exposure to cocktails of toxic substances under realistic climatological conditions. We also examined at the ten AutoOil domains the geographical generalisation of the forecasts for CO and NO2 at 1065 European urban areas on the basis of their population and the local population density. PMID- 27117118 TI - The obligation to declare our bonds of interest is formalized. PMID- 27117119 TI - Principles of tendon transfers. AB - Tendon transfers are carried out to restore functional deficits by rerouting the remaining intact muscles. Transfers are highly attractive in the context of hand surgery because of the possibility of restoring the patient's ability to grip. In palsy cases, tendon transfers are only used when a neurological procedure is contraindicated or has failed. The strategy used to restore function follows a common set of principles, no matter the nature of the deficit. The first step is to clearly distinguish between deficient muscles and muscles that could be transferred. Next, the type of palsy will dictate the scope of the program and the complexity of the gripping movements that can be restored. Based on this reasoning, a surgical strategy that matches the means (transferable muscles) with the objectives (functions to restore) will be established and clearly explained to the patient. Every paralyzed hand can be described using three parameters. 1) Deficient segments: wrist, thumb and long fingers; 2) mechanical performance of muscles groups being revived: high energy-wrist extension and finger flexion that require strong transfers with long excursion; low energy-wrist flexion and finger extension movements that are less demanding mechanically, because they can be accomplished through gravity alone in some cases; 3) condition of the two primary motors in the hand: extrinsics (flexors and extensors) and intrinsics (facilitator). No matter the type of palsy, the transfer surgery follows the same technical principles: exposure, release, fixation, tensioning and rehabilitation. By performing an in-depth analysis of each case and by following strict technical principles, tendon transfer surgery leads to reproducible results; this allows the surgeon to establish clear objectives for the patient preoperatively. PMID- 27117120 TI - Robotically assisted harvest of the latissimus dorsi muscle: A cadaver feasibility study and clinical test case. AB - The applications of robotic surgery have quickly spread into a variety of surgical fields. Interest in robotic endoscopic surgery is high because of the small size of the incisions, cosmetic advantages, less invasive surgical techniques, decreased scar tissue, shorter duration of hospitalization and increased cost-effectiveness. We will describe an anatomical feasibility study and a clinical test case of robotically assisted pedicled transposition of the latissimus dorsi muscle. PMID- 27117121 TI - Tips and tricks for end-to-side anastomosis arteriotomies. AB - Arteriotomy is a critical step during end-to-side anastomosis procedures. However, it is challenging to carry out because of the concentric lamellar structure of blood vessels and the need for clean margins. We performed a review of the literature to identify the advantages and disadvantages of the available arteriotomy methods. The techniques were classified into (1) single-cut or slit arteriotomy (longitudinal and transverse) or (2) excision arteriotomy. The latter techniques can be performed from either outside-in (excision with straight microscissors, curved microscissors, Acland-Banis arteriotomy clamp, micro arteriotomy scissors, or triangular cutting scissors, and vaporization with Excimer((r)) laser) or inside-out (excision with punch/micropunch). Microsurgeons have multiple arteriotomy methods at their disposal. By being familiar with these methods, they can select the most appropriate one for the situation at hand. PMID- 27117122 TI - Robot-assisted C7 nerve root transfer from the contralateral healthy side: A preliminary cadaver study. AB - Patients with cerebral palsy and spastic hemiplegia may have extremely poor upper extremity function. Unfortunately, many current therapies and treatments for patients with spastic hemiplegia offer very limited improvements. One innovative technique for treating these patients is the use a contralateral C7 nerve root transfer to neurotize the C7 nerve root in the affected limb. This may result not only in less spasticity in the affected limb, but also improved control and motor function vis-a-vis the new connection to the normal cerebral hemisphere. However, contralateral C7 transfers can require large incisions and long nerve grafts. The aim of this study was to test the feasibility of a contralateral C7 nerve root transfer procedure with the use of a prevertebral minimally invasive robot assisted technique. In a cadaver, both sides of the C7 root were dissected. The right recipient C7 root was resected as proximally as possible, while the left donor C7 root was resected as distally as possible. With the use of the da Vinci ((r)) SI surgical robot (Intuitive Surgical TM, Sunnyvale, CA, USA), we were able to eliminate the large incision and use a much shorter nerve graft when performing contralateral C7 nerve transfer. PMID- 27117123 TI - Carpal height and postoperative strength after proximal row carpectomy or four corner arthrodesis: Clinical, anatomical and biomechanical study. AB - Proximal row carpectomy (PRC) and four-corner arthrodesis (4CA) are the two most commonly performed surgical procedures to treat wrist arthritis. Postoperative strength is one of the criteria for choosing between the two techniques. Some authors believe that strength is correlated with residual carpal height. The goal of this study was to determine if postoperative carpal height was predictive of postoperative strength. This study consisted of two parts: a clinical evaluation of grip strength after 4CA or PRC; anatomical and radiological measurements of carpal height before and after 4CA or PRC. Grip strength was better preserved after PRC (87.5%) than after 4CA (76.1%), when expressed relative to the opposite hand (P=0.053). There was a significant decrease in carpal height for the PRC group with a Youm's index of 0.37 versus 0.50 for the 4CA group (P<0.0001). Our clinical results and analysis of the literature indicate that 4CA is not superior to PRC when it comes to grip strength, whereas carpal height is significantly decreased after PRC. The decreased tendon excursion after PRC is balanced by an increase in joint stresses after 4CA. PMID- 27117124 TI - Use of the entire flexor carpi radialis tendon for basal thumb ligament reconstruction interposition arthroplasty. AB - Recent studies seem to show that ligament reconstruction with tendon interposition (LRTI) does not provide any benefit over trapezium excision alone; however dorsal subluxation was not measured in these studies. We believe it is logical to perform ligamentoplasty in order to obtain long-term stability and therefore treat dorsal subluxation. Our aim is to verify this hypothesis in an observational prospective study of LRTI using the entire flexor carpi radialis (FCR) tendon. Patients who had failed to respond to nonoperative treatment for advanced thumb basal joint arthritis were recruited prospectively between 2007 and 2011. They all received the same surgical treatment, which consisted of LRTI using the entire FCR tendon. Pre- and postoperative pain, range of motion, strength, stability of the base of the first metacarpal and DASH scores were evaluated. Forty-three patients (49 thumbs) were included with a mean follow-up of 37months (range: 29-72months). Patients showed significant improvements in pain, range of motion and pinch strength. The dorsoradial subluxation was no longer present in any of the thumbs, and the grind test was positive in only three thumbs. The DASH score was improved from 49/100 preoperatively to 22/100 postoperatively. No ulnar deviation of the wrist was observed at the longest follow-up and grip strength was not altered by the procedure. This study showed that the use of the full FCR tendon for LRTI in combination with trapeziectomy is an efficient and safe treatment for advanced carpometacarpal osteoarthritis as it provides a strong ligamentoplasty with a bulky interposition. LEVEL OF EVIDENCE: Clinical study, Therapeutic Study: Level IV. PMID- 27117125 TI - Functional and radiographic evaluation of the treatment of traumatic bone loss of the hand using the Masquelet technique. AB - This study was a retrospective evaluation of 18 patients with traumatic bone loss affecting the fingers, hand and wrist who were treated using the induced-membrane technique. Sixteen men and two women, mean age 54years (27-74) presented a hand injury including bone loss. Sixteen patients were treated on an emergency basis and two following nonunion of their fractures. There were 13 cases of open fracture of the phalanx and 5 cases of metacarpal fractures. These patients were treated with debridement and the injuries were covered when necessary. To address the bone loss, the first step of the induced-membrane technique involved placing a cement spacer (polymethylmethacrylate [PMMA]) without antibiotics in the defect. During the second step, the cement spacer was removed and replaced by autologous cancellous bone graft. The graft was placed within the biological tube left empty after removal of the cement. For each patient, bone union was assessed with radiographs and/or CT scan. Failure was defined as nonunion at 1year. In 16 patients, the fractures had healed after 4months (1.5-12months) on average. Two failures were noted (one nonunion treated using a PIP prosthesis and one case of delayed union). Mobility of the fingers, evaluated using the Total Active Motion (TAM) was 145 degrees (75 degrees -270 degrees ). The Kapandji score reached 8 for the thumb. Grip strength reached 21kg/F and pinch strength was 5kg/F; these values were 50% of those in the healthy hand. The induced-membrane technique is simple and can be used to treat traumatic bone loss in an emergency, thus avoiding amputation and limb shortening, while preserving limb function. It provides immediate stability and allows early mobilization. PMID- 27117126 TI - Duration of sick leave after surgical repair of the ulnar collateral ligament of the thumb metacarpophalangeal joint with K-wire immobilization: Prospective case series of 21 patients. AB - Surgical repair of the ulnar collateral ligament (UCL) of the thumb metacarpophalangeal (MCP) joint after complete rupture is usually protected by cast immobilization, which hinders return to work. The goal of this study was to determine the duration of sick leave for patients who had 6 weeks of K-wire immobilization instead of cast immobilization after surgical repair of the UCL. This prospective, observational, non-comparative study included patients who had surgical repair of the UCL of the thumb MCP joint followed by K-wire immobilization. Manual laborers were excluded. The main outcome measure was the duration of sick leave. The other outcomes were the need to adapt to the work duties and the patient's subjective assessment of the result. The data were collected by telephone interview. Twenty-one patients were included, 13 (62%) of whom returned to work within 7 days. The average sick leave duration was 3 weeks and 2 days; 10% of patients required adaptation of the work duties. The average satisfaction score was 4.4 out of 5. The average follow-up was 3 years and 5 months. There were no complications. In conclusion, K-wire immobilization after surgical repair of the UCL of the thumb MCP joint, along with precautionary measures is an option that allows early return to work, except for manual labourers. PMID- 27117127 TI - Open volar radiocarpal dislocation with extensive dorsal ligament and extensor tendon damage: A case report and review of literature. AB - The authors present the case of a patient with a rare combination of open volar radiocarpal dislocation and complete destruction of the dorsal capsule-ligament complex and tendons. The treatment consisted of open reduction and arthrorisis (temporary arthrodesis during 45 days) with four K-wires (radiocarpal and radioulnar). The capsule-ligament complex was fixed with anchors and the extensor tendons were repaired by suturing. A long-arm cast was applied for six weeks. After an 18-month follow-up, the Cooney-modified Green and O'Brien score was 70 and the wrist range of motion was 85 degrees . Dynamic intraoperative X-rays are needed to look for bone or ligament (intracarpal or radioulnocarpal) injuries. Arthrography, arthroscopy or MRI may provide additional information. In cases of stable lesions without intracarpal ligament injuries, conservative treatment may be sufficient. Otherwise, surgical treatment is required, using temporary external fixation or arthrorisis (temporary arthrodesis) associated with anatomic repair of capsular ligaments. The average duration of postoperative immobilization is 6.6 weeks. An external fixator seems to be useful for reduction and for placing optimal tension on repaired ligament repair. Twenty-three cases of volar radiocarpal dislocation are described in published studies. None of them was associated with bone, tendon, skin or capsule-ligament complex injuries. Few studies describe the long-term functional and radiological outcomes of these injuries. PMID- 27117128 TI - A rare complication of scaphoid nonunion: Multiple flexor tendon lesions. A case report and review of literature. AB - This case report describes a patient who presented with a complete rupture of the flexor pollicis longus (FPL) tendon and partial rupture of the flexor digitorum profundus of the index finger, secondary to scaphoid nonunion. This is a rare, late complication that deserves to be described because of the potential diagnostic confusion with anterior interosseous nerve palsy. No case has been reported since 1999 in the literature. The mechanism was an attrition rupture due to sharp osteophytes. The scaphoid osteophytes were removed and the FPL was repaired by tendon transfer. The results were satisfactory at the last follow-up. PMID- 27117129 TI - Recurrent posttraumatic trapeziometacarpal joint dislocation in a child: A case report. AB - Traumatic trapeziometacarpal joint dislocation of the thumb accounts for less than 1% of all hand injuries. This injury is even less common in children. Optimal treatment strategies for this injury are still the subject of debate for both children and adults. We report a case of recurrent posttraumatic trapeziometacarpal joint dislocation in an eight-year-old girl. We believe our case is the first report of recurrent acute dislocation leading to chronic dislocation in the English medical literature. Restoring the anatomy and biomechanics of the trapeziometacarpal joint is essential when treating these injuries; for this reason, surgical treatment is usually indicated. Overall, the prognosis of trapeziometacarpal dislocation treated acutely is favorable and stable over time. However, the role of open surgery and ligament reconstruction remains controversial, especially in children. PMID- 27117130 TI - Use of an index finger as a bank in thumb reconstruction after tumor resection: About one case. AB - The use of a "bank finger" by its very nature is almost exclusively reserved for the management of traumatic hand injuries. Here, we described one case of thumb reconstruction using the patient's index finger as a "bank finger" after the excision of a grade II malignant fibrous histiocytoma. PMID- 27117131 TI - Composite neuromusculo-fasciocutaneous triceps brachii free flap for complex foot reconstructive surgery. AB - Since it was first described by Song in 1982, then by Katsaros in 1984, the lateral arm flap has become a workhorse technique for upper limb reconstruction. Herein we describe a clinical case of complex foot defect and bring up the possibility of using a composite neuromusculo-fasciocutaneous lateral arm/triceps free flap for its reconstruction. A 19-year-old male nonsmoker suffered ballistic trauma to his right foot with open multifragment Gustilo-IIIb fractures of the first to fifth metatarsal bones. Two weeks after debridement and V.A.C.TM therapy performed in another hospital, we decided to reconstruct the remaining defect with a neuromusculo-fasciocutaneous medial triceps/lateral arm free flap anastomosed with the anterior tibial pedicle. The posterior brachial cutaneous nerve was sutured to a sensory branch of the superficial fibular nerve. The advantages and drawbacks of this technique are discussed and other options for this type of complex foot reconstruction are reviewed. After 3 years' follow-up, the metatarsal bones were consolidated without residual defect or chronic infection. The foot had sensation with full mobility and no pain. At the donor site, there was no complaint of scarring. Elbow extension/flexion was 0-0-130. Wrist extension/flexion was 60-0-60 and there was no extension deficit of the metacarpophalangeal joints. The composite neuromusculo-fasciocutaneous triceps brachii free flap was an excellent option for this complex foot defect. The choice of this reconstructive procedure among other options was made during our reconstruction board meeting while taking the patient's specific condition and our own experiences into account. PMID- 27117132 TI - Oligophrenin1 protects mice against myocardial ischemia and reperfusion injury by modulating inflammation and myocardial apoptosis. AB - The Rho family of small GTPases has been analyzed in cardiac physiology and pathophysiology including myocardial infarction (MI) in the last years. Contradictory results show either a protective or a declined effect of RhoA and the RhoA effector Rho-associated protein kinase (ROCK) in myocardial ischemia and reperfusion injury that is associated with cardiomyocyte survival and caspase-3 activation. Cardiac-specific deletion of Rac1 reduced ischemia reperfusion injury in diabetic hearts, whereas cardiomyocyte specific overexpression of active Rac1 predisposes the heart to increased myocardial injury with enhanced contractile dysfunction. GTPase-activating proteins (GAPs) control the activation of Rho proteins through stimulation of GTP hydrolysis. However, the impact of GAPs in myocardial ischemia and reperfusion injury remains elusive. Here we analyzed the role of oligophrenin1 (OPHN1), a RhoGAP with Bin/Amphiphysin/Rvs (BAR) domain known to regulate the activity of RhoA, Rac1 and Cdc42 in MI. The expression of Ophn1, RhoA and Rac1 is strongly upregulated 24h after myocardial ischemia. Loss of OPHN1 induced enhanced activity of Rho effector molecules leading to elevated cardiomyocyte apoptosis and increased migration of inflammatory cells into the infarct border zone of OPHN1 deficient mice. Consequently, echocardiography 24h after myocardial ischemia revealed declined left ventricle function in OPHN1 deficient mice. Our results indicate that OPHN1 mediated regulation of RhoA, Rac1 and Cdc42 is crucial for the preservation of cardiac function after myocardial injury. PMID- 27117133 TI - Glycosaminoglycans are required for translocation of amphipathic cell-penetrating peptides across membranes. AB - Cell-penetrating peptides (CPPs) are considered as one of the most promising tools to mediate the cellular delivery of various biologically active compounds that are otherwise cell impermeable. CPPs can internalize into cells via two different pathways - endocytosis and direct translocation across the plasma membrane. In both cases, the initial step of internalization requires interactions between CPPs and different plasma membrane components. Despite the extensive research, it is not yet fully understood, which of these cell surface molecules mediate the direct translocation of CPPs across the plasma- and endosomal membrane. In the present study we used giant plasma membrane vesicles (GPMVs) as a model membrane system to elucidate the specific molecular mechanisms behind the internalization and the role of cell surface glycosaminoglycans (GAGs) in the translocation of four well-known CPPs, classified as cationic (nona arginine, Tat peptide) and amphipathic (transportan and TP10). We demonstrate here that GAGs facilitate the translocation of amphipathic CPPs, but not the internalization of cationic CPPs; and that the uptake is not mediated by a specific GAG class, but rather the overall amount of these polysaccharides is crucial for the internalization of amphipathic peptides. PMID- 27117134 TI - Unmet healthcare needs and community health center utilization among the low income population based on a nationwide community health survey. AB - BACKGROUND: The Korean government has established community health centers (CHC) since the end of the 20th century to improve community public health and access to healthcare. In this study, we investigated the reasons for unmet healthcare needs and the reasons/purposes for using CHC based on income level. METHODS: We used data from the 2012 Community Health Survey, which was administered by the Korean Centers for Disease Control and Prevention (n=208,399). We performed the chi(2) test to examine differences between unmet healthcare needs and utilization of CHC based on various patient characteristics. Survey logistic regression models were used to examine unmet healthcare needs and utilization of CHC by income level. We also analyzed subgroup models to explain the reasons for the outcome variables. RESULTS: A total of 22,901 (11.0%) individuals experienced unmet healthcare needs and 75,137 (36.1%) utilized CHC. Results of the survey logistic regression analysis revealed that the lowest-income population had a higher odds ratio (OR) for experiencing unmet healthcare needs (OR=1.61) and utilized CHC more frequently (OR=1.66). Their main reasons for unmet healthcare needs were economic (OR=5.75) and difficulties in transportation (OR=2.17). The lowest-income population visited CHC because of lower costs (OR=1.76) and close proximity to home (OR=1.56). The lowest-income population visited CHC for primary care (OR=1.22) and vaccinations (OR=1.23). In contrast, the highest-income group visited CHC primarily to obtain government-issued documents (OR=0.82). CONCLUSIONS: Our results indicate different reasons/purposes for unmet healthcare needs and utilization of CHC based on income level. The government should use a management strategy to reduce unmet healthcare needs among the low-income population and redefine the roles of CHC. PMID- 27117135 TI - Imaging of sarcopenia. AB - Sarcopenia is currently considered a geriatric syndrome increasing in older people. The consequences of sarcopenia - in terms of impaired mobility, limited self-sufficiency and disability - have been amply demonstrated, increasing the need to develop methods to identify muscle mass loss as early as possible. Although sarcopenia involves a reduction in both muscle mass and function, loss of muscle mass remains the essential criterion for diagnosing this condition in daily practice. Computed tomography and magnetic resonance imaging represent the gold standard for studying body composition, and can identify quantitative and qualitative changes in muscle mass. These techniques are costly, time-consuming and complex, however, so their applicability is limited to the research field. Sonography, on the other hand, has the advantage of being a relatively quick and inexpensive method for detecting loss of muscle fibers and fat infiltration by analyzing muscle thickness and echo intensity. To the best of our knowledge, however, only few studies have compared the results of ultrasound with those obtained by other methods in order to establish its reliability in this setting. Dual X-ray absorptiometry thus remains the most often used technology for studying body composition, detecting quantitative changes in muscle mass with the advantages of a low radiation dose, a simple technology and a rapid assessment. PMID- 27117136 TI - Impaired context processing during irony comprehension in schizotypy: An ERPs study. AB - Mentalizing deficits are a core manifestation of schizophrenia spectrum disorders. They contribute to the social handicap associated with the pathology, leading to disruption in autonomy, professional achievement, and interpersonal relationships. However, the underlying mechanisms of these deficits remain poorly understood. The aim of the present study was to test the hypothesis that context processing deficits would be responsible for mentalizing difficulties in schizotypy (personality traits considered as attenuated manifestations of schizophrenic symptoms) by using an irony comprehension task. Irony processing is a mentalizing exercise that requires the ability to take into account the semantic context to understand the literal meaning of the utterance, and to integrate the pragmatic context to infer the speaker's intention. These two steps of processing can be indexed by the N400 and P600 components, respectively, of event-related brain potentials (ERPs). Forty participants were assigned to high or low schizotypy groups according to their Schizotypal Personality Questionnaire (SPQ) score, and ERPs were recorded while they read short stories ending with a literal, ironic, or incompatible statement. In the low-SPQ group, there was a significant N400 semantic context effect (literal targets elicited less negative N400 amplitudes compared to incompatible targets) followed by a P600 pragmatic context effect (ironic targets evoked greater positive P600 amplitudes than literal targets). In contrast, there was neither a N400 nor P600 effect in the high-SPQ group. These abnormalities were associated with high interpersonal SPQ factor scores. These results show a strong association between context processing, mentalizing abilities, and interpersonal functioning in schizophrenia spectrum. PMID- 27117137 TI - Phylogenetic grouping and distribution of virulence genes in Escherichia coli along the production and supply chain of pork around Hubei, China. AB - Escherichia coli is an important foodborne zoonotic pathogen. A total of 285 strains of E. coli were isolated from the production and supply chain of pork in Hubei, China and characterized. Their phylogroups (A, B1, B2, and D) and virulence genes of public health importance become more and more diverse along the production and supply chain. PMID- 27117138 TI - First case report of Nocardia brasiliensis infection causing necrotizing fasciitis in an immunocompetent patient. PMID- 27117139 TI - Specialized Oral Diet Improved Clinical Outcome of a Patient with Severe Intestinal Insufficiency in a Late Postoperative Period: A Case Report in Clinical Nutrition. PMID- 27117140 TI - Mutation analysis of metastatic melanomas in the central nervous system: results of a panel of 5 genes in 48 cases. AB - Melanocytic lesions in the central nervous system (CNS) may be primary to the site but are more commonly metastases from cutaneous primaries. In fact, melanomas are one of the most common malignancies that can metastasize to the brain, and some patients may not have a diagnosis of melanoma prior to the discovery of the CNS lesion. In such cases, identifying the primary site may be challenging. We reviewed the archives of a large referral center for melanocytic tumors involving the CNS and selected 48 patients for this study based on our inclusion criteria. We used sequencing to identify mutation status of these tumors and compared these with clinicopathological features. Mutations in exon 9, 11, 13, 17, and 18 of KIT gene, exon 15 of BRAF gene, exon 2 and 3 of NRAS gene, exon 4 and 5 of GNAQ and GNA11 genes were analyzed. Mutations in BRAF-exon 15 were the most common among tumors (58.3%). NRAS-exon 2 and NRAS-exon 3 mutations were detected in 3 and 7 cases, respectively. GNAQ-exon 4, GNAQ-exon 5 and GNA11 exon 5 mutation were present in 1 tumor each. Eight tumors were wild type for all 5 genes, and 6 of these were not known primary despite a work-up and clinical follow-up. Only 1 of these tumors showed a mutation in exon 11 of KIT gene. When compared to primary melanocytic lesions of the CNS, metastatic melanomas were characterized by BRAF gene mutations and wild-type GNAQ and GNA11 genes. PMID- 27117141 TI - The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice. AB - RATIONALE: VRP26 displays mu opioid receptor agonist and delta opioid receptor antagonist activity in vitro, a pharmacological profile purported to produce reduced tolerance, dependence, and rewarding effects. We hypothesized that VRP26 would display reduced adverse effects after chronic administration as compared with the traditional opioid analgesic fentanyl. OBJECTIVE: The aim of this study is to explore the development of tolerance, dependence, and conditioned place preference of VRP26 as compared with the traditional opioid analgesic fentanyl. METHODS: The antinociceptive effects of VRP26 and fentanyl were assessed using the mouse warm water tail withdrawal (WWTW) assay. Measurement of antinociceptive tolerance and physical dependence occurred after 7 days of continuous administration of either fentanyl (0.3 mg/kg/day) or VRP26 (10 mg/kg/day); tolerance was measured by a shift in the antinociceptive dose response curve in the WWTW assay. Physical dependence was determined by observation of withdrawal symptoms after precipitated withdrawal. Rewarding effects were measured by the ability of VRP26 or fentanyl to produce conditioned place preference. RESULTS: Fentanyl produced significant tolerance and dependence, as well as significant conditioned place preference. VRP26 produced neither tolerance nor physical dependence, nor did it produce significant conditioned place preference. CONCLUSIONS: These results suggest that chronic treatment with VRP26 may produce less tolerance or physical dependence than chronic treatment with clinically available mu opioid analgesics such as fentanyl. Additionally, VRP26 produces less rewarding effects than fentanyl. This desirable in vivo profile may be due to the mixed efficacy nature of VRP26 and could provide the framework for safer opioid analgesics. PMID- 27117142 TI - Behavioral and qEEG effects of the PDE10A inhibitor THPP-1 in a novel rhesus model of antipsychotic activity. AB - RATIONALE: Much preclinical data, almost exclusively using rodent, supports the notion that phosphodiesterase 10A (PDE10A) inhibition may offer an alternative to the current standard of care in schizophrenia. However, concerns persist regarding the clinical translatability of these models for newer drug classes like PDE10A inhibitors. OBJECTIVES: We therefore sought to characterize the clinical standard risperidone and the PDE10A inhibitor THPP-1 in nonhuman primate, both alone and when used as a combination therapy. METHODS: THPP-1 and risperidone were tested in a novel rhesus model of stimulant-induced motor activity (SIMA) and in rhesus electroencephalography (EEG). RESULTS: Consistent with rodent data, both THPP-1 and risperidone significantly attenuated the stimulant effects in SIMA when administered alone, though some differences were noted. Combination therapy with a low dose of risperidone produced significantly more robust effects. THPP-1 and risperidone also produced a marked reduction of wake cycle time and gamma frequency power in EEG. However, THPP-1 differed from risperidone by reducing spectral power of lower frequencies (delta). CONCLUSIONS: SIMA results suggest that PDE10A inhibition produces antipsychotic-like effects in higher species, and that combination therapy with PDE10A inhibitors may produce more robust efficacy compared to monotherapies. EEG and qEEG results confirm that PDE10A inhibition does share some central signaling effects with clinically effective antipsychotics. The present combination therapy results may carry implications for the manner in which clinical testing of PDE10A inhibitors is conducted. PMID- 27117143 TI - Effects of BMAL1-SIRT1-positive cycle on estrogen synthesis in human ovarian granulosa cells: an implicative role of BMAL1 in PCOS. AB - Brain and muscle ARNT-like protein 1 (BMAL1) is necessary for fertility and has been found to be essential to follicle growth and steroidogenesis. Sirtuin1 (SIRT1) has been reported to interact with BMAL1 and function in a circadian manner. Evidence has shown that SIRT1 regulates aromatase expression in estrogen producing cells. We aimed to ascertain if there is a relationship between polycystic ovary syndrome (PCOS) and BMAL1, and whether and how BMAL1 takes part in estrogen synthesis in human granulosa cells (hGCs). Twenty-four women diagnosed with PCOS and 24 healthy individuals undergoing assisted reproduction were studied. BMAL1 expression in their granulosa cells (GCs) was observed by quantitative real-time polymerase chain reaction (qRT-PCR). The level of expression in the PCOS group was lower than that of the group without PCOS (p < 0.05). We also analyzed estrogen synthesis and aromatase expression in KGN cell lines. Both were downregulated after BMAL1 and SIRT1 knock-down and, conversely, upregulated after overexpression treatments of these two genes in KGN cells. Both BMAL1 and SIRT1 had a mutually positive regulation, as did the phosphorylation of JNK. Furthermore, JNK overexpression increased estrogen synthesis activity and the expression levels of aromatase, BMAL1, and SIRT1. In KGN and hGCs, estrogen synthesis and aromatase expression were downregulated after treatment with JNK and SIRT1 inhibitors. In addition, BMAL1, SIRT1, and JNK expression levels were all downregulated. Our results demonstrate the effects of BMAL1 on estrogen synthesis in hGCs and suggest a BMAL1-SIRT1-JNK positive feedback cycle in this process, which points out an important role of BMAL1 in the development of PCOS. PMID- 27117144 TI - Effect of DHA supplementation in a very low-calorie ketogenic diet in the treatment of obesity: a randomized clinical trial. AB - A VLCK diet supplemented with DHA, commercially available, was tested against an isocaloric VLCK diet without DHA. The main purpose of this study was to compare the effect of DHA supplementation in classic cardiovascular risk factors, adipokine levels, and inflammation-resolving eicosanoids. A total of obese patients were randomized into two groups: a group supplemented with DHA (n = 14) (PnK-DHA group) versus a group with an isocaloric diet free of supplementation (n = 15) (control group). The follow-up period was 6 months. The average weight loss after 6 months of treatment was 20.36 +/- 5.02 kg in control group and 19.74 +/- 5.10 kg in PnK-DHA group, without statistical differences between both groups. The VLCK diets induced a significant change in some of the biological parameters, such as insulin, HOMA-IR, triglycerides, LDL cholesterol, C-reactive protein, resistin, TNF alpha, and leptin. Following DHA supplementation, the DHA-derived oxylipins were significantly increased in the intervention group. The ratio of proresolution/proinflammatory lipid markers was increased in plasma of the intervention group over the entire study. Similarly, the mean ratios of AA/EPA and AA/DHA in erythrocyte membranes were dramatically reduced in the PnK-DHA group and the anti-inflammatory fatty acid index (AIFAI) was consistently increased after the DHA treatment (p < 0.05). The present study demonstrated that a very low-calorie ketogenic diet supplemented with DHA was significantly superior in the anti-inflammatory effect, without statistical differences in weight loss and metabolic improvement. PMID- 27117145 TI - Youths' perception and knowledge towards environmental problems in a developing country: in the case of Ataturk University, Turkey. AB - This study explores the perception and knowledge of environmental problems among students of Ataturk University, Turkey, as a developing country, by comparing their perceptions with known facts about environmental problems at local, national, and global levels. In addition, the correlation between the student groups and their knowledge levels and the differences between the student groups according to their knowledge levels when taking age and gender into account are explored. To this end, the research designed as a case study and pursued an exploratory approach revealed that major perceived environmental problems show differences at local, national, and global levels; that consensus on both major perceived problems and knowledge decreases from a local to global level; that a weak correlation exists between the age (r (205) = -.010; .002; -.071) and gender groups (r (205) = -.099; -.125; .065) in terms of their knowledge at local, national, and global level, respectively; and that the contribution of knowledge at a national level can help to explain differences among the age groups (-.304; .102; -.148) at national level and the gender groups (.131; -.205) at national and global levels. PMID- 27117146 TI - Prenatal low-level mercury exposure and infant neurodevelopment at 12 months in rural northern China. PMID- 27117147 TI - Coupled urbanization and agricultural ecosystem services in Guanzhong-Tianshui Economic Zone. AB - Ecosystems offer material and environmental support for human habitation and development in those areas of the earth where people choose to live. However, urbanization is an inexorable trend of human social development and threatens the health of those ecosystems inhabited by humans. This study calculates the values of NPP (net primary productivity), carbon sequestration, water interception, soil conservation, and agricultural production in the Guanzhong-Tianshui Economic Zone. At the same time, we combined DMSP/OLS (Defense Meteorological Satellite Program Operational Line Scanner) night lights remote sensing data and statistical data to analyze the level of urbanization. Quantitative analysis was performed on the interactions between the ecosystem service functions and urbanization based on the calculations of their coupled coordination degrees. The results were the following: (1) The values of NPP, carbon sequestration, and agricultural production showed a trend of increase. However, water interception decreased before increasing, while soil conservation showed the reverse trend; (2) Urbanization levels in the Guanzhong-Tianshui Economic Zone for the last 10 years have proceeded at a fast pace with comprehensive promotion; and (3) Coupled and coupled coordination degrees between urbanization and ecosystem services show increasing trends. This research can provide a theoretical basis for the region's rapid economic development in the balance. PMID- 27117148 TI - Vermiremediation of toxic jute mill waste employing Metaphire posthuma. AB - India has a giant jute-producing basket which produces considerable quantity of toxic jute mill waste (JMW). Conversely, report on usability potential of JMW is rather scanty. The present study illustrates the efficiency of vermicomposting in bioconversion of JMW for agricultural use. Various combinations of JMW, cow dung, and vegetable waste were fed to Metaphire posthuma in vermireactors. Rapid increment of earthworm count, body weight, and cocoon production was evidenced. Total organic carbon and pH reduction was noteworthy, but N, P, and K availability, formation of stable humic acid C, fulvic acid C, and microbial biomass C substantially increased due to vermicomposting. FTIR spectroscopy confirmed a higher stability of vermicomposted JMW over the composted product. A significant decline in heavy metal concentration (Cr, Pb, Fe, and Zn) in the vermicomposted JMW further establishes the potential of vermicomposting with M. posthuma in successful conversion of the toxic JMW into valuable product. PMID- 27117149 TI - Sediment pollution and dynamic in the Mar Piccolo of Taranto (southern Italy): insights from bottom sediment traps and surficial sediments. AB - Major and trace element, PAH, and PCB concentrations were measured in surface sediments and particles from sediment traps collected in the First and Second Basin of the Mar Piccolo (Gulf of Taranto) in two periods (June-July and August September, 2013). The aim of the study was to evaluate pollution degree, sediment transport and particle redistribution dynamic within the area. Results confirm the higher contamination of sediments from the First Basin observed by previous researches, particularly for Cu, Hg, Pb, total PAHs, and total PCBs. Advective transport from the First to the Second Basin appears to be the leading transfer mechanism of particles and adsorbed contaminants, as evidenced by measured fluxes and statistical analyses of contaminant concentrations in surficial sediments and particles from sediment traps. Long-range selective transports of PAHs and microbial anaerobic degradation processes for PCBs have been also observed. These results are limited to a restricted time window but are consistent with the presence of transport fluxes at the bottom of the water column. This mechanism deserves further investigation and monitoring activities, potentially being the main responsible of pollutant delivering to the less contaminated sectors of the Mar Piccolo. PMID- 27117151 TI - Dust aerosol properties and radiative forcing observed in spring during 2001-2014 over urban Beijing, China. AB - The ground-based characteristics (optical and radiative properties) of dust aerosols measured during the springtime between 2001 and 2014 were investigated over urban Beijing, China. The seasonal averaged aerosol optical depth (AOD) during spring of 2001-2014 was about 0.78 at 440 nm. During dust days, higher AOD occurred associated with lower Angstrom exponent (AE). The mean AE440-870 in the springtime was about 1.0, indicating dominance of fine particles over the region. The back-trajectory analysis revealed that the dust was transported from the deserts of Inner Mongolia and Mongolia arid regions to Beijing. The aerosol volume size distribution showed a bimodal distribution pattern, with its highest peak observed in coarse mode for all episodes (especially for dust days with increased volume concentration). The single scattering albedo (SSA) increased with wavelength on dust days, indicating the presence of more scattering particles. Furthermore, the complex parts (real and imaginary) of refractive index showed distinct characteristics with lower imaginary values (also scattering) on dust days. The shortwave (SW; 0.2-4.0 MUm) and longwave (LW; 4-100 MUm) aerosol radiative forcing (ARF) values were computed from the Santa Barbara DISORT Atmospheric Radiative Transfer (SBDART) model both at the top of atmosphere (TOA) and the bottom of atmosphere (BOA) during dust and non-dust (dust free) days, and the corresponding heating rates and forcing efficiencies were also estimated. The SW (LW) ARF, therefore, produced significant cooling (warming) effects at both the TOA and the BOA over Beijing. PMID- 27117150 TI - Metal bioleaching from anaerobic sediments from Reconquista River basin (Argentina) as a potential remediation strategy. AB - Anaerobic sediments of urban watercourses are subjected to industrial pollution and frequently tend to accumulate heavy metals. The biocatalyzed oxidation and reduction of sulphur compounds that occur within the sediment are key reactions that determine mobility of metals such as that occurred in mine acidic drainage reactions. The aim of this work was to study the application of these processes using heap leaching technology for the remediation of anaerobic contaminated sediments from Reconquista River basin. The bioleaching potentiality for remediation was demonstrated through batch tests in shake flasks with different pulp densities of anaerobic sediment containing 338 mg kg-1 of Zn and 117 mg kg-1 of Cu. Subsequently, bioleaching heap systems were compiled into columns of 12-cm height and 6-cm diameter, fitted with perlite to improve drainage. In order to assess the effect of elementary sulphur over the mobility of metals from the bioheap to the aqueous solution, increasing concentrations of elementary sulphur (1, 2, 5 % w/w) were added. After 3 months of acidification generated by periodic watering, the extraction of 70 % of the initial Zn and 43 % of the initial Cu was achieved. Polluted sediments from waterways as Reconquista River should not be indiscriminately manipulated if acid drainage is possible. Remediation by a simple and economically viable strategy like heap leaching is feasible. PMID- 27117152 TI - Bioelectrochemical denitrification on biocathode buried in simulated aquifer saturated with nitrate-contaminated groundwater. AB - Nitrate contamination in aquifers has posed human health under high risk because people still rely on groundwater withdrawn from aquifers as drinking water and running water sources. These days, bioelectrochemical technologies have shown a great number of benefits for nitrate remediation via autotrophic denitrification in groundwater. This study tested the working possibility of a denitrifying biocathode when installed into a simulated aquifer. The reactors were filled with sand and synthetic groundwater at various ratios (10, 50, and 100 %) to clarify the effect of various biocathode states (not-buried, half-buried, and fully buried) on nitrate reduction rate and microbial communities. Decreases in specific nitrate reduction rates were found to be correlated with increases in sand/medium ratios. A specific nitrate reduction rate of 322.6 mg m(-2) day(-1) was obtained when the biocathode was fully buried in an aquifer. Microbial community analysis revealed slight differences in the microbial communities of biocathodes at various sand/medium ratios. Various coccus- and rod-shaped bacteria were found to contribute to bioelectrochemical denitrification including Thiobacillus spp. and Paracoccus spp. This study demonstrated that the denitrifying biocathode could work effectively in a saturated aquifer and confirmed the feasibility of in situ application of microbial electrochemical denitrification technology. PMID- 27117153 TI - Adaptability comparison of E. fetida in vermicomposting against sludge from livestock wastewater treatment plant based on their several growth stages. AB - Vermicomposting is a low-cost, eco-efficient process to deal with organic wastes. Mixtures of swine manure (SM), cow dung (CD), and animal wastewater treatment plant sludge (S) were applied as feeds, and Eisenia fetida was employed in this study to investigate the vermicomposting efficiency based on their several growth stages. The hatching test resulted in a 100 % hatching rate in S60SM40 (60 % S + 40 % SM) mixture, while 4.40 hatchlings per cocoon were observed. The growth of infancy performed best in 0-20 % CD mixtures (0.05 +/- 0.002 g), followed by in SM + CD (0.04 +/- 0.003 g). The highest growth rate of young and adult E. fetida was noticed in CD + S mixtures (11.14 +/- 0.01 and 6.00 +/- 0.02 mg/d/worm, respectively), while the higher cocoon production of adults was noticed in S + SM mixtures especially in S40SM60 (537 +/- 5 worms). Moreover, the conversion of solids; the modified pH value; the reduction in total organic carbon (TOC); total Kjeldahl nitrogen (TKN), NH4-N, NO3-N, and C:N ratio; and the rich in total available phosphorus (TAP) and total potassium (TK) content by young and adult E. fetida were related to the growth of worms. Such work would benefit understanding and to increase the efficiency of vermicompost processing of different wastes. PMID- 27117154 TI - Predicting plant uptake and toxicity of lead (Pb) in long-term contaminated soils from derived transfer functions. AB - Regulatory assessment of lead (Pb) in contaminated soils is still expressed primarily as total Pb concentrations in soil. In this study, we estimated effective concentrations (ECx) of Pb to Cucumis sativa L. (cucumber) focusing primarily on pore-water Pb data from 10 different soils after 12 weeks ageing. Phytotoxicity expressed in terms of Pb(2+) was observed to occur in the nanomolar range in neutral to alkaline soils (EC50 values 90 to 853 nM) and micromolar levels for acidic soils (EC50 values 7.35 to 9.66 MUM). Internal Pb concentrations relating to toxicity (PT50) in roots and shoots also decreased with increasing pore-water pH (R (2) = 0.52 to 0.53). From a series of dose response studies, we developed transfer functions predicting Pb uptake in C. sativa and we validated these functions with long-term Pb contaminated soils. The significant independent parameters were pore-water Pb(2+) and dissolved Pb plus dissolved organic carbon (DOC). The observed RMSE for the Pb-DOC model and Pb(2+) were 2.6 and 8.8, respectively. The Pb-DOC model tended to under-predict Pb, whilst Pb(2+) tended to over-predict accumulation despite reasonable RMSE values. Further validation is needed in soils with higher pore-water Pb solubility. PMID- 27117155 TI - Effective degradation of rhodamine B by electro-Fenton process, using ferromagnetic nanoparticles loaded on modified graphite felt electrode as reusable catalyst: in neutral pH condition and without external aeration. AB - Polytetrafluoroethylene/ferromagnetic nanoparticle/carbon black (PTFE/MNP/CB) modified graphite felt (GF) was successfully applied as cathode for the mineralization of rhodamine B (RhB) in electro-Fenton (EF) process. The modified cathode showed high decolorization efficiency for RhB solution even in neutral pH condition and without external aeration, achieving nearly complete decolorization and 89.52 % total organic carbon (TOC) removal after 270-min oxidation with the MNP load 1.2 g at 50 A/m(2). Moreover, the operational parameters (current density, MNP load, initial pH, and airflow rate) were optimized. After that, adsorption isotherm was also conducted to compare the absorption quantity of CB and carbon nanotube (CNT). Then, the surface morphologies of MNPs were characterized by transmission electron microscope (TEM), energy-dispersive X-ray detector (EDX), and Fourier transform infrared spectroscopy (FTIR); and the modified cathode was characterized by SEM and contact angle. Finally, the stability and reusability of modified cathode were tested. Result uncovered that the PTFE/MNP/CB-modified cathode has the potential for industrial application and the solution after treatment was easily biodegradable. PMID- 27117156 TI - Microbial community structures and metabolic profiles response differently to physiochemical properties between three landfill cover soils. AB - Landfills are always the most important part of solid waste management and bear diverse metabolic activities involved in element biogeochemical cycling. There is an increasing interest in understanding the microbial community and activities in landfill cover soils. To improve our knowledge of landfill ecosystems, we determined the microbial physiological profiles and communities in three landfill cover soils (Ninghai: NH, Xiangshan: XS, and Fenghua: FH) of different ages using the MicroResp(TM), phospholipid fatty acid (PLFA), and high-throughput sequencing techniques. Both total PLFAs and glucose-induced respiration suggested more active microorganisms occurred in intermediate cover soils. Microorganisms in all landfill cover soils favored L-malic acid, ketoglutarate, and citric acid. Gram negative bacterial PLFAs predominated in all samples with the representation of 16:1omega7, 18:1omega7, and cy19:0 in XS and NH sites. Proteobacteria dominated soil microbial phyla across different sites, soil layers, and season samples. Canonical correspondence analysis showed soil pH, dissolved organic C (DOC), As, and total nitrogen (TN) contents significantly influenced the microbial community but TN affected the microbial physiological activities in both summer and winter landfill cover soils. PMID- 27117157 TI - National Cross-Sectional Survey on Blood Pressure: A Gateway to a Better Appraisal of Hypertension in the Young. PMID- 27117158 TI - The Nordic SentiMag trial: a comparison of super paramagnetic iron oxide (SPIO) nanoparticles versus Tc(99) and patent blue in the detection of sentinel node (SN) in patients with breast cancer and a meta-analysis of earlier studies. AB - The aim of the study is to compare the efficacy of SPIO as a tracer in sentinel node biopsy (SNB) in breast cancer with Tc and patent blue in a multicentre prospective study and perform a meta-analysis of all published studies. It also aims to follow skin discoloration after SPIO injection and describe when and how it resolves. Totally 206 patients with early breast cancer were recruited. Tc and patent blue were administered in standard fashion. Patients were injected with SPIO (Sienna+) preoperatively. SNB was performed and detection rates were recorded for both methods. Skin discoloration was followed and documented postoperatively. Data extraction and subsequent meta-analysis of all previous studies were also performed. SN detection rates were similar between standard technique succeeded and SPIO both per patient (97.1 vs. 97.6 %, p = 0.76) as well as per node (91.3 vs. 93.3 %, p = 0.34), something which was not affected by the presence of malignancy. Concordance rates were also consistently high (98.0 % per patient and 95.9 % per node). Discoloring was present in 35.5 % of patients postoperatively, almost exclusively in breast conservation. It fades slowly and is still detectable in 8.6 % of patients after 15 months. Meta-analysis depicted similar detection rates (p = 0.71) and concordance rates (p = 0.82) per patient. However, it seems that SPIO is characterized by higher nodal retrieval (p < 0.001). SPIO is an effective method for the detection of SN in patients with breast cancer. It is comparable to the standard technique and seems to simplify logistics. Potential skin discoloration is something of consideration in patients planned for breast conservation. PMID- 27117160 TI - Association of adiposity, dysmetabolisms, and inflammation with aggressive breast cancer subtypes: a cross-sectional study. AB - Obesity and metabolic syndrome are risk and prognostic factors for breast cancer (BC) and are associated with chronic inflammation. We investigated the association between distinct BC subtypes and markers of adiposity, dysmetabolisms, and inflammation. We analyzed 1779 patients with primary invasive BC treated at a single institution, for whom anthropometric and clinical pathological data were archived. BC subtypes were classified by immunohistochemical staining of ER, PR, HER2, and Ki67, and their relations with the study markers were assessed by multinomial logistic regression. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated taking luminal A as reference. All subtypes more aggressive than luminal A were significantly more frequent in younger (<45 years) than older women. Before menopause, luminal B HER2-negative tumors were positively associated with large waist (OR 2.55, 95 % CI 1.53-4.24) and insulin resistance (OR 1.90, 95 % CI 1.05-3.41); luminal B HER2 positive tumors with large waist (OR 2.11, 95 % CI 1.03-4.35) and triple-negative tumors with overweight (OR 3.04, 95 % CI 1.43-6.43) and high C-reactive protein (p trend = 0.026). In postmenopausal women aged <65, luminal B HER2-negative (OR 1.94, 95 % CI 1.16-3.24) and luminal B HER2-positive tumors (OR 2.48, 95 % CI 1.16-5.27) were positively related with metabolic syndrome. Dysmetabolisms and inflammation may be related to different BC subtypes. Before menopause, triple negative cancers were related to obesity and chronic inflammation, and aggressive luminal subtypes to abdominal adiposity. After menopause, in women aged <65 these latter subtypes were related to metabolic syndrome. Control of adiposity and dysmetabolism can reduce the risk of aggressive BC subtypes, improving the prognosis. PMID- 27117159 TI - An international survey of surveillance schemes for unaffected BRCA1 and BRCA2 mutation carriers. AB - Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed. PMID- 27117161 TI - Morphological and molecular description of immature stages of Ornithodoros savignyi (Acari: Argasidae). AB - This study was designed to provide more details about larva, first nymph, and second nymph of Ornithodoros savignyi using a combination of light microscopy (LM), scanning electron microscopy (SEM), and partial sequence of mitochondrial 16S ribosomal ribonucleic acid (rRNA). The main characteristics of larva are wrinkled integument with many grooves, gnathosoma without camerostome cheeks, hypostome with a pair of large teeth apically, and tarsus without humps. The comparisons between the first and the second nymphs are different shape and distribution of dorsal grooves; a few spots without mammilla on the dorsal surface of the second nymph; 27 and 63-65 pairs of setae on the dorsal surface of the first and second nymphs, respectively; small holes on mammillae that are more dense in the second nymph; basis capitulum with two pairs of small setae in the second nymph; and one pair of sate in the first nymph, hypostome with dental formula 2/2 in the first nymph, and 3/3 in the second nymph. The partial 16S rRNA sequence of the second nymph that was determined as O. savignyi (450 bp) was deposited in GenBank under the accession number KU163242. PMID- 27117162 TI - Morphological characteristics of Mesocestoides canislagopodis (Krabbe 1865) tetrathyridia found in rock ptarmigan (Lagopus muta) in Iceland. AB - Necropsies of 1010 rock ptarmigans (Lagopus muta) sampled in autumn 2006-2015 in northeast Iceland revealed Mesocestoides canislagopodis tetrathyridia infections in six birds (0.6 %), two juvenile birds (3 month old), and four adult birds (15 months or older). Four birds had tetrathyridia in the body cavity, one bird in the liver, and one bird both in the body cavity and the liver. There were more tetrathyridia in the body cavity of the two juveniles (c. 50 in each) than in three adults (10-40), possibly indicating a host-age-related tetrathyridia mortality. Approximately, half of tetrathyridia in the body cavity were free or loosely attached to the serosa, the other half were encapsulated in a thin, loose connective tissue stroma, frequently attached to the lungs and the liver. Tetrathyridia in the liver parenchyma incited variably intense inflammation. Tetrathyridia from the juvenile hosts were whitish, heart-shaped, and flattened, with unsegmented bodies with a slightly pointed posterior end. In the adult hosts, tetrathyridia were sometimes almost rectangular-shaped, slightly wider compared to those in the juveniles, but more than twice as long as the younger aged tetrathyridia. Tetrathyridia infections are most likely acquired during the brief insectivorous feeding phase of ptarmigan chicks, and the tetrathyridia persist throughout the lifespan of the birds. PMID- 27117163 TI - New Insights for Diagnosis of Pineapple Fusariosis by MALDI-TOF MS Technique. AB - Fusarium is one of the most economically important fungal genus, since it includes many pathogenic species which cause a wide range of plant diseases. Morphological or molecular biology identification of Fusarium species is a limiting step in the fast diagnosis and treatment of plant disease caused by these fungi. Mass spectrometry by matrix-assisted laser/desorption ionisation time-of-flight (MALDI-TOF)-based fingerprinting approach was applied to the fungal growth monitoring and direct detection of strain Fusarium guttiforme E-480 inoculated in both pineapple cultivars Perola and Imperial side shoots, that are susceptible and resistant, respectively, to this fungal strain. MALDI-TOF MS technique was capable to detect fungal molecular mass peaks in the susceptible pineapple stem side shoot tissue. It is assumed that these molecular masses are mainly constituted by ribosomal proteins. MALDI-TOF-based fingerprinting approach has herein been demonstrated to be sensitive and accurate for the direct detection of F. guttiforme E-480 molecular masses on both susceptible and resistant pineapple side stem free of any pre-treatment. According to the results obtained, the changing on molecular mass peaks of infected susceptible pineapple tissue together with the possibility of fungal molecular masses analysis into this pineapple tissue can be a good indication for an early diagnosis by MALDI TOF MS of pineapple fusariosis. PMID- 27117165 TI - Tracheal Secondary Involvement by mucosa-associated lymphoid tissue Lymphoma - A Rare Diagnosis. PMID- 27117164 TI - Molecular Components of the Sporothrix schenckii Complex that Induce Immune Response. AB - Sporotrichosis is a fungal disease caused by the Sporothrix schenckii complex that includes species such as S. brasiliensis, S. schenckii sensu stricto, S. globosa, S. luriei, S. mexicana, and S. pallida, which exhibit different potentially antigenic molecular components. The immune response of susceptible hosts to control infection and disease caused by these fungi has been little studied. Besides, the fungus-host interaction induces the activation of different types of immune response. This mini-review analyzes and discusses existing reports on the identification and functional characterization of molecules from species of the S. schenckii complex with clinical relevance, and the mechanisms that mediate the type and magnitude of the immune response in experimental models in vivo and in vitro. This knowledge is expected to contribute to the development of protective and therapeutic strategies against sporotrichosis and other mycoses. PMID- 27117166 TI - Intrathoracic Rib; when to use tomography? PMID- 27117167 TI - Antibodies to alpha5 chain of collagen IV are pathogenic in Goodpasture's disease. AB - Autoantibody against glomerular basement membrane (GBM) plays a direct role in the initiation and development of Goodpasture's (GP) disease. The principal autoantigen is the non-collagenous domain 1 (NC1) of alpha3 chain of collagen IV, with two immunodominant epitopes, EA-alpha3 and EB-alpha3. We recently demonstrated that antibodies targeting alpha5NC1 are bound to kidneys in GP patients, suggesting their pathogenic relevance. In the present study, we sought to assess the pathogenicity of the alpha5 autoantibody with clinical and animal studies. Herein, we present a special case of GP disease with circulating autoantibody reactive exclusively to the alpha5NC1 domain. This autoantibody reacted with conformational epitopes within GBM collagen IV hexamer and produced a linear IgG staining on frozen sections of human kidney. The antibody binds to the two regions within alpha5NC1 domain, EA and EB, and inhibition ELISA indicates that they are targeted by distinct sub-populations of autoantibodies. Sequence analysis highlights five residues that determine specificity of antibody targeting EA and EB epitopes of alpha5NC1 over homologous regions in alpha3NC1. Furthermore, immunization with recombinant alpha5NC1 domain induced crescentic glomerulonephritis and alveolar hemorrhage in Wistar-Kyoto rats. Thus, patient data and animal studies together reveal the pathogenicity of alpha5 antibodies. Given previously documented cases of GP disease with antibodies selectively targeting alpha3NC1 domain, our data presents a conundrum of why alpha3-specific antibodies developing in majority of GP patients, with alpha5-specific antibodies emerged in isolated cases, the answer for which is critical for understanding of etiology and progression of the GP disease. PMID- 27117168 TI - Anatomical landmarks of the distal femoral condyles are not always parallel to the tibial bone cut surface in flexion during total knee arthroplasty. AB - BACKGROUND: Soft tissue balancing is crucial to the success of total knee arthroplasty (TKA). To create a rectangular flexion joint gap, the rotation of the femoral component is important. The purpose of this study is to determine whether or not anatomical landmarks of the distal femoral condyles are parallel to the tibial bone cut surface in flexion. METHODS: Forty-eight patients (three male and 45 female) with a mean age of 74years were examined. During the operation, we estimated the flexion joint gap with the following three techniques. 1) a three degree external cut to the posterior condylar line (MR1), 2) a parallel cut to the surgical transepicondylar axis (MR2), and 3) a parallel cut to the anatomical transepicondylar axis (MR3). RESULTS: The flexion joint gap was 1.1+/-3.0 degrees (mean+/-standard deviation (SD)) in internal rotation in the case of MR1, 0.9+/-3.4 degrees in internal rotation in the case of MR2, and 2.1+/-3.4 degrees in external rotation in the case of MR3. An outlier (flexion joint gap >3.0 degrees ) was observed in 12 cases (25%) in MR1, 13 cases (27%) in MR2, and 15 cases (31%) in MR3. CONCLUSIONS: The anatomical landmarks of the distal femoral condyles are not always parallel to the tibial bone cut surface in flexion. To create a rectangular flexion joint gap, the rotation of the femoral component rotation is based not only on the anatomical landmarks but also on the ligament balance. PMID- 27117169 TI - Reliability of predictive models for non-operative healing potential of stable juvenile osteochondritis dissecans knee lesions. AB - BACKGROUND: While juvenile osteochondritis dissecans (JOCD) lesions have greater healing potential than equivalent lesions in adults, only 50% of JOCD lesions demonstrate radiographic healing after six months of non-operative treatment. Two previous studies have produced nomograms to predict a patient's probability of healing with non-operative treatment based on patient and lesion characteristics. The purpose of this study was to determine inter- and intra-observer reliability of the predictive nomograms. METHODS: A consecutive series of 34 skeletally immature patients (40 knees), who underwent non-operative treatment for stable JOCD lesions was retrospectively reviewed. At two time points at least one week apart, two medical students, two orthopaedic surgeons, and a radiologist made measurements of the JOCD lesions. These measurements, along with patient ages and pain type, were used to generate a point value for each lesion based on both nomograms. Intra-class correlations (ICCs) were calculated to determine inter- and intra-rater reliability. RESULTS: We found near perfect intra-rater correlation (ICC) for all raters' individual OCD measurements, as well as total point score for the two nomograms (ICC range, 0.780-0.929). Additionally, there was near perfect inter-rater reliability among raters for total scores and individual components of each nomogram (ICC range, 0.721-0.974). CONCLUSIONS: There is high inter- and intra-rater reliability for both point systems for predicting healing of JOCD lesions. Clinicians should be aware of these as tools to help guide decision making in patients with JOCD lesions. PMID- 27117170 TI - Identification of Sirex noctilio (Hymenoptera: Siricidae) Using a Species Specific Cytochrome C Oxidase Subunit I PCR Assay. AB - Sirex noctilio F. (Hymenoptera: Siricidae: Siricinae), a new invasive species in China, is a significant international forestry quarantine pest. Transportation of Sirex in logs, and related wood packing materials, has led to environmental damage and substantial economic loss in many countries around the world. Traditional morphological characteristics are not reliable for identification of the Siricidae family, particularly the larvae. Furthermore, specimens are frequently not in a suitable condition to permit morphological identification. The majority of damage is caused by the larval stage, which excavates galleries that can penetrate to the center of tree boles. Thus, development of a rapid, accurate, and effective molecular identification technique for S. noctilio, which does not require expert morphological knowledge, is necessary. Here, we describe a molecular identification tool based on the mitochondrial DNA gene, cytochrome C oxidase subunit I (COI). We designed a species-specific COI (SS-COI) PCR assay, which allows direct identification of S. noctilio, regardless of developmental stage. Six woodwasp species commonly found in China, Sirex noctilio, Sirex nitobei, Sirex sp., Tremex fuscicornis Fabr., Tremex apicalis Matsumura, and Xeris spectrum, were included in our analyses. Moreover, specimens of S. noctilio from 16 different areas were analyzed. The results demonstrate that our molecular assay is effective and accurate, regardless of developmental stage or type of specimen, consistent with use for quarantine purposes, to prevent the harmful consequences of S. noctilio spread. PMID- 27117171 TI - Putting health inequalities to music. PMID- 27117172 TI - Association of an Index of Healthy Aging With Incident Cardiovascular Disease and Mortality in a Community-Based Sample of Older Adults. AB - BACKGROUND: The healthy aging index (HAI) was developed as a marker of health in multiple systems that can identify individuals who age most successfully. METHODS: We calculated an HAI in 934 Framingham Offspring Study participants aged 60 or older at baseline. Heart rate and C-reactive protein (CRP) were added in modified versions of the HAI. Cox proportional hazard models were used to quantify the association of the HAI with mortality, cardiovascular disease (CVD), and cancer. We used fully conditional specification to multiply impute missing values for HAI components, increasing the sample size by 44%. RESULTS: Over 10 years of follow-up, there were 138 deaths, 103 incident cases of CVD, and 138 incident cases of cancer. In models adjusted for age, sex, and behavioral risk factors, the HAI was associated with mortality (hazard ratio [HR] per unit of HAI 1.24, 95% confidence interval [CI] 1.13-1.36) and with CVD (HR 1.27, 95% CI 1.13 1.42), but not with cancer (HR 1.01, 95% CI 0.91-1.11) in observed (non-missing) data. In multivariable models further adjusting for prevalent diseases, results were slightly attenuated. When including heart rate and CRP, a modified HAI gave stronger associations. Results with imputed data are similar to results from complete case analyses. CONCLUSIONS: In our large community-based sample, the HAI is a strong predictor of mortality and CVD. Other factors that are strongly associated with mortality, such as heart rate and CRP can improve the ability of the HAI to identify the healthiest older adults. PMID- 27117173 TI - Bacillus loiseleuriae sp. nov., isolated from rhizosphere soil from a loiseleuria plant. AB - A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterium, designated strain FJAT-27997T, was isolated from the rhizosphere soil of a Loiseleuria plant collected from Sichuan province in China. Growth was observed aerobically between 20 and 35 degrees C (optimum 30 degrees C), between 0 and 3.0 % (w/v) NaCl (optimum at 0 %) concentration and pH in the range 6.0-9.0 (optimum at pH 7.0). The cell-wall peptidoglycan contained meso-diaminopimelic acid and the major isoprenoid quinone was menaquinone MK-7. The main fatty acids were iso-C15 : 0, anteiso-C15 : 0, iso-C14 : 0, C16 : 0 and C14 : 0. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Phylogenetic analyses based on 16S rRNA gene sequences showed that isolate FJAT-27997T was a member of the genus Bacillus and was related most closely to Bacillus simplex DSM 1321T (97.95 % similarity), followed by Bacillushuizhouensis GSS03T (97.9 %). The average nucleotide identity value between strain FJAT-27997T and the most closely related species, B. simplex DSM 1321T, was 71.60 % (JSpecies), less than the previously proposed cut-off value of 96 % for differentiating species within the genus. The in silico DNA-DNA hybridization values between strain FJAT-27997T and its most closely related species were <70 %, again indicating they belong to different taxa. The main fatty acids were iso-C15 : 0 and anteiso-C15 : 0. The novel strain could be differentiated from other known Bacillus species on the basis of several phenotypic characters and fatty acid profiles. This taxononomic/genomic study revealed that strain FJAT-27997T represents a novel Bacillus species, for which the name Bacillus loiseleuriae sp. nov. (type strain FJAT-27997T =CCTCC AB 2015285T=DSM 101776T) is proposed. PMID- 27117174 TI - Admission systolic blood pressure and outcomes in large vessel occlusion strokes treated with endovascular treatment. AB - BACKGROUND AND PURPOSE: High admission blood pressure (BP) levels have been associated with lower recanalization rates after endovascular treatment (EVT) for patients with acute ischemic stroke (AIS) with emergent large vessel occlusion (ELVO). We sought to evaluate the association of admission BP with early outcomes in patients with ELVO treated with EVT. METHODS: Consecutive patients with AIS presenting with ELVO in a tertiary stroke center during a 4-year period were prospectively evaluated. Admission systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using automated cuff recordings. A blinded neuroradiologist calculated the final infarct volume (FIV) using standardized ABC/2 methodology. A favorable functional outcome (FFO) at 3 months was defined as modified Rankin Scale score of 0-2. RESULTS: Our study population consisted of 116 patients with AIS (mean age 63+/-13 years, median NIH Stroke Scale score 17 points (IQR 14-21), median FIV 30 cm3 (IQR 8-94)). Higher admission SBP correlated with higher FIV (r +0.225; p=0.020). Patients with FFO had lower admission SBP (151+/-24 mm Hg vs 165+/-28 mm Hg; p=0.010), while admission SBP levels were higher in patients who died during hospitalization (169+/-34 mm Hg vs 156+/-24 mm Hg; p=0.043). A 10 mm Hg increment in admission SBP was independently (p=0.010) associated with an increase of 12 cm3 in FIV (95% CI 3 to 21) in multiple linear regression models adjusting for potential confounders. A 10 mm Hg increment in admission SBP was independently (p=0.012) associated with a lower likelihood of FFO at 3 months (OR 0.64; 95% CI 0.45 to 0.91) in multiple logistic regression models adjusting for potential confounders. CONCLUSIONS: Higher admission SBP is an independent predictor of increased FIV and lower likelihood of 3-month FFO in patients with ELVO treated with EVT. PMID- 27117175 TI - Effects of circuit albumin coating on coagulation and inflammatory response for patients receiving aortic arch replacement: a randomized controlled trial. AB - OBJECTIVE: To investigate whether human serum albumin coating before cardiopulmonary bypass (CPB) could improve platelet function and hemostasis and mitigate the inflammatory response among patients receiving aortic arch replacement with deep hypothermic circulatory arrest (DHCA). METHODS: Sixty patients were included and randomized into two groups: the Control Group (CG, receiving 40 g human albumin 5 minutes after the initiation of CPB) and the Study Group (SG, circulating the prime with 40 g albumin for 5 minutes before CPB). Rapid thromboelastography, complete blood count, coagulation tests and cytokines (IL-1, IL-6, IL-10, TNF-alpha and PAF) were measured at two intervals: after anesthesia induction and before CPB (T1) and 10 minutes after heparin reversal before any blood product transfusion (T2). RESULTS: Compared with T1, the fibrinogen and MA levels in both groups reduced significantly after heparin reversal and fell within the normal range for most patients. The platelet count reduction (DeltaPLT) in the Study Group was significantly less than in the Control Group (p=0.031). Despite the inflammatory factor levels increasing after CPB (p<0.001), no differences were found between the Control Group and the Study Group. Fewer red blood cells were given in the Study Group, but this was not significant (p=0.05). CONCLUSION: Most patients receiving aortic arch replacement with DHCA have normal platelet function and fibrinogen levels after heparin reversal. Albumin coating before CPB may mitigate the platelet count reduction, but not platelet dysfunction. There is a trend that the patients treated with albumin coating received less red blood cell transfusions. PMID- 27117176 TI - Labeling of target mRNAs using a photo-reactive microRNA probe. AB - To identify target mRNAs of an miRNA, we synthesized photo-reactive miRNA probes, which contained a photo-reactive nucleoside analog, 1-O-[4-(3-trifluoromethyl-3H diazirine-3-yl)]benzyl-beta-d-ribofuranose, in the middle of the strand. The photo-reactive miRNA-145 probe was found to specifically label the target mRNAs, FSCN1 and KLF4, by UV-A irradiation in human colon cancer DLD-1 cells. PMID- 27117177 TI - ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer. AB - BACKGROUND AND PURPOSE: Nelfinavir can enhance intrinsic radiosensitivity, reduce hypoxia and improve vascularity. We conducted a phase II trial combining nelfinavir with chemoradiotherapy (CRT) for locally advanced inoperable pancreatic cancer (LAPC). MATERIALS AND METHODS: Radiotherapy (50.4Gy/28 fractions; boost to 59.4Gy/33 fractions) was administered with weekly gemcitabine and cisplatin. Nelfinavir started 3-10days before and was continued during CRT. The primary end-point was 1-year overall survival (OS). Secondary end-points included histological downstaging, radiological response, 1-year progression free survival (PFS), overall survival (OS) and treatment toxicity. An imaging sub study (n=6) evaluated hypoxia ((18)F-Fluoromisonidazole-PET) and perfusion (perfusion CT) during induction nelfinavir. RESULTS: The study closed after recruiting 23 patients, due to non-availability of Nelfinavir in Europe. The 1 year OS was 73.4% (90% CI: 54.5-85.5%) and median OS was 17.4months (90% CI: 12.8 18.8). The 1-year PFS was 21.8% (90% CI: 8.9-38.3%) and median PFS was 5.5months (90% CI: 4.1-8.3). All patients experienced Grade 3/4 toxicity, but many were asymptomatic laboratory abnormalities. Four of 6 patients on the imaging sub study demonstrated reduced hypoxia and increased perfusion post-nelfinavir. CONCLUSIONS: CRT combined with nelfinavir showed acceptable toxicity and promising survival in pancreatic cancer. PMID- 27117178 TI - Assessing and understanding sedentary behaviour in office-based working adults: a mixed-method approach. AB - BACKGROUND: Sedentary behaviours (SB) can be characterized by low energy expenditure in a reclining position (e.g., sitting) often associated with work and transport. Prolonged SB is associated with increased risk for chronic conditions, and due to technological advances, the working population is in office settings with high occupational exposure to SB. This study aims to assess SB among office workers, as well as barriers and strategies towards reducing SB in the work setting. METHODS: Using a mixed-methods approach guided by the socio ecological framework, non-academic office workers from a professional school in a large public university were recruited. Of 180 eligible office workers, 40 enrolled and completed all assessments. Self-reported and objectively measured SB and activity levels were captured. Focus group discussion (FGD) were conducted to further understand perceptions, barriers, and strategies to reducing workplace SB. Environmental factors were systematically evaluated by trained research staff using an adapted version of the Checklist for Health Promotion Environments at Worksites (CHEW). Thematic analysis of FGD was conducted and descriptive analysis of quantitative data was performed. RESULTS: The sample was mostly Chinese (n = 33, 80 %) with a total of 24 (60 %) female participants. Most participants worked five days a week for about 9.5(0.5) hrs/day. Accelerometer data show that participants spend the majority of their days in sedentary activities both on workdays (76.9 %) and non-workdays (69.5 %). Self-report data confirm these findings with median sitting time of 420(180) minutes at work. From qualitative analyses, major barriers to reducing SB emerged, including the following themes: workplace social and cultural norms, personal factors, job scope, and physical building/office infrastructure. CHEW results confirm a lack of support from the physical infrastructure and information environment to reducing SB. CONCLUSIONS: There is high SB among office workers in this sample. We identified multiple levels of influence for prolonged occupational SB, with a particular emphasis on workplace norms and infrastructure as important barriers to reducing SB and increasing PA. A larger, representative sample of the Singaporean population is needed to confirm our findings but it seems that any intervention aimed at reducing SB in the workplace should target individual, environmental, and organizational levels. PMID- 27117179 TI - What we learned about the role of antenatal magnesium sulfate for the prevention of cerebral palsy. AB - Based on the convincing case control study of Nelson and Grether which suggested that the administration of magnesium sulfate to mothers prior to early preterm birth might protect their offspring from cerebral palsy, and a pilot study by John Hauth et al. at the University of Alabama at Birmingham, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, with co-funding from the National Institute of Neurologic Disorders and Stroke embarked on the Beneficial Effects of Antenatal Magnesium (BEAM) Trial in 1997. PMID- 27117180 TI - Retraction Note: Drying of a plasmid containing formulation: chitosan as a protecting agent. PMID- 27117181 TI - Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results. AB - PURPOSE: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. EXPERIMENTAL DESIGN: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. RESULTS: Forty-two patients with advanced malignancies received Schedule A (0.1-0.9 mg/m(2) over 1-10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075-0.6 mg/m(2) over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m(2) over 10 minutes; Schedule B was 0.5 mg/m(2) over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (~15-416 L) and clearance (~0.9-22 L/minutes). CONCLUSIONS: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559-66. (c)2016 AACR. PMID- 27117182 TI - In Vivo Fluorescence Imaging of the Activity of CEA TCB, a Novel T-Cell Bispecific Antibody, Reveals Highly Specific Tumor Targeting and Fast Induction of T-Cell-Mediated Tumor Killing. AB - PURPOSE: CEA TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody, engaging CD3epsilon upon binding to carcinoembryonic antigen (CEA) on tumor cells. Containing an engineered Fc region, conferring an extended blood half-life while preventing side effects due to activation of innate effector cells, CEA TCB potently induces tumor lysis in mouse tumors. Here we aimed to characterize the pharmacokinetic profile, the biodistribution, and the mode of action of CEA TCB by combining in vitro and in vivo fluorescence imaging readouts. EXPERIMENTAL DESIGN: CEA-expressing tumor cells (LS174T) and human peripheral blood mononuclear cells (PBMC) were cocultured in vitro or cografted into immunocompromised mice. Fluorescence reflectance imaging and intravital 2-photon (2P) microscopy were employed to analyze in vivo tumor targeting while in vitro confocal and intravital time-lapse imaging were used to assess the mode of action of CEA TCB. RESULTS: Fluorescence reflectance imaging revealed increased ratios of extravascular to vascular fluorescence signals in tumors after treatment with CEA TCB compared with control antibody, suggesting specific targeting, which was confirmed by intravital microscopy. Confocal and intravital 2P microscopy showed CEA TCB to accelerate T-cell-dependent tumor cell lysis by inducing a local increase of effector to tumor cell ratios and stable crosslinking of multiple T cells to individual tumor cells. CONCLUSIONS: Using optical imaging, we demonstrate specific tumor targeting and characterize the mode of CEA TCB mediated target cell lysis in a mouse tumor model, which supports further clinical evaluation of CEA TCB. Clin Cancer Res; 22(17); 4417-27. (c)2016 AACRSee related commentary by Teijeira et al., p. 4277. PMID- 27117183 TI - Cardiorespiratory fitness and sports activities in children and adolescents with solitary functioning kidney. AB - BACKGROUND: An increasing number of children with chronic disease require a complete medical examination to be able to practice physical activity. Particularly children with solitary functioning kidney (SFK) need an accurate functional evaluation to perform sports activities safely. The aim of our study was to evaluate the influence of regular physical activity on the cardiorespiratory function of children with solitary functioning kidney. METHOD: Twenty-nine patients with congenital SFK, mean age 13.9 +/- 5.0 years, and 36 controls (C), mean age 13.8 +/- 3.7 years, underwent a cardiorespiratory assessment with spirometry and maximal cardiopulmonary exercise testing. All subjects were divided in two groups: sedentary (S) and trained (T) patients, by means of a standardized questionnaire about their weekly physical activity. RESULTS: We found that mean values of maximal oxygen consumption (VO2max) and exercise time (ET) were higher in T subjects than in S subjects. Particularly SFK T presented mean values of VO2max similar to C-T and significantly higher than C S (SFK-T: 44.7 +/- 6.3 vs C-S: 37.8 +/- 3.7 ml/min/kg; p < 0.0008). We also found significantly higher mean values of ET (minutes) in minutes in SFK-T than C-S subjects (SFK-T: 12.9 +/- 1.6 vs C-S: 10.8 +/- 2.5 min; p <0.02). CONCLUSION: Our study showed that regular moderate/high level of physical activity improve aerobic capacity (VO2max) and exercise tolerance in congenital SFK patients without increasing the risks for cardiovascular accidents and accordingly sports activities should be strongly encouraged in SFK patients to maximize health benefits. PMID- 27117184 TI - The importance of pharmacist and researcher collaboration to inform clinical audit and optimise medicine services in aged care facilities. PMID- 27117185 TI - A conceptual framework toward identifying and analyzing challenges to the advancement of pharmacy. AB - BACKGROUND: Pharmacists and health care professionals are faced with increasing and changing health care needs around the world. To meet these demands, they are required to continuously upgrade and develop their professions. Reprofessionalization is therefore crucial to the successful delivery of health services, but traditional theories might provide little practical guidance to evaluating the overall status of a profession. OBJECTIVE: This study proposes a new conceptual framework of three interrelated professional sectors: education, regulation and practice, and uses it to identify and analyze challenges facing the pharmacy profession in Jordan. METHODS: A multiple-method qualitative study comprised of semi-structured interviews and focus groups was conducted in Amman, Jordan. To explore and identify the challenges, a purposively recruited cross sector sample of 53 key informants, stakeholders and pharmacists were interviewed. Interview transcripts were translated and analyzed using QSR NVivo 10. Thematic analysis identified eight main challenges facing pharmacy in Jordan. The original participants were then invited to participate in focus groups, the purpose of which was to validate the interview findings, map them against the conceptual framework and discuss recommendations for development. RESULTS: The eight validated challenges span the following areas: graduates preparedness for practice, pharmacy education accreditation and quality assurance, pre registration requirements, workforce development, workforce planning, remuneration and wage rate, pharmacy assistants, and Pharm.D. pharmacists. Focus group participants used the framework to map each of the challenges to the primary sector-to-sector disconnect that they perceived to explain it. A list of recommendations addressing each of the challenges was also devised. CONCLUSIONS: The framework was found to offer valuable insight as an explanatory and diagnostic tool in policy-relevant research. By emphasizing the processual and contextual nature of reprofessionalization, the framework presents an alternative approach to traditional theories. This study also raises important questions regarding the status of pharmacy in Jordan and aims to provide guidance for local development and much-needed reprofessionalization drives. PMID- 27117186 TI - Is there a link between the growing drug selling outlets, licensure type, and rising OTC antibiotics utilization in Pakistan? PMID- 27117187 TI - Injecting drugs in tight spaces: HIV, cocaine and collinearity in the Downtown Eastside, Vancouver, Canada. AB - This commentary revisits the political turmoil and scientific controversy over epidemiological study findings linking high HIV seroincidence to syringe exchange attendance in Vancouver in the mid-1990s. The association was mobilized polemically by US politicians and hard-line drug warriors to attack needle exchange policies and funding. In turn, program restrictions limiting access to syringes at the Vancouver exchange may have interfaced with a complex conjunction of historical, geographic, political economic and cultural forces and physiological vulnerabilities to create an extraordinary HIV risk environment: (1) ghettoization of services for indigent populations in a rapidly gentrifying, post-industrial city; (2) rural-urban migration of vulnerable populations subject to historical colonization and current patterns of racism; and (3) the flooding of North America with inexpensive powder cocaine and heroin, and the popularity of crack. In fact, we will never know with certainty the precise cause for the extreme seroincidence rates in Vancouver in the early to mid-1990s. The tendency for modern social epidemiology to decontextualize research subjects and assign excessive importance to discrete, "magic bullet" variables resulted in a counterproductive scientific and political debate in the late 1990s that has obfuscated potentially useful practical lessons for organizing the logistics of harm reduction services - especially syringe exchange - to better serve the needs of vulnerable populations and to mitigate the effects of political-economically imposed HIV risk environments. We would benefit from humbly acknowledging the limits of public health science and learn to recognize the unintended consequences of well-intentioned interventions rather than sweep embarrassing histories under the rug. PMID- 27117188 TI - Comparison of French training and non-training general practices: a cross sectional study. AB - BACKGROUND: As the medicine practiced in hospital settings has become more specialized, training in primary care is becoming increasingly essential for medical students, especially for future general practitioners (GPs). Only a few limited studies have investigated the representativeness of medical practices delivering this training. The aim of this study was to assess the representativeness of French GP trainers in terms of socio-demographics, patients and activities. METHODS: We conducted a cross-sectional study covering all private GPs practicing in the Rhone-Alpes region of France in 2011. This population consisted of 4992 GPs, including 623 trainers and 4369 non-trainers, managing 8,198,684 individual patients. Data from 2011 to 2012 were provided by the Regional Health Care Insurance (RHCI). We compared GP trainers with non trainers using the Pearson chi-square test for qualitative variables and the Student t-test for quantitative variables RESULTS: GP trainers do not differ from non-trainers for gender, but they tend to be younger, more frequently in mid career, and more likely to practice in a rural area. Their patients are broadly representative of patients attending general practice for age (with the exception of a higher consultation rate for infants), but patients with medical fee exemption status relating to low income are underrepresented. GP trainers have a heavier workload in terms of office visits and on-call duties. They prescribe a higher proportion of generic drugs, perform more electrocardiograms and cervical smears, and fewer plaster casts. GP trainers show better performance in diabetes follow-up, and to a lesser extent for seasonal flu vaccination and mammograms. CONCLUSIONS: GPs and patients of training practices are globally representative, which is particularly critical in countries such as France, where the length of specialty training in a general practice setting is still limited to a few months. In addition, GP trainers tend to have better clinical performance, which conforms to their teaching modelling role and may encourage other GPs to become trainers. PMID- 27117190 TI - Being smart or getting smarter: Implicit theory of intelligence moderates stereotype threat and stereotype lift effects. AB - This research explores implicit theory of intelligence (TOI) as a moderator of stereotype activation effects on test performance for members of negatively stereotyped and of favourably stereotyped groups. In Germany, Turkish-origin migrants are stereotyped as low in verbal ability. We predicted that on a test diagnostic of verbal intelligence, endorsement of an entity TOI predicts stereotype threat effects for Turkish-origin students and stereotype lift effects for German students. This effect could account for some of the performance gap between immigrants and host society members after stereotype activation. Study 1 (N = 107) established structural equivalence of implicit theories across the ethnic groups. In two experimental studies (Study 2: N = 182, Study 3: N = 190), we tested the moderating effect of TOI in a 2 (stereotype activation: diagnostic vs. non-diagnostic test) * 2 (ethnicity: German vs. Turkish migration background) experimental design. The results showed that when the test was described as diagnostic of verbal intelligence, higher entity theory endorsement predicted stereotype threat effects for Turkish-origin students (Study 2 and Study 3) and stereotype lift effects for German students (Study 3). The results are discussed in terms of practical implications for educational settings and theoretical implications for processes underlying stereotype activation effects. PMID- 27117189 TI - The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules. AB - The nucleosome remodeling deacetylase (NuRD) complex is a highly conserved regulator of chromatin structure and transcription. Structural studies have shed light on this and other chromatin modifying machines, but much less is known about how they assemble and whether stable and functional sub-modules exist that retain enzymatic activity. Purification of the endogenous Drosophila NuRD complex shows that it consists of a stable core of subunits, while others, in particular the chromatin remodeler CHD4, associate transiently. To dissect the assembly and activity of NuRD, we systematically produced all possible combinations of different components using the MultiBac system, and determined their activity and biophysical properties. We carried out single-molecule imaging of CHD4 in live mouse embryonic stem cells, in the presence and absence of one of core components (MBD3), to show how the core deacetylase and chromatin-remodeling sub-modules associate in vivo. Our experiments suggest a pathway for the assembly of NuRD via preformed and active sub-modules. These retain enzymatic activity and are present in both the nucleus and the cytosol, an outcome with important implications for understanding NuRD function. PMID- 27117192 TI - Menthoxypropanediol inhibits nerve growth factor-induced nerve fibre sprouting in coculture models of sensory neurons and skin cells. PMID- 27117191 TI - The effect of concomitant peripheral injury on traumatic brain injury pathobiology and outcome. AB - BACKGROUND: Traumatic injuries are physical insults to the body that are prevalent worldwide. Many individuals involved in accidents suffer injuries affecting a number of extremities and organs, otherwise known as multitrauma or polytrauma. Traumatic brain injury is one of the most serious forms of the trauma induced injuries and is a leading cause of death and long-term disability. Despite over dozens of phase III clinical trials, there are currently no specific treatments known to improve traumatic brain injury outcomes. These failures are in part due to our still poor understanding of the heterogeneous and evolving pathophysiology of traumatic brain injury and how factors such as concomitant extracranial injuries can impact these processes. MAIN BODY: Here, we review the available clinical and pre-clinical studies that have investigated the possible impact of concomitant injuries on traumatic brain injury pathobiology and outcomes. We then list the pathophysiological processes that may interact and affect outcomes and discuss promising areas for future research. Taken together, many of the clinical multitrauma/polytrauma studies discussed in this review suggest that concomitant peripheral injuries may increase the risk of mortality and functional deficits following traumatic brain injury, particularly when severe extracranial injuries are combined with mild to moderate brain injury. In addition, recent animal studies have provided strong evidence that concomitant injuries may increase both peripheral and central inflammatory responses and that structural and functional deficits associated with traumatic brain injury may be exacerbated in multiply injured animals. CONCLUSIONS: The findings of this review suggest that concomitant extracranial injuries are capable of modifying the outcomes and pathobiology of traumatic brain injury, in particular neuroinflammation. Though additional studies are needed to further identify the factors and mechanisms involved in central and peripheral injury interactions following multitrauma and polytrauma, concomitant injuries should be recognized and accounted for in future pre-clinical and clinical traumatic brain injury studies. PMID- 27117194 TI - EDITORIAL: AN INTRODUCTION TO THE NEW STUDY DESIGN GLOSSARY. PMID- 27117193 TI - Detection of capecitabine (Xeloda(r)) on the skin surface after oral administration. AB - Palmoplantar erythrodysesthesia (PPE), or hand-foot syndrome, is a cutaneous toxicity under various chemotherapeutics contributing to the most frequent side effects in patients treated with capecitabine (Xeloda(r)). The pathomechanism of PPE has been unclear. Here, the topical detection of capecitabine in the skin after oral application was shown in 10 patients receiving 2500 mg/m 2 /day 2500 mg/m2/day capecitabine. Sweat samples were taken prior to and one week after oral administration of capecitabine. Using high-resolution continuum source absorption spectrometry, the changes in concentrations of fluorine, which is an ingredient of capecitabine, were quantified and statistically analyzed. Here, we show an increase in fluorine concentrations from 40+/-10 ppb 40+/-10 ppb (2+/-0.5 pM 2+/-0.5 pM ) before capecitabine administration to 27.7+/-11.8 ppm 27.7+/-11.8 ppm (14.6+/-6.5 nM 14.6+/-6.5 nM ) after application, p<0.001 p<0.001 . The results show the secretion of capecitabine on the skin surface after oral administration, indicating a local toxic effect as a possible pathomechanism of PPE. PMID- 27117195 TI - DOSIMETRIC CONSEQUENCES OF USING CONTRAST-ENHANCED COMPUTED TOMOGRAPHIC IMAGES FOR INTENSITY-MODULATED STEREOTACTIC BODY RADIOTHERAPY PLANNING. PMID- 27117197 TI - Vomiting in a Teenager with Down Syndrome. PMID- 27117198 TI - Reportable Bacterial Infections among New York City-Born Infants, 2001-2009. AB - OBJECTIVE: To determine rates of reportable bacterial infections among infants in New York City and identify populations at risk and preventable causes of morbidity. STUDY DESIGN: This retrospective cohort study matched live births in New York City from 2001-2009 to reported cases of bacterial infections among infants less than 1 year of age. Characteristics recorded on birth certificates were compared between infants with bacterial enteric infection, bacterial nonenteric infection, and no reportable bacterial infection. Multinomial logistic regression and multivariable logistic regression were used to identify risk factors for infection. RESULTS: Bacterial infection was reported in 4.6 cases per 1000 live births. Of 4524 infants with a reportable infection, the majority (2880, 63%) had an enteric infection. Asian/Pacific Islanders in Brooklyn were the borough-level race/ethnic group with the highest enteric infection rate (8.5 per 1000 live births). Citywide, infants with enteric infections were disproportionately male, from higher poverty neighborhoods, born to foreign-born mothers, and enrolled in Special Supplemental Food Program for Women, Infants, and Children or Medicaid. In contrast, infants with nonenteric infections were more likely to have low birthweight and mothers characterized by US birth and black race or white Hispanic race/ethnicity. CONCLUSIONS: Distinct patterns of risk factors for enteric and nonenteric bacterial infections among infants were identified. The results suggest that infants born to Asian/Pacific Islander mothers residing in Brooklyn should be a focus of enteric disease prevention. More research is necessary to better understand what behaviors increase the risk of enteric disease in this population. PMID- 27117199 TI - To have sepsis or to be septic-is the difference between these clinical conditions important? PMID- 27117196 TI - Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants. AB - OBJECTIVE: To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. STUDY DESIGN: We evaluated blood spots collected from 943 infants born at <=1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. RESULTS: The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1alpha, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. CONCLUSIONS: Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants. PMID- 27117200 TI - Active screening and surveillance in the United Kingdom for Middle East respiratory syndrome coronavirus in returning travellers and pilgrims from the Middle East: a prospective descriptive study for the period 2013-2015. AB - BACKGROUND: Over 25000 pilgrims from the UK visit Saudi Arabia every year for the Umrah and Hajj pilgrimages. The recent outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) in South Korea and the continuing reports of MERS CoV cases from Saudi Arabia highlight the need for active surveillance for MERS CoV in returning pilgrims or travellers from the Middle East. Public Health England Birmingham Laboratory (PHEBL) is one of a few selected UK public health laboratories responsible for MERS-CoV screening in travellers returning to the UK from the Middle East who present to hospital with severe respiratory symptoms. The results of the PHEBL MERS-CoV screening and surveillance over the past 3 years is presented. METHODS: UK travellers/pilgrims who returned from the Middle East and presented to a hospital with respiratory symptoms were studied over the period February 1, 2013 to December 31, 2015. Patients with respiratory symptoms, who satisfied the Public Health England MERS-CoV case algorithm, were tested for MERS-CoV and other respiratory tract viruses on admission to hospital. RESULTS: Two hundred and two patients suspected of having MERS-CoV were tested. None of them had a laboratory-confirmed MERS-CoV infection. A viral aetiology was detected in half (50.3%) of the cases, with rhinoviruses, influenza A (H1N1 and H3N2), and influenza B being most frequent. Peak testing occurred following the annual Hajj season and in other periods of raised national awareness. CONCLUSIONS: Respiratory tract infections in travellers/pilgrims returning to the UK from the Middle East are mainly due to rhinoviruses, influenza A, and influenza B. Whilst MERS-CoV was not detected in the 202 patients studied, heightened awareness of the possibility of MERS-CoV and continuous proactive surveillance are essential to rapidly identify cases of MERS-CoV and other seasonal respiratory tract viruses such as avian influenza, in patients presenting to hospital. Early identification and isolation may prevent outbreaks in nosocomial settings. PMID- 27117201 TI - Sepsis and septic shock in low-income and middle-income countries: need for a different paradigm. PMID- 27117202 TI - Maternal serum 25-hydroxyvitamin D and C-reactive protein levels in pregnancies complicated with threatened preterm labour. AB - OBJECTIVE AND METHODS: To measure 25-hydroxyvitamin D [25(OH)D] and C-reactive protein (CRP) serum levels in singleton gestations complicated with threatened preterm labour (TPL, n = 59) and compare to normal controls matched for gestational age (n = 64). Cases were treated after blood sample according to institutional protocol. Also, analyte levels were compared among cases according to the outcome. RESULTS: Mean serum 25(OH)D levels were similar between cases and controls, with median white blood cell count and CRP levels found significantly higher in TPL cases. Women with TPL delivering preterm displayed shorter mean cervical lengths along with higher CRP and lower 25(OH)D serum levels when compared to those delivering at term. Two multiple linear regression models were constructed to analyse factors related to gestational age at delivery (pooled analysis and only those with TPL). In both models, gestational age positively correlated to cervical length and inversely to CRP levels; whereas, in the TPL model, only 25(OH)D levels correlated positively. CONCLUSION: Women complicated with TPL showed similar serum 25(OH)D yet higher CRP levels as compared to controls. TPL cases delivering preterm displayed lower 25(OH)D and higher CRP correlated levels. PMID- 27117203 TI - Linking pollen quality and performance of Neoseiulus californicus (Acari: Phytoseiidae) in two-spotted spider mite management programmes. AB - BACKGROUND: It has been shown that pollen as a dietary supplement may increase the establishment of generalist predatory mites, and therefore pest control by these mites can be provided. Life table studies were performed to evaluate the nutritional value of seven different pollens (almond, castor-bean, date-palm, maize, bitter-orange, sunflower and mixed bee pollen) as a supplementary food source for the spider mite predator Neoseiulus californicus McGregor. In addition, the nutritional quality of each pollen species was assessed through morphological and chemical analysis. RESULTS: Preadult duration was longer when the predator fed on castor-bean pollen (10.01 days) and bee pollen (9.94 days) compared with the others (5.58-7.27 days). The cohort reared on almond pollen had the highest intrinsic rate of increase (r) (0.231 day-1 ), and those on mixed bee pollen had the lowest r (0.005 day-1 ). The levels of nutritional content (sugar, lipid and protein) were significantly different among tested pollens. CONCLUSIONS: Comparison of N. californicus life table parameters on different diets revealed that the almond pollen (and after that the maize pollen) was a more suitable diet than the others. These findings will be useful in developing appropriate strategies for conservation of N. californicus to control spider mites. (c) 2016 Society of Chemical Industry. PMID- 27117204 TI - Migraine with atypical aura: is there a role for cerebral perfusion studies? PMID- 27117205 TI - Comparison of the radiotoxicity of the 99mTc-labeled compounds 99mTc pertechnetate, 99mTc-HMPAO and 99mTc-MIBI. AB - PURPOSE: In addition to gamma radiation, 99mTc emits low-energy Auger electrons with path-lengths of nanometers to micrometers that cannot be utilized for diagnostic procedures; however, they have frequently been discussed for therapeutic applications. We compared radiotoxicity of three 99mTc-labeled radiopharmaceuticals with differences in the subcellular distribution. MATERIALS AND METHODS: The intracellular radionuclide uptake and subcellular distribution of [99mTc]-pertechnetate (99mTc-pertechnetate), [99mTc]Tc-hexamethyl-propylene aminoxime (99mTc-HMPAO) and [99mTc]Tc-hexakis-2-methoxyisobutylisonitrile (99mTc MIBI) were quantified in rat thyroid FRTL-5 cells. Radiotoxicity was compared using late phosphorylated histone H2AX (gammaH2AX) foci as a marker for unrepaired DNA double-strand breaks (DNA-DSB) and clonogenic cell survival. RESULTS: 99mTc-HMPAO showed a substantially higher uptake into the nucleus and the membrane/organelles than 99mTc-pertechnetate or 99mTc-MIBI. The colony forming assay showed that 99mTc-pertechnetate and 99mTc-HMPAO caused a similar reduction in cell survival. 99mTc-MIBI is less radiotoxic in terms of the estimated nucleus dose and induced the fewest number of gammaH2AX foci compared with the other 99mTc-tracers, and 99mTc-HMPAO induced a fewer number of gammaH2AX foci than 99mTc-pertechnetate. CONCLUSIONS: Our findings reveal that clonogenic cellular survival is not solely determined by the DNA-DSB response. This finding may suggest the involvement of extra-nuclear radiosensitive targets in cell inactivation. For example, the mitochondria or the cell membrane could be affected by 99mTc-HMPAO. PMID- 27117206 TI - A false positive newborn screening result due to a complex allele carrying two frequent CF-causing variants. AB - The detection of two frequent CFTR disease-causing variations in the context of a newborn screening program (NBS) usually leads to the diagnosis of cystic fibrosis (CF) and a relevant genetic counseling in the family. In the present study, CF causing variants p.Phe508del (F508del) and c.3140-26A>G (3272-26A>G) were identified on a neonate with positive ImmunoReactive Trypsinogen test by the ElucigeneTM CF30 kit. The CF diagnosis initially suggested, despite three inconclusive Sweat Chloride Tests (SCT), was finally ruled out after the familial segregation study combined with a negative SCT. Haplotype studies, based on the comparison of 80 p.Phe508del haplotypes, suggested a probable de novo occurrence of c.3140-26A>G on the p.Phe508del ancestral allele in this family. This false positive case emphasizes the importance of SCT in the NBS strategy. Moreover, it raises the need for familial segregation studies in CF and in overall molecular diagnosis strategy of autosomal recessive diseases. PMID- 27117208 TI - [Greeting the arrival of digitalized era of oral medicine]. PMID- 27117207 TI - Type conversion of secretomes in a 3D TAM2 and HCC cell co-culture system and functional importance of CXCL2 in HCC. AB - Macrophages play important roles in the tumor microenvironment, driving cancer progression and metastasis, particularly in hepatocellular carcinoma (HCC). However, few studies have assessed the exact secretome composition in HCC. In the present study, the impact of different phenotype of macrophages on HCC cells was investigated. Alternatively activated macrophages (M2) were found to significantly increase the proliferation, migration, and invasion abilities of SMMC7721 cells (all P < 0.05). M2 were then co-cultured with SMMC7721 cells to reconstruct the tumor microenvironment. Conditioned medium from 3D single cultures of M2, SMMC7721 cells, and their co-culture system were analyzed using quantitative proteomics via iTRAQ labeling combined with mass spectrometric analysis. Secretome analysis revealed a total of 159 differential secreted proteins in the co-culture system compared to the single culture systems, with 63 being up-regulated (>1.3-fold) and 96 down-regulated (<0.7-fold). CXCL2 was confirmed to have higher expression in the co-culture system and HCC tissues, and was selected for further investigation. Functional effects data suggested that recombinant human CXCL2 significantly enhanced the migration, invasion ability of SMMC7721 cells, and weakened adhesion ability. While CXCL2 neutralization and CXCR2 blockage significantly inhibited the effects of CXCL2 on SMMC7721 cells, indicating that CXCL2 may play pivotal role in HCC metastasis. PMID- 27117209 TI - [The elementary discussion on digital implant dentistry]. AB - It is a digital age today. Exposed to all kinds of digital products in many fields. Certainly, implant dentistry is not exception. Digitalization could improve the outcomes and could decrease the complications of implant dentistry. This paper introduces the concepts, definitions, advantages, disadvantages, limitations and errors of digital implant dentistry. PMID- 27117210 TI - [Digital oral-maxillofacial imaging: present and future]. AB - Digital imaging has been widely used in the field of oral and maxillofacial radiology. The present work summarizes the use of digital imaging from the following aspects: 1The origin of digital oral and maxillofacial imaging; 2The influence of digital imaging on the work mode and work flow of oral and maxillofacial radiology; 3 Application of picture archiving and communication system(PACS)in oral and maxillofacial radiology; 4The influence of three dimensional medical data sets on diagnosis, prognosis and treatment plan; 5Digital imaging facilitates the development of telemedicine and internet medicine; 6The significance of establishing a medical database or data center; 7Problems and challenges. PMID- 27117211 TI - [Impact of digital technology on clinical practices: perspectives from surgery]. AB - Digital medical technologies or computer aided medical procedures, refer to imaging, 3D reconstruction, virtual design, 3D printing, navigation guided surgery and robotic assisted surgery techniques. These techniques are integrated into conventional surgical procedures to create new clinical protocols that are known as "digital surgical techniques". Conventional health care is characterized by subjective experiences, while digital medical technologies bring quantifiable information, transferable data, repeatable methods and predictable outcomes into clinical practices. Being integrated into clinical practice, digital techniques facilitate surgical care by improving outcomes and reducing risks. Digital techniques are becoming increasingly popular in trauma surgery, orthopedics, neurosurgery, plastic and reconstructive surgery, imaging and anatomic sciences. Robotic assisted surgery is also evolving and being applied in general surgery, cardiovascular surgery and orthopedic surgery. Rapid development of digital medical technologies is changing healthcare and clinical practices. It is therefore important for all clinicians to purposefully adapt to these technologies and improve their clinical outcomes. PMID- 27117212 TI - [Overall digitalization: leading innovation of endodontics in big data era]. AB - In big data era, digital technologies bring great challenges and opportunities to modern stomatology. The applications of digital technologies, such as cone-beam CT(CBCT), computer aided design,(CAD)and computer aided manufacture(CAM), 3D printing and digital approaches for education , provide new concepts and patterns to the treatment and study of endodontic diseases. This review provides an overview of the application and prospect of commonly used digital technologies in the development of endodontics. PMID- 27117213 TI - [Development and prospect of digital technology in the field of prosthodontics]. AB - The development of digital technology is gradually changing clinical practice and laboratory procedure of prosthodontics. After decades of exploration and development, the modern digital technology has been perfectly merged with prosthodontics and created a brand new treatment mode. The application of digital impression, digital design and digital processing has changed the way we treat patients and the way we communicate with patients. The data storage also provides a basis for long-term follow-up. The establishment of digital remote system, transferring data through internet, has improved communication in dental technique, tracing analysis of patient's condition, sharing and management of medical data, and popularization and promotion of knowledge. Digital technology promoted the development of prosthodontics in the direction of more precision, more convenience, more efficiency and more simulation in functional recovery, which will be one of the development directions of dentistry and even the medical science in the future. PMID- 27117214 TI - [Occlusal evaluation and design of dental implant therapy in defect dentition]. AB - Implant prosthesis of dentition defect is characteristic of remaining teeth and implants exist at the same time, so the remaining teeth occlusal conditions related to the final occlusal design is to maintain, adjust or re-establish the original dentition occlusion. Therefore, full evaluation of remaining teeth occlusion before restoration, clear prognosis, balancing the occlusal force distribution of natural teeth and implants, and carrying out the predictable occlusal design in the entire process of implant prosthesis can minimize the adverse events after implant prosthesis. Based on the typical cases in this paper, three occlusal design types of occlusal maintain-implant restoration, occlusal adjustment-implant restoration and occlusal reconstruction-implant restoration will be expounded respectively. PMID- 27117215 TI - [Aging changes of the root canal morphology in maxillary first premolars observed by cone-beam computerized tomography]. AB - OBJECTIVE: To observe the morphological changes of root canals with aging in maxillary first premolars by using cone-beam computerized tomography(CBCT)in order to facilitate endodontic management of root canals in various aged patients. METHODS: The digital CBCT data of the maxillary first premolars in 405 cases from the patients in Oral Medical Center of The First Affiliated Hospital, Jinan University from March 2011 to June 2015 were collected. The CBCT images were divided into 6 groups according to the patients' ages: groups 11-20, 21-30, 31-40, 41-50, 51-60 and >60 years-olds, respectively. Changes of morphologies of root canals with aging including such parameters as types of the root canal, incidence of double root canals in single rooted teeth, distance between both root canal orifices of double rooted canals, and morphological change of the cross section of roots. Chi-square test and liner trend test were adopted in statistical analysis in the present study. RESULTS: The distribution of various types of the root canals were significantly different amongst various aged groups(P<0.05). Type IV is the most common type(210/405, 51.8%), and the following groups were typeII(65/405, 16.0%), typeI(55/405, 13.6%)and type III(27/405, 6.7%). Along with aging, the percentages of type I and type III decreased while type II increased. However, there were no remarkable changes of type IV observed. The incidence of double rooted canals in single rooted teeth gradually increased with aging especially in 20-years-old and above groups, e.g. 51.7%(31/60)in group 11-20 years-olds and 83.0%(44/53)in group 21-30 years-olds. However, there was no significant increase observed after the age of 40. The distance between both root canal orifices of double rooted canals became shorter with aging except in groups of 40-years-olds and above. The morphologies of the cross sections in most aged groups were flat shaped(1 020/2 105, 48.5%)and oval shape(594/2 105, 28.2%). Along with aging, the percentage of circular shape gradually increased while flat and oval shapes decreased. CONCLUSIONS: The morphology of root canal could be clearly showed by the CBCT images. The change of morphologies of the root canals in maxillary first premolars was significantly related to aging. Along with aging, the morphology of the root canal became more and more complicated. PMID- 27117216 TI - [Effects of exogenous enzymes on the degradation of adhesive-dentin interfaces]. AB - OBJECTIVE: To compare the effects of exogenous enzymes on the degradation of adhesive-dentin interface. METHODS: Forty molars were sectioned to expose the middle-coronal dentin surface and randomly divided into two adhesive systems: an etch-and-rinse adhesive Adper Single Bond 2 and a self-etching adhesive G-Bond. After composite building up, the specimens were then randomly assigned to four groups(n=5 for each group)as follows: group 1, 24 h of water storage(the control group); group 2, six months of water storage; group 3, twelve weeks storage in artificial saliva containing clostridium histolyticum collagenase; group 4, twelve weeks storage in artificial saliva containing cholesterolesterase. The microtensile bond strengths(MTBS)were then tested. The failure modes and nanoleakage were analyzed. RESULTS: After aging treatments, the three aging groups showed significantly lower MTBS compared with the control group in both adhesive systems(P<0.05). For etch-and-rinse adhesive Adper Single Bond 2, the MTBS of group 3([19.6+/-3.5]MPa)was lower than that of group 2([23.4+/ 4.2]MPa)and group 4([24.2+/-4.2]MPa)(P<0.05). For self-etching adhesive G-Bond, there was no difference on MTBS among different aging groups(P>0.05). SEM observation showed that, compared with the control group, water storage(group 2)and the exogenous enzymes(group 3 and 4)increased the nanoleakage expression(silver deposition)of both adhesive systems. Adhesive failure was the predominant fracture modes in all groups. CONCLUSIONS: Storage in artificial saliva containing clostridium histolyticum collagenase or cholesterol esterase could be used to accelerate the degradation process of adhesive-dentine interface. PMID- 27117217 TI - [Effect of trichostatin A on the osteogenic differentiation potential of periodontal ligament stem cells in inflammatory microenvironment induced by tumor necrosis factor-alpha stimulation]. AB - OBJECTIVE: To compare the expression of histone deacetylase(HDAC)1-11 of human periodontal ligament stem cells(PDLSC)in normal and inflammatory microenvironments, and to investigate the effect of histone deacetylase inhibitor trichostatin A(TSA)on the osteogenic differentiation potential of PDLSC in inflammatory microenvironment induced by tumor necrosis factor-alpha(TNF alpha)stimulation. METHODS: PDLSC were isolated from periodontal ligament tissues obtained from the surgically extracted human teeth and cultured by single-colony selection. The expression of HDAC1-11 in cells with or without TNF-alpha(10 MUg/L)stimulation was evaluated by quantitative real time-PCR(RT-PCR). The effect of TSA on cell proliferation was investigated by methyl thiazolyl tetrazolium(MTT)assay. The influence of TSA on osteogenic differentiation of PDLSC in inflammatory microenvironment with TNF-alpha stimulation was assessed by alizarin red staining, quantitative RT-PCR and Western blotting, respectively. RESULTS: The expression of HDAC in PDLSC with TNF-alpha stimulation was significantly higher than that in normal PDLSC(P<0.05)(except HDAC7, P=0.243). TSA had no significant effect on PDLSC proliferation at the concentration of 50 nmol/L(P=0.232). The alizarin red staining showed that PDLSC in TNF-alpha group generated less mineralized nodule than the control group, while the cell matrix mineralization in TSA group was improved obviously. TNF-alpha had an inhibitory effect on the expression of osteogenesis related genes, runt-related transcription factor-2(RUNX2)and alkaline phosphatase(ALP), with relative gene expression ratio(experimental/control)decreased to 0.17 +/- 0.02 and 0.32 +/- 0.03, while TSA could significantly increase the genes' expression to 0.67+/-0.03 and 0.89+/-0.02(P<0.01). Western blotting test showed that in TNF-alpha group the expression of osteogenesis related proteins was obviously reduced, and compared with the TNF-alpha group, TSA could significantly promote the expression of proteinsin inflammatory microenvironment. CONCLUSIONS: PDLSC in inflammatory microenvironment by TNF-alpha stimulation had a higher expression of HDAC than that in normal conditions. TSA, as a histone deacetylase inhibitor, could significantly promote the osteogenic differentiation potential of PDLSC in inflammatory microenvironment by suppressing HDAC. PMID- 27117218 TI - [Study of post-transcriptional regulation of secreted frizzle-related protein 1 in MC3T3-E1 cells]. AB - OBJECTIVE: To study the molecular mechanisms underlying the post-transcriptional regulation of secreted frizzle-related protein 1(SFRP1)gene in MC3T3-E1 murine pre-osteoblast cells using a newly constructed plasmid pMIR-REPORT-SFRP1UTR in which the expression of luciferase was regulated by the 3'UTR of mouse SFRP1 gene. METHODS: The mRNA and protein levels of SFRP1 gene in MC3T3-E1 cells were measured using real-time quantitative polymerase chain reaction and Western blotting at 0, 7 and 10 days respectively after osteogenic differentiation was induced in these cells using 50 mg/L of ascorbic acid. Glyceraldehyde-3-phosphate dehydrogenase(GAPDH)and beta-actin served as controls, respectively. The 3'UTR of mouse SFRP1 gene was then amplified from total RNA isolated from MC3T3-E1 cells using PCR. The SFRP1 3'UTR fragment was then subcloned into the vector, pMIR REPORT, resulting in a new plasmid named as pMIR-REPORT-SFRP1UTR. pMIR-REPORT SFRP1UTR was transfected into MC3T3-E1 and NIH3T3 cells, and the luciferase levels were determined.Cells transfected with pMIR-REPORT-SFRP1UTR were assigned to pMIR-REPORT-SFRP1UTR group, and cells transfected with pMIRREPORT were assigned to pMIR-REPORT group. RESULTS: SFRP1 mRNA levels in MC3T3-E1 cells treated with ascorbic acid for 0, 7 and 10 days were 1.00+/-0.12, 1.97+/ 0.34(P>0.05, vs. 0 d group)and 4.98+/-0.99(P<0.05, vs. 0 d group), respectively. After treated with ascorbic acid for 0, 7 and 10 days, the protein levels of SFRP1 in MC3T3-E1 cells were 0.94 +/- 0.13,1.26 +/- 0.16(P>0.05, vs. 0 d group)and 1.30 +/- 0.15(P>0.05, vs. 0 d group), respectively. Luciferase levels in MC3T3-E1 cells transfected with pMIR-REPORT-SFRP1UTR and pMIRREPORT were 74 +/ 10 and 487 +/- 34, respectively(P<0.05). In contrast, luciferase levels in NIH3T3 cells transfected with pMIR-REPORT-SFRP1UTR and pMIR-REPORT were 2 240+/ 175 and 2 707+/-117, respectively(P<0.05). CONCLUSIONS: The 3'UTR of mouse SFRP1 gene was successfully amplified and subcloned into pMIRREPORT. The3'UTR of SFRP1 geneis involved in the cell-specific post-transcriptional regulation of SFRP1 gene. PMID- 27117219 TI - [Modification of the composite resin with the hyperbranched polyester and evaluation of the mechanical properties of the modified composite resin]. AB - OBJECTIVE: To study the effect of hyperbranched polyester(HBP)on mechanical properties of the conventional resin matrix. METHODS: Two hyperbranched monomers(HBP2-X and HBP2-Y)were synthesized and incorporated at 40%(by mass)into a 2?1(by mass)bisphenol-A diglycidyl methacrylate(Bis-GMA): triethylene glycol dimethacrylate(TEGDMA)resin. Bis-GMA/TEGDMA without the incorporation of hyperbranched polyester was used as control(n=8 per group). The mechanical properties of the modified neat resin, including polymerization volumetric shrinkage, Vickers hardness, water absorption and dissolution rate, as well as the flexural strength, compressive strength and diametral tensile strength of the composite resin with different content of filler(0%, 30%, 50%, 70%)were measured. Mechanical properties of the composite resin were measured by universal testing machine. The results were analyzed by the ANOVA and LSD-t-test. RESULTS: The resin with HBP greatly decreased the polymerization shrinkage of the composite resin, and the value of group X was(6.32+/-0.49)%, and that of group Y was(6.31+/ 0.68)%, whereas that of the control group was(8.14 +/- 0.53)%. The value of volumetric shrinkage of the modified groups were significantly lower than that of the control group(P<0.05). By adding HBP, the hardness value of group X([198 +/- 5]MPa)and group Y([177 +/- 4]MPa)were significantly lower than that of the control group([214+/-6]MPa)(P<0.05). The HBP significantly influenced the water sorption and solubility of the neat resin(P<0.05). For the composite materials, with 70% inorganic filler, there were no significant difference in the value of flexural strength among the groups(P>0.05). There was no significant difference in the value of compressive strength, between group X([244 +/- 13]MPa)and the standard group([234 +/- 17]MPa)(P>0.05). However, they were significantly higher than that in group Y([204 +/- 24]MPa)(P<0.05). For the value of diametral tensile strength, there was no significant difference between group Y([36.4 +/- 2.1]MPa)and the control group([34.4 +/- 2.9]MPa)(P>0.05), but both were significantly lower than that in group X([41.1 +/- 3.0]MPa)(P<0.05). CONCLUSIONS: Although there were certain effect on the mechanical properties of the resin that was modified with the HBP, we should make further analysis and study based on the property of low volumetric shrinkage, to strive for the development of low volumetric shrinkage of HBP, without affecting its mechanical properties. PMID- 27117220 TI - [Joint endodontic and periodontal treatment of anterior teeth with dens in dente: a case report]. PMID- 27117221 TI - Reconstruction of human oncological tracheal defects with xenogenic acellular dermal matrix. AB - OBJECTIVE: This study aimed to explore the effectiveness of xenogenic acellular dermal matrix (xeno-ADM) in tracheal reconstruction. METHOD: Two patients were treated with this surgical method to reconstruct the trachea in 2013. The patients were diagnosed with tracheal adenoid cystic carcinoma by histopathological biopsy. The tumor was resected with half of the tracheal circumference and repaired by xeno-ADM. The patients were followed up for 31 and 33 months, respectively. RESULT: No infection or tracheal fistula was observed. The grafts were clear. Both patients were successfully decannulated without dyspnea and could breathe and speak without prosthesis. The cervical mobility was not impaired. CONCLUSION: Xeno-ADM was successfully used to reconstruct a stable and well-functioning trachea. This surgical method is simple, safe, and effective with fewer complications. PMID- 27117223 TI - Determination of the appropriate propofol infusion rate for outpatient upper gastrointestinal endoscopy-a randomized prospective study. AB - BACKGROUND: Pain and discomfort related to endoscopy sessions can be alleviated by sedation, which minimizes anxiety and allows safe examination. For outpatient endoscopy, reliable short-term sedation without secondary effects is required. This study aimed to assess the effects of intravenous propofol rates on sedation in outpatients undergoing upper gastrointestinal endoscopy. METHODS: This randomized prospective study evaluated 300 outpatients submitted to upper gastrointestinal endoscopy. Patients received propofol at 500, 1000 or 2000 ml/h. The primary outcome assessed was hypoxemia incidence. In addition, time to sedation and incidence of hypotension, deep sedation, extremity motor activity, cough, nausea, hiccough, and awareness were evaluated. RESULTS: Recovery time and incidence of hypoxemia, hypotension, and deep sedation were significantly increased in individuals treated at 2000 ml/h in comparison with values obtained for 500 and 1000 ml/h groups (P < 0.01). Compared with the 500 ml/h group, motor activity of the extremities, cough, nausea, hiccough, and awareness were significantly decreased and the mean scores for endoscopist's and patients' satisfaction were significantly increased in the 1000 and 2000 ml/h groups (P < 0.01). CONCLUSION: Propofol infused at 1000 ml/h appeared to be the most suitable infusion rate for outpatient upper gastrointestinal endoscopy. TRIAL REGISTRATION: REGISTRATION NUMBER: ChiCTR-TRC-14004786 ; Registration date: 2014 06-04. PMID- 27117222 TI - In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy. AB - Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, beta-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy. PMID- 27117224 TI - Downregulation of toll-like receptor 4 and IL-6 following irradiation of the rat urinary bladder. AB - The pathophysiology behind radiation cystitis is poorly understood. Here we investigated whether bladder irradiation affects the immune system of the rat urinary bladder. Female rats were sedated and exposed to one single radiation dose of 20 Gy or only sedated (controls) and killed 16 h to 14 days later. Rats were placed in a metabolic cage at 16 h, 3 days, 7 days and 14 days following bladder irradiation. The urinary bladders were harvested and analysed with qPCR, immunohistochemistry and/or Western blot for the expression of interferon (IFN) gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, nitric oxide synthases (eNOS, iNOS and nNOS), tumour necrosis factor (TNF)-alpha and toll-like receptor 4 (TLR4). Urine was collected and analysed for IL-6 and nitrite (reflecting nitric oxide activity) with ELISA and the Griess reaction, respectively. Irradiation increased bladder frequency and decreased voiding volumes 14 days following bladder irradiation. Bladder irradiation increased the expression of IL-10 and collagen in the bladder, while TLR4 and IL-6 expressions were decreased in the urothelium concomitantly with a decrease in mast cells in the submucosa and urine levels of IL-6 and nitrite. The present findings show that bladder irradiation leads to urodynamic changes in the bladder and may suppress important immunoregulatory pathways in the urinary bladder. PMID- 27117225 TI - Pronounced peptide selectivity for melanoma through tryptophan end-tagging. AB - Effects of oligotryptophan end-tagging on the uptake of arginine-rich peptides into melanoma cells was investigated under various conditions and compared to that into non-malignant keratinocytes, fibroblasts, and erythrocytes, also monitoring resulting cell toxicity. In parallel, biophysical studies on peptide binding to, and destabilization of, model lipid membranes provided mechanistic insight into the origin of the selectivity between melanoma and non-malignant cells. Collectively, the results demonstrate that W-tagging represents a powerful way to increase selective peptide internalization in melanoma cells, resulting in toxicity against these, but not against the non-malignant cells. These effects were shown to be due to increased peptide adsorption to the outer membrane in melanoma cells, caused by the presence of anionic lipids such as phosphatidylserine and ganglioside GM1, and to peptide effects on mitochondria membranes and resulting apoptosis. In addition, the possibility of using W-tagged peptides for targeted uptake of nanoparticles/drug carriers in melanoma was demonstrated, as was the possibility to open up the outer membrane of melanoma cells in order to facilitate uptake of low Mw anticancer drugs, here demonstrated for doxorubicin. PMID- 27117227 TI - Managing Hodgkin lymphoma without chemotherapy: a novel, yet 'welcomed', challenge. PMID- 27117226 TI - Identification and characterization of rabbit ROSA26 for gene knock-in and stable reporter gene expression. AB - The laboratory rabbit has been a valuable model system for human disease studies. To make the rabbit model more amendable to targeted gene knockin and stable gene over-expression, we identified a rabbit orthologue of the mouse Rosa26 locus through genomic sequence homology analysis. Real-time PCR and 5' RACE and 3' RACE experiments revealed that this locus encodes two transcript variants of a long noncoding RNA (lncRNA) (rbRosaV1 and rbRosaV2). Both variants are expressed ubiquitously and stably in different tissues. We next targeted the rabbit Rosa26 (rbRosa26) locus using CRISPR/Cas9 and produced two lines of knock-in rabbits (rbRosa26-EGFP, and rbRosa26-Cre-reporter). In both lines, all the founders and their offspring appear healthy and reproduce normally. In F1 generation animals, the rbRosa26-EGFP rabbits express EGFP, and the rbRosa26-Cre-reporter rabbits express tdTomato ubiquitously in all the tissues examined. Furthermore, disruption of rbRosa26 locus does not adversely impact the animal health and reproduction. Therefore, our work establishes rbRosa26 as a safe harbor suitable for nuclease mediated gene targeting. The addition of rbRosa26 to the tool box of transgenic research is expected to allow diverse genetic manipulations, including gain-of function, conditional knock out and lineage-tracing studies in rabbits. PMID- 27117229 TI - Interface Properties of Atomic-Layer-Deposited Al2O3 Thin Films on Ultraviolet/Ozone-Treated Multilayer MoS2 Crystals. AB - We report the interface properties of atomic-layer-deposited Al2O3 thin films on ultraviolet/ozone (UV/O3)-treated multilayer MoS2 crystals. The formation of S-O bonds on MoS2 after low-power UV/O3 treatment increased the surface energy, allowing the subsequent deposition of uniform Al2O3 thin films. The capacitance voltage measurement of Au-Al2O3-MoS2 metal oxide semiconductor capacitors indicated n-type MoS2 with an electron density of ~10(17) cm(-3) and a minimum interface trap density of ~10(11) cm(-2) eV(-1). These results demonstrate the possibility of forming a high-quality Al2O3-MoS2 interface by proper UV/O3 treatment, providing important implications for their integration into field effect transistors. PMID- 27117228 TI - Platelet-cytokine Complex Suppresses Tumour Growth by Exploiting Intratumoural Thrombin-dependent Platelet Aggregation. AB - Tumours constitute unique microenvironments where various blood cells and factors are exposed as a result of leaky vasculature. In the present study, we report that thrombin enrichment in B16F10 melanoma led to platelet aggregation, and this property was exploited to administer an anticancer cytokine, interferon-gamma induced protein 10 (IP10), through the formation of a platelet-IP10 complex. When intravenously infused, the complex reached platelet microaggregates in the tumour. The responses induced by the complex were solely immune-mediated, and tumour cytotoxicity was not observed. The complex suppressed the growth of mouse melanoma in vivo, while both platelets and the complex suppressed the accumulation of FoxP3(+) regulatory T cells in the tumour. These results demonstrated that thrombin-dependent platelet aggregation in B16F10 tumours defines platelets as a vector to deliver anticancer cytokines and provide specific treatment benefits. PMID- 27117230 TI - Equilibrium Phase Behavior of the Square-Well Linear Microphase-Forming Model. AB - We have recently developed a simulation approach to calculate the equilibrium phase diagram of particle-based microphase formers. Here, this approach is used to calculate the phase behavior of the square-well linear model for different strengths and ranges of the linear long-range repulsive component. The results are compared with various theoretical predictions for microphase formation. The analysis further allows us to better understand the mechanism for microphase formation in colloidal suspensions. PMID- 27117231 TI - Adsorption of indole and quinoline from a model fuel on functionalized MIL-101: effects of H-bonding and coordination. AB - Denitrogenation of a model fuel was studied by employing the adsorption of indole (IND) and quinoline (QUI) over a metal-organic framework (MOF), MIL-101, with or without functionalization. Five MIL-101 MOFs were obtained by direct syntheses, grafting, and hydrogenation. The adsorption capacity of IND increased significantly (up to 1.7 times that of MIL-101) upon introducing amino functional groups into MIL-101, despite the decrease in the porosity of the MOF after modification. However, the adsorption of QUI decreased when MIL-101 was modified using both amino and butyl groups because of the reduced porosity. The adsorption capacity for IND (based on the unit surface area of MIL-101s) showed that MIL 101s with amino groups had an adsorption capacity of around 2.3 times those of MIL-101 or MIL-101 with butyl groups, showing the importance of H-bonds for the adsorption of IND over MIL-101s. However, for the adsorption of QUI, only the porosity is important, and coordination of QUI on open metal sites does not play a dominant role, probably because of the low basicity of QUI. Moreover, there is little contribution of H-bonds (between N of QUI and H of -NH2 of MOF) in the adsorption of QUI over amino-MIL-101s, and this is probably due to a similar reason. Preparation methods for MIL-101 having a free amino group did not have any effect on the adsorption (based on surface area) of QUI or IND. PMID- 27117232 TI - Neighbourhood walkability, road density and socio-economic status in Sydney, Australia. AB - BACKGROUND: Planning and transport agencies play a vital role in influencing the design of townscapes, travel modes and travel behaviors, which in turn impact on the walkability of neighbourhoods and residents' physical activity opportunities. Optimising neighbourhood walkability is desirable in built environments, however, the population health benefits of walkability may be offset by increased exposure to traffic related air pollution. This paper describes the spatial distribution of neighbourhood walkability and weighted road density, a marker for traffic related air pollution, in Sydney, Australia. As exposure to air pollution is related to socio-economic status in some cities, this paper also examines the spatial distribution of weighted road density and walkability by socio-economic status (SES). METHODS: We calculated walkability, weighted road density (as a measure of traffic related air pollution) and SES, using predefined and validated measures, for 5858 Sydney neighbourhoods, representing 3.6 million population. We overlaid tertiles of walkability and weighted road density to define "sweet spots" (high walkability-low weighted road density), and "sour- spots" (low walkability-high weighted road density) neighbourhoods. We also examined the distribution of walkability and weighted road density by SES quintiles. RESULTS: Walkability and weighted road density showed a clear east-west gradient across the region. Our study found that only 4 % of Sydney's population lived in sweet spot" neighbourhoods with high walkability and low weighted road density (desirable), and these tended to be located closer to the city centre. A greater proportion of neighbourhoods had health limiting attributes of high weighted road density or low walkability (about 20 % each), and over 5 % of the population lived in "sour-spot" neighbourhoods with low walkability and high weighted road density (least desirable). These neighbourhoods were more distant from the city centre and scattered more widely. There were no linear trends between walkability/weighted road density and neighbourhood SES. CONCLUSIONS: Our walkability and weighted road density maps and associated analyses by SES can help identify neighbourhoods with inequalities in health-promoting or health limiting environments. Planning agencies should seek out opportunities for increased neighbourhood walkability through improved urban development and transport planning, which simultaneously minimizes exposure to traffic related air pollution. PMID- 27117233 TI - An intramolecular disulfide bond designed in myoglobin fine-tunes both protein structure and peroxidase activity. AB - Disulfide bond plays crucial roles in stabilization of protein structure and in fine-tuning protein functions. To explore an approach for rational heme protein design, we herein rationally introduced a pair of cysteines (F46C/M55C) into the scaffold of myoglobin (Mb), mimicking those in native neuroglobin. Molecular modeling suggested that it is possible for Cys46 and Cys55 to form an intramolecular disulfide bond, which was confirmed experimentally by ESI-MS analysis, DTNB reaction and CD spectrum. Moreover, it was shown that the spontaneously formed disulfide bond of Cys46-Cys55 fine-tunes not only the heme active site structure, but also the protein functions. The substitution of Phe46 with Ser46 in F46S Mb destabilizes the protein while facilitates H2O2 activation. Remarkably, the formation of an intramolecular disulfide bond of Cys46-Cys55 in F46C/M55C Mb improves the protein stability and regulates the heme site to be more favorable for substrate binding, resulting in enhanced peroxidase activity. This study provides valuable information of structure-function relationship for heme proteins regulated by an intramolecular disulfide bond, and also suggests that construction of such a covalent bond is useful for design of functional heme proteins. PMID- 27117235 TI - An ab initio study of the nickel-catalyzed transformation of amorphous carbon into graphene in rapid thermal processing. AB - Ab initio molecular dynamics (AIMD) simulations are employed to investigate the chemical mechanism underlying the Ni-catalyzed transformation of amorphous carbon (a-C) into graphene in the rapid thermal processing (RTP) experiment to directly grow graphene on various dielectric surfaces via the evaporation of surplus Ni and C at 1100 degrees C (below the melting point of bulk Ni). It is found that the a-C-to-graphene transformation entails the metal-induced crystallization and layer exchange mechanism, rather than the conventional dissolution/precipitation mechanism typically involved in Ni-catalyzed chemical vapor deposition (CVD) growth of graphene. The multi-layer graphene can be tuned by changing the relative thicknesses of deposited a-C and Ni thin films. Our AIMD simulations suggest that the easy evaporation of surplus Ni with excess C is likely attributed to the formation of a viscous-liquid-like Ni-C solution within the temperature range of 900-1800 K and to the faster diffusion of C atoms than that of Ni atoms above 600 K. Even at room temperature, sp(3)-C atoms in a-C are quickly converted to sp(2)-C atoms in the course of the simulation, and the graphitic C formation can occur at low temperature. When the temperature is as high as 1200 K, the grown graphitic structures reversely dissolve into Ni. Because the rate of temperature increase is considerably faster in the AIMD simulations than in realistic experiments, defects in the grown graphitic structures are kinetically trapped. In this kinetic growth stage, the carbon structures grown from sp(3)-carbon or from sp(2)-carbon exhibit marked differences. PMID- 27117234 TI - The biological inorganic chemistry of zinc ions. AB - The solution and complexation chemistry of zinc ions is the basis for zinc biology. In living organisms, zinc is redox-inert and has only one valence state: Zn(II). Its coordination environment in proteins is limited by oxygen, nitrogen, and sulfur donors from the side chains of a few amino acids. In an estimated 10% of all human proteins, zinc has a catalytic or structural function and remains bound during the lifetime of the protein. However, in other proteins zinc ions bind reversibly with dissociation and association rates commensurate with the requirements in regulation, transport, transfer, sensing, signalling, and storage. In contrast to the extensive knowledge about zinc proteins, the coordination chemistry of the "mobile" zinc ions in these processes, i.e. when not bound to proteins, is virtually unexplored and the mechanisms of ligand exchange are poorly understood. Knowledge of the biological inorganic chemistry of zinc ions is essential for understanding its cellular biology and for designing complexes that deliver zinc to proteins and chelating agents that remove zinc from proteins, for detecting zinc ion species by qualitative and quantitative analysis, and for proper planning and execution of experiments involving zinc ions and nanoparticles such as zinc oxide (ZnO). In most investigations, reference is made to zinc or Zn2+ without full appreciation of how biological zinc ions are buffered and how the d-block cation Zn2+ differs from s-block cations such as Ca2+ with regard to significantly higher affinity for ligands, preference for the donor atoms of ligands, and coordination dynamics. Zinc needs to be tightly controlled. The interaction with low molecular weight ligands such as water and inorganic and organic anions is highly relevant to its biology but in contrast to its coordination in proteins has not been discussed in the biochemical literature. From the discussion in this article, it is becoming evident that zinc ion speciation is important in zinc biochemistry and for biological recognition as a variety of low molecular weight zinc complexes have already been implicated in biological processes, e.g. with ATP, glutathione, citrate, ethylenediaminedisuccinic acid, nicotianamine, or bacillithiol. PMID- 27117236 TI - Modeling Symptoms of Attention-Deficit Hyperactivity Disorder in a Rat Model of Fetal Alcohol Syndrome. AB - AIMS: Several studies indicate the similarity between the symptoms of fetal alcohol syndrome and attention-deficit hyperactivity disorder (ADHD). This study hypothesized that prenatal exposure to ethanol (EtOH) can be used as an animal model of ADHD in Wistar rats. METHODS: At the first stage of the study, alcohol was delivered to the pregnant dams (237-252 g) by intra-gastric route throughout Gestation Days 8-20 at a dose of 6 g/kg/day. Untreated control group with isocaloric sucrose intubation was also included. Of the 16 male pups (174-180 g), 8 were in the fetal alcohol effects (FAE) group and 8 were in the untreated control group. Subjects went through behavior shaping, discrimination learning and reversal learning. Number of sessions to learn the tasks, response frequency to inhibitory (S-) and excitatory (S+) stimulus features, response latency and inter-response time (IRT) were measured. RESULTS: Significant differences were obtained on only the reversal task. Rats with FAE needed greater number of sessions to learn the reversal task, and they had a higher frequency of incorrect responses in specifically the latter part of the sessions. CONCLUSION: Our results suggest that reversal learning of FAE rats exhibits deficit in the inhibition of pre-learned responses. Responses behaviorally mimicked attention deficit and impulsivity symptoms of human ADHD. However, the experimental design of the study was not conducive to hyperactivity. Accordingly, rats with FEA can be an alternative to other models since it is not, for example, based on a symptom that is atypical (such as hypertension) to ADHD. SHORT SUMMARY: Significant difference was obtained in a reversal task between male rats prenatally exposed to ethanol and matched controls. The greater number of sessions for learning and higher frequency of incorrect responses behaviorally mimicked symptoms of ADHD, suggesting that rats with fetal ethanol effects can serve as a useful animal model. PMID- 27117237 TI - Alcohol-Induced Stimulation Mediates the Effect of a GABRA2 SNP on Alcohol Self Administrated among Alcohol-Dependent Individuals. AB - BACKGROUND: A single-nucleotide polymorphism (SNP) in GABRA2 (rs279858) may moderate subjective response (SR) to alcohol. Results of studies in non-dependent drinkers examining this GABRA2 SNP on SR have been equivocal. This study examined this SNP's direct and indirect effects on alcohol self-administration in dependent drinkers. METHOD: The sample consisted of 63 Caucasian, non-treatment seeking individuals with alcohol dependence. Subjective stimulation was assessed using the Biphasic Alcohol Effects Scale following consumption of an alcoholic priming drink (target breath alcohol content = 0.02 g%). Participants were subsequently offered the opportunity to self-administer up to eight additional drinks. RESULTS: Controlling for baseline stimulation, T-allele homozygotes, relative to individuals with at least one copy of the C-allele, reported greater initial stimulation, t(58) = 2.011, p = 0.049. Greater stimulation predicted greater subsequent alcohol self-administration, t(57) = 2.522, p = 0.015. Although rs279858 genotype did not directly impact self-administration (t(57) = 0.674, p = 0.503), it did have an indirect effect (95% confidence interval [0.068, 1.576]), such that T-allele homozygotes reported greater stimulation, which in turn predicted greater self-administration. CONCLUSION: These results suggest that the influence of this SNP on SR differs depending on dose or stage of dependence. This study is the first to demonstrate an indirect effect of rs279858 genotype on drinking through SR. Although C-allele carriers have been shown to have an increased risk for alcohol dependence, in our dependent sample, greater stimulation was found among T-allele homozygotes, suggesting that the influence of SR on developing and maintaining dependence differs based on rs279858 genotype.This study demonstrates an indirect effect of rs279858 genotype on drinking through SR. Although C-allele carriers have an increased risk for alcohol dependence, in our dependent sample, greater stimulation was found among T-allele homozygotes, suggesting that the influence of SR on developing dependence differs based on rs279858 genotype. PMID- 27117238 TI - Alcohol Control Policies and Alcohol-Related Mortality in Russia: Reply to Razvodovsky and Nemtsov. PMID- 27117239 TI - Russian Alcohol Policy in False Mirror. PMID- 27117240 TI - Prevalence of Ectopic Breast Tissue and Tumor: A 20-Year Single Center Experience. AB - BACKGROUND: Ectopic breast tissue, which includes both supernumerary breast and aberrant breast tissue, is the most common congenital breast abnormality. Ectopic breast cancers are rare neoplasms that occur in 0.3% to 0.6% of all cases of breast cancer. PATIENTS AND METHODS: We retrospectively report, using a large series of breast abnormalities diagnosed and treated, our clinical experience on the management of the ectopic breast cancer. In 2 decades, we observed 327 (2.7%) patients with ectopic breast tissue out of a total of 12,177 subjects undergoing a breast visit for lesions. All patients were classified into 8 classes, according to the classification of Kajava, and assessed by a physician examination, ultrasounds, and, when appropriate, further studies with fine needle aspiration cytology and mammography. All specimens were submitted to the anatomo pathologist. The most frequent benign histological diagnosis was fibrocystic disease. A rare granulosa cell tumor was also found in the right anterior thoracic wall of 1 patient. Four malignancies were also diagnosed in 4 women: an infiltrating lobular cancer in 1 patient with a lesion classified as class I, and an infiltrating apocrine carcinoma, an infiltrating ductal cancer, and an infiltrating ductal cancer with tubular pattern, occurring in 3 patients with lesions classified as class IV. Only 1 recurrence was observed. We recommend an earlier surgical approach for patients with lesions from class I to IV. PMID- 27117241 TI - Adjuvant Surgical Oophorectomy Plus Tamoxifen in Premenopausal Women With Operable Hormone Receptor-Positive Breast Cancer: A Global Treatment Option. AB - One third of annual new cases of breast cancer globally are now hormone receptor positive tumors in premenopausal women from low- and middle-income countries. For this subgroup of women with breast cancer, high-income country guidelines suggest impractical and unaffordable adjuvant treatments. The balance of clinical trial evidence now suggests that surgical oophorectomy plus tamoxifen is a safe and practical treatment for these women in low- and middle-income countries. Additionally, new randomized trial data suggest that women in the second half of an anovulatory cycle benefit minimally from surgical oophorectomy done at this time, which implies that regularly cycling women will benefit more than has been shown from this procedure. Allred scoring of levels of hormone receptors is a practical and inexpensive approach to the assessment of magnitudes of response to oophorectomy plus tamoxifen. These circumstances suggest that more detailed consideration of this option should characterize clinical practice guidelines in high-income countries because of their global impact. PMID- 27117242 TI - Association of plant growth-promoting Serratia spp. with the root nodules of chickpea. AB - Serratia species-affiliated DNA sequences have recently been discovered in the root nodules of two chickpea cultivars; however, little is known about their potential influence on chickpea plant growth. All Serratia-affiliated sequences (1136) could be grouped into two clusters at 98% DNA similarity. The major cluster, represented by 96% of sequences, was closely associated with Serratia marcescens sequences from GenBank. In the current study, we isolated two Serratia strains, 5D and RTL100, from root nodules of a field-grown Desi cultivar from Faisalabad and Thal areas, respectively. In vitro, strain 5D showed significantly higher phosphate (P) solubilization and lactic acid production than RTL100, whereas a comparable concentration of phytohormone was produced by both isolates. The application of Serratia strain 5D as an inoculum resulted in 25.55% and 30.85% increases in the grain yield of crops grown on fertile soil in irrigated areas and nutrient-deficient soil in rainfed areas, respectively, compared to the non-inoculated control. Results of plant inoculations indicated that Serratia sp. 5D and RTL100 can serve as effective microbial inoculants, particularly in nutrient-deficient soils in rainfed areas, where chickpea is the only major crop grown during the entire year. PMID- 27117243 TI - Participatory Genomic Testing as an Educational Experience. AB - Several institutions have incorporated participatory genomic testing into their curricula to engage students in experiential learning, and this has raised ethical concerns. We summarize strategies for managing these concerns and review evidence of the influence of this experiential approach on student knowledge and attitudes towards genomics. PMID- 27117244 TI - Beta-cell Specific Autoantibodies: Are they Just an Indicator of Type 1 Diabetes? AB - BACKGROUND: Autoantibodies (AAbs) against islet autoantigens (AAgs) are used for type 1 diabetes (T1D) diagnosis and prediction. Islet-specific AAbs usually appear early in life and may fluctuate in terms of number and titer sometimes for over 20 years before T1D develops. Whereas their predictive power is high for pediatric subjects with high genetic risk who rapidly progress to multiple AAb positivity, they are less reliable for children with low genetic risk, single AAb positivity and slow disease progression. OBJECTIVE: It is unknown how AAbs develop and whether they are involved in T1D pathogenesis. So far an increase in AAb number seems to only indicate AAg spreading and progression towards clinical T1D. The goal of this review is to shed light on the possible involvement of AAbs in T1D development. METHOD: We thoroughly review the current literature and discuss possible mechanisms of AAb development and the roles they may play in disease pathogenesis. RESULTS: Genetic and environmental factors instigate changes at the molecular and cellular levels that promote AAb development. Although direct involvement of AAbs in T1D is less clear, autoreactive B cells are clearly involved in various immune and autoimmune responses via antigen presentation, immunoregulation and cytokine production. CONCLUSION: Our analysis suggests that understanding the mechanisms that lead to islet-specific AAb development and the diabetogenic processes that autoreactive B cells promote may uncover additional biomarkers and therapeutic targets. PMID- 27117245 TI - Cloning and characterization of a novel lipase from Stenotrophomonas maltophilia GS11: The first member of a new bacterial lipase family XVI. AB - Bacterial lipases are an important group of enzymes that offer enormous potential in organic synthesis, and there is considerable interest in identifying and developing novel bacterial lipases. In previous studies, strains of the genus Stenotrophomonas were proved to be potential source of lipases, but there is little genetic information describing lipase from the genus Stenotrophomonas. We have cloned and characterized a novel lipase (LipSM54), the first lipase described from the genus Stenotrophomonas. Enzymatic study showed that LipSM54 was a cold-active, solvent-tolerant and alkaline lipase. Using bioinformatics tools, LipSM54 was found to be related only to several putative lipases from different bacterial origins, none of which could be assigned to any previously described bacterial lipase family. LipSM54 and these related putative lipases share four conserved motifs around the catalytic residues. These motifs clearly distinguish them from the known bacterial lipase families. Consequently, LipSM54 is the first characterized member of the novel bacterial lipase family. PMID- 27117246 TI - A novel presentation of homozygous loss-of-function STAT-1 mutation in an infant with hyperinflammation-A case report and review of the literature. PMID- 27117247 TI - Fate of Distal False Aneurysms Complicating Internal Carotid Artery Dissection: A Systematic Review. AB - BACKGROUND: False aneurysm formation occurs in 13-49% of internal carotid artery dissections (ICADs). In light of the uncertainty regarding the clinical course, expansion rates and optimal treatment of post-ICAD false aneurysms, a systematic review of the literature was undertaken to establish the fate of the nonoperated distal ICA false aneurysm after ICAD. METHODS: PubMed/MEDLINE, Embase, and Cochrane databases were systematically searched up to 13 August 2015 for studies reporting clinical outcomes and imaging surveillance in patients who were found to have developed a false aneurysm associated with ICAD, with specific emphasis on the fate of the nonoperated false aneurysm. RESULTS: Eight studies reported on the course/clinical outcome of ICAD-associated false aneurysms in 166 patients. Of these, five of 166 false aneurysms (3%) increased in size; 86 of 166 (52%) remained unchanged in diameter; 35 of 166 (21%) diminished in size; 32 of 166 (19%) resolved completely; three of 166 (2%) thrombosed; and five 166 (3%) were repaired surgically. Another four of 166 (2%) underwent late surgery (0.5-5.0 years later). During the course of surveillance, none of the nonoperated false aneurysms associated with spontaneous ICAD gave rise to any new neurological or compressive symptoms. CONCLUSIONS: In this systematic review, >95% of nonoperated false aneurysms affecting the distal internal carotid artery that developed after an ICAD did not increase in size and were not associated with any delayed neurological symptoms suggesting that conservative management and serial surveillance is the optimal mode of treatment. As nearly all studies suffered from serious bias, reporting standards for diagnosis and follow-up are needed in order to better define their natural history. PMID- 27117248 TI - Ultrasonography of Skin Changes in Legs with Chronic Venous Disease. AB - BACKGROUND: In daily practice, ultrasonography (US) is used only to designate the location and pattern of venous lesions. Skin US is not performed between routine venous investigations. METHODS: Skin morphology is evaluated by the same probes used for routine Duplex evaluation of superficial veins. US findings from evident skin lesions are comparatively evaluated with those from the surrounding apparently normal skin and from the contralateral leg. RESULTS: Inflammation and dermal edema can be found in the apparently normal skin of C2 legs. Swollen legs show thickening of the subcutaneous layer as a result of diffuse soaking or anechoic cavities, with or without dermal edema. Chronic hypodermitis is characterized by inflammatory edema in initial phases, and by liposclerosis in advanced cases. Recrudescence of inflammation provokes focal rarefactions of the subcutaneous layer, possibly related to ulcer opening. CONCLUSION: In legs with venous disorders, sonography refines clinical evaluation of the skin and may reveal changes not highlighted by inspection. Some of these changes could require further investigation because they have not yet been explained or described. Skin sonography should improve knowledge of the natural history of skin changes, as well as contribute to a better grading of venous diseases severity In particular, US evidence of cutaneous and subcutaneous changes in C2 legs should be considered to stratify the treatment in C2 legs, by identifying those in which varicose veins are not simply a cosmetic problem. PMID- 27117249 TI - The molecular neurobiology of the sleep-deprived, fuzzy brain. AB - Sleep deprivation is well established to cause diminution of cognitive function, including disruption of both minute-to-minute working memory and decrements in the stabilization of long-term memories. Moreover, "replay" during sleep of episodes and sequences of events that were experienced during wakefulness has been implicated in consolidation of long-term memories. However, the molecular mechanisms underlying the role of sleep in memory function are just starting to be defined. In this issue of Science Signaling, Tudor et al identify one molecular component underlying the effects of sleep on memory function: dynamic experience-dependent regulation of protein synthesis in the hippocampus. PMID- 27117250 TI - How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD. AB - Both synaptic long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical for memory formation. Dell'Acqua and co-workers now demonstrate that transient postsynaptic incorporation of Ca(2+)-permeable (CP) alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is required for LTD in the exemplary hippocampal CA1 region in 2-week-old mice. Mechanistically, LTD depends on AKAP150-anchored protein kinase A (PKA) to promote the initial functional recruitment of CP-AMPARs during LTD induction and on AKAP150-anchored protein phosphatase 2B (PP2B) to trigger their subsequent removal as part of the lasting depression of synaptic transmission. PMID- 27117251 TI - Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis. AB - Sleep deprivation is a public health epidemic that causes wide-ranging deleterious consequences, including impaired memory and cognition. Protein synthesis in hippocampal neurons promotes memory and cognition. The kinase complex mammalian target of rapamycin complex 1 (mTORC1) stimulates protein synthesis by phosphorylating and inhibiting the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2). We investigated the involvement of the mTORC1-4EBP2 axis in the molecular mechanisms mediating the cognitive deficits caused by sleep deprivation in mice. Using an in vivo protein translation assay, we found that loss of sleep impaired protein synthesis in the hippocampus. Five hours of sleep loss attenuated both mTORC1-mediated phosphorylation of 4EBP2 and the interaction between eukaryotic initiation factor 4E (eIF4E) and eIF4G in the hippocampi of sleep-deprived mice. Increasing the abundance of 4EBP2 in hippocampal excitatory neurons before sleep deprivation increased the abundance of phosphorylated 4EBP2, restored the amount of eIF4E-eIF4G interaction and hippocampal protein synthesis to that seen in mice that were not sleep-deprived, and prevented the hippocampus-dependent memory deficits associated with sleep loss. These findings collectively demonstrate that 4EBP2-regulated protein synthesis is a critical mediator of the memory deficits caused by sleep deprivation. PMID- 27117252 TI - Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation. AB - Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A165, a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR 2 activation. PMID- 27117253 TI - Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. AB - PEN is an abundant peptide in the brain that has been implicated in the regulation of feeding. We identified a receptor for PEN in mouse hypothalamus and Neuro2A cells. PEN bound to and activated GPR83, a G protein (heterotrimeric guanine nucleotide)-binding protein)-coupled receptor (GPCR). Reduction of GPR83 expression in mouse brain and Neuro2A cells reduced PEN binding and signaling, consistent with GPR83 functioning as the major receptor for PEN. In some brain regions, GPR83 colocalized with GPR171, a GPCR that binds the neuropeptide bigLEN, another neuropeptide that is involved in feeding and is generated from the same precursor protein as is PEN. Coexpression of these two receptors in cell lines altered the signaling properties of each receptor, suggesting a functional interaction. Our data established PEN as a neuropeptide that binds GPR83 and suggested that these two ligand-receptor systems-PEN-GPR83 and bigLEN-GPR171-may be functionally coupled in the regulation of feeding. PMID- 27117254 TI - Non-target time trend screening: a data reduction strategy for detecting emerging contaminants in biological samples. AB - Non-targeted mass spectrometry-based approaches for detecting novel xenobiotics in biological samples are hampered by the occurrence of naturally fluctuating endogenous substances, which are difficult to distinguish from environmental contaminants. Here, we investigate a data reduction strategy for datasets derived from a biological time series. The objective is to flag reoccurring peaks in the time series based on increasing peak intensities, thereby reducing peak lists to only those which may be associated with emerging bioaccumulative contaminants. As a result, compounds with increasing concentrations are flagged while compounds displaying random, decreasing, or steady-state time trends are removed. As an initial proof of concept, we created artificial time trends by fortifying human whole blood samples with isotopically labelled standards. Different scenarios were investigated: eight model compounds had a continuously increasing trend in the last two to nine time points, and four model compounds had a trend that reached steady state after an initial increase. Each time series was investigated at three fortification levels and one unfortified series. Following extraction, analysis by ultra performance liquid chromatography high-resolution mass spectrometry, and data processing, a total of 21,700 aligned peaks were obtained. Peaks displaying an increasing trend were filtered from randomly fluctuating peaks using time trend ratios and Spearman's rank correlation coefficients. The first approach was successful in flagging model compounds spiked at only two to three time points, while the latter approach resulted in all model compounds ranking in the top 11 % of the peak lists. Compared to initial peak lists, a combination of both approaches reduced the size of datasets by 80-85 %. Overall, non-target time trend screening represents a promising data reduction strategy for identifying emerging bioaccumulative contaminants in biological samples. Graphical abstract Using time trends to filter out emerging contaminants from large peak lists. PMID- 27117255 TI - Effects of dissolved organic matter (DOM) sources and nature of solid extraction sorbent on recoverable DOM composition: Implication into potential lability of different compound groups. AB - Noting the source-dependent properties of dissolved organic matter (DOM), this study explored the recoverable compounds by solid phase extraction (SPE) of two common sorbents (C18 and PPL) eluted with methanol solvent for contrasting DOM sources via fluorescence excitation-emission matrix coupled with parallel factor analysis (EEM-PARAFAC) and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). Fresh algae and leaf litter extracts DOM, one riverine DOM, and one upstream lacustrine DOM were selected for the comparison. C18 sorbent was generally found to extract more diverse molecular formula, relatively higher molecular weight, and more heteroatomic DOM compounds within the studied mass range than PPL sorbent except for the leaf litter extract. Even with the same sorbent, the main molecular features of the two end member DOM were distributed on different sides of the axes of a multivariate ordination, indicating the source-dependent characteristics of the recoverable compounds by the sorbents. In addition, further examination of the molecular formula uniquely present in the two end members and the upstream lake DOM suggested that proteinaceous, tannin-like, and heteroatomic DOM constituents might be potential compound groups which are labile and easily degraded during their mobilization into downstream watershed. This study provides new insights into the sorbent selectivity of DOM from diverse sources and potential lability of various compound groups. PMID- 27117256 TI - Corrigendum to "multiple symptoms, functioning, and general health perception in people with severe COPD over time" [Applied Nursing Research 29C (2016) 76-82]. PMID- 27117257 TI - First report on fish cysteine as a biomarker of contamination in the River Chenab, Pakistan. AB - The eastern and southern parts of the Faisalabad city produce considerable quantities of industrial and municipal pollutants, much of which is drained into the River Chenab, reducing the productivity of fauna and flora in the river. This study was aimed to determine whether cysteine is useful as a biomarker of exposure to polluted fresh water. The amino acid profile of fish muscle was analyzed by paper chromatography in Cirrhinus mrigala and Labeo rohita from the River Chenab to determine habitat related variations due to the pollution from industrial and domestic sources. C. mrigala showed higher level of metal contamination in muscle tissues for Sn, Cr, Pb, Zn, Mn, Cu, and Cd when compared to L. rohita. Both fish species collected from polluted areas of the river Chenab showed significantly (P < 0.01) higher levels of metals in comparison to upstream and farmed fish. Farmed C. mrigala showed cysteine concentrations in the muscle tissue as 22 +/- 1 mg/g dry weight, but concentrations increased to 45 +/- 2 mg/g dry weight for fish from a mildly polluted section of the river, and further increased to 83 +/- 2 mg/g dry weight in more heavily polluted sections. Cysteine concentration in farmed L. rohita was detected as 28 +/- 2 and 25 +/- 4 mg/g dry weight, respectively for farmed fish and fish from a mildly polluted section of the river, and then increased to 94 +/- 3 mg/g dry weight for fish from highly polluted water. C. mrigala from a mildly polluted area of the river also had higher levels of cysteine in the muscle, along with increases in aspartic acid, glutamic acid, and alanine. Elevated concentrations of cysteine seem to be associated with a threat to these fish species in polluted sections of the river, and thus may be used as a biomarker. PMID- 27117258 TI - Alterations in locomotor activity of feeding zebrafish larvae as a consequence of exposure to different environmental factors. AB - Behavioral studies are important tools for understanding the development and pathology of neurological diseases. Zebrafish are an emerging alternative model in behavioral and neurological studies as the behavioral repertoire of zebrafish (Danio rerio) is similar to humans, and nervous system structures and functions are highly conserved. In this study, we investigated alterations in day/night locomotor activity of free swimming, feeding wild-type zebrafish larvae (8-15dpf) due to changes in the rhythm of light/dark cycles or caloric content of food. We furthermore exposed zebrafish larvae to continuous stress by applying alternated minor vibrations. Under altered rhythms of light/dark cycle's zebrafish larvae still expressed a distinct light/dark activity pattern but the total activity was reduced compared to control animals. When the larvae were exposed to continuous light, they still had coordinated resting cycles but maximal activity and excitation rates after feeding were increased, indicating that food became the new zeitgeber. Feeding food of high caloric content induced continuously high activity levels during light cycles and significantly elevated activity levels during the dark. Exposure to continuous vibrations lowered total activity levels. We showed previously that changes in environmental factors like light/dark cycles or changes in caloric content of food can affect adipogenesis, lipid composition, and circadian rhythm of free swimming, feeding larvae but this is the first time showing how theses factor alter behavior. PMID- 27117259 TI - Efficient one-pot synthesis of amino-benzotriazolodiazocinone scaffolds via catalyst-free tandem Ugi-Huisgen reactions. AB - Herein we describe a catalyst-free, one-pot procedure employing an Ugi-4CR between propargyl glycine, functionalised 2-azidoanilines, different isocyanides and aldehydes, followed by a thermal azide-alkyne Huisgen cycloaddition to generate a 14-member set of amino-benzotriazolodiazocine-bearing dipeptides with multiple points of diversification and high atom economy. These structures were derivatized by means of Suzuki-Miyaura cross-coupling reactions at two positions with good to excellent yields, leading to conformationally constrained tricyclic structures. In silico and NMR conformational analysis studies demonstrated that turn conformations are adopted by these structures. PMID- 27117260 TI - Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase. AB - Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2'-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5 aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity. PMID- 27117261 TI - Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test. AB - To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2 a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50=35nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9- condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2 cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3 yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile. PMID- 27117262 TI - Synthesis of 24(S)-hydroxycholesterol esters responsible for the induction of neuronal cell death. AB - We synthesized several candidates of 24(S)-hydroxycholesterol (24S-OHC) esters, which are involved in neuronal cell death, through catalysis with acyl CoA:cholesterol acyltransferase-1 (ACAT-1). We studied the regioselectivity of the acylation of the secondary alcohol at the 3- or 24-position of 24S-OHC. The appropriate saturated and unsaturated long-chain fatty acids were esterified with the protected 24S-OHC and then de-protected to afford the desired esters at a satisfactory yield. We then confirmed by HPLC monitoring that the retention times of four esters of 24S-OHC, namely 3-oleate, 3-linoleate, 3-arachidonoate and 3 docosahexaenoate, were consistent with those of 24S-OHC esters observed in 24S OHC-treated SH-SY5Y cells. PMID- 27117263 TI - Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3 dihydroquinazolin-4(1H)-ones as potent and selective PKCtheta inhibitors. AB - A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-theta (PKCtheta) inhibitor. Using the docking model of compound 1 bound to PKCtheta as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCtheta inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCtheta confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse. PMID- 27117265 TI - Bronchogenic cyst at esophagogastric junction treated by laparoscopic full thickness resection and hand-sewn closure: a case report. AB - BACKGROUND: We herein report a case of a bronchogenic cyst arising from the esophagogastric junction treated by laparoscopic full-thickness extirpation. The full-thickness defect was closed by hand sewing a T-shaped line over the gastroendoscope as a bougie to prevent postoperative deformity or stenosis. Partial fundoplication (Toupet fundoplication) was added to prevent reflux. CASE PRESENTATION: A 32-year-old woman with a body mass index of 43 kg/m(2) was admitted for treatment of a cyst-forming submucosal tumor (60 mm in diameter) on the anterior wall of the esophagogastric junction, which was detected during screening endoscopy before bariatric surgery. The tumor was an extraluminal growing type but exhibited severe erosion at the mucosal site. A cystic tumor such as a duplication cyst, bronchogenic cyst, or cyst-forming gastrointestinal stromal tumor was suspected, and the abovementioned surgery was carried out. The postoperative course was uneventful. The pathological findings revealed the tumor to be a benign bronchogenic cyst. Endoscopic examination 3 months postoperatively showed no deformity or stenosis, and the patient complained of no reflux symptoms. CONCLUSION: This procedure may be an efficient option for treatment of submucosal tumors on the esophagogastric junction to maintain function or avoid excessive surgery. PMID- 27117264 TI - Cardiovascular magnetic resonance as a reliable alternative to cardiovascular computed tomography and transesophageal echocardiography for aortic annulus valve sizing. AB - To assess the accuracy and reproducibly of cardiovascular magnetic resonance (CMR) in the measurement of the aortic annulus and in process of valve sizing as compared to intra-operative sizing, cardiovascular computed tomography (CCT) and transesophageal echocardiography (TEE). Retrospective study on 42 patients who underwent aortic valve replacement from September 2010 to September 2015, with available records of pre surgery annulus assessment by CMR, CCT and TEE and of peri-operative assessment. In CCT and CMR, the annular plane was considered a virtual ring formed by the lowest hinge points of the valvular attachments to the aorta. In TEE the annulus was measured at the base of leaflet insertion in the mid-esophageal long-axis view using the X-plane technique. Two double-blinded operators performed the assessments for each imaging technique. Intra-operative evaluation was performed using Hegar dilators. Continuous variables were studied with within-subject ANOVA, Bland-Altman (BA) plots, Wilcoxon's and Friedman's tests; trends were explored with scatter plots. Categorical variables were studied with Fisher's exact test. The intra- and inter-operator reliability was satisfying. There were no significant differences between the annulus dimensions measured by CMR and either one of the three references. Valve sizing for CoreValve by CMR had the same good agreement with CCT and TEE, with a 78 % match rate; for SAPIEN XT the agreement was slightly better (82 %) for CCT than for TEE (66 %). MR performs well when compared to the surgical reference of intra operative sizing and stands up to the level of the most used imaging references (CCT and TEE). PMID- 27117266 TI - Quantitative imaging analysis of posterior fossa ependymoma location in children. AB - PURPOSE: Imaging descriptions of posterior fossa ependymoma in children have focused on magnetic resonance imaging (MRI) signal and local anatomic relationships with imaging location only recently used to classify these neoplasms. We developed a quantitative method for analyzing the location of ependymoma in the posterior fossa, tested its effectiveness in distinguishing groups of tumors, and examined potential associations of distinct tumor groups with treatment and prognostic factors. METHODS: Pre-operative MRI examinations of the brain for 38 children with histopathologically proven posterior fossa ependymoma were analyzed. Tumor margin contours and anatomic landmarks were manually marked and used to calculate the centroid of each tumor. Landmarks were used to calculate a transformation to align, scale, and rotate each patient's image coordinates to a common coordinate space. Hierarchical cluster analysis of the location and morphological variables was performed to detect multivariate patterns in tumor characteristics. The ependymomas were also characterized as "central" or "lateral" based on published radiological criteria. Therapeutic details and demographic, recurrence, and survival information were obtained from medical records and analyzed with the tumor location and morphology to identify prognostic tumor characteristics. RESULTS: Cluster analysis yielded two distinct tumor groups based on centroid location The cluster groups were associated with differences in PFS (p = .044), "central" vs. "lateral" radiological designation (p = .035), and marginally associated with multiple operative interventions (p = .064). CONCLUSIONS: Posterior fossa ependymoma can be objectively classified based on quantitative analysis of tumor location, and these classifications are associated with prognostic and treatment factors. PMID- 27117267 TI - Isolated traumatic retroclival hematoma: case report and review of literature. AB - BACKGROUND: Retroclival hematomas are a rare entity. The pathology can be categorized into epidural hematoma or subdural hematoma based on the anatomy of the tectorial membrane. Frequently, the etiology is related to accidental trauma, though other mechanisms have been observed, including coagulopathy, non accidental trauma, and pituitary apoplexy. There have been only 2 prior cases where both epidural and subdural hematoma co-present. CASE PRESENTATION: An 8 year-old male was involved in a high-speed motor vehicle accident. He presented with a Glasgow Coma Score (GCS) of 14 with bilateral abducens nerve palsies. Computed tomography (CT) revealed a hemorrhage along the dorsum sella, clivus, and dens. Magnetic resonance imaging (MRI) demonstrated the retroclival hematoma in both the subdural and epidural space. At discharge, 19 days after the accident, the abducens nerve palsies had resolved without medical or operative intervention. CONCLUSION: Retroclival hematoma may present after trauma. Although most cases exhibit a benign clinical course with conservative management, significant and profound morbidity and mortality have been reported. Prompt diagnosis with close observation is prudent. Surgical management is indicated in the presence of hydrocephalus, symptomatic brainstem compression, and occipito cervical instability. PMID- 27117268 TI - Caenibacillus caldisaponilyticus gen. nov., sp. nov., a thermophilic, spore forming and phospholipid-degrading bacterium isolated from acidulocompost. AB - A thermophilic and phospholipid-degrading bacterium, designated strain B157T, was isolated from acidulocompost, a garbage compost processed under acidic conditions at moderately high temperature. The organism was Gram-stain-positive, aerobic, spore-forming and rod-shaped. Growth was observed to occur at 40-65 degrees C and pH 4.8-8.1 (optimum growth: 50-60 degrees C, pH 6.2). The strain was catalase- and oxidase-positive. The cell wall contained meso-diaminopimelic acid, alanine, glutamic acid and galactose. The predominant respiratory quinone was menaquinone-7 (MK-7) and the major fatty acids were anteiso-C17 : 0 and iso-C17 : 0. Comparative 16S rRNA gene sequence analysis showed that strain B157T was related most closely to Tuberibacillus calidus 607T (94.8 % identity), and the phylogenetic analysis revealed that it belonged to the family Sporolactobacillaceae. The DNA G+C content was determined as 51.8 mol%. In spite of many similarities with the type strains of members of the family Sporolactobacillaceae, genotypic analyses suggest that strain B157T represents a novel species of a new genus, Caenibacilluscaldisaponilyticus gen. nov., sp. nov. The type strain of Caenibacilluscaldisaponilyticus is B157T (=NBRC 111400T=DSM 101100T). PMID- 27117269 TI - Sixty seconds on . . . placing GPs in hospital emergency departments. PMID- 27117270 TI - Intergenerational Relations in Older Stepfamilies: A Comparison of France, Germany, and Russia. AB - OBJECTIVES: Our study examines cross-national variations in intergenerational relations of partnered parents aged 50 and older with adult non-coresident children by family structure (intact vs stepfamilies) and parent-child relationship type (biological tie vs steprelation). We focus on three European countries-France, Germany, and Russia-which have in common a relatively large proportion of stepfamilies, but differ with regard to contextual characteristics potentially impacting the stepfamily-intergenerational-relations nexus. METHOD: The analysis is based on data from the Generations and Gender Survey (Wave 1). Our pooled analytical sample consists of 14,309 parent-child relationships derived from responses by 6,590 surveyed parents with adult children living outside the parental household. We consider two core dimensions of intergenerational solidarity as dependent variables, namely frequency of contact and emotional closeness. RESULTS: Our results support the notion of commonly weaker intergenerational relations in stepfamilies. We also observe differences between biological parent-child ties and steprelations. Compared with their French and German counterparts, there is a weaker association between having a steprelation and parent-child contact frequency as well as a stronger negative correlation between having a steprelation and emotional closeness among Russian respondents. DISCUSSION: The observed cross-national differences are proposed to result from different economic incentives to form a stepfamily, translating into a stronger "functional" basis of stepfamily intergenerational relations in the Russian context. PMID- 27117271 TI - Factors associated with pre-ART loss-to-follow up in adults in rural KwaZulu Natal, South Africa: a prospective cohort study. AB - BACKGROUND: Timely initiation of antiretroviral treatment (ART) requires sustained engagement in HIV care before treatment eligibility. We assessed loss to follow-up (LTFU) correlates in HIV-positive adults accessing HIV treatment and care, not yet ART-eligible (CD4 >500 cells/mm(3)). METHODS: This was a sub-study of a prospective cohort study (focusing on sexual behaviour) in an area of high HIV prevalence and widespread ART availability in rural KwaZulu-Natal, South Africa. Psychosocial, clinical and demographic data were collected at recruitment from individuals with CD4 >500 cells/mm(3). LTFU was defined as not attending clinic within 13 months of last visit or before death. Individuals starting ART were censored at ART initiation. Data were collected between January 2009 and January 2013. Analysis used Competing Risks regression. RESULTS: Two hundred forty-seven individuals (212 females) were recruited (median follow-up 2.13 years, total follow-up 520.15 person-years). 86 remained in pre-ART care (34.8 %), 94 were LTFU (38.1 %), 58 initiated ART (23.5 %), 7 died (2.8 %), 2 transferred out (0.8 %). The LTFU rate was 18.07 per 100 person-years (95 % CI 14.76-21.12). LTFU before a competing event was 13.5 % at one and 34.4 % at three years. Lower LTFU rates were significantly associated with age (>37 versus <=37 years: adjusted sub-Hazard ratio (aSHR) 0.51, 95 % CI 0.30-0.87), openness with family/friends (a little versus not at all, aSHR 0.81, 95 % CI 0.45-1.43; a lot versus not at all, aSHR 1.57, 95 % CI 0.94-2.62), children (0 versus 4+, aSHR 0.68, 95 % CI 0.24-1.87; 1 versus 4+, aSHR 2.05 95 % CI 1.14-3.69, 2 versus 4+; aSHR 1.71, 95 % CI 0.94-3.09; 3 versus 4a, aSHR 1.14, 95 % CI 0.57-2.30), previous CD4 counts (1 versus 0, aSHR 0.81, 95 % CI 0.45-1.43; 2+ versus 0, aSHR 0.43, 95 % CI 0.25-0.73), and most recent partner HIV status (not known versus HIV-positive, aSHR 0.77, 95 % CI 0.50-1.19; HIV-negative versus HIV-positive, aSHR 2.40, 95 % CI 1.18-4.88). The interaction between openness with family/friends and HIV partner disclosure was close to significance (p = 0.06). Those who had neither disclosed to partners nor were open with family/friends had lowest LTFU rates. CONCLUSIONS: Strategies to retain younger people in pre-ART care are required. How openness with others, partner HIV status and disclosure, and children relate to LTFU needs further exploration. PMID- 27117272 TI - In vivo Wnt pathway inhibition of human squamous cell carcinoma growth and metastasis in the chick chorioallantoic model. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with poor overall survival. New therapeutic strategies that target specific molecular lesions driving advanced disease are needed. Herein we demonstrate the utility of the chicken chorioallantoic membrane (CAM) assay for in vivo human HNSCC tumor growth and metastasis and the tumor suppressive effects of a new chemotherapeutic agent. METHODS: We tested anti-metastatic effects of a WNT pathway inhibitor, WNT974 (also known as LGK974), which targets porcupine (PORCN) the palmityl-transferase that is essential for secretion of Wnt proteins. CAM assays were performed with 8 HNSCC cell lines: UM-SCC-1, UM-SCC-10A, UM-SCC-10B, UM-SCC-11A, UM-SCC-14A UM-SCC-17A, UM-SCC-17B, UM-SCC-25, and UM-SCC-34. RESULTS: UM-SCC-1 (University of Michigan Squamous Cell Carcinoma cell line) CAM xenografts contain CD44+ and ALDH+ cancer stem cell (CSC) proportions similar to UM-SCC-1 mouse xenografts supporting the applicability of the CAM assay for study of CSCs. Inhibition of WNT signaling by the PORCN inhibitor WNT974 reduced metastatic spread of UM-SCC cells, especially in UM-SCCs with Notch1 deficiency. CONCLUSIONS: Our data demonstrate decreased tumor growth and metastases in tumors from cell lines that showed in vitro responses to WNT974, providing evidence that this agent may have a role in future HNSCC therapy. PMID- 27117273 TI - What do international ethics guidelines say in terms of the scope of medical research ethics? AB - BACKGROUND: In research ethics, the most basic question would always be, "which is an ethical issue, which is not?" Interestingly, depending on which ethics guideline we consult, we may have various answers to this question. Though we already have several international ethics guidelines for biomedical research involving human participants, ironically, we do not have a harmonized document which tells us what these various guidelines say and shows us the areas of consensus (or lack thereof). In this manuscript, we attempted to do just that. METHODS: We extracted the imperatives from five internationally-known ethics guidelines and took note where the imperatives came from. In doing so, we gathered data on how many guidelines support a specific imperative. RESULTS: We found that there is no consensus on the majority of the imperatives and that in only 8.2% of the imperatives were there at least moderate consensus (i.e., consensus of at least 3 of the 5 ethics guidelines). Of the 12 clusters (Basic Principles; Research Collaboration; Social Value; Scientific Validity; Participant Selection; Favorable Benefit/Risk Ratio; Independent Review; Informed Consent; Respect for Participants; Publication and Registration; Regulatory Sanctions; and Justified Research on the Vulnerable Population), Informed Consent has the highest level of consensus and Research Collaboration and Regulatory Sanctions have the least. CONCLUSION: There was a lack of consensus in the majority of imperatives from the five internationally-known ethics guidelines. This may be partly explained by the differences among the guidelines in terms of their levels of specification as well as conceptual/ideological differences. PMID- 27117274 TI - A de novo self-assembling peptide hydrogel biosensor with covalently immobilised DNA-recognising motifs. AB - We report here the first experimental evidence of a self-assembling three dimensional (3D) peptide hydrogel, with recognition motifs immobilized on the surface of fibres capable of sequence-specific oligonucleotide detection. These systems have the potential to be further developed into diagnostic and prognostic tools in human pathophysiology. PMID- 27117275 TI - The Perception of History: Seeing Causal History in Static Shapes Induces Illusory Motion Perception. AB - The perception of shape, it has been argued, also often entails the perception of time. A cookie missing a bite, for example, is seen as a whole cookie that was subsequently bitten. It has never been clear, however, whether such observations truly reflect visual processing. To explore this possibility, we tested whether the perception of history in static shapes could actually induce illusory motion perception. Observers watched a square change to a truncated form, with a "piece" of it missing, and they reported whether this change was sudden or gradual. When the contours of the missing piece suggested a type of historical "intrusion" (as when one pokes a finger into a lump of clay), observers actually saw that intrusion occur: The change appeared to be gradual even when it was actually sudden, in a type of transformational apparent motion. This provides striking phenomenological evidence that vision involves reconstructing causal history from static shapes. PMID- 27117276 TI - Vagal Tone and Children's Delay of Gratification: Differential Sensitivity in Resource-Poor and Resource-Rich Environments. AB - Children from different socioeconomic backgrounds have differing abilities to delay gratification, and impoverished children have the greatest difficulties in doing so. In the present study, we examined the role of vagal tone in predicting the ability to delay gratification in both resource-rich and resource-poor environments. We derived hypotheses from evolutionary models of children's conditional adaptation to proximal rearing contexts. In Study 1, we tested whether elevated vagal tone was associated with shorter delay of gratification in impoverished children. In Study 2, we compared the relative role of vagal tone across two groups of children, one that had experienced greater impoverishment and one that was relatively middle-class. Results indicated that in resource-rich environments, higher vagal tone was associated with longer delay of gratification. In contrast, high vagal tone in children living in resource-poor environments was associated with reduced delay of gratification. We interpret the results with an eye to evolutionary-developmental models of the function of children's stress-response system and adaptive behavior across varying contexts of economic risk. PMID- 27117278 TI - [Hypertrophic pyloric stenosis in adults]. PMID- 27117277 TI - Infectious SIV resides in adipose tissue and induces metabolic defects in chronically infected rhesus macaques. AB - BACKGROUND: HIV reservoirs pose major challenges to viral eradication. The main cellular reservoirs include CD4 T cells and macrophages, whereas anatomic reservoirs are thought to be primarily lymphoid tissues. Adipose tissue represents a potentially important non-lymphoid location for HIV replication and persistence because the stromal-vascular-fraction (AT-SVF) contains activated innate and adaptive immune cells that increase in number during infections, obesity, and chronic inflammation. RESULTS: Adipose tissue from two groups of SHIV-SF162p3-infected (~4 weeks acute infection) or SIVmac251-infected (~38 weeks chronic infection) rhesus macaques (N = 8 for each group) were studied for immune cell content, viral infectiousness, and metabolic health. The AT-SVF cells from SHIV-infected monkeys contained abundant memory CD4 and CD8 T cells, with fewer NKT cells and macrophages, and no B cells. Proviral DNA (Gag and Env) was readily detectable by nested PCR in AT-SVF cells from multiple adipose depots (subcutaneous and visceral) of acutely infected monkeys, but mostly from visceral fat. More importantly, viral outgrowth assays using input CD4 T cells derived from AT-SVF cells or peripheral blood of chronically infected monkeys resulted in robust replication of infectious virus from both AT-SVF and peripheral blood CD4 T cells. Chronically infected monkeys also experienced adipocyte dysfunction (suppression of major adipogenic genes) and systemic dyslipidemia (decreased serum total cholesterol and free fatty acids, and increased triglycerides), similar to metabolic abnormalities of HIV patients. CONCLUSIONS: Adipose tissues of SIV-infected rhesus macaques become major compartments for infected immune cells, which in turn induce defects in adipose tissue metabolism. PMID- 27117279 TI - Applying quantitative and semi-quantitative histopathology to address the interaction between sediment-bound polycyclic aromatic hydrocarbons in fish gills. AB - Even though PAHs are considered priority marine pollutants, information on the interaction effects between these compounds is scarce, furthermore under ecologically-relevant circumstances. Semi-quantitative and quantitative histological analyses were enforced on the gills of the seabass (Dicentrarchus labrax), exposed to two model PAHs, single or combined, through a series of 28 day laboratory bioassays. Fish exposed to sediments contaminated with either PAH (250-800ngg(-1)), isolated or combined, exhibited most significant gill histopathological alterations after 28 days of exposure, as determined through weighted condition indices, especially in animals exposed to the potential carcinogen benzo[b]fluoranthene (B[b]F) and to mixtures of this compound with its lower, non-carcinogenic counterpart Phenanthrene (Phe). Negative correlations between interlamellar hyperplasia (the most remarkable alteration) and goblet cell counts suggest that fish exposed to sediments contaminated with B[b]F or mixed PAHs increased the thickness of epithelial cells as a response to insult, albeit compromising cell differentiation, to which is likely added impaired gas exchange and osmotic balance. In contrast, animals exposed to Phe increased the number of chloride and goblet cells relatively to control fish at early stages of exposure, suggesting then a more efficient protective mechanism. The results also showed that histopathological alterations in mixture-exposed animals do not match the expected additive effects. Overall, the findings indicate that chronic exposures to sediment-bound PAHs, under realistic scenarios, may induce lesions in gills that may imply significant hindering of basal metabolic/homeostatic pathways in marine fish whose interpretation may be hindered by complicated interaction effects and unknown factor involving, more that dose-response, time dependent effects. PMID- 27117280 TI - Evaluation of dose-efficacy of sorafenib and effect of transarterial chemoembolization in hepatocellular carcinoma patients: a retrospective study. AB - BACKGROUND: Transarterial chemoembolization (TACE) and sorafenib are the therapeutic standard for intermediate and advanced stage hepatocellular carcinoma (HCC) patients respectively. High costs with adverse events (AE) of sorafenib might limit sorafenib dosage, further affecting therapeutic response. To attain greatest benefit, we evaluated the efficacy of different doses and effect of TACE during and after sorafenib discontinuation in patients representing Child-Pugh Classification Class A with venous or extra-hepatic invasion. METHODS: A total 156 patients met the criteria and were divided into Groups I (n = 52) accepting 800 mg/day; II (n = 58) accepting 800 mg/day and reduced to 400 mg/day owing to AE; and III (n = 46) accepting 400 mg/day. TACE was performed during and after sorafenib discontinuation and therapeutic response bimonthly to four-monthly was rated thereafter. RESULTS: Median duration of sorafenib treatment and patients' survival were 4.00 +/- 0.45 and 7.50 +/- 1.44 months in all cases; 2.50 +/- 0.90 and 5.00 +/- 1.10 months in Group I; 5.50 +/- 1.27 and 16.50 +/- 1.86 months in Group II; 4.00 +/- 0.94 and 6.50 +/- 2.49 months in Group III. Group II presented the best response and survival benefit (p = 0.010 and p = 0.011 respectively). Child-Pugh Classification score 5 (Hazard Ratio = 0.492, p = 0.049), absent AE (3.423, p = 0.015), tumor numbers <= 3 (0.313, p = 0.009), sorafenib duration <= 1 cycle (3.694, p = 0.004), and absent TACE (3.197, p = 0.008) significantly correlated with patient survival. TACE benefit appeared in separate and total cases during (p = 0.002, p = 0.595, p = 0.074, p = 0.002 respectively) and after discontinuation of sorafenib administration (p = 0.001, p = 0.034, p = 0.647, p = 0.001 respectively). CONCLUSIONS: Low-dosage sorafenib not only appeared tolerable and lowered economic pressure but also provided satisfactory results. TACE benefited patient's survival during and after sorafenib discontinuation. PMID- 27117281 TI - Recent History of Effector Use Modulates Practice-Dependent Changes in Corticospinal Excitability but Not Motor Learning. AB - BACKGROUND: The theory of homeostatic metaplasticity has significant implications for human motor cortical plasticity and motor learning. Previous work has shown that the extent of recent effector use before exogenously-induced plasticity can affect the direction, magnitude and variability of aftereffects. However, the impact of recent effector use on motor learning and practice-dependent plasticity is not known. HYPOTHESIS: We hypothesized that reducing effector use for 8 hours via hand/wrist immobilization would facilitate practice-dependent changes in corticospinal excitability and TMS-evoked thumb movement kinematics, while also promoting 24-hour retention of a ballistic motor skill. METHODS: Subjects participated in a crossover study involving two conditions. During the immobilization condition, subjects wore a splint that restricted motion of the left hand and thumb for 8 hours. While wearing the splint, subjects were instructed to avoid using their left hand as much as possible. During the control condition, subjects did not wear a splint at any time nor were they instructed to avoid hand use. After either an 8 hour period of immobilization or normal hand use, we collected MEP and TMS-evoked thumb movement recruitment curves, and subjects practiced a ballistic motor skill involving rapid thumb extension. After motor practice, MEP and TMS-evoked thumb movement recruitment curves were re tested. Retention of the motor skill was tested 30 minutes and 24 hours after motor practice. RESULTS: Reduced effector use did not impact pre-practice corticospinal excitability but did facilitate practice-dependent changes in corticospinal excitability, and this enhancement was specific to the trained muscle. In contrast, reducing effector use did not affect practice-dependent changes in TMS-evoked thumb movements nor did it promote acquisition or retention of the skill. Finally, we detected some associations between pre-practice excitability levels, plasticity effects and learning effects, but these did not reach our adjusted criterion for significance. CONCLUSION: Experimentally enhancing practice-dependent changes in corticospinal excitability is not sufficient to promote learning or memory of a ballistic motor skill. PMID- 27117282 TI - Effect of Repetitive Transcranial Magnetic Stimulation on Physical Function and Motor Signs in Parkinson's Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The short-term beneficial effects of repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease (PD) have been addressed by previous meta-analyses while its long-term effects remain undetermined. Although deterioration of walking and upper limb function greatly affects the participation in activities and quality of life of PD sufferers, the effect of rTMS thereon has not been systematically studied. OBJECTIVE: This systematic review aimed to examine the efficacy of rTMS on improving physical function and motor signs over the short- and long-terms in people with PD. METHODS: Five electronic databases were systematically searched for English language full-text articles using relevant search terms. Only randomized placebo-controlled trials investigating the effects of rTMS in PD were considered. The primary outcomes were walking performance, upper limb function, and unified Parkinson's disease rating scale (UPDRS) section III. Trials with similar outcomes were pooled by calculating Hedges' g using random-effects model. RESULTS: Twenty-two trials comprising 555 people with PD were included. Pooled estimates of effect of rTMS indicated significantly improved short-term upper limb function (Hedges' g, 0.40, P = 0.007), short-term (Hedges' g, 0.61, P = 0.03) and long-term walking performance (Hedges' g, 0.89, P = 0.03), short-term (Hedges' g, 0.31, P = 0.003) and long-term (Hedges' g, 0.54, P = 0.003) UPDRS III scores. Subgroup analyses suggest a more prominent effect for M1 stimulation. Meta-regression revealed that a greater number of total stimulation pulses were associated with more UPDRS III improvements over the long-term. CONCLUSION: The pooled evidence suggests that rTMS improves upper limb function in the short-term, walking performance and UPDRS III in the short- and long-terms in PD sufferers. Further studies are required to develop optimal rTMS therapeutic protocols for PD. PMID- 27117283 TI - Randomized Single Blind Sham Controlled Trial of Adjunctive Home-Based tDCS after rTMS for Mal De Debarquement Syndrome: Safety, Efficacy, and Participant Satisfaction Assessment. AB - BACKGROUND: Mal de debarquement syndrome is a medically refractory disorder characterized by chronic rocking dizziness that occurs after exposure to passive motion. Repetitive transcranial magnetic stimulation (rTMS) can acutely suppress the rocking dizziness but treatment options that extend the benefit of rTMS are needed. OBJECTIVES: 1) To determine whether transcranial direct current stimulation (tDCS) added after rTMS can extend the benefit of rTMS; 2) to determine whether participants can safely perform tDCS at home. METHODS: Participants were given five days of rTMS (1 Hz right DLPFC/10 Hz left DLPFC in right-handers, vice versa in left-handers), according to a previously piloted protocol. They received three days of training on tDCS self-administration and were then randomized to either real or sham tDCS for four-weeks (anode left DLPFC/cathode right DLPFC for right-handers, vice versa for left-handers). RESULTS: Twenty-three participants completed the study. Those who received real tDCS after rTMS showed significant improvements in the degree of rocking perception as measured by the MdDS Balance Rating Scale and anxiety ratings by Week 4 of tDCS and a trend for improvement on the Dizziness Handicap Inventory. Two rTMS non-responders responded well to subsequent open-label tDCS. Side effects were mild and not different between real and sham tDCS. There were no episodes of skin burns in a group total of 556 sessions of tDCS. Satisfaction was rated high. CONCLUSIONS: Home-based tDCS can be performed safely and may be beneficial in selected individuals. Adequate teaching, automatic device safety features, and a good communications infrastructure are components of successful home therapy. PMID- 27117284 TI - Is a Price Increase Policy Enough for Adolescent Smokers?: Factors Affecting the Effectiveness of Increasing Cigarette Prices Among Korean Adolescent Smokers. AB - BACKGROUND: Cigarette pricing policy is one tool for controlling smoking behavior on a national scale. It is unclear, however, what effects such policy has on adolescents and which characteristic subgroups of adolescents are more or less sensitive to cigarette pricing policy. MATERIALS AND METHODS: Our data came from the 2013 Korea Youth Risk Behavior Web-based Survey. The dependent variable was whether or not a participant was classified as a "persistent smokers," defined as a smoker who would continue smoking despite any price increase. Other variables of interest were smoking days (quantity), previous attempts to stop smoking, and previous education on smoking cessation. The statistical analysis was performed using weighted data and the SURVEYFREQ and SURVEYLOGISTIC procedures in SAS 9.3. RESULTS: Among 7094 adolescent smokers (5349 males and 1745 females), 19.9% of males and 25.1% of females reported as persistent smokers. Compared with light smokers, heavy smokers are more likely to be persistent smokers (male: odds ratio [OR] = 2.45, 95% confidence interval [CI] = 2.04-2.95, P value < .001; female: OR = 3.23, 95% CI = 2.44-4.27, P value < .001). When we stratified the data by household income, previous attempts to stop smoking, and previous education on smoking cessation, that trend remained statistically significant. CONCLUSIONS: Because heavier smokers with higher risk of health-related consequences were less sensitive to pricing policy than mild smokers, pricing policy alone is not enough to reduce the societal burden caused by smoking. We suggest that additional cessation policy is needed along with pricing policy for adolescents with heavier smoking behavior in Korea. IMPLICATION: This study shows that heavy smokers are more likely to be persistent smokers despite the cigarette price increase policy, compared with light smokers in Korean adolescents. Because heavier smokers were less sensitive to pricing policy than mild smokers, pricing policy alone is not enough to reduce the societal burden caused by smoking. We suggest that additional tobacco control policies should be evaluated and effective ones implemented in addition to cigarette prices to reduce smoking among regular adolescent smokers. PMID- 27117285 TI - Varenicline for Smoking Cessation in Light Smokers. AB - INTRODUCTION: As the prevalence of cigarette smoking has declined, the proportion of smokers who smoke less than 10 cigarettes/day (cpd) has increased. Varenicline may provide an effective pharmacotherapeutic treatment option for increasing smoking abstinence rates among light smokers. METHODS: We conducted a randomized, placebo-controlled clinical trial evaluating the efficacy of varenicline for increasing smoking abstinence rates among light smokers (5-10 cpd). Participants received varenicline or placebo for 12 weeks. Outcomes were assessed at 3 and 6 months. RESULTS: Ninety-three participants were randomized. Fifty-two percent of participants terminated the study early. At end-of-treatment (3 months), the point prevalence smoking abstinence rate was 53.3% in the varenicline group compared to 14.5% in placebo (odds ratio [OR]: 6.69, 95% confidence interval [CI]: 2.48-18.06, P < .001), and the prolonged smoking abstinence rate was 40.0% and 8.3%, respectively (OR: 7.33, 95% CI: 2.24-23.98, P = .001). At end-of-study (6 months), the point prevalence smoking abstinence rate was 40.0% in the varenicline group compared to 20.8% in placebo (OR: 2.53, 95% CI: 1.01-6.34, P = .047), and the prolonged smoking abstinence rate was 31.1% and 8.3%, respectively (OR: 4.97, 95% CI: 1.49-16.53, P = .009). The estimated magnitude of the treatment effect remained consistent across the various missing data assumptions and in analyses that adjusted for gender. Nausea and sleep disturbance were more commonly reported in the varenicline group. CONCLUSIONS: Varenicline was safe and effective for increasing long-term smoking abstinence rates in a population of predominantly White light cigarette smoker. The efficacy of varenicline in this study was comparable to that observed in heavier smokers. IMPLICATIONS: Our findings demonstrate that varenicline is effective for increasing smoking cessation in light smokers. Our findings have implications for advancing the treatment of light smokers in clinical practice. PMID- 27117287 TI - Steroid Induced Bilateral Avascular Necrosis of Head of Femur in an Adult Male Patient - A Case Report. AB - A 28 year old male patient, known case of pemphigus vulgaris was on dexamethasone pulse therapy. Total 7 pulses were given after that he developed avascular necrosis of head of femur on both sides, which was confirmed by digital X- ray and MRI. Avascular necrosis is a disabling and progressive condition in young patients gradually leads to femoral head collapse and eventual total hip arthroplasty. As per WHO-UMC causality assessment criteria, the association between reaction and drug was possible, Naranjo's score was 7. According to Modified Schumock and Thornton's criteria, this reaction was not preventable. The Modified Hartwig and Siegel's scale showed that the reaction was severe (level 6). Here we present a case where the use of steroid for pemphigus vulgaris resulting in the development of bilateral avascular necrosis of head of femur. PMID- 27117286 TI - The Ecdysone and Notch Pathways Synergistically Regulate Cut at the Dorsal Ventral Boundary in Drosophila Wing Discs. AB - Metazoan development requires coordination of signaling pathways to regulate patterns of gene expression. In Drosophila, the wing imaginal disc provides an excellent model for the study of how signaling pathways interact to regulate pattern formation. The determination of the dorsal-ventral (DV) boundary of the wing disc depends on the Notch pathway, which is activated along the DV boundary and induces the expression of the homeobox transcription factor, Cut. Here, we show that Broad (Br), a zinc-finger transcription factor, is also involved in regulating Cut expression in the DV boundary region. However, Br expression is not regulated by Notch signaling in wing discs, while ecdysone signaling is the upstream signal that induces Br for Cut upregulation. Also, we find that the ecdysone-Br cascade upregulates cut-lacZ expression, a reporter containing a 2.7 kb cut enhancer region, implying that ecdysone signaling, similar to Notch, regulates cut at the transcriptional level. Collectively, our findings reveal that the Notch and ecdysone signaling pathways synergistically regulate Cut expression for proper DV boundary formation in the wing disc. Additionally, we show br promotes Delta, a Notch ligand, near the DV boundary to suppress aberrant high Notch activity, indicating further interaction between the two pathways for DV patterning of the wing disc. PMID- 27117288 TI - Impairment of Lung Function During Adjuvant Oxaliplatin Treatment in Patients with Colorectal Cancer: A Prospective Trial. AB - BACKGROUND: Forty-seven cases (38 men and 9 women) of pulmonary toxicity caused by oxaliplatin have previously been published, but the issue has not been investigated in a prospective setting. Our purpose was to assess how oxaliplatin affects the pulmonary function in colorectal cancer patients during adjuvant treatment. MATERIAL AND METHODS: Forty patients (median age 57.5 years, range 33 74) radically resected for colorectal cancer, underwent three pulmonary function tests during post-surgery adjuvant treatment with oxaliplatin. RESULTS: Mean+/-sd haemoglobin corrected diffusion capacity (DLCOc) in the entire patient cohort were 7.65+/-2.24 at baseline, 7.11+/-2.11 during and 7.12+/-1.99 three months after oxaliplatin treatment (p=0.0002). The decrease was similar in men (n=22, p=0.02) and women (n=18, p=0.01), but most prominent in smokers (n=23, p=0.0005) and in patients exposed to occupational dust (n=21, p=0.0009). Besides a small decrease in the FEV1/FVC ratio (p=0.03), all other pulmonary parameters remained constant and no clinical signs of pulmonary failure were observed during the study period. CONCLUSION: A decline in DLCOc was detected in a majority of the examined patients, but none reported any clinical symptoms of pulmonary distress. The subtle decrease in DLCOc does not appear to be an isolated predictor of PT. Our data suggest that smoking and dust exposure might aggravate the effect of oxaliplatin on DLCOc. Routine pulmonary function test in patients treated with oxaliplatin is not recommended, but it is important to be aware of the early signs of pulmonary toxicity. PMID- 27117289 TI - A Case Report of Antitubercular Drugs Induced Exanthematous Reaction Complicated by Acute Onset Levofloxacin Induced Toxic Epidermal Necrolysis (TEN). AB - BACKGROUND: We report a case of 25 years old male patient with antitubercular drugs induced exanthematous reaction and hepatotoxicity that was complicated by levofloxacin induced toxic epidermal necrolysis. The patient was allergic to ciprofloxacin and ofloxacin. Cross reactivity between ciprofloxacin and levofloxacin might be responsible for causing this reaction. CONCLUSION: Issues of cross sensitivity should be kept in mind and the same class of drugs should strictly be avoided to prevent such complications. PMID- 27117290 TI - Health effects of non-occupational exposure to oil extraction. AB - Oil extraction may cause extensive environmental impact that can affect health of populations living in surrounding areas. Large populations are potentially exposed to oil extraction related contamination through residence in areas where oil extraction is conducted, especially in low and middle income countries (LMICs). Health effects among people residentially exposed to upstream oil industry contaminants have been poorly studied. Health effects of exposure to oil related contamination have been mainly studied among cleanup workers after oil spills from tankers or offshore platforms.In this paper we aim to identify the type and extension of residential exposures related to oil extraction activities and to comment on the few health studies available. We estimated that 638 million persons in LMICs inhabit rural areas close to conventional oil reservoirs. It is relevant to specifically study people residentially exposed to upstream oil industry for the following reasons: First, persons are exposed during long periods of time to oil related contamination. Second, routes of exposure differ between workers and people living close to oil fields, who can be exposed by ingestion of contaminated waters/foods and by dermal contact with contaminated water and/or land during daily activities (e.g. bathing, agricultural activities, etc.). Third, individuals potentially more susceptible to the effect of oil related contamination and not normally occupationally exposed, such as infants, children, pregnant women, elderly or people with previous health conditions, are also exposed.There are few papers studying the potential health effects of residential exposure to oil related contamination, and most of them share important limitations. There is a need for more research through the conduct of methodologically robust studies in exposed populations worldwide. Despite the difficulties in the conduct of studies in remote areas, novel approaches, such as measurement of individual exposure using biomarkers of exposure and effect, should be used. These studies should be promoted to understand the health risks associated to residential exposure to oil related contamination, support effective control policies to avoid such contamination and to sustain public health recommendations and policies to avoid exposure in already contaminated areas. PMID- 27117291 TI - Biorefinery approach for cassava-based industrial wastes: Current status and opportunities. AB - Cassava, an important food crop, has been extensively employed as raw materials for various agri-industries to produce starch, bioethanol and other biobased products/chemicals. These cassava-based industries also generate large quantities of wastes/residues, rich in organic matter and suspended solids, and pose significant environmental issues. Their complex biochemical composition with high organic content endows them with a great potential for bioconversion into value added products via biorefinery thereby providing economic and environmental sustainability to cassava industries. This state-of-the-art review covers the source, composition and characteristics of cassava industrial wastes and residues, and their bioconversion into value-added products, mainly biofuels (ethanol and butanol), biogas, biosurfactant, organic acids and other valuable biochemicals among others. This paper also outlines future perspectives with respect to developing more effective and efficient bioconversion processes for converting the cassava wastes and residues into high-value products. PMID- 27117292 TI - The radiodensity of cerebrospinal fluid and vitreous humor as indicator of the time since death. AB - PURPOSE: After death, a series of changes occur naturally in the human body in a fairly regular pattern. These postmortem changes are detectable on postmortem CT scans (PMCT) and may be useful in estimating the postmortem interval (PMI). The purpose of our study is to correlate the PMCT radiodensities of the cerebrospinal fluid (CSF) and vitreous humor (VH) to the PMI. METHODS: Three patient groups were included: group A consisted of 5 donated cadavers, group B, 100 in-hospital deceased patients, and group C, 12 out-of-hospital forensic cadavers. Group A were scanned every hour for a maximum of 36 h postmortem, and the tympanic temperature was measured prior to each scan. Groups B and C were scanned once after death (PMI range 0.2-63.8 h). Radiodensities of the VH and CSF were measured in Hounsfield units. Correlation between density and PMI was determined using linear regression and the influence of temperature was assessed by a multivariate regression model. Results from group A were validated in groups B and C. RESULTS: Group A showed increasing radiodensity of the CSF and VH over time (r (2) CSF, 0.65). PMI overruled the influence of temperature (r = 0.99 and p = 0.000). Groups B and C showed more diversity, with CSF and VH radiodensities below the mean regression line of Group A. The formula of this upper limit indicated the maximum PMI and was correct for >95 % of the cadavers. CONCLUSION: The results of group A showed a significant correlation between CSF radiodensity and PMI. The radiodensities in groups B and C were higher than in group A, therefore the maximum PMI can be estimated with the upper 95 % confidence interval of the correlation line of group A. PMID- 27117293 TI - Should patients with risk factors be tested for hypersensitivity to contrast media: a prospective study. AB - BACKGROUND: Previous hypersensitivity reactions to contrast media (CM), atopy, atopic disease, drug allergy, and age (20-29 or >55) are risk factors for CM hypersensitivity reactions. Our aim was to evaluate whether these risk factors should prompt skin testing for diagnosing CM allergy. METHODS: The study was conducted among patients referred for allergy testing with CM. Skin tests were performed with non ionic or gadolinium CM, recommended by a radiologist. After completion of tests patients were telephonically queried on their symptoms of reactions. RESULTS: 151 risk patients (53 men, 98 women; mean age 55.2) were included in the study. Only 13 (9 %) had a history of hypersensitivity reaction to CM. Compared with the other patients, atopy was significantly more common in patients with a history of CM hypersensitivity reactions. Female gender and mean age were also higher, but not significant. All of the tests with CMs were negative. Only one patient reported urticaria within 1-2 min after administration of CM (telephonically). CONCLUSIONS: Atopy can increase the risk of CM allergy. However, skin tests with CMs may be inefficient, unnecessary, and time-consuming, except in cases with a history of CM allergy. Premedication protocols appear to be beneficial in patients with a history of CM allergy and cannot be recommended for patients with well-controlled asthma, rhinitis, atopic dermatitis or history of drug allergy. PMID- 27117294 TI - Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency. AB - Deficiency of the mitochondrial trifunctional protein (TFP) and long-chain 3 Hydroxy Acyl-CoA dehydrogenase (LCHAD) impairs long-chain fatty acid oxidation and presents with hypoglycemia, cardiac, liver, eye, and muscle involvement. Without treatment, both conditions can be life-threatening. These diseases are identified by newborn screening (NBS), but the impact of early treatment on long term clinical outcome is unknown. Moreover, there is lack of consensus on treatment, particularly on the use of carnitine supplementation. Here, we report clinical and biochemical data in five patients with TFP/LCHAD deficiency, three of whom were diagnosed by newborn screening. All patients had signs and symptoms related to their metabolic disorder, including hypoglycemia, elevated creatine kinase (CK), and rhabdomyolysis, and experienced episodes of metabolic decompensation triggered by illness. Treatment was started shortly after diagnosis in all patients and consisted of a diet low in long-chain fats supplemented with medium chain triglycerides (MCT), essential fatty acids, and low-dose carnitine (25 mg/kg/day). Patients had growth restriction early in life that resolved after 2 years of age. All patients but the youngest (2 years old) developed pigmentary retinopathy. Long-chain hydroxylated acylcarnitines did not change significantly with age, but increased during acute illnesses. Free carnitine levels were maintained within the normal range and did not correlate with long-chain hydroxylated acylcarnitines. These results show that patients with LCHAD deficiency can have normal growth and development with appropriate treatment. Low-dose carnitine supplements prevented carnitine deficiency and did not result in increased long-chain hydroxylated acylcarnitines or any specific toxicity. PMID- 27117295 TI - Acute Metabolic Crises in Maple Syrup Urine Disease After Liver Transplantation from a Related Heterozygous Living Donor. AB - Maple syrup urine disease (MSUD) is an autosomal recessive disorder associated with impaired metabolism of branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Children with MSUD suffer from bouts of metabolic decompensation, which may lead to neurological damage. Liver transplantation from unrelated deceased donors has been considered curative. The natural history of the disease following transplantation using a haploidentical (obligate heterozygous) living donor is still unclear, although previously described as favorable. We describe acute metabolic crises in a 20-month-old child with MSUD type II. The first well-documented one occurred 5 months after a successful liver transplantation from his mother. The patient developed encephalopathy with progressive lethargy and seizures after an episode of gastroenteritis with dehydration. Plasma levels of leucine, isoleucine, and valine were markedly elevated and alloisoleucine was detected. He promptly responded to dialysis and BCAA-free dietetic management and subsequently could resume a normal diet. Since then he has had another symptomatic metabolic crisis with seizures. This case strongly suggests that some recipients of liver transplantation from a haploidentical parent possess limited capacity to oxidize BCAA at the time of catabolic stress and dehydration and remain at risk of severe metabolic crises. Thus, careful metabolic monitoring and prompt treatment post liver transplantation are still required to avoid neurological sequelae of MSUD, particularly if the donor is heterozygous for MSUD. PMID- 27117296 TI - Phenylobacterium panacis sp. nov., isolated from the rhizosphere of rusty mountain ginseng. AB - A novel, Gram-stain-negative, rod-shaped bacterial strain, designated as DCY109T, was isolated from the rhizosphere of rusty mountain ginseng root located on Hwacheon mountain of Gangwon province, South Korea. 16S rRNA gene sequence analysis revealed that strain DCY109T belonged to the genus Phenylobacterium and was related closely to Phenylobacterium muchangponense KACC 15042T (98.2 % similarity), Phenylobacterium immobile DSM 1986T (96.9 %) and Phenylobacterium koreense KCTC 12206T (96.7 %). The predominant isoprenoid quinone was ubiquinone (Q-10) and the DNA G+C content was 66.9 mol%. The major polar lipids were phosphatidylglycerol, an unidentified glycolipid and an unidentified lipid. The major fatty acids (>10 %) were C16 : 0, summed feature 3 (which comprised C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (which comprised C18 : 1omega7c and/or C18 : 1omega6c). Mean DNA-DNA relatedness between strain DCY109T and its closest relative, P. muchangponense KACC 15042T, was 15.1+/-3.9 %. Based on the physiological, biochemical, chemotaxonomic and genetic analyses, strain DCY109T is considered to represent a novel species of the genus Phenylobacterium, for which the name Phenylobacterium panacis sp. nov. is proposed. The type strain is DCY109T (=KCTC 42749T=JCM 31045T). PMID- 27117298 TI - Focus on Japan: Challenges for women in health science academic positions. PMID- 27117297 TI - Painful and swollen hands 3 months after lungs graft: Suracute voriconazole induced periostitis and exostosis. PMID- 27117299 TI - Commentary on Tan MF et al. "Nursing management of aggression in a Singapore emergency department: A qualitative study". Nursing and Health Sciences. 2015; 17: 307-312. PMID- 27117300 TI - Diagnostic imaging in spontaneous rupture of a thoracic duct cyst in the mediastinum. AB - Thoracic duct cysts in the mediastinum are extremely rare; they can give rise to chylothorax when they spontaneously rupture or after they are operated on. We present the case of an adult woman with a thoracic duct cyst in the mediastinum and chylothorax from its spontaneous rupture; to our knowledge, this phenomenon has not been specifically reported before. We describe the clinical and radiological findings, the therapeutic management, and the pathology findings, reviewing the literature for this entity. PMID- 27117301 TI - Expression of interferon-inducible transmembrane proteins in the chicken and possible role in prevention of viral infections. AB - In mammals, interferon-inducible transmembrane proteins (IFITMs) prevent infections by various enveloped viruses. The expression of IFITMs in chicken was herein examined in the adult and embryonic organs using a quantitative reverse transcription-polymerase chain reaction. The results obtained revealed that IFITM3 was expressed at a higher level than IFITM1, 2 and 5, in both embryonic and adult organs. However, the expression levels of IFITMs in embryonic organs were less than 5 % of those in adult lungs. Among the embryonic tissues examined, primordial germ cells (PGCs) at day 2.5 expressed relatively higher levels of IFITM3. IFITM3 expression levels were 1.5-fold higher in the chicken cell line DF 1 than in PGCs. The knockdown of IFITM3 in DF-1 cells by siRNA increased the infectivity of a vesicular stomatitis virus G protein-pseudotyped lentiviral vector, suggesting that lower levels of IFITM3 are still sufficient to restrict this viral vector. PMID- 27117302 TI - Location estimation of approaching objects is modulated by the observer's inherent and momentary action capabilities. AB - Action capability may be one of the factors that can influence our percept of the world. A distinction can be made between momentary action capability (action capability at that particular moment) and inherent action capability (representing a stable action capability). In the current study, we investigated whether there was a biasing effect of these two forms of action capability on visual perception of location. In a virtual reality room, subjects had to stop a moving ball from hitting a pillar. On some trials, the ball disappeared automatically during its motion. Subjects had to estimate the location of the ball's disappearance in these trials. We expected that if action is necessary but action capability (inherent or momentary) is limiting performance, the location of approaching objects with respect to the observer is underestimated. By judging the objects to be nearer than they really are, the need to select and execute the appropriate action increases, thereby facilitating quick action (Cole et al. in Psychol Sci 24(1):34-40, 2013. doi: 10.1177/0956797612446953 ). As a manipulation of inherent action capability in a virtual environment, two groups of participants (video game players vs. non-video game players) were entered into the study (high and low action capability). Momentary action capability was manipulated by using two difficulty levels in the experiment (Easy vs. Difficult). Results indicated that inherent and momentary action capabilities interacted together to influence online location judgments: Non-players underestimated locations when the task was Difficult. Taken together, our data suggest that both inherent and momentary action capabilities influence location judgments. PMID- 27117303 TI - Intraoperative imaging to detect coronary stenosis in no-angiography patients. AB - Sometimes, patients scheduled for cardiac operations other than coronary artery bypass may be unsuitable for preoperative coronary angiography. We routinely use intraoperative high-resolution epicardial ultrasound to select the proper target for the graft and to check graft anastomosis integrity. We describe 3 patients who could not undergo preoperative coronary angiography for different reasons. In all cases, we discovered significant stenosis in the left anterior descending coronary artery, which required bypass grafting. Intraoperative verification by transit-time flow measurements confirmed the significant stenosis detected by imaging. PMID- 27117304 TI - Abstracts of the 50th Annual Scientific Meeting of the European Society for Clinical Investigation Paris, France, 27 - 29 April 2016. PMID- 27117305 TI - Cognitively Stimulating Leisure Activity and Subsequent Cognitive Function: A SHARE-based Analysis. AB - Purpose of the Study: The aim of the inquiry was to examine whether cognitively stimulating leisure activity (CSLA) can delay or reduce cognitive decline in late life and whether its effect is moderated by education, age, or activity pattern. Design and Methods: Employing secondary analysis of data on respondents aged 65 and older from the 4th and 5th waves of the Survey of Health, Ageing and Retirement in Europe (N = 16,572), the inquiry regressed cognitive function (memory, numeracy, and fluency) at Time 2 on frequency of engagement in CSLA at baseline, controlling for cognitive function scores at baseline and a range of confounders. The study also considered education by CSLA and age by CSLA interactions, as well as the effect of CSLA patterns. Results: CSLA frequency was found to be positively related to subsequent cognitive functioning on all measures, 2 years later. The effect of CSLA on memory and fluency was stronger among those with lower education, whereas the age by CSLA interaction was not significant. Respondents who started CSLA after baseline showed better cognitive functioning at Time 2 than those who did not engage in CSLA at all and those who had engaged in such activity at baseline but stopped. Implications: The study documents that CSLAs constitute a potential source for the delay or reduction of cognitive decline, regardless of one's age. As such, practitioners should recognize the value of this medium and encourage its greater use in appropriate settings. PMID- 27117306 TI - [Male osteoporosis]. AB - BACKGROUND: Osteoporosis in men is an important public health problem with more than 1 million cases in Germany. Although osteoporotic fractures have a much higher mortality in men than in women, male patients are still underdiagnosed and undertreated. OBJECTIVE: Epidemiology of male osteoporosis and current treatment situation, pathophysiological aspects at the hormonal level, risk factors, diagnostic work-up and therapeutic options. MATERIAL AND METHODS: Overview of data concerning male osteoporosis, recommendations for diagnostic work-up and presentation of the study situation on pharmaceutical therapies. RESULTS: As risk factors for osteoporosis are present in 50-70 % of male patients, a detailed patient history is necessary for assessment of the risk factors. Radiological imaging of the spine is primarily recommended to identify individuals with prevalent vertebral fractures, as approximately 10 % of males above the age of 50 years have suffered a vertebral fracture. Laboratory testing of relevant parameters helps to rule out other metabolic bone diseases. In Germany, specific medications available for the treatment of male osteoporosis comprise the active vitamin D analogue alfacalcidol, the oral bisphosphonates alendronate and risedronate, the intravenous biphosphonate zoledronic acid, the anti- receptor activator of NF-kappaB ligand (RANKL) antibody denosumab, which can be given as intravenous injection and strontium ranelate, a drug with a complex mode of action. Teriparatide, a recombinant form of the 34 N-terminal amino acid sequence of parathyroid hormone is the only anabolic agent approved for male osteoporosis. CONCLUSION: Osteoporosis in men is increasingly being recognized as an important public health problem and affected patients need to be adequately diagnosed and treated. Nowadays, a broad spectrum of well-proven therapeutic options with different modes of action allow individual treatment strategies for male osteoporosis patients. PMID- 27117307 TI - Prevalence of chronic kidney disease risk factors among low birth weight adolescents. AB - BACKGROUND: By adulthood, low birth weight infants have an increased risk for chronic kidney disease (CKD). The extent to which objective CKD risk factors are present at earlier ages is unclear. METHODS: We analyzed 5352 participants aged 12-15 years in the National Health and Nutrition Examination Survey, 1999-2012. Participants were classified as low birth weight (LBW; < 2500 g), very low birth weight (VLBW; < 1500 g), or normal (2500-4000 g) by parental/proxy recall. Albuminuria (albumin/creatinine 30 - <300 mg/g), decreased estimated glomerular filtration rate (eGFR; < 90 ml/min/1.73 m(2); Counahan-Barratt), and elevated systolic blood pressure (BP; >= 95th percentile for age, height, and sex) were considered CKD risk factors. RESULTS: While albuminuria did not vary by birth weight, elevated blood pressure (BP) and decreased eGFR occurred more frequently in LBW/VLBW adolescents (elevated BP: LBW 6.0 %, VLBW 11.2 %, normal 2.4 %; decreased eGFR: LBW 23.2 %, VLBW 32.5 %, normal 16.1 %). After multivariable adjustment, LBW/VLBW adolescents had greater odds for both elevated BP (LBW: OR 2.90, 95 % CI 1.48-5.71; VLBW: 5.23; 1.11-24.74) and decreased eGFR (LBW: 1.49, 95 % CI 1.06-2.10; VLBW 2.49, 95 % CI 1.20-5.18). CONCLUSIONS: In the U.S. population, both decreased eGFR and elevated systolic BP occur frequently among adolescents with history of LBW/VLBW. PMID- 27117308 TI - Safety and comfort of long-term continuous combined transdermal estrogen and intrauterine levonorgestrel administration for postmenopausal hormone substitution - a review. AB - OBJECTIVE: To review the endometrial safety and patient acceptability of long term use of continuous transdermal estrogen substitution combined with intrauterine release of levonorgestrel (LNG) in postmenopausal women. DESIGN: One hundred and fifty-three women who utilized the regimen for 2 IUD cycles were followed-up for a period of 10 years. Histology of the endometrium was evaluated at the end of this period to assess endometrial safety and the acceptability of the method was assessed based on the replacement rate of the LNG-IUS and continuation of ET. RESULTS: The regimen, administered over a 10-year period, was very well tolerated and the IUD was retained well and no expulsions occurred. The dominant endometrial histologic picture was that of inactive endometrium characterized by glandular atrophy and stroma decidualization (Kurman classification 5b). No cases of endometrial hyperplasia were found. CONCLUSION: The low systemic absorption of LNG could be desirable, thus allowing for maximization of the beneficial effects of ET on organ tissues (e.g. cardiovascular tissues and breast). Repeat LNG-IUS is associated with high patient satisfaction. If started before the age of 60, this regimen could be advised for lifelong prevention of cardiovascular disease and other prevention measures. The LNG-IUS was shown to effectively oppose the secondary effects of systemic estrogen on the endometrium tissue resulting in strong suppression during the entire period of EPT. PMID- 27117309 TI - Protein-protein interaction inference based on semantic similarity of Gene Ontology terms. AB - Identifying protein-protein interactions is important in molecular biology. Experimental methods to this issue have their limitations, and computational approaches have attracted more and more attentions from the biological community. The semantic similarity derived from the Gene Ontology (GO) annotation has been regarded as one of the most powerful indicators for protein interaction. However, conventional methods based on GO similarity fail to take advantage of the specificity of GO terms in the ontology graph. We proposed a GO-based method to predict protein-protein interaction by integrating different kinds of similarity measures derived from the intrinsic structure of GO graph. We extended five existing methods to derive the semantic similarity measures from the descending part of two GO terms in the GO graph, then adopted a feature integration strategy to combines both the ascending and the descending similarity scores derived from the three sub-ontologies to construct various kinds of features to characterize each protein pair. Support vector machines (SVM) were employed as discriminate classifiers, and five-fold cross validation experiments were conducted on both human and yeast protein-protein interaction datasets to evaluate the performance of different kinds of integrated features, the experimental results suggest the best performance of the feature that combines information from both the ascending and the descending parts of the three ontologies. Our method is appealing for effective prediction of protein-protein interaction. PMID- 27117310 TI - Otis Brawley-one of the first to question the value of screening. PMID- 27117311 TI - Food allergy needs assessment, training curriculum, and knowledge assessment for child care. AB - BACKGROUND: More than half of preschool-aged children are enrolled in child care in the United States. Roughly 8% of children between 3 and 5 years of age have a food allergy. Child care center workers (CCCWs) are important caregivers who frequently encounter food allergies, but little is known about their education and understanding of food allergy and anaphylaxis. OBJECTIVE: To perform a food allergy and anaphylaxis educational needs assessment, provide a training curriculum for CCCWs, and assess the effectiveness of the training curriculum. METHODS: An online educational needs assessment and live training curriculum addressing food allergy recognition, treatment, and food labeling with pretests and posttests were created, and content and face validity were obtained. A needs assessment survey was sent to centers in Dallas and Tarrant counties. The training curriculum was performed at continuing education conferences. RESULTS: Seventy-three workers responded to the needs assessment, with 46% reporting prior food allergy training. They reported information sources as parents (73%), self (54%), educational curricula (21%), and conferences (19%). Most believed they have a high or moderately high proficiency in food allergy management. Forty-five workers participated in the training curriculum. Total scores improved from 54% correct on the pretest to 83% correct on the posttest (P < .001). Categorical subanalysis reveals similar results, with statistically significant improvement in all areas. CONCLUSION: CCCWs have diverse educational backgrounds and infrequently experience standardized training about food allergies. There is a significant lack of knowledge regarding food allergies and anaphylaxis. The curriculum was successful at increasing food allergy knowledge among CCCWs. PMID- 27117313 TI - In-plane trapping and manipulation of ZnO nanowires by a hybrid plasmonic field. AB - In general, when a semiconductor nanowire is trapped by conventional laser beam tweezers, it tends to be aligned with the trapping beam axis rather than confined in the horizontal plane, and this limits the application of these nanowires in many in-plane nanoscale optoelectronic devices. In this work, we achieve the in plane trapping and manipulation of a single ZnO nanowire by a hybrid plasmonic tweezer system on a flat metal surface. The gap between the nanowire and the metallic substrate leads to an enhanced gradient force caused by deep subwavelength optical energy confinement. As a result, the nanowire can be securely trapped in-plane at the center of the excited surface plasmon polariton field, and can also be dynamically moved and rotated by varying the position and polarization direction of the incident laser beam, which cannot be performed using conventional optical tweezers. The theoretical results show that the focused plasmonic field induces a strong in-plane trapping force and a high rotational torque on the nanowire, while the focused optical field produces a vertical trapping force to produce the upright alignment of the nanowire; this is in good agreement with the experimental results. Finally, some typical ZnO nanowire structures are built based on this technique, which thus further confirms the potential of this method for precise manipulation of components during the production of nanoelectronic and nanophotonic devices. PMID- 27117312 TI - Effect of treatment with geraniol on ovalbumin-induced allergic asthma in mice. AB - BACKGROUND: Asthma, a complex highly prevalent airway disease, is a major public health problem for which current treatment options are inadequate. OBJECTIVE: To evaluate the antiasthma activity of geraniol and investigate its underlying molecular mechanisms. METHODS: In a standard experimental asthma model, Balb/c mice were sensitized with ovalbumin, treated with geraniol (100 or 200 mg/kg) or a vehicle control, during ovalbumin challenge. RESULTS: Treatment of ovalbumin sensitized/challenged mice with geraniol significantly decreased airway hyperresponsiveness to inhaled methacholine. Geraniol treatment reduced eotaxin levels in bronchoalveolar lavage fluid and attenuated infiltration of eosinophils induced by ovalbumin. Geraniol treatment reduced TH2 cytokines (including interleukins 4, 5, and 13), increased TH1 cytokine interferon gamma in bronchoalveolar lavage fluid, and reduced ovalbumin-specific IgE in serum. In addition, treatment of ovalbumin-sensitized/challenged mice with geraniol enhanced T-bet (TH1 response) messenger RNA expression and reduced GATA-3 (TH2 response) messenger RNA expression in lungs. Furthermore, treatment of ovalbumin sensitized/challenged mice with geraniol further enhanced Nrf2 protein expression and activated Nrf2-directed antioxidant pathways, such as glutamate-cysteine ligase, superoxide dismutase, and glutathione S-transferase, and enhanced formation of reduced glutathione and reduced formation of malondialdehyde in lungs. CONCLUSION: Geraniol attenuated important features of allergic asthma in mice, possibly through the modulation of TH1/TH2 balance and activation the of Nrf2/antioxidant response element pathway. PMID- 27117314 TI - Home and health among different sub-groups of the ageing population: a comparison of two cohorts living in ordinary housing in Sweden. AB - BACKGROUND: At present a majority of older people remain in their ordinary homes. Research has generated knowledge about home and health dynamics and increased the awareness of the complexity of housing as related to ageing. As this knowledge is based mainly on research on very old, single-living people in ordinary housing there is a need to study other sub-groups of the ageing population. Thus, the aim of the present descriptive study was to compare a younger old cohort with a very old cohort living in ordinary housing in Sweden in order to shed new light on home and health dynamics in different sub-groups of the ageing population. METHODS: Cross-sectional study of two population-based cohorts: one aged 67-70 years (n = 371) and one aged 79-89 years (n = 397) drawn from existing Swedish databases. Structured interviews and observations were conducted to collect data about socio-demographics, aspects of home, and symptoms. Besides descriptive statistics we computed tests of differences using the Chi-squared test and Mann Whitney U-test. RESULTS: Accessibility was significantly lower in the very old cohort compared to the younger old cohort even though the former were objectively assessed to have fewer environmental barriers. Those in the very old cohort perceived aspects of their housing situation as worse and were more dependent on external influences managing their housing situation. Although a larger proportion of the very old cohort had more functional limitations 22% were independent in ADL. In the younger old cohort 17% were dependent in ADL. CONCLUSIONS: Keeping in mind that there were cohort differences beyond that of age, despite fewer environmental barriers in their dwellings the very old community-living cohort lived in housing with more accessibility problems compared to those of the younger old cohort, caused by their higher prevalence of functional limitations. Those in the very old cohort perceived themselves in a less favourable situation, but still as satisfied with housing as those in the younger old cohort. This kind of knowledge is indicative for prevention and intervention in health care and social services as well as for housing provision and societal planning. Further studies based on truly comparable cohorts are warranted. PMID- 27117315 TI - Effectiveness of the Polish program for the treatment of severe allergic asthma with omalizumab: a single-center experience. AB - BACKGROUND: A national program for the treatment of severe allergic (IgE dependent) asthma with omalizumab (OMA) was implemented in Poland in 2013. This observational study evaluated the effectiveness of the Polish OMA program and monitored asthma control after treatment discontinuation. METHODS: In the first year of the program, 53 patients (23 new/30 continuing treatment) received OMA in the Barlicki Hospital, Poland. Patients were evaluated at baseline and after 16 weeks of OMA treatment by spirometry, mean dose of inhaled corticosteroids (ICS) and oral corticosteroids (OCS), number of asthma exacerbations, the Asthma Control Questionnaire (ACQ), and the Asthma Quality of Life Questionnaire (AQLQ). OMA treatment responses were determined using the global effectiveness of treatment evaluation scale. Fourteen patients ceased OMA treatment following >=36 months of therapy and entered follow up. RESULTS: All patients treated with OMA de novo for at least 16 weeks had a decrease in asthma exacerbations and showed a good (15/16, 94 %) or an excellent (1/16, 6 %) response to treatment. We observed a reduction in OCS dose (>=5 mg/day) in 14/16 (88 %) patients. ACQ and AQLQ scores improved by >=0.5 points in 15/16 (94 %) and 14/16 (88 %) patients, respectively. After OMA cessation, 11/14 (79 %) patients showed worsening of asthma control and severe exacerbations. CONCLUSIONS: Patients in the OMA program show significant benefits, including reduced use of OCS, improved asthma control and quality of life. After OMA discontinuation, frequent severe exacerbations were observed primarily in patients whose asthma was previously uncontrolled by high OCS doses. PMID- 27117317 TI - Opportunistic diseases among HIV-infected patients: a multicenter-nationwide Korean HIV/AIDS cohort study, 2006 to 2013. AB - BACKGROUND/AIMS: The frequencies of opportunistic diseases (ODs) vary across countries based on genetic, environmental, and social differences. The Korean HIV/AIDS cohort study was initiated in 2006 to promote research on human immunodeficiency virus (HIV) infection in Korea, and to provide a logistical network to support multicenter projects on epidemiological, clinical, and laboratory aspects of HIV infection. This study evaluated the prevalence of ODs among HIV-infected patients in the era of highly active antiretroviral therapy, and the risk factors associated with ODs. METHODS: The study enrolled 1,086 HIV infected patients from 19 hospitals. This study examined the baseline data of the HIV/AIDS Korean cohort study at the time of enrollment from December 2006 to July 2013. RESULTS: Candidiasis was the most prevalent opportunistic infection (n = 176, 16.2%), followed by Mycobacterium tuberculosis infection (n = 120, 10.9%), Pneumocystis jirovecii pneumonia (n = 121, 11.0%), cytomegalovirus infection (n = 52, 4.7%), and herpes zoster (n = 44, 4.0%). The prevalence rates of Kaposi's sarcoma (n = 8, 0.7%) and toxoplasmosis (n = 4, 0.4%) were very low compared with other countries. The risk factors for ODs were a low CD4 T cell count at the time of HIV diagnosis (odds ratio [OR], 1.01; p < 0.01), current smoking (OR, 2.27; p = 0.01), current alcohol use (OR, 2.57; p = 0.04), and a history of tuberculosis (OR, 5.23; p < 0.01). CONCLUSIONS: Using recent Korean nationwide data, this study demonstrated that an important predictor of ODs was a low CD4 T cell count at the time of HIV diagnosis. Tuberculosis remains one of the most important ODs in HIV-infected patients in Korea. PMID- 27117316 TI - Vitamin D and its effects on cardiovascular diseases: a comprehensive review. AB - Vitamin D is a molecule that is actively involved in multiple metabolic pathways. It is mostly known for its implications related to calcium metabolism. It has also been determined that it actively participates in the cardiovascular system, influencing blood pressure, coronary artery disease and other vascular diseases, such as heart failure and atrial fibrillation. Furthermore, it has been established that this vitamin is extensively involved in the regulation of both the renin angiotensin aldosterone system and the immune system. In this review, we present the different vitamin D metabolic pathways associated with the cardiovascular pathophysiology, and we include studies in animal and human models, as well as some of the controversies found in the literature. This review also incorporates an overview of the implications in the molecular biology and public health fields. PMID- 27117318 TI - Incidence and risk factors of hepatitis C virus infection among human immunodeficiency virus (HIV) patients in a large HIV clinic in South Korea. AB - BACKGROUND/AIMS: Increasing incidences of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected men who have sex were reported in the United States and Europe. However, few studies regarding the epidemiology of HCV infection in HIV-infected patients in Asian countries have been reported. METHODS: To determine the prevalence and incidence of HCV infection in HIV infected patients, a retrospective cohort study was conducted. All HIV-infected patients who visited a tertiary care hospital in Korea from 2000 to 2013 were identified. Patients with >= 1 HCV antibody (Ab) test were included and observed until December 2014. RESULTS: Among 996 HIV-infected patients, 790 patients (79%) had baseline HCV Ab tests and 41 (5.2%) were positive at baseline and four at follow-up. Experience of injecting drug use (IDU; adjusted odds ratio, 16.20; 95% confidence interval [CI], 1.56 to 167.89; p < 0.01) was significantly associated with prevalent HCV infection. Conversion to HCV Ab positivity was observed in four of 384 included patients, with an incidence rate of 2.22 (95% CI, 0.60 to 5.80)/1,000 person-years (PYs); 164.89 (95% CI, 34.00 to 481.88)/1,000 PYs in patients with IDU, and 1.40 (95% CI, 0.35 to 7.79)/1,000 PYs in men who have sex with men who denied IDU. There was no significant increase in incidence rate of HCV in HIV-infected patients from 2009 to 2014 (p = 0.119). Among 19 patients who were positive for HCV RNA, genotype 1b (73%) was the most common following 2a/2c (20%). CONCLUSIONS: IDU was an independent risk factor for prevalent HCV infection. Prevalence of HCV infection was low and incidence of HCV infection was not significantly increased in HIV-infected patients in South Korea. PMID- 27117319 TI - Combating radiation therapy-induced damage to the ovarian environment. PMID- 27117320 TI - Neck spasms: A late sequela of head and neck irradiation. PMID- 27117321 TI - Virulence and serological studies of recombinant infectious hematopoietic necrosis virus (IHNV) in rainbow trout. AB - Infectious hematopoietic necrosis virus is a highly contagious disease of juvenile salmonid species. From the IHNV HLJ-09 isolated in China, two recombinant viruses were generated by reverse genetics using the RNA polymerase II transcription system. The recombinant viruses were confirmed by RT-PCR, indirect immunofluorescence assay and electron microscopy. They were referred to as rIHNV HLJ-09 and rIHNV-EGFP. rIHNV HLJ-09 and rIHNV-EGFP could stably replicate in EPC cell lines and had the same cellular tropism as wtIHNV HLJ-09. But the titer of rIHNV-EGFP was significantly lower than rIHNV HLJ-09 and wtIHNV HLJ-09. rIHNV-EGFP strain could express EGFP stably at least in 20 passages, and the fluorescence could be observed clearly. To assess the virulence and pathogenicity of the recombinant viruses in vivo, juvenile rainbow trout were challenged by intraperitoneal injection with 20MUl of rIHNV HLJ-09, rIHNV-EGFP or wtIHNV HLJ-09 (1*10(6)pfuml(-1)). Fish challenged with rIHNV HLJ-09 and wtIHNV HLJ-09 exhibited clinical signs typical of IHN disease and both produced 90% cumulative percent mortality, whlie rIHNV-EGFP produced only 5%. Pathological sectioning results showed that the tissues (liver, kidney, heart muscle, back muscle) of the fish infected with rIHNV HLJ-09 exhibited pathological changes, with the exception of cerebral neurons and the cheek. However, no lesions of liver, kidney, heart, muscle, brain in rainbow trout of rIHNV-EGFP or the control group were observed. Indirect ELISA results showed that a high level of serum antibody was detected in the experimental fish challenged with rIHNV HLJ-09, just as the same as wtIHNV HLJ-09, while a lower titer was detecred in the fish infected with rIHNV-EGFP. This indicated that the recombinant viruses could induce humoral immune response in the experimental fish. The recombinant viruses had unique genetic tags and could be used for genetic engineering, laying new ground for further investigation of IHNV pathopoiesis molecular mechanism, host tropism and the development of novel vaccines against IHN. PMID- 27117322 TI - Dual infections of equine herpesvirus 1 and equine arteritis virus in equine respiratory mucosa explants. AB - Equine herpesvirus 1 (EHV-1) and equine arteritis virus (EAV) induce respiratory problems and abortion in horses and are considered as two serious threats to equine industry. Both EHV-1 and EAV misuse patrolling leukocytes in the upper respiratory tract to breach the basement membrane (BM) and to migrate to blood vessels. So far, the behavior and impact of a double infection in the respiratory mucosa of a horse are unknown. In the present study, the outcome of double infections with EHV-1 and the low virulent EAV strain 08P187 (superinfection with an interval of 12h or co-infection) were compared with single infections in fully susceptible RK-13 cells and equine upper respiratory mucosa explants. When RK-13 cells were inoculated with either EHV-1 or EAV 12h prior to the subsequent EAV or EHV-1 inoculation, the latter EAV or EHV-1 infection was clearly suppressed at 24hpi or 36hpi, respectively, without EHV-1 and EAV co-infecting the same RK-13 cells. After simultaneous infection with EHV-1 and EAV, higher numbers of EAV infected cells but similar numbers of EHV-1 infected cells were found compared to the single infections, with a low number of EHV-1 and EAV co-infected RK-13 cells at 48hpi and 72hpi. In the upper respiratory mucosa exposed to EAV 12h prior to EHV-1, the number and size of the EHV-1-induced plaques were similar to those of the EHV-1 single infected mucosa explants. In nasal and nasopharyngeal mucosae, EAV and EHV-1 pre-infections slightly reduced the number of EHV-1 and EAV infected leukocytes compared to the single infections and co-infection. In double EAV and EHV-1 infected explants, no co-infected leukocytes were detected. From these results, it can be concluded that EAV and EHV-1 are only slightly influencing each other's infection and that they do not infect the same mucosal leukocytes. PMID- 27117323 TI - Leakage of albumin in major abdominal surgery. AB - BACKGROUND: The time course of plasma albumin concentration (P-alb) and cumulative perioperative albumin shift as a measure of albumin extravasation in major abdominal surgery is not well described. Knowledge of these indices of the vascular barrier and vascular content are important for our understanding of fluid physiology during surgery and anesthesia. METHODS: Patients (n = 10) were studied during esophageal or pancreatic surgery. P-alb was repeatedly measured over 72 h, and the mass balance of albumin and hemoglobin were obtained from measures of P-alb, blood hemoglobin and hematocrit. RESULTS: P-alb decreased rapidly from baseline (32.8 +/- 4.8 g/L) until the start of surgical reconstruction (18.7 +/- 4.8 g/L; p < 0.001), and was thereafter stable until postoperative day 3. Cumulative perioperative albumin shift increased until 1 h after the end of surgery, when 24 +/- 17 g (p < 0.001) had been lost from the circulation. CONCLUSIONS: The rapid fall in P-alb of more than 40 % consistently occurred during the first part of the surgical procedure, but albumin leakage progressed until 1 h after the end of surgery. After the initial drop, P-alb was stable for 72 h. PMID- 27117325 TI - Assessment of oral mucosal lesions with autofluorescence imaging and reflectance spectroscopy. AB - BACKGROUND: The aim of this prospective study was to evaluate the efficacy of a new form of autofluorescence imaging and tissue reflectance spectroscopy (Identafi, DentalEZ) in examining patients with oral mucosal lesions. METHODS: The authors examined 88 patients with 231 oral mucosal lesions by conventional oral examination (COE) using white-light illumination and *2.5 magnification loupes, followed by examination using Identafi. The authors noted fluorescence visualization loss, the presence of blanching, and diffuseness of vasculature. They performed incisional biopsies to provide definitive histopathologic diagnosis. RESULTS: Identafi's white light produced lesion visibility and border distinctness equivalent to COE. Identafi's violet light displayed a sensitivity of 12.5% and specificity of 85.4% for detection of oral epithelial dysplasia (OED). The authors noted visible vasculature using the green-amber light in 40.9% of lesions. CONCLUSIONS: Identafi's intraoral white light provided detailed visualization of oral mucosal lesions comparable with examination using an extraoral white-light source with magnification. A high level of clinical experience is required to interpret the results of autofluorescence examination as the violet light displayed low sensitivity for detection of OED. The green amber light provided additional clinical information in relation to underlying vasculature and inflammation of lesions. PRACTICAL IMPLICATIONS: Examination using Identafi can provide clinicians with more clinical data than a standard COE with yellow incandescent light, but the clinical and optical findings should be interpreted as a whole and not in isolation. Clinicians should use the light features of Identafi in a sequential and differential manner. PMID- 27117324 TI - Exposure to extreme heat and precipitation events associated with increased risk of hospitalization for asthma in Maryland, U.S.A. AB - BACKGROUND: Several studies have investigated the association between asthma exacerbations and exposures to ambient temperature and precipitation. However, limited data exists regarding how extreme events, projected to grow in frequency, intensity, and duration in the future in response to our changing climate, will impact the risk of hospitalization for asthma. The objective of our study was to quantify the association between frequency of extreme heat and precipitation events and increased risk of hospitalization for asthma in Maryland between 2000 and 2012. METHODS: We used a time-stratified case-crossover design to examine the association between exposure to extreme heat and precipitation events and risk of hospitalization for asthma (ICD-9 code 493, n = 115,923). RESULTS: Occurrence of extreme heat events in Maryland increased the risk of same day hospitalization for asthma (lag 0) by 3 % (Odds Ratio (OR): 1.03, 95 % Confidence Interval (CI): 1.00, 1.07), with a considerably higher risk observed for extreme heat events that occur during summer months (OR: 1.23, 95 % CI: 1.15, 1.33). Likewise, summertime extreme precipitation events increased the risk of hospitalization for asthma by 11 % in Maryland (OR: 1.11, 95 % CI: 1.06, 1.17). Across age groups, increase in risk for asthma hospitalization from exposure to extreme heat event during the summer months was most pronounced among youth and adults, while those related to extreme precipitation event was highest among <=4 year olds. CONCLUSION: Exposure to extreme heat and extreme precipitation events, particularly during summertime, is associated with increased risk of hospitalization for asthma in Maryland. Our results suggest that projected increases in frequency of extreme heat and precipitation event will have significant impact on public health. PMID- 27117326 TI - Stigma, explanatory models and unmet needs of caregivers of children with developmental disorders in a low-income African country: a cross-sectional facility-based survey. AB - BACKGROUND: Understanding the perspectives of caregivers of children with developmental disorders living in low-income countries is important to inform intervention programmes. The purpose of this study was to examine the stigma experiences, explanatory models, unmet needs, preferred interventions and coping mechanisms of caregivers of children with developmental disorders in Ethiopia. METHODS: Participants comprised caregivers (n = 102) of children with developmental disorders attending two child mental health clinics in Addis Ababa. The majority (66.7%; n = 68) had a diagnosis of intellectual disability (ID); 34 children (33.3%) had autism spectrum disorder (ASD) as their primary diagnosis. All caregivers were administered a structured questionnaire via a face-to-face interview, which included an adaptation of the Family Interview Schedule, closed questions about socio-demographic characteristics, explanatory models of illness, type of interventions used or desired and coping strategies, and an open ended question regarding the family's unmet needs. RESULTS: Most caregivers reported experience of stigma: 43.1% worried about being treated differently, 45.1% felt ashamed about their child's condition and 26.7% made an effort to keep their child's condition secret. Stigma did not depend on the type of developmental disorder, the child's age or gender, or on the age or level of education of the caregiver (all p > 0.05). Reported stigma was significantly higher in caregivers who had sought traditional help (p < 0.01), provided supernatural explanations for their child's condition (p = .02) and in caregivers of Orthodox Christian faith (p = .03). Caregivers gave a mixture of biomedical explanations (e.g. head injury (30.4%) or birth complications (25.5%)) and supernatural explanations (e.g. spirit possession (40.2%) or sinful act (27.5%)) for their child's condition. The biggest reported unmet need was educational provision for their child (74.5%), followed by treatment by a health professional (47.1%), financial support (30.4%) and expert help to support their child's development (27.5%). Most caregivers reported that talking to health professionals (86.3%) and family (85.3%) helped them to cope. Many caregivers also used support from friends (76.5%) and prayer (57.8%) as coping mechanisms. CONCLUSIONS: This study highlights the stigma experienced by families caring for a child with a developmental disorder. Designing interventions appropriate for low-income settings that improve awareness about developmental disorders, decrease stigma, improve access to appropriate education and strengthen caregivers' support are needed. PMID- 27117327 TI - Absolute quantification of HTLV-1 basic leucine zipper factor (HBZ) protein and its plasma antibody in HTLV-1 infected individuals with different clinical status. AB - BACKGROUND: Human T cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), which is encoded by a minus strand mRNA, is thought to play important roles in the development of adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive analysis of HBZ, including mRNA and protein expression, humoral immunoreactivity against HBZ, and HTLV-1 proviral load (PVL), in HTLV-1-infected individuals with different clinical status has not been reported previously. RESULTS: In this study, using novel monoclonal antibody-based in-house enzyme linked immunosorbent assay systems, we report the absolute quantification of HBZ protein and its plasma antibody in clinical samples from HTLV-1-infected individuals with different clinical status. The data were compared to both HBZ mRNA levels and PVL. The results showed that plasma anti-HBZ antibody was detectable only in 10.4 % (5/48) of asymptomatic carriers (ACs), 10.8 % (13/120) of HAM/TSP patients, and 16.7 % (7/42) of ATL patients. HBZ protein was detected in three out of five patients with acute ATL, but was not detected in patients with HAM/TSP (0/10) or ACs (0/4). Thus, an antibody response to HBZ was not associated with the PVL or the expression of HBZ (both at the mRNA and protein levels) or the clinical status of the infection. CONCLUSIONS: The present results emphasize the extremely low expression and immunogenicity of HBZ in natural HTLV 1 infection. However, there is a possibility that the low but distinct expression of HBZ protein in PBMCs is associated with the survival of HTLV-1-infected cells and the development of ATL. PMID- 27117328 TI - The molecular clutch model for mechanotransduction evolves. AB - Many biological processes are influenced by the mechanical rigidity of surrounding tissues. Now, a combination of experiments and mathematical modelling has been used to describe the precise molecular and physical mechanism by which cells sense and respond to the mechanical properties of their extracellular environment through integrin-based adhesions. PMID- 27117329 TI - Directing lipid transport at membrane contact sites. AB - Contact sites between the endoplasmic reticulum and the plasma membrane mediate receptor signalling. How this function is controlled physically and functionally is poorly understood. Extended synaptotagmins are now shown to shuttle the lipid metabolite diacylglycerol from the plasma membrane to the endoplasmic reticulum in receptor-stimulated cells. PMID- 27117330 TI - Orchestrating Wnt signalling for metabolic liver zonation. AB - Wnt/beta-catenin signalling is an important regulator of liver development, zonation and regeneration. The cell surface complex RSPO-LGR4/5-ZNF3/RNF43 is now shown to direct Wnt/beta-catenin signalling in orchestrating the division of the liver into functionally distinct metabolic zones, providing insights into the mechanisms that influence organ development and regeneration. PMID- 27117331 TI - Fibroblasts form a hospitable metastatic niche in the liver. AB - The liver is the most common metastatic route of pancreatic cancer. Early recruitment of granulin-secreting inflammatory monocytes to the liver is now shown to reprogram hepatic stellate cells into myofibroblasts that modulate the liver microenvironment to support the growth of metastasizing tumour cells. PMID- 27117332 TI - Cyclic Opioid Peptides. AB - For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides. PMID- 27117333 TI - Integral Light-Harvesting Complex Expression In Symbiodinium Within The Coral Acropora aspera Under Thermal Stress. AB - Coral reef success is largely dependent on the symbiosis between coral hosts and dinoflagellate symbionts belonging to the genus Symbiodinium. Elevated temperatures can result in the expulsion of Symbiodinium or loss of their photosynthetic pigments and is known as coral bleaching. It has been postulated that the expression of light-harvesting protein complexes (LHCs), which bind chlorophylls (chl) and carotenoids, are important in photobleaching. This study explored the effect a sixteen-day thermal stress (increasing daily from 25-34 degrees C) on integral LHC (chlorophyll a-chlorophyll c2-peridinin protein complex (acpPC)) gene expression in Symbiodinium within the coral Acropora aspera. Thermal stress leads to a decrease in Symbiodinium photosynthetic efficiency by day eight, while symbiont density was significantly lower on day sixteen. Over this time period, the gene expression of five Symbiodinium acpPC genes was quantified. Three acpPC genes exhibited up-regulated expression when corals were exposed to temperatures above 31.5 degrees C (acpPCSym_1:1, day sixteen; acpPCSym_15, day twelve; and (acpPCSym_18), day ten and day sixteen). In contrast, the expression of acpPCSym_5:1 and acpPCSym_10:1 was unchanged throughout the experiment. Interestingly, the three acpPC genes with increased expression cluster together in a phylogenetic analysis of light-harvesting complexes. PMID- 27117334 TI - Lower motor neuron dysfunction in ALS. AB - In the motor system there is a complex interplay between cortical structures and spinal cord lower motor neurons (LMN). In this system both inhibitory and excitatory neurons have relevant roles. LMN loss is a marker of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Conventional needle electromyography (EMG) does not allow LMN loss to be quantified. Measurement of compound muscle action potential (CMAP) amplitude or area, and the neurophysiological index, provide a surrogate estimate of the number of functional motor units. Increased motor neuronal excitability is a neurophysiological marker of ALS in the context of a suspected clinical and electrophysiological diagnosis. In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. Reinnervation is best investigated by needle EMG although other methods can be explored. Moreover needle EMG give information about the temporal profile of the reinnervation process, important ancillary data. Quantitative motor unit potential analysis is a valuable method of evaluating reinnervation. The importance of FPs has been recognized in the Awaji criteria for the electrodiagnosis of ALS, criteria that are a sensitive adjunct to the revised El Escorial criteria. Finally, functionality of LMN's, and perhaps excitability studies in motor nerves, aids understanding of the disease process, allowing measurement of potential treatment effects in clinical trials. Other investigational techniques, such as electrical impedance myography, muscle and nerve ultrasound, and spinal cord imaging methods may prove useful in future. PMID- 27117335 TI - Know where your clients are: subcellular localization and targets of calcium dependent protein kinases. AB - Calcium-dependent protein kinases (CDPKs) are at the forefront of decoding transient Ca(2+) signals into physiological responses. They play a pivotal role in many aspects of plant life starting from pollen tube growth, during plant development, and in stress response to senescence and cell death. At the cellular level, Ca(2+) signals have a distinct, narrow distribution, thus requiring a conjoined localization of the decoders. Accordingly, most CDPKs have a distinct subcellular distribution which enables them to 'sense' the local Ca(2+) concentration and to interact specifically with their targets. Here we present a comprehensive overview of identified CDPK targets and discuss them in the context of kinase-substrate specificity and subcellular distribution of the CDPKs. This is particularly relevant for calcium-mediated phosphorylation where different CDPKs, as well as other kinases, were frequently reported to be involved in the regulation of the same target. However, often these studies were not performed in an in situ context. Thus, considering the specific expression patterns, distinct subcellular distribution, and different Ca(2+) affinities of CDPKs will narrow down the number of potential CDPKs for one given target. A number of aspects still remain unresolved, giving rise to pending questions for future research. PMID- 27117337 TI - Interrelated modules in cyanobacterial photosynthesis: the carbon-concentrating mechanism, photorespiration, and light perception. AB - Here we consider the cyanobacterial carbon-concentrating mechanism (CCM) and photorespiration in the context of the regulation of light harvesting, using a conceptual framework borrowed from engineering: modularity. Broadly speaking, biological 'modules' are semi-autonomous functional units such as protein domains, operons, metabolic pathways, and (sub)cellular compartments. They are increasingly recognized as units of both evolution and engineering. Modules may be connected by metabolites, such as NADPH, ATP, and 2PG. While the Calvin-Benson Bassham Cycle and photorespiratory salvage pathways can be considered as metabolic modules, the carboxysome, the core of the cyanobacterial CCM, is both a structural and a metabolic module. In photosynthetic organisms, which use light cues to adapt to the external environment and which tune the photosystems to provide the ATP and reducing power for carbon fixation, light-regulated modules are critical. The primary enzyme of carbon fixation, RuBisCO, uses CO2 as a substrate, which is accumulated via the CCM. However RuBisCO also has a secondary reaction in which it utilizes O2, a by-product of the photochemical modules, which leads to photorespiration. A complete understanding of the interplay among CCM and photorespiration is predicated on uncovering their connections to the light reactions and the regulatory factors and pathways that tune these modules to external cues. We probe this connection by investigating light inputs into the CCM and photorespiratory pathways in the chromatically acclimating cyanobacterium Fremyella diplosiphon. PMID- 27117336 TI - Arabidopsis FIM5 decorates apical actin filaments and regulates their organization in the pollen tube. AB - The actin cytoskeleton is increasingly recognized as a major regulator of pollen tube growth. Actin filaments have distinct distribution patterns and dynamic properties within different regions of the pollen tube. Apical actin filaments are highly dynamic and crucial for pollen tube growth. However, how apical actin filaments are generated and properly constructed remains an open question. Here we showed that Arabidopsis fimbrin5 (FIM5) decorates filamentous structures throughout the entire tube but is apically concentrated. Apical actin structures are disorganized to different degrees in the pollen tubes of fim5 loss-of function mutants. Further observations suggest that apical actin structures are not constructed properly because apical actin filaments cannot be maintained at the cortex of fim5 pollen tubes. Actin filaments appeared to be more curved in fim5 pollen tubes and this was confirmed by measurements showing that the convolutedness and the rate of change of convolutedness of actin filaments was significantly increased in fim5 pollen tubes. This suggests that the rigidity of the actin filaments may be compromised in fim5 pollen tubes. Further, the apical cell wall composition is altered, implying that tip-directed vesicle trafficking events are impaired in fim5 pollen tubes. Thus, we found that FIM5 decorates apical actin filaments and regulates their organization in order to drive polarized pollen tube growth. PMID- 27117338 TI - An evolutionary view on thylakoid protein phosphorylation uncovers novel phosphorylation hotspots with potential functional implications. AB - The regulation of photosynthetic light reactions by reversible protein phosphorylation is well established today, but functional studies have so far mostly been restricted to processes affecting light-harvesting complex II and the core proteins of photosystem II. Virtually no functional data are available on regulatory effects at the other photosynthetic complexes despite the identification of multiple phosphorylation sites. Therefore we summarize the available data from 50 published phospho-proteomics studies covering the main complexes involved in photosynthetic light reactions in the 'green lineage' (i.e. green algae and land plants) as well as its cyanobacterial counterparts. In addition, we performed an extensive orthologue search for the major photosynthetic thylakoid proteins in 41 sequenced genomes and generated sequence alignments to survey the phylogenetic distribution of phosphorylation sites and their evolutionary conservation from green algae to higher plants. We observed a number of uncharacterized phosphorylation hotspots at photosystem I and the ATP synthase with potential functional relevance as well as an unexpected divergence of phosphosites. Although technical limitations might account for a number of those differences, we think that many of these phosphosites have important functions. This is particularly important for mono- and dicot plants, where these sites might be involved in regulatory processes such as stress acclimation. PMID- 27117339 TI - Dynamic QTLs for sugars and enzyme activities provide an overview of genetic control of sugar metabolism during peach fruit development. AB - Knowledge of the genetic control of sugar metabolism is essential to enhance fruit quality and promote fruit consumption. The sugar content and composition of fruits varies with species, cultivar and stage of development, and is controlled by multiple enzymes. A QTL (quantitative trait locus) study was performed on peach fruit [Prunus persica (L.) Batsch], the model species for Prunus Progeny derived from an interspecific cross between P. persica cultivars and P. davidiana was used. Dynamic QTLs for fresh weight, sugars, acids, and enzyme activities related to sugar metabolism were detected at different stages during fruit development. Changing effects of alleles during fruit growth were observed, including inversions close to maturity. This QTL analysis was supplemented by the identification of genes annotated on the peach genome as enzymes linked to sugar metabolism or sugar transporters. Several cases of co-locations between annotated genes, QTLs for enzyme activities and QTLs controlling metabolite concentrations were observed and discussed. These co-locations raise hypotheses regarding the functional regulation of sugar metabolism and pave the way for further analyses to enable the identification of the underlying genes. In conclusion, we identified the potential impact on fruit breeding of the modification of QTL effect close to maturity. PMID- 27117341 TI - The J-protein AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling. AB - AtDjB1 is a mitochondria-located J-protein in Arabidopsis thaliana It is involved in the regulation of plant growth and development; however, the exact mechanisms remain to be determined. We performed comparison analyses of phenotypes, auxin signalling, redox status, mitochondrial structure and function using wild-type plants, AtDjB1 mutants, rescued AtDjB1 mutants by AtDjB1 or YUCCA2 (an auxin synthesis gene), and AtDjB1 overexpression plants. AtDjB1 mutants (atj1-1 or atj1 4) exhibited inhibition of growth and development and reductions in the level of IAA and the expression of YUCCA genes compared to wild-type plants. The introduction of AtDjB1 or YUCCA2 into atj1-1 largely rescued phenotypic defects and the IAA level, indicating that AtDjB1 probably regulates growth and development via auxin. Furthermore, atj1-1 plants displayed a significant reduction in amount/activity of mitochondrial complex I compared to wild-type plants; this resulted in the accumulation of reactive oxygen species (ROS). Moreover, exogenous H2O2 markedly inhibited the expression of YUCCA genes in wild type plants. In contrast, the reducing agent ascorbate increased the expression of YUCCA genes and IAA level in atj1-1 plants, indicating that the low auxin level observed in atj1-1 was probably due to the high oxidation status. Overall, the data presented here suggest that AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling in Arabidopsis. PMID- 27117340 TI - Use of transcriptomics and co-expression networks to analyze the interconnections between nitrogen assimilation and photorespiratory metabolism. AB - Nitrogen is one of the most important nutrients for plants and, in natural soils, its availability is often a major limiting factor for plant growth. Here we examine the effect of different forms of nitrogen nutrition and of photorespiration on gene expression in the model legume Lotus japonicus with the aim of identifying regulatory candidate genes co-ordinating primary nitrogen assimilation and photorespiration. The transcriptomic changes produced by the use of different nitrogen sources in leaves of L. japonicus plants combined with the transcriptomic changes produced in the same tissue by different photorespiratory conditions were examined. The results obtained provide novel information on the possible role of plastidic glutamine synthetase in the response to different nitrogen sources and in the C/N balance of L. japonicus plants. The use of gene co-expression networks establishes a clear relationship between photorespiration and primary nitrogen assimilation and identifies possible transcription factors connected to the genes of both routes. PMID- 27117342 TI - Short-term effect of bisphenol-a on oxidative stress responses in Atlantic salmon kidney cell line: a transcriptional study. AB - Bisphenol A (BPA) is regularly detected in aquatic ecosystems due to increased use of products based on polycarbonate plastics and epoxy resins. It migrates from these products directly into rivers and marine waters or indirectly through effluents from wastewater treatment plants and landfilled sites. BPA can affect aquatic organisms both chronically and acutely at sensitive live stages. Despite reports indicating harmful effects of BPA, little is known about its role in oxidative stress responses in fish. In this study, we investigated the transcriptional effect of BPA (0, 1, 10, 100 MUM) on an Atlantic salmon kidney (ASK) cell line for 6 h and 24 h by monitoring expression of 11 genes: elongation factor 1-alpha (ef1a), 18S ribosomal RNA (18s), gluthation (gsh), superoxide dismutase (sod), thioredoxin (txd), Salmo salar oxidative stress-responsive serine-rich 1 (oxr), glucose-regulated protein 78 (grp78), heat shock protein 70 (hsp70), sequestosome1 (p62), interleukin-1 beta (il-1beta) and toll-like receptor 8 (tlr8). In general, only the 100 MUM concentration treatment altered the mRNA expression. BPA down-regulated the expression of gsh and sod genes for both exposure-times while txd gene was the only down-regulated after 6-h exposure. The up-regulation of genes in the ASK cell line exposed for 6 h was only observed in il-1beta, while the 24-h exposure resulted in the up-regulation of oxr, tlr8, hsp70, p62 and il-1beta genes. The last three genes increased several fold compared to the others. The results showed that BPA exposure at 100 MUM imposed oxidative stress on the ASK cell line and longer exposure time involved transcriptional responses of immune-related genes. This may indicate the possible role of BPA-associated oxidative stress in induction of inflammatory response in this macrophage-like cell type. PMID- 27117343 TI - Degradation of nano-scale cathodes: a new paradigm for selecting low-temperature solid oxide cell materials. AB - Oxygen electrodes have been able to meet area specific resistance targets for solid oxide cell operating temperatures as low as ~500 degrees C, but their stability over expected device operation times of up to 50 000 h is unknown. Achieving good performance at such temperatures requires mixed ionically and electronically-conducting electrodes with nano-scale structure that makes the electrode susceptible to particle coarsening and, as a result, electrode resistance degradation. Here we describe accelerated life testing of nanostructured Sm0.5Sr0.5CoO3-Ce0.9Gd0.1O2 electrodes combining impedance spectroscopy and microstructural evaluation. Measured electrochemical performance degradation is accurately fitted using a coarsening model that is then used to predict cell operating conditions where required performance and long-term stability are both achieved. A new electrode material figure of merit based on both performance and stability metrics is proposed. An implication is that cation diffusion, which determines the coarsening rate, must be considered along with oxygen transport kinetics in the selection of optimal electrode materials. PMID- 27117344 TI - Do quality indicators for general practice teaching practices predict good outcomes for students? AB - Keele medical students spend 113 days in general practices over our five-year programme. We collect practice data thought to indicate good quality teaching. We explored the relationships between these data and two outcomes for students; Objective Structured Clinical Examination (OSCE) scores and feedback regarding the placements. Though both are surrogate markers of good teaching, they are widely used. We collated practice and outcome data for one academic year. Two separate statistical analyses were carried out: (1) to determine how much of the variation seen in the OSCE scores was due to the effect of the practice and how much to the individual student. (2) to identify practice characteristics with a relationship to student feedback scores. (1) OSCE performance: 268 students in 90 practices: six quality indicators independently influenced the OSCE score, though without linear relationships and not to statistical significance. (2) Student satisfaction: 144 students in 69 practices: student feedback scores are not influenced by practice characteristics. The relationships between the quality indicators we collect for practices and outcomes for students are not clear. It may be that neither the quality indicators nor the outcome measures are reliable enough to inform decisions about practices' suitability for teaching. PMID- 27117345 TI - An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics. AB - Tumour growth, angiogenesis and oxygenation vary substantially among tumours and significantly impact their treatment outcome. Imaging provides a unique means of investigating these tumour-specific characteristics. Here we propose a computational model to simulate tumour-specific oxygenation changes based on the molecular imaging data. Tumour oxygenation in the model is reflected by the perfused vessel density. Tumour growth depends on its doubling time (T d) and the imaged proliferation. Perfused vessel density recruitment rate depends on the perfused vessel density around the tumour (sMVDtissue) and the maximum VEGF concentration for complete vessel dysfunctionality (VEGFmax). The model parameters were benchmarked to reproduce the dynamics of tumour oxygenation over its entire lifecycle, which is the most challenging test. Tumour oxygenation dynamics were quantified using the peak pO2 (pO2peak) and the time to peak pO2 (t peak). Sensitivity of tumour oxygenation to model parameters was assessed by changing each parameter by 20%. t peak was found to be more sensitive to tumour cell line related doubling time (~30%) as compared to tissue vasculature density (~10%). On the other hand, pO2peak was found to be similarly influenced by the above tumour- and vasculature-associated parameters (~30-40%). Interestingly, both pO2peak and t peak were only marginally affected by VEGFmax (~5%). The development of a poorly oxygenated (hypoxic) core with tumour growth increased VEGF accumulation, thus disrupting the vessel perfusion as well as further increasing hypoxia with time. The model with its benchmarked parameters, is applied to hypoxia imaging data obtained using a [(64)Cu]Cu-ATSM PET scan of a mouse tumour and the temporal development of the vasculature and hypoxia maps are shown. The work underscores the importance of using tumour-specific input for analysing tumour evolution. An extended model incorporating therapeutic effects can serve as a powerful tool for analysing tumour response to anti-angiogenic therapies. PMID- 27117346 TI - Joy and happiness: a simultaneous and evolutionary concept analysis. AB - AIM: To report a simultaneous and evolutionary analysis of the concepts of joy and long-term happiness. BACKGROUND: Joy and happiness are underrepresented in the nursing literature, though negative concepts are well represented. When mentioned in the literature, neither joy nor happiness is adequately defined, explained, or clearly understood. To promote further investigation of these concepts in nursing and to explore their relationship with health and healing, conceptual clarity is an essential first step. DESIGN: Concept analysis. DATA SOURCES: The following databases were searched, without time restrictions, for articles in English: Academic Search Complete, Anthropology Plus; ATLA Religious Database with ATLASerials; Cumulative Index of Nursing and Allied Health Literature (CINAHL); Education Research Complete; Humanities International Complete; Psych EXTRA; and SocINDEX with Full Text. The final sample size consists of 61 articles and one book, published between 1978-2014. METHOD: An adapted combination of Rodgers' Evolutionary Model and Haase et al.'s Simultaneous Concept Analysis (SCA) method. RESULTS: Though both are positive concepts, joy and happiness have significant differences. Attributes of joy describe a spontaneous, sudden and transient concept associated with connection, awareness, and freedom. Attributes of happiness describe a pursued, long-lasting, stable mental state associated with virtue and self-control. CONCLUSION: Further exploration of joy and happiness is necessary to ascertain their relationship with health and their value to nursing practice and theory development. Nurses are encouraged to consider the value of positive concepts to all areas of nursing. PMID- 27117347 TI - Identification of fluocinolone acetonide to prevent paclitaxel-induced peripheral neuropathy. AB - Paclitaxel (PTX) is among the most commonly used cancer drugs that cause chemotherapy-induced peripheral neuropathy (CIPN), a debilitating and serious dose-limiting side effect. Currently, no drugs exist to prevent CIPN, and symptomatic therapy is often ineffective. In order to identify therapeutic candidates to prevent axonal degeneration induced by PTX, we carried out a phenotypic drug screening using primary rodent dorsal root ganglion sensory neurons. We identified fluocinolone acetonide as a neuroprotective compound and verified it through secondary screens. Furthermore, we showed its efficacy in a mouse model of PTX-induced peripheral neuropathy and confirmed with four different cancer cell lines that fluocinolone acetonide does not interfere with PTX's antitumor activity. Our study identifies fluocinolone acetonide as a potential therapy to prevent CIPN caused by PTX. PMID- 27117348 TI - Towards 3D in vitro models for the study of cardiovascular tissues and disease. AB - The field of tissue engineering is developing biomimetic biomaterial scaffolds that are showing increasing therapeutic potential for the repair of cardiovascular tissues. However, a major opportunity exists to use them as 3D in vitro models for the study of cardiovascular tissues and disease in addition to drug development and testing. These in vitro models can span the gap between 2D culture and in vivo testing, thus reducing the cost, time, and ethical burden of current approaches. Here, we outline the progress to date and the requirements for the development of ideal in vitro 3D models for blood vessels, heart valves, and myocardial tissue. PMID- 27117349 TI - Development of cell therapy medicinal products by academic institutes. AB - In the rapidly evolving fields of cellular immunotherapy, gene therapy and regenerative medicine, a wide range of promising cell therapy medicinal products are in clinical development. Most products originate from academic research and are explored in early exploratory clinical trials. However, the success rate toward approval for regular patient care is disappointingly low. In this paper, we define strengths and hurdles applying to the development of cell therapy medicinal products in academic institutes, and analyze why only a few promising cell therapies have reached late-stage clinical development. Subsequently, we provide recommendations to stakeholders involved in development of cell therapies to exploit their potential clinical benefit. PMID- 27117352 TI - Is the future of the pediatric nursing specialty at risk? PMID- 27117351 TI - Giant Biliary Cyst. PMID- 27117350 TI - Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level. AB - In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 A of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free-energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. (c) 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 27117353 TI - Pressure on oxygen levels of Jakarta Bay. AB - Jakarta Bay is subject to inputs of large amounts of dissolved inorganic nutrients and organic matter deriving from the Jakarta Metropolitan Area and its hinterland. As a consequence, inorganic and organic nutrient concentrations in the nearshore area are considerably increased. The hydrographic pattern inside the bay fosters phytoplankton bloom formation due to pronounced vertical density gradients. High Biomass Blooms (HBB) of phytoplankton are observed recurrently, representing an additional source for oxygen consuming degradable organic matter. An oxygen deficiency area of 20km(2) can be identified in the eastern part of Jakarta Bay where oxygen levels decrease to 60% saturation, equaling a noxiously low concentration of 4.0mg.dm(-3) O2. The absolute minimum detected was 51% O2 or 3.2mg.dm(-3) O2. The observed oxygen concentrations fail Indonesian quality standards for seawater. PMID- 27117354 TI - Distribution of beach litter along the coastline of Cadiz, Spain. AB - A total of 59 categories of litter items were found at 20 beaches (13 mechanically cleaned, 7 non-cleaned) in the Cadiz tourist environment, Spain. Cluster Analysis and Principal Components Analysis were used to highlight similarities and contrasts between sites and/or associations between litter categories. Multivariate analyses separated beaches according to the total numbers of litter items present. Non-cleaned sites showed a variety of litter category abundance with distinct origins and abundant, ubiquitous items (plastic and glass fragments). Of the 7 non-cleaned beaches (49 litter categories) river mouth sites were distinct due with high numbers of litter items. The sheltered inner part of Cadiz Bay beaches had a wide range of litter type. Many sites were associated with locally deposited recreational litter categories; while industrial/commercial/fishing categories were abundant only at a few sites, indicating items transported onto the shore from the Guadalete river. PMID- 27117355 TI - Initial rigid response and softening transition of highly stretchable kirigami sheet materials. AB - We study, experimentally and theoretically, the mechanical response of sheet materials on which line cracks or cuts are arranged in a simple pattern. Such sheet materials, often called kirigami (the Japanese words, kiri and gami, stand for cut and paper, respectively), demonstrate a unique mechanical response promising for various engineering applications such as stretchable batteries: kirigami sheets possess a mechanical regime in which sheets are highly stretchable and very soft compared with the original sheets without line cracks, by virtue of out-of-plane deformation. However, this regime starts after a transition from an initial stiff regime governed by in-plane deformation. In other words, the softness of the kirigami structure emerges as a result of a transition from the two-dimensional to three-dimensional deformation, i.e., from stretching to bending. We clarify the physical origins of the transition and mechanical regimes, which are revealed to be governed by simple scaling laws. The results could be useful for controlling and designing the mechanical response of sheet materials including cell sheets for medical regeneration and relevant to the development of materials with tunable stiffness and mechanical force sensors. PMID- 27117356 TI - 0.26-Hz-linewidth ultrastable lasers at 1557 nm. AB - Narrow-linewidth ultrastable lasers at 1.5 MUm are essential in many applications such as coherent transfer of light through fiber and precision spectroscopy. Those applications all rely on the ultimate performance of the lasers. Here we demonstrate two ultrastable lasers at 1557 nm with a most probable linewidth of 0.26 Hz by independently frequency-stabilizing to the resonance of 10-cm-long ultrastable Fabry-Perot cavities at room temperature. The fractional frequency instability of each laser system is nearly 8 * 10(-16) at 1-30 s averaging time, approaching the thermal noise limit of the reference cavities. A remarkable frequency instability of 1 * 10(-15) is achieved on the long time scale of 100 4000 s. PMID- 27117357 TI - [MR-APT imaging: development from research to practice and from macro to molecule]. PMID- 27117358 TI - [Diffusion-weighted imaging characteristics of uterine leiomyomas with different pathological subtypes at 3.0 T]. AB - OBJECTIVE: To investigate the imaging features of uterine leiomyomas with different pathological subtypes on DWI. METHODS: Clinical records and MR images of pathologically confirmed uterine leiomyomas were retrospectively collected from the Second Affiliated Hospital of Wenzhou Medical University from June 2012 to April 2015. A total of 60 uterine leiomyomas were found and evaluated.All the patients were divided into three groups according to different pathological types, which included 17 cases of cellular leiomyomas, 10 cases of degenerated leiomyomas and 33 cases of ordinary leiomyomas.The DWI signal and ADC values in cellular portion of the lesions and adjacent normal myometrium (the control group) were measured. RESULTS: (1) Most cellular leiomyomas showed hyperintensity on DWI (15/17), while degenerated leiomyomas manifested hypointensity, isointensity or hyperintensity signal on DWI, and most ordinary leiomyomas displayed isointensity signal on DWI (57.6%, 19/33). (2) The ADC values of cellular leiomyomas, degenerated leiomyomas and ordinary leiomyomas were (1.01+/ 0.14)*10(-3) mm(2)/s, (1.73+/-0.49)*10(-3) mm(2)/s and (1.38+/-0.22)*10(-3) mm(2)/s respectively.The ADC values of adjacent normal myometrium (the control group) were (1.35+/-0.16)*10(-3) mm(2)/s.There were no significant statistical differences in the ADC values between ordinary leiomyomas and adjacent normal myometrium (P=0.623). There were significant statistical differences in the ADC values among other groups(all P<0.05). (3)The ROC curve showed that the diagnostic threshold for cellular leiomyomas was 1.11*10(-3) mm(2)/s, the sensitivity and specificity were 88.2%and 93.0% respectively. CONCLUSION: The signal intensity on DWI and the ADC values are different in uterine leiomyomas with different pathological subtypes.Combination of these two parameters in clinical practice may be helpful to reflect the histopathological characteristics of uterine leiomyomas. PMID- 27117359 TI - [Preliminary study on intravoxel incoherent motion (IVIM) imaging in laryngeal and hypopharyngeal squamous cell carcinoma]. AB - OBJECTIVE: To evaluate the diagnostic performance of bi-exponential modeling of intravoxel incoherent motion (IVIM) imaging for laryngeal and hypopharyngeal carcinoma. METHODS: A total of 32 patients with pathologically proven laryngeal and hypopharyngeal squamous cell carcinoma were included in this study from November 2014 to August 2015.All patients underwent IVIM-DWI by using twelve b values (0, 10, 20, 30, 50, 70, 100, 150, 200, 400, 800 and 1 000 s/mm(2)). Using the IVIM approach, D, D(*) and f values were extracted using a bi-exponential fit.These quantitative parameters of primary carcinoma and normal pharyngeal tissue were compared.Statistical methods were used to assess differences between the tumor and normal pharyngeal tissue. RESULTS: There were no significant differences of D (P=0.903) and f (P=0.223) values observed among laryngeal carcinoma and hypopharyngeal carcinoma, and D(*) value was significantly different among the two groups (P=0.028). The values of D, D(*,) and f for primary carcinoma were (0.84+/-0.22)*10(-3) mm(2)/s, (65.71+/-19.66)*10(-3) mm(2)/s, and 45%+/-14%, respectively; for normal pharyngeal tissue were (1.48+/ 1.04)*10(-3) mm(2)/s, (37.85+/-14.04)*10(-3) mm(2)/s, and 36%+/-12%, respectively (P=0.001, 0.000, and 0.006, respectively). Setting D value 0.949*10(-3) mm(2)/s was threshold to distinguish abnormal and normal tissues, the sensitivity, specificity and accuracy were 91.2%, 88.2% and 92.5%, respectively.There was no statistically significant difference of D and f values(both P>0.05)in different pathological grades of primary carcinoma, and there was statistically significant difference in D(*) values found among the different pathological grades of primary carcinoma (P=0.001). There were statistically significant differences in D(*) values between the well differentiated group and the other two group (both P<0.05), and there was no statistically significant difference between the moderately differentiated group and poorly differentiated group (P>0.05). CONCLUSION: IVIM parameters can reflect the difference between laryngeal and hypopharyngeal carcinoma and normal pharyngeal tissue, and the D value has the best diagnostic performance.D(*) value in different pathological grades of laryngeal and hypopharyngeal squamous cell carcinoma is distinct, and it could reflect the pathological grade of tumor to some extent. PMID- 27117360 TI - [Value of R2(*) in evaluating the biological behavior of primary hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the correlation between R2(*) value of enhanced T2 star weighted angiography (ESWAN) sequence and primary hepatocellular carcinoma infiltration and tumor thrombus, and investigate the biological behavior of HCC. METHODS: A total of 221 cases of patients' imaging data with MRI examination(including ESWAN sequence) diagnosed as primary HCC were retrospectively analyzed.All the patients were collected from January 2014 to September 2015 in the First Affiliated Hospital of Dalian Medical University.The differences of R2(*) values in different MR types of HCC were analyzed.All patients were divided into infiltration group and non-infiltration group, tumor thrombus group and non-tumor thrombus group, the R2(*) values of the paired groups were compared.The diagnostic efficiency of R2(*) in HCC infiltration and tumor thrombus were evaluated by ROC curve, and to find out the threshold values. RESULTS: The MR types of 221 patients included 90 cases of nodular type, 62 cases of massive type, 69 cases of diffuse type.70 patients had tumor thrombus.The R2(*) values of different MR types were (21.82+/-8.52), (24.17+/-8.84)and (34.45+/-11.73) Hz, respectively.There was no statistically significant difference between the nodular and the massive types (P=0.144), while the difference between the nodular and diffuse type, the massive and diffuse types were statistically significant(P=0.000). The R2(*) values of infiltration group and non-infiltration group were (34.45+/-11.73) and (22.78+/-8.70) Hz , the R2(*) values of tumor thrombus group and non-tumor thrombus group were (31.20+/-12.17) and (24.21+/-9.90) Hz, the difference also had statistically significant(t=7.397 and 4.534, P=0.000 and 0.000). The AUC of R2(*) values for infiltration and tumor thrombus were 0.804, 0.681. R2(*) >=24.68 Hz was the threshold value to diagnose the infiltration and tumor thrombus. CONCLUSION: R2(*) value can be used as a MR non-enhancement quantitative index to evaluate the biological behavior of HCC. PMID- 27117361 TI - [Manganese enhanced magnetic resonance imaging investigation in the central auditory pathway of the cat]. AB - OBJECTIVE: To compare enhancement of the central auditory pathway in cats receiving auditory stimulation between manganese enhanced magnetic resonance imaging (MEMRI) with intraperitoneal manganese injection route and MEMRI with intratympanic manganese injection route, and investigate the optimal method for displaying enhancement of the central auditory pathway. METHODS: Twenty-seven normal hearing adult cats were randomly divided into three groups, receiving intraperitoneal manganese injection, left intratympanic manganese injection or left intratympanic gadolinium injection respectively.All cats received white noise stimulation of 80 dB in twenty-four hours after injection.Three dimensionally coronal T1-weighted imaging of the cat brain was obtained with an animal dedicated MRI scanner.The signal noise ratios (SNRs) of bilateral cochlear nuclei (CN), dorsal nuclei of the trapezoid bodies (DNTB), caudal colliculi (CC) and auditory cortices (AC) were measured on reconstructed images and compared. RESULTS: Obvious increased SNRs on both sides were shown in intraperitoneal mangasese injection group while left predilection was shown in intratympanic manganese injection group: left CN 45.7+/-6.0, 37.4+/-11.9, 23.9+/-2.7, F=17.694, P=0.000; left DNTB 50.5+/-11.2, 37.1+/-11.2, 27.6+/-7.3, F=11.781, P=0.000; left CC 37.6+/-3.9, 22.6+/-3.1, 17.9+/-0.7, F=111.898, P=0.000; left AC 27.7+/-2.5, 17.3+/-2.3, 14.5+/-1.0, F=105.132, P=0.000; right CN 42.7+/-8.3, 23.9+/-3.0, 22.7+/-2.1, F=41.492, P=0.000; right DNTB 44.1+/-8.3, 21.9+/-3.0, 23.9+/-4.0, F=27.862, P=0.000; right CC 38.0+/-4.0, 21.9+/-3.0, 17.6+/-0.9, F=120.032, P=0.000; right AC 26.7+/-3.4, 17.1+/-2.9, 14.9+/-1.3, F=64.587, P=0.000.Compared with the left intratympanic gadolinium injection group, the intraperitoneal manganese injection group showed higher SNRs in bilateral CN and CC (P<0.05), and the left intratympanic manganese injection group showed higher SNRs in left CN, AC and bilateral CC.The SNRs of right CN, bilateral DNTB, CC and AC were significantly higher in the intraperitoneal manganese injection group than those in the left intratympanic manganese injection group (P<0.05). CONCLUSION: MEMRI with intraperitoneal manganese injection might be the optimal method for displaying enhancement of the central auditory pathway in cats receiving auditory stimulation. PMID- 27117362 TI - [Information processing speed and influential factors in multiple sclerosis]. AB - OBJECTIVE: To study the information processing speed and the influential factors in multiple sclerosis (MS) patients. METHODS: A total of 36 patients with relapsing-remitting MS (RRMS), 21 patients with secondary progressive MS (SPMS), and 50 healthy control subjects from Xuanwu Hospital of Capital Medical University between April 2010 and April 2012 were included into this cross sectional study.Neuropsychological tests was conducted after the disease had been stable for 8 weeks, including information processing speed, memory, executive functions, language and visual perception.Correlation between information processing speed and depression, fatigue, Expanded Disability Status Scale (EDSS) were studied. RESULTS: (1)MS patient groups demonstrated cognitive deficits compared to healthy controls.The Symbol Digit Modalities Test (SDMT) (control group 57+/-12; RRMS group 46+/-17; SPMS group 35+/-10, P<0.05) and Paced Auditory Serial Addition Task (PASAT) (control group 85+/-18; RRMS group 77+/-20; SPMS group 57+/-20, P<0.05) impaired most.SPMS patients were more affected compared to patients with RRMS subtypes, and these differences were attenuated after control for physical disability level as measured by the EDSS scores.MS patients, especially SPMS subtype, were more severely impaired than control group in the verbal learning test, verbal fluency, Stroop C test planning time, while visual spatial function and visual memory were relatively reserved in MS patients.(2) According to the Pearson univariate correlation analysis, age, depression, EDSS scores and fatigue were related with PASAT and SDMT tests (r=-0.41--0.61, P<0.05). Depression significantly affected the speed of information processing (P<0.05). CONCLUSIONS: Impairment of information processing speed, verbal memory and executive functioning are seen in MS patients, especially in SPMS subtype, while visual-spatial function is relatively reserved.Age, white matter change scales, EDSS scores, depression are negatively associated with information processing speed. PMID- 27117363 TI - [Long-term outcome of surgical revascularization in patients with ischemic heart disease and left ventricular dysfunction]. AB - OBJECTIVE: To analyze the long-term results and risk factors of surgical revascularization in patients with ischemic heart disease (IHD) and left ventricular dysfunction (LVD). METHODS: From January 2003 to July 2013, 2 132 patients underwent coronary artery bypass grafting (CABG) in our institution. Among them, 318 patients with LVD[left ventricular ejection fraction (LVEF) <=50%]were included in the final study. There were 26 6 male and 52 female patients with age from 36 to 83 (63+/-9) years old. 76 patients underwent off pump CABG (OPCAB) and 242 patients underwent conventional CABG (CCABG). Risk factors, perioperative results and follow-up data were collected and analyzed with cox hazard ratio model. RESULTS: Among 318 patients, 6 cases died of the operation with a hospital mortality of 1.9%. With follow-up time from 1 to 128(45.5+/-32.4)months, 25 patients were lost of follow-up, causing a follow-up rate of 92.0%. Among the 287 cases with long-term follow-up results, all-cause death, cardiogenic death and re-hospitalization due to heart failure were 14.6% (42/287), 5.9%(17/287), 14.6% (42/287), respectively. Re-revascularization rate, recurrent angina and myocardial infarction rate and cerebral incidence were 3.5%(10/287), 13.6% (39/287), 1.7%(5/287), respectively. The five-year survival rate was 85.6%. With all-cause death as the endpoint, preoperative LVEF (HR=0.943, 95%CI: 0.893-0.995, P=0.031) and perioperative implantation of IABP (HR=2.509, 95%CI: 1.051-5.992, P=0.038) emerged as the risk factors that affected the long term survival. The five-year survival rate of patients with severe LVD (LVEF<=35%) was significantly lower than that of patients with mild to moderate LVD (35%0.05). All patients in our study were cured and discharged without severe side effects and complications, and follow-ups showed that no patients showed evidence of rebound phenomenon. CONCLUSIONS: Different concentrations of lipid infusionare safe and effective in relieving the intensity of dexmedetomidinepoisoning, and promoting the clinical recovery.What's more, the therapeutic efficacy of 20% lipid infusion is greater than 10% lipid infusion. PMID- 27117369 TI - [Characteristics of cognitive impairment of different infarct locations among patients after acute ischemic stroke]. AB - OBJECTIVE: To investigate the characteristics of cognitive function changes of different infarct sites among patients after acute ischemic stroke, so as to provide theoretical basis for preventing and treating vascular cognitive dysfunction. METHODS: One hundred and five cases of acute ischemic stroke within fourteen days meeting the standard set were enrolled, and they were tested by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). And the characteristics of cognitive changes with different infarction sites were analyzed. RESULTS: Patients with acute stroke suffered cognitive impairment.The significantly impaired cognitive domains in MMSE were: graphics execution in patients with left hemisphere infarction (P=0.027); verbal repetition in frontal infarction (P=0.003); short memory (P=0.04) and verbal repetition (P=0.007) in parietal infarction.The significantly impaired cognitive domains in MoCA were: language (P=0.002), naming (P=0.011), attention (P=0.028) and time orientation (P=0.031) in frontal infarction; delayed memory (P<0.001), attention (P=0.041), language (P=0.049) and visual space and executive ability (P=0.049) in parietal infarction; attention in temporal infarction (P=0.045); language (P=0.009) and time orientation (P=0.026) in basal ganglia region infarction. CONCLUSION: Most ischemic stroke patients at acute phase suffered cognitive impairment and the characteristics of cognitive changes differed according to different infarction sites.Comprehensive assessment of cognitive impairment after acute stroke is of great importance. PMID- 27117370 TI - [Morphological alterations in gray matter related to primary dysmenorrhea]. AB - OBJECTIVE: To investigate the structural changes of gray matter in women with primary dysmenorrhea (PDM) and discuss the potential relationships between the changes and etiology of the disease. METHODS: We used an optimized voxel-based morphometry (VBM) approach to compare total and regional volumetric changes of gray matter in 20 primary dysmenorrhea patients with 20 healthy age and menstrual cycle matched controls.All subjects were patients from the outpatient department of Tongji Hospital in 2015. RESULTS: Abnormal volumetric decreases of gray matter were found in the left and right parahippocampus, the left and right middle temporal gyrus, the left and right superior parietal lobule, the left postcentral cortex, the left and right inferior parietal lobule, which involved in pain transmission, pain modulation and somatic sensation. CONCLUSION: Abnormal gray matter volume changes are present in some encephalic regions of PDM patients.The functions of these regions are associated with pain modulation and somatic sensation, which suggests the changes are related with PDM. PMID- 27117371 TI - [Influence factors of dislocation after bipolar prosthetic replacement]. AB - OBJECTIVE: To discuss the influence factors of dislocation after bipolar prosthetic replacement. METHODS: A total of 374 patients who received bipolar prosthetic replacement in our hospital from October 2001 to October 2015 were retrospectively studied. The clinic data of patients with dislocation after operation was summarized to analyze the causes. RESULTS: Dislocation happened in 12 patients among all the 374 patients.10 cases received manual relocation, 2 cases open relocation. Most of the 12 patients were accompanied with neurological and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, sequelae of cerebral infarction, etc. Some factors like improper body position caused by these complications were the main influence factors of dislocation. CONCLUSION: Accompanied with neurological and psychiatric disorders is the important influence factor of dislocation after bipolar prosthetic replacement. PMID- 27117372 TI - [Investigation on folic acid supplementation status among Chinese women in the first trimester of pregnancy]. AB - OBJECTIVE: To investigate folic acid (FA) supplementation status among Chinese rural reproductive women in their early pregnancy, and to provide evidence for the evaluation of FA supplementation project from national basic public health services. METHODS: The data on intake status of FA supplementation from "National Free Preconception Health Examination Project (NFPHEP)" database between January 1, 2010 and December 31, 2012 was used and analyzed.A total of 902 270 women who achieved follow-up during early pregnancy from 220 pilot counties of 31 provinces were recruited. RESULTS: From 2010 to 2012, the rate of FA intake among women recuited were 73.58% (134 131/182 289), 75.88% (329 288/433 970) and 76.53% (218 896/286 011), respectively, which increased year by year (chitrend(2)=13 371.8, P<0.001). Among 682 315 women who took FA, 350 738(51.40%) women began to take FA 3 months before amenorrhea; 130 683 (19.15%) women began to take FA 1-2 months before amenorrhea, and 200 894 (29.44%) began to take FA after amenorrhea.Among 682 315 women who took FA, 645 310 (94.58%) women took it regularly, and 342 418 (50.18%) women took FA in a standardized way. CONCLUSIONS: The status of FA intake among Chinese rural women in the first trimester of pregnancy was good, and 75.62% (682 315/902 270) of them took FA.It is also important for basic public health services to improve the rate of FA intake and increase the rate of taking FA in a standardized way in Chinese rural pregnant women. PMID- 27117373 TI - Endometrial expression and in vitro modulation of the iron transporter divalent metal transporter-1: implications for endometriosis. AB - OBJECTIVE: To evaluate divalent metal transporter-1 (DMT1) expression in healthy women's and endometriosis patients' endometrium and to analyze DMT1 and ferritin light chain (Fn-L) expression modulation by iron overload and IL-1beta in endometrial stromal cells (ESCs). DESIGN: Observational and experimental study. SETTING: University hospital research laboratory. PATIENT(S): Thirty-one healthy women and 24 endometriosis patients. INTERVENTION(S): Menstrual, proliferative, and secretory endometrial biopsies. Isolated ESCs from seven endometrial biopsies incubated with IL-1beta or FeSO4 overload for 24 hours. MAIN OUTCOME MEASURE(S): Divalent metal transporter-1 endometrial protein expression assessed by immunohistochemistry and Western blot. Divalent metal transporter-1 and Fn-L proteins expression in stimulated ESCs evaluated by Western blot. RESULT(S): Divalent metal transporter-1 is expressed throughout the menstrual cycle in human endometrium. Four endometrial DMT1 variants were identified accordingly to their molecular weight: DMT-80, -65, -55, and -50. Endometrial expression of DMT-80 and -55 is higher in endometriosis patients than in healthy women. In ESCs, iron overload induces an overexpression of DMT-80, DMT-50, and Fn-L, whereas IL-1beta increases DMT-80 and -50 expressions and decreases Fn-L expression. CONCLUSION(S): Divalent metal transporter-1 overexpression in endometriosis patients' endometrium can increase iron influx to endometrial cells, inducing oxidative stress-mediated proinflammatory signaling. In turn, endometriosis related conditions, as iron overload and inflammation (IL-1beta), enhance endometriosis patients endometrial DMT1 expression, creating a vicious circle on DMT-1-modulated pathways. PMID- 27117374 TI - Introduction: Imaging in reproduction. AB - The authors of this Views and Reviews outline in detail the indispensable role of imaging tools-ultrasound, computed tomography, and magnetic resonance imaging-in the diagnosis and treatment of female and male factor infertility. Equipment producing diagnostic images, coupled with ever-increasing computing power, will pave the way for novel functional dynamic studies that will expand the understanding of reproductive processes and their management. PMID- 27117375 TI - CYP1A1 3801T>C polymorphism implicated in altered xenobiotic metabolism is not associated with variations in sperm production and function as measured by total motile sperm and fertilization rates with intracytoplasmic sperm injection. AB - OBJECTIVE: To evaluate the cytochrome P450 3801T>C polymorphism's frequency in relation to semen production, as determined by semen analysis parameters, and sperm function, as determined by fertilization rates with intracytoplasmic sperm injection (ICSI). DESIGN: Case-control study. SETTING: Academic-affiliated private practice. PATIENT(S): This study included patients undergoing IVF from 2004 to 2014 grouped into categories based on semen analysis parameters performed at a single andrology laboratory. Cases were patients with total motile sperm (TMS) counts of <=20 * 10(6). Frequency-matched controls were selected with TMS of >20 * 10(6). INTERVENTION(S): The 3801T>C polymorphism was identified using DNA from serum samples with real-time quantitative polymerase chain reaction. MAIN OUTCOME MEASURE(S): CYP1A1 3801T>C polymorphism frequency in TMS groups and distribution in fertilization rate outcomes with ICSI. RESULT(S): A total of 460 cases were identified with <=20 * 10(6) TMS, and 489 age-matched controls with >20 * 10(6) TMS were selected across the study time frame. For those with <5 * 10(6) vs. >20 * 10(6) TMS there was no difference when comparing heterozygous (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.66-1.40) or homozygous mutant (OR 1.33; 95% CI 0.52-3.20) with the wild-type patients. Additionally, no difference was seen when analyzing subgroups <5 * 10(6), 5-20 * 10(6), and >20 * 10(6) TMS in a similar fashion. Receiver operating characteristic (ROC) curve analysis did not find a significant TMS count based on presence of the polymorphism (area under the ROC curve = 0.51). There were 460 patients who underwent IVF/ICSI, and fertilization rates did not differ with presence of the polymorphism (area under the ROC curve = 0.50). CONCLUSION(S): Allele frequency of the 3801T>C polymorphism does not correlate with semen production as determined by TMS counts or sperm function as determined by fertilization rates with ICSI. The use of neither semen analysis parameters nor fertilization rates with ICSI helps identify CYP1A1 polymorphism carriers. PMID- 27117376 TI - Age, independent from ovarian reserve status, is the main prognostic factor in natural cycle in vitro fertilization. AB - OBJECTIVE: To analyze natural cycle IVF (NC-IVF) results according to patient age, ovarian reserve status following the Bologna criteria, cause of infertility, and modification of the cycle with the use of GnRH antagonist. DESIGN: Retrospective cohort study. SETTING: Tertiary-care university hospital. PATIENT(S): Nine hundred forty-seven natural cycles carried out in 320 patients. INTERVENTION(S): Analysis of 947 NC-IVF outcomes performed in one single center between January 2010 and December 2014. MAIN OUTCOME MEASURE(S): Pregnancy rates per cycle started, per ET, and per patient, as well as ongoing pregnancy rate at a minimum of 12 weeks of gestation. RESULT(S): Among the three age groups analyzed (<=35 years, 36-39 years, and >=40 years), pregnancy rates per cycle were significantly lower in the older group of patients (11.4% vs. 11.6% vs. 5.9%). In addition, miscarriage rate (7.7% vs. 34.4% vs. 50%) and ongoing pregnancy rate (10.6% vs. 7.6%vs. 3.0%) were negatively affected by patient age. However, no differences were observed according to patient ovarian reserve status, cause of infertility, or modification of the cycle with GnRH antagonist. The multivariate logistic regression confirmed that patient age was the only variable that could predict pregnancy in NC-IVF cycles (odds ratio, 0.93; 95% confidence interval, 0.88-0.98). CONCLUSION(S): NC-IVF is a feasible and "patient friendly" option to be offered to young patients, independent of their ovarian reserve status. PMID- 27117377 TI - LL-37: Cathelicidin-related antimicrobial peptide with pleiotropic activity. AB - Antimicrobial peptides (AMPs) is a large family of compounds serving as natural antibiotics, widely distributed across the organism, mainly in mucus layers. They are designed to prevent pathogens from colonization. Among them, defensins and cathelicidins could be found. LL-37, the sole human cathelicidin draws particular attention because of its outstanding abilities. In addition to being a broad spectrum antibiotic, LL-37 has potent chemotactic and immunomodulatory properties. In this review, we discussed the potency of LL-37 as a therapeutic agent in four systems: immunological, respiratory, gastrointestinal and in the skin. We analyzed the main molecular pathways dependent on human cathelicidin and related them to specific diseases. We conclude that LL-37 shows a great potential to be further investigated and developed as a drug with clinical use. PMID- 27117378 TI - Inflammatory bowel diseases and reproductive health. AB - Inflammatory bowel diseases (IBD) constitute a group of chronic intestinal diseases, including Crohn's disease and ulcerative colitis, which typically involve patients of reproductive age and may influence several features of human reproduction. There are many concerns regarding the interactions between the course of IBD, applied treatment (pharmacological or surgical), and fertility, reproductive outcomes, and also neonatal outcomes. To review the literature describing fertility in IBD patients (separately for female and male), and possible infertility treatment in this group of patients, a PubMed search for English only publications (articles and/or abstracts) was conducted. Initially, the titles of publications and their abstracts were screened, and the most appropriate articles were selected and reviewed. Overall, in patients with quiescent IBD, fertility is almost identical to the general population, but particular subgroups of patients (with active disease, on pharmacological treatment, and after pelvic or abdominal surgery) may be affected by reduced fertility. Additionally, patients with IBD have fewer children than the general population, mainly as a result of voluntary childlessness. The main objectives for successful reproductive outcomes in IBD patients are proper guidance and also optimal treatment for achieving and maintaining disease remission. Recently, the European Evidence-Based Consensus on Reproduction and Pregnancy in IBD (the European Crohn's and Colitis Organization Guidelines) has been established to optimize preconceptional counseling and to promote an appropriate clinical management for patients planning to conceive. However, further studies are needed regarding the preservation of fertility in IBD patients and introduction of optimal infertility treatment in this group of patients. PMID- 27117379 TI - Is insulin-like growth factor 1 (IGF-1) system an attractive target inflammatory bowel diseases? Benefits and limitation of potential therapy. AB - Inflammatory bowel diseases (IBD) are chronic gastrointestinal disorders with unknown etiology, whose incidence dramatically increased over the past 50 years. Currently available strategies for IBD treatment, such as biological therapies, corticosteroids, and immunosuppressive agents are effective, but their side effects and economic costs cannot be ignored. Better understanding of IBD etiology and new therapeutics are thus needed. The aim of this paper is to briefly discuss IGF-1 dependent functions, with particular focus on IGF-1 use in IBD therapy. Data collection was based on records found in medical literature. Data analysis included records published between 1984 and 2014. The IGF-1 system is involved in major physiological functions, such as cell proliferation and metabolism, and growth promotion. Most importantly IGF-1 has anti-inflammatory properties and its use in IBD treatment can be recommended. However, potential IGF-1 therapy has some limitations, which include aggravation of fibrosis in Crohn's patients and facilitated transformation to malignancy. Taken into consideration their possible side effects, IGF-1 analogs and recombinants are nonetheless a promising target for IBD therapy for a specific group of patients. Further studies, at the clinical level are thus recommended. PMID- 27117380 TI - Fatal Outcome of Accidental Vitamin D Overdose. PMID- 27117382 TI - Rapid Aspiration Screening for Suspected Stroke: Part 1: Development and Validation. AB - OBJECTIVE: To develop and validate a nurse-administered screening tool to identify aspiration risk in patients with suspected stroke. DESIGN: Validity study comparing evidence-based swallowing screening items with the videofluoroscopic swallowing study (VFSS) results. SETTING: A certified primary stroke center in a major metropolitan medical facility. PARTICIPANTS: Consecutive patients (N=250) admitted with suspected stroke. INTERVENTIONS: Patients were administered evidence-based swallowing screening items by nurses. A VFSS was completed within 2 hours of swallowing screening. MAIN OUTCOME MEASURES: Validity relative to identifying VFSS-determined aspiration for each screening item and for various combinations of items. RESULTS: Aspiration was identified in 29 of 250 participants (12%). Logistic regression revealed that age (P=.012), dysarthria (P=.001), abnormal volitional cough (P=.030), and signs related to the water swallow trial (P=.021) were significantly associated with aspiration. Validity was then determined on the basis of the best combination of significant items for predicting aspiration. The results revealed that age >70 years, dysarthria, or signs related to the water swallow trial (ie, cough, throat clear, wet vocal quality, and inability to continuously drink 90mL water) yielded 93% sensitivity and 98% negative predictive value. CONCLUSIONS: The final validated tool, Rapid Aspiration Screening for Suspected Stroke, is a valid nurse administered tool to detect risk of aspiration in patients presenting with suspected stroke. PMID- 27117381 TI - Rapid Aspiration Screening for Suspected Stroke: Part 2: Initial and Sustained Nurse Accuracy and Reliability. AB - OBJECTIVE: To determine registered nurses' (RNs') ability to obtain and maintain accurate procedural skills and reliable interpretation of the screening items under study to develop the Rapid Aspiration Screening for Suspected Stroke. DESIGN: Prospective, observation study. SETTING: A certified primary stroke center in a major metropolitan medical facility. PARTICIPANTS: RNs (N=15) were recruited and trained in the administration and interpretation of the screening items under study to develop the Rapid Aspiration Screening for Suspected Stroke. INTERVENTIONS: RNs completed a total of 239 screenings of patients admitted with suspected stroke over a 2-year period. RNs administered the swallowing screening items and interpreted the patient's response to each item. Independent of the RN, a speech-language pathologist simultaneously interpreted the response of the participant with stroke to each swallowing screening item. MAIN OUTCOME MEASURES: Reliability of the interpretation and accuracy of the administration of the swallowing screening items. RESULTS: The average accuracy rate for the administration of the Rapid Aspiration Screening for Suspected Stroke was 98.33%, with the overall accuracy rate for each procedural task ranging from 95.42% to 100%. For the specific swallowing screening items that formed the Rapid Aspiration Screening for Suspected Stroke, dysarthria and a positive sign after water swallow, reliability was high (k=.817). The accuracy rate for the administration and reliability of the interpretation of the swallowing screening items improved as RNs gained experience, and both were maximized at 20 screening opportunities. CONCLUSIONS: RNs demonstrate both excellent accuracy of procedural administration and reliability of interpretation of the items of the Rapid Aspiration Screening for Suspected Stroke. With feedback and repeated opportunities to practice, maintenance of skills is achievable. PMID- 27117383 TI - Communication Partner Training in Aphasia: An Updated Systematic Review. AB - OBJECTIVES: To update a previous systematic review describing the effect of communication partner training on individuals with aphasia and their communication partners, with clinical questions addressing effects of partner training on language, communication activity/participation, psychosocial adjustment, and quality of life. DATA SOURCES: Twelve electronic databases were searched using 23 search terms. References from relevant articles were hand searched. STUDY SELECTION: Three reviewers independently reviewed abstracts, excluding those that failed to meet inclusion criteria. Thirty-two full text articles were reviewed by 2 independent reviewers. Articles not meeting inclusion criteria were eliminated, resulting in a corpus of 25 articles for full review. DATA EXTRACTION: For the 25 articles, 1 reviewer extracted descriptive data regarding participants, intervention, outcome measures, and results. A second reviewer verified the accuracy of the extracted data. DATA SYNTHESIS: The 3 member review team classified studies using the American Academy of Neurology levels of evidence. Two independent reviewers evaluated each article using design specific tools to assess research quality. CONCLUSIONS: All 25 of the current review articles reported positive changes from partner training. Therefore, to date, 56 studies across 2 systematic reviews have reported positive outcomes from communication partner training in aphasia. The results of the current review are consistent with the previous review and necessitate no change to the earlier recommendations, suggesting that communication partner training should be conducted to improve partner skill in facilitating the communication of people with chronic aphasia. Additional high-quality research is needed to strengthen the original 2010 recommendations and expand recommendations to individuals with acute aphasia. High-quality clinical trials are also needed to demonstrate implementation of communication partner training in complex environments (eg, health care). PMID- 27117384 TI - Transfer Technique Is Associated With Shoulder Pain and Pathology in People With Spinal Cord Injury: A Cross-Sectional Investigation. AB - OBJECTIVES: To evaluate how transfer technique and subject characteristics relate to ultrasound measures of shoulder soft tissue pathology and self-reported shoulder pain during transfers in a sample of wheelchair users with spinal cord injury (SCI). DESIGN: Cross-sectional observational study. SETTING: Research laboratory, national and local veterans' wheelchair sporting events. PARTICIPANTS: A convenience sample of wheelchair users (N=76) with nonprogressive SCI. Participants were aged >18 years, >1 year postinjury, and could complete repeated independent wheelchair transfers without the use of their leg muscles. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Transfer pain items from the Wheelchair User's Shoulder Pain Index; transfer technique assessed using the Transfer Assessment Instrument (TAI); and shoulder pathology markers examined using the Ultrasound Shoulder Pathology Rating Scale (USPRS). RESULTS: Better transfer technique (higher TAI) correlated with less injury (lower USPRS) (partial eta(2)=.062, P<.05) and less pain during transfers (partial eta(2)=.049, P<.10). Greater age was the strongest predictor of greater pathology (USPRS total: partial eta(2)=.225, supraspinatus grade: partial eta(2)=.174, P<.01). An interaction between technique and weight was found (P<.10): participants with lower body weights showed a decrease in pathology markers with better transfer technique (low weight: R(2)=.422, P<.05; middle weight: R(2)=.200, P<.01), while those with higher weight showed little change with technique (R(2)=.018, P>.05). CONCLUSIONS: Participants with better transfer technique exhibited less shoulder pathology and reported less pain during transfers. The relationship between technique and pathology was strongest in lower-weight participants. While causation cannot be proven because of study design, it is possible that using a better transfer technique and optimizing body weight could reduce the incidence of shoulder pathology and pain. PMID- 27117385 TI - Matching Task Difficulty to Patient Ability During Task Practice Improves Upper Extremity Motor Skill After Stroke: A Proof-of-Concept Study. AB - OBJECTIVE: To test the feasibility of the Fugl-Meyer Assessment of the Upper Extremity "keyform," derived from Rasch analysis, as a method for systematically planning and progressing rehabilitation. DESIGN: Feasibility study, single group design. SETTING: University rehabilitation research laboratory. PARTICIPANTS: Participants (N=10; mean age, 59.70+/-9.96y; 24.1+/-30.54mo poststroke) with ischemic or hemorrhagic stroke >3 months prior, voluntarily shoulder flexion >=30 degrees , and simultaneous elbow extension >=20 degrees . INTERVENTIONS: The keyform method defined initial rehabilitation targets (goals) and progressed the rehabilitation program after every third session. Targets were repetitively practiced within the context of client-selected functional tasks not in isolation. MAIN OUTCOME MEASURES: Feasibility was defined by subject's pain or fatigue, upper extremity motor function (Wolf Motor Function Test), and movement patterns (kinematics). Assessments were administered pre- and posttreatment and compared using paired t tests. Task-difficulty and patient-ability measures were calculated using Rasch analysis and compared using paired t tests (P<.05). RESULTS: Ten participants completed 9 sessions, 200 movement repetitions per session in <2 hours without pain or fatigue. Participants gained upper extremity motor function (Wolf Motor Function Test: pretreatment, 22.23+/-24.26s; posttreatment, 15.46+/-22.12s; P=.01), improved shoulder-elbow coordination (index of curvature: pretreatment, 1.30+/-0.15; posttreatment, 1.21+/-0.11; P=.01), and exhibited reduced trunk compensatory movement (trunk displacement: pretreatment, 133.97+/-74.15mm; posttreatment, 108.08+/-64.73mm; P=.02). Task difficulty and patient-ability measures were not statistically different throughout the program (person-ability measures of 1.01+/-0.05, 1.64+/-0.45, and 2.22+/-0.65 logits and item-difficulty measures of 0.93+/-0.37, 1.70+/-0.20, and 2.06+/-0.24 logits at the 3 testing time points, respectively; P>.05). CONCLUSIONS: The Fugl-Meyer Assessment of the Upper Extremity keyform is a feasible method to ensure that the difficulty of tasks practiced were well matched to initial and evolving levels of upper extremity motor ability. PMID- 27117386 TI - Acute encephalopathy with biphasic seizures and late reduced diffusion associated with staphylococcal toxic shock syndrome caused by burns. AB - We report a case of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) associated with toxic shock syndrome caused by burns. A one-year old girl was admitted to our hospital for treatment of severe burns. On day 3, she exhibited a fever, generalized rash and multiple organ failure. She was diagnosed with toxic shock syndrome after burns. She had seizures with fever twice on the same day, followed by secondary seizures on day 8 and transient deterioration of the gross motor functions involved in sitting alone and rolling over. On day 9, MRI diffusion-weighted images showed bright tree appearance (BTA). We conclude that she developed AESD. PMID- 27117387 TI - Global review of delay time in seeking medical care for chest pain: An integrative literature review. AB - OBJECTIVES: The aim of this review is to summarise research from a range of countries describing the differences in time taken to seek medical care for chest pain and factors which contribute to delay times. METHODS: An integrative literature review was undertaken using the Medline, CINAHL and Scopus databases for publications between 1994 and 2014. Articles dealing with delay time, and the factors associated with delay time, were extracted from the literature. RESULTS: The search yielded 395 articles of which 205 full-text articles were assessed for eligibility. Finally, twenty-three articles met the inclusion criteria for the review. It was found that time to seeking treatment (delay times) varied between countries, ranging from 1.6 to 12.9h, with a mean of 3.4h. The mean delay times reported in all the selected studies were greater than the recommended time-frame for seeking treatment. As well, time to decision to seek treatment (decision time) was reported as a major component of delay time. Meanwhile, the utilisation rates of ambulance services ranged from 3.1% in Brazil to 61.0% in Australia. A majority of the reviewed studies reported on the factors associated with longer delay times, including old age, female gender, ethnicity, low education level, history of chronic disease, lack of knowledge of the symptoms, and underutilisation of ambulance services. Only three studies included a sub analysis by ethnicity, reporting that ethnic groups had longer delay times than Caucasians. CONCLUSION: Variability in delay times occurred across countries and within continents. The mean time taken to seek care for chest pain in the countries reviewed did not meet the recommended times according to international guidelines. Demographic and social factors, as well as cognitive and emotional factors, influenced delay times. Further research on these influencing factors is recommended, including the impact of ethnicity on patient's care-seeking behaviours for chest pain. PMID- 27117388 TI - Positional distribution of transcription factor binding sites in Arabidopsis thaliana. AB - Binding of a transcription factor (TF) to its DNA binding sites (TFBSs) is a critical step to initiate the transcription of its target genes. It is therefore interesting to know where the TFBSs of a gene are likely to locate in the promoter region. Here we studied the positional distribution of TFBSs in Arabidopsis thaliana, for which many known TFBSs are now available. We developed a method to identify the locations of TFBSs in the promoter sequences of genes in A. thaliana. We found that the distribution is nearly bell-shaped with a peak at 50 base pairs (bp) upstream of the transcription start site (TSS) and 86% of the TFBSs are in the region from -1,000 bp to +200 bp with respect to the TSS. Our distribution was supported by chromatin immunoprecipitation sequencing and microarray data and DNase I hypersensitive site sequencing data. When TF families were considered separately, differences in positional preference were observed between TF families. Our study of the positional distribution of TFBSs seems to be the first in a plant. PMID- 27117389 TI - Correction: The auditory representation of speech sounds in human motor cortex. PMID- 27117390 TI - The importance of DNA methylation in prostate cancer development. AB - After briefly reviewing the nature of DNA methylation, its general role in cancer and the tools available to interrogate it, we consider the literature surrounding DNA methylation as relating to prostate cancer. Specific consideration is given to recurrent alterations. A list of frequently reported genes is synthesized from 17 studies that have reported on methylation changes in malignant prostate tissue, and we chart the timing of those changes in the diseases history through amalgamation of several previously published data sets. We also review associations with genetic alterations and hormone signalling, before the practicalities of investigating prostate cancer methylation using cell lines are assessed. We conclude by outlining the interplay between DNA methylation and prostate cancer metabolism and their regulation by androgen receptor, with a specific discussion of the mitochondria and their associations with DNA methylation. PMID- 27117391 TI - Description of strain FC3T as the neotype strain of Actinobaculum massiliense. AB - Actinobaculum massiliense (Euzeby, 2006) was isolated from the urine of an elderly woman in 2001. Unfortunately, the strain deposited as the type strain was, by error, an Actinobaculum schaalii strain (Yassin et al., 2015). In 2015, we isolated a new strain of A. massiliense, FC3, from the urine of a 12-year-old patient with acute cystitis. We herein present the characteristics of strain FC3 (=CSUR P1982=DSM 100580) and formally propose it as the neotype strain of A. massiliense. PMID- 27117392 TI - A Study on the Growth Behavior and Stability of Molecular Layer Deposited Alucone Films Using Diethylene Glycol and Trimethyl Aluminum Precursors, and the Enhancement of Diffusion Barrier Properties by Atomic Layer Deposited Al2O3 Capping. AB - As a route to the production of organic-inorganic hybrid multilayers, the growth behavior of molecular layer deposited (MLD) alucone and atomic layer deposited (ALD) Al2O3 films on top of each other was examined. MLD alucone films were prepared using trimethyl aluminum and diethylene glycol precursors, the latter resulting in faster growth rates than ethylene glycol precursors. The sensitivity of individual alucone films with respect to ambient exposure was found to be related to moisture permeation and hydration reactions, of which the mechanism is studied by density functional theory calculations. Deleterious effects such as thickness reduction over time could be suppressed by applying a protective Al2O3 layer on top of alucone. A preliminary nucleation period was required in the ALD process of Al2O3 films on alucone surfaces, prior to reaching a linear regime where the thickness increases linearly with respect to the number of ALD cycles. The same behavior was observed for alucone growing on Al2O3. The protective Al2O3 films were found to effectively suppress moisture permeation, thus isolating the underlying alucone from the surrounding environment. The water vapor transmission rate was greatly reduced when an Al2O3/alucone/Al2O3 multilayer stack was formed, which suggests that proper combinations of organic/inorganic hybrid structures may provide chemically stable platforms, especially for mechanically flexible applications. PMID- 27117393 TI - Tough Physical Double-Network Hydrogels Based on Amphiphilic Triblock Copolymers. AB - A series of physical double-network hydrogels is synthesized based on an amphiphilic triblock copolymer. The gel, which contains strong hydrophobic domains and sacrificial dynamic bonds of hydrogen bonds, is stiff and tough, and even stiffens in concentrated saline solution. Furthermore, due to its supramolecular structure, the gel features improved self-healing and self recovery abilities. PMID- 27117394 TI - Parental perception of treatment and medical care in children with craniosynostosis. AB - Surgery for craniosynostosis implies a relevant strain on the child and the parents. The development of the child's self-perception and self-confidence is mainly influenced by parental attitudes. The outcomes of 46 patients were analysed, taking into consideration parental perceptions. Parents were asked to indicate their satisfaction with the medical care and treatment provided using a questionnaire. Aesthetics were evaluated by the parents and doctors using a score (1=perfect, 5=deficient). Major surgical complications (2.2%) were reported only in the case of complex synostosis. Reoperation was necessary in 2.9% of isolated cases and 45.5% of complex cases. In general, parents were satisfied with the medical (1.3) and nursing (1.6) inpatient care. Aesthetic assessments differed between parents and surgeons, although not significantly (P=0.27). The surgeons perceived the results to be better than the parents, especially for complex synostosis (1.3 vs. 2.7). Alopecia and persistent asymmetry led to a worse perception of aesthetics. Persistent bone defects did not influence parental satisfaction. All participating parents would opt for surgery again. Surgery led to satisfactory results with a low risk of severe complications. Nevertheless, the outcomes and limits of the surgical procedure must be communicated effectively to parents, especially in complex cases, to avoid a mismatch in expectations. It would be desirable to implement structured interviews with parents during regular treatment management. PMID- 27117395 TI - Scale-Dependent Viscosity in Polymer Fluids. AB - In this communication, we use simple physical arguments to construct a "phase diagram" of various frequency and wave vector-dependent regimes of effective viscosity for polymer fluids, including nonentangled and entangled melts, semidilute solutions without and with hydrodynamic interactions, as well as the more exotic case of a melt of unconcatenated ring polymers. PMID- 27117396 TI - Endoscopic stenting of acutely obstructing colorectal cancer: a 10-year review from a tertiary referral centre. AB - BACKGROUND: Insertion of self-expanding metallic stents for obstructing colorectal cancer (CRC) is a potential alternative to emergency resection, but evidence regarding efficacy is inconclusive. We aim to assess local efficacy of stent insertion for obstructing CRC, and to establish whether the service could be offered regionally. METHOD: Retrospective patient data analysis using local paper notes and electronic records was performed. All patients underwent stent insertion for an obstructing CRC from April 2004 to March 2014. The main outcome measures were success of stent insertion, complications, further surgery and overall mortality. RESULTS: Eighty-nine stent insertions were performed. Twenty five were performed as a bridge to surgery, 49 due to advanced disease, 11 due to patient co-morbidity and four due to patient choice. Time from referral to stent insertion for emergency referrals was 1-360 h (median 23). Eighty-seven stents were successfully deployed. Perforation occurred in three patients and migration in nine patients. Twenty-one patients underwent planned surgery (time to surgery was 2-208 days, median 24), 14 patients underwent emergency surgery (time to surgery was 0-277 days, median 11). Forty-six patients have died since stent insertion (time to death was 0-42 months, median 6.04). CONCLUSION: Stent insertion for obstructing CRC is a viable alternative to emergency resection, with a low complication rate. Stent insertion may allow a proportion of patients to later undergo planned surgery. Stent insertion carries a lower peri-procedure mortality than emergency resection. An acute stent insertion service for obstructing CRC could potentially be offered at regional level in our Trust. PMID- 27117397 TI - Co3O4 nanosheets as a high-performance catalyst for oxygen evolution proceeding via a double two-electron process. AB - The apparent four-electron oxygen evolution catalyzed by Co3O4 nanosheets indeed proceeds via a double two-electron process, because the generated Co(III)/Co(IV) redox couple can synchronously, quickly, and effectively oxidate the intermediate OOH(ads), and thus accelerate O generation. PMID- 27117398 TI - COSMOS Project: Hemodialysis scenario in Europe. PMID- 27117399 TI - An efficient iron-promoted synthesis of 6H-indolo[2,3-b]quinolines and neocryptolepine derivatives. AB - A facile and practical method for the preparation of 6H-indolo[2,3-b]quinolines and neocryptolepines was developed under the promotion of the easily available ferric trichloride, affording the desired products with moderate to good yields. PMID- 27117400 TI - Lipids and the eye. PMID- 27117401 TI - Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2. AB - During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. Accordingly, HNRNPH levels decline while TRF2-S levels increase during neuronal differentiation. In addition, CRISPR/Cas9-mediated deletion of hnRNPH2 selectively accelerates the NGF-triggered differentiation of rat pheochromocytoma cells into neurons. In sum, HNRNPH is a splicing regulator of Trf2 pre-mRNA that prevents the expression of TRF2-S, a factor implicated in neuronal differentiation. PMID- 27117402 TI - Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers. AB - The molecular linkage between neocortical projection neuron subtype and area development, which enables the establishment of functional areas by projection neuron populations appropriate for specific sensory and motor functions, is poorly understood. Here, we report that Ctip1 controls precision of neocortical development by regulating subtype identity in deep-layer projection neurons. Ctip1 is expressed by postmitotic callosal and corticothalamic projection neurons but is excluded over embryonic development from corticospinal motor neurons, which instead express its close relative, Ctip2. Loss of Ctip1 function results in a striking bias in favor of subcerebral projection neuron development in sensory cortex at the expense of corticothalamic and deep-layer callosal development, while misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. As we report in a paired paper, Ctip1 also controls acquisition of sensory area identity. Therefore, Ctip1 couples subtype and area specification, enabling specific functional areas to organize precise ratios of appropriate output projections. PMID- 27117403 TI - A Molecular-Level Account of the Antigenic Hantaviral Surface. AB - Hantaviruses, a geographically diverse group of zoonotic pathogens, initiate cell infection through the concerted action of Gn and Gc viral surface glycoproteins. Here, we describe the high-resolution crystal structure of the antigenic ectodomain of Gn from Puumala hantavirus (PUUV), a causative agent of hemorrhagic fever with renal syndrome. Fitting of PUUV Gn into an electron cryomicroscopy reconstruction of intact Gn-Gc spike complexes from the closely related but non pathogenic Tula hantavirus localized Gn tetramers to the membrane-distal surface of the virion. The accuracy of the fitting was corroborated by epitope mapping and genetic analysis of available PUUV sequences. Interestingly, Gn exhibits greater non-synonymous sequence diversity than the less accessible Gc, supporting a role of the host humoral immune response in exerting selective pressure on the virus surface. The fold of PUUV Gn is likely to be widely conserved across hantaviruses. PMID- 27117404 TI - Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5. AB - Fbxo30 is an orphan member of the F-box protein family with no known substrate or function. Here we report that, while Fbxo30(-/-) mice exhibit normal development, growth, lifespan, and fertility, the females fail to nurture their offspring as a result of defective mammopoiesis. Mass spectrometry analysis of Fbxo30-associated proteins revealed that Fbxo30 specifically interacts with the bipolar spindle kinesin EG5 (encoded by Kif11). As a result, Fbxo30 targets Eg5 for ubiquitinylation and controls its oscillation during the cell cycle. Correlated with EG5 dysregulation, Fbxo30(-/-) mammary epithelial cells exhibit multiple defects in centrosome homeostasis, mitotic spindle formation, and proliferation. Effects on proliferation, centrosome homeostasis, and mammopoiesis in the Fbxo30( /-) mice were rescued through normalization of Eg5 activity using shRNA and/or an EG5 inhibitor. Our data reveal the Fbxo30-Eg5 interaction as a critical checkpoint in mammopoiesis and a critical role for ubiquitinylation-regulated Eg5 oscillation in the cell cycle. PMID- 27117405 TI - Optimal ROS Signaling Is Critical for Nuclear Reprogramming. AB - Efficient nuclear reprogramming of somatic cells to pluripotency requires activation of innate immunity. Because innate immune activation triggers reactive oxygen species (ROS) signaling, we sought to determine whether there was a role of ROS signaling in nuclear reprogramming. We examined ROS production during the reprogramming of doxycycline (dox)-inducible mouse embryonic fibroblasts (MEFs) carrying the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc [OSKM]) into induced pluripotent stem cells (iPSCs). ROS generation was substantially increased with the onset of reprogramming. Depletion of ROS via antioxidants or Nox inhibitors substantially decreased reprogramming efficiency. Similarly, both knockdown and knockout of p22(phox)-a critical subunit of the Nox (1-4) complex-decreased reprogramming efficiency. However, excessive ROS generation using genetic and pharmacological approaches also impaired reprogramming. Overall, our data indicate that ROS signaling is activated early with nuclear reprogramming, and optimal levels of ROS signaling are essential to induce pluripotency. PMID- 27117407 TI - Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia. AB - WHRN (DFNB31) mutations cause diverse hearing disorders: profound deafness (DFNB31) or variable hearing loss in Usher syndrome type II. The known role of WHRN in stereocilia elongation does not explain these different pathophysiologies. Using spontaneous and targeted Whrn mutants, we show that the major long (WHRN-L) and short (WHRN-S) isoforms of WHRN have distinct localizations within stereocilia and also across hair cell types. Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction. WHRN-S expression, however, is sufficient to maintain stereocilia bundle morphology and function in a subset of hair cells, resulting in some auditory response and no overt vestibular dysfunction. WHRN-S interacts with EPS8, and both are required at stereocilia tips for normal length regulation. WHRN-L localizes midway along the shorter stereocilia, at the level of inter stereociliary links. We propose that differential isoform expression underlies the variable auditory and vestibular phenotypes associated with WHRN mutations. PMID- 27117406 TI - TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection. AB - Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase 1 (Arg1) expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice, type 2 nitric oxide (NO) synthase (NOS2) was detected in inflammatory dendritic cells or macrophages, some of which co-expressed Arg1. In TNF-deficient mice, Arg1 was hyperexpressed, causing an impaired production of NO in situ. A similar phenotype was seen in L. major-infected BALB/c mice. Arg1 deletion in hematopoietic cells protected these mice from an otherwise lethal disease, although their disease-mediating T cell response (Th2, Treg) was maintained. Thus, deletion or TNF-mediated restriction of Arg1 unleashes the production of NO by NOS2, which is critical for pathogen control. PMID- 27117408 TI - KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes. AB - Secretion of RNAs in extracellular vesicles is a newly recognized form of intercellular communication. A potential regulatory protein for microRNA (miRNA) secretion is the critical RNA-induced silencing complex (RISC) component Argonaute 2 (Ago2). Here, we use isogenic colon cancer cell lines to show that overactivity of KRAS due to mutation inhibits localization of Ago2 to multivesicular endosomes (MVEs) and decreases Ago2 secretion in exosomes. Mechanistically, inhibition of mitogen-activated protein kinase kinases (MEKs) I and II, but not Akt, reverses the effect of the activating KRAS mutation and leads to increased Ago2-MVE association and increased exosomal secretion of Ago2. Analysis of cells expressing mutant Ago2 constructs revealed that phosphorylation of Ago2 on serine 387 prevents Ago2-MVE interactions and reduces Ago2 secretion into exosomes. Furthermore, regulation of Ago2 exosomal sorting controls the levels of three candidate miRNAs in exosomes. These data identify a key regulatory signaling event that controls Ago2 secretion in exosomes. PMID- 27117409 TI - The Kinesin KIF21B Regulates Microtubule Dynamics and Is Essential for Neuronal Morphology, Synapse Function, and Learning and Memory. AB - The kinesin KIF21B is implicated in several human neurological disorders, including delayed cognitive development, yet it remains unclear how KIF21B dysfunction may contribute to pathology. One limitation is that relatively little is known about KIF21B-mediated physiological functions. Here, we generated Kif21b knockout mice and used cellular assays to investigate the relevance of KIF21B in neuronal and in vivo function. We show that KIF21B is a processive motor protein and identify an additional role for KIF21B in regulating microtubule dynamics. In neurons lacking KIF21B, microtubules grow more slowly and persistently, leading to tighter packing in dendrites. KIF21B-deficient neurons exhibit decreased dendritic arbor complexity and reduced spine density, which correlate with deficits in synaptic transmission. Consistent with these observations, Kif21b null mice exhibit behavioral changes involving learning and memory deficits. Our study provides insight into the cellular function of KIF21B and the basis for cognitive decline resulting from KIF21B dysregulation. PMID- 27117411 TI - Wnt Ligands Secreted by Subepithelial Mesenchymal Cells Are Essential for the Survival of Intestinal Stem Cells and Gut Homeostasis. AB - Targeting of Wnt signaling represents a promising anti-cancer therapy. However, the consequences of systemically attenuating the Wnt pathway in an adult organism are unknown. Here, we globally prevent Wnt secretion by genetically ablating Wntless. We find that preventing Wnt signaling in the entire body causes mortality due to impaired intestinal homeostasis. This is caused by the loss of intestinal stem cells. Reconstitution of Wnt/beta-catenin signaling via delivery of external Wnt ligands prolongs the survival of intestinal stem cells and reveals the essential role of extra-epithelial Wnt ligands for the renewal of the intestinal epithelium. Wnt2b is a key extra-epithelial Wnt ligand capable of promoting Wnt/beta-catenin signaling and intestinal homeostasis. Wnt2b is secreted by subepithelial mesenchymal cells that co-express either Gli1 or Acta2. Subepithelial mesenchymal cells expressing high levels of Wnt2b are predominantly Gli1 positive. PMID- 27117410 TI - Mechanistic Insights into Cofactor-Dependent Coupling of RNA Folding and mRNA Transcription/Translation by a Cobalamin Riboswitch. AB - Riboswitches are mRNA elements regulating gene expression in response to direct binding of a metabolite. While these RNAs are increasingly well understood with respect to interactions between receptor domains and their cognate effector molecules, little is known about the specific mechanistic relationship between metabolite binding and gene regulation by the downstream regulatory domain. Using a combination of cell-based, biochemical, and biophysical techniques, we reveal the specific RNA architectural features enabling a cobalamin-dependent hairpin loop docking interaction between receptor and regulatory domains. Furthermore, these data demonstrate that docking kinetics dictate a regulatory response involving the coupling of translation initiation to general mechanisms that control mRNA abundance. These results yield a comprehensive picture of how RNA structure in the riboswitch regulatory domain enables kinetically constrained ligand-dependent regulation of gene expression. PMID- 27117412 TI - Distributed Representation of Curvilinear Self-Motion in the Macaque Parietal Cortex. AB - Information about translations and rotations of the body is critical for complex self-motion perception during spatial navigation. However, little is known about the nature and function of their convergence in the cortex. We measured neural activity in multiple areas in the macaque parietal cortex in response to three different types of body motion applied through a motion platform: translation, rotation, and combined stimuli, i.e., curvilinear motion. We found a continuous representation of motion types in each area. In contrast to single-modality cells preferring either translation-only or rotation-only stimuli, convergent cells tend to be optimally tuned to curvilinear motion. A weighted summation model captured the data well, suggesting that translation and rotation signals are integrated subadditively in the cortex. Interestingly, variation in the activity of convergent cells parallels behavioral outputs reported in human psychophysical experiments. We conclude that representation of curvilinear self-motion perception is widely distributed in the primate sensory cortex. PMID- 27117413 TI - PYY-Dependent Restoration of Impaired Insulin and Glucagon Secretion in Type 2 Diabetes following Roux-En-Y Gastric Bypass Surgery. AB - Roux-en-Y gastric bypass (RYGB) is a weight-reduction procedure resulting in rapid resolution of type 2 diabetes (T2D). The role of pancreatic islet function in this restoration of normoglycemia has not been fully elucidated. Using the diabetic Goto-Kakizaki (GK) rat model, we demonstrate that RYGB restores normal glucose regulation of glucagon and insulin secretion and normalizes islet morphology. Culture of isolated islets with serum from RYGB animals mimicked these effects, implicating a humoral factor. These latter effects were reversed following neutralization of the gut hormone peptide tyrosine tyrosine (PYY) but persisted in the presence of a glucagon-like peptide-1 (GLP-1) receptor antagonist. The effects of RYGB on secretion were replicated by chronic exposure of diabetic rat islets to PYY in vitro. These findings indicate that the mechanism underlying T2D remission may be mediated by PYY and suggest that drugs promoting PYY release or action may restore pancreatic islet function in T2D. PMID- 27117415 TI - Independent Regulation of Type VI Secretion in Vibrio cholerae by TfoX and TfoY. AB - Type VI secretion systems (T6SSs) are nanomachines used for interbacterial killing and intoxication of eukaryotes. Although Vibrio cholerae is a model organism for structural studies on T6SSs, the underlying regulatory network is less understood. A recent study showed that the T6SS is part of the natural competence regulon in V. cholerae and is activated by the regulator TfoX. Here, we identify the TfoX homolog TfoY as a second activator of the T6SS. Importantly, despite inducing the same T6SS core machinery, the overall regulons differ significantly for TfoX and TfoY. We show that TfoY does not contribute to competence induction. Instead, TfoY drives the production of T6SS-dependent and T6SS-independent toxins, together with an increased motility phenotype. Hence, we conclude that V. cholerae uses its sole T6SS in response to diverse cues and for distinctive outcomes: either to kill for the prey's DNA, leading to horizontal gene transfer, or as part of a defensive escape reaction. PMID- 27117414 TI - Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. AB - Converging evidence indicates that microRNAs (miRNAs) may contribute to disease risk for schizophrenia (SZ). We show that microRNA-9 (miR-9) is abundantly expressed in control neural progenitor cells (NPCs) but also significantly downregulated in a subset of SZ NPCs. We observed a strong correlation between miR-9 expression and miR-9 regulatory activity in NPCs as well as between miR-9 levels/activity, neural migration, and diagnosis. Overexpression of miR-9 was sufficient to ameliorate a previously reported neural migration deficit in SZ NPCs, whereas knockdown partially phenocopied aberrant migration in control NPCs. Unexpectedly, proteomic- and RNA sequencing (RNA-seq)-based analysis revealed that these effects were mediated primarily by small changes in expression of indirect miR-9 targets rather than large changes in direct miR-9 targets; these indirect targets are enriched for migration-associated genes. Together, these data indicate that aberrant levels and activity of miR-9 may be one of the many factors that contribute to SZ risk, at least in a subset of patients. PMID- 27117416 TI - Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity. AB - Growth of a properly complex dendrite arbor is a key step in neuronal differentiation and a prerequisite for neural circuit formation. Diverse cell surface molecules, such as the clustered protocadherins (Pcdhs), have long been proposed to regulate circuit formation through specific cell-cell interactions. Here, using transgenic and conditional knockout mice to manipulate gamma-Pcdh repertoire in the cerebral cortex, we show that the complexity of a neuron's dendritic arbor is determined by homophilic interactions with other cells. Neurons expressing only one of the 22 gamma-Pcdhs can exhibit either exuberant or minimal dendrite complexity, depending only on whether surrounding cells express the same isoform. Furthermore, loss of astrocytic gamma-Pcdhs, or disruption of astrocyte-neuron homophilic matching, reduces dendrite complexity cell non autonomously. Our data indicate that gamma-Pcdhs act locally to promote dendrite arborization via homophilic matching, and they confirm that connectivity in vivo depends on molecular interactions between neurons and between neurons and astrocytes. PMID- 27117417 TI - Single-Molecule Imaging Reveals a Collapsed Conformational State for DNA-Bound Cohesin. AB - Cohesin is essential for the hierarchical organization of the eukaryotic genome and plays key roles in many aspects of chromosome biology. The conformation of cohesin bound to DNA remains poorly defined, leaving crucial gaps in our understanding of how cohesin fulfills its biological functions. Here, we use single-molecule microscopy to directly observe the dynamic and functional characteristics of cohesin bound to DNA. We show that cohesin can undergo rapid one-dimensional (1D) diffusion along DNA, but individual nucleosomes, nucleosome arrays, and other protein obstacles significantly restrict its mobility. Furthermore, we demonstrate that DNA motor proteins can readily push cohesin along DNA, but they cannot pass through the interior of the cohesin ring. Together, our results reveal that DNA-bound cohesin has a central pore that is substantially smaller than anticipated. These findings have direct implications for understanding how cohesin and other SMC proteins interact with and distribute along chromatin. PMID- 27117418 TI - Critical Role of CD2 Co-stimulation in Adaptive Natural Killer Cell Responses Revealed in NKG2C-Deficient Humans. AB - Infection by human cytomegalovirus (HCMV) leads to NKG2C-driven expansion of adaptive natural killer (NK) cells, contributing to host defense. However, approximately 4% of all humans carry a homozygous deletion of the gene that encodes NKG2C (NKG2C(-/-)). Assessment of NK cell repertoires in 60 NKG2C(-/-) donors revealed a broad range of NK cell populations displaying characteristic footprints of adaptive NK cells, including a terminally differentiated phenotype, functional reprogramming, and epigenetic remodeling of the interferon (IFN)-gamma promoter. We found that both NKG2C(-) and NKG2C(+) adaptive NK cells expressed high levels of CD2, which synergistically enhanced ERK and S6RP phosphorylation following CD16 ligation. Notably, CD2 co-stimulation was critical for the ability of adaptive NK cells to respond to antibody-coated target cells. These results reveal an unexpected redundancy in the human NK cell response to HCMV and suggest that CD2 provides "signal 2" in antibody-driven adaptive NK cell responses. PMID- 27117419 TI - Macroautophagy Proteins Control MHC Class I Levels on Dendritic Cells and Shape Anti-viral CD8(+) T Cell Responses. AB - The macroautophagy machinery has been implicated in MHC class II restricted antigen presentation. Here, we report that this machinery assists in the internalization of MHC class I molecules. In the absence of the autophagy factors Atg5 and Atg7, MHC class I surface levels are elevated due to decreased endocytosis and degradation. Internalization of MHC class I molecules occurs less efficiently if AAK1 cannot be recruited via Atg8/LC3B. In the absence of Atg dependent MHC class I internalization, dendritic cells stimulate CD8(+) T cell responses more efficiently in vitro and in vivo. During viral infections, lack of Atg5 results in enhanced influenza- and LCMV-specific CD8(+) T cell responses in vivo. Elevated influenza-specific CD8(+) T cell responses are associated with better immune control of this infection. Thus, the macroautophagy machinery orchestrates T cell immunity by supporting MHC class II but compromises MHC class I restricted antigen presentation. PMID- 27117420 TI - KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response. AB - The endoplasmic reticulum (ER) unfolded protein response (UPR(er)) pathway plays an important role in helping pancreatic beta cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPR(er) gene expression appears in rodent and human type 2 diabetic (T2D) islets, the underlying molecular mechanisms remain unknown. We show here that germline and beta cell-specific disruption of the lysine acetyltransferase 2B (Kat2b) gene in mice leads to impaired insulin secretion and glucose intolerance. Genome-wide analysis of Kat2b-regulated genes and functional assays reveal a critical role for Kat2b in maintaining UPR(er) gene expression and subsequent beta cell function. Importantly, Kat2b expression is decreased in mouse and human diabetic beta cells and correlates with UPR(er) gene expression in normal human islets. In conclusion, Kat2b is a crucial transcriptional regulator for adaptive beta cell function during metabolic stress by controlling UPR(er) and represents a promising target for T2D prevention and treatment. PMID- 27117421 TI - Accuracy of bioimpedance vector analysis and brain natriuretic peptide in detection of peripheral edema in acute and chronic heart failure. AB - OBJECTIVE: To evaluate the role of bioelectrical impedance vector analysis (BIVA) and brain natriuretic peptide (BNP) in detecting peripheral congestion in heart failure (HF). BACKGROUND: BIVA/BNP are biomarkers for congestion in acute (ADHF) and chronic HF. METHODS: 487 ADHF and 413 chronic HF patients underwent BIVA and BNP tests. RESULTS: BIVA was more accurate than BNP in detecting peripheral congestion both in ADHF (AUC 0.88 vs 0.57 respectively; p < 0.001) and chronic HF patients (AUC 0.89 vs 0.68, respectively; p < 0.001). In ADHF patients, the optimal BNP cut-off for discriminating presence or absence of edema was >870 pg/mL (PPV = 48% and NPV = 58%) whereas in chronic HF it was >216 pg/mL (PPV = 18% and NPV = 95%). The BIVA detected edema when the vector fell into the lower pole of 75th percentile tolerance ellipse (PPV = 84% and NPV = 78%) in ADHF, the lower pole of 50% (PPV = 68% and NPV = 95%) in chronic HF. CONCLUSIONS: In HF patients, BIVA is an easy, fast technique to assess peripheral congestion, and is even more accurate than BNP. PMID- 27117422 TI - Assessment of accuracy and precision of 3D reconstruction of unicompartmental knee arthroplasty in upright position using biplanar radiography. AB - This study aimed to evaluate the precision and accuracy of 3D reconstruction of UKA component position, contact location and lower limb alignment in standing position using biplanar radiograph. Two human specimens with 4 medial UKAs were implanted with beads for radiostereometric analysis (RSA). The specimens were frozen in standing position and CT-scanned to obtain relative positions between the beads, bones and UKA components. The specimens were then imaged using biplanar radiograph (EOS). The positions of the femur, tibia, UKA components and UKA contact locations were obtained using RSA- and EOS-based techniques. Intraclass correlation coefficient (ICC) was calculated for inter-observer reliability of the EOS technique. The average (standard deviation) of the differences between two techniques in translations and rotations were less than 0.18 (0.29) mm and 0.39 degrees (0.66 degrees ) for UKA components. The root mean-square-errors (RMSE) of contact location along the anterior/posterior and medial/lateral directions were 0.84mm and 0.30mm. The RMSEs of the knee rotations were less than 1.70 degrees . The ICCs for the EOS-based segmental orientations between two raters were larger than 0.98. The results suggest the EOS-based 3D reconstruction technique can precisely determine component position, contact location and lower limb alignment for UKA patients in weight-bearing standing position. PMID- 27117423 TI - Bilateral robots for upper-limb stroke rehabilitation: State of the art and future prospects. AB - Robot-assisted bilateral upper-limb training grows abundantly for stroke rehabilitation in recent years and an increasing number of devices and robots have been developed. This paper aims to provide a systematic overview and evaluation of existing bilateral upper-limb rehabilitation devices and robots based on their mechanisms and clinical-outcomes. Most of the articles studied here were searched from nine online databases and the China National Knowledge Infrastructure (CNKI) from year 1993 to 2015. Devices and robots were categorized as end-effectors, exoskeletons and industrial robots. Totally ten end-effectors, one exoskeleton and one industrial robot were evaluated in terms of their mechanical characteristics, degrees of freedom (DOF), supported control modes, clinical applicability and outcomes. Preliminary clinical results of these studies showed that all participants could gain certain improvements in terms of range of motion, strength or physical function after training. Only four studies supported that bilateral training was better than unilateral training. However, most of clinical results cannot definitely verify the effectiveness of mechanisms and clinical protocols used in robotic therapies. To explore the actual value of these robots and devices, further research on ingenious mechanisms, dose-matched clinical protocols and universal evaluation criteria should be conducted in the future. PMID- 27117424 TI - Design, synthesis and biological evaluation of potent FAAH inhibitors. AB - A new series of 3-carboxamido-5-aryl-isoxazoles was designed, synthesized and evaluated for their biological activity. Different pharmacomodulations have been explored and the lipophilicity of these compounds was assessed. Investigation of the in vitro biological activity led to the identification of 5 compounds as potent FAAH inhibitors, their good FAAH inhibition capacity is probably correlated with their suitable lipophilicity. Specifically, compound 25 showed similar inhibition potency against FAAH in comparison with URB597, one of the most potent FAAH inhibitor known to date. PMID- 27117425 TI - Comparison of small molecules and oligonucleotides that target a toxic, non coding RNA. AB - Potential RNA targets for chemical probes and therapeutic modalities are pervasive in the transcriptome. Oligonucleotide-based therapeutics are commonly used to target RNA sequence. Small molecules are emerging as a modality to target RNA structures selectively, but their development is still in its infancy. In this work, we compare the activity of oligonucleotides and several classes of small molecules that target the non-coding r(CCUG) repeat expansion (r(CCUG)(exp)) that causes myotonic dystrophy type 2 (DM2), an incurable disease that is the second-most common cause of adult onset muscular dystrophy. Small molecule types investigated include monomers, dimers, and multivalent compounds synthesized on-site by using RNA-templated click chemistry. Oligonucleotides investigated include phosphorothioates that cleave their target and vivo morpholinos that modulate target RNA activity via binding. We show that compounds assembled on-site that recognize structure have the highest potencies amongst small molecules and are similar in potency to a vivo-morpholino modified oligonucleotide that targets sequence. These studies are likely to impact the design of therapeutic modalities targeting other repeats expansions that cause fragile X syndrome and amyotrophic lateral sclerosis, for example. PMID- 27117426 TI - The alkyl linkers in tandem-homodimers of a beta-sheet-forming nonapeptide affect the self-assembled nanostructures. AB - There is increasing interest in designing smart biomaterials by employing the self-assembly characteristics of synthetic peptides. The use of amyloid-like fibrils is one approach to nanometer- and micrometer-sized supramolecular structures. However, it is generally difficult to predict and/or analyze peptide conformations in nanostructures generated by the self-assembly of beta-sheet forming peptides such as amyloid-beta peptide because each peptide experiences a slightly different environment. Therefore, a methodology for rationally designing peptide-based smart materials is required. In this study, we demonstrate the design and synthesis of tandem-homodimers of a beta-sheet-forming peptide where the amino acid sequence is duplicated in series and joined via alkyl linkers of different chain length. The conformations of these tandem-homodimers within the self-assembled nanoarchitectures in aqueous solution were characterized. Our findings demonstrate that the hydrophobicity and/or flexibility of the alkyl linkers significantly affect the peptide conformation (extended or bent) of the self-assembled peptide nanostructures. We believe that the present tandem homodimerization method represents a new direction for the rational design of peptide-based smart biomaterials. PMID- 27117427 TI - Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors. AB - Fibroblast growth factor receptors (FGFRs) are important oncology targets due to the dysregulation of this signaling pathway in a wide variety of human cancers. We identified a series of pyrazolylaminoquinazoline derivatives as potent FGFR inhibitors with low nanomolar potency. The representative compound 29 strongly inhibited FGFR1-3 kinase activity and suppressed FGFR signaling transduction in FGFR-addicted cancer cells; FGFRs-driven cell proliferation was also strongly inhibited regardless of mechanistic complexity implicated in FGFR activation, which further confirmed that 29 was a potent pan-FGFR inhibitor. The flexibility of our structure offered the potential to preserve good affinity for mutant FGFR, which is important for developing TKIs with long-term efficacy. PMID- 27117428 TI - 1-Sulfonyl-6-Piperazinyl-7-Azaindoles as potent and pseudo-selective 5-HT6 receptor antagonists. AB - A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3, the demethylated version of compound 1c, was profiled against a panel of 106 receptors, channels and transporters, indicating only D3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT6R/D2R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT6R antagonists. PMID- 27117429 TI - Design, synthesis and biological evaluation of 5-fluorouracil-derived benzimidazoles as novel type of potential antimicrobial agents. AB - A series of 5-fluorouracil benzimidazoles as novel type of potential antimicrobial agents were designed and synthesized for the first time. Bioactive assay manifested that some of the prepared compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains in comparison with reference drugs norfloxacin, chloromycin and fluconazole. Noticeably, 3-fluorobenzyl benzimidazole derivative 5c gave remarkable antimicrobial activities against Saccharomyces cerevisiae, MRSA and Bacillus proteus with MIC values of 1, 2 and 4MUg/mL, respectively. Experimental research revealed that compound 5c could effectively intercalate into calf thymus DNA to form compound 5c-DNA complex which might block DNA replication and thus exert antimicrobial activities. Molecular docking indicated that compound 5c should bind with DNA topoisomerase IA through three hydrogen bonds by the use of fluorine atom and oxygen atoms in 5-fluorouracil with the residue Lys 423. PMID- 27117430 TI - Effective molarity in a nucleic acid-controlled reaction. AB - Positioning of reactive functional groups within a DNA duplex can enable chemical reactions that otherwise would not occur to an appreciable extent. However, few studies have quantitatively defined the extent to which the enforced proximity of reaction partners in duplex DNA can favor chemical processes. Here, we measured substantial effective molarities (as high as 25M) afforded by duplex DNA to a reaction involving interstrand cross-link formation between 2'-deoxyadenosine and a 2-deoxyribose abasic (Ap) site. PMID- 27117431 TI - The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21 activated kinase 4 inhibitor. AB - p21-Activated kinases (PAKs) which belong to the family of ste20 serine/threonine protein kinases regulate cytoskeletal reorganization, cell motility, cell proliferation, and oncogenic transformation which are all related to the cellular functions during cancer induction and metastasis. The fact that PAK mutations are detected in multiple tumor tissues makes PAKs a novel therapeutic drug target. In this study, an imidazo[4,5-b]pyridine-based PAK4 inhibitor, KY-04045 (6-Bromo-2 (3-isopropyl-1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridine), was discovered using a virtual site-directed fragment-based drug design and was validated using an inhibition assay. Although PAK4 affinity to KY-04045 seems much weaker than that of the reported PAK4 inhibitors, the location of KY-04045 is clearly defined in the structure of PAK4 co-crystallized with KY-04045. The crystal structure illustrates that the pyrazole and imidazopyridine rings of KY-04045 are sufficient for mediating PAK4 hinge loop interaction. Hence, we believe that KY 04045 can be exploited as a basic building block in designing novel imidazo[4,5 b]pyridine-based PAK4 inhibitors. PMID- 27117432 TI - Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer. AB - We synthesized the novel tricyclic thiolactams 2a-d, 3d-k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco's modified Eagle's medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4'-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68MUM) although the moderate preferential cytotoxicity (PC50 1.68MUM in NDM vs PC50 20MUM in DMEM). The 3'-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96MUM in NDM vs less than 50% inhibition at 30MUM in DMEM). The benzyl 2a and halogenated benzyl derivatives 2b,c showed no cytotoxicity in NDM. In addition, the indole (10, PC50 173.7MUM), lactone (11, PC50 131.7MUM), and lactam (12, PC50 44.8MUM) derivatives showed week or moderate cytotoxicity in NDM. These results indicated that the hydroxy group on the benzyl substituent and tricyclic thiolactam ring were essential for the cytotoxicity in NDM against PANC-1 cell line. Moreover, 3'-hydroxy derivative 3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo. PMID- 27117433 TI - Psychogenic non-epileptic seizures (PNES). AB - Psychogenic non-epileptic seizures (PNES) are defined as change in behavior or consciousness resembling epileptic seizures but which have a psychological origin. PNES are categorized as a manifestation of dissociative or somatoform (conversion) disorders. Video-EEG recording of an event is the gold standard for diagnosis. PNES represent a symptom, not the underlying disease and the mechanism of dissociation is pivotal in the pathophysiology. Predisposing, precipitating and perpetuating factors should be carefully assessed on a case-by-case basis. The process of communicating the diagnosis using a multidisciplinary approach is an important and effective therapeutic step. PMID- 27117434 TI - Plexiform neurolymphomatosis. PMID- 27117435 TI - Super-resolved insights into human immunodeficiency virus biology. AB - The recent development of fluorescence microscopy approaches overcoming the diffraction limit of light microscopy opened possibilities for studying small scale cellular processes. The spatial resolution achieved by these novel techniques, together with the possibility to perform live-cell and multicolor imaging, make them ideally suited for visualization of native viruses and subviral structures within the complex environment of a host cell or organ, thus providing fundamentally new possibilities for investigating virus-cell interactions. Here, we review the use of super-resolution microscopy approaches to study virus-cell interactions, and discuss recent insights into human immunodeficiency virus biology obtained by exploiting these novel techniques. PMID- 27117436 TI - Increased mood symptoms in postmenopausal women related to the polymorphism rs743572 of the CYP17 A1 gene. AB - BACKGROUND: Menopausal and depressive symptoms are highly prevalent after the menopause; but may vary from one population to another and genetics play a key role. OBJECTIVE: To analyze the intensity of these symptoms in relation to the genetic variants of the rs743572 polymorphism of the CYP17 A1 gene in postmenopausal women. METHODS: DNA was extracted from the whole blood of 168 natural postmenopausal women (40-65 years) and tested for the rs743572 polymorphism of the CYP17 A1 gene. Intensity of menopausal (Menopause Rating Scale, MRS) and depressive symptoms (Hospital Anxiety and Depressive Scale, HADS) were correlated to polymorphism genotypes. RESULTS: Women with the GG genotype of the rs743572 polymorphism displayed significantly higher scores for the MRS (items 5 and 6 [irritability and anxiety] and the psychological subscale) and the HADS (total and subscales). CONCLUSION: The intensity of menopausal symptoms related to mood was found higher among postmenopausal women presenting the GG genotype of the rs743572 polymorphism of the CYP17 A1 gene. There is a need for more research in this regard. PMID- 27117437 TI - Pain in Malignant Pleural Mesothelioma: A Prospective Characterization Study. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is associated with severe pain. The underlying neurobiology of this is complex. The primary aim of this study was to characterize pain in MPM. METHODS: This study was undertaken as part of a trial examining radiotherapy for the treatment of pain in MPM (ISRCTN 10644347). Patients had MPM with associated pain for which radiotherapy was planned and a worst pain score >= 4/10. The following assessments were undertaken: clinical neuropathic pain assessment, Brief Pain Inventory (BPI), Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Short form of the McGill Pain Questionnaire (SF-MPQ), and Quantitative Sensory Testing (QST). The relationship of these characteristics and response to radiotherapy was assessed. Unless stated, medians and interquartile range (IQR) are used. RESULTS: Thirty seven patients were recruited. Average pain and worst pain was 4 (4-6) and 8 (6 8), respectively. Higher average pain and higher worst pain scores were associated with higher interference scores on the BPI, P < 0.001 and P < 0.0005. Twenty patients (54%) had a clinical diagnosis of neuropathic pain, and of these, only six patients (40%) screened positively for neuropathic pain using the LANSS. Patients with a high LANSS also had higher BPI and SF-MPQs. The presence of neuropathic pain (clinically or by LANSS) did not predict response to radiotherapy, P < 0.05. The SF-MPQ scores were higher in those with abnormal cool sensation on QST (P = 0.016). CONCLUSION: Pain in mesothelioma varies among patients and may have neuropathic components. An adequate pain assessment is necessary to guide the clinician in the appropriate choice of analgesics. PMID- 27117438 TI - Rigorous Epidemiologic Work Shows Positive Impact of VHA's Efforts to Rein in Opioid Prescribing. PMID- 27117439 TI - Immunosuppressive Environment in Basal Cell Carcinoma: The Role of Regulatory T Cells. AB - Interaction between tumour survival tactics and anti-tumour immune response is a major determinant for cancer growth. Regulatory T cells (T-regs) contribute to tumour immune escape, but their role in basal cell carcinoma (BCC) is not understood. The fraction of T-regs among T cells was analysed by immunohistochemistry followed by automated image analysis in facial BCC, peritumoural skin and normal, buttock skin. Quantitative real-time PCR (qRT-PCR) was performed for FOXP3 and cytokines involved in T-reg attraction and T-cell activation. T-regs comprised 45% of CD4-cells surrounding BCC. FOXP3 was highly expressed in BCC, but absent in buttock skin. Unexpectedly, expression of FOXP3 was increased in peritumoural skin, with the FOXP3/CD3 fractions exceeding those of BCC (p?=?0.0065). Transforming growth factor (TGF)-? and T-reg chemokine expression was increased in BCC and peritumoural skin, but not in buttock skin, with expression levels correlating with FOXP3. T-regs are abundantly present both in BCC and in peritumoural skin, mediating an immunosuppressed microenvironment permissive for skin cancer. PMID- 27117440 TI - 9-Month Efficacy and Safety Study of Testosterone Solution 2% for Sex Drive and Energy in Hypogonadal Men. AB - PURPOSE: We evaluated the continued safety and efficacy of testosterone solution 2% (T-sol) in a 6-month open label extension study following a 3-month, double blind, placebo controlled study in which T-sol was safe and efficacious for sex drive in men with androgen deficiency. MATERIALS AND METHODS: A total of 558 hypogonadal participants with a mean (SD) age of 55 (11) years entered the open label treatment study. Of these patients 275 had previously received placebo (formerly placebo group) and 283 had received active treatment with T-sol (continuing active group) during the double-blind phase. Outcome measures were the proportion of men with total testosterone levels within the normal range; assessment of treatment induced change in sex drive measured using the Sexual Arousal, Interest, and Drive scale; and assessment of treatment induced change in energy measured using the Hypogonadism Energy Diary. RESULTS: At the completion of the open label phase 60% and 66% of the participants had total testosterone levels within the normal range in the formerly placebo and continuing active groups, respectively. Participants assigned to both groups showed baseline to end point improvement in Sexual Arousal, Interest, and Drive score (both p <0.001) and Hypogonadism Energy Diary score (both p <0.001) during the open label phase. No new safety concerns were reported. CONCLUSIONS: Once daily T-sol administered for 6 months in an open label study did not indicate new safety concerns, and the outcomes of low sex drive and low energy showed further improvement after the double-blind phase. PMID- 27117441 TI - Clinical Phenotyping Does Not Differentiate Hunner Lesion Subtype of Interstitial Cystitis/Bladder Pain Syndrome: A Relook at the Role of Cystoscopy. AB - PURPOSE: Identifying Hunner lesions in patients with interstitial cystitis/bladder pain syndrome presents an opportunity for objective classification into Hunner lesion interstitial cystitis/bladder pain syndrome (classic interstitial cystitis) and nonHunner lesion bladder pain syndrome. While currently the former diagnosis requires cystoscopy, limited data suggest that these subtypes can be distinguished without endoscopy based on the degree of bladder focused centricity and the infrequent association with generalized pain conditions. MATERIALS AND METHODS: Patients in a prospective, single center database of interstitial cystitis/bladder pain syndrome who had documented cystoscopic findings were categorized with Hunner lesion interstitial cystitis/bladder pain syndrome or nonHunner lesion bladder pain syndrome. Demographics, pain and symptom scores, voiding symptoms, irritable bowel syndrome and clinical UPOINT (urinary, psychosocial, organ specific, infection, neurological and tenderness) scoring were comparatively analyzed. RESULTS: We reviewed the records of 469 patients, including 359 with documented local anesthetic cystoscopic findings, 44 (12.3%) with Hunner lesion interstitial cystitis/bladder pain syndrome and 315 (87.7%) with nonHunner bladder pain syndrome. Patients with Hunner lesions were older (p = 0.004) and had greater urinary frequency (p = 0.013), more nocturia (p = 0.0004) and higher ICSI (Interstitial Cystitis Symptom Index) scores (p = 0.017). Hunner lesion prevalence was significantly lower in those younger than 50 years vs those 50 years old or older (7.8% vs 14.9%, p = 0.0095). There was no difference in the number of UPOINT phenotype domains reported, overall UPOINT scores or the prevalence of irritable bowel syndrome between the groups. CONCLUSIONS: A subtype of interstitial cystitis with Hunner lesions has worse bladder centric symptoms but did not show a distinct bladder centric phenotype. Given the management implications of distinguishing classic interstitial cystitis from nonHunner lesion bladder pain syndrome, we recommend cystoscopy with local anesthesia in patients diagnosed with interstitial cystitis/bladder pain syndrome. PMID- 27117442 TI - Pregnancy Rates after Testicular Torsion. AB - PURPOSE: To our knowledge the effect of testicular torsion on the pregnancy rate is unknown. In this study we focused on the pregnancy rate, which is the ultimate index of fertility status. MATERIALS AND METHODS: We reviewed the records of 273 patients who presented to our emergency room with testicular torsion between 1994 and 2014. Study inclusion criteria included being in a relationship with the intent to conceive for at least 1 year, age greater than 25 years and a normal contralateral testis. Patients with primary infertility, those who were unwilling to participate or unreachable and those with a history of undescended testis and/or varicocele were excluded from analysis. Patients were contacted by telephone and interviewed according to a standardized questionnaire. Pregnancy rates in the orchiopexy and orchiectomy groups were compared to each other and to the accepted pregnancy rate in the literature. RESULTS: A total of 63 patients met study inclusion criteria, including 41 and 22 in the orchiopexy and orchiectomy groups, respectively. The pregnancy rate in the orchiopexy and orchiectomy groups was 90.2% and 90.9%, respectively (p = 1.0). The accepted pregnancy rate in the general population is 82% to 92%. Mean +/- SD time to pregnancy in the orchiopexy and orchiectomy groups was 6.6 +/- 5.50 and 7.2 +/- 5.4 months, respectively (p = 0.27). CONCLUSIONS: Several studies suggest decreased fertility potential in patients with a history of testicular torsion. However, in the current study in couples in which the male had a history of testicular torsion the pregnancy rate and the interval to pregnancy were within the accepted range of the general population. PMID- 27117443 TI - Serial Anatomical Prostate Ultrasound during Prostate Cancer Active Surveillance. AB - PURPOSE: The growth potential of low grade prostate cancer is unknown and yet it is potentially impactful for the practice of active surveillance. We evaluated the incidence, growth dynamics and clinical significance of changes in prostate lesions on serial transrectal ultrasound among a large cohort of men with prostate cancer managed by active surveillance. MATERIALS AND METHODS: This retrospective study included men with prostate cancer treated with active surveillance at UCSF (University of California-San Francisco) from 2000 to 2014 who underwent a minimum of 2 transrectal ultrasound studies. Study inclusion criteria were prostate specific antigen 20 ng/ml or less, clinical stage T2 or less and biopsy Gleason grade 3 + 4 or less. Progression end points included an increase in imaging stage, a 50% or greater increase in volume and an increase in the number of sites (sextants) with apparent lesions. The relationship between transrectal ultrasound progression and biopsy Gleason upgrade was assessed by univariate and multivariate logistic regression models. RESULTS: The 875 identified patients underwent a median of 5 transrectal ultrasound studies (IQR 3 8). Median followup was 49 months (IQR 27-81). Of the patients 345 (39%) progressed on serial transrectal ultrasound, including 51 by size, 265 by the number of lesion sites and 279 by stage. Median time to progression was 14 months. Transrectal ultrasound progression was independently associated with biopsy upgrade (OR 1.8, 95% CI 1.3-2.5, p <0.01). CONCLUSIONS: Local progression on transrectal ultrasound was associated with Gleason upgrade at biopsy. These results suggest that stable imaging findings on transrectal ultrasound may allow for increased intervals between biopsies among men on active surveillance. A prospective study is required to evaluate the usefulness of such a practice. PMID- 27117444 TI - Metals in sediments: bioavailability and toxicity in a tropical reservoir used for public water supply. AB - Sediments may be a repository of contaminants in freshwater ecosystems. One way to assess the quality of this compartment, in terms of potentially bioavailable metals, is by the analysis of acid-volatile sulfide (AVS) and simultaneously extracted metals (SEM). In order to investigate the bioavailability, toxicity, and compartmentalization of different metals (Cd, Cr, Cu, Ni, Pb, Zn), sampling of surface sediments was performed at nine stations along the Paiva Castro reservoir (Sao Paulo, Brazil). The metals were analyzed using atomic absorption spectroscopy. Sediment organic matter (OM), organic carbon (OC), and grain size were also measured. The parameters pH, EH, temperature, and dissolved oxygen were determined at the sediment-water interface. Chronic and acute toxicological tests were performed with sediments from the area where water was extracted for the public water supply. Low levels of OM, associated with loss of stratification in the water column, explained the relatively low AVS values. The molar ratio ?[SEM] [AVS]/fOC was less than 130 mmol/kg(-1) for all the sampling stations, indicating that the metals were not bioavailable. With the exception of Cd, metal levels were in accordance with background concentrations and the threshold effect level (TEL) established by the Canadian Council of Ministers of the Environment. The ecotoxicological tests confirmed the absence of toxic effects to biota. Application of principal component analysis indicated the presence of four compartments along the reservoir: (1) a riverine zone, potentially threatened by contamination with Cd; (2) an intermediate zone; (3) a limnic area; and (4) the area where water was taken for the public water supply. PMID- 27117445 TI - Assessment of eco-environmental quality of Western Taiwan Straits Economic Zone. AB - Regional eco-environmental quality is the key and foundation to the sustainable socio-economic development of a region. Eco-environmental quality assessment can reveal the capacity of sustainable socio-economic development in a region and the degree of coordination between social production and the living environment. As part of a new development strategy for Fujian Province, the Western Taiwan Straits Economic Zone (hereafter referred to as the Economic Zone) provides an important guarantee for the development of China's southeastern coastal area. Based on ecological and remote sensing data on the Economic Zone obtained in 2000, 2005, and 2010, this study investigated county-level administrative regions with a comprehensive index of eco-environmental indicators. An objective weighting method was used to determine the importance of each indicator. This led to the development of an indicator system to assess the eco-environmental quality of the economic zone. ArcGIS software was used to assess the eco-environmental quality of the economic zone based on each indicator. The eco-environmental quality index (EQI) of the county-level administrative regions was calculated. The overall eco-environmental quality of the Economic Zone during the period studied is described and analyzed. The results show that the overall eco environmental quality of the Economic Zone is satisfactory, but significant intraregional differences still exist. The key to improving the overall eco environmental quality of this area is to restore vegetation and preserve biodiversity. PMID- 27117446 TI - Vancomycin dosing nomograms targeting high serum trough levels in different populations: pros and cons. AB - PURPOSE: Utilization of higher doses of vancomycin to achieve the trough concentrations of 15-20 mg/L for complicated infections has been recommended by the Infectious Diseases Society of America clinical practice guideline in recent years. Concerning this recommendation, several nomograms have been constructed targeting this optimal trough level range in different populations of patients. In this review, we have collected available nomograms targeting high trough serum levels of vancomycin, particularly comparing their advantages and limitations. METHOD: The data were collected by searching Scopus, PubMed, Google scholar, Medline, and Cochrane database systematic reviews. The key words used as search terms were "vancomycin", "high trough level", "dosing nomogram", "dosing strategy", "neonates", "critically ill", "pediatrics", and "hemodialysis". We have included 17 related human studies published up to the date of this publication. RESULTS & CONCLUSION: Most of the available nomograms have determined the doses according to body weight and renal function. Their initial predicting success rate were 44-76 % for non-critically ill patients, 42-84 % for critically ill patients, 54 % for one nomogram specially designed for hemodialysis patients, and 71 % for the only nomogram developed for neonates. Based on validation studies, in most of cases, using a vancomycin dosing nomogram significantly improved and accelerated achievement of target trough concentrations. However, it should be noted that there are limited data about patients' clinical and microbiological outcomes and they are only validated in narrow groups of patients. Thus, their widespread application could not be encouraged for all patients before performing adequately powered, prospective randomized studies. PMID- 27117447 TI - Sandwich electrode designed for high performance lithium-ion battery. AB - We fabricated a sandwich structure Li-ion battery electrode by trapping micron sized silicon between a copper current collector and a graphene coating. During dynamic electrochemical cycles, the volume change of the silicon can be buffered by the coating through the deformation of soft graphenes. This structure can effectively prevent the silicon particles from escaping from the current collector while keeping the buffered graphene coating integrated and unbroken during deformation. The electrodes could be maintained for 400 cycles at a constant charge capacity of 1000 mA h g(-1). PMID- 27117448 TI - Development and validation of the Patient Benefit Index for the dermatocosmetic treatment of aged skin. AB - This study aimed to develop and validate an instrument for the assessment of patient-relevant benefit in dermatocosmetic treatment, i.e., skin care, of aged skin. Based on an open item collection with 33 elderly persons, items on patient relevant treatment goals were collected. An expert panel selected 20 items to be most relevant and feasible for the questionnaire named Patient Benefit Index for Aged Skin (PBI-AS). The instrument, which assesses goal importance and achievement, was tested in a cognitive debriefing and validated in a longitudinal study (n = 80) along with the Dry Skin Area and Severity Index (DASI) and the Dermatology Quality of Life Index (DLQI) as convergent validation criteria. The cognitive debriefing showed the good practicability and feasibility of the instrument. Significant correlation with change in DASI (r = -0.527; p < 0.001) supports convergent validity of the PBI-AS. By contrast, correlation with DLQI was poor, indicating the different constructs. The PBI-AS is a valid and feasible tool for the patient-centered assessment of dermatocosmetic treatment benefit in aged skin. PMID- 27117449 TI - Establishing a baseline on the distribution and pattern of occurrence of Salvadora persica L. with meteorological data and assessing its adaptation in the adjacent warmed-up zones. AB - The natural occurrence of Salvadora persica L., stretching from the coastal area of the Arabian sea to northward along the Indus floodplains, was surveyed to document the pattern of its occurrence with the available meteorological record showing increasing trends of frost northwards. Information was compiled from various sources to generate the past and present temperature data in order to establish relationship between the changing temperature factors and the extent of the area available due to climate change over the years for introducing species beyond its range of natural distribution. In addition, the species was experimentally introduced in the warmed-up zones to monitor its performance and to evaluate its adaptability. The reconnaissance survey showed that the natural populations of thorn forest communities with S. persica, as associate, are now surviving only as degraded remnants. Its common occurrence is documented in zones where the mean winter temperatures are above the threshold level of frost, whereas it is rarely found in zones where it drops below this level for a single month, which seems to be its range edge. S. persica does not occur in zones where low temperature could persist for 2 months. Recent temperature data suggests that the month of December has warmed up above the threshold level; therefore, it was expected that correspondingly the range edge of the frost-sensitive species has potentially shifted further northwards. The response of the species introduced at the experimental sites beyond its natural occurrence suggests high survival and growth, demonstrating its adaptability to the new sites beyond its limit of distribution. PMID- 27117450 TI - Sex hormone-binding globulin has no effect on salivary testosterone. PMID- 27117451 TI - Erratum to: prostate cancer arising in ectopic prostatic tissue within the left seminal vesicle: a rare case diagnosed with multi-parametric magnetic resonance imaging and magnetic resonance imaging-transrectal ultrasound fusion biopsy. PMID- 27117452 TI - Obinutuzumab for the treatment of indolent lymphoma. AB - Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody designed for strong induction of direct cell death and antibody-dependent cell-mediated cytotoxicity. The Phase III GADOLIN trial tested the clinical efficacy of obinutuzumab plus bendamustine followed by obinutuzumab monotherapy in rituximab refractory indolent non-Hodgkin lymphoma versus treatment with bendamustine alone. It demonstrated significantly longer progression-free survival for the obinutuzumab-containing regimen in this difficult to treat patient group. Based on the results of this trial, US FDA approval was most recently granted for obinutuzumab in the treatment of follicular lymphoma that has relapsed after or was refractory to a rituximab-containing regimen. This article summarizes the available data on chemistry, pharmacokinetics, clinical efficacy and safety of obinutuzumab in the treatment of indolent non-Hodgkin lymphoma. PMID- 27117453 TI - Corrigendum to "Zearalenone impairs the male reproductive system functions via inducing structural and functional alterations of sertoli cells" [Environ. Toxicol. Pharmacol. 42 (2016) 146-155]. PMID- 27117454 TI - NHS England provides a major boost for general practice. PMID- 27117455 TI - Ultrathin bronchoscopy for solitary pulmonary lesions in a region endemic for tuberculosis: a randomised pilot trial. AB - BACKGROUND: The evaluation of solitary pulmonary lesions (SPL) requires a balance between procedure-related morbidity and diagnostic yield, particularly in areas where tuberculosis (TB) is endemic. Data on ultrathin bronchoscopy (UB) for this purpose is limited. To evaluate feasibility and safety of UB compared to SB for diagnosis of SPL in a TB endemic region. METHODS: In this prospective randomised trial we compared diagnostic yield and adverse events of UB with standard-size bronchoscopy (SB), both combined with fluoroscopy, in a cohort of patients with SPL located beyond the visible range of SB. RESULTS: We included 40 patients (mean age 55.2 years, 45 % male) with malignant SPL (n = 16; 40 %), tuberculous SPL (n = 11; 27.5 %) and other benign SPL (n = 13; 32.5 %). Mean procedure time in UB and SB was 30.6 and 26.0 min, respectively (p = 0.15). By trend, adverse events were recorded more often with UB than with SB (30.0 vs. 5.0 %, p = 0.091), including extensive coughing (n = 2), blocked working channel (n = 2), and arterial hypertension requiring therapeutic intervention (n = 1), all with UB. The overall diagnostic yield of UB compared to SB was 55.0 % vs. 80.0 %, respectively (p = 0.18). Sensitivity for the diagnosis of malignancy of UB and SB was 50.0 % and 62.5 %, respectively (p = 0.95). CONCLUSION: UB is not superior to SB for the evaluation of SPL in a region endemic with tuberculosis, when combined with fluoroscopic guidance only. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02490059 ). PMID- 27117456 TI - MicroRNA Target Recognition: Insights from Transcriptome-Wide Non-Canonical Interactions. AB - MicroRNAs (miRNAs) are small non-coding RNAs (~22 nucleotides) regulating gene expression at the post-transcriptional level. By directing the RNA-induced silencing complex (RISC) to bind specific target mRNAs, miRNA can repress target genes and affect various biological phenotypes. Functional miRNA target recognition is known to majorly attribute specificity to consecutive pairing with seed region (position 2-8) of miRNA. Recent advances in a transcriptome-wide method of mapping miRNA binding sites (Ago HITS-CLIP) elucidated that a large portion of miRNA-target interactions in vivo are mediated not only through the canonical "seed sites" but also via non-canonical sites (~15-80%), setting the stage to expand and determine their properties. Here we focus on recent findings from transcriptome-wide non-canonical miRNA-target interactions, specifically regarding "nucleation bulges" and "seed-like motifs". We also discuss insights from Ago HITS-CLIP data alongside structural and biochemical studies, which highlight putative mechanisms of miRNA target recognition, and the biological significance of these non-canonical sites mediating marginal repression. PMID- 27117457 TI - Navigating sticky areas in transdermal product development. AB - The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form. PMID- 27117458 TI - A bridge to silencing: Co-assembling anionic nanoparticles of siRNA and hyaluronan sulfate via calcium ion bridges. AB - Therapeutic implementation of RNA interference (RNAi) through delivery of short interfering RNA (siRNA) is still facing several critical hurdles, which mostly can be solved through the use of an efficient delivery system. We hereby introduce anionic siRNA nanoparticles (NPs) co-assembled by the electrostatic interactions of the semi-synthetic polysaccharide hyaluronan-sulfate (HAS), with siRNA, mediated by calcium ion bridges. The NPs have an average size of 130nm and a mild (-10mV) negative surface charge. Transmission electron microscopy (TEM) using gold-labeled components and X-ray photoelectron spectroscopy (XPS) demonstrated the spatial organization of siRNA molecules in the particle core, surrounded by a layer of HAS. The anionic NPs efficiently encapsulated siRNA, were stable in physiological-relevant environments and were cytocompatible, not affecting cell viability or homeostasis. Efficient cellular uptake of the anionic siRNA NPs, associated with potent gene silencing (>80%), was observed across multiple cell types, including murine primary peritoneal macrophages and human hepatocellular carcinoma cells. In a clinically-relevant model of acute inflammatory response in IL-6-stimulated human hepatocytes, STAT3 silencing induced by HAS-Ca(2+)-siRNA NPs resulted in marked decrease in the total and activated STAT3 protein levels, as well as in the expression levels of downstream acute phase response genes. Collectively, anionic NPs prove to be an efficient and cytocompatible delivery system for siRNA. PMID- 27117459 TI - Hypoalbuminemia predicts clinical outcome in patients with type B acute aortic dissection after endovascular therapy. AB - BACKGROUND: Few studies have reported that serum albumin (SA) levels on admission were associated with increased risk of long-term outcomes in patients with type B acute aortic dissection (AAD). The aim of this study was to investigate the effect of admission levels of SA on survival among patients with type B AAD undergoing endovascular therapy (EVT). METHODS: A total of 131 patients with type B AAD undergoing EVT were retrospectively enrolled and followed up for 2.1years. They were divided into hypoalbuminemia and nonhypoalbuminemia groups. We analyzed the incidence of inhospital complications and long-term mortality. Kaplan-Meier curves and multivariable Cox regression analyses were used to investigate the associations between SA levels and survival. RESULTS: Among 131 type B AAD patients, hypoalbuminemia was detected in 61 (46.6%) at admission. Compared to those without hypoalbuminemia, patients with hypoalbuminemia did not have higher inhospital complications; however, Kaplan-Meier analysis showed that they did have a significantly lower survival rate (73.8% vs 92.5%; log-rank chi(2)=9.8; P=.002). Multivariable Cox regression analysis further revealed that hypoalbuminemia was an independent predictor of long-term mortality among patients with type B AAD (hazard ratio, 4.28; 95% confidence interval, 1.36 13.47; P=.013), over 2.1years. CONCLUSIONS: Hypoalbuminemia is common in type B AAD patients and is independently associated with increased risk of long-term death. Renal dysfunction may be the main pathophysiological mechanism underlying hypoalbuminemia in patients with type B AAD. PMID- 27117460 TI - Impending paradoxical embolus: A bedside diagnosis in the Emergency Department. PMID- 27117461 TI - The role of combined electrocardiogram criteria in differential diagnosis of acute pericarditis: PR segment and QT interval. PMID- 27117462 TI - Injury patterns and outcomes of ice-fishing in the United States. AB - INTRODUCTION: Fishing is a common pastime. In the developed world, it is commonly performed as a recreational activity. We aim to determine injury patterns and outcomes among patients injured while ice fishing. METHODS: Data on initial emergency department visits from the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) from 2009-2014 were analyzed. All patients with fishing related injuries were included. Primary endpoint was rate of admission or transfer. Secondary endpoints were defined a priori anatomical injury categories and patients were assigned into groups. Descriptive and power analysis was performed between patients with ice-fishing and traditional fishing related injuries. RESULTS: We identified 8220 patients who sustained fishing related injuries, of which n=85 (1%) involved ice fishing. Ice fishing injuries occurred primarily in males (88%) with a mean age of 39.4years +/-17.5 (std dev). The most common injuries related to ice fishing were: orthopedic/musculoskeletal (46%), minor trauma (37%), and major trauma (6%). Hot thermal injuries (burns) were the fourth most common type of ice-fishing injury (5%) but rarely occurred in warmer fishing months (<1%, P=.004). Cold thermal injuries (1%) and hypothermia (0%) were rare among ice-fishing injuries and immersion/drowning occurred in 5% of cases. The rate of admission/transfer was significantly greater in ice-fishing (11%) than the traditional fishing patients 3%, (P<.001), power was 90%. CONCLUSION: Ice fishing is associated with more severe injury patterns and more thermal injuries and immersion injuries than traditional fishing. Providers and participants should be aware of the potential risks and benefits and counseled appropriately. PMID- 27117463 TI - Ultrasonography as a tool for prehospital recognition of tension pneumothorax: Preliminary data. PMID- 27117464 TI - Use of WhatsApp application for orthopedic consultations in the ED. PMID- 27117465 TI - The effectiveness of a newly developed reduction method of anterior shoulder dislocations; Sool's method. AB - OBJECTIVE: Nearly a dozen reduction methods for the treatment of anterior shoulder dislocation have been reported, but the majority are painful and require patients to be in the supine or prone position. METHODS: This retrospective cohort study was conducted in a university-affiliated emergency department (ED). Sool's method and traditional shoulder reduction methods (TSRMs) were performed for the patient with anterior shoulder dislocation. Fifty-nine eligible patients were recruited; 35 were treated with TSRMs, wherease 24 were treated with Sool's method. RESULTS: The rate of successful reduction was 80% (26/35) in the TSRM group and 75% (18/24) in the Sool's method group (P=.75). The length of stay in the ED was 72.3minutes in the Sool's method group and 98.4minutes in the TSRM group (P=.037). No significant difference was observed between the neurovascular deficit before and after reduction in either group. The procedural time of successfully reduced cases in patients treated by Sool's method was shorter than that of the failed cases (P=.015). CONCLUSIONS: Sool's method was as successful as other methods at reducing shoulder dislocation and has demonstrated encouraging results, including significant reduction in length of stay in the ED and unnecessary use of sedation. Sool's method is technically easy and requires only a place to sit and a single operator. PMID- 27117466 TI - In Reply. PMID- 27117467 TI - Sequencing Circulating Cell-Free DNA: The Potential to Refine Precision Cancer Medicine. PMID- 27117468 TI - Impact of High-Sensitivity Troponin I Testing with Sex-Specific Cutoffs on the Diagnosis of Acute Myocardial Infarction. AB - BACKGROUND: High-sensitivity cardiac troponin I (hs-cTnI) assays show sex dependent differences in the 99th percentile of healthy populations, with concentrations in women approximately 50% lower. The adoption of sex-specific cutoffs seems appropriate, although it is not yet clear what effect these will have on acute myocardial infarction (AMI) diagnosis and management. METHODS: We conducted a retrospective pre- and postchangeover analysis of troponin I testing in the 6 months before and after moving from the contemporary Abbott Architect TnI assay (cTnI) to hs-cTnI at 2 tertiary centers in Australia and New Zealand. The cTnI cutoff was 30 ng/L for both sexes, whereas a female-specific cutoff of 16 ng/L was adopted upon changeover to hsTnI. RESULTS: Changeover from the cTnI assay to the hs-cTnI assay increased the number of female patients with increased troponin I concentrations at both sites (from 29.7% to 34.9% and from 22.4% to 30.8%; P < 0.001). There was no statistically significant change in the number of men with increased concentrations in the same time period (P = 0.09). The increased percentage of women with increased troponin I was not associated with an increase in the number of women with AMI diagnoses at either center. Angiographic data available from 1 center showed no change in the percentage of angiograms performed in women. CONCLUSIONS: Although increasing the proportion of women with increased troponin I, adopting sex-specific cutoffs with the hs-cTnI assay did not lead to an increase in AMI diagnoses in females, or in the number of women undergoing angiography. PMID- 27117469 TI - Cell-Free DNA Analysis of Targeted Genomic Regions in Maternal Plasma for Non Invasive Prenatal Testing of Trisomy 21, Trisomy 18, Trisomy 13, and Fetal Sex. AB - BACKGROUND: There is great need for the development of highly accurate cost effective technologies that could facilitate the widespread adoption of noninvasive prenatal testing (NIPT). METHODS: We developed an assay based on the targeted analysis of cell-free DNA for the detection of fetal aneuploidies of chromosomes 21, 18, and 13. This method enabled the capture and analysis of selected genomic regions of interest. An advanced fetal fraction estimation and aneuploidy determination algorithm was also developed. This assay allowed for accurate counting and assessment of chromosomal regions of interest. The analytical performance of the assay was evaluated in a blind study of 631 samples derived from pregnancies of at least 10 weeks of gestation that had also undergone invasive testing. RESULTS: Our blind study exhibited 100% diagnostic sensitivity and specificity and correctly classified 52/52 (95% CI, 93.2%-100%) cases of trisomy 21, 16/16 (95% CI, 79.4%-100%) cases of trisomy 18, 5/5 (95% CI, 47.8%-100%) cases of trisomy 13, and 538/538 (95% CI, 99.3%-100%) normal cases. The test also correctly identified fetal sex in all cases (95% CI, 99.4%-100%). One sample failed prespecified assay quality control criteria, and 19 samples were nonreportable because of low fetal fraction. CONCLUSIONS: The extent to which free fetal DNA testing can be applied as a universal screening tool for trisomy 21, 18, and 13 depends mainly on assay accuracy and cost. Cell-free DNA analysis of targeted genomic regions in maternal plasma enables accurate and cost effective noninvasive fetal aneuploidy detection, which is critical for widespread adoption of NIPT. PMID- 27117470 TI - Ready, Set, Type! Proteomics vs Agglutination for Escherichia coli H Antigen Confirmation. PMID- 27117471 TI - A Novel Peptidomic Approach to Strain Typing of Clinical Acinetobacter baumannii Isolates Using Mass Spectrometry. AB - BACKGROUND: Acinetobacter baumannii is a common nosocomial pathogen and strain typing methods play an important role in hospital outbreak investigations and epidemiologic surveillance. We describe a method for identifying strain-specific peptide markers based on LC-MS/MS profiling of digested peptides. This method classified a test set of A. baumannii isolates collected from a hospital outbreak with discriminatory performance exceeding that of MALDI-TOF mass spectrometry. METHODS: Following the construction of a species "pan-peptidome" by in silico translation and digestion of whole genome sequences, a hypothetical set of genome specific peptides for an isolate was constructed from the disjoint set of the pan peptidome and the isolate's calculated peptidome. The genome-specific peptidome guided selection of highly expressed genome-specific peptides from LC-MS/MS experimental profiles as potential peptide markers. The species specificity of each experimentally identified genome-specific peptide was confirmed through a Unipept lowest common ancestor analysis. RESULTS: Fifteen A. baumannii isolates were analyzed to derive a set of genome- and species-specific peptides that could be used as peptide markers. Identified peptides were cross-checked with protein BLAST against a set of 22 A. baumannii whole genome sequences. A subset of these peptide markers was confirmed to be present in the actual peptide profiles generated by multiple reaction monitoring and targeted LC-MS/MS. The experimentally identified peptides separated these isolates into 6 strains that agreed with multilocus sequence typing analysis performed on the same isolates. CONCLUSIONS: This approach may be generalizable to other bacterial species, and the peptides may be useful for rapid MS strain tracking of isolates with broad application to infectious disease diagnosis. PMID- 27117472 TI - Acceptable Analytical Variation May Exceed High-Sensitivity Cardiac Troponin I Cutoffs in Early Rule-Out and Rule-In Acute Myocardial Infarction Algorithms. PMID- 27117473 TI - Is the 2-h Sample Really Necessary in the Oral Glucose Tolerance Test in Pregnant Females? PMID- 27117474 TI - The paradox of the evidence about invasive fungal infection prevention. PMID- 27117475 TI - Clobetasol promotes remyelination in a mouse model of neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can produce marked neurological deficit. Current NMO therapies include immunosuppressants, plasma exchange and B-cell depletion. Here, we evaluated 14 potential remyelinating drugs emerging from prior small molecule screens done to identify drugs for repurposing in multiple sclerosis and other demyelinating neurological diseases. Compounds were initially evaluated in oligodendrocyte precursor cell (OPC) and cerebellar slice cultures, and then in a mouse model of NMO produced by intracerebral injection of anti-AQP4 autoantibody (AQP4-IgG) and human complement characterized by demyelination with minimal axonal damage. The FDA-approved drug clobetasol promoted differentiation in OPC cultures and remyelination in cerebellar slice cultures and in mice. Intraperitoneal administration of 2 mg/kg/day clobetasol reduced myelin loss by ~60 %, even when clobetasol was administered after demyelination occurred. Clobetasol increased the number of mature oligodendrocytes within lesions without significantly altering initial astrocyte damage or inflammation. These results provide proof-of-concept for the potential utility of a remyelinating approach in the treatment of NMO. PMID- 27117476 TI - Body composition, nutritional status, and endothelial function in physically active men without metabolic syndrome--a 25 year cohort study. AB - BACKGROUND: The purpose of this analysis was to investigate the relationship between body composition, metabolic parameters and endothelial function among physically active healthy middle-aged and older men. METHODS: Out of 101 asymptomatic men prospectively tracked for traditional cardiovascular risk factors (mean observation period 25.1 years), 55 metabolically healthy individuals who maintained stable leisure time physical activity (LTPA) level throughout the observation and agreed to participate in the body composition assessment were recruited (mean age 60.3 +/- 9.9 years). Body composition and raw bioelectrical parameters were measured with bioelectrical impedance analysis (BIA). Microvascular endothelial function was evaluated by means of the reactive hyperemia index (RHI) using Endo-PAT2000 system. RESULTS: Strong correlations were observed between lifetime physical activity (PA), aerobic fitness and most of analyzed body composition parameters. The strongest inverse correlation was found for fat mass (p < 0.01) while positive relationship for fat-free mass (p < 0.01), total body water (p < 0.05 for current aerobic capacity and p < 0.01 for historical PA), body cell mass (p < 0.001), muscle mass (p < 0.001), calcium and potassium (p < 0.01 and p < 0.001 for current aerobic capacity and p < 0.001 and p < 0.01 for historical PA, respectively) and glycogen mass (p < 0.001). Among metabolic parameters, HDL cholesterol (HDL-C) and uric acid were significantly associated with most body composition indicators. Regarding endothelial function, a negative correlation was found for RHI and body mass (p < 0.05) while positive relationship for RHI and body cell mass (p < 0.05), calcium (p < 0.05) and potassium mass (p < 0.05). Impaired endothelial function was observed among 8 subjects. Among bioelectrical parameters, impedance (Z) and resistance (R) normalized for subjects' height were negatively related with body mass, body mass index (BMI) and waist circumference (p < 0.001); while reactance (Xc) normalized for patients' height was negatively related with body mass (p < 0.05). The mean phase angle value was relatively high (8.83 +/- 1.22) what reflects a good level of cellularity and cell function. Phase angle was positively related with body mass and BMI (p < 0.05). CONCLUSIONS: Both fat mass and muscle mass components are important predictors of metabolic profile. Maintaining regular high PA level and metabolically healthy status through young and middle adulthood may have beneficial influence on body composition parameters and may prevent age-related decrease of fat-free mass and endothelial dysfunction. PMID- 27117477 TI - NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation. AB - How neuronal proteomes self-organize is poorly understood because of their inherent molecular and cellular complexity. Here, focusing on mammalian synapses we use blue-native PAGE and 'gene-tagging' of GluN1 to report the first biochemical purification of endogenous NMDA receptors (NMDARs) directly from adult mouse brain. We show that NMDARs partition between two discrete populations of receptor complexes and ~1.5 MDa supercomplexes. We tested the assembly mechanism with six mouse mutants, which indicates a tripartite requirement of GluN2B, PSD93 and PSD95 gate the incorporation of receptors into ~1.5 MDa supercomplexes, independent of either canonical PDZ-ligands or GluN2A. Supporting the essential role of GluN2B, quantitative gene-tagging revealed a fourfold molar excess of GluN2B over GluN2A in adult forebrain. NMDAR supercomplexes are assembled late in postnatal development and triggered by synapse maturation involving epigenetic and activity-dependent mechanisms. Finally, screening the quaternary organization of 60 native proteins identified numerous discrete supercomplexes that populate the mammalian synapse. PMID- 27117478 TI - Terminalia Chebula provides protection against dual modes of necroptotic and apoptotic cell death upon death receptor ligation. AB - Death receptor (DR) ligation elicits two different modes of cell death (necroptosis and apoptosis) depending on the cellular context. By screening a plant extract library from cells undergoing necroptosis or apoptosis, we identified a water extract of Terminalia chebula (WETC) as a novel and potent dual inhibitor of DR-mediated cell death. Investigation of the underlying mechanisms of its anti-necroptotic and anti-apoptotic action revealed that WETC or its constituents (e.g., gallic acid) protected against tumor necrosis factor induced necroptosis via the suppression of TNF-induced ROS without affecting the upstream signaling events. Surprisingly, WETC also provided protection against DR mediated apoptosis by inhibition of the caspase cascade. Furthermore, it activated the autophagy pathway via suppression of mTOR. Of the WETC constituents, punicalagin and geraniin appeared to possess the most potent anti apoptotic and autophagy activation effect. Importantly, blockage of autophagy with pharmacological inhibitors or genetic silencing of Atg5 selectively abolished the anti-apoptotic function of WETC. These results suggest that WETC protects against dual modes of cell death upon DR ligation. Therefore, WETC might serve as a potential treatment for diseases characterized by aberrantly sensitized apoptotic or non-apoptotic signaling cascades. PMID- 27117480 TI - Knowledge on legislation of abortion and experience of abortion among female youth in Nepal: A cross sectional study. AB - BACKGROUND: Abortion has been legal in Nepal since 2002 and the country has made striking progress in rolling out induced abortion services. It led to well-known changes in reproductive behavior, however knowledge about legislation and abortion experience by female youth has been least investigated. This paper is an attempt to examine knowledge about legislation of abortion and abortion experiences among female youth in Nepal. METHODS: This paper uses data from the Nepal Demographic and Health Survey (NDHS 2011). The analysis is confined to female youth aged 15-24 (n = 5050). Both bivariate and multivariate analyses have been performed to describe the knowledge about law and experience of abortion. The bivariate analysis (chi-square test) was applied to examine the association between dependent variables and female youth's demographic, socioeconomic, and cultural characteristics. Besides bivariate analysis, the net effect of each independent variable on the dependent variable after controlling for the effect of other predictors has also been measured through multivariate analysis (logistic regression). RESULTS: Only two-fifth (41%) female youth was aware of abortion legislation in the country. Knowledge on at least one condition of abortion law is even lower (21%). Less than two percent (1.5%) female youth reported that they ever had an abortion. The multivariate analysis found that the knowledge and experience of abortion varied with different settings. Youth aged 20-24 [adjusted odds ratio (aOR) = 1.3; 95% CI 1.7-5.0)], who have higher education (primary aOR = 1.89, ; 95% CI 1.5-2.5 secondary aOR = 4.6; 95% CI 3.7 5.9), who were from rich households (aOR = 1.5; 95% CI 1.2-1.7), who had high autonomy (aOR = 1.29; 95% CI 1.02-1.64) were more likely to be aware compared to their counterparts about legislation of abortion. In the other hand, female from Dalit (aOR = 0.55; 95% CI 0.5-0.7 and Janajati aOR = 0.72; 95% CI 0.6-0.8) caste, who were married (aOR = 0.80; 95% CI 0.7-0.9), who were from Muslim (aOR = 0.54; 95% CI 0.3-0.9) and who resided in Hill (aOR = 0.63 ; 95% CI 0.5-0.8) and Terai/plain area (aOR = 0.74; 95% CI 0.6-0.9) were less likely to be aware about the law. Similarly, female youth who have knowledge on abortion law (aOR = 2.8; ; 95% CI 1.6-4.8), who have primary (aOR = 5.2; 95% CI 1.6-16.9) and secondary education (aOR = 3.8; 95% CI 1.2-12.8), married (aOR = 7.7; 95% CI 3.8-12.9), who had higher number of children ever born [1-2 children aOR = 1.9; 95% CI 1.1-3.6 and 3 or more children aOR = 3.4; 95% CI 1.1-10.9), who were from rich households (aOR = 2.62 ;95% CI 1.3-5.4), who have high autonomy (aOR = 3.0; 95% CI 1.6-5.8), who had experienced sexual violence (aOR = 1.91; 95% CI 1.1-8.7) were more likely to undergone abortion compared to their counterparts. CONCLUSION: Knowledge about legislation of abortion and conditions of abortion law is low among female youth. Awareness program should target these youth as they are more likely to be sexually active. There is a need of comprehensive education about abortion to these youth which can help eventually reduce unsafe abortion that take a large toll on women's life. PMID- 27117479 TI - Impact of a well-developed primary care system on the length of stay in emergency departments in the Netherlands: a multicenter study. AB - BACKGROUND: The Netherlands has a well-developed primary care system, which increasingly collaborates with hospital emergency departments (EDs). In this setting, insight into crowding in EDs is limited. This study explored links between patients' ED Length of Stay (LOS) and their care pathways. METHODS: Observational multicenter study of 7000 ED patient records from 1 February 2013. Seven EDs spread over the Netherlands, representing overall Dutch EDs, were included. This included three EDs with and four EDs without an integrated primary care-physician (PCP) cooperative, forming one Emergency Care Access Point (ECAP). The main outcome was LOS of patients comparing different care pathways (origin and destination of ED attenders). RESULTS: The median LOS of ED attenders was 130.0 min (IQR 79.0-140.0), which increased with patients' age. Random coefficient regression analysis showed that LOS for patients referred by medical professionals was 32.9 min longer compared to self-referred patients (95% CI 27.7 38.2 min). LOS for patients admitted to hospital was 41.2 min longer compared to patients followed-up at the outpatient clinic (95% CI 35.3-46.6 min), 49.9 min longer compared to patients followed-up at the PCP (95% CI 41.5-58.3 min) and 44.6 min longer compared to patients who did not receive follow-up (95% CI 38.3 51.0 min). There was no difference in LOS between hospitals with or without an ECAP. CONCLUSIONS: With 130 min, the median LOS in Dutch EDs is relatively short, comparing to other Western countries, which ranges from 176 to 480 min. Although integration of EDs with out-of-hours primary care was not related to LOS, the strong primary care system probably contributed to the overall short LOS of ED patients in the Netherlands. PMID- 27117481 TI - A qualitative exploration of health workers' and clients' perceptions of barriers to completing four antenatal care visits in Morogoro Region, Tanzania. AB - Antenatal care (ANC) remains an important contact point on the continuum of care for mothers and children in low- and middle-income countries. In Tanzania, the proportion of pregnant women completing at least four ANC visits (ANC-4) dropped from 70% to 43% between 1999 and 2010. To identify potential causes of the decline in the number of ANC visits, we conducted qualitative research at 18 health centres in Morogoro Region, exploring providers' communication about ANC visits and clients' and providers' perceptions of changes in ANC services and barriers to completing four visits. We also observed counselling messages delivered during 203 ANC consultations. Our results indicate that provider communication about ANC visit recommendations is inadequate, and confusion exists among clients about when and how often they should attend. Participants highlighted how the scale up of Prevention of Mother-to-Child Transmission, with routine human immunodeficiency virus testing for women and their male partners, presents additional barriers for some women. Changes to the timing and content of ANC services following the adoption of the Focused ANC model was described by participants as changing women's perceptions and decisions in how they utilize ANC services. In particular, condensed delivery of technical interventions fostered a sense among clients that multiple visits are unnecessary. Other barriers that may contribute to declining ANC-4 include changing norms about family planning and birth spacing, out-of-pocket costs for clients and informal practices adopted by health facilities and providers such as turning women away who attend early in pregnancy or are not accompanied by male partners. Further research is needed to determine the role and extent that these barriers may be contributing to declining ANC-4. Issues of poor communication, supply inadequacies and informal practices, deserve immediate attention from the health system. PMID- 27117482 TI - How to do (or not to do)... gender analysis in health systems research. AB - Gender-the socially constructed roles, behaviours, activities and attributes that a given society considers appropriate for males, females and other genders affects how people live, work and relate to each other at all levels, including in relation to the health system. Health systems research (HSR) aims to inform more strategic, effective and equitable health systems interventions, programs and policies; and the inclusion of gender analysis into HSR is a core part of that endeavour. We outline what gender analysis is and how gender analysis can be incorporated into HSR content, process and outcomes Starting with HSR content, i.e. the substantive focus of HSR, we recommend exploring whether and how gender power relations affect females and males in health systems through the use of sex disaggregated data, gender frameworks and questions. Sex disaggregation flags female-male differences or similarities that warrant further analysis; and further analysis is guided by gender frameworks and questions to understand how gender power relations are constituted and negotiated in health systems. Critical aspects of understanding gender power relations include examining who has what (access to resources); who does what (the division of labour and everyday practices); how values are defined (social norms) and who decides (rules and decision-making). Secondly, we examine gender in HSR process by reflecting on how the research process itself is imbued with power relations. We focus on data collection and analysis by reviewing who participates as respondents; when data is collected and where; who is present; who collects data and who analyses data. Thirdly, we consider gender and HSR outcomes by considering who is empowered and disempowered as a result of HSR, including the extent to which HSR outcomes progressively transform gender power relations in health systems, or at least do not further exacerbate them. PMID- 27117483 TI - Does distrust in providers affect health-care utilization in China? AB - How trust affects health-care utilization is not well-understood, especially in low- and middle-income countries. This article focuses on China, a middle-income country where low trust in health-care settings has become a prominent issue, but actual levels of distrust and their implications for utilization are unknown. We conducted a nationally representative survey of the Chinese population (November 2012 to January 2013), which resulted in a sample of 3680 adult men and women. Respondents rated their trust in different types of health-care providers. Using multivariate logistic and negative binomial regression models, we estimated the association between distrust in clinics and respondents' hospital visits in the last year; whether they had sought hospital treatment first for two common symptoms (headache, cold) in the last 2 months; and whether they said they would go first to a hospital if they had a minor or major illness. We analysed these associations before and after adjusting for performance evaluations of clinics and hospitals, controlling for sex, age, education, income, insurance status, household registration and self-assessed health. We found that distrust in hospitals is low, but distrust in clinics is high and strongly associated with increased hospital utilization, especially for minor symptoms and illnesses. Further research is needed to understand the reasons for distrust in clinics because its effects are not fully accounted for by poor evaluations of their competence. PMID- 27117484 TI - Anti-biofilm activity of the metabolites of Streptomyces chrestomyceticus strain ADP4 against Candida albicans. AB - Candida albicans is a commensal but a significant opportunistic pathogen. It forms biofilms, which protect them against anti-Candida compounds. Therefore, an agent capable of disrupting the Candida biofilms will be useful in the treatment of such infections. The metabolites of Streptomyces chrestomyceticus strain ADP4 displayed strong anti-Candida activity, hence were investigated further for their ability to inhibit biofilm. Strong inhibition of biofilms produced by several reference strains of C. albicans was observed with BIC90 values ranging from 4 to 8 MUg/mL. The anti-biofilm activity of ADP4 metabolites appeared to involve membrane disruption and leakage of cellular materials. Also, it effectively inhibited Candida cells from adhering to polystyrene surface and inhibited their conversion to the hyphal state, thereby preventing further development of the biofilm by the adherent cells. This is the first such report on the metabolites produced by any strain of S. chrestomyceticus. PMID- 27117485 TI - A framework for visual communication at Nature. AB - The scientific journal Nature, published weekly since 1869, serves as an excellent case study in visual communication. While journals are becoming increasingly specialist, Nature remains firmly multidisciplinary; and unlike many scientific journals, it contains original journalism, opinion pieces, and expert analysis in addition to peer-reviewed research papers. This variety of content types-covering an extensive range of scientific disciplines-translates into a wide and varied audience, and the need to employ an equally wide variety of communication styles. For example, a research paper may employ technical language to communicate to a highly specialized audience in that field, whereas a news story on the same subject will explain the science to an educated lay audience, often adding a wider context and stripping out acronyms. Each type of piece will use a communication approach tailored for its intended audience. This is true for visual content as well: the intended audience of a scientific figure, illustration or data visualization will determine the design approach to that visual. At Nature, given the high volume of content plus high quality standards, this process is applied in a fairly systematic way, using a framework to guide creative decision-making. That framework is described here, along with a discussion of best practices for the design of research figures and graphics by context. PMID- 27117486 TI - Taking climate change seriously: An analysis of op-ed articles in Spanish press. AB - In this article, we study the evolution of opinion genres regarding climate change in three Spanish newspapers ( El Pais, El Mundo, and ABC). Analyzing the op-ed articles in these newspapers, we observe a significant change in the evolution of opinion. While denialism was very present in conservative press in 2007, 7 years later it is almost absent from El Mundo, and its presence in ABC is much lower and inactive: this shows that scientific consensus has prevailed over time and Spanish denialism has weakened, exclusively supported by political arguments by the most conservative parties. PMID- 27117487 TI - A cross-cultural comparison of high school students' responses to a science centre show on the physics of sound in South Africa. AB - We report on the attitudes and ideas developed by students from three distinct school groups to a science show about sound. We addressed two research questions: (1) How do the students compare with respect to their (a) attitudes to the sound show and to science in general and (b) changes in conceptual understanding as a result of the show and (2) what changes could be made to the show, and to science shows in general, that would be sensitive to the cultural and language differences of the groups? These were addressed by multiple-choice, pre- and post tests comprising both attitudinal and conceptual questions. Our results pointed to a common enjoyment of the show but a different understanding of concepts and consequent learning, which suggest that science shows (and science teaching) need to be adjusted to accommodate different cultural groups for maximum impact. PMID- 27117488 TI - Gender and support for expert advisers and elected officials in the US public sphere. AB - This article uses data from the US General Social Survey to examine the relationship between gender and support for different forms of cultural authority. An analysis of public attitudes about expert advisers and elected officials involved in policy decisions related to science reveals that women assign more influence than men to experts in decisions about global warming and stem cell research but not genetically modified food. In contrast, men assign more influence than women to elected leaders across policy domains. Importantly, gender differences in support for expert advisers and elected leaders are independent of variation in more general attitudes about science and politics. Overall, this article suggests that there are underlying differences in men's and women's attitudes about cultural authority and it highlights the importance of gender in understanding the political legitimacy of scientists in the United States. PMID- 27117489 TI - Which question do polls about evolution and belief really ask, and why does it matter? AB - Data from studies conducted to determine acceptance rates for evolution are often misleading. The questions that are asked and compared to one another do not always give an authentic picture of respondents' views. Quite often, polls, such as those by IPSOS, Gallup, and PEW, also run together questions asking respondents' beliefs in concepts like God with questions asking respondents' beliefs about concepts like evolution. The two are distinct and should not be confused. One might believe in evolution while having wrong beliefs about it, whereas someone else might decide not to believe in evolution while having accurate beliefs about it. Distinguishing between " belief in" and " belief about" might help remove an unrecognized confounding element from these studies. PMID- 27117490 TI - Pyridine Based Antitumour Compounds Acting at the Colchicine Site. AB - Antimitotics binding at the colchicine site of tubulin are important antitumour and vascular disrupting agents. Pyridines and azines are privileged scaffolds in medicinal chemistry and in recent years many colchicine site ligands (CSL) have incorporated them into their structures with the aim of improving their pharmacokinetic and pharmacodynamics properties. CSL have been classified according to their chemical structures and the chemical structures of the pyridine and azine containing antimitotic compounds are described. The designed principles behind the structural modifications and the achieved effect on the biological activity upon inclusion of these heterocycles are also discussed. Lessons from the achievements and failures have been extracted and future perspectives delineated. PMID- 27117491 TI - First study of fossil rodent middens as source of paleoparasitological evidences (northwestern Patagonia, Argentina). PMID- 27117492 TI - Two novel bi-functional hybrid materials constructed from POMs and a Schiff base with excellent third-order NLO and catalytic properties. AB - The first polyoxometalates modified by a porphyrin-resembling planar Schiff base have been successfully designed and synthesized under hydrothermal conditions. The third-order NLO responses indicated that they are excellent third-order NLO materials. Their catalytic performances are also investigated. PMID- 27117493 TI - Severe, reversible nelarabine-induced neuropathy and myelopathy. PMID- 27117494 TI - Chronic cerebrovascular dysfunction after traumatic brain injury. AB - Traumatic brain injuries (TBI) often involve vascular dysfunction that leads to long-term alterations in physiological and cognitive functions of the brain. Indeed, all the cells that form blood vessels and that are involved in maintaining their proper function can be altered by TBI. This Review focuses on the different types of cerebrovascular dysfunction that occur after TBI, including cerebral blood flow alterations, autoregulation impairments, subarachnoid hemorrhage, vasospasms, blood-brain barrier disruption, and edema formation. We also discuss the mechanisms that mediate these dysfunctions, focusing on the cellular components of cerebral blood vessels (endothelial cells, smooth muscle cells, astrocytes, pericytes, perivascular nerves) and their known and potential roles in the secondary injury cascade. (c) 2016 Wiley Periodicals, Inc. PMID- 27117496 TI - Corrigendum. PMID- 27117495 TI - A framework for in vitro systems toxicology assessment of e-liquids. AB - Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful. Research assessing the potential effects of ENDS exposure in humans is currently limited and inconclusive. New products are emerging with numerous variations in designs and performance parameters within and across brands. Acknowledging these challenges, we present here a proposed framework for an in vitro systems toxicology assessment of e-liquids and their aerosols, intended to complement the battery of assays for standard toxicity assessments. The proposed framework utilizes high-throughput toxicity assessments of e-liquids and their aerosols, in which the device-to-device variability is minimized, and a systems-level investigation of the cellular mechanisms of toxicity is an integral part. An analytical chemistry investigation is also included as a part of the framework to provide accurate and reliable chemistry data solidifying the toxicological assessment. In its simplest form, the framework comprises of three main layers: (1) high-throughput toxicity screening of e-liquids using primary human cell culture systems; (2) toxicity-related mechanistic assessment of selected e liquids, and (3) toxicity-related mechanistic assessment of their aerosols using organotypic air-liquid interface airway culture systems. A systems toxicology assessment approach is leveraged to enable in-depth analyses of the toxicity related cellular mechanisms of e-liquids and their aerosols. We present example use cases to demonstrate the suitability of the framework for a robust in vitro assessment of e-liquids and their aerosols. PMID- 27117497 TI - Protein environmental effects on iron-sulfur clusters: A set of rules for constructing computational models for inner and outer coordination spheres. AB - The structural properties and reactivity of iron-sulfur proteins are greatly affected by interactions between the prosthetic groups and the surrounding amino acid residues. Thus, quantum chemical investigations of the structure and properties of protein-bound iron-sulfur clusters can be severely limited by truncation of computational models. The aim of this study was to identify, a priori, significant interactions that must be included in a quantum chemical model. Using the [2Fe-2S] accessory cluster of the FeFe-hydrogenase as a demonstrative example with rich electronic structural features, the electrostatic and covalent effects of the surrounding side chains, charged groups, and backbone moieties were systematically mapped through density functional theoretical calculations. Electron affinities, spin density differences, and delocalization indexes from the quantum theory of atoms in molecules were used to evaluate the importance of each interaction. Case studies for hydrogen bonding and charged side-chain interactions were used to develop selection rules regarding the significance of a given protein environmental effect. A set of general rules is proposed for constructing quantum chemical models for iron-sulfur active sites that capture all significant interactions from the protein environment. This methodology was applied to our previously used models in galactose oxidase and the 6Fe-cluster of FeFe-hydrogenase. (c) 2016 Wiley Periodicals, Inc. PMID- 27117498 TI - An analysis of tumor control probability of stereotactic body radiation therapy for lung cancer with a regrowth model. AB - We report a modeling study of tumor response after stereotactic body radiation therapy (SBRT) for early-stage non-small-cell lung carcinoma using published clinical data with a regrowth model. A linear-quadratic inspired regrowth model was proposed to analyze the tumor control probability (TCP) based on a series of published data of SBRT, in which a tumor is controlled for an individual patient if number of tumor cells is smaller than a critical value K cr. The regrowth model contains radiobiological parameters such as alpha, alpha/beta the potential doubling time T p. This model also takes into account the heterogeneity of tumors and tumor regrowth after radiation treatment. The model was first used to fit TCP data from a single institution. The extracted fitting parameters were then used to predict the TCP data from another institution with a similar dose fractionation scheme. Finally, the model was used to fit the pooled TCP data selected from 48 publications available in the literature at the time when this manuscript was written. Excellent agreement between model predictions and single institution data was found and the extracted radiobiological parameters were alpha = 0.010 +/- 0.001 Gy(-1), alpha /beta = 21.5 +/- 1.0 Gy and T p = 133.4 +/- 7.6 d. These parameters were alpha = 0.072 +/- 0.006 Gy(-1), alpha/beta = 15.9 +/- 1.0 Gy and T p = 85.6 +/- 24.7 d when extracted from multi-institution data. This study shows that TCP saturates at a BED of around 120 Gy. A few new dose-fractionation schemes were proposed based on the extracted model parameters from multi-institution data. It is found that the regrowth model with an alpha/beta around 16 Gy can be used to predict the dose response of lung tumors treated with SBRT. The extracted radiobiological parameters may be useful for comparing clinical outcome data of various SBRT trials and for designing new treatment regimens. PMID- 27117499 TI - Re: Letter to the Editor in response to 'How much excess body weight, blood sugar, or age can double the risk of hypertension'? PMID- 27117500 TI - Prevalence and risk factors of child neglect in the general population. AB - OBJECTIVES: Child neglect is a major public health problem. It is the most frequently reported and substantiated form of maltreatment in youth protective services, and its effects are the most harmful to children. Yet, very few studies have documented its extent and risk factors in the general population. This study aims at documenting the annual prevalence and risk factors of child-neglect behaviours in the general population according to child age and parental gender. STUDY DESIGN: Cross-sectional population survey. METHODS: A sample consisting of 3298 mothers and 1104 fathers of children between six months and 15 years old responded to a telephone survey. The prevalence of neglect was documented using the short version of the Parent-Report Multidimensional Neglectful Behaviour Scale for three child-age categories. RESULTS: Annual prevalence rates vary between 20.6% (95% CI 18.2-23.1) and 29.4% (95% CI 26.6-32.4) depending on the children's age. Although statements do not vary by parent gender, the factors associated with neglect depend on whether they are reported by the mother or the father. Mothers present more mental health problems, while fathers struggle more commonly with difficulties related to their life context. CONCLUSIONS: Measuring neglect in the population presents numerous challenges. Nonetheless, this study made it possible to document the extent of neglectful behaviours in the general population. The results confirm that the risk factors related to neglectful behaviours are similar to those documented in studies concerning situations of neglect reported to the authorities. Other studies are needed to better understand how this phenomenon is manifested in the population. PMID- 27117501 TI - Failure of NIMV and operator factor: when making things work, sometimes it is hard. PMID- 27117503 TI - Benefits of Zubex beyond glycemic control: Evidence of the antiatherogenic effect. AB - OBJECTIVE: To determine the effect of Zubex (aqueous extract of Curcuma longa linn, Iron murakab, Eugenia jambolana, Lin seed or flflax seed, processed egg shell calcium and Asphaltum) on plasma sialic acid (PSA) along with cardiovascular (CV) risk factors in streptozotocin-induced diabetic rats. METHODS: Thirty male albino rats were divided into groups (1-6) with 5 rats in each group. Group 1 and 2 served as normal control (NC) and diabetic control (DC), respectively, and were given normal saline only. Groups 3-5 were given Zubex in different doses 100-400 mg/(kg day). Group 6 received glibenclamide 600 MUg/(kg day) orally as a reference drug. Fasting plasma glucose (FPG) and PSA levels were determined at baseline after every 2 weeks for 10 weeks. The other parameters including blood lipids and hepatic enzymes were determined at baseline and at the end of the study. Finally, the liver was subjected to histological examination. RESULTS: Compared with DC group, Zubex treated groups showed signifificant decline in FPG levels (P<0.05). At the endpoint, the decrease in PSA concentration was significant (P<0.05) from baseline at the doses of 200 and 400 mg/(kg day) only and insignifificant at the dose of 100 mg/ (kg day). Statistically signifificant improvements were observed in blood lipids at the doses of 200 and 400 mg/kg (P<0.05) compared with DC; but, the improvement was insignifificant in low density lipoprotein-cholesterol and high density lipoprotein-cholesterol at the dose of 100 mg/ (kg day). Signifificant decreases were also found in hepatic enzyme levels at all the doses of Zubex (P<0.05). Histological examination showed marked improvement in streptozotocin induced liver injury after treatment of all the 3 doses of Zubex. CONCLUSION: Zubex could ameliorate PSA and other diabetic complications effectively and may be a useful alternative/adjuvant in diabetes treatment. PMID- 27117502 TI - A single active catalytic site is sufficient to promote transport in P glycoprotein. AB - P-glycoprotein (Pgp) is an ABC transporter responsible for the ATP-dependent efflux of chemotherapeutic compounds from multidrug resistant cancer cells. Better understanding of the molecular mechanism of Pgp-mediated transport could promote rational drug design to circumvent multidrug resistance. By measuring drug binding affinity and reactivity to a conformation-sensitive antibody we show here that nucleotide binding drives Pgp from a high to a low substrate-affinity state and this switch coincides with the flip from the inward- to the outward facing conformation. Furthermore, the outward-facing conformation survives ATP hydrolysis: the post-hydrolytic complex is stabilized by vanadate, and the slow recovery from this state requires two functional catalytic sites. The catalytically inactive double Walker A mutant is stabilized in a high substrate affinity inward-open conformation, but mutants with one intact catalytic center preserve their ability to hydrolyze ATP and to promote drug transport, suggesting that the two catalytic sites are randomly recruited for ATP hydrolysis. PMID- 27117504 TI - Secretory pathway retention of mutant prion protein induces p38-MAPK activation and lethal disease in mice. AB - Misfolding of proteins in the biosynthetic pathway in neurons may cause disturbed protein homeostasis and neurodegeneration. The prion protein (PrP(C)) is a GPI anchored protein that resides at the plasma membrane and may be misfolded to PrP(Sc) leading to prion diseases. We show that a deletion in the C-terminal domain of PrP(C) (PrPDelta214-229) leads to partial retention in the secretory pathway causing a fatal neurodegenerative disease in mice that is partially rescued by co-expression of PrP(C). Transgenic (Tg(PrPDelta214-229)) mice show extensive neuronal loss in hippocampus and cerebellum and activation of p38-MAPK. In cell culture under stress conditions, PrPDelta214-229 accumulates in the Golgi apparatus possibly representing transit to the Rapid ER Stress-induced ExporT (RESET) pathway together with p38-MAPK activation. Here we describe a novel pathway linking retention of a GPI-anchored protein in the early secretory pathway to p38-MAPK activation and a neurodegenerative phenotype in transgenic mice. PMID- 27117505 TI - UK FASHIoN: feasibility study of a randomised controlled trial of arthroscopic surgery for hip impingement compared with best conservative care. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a syndrome of hip or groin pain associated with shape abnormalities of the hip joint. Treatments include arthroscopic surgery and conservative care. This study explored the feasibility of a randomised controlled trial to compare these treatments. OBJECTIVES: The objectives of this study were to estimate the number of patients available for a full randomised controlled trial (RCT); to explore clinician and patient willingness to participate in such a RCT; to develop consensus on eligibility criteria, surgical and best conservative care protocols; to examine possible outcome measures and estimate the sample size for a full RCT; and to develop trial procedures and estimate recruitment and follow-up rates. METHODS: Pre-pilot work: we surveyed all UK NHS hospital trusts (n = 197) to identify all FAI surgeons and to estimate how much arthroscopic FAI surgery they performed. We interviewed a purposive sample of 18 patients, 36 physiotherapists, 18 surgeons and two sports physicians to explore attitudes towards a RCT and used consensus building methods among them to develop treatment protocols and patient information. Pilot RCT: we performed a pilot RCT in 10 hospital trusts. Patients were randomised to receive either hip arthroscopy or best conservative care and then followed up at 3, 6 and 12 months using patient-reported questionnaires for hip pain and function, activity level, quality of life, and a resource-use questionnaire. Qualitative recruitment intervention: we performed semistructured interviews with all researchers and clinicians involved in the pilot RCT in eight hospital trusts and recorded and analysed diagnostic and recruitment consultations with eligible patients. RESULTS: We identified 120 surgeons who reported treating at least 1908 patients with FAI by hip arthroscopy in the NHS in the financial year 2011/12. There were 34 hospital trusts that performed >= 20 arthroscopic FAI operations in the year. We found that clinicians were positive about a RCT: only half reported equipoise, but most said that they would be prepared to randomise patients. Patients strongly supported a RCT, but expressed concerns about its design; these were used to develop patient information for the pilot RCT. We developed a surgical protocol and showed that this could be used in a RCT. We developed a physiotherapy-led exercise-based package of best conservative care called 'personalised hip therapy' and showed that this was practicable. In the pilot RCT, we recruited 42 out of 60 eligible patients (70%) across nine sites. The mean duration and recruitment rate across all sites were 4.5 months and one patient per site per month, respectively. The lead site recruited for the longest period (9.3 months) and accrued the largest number of patients (2.1 patients per month). We recorded and analysed 84 diagnostic and recruitment consultations in 60 patients and used these to develop a model for an optimal recruitment consultation. We identified the International Hip Outcome Tool at 12 months as an appropriate outcome measure and estimated the sample size for a full trial as 344 participants: a number that could be recruited in 25 centres over 18 months. CONCLUSION: We have demonstrated that it is feasible to perform a RCT to establish the clinical effectiveness of hip arthroscopy compared with best conservative care for FAI. We have designed a full trial and developed and tested procedures for it, including an innovative approach to recruitment. We propose that a full trial be implemented. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27117506 TI - The role of dendritic cells in immune regulation of nasal polyps. AB - Nasal polyps (NPs) are caused by a variety of immune cells and inflammatory cells. However, as the most potent antigen-presenting cells in the immune system, the role of dendritic cells (DCs) in NPs is still unclear. In the present research, we studied the role of DCs in immune regulation of NPs. Thirty patients with NPs, who served as the experimental group, received systemic and local glucocorticoids for 4-7 d, and specimens were collected prior to hormone treatment and during surgery. Normal middle turbinate mucosa tissues from 18 patients who underwent nasal septum surgery were collected as controls. The expression levels of CD83, tumor necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and eosinophils (EOS) in NP tissues before and after glucocorticoid therapy and in control middle turbinate mucosa tissues were studied. After glucocorticoid therapy, the expression levels of CD83, TNF-alpha, IL-4 and EOS decreased significantly. In addition, the expression of IL-4 was lower than that of TNF-alpha, reversing the Th2 cytokine-dominant condition. CD83 and EOS showed a positive correlation. DCs participated in the development and progression of NPs and could promote the generation of Th2 cytokines. After interference by glucocorticoid therapy, DCs could inhibit the expression of Th2 cytokines and induce secretion of Th1 cytokines. DCs and EOS thus might both play roles in promoting the development and progression of NPs, but the underlying mechanism requires further study. PMID- 27117507 TI - Boron-doped diamond oxidation of amoxicillin pharmaceutical formulation: Statistical evaluation of operating parameters, reaction pathways and antibacterial activity. AB - The electrochemical oxidation of a commercial amoxicillin formulation over a boron-doped diamond (BDD) anode was investigated. The effect of initial COD concentration (1-2 g/L), current density (30-50 mA/cm2), treatment time (15-90 min), initial pH (3-9) and electrolyte concentration (2-4 g/L NaCl) on COD removal was assessed through a factorial design methodology. For the range of conditions in question, the first three single effects, as well as the interaction between COD and time were the most important ones in terms of mass of COD removed. Liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) was employed to identify major transformation by-products (TBPs); thirteen compounds were detected as TBPs of AMX electrochemical degradation, while several others appear in the original formulation. AMX degradation occurs though the following pathways: (i) hydroxylation mainly in the benzoic ring, (ii) opening of beta-lactam ring followed by decarboxylation, hydroxylation and re-arrangement, and (iii) bond cleavage between the carbons of amino and amide groups. Furthermore, the process is accompanied by the release of several ions, i.e. nitrate, sulfate and ammonium. The antibiotic activity of AMX up to 1000 mg/L was tested against Klebsiella pneumoniae and Enterococcus faecalis reference strains; both bacteria are completely inactivated at this concentration but the activity is reduced substantially at lower concentrations. Oxidized samples still exhibit some antibacterial activity (50-60%) which is due to TBPs and active chlorine species present in the liquid phase. The latter are generated from chloride ions and enhance considerably AMX degradation rates. PMID- 27117508 TI - Bioavailability and risk assessment of potentially toxic elements in garden edible vegetables and soils around a highly contaminated former mining area in Germany. AB - Although soil contamination by potentially toxic elements (PTEs) in Europe has a history of many centuries, related problems are often considered as having been dealt with due to the enforcement of tight legislations. However, there are many unsolved issues. We aimed to assess PTE levels in highly contaminated soils and in garden edible vegetables using human health risk indices in order to evaluate the availability and mobilization of arsenic (As), copper (Cu), manganese (Mn), mercury (Hg), lead (Pb), and zinc (Zn). In four gardens in Germany, situated on, or in the vicinity of, a mine dump area, we planted beans (Phaseolus vulgaris ssp. nanus), carrots (Daucus sativus) and lettuce (Lactuca sativa ssp. capitata). We examined soil-to-plant mobilization of elements using transfer coefficient (TC), as well as soil contamination using contamination factor (CF), enrichment factor (EF), and bioaccumulation index (Igeo). In addition, we tested two human health risk assessment indices: Soil-induced hazard quotient (HQS) (representing the "direct soil ingestion" pathway), and vegetable-induced hazard quotient (HQV) (representing the "vegetable intake" pathway). The studied elements were highly elevated in the soils. The values in garden 2 were especially high (e.g., Pb: 13789.0 and Hg: 36.8 mg kg-1) and largely exceeded the reported regulation limits of 50 (for As), 40 (Cu), 400 (Pb), 150 (Zn), and 5 (Hg) mg kg-1. Similarly, element concentrations were very high in the grown vegetables. The indices of CF, EF and Igeo were enhanced even to levels that are rarely reported in the literature. Specifically, garden 2 indicated severe contamination due to multi element deposition. The contribution of each PTE to the total of measured HQS revealed that Pb was the single most important element causing health risk (contributing up to 77% to total HQS). Lead also posed the highest risk concerning vegetable consumption, contributing up to 77% to total HQV. The presence of lead in both cases was followed by that of As, Mn and Hg. We conclude that in multi-element contamination cases, along with high-toxicity elements (here, Pb, As and Hg) other elements may also be responsible for increasing human health risks (i.e., Mn), due to the possibility of adverse synergism of the PTEs. PMID- 27117509 TI - Management of obesity in patients with type 2 diabetes mellitus in primary care. AB - AIMS: Obesity and being overweight is the most powerful risk factor accounting for 80-90% of patients with type 2 diabetes mellitus (T2DM). The epidemic of obesity is driving the diabetes epidemic to alarming levels and primary care is becoming an important setting for obesity management in T2DM in India. Yet many primary care providers feel ill-equipped or inadequately supported to address obesity in patients with diabetes. This article reviews the most recent and strongest evidence-based strategies that may aid physicians in management of obesity in patients with T2DM in primary care. MATERIAL AND METHODS: A systematic literature search of MEDLINE using the search terms Obesity, Obesity in T2DM, weight loss and Primary Care was conducted. The American Diabetes Association, National Institute for Health, National Institute of Health and Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN) and World Health Organization websites were also searched. Most studies in this area are observational in design with few randomized controlled trials (RCTs). Articles and studies involving meta-analysis or RCTs were preferred over other types. RESULTS AND CONCLUSION: Effective weight management treatment in T2DM patient can be implemented in the primary care setting. Evidence based individualized lifestyle and pharmacologic measures supported by behavioral intervention and counseling with appropriate and informed surgical referrals has the potential to improve the success of weight management within primary care. PMID- 27117510 TI - Regulatory T Cells in Infections: Getting It Just Right. PMID- 27117511 TI - In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) reactivation is accompanied by a sustained influx of CD4(+) and CD8(+) T cells that persist in genital tissue for extended periods. While CD4(+) T cells have long been recognized as being present in herpetic ulcerations, their role in subclinical reactivation and persistence is less well known, especially the role of CD4(+) regulatory T cells (Tregs). METHODS: We characterized the Treg (CD4(+)Foxp3(+)) population during human HSV-2 reactivation in situ in sequential genital skin biopsy specimens obtained from HSV-2-seropositive subjects at the time of lesion onset up to 8 weeks after healing. RESULTS: High numbers of Tregs infiltrated to the site of viral reactivation and persisted in proximity to conventional CD4(+) T cells (Tconvs) and CD8(+) T cells. Treg density peaked during the lesion stage of the reactivation. The number of Tregs from all time points (lesion, healed, 2 weeks after healing, 4 weeks after healing, and 8 weeks after healing) was significantly higher than in control biopsy specimens from unaffected skin. There was a direct correlation between HSV-2 titer and Treg density. CONCLUSIONS: The association of a high Treg to Tconv ratio with high viral shedding suggests that the balance between regulatory and effector T cells influences human HSV-2 disease. PMID- 27117512 TI - The Oxygen quantum yield in diverse algae and cyanobacteria is controlled by partitioning of flux between linear and cyclic electron flow within photosystem II. AB - We have measured flash-induced oxygen quantum yields (O2-QYs) and primary charge separation (Chl variable fluorescence yield, Fv/Fm) in vivo among phylogenetically diverse microalgae and cyanobacteria. Higher O2-QYs can be attained in cells by releasing constraints on charge transfer at the Photosystem II (PSII) acceptor side by adding membrane-permeable benzoquinone (BQ) derivatives that oxidize plastosemiquinone QB(-) and QBH2. This method allows uncoupling PSII turnover from its natural regulation in living cells, without artifacts of isolating PSII complexes. This approach reveals different extents of regulation across species, controlled at the QB(-) acceptor site. Arthrospira maxima is confirmed as the most efficient PSII-WOC (water oxidizing complex) and exhibits the least regulation of flux. Thermosynechococcus elongatus exhibits an O2-QY of 30%, suggesting strong downregulation. WOC cycle simulations with the most accurate model (VZAD) show that a light-driven backward transition (net addition of an electron to the WOC, distinct from recombination) occurs in up to 25% of native PSIIs in the S2 and S3 states, while adding BQ prevents backward transitions and increases the lifetime of S2 and S3 by 10-fold. Backward transitions occur in PSIIs that have plastosemiquinone radicals in the QB site and are postulated to be physiologically regulated pathways for storing light energy as proton gradient through direct PSII-cyclic electron flow (PSII-CEF). PSII-CEF is independent of classical PSI/cyt-b6f-CEF and provides an alternative proton translocation pathway for energy conversion. PSII-CEF enables variable fluxes between linear and cyclic electron pathways, thus accommodating species dependent needs for redox and ion-gradient energy sources powered by a single photosystem. PMID- 27117513 TI - Role of IGF Binding Proteins in Regulating Metabolism. AB - Insulin-like growth factors (IGFs) circulate in extracellular fluids bound to a family of binding proteins. Although they function in a classical manner to limit the access of the IGFs to their receptors they also have a multiplicity of actions that are independent of this property; they bind to their own receptors or are transported to intracellular and intranuclear sites to influence cellular functions that may directly or indirectly modify IGF actions. The availability of genetically modified animals has helped to determine their functions in a physiological context. These results show that many of their actions are cell type- and context-specific, and have led to a broader understanding of how these proteins function coordinately with IGF-I and -II to regulate growth and metabolism. PMID- 27117514 TI - Emergence of fluoroquinolone-resistant Stenotrophomonas maltophilia in blood isolates causing bacteremia: molecular epidemiology and microbiologic characteristics. AB - Among 127 Stenotrophomonas maltophilia isolates causing bacteremia, 41 (32.3%) were nonsusceptible to levofloxacin, in which four sequence types and 24 diverse allelic profiles were detected. The most prevalent ST was ST77 (n = 8, 19.5%), followed by ST28 (n = 3, 7.3%). Amino acid substitutions were found in the gyrB and parC genes of 10 and 1 isolates, respectively. No amino acid substitutions were identified in gyrA. Twenty-three (56.1%) isolates showed amino acid substitutions in the parE gene. These results suggest that quinolone resistance determining regions of parE may not be the primary targets, but an important determining factor of high levels of fluoroquinolone resistance. PMID- 27117515 TI - Bacteremia with the bovis group streptococci: species identification and association with infective endocarditis and with gastrointestinal disease. AB - DNA sequencing of the intergenic spacer (ITS) region was used to identify 53 blood culture isolates that had previously been designated to the bovis group streptococci and clinical data was collected retrospectively from patients' records using a standardized protocol. ITS sequencing identified 19 (35.8%) isolates as Streptococcus gallolyticus subsp. gallolyticus, 12 (22.6%) as S. gallolyticus subsp. pasteurianus, two (3.8%) as S. gallolyticus subsp. macedonicus, seven (13.2%) as S. infantarius subsp. infantarius, 12 (22.6%) as S. lutetiensis and one (1.9%) as S. equinus. The association of S. gallolyticus subsp. gallolyticus with colorectal neoplasia and with infective endocarditis and the association between S. gallolyticus subsp. pasteurianus and pancreatic cancer were found to be clinically important. Also, a very high 1-year mortality rate with S. lutetiensis (66.7%) and S. gallolyticus subsp. pasteurianus (58.7%) bacteremia calls for intensive investigation for underlying disease focusing on the pancreas and the hepatobiliary system. PMID- 27117516 TI - Mycobacterium mucogenicum bacteremia in immune-compromised patients, 2008-2013. AB - Mycobacterium mucogenicum (MM) is a rapidly growing nontuberculous mycobacterium that may rarely cause bacteremia in immune-compromised hosts. All MM cases from 2008 to 2013 were analyzed across 4 risk groups: stem cell transplantation (SCT), hematologic malignancy, solid tumors, and others. Descriptive analysis was performed, as well as comparative analysis of neutropenic patients (absolute neutrophil count <=1000/MUL) with nonneutropenic patients. Of 39 MM cases, 27 patients had undergone SCT. Neutropenia was present in 12 patients. There was a significant difference in the presence of fever at the time of MM bacteremia between neutropenic and nonneutropenic groups (92% versus 42%; P=0.005). Central venous catheter (CVC) was present in 33 cases. All patients were treated with >1 antibiotic. Most frequently used combination antibiotic regimen involved clarithromycin and amikacin. Median duration of antibiotic treatment was 42days. Bacteremia resolved in all cases with CVC removal and combination antibiotic treatment. PMID- 27117517 TI - Rapid detection of measles virus using reverse transcription loop-mediated isothermal amplification coupled with a disposable lateral flow device. AB - The measles virus (MeV) causes a highly contagious disease and efforts to reduce its spread are critical. A reverse transcription loop-mediated isothermal amplification assay coupled with a disposable lateral flow device (RT-LAMP-LFD) was developed for the rapid detection of MeV. The assay was performed in 40 min at an optimal temperature of 58 degrees C, with endpoint results visualized directly. A probe that was complementary to the RT-LAMP amplicon was designed to enhance assay specificity. Detection limit of the assay was 8.8 copies/MUL synthetic RNA, which equals the sensitivity of real-time RT-PCR. Clinical specimens were used to validate the RT-LAMP-LFD in provincial Center for Disease Control and Prevention (CDC) (n = 245) and six municipal CDCs (n = 249). The results obtained using RT-LAMP-LFD and real-time RT-PCR were highly concordant. The RT-LAMP-LFD is rapid, stable, and does not require expensive equipment, which can be used for routine MeV monitoring in CDC laboratories. PMID- 27117518 TI - Rapid identification of microorganisms from positive blood cultures by testing early growth on solid media using matrix-assisted laser desorption ionization time of flight mass spectrometry. AB - We performed a retrospective analysis of a simple modification to MALDI-TOF MS for microorganism identification to accurately improve the turnaround time (TAT) for identification of Enterobacteriaceae recovered in blood cultures. Relative to standard MALDI-TOF MS procedures, we reduced TAT from 28.3 (n=90) to 21.2h (n=107). PMID- 27117519 TI - A life course approach to explore the biological embedding of socioeconomic position and social mobility through circulating inflammatory markers. AB - Lower socioeconomic position (SEP) has consistently been associated with poorer health. To explore potential biological embedding and the consequences of SEP experiences from early life to adulthood, we investigate how SEP indicators at different points across the life course may be related to a combination of 28 inflammation markers. Using blood-derived inflammation profiles measured by a multiplex array in 268 participants from the Italian component of the European Prospective Investigation into Cancer and Nutrition cohort, we evaluate the association between early life, young adulthood and later adulthood SEP with each inflammatory markers separately, or by combining them into an inflammatory score. We identified an increased inflammatory burden in participants whose father had a manual occupation, through increased plasma levels of CSF3 (G-CSF; beta = 0.29; P = 0.002), and an increased inflammatory score (beta = 1.96; P = 0.029). Social mobility was subsequently modelled by the interaction between father's occupation and the highest household occupation, revealing a significant difference between "stable Non-manual" profiles over the life course versus "Manual to Non-manual" profiles (beta = 2.38, P = 0.023). Low SEP in childhood is associated with modest increase in adult inflammatory burden; however, the analysis of social mobility suggests a stronger effect of an upward social mobility over the life course. PMID- 27117520 TI - The ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs. AB - Translation is a core cellular process carried out by a highly conserved macromolecular machine, the ribosome. There has been remarkable evolutionary adaptation of this machine through the addition of eukaryote-specific ribosomal proteins whose individual effects on ribosome function are largely unknown. Here we show that eukaryote-specific Asc1/RACK1 is required for efficient translation of mRNAs with short open reading frames that show greater than average translational efficiency in diverse eukaryotes. ASC1 mutants in S. cerevisiae display compromised translation of specific functional groups, including cytoplasmic and mitochondrial ribosomal proteins, and display cellular phenotypes consistent with their gene-specific translation defects. Asc1-sensitive mRNAs are preferentially associated with the translational 'closed loop' complex comprised of eIF4E, eIF4G, and Pab1, and depletion of eIF4G mimics the translational defects of ASC1 mutants. Together our results reveal a role for Asc1/RACK1 in a length-dependent initiation mechanism optimized for efficient translation of genes with important housekeeping functions. PMID- 27117521 TI - Neuroendocrine Differentiation of a Primary BRAF Mutant Colon Cancer in a Patient With a History of Hairy Cell Leukemia. PMID- 27117522 TI - Oxidative stress-induced DNA damage of mouse zygotes triggers G2/M checkpoint and phosphorylates Cdc25 and Cdc2. AB - In vitro fertilized (IVF) embryos show both cell cycle and developmental arrest. We previously showed oxidative damage activates the ATM -> Chk1 -> Cdc25B/Cdc25C cascade to mediate G2/M cell cycle arrest for repair of hydrogen peroxide (H2O2) induced oxidative damage in sperm. However, the mechanisms underlying the developmental delay of zygotes are unknown. To develop a model of oxidative damaged zygotes, we treated mouse zygotes with different concentrations of H2O2 (0, 0.01, 0.02, 0.03, 0.04, 0.05 mM), and evaluated in vitro zygote development, BrdU incorporation to detect the duration of S phase. We also examined reactive oxygen species level and used immunofluorescence to detect activation of gammaH2AX, Cdc2, and Cdc25. Oxidatively damaged zygotes showed a delay in G2/M phase and produced a higher level of ROS. At the same time, gammaH2AX was detected in oxidatively damaged zygotes as well as phospho-Cdc25B (Ser323), phospho-Cdc25C (Ser216), and phospho-Cdc2 (Tyr15). Our study indicates that oxidative stress-induced DNA damage of mouse zygotes triggers the cell cycle checkpoint, which results in G2/M cell cycle arrest, and that phospho-Cdc25B (Ser323), phospho-Cdc25C (Ser216), and phospho-Cdc2 (Tyr15) participate in activating the G2/M checkpoint. PMID- 27117523 TI - The Unique Challenges of Conserving Large Old Trees. AB - Large old trees play numerous critical ecological roles. They are susceptible to a plethora of interacting threats, in part because the attributes that confer a competitive advantage in intact ecosystems make them maladapted to rapidly changing, human-modified environments. Conserving large old trees will require surmounting a number of unresolved challenges. PMID- 27117524 TI - A CRISPR/Cas9 mediated point mutation in the alpha 6 subunit of the nicotinic acetylcholine receptor confers resistance to spinosad in Drosophila melanogaster. AB - Spinosad, a widely used and economically important insecticide, targets the nicotinic acetylcholine receptor (nAChRs) of the insect nervous system. Several studies have associated loss of function mutations in the insect nAChR alpha6 subunit with resistance to spinosad, and in the process identified this particular subunit as the specific target site. More recently a single non synonymous point mutation, that does not result in loss of function, was identified in spinosad resistant strains of three insect species that results in an amino acid substitution (G275E) of the nAChR alpha6 subunit. The causal role of this mutation has been called into question as, to date, functional evidence proving its involvement in resistance has been limited to the study of vertebrate receptors. Here we use the CRISPR/Cas9 gene editing platform to introduce the G275E mutation into the nAChR alpha6 subunit of Drosophila melanogaster. Reverse transcriptase-PCR and sequencing confirmed the presence of the mutation in Dalpha6 transcripts of mutant flies and verified that it does not disrupt the normal splicing of the two exons in close vicinity to the mutation site. A marked decrease in sensitivity to spinosad (66-fold) was observed in flies with the mutation compared to flies of the same genetic background minus the mutation, clearly demonstrating the functional role of this amino acid substitution in resistance to spinosad. Although the resistance levels observed are 4.7-fold lower than exhibited by a fly strain with a null mutation of Dalpha6, they are nevertheless predicated to be sufficient to result in resistance to spinosad at recommended field rates. Reciprocal crossings with susceptible fly strains followed by spinosad bioassays revealed G275E is inherited as an incompletely recessive trait, thus resembling the mode of inheritance described for this mutation in the western flower thrips, Frankliniella occidentalis. This study both resolves a debate on the functional significance of a target-site mutation and provides an example of how recent advances in genome editing can be harnessed to study insecticide resistance. PMID- 27117525 TI - iPad experience during clinical rotations from seven medical schools in the United States: Lessons learned. AB - BACKGROUND: Since 2010, many US medical schools have introduced the use of mobile technology into their curriculum. Preclinical use of mobile technologies has been well studied, but use in the clinical years has been less explored. Our objective was to identify the clinical uses and limitations of mobile technology in the clinical curriculum. METHODS: Interviews were conducted with key personnel at seven U. S. medical schools who introduced iPad programs during the clinical years. Interviews were qualitatively analyzed using a constant comparison technique. RESULTS AND RECOMMENDATIONS: Eight "best practices" for introducing mobile technology in the clinical years were identified: (1) plan before implementation, (2) define focused goals, (3) establish a tablet "culture," (4) recruit appropriate implementation team, (5) invest in training, (6) involve students in mentoring, (7) accept variable use, and (8) encourage innovation. CONCLUSIONS: There is growing interest in using mobile technology for teaching and learning in the clinical curriculum. Following the identified best practices may assist schools with the integration of the technology into the curriculum and better prepare medical students to handle the increasing use of technology. PMID- 27117526 TI - Construction of Molecularly Imprinted Polymer Microspheres by Using Helical Substituted Polyacetylene and Application in Enantio-Differentiating Release and Adsorption. AB - Chiral molecularly imprinted polymer microspheres (MIPMs) reported so far are majorly limited to being constructed by using achiral polymer together with chiral template. The present contribution reports on a unique type of chiral MIPMs consisting of chirally helical substituted polyacetylene, which are prepared through suspension polymerization by using (a)chiral acetylenics as monomer and chiral Boc-d/l-proline as template. The resulting MIPMs after removing the template show optical activity that is derived from the chirally helical structures of substituted polyacetylene. The microspheres demonstrate enantio-differentiating ability in releasing the enantiopure templates. A complete release of the template provides the chiral MIPMs. Worthy to mention is that the two chiral sources (chirally helical conformation and chiral template configuration) work in a synergistic way, obviously increasing the MIPMs' enantiodiscrimination ability. The present study develops a strategy for preparing chiral MIPMs, which are expected to find significant applications in chiral separation, enantioselective release of chiral drugs, etc. PMID- 27117527 TI - Erectile Dysfunction in Male Survivors of Childhood Cancer-A Report From the Childhood Cancer Survivor Study. AB - INTRODUCTION: With survival rates higher than 80%, the number of survivors from pediatric cancer continues to increase. Late effects resulting from cancer and cancer therapy are being characterized, but little information exists on sexual health for men who have survived childhood cancer. AIM: To assess erectile dysfunction (ED) in men who survived childhood and adolescent cancers and to identify potential risk factors for ED. METHODS: In total, 1,622 men and 271 eligible brothers in the Childhood Cancer Survivor Study cohort completed the Male Health Questionnaire, which provided information on sexual practices and sexual function. Combined with demographic, cancer, and treatment information from medical record abstraction, results of the Male Health Questionnaire were analyzed using multivariable modeling. The International Index of Erectile Function was used to identify ED in subjects. MAIN OUTCOME MEASURE: International Index of Erectile Function. RESULTS: Survivors (mean age = 37.4 years, SD = 7.3 years) reported significantly lower sexual activity in the year before the survey than the brothers (mean age = 38.8 years, SD = 8.5 years) without cancer. ED was reported by 12.3% (95% CI = 10.4-14.3) of survivors and 4.2% (95% CI = 2.0-7.9) of brothers. Survivors showed significantly higher relative risk (RR) for ED (RR = 2.63, 95% CI = 1.40-4.97). In addition to older age, survivors who were exposed to higher-dose (>=10 Gy) testicular radiation (RR = 3.55, 95% CI = 1.53-8.24), had surgery on the spinal cord or nerves (RR = 2.87, 95% CI = 1.36-6.05), prostate surgery (RR = 6.56, 95% CI = 3.84-11.20), or pelvic surgery (RR = 2.28, 95% CI = 1.04-4.98) were at higher risk for ED. CONCLUSION: Men who have survived childhood cancer have a greater than 2.6-fold increased risk for ED and certain cancer-specific treatments are associated with increased risk. Attention to sexual health, with its physical and emotional implications, and opportunities for early detection and intervention in these individuals could be important. PMID- 27117528 TI - Quality of Life of Transgender Women From China and Associated Factors: A Cross Sectional Study. AB - INTRODUCTION: Transgender women are exposed to stressful situations such as gender transition and transition-related discrimination because of their limited acceptance by the general population and inadequate government-supplied resources, which can compromise their quality of life (QOL). However, there is a paucity of research on the QOL of transgender women from China. AIMS: To assess the QOL of transgender women from China and explore its associated factors. METHODS: A cross-sectional study was performed by convenience sampling in Shenyang, China from January 2014 to July 2014. This sample consisted of 209 transgender women. The women were interviewed face-to-face to assess their QOL and related factors using the 36-item Short-Form Health Survey, the Adult Dispositional (Trait) Hope Scale, and the EGO Resilience Scale. MAIN OUTCOME MEASURES: Response scores were calculated based on a questionnaire design. Hierarchical multiple regression analysis was performed to explore factors associated with QOL. RESULTS: Transgender women who used hormone therapy reported significantly lower levels of the physical component summary (PCS) and the mental component summary (MCS) compared with those who did not (P < .05). Hierarchical multiple regression analysis showed that of the 23 independent variables, 8 were significantly associated with the PCS and 9 were significantly associated with the MCS. The PCS was significantly and negatively associated with age and being chased or insulted by law enforcement officials. The PCS was positively associated with not using hormone therapy, having no casual partners, less discrimination from friends, knowledge of HIV prevention, hope, and resilience. Educational level and being chased or insulted by law enforcement officials were negatively associated with the MCS, whereas not using hormone therapy, having no regular partners or casual partners, less discrimination from friends, less social discrimination, knowledge of HIV prevention, and hope were positively associated with the MCS. CONCLUSION: Chinese transgender women reported high levels of physical QOL but low levels of mental QOL. Their mental QOL was more pronounced than their physical QOL. Transition status and sexual partnership played the most important roles in physical and mental health. Furthermore, mental QOL was best predicted by assessing positive capabilities, such as levels of hope. Future interventions should focus on recognizing transition status and identifying risky sexual partnerships, especially for the casual partners involved in these partnerships. In addition, positive capabilities are needed to ameliorate the negative impact of transition on QOL in Chinese transgender women. PMID- 27117529 TI - WHOQOL-100 Before and After Sex Reassignment Surgery in Brazilian Male-to-Female Transsexual Individuals. AB - INTRODUCTION: The 100-item World Health Organization Quality of Life Assessment (WHOQOL-100) evaluates quality of life as a subjective and multidimensional construct. Currently, particularly in Brazil, there are controversies concerning quality of life after sex reassignment surgery (SRS). AIM: To assess the impact of surgical interventions on quality of life of 47 Brazilian male-to-female transsexual individuals using the WHOQOL-100. METHODS: This was a prospective cohort study using the WHOQOL-100 and sociodemographic questions for individuals diagnosed with gender identity disorder according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The protocol was used when a transsexual person entered the ambulatory clinic and at least 12 months after SRS. MAIN OUTCOME MEASURES: Initially, improvement or worsening of quality of life was assessed using 6 domains and 24 facets. Subsequently, quality of life was assessed for individuals who underwent new surgical interventions and those who did not undergo these procedures 1 year after SRS. RESULTS: The participants showed significant improvement after SRS in domains II (psychological) and IV (social relationships) of the WHOQOL-100. In contrast, domains I (physical health) and III (level of independence) were significantly worse after SRS. Individuals who underwent additional surgery had a decrease in quality of life reflected in domains II and IV. During statistical analysis, all results were controlled for variations in demographic characteristics, without significant results. CONCLUSION: The WHOQOL-100 is an important instrument to evaluate the quality of life of male-to-female transsexuals during different stages of treatment. SRS promotes the improvement of psychological aspects and social relationships. However, even 1 year after SRS, male-to-female transsexuals continue to report problems in physical health and difficulty in recovering their independence. PMID- 27117530 TI - Reply to the letter to the editor 'Abandoning diesel because of health perspectives: are there reasonable alternatives?' by Vreugdenhil and Mannaerts. PMID- 27117531 TI - Systematic evaluation of pembrolizumab dosing in patients with advanced non-small cell lung cancer. AB - BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. PATIENTS AND METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology. RESULTS: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss 6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC. CLINICALTRIALSGOV REGISTRY: NCT01295827. PMID- 27117532 TI - Precision medicine and oncology: an overview of the opportunities presented by next-generation sequencing and big data and the challenges posed to conventional drug development and regulatory approval pathways. PMID- 27117533 TI - P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer. AB - BACKGROUND: Therapeutic resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) is attributed to various cellular mechanisms and signaling molecules that influence as a single factor or in combination. DESIGN: In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance. RESULTS: Pak1 kindles resistance via modulation of epithelial-mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-kappaB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor beta-activated kinase 1-a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression. CONCLUSION: To our knowledge, this is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC. PMID- 27117534 TI - Benefit of therapeutic drug monitoring to disclose pharmacokinetic interaction between sunitinib and calcium channel blocker. PMID- 27117535 TI - Cervical esophageal cancer: a gap in cancer knowledge. AB - BACKGROUND: The aim of this systematic review is to provide an overview of the diagnosis, treatment options and treatment-related complications of cervical esophageal carcinoma (CEC) and to subsequently provide recommendations to improve quality of care. DESIGN: Studies were identified in PubMed, EMBASE and Web of Science. A total of 107 publications fulfilled the inclusion criteria and were included. RESULTS: CEC is uncommon, accounting for 2%-10% of all esophageal carcinomas. These tumors are often locally advanced at presentation and have a poor prognosis, with a 5-year overall survival of 30%. Tobacco and alcohol consumption seem to be the major risk factors for developing CEC. Surgery is usually not possible due to the very close relationship to other organs such as the larynx, trachea and thyroid gland. Therefore, the current standard of care is definitive chemoradiation (dCRT) with curative intent. Treatment regimens used to treat CEC are adapted by established regimens in lower esophageal squamous cell carcinoma and head and neck squamous cell carcinoma. However, dCRT may be accompanied by severe side-effects and complications. Several diagnostic and predictive markers have been studied, but currently, there is no other biomarker than clinical stage to determine patient management. Suggestions to improve patient outcomes are to determine the exact radiation dose needed for adequate locoregional control and to combine radiotherapy with optimal systemic therapy backbone. CONCLUSION: CEC remains unchartered territory for many practising physicians and patients with CEC have a poor prognosis. To improve the outcome for CEC patients, future studies should focus on the identification of new diagnostic biomarkers or targets for radiosensitizers, amelioration of radiation schedules, optimal combination of chemotherapeutic agents and/or new therapeutic targets. PMID- 27117536 TI - Clinical, pathological and genetic features of follicular lymphoma grade 3A: a joint analysis of the German low-grade and high-grade lymphoma study groups GLSG and DSHNHL. AB - BACKGROUND: Histologically, follicular lymphoma (FL) grades 1, 2 and 3A are composed of two distinct cell types, centroblasts and centrocytes. FL grade 3B is composed only of centroblasts and has been shown to differ in immunophenotype and genetics from FL that contain centrocytes. We aimed to understand the pathogenetic and clinical relation between FL grade 3A to FL grade 1/2 on the one hand and FL grade 3B on the other hand. PATIENTS AND METHODS: Trial patients with long-term follow-up and diagnosis of FL grade 3 were selected and samples underwent a second central pathological review using a multiple-observer approach to assess grading. RESULTS: Interobserver variability for diagnosing FL grade 3 was high. FL grade 3A frequently harbored areas of FL grade 1/2 within the same tissue specimen. FL grade 3B rarely coexisted with grade 1/2 or 3A, suggesting divergent pathogenesis. There was no statistically significant difference in outcome between 47 cases of FL grade 3A and 14 cases of grade 3B. Compared with grade 1/2 FL, both groups showed longer progression-free survival without late events, especially after immunochemotherapy; this outcome difference was retained after adjustment for clinical prognostic factors. The subgroup of FL grade 3A with an additional FL grade 1/2 component or a translocation t(14;18) showed a poorer outcome. In contrast, the FL grade 3A lacking t(14;18) and of localized stage resembled the pediatric type of FL and showed a very good outcome. FL3 with MYC breaks showed a poor outcome. CONCLUSIONS: The results suggest that first line immunochemotherapy might allow long-lasting remissions in a subgroup of FL grade 3A similar to diffuse large B-cell lymphoma. Within FL3A, prognostic subgroups can be identified by analyzing for coexisting FL1/2 and MYC breaks. PMID- 27117537 TI - Genetic-Quantitative Study of the First-Service Pregnancy Probability of Murrah Heifers. AB - Because of the importance of reproduction in stock breeding systems, it is necessary to find selection criteria that increase reproductive efficiency. The aim of this study was to estimate genetic parameters for the probability of conception on first service (PROB) in Murrah heifers, and its association with other traits of economic interest [age at first calving (AFC), service period, calving interval and milk yield at 270 days], with the purpose of evaluating their use as selection criteria. Reproductive information and first lactation records of 1200 Murrah heifers were used to perform two-trait analyses between PROB and the other characteristics. Bayesian inference was used to estimate the variance components, considering PROB as threshold and the other as linear factors. The results demonstrate that this trait has heritability of 0.15, indicating the possibility of a genetic gain by using it for selection. With respect to the genetic correlation estimates, the only high-magnitude association was with AFC (-0.899), which is the current criterion indicating sexual precocity of females. In the light of the parameters estimated, the first-service pregnancy rate is an alternative for indication of sexual precocity, although presenting a smaller genetic gain than the current standard AFC. Nevertheless, additional research should be conducted regarding this trait to assess the economic importance of its use in dairy buffalo production systems. PMID- 27117538 TI - [Skeletal dysplasias: New medical treatments]. PMID- 27117539 TI - [Clinical interventions in overweight and obesity: a systematic literature review 2009-2014]. AB - OBJECTIVE: To update the literature review on the effectiveness of clinical interventions on childhood obesity, proposed in Clinical Practice Guidelines, excluding prevention and pharmacological and surgical treatments. METHOD: A systematic review was carried out in electronic databases of the Cochrane Database of Systematic Reviews (The Cochrane Library), MEDLINE, and SCOPUS, replicating the search for the Clinical Practice Guidelines, from 2009 to 2014. The Clinical Practice Guidelines of National Institute for Health and Care Excellence were taken as a reference. Systematic reviews were given priority, and the quality of the studies was assessed. RESULTS: Out of a total of 3,703 documents initially identified, 48 were finally included. Studies showed great heterogeneity in the type and duration of interventions, and in outcome measures. Adherence to treatment was, in general, low. Multi-component interventions including diet, physical activity, sedentary lifestyle, and behaviour changes, involving the family, and starting at early ages, were the most effective for reducing body mass index. There is no consensus on criteria for referral to specialised care. CONCLUSIONS: It is recommended to implement multi-component programs conducted by professionals with previous training, involving the family, and addressing behavioural, individual and socio-demographic aspects. Lack of adherence is one of the reasons for failure of interventions. Diagnostic and referral criteria, the outcome measures, and the type and duration of interventions need to be improved and standardised. PMID- 27117540 TI - Gramella sediminilitoris sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-spore-forming, motile by gliding and coccoid, ovoid or rod-shaped bacterial strain, designated GHTF-27T, was isolated from a tidal flat at Goheung, South Korea, and subjected to a taxonomic study using a polyphasic approach. The novel strain grew optimally at 30 degrees C, at pH 7.0 8.0 and in the presence of 2.0-5.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain GHTF-27T belongs to the genus Gramella. It exhibited 16S rRNA gene sequence similarity values of 97.6-98.3 % to the type strains of Gramella aestuariivivens, Gramella echinicola, Gramella gaetbulicola, Gramella aquimixticola, Gramella aestuarii and Gramella portivictoriae, respectively, and of 93.8-96.7 % to the type strains of the other species of the genus Gramellawith validly published names. Strain GHTF-27T contained MK-6 as the predominant menaquinone and iso-C15 : 0 and iso-C17 : 0 3-OH as the major fatty acids. The major polar lipids of strain GHTF-27T were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain GHTF-27T was 39.7 mol% and DNA-DNA relatedness values with the type strains of the six phylogenetically closely related species of the genus Gramellawere 12-28 %. The differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain GHTF-27T is separated from other species of the genus Gramella. On the basis of the data presented, strain GHTF-27T is considered to represent a novel species of the genus Gramella, for which the name Gramella sediminilitorissp. nov. is proposed. The type strain is GHTF-27T (=KCTC 52208T =NBRC 111992T). PMID- 27117541 TI - Degenerative changes and immune response after transcatheter aortic valve implantation. Comparison with surgical aortic valve replacement. AB - BACKGROUND: Little is known about the valve degeneration process after transcutaneous aortic valve implantations (TAVI) that can have an important impact on patients' long-term prognosis. AIM: To evaluate degenerative changes of TAVI using computed tomography (CT) compared to findings in patients that underwent surgical aortic valve replacement (SAVR). Subsequently, to compare the level of immune and inflammatory markers in both groups and test their possible role in the valve degeneration process. METHODS AND RESULTS: 49 patients after TAVI and 29 patients in the control group after SAVR underwent 2 years of follow up and 8 patients from the TAVI group and 7 patients after SAVR underwent five years of follow-up. CT was performed in all patients and calcifications on prosthesis cusps in both groups were measured using Agatson calcium score. TAVI patients were older compared to patients who underwent SAVR [82 (62;86) vs. 74 (64;84) years, p<0.001], and had more comorbidities - higher EuroScore I [21.0 (5.0;46.0) vs. 6.15 (2.54;11.17), p<0.001]. TAVI patients had more often concomitant coronary artery disease (69.4% vs. 13.8%, p<0.001) and previous history of cardiac surgery (32.7% vs. 0.0%, p<0.001). Slight calcifications (mean Agatson score 50.76) on prosthetic cusps were found in 2 patients 4-5 years after TAVI and in 1 patient 2 years after SAVR (p=NS). Even though significant differences were found in values of tumor necrosis factor-alpha and E-selectin before, 1 year, and 2 years after implantation, no significant changes in values of inflammatory markers were observed during follow-up period in both groups of patients. Detailed analysis revealed no significant difference between values of inflammatory markers of patients with and without calcifications present on CT. CONCLUSION: Minimal degenerative changes on TAVI prosthesis were observed in mid- and long-term follow-up. Systemic immune response did not differ between patients after TAVI and SAVR. PMID- 27117542 TI - Laparoscopic repeat liver resection for recurrent hepatocellular carcinoma. AB - BACKGROUND: Repeat liver resection is effective for recurrent hepatocellular carcinoma (rHCC). This study aimed to determine the outcomes of laparoscopic repeat liver resection (LRLR) for rHCC. METHODS: Eight consecutive patients who underwent LRLR for rHCC were retrospectively reviewed. RESULTS: Six patients had previous open and two had laparoscopic liver resection (LLR). There was one (12.5%) open conversion for bleeding and one (12.5%) post-operative morbidity. The median tumour size was 24 mm (range: 8-50 mm). LRLR was performed for rHCC in the ipsilateral lobe as compared to the index surgery in 4/8 (50%) patients. Five of eight (62.5%) patients had rHCC in the difficult posterosuperior segments. Six patients had previous open LR, and two had previous LLR. One patient (patient 4) had two prior open LR for rHCC, and LRLR was performed for the second recurrence. The median duration from the first surgery to LRLR was 29 months (range: 6-109 months). The median post-operative stay was 3.5 days. All eight patients had R0 resections, and at a median follow-up of 7.5 months, all patients were disease free. CONCLUSION: LRLR for rHCC is feasible and safe. This can be performed even for patients with previous open liver resections, cirrhosis, lesions in the posterosuperior segments and prior LR of the ipsilateral lobe. LRLR for rHCC is feasible and safe in highly selected patients. PMID- 27117543 TI - Palladium-catalyzed directing group-assisted C8-triflation of naphthalenes. AB - The transition-metal-catalyzed direct triflation of naphthyl amides and naphthyl ketones has been accomplished for the first time. Benzophenone (BP) was found to be a suitable ligand for the cross-coupling reactions. Density functional theory (DFT) calculations revealed that excessive amounts of HOTf inhibit the reductive elimination of the C-F bond to realize the unusual reductive elimination of the C OTf bond. PMID- 27117544 TI - Role of certain amino acid residues of the coelenterazine-binding cavity in bioluminescence of light-sensitive Ca(2+)-regulated photoprotein berovin. AB - Bright bioluminescence of ctenophores is caused by Ca(2+)-regulated photoproteins. Although these photoproteins are functionally identical to and share many properties of cnidarian photoproteins, like aequorin and obelin, and retain the same spatial architecture, they are extremely sensitive to light, i.e. lose the ability to bioluminesce on exposure to light over the entire absorption spectrum. In addition, the degree of identity of their amino acid sequences with those of cnidarian photoproteins is only 29.4%. This suggests that the residues involved in bioluminescence of ctenophore and cnidarian photoproteins significantly differ. Here we describe the bioluminescent properties of berovin mutants with substitution of the residues located in the photoprotein internal cavity. Since the spatial structure of berovin bound with a substrate is not determined yet, to identify these residues we have modeled it with an accommodated substrate using the structures of some cnidarian Ca(2+)-regulated photoproteins with bound coelenterazine or coelenteramide as templates in order to obtain an adequate sampling and to take into account all possible conformers and variants for ligand-protein docking. Based on the impact of substitutions on the bioluminescent properties and model structures we speculate that within the internal cavity of ctenophore photoproteins, coelenterazine is bound as a 2 peroxy anion adduct which is stabilized owing to Coulomb interaction with a positively charged guanidinium group of Arg41 paired with Tyr204. In this case, the bioluminescence reaction is triggered by only calcium-induced conformational changes leading to the disturbance of charge-charge interaction. PMID- 27117545 TI - [Differences in austerity and healthcare privatisation between autonomous communities in times of crisis in Spain. Replay]. PMID- 27117546 TI - Establishment of childhood pneumonia cause in the era of pneumococcal conjugate vaccines. PMID- 27117548 TI - 26th European Congress of Clinical Microbiology and Infectious Diseases. PMID- 27117547 TI - Aetiology of childhood pneumonia in a well vaccinated South African birth cohort: a nested case-control study of the Drakenstein Child Health Study. AB - BACKGROUND: Pneumonia is a leading cause of mortality and morbidity in children globally. The cause of pneumonia after introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) has not been well studied in low-income and middle income countries, and most data are from cross-sectional studies of children admitted to hospital. We aimed to longitudinally investigate the incidence and causes of childhood pneumonia in a South African birth cohort. METHODS: We did a nested case-control study of children in the Drakenstein Child Health Study who developed pneumonia from May 29, 2012, to Dec 1, 2014. Children received immunisations including acellular pertussis vaccine and PCV13. A nested subgroup had nasopharyngeal swabs collected every 2 weeks throughout infancy. We identified pneumonia episodes and collected blood, nasopharyngeal swabs, and induced sputum specimens. We used multiplex real-time PCR to detect pathogens in nasopharyngeal swabs and induced sputum of pneumonia cases and in nasopharyngeal swabs of age-matched and site-matched controls. To show associations between organisms and pneumonia we used conditional logistic regression; results are presented as odds ratios (ORs) with 95% CIs. FINDINGS: 314 pneumonia cases occurred (incidence of 0.27 episodes per child-year, 95% CI 0.24-0.31; median age 5 months [IQR 3-9]) in 967 children during 1145 child-years of follow-up. 60 (21%) cases of pneumonia were severe (incidence 0.05 episodes per child-year [95% CI 0.04-0.07]) with a case fatality ratio of 1% (three deaths). A median of five organisms (IQR 4-6) were detected in cases and controls with nasopharyngeal swabs, and a median of six organisms (4-7) recorded in induced sputum (p=0.48 compared with nasopharyngeal swabs). Bordetella pertussis (OR 11.08, 95% CI 1.33 92.54), respiratory syncytial virus (8.05, 4.21-15.38), or influenza virus (4.13, 2.06-8.26) were most strongly associated with pneumonia; bocavirus, adenovirus, parainfluenza virus, Haemophilus influenzae, and cytomegalovirus were also associated with pneumonia. In cases, testing of induced sputum in addition to nasopharyngeal swabs provided incremental yield for detection of B pertussis and several viruses. INTERPRETATION: Pneumonia remains common in this highly vaccinated population. Respiratory syncytial virus was the most frequently detected pathogen associated with pneumonia; influenza virus and B pertussis were also strongly associated with pneumonia. Testing of induced sputum increases the yield for detection of several organisms. New vaccines and strategies are needed to address the burden of childhood pneumonia. FUNDING: Bill & Melinda Gates Foundation, Medical Research Council South Africa, National Research Foundation South Africa, National Institute of Health, and H3Africa. PMID- 27117549 TI - Development of Clinical Pharmacology in the Russian Federation. AB - PURPOSE: The article aims to provide the history, organization, and approaches to clinical pharmacology in the Russian Federation. METHODS: This article is based on major international and Russian documents, along with groundbreaking historical facts and scientific articles related to the development of modern clinical pharmacology the Russian Federation. FINDINGS: Improving the quality of drug therapy is the main goal of clinical pharmacology in the Russian Federation. Decisions of the World Health Organization, scientific achievements, and the work of well-known scientists among the world community and in the Russian Federation have strongly influenced the development of clinical pharmacology the Russian Federation. Clinical pharmacology in the Russian Federation addresses a wide range of problems; it actively engages in modern scientific research, education; and clinical practice. Clinical pharmacologists participate in studies of new drugs and often have a specific area of expertise. IMPLICATIONS: The future development of clinical pharmacology in the Russian Federation will be related to improvements in training, refinement of the framework that regulates clinical pharmacologists, and the creation of clinical pharmacology laboratories with modern equipment. PMID- 27117551 TI - Severe early-onset epileptic encephalopathy due to mutations in the KCNA2 gene: Expansion of the genotypic and phenotypic spectrum. AB - BACKGROUND: Recently, de novo loss- or gain-of-function mutations in the KCNA2 gene; have been described in individuals with epileptic encephalopathy, ataxia or intellectual disability. CASE DESCRIPTION: In this report, we describe a further case of KCNA2-early-onset epileptic encephalopathy. The patient presented since birth with intractable seizures, progressive microcephaly, developmental delay, and progressive brain atrophy. Whole-exome sequencing showed a novel de novo mutation in the KCNA2 gene: c.1120A > G (p.Thr374Ala). CONCLUSION: This case expands the genotypic and phenotypic disease spectrum of this genetic form of KCNA2-early onset epileptic encephalopathy. PMID- 27117550 TI - Capsid-deficient alphaviruses generate propagative infectious microvesicles at the plasma membrane. AB - Alphavirus budding is driven by interactions between nucleocapsids assembled in the cytoplasm and envelope proteins present at the plasma membrane. So far, the expression of capsid and envelope proteins in infected cells has been considered an absolute requirement for alphavirus budding and propagation. In the present study, we show that Semliki Forest virus and Sindbis virus lacking the capsid gene can propagate in mammalian and insect cells. This propagation is mediated by the release of infectious microvesicles (iMVs), which are pleomorphic and have a larger size and density than wild-type virus. iMVs, which contain viral RNA inside and viral envelope proteins on their surface, are released at the plasma membrane and infect cells using the endocytic pathway in a similar way to wild type virus. iMVs are not pathogenic in immunocompetent mice when injected intravenously, but can infect different organs like lungs and heart. Finally, we also show that alphavirus genomes without capsid can mediate the propagation of heterologous genes, making these vectors potentially interesting for gene therapy or vaccination studies. The minimalist infectious system described in this study shows that a self-replicating RNA able to express membrane proteins with binding and fusion properties is able to propagate, providing some insights into virus evolution. PMID- 27117552 TI - Valproate effect on ketosis in children under ketogenic diet. AB - INTRODUCTION: Although ketogenic diet has been proven useful in the management of intractable seizures, interactions with other medicines have been reported. This study reports two patients on co-administration with ketogenic diet and valproate appearing undesirable side effects after increase or decrease of valproate pharmaceutical levels. METHODS: Totally 75 patients suffering from drug-resistant epilepsy were treated with ketogenic diet in our departments. Their age varied from 6 months to 9 years. All patients were followed for at least 12 months and up to five years. Clinical and laboratory variables have been regularly assessed. RESULTS: In 75 patients treated with ketogenic diet and valproate at the same time treatment was well tolerated. Two patients presented mild to moderate undesirable effects. In these patients the removal of valproate treatment resulted in an increase of ketosis with respective clinical signs. The conversion of the diet from 4:1 to 1:1 and 2,5:1 respectively resulted in reduction of ketosis and clinical improvement. CONCLUSION: In the majority of cases co administration of valproate and ketogenic diet seems to be safe. In two cases, valproate appeared to have a negative effect on ketosis (and weaning it led to over-ketosis). This interaction is worthy of future study. PMID- 27117553 TI - Erratum to: Glomerulopathy in patients with distal duplication of chromosome 6p. PMID- 27117554 TI - Population pharmacokinetics analysis of olanzapine for Chinese psychotic patients based on clinical therapeutic drug monitoring data with assistance of meta analysis. AB - PURPOSE: The aim of this study was to build an eligible population pharmacokinetic (PK) model for olanzapine in Chinese psychotic patients based on therapeutic drug monitoring (TDM) data, with assistance of meta-analysis, to facilitate individualized therapy. METHODS: Population PK analysis for olanzapine was performed using NONMEM software (version 7.3.0). TDM data were collected from Guangzhou Brain Hospital (China). Because of the limitations of TDM data, model based meta-analysis was performed to construct a structural model to assist the modeling of TDM data as prior estimates. After analyzing related covariates, a simulation was performed to predict concentrations for different types of patients under common dose regimens. RESULTS: A two-compartment model with first order absorption and elimination was developed for olanzapine oral tablets, based on 23 articles with 390 data points. The model was then applied to the TDM data. Gender and smoking habits were found to be significant covariates that influence the clearance of olanzapine. To achieve a blood concentration of 20 ng/mL (the lower boundary of the recommended therapeutic range), simulation results indicated that the dose regimen of olanzapine should be 5 mg BID (twice a day), >= 5 mg QD (every day) plus 10 mg QN (every night), or >10 mg BID for female nonsmokers, male nonsmokers and male smokers, respectively. CONCLUSION: The population PK model, built using meta-analysis, could facilitate the modeling of TDM data collected from Chinese psychotic patients. The factors that significantly influence olanzapine disposition were determined and the final model could be used for individualized treatment. PMID- 27117556 TI - Sexual function and quality of life in gynecological cancer pre- and post-short term brachytherapy: a prospective study. AB - PURPOSE: To evaluate the sexual function and quality of life pre- and post gynecological cancer treatment with high-dose rate brachytherapy in the short term. METHODS: This is a descriptive and prospective study involving 20 women diagnosed with gynecological cancer aged between 18 and 70 years, resident in Florianopolis and the surrounding region. We used the Quality of Life Questionnaire Core-30 (QLQ-C30) 3.0 to assess quality of life pre- and post brachytherapy treatment and the Female Sexual Function Index (FSFI) to assess sexual function. RESULTS: Regarding quality of life, significant worsening was observed for the items loss of appetite (p = 0.002) and diarrhea (p = 0.045) from pre- to post-brachytherapy treatment, whereas constipation (p = 0.013) improved. For sexual function, the statistical difference was found exclusively in the domain of lubrication reduction (p = 0.046). Only nine women were sexually active before and after brachytherapy treatment. CONCLUSIONS: There was a worsening of quality of life in comparing pre- and post-evaluations related to gastrointestinal symptoms over a period equivalent to 40 days. Regarding sexual function, lack of lubrication was identified in short-term post-gynecological cancer brachytherapy. PMID- 27117555 TI - The Children's Attention-Deficit Hyperactivity Disorder Telemental Health Treatment Study: Caregiver Outcomes. AB - The Children's Attention-deficit Hyperactivity Disorder (ADHD) Telemental Health Treatment Study (CATTS) tested the hypotheses that children and caregivers who received guideline-based treatment delivered through a hybrid telehealth service delivery model would experience greater improvements in outcomes than children and caregivers receiving treatment via a comparison delivery model. Here, we present caregiver outcomes. 88 primary care providers (PCPs) in seven geographically underserved communities referred 223 children (ages 5.5 - 12.9 years) to the randomized controlled trial. Over 22 weeks, children randomized to the CATTS service delivery model received six sessions of telepsychiatry and six sessions of caregiver behavior management training provided in person by community therapists who were trained and supervised remotely. Children randomized to the comparison Augmented Primary Care (APC) service model received management in primary care augmented by a single telepsychiatry consultation. Caregiver outcomes included changes in distress, as measured by the Patient Health Questionnaire (PHQ-9), Parenting Stress Index (PSI), Caregiver Strain Questionnaire (CSQ) and Family Empowerment Scale (FES). Caregivers completed five assessments. Multilevel mixed effects regression modeling tested for differences between the two service delivery models in caregiver outcomes from baseline to 25 weeks. Compared to caregivers of children in the APC model, caregivers of children in the CATTS service model showed statistically significantly greater improvements on the PHQ-9 (beta = -1.41, 95 % CI = [-2.74, -0.08], p < .05), PSI (beta = -4.59, 95 % CI = [-7.87, - 1.31], p < .001), CSQ (beta = -5.41, 95 % CI = [- 8.58, -2.24], p < .001) and FES (beta = 6.69, 95 % CI = [2.32, 11.06], p < .01). Improvement in child ADHD symptoms mediated improved caregiver scores on the PSI and CSQ. Improvement in child ODD behaviors mediated caregiver CSQ scores. The CATTS trial supports the effectiveness of a hybrid telehealth service delivery model for reducing distress in caregivers of children with ADHD and suggests a mechanism through which the service model affected caregiver distress. PMID- 27117557 TI - EGFR inhibitor-induced skin reactions: differentiating acneiform rash from superimposed bacterial infections. AB - PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors are approved for use as targeted chemotherapeutic agents against multiple solid-organ malignancies. The most common side effect associated with EGFR inhibitor therapy is a papulopustular eruption, which can easily be confused with bacterial folliculitis. In this study, we examine the relative timing and location of the EGFR-induced papulopustular eruption compared to the associated bacterial superinfections. METHODS: In this retrospective chart review, patients enrolled in our institution's IRB-approved prospective registry of cutaneous reactions to chemotherapy were screened for inclusion. All patients who received an EGFR inhibitor and developed either a papulopustular eruption or bacterial superinfection at some point during treatment were included. RESULTS: Of the 157 patients who met inclusion criteria, 36 (23 %) developed bacterial superinfections at some point during EGFR therapy. Papulopustular eruptions developed in a highly predictable time course, with a mean time to onset of 1.5 weeks and mean duration of 9.4 weeks. Bacterial superinfections occurred at widely variable time points during therapy with a mean time to onset of 27.7 weeks. Papulopustular eruptions much more frequently affected the face (97 %), chest (75 %), and back (61 %), while bacterial superinfections occurred more commonly on the upper extremity (64 %), lower extremity (47 %), and abdomen (39 %). CONCLUSIONS: The EGFR inhibitor-induced papulopustular eruption has a stereotypical time course and occurs in a characteristic distribution affecting the central face, upper chest, and back. Bacterial superinfections more frequently affect the extremities, abdomen, and groin and may occur at any point during EGFR therapy. PMID- 27117558 TI - Fatigue in adolescent and adult survivors of non-CNS childhood cancer: a report from project REACH. AB - PURPOSE: Studies of fatigue in childhood cancer survivors (CCS) are inconclusive, with some reporting increased fatigue prevalence in this population while others do not. Given the potentially significant consequences of unmanaged fatigue, we sought to estimate the prevalence of fatigue and to identify factors associated with fatigue in a population of non-CNS CCS ranging from adolescence to middle adulthood using a single fatigue measurement tool. METHODS: Two hundred sixty eight CCS ages 12-49 years followed in a survivorship clinic at a single cancer center completed validated self-report measures of fatigue, depression, and quality of life. Demographic and current health data were collected by study questionnaire and chart review RESULTS: Based on age-adjusted population norms, the prevalence of fatigue was 13.8 %, which is not significantly different compared to results in healthy populations. Fatigue was independently associated with having >=3 chronic health conditions (OR 4.27, 95 % CI 1.52-11.99). Fatigued participants reported lower overall quality of life scores (OR 0.86, 95 % CI 0.82 0.89) and were more likely to be depressed compared to non-fatigued patients (20.4 vs. 1.4 %, respectively, p < 0.0001). There were 41(78.8 %) survivors with fatigue in our population who did not report significant depression. CONCLUSIONS: CCS did not demonstrate increased fatigue compared to age-matched normative data. Fatigued survivors were more likely to have multiple chronic conditions, depression, and decreased quality of life. Longitudinal study will promote better understanding of the relationship between fatigue and specific chronic conditions, thereby facilitating early identification of those individuals most at risk. PMID- 27117560 TI - Quality of patient care in the critical care unit in relation to nurse patient ratio: A descriptive study. AB - BACKGROUND: Intensive care is one of the most resource-intensive forms of medical care due to severely ill patients that are cared for in units with high staffing levels. Nursing's impact on the health of patients has shown that the number of nurses per patient and nurse education effects patient outcome. However, there are a lack of studies investigating highly specialised nurses in intensive care and their relation to patient outcome. METHOD: This is a retrospective study of critical care registry data (all patients >15 years) in general critical care units at seven university hospitals. RESULTS: Patient care and complications in relation to nurse/patient ratio showed that unplanned extubations occurred in 3 5.7% of cases. A difference between hospital patients' length of time on ventilation was found with the hospitals with the least amount of patients and with 0.5-0.6 specialist-nurse/patient a longer time on ventilation was noted. The length of ICU stay showed differences between the hospitals and nurse/patient ratios, with higher nurse/patient ratio with the longer length of ICU stay. CONCLUSION: Despite similarities between hospitals in relation to SAPS III on admission to critical care, there was a difference in nurse/patient ratios ranging from 1:1 to 0.5:1 and mean time on both invasive and noninvasive ventilation. PMID- 27117559 TI - The relationship between exercise induced bronchial obstruction and health related quality of life in female and male adolescents from a general population. AB - BACKGROUND: Previous studies have observed that exercise-induced bronchoconstriction (EIB) is more common and more strongly related to exercise related breathing problems in female adolescents than male adolescents. However, few studies have investigated the association between EIB and health related quality of life (HRQoL) from a gender perspective. The aim of this study was to examine the association between EIB and HRQoL and physical activity level in female and male adolescents with and without EIB. METHODS: From a population based study on exercise-induced breathing problems among adolescents (13-15 years, n = 3838) a cross sectional study with prospective data collection was carried out in a random subsample of 140 adolescents. The subjects in the sample were tested for EIB with a standardised exercise test, of which 49 adolescents were tested positive. HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) and the adolescents' physical activity levels were measured objectively with accelerometer. RESULTS: The female subjects with EIB reported a lower HRQoL, both in total score (p = 0.03) and physical functioning score (p = 0.009) and had a lower baseline FEV1 compared to females without EIB (88 vs. 94 % predicted, p = 0.001). No differences were found in HRQoL or baseline lung function between males with or without EIB. There were no differences in minutes of moderate to vigorous physical activity per day between females or males with and without EIB. CONCLUSION: In a general population, the female adolescents with EIB had lower HRQoL and poorer baseline lung function compared to counterparts without EIB. These differences were not observed in males. EIB does not appear to affect the level of daily physical activity neither in females nor males. PMID- 27117561 TI - Delivering on the promise of universal health coverage. PMID- 27117562 TI - A Japanese case of hereditary chin trembling responsive to arotinolol. PMID- 27117563 TI - Resting-state fMRI reveals potential neural correlates of impaired cognition in Huntington's disease. AB - BACKGROUND: Huntington's Disease (HD) is characterized by motor, cognitive and psychiatric dysfunction. Functional MRI (fMRI) provides new insight into the pathologic mechanism underlying the cognitive symptoms. Previous fMRI studies of HD focused on functional synchronization of various brain areas by measuring functional connectivity, a method that is unable to identify regional intrinsic neural activity changes in the brain. To fill in this gap, we utilized amplitude of low frequency fluctuations (ALFF). OBJECTIVE: To investigate alterations in regional brain activity and their association with clinical characteristics in the early stages of HD. METHODS: Ten early stage HD patients and 20 age- and sex matched healthy controls were scanned to obtain imaging data. HD patients were assessed with the Unified Huntington's Disease Rating Scale, Mini-Mental State Exam (MMSE), Stroop test, Symbol Digit Modalities Test (SDMT), Verbal Fluency Test and Beck Depression Index. RESULTS: Gray matter volume (GMV) reduction was detected in bilateral striatum and left calcarine cortex in the HD group. After correcting for GMV, HD patients demonstrated significantly decreased ALFF in the right precuneus and angular gyrus, and increased ALFF in bilateral inferior temporal gyrus (ITG) and left superior frontal gyrus. Increased mean values of ALFF in the left ITG were correlated with worse performance in SDMT, and decreased mean values of ALFF in the precuneus were correlated with worse performance in the Stroop test and SDMT. CONCLUSIONS: Our results suggest that intrinsic brain activity alterations in the precuneus and cortico-striatal circuit may be the mechanism underlying impaired cognition in early HD. PMID- 27117564 TI - Normal phase HPLC-based activity profiling of non-polar crude plant extracts - acetylcholinesterase inhibiting guttiferones from Montrouziera cauliflora as a case study. AB - The study describes bioactive compounds as inhibitors of acetylcholinesterase (AChE), from the stem bark extract of Montrouziera cauliflora, selected among 19 dichloromethane extracts from Clusiaceae species. Our work focused on the development of an original normal phase HPLC microfractionation strategy to rapidly assess highly active zones from this crude active non-polar plant extract. Two different microfraction collection methods were evaluated for the assessment of the AChE inhibition. Two guttiferones and a tocotrienol were directly isolated among five compounds identified off-line by NMR after upscaling the fractionation and their AChE inhibition was evaluated. The strengths and weaknesses of the two microfractionation collection methods for HPLC-AChE activity-based profiling are discussed. PMID- 27117565 TI - Amputations in Sickle Cell Disease: Case Series and Literature Review. AB - In this study, we describe four new patients with sickle cell disease who had limb amputations. Two of the patients had sickle cell anemia [Hb S (HBB: c.20A > T) (beta(S)/beta(S))] with refractory leg ulcers that required amputations. The third patient had sickle cell trait with an extensive leg ulcer that was associated with epidermoid carcinoma. The fourth patient had amputations of both forearms and feet due to a misdiagnosis of dactylitis. Review of the literature showed that the indications for amputations in sickle cell disease included three distinct categories: mythical beliefs, therapeutic and malpractice. All therapeutic amputations were for severely painful, large, recalcitrant leg ulcers that failed non-interventional therapies. Amputation resulted in pain relief and better quality of life. Phantom neuropathic pain was not a major issue post operatively. It was absent, transient or well controlled with antidepressants. Limb function was restored post-amputation with prosthetic artificial limbs, wheelchairs or crutches. Malpractice amputations were due to misdiagnosis or to cryotherapy by exposing the painful limb to ice water resulting in thrombosis, gangrene and amputation. We strongly suggest that leg amputations should be considered in the management of certain patients with severe extensive refractory leg ulcers, and topical cryotherapy should never be used to manage sickle cell pain. PMID- 27117566 TI - Molecular Epidemiology of Hemoglobinopathies in Cambodia. AB - Determining the magnitude of the thalassemia problem in a country is important for implementing a national prevention and control program. In order to acquire accurate thalassemia prevalence data, the gene frequency of alpha- and beta thalassemia (alpha- and beta-thal) in different regions of a country should be determined. The molecular basis of thalassemia in Cambodia was performed by polymerase chain reaction (PCR)-based techniques in a community-based cross sectional survey of 1631 unrelated individuals from three regions, Battambang, Preah Vihear and Phnom Penh. Thalassemia mutations were detected in 62.7% of the three studied population of Cambodia. Hb E (HBB: c.79G > A) was the most common beta-globin gene mutation with a frequency ranging from 0.139 to 0.331, while the most frequent alpha-globin gene mutation was the -alpha(3.7) (rightward) deletion (0.098-0.255). The other frequencies were 0.001-0.003 for beta-thal, 0.008-0.011 for alpha-thal-1 (- -(SEA)), 0.003-0.008 for alpha-thal-2 [-alpha(4.2) (leftward deletion)], 0.021-0.044 for Hb Constant Spring (Hb CS, HBA2: c.427T > C) and 0.009-0.036 for Hb Pakse (HBA2: c.429A > T). A regional specific thalassemia gene frequency was observed. Preah Vihear had the highest prevalence of Hb E (55.9%), alpha-thal-2 (24.0%) and nondeletional alpha-thal (15.1%), whereas Phnom Penh had the lowest frequency of thalassemia genes. Interestingly, in Preah Vihear, the frequency of Hb Pakse was extremely high (0.036), almost equivalent to that of Hb CS (0.044). Our results indicate the importance of micromapping and epidemiology studies of thalassemia, which will assist in establishing the national prevention and control program in Cambodia. PMID- 27117567 TI - Molecular Characterization of beta-Thalassemia Intermedia in Southeast Iran. AB - Inheritance of mild mutations within the beta-globin gene and coinheritance of alpha-thalassemia (alpha-thal) are known as two important genetic modifiers in beta-thalassemia (beta-thal) intermedia (beta-TI). We aimed to evaluate the spectrum of beta- and alpha-thal mutations in beta-TI patients in Southeast Iran. Common beta- and alpha-globin gene mutations were detected by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and multiplex gap PCR, respectively. There were 26 male (57.8%) and 19 female (42.2%) patients. HBB: c.92 + 5T > C [IVS-I-5 (G > C)] and HBB: c.-138C + 1G > A [IVS-II-I (G > A)] represented the prevalent alleles with respective frequencies of 60.0 and 10.0%. Other beta-globin mutations included HBB: c.-138C > T [-88 (C > T)], HBB: c.27_28insG [frameshift codons (FSC) 8/9 (+G)], HBB: c.46delT [codon 15 (-T)], HBB: c.93-22_95del (IVS-I, 25 del), and the 619 bp deletion (NG_000007.3: g.71609_72227del619). The predominant genotypic combinations were beta(0)/beta(0) (68.9%), beta(0)/beta(+ )(8.9%) and beta(+)/beta(+ )(2.2%). Coinheritance of alpha-thal was observed in 33.0% of the patients, with the -alpha(3.7) (rightward) (NG_000006.1: g.34164_37967del3804) as the most common deletion (86.0%). One patient was diagnosed with the -alpha(4.2) (leftward) (AF221717) and one with the - -(MED) (g.24664_41064del16401) deletions, while no patients carried the -(alpha)(20.5) (g.15164_37864del22701), alpha(-5 nt) (HBA2: c.95 + 2_95_6delTGAGG) or codon 19 (-G) (HBA2: c.56delG) mutations. The alleviating molecular mechanism was not explainable by beta(+ )or concurrent alpha-thal in more than half of our beta-TI patients. This encourages conducting more studies to identify other contributing factors, especially Hb F-inducing genetic modifiers. PMID- 27117568 TI - A Family with gamma-Thalassemia and High Hb A2 Levels. AB - We describe a family carrying a gamma-globin gene deletion associated with an increase of Hb A2 level beyond the normal range. The family included the proband, his sister and their father, all with increased Hb A2 and normal Hb F levels. The proband and his sister showed borderline values of mean corpuscular volume (MCV) and reduced values of mean corpuscular hemoglobin (Hb) (MCH). The proband was referred to our Medical Genetics Service for preconception counseling together with his partner, a typical beta-thalassemia (beta-thal) carrier. The results were negative for the most frequent alpha-thalassemia (alpha-thal) mutations, and had no significant sequence variations of the coding sequences and promoter of the beta- and delta-globin genes. Quantitative analysis by multiplex ligation dependent probe amplification (MPLA) of the beta-globin gene cluster detected a heterozygous deletion, ranging between 2.1 and 4.7 kb, in the proband, his sister and the father. The deletion involved the (G)gamma gene and (G)gamma-(A)gamma intergenic region, whereas the 3' region of the (A)gamma gene was preserved. A subsequent gap-polymerase chain reaction (gap-PCR) showed that a hybrid (GA)gamma fusion gene was present. The deletion segregated with the elevation of Hb A2. The MLPA analysis of the beta-globin gene cluster in 150 control alleles excluded a common polymorphism. Despite stronger evidence being needed, the described family suggests a possible role of this gamma-globin gene deletion in contributing to Hb A2 elevation, possibly by altering the transcription regulation of the cluster. We propose gamma-globin gene dosage analysis to be performed in patients with unexplained elevated Hb A2 levels. PMID- 27117569 TI - The Impact of XmnI-HBG2, BCL11A and HBS1L-MYB Single Nucleotide Polymorphisms on Hb F Variation of Hematologically Normal Iranian Individuals. AB - The impact of Hb F on severity of sickle cell disease and beta-thalassemia (beta thal) is well documented. The XmnI-HBG2, BCL11A and HBS1L-MYB single nucleotide polymorphisms (SNPs) have been introduced as the most important factors causing variation in fetal hemoglobin (Hb F) levels in different population studies. However, the extent of their effect could be population-specific. In this study, multivariate linear regression analysis was used to evaluate the association of Hb F with age, sex, and eight SNPs, including XmnI-HBG2, four BCL11A, two HBS1L MYB SNPs and the polymorphic palindromic 5' hypersensitive 4-locus control region (5'HS4-LCR). One hundred and twenty-two hematologically normal individuals, from a previous study cohort, constituted our study population. In multivariate regression analyses, no association of Hb F was observed with age or sex of the individuals and SNPs in this study. We conducted a univariate regression analysis to further investigate the results, which among all the factors only detected XmnI-HBG2 and 5'HS4 SNPs as significant modifiers of Hb F. The significance of these two factors disappeared in a bivariate analysis. These results suggest that either XmnI-HBG2 or 5'HS4-LCR have a stronger contribution in Hb F variations of the Iranian population than BCL11A and HBS1L-MYB SNPs. Furthermore, the effect of low population size and technical limitations on obtained results could not be ruled out. PMID- 27117570 TI - Diagnostic Dilemma of Hb Perth [beta32(B14)Leu->Pro; HBB: c.98T > C] in Mainland China. AB - Unstable hemoglobin (Hb) variants represent a rare etiology of congenital hemolytic anemia. Correct diagnosis can be a challenge due to the relative rarity or lack of awareness of this disorder. We report an 18-month-old girl, who presented with a long-standing hemolytic anemia. Her diagnosis of unstable Hb Perth [beta32(B14)Leu->Pro, HBB: c.98T > C] had not been made until gene sequencing of the beta-globin gene was performed. PMID- 27117571 TI - Spectrum of Common alpha-Globin Deletion Mutations in the Southern Region of Vietnam. AB - The common deletion mutations of alpha-globin genes in the Vietnamese population is not well known. Here we report the presence of five deletional mutations of Southeast Asia in the southern region of Vietnam. The - -(SEA) (NG_000006.1: g.26264_45564del19301) mutation is the most common type of deletion (87.35%), followed by the -alpha(3.7) (rightward) (NG_000006.1: g.34164_37967del3804) deletion (9.64%), -alpha(4.2) (leftward) (AF221717) deletion (2.41%) and - (THAI) (NG_000006.1: g.10664_44164del33501) (0.6%) mutation in this region. The - -(FIL) (NG_000006.1: g.11684_43534del31581) mutation was not detected in this study. This result provided a view of the distribution of common alpha-globin gene mutations in Vietnam and could serve as a baseline for further investigations into these genetic defects. PMID- 27117572 TI - Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A). AB - We report an infant with a compound heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A) and a phenotype of mild microcytic anemia with target cell morphology but without overt hemolysis. PMID- 27117573 TI - A New delta-Globin Gene Variant: Hb A2-Fengshun [delta121(GH4)Glu->Lys (HBD: c.364G > A)]. AB - An elevated Hb A2 (alpha2delta2 level) is a diagnostic marker for heterozygous beta-thalassemia (beta-thal). Mutations in the delta-globin gene can cause decreased expression of Hb A2, compromising screening for heterozygous beta-thal. In this report, we describe a novel missense mutation of the delta-globin [Hb A2 Fengshun or delta121(GH4)Glu->Lys, HBD: c.364G > A] in a Chinese individual who had coinherited a heterozygous beta-thal with a normal Hb A2 level. PMID- 27117574 TI - The Natural History of Hb S/Hereditary Persistence of Fetal Hemoglobin in 13 Children from the State of Minas Gerais, Brazil. AB - Children with Hb S (HBB: c.20A > T)/hereditary persistence of fetal hemoglobin (Hb S/HPFH) have a mild clinical phenotype, but some complications have been reported. The natural history of Hb S/HPFH in children from the State of Minas Gerais, Brazil newborn cohort is described. Clinical and hematological data regarding participants' phenotypes were retrieved from medical records. The HPFH 1, HPFH-2, and HPFH-3 and alpha-thalassemia (alpha-thal) deletions were detected by gap-polymerase chain reaction (gap-PCR). Thirteen children were included, nine (69.2%) had the Hb S/HPFH-2 deletion, and four (30.8%) had Hb S/HPFH-1 deletion; 11 children (84.6%) had alphaalpha/alphaalpha, and two (15.4%) carried the alphaalpha/-alpha(3.7) (rightward) deletion. The mean concentration of total hemoglobin (Hb) and Hb F was 12.52 +/- 0.56 g/dL and 42.31% +/- 1.97%, respectively. Mild microcytosis and hypochromia were observed. We found acute clinical manifestations of sickle cell disease, such as acute chest syndrome (ACS) and acute pain crisis in four children; nine (69.2%) children were completely asymptomatic during the follow-up period. All children were classified as having low-risk transcranial Doppler (TDC). In conclusion, children with Hb S/HPFH have a mild clinical phenotype of sickle cell disease, although acute clinical manifestations may occur. High Hb F levels and absence of anemia are common hematological characteristics. PMID- 27117575 TI - Diffusing colloidal probes of cell surfaces. AB - Measurements and analyses are reported to quantify dynamic and equilibrium interactions between colloidal particles and live cell surfaces using dark field video microscopy. Two-dimensional trajectories of micron-sized polyethylene glycol (PEG)-coated silica colloids relative to adherent epithelial breast cancer cell perimeters are determined allowing measurement of position dependent diffusivities and interaction potentials. PEG was chosen as the material system of interest to assess non-specific interactions with cell surfaces and establishes a basis for investigation of specific interactions in future studies. Analysis of measured potential energies on cell surfaces reveals the spatial dependence in cell topography. With the measured cell topography and models for particle-cell surface hydrodynamic interactions, excellent agreement is obtained between theoretical and measured colloidal transport on cell surfaces. Quantitative analyses of association lifetimes showed that PEG coatings act to stabilize colloids above the cell surface through net repulsive, steric interactions. Our results demonstrate a self-consistent analysis of diffusing colloidal probe interactions due to conservative and non-conservative forces to characterize biophysical cell surface properties. PMID- 27117577 TI - Impact of central node dissection on postoperative morbidity in pediatric patients with suspected or proven thyroid cancer. AB - BACKGROUND: Pediatric risk factors for postoperative morbidity after central node dissection are ill-defined. METHODS: This outcome study aimed to evaluate operative morbidity in patients aged <=18 years after total thyroidectomy with or without central node dissection for suspected or proven thyroid cancer. RESULTS: Included were 102 patients with hereditary C-cell hyperplasia, 66 patients with medullary, 60 patients with papillary, and 2 patients with follicular thyroid cancer. In all 230 patients, 131 of whom underwent central node dissection, transient recurrent laryngeal nerve palsy was significantly associated only with central node dissection (100% vs 55%; P = .010). Transient and permanent hypoparathyroidism were significantly associated with age (means of 11.9 years versus 7.8 years, and 12.9 years versus 8.5 years; P <= .002); central node dissection (80% vs 50%, and 100% vs 54%; P <= .001); and the number of central lymph nodes cleared (means of 12.2 nodes versus 5.4 nodes, and 26.9 nodes versus 5.8 nodes, P < .001). These effects were stronger for permanent than transient hypoparathyroidism. Correlations between permanent hypoparathyroidism and the number of nodes cleared on central node dissection (r = 0.35) were closer than those between permanent hypoparathyroidism and age (r = 0.15), but similar for transient hypoparathyroidism (r = 0.22 and r = 0.25). CONCLUSION: Owing to the incremental morbidity from central node dissection, the extent of a neck operation, in experienced hands, should be tailored to the extent of the underlying disease regardless of the child's age. The notion that the experience of the center and surgeons may be more important than the age of the child requires validation in independent series across different health care settings. PMID- 27117576 TI - The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3. AB - We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped >2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P=5.045*10(-6)) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P=0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P=2.563*10(-7)). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P=0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was -3.8% (P=8.526*10(-8)). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8. PMID- 27117578 TI - Clinical applications of amylase: Novel perspectives. AB - BACKGROUND: Amylase was the first enzyme to be characterized, and for the previous 200 years, its clinical role has been restricted to a diagnostic aid. Recent interface research has led to a substantial expansion of its role into novel, viable diagnostic, and therapeutic applications to cancer, infection, and wound healing. This review provides a concise "state-of-the-art" overview of the genetics, structure, distribution, and localization of amylase in humans. METHOD: A first-generation literature search was performed with the MeSH search string "Amylase AND (diagnost* OR therapeut$)" on OVIDSP and PUBMED platforms. A second generation search was then performed by forward and backward referencing on Web of KnowledgeTM and manual indexing, limited to the English Language. RESULTS: "State of the Art" in amylase genetics, structure, function distribution, localisation and detection of amylase in humans is provided. To the 4 classic patterns of hyperamylasemia (pancreatic, salivary, macroamylasemia, and combinations) a fifth, the localized targeting of amylase to specific foci of infection, is proposed. CONCLUSIONS: The implications are directed at novel therapeutic and diagnostic clinical applications of amylase such as the novel therapeutic drug classes capable of targeted delivery and "smart release" in areas of clinical need. Future directions of research in areas of high clinical benefit are reported. PMID- 27117579 TI - Commentary: Can we go further in the tailoring of bariatric operations? PMID- 27117580 TI - Long term results of treatment of breast cancer without axillary surgery - Predicting a SOUND approach? AB - BACKGROUND: Traditionally axillary surgery has been used to provide staging information and until recently was thought to improve loco-regional control. However, a more minimal approach to the axilla is now being adopted. The aim of this study was to assess long term outcomes of patients with 'low-risk' breast cancers who did not undergo any axillary surgery. 'Low-risk' criteria were: postmenopausal, <20 mm grade 1 or <15 mm grade 2, LVI-ve, ER +ve. METHODS: Women with invasive breast cancer that did not undergo any axillary surgery were identified. Patients were censored when an event or death occurred or at last follow-up at breast clinic or with their General Practitioner. RESULTS: Between 05/01/1995-20/11/2006, 194 patients (199 tumours) were operated upon without axillary surgery. Median follow-up was 10.4 years. 128 patients met low-risk criteria and 71 did not (patient choice = 42, medical fitness = 29). In the 'low risk' cohort there were two axillary recurrences, with a cumulative incidence of 0.8% and 1.9% at 5 and 10 years respectively. DDFS was 99.2% (94.1-99.9%), and 97% (90.0-99%) at 5 and 10 years respectively and DFS was 96.6% (91.1-98.7%) and 91.2% (82.6-95.6%). OS was 90.3% (95% CI: 83.6-94.4) and 75.5% (95% CI: 65.9 82.8) at 5 and 10 years respectively. CONCLUSION: Axillary recurrence and DDFS in this low-risk cohort is favourable. In the modern era of breast cancer management it is possible to define a group of women in whom axillary surgery can be omitted. PMID- 27117581 TI - The Relevance of Geriatric Impairments in Patients Starting Dialysis: A Systematic Review. AB - BACKGROUND AND OBJECTIVES: With aging of the general population, patients who enter dialysis therapy will more frequently have geriatric impairments and a considerable comorbidity burden. The most vulnerable among these patients might benefit from conservative therapy. Whether assessment of geriatric impairments would contribute to the decision-making process of dialysis initiation is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic Medline and Embase search was performed on December 1, 2015 to identify studies assessing the association between risk of mortality or hospitalization and one or more geriatric impairments at the start of dialysis therapy, including impairment of cognitive function, mood, performance status or (instrumental) activities of daily living, mobility (including falls), social environment, or nutritional status. RESULTS: Twenty-seven studies were identified that assessed one or more geriatric impairments with respect to prognosis. The quality of most studies was moderate. Only seven studies carried out an analysis of elderly patients (>=70 years old). Malnutrition and frailty were systematically assessed, and their relation with mortality was clear. In addition, cognitive impairment and functional outcomes at the initiation of dialysis were related to an increased mortality in most studies. However, not all studies applied systematic assessment tools, thereby potentially missing relevant impairment. None of the studies applied a geriatric assessment across multiple domains. CONCLUSIONS: Geriatric impairment across multiple domains at dialysis initiation is related to poor outcome. However, information in the elderly is sparse, and a systematic approach of multiple domains with respect to poor outcome has not been performed. Because a geriatric assessment has proved useful in predicting outcome in other medical fields, its potential role in the ESRD population should be the subject of future research. PMID- 27117582 TI - Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. AB - BACKGROUND: A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies. METHODS: Immunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment. RESULTS: Median survival after BCBM excision was 18.3 months (range 0-99). Median number of CD4+, CD8+ TILs and CD68+ was 49, 69 and 76 per 1 mm(2), respectively. PD-L1 and PD-L2 expression in BCBM was present in 53 % and 36 % of cases, and was not related to BCBM phenotype. PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs (r = 0.26 and 0.33), and so did CD68+ (r = 0.23 and 0.27, respectively). In the multivariate analysis, survival after BCBM excision positively correlated with PD-1 expression on TILs (hazard ratio (HR) = 0.3, P = 0.003), CD68+ infiltration (HR = 0.2, P < 0.001), brain radiotherapy (HR = 0.1, P < 0.001), endocrine therapy (HR = 0.1, P < 0.001), and negatively with hormone-receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive phenotype of primary tumor (HR = 2.6, P = 0.01), HER2 expression in BCBM (HR = 4.9, P = 0.01). CONCLUSIONS: PD-L1 and PD-L2 expression is a common occurrence in BCBM, irrespective of primary tumor and BCBM phenotype. Favorable prognostic impact of PD-1 expression on TILs suggests a beneficial effect of preexisting immunity and implies a potential therapeutic role of immune checkpoint inhibitors in BCBM. PMID- 27117583 TI - Evaluation of role of telmisartan in combination with 5-fluorouracil in gastric cancer cachexia. AB - BACKGROUND: The objective of the present study was to evaluate the effect of combination of telmisartan with 5-flourouracil (5-FU) in gastric cancer cachexia induced by administering N-methyl-N'-methyl-N-nitrosoguanidine (MNNG). METHOD: MNND was administered once daily by oral gavage for two weeks, and saturated NaCl (1ml per rat) was then given once every 3days for 4weeks. 5-FU (75mg/kg, i.v.) was administered once three weeks from 7th to 22nd week. From 7th to 22nd week, telmisartan (5mg/kg, p.o.) was also administered along with 5-FU. RESULT: MNNG produced significant decrease in food intake, body weight, caused hyperglycemia, dyslipidemia, hypertension worsened hemodyanamics, increased cachexia markers and increased tumor markers like lactate dehydrogenase and gamma-glutamyltransferase. MNNG also produced oxidative stress in the stomach tissue. Treatment with combination of telmisartan with 5-FU produced significant increase in food intake and body weight, controlled hyperglycemia and dyslipidemia, preserved hemodynamic function, and decreased the cachexia markers while 5-FU alone did not produce any such effects. Further, the combination of telmisartan with 5-FU significantly reduced tumor marker levels, oxidative stress and also significantly decreased the cell proliferation, apoptosis, hyperkeratosis, keratohyaline granules and invasive carcinoma of forestomach and reduced muscle atrophy in tibilias anterior skeletal muscle. CONCLUSION: Our data suggests that combination of telmisartan with 5-FU treatment is beneficial in controlling cancer cachexia. Telmisartan can be used as an add-on therapy with 5-FU or other traditional chemotherapeutic agents. PMID- 27117584 TI - The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats. AB - AIMS: Cerebral ischemia reperfusion (IR) injury is a process in which oxidative and apoptotic mechanisms play a part. Neuroprotective agents to be found could work out well for the efficient and safe minimization of cerebral IR injury. Crocin is a strong antioxidant agent; however the influence of this agent on the experimental cerebral ischemia model has not been studied extensively and thus it is not well-known. The objective of our study was to investigate the antioxidant, antiapoptotic and protective effects of crocin on the global cerebral IR induced by four-vessel occlusion. MAIN METHODS: A total of 30 adult female Sprague-Dawley rats were equally and randomly separated into three groups as follows: sham, IR and IR+crocin (40mg/kg/day orally for 10days). 24h after electrocauterization of bilateral vertebral arteries, bilateral common carotid arteries were occluded for 30min and reperfused for 30min. Oxidative stress parameters (TAS, TOS, OSI), haematoxylin and eosin staining, caspase-3 and hypoxia-inducible factor-1 alpha (HIF-1alpha) expressions and TUNEL methods were investigated. KEY FINDINGS: There was a significant difference between the IR and sham groups by means of OSI level, histopathological scoring, caspase-3, HIF-1alpha and TUNEL-positive cell parameters. We have also observed that pre-treatment with crocin reduced these parameter levels back to the baseline. SIGNIFICANCE: The data obtained from the present study suggest that crocin may exert antiapoptotic, antioxidant and protective effects in IR-mediated brain injury induced by four-vessel occlusion. To the best of our knowledge, this would be the first study to be conducted in this field. PMID- 27117585 TI - Bacterial superglue enables easy development of efficient virus-like particle based vaccines. AB - BACKGROUND: Virus-like particles (VLPs) represent a significant advance in the development of subunit vaccines, combining high safety and efficacy. Their particulate nature and dense repetitive subunit organization makes them ideal scaffolds for display of vaccine antigens. Traditional approaches for VLP-based antigen display require labor-intensive trial-and-error optimization, and often fail to generate dense antigen display. Here we utilize the split-intein (SpyTag/SpyCatcher) conjugation system to generate stable isopeptide bound antigen-VLP complexes by simply mixing of the antigen and VLP components. RESULTS: Genetic fusion of SpyTag or SpyCatcher to the N-terminus and/or C terminus of the Acinetobacter phage AP205 capsid protein resulted in formation of stable, nonaggregated VLPs expressing one SpyCatcher, one SpyTag or two SpyTags per capsid protein. Mixing of spy-VLPs with eleven different vaccine antigens fused to SpyCatcher or SpyTag resulted in formation of antigen-VLP complexes with coupling efficiencies (% occupancy of total VLP binding sites) ranging from 22-88 %. In mice, spy-VLP vaccines presenting the malaria proteins Pfs25 or VAR2CSA markedly increased antibody titer, affinity, longevity and functional efficacy compared to corresponding vaccines employing monomeric proteins. The spy-VLP vaccines also effectively broke B cell self-tolerance and induced potent and durable antibody responses upon vaccination with cancer or allergy-associated self-antigens (PD-L1, CTLA-4 and IL-5). CONCLUSIONS: The spy-VLP system constitutes a versatile and rapid method to develop highly immunogenic VLP-based vaccines. Our data provide proof-of-concept for the technology's ability to present complex vaccine antigens to the immune system and elicit robust functional antibody responses as well as to efficiently break B cell self tolerance. The spy-VLP-system may serve as a generic tool for the cost-effective development of effective VLP-vaccines against both infectious- and non communicable diseases and could facilitate rapid and unbiased screening of vaccine candidate antigens. PMID- 27117586 TI - Sudden sensorineural hearing loss is associated with chronic rhinosinusitis: population-based study. AB - BACKGROUND: This study aimed to evaluate the association of chronic rhinosinusitis with sudden sensorineural hearing loss using a population-based database. METHODS: Sampled subject data were obtained from the Taiwan Longitudinal Health Insurance Database 2000. A total of 3325 patients with sudden sensorineural hearing loss were identified and 9975 controls were randomly selected. A conditional logistic regression was used to calculate the odds ratio for having been previously diagnosed with chronic rhinosinusitis, for cases and controls. RESULTS AND CONCLUSION: The adjusted odds ratio of having prior chronic rhinosinusitis among cases compared to controls was 1.36 (95 per cent confidence interval = 1.16-1.60). The significant relationship between sudden sensorineural hearing loss and chronic rhinosinusitis was most pronounced among those patients aged 44 years or less (compared to controls) (odds ratio = 2.18; 95 per cent confidence interval = 1.63-2.92). However, the significant relationship between sudden sensorineural hearing loss and prior chronic rhinosinusitis was not sustained for patients older than 60 years compared to controls. PMID- 27117587 TI - Plasmodium meets AAV-the (un)likely marriage of parasitology and virology, and how to make the match. AB - The increasing use of screening technologies in malaria research has substantially expanded our knowledge on cellular factors hijacked by the Plasmodium parasite in the infected host, including those that participate in the clinically silent liver stage. This rapid gain in our understanding of the hepatic interaction partners now requires a means to validate and further disentangle parasite-host networks in physiologically relevant liver model systems. Here, we outline seminal work that contributed to our present knowledge on the intrahepatic Plasmodium host factors, followed by a discussion of surrogate models of mammalian livers or hepatocytes. We finally describe how Adeno-associated viruses could be engineered and used as hepatotropic tools to dissect Plasmodium-host interactions, and to deliberately control these networks for antimalaria vaccination or therapy. PMID- 27117588 TI - Epigenetic profiles signify cell fate plasticity in unipotent spermatogonial stem and progenitor cells. AB - Spermatogonial stem and progenitor cells (SSCs) generate adult male gametes. During in vitro expansion, these unipotent murine cells spontaneously convert to multipotent adult spermatogonial-derived stem cells (MASCs). Here we investigate this conversion process through integrative transcriptomic and epigenomic analyses. We find in SSCs that promoters essential to maintenance and differentiation of embryonic stem cells (ESCs) are enriched with histone H3 lysine4 and -lysine 27 trimethylations. These bivalent modifications are maintained at most somatic promoters after conversion, bestowing MASCs an ESC like promoter chromatin. At enhancers, the core pluripotency circuitry is activated partially in SSCs and completely in MASCs, concomitant with loss of germ cell-specific gene expression and initiation of embryonic-like programs. Furthermore, SSCs in vitro maintain the epigenomic characteristics of germ cells in vivo. Our observations suggest that SSCs encode innate plasticity through the epigenome and that both conversion of promoter chromatin states and activation of cell type-specific enhancers are prominent features of reprogramming. PMID- 27117589 TI - Effect of pharmacist intervention on physician prescribing in patients with chronic schizophrenia: a descriptive pre/post study. AB - BACKGROUND: Although pharmacotherapy is one of the most important treatments for schizophrenia, the prominent levels of antipsychotic polypharmacy and high-dose regimens used in Japan are thought to be inconsistent with treatment regimens used in other countries. In this study, we evaluated the effect of pharmacist intervention on physician prescribing in patients with chronic schizophrenia. METHODS: Participants comprised 52 inpatients at Sawa Hospital (Osaka, Japan), treated with at least one antipsychotic agent, who received pharmacist intervention for 1 year (2012). We compared the dose and the number of antipsychotics prescribed, and the rate of concurrent prescribing of anti Parkinson, benzodiazepine and mood-stabilizer medication, pre- and post pharmacist intervention. As an indicator of psychosis symptoms, the rate of seclusion room use was recorded. Additionally, we evaluated the impact of pharmacist intervention on medicine costs. Continuous variables were analyzed by Wilcoxon signed-rank sum tests, and categorical data were analyzed using Fisher's exact tests. RESULTS: Compared with pre-intervention, the dose (982.6 mg pre vs. 857.6 mg post; p < 0.01) and the number of antipsychotics (2.0 pre vs. 2.0 post; p < 0.05) at 1 year were significantly lower post-intervention. The seclusion room use rate was not significantly different but tended to be lower post intervention than pre-intervention (p < 0.1). The cost (in USD) for all medicines (10.33 pre vs. 8.76 post; p < 0.05), antipsychotics (8.04 pre vs. 6.48 post; p < 0.05), and psychotropics (9.24 pre vs. 7.68 post; p < 0.01) were significantly lower post-intervention than pre-intervention. CONCLUSION: Pharmacist intervention has the potential to optimize medication prescribing and reduce medication costs in patients with chronic schizophrenia. It might be suggested that clinical practitioners as well as medical hospital administrators consider the pharmacists' ability to rationalize medication therapy in schizophrenia. PMID- 27117590 TI - Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer. AB - BACKGROUND: Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities-such as radiation pneumonitis-during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors. METHODS: We performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines. RESULTS: miRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR 29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation. CONCLUSIONS: miR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity. PMID- 27117591 TI - Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer. AB - BACKGROUND & AIMS: Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability of these tumors. METHODS: Here we established an orthotopic engraftment technique to model a series of patient-derived tumor xenograft (PDTX) from pediatric liver cancers of all major histologic subtypes: hepatoblastoma, hepatocellular cancer and hepatocellular malignant neoplasm. We utilized standard (immuno) staining methods for histological characterization, RNA sequencing for gene expression profiling and genome sequencing for identification of druggable targets. We also adapted stem cell culturing techniques to derive two new pediatric cancer cell lines from the xenografted mice. RESULTS: The patient derived tumor xenografts recapitulated the histologic, genetic, and biological characteristics-including the metastatic behavior-of the corresponding primary tumors. Furthermore, the gene expression profiles of the two new liver cancer cell lines closely resemble those of the primary tumors. Targeted therapy of PDTX from an aggressive hepatocellular malignant neoplasm with the MEK1 inhibitor trametinib and pan-class I PI3 kinase inhibitor NVP-BKM120 resulted in significant growth inhibition, thus confirming this PDTX model as a valuable tool to study tumor biology and patient-specific therapeutic responses. CONCLUSIONS: The novel metastatic xenograft model and the isogenic xenograft-derived cell lines described in this study provide reliable tools for developing mutation- and patient-specific therapies for pediatric liver cancer. LAY SUMMARY: Pediatric liver cancer is a rare but serious disease and no experimental animal model currently captures the complexity and metastatic capability of these tumors. We have established a novel animal model using human tumor tissue that recapitulates the genetic and biological characteristics of this cancer. We demonstrate that our patient-derived animal model, as well as two new cell lines, are useful tools for experimental therapies. PMID- 27117592 TI - Image-based compound profiling reveals a dual inhibitor of tyrosine kinase and microtubule polymerization. AB - Small-molecule compounds are widely used as biological research tools and therapeutic drugs. Therefore, uncovering novel targets of these compounds should provide insights that are valuable in both basic and clinical studies. I developed a method for image-based compound profiling by quantitating the effects of compounds on signal transduction and vesicle trafficking of epidermal growth factor receptor (EGFR). Using six signal transduction molecules and two markers of vesicle trafficking, 570 image features were obtained and subjected to multivariate analysis. Fourteen compounds that affected EGFR or its pathways were classified into four clusters, based on their phenotypic features. Surprisingly, one EGFR inhibitor (CAS 879127-07-8) was classified into the same cluster as nocodazole, a microtubule depolymerizer. In fact, this compound directly depolymerized microtubules. These results indicate that CAS 879127-07-8 could be used as a chemical probe to investigate both the EGFR pathway and microtubule dynamics. The image-based multivariate analysis developed herein has potential as a powerful tool for discovering unexpected drug properties. PMID- 27117593 TI - Social Inequalities in Inflammation: Age Variations in Older Persons. AB - OBJECTIVE: Systemic inflammation is an important risk factor for cardiovascular diseases and inequalities by race/ethnicity, gender, and education have been documented. However, there is incomplete knowledge as to how these disparities present across age, especially in late life. This study assesses whether differences in C-reactive protein (CRP), a marker of inflammation, are contingent on age among older persons. METHOD: Data are from the 2006/2008 Health and Retirement Study ( n = 10,974) biomarker assessment. CRP was regressed on interactions between age and other status characteristics. RESULTS: Racial/ethnic differences in inflammation do not vary significantly by age. However, gender and education differences are greatest at younger ages and then narrow steadily with increasing age. DISCUSSION: There is considerable heterogeneity in how disparities in inflammation present across age and characteristics such as race/ethnicity, gender, and education. Understanding status differences in the influence of age on factors affecting late-life health is useful for health disparities research. PMID- 27117594 TI - Adrenal Metastasis from Uterine Papillary Serous Carcinoma. AB - BACKGROUND : Uterine papillary serous carcinoma (UPSC) is a highly malignant form of endometrial cancer with a high propensity for metastases and recurrences even when there is minimal or no myometrial invasion. It usually metastasizes to the pelvis, retroperitoneal lymph nodes, upper abdomen, and peritoneum. However, adrenal metastases from UPSC is extremely rare. Here, we present a case of UPSC with adrenal metastasis that occurred 6 years after the initial diagnosis. CASE REPORT: A 60-year-old woman previously diagnosed with uterine papillary serous carcinoma at an outside facility presented in September of 2006 with postmenopausal bleeding. She underwent comprehensive surgical staging with FIGO (International Federation of Gynecology and Obstetrics) stage 2. Post operatively, the patient was treated with radiation and chemotherapy. The treatment was completed in April of 2007. The patient had no evidence of disease until July 2009 when she was found to have a mass highly suspicious for malignancy. Subsequently, she underwent right upper lobectomy. The morphology of the carcinoma was consistent with UPSC. She refused chemotherapy due to a previous history of chemotherapy-induced neuropathy. The patient was followed up with regular computed tomography (CT) scans. In October 2012 a new right adrenal nodule was seen on CT, which showed intense metabolic uptake on positron emission tomography (PET)/CT scan. The patient underwent right adrenalectomy. Pathology of the surgical specimen was consistent with UPSC. CONCLUSIONS: UPSC is an aggressive variant of endometrial cancer associated with high recurrence rate and poor prognoses. Long-term follow-up is needed because there is a possibility of late metastases, as in this case. PMID- 27117595 TI - The cost of Pancreatoduodenectomy - An analysis of clinical determinants. AB - BACKGROUND: Health care spending is increasing the world over. Determining preventable or correctable factors may offer us valuable insights into developing strategies aimed at reducing costs and improving patient care. The aim of this study was to conduct an exploratory analysis of clinical factors influencing costs of Pancreatoduodenectomy (PD). METHODS: The financial and clinical records of 173 consecutive patients who underwent PD at a tertiary care referral centre, between January 2013 and June 2015 were analysed. RESULTS: Complications, by themselves, did not increase costs associated with PD unless they resulted in an increase in the duration of stay more than 11 days. Intraoperative blood transfusion (p-.098) and performance of an end-to-side PJ (p-.043) were independent factors significantly affecting costs. Synchronous venous resections significantly increased costs (p-.006) without affecting duration of stay. Advancing age, hypertension, neurological and respiratory disorders, preoperative endoscopic retrograde cholangiopancreatography (ERCP), performance of a feeding jejunostomy, and surgical complications eg PPH, POPF and DGE significantly increased the duration of stay sufficient enough to influence costs of PD. CONCLUSIONS: It is not the merely the development, but severity of complications that significantly increase the cost of PD by increasing hospital stay. Strategies aimed at reducing intraoperative blood transfusion requirement as well as minimising the development of POPF can help reduce costs. Synchronous venous resections significantly increase costs independent of hospital stay. This study identified nine factors that may be included in the development of a preoperative nomogram that could be used in preoperative financial counselling of patients undergoing PD. PMID- 27117596 TI - A novel IgA/Delta-like 4/Notch axis induces immunosuppressive activity in human dendritic cells. PMID- 27117597 TI - Current status and future prospects for the treatment of antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is a prothrombotic disease characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (apL). Management of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. Primary thrombo prophylaxis is recommended in patients with systemic lupus erythromatosus (SLE) and obstetric APS. Obstetric APS care is based on high-risk management and treatment with aspirin and heparin. Possible future therapies include statins, hydroxychloroquine, rituximab, and new anticoagulant drugs. Current research is focused on targeting components of the complement system, interfering with aPL mediated cell activation and using tailored peptides to block the pathogenic subpopulation of aPL. PMID- 27117598 TI - Elution by Le Chatelier's principle for maximum recyclability of adsorbents: applied to polyacrylamidoxime adsorbents for extraction of uranium from seawater. AB - Amidoxime-based polymer adsorbents have attracted interest within the last decade due to their high adsorption capacities for uranium and other rare earth metals from seawater. The ocean contains an approximated 4-5 billion tons of uranium and even though amidoxime-based adsorbents have demonstrated the highest uranium adsorption capacities to date, they are still economically impractical because of their limited recyclability. Typically, the adsorbed metals are eluted with a dilute acid solution that not only damages the amidoxime groups (metal adsorption sites), but is also not strong enough to remove the strongly bound vanadium, which decreases the adsorption capacity with each cycle. We resolved this challenge by incorporating Le Chatelier's principle to recycle adsorbents indefinitely. We used a solution with a high concentration of amidoxime-like chelating agents, such as hydroxylamine, to desorb nearly a 100% of adsorbed metals, including vanadium, without damaging the metal adsorption sites and preserving the high adsorption capacity. The method takes advantage of knowing the binding mode between the amidoxime ligand and the metal and mimics it with chelating agents that then in a Le Chatelier's manner removes metals by shifting to a new chemical equilibrium. For this reason the method is applicable to any ligand-metal adsorbent and it will make an impact on other extraction technologies. PMID- 27117599 TI - Introduction to this Special Issue - Research on Child Victims and Witnesses: From Attitudes and Investigations to Courtroom Decisions. PMID- 27117600 TI - Developmental Differences across Middle Childhood in Memory and Suggestibility for Negative and Positive Events. AB - In the present study, we investigated age differences in children's eyewitness memory and suggestibility for negative and positive events that children often experience during middle childhood. We first examined 216 ratings by children aged 8-12 years of the frequency and intensity of personal negative and positive experiences (Study 1). Based on those ratings, videotapes depicting the most frequent and intense negative (an accident) and positive (a family excursion) events were developed. A new sample of 227 children aged 8-12 years was tested for recognition memory of the videotapes using the three-stage post-event misinformation procedure (Study 2). Compared with 8- to 9-year-olds, 10- to 12 year-olds exhibited less memory malleability and less compliance with false information. Age improvements in recognition accuracy were also evident for children who watched the negative event, but not for those who watched the positive event. Compliance predicted misinformation effects, particularly in regard to peripheral details. Thus, using ecologically representative emotional events, age differences in suggestibility and memory accuracy emerged, especially for negative events.Theoretical and forensic implications concerning children's eyewitness memory and suggestibility are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27117601 TI - Low-SES Preschool Children's Eyewitness Memory: The Role of Narrative Skill. AB - This study investigated the relation between narrative skill and eyewitness memory in young children from low-socioeconomic status (SES) communities. A total of 176 children aged 3-5 years were interviewed about a conflict event they witnessed. The quality of their narratives about the event and their ability to narrate a story from a picture book were examined in relation to memory of the event. Comprehensive measures of individual differences in vocabulary skill, adaptive language use, and behavioral characteristics were also administered. The results revealed that children who produced longer, more descriptive, and more cohesive narratives about the event recalled more accurate details and made fewer memory errors, independent of their language ability and behavioral characteristics. The quality of story narratives did not make any independent contributions to memory. Child's age was a robust predictor of memory for the event. Implications of the findings for understanding eyewitness memory in low SES children are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27117602 TI - Getting to Know You: Familiarity, Stereotypes, and Children's Eyewitness Memory. AB - The present study concerned how the acquisition of social information, specifically knowledge about personal characteristics, influences young children's memory and suggestibility. Effects of two sources of knowledge about a target person were systematically examined: familiarity and stereotypes. Children, aged 4-5 and 7-9 years (N = 145), were randomly assigned, per age group, to experimental conditions based on a familiarity (6 hours vs. no prior exposure) * stereotype (negative depiction as messy and clumsy vs. no stereotype) factorial design. Children then watched the target person engage in a target event (a series of contests) at a preschool ("Camp Ingrid"). The children's memory and suggestibility about the target person and target event were tested after a delay of 2 weeks. Results indicated that the negative stereotype resulted in an increase in children's correct responses both to free-recall stereotype related questions (when children were unfamiliar with the target person) and to closed-ended questions overall (for younger children). However, the stereotype was associated with greater error to stereotype-related closed-ended questions. Moreover, familiarity increased children's accuracy to closed-ended questions. Implications for theory and application are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27117603 TI - Variation in Acceptable Child Discipline Practices by Child Age: Perceptions of Community Norms by Medical and Legal Professionals. AB - Mandated child abuse reporters may judge specific disciplinary practices as unacceptable for young children, whereas child law professionals arbitrating allegations may be less inclusive. Do the views of these groups diverge, by child age, regarding discipline? Judgments of community norms across a wide range of children's ages were obtained from 380 medical and legal professionals. Because the Parent-Child Conflict Tactics Scale (PC-CTS) can be used to assess the epidemiology of child disciplinary behaviors and as a proxy to examine the incidence or prevalence of child abuse, the disciplinary practices described on the PC-CTS were presented as triggers for questions. Significant child age effects were found for disciplinary practices classified as "harsh." The consistencies between legal and medical professionals were striking. Both groups reflected changes in United States norms, as non-physical approaches were the most approved. We conclude that instruments estimating the prevalence of child maltreatment by parent-report should consider modifying how specific disciplinary practices are classified. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27117604 TI - The Diagnostic Value of Children's Responses to Cross-Examination Questioning. AB - In response to a widespread belief within the legal system that cross-examination is instrumental in uncovering the truth, we examined the effect of cross examination questioning on the reports of children who had-and had not-been coached to lie. A group of children, aged 6-11 years (N = 65), played three computer games with one of their parents. For half of the pairs, the parents-who acted as confederates-coached their children to make lies of commission concerning the occurrence of two target activities. For the remaining pairs, these two target activities actually occurred, and there was no coaching. Immediately afterwards, children were interviewed about the two activities. Those who-correctly or incorrectly-reported that both activities occurred were retained for the final sample (n = 56); these children were then interviewed again with both neutral questions and cross-examination-style challenges. Neither style of questioning elicited responses that discriminated between liars and truth tellers: although the accuracy of children who were lying increased in response to cross-examination questions, the accuracy of truth-telling children saw a corresponding decrease. When asked neutral questions, children's responses tended to be consistent with their earlier responses, whether or not those responses were lies. These findings raise important questions about the function that cross examination might serve in trials involving child witnesses. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27117605 TI - A California Multidisciplinary Juvenile Court: Serving Sexually Exploited and At Risk Youth. AB - Research suggests that 90% of youth in the juvenile justice system have experienced at least one traumatic event (Arroyo, ). One such traumatic event is the commercialized sexual exploitation of children and youth (CSEC). Over the past decade, governmental organizations and community agencies have recognized that the sexual exploitation of children is a significant problem in the United States. In California alone, human trafficking task forces have identified 1200 youth as victims of sexual exploitation from 2010 to 2012 (Walker, ). Youth who have experienced sexual exploitation often become involved in the juvenile justice system and present with unique challenges and needs. This article reviews recent public policy and community responses related to the needs of CSEC youth involved in the juvenile justice system. A case example from Sacramento, CA, is used to illustrate the key components, innovations, multidisciplinary collaborations, and challenges of creating a specialized court. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27117606 TI - Elucidating the Mechanism of Tofacitinib Oxidative Decyanation. AB - BACKGROUND: Tofacitinib is known to generate two metabolites M2 (alcohol) and M4 (acid), which are formed as the result of oxidation and loss of the nitrile [1]. METHOD: Systematic in vitro investigation into generation of M2 and M4 from tofacitinib. RESULTS: In vitro using human liver microsomes, we found a new geminal diol metabolite of tofacitinib (MX) that lost the nitrile. MX was further reduced or oxidized to M2 (alcohol) and M4 (acid), respectively by enzymes such as aldo-keto reductase 1C1, aldehyde oxidase and possibly CYP3A4. Stable label studies using H2 18O and D2O suggested the source of oxygen was from water in the media. This was due to rapid water exchange with MX in the media prior to reduction to M2. In case of deuterium, one was incorporated in M2 and this was mainly as a result of tofacitinib rapid exchange of two deuterium atoms from D2O onto methylene position. After formation of MX, there was one deuterium that no longer exchanged with water and therefore retained in M2 for further reduction. CONCLUSION: The proposed mechanism involved the initial oxidation by P450 at the alpha-carbon to the nitrile group generating an unstable cyanohydrin intermediate; followed by the loss of the nitrile group to form a new geminal diol metabolite (MX). PMID- 27117608 TI - Heavy metals in vegetables sold in the local market in Jordan. AB - Heavy metals (As, Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn) in various vegetables (cabbage, green onion, lettuce, parsley, rocket, spinach, carrot, onion, potato and cauliflower) from the market in Jordan were measured using inductively coupled plasma-mass spectrometry. As, Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn ranged from 0.009-0.275 mg kg(-1) wet weight, 0.004-0.060 mg kg(-1), 0.003-0.401 mg kg( 1), 0.105-3.51 mg kg(-1), 0.15-1.15 mg kg(-1), 0.93-14.39 mg kg(-1), 0.044-0.702 mg kg(-1), 0.072-0.289 mg kg(-1) and 2.23-6.65 mg kg(-1), respectively. Parsley, followed by spinach, contained the highest concentration of heavy metals. Onion contained high levels of toxic heavy metals. The content of Cu in parsley and spinach and Pb in onion exceeded the Codex limits. However, the daily intake of heavy metals from the tested vegetables was lower than the maximum limits for allowable intake. PMID- 27117609 TI - Analysis of the bond-valence method for calculating (29) Si and (31) P magnetic shielding in covalent network solids. AB - (29) Si and (31) P magnetic-shielding tensors in covalent network solids have been evaluated using periodic and cluster-based calculations. The cluster-based computational methodology employs pseudoatoms to reduce the net charge (resulting from missing co-ordination on the terminal atoms) through valence modification of terminal atoms using bond-valence theory (VMTA/BV). The magnetic-shielding tensors computed with the VMTA/BV method are compared to magnetic-shielding tensors determined with the periodic GIPAW approach. The cluster-based all electron calculations agree with experiment better than the GIPAW calculations, particularly for predicting absolute magnetic shielding and for predicting chemical shifts. The performance of the DFT functionals CA-PZ, PW91, PBE, rPBE, PBEsol, WC, and PBE0 are assessed for the prediction of (29) Si and (31) P magnetic-shielding constants. Calculations using the hybrid functional PBE0, in combination with the VMTA/BV approach, result in excellent agreement with experiment. (c) 2016 Wiley Periodicals, Inc. PMID- 27117610 TI - [Osteoimmunology-overview]. AB - Bone serves not only as a locomotive organ but also as an organ instrumental in many other functions such as hematopoiesis. To this end, bone undergoes renewal by sequential resorption and formation. Bone resorption and formation are regulated by many systems including the endocrine, the nervous and the immune systems. The skeletal and the immune systems are closely related because they share many regulatory molecules such as cytokines and transcription factors. Studies on such shared molecules and inflammatory bone destruction in rheumatoid arthritis have fostered a novel interdisciplinary field, "osteoimmunology". Advances in osteoimmunology may lead to the novel therapeutic strategies in bone and immune diseases. PMID- 27117611 TI - [The niche for hematopoietic stem and progenitor cells in bone marrow]. AB - It has been hypothesized that the special microenvironments known as niches in the bone marrow play an essential role in maintaining hematopoietic stem and progenitor cells(HSPCs), and the identification of the HSPC niche has been a subject of long-standing argument. Recent studies identified candidate cells meeting the criteria for HSPC niches and the critical transcription factor of their development and maintenance. PMID- 27117607 TI - The status of diabetic embryopathy. AB - Diabetic embryopathy is a theoretical enigma and a clinical challenge. Both type 1 and type 2 diabetic pregnancy carry a significant risk for fetal maldevelopment, and the precise reasons for the diabetes-induced teratogenicity are not clearly identified. The experimental work in this field has revealed a partial, however complex, answer to the teratological question, and we will review some of the latest suggestions. PMID- 27117612 TI - [Cellular interplay of bone cells and vascular endothelial cells in bone]. AB - During endochondral bone development, the longitudinal vascular invasion into cartilage primordium initially takes place, by which mineralized cartilage matrix would be exposed into bone. Thereafter, osteogenic cells differentiate into mature osteoblasts to deposit new bone onto the exposed mineralized cartilage. New bone formation at the chondro-osseous junction appears to be achieved by the process of modeling, but not by bone remodeling based on cellular coupling between osteoclasts and osteoblasts. Recently, a specific vessel subtype in bone was reported:Vascular endothelial cells close to the chondro-oseous junction showed intense CD31/Endomucin(CD31(hi)Emcn(hi), type H), while the endothelial cells of sinusoidal vessels in diaphysis revealed only weak CD31/Endomucin(CD31(lo)Emcnlo, type L). It is suggested crucial roles of endothelial HIF in controlling bone angiogenesis, type H vessel abundance, endothelial growth factor expression and osteogenesis. PMID- 27117613 TI - [Immune molecules and the mechanism of joint destruction]. AB - Inflammation and joint destruction are the major symptom of rheumatoid arthritis(RA).Inflammation leads to osteoclast differentiation, resulting in bone destruction. Immune-related molecules such as inflammatory cytokines not only exacerbate inflammation but also bone destruction in RA. In vivo analysis using animal models of RA has contributed to the identification of synovial fibroblasts as a major osteoclastogenic cell type and a synergy between a novel Th17 subset and synovial fibroblasts as one of the primary axes in the joint destruction. Increasing numbers of immune-regulating factors including immune-complexes have been identified as new bone-regulating factors and are attractive therapeutic targets for bone destruction in RA. PMID- 27117614 TI - [Fibrodysplasia ossificans progressiva and osteoimmunology]. AB - Fibrodysplasia ossificans progressive (FOP) is a genetic disorder characterized by progressive heterotopic ossification (HO) in skeletal muscle, tendons and ligaments. FOP is caused by gain-of-function mutations of ALK2, a receptor of bone morphogenetic proteins. Immune responses have been suggested to be involved in HO in FOP, because muscle trauma induces acute HO in patients with FOP. Recently, Activin A, a non-osteogenic ligand, was identified as a ligand of the mutated ALK2 to induce HO. It was suggested that Activin A is a novel interface between FOP and osteoimmunology. PMID- 27117615 TI - [Mechanisms of myeloma-induced bone disease]. AB - Multiple myeloma(MM)develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. MM cells produce a variety of cytokines to stimulate RANKL-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. Furthermore, osteocyte apoptosis has been demonstrated to be induced in parallel with enhanced osteoclast recruitment and osteoclastogenesis in myeloma bone lesions. Of note, osteocytes physically interact with myeloma cells to skew their signaling pathways and thereby production of mediators responsible for exacerbated bone resorption and suppressed bone formation in myeloma. The role of osteocytes in myeloma-induced bone lesions remains to be further clarified. PMID- 27117616 TI - [Lymphopoiesis supported by osteolineage cells]. AB - Bone marrow(BM)and thymus are known as the primary lymphoid organs for B and T cells, respectively. However, the cell fate for T cell lineage commitment is already determined in the BM. Thus, the lymphopoiesis is critically controlled in the BM and, according to the recent advances in genetic mouse models, it appears that this process is strictly regulated by a series of osteolineage mesenchymal populations. PMID- 27117617 TI - [Elucidation of the role of metabolic reprogramming in osteoclast differentiation]. AB - Osteoclasts dramatically alter their metabolic activity during cell differentiation. This change in the metabolic status is termed'metabolic reprogramming',but its role in osteoclast is not fully understood. Using metabolomics approach, we found that metabolic reprogramming during osteoclast differentiation increased intracellular S-adenosyle methionine (SAM), a metabolite of the methionine cycle. SAM is the universal methyl donor for methylation reactions, including histone and DNA methylation. Furthermore, SAM mediated DNA methylation is required for osteoclast differentiation. These findings reveal the novel role of SAM metabolism in regulating osteoclast differentiation. PMID- 27117618 TI - [The regulation of various organs by osteoblasts]. AB - It has been recently demonstrated that osteocalcin, which is secreted from osteoblasts, plays a significant role in glucose metabolism, fat metabolism, mail fertility, and brain functions. It has been also revealed that fibroblast growth factor 23 (FGF23), which is secreted from osteocytes, has an important role in phosphate metabolism or calcium homeostasis. These findings suggest that bone is not only a target organ of hormones but also involved in regulating other organs as an endocrine organ. Bone forms regulatory network with various organs to maintain the whole body homeostasis. This review introduces the regulation of various organs by osteoblasts. PMID- 27117619 TI - [Analysis of bone tissues by intravital imaging]. AB - In recent years,"the fluorescent imaging techniques"has made rapid advances, it has become possible to observe the dynamics of living cells in individuals or tissues. It has been considered that it is extremely difficult to observe the living bone marrow directly because bone marrow is surrounded by a hard calcareous. But now, we established a method for observing the cells constituting the bone marrow of living mice in real time by the use of the intravital two photon imaging system. In this article, we show the latest data and the reports about the hematopoietic stem cells and the leukemia cells by using the intravital imaging techniques, and also discuss its further application. PMID- 27117620 TI - [Mechanism of bone destruction in rheumatoid arthritis and perspectives of the treatment]. AB - Rheumatoid arthritis (RA) is an autoimmune diseases characterized by inflammation and destruction of bone and cartilage. Osteoclastogenesis induced by inflammatory cytokines contributes to focal and systemic bone and cartilage destruction including secondary osteoporosis. Recent progress in treatment enables us to prevent disease activity. Not only anti-inflammatory management but also therapies directly targeting bone metabolism can further prevent bone destruction in RA. PMID- 27117621 TI - [Vitamin D and osteoimmunology]. AB - Vitamin D was considered to be one of nutrients which has an important role in the maintenance of calcium and phosphate metabolism. It was then revealed that 1,25-dihydroxyvitamin D metabolized from vitamin D works as a calciotropic hormone. Vitamin D metabolites were further shown to affect cell proliferation and differentiation. In immune system, vitamin D metabolites modulate both innate and adaptive immunity. Epidemiological studies indicated the associations between vitamin D deficiency and various diseases such as autoimmune diseases, allergy, infection and malignancy. In addition, vitamin D supplementation was shown to improve some these diseases. PMID- 27117622 TI - [Periodontal destruction and trends in periodontal treatment for patients]. AB - Periodontal diseases are chronic inflammatory disorders caused by the accumulation of a bacterial biofilm, characterized by the destruction of periodontal tissues, and result in loss of tooth. Recently, a part of mechanism of alveolar bone destruction has been revealed with advances in osteoimmunology. Here, we review the possible mechanisms of periodontal destruction. In addition, we described future outlook of our translational research for periodontal regenerative medicine. PMID- 27117623 TI - [Potential of bone regenerative therapy with mesenchymal stem cells in rheumatoid arthritis]. AB - Mesenchymal stem cell(MSC)exists throughout the body. The discovery of the immunosuppressive effect with low immunogenicity has led MSC as a new tool for cell therapy in various diseases. Within the arthritis animal model, periarticular implantation of bone marrow derived MSC with a scaffold has demonstrated treatment effect with low cell number whereas systemic administration had limited effect. Bone marrow derived MSC suppressed in vitro osteoclastogenesis and osteoblastogenesis of MSC was enhanced in the presence of IL-1beta.On the other hand, experiments with adipose-derived MSC suggested the involvement in abnormal tissue calcification in the presence of IL-6. Therefore, MSC generated from the appropriate tissue and clarification of the major cytokines involved in pathogenesis is necessary when considering regenerative therapy for destructed joint in RA patients. PMID- 27117624 TI - [Understanding and treatment strategy of the pathogenesis of periodontal disease based on chronic inflammation]. AB - Prolonged inflammation continuously promotes the infiltration of macrophages in the organization and chronically induces the production of pro-inflammatory cytokines such as TNF and IL-1. In periodontal tissues, these inflammatory cytokines enhance the differentiation and activity of osteoclasts, which cause destruction of the alveolar bone. Therefore, inhibition of inflammatory cytokine production leads to the prevention or treatment of periodontal disease. IL-1 is a pro-inflammatory cytokine that strongly enhances the bone-resorbing activity of osteoclasts. Elucidation of mechanisms for the production of IL-1 is critical for understanding the pathogenesis of periodontal disease. This paper reviews recent findings of the molecular mechanisms regulating IL-1 production and focuses on inflammasome. PMID- 27117625 TI - Comparison of the Cortinez and the Schnider models with a targeted effect-site TCI of 3 mcg/ml in biophase in healthy volunteers. AB - OBJECTIVE: To compare the Cortinez and Schnider models in effect-site TCI mode (3 mcg/ml) in healthy volunteers. METHODS: Ten healthy volunteers were prospectively studied on 2 occasions. Propofol was administered with the Cortinez or the Schnider models, as randomly assigned. Times and predicted concentrations at the time of loss and recovery of consciousness (LOC and ROC), mass of drug administered, BIS, and haemodynamic variables were compared. Statistical analysis was with paired Wilcoxon test. A P<.05 was considered significant. RESULTS: The propofol bolo was higher (1.4 [1.3-1.6] versus 0.9 [0.7-1.3] mg/kg, P=.005) and the LOC occurred earlier (1.33 [0.67-6.83] versus 3.87 [1.66-11.08] minutes, P=.02) with the Cortinez model compared to the Schnider model. With the Cortinez model, LOC occurred at an effect site concentrations of 2.6 (1.65-3.0) mcg/ml. With the Schnider model, LOC occurred at 3.87 min (1.66-11.8) after reaching the target of 3 mcg/ml. (P=.001). BIS values, infusion rates, and haemodynamic variables were similar between models after 20minutes of infusion (P>.5). Recovery (ROC) was longer with the Cortinez model (11.6 [8.1-16.2] vs. 8.5 [4.7 15.5] min, P=.003). CONCLUSIONS: The Cortinez model is a good alternative to the Schnider model for use in effect-site TCI mode in normal weight subjects. With the target used in this study (3 mcg/ml), the slower Ke0 incorporated into the Cortinez model better discriminated the LOC time. PMID- 27117626 TI - Acute exacerbations of COPD: reflections of an unfinished story. PMID- 27117627 TI - Identification of miRNomes reveals ssc-miR-30d-R_1 as a potential therapeutic target for PRRS viral infection. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is known to cause reproductive disorders, such as abortion, in pregnant sows as well as immunosuppressive respiratory complications, leading to severe respiratory tract infections in young pigs. In this study, an in-depth analysis of the miRNomes in mock- and virus-infected pig lungs was carried out. We found that highly expressed ssc-miR-30d-R_1 was decreased in infected lungs, and reduced levels were significantly correlated with infection by PRRSV. Moreover, ssc-miR-30d-R_1 was shown to target Toll-like receptor 4 (TLR4) and to suppress the production of immune cytokines through inhibition of the TLR4/MyD88/NF-kappaB pathway. ssc-miR 30d-R_1 significantly reduced viral infections and pathological changes in pig lungs in vivo. Our current study reveals the miRNomes of PRRSV-infected pig lungs and indicates that ssc-miR-30d-R_1 is potential therapeutic agent for controlling PRRSV infection. PMID- 27117628 TI - Cancer-specific binary expression system activated in mice by bacteriophage HK022 Integrase. AB - Binary systems based on site-specific recombination have been used for tumor specific transcription targeting of suicide genes in animal models. In these binary systems a site specific recombinase or integrase that is expressed from a tumor specific promoter drives tumor specific expression of a cytotoxic gene. In the present study we developed a new cancer specific binary expression system activated by the Integrase (Int) of the lambdoid phage HK022. We demonstrate the validity of this system by the specific expression of a luciferase (luc) reporter in human embryonic kidney 293T (HEK293T) cells and in a lung cancer mouse model. Due to the absence viral vectors and of cytotoxicity the Int based binary system offers advantages over previously described counterparts and may therefore be developed into a safer cancer cell killing system. PMID- 27117629 TI - Willingness of Australian health educators and health promotion officers to conduct rapid HIV testing. AB - Issue addressed: Rapid HIV tests were recently approved by the Australian government. This paper examines the attitudes and willingness to conduct rapid HIV testing (RHT) of Australian health educators and health promotion officers (HE/HPO) from various settings and disciplines.Methods: The aim of the Promoting Research on Methods in Screening Expertise study was to explore knowledge of HIV, attitudes towards people living with HIV, and willingness to conduct RHT among HE/HPO in Australia; this information was attained via an online survey of HE/HPO. Descriptive statistics, chi2 tests, t-tests, and multivariate logistic regression were then conducted.Results: Data from 156 HE/HPOs were analysed. Overall, 60% of participants believed that HE/HPO should offer RHT. Additionally, 70% were personally willing to undergo training in conducting RHT. Fifty-nine percent of participants scored as having 'high' HIV knowledge (at least 12 out of 13 correct answers), with 32% answering all questions correctly. Knowledge was strongly associated with willingness to be trained to conduct RHT.Conclusions: HE/HPO with advanced training in developing evidence-based approaches to improve the health and wellbeing of marginalised and disadvantaged groups may be an appropriate workforce to train to conduct RHT and counselling.So what?: As government agencies and community-based organisations plan to expand RHT, HE/HPO, including those who work outside of sexual health, should be considered as a viable workforce to upskill. PMID- 27117630 TI - Use of a Lucas-Kanade-Based Template Tracking Algorithm to Examine In Vivo Tendon Excursion during Voluntary Contraction Using Ultrasonography. AB - Ultrasound imaging can be used to study tendon movement during muscle contraction to estimate the tendon force-length relationship in vivo. Traditionally, such tendon displacement measurements are made manually (time consuming and subjective). Here we evaluated a Lucas-Kanade-based tracking algorithm with an optic flow extension that accounts for tendon movement characteristics between consecutive frames of an ultrasound image sequence. Eleven subjects performed 12 voluntary isometric plantar flexion contractions on a dynamometer. Simultaneously, the gastrocnemius medialis tendon was visualized via ultrasonography. Tendon displacement was estimated manually and by using two different automatic tracking algorithms. Maximal tendon elongation (manual: 17.9 +/- 0.3 mm, automatic: 17.0 +/- 0.3 mm) and tendon stiffness (209 +/- 4 N/mm, 218 +/- 5 N/mm) generated by the developed algorithm correlated with those obtained with the manual method (0.87 <= R <= 0.91), with no differences between methods. Our results suggest that optical flow methods can potentially be used for automatic estimation of tendon movement during contraction in ultrasound images, which is further improved by adding a penalty function. PMID- 27117631 TI - Influence of Scan Duration on Pulmonary Capillary Hemorrhage Induced by Diagnostic Ultrasound. AB - Diagnostic ultrasound can induce pulmonary capillary hemorrhage (PCH) in rats and display this as "comet tail" artifacts (CTAs) after a time delay. To test the hypothesis that no PCH occurs for brief scans, anesthetized rats were scanned using a 6-MHz linear array for different durations. PCH was characterized by ultrasound CTAs, micro-computed tomography (MUCT), and measurements of fixed lung tissue. The MUCT images revealed regions of PCH, sometimes penetrating the entire depth of a lobe, which were reflected in the fixed tissue measurements. At -3 dB of power, PCH was substantial for 300-s scans, but not significant for 25-s scans. At 0 dB, PCH was not strongly dependent on scan durations of 300 to 10 s. Contrary to the hypothesis, CTAs were not evident during most 10-s scans (p > 0.05), but PCH was significant (p = 0.02), indicating that PCH could occur without evidence of the injury in the images. PMID- 27117632 TI - Erythrocyte oxidative stress markers in children with sickle cell disease. AB - OBJECTIVE: To determine eight parameters of oxidative stress markers in erythrocytes from children with sickle cell disease and compare with the same parameters in erythrocytes from healthy children, since oxidative stress plays an important role in the pathophysiology of sickle cell disease and because this disease is a serious public health problem in many countries. METHODS: Blood samples were obtained from 45 children with sickle cell disease (21 males and 24 females with a mean age of 9 years; range: 3-13 years) and 280 blood samples were obtained from children without hemoglobinopathies (137 males and 143 females with a mean age of 10 years; range: 8-11 years), as a control group. All blood samples were analyzed for methemoglobin, reduced glutathione, thiobarbituric acid reactive substances, percentage of hemolysis, reactive oxygen species, and activity of the enzymes glucose 6-phosphate dehydrogenase, superoxide dismutase, and catalase. Data were analyzed using Student's t-test and were expressed as the mean+/-standard deviation. A p-value of <0.05 was considered significant. RESULTS: Significant differences were observed between children with sickle cell disease and the control group for the parameters methemoglobin, thiobarbituric acid reactive substances, hemolysis, glucose 6-phosphate dehydrogenase activity, and reactive oxygen species, with higher levels in the patients than in the controls. CONCLUSIONS: Oxidative stress parameters in children's erythrocytes were determined using simple laboratory methods with small volumes of blood; these biomarkers can be useful to evaluate disease progression and outcomes in patients. PMID- 27117633 TI - In situ Electrochemical-AFM Study of LiFePO4 Thin Film in Aqueous Electrolyte. AB - Lithium-ion (Li-ion) batteries have been widely used in various kinds of electronic devices in our daily life. The use of aqueous electrolyte in Li-ion battery would be an alternative way to develop low cost and environmentally friendly batteries. In this paper, the lithium iron phosphate (LiFePO4) thin film cathode for the aqueous rechargeable Li-ion battery is prepared by radio frequency magnetron sputtering deposition method. The XRD, SEM, and AFM results show that the film is composed of LiFePO4 grains with olivine structure and the average size of 100 nm. Charge-discharge measurements at current density of 10 MUAh cm(-2) between 0 and 1 V show that the LiFePO4 thin film electrode is able to deliver an initial discharge capacity of 113 mAh g(-1). Specially, the morphological changes of the LiFePO4 film electrode during charge and discharge processes were investigated in aqueous environment by in situ EC-AFM, which is combined AFM with chronopotentiometry method. The changes in grain area are measured, and the results show that the size of the grains decreases and increases during the charge and discharge, respectively; the relevant mechanism is discussed. PMID- 27117634 TI - Illumination Effect on Bipolar Switching Properties of Gd:SiO2 RRAM Devices Using Transparent Indium Tin Oxide Electrode. AB - To discuss the optoelectronic effect on resistive random access memory (RRAM) devices, the bipolar switching properties and electron-hole pair generation behavior in the transparent indium tin oxide (ITO) electrode of Gd:SiO2 thin films under the ultraviolet (lambda = 400 nm) and red-light (lambda = 770 nm) illumination for high resistance state (HRS)/low resistance state (LRS) was observed and investigated. In dark environment, the Gd:SiO2 RRAM devices exhibited the ohmic conduction mechanism for LRS, exhibited the Schottky emission conduction and Poole-Frankel conduction mechanism for HRS. For light illumination effect, the operation current of the Gd:SiO2 RRAM devices for HRS/LRS was slightly increased. Finally, the electron-hole pair transport mechanism, switching conduction diagram, and energy band of the RRAM devices will be clearly demonstrated and explained. PMID- 27117635 TI - Vertically Free-Standing Ordered Pb(Zr0.52Ti0.48)O3 Nanocup Arrays by Template Assisted Ion Beam Etching. AB - In this report, vertically free-standing lead zirconate titanate Pb(Zr0.52Ti0.48)O3 (PZT) nanocup arrays with good ordering and high density (1.3 * 10(10) cm(-2)) were demonstrated. By a template-assisted ion beam etching (IBE) strategy, the PZT formed in the pore-through anodic aluminum oxide (AAO) membrane on the Pt/Si substrate was with a cup-like nanostructure. The mean diameter and height of the PZT nanocups (NCs) was about 80 and 100 nm, respectively, and the wall thickness of NCs was about 20 nm with a hole depth of about 80 nm. Uppermost, the nanocup structure with low aspect ratio realized vertically free standing arrays when losing the mechanical support from templates, avoiding the collapse or bundling when compared to the typical nanotube arrays. X-ray diffraction (XRD) and Raman spectrum revealed that the as-prepared PZT NCs were in a perovskite phase. By the vertical piezoresponse force microscopy (VPFM) measurements, the vertically free-standing ordered ferroelectric PZT NCs showed well-defined ring-like piezoresponse phase and hysteresis loops, which indicated that the high-density PZT nanocup arrays could have potential applications in ultra-high non-volatile ferroelectric memories (NV-FRAM) or other nanoelectronic devices. PMID- 27117636 TI - Improving the Context Supporting Quality Improvement in a Neonatal Intensive Care Unit Quality Collaborative: An Exploratory Field Study. AB - Successful quality improvement (QI) requires a supportive context. The goal was to determine whether a structured curriculum could help QI teams improve the context supporting their QI work. An exploratory field study was conducted of 43 teams participating in a neonatal intensive care unit QI collaborative. Using a curriculum based on the Model for Understanding Success in Quality, teams identified gaps in their context and tested interventions to modify context. Surveys and self-reflective journals were analyzed to understand how teams developed changes to modify context. More than half (55%) targeted contextual improvements within the microsystem, focusing on motivation and culture. "Information sharing" interventions to communicate information about the project as a strategy to engage more staff were the most common interventions tested. Further study is needed to determine if efforts to modify context consistently lead to greater outcome improvements. PMID- 27117637 TI - Impact of Frailty and Sociodemographic Factors on Hospital Admission From an Emergency Department Observation Unit. AB - Understanding factors associated with an increased risk of hospital admission from emergency department (ED) observation units (OUs) could be valuable in disposition decisions. To evaluate the impact of frailty and sociodemographic factors (SDFs) on admission risk, patients in an ED OU were surveyed. Survey measures included SDFs, social habits, and frailty measured by the Katz Index of Independence in Activities of Daily Living. Of 306 surveyed, 18% were admitted and 82% were discharged. Demographics were similar between groups. More admitted patients responded positively to the Katz Index (28% vs 13%, P = .007; odds ratio = 2.73; 95% CI = 1.35-5.51). College graduation and current employment favored the discharge group, while admitted patients were more likely to receive Social Security disability insurance. Frailty remained associated with admission on multivariable analysis. Frailty, disability insurance, and lower education are predictors of admission from an OU and could serve as screening criteria in disposition decisions. PMID- 27117638 TI - A Systematic Review of Patient Safety Measures in Adult Primary Care. AB - Safety measure development has focused on inpatient care despite outpatient visits far outnumbering inpatient admissions. Some measures are clearly identified as outpatient safety measures when published, yet outcomes from quality improvement studies also may be useful measures. The authors conducted a systematic review of the literature to identify published articles detailing safety measures applicable to adult primary care. A total of 21 articles were identified, providing specifications for 182 safety measures. Each measure was classified into one of 6 outpatient safety dimensions: medication management, sentinel events, care coordination, procedures and treatment, laboratory testing and monitoring, and facility structures/resources. Compared to the multitude of available inpatient safety measures, the number of existing adult primary care measures is low. The measures identified by this systematic review may yield further insight into the breadth of safety events causing harm in primary care, while also identifying areas of patient safety in primary care that may be understudied. PMID- 27117639 TI - Adding Value to the Health Care System: Identifying Value-Added Systems Roles for Medical Students. AB - To catalyze learning in Health Systems Science and add value to health systems, education programs are seeking to incorporate students into systems roles, which are not well described. The authors sought to identify authentic roles for students within a range of clinical sites and explore site leaders' perceptions of the value of students performing these roles. From 2013 to 2015, site visits and interviews with leadership from an array of clinical sites (n = 30) were conducted. Thematic analysis was used to identify tasks and benefits of integrating students into interprofessional care teams. Types of systems roles included direct patient benefit activities, including monitoring patient progress with care plans and facilitating access to resources, and clinic benefit activities, including facilitating coordination and improving clinical processes. Perceived benefits included improved value of the clinical mission and enhanced student education. These results elucidate a framework for student roles that enhance learning and add value to health systems. PMID- 27117640 TI - Breastfeeding among Somali mothers living in Norway: Attitudes, practices and challenges. AB - BACKGROUND: Data from previous studies indicate a short duration of breastfeeding, especially exclusive breastfeeding, among infants of immigrant mothers living in Norway and other Western countries. Norway has a long tradition of supporting breastfeeding. AIM: To explore infant feeding practices among Somali-born mothers in Norway, and the ways in which they navigate among different information sources. METHODS: Qualitative in-depth interviews and focus groups were carried out with mothers of children 6, 12 and 24 months of age. Women were recruited by a multi-recruitment strategy. Twenty-one mothers participated in interviews and twenty-two in five focus groups. The analysis was guided by Grounded Theory. FINDINGS: The mothers had positive attitudes to breastfeeding, but were unfamiliar with the concept of exclusive breastfeeding. Early introduction of water and infant formula was a common practice that interfered with exclusive breastfeeding. The mothers experienced challenges of dealing with conflicting recommendations and expectations regarding infant feeding. They navigated among different sources of information, taking into consideration traditional values, experiences and habits from living in Norway, and research-based knowledge. Their prioritization of the different information sources varied with different life situations, children's age, and the extent to which the mothers trusted the information sources. DISCUSSION AND CONCLUSIONS: Despite the strong focus on breastfeeding in Norway, Somali-born mothers encounter obstacles in their breastfeeding practices. These may be due to lack of information about exclusive breastfeeding and to the conflicting information they received. Breastfeeding practices may be enhanced by promoting culturally sensitive communication, and relations of trust at health-care centers. PMID- 27117641 TI - Lipid rafts-mediated endocytosis and physiology-based cell membrane traffic models of doxorubicin liposomes. AB - The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts (B) into saturable binding (SB) and nonsaturable binding (NSB) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e., cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox. PMID- 27117642 TI - Interactions of lauryl gallate with phospholipid components of biological membranes. AB - The effect of different amounts of lauryl gallate (LG) on properties of the model membranes of phosphatidylcholines (PC), differing in the presence of double bonds in the hydrocarbon chains, and phosphatidylglycerol (PG) was described in terms of phase behaviour of mixtures, interactions between both components, monolayers stability and their organization. The Langmuir monolayer technique was used to monitor the surface thermodynamics (i.e. the excess area and excess Gibbs energy of mixing) on the basis of surface pressure-area per molecule (pi-A) isotherms. Simultaneously, morphology of the studied monolayers was visualized by the Brewster angle microscopy (BAM). This allowed evaluating the kind and magnitude of interactions which influence on the phase behaviour and structural properties of the monolayers. The obtained results can be helpful to reveal the mechanism of phospholipid antioxidant protection and important pharmacological (antimicrobial) role of lauryl gallate for production of effective therapeutic substances. PMID- 27117644 TI - Ethics and health in WHO Regional Office for the Eastern Mediterranean. PMID- 27117643 TI - Wild-type opsin does not aggregate with a misfolded opsin mutant. PMID- 27117645 TI - Improved water and child health in Egypt: impact of interrupted water supply and storage of household water on the prevalence of diarrhoea. AB - Egypt is approaching universal access to improved water supply, but the variable quality of improved water may have a measureable health impact. We investigated the impact of different measures of improved water access on the prevalence of diarrhoea among children aged under 5 years. Using data from the 2008 Egypt Demographic and Health Survey and propensity score matching techniques we compared children in households with improved water supplies, with/without interruptions to supplies and with/without in-home storage of water. Access to improved water that was not subject to cuts resulted in a significant 2.6 percentage point reduction in the prevalence of diarrhoea (4.7% reduction in rural areas), and access to improved water that was not stored prior to use resulted in a 3.5% reduction. Further research is needed to better understand the nature and causes of piped water interruptions in Egypt, in order to address potential infrastructure challenges that are leading to poorer health outcomes. PMID- 27117646 TI - Relative inequalities in geographic distribution of health care resources in Kermanshah province, Islamic Republic of Iran. AB - This study aimed to evaluate inequalities in the geographical distribution of human and physical resources in the health sector of Kermanshah province, Islamic Republic of Iran. In a retrospective, cross-sectional study, data from the Statistical Centre of Iran were used to calculate inequality measures (Gini coefficient and index of dissimilarity) over the years 2005-11. The highest Gini coefficient for human resources was observed for pharmacists in 2005 (0.75) and the lowest for paramedics in 2010 and 2011 (0.10). The highest indices of dissimilarity were also for pharmacists in 2005 (29%) and paramedics in 2011 (3%). For physical resources, the highest and lowest Gini coefficients were for rehabilitation centres in 2010 (0.59) and health houses in 2011 (0.12) respectively. Generally, inequalities in the distribution of health care resources were lower at the end of the study period, although there was potential for more equitable distribution of pharmacists, specialists, health houses and beds. PMID- 27117647 TI - Meals served to hypertensive and cardiac inpatients in Jordan: comparison with WHO and NIH dietary guidelines. AB - This study aimed to evaluate the compliance of daily meals served to hypertensive and cardiac inpatients in Jordan according to WHO guidelines and the Therapeutic Lifestyle Changes (TLC) and Dietary Approach to Stop Hypertension (DASH) diets plans. Weekly cycle menus from the food service department of major hospitals in Jordan (n = 16) were analysed using ESHA Food Processor software to obtain data about macroand micronutrient contents and food groups represented. The results showed inappropriate amounts of several nutrients in the menus provided, along with a general noncompliance with the DASH, TLC and WHO guidelines. Meals had higher than recommended sodium content coupled with low potassium content. Fatty acid profiles were often outside the recommended ranges. Meals provided to cardiac inpatients in Jordan need to be revised to meet the guidelines specified for the health conditions of these patients. PMID- 27117648 TI - Prevalence of oro-dental anomalies among schoolchildren in Sana'a city, Yemen. AB - Practitioners and policy-makers need information about the relative frequency of dental anomalies among children in their region. This study investigated the prevalence of different oral anomalies among schoolchildren in Sana'a city, Yemen. A sample of 1000 private and public schoolchildren aged 4-12 years were examined by the same examiner using disposable tongue blades. The total prevalence of oral anomalies was 15.1%, most commonly in boys (male:female ratio 3.2:1) aged 7-12 years. The most prevalent dental anomaly related to hard tissues was tooth hypoplasia (2.8%), followed by hypocalcification (2.6%), then microdontia (0.5%), macrodontia (0.4%), hypodontia (0.4%), supernumerary teeth (0.3%), tooth transposition (0.3%), dental fusion (0.2%) and gemination (0.2%). The most prevalent soft tissues anomaly was fissured tongue (4.0%), followed by ankyloglossia (1.8%), geographic tongue (0.9%), macroglossia (0.4%) and hairy tongue (0.3%). Appropriate measures need to be taken early to mitigate the negative impact and later costs of treatment of anomalies. PMID- 27117649 TI - Prevalence of and factors associated with smoking among students in Sousse, Tunisia. AB - Within the framework of the fight against tobacco among young people, we conducted a descriptive cross-sectional study in 2013 to estimate the prevalence of smoking and to identify associated factors among students in Sousse. A questionnaire was administered to a representative sample of 556 students in 5 academic institutions in Sousse randomly drawn. The age of the participants was between 17 and 35 years. The prevalence of tobacco consumption in the past 12 months was 22.1% and consumption during the past 3 months was 65.3%. The average age of starting smoking was 17 years. Smoking prevalence was significantly higher for males (P < 0.001) and those aged over 25 years (P = 0.002). Students from 2 of the institutions were using more tobacco than their colleagues in the other institutions (P = 0.027). The high prevalence of smoking found among the students means that prevention measures are essential; this requires increasing self esteem and evaluating intervention programmes implemented before smoking the first cigarette. PMID- 27117650 TI - Paediatric continuing medical education needs and preferences of UNRWA physicians in Jordan. AB - Most physicians who work in the United Nations Relief and Works Agency (UNRWA) infant and child health programme in Jordan are general practitioners with no postgraduate training in paediatrics. Furthermore, in resource-poor or remote settings, the ability to deliver live continuing medical education (CME) is often limited. A questionnaire exploring the resources available for accessing CME, preferences for types of CME, current sources of CME and topics of interest in the field of paediatric care was sent to all 92 physicians practising in UNRWA clinics in Jordan. Of the 89 respondents 80% had attended live medical lectures for CME and 70% CME meetings. Despite most physicians having access to the Internet only 52.8% were interested in Internet-based courses for accessing CME. There was a statistically significant relationship between year of graduation from medical school and preference for Internet-based CME. Implications for CME participation and paediatric CME topics are discussed. PMID- 27117651 TI - Compiling comprehensive national health statistics in a fragmented health information system: lessons learned from Lebanon. AB - In view of the rapid health transition faced by the country and a highly dominant private sector, the issue of obtaining reliable health statistics is becoming a priority for Lebanon. This paper reviews the process of compiling and disseminating national health statistics from the multitude of public, private and nongovernmental partners in the country. The lessons learned from preparing two editions of the National health statistics report in Lebanon allow identification of some challenges and strengths of the current health information system in Lebanon. The experience emphasizes the need for a close partnership with all stakeholders, an efficient management system, adequate human resources and predefined systems and procedures. The process would benefit from having an interactive website for exchange of data and information among stakeholders and the public. The existence of clear guidelines with consistent definitions and standardized forms would also facilitate the collection and analysis of data. PMID- 27117652 TI - Multidrug-resistant disseminated tuberculosis in a 9-month-old infant. PMID- 27117653 TI - Ethics in health practice and research: an EMR perspective. PMID- 27117655 TI - Association between occupational exposures to pesticides with heterogeneous chemical structures and farmer health in China. AB - This study analyzed the associations of farmers' exposure to organophosphates (OPs), organosulfurs (OSs), organonitrogens (ONs) and pyrethroids (PYRs) with parameters of the blood complete counts (CBC), a blood chemistry panel (BCP) and the conventional nerve conduction studies among 224 farmers in China in 2012. Two health examinations and a series of follow-up field surveys were conducted. Multiple linear regression analyses were used to evaluate the associations. The results show considerable associations between multiple groups of pesticides and several CBC parameters, but it was not enough to provide evidence of hematological disorders. The short- and medium-term OPs exposures were mainly associated with liver damage and peripheral nerve impairment, respectively, while OSs exposure might induce liver damage and renal dysfunction. The neurotoxicity of ONs was second only to OPs in addition to its potential liver damage and the induced alterations in glucose. In comparison, the estimated results show that PYRs would be the least toxic in terms of the low-dose application. In conclusion, occupational exposures to pesticides with heterogeneous chemical structures are associated with farmer health in different patterns, and the association between a specific group of pesticides and farmer health also differs between the short- and medium-term exposures. PMID- 27117656 TI - Trends in hospital ED closures nationwide and across Medicaid expansion, 2006 2013. AB - STUDY HYPOTHESIS: Low reimbursement from the uninsured has been claimed to threaten hospital finances and even hospital emergency department (ED) closure. We hypothesized in advance of beginning data collection that states that expanded Medicaid ("expansion states") under the 2010 Patient Protection and Affordable Care Act would experience a reduced rate of ED closure compared with states that did not. METHODS: We compiled a national census of EDs from 2006 through 2013 from federal databases and manually confirmed each closure. We used difference-in differences regression on this longitudinal panel to compare the probability over time that a hospital was in operation in expansion states to nonexpansion states. RESULTS: The number of hospitals grew every year nationally and in nonexpansion states. In expansion states, the number fell from 2027 in 2009 to 2019 in 2010, not surpassing the 2009 peak until 2012. In regression estimates, hospitals in expansion states were 2.2% (95% confidence interval, 0.3%-4.1%) less likely to be in operation after 2010 compared with the trend in nonexpansion states. CONCLUSIONS: States that expanded Medicaid experienced increased, rather than reduced, ED closure rates from 2010 through 2013. The financial benefits of the Affordable Care Act may be poorly targeted to the hospitals most vulnerable to closure. PMID- 27117654 TI - Macrophages and cellular immunity in Drosophila melanogaster. AB - The invertebrate Drosophila melanogaster has been a powerful model for understanding blood cell development and immunity. Drosophila is a holometabolous insect, which transitions through a series of life stages from embryo, larva and pupa to adulthood. In spite of this, remarkable parallels exist between Drosophila and vertebrate macrophages, both in terms of development and function. More than 90% of Drosophila blood cells (hemocytes) are macrophages (plasmatocytes), making this highly tractable genetic system attractive for studying a variety of questions in macrophage biology. In vertebrates, recent findings revealed that macrophages have two independent origins: self-renewing macrophages, which reside and proliferate in local microenvironments in a variety of tissues, and macrophages of the monocyte lineage, which derive from hematopoietic stem or progenitor cells. Like vertebrates, Drosophila possesses two macrophage lineages with a conserved dual ontogeny. These parallels allow us to take advantage of the Drosophila model when investigating macrophage lineage specification, maintenance and amplification, and the induction of macrophages and their progenitors by local microenvironments and systemic cues. Beyond macrophage development, Drosophila further serves as a paradigm for understanding the mechanisms underlying macrophage function and cellular immunity in infection, tissue homeostasis and cancer, throughout development and adult life. PMID- 27117658 TI - Human carbon monoxide factory. PMID- 27117657 TI - Routine biological tests in self-poisoning patients: results from an observational prospective multicenter study. AB - CONTEXT: Routine biological tests are frequently ordered in self-poisoning patients, but their clinical relevance is poorly studied. MATERIALS AND METHODS: This is a prospective multicentric observational study conducted in the emergency departments and intensive care units of 5 university and nonuniversity French hospitals. Adult self-poisoning patients without severely altered vital status on admission were prospectively included. RESULTS: Routine biological test (serum electrolytes and creatinine, liver enzymes, bilirubin, blood cell count, prothrombin time) ordering and results were analyzed. A total of 1027 patients were enrolled (age, 40.2 +/- 14 years; women, 61.5%); no patient died during the hospital stay. Benzodiazepine was suspected in more than 70% of cases; 65% (range, 48%-80%) of patients had at least 1 routine biological test performed. At least 1 abnormal test was registered in 23% of these patients. Three factors were associated with abnormal test results: age older than 40 years, male sex, and poisoning with a drug known to alter routine tests (ie, acetaminophen, NSAIDs, metformine, lithium). Depending on these factors, abnormal results ranged from 14% to 48%. Unexpected severe life-threatening conditions were recorded in 6 patients. Only 3 patients were referred to the intensive care unit solely because of abnormal test results. CONCLUSION: Routine biological tests are commonly prescribed in nonsevere self-poisoning patients. Abnormal results are frequent but their relevance at bedside remains limited. PMID- 27117659 TI - Capillary Electrophoresis-Mass Spectrometry for Clinical Metabolomics. AB - In clinical metabolomics, capillary electrophoresis-mass spectrometry (CE-MS) has become a very useful technique for the analysis of highly polar and charged metabolites in complex biologic samples. A comprehensive overview of recent developments in CE-MS for metabolic profiling studies is presented. This review covers theory, CE separation modes, capillary coatings, and practical aspects of CE-MS coupling. Attention is also given to sample pretreatment and data analysis strategies used for metabolomics. The applicability of CE-MS for clinical metabolomics is illustrated using samples ranging from plasma and urine to cells and tissues. CE-MS application to large-scale and quantitative clinical metabolomics is addressed. Conclusions and perspectives on this unique analytic strategy are presented. PMID- 27117660 TI - Metabolomics in Newborns. AB - Metabolomics is the quantitative analysis of a large number of low molecular weight metabolites that are intermediate or final products of all the metabolic pathways in a living organism. Any metabolic profiles detectable in a human biological fluid are caused by the interaction between gene expression and the environment. The metabolomics approach offers the possibility to identify variations in metabolite profile that can be used to discriminate disease. This is particularly important for neonatal and pediatric studies especially for severe ill patient diagnosis and early identification. This property is of a great clinical importance in view of the newer definitions of health and disease. This review emphasizes the workflow of a typical metabolomics study and summarizes the latest results obtained in neonatal studies with particular interest in prematurity, intrauterine growth retardation, inborn errors of metabolism, perinatal asphyxia, sepsis, necrotizing enterocolitis, kidney disease, bronchopulmonary dysplasia, and cardiac malformation and dysfunction. PMID- 27117661 TI - Maternal Plasma DNA and RNA Sequencing for Prenatal Testing. AB - Cell-free DNA (cfDNA) testing has recently become indispensable in diagnostic testing and screening. In the prenatal setting, this type of testing is often called noninvasive prenatal testing (NIPT). With a number of techniques, using either next-generation sequencing or single nucleotide polymorphism-based approaches, fetal cfDNA in maternal plasma can be analyzed to screen for rhesus D genotype, common chromosomal aneuploidies, and increasingly for testing other conditions, including monogenic disorders. With regard to screening for common aneuploidies, challenges arise when implementing NIPT in current prenatal settings. Depending on the method used (targeted or nontargeted), chromosomal anomalies other than trisomy 21, 18, or 13 can be detected, either of fetal or maternal origin, also referred to as unsolicited or incidental findings. For various biological reasons, there is a small chance of having either a false positive or false-negative NIPT result, or no result, also referred to as a "no call." Both pre- and posttest counseling for NIPT should include discussing potential discrepancies. Since NIPT remains a screening test, a positive NIPT result should be confirmed by invasive diagnostic testing (either by chorionic villus biopsy or by amniocentesis). As the scope of NIPT is widening, professional guidelines need to discuss the ethics of what to offer and how to offer. In this review, we discuss the current biochemical, clinical, and ethical challenges of cfDNA testing in the prenatal setting and its future perspectives including novel applications that target RNA instead of DNA. PMID- 27117663 TI - Apoptosis Markers in Breast Cancer Therapy. AB - Cancer is a disease characterized by a very little apoptosis, ie, genetically programmed cell death. Aberrations in apoptotic pathways are central to tumorigenesis, tumor progression, and overall tumor growth and regression in response to chemotherapy. It is now increasingly accepted that chemotherapeutic drug efficacy is partially related to its ability to induce apoptosis. Apoptosis, therefore, represents not only a vital target in cancer therapy but also a unique biomarker opportunity that has thus far been largely unexploited. In response to therapy, tumor cells undergo apoptosis and release their cellular components in the circulation. As such, these materials may serve as biomarkers to assess response. Apoptosis markers in breast cancer include circulating soluble FasL, granzyme B, and cytochrome c that increase following chemotherapy. Unfortunately, there is a paucity of information in the literature with respect to this approach. As such, large-scale prospective studies are clearly needed to validate this approach and more fully elucidate clinical usefulness. PMID- 27117662 TI - Tumor-Derived Exosomes and Their Role in Cancer Progression. AB - Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation. PMID- 27117664 TI - Medical Functions of Hydrogen Sulfide. AB - Hydrogen sulfide (H(2)S) is a gasomediator synthesized from L- and D-cysteine in various tissues. It is involved in a number of physiological and pathological processes. H(2)S exhibits antiatherosclerotic, vasodilator, and proangiogenic properties, and protects the kidney and heart from damage following ischemia/reperfusion injury. H(2)S donors may be natural or synthetic, and may be used for the safe treatment of a wide range of diseases. This review article summarizes the current state of knowledge of the therapeutic function of H(2)S. PMID- 27117665 TI - Preface. PMID- 27117666 TI - Reticulons Regulate the ER Inheritance Block during ER Stress. AB - Segregation of functional organelles during the cell cycle is crucial to generate healthy daughter cells. In Saccharomyces cerevisiae, ER stress causes an ER inheritance block to ensure cells inherit a functional ER. Here, we report that formation of tubular ER in the mother cell, the first step in ER inheritance, depends on functional symmetry between the cortical ER (cER) and perinuclear ER (pnER). ER stress induces functional asymmetry, blocking tubular ER formation and ER inheritance. Using fluorescence recovery after photobleaching, we show that the ER chaperone Kar2/BiP fused to GFP and an ER membrane reporter, Hmg1-GFP, behave differently in the cER and pnER. The functional asymmetry and tubular ER formation depend on Reticulons/Yop1, which maintain ER structure. LUNAPARK1 deletion in rtn1Deltartn2Deltayop1Delta cells restores the pnER/cER functional asymmetry, tubular ER generation, and ER inheritance blocks. Thus, Reticulon/Yop1 dependent changes in ER structure are linked to ER inheritance during the yeast cell cycle. PMID- 27117667 TI - Where's my entourage? The curious case of 2-oleoylglycerol, 2-linolenoylglycerol, and 2-palmitoylglycerol. AB - 2-Arachidonoylglycerol (2-AG) is the most abundant endogenous cannabinoid in the brain and an agonist at two cannabinoid receptors (CB1 and CB2). The synthesis, degradation and signaling of 2-AG have been investigated in detail but its relationship to other endogenous monoacylglycerols has not been fully explored. Three congeners that have been isolated from the CNS are 2-linoleoylglycerol (2 LG), 2-oleoylglycerol (2-OG), and 2-palmitoylglycerol (2-PG). These lipids do not orthosterically bind to cannabinoid receptors but are reported to potentiate the activity of 2-AG, possibly through inhibition of 2-AG degradation. This phenomenon has been dubbed the 'entourage effect' and has been proposed to regulate synaptic activity of 2-AG. To clarify the activity of these congeners of 2-AG we tested them in neuronal and cell-based signaling assays. The signaling profile for these compounds is inconsistent with an entourage effect. None of the compounds inhibited neurotransmission via CB1 in autaptic neurons. Interestingly, each failed to potentiate 2-AG-mediated depolarization-induced suppression of excitation (DSE), behaving instead as antagonists. Examining other signaling pathways we found that 2-OG interferes with agonist-induced CB1 internalization while 2-PG modestly internalizes CB1 receptors. However in tests of pERK, cAMP and arrestin recruitment, none of the acylglycerols altered CB1 signaling. Our results suggest 1) that these compounds do not serve as entourage compounds under the conditions examined, and 2) that they may instead serve as functional antagonists. Our results suggest that the relationship between 2-AG and its congeners is more nuanced than previously appreciated. PMID- 27117668 TI - Label-free cell phenotypic profiling and pathway deconvolution of neurotensin receptor-1. AB - Neurotensin (NT), an endogenous peptide found in the central nervous system and in peripheral tissues, contributes to the pathophysiology of neurodegenerative and psychiatric diseases, cancer, inflammation, and immunomodulatory disease. NT exerts its physiological effects predominantly through its cognate high-affinity neurotensin receptor-1 (NTS1). NTS1 emerges as a druggable target; however, there are limited numbers of NTS1 active compounds reported to date. Here we reported a label-free cell phenotypic profiling model for screening NTS1 ligands and differentiating their biased agonism. Resonant waveguide grating enabled dynamic mass redistribution (DMR) assay was first optimized against cell confluency and then used to characterize the endogenous NTS1 in HT-29 cell using known agonists and antagonists. Pathway modulators were also used to deconvolute the signaling pathways of endogenous NTS1. Results showed that the NTS1 DMR assay is robust for screening and can differentiate biased agonism; and the activation of NTS1 in HT 29 triggers multiple pathways including Gq signaling and epidermal growth factor receptor transactivation. This study highlighted the power of label-free DMR assay to characterize receptor signaling and pharmacology of distinct classes of ligands for NTS1, G protein-coupled receptors in general. PMID- 27117669 TI - Immunoregulatory function of neonatal nucleated red blood cells in humans. AB - We found that human cord blood nucleated red blood cells (NRBCs) have a regulatory function in the innate immune reaction. These cells suppressed the production of inflammatory cytokines including TNF-alpha and IL-1beta from monocytes in response to lipopolysaccharide (LPS). The NRBCs exerted their regulatory function even without cell-to-cell contact with the monocytes. However, IL-10 production from the monocytes by LPS stimulation in the presence of NRBCs was higher than that from LPS-stimulated monocytes cultured in the absence of NRBCs. Addition of an anti-IL-10 receptor blocking antibody restored the inflammatory cytokine production from the monocytes, suggesting that the functional change of the monocytes caused by the interaction with NRBCs was mediated by the increased IL-10 production. A whole-genome microarray analysis revealed that the monocytes expressed increased amounts of IL-10 superfamily genes after interacting with NRBCs. IL-19, which is a member of the IL-10 superfamily, enhanced IL-10 production from the monocytes, which suggested a cooperative role of the IL-10 superfamily in the suppression of inflammatory cytokine production from monocytes. Arginase, which was reported to play an important role in the suppressive function of NRBCs in mice monocytes, was found to have no significant role in human monocytes. The NRBCs seem to have a regulatory role through the induction of IL-10/IL-19 production by monocytes to suppress a vigorous innate immune reaction, which can be harmful to fetuses. PMID- 27117670 TI - Development of cognitive processing and judgments of knowledge in medical students: Analysis of progress test results. AB - BACKGROUND: Beside acquiring knowledge, medical students should also develop the ability to apply and reflect on it, requiring higher-order cognitive processing. Ideally, students should have reached higher-order cognitive processing when they enter the clinical program. Whether this is the case, is unknown. We investigated students' cognitive processing, and awareness of their knowledge during medical school. METHODS: Data were gathered from 347 first-year preclinical and 196 first year clinical students concerning the 2008 and 2011 Dutch progress tests. Questions were classified based upon Bloom's taxonomy: "simple questions" requiring lower and "vignette questions" requiring higher-order cognitive processing. Subsequently, we compared students' performance and awareness of their knowledge in 2008 to that in 2011 for each question type. RESULTS: Students' performance on each type of question increased as students progressed. Preclinical and first-year clinical students performed better on simple questions than on vignette questions. Third-year clinical students performed better on vignette questions than on simple questions. The accuracy of students' judgment of knowledge decreased over time. CONCLUSIONS: The progress test is a useful tool to assess students' cognitive processing and awareness of their knowledge. At the end of medical school, students achieved higher-order cognitive processing but their awareness of their knowledge had decreased. PMID- 27117671 TI - Requirements for Forming Efficient 3-D Charge Transport Pathway in Diketopyrrolopyrrole-Based Copolymers: Film Morphology vs Molecular Packing. AB - To achieve extremely high planarity and processability simultaneously, we have newly designed and synthesized copolymers composed of donor units of 2,2'-(2,5 dialkoxy-1,4-phenylene)dithieno[3,2-b]thiophene (TT-P-TT) and acceptor units of diketopyrrolopyrrole (DPP). These copolymers consist of a highly planar backbone due to intramolecular interactions. We have systematically investigated the effects of intermolecular interactions by controlling the side chain bulkiness on the polymer thin-film morphologies, packing structures, and charge transport. The thin-film microstructures of the copolymers are found to be critically dependent upon subtle changes in the intermolecular interactions, and charge transport dynamics of the copolymer based field-effect transistors (FETs) has been investigated by in-depth structure-property relationship study. Although the size of the fibrillar structures increases as the bulkiness of the side chains in the copolymer increases, the copolymer with the smallest side chain shows remarkably high charge carrier mobility. Our findings reveal the requirement for forming efficient 3-D charge transport pathway and highlight the importance of the molecular packing and interdomain connectivity, rather than the crystalline domain size. The results obtained herein demonstrate the importance of tailoring the side chain bulkiness and provide new insights into the molecular design for high-performance polymer semiconductors. PMID- 27117672 TI - The V1 region of gp120 is preferentially selected during SIV/HIV transmission and is indispensable for envelope function and virus infection. AB - A transmission bottleneck occurs during each human immunodeficiency virus (HIV) transmission event, which allows only a few viruses to establish new infection. However, the genetic characteristics of the transmitted viruses that are preferentially selected have not been fully elucidated. Here, we analyzed amino acids changes in the envelope protein during simian immunodeficiency virus (SIV)/HIV deep transmission history and current HIV evolution within the last 15 20 years. Our results confirmed that the V1V2 region of gp120 protein, particularly V1, was preferentially selected. A shorter V1 region was preferred during transmission history, while during epidemic, HIV may evolve to an expanded V1 region gradually and thus escape immune recognition. We then constructed different HIV-1 V1 mutants using different HIV-1 subtypes to elucidate the role of the V1 region in envelope function. We found that the V1 region, although highly variable, was indispensable for virus entry and infection, probably because V1 deletion mutants exhibited impaired processing of gp160 into mature gp120 and gp41. Additionally, the V1 region affected Env incorporation. These results indicated that the V1 region played a critical role in HIV transmission and infection. PMID- 27117673 TI - Simulating Gas-Liquid-Water Partitioning and Fluid Properties of Petroleum under Pressure: Implications for Deep-Sea Blowouts. AB - With the expansion of offshore petroleum extraction, validated models are needed to simulate the behaviors of petroleum compounds released in deep (>100 m) waters. We present a thermodynamic model of the densities, viscosities, and gas liquid-water partitioning of petroleum mixtures with varying pressure, temperature, and composition based on the Peng-Robinson equation-of-state and the modified Henry's law (Krychevsky-Kasarnovsky equation). The model is applied to Macondo reservoir fluid released during the Deepwater Horizon disaster, represented with 279-280 pseudocomponents, including 131-132 individual compounds. We define >n-C8 pseudocomponents based on comprehensive two dimensional gas chromatography (GC * GC) measurements, which enable the modeling of aqueous partitioning for n-C8 to n-C26 fractions not quantified individually. Thermodynamic model predictions are tested against available laboratory data on petroleum liquid densities, gas/liquid volume fractions, and liquid viscosities. We find that the emitted petroleum mixture was ~29-44% gas and ~56-71% liquid, after cooling to local conditions near the broken Macondo riser stub (~153 atm and 4.3 degrees C). High pressure conditions dramatically favor the aqueous dissolution of C1-C4 hydrocarbons and also influence the buoyancies of bubbles and droplets. Additionally, the simulated densities of emitted petroleum fluids affect previous estimates of the volumetric flow rate of dead oil from the emission source. PMID- 27117674 TI - Improving outcomes following reconstruction of pressure sores in spinal injury patients: A multidisciplinary approach. AB - BACKGROUND AND AIM: Pressure sore treatment in spinal injury patients is challenging. A multidisciplinary approach with joint management by the plastic surgery and spinal injury teams was initiated at our institution in 2005 to improve patient care and surgical outcomes following reconstruction. This study assessed the surgical outcomes following reconstruction using the team approach and to compare inpatient stay and readmissions for complications before and after the multidisciplinary protocol was introduced. METHODS: A retrospective review of consecutive patients in the multidisciplinary pressure sore clinic was performed. Data were collected on patient demographics, reconstructive techniques, surgical outcomes and readmission for any complications. RESULTS: In total, 45 patients with 60 pressure sores (grade 3 or 4) were reviewed in the joint clinic between 2005 and 2011. The majority of patients were paraplegic (78%), while the remaining 22% were tetraplegic. Ischial sores were the most common (45%) followed by trochanteric (23%) and sacral (20%) sores. Multiple sores were noted in 44% of patients. Flap reconstruction was required in 32 patients (71%); after a mean follow-up time of 33 months (range 25-72 months), there were three (9%) major complications (two recurrences of pressure sores and one sinus) and seven (22%) minor complications. After introduction of patient care pathways through the multidisciplinary approach, the rate of readmission for complications decreased from 14% to 5.5% and inpatient stay upon readmission reduced from 65 to 45 days. CONCLUSIONS: Implementation of a multidisciplinary approach was key to optimising surgical outcomes, achieving a low recurrence rate (6%) and reducing readmissions. PMID- 27117675 TI - Evaluation of ADAM-rWBC for counting residual leucocytes in leucocyte-reduced whole blood and apheresis platelet concentrates. PMID- 27117676 TI - Evidence for an agitated-aggressive syndrome in early-onset psychosis correlated with antisocial personality disorder, forensic history, and substance use disorder. AB - OBJECTIVE: Agitation, aggression, and violence are increased in psychotic disorders. Additionally, an earlier age at onset may be associated with aggressive behavior. However, the relationship of age at onset, an agitated aggressive syndrome as measured with the Positive And Negative Syndrome Scale for Schizophrenia - Excited Component (PANSS-EC), and its potential correlates in first-episode psychosis (FEP) has not been studied. METHOD: This study assessed the association between age at onset, an agitated-aggressive syndrome, and its potential correlates in a prospective sample of 52 FEP patients with early-onset and adult-onset followed up for 12months. RESULTS: Twenty-six patients conformed to the criteria of early-onset psychosis. Early age at onset was associated with antisocial personality disorder (p=0.004; phic=0.39), a history of legal involvement (p=0.005; phic=0.39), and higher rates of lifetime substance use disorder (SUD; p=0.002; phic=0.42). Early-onset patients had significantly higher PANSS-EC scores over the course of observation (F(1,44.4)=5.39; p=0.025; d=0.656), but no significant group differences emerged for the remaining PANSS subscores. PANSS-EC scores were correlated positively with antisocial personality disorder and forensic history at 6weeks, 3months, 6months, and 12months, and with lifetime substance use disorder at 3months and 6months. CONCLUSIONS: Patients with early onset psychosis may have increased levels of agitation/aggressiveness, and, more likely, antisocial personality disorder, forensic history, and lifetime substance use disorder. These variables were linked to suicidality, aggressiveness, and involuntary treatment. PMID- 27117677 TI - Social cognition in schizophrenia in comparison to bipolar disorder: A meta analysis. AB - OBJECTIVE: Cognitive dysfunction is a common characteristic of both schizophrenia and bipolar disorder (BP). While these deficits are more severe in schizophrenia, there is a significant overlap between conditions. However, it was hypothesized that social cognitive deficits might be more specific to schizophrenia. METHODS: We conducted a meta-analysis of studies comparing facial emotion recognition and theory of mind (ToM) abilities in schizophrenia and BP. 26 studies comparing 1301 patients with schizophrenia and 1075 with BP were included. RESULTS: Schizophrenia patients significantly underperformed compared with BP patients in both facial emotion recognition (d=0.39) and ToM (d=0.57). Neurocognitive deficits significantly contributed to schizophrenia-BP group differences for ToM. However, between-group differences for social cognition were not statistically more severe than neurocognition. CONCLUSION: Social cognitive impairment is more severe in schizophrenia in comparison to BP. However, between-group differences are modest and are comparable to other neurocognitive differences between schizophrenia and BP. There is significant overlap in social cognitive performance deficits observed in both schizophrenia and BP. PMID- 27117678 TI - HaloTag mediated artificial cellulosome assembly on a rolling circle amplification DNA template for efficient cellulose hydrolysis. AB - We report here the generation of four-component artificial cellulosomes onto a DNA scaffold using the self-labeling HaloTag for DNA conjugation. The resulting structures exhibited significantly improved cellulosome assembly as well as cellulose hydrolysis over compatible structures generated using protein scaffolds. Cellulose hydrolysis was further enhanced by 2-fold using the more complex cellulosome structures assembled onto DNA templates generated by rolling circle amplification (RCA). The flexibility to insert additional hybridization sites in a multiplexing manner using RCA should enable the assembly of a larger array of cellulases to better mimic the enzyme diversity of naturally occurring cellulosomes. PMID- 27117679 TI - Fatal intraperitoneal hepatic bleeding due to metastatic deposit of unknown primary: a tribulation for a regional surgeon. PMID- 27117680 TI - Prevalence of Tick-Borne Pathogens in Host-Seeking Amblyomma americanum (Acari: Ixodidae) and Odocoileus virginianus (Artiodactyla: Cervidae) in Florida. AB - Amblyomma americanum (L.), the lone star tick, is an aggressive tick that is expanding its geographic range within the United States. This tick is the vector for the human and veterinary pathogens Ehrlichia chaffeensis and Ehrlichia ewingii and is associated with other microbes of unspecified pathogenicity including Rickettsia amblyommii, Panola Mountain Ehrlichia, and Borrelia lonestari In Florida, there has been sparse contemporary data on the prevalence of these organisms in host-seeking lone star ticks. To determine the prevalence of this tick and associated microbes in North Central Florida state parks, ~1,500 lone star tick specimens were collected between 2010 and 2012 analyzed by polymerase chain reaction (PCR) sequencing. Additionally, 393 white-tailed deer, Odocoileus virginianus (Zimmerman), samples were analyzed for pathogen prevalence using molecular methods and serology. In lone star ticks, 14.6, 15.6, and 57.1% were positive for E. chaffeensis, E. ewingii, and Rickettsia spp. DNA, respectively. Panola Mountain Ehrlichia or B. lonestari DNA were each detected in nearly 2% of tick specimens. In white-tailed deer, 7.3% were PCR positive for E. chaffeensis, 6.0% for E. ewingii, and 3.2% for rickettsial species. Approximately 45% of white-tailed deer specimens had antibodies to Ehrlichia spp., and <1% had antibodies to Borrelia burgdorferi In summary, E. chaffeensis, E. ewingii, and spotted fever group rickettsia are highly prevalent in host-seeking lone star ticks and in white-tailed deer in Florida. The molecular and serological evidence of these microbes underscore their zoonotic potential in this region. PMID- 27117681 TI - Paludibacterium purpuratum sp. nov., isolated from wetland soil. AB - A novel bacterium, designated KJ031T, was isolated from a wetland soil sample taken from Jeju island, Republic of Korea. Cells were Gram-stain-negative, curved rod shaped, oxidase- and catalase- positive, motile and facultatively anaerobic. Growth was observed at pH 6.0-8.0 and at 20-37 degrees C on R2A agar. Comparative analysis of 16S rRNA gene sequences revealed that strain KJ031T is a member of the genus Paludibacterium, sharing highest sequence similarities with Paludibacterium paludis KBP-21T (96.2 %) and Paludibacterium. yongneupense 5YN8 15T (96.0 %). The major fatty acids were summed feature 3 (C16 : 1 omega7c and/or C16 : 1 omega6c), C16 : 0 and summed feature 8 (C18 : 1 omega7c and/or C18 : 1 omega6c). The predominant respiratory quinone was Q-8. The major polar lipids of strain KJ031T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminophospholipid, two unidentified phospholipids and one unidentified polar lipid. The DNA G+C content was 59.2 mol%. On the basis of the evidence presented in this study, strain KJ031T represents a novel species of the genus Paludibacterium, for which the name Paludibacterium purpuratum sp. nov. is proposed. The type strain is KJ031T (=KCTC 42852T =CECT 8976T). PMID- 27117682 TI - Geriatric nutritional risk index, muscle function, quality of life and clinical outcome in hemodialysis patients. AB - BACKGROUND & AIMS: The geriatric nutritional risk index (GNRI) has been reported as a useful predictor of prognosis in maintenance hemodialysis (MHD) patients, demonstrating GNRI less than 90 as a marker of a poorer nutritional status and significantly increased mortality. We tested whether GNRI as a whole associated stronger with clinical and laboratory surrogates of nutrition and inflammation, muscle function, health-related quality of life (QoL), and predicts all-cause and cardiovascular (CV) morbidity and mortality in this population better than its individual components (albumin and body weight to ideal body weight ratio). METHODS: A prospective observational study with a median follow-up of 30 months (interquartile range - 19-41 months) was performed on 352 MHD outpatients (38.0% women) with a mean age of 67.4 +/- 13.2 years. All-cause and cardiovascular hospitalization and mortality, GNRI, handgrip strength (HGS), body composition parameters (anthropometry and bioimpedance) and short form 36 (SF-36) quality-of life scores were measured. Multivariate linear regression analyses were performed to obtain adjusted correlations. Receiver operating characteristic (ROC) curves were generated and multivariate Cox proportional hazards models were applied to identify the predictive value of GNRI and its components separately. RESULTS: GNRI positively correlated with total score (r = 0.15, P < 0.05), the physical health dimension (r = 0.14, P < 0.05), the general health (r = 0.18, P < 0.01) and some other scales of the SF-36. A significant correlation of GNRI with HGS in male patients didn't stand up to multivariable adjustments. For each one unit increase in baseline GNRI levels, the first hospitalization hazard ratio (HR) after adjustments for confounders was 0.98 (95% confidence interval (CI), 0.97 to 0.99) and the first CV event HR was 0.98 (95% CI, 0.97 to 0.99); all-cause death HR was 0.97 (95% CI, 0.96 to 0.99) and CV death HR was 0.97 (95% CI, 0.95-0.99). Albumin was related to QoL and clinical outcomes with higher strength and magnitude than GNRI. CONCLUSIONS: Despite the significant relationship with clinical outcomes and QOL, GNRI is not better and is even slightly worse than albumin's performance. This raises doubts as to the clinical utility of GNRI as a prognostic tool in the MHD population. PMID- 27117683 TI - [Macrocheilia revealing an acute promyelocytic leukemia]. AB - INTRODUCTION: Macrocheilia is a rare presentation for acute promyelocytic leukemia (APL). CASE REPORT: A 18 year-old man was referred to our department for an acute swollen lower lip, multiple swollen cervical lymph nodes and spontaneous gum bleeding. The diagnosis of APL was made and the treatment was rapidly started in an intensive care unit. DISCUSSION: APL is often found because of stomatologic symptoms but macrocheilia is rarely reported. APL is a vital emergency. PMID- 27117684 TI - [Shave excision of an acral fibrokeratoma of the proximal nail matrix associated with a subungual exostosis of the thumb]. PMID- 27117685 TI - Decreased Composite Indices of Femoral Neck Strength in Young Obese Men. PMID- 27117686 TI - Quantifying the health impacts of ambient air pollutants: methodological errors must be avoided. PMID- 27117687 TI - Factors affecting quality of life in patients on haemodialysis: a cross-sectional study from Palestine. AB - BACKGROUND: Haemodialysis (HD) is a life-sustaining treatment for patients with end-stage renal disease (ESRD). HD can bring about significant impairment in health-related quality of life (HRQOL) and outcomes. Therefore, we sought to describe the patterns of HRQOL and determine the independent factors associated with poor HRQOL in Palestinian patients on HD. METHODS: A multicenter cross sectional study was performed from June 2014 to January 2015 using the EuroQOL-5 Dimensions instrument (EQ-5D-5L) for the assessment of HRQOL. ESRD patients undergoing HD in all dialysis centres in the West Bank of Palestine were approached and recruited for this study. Multiple linear regression was carried out to identify factors that were significantly associated with HRQOL. RESULTS: Two hundred and sixty-seven patients were participated in the current study giving response rate of 96 %. Overall, 139 (52.1 %) were male, and the mean +/- standard deviation age was 53.3 +/- 16.2 years. The reported HRQOL as measured by mean EQ-5D-5L index value and Euro QOL visual analogue scale (EQ-VAS) score was 0.37 +/- 0.44 and 59.38 +/- 45.39, respectively. There was a moderate positive correlation between the EQ-VAS and the EQ-5D-5L index value (r = 0.42, p < 0.001). The results of multiple linear regression showed a significant negative association between HRQOL with age, total number of chronic co-morbid diseases and the total number of chronic medications. However, a significant positive association was found between HRQOL with male gender, university education level and patients who live in village. CONCLUSION: Our results provided insight into a number of associations between patient variables and their HRQOL. Healthcare providers should be aware of low HRQOL among patients with no formal education, female gender, patient's residents of refugee camps, multiple co-morbid diseases, multiple chronic medications, and elderly patients to improve their quality of life. PMID- 27117688 TI - Dynamic changes in mitochondrial distribution in human oocytes during meiotic maturation. AB - PURPOSE: The change of mitochondrial distribution in human oocytes during meiotic maturation was assessed using 223 human oocytes donated from patients undergoing fertility treatment between June 2013 and February 2016. METHODS: Live cell images of fluorescence-labelled mitochondria in human oocytes were analysed to investigate dynamic changes in mitochondrial distribution during meiotic maturation using a confocal microscope combined with an incubator in the presence or absence of colchicine and cytochalasin B, inhibitors for tubulin and actin filament, respectively. Subcellular distribution of mitochondria in human oocytes was also assessed at various stages using a transmission electron microscope (TEM). RESULTS: Live cell imaging analysis revealed that the mitochondria occupied cytoplasmic area decreased from 83 to 77 % of the total cytoplasmic area around 6 h before germinal vesicle breakdown (GVBD) and that mitochondria accumulated preferentially close to the perinuclear region. Then, the mitochondria-distributed area rapidly increased to 85 % of total cytoplasm at the time of GVBD. On the other hand, there was no significant change in mitochondrial distribution before and after polar body extrusion. Such changes in mitochondrial localization were affected differently by colchicine and cytochalasin B. Most of mitochondria in the cytoplasm formed cluster-like aggregates before GVBD while they distributed homogeneously after GVBD. CONCLUSIONS: Most mitochondria localized predominantly in the non-cortical region of the cytoplasm of GV stage oocytes, while the mitochondria-occupied area decreased transiently before GVBD and increased rapidly to occupy the entire area of the cytoplasm at GVBD by some cytoskeleton-dependent mechanism. PMID- 27117689 TI - Postoperative complications following aggressive repeat hepatectomy for colorectal liver metastasis have adverse oncological outcomes. AB - PURPOSES: Repeat hepatectomy remains the only curative treatment for recurrent colorectal liver metastasis (CLM) after primary hepatectomy. However, the repeat resection rate is still low, and there is insufficient data on the outcomes after repeat hepatectomy. The aim of this study was to investigate the feasibility and prognostic benefit of aggressive repeat hepatectomy for recurrent CLM. METHODS: Data were reviewed from 282 consecutive patients who underwent primary curative hepatectomy for CLM between January 1994 and March 2015. The short- and long-term outcomes were analyzed. RESULTS: One hundred ninety-three patients (68 %) developed recurrence, and repeat hepatectomy was conducted in 62 patients. Overall, 62 s, 11 third, 4 fourth, and 1 fifth hepatectomies were performed. The postoperative morbidity and mortality rates were low (11.5 and 1.3 %, respectively). The overall survival rates at 3 and 5 years after primary hepatectomy for CLM in the repeat hepatectomy group were 79.5 and 57.4 %, respectively. A multivariate analysis indicated that postoperative complications were independently associated with overall survival after repeat hepatectomy. CONCLUSIONS: Repeat hepatectomy for CLM is feasible, with acceptable rates of perioperative morbidity and mortality, and the potential for long-term survival. However, postoperative complications following aggressive repeat hepatectomy for CLM are associated with adverse oncological outcomes. PMID- 27117690 TI - Prospective analysis of functional swallowing outcome after resection of T2 glottic carcinoma using transoral laser surgery and external vertical hemilaryngectomy. AB - 56 patients affected by T2 glottic carcinoma were treated in two institutes using transoral laser microsurgery (TLM) in 40 cases and vertical hemilaryngectomy in 16 cases between September 2012 and September 2015. In the TLM group, different subtypes of type V cordectomy were used according to the extent of tumor. In the vertical hemilaryngectomy group, classical operation was used in most of the cases and the resection was extended in few cases. Analysis of post-operative swallowing function was done using videofluoroscopy (VFS), functional endoscopic evaluation of swallowing, and subjectively using MD Anderson dysphagia inventory. Objective evaluation of swallowing has been made by obtaining different measures from VFS (pharyngeal transit time, pharyngeal constriction ratio, and hyoid displacement for example). Analysis also included the need and duration of tracheostomy and nasogastric tube, ICU admission, and hospitalization time. Statistical analysis was performed with the Mann-Whitney U and Pearson Chi-square tests. Comparison of incidence of aspiration and swallowing outcome showed significantly better results in the laser group than in the vertical group (p < 0.001). The duration of ICU, tracheostomy, nasogastric tube, and hospital stay was also significantly shorter in the laser group (p < 0.001). This study shows that TLM had significantly better overall postoperative outcome than vertical hemilaryngectomy. It was associated with significantly shorter hospital stay and less need for tracheostomy, nasogastric tube, and ICU admission). Measures obtained from VFS are useful for detection and follow-up of postoperative aspiration, because it is a definitive technique for anatomical and physiological study of swallowing. PMID- 27117691 TI - 3D-QSAR-aided design, synthesis, in vitro and in vivo evaluation of dipeptidyl boronic acid proteasome inhibitors and mechanism studies. AB - Proteasome had been clinically validated as an effective target for the treatment of cancers. Up to now, many structurally diverse proteasome inhibitors were discovered. And two of them were launched to treat multiple myeloma (MM) and mantle cell lymphoma (MCL). Based on our previous biological results of dipeptidyl boronic acid proteasome inhibitors, robust 3D-QSAR models were developed and structure-activity relationship (SAR) was summarized. Several structurally novel compounds were designed based on the theoretical models and finally synthesized. Biological results showed that compound 12e was as active as the standard bortezomib in enzymatic and cellular activities. In vivo pharmacokinetic profiles suggested compound 12e showed a long half-life, which indicated that it could be administered intravenously. Cell cycle analysis indicated that compound 12e inhibited cell cycle progression at the G2M stage. PMID- 27117692 TI - The emergence and evolution of antimicrobial resistance: Impact on a global scale. AB - The evolution of antimicrobial resistance is a multifaceted issue that is influenced by numerous factors. This growing healthcare problem has significantly impacted the public welfare and has substantially burdened the economic system on a global scale. In an effort to combat this rising problem, several strategies have been implemented in the recent years to stall the progression and decrease the emergence of antimicrobial resistance. The aim of this review article is to describe the various factors that have contributed to the current state of antimicrobial resistance and to evaluate potential strategies developed to reduce the burden of antimicrobial resistance. PMID- 27117693 TI - Synthesis and biological evaluation of sialyl-oligonucleotide conjugates targeting leukocyte B trans-membranal receptor CD22 as delivery agents for nucleic acid drugs. AB - Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins. PMID- 27117694 TI - Erratum to "The automatic pelvic floor muscle response to the active straight leg raise in cases with pelvic girdle pain and matched controls" [Man Ther 18 (4) (2013) 327-332]. PMID- 27117695 TI - Chemical composition, antioxidant, antibacterial and cytotoxic effects of Artemisia marschalliana Sprengel extract. AB - The present study was to investigate the gas chromatography/mass spectrometry (GC/MS), in vitro antioxidant, antibacterial and anticancer activity of the ethanolic extract from aerial parts of Artemisia marschalliana Sprengel against human gastric carcinoma (AGS) and L929 cell lines. Phytochemical analysis of A. marschalliana Sprengel extract showed 22 major components and the most dominant compounds were trans-phytol (29.22%), alpha-Linolenic acid (13.47%) and n Hexadecanoic acid (9.28%). In addition, the antioxidant and anticancer activity of A. marschalliana Sprengel extract were evaluated using 1,1-diphenyl-2 picrylhydrazyl (DPPH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) methods, respectively. Antibacterial activity against selected pathogenic bacteria was also determined. According to the present obtained results, it seems that this plant has potential uses for pharmaceutical industries and further studies of pharmaceutical importance were suggested to be performed on A. marschalliana Sprengel. PMID- 27117696 TI - Efficacy of tranexamic acid in reducing allogeneic blood products in adolescent idiopathic scoliosis surgery. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) surgery usually require prolonged operative times with extensive soft tissue dissection and significant perioperative blood loss, and allogeneic blood products are frequently needed. Methods to reduce the requirement for transfusion would have a beneficial effect on these patients. Although many previous studies have revealed the efficacy of tranexamic acid (TXA) in spinal surgery, there is still a lack of agreement concerning the reduction of both blood loss and transfusion requirements of large dose tranexamic acid (TXA) in surgery for adolescent idiopathic scoliosis (AIS). The objective of this study was to elevate the efficacy and safety of a large dose tranexamic acid (TXA) in reducing transfusion requirements of allogeneic blood products in adolescent idiopathic scoliosis (AIS) surgery using a retrospective study designed with historical control group. METHODS: One hundred thirty seven consecutive AIS patients who underwent surgery treatment with posterior spinal pedicle systems from August 2011 to March 2015 in our scoliosis center were retrospectively reviewed. Patients were divided into two groups, the TXA group and the historical recruited no TXA group (NTXA). Preoperative demographics, radiographic parameters, operative parameters, estimated blood loss (EBL), total irrigation fluid, number of patients requiring blood transfusion, mean drop of Hb (Pre-op Hb-Post-op Hb), haematocrit pre and post-surgery, mean volume of blood transfusion, hospitalization time, and adverse effect were recorded and compared. RESULTS: All the patients were successfully treated with satisfied clinical and radiographic outcomes. There were 71 patients in the TXA group and 66 patients in the NTXA group. The preoperative demographics were homogeneity between two groups (P > 0.05). There were no significant difference in average operative time between two groups (209 min vs 215 min, p >0.05). Number of patients in the TXA group showed a significant decrease in transfusion requirements with an associated reduced intraoperative blood loss of nearly 45% compared with those in NTXA group (8 vs 37, 619 ml vs 1125 ml, P < 0.05). There were no significant difference in total irrigation fluid between two groups (540 vs 550, p >0.05). Additional, patients in NTXA group showed significant decrease of Hb compared with patients in TXA group (5.2 g/dL vs 3.3 g/dL, P < 0.05), No significant difference were found in hospitalization time between two groups (6.3 vs 7.2 days, P > 0.05). No minor adverse effects associated with use of TXA were noted. CONCLUSIONS: Use of large dose tranexamic acid routinely seems to be effective and safe in reducing allogenic blood transfusion and blood loss in adolescent idiopathic scoliosis surgery. PMID- 27117697 TI - Quality assessment of studies comparing percutaneous ablative treatments in hepatocellular carcinoma. PMID- 27117698 TI - Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. AB - OBJECTIVES: To investigate the efficacy and safety of switching from infliximab reference product (RP) to its biosimilar or maintaining biosimilar treatment in patients with ankylosing spondylitis (AS). METHODS: This open-label extension study recruited patients with AS who completed a 54-week, randomised controlled study comparing CT-P13 with RP (PLANETAS). CT-P13 (5 mg/kg) was administered intravenously every 8 weeks from week 62 to week 102. Efficacy end points included the proportion of patients achieving Assessment of SpondyloArthritis international Society (ASAS)20. Antidrug antibodies (ADAs) were measured using an electrochemiluminescent method. Data were analysed for patients treated with CT P13 in the main PLANETAS study and the extension (maintenance group) and those who were switched to CT-P13 during the extension study (switch group). RESULTS: Overall, 174 (82.9%) of 210 patients who completed the first 54 weeks of PLANETAS and agreed to participate in the extension were enrolled. Among these, 88 were maintained on CT-P13 and 86 were switched to CT-P13 from RP. In these maintenance and switch groups, respectively, ASAS20 response rates at week 102 were 80.7% and 76.9%. ASAS40 and ASAS partial remission were also similar between groups. ADA positivity rates were comparable (week 102: 23.3% vs 27.4%). Adverse events led to treatment discontinuation during the extension study in 3 (3.3%) and 4 (4.8%) patients, respectively. CONCLUSIONS: This is the first study to show that switching from RP to its biosimilar CT-P13 is possible without negative effects on safety or efficacy in patients with AS. In the maintenance group, CT-P13 was effective and well tolerated over 2 years of treatment. TRIAL REGISTRATION NUMBER: NCT01571206; Results. PMID- 27117699 TI - The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor. AB - OBJECTIVE: Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti CarP antibodies in relation to ACPA and rheumatoid factor (RF). METHODS: 576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5 years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated. RESULTS: Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75*10-13) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified). CONCLUSIONS: Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients. PMID- 27117700 TI - Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. AB - OBJECTIVES: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities. METHODS: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1*106, 3*106 or 10*106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood. RESULTS: There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10*106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high. CONCLUSION: IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10*106 tolDC but no systemic clinical or immunomodulatory effects were detectable. TRIAL REGISTRATION NUMBER: NCT01352858. PMID- 27117701 TI - Call for preventive care for rheumatic heart disease in refugee children. PMID- 27117702 TI - The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. AB - METTL3 is an RNA methyltransferase implicated in mRNA biogenesis, decay, and translation control through N(6)-methyladenosine (m(6)A) modification. Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. In contrast to current models that invoke m(6)A reader proteins downstream of nuclear METTL3, we find METTL3 associates with ribosomes and promotes translation in the cytoplasm. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. METTL3 expression is elevated in lung adenocarcinoma and using both loss- and gain-of-function studies, we find that METTL3 promotes growth, survival, and invasion of human lung cancer cells. Our results uncover an important role of METTL3 in promoting translation of oncogenes in human lung cancer. PMID- 27117704 TI - Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, gamma-Glutamyl Transpeptidase, Cathepsin B, Flavin Containing Monooxygenase, and ADP-Ribosyltransferase. AB - The significant roles that cytochrome P450 (P450) and UDP-glucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of GDC-0834 (N-[3-[6-[4-[(2R)-1,4-dimethyl-3-oxopiperazin-2 yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1 benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450 mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non P450- and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery. PMID- 27117703 TI - A complex behavioural change intervention to reduce the risk of diabetes and prediabetes in the pre-conception period in Malaysia: study protocol for a randomised controlled trial. AB - BACKGROUND: Over the past two decades, the population of Malaysia has grown rapidly and the prevalence of diabetes mellitus in Malaysia has dramatically increased, along with the frequency of obesity, hyperlipidaemia and hypertension. Early-life influences play an important role in the development of non communicable diseases. Indeed, maternal lifestyle and conditions such as gestational diabetes mellitus or obesity can affect the risk of diabetes in the next generation. Lifestyle changes can help to prevent the development of type 2 diabetes mellitus. This is a protocol for an unblinded, community-based, randomised controlled trial in two arms to evaluate the efficacy of a complex behavioural change intervention, combining motivational interviewing provided by a community health promoter and access to a habit formation mobile application, among young Malaysian women and their spouses prior to pregnancy. METHOD/DESIGN: Eligible subjects will be Malaysian women in the age group 20 to 39 years, who are nulliparous, not diagnosed with diabetes and own a smartphone. With an alpha value of 0.05, a statistical power of 90 %, 264 subjects will need to complete the study. Subjects with their spouses will be randomised to either the intervention or the control arm for an 8-month period. The primary endpoint is change in waist circumference from baseline to end of intervention period and secondary endpoints are changes in anthropometric parameters, biochemical parameters, change in health literacy level, dietary habits, physical activity and stress level. Primary endpoint and the continuous secondary endpoints will be analysed in a linear regression model, whereas secondary endpoints on an ordinal scale will be analysed by using the chi-squared test. A multivariate linear model for the primary endpoint will be undertaken to account for potential confounders. This study has been approved by the Medical Research and Ethics Committee of the Ministry of Health Malaysia (protocol number: NMRR-14-904-21963) on 21 September 2015. DISCUSSION: This study protocol describes the first community-based randomised controlled trial, to examine the efficacy of a complex intervention in improving the pre-pregnancy health of young Malaysian women and their spouses. Results from this trial will contribute to improve policy and practices regarding complex behavioural change interventions to prevent diabetes in the pre conception period in Malaysia and other low- and middle-income country settings. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (www.clinicaltrials.gov) on 30 November 2015, Identifier: NCT02617693 . PMID- 27117706 TI - Spectral study of specific interactions between zwitterionic compounds and protic solvents. AB - The zwitterionic compounds, like ylids, can interact both by universal and specific forces with the protic solvents. Ylids have a visible electronic absorption band with intramolecular charge transfer (ICT), very sensitive to the solvent nature and considered as an indicator of their stability. Two zwitterionic compounds: pyridinium dicarbethoxy methylid and iso-quinolinium dicarbethoxy methylid were studied from solvatochromic point of view and the contribution of solute-solvent specific interactions to the total spectral shift of the visible ICT band was established. Ternary solutions of the studied ylids were used to estimate the difference of interaction energies in molecular pairs ylid-protic solvent and ylid-aprotic solvent in the limits of the cell model of three component solutions. PMID- 27117705 TI - Quality of life in Arab women with breast cancer: a review of the literature. AB - BACKGROUND: Quality of life has become an important concept in cancer care. Among the quality of lifestudies in cancer patients, breast cancer has received most attention. This review reports on quality of life in Arab patients with breast cancer. METHODS: The search was conducted using inclusion and exclusion criteria and in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). The databases consulted were PubMed, Sciences Direct, Index Medicus for Wordl Health Organization Eastern Mediterranean, African Journals Online and African Index Medicus. RESULTS: Thirteen articles from eight countries met the inclusion criteria. The EORTC quality of life questionnaires (QLQ-C30 and QLQ-BR23) were the most used instrument (7 out of 13). The results showed that good scores of global health were recorded at Arab women living in United Arab Emirates (mean score = 74.6) compared to other countries. The results indicated that there was a difference in quality of life scores and its associated factors among Arab women with breast cancer. CONCLUSION: This paper is the first that reviewed published research on quality of life among Arab women with breast cancer. We found that insufficient results-related information is available. PMID- 27117707 TI - Comparison of iron-bearing minerals in ordinary chondrites from H, L and LL groups using Mossbauer spectroscopy with a high velocity resolution. AB - Ordinary chondrites from H, L and LL groups were studied using Mossbauer spectroscopy with a high velocity resolution. Mossbauer parameters of spectral components were obtained using new fitting model excluding the effect of previous misfits of troilite component. Obtained parameters were related to corresponding iron-bearing minerals in ordinary chondrites. The differences of these minerals content as well as small differences in the hyperfine parameters of the same iron bearing minerals were revealed for different meteorites. The temperatures of equilibrium cations distribution in silicates were estimated and suitable parameters for classification of H, L and LL chondrites were supposed using Mossbauer parameters. PMID- 27117708 TI - Maraviroc reduces neuropathic pain through polarization of microglia and astroglia - Evidence from in vivo and in vitro studies. AB - Recent studies suggest that CCR5 and its ligands are important regulators for the development of neuropathic pain and that their modulation can have some beneficial properties. Therefore, the aim of our study was to investigate the influence of maraviroc (MVC, a CCR5 antagonist) on glial polarization markers and intracellular signaling pathways in the spinal cord 7 days after chronic constriction injury (CCI) to the sciatic nerve and in primary glial cultures after LPS stimulation. Our results demonstrated that chronic intrathecal administration of MVC diminished neuropathic pain symptoms and nociceptive threshold ~60 min after drug administration on days 3 and 7 post-CCI. MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-kappaB proteins in the spinal cord and upregulated STAT3 in the dorsal root ganglia (DRG). Additionally, using Western blot analysis, we demonstrated that MVC effectively diminished "classical" activation markers: IL-1beta, IL-18, IL-6 and NOS2 in the spinal cord. In contrast, MVC upregulated "alternative" antinociceptive activation markers: IL-1RA, IL-18BP and IL-10 in the spinal cord. In parallel, MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-kappaB proteins and upregulated STAT3 in microglial and astroglial cell cultures. Similarly, MVC reduced pronociceptive (IL-1beta, IL-18, IL-6, NOS2) and enhanced the antinociceptive (IL-1RA, IL-18BP, IL-10) factors after LPS stimulation. Our studies provide new evidence that MVC attenuates neuropathy symptoms, promotes spinal glial "alternative" polarization and restores the balance between pro- and antinociceptive factors. Our results suggest the modulation of CCR5 by MVC as a novel therapeutic approach for neuropathy. PMID- 27117710 TI - Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier. AB - Unraveling the mechanisms of nanoparticle transport across the intestinal barrier is essential for designing more efficient nanoparticles for oral administration. The physicochemical parameters of the nanoparticles (e.g., size, surface charge, chemical composition) dictate nanoparticle fate across the intestinal barrier. This review aims to address the most important findings regarding polymeric and lipidic nanoparticle transport across the intestinal barrier, including the evaluation of critical physicochemical parameters of nanoparticles that affect nanocarrier interactions with the intestinal barrier. PMID- 27117711 TI - Clinical challenges in HIV/AIDS: Hints for advancing prevention and patient management strategies. AB - Acquired immune deficiency syndrome has been one of the most devastating epidemics of the last century. The current estimate for people living with the HIV is 36.9 million. Today, despite availability of potent and safe drugs for effective treatment, lifelong therapy is required for preventing HIV re-emergence from a pool of latently infected cells. However, recent evidence show the importance to expand HIV testing, to offer antiretroviral treatment to all infected individuals, and to ensure retention through all the cascade of care. In addition, circumcision, pre-exposure prophylaxis, and other biomedical tools are now available for included in a comprehensive preventive package. Use of all the available tools might allow cutting the HIV transmission in 2030. In this article, we review the status of the epidemic, the latest advances in prevention and treatment, the concept of treatment as prevention and the challenges and opportunities for the HIV cure agenda. PMID- 27117712 TI - Use of Cancer Genetics Services in African-American Young Breast Cancer Survivors. AB - INTRODUCTION: African-American women have higher rates of early-onset breast cancer compared with their Caucasian counterparts; yet, when diagnosed with breast cancer at a young age, they underuse genetic counseling and testing to manage their risk of developing future cancers. METHODS: Self-reported baseline data were collected between September 2012 and January 2013 and analyzed in 2014 from a subpopulation of 340 African-American young breast cancer survivors (YBCSs) enrolled in an RCT. YBCSs were diagnosed with invasive breast cancer or ductal carcinoma in situ between ages 20 and 45 years and were randomly selected from a statewide cancer registry. Logistic regression examined predictors of using cancer genetics services. RESULTS: Overall, 28% of the sample reported having genetic counseling and 21% reported having genetic testing, which were significantly lower (p<=0.005) compared with white/other YBCSs participating in the parent study. In a multivariate analysis, income was positively associated with counseling (B=0.254, p<=0.01) and testing (B=0.297, p<=0.01), whereas higher education levels (B=-0.328, p<=0.05) and lack of access to healthcare services owing to cost (B=-1.10, p<=0.03) were negatively associated with genetic counseling. Lower income and lack of care because of high out-of-pocket costs were commonly reported barriers. CONCLUSIONS: Despite national recommendations for genetic evaluation among women with early-onset breast cancer, few African American YBCSs reported undergoing genetic counseling and testing. Most reported that their healthcare provider did not recommend these services. Interventions addressing patient, provider, and structural healthcare system barriers to using genetic counseling and testing in this population are needed. PMID- 27117713 TI - The impact of time factors on overall survival in patients with nasopharyngeal carcinoma: a population-based study. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is most common in Southeast Asia. The purpose of this study is to investigate the correlation between wait time and length of radiotherapy and overall survival (OS) of NPC patients in Taiwan. METHODS: From Taiwan's National Health Insurance Research Database, this nationwide population-based cohort study identified 3605 NPC patients who received radiotherapy between 2008 and 2011. The impact of time factors on NPC survival rates was estimated with Kaplan-Meier survival curves. A multivariable Cox hazards regression model tested the significance of results after adjustment for other covariables. RESULTS: In all, 317 patients had wait times >4 weeks, 1404 patients had longer duration of radiotherapy (i.e., >10 weeks) and 499 died. Patients with wait times > 4 weeks and length of radiotherapy <= 10 weeks didn't have significantly inferior survival. Patients with wait times >4 weeks and length of radiotherapy >10 weeks had significantly lower OS than other groups, with an adjusted hazard ratio of 1.7 (95 % CI, 1.10-2.60). CONCLUSION: Time was a significant prognostic factor for NPC patients who had both >4 weeks wait times and length of radiotherapy >10 weeks. Patients with wait time > 4 weeks and length of radiotherapy <= 10 weeks had a trend toward an inferior survival. PMID- 27117714 TI - An exploration of clinical practice in sites with and without clinical nurse or midwife specialists or advanced nurse practitioners, in Ireland. AB - BACKGROUND: Clinical specialist (CS) and advanced practitioner (AP) roles have increased in nursing and midwifery internationally. This study explored clinical practice in sites with and without clinical nurse or midwife specialists or advanced nurse practitioners in Ireland. METHODS: Using a case study design, interview, observational and documentary data from postholding sites (CSs or APs employed) were compared with data from non-postholding sites (no CSs or APs employed). Interviews and observations were conducted with postholders (n = 23), and compared with data from healthcare professionals (nurses or midwives, doctors) (n = 23) in matched services. Interviews were held with Directors of Nursing and Midwifery (n = 23), healthcare professionals (n = 41), service users (n = 41) with experience of receiving care or working with postholders, and non postholders in matched services. The data were analysed using Nvivo (Version 8). RESULTS: The findings suggest that postholders' practice appeared to differ from non-postholders' in relation to case management and service provision. Postholders were seen as having an impact on readmission rates, waiting lists/times, collaborative decision-making, continuity of care and workload management. Postholders' autonomy to manage caseloads was perceived to lead to smoother transition of patients/clients through the healthcare system. Service users' self-reports appeared to appreciate the individualised holistic care provided by postholders. Postholders' role in facilitating person-centred care and promoting interprofessional team working, are essential elements in quality care provision and in global healthcare workforce planning. CONCLUSIONS: To meet changing healthcare demands, promote person-centred care, and improve service delivery, more specialist and advanced practice posts in nursing and midwifery should be developed and supported within healthcare. PMID- 27117715 TI - Use of video to facilitate sideline concussion diagnosis and management decision making. AB - OBJECTIVES: Video analysis can provide critical information to improve diagnostic accuracy and speed of clinical decision-making in potential cases of concussion. The objective of this study was to validate a hierarchical flowchart for the assessment of video signs of concussion, and to determine whether its implementation could improve the process of game day video assessment. DESIGN: Prospective cohort study. METHODS: All impacts and collisions potentially resulting in a concussion were identified during 2012 and 2013 Australian Football League (AFL) seasons. Consensus definitions were developed for clinical signs associated with concussion. A hierarchical flowchart was developed based on the reliability and validity of the video signs of concussion. Ninety videos were assessed, with 45 incidents of clinically confirmed concussion, and 45 cases where no concussion was sustained. Each video was examined using the hierarchical flowchart, and a single response was given for each video based on the highest ranking element in the flowchart. RESULTS: No protective action, impact seizure, motor incoordination or blank/vacant look were the highest ranked video signs in almost half of the clinically confirmed concussions, but in only 8.8% of non concussed individuals. The presence of facial injury, clutching at the head and slow to get up were the highest ranked sign in 77.7% of non-concussed individuals. CONCLUSIONS: This study suggests that the implementation of a flowchart model could improve timely assessment of concussion, and it identifies the video signs that should trigger automatic removal from play. PMID- 27117709 TI - Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. AB - Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 * 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER negative breast cancer aetiology. All ER-negative loci combined account for ~11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. PMID- 27117716 TI - Potential of the beneficial fungus Trichoderma to enhance ecosystem-service provision in the biofuel grass Miscanthus x giganteus in agriculture. AB - The sterile hybrid grass Miscanthus x giganteus (Mxg) can produce more than 30 t dry matter/ha/year. This biomass has a range of uses, including animal bedding and a source of heating fuel. The grass provides a wide range of other ecosystem services (ES), including shelter for crops and livestock, a refuge for beneficial arthropods, reptiles and earthworms and is an ideal cellulosic feedstock for liquid biofuels such as renewable (drop-in) diesel. In this study, the effects of different strains of the beneficial fungus Trichoderma on above- and below-ground biomass of Mxg were evaluated in glasshouse and field experiments, the latter on a commercial dairy farm over two years. Other ES benefits of Trichoderma measured in this study included enhanced leaf chlorophyll content as well as increased digestibility of the dried material for livestock. This study shows, for the first time for a biofuel feedstock plant, how Trichoderma can enhance productivity of such plants and complements other recent work on the wide-ranging provision of ES by this plant species. PMID- 27117717 TI - Rare presentation of small bowel intussusception in childhood. AB - Small bowel intussusception complicated simultaneously by volvulus in an older child is rare but clinically significant, necessitating urgent operative management. We report a local case of jejuno-jejunal intussusception complicated by volvulus and bowel infarction in a 9-year-old Chinese girl, with diagnosis made on preoperative computed tomography and confirmed at laparotomy. An intestinal polyp as the lead point for intussusception was identified operatively. PMID- 27117718 TI - Hemostatic Techniques for Laparoscopic Management of Cornual Pregnancy: Double Impact Devascularization Technique. PMID- 27117719 TI - Biologic therapies in the treatment of sarcoidosis. AB - Sarcoidosis is a disease of remarkable heterogeneity in organ manifestation, severity and natural history, characterized by the presence of non-caseating granulomas. The majority of cases are acute and self-limited or remit with short courses of glucocorticoids; however, a proportion progress to a life-threatening obliterative fibrotic type associated with significant disability related to pulmonary, cardiac, ocular or central nervous system involvement. Biologic agents have been demonstrated in the successful treatment of refractory organ threatening sarcoidosis; and though sarcoidosis remains elusive in predictability of progression, strong evidence suggests an indisputably efficacious role for these agents in efforts to stave morbidity and mortality related to sarcoidosis. This paper provides a review of sarcoidosis mechanistic etiopathogenesis to highlight the hypothetical underpinnings of the utility and concerns of current biologic treatments in current use and the potential future applications of newer agents and those under development. PMID- 27117720 TI - Cardiac Findings of Pulmonary Thromboembolism by Autopsy: A Review of 48 Cases. AB - BACKGROUND To identify the overall effects of pulmonary thromboembolism (PTE) on the heart, we evaluated the heart findings and clinical characteristics of deceased patients diagnosed with PTE. MATERIAL AND METHODS PTEs were classified into 2 categories: fatal and contributory. Cases with a history of cardiopulmonary disease or a finding of significant disease at autopsy, including valvular heart disease and coronary artery obstruction >50%, were excluded from the cardiac evaluation. We defined an LV wall >=1.2 cm thick and an RV wall >=0.8 cm thick as abnormal. RESULTS Forty-eight cases were included to the study (21 males and 27 females). The mean age was 41.42 +/- 16.5 years. Of the 48 cases, 5 were excluded due to cardiopulmonary diseases for determining heart findings. The thicknesses of the LV and RV walls were not measured in some patients. In the 43 cases, cardiac hypertrophy was detected in 28 patients (65.1%). The mean heart weight was 387 +/- 83.5 g. The mean thickness of the left ventricle (LV) wall was 1.40 +/- 0.41 cm in 40 cases, and the mean thickness of the RV wall was 0.41 +/- 0.135 cm in 41 cases. The LV walls of 35 (87.5%) cases and the RV walls of 2 cases met criteria for abnormal wall thickness. There were histopathological findings of heart in 24/43 cases (56%); these findings were necrosis, fibrosis, and hypertrophy. CONCLUSIONS The RV is affected by massive pulmonary embolism; however, the LV may also play a role in the pathogenesis of PTE. PMID- 27117721 TI - Reversible control of the chromium valence in chemically reduced Cr-doped SrTiO3 bulk powders. AB - The effect of chemical reduction by NaBH4 on the electronic structure of Cr-doped SrTiO3-delta bulk powders prepared by a solid-state reaction was systematically studied as a function of reduction temperature. Electron paramagnetic resonance (EPR) and diffuse reflectance spectroscopies (DRS) were utilized to monitor changes in the electronic structures of both intrinsic defects (oxygen vacancies and/or Ti(3+)) and extrinsic dopants (Cr(3+)) at different reduction temperatures. We identify the existence of two temperature regimes where changes occur within 30 min. The first temperature regime occurs between 300-375 degrees C and results in (1) reduction of oxygen-related surface defects, and (2) an increase in the concentration of Cr(3+) by over an order of magnitude, suggesting that EPR-silent Cr(4+) or Cr(6+) is being reduced to Cr(3+) by NaBH4. The second temperature regime occurs between 375-430 degrees C where we observe clear evidence of Ti(3+) formation by EPR spectroscopy that indicates chemical reduction of the SrTiO3 lattice. In addition, the oxygen-related surface defects observed in regime 1 are not formed in regime 2, but instead lattice oxygen vacancies (VO) are observed by EPR. The changes to the Cr-doped SrTiO3 electronic structure after chemical reduction in regime 1 are quantitatively reversible after aerobic annealing at 400 degrees C for 30 min. The internal oxygen vacancies formed during the higher temperature reductions in regime 2 require increased temperatures of at least 600 degrees C to be fully reoxidized in 30 min. The effect of these different oxygen-related defects on the EPR spectrum of substitutional Cr(3+) dopants is discussed. These results allow us to independently tune the dopant and host electronic structures of a technologically relevant multifunctional material by a simple ex situ chemical perturbation. PMID- 27117722 TI - Vascularized fibular grafts extended with vascularized periosteum in children. AB - PURPOSE: The purpose of this report is to evaluate the results of extending vascularized fibular grafts (VFG) with vascularized periosteum (VPG) in bone defect reconstruction in children. METHODS: Retrospective study of 10 children, mean age at surgery was 9.8 years (range, 4-16 years). Origin of one defect was oncological (n = 5), septical (n = 2), traumatic (n = 2), or congenital (n = 1). In five cases the flap consisted of a VFG and a vascularized epiphyseal transfer (VFET) in five. Mean bone defect was 8.5 cm .Mean length of the vascularized periosteal extension was 5.5 cm (range 3.5-8) for VFET, 4.8 cm for VFG (range 3 8). Bone union was assessed with monthly radiographs. RESULTS: Radiographs showed a periosteal callus at 4 weeks in all cases. Bone union was achieved at a mean of 8.4 weeks (range 4-12). Donor site complications included two cases of flexor hallucis longus contracture, and one case of surgical wound marginal necrosis following FVG. One transient tibialis anterior weakness and one tibialis anterior contracture occurred following VFET harvest. None required surgical treatment. Mean follow-up was 28.7 months (range 7-72). CONCLUSIONS: The association of a vascularized periosteal extension with fibular flaps seems to accelerate flap to recipient bone union. (c) 2016 Wiley Periodicals, Inc. Microsurgery 37:410-415, 2017. PMID- 27117723 TI - Ethnic differences in sudden cardiac arrest resuscitation. AB - OBJECTIVE: Ethnic differences in sudden cardiac arrest resuscitation have not been fully explored and studies have yielded inconsistent results. We examined the association of ethnicity with factors affecting sudden cardiac arrest outcomes. METHODS: Retrospective cohort study of 3551 white, 440 black and 297 Asian sudden cardiac arrest cases in Seattle and King County, Washington, USA. RESULTS: Compared with whites, blacks and Asians were younger, had lower socioeconomic status and were more likely to have diabetes, hypertension and end stage renal disease (all p<0.001). Blacks and Asians were less likely to have a witnessed arrest (whites 57.6%, blacks 52.1%, Asians 46.1%, p<0.001) or receive bystander cardiopulmonary resuscitation (whites 50.9%, blacks 41.4%, Asians 47.1%, p=0.001), but had shorter average emergency medical services response time (mean in minutes: whites 5.18, blacks 4.75, Asians 4.85, p<0.001). Compared with whites, blacks were more likely to be found in pulseless electrical activity (blacks 20.9% vs whites 16.6%, p<0.001), and Asians were more likely to be found in asystole (Asians 41.1% vs whites 30.0%, p<0.001). One of the strongest predictors of resuscitation outcomes was initial cardiac rhythm with 25% of ventricular fibrillation, 4% of patients with pulseless electrical activity and 1% of patients with asystole surviving to hospital discharge (adjusted OR of resuscitation in pulseless electrical activity compared with ventricular fibrillation: 0.30, 95% CI 0.24 to 0.34, p<0.001, adjusted OR of resuscitation in asystole relative to ventricular fibrillation 0.21, 95% CI 0.17 to 0.26, p<0.001). Survival to hospital discharge was similar across all three ethnicities. CONCLUSIONS: While there were differences in some prognostic characteristics between blacks, whites and Asians, we did not detect a significant difference in survival following sudden cardiac arrest between the three ethnic groups. There was, however, an ethnic difference in presenting rhythm, with pulseless electrical activity more prevalent in blacks and asystole more prevalent in Asians. PMID- 27117724 TI - The efficacy of submucosal corticosteroid injection and dilatation in subglottic stenosis of different aetiology. AB - OBJECTIVE: To determine the long-term efficacy of submucosal corticosteroid injection plus dilatation for subglottic stenosis as a single modality treatment in granulomatosis with polyangiitis and relapsing polychondritis, as compared with idiopathic subglottic stenosis and traumatic subglottic stenosis. METHOD: Patients who underwent dilatation for autoimmune causes were identified. Corticosteroid injection into the submucosa of a stenotic segment was followed by serial dilatation. Definitive improvement was defined as good airway patency for more than 24 months with no further procedures needed. Clinical, demographic and procedural data were recorded. RESULTS: Patients (n = 45) were divided into three subglottic stenosis groups: traumatic (n = 24), idiopathic (n = 9) and autoimmune (n = 12). Patients were treated with dilatations, with a median follow-up time of 76 months. Six patients were tracheostomy-dependent. There were no statistical differences in the number of final improvements between autoimmune, idiopathic and traumatic groups, with values of 75, 56 and 71 per cent, respectively. There was no statistical difference between granulomatosis with polyangiitis plus relapsing polychondritis and idiopathic subglottic stenosis in terms of decannulation rates. CONCLUSION: Granulomatosis with polyangiitis and relapsing polychondritis patients have better improvement rates than patients with other subglottic stenosis types. PMID- 27117725 TI - Effectiveness of Acupuncture Therapies to Manage Musculoskeletal Disorders of the Extremities: A Systematic Review. AB - Study Design Systematic review. Background Little is known about the effectiveness of acupuncture therapies for musculoskeletal disorders. Objective To assess the effectiveness and safety of acupuncture therapies for musculoskeletal disorders of the extremities. Methods We searched MEDLINE, Embase, CINAHL, PsycINFO, and Cochrane Central Register of Controlled Trials from 1990 to 2015 for randomized controlled trials, cohort studies, and case-control studies. Eligible studies were appraised with Scottish Intercollegiate Guidelines Network criteria. A best-evidence synthesis was performed to synthesize results from included studies with a low risk of bias. A sensitivity analysis was conducted to determine the impact of excluding studies with a high risk of bias. Results The search revealed 5180 articles; 15 were included (10 with a low risk of bias, 5 with a high risk of bias). The studies with a low risk of bias suggested that (1) traditional needle acupuncture was superior to oral steroids (1 RCT, n = 77) and may be superior to vitamin B1/B6 supplements (1 RCT, n = 64) for carpal tunnel syndrome (CTS), and was superior to exercise for Achilles tendinopathy (1 RCT, n = 64). Traditional needle acupuncture did not provide important benefit over placebo for upper extremity pain (1 RCT, n = 128), or no intervention for patellofemoral pain (1 RCT, n = 75), and was inconclusive for shoulder pain (2 RCTs, n = 849), suggesting no important benefit; (2) electroacupuncture may be superior to placebo for shoulder injuries (1 RCT, n = 130) and may not be superior to night splinting for persistent CTS (1 RCT, n = 78); and (3) dry needling may be superior to placebo for plantar fasciitis (1 RCT, n = 84). Sensitivity analysis suggests that including studies with a high risk of bias might have impacted the evidence synthesis in support of managing shoulder pain with traditional needle acupuncture, and that would suggest traditional needle acupuncture may be effective for lateral epicondylitis and piriformis syndrome. Conclusion Evidence for the effectiveness of acupuncture for musculoskeletal disorders of the extremities was inconsistent. Traditional needle acupuncture may be beneficial for CTS and Achilles tendinopathy, but not for nonspecific upper extremity pain and patellofemoral syndrome. Electroacupuncture may be effective for shoulder injuries and may show similar effectiveness to that of night wrist splinting for CTS. The effectiveness of dry needling for plantar fasciitis is equivocal. Level of Evidence Therapy, 1a-. J Orthop Sports Phys Ther 2016;46(6):409-429. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6270. PMID- 27117726 TI - Does Physical Activity Increase After Total Hip or Knee Arthroplasty for Osteoarthritis? A Systematic Review. AB - Study Design Systematic review. Background Despite improvements in self-reported symptoms and perceived functional ability after total hip arthroplasty (THA) and total knee arthroplasty (TKA), it is unclear whether changes in objectively measured physical activity (PA) occur after surgery. Objective To determine if objectively measured PA increases after THA and TKA in adults with osteoarthritis. Methods Five electronic databases were searched from inception to March 3, 2015. All study designs objectively measuring PA before and after THA or TKA were eligible, including randomized controlled trials, cohort studies, and case-control studies. Two reviewers independently screened abstracts and full texts and extracted study demographic, PA, and clinical outcome data. Standardized mean differences (SMDs) and 95% confidence intervals were calculated for accelerometer- and pedometer-derived estimates of PA. Risk of methodological bias was assessed with Critical Appraisal Skills Programme checklists. Results Eight studies with a total of 373 participants (238 TKA, 135 THA) were included. Findings were mixed regarding improvement in objectively measured PA at 6 months after THA (SMDs, -0.20 to 1.80) and TKA (SMDs, -0.36 to 0.63). Larger improvements from 2 studies at 1 year postsurgery were generally observed after THA (SMDs, 0.39 to 0.79) and TKA (SMDs, 0.10 to 0.85). However, at 1 year, PA levels were still considerably lower than those of healthy controls (THA SMDs, 0.25 to -0.77; TKA SMDs, -1.46 to -1.80). Risk-of-bias scores ranged from 3 to 9 out of 11 (27%-82%) for cohort studies, and from 3 to 8 out of 10 (30%-80%) for case-control studies. Conclusion The best available evidence indicates negligible changes in PA at 6 months after THA or TKA, with limited evidence for larger changes at 1 year after surgery. In the 4 studies that reported control-group data, postoperative PA levels were still considerably less than those of healthy controls. Improved perioperative strategies to instill behavioral change are required to narrow the gap between patient-perceived functional improvement and the actual amount of PA undertaken after THA and TKA. Registered with PROSPERO (registration number CRD42014010155). Level of Evidence Therapy, level 2a. J Orthop Sports Phys Ther 2016;46(6):431-442. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6449. PMID- 27117727 TI - Movement-Pattern Training to Improve Function in People With Chronic Hip Joint Pain: A Feasibility Randomized Clinical Trial. AB - Study Design Feasibility randomized clinical trial. Background Rehabilitation may be an appropriate treatment strategy for patients with chronic hip joint pain; however, the evidence related to the effectiveness of rehabilitation is limited. Objectives To assess feasibility of performing a randomized clinical trial to investigate the effectiveness of movement-pattern training (MPT) to improve function in people with chronic hip joint pain. Methods Thirty-five patients with chronic hip joint pain were randomized into a treatment (MPT) group or a control (wait-list) group. The MPT program included 6 one-hour supervised sessions and incorporated (1) task-specific training for basic functional tasks and symptom provoking tasks, and (2) strengthening of hip musculature. The wait-list group received no treatment. Primary outcomes for feasibility were patient retention and adherence. Secondary outcomes to assess treatment effects were patient reported function (Hip disability and Osteoarthritis Outcome Score), lower extremity kinematics, and hip muscle strength. Results Retention rates did not differ between the MPT (89%) and wait-list groups (94%, P = 1.0). Sixteen of the 18 patients (89%) in the MPT group attended at least 80% of the treatment sessions. For the home exercise program, 89% of patients reported performing their home program at least once per day. Secondary outcomes support the rationale for conduct of a superiority randomized clinical trial. Conclusion Based on retention and adherence rates, a larger randomized clinical trial appears feasible and warranted to assess treatment effects more precisely. Data from this feasibility study will inform our future clinical trial. Level of Evidence Therapy, level 2b-. J Orthop Sports Phys Ther 2016;46(6):452-461. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6279. PMID- 27117728 TI - The Association Between Knee Confidence and Muscle Power, Hop Performance, and Postural Orientation in People With Anterior Cruciate Ligament Injury. AB - Study Design Cross-sectional. Background The association between muscle function and lack of knee confidence in people with anterior cruciate ligament (ACL) injury has not been well investigated. Such knowledge would help in the design of training programs for this population. Objective To investigate associations between self-reported knee confidence and muscle function in patients with ACL injury. Methods Cross-sectional data from 54 patients (mean age, 30 years; range, 20-39 years; 28% women) with ACL injury, treated with training and reconstructive surgery (n = 36) or training only (n = 18), were assessed 3 +/- 1 years after injury. Univariate and multivariable ordinal regression analyses were conducted to test the association between the patient's knee confidence (question 3 from the Knee injury and Osteoarthritis Outcome Score as the dependent variable) and performance on tests of muscle power, hop performance, and postural orientation (test for substitution patterns score) as independent variables (absolute value on the injured leg, and limb symmetry index [LSI; injured leg/uninjured leg * 100] or absolute difference between the injured and uninjured legs). Results Sixteen patients reported no trouble with lack of knee confidence, 24 mild trouble, 10 moderate trouble, and 4 severe or extreme trouble. Univariate analyses revealed significant associations between worse knee confidence and lower (worse) LSIs for knee extension power, vertical jump, and side hop, and worse test for substitution patterns scores. In the multivariable analysis, worse vertical jump LSI (P = .043) and worse side hop LSI (P = .012) significantly accounted for 25% of the variation in perceived knee confidence. Conclusion Between-leg differences during demanding tasks are associated with knee confidence in individuals with ACL injury. J Orthop Sports Phys Ther 2016;46(6):477-482. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6374. PMID- 27117729 TI - Validity and Reliability of a Commercial Fitness Watch for Measuring Running Dynamics. AB - Study Design Validity and reliability study. Background Providing feedback on running mechanics is a common intervention to decrease the risk of injury or to restore running after an injury. Commercially available devices are able to measure running dynamics, such as cadence, ground contact time (GCT), and vertical oscillation (VO), but there is limited evidence on the validity and reliability of these measures. Objective To determine the validity and reliability of measures of cadence, GCT, and VO with a fitness watch compared to a motion-analysis system. Methods Twenty runners ran in 3 conditions: (1) baseline (self-selected speed and cadence), (2) higher cadence, and (3) decreased vertical motion (minimal oscillation). Ten runners also performed an additional baseline running session to measure intrasession reliability. For each condition, the average cadence, GCT, and VO were collected from a watch and from a motion capture system. Intraclass correlation coefficients (ICCs) were used to assess validity between devices. An analysis of variance with 2 repeated measures was used to determine the ability of the watch and motion analysis to detect change in running dynamics. Results The ICCs between the 2 measuring systems were 0.931, 0.963, and 0.749 for cadence, VO, and GCT, respectively (P<.01). The minimal detectable changes at the 95% confidence interval for cadence, VO, and GCT were 2.53 steps per minute, 0.45 cm, and 0.01 seconds, respectively, for the watch. There were no interaction effects, but there was a main effect for condition; both devices detected changes in running dynamics. Conclusion The watch is a valid and reliable tool for detecting changes in cadence, VO, and GCT. J Orthop Sports Phys Ther 2016;46(6):471-476. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6391. PMID- 27117730 TI - The 5- or 10-km Marikenloop Run: A Prospective Study of the Etiology of Running Related Injuries in Women. AB - Study Design Prospective cohort. Background The popularity of running events is still growing, particularly among women; however, little is known about the risk factors for running-related injuries in female runners. Objectives The aims of this study were to determine the incidence and characteristics (site and recurrence) of running-related injuries and to identify specific risk factors for running-related injuries among female runners training for a 5- or 10-km race. Methods Four hundred thirty-five women registered for the Marikenloop run of 5 or 10 km were recruited. Follow-up data were collected over 12 weeks using questionnaires, starting 8 weeks before the event and ending 4 weeks after the event. Two orthopaedic tests (navicular drop test and extension of the first metatarsophalangeal joint) were performed in the 8 weeks before the event. Running-related injuries, defined as running-related pain of the lower back and/or the lower extremity that restricted running for at least 1 day, were assessed at 1-, 2-, and 3-month follow-ups. Results Of 417 female runners with follow-up data (96%), 93 runners (22.3%) reported 109 running-related injuries, mainly of the hip/groin, knee, and lower leg. Multivariable Cox regression analysis showed that a weekly training distance of more than 30 km (hazard ratio = 3.28; 95% confidence interval [CI]: 1.23, 8.75) and a previous running injury longer than 12 months prior (hazard ratio = 1.88; 95% CI: 1.03, 3.45) were associated with the occurrence of running-related injuries. Conclusion Hip/groin, knee, and lower-leg injuries were common among female runners. Only weekly training distance (greater than 30 km) and previous running injury (greater than 12 months prior) were associated with running-related injuries in female runners training for a 5- or 10-km event. Level of Evidence Etiology, 2b. J Orthop Sports Phys Ther 2016;46(6):462-470. Epub 26 Apr 2016. doi:10.2519/jospt.2016.6402. PMID- 27117731 TI - Inactivation of Anisakis simplex L3 in the flesh of white spotted conger (Conger myriaster) by high hydrostatic pressure and its effect on quality. AB - Koreans consume much seafood; the country is surrounded on the east, west and south by the sea. Koreans have eaten raw sashimi for a long time. However, a concern in the raw sea food industry is that the parasitic nematode Anisakis simplex L3 occurs naturally in marine fish. Thus, the fishery industry needs a non-thermal processing method. High hydrostatic pressure (HPP) has been demonstrated to be effective. White spotted conger flesh containing 20 live larvae was exposed to different pressures (150 and 200 MPa for 1 and 5 min; 250 and 300 MPa each for 1 min). The viability of A. simplex L3 was significantly (p < 0.05) reduced in the flesh of white spotted conger by the stepwise increase of high pressure and time. The conditions required to eliminate A. simplex L3 were as follows: 200 MPa for 5 min or 300 MPa for 1 min. The flesh of the white spotted conger treated at 300 MPa for 1 min was whiter and yellower than untreated controls or that treated at 200 MPa for 5 min. No significant changes (p > 0.05) in any of the Hunter colour ('L', 'a' and 'b') values were found after HPP at 200 MPa for 5 min. The fresh treated at 300 MPa for 1 min scored < 4.0 (the defect limit of quality) of flavour, texture and overall acceptability in untrained sensory evaluation using a seven-point hedonic scale. However, the flesh treated at 200 MPa for 5 min scored > 5.0 ('like') for all sensory parameters. This study suggested that HPP at 200 MPa for 5 min could potentially be used for the inactivation of A. simplex L3 in raw fishery food products without any concomitant changes in their colour or sensory qualities. PMID- 27117733 TI - Recognizing Clinical Excellence. PMID- 27117732 TI - Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance. AB - BACKGROUND: The seroclearance of hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B (CHB) is considered to be associated with favourable clinical outcomes. However, previous studies with inconsistent findings reported that hepatocellular carcinoma (HCC) could still develop in those patients. AIM: To establish the proportion of HCC occurrence in CHB patients after HBsAg seroclearance, a systematic review and meta-analysis was performed. METHODS: Databases of Medline, Web of Science and Embase were searched from inception to July 2015. The proportion of patients who developed HCC after HBsAg seroclearance was pooled by a random-effects model. RESULTS: Twenty-eight studies were finally included, involving 34 952 patients with HBsAg seroclearance. The overall pooled proportion suggested that 2.29% (95% CI: 1.19-4.37%) CHB patients would develop HCC despite HBsAg seroclearance. In HBsAg seroclearance patients without cirrhosis and HCV co-infection, the pooled proportion of HCC development was 1.55% (95% CI: 0.92-2.61%). Moreover, patients with cirrhosis or age greater than 50 years at the time of HBsAg seroclearance were at significantly higher risk for HCC development. Nonetheless, the seroclearance of HBsAg was significantly associated with a reduced risk for HCC compared with persistently positive HBsAg (RR = 0.34, 95% CI: 0.20-0.56, P < 0.001). CONCLUSIONS: Despite that HBsAg seroclearance can significantly reduce the risk for HCC, HCC can still develop in a proportion of CHB patient after HBsAg seroclearance. Closer attention should be paid to those patients with established cirrhosis or older age than 50 years at the time of HBsAg seroclearance. PMID- 27117734 TI - Inexpensive Orthodontic Treatment with a Prescription Custom-Base System. PMID- 27117735 TI - Upper-Molar Distalization and the Distal Jet. PMID- 27117737 TI - Immediate Pontic Fabrication Using Flowable Resin. PMID- 27117738 TI - Rapid Canine Retraction by Distraction of the Periodontal Ligament. PMID- 27117736 TI - Translucency, Stain Resistance, and Hardness of Composites Used for Invisalign Attachments. PMID- 27117739 TI - Attachment Beauty Queen: The "Sash" for Rotation Correction of Upper Lateral Incisors. PMID- 27117740 TI - 2016 Eugene L. Gottlieb JCO Student of the Year: Dr. Krystian Jarosz. PMID- 27117741 TI - The Influence of Ionizing Radiation on Exosome Composition, Secretion and Intercellular Communication. AB - A large variety of vesicles is actively secreted into the extracellular space by most type of cells. The smallest nanoparticles (30-120 nm), called exosomes, are known to transport their cargo (nucleic acids, proteins and lipids) between diverse locations in the body. Specific content of exosomes and their influence on recipient cells depends primarily on the type of the secretory (donor) cell, yet several studies highlight the importance of environmental stress on which the donor cells are exposed. Ionizing radiation, which induces damage to DNA and other structures of a target cell, is one of well-recognized stress conditions influencing behavior of affected cells. A few recent studies have evidenced radiationinduced changes in composition of exosomes released from irradiated cells and their involvement in radiation-related communication between cells. Inducible pathways of exosome secretion activated in irradiated cells are regulated by TSAP6 protein (the transmembrane protein tumor suppressor-activated pathway 6), which is transcriptionally regulated by p53, hence cellular status of this major DNA damage response factor affects composition and secretion rate of exosomes released from target cells. Moreover, exosomes released from irradiated cells have been shown to mediate the radiation-induced bystander effect. Understanding radiation-related mechanisms involved in exosome formation and "makeup" of their cargo would shed light on the role of exosomes in systemic response of cells, tissues and organisms to ionizing radiation which may open new perspectives in translational medicine and anticancer-treatment. PMID- 27117742 TI - Limbic encephalitis associated with glutamic acid decarboxylase antibodies in a young adolescent. PMID- 27117743 TI - Protecting enzymatic function through directed packaging into bacterial outer membrane vesicles. AB - Bacteria possess innate machinery to transport extracellular cargo between cells as well as package virulence factors to infect host cells by secreting outer membrane vesicles (OMVs) that contain small molecules, proteins, and genetic material. These robust proteoliposomes have evolved naturally to be resistant to degradation and provide a supportive environment to extend the activity of encapsulated cargo. In this study, we sought to exploit bacterial OMV formation to package and maintain the activity of an enzyme, phosphotriesterase (PTE), under challenging storage conditions encountered for real world applications. Here we show that OMV packaged PTE maintains activity over free PTE when subjected to elevated temperatures (>100-fold more activity after 14 days at 37 degrees C), iterative freeze-thaw cycles (3.4-fold post four-cycles), and lyophilization (43-fold). We also demonstrate how lyophilized OMV packaged PTE can be utilized as a cell free reagent for long term environmental remediation of pesticide/chemical warfare contaminated areas. PMID- 27117744 TI - Synthesis, characterization, and in vitro cytocompatibility of Ga-bioactive glass/polymer hydrogel composites. AB - A bioactive glass series (0.42SiO2-0.10Na2O-0.08CaO-(0.40-x)ZnO-(x)Ga2O3) was incorporated in carboxymethyl cellulose-dextran hydrogels at three different loadings (0.05, 0.10, and 0.25 m2), and the resulting composites were characterized using scanning electron microscopy, physical swelling characteristics, and inductively coupled plasma optical emission spectroscopy. In vitro cytocompatibility was also evaluated for composite extracts in contact with L-929 mouse fibroblasts and MC3T3-E1 human osteoblasts. Scanning electron microscopy confirmed that glass particles were distributed throughout the hydrogels, and swelling studies showed that glass presence can increase the amount of fluid that can be absorbed by the hydrogels after seven days of immersion in phosphate-buffered saline by up to 180%. Several trends were observed in the inductively coupled plasma optical emission spectroscopy data, with the most important being the release of Ga3+ from both Ga-containing glasses at all three loadings, with a maximum of 4.7 mg/L released after 30 days of incubation in phosphate-buffered saline. Cell viability analysis suggested that most composite extracts did not decrease neither fibroblast nor osteoblast viability. These results indicate that it is possible to embed bioactive glass particles into carboxymethyl cellulose-dextran hydrogels, and upon submersion in aqueous media, release ions from the glass particles that may elicit therapeutic effects. PMID- 27117745 TI - Potent antimicrobial and antibiofilm activities of bacteriogenically synthesized gold-silver nanoparticles against pathogenic bacteria and their physiochemical characterizations. AB - The objective of this study was to develop a bimetallic nanoparticle with enhanced antibacterial activity that would improve the therapeutic efficacy against bacterial biofilms. Bimetallic gold-silver nanoparticles were bacteriogenically synthesized using gamma-proteobacterium, Shewanella oneidensis MR-1. The antibacterial activities of gold-silver nanoparticles were assessed on the planktonic and biofilm phases of individual and mixed multi-cultures of pathogenic Gram negative (Escherichia coli and Pseudomonas aeruginosa) and Gram positive bacteria (Enterococcus faecalis and Staphylococcus aureus), respectively. The minimum inhibitory concentration of gold-silver nanoparticles was 30-50 uM than that of other nanoparticles (>100 uM) for the tested bacteria. Interestingly, gold-silver nanoparticles were more effective in inhibiting bacterial biofilm formation at 10 uM concentration. Both scanning and transmission electron microscopy results further accounted the impact of gold silver nanoparticles on biocompatibility and bactericidal effect that the small size and bio-organic materials covering on gold-silver nanoparticles improves the internalization and thus caused bacterial inactivation. Thus, bacteriogenically synthesized gold-silver nanoparticles appear to be a promising nanoantibiotic for overcoming the bacterial resistance in the established bacterial biofilms. PMID- 27117747 TI - Health literacy of mothers accessing child development services: a model of information use. AB - This study aimed to explore how mothers use information in home therapy programs within child development services. A grounded theory study using semistructured interviews was conducted with 14 mothers of children aged 3-6 years accessing occupational therapy, physiotherapy and speech pathology services for developmental needs. A conceptual model of mothers' information use was developed. Findings showed that the mothers went through a cyclical process of information use and decision making: acquisition (collaboration, learning preferences), appraisal (understanding, relevance), application (capacity, resourcefulness) and review (evaluation, modification), with contextual factors including information characteristics, environment, personal characteristics and relationships. Mothers who used information effectively had a sense of confidence, control and mastery, and were empowered to apply information to make decisions and adapt their child's home therapy. This study adds to knowledge about health literacy, specifically how mothers interpret and use health-related information at home. Findings will enable health professionals to address families' unique health literacy needs and empower them to support their child's optimal development, functioning and participation at their stage of life. PMID- 27117746 TI - Semiconductor Electronic Label-Free Assay for Predictive Toxicology. AB - While animal experimentations have spearheaded numerous breakthroughs in biomedicine, they also have spawned many logistical concerns in providing toxicity screening for copious new materials. Their prioritization is premised on performing cellular-level screening in vitro. Among the screening assays, secretomic assay with high sensitivity, analytical throughput, and simplicity is of prime importance. Here, we build on the over 3-decade-long progress on transistor biosensing and develop the holistic assay platform and procedure called semiconductor electronic label-free assay (SELFA). We demonstrate that SELFA, which incorporates an amplifying nanowire field-effect transistor biosensor, is able to offer superior sensitivity, similar selectivity, and shorter turnaround time compared to standard enzyme-linked immunosorbent assay (ELISA). We deploy SELFA secretomics to predict the inflammatory potential of eleven engineered nanomaterials in vitro, and validate the results with confocal microscopy in vitro and confirmatory animal experiment in vivo. This work provides a foundation for high-sensitivity label-free assay utility in predictive toxicology. PMID- 27117748 TI - Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction. AB - Type 5 adenylyl cyclase (AC5) plays an important role in the development of chronic catecholamine stress-induced heart failure and arrhythmia in mice. Epac (exchange protein activated by cAMP), which is directly activated by cAMP independent of protein kinase A, has been recently identified as a novel mediator of cAMP signaling in the heart. However, the role of Epac in AC5-mediated cardiac dysfunction and arrhythmias remains poorly understood. We therefore generated AC5 transgenic mice (AC5TG) with selective disruption of the Epac1 gene (AC5TG Epac1KO), and compared their phenotypes with those of AC5TG after chronic isoproterenol (ISO) infusion. Decreased cardiac function as well as increased susceptibility to pacing-induced atrial fibrillation (AF) in response to ISO were significantly attenuated in AC5TG-Epac1KO mice, compared to AC5TG mice. Increased cardiac apoptosis and cardiac fibrosis were also concomitantly attenuated in AC5TG-Epac1KO mice compared to AC5TG mice. These findings indicate that Epac1 plays an important role in AC5-mediated cardiac dysfunction and AF susceptibility. PMID- 27117750 TI - More Is More: Disentangling the Importance of Ejaculation Frequency. PMID- 27117749 TI - The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results. AB - BACKGROUND: White light (WL) is the established imaging modality for transurethral resection of bladder tumour (TURBT). Narrow band imaging (NBI) is a promising addition. OBJECTIVES: To compare 12-mo recurrence rates following TURBT using NBI versus WL guidance. DESIGN, SETTING, AND PARTICIPANTS: The Clinical Research Office of the Endourological Society (CROES) conducted a prospective randomised single-blind multicentre study. Patients with primary non-muscle invasive bladder cancer (NMIBC) were randomly assigned 1:1 to TURBT guided by NBI or WL. INTERVENTION: TURBT for NMIBC using NBI or WL. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Twelve-month recurrence rates were compared by chi-square tests and survival analyses. RESULTS AND LIMITATIONS: Of the 965 patients enrolled in the study, 481 patients underwent WL-assisted TURBT and 484 patients received NBI-assisted TURBT. Of these, 294 and 303 patients, respectively, completed 12-mo follow-up, with recurrence rates of 27.1% and 25.4%, respectively (p=0.585, intention-to-treat [ITT] analysis). In patients at low risk for disease recurrence, recurrence rates at 12 mo were significantly higher in the WL group compared with the NBI group (27.3% vs 5.6%; p=0.002, ITT analysis). Although TURBT took longer on average with NBI plus WL compared with WL alone (38.1 vs 35.0min, p=0.039, ITT; 39.1 vs 35.7min, p=0.047, per protocol [PP] analysis), lesions were significantly more often visible with NBI than with WL (p=0.033). Frequency and severity of adverse events were similar in both treatment groups. Possible limitations were lack of uniformity of surgical resection, data on smoking status, central pathology review, and specific data regarding adjuvant intravesical instillation therapy. CONCLUSIONS: NBI and WL guidance achieved similar overall recurrence rates 12 mo after TURBT in patients with NMIBC. NBI assisted TURBT significantly reduced the likelihood of disease recurrence in low risk patients. PATIENT SUMMARY: Use of a narrow band imaging technique might provide greater detection of bladder tumours and subsequent treatment leading to reduced recurrence in low-risk patients. PMID- 27117752 TI - Redo Laparoscopic Gastric Bypass: One-Step or Two-Step Procedure? AB - BACKGROUND: The adjustable gastric band (AGB) is a bariatric procedure that used to be widely performed. However, AGB failure-signifying band-related complications or unsatisfactory weight loss, resulting in revision surgery (redo operations)-frequently occurs. Often this entails a conversion to a laparoscopic Roux-en-Y gastric bypass (LRYGB). This can be performed as a one-step or two-step (separate band removal) procedure. METHODS: Data were collected from patients operated from 2012 to 2014 in a single bariatric centre. We compared 107 redo LRYGB after AGB failure with 1020 primary LRYGB. An analysis was performed of the one-step vs. two-step redo procedures. All redo procedures were performed by experienced bariatric surgeons. RESULTS: No difference in major complication rate was seen (2.8 vs. 2.3 %, p = 0.73) between redo and primary LRYGB, and overall complication severity for redos was low (mainly Clavien-Dindo 1 or 2). Weight loss results were comparable for primary and redo procedures. The one-step and two-step redos were comparable regarding complication rates and readmissions. The operating time for the one-step redo LRYGB was 136 vs. 107.5 min for the two-step (median, p < 0.001), excluding the operating time of separate AGB removal (mean 61 min, range 36-110). CONCLUSIONS: Removal of a failed AGB and LRYGB in a one step procedure is safe when performed by experienced bariatric surgeons. However, when erosion or perforation of the AGB occurs, we advise caution and would perform the redo LRYGB as a two-step procedure. Equal weights can be achieved at 1 year post redo LRYGB as after primary LRYGB procedures. PMID- 27117751 TI - Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer. AB - BACKGROUND: The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. OBJECTIVE: To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. DESIGN, SETTING, AND PARTICIPANTS: Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. RESULTS AND LIMITATIONS: Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; p<0.0001), and in biopsy tissue taken before (HS 80, IQR 30-136.3) compared to after (HS 140, IQR 105-167.5; p=0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004-1.020; p=0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. CONCLUSIONS: We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. PATIENT SUMMARY: In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. PMID- 27117753 TI - Desmopressin after cardiac surgery in bleeding patients. A multicenter randomized trial. AB - BACKGROUND: Previous studies showed that desmopressin decreases post-operative blood loss in patients undergoing cardiac surgery. These studies were small and never studied the effect of desmopressin in patients with active bleeding. Objective of the study was to determine whether desmopressin reduces red blood cells transfusion requirements in patients with active bleeding after cardiac surgery who had been pre-treated with tranexamic acid. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study randomized elective patients with bleeding after cardiac surgery despite pre-treatment with tranexamic acid, to receive placebo (saline solution) or a single administration of desmopressin (0.3 MUg/kg in saline solution). The primary endpoint was the number of patients requiring red blood cells transfusion after randomization and during hospital stay. Secondary end points were: blood loss from chest tubes during the first 24 h after study drug administration, hours of mechanical ventilation, intensive care unit stay, and in-hospital mortality. RESULTS: The study was interrupted after inclusion of 67% of the planned patients for futility. The number of patients requiring red blood cells transfusion after randomization was 37/68 (54%) in desmopressin group and 33/67 (49%) in placebo group (P = 0.34) with no difference in blood loss: 575 (interquartile 422-770) ml in desmopressin group and 590 (476-1013) ml in placebo group (P = 0.42), mechanical ventilation, intensive care unit stay or mortality. CONCLUSIONS: This multicenter randomized trial demonstrated that, in patients pre-treated with tranexamic acid, desmopressin should not be expected to improve treatment of patients who experience bleeding after cardiac surgery. PMID- 27117755 TI - Erratum to "Peer-Delivered Recovery Support Services for Addictions in the United States: A Systematic Review" [Journal of Substance Abuse Treatment 63 (2016) 1 9]. PMID- 27117754 TI - Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients. AB - Regorafenib monotherapy is a potential option for metastatic colorectal cancer patients. However, the lack of predictive factors and the severe toxicities related to treatment have made its use in clinical practice challenging. Polymorphisms of VEGF and its receptor (VEGFR) genes might regulate angiogenesis and thus potentially influence outcome during anti-angiogenesis treatment such as regorafenib. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. We retrospectively collected clinical data and samples (tumour or blood) of 138 metastatic colorectal cancer patients treated with regorafenib. We analysed the correlation of different VEGF-A, VEGF-C and VEGFR 1,2,3 single nucleotide polymorphisms (SNPs) with patients' progression-free survival (PFS) and overall survival (OS). Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS. Among clinical factors only ECOG PS was independently correlated with OS, whereas no correlation with PFS was evident. Grouping together those results allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of optimal candidates for regorafenib therapy. PMID- 27117756 TI - Developing a broad categorisation scheme to describe risk factors for mental illness, for use in prevention policy and planning. AB - OBJECTIVES: The prevention of mental illness involves identifying and modifying those characteristics and exposures of an individual that threaten their mental health - commonly referred to as risk factors. Existing categorisations of risk factors for mental illness are either limited in their scope or oversimplified in their description. As part of a large mental health workforce and service planning project, we set out to develop a more detailed and comprehensive categorisation scheme to describe risk factors for mental illness. METHODS: We conducted a rapid review of MEDLINE and Google Scholar for meta-analytic studies that examined the characteristics and exposures that typify the population with mental illness in order to identify and categorise potential risk factors. RESULTS: The search uncovered 1628 relevant studies, from which 10 primary and 23 secondary categories of risk factors were identified, ranging from genetic and biomedical to psychological and sociocultural. The review revealed interesting distortions in the focus of the literature, with the majority of studies focused on a few disorders (schizophrenia, depression and neurodegenerative disorders) and genetic, psychological and physiological risks. In contrast, environmental (e.g. media exposure) and occupational (e.g. employee health) were under represented. CONCLUSION: The categorisation scheme developed in this paper is a step towards a more detailed taxonomy of risk factors for mental illness; this will be most useful in guiding clinicians, researchers and policy-makers in driving the prevention agenda forward. PMID- 27117757 TI - Efficacy of ProTaper NEXT Compared with Reciproc in Removing Obturation Material from Severely Curved Root Canals: A Micro-Computed Tomography Study. AB - INTRODUCTION: The aim of this study was to compare the remaining root canal obturation, volume of dentin removed, and apical transportation after retreatment of severely curved root canals by using Reciproc (REC) or ProTaper NEXT (PTN) systems. METHODS: Twenty-eight mesial canals of mandibular molars were instrumented and then obturated with gutta-percha and sealer and allocated into 2 balanced groups (n = 14), the REC group (R25 file) and the PTN group (X3 and X2 files). Micro-computed tomography analysis was performed to assess the percentage of residual obturation material, the amount of dentin removed, and apical transportation. The effective time for the removal of obturation and procedural errors were recorded. RESULTS: Obturation was effectively removed from the root canal in the REC and PTN groups (P <= .001), and the percentages of remaining obturation material were similar between both groups (84.8% PTN vs 86.5% REC) (P > .05). The amount of dentin removed (3.17 +/- 2.64 mm(3) PTN versus 3.50 +/- 2.82 mm(3) REC), apical transportation (at 1 mm: 0.096 +/- 0.189 mm PTN versus 0.093 +/- 0.186 mm REC; at 3 mm: 0.059 +/- 0.069 mm PTN versus 0.082 +/- 0.080 mm REC; at 5 mm: 0.097 +/- 0.093 mm PTN versus 0.133 +/- 0.138 mm REC), and the working time (269.69 +/- 19.25 seconds PTN versus 268.62 +/- 16.37 seconds REC) were also similar in both groups (P > .05). One file fractured in the REC group. CONCLUSIONS: Both systems were equally effective in the removal of obturation from severely curved canals and can be used for retreatment. Neither system could completely remove the obturation material; therefore, additional techniques are needed to improve cleaning of the root canal. PMID- 27117758 TI - Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. AB - Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance. PMID- 27117760 TI - Impact of definition and procedures used for absent blood culture data on the rate of intravascular catheter infection during parenteral nutrition. AB - BACKGROUND: Diagnosis of intravascular catheter infection may be affected by the definition and procedures applied in the absence of blood culture data. AIM: To examine the extent to which different definitions of catheter infection and procedures for handling absent blood culture data can affect reported catheter infection rates. METHODS: Catheter infection rates were established in a cohort of hospitalized patients administered parenteral nutrition according to three clinical and four published definitions. Paired and unpaired comparisons were made using available case analyses, sensitivity analyses and intention-to categorize analyses. FINDINGS: Complete data were available for each clinical definition (N = 193), and there were missing data (4.1-26.9%) for the published definitions. In an available case analysis, the catheter infection rate was 13.0 36.8% for the clinical definitions and 2.1-12.4% for the published definitions. For the published definitions, the rate was 1.6-32.1% in a sensitivity analysis and 11.4-16.9% in an intention-to-categorize analysis, with suggestion of bias towards a higher catheter infection rate in those with missing data, in keeping with the analyses of the clinical definitions. For paired comparisons, the strength of agreement between definitions varied from 'poor' (Cohen's kappa <0.21) to 'very good' (Cohen's kappa >=0.81). CONCLUSION: The use of different definitions of catheter infection and procedures applied in the absence of blood culture data produced widely different catheter infection rates, which could compromise measurements or comparisons of service quality or study outcome. As such, there is a need to establish and use a valid, consistent and practical definition. PMID- 27117762 TI - Resistance of Mycobacterium tuberculosis to daptomycin. PMID- 27117761 TI - Outbreak of multidrug-resistant Escherichia coli sequence type 131 in a neonatal intensive care unit: efficient active surveillance prevented fatal outcome. AB - BACKGROUND: Outbreaks of infections with multidrug-resistant bacteria in neonatal intensive care units (NICUs) pose a major threat, especially to extremely preterm infants. This study describes a 35-day outbreak of multidrug-resistant Escherichia coli (E. coli) in a tertiary-level NICU in Germany. AIM: To underline the importance of surveillance policies in the particularly vulnerable cohort of preterm infants and to describe the efficacy of outbreak control strategies. METHODS: Data were collected retrospectively from medical reports. Infants and environment were tested for E. coli. FINDINGS: The outbreak affected a total of 13 infants between 25(+1) and 35(+0) weeks of gestation with seven infants showing signs of infection. The outbreak strain was identified as E. coli sequence type 131. Environmental screening provided no evidence for an environmental source. Through colonization surveillance and immediate and adequate treatment of potentially infected preterm infants, no fatalities occurred. Outbreak control was achieved by strict contact precautions, enhanced screening and temporary relocation of the NICU. Relocation and reconstruction improved the NICU's structural layout, focusing on isolation capacities. Follow up indicated carriage for several months in some infants. CONCLUSION: Routine surveillance allowed early detection of the outbreak. The identification of carriers of the outbreak strain was successfully used to direct antibiotic treatment in case of infection. Enhanced hygienic measures and ward relocation were instrumental in controlling the outbreak. PMID- 27117763 TI - Bright YAG:Ce Nanorod Phosphors Prepared via a Partial Wet Chemical Route and Biolabeling Applications. AB - Cerium-doped yttrium aluminum garnet (YAG:Ce) nanorods were prepared via a partial wet chemical route followed by a calcination process by using Al2O3 nanorods as both templates and the reactant. These novel well-crystallized YAG:Ce phosphors with a 200-300 nm diameter and a 2-3 MUm length have a high specific surface area while being virtually devoid of surface defects. The YAG:Ce nanorod phosphors possess good luminescent properties compared with granular YAG:Ce phosphors. Photoluminescence quantum yields of YAG:Ce nanorod phosphors are higher than those of granular ones. The YAG:Ce nanorod phosphors exhibit two luminescent decay times due to their unique morphology. The YAG:Ce nanorods exhibited good cytocompatibility with bone marrow mesenchymal stem cells and can be used as biolabel nanoparticles in bioimaging. PMID- 27117764 TI - Detection of Human Enteric Viruses in Freshwater from European Countries. AB - The transmission of water-borne pathogens typically occurs by a faecal-oral route, through inhalation of aerosols, or by direct or indirect contact with contaminated water. Previous molecular-based studies have identified viral particles of zoonotic and human nature in surface waters. Contaminated water can lead to human health issues, and the development of rapid methods for the detection of pathogenic microorganisms is a valuable tool for the prevention of their spread. The aims of this work were to determine the presence and identity of representative human pathogenic enteric viruses in water samples from six European countries by quantitative polymerase chain reaction (q-PCR) and to develop two quantitative PCR methods for Adenovirus 41 and Mammalian Orthoreoviruses. A 2-year survey showed that Norovirus, Mammalian Orthoreovirus and Adenoviruses were the most frequently identified enteric viruses in the sampled surface waters. Although it was not possible to establish viability and infectivity of the viruses considered, the detectable presence of pathogenic viruses may represent a potential risk for human health. The methodology developed may aid in rapid detection of these pathogens for monitoring quality of surface waters. PMID- 27117765 TI - Recent advances in the treatment of renal diseases with nebivolol: A literature review. AB - Reactive oxygen species play an important role in both acute and chronic kidney diseases. Chronic kidney disease is associated with various consequences to the cardiovascular system and metabolic profiles. Nebivolol, a highly cardioselective third-generation beta-blocker, has nitric oxide (NO) induced vasodilation and antioxidant properties. Nebivolol affects the endothelial NO pathway in two complementary ways: it increases endothelial mediated NO expression and has antioxidant action, which leads to a decrease in degradation. Central blood pressure can be effectively lowered by nebivolol in the prehypertension phase. Clinically nebivolol's ability to modulate endothelial dysfunction may offer additional vascular protection in treating hypertension. As well, pre-treatment with 5mg nebivolol every 24 hours for 4 days is protective against nephrotoxic effects of contrast media. The aim of this study is to review the current literature on the efficacy and safety of nebivolol in the treatment of various states of renal diseases. PMID- 27117767 TI - Results of the essay competition on the 'deficit concept'. PMID- 27117766 TI - [Randall-type monoclonal immunoglobulin deposition disease: From diagnosis to treatment]. AB - Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. MIDD should be suspected in patients presenting with glomerular proteinuria and monoclonal gammopathy, but none of these criteria is necessary for the diagnosis although renal involvement is prominent. Since an abnormal serum kappa/lambda ratio is found in virtually all MIDD patients, including those with HCDD, serum free light chain assay should be included in the initial workup in patients older than 50 presenting with kidney disease. Bortezomib-based regimens are efficient and well tolerated, resulting in improvement in both renal and global survival, comparatively to historical series. High dose melphalan with autologous stem cell transplantation may be proposed as second line therapy in selected patients. The achievement of hematological response, based on the difference between involved and uninvolved serum free light chains (dFLC), is mandatory. In a recent series, post-treatment dFLC<40mg/L was the major predictive factor of renal response and was associated with improvement of both renal and global survival. In MIDD, bortezomib-based therapy is safe and efficient when introduced early after diagnosis. dFLC response is a favorable prognostic factor for renal survival. PMID- 27117759 TI - Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. AB - The influence of diet and environment on human health has been known since ages. Plant-derived natural bioactive compounds (phytochemicals) have acquired an important role in human diet as potent antioxidants and cancer chemopreventive agents. In past few decades, the role of epigenetic alterations such as DNA methylation, histone modifications and non-coding RNAs in the regulation of mammalian genome have been comprehensively addressed. Although the effects of dietary phytochemicals on gene expression and signaling pathways have been widely studied in cancer, the impact of these dietary compounds on mammalian epigenome is rapidly emerging. The present review outlines the role of different epigenetic mechanisms in the regulation and maintenance of mammalian genome and focuses on the role of dietary phytochemicals as epigenetic modifiers in cancer. Above all, the review focuses on summarizing the progress made thus far in cancer chemoprevention with dietary phytochemicals, the heightened interest and challenges in the future. PMID- 27117768 TI - The lure of rationality: Why does the deficit model persist in science communication? AB - Science communication has been historically predicated on the knowledge deficit model. Yet, empirical research has shown that public communication of science is more complex than what the knowledge deficit model suggests. In this essay, we pose four lines of reasoning and present empirical data for why we believe the deficit model still persists in public communication of science. First, we posit that scientists' training results in the belief that public audiences can and do process information in a rational manner. Second, the persistence of this model may be a product of current institutional structures. Many graduate education programs in science, technology, engineering, and math (STEM) fields generally lack formal training in public communication. We offer empirical evidence that demonstrates that scientists who have less positive attitudes toward the social sciences are more likely to adhere to the knowledge deficit model of science communication. Third, we present empirical evidence of how scientists conceptualize "the public" and link this to attitudes toward the deficit model. We find that perceiving a knowledge deficit in the public is closely tied to scientists' perceptions of the individuals who comprise the public. Finally, we argue that the knowledge deficit model is perpetuated because it can easily influence public policy for science issues. We propose some ways to uproot the deficit model and move toward more effective science communication efforts, which include training scientists in communication methods grounded in social science research and using approaches that engage community members around scientific issues. PMID- 27117769 TI - In science communication, why does the idea of the public deficit always return? Exploring key influences. AB - Despite mounting criticism, the deficit model remains an integral part of science communication research and practice. In this article, I advance three key factors that contribute to the idea of the public deficit in science communication, including the purpose of science communication, how communication processes and outcomes are conceptualized, and how science and scientific knowledge are defined. Affording science absolute epistemic privilege, I argue, is the most compelling factor contributing to the continued use of the deficit model. In addition, I contend that the deficit model plays a necessary, though not sufficient, role in science communication research and practice. Areas for future research are discussed. PMID- 27117770 TI - In science communication, why does the idea of a public deficit always return? How do the shifting information flows in healthcare affect the deficit model of science communication? AB - The healthcare field contains a multitude of opportunities for science communication. Given the many stakeholders dancing together in a multidirectional tango of communication, we need to ask how much does the deficit model apply to the health field? History dictates that healthcare professionals are the holders of all knowledge, and the patients and other stakeholders are the ones that need the scientific information communicated to them. This essay argues otherwise, in part due to the rise of shared decision-making and patients and other stakeholders acting as partners in healthcare. The traditional deficit model in health held that: (1) doctors were experts and patients were consumers, (2) it is impossible for the public to grasp the many disciplines of knowledge in medicine, (3) if experts have trouble keeping up with medical research then the public surely can't keep up, and (4) it is safer for healthcare professionals to communicate to the public using a deficit model. However, with the rise of partnerships with patients in healthcare decision-making, the deficit model might be weakening. Examples of public participation in healthcare decision-making include: (1) crowd-sourcing public participation in systematic reviews, (2) public participation in health policy, (3) public collaboration in health research, and (4) health consumer groups acting as producers of health information. With the challenges to the deficit model in science communication in health, caution is needed with the increasing role of technology and social media, and how these may affect the legitimacy of healthcare information flows away from the healthcare professional. PMID- 27117771 TI - In science communication, why does the idea of a public deficit always return? AB - For centuries, science communication has been widely perceived, irrespective of context, as a didactic enterprise. That understanding does not accommodate a political category of science communication, featuring citizens on an equal footing - some of them scientists - who share responsibility for public affairs and represent different points of view and ways of reasoning. That may harm, at the same time and for the same reasons, democratic knowledge societies as political entities and science as a body of knowledge and rational methodology. Scientists are discursively excluded from the public. The public is perceived in terms of knowledge deficiency. The latter perception has survived decades of critique, accompanied by attempts, along an everyman-as-scientist logic, to include all citizens in the scientific endeavour. But why should all be scientists? With respect to practical-political issues - as distinct from technical-scientific ones - the acknowledgement of the citizenship of scientists seems more relevant. Only, this would challenge the widespread understanding of science as an all-purpose problem solver and the consequent ideas of politics. PMID- 27117772 TI - In science communication, why does the idea of a public deficit always return? The eternal recurrence of the public deficit. AB - After several years of loud and clear rejection, the idea of a public cognitive deficit insistently reappears in the agenda of Science Communication and Public Understanding of Science studies. This essay addresses two different kinds of reason - practical and epistemic - converging at that point. In the first part, it will be argued that the hypothesis of the lack of knowledge among laypeople and its controversial relationships with their interests and attitudes towards science prevails because it is an intuitive and optimistic way to frame the gap between science and society and, therefore, to cope with its causes and consequences. In the second part, a deeper level of reasons will be examined, in order to show that the persistence of the idea has its roots in the objective epistemic asymmetry between scientists and the public, the scope of which is not always properly judged. To recognize this asymmetry as a previous condition for their interactions may help to surpass the byzantine debate: deficit yes or no and open up original questions for the field, summarized in the closing remarks. PMID- 27117773 TI - In science communication, why does the idea of a public deficit always return? AB - Taking Isabelle Stengers' "ecology of practices" as an inspiration, the author answers the question animating the essay competition in four ways, each (it is hoped) generating progressively more inter+est between the communities concerned. PMID- 27117775 TI - Photoperiodic and thermosensory pathways interact through CONSTANS to promote flowering at high temperature under short days. AB - Plants detect changes in day length to induce seasonal patterns of flowering. The photoperiodic pathway accelerates the flowering of Arabidopsis thaliana under long days (LDs) whereas it is inactive under short days (SDs), resulting in delayed flowering. This delay is overcome by exposure of plants to high temperature (27 degrees C) under SDs (27 degrees C-SD). Previously, the high temperature flowering response was proposed to involve either the impaired activity of MADS-box transcription factor (TF) floral repressors or PHYTOCHROME INTERACTING FACTOR 4 (PIF4) TF-mediated activation of FLOWERING LOCUS T (FT), which encodes the output signal of the photoperiodic pathway. We integrate these observations by studying several PIFs, the MADS-box SHORT VEGETATIVE PHASE (SVP) and the photoperiodic pathway under 27 degrees C-SD. We find that the mRNAs of FT and its paralogue TWIN SISTER OF FT (TSF) are increased at dusk under 27 degrees C-SD compared with 21 degrees C-SD, and that this requires PIF4 and PIF5 as well as CONSTANS (CO), a TF that promotes flowering under LDs. The CO and PIF4 proteins are present at dusk under 27 degrees C-SD, and they physically interact. Although Col-0 plants flower at similar times under 27 degrees C-SD and 21 degrees C-LD the expression level of FT is approximately 10-fold higher under 21 degrees C-LD, suggesting that responsiveness to FT is also increased under 27 degrees C-SD, perhaps as a result of the reduced activity of SVP in the meristem. Accordingly, only svp-41 ft-10 tsf-1 plants flowered at the same time under 21 degrees C-SD and 27 degrees C-SD. Thus, we propose that under non-inductive SDs, elevated temperatures increase the activity and sensitize the response to the photoperiod pathway. PMID- 27117776 TI - Autologous plasma and its supporting role in fat graft survival: A relevant vector to counteract resorption in lipofilling. AB - Fat grafting has become a widespread technique for different reconstructive and esthetic purposes. However, the disadvantage of fat grafting is the unpredictable resorption rate that often necessitates repetitive procedures, which in turn may have an impact on the morbidity. During the immediate, post-graft, ischemic period, cells survive due to the process of plasmatic imbibition. This biological phenomenon precedes the ingrowth of neo-capillaries that eventually nourish the graft and help establish a long-term homeostatic equilibrium. Both partners, the graft and the recipient bed, contribute to the revascularization process. Hypothetically, enrichment of the recipient site with autologous plasma could have a beneficial role to enhance fat graft survival. We investigated whether plasma supported the viability of the lipoaspirate (LA) material. Plasma was isolated from blood samples collected from eight patients during the elective lipofilling procedures. An in vitro study assessed the viability of LA cells using plasma as a culture medium compared to the traditional culture media. In vitro analysis confirmed sustained viability of LA cells compared to the standard media and control media during 7 consecutive days. The behavior of the fat grafts in plasma showed similarities with those incubated in the traditional culture media. In future, these findings could be translated to a clinical setting. Plasma is the only autologous substrate available in large quantities in the human body. The addition of the supporting agents, such as plasma, could contribute to a better graft survival with more stable clinical outcomes in the long term. The rationale behind the technique is based on the phenomenon of plasmatic imbibition and the reasoning that the extracellular matrix plays a pivotal role in cellular survival. PMID- 27117777 TI - Photoenergy storage and power amplification strategy in membrane-less photoelectrochemical biofuel cells. AB - The photoelectrochemical biofuel cell (PBFC) has drawn great attention because of its potential in the conversion of both photoenergy and chemical energy from biomass into electricity. Herein, we proposed a novel integrated PBFC by insetting a third electrode with high efficiency energy storage and release between the bioelectrode and the photoelectrode, resulting in a higher power output than that of the original PBFC. PMID- 27117778 TI - Tailoring of Electron-Collecting Oxide Nanoparticulate Layer for Flexible Perovskite Solar Cells. AB - Low-temperature-processed perovskite solar cells (PSCs), especially those fabricated on flexible substrates, exhibit device performance that is worse than that of high-temperature-processed PSCs. One of the main reasons for the inferior performance of low-temperature-processed PSCs is the loss of photogenerated electrons in the electron collection layer (ECL) or related interfaces, i.e., indium tin oxide/ECL and ECL/perovskite. Here, we report that tailoring of the energy level and electron transporting ability in oxide ECLs using Zn2SnO4 nanoparticles and quantum dots notably minimizes the loss of photogenerated electrons in the low-temperature-fabricated flexible PSC. The proposed ECL with methylammonium lead halide [MAPb(I0.9Br0.1)3] leads to fabrication of significantly improved flexible PSCs with steady-state power conversion efficiency of 16.0% under AM 1.5G illumination of 100 mW cm(-2) intensity. These results provide an effective method for fabricating high-performance, low temperature solution-processed flexible PSCs. PMID- 27117779 TI - Mimicry for all modalities. AB - Mimicry is a canonical example of adaptive signal design. In principle, what constitutes mimicry is independent of the taxonomic identity of the mimic, the ecological context in which it operates, and the sensory modality through which it is expressed. However, in practice the study of mimicry is inconsistent across research fields, with theoretical and empirical advances often failing to cross taxonomic and sensory divides. We propose a novel conceptual framework whereby mimicry evolves if a receiver perceives the similarity between a mimic and a model and as a result confers a selective benefit onto the mimic. Here, misidentification and/or deception are no longer formal requirements, and mimicry can evolve irrespective of the underlying proximate mechanisms. The centrality of receiver perception in this framework enables us to formally distinguish mimicry from perceptual exploitation and integrate mimicry and multicomponent signalling theory for the first time. In addition, it resolves inconsistencies in our understanding of the role of learning in mimicry evolution, and shows that imperfect mimicry is expected to be the norm. Mimicry remains a key model for understanding signal evolution and cognition, and we recommend the adoption of a unified approach to stimulate future interdisciplinary developments in this fascinating area of research. PMID- 27117780 TI - Acanthamoeba Keratitis among Rigid Gas Permeable Contact Lens Wearers in the United States, 2005 through 2011. AB - PURPOSE: To describe the clinical presentation and outcomes of Acanthamoeba keratitis (AK) in rigid gas permeable (RGP) contact lens wearers and to identify modifiable risk factors. DESIGN: Case-control investigation. PARTICIPANTS: Patients were RGP contact lens-wearing United States residents with a diagnosis of AK from 2005 through 2011. Controls were RGP contact lens wearers with no history of AK who were at least 12 years of age. METHODS: Patients were identified during 2 multistate AK outbreak investigations. Controls from the first investigation in 2007 were identified using a reverse address directory. In the second investigation, controls were recruited from participating ophthalmology and optometry practices. Patients and controls were interviewed by phone using a standardized questionnaire. Odds ratios (ORs) and Fisher exact P values were calculated to assess risk factors associated with infection. MAIN OUTCOME MEASURES: Acanthamoeba keratitis, a rare eye disease primarily affecting contact lens wearers, is caused by free-living amebae, Acanthamoeba species. RESULTS: We identified 37 patients in the 2 investigations, 10 (27%) from the 2007 investigation and 27 (73%) from 2011. There were 17 healthy controls, 9 (53%) from 2007 and 8 (47%) from 2011. Among patients, 9 (24%) wore RGP lenses for orthokeratology or therapeutic indication; no controls wore RGP lenses for these indications. Significant risk factors for AK were wearing lenses for orthokeratology (OR, undefined; P = 0.02), sleeping while wearing lenses (OR, 8.00; P = 0.04), storing lenses in tap water (OR, 16.00; P = 0.001), and topping off contact lens solution in the case (OR, 4.80; P = 0.01). After stratifying by use of RGP lenses for orthokeratology, storing lenses in tap water and topping off remained significant exposures. CONCLUSIONS: Nearly one quarter of patients were orthokeratology wearers. Using tap water to store RGP lenses and topping off solution in the lens case were modifiable risk behaviors identified in RGP wearers who wore lenses for both orthokeratology and nonorthokeratology indications. Rigid gas permeable wearers should avoid exposing their lenses to tap water and should empty their cases and use fresh lens solution each time they take out their lenses. PMID- 27117781 TI - African Descent and Glaucoma Evaluation Study (ADAGES): Racial Differences in Optic Disc Hemorrhage and Beta-Zone Parapapillary Atrophy. AB - PURPOSE: To investigate the differences in the frequency of optic disc hemorrhage (DH) and prevalence of beta-zone parapapillary atrophy (betaPPA) between individuals of African descent (AD) and European descent (ED). DESIGN: Prospective, multicenter, observational cohort. PARTICIPANTS: A total of 1950 eyes of 1172 participants of the African Descent and Glaucoma Evaluation Study (ADAGES). METHODS: Stereoscopic disc photographs of subjects with and without glaucomatous optic neuropathy (GON) followed during the first 13 years of the ADAGES underwent masked review searching for DH and betaPPA. A total of 928 eyes (non-GON, 581; GON, 347) of 551 AD patients (non-GON, 334; GON, 217) and 1022 eyes (non-GON, 568; GON, 454) of 611 ED patients (non-GON, 334; GON, 277) were included. We compared the number of eyes with detected DH at any time during follow-up and eyes with betaPPA between the AD and ED groups. The analyses were then adjusted for clinical parameters using multivariable logistic regression. MAIN OUTCOME MEASURES: Differences in frequency of DH and prevalence of betaPPA. RESULTS: A total of 9395 stereoscopic disc photographs were reviewed. More ED eyes experience DH than AD eyes (49/1022 [4.8%] vs. 10/928 eyes [1.1%], respectively; P < 0.001), whereas betaPPA had higher prevalence in AD eyes (675 eyes [72%] vs. 659 eyes [64%]; P < 0.001). In the final multivariable model, after controlling for confounders, AD eyes were less likely to have at least 1 detected DH than ED eyes (odds ratio [OR], 0.21; 95% CI, 0.10-0.45; P < 0.001) but were more likely to have betaPPA than ED eyes (OR, 1.55; 95% CI, 1.12-2.14; P = 0.008). CONCLUSIONS: Subjects of ED are at higher risk for developing DH compared with AD subjects, whereas AD subjects have greater prevalence of betaPPA. These findings suggest that there are structural differences within the optic nerve complex between these groups. Further research is needed to determine whether racial differences in the frequency of DH and prevalence of betaPPA affect the likelihood of glaucomatous progression. PMID- 27117782 TI - Cyclic AMP Signaling through Epac Axis Modulates Human Hemogenic Endothelium and Enhances Hematopoietic Cell Generation. AB - Hematopoietic cells emerge from hemogenic endothelium in the developing embryo. Mechanisms behind human hematopoietic stem and progenitor cell development remain unclear. Using a human pluripotent stem cell differentiation model, we report that cyclic AMP (cAMP) induction dramatically increases HSC-like cell frequencies. We show that hematopoietic cell generation requires cAMP signaling through the Exchange proteins activated by cAMP (cAMP-Epac) axis; Epac signaling inhibition decreased both hemogenic and non-hemogenic endothelium, and abrogated hematopoietic cell generation. Furthermore, in hematopoietic progenitor and stem like cells, cAMP induction mitigated oxidative stress, created a redox-state balance, and enhanced C-X-C chemokine receptor type 4 (CXCR4) expression, benefiting the maintenance of these primitive cells. Collectively, our study provides insights and mechanistic details on the previously unrecognized role of cAMP signaling in regulating human hematopoietic development. These findings advance the mechanistic understanding of hematopoietic development toward the development of transplantable human hematopoietic cells for therapeutic needs. PMID- 27117783 TI - Basal Progenitors Contribute to Repair of the Prostate Epithelium Following Induced Luminal Anoikis. AB - Contact with the extracellular matrix is essential for maintenance of epithelial cells in many tissues, while in its absence epithelial cells can detach and undergo anoikis. Here, we show that anoikis of luminal cells in the prostate epithelium is followed by a program of tissue repair that is mediated in part by differentiation of basal epithelial cells to luminal cells. We describe a mouse model in which inducible deletion of E-cadherin in prostate luminal cells results in their apoptotic cell death by anoikis, in the absence of phenotypic effects in the surrounding stroma. Quantitative assessments of proliferation and cell death in the luminal and basal compartments indicate that basal cells can rapidly generate luminal cells. Thus, our findings identify a role for basal-to-luminal differentiation in prostate epithelial repair, and provide a normal context to analogous processes that may occur during prostate cancer initiation. PMID- 27117784 TI - A Subpopulation of Label-Retaining Cells of the Kidney Papilla Regenerates Injured Kidney Medullary Tubules. AB - To determine whether adult kidney papillary label-retaining cells (pLRCs) are specialized precursors, we analyzed their transcription profile. Among genes overexpressed in pLRCs, we selected candidate genes to perform qPCR and immunodetection of their encoded proteins. We found that Zfyve27, which encodes protrudin, identified a subpopulation of pLRCs. With Zfyve27-CreERT2 transgenic and reporter mice we generated bitransgenic animals and performed cell-lineage analysis. Post tamoxifen, Zfyve27-CreERT2 marked cells preferentially located in the upper part of the papilla. These cells were low cycling and did not generate progeny even after long-term observation, thus they did not appear to contribute to kidney homeostasis. However, after kidney injury, but only if severe, they activated a program of proliferation, migration, and morphogenesis generating multiple and long tubular segments. Remarkably these regenerated tubules were located preferentially in the kidney medulla, indicating that repair of injury in the kidney is regionally specified. These results suggest that different parts of the kidney have different progenitor cell pools. PMID- 27117785 TI - Comparative miRNA-Based Fingerprinting Reveals Biological Differences in Human Olfactory Mucosa- and Bone-Marrow-Derived Mesenchymal Stromal Cells. AB - Previously we reported that nestin-positive human mesenchymal stromal cells (MSCs) derived from the olfactory mucosa (OM) enhanced CNS myelination in vitro to a greater extent than bone-marrow-derived MSCs (BM-MSCs). miRNA-based fingerprinting revealed the two MSCs were 64% homologous, with 26 miRNAs differentially expressed. We focused on miR-146a-5p and miR-140-5p due to their reported role in the regulation of chemokine production and myelination. The lower expression of miR-140-5p in OM-MSCs correlated with higher secretion of CXCL12 compared with BM-MSCs. Addition of CXCL12 and its pharmacological inhibitors to neural co-cultures supported these data. Studies on related miR 146a-5p targets demonstrated that OM-MSCs had lower levels of Toll-like receptors and secreted less pro-inflammatory cytokines, IL-6, IL-8, and CCL2. OM-MSCs polarized microglia to an anti-inflammatory phenotype, illustrating potential differences in their inflammatory response. Nestin-positive OM-MSCs could therefore offer a cell transplantation alternative for CNS repair, should these biological behaviors be translated in vivo. PMID- 27117786 TI - [Satisfaction of principal caregivers of patients followed-up by palliative care teams]. AB - OBJECTIVE: To determine the satisfaction of main caregivers of deceased patients followed-up by palliative care teams. METHOD: Web research on electronic data bases: PubMed and MEDES, using "Palliative Care" and "Patient Satisfaction" as main descriptors, and "Family", "Professional-Family Relations", "Quality of Health Care" and "Quality Assurance, Health Care" as secondary descriptors. Studies written in Spanish and English were included. RESULTS: Profile of principal caregiver: a woman between her mid-forties and her mid-fifties, usually related with the patient as a daughter, and of primary educational level. The items that the main caregivers valued the most were: a kind manner, feeling free to ask questions about problems during the process, tactful explanations, receiving information, pain management, time for answering questions, interest for emotional problems, and information about treatment. The worse valued items were: symptoms control, lack of psychological support after death, preparation for a death of a relative, keeping in touch after death, help to resolve outstanding issues, and help during grief. In general, a great majority of palliative care teams achieved excellent results. CONCLUSION: In spite of the good results obtained in satisfaction surveys from caregivers with regard to palliative care teams, it is essential to improve the quality of scientific technical training (both from the medical and the psychological point of view), as well as to improve communicational skills among palliative care staff. PMID- 27117787 TI - [Cardiotoxicity. A reality that the primary care physician should be aware]. PMID- 27117788 TI - [The eternal problem of false positives in mammography screening]. PMID- 27117789 TI - Yamadazyma endophytica f.a. sp. nov., an ascomycetous yeast species isolated from leaf tissue. AB - Strain DMKU-CE23T representing a novel yeast species was isolated from tissue of a corn leaf (Zea may L.) collected in Thailand. A phylogenetic analysis based on the combined sequences of the internal transcribed spacer (ITS) region and the D1/D2 region of the LSU rRNA gene indicated that strain DMKU-CE23T belongs to the Yamadazyma clade and is clearly distinct from other related species. It therefore represents a novel species of the genus Yamadazyma although the formation of ascospores was not observed. The strain of novel species was most closely related to the type strain of Yamadazyma epiphylla but with 5.1 % nucleotide substitutions in the ITS region and 3.7 % nucleotide substitutions in the D1/D2 region of the LSU rRNA gene. The name Yamadazyma endophytica f.a., sp. nov. is proposed. The type strain is DMKU-CE23T (=CBS 14163T=TBRC 5174T). PMID- 27117790 TI - The survival impact of plasma to red blood cell ratio in massively transfused non trauma patients. AB - PURPOSE: High ratios of Plasma to Packed Red Blood Cells (FFP:PRBC) improve survival in massively transfused trauma patients. We hypothesized that non-trauma patients also benefit from this transfusion strategy. METHODS: Non-trauma patients requiring massive transfusion from November 2003 to September 2011 were reviewed. Logistic regression was performed to identify independent predictors of mortality. The population was stratified using two FFP:PRBC ratio cut-offs (1:2 and 1:3) and adjusted mortality derived. RESULTS: Over 8 years, 29 % (260/908) of massively transfused surgical patients were non-trauma patients. Mortality decreased with increasing FFP:PRBC ratios (45 % for ratio <=1:8, 33 % for ratio >1:8 and <=1:3, 27 % for ratio >1:3 and <=1:2 and 25 % for ratio >1:2). Increasing FFP:PRBC ratio independently predicted survival (AOR [95 % CI]: 1.91 [1.35-2.71]; p < 0.001). Patients achieving a ratio >1:3 had improved survival (AOR [95 % CI]: 3.24 [1.24-8.47]; p = 0.016). CONCLUSION: In non-trauma patients undergoing massive transfusion, increasing FFP:PRBC ratio was associated with improved survival. A ratio >1:3 significantly improved survival probability. PMID- 27117791 TI - The nutritional state of children and adolescents with cerebral palsy is associated with oral motor dysfunction and social conditions: a cross sectional study. AB - BACKGROUND: Cerebral palsy (CP) is the main cause of severe physical impairment during childhood and has commonly shown oral motor association. It has been considered as the main cause of the high prevalence of problems in children's nutrition. Respiration, chewing, swallowing, speaking and facial expressionare part of the orofacial motor functions and when affected they can interfere in children's well-being. The aim of this study was to correlate two methods of orofacial motor evaluation, analyze the influence of orofacial motor functional impairment on the nutritional status of children and adolescents with CP, and the association between socioeconomic factors. METHODS: Seventy children and adolescents with CP were selected, age range 6-16 years and following the exclusion criteria previously determined; 129 normoreactive children (control group), sex and age-matched to patients with CP. For the orofacial motor analysis two evaluation instruments were applied, the "Oral Motor Assessment Scale" (OMAS) and "Nordic Orofacial Test-Screening" (NOT-S). The anthropometric evaluation was based on the World Health Organization (WHO) and followed the criteria recommended by the Brazilian Ministry of Health. RESULTS: There was statistically significant correlation between the oral motor methods of evaluation (r = -0.439, p < 0.0001). Concerning the nutritional status evaluation, being overweight was associated with dystonic and mixed CP forms variables (p = 0.034), mother with no partnership (p = 0.045) and mild oral motor impairment (p = 0.028). CONCLUSION: It could be concluded that, the weight's gain by children and adolescents might be favored by a better functional oral motor performance and social factors. PMID- 27117792 TI - Nutritional quality assessment of tomato fruits after exposure to uncoated and citric acid coated cerium oxide nanoparticles, bulk cerium oxide, cerium acetate and citric acid. AB - Little is known about the effects of surface modification on the interaction of nanoparticles (NPs) with plants. Tomato (Solanum lycopersicum L.) plants were cultivated in potting soil amended with bare and citric acid coated nanoceria (nCeO2, nCeO2+CA), cerium acetate (CeAc), bulk cerium oxide (bCeO2) and citric acid (CA) at 0-500 mg kg-1. Fruits were collected year-round until the harvesting time (210 days). Results showed that nCeO2+CA at 62.5, 250 and 500 mg kg-1 reduced dry weight by 54, 57, and 64% and total sugar by 84, 78, and 81%. At 62.5, 125, and 500 mg kg-1 nCeO2+CA decreased reducing sugar by 63, 75, and 52%, respectively and at 125 mg kg-1 reduced starch by 78%, compared to control. The bCeO2 at 250 and 500 mg kg-1, increased reducing sugar by 67 and 58%. In addition, when compared to controls, nCeO2 at 500 mg kg-1 reduced B (28%), Fe (78%), Mn (33%), and Ca (59%). At 125 mg kg-1 decreased Al by 24%; while nCeO2+CA at 125 and 500 mg kg-1 increased B by 33%. On the other hand, bCeO2 at 62.5 mg kg 1 increased Ca (267%), but at 250 mg kg-1 reduced Cu (52%), Mn (33%), and Mg (58%). Fruit macromolecules were mainly affected by nCeO2+CA, while nutritional elements by nCeO2; however, all Ce treatments altered, in some way, the nutritional quality of tomato fruit. To our knowledge, this is the first study comparing effects of uncoated and coated nanoceria on tomato fruit quality. PMID- 27117793 TI - Vasculogenic potential evaluation of bottom-up, PCL scaffolds guiding early angiogenesis in tissue regeneration. AB - Vascularization is a key factor in the successful integration of tissue engineered (TE) grafts inside the host body. Biological functions of the newly formed tissue depend, in fact, on a reliable and fast spread of the vascular network inside the scaffold. In this study, we propose a technique for evaluating vascularization in TE constructs assembled by a bottom-up approach. The rational, ordered assembly of building blocks (BBs) into a 3D scaffold can improve vessel penetration, and-unlike most current technologies-is compatible with the insertion of different elements that can be designed independently (e.g. structural units, growth factor depots etc.). Poly(epsilon-caprolactone) scaffolds composed of orderly and randomly assembled sintered microspheres were used to assess the degree of vascularization in a pilot in vivo study. Scaffolds were implanted in a rat subcutaneous pocket model, and retrieved after 7 days. We introduce three quantitative factors as a measure of vascularization: the total percentage of vascularization, the vessels diameter distribution and the vascular penetration depth. These parameters were derived by image analysis of microcomputed tomographic scans of biological specimens perfused with a radiopaque polymer. The outcome of this study suggests that the rational assembly of BBs helps the onset and organization of a fully functional vascular network. PMID- 27117794 TI - Dissolution and drug release profiles of phosphate glasses doped with high valency oxides. AB - This paper investigates phosphate glasses incorporating vanadium and molybdenum oxides for effective management of dissolution and drug release. These glass formulations are found to reduce the rate of dissolution from the glass surfaces. The drug functional groups of vancomycin molecules loaded by immersion showed stronger hydrogen bonding with Vanadium doped glasses and consequently lower rate of drug release over 2 weeks indicating better surface attachment with the drug molecules and slow drug release profiles. This can be explained by the strong adherence of drug molecules to glass surfaces compared with the molybdenum containing glasses (PM5 and PM10). The strong attachment relates to hydrogen bonding between the amino-functional groups of vancomycin and the hydrated P-O-H groups in the glass network. In conclusion, the rate of dissolution of doped glasses and the rate of drug release can be administered to deliver the drug molecules over weeks. PMID- 27117795 TI - Children Who Use Communication Aids Instructing Peer and Adult Partners During Play-Based Activity. AB - Little is known about how children with severe motor impairments who use communication aids provide instructions when given control over interaction. In this study, 35 children - 18 who used communication aids and 17 who used natural speech - were videotaped in play-based activities. Both groups successfully instructed partners to build replications of models the partners could not see. The results demonstrate that children using communication aids can also have an active role in play-based activities using language, but that their experience with activities may be limited and their instructions may take longer to give. The children who used natural speech provided more detailed instructions and were more successful in guiding their partners. Creating opportunities for active participation in play may be important for the development of communicative autonomy. PMID- 27117796 TI - Melding the Old with the New: Trends in Methods Used to Identify, Monitor, and Control Microorganisms on Cultural Heritage Materials. AB - Microbial activity has an important impact on the maintenance of cultural heritage materials, owing to the key role of microorganisms in many deterioration processes. In order to minimize such deleterious effects, there is a need to fine tune methods that detect and characterize microorganisms. Trends in microbiology indicate that this need can be met by incorporating modern techniques. All of the methods considered in this review paper are employed in the identification, surveillance, and control of microorganisms, and they have two points in common: They are currently used in microbial ecology (only literature from 2009 to 2015 is included), and they are often applied in the cultural heritage sector. More than 75 peer-reviewed journal articles addressing three different approaches were considered: molecular, sensory and morphological, and biocontrol methods. The goal of this review is to highlight the usefulness of the traditional as well as the modern methods. The general theme in the literature cited suggests using an integrated approach. PMID- 27117797 TI - Relative Importance of Individual Climatic Drivers Shaping Arbuscular Mycorrhizal Fungal Communities. AB - The physiological tolerance hypothesis (PTH) postulates that it is the tolerance of species to climatic factors that determines overall community richness. Here, we tested whether a group of mutualistic microbes, Glomeromycota, is distributed in semi-arid environments in ways congruent with the PTH. For this purpose, we modeled with climatic predictors the niche of each of the four orders of Glomeromycota and identified predictors of arbuscular mycorrhizal (AM) fungal operational taxonomic unit (OTU) richness. Our dataset consisted of 50 paired grassland and farmland sites in the farming-pastoral ecotone of northern China. We observed shifts in the relative abundance of AM fungal orders in response to climatic variables but also declines in OTU richness in grassland sites that had experienced high precipitation during the preceding year which was incongruous with the PTH. We found pronounced differences across groups of Glomeromycotan fungi in their responses to climatic variables and identified strong dependencies of AM fungal communities on precipitation. Given that precipitation is expected to further decline in the farming-pastoral ecotone over the coming years and that mycorrhiza represents an integral constituent of ecosystem functioning, it is likely that the ecosystem services in the region will change accordingly. PMID- 27117798 TI - Clinical and Immunological Benefits of OM-85 Bacterial Lysate in Patients with Allergic Rhinitis, Asthma, and COPD and Recurrent Respiratory Infections. AB - PURPOSE: The aim of this study was to evaluate the efficacy of OM-85 in reducing the incidence of respiratory tract infections (RTIs) in patients with allergic rhinitis, asthma, or chronic obstructive pulmonary disease (COPD), and its effect on immunological parameters, namely serum and secretory IgA levels. METHODS: This was an open-label, prospective, sequential study which included 84 consecutive patients aged 16-65 years, who presented with recurrent (three or more) respiratory infections during the year prior to study entry. In the first year of the study, patients received standard optimized care (SOC), according to their underlying disease condition (asthma, allergic rhinitis, or COPD). In the following year, patients received treatment with OM-85 oral bacterial lysate (one 7 mg capsule daily for ten consecutive days per month, for 3 months), with a 6 month follow-up. Medical history, clinical symptoms, serum, and secretory IgA levels, and the number of infections and exacerbations were evaluated before and after treatment. RESULTS: There was a decrease in the total number of RTIs before the OM-85 treatment period (SOC only) compared to the year before the study start [69/266 (corresponding to a 74 % reduction)] and an additional decrease [38/69 (corresponding to a 45 % reduction)] after OM-85 treatment; p < 0.05. There was also a significant reduction in the total number of exacerbations related to the patients' underlying medical conditions, which decreased from 55 to 35 during OM 85 (+SOC) treatment, corresponding to a reduction of 36 %. In addition, an increase in serum and secretory IgA levels which coincided with the administration of OM-85 was observed. CONCLUSIONS: Our results showed the clinical benefits of OM-85 in reducing RTIs and exacerbations of the underlying medical condition, in patients with allergic rhinitis, asthma, or COPD. PMID- 27117799 TI - Historical aspects of Mexican psychiatry. AB - Mexican psychiatry initiated since pre-Hispanic times. Historically, treatments were a mixture of magic, science and religion. Ancient Nahuas had their own medical concepts with a holistic view of medicine, considering men and cosmos as a whole. The first psychiatric hospital appeared in 1566 and a more modern psychiatric asylum emerged until 1910. International exchanges of theoretical approaches started in the National University with the visit of Pierre Janet. There were other important figures that influenced Mexican psychiatry, such as Erich Fromm, Henri Ey, Jean Garrabe and Yves Thoret. Regarding Mexican psychiatrists, some of the most important contributors to Mexican psychiatry were Jose Luis Patino Rojas, Manuel Guevara Oropeza and Ramon de la Fuente Muniz. This article includes excerpts from "Clinical Psychiatry", a book by Patino Rojas where he tries to understand and describe the inner world experienced by patients with schizophrenia; also, the thesis conducted by Guevara Oropeza ("Psychoanalisis"), which is a critical comparison between the theories of Janet and Freud. Finally, we include "The study of consciousness: current status" by Ramon de la Fuente, which leads us through the initial investigations concerning consciousness, its evolution, and the contributions made by psychology, philosophy and neurobiology. PMID- 27117800 TI - Primary renal magnesium wasting: an unusual clinical picture of exercise-induced symptoms. AB - Magnesium is one of the most abundant cations in the human body and plays a key role as a metabolic enzyme cofactor and regulatory ion for neurons and cardiomyocytes. Hypomagnesemia due to isolated primary renal magnesium wasting is a rare clinical condition typically associated with neurological hyperexcitability. Exercise-related gastrointestinal symptoms are caused by ischemic, mechanical, or neurohormonal changes. The role of hypomagnesemia in gastrointestinal symptoms is not well understood. We present a case of a 15-year old male who presented with exercise-induced abdominal pain, nausea, and vomiting, who was found to have profound hypomagnesemia and inappropriately elevated fractional excretion of magnesium (FEMg). Testing for multiple intrinsic and extrinsic etiologies of renal magnesium wasting was inconclusive. He was diagnosed with primary renal magnesium wasting and his symptoms resolved acutely with intravenous magnesium sulfate and with long-term oral magnesium chloride. Primary renal magnesium wasting is a rare clinical entity that can cause extreme hypomagnesemia. It has not been associated previously with exercise-induced gastrointestinal symptoms. The effects of hypomagnesemia on the human gastrointestinal tract are not well established. This case offers unique insights into the importance of magnesium homeostasis in the gastrointestinal tract. Exercise-induced splanchnic hypoperfusion may contribute to gastrointestinal symptoms observed in this chronically hypomagnesemic patient. PMID- 27117801 TI - Functional and transport analyses of CLCN5 genetic changes identified in Dent disease patients. AB - Dent disease type 1, an X-linked inherited kidney disease is caused by mutations in electrogenic Cl(-)/H(+) exchanger, ClC-5. We functionally studied the most frequent mutation (S244L) and two mutations recently identified in RKSC patients, Q629X and R345W. We also studied T657S, which has a high minor-allele frequency (0.23%) in the African-American population, was published previously as pathogenic to cause Dent disease. The transport properties of CLC-5 were electrophysiologically characterized. WT and ClC-5 mutant currents were inhibited by pH 5.5, but not affected by an alkaline extracellular solution (pH 8.5). The T657S and R345W mutations showed the same anion selectivity sequence as WT ClC-5 (SCN(-)>NO3(-)~Cl(-)>Br(-)>I(-)). However, the S244L and Q629X mutations abolished this anion conductance sequence. Cell surface CLC-5 expression was quantified using extracellular HA-tagged CLC-5 and a chemiluminescent immunoassay. Cellular localization of eGFP-tagged CLC-5 proteins was also examined in HEK293 cells with organelle-specific fluorescent probes. Functional defects of R345W and Q629X mutations were caused by the trafficking of the protein to the plasma membrane since proteins were mostly retained in the endoplasmic reticulum, and mutations showed positive correlations between surface expression and transport function. In contrast, although the S244L transport function was significantly lower than WT, cell surface, early endosome, and endoplasmic reticulum expression was equal to that of WT CLC-5. Function and trafficking of T657S was equivalent to the WT CLC-5 suggesting this is a benign variant rather than pathogenic. These studies demonstrate the useful information that can be gained by detailed functional studies of mutations predicted to be pathogenic. PMID- 27117802 TI - Effect of NBCe1 deletion on renal citrate and 2-oxoglutarate handling. AB - The bicarbonate transporter, NBCe1 (SLC4A4), is necessary for at least two components of the proximal tubule contribution to acid-base homeostasis, filtered bicarbonate reabsorption, and ammonia metabolism. This study's purpose was to determine NBCe1's role in a third component of acid-base homeostasis, organic anion metabolism, by studying mice with NBCe1 deletion. Because NBCe1 deletion causes metabolic acidosis, we also examined acid-loaded wild-type adult mice to determine if the effects of NBCe1 deletion were specific to NBCe1 deletion or were a non-specific effect of the associated metabolic acidosis. Both NBCe1 KO and acid-loading decreased citrate excretion, but in contrast to metabolic acidosis alone, NBCe1 KO decreased expression of the apical citrate transporter, NaDC-1. Thus, NBCe1 expression is necessary for normal NaDC-1 expression, and NBCe1 deletion induces a novel citrate reabsorptive pathway. Second, NBCe1 KO increased 2-oxoglutarate excretion. This could not be attributed to the metabolic acidosis as experimental acidosis decreased excretion. Increased 2-oxoglutarate excretion could not be explained by changes in plasma 2-oxoglutarate levels, the glutaminase I or the glutaminase II generation pathways, 2-oxoglutarate metabolism, its putative apical 2-oxoglutarate transporter, OAT10, or its basolateral transporter, NaDC-3. IN SUMMARY: (1) NBCe1 is necessary for normal proximal tubule NaDC-1 expression; (2) NBCe1 deletion results in stimulation of a novel citrate reabsorptive pathway; and (3) NBCe1 is necessary for normal 2 oxoglutarate metabolism through mechanisms independent of expression of known transport and metabolic pathways. PMID- 27117803 TI - Pronounced expression of the lipolytic inhibitor G0/G1 Switch Gene 2 (G0S2) in adipose tissue from brown bears (Ursus arctos) prior to hibernation. AB - Prior to hibernation, the brown bear (Ursus arctos) exhibits unparalleled weight gain. Unlike humans, weight gain in bears is associated with lower levels of circulating free fatty acids (FFA) and increased insulin sensitivity. Understanding how free-ranging brown bears suppress lipolysis when gaining weight may therefore provide novel insight toward the development of human therapies. Blood and subcutaneous adipose tissue were collected from immobilized free ranging brown bears (fitted with GPS-collars) during hibernation in winter and from the same bears during the active period in summer in Dalarna, Sweden. The expression of lipid droplet-associated proteins in adipose tissue was examined under the hypothesis that bears suppress lipolysis during summer while gaining weight by increased expression of negative regulators of lipolysis. Adipose triglyceride lipase (ATGL) expression did not differ between seasons, but in contrast, the expression of ATGL coactivator Comparative gene identification-58 (CGI-58) was lower in summer. In addition, the expression of the negative regulators of lipolysis, G0S2 and cell-death inducing DNA fragmentation factor-a like effector (CIDE)C markedly increased during summer. Free-ranging brown bears display potent upregulation of inhibitors of lipolysis in adipose tissue during summer. This is a potential mechanism for increased insulin sensitivity during weight gain and G0S2 may serve as a target to modulate insulin sensitivity. PMID- 27117804 TI - Cardiometabolic risk factors predict cerebrovascular health in older adults: results from the Brain in Motion study. AB - Aging and physical inactivity are associated with an increased risk of developing metabolic syndrome (MetS). With the rising prevalence of MetS, it is important to determine the extent to which it affects cerebrovascular health. The primary purpose of this report is to examine the impact of MetS on cerebrovascular health (resting cerebral blood flow (CBF) peak velocity (V-P), cerebrovascular conductance (CVC), and CBF responses to hypercapnia) in healthy older adults with normal cognition. A secondary goal was to examine the influence of apolipoprotein E (APOE) epsilon4 expression on these indices. In a sample of 258 healthy men and women older than 53 years, 29.1% met criteria for MetS. MetS, sex, and age were found to be significant predictors of CVC, and V-P, MetS, and APOE status were significant predictors of V-P-reactivity, and CVC-reactivity was best predicted by MetS status. After controlling for these factors, participants with MetS demonstrated lower cerebrovascular measures (CVC, V-P, CVC-reactivity, and V-P reactivity) compared to participants without MetS. APOE epsilon4 carriers had higher V-P-reactivity than noncarriers. These results provide evidence that cardiometabolic and vascular risk factors clustered together as the MetS predict measures of cerebrovascular health indices in older adults. Higher V-P-reactivity in APOE epsilon4 carriers suggests vascular compensation for deleterious effects of this known risk allele for Alzheimer's disease and stroke. PMID- 27117805 TI - Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness. AB - The inwardly rectifying potassium current (IK 1) conducted through Kir2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered IK 1 inhibitor PA-6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK-293 cells expressing IK 1 were voltage-clamped with ramp protocols. Langendorff-perfused heart experiments were performed on male Sprague Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA-6 perfusion. 200 nmol/L PA-6 resulted in a significant time-latency in drug effect on the IK 1 current expressed in HEK-293 cells, giving rise to a maximal effect at 20 min. In the Langendorff-perfused heart experiments, PA-6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 +/- 6.5 msec to 72.6 +/- 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA-6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 +/- 4.6 msec to 58.1 +/- 14.7 msec, 67%, P < 0.01, n = 6). PA-6 increased the short-term beat-to-beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA-6 application. The results show that pharmacological inhibition of cardiac IK 1 affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts. PMID- 27117806 TI - PlanHab (Planetary Habitat Simulation): the combined and separate effects of 21 days bed rest and hypoxic confinement on human skeletal muscle miRNA expression. AB - The study concerns effects of 21 days of sustained bedrest and hypoxia, alone and in combination, on skeletal muscle microRNA (miRNA) expression. It is expected that astronauts undertaking long-duration missions will be exposed not only to microgravity but also to a hypoxic environment. The molecular machinery underlying microgravity-induced alterations in skeletal muscle structure and function is still largely unknown. One possible regulatory mechanism is altered expression of miRNAs, a group of noncoding RNAs which down-regulate many different target genes through increased degradation or translation of their messenger RNA Thirteen healthy men underwent three 21-day interventions, interspersed by 4-month washout periods: horizontal bedrest in normoxia, bedrest in hypoxia, ambulation in hypoxia. The level of hypoxia corresponded to 4000 m altitude. miRNAs from v. lateralis muscle biopsies were analyzed using a microarray covering ~4000 human miRNAs. Sixteen mature miRNAs were up-regulated and three down-regulated after bedrest. The magnitudes of these changes were small and a large portion of the miRNAs affected by bedrest was also differentially expressed after washout periods. In fact, the number of differentially expressed probe sets over time was substantially larger than what could be detected after bedrest. Still, the majority of the miRNAs (let-7, miR 15, miR-25, miR-199, miR-133) that were differentially expressed following bedrest, belong to miRNA families previously reported in the context of muscle physiology, in particular to respond to changes in mechanical loading. Since only minor changes in miRNA expression could be detected after bedrest, our data indicate miRNA to play only a minor role in the substantial change in muscle phenotype seen with unloading. PMID- 27117807 TI - Widespread activation of immunity and pro-inflammatory programs in peripheral blood leukocytes of HIV-infected patients with impaired lung gas exchange. AB - HIV infection is associated with impaired lung gas transfer as indicated by a low diffusing capacity (DLCO), but the mechanisms are not well understood. We hypothesized that HIV-associated gas exchange impairment is indicative of system wide perturbations that could be reflected by alterations in peripheral blood leukocyte (PBL) gene expression. Forty HIV-infected (HIV(+)) and uninfected (HIV( )) men with preserved versus low DLCO were enrolled. All subjects were current smokers and those with acute illness, lung diseases other than COPD or asthma were excluded. Total RNA was extracted from PBLs and hybridized to whole-genome microarrays. Gene set enrichment analysis (GSEA) was performed between HIV(+) versus HIV(-) subjects with preserved DLCO and those with low DLCO to identify differentially activated pathways. Using pathway-based analyses, we found that in subjects with preserved DLCO, HIV infection is associated with activation of processes involved in immunity, cell cycle, and apoptosis. Applying a similar analysis to subjects with low DLCO, we identified a much broader repertoire of pro-inflammatory and immune-related pathways in HIV(+) patients relative to HIV( ) subjects, with up-regulation of multiple interleukin pathways, interferon signaling, and toll-like receptor signaling. We confirmed elevated circulating levels of IL-6 in HIV(+) patients with low DLCO relative to the other groups. Our findings reveal that PBLs of subjects with HIV infection and low DLCO are distinguished by widespread enrichment of immuno-inflammatory programs. Activation of these pathways may alter the biology of circulating leukocytes and play a role in the pathogenesis of HIV-associated gas exchange impairment. PMID- 27117808 TI - A novel mutation affecting the arginine-137 residue of AVPR2 in dizygous twins leads to nephrogenic diabetes insipidus and attenuated urine exosome aquaporin-2. AB - Mutations in the vasopressin V2 receptor gene AVPR2 may cause X-linked nephrogenic diabetes insipidus by defective apical insertion of aquaporin-2 in the renal collecting duct principal cell. Substitution mutations with exchange of arginine at codon 137 can cause nephrogenic syndrome of inappropriate antidiuresis or congenital X-linked nephrogenic diabetes insipidus. We present a novel mutation in codon 137 within AVPR2 with substitution of glycine for arginine in male dizygotic twins. Nephrogenic diabetes insipidus was demonstrated by water deprivation test and resistance to vasopressin administration. While a similar urine exosome release rate was shown between probands and controls by western blotting for the marker ALIX, there was a selective decrease in exosome aquaporin-2 versus aquaporin-1 protein in probands compared to controls. PMID- 27117809 TI - Bremsstrahlung radiation detection for small animal imaging using a CCD detector. AB - The use of optical methods for the detection of radionuclides is becoming an established tool for preclinical molecular imaging experiments. In this paper we present a set of proof of principle experiments showing that planar bremsstrahlung radiation images can be detected with an intensifying screen using a small animal optical imager based on charge coupled device detector. We develop a bremsstrahlung source using a (32)P-ATP vial placed in a Plexiglas box, the source with an intensifying screen on top was placed inside a small animal optical imaging system. Bremsstrahlung radiation images were produced with the (32)P-ATP source only and also with a pair of pliers placed between the source and the screen. We found that the pair of pliers absorption image matches the shape of the object. Spatial resolution measurements were not performed however, the bremsstrahlung image of the pliers show that the resolution is relatively poor due to a large penumbra effect. We conclude that it is possible to produce planar bremsstrahlung images using optical imaging devices. PMID- 27117810 TI - Shoulder joint replacement can improve quality of life and outcome in patients with dysmelia: a case series. AB - BACKGROUND: Arthroplasty is a proven treatment option for glenohumeral osteoarthritis. Common indications include primary or posttraumatic osteoarthritis, avascular necrosis of the humeral head, rotator cuff tear arthropathy and rheumatoid osteoarthritis. Arthroplasty is rarely performed among patients with glenohumeral dysmelia. An overuse of the upper limb in patients with thalidomide-induced phocomelia and people with similar congenital deformities like dysmelia results in premature wear of the shoulder joint. This study aims to evaluate our experience with cases of glenohumeral osteoarthritis caused by dysmelia and treated with arthroplasty. To date, few reports on the outcome of shoulder arthroplasty exist on this particular patient group. CASE PRESENTATION: We included four dysmelic patients (five shoulders) with substantial glenoid dysplasia in a prospective database after approval by the local ethics committee. Once conservative treatment options had been exhausted, the patients were treated with shoulder arthroplasty and assessed clinically and radiographically before and after surgery. The mean patient age at the time of surgery was 50.4 years. The minimum follow-up time was 24 months (24-91 months). All patients experienced a considerable improvement of range of motion (ROM) and a relief of pain. No intra- or postoperative complications appeared. CONCLUSION: Patients with dysmelia have acceptable short and mid-term results with resurfacing hemiarthroplasty. It is an effective although somewhat complicated method to relieve pain and improve movement. Long-term performance of arthroplasty in patients with dysmelia remains to be seen, particularly with regard to the remaining problem of the altered and often deficient glenoid. PMID- 27117811 TI - Gender dysphoria: shared care is the answer. PMID- 27117812 TI - Web-based oral health promotion program for older adults: Development and preliminary evaluation. AB - OBJECTIVE: This study reports on the impact evaluation of a Web-based oral health promotion programme aimed at improving the oral health knowledge, attitudes, practices and self-efficacy of independent-living older adults from Melbourne, Australia. METHODS: With ethics approval from the University of Melbourne, a convenience sample of volunteers 55 years or older was invited to participate in a study to test a web-based oral health promotion program. Consenting volunteers were asked to undergo a structured interview as part of the pre-intervention data collection. The intervention was based on the ORHIS (Oral Health Information Seminars/Sheets) Model and involved computer interaction with six oral health presentations, with no direct oral health professional input. A one group pre test-post-test quasi-experimental design was chosen to evaluate the intervention. A series of paired t-tests were used to compare pre-test with post-test results. RESULTS: Forty-seven active, independent-living older adults participated in this evaluation. After the intervention participants responded with higher levels of achievement than before participating in this Web-based oral health program. Participants showed significant improvements in oral health attitudes (4.10 vs. 4.94; p<0.01), knowledge (18.37 vs. 23.83; p<0.0001), and self-efficacy (84.37 vs.89.23; p<0.01), as well as, self-reported oral hygiene practices (i.e., frequency of use of dental floss) (p<0.05). CONCLUSION: The e-ORHIS approach was successful in improving oral health knowledge, attitudes and self-efficacy. As such, it represents a helpful approach for the design of (oral) health interventions in older adults. Further evaluation with a larger sample is required to test the long-term impact including the economic evaluation of the e ORHIS approach. PMID- 27117813 TI - Transmission mechanisms of an emerging insect-borne rickettsial pathogen. AB - BACKGROUND: Vector-borne pathogens must overcome arthropod infection and escape barriers (e.g. midgut and salivary glands) during the extrinsic incubation period (EIP) before subsequent transmission to another host. This particular timespan is undetermined for the etiological agent of flea-borne spotted fever (Rickettsia felis). Artificial acquisition of R. felis by blood-feeding cat fleas revealed dissemination to the salivary glands after seven days; however, this length of time is inconsistent with co-feeding studies that produced infectious cat fleas within 24 h of infection. In the current study, we demonstrated that an alternative mechanism is responsible for the early-phase transmission that typifies flea-borne R. felis spread. METHODS: Co-feeding transmission bioassays were constructed to assess temporal dynamics of R. felis amongst cat fleas, including exposure time to produce infectious fleas and association time to transmit infection to naive fleas. Additional experiments examined the proportion of R. felis-exposed cat fleas with contaminated mouthparts, as well as the likelihood for cat fleas to release R. felis from their mouthparts following exposure to an infectious bloodmeal. The potential for mechanical transmission of R. felis by co-feeding cat fleas was further examined using fluorescent latex beads, as opposed to a live pathogen, which would not require a biological mechanism to achieve transmission. RESULTS: Analyses revealed that R. felis infected cat fleas were infectious to naive fleas less than 24 h after exposure to the pathogen, but showed no rickettsial dissemination to the salivary glands during this early-phase transmission. Additionally, the current study revealed that R. felis-infected cat fleas must co-feed with naive fleas for more than 12 h in order for early-phase transmission to occur. Further evidence supported that contaminated flea mouthparts may be the source of the bacteria transmitted early, and demonstrated that R. felis is released from the mouthparts during brief probing events. Moreover, the use of fluorescent latex beads supports the notion that early-phase transmission of R. felis is a mechanical mechanism. CONCLUSIONS: Determination of the transmission mechanisms utilized by R. felis is essential to fully understand the vulnerability of susceptible vertebrate hosts, including humans, to this pathogen. PMID- 27117814 TI - Interfacial free energy adjustable phase field crystal model for homogeneous nucleation. AB - To describe the homogeneous nucleation process, an interfacial free energy adjustable phase-field crystal model (IPFC) was proposed by reconstructing the energy functional of the original phase field crystal (PFC) methodology. Compared with the original PFC model, the additional interface term in the IPFC model effectively can adjust the magnitude of the interfacial free energy, but does not affect the equilibrium phase diagram and the interfacial energy anisotropy. The IPFC model overcame the limitation that the interfacial free energy of the original PFC model is much less than the theoretical results. Using the IPFC model, we investigated some basic issues in homogeneous nucleation. From the viewpoint of simulation, we proceeded with an in situ observation of the process of cluster fluctuation and obtained quite similar snapshots to colloidal crystallization experiments. We also counted the size distribution of crystal like clusters and the nucleation rate. Our simulations show that the size distribution is independent of the evolution time, and the nucleation rate remains constant after a period of relaxation, which are consistent with experimental observations. The linear relation between logarithmic nucleation rate and reciprocal driving force also conforms to the steady state nucleation theory. PMID- 27117815 TI - Serotonin release in the subfornical organ area induced by sodium and water intake in the rat. AB - Previous studies have shown that the subfornical organ (SFO) is involved in the modulation of sodium intake in rats. To clarify whether serotonergic mechanisms in the SFO participate in the modulatory system, the present study was carried out to examine the effects of sodium and water intake on serotonin (5 hydroxytryptamine, 5-HT) release in the subfornical organ (SFO) in freely moving rats. The ingestion of 0.3M NaCl and water was induced by subcutaneous injections of the diuretic furosemide (FURO, 10mg/kg) and the angiotensin converting enzyme inhibitor captopril (CAP, 5mg/kg), and extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the region of the SFO were measured using intracerebral microdialysis techniques. The combined treatment with FURO and CAP elicited significant decreases in the 5-HT and 5-HIAA levels in the SFO area. The 0.3M NaCl and water intake caused by the treatment significantly enhanced the 5-HT and 5-HIAA concentrations in the SFO area compared with the basal levels. No significant changes in the 5-HT and 5-HIAA levels caused by either the FURO and CAP treatment or water and NaCl intake were observed in the sites away from the SFO. These results suggest that the serotonergic mechanism in the SFO may be important for the control of sodium appetite and thirst. PMID- 27117816 TI - Differences in the association between behavior and neutrophil gelatinase associated lipocalin in male and female rats after coronary artery ligation. AB - Heart failure is associated with an increased risk of developing depression and cognitive dysfunction, which negatively affects prognosis. Plasma levels of neutrophil gelatinase associated lipocalin (NGAL) are increased in heart failure and depression. Moreover, NGAL levels are associated with depression in heart failure patients. Since women are at a higher risk of developing comorbid depression with heart failure, the aim of this study was to examine sex differences in the link between NGAL and behavior in a rat model of heart failure. In young adult male and female Wistar rats, myocardial infarction (MI) was induced by means of coronary artery ligation, while control rats received sham surgery. We analyzed aspects of cognition and depression/anxiety using various behavioral tests starting three weeks after surgery. Hemodynamic measurements were performed and hearts and lungs were weighed. NGAL levels in plasma, cerebrospinal fluid (CSF) and brain tissue were analyzed. MI induced impairment in cardiac contractility and relaxation, and an increase in lung weight. NGAL correlated with signs of heart failure in male, but not female rats. Male MI rats displayed cognitive problems, but not depressive-like or anxiety like behavior. No behavioral effects of MI were observed in female rats. Plasma NGAL levels were higher in male than female rats with higher concentrations in MI compared to sham. CSF NGAL was higher in MI rats compared to sham and higher in males compared to females. The number of NGAL positive cells in the paraventricular nucleus of the hypothalamus (PVN) was only increased in male MI rats. In male, but not in female rats, NGAL levels correlated with depressive like behavior and cognitive dysfunction. Data indicate that while MI increased NGAL levels in plasma, CSF and PVN, correlations of NGAL with behavior are sex specific, but independent of whether sham or MI surgery was performed. This suggests that inflammatory processes related to thorax surgery and their potential effects on depressive-like behavior and cognition may be sex-specific. PMID- 27117817 TI - Behavioural, brain and cardiac responses to hypobaric hypoxia in broiler chickens. AB - A novel approach to pre-slaughter stunning of chickens has been developed in which birds are rendered unconscious by progressive hypobaric hypoxia. Termed Low Atmospheric Pressure Stunning (LAPS), this approach involves application of gradual decompression lasting 280s according to a prescribed curve. We examined responses to LAPS by recording behaviour, electroencephalogram (EEG) and electrocardiogram (ECG) in individual male chickens, and interpreted these with regard to the welfare impact of the process. We also examined the effect of two temperature adjusted pressure curves on these responses. Broiler chickens were exposed to LAPS in 30 triplets (16 and 14 triplets assigned to each pressure curve). In each triplet, one bird was instrumented for recording of EEG and ECG while the behaviour of all three birds was observed. Birds showed a consistent sequence of behaviours during LAPS (ataxia, loss of posture, clonic convulsions and motionless) which were observed in all birds. Leg paddling, tonic convulsions, slow wing flapping, mandibulation, head shaking, open bill breathing, deep inhalation, jumping and vocalisation were observed in a proportion of birds. Spectral analysis of EEG responses at 2s intervals throughout LAPS revealed progressive decreases in median frequency at the same time as corresponding progressive increases in total power, followed later by decreases in total power as all birds exhibited isoelectric EEG and died. There was a very pronounced increase in total power at 50-60s into the LAPS cycle, which corresponded to dominance of the signal by high amplitude slow waves, indicating loss of consciousness. Slow wave EEG was seen early in the LAPS process, before behavioural evidence of loss of consciousness such as ataxia and loss of posture, almost certainly due to the fact that it was completely dark in the LAPS chamber. ECG recordings showed a pronounced bradycardia (starting on average 49.6s into LAPS), often associated with arrhythmia, until around 60s into LAPS when heart rate levelled off. There was a good correlation between behavioural, EEG and cardiac measures in relation to loss of consciousness which collectively provide a loss of consciousness estimate of around 60s. There were some effects of temperature adjusted pressure curves on behavioural latencies and ECG responses, but in general responses were consistent and very similar to those reported in previous research on controlled atmosphere stunning with inert gases. The results suggest that the process is humane (slaughter without avoidable fear, anxiety, pain, suffering and distress). In particular, the maintenance of slow wave EEG patterns in the early part of LAPS (while birds are still conscious) is strongly suggestive that LAPS is non-aversive, since we would expect this to be interrupted by pain or discomfort. PMID- 27117819 TI - Aggregation dynamics and foraging behaviour of striped red mullet Mullus surmuletus in the western Mediterranean Sea. AB - Habitat-related heterogeneity of striped red mullet Mullus surmuletus heterospecific foraging assemblages was examined off the coast of Spain. Video based focal-follows conducted on 122 M. surmuletus assemblages (446 total individuals) revealed an array of attendant species (n = 7) with composition linked to benthic habitat complexity; bare sandy substrata were characterized by homospecific groups of M. surmuletus, while habitats with rock and vegetation attracted a variety of scrounging labrids and sparids. Although the nature of the relationship between M. surmuletus and attendants requires further exploration, the present study indicates that substratum composition can be a driving factor explaining the dynamics of this heterospecific assemblage. PMID- 27117818 TI - Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. AB - Brown adipose tissue (BAT) dissipates energy and its activity correlates with leanness in human adults. (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography coupled with computer tomography (PET/CT) is still the standard for measuring BAT activity, but exposes subjects to ionizing radiation. To study BAT function in large human cohorts, novel diagnostic tools are needed. Here we show that brown adipocytes release exosomes and that BAT activation increases exosome release. Profiling miRNAs in exosomes released from brown adipocytes, and in exosomes isolated from mouse serum, we show that levels of miRNAs change after BAT activation in vitro and in vivo. One of these exosomal miRNAs, miR-92a, is also present in human serum exosomes. Importantly, serum concentrations of exosomal miR-92a inversely correlate with human BAT activity measured by (18)F FDG PET/CT in two unique and independent cohorts comprising 41 healthy individuals. Thus, exosomal miR-92a represents a potential serum biomarker for BAT activity in mice and humans. PMID- 27117821 TI - MicroRNAs underlying memory deficits in neurodegenerative disorders. AB - Neurodegenerative disorders are defined by neuronal loss and often associated with dementia. Understanding the multifactorial nature of cognitive decline is of particular interest. Cell loss is certainly a possibility but also an early imbalance in the complex gene networks involved in learning and memory. The small (~22nt) non-coding microRNAs play a major role in gene expression regulation and have been linked to neuronal survival and cognition. Interestingly, changes in microRNA signatures are associated with neurodegenerative disorders. In this review, we explore the role of three microRNAs, namely miR-132, miR-124 and miR 34, which are dysregulated in major neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Interestingly, these microRNAs have been associated with both memory impairment and neuronal survival, providing a potential common molecular mechanism contributing to dementia. PMID- 27117820 TI - Tryptophan via serotonin/kynurenine pathways abnormalities in a large cohort of aggressive inmates: markers for aggression. AB - Aggressive behavior is one of the most challenging symptoms in psychiatry, and biological markers for aggression lack of large sample validations. Serotonin (5 HT) and other neuroactive compounds deriving from Tryptophan (Trp), including kynurenine (Kyn), have not yet been investigated in large cohorts of aggressive individuals to validate their potential as biomarkers of aggression. In 361 male inmates we measured serum levels of Trp, 5-hydroxytryptophan, 5-HT, Kyn, the ratios 5-HT/Trp*1000 and Kyn/Trp*1000, and performed Structured Clinical Interview for DSM-IV Axis-I and -II Disorders (SCID-I and -II), global assessment of functioning (GAF), and scales for aggressive behavior, impulsivity, adult attention-deficit/hyperactivity disorder (ADHD), and intelligent quotient (IQ). Aggressive compared to non-aggressive inmates exhibited lower Trp and Kyn serum levels but higher levels of 5-HT and 5-HT/Trp*1000, higher levels of impulsivity and ADHD indices, lower IQ and GAF, higher prevalence of mood disorders, drug abuse/dependence, and borderline, conduct and antisocial behaviors. Interestingly, Kyn/Trp*1000 was positively correlated to the number of severe aggressive acts (r=0.593, P<0.001). After adjusting for confounding factors, logistic regression analysis indicated that 5-HT/Trp*1000, antisocial behavior, and GAF were predictors of aggressive behavior. The model combining these three predictors had an area under the ROC curve of 0.851 (95% CI 0.806-0.895). This study indicates that while circulating Trp is reduced in aggressive individuals, the combination of biological (5-HT/Trp ratio) and psychopathological (antisocial behavior and GAF) markers discriminates between aggressive and non-aggressive behavior suggesting the potential of a multi-marker approach in psychiatry given the heterogenic nature of mental diseases. PMID- 27117822 TI - Follow-up on commitments at the Third Global Forum on Human Resources for Health: Indonesia, Sudan, Tanzania : "A commitment is a promise, a promise is a debt". AB - This study sought to assess actions which Indonesia, Sudan, and Tanzania took to implement the health workforce commitments they made at the Third Global Forum on Human Resources for Health (HRH) in November 2013. The study was conducted through a survey of published and gray literature in English and field research consisting of direct contacts with relevant ministries and agencies. Results show that the three countries implemented interventions to translate their commitments into actions. The three countries focused their commitments on improving the availability, geographical accessibility, quality of education, and performance of health workers. The implementation of the Recife commitments primarily entailed initiatives at the central level, such as the adoption of new legislation or the development of accreditation mechanisms. This study shows that action is more likely to take place when policy documents explicitly recognize and document HRH problems, when stakeholders are involved in the formulation and the implementation of policy changes, and when external support is available. The Recife Forum appears to have created an opportunity to advance the HRH policy agenda, and advocates of health workforce development in these three countries took advantage of it. PMID- 27117823 TI - Validation of Improvement of Basic Competency in Arthroscopic Knot Tying Using a Bench Top Simulator in Orthopaedic Residency Education. AB - PURPOSE: To validate basic competency in arthroscopic knot tying using a unique simulator device to compare the level of training needed for learning and tying the arthroscopic knot by evaluating the tensile properties of the arthroscopic knots. METHODS: Three groups of surgeons of various experience levels (postgraduate year [PGY] 1, PGY 3, and experienced surgeons) tied 2 different arthroscopic knots (Tennessee Slider, considered easier, and Weston, considered more difficult) over a 10-week period. Each group went through 3 separate stages of knot tying: stage 1, tying 8 knots without cannula or knot pusher; stage 2, tying 12 knots with knot pusher; and stage 3, tying 20 knots with knot pusher through a cannula that simulates knot tying during surgery. A single load-to failure test was performed and ultimate clinical failure loads were recorded. Time needed to tie each knot was also recorded. RESULTS: At stages 1 and 2, the PGY 1 group had a significantly weak knot tensile strength (Tennessee Slider stage 1: 60 v 129 N, P = .001; Tennessee Slider stage 2: 69 v 132 N, P = .0029; Weston stage 1: 73 v 184 N, P = .0000; Weston stage 2: 125 v 173 N, P = .0045) and were slower (Weston: 56 v 30 seconds, P = .0010) than the experienced surgeon group for both knots. At stage 3, only the initial 2 weeks of Tennessee Slider showed a significant difference between groups 1 and 3 (week 6: 87 v 118 N, P = .0492; week 7: 89 v 126, P = .01485). Even though the Tennessee Slider knot is one of the easier arthroscopic knots to learn to tie, the results showed a slow trend of improvement in this knot-tying skill for group 1 after each stage. CONCLUSIONS: The data validated an important learning effect in all trainees in arthroscopic knot tying over a 10-week period and showed that inexperienced trainees will be able to improve their knot-tying skill with training in 3 stages with a simulator environment. CLINICAL RELEVANCE: The findings of this study indicated the importance of hands-on experience in performing arthroscopic knot tying, as determined by both knot performance and ultimate suture loop strength. In addition, each orthopaedic resident learned and developed his or her arthroscopic knot-tying skills and provided a foundation for his or her future practice in orthopaedic medicine. PMID- 27117824 TI - Profile of Current Opinion on Arthroscopic Acromioplasty: A Video Survey Study. AB - PURPOSE: To provide a baseline profile of current opinion on use of arthroscopic acromioplasty and evaluate the consistency of surgical decision making on whether or not to perform acromioplasty across different surgeon practices. METHODS: Twenty-two fellowship-trained orthopaedic shoulder surgeons from the Association of Clinical Elbow and Shoulder Surgeons completed an Internet-based survey on practices associated with acromioplasty, including questions related to 15 arthroscopic videos. Based on video cases, interobserver and intraobserver agreement regarding clinically based decisions related to acromioplasty were assessed. RESULTS: Acromioplasty was uncommonly performed in isolation among this group and was most commonly performed in conjunction with repair of full thickness rotator cuff tears. Nineteen of 22 (86%) surgeons favored an arthroscopic approach for acromioplasty. Depth of bony resection was determined most commonly based on clinical judgment and experience (68%). The video portion of the survey revealed slight interobserver agreement for classification of acromion morphology (kappa = 0.099), need for acromioplasty (kappa = 0.020), and adequacy of decompression (kappa = 0.1). In contrast, there was fair intraobserver reliability regarding acromion morphology (kappa = 0.370) and decision whether to perform acromioplasty in a given case (kappa = 0.348) whereas there was moderate intraobserver reliability in the presence of a reparable rotator cuff tear (kappa = 0.507) and assessment of the adequacy of decompression (kappa = 0.453). CONCLUSIONS: Although surgeons had similarities regarding principles of acromioplasty, including indications, surgical approach, and technique, there was lack of consensus when surgeons reviewed the video of clinical cases. Although surgeons may have similar goals in terms of treatment of pathology related to subacromial impingement, individual surgeon thresholds for the need and adequacy of decompression are varied and are not standardized. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 27117825 TI - Understanding and promoting treatment-seeking for eating disorders and body image concerns on college campuses through online screening, prevention and intervention. AB - While there have been important recent advances in the development of effective universal prevention and intervention programs, it is not yet clear how to engage large numbers of students in these programs. In this paper, we report findings from a two-phase pilot study. In the first phase, we used a population-level, online survey to assess eating disorder symptom level and habits/attitudes related to service utilization (N=2180). Using validated screening tools, we found that roughly one in three students has significant symptoms of eating disorders or elevated weight concerns, the vast majority of whom (86.5%) have not received treatment. In the second phase, we referred students to online prevention and selective/indicated intervention programs based on symptom classification (N=1916). We find that program enrollment is highest for students in the indicated intervention (18.1%) and lowest for students in the universal prevention (4.1%). We find that traditionally-emphasized barriers such as stigma, misinformation, and financial limitations do not appear to be the most important factors preventing treatment-seeking. Rather students report not seeking help for reasons such as lack of time, lack of perceived need, and a desire to deal with the issue "on my own." Findings offer insight into the treatment-seeking habits and attitudes of college students, including those barriers that may be overcome by offering online programs and those that persist despite increased access to and convenience of relevant resources. PMID- 27117826 TI - Competition between global and local online social networks. AB - The overwhelming success of online social networks, the key actors in the Web 2.0 cosmos, has reshaped human interactions globally. To help understand the fundamental mechanisms which determine the fate of online social networks at the system level, we describe the digital world as a complex ecosystem of interacting networks. In this paper, we study the impact of heterogeneity in network fitnesses on the competition between an international network, such as Facebook, and local services. The higher fitness of international networks is induced by their ability to attract users from all over the world, which can then establish social interactions without the limitations of local networks. In other words, inter-country social ties lead to increased fitness of the international network. To study the competition between an international network and local ones, we construct a 1:1000 scale model of the digital world, consisting of the 80 countries with the most Internet users. Under certain conditions, this leads to the extinction of local networks; whereas under different conditions, local networks can persist and even dominate completely. In particular, our model suggests that, with the parameters that best reproduce the empirical overtake of Facebook, this overtake could have not taken place with a significant probability. PMID- 27117827 TI - Treatment of open fractures with a computer-assisted external fixator system without the use of fluoroscopy. AB - BACKGROUND: Developed for the treatment of deformity correction, computer assisted circular external fixators in recent years have also been used for fracture fixation. In this study, we aimed to present the efficacy of computer assisted circular external fixator use in open long bone fractures with our new technique. METHODS: Between February 2013 and June 2014, 14 patients (mean age 24.5 (range 20-32)) with open tibial or femoral open fractures were treated with the computer-assisted fixation system (Spider Frame-Tasarim Medikal, Istanbul, Turkey). In all patients, appropriate positions of the rings and Schanz screws were determined by measurements on preoperative radiographs. The length of the Schanz screws were determined by depth measure marks on drill bits. Obvious deformities were corrected intraoperatively by manipulations, but residual deformities were corrected by a software program (Spiderfix, Tasarim Medikal, Istanbul, Turkey). We did not use fluoroscopy during the procedures. RESULTS: Ten patients had tibia diaphyseal and four patients had femoral diaphyseal fractures. Mean surgical time was 24.2 (range 18-28) min. Average follow-up time was 10.2 (range 9-14) months. Mean time for deformity correction was 3.1 (2-5) days. Complete union was observed in all patients with a mean of 4.9 (range 3-9) months. There were two grade 2 pin site infections treated with oral antibiotherapy and pin site care. We did not detect any Schanz screw breakage, loosening, deep infection, nonunion, or malunion. CONCLUSIONS: Computer-assisted external fixation systems can be used in the treatment of open fractures, and they provide the chance for acute or gradual correction. Preoperative planning and assistant devices with depth measures may decrease the procedure time and the need for fluoroscopy use. PMID- 27117828 TI - Advanced glycation endproducts and their receptor in different body compartments in COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by chronic airway inflammation and emphysema, and is caused by exposure to noxious particles or gases, e.g. cigarette smoke. Smoking and oxidative stress lead to accelerated formation and accumulation of advanced glycation end products (AGEs), causing local tissue damage either directly or by binding the receptor for AGEs (RAGE). This study assessed the association of AGEs or RAGE in plasma, sputum, bronchial biopsies and skin with COPD and lung function, and their variance between these body compartments. METHODS: Healthy smoking and never-smoking controls (n = 191) and COPD patients (n = 97, GOLD stage I-IV) were included. Autofluorescence (SAF) was measured in the skin, AGEs (pentosidine, CML and CEL) and sRAGE in blood and sputum by ELISA, and in bronchial biopsies by immunohistochemistry. eQTL analysis was performed in bronchial biopsies. RESULTS: COPD patients showed higher SAF values and lower plasma sRAGE levels compared to controls and these values associated with decreased lung function (p <0.001; adjusting for relevant covariates). Lower plasma sRAGE levels significantly and independently predicted higher SAF values (p < 0.001). One SNP (rs2071278) was identified within a region of 50 kB flanking the AGER gene, which was associated with the gene and protein expression levels of AGER and another SNP (rs2071278) which was associated with the accumulation of AGEs in the skin. CONCLUSION: In COPD, AGEs accumulate differentially in body compartments, i.e. they accumulate in the skin, but not in plasma, sputum and bronchial biopsies. The association between lower sRAGE and higher SAF levels supports the hypothesis that the protective mechanism of sRAGE as a decoy receptor is impaired in COPD. PMID- 27117829 TI - Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis. AB - BACKGROUND AND AIMS: Intestinal microbiota is required to maintain immune homeostasis and intestinal barrier function. At the same time, intraluminal bacteria are considered to be involved in inflammatory bowel disease and are required for colitis induction in animal models, with the possible exception of dextran sulphate sodium [DSS] colitis. This study was carried out to ascertain the mechanism underlying the induction of colitis by DSS in the absence of bacteria. METHODS: Conventional and germ-free [GF] Naval Medical Research Institute [NMRI] mice were used, plus conventional mice treated with an antibiotic cocktail to deplete the intestinal microbiota ['pseudo-GF' or PGF mice]. The differential response to DSS was assessed. RESULTS: Conventional mice developed DSS-induced colitis normally, whereas GF mice showed only minimal inflammation [no colonic thickening, lower myeloperoxidase activity, IL-6, IL-17, TNF-alpha, and IFN-gamma secretion by splenocytes and mesenteric cell cultures, etc.]. However, these mice suffered enhanced haemorrhage, epithelial injury and mortality as a consequence of a weakened intestinal barrier, as shown by lower occludin, claudin 4, TFF3, MUC3, and IL-22. In contrast, PGF mice had a relatively normal, albeit attenuated, inflammatory response, but were less prone to haemorrhage and epithelial injury than GF mice. This was correlated with an increased expression of IL-10 and Foxp3 and preservation barrier-related markers. CONCLUSIONS: We conclude that enteric bacteria are essential for the development of normal DSS-induced colitis. The absence of microbiota reduces DSS colonic inflammation dramatically but it also impairs barrier function, whereas subtotal microbiota depletion has intermediate effects at both levels. PMID- 27117830 TI - Treatment and monitoring of hypersensitivity pneumonitis. AB - INTRODUCTION: Hypersensitivity pneumonitis (HP) is an immunologically induced lung disease that develops after inhalation of certain environmental antigens only in subjects with susceptibility to antigens. Therefore, both environmental and host immunological factors play important roles in the aetiology and pathogenesis of HP. AREAS COVERED: Determination of an inciting antigen is crucial for diagnosis, treatment and monitoring. For treatment, modification of the environment and of the host immune response are important. The former includes reduction of antigenic burden (i.e. disinfectant, cleaning), protective devices (i.e. filter, respiratory protection mask, ventilation) and avoidance of inciting antigens. The latter includes corticosteroids, lung transplantation and smoking cessation. For monitoring, measurement of serum Krebs von den Lungen (KL) 6 and surfactant protein (SP)-D concentrations can be used to screen for HP and to detect HP activity. Expert commentary: Measurement of an inciting antigen may be useful to predict the progression and prognosis of the disease. Treatment and monitoring are challenging in chronic HP with fibrosis. PMID- 27117831 TI - Blue rubber bleb nevus syndrome with knee joint disorder. AB - Blue rubber bleb nevus syndrome (BRBNS) involves cutaneous vascular malformation characterized by multiple venous malformations. This commonly affects the skin and gastrointestinal tract. BRBNS is associated with anemia and occasionally involves orthopedic manifestations. A 6-year-old boy was referred to hospital for evaluation of anemia. He presented with a rubber-like soft-tissue mass in the left knee and the right side of the neck, recurrent pain, and fixed flexion contracture of the knee. Blood examination indicated consumption coagulopathy and anemia caused by not only iron-deficiency anemia but also microangiopathy. Endoscopy of the gastrointestinal tract indicated multiple bluish-black sessile venous malformations. Ultrasonography and magnetic resonance imaging of the knee showed intra-articular and intramuscular involvement. Based on these findings, BRBNS with knee joint disorder was diagnosed. With regard to vascular malformations, like other diseases such as inflammatory arthropathy, ultrasonography of the joint may become a new diagnostic approach for evaluating orthopedic manifestations. PMID- 27117832 TI - PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors. AB - INTRODUCTION: Thymic epithelial tumors (TETs) are rare tumors originating from the epithelium of the thymus with limited therapeutic options beyond surgery. The pathogenesis of TETs is poorly understood, and the scarcity of model systems for these rare tumors makes the study of their biology very challenging. METHODS: A new cell line (MP57) was established from a thymic carcinoma specimen and characterized using standard biomarker analysis, as well as next-generation sequencing (NGS) and functional assays. Sanger sequencing was used to confirm the mutations identified by NGS. RESULTS: MP57 possesses all the tested thymic epithelial markers and is deemed a bona fide thymic carcinoma cell line. NGS analysis of MP57 identified a mutation in the gene PIK3R2, which encodes a regulatory subunit of PI3K. Further analysis identified different mutations in multiple PI3K subunit genes in another cell line and several primary thymic carcinoma samples, including two catalytic subunits (PIK3CA and PIK3CG) and another regulatory subunit (PIK3R4). Inhibiting PI3K with GDC-0941 resulted in in vitro antitumor activity in TET cells carrying mutant PI3K subunits. CONCLUSIONS: Alterations of PI3K due to mutations in its catalytic or regulatory subunits are observed in a subgroup of TETs, in particular, thymic carcinomas. Targeting PI3K may be an effective strategy to treat these tumors. PMID- 27117834 TI - Ruthenium complexes of P-stereogenic phosphines with a heterocyclic substituent. AB - The synthesis via phosphine-boranes of 13 new optically pure P-stereogenic diarylphosphines P(Het)PhR (Het = 4-dibenzofuranyl (DBF), 4-dibenzothiophenyl (DBT), 4-dibenzothiophenyl-S,S-dioxide (DBTO2) and 1-thianthrenyl (TA); R = OMe, Me, i-Pr, Fc (ferrocenyl)) following the Juge-Stephan method is described. The ligands were designed with the aim of having a heteroatom in a position capable of interacting with a metal upon coordination. The ligands and their precursors have been fully characterised, including the determination of two crystal structures of phosphine-boranes. Ru neutral complexes of the type [RuCl2(eta(6) arene)(kappaP-P)] (arene = p-cymene and methyl benzoate) have been prepared and characterised, including three crystal structure determinations. Treatment of solutions of the complexes with TlPF6 allowed the preparation of well-defined cationic complexes [RuCl(eta(6)-arene)(kappa(2)P,S-P)]PF6 for DBT- and TA-based phosphines. The complexes possess a stereogenic Ru atom and in most of the cases they are present as a single isomer in solution. All the Ru complexes have been used in the asymmetric transfer hydrogenation of acetophenone in refluxing 2 propanol, with good activities and up to 70% ee. PMID- 27117833 TI - PD-L1 Expression in Lung Cancer. AB - Immunotherapies targeted against programmed death ligand 1 (PD-L1) and its receptor (PD-1) have improved survival in a subset of patients with advanced lung cancer. PD-L1 protein expression has emerged as a biomarker that predicts which patients are more likely to respond to immunotherapy. The understanding of PD-L1 as a biomarker is complicated by the history of use of different immunohistochemistry platforms with different PD-L1 antibodies, scoring systems, and positivity cut-offs for immunotherapy clinical trials with different anti-PD L1 and anti-PD-1 drugs. Herein, we summarize the brief history of PD-L1 as a biomarker and describe the challenges remaining to harmonize PD-L1 detection and interpretation for best patient care. PMID- 27117835 TI - Studying self-awareness in children: validation of the Questionnaire of Executive Functioning (QEF). AB - OBJECTIVE: People with accurate representations of their own cognitive functioning (i.e. cognitive self-awareness) tend to use appropriate strategies to regulate their behavior. Due to the lack of appropriate instruments, few studies have examined the development of this ability among children. METHOD: This study tested the measurement properties of the self-rating and other-rating forms of the Questionnaire of Executive Functioning (QEF), designed to tap children's knowledge of their executive functioning. Specifically, the construct, convergent, and discriminant validities were investigated and a self-other discrepancy score was computed to assess children's executive self-awareness. Participants were 317 children aged 7-14 years old. RESULTS: Confirmatory factor analyses carried out on the QEF confirmed the eight-factor structure of both versions. There were significant correlations between the QEF and the parent versions of the Behavior Rating Inventory of Executive Function, the Dysexecutive Questionnaire for Children, and the Childhood Executive Functioning Inventory. Both forms of the QEF were able to distinguish between children who had sustained a traumatic brain injury (TBI) and control participants. A statistical difference was observed between the TBI and control groups on this score, suggesting that TBI may trigger self-awareness impairments in children. CONCLUSION: The good psychometric properties of the two forms of the QEF were established. Furthermore, results of the analyses carried out on the different discrepancy scores seem to indicate that the QEF could help clinicians to detect patients with self-awareness deficits. PMID- 27117836 TI - Association between autism symptoms and functioning in children with ADHD. AB - OBJECTIVE: To examine the association between autism spectrum disorder (ASD) symptoms and (a) social functioning, (b) mental health, (c) quality of life and (d) sleep in children with and without attention-deficit hyperactivity disorder (ADHD). METHODS: Participants were 6-10-year-old children with ADHD (N=164) and without ADHD (N=198). ADHD was assessed via community-based screening (wave 1) and case confirmation using the Diagnostic Interview Schedule for Children IV (DISC-IV) (wave 2). ASD symptoms were identified using the Social Communication Questionnaire (SCQ). Outcome measures were social functioning (Strengths and Difficulties Questionnaire (SDQ)), mental health (DISC-IV, SDQ), quality of life (QoL, Pediatric Quality of Life Inventory 4.0) and sleep problem severity. RESULTS: Greater ASD symptoms were associated with more parent and teacher reported peer problems and emotional and conduct problems. For every SD increase in SCQ scores, internalising (OR 1.8, 95% CI 1.3 to 2.6, p=0.001) and externalising disorders (OR 1.5, 95% CI 1.1 to 2.1, p=0.02) increased, QoL decreased by 6.7 units (p<0.001), and moderate/severe sleep problems increased (OR 1.5, 95% CI 1.0 to 2.2, p=0.04). Most findings held in analyses adjusting for socio-demographic factors, ADHD symptom severity and comorbidities (when not the outcome), with the exception of externalising disorders and sleep problems. CONCLUSIONS: ASD symptoms are associated with poorer functioning in children with ADHD. It is important to identify and potentially manage ASD symptoms in children with ADHD given that they exacerbate functional impairments in this already vulnerable group. PMID- 27117837 TI - Back to school: challenges and rewards of engaging young children in scientific research. PMID- 27117838 TI - Toxic shock syndrome in Australian children. AB - BACKGROUND: There are limited data describing the epidemiology, management and outcomes of children with toxic shock syndrome (TSS), a potentially life threatening illness. Here, we describe the incidence, clinical features, treatment and outcome of children with staphylococcal and streptococcal TSS in Victoria, Australia. METHODS: Retrospective chart review of children admitted between 2003 and 2014 to two tertiary paediatric referral centres who fulfilled the Centers for Disease Control and Prevention case definition of TSS. RESULTS: There were 62 cases over the 11-year period; 43 staphylococcal TSS and 19 streptococcal TSS. The majority (46 (74%)) of cases were admitted to an intensive care unit and 44 (71%) required inotropic support. Compared with those with staphylococcal TSS, patients with streptococcal TSS were younger, more unwell and more likely to have residual morbidity. Adjunctive therapy with intravenous immunoglobulin or clindamycin was used in 58 (94%) of cases and fresh frozen plasma was used in 15 (24%). Seven patients received extracorporeal membrane oxygenation. All patients survived. CONCLUSIONS: This study highlights the importance of early recognition of TSS and supports rapid tertiary referral and intensive care management, which includes the use of adjunctive therapy with intravenous immunoglobulin and clindamycin. PMID- 27117839 TI - Melatonin attenuates traumatic brain injury-induced inflammation: a possible role for mitophagy. AB - Melatonin functions as a crucial mediator of sterile neuroinflammation; however, the underlying mechanisms remain poorly understood. Dysfunctional mitochondria, a main source of reactive oxygen species, are impacted in inflammation activation. This study aimed to examine the effect of melatonin on inflammation via elimination of damaged mitochondria after controlled cortical impact, an in vivo model of traumatic brain injury (TBI). Here, we demonstrated that inhibition of mitophagy, the selective degradation of damaged mitochondria by autophagy, markedly enhanced inflammation induced by TBI. Melatonin treatment activated mitophagy through the mTOR pathway, then to attenuate TBI-induced inflammation. Furthermore, treatment with melatonin significantly ameliorated neuronal death and behavioral deficits after TBI, while 3-methyladenine reversed this effect by inhibiting mitophagy. Taken together, these results highlight a role for melatonin in protecting against TBI-triggered immunopathology, which is accomplished by negatively regulating inflammation activation and IL-1beta secretion via the autophagy of damaged mitochondria. PMID- 27117840 TI - Sleep, circadian rhythm and body weight: parallel developments. AB - Circadian alignment is crucial for body-weight management, and for metabolic health. In this context, circadian alignment consists of alignment of sleep, meal patterns and physical activity. During puberty a significant reduction in sleep duration occurs, and pubertal status is inversely associated with sleep duration. A consistent inverse association between habitual sleep duration and body-weight development occurs, independent of possible confounders. Research on misalignment reveals that circadian misalignment affects sleep-architecture and subsequently disturbs glucose-insulin metabolism, substrate oxidation, leptin- and ghrelin concentrations, appetite, food reward, hypothalamic-pituitary-adrenal-axis activity and gut-peptide concentrations enhancing positive energy balance and metabolic disturbance. Not only aligning meals and sleep in a circadian way is crucial, also regular physical activity during the day strongly promotes the stability and amplitude of circadian rhythm, and thus may serve as an instrument to restore poor circadian rhythms. Endogenicity may play a role in interaction of these environmental variables with a genetic predisposition. In conclusion, notwithstanding the separate favourable effects of sufficient daily physical activity, regular meal patterns, sufficient sleep duration and quality sleep on energy balance, the overall effect of the amplitude and stability of the circadian rhythm, perhaps including genetic predisposition, may integrate the separate effects in an additive way. PMID- 27117841 TI - eSTGt: a programming and simulation environment for population dynamics. AB - BACKGROUND: We have previously presented a formal language for describing population dynamics based on environment-dependent Stochastic Tree Grammars (eSTG). The language captures in broad terms the effect of the changing environment while abstracting away details on interaction among individuals. An eSTG program consists of a set of stochastic tree grammar transition rules that are context-free. Transition rule probabilities and rates, however, can depend on global parameters such as population size, generation count and elapsed time. In addition, each individual may have an internal state, which can change during transitions. RESULTS: This paper presents eSTGt (eSTG tool), an eSTG programming and simulation environment. When executing a program, the tool generates the corresponding lineage trees as well as the internal states values, which can then be analyzed either through the tool's GUI or using MATLAB's command-line environment. CONCLUSIONS: The presented tool allows researchers to use existing biological knowledge in order to model the dynamics of a developmental process and analyze its behavior throughout the historical events. Simulated lineage trees can be used to validate various hypotheses in silico and to predict the behavior of dynamical systems under various conditions. Written under MATLAB environment, the tool also enables to easily integrate the output data within the user's downstream analysis. PMID- 27117842 TI - Clinical and Pathologic Predictors of Lymph Node Metastasis and Recurrence in Papillary Thyroid Microcarcinoma. AB - BACKGROUND: The treatment for patients with papillary thyroid microcarcinoma (PTMC) is controversial because PTMC is often found incidentally and its prognosis is very good. Lymph node metastasis (LNM) is one of the main predictors of recurrence and survival. This retrospective study aimed to identify clinical and pathologic factors that increase the risk of metastasis or recurrence, in order to isolate clinically unfavorable PTMCs to help guide therapy. METHODS: Clinical and pathologic data were collected from 273 patients diagnosed with PTMC at The University of Chicago Medical Center between 2000 and 2011. Data points included age, sex, race/ethnicity, tumor size, multifocality, thyroiditis, extrathyroidal extension (ETE), surgical margins, preoperative clinical suspicion of cancer, central/lateral lymph nodes removed and lymph nodes with metastatic carcinoma, treatment, local recurrence, distant recurrence, and survival. RESULTS: Multivariate logistic regression showed that age <45 years (odds ratio [OR] = 3.565 [confidence interval (CI) 1.137-11.177]), multifocality (OR = 3.556 [CI 1.066-11.855]), and ETE (OR = 4.622 [CI = 1.068-20.011]) significantly increased the risk of central LNM (CLNM). However, sex, size of tumor, thyroiditis, positive margins, and clinical suspicion were not correlated with an increased risk for CLNM. Multivariate logistic regression showed that only ETE (OR = 16.066 [CI 1.850-139.488]) significantly increased the risk of lateral LNM. In the cohort of 202 patients with follow-up data, only six recurred. Median time to recurrence was approximately 12 months (range 3.5-120 months), and median follow-up was 42 months. No patient had distant metastasis, and no patients died. CONCLUSIONS: PTMC is an indolent disease, but does pose a risk for LNM and local recurrence. More aggressive treatment or more frequent follow-up could be considered for patients with unfavorable features (age <45 years, multifocality, ETE), especially in the setting of involved lymph nodes at the time of surgical resection, as these patients may be at an increased risk for recurrence. PMID- 27117843 TI - Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis. AB - BACKGROUND: Patients with Crohn's disease (CD) have serologic responses to various microbial antigens. Serologic markers are associated with aggressive forms of disease and can be detected before onset of symptoms. Their utility in pre-clinical disease or prediction of complicated disease course before diagnosis is unclear. AIM: To evaluate the pattern of serologic anti-microbial antibodies long prior to diagnosis and the subsequent risk of complicated Crohn's disease at diagnosis. METHODS: Sera from 100 US military personnel with Crohn's disease were obtained from the Department of Defense Serum Repository. For each patient, four samples were obtained at different time points before and around diagnosis, and were tested for 6 microbiota-directed antibodies (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2 and anti-FlaX). Associations between the presence and accumulation of Crohn's disease anti-microbial antibodies before diagnosis and with the later development of complications were evaluated. RESULTS: Overall, 65 patients were positive for at least one Crohn's disease associated anti-microbial antibody in the earliest available sample, at a median of 6 years before Crohn's disease diagnosis (interquartile range, 5.6-8.2). The number of positive anti microbial antibodies increased up to the time of Crohn's disease diagnosis. Complicated disease developed around the time of diagnosis in 24 patients. The proportion of positive antimicrobial antibodies before diagnosis was higher in patients with complicated vs. noncomplicated Crohn's disease. There was an inverse relationship between the time to first complication and the magnitude of serologic response before diagnosis. CONCLUSION: The presence and accumulation of circulating anti-microbial antibodies years before Crohn's disease diagnosis was associated with complicated Crohn's disease at or shortly after diagnosis. PMID- 27117844 TI - Calcium and Vitamin D Deficiency in Vietnamese: Recommendations for an Intervention Strategy. AB - In recent years, reports have described various roles of vitamin D in human health. Vitamin D deficiency has emerged as a significant public health problem throughout the world. Even in the Vietnamese context, it has been reported to be present in a majority of the population in spite of the wide availability of sunlight. Vitamin D and calcium are essential nutrients for bone health. The proposed health benefits of vitamin D and calcium have attracted increased interest from health care professionals, the media, and the public. The aim of this paper is to summarize the published data on vitamin D and calcium intake as well as on the prevalence of vitamin D deficiency in the Vietnamese population, and to provide recommendations for a proper strategy to control calcium and vitamin D deficiency in this population. The national authorities should adopt policies aimed at improving vitamin D and calcium status by using measures such as dietary recommendations, food fortification, vitamin D supplementation, and judicious sun exposure. PMID- 27117845 TI - Administration of Thiamine and Thiochrome Enhanced Reproduction of Chlorella, Drosophila melanogaster, and Danio. AB - Thiochrome, a natural metabolite of thiamine, has scarcely attracted the attention of researchers, since many of them considered it to be a biologically inactive substance. We examined a possible effect of thiochrome upon the reproduction of the organisms of Chlorella, Drosophila, and Danio. We added thiamine or thiochrome to the culture medium or to the aquaria. Our data showed that the number of cells and organisms were increased in the presence of thiamine and thiochrome. We suggest possible effect(s) of thiamine and thiochrome on the reproduction of these organisms. PMID- 27117846 TI - Dehydroepiandrosterone Alters Retinol Status and Expression of the beta-Carotene 15,15'-Monooxygenase and Lecithin:Retinol Acyltransferase Genes. AB - Dehydroepiandrosterone (DHEA) and its sulfate ester DHEA-sulfate (DHEA-S) are the most abundant adrenal steroids in humans. DHEA has a critical role as a steroidal precursor of androgens and/or estrogens, and in human studies and animal experiments, both DHEA and DHEA-S have multiple beneficial effects. However, there are few reports regarding the relationship between DHEA and nutrient status, especially for vitamins. Therefore, we elucidated the effect of DHEA administration on retinol status. Wistar rats were fed with a standard diet containing 0.4% (wt/wt) DHEA for 2 wk. We assessed retinol status and the expression of retinol-related proteins, including metabolic enzymes, binding proteins, cytochrome P450 (CYP) enzymes, and antioxidant enzymes. Retinol levels in the plasma and the liver of DHEA-fed rats were lower than those of controls. Expression of beta-carotene 15,15'-monooxygenase (BCMO) in the liver and intestine of DHEA-fed rats was lower, whereas BCMO expression in the testes of DHEA-fed rats was higher than that of controls. Expression of the retinol metabolizing aldehyde dehydrogenase (ALDH) enzyme ALDH1A2 was repressed in the liver of DHEA rats, whereas ALDH1A1 expression was unaltered. Hepatic expression of lecithin:retinol acyltransferase (LRAT) and CYP26A1 was lower in DHEA-fed rats than in controls. Retinol status in DHEA-fed rats might be affected by altered BCMO expression in the liver and intestine and hepatic LRAT expression, whereas BCMO expression in peripheral tissues may be regulated in a tissue-specific manner. We have shown that DHEA administration may influence retinol status and the expression of retinol-related proteins. PMID- 27117847 TI - The Effects of Light and Temperature on Biotin Synthesis in Pea Sprouts. AB - Biotin is an essential micronutrient, and is a cofactor for several carboxylases that are involved in the metabolism of glucose, fatty acids, and amino acids. Because plant cells can synthesize their own biotin, a wide variety of plant based foods contains significant amounts of biotin; however, the influence of environmental conditions on the biotin content in plants remains largely unclear. In the present study, we investigated the effects of different cultivation conditions on the biotin content and biotin synthesis in pea sprouts (Pisum sativum). In the experiment, the pea sprouts were removed from their cotyledons and cultivated by hydroponics under five different lighting and temperature conditions (control [25oC, 12-h light/12-h dark cycle], low light [25oC, 4-h light/20-h dark cycle], dark [25oC, 24 h dark], low temperature [12oC, 12-h light/12-h dark cycle], and cold [6oC, 12-h light/12-h dark cycle]) for 10 d. Compared to the biotin content of pea sprouts under the control conditions, the biotin contents of pea sprouts under the low-light, dark, and cold conditions had significantly decreased. The dark group showed the lowest biotin content among the groups. Expression of the biotin synthase gene (bio2) was also significantly decreased under the dark and cold conditions compared to the control condition, in a manner similar to that observed for the biotin content. No significant differences in the adenosine triphosphate content were observed among the groups. These results indicate that environmental conditions such as light and temperature modulate the biotin content of pea plant tissues by regulating the expression of biotin synthase. PMID- 27117848 TI - Folic Acid Supplementation Reduces the Mutagenicity and Genotoxicity Caused by Benzo(a)pyrene. AB - Folate is a vital vitamin for the human being and its deficiency can lead to a variety of clinical abnormalities ranging from neural tube defects to cancers. Benzo(a)pyrene (BaP), a strong mutagen and carcinogen, is considered one of the common contaminants in food. The aim of this study was to investigate the positive effect of folate on cancer prevention at a fundamental level. In the present study, we investigated the impact of folic acid on BaP-induced mutagenicity and genotoxicity by means of in vitro and in vivo experiments. The reformed Ames test was applied to study the antimutagenicity of folic acid against BaP. The protective effect of folic acid on cytotoxicity caused by BaP in human liver cell line L02 was evaluated by MTT assay. In addition, the effect of folic acid on the BaP-induced genotoxicity in vivo was assessed by mouse bone marrow micronucleus assay. The results indicated that folic acid significantly inhibited the reverse mutation of Salmonella typhimurium strains TA98 and TA100, and protected the viability of human liver cells against BaP (p<0.01). The micronucleus test showed that all doses of folic acid had a remarkable protective effect for the female mice (p<0.01). In conclusion, folic acid was found to reduce the mutagenicity and genotoxicity induced by BaP. PMID- 27117849 TI - Capric Acid Up-Regulates UCP3 Expression without PDK4 Induction in Mouse C2C12 Myotubes. AB - Uncoupling protein 3 (UCP3) and pyruvate dehydrogenase kinase 4 (PDK4) in skeletal muscle are key regulators of the glucose and lipid metabolic processes that are involved in insulin resistance. Medium-chain fatty acids (MCFAs) have anti-obesogenic effects in rodents and humans, while long-chain fatty acids (LCFAs) cause increases in body weight and insulin resistance. To clarify the beneficial effects of MCFAs, we examined UCP3 and PDK4 expression in skeletal muscles of mice fed a MCFA- or LCFA-enriched high-fat diet (HFD). Five-week feeding of the LCFA-enriched HFD caused high body weight gain and induced glucose intolerance in mice, compared with those in mice fed the MCFA-enriched HFD. However, the amounts of UCP3 and PDK4 transcripts in the skeletal muscle of mice fed the MCFA- or LCFA-enriched HFD were similar. To further elucidate the specific effects of MCFAs, such as capric acid (C10:0), on lipid metabolism in skeletal muscles, we examined the effects of various FAs on expression of UCP3 and PDK4, in mouse C2C12 myocytes. Although palmitic acid (C16:0) and lauric acid (C12:0) significantly induced expression of both UCP3 and PDK4, capric acid (C10:0) upregulated only UCP3 expression via activation of peroxisome proliferator-activated receptor-delta. Furthermore, palmitic acid (C16:0) disturbed the insulin-induced phosphorylation of Akt, while MCFAs, including lauric (C12:0), capric (C10:0), and caprylic acid (C12:0), did not. These results suggest that capric acid (C10:0) increases the capacity for fatty acid oxidation without inhibiting glycolysis in skeletal muscle. PMID- 27117850 TI - The Effects of a Hypocaloric Diet on Diet-Induced Thermogenesis and Blood Hormone Response in Healthy Male Adults: A Pilot Study. AB - Calorie restriction is a common strategy for weight loss and management. Consumption of food and nutrients stimulates diet-induced thermogenesis (DIT), as well as pancreatic and gastrointestinal hormone secretion that may regulate energy metabolism. Yet, little is known about the impact of hypocaloric diets on energy metabolism-related parameters. In this study, we assessed the effects of hypocaloric diets on hormonal variance in relation to DIT in healthy adults. Ten healthy male adults were enrolled in a randomized crossover study comprising three meal trials. Each subject was given a meal of 200 (extremely hypocaloric), 400 (moderately hypocaloric), or 800 kcal (normocaloric). Postprandial blood variables and energy expenditure were measured for 4 h (after the 200- and 400 kcal meals) or 6 h (after the 800-kcal meal). DIT and postprandial changes in blood pancreatic peptide and ghrelin were significantly smaller after the extremely or moderately hypocaloric diet than after the normocaloric diet but were similar between the hypocaloric diets. Postprandial blood insulin, amylin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide type-1 (GLP-1) increased in a calorie-dependent manner. Thermogenic efficiency (DIT per energy intake) was negatively correlated with the maximum blood level (Cmax) (p=0.01) and incremental area under the curve (p=0.01) of the blood GIP response. Calorie restriction thus leads to hormonal responses and lower DIT in healthy adults. Extreme calorie restriction, however, led to greater thermogenic efficiency compared with moderate calorie restriction. The postprandial GIP response may be a good predictor of postprandial thermogenic efficiency. PMID- 27117851 TI - Factors Associated with Dietary Supplement Use among Preschool Children: Results from a Nationwide Survey in Japan. AB - This study was performed to reveal factors associated with dietary supplement use among Japanese preschool children in a nationwide survey. A cross-sectional, Internet survey was conducted among 2,058 mothers aged 20-40 y old who had preschool children and were registrants of a Japanese social research company in February 2013. The questionnaires assessed dietary supplement use, lifestyle and eating habits in both children and their mothers, eating awareness among mothers and the mothers' sources of health information. The study employed logistic regression analysis to evaluate the association between dietary supplement use and other variables. Dietary supplements were used by 8.0% of the children. Children who used supplements tended to be older in age, less likely to "get up cheerfully every morning," more likely to skip breakfast, eat out more frequently, and have mothers who used supplements, than children who did not use supplements. Mothers' level of education and household income were not associated with supplement use among their children. It is likely that mothers' anxiety about their children's health or unhealthy eating habits has a striking effect on supplement use among children. However, the actual dietary balance and daily rhythms of child supplement users were not irregular or unhealthy. It is necessary to give more accurate information on children's dietary habits and health to address mothers' anxiety. PMID- 27117852 TI - Efficacy of Ascorbic Acid (Vitamin C) and/N-Acetylcysteine (NAC) Supplementation on Nutritional and Antioxidant Status of Male Chronic Obstructive Pulmonary Disease (COPD) Patients. AB - Antioxidant therapy has a potential to be introduced as therapeutic modality for chronic obstructive pulmonary disease (COPD) patients. This study aimed to determine the effect of antioxidant supplementation [ascorbic acid and N Acetylcysteine (NAC)] on nutritional and antioxidant status in male COPD patients. A parallel and single blind randomised controlled clinical trial (RCT) was conducted at two medical centers in Kuala Lumpur, Malaysia. Seventy-nine subjects were recruited and randomly divided into four trial arms (i.e., NAC, vitamin C, NAC+vitamin C and control groups) for six mo. The primary outcome was changes in body mass index by estimating power of 90% and significance level of p<0.05. Repeated Measure ANOVA showed that there was a significant interaction effect on BMI (p=0.046) and carbohydrate intake (p=0.030), especially in the NAC group. Plasma glutathione (GSH) increased significantly in all intervention groups, especially in vitamin C (p=0.005). A single supplementation of NAC or vitamin C improved nutritional and antioxidant status of subjects. PMID- 27117853 TI - Effects of Resistant Glucan Mixture on Bowel Movement in Female Volunteers. AB - Resistant glucan (RG) is a water-soluble polysaccharide resistant to hydrolysis by digestive enzymes in the human gastrointestinal system. RG mixture (RGM) contains more than 75% RG as dietary fiber and other saccharides. The effects of ingestion of 3.3, 6.6, and 13.2 g/d of RGM (containing of 2.5, 5.0, and 10.0 g/d RG as dietary fiber) on the fecal properties and the frequency of defecation were investigated in 60 female volunteers with constipation. The study was designed as a randomized, single-blinded, and placebo-controlled parallel-group trial. Each subject consumed RGM or a placebo (digestible maltodextrin) for 2 wk. Questionnaire data on the effects on bowel movement were analyzed according to defecation days, defecation frequency, fecal volume, fecal shapes, fecal color, fecal odor, and fecal excretory feeling. The results showed significant increases in defecation frequency (p<0.05), defecation days (p<0.05), and fecal volume (p<0.05) during the 13.2 g/d RGM ingestion period. The effects of RGM on defecation days and frequency showed a dose-dependent increase (p<0.05). These results suggested that the intake of RGM increased defecation days, defecation frequency, and fecal volume. In the gastrointestinal tract, RGM is useful as a water-soluble dietary fiber for the improvement of bowel movements. PMID- 27117855 TI - Errata. PMID- 27117854 TI - Immune Milk Suppresses Herpes Simplex Virus Type 1. AB - Immune milk has been developed as a substitute for colostrum and contains a high concentration of IgG antibodies specific to the immunized pathogens. Meanwhile, bovine herpesvirus type-1 (BHV-1) naturally infects cattle worldwide, and its antibody is found in milk. Moreover, BHV-1 glycoprotein K, the major antigen, exhibits substantial homology with human herpes virus simplex 1 (HSV-1) glycoprotein K. On the basis of this evidence, we hypothesized BHV-1 antibody exists in immune milk and suppresses HSV-1 activity. This study investigated whether immune milk IgG recognizes HSV-1 and suppresses HSV-1 activity. IgG in immune milk was purified by affinity Protein A columns, and HSV-1-reactive IgG in immune milk IgG was detected and quantified by ELISA. The efficacy of the IgG against HSV-1 was analyzed using a reduction assay based on the cytopathic effect due to HSV-1 in the presence of macrophages. We detected a high concentration of HSV-1-reactive IgG in immune milk. Furthermore, IgG suppressed HSV-1 pathogenicity in the presence of macrophages. These results indicate immune milk has protective activity against HSV-1 by opsonic activity owing to its high concentration of HSV-1-reactive IgG, which is likely the BHV-1 antibody. HSV-1 is currently a refractory infection with a worldwide distribution. Primary infection occurs via the oral cavity, but there is no effective precaution at this time. However, the present results suggest that taking oral immune milk may be an effective measure to prevent primary HSV-1 infection in the oral cavity. PMID- 27117856 TI - Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C]( R)PK11195. AB - The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BPND) in various brain regions using a first-generation translocator protein (TSPO) tracer [11C]( R)PK11195 and a second-generation tracer [11C]DPA713. The BPND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer's disease (AD) and were correlated with clinical scores. An analysis of variance showed category-dependent elevation in levels of [11C]DPA713 BPND in all brain regions and showed a significant increase in the AD group, whereas no significant changes among groups were found when [11C]( R)PK11195 BPND was used. Cognito-mnemonic scores were significantly correlated with [11C]DPA713 BPND levels in many brain regions, whereas [11C]( R)PK11195 BPND failed to correlate with the scores. As mentioned elsewhere, the present results confirmed that the second-generation TSPO tracer [11C]DPA713 has a greater sensitivity to TSPO in both aging and neuronal degeneration than [11C]( R)PK11195. Positron emission tomography with [11C]DPA713 is suitable for the delineation of in vivo microglial activation occurring globally over the cerebral cortex irrespective of aging and degeneration. PMID- 27117857 TI - Switching to biosimilar infliximab (CT-P13): Evidence of clinical safety, effectiveness and impact on public health. AB - CT-P13, the biosimilar of infliximab, has been recently approved in the EU, Australia, Canada, Japan and many other countries. Thus, it was the first biosimilar approved in the field of rheumatology, dermatology and gastroenterology. Since there has been debate about the issue of switching from RMP to the biosimilar and some national societies have expressed concerns, this review was written with the following objectives: The review concludes that whilst prudent switching practices should be employed, growing safety experience accumulated thus far with CT-P13 and other biosimilars is favorable and does not raise any specific concerns. PMID- 27117858 TI - 3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response. AB - 3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter's improved long-term stability and mechanical performance. PMID- 27117859 TI - Resourcing an evolution of roles in general-practice: a study to determine the validity and reliability of tools to assist nurses and patients to assess physical activity. AB - Traditionally, GPs have been responsible for physical activity (PA) assessment within the general practice setting. Multiple questionnaires are available to support uptake of PA assessment but less than 30% of patients are assessed. A range of barriers hamper uptake. Evidence indicates that practice nurses (PNs) and patients are resourceful members of the general practice team but have been underutilised. This study assessed the validity and reliability of two instruments for assessing PA, administered by PNs and patients. The study aimed to identify robust tool(s) to support the evolving role of PNs and patients in prevention and management strategies in general practice. A purposive sample of PNs and patients from general practices in Sydney was invited to participate. The results of the PN- or patient-administered general practice physical activity questionnaire (GPPAQ) and the three-question physical activity questionnaire (3Q) were compared against accelerometer activity. The study examined agreement in classification of PA levels according to Australian PA recommendations. Validity showed low-moderate correlations between accelerometer and GPPAQ (rho=0.26), 3Q (rho=0.45). Seven-day test-retest reliability intraclass correlation coefficients (ICCs) were 0.82-0.95 for GGPAQ and 0.94-0.98 for 3Q. Agreement with PA recommendations was moderate for GPPAQ (kappa 0.73, 95% CI, 0.56-0.85) and fair for 3Q (kappa 0.62, 95% CI, 0.47-0.78). Although 3Q demonstrated higher correlation with accelerometry, GPPAQ demonstrated higher agreement with PA guidelines. Given GPPAQ showed reasonable rigour, it may prove useful for PN and patient use. PMID- 27117860 TI - The effect of maneuvers for shoulder delivery on perineal trauma: a randomized controlled trial. AB - INTRODUCTION: Approximately 85% of vaginal deliveries are accompanied by perineal trauma. The objective of this trial was to compare the incidence of perineal trauma after primary delivery of either the anterior or posterior shoulder during vaginal delivery. MATERIAL AND METHODS: This was a randomized single-blinded trial comparing primary delivery of either the anterior or posterior shoulder in women having their first vaginal delivery. Primary outcome was any perineal trauma. Results were analyzed according to the intention-to-treat principle and supplemented with a per-protocol and as-treated analysis. RESULTS: Between June 2013 and March 2015, 650 women were randomized, and 543 (posterior, n = 281; anterior, n = 262) were included in the final intention-to-treat analysis. Most group characteristics were similar. The frequency of any perineal trauma did not differ between the two groups (posterior: 91.5%, anterior: 90.5%; odds ratio 1.130, 95% confidence interval 0.628-2.032, p = 0.684). The results did not change after adjustment for basic characteristics with significant group differences (a1 odds ratio 1.174, 95% confidence interval 0.632-2.179, p = 0.612) or predefined risk factors (a2 odds ratio 1.139, 95% confidence interval 0.599 2.166, p = 0.691). The rate of perineal trauma also did not differ between the groups in a "per-protocol" and "as-treated" analysis. CONCLUSIONS: There was no difference in the degree of perineal trauma after primary delivery of either the anterior or posterior shoulder. Consequently both maneuvers for shoulder delivery can be used at vaginal delivery, but further trials are warranted before certain methods can be recommended. PMID- 27117861 TI - De novo assembly of complete genome sequence of Planococcus kocurii ATCC 43650(T), a potential plant growth promoting bacterium. AB - Planococcus kocurii ATCC 43650(T) is a halotolerant and psychrotolerant bacterium isolated from the skin of a North sea cod. Here, we present the first complete genome and annotation of P. kocurii ATCC 43650(T), identifying its potential as a plant growth promoting bacterium and its capability in the biosynthesis of butanol. PMID- 27117862 TI - Generation of exogenous germ cells in the ovaries of sterile NANOS3-null beef cattle. AB - Blastocyst complementation (BC) systems have enabled in vivo generation of organs from allogeneic pluripotent cells, compensating for an empty germ cell niche in gene knockout (KO) animals. Here, we succeeded in producing chimeric beef cattle (Wagyu) by transferring allogenic germ cells into ovaries using somatic cell nuclear transfer and BC technology. The KO of NANOS3 (NANOS3(-/-)) in Wagyu bovine ovaries produced a complete loss of germ cells. Holstein blastomeres (NANOS3(+/+)) were injected into NANOS3(-/-) Wagyu embryos. Subsequently, exogenous germ cells (NANOS3(+/+)) were identified in the NANOS3(-/-) ovary. These results clearly indicate that allogeneic germ cells can be generated in recipient germ cell-free gonads using cloning and BC technologies. PMID- 27117863 TI - Structural insights into ribosome translocation. AB - During protein synthesis, tRNA and mRNA are translocated from the A to P to E sites of the ribosome thus enabling the ribosome to translate one codon of mRNA after the other. Ribosome translocation along mRNA is induced by the universally conserved ribosome GTPase, elongation factor G (EF-G) in bacteria and elongation factor 2 (EF-2) in eukaryotes. Recent structural and single-molecule studies revealed that tRNA and mRNA translocation within the ribosome is accompanied by cyclic forward and reverse rotations between the large and small ribosomal subunits parallel to the plane of the intersubunit interface. In addition, during ribosome translocation, the 'head' domain of small ribosomal subunit undergoes forward- and back-swiveling motions relative to the rest of the small ribosomal subunit around the axis that is orthogonal to the axis of intersubunit rotation. tRNA/mRNA translocation is also coupled to the docking of domain IV of EF-G into the A site of the small ribosomal subunit that converts the thermally driven motions of the ribosome and tRNA into the forward translocation of tRNA/mRNA inside the ribosome. Despite recent and enormous progress made in the understanding of the molecular mechanism of ribosome translocation, the sequence of structural rearrangements of the ribosome, EF-G and tRNA during translocation is still not fully established and awaits further investigation. WIREs RNA 2016, 7:620-636. doi: 10.1002/wrna.1354 For further resources related to this article, please visit the WIREs website. PMID- 27117864 TI - Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia. AB - Dietary strategies to alter the immune response to acute inflammation have the potential to improve outcomes in critically ill patients. A eucaloric ketogenic diet (EKD), composed predominantly of fat with very small amounts of carbohydrate, can provide adequate caloric support while minimizing spikes in blood glucose and reducing oxidative stress. The purpose of this study was to evaluate the effects of an EKD on glycemic control and the inflammatory response after acute endotoxemia in mice. Mice received either an EKD or a carbohydrate based control diet (CD) for 4 weeks. Animals subsequently underwent either a 2-h fast (postprandial) or an overnight fast (postabsorptive), and half of the animals in each diet group were randomized to receive either intraperitoneal lipopolysaccharide (1 mg/kg) or an equivalent volume of saline. Glycemic response, insulin resistance, inflammatory cytokine levels, and the expression of key inflammatory and metabolic genes were measured. After endotoxin challenge, hypoglycemia was more frequent in mice fed a CD than an EKD in the postprandial period. This was due in part to the preservation of hepatic glycogen stores despite endotoxin exposure and prolonged fasting in mice fed an EKD. Furthermore, mice fed the CD had higher levels of IL-6 and TNF-alpha in the postabsorptive period, with a fivefold higher expression of hepatic NFkappaB compared to mice fed the EKD in both fasting periods. These results suggest that the unique metabolic state induced by an EKD can alter the response to acute inflammation in mice. PMID- 27117866 TI - Arthroscopic Management of Hip Chondral Defects: A Systematic Review of the Literature. AB - PURPOSE: To critically evaluate the evidence for arthroscopic management of chondral defects in the hip through a systematic literature review. METHODS: A systematic literature review was performed to identify all articles addressing the arthroscopic management of chondral defects about the hip. Case reports, open techniques, and those associated with osteonecrosis were excluded. Articles were assessed for sample size, location, severity, and size of chondral defects, and the surgical technique. Associated injuries, follow-up duration (months), and functional outcomes were recorded. Study cohorts were defined by a surgical technique (debridement v microfracture v autologous chondrocyte transplantation [ACT]). Statistical analysis was performed with a chi(2) test and analysis of variance with post hoc pairwise analysis for categorical and continuous data, respectively, with significance defined as P < .05. RESULTS: The literature search identified 269 articles, of which 12 clinical studies met inclusion criteria for this analysis. After pooling the data, there were 579 (64.7%) debridements, 279 (31.2%) microfracture, and 37 (4.1%) ACT performed. Patients were followed for an average of 27.1 months (range: 5 to 72 months). All lesions treated with either a microfracture or ACT were high grade (Outerbridge 3 to 4). However, lesion size was significantly larger in ACT-treated patients compared with those who underwent microfracture (357.3 +/- 96.0 mm(2)v 149.5 +/- 20.7 mm(2); P = .020). All cohorts showed significant improvement in functional outcomes after hip arthroscopy (P < .001). CONCLUSIONS: This systematic review showed that arthroscopic debridement, microfracture, and ACT are associated with equivalent improvement in clinical outcomes in patients with high-grade chondral defects in the hip in the short- and midterm follow-up. In addition, although there were no differences in patient characteristics and demographics based on the surgical technique, we confirmed the hypothesis that lesion size varied significantly between arthroscopic techniques, and that the decision to use one technique over another may be determined by the size of the defect. Therefore, lesion size is likely to influence the development of hip- and technique-specific indications, and may also represent a useful metric for success of surgical intervention. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 27117867 TI - 5-hydroxymethylcytosine is detected in RNA from mouse brain tissues. AB - 5-hydroxymethylcytosine (5hmC) is considered as a novel DNA modification and plays an important role in cancer, stem cells, and developmental diseases. In this study, we demonstrated the existence of RNA 5hmC modification in mouse brain RNA by using a dot blot analysis method. Our data indicated that 5hmC modification in RNA samples was less than that in DNA samples. Further, we optimized the conditions for 5hmC detection in RNA samples such as DNase treatment, denature reagents, denature time, sample air-dry time, and the cross linking time between RNA and membrane. Our results demonstrated that DNase treatment and denature reagents were two important factors that affected the 5hmC detection in RNA samples. By using the optimal conditions for RNA 5hmC detection, we found that the brainstem, the hippocampus, and the cerebellum had high levels of 5hmC modification and 5mC modification in RNA. Finally, we found that RNA 5hmC modification decreased in MPTP-induced Parkinson's disease model in mice. These suggest that 5hmC modification in RNA might play an important regulative role on protein or microRNA expression in these brain tissues. Because DNA 5hmC modification plays an important role in neural differentiation and development as well as neurological diseases, the significance of 5hmC modification in RNA in different neurological diseases needs further investigation. In summary, our study demonstrated for the first time the abundance of 5hmC modification in brain RNA by using a dot blot analysis method and proved that dot blot analysis is a useful method for 5hmC detection in RNA samples. PMID- 27117868 TI - The motor and visual networks in preterm infants: An fMRI and DTI study. AB - Knowledge regarding the association between functional connectivity and white matter (WM) maturation of motor and visual networks in preterm infants at term equivalent age (TEA) and their association with behavioral outcome is currently limited. Thirty-two preterm infants born <34 weeks gestational-age without major brain abnormalities were included in this study, underwent resting-state fMRI at TEA. Thirteen infants also underwent diffusion tensor imaging (DTI). Neurobehavioral assessments were performed at one and two years corrected age using the Griffiths Mental Developmental Scales. Functional connectivity between homolog motor and visual regions were detected, which may reflect that a level of organization in these domains is present already at TEA. DTI parameters of WM tracts at TEA demonstrated spatial-temporal variability, with the splenium of the corpus-callosum (CC) found to be the most mature fiber bundle. Correlations between DTI parameters, functional connectivity and behavioral outcome were detected, yet did not show the same pattern of diffusivity changes in the different networks. Visual functional connectivity was negatively correlated with radial-diffusivity (RD) in the optic radiation, while motor functional connectivity was positively correlated with RD in the splenium. In addition, axial-diffusivity (AD) and RD in the genu and midbody of the CC were positively correlated with neurobehavioral outcome at one and 2 years of age. This study highlights the importance of understanding the spatial-temporal changes occurring during this sensitive period of development and the potential effect of extrauterine exposure on the microstructural changes as measured by DTI; their correlation with functional connectivity; and their long term relationship with neuro-behavioral development. PMID- 27117865 TI - Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias. AB - The first discovered member of the mammalian FABP family, liver fatty acid binding protein (FABP1, L-FABP), occurs at high cytosolic concentration in liver, intestine, and in the case of humans also in kidney. While the rat FABP1 is well studied, the extent these findings translate to human FABP1 is not clear especially in view of recent studies showing that endocannabinoids and cannabinoids represent novel rat FABP1 ligands and FABP1 gene ablation impacts the hepatic endocannabinoid system, known to be involved in non-alcoholic fatty liver (NAFLD) development. Although not detectable in brain, FABP1 ablation nevertheless also impacts brain endocannabinoids. Despite overall tertiary structure similarity, human FABP1 differs significantly from rat FABP1 in secondary structure, much larger ligand binding cavity, and affinities/specificities for some ligands. Moreover, while both mouse and human FABP1 mediate ligand induction of peroxisome proliferator activated receptor alpha (PPARalpha), they differ markedly in pattern of genes induced. This is critically important because a highly prevalent human single nucleotide polymorphism (SNP) (26-38 % minor allele frequency and 8.3 +/- 1.9 % homozygous) results in a FABP1 T94A substitution that further accentuates these species differences. The human FABP1 T94A variant is associated with altered body mass index (BMI), clinical dyslipidemias (elevated plasma triglycerides and LDL cholesterol), atherothrombotic cerebral infarction, and non-alcoholic fatty liver disease (NAFLD). Resolving human FABP1 and the T94A variant's impact on the endocannabinoid and cannabinoid system is an exciting challenge due to the importance of this system in hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety. PMID- 27117869 TI - Non-symbolic and symbolic notations in simple arithmetic differentially involve intraparietal sulcus and angular gyrus activity. AB - Addition problems can be solved by mentally manipulating quantities for which the bilateral intraparietal sulcus (IPS) is likely recruited, or by retrieving the answer directly from fact memory in which the left angular gyrus (AG) and perisylvian areas may play a role. Mental addition is usually studied with problems presented in the Arabic notation (4+2), and less so with number words (four+two) or dots (:: +..). In the present study, we investigated how the notation of numbers influences processing during simple mental arithmetic. Twenty five highly educated participants performed simple arithmetic while their brain activity was recorded with functional magnetic resonance imaging. To reveal the effect of number notation, arithmetic problems were presented in a non-symbolic (Dots) or symbolic (Arabic; Words) notation. Furthermore, we asked whether IPS processing during mental arithmetic is magnitude specific or of a more general, visuospatial nature. To this end, we included perception and manipulation of non magnitude formats (Colors; unfamiliar Japanese Characters). Increased IPS activity was observed, suggesting magnitude calculations during addition of non symbolic numbers. In contrast, there was greater activity in the AG and perisylvian areas for symbolic compared to non-symbolic addition, suggesting increased verbal fact retrieval. Furthermore, IPS activity was not specific to processing of numerical magnitude but also present for non-magnitude stimuli that required mental visuospatial processing (Color-mixing; Character-memory measured by a delayed match-to-sample task). Together, our data suggest that simple non symbolic sums are calculated using visual imagery, whereas answers for simple symbolic sums are retrieved from verbal memory. PMID- 27117870 TI - Injury to the nervous system: A look into the ER. AB - Injury to the central or peripheral nervous systems leads to the loss of cognitive and/or sensorimotor capabilities that still lack an effective treatment. Although injury to the nervous system involves multiple and complex molecular factors, alteration to protein homeostasis is emerging as a relevant pathological mechanism. In particular, chronic endoplasmic reticulum (ER) stress is proposed as a possible driver of neuronal dysfunction in conditions such as spinal cord injury, stroke and damage to peripheral nerves. Importantly, manipulation of the unfolded protein response (UPR), a homeostatic pathway engaged by ER stress, has proved effective in improving cognitive and motor recovery after nervous system injury. Here we provide an overview on recent findings depicting a functional role of the UPR to the functional recovery after injury in the peripheral and central nervous systems. This article is part of a Special Issue entitled SI:ER stress. PMID- 27117871 TI - Endoplasmic reticulum stress in human photoreceptor diseases. AB - Photoreceptors are specialized sensory neurons essential for light detection in the human eye. Photoreceptor cell dysfunction and death cause vision loss in many eye diseases such as retinitis pigmentosa and achromatopsia. Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling have been implicated in the development and pathology of heritable forms of retinitis pigmentosa and achromatopsia. We review the role of ER stress and UPR in retinitis pigmentosa arising from misfolded rhodopsins (RHO) and in achromatopsia arising from genetic mutations in Activating Transcription Factor 6 (ATF6). This article is part of a Special Issue entitled SI:ER stress. PMID- 27117872 TI - sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss. AB - sFRP4 is an extracellular Wnt antagonist that fine-tunes its signal activity by direct binding to Wnts. Bone fragility under oxidative stress by diabetes and aging is partly related to the suppression of the Wnt signal through upregulated sFRP4. Here, to explore the functions of sFRP4 as a balancer molecule in bone development and remodeling, we analyzed the sFRP4 knock-in mouse strain. X-gal and immunohistochemically stained signals in sFRP4-LacZ heterozygous mice were detectable in restricted areas, mostly in osteoblasts and osteoclasts, of the femoral diaphysis after neonatal and postnatal stages. Histological and MUCT analyses showed increased trabecular bone mass with alteration of the Wnt signal and osteogenic activity in sFRP4 mutants; this augmented the effect of the buildup of trabecular bone during the ageing period. Our results indicate that sFRP4 plays a critical role in bone development and remodeling by regulating osteoblasts and osteoclasts, and that its functional loss prevents age-related bone loss in the trabecular bone area. These findings imply that sFRP4 functions as a key potential endogenous balancer of the Wnt signaling pathway by efficiently having direct influence on both bone formation and bone absorption during skeletal bone development and maintenance through remodeling. PMID- 27117873 TI - Determining and characterizing hapten loads for carrier proteins by MALDI-TOF MS and MALDI-TOF/RTOF MS. AB - The increasing number of bioconjugates used for bioanalytical purposes and in pharmaceutical industries has led to an increasing demand for robust quality control of products derived from covalently linking small molecules to proteins. Here we report, for the first time, a matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF)-based method to determine the quantity and location of the hapten zearalenone (ZEN) introduced to the carrier protein conalbumin (Con). This bioconjugate is of special interest because of its application in lateral flow immunoassays commercially available for fast testing of food and feed for the presence of ZEN, a common contaminant of all major cereal grains worldwide. Mass spectrometry (MS) analysis of the intact protein turned out to be highly reproducible allowing for the determination of the average hapten load of the carrier protein. In that way an easy and fast method to screen for changes in ZEN load after bioconjugate synthesis was established. For a more detailed hapten load characterization, measurements at the peptide level were of importance. Systematic studies, implementing post-source decay (PSD) and high- and low-energy collision-induced dissociation (CID), showed characteristic fragmentation pattern for three model peptides carrying between one and three lysines (the primary target for the ZEN modification) besides other, less obvious modification sites (serine, arginine and the N-terminus). By this, indicative reporter ions (m/z 203 and 316) and neutral losses (Deltam/z 373 and 317) for the ZEN modification in general, plus immonium ions (m/z 87, 142 and 159) for the lysine modification in particular were identified. Based on these findings, proteolytic peptides, tentatively assigned to be modified, were unequivocally confirmed to be affected by bioconjugation. For a protein carrying on average only 2-3 modifications per molecule 29 Lys out of 59 potential modifications sites were actually modified. Considerations taking the protein structure into account showed that the affected Lys were predominantly located on the protein's surface. PMID- 27117874 TI - A Randomized Controlled Noninferiority Trial of Single Dose of Oral Dexamethasone Versus 5 Days of Oral Prednisone in Acute Adult Asthma. AB - STUDY OBJECTIVE: Oral dexamethasone demonstrates bioavailability similar to that of oral prednisone but has a longer half-life. We evaluate whether a single dose of oral dexamethasone plus 4 days of placebo is not inferior to 5 days of oral prednisone in treatment of adults with mild to moderate asthma exacerbations to prevent relapse defined as an unscheduled return visit for additional treatment for persistent or worsening asthma within 14 days. METHODS: Adult emergency department patients (aged 18 to 55 years) were randomized to receive either a single dose of 12 mg of oral dexamethasone with 4 days of placebo or a 5-day course of oral prednisone 60 mg a day. Outcomes including relapse were assessed by a follow-up telephone interview at 2 weeks. RESULTS: One hundred seventy-three dexamethasone and 203 prednisone subjects completed the study regimen and telephone follow-up. The dexamethasone group by a small margin surpassed the preset 8% difference between groups for noninferiority in relapse rates within 14 days (12.1% versus 9.8%; difference 2.3%; 95% confidence interval -4.1% to 8.6%). Subjects in the 2 groups had similar rates of hospitalization for their relapse visit (dexamethasone 3.4% versus prednisone 2.9%; difference 0.5%; 95% confidence interval -4.1% to 3.1%). Adverse effect rates were generally the same in the 2 groups. CONCLUSION: A single dose of oral dexamethasone did not demonstrate noninferiority to prednisone for 5 days by a very small margin for treatment of adults with mild to moderate asthma exacerbations. Enhanced compliance and convenience may support the use of dexamethasone regardless. PMID- 27117875 TI - Seroprevalence and risk factors of severe fever with thrombocytopenia syndrome virus infection in endemic areas. AB - BACKGROUND: To determine the seroprevalence, latent infection rate and risk factors for severe fever with thrombocytopenia syndrome virus (SFTSV) infection, a cross-sectional study was conducted in the general population of the Western region of Anhui Province of China from 1 September to 31 December 2014. METHODS: Twelve villages with the highest rates of endemic SFTS infection were selected from six towns in two counties in the western region of Anhui Province. Blood samples were collected and tested for the presence of SFTSV-IgG antibodies by ELISA. Each participant was interviewed using a structured questionnaire before blood collection. Participants with seropositive specimens were further investigated using another structured questionnaire. RESULTS: Of 2126 blood specimens collected, 99 (4.66%) were seropositive for SFTSV. None of the participants had been diagnosed with SFTS before the blood collection or were accompanied by fever, thrombocytopenia and leukocytopenia after blood collection. Multivariate logistic regression model analysis revealed living in areas of uncontrolled vegetation growth, long-term residents of the locality and tick bites as high risk factors for SFTSV infection. CONCLUSIONS: The overall seroprevalence of SFTSV is higher in the western region of Anhui, possibly due to latent infection, with the main risk factors being living in areas of uncontrolled vegetation growth, long-term residents of the locality and tick bites. Further investigations are warranted to clarify the modes of SFTS virus transmission, while vector management, education on tick bite prevention and personal hygiene management should be implemented for high risk groups in endemic areas. PMID- 27117876 TI - A Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity. AB - The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta2-microglobulin (beta2m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone ITrans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding. PMID- 27117877 TI - Coupling of dyspnea perception and occurrence of tachypnea during exercise. AB - During exercise, tidal volume initially contributes to ventilatory responses more than respiratory frequency, and respiratory frequency then increases rapidly while tidal volume stabilizes. Dyspnea intensity is also known to increase in a threshold-like manner. We tested the possibility that the threshold of tachypneic breathing is equal to that of dyspnea perception during cycle ergometer exercise (n = 27). Dyspnea intensity was scored by a visual analog scale. Thresholds were expressed as values of pulmonary O2 uptake at each breakpoint. Dyspnea intensity and respiratory frequency started increasing rapidly once the intensity of stimuli exceeded a threshold level. The thresholds for dyspnea intensity and for occurrence of tachypnea were significantly correlated. An intraclass correlation coefficient of 0.71 and narrow limits of agreement on the Bland-Altman plot indicated a good agreement between these thresholds. These results suggest that the start of tachypneic breathing coincides with the threshold for dyspnea intensity during cycle ergometer exercise. PMID- 27117878 TI - Dietary astaxanthin supplementation attenuates disuse-induced muscle atrophy and myonuclear apoptosis in the rat soleus muscle. AB - Extended periods of skeletal muscle disuse results in muscle atrophy and weakness. Currently, no therapeutic treatment is available for the prevention of this problem. Nonetheless, growing evidence suggests that prevention of disuse induced oxidative stress in inactive muscle fibers can delay inactivity-induced muscle wasting. Therefore, this study tested the hypothesis that dietary supplementation with the antioxidant astaxanthin would protect against disuse muscle atrophy, in part, by prevention of myonuclear apoptosis. Wistar rats (8 weeks old) were divided into control (CT, n = 9), hindlimb unloading (HU, n = 9), and hindlimb unloading with astaxanthin (HU + AX, n = 9) groups. Following 2 weeks of dietary supplementation, rats in the HU and HU + AX groups were exposed to unloading for 7 days. Seven-day unloading resulted in reduced soleus muscle weight and myofiber cross-sectional area (CSA) by ~30 and ~47 %, respectively. Nonetheless, relative muscle weights and CSA of the soleus muscle in the HU + AX group were significantly greater than those of the HU group. Moreover, astaxanthin prevented disuse-induced increase in the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive nuclei. We conclude that astaxanthin supplementation prior to and during hindlimb unloading attenuates soleus muscle atrophy, in part, by suppressing myonuclear apoptosis. PMID- 27117879 TI - P-class pentatricopeptide repeat protein PTSF1 is required for splicing of the plastid pre-tRNA(I) (le) in Physcomitrella patens. AB - Pentatricopeptide repeat (PPR) proteins are widely distributed in eukaryotes and are mostly localized in mitochondria or plastids. PPR proteins play essential roles in various RNA processing steps in organelles; however, the function of the majority of PPR proteins remains unknown. To examine the function of plastid PPR proteins, PpPPR_4 gene knock-out mutants were characterized in Physcomitrella patens. The knock-out mosses displayed severe growth retardation and reduced effective quantum yield of photosystem II. Immunoblot analysis showed that knock out of PpPPR_4 resulted in a strongly reduced level of plastid-encoded proteins, such as photosystem II reaction center protein D1, the beta subunit of ATP synthase, and the stromal enzyme, Rubisco. To further investigate whether knock out of the PpPPR_4 gene affects plastid gene expression, we analyzed steady-state transcript levels of protein- and rRNA-coding genes by quantitative RT-PCR. This analysis showed that the level of many protein-coding transcripts increased in the mutants. In contrast, splicing of a spacer tRNA(I) (le) precursor encoded by the rrn operon was specifically impaired in the mutants, whereas the accumulation of other plastid tRNAs and rRNAs was not largely affected. Thus, the defect in tRNA(I) (le) splicing leads to a considerable reduction of mature tRNA(I) (le) , which may be accountable for the reduced protein level. An RNA mobility shift assay showed that the recombinant PpPPR_4 bound preferentially to domain III of the tRNA(I) (le) group-II intron. These results provide evidence that PpPPR_4 functions in RNA splicing of the tRNA(I) (le) intron, and hence PpPPR_4 was named plastid tRNA splicing factor 1 (PTSF1). PMID- 27117880 TI - Actinomadura adrarensis sp. nov., an actinobacterium isolated from Saharan soil. AB - A novel actinobacterial strain, designated ACD12T, was isolated from a Saharan soil sample collected from Adrar province, southern Algeria. A polyphasic study was carried out to establish the taxonomic position of this strain. Strain ACD12T was observed to form extensively branched substrate mycelia. Aerial mycelium was absent or was weakly produced on all media tested, while spore chains were short with a hooked and irregular spiral form (2-3 turns). The dominant diaminopimelic acid isomer in the cell wall was meso-diaminopimelic acid. Glucose, ribose, galactose, mannose and madurose occured in whole-cell hydrolysates. The major phospholipid was diphosphatidylglycerol and phosphatidylinositol. The predominant menaquinone was MK-9(H6). The fatty acid profile was characterized by the presence of C16 : 0, C17 : 0, C15 : 0, C18 : 0, C18 : 1 cis9 and iso-C16 : 0. Results of 16S rRNA gene sequence comparisons revealed that strain ACD12T shared the highest degree of 16S rRNA gene sequence similarity with Actinomadura sputi DSM 45233T (98.3 %) and Actinomadura hallensis DSM 45043T (97.8 %). All tree making algorithms used also supported strain ACD12T forming a distinct clade with its most closely related species. In addition, DNA-DNA hybridization indicated only 39.8 % relatedness with A. sputi DSM 45233T and 18.7 % relatedness with A. hallensis DSM 45043T. The combined phenotypic and genotypic data show that the novel isolate represents a novel species of the genus Actinomadura, for which the name Actinomadura adrarensis sp. nov., is proposed, with the type strain ACD12T (=DSM 46745T =CECT 8842T). PMID- 27117881 TI - Effect of Water Adsorption on the Photoluminescence of Silicon Quantum Dots. AB - The optical properties of silicon quantum dots (Si QDs) are strongly influenced by circumjacent surface-adsorbed molecules, which would highly affect their applications; however, water, as the ubiquitous environment, has not received enough attention yet. We employed the time-dependent density functional calculations to investigate the water effect of photoluminescence (PL) spectra for Si QDs. In contrast with the absorption spectra, PL spectra exhibit distinct characteristics. For Si32H38, PL presents the single maximum in the dry and humid environment, while the emission spectrum displays a dual-band fluorescence spectroscopy in the low-humidity environment. This phenomenon is also observed in the larger Si QDs. The distinct character in spectroscopy is dominated by the stretching of the Si-Si bond, which could be explained by the self-trapped exciton model. Our results shed light on the Si-water interaction that is important for the development of optical devices based on Si-coated surfaces. PMID- 27117883 TI - Correction to Lancet Diabetes Endocrinol 2015; 3: 339-55. PMID- 27117882 TI - Explaining geographical variation in the presentation of primary hyperparathyroidism. PMID- 27117884 TI - Combining solid-state NMR spectroscopy with first-principles calculations - a guide to NMR crystallography. AB - Recent advances in the application of first-principles calculations of NMR parameters to periodic systems have resulted in widespread interest in their use to support experimental measurement. Such calculations often play an important role in the emerging field of "NMR crystallography", where NMR spectroscopy is combined with techniques such as diffraction, to aid structure determination. Here, we discuss the current state-of-the-art for combining experiment and calculation in NMR spectroscopy, considering the basic theory behind the computational approaches and their practical application. We consider the issues associated with geometry optimisation and how the effects of temperature may be included in the calculation. The automated prediction of structural candidates and the treatment of disordered and dynamic solids are discussed. Finally, we consider the areas where further development is needed in this field and its potential future impact. PMID- 27117885 TI - Pneumopericardium after pericardiostomy. PMID- 27117886 TI - Establishing and evaluating FRAX(r) probability thresholds in Taiwan. AB - BACKGROUND/PURPOSE: The Taiwanese FRAX(r) calculator was launched in 2010. However, cost-effectiveness thresholds for the prescription of antiosteoporosis medications were not established. This study aims to establish and evaluate FRAX(r)-based probability thresholds in Taiwan. METHODS: Using previous data from Taiwan and literature, we determined cost-effectiveness thresholds for prevention of osteoporotic fractures by alendronate with a Markov model, as well as using two other translational approaches. Sensitivity analysis was applied using different alendronate prices. A clinical sample was used to test these Taiwan specific thresholds by determining the percentages of high-risk patients who would be qualified for current National Health Insurance reimbursement. RESULTS: With the Markov model, the intervention threshold for hip fracture was 7% for women and 6% for men; for major osteoporotic fracture, it was 15% for women and 12.5% for men. Both translational approach models were cost effective only for certain age groups. However, if branded alendronate was reimbursed at 60% of the current price, they became cost effective in almost all age groups. This clinical screening study showed that the National Health Insurance Administration model identified the highest proportion (44%) of patients qualified for National Health Insurance reimbursements, followed by the Markov model (30%), and the United States model (22%). CONCLUSION: Three FRAX(r)-based models of alendronate use were established in Taiwan to help optimize treatment strategies. The government is encouraged to incorporate FRAX(r)-based approaches into the reimbursement policy for antiosteoporosis medicines. PMID- 27117887 TI - Serial follow-up of presurgical treatment using pasireotide long-acting release with or without octreotide long-acting release for naive active acromegaly. AB - The aim of the present study was to evaluate the serial changes of GH and IGF-1 in seven patients with naive, active acromegaly following presurgical treatment of the somatostatin analog pasireotide long-acting release (LAR) and octreotide LAR. The patients were treated with pasireotide LAR with or without octreotide LAR for two years and underwent transsphenoidal adenomectomy. After treatment with the somatostatin analogs, the surgical cure rate was similar to that in patients who underwent transsphenoidal surgery alone. Diabetes insipidus was not identified in any patients after the operation. Pasireotide LAR was effective on GH as well as IGF-1 suppression and tumor size decreasing when used as the primary therapy. Future large-population studies to investigate the surgical curative rate after presurgical treatment with somatostatin analogs in patients with acromegaly and macroadenomas close to the cavernous sinus are warranted. However, that hyperglycemia developed following pre-surgical treatment with pasireotide should take into consideration. PMID- 27117888 TI - Impact of Saharan dust events on radionuclide levels in Monaco air and in the water column of the northwest Mediterranean Sea. AB - Characterization of atmospheric aerosols collected in Monaco (2004-2008) and in sediment traps at 200 m and 1000 m water depths at the DYFAMED (Dynamics of Atmospheric Fluxes in the Mediterranean Sea) station (2004) was carried out to improve our understanding of the impact of Saharan dust on ground-level air and on the water column. Activity concentrations of natural (210Pb, 210Po, uranium and radium isotopes) and anthropogenic (137Cs, 239Pu, 240Pu, and 239+240Pu) radionuclides and their isotopic ratios confirmed a Saharan impact on the investigated samples. In association with a large particulate matter deposition event in Monaco on 20 February 2004, the 137Cs (~40 Bq kg-1) and 239+240Pu (~1 Bq kg-1) activities were almost a factor of two higher than other Saharan deposition dust events. This single-day particle flux represented 72% of the annual atmospheric deposition in Monaco. The annual deposition of Saharan dust on the sea was 232-407 mBq m-2 for 137Cs and 6.8-9.8 mBq m-2 for 239+240Pu and contributed significantly (28-37% for 137Cs and 34-45% for 239+240Pu) to the total annual atmospheric input to the northwest Mediterranean Sea. The 137Cs/239+240Pu activity ratios in dust samples collected during different Saharan dust events confirmed their global fallout origin or mixing with local re suspended soil particles. In the sediment trap samples the 137Cs activity varied by a factor of two, while the 239+240Pu activity was constant, confirming the different behaviors of Cs (dissolved) and Pu (particle reactive) in the water column. The 137Cs and 239+240Pu activities of sinking particles during the period of the highest mass flux collected in 20 February 2004 at the 200 m and 1000 m water depths represented about 10% and 15%, respectively, of annual deposition from Saharan dust events. PMID- 27117889 TI - The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities. AB - BACKGROUND: Epidemiological observations regarding certain population-wide parameters (e.g., disease-prevalence, recurrence-risk in relatives, gender predilections, and the distribution of common genetic-variants) place important constraints on the possibilities for the genetic-basis underlying susceptibility to multiple sclerosis (MS). METHODS: Using very broad range-estimates for the different population-wide epidemiological parameters, a mathematical model can help elucidate the nature and the magnitude of these constraints. RESULTS: For MS no more than 8.5 % of the population can possibly be in the "genetically susceptible" subset (defined as having a life-time MS-probability at least as high as the overall population average). Indeed, the expected MS-probability for this subset is more than 12 times that for every other person of the population who is not in this subset. Moreover, provided that those genetically susceptible persons (genotypes), who carry the well-established MS susceptibility allele (DRB1*1501), are equally or more likely to get MS than those susceptible persons, who don't carry this allele, then at least 84 % of MS-cases must come from this "genetically susceptible" subset. Finally, because men, compared to women, are at least as likely (and possibly more likely) to be susceptible, it can be demonstrated that women are more responsive to the environmental factors that are involved in MS-pathogenesis (whatever these are) and, thus, susceptible women are more likely actually to develop MS than susceptible men. Finally, in contrast to genetic susceptibility, more than 70 % of men (and likely also women) must have an environmental experience (including all of the necessary factors), which is sufficient to produce MS in a susceptible individual. CONCLUSIONS: As a result, because of these constraints, it is possible to distinguish two classes of persons, indicating either that MS can be caused by two fundamentally different pathophysiological mechanisms or that the large majority of the population is at no risk of the developing this disease regardless of their environmental experience. Moreover, although environmental-factors would play a critical role in both mechanisms (if both exist), there is no reason to expect that these factors are the same (or even similar) between the two. PMID- 27117890 TI - Quality of diabetic care in an urban slum area of Mysore: A community based study. AB - AIMS: MATERIALS AND METHODS: Community based cross sectional study was conducted in an urban slum of Mysore. Data was collected between July and August 2011. Known diabetics residing in this area were included in the study. Socio demographic information of diabetic patients, history, physicians advice and the extent of compliance of patients towards treatment were assessed. Descriptive statistics, like percentages were calculated. RESULTS: Study comprised of 104 patients. Mean fasting and post prandial blood glucose was 163+/-70mg/dl and 239+/-89mg/dl respectively. Common co-morbid conditions were hypertension and obesity. Key process indicators of care, indicated that adherence to medication advice was maximum and less than one fourth of them had an annual Hba1c and lipid profile examinations. CONCLUSIONS: To prevent long term complications associated with diabetes, doctors must adhere to the guidelines. There is a need to improve the health system, in terms of developing facilities to provide annual eye examination, annual lipid profile, urea, creatinine testing for diabetic patient. PMID- 27117891 TI - Translation into Portuguese and validation of the Rhinitis Control Assessment Test (RCAT) questionnaire. AB - INTRODUCTION: The Rhinitis Control Assessment Test (RCAT) is a simple self administered questionnaire developed to assess control of rhinitis. OBJECTIVES: Translate into Brazilian Portuguese and validate the RCAT. METHODS: The RCAT was translated into Portuguese by two translators and subsequently back-translated into English. It was then applied to 141 adolescents with allergic rhinitis. RESULTS: The internal consistency of the RCAT was 0.73. The questionnaire scores showed significant correlation with total nasal and extra-nasal symptom scores and nasal peak inspiratory flow (r: -0.73, -0.58 and 0.52, respectively; p<0.001) and were significantly different when divided by physician global assessment and total nasal symptom score severity. Cutoff points between 22 and 24 had the higher areas under the ROC curve to identify patients with rhinitis control. Total nasal and extra-nasal symptom scores were significantly different when a cutoff point of 22 was used (median: 4.0 vs. 8.0 and 2.0 vs. 5.0; p<0.001). CONCLUSIONS: The Brazilian Portuguese version of the RCAT was shown to be a valid and discriminant tool to identify patients with controlled and uncontrolled allergic rhinitis. PMID- 27117892 TI - Human papillomavirus in oral cavity and oropharynx carcinomas in the central region of Brazil. AB - INTRODUCTION: Molecular studies about carcinomas of the oral cavity and oropharynx demonstrate the presence of human papilomavirus genome in these tumors, reinforcing the participation of human papilomavirus in oral carcinogenesis. OBJECTIVES: This study aimed to determine the prevalence of human papilomavirus and genotype distribution of HPV16 and HPV18 in oral cavity and oropharynx carcinomas, as well as their association with clinical characteristics of the tumors. METHODS: This is a retrospective study, with clinical data collected from 82 patients. Human papilomavirus detection was conducted on specimens of oral cavity and oropharynx carcinomas included in paraffin blocks. Patients were assisted in a cancer reference center, in the central region of Brazil, between 2005 and 2007. Polymerase chain reaction was used for the detection and genotyping of human papilomavirus. RESULTS: Among the patients evaluated, 78% were male. The average age of the group was about 58 years. Risk factors, such as smoking (78%) and alcohol consumption (70.8%) were recorded for the group. HPV DNA was detected in 21 cases (25.6%; 95% confidence interval 16.9 36.6) of which 33.3% were HPV16 and 14.3% were HPV18. The presence of lymph node metastases and registered deaths were less frequent in human papilomavirus positive tumors, suggesting a better prognosis for these cases; however, the differences between the groups were not statistically significant. CONCLUSION: The results obtained in the present study, with respect to the presence of the high-risk HPV16 and HPV18 genotypes, highlight the importance of human papilomavirus vaccination in the control of oral cavity and oropharynx carcinomas. PMID- 27117893 TI - Cavernous hemangioma in unusual location: pterygopalatine fossa. PMID- 27117896 TI - Comparative and transcriptional analysis of the predicted secretome in the lignocellulose-degrading basidiomycete fungus Pleurotus ostreatus. AB - Fungi interact with their environment by secreting proteins to obtain nutrients, elicit responses and modify their surroundings. Because the set of proteins secreted by a fungus is related to its lifestyle, it should be possible to use it as a tool to predict fungal lifestyle. To test this hypothesis, we bioinformatically identified 538 and 554 secretable proteins in the monokaryotic strains PC9 and PC15 of the white rot basidiomycete Pleurotus ostreatus. Functional annotation revealed unknown functions (37.2%), glycosyl hydrolases (26.5%) and redox enzymes (11.5%) as the main groups in the two strains. When these results were combined with RNA-seq analyses, we found that the relative importance of each group was different in different strains and culture conditions and the relevance of the unknown function proteins was enhanced. Only a few genes were actively expressed in a given culture condition in expanded multigene families, suggesting that family expansi on could increase adaptive opportunities rather than activity under a specific culture condition. Finally, we used the set of P. ostreatus secreted proteins as a query to search their counterparts in other fungal genomes and found that the secretome profiles cluster the tested basidiomycetes into lifestyle rather than phylogenetic groups. PMID- 27117897 TI - Corrigendum. PMID- 27117898 TI - Designing and validation of a yoga-based intervention for obsessive compulsive disorder. AB - Some yoga-based practices have been found to be useful for patients with obsessive compulsive disorder (OCD). The authors could not find a validated yoga therapy module available for OCD. This study attempted to formulate a generic yoga-based intervention module for OCD. A yoga module was designed based on traditional and contemporary yoga literature. The module was sent to 10 yoga experts for content validation. The experts rated the usefulness of the practices on a scale of 1-5 (5 = extremely useful). The final version of the module was pilot-tested on patients with OCD (n = 17) for both feasibility and effect on symptoms. Eighty-eight per cent (22 out of 25) of the items in the initial module were retained, with modifications in the module as suggested by the experts along with patients' inputs and authors' experience. The module was found to be feasible and showed an improvement in symptoms of OCD on total Yale-Brown Obsessive-Compulsive Scale (YBOCS) score (p = 0.001). A generic yoga therapy module for OCD was validated by experts in the field and found feasible to practice in patients. A decrease in the symptom scores was also found following yoga practice of 2 weeks. Further clinical validation is warranted to confirm efficacy. PMID- 27117899 TI - Subfoveal choroidal thickness as a predictor of treatment response to anti vascular endothelial growth factor therapy for polypoidal choroidal vasculopathy. PMID- 27117900 TI - A phase I dose escalation study using simultaneous integrated-boost IMRT with temozolomide in patients with unifocal glioblastoma. AB - PURPOSE: To evaluate the maximum tolerated dose of simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) associated with temozolomide in patients with glioblastoma. PATIENTS AND METHODS: Between November 2009 and January 2012, nine patients with malignant glioma were enrolled in this phase I clinical trial. Radiotherapy was delivered using fractions of 2.5Gy on the planning target volume b and of 1.9Gy on the planning target volume a. Volumes were defined as follow: gross tumour volume b: tumour taking up contrast on T1 weighted MRI images; clinical target volume b: gross tumour volume b+0.5cm (adapted to the anatomical structures) and lastly planning target volume b: clinical target volume b+0.5cm; gross tumour volume a: tumour (gross tumour volume b)+2cm and including oedema outlined on T2Flair MRI sequences; clinical target volume a gross tumour volume a+0.5cm (adapted to the anatomical structures); planning target volume a: clinical target volume a+0.5cm. Three patients were enrolled at each of the three levels of dose (70, 75 and 80Gy prescribed on the planning target volume b and 56, 60 and 60.8Gy on the planning target volume a). Radiotherapy was delivered with temozolomide according to the standard protocol. Dose-limiting toxicities were defined as any haematological toxicities at least grade 4 or as any radiotherapy-related non-haematological acute toxicities at least grade 3, according to the Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Until the last dose level of 80Gy, no patient showed dose-limiting toxicity. CONCLUSIONS: SIB-IMRT, at least until a dose of 80Gy in 32 daily fractions, associated with temozolomide is feasible and well tolerated. PMID- 27117901 TI - Three-dimensional computed tomographic analysis of variations of the carotid artery. AB - BACKGROUND: Although the terms tortuous, coiling, and kinking have been used to describe the curvature of the carotid artery, the prevalence rates of these patterns have differed among studies. We morphologically evaluated the characteristics of the carotid artery by means of three-dimensional computed tomography (3DCT) to clarify the prevalence of tortuosity, coiling, and kinking. We present our results and discuss the clinical impact of our findings. METHODS: A total 148 patients underwent contrast-enhanced CT (including 55 patients who underwent dynamic CT), and anatomical variations were analyzed on the basis of 3DCT images. RESULTS: Among the 296 arteries, tortuosity was present in 254 (85.8%), coiling in 9 (3.0%), kinking in 3 (1.0%), and occlusion in 2 (0.7%). CONCLUSION: 3DCT image reconstruction is an effective means for classifying morphological variations of the ICA and detecting abnormalities of the carotid artery. It can thereby potentially reduce the risk of serious complications during neck surgery. PMID- 27117902 TI - Tracing Spasmodic Dysphonia: The Source of Ludwig Traube's Priority. AB - OBJECTIVES: Since the mid-20th century, one citation is given historical priority as the first description of spasmodic dysphonia (SD): Ludwig Traube's 1871 case of the "spastic form of nervous hoarseness." Our objective is to understand how this case serves as the foundation of understanding laryngeal movement disorders. METHODS: The original German paper was located and translated. Bibliographical and bibliometric methods are used to determine the citation history of this original source over the past 140 years. RESULTS: Although secondary citations in contemporary publications typically credit Traube for establishing the clinical entity SD, his case does not conform to currently accepted diagnostic features. Citation patterns indicate the source of Traube's priority is publications by Arnold and Luchsinger, mid-20th-century ENT clinicians, particularly their influential 1965 textbook used to train US and UK clinicians on voice disorders for several generations. CONCLUSIONS: Sometimes secondary citations in medical literature lead to the inadvertent perpetuation of factual misrepresentation. The clinical picture of Traube's original case does not represent what clinicians would recognize as SD today. The rich 19th-century literature on voice disorders is a valuable resource for present day clinicians. PMID- 27117903 TI - Combined Surgical Approach to Giant Cholesteatoma: A Case Report and Literature Review. AB - OBJECTIVES: Cholesteatomas can grow to a remarkable size before clinically making their presence felt. Managing giant cholesteatomas and their complications can become a challenge for the otological surgeon. METHODS: We describe a case of a giant congenital cholesteatoma of the mastoid in an adult. The lesion extended to the sigmoid sinus, jugular bulb, carotid canal, occipital condyle, and the lateral portion of the first cervical vertebra. Surgical excision was performed using a combined microscopic and endoscopic surgical approach. RESULTS: Our combined surgical technique enabled a more accurate removal of the cholesteatoma than a microscopic approach alone, with no surgical complications or damage to the structures affected by the disease. CONCLUSIONS: Using endoscopic instruments to manage giant cholesteatomas can help to avoid complications and improve surgical radicality. PMID- 27117904 TI - Penetrating Neck Trauma: An Unusual Case Presentation and Review of the Literature. AB - OBJECTIVES: The aim of this report is to describe a case of a retained projectile metal object to the neck that occurred after airbag deployment during a motor vehicle accident. METHODS: Case report with literature review. RESULTS: After a motor vehicle accident on the interstate, a 19-year-old man presents to the emergency department for several open extremity fractures, a neck laceration, and a C1 lateral mass fracture. The trauma surgery team repaired the neck laceration with no further evidence of injury. Several weeks later on follow-up, the patient presents with dysphagia and pain when turning his head to the right. A repeat computed tomography angiography (CTA) scan revealed a metallic foreign body in the left posterior pharyngeal, prevertebral soft tissues, which was subsequently removed during exploratory surgery 2 months after his initial accident. CONCLUSIONS: This is the first report, to our knowledge, of a projectile metal object to the neck that may be related to airbag deployment. The car involved in this accident was under recall for airbags that were associated with projectile objects, which warrants further investigation into the possible risks of such airbags. PMID- 27117905 TI - Superficial siderosis complicated by hydrocephalus: bleeding from the dura mater in the cerebrospinal fluid cavity after brain tumor surgery. AB - BACKGROUND: In most patients with superficial siderosis of the central nervous system, the exact source of bleeding remains unknown and a treatment has not yet been established. METHODS: We herein presented a case of superficial siderosis complicated by hydrocephalus 19 years after supratentorial brain tumor resection. RESULTS: The bleeding source was identified as the dura mater in the intracranial cerebrospinal fluid cavity, and not a recurrent tumor. CONCLUSION: Chronic intracranial bleeding from the dura mater was successfully arrested by replacement of the dura mater with the autologous fascia of the thigh, and hydrocephalus was treated with endoscopic surgery. PMID- 27117906 TI - Clinical outcomes during the learning curve of MIDline Lumbar Fusion (MIDLF(r)) using the cortical bone trajectory. AB - OBJECTIVE: The objective of this study is to review the clinical outcomes of a novel minimally invasive surgery (MIS) technique for the treatment of instability of the lumbar spine using the cortical bone trajectory (CBT). We present a prospective review of the clinical outcomes from the first 25 consecutive cases in a single unit during the initial learning phase. MATERIALS AND METHODS: The investigation group included the first 25 patients (eight males and 17 females) who underwent MIDLF(r) since the introduction of this technique in a single unit. All patients were operated on by the same surgeon. Patients' demographics, as well as duration their surgery, intraoperative blood loss, duration of hospitalization, and complications were analyzed. From the patients' satisfaction survey; pre and post-operative analgesics use, visual analogue scale (VAS) score for both back pain and radicular symptoms, as well as the Oswestry disability index (ODI) were measured and analyzed. RESULTS: There was a clear improvement in all measured parameters. The median intraoperative blood loss was 250 ml (200 700) with an average operative time of 190 (+/-46) and 237 (+/-14) min for one- and two-level fixation respectively and a median hospital stay of 2 days (1-12) inclusive of the day of surgery. The mean preoperative ODI was 59 % (+/-18.7) versus 34 % (+/-19.5) post-operatively. In this series, 84 % of the patients (n = 21) reported a significant reduction in the use of analgesia, and 44 % (n = 11) reported total freedom from intake of painkillers. The median postoperative pain free walking distance increased from 50 (0-3520) to 1000 (0-8880) yards. Three complications were reported without any significant postoperative morbidity. While in this case series the preoperative ODI and back pain VAS significantly predicted the post-operative variable, the same could not be demonstrated for leg pain, preoperative walking distance, number of pain killers, or the patient body mass index (BMI). CONCLUSIONS: Our results indicate that lumbar instrumentation using CBT is safe and effective with comparable results to those published for posterior lumbar interbody fusion (PLIF) even with the learning curve of new procedures. Patients who underwent a MIDLF(r) needed a shorter operative time, and they were mobilized and discharged quicker, with figures almost similar to those from non-instrumented surgery. While in this case series the preoperative ODI and back pain VAS significantly predicted the post-operative variable, the same could not be demonstrated for leg pain, preoperative walking distance, number of pain killers, or the patient BMI. Larger studies with longer follow-up are needed in order to better understand and assess the possible advantages of this technique. PMID- 27117907 TI - Endoscopic endonasal anatomy of the ophthalmic artery in the optic canal. AB - BACKGROUND: The endoscopic endonasal opening of the optic canal has been recently proposed for tumors with medial invasion of this canal, such as tuberculum sellae meningiomas. Injury of the ophthalmic artery represents a dramatic risk during this maneuver. Therefore, the aim of this study was to analyze the endoscopic endonasal anatomy of the precanalicular and canalicular portion of this vessel, discussing its clinical implication. METHODS: The course of the ophthalmic artery was analyzed through five endoscopic endonasal dissections, and 40 nonpathological consecutive MRAs were reviewed. RESULTS: The ophthalmic artery arises from the intradural portion of the supraclinoid internal carotid artery, in 93 % of cases about 1.9 mm (range: 1-3) posterior to the falciform ligament. At the entrance into the optic canal, the ophthalmic artery is located infero medially to the optic nerve in 13 % of cases. In 50 % of these cases the artery moves infero-laterally along its course, remaining in a medial position in the others. In cases with an non medial entrance of the ophthalmic artery, it runs infero-lateral to the optic nerve for its entire canalicular portion, with just one exception. CONCLUSION: The endoscopic endonasal approach gives a direct, extensive and panoramic view of the course of the precanalicular and canalicular portion of the ophthalmic artery. Dedicated high-field neuroimaging studies are of paramount importance in preoperative planning to evaluate the anatomy of the ophthalmic artery, reducing the risk of jeopardizing the vessel, particularly for those uncommon cases with an infero-medial course of the artery. PMID- 27117908 TI - [Acute myocardial infarction in a patient with no cardiovascular risk factors. A look backwards]. PMID- 27117909 TI - [Abdominal aneurism screening in Primary Care]. AB - OBJECTIVES: To obtain the percentage of abdominal aortic aneurism (AAA) determined in men between 65-74 years old in a health centre using ultrasound, and to describe the distribution of risk factors in the whole sample and in patients with aneurism, as well as determining how many AAA are confirmed at the hospital and those cases of uncertain diagnosis. PATIENTS AND METHOD: A cross sectional study conducted on patients included from September 2014 to February 2015. From a total of 212 randomised patients, a clinical interview and abdominal ultrasound were performed on 115 men, aged 65 to 74, telephone-recruited from a total of 171 that fulfilled inclusion criteria. RESULTS: An infra-renal AAA was found in 2.6% of the sample (95% CI 0.54-7.4). Just over half (51.3%) of the sample had arterial hypertension, and 76.1% were smokers or former smokers. The 3 AAA found, one of which had an initial doubtful diagnosis, were confirmed by the Hospital Universitario Fundacion Jimenez Diaz. There were no losses. All of the patients with AAA were active smokers and had at least one other risk factor. CONCLUSION: The percentage of infra-renal AAA in the sample was lower than expected, but higher than the percentage found in other studies that did not consider smoking in the inclusion criteria. PMID- 27117910 TI - Autobiography Series: A Celebration of Memorable and Remarkable Teachers. PMID- 27117911 TI - The prevalence of periarticular lesions detected on magnetic resonance imaging in middle-aged and elderly persons: a cross-sectional study. AB - BACKGROUND: Previous studies showed that among persons with radiographic knee OA, periarticular lesions were significantly more common among participants with knee pain than those without. However, data were derived mostly from persons with knee OA, and there were few normal participants without knee OA in the data analyses. The objectives of this study were to investigate the prevalence of periarticular lesions detected by magnetic resonance imaging (MRI), and to examine their prevalence according to the presence of knee pain and radiographic knee osteoarthritis (OA) in community residents in Korea. METHODS: Demographic and knee pain data were obtained by questionnaire from 358 participants of the population-based Hallym Aging Study who were recruited irrespective of the presence of knee OA or pain. Radiographic evaluations consisted of weight-bearing knee anteroposterior radiographs and 1.5-T MRI scans. Periarticular lesions included prepatellar or anserine bursitis, Baker's cyst, and tibiofibular cyst. The prevalence of each lesion in subjects with knee OA or knee pain compared to those without was examined by a chi-square test. RESULTS: The mean age of the subjects was 72 years and 50.6% were female. Radiographic knee OA was present in 34.5%. The most prevalent peri-articular lesion was Baker's cyst (27.9%), followed by tibiofibular cyst (9.5%). Anserine bursitis and tibulofibular cyst were more common in subjects with knee OA (17.5% vs 2.2% for anserine bursitis, 15.8% vs 6.1% for tibiofibular cyst in subjects with and without OA, respectively), while Baker's cyst and anserine bursitis were more common in subjects with knee pain (36.3% vs 21.8% for Baker's cyst, 14.4% vs 2.5% for anserine bursitis in subjects with and without knee pain, respectively). CONCLUSIONS: Periarticular lesions on MRI of the knee are common in middle-aged and elderly persons. Anserine bursitis and Baker's cysts are more common in subjects with knee pain compared to those without. PMID- 27117912 TI - Bioelectrochemical enhancement of methane production in low temperature anaerobic digestion at 10 degrees C. AB - Anaerobic digestion at low temperature is an attractive technology especially in moderate climates, however, low temperature results in low microbial activity and low rates of methane formation. This study investigated if bioelectrochemical systems (BESs) can enhance methane production from organic matter in low temperature anaerobic digestion (AD). A bioelectrochemical reactor was operated with granular activated carbon as electrodes at 10 degrees C. Our results showed that bioelectrochemical systems can enhance CH4 yield, accelerate CH4 production rate and increase acetate removal efficiency at 10 degrees C. The highest CH4 yield of 31 mg CH4-COD/g VSS was achieved in the combined BES-AD system at a cathode potential of -0.90 V (Ag/AgCl), which was 5.3-6.6 times higher than that in the AD reactor at 10 degrees C. CH4 production rate achieved in the combined BES-AD system at 10 degrees C was only slightly lower than that in the AD reactor at 30 degrees C. The presence of an external circuit between the acetate oxidizing bioanode and methane-producing cathode provided an alternative pathway from acetate via electrons to methane, potentially via hydrogen. This alternative pathway seems to result in higher CH4 production rates at low temperature compared with traditional methanogenesis from acetate. Integration of BES with AD could therefore be an attractive alternative strategy to enhance the performance of anaerobic digestion in cold areas. PMID- 27117913 TI - The larvicidal effects of black pepper (Piper nigrum L.) and piperine against insecticide resistant and susceptible strains of Anopheles malaria vector mosquitoes. AB - BACKGROUND: Insecticide resistance carries the potential to undermine the efficacy of insecticide based malaria vector control strategies. Therefore, there is an urgent need for new insecticidal compounds. Black pepper (dried fruit from the vine, Piper nigrum), used as a food additive and spice, and its principal alkaloid piperine, have previously been shown to have larvicidal properties. The aim of this study was to investigate the larvicidal effects of ground black pepper and piperine against third and fourth instar Anopheles larvae drawn from several laboratory-reared insecticide resistant and susceptible strains of Anopheles arabiensis, An. coluzzii, An. gambiae, An. quadriannulatus and An. funestus. METHODS: Larvae were fed with mixtures of standard larval food and either ground black pepper or piperine in different proportions. Mortality was recorded 24 h after black pepper and 48 h after piperine were applied to the larval bowls. RESULTS: Black pepper and piperine mixtures caused high mortality in the An. gambiae complex strains, with black pepper proving significantly more toxic than piperine. The An. funestus strains were substantially less sensitive to black pepper and piperine which may reflect a marked difference in the feeding habits of this species compared to that of the Gambiae complex or a difference in food metabolism as a consequence of differences in breeding habitat between species. CONCLUSIONS: Insecticide resistant and susceptible strains by species proved equally susceptible to black pepper and piperine. It is concluded that black pepper shows potential as a larvicide for the control of certain malaria vector species. PMID- 27117914 TI - A cell cycle kinase with tandem sensory PAS domains integrates cell fate cues. AB - All cells must integrate sensory information to coordinate developmental events in space and time. The bacterium Caulobacter crescentus uses two-component phospho-signalling to regulate spatially distinct cell cycle events through the master regulator CtrA. Here, we report that CckA, the histidine kinase upstream of CtrA, employs a tandem-PAS domain sensor to integrate two distinct spatiotemporal signals. Using CckA reconstituted on liposomes, we show that one PAS domain modulates kinase activity in a CckA density-dependent manner, mimicking the stimulation of CckA kinase activity that occurs on its transition from diffuse to densely packed at the cell poles. The second PAS domain interacts with the asymmetrically partitioned second messenger cyclic-di-GMP, inhibiting kinase activity while stimulating phosphatase activity, consistent with the selective inactivation of CtrA in the incipient stalked cell compartment. The integration of these spatially and temporally regulated signalling events within a single signalling receptor enables robust orchestration of cell-type-specific gene regulation. PMID- 27117916 TI - Effects of 3,5-dichlorophenol on excess biomass reduction and bacterial community dynamics in activated sludge as revealed by a polyphasic approach. AB - The effects of 3,5-dichlorophenol (DCP) on excess sludge reduction and microbial community dynamics were studied using laboratory-scale activated sludge reactors. The addition of 3,5-DCP at an interval of 7-8 days of operation resulted in effective reduction of growing biomass without a significant decrease in substrate removal activity. However, this uncoupling effect completely disappeared after 30 days of operation. Quinone profiling showed that a drastic component shift from ubiquinone-8 (Q-8) to Q-10 as the major homolog took place during this period of operation, suggesting that Q-10-containing bacteria, i.e., Alphaproteobacteria, became predominant at the uncoupler-ineffective stage. This result was supported by PCR-aided denaturating gradient gel electrophoresis and clone library analyses of 16S rRNA genes and fluorescence in situ hybridization. Among the gene clones detected, those corresponding to Brevundimonas predominated at the uncoupler-ineffective stage. The uncoupler-added reactor yielded 3,5-DCP resistant Pseudomonas strains as the predominant cultivable bacteria and non-3,5 DCP-resistant Brevundimonas strains as the second most abundant isolates These results suggest that the disappearance of the uncoupling function of 3,5-DCP during the long-term operation of the reactor is related to the drastic community change with increasing populations of Alphaproteobacteria. Most of these alphaproteobacteria represented by Brevundimonas are not resistant to 3,5-DCP but, by an unknown mechanism, may support the bioprotection of the microbial community from the uncoupling effect. PMID- 27117917 TI - In vitro formation of vascular-like networks using hydrogels. AB - Tissue engineering has great potential to create tissue and organ constructs of clinically relevant sizes. The main obstacle to creating volumetric tissue constructs was the lack of a technique for fabricating dense and perfusable vascular networks in vitro within the constructs. In significant efforts to develop such a technique, hydrogels have been used as materials for templates and support architectures of vascular-like networks because of their excellent properties, such as high biocompatibility, flexibility, and the rapid diffusion of oxygen and nutrients compared with solid materials. Herein, we reviewed current hydrogel-based strategies to fabricate vascular-like networks in vitro. The first strategy was based on the ability of vascular endothelial cells to form capillary-like tubes. The second was an engineering-based strategy that can be categorized into templating, modular assembly, microfabrication, rapid prototyping technique, and their hybrid model. Finally, we discussed future directions in tissue engineering for creating transplantable and volumetric constructs. PMID- 27117918 TI - Isoliquiritigenin impairs insulin signaling and adipocyte differentiation through the inhibition of protein-tyrosine phosphatase 1B oxidation in 3T3-L1 preadipocytes. AB - Isoliquritigenin (ISL) is an abundant dietary flavonoid with a chalcone structure, which is an important constituent in Glycyrrhizae Radix (GR). ISL exhibits anti-oxidant activity, and this activity has been shown to play a beneficial role in various health conditions. However, it is unclear whether the anti-oxidant activity of ISL affects insulin signaling pathway and lipid accumulation of adipocytes. We sought to investigate the effects and molecular mechanisms of ISL on insulin-stimulated adipogenesis in 3T3-L1 cells. We investigated whether ISL attenuates insulin-induced Reactive Oxygen Species (ROS) generation, and whether ISL inhibits the lipid accumulation and the expression of adipogenic-genes during the differentiation of 3T3-L1 cells. ISL blocked the ROS generation, suppressed the lipid accumulation and the expression of adipocyte specific proteins, which are increased in response to insulin stimulation during adipocyte differentiation of 3T3-L1 cells. We also investigated whether the anti oxidant capacity of ISL is involved in regulating the molecular events of insulin signaling cascade in 3T3-L1 adipocytes. ISL restores PTP1B activity by inhibiting PTP1B oxidation and IR/PI3K/AKT phosphorylation during the early stages of insulin-induced adipogenesis. Our findings show that the anti-oxidant capacity of ISL attenuated insulin IR/PI3K/AKT signaling through inhibition of PTP1B oxidation, and ultimately attenuated insulin-induced adipocyte differentiation of 3T3-L1 cells. PMID- 27117919 TI - Food-grade titanium dioxide exposure exacerbates tumor formation in colitis associated cancer model. AB - Colorectal cancer is the fourth worldwide cause of death and even if some dietary habits are consider risk factors, the contribution of food additives including foodgrade titanium dioxide (TiO2), designated as E171, has been poorly investigated. We hypothesized that oral E171 intake could have impact on the enhancement of colorectal tumor formation and we aimed to investigate if E171 administration could enhance tumor formation in a colitis associated cancer (CAC) model. BALB/c male mice were grouped as follows: a) control, b) E171, c) CAC and d) CAC + E171 group (n = 6). E171 used in this study formed agglomerates of 300 nm in water. E171 intragastric administration (5 mg/kg body weight/5 days/10 weeks) was unable to induce tumor formation but dysplastic alterations were observed in the distal colon but enhanced the tumor formation in distal colon (CAC + E171 group) measured by tumor progression markers. Some E171 particles were internalized in colonic cells of the E171 and CAC + E171 groups and both groups showed a decrease in goblet cells in the distal colon. However the CAC + E171 group showed a higher decrease of these cells that act as protection barrier in colon. These results suggest that E171 could worsen pre-existent intestinal diseases. PMID- 27117920 TI - Variations of body geometry in Brycon henni (Teleostei: Characiformes, Bryconidae) in different rivers and streams. AB - Landmark-based geometric morphometrics were used to evaluate the effect of flow and depth in the water column on the body size and shape of Brycon henni from river and stream populations. The dendrogram showed that stream populations clustered apart and showed significantly smaller centroid size and narrower bodies than river populations, indicating a role for flow and depth on whole body morphometric variation. The results are concordant with morphometric variation described in other fish species and provide the first insights into phenotypic variation in natural populations of B. henni. PMID- 27117921 TI - Health personnel retention strategies in a peri-urban community: an exploratory study on Epworth, Zimbabwe. AB - BACKGROUND: The need to retain health personnel is a policy challenge undermining health system reform of the 21st century. The need to resolve this global health workforce crisis resulted in the First Global Forum on Human Resources for Health in 2008 from which the Kampala Declaration and Agenda for Global Action was formulated. However, whilst there have been several studies exploring the retention of health personnel towards this end, available literature does not provide a detailed narrative on strategies used in peri-urban communities. The aim of this study was to explore retention strategies implemented in a Zimbabwean peri-urban community between 2009 and 2014 and implications for peri-urban communities towards the health system reform agenda. METHODS: The study was carried out in Epworth, a peri-urban community in Harare, Zimbabwe. The research design was a cross-sectional survey, in which qualitative methods were used in sampling, data collection, reporting and analysis. Qualitative tools were used to collect data through in-depth interviews with purposively selected health personnel managers at 10 local clinics and sample interviews with purposively selected healthcare workers who included registered general nurses, state certified nurses, midwives, environmental health technicians, nurse aids and community health volunteers at each clinic. Two focus group discussions were carried out with community health volunteers. Qualitative data was subjected to thematic analysis, with coding being performed manually. RESULTS: A programme specific strategic partnership between the government and donor community contributed towards the mobilisation of more health personnel, health facilities, worker development and remuneration. To complement this, the Ministry of Health intervened through the review and payment of salaries, support towards post-basic training and development, and protection. The local board, mission and donors contributed through the payment of top-up allowances and provision of non monetary incentives. CONCLUSIONS: The review of salaries, engagement of international strategic partners, payment of top-up allowances, support towards post-basic training and development, mobilisation of more health personnel, non monetary incentives and healthcare worker protection were critical towards the retention of health personnel in the Epworth peri-urban community between 2009 and 2014. PMID- 27117922 TI - Squamous cell carcinoma antigen (SCC-Ag) during follow-up of cervical cancer patients: Role in the early diagnosis of recurrence. AB - OBJECTIVE: The aim of this study was to assess the potential benefit of routine squamous cell carcinoma antigen (SCC-Ag) assessment during follow-up of patients after treatment for early cervical cancer with regard to early diagnosis of cancer recurrence before clinical signs and symptoms occur. METHODS: All clinical, pathological, and serological data of patients referred to the Department of Gynecologic Oncology between July 1999 and June 2014, were retrospectively collected and analyzed. The SCC-Ag levels of 197 patients with diagnosis of stage I or II cervical squamous carcinoma, were performed. RESULTS: In the univariate analysis, serum SCC-Ag was not significantly associated with grading (p=0.85), LVSI (p=0.95) and FIGO stage (p=0.83) but it was significantly associated with recurrence of disease (p<0.001). The Cox multivariate analyses showed that serum SCC-Ag level was an independent and statistically significant prognostic factor for OS and PFS. The median time interval between SCC-Ag test and diagnosis of recurrence were 0.3 and 1.8months for positive and negative SCC Ag groups respectively (p=0.01). Considering patients with recurrence, no significant difference in terms of DFS and OS was found between women with high or low SCC-Ag levels. CONCLUSIONS: Serum SCC-Ag reflects the response to treatment, and rising antigen levels often precede the clinical detection of recurrent disease, and may lead to early diagnosis. However such an advantage does not seem to improve the cure rate of patients with elevated SCC-Ag levels, most likely due to the lack of curative salvage treatments. PMID- 27117924 TI - Corrections. PMID- 27117923 TI - Clinicopathologic characteristics and survival of patients with gynecologic malignancies metastatic to the brain. AB - OBJECTIVE: No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment. METHODS: This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Student's paired t-test (for marker expression) and Kaplan-Meier test (for correlations). RESULTS: On univariate analysis, primary ovarian disease, CA-125<81units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19-5.93; p=0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls (p<0.0001). None of the molecular markers were significantly associated with survival. CONCLUSIONS: Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases. PMID- 27117925 TI - Screening for mental problems in people presenting with hypertension and comorbidities. PMID- 27117926 TI - Updated guidelines (2015) for management and monitoring of adult and adolescent asthmatic patients (from 12 years and older) of the Societe de pneumologie de langue francaise (SPLF) (summary). PMID- 27117927 TI - ? PMID- 27117928 TI - Incommensurate spin correlations in highly oxidized cobaltates La2-xSrxCoO4. AB - We observe quasi-static incommensurate magnetic peaks in neutron scattering experiments on layered cobalt oxides La2-xSrxCoO4 with high Co oxidation states that have been reported to be paramagnetic. This enables us to measure the magnetic excitations in this highly hole-doped incommensurate regime and compare our results with those found in the low-doped incommensurate regime that exhibit hourglass magnetic spectra. The hourglass shape of magnetic excitations completely disappears given a high Sr doping. Moreover, broad low-energy excitations are found, which are not centered at the incommensurate magnetic peak positions but around the quarter-integer values that are typically exhibited by excitations in the checkerboard charge ordered phase. Our findings suggest that the strong inter-site exchange interactions in the undoped islands are critical for the emergence of hourglass spectra in the incommensurate magnetic phases of La2-xSrxCoO4. PMID- 27117929 TI - Overgrowth of the femoral neck after hip fractures in children. AB - BACKGROUND: Overgrowth after pediatric femoral shaft fractures is well documented; however, overgrowth of the femoral neck after hip fractures has not been especially reported previously. The purpose of this study was to evaluate the incidence and characteristics of femoral neck overgrowth after hip fractures in children. METHODS: From January 1990 to December 2012, there were 30 consecutive patients with pediatric hip fractures. We retrospectively reviewed the medical record of all the patients, including age at injury, gender, injury mechanism, fracture type, methods of treatment, time to bony union, and complications. The functional outcome was evaluated by Ratliff's criteria. The radiography of the pelvis was performed in controlled positions of abduction and external rotation. The length of the femoral neck was measured by two observers. The overgrowth of the femoral neck was defined as lengthening more than 3 mm in comparison with the uninjured hip. RESULTS: At a mean follow-up of 4.9 years (range 2-8 years), 12 patients (40 %) had an overgrowth of the femoral neck. The average overgrowth of the femoral neck was 6.2 mm (range 3.2-8.5 mm). The patients with femoral neck overgrowth were younger (p = 0.0002), have lower rate of avascular necrosis of the femoral head (p = 0.0006), and have better functional outcome (p = 0.0026). CONCLUSIONS: Our results provide evidence that overgrowth of the femoral neck following hip fractures may occur in children and the overgrowth phenomenon in the femoral neck was a predictor of good outcomes after treatment. PMID- 27117930 TI - Protein substitutes for phenylketonuria in Europe: access and nutritional composition. AB - BACKGROUND/OBJECTIVES: Protein substitutes (PS) are an essential component in the dietary management of phenylketonuria (PKU). PS are available as phenylalanine free amino-acid mixtures (AAM), glycomacropeptide-based PS (GMP) and large neutral amino acids (LNAA). There is a lack of information regarding their availability in different countries and comparison of their nutritional composition is limited. The objectives of this study were to identify the number of PS available in different European countries and Turkey and to compare their nutritional composition. SUBJECTS/METHODS: Members of the European Nutritionist Expert Panel on PKU (ENEP) (Portugal, Spain, Belgium, Italy, Germany, Netherlands, United Kingdom, Denmark and Turkey) provided data on PS available in each country. The nutritional composition of PS available in Portugal was analyzed. RESULTS: The number of PS available in each country varied from 30 (Turkey) to 105 (Germany), with a median of 64. GMP was available only in Portugal, whereas LNAA was an option in Portugal, Italy, Turkey and Denmark. Some PS were designed for weaning. Many PS did not contain added fat and fiber. GMP contained the highest carbohydrate (CHO) and energy content as well as higher LNAA content compared with AAM. Only one AAM contained added fructo oligosaccharides and galacto-oligosaccharides. AAM designed for the first year of life had the highest CHO, fat and LNAA contribution. Liquid AAM had lower CHO and fat contents compared with powdered AAM, but contained higher LNAA. CONCLUSIONS: There was widely dissimilar numbers of PS available in different countries. Nutritional composition of different PS was variable and should be considered before prescription. PMID- 27117931 TI - Assessment of vitamin D status and serum CrossLaps levels in adults with primary lactose malabsorption. AB - BACKGROUND/OBJECTIVES: Primary adult-type lactose malabsorption (PALM) is a widespread inherited autosomal recessive condition, which is considered to be associated with osteoporosis. This prospective study aimed at assessing the 25 hydroxy-vitamin D (25(OH)D) status and serum CrossLaps levels in individuals with PALM and normal controls. SUBJECTS/METHODS: All participants (n=210) underwent genotyping for the LCT C/T-13910 polymorphism, 25(OH)D and CrossLaps measurements and clinical examinations. In addition, the anthropometric data (that is, height, weight and body mass index) were determined. RESULTS: Fifty-five individuals with PALM (that is, LCT C/C-13910 homozygotes) showed lower 25(OH)D (mean: 24.95+/ 10.04 vs 28.59+/-9.56 ng/ml, P=0.018) and higher CrossLaps serum levels (mean: 0.46+/-0.31 vs 0.43+/-0.49 ng/ml, P=0.251) compared with 155 normal controls (that is, LCT C/T-13910 hetero- or T/T-13910 homozygotes). Anthropometric data were similar between PALM probands and controls. CONCLUSIONS: Individuals with PALM were found to have lower 25(OH)D and higher CrossLaps serum levels compared with normal controls. In order to preserve life-long bone health, routine 25(OH)D and CrossLaps serum measurements should be performed in individuals with PALM. PMID- 27117932 TI - Outcome of intestinal failure after bariatric surgery: experience from a national UK referral centre. AB - BACKGROUND/OBJECTIVES: Bariatric surgery for morbid obesity provides sustained weight loss. Complications of bariatric surgery include severe nutritional decline, but minimal data describing occurrence and outcome of intestinal failure (IF) exist. SUBJECTS/METHODS: All patients referred to one of the UK's National IF units (IFU) are prospectively entered onto a database; case notes were assessed for bariatric surgery details, IF onset, outcomes, resulting intestinal anatomy, mortality and catheter-related bloodstream infections (CRBSIs). RESULTS: A total of six patients (mean referral age 54.0 years; 95% confidence interval (CI): 44.6-63.4; 5 female) were identified with IF after bariatric surgery from 457 patients (total cohort) managed on home parenteral nutrition (HPN) at the IFU between 2008 and 2014. In all, 6/6 had Roux-en-Y gastric bypass bariatric surgery. Median (range) time from index bariatric surgery to IF development was 28.7 months (1.7-106). IF aetiology was internal herniation (4/6), ischaemia (1/6) and anastomotic leak (1/6); all patients required HPN for a median of 26.4 months (15.3-34.7). CRBSI occurred on 7 occasions in 3 patients, equivalent to 1.5/1000 catheter days in these 6 compared with 0.32/1000 in the 451 IFU HPN patients during this time period. In all, 0/6 patients died, 6/6 had continuity restored in a median of 16.5 months (6.5-32.5) after IF diagnosis and 3/6 (50%) were weaned from PN by a median of 2.2 months (0.6-12.8). CONCLUSIONS: Bariatric surgery, an increasingly common operation, can be associated with IF necessitating long-term HPN. The cohort presented had a higher CRBSI compared with other HPN patients; more stringent approaches to catheter care may be required in this patient group, although more collective data are required. PMID- 27117933 TI - Body composition analysis by dual-energy X-ray absorptiometry in young preschool children. AB - BACKGROUND/OBJECTIVES: Dual-energy X-ray absorptiometry (DXA) is considered a specific method for measuring body composition to assess obesity and osteoporosis, although few studies have been conducted in preschool children. The aim of this study was to provide sex - and age-specific references for bone mineral density (BMD), bone mineral content (BMC), fat mass (FM) and fat-free mass (FFM) normative data for children aged 2 to <6 years. SUBJECTS/METHODS: One hundred and eighty seven healthy white children from Buenos Aires City suburbs, Argentina, were studied by the Lunar DPX-L DXA, pediatric software: BMC less head (g), BMD (g/cm2), FM (%) and FFM (g). RESULTS: BMD and BMC increased significantly with age (P<0.0001), but only BMD was significantly different between boys and girls of similar age, being greater for boys (P=0.013). FM was not significantly different among the various age groups of boys and girls. However, the FFM/height was higher in boys and the BMC/FFM was higher in girls. The Z-scores and centile curves were derived separately for each sex and age. Q-Q detrended plots and LMS curves produced robust, unbiased fits that generated references for the 3rd, 50th and 97th percentiles for BMD, BMC, FM and FFM data, respectively. CONCLUSIONS: These DXA scans add to the scarcity of accurate measurements of body composition of white young children. The data analyses provided greater accuracy, particularly at the upper and lower ends of the distribution, which is important in clinical settings for identification of children with impaired body composition. PMID- 27117934 TI - A survey of people with inflammatory bowel disease to investigate their views of food and nutritional issues. AB - Survey aims were to investigate the dietary concerns, beliefs and opinions of people with inflammatory bowel disease (IBD), and differences between those with Crohn's disease (CD) or ulcerative colitis (UC). A cross-sectional postal questionnaire was sent to people with IBD who were booked into an adult IBD or Gastroenterology clinic over a 6-week period. There were 416 eligible people and 168 (40%) responded. Sixty-four (42%) people indicated that food affects their symptoms a lot or severely. Eighty (51%) respondents indicated that diet was important or extremely important in controlling symptoms. Significantly more people with CD reported meat, fatty foods, chocolate and salad as a trigger than people with UC. Significantly more people with UC reported wheat as a trigger. More people with CD avoided meat and chocolate than UC. This survey highlights the importance of nutrition and diet to people with IBD. Frequent food avoidance was reported. This may impact on nutrition-related health problems. PMID- 27117935 TI - Patterns of molecular evolution of RNAi genes in social and socially parasitic bumblebees. AB - The high frequency of interactions amongst closely related individuals in social insect colonies enhances pathogen transmission. Group-mediated behavior supporting immune defenses tends to decrease selection acting on immune genes. Along with low effective population sizes this might result in relaxed constraint and rapid evolution of immune system genes. Here, we show that antiviral siRNA genes show high rates of molecular evolution with argonaute 2, armitage and maelstrom evolving faster in social bumblebees compared to their socially parasitic cuckoo bumblebees that lack a worker caste. RNAi genes show frequent positive selection at the codon level additionally supported by the occurrence of parallel evolution. Their evolutionary rate is linked to their pathway specific position with genes directly interacting with viruses showing the highest rates of molecular evolution. We suggest that higher pathogen load in social insects indeed drives the molecular evolution of immune genes including antiviral siRNA, if not compensated by behavior. PMID- 27117936 TI - Lack of specific alleles for the bovine chemokine (C-X-C) receptor type 4 (CXCR4) gene in West African cattle questions its role as a candidate for trypanotolerance. AB - A panel of 81 Asian, African and European cattle (Bos taurus and B. indicus) was analysed for the whole sequence of the CXCR4 gene (3844bp), a strong candidate for cattle trypanotolerance. Thirty-one polymorphic sites identified gave 31 different haplotypes. Neutrality tests rejected the hypothesis of either positive or purifying selection. Bayesian phylogenetic tree showed differentiation of haplotypes into two clades gathering genetic variability predating domestication. Related with clades definition, linkage disequilibrium analyses suggested the existence of one only linkage block on the CXCR4 gene. Two tag SNPs identified on exon 2 captured 50% of variability. Whatever the analysis carried out, no clear separation between cattle groups was identified. Most haplotypes identified in West African taurine cattle were also found in European cattle and in Asian and West African zebu. West African taurine samples did not carry unique variants on the CXCR4 gene sequence. The current analysis failed in identifying a causal mutation on the CXCR4 gene underlying a previously reported QTL for cattle trypanotolerance on BTA2. PMID- 27117937 TI - Highly selective luminescence sensing of nitrite and benzaldehyde based on 3d-4f heterometallic metal-organic frameworks. AB - Framework-isomeric three-dimensional (3D) Zn-Ln heterometallic metal-organic frameworks, {[Ln2Zn(abtc)2(H2O)4].2H2O}infinity {Ln = Sm(1), Tb(2)}, were synthesized using a convenient solvothermal reaction. They can serve as excellent sensors for the specific identification of benzaldehyde and NO2(-) through a fluorescence quenching process. PMID- 27117938 TI - Clinical utility of the memory complaints inventory to detect invalid test performance. AB - OBJECTIVE: This investigation was designed to examine the classification statistics of Memory Complaints Inventory (MCI) scores relative to the Medical Symptom Validity Test (MSVT) and the Non-Verbal Medical Symptom Validity Test (NV MSVT), as well as various validity scales on the Personality Assessment Inventory (PAI) and Minnesota Multiphasic Personality Inventory-2 Restructured Form(MMPI-2 RF). METHOD: The sample consisted of 339 active duty service members with a history of concussion who completed performance validity tests (PVTs), symptom validity tests (SVTs), and the MCI. RESULTS: Those who failed the MSVT and NV MSVT had significantly higher scores across all MCI scales. In addition, those who scored above specified cut scores on the evaluated PAI and MMPI-2-RF validity scales also had significantly higher MCI scale scores. Receiver operator characteristics analysis demonstrated acceptable area under the curve (AUC) across the evaluated SVTs for the mean of all MCI subtests with values ranging from (.77 to .86), with comparable findings for PVTs (MSVT AUC = .75; NV-MSVT AUC = .72). CONCLUSIONS: In general the MCI scales demonstrated better classification statistics relative to SVTs vs. PVTs, which is consistent with the nature of the MCI as a self-report instrument. PMID- 27117939 TI - Long-term efficacy and safety of transanal irrigation in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is the commonest disabling neurological disease in young adults. A majority of patients experience bowel dysfunction, reporting a wide spectrum of bowel symptoms that significantly negatively impact social activities and emotional state. Transanal irrigation (TAI) is a method of managing such bowel symptoms. We aimed to investigate long-term efficacy of TAI, to measure health status-related quality of life and identify factors predictive of TAI outcome. METHODS: Forty-nine consecutive MS patients (37 female; mean age 51, range 26-80) were studied. We investigated predominant symptoms, reason for beginning TAI and medical comorbidity. All patients underwent anorectal physiology testing. They completed Neurogenic Bowel Dysfunction and EQ-5D questionnaires at baseline and annual follow-up. KEY RESULTS: Mean follow-up was 40 months, at which there was 55% rate of continuation of TAI. Severe bowel dysfunction was present in 47% at baseline, falling to 18%. The EQ-5D scores at latest follow-up were not statistically significant, but 42% had improved visual analog scores. The only predictive factor for successful therapy was impaired anal electrosensitivity (p = 0.008). CONCLUSIONS & INFERENCES: Long-term continuation of TAI, with improved bowel symptomatology, is seen in the majority of patients. The EQ-5D is insufficiently sensitive to show change in MS patients that using TAI. PMID- 27117940 TI - The clinical value of metabolic syndrome and risks of cardiometabolic events and mortality in the elderly: the Rotterdam study. AB - BACKGROUND: To evaluate the clinical value of metabolic syndrome based on different definitions [American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), International Diabetes Federation (IDF) and European Group for the Study of Insulin Resistance (EGIR)] in middle-aged and elderly populations. METHODS: We studied 8643 participants from the Rotterdam study (1990 2012; mean age 62.7; 57.6 % female), a large prospective population-based study with predominantly elderly participants. We performed cox-proportional hazards models for different definitions, triads within definitions and each separate component for the risk of incident type 2 diabetes mellitus, coronary heart disease, stroke, cardiovascular- and all-cause mortality. RESULTS: In our population of 8643 subjects, metabolic syndrome was highly prevalent (prevalence between 19.4 and 42.4 %). Metabolic syndrome in general was associated with incident type 2 diabetes mellitus (median follow-up of 6.8 years, hazard ratios 3.13-3.78). The associations with coronary heart disease (median follow-up of 7.2 years, hazard ratios 1.08-1.32), stroke (median follow-up of 7.7 years, hazard ratios 0.98-1.32), cardiovascular mortality (median follow-up of 8.2 years, ratios 0.95-1.29) and all-cause mortality (median follow-up of 8.7 years, hazard ratios 1.05-1.10) were weaker. AHA/NHLBI- and IDF-definitions showed similar associations with clinical endpoints compared to the EGIR, which was only significantly associated with incident type 2 diabetes mellitus. All significant associations disappeared after correcting metabolic syndrome for its individual components. CONCLUSIONS: Large variability exists between and within definitions of the metabolic syndrome with respect to risk of clinical events and mortality. In a relatively old population the metabolic syndrome did not show an additional predictive value on top of its individual components. So, besides as a manner of easy identification of high risk patients, the metabolic syndrome does not seem to add any predictive value for clinical practice. PMID- 27117941 TI - Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (gamma-GCS, HO-1, NQO1) in ultraviolet radiation-treated normal human epidermal keratinocytes (NHEK). AB - Melatonin is an ubiquitous molecule with a variety of functions including potent antioxidative properties. Due to its lipophilic character, it easily crosses cellular and intracellular membranes and reaches all subcellular organelles. Because of its ability to scavenge free radicals, melatonin protects against oxidative stress, for example, induced by ultraviolet radiation (UVR). Here, we investigated, in a dose-dependent (0, 10, 25, and 50 mJ/cm(2) ) and time dependent (0, 4, 24, 48 hr post-UVR) manner, whether melatonin prevents the UVR mediated alterations in ATP synthesis and the generation of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEK). Additionally, we evaluated the molecular mechanism of action of melatonin with regard to activation of phase-2 antioxidative enzymes via nuclear erythroid 2-related factor (Nrf2). We found that (i) melatonin counteracted UVR-induced alterations in the ATP synthesis and reduced free radical formation; (ii) melatonin induced the translocation of Nrf2 transcription factor from the cytosol into the nucleus resulting in, (iii) melatonin enhanced gene expression of phase-2 antioxidative enzymes including gamma-glutamylcysteine synthetase (gamma-GCS), heme oxygenase-1 (HO-1), and NADPH: quinone dehydrogenase-1 (NQO1) representing an elevated antioxidative response of keratinocytes. These results suggest that melatonin not only directly scavenges ROS, but also significantly induces the activation of phase-2 antioxidative enzymes via the Nrf2 pathway uncovering a new action mechanism that supports the ability of keratinocytes to protect themselves from UVR-mediated oxidative stress. PMID- 27117942 TI - Ethics of Clinical Decision-Making for Older Drivers: Reporting Health-Related Driving Risk. AB - The number of older drivers will continue to increase as the population ages. Health care professionals have the responsibility of providing care and maintaining confidentiality for their patients while ensuring public safety. This article discusses the ethics of clinical decision-making pertaining to reporting health-related driving risk of older drivers to licensing authorities. Ethical considerations inherent in reporting driving risk, including autonomy, confidentiality, therapeutic relationships, and the uncertainty about determining individual driving safety and risk, are discussed. We also address the moral agency of reporting health-related driving risk and raise the question of whose responsibility it is to report. Issues of uncertainty surrounding clinical reasoning and concepts related to risk assessment are also discussed. Finally, we present two case studies to illustrate some of the issues and challenges faced by health care professionals as they seek to balance their responsibilities for their patients while ensuring road safety for all citizens. PMID- 27117943 TI - Radioiodine Therapy Does Not Change the Atherosclerotic Burden of the Carotid Arteries. AB - BACKGROUND AND AIM: Atherosclerosis evolves or accelerates when arteries are exposed to ionizing radiation, both early and late after exposure. Radioiodine therapy of benign thyroid disease exposes the carotid arteries to 4-50 Gy, and may thereby increase the risk of atherosclerosis. Increased risk of cerebrovascular events has been reported after radioiodine therapy. This study aimed to examine whether atherosclerosis develops early or late after radioiodine therapy of benign thyroid disease. METHOD: Patients treated for benign thyroid disorders (nontoxic goiter, adenoma, and hyperthyroidism) were examined with ultrasound for the main outcome, carotid intima media thickness (CIMT), and for plaque presence (plaque presence only in late damage). Signs of early damage from radioiodine were studied in 39 radioiodine-treated patients, who were examined before treatment and at 1, 3, 6, and 12 months after treatment. Late changes were studied in a cross-sectional case-control design, with radioiodine-treated patients as cases (n = 193) and patients treated with surgery as controls (n = 95). Data were analyzed with repeated measurement for longitudinal data, and with multivariate regression for cross-sectional data. Results were adjusted for age, sex, cholesterol, smoking status, known atherosclerotic disease, and body mass index. RESULTS: No changes in CIMT were found in the patients followed prospectively for one year after treatment with radioactive iodine for benign thyroid disease (p = 0.58). In the study on late effects, there was no difference in CIMT (p = 0.25) or presence of plaques (p = 0.70) between those treated with radioactive iodine and those treated with surgery (9.8 and 5.6 years since treatment, respectively). Furthermore, the level of thyrotropin (TSH) did not influence these atherosclerosis markers. CONCLUSION: No early changes in CIMT were detected in patients treated with radioactive iodine for benign thyroid disease. No signs of late effects of radioactive iodine on CIMT or plaque presence were found after 10 years of follow-up. The radiation to the carotid arteries by radioactive iodine therapy for benign thyroid disease may therefore have no or low effect on atherosclerotic burden of the carotid arteries in general. PMID- 27117944 TI - Clinical outcomes after coronary angiography in nonalcoholic fatty liver disease. PMID- 27117945 TI - Preface. PMID- 27117946 TI - Construction of dynamic probabilistic protein interaction networks for protein complex identification. AB - BACKGROUND: Recently, high-throughput experimental techniques have generated a large amount of protein-protein interaction (PPI) data which can construct large complex PPI networks for numerous organisms. System biology attempts to understand cellular organization and function by analyzing these PPI networks. However, most studies still focus on static PPI networks which neglect the dynamic information of PPI. RESULTS: The gene expression data under different time points and conditions can reveal the dynamic information of proteins. In this study, we used an active probability-based method to distinguish the active level of proteins at different active time points. We constructed dynamic probabilistic protein networks (DPPN) to integrate dynamic information of protein into static PPI networks. Based on DPPN, we subsequently proposed a novel method to identify protein complexes, which could effectively exploit topological structure as well as dynamic information of DPPN. We used three different yeast PPI datasets and gene expression data to construct three DPPNs. When applied to three DPPNs, many well-characterized protein complexes were accurately identified by this method. CONCLUSION: The shift from static PPI networks to dynamic PPI networks is essential to accurately identify protein complex. This method not only can be applied to identify protein complex, but also establish a framework to integrate dynamic information into static networks for other applications, such as pathway analysis. PMID- 27117947 TI - Matrix metalloproteinase (MMP)-9: A realiable marker for inflammation in early human trichinellosis. AB - Matrix Metalloproteinases (MMPs) are involved in many physiological and pathological processes. As regards parasitic infections, the role of these proteins has been particularly studied in malaria, neurocysticercosis and angiostrongyloidosis. Recently, we evaluated serum levels of MMP-9 and -2 (gelatinases) in mice experimentally infected with Trichinella spiralis or Trichinella pseudospiralis, which cause different degrees of myositis and we found their significant increase in the former and, at a lesser extent, in the latter, thus suggesting the possibility that these gelatinases, particularly MMP 9, represent a marker of inflammation. Our aim was to evaluate the levels of MMP 9 and 2 in trichinellosis patients, to assess their possible clinical significance. Serum samples from 31 Trichinella britovi-infected individuals (20 males and 11 females), living in Tuscany, Central Italy, were analysed for MMP-9 and MMP-2 serum levels. Patients acquired infection with Trichinella after consuming raw or undercooked meat of wild boar. Their median age was 49+/ 0.33years (range from 7 to 91). Sera was collected before starting anti inflammatory treatment, aliquoted and stored at -20 degrees C until use. Sera from healthy subjects was considered as controls. The gelatinolytic activity of MMPs was analysed by gelatin zymography on 8% polyacrylamide-SDS gels containing 0.1% porcine gelatin, under non-reducing conditions. Clear bands corresponding to the digested areas were evaluated with an appropriate software. MMP-9 levels were additionally determined in 15 patients using a commercial ELISA kit for human MMP 9. The zymographic analysis of the gels showed the presence in serum samples of gelatinase bands at approximately 125-kDa, 92-kDa and 72-kDa, corresponding to the MMP-9/Neutrophil gelatinase-associated lipocalin (NGAL) complex and proenzyme forms of MMP-9 and MMP-2, respectively. A significant (p<0.01) increase in gelatinolytic activity in patients compared to the control group was observed for pro-MMP-9 in 25 out of 31. The mean increase in activity was 39.25%+/-16.67%. No significant differences were observed for pro-MMP-2 activity. The MMP-9 levels detected by ELISA showed significant correlation with zymographic data (r2=0.62, p<0.003) and were higher in more affected patients (suffering diarrhea, facial edemas and myalgia). In conclusion, MMP-9 might be considered as a marker of inflammation in T. britovi patients. On the contrary, MMP-2 did not result significantly different in patients, compared to controls. PMID- 27117948 TI - Three-Dimensional Printing: An Enabling Technology for IR. AB - Rapid prototyping, also known as three-dimensional (3D) printing, is a recent technologic advancement with tremendous potential for advancing medical device design. A wide range of raw materials can be incorporated into complex 3D structures, including plastics, metals, biocompatible polymers, and even living cells. With its promise of highly customized, adaptable, and personalized device design at the point of care, 3D printing stands to revolutionize medical care. The present review summarizes the methods for 3D printing and their current and potential roles in medical device design, with an emphasis on their potential relevance to interventional radiology. PMID- 27117949 TI - Technical and Anatomic Factors Influencing the Success of Inferior Vena Caval Stent Placement for Malignant Obstruction. AB - PURPOSE: To evaluate the outcomes of inferior vena cava (IVC) stent placement for malignant obstruction and to identify anatomic and procedural factors influencing technical and clinical success. MATERIALS AND METHODS: A total of 57 patients (37 male, 20 female; age range, 22-86 y) underwent 62 IVC stent placement procedures using 97 stents (47 Wallstents, 15 S.M.A.R.T. stents, 18 Wallflex stents, 17 others) from 2005 to 2016 for malignant IVC obstruction caused by hepatic metastases (n = 22; 39%), primary hepatic malignancy (n = 16; 28%), retroperitoneal metastases (n = 16; 28%), or other primary malignancy (n = 5; 9%). Presenting symptoms included lower-extremity edema (n = 54; 95%), ascites (n = 28; 50%), and perineal edema (n = 14; 25%). Sixteen percent (n = 10) and 10% (n = 6) of the procedures involved tumor and bland thrombus, respectively. RESULTS: Stent placements resulted in 100% venographic patency and significantly decreased pressure gradients (P < .0001). Lower-extremity swelling, perineal swelling, and abdominal distension improved within 7 days in 83% (35 of 42), 100% (9 of 9), and 40% (6 of 15) of patients, respectively, and at 30 days after the procedure in 86% (25 of 29), 89% (8 of 9), and 80% (4 of 5) of patients, respectively. Increased pre- and post-stent placement pressure gradients were associated with worse outcomes. A 4% stent misplacement rate (4 of 97) was related to the use of Wallstents with caudal stent tapering, asymmetric deployment superior to the obstruction, suprahepatic IVC involvement, and decreased stent adherence to the IVC wall as a result of local mechanical factors. CONCLUSIONS: Stent placement is reliable, rapid, and durable in improving malignant IVC syndrome. Understanding of technical and anatomic factors can improve accuracy and avoid complications of stent misplacement. PMID- 27117950 TI - Stress Test of Contrast-Enhanced US with Phenylephrine in a Rabbit VX2 Liver Tumor Model: Differentiating Benign Periablational Enhancement from Residual Tumor after Radiofrequency Ablation. AB - PURPOSE: To differentiate benign periablational enhancement (BPE) from residual tumor after radiofrequency (RF) ablation by using a stress contrast-enhanced ultrasonography (US) test with phenylephrine in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 tumors were implanted in the livers of 40 rabbits for two experiments. In experiment one, liver tumors from 32 animals were completely ablated. On days 2, 7, 14, and 21 after RF ablation, eight animals were randomly chosen for contrast-enhanced US before and after phenylephrine administration, and the microvessel density (MVD) of BPE at these four time points was assessed. In experiment two, liver tumors from eight animals were partly ablated, and each animal underwent contrast-enhanced US before and after phenylephrine administration on day 7 after RF ablation. Perfusion parameters were observed, including maximum intensity (IMAX), rise time (ie, time between 10% and 90% of IMAX), time to peak, mean transit time, and area under the curve (AUC), along with the profile of time-intensity curves (TICs) in BPE and residual tumor in response to phenylephrine. RESULTS: Among the four time points after ablation, the IMAX and AUC before phenylephrine administration and the MVD of BPE were greatest on day 7 (P < .05). The profile of TICs and the corresponding perfusion parameters in residual tumor did not change significantly in response to phenylephrine. However, those from BPE changed significantly (P < .05). CONCLUSIONS: Contrast-enhanced US with phenylephrine stress may be helpful in differentiating BPE from residual tumor after RF ablation in hepatocellular carcinoma. PMID- 27117951 TI - Variation in NICU Admission Rates Without Identifiable Cause. AB - OBJECTIVES: Admission to the NICU is influenced by physiologic compromise and by hospital care protocols. Providing appropriate care must be balanced with adverse consequences of NICU admission, such as interrupting maternal-infant bonding and unnecessary interventions. This study aims to determine the variation in NICU admissions in term and late preterm infants among 19 hospitals. METHODS: We used the Consortium on Safe Labor (CSL) database to determine NICU admission rates. This database includes data from 217 442 infants aged 35 to 42 weeks within 19 US maternal delivery hospitals from 2002 to 2008. NICU admission rates were evaluated for absolute factors including, but not limited to, sepsis, asphyxia, respiratory distress, and intracranial hemorrhage, as well as relative factors, such as maternal drug use, chorioamnionitis, and infant birth weight <= 2500 g. RESULTS: Percentage of infants 35 to 42 weeks' gestation admitted to the NICU without an identifiable absolute or relative cause for intensive care services ranged from 0% to 59.4% (mean, 10.8%; P < .001). Among infants 35 to 42 weeks' gestation and >= 2500 g, infants without absolute or relative identified cause accounted for 9.1% of total NICU days and had lower length of stays (-2.7 days; 95% confidence interval -3.4; -2.1) compared to those with an identified reason. CONCLUSIONS: There is significant variation in admission rates among NICUs that cannot be explained by infant health conditions. Further analysis is needed to determine the cause of between-site variation and potential opportunities to refine protocols and optimize use of NICU services. PMID- 27117952 TI - Passive interventions in primary healthcare waiting rooms are effective in promoting healthy lifestyle behaviours: an integrative review. AB - Primary healthcare waiting rooms have the potential to provide health-promoting environments to support healthy lifestyle behaviours such as smoking cessation, weight management and safe contraception. Passive interventions are cost effective and continually available within an environment or setting, allowing individuals to interact, engage and learn about topics. The aim of this study was to undertake an integrative review to investigate the effectiveness of passive health-related waiting room interventions in improving healthy lifestyle behaviours, as well as precursors to behaviour change. The integrative review encompassed five phases: problem identification, literature search, data evaluation, data analysis and presentation of results. Quantitative, qualitative and mixed methods studies were included. Of the 9205 studies originally identified, 33 publications were included and grouped under four areas: knowledge about a health condition or behaviour, attitudes and intentions towards a health condition or behaviour, healthcare use and interactions, and health-related behaviours. Overall, the passive interventions had a general positive influence on knowledge, intentions, healthcare use and behaviours. Variable outcomes were reported regarding attitude towards a health topic. Few studies were assessed as both high quality and the highest suitability to assess effectiveness of interventions. Consideration of the clinical significance of improvements is warranted before implementation of future interventions. Overall, passive waiting room interventions appear to be effective in promoting healthy lifestyle behaviours. PMID- 27117953 TI - Excretion of dengue virus RNA by Aedes aegypti allows non-destructive monitoring of viral dissemination in individual mosquitoes. AB - Successful transmission of a vector-borne pathogen relies on a complex life cycle in the arthropod vector that requires initial infection of the digestive tract followed by systemic viral dissemination. The time interval between acquisition and subsequent transmission of the pathogen, called the extrinsic incubation period, is one of the most influential parameters of vector-borne pathogen transmission. However, the dynamic nature of this process is often ignored because vector competence assays are sacrificial and rely on end-point measurements. Here, we report that individual Aedes aegypti mosquitoes release large amounts of dengue virus (DENV) RNA in their excreta that can be non sacrificially detected over time following oral virus exposure. Further, we demonstrate that detection of DENV RNA in excreta from individual mosquitoes is correlated to systemic viral dissemination with high specificity (0.9-1) albeit moderate sensitivity (0.64-0.89). Finally, we illustrate the potential of our finding to detect biological differences in the dynamics of DENV dissemination in a proof-of-concept experiment. Individual measurements of the time required for systemic viral dissemination, a prerequisite for transmission, will be valuable to monitor the dynamics of DENV vector competence, to carry out quantitative genetics studies, and to evaluate the risk of DENV transmission in field settings. PMID- 27117954 TI - The many faces of interleukin-17 in inflammatory skin diseases. AB - Interleukin (IL)-17 is an emerging target for inflammatory skin disorders. Given the remarkable success of its therapeutic inhibition in psoriasis, the pathogenic role of this cytokine is being explored in other immune-mediated diseases. Interestingly, IL-17 is linked to particular skin conditions where its activation coincides with disease flares. The leading hypothesis for its contribution to proinflammatory signalling cascades is driving inflammasome activation. However, IL-17 stimulation also releases a range of noninflammasome-related cytokines from human skin. Furthermore, a role in cytotoxic responses and an important interplay with the microbiome is hypothesized. While treatment failure would be surprising in neutrophilic dermatoses, the picture might be more complex in lymphocyte mediated conditions. Nonetheless, increasing insights into the pathogenesis suggest that beneficial responses are also probable in the latter conditions. Study of this pathway in the skin reveals some intriguing aspects of the IL-17 related immunological network. PMID- 27117955 TI - Calcitonin Gene-Related Peptide Downregulates Expression of Inducible Nitride Oxide Synthase and Caspase-3 after Intestinal Ischemia-Reperfusion Injury in Rats. AB - BACKGROUND: Various investigations have demonstrated that calcitonin gene-related peptide (CGRP) plays an important role in mediating ischemic preconditioning. CGRP has been shown to mimic the protective effects of ischemic preconditioning and mitigate ischemia-reperfusion (I/R) injury in the heart, brain, gastrointestinal system, and other tissues. This study aimed to examine whether CGRP, a proven intestinal cytoprotective molecule, exerted its protective effects through modulation of inducible nitride oxide synthase (iNOS) and apoptosis after intestinal I/R injury. METHODS: This animal study randomly divided 30 rats into the following five groups: (1) the normal control group, (2) the ischemia group with normal saline, (3) the I/R group with normal saline, (4) the ischemia group with CGRP (300 MUg/kg), and (5) the I/R group with CGRP (300 MUg/kg). Levels of iNOS messenger RNA (mRNA) and protein, and caspase-3 protein were determined by real-time quantitative polymerase chain reaction and Western blotting analyses, respectively. Statistical analysis was performed using analysis of variance with Dunn test. RESULTS: The mRNA levels of iNOS increased after the intestinal ischemia or intestinal reperfusion phase (p < 0.01), and CGRP pretreatment significantly decreased iNOS mRNAs and protein levels (p < 0.01). The expression protein levels of caspase-3 increased after the intestinal ischemia or intestinal reperfusion phase. CGRP pretreatment significantly decreased the levels of caspase-3 proteins. CGRP intestinal cytoprotection is mediated, in part, by downregulation of expression of iNOS and caspase-3 after intestinal I/R injury. CONCLUSION: The study indicates that the cytoprotective role of CGRP (i.e., antiapoptotic effect) after I/R injury could be via downregulation of iNOS, which may relieve I/R tissue damage by blocking iNOS activity. PMID- 27117956 TI - Resting electrical network activity in traps of the aquatic carnivorous plants of the genera Aldrovanda and Utricularia. AB - In this study the MEA (multielectrode array) system was used to record electrical responses of intact and halved traps, and other trap-free tissues of two aquatic carnivorous plants, Aldrovanda vesiculosa and Utricularia reflexa. They exhibit rapid trap movements and their traps contain numerous glands. Spontaneous generation of spikes with quite uniform shape, propagating across the recording area, has been observed for all types of sample. In the analysis of the electrical network, higher richer synchronous activity was observed relative to other plant species and organs previously described in the literature: indeed, the time intervals between the synchronized clusters (the inter-spike intervals) create organized patterns and the propagation times vary non-linearly with the distance due to this synchronization. Interestingly, more complex electrical activity was found in traps than in trap-free organs, supporting the hypothesis that the nature of the electrical activity may reflect the anatomical and functional complexity of different organs. Finally, the electrical activity of functionally different traps of Aldrovanda (snapping traps) and Utricularia (suction traps) was compared and some differences in the features of signal propagation were found. According to these results, a possible use of the MEA system for the study of different trap closure mechanisms is proposed. PMID- 27117957 TI - What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder. AB - During the progression of a pilot nutrition intervention designed to teach cooking skills to young adults with autism spectrum disorder (ASD), one participant-Paul-fell in the parking lot. Prior to the accident, Paul had been making significant gains in the program and had communicated in a number of ways his enthusiasm. After his accident, which resulted in broken and dislocated bones in his ankle, his demeanor was dramatically altered, program gains were lost, and staff noted the appearance of many new challenging behaviors. This article analyzes Paul's behavior in reference to the pain response in autism. For some time, it was believed that many individuals with ASD did not experience pain based on anecdotal reports of how individuals responded to injury with seeming indifference. This view has given way of late to a more nuanced understanding of how atypical sensory processing and stimulus over-selectivity spill over into pain pathways and pain amplification mechanisms. The consequence is not a reduction in pain sensation, but a different expression of pain, determined by that individual's particular communicative, cognitive, or physiological challenges. From this perspective, many of the disruptive and harmful behaviors that emerged after Paul's accident can be seen as a delayed response to the incident. This article concludes by arguing that professionals across all domains of health care need to begin to see behavior as communicative for those with ASD. This is particularly true of changes in behavior, which can be significant indicators of health care problems rather than something to be dismissed as another manifestation of the condition. PMID- 27117958 TI - The Experiences of Young Adult Offenders Who Completed a Drug Court Treatment Program. AB - Although there has been a proliferation of studies on the effectiveness of drug court programs, these studies are largely quantitative in nature. Little is known about the experiences of persons who participate in drug court. In this study, we aimed to fill this knowledge gap by exploring experiences of young adults who completed an adult drug court treatment program. Nine semi-structured interviews were conducted, typed into a word-processing program, and then entered into a data analysis software program. Using grounded theory strategies, analysis revealed several emergent themes, which are presented chronologically to provide a narrative of study participants' experiences before, during, and after the program. Findings provide insights on how participants perceive drug courts and experiences that might facilitate or impede completion of drug court programs. Our findings are particularly important for drug court professionals as they attempt to develop appropriate recommendations for best practices and new policy initiatives. PMID- 27117959 TI - How Do People With COPD Value Different Activities? An Adapted Meta-Ethnography of Qualitative Research. AB - Chronic Obstructive Pulmonary Disease (COPD) is a long-term condition where activities of daily living (ADLs) may be very restricted; people with COPD need to prioritize what is important to them. We conducted a meta-ethnography to understand which ADLs are valued and why, systematically searching for articles including experiences of ADLs and organizing themes from the articles into five linked concepts: (a) caring for the body, (b) caring for the personal environment, (c) moving between spaces, (d) interacting with others, and (e) selfhood across time. In addition, we identified three key aspects of personal integrity: effectiveness, connectedness, and control. We found that ADLs were valued if they increased integrity; however, this process was also informed by gendered roles and social values. People whose sense of control depended on effectiveness often found accepting help very difficult to bear; therefore, redefining control as situational and relational may help enjoyment of activities that are possible. PMID- 27117960 TI - Finding Qualitative Research Evidence for Health Technology Assessment. AB - Health technology assessment (HTA) agencies increasingly use reviews of qualitative research as evidence for evaluating social, experiential, and ethical aspects of health technologies. We systematically searched three bibliographic databases (MEDLINE, CINAHL, and Social Science Citation Index [SSCI]) using published search filters or "hedges" and our hybrid filter to identify qualitative research studies pertaining to chronic obstructive pulmonary disease and early breast cancer. The search filters were compared in terms of sensitivity, specificity, and precision. Our screening by title and abstract revealed that qualitative research constituted only slightly more than 1% of all published research on each health topic. The performance of the published search filters varied greatly across topics and databases. Compared with existing search filters, our hybrid filter demonstrated a consistently high sensitivity across databases and topics, and minimized the resource-intensive process of sifting through false positives. We identify opportunities for qualitative health researchers to improve the uptake of qualitative research into evidence-informed policy making. PMID- 27117961 TI - Illness Narratives of African Americans Living With Coronary Heart Disease: A Critical Interactionist Analysis. AB - How African American men and women respond to and manage living with coronary heart disease (CHD) is not well understood despite the well-documented disproportionate burden of CHD and its complications among African Americans in the United States. Through a critical interactionist perspective, we explore illness experiences of African Americans living with CHD and describe a broad range of micro-, meso-, and macro-contextual factors that influence their illness experiences. For participants in this study, CHD has become a "Black disease" wherein certain bodies have become historically and racially marked; a conceptualization maintained and passed on by African Americans themselves. Such findings highlight that CHD is more than a "lifestyle disease" where high-risk behaviors and lack of healthy choices are ultimate culprits. Rather, CHD is perceived by African Americans who have it as yet another product of ongoing racial and socio-structural dynamics through which their health burdens are created, sustained, and reproduced. PMID- 27117962 TI - Stomach arteriovenous malformation resected by laparoscopy-assisted surgery: A case report. AB - Arteriovenous malformations of the stomach are an uncommon cause of upper GI bleeding. We report a case of stomach arteriovenous malformation in an 85-year old Asian man who presented with massive hematemesis. Initial esophagogastroduodenoscopy did not detect this lesion, but contrast multi detector CT confirmed GI bleeding. Multi-detector CT revealed a mass of blood vessels underlying the submucosa that arose from the right gastroepiploic artery. Repeat esophagogastroduodenoscopy showed that the lesion was a submucosal tumor with erosion and without active bleeding in the lower body of the stomach on the greater curvature. We performed partial gastrectomy via laparoscopy-assisted surgery. The histopathological diagnosis was arteriovenous malformation. PMID- 27117963 TI - Chylous leakage from a remaining duplicated left-sided thoracic duct after esophagectomy successfully treated by ligation of the left-sided thoracic duct with left-sided video-assisted thoracoscopic surgery with the patient in the prone position. AB - A 69-year-old man who had undergone an esophagectomy was diagnosed with chylous leakage on postoperative day 2, and his pleural effusion output gradually increased daily. On postoperative day 6, intranodal lymphangiography using lipiodol demonstrated chylous leakage from branches of an incomplete duplicated left-sided thoracic duct; it also indicated successful ligation of the right sided thoracic duct at initial operation. After lymphangiography, the chylous leakage did not heal and remained uncontrollable. Based on the preoperative lymphangiographic findings, we ligated the left-sided thoracic duct with left sided video-assisted thoracoscopic surgery, with the patient in the prone position, on postoperative day 9. The patient experienced no other postoperative complications. The use of the prone position with pneumothorax treatment was helpful in providing a wide operative field in the posterior mediastinum, thus allowing for a better chance for a successful postoperative outcome. PMID- 27117964 TI - Combined laparoscopic abdominoperineal resection and robotic-assisted prostatectomy for synchronous double cancer of the rectum and the prostate. AB - Here we report a combined laparoscopic abdominoperineal resection and robotic assisted prostatectomy. A 74-year-old man was diagnosed with T4b low rectal and prostate cancer. The operation was performed after neoadjuvant chemotherapy for the rectal cancer. The procedure used eight ports in total, five for laparoscopic abdominoperineal resection and six for robotic-assisted prostatectomy. First, laparoscopic total mesorectal excision including division of the inferior mesenteric artery was performed, and then, robotic dissection of the prostate was performed. The en bloc specimen was removed through the perineal wound. Then, robotic urethrovesical anastomosis was performed. An extraperitoneal end colostomy was created to finish the operation. The operating time was 545 min, and blood loss was 170 mL. The postoperative course was uneventful, and the patient discharged on postoperative day 17. The combined laparoscopic abdominoperineal resection and robotic-assisted prostatectomy were performed safely without any additional technical difficulty, as both procedures shared port settings and patient positions. PMID- 27117965 TI - Postoperative Mycoplasma hominis infection after robot-assisted laparoscopic radical prostatectomy: A case report. AB - A 59-year-old man developed a high fever, elevated white blood cell count, elevated C-reactive protein level, and perineal pain 5 days after robot-assisted laparoscopic radical prostatectomy. Treatment with cefmetazole was ineffective. A urine specimen was submitted for culture on postoperative day 7, and Mycoplasma hominis (M. hominis) was detected 1 week later. Cefmetazole was therefore switched to quinolone. The clinical symptoms and laboratory data immediately showed marked improvement. M. hominis has been shown to inhabit the genitourinary tract. Although it is considered to induce urethritis, its pathogenicity in healthy male subjects has not been investigated. M. hominis is difficult to detect and is resistant to beta-lactams because it lacks a cell wall. Urine culture sometimes results in false-negative results. In cases where empirical therapy for postoperative infection is ineffective, surgeons should recognize the possibility of M. hominis involvement and consider changing the antibiotic used. PMID- 27117966 TI - Two-stage surgery to repair a dissecting abdominal aortic aneurysm in a severely obese patient: Open bifurcated graft replacement after laparoscopic sleeve gastrectomy. AB - With the increasing prevalence of severe obesity worldwide, surgical treatment for severely obese patients is becoming more popular. Bariatric surgery has occasionally been performed as a precursor to major operations for serious diseases to make these difficult surgeries safer for severely obese patients. We present the case of a severely obese patient with a dissected abdominal aortic aneurysm and left iliac artery aneurysm. Initially, we performed bariatric surgery on this patient to reduce perioperative risk and then subsequently performed bifurcated graft replacement. A 54-year-old man presented at our hospital for bariatric surgery before open abdominal aortic aneurysm repair. Laparoscopic sleeve gastrectomy was performed; 15 months later, the patient's weight and BMI had decreased from 139.0 kg to 97.6 kg and from 48.7 kg/m(2) to 34.2 kg/m(2) , respectively. Bifurcated graft replacement was performed safely without postoperative complications. Bariatric surgery was also effective in controlling the patient's blood pressure during the interval between surgeries. PMID- 27117967 TI - Indications for the laparoscopic approach to acute small bowel obstruction: A retrospective review of 50 cases, a literature review, and a single hospital's preliminary experience. AB - Small bowel obstruction (SBO) is mainly caused by postoperative adhesions, but a broad spectrum of diseases may cause this pathogenetic condition. Laparoscopic treatment represents an efficient approach to SBO. The aim of this paper was to review a single center's experience with a minimally invasive approach to multiple pathologic scenarios causing SBO. From January 2010 to December 2012, 50 consecutive patients underwent laparoscopic surgery for mechanical SBO. In 90% of patients, the surgical procedure was totally laparoscopic, while 10% required conversion to midline laparotomy. In-hospital morbidity was 15% among totally laparoscopic patients and 40% among those who underwent conversion to midline laparotomy. Thirty-day mortality was zero. One patient died 4 months postoperatively from neoplastic disease progression; the remaining patients were free from occlusive symptoms at follow-up. The minimally invasive technique applies to a broad spectrum of cases. A larger cohort of patients seems necessary to reproduce our results and confirm the effectiveness of a laparoscopic approach to SBO. PMID- 27117968 TI - Laparoscopic repair of left paraduodenal hernia: Report of two cases and review of the literature. AB - Internal hernia is the cause of only 1% of intestinal obstructions, and left paraduodenal hernias (PDH) comprise about 50% of these cases. As the presentation of PDH is varied, diagnosis is often delayed. Here, we report two patients with left PDH presenting in a subacute manner and diagnosed rapidly with the help of a CT scan. Both underwent successful laparoscopic repair; one patient had closure of the defect, and the other required excision of the sac prior to the closure. We review 21 cases of left PDH treated laparoscopically that were previously reported in the literature, including 14 from Asian countries. PMID- 27117969 TI - Laparoscopic Hartmann reversal: Video presentation of a case. AB - INTRODUCTION: Laparoscopic Hartmann reversal (LHR) has decreased postoperative recovery time and a lower wound infection rate compared to open HR. However its technical difficulty and high conversion rates make it a challenging procedure. We aim to demonstrate the technique of LHR via a video presentation. Our patient, a 64 year old Chinese man with no history of previous surgery underwent a Hartmann procedure for an obstructing sigmoid stricture secondary to diverticular disease. Three months later, he underwent an elective LHR. MATERIALS AND SURGICAL TECHNIQUE: A 10 mm port was initially inserted in the right iliac fossa under direct vision away from expected adhesions due to the previous midline incision. Additional 5mm working ports were inserted in the right flank and right hypochondrium. An additional 10mm optical port was then inserted in the epigastrium and the laparoscopic camera was switched to the epigastric port. Omental adhesions to abdominal wall were taken down. The left colon was then brought down to the pelvis to ensure adequate length of bowel for anastomosis. A colorectal side to end anastomosis was then performed. The stoma wound was closed and the patient was discharged well on post-operative day 5. DISCUSSION: LHR can be adopted as an initial approach to visualize intra-abdominal adhesions and determine feasibility of operation. With experienced hands, LHR can achieve good patient outcomes. PMID- 27117970 TI - Stealth surgery for congenital muscular torticollis. AB - INTRODUCTION: We report a case of congenital muscular torticollis managed successfully by the endoscopic transaxillary subcutaneous approach without any neck incision. MATERIALS AND SURGICAL TECHNIQUE: A 10-year-old girl was diagnosed as having right torticollis. After her condition and the necessary procedure were explained to her parents, the patient underwent surgery. The patient was placed in the supine position. A subcutaneous tunnel was made from the anterior axillary fold up to the right sternocleidomastoid muscle. Flow rate and pressure were gradually increased during this process. Then the sternocleidomastoid muscle's sternal and clavicular attachments were dissected and divided. DISCUSSION: Scarless surgery is in great demand today. Stealth surgery refers to endoscopic subcutaneous procedures performed without leaving any obvious evidence that an operation has occurred. It involves the excision of benign subcutaneous lesions of the head and neck in children through an incision in the axilla or a hidden incision in the scalp. PMID- 27117971 TI - Endoscopy-assisted transanal repair of afferent limb obstruction and long efferent limb with ileopexy after ileal J-pouch-anal anastomosis. AB - Afferent limb obstruction can be a persistent complication after restorative proctocolectomy with ileal pouch-anal anastomosis. We present a case of afferent limb obstruction complicated by a long efferent limb of the ileal pouch that we successfully treated with side-to-side anastomosis of the afferent and efferent limbs. The procedure involved using a transanal endoscopic stapling device assisted by transanal endoscopy with a thin intestinal video endoscope. This allowed reliable, safe visualization of the lesion from the tight pouch-anal anastomosis and facilitated repair with an endoscopic stapling device. Because the technique was performed without enterotomy, it reduced the risks of contamination and leakage from transabdominal small bowel anastomosis. Laparotomy view also prevented of injury to the pouch itself and entrapment of the mesentery of the afferent and efferent limbs of the pouch between the stapler anvils. PMID- 27117973 TI - A 'spot' diagnosis. PMID- 27117972 TI - German Center Subanalysis of the LEVANT 2 Global Randomized Study of the Lutonix Drug-Coated Balloon in the Treatment of Femoropopliteal Occlusive Disease. AB - PURPOSE: To report a subanalysis of the German centers enrolling patients in the prospective, global, multicenter, randomized LEVANT 2 pivotal trial (ClinicalTrials.gov identifier NCT01412541) of the Lutonix drug-coated balloon (DCB) for the treatment of femoropopliteal occlusive disease. METHODS: Among the 476 patients in LEVANT 2, 126 patients (mean age 67.1+/-9.6 years; 79 men) were enrolled at the 8 participating German sites between August 2011 and July 2012 and were randomized 2:1 to treatment with the Lutonix DCB (n=83) vs an uncoated balloon during percutaneous transluminal angioplasty (PTA, n=43). All patients had intermittent claudication or rest pain (Rutherford categories 2-4). Average lesion length was 58 mm and average treated length was 100 mm. Severe calcification was present in 11% of lesions, and 23% were total occlusions. The efficacy outcome was primary patency at 12 months, and the safety outcome was 12 month freedom from a composite of perioperative death, index limb-related death, amputation (below or above the ankle), and index limb revascularization. Secondary endpoints included target lesion revascularization (TLR), major adverse events, and functional outcomes. RESULTS: Demographic, clinical, and lesion characteristics were matched between Lutonix DCB and PTA groups, as were the final percent diameter stenosis (19%) and procedure success (91%). By Kaplan Meier analysis, the 12-month primary patency rate was 80% vs 58% (p=0.015) and the composite safety endpoint rate was 94% vs 72% (p=0.001), respectively. Freedom from TLR was higher for DCBs (96%) vs PTA (82%, p=0.012). Major adverse events were similar for both groups. The benefit favoring DCB over PTA was observed in German men and women. Compared to the non-German LEVANT 2 cohort, there was a shorter time between insertion and inflation of treatment balloons (21.8 vs 39.5 seconds, p<0.001) in the German cohort. Balloons were inflated to higher pressures (9.0 vs 7.7 atm, p<0.001) but for a shorter period of time (130 vs 167 seconds, p<0.001), and although treated lesions in the German cohort had a higher baseline stenosis, final postprocedure diameter stenosis was lower (19% vs 22%, p=0.04) than in the non-German patients. CONCLUSION: Superiority of DCB over PTA in the German cohort of LEVANT 2 was demonstrated for primary patency, composite safety, and freedom from TLR. The benefit of DCB was also consistent for both genders. Geographic or regional differences in procedural variables may account for the different outcomes between the German and non-German cohorts. PMID- 27117974 TI - A neonate with abdominal distension and failure to thrive. PMID- 27117976 TI - Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells. AB - Chlorpyrifos (CPS) is an organophosphorus compound (OP) capable of causing well known cholinergic and delayed syndromes through the inhibition of acetylcholinesterase and Neuropathy Target Esterase (NTE), respectively. CPS is also able to induce neurodevelopmental toxicity in animals. NTE is codified by the Pnpla6 gene and plays a central role in differentiation and neurodifferentiation. We tested, in D3 mouse embryonic stem cells under differentiation, the effects of the NTE inhibition by the OPs mipafox, CPS and its main active metabolite chlorpyrifos-oxon (CPO) on the expression of genes Vegfa, Bcl2, Amot, Nes and Jun, previously reported to be under- or overexpressed after Pnpla6 silencing in this same cellular model. Mipafox did not significantly alter the expression of such genes at concentrations that significantly inhibited NTE. However, CPS and CPO at concentrations that caused NTE inhibition at similar levels to mipafox statistically and significantly altered the expression of most of these genes. Paraoxon (another OP with capability to inhibit esterases but not NTE) caused similar effects to CPS and CPO. These findings suggest that the molecular mechanism for the neurodevelopmental toxicity induced by CPS is not based on NTE inhibition, and that other unknown esterases might be potential targets of neurodevelopmental toxicity. PMID- 27117975 TI - Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond. AB - Tremendous strides have been made in the treatment of various oncological diseases such that patients are surviving longer and are having better quality of life. However, the success has been tainted by the iatrogenic cardiac toxicities. This is especially concerning in the younger population who are facing cardiac disease such as heart failure in their 30s and 40s as the consequence of the anthracycline's side effects (used for childhood leukemia and lymphoma). This resulted in the awareness of cardiotoxic effects of anticancer drugs and emergence of a new discipline: oncocardiology. Since then, numerous anticancer drugs have been correlated to cardiomyopathy. Additionally, other cardiovascular effects have been identified, which includes but is not limited to myocardial infarction, thrombosis, hypertension, arrhythmias, and pulmonary hypertension. In this review we examine some of the anticancer agents that mitigate cardiotoxicity and present current knowledge of molecular mechanism(s). The aim of the review is to ignite awareness of emerging cardiotoxic effects as new generations of anticancer agents are being tested in clinical trials and introduced as part of the therapeutic armamentarium to our oncological patients. PMID- 27117977 TI - Role of EGF receptor ligands in TCDD-induced EGFR down-regulation and cellular proliferation. AB - In cultures of normal human epidermal keratinocytes (NHEKs), 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) induces the expression of the epidermal growth factor receptor ligands transforming growth factor-alpha (TGF-alpha) and epiregulin (EREG). TCDD also down-regulates EGF receptors (EGFR), suggesting that decreases in signaling contribute to the effects of TCDD. In this study, we treated post-confluent NHEKs with 10 nM TCDD and assessed its effects on EGFR binding, EGFR ligand secretion, basal ERK activity, and proliferation. TCDD caused time-dependent deceases in [(125)I]-EGF binding to levels 78% of basal cell values at 72 h. Amphiregulin (AREG) levels increased with time in culture in basal and TCDD-treated cells, while TGF-alpha and epiregulin (EREG) secretion were stimulated by TCDD. Inhibiting EGFR ligand release with the metalloproteinase inhibitor batimastat prevented EGFR down-regulation and neutralizing antibodies for AREG and EREG relieved receptor down-regulation. In contrast, neutralizing TGF-alpha intensified EGFR down-regulation. Treating NHEKs with AREG or TGF-alpha caused rapid internalization of receptors with TGF-alpha promoting recycling within 90 min. EREG had limited effects on rapid internalization or recycling. TCDD treatment increased ERK activity, a response reduced by batimastat and the neutralization of all three ligands indicating that the EGFR and its ligands maintain ERK activity. All three EGFR ligands were required for the maintenance of total cell number in basal and TCDD-treated cultures. The EGFR inhibitor PD1530305 blocked basal and TCDD-induced increases in the number of cells labeled by 5-ethynyl-2'-deoxyuridine, identifying an EGFR dependent pool of proliferating cells that is larger in TCDD-treated cultures. Overall, these data indicate that TCDD-induced EGFR down-regulation in NHEKs is caused by AREG, TGF-alpha, and EREG, while TGF-alpha enhances receptor recycling to maintain a pool of EGFR at the cell surface. These receptors are required for ERK activity, maintenance of total cell number, and stimulating the proliferation of a small subset cells. PMID- 27117978 TI - Coding deficits in hidden hearing loss induced by noise: the nature and impacts. AB - Hidden hearing refers to the functional deficits in hearing without deterioration in hearing sensitivity. This concept is proposed based upon recent finding of massive noise-induced damage on ribbon synapse between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in the cochlea without significant permanent threshold shifts (PTS). Presumably, such damage may cause coding deficits in auditory nerve fibers (ANFs). However, such deficits had not been detailed except that a selective loss of ANFs with low spontaneous rate (SR) was reported. In the present study, we investigated the dynamic changes of ribbon synapses and the coding function of ANF single units in one month after a brief noise exposure that caused a massive damage of ribbon synapses but no PTS. The synapse count and functional response measures indicates a large portion of the disrupted synapses were re-connected. This is consistent with the fact that the change of SR distribution due to the initial loss of low SR units is recovered quickly. However, ANF coding deficits were developed later with the re-establishment of the synapses. The deficits were found in both intensity and temporal processing, revealing the nature of synaptopathy in hidden hearing loss. PMID- 27117979 TI - A simplified protocol for high-yield expression and purification of bacterial topoisomerase I. AB - Type IA topoisomerases represent promising antibacterial drug targets. Data exists suggesting that the two bacterial type IA topoisomerase enzymes topoisomerase I and topoisomerase III-share an overlapping biological role. Furthermore, topoisomerase I has been shown to be essential for the survival of certain organisms lacking topoisomerase III. With this in mind, it is plausible that topoisomerase I may represent a potential target for selective antibacterial drug development. As many reported bacterial topoisomerase I purification protocols have either suffered from relatively low yield, numerous steps, or a simple failure to report target protein yield altogether, a high-yield and high purity bacterial topoisomerase I expression and purification protocol is highly desirable. The goal of this study was therefore to optimize the expression and purification of topoisomerase I from Streptococcus mutans, a clinically relevant organism that plays a significant role in oral and extra-oral infection, in order to quickly and easily attain the requisite quantities of pure target enzyme suitable for use in assay development, compound library screening, and carrying out further structural and biochemical characterization analyses. Herein we report the systematic implementation and analysis of various expression and purification techniques leading to the development and optimization of a rapid and straightforward protocol for the auto-induced expression and two-step, affinity tag purification of Streptococcus mutans topoisomerase I yielding >20 mg/L of enzyme at over 95% purity. PMID- 27117980 TI - Is There a Role for Robotic Surgery in the Treatment of Head and Neck Cancer? AB - OPINION STATEMENT: Given the potential for long-term toxicities from concurrent chemoradiation, there is great interest in surgery as a primary treatment modality for head and neck cancers, particularly in the younger HPV-positive oropharyngeal cancer patient. Transoral robotic surgery (TORS) has proven to be an effective technique to safely treat oropharyngeal and select supraglottic tumors surgically. Sound, traditional surgical principles are employed using improved endoscopic visualization and precise instrumentation to perform oncologic surgery without the morbidity of transmandibular or transcervical approaches. Although level 1 evidence prospective clinical trials are currently underway for TORS, the literature supports its safety and efficacy based on numerous studies. Currently, prospective randomized trials are underway to provide better evidence for or against TORS in oropharyngeal cancer. Patient selection based on comorbidities, anatomy, and available pathological data is critical in choosing patients for TORS. PMID- 27117981 TI - Emergence of blaCTX-M-15, blaTEM-169 and blaPER-1 extended-spectrum beta lactamase genes among different Salmonella enterica serovars from human faecal samples. AB - BACKGROUND: Broad-spectrum beta-lactams are used for empirical therapy of severe infections with non-typhoid Salmonella serotypes; however, activities of these drugs against the strains producing different beta-lactamase is not so clear. This study investigated the prevalence of beta-lactamase genes among isolates of S. enterica serovars from human faecal samples and determined their diversity in activity against different beta-lactams. METHODS: Antimicrobial resistance of faecal isolates of S. enterica to extended-spectrum cephalosporins was analysed and MIC values were determined for the strains presenting extended-spectrum beta lactamases (ESBLs) phenotypes. The beta-lactamase genes were identified by PCR and sequencing. beta-lactamase activity of the Salmonella strains exhibiting ESBL phenotype was detected by biological, iodometric, spectrophotometry and nitrocefin assays. RESULTS: Out of 202 S. enterica isolates, ESBLs phenotype was detected among 3.4% (7/202) of the strains. blaTEM-1 and blaCTX-M-15 were among the frequent beta-lactamase genes. Detection of blaTEM-169 in S. enterica serovar Typhimurium and S. enterica serovar Bredeney and blaPER-1 in S. enterica serovar Infantis was a new finding in this experiment. Location of blaCTX-M-15/blaTEM 169/blaPER-1 genes on plasmid was confirmed in a transformation experiment. While crude extracts of the enzymes from each strain showed higher activity against cephalothin and cefotaxime, the lowest activity was detected against ceftazidime. The greatest synergistic activity was seen in a strain of S. enterica that carried blaCTX-M-15 and blaPER-1 genes compared with those presenting blaCTX-M 15/blaTEM-169 or blaCTX-M-15/blaTEM-1 genotypes. CONCLUSIONS: The results show dissemination of ESBLs encoding genes and their combined activity among different serovars of S. enterica that are a threat for future treatment options. PMID- 27117983 TI - Histone modifications interact with DNA methylation at the GATA4 promoter during differentiation of mesenchymal stem cells into cardiomyocyte-like cells. AB - OBJECTIVES: A previous study of ours confirmed that Islet-1 specifically induces differentiation of MSCs into cardiomyocytes, and that one of the mechanisms underlying that process is regulation of histone acetylation. Here, we further explore the mechanism of MSC differentiation into cardiomyocytes from the perspective of interactions between epigenetic modifications. MATERIALS AND METHODS: We used lentiviral vectors to overexpress Islet-1 in MSCs, and ChIP qPCR, MSP and BSP were performed to detect levels of histone acetylation/methylation and DNA methylation in the GATA4 and Nkx2.5 promoters. To further explore relationships between these epigenetic modifications, we used 5 aza or TSA to interfere with DNA methylation and histone acetylation, respectively, and detected effects on the other two modifications. RESULTS: Histone acetylation level increased and its methylation level decreased at GATA4 and Nkx2.5 promoters; DNA methylation level was reduced at the GATA4 promoter but did not change at the Nkx2.5 promoter. Furthermore, 5-aza increased histone acetylation level and reduced its methylation level at the GATA4 promoter but had no effect on the Nkx2.5 promoter; TSA reduced histone methylation and DNA methylation levels at the GATA4 promoter, but it only reduced histone methylation level at the Nkx2.5 promoter. CONCLUSIONS: Histone acetylation/methylation and DNA methylation were both involved in regulating GATA4 expression, but Nkx2.5 expression was not regulated by DNA methylation. These three modifications had high correlation with each other during regulation of GATA4 and produced a regulation loop at the GATA4 promoter. PMID- 27117984 TI - A Single In-Vial Dual Extraction Strategy for the Simultaneous Lipidomics and Proteomics Analysis of HDL and LDL Fractions. AB - A single in-vial dual extraction (IVDE) procedure for the subsequent analysis of lipids and proteins in the high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions derived from the same biological sample is presented. On the basis of methyl-tert-butyl ether (MTBE) extraction, IVDE leads to the formation of three phases: a protein pellet at the bottom, an aqueous phase with polar compounds, and an ether phase with lipophilic compounds. After sample extraction, performed within a high-performance liquid chromatography vial insert, the ether phase was directly injected for lipid fingerprinting, while the protein pellet, after evaporation of the remaining sample, was used for proteomics analysis. Human HDL and LDL isolates were used to test the suitability of the IVDE methodology for lipid and protein analysis from a single sample in terms of data quality and matching composition to that of HDL and LDL. Subsequently, HDL and LDL fractions isolated from ApoE-KO and wild-type mice were used to validate the capacity of IVDE for revealing changes in lipid and protein abundance. Results indicate that IVDE can be successfully used for the subsequent analysis of lipids and proteins with the advantages of time saving, simplicity, and reduced sample amount. PMID- 27117985 TI - Radionecrosis versus disease progression in brain metastasis. Value of (18)F-DOPA PET/CT/MRI. AB - The use of (18)F-DOPA PET/CT with magnetic resonance imaging fusion and the use of visual methods and quantitative analysis helps to differentiate between changes post-radiosurgery vs. suspicion of disease progression in a patient with brain metastases from melanoma, thus facilitating taking early surgical action. PMID- 27117986 TI - Towards the application of HD-EMG decomposition in clinical practice. PMID- 27117987 TI - Effects of a TiC substrate on the catalytic activity of Pt for NO reduction. AB - Density functional theory calculations are used to elucidate the catalytic properties of a Pt monolayer supported on a TiC(001) substrate (Pt/TiC) toward NO reduction. It is found that the compound system of Pt/TiC has a good stability due to the strong Pt-TiC interaction. The diverse dissociation paths (namely the direct dissociation mechanism and the dimeric mechanism) are investigated. The transition state searching calculations suggest that NO has strong diffusion ability and small activation energy for dissociation on the Pt/TiC. For NO reduction on the Pt/TiC surface, we have found that the direct dissociation mechanisms (NO + N + O -> NO2 + N and NO + N + O -> N2 + O + O) are easier with a smaller dissociation barrier than those on the Pt(111) surface; and the dimeric process (NO + NO -> (NO)2 -> N2O + O -> N2 + O + O) is considered to be dominant or significant with even a lower energy barrier than that of the direct dissociation. The results show that Pt/TiC can serve as an efficient catalyst for NO reduction. PMID- 27117988 TI - Factors influencing anesthesia residency selection: impact of global health opportunities. AB - PURPOSE: There is growing evidence to suggest that the current generation of medical students and young physicians is interested in global health. However, there are few data on the interest in global health by students pursuing a career in anesthesiology. The objective of this survey was to evaluate the importance of global health opportunities in regard to applicants' choice of anesthesiology residency programs. METHODS: Anesthesiology residency program directors in the United States were invited to distribute an online survey to recently matched residents. To reduce study bias, the survey included a wide selection of reasons for program choices in addition to global health. Participants were asked to rate independently, on a scale of 1 to 10 (1 = least important, 10 = most important), the importance that each factor had on their selection of an anesthesiology residency program. RESULTS: Of the 117 U.S. anesthesiology programs contacted, 87 (74%) distributed the survey. Completed surveys were obtained from 582 of 1,092 (53%) polled participants. All factors assessed were rated between 5 and 9 and the global health median [interquartile range] rating was 6 [3-7]. Nearly half of the survey respondents were interested in incorporating global health into future careers. More than three-quarters reported being interested in participating in, or reading about, global health activities during their residency. Responders with previous global health experience, or who were interested in an "in-country" experience, were more likely to choose programs that had global health opportunities available during residency. CONCLUSIONS: Anesthesia residency program applicants are interested in global health. Having a global health opportunity was an important reason for choosing a residency program, comparable to some more traditional factors. Regardless of previous global health experience, the majority of future anesthesia residents are either planning or considering participation in global health activities during or after training. PMID- 27117990 TI - A place that is easier to get into than to get out of! PMID- 27117991 TI - Prolonged transesophageal echocardiography during percutaneous closure of the left atrial appendage without general anesthesia: the utility of the Janus mask. AB - PURPOSE: Left atrial appendage (LAA) closure is an interventional procedure increasingly used to prevent stroke in patients with permanent atrial fibrillation and contraindications to anticoagulation therapy. As this procedure requires a relatively immobile patient and performance of continuous and prolonged transesophageal echocardiography (TEE), it is usually performed under general anesthesia. In this case series, we describe the feasibility of prolonged TEE for percutaneous LAA closure using a new noninvasive ventilation device that can avoid the need for endotracheal intubation and general anesthesia. CLINICAL FEATURES: Percutaneous LAA closure was performed under deep sedation in three elderly patients with permanent atrial fibrillation. Sedation was obtained with a combination of midazolam, propofol, and remifentanil. Continuous intraoperative TEE was performed through the port of the newly available Janus mask (Biomedical Srl; Florence, Italy), allowing for noninvasive ventilation (pressure support = 12-16 cm H2O; positive end-expiratory pressure = 7 cm H2O; FIO2 = 0.3) in these spontaneously breathing patients. The total procedure times ranged from 75-90 min. The patients reported excellent satisfaction with the sedation received in terms of discomfort experienced during the procedure, capacity to recall the procedure, and comfort with the mask. The operators also rated the procedural conditions as excellent. CONCLUSION: Deep sedation with noninvasive ventilation may be a reasonable and safe alternative to general endotracheal anesthesia in patients requiring prolonged TEE for noninvasive cardiac procedures, including LAA closure. PMID- 27117992 TI - Description of Comamonas sediminis sp. nov., isolated from lagoon sediments. AB - Strain S3T was isolated from lagoon sediments, and appeared as transparent colonies on agar plates, with cells staining Gram-negative. Catalase and oxidase were positive. S3T hydrolyzed starch, casein and tween-20, while urea, chitin, gelatin and tween-80 were not hydrolysed. C18 : 1omega6c/C18 : 1omega7c, C16 : 1omega6c/C16 : 1omega7c,C17 : 0 cyclo and C16 : 0 were the predominant fatty acids with minor amounts of C10 : 0 3-OH, C12 : 0, C14 : 0 and C16 : 0 2-OH. S3T contained diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) as major polar lipids with minor amounts of unidentified phospholipid (PL) and unidentified lipids (L1-2). Genomic DNA G+C content was 68.3 mol%. 16S rRNA gene sequence comparisons indicated that S3T represents a member of the genus Comamonas in family Comamonadaceae of the class Betaproteobacteria. S3T has a sequence similarity of 98.96 % with Comamonas koreensis YH12T, 97.93 % with Comamonas guangdongensis CY01T and <96.97 % with other members of the genus Comamonas. DNA-DNA hybridization values between S3T and the type strains of the most closely related species were clearly below the 70 % threshold. On the basis of phenotypic, genotypic and phylogenetic analysis, it is proposed that S3T represents a novel species of the genus Comamonas, for which the name Comamonas sediminis sp. nov. is proposed. The type strain is S3T (=KEMB 563-466T =JCM 31169T). PMID- 27117993 TI - [Exercise therapy in the treatment of idiopathic adolescent scoliosis: Is it useful?]. AB - Many practitioners, pediatricians, and general practitioners prescribe physical therapy when tracking scoliosis. However, has physical therapy alone proved its efficacy in the care of the scoliosis to slow down progression? Our purpose is to report the results of a literature review on the effectiveness of rehabilitation in idiopathic scoliosis. No current study presents sufficient scientific proof to validate the efficacy of isolated exercise therapy in scoliosis. Learned societies recognize, however, the efficacy of combining conservative therapy (brace+physiotherapy) in idiopathic scoliosis. Should we then still prescribe rehabilitation without brace treatment? Although physical therapy alone does not seem effective in treating scoliosis, it can limit potential painful phenomena and be beneficial for respiratory function. The physical therapist can also teach the teenager the classic principles of hygiene of the back. It may therefore be appropriate to prescribe physical therapy, but the principles and objectives must be explained to the patient and family in light of current evidence-based medicine. PMID- 27117994 TI - [Pilot study evaluating the ratio of medication errors related to antimicrobials compared to their consumption]. AB - INTRODUCTION: As part of our antimicrobial stewardship program, we were interested in the use of anti-infectious drugs and the prevalence of medication errors associated with the use of these drugs. METHODS: The retrospective and descriptive study was conducted over a 1-year-period between 1 April 2012 and 31 March 2013 in a teaching mother-child hospital. The aim of the study was to determine the number and the type of medication errors related to anti-infectious drugs. We evaluated the importance, the significance, and the severity of medication errors and at the same time we evaluated antimicrobial consumption. Therefore, we determined the ratio of medication errors per 10,000 defined daily doses (DDD) or 10,000 days of therapy (DOT). The secondary objective of the study was to compare the medication errors related to anti-infectious drugs with the data published in the Quebec Registry of Incidents and Accidents. RESULTS: We found a total of 2164 medication errors including 301 (14%) medication errors related to anti-infectious drugs during the 2012-2013 fiscal year. The majority (95%) of the medication errors related to anti-infectious drugs was not harmful, with no consequences for the patient. Seventy-four percent of medication errors related to anti-infectious drugs were part of the C class on the severity scale. Omission (26%) and wrong dose administration were the two most frequently reported events. Eighty percent (n=242/301) of medication errors occurred during the administration step while only 8% (n=24/301) occurred during the prescribing step. Three anti-infectious drugs had the highest ratio of medication errors per 10,000 DDD or DOT: linezolid (376 medication errors per 10,000 DDD), doxycycline (357 medication errors per 10,000 DDD), and acyclovir (202 medication errors per 10,000 DDD). The nonparametric tests showed no significant differences between frequently used and infrequently used anti-infectious drugs for the ratio of medication errors per 10,000 DOT. This pilot study showed a ratio of 65.4 medication errors/10,000 DDD of anti-infectious drugs and a ratio of 41.9 medication errors/10,000 DOT of anti-infectious drugs. CONCLUSION: The use of these ratios could contribute to focusing on monitoring anti-infectious drugs and improving the risk management system associated with this class of drugs. It also shows that less frequently used anti-infectious drugs should be managed with greater caution. Anti-infectious stewardship programs should also consider ratios of medication errors for anti-infectious drugs used in order to improve patient safety and optimize use of drugs. PMID- 27117995 TI - [Newborn hearing screening and deafness care in deaf families: Be careful of tactlessness!]. PMID- 27117996 TI - [Assessment and management of gender dysphoria in children and adolescents]. AB - Gender dysphoria, originally called gender identity disorder, is characterized by the dissociation between one's expressed gender and the gender of rearing as assigned at birth, which generates significant clinical distress and social, academic, and other important forms of isolation. This state is also known as transgender or transsexualism and is recognized as a medical disease. Adults with gender dysphoria can benefit from psychological, medical, and surgical care. However, gender dysphoria rarely occurs in adulthood but rather emerges in childhood or adolescence, generating deep social and academic difficulties, especially at puberty. For the last 10years, the management of gender dysphoria in children and adolescents has developed in several countries, specifically in Europe, but remains under-recognized in France. Since 2013, several pediatric psychiatry and endocrinology departments have initiated a multidisciplinary evaluation and management approach for these patients. This article reviews the clinical criteria helping diagnose gender dysphoria and presents the different steps in the assessment and management of these patients in accordance with international guidelines. PMID- 27117997 TI - [Drugs news]. PMID- 27117998 TI - [Constipation in infants and children: How should it be treated?]. AB - Functional constipation is a common pediatric problem in general practice and even more so in pediatric gastroenterology clinics. Treatment is often delayed with psychosocial and digestive consequences. However, treatment is well codified and effective. Hyperosmotic mineral water, diet, and endoanal medications are not treatments for established constipation, whatever the age. The lactulose/lactitol based medications are authorized and effective before 6 months of age and polyethylene-glycol for infants over 6 months. Mineral oil is less prescribed. The rule for treatment is a sufficient dose for a long time. In case of fecal impaction with or without fecal incontinence, the first stage is fecal disimpaction, using a high dose of PEG the first few days, or repeated phosphate enemas. Education regarding the adaptation of toilets and a daily bowel movement should restore colic motility and avoid relapses when the treatment is discontinued. Psychological concerns should be evaluated and treated. PMID- 27117999 TI - [Nephrotic syndrome in children at the Dakar University Hospital]. PMID- 27118000 TI - An evaluation of perinatal mental health interventions: An integrative literature review. AB - BACKGROUND: National statistics related specifically to the mental health of women in the perinatal period is poorly acknowledged in Australia. Maternal deaths related to mental health in the perinatal period can be attributed to a lack of appropriate treatment and/or support. A barrier to women's help-seeking behaviors is the lack of discrete, perinatal specific interventions where women can self-assess and access support. AIM: This review examines original research evaluating perinatal mental health interventions used by women to improve mental health. METHOD: An integrative literature review was undertaken. A comprehensive search strategy using 5 electronic databases resulted in the retrieval of 1898 articles. Use of an inclusion and exclusion criteria and Critical Appraisal Skills Program tools resulted in 4 original research papers. Thematic analysis identified universal themes. FINDINGS: Cognitive Behavioral Therapy, Behavioral Activation and Mindfulness-based interventions, specifically adapted to meet the needs of women in the perinatal period, demonstrate an overall improvement in mental health. Women involved in the interventions experienced both improvements in symptoms of anxiety and depression as well as secondary benefits from participating in the research. CONCLUSION: To improve perinatal mental health outcomes, innovative modes of providing effective perinatal mental health interventions that address the unique needs of women in the perinatal period are needed. Future development of perinatal mental health interventions require adaptions of Cognitive Behavioral Therapy, Behavioral Activation and/or Mindfulness-based methods to address mental health outcomes for women in the perinatal period. PMID- 27118001 TI - Stressful events, social health issues and psychological distress in Aboriginal women having a baby in South Australia: implications for antenatal care. AB - BACKGROUND: Around 6% of births in Australia are to Aboriginal and Torres Strait Islander families. Aboriginal and Torres Strait Islander women are 2-3 times more likely to experience adverse maternal and perinatal outcomes than non-Aboriginal women in Australia. METHODS: Population-based study of mothers of Aboriginal babies born in South Australia, July 2011 to June 2013. Mothers completed a structured questionnaire at a mean of 7 months postpartum. The questionnaire included measures of stressful events and social health issues during pregnancy and maternal psychological distress assessed using the Kessler-5 scale. RESULTS: Three hundred forty-four women took part in the study, with a mean age of 25 years (range 15-43). Over half (56.1%) experienced three or more social health issues during pregnancy; one in four (27%) experienced 5-12 issues. The six most commonly reported issues were: being upset by family arguments (55%), housing problems (43%), family member/friend passing away (41%), being scared by others people's behavior (31%), being pestered for money (31%) and having to leave home because of family arguments (27%). More than a third of women reporting three or more social health issues in pregnancy experienced high/very high postpartum psychological distress (35.6% versus 11.1% of women reporting no issues in pregnancy, Adjusted Odds Ratio = 5.4, 95% confidence interval 1.9-14.9). CONCLUSIONS: The findings highlight unacceptably high rates of social health issues affecting Aboriginal women and families during pregnancy and high levels of associated postpartum psychological distress. In order to improve Aboriginal maternal and child health outcomes, there is an urgent need to combine high quality clinical care with a public health approach that gives priority to addressing modifiable social risk factors for poor health outcomes. PMID- 27118002 TI - Low Risk of Skin and Nipple Sensitivity and Lactation Issues After Primary Breast Augmentation with Form-Stable Silicone Implants: Follow-Up in 4927 Subjects. AB - BACKGROUND: Natrelle 410 implants (Allergan, Inc., Irvine, CA) are approved in the United States for breast augmentation, reconstruction, and revision. OBJECTIVES: To assess the risk of nipple and skin sensation changes and lactation issues in subjects receiving implants for primary breast augmentation and ascertain whether differences based on incision site exist. METHODS: We used 410 Continued Access study data to assess safety and effectiveness of devices implanted via inframammary or periareolar incision sites. Subjects were evaluated preoperatively and at 4 weeks, 6 months, and annually up to 10 years postoperatively. Lactation issues and nipple and skin sensation changes (hypersensitivity/paresthesia, loss of sensation) were assessed. RESULTS: The inframammary and periareolar cohorts comprised 9217 and 610 implanted devices, with mean follow-up of 4.1 years (range, 0-10.1 years) and 4.8 years (range, 0 10.1 years), respectively. In the inframammary cohort, risk of first occurrence of nipple sensation changes was 0.3% (95% CI: 0.2-0.5) at week 4 and month 6, and 0.4% (0.3-0.7) at year 10. Risk of skin sensation changes was 0.0% (95% CI: 0.0 0.2) at week 4, 0.1% (0.0-0.2) at month 6, and 0.1% (0.0-0.3) at all subsequent time points. No nipple or skin changes occurred in the periareolar cohort. Incidence of lactation issues was similar to that reported in postpartum women who did not have breast implants. CONCLUSIONS: We found that the risk of nipple or skin sensation changes and lactation issues is low and provide long-term safety and effectiveness data on subjects receiving implants for primary breast augmentation. LEVEL OF EVIDENCE 3: Therapeutic. PMID- 27118003 TI - Response to "Comments on 'Maximizing the Volume of Latissimus Dorsi Flap in Autologous Breast Reconstruction with Simultaneous Multisite Fat Grafting'". PMID- 27118004 TI - Comments on "Maximizing the Volume of Latissimus Dorsi Flap in Autologous Breast Reconstruction with Simultaneous Multisite Fat Grafting". PMID- 27118005 TI - Commentary on: Micro-Shuttle Lifting of the Neck: A Percutaneous Loop Suspension Method Using a Novel Double-Ended Needle. PMID- 27118006 TI - Changing society's whole approach to psychosis. PMID- 27118007 TI - [Medical care for migrants]. PMID- 27118008 TI - [Therapeutic algorithm for lipoprotein apheresis and PCSK9 inhibition for severe hypercholesterolemia or isolated lipoprotein(a) hyperlipoproteinemia]. PMID- 27118009 TI - Detection of Cardiac Abnormalities from Multilead ECG using Multiscale Phase Alternation Features. AB - The cardiac activities such as the depolarization and the relaxation of atria and ventricles are observed in electrocardiogram (ECG). The changes in the morphological features of ECG are the symptoms of particular heart pathology. It is a cumbersome task for medical experts to visually identify any subtle changes in the morphological features during 24 hours of ECG recording. Therefore, the automated analysis of ECG signal is a need for accurate detection of cardiac abnormalities. In this paper, a novel method for automated detection of cardiac abnormalities from multilead ECG is proposed. The method uses multiscale phase alternation (PA) features of multilead ECG and two classifiers, k-nearest neighbor (KNN) and fuzzy KNN for classification of bundle branch block (BBB), myocardial infarction (MI), heart muscle defect (HMD) and healthy control (HC). The dual tree complex wavelet transform (DTCWT) is used to decompose the ECG signal of each lead into complex wavelet coefficients at different scales. The phase of the complex wavelet coefficients is computed and the PA values at each wavelet scale are used as features for detection and classification of cardiac abnormalities. A publicly available multilead ECG database (PTB database) is used for testing of the proposed method. The experimental results show that, the proposed multiscale PA features and the fuzzy KNN classifier have better performance for detection of cardiac abnormalities with sensitivity values of 78.12 %, 80.90 % and 94.31 % for BBB, HMD and MI classes. The sensitivity value of proposed method for MI class is compared with the state-of-art techniques from multilead ECG. PMID- 27118010 TI - Designing a Model of a Digital Ecosystem for Healthcare and Wellness Using the Business Model Canvas. AB - Wellness is a term often used to talk about optimal health as "dynamic balance of physical, emotional, social, spiritual, and intellectual health." While healthcare is a term about care offered to patients for improving their health. We use both terms, as well as the Business Model Canvas (BMC) methodology, to design a digital ecosystem model for healthcare and wellness called DE4HW; the model considers economic, technological, and legal asymmetries, which are present on e-services beyond geographical regions. BMC methodology was embedded into the global project strategy called: IBOT (Initiate, Build, Operate and Transfer); it is a methodology to establish a functional, integrated national telemedicine network and virtual education network; of which we took its phases rationale. The results in this work illustrate the design of DE4HW model, into the first phase of IBOT, enriched with the BMC, which enables us to define actors, their interactions, rules and protocols, in order to build DE4HW, while IBOT strategy manages the project goal, up to the transfer phase, where an integral service platform of healthcare and wellness is turned over to stakeholders. PMID- 27118011 TI - Telemedicine Use in Rural Native American Communities in the Era of the ACA: a Systematic Literature Review. AB - Native American communities face serious health disparities and, living in rural areas, often lack regular access to healthcare services as compared to other Americans. Since the early 1970's, telecommunication technology has been explored as a means to address the cost and quality of, as well as access to, healthcare on rural reservations. This systematic review seeks to explore the use of telemedicine in rural Native American communities using the framework of cost, quality, and access as promulgated by the Affordable Care Act of 2010 and urge additional legislation to increase its use in this vulnerable population. As a systematic literature review, this study analyzes 15 peer-reviewed articles from four databases using the themes of cost, quality, and access. The theme of access was referenced most frequently in the reviewed literature, indicating that access to healthcare may be the biggest obstacle facing widespread adoption of telemedicine programs on rural Native American reservations. The use of telemedicine mitigates the costs of healthcare, which impede access to high quality care delivery and, in some cases, deters prospective patients from accessing healthcare at all. Telemedicine offers rural Native American communities a means of accessing healthcare without incurring high costs. With attention to reimbursement policies, educational services, technological infrastructure, and culturally competent care, telemedicine has the potential to decrease costs, increase quality, and increase access to healthcare for rural Native American patients. While challenges facing the implementation of telemedicine programs exist, there is great potential for it to improve healthcare delivery in rural Native American communities. Public policy that increases funding for programs that help to expand access to healthcare for Native Americans will improve outcomes because of the increase in access. PMID- 27118012 TI - Microbial community characterization and functional gene quantification in RDX degrading microcosms derived from sediment and groundwater at two naval sites. AB - The explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) has long been recognized as a problematic environmental pollutant, and efforts to remediate contaminated soils, sediments, and groundwater have been going on for decades. In recent years, much interest has focused on using bioremediation to clean up these sites. The current study investigated the microorganisms (16S rRNA genes, Illumina) and functional genes (xenA, xenB, and xplA) linked to RDX biodegradation in microcosms composed of sediment or groundwater from two Navy sites. For this, experiments included sediment samples from three depths (5 to 30 ft) from two wells located in one Navy site. In addition, the groundwater upstream and downstream of an emulsified oil biobarrier was examined from another Navy site. Further, for the groundwater experiments, the effect of glucose addition was explored. For the sediment experiments, the most enriched phylotypes during RDX degradation varied over time, by depth and well locations. However, several trends were noted, including the enrichment of Pseudomonas, Rhodococcus, Arthrobacter, and Sporolactobacillus in the sediment microcosms. For the groundwater-based experiments, Pseudomonas, unclassified Rhodocyclaceae, Sphingomonas, and Rhodococcus were also highly abundant during RDX degradation. The abundance of both xplA and xenA significantly increased during RDX degradation compared to the control microcosms for many treatments (both groundwater and sediment microcosms). In a limited number of microcosms, the copy number of the xenB gene increased. Phylotype data were correlated with functional gene data to highlight potentially important biomarkers for RDX biodegradation at these two Navy sites. PMID- 27118013 TI - Production of hydrophobic amino acids from biobased resources: wheat gluten and rubber seed proteins. AB - Protein hydrolysis enables production of peptides and free amino acids that are suitable for usage in food and feed or can be used as precursors for bulk chemicals. Several essential amino acids for food and feed have hydrophobic side chains; this property may also be exploited for subsequent separation. Here, we present methods for selective production of hydrophobic amino acids from proteins. Selectivity can be achieved by selection of starting material, selection of hydrolysis conditions, and separation of achieved hydrolysate. Several protease combinations were applied for hydrolysis of rubber seed protein concentrate, wheat gluten, and bovine serum albumin (BSA). High degree of hydrolysis (>50 %) could be achieved. Hydrophobic selectivity was influenced by the combination of proteases and by the extent of hydrolysis. Combination of Pronase and Peptidase R showed the highest selectivity towards hydrophobic amino acids, roughly doubling the content of hydrophobic amino acids in the products compared to the original substrates. Hydrophobic selectivity of 0.6 mol hydrophobic/mol-total free amino acids was observed after 6 h hydrolysis of wheat gluten and 24 h hydrolysis of rubber seed proteins and BSA. The results of experiments with rubber seed proteins and wheat gluten suggest that this process can be applied to agro-industrial residues. PMID- 27118014 TI - Manufacturing demonstration of microbially mediated zinc sulfide nanoparticles in pilot-plant scale reactors. AB - The thermophilic anaerobic metal-reducing bacterium Thermoanaerobacter sp. X513 efficiently produces zinc sulfide (ZnS) nanoparticles (NPs) in laboratory-scale (<= 24-L) reactors. To determine whether this process can be up-scaled and adapted for pilot-plant production while maintaining NP yield and quality, a series of pilot-plant scale experiments were performed using 100-L and 900-L reactors. Pasteurization and N2-sparging replaced autoclaving and boiling for deoxygenating media in the transition from small-scale to pilot plant reactors. Consecutive 100-L batches using new or recycled media produced ZnS NPs with highly reproducible ~2-nm average crystallite size (ACS) and yields of ~0.5 g L( 1), similar to the small-scale batches. The 900-L pilot plant reactor produced ~320 g ZnS without process optimization or replacement of used medium; this quantity would be sufficient to form a ZnS thin film with ~120 nm thickness over 0.5 m width * 13 km length. At all scales, the bacteria produced significant amounts of acetic, lactic, and formic acids, which could be neutralized by the controlled addition of sodium hydroxide without the use of an organic pH buffer, eliminating 98 % of the buffer chemical costs. The final NP products were characterized using XRD, ICP-OES, TEM, FTIR, PL, DLS, HPLC, and C/N analyses, which confirmed that the growth medium without organic buffer enhanced the ZnS NP properties by reducing carbon and nitrogen surface coatings and supporting better dispersivity with similar ACS. PMID- 27118015 TI - A case of arthritis under pembrolizumab. PMID- 27118016 TI - Risk of postoperative infections and the discontinuation of TNF inhibitors in patients with rheumatoid arthritis: A meta-analysis. AB - OBJECTIVE: To determine whether continuation of tumor necrosis factor inhibitors (TNFi) before surgery increases the risk of surgical site infection (SSI) in rheumatoid arthritis (RA) patients. METHODS: A systematic review of the literature was conducted from January 2000 to May first 2014, using the databases of PubMed, Cochrane review, Embase, and manual research of abstracts presented in scientific congresses. Most included studies were retrospective. We compared the risk of SSI in the case of discontinuation of TNFi versus continuing TNFi treatment before a surgery. RESULTS: Six studies, with a total of 2743 patients (1360 in the group continuing TNFi agent and 1383 in the group discontinuing TNFi) were included. There was a decreased risk of SSI in patients stopping TNFi (relative risk [RR]=0.62 [95% confidence interval [CI] 0.43-0.89], P=0.99, I2=0%). Concerning overall complications, there was also a decreased risk in patients discontinuing TNFi treatment (RR=0.60 [95% CI 0.42-0.87], P=0.26, I2=25%). CONCLUSION: This meta-analysis showed an increased risk of SSI in patients under TNF inhibitor, and a decreased risk of SSI in case of interruption of treatment during the perioperative time. PMID- 27118017 TI - Stress fractures healing with bisphosphonates in Paget's disease. PMID- 27118018 TI - Glycated albumin increases with disease activity in rheumatoid factor positive rheumatoid arthritis patients with normal fasting glucose and HbA1c. PMID- 27118019 TI - Diminished bone resorption in overweight/obese women despite vitamin D insufficiency. PMID- 27118020 TI - Images of thoracic spinal cord compression due to intraspinal gouty tophus in two patients. PMID- 27118021 TI - Early clinical response predicts low disease activity at one year in rheumatoid arthritis patients on treatment with certolizumab in real-life settings. An appraisal of the Italian registry GISEA. AB - OBJECTIVES: The aim of this study was to assess whether good EULAR response assessed at 3months may predict the achievement of low disease activity (LDA) at 1year in rheumatoid arthritis (RA) patients on treatment with certolizumab pegol (CZP). METHODS: From the nationwide Italian registry, we analysed 278 RA patients (age 54.8+/-12years, duration of disease 9.8+/-8years, female 84%) initiating CZP as first line (68%) or>=second line (32%) of biological treatment because of their active disease. Assessment of disease activity was based on 28 joint Disease Activity Score (DAS28). A reduction of DAS28>1.2 (good EULAR response) was assessed at 3months, and the achievement of LDA (DAS28<=3.2) was evaluated at 1year. Multiple regression models were used to estimate predictors of early good EULAR response or LDA. RESULTS: The percentages of patients attaining good EULAR response were 52% at 3, 65% at 6, and 66% at 12months. Furthermore, 51.2% (98/192) of the patients reached LDA at 12months. Patients taking CZP as first biological treatment had adjusted odds ratios (OR) of good EULAR response at 3months 6 folds higher than in those with>=1 prior biological drug (OR 6.7, 95% CI 1.97-23.1). While, the strongest variable correlating with 12months LDA was the achievement of good EULAR response at 3months (OR 11.3, 95% CI 13.1-34.8). CONCLUSIONS: Our findings showed that attaining good EULAR response at 3months strongly predicted 1year LDA in RA patients treated with CZP in real-life settings. PMID- 27118022 TI - Antineutrophilic cytoplasmic antibody-associated vasculitis and malignant hemopathies, a retrospective study of 16 cases. AB - OBJECTIVES: ANCA-associated vasculitis are severe autoimmune pathologies that are characterized by inflammation and necrosis of the small vessels. The physiopathological mechanisms are complex and have yet to be totally elucidated. Several environmental factors have been described as being associated: medications, infectious agents... and rarely, neoplasms. METHODS: We performed a retrospective multicenter study over a period of 12 years with a view to describing the association of ANCA-associated vasculitis and malignant hemopathies, excluding hemopathies secondary to vasculitis treatment. RESULTS: Sixteen patients with ANCA-associated vasculitis with an hemopathy were identified. The gender ratio was 7 and the mean age was 65 years. The frequency of this association is estimated at 1%. The ANCA-associated vasculitis were micropolyangiitis (n=7), followed by granulomatous polyangiitis (n=4), vasculitis limited to the kidney (n=3), and eosinophilic granulomatous polyangiitis (n=2). The associated malignant hemopathies were mainly non-Hodgkin's lymphoma in seven cases and myelodysplasia in five cases. The other hemopathies were: Hodgkin's disease, hypereosinophilic syndrome, and Waldenstrom's macroglobulinemia. Hemopathy treatment was associated with vasculitis treatment in seven cases. CONCLUSION: The association of ANCA-associated vasculitis and malignant hemopathy is rare but must nevertheless be recognized because: (i) the clinical signs of both pathologies are not specific, (ii) the survival scores that are used for ANCA-associated vasculitis do not appear to be applicable, (iii) both pathologies must be taken into account in order to implement an effective therapeutic strategy that limits the inherent risks. PMID- 27118023 TI - Very early renal relapse of microscopic polyangiitis after kidney transplantation. PMID- 27118024 TI - Comparison of modified disease-activity scores with original composite scores for prediction of structural damages in rheumatoid arthritis: Data from the ESPOIR cohort. PMID- 27118025 TI - Only complementary voices tell the truth: a reevaluation of validity in multi informant approaches of child and adolescent clinical assessments. AB - Multi-informant approaches are thought to be key to clinical assessment. Classical theories of psychological measurements assume that only convergence among different informants' reports allows for an estimate of the true nature and causes of clinical presentations. However, the integration of multiple accounts is fraught with problems because findings in child and adolescent psychiatry do not conform to the fundamental expectation of convergence. Indeed, reports provided by different sources (self, parents, teachers, peers) share little variance. Moreover, in some cases informant divergence may be meaningful and not error variance. In this review, we give an overview of conceptual and theoretical foundations of valid multi-informant assessment and discuss why our common concepts of validity need revaluation. PMID- 27118026 TI - How half sandwich ruthenium compounds interact with DNA while not being hydrolyzed; a comparative study. PMID- 27118027 TI - Pervanadate induces Mammalian Ste20 Kinase 3 (MST3) tyrosine phosphorylation but not activation. AB - The yeast Ste20 (sterile) protein kinase, which is a serine/threonine kinase, responds to the stimulation of the G proteincoupled receptor (GPCR) pheromone receptor. Ste20 protein kinase serves as the critical component that links signaling from the GPCR/G proteins to the mitogen-activated protein kinase (MAPK) cascade in yeast. The yeast Ste20p functions as a MAP kinase kinase kinase kinase (MAP4K) in the pheromone response. Ste20-like kinases are structurally conserved from yeast to mammals. The mechanism by which MAP4K links GPCR to the MAPK pathway is less clearly defined in vertebrates. In addition to MAP4K, the tyrosine kinase cascade bridges G proteins and the MAPK pathway in vertebrate cells. Mammalian Ste20 Kinase 3 (MST3) has been categorized into the Ste20 family and has been reported to function in the regulation of cell polarity and migration. However, whether MST3 tyrosine phosphorylation regulates diverse signaling pathways is unknown. In this study, the tyrosine phosphatase inhibitor pervanadate was found to induce MST3 tyrosine phosphorylation in intact cells, and the activity of tyrosine-phosphorylated MST3 was measured. This tyrosine directed phosphorylation was independent of MST3 activity. Parameters including protein conformation, Triton concentration and ionic concentration influenced the sensitivity of MST3 activity. Taken together, our data suggests that the serine/threonine kinase MST3 undergoes tyrosinedirected phosphorylation. The tyrosine-phosphorylated MST3 may create a docking site for the structurally conserved SH2/SH3 (Src Homology 2 and 3) domains within the Src oncoprotein. The unusual tyrosinephosphorylated MST3 may recruit MST3 to various signaling components. PMID- 27118028 TI - Synthesis of novel Iron(III) chelators based on triaza macrocycle backbone and 1 hydroxy-2(H)-pyridin-2-one coordinating groups and their evaluation as antimicrobial agents. AB - Several novel chelators based on 1-hydroxy-2(1H)-pyridinone coordinating groups decorating a triaza macrocyclic backbone scaffold were synthesised as potential powerful Fe(3+) chelators capable of competing with bacterial siderophores. In particular, a novel chloromethyl derivative of 1-hydroxy-2(1H)-pyridinone exploiting a novel protective group for this family of coordinating groups was developed. These are the first examples of hexadentate chelators based on 1 hydroxy-2(1H)-pyridinone to be shown to have a biostatic activity against a range of pathogenic bacteria. Their efficacy as biostatic agents was assessed revealing that minor variations in the structure of the chelator can affect efficacy profoundly. The minimal inhibitory concentrations of our best tested novel chelators approach or are comparable to those for 1,4,7-tris(3-hydroxy-6-methyl-2 pyridylmethyl)-1,4,7-triazacyclononane, the best Fe(3+) chelator known to date. The retarding effect these chelators have on microbial growth suggests that they could have a potential application as a co-active alongside antibiotics in the fight against infections. PMID- 27118029 TI - Cell cycle, apoptosis, cellular uptake and whole-transcriptome microarray gene expression analysis of HeLa cells treated with a ruthenium(II)-arene complex with an isoquinoline-3-carboxylic acid ligand. AB - Ruthenium(II)-arene complexes are promising drug candidates for the therapy of solid tumors. In previous work, seven new compounds of the general formula [Ru(eta6-p-cymene)(L1-7)Cl] were synthesized and characterized, of which the complex with L=isoquinoline-3-carboxylic acid (RuT7) was two times as active on HeLa cells compared to normal cell line MRC-5, as indicated by IC50 values determined after 48h of incubation (45.4+/-3.0 vs. 84.2+/-5.7MUM, respectively). In the present study, cell cycle analysis of HeLa cells treated with RuT7 showed S phase arrest and an increase in sub-G1 population. The apoptotic potential of the title compound was confirmed with the Annexin V-FITC/PI assay together with a morphological evaluation of cells using fluorescent microscopy. Analysis of the intracellular accumulation of ruthenium showed 8.9ng Ru/106 cells after 6h of incubation. To gain further insight in the molecular mechanism of action of RuT7 on HeLa cells, a whole-transcriptome microarray gene expression analysis was performed. Analysis of functional categories and signaling and biochemical pathways associated with the response of HeLa cells to treatment with RuT7 showed that it leads the cells through the intrinsic (mitochondrial) apoptotic pathway, via indirect DNA damage due to the action of reactive oxygen species, and through direct DNA binding of RuT7. Statistical analysis for enrichment of gene sets associated with known drug-induced toxicities identified fewer associated toxicity profiles in RuT7-treated cells compared to cisplatin treatment. Altogether these results provide the basis for further development of RuT7 in animal and pre-clinical studies as a potential drug candidate. PMID- 27118030 TI - Influence of chelation strength and bacterial uptake of gallium salicylidene acylhydrazide on biofilm formation and virulence of Pseudomonas aeruginosa. AB - Development of antibiotic resistance in bacteria causes major challenges for our society and has prompted a great need for new and alternative treatment methods for infection. One promising approach is to target bacterial virulence using for example salicylidene acylhydrazides (hydrazones). Hydrazones coordinate metal ions such as Fe(III) and Ga(III) through a five-membered and a six-membered chelation ring. One suggested mode of action is via restricting bacterial Fe uptake. Thus, it was hypothesized that the chelating strength of these substances could be used to predict their biological activity on bacterial cells. This was investigated by comparing Ga chelation strength of two hydrazone complexes, as well as bacterial Ga uptake, biofilm formation, and virulence in the form of production and secretion of a toxin (ExoS) by Pseudomonas aeruginosa. Equilibrium constants for deprotonation and Ga(III) binding of the hydrazone N'-(5-chloro-2 hydroxy-3-methylbenzylidene)-2,4-dihydroxybenzhydrazide (ME0329), with anti virulence effect against P. aeruginosa, were determined and compared to bacterial siderophores and the previously described Ga(III) 2-oxo-2-[N-(2,4,6-trihydroxy benzylidene)-hydrazino]-acetamide (Ga-ME0163) and Ga-citrate complexes. In comparison with these two complexes, it was shown that the uptake of Ga(III) was higher from the Ga-ME0329 complex. The results further show that the Ga-ME0329 complex reduced ExoS expression and secretion to a higher extent than Ga-citrate, Ga-ME0163 or the non-coordinated hydrazone. However, the effect against biofilm formation by P. aeruginosa, by the ME0329 complex, was similar to Ga-citrate and lower than what has been reported for Ga-ME0163. PMID- 27118032 TI - Sn-doped Bi1.1Sb0.9Te2S bulk crystal topological insulator with excellent properties. AB - A long-standing issue in topological insulator research has been to find a bulk single crystal material that provides a high-quality platform for characterizing topological surface states without interference from bulk electronic states. This material would ideally be a bulk insulator, have a surface state Dirac point energy well isolated from the bulk valence and conduction bands, display quantum oscillations from the surface state electrons and be growable as large, high quality bulk single crystals. Here we show that this material obstacle is overcome by bulk crystals of lightly Sn-doped Bi1.1Sb0.9Te2S grown by the vertical Bridgman method. We characterize Sn-BSTS via angle-resolved photoemission spectroscopy, scanning tunnelling microscopy, transport studies, X ray diffraction and Raman scattering. We present this material as a high-quality topological insulator that can be reliably grown as bulk single crystals and thus studied by many researchers interested in topological surface states. PMID- 27118031 TI - The challenging interplay between rheumatoid arthritis, ageing and comorbidities. AB - BACKGROUND: The incidence of rheumatoid arthritis (RA) is expected to increase over the next 10 years in the European Union because of the increasing proportion of elderly people. As both RA and ageing are associated with emerging comorbidities such as cardiovascular disease, malignancies and osteoporosis, these factors will have a profound effect on the management of RA. In addition, both increasing age and comorbidities may independently alter commonly used RA specific outcome measures. DISCUSSION: Age-related decline in immune cell functions (immunosenescence), such as a decrease in T-cell function, may contribute to the development of RA, as well as comorbidity. The chronic immune stimulation that occurs in RA may also lead to premature ageing and comorbidity. The interplay between RA, ageing and (emerging) comorbidities is interesting but complex. Cardiovascular disease, lung disease, malignancies, bone and muscle wasting and neuropsychiatric disease all occur more frequently in RA patients as compared to the general population. It is unclear how RA should be managed in 'today's world of multiple comorbidities'. Evidence that treatment of RA improves comorbidities is currently lacking, although some promising indirect observations are available. On the other hand, there is limited evidence that medication regularly prescribed for comorbidities, such as statins, might improve RA disease activity. Both ageing and comorbidity have an independent effect on commonly used outcome measures in the RA field, such as the Health Assessment Questionnaire (HAQ) and the clinical disease activity index (CDAI). Prospective studies, that also account for the presence of comorbidity in (elderly) RA patients are therefore urgently needed. To address gaps in knowledge, future research should focus on the complex interdependencies between RA, ageing and comorbidity. In addition, these findings should be integrated into daily clinical practice by developing and testing integrated and coordinated health care services. Adaptation of management recommendations is likely required. The elderly RA patient who also deals with (emerging) comorbidities presents a unique challenge to treating clinicians. A paradigm shift from disease-centered to goal-oriented approach is needed to develop adequate health care services for these patients. PMID- 27118033 TI - [Urological complications after kidney transplantation from extended criteria donors: Ureteroneocystostomy versus pyelo-ureterostomy]. AB - INTRODUCTION: The use of transplants from extended criteria donors increases the number of urological complications after renal transplantation. Two different anastomosis techniques used to restore urinary continuity are compared in this study. PATIENTS AND METHODS: Retrospective study, bi-center over a period of 5 years. One hundred and seventy six patients operated at Hospices Civils de Lyon benefited from ureteroneocystostomy according to De Campos-Freire (group 1) and 167 patients operated at the Necker Hospital in Paris had a pyelo-ureterostomy (group 2). The various urological complications (fistulas, strictures, seromas, haematomas and vesico-ureteric reflux) and their care were compared. Risk factors were sought. RESULTS: The waiting time before transplantation was longer in group 2 than in group 1 (51 and 33.84 months) as the percentage of anuric patients (52.9 % against 32.9 %) (P<0.001). The cold ischemic time was shorter in group 1 (939.3minutes on average against 1325.3minutes for group 2) (P<0.001). A double J stent was put in place in 97.6 % of cases in group 2 against 84.2 % for group 1 (P<0.001). We did not find any significant difference in the occurrence of stenosis and fistulas (major complications) between the 2 groups. There were more minor complications (hematoma, seroma and vesico-ureteric reflux) in group 1 (P=0.033). There was a difference in the treatment of these complications, especially stenosis (P=0.024) with a significantly more conservative approach in group 2. Multivariate analysis found anuria, sex of recipients and donor age as independent risk factors in the onset of complications and the double J stent as a protective factor. CONCLUSION: This study does not demonstrate the superiority of a urinary anastomosis technique. The establishment of a double J stent reduces the risk of complications. Analysis of risk factors allows to propose a decision tree to guide the surgical strategy, particularly in the population of anuric recipients. LEVEL OF EVIDENCE: 5. PMID- 27118034 TI - Detrusor contractility in women: Influence of ageing and clinical conditions. AB - AIMS: We assume that the voiding process in women is governed by the detrusor contractility and a "urethral resistance". The value of these 2 parameters, respectively named k and U in the VBN (Valentini-Besson-Nelson) mathematical model of micturition is deduced from the VBN analysis of pressure-flow recordings (PFs). Our objectives were to search for a correlation between these 2 parameters and clinically relevant variables such as chief complaint, urodynamic diagnosis (UD), and age by decades. METHODS: PFs from 125 non-neurogenic women (mean age 58.0+/-17.2years [range 20-90years]) were retrospectively analyzed using the VBN model. VBN criteria for inclusion were maximum flow rate>2mL/s, voided volume>100mL, and non-interrupted flow. Evaluated parameters were k (without unit) and U (unit: cm H2O). Standard values were k=1.0 and U=0. RESULTS: VBN parameter ranges were k [0.14-1.55] and U [0.0-73.0cm H2O]. There was a significant correlation between k and U for the whole population (P<0.0001) with k=(.259+0.015*U) (R(2)=0.723) and each chief complaint. For UD, significant difference comparing k and U in phasic detrusor overactivity with intrinsic sphincter deficiency and urodynamic stress incontinence was noted. In sub-groups defined according to decades of age, the values of k and U remained similar in sub-groups for those who are less than 50years old and decreased regularly with ageing. CONCLUSION: The detrusor contractility can be easily evaluated in women; lower than in men, its range is less spread out but also adjusted to compensate a "urethral resistance". Phasic detrusor overactivity and post-menopausal age significantly affect detrusor force value. LEVEL OF EVIDENCE: 3. PMID- 27118035 TI - Arsenic in private well water part 3 of 3: Socioeconomic vulnerability to exposure in Maine and New Jersey. AB - Arsenic is a naturally occurring toxic element often concentrated in groundwater at levels unsafe for human consumption. Private well water in the United States is mostly unregulated by federal and state drinking water standards. It is the responsibility of the over 13 million U.S. households regularly depending on private wells for their water to ensure it is safe for drinking. There is a consistent graded association with health outcomes at all levels of socioeconomic status (SES) in the U.S. Differential exposure to environmental risk may be contributing to this persistent SES-health gradient. Environmental justice advocates cite overwhelming evidence that income and other SES measures are consistently inversely correlated with exposure to suboptimal environmental conditions including pollutants, toxins, and their impacts. Here we use private well household surveys from two states to investigate the association between SES and risks for arsenic exposure, examining the potentially cumulative effects of residential location, testing and treatment behavior, and psychological factors influencing behavior. We find that the distribution of natural arsenic hazard in the environment is socioeconomically random. There is no evidence that higher SES households are avoiding areas with arsenic or that lower SES groups are disproportionately residing in areas with arsenic. Instead, disparities in exposure arise from differing rates of protective action, primarily testing well water for arsenic, and secondly treating or avoiding contaminated water. We observe these SES disparities in behavior as well as in the psychological factors that are most favorable to these behaviors. Assessment of risk should not be limited to the spatial occurrence of arsenic alone. It is important that social vulnerability factors are incorporated into risk modeling and identifying priority areas for intervention, which should include strategies that specifically target socioeconomically vulnerable groups as well as all the conditions which cause these disparities in testing and treatment behavior. PMID- 27118036 TI - 'Journal Bias' in peer-reviewed literature: an analysis of the surgical high grade glioma literature. AB - The core premise of evidence-based medicine is that clinical decisions are informed by the peer-reviewed literature. To extract meaningful conclusions from this literature, one must first understand the various forms of biases inherent within the process of peer review. We performed an exhaustive search that identified articles exploring the question of whether survival benefit was associated with maximal high-grade glioma (HGG) resection and analysed this literature for patterns of publication. We found that the distribution of these 108 articles among the 26 journals to be non-random (p<0.01), with 75 of the 108 published articles (69%) appearing in 6 of the 26 journals (25%). Moreover, certain journals were likely to publish a large number of articles from the same medical academic genealogy (authors with shared training history and/or mentor). We term the tendency of certain types of articles to be published in select journals 'journal bias' and discuss the implication of this form of bias as it pertains to evidence-based medicine. PMID- 27118037 TI - Ocular blood flow values measured by laser speckle flowgraphy correlate with the postmenstrual age of normal neonates. AB - PURPOSE: To evaluate the relationships between optic nerve head (ONH) blood flow by laser speckle flowgraphy (LSFG), and postmenstrual age and body weight in normal neonates. METHODS: During their normal sleep, we studied 24 infants (postmenstrual age, 248-295 days) whose ocular blood flow could be measured three consecutive times. While the subjects slept in the supine position, three mean blur rate (MBR) values of the ONH were obtained: the MBR-A (mean of all values), MBR-V (vessel mean) and MBR-T (tissue mean) in the ONH. With regard to eye diseases, no retinopathy of prematurity (ROP) was observed, and no severe systemic diseases requiring treatment were noted in the subjects. Pearson's correlation coefficients were used to determine the relationship between the MBR A, -V, -T and postmenstrual age (days) and body weight (g). RESULTS: Postmenstrual age was significantly correlated with MBR-A (r = 0.64, p = 0.0007), MBR-V (r = 0.62, p = 0.0012) and MBR-T (r = 0.62, p = 0.0012). However, the body weight was not correlated with the MBR (MBR-A: r = 0.37, p = 0.07, MBR-V: r = 0.31, p = 0.14, MBR-T: r = 0.38, p = 0.06). CONCLUSIONS: Our results clarified that the values of ocular blood flow measured by LSFG correlate with the postmenstrual age of normal neonates. PMID- 27118038 TI - Analyzing biomechanical parameters of the cornea with glaucoma severity in open angle glaucoma. AB - PURPOSE: The purpose was to investigate a possible association of corneal hysteresis (CH) and corneal resistance factor (CRF) with open-angle glaucoma and the severity of disease. METHODS: In this prospective cross-sectional study we recruited 86 open-angle glaucoma patients, 16 patients with ocular hypertension (OHT,) and 44 age-matched controls. Each participant had a complete glaucoma workup including measurements with the Ocular Response Analyzer and computerized perimetry with the Humphrey 30-2 SITA Standard program. Visual field damage was based on mean deviation (MD) and considered as early glaucomatous with a MD > - 6 dB, moderate glaucomatous between -6 and -12 dB and advanced glaucomatous < -12 dB. The association between ORA parameters, glaucoma, and disease severity was evaluated using univariate and multivariate linear regression analyses. RESULTS: There was a statistically significant correlation between the biomechanical parameters and intraocular pressure, central corneal thickness, axial length, and age. On average, glaucoma patients had the lowest adjusted CH (8.96 +/- 1.43 mmHg) and CRF (9.07 +/- 1.93 mmHg) values in comparison to OHT patients (CH: 10.2 +/- 1.5 mmHg; CRF: 10.6 +/- 2.1 mmHg) and controls (CH: 9.7 +/- 1.4 mmHg; CRF: 10.2 +/- 1.9 mmHg). This difference was statistically significant (CH: p = 0.003; CRF: p = 0.008). There was also a statistically significant difference in adjusted CH (p = 0.001) and CRF (p = 0.004) values between the controls and the visual field groups, with the lowest values being in the most advanced group. CONCLUSIONS: Before interpreting corneal biomechanical parameters, it seems important to adjust the measured data for their underlying influencing factors. Glaucoma patients with lower adjusted CH and CRF probably have more advanced disease and should, therefore, be treated more aggressively and monitored more carefully and frequently. PMID- 27118039 TI - [Exercise-induced shear stress: Physiological basis and clinical impact]. AB - The physiological regulation of vascular function is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the major risk factors for cardiovascular disease, where an imbalance between synthesis of vasodilator and vasoconstrictor molecules is one of its main mechanisms. In this context, the shear stress is one of the most important mechanical stimuli to improve vascular function, due to endothelial mechanotransduction, triggered by stimulation of various endothelial mechanosensors, induce signaling pathways culminating in increased bioavailability of vasodilators molecules such as nitric oxide, that finally trigger the angiogenic mechanisms. These mechanisms allow providing the physiological basis for the effects of exercise on vascular health. In this review it is discussed the molecular mechanisms involved in the vascular response induced by shear stress and its impact in reversing vascular injury associated with the most prevalent cardiovascular disease in our population. PMID- 27118040 TI - Identifying factors associated with concordance with the American College of Rheumatology rheumatoid arthritis treatment recommendations. AB - BACKGROUND: Factors associated with care concordant with the American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) are unknown. METHODS: We identified a national cohort of biologic-naive patients with RA with visits between December 2008 and February 2013. Treatment acceleration (initiation or dose escalation of biologic and nonbiologic DMARDs) in response to moderate to high disease activity (using the Clinical Disease Activity Index) was assessed. The population was divided into two subcohorts: (1) methotrexate (MTX)-only users and (2) multiple nonbiologic DMARD users. In both subcohorts, we compared the characteristics of patients who received care consistent with the ACR recommendations (e.g., prescriptions for treatment acceleration) and their providers with the characteristics of those who did not at the conclusion of one visit and over two visits, using logistic regression and adjusting for clustering of patients by rheumatologist. RESULTS: Our study included 741 MTX monotherapy and 995 multiple nonbiologic DMARD users cared for by 139 providers. Only 36.2 % of MTX monotherapy users and 39.6 % of multiple nonbiologic DMARD users received care consistent with the recommendations after one visit, which increased over two visits to 78.3 % and 76.2 %, respectively (25-30 % achieved low disease activity by the second visit without DMARD acceleration). Increasing time since the ACR publication on RA treatment recommendations was not associated with improved adherence. CONCLUSIONS: Allowing two encounters for treatment acceleration was associated with an increase in care concordant with the recommendations; however, time since publication was not. PMID- 27118042 TI - Promoting oral cancer examinations to medical primary care providers: a cluster randomized trial. AB - OBJECTIVES: To compare the percentage of patients who had an oral cancer examination (OCE) by their primary care provider (PCP) in medical clinics participating in a web-based education with poster reminder intervention to that of patients in control clinics. To also determine the effects for PCPs in medical clinics participating in the web-based education with poster reminder intervention as compared with those in control clinics regarding: a) index of knowledge of oral cancer risk factors (RiskOC) and b) index of knowledge of oral cancer diagnostic procedures (DiagOC). METHODS: Six medical clinics were recruited to participate in this study and randomly assigned to an intervention group or a control group. PCPs (physicians, physician assistants, and advanced practice registered nurses) took a pretest; 2 weeks later, they participated in the web-based educational program, including a posttest (intervention group) or took a posttest only (control group). In each clinic, 1 week following completion of the PCPs' posttests, 94 patients were recruited to complete a one-page survey. RESULTS: The intervention clinics were found to be a significant factor for the PCPs to perform patient OCEs, after controlling for significant covariates, that is, age, main reason for clinic visit, OCE for patient in the past year, clinic's mean DiagOC score, and clinic's mean RiskOC score. The intervention also resulted in the PCPs increasing their pretest to posttest RiskOC scores. CONCLUSIONS: The use of intervention has the potential to increase PCPs' short-term knowledge and to increase the frequency of PCPs' routine, nonsymptomatic opportunistic OCE on patients. PMID- 27118043 TI - Long-term adaptation to hypoxia preserves hematopoietic stem cell function. AB - Molecular oxygen sustains aerobic life, but it also serves as the substrate for oxidative stress, which has been associated with the pathogenesis of disease and with aging. Compared with mice housed in normoxia (21% O2), reducing ambient oxygen to 10% O2 (hypoxia) resulted in increased hematopoietic stem cell (HSC) function as measured by bone marrow (BM) cell engraftment onto lethally irradiated recipients. The number of BM c-Kit(+)Sca-1(+)Lin(-) (KSL) cells as well as the number of cells with other hematopoietic stem and progenitor cell markers were increased in hypoxia mice, whereas the BM cells' colony-forming capacity remained unchanged. KSL cells from hypoxia mice showed a decreased level of oxidative stress and increased expression of transcription factor Gata1 and cytokine receptor c-Mpl, consistent with the observations of increased erythropoiesis and enhanced HSC engraftment. These observations demonstrate the benefit of a hypoxic HSC niche and suggest that hypoxic conditions can be further optimized to preserve stem cell integrity in vivo. PMID- 27118044 TI - Microenvironmental oxygen partial pressure in acute myeloid leukemia: Is there really a role for hypoxia? AB - Reduced oxygen partial pressure (pO2) has been recognized as being relevant in hematopoiesis and the pathophysiology of malignant diseases. Although hypoxic (meaning insufficient supply of oxygen) and anoxic areas are present and of pathophysiologic importance (by hypoxia-induced pathways such as HiF1alpha) in solid tumors, this may not be true for (malignant) hematologic cells. Hematopoiesis occurs in the stem cell niche, which is characterized, among other things, by extremely low pO2. However, in contrast to solid tumors, in this context, the low pO2 is physiological and this feature, among others, is shared by the malignant stem cell niche harboring leukemia-initiating cells. Upon differentiation, hematopoietic cells are constantly exposed to changes in pO2 as they travel throughout the human body and encounter arterial and venous blood and migrate into oxygen-carrier-free tissue with low pO2. Hematologic malignancies such as acute myeloid leukemia (AML) make little difference in this respect and, whereas low oxygen is the usual environment of AML cells, recent evidence suggests no role for real hypoxia. Although there is no evidence that AML pathophysiology is related to hypoxia, leukemic blasts still show several distinct biological features when exposed to reduced pO2: they down- or upregulate membrane receptors such as CXCR4 or FLT3, activate or inhibit intracellular signaling pathways such as PI3K, and specifically secrete cytokines (IL-8). In summary, reduced pO2 should not be mistaken for hypoxia (nor should it be so called), and it does not automatically induce hypoxia-response mechanisms; therefore, a strict distinction should be made between physiologically low pO2 (physoxia) and hypoxia. PMID- 27118045 TI - Rapid, facile microwave-assisted synthesis of xanthan gum grafted polyaniline for chemical sensor. AB - Grafting method, through microwave radiation procedure is extremely productive in terms of time consumption, cost effectiveness and environmental friendliness. In this study, conductive and thermally stable composite (mwXG-g-PANi) was synthesized by grafting of aniline (ANi) on to xanthan gum (XG) using catalytic weight of initiator, ammonium peroxydisulfate in the process of microwave irradiation in an aqueous medium. The synthesis of mwXG-g-PANi were confirm by FTIR, XRD, TGA, and SEM. The influence of altering the microwave power, exposure time of microwave, concentration of monomer and the amount of initiator of graft polymerization were studied over the grafting parameters, for example, grafting percentage (%G) and grafting efficiency (%E). The maximum %G and %E achieved was 172 and 74.13 respectively. The outcome demonstrates that the microwave irradiation strategy can increase the reaction rate by 72 times over the conventional method. Electrical conductivity of XG and mwXG-g-PANi composite film was performed. The fabricated grafted sample film were then examined for the chemical sensor. The mwXG-g-PANi, effectively integrated and handled, are NH3 sensitive and exhibit a rapid sensing in presence of NH3 vapor. Chemiresistive NH3 sensors with superior room temperature sensing performance were produced with sensor response of 905 at 1ppb and 90% recovery within few second. PMID- 27118046 TI - Separation of macromolecular proteins and removal of humic acid by cellulose acetate modified UF membranes. AB - Surface modifying macromolecules (SMMs) were synthesized with various polyurethane pre polymers end-capped with different groups and blended into the casting solution of cellulose acetate (CA) to prepare surface modified ultra filtration (UF) membranes for water filtration applications. The surface modification of the CA membranes was confirmed by the FTIR and static contact angle (SCA) measurements. The membranes so prepared had the typical characteristics of UF membranes as confirmed by scanning electron microscopy (SEM). Membrane properties were studied in terms of membrane compaction, percentage water content (%WC), pure water flux (PWF), membrane hydraulic resistance (Rm), molecular weight cut-off (MWCO), average pore size and porosity. The result showed that PWF, %WC, MWCO and pore size increased whereas the Rm decreased by the addition of SMMs. The significant effect of SMMs on the fouling by humic acid (HA) was also observed. It was found that the cSMM-3 membrane, in which SMM was synthesized with diethylene glycol (DEG) and hydroxyl benzene sulfonate (HBS) was blended, had the highest flux recovery ratio FRR (84.6%), as well as the lowest irreversible fouling (15.4%), confirming their improved antifouling properties. Thus, the SMM modified CA membranes had proven, to play an important role in the water treatment by UF. PMID- 27118047 TI - Chemoradiotherapy for anal squamous cell carcinoma. AB - BACKGROUND AND PURPOSE: Anal cancer is a relatively rare cancer, making up approximately 0.4% of all new diagnoses of cancer.(1) The incidence of anal cancer, however, has increased in recent years.(2) The aim of this paper is to review current treatment of anal squamous cell carcinoma (SCC), the most common type of anal cancer. METHODS: This review article focuses on recent and ongoing trials studying the outcomes of various chemoradiotherapy (CRT) regimens in the treatment of anal SCC. PubMed was initially searched for relevant trials. This search was then supplemented by hand searches of reference lists and abstracts of relevant conferences. MAIN FINDINGS: CRT with mitomycin C (MMC) and 5 fluorouracil (5-FU) has been proven to have effective results in the treatment of anal SCC. Salvage surgery has a role in some patients in the treatment of persistent or recurrent disease beyond 26 weeks. The addition of induction or maintenance chemotherapy to CRT has not been shown to have any benefit. CONCLUSIONS: Primary CRT with MMC and 5-FU is the current standard treatment for anal SCC. There is currently no role for induction or maintenance chemotherapy. PMID- 27118048 TI - Changing R&D models in research-based pharmaceutical companies. AB - New drugs serving unmet medical needs are one of the key value drivers of research-based pharmaceutical companies. The efficiency of research and development (R&D), defined as the successful approval and launch of new medicines (output) in the rate of the monetary investments required for R&D (input), has declined since decades. We aimed to identify, analyze and describe the factors that impact the R&D efficiency. Based on publicly available information, we reviewed the R&D models of major research-based pharmaceutical companies and analyzed the key challenges and success factors of a sustainable R&D output. We calculated that the R&D efficiencies of major research-based pharmaceutical companies were in the range of USD 3.2-32.3 billion (2006-2014). As these numbers challenge the model of an innovation-driven pharmaceutical industry, we analyzed the concepts that companies are following to increase their R&D efficiencies: (A) Activities to reduce portfolio and project risk, (B) activities to reduce R&D costs, and (C) activities to increase the innovation potential. While category A comprises measures such as portfolio management and licensing, measures grouped in category B are outsourcing and risk-sharing in late-stage development. Companies made diverse steps to increase their innovation potential and open innovation, exemplified by open source, innovation centers, or crowdsourcing, plays a key role in doing so. In conclusion, research-based pharmaceutical companies need to be aware of the key factors, which impact the rate of innovation, R&D cost and probability of success. Depending on their company strategy and their R&D set-up they can opt for one of the following open innovators: knowledge creator, knowledge integrator or knowledge leverager. PMID- 27118050 TI - Unequal treatment of transgender people. PMID- 27118049 TI - The tract terminations in the temporal lobe: Their location and associated functions. AB - Temporal lobe networks are associated with multiple cognitive domains. Despite an upsurge of interest in connectional neuroanatomy, the terminations of the main fibre tracts in the human brain are yet to be mapped. This information is essential given that neurological, neuroanatomical and computational accounts expect neural functions to be strongly shaped by the pattern of white-matter connections. This paper uses a probabilistic tractography approach to identify the main cortical areas that contribute to the major temporal lobe tracts. In order to associate the tract terminations to known functional domains of the temporal lobe, eight automated meta-analyses were performed using the Neurosynth database. Overlaps between the functional regions highlighted by the meta analyses and the termination maps were identified in order to investigate the functional importance of the tracts of the temporal lobe. The termination maps are made available in the Supplementary Materials of this article for use by researchers in the field. PMID- 27118051 TI - Contemporary outcomes after pericardial window surgery: impact of operative technique. AB - BACKGROUND: The optimal window procedure for drainage of a large pericardial effusion has yet to be established. The purpose of this study was to compare the outcomes associated with the subxiphoid and thoracotomy pericardial window techniques, with a focus on perioperative pain and effusion recurrence rates. METHODS: A retrospective single-center observational study of all pericardial window operations was performed, with the incision based on surgeon preference. Perioperative data was recorded including time to extubation, narcotic requirements, and the development of a recurrent pericardial effusion. RESULTS: From 2002 to 2015, 179 patients with a large pericardial effusion underwent either a subxiphoid (n = 127) or left anterior mini-thoracotomy (n = 52) pericardial window procedure. Patients (mean age 73.2 years, 56 % female) had a high incidence of previous malignancy (49 %), chronic anticoagulation (34 %), recent infection (26 %), or renal failure (18 %). Cardiac tamponade was present in 50 %, and 12 % had undergone previous pericardiocentesis. Comparing the two techniques, there was no difference in the amount of fluid drained or in the perioperative mortality rate. Postoperatively, patients who had the subxiphoid approach required less time before extubation (P = 0.002) and needed less narcotics within 48 h after surgery (P = 0.0001) compared to thoracotomy patients. However, patients treated with the subxiphoid technique more often developed recurrent moderate or large pericardial effusions (P = 0.02), and there was a trend towards more repeat operations needed (P = 0.15). CONCLUSION: Pericardial window surgery via a subxiphoid incision is associated with less postoperative pain and faster time to extubation. However, the thoracotomy approach may be more effective at preventing effusion recurrence and the need for repeat surgery. PMID- 27118052 TI - Influence of Weight on Shared Core Symptoms in Eating Disorders: Support or Challenge for a Transdiagnostic Perspective? AB - In terms of the transdiagnostic model of eating disorders, Anorexia Nervosa (AN), Bulimia Nervosa (BN), and Binge Eating Disorder (BED) share the same distinctive psychopathology. However, empirical evidence showing similarities between these eating disorder diagnoses for core symptoms is scarce, and the role of weight status is unclear. Data from a total of 168 female participants were collected between April 2004 and April 2008, at an outpatient unit specialized in eating disorder treatment. Core symptoms of eating disorders were measured via self report questionnaires. In particular, women with BED and BN showed similar patterns of core symptomatology compared with AN. However, when body mass index (BMI) was considered in the analyses, there were no differences between the three diagnostic groups in relation to body image. Differences in eating behavior are not solely triggered by weight differences, whereas body image disturbances are a transdiagnostic phenomenon among EDs and should also be considered in the treatment of BED. PMID- 27118053 TI - Comparing Versions of the Good Behavior Game: Can a Positive Spin Enhance Effectiveness? AB - Disruptions can prevent the classroom from being an effective learning environment. The Good Behavior Game (GBG) is a group contingency that has been proven to effectively prevent disruptions and increase engagement. However, the traditional methods of the GBG include teacher scanning for negative student behaviors, and may not align with Positive Behavioral Interventions and Supports (PBIS), which is becoming widely adopted in many schools. Extending the findings of Wright and McCurdy, the current study compared the effects of the GBG and a positive version of the GBG, called the Caught Being Good Game (CBGG), on student behavior, including engagement and off-task behaviors, as well as teachers' use of positive and negative statements. Results showed both the GBG and the CBGG improved student behavior, with data not clearly indicating one was superior. Neither intervention led to an increase in positive teacher statements. Implications for teachers and suggestions for further research are discussed. PMID- 27118054 TI - The Extinction and Return of Fear of Public Speaking. AB - Prior studies indicate extinguished fear often partially returns when participants are later tested outside the extinction context. Cues carried from the extinction context to the test context sometimes reduce return of fear, but it is unclear whether such extinction cues (ECs) reduce return of fear of public speaking. Here we assessed return of fear of public speaking, and whether either of two types of ECs can attenuate it. Participants gave speeches of increasing difficulty during an exposure practice session and were tested 2 days later in a different context. Testing occurred in the presence of physical ECs, after mentally rehearsing the exposure session, or without either reminder. Practice reduced fear of public speaking, but fear partially returned at test. Neither physical nor mental ECs reduced partial return of fear of public speaking. The return of extinguished fear of public speaking, although small, was reliable, but not appreciably sensitive to presence of ECs. PMID- 27118055 TI - Improving ethanol yield in acetate-reducing Saccharomyces cerevisiae by cofactor engineering of 6-phosphogluconate dehydrogenase and deletion of ALD6. AB - BACKGROUND: Acetic acid, an inhibitor of sugar fermentation by yeast, is invariably present in lignocellulosic hydrolysates which are used or considered as feedstocks for yeast-based bioethanol production. Saccharomyces cerevisiae strains have been constructed, in which anaerobic reduction of acetic acid to ethanol replaces glycerol formation as a mechanism for reoxidizing NADH formed in biosynthesis. An increase in the amount of acetate that can be reduced to ethanol should further decrease acetic acid concentrations and enable higher ethanol yields in industrial processes based on lignocellulosic feedstocks. The stoichiometric requirement of acetate reduction for NADH implies that increased generation of NADH in cytosolic biosynthetic reactions should enhance acetate consumption. RESULTS: Replacement of the native NADP(+)-dependent 6 phosphogluconate dehydrogenase in S. cerevisiae by a prokaryotic NAD(+)-dependent enzyme resulted in increased cytosolic NADH formation, as demonstrated by a ca. 15% increase in the glycerol yield on glucose in anaerobic cultures. Additional deletion of ALD6, which encodes an NADP(+)-dependent acetaldehyde dehydrogenase, led to a 39% increase in the glycerol yield compared to a non-engineered strain. Subsequent replacement of glycerol formation by an acetate reduction pathway resulted in a 44% increase of acetate consumption per amount of biomass formed, as compared to an engineered, acetate-reducing strain that expressed the native 6 phosphogluconate dehydrogenase and ALD6. Compared to a non-acetate reducing reference strain under the same conditions, this resulted in a ca. 13% increase in the ethanol yield on glucose. CONCLUSIONS: The combination of NAD(+)-dependent 6-phosphogluconate dehydrogenase expression and deletion of ALD6 resulted in a marked increase in the amount of acetate that was consumed in these proof-of principle experiments, and this concept is ready for further testing in industrial strains as well as in hydrolysates. Altering the cofactor specificity of the oxidative branch of the pentose-phosphate pathway in S. cerevisiae can also be used to increase glycerol production in wine fermentation and to improve NADH generation and/or generation of precursors derived from the pentose phosphate pathway in other industrial applications of this yeast. PMID- 27118056 TI - Long-term Follow-up of Coronary Artery Bypass Patients With Preoperative and New Postoperative Native Coronary Artery Chronic Total Occlusion. AB - BACKGROUND: Chronic total occlusions (CTOs) of native coronary arteries are a frequent finding among patients who are referred for surgical revascularization with coronary artery bypass grafting (CABG). The long-term clinical significance of native coronary artery CTO identified at baseline and 1 year after CABG is unknown. METHODS: All patients who underwent 1-year follow-up angiography as part of the multicentre Radial Artery Patency Study (RAPS) were assessed for late clinical events. RESULTS: At a mean follow-up of 7.3 +/- 2.9 years, the study group of 388 patients had the following outcomes: 39 (10%) deaths, 6 (1.5%) cases of nonfatal myocardial infarction, and 19 (4.9%) cases of percutaneous coronary intervention (PCI). CTO of >= 1 native coronary artery in the baseline preoperative coronary angiogram was demonstrated in 240 (61.9%) patients. The composite of all-cause death, nonfatal myocardial infarction, and PCI occurred significantly more often in patients with at least 1 preoperative CTO than in patients without a preoperative CTO (20% vs 11%; P = 0.048). A new native coronary artery CTO 1 year after surgery occurred in 169 (43.6%) patients. The composite of all-cause death, nonfatal myocardial infarction, and PCI occurred significantly more often in patients with a new CTO 1 year after CABG compared with those without a new CTO (21.3% vs 12.8%; P = 0.028). CONCLUSIONS: In patients undergoing CABG, both preoperative CTOs and new CTOs that develop 1 year after surgery are associated with adverse long-term clinical outcomes. PMID- 27118057 TI - Net Clinical Benefit of Dabigatran Over Warfarin in Patients With Atrial Fibrillation Stratified by CHA2DS2-VASc and Time in Therapeutic Range. AB - BACKGROUND: Although dabigatran is 1 of the preferred agents for stroke prevention in atrial fibrillation, warfarin remains the mainstay treatment in many publicly financed health care systems. Little is known about the net clinical benefit of switching patients who are receiving warfarin and have different risk profiles and time in therapeutic range (TTR) to dabigatran. In this study, we aimed to investigate the net clinical benefit of switching warfarin to dabigatran in relation to CHA2DS2-VASc and TTR. METHODS: This was a hospital-based observational registry. RESULTS: A total of 2153 patients (72.7 +/ 12.2 years; CHA2DS2-VASc, 3.65 +/- 1.94) were included in the analysis: 1686 patients were receiving warfarin, and 467 were receiving dabigatran. After a 4.2 year follow-up, the incidence of ischemic stroke among patients receiving warfarin and dabigatran were 4.25%/y and 1.89%/y, respectively. Among patients receiving warfarin, ischemic stroke risk was positively correlated with CHA2DS2 VASc score and negatively correlated with TTR. It was found on regression analysis that for every 10% increase in TTR, the incidence of annual ischemic stroke decreased by 0.74%/y (R2 = 0.77; P = 0.04). Patients with higher CHA2DS2 VASc scores had greater ischemic stroke risk reductions per 10% TTR increment (ie, for CHA2DS2-VASc score <= 2, 3-4, and >= 5, the reductions were -0.38%/y, 0.60%/y, and -0.84%/y, respectively). Similar trends were also observed in intracranial hemorrhage. The net clinical benefit favoured switching from warfarin to dabigatran for all patients, but the best benefit was found in those with high CHA2DS2-VASc and poor TTR. CONCLUSIONS: The combination of CHA2DS2-VASc and TTR facilitates patient prioritization for dabigatran. The best net clinical benefit for switching from warfarin to dabigatran was found in those with both high CHA2DS2-VASc and poor TTR. PMID- 27118058 TI - Prevention, Detection, and Management of Chemotherapy-Related Cardiac Dysfunction. AB - Cancer treatment-related cardiac dysfunction (CTRCD) occurs with many agents used in the treatment of cancer. This is most relevant in patients receiving cancer treatment with curative intent as opposed to those treated with a palliative intent where lifespan is more likely to be limited by the cancer diagnosis. Clinicians need to be aware of methods to prevent, detect, and manage CTRCD. This article frames an approach to CTCRD based on the American College of Cardiology/American Heart Association stages of heart failure (HF). In patients who are at risk for CTRCD (stage A HF), risk reduction methods may be warranted, including management of cardiovascular risk factors, modification of cancer treatment, and universal preventive therapy. Once cancer therapy begins, it is prudent to detect and promptly treat myocardial dysfunction (stage B HF). This can be achieved by careful monitoring during therapy using echocardiography, multigated acquisition scans, or cardiac MRI. Subclinical myocardial systolic dysfunction (ie, without a drop in ejection fraction) can be identified using either echocardiography measured peak systolic global longitudinal strain or cardiac troponin I. At present, there is insufficient evidence to institute preventive interventions based on changes in these preclinical markers. Finally, in patients with stage C/D HF, management strategies should follow existing guidelines. Advanced treatment including cardiac transplantation and mechanical circulatory support may be considered in appropriate circumstances. PMID- 27118059 TI - Predictors for Progression of Atrial Fibrillation in Patients Awaiting Atrial Fibrillation Ablation. AB - BACKGROUND: Success rates of atrial fibrillation (AF) ablation have been shown to be significantly lower for patients with persistent AF. However, little is known about the risk factors predicting progression to persistent AF in patients awaiting AF ablation. METHODS: We performed a retrospective, single-centre investigation of patients with paroxysmal AF at the time of placement on the ablation waiting list. Patients were defined as having progressed if they had developed self-reported or electrocardiogram-recorded AF durations more than 7 days while awaiting ablation. After ablation, clinical visits at 3, 6, 9, 12, and 18 months were performed with a minimum of a 48-hour-Holter and electrocardiogram. Baseline characteristics including left atrial diameter (LA) and the HATCH score were analyzed by univariable and multivariable analysis for predicting progression to persistent AF. RESULTS: During a median waiting time of 9.7 (6.1, 14.2) months, 60 of 564 patients (11%) progressed to persistent AF. In patients who progressed, ablation took longer (180 [150, 249] minutes vs 157 [125, 210] minutes; P = 0.009) and was associated with a higher rate of recurrence after a median of 12 months (53.3% vs 39.1%; P < 0.001). The HATCH score was a poor predictor of AF progression (area under the curve 0.54), whereas an LA diameter of more than 45 mm (odds ratio 3.46, P < 0.001) and heart failure (odds ratio 3.11, P = 0.036) were strong and independent predictors of AF progression in multivariable analysis. CONCLUSIONS: Patients with an increased LA diameter or heart failure have a significantly increased risk of progression to persistent AF. These characteristics may define patients who should undergo earlier catheter ablation to optimize outcome. PMID- 27118060 TI - Does Milk Consumption Contribute to Cardiometabolic Health and Overall Diet Quality? AB - Although milk consumption is recommended in most dietary guidelines around the world, its contribution to overall diet quality remains a matter of debate in the scientific community as well as in the public domain. This article summarizes the discussion among experts in the field on the place of milk in a balanced healthy diet. The evidence to date suggests at least a neutral effect of milk intake on health outcomes. The possibility that milk intake is simply a marker of diets higher in nutritional quality cannot be ruled out. This review also identifies a number of key research gaps pertaining to the impact of milk consumption on health. These need to be addressed to better inform future dietary guidelines. PMID- 27118061 TI - Consensus pan-genome assembly of the specialised wine bacterium Oenococcus oeni. AB - BACKGROUND: Oenococcus oeni is a lactic acid bacterium that is specialised for growth in the ecological niche of wine, where it is noted for its ability to perform the secondary, malolactic fermentation that is often required for many types of wine. Expanding the understanding of strain-dependent genetic variations in its small and streamlined genome is important for realising its full potential in industrial fermentation processes. RESULTS: Whole genome comparison was performed on 191 strains of O. oeni; from this rich source of genomic information consensus pan-genome assemblies of the invariant (core) and variable (flexible) regions of this organism were established. Genetic variation in amino acid biosynthesis and sugar transport and utilisation was found to be common between strains. Furthermore, we characterised previously-unreported intra-specific genetic variations in the natural competence of this microbe. CONCLUSION: By assembling a consensus pan-genome from a large number of strains, this study provides a tool for researchers to readily compare protein-coding genes across strains and infer functional relationships between genes in conserved syntenic regions. This establishes a foundation for further genetic, and thus phenotypic, research of this industrially-important species. PMID- 27118062 TI - Bioinformatic analysis reveals pancreatic cancer molecular subtypes specific to the tumor and the microenvironment. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a dense desmoplastic reaction surrounding malignant epithelial cells. Interaction between the epithelial and stromal compartments is suggested to enhance its aggressive nature. Indeed, therapies targeting the stroma, as well as the tumor cells, may improve survival outcomes for patients. The evaluated study by Moffitt et al. used bioinformatic techniques to separate gene expression patterns of normal tissues from PDAC and stroma in a large cohort of samples. The researchers identified two different subtypes of PDAC ('classical' and 'basal-like') and surrounding stroma ('normal' and 'activated'). The basal-like subtype was associated with worse prognosis and a trend towards better response to adjuvant therapy. Hopefully, the molecular stratification of PDAC will potentially allow more personalized treatment strategies and guide clinical decision making. PMID- 27118063 TI - Hepatitis C management in prisons: An insight into daily clinical practice in three major Italian correctional houses. PMID- 27118064 TI - Field-driven Domain Wall Motion in Ferromagnetic Nanowires with Bulk Dzyaloshinskii-Moriya Interaction. AB - Field-driven domain wall (DW) motion in ferromagnetic nanowires with easy- and hard-axis anisotropies was studied theoretically and numerically in the presence of the bulk Dzyaloshinskii-Moriya interaction (DMI) based on the Landau-Lifshitz Gilbert equation. We propose a new trial function and offer an exact solution for DW motion along a uniaxial nanowire driven by an external magnetic field. A new strategy was suggested to speed up DW motion in a uniaxial magnetic nanowire with large DMI parameters. In the presence of hard-axis anisotropy, we find that the breakdown field and velocity of DW motion was strongly affected by the strength and sign of the DMI parameter under external fields. This work may be useful for future magnetic information storage devices based on DW motion. PMID- 27118065 TI - Phospholipophilicity of CxHyN(+) amines: chromatographic descriptors and molecular simulations for understanding partitioning into membranes. AB - Using immobilized artificial membrane high-performance liquid chromatography (IAM HPLC) the sorption affinity of 70 charged amine structures to phospholipids was determined. The amines contained only 1 charged moiety and no other polar groups, the rest of the molecule being aliphatic and/or aromatic hydrocarbon groups. We systematically evaluated the influence of the amine type (1 degrees , 2 degrees , 3 degrees amines and quaternary ammonium), alkyl chain branching, phenyl ring positioning, charge positioning (terminal vs. central in the molecule) on the phospholipid-water partitioning coefficient (KPLIPW). These experimental results were compared with quantum-chemistry based three-dimensional (3D) molecular simulations of the partitioning of charged amines, including the most likely solute conformers, using a hydrated phospholipid bilayer in the COSMOmic module of COSMOtherm software. Both IAM-HPLC retention data and the simulations suggest that the molecular orientation of charged amines at the location in the bilayer with the lowest calculated Gibbs free energy exerts a strong influence over the partitioning within the membrane. The most favourable position of charged amines coincides with the region where the phosphate anions in the phospholipid bilayer are most abundant. Hydrocarbon units oriented in this layer are located more towards the aqueous phase and contribute less to the overall membrane affinity than hydrocarbon units extending into the more hydrophobic core of the bilayer. COSMOmic simulations explain most of the trends between the structural differences observed in IAM-HPLC based KPLIPW. For this set of cationic structures, the mean absolute difference between COSMOmic simulations and IAM HPLC data, accounting only for amine type corrective increments, is 0.31 log units. PMID- 27118066 TI - Older Adults and the Fear of Death: The Protective Function of Generativity. AB - Terror management theory (TMT) posits that cultural worldviews function to allay concerns about human mortality. Preliminary research with older adults has indicated that seniors do not respond to death reminders in the same way as their younger counterparts. The purpose of the current study was to test a developmentally relevant construct that may buffer death anxiety in later life. It was hypothesized that Erikson's concept of generativity may encompass death denying properties for older adults. One hundred and seventy-nine seniors were recruited to determine if subtle mortality salience inductions would lead participants to rate their own generativity as higher than after a blatant induction, or no induction, after controlling for pre-induction generativity. As expected, participants exposed to subtle death primes rated themselves as having higher levels of generativity than the other two groups after co-varying pre induction generativity. Explanations are discussed in light of the literatures on TMT and generativity. PMID- 27118067 TI - Accuracy of computed tomographic angiography in the diagnosis of patients with inferior vena cava partial obstruction in Budd-Chiari syndrome. AB - BACKGROUND AND AIM: The diagnosis of the partially obstructed inferior vena cava (IVC) in Budd-Chiari syndrome (BCS) patients has received little attention. We aimed to evaluate the diagnostic accuracy of computed tomographic angiography (CTA) for patients with BCS and a partially obstructed IVC. METHODS: A total of 329 patients with BCS and an obstructed IVC were endovascularly treated with balloon dilation and/or stent placement. All patients underwent a CTA examination prior to endovascular treatment, and the data were retrospectively reviewed. The presence of a round, oval, irregular shape or jet sign low-density area without enhancement within the enhanced proximal IVC was considered a sign of a partially obstructed IVC. Digital subtraction angiography was used as the gold standard. RESULTS: The results from the digital subtraction angiography revealed a partially obstructed IVC in 108 BCS patients and a complete obstruction in 221 patients. The CTA discovered a partially obstructed IVC in 99 patients and a completely obstructed IVC in 230 patients. From the CTA results, 15 were false negatives, and six were false positives. The patient-based evaluation yielded an accuracy of 93.6%, a sensitivity of 86.1%, specificity of 97.3%, positive predictive value of 93.9%, and negative predictive value of 93.5% for the detection of BCS patients with a partial IVC obstruction. CONCLUSIONS: Computed tomographic angiography offered a high diagnostic accuracy and sensitivity in BCS patients with a partially obstructed IVC. The low-density area within the enhanced proximal IVC above the membrane in artery phase can be considered a reliable indicator of a stenotic IVC in BCS patients. PMID- 27118068 TI - Which adherence measure - self-report, clinician recorded or pharmacy refill - is best able to predict detectable viral load in a public ART programme without routine plasma viral load monitoring? AB - OBJECTIVE: Combination antiretroviral therapy (cART) suppresses viral replication to an undetectable level if a sufficiently high level of adherence is achieved. We investigated which adherence measurement best distinguishes between patients with and without detectable viral load in a public ART programme without routine plasma viral load monitoring. METHOD: We randomly selected 870 patients who started cART between May 2009 and April 2012 in 10 healthcare facilities in Addis Ababa, Ethiopia. Six hundred and sixty-four (76.3%) patients who were retained in HIV care and were receiving cART for at least 6 months were included and 642 had their plasma HIV-1 RNA concentration measured. Patients' adherence to cART was assessed according to self-report, clinician recorded and pharmacy refill measures. Multivariate logistic regression model was fitted to identify the predictors of detectable viremia. Model accuracy was evaluated by computing the area under the receiver operating characteristic (ROC) curve. RESULT: A total of 9.2% and 5.5% of the 642 patients had a detectable viral load of >=40 and >=400 RNA copies/ml, respectively. In the multivariate analyses, younger age, lower CD4 cell count at cART initiation, being illiterate and widowed, and each of the adherence measures were significantly and independently predictive of having >=400 RNA copies/ml. The ROC curve showed that these variables altogether had a likelihood of more than 80% to distinguish patients with a plasma viral load of >=400 RNA copies/ml from those without. CONCLUSION: Adherence to cART was remarkably high. Self-report, clinician recorded and pharmacy refill non adherence were all significantly predictive of detectable viremia. The choice for one of these methods to detect non-adherence and predict a detectable viral load can therefore be based on what is most practical in a particular setting. PMID- 27118069 TI - Thigh burns from exploding e-cigarette lithium ion batteries: First case series. AB - E-cigarette (EC) use has risen meteorically over the last decade. The majority of these devices are powered by re-chargeable lithium ion batteries, which can represent a fire hazard if damaged, over-heated, over-charged or stored inappropriately. There are currently no reports in the medical literature of lithium ion battery burns related to EC use and no guidance on the appropriate management of lithium ion battery associated injuries. We report two individual cases of burn resulting from explosion of EC re-chargeable lithium ion batteries. Both patients required in-patient surgical management. We provide evidence that lithium ion battery explosions can be associated with mixed thermal and alkali chemical burns, resulting from the significant discharge of thermal energy and the dispersal of corrosive lithium ion compounds. We would recommend, as with other elemental metal exposures, caution in exposing lithium ion battery burns to water irrigation. Early and thorough cleaning and debridement of such burns, to remove residual lithium contamination, may limit the risk of burn wound extension and potentially improve outcomes. PMID- 27118070 TI - Intranasal application of polyethyleneimine suppresses influenza virus infection in mice. PMID- 27118071 TI - Switching of the rotational direction of rhizoidal colonies in a newly isolated Bacillus mycoides strain Ko01. AB - Bacillus mycoides are known to form rhizoidal colonies on solid medium. In this study, a new strain of B. mycoides, strain Ko01, was isolated from soil. Genetic and growth patterns indicated that this strain belongs to subgroup II of the B. cereus group. Strain Ko01 forms extensive rhizoidal colonies with predictable directions of rotation. The concentration of the agar, and not the chemical composition, altered the direction of the colony rotation, switching from counterclockwise to clockwise. Agar concentration-dependent switching of rotation direction was unique to strain Ko01 and was not seen in colonies of other B. mycoides strains that were tested. Factors affecting colony chirality patterns appeared to be variable among B. mycoides strains. This feature can be used for the classification of B. mycoides strains. PMID- 27118072 TI - Impeding Bacillus spore germination in vitro and in milk by soy glycinin during long cold storage. AB - This paper presents a study of the magnitude and mechanism of impeding the emergent spore germination of Bacillus subtilis (non-hemolytic strain) and Bacillus licheniformis (hemolytic strain) under the action of soybean glycinin and its basic subunit (BS). Incubating B. licheniformis spores with 100 MUg/ml of glycinin or BS at 35 degrees C for 24 h totally prevented the hemolytic activity associated with the emergent vegetative cells on blood agar during 3-5 days of incubation at 35 degrees C in contrast to the control. Glycinin and BS (100 MUg/ml) also resulted in the leakage of 70 and 73% of the initially germinating spore contents of A260 absorbing materials of the two bacterial species after 2 h of incubation at 35 degrees C, respectively. Increasing the concentration of glycinin and BS up to 400 MUg/ml increased the germinating spore leakage to 83 and 88%, respectively. Spore germination in Muller Hinton Broth containing glycinin and BS (100 MUg/ml) was practically nil after 4 days of incubation at 35 degrees C. Supplementing milk preheated at 80 degrees C/5 min with both glycinin and BS kept the final vegetative cell counts down to about 30 and 20% of the corresponding control, respectively, after 50 days of storage at 4 degrees C. Both light, and transmission electron, microscopy images revealed significant morphological and structural distorting changes in BS-treated spores of B. licheniformis. PMID- 27118073 TI - Characterization of N-acyl homoserine lactones (AHLs) producing bacteria isolated from vacuum-packaged refrigerated turbot (Scophthalmus maximus) and possible influence of exogenous AHLs on bacterial phenotype. AB - Quorum sensing (QS) is a cell-to-cell communication mechanism through which microbial cells communicate and regulate their wide variety of biological activities. N-acyl homoserine lactones (AHLs) are considered to be the most important QS signaling molecules produced by several Gram-negative bacteria. The present study aimed to screen the AHLs-producing bacteria from spoiled vacuum packaged refrigerated turbot (Scophthalmus maximus) by biosensor assays, and the profiles of AHLs produced by these bacteria were determined using reversed-phase thin-layer chromatography (RP-TLC) and gas chromatography-mass spectrometry (GC MS). Effects of exogenous AHLs and QS inhibitor (QSI) on the phenotypes (i.e., extracellular proteolytic activity and biofilm formation) of the AHLs-producing bacteria were also evaluated. Our results demonstrated that eight out of twenty two isolates were found to produce AHLs. Three of the AHLs-producing isolates were identified as Serratia sp., and the other five were found to belong to the family of Aeromonas. Two isolates (i.e., S. liquefaciens A2 and A. sobria B1) with higher AHLs-producing activities were selected for further studies. Mainly, RP-TLC and GC-MS analysis revealed three AHLs, i.e., 3-oxo-C6-HSL, C8-HSL and C10 HSL were produced by S. liquefaciens A2, while five AHLs, i.e., C4-HSL, C6-HSL, C8-HSL, C10-HSL, and C12-HSL, were produced by A. sobria B1. Moreover, production of AHLs in both bacterial strains were found to be density-dependent, and the AHLs activity reached a maximum level in their middle logarithmic phase and decreased in the stationary phase. The addition of exogenous AHLs and QSI decreased the specific protease activity both of the Serratia A2 and Aeromonas B1. Exogenous AHLs inhibited the biofilm formation of Serratia A2 while it enhanced the biofilm formation in Aeromonas B1. QSI inhibited the specific protease activity and biofilm formation in both bacterial strains. PMID- 27118074 TI - Development of corn silk as a biocarrier for Zymomonas mobilis biofilms in ethanol production from rice straw. AB - Z. mobilis cell immobilization has been proposed as an effective means of improving ethanol production. In this work, polystyrene and corn silk were used as biofilm developmental matrices for Z. mobilis ethanol production with rice straw hydrolysate as a substrate. Rice straw was hydrolyzed by dilute sulfuric acid (H2SO4) and enzymatic hydrolysis. The final hydrolysate contained furfural (271.95 +/- 76.30 ppm), 5-hydroxymethyl furfural (0.07 +/- 0.00 ppm), vanillin (1.81 +/- 0.00 ppm), syringaldehyde (5.07 +/- 0.83 ppm), 4-hydroxybenzaldehyde (4 HB) (2.39 +/- 1.20 ppm) and acetic acid (0.26 +/- 0.08%). Bacterial attachment or biofilm formation of Z. mobilis strain TISTR 551 on polystyrene and delignified corn silk carrier provided significant ethanol yields. Results showed up to 0.40 +/- 0.15 g ethanol produced/g glucose consumed when Z. mobilis was immobilized on a polystyrene carrier and 0.51 +/- 0.13 g ethanol produced/g glucose consumed when immobilized on delignified corn silk carrier under batch fermentation by Z. mobilis TISTR 551 biofilm. The higher ethanol yield from immobilized, rather than free living, Z. mobilis could possibly be explained by a higher cell density, better control of anaerobic conditions and higher toxic tolerance of Z. mobilis biofilms over free cells. PMID- 27118075 TI - Isolation of lactic acid bacteria exhibiting high scavenging activity for environmental hydrogen peroxide from fermented foods and its two scavenging enzymes for hydrogen peroxide. AB - To obtain lactic acid bacteria that scavenge environmental hydrogen peroxide, we developed a specialized enrichment medium and successfully isolated Pediococcus pentosaceus Be1 strain from a fermented food. This strain showed vigorous environmental hydrogen peroxide scavenging activity over a wide range of hydrogen peroxide concentrations. High Mn-catalase and NADH peroxidase activities were found in the cell-free extract of the P. pentosaceus Be1 strain, and these two hydrogen peroxide scavenging enzymes were purified from the cell-free extract of the strain. Mn-catalase has been purified from several microorganisms by several researchers, and the NADH peroxidase was first purified from the original strain in this report. After cloning the genes of the Mn-catalase and the NADH peroxidase, the deduced amino acid sequences were compared with those of known related enzymes. PMID- 27118076 TI - Exploration of a N-terminal disulfide bridge to improve the thermostability of a GH11 xylanase from Aspergillus niger. AB - To improve the thermostability of xylanase XynZF-2 from Aspergillus niger XZ-3S, a disulfide bridge was introduced in the N-terminal domains by site-directed mutagenesis (V1C and E27C). Simultaneously, the active sites of XynZF-2 were predicted by bioinformatics software and verified by site-directed mutagenesis (E103D and E194D). The mutated active sites xynED- and the mutated disulfide bridge xynDC-encoding genes were constructed and expressed in Escherichia coli BL21 (DE3). Compared to the native xylanase, it was found that the residual activity of the mutated XynED was 0.17%. The optimum temperature of the variant XynDC was increased to 45 degrees C from 40 degrees C of XynZF-2. After treatment at 40 degrees C for 60 min, the variant XynDC retained 66.77% of their original activity, while the XynZF-2 retained about 44.36% residual activity. t1/2(45 degrees C) of the variant XynDC also increased from 7 min to 14 min. The results of the mutated xylanases indicated that the active center of XynZF-2 mainly consisted of two catalytic residues (Glu103 and Glu194), and the introduction of a disulfide bridge in the N-terminal domains can improve the thermostability of XynZF-2. PMID- 27118077 TI - Bio-statistical enhancement of acyl transfer activity of amidase for biotransformation of N-substituted aromatic amides. AB - Acyl transfer activity (ATA) of amidase transfers an acyl group of different amides to hydroxylamine to form the corresponding hydroxamic acid. Bacterial isolate BR-1 was isolated from cyanogenic plant Cirsium vulgare rhizosphere and identified as Pseudomonas putida BR-1 by 16S rDNA sequencing. This organism exhibited high ATA for the biotransformation of N-substituted aromatic amide to the corresponding hydroxamic acid. Optimization of media, tryptone (0.6%), inducer, pH 8.5, and a growth temperature 25 degrees C for 56 h, resulted in a 7 fold increase in ATA. Further, Response Surface Methodology (RSM) and multiple feeding approach (20 mM after 14 h) of inducer led to a 29% enhancement of ATA from this organism. The half life (t1/2) of this enzyme at 50 degrees C and 60 degrees C was 3 h and 1 h, respectively. The ATA of amidase of Pseudomonas putida BR-1 makes it a potential candidate for the production of a variety of N substituted aromatic hydroxamic acid. PMID- 27118078 TI - Identification of sirtuin and its target as the ribosomal protein S4 in Lactobacillus paracasei. AB - Sirtuin is a protein with an enzymatic activity of NAD(+)-dependent protein deacetylation. It was first identified in yeast and its homologous genes have been widely found in various organisms. In bacteria, sirtuin gene was first described as cobB, encoding a cobalamin processing enzyme; and later its potential involvement in regulating acetylation levels of metabolic enzymes, transcription factors, chemotactic proteins and others have been reported. In order to study its physiological relevance in probiotic lactic acid bacteria, we analyzed the whole genome of three L. paracasei strains. All strains tested had sirtuin homolog genes designated hereby as sirA, and one of them had an additional gene designated as sirB. Following confirmation of their coding sequences by individual gene cloning, corresponding recombinant proteins have been generated and purified. The enzymatic characterization revealed that the intrinsic NAD(+)-dependent deacetylation activity of LpSirA (protein encoded by sirA) is comparable to human SIRT1. Furthermore, by blocking sirtuin activity using nicotinamide in vivo, together with an in vitro deacetylation reaction using recombinant LpSirA, we identified one of the target proteins in the lactic acid bacteria as the 30S ribosomal protein S4 (rpsD product). PMID- 27118079 TI - Expressions of alkaline phosphatase genes during phosphate starvation are under positive influences of multiple cell wall hydrolase genes in Bacillus subtilis. PMID- 27118080 TI - Gingival Bleeding and Bloody Dialysate: A Case Report of Scurvy in a Child With End-Stage Renal Disease Receiving Peritoneal Dialysis. AB - Patients with chronic kidney disease (CKD) or end-stage renal disease are at risk for vitamin C deficiency and scurvy due to diet restriction, increased urinary loss of the water-soluble vitamin C with diuretics, and in case of patients who are on dialysis, through dialysates. The condition may be overlooked as the clinical manifestation of scurvy may be subtle, and some presentations may mimic clinical signs in CKD. We reported a case of scurvy presenting with gingival bleeding and blood dialysate in a 6-year-old girl with end-stage renal disease who was on continuous ambulatory peritoneal dialysis. Physical examination showed gingival hyperplasia and bleeding, and the pathognomonic bleeding of perifollicular hemorrhage. The typical radiographic changes were present. The clinical signs and symptoms resolved after ascorbic acid treatment. This case underscores the importance of awareness of the increased risk for vitamin C deficiency in patients with CKD and receiving dialysis. PMID- 27118082 TI - Changes in the central and peripheral circulatory system in response to the cold: own studies using impedance plethysmography and Doppler ultrasound. AB - The aim of the study was to determine the cardiovascular response to continuous (4 degrees C for 60 min) and intermittent (10 min at 4 degrees C and 10 min at room temperature alternately) exposure to the cold in 30 healthy young men. The subjects were equipped with a set of identical clothing (insulation 2.1 clo) and during the stay in the chamber and outside performed the same activities, i.e., walking on a treadmill at a speed of 0.5 km/h. The tests included assessing the central circulatory system using the Holter system and assessing the peripheral circulatory system using impedance plethysmography and Doppler ultrasound. The analysis of the parameters that describe the central and peripheral circulation poses a difficulty in determining which variant of exposure constitutes a greater load on the circulatory system. It should be noted that even the conditions used in the study may cause adverse effects in the cardiovascular system. PMID- 27118081 TI - Increased and prolonged human norovirus infection in RAG2/IL2RG deficient gnotobiotic pigs with severe combined immunodeficiency. AB - Application of genetically engineered (GE) large animals carrying multi-allelic modifications has been hampered by low efficiency in production and extended gestation period compared to rodents. Here, we rapidly generated RAG2/IL2RG double knockout pigs using direct injection of CRISPR/Cas9 system into developing embryos. RAG2/IL2RG deficient pigs were immunodeficient, characterized by depletion of lymphocytes and either absence of or structurally abnormal immune organs. Pigs were maintained in gnotobiotic facility and evaluated for human norovirus (HuNoV) infection. HuNoV shedding lasted for 16 days in wild type pigs, compared to 27 days (until the end of trials) in RAG2/IL2RG deficient pigs. Additionally, higher HuNoV titers were detected in intestinal tissues and contents and in blood, indicating increased and prolonged HuNoV infection in RAG2/IL2RG deficient pigs and the importance of lymphocytes in HuNoV clearance. These results suggest that GE immunodeficient gnotobiotic pigs serve as a novel model for biomedical research and will facilitate HuNoV studies. PMID- 27118083 TI - Ear-body lift and a novel thrust generating mechanism revealed by the complex wake of brown long-eared bats (Plecotus auritus). AB - Large ears enhance perception of echolocation and prey generated sounds in bats. However, external ears likely impair aerodynamic performance of bats compared to birds. But large ears may generate lift on their own, mitigating the negative effects. We studied flying brown long-eared bats, using high resolution, time resolved particle image velocimetry, to determine the aerodynamics of flying with large ears. We show that the ears and body generate lift at medium to cruising speeds (3-5 m/s), but at the cost of an interaction with the wing root vortices, likely reducing inner wing performance. We also propose that the bats use a novel wing pitch mechanism at the end of the upstroke generating thrust at low speeds, which should provide effective pitch and yaw control. In addition, the wing tip vortices show a distinct spiraling pattern. The tip vortex of the previous wingbeat remains into the next wingbeat and rotates together with a newly formed tip vortex. Several smaller vortices, related to changes in circulation around the wing also spiral the tip vortex. Our results thus show a new level of complexity in bat wakes and suggest large eared bats are less aerodynamically limited than previous wake studies have suggested. PMID- 27118084 TI - Chitosan nanoparticles enhance the efficiency of methylene blue-mediated antimicrobial photodynamic inactivation of bacterial biofilms: An in vitro study. AB - BACKGROUND: Biodegradable chitosan nanoparticles (CSNPs) with an intrinsic antimicrobial activity may be a good choice to improve the effectiveness of antimicrobial photodynamic inactivation (APDI). The aim of this study was to investigate the effect of CSNPs on the efficiency of methylene blue (MB)-mediated APDI of Staphylococcus aureus and Pseudomonas aeruginosa biofilms. We also assessed the phototoxicity of MB+CSNPs towards human fibroblasts. METHODS: CSNPs were prepared using ionic gelation method and characterized by dynamic light scattering (DLS) and field-emission scanning electron microscope (FESEM). Biofilms were developed in a 96-well polystyrene plate for 24h. In vitro phototoxic effect of MB+CSNPs (at final concentrations of 50MUM MB) at fluence of 22.93J/cm(2)) on biofilms were studied. Appropriate controls were included. Also, in vitro cytotoxicity and phototoxicity of the above mixture was assessed on human dermal fibroblasts. RESULTS: DLS and FESEM measurements confirmed the nanometric size of the prepared CSNPs. APDI mediated by the mixture of MB and CSNPs showed significant anti-biofilm photoinactivation (P<0.001, >3 and >2 log10 CFU reduction in S. aureus and P. aeruginosa biofilms, respectively) while MB induced APDI led to approximately <1 log10 CFU reduction. At the same experimental conditions, only 25.1% of the fibroblasts were photoinactivated by MB+CSNPs. CONCLUSION: Our findings showed that CSNPs enhanced the efficacy of MB APDI; it may be due to the disruption of biofilm structure by polycationic CSNPs and subsequently deeper and higher penetration of MB into the biofilms. PMID- 27118085 TI - Potential of curcumin-mediated photodynamic inactivation to reduce oral colonization. AB - OBJECTIVE: The present study assessed the susceptibility of salivary pathogens to photodynamic inactivation (PDI), mediated by a water-soluble mixture of curcuminoids (CRM) and LED light. METHODS: A 10mL sample of unstimulated saliva was collected from volunteers. The inoculum was prepared using 9mL of saline and 1mL of saliva. Inoculum suspensions were divided into 14 groups and treated according to the description below. Groups that received the PDI treatment (light for 1min or 5min and 1.5g/L or 3.0g/L of CRM concentration) were called C1.5L1.8, C1.5L9.0, C3.0L1.8, C3.0L9.0. To evaluate the CRM decontamination alone, the C1.5/1,C1.5/5,C3.0/1 and C3.0/5 groups were assessed. Likewise, light alone was evaluated through the L1.8 and L9.0 groups. Chlorhexidine at 0.12% (CLX) for 1 or 5min was used for the positive control groups (CLX1 and CLX5, respectively); saline was used for 1 or 5min (CTR1, CTR5, respectively) for the negative control groups. After the tests, serial dilutions were performed, and the resulting samples were plated on blood agar in microaerophilic conditions. The number of colony forming units (CFU/mL) was determined and log10-transformed. Data were analyzed using a One-way Analysis of Variance with Welch correction, followed by the Games Howell's test (alpha=0.05). Log reduction (LR) measure for antimicrobial efficacy was also calculated using data from the CTR5 as untreated samples. RESULTS: The CHX5 showed the best antimicrobial result, followed by the CLX1. The antimicrobial effect of CRM was more pronounced when associated with light (PDI), but significantly lower than the CLX5 effect. The C3.0L9.0 protocol showed similar results to the CLX1. CONCLUSION: The results show that PDI with CRM at the studied concentrations is as effective for oral decontamination in clinical dental care conditions as the CLX at 0.12% for 1min. PMID- 27118086 TI - Infection with Babesia microti in humans with non-specific symptoms in North East Poland. AB - AIM: The aim of the study was to evaluate the clinical course and effectiveness of diagnostics tools for Babesia spp. infection in patients bitten by ticks. MATERIALS AND METHODS: Five hundred and forty-eight patients hospitalised or seen in outpatients department because of various symptoms after a tick bite were included in the study. PCR, nucleotide sequencing of Babesia 18S rRNA gene fragment, blood smears and serological tests for Babesia spp., TBEV, A. phagocytophilum and B. burgdorferi were performed in all patients. Six patients infected with Babesia were included in the final analysis. They had PCR, Babesia 18S rRNA gene fragment nucleotide sequencing, blood smears and serological tests for Babesia spp., TBEV, A. phagocytophilum and B. burgdorferi performed twice. RESULTS: Tick-borne infection with Babesia microti in six immunocompetent patients with non-specific symptoms was confirmed for the first time in Poland. No severe course of the disease was seen. No piroplasm forms were noticed within erythrocytes on blood smear. Three patients developed a serological response. CONCLUSIONS: Immunocompetent patients may be unaware of infection with Babesia microti after a tick bite. It must be included in the differential diagnosis after the tick bite. In patients with low parasitaemia PCR and serology seem useful when blood smear is negative. Self-elimination of Babesia spp. is possible, especially in cases with low parasitaemia. PMID- 27118087 TI - Contour junctions underlie neural representations of scene categories in high level human visual cortex. AB - Humans efficiently grasp complex visual environments, making highly consistent judgments of entry-level category despite their high variability in visual appearance. How does the human brain arrive at the invariant neural representations underlying categorization of real-world environments? We here show that the neural representation of visual environments in scene-selective human visual cortex relies on statistics of contour junctions, which provide cues for the three-dimensional arrangement of surfaces in a scene. We manipulated line drawings of real-world environments such that statistics of contour orientations or junctions were disrupted. Manipulated and intact line drawings were presented to participants in an fMRI experiment. Scene categories were decoded from neural activity patterns in the parahippocampal place area (PPA), the occipital place area (OPA) and other visual brain regions. Disruption of junctions but not orientations led to a drastic decrease in decoding accuracy in the PPA and OPA, indicating the reliance of these areas on intact junction statistics. Accuracy of decoding from early visual cortex, on the other hand, was unaffected by either image manipulation. We further show that the correlation of error patterns between decoding from the scene-selective brain areas and behavioral experiments is contingent on intact contour junctions. Finally, a searchlight analysis exposes the reliance of visually active brain regions on different sets of contour properties. Statistics of contour length and curvature dominate neural representations of scene categories in early visual areas and contour junctions in high-level scene-selective brain regions. PMID- 27118089 TI - Plasma cardiac troponin I concentrations in healthy neonates, children and adolescents measured with a high sensitive immunoassay method: High sensitive troponin I in pediatric age. AB - Over the past 10years cardiac troponin (cTn) immunoassays have been improved in analytical sensitivity and precision thereby allowing the measurement of cTn in adult healthy subjects. However, there are currently substantial gaps in our knowledge on circulating levels of cTn in healthy children. The aim of this study is to evaluate the distribution of plasma troponin concentration in apparently healthy pediatric subjects using a high sensitive immunoassay for cTnI measurement (hs-cTnI). Blood samples were obtained from 357 healthy pediatric subjects [204 males; age range 0-18years; mean (SD): 8.7(6) years], including 36 subjects aged <1month (neonates), 57 between 1 and 12months (infants), 65 between 1 and 10years (toddlers), and 223 between 10 and 18years (adolescents). The percentages of healthy population with cTnI values equal or less than the calculated and LOD value were 13.1%. cTnI plasma levels were highest in the first month of life with a progressive decline in the next years and were lower in female. At multivariate analysis, only age was predictor of hs-cTnI plasma levels. The age and sex of children influence normal and physiologically released circulating concentrations of hs-cTnI, suggesting the need of reference intervals specific for age and sex. PMID- 27118090 TI - Results from external quality assurance (EQA) schemes should be interpreted with caution: A practical example. PMID- 27118088 TI - Classification of schizophrenia and bipolar patients using static and dynamic resting-state fMRI brain connectivity. AB - Recently, functional network connectivity (FNC, defined as the temporal correlation among spatially distant brain networks) has been used to examine the functional organization of brain networks in various psychiatric illnesses. Dynamic FNC is a recent extension of the conventional FNC analysis that takes into account FNC changes over short periods of time. While such dynamic FNC measures may be more informative about various aspects of connectivity, there has been no detailed head-to-head comparison of the ability of static and dynamic FNC to perform classification in complex mental illnesses. This paper proposes a framework for automatic classification of schizophrenia, bipolar and healthy subjects based on their static and dynamic FNC features. Also, we compare cross validated classification performance between static and dynamic FNC. Results show that the dynamic FNC significantly outperforms the static FNC in terms of predictive accuracy, indicating that features from dynamic FNC have distinct advantages over static FNC for classification purposes. Moreover, combining static and dynamic FNC features does not significantly improve the classification performance over the dynamic FNC features alone, suggesting that static FNC does not add any significant information when combined with dynamic FNC for classification purposes. A three-way classification methodology based on static and dynamic FNC features discriminates individual subjects into appropriate diagnostic groups with high accuracy. Our proposed classification framework is potentially applicable to additional mental disorders. PMID- 27118091 TI - Characterization of left atrial dysfunction in hypereosinophilic syndrome - Insights from the Motion analysis of the heart and great vessels by three dimensional speckle tracking echocardiography in pathological cases (MAGYAR-Path) Study. AB - INTRODUCTION: The present study was designed to compare three-dimensional speckle tracking echocardiography (3DSTE)-derived left atrial (LA) volumetric, volume based functional and strain parameters between patients with hypereosinophilic syndrome (HES) and matched controls. METHODS: A total of 10 HES patients and 19 age- and gender-matched healthy controls were included in the study. Complete two dimensional Doppler echocardiography and 3DSTE were performed in all HES cases and controls. RESULTS: Significantly increased maximum (72.9+/-38.8 ml vs. 45.6+/ 15.5 ml, p=0.01) and minimum (46.3+/-33.3 ml vs. 26.0+/-15.0 ml, p=0.03) LA volumes and LA volume before atrial contraction (62.0+/-36.0 ml vs. 36.5+/-16.6 ml, p=0.01) were found in HES patients compared to controls. Both peak global (18.3+/-6.7% vs. 25.6+/-9.0%, p=0.03) and mean segmental (22.2+/-6.0% vs. 31.0+/ 12.1%, p=0.04) circumferential strains were significantly reduced in HES patients, suggesting decreased LA reservoir function. CONCLUSION: Increased LA volumes can be demonstrated in HES patients, accompanied by reduced LA peak circumferential strain as assessed by 3DSTE, suggesting LA remodeling. PMID- 27118092 TI - Proteomic analysis associated with coronary artery dilatation caused by Kawasaki disease using serum exosomes. AB - INTRODUCTION: The aim of this study was to investigate the serum exosome proteome profile of coronary artery dilatation (CAD) caused by Kawasaki disease (KD). METHODS: Two-dimensional electrophoresis was implemented on proteins of serum exosomes obtained from children with CAD caused by KD and from healthy controls. Differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry analysis. RESULTS: We identified 38 differentially expressed proteins (13 up-regulated and 25 down-regulated) from serum exosomes of patients with CAD caused by KD compared with healthy controls. Expression levels of three differentially expressed proteins (leucine-rich alpha-2-glycoprotein, sex hormone-binding globulin, and serotransferrin) were validated using western blot analysis. Classification and protein-protein network analysis showed that they are associated with multiple functional groups involved in the acute inflammatory response, defense response, complement activation, humoral immune response, and response to wounding. The majority of the proteins are involved in the inflammation and coagulation cascades. CONCLUSIONS: These findings establish a comprehensive proteome profile of CAD caused by KD and increase our knowledge of scientific insight into its mechanisms. PMID- 27118093 TI - Computed tomography-guided pericardiocentesis - A single-center experience. AB - INTRODUCTION AND OBJECTIVES: Pericardial effusion is a common complication in clinical situations such as cardiothoracic surgery and cancer, in which pericardiocentesis may be essential. Pericardiocentesis can be guided by different imaging techniques, most commonly echocardiography. Computed tomography (CT) has significant advantages but there is still little evidence supporting its use in this context. In this work we describe our experience with CT-guided pericardiocentesis (CTP) in a single center. METHODS: Patients referred for CTP between August 2008 and February 2014 were retrospectively analyzed. We assessed demographics, etiology of the effusion, international normalized ratio during the procedure, radiation doses, success rate and complications. Results were compared with those in the literature. RESULTS: During this period, 51 procedures were performed, in 46 patients. Five patients underwent a repeat procedure due to recurrence of effusion. The most common etiologies were post-surgical (48%, 22 patients) and neoplasm-related (17%, eight patients). Drainage was considered completely successful in 46 cases (90%), partially successful in two (4%) and unsuccessful in three (6%). The median duration of the procedure was 65 min (interquartile range 50-80) and median effective radiation exposure was 3.3 mSv (interquartile range 2.4-5.2 mSv). There were no significant adverse events related to the procedure. CONCLUSIONS: By providing high-definition three dimensional images, CTP enables accurate positioning of pericardiocentesis material. It was shown to be an accurate, effective and safe method, in agreement with previous findings. CTP should be considered a good option in centers with CT facilities. PMID- 27118094 TI - Prevalence, predictors and prognosis of ventricular reverse remodeling in idiopathic dilated cardiomyopathy. AB - INTRODUCTION: Cardiac remodeling is manifested as changes in size, shape and function of the heart. We studied the prevalence, prognosis and predictors of left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (IDCM) after optimized medical therapy. METHODS: A total of 113 IDCM patients were followed for 7.1+/-5.6 years. LVRR was defined as an increase of 10 units in ejection fraction (EF) and decrease in left ventricular diastolic diameter (LVDD), in the absence of resynchronization therapy. RESULTS: Baseline EF was 27+/-8% and LVDD index was 37.1+/-6.3 mm/m(2). LVRR occurred in 34.5% within 22.6 months. Final EF was 47.5+/-10.1%, LVDD index was 30.2+/-3.9 mm/m(2). LVRR was associated with better NYHA class (I-II) and lower BNP (p<0.01) and all patients were alive. Univariate predictive factors of LVRR (p<0.05) were mild hypertension, atrial fibrillation, ventricular hypertrophy on ECG, absence of left bundle branch block, shorter QRS duration, higher hematocrit, lower LVDD index, higher peak oxygen uptake efficiency (VO2/log 10[VE]) and lower dVE/VCO2/VO2, treatment with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) and use of maximal doses of ACEI/ARB and beta-blockers. Multivariate regression analysis showed that higher doses of ACEI/ARB (OR: 0.32, 95% CI 0.11-0.92) were independently associated with LVRR. Non-transmural late enhancement on cardiac MRI was not a predictor of LVRR. CONCLUSIONS: LVRR occurred in one third of IDCM patients, especially in those with mild hypertension and with less advanced disease, who may have benefited from maximal drug titration. PMID- 27118096 TI - A closer look at acute heart failure: Putting Portuguese and European data into perspective. AB - INTRODUCTION AND OBJECTIVES: Acute heart failure (AHF) is a heterogeneous clinical syndrome requiring urgent therapy. The prognosis is poor after the index hospitalization, with a high risk for rehospitalization and early death. The costs of managing AHF are thus increasing rapidly. A literature review was performed to gather and compare data on prevalence and treatment and to identify gaps in AHF management, based on European and Portuguese studies. METHODS: A literature search from 1995 to 2014 was conducted in selected databases (BIOSIS Previews, EMBASE and Ovid MEDLINE). RESULTS AND DISCUSSION: Seven Portuguese and nine European studies were analyzed. The mean age of AHF patients was >=65 years and 30-50% were women. Coronary artery disease (42.3% vs. 61.9%) and hypertension (53.3% vs. 76.7%) were identified as primary etiologies in Europe and in Portugal. Similar proportions of heart failure with preserved ejection fraction were found in the Portuguese (19.9-44.7%) and European (32.8-39.1%) studies. Overall, all-cause mortality rates were comparable (six months: 9.3-25.5% vs. 13.5-27.4%; one year: 15.9-31% vs. 17.4-46.5%), as was in-hospital mortality (5.5 14% vs. 3.8-12%) in Portuguese and European studies, respectively. Length of stay was comparable. The studies were performed in very different hospital settings and data on treatment were scarce. CONCLUSIONS: Gaps were identified in treatment and clinical pathways of patients with AHF. Based on the results of this review, collection and investigation of data on the disease and treatment solutions, training in disease management, and improved organization of healthcare should be the subject of further investment. PMID- 27118095 TI - Two potentially fatal surprises in the preoperative assessment of an asymptomatic young adult. AB - Isolated left ventricular non-compaction is a rare disease classified as a primary genetic cardiomyopathy and is characterized by heart failure, systemic embolism and ventricular arrhythmias. The diagnosis is established by Doppler echocardiography. We report the case of an asymptomatic young adult, with no history of heart disease, who underwent preoperative assessment for low-risk orthopedic surgery. The electrocardiogram showed left bundle branch block, which prompted further investigation with Doppler echocardiography, cardiac computed tomography angiography and cardiac magnetic resonance imaging. A diagnosis of isolated left ventricular non-compaction and pulmonary embolism was made. Some aspects of preoperative assessment in low-risk surgical patients are discussed. PMID- 27118097 TI - Hemiarthroplasty versus reverse shoulder arthroplasty in 4-part displaced fractures of the proximal humerus: Multicenter retrospective study. AB - INTRODUCTION: Complex 4-part fractures of the proximal humerus are one of the most difficult fractures to manage. For several years, reverse total arthroplasty (RSA) has been proposed as an alternative to hemiarthroplasty (HA) when internal fixation is insufficient. The goal of this study was to compare the short and intermediate term results of these 2 different types of arthroplasty. MATERIALS AND METHODS: In a retrospective, multicenter study, 57 HA and 41 RSA were reviewed after a follow-up of at least 2 years. The clinical evaluation was based on the absolute and adjusted Constant scores, Simple shoulder value (SSV) and the quick-DASH scores. The radiological assessment included standard radiological tests. RESULTS: After a mean follow-up of 39 months, the RSA group had a significantly higher adjusted Constant score than the HA group (83% vs 73%, respectively P=0.02). However, there was no significant difference in the absolute Constant score, the quick-DASH or the SSV scores. Active anterior elevation was better in the RSA group, while internal rotation was better in the HA group (130 degrees vs 112 degrees , P=0.01; sacrum vs L3, P=0.03). There was no significant difference in external rotation (28 degrees vs 23 degrees , P=0.31). The rate of complications was higher in the HA group than in the RSA group (24% vs 10%, P=0.01). The radiological rate of union of the greater tuberosity was similar in both groups (70%) and scapular notching was found in 23% of the RSA group. CONCLUSION: The short and intermediate term clinical outcomes are better with RSA than with HA. The complication rate is higher with HA. Nevertheless, scapular notching occurred in more than 20% of patients with RSA, suggesting that care should be taken when using this prosthesis in young, active patients. PMID- 27118098 TI - Determining Waiting Room Occupancy at an Outpatient Clinic Using Simulated Observations and Probability-Duration Curves. AB - Adequate allocation of physical resources in hospitals has become increasingly important with the rise of health care costs. Seat utilization in outpatient clinic waiting rooms is one resource that is particularly important to monitor, to not only ensure patient satisfaction but also accommodate patient flow. Currently, very few studies are available on seat occupancy and patient flow in standard waiting rooms, and studies often neglect important factors, such as hourly patterns of patient influx and occupancy duration. These factors were taken into consideration in our study of visitor occupancy and patient flow in an imaging-facility waiting room. This paper discusses the simulated observation approach that we have developed, which coupled in-person observations with RIS data analysis. Using RIS data to guide our initial in-person observations, we built a model for simulated observations, based on the merged RIS and observation data. To determine the appropriate number of seats needed to accommodate patients and their companions, simulated observation results were analyzed using a probability-duration curve. This curve considers maximum room occupancies as temporal events, with certain probabilities and durations. We demonstrated how simulated observations and probability-duration curves can provide hospital managers with an efficient and pragmatic way to determine waiting room occupancy. PMID- 27118099 TI - Changing Utilization Patterns of Cervical Spine Imaging in the Emergency Department: Perspectives From Two Decades of National Medicare Claims. AB - PURPOSE: The aim of this study was to assess the changing use of emergency department (ED) cervical spine imaging in the Medicare population. METHODS: Using national aggregate Medicare claims data from 1994 through 2012, all cervical spine radiographic, CT, and MR examinations performed in the ED setting were identified. Shifts in modalities and providers and changes in utilization rates were studied. RESULTS: Between 1994 and 2004, ED cervical spine radiography volumes in the Medicare fee-for-service population increased from 203,645 to 306,442 (+50.5%) and then declined to 152,755 (-50.2%) by 2012. CT volumes increased every year, overall by +8,864% from 1994 through 2012 (from 6,360 to 570,121). MR grew by +1,381%, but volumes overall were small (from 944 to 13,979). With these changes, CT overtook radiography as the dominant ED cervical spine imaging modality in 2007. Per 1,000 Medicare beneficiaries, utilization rates of radiography, CT, and MR changed by -27%, +8,682%, and +1,351% from 1994 through 2012 (from 6.3 to 4.6, from 0.2 to 17.3, and from 0.0 to 0.4). For all years, compared with other specialists, radiologists remained by far the dominant providers of radiography, CT, and MR (+91.7%, +93.4%, and +96.0% in 1994 and +96.9%, +99.3%, and +99.0% in 2012) in the ED setting. CONCLUSIONS: Between 1994 and 2012, the overall utilization rate of cervical spine imaging for Medicare beneficiaries in the ED setting more than tripled. With a small decline in radiography (-27%) but a dramatic increase in CT (+8,864%), CT is now by far the dominant modality for imaging the cervical spine in the ED. Radiologists remain overwhelmingly the dominant providers of these interpretive services. PMID- 27118100 TI - Risk factors for cancer in the Australian Aboriginal and Torres Strait Islander population: a systematic review. AB - Cancer incidence in the Australian Aboriginal and Torres Strait Islander population is higher and survival lower compared with non-Indigenous Australians. A proportion of these cancers are potentially preventable if factors associated with carcinogenesis are known and successfully avoided. We conducted a systematic review of the published literature to examine risk factors for cancer in the Australian Aboriginal and Torres Strait Islander population. Electronic databases Medline, Web of Science and the Australian Aboriginal and Torres Strait Islander Health Bibliographic Index were searched through August 2014 using broad search terms. Studies reporting a measure of association between a risk factor and any cancer site in the Australian Aboriginal and Torres Strait Islander population were eligible for inclusion. Ten studies (1991-2014) were identified, mostly with small sample sizes, showing marked heterogeneity in terms of methods used to assess exposure and capture outcomes, and often using descriptive comparative analyses. Relatively young (as opposed to elderly) and geographically remote Aboriginal and Torres Strait Islanders were found to be at increased risk for selected cancers while most modifiable lifestyle and behavioural risk factors were rarely assessed. Further studies examining associations between potential risk factors and cancer will help define public health policy for cancer prevention in the Australian Aboriginal and Torres Strait Islander population. PMID- 27118101 TI - Microfluidics for simultaneous quantification of platelet adhesion and blood viscosity. AB - Platelet functions, including adhesion, activation, and aggregation have an influence on thrombosis and the progression of atherosclerosis. In the present study, a new microfluidic-based method is proposed to estimate platelet adhesion and blood viscosity simultaneously. Blood sample flows into an H-shaped microfluidic device with a peristaltic pump. Since platelet aggregation may be initiated by the compression of rotors inside the peristaltic pump, platelet aggregates may adhere to the H-shaped channel. Through correlation mapping, which visualizes decorrelation of the streaming blood flow, the area of adhered platelets (APlatelet) can be estimated without labeling platelets. The platelet function is estimated by determining the representative index IA.T based on APlatelet and contact time. Blood viscosity is measured by monitoring the flow conditions in the one side channel of the H-shaped device. Based on the relation between interfacial width (W) and pressure ratio of sample flows to the reference, blood sample viscosity (MU) can be estimated by measuring W. Biophysical parameters (IA.T, MU) are compared for normal and diabetic rats using an ex vivo extracorporeal model. This microfluidic-based method can be used for evaluating variations in the platelet adhesion and blood viscosity of animal models with cardiovascular diseases under ex vivo conditions. PMID- 27118103 TI - Corrigendum to "DHEA improves the antioxidant capacity of endometrial stromal cells and improves endometrium receptivity via androgen receptor" [Eur. J. Obstet. Gynecol. Reprod. Biol. 198 (2016) 120-126]. PMID- 27118102 TI - Real-world treatment practice in patients with advanced melanoma in the era before ipilimumab: results from the IMAGE study. AB - The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second line/subsequent treatment (index therapy) for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had >=1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued index treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months (95% confidence interval [CI], 2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies. PMID- 27118104 TI - Adsorption of Lysine on Na-Montmorillonite and Competition with Ca(2+): A Combined XRD and ATR-FTIR Study. AB - Lysine adsorption at clay/aqueous interfaces plays an important role in the mobility, bioavailability, and degradation of amino acids in the environment. Knowledge of these interfacial interactions facilitates our full understanding of the fate and transport of amino acids. Here, X-ray diffraction (XRD) and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) measurements were used to explore the dynamic process of lysine adsorption on montmorillonite and the competition with Ca(2+) at the molecular level. Density functional theory (DFT) calculations were employed to determine the peak assignments of dissolved lysine in the solution phase. Three surface complexes, including dicationic, cationic, and zwitterionic structures, were observed to attach to the clay edge sites and penetrate the interlayer space. The increased surface coverage and Ca(2+) competition did not affect the interfacial lysine structures at a certain pH, whereas an elevated lysine concentration contributed to zwitterionic-type coordination at pH 10. Moreover, clay dissolution at pH 4 could be inhibited at a higher surface coverage with 5 and 10 mM lysine, whereas the inhibition effect was inconspicuous or undetected at pH 7 and 10. The presence of Ca(2+) not only could remove a part of the adsorbed lysine but also could facilitate the readsorption of dissolved Si(4+) and Al(3+) and surface protonation. Our results provide new insights into the process of lysine adsorption and its effects on montmorillonite surface sites. PMID- 27118105 TI - Correlates of attitudes and perceived behavioural control towards oral care provision among trained and untrained nursing home caregivers in Singapore. AB - AIMS AND OBJECTIVES: To investigate the perspectives of nursing home caregivers towards oral care and the determinants of their attitudes and perceived behavioural control. BACKGROUND: There are few studies analysing nursing home caregivers' perspectives on the provision of oral care and factors correlated with these perspectives. DESIGN: Cross-sectional study. METHODS: Interviewer administered survey questionnaires were completed by caregivers from five nursing homes in Singapore (n = 94). The rating-scale questionnaire items explored caregivers' attitudes, subjective norms and perceived behavioural control, as guided by the theory of planned behaviour. Demographic characteristics, oral care training received, years of work experience, oral hygiene behaviour and dental visit frequency of the caregivers, as well as organisational characteristics such as a requirement for oral care and the number of patients under their care, were obtained. RESULTS: Caregivers had very positive attitudes towards the provision of oral care. Half of the caregivers lacked confidence in providing oral care without harming the patients and this was not different by oral care training received. Multivariable linear regression analysis found that receiving oral care training and having a requirement by the nursing home to provide oral care were related to higher attitude scores but not perceived behaviour control. Having more residents under their care and on-the-job caregiver training were associated with lower perceived behavioural control. CONCLUSIONS: This study found that nursing home caregivers had positive attitudes towards providing oral care, but more modest perspectives about their ability to perform that behaviour. RELEVANCE TO CLINICAL PRACTICE: These findings have useful implications for the oral care training of nursing home caregivers. While attitudes towards the importance of oral care may be positive among nursing home caregivers, our study suggests that future interventions should include practical skills training for oral care management and consider organisational strategies for encouraging oral care provision. PMID- 27118106 TI - Study of the binding mechanism between aptamer GO18-T-d and gonyautoxin 1/4 by molecular simulation. AB - GTX1/4 can induce the formation of an antiparallel G-quadruplex structure in aptamer GO18-T-d and combine steadily in the groove at the top of the G quadruplex structure. The complex structures and special induced fit mechanism between aptamer and small molecules provide a reference for aptamer development in molecular diagnostics and therapeutic application. PMID- 27118107 TI - Suppression of plasma free fatty acids reduces myocardial lipid content and systolic function in type 2 diabetes. AB - BACKGROUND AND AIM: Type 2 diabetes (T2DM) is closely associated with the development of heart failure, which might be related with impaired substrate metabolism and accumulation of myocardial lipids (MYCL). The aim of this study was to investigate the impact of an acute pharmacological inhibition of adipose tissue lipolysis leading to reduced availability of circulating FFA on MYCL and heart function in T2DM. METHODS AND RESULTS: 8 patients with T2DM (Age: 56 +/- 11; BMI: 28 +/- 3.5 kg/m(2); HbA1c: 7.29 +/- 0.88%) were investigated on two study days in random order. Following administration of Acipimox or Placebo MYCL and heart function were measured by (1)H-magnetic-resonance-spectroscopy and tomography at baseline, at 2 and at 6 h. Acipimox reduced circulating FFA by -69% (p < 0.001), MYCL by -39 +/- 41% (p < 0.001) as well as systolic heart function (Ejection Fraction (EF): -13 +/- 8%, p = 0.025; Cardiac Index: -16 +/- 15%, p = 0.063 compared to baseline). Changes in plasma FFA concentrations strongly correlated with changes in MYCL (r = 0.707; p = 0.002) and EF (r = 0.651; p = 0.006). Diastolic heart function remained unchanged. CONCLUSIONS: Our results indicate, that inhibition of adipose tissue lipolysis is associated with a rapid depletion of MYCL-stores and reduced systolic heart function in T2DM. These changes were comparable to those previously found in insulin sensitive controls. MYCL thus likely serve as a readily available energy source to cope with short time changes in FFA availability. PMID- 27118110 TI - Effects of Temperature and Photoperiod on the Reproductive Biology and Diapause of Oobius agrili (Hymenoptera: Encyrtidae), an Egg Parasitoid of Emerald Ash Borer (Coleoptera: Buprestidae). AB - Oobius agrili Zhang and Huang (Hymenoptera: Encyrtidae) is a solitary egg parasitoid of the invasive emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), and has been introduced to the United States for classical biological control. We characterized the weekly survivorship, fecundity, and diapause patterns of both diapaused and nondiapaused populations of O. agrili under four different temperature-photophase combinations: 30 degrees C (warm) and 20 degrees C (cold) temperatures with both long-day (16 h) and short day (8 h) photophase. Results of this study showed that regardless of the length of photophase, parental parasitoids of both diapaused and nondiapaused O. agrili survived significantly longer at 20 degrees C than at 30 degrees C. Both populations also laid their eggs faster at 30 degrees C compared with those at 20 degrees C. Higher proportions of the progeny produced by both populations of O. agrili were induced into diapause by short-day (8 h) photophase, regardless of rearing temperature. In addition, the diapaused parasitoids in the short-day photophase treatment at both warm and cold temperatures produced increasing proportions of diapaused progeny over time, whereas no significant differences were observed in the proportions of diapaused progeny by the nondiapaused parasitoids over different sampling times. These findings suggest that O. agrili should be continuously reared under warm temperature and long-day photoperiod (to avoid diapause for increased reproduction). In addition, we recommend that diapaused adults be used for field releases in early summer when temperatures are still relatively low (~20 degrees C) and host eggs are available so that they can produce multiple generations prior to overwintering. PMID- 27118108 TI - Effects of moderate beer consumption on health and disease: A consensus document. AB - A large evidence-based review on the effects of a moderate consumption of beer on human health has been conducted by an international panel of experts who reached a full consensus on the present document. Low-moderate (up to 1 drink per day in women, up to 2 in men), non-bingeing beer consumption, reduces the risk of cardiovascular disease. This effect is similar to that of wine, at comparable alcohol amounts. Epidemiological studies suggest that moderate consumption of either beer or wine may confer greater cardiovascular protection than spirits. Although specific data on beer are not conclusive, observational studies seem to indicate that low-moderate alcohol consumption is associated with a reduced risk of developing neurodegenerative disease. There is no evidence that beer drinking is different from other types of alcoholic beverages in respect to risk for some cancers. Evidence consistently suggests a J-shaped relationship between alcohol consumption (including beer) and all-cause mortality, with lower risk for moderate alcohol consumers than for abstainers or heavy drinkers. Unless they are at high risk for alcohol-related cancers or alcohol dependency, there is no reason to discourage healthy adults who are already regular light-moderate beer consumers from continuing. Consumption of beer, at any dosage, is not recommended for children, adolescents, pregnant women, individuals at risk to develop alcoholism, those with cardiomyopathy, cardiac arrhythmias, depression, liver and pancreatic diseases, or anyone engaged in actions that require concentration, skill or coordination. In conclusion, although heavy and excessive beer consumption exerts deleterious effects on the human body, with increased disease risks on many organs and is associated to significant social problems such as addiction, accidents, violence and crime, data reported in this document show evidence for no harm of moderate beer consumption for major chronic conditions and some benefit against cardiovascular disease. PMID- 27118111 TI - Oviposition Preferences of Pickleworm (Lepidoptera: Crambidae) in Relation to a Potential Push-Pull Cropping Management Approach. AB - Pickleworm, Diaphania nitidalis Cramer (Lepidoptera: Crambidae), is a major pest of cucurbits. The current management approach for this pest is weekly insecticide applications. A push-pull cropping approach may be an alternative management practice and could reduce reliance on pesticides. One potential push-pull scenario is the use of squash (Cucurbita pepo L.) as a trap crop and watermelon (Citrullus lanatus [Thunb.] Matsum. & Nakai) as a deterrent intercrop to manage pickleworm on cantaloupe (Cucumis melo L.). This study investigated if the underlying mechanism required for the success of this management approach (a female oviposition preference or nonpreference among squash, cantaloupe, and watermelon) is present. A series of oviposition preference experiments was conducted to see how individual females responded when presented with different host plants for oviposition. Under laboratory conditions, when females had the choice of a leaf from squash, cantaloupe, and watermelon, they laid a higher proportion of their eggs on the cantaloupe leaf. However, under greenhouse conditions, when females were presented with whole plants of the three different species, they laid a higher percent of their eggs on the squash plant. Females laid a similar number of eggs on watermelon as compared with cantaloupe under greenhouse conditions, and appeared to not be averse to laying their eggs on watermelon. However, when presented with a noncucurbit, such as bean, females laid a low number of total eggs. Overall, it appears that squash may be more preferred as an oviposition substrate than cantaloupe or watermelon and may be a useful trap crop or pull. Further study to determine a suitable deterrent intercrop or push and evaluation of the proposed system under field conditions are needed. PMID- 27118109 TI - Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. AB - This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B cell non-Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28-d cycles of 85 mg/m(2) pixantrone dimaleate (equivalent to 50 mg/m(2) in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2-6) with pixantrone and 3 (2-6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23.1% vs. 5.1% comparator, P = 0.047) and overall response rate (ORR, 43.6% vs. 12.8%, P = 0.005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45.0% vs. 11.1%, P = 0.033), CR (30.0% vs. 5.6%, P = 0.093) and progression-free survival (median 5.4 vs. 2.8 months, hazard ratio 0.52, 95% confidence interval 0.26-1.04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B-cell NHL in the 3rd or 4th line setting, independently of previous rituximab. PMID- 27118112 TI - Uteroplacental Insufficiency Alters the Retinoid Pathway and Lung Development in Newborn Rats. AB - BACKGROUND: Intrauterine growth retardation (IUGR) is associated with reduced lung function during infancy and perhaps throughout adulthood. The retinoic acid (RA) signaling pathway modulates pre- and postnatal lung development. This study was conducted to test our hypothesis that uteroplacental insufficiency alters the elements of the retinoid pathway in developing lungs. METHODS: On Gestation Day 18, either uteroplacental insufficiency was induced through bilateral uterine vessel ligation (IUGR group) or sham surgery (control group) was performed. Lung tissues from the offspring were examined through Western blotting, immunohistochemistry, and morphometry on Postnatal Day 3 and Postnatal Day 7. RESULTS: Compared with control rats, the IUGR rats exhibited significantly lower body weights on Postnatal Day 3 and Postnatal Day 7 and significantly lower lung weights on Postnatal Day 3. Uteroplacental insufficiency significantly increased RA receptor (RAR)-beta protein expression on Postnatal Day 3. The expression of RAR-alpha, RAR-gamma, cellular RA-binding protein-1, and cellular RA-binding protein-2 between the control and IUGR rats was comparable on Postnatal Day 3 and Postnatal Day 7. Compared with the control rats, the IUGR rats exhibited a significantly higher volume fraction of alveolar airspace on Postnatal Day 3 and Postnatal Day 7 and a significantly lower volume fraction of alveolar walls on Postnatal Day 3. CONCLUSION: Uteroplacental insufficiency causes defective alveolarization and transient increases in RAR-beta expression in the lungs of newborn rats. The retinoid pathway may be one of the probable pathways mediating lung abnormalities caused by uteroplacental insufficiency. PMID- 27118113 TI - Nationwide Population-Based Epidemiologic Study of Hirschsprung's Disease in Taiwan. PMID- 27118114 TI - From research to practice: dissemination of the Contraceptive CHOICE Project. AB - Unintended pregnancy is a public health problem with societal consequences. The Contraceptive CHOICE Project (CHOICE) demonstrated a reduction in teen pregnancy and abortion by removing barriers to effective contraception. The purpose of the study was to describe the dissemination approach used to create awareness of and promote desire to adopt the CHOICE model among selected audiences. We used a 4 stage approach and detail the work completed in the first 2 stages. We describe stakeholder involvement in the first stage and the process of undertaking core strategies in the second stage. We examine insights gained throughout the process. Through our dissemination approach, we reached an estimated 300,000 targeted individuals, not including the population reached through media. We were contacted by 141 entities for technical assistance. The completion and reporting of dissemination processes is an important component of research. There is a need to fully document and disseminate strategies that can help facilitate practice change. PMID- 27118117 TI - Stroke and aphasia quality-of-life scale-39: Reliability and validity of the Turkish version. AB - PURPOSE: The aim of this study was to adapt the stroke and aphasia quality-of life scale-39 (SAQoL-39) to the Turkish language and carry out a reliability and validity study of the instrument in a group of patients with aphasia. METHOD: The study was a descriptive study and contained three phases: adaptation of the SAQoL 39 to the Turkish language, administration of the scale to 30 aphasia patients and reliability and validity studies of the scale. Internal consistency was assessed with Cronbach's alpha and test-re-test reliability was explored (n = 14). The adaptation process was completed based on inter-rater agreement on the translated items and within the scope of final editing by the authors of the study. RESULT: The SAQoL-39 in Turkish exhibited high test-re-test reliability (ICC =0.97) as well as acceptability with minimal missing data (0-1.4). This instrument exhibited high internal consistency (Cronbach's alpha = 0.70-0.97), domain-total correlations (r = 0.76-0.85) and inter-domain correlations (r = 0.40 0.68). CONCLUSION: The analysis shows that the Turkish version of SAQoL-39 is a scale that is highly acceptable, valid and reliable and can be easily used in evaluating the quality-of-life of Turkish people with aphasia. PMID- 27118115 TI - Exploring the theoretical pathways through which asthma app features can promote adolescent self-management. AB - Asthma apps often lack strong theoretical underpinnings. We describe how specific features of asthma apps influenced adolescents' self-observation, self-judgment, and self-reactions, which are key constructs of Self-Regulation Theory (SRT). Adolescents (ages 12-16) with persistent asthma (n = 20) used two asthma self management apps over a 1-week period. During semi-structured interviews, participants identified their asthma goals and the app features that best promoted self-observation, self-judgment, and fostered positive self-reactions. Interviews were digitally recorded, transcribed verbatim, and analyzed thematically using MAXQDA. Adolescents' goals were to reduce the impact of asthma on their lives. Adolescents reported that self-check quizzes, reminders, and charting features increased their ability to self-observe and self-judge their asthma, which, in turn, helped them feel more confident they could manage their asthma independently and keep their asthma well-controlled. Asthma apps can positively influence adolescents' self-management behaviors via increased self observation, self-judgment, and increased self-efficacy. PMID- 27118116 TI - Filimonas zeae sp. nov., an endophytic bacterium isolated from maize root. AB - A novel Gram-stain-negative, aerobic, motile by gliding and filamentous strain, designated 772T,was isolated from surface-sterilized root tissue of maize planted in the Fangshan District of Beijing, China. 16S rRNA gene sequence analysis indicated that strain 772T was closely related to Filimonas endophytica SR2-06T andFilimonas lacunae YT21T of the family Chitinophagaceae with sequence similarities of 99.0 and 96.9 %, respectively. However, the new isolate exhibited relatively low levels of DNA-DNA relatedness with respect to Filimonas. endophytica KCTC 42060T (18.7+/-1.8 %) and Filimonas. lacunae DSM 21054T (17.9+/ 2.0%). The DNA G+C content of strain 772T was 44.9 mol%. The respiratory quinone was menaquinone-7 and the polar lipid profile consisted of phosphatidylethanolamine, two unidentified aminophospholipids, two unidentified phospholipids and one unidentified lipid. The major fatty acids were iso-C15 : 0 and iso-C15 : 1 G. The results of the physiological and biochemical tests and minor differences in the fatty acid profiles allowed the clear phenotypic differentiation of strain 772T from the closely related species Filimonas. endophytica andF. lacunae. Strain 772T thus represents a novel species within the genus Filimonas, for which the name Filimonas zeae sp. nov. is proposed. The type strain is 772T (=CGMCC 1.15290T=DSM 100760T). PMID- 27118118 TI - The impact of caesarean section on breastfeeding initiation, duration and difficulties in the first four months postpartum. AB - BACKGROUND: The caesarean section (c-section) rate in Canada is 27.1%, well above the 5-15% of deliveries suggested by the World Health Organization in 2009. Emergency and planned c-sections may adversely affect breastfeeding initiation, milk supply and infant breastfeeding receptivity compared to vaginal deliveries. Our study examined mode of delivery and breastfeeding initiation, duration, and difficulties reported by mothers at 4 months postpartum. METHODS: The All Our Babies study is a prospective pregnancy cohort in Calgary, Alberta, that began in 2008. Participants completed questionnaires at <25 and 34-36 weeks gestation and approximately 4 months postpartum. Demographic, mental health, lifestyle, and health services data were obtained. Women giving birth to singleton infants were included (n = 3021). Breastfeeding rates and difficulties according to mode of birth (vaginal, planned c-section and emergency c-section) were compared using cross-tabulations and chi-square tests. A multivariable logistic regression model was created to examine the association between mode of birth on breastfeeding duration to 12 weeks postpartum. RESULTS: More women who delivered by planned c section had no intention to breastfeed or did not initiate breastfeeding (7.4% and 4.3% respectively), when compared to women with vaginal births (3.4% and 1.8%, respectively) and emergency c-section (2.7% and 2.5%, respectively). Women who delivered by emergency c-section were found to have a higher proportion of breastfeeding difficulties (41%), and used more resources before (67%) and after (58%) leaving the hospital, when compared to vaginal delivery (29%, 40%, and 52%, respectively) or planned c-sections (33%, 49%, and 41%, respectively). Women who delivered with a planned c-section were more likely (OR = 1.61; 95% CI: 1.14, 2.26; p = 0.014) to discontinue breastfeeding before 12 weeks postpartum compared to those who delivered vaginally, controlling for income, education, parity, preterm birth, maternal physical and mental health, ethnicity and breastfeeding difficulties. CONCLUSIONS: We found that when controlling for socio-demographic and labor and delivery characteristics, planned c-section is associated with early breastfeeding cessation. Anticipatory guidance around breastfeeding could be provided to women considering a planned c-section. As well, additional supportive care could be made available to lactating women with emergency c sections, within the first 24 hours post birth and throughout the early postpartum period. PMID- 27118119 TI - Use of class I histone deacetylase inhibitor romidepsin in combination regimens. AB - Histone deacetylase (HDAC) inhibitors are epigenetic-modifying agents that have shown promise as anticancer therapies. Several HDAC inhibitors have been approved by the US Food and Drug Administration (FDA) as single-agent therapies to treat T cell lymphoma. The synergistic combination of HDAC inhibitors with other anticancer agents has the potential to constitute treatment regimens with enhanced efficacy. Romidepsin is a structurally unique, potent, bicyclic class 1 selective HDAC inhibitor approved by the FDA for the treatment of patients with peripheral T-cell lymphoma who have had at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have had at least 1 prior systemic therapy. Here, we review data that support the use of romidepsin in combination with other anticancer agents for the treatment of various malignancies. Promising results have emerged from early clinical studies, supporting the potential for romidepsin combination regimens to constitute safe and effective treatments for cancer. PMID- 27118121 TI - [Value of intraoperative frozen section of sentinel lymph node in breast cancer. Retrospective study about 293 patients]. AB - OBJECTIVES: Intraoperative positive frozen section of sentinel axillary lymph node in breast cancer allows the full node dissection at the same time of the breast surgery and the enhancement of adjuvant therapies with no delay. The low frequency of node involvement and the high rate of false-negative, make consider the value of intraoperative frozen section. The aim of this study was to analyze the potential advantage of intraoperative frozen section performed routinely. METHODS: Retrospective monocentric study of 293 patients, operated on for stage pT1 or pT2 breast cancer with a sentinel node biopsy (SNB). RESULTS: A total of 289 patients had an intraoperative frozen section of the SNB. A sentinel node was identified in 98.6% of the cases. On intraoperative section, sentinel node was negative, positive or was not performed in 252 (86%), 37 (12.6%) and 4 (1.4%) cases respectively. In total, ibtraoperative frozen sections identified 48.7% of the metastatic SNB (37/76). The metastatic lymph node distribution, after final histological analysis, was as follows: 17% macro metastasis, 5.8% micro metastasis and 3% isolated tumor cells. The false-negatives rate was 13.5%. Fifty eight patients (19.8%) underwent axillary full lymph node dissection: 39 during a primary surgery and 19 during a secondary one. Histological analysis of the lymph nodes was totally negative in 62% of cases. Intraoperative frozen sections benefited to 12.8% of the patients who had their full lymph node dissection at the same surgery. CONCLUSION: The intraoperative frozen section of SNB benefits to a limited number of patients, due to its high rate of false-negatives. Sensitivity of frozen sections could be lowered if the preoperative axillary ultrasound examination becomes a routine, which would question its value. PMID- 27118122 TI - [How I do... mini-invasive vaginal hysterectomy using thermofusion]. PMID- 27118120 TI - Chaperonin 60 regulation of SOX9 ubiquitination mitigates the development of knee osteoarthritis. AB - Articular cartilage integrity loss is a prominently deleterious feature of osteoarthritis (OA). The mechanistic underlying the development of OA warrants characterization. Heat shock proteins (HSPs), members of the chaperone family, reportedly orchestrate tissue homeostasis and remodeling in response to detrimental stress. This study was undertaken to characterize the biological role of HSP60 in the pathogenesis of OA knee. Articular specimens from OA knee patients displayed severe articular damage histopathology concomitant with low HSP60 concentrations in cartilage and synovial fluid compared to non-OA patients. In vitro, a gain of HSP60 signaling counteracted the IL-1beta-mediated suppression of mitochondrial biogenesis, chondrogenic transcription factor SOX9, and cartilage matrix expression of human chondrocytes cultures. Transgenic mice that overexpressed human HSP60 (TgHSP60) had higher chondrocyte proliferation and thicker articular cartilage than wild-type mice. In collagenase-induced OA knees, analyses of CatWalk, 2-deoxyglucose-probed fluorescence imaging, and MUCT revealed that affected knees of TgHSP60 mice showed minor footprint irregularity, joint inflammation, and osteophyte formation. HSP60 overexpression also alleviated the histopathology of cartilage damage, synovial hypervascularization, and macrophage infiltration within joint lesions. Intra-articular administration of exogenous HSP60 ameliorated the pathogenesis of cartilage deterioration, synovitis, and osteophyte accumulation, thereby improving gait profiles of the collagenase-injured knees. HSP60 signaling maintains SOX9 levels by attenuating SOX9 hyper-ubiquitination of affected joints. Taken together, HSP60 deficiency in articular compartments was relevant to OA knee incidence. Sustained HSP60 signaling is favorable to mitigate the progression of OA. This study highlights the joint-anabolic actions of HSP60 and provides perspective on its therapeutic potential for OA. KEY MESSAGES: HSP60 deficiency is relevant to the existence of end-stage knee osteoarthritis. HSP60 overexpression attenuates cartilage matrix loss of inflammatory chondrocytes. HSP60 transgenic mice showed mild articular injury during knee osteoarthritis. HSP60 maintains knee joint homeostasis through reducing SOX9 ubiquitination. Control of cartilage-anabolic regulator HSP60 ameliorates knee osteoarthritis. PMID- 27118123 TI - Penalized estimation for competing risks regression with applications to high dimensional covariates. AB - High-dimensional regression has become an increasingly important topic for many research fields. For example, biomedical research generates an increasing amount of data to characterize patients' bio-profiles (e.g. from a genomic high throughput assay). The increasing complexity in the characterization of patients' bio-profiles is added to the complexity related to the prolonged follow-up of patients with the registration of the occurrence of possible adverse events. This information may offer useful insight into disease dynamics and in identifying subset of patients with worse prognosis and better response to the therapy. Although in the last years the number of contributions for coping with high and ultra-high-dimensional data in standard survival analysis have increased (Witten and Tibshirani, 2010. Survival analysis with high-dimensional covariates. Statistical Methods in Medical Research 19: (1), 29-51), the research regarding competing risks is less developed (Binder and others, 2009. Boosting for high dimensional time-to-event data with competing risks. Bioinformatics 25: (7), 890 896). The aim of this work is to consider how to do penalized regression in the presence of competing events. The direct binomial regression model of Scheike and others (2008. Predicting cumulative incidence probability by direct binomial regression. Biometrika 95: (1), 205-220) is reformulated in a penalized framework to possibly fit a sparse regression model. The developed approach is easily implementable using existing high-performance software to do penalized regression. Results from simulation studies are presented together with an application to genomic data when the endpoint is progression-free survival. An R function is provided to perform regularized competing risks regression according to the binomial model in the package timereg (Scheike and Martinussen, 2006. Dynamic Regression models for survival data New York: Springer), available through CRAN. PMID- 27118124 TI - Therapeutic Work as a Facilitator for Return to Paid Work in Cancer Survivors. AB - Purpose The increase of flexible employment in European labour markets has contributed to workers' risk of job loss. For sick-listed workers with chronic illnesses, such as cancer, and especially those without an employment contract, participation in therapeutic work may be an important step towards paid employment. The purpose of this study was to determine the role of therapeutic employment as facilitator for return to paid work, in a cohort of sick-listed cancer survivors (CSs) with and without an employment contract. Methods In this longitudinal study, data were used from a cohort of Dutch CSs (N = 192), who applied for disability benefits after 2 years of sick leave. The primary outcome measure was return to paid work after 1 year. Logistic regression analysis was applied. Results Of the participating CSs (mean age 50.7 years, 33 % male), 69 % had an employment contract at baseline. CSs without an employment contract participated significantly less in therapeutic work (p < 0.001) and were less likely to return to paid work after 1 year (p = 0.001), than those with a contract. Participation in therapeutic work significantly increased the chance of return to paid work after 1 year (OR 6.97; 95 % CI 2.94-16.51), adjusted for age, gender, level of work disability and having an employment contract. Conclusions Participation in therapeutic work could be an important facilitator for return to paid work in sick-listed CSs. The effectiveness of therapeutic work as a means to return to paid employment for sick-listed workers should be studied in an experimental setting. PMID- 27118125 TI - Homotypic cell competition regulates proliferation and tiling of zebrafish pigment cells during colour pattern formation. AB - The adult striped pattern of zebrafish is composed of melanophores, iridophores and xanthophores arranged in superimposed layers in the skin. Previous studies have revealed that the assembly of pigment cells into stripes involves heterotypic interactions between all three chromatophore types. Here we investigate the role of homotypic interactions between cells of the same chromatophore type. Introduction of labelled progenitors into mutants lacking the corresponding cell type allowed us to define the impact of competitive interactions via long-term in vivo imaging. In the absence of endogenous cells, transplanted iridophores and xanthophores show an increased rate of proliferation and spread as a coherent net into vacant space. By contrast, melanophores have a limited capacity to spread in the skin even in the absence of competing endogenous cells. Our study reveals a key role for homotypic competitive interactions in determining number, direction of migration and individual spacing of cells within chromatophore populations. PMID- 27118126 TI - The 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma: the "evidence-based" refusal to endorse them by EANM due to the "not evidence-based" marginalization of the role of Nuclear Medicine. PMID- 27118127 TI - Prognostic impact of incomplete surgical clearance of radioiodine sensitive local lymph node metastases diagnosed by post-operative (124)I-NaI-PET/CT in patients with papillary thyroid cancer. AB - PURPOSE: Nodal involvement is an independent risk factor of recurrence in papillary thyroid cancer (PTC). Neither the international guidelines nor the recently introduced ongoing risk adaptation concept consider the extent of initial surgical clearance of radioiodine sensitive lymph node metastases in their stratification systems. We investigated the prognostic relevance of incomplete initial surgical clearance in patients with purely lymphogeneous metastatic PTC (pN1 M0) despite successful radioiodine therapy. Accurate assessment of pre-ablative nodal status was attempted using PET/CT studies with both (124)I-NaI and (18)F-FDG along with high-resolution cervical ultrasound. METHODS: Sixty-five patients with histologically diagnosed lymph node metastases (pN1 M0) were retrospectively analyzed. Patients with iodine-negative lymph node metastases diagnosed by (18)F-FDG PET/CT or distant metastases were excluded from the analysis. The association of disease recurrence with the pre-ablative nodal status, as well as other baseline characteristics, were examined applying nonparametric tests for independent samples and multiple regression analysis. Patients with persistent lymph node metastases in (124)I-NaI PET/CT were further divided according to the additional presence or absence of FDG-uptake in (18)F FDG PET/CT. Survival analyses were performed using Kaplan-Meier curves and the Cox proportional hazards model for uni- and multivariate analyses to assess the influence of prognostic factors on progression free survival (PFS). RESULTS: Incomplete metastatic lymph node resection captured by (124)I-NaI PET/CT (n = 33) was an independent risk factor for recurrence (61 % vs 25 %, p = 0.006) and shorter PFS (46 months vs not reached, HR 4.0 [95 %-CI, 1.7-9.2], p = 0.001). Ultrasound could detect lymph node metastases only in 19/33 patients (58 %). Among patients with positive nodal status, FDG-avidity of metastatic iodine positive lymph nodes worsened the outcome (16 vs 69 months, p = 0.047). From all other investigated factors including age, N-stage (N1a vs N1b), and T-Stage (T4 vs T1-3), only large tumor size (pT4) had a significant impact on PFS (HR 2.9 [95 %-CI, 1.3-6.4], p = 0.007). CONCLUSIONS: Incomplete initial surgical clearance of lymph node metastases even after successful radioiodine therapy may increase the chances of recurrence and is an independent risk factor for impaired survival of patients with PTC. Pre-ablative (dual tracer PET/CT) imaging with (124)I-Na and (18)F provides a prognostic tool for these patients and may considerably complement the current risk stratification systems. PMID- 27118128 TI - Carboxyspermidine decarboxylase of the prominent intestinal microbiota species Bacteroides thetaiotaomicron is required for spermidine biosynthesis and contributes to normal growth. AB - Recent studies have indicated that polyamines produced by gut microbes significantly influence host health; however, little is known about the microbial polyamine biosynthetic pathway except for that in Escherichia coli, a minor component of the gastrointestinal microbiota. Here, we investigated the polyamine biosynthetic ability of Bacteroides thetaiotaomicron, a predominant gastrointestinal bacterial species in humans. High-performance liquid chromatography analysis revealed that B. thetaiotaomicron cultured in polyamine free minimal medium accumulated spermidine intracellularly at least during the mid-log and stationary phases. Deletion of the gene encoding a putative carboxyspermidine decarboxylase (casdc), which converts carboxyspermidine to spermidine, resulted in the depletion of spermidine and loss of decarboxylase activity in B. thetaiotaomicron. The Deltacasdc strain also showed growth defects in polyamine-free growth medium. The complemented Deltacasdc strain restored the spermidine biosynthetic ability, decarboxylase activity, and growth. These results indicate that carboxyspermidine decarboxylase is essential for synthesizing spermidine in B. thetaiotaomicron and contributes to the growth of this species. PMID- 27118129 TI - No clear benefit or drawback to the use of closed drainage after primary total knee arthroplasty: a systematic review and meta-analysis. AB - BACKGROUND: Closed drainage after primary total knee arthroplasty (TKA) has been used routinely for many decades, but controversies have arisen in recent years. The purposes of this study were to compare the clinical outcomes of closed drainage with nondrainage after primary TKA; and to assess the benefit and drawback of closed drainage. METHODS: Electronic databases (PubMed/Medline, CENTRAL, Embase and Web of Science) were systematically searched for randomised controlled trials (RCTs) that investigated the efficacy and risks of closed drainage after primary TKA. Two investigators independently reviewed studies for eligibility, assessed the risk of bias and extracted the data. A meta-analysis was then performed using Review Manager Software. RESULTS: Twelve RCTs totalling 889 TKAs were identified. No significant differences in infection rate or blood loss were found between the closed drainage and nondrainage TKAs, and there was also no significant difference in haematoma formation, deep venous thrombosis, postoperative VAS score or range of motion between the two groups. CONCLUSIONS: There appears to be no clear benefit or drawback to the use of closed drainage after primary TKA. Improving the use of closed drainage might provide better outcomes. PMID- 27118130 TI - On-plot drinking water supplies and health: A systematic review. AB - Many studies have found that household access to water supplies near or within the household plot can reduce the probability of diarrhea, trachoma, and other water-related diseases, and it is generally accepted that on-plot water supplies produce health benefits for households. However, the body of research literature has not been analyzed to weigh the evidence supporting this. A systematic review was conducted to investigate the impacts of on-plot water supplies on diarrhea, trachoma, child growth, and water-related diseases, to further examine the relationship between household health and distance to water source and to assess whether on-plot water supplies generate health gains for households. Studies provide evidence that households with on-plot water supplies experience fewer diarrheal and helminth infections and greater child height. Findings suggest that water-washed (hygiene associated) diseases are more strongly impacted by on-plot water access than waterborne diseases. Few studies analyzed the effects of on plot water access on quantity of domestic water used, hygiene behavior, and use of multiple water sources, and the lack of evidence for these relationships reveals an important gap in current literature. The review findings indicate that on-plot water access is a useful health indicator and benchmark for the progressive realization of the Sustainable Development Goal target of universal safe water access as well as the human right to safe water. PMID- 27118132 TI - Production and turnover of ectomycorrhizal extramatrical mycelial biomass and necromass under elevated CO2 and nitrogen fertilization. AB - Extramatrical mycelia (EMM) of ectomycorrhizal fungi are important in carbon (C) and nitrogen (N) cycling in forests, but poor knowledge about EMM biomass and necromass turnovers makes the quantification of their role problematic. We studied the impacts of elevated CO2 and N fertilization on EMM production and turnover in a Pinus taeda forest. EMM C was determined by the analysis of ergosterol (biomass), chitin (total bio- and necromass) and total organic C (TOC) of sand-filled mycelium in-growth bags. The production and turnover of EMM bio- and necromass and total C were estimated by modelling. N fertilization reduced the standing EMM biomass C to 57% and its production to 51% of the control (from 238 to 122 kg C ha(-1) yr(-1) ), whereas elevated CO2 had no detectable effects. Biomass turnover was high (~13 yr(-1) ) and unchanged by the treatments. Necromass turnover was slow and was reduced from 1.5 yr(-1) in the control to 0.65 yr(-1) in the N-fertilized treatment. However, TOC data did not support an N effect on necromass turnover. An estimated EMM production ranging from 2.5 to 6% of net primary production stresses the importance of its inclusion in C models. A slow EMM necromass turnover indicates an importance in building up forest humus. PMID- 27118133 TI - Brain STAT5 signaling and behavioral control. AB - Several growth factors and cytokines recruit the signal transducer and activator of transcription 5 (STAT5) signaling pathway to control cell proliferation, differentiation and apoptosis. Nonetheless, the importance of this transcription factor for brain functions is still poorly understood. Because some STAT5 inducing hormones, such as prolactin and leptin, act in the brain to regulate the expression of motivated behaviors, this signaling pathway is likely involved in behavioral modulation. Therefore, the objective of the present review was to summarize and discuss the available data regarding the possible role of central STAT5 signaling in the regulation of brain functions, especially on behavioral control. We discussed studies that investigated the importance of STAT5 signaling in the regulation of maternal and feeding behaviors. Additionally, we highlighted other behaviors that could be potentially affected by STAT5 signaling. This knowledge may help to understand how motivated behaviors are regulated at the cellular level. PMID- 27118134 TI - A place for the hippocampus in the cocaine addiction circuit: Potential roles for adult hippocampal neurogenesis. AB - Cocaine addiction is a chronic brain disease in which the drug seeking habits and profound cognitive, emotional and motivational alterations emerge from drug induced neuroadaptations on a vulnerable brain. Therefore, a 'cocaine addiction brain circuit' has been described to explain this disorder. Studies in both cocaine patients and rodents reveal the hippocampus as a main node in the cocaine addiction circuit. The contribution of the hippocampus to cocaine craving and the associated memories is essential to understand the chronic relapsing nature of addiction, which is the main obstacle for the recovery. Interestingly, the hippocampus holds a particular form of plasticity that is rare in the adult brain: the ability to generate new functional neurons. There is an active scientific debate on the contributions of these new neurons to the addicted brain. This review focuses on the potential role(s) of adult hippocampal neurogenesis (AHN) in cocaine addiction. Although the current evidence primarily originates from animal research, these preclinical studies support AHN as a relevant component for the hippocampal effects of cocaine. PMID- 27118135 TI - Animal models of Central Diabetes Insipidus: Human relevance of acquired beyond hereditary syndromes and the role of oxytocin. AB - The aim of this study was to review different animal models of Central Diabetes Insipidus, a neurobiological syndrome characterized by the excretion of copious amounts of diluted urine (polyuria), a consequent water intake (polydipsia), and a rise in the serum sodium concentration (hypernatremia). In rodents, Central Diabetes Insipidus can be caused by genetic disorders (Brattleboro rats) but also by various traumatic/surgical interventions, including neurohypophysectomy, pituitary stalk compression, hypophysectomy, and median eminence lesions. Regardless of its etiology, Central Diabetes Insipidus affects the neuroendocrine system that secretes arginine vasopressin, a neurohormone responsible for antidiuretic functions that acts trough the renal system. However, most Central Diabetes Insipidus models also show disorders in other neurobiological systems, specifically in the secretion of oxytocin, a neurohormone involved in body sodium excretion. Although the hydromineral behaviors shown by the different Central Diabetes Insipidus models have usually been considered as very similar, the present review highlights relevant differences with respect to these behaviors as a function of the individual neurobiological systems affected. Increased understanding of the relationship between the neuroendocrine systems involved and the associated hydromineral behaviors may allow appropriate action to be taken to correct these behavioral neuroendocrine deficits. PMID- 27118136 TI - Malaria, helminths and malnutrition: a cross-sectional survey of school children in the South-Tongu district of Ghana. AB - BACKGROUND: As part of malaria characterization study in the South-Tongu district of Ghana, the current study was conducted to explore relationships between malaria, schistosomiasis, soil transmitted helminths and malnutrition in riparian community settings that had hitherto encountered episodes of mass deworming exercises. METHODS: School-age children were enrolled in a cross-sectional study from April through July 2012. Stool and urine samples were examined respectively for helminths and Schistosoma haematobium. Blood samples were analyzed for malaria parasites and haemoglobin (Hb) concentrations, respectively. Anthropometric indices were measured. Relationships were determined using generalized linear models. RESULTS: The results show low numbers of asymptomatic Plasmodium falciparum (9.2%, n = 37/404) and S. haematobium (2.5%, n = 10/404) infections. The associations between significance terms in the multivariate analysis for P. falciparum infections were further assessed to test the significance of the product terms directly i.e., age in years [adjusted odds ratio (AOR), 3.1; 95% confidence interval (CI) 1.1-5.6], Hb concentration (AOR = 0.71; 95% CI 0.42-2.3), and stunted malnutrition (AOR, 8.72; 95% CI 4.8-25.1). The P. falciparum-associated decrease in mean Hb concentration was 2.82 g/dl (95% CI 1.63-4.1 g/dl; P = 0.001) in stunted children, and 0.75 g/dl (95% CI 1.59 0.085 g/dl; P = 0.076) in the non-stunted cohort. The anaemia-associated decrease in mean parasitaemia in stunted children was 3500 parasites/ul of blood (95% CI 262.46-6737.54 parasites/ul of blood; P = 0.036), and in non-stunted children 2127 parasites/ul of blood (95% CI -0.27 to 4.53; P = 0.085). Stunted malnutrition was the strongest predictor of S. haematobium infection (AOR = 11; 95% CI 3.1-33.6) but significant associations as described for P. falciparum infections were absent. The population attributable risk of anaemia due to P. falciparum was 6.3% (95% CI 2.5-9.3), 0.9% (95% CI 0.4-2.3) for S. haematobium, and 12.5% (95% CI 9.11-19.52) for stunted malnutrition. CONCLUSION: Plasmodium falciparum, S. haematobium, intestinal helminths and their co-infections were uncommon in our school-age children. Stunting exacerbated the extent to which malaria was associated with loss in Hb concentration. PMID- 27118137 TI - The tobacco paradox in acute coronary syndrome. The prior cessation of smoking as a marker of a better short-term prognosis. AB - OBJECTIVE: The tobacco paradox is a phenomenon insufficiently explained by previous studies. This study analyses the prognostic role of prior or active smoking in patients with acute coronary syndrome. METHODS: We obtained data from the ARIAM registry, between 2001 and 2012. The study included 42,827 patients with acute coronary syndrome (mean age, 65+/-13 years; 26.4% women). The influence of smoking and that of being an ex-smoker on mortality was analysed using a multivariate analysis. RESULTS: The smokers were younger, were more often men, had less diabetes, hypertension and prior history of heart failure, stroke, arrhythmia and renal failure and more frequently had ST-elevation and a family history of smoking. The ex-smokers had more dyslipidaemia and history of angina, myocardial infarction, ischemic heart disease, peripheral vasculopathy and chronic bronchial disease. Smokers and ex-smokers less frequently developed cardiogenic shock (smokers 4.2%, ex-smokers 4.7% and nonsmokers 6.9%, P<.001). Hospital mortality was 7.8% for the nonsmokers, 4.9% for the ex-smokers and 3.1% for the smokers (P<.001). In the multivariate analysis, the smoker factor lost its influence in the prognosis (-0.26%, p=.52 using an inverse probability calculation; and+0.26%, P=.691 using a propensity analysis). However, the exsmoker factor showed a significant reduction in mortality in both tests (-2.4% in the inverse probability analysis, P<.001; and -1.5% in the propensity analysis, P=.005). CONCLUSIONS: The tobacco paradox is a finding that could be explained by other prognostic factors. Smoking cessation prior to hospitalization for acute coronary syndrome is associated with a better prognosis. PMID- 27118138 TI - The Prevalence of Food Security and Insecurity Among Illinois University Students. AB - OBJECTIVE: This study aims to define the food security status of Illinois university students and whether sociodemographic characteristics are related to that status. DESIGN: A cross-sectional research design was used to analyze the food security status of undergraduate Illinois university students, employing a survey containing the Household Food Security Survey Module that was distributed via e-mail to student participants. SETTING: Four public Illinois universities were highlighted, including Eastern Illinois University, Northern Illinois University, Southern Illinois University, and Western Illinois University. PARTICIPANTS: A total of 1,882 undergraduate students participated in the research study in April, 2013. MAIN OUTCOME MEASURE: Variables include food security status and sociodemographic characteristics such as age, sex, race, and academic standing. ANALYSIS: Statistical analysis included frequencies and chi square tests. RESULTS: The percentage of student respondents in the total sample who were considered food insecure was 35.0%. There were significant relationships between food security status and sociodemographic variables including race, grade point average, loan use, and living location. CONCLUSIONS AND IMPLICATIONS: This study suggests that 35% of respondents were food insecure based on quantitative assessment. Understanding the significant relationship between food security status and race, grade point average, loan use, and living location may be useful in developing services for those in need. PMID- 27118139 TI - Atractylenolide I modulates ovarian cancer cell-mediated immunosuppression by blocking MD-2/TLR4 complex-mediated MyD88/NF-kappaB signaling in vitro. AB - BACKGROUND: TLR4/MD-2 complex-mediated MyD88-dependent activation of NF-kappaB and Akt promotes tumor-associated immunosuppression in epithelial ovarian cancer (EOC) via induction of immunesuppressive cytokines and indoleamine 2,3 dioxygenase (IDO). Atractylenolide I (AO-1) is a naturally occurring sesquiterpene lactone known to change the conformational ensemble of human MD-2 on EOC cells. This study examined the modulation by AO-1 of TLR4/MD-2 complex mediated MyD88/NF-kappaB signaling. METHODS: The expression and activation of NF kappaB, Akt and IDO1 by MyD88(+) EOC SKOV3 cells was determined using western blot; the TLR4/MD-2 complex on SKOV3 cells and the phenotype of T lymphocytes were determined using flow cytometry; IDO activity was evaluated by measuring L kynurenine; Immunesuppressive cytokines were detected using ELISA; T-cell proliferation to mitogen stimulation was assessed by MTT assay; the cytotoxicity of lymphocytes and NK cells was measured using LDH-cytotoxicity assay. RESULTS: AO-1 could down-regulate expression of TLR4/MD-2 complex, resulting in downregulation of MyD88/NF-kappaB signaling and activation of NF-kappaB, Akt and IDO1 and secretion of IL-6, TGF-beta1, VEGF and IL-17A by EOC SKOV3 cells, and further reduce increased levels of regulatory T cells (Treg cells) and improve decreased proliferative response and antitumor cytotoxicity of T lymphocytes exposed to EOC SKOV3 cell supernatant. CONCLUSION: AO-1 may reverse EOC cell mediated immunosuppression through blocking TLR4/MD-2 complex-mediated MyD88/NF kappaB signaling. PMID- 27118140 TI - Influence of body mass index on outcomes after minimal-access aortic valve replacement through a J-shaped partial upper sternotomy. AB - BACKGROUND: Minimal-access aortic valve replacement (MAAVR) may reduce post operative blood loss and transfusion requirements, decrease post-operative pain, shorten length stay and enhance cosmesis. This may be particularly advantageous in overweight/obese patients, who are at increased risk of post-operative complications. Obese patients are however often denied MAAVR due to the perceived technical procedural difficulty. This retrospective analysis sought to determine the effect of BMI on post-operative outcomes in patients undergoing MAAVR. METHODS: Ninety isolated elective MAAVR procedures performed between May 2006 October 2013 were included. Intra- and post-operative data were prospectively collected. Ordinary least squares univariate linear regression analysis was performed to determine the effect of BMI as a continuous variable on post operative outcomes. One-way ANOVA and Chi-squared testing was used to assess differences in outcomes between patients with BMI <25 (n = 36) and BMI >=25 (n = 54) as appropriate. RESULTS: There was no peri-operative mortality, myocardial infarction or stroke. Univariate regression demonstrated longer cross-clamp times (p = 0.0218) and a trend towards increased bypass times (p = 0.0615) in patients with higher BMI. BMI >=25 was associated with an increased incidence of hospital acquired pneumonia (p = 0.020) and new-onset atrial fibrillation (p = 0.036) compared to BMI <25. However, raised BMI did not extend ICU (p = 0.3310) or overall hospital stay (p = 0.2614). Similar rates of sternal wound complications, inotrope requirements and renal dysfunction were observed in both normal- and overweight/obese-BMI groups. Furthermore, increasing BMI correlated with reduced mechanical ventilation time (p = 0.039) and early post-operative blood loss (p = 0.004). CONCLUSIONS: Our results demonstrate that within the range of this study, MAAVR is a safe, reproducible and effective procedure, affording equivalent clinical outcomes in both overweight/obese and normal-weight patients considered for an isolated first-time AVR, with low post-operative morbidity and mortality. MAAVR should therefore be considered as an alternative surgical strategy to reduce obesity-related complications in patients requiring aortic valve replacement. PMID- 27118141 TI - Determination of the foraging behaviour and blood meal source of malaria vector mosquitoes in Trincomalee District of Sri Lanka using a multiplex real time polymerase chain reaction assay. AB - BACKGROUND: Studies of host preference patterns in blood-feeding anopheline mosquitoes are crucial to incriminating malaria vectors. However, little information is available on host preferences of Anopheles mosquitoes in Sri Lanka. METHODS: Adult Anopheles mosquitoes were collected from five selected sentinel sites in Trincomalee District during June-September 2011. Each blood-fed mosquito was processed on filter papers. DNA was extracted using the dried blood meal protocol of the QIAmp DNA mini kit. A multiplexed, real-time PCR assay targeting eight animals was developed for two panels to identify the host meal of Anopheles. Human blood index (HBI), forage ratio (FR) and host feeding index (HFI) were calculated. RESULTS: A total of 280 field-caught, freshly engorged female mosquitoes belonging to 12 anopheline species were analysed. The overall HBI and HFI in the present study were low indicating that humans were not the preferred host for the tested anopheline species. Nevertheless, a small proportion engorged Anopheles aconitus, Anopheles culicifacies, Anopheles barbirostris, Anopheles annularis, Anopheles subpictus, Anopheles peditaeniatus, Anopheles pseudojamesi, and Anopheles barbumbrosus contained human blood. CONCLUSION: The presence of human blood in mosquito species indicates the possibility of them transmitting malaria. Further studies on vector competence are needed to determine the role of each of the above anopheline species as efficient vectors of malaria. PMID- 27118142 TI - Diagnostic approach to cardiac amyloidosis: A case report. AB - The authors present a case of systemic amyloidosis with cardiac involvement. We discuss the need for a high level of suspicion to establish a diagnosis, diagnostic techniques and treatment options. Our patient was a 78-year-old man with chronic renal disease and atrial fibrillation admitted with acute decompensated heart failure of unknown cause. The transthoracic echocardiogram revealed severely impaired left ventricular function with phenotypic overlap between hypertrophic and restrictive cardiomyopathy. After an extensive diagnostic workup, which included an abdominal fat pad biopsy, the final diagnosis was amyloidosis. PMID- 27118144 TI - Are current ICER thresholds outdated? Valuing medicines in the era of personalized healthcare. PMID- 27118145 TI - Successful antiviral treatment of chronic hepatitis C leads to a rapid decline of liver stiffness without an early effect on spleen stiffness. PMID- 27118143 TI - Integrative analysis of the Trypanosoma brucei gene expression cascade predicts differential regulation of mRNA processing and unusual control of ribosomal protein expression. AB - BACKGROUND: Trypanosoma brucei is a unicellular parasite which multiplies in mammals (bloodstream form) and Tsetse flies (procyclic form). Trypanosome RNA polymerase II transcription is polycistronic, individual mRNAs being excised by trans splicing and polyadenylation. We previously made detailed measurements of mRNA half-lives in bloodstream and procyclic forms, and developed a mathematical model of gene expression for bloodstream forms. At the whole transcriptome level, many bloodstream-form mRNAs were less abundant than was predicted by the model. RESULTS: We refined the published mathematical model and extended it to the procyclic form. We used the model, together with known mRNA half-lives, to predict the abundances of individual mRNAs, assuming rapid, unregulated mRNA processing; then we compared the results with measured mRNA abundances. Remarkably, the abundances of most mRNAs in procyclic forms are predicted quite well by the model, being largely explained by variations in mRNA decay rates and length. In bloodstream forms substantially more mRNAs are less abundant than predicted. We list mRNAs that are likely to show particularly slow or inefficient processing, either in both forms or with developmental regulation. We also measured ribosome occupancies of all mRNAs in trypanosomes grown in the same conditions as were used to measure mRNA turnover. In procyclic forms there was a weak positive correlation between ribosome density and mRNA half-life, suggesting cross-talk between translation and mRNA decay; ribosome density was related to the proportion of the mRNA on polysomes, indicating control of translation initiation. Ribosomal protein mRNAs in procyclics appeared to be exceptionally rapidly processed but poorly translated. CONCLUSIONS: Levels of mRNAs in procyclic form trypanosomes are determined mainly by length and mRNA decay, with some control of precursor processing. In bloodstream forms variations in nuclear events play a larger role in transcriptome regulation, suggesting aquisition of new control mechanisms during adaptation to mammalian parasitism. PMID- 27118146 TI - Detection of driver pathways using mutated gene network in cancer. AB - Distinguishing driver pathways has been extensively studied because they are critical for understanding the development and molecular mechanisms of cancers. Most existing methods for driver pathways are based on high coverage as well as high mutual exclusivity, with the underlying assumption that mutations are exclusive. However, in many cases, mutated driver genes in the same pathways are not strictly mutually exclusive. Based on this observation, we propose an index for quantifying mutual exclusivity between gene pairs. Then, we construct a mutated gene network for detecting driver pathways by integrating the proposed index and coverage. The detection of driver pathways on the mutated gene network consists of two steps: raw pathways are obtained using a CPM method, and the final driver pathways are selected using a strict testing strategy. We apply this method to glioblastoma and breast cancers and find that our method is more accurate than state-of-the-art methods in terms of enrichment of KEGG pathways. Furthermore, the detected driver pathways intersect with well-known pathways with moderate exclusivity, which cannot be discovered using the existing algorithms. In conclusion, the proposed method provides an effective way to investigate driver pathways in cancers. PMID- 27118147 TI - Discovery of new MD2 inhibitor from chalcone derivatives with anti-inflammatory effects in LPS-induced acute lung injury. AB - Acute lung injury (ALI) is a life-threatening acute inflammatory disease with limited options available for therapy. Myeloid differentiation protein 2, a co receptor of TLR4, is absolutely required for TLR4 sense LPS, and represents an attractive target for treating severe inflammatory diseases. In this study, we designed and synthesized 31 chalcone derivatives that contain the moiety of (E)-4 phenylbut-3-en-2-one, which we consider the core structure of current MD2 inhibitors. We first evaluated the anti-inflammatory activities of these compounds in MPMs. For the most active compound 20, we confirmed that it is a specific MD2 inhibitor through a series of biochemical experiments and elucidated that it binds to the hydrophobic pocket of MD2 via hydrogen bonds with Arg(90) and Tyr(102) residues. Compound 20 also blocked the LPS-induced activation of TLR4/MD2 -downstream pro-inflammatory MAPKs/NF-kappaB signaling pathways. In a rat model with ALI induced by intracheal LPS instillation, administration with compound 20 exhibited significant protective effect against ALI, accompanied by the inhibition of TLR4/MD2 complex formation in lung tissues. Taken together, the results of this study suggest the specific MD2 inhibitor from chalcone derivatives we identified is a potential candidate for treating acute inflammatory diseases. PMID- 27118148 TI - The Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN) Study: Design and Methods for Complex DNA Analysis. AB - The Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure (InterGEN) study aims to delineate the independent and interaction effects of genomic (genetic and epigenetic) and psychological-environmental (maternally perceived racial discrimination, mental health, and parenting behavior) factors on blood pressure (BP) among African American mother-child dyads over time. The purpose of this article is to describe the two-step genetic and epigenetic approach that will be executed to explore Gene * Environment interactions on BP using a longitudinal cohort design. Procedure for the single collection of DNA at Time 1 includes the use of the Oragene 500-format saliva sample collection tube, which provides enough DNA for both the Illumina Multi Ethnic Genotyping and 850K EPIC methylation analyses. BP readings, height, weight, percentage of body fat, and percentage of body water will be measured on all participants every 6 months for 2 years for a total of 4 time points. Genomic data analyses to be completed include multivariate modeling, assessment of population admixture and structure, and extended analyses including Bonferroni correction, false discovery rate methods, Monte Carlo approach, EIGENSTRAT methods, and so on, to determine relationships among both main and interaction effects of genetic, epigenetic, and psychological environmental factors on BP. PMID- 27118150 TI - Early warning epidemic surveillance in the Pacific island nations: an evaluation of the Pacific syndromic surveillance system. AB - OBJECTIVE: The Pacific Syndromic Surveillance System (PSSS), launched in 2010, provides a simple mechanism by which 121 sentinel surveillance sites in 21 Pacific island countries and areas perform routine indicator- and event-based surveillance for the early detection of infectious disease outbreaks. This evaluation aims to assess whether the PSSS is meeting its objectives, what progress has been made since a formative evaluation of the system was conducted in 2011, and provides recommendations to enhance the PSSS's performance in the future. METHODS: Twenty-one informant interviews were conducted with national operators of the system and regional public health agencies that use information generated by it. Historic PSSS data were analysed to assess timeliness and completeness of reporting. RESULTS: The system is simple, acceptable and useful for public health decision-makers. The PSSS has greatly enhanced Pacific island countries' ability to undertake early warning surveillance and has contributed to efforts to meet national surveillance-related International Health Regulation (2005) capacity development obligations. Despite this, issues with timeliness and completeness of reporting, data quality and system stability persist. CONCLUSION: A balance between maintaining the system's simplicity and technical advances will need to be found to ensure its long-term sustainability, given the low-resource context for which it is designed. PMID- 27118149 TI - Risk and predictors of hepatocellular carcinoma for chronic hepatitis B patients with newly developed cirrhosis. AB - BACKGROUND AND AIMS: Most studies on risk predictors of hepatocellular carcinoma (HCC) among cirrhotic chronic hepatitis B patients do not confirm the date at cirrhosis diagnosis. We examined HCC risk and predictors in chronic hepatitis B patients with newly diagnosed cirrhosis. METHODS: 4155 HBsAg seropositive participants were followed every 6-12 months with seromarker testing. Cirrhosis was ascertained through abdominal ultrasonography and computerized linkage with national health insurance profiles. Predictors included in Cox proportional hazards models were age, HBeAg serostatus, serum levels of HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and ALDH2 rs671 genotypes. RESULTS: A total of 301 patients developed cirrhosis, 76 of whom later developed HCC after 2462 person-years, showing an average annual incidence of 3.1%. The 15 year cumulative HCC risk among cirrhotics was 39.8% with a lifetime (30-80 years old) HCC risk of 78.5%. The adjusted HR's (95% CI, P-value) were 14.26 (3.17 64.08, P = 0.0005) for age at cirrhosis diagnosis of >=60 years (vs 30-39 years), 2.85 (1.49-5.46, P = 0.0015) for HBeAg seropositivity (vs HBeAg seronegativity with HBsAg levels <1000 IU/mL), 0.35 (0.20-0.59, P < 0.0001) for AA/AG genotypes of rs671 (vs GG genotype), 3.68 (1.70-7.99, P = 0.0010) for ALT levels >45 U/L (vs <15 U/L), 3.52 (1.78-6.93, P = 0.0003) for AFP levels >20 ng/mL (vs <10 ng/mL), and 2.64 (1.38-5.07, P = 0.0035) for HBsAg levels >=1000 IU/mL (vs <1000 IU/mL among HBeAg seronegatives). CONCLUSIONS: Older age, GG genotype of ALDH2 rs671, HBeAg seropositivity, and elevated serum levels of ALT, AFP, and HBsAg at cirrhosis diagnosis were HCC risk predictors in cirrhotic chronic hepatitis B patients. PMID- 27118151 TI - Arsenic in private well water part 1 of 3: Impact of the New Jersey Private Well Testing Act on household testing and mitigation behavior. AB - Regularly ingesting water with elevated arsenic increases adverse health risks. Since September 2002, the NJ Private Well Testing Act (PWTA) has required testing untreated well water for arsenic during real estate transactions in 12 counties. Its implementation provides an opportunity to investigate the effects of policy intervention on well testing and treatment behavior. Here we analyze results of a survey mailed to 1943 random addresses (37% response), including responses from 502 private well households who purchased their homes prior to PWTA commencement and 168 who purchased after. We find the PWTA has significantly increased arsenic testing rates in an area where 21% of wells contain arsenic above the 5MUg/L NJ drinking water standard. The PWTA has allowed identification of more wells with arsenic (20% of post-PWTA vs. 4% of pre-PWTA households) and more treatment for arsenic (19% of post-PWTA vs. 3% of pre-PWTA households). Such an Act is a partial answer to significant socioeconomic disparities in testing observed among households for whom it is not required. Additionally residents purchasing homes since 2002 are younger and disproportionately more likely to have children in their household (60% vs. 32%), a priority group given their particular vulnerability to effects of arsenic. Despite more wells tested under the PWTA, post-PWTA well owners forget or misremember arsenic test results more often, are more likely to report not knowing what kind of treatment they are using, and are not reporting better maintenance or monitoring of their treatment systems than pre-PWTA households. This suggests serious challenges to reducing arsenic exposure remain even when testing is a requirement. Furthermore, only a fraction of wells have been tested under the PWTA due to the slow pace of housing turnover. We recommend more public resources be made available to support private well testing among socially and biologically vulnerable groups. PMID- 27118152 TI - Size and Fiber Density Controlled Synthesis of Fibrous Nanosilica Spheres (KCC 1). AB - We report a facile protocol for the synthesis of fibrous nano-silica (KCC-1) with controllable size and fiber density. In this work, we have shown that the particle size, fiber density, surface area and pore volume of KCC-1 can be effectively controlled and tuned by changing various reaction parameters, such as the concentrations of urea, CTAB, 1-pentanol, reaction time, temperature, solvent ratio, and even outside stirring time. For the first time, we were able to control the particle size ranging from as small as 170 nm to as large as 1120 nm. We were also able to control the fiber density from low to medium to very dense, which consequently allowed the tuning of the pore volume. We were able to achieve a pore volume of 2.18 cm(3)/g, which is the highest reported for such a fibrous material. Notably we were even able to increase the surface area up to 1244 m(2)/g, nearly double the previously reported surface area of KCC-1. Thus, one can now synthesize KCC-1 with various degrees of size, surface area, pore volume, and fiber density. PMID- 27118153 TI - Dissection of allelic interactions among Pto-miR257 and its targets and their effects on growth and wood properties in Populus. AB - MicroRNAs (miRNAs) have important roles in the regulation of genes; however, for trees few studies have explored the potential impact of the interactions between miRNAs and their target genes. Here, we performed transcript profiling and association genetics (single-SNP, haplotype-based and multi-SNP associations) to study the genetic regulatory relationship of Pto-miR257 and its 12 target genes in 435 individuals of a natural population of Populus tomentosa. Expression profiling of Pto-miR257 and its targets showed a negative relationship between their expression levels. Of the 61 single-nucleotide polymorphisms (SNPs) detected in Pto-miR257, 6 in the pre-mature region strongly affected its secondary stability and 1 in the mature region could alter its target spectrum. Among the 1029 SNPs in the targets, 3 were located in target sites that could change the binding affinity of Pto-miR257. Single-SNP association analysis revealed that SNPs in Pto-miR257 and target genes associated with both growth and wood property traits, in agreement with haplotype-based identifications. Multi SNP association found that 10 targets shared at least one common trait with Pto miR257, with phenotypic variance from 0.5 to 8.5%, suggesting a possible internal genetic interaction between them. Epistasis analysis showed significant epistatic interactions among Pto-miR257 and its targets. Therefore, our study demonstrated Pto-miR257 and its 12 targets had roles in wood formation and revealed the genetic interaction network between the miRNA and its targets under additive, dominant and epistatic models. Thus, association genetics can be used to decipher the interactions between miRNAs and their target genes and to help understand the genetic architecture of complex traits. PMID- 27118154 TI - Improvement in nitrogen fixation capacity could be part of the domestication process in soybean. AB - Biological nitrogen fixation (BNF) in soybeans is a complex process involving the interplay between the plant host and the symbiotic rhizobia. As nitrogen supply has a crucial role in growth and development, higher nitrogen fixation capacity would be important to achieve bigger plants and larger seeds, which were important selection criteria during plant domestication by humans. To test this hypothesis, we monitored the nitrogen fixation-related performance in 31 cultivated and 17 wild soybeans after inoculation with the slow-growing Bradyrhizobium diazoefficiens sp. nov. USDA110 and the fast-growing Sinorhizobium (Ensifer) fredii CCBAU45436. Our results showed that, in general, cultivated soybeans gave better performance in BNF. Electron microscopic studies indicated that there was an exceptionally high accumulation of poly-beta-hydroxybutyrate bodies in bacteroids in the nodules of all wild soybeans tested, suggesting that the C/N balance in wild soybeans may not be optimized for nitrogen fixation. Furthermore, we identified new quantitative trait loci (QTLs) for total ureides and total nodule fresh weight by employing a recombinant inbred population composed of descendants from a cross between a cultivated and a wild parent. Using nucleotide diversity (thetapi), divergence index (Fst) and distribution of fixed single-nucleotide polymorphisms as parameters, we found that some regions in the total ureides QTL on chromosome 17 and the total nodule fresh weight QTL on chromosome 12 exhibited very low diversity among cultivated soybeans, suggesting that these were traits specially selected during the domestication and breeding process. PMID- 27118155 TI - Moderate genetic drift is driven by extreme recruitment events in the invasive mollusk Crepidula fornicata. AB - Effective population size (Ne) is a measure of genetic drift and is thus a central parameter in evolution, conservation genetics and invasion biology. Interestingly, in native marine species, Ne is typically several orders of magnitude lower than the census size. This pattern has often been explained by high fecundity, variation in reproductive success and pronounced early mortality, resulting in genetic drift across generations. Data documenting genetic drift and/or Ne in marine invasive species are, however, still scarce. We examined the importance of genetic drift in the invasive species Crepidula fornicata by genotyping 681 juveniles sampled during each annual recruitment peak over nine consecutive years in the Bay of Morlaix (Brittany, France). Observed variations in genetic diversity were partially explained by variation in recruitment intensity. In addition, substantial temporal genetic differentiation was documented (that is, genetic drift), and was attributed to nonrandom variance in the reproductive success of different breeding groups across years in the study species. Using a set of single-sample and temporal estimators for Ne, we estimated Ne to be three or four orders of magnitude smaller than the census size (Nc). On one hand, this reduction in Ne relative to Nc appeared congruent with, although slight higher than, values commonly observed in native marine species. Particular life-history traits of this invasive species may play an important role in buffering genetic drift. On the other hand, Ne still remained far below Nc, hence, possibly reducing the efficiency of selection effects. PMID- 27118157 TI - Demographic inference under a spatially continuous coalescent model. AB - In contrast with the classical population genetics theory that models population structure as discrete panmictic units connected by migration, many populations exhibit heterogeneous spatial gradients in population connectivity across semi continuous habitats. The historical dynamics of such spatially structured populations can be captured by a spatially explicit coalescent model recently proposed by Etheridge (2008) and Barton et al. (2010a, 2010b) and whereby allelic lineages are distributed in a two-dimensional spatial continuum and move within this continuum based on extinction and coalescent events. Though theoretically rigorous, this model, which we here refer to as the continuum model, has not yet been implemented for demographic inference. To this end, here we introduce and demonstrate a statistical pipeline that couples the coalescent simulator of Kelleher et al. (2014) that simulates genealogies under the continuum model, with an approximate Bayesian computation (ABC) framework for parameter estimation of neighborhood size (that is, the number of locally breeding individuals) and dispersal ability (that is, the distance an offspring can travel within a generation). Using empirically informed simulations and simulation-based ABC cross-validation, we first show that neighborhood size can be accurately estimated. We then apply our pipeline to the South African endemic shrub species Berkheya cuneata to use the resulting estimates of dispersal ability and neighborhood size to infer the average population density of the species. More generally, we show that spatially explicit coalescent models can be successfully integrated into model-based demographic inference. PMID- 27118156 TI - The contribution of dominance to phenotype prediction in a pine breeding and simulated population. AB - Pedigrees and dense marker panels have been used to predict the genetic merit of individuals in plant and animal breeding, accounting primarily for the contribution of additive effects. However, nonadditive effects may also affect trait variation in many breeding systems, particularly when specific combining ability is explored. Here we used models with different priors, and including additive-only and additive plus dominance effects, to predict polygenic (height) and oligogenic (fusiform rust resistance) traits in a structured breeding population of loblolly pine (Pinus taeda L.). Models were largely similar in predictive ability, and the inclusion of dominance only improved modestly the predictions for tree height. Next, we simulated a genetically similar population to assess the ability of predicting polygenic and oligogenic traits controlled by different levels of dominance. The simulation showed an overall decrease in the accuracy of total genomic predictions as dominance increases, regardless of the method used for prediction. Thus, dominance effects may not be accounted for as effectively in prediction models compared with traits controlled by additive alleles only. When the ratio of dominance to total phenotypic variance reached 0.2, the additive-dominance prediction models were significantly better than the additive-only models. However, in the prediction of the subsequent progeny population, this accuracy increase was only observed for the oligogenic trait. PMID- 27118158 TI - How Well Do All Patient Refined-Diagnosis-Related Groups Explain Costs of Pediatric Cancer Chemotherapy Admissions in the United States? AB - PURPOSE: State-based Medicaid programs have begun using All Patient Refined Diagnosis-Related Groups (APR-DRGs) to determine hospital reimbursement rates. Medicaid provides coverage for 45% of childhood cancer admissions. This study aimed to examine how well APR-DRGs reflect admission costs for childhood cancer chemotherapy to inform clinicians, hospitals, and policymakers in the wake of policy changes. METHODS: We identified 25,613 chemotherapy admissions in the 2009 Kids' Inpatient Database. To determine how well APR-DRGs explain costs, we applied a hierarchic linear regression model of hospital costs, allowing for a variety of patient, hospital, and geographic confounders. RESULTS: APR-DRGs proved to be the most important predictors of admission costs (P < .001), with costs increasing by DRG severity code. Diagnosis, age, and hospital characteristics also predicted costs above and beyond those explained by APR DRGs. Compared with admissions for patients with acute lymphoblastic leukemia, costs of admissions for patients with acute myelomonocytic leukemia were 82% higher; non-Hodgkin lymphoma, 20% higher; Hodgkin lymphoma, 25% lower; and CNS tumors, 27% lower. Admissions for children who were 10 years of age or older cost 26% to 35% more than admissions for infants. Admissions to children's hospitals cost 46% more than admissions to other hospital types. CONCLUSION: APR-DRGs developed for adults are applicable to childhood cancer chemotherapy but should be refined to account for cancer diagnosis and patient age. Possible policy and clinical management changes merit further study to address factors not captured by APR-DRGs. PMID- 27118159 TI - Young Men With Cancer Experience Low Referral Rates for Fertility Counseling and Sperm Banking. AB - PURPOSE: With improved cancer survival rates and the current trend of delaying parenthood, fertility is a growing issue among cancer patients. The purpose of this study was to evaluate the incidence of fertility counseling and sperm banking in reproductive-age male cancer patients and to assess factors that influence counseling and banking. MATERIALS AND METHODS: Male patients ages 13 to 50 years who received a new cancer diagnosis from January 1, 2013, to May 1, 2015, and planned to initiate curative chemotherapy at our center were identified. Documentation of fertility counseling and sperm cryopreservation was abstracted from the medical record. Univariable and multivariable logistic regression modeling was used to examine variables associated with fertility counseling and sperm banking. RESULTS: Of 201 patients who fit the study criteria, 59 (29%) received fertility counseling and 23 (11%) attempted sperm banking. All patients who banked sperm had documentation of fertility counseling. Younger patients were significantly more likely to be counseled, with mean ages of 27.4 and 40.4 years for counseled and noncounseled patients, respectively (P < .001). Among counseled patients, those with a lower median income (P = .038) or who had Medicaid or no insurance (P = .042) were less likely to bank sperm. In a multivariable logistic regression model, older age (5-year odds ratio, 0.61; P < .001) and presence of comorbidities (odds ratio, 0.15; P = .03) remained significantly associated with a lower counseling rate. CONCLUSION: There is a low rate of fertility counseling and referral for sperm banking in young men with cancer receiving chemotherapy. Further work is needed to develop interventions to improve fertility counseling rates and opportunities for sperm banking. PMID- 27118161 TI - Amputations and mortality in in-hospital treated patients with peripheral artery disease and diabetic foot syndrome. AB - AIMS: The prevalence of diabetes mellitus (DM) and its associated complications such as peripheral artery disease (PAD) and diabetic foot syndrome (DFS) are increasing worldwide. We aimed to determine the contemporary acute and long-term outcome of patients with PAD and DFS in Germany. METHODS: Nationwide, anonymized data of 40,335 patients hospitalized for PAD and/or DFS from the years 2009-2011 were analyzed and followed up until 2013. Patients were classified into 3 groups: DFS, PAD+DM and PAD without DM. In-hospital and long-term outcome (1156days, 95% CI 1.151-1.161) regarding major and minor amputation and mortality was assessed. Cumulative amputation-free survival and overall survival rates were calculated using Kaplan-Meier analysis. RESULTS: The proportion of DFS, PAD+DM and PAD only was 17.3%, 21.5% and 61.2%, respectively. At index-hospitalization, DFS patients had the highest amputation (31.9% vs. 11.1% vs. 6.0%), yet the lowest revascularization rate (18.2% vs. 67.8% vs. 71.6%) compared to patients with PAD only and PAD+DM (P<0.001). Cumulative 4-year survival (57.4%, 60.8% and 70.0%) and amputation-free-survival (45.4%, 74.4% and 86.5%) were lowest for DFS followed by PAD+DM and PAD only (P<0.001). CONCLUSIONS: Patients with diabetes, particularly those with DFS, have persistent high rates of limb amputation and of mortality in a real-world setting. Our data emphasize the need for further dedicated research to identify and target the underlying causes of the extraordinary poor outcome in this high risk population. PMID- 27118162 TI - Erratum to "The impact of nutritional status on treatment outcomes of patients with limb-threatening diabetic foot ulcers" [Journal of Diabetes and Its Complications 30 (2016) 138-142]. PMID- 27118163 TI - Diabetes distress in adults with type 1 diabetes: Prevalence, incidence and change over time. AB - AIMS: To document the prevalence and 9-month incidence of elevated diabetes distress (DD) and the stability of DD over time using both single threshold and minimal clinically important differences (MCID) approaches. METHODS: Adults with type 1 diabetes (T1D) (N=224) completed the 28-item T1-Diabetes Distress Scale (T1-DDS) at baseline and 9months. A T1-DDS threshold was identified with spline analysis and MCID was calculated from the standard error of measurement. RESULTS: Analyses supported a cut-point of >=2.0 for elevated DD. The prevalence and 9 month incidence of elevated DD was 42.1% and 54.4%, respectively. MCID was +/ 0.19 but varied by subscale (.26 to .50). Elevated DD was stable: only 20% crossed 2.0 over 9months. MCID analyses showed that change also occurred among those who remained either below or above 2.0 over time. Change varied by source of distress, with Powerlessness the most prevalent and stable. Using MCID, only participant age, gender and number of complications predicted change. CONCLUSIONS: The prevalence, 9-month incidence and stability of elevated DD are high among adults with T1D, with change based on source of DD. We propose a combined cut-point/MCID framework for measuring change in DD, since each approach reflects unique characteristics of change over time. PMID- 27118164 TI - Long-Range Interactions Restrict Water Transport in Pyrophyllite Interlayers. AB - Water diffusion within smectite clay interlayers is reduced by confinement and hence is highly determined by the interlayer spacings that are adopted during swelling. However, a molecular understanding of the short- and long-range forces governing interlayer water structure and dynamics is lacking. Using molecular dynamics simulations of water intercalated between pyrophyllite (smectite prototype) layers we provide a detailed picture of the variation of interlayered water mobility accompanying smectite expansion. Subtle changes in hydrogen bond network structure cause significant changes in water mobility that is greater for stable hydration states and reduced for intermediate separations. By studying pyrophyllite with and without external water we reveal that long-range electrostatic forces apply a restraining effect upon interlayer water mobility. Our findings are relevant for broad range of confining nanostructures with walls thin enough to permit long-range interactions that could affect the mobility of confined solvent molecules and solute species. PMID- 27118165 TI - Preparation, Physicochemical Properties, and Transfection Activities of Tartaric Acid-Based Cationic Lipids as Effective Nonviral Gene Delivery Vectors. AB - In this work two novel cationic lipids using natural tartaric acid as linking backbone were synthesized. These cationic lipids were simply constructed by tartaric acid backbone using head group 6-aminocaproic acid and saturated hydrocarbon chains dodecanol (T-C12-AH) or hexadecanol (T-C16-AH). The physicochemical properties, gel electrophoresis, transfection activities, and cytotoxicity of cationic liposomes were tested. The optimum formulation for T-C12 AH and T-C16-AH was at cationic lipid/dioleoylphosphatidylethanolamine (DOPE) molar ratio of 1 : 0.5 and 1 : 2, respectively, and N/P charge molar ratio of 1 : 1 and 1 : 1, respectively. Under optimized conditions, T-C12-AH and T-C16-AH showed effective gene transfection capabilities, superior or comparable to that of commercially available transfecting reagent 3beta-[N-(N',N' dimethylaminoethyl)carbamoyl]cholesterol (DC-Chol) and N-[2,3-dioleoyloxypropyl] N,N,N-trimethylammonium chloride (DOTAP). The results demonstrated that the two novel tartaric acid-based cationic lipids exhibited low toxicity and efficient transfection performance, offering an excellent prospect as nonviral vectors for gene delivery. PMID- 27118166 TI - Bacteriocins from lactic acid bacteria and their applications in meat and meat products. AB - Meat and meat products have always been an important part of human diet, and contain valuable nutrients for growth and health. Nevertheless, they are perishable and susceptible to microbial contamination, leading to an increased health risk for consumers as well as to the economic loss in meat industry. The utilization of bacteriocins produced by lactic acid bacteria (LAB) as a natural preservative has received a considerable attention. Inoculation of bacteriocin producing LAB cell as starter or protective cultures is suitable for fermented meats, whilst the direct addition of bacteriocin as food additive is more preferable when live cells of LAB could not produce bacteriocin in the real meat system. The incorporation of bacteriocins in packaging is another way to improve meat safety to avoid direct addition of bacteriocin to meat. Utilization of bacteriocins can effectively contribute to food safety, especially when integrated into hurdle concepts. In this review, LAB bacteriocins and their applications in meat and meat products are revisited. The molecular structure and characteristics of bacteriocins recently discovered, as well as exemplary properties are also discussed. PMID- 27118167 TI - Affinity Proteomics in the mountains: Alpbach 2015. AB - The 2015 Alpbach Workshop on Affinity Proteomics, organised by the EU AFFINOMICS consortium, was the 7th workshop in this series. As in previous years, the focus of the event was the current state of affinity methods for proteome analysis, including complementarity with mass spectrometry, progress in recombinant binder production methods, alternatives to classical antibodies as affinity reagents, analysis of proteome targets, industry focus on biomarkers, and diagnostic and clinical applications. The combination of excellent science with Austrian mountain scenery and winter sports engender an atmosphere that makes this series of workshops exceptional. The articles in this Special Issue represent a cross section of the presentations at the 2015 meeting. PMID- 27118168 TI - Reasons given for not receiving an influenza vaccination, 2011-12 influenza season, United States. AB - BACKGROUND: Influenza vaccination coverage in the United States remains below national targets and racial/ethnic differences persist. OBJECTIVES: To gain insights into potential strategies for improving influenza vaccination by examining reasons given for not receiving an influenza vaccination during the 2011-12 influenza season. METHODS: Data from the National Flu Survey were analyzed for the 2011-12 influenza season. Tests of association between reasons for non-vaccination and demographic variables were conducted using Wald chi square tests. Multivariable logistic regression analyses were used to determine variables independently associated with each reason for non-vaccination. RESULTS: For adults and children, there were no racial/ethnic differences in the overall most frequent reason for non-vaccination: "unlikely to get very sick from the flu". Regarding adults, there were racial/ethnic differences in seven of the twelve reasons for non-vaccination in bivariate analyses, but only three remained significant in the multivariable models. Most notable of these was that blacks (40.9%) were more likely than Hispanics (27.0%), whites (25.2%), and adults of other/multiple races (21.2%) to report concerns about getting the flu from the vaccination and blacks (39.8%) were more likely than whites (28.4%) and adults of other/multiple races (29.3%) to report concerns about side effects from the vaccine. Regarding children, there were racial/ethnic differences for three of the reasons for non-vaccination, and these remained significant in the multivariable models. The most noteworthy of these was that more black (44.4%) than white (24.0%) and other/multiple race (19.0%) parents had concerns about their child getting the flu from the vaccination. Other demographic variables (age, gender income, MSA for adults and age and income for children) were also associated with reasons for non-vaccination based on the multivariable models. CONCLUSIONS: There are racial/ethnic group differences in reasons for not receiving an influenza vaccination; recognition of these differences should guide the choice of interventions to increase vaccination rates. PMID- 27118169 TI - Diagnostic performance of matrix-assisted laser desorption ionisation time-of flight mass spectrometry in blood bacterial infections: a systematic review and meta-analysis. AB - BACKGROUND: Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) has shown promise in decreasing time to identification of causative organisms compared to traditional methods; however, the utility of MALDI-TOF MS in a heterogeneous clinical setting is uncertain. OBJECTIVES: To perform a systematic review on the operational performance of the Bruker MALDI-TOF MS system and evaluate published cut-off values compared to traditional blood cultures. METHODS: A comprehensive literature search was performed. Studies were included if they performed direct MALDI-TOF MS analysis of blood culture specimens in human patients with suspected bacterial infections using the Bruker Biotyper software. Sensitivities and specificities of the combined studies were estimated using a hierarchical random effects linear model (REML) incorporating cut-off scores of >=1.7 and >=2.0. RESULTS: Fifty publications were identified, with 11 studies included after final review. The estimated sensitivity utilising a cut-off of >=2.0 from the combined studies was 74.6% (95% CI = 67.9-89.3%), with an estimated specificity of 88.0% (95% CI = 74.8-94.7%). When assessing a cut-off of >=1.7, the combined sensitivity increases to 92.8% (95% CI = 87.4-96.0%), but the estimated specificity decreased to 81.2% (95% CI = 61.9-96.6%). CONCLUSIONS: In this analysis, MALDI-TOF MS showed acceptable sensitivity and specificity in bacterial speciation with the current recommended cut-off point compared to blood cultures; however, lowering the cut-off point from >=2.0 to >=1.7 would increase the sensitivity of the test without significant detrimental effect on the specificity, which could improve clinician confidence in their results. PMID- 27118170 TI - Colorectal anastomotic leakage can be predicted by abdominal aortic calcification on preoperative CT scans: A pilot study. AB - BACKGROUND: There have been no solid data regarding whether patients with aortic calcification (AC) who have undergone colorectal surgery are at increased risk for anastomotic leakage. Our study aim to investigate the impact of AC on anastomotic leakage (AL) and postoperative morbidity after colorectal resection. METHODS: This was a cohort study of 60 patients who were prospectively registered in a database. We evaluated the relationship between an aortic calcification score (ACS), measured on preoperative computed tomography (CT) imaging, and surgical complications in patients undergoing colorectal surgery. RESULTS: ACS was strongly correlated with mortality rate. All three of the deceased patients were in the ACS-2 group (5%; P=0.021). The rate of AL was positively correlated with ACS; no leakage was found cases of ACS-0, with a rate of 18% in cases of ACS 1 and 44% in cases of ACS-2 (P=0.022). The consequences of AL were more serious according to the grade of ACS. DISCUSSION: This study suggested that aortic calcification score is correlated with surgical outcomes, particularly anastomosis leakage, after colorectal surgery. These findings could provide useful tools for adapting surgical strategies by delaying colorectal anastomosis in high-risk patients. PMID- 27118171 TI - Feasibility prospective study of laparoscopic cholecystectomy with suprapubic approach. AB - BACKGROUND: Since the publication of laparoscopic cholecystectomy (LC) using three ports instead of four, no significant evolution has impacted on our clinical practice in order to improve length of stay, postoperative pain, time of recovery and cosmetic results. Recently, a renewed interest has been observed with the suprapubic approach, called occult scar laparoscopic cholecystectomy (OSLC). The aim of this prospective multicentric study was to evaluate the feasibility of OSLC in 2 French centers. METHODS: From March to September 2014, 60 patients were prospectively included in this study. The operation incisions consisted of an umbilical incision for camera; an incision in the right groin for maneuvers of exposition and a suprapubic incision for instrumental dissection and clipping. Outcome was by operative time, operative complications, hospital length of stay, analgesia required after surgery, and cosmetic outcomes. The Patient Satisfaction Scale and Visual Analog Score (VAS) also were used to evaluate the level of cosmetic result and postoperative pain. RESULTS: No laparoscopy was converted to an open procedure, the mean operative time was 53+/-20min. No patient had intraoperative bile duct injury or significant bleeding. The mean length of stay was 1.70+/-0.76 days. Two patients (3%) experienced postoperative complication (1 intra-abdominal abscess treated by antibiotics and 1 subcutaneous seroma of the 11-mm port wound treated successfully by needle aspiration). CONCLUSION: The technique proved to be safe and feasible with no specific complication and without specific instrument. It offers satisfactory postoperative pain level and good cosmetic results. PMID- 27118172 TI - Response to Letter to the Editor on "Antioxidants as a treatment for acute pancreatitis: A meta-analysis". PMID- 27118173 TI - Peptide-induced de novo bone formation after tooth extraction prevents alveolar bone loss in a murine tooth extraction model. AB - Tooth extraction causes bone resorption of the alveolar bone volume. Although recombinant human bone morphogenetic protein 2 (rhBMP-2) markedly promotes de novo bone formation after tooth extraction, the application of high-dose rhBMP-2 may induce side effects, such as swelling, seroma, and an increased cancer risk. Therefore, reduction of the necessary dose of rhBMP-2 which can still obtain sufficient bone mass is necessary by developing a new osteogenic reagent. Recently, we showed that the systemic administration of OP3-4 peptide, which was originally designed as a bone resorption inhibitor, had osteogenic ability both in vitro and in vivo. This study evaluated the ability of the local application of OP3-4 peptide to promote bone formation in a murine tooth extraction model with a very low-dose of BMP. The mandibular incisor was extracted from 10-week old C57BL6/J male mice and a gelatin hydrogel containing rhBMP-2 with or without OP3-4 peptide (BMP/OP3-4) was applied to the socket of the incisor. Bone formation inside the socket was examined radiologically and histologically at 21 days after the extraction. The BMP/OP3-4-group showed significant bone formation inside the mandibular extraction socket compared to the gelatin-hydrogel-carrier control group or rhBMP-2-applied group. The BMP/OP3-4-applied mice showed a lower reduction of alveolar bone and fewer osteoclast numbers, suggesting that the newly formed bone inside the socket may prevent resorption of the cortical bone around the extraction socket. Our data revealed that OP3-4 peptide promotes BMP mediated bone formation inside the extraction socket of mandibular bone, resulting in preservation from the loss of alveolar bone. PMID- 27118174 TI - Protective effects of a dimeric derivative of ferulic acid in animal models of Alzheimer's disease. AB - Ferulic acid is a compound with potent anti-oxidant and anti-inflammatory activities. We previously reported the protective effects of ferulic acid administration against two animal models of Alzheimer's disease (AD): intracerebroventricular (i.c.v.) injection of Abeta1-42 in mice and APP/PS1 mutant transgenic mice. In this study using the same AD animal models, we examined the effect of KMS4001, one of dimeric derivatives of ferulic acid. Intragastric pretreatment of mice with KMS4001 (30mg/kg/day) for 5 days significantly attenuated the Abeta1-42 (i.c.v.)-induced memory impairment both in passive avoidance test and in Y-maze test. APP/PS1 mutant transgenic mice at KMS4001 doses of 3 and 30mg/kg/day via drinking water showed the significantly enhanced novel-object recognition memory at both 1.5 and 3 months after the start of KMS4001 treatment. Treatment of APP/PS1 mutant transgenic mice with KMS4001 for 3 months at the doses of 3 and 30mg/kg/day markedly decreased Abeta1-40 and Abeta1-42 levels in the frontal cortex. The KMS4001 dose-response relationships for Abeta decrease and for improvement in novel-object recognition test corresponded to each other. Taken together, these results suggest that KMS4001 could be an effective drug candidate against AD. PMID- 27118176 TI - Prevention of cardiovascular disease in rural Australian primary care: an exploratory study of the perspectives of clinicians and high-risk men. AB - Rural primary care services have the potential to play a major role in reducing the gap in cardiovascular disease (CVD) outcomes between rural and metropolitan Australians, particularly in men at high risk of CVD. The aim of this study was to explore the self-reported behaviours and satisfaction with their general practice/practitioner of men at high risk of CVD, and attitudes of rural primary care clinicians regarding the role of primary care in CVD prevention. This observational research was addressed through survey questionnaires with rural men at high risk of CVD and semi-structured interviews with rural primary care clinicians. Fourteen rural primary care practices from towns with populations less than 25000 participated. One hundred and fifty-eight high-risk men completed the questionnaire. Their responses demonstrated poorly controlled risk factors despite a willingness to change. Alternatively, rural primary care clinicians (n=20) reported that patients were unlikely to change and that illness-based funding models inhibited cardiovascular preventive activities. Australians living in rural areas have worse CVD outcomes. In addition, there is a disparity in the assumptions of health providers and male patients at high risk of CVD in rural areas. This necessitates innovative rural primary care models that include a blended payment system that incentivises or funds preventive care alongside an emphasis on lifestyle advice, as well as an explicit strategy to influence clinician and patient behaviour to help address the disparity. PMID- 27118175 TI - Enhanced nitric oxide generation from nitric oxide synthases as the cause of increased peroxynitrite formation during acute restraint stress: Effects on carotid responsiveness to angiotensinergic stimuli in type-1 diabetic rats. AB - Diabetes mellitus is associated with reactive oxygen and nitrogen species accumulation. Behavioral stress increases nitric oxide production, which may trigger a massive impact on vascular cells and accelerate cardiovascular complications under oxidative stress conditions such as Diabetes. For this study, type-1 Diabetes mellitus was induced in Wistar rats by intraperitoneal injection of streptozotocin. After 28 days, cumulative concentration-response curves for angiotensin II were obtained in endothelium-intact carotid rings from diabetic rats that underwent to acute restraint stress for 3h. The contractile response evoked by angiotensin II was increased in carotid arteries from diabetic rats. Acute restraint stress did not alter angiotensin II-induced contraction in carotid arteries from normoglycaemic rats. However acute stress combined with Diabetes increased angiotensin II-induced contraction in carotid rings. Western blot experiments and the inhibition of nitric oxide synthases in functional assays showed that neuronal, endothelial and inducible nitric oxide synthase isoforms contribute to the increased formation of peroxynitrite and contractile hyperreactivity to angiotensin II in carotid rings from stressed diabetic rats. In summary, these findings suggest that the increased superoxide anion generation in carotid arteries from diabetic rats associated to the increased local nitric oxide synthases expression and activity induced by acute restrain stress were responsible for exacerbating the local formation of peroxynitrite and the contraction induced by angiotensin II. PMID- 27118177 TI - High-mobility ZrInO thin-film transistor prepared by an all-DC-sputtering method at room temperature. AB - Thin-film transistors (TFTs) with zirconium-doped indium oxide (ZrInO) semiconductor were successfully fabricated by an all-DC-sputtering method at room temperature. The ZrInO TFT without any intentionally annealing steps exhibited a high saturation mobility of 25.1 cm(2)V(-1)s(-1). The threshold voltage shift was only 0.35 V for the ZrInO TFT under positive gate bias stress for 1 hour. Detailed studies showed that the room-temperature ZrInO thin film was in the amorphous state with low carrier density because of the strong bonding strength of Zr-O. The room-temperature process is attractive for its compatibility with almost all kinds of the flexible substrates, and the DC sputtering process is good for the production efficiency improvement and the fabrication cost reduction. PMID- 27118178 TI - Evolution of circoviruses in lorikeets lags behind its hosts. AB - The presence of endogenous viral elements in host genomes hints towards much older host-virus relationships than predicted by exogenous phylogenies, with highly mutable single-stranded DNA (ssDNA) viruses and RNA viruses often occupying entangled multispecies ecological niches. The difficulty lies in unravelling the long-term evolutionary history of vertebrate virus-host relationships and determining the age of a potentially ancient tree based only fresh shoots at the tips. Resolving such lineages, and the sometimes great discrepancy amongst evolutionary timescales, is problematic, especially when purifying selection or recombination can significantly alter the accuracy of phylogenetic reconstruction methods. Pathogens which occupy entangled multispecies ecological niches add a further layer of complexity but we show that multi-host scenarios may also provide opportunities to identify allopatric or sympatric paleobiological signals that can unlock longer term phylogenies. We identified host-based, cryptic, sympatric differentiation in beak and feather disease virus in the Psittaciformes tribe Loriini along with endogenous circovirus motifs in Kea (Nestor notabilis) and Gondwanan vicariance estimates to infer the evolutionary timescale of the circoviruses. This demonstrated a chronology of psittacine circovirus speciation aligned to conservative Zealandic divergences for relic circovirus motifs in Kea and a 10million year divergence coinciding with the Papuan central range orogeny that triggered the radiation of Loriini and segregation of an antecedent viral clade in Australian lorikeets. Estimates of circovirus speciation in birds highlighted a Gondwanan dominant group in Neoaves with passerine, columbid and larid circoviruses deeply separated from those in waterfowl, consistent with a Triassic divergence of Galloanserae. The circovirus tree had a deep ancestry in invertebrates with a Palaeozoic expansion in fish and mammals. We show that longer term evolutionary relationships in viruses which have a high rate of mutation and admixture can be disentangled, highlighting that contemporary virus host-switching can be explained by deep intra-lineage host phylogeny. PMID- 27118180 TI - Phylogeny, phylogeography, and evolution in the Mediterranean region: News from a freshwater mussel (Potomida, Unionida). AB - The Potomida genus (Bivalvia, Unionida) has a Circum-Mediterranean distribution and like other freshwater mussel species, its populations have suffered dramatic declines. Although this genus is currently considered as monotypic, it has a long history of taxonomic revisions and presently many aspects of its systematics and evolutionary history are unclear. We sampled a total of 323 individuals from 39 different sites across the Potomida genus distribution, and sequenced two mitochondrial (16S rDNA and Cytochrome c Oxidase Subunit I) and one nuclear (28S rDNA) genes to clarify its phylogeny and phylogeographic history. Our results show that the genus includes two well-supported clades, one comprising solely the western Mediterranean species Potomida littoralis, and the other including two eastern Mediterranean species, the Greek endemic P. acarnanica and the Anatolian and Middle Eastern P. semirugata. We suggest that Potomida started radiating during the upper Miocene, and that both vicariance and dispersal events shaped the diversification and distribution of the genus along the Mediterranean region. P. littoralis is further divided in two mitochondrial lineages, one restricted to Europe and the other occurring mostly in North Africa. Moreover, some European basins present both lineages in sympatry. The conservation status of the three recognized species should be reevaluated, particularly P. acarnanica, since it is restricted to two Greek river basins presenting a high risk of extinction. Overall, our results clarify some important gaps in knowledge concerning the phylogeny, phylogeography and evolution of the Potomida genus in the Mediterranean region with important taxonomical, ecological and conservational implications. PMID- 27118179 TI - Molecular phylogeny of Panaspis and Afroablepharus skinks (Squamata: Scincidae) in the savannas of sub-Saharan Africa. AB - African snake-eyed skinks are relatively small lizards of the genera Panaspis and Afroablepharus. Species allocation of these genera frequently changed during the 20th century based on morphology, ecology, and biogeography. Members of these genera occur primarily in savanna habitats throughout sub-Saharan Africa and include species whose highly conserved morphology poses challenges for taxonomic studies. We sequenced two mitochondrial (16S and cyt b) and two nuclear genes (PDC and RAG1) from 76 Panaspis and Afroablepharus samples from across eastern, central, and southern Africa. Concatenated gene-tree and divergence-dating analyses were conducted to infer phylogenies and biogeographic patterns. Molecular data sets revealed several cryptic lineages, with most radiations occurring during the mid-Miocene to Pliocene. We infer that rifting processes (including the formation of the East African Rift System) and climatic oscillations contributed to the expansion and contraction of savannas, and caused cladogenesis in snake-eyed skinks. Species in Panaspis and Afroablepharus used in this study, including type species for both genera, formed a monophyletic group. As a result, the latter genus should be synonymized with the former, which has priority. Conservatively, we continue to include the West African species P. breviceps and P. togoensis within an expanded Panaspis, but note that they occur in relatively divergent clades, and their taxonomic status may change with improved taxon sampling. Divergence estimates and cryptic speciation patterns of snake-eyed skinks were consistent with previous studies of other savanna vertebrate lineages from the same areas examined in this study. PMID- 27118181 TI - Phylogeographic patterns in New Zealand and temperate Australian cantharidines (Mollusca: Gastropoda: Trochidae: Cantharidinae): Trans-Tasman divergences are ancient. AB - Current taxonomic treatments of New Zealand and temperate Australian members of the gastropod subfamily Cantharidinae imply that species on either side of the Tasman Sea are closely related and, in some cases, congeneric. Such a close relationship, however, entails a relatively recent divergence of Australian and New Zealand lineages, which seems inconsistent with what is known about cantharidine larval development in general. In order to address these issues, mitochondrial and nuclear DNA sequences were used to ascertain how cantharidine genera became established over the wide geographical range of temperate Australia and New Zealand, including their subantarctic islands. Our robust and dated phylogenies (based on 16S, COI, 12S and 28S sequences) revealed that Australian and New Zealand species fall into endemic clades that have been separated for, at most, 35million years. This divergence date postdates a vicariant split by around 50million years and we suggest that, once again, long-distance trans-Tasman dispersal has played a pivotal role in molluscan evolution in this part of the world. Our results also show that the current classification requires revision. We recognize three genera (Cantharidus [comprising 2 subgenera: Cantharidus s.str. and Pseudomargarella n. subgen.], Micrelenchus [comprising 2 subgenera: Micrelenchus s.str. and Mawhero] and Roseaplagis n. gen.) for New Zealand cantharidine species. In our dated BEAST tree, these genera form a clade with the endemic Australian Prothalotia and South African Oxystele. Other temperate Australian cantharidines in our study fall into previously recognized genera (Phasianotrochus, Thalotia, Calthalotia), which are all quite distinct from Cantharidus in spite of some authors considering various of them to be possible synonyms. Finally, we remove the Australian genus Cantharidella from the Cantharidinae to the subfamily Trochinae and erect a new genus, Cratidentium n. gen., also in the Trochinae, to accommodate several Australian species previously considered to belong to Cantharidella. PMID- 27118182 TI - Aspirin Can Be Used as Prophylaxis for Prevention of Venous Thromboembolism After Revision Hip and Knee Arthroplasty. AB - BACKGROUND: The optimal prophylaxis for prevention of venous thromboembolic events (VTEs) after revision total joint arthroplasty (TJA) remains unknown. The objective of this study was to evaluate whether aspirin, known to be effective for prevention of VTEs after primary arthroplasty, is also effective after revision TJA. METHODS: We studied 2997 consecutive patients who underwent revision TJA between 2005 and 2013 and were treated with intermittent pneumatic compression devices and either aspirin (534 patients) or warfarin (2463 patients) for VTE prophylaxis. Pertinent data including the incidence of symptomatic VTEs, bleeding events, infection, and mortality were retrieved from our prospectively collected database. RESULTS: The incidence of symptomatic VTEs was significantly higher in the warfarin group at 1.75% (43 of 2463) compared with 0.56% (3 of 534) in the aspirin group (odds ratio: 3.2; 95% CI: 1.03-16.3; P = .03). There was a higher rate of bleeding events with administration of warfarin (1.5%) compared with aspirin (0.4%; P = .02; odds ratio: 4.1; 95% CI: 1.2-34.0). The rate of surgical site infection was similar between the aspirin group and the warfarin group (1.61% and 1.70%, respectively). CONCLUSION: Administration of aspirin as prophylaxis against VTEs after revision arthroplasty may be a viable option as it appears to be more effective than warfarin in prevention of symptomatic VTEs and is associated with a lower rate of complications. PMID- 27118183 TI - Generating an agricultural risk map based on limited ecological information: A case study using Sicyos angulatus. AB - In this study, we propose a method for estimating the risk of agricultural damage caused by an invasive species when species-specific information is lacking. We defined the "risk" as the product of the invasion probability and the area of potentially damaged crop for production. As a case study, we estimated the risk imposed by an invasive weed, Sicyos angulatus, based on simple cellular simulations and governmental data on the area of crop that could potentially be damaged in Miyagi Prefecture, Japan. Simulation results revealed that the current distribution range was sufficiently accurate for practical purposes. Using these results and records of crop areas, we present risk maps for S. angulatus in agricultural fields. Managers will be able to use these maps to rapidly establish a management plan with minimal cost. Our approach will be valuable for establishing a management plan before or during the early stages of invasion. PMID- 27118184 TI - Better than nothing? maternal, newborn, and child health services and perinatal mortality, Lubumbashi, democratic republic of the Congo: a cohort study. AB - BACKGROUND: The Democratic Republic of Congo (DRC) has a high rate of perinatal mortality (PMR), and health measures that could reduce this high rate of mortality are not accessible to all women. Where they are in place, their quality is not optimal. This study was initiated to assess the relationship between these suboptimal maternal, newborn and child health (MNCH) services and perinatal mortality (PM) in Lubumbashi, DRC's second-largest city. METHODS: We conducted a prospective cohort study, comparing women who had no, low, moderate, or high numbers of antenatal care (ANC) visits; three different levels of delivery care; and who did or did not attend postnatal care (PNC). Women were followed for 50 days after delivery, with PM as the primary endpoint. RESULTS: Uptake of recommended prenatal interventions was between 11-43% among ANC attenders, regardless of the frequency of their visits. PM was 26 per 1000. ANC attendance was associated with PM. Newborns of mothers who had the lowest attendance had a mortality two times higher than newborns of women who had not attended ANC (low visits: adjusted odds ratio (aOR) = 2.2; 95% confidence interval (CI) = 1.4-3.8). However, moderate (aOR = 1.4; 95% CI =0.7-2.2) and high (aOR = 1.3; 95% CI 0.7 2.2) attendance were not statistically significantly associated with PM. PNC attendance was not significantly associated with lower PM (relative risk 0.4, 95% CI 0.1-2.6). Emergency obstetric and newborn care (EmONC) was significantly associated with a reduction in mortality (aOR = 0.2; 95% CI = 0.2-0.8), with an 84.4% reduction among newborns at risk, and an overall reduction in mortality of 10% for all births. CONCLUSION: Perinatal mortality was high among the infants of women in the cohort under study (26 per 1000 live births). Availability of MNCH, specifically EmONC, was associated with lower perinatal mortality, and if this association is causal, might avert 84.4% of perinatal deaths among newborns at high-risk. PMID- 27118185 TI - Structure and function of the elastic organ in the tibia of a tenebrionid beetle. AB - Many insects have a pair of claws on the tip of each foot (tarsus and pretarsus). The movement of the pretarsal claws is mediated by a long apodeme that originates from the claw retractor muscles in the femur. It is generally accepted that the pulling of the apodeme by the muscles flexes the claws to engage with a rough surface of a substrate, and the flexed claws return to their initial position by passive elastic forces within the tarso-pretarsal joint. We found that each tibia of the tenebrionid beetle Zophobas atratus had a chordal elastic organ that tied the apodeme to the distal end of the tibia and assisted the pulled apodeme to return smoothly. The elastic body of the elastic organ consists of a bundle of more than 1000 thin fibrils (0.3-1.5 MUm in diameter) with a hairy yarn-shaped structure made by assemblies of intricately interwoven microfibers. Both ends of the fibrillar elastic body were supported by clusters of columnar cells. Ablation of the elastic organ often disturbed the rapid and smooth return of claws from a flexed position when the tarsal segments were forced to curve in order to increase the friction between the apodeme and surrounding tissues in the segments. The result suggests that rapid claw disengagement is an important step in each cycle of leg movements, and the elastic organ may have evolved to assist the reliable detachment of claws that engage tightly with the substrate when climbing or traversing inverted surfaces. PMID- 27118186 TI - Salipaludibacillus aurantiacus gen. nov., sp. nov. a novel alkali tolerant bacterium, reclassification of Bacillus agaradhaerens as Salipaludibacillus agaradhaerens comb. nov. and Bacillus neizhouensis as Salipaludibacillus neizhouensis comb. nov. AB - Two novel (S9T and S12) Gram-stain-positive, rod shaped, non-motile and endospore forming bacteria were isolated from Narayan Sarovar lake, in India. The high 16S rRNA gene sequence similarity (99.9 %) and DNA-DNA relatedness (86+/-2 %) indicated that strains S9T and S12 were members of a single species. Based on the 16S rRNA gene sequence analysis, these strains were identified as belonging to the class Firmibacteria and were most closely related to Bacillus agaradhaerens PN-105T (96.8 % sequence similarity), Bacillus neizhouensis JSM 071004T (96.5 %) and Bacillus luteus JC167T (96.1 %). However, these strains shared only 90.3 % 16S rRNA gene sequence similarity with Bacillus subtilis subsp. subtilis DSM 10T, indicating that they might not be members of the genus Bacillus. The cell-wall peptidoglycan contained meso-diaminopimelic acid. Polar lipids included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unknown phospholipid and an unknown lipid. The predominant isoprenoid quinone was MK-7. Major fatty acids (>5 %) included anteiso-C15 : 0, C16 : 0, iso-C15 : 0, anteiso-C17 : 0, iso-C16 : 0 and summed feature 3. The results of phylogenetic, chemotaxonomic and biochemical tests allowed a clear differentiation of strains S9T and S12 from all other members of the family Bacillaceae.The strains therefore represent a novel member of a new genus from the family Bacillaceae, for which the name Salipaludibacillus aurantiacus gen. nov., sp. nov. is proposed. The type strain is S9T (=KCTC 33633T=LMG 28644T). Based on the present study, it is also proposed to transfer Bacillus agaradhaerens and Bacillus neizhouensis to this new genus as Salipaludibacillus agaradhaerens comb. nov. and Salipaludibacillus neizhouensis comb. nov. PMID- 27118187 TI - Functionalization of Polydopamine via the Aza-Michael Reaction for Antimicrobial Interfaces. AB - Polydopamine (pDA) coatings afford tremendous versatility due to their capabilities to provide substrate-independent functionalization with a wide range of amine- and thiol-containing molecules. In this work, we developed a new and facile conjugation approach to the formation of beta-amino carbonyl linkages between pDA and acrylate/acrylamide molecules via the aza-Michael reaction. Sulfobetaine acrylamide (SBAA), sulfobetaine methacrylate (SBMA), and poly(ethylene glycol) methacrylate (PEGMA) were employed to graft onto pDA films, giving rise to formation of antifouling coatings. Because of the universal adhesive property of pDA, the coating strategy was applied to different substrates, including TiO2, gold, SiO2, Nitinol alloy, polystyrene, and poly(dimethylsiloxane). The variation of surface chemistry and surface wettability upon pDA modification and subsequent conjugation was monitored with X ray photoelectron spectroscopy (XPS) and water contact angle measurements. Antifouling properties of coatings were challenged by three common Gram-negative and Gram-positive bacteria. Cytocompatibility of the coatings with NIH-3T3 fibroblasts was accessed using MTT assay. The results showed that pDA coatings grafted with SBAA exhibited superhydrophilicity and excellent fouling resistance likely due to the high chemical reactivity of acrylamide, leading to high grafting density. In addition, dual functional coatings containing passive and active antibacterial components were constructed through the in situ deposition of antimicrobial agent, silver nanoparticles, in pDA, followed by the grafting of SBAA for bacterial repellence. The composite coatings allowed reducing adsorption of E. coli by >95%, while killing attached bacteria by up to 98% upon the releasing of Ag(+) ions as measured by inductively coupled plasma mass spectrometry. Consequently, this work paves a new avenue to the grafting strategy to engineer pDA and to the functional bioinspired antifouling interfaces in a substrate-independent fashion. PMID- 27118188 TI - The role of halide ions in the anisotropic growth of gold nanoparticles: a microscopic, atomistic perspective. AB - We provide a microscopic view of the role of halides in controlling the anisotropic growth of gold nanorods through a combined computational and experimental study. Atomistic molecular dynamics simulations unveil that Br(-) adsorption is not only responsible for surface passivation, but also acts as the driving force for CTAB micelle adsorption and stabilization on the gold surface in a facet-dependent way. The partial replacement of Br(-) by Cl(-) decreases the difference between facets and the surfactant density. Finally, in the CTAC solution, no halides or micellar structures protect the gold surface and further gold reduction should be uniformly possible. Experimentally observed nanoparticle's growth in different CTAB/CTAC mixtures is more uniform and faster as the amount of Cl(-) increases, confirming the picture from the simulations. In addition, the surfactant layer thickness measured on nanorods exposed to CTAB and CTAC quantitatively agrees with the simulation results. PMID- 27118189 TI - Molecular imaging using PSMA PET/CT versus multiparametric MRI for initial staging of prostate cancer: comparing apples with oranges? PMID- 27118190 TI - Neuroretinal rim in non-glaucomatous large optic nerve heads: a comparison of confocal scanning laser tomography and spectral domain optical coherence tomography. AB - BACKGROUND/AIMS: To compare margin-based rim area measurements from confocal scanning laser tomography (CSLT) with Bruch's membrane opening (BMO)-based measurements from spectral domain optical coherence tomography (SD-OCT) by analysis of a group of non-glaucomatous eyes with large optic discs, so-called macrodiscs (disc size >2.45 mm2 in CSLT). Objective is to create a reference base for large optic nerve heads in SD-OCT diagnostics. METHODS: 102 eyes received CSLT and SD-OCT measurements and clinical examination on the same day. Visual field testing confirmed absence of glaucomatous defects. Statistical and correlation analysis was performed for rim area by CSLT as well as retinal nerve fibre layer thickness (RNFLT) and BMO minimal rim width (BMO-MRW) by SD-OCT. RESULTS: Mean disc size in CSLT was 2.98+/-0.4 mm2 (range 2.45-4.23), mean rim area of 1.55+/-0.4 mm2. BMO area was 2.51+/-0.33 mm2 (range 1.61-3.51), mean global RNFLT was 79.55+/-17.2 MUm, mean global BMO-MRW was 234.84+/-48.3 MUm. Correlation of BMO-MRW to global RNFLT was stronger (r=0.60, p<10-5) than correlation of CSLT rim area to global RNFLT (r=0.26, p=0.24). BMO-MRW and CSLT rim area correlated with r=0.59 (p<10-5). BMO-MRW and RNFLT significantly decreased with increasing age (p<0.001). Annual loss of BMO-MRW was 0.8 MUm/year (R2=0.14, p<0.001), loss of RNFLT was 0.27 MUm/year (R2=0.17, p=0.001). CONCLUSIONS: In large optic discs, BMO-MRW is thinner compared with normal-sized discs and correlates better than CSLT parameters with the RNFLT. An age-depended loss of BMO-MRW needs to be taken into account in evaluation of the neuroretinal rim. PMID- 27118191 TI - Is LabTutor a helpful component of the blended learning approach to biosciences? AB - AIMS AND OBJECTIVES: To evaluate the use of LabTutor (a physiological data capture and e-learning package) in bioscience education for student nurses. BACKGROUND: Knowledge of biosciences is important for nurses the world over, who have to monitor and assess their patient's clinical condition, and interpret that information to determine the most appropriate course of action. Nursing students have long been known to find acquiring useable bioscience knowledge challenging. Blended learning strategies are common in bioscience teaching to address the difficulties students have. Student nurses have a preference for hands-on learning, small group sessions and are helped by close juxtaposition of theory and practice. DESIGN: An evaluation of a new teaching method using in-classroom voluntary questionnaire. METHODS: A structured survey instrument including statements and visual analogue response format and open questions was given to students who participated in Labtutor sessions. The students provided feedback in about the equipment, the learning and the session itself. RESULTS: First year (n = 93) and third year (n = 36) students completed the evaluation forms. The majority of students were confident about the equipment and using it to learn although a few felt anxious about computer-based learning. They all found the equipment helpful as part of their bioscience education and they all enjoyed the sessions. CONCLUSION: This equipment provides a helpful way to encourage guided independent learning through practice and discovery and because each session is case study based and the relationship of the data to the patient is made clear. Our students helped to evaluate our initial use of LabTutor and found the sessions enjoyable and helpful. LabTutor provides an effective learning tool as part of a blended learning strategy for biosciences teaching. RELEVANCE TO CLINICAL PRACTICE: Improving bioscience knowledge will lead to a greater understanding of pathophysiology, treatments and interventions and monitoring. PMID- 27118192 TI - Bone mineral disorder in chronic kidney disease: Klotho and FGF23; cardiovascular implications. AB - Cardiovascular factors are one of the main causes of morbidity and mortality in patients with chronic kidney disease. Bone mineral metabolism disorders and inflammation are pathological conditions that involve increased cardiovascular risk in chronic kidney disease. The cardiovascular risk involvement of bone mineral metabolism classical biochemical parameters such as phosphorus, calcium, vitamin D and PTH is well known. The newest markers, FGF23 and klotho, could also be implicated in cardiovascular disease. PMID- 27118193 TI - PrEFiNe Plan: Strategic plan for Fabry diseases in Nephrology. AB - BACKGROUND: Renal failure is one of the main causes of death in patients with Fabry disease (FD). Due to the low prevalence of FD, delayed diagnosis and misdiagnosis, often the correct diagnosis is made when organ damage is already present. Early recognition of the disease would allow the prevention of severe complications and the premature death of patients with FD. OBJECTIVE: We present here the PrEFiNE project, which includes a wide spectrum of activities with the aim of improve knowledge and diagnosis of FD. The project is sponsored by Shire Iberia (http://shireiberica.com/) METHODS: From January 2016 to the end of 2017 several activities will be carried out, starting with a survey to evaluate current FD knowledge among nephrologists; in addition some studies to assess prevalence of this disease will be performed. One study will include patients receiving dialysis, another study will cover kidney transplant patients, and a pilot study in chronic kidney disease in stage 3-5 predialysis. Also planned is a pharmacoeconomic study to focus on burden of FD. At the same time medical education activities will be conducted both on line and on site. Plan for dissemination will include medical publications and diffusion to media. PrEFiNE Project will finish with the publication of a compilation book on FD in Nephrology including all planned activities and proposing recommendations based on results and detected unmet needs. PrEfiNE Plan will be coordinated by severa scientific committees, one at national level and 10 other regionals comittees, tha will be responsible to ensure the maximum scientific quality of proposed activities. An advisory board will supervise the project. DISCUSSION: PrEfiNE project will evaluate an action plan focused on improving FD knowledge to make necessary recommendations for an early recognition of the disease. In addition will generate a plan to improve previously undetected needs. PMID- 27118195 TI - Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. PMID- 27118194 TI - Weekly injections of Hylan G-F 20 delay cartilage degeneration in partial meniscectomized rat knees. AB - BACKGROUND: Cross-linked hyaluronan--also called Hylan G-F 20--is a medical device developed to treat osteoarthritis of the knee. However, it is still controversial whether Hylan G-F 20 has a cartilage protective effect in trauma induced osteoarthritis. We investigated whether Hylan G-F 20 delayed osteoarthritis progression in a partial meniscectomized rat model. METHODS: Lewis rats were used for the experiments. The anterior medial meniscus was resected at the level of the medial collateral ligament in both knees. From 1 week after the surgery, 50 MUl of Hylan G-F 20 was injected weekly into the left knee and phosphate buffered saline was injected into the right knee. Cartilage was evaluated for macroscopic findings, histology with safranin-o, and expression of type II collagen at 2, 4, and 8 weeks. Synovitis was also evaluated, and immunohistochemical analysis was performed for ED1. RESULTS: Macroscopic findings demonstrated that India ink positive area, representing fibrillated cartilage, was significantly smaller in the Hylan G-F 20 group than in the control group at 2, 4, and 8 weeks (n = 5). There were no significant differences in osteophyte score between the Hylan G-F 20 group and the control group at 2, 4, and 8 weeks. Histologically, the cartilage in the medial tibial plateau was destroyed at 8 weeks in the control group, while type II collagen expression was still observed at 8 weeks in the Hylan G-F 20 group. OARSI score for cartilage histology was significantly lower in the Hylan G-F 20 group than in the control group at 4 and 8 weeks (n = 5). There were no significant differences in synovial cell number or modified synovitis score between the Hylan G-F 20 group and the control group at 2, 4, and 8 weeks (n = 5). In the Hylan G-F 20 group, foreign bodies surrounded by ED1 positive macrophages were observed in the synovium. CONCLUSION: Weekly injections of Hylan G-F 20 starting 1 week after surgery delayed cartilage degeneration after meniscectomy in a rat model. Synovitis induced by meniscectomy was not alleviated by Hylan G-F 20. Insoluble gels were observed in the synovium after the Hylan G-F 20 injection. PMID- 27118198 TI - The Primary Structure of beta(I)-Chain of Hemoglobin from Snake Sindhi Krait (Bungarus sindanus sindanus). AB - The amino acid sequence of beta(I)-globin chain from Sindhi Krait (Bungarus sindanus sindanus) was determined to study the molecular evolution among snakes. The hemoglobin was isolated from the red blood cells and was analyzed by ion exchange chromatography (IEX). The crude globin was subjected to reversed phased high performance liquid chromatography (RP-HPLC) using C4 column. The N-terminal sequences of intact globin chains and tryptic peptides were determined by Edman degradation in a pulsed liquid gas phase sequencer using an online Phenylthiohydantoin analyzer. Sindhi Krait is expected to express three hemoglobin components that are composed of beta(II), beta(I), alpha(D) and alpha(A)-globin chains, as apparent by IEX, RP-HPLC and N-terminal sequence analyses. Sequence alignment and phylogenetic analyses of beta(I) globin chain from Sindhi Krait showed closest relationship with beta(I) globin chain from Rattlesnake, Water snake and Indigo snake. Interestingly, comparison of primary sequence of beta(I) globin chain of Sindhi Krait with human beta chain revealed 63 % similarity along with the retention of all heme contact points. Variations among the two sequences were prominent at alphabeta contact points and in regions directly not important for function. PMID- 27118197 TI - Hybrid intravascular imaging: recent advances, technical considerations, and current applications in the study of plaque pathophysiology. AB - Cumulative evidence from histology-based studies demonstrate that the currently available intravascular imaging techniques have fundamental limitations that do not allow complete and detailed evaluation of plaque morphology and pathobiology, limiting the ability to accurately identify high-risk plaques. To overcome these drawbacks, new efforts are developing for data fusion methodologies and the design of hybrid, dual-probe catheters to enable accurate assessment of plaque characteristics, and reliable identification of high-risk lesions. Today several dual-probe catheters have been introduced including combined near infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), that is already commercially available, IVUS-optical coherence tomography (OCT), the OCT-NIRS, the OCT-near infrared fluorescence (NIRF) molecular imaging, IVUS-NIRF, IVUS intravascular photoacoustic imaging and combined fluorescence lifetime-IVUS imaging. These multimodal approaches appear able to overcome limitations of standalone imaging and provide comprehensive visualization of plaque composition and plaque biology. The aim of this review article is to summarize the advances in hybrid intravascular imaging, discuss the technical challenges that should be addressed in order to have a use in the clinical arena, and present the evidence from their first applications aiming to highlight their potential value in the study of atherosclerosis. PMID- 27118196 TI - Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. PMID- 27118200 TI - Physical activity in axial spondyloarthritis-tails from bench to bedside. AB - Physical therapy and exercise (recreational activity) are the cornerstones of non pharmacologic therapy in axial spondyloarthritis (AxSpA) [1, 2]. These are components of physical activity, though physical activity is made up of activities beyond these and also include occupational activity. Not all activities in AxSpA appear to derive the same benefit for patients. In fact, it might be that while some activities are extremely beneficial for disease activity, function, and other outcomes, other activities may be harmful for the disease. The following review will examine animal model-based evidence and epidemiologic studies on physical activity in AxSpA. PMID- 27118199 TI - Risk factors for malignancy in systemic sclerosis patients. AB - Systemic sclerosis (SSc) is an autoimmune connective tissue disease with multisystem involvement. An increased incidence of cancer in SSc patients compared with the general population has been reported in several reports. Our aims in this study were to determine the most common malignancies and to investigate the possible risk factors for the development of malignancy in patients with SSc. Three hundred forty SSc patients from 13 centers were included to the study. Data of the patients were obtained by evaluating their medical records retrospectively. A total of 340 patients with SSc were evaluated. Twenty five of the patients had 19 different types of malignancy. Bladder cancer was the most common type of cancer with four patients and was followed by breast cancer with three patients, and cervix cancer and ovarian cancer with two patients each. Other types of cancers such as squamous cell skin cancer, adenocancer with an unknown origin, multiple myeloma, chronic myeloid leukemia, papillary thyroid cancer, larynx cancer, non-small cell lung cancer, follicular type non-Hodgkin lymphoma (NHL), endometrium cancer, colon cancer, uterus cancer, neuroendocrine tumor, glioblastoma multiforme, and soft tissue sarcoma were diagnosed in one patient each. The only cancer type that showed an association with cyclophosphamide dose was bladder carcinoma. Other malignancies did not show a correlation with age, sex, smoking, type and duration of the disease, autoantibodies, organ involvement, and dose and duration of cyclophosphamide therapy. Cancer may develop in any organ in patients with SSc. Continuous screening of the patients during a follow-up period is necessary for the early detection of the tumor development. PMID- 27118202 TI - Sequencing and characterization of a multi-organ Arctic charr transcriptome: A toolbox for investigating polymorphism and seasonal life in a high Arctic fish. AB - The Arctic charr (Salvelinus alpinus L.) inhabits fresh water ecosystems of the high North. The species has developed a strong phenotypic plasticity and variability in life history characteristics which has made this species an attractive model for investigations on phenotype plasticity, morph formation and ecological speciation. Further, the extreme seasonal variations in environmental conditions (e.g. food availability) in the high North induce seasonal changes in phenotype, which require precise timing mechanisms and physiological preparations. Individual gating of life-history strategies (e.g. formation of resident and sea-migrating morphs) and transitions (e.g. maturation) depends on conditional traits (size/energy status) at specific assessment time windows, and complex neuroendocrine regulation, which so far is poorly understood. In the absence of a reference genome, and in order to facilitate the investigation of the complex biological mechanisms of this unique fish model, the present study reveals a reference transcriptome for the Arctic charr. Using Roche 454 GS FLX+, we targeted various organs being either at the crossroads of many key pathways (neuroendocrine, metabolic, behavioral), of different ontological origins or displaying complementary physiological functions. The assemblage yielded 34,690 contigs greater than 1000bp with an average length (1690bp) and annotation rate (52%) within the range, or even higher, than what has been previously obtained with other teleost de novo transcriptomes. We dramatically improve the publically available transcript data on this species that may indeed be useful for various disciplines, from basic research to applied aspects related to conservation issues and aquaculture. PMID- 27118201 TI - Right atrial morphology and function in patients with systemic sclerosis compared to healthy controls: a two-dimensional strain study. AB - Enlargement and dysfunction of the right atrium might be an early sign for pulmonary hypertension in systemic sclerosis (SSc). This is the first study to analyse right atrial morphology and function in SSc patients compared to healthy controls by speckle-tracking two-dimensional strain echocardiography (2DSE) at rest and during exercise. Furthermore, right atrial function was correlated with further clinical findings. Adult patients with SSc for >3 years (n = 90) and 55 age- and gender-matched healthy controls underwent a panel of non-invasive assessments including transthoracic echocardiography, pulsed Doppler myocardial imaging and 2DSE at rest and during exercise. Furthermore, serological tests and high-resolution chest computed tomography were performed. SSc patients showed significant impairment of right atrial function and the right atrial enlargement, measured by 2DSE at rest and during exercise compared to controls (both p < 0.001). These findings were more evident in SSc patients with pulmonary fibrosis (p < 0.001) and in patients with high pulmonary artery systolic pressures (PAPs) during exercise. In the SSC patients, right atrial lateral strain was significantly associated with PAPs during effort, right atrial area, left ventricle stroke volume and inferior vena cava diameter using multivariable analysis. The findings of this study suggest that a high proportion of SSc patients reveal right atrial dysfunction even without manifest pulmonary hypertension. Impaired right atrial function occurred mostly in patients with pulmonary fibrosis and/or elevated PAPs during exercise, was independently associated with prognostic factors and may therefore be useful for risk stratification. Further studies are needed to analyse if right atrial dysfunction assessed by 2DSE may help to improve early diagnosis of pulmonary hypertension. PMID- 27118203 TI - Microorganisms in the rumen and reticulum of buffalo (Bubalus bubalis) fed two different feeding systems. AB - BACKGROUND: The community of microorganisms in the rumen and reticulum is influenced by feeding as well as the species and geographical distribution of ruminant animals. Bacteria, methanogenic archaea and ciliate protozoa existing in the rumen and reticulum were evaluated by real-time polymerase chain reaction and light microscopy in buffalo in two feeding systems, grazing and feedlot. RESULTS: No significant differences were observed in the total concentrations of bacteria/mL and archaea between rumen and reticulum, and between pasture and feedlots, or interactions between variables. However, the largest density of bacteria and smallest density of archaea was observed in the rumen of grazing animals. The total ciliates protozoa community was higher in grazing buffalo than those in the feedlot on a concentrated diet. There were significant interactions between location in the gastrointestinal tract (rumen vs reticulum) and types of diets (grazing vs feedlot) in the composition of ciliates. CONCLUSIONS: Our data showed differences in the microbial community of the rumen and reticulum between grazing and feedlot feeding systems demonstrating relevant changes in the microorganism:host relationship existing on rumen-reticulum ecosystem. PMID- 27118205 TI - An immunocompetent 49-year-old man with a disseminated infection. PMID- 27118204 TI - Effects of vagus nerve stimulation on cognitive functioning in rats with cerebral ischemia reperfusion. AB - BACKGROUND: Vagus nerve stimulation (VNS) has become the most common non pharmacological treatment for intractable drug-resistant epilepsy. However, the contribution of VNS to neurological rehabilitation following stroke has not been thoroughly examined. Therefore, we investigated the specific role of acute VNS in the recovery of cognitive functioning and the possible mechanisms involved using a cerebral ischemia/reperfusion (I/R) injury model in rats. METHODS: The I/R related injury was modeled using occlusion and reperfusion of the middle cerebral artery (MCAO/R) in Sprague-Dawley rats. VNS was concurrently applied to the vagus nerve using a stimulation intensity of 1 mA at a fixed frequency of 20 Hz with a 0.4-ms bipolar pulse width. The stimulation duration and inter-train interval were both 3 s. Next, Morris water maze and shuttle-box behavioral experiments were conducted to assess the effects of VNS on the recovery of learning, memory, and inhibitory avoidance following I/R injury. Intracerebroventricular injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective neurotoxin for noradrenergic neurons, was used to evaluate the role of norepinephrine (NE) as a mediator of therapeutic effects of VNS on cognitive recovery. RESULTS: Compared with the MCAO/R group, the VNS+MCAO/R group had improved spatial memory as indicated by swimming path lengths and escape latencies in the Morris water maze, and fear memory, as indicated by the avoidance conditioned response rate, mean shock duration, and avoidance time in shuttle-box behavior experiments. Compared with the VNS+MCAO/R group, the DSP 4+VNS+MCAO/R group, which had reduced NE levels in cortical and hippocampal brain regions, showed a reversal of the VNS-induced benefits on spatial and fear memory performance. CONCLUSIONS: VNS improves spatial and fear memory in a rat model of MCAO/R injury. However, a reduction in NE from the administration of DSP-4 blocks these protective effects, suggesting that NE may contribute to the influence exhibited by VNS on memory performance in rats with cerebral I/R-related injury. PMID- 27118206 TI - Comparison of low-normal and high-normal IGF-1 target levels during growth hormone replacement therapy: A randomized clinical trial in adult growth hormone deficiency. AB - BACKGROUND: Current guidelines state that the goals of growth hormone (GH) therapy in adults should be an appropriate clinical response, avoidance of side effects, and an IGF-1 value within the age-adjusted reference range. There are no published studies on the target level for IGF-1 that offer specific guidance in this regard. OBJECTIVES: To compare low-normal and high-normal target levels of IGF-1 on efficacy and safety of GH treatment. METHODS: A randomized, open-label, clinical trial including thirty-two adults from one university hospital receiving GH therapy for at least one year with a stable IGF-1 concentration between -1 and 1 SD score (SDS). Subjects were randomized to receive either a decrease (IGF-1 target level of -2 to -1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24weeks. The effect on cardiovascular risk factors and physical performance, next to tolerability, was compared. RESULTS: Thirty subjects (65.6% men, mean age 46.6 (SD 9.9) years) could be analyzed. In subjects with a high-normal IGF-1 target level, waist circumference decreased (p=0.05), and overall they felt better (p=0.04), compared to subjects with a low normal IGF-1 target level. However, increasing IGF-1 levels led to more myalgia, and decreasing IGF-1 levels to more fatigue. There was a gender-dependent difference in effect on HDL cholesterol. CONCLUSION: Although increasing GH dose to IGF-1 levels between 1 and 2 SDS improved waist circumference and well-being, safety was not guaranteed with the demonstrated effect on HDL cholesterol in men, and reported myalgia. PMID- 27118207 TI - Gene delivery to neuroblastoma cells by poly (l-lysine)-grafted low molecular weight polyethylenimine copolymers. AB - Polyethylenimine (PEI) and poly (l-lysine) (PLL) are among the most investigated non-viral gene carriers. However, both polymers contain deficiencies that restrict their applications. In the present study, we synthesized PLL-alkyl-PEI conjugates via 6-carbon alkyl linker and investigated their possible advantages in gene delivery. Four PLL copolymers were synthesized with different molecular weights and ratios of PEI. The physiochemical properties of synthesized conjugates such as size, zeta potential, DNA condensation ability, buffering capacity and cytotoxicity were investigated. Renilla luciferase assay was employed to evaluate the gene transfection efficiency of pDNA-polymer to Neuro2A cell line. DNA condensation and particle size measurements showed that new PLL PEI conjugates could form polyplexes in nano-scale size in the range of 99-122 nm and were able to condense DNA at low concentration. While cytotoxicity reduced in some groups, the transfection efficiency increased about 2.8 and 4 fold as compared to the unmodified PEI 1.8 kDa and 10 kDa, respectively. The results of the present study showed that the chemical modifications of PEI with PLL could significantly improve transfection efficiency and PLP10-10% shows the most promise as a new gene carrier. PMID- 27118208 TI - Intrathoracic splenosis - lesson learned: a case report. AB - BACKGROUND: Intrathoracic splenosis presents an extremely rare thoracic lesion occurring after a simultaneous rupture of the spleen and diaphragm as a consequence of heterotopic autotransplantation and implantation of splenic tissue. Intrathoracic splenosis is usually an asymptomatic, incidental finding, which should be ideally managed without surgical intervention. CASE PRESENTATION: We present a case of 68-year old woman with intrathoracic splenosis. Patient presented with a 2-month history of a dry cough unresponsive to administered antibiotics and antimycotics. Computed tomography (CT) of the chest revealed two homogeneous pleural nodules (diameters of 2 and 4 cm) in the left upper lung field. Two consequent CT-assisted transthoracic core-cut biopsies were performed. Histopathology examination of both biopsy specimens was inconclusive (haemorrhagic and non-specific tissue). After that, patient was referred to the department of thoracic surgery with a suspicion of malignant mesothelioma or metastatic lesions. Thoracoscopic revision of the left pleural cavity was performed and the presence of pleural nodules was confirmed. Bloody looking nodules were resected (standard thoracoscopic resection). Postoperative recovery was uneventful. The histopathology examination of the specimen showed normal splenic tissue. Only with the histopathology report in hand, a detailed medical history was taken. It revealed a gunshot injury requiring splenectomy (without known diaphragm or lung injury) 44 years ago (one of the longest time periods in the literature). CONCLUSIONS: We would like to point out that following the recommendations regarding splenosis may be very difficult in daily routine practice. The simple question regarding abdominal trauma in a patient's history can lead the clinician to the diagnosis of splenosis, which can be unequivocally established via scintigraphy. The importance of thorough medical history taking, therefore, cannot be underestimated. PMID- 27118209 TI - TCR-CD3zeta gene polymorphisms and expression profile in rheumatoid arthritis. AB - OBJECTIVES: Recent evidence has demonstrated that CD3zeta (also called CD247) play a vital role in multiple autoimmune diseases. In this study, we explored the association between CD247 gene single-nucleotide polymorphisms (SNPs) and rheumatoid arthritis (RA) in a Chinese Han population. We also evaluated the CD3zeta expression profile in peripheral blood mononuclear cells (PBMCs) from patients with RA and health controls. METHODS: Three CD247 polymorphisms (rs704853, rs1214611 and rs858554) were studied in 612 patients with RA and 848 controls in a Chinese population. Genotyping was performed using the Fluidigm 192.24 Dynamic ArrayTM Integrated Fluidic Circuit (IFC). For gene expression study, CD3zeta mRNA levels of 36 patients with RA and 39 healthy individuals were assessed by real-time polymerase chain reaction (RT-PCR). Data were analyzed by SPSS 11.5 software. RESULTS: A significant association between rs858554 polymorphism and RA was found under all genetic models (all p < 0.05). Moreover, we found the genotype distribution and allele frequency of rs858554 were significant associated with ACCP+ and RF+ phenotype as compare to health controls (all p < 0.05). Unfortunately, we did not detect any significant associations between rs704853, rs1214611 and RA susceptibility and autoantibody profiles (all p > 0.05). The gene expression assays showed that CD3zeta mRNA levels were downregulated in PBMCs of patients with RA when compared to healthy controls. CONCLUSIONS: Our results, the first reported for distinct Chinese populations, support a role of the CD247 gene in the susceptibility to RA. Further studies with more sample size are necessary to clarify the exact role of CD247 gene in the pathogenesis of RA. PMID- 27118210 TI - Optical painting and fluorescence activated sorting of single adherent cells labelled with photoswitchable Pdots. AB - The efficient selection and isolation of individual cells of interest from a mixed population is desired in many biomedical and clinical applications. Here we show the concept of using photoswitchable semiconducting polymer dots (Pdots) as an optical 'painting' tool, which enables the selection of certain adherent cells based on their fluorescence, and their spatial and morphological features, under a microscope. We first develop a Pdot that can switch between the bright (ON) and dark (OFF) states reversibly with a 150-fold contrast ratio on irradiation with ultraviolet or red light. With a focused 633-nm laser beam that acts as a 'paintbrush' and the photoswitchable Pdots as the 'paint', we select and 'paint' individual Pdot-labelled adherent cells by turning on their fluorescence, then proceed to sort and recover the optically marked cells (with 90% recovery and near 100% purity), followed by genetic analysis. PMID- 27118211 TI - Seasonal influenza vaccine (A/New York/39/2012) effectiveness against influenza A virus of health care workers in a long term care facility attached with the hospital, Japan, 2014/15: A cohort study. AB - The 2014/15 influenza season started earlier than usual, and intense activity was reflection of circulation of antigenically-drifted and vaccine-mismatched dominant A(H3N2) viruses. Although inpatients and health-care workers (HCWs) had a high influenza vaccination coverage rate well prior to the beginning of influenza season, numerous outbreaks of influenza A(H3N2) infection with fatal cases were reported in long-term care facilities (LTCFs) in Japan during 2014/15 influenza season. In January 2015, we were given opportunity to conduct outbreak investigation of influenza A at facility A (LTCF attached with hospital) in Western part of Japan. We evaluated overall and occupation-stratified influenza vaccine effectiveness (VE) among HCWs at facility A using a retrospective cohort design. Overall VE, occupation-stratified VE and adjusted VE (AVE) with 95% confidence intervals (CIs) were estimated using the following formula: (1 relative risks (RR) or 1-adjusted RR) * 100%. Overall vaccine coverage rate among HCWs was 85%. Overall VE for HCWs was 28% (95% CI: -70 to 67) and overall AVE was 3% (95% CI: -34 to 30). Although there was no severe cases, our results indicated that even with high vaccination coverage rate with appropriate vaccination timing, the VE was low for HCWs, which echoes with previously reported VE from other northern hemisphere countries. However, rehabilitation group who had high awareness against influenza as a group and carried out intensive precautions from early influenza season had no cases. We conclude that multiple preventive measures in addition to high vaccination rate is necessary for preventing influenza of HCWs working at LCTFs. PMID- 27118212 TI - Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria. AB - BACKGROUND: Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not be able to take the oral drug reliably. A comparison between the pharmacokinetics of oral syrup and intramuscular paracetamol given to patients with acute falciparum malaria and high body temperature was performed. METHODS: A randomized, open label, two-treatment, crossover, pharmacokinetic study of paracetamol dosed orally and intramuscularly was conducted. Twenty-one adult patients with uncomplicated falciparum malaria were randomized to receive a single 600 mg dose of paracetamol either as syrup or intramuscular injection on day 0 followed by a single dose administered by the alternative route on day 1. Paracetamol plasma concentrations were quantified frequently and modelled simultaneously using nonlinear mixed-effects modelling. The final population pharmacokinetic model was used for dose optimization simulations. Relationships between paracetamol concentrations with temperature and parasite half-life were investigated using linear and non-linear regression analyses. RESULTS: The population pharmacokinetic properties of paracetamol were best described by a two compartment disposition model, with zero-order and first-order absorption for intramuscular and oral syrup administration, respectively. The relative bioavailability of oral syrup was 84.4 % (95 % CI 68.2-95.1 %) compared to intramuscular administration. Dosing simulations showed that 1000 mg of intramuscular or oral syrup administered six-hourly reached therapeutic steady state concentrations for antipyresis, but more favourable concentration-time profiles were achieved with a loading dose of 1500 mg, followed by a 1000 mg maintenance dose. This ensured that maximum therapeutic concentrations were reached rapidly during the first 6 h. No significant relationships between paracetamol concentrations and temperature or parasite half-life were found. CONCLUSIONS: Paracetamol plasma concentrations after oral syrup and intramuscular administration in patients with acute falciparum malaria were described successfully by a two-compartment disposition model. Relative oral bioavailability compared to intramuscular dosing was estimated as 84.4 % (95 % CI 68.2-95.1 %). Dosing simulations showed that a loading dose followed by six hourly dosing intervals reduced the time delay to reach therapeutic drug levels after both routes of administration. The safety and efficacy of loading dose paracetamol antipyretic regimens now needs to be established in larger studies. PMID- 27118213 TI - Appendectomy in the pediatric population-a German nationwide cohort analysis. AB - BACKGROUND: Meta-analyses indicate advantages of laparoscopic compared to open appendectomy. Nationwide analyses on results of laparoscopic appendectomy are scarce and studies from Germany are not available. This observational cohort study based on a nationwide insurance database was performed to analyze results of pediatric laparoscopic versus open appendectomy in general use. METHODS: Data were extracted from the largest German statutory health insurance TK (~9 million clients) in a 3-year period (2010-2012). All patients aged 4-17 years with International Classification of Procedures in Medicine (ICPM) code "appendectomy" were included. Logistic regression analysis for the risk of a surgical complication within 180 postoperative days was performed. RESULTS: Appendectomy was performed in 8110 patients (52.6 % male; 47.4 % female) and conducted laparoscopically in 75.0 % of the patients (conversion rate = 1.2 %). Laparoscopic compared to open surgery was associated with a shorter length of hospital stay in both uncomplicated and complicated appendicitis. Patients with complicated appendicitis had lower readmission rates for surgical complications after laparoscopic appendectomy and logistic regression analysis confirmed a significantly lower risk of readmission for surgical complications after laparoscopic compared to open operation in adolescents. Pediatric surgeons operated 23.9 % and general surgeons 76.1 % of patients. Laparoscopy was less frequently used and the conversion rate was significantly higher in pediatric surgical departments. CONCLUSION: This first nationwide German cohort study confirms that laparoscopic appendectomy is associated with a less complicated postoperative course compared to open appendectomy, particularly in patients with complicated appendicitis. Pediatric surgeons used laparoscopy less frequently compared to general surgeons. Laparoscopic appendectomy should therefore be further promoted in pediatric surgical centers in Germany. PMID- 27118214 TI - Supporting community annotation and user collaboration in the integrated microbial genomes (IMG) system. AB - BACKGROUND: The exponential growth of genomic data from next generation technologies renders traditional manual expert curation effort unsustainable. Many genomic systems have included community annotation tools to address the problem. Most of these systems adopted a "Wiki-based" approach to take advantage of existing wiki technologies, but encountered obstacles in issues such as usability, authorship recognition, information reliability and incentive for community participation. RESULTS: Here, we present a different approach, relying on tightly integrated method rather than "Wiki-based" method, to support community annotation and user collaboration in the Integrated Microbial Genomes (IMG) system. The IMG approach allows users to use existing IMG data warehouse and analysis tools to add gene, pathway and biosynthetic cluster annotations, to analyze/reorganize contigs, genes and functions using workspace datasets, and to share private user annotations and workspace datasets with collaborators. We show that the annotation effort using IMG can be part of the research process to overcome the user incentive and authorship recognition problems thus fostering collaboration among domain experts. The usability and reliability issues are addressed by the integration of curated information and analysis tools in IMG, together with DOE Joint Genome Institute (JGI) expert review. CONCLUSION: By incorporating annotation operations into IMG, we provide an integrated environment for users to perform deeper and extended data analysis and annotation in a single system that can lead to publications and community knowledge sharing as shown in the case studies. PMID- 27118215 TI - Overview of the CSIRO Australian Animal Health Laboratory. AB - Emerging infectious diseases arising from livestock and wildlife pose serious threats to global human health, as shown by a series of continuous outbreaks involving highly pathogenic influenza, SARS, Ebola and MERS. The risk of pandemics and bioterrorism threats is ever present and growing, but our ability to combat them is limited by the lack of available vaccines, therapeutics and rapid diagnostics. The use of high bio-containment facilities, such as the CSIRO Australian Animal Health Laboratory, plays a key role studying these dangerous pathogens and facilitates the development of countermeasures. To combat diseases like MERS, we must take a holistic approach that involves the development of early biomarkers of infection, a suite of treatment options (vaccines, anti-viral drugs and antibody therapeutics) and appropriate animal models to test the safety and efficacy of candidate treatments. PMID- 27118216 TI - Molecular dissection of Oryza sativa salt-induced RING Finger Protein 1 (OsSIRP1): possible involvement in the sensitivity response to salinity stress. AB - Ubiquitination-mediated protein degradation via Really Interesting New Gene (RING) E3 ligase plays an important role in plant responses to abiotic stress conditions. Many plant studies have found that RING proteins regulate the perception of various abiotic stresses and signal transduction. In this study, Oryza sativa salt-induced RING Finger Protein 1 (OsSIRP1) gene was selected randomly from 44 Oryza sativa RING Finger Proteins (OsRFPs) genes highly expressed in rice roots exposed to salinity stress. Transcript levels of OsSIRP1 in rice leaves after various stress treatments, including salt, heat, drought and hormone abscisic acid (ABA), were observed. Poly-ubiquitinated products of OsSIRP1 were investigated via an in vitro ubiquitination assay.35S:OsSIRP1-EYFP was distributed in the cytosol of untreated and salt-treated rice protoplasts. Heterogeneous overexpression of OsSIRP1 in Arabidopsis reduced tolerance for salinity stress during seed germination and root growth. Our findings indicate that OsSIRP1 acts as a negative regulator of salinity stress tolerance mediated by the ubiquitin 26S proteasome system. PMID- 27118217 TI - Autofluorescent micelles self-assembled from an AIE-active luminogen containing an intrinsic unconventional fluorophore. AB - Autofluorescent micelles were constructed via the self-assembly of amphiphilic molecules containing an intrinsic fluorophore. The amphiphilic molecule was an AIE-active luminogen without a conventional pi-pi conjugated structure. In this unconventional luminogenic system, the hydrogen-bonded amide groups were assigned as the emitting sources. PMID- 27118218 TI - Functional changes in gut microbiota during hematopoietic stem cell transplantation for severe combined immunodeficiency. PMID- 27118219 TI - Cadherin-11 (CDH11) expression in the peripheral blood of patients with active Multiple Myeloma. PMID- 27118220 TI - Migraine and incidence of ischemic stroke: A nationwide population-based study. AB - Background The association between migraine and the incidence of ischemic stroke varies in different subgroups of patients. We aimed to clarify this association using a population-based database. Method A nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Two cohorts were extracted: a neurologist-diagnosed migraine cohort, and a non headache, propensity score-matched comparison cohort. All participants were enrolled in this study between 2005 and 2009, and were followed through the end of 2010, death, or the occurrence of ischemic stroke. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated with a Cox proportional hazards model to compare the between-group risks. Results Both cohorts ( n = 119,017 each) were followed for a mean period of 3.6 +/- 1.3 years. A total of 744 migraine patients (429,741 person-years) and 617 matched comparison individuals (436,141 person-years) developed ischemic stroke during the research period. Compared to the comparison cohort, patients with migraine were at an increased risk of ischemic stroke (aHR: 1.24, 95% CI: 1.12-1.38, p < 0.001). Subgroup analysis by age and sex revealed the highest risk in women aged <= 45 years (aHR: 3.44, 95% CI: 2.20-5.39, p < 0.001), especially among those with migraine with aura (aHR: 4.58, 95% CI: 2.45 - 8.56, p < 0.001). A trend for increased stroke risk was observed in men aged <= 45 years (aHR: 1.54, 95% CI: 0.96-2.48, p = 0.075). Conclusion Migraine is associated with an increased risk of ischemic stroke, especially in younger (age <= 45 years) women with migraine with aura. The trend toward ischemic stroke in younger men merits further exploration. PMID- 27118221 TI - Anterior horn syndrome: A rare manifestation of primary Sjogren's syndrome. AB - The authors report an exceptional case of an anterior horn syndrome associated with Sjogren's syndrome in a 58-year-old patient with a flaccid tetraparesis revealed by asymmetric atrophy and diffuse fasciculations associated with xerostomia and xerophthalmia. The electroneuromyography objectified a diffuse anterior horn syndrome. The brain MRI and spinal cord were normal. Laboratory tests revealed positive anti-SSA and anti-SSB antibody. The salivary glands biopsy objectified lymphocytic sialadenitis grade 3 of Chisholm. The Schirmer's test was abnormally low. Diagnosis of anterior horn syndrome as part of Sjogren's syndrome was retained. The methylprednisolone bolus allowed partial clinical improvement after 12 months of evolution. Therefore, in patients with isolated anterior horn involvement, a correct diagnosis of the underlying SS is often delayed or overlooked entirely; in these instances, standard clinicoserological assessment is recommendable. PMID- 27118222 TI - Missed Appointments at a Diabetes Centre: Not a Small Problem. PMID- 27118223 TI - Smartphone Imaging in Ophthalmology: A Comparison with Traditional Methods on the Reproducibility and Usability for Anterior Segment Imaging. AB - INTRODUCTION: This study aimed to determine the reproducibility and usability of anterior segment images taken from a smartphone stabilised on a slit-lamp with those taken from a custom-mounted slit-lamp camera. MATERIALS AND METHODS: This was a prospective, single- blind comparative digital imaging validation study. Digital photographs of patients with cataract were taken using a smartphone camera (an iPhone 5) on a telescopic mount and a Canon EOS 10D anterior segment camera. Images were graded and compared according to the Lens Opacification Classification System III (LOCS III). RESULTS: A total of 440 anterior segment images were graded independently by 2 ophthalmologists, 2 residents and 2 medical students. Intraclass correlation (ICC) between the iPhone and anterior segment camera images were fair for nuclear opalescence (NO) and nuclear colour (NC), and excellent for cortical (C) and posterior subcapsular (PSC) (NO: ICC 0.40, 95% CI, 0.16 to 0.57; NC: ICC 0.47, 95% CI, 0.16 to 0.66; C: ICC 0.76, 95% CI, 0.71 to 0.81; PSC: ICC 0.81, 95% CI, 0.76 to 0.85). There was no difference in grader impression of confidence and images usability between both cameras (P = 0.66 and P = 0.58, respectively). CONCLUSION: Anterior segment images taken from an iPhone have good reproducibility for retro-illuminated images, but fair reproducibility for NO and NC under low light settings. There were no differences in grader confidence and subjective image suitability. PMID- 27118224 TI - Comparison of Medication Adherence and Treatment Persistence between New Oral Anticoagulant and Warfarin among Patients. AB - INTRODUCTION: This study aimed to compare medication adherence and treatment persistence of patients on warfarin versus rivaroxaban in Singapore. A secondary objective was to identify significant covariates influencing adherence. MATERIALS AND METHODS: A retrospective cohort study was conducted where data from September 2009 to October 2014 was retrieved from the hospital electronic databases. Prescription records of rivaroxaban patients with 3 months or more of continuous prescription were extracted and compared against those of patients on warfarin. Primary outcome of adherence was determined based on the medication possession ratio (MPR), while treatment persistence was determined by outpatient clinic appointment gaps. RESULTS: A total of 94 rivaroxaban and 137 warfarin users were analysed by complete case analysis. The MPR of warfarin patients was lower than rivaroxaban patients by 10% (95% CI, 6.4% to 13.6%; P <0.0001). Also, there were more warfarin patients who had gaps in treatment persistence compared to those prescribed rivaroxaban (8.0% vs 1.1%; P = 0.03). Significant factors affecting medication adherence were age and duration of anticoagulant use. For every 10 year increase in age, MPR increased by 1.7% (95% CI, 0.7% to 2.8%). Similarly, for every year increase in duration of use, MPR increased by 1.8% (95% CI, 0.6% to 3.0%). Race, gender, concomitant medication and type of residence were not found to be significant covariates in the multivariable analysis. CONCLUSION: Patients on rivaroxaban are likely to be more adherent to their prescribed oral anticoagulant with increasing age and duration of treatment influencing adherence. PMID- 27118225 TI - Prevalence, Presentation, and Outcome of Heart Failure with Preserved Ejection Fraction among Patients Presenting with Undifferentiated Dyspnoea to the Emergency Room: A 10-year Analysis from a Tertiary Centre. AB - INTRODUCTION: We assessed the local prevalence, characteristics and 10-year outcomes in a heart failure (HF) cohort from the emergency room (ER). MATERIALS AND METHODS: Patients presenting with acute dyspnoea to ER were prospectively enrolled from December 2003 to December 2004. HF was diagnosed by physicians' adjudication based on clinical assessment and echocardiogram within 12 hours, blinded to N-terminal-pro brain natriuretic peptide (NT-proBNP) results. They were stratified into heart failure with preserved (HFPEF) and reduced ejection fraction (HFREF) by left ventricular ejection fraction (LVEF). RESULTS: At different cutoffs of LVEF of >=50%, >=45%, >=40%, and >50% plus excluding LVEF 40% to 50%, HFPEF prevalence ranged from 38% to 51%. Using LVEF >=50% as the final cutoff point, at baseline, HFPEF (n = 35), compared to HFREF (n = 55), had lower admission NT- proBNP (1502 vs 5953 pg/mL, P <0.001), heart rate (86 +/- 22 vs 98 +/- 22 bpm, P = 0.014), and diastolic blood pressure (DBP) (75 +/- 14 vs 84 +/- 20 mmHg, P = 0.024). On echocardiogram, compared to HFREF, HFPEF had more LV concentric remodelling (20% vs 2%, P = 0.003), less eccentric hypertrophy (11% vs 53%, P <0.001) and less mitral regurgitation from functional mitral regurgitation (60% vs 95%, P = 0.027). At 10 years, compared to HFREF, HFPEF had similar primary endpoints of a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and rehospitalisation for congestive heart failure (CHF) (HR 0.886; 95% CI, 0.561 to 1.399; P = 0.605), all-cause mortality (HR 0.663; 95% CI, 0.400 to 1.100; P = 0.112), but lower cardiovascular mortality (HR 0.307; 95% CI, 0.111 to 0.850; P = 0.023). CONCLUSION: In the long term, HFPEF had higher non-cardiovascular mortality, but lower cardiovascular mortality compared to HFREF. PMID- 27118226 TI - Time for Action on Viral Hepatitis. AB - The recent outbreak of hepatitis C virus (HCV) at Singapore General Hospital (SGH) has highlighted the dangers of viral hepatitis. In this case, infection control and environmental contamination were the culprits, particularly, a drop of blood containing 5 million IU HCV. From a broader perspective, there has been a revolution in HCV therapy with the recent rapid evolution of short-term (12 weeks) safe, all oral directly- acting antiviral (DAA) therapy leading to cure rates of 90% to 100%, even in previously difficult to treat patients with liver cirrhosis, previous treatment failure and those on immunosuppression. Consequently, treating HCV in risk groups such as renal dialysis and haemophiliacs can eliminate a pool of infected patients to prevent future outbreaks. A seroprevalence study is needed to identify a possible "birth cohort" effect that could aid screening. For HBV, vaccination has reduced prevalence to 3.8%, but these patients are prone to complications such as HBV flares. Since 2014, 13 patients developed liver failure and were listed for liver transplantation at National University Hospital (NUH) but 6 died beforehand. This avoidable catastrophe is due to undiagnosed HBV infection or patients who did not return for follow-up. Good antiviral therapy is available, but the issues are similar to HCV, identification of patients and linkage to care. A cure seems likely in the future as pharmaceutical companies are developing new agents. Singapore has joined in this initiative with a recent award of a national research translational grant to better understand the pathophysiology and the processes needed for a cure of HBV. PMID- 27118227 TI - Transvaginal Drainage of Pelvic Collections: a 5-year Retrospective Review in a Tertiary Gynaecology Centre. PMID- 27118228 TI - Demographics of Multiligamentous Knee Injuries at a Level 1 Trauma Centre. PMID- 27118229 TI - Professor Feng Pao Hsii (1936 - 2015). PMID- 27118230 TI - Improvement of Left Ventricular Remodelling by Inhibition of NF-kappaB in a Rat Model of Myocardial Infarction. AB - BACKGROUND: To investigate the effects of inhibition of NF-kappaB activation on left ventricular (LV) remodelling in a rat model of myocardial infarction (MI). METHODS: The acute MI model was established by ligation of left anterior descending coronary artery. Pyrrolidine dithiocarbamate (PDTC) (20mg/kg, Qd) was administered intraperitoneally to inhibit NF-kappaB activation. Eight weeks later, the cardiac structure and LV ejection fraction were assessed with echocardiography. The rat body, heart, and LV weights were measured to calculate LV mass indices. Activation of NF-kappaB in non-infarcted myocardium was detected by a TransAM NF-kappaB p65 Transcription Factor Assay Kit. Cardiac collagen volume fraction was evaluated by Masson staining. RESULTS: Eight weeks after the MI model was established, the LV posterior wall thickness in PDTC and MI group was 1.75+/-0.07mm and 1.85+/-0.07mm respectively (p<0.05). The LV mass index in the PDTC group (2.53+/-0.09) was lower than in the MI group (2.65+/-0.08, p<0.05). The LVEF in the PDTC group (63.89%+/-4.21%) was higher than in the MI group (42.73%+/-8.94%, p<0.05). The interstitial collagen deposition in the non infarcted myocardium in the PDTC group was less than in the MI group (7.25%+/ 1.88% vs. 10.09%+/-2.19%, p<0.05). CONCLUSION: Inhibition of activation of NF kappaB may result in improvement of myocardial remodelling after myocardial infarction, which is possibly attributable to reduced collagen deposition in non infarcted areas. PMID- 27118231 TI - Monocyte to HDL Cholesterol Ratio Predicts Coronary Artery Disease Severity and Future Major Cardiovascular Adverse Events in Acute Coronary Syndrome. AB - BACKGROUND: We aimed to investigate the usefulness of monocyte to HDL cholesterol ratio (MHR) in predicting coronary artery disease severity and future major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS). METHODS: 2661 patient with ACS were enrolled and followed up during median 31.6 months. RESULTS: MHR were significantly positively correlated with neutrophil to lymphocyte ratio (r=0.438), CRP (r=0.394), Gensini (r=0.407), and SYNTAX score (r=0.333). During in-hospital and long-term follow-up, MACE, stent thrombosis, non-fatal MI, and mortality occurred more frequently in the third tertile group. Kaplan-Meier analysis revealed the higher occurrence of MACE in the third tertile group compared with other tertiles. Adjusting for other factors, a MHR value in the third tertile group was determined as an independent predictor of in-hospital and long-term MACE. CONCLUSIONS: MHR as a novel inflammation-based marker seemed to be an independent predictor of severity of coronary artery disease and future cardiovascular events in patients with ACS. MHR may utilise the identification of patients who are at higher risk for MACE and individualisation of targeted therapy. PMID- 27118232 TI - Systolic Right Ventricular Function in Children with Cystic Fibrosis. PMID- 27118233 TI - Parallel Running Two-way Right Ventricles as a Cause of Refractory Right Heart Failure. PMID- 27118235 TI - Corrigendum on: Diaz-Gallardo P, Francisco S and Allende C. Traumatic midcarpal dislocation in an 8-year-old girl. J Hand Surg Eur. Epub ahead of print 19th February 2016. DOI: 10.1177/1753193416632155. PMID- 27118234 TI - Soluble Guanylate Cyclase Stimulators: a Novel Treatment Option for Heart Failure Associated with Cardiorenal Syndromes? AB - Heart failure in the setting of chronic kidney disease (CKD) is an increasingly common scenario and carries a poor prognosis. Clinicians lack tools for primary or secondary heart failure prevention in patients with cardiorenal syndromes. In patients without CKD, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) and statins mitigate cardiovascular risk in large part due to salutary effects on the endothelium. In the setting of CKD, use of these therapies is limited by adverse effects of hyperkalemia in pre-dialysis CKD (ACE-I/ARB), or potential increased risk of stroke in end-stage renal disease (statins). The soluble guanylate cyclase (sGC) stimulators are a novel class of medications that promote endothelial and myocardial function with no known risk of hyperkalemia or stroke. In this review, we discuss the evidence emerging from recent clinical trials of sGC stimulators in pulmonary hypertension and heart failure, the diseased pathways involved in cardiorenal syndromes likely to be restored by sGC stimulators, and several strategies for designing future clinical trials of cardiorenal syndromes that might shorten the timeline for discovery and approval of effective cardiovascular therapies in these high-risk patients. PMID- 27118236 TI - Stick-slip at soft adhesive interfaces mediated by slow frictional waves. AB - Stick-slip is a friction instability that governs diverse phenomena from squealing automobile brakes to earthquakes. At soft adhesive interfaces, this instability has long been attributed to Schallamach waves, which are a type of slow frictional wave. We use a contact configuration capable of isolating single wave events, coupled with high speed in situ imaging, to demonstrate the existence of two new stick-slip modes. It is shown that these modes also correspond to the passage of slow waves-separation pulse and slip pulse-with distinct nucleation and propagation characteristics. The slip pulse, characterized by a sharp stress front, propagates in the same direction as the Schallamach wave. In contrast, the separation pulse, involving local interface detachment and resembling a tensile neck, travels in exactly the opposite direction. A change in the stick-slip mode from the separation to the slip pulse is effected simply by increasing the normal force. Taken together, the three waves constitute all possible stick-slip modes in low-velocity sliding. The detailed observations enable us to present a phase diagram delineating the domains of occurrence of these waves. We suggest a direct analogy between the observed slow frictional waves and well known muscular locomotory waves in soft bodied organisms. Our work answers basic questions about adhesive mechanisms of frictional instabilities in natural and engineered systems, with broader implications for slow surface wave phenomena. PMID- 27118237 TI - A neutron spectrometer concept implementing RENS for studies in life sciences. AB - BACKGROUND: Resolution Elastic Neutron Scattering (RENS) method involves performing elastic scattering intensity scans as a function of the instrumental energy resolution and as a function of temperature. METHODS: In the framework of RENS, numerical simulation and experimental data show that in the measured elastic scattering law against the logarithm of the instrumental energy resolution an inflection point occurs when the resolution time intersects the system relaxation time; conversely, in the measured elastic scattering law against temperature an inflection point turns up when the system relaxation time intersects the resolution time. RESULTS: For practical implementation of the RENS technique, a dedicated neutron spectrometer would be needed. Here we propose a concept of such a spectrometer that utilizes mechanical velocity selection of both incident and scattered neutrons over a wide angular range. The instrument is able to collect intensity scans vs energy resolution where the instrumental resolution time changes crisscrossing the system relaxation time, and intensity scans vs temperature where the system relaxation time changes intersecting the instrumental resolution time. CONCLUSIONS: We propose a RENS spectrometer concept based on velocity selection of incident neutrons and wide-angle velocity selection of scattered neutrons achieved by the same rotating collimator-type mechanical device with the optimized shape of blades. GENERAL SIGNIFICANCE: RENS spectrometer is strongly appealing and innovative because of the simultaneous data collection as a function of energy resolution, wide wavevector range and temperature. Such a spectrometer would be the first practical implementation of RENS concept with a broad range of applications in Life Sciences. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazu and Dr. Federica Migliardo. PMID- 27118238 TI - Hepatitis C genotype 4R resistance-associated polymorphisms: The achilles heel of the nonstructural 5A inhibitors? PMID- 27118239 TI - The effects of topical diclofenac, topical flurbiprofen, and humidity on corneal sensitivity in normal dogs. AB - PURPOSE: To determine the immediate and chronic effects of topical 0.1% diclofenac and 0.03% flurbiprofen on corneal sensitivity in normal canine eyes. ANIMALS STUDIED: Eighteen normal, nonbrachycephalic dogs. METHODS: A prospective, randomized, masked, crossover study was performed. To determine the immediate effects associated with treatment, the study drug was instilled into the eye every 5 min for five doses, and corneal sensitivity of treated and untreated eyes was obtained prior to treatment and every 15 min post-treatment for 60 min. To determine the chronic effects, the study drug was instilled every 12 h for 30 days, and corneal sensitivity of treated and untreated eyes was obtained prior to treatment on days 0 and 30. A washout period of at least 30 days occurred between drug crossover. Ambient temperature and humidity were measured throughout the study. RESULTS: After multiple instillations, there was no difference in corneal sensitivity between eyes over time for diclofenac (P = 0.67) or flurbiprofen (P = 0.54), with a median sensitivity of 25 mm (1.8 g/mm2 ). After chronic dosing, there was no difference in corneal sensitivity between eyes over time for diclofenac (P = 0.82) or flurbiprofen (P = 0.56), with a median sensitivity of 35 mm (1.0 g/mm2 ). Decreasing ambient humidity was associated with an increase in sensitivity measurements (P = 0.0001). CONCLUSIONS: Neither diclofenac nor flurbiprofen had an effect on corneal sensitivity after multiple-drops or twice daily dosing for 30 days. Ambient humidity may have an effect on corneal sensitivity measurements, with a longer filament length eliciting a blink response at lower humidity. PMID- 27118241 TI - Corrigendum. PMID- 27118240 TI - KRAS mutation analysis by next-generation sequencing in endoscopic ultrasound guided sampling for solid liver masses. AB - BACKGROUND AND AIM: KRAS mutation analysis may provide ancillary diagnostic yield in an endoscopic ultrasound (EUS)-guided histopathological evaluation. We evaluated the clinical impact of KRAS mutation analysis with cytological and histological evaluations in EUS-guided tissue sampling, using a core biopsy needle for solid liver masses. METHODS: EUS-guided fine needle biopsy (EUS-FNB) using a core biopsy needle was performed in patients with primary or metastatic liver masses that were suspected malignancies. KRAS mutations were analyzed in all specimens obtained. The peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping method was compared with a next-generation sequencing (NGS) method for detecting KRAS mutations. RESULTS: EUS-FNB with a core biopsy needle was performed in 28 patients with solid liver masses located in the liver's left lobe. The diagnostic accuracies for malignancy of on-site cytology, cytology using Papanicolaou staining, and histology including immunohistochemical stains were 82.1%, 85.7%, and 89.3%, respectively. KRAS gene mutations were observed in 14.3% of patients by the PNA-PCR clamping method. The NGS method detected more KRAS mutations than the PNA-PCR clamping method: in 25% of patients. Adding the results of KRAS mutation analysis to the cytohistopathological evaluation, the overall diagnostic accuracy of EUS-guided tissue sampling was 96.4%. CONCLUSIONS: EUS-guided tissue sampling for solid liver masses in the left lobe provided high diagnostic accuracy from cytological and histological evaluations. KRAS mutation analysis provided additional diagnostic yield in patients with inconclusive cytohistopathological results from EUS-guided tissue sampling. The NGS method detected additional KRAS mutations in patients with negative PNA-mediated PCR clamping test results. PMID- 27118242 TI - Recognition of acyl carrier proteins by ketoreductases in assembly line polyketide synthases. AB - Ketoreductases (KRs) are the most widespread tailoring domains found in individual modules of assembly line polyketide synthases (PKSs), and are responsible for controlling the configurations of both the alpha-methyl and beta hydroxyl stereogenic centers in the growing polyketide chain. Because they recognize substrates that are covalently bound to acyl carrier proteins (ACPs) within the same PKS module, we sought to quantify the extent to which protein protein recognition contributes to the turnover of these oxidoreductive enzymes using stand-alone domains from the 6-deoxyerythronolide B synthase (DEBS). Reduced 2-methyl-3-hydroxyacyl-ACP substrates derived from two enantiomeric acyl chains and four distinct ACP domains were synthesized and presented to four distinct KR domains. Two KRs, from DEBS modules 2 and 5, displayed little preference for oxidation of substrates tethered to their cognate ACP domains over those attached to the other ACP domains tested. In contrast, the KR from DEBS module 1 showed an ~10-50-fold preference for substrate attached to its native ACP domain, whereas the KR from DEBS module 6 actually displayed an ~10-fold preference for the ACP from DEBS module 5. Our findings suggest that recognition of the ACP by a KR domain is unlikely to affect the rate of native assembly line polyketide biosynthesis. In some cases, however, unfavorable KR-ACP interactions may suppress the rate of substrate processing when KR domains are swapped to construct hybrid PKS modules. PMID- 27118244 TI - Development of Loop-Mediated Isothermal Amplification (LAMP) Assay for Rapid Detection of Cannabis sativa. AB - In many parts of the world, the possession and cultivation of Cannabis sativa L. are restricted by law. As chemical or morphological analyses cannot identify the plant in some cases, a simple yet accurate DNA-based method for identifying C. sativa is desired. We have developed a loop-mediated isothermal amplification (LAMP) assay for the rapid identification of C. sativa. By optimizing the conditions for the LAMP reaction that targets a highly conserved region of tetrahydrocannabinolic acid (THCA) synthase gene, C. sativa was identified within 50 min at 60-66 degrees C. The detection limit was the same as or higher than that of conventional PCR. The LAMP assay detected all 21 specimens of C. sativa, showing high specificity. Using a simple protocol, the identification of C. sativa could be accomplished within 90 min from sample treatment to detection without use of special equipment. A rapid, sensitive, highly specific, and convenient method for detecting and identifying C. sativa has been developed and is applicable to forensic investigations and industrial quality control. PMID- 27118243 TI - Synthesis and antibacterial activity of novel 11-[3 [(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12 O-cyclic carbamate derivatives. AB - A series of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3 oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives (6a-h) were designed, synthesized and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against two groups of pathogens of Methicillin-sensitive Staphylococcus aureus (MIC50=0.031-2 MUg ml-1) except 6g and Methicillin-sensitive S. epidermidis (MIC50=0.031-0.5 MUg ml-1). MIC90 of 6d against Methicillin-resistant S. epidermidis was at least 16-fold better than that of erythromycin (EMA), azithromycin (AZM) and ABT-773. 6d and 6e had more potent antibacterial activity against S. pneumoniae than EMA, AZM and ABT-773. In particular, compounds 6d and 6e also showed relatively potent activity against Haemophilus influenzae and Streptococcus hemolyticus. PMID- 27118245 TI - High levels of susceptibility to measles, mumps and rubella (MMR) in HIV-infected individuals in Ireland. PMID- 27118246 TI - Experience and information loss in auditory and visual memory. AB - Recent studies show that recognition memory for sounds is inferior to memory for pictures. Four experiments were conducted to examine the nature of auditory and visual memory. Experiments 1-3 were conducted to evaluate the role of experience in auditory and visual memory. Participants received a study phase with pictures/sounds, followed by a recognition memory test. Participants then completed auditory training with each of the sounds, followed by a second memory test. Despite auditory training in Experiments 1 and 2, visual memory was superior to auditory memory. In Experiment 3, we found that it is possible to improve auditory memory, but only after 3 days of specific auditory training and 3 days of visual memory decay. We examined the time course of information loss in auditory and visual memory in Experiment 4 and found a trade-off between visual and auditory recognition memory: Visual memory appears to have a larger capacity, while auditory memory is more enduring. Our results indicate that visual and auditory memory are inherently different memory systems and that differences in visual and auditory recognition memory performance may be due to the different amounts of experience with visual and auditory information, as well as structurally different neural circuitry specialized for information retention. PMID- 27118247 TI - A hybrid system with highly enhanced graphene SERS for rapid and tag-free tumor cells detection. AB - By dint of unique physical/chemical properties and bio-compatibility, graphene can work as a building block for a SERS substrate and open up a unique platform for tumor cells detection with high sensitivity. Herein we demonstrate a facile system with highly enhanced surface enhanced Raman spectroscopy of graphene (G SERS). The system consists of a reduced graphene oxide (rGO) sandwiched by silver and gold nanostructures. Due to the ultrasmall thickness of rGO, the inter coupling between Ag and Au nanoparticles is precisely controlled and the local field enhancement has been improved to more than 70 times. Associated with the unique chemical mechanism of rGO, the hybrid system has been utilized to identify tumor cells without using any biomarkers. We believe this research will be important for the applications of rGO in cancer screening. PMID- 27118248 TI - The Potential Impact on Children of New CDC Opioid Guidelines. PMID- 27118249 TI - Rapid Stencil Mask Fabrication Enabled One-Step Polymer-Free Graphene Patterning and Direct Transfer for Flexible Graphene Devices. AB - We report a one-step polymer-free approach to patterning graphene using a stencil mask and oxygen plasma reactive-ion etching, with a subsequent polymer-free direct transfer for flexible graphene devices. Our stencil mask is fabricated via a subtractive, laser cutting manufacturing technique, followed by lamination of stencil mask onto graphene grown on Cu foil for patterning. Subsequently, micro sized graphene features of various shapes are patterned via reactive-ion etching. The integrity of our graphene after patterning is confirmed by Raman spectroscopy. We further demonstrate the rapid prototyping capability of a stretchable, crumpled graphene strain sensor and patterned graphene condensation channels for potential applications in sensing and heat transfer, respectively. We further demonstrate that the polymer-free approach for both patterning and transfer to flexible substrates allows the realization of cleaner graphene features as confirmed by water contact angle measurements. We believe that our new method promotes rapid, facile fabrication of cleaner graphene devices, and can be extended to other two dimensional materials in the future. PMID- 27118250 TI - The establishment of DOHaD working groups in Australia and New Zealand. AB - The evidence underpinning the developmental origins of health and disease (DOHaD) is overwhelming. As the emphasis shifts more towards interventions and the translational strategies for disease prevention, it is important to capitalize on collaboration and knowledge sharing to maximize opportunities for discovery and replication. DOHaD meetings are facilitating this interaction. However, strategies to perpetuate focussed discussions and collaborations around and between conferences are more likely to facilitate the development of DOHaD research. For this reason, the DOHaD Society of Australia and New Zealand (DOHaD ANZ) has initiated themed Working Groups, which convened at the 2014-2015 conferences. This report introduces the DOHaD ANZ Working Groups and summarizes their plans and activities. One of the first Working Groups to form was the ActEarly birth cohort group, which is moving towards more translational goals. Reflecting growing emphasis on the impact of early life biodiversity - even before birth - we also have a Working Group titled Infection, inflammation and the microbiome. We have several Working Groups exploring other major non cancerous disease outcomes over the lifespan, including Brain, behaviour and development and Obesity, cardiovascular and metabolic health. The Epigenetics and Animal Models Working Groups cut across all these areas and seeks to ensure interaction between researchers. Finally, we have a group focussed on 'Translation, policy and communication' which focusses on how we can best take the evidence we produce into the community to effect change. By coordinating and perpetuating DOHaD discussions in this way we aim to enhance DOHaD research in our region. PMID- 27118251 TI - Cellular and Animal Studies: Insights into Pathophysiology and Therapy of PCOS. AB - Basic science studies have advanced our understanding of the role of key enzymes in the steroidogenesis pathway and those that affect the pathophysiology of PCOS. Studies with ovarian theca cells taken from women with PCOS have demonstrated increased androgen production due to increased CYP17A1 and HSD3B2 enzyme activities. Furthermore, overexpression of DENND1A variant 2 in normal theca cells resulted in a PCOS phenotype with increased androgen production. Notably, cellular steroidogenesis models have facilitated the understanding of the mechanistic effects of pharmacotherapies, including insulin sensitizers (e.g., pioglitazone and metformin) used for the treatment of insulin resistance in PCOS, on androgen production. In addition, animal models of PCOS have provided a critical platform to study the effects of therapeutic agents in a manner closer to the physiological state. Indeed, recent breakthroughs have demonstrated that natural derivatives such as the dietary medium-chain fatty acid decanoic acid (DA) can restore estrous cyclicity and lower androgen levels in an animal model of PCOS, thus laying the platform for novel therapeutic developments in PCOS. This chapter reviews the current understanding on the pathways modulating androgen biosynthesis, and the cellular and animal models that form the basis for preclinical research in PCOS, and sets the stage for clinical research. PMID- 27118252 TI - Sonographic evaluation of polycystic ovaries. AB - The morphological features of the ovaries in women with polycystic ovary syndrome (PCOS) have been well described by ultrasound imaging technology. These include enlarged ovary size, multiple small follicles of similar size, increased ovarian stromal volume and echogenicity, peripheral distribution of the follicles, and higher stromal blood flow. Ultrasound identification of the presence of polycystic ovarian morphology (PCOM) has been recognized as a component of PCOS diagnosis. With the advance of ultrasound technology, new definition has been proposed recently. There is, however, a paucity of data for the ovarian morphology in normal and PCOS adolescents. Magnetic resonance imaging has the potential to be an alternative imaging modality for diagnosing PCOM in adolescence. PMID- 27118253 TI - Socio-economic differences in HIV/AIDS mortality in South Africa. AB - OBJECTIVES: To quantify socio-economic differences in the risk of HIV/AIDS mortality in South Africa for different measures of socio-economic status. METHODS: Systematic literature search in Web of Knowledge and PubMed. Measures of relative risk (RR) were pooled separately for education, income, assets score and employment status as measures of socio-economic status, using inverse-variance weighted DerSimonian-Laird random effects meta-analyses. RESULTS: Ten studies were eligible for inclusion comprising over 175 000 participants and 6700 deaths. For income (RR 1.55, 95% confidence interval (CI) 1.15-2.09), assets score (RR 1.63, 95% CI 1.12-2.36) and employment status (RR 1.52, 95% CI 1.21-1.92), persons of low socio-economic status had an over 50% higher risk of dying from HIV/AIDS. The RR of 1.10 for education was not significant (95% CI 0.74-1.65). CONCLUSIONS: Future research should identify effective strategies to reduce HIV/AIDS mortality and alleviate the consequences of HIV/AIDS deaths, particularly for poorer households. PMID- 27118254 TI - Early transcriptomic response of Arabidopsis thaliana to polymetallic contamination: implications for the identification of potential biomarkers of metal exposure. AB - Heavy metal contaminated sites are frequently characterized by the simultaneous presence of several heavy metals. However, many studies report metal-induced plant responses after long-term exposure to just one metal. By contrast, whole genome expression microarrays were employed here to investigate the early (3 h) transcriptional responses of Arabidopsis thaliana plants exposed to polymetallic treatment (Pb, Hg, Cu, Cd, Co, Ni, Zn, and Mn) at low (L) and high (H) concentrations. After 3 h of exposure to polymetallic treatment, a total of 1315 noticeably (>=2-fold) and significantly (P < 0.05) differentially expressed genes were identified: 656 and 351 upregulated and 314 and 200 downregulated genes in L and H treatments, respectively. Functional analysis revealed that many genes involved in oxidative stress and perception/signalling/regulation systems were activated. Genes encoding proteins involved in hormone regulation (jasmonic acid, abscisic acid, ethylene, and auxins), glucosinolate metabolism and sulphur and nitrogen transport were also modulated. RT-qPCR analysis of four downregulated (AOP2, SAUR16, BBX31, and MTPC3) and upregulated genes (ASN1, DIN2, BT2, and EXL5), markedly responsive to both L and H treatments, validated our microarray data and suggested the potential of some of these genes (AOP2, SAUR16, ASN1, and DIN2) as early biomarkers of metal exposure. Relevant changes in gene expression occur as early as 3 h after exposure to polymetallic treatment. Four genes deserve further studies as novel putative biomarkers of early metal exposure and also owing to their potential implications in stress-related mechanisms: sulphur balance (AOP2), phytohormone regulation of plant growth and development (SAUR16), ammonium detoxification (ASN1) and senescence (DIN2). PMID- 27118255 TI - Comparison of various bone cement ossiculoplasty techniques and functional results. AB - OBJECTIVE: In this study, functional results of different bone cement ossiculoplasty techniques are compared. METHODS: Retrospective case review at a tertiary referral center. Patients who underwent middle ear surgery and bone cement ossiculoplasty between 2006-2012 were included. A total of 52 patients, including 30 patients with 'Incus to stapes' (Group 1) and 13 patients with 'malleus to stapes' (Group 2), five patients with 'incudoplasty + stapedotomy' (Group 3), and four patients with 'malleus to incus' (Group 4) ossiculoplasty were enrolled in the study. Pre-operative and post-operative audiological findings of each group were evaluated. RESULTS: The mean hearing gain (the difference between pre-operative and post-operative air bone gap (ABG)) was 13 dB for Group 1, 30 dB for Group 2, 24 dB for Group 3, and 9 dB for Group 4. The pre operative air pure tone averages (PTA) of groups 1, 2, and 3 improved significantly in the post-operative period (p < 0.05). Closure of post-operative ABG of patients to less than 20 dB and 10 dB were as follows: ~70% and 43% in group 1; 86% and 76% in group 2; 100% and 60% in group 3; and 75% and 50% in group 4, respectively. CONCLUSIONS: The results showed that glass ionomer cement is a simple and effective method for reconstruction of ossicular discontinuity in various ossicular chain pathologies and can be an alternative to conventional rebridging techniques such as sculpted incus interposition or partial ossicular replacement prosthesis (PORP). PMID- 27118256 TI - Hand grip strength as a screening tool for frailty in older patients with haematological malignancies. AB - OBJECTIVES: Frailty is a geriatric syndrome characterized by decreased physiological reserves and an age-related vulnerability to stressors with higher risk of adverse health outcomes. Comprehensive geriatric assessment (CGA) might detect frailty but is time-consuming, implying the need for initial frailty screening. Most frailty screening tools do not include functional measures. Hand grip strength (HGS) is a reliable surrogate for overall muscle strength and predicts functional decline, morbidity and mortality. No studies are available in cancer patients on HGS as screening tool for frailty. We aimed to assess whether HGS can be used as a screening tool to predict an abnormal CGA and therefore frailty. METHODS: Single centre cohort study in 59 patients aged 70 years or more with a haematological malignancy. HGS was measured using a vigorimeter. A patient was considered frail if any of the CGA elements were impaired. RESULTS: Mean HGS before start of therapy in women was 37.0 +/- 14.3 kPa and in men 66.1 +/- 13.1 kPa. An abnormal CGA was present in 52 subjects (88%). HGS was associated with concurrent abnormal CGA (p = 0.058 in women, p = 0.009 in men). AUC was 0.800 (SE = 0.130) in women and 0.847 (SE = 0.118) in men. Optimal HGS cut-off points for likelihood of abnormal CGA were <=52 kPa in women and <=80 kPa in men. DISCUSSION: In older patients with haematological malignancies, impairment in muscle function is present at diagnosis. HGS seems a promising screening tool to identify patients with abnormal CGA. PMID- 27118257 TI - Association of Notch pathway down-regulation with Triple Negative/Basal-like breast carcinomas and high tumor-infiltrating FOXP3+ Tregs. AB - T regulatory cells (Tregs) are a lineage of lymphocytes involved in immune response suppression that are characterized by the expression of the forkhead box P3 (FOXP3) transcription factor. Notch pathway regulates FOXP3 transcription in Tregs, but its role in breast cancer is unknown. We aimed at studying whether Notch pathway regulates FOXP3 expression and Tregs content in breast cancer, and its association with luminal breast carcinomas. We analyzed by quantitative Real Time PCR the mRNA levels of FOXP3, Notch pathway genes (Notch1, Notch2, Notch4 and Jagged1) and STAT3 in a series of 152 breast carcinomas including hormone receptor-positive and -negative phenotypes (luminal and Triple Negative/Basal like). We also studied the protein expression of Notch1, STAT3 and FOXP3 by immunohistochemistry. High FOXP3 mRNA levels correlated with larger tumor size (p=0.010), histological grade 3 (p=0.008) and positive lymph-node status (p=0.031). Also, low levels of Notch pathway genes mRNA correlated with poor prognostic factors such as larger tumor size, positive lymph-node status, tumor phenotype and infiltrating tumor Tregs. A survival analysis for the patients showed that large tumor size, histological grade 3, vascular invasion, infiltrating Tregs and low Notch1 mRNA expression were significantly associated with a decreased patients' overall survival (p<=0.05). On a multivariate analysis, high Tregs content (HR=3.00, 95% CI 1.04-8.90, p=0.042) and low Notch1 mRNA levels (HR=3.33, 95% CI 1.02-10.86, p=0.046) were independent markers for overall survival. Our results support that the Notch pathway up-regulation promotes luminal breast carcinomas, whereas down-regulation correlates with the expression of FOXP3, favors tumor Tregs infiltration and associates with Triple Negative/Basal-like tumors. PMID- 27118259 TI - Halostella salina gen. nov., sp. nov., an extremely halophilic archaeon isolated from solar salt. AB - A novel halophilic archaeon designated strain CBA1114T was isolated from solar salt in the Republic of Korea. Strain CBA1114T, cells of which were coccoid and Gram-stain-negative, grew in the presence of 15-30 % (w/v) NaCl (optimum, 20 %) and at 20-50 degrees C (optimum, 40 degrees C) and pH 7.0-9.0 (optimum, pH 8.0). Strain CBA1114T required Mg2+ for growth. Strain CBA1114T had three 16S rRNA genes, rrnA, rrnB and rrnC; levels of similarity between the sequences were 99.7-99.9 %. The 16S rRNA gene sequence of strain CBA1114T showed 91.7 % similarity to that of Haloterrigena thermotolerans PR5T. In multilocus sequence analysis (MLSA), five housekeeping genes, atpB, EF-2, radA, rpoB' and secY, were found to be closely related to those of the members of the genera Halorientalis(89.7 % similarity of the atpB gene sequence), Halomicroarcula(91.9 %, EF-2), Haloterrigena(85.4 %, radA), Natronoarchaeum(89.2 %, rpoB') and Natrinema(75.7 %, secY). A phylogenetic tree generated from the results of MLSA of the five housekeeping genes showed that strain CBA1114T was closely related to species of the genus Halorientalis in the family Halobacteriaceae. The major polar lipids were identified as phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and unidentified lipids. The G+C content of the genomic DNA of strain CBA1114T was 68.1 mol%. According to the results of phylogenetic, phenotypic and chemotaxonomic analyses, we designate strain CBA1114T (=JCM 30111T=KCTC 4206T) as the type strain of Halostella salina gen. nov., sp. nov., a novel species of a new genus within the family Halobacteriaceae. PMID- 27118258 TI - Risks of developing breast and colorectal cancer in association with incomes and geographic locations in Texas: a retrospective cohort study. AB - BACKGROUND: No study has been conducted to investigate the spatial pattern and association of socioeconomic status (such as income) with breast and colorectal cancer incidence in Texas, United States. This study aimed to determine whether median household income was associated with the risk of developing breast and colorectal cancer in Texas and to identify higher cancer risks by race/ethnicity and geographic areas. METHODS: This was a retrospective cohort study with an ecological component in using aggregated measures at the county level. We identified 243,677 women with breast cancer and 155,534 men and women with colorectal cancer residing in 254 counties in Texas in 1995-2011 from the public use dataset of Texas Cancer Registry. The denominator population and median household income at the county level was obtained from the U.S. Bureau of the Census. Cancer incidence rates were calculated as number of cases per 100,000 persons and age-adjusted using the 2000 US population data. We used the ArcGIS v10.1 (geographic information system software) to identify multiple clustered counties with high and low cancer incidences in Texas. RESULTS: Age-adjusted breast cancer incidence rate in the highest median income quintile group was 151.51 cases per 100,000 in 2008-2011 as compared to 98.95 cases per 100,000 in the lowest median income quintile group. The risk of colorectal cancer appeared to decrease with increasing median income in racial/ethnic population. Spatial analysis revealed the significant low breast cancer incidence cluster regions located in southwest US-Mexico border counties in Texas. CONCLUSIONS: This study demonstrated that higher income was associated with an increased risk of breast cancer and a decreased risk of colorectal cancer in Texas. There were geographic variations with cancer incidence clustered in high risk areas in Texas. Future studies may need to explore more factors that might explain income and cancer risk associations and their geographic variations. PMID- 27118261 TI - ECG telemetry in conscious guinea pigs. AB - INTRODUCTION: During preclinical drug development, monitoring of the electrocardiogram (ECG) is an important part of cardiac safety assessment. To detect potential pro-arrhythmic liabilities of a drug candidate and for internal decision-making during early stage drug development an in vivo model in small animals with translatability to human cardiac function is required. METHODS: Over the last years, modifications/improvements regarding animal housing, ECG electrode placement, and data evaluation have been introduced into an established model for ECG recordings using telemetry in conscious, freely moving guinea pigs. Pharmacological validation using selected reference compounds affecting different mechanisms relevant for cardiac electrophysiology (quinidine, flecainide, atenolol, dl-sotalol, dofetilide, nifedipine, moxifloxacin) was conducted and findings were compared with results obtained in telemetered Beagle dogs. RESULTS AND CONCLUSION: Under standardized conditions, reliable ECG data with low variability allowing largely automated evaluation were obtained from the telemetered guinea pig model. The model is sensitive to compounds blocking cardiac sodium channels, hERG K(+) channels and calcium channels, and appears to be even more sensitive to beta-blockers as observed in dogs at rest. QT interval correction according to Bazett and Sarma appears to be appropriate methods in conscious guinea pigs. Overall, the telemetered guinea pig is a suitable model for the conduct of early stage preclinical ECG assessment. PMID- 27118260 TI - Chaotic time series prediction for prenatal exposure to polychlorinated biphenyls in umbilical cord blood using the least squares SEATR model. AB - Chaotic time series prediction based on nonlinear systems showed a superior performance in prediction field. We studied prenatal exposure to polychlorinated biphenyls (PCBs) by chaotic time series prediction using the least squares self exciting threshold autoregressive (SEATR) model in umbilical cord blood in an electronic waste (e-waste) contaminated area. The specific prediction steps basing on the proposal methods for prenatal PCB exposure were put forward, and the proposed scheme's validity was further verified by numerical simulation experiments. Experiment results show: 1) seven kinds of PCB congeners negatively correlate with five different indices for birth status: newborn weight, height, gestational age, Apgar score and anogenital distance; 2) prenatal PCB exposed group at greater risks compared to the reference group; 3) PCBs increasingly accumulated with time in newborns; and 4) the possibility of newborns suffering from related diseases in the future was greater. The desirable numerical simulation experiments results demonstrated the feasibility of applying mathematical model in the environmental toxicology field. PMID- 27118262 TI - LncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats mediated by P2X7 receptor in SCG. AB - Diabetic autonomic neuropathy includes the sympathetic ganglionic dysfunction. P2X7 receptor in superior cervical ganglia (SCG) participated in the pathological changes of cardiac dysfunction. Abnormal expression of long noncoding RNAs (lncRNAs) was reported to be involved in nervous system diseases. Our preliminary results obtained from rat lncRNA array profiling revealed that the expression of the uc.48+ was significantly increased in the rat SCG in response to diabetic sympathetic pathology. In this study, we found that lncRNAuc.48+ and P2X7 receptor in the SCG were increased in type 2 diabetic rats and were associated with the cardiac dysfunction. The uc.48+ small interference RNA (siRNA) improved the cardiac autonomic dysfunction and decreased the up-regulation P2X7 and the ratio of phosphorylated extracellular regulated protein kinases1/2 (p-ERK1/2) to ERK1/2 in SCG of type 2 diabetic rats. In conclusion, lncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats through regulating the expression of P2X7 and ERK signaling in SCG. PMID- 27118263 TI - How different is the proteome of the extended spectrum beta-lactamase producing Escherichia coli strains from seagulls of the Berlengas natural reserve of Portugal? AB - beta-Lactam antibiotics like cefotaxime are the most commonly used antibacterial agents. Escherichia coli strains 5A, 10A, 12A and 23B isolated from Seagulls feces, are cefotaxime-resistant strains that produces extended-spectrum beta lactamases. Bacterial resistance to these antibiotics occurs predominantly through structural modification on the penicillin-binding proteins and enzymatic inactivation by extended-spectrum beta-lactamases. Using classical proteomic techniques (2D-GE) coupled to mass spectrometry and bioinformatics extended analysis, in this study, we report several significant differences in cytoplasmic proteins expression when the strains were submitted to antibiotic stress and when the resistant strains were compared with a non-resistant strain. A total of 79 differentially expressed spots were collected for protein identification. Significant level of expression was found in antibiotic resistant proteins like beta-lactamase CTX-M-1 and TEM and also in proteins related with oxidative stress. This approach might help us understand which pathways form barriers for antibiotics, another possible new pathways involved in antibiotic resistance to devise appropriate strategies for their control already recognized by the World Health Organization and the European Commission. BIOLOGICAL SIGNIFICANCE: This study highlights the protein differences when a resistant strain is under antibiotic pressure and how different can be a sensible and resistant strain at the protein level. This survey might help us to understand the specifics barriers for antibiotics and which pathways are involved in its resistance crosswise the wildlife. PMID- 27118264 TI - Monosomy 22 and partial loss of INI1 expression in a biphasic synovial sarcoma with an Ewing sarcoma-like poorly differentiated component: Report of a case. AB - Poorly differentiated synovial sarcoma (PDSS) is a less common subtype of synovial sarcoma (SS) associated with a poor prognosis. We present a case of a SS with a poorly differentiated component that resembles Ewing sarcoma (ES). Initial immunohistochemical staining revealed a characteristic and strong expression of transducin-like enhancer of split 1 (TLE1) and weak to absent expression of integrase integrator 1 (INI1) staining. Stainings for keratin and epithelial membrane antigen (EMA) were negative in the tumoral lesion. Fluorescence In Situ Hybridization (FISH) analysis showed a rearrangement of the synaptotagmin (SYT) gene, confirming the diagnosis of SS. FISH analysis for the EWS RNA-binding protein 1 (EWSR1) gene revealed monoallelic loss of EWSR1. This finding was confirmed by an array comparative genomic hybridization (aCGH), showing complete loss of chromosome 22. Based on literature review, showing only a handful of cases of cytogenetically studied SS with loss of chromosome 22, this is probably a rare event in SS. Therefore, we assume that monoallelic loss of chromosome 22 cannot fully elaborate the underlying mechanism of the INI1 staining pattern in all SS, but it could account for the weak to absent INI1 staining in at least some cases. PMID- 27118265 TI - Ethnic Differences in Coronary Revascularisation following an Acute Coronary Syndrome in New Zealand: A National Data-linkage Study (ANZACS-QI 12). AB - BACKGROUND: The aim of this study was to describe ethnic differences in angiography and revascularisation rates following an acute coronary syndrome (ACS) in New Zealand. METHODS: National hospitalisation and mortality data were anonymously linked to determine receipt of angiography and revascularisation for 30-84 year-olds hospitalised with ACS between 2007 and 2012. Multilevel Cox regression, accounting for individual factors and admitting hospital, was used to estimate adjusted procedural rates within 30 days of admission. RESULTS: Of the 50,324 ACS patients included, 10% were Maori, 4% Pacific, 3% Indian and 83% New Zealand European or Other ethnicities (NZEO). A larger proportion of Maori (48%) than NZEO (36%), Pacific (19%) and Indian (14%) patients were admitted to hospitals without catheterisation facilities. More Maori and Pacific (22-24%) than NZEO and Indian patients (12-13%) had severe comorbidities. Maori and Pacific were less likely than NZEO patients to receive angiography (adjusted HRs 0.94 [0.91-0.98] and 0.93 [0.87-0.98] respectively) and revascularisation (adjusted HRs 0.79 [0.75-0.83] and 0.77 [0.71-0.83]), even after adjusting for important demographic and clinical factors. CONCLUSIONS: A higher comorbidity burden in Maori and Pacific patients and reduced access to catheterisation facilities for non-urban Maori contributed to lower procedure rates after ACS admission. Ethnic differences remained after adjustment for these factors and require further investigation. PMID- 27118266 TI - Efficacy and Safety of Spironolactone in Patients with Resistant Hypertension: A Meta-analysis of Randomised Controlled Trials. AB - BACKGROUND: The treatment of resistant hypertension (RH) is challenging. Several observational studies have suggested that the addition of spironolactone to triple-drug therapy might have a promising anti-hypertensive effect on RH. To provide more definite evidence for the benefit of spironolactone, we performed a meta-analysis of randomised controlled trials (RCTs) to evaluate the efficacy and safety of spironolactone in RH patients. METHODS: Articles were searched from PubMed, EMBASE and Cochrane Library. Randomised controlled trials investigating the effect of additional spironolactone on office blood pressure (BP), ambulatory BP or adverse events in RH patients were included for analysis. Then quality assessment, subgroup, sensitivity, and publication bias analyses were performed. RESULTS: Five RCTs involving a total of 553 patients were eligible for inclusion. Compared with control therapies, additional spironolactone treatment in RH patients significantly decreased 24-h ambulatory systolic BP (ASBP, weight mean difference [WMD]= -10.50, 95% confidence interval [CI] = -12.30 to -8.71, P<0.001), 24-h ambulatory diastolic BP (ADBP, WMD = -4.09, 95% CI = -5.28 to 2.91, P<0.001), daytime ASBP (WMD = -10.20, 95% CI = -12.41 to -7.99, P<0.001), daytime ADBP (WMD = -4.14, 95% CI = -5.50 to -2.78, P<0.001), night-time ASBP (WMD = -10.02, 95% CI = -12.63 to -7.41), night-time ADBP (WMD=-3.21, 95% CI= 4.84 to -1.58, P<0.001), office systolic BP (WMD=-16.99, 95% CI=-25.04 to -8.95, P<0.001) and office diastolic BP (WMD=-6.18, 95% CI=-9.30 to -3.05, P<0.001). However, serum potassium might be slightly elevated by additional spironolactone (WMD=0.181, 95% CI=0.042 to 0.319, P=0.011). CONCLUSION: Spironolactone combined with triple-drug therapy may be an effective and relatively safe strategy for the management of RH patients. PMID- 27118267 TI - Multimodality Approach to Diagnose Pseudomalignant Myxoma of the Heart. PMID- 27118269 TI - CO oxidation by MoS2-supported Au19 nanoparticles: effects of vacancy formation and tensile strain. AB - The mechanism of the catalytic oxidation of CO activated by MoS2-supported Au19 nanoparticles (NPs) was studied using density functional theory calculations. Of particular interest were the effects of the physical/chemical modification of a MoS2 support on the CO oxidation pathway and the activation of specific reactive centers, i.e., the Au atoms of Au19 or the Au-MoS2 perimeter sites. We systematically modified MoS2 by introducing an S vacancy or 5% tensile strain and studied the shift of each reaction step and the overall change in the reaction pathway and activity. Despite the lack of direct involvement of the Au-MoS2 perimeter in the reaction, the combination of an S vacancy and the tensile strain in the MoS2 support was found to improve the stability and catalytic activity of Au NPs for CO oxidation. The results show that support modification can provide information for new pathways for the rational design of Au-based catalysts. PMID- 27118268 TI - In-bore magnetic resonance-guided transrectal biopsy for the detection of clinically significant prostate cancer. AB - PURPOSE: To determine the safety and efficacy of in-bore magnetic resonance guided prostate biopsy (MRGB) for detection of clinically significant disease (CSD) in untreated men with known or suspected prostate cancer (PCa). METHODS: 512 patients underwent multiparametric magnetic resonance imaging (Mp-MRI) followed by MRGB at one of three centers in this IRB-approved, HIPAA-compliant, retrospective study. Exclusion criteria were prior prostate cancer therapy and incomplete Mp-MRI (n = 51). Patients (n = 461) were analyzed in two subcohorts: no prior PCa (NP) (n = 381) and active surveillance (AS) (n = 80). Detection rates of PCa and CSD (Gleason Score >=3 + 4) were calculated and compared among subcohorts and by Mp-MRI assessment grade. Logistic regression was performed to identify predictors for detection of PCa and CSD. RESULTS: Mean patient age was 66 years, median prostate-specific antigen (PSA) was 7.5 ng/mL, and median prostate volume was 54 cc. A mean of 1.7 targets was sampled per gland. Significant adverse events (urosepsis and hematuria with obstruction) occurred in 1% (5/461). Overall PCa detection rates were 51% per patient (233/461) and 37% per lesion (282/757). 65% (151/233) of men with detected PCa had CSD. Per-patient PCa detection rates in the NP and AS subcohorts were 47% (178/381) and 69% (55/80), respectively, significantly higher in the AS group (p < 0.001). CSD was detected in 10% (47/451), 43% (96/225) and 84% (68/81) of lesions with Mp-MRI assessment grades of 3, 4, and 5, respectively. Older age, higher PSA, and lower prostate volume predicted MRGB detection of CSD (OR 1.07 and p = 0.003, OR 1.1 and p = 0.014, and OR 0.98 and p = 0.032, respectively). CONCLUSIONS: In-bore MRGB is safe and high yield for detection of CSD. PMID- 27118270 TI - Principles of safe laparoscopic entry. PMID- 27118271 TI - Commentary: Writing and Evaluating Qualitative Research Reports. AB - OBJECTIVE: To provide an overview of qualitative methods, particularly for reviewers and authors who may be less familiar with qualitative research. METHODS: A question and answer format is used to address considerations for writing and evaluating qualitative research. RESULTS AND CONCLUSIONS: When producing qualitative research, individuals are encouraged to address the qualitative research considerations raised and to explicitly identify the systematic strategies used to ensure rigor in study design and methods, analysis, and presentation of findings. Increasing capacity for review and publication of qualitative research within pediatric psychology will advance the field's ability to gain a better understanding of the specific needs of pediatric populations, tailor interventions more effectively, and promote optimal health. PMID- 27118272 TI - Developmental Course and Determinants of Sleep Disturbances in Adolescents With Spina Bifida. AB - OBJECTIVES: To examine (1) trajectories of sleep disturbances in adolescents with spina bifida (SB) compared with a typically developing (TD) group over a 10-year period and (2) individual, family, and socioeconomic determinants of changes in sleep disturbances. METHODS: Participants were 68 families of youth with SB and 68 families of TD youth. Parent-report of adolescent sleep was collected every 2 years at 6 time points (T1: ages 8-9; T6: ages 18-19). Multiple informants and measures were used to examine internalizing, externalizing, and inattention symptoms, dyadic/family conflict, socioeconomic status (SES), and family income. RESULTS: Sleep disturbances increased over the 10-year period. Youth with SB had greater sleep disturbances during early adolescence. Greater preadolescent externalizing symptoms, greater parent-child and marital conflict, and lower SES predicted increased sleep disturbances. CONCLUSIONS: Sleep disturbances are common and persistent in adolescents with SB. Sleep assessment and management are important clinical and research priorities in this population. PMID- 27118273 TI - International Olympic Committee consensus statement: harassment and abuse (non accidental violence) in sport. AB - Despite the well-recognised benefits of sport, there are also negative influences on athlete health, well-being and integrity caused by non-accidental violence through harassment and abuse. All athletes have a right to engage in 'safe sport', defined as an athletic environment that is respectful, equitable and free from all forms of non-accidental violence to athletes. Yet, these issues represent a blind spot for many sport organisations through fear of reputational damage, ignorance, silence or collusion. This consensus statement extends the 2007 IOC Consensus Statement on Sexual Harassment and Abuse in Sport, presenting additional evidence of several other types of harassment and abuse-psychological, physical and neglect. All ages and types of athletes are susceptible to these problems but science confirms that elite, disabled, child and lesbian/gay/bisexual/trans-sexual (LGBT) athletes are at highest risk, that psychological abuse is at the core of all other forms and that athletes can also be perpetrators. Harassment and abuse arise from prejudices expressed through power differences. Perpetrators use a range of interpersonal mechanisms including contact, non-contact/verbal, cyber-based, negligence, bullying and hazing. Attention is paid to the particular risks facing child athletes, athletes with a disability and LGBT athletes. Impacts on the individual athlete and the organisation are discussed. Sport stakeholders are encouraged to consider the wider social parameters of these issues, including cultures of secrecy and deference that too often facilitate abuse, rather than focusing simply on psychopathological causes. The promotion of safe sport is an urgent task and part of the broader international imperative for good governance in sport. A systematic multiagency approach to prevention is most effective, involving athletes, entourage members, sport managers, medical and therapeutic practitioners, educators and criminal justice agencies. Structural and cultural remedies, as well as practical recommendations, are suggested for sport organisations, athletes, sports medicine and allied disciplines, sport scientists and researchers. The successful prevention and eradication of abuse and harassment against athletes rests on the effectiveness of leadership by the major international and national sport organisations. PMID- 27118274 TI - Prognostic role of phase angle in hospitalized patients with acute decompensated heart failure. AB - BACKGROUND & AIMS: Patients with acute decompensated heart failure (ADHF) have exacerbation of symptoms and fluid retention, and high risk of re hospitalizations and mortality. The aim of this study was to evaluate the role of phase angle at hospital admission as a prognostic marker of mortality in patients with ADHF. METHODS: Patients hospitalized for ADHF, with left ventricular ejection fraction (LVEF) <45% and BOSTON criteria >=8 points were included. The patients were evaluated at hospital admission (first 36 h) and then followed up for assessment of outcomes. Phase angle was measured with tetra polar bioelectrical impedance device. Mortality data was obtained from an average of 24 months after discharge, from the medical records of the hospital and outpatient or telephone contact with patients or family members. The best-discriminatory level of phase angle was selected based on the ROC curve for mortality. RESULTS: Seventy-one patients were included and the majority was male (63%), with a mean age of 61 +/- 12 years, ischemic etiology being the most prevalent (48%) and LVEF average of 26 +/- 8%. Mortality was 49% at an average of 24 months after hospital discharge. The average phase angle at hospital admission was 5.6 +/- 2 degrees , and lower values were associated with higher mortality. Survivors were compared to died patients in the risk factor variables for mortality. In multivariate analysis adjusting for age, LVEF and urea, phase angle <4.8 degrees was independently associated with increased mortality (HR 2.67; p = 0.015). CONCLUSIONS: Phase angle seems to be a prognostic marker in patients with ADHF independently of other known risk factors. PMID- 27118275 TI - Effect of two polymorphisms of the resistin gene (rs10401670 and rs1862513) on resistin levels and biochemical parameters in morbidly obese patients 1 year after a biliopancreatic diversion surgery. AB - BACKGROUND & AIMS: Two single nucleotide polymorphisms (SNPs) of the resistin gene RETN have been described: rs10401670 and rs1862513. The objective of this study was to investigate the effect of these SNPs on changes in serum resistin levels, biochemical parameters and weight after biliopancreatic diversion surgery in morbidly obese patients without diabetes mellitus. METHODS: A sample of 155 patients with morbid obesity without diabetes mellitus was enrolled. Anthropometric and biochemical evaluations were realized at the basal visit and at 12 months. The percentage of subjects with hypertension and hyperlipidemia was also reported. RESULTS: Initial percentage excess weight loss, body mass index, weight, waist circumference, fat mass, blood pressure, low-density lipoprotein cholesterol, total cholesterol, triglycerides levels, insulin and the homeostasis model assessment for insulin sensitivity (HOMA-IR) improve after 12 months. No differences in these improvements were detected between the two genotypes (wild vs mutant group) in each SNP analysis. Resistin levels only changed after surgery in wild genotypes of both SNPs (rs1862513 and rs10401670). The improvement in insulin levels was lower in the mutant group of rs1862513 (-3.4 +/- 0.4 UI/dl vs 2.3 +/- 0.2 UI/dl; P < 0.05) and rs1040167 (-3.3 +/- 0.2 UI/dl vs -1.9 +/- 0.3 UI/dl; P < 0.05). The decrease of HOMA-IR was lower in mutant group of rs1862513 (-1.4 +/- 0.1 units vs -0.9 +/- 0.3 units; P < 0.05) and rs10401670 (-1.2 +/- 0.2 units vs -0.9 +/- 0.3 units; P < 0.05). CONCLUSIONS: The main result of this study was that the mutant genotype of two SNPs of the RETN gene (rs1862513 and rs10401670) was associated with a lack of change in resistin secondary to biliopancreatic diversion. The improvement in insulin levels and HOMA-IR was also lower in these patients. PMID- 27118276 TI - The Role of Nuclear Factor-E2-Related Factor 1 in the Oxidative Stress Response in MC3T3-E1 Osteoblastic Cells. AB - BACKGROUND: Reactive oxygen species (ROS) and antioxidants are associated with maintenance of cellular function and metabolism. Nuclear factor-E2-related factor 1 (NFE2L1, Nrf1) is known to regulate the expression of a number of genes involved in oxidative stress and inflammation. The purpose of this study was to examine the effects of NFE2L1 on the response to oxidative stress in osteoblastic MC3T3-E1 cells. METHODS: The murine calvaria-derived MC3T3-E1 cell line was exposed to lipopolysaccharide (LPS) for oxidative stress induction. NFE2L1 effects were evaluated using small interfering RNA (siRNA) for NFE2L1 mRNA. ROS generation and the levels of known antioxidant enzyme genes were assayed. RESULTS: NFE2L1 expression was significantly increased 2.4-fold compared to the control group at 10 MUg/mL LPS in MC3T3-E1 cells (P<0.05). LPS increased formation of intracellular ROS in MC3T3-E1 cells. NFE2L1 knockdown led to an additional increase of ROS (20%) in the group transfected with NFE2L1 siRNA compared with the control group under LPS stimulation (P<0.05). RNA interference of NFE2L1 suppressed the expression of antioxidant genes including metallothionein 2, glutamatecysteine ligase catalytic subunit, and glutathione peroxidase 1 in LPS-treated MC3T3-E1 cells. CONCLUSION: Our results suggest that NFE2L1 may have a distinct role in the regulation of antioxidant enzymes under inflammation-induced oxidative stress in MC3T3-E1 osteoblastic cells. PMID- 27118277 TI - Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists. AB - Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP 1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP 1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes. PMID- 27118278 TI - Endocrine Risk Factors for Cognitive Impairment. AB - Cognitive impairment, including Alzheimer's disease and other kinds of dementia, is a major health problem in older adults worldwide. Although numerous investigators have attempted to develop effective treatment modalities or drugs, there is no reasonably efficacious strategy for preventing or recovering from cognitive impairment. Therefore, modifiable risk factors for cognitive impairment have received attention, and the growing literature of metabolic risk factors for cognitive impairment has expanded from epidemiology to molecular pathogenesis and therapeutic management. This review focuses on the epidemiological evidence for the association between cognitive impairment and several endocrine risk factors, including insulin resistance, dyslipidemia, thyroid dysfunction, vitamin D deficiency, and subclinical atherosclerosis. Researches suggesting possible mechanisms for this association are reviewed. The research investigating modifiable endocrine risk factors for cognitive impairment provides clues for understanding the pathogenesis of cognitive impairment and developing novel treatment modalities. However, so far, interventional studies investigating the beneficial effect of the "modification" of these "modifiable risk factors" on cognitive impairment have reported variable results. Therefore, well-designed, randomized prospective interventional studies are needed. PMID- 27118279 TI - Usefulness of Measuring Thyroid Stimulating Antibody at the Time of Antithyroid Drug Withdrawal for Predicting Relapse of Graves Disease. AB - BACKGROUND: Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse. METHODS: This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal. RESULTS: Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%. CONCLUSION: TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease. PMID- 27118281 TI - Correction. Determinants for tuberculosis in HIV-infected adults in Northwest Ethiopia: a multicentre case-control study. PMID- 27118280 TI - A survey on beliefs and attitudes of trainee surgeons towards placebo. AB - BACKGROUND: The aim of this study was to investigate the beliefs and attitudes of trainee surgeons regarding placebo interventions, in surgical practice and in research, and to compare them to those of senior orthopaedic surgeons. METHODS: An invitation to participate in an online survey was sent to all the email addresses in the members' database of the British Orthopaedic Trainees Association (BOTA). RESULTS: All 987 members of BOTA were invited to participate in the survey and 189 responded (19 %). The majority of trainees think that the placebo effect is real (88 %), has therapeutic benefits (88 %) and that placebo manipulations are permissible (98 %). Sixty per cent of respondents agree that placebo can be used outside of research, most commonly, to distinguish between organic and non-organic symptoms (36 %). Trainees are more likely than senior surgeons to use placebo for pain management (34 % vs. 12 %). They are mainly concerned about the risk of side effects associated with the use of placebo (80 %) and prefer placebo interventions with minimal invasiveness. Seventy-three per cent respondents would recruit patients into the proposed randomised controlled surgical trial. CONCLUSIONS: The views regarding efficacy, permissibility and indications for placebo among trainees are similar to those of orthopaedic consultants. Orthopaedic trainees regard placebo as permissible and show willingness to recruit into placebo-controlled trials. However, they seem to have limited understanding of mechanisms of placebo effect and underestimate its ubiquity. PMID- 27118282 TI - Correction. Social inequalities in prevalence of diagnosed and undiagnosed diabetes and impaired glucose regulation in participants in the Health Surveys for England series. PMID- 27118283 TI - Correction. Measurement of Exercise Tolerance before Surgery (METS) study: a protocol for an international multicenter prospective cohort study of cardiopulmonary exercise testing prior to major noncardiac surgery. PMID- 27118285 TI - Association between alcohol drinking behaviour and cognitive function: results from a nationwide longitudinal study of South Korea. AB - OBJECTIVES: This research intends to determine how drinking behaviour, such as episodic heavy drinking, is related to cognitive performance in middle-aged and old-aged people in South Korea. METHODS: A cohort data of 5157 adults, age 45 years or older, with normal cognitive function (the Korean version of the Mini mental state examination (K-MMSE) >=24) at baseline (2006), was derived from the Korean Longitudinal Study of Aging. Alcohol drinking behaviour was assessed using the CAGE (Cut down, Annoyed, Guilty, Eye-opener) questionnaire. The relationships between baseline drinking behaviour (in 2006) to the extent of cognitive decline (between 2006 and 2012) and development of cognitive impairment (in 2012) were assessed. RESULTS: Individuals with problematic drinking behaviour at baseline experienced a faster decline in cognitive function than those with non problematic drinking (p<0.05) during 6 years of follow-up, especially among those with relatively lownormal K-MMSE score (24-26) at baseline (p<0.05). Problematic alcohol drinking behaviour was also significantly associated with onset of severe cognitive impairment (SCI) (K-MMSE score <=17) among those with relatively low normal K-MMSE score (adjusted OR (aOR)=3.76, 95% CI 1.46 to 9.67). In addition, abstinence, compared with non-problematic drinking, was related to higher risk for developing SCI among men (aOR=1.62, 95% CI 1.09 to 2.39). CONCLUSIONS: Our results suggest that those with problematic alcohol drinking behaviour could be at an increased risk of cognitive impairment/decline. While further research will provide stronger evidence, intervention targeting alcohol abuse may play a role in prevention of cognitive impairment. PMID- 27118284 TI - Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study. AB - INTRODUCTION: Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites. METHODS AND ANALYSIS: 3 cohorts of children and adolescents (aged 6-17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public. TRIAL REGISTRATION NUMBER: NCT01470261. PMID- 27118286 TI - The iMpact on practice, oUtcomes and costs of New roles for health pROfeSsionals: a study protocol for MUNROS. AB - INTRODUCTION: The size and composition of the European Union healthcare workforce are key drivers of expenditure and performance; it now includes new health professions and enhanced roles for established professions. This project will systematically analyse how this has contributed to health service redesign, integration and performance in 9 European countries (Scotland, England, Netherlands, Germany, Italy, Czech Republic, Poland, Norway, and Turkey(i)). This paper describes the protocol for collection of survey data in 3 distinct care pathways, and sets it in the context of the wider programme. METHODS: Questionnaires will be distributed to healthcare professionals (n=14,580), managers (n=3564) and patients (n=19,440) in 3 care pathways (breast cancer; type 2 diabetes; and coronary heart disease) within 12 hospitals and associated primary care settings in each country. Questionnaire topics will include demography, the different professionals working on the care pathway, the tasks they do and the time taken, their decision-making abilities when considering skill mix, specialisation and integration of care. Patient satisfaction, healthcare utilisation and preferences will be explored. In later work, register data and data from patient records will be used to record clinical outcomes. Data will also be collected on workforce and procedure costs. Descriptive analysis will identify the different models of care and multivariate analysis will establish the most clinically and cost-effective models. ETHICS AND DISSEMINATION: This protocol was approved by ethical committees in each country. Findings will be disseminated through national/international clinical, health services research and health workforce conferences, and publications in national/international peer-reviewed journals. PMID- 27118287 TI - Conflicts of interest and spin in reviews of psychological therapies: a systematic review. AB - OBJECTIVE: To explore conflicts of interest (COI) and their reporting in systematic reviews of psychological therapies, and to evaluate spin in the conclusions of the reviews. METHODS: MEDLINE and PsycINFO databases were searched for systematic reviews published between 2010 and 2013 that assessed effects of psychological therapies for anxiety, depressive or personality disorders, and included at least one randomised controlled trial. Required COI disclosure by journal, disclosed COI by review authors, and the inclusion of own primary studies by review authors were extracted. Researcher allegiance, that is, that researchers concluded favourably about the interventions they have studied, as well as spin, that is, differences between results and conclusions of the reviews, were rated by 2 independent raters. RESULTS: 936 references were retrieved, 95 reviews fulfilled eligibility criteria. 59 compared psychological therapies with other forms of psychological therapies, and 36 psychological therapies with pharmacological interventions. Financial, non-financial, and personal COI were disclosed in 22, 4 and 1 review, respectively. 2 of 86 own primary studies of review authors included in 34 reviews were disclosed by review authors. In 15 of the reviews, authors showed an allegiance effect to the evaluated psychological therapy that was never disclosed. Spin in review conclusions was found in 27 of 95 reviews. Reviews with a conclusion in favour of psychological therapies (vs pharmacological interventions) were at high risk for a spin in conclusions (OR=8.31 (1.41 to 49.05)). Spin was related in trend to the inclusion of own primary studies in the systematic review (OR=2.08 (CI 0.83 to 5.18) p=0.11) and researcher allegiance (OR=2.63 (0.84 to 8.16) p=0.16). CONCLUSIONS: Non-financial COI, especially the inclusion of own primary studies into reviews and researcher allegiance, are frequently seen in systematic reviews of psychological therapies and need more transparency and better management. PMID- 27118288 TI - Impact of clinical registries on quality of patient care and health outcomes: protocol for a systematic review. AB - INTRODUCTION: Many developed countries have regional and national clinical registries aimed at improving health outcomes of patients diagnosed with particular diseases or cared for in particular healthcare settings. Clinical quality registries (CQRs) are clinical registries established with the purpose of monitoring quality of care and providing feedback to improve health outcomes. The aim of this systematic review is to understand the impact of CQRs on (1) mortality/survival; (2) measures of outcome that reflect a process or outcome of healthcare; (3) healthcare utilisation and (4) costs. METHODS AND ANALYSIS: The PRISMA-P methodology, checklist and standard strategy using predefined inclusion and exclusion criteria and structured data abstraction tools will be followed. A search of the electronic databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL will be undertaken, in addition to Google Scholar and grey literature, to identify studies in English covering the period January 1980 to December 2014. Case-control, cohort, randomised controlled trials and controlled clinical trials which describe the registry as an intervention will be eligible for inclusion. Narrative synthesis of study findings will be conducted, guided by a conceptual framework developed to analyse the outcome measure of the registry using defined criteria. If sufficient studies are identified with a similar outcome of interest and measure using the same comparator and time of interval, results will be pooled for random-effects meta analysis. Test for heterogeneity and sensitivity analysis will be conducted. To identify reporting bias, forest plots and funnel plots will be created and, if required, Egger's test will be conducted. ETHICS AND DISSEMINATION: Ethical approval is not required as primary data will not be collected. Review results will be published as a part of thesis, peer-reviewed journal and conferences. TRIAL REGISTRATION NUMBER: CRD42015017319. PMID- 27118289 TI - Balancing student/trainee learning with the delivery of patient care in the healthcare workplace: a protocol for realist synthesis. AB - INTRODUCTION: A national survey was recently conducted to explore medical education research priorities in Scotland. The identified themes and underlying priority areas can be linked to current medical education drivers in the UK. The top priority area rated by stakeholders was: 'Understanding how to balance service and training conflicts'. Despite its perceived importance, a preliminary scoping exercise revealed the least activity with respect to published literature reviews. This protocol has therefore been developed so as to understand how patient care, other service demands and student/trainee learning can be simultaneously facilitated within the healthcare workplace. The review will identify key interventions designed to balance patient care and student/trainee learning, to understand how and why such interventions produce their effects. Our research questions seek to address how identified interventions enable balanced patient care-trainee learning within the healthcare workplace, for whom, why and under what circumstances. METHODS AND ANALYSIS: Pawson's five stages for undertaking a realist review underpin this protocol. These stages may progress in a non-linear fashion due to the iterative nature of the review process. We will: (1) clarify the scope of the review, identifying relevant interventions and existing programme theories, understanding how interventions act to produce their intended outcomes; (2) search journal articles and grey literature for empirical evidence from 1998 (introduction of the European Working Time Directive) on the UK multidisciplinary team working concerning these interventions, theories and outcomes, using databases such as ERIC, Scopus and CINAHL; (3) assess study quality; (4) extract data; and (5) synthesise data, drawing conclusions. ETHICS AND DISSEMINATION: A formal ethical review is not required. These findings should provide an important understanding of how workplace-based interventions influence the balance of trainee learning and service provision. They should benefit various stakeholders involved in workplace-based learning interventions, and inform the medical education research agenda in the UK. PMID- 27118290 TI - Giant atrial septal aneurysm originating from the right coronary artery. AB - Giant coronary artery aneurysm is a rare clinical entity and its involvement in the interatrial space is extremely rare. We here report the rare surgical case of a 67-year old man with giant right coronary artery aneurysm located in the atrial septum with fistula formation to the right atrium, complicated with congestive heart failure, rapid atrial fibrillation and left atrial appendage thrombus. The patient eventually recovered fully without sequelae. PMID- 27118292 TI - Hypertension Canada's 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, and Assessment of Risk of Pediatric Hypertension. AB - We present the inaugural evidence-based Canadian recommendations for the measurement of blood pressure in children and the diagnosis and evaluation of pediatric hypertension. Rates of pediatric hypertension are increasing concomitant with increased rates of childhood obesity. With this, there is growing awareness of the need to measure blood pressure in children. Consequently, the present recommendations have been developed to address an important gap and improve the clinical care of children. For 2016, a total of 15 recommendations are presented. These are categorized in a fashion similar to that of the existing adult recommendations. Specifically, we present recommendations on (1) accurate measurement of blood pressure in children, (2) criteria for diagnosis of hypertension in children, (3) assessment of overall cardiovascular risk in hypertensive children, (4) routine laboratory tests for the investigation of children with hypertension, (5) ambulatory blood pressure measurement in children, and (6) the role of echocardiography. We discuss the rationale for the recommendations and present additional supporting material for the clinician, including tables with standardized techniques for blood pressure measurement and determination of normative blood pressure values for children. Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force will update the recommendations annually and develop future evidence-based recommendations to guide prevention and treatment of pediatric hypertension. PMID- 27118291 TI - Hypertension Canada's 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. AB - Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force provides annually updated, evidence-based recommendations to guide the diagnosis, assessment, prevention, and treatment of hypertension. This year, we present 4 new recommendations, as well as revisions to 2 previous recommendations. In the diagnosis and assessment of hypertension, automated office blood pressure, taken without patient-health provider interaction, is now recommended as the preferred method of measuring in-office blood pressure. Also, although a serum lipid panel remains part of the routine laboratory testing for patients with hypertension, fasting and nonfasting collections are now considered acceptable. For individuals with secondary hypertension arising from primary hyperaldosteronism, adrenal vein sampling is recommended for those who are candidates for potential adrenalectomy. With respect to the treatment of hypertension, a new recommendation that has been added is for increasing dietary potassium to reduce blood pressure in those who are not at high risk for hyperkalemia. Furthermore, in selected high-risk patients, intensive blood pressure reduction to a target systolic blood pressure <= 120 mm Hg should be considered to decrease the risk of cardiovascular events. Finally, in hypertensive individuals with uncomplicated, stable angina pectoris, either a beta-blocker or calcium channel blocker may be considered for initial therapy. The specific evidence and rationale underlying each of these recommendations are discussed. Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force will continue to provide annual updates. PMID- 27118294 TI - The Noninvasive Assessment of Vascular Aging. AB - The growing interest in the clinical measurement of arterial aging through the noninvasive assessment of arterial stiffness is associated with important developments in novel methods and apparatus. In this review, we aimed to describe the major principles of the measurement of arterial stiffness and to critically review the advantages and limitations of the different methods. The measurement of regional stiffness is recommended by international guidelines for routine clinical practice. It is most often determined through pulse wave velocity (PWV) between 2 arterial sites. Methods using a single-site cuff-based measurement are promising. Local determination of arterial stiffness, obtained either with the well-established, high-resolution echo tracking systems or more recently with magnetic resonance imaging, is indicated for pathophysiological and pharmacologic studies. Novel apparatus that were developed for determining arterial stiffness claimed superiority over pioneering methods either through greater simplicity of use, better repeatability, or a more pertinent arterial pathway. However, the true additive value of measuring arterial aging with a given apparatus had to be translated into the predictive value of arterial stiffness as an intermediate end point, ie, the higher the arterial stiffness the higher the number of cardiovascular (CV) events. Thus, another important aim of this review was to analyze the amount of epidemiologic evidence obtained with a given method regarding the predictive value of arterial stiffness for CV events. PMID- 27118293 TI - Vascular Fibrosis in Aging and Hypertension: Molecular Mechanisms and Clinical Implications. AB - Aging is the primary risk factor underlying hypertension and incident cardiovascular disease. With aging, the vasculature undergoes structural and functional changes characterized by endothelial dysfunction, wall thickening, reduced distensibility, and arterial stiffening. Vascular stiffness results from fibrosis and extracellular matrix (ECM) remodelling, processes that are associated with aging and are amplified by hypertension. Some recently characterized molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor-beta1/SMAD signalling, upregulation of galectin-3, and activation of proinflammatory and profibrotic signalling pathways. These events can be induced by vasoactive agents, such as angiotensin II, endothelin-1, and aldosterone, which are increased in the vasculature during aging and hypertension. Complex interplay between the "aging process" and prohypertensive factors results in accelerated vascular remodelling and fibrosis and increased arterial stiffness, which is typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of "early" or "premature" vascular aging is now often used to describe hypertension-associated vascular disease. We review the vascular phenotype in aging and hypertension, focusing on arterial stiffness and vascular remodelling. We also highlight the clinical implications of these processes and discuss some novel molecular mechanisms of fibrosis and ECM reorganization. PMID- 27118295 TI - Accelerated Vascular Aging as a Paradigm for Hypertensive Vascular Disease: Prevention and Therapy. AB - Aging is considered the most important nonmodifiable risk factor for cardiovascular disease and death after age 28 years. Because of demographic changes the world population is expected to increase to 9 billion by the year 2050 and up to 12 billion by 2100, with several-fold increases among those 65 years of age and older. Healthy aging and prevention of aging-related diseases and associated health costs have become part of political agendas of governments around the world. Atherosclerotic vascular burden increases with age; accordingly, patients with progeria (premature aging) syndromes die from myocardial infarctions or stroke as teenagers or young adults. The incidence and prevalence of arterial hypertension also increases with age. Arterial hypertension-like diabetes and chronic renal failure-shares numerous pathologies and underlying mechanisms with the vascular aging process. In this article, we review how arterial hypertension resembles premature vascular aging, including the mechanisms by which arterial hypertension (as well as other risk factors such as diabetes mellitus, dyslipidemia, or chronic renal failure) accelerates the vascular aging process. We will also address the importance of cardiovascular risk factor control-including antihypertensive therapy-as a powerful intervention to interfere with premature vascular aging to reduce the age-associated prevalence of diseases such as myocardial infarction, heart failure, hypertensive nephropathy, and vascular dementia due to cerebrovascular disease. Finally, we will discuss the implementation of endothelial therapy, which aims at active patient participation to improve primary and secondary prevention of cardiovascular disease. PMID- 27118296 TI - Evidence for Charge Transfer at the Interface between Hybrid Phosphomolybdate and Epitaxial Graphene. AB - The interfacing of polyoxometalates and graphene can be considered to be an innovative way to generate hybrid structures that take advantage of the properties of both components. Polyoxometalates are redox-sensitive and photosensitive compounds with high temperature stability (up to 400 degrees C for some), showing tunable properties depending on the metal incorporated inside the complex. Graphene has a unique electronic band structure combined with good material properties for electrical and optical applications. The spontaneous, rather than electrochemical, functionalization of epitaxial graphene on SiC with Keggin phosphomolybdate derivative TBA3[PMo11O39{Sn(C6H4)C=C(C6H4)N2}] (named K(Mo)Sn[N2(+)]) bearing a phenyl diazonium unit is investigated. Graphene decoration is evidenced by means of AFM, Raman, XPS, and cyclic voltammetry, indicating a successful immobilization of the polyoxomolybdate. The covalent bonding of the polyoxometalate to the graphene substrate can be deduced from the appearance of a D band in the Raman spectra and from the loss of mobility in the electrical conduction. High-resolution XPS spectra reveal an electron transfer from the graphene to the Mo complex. The comparison of charge-carrier density measurements before and after grafting supports the p-type doping effect, which is further evidenced by work function UPS measurements. PMID- 27118297 TI - Performance of manual hyperinflation: consistency and modification of the technique by intensive care unit nurses during physiotherapy. AB - AIMS AND OBJECTIVES: To assess the consistency and safety of manual hyperinflation delivery by nurses of variable clinical experience using a resuscitator bag during physiotherapy treatment. BACKGROUND: Manual hyperinflation involves the delivery of larger than normal gas volumes to intubated patients and is routinely used by nurses in collaboration with physiotherapists for the management of retained sputum. The aim is to deliver slow deep breaths with an inspiratory hold without unsafe airway pressures, lung volumes or haemodynamic changes. In addition, nursing staff should be able to 'feel' differences in resistance and adjust their technique accordingly. DESIGN: Prospective observational study utilising the simulation of a mechanically ventilated patient. METHODS: Thirty-three nurses delivered manual hyperinflation to a SimMan3G mannequin who had three distinct lung scenarios applied (normal; asthma; Acute Respiratory Distress Syndrome) in randomised order during simulated physiotherapy treatment. Respiratory rate, tidal volume (Vt ), mean inspiratory flow rate (Vt /Ti), and peak airway pressure data were generated. RESULTS: Over all scenarios, mean respiratory rate = 12.3 breaths/minute, mean Vt = 638.6 mls, mean inflation time = 1.3 seconds and peak airway pressure exceeded 40 cm H2 O in 41% of breaths, although only in 10% of breaths during the 'normal' lung scenario. CONCLUSIONS: Experienced nurses were able to manually hyperinflate 'normal' patients in a simulated setting safely. Despite their knowledge of barotrauma, unsafe airway pressures were delivered in some scenarios. RELEVANCE TO CLINICAL PRACTICE: Training with regard to safe airway pressures, breath hold and adequate volumes is recommended for all nurses undertaking the procedure. Nurses and physiotherapists must closely monitor the patient's condition during manual hyperinflation thereby recognising changes with regard to lung compliance and airway resistance, with nurses responding by altering their technique. The addition of a pressure manometer in the circuit may improve patient safety when performing manual hyperinflation. PMID- 27118298 TI - Adult-onset severe methylenetetrahydrofolate reductase deficiency characterized by reversible spastic paraplegia with a novel mutation. PMID- 27118299 TI - Semiparametric partially linear varying coefficient models with panel count data. AB - This paper studies semiparametric regression analysis of panel count data, which arise naturally when recurrent events are considered. Such data frequently occur in medical follow-up studies and reliability experiments, for example. To explore the nonlinear interactions between covariates, we propose a class of partially linear models with possibly varying coefficients for the mean function of the counting processes with panel count data. The functional coefficients are estimated by B-spline function approximations. The estimation procedures are based on maximum pseudo-likelihood and likelihood approaches and they are easy to implement. The asymptotic properties of the resulting estimators are established, and their finite-sample performance is assessed by Monte Carlo simulation studies. We also demonstrate the value of the proposed method by the analysis of a cancer data set, where the new modeling approach provides more comprehensive information than the usual proportional mean model. PMID- 27118300 TI - Swedish isolates of Vibrio cholerae enhance their survival when interacted intracellularly with Acanthamoeba castellanii. AB - Vibrio cholerae is a Gram-negative bacterium that occurs naturally in aquatic environment. Only V. cholerae O1 and V. cholerae O139 produce cholera toxin and cause cholera, other serogroups can cause gastroenteritis, open wounds infection, and septicaemia. V. cholerae O1 and V. cholerae O139 grow and survive inside Acanthamoeba castellanii. The aim of this study is to investigate the interactions of the Swedish clinical isolates V. cholerae O3, V. cholerae O4, V. cholerae O5, V. cholerae O11, and V. cholerae O160 with A. castellanii. The interaction between A. castellanii and V. cholerae strains was studied by means of amoeba cell counts, viable counts of the bacteria in the absence or presence of amoebae, and of the intracellularly growing bacteria, visualised by electron microscopy. These results show that all V. cholerae can grow and survive outside and inside the amoebae, disclosing that V. cholerae O3, V. cholerae O4, V. cholerae O5, V. cholerae O11, and V. cholerae O160 all can be considered as facultative intracellular bacteria. PMID- 27118301 TI - Physical Activity in School-Aged Children with Asthma in an Urban City of Taiwan. AB - BACKGROUND: It has been reported that physical activity is limited in children with asthma. The aims of this study were to compare and quantify the physical activity levels between asthmatic children and their healthy peers. Factors associated with limitation of physical activity in asthmatic children were also investigated. METHODS: A total of 120 asthmatic children and 262 age-matched healthy controls were enrolled in this study. Clinical phenotype including severity and lung function were obtained from medical records. A questionnaire addressing physical activity, asthma diagnosis, symptoms, parental health beliefs, physician's advice and, community resources was accomplished by children and their parents. The physical activity levels of children with and without asthma were compared. Factors that might limit the activity level were analyzed. RESULTS: Children with asthma were less active than their peers. The significant difference was between normal controls and moderate-to-severe asthmatic children, but not children with mild asthma. Among children with asthma, physical activity was associated with the severity level but not parental health beliefs, physician's advice, or the convenience for physical activity. Children with moderate or severe persistent asthma were more likely to be inactive. CONCLUSION: Children with asthma had a lower level of physical activity, particularly those with moderate-to-severe asthma. To achieve an appropriate level of physical activity, improvement of asthma management and control is considered important. PMID- 27118303 TI - Serologic and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation: A systematic review and meta-analysis. AB - INTRODUCTION: Recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC) is a major cause of mortality. Knowledge on biomarkers may contribute to better surveillance based on the patients' risk of recurrence. Reviewing the literature, we aimed to identify serological and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation. METHODS: A literature search was performed in the databases PubMed and Scopus to identify observational studies evaluating serological or molecular biomarkers for recurrence of HCC after LT using adjusted analysis to correct for confounding. RESULTS: Of 502 records, 69 mainly retrospective studies were included with a total of 15,213 patients. Of these, 41 studies were suitable for meta-analyses, which showed that the serum markers pre-transplant alpha fetoprotein (AFP) (hazard ratio (HR) 2.69 [2.08-3.47]), pre-transplant des-gamma carboxy prothrombin (DCP) (HR 5.99 [3.27-10.98]), and allelic imbalance in microsatellites in DNA of tumor tissue (HR 13.49 [3.17-57.30]) were related to recurrence. CONCLUSIONS: AFP, DCP and allelic imbalance in microsatellites may be used to predict recurrence. Together with other modalities, biomarkers may be used in future transplantation criteria to optimize selection of suitable patients. PMID- 27118302 TI - Primary bone diffuse large B-cell lymphoma: a retrospective evaluation on 76 cases from French institutional and LYSA studies. AB - Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare DLBCL location variant. We treated 76 PB-DLBCL patients by immuno-chemotherapy, resulting in an 84% sustained complete remission rate and a 78.9% survival over a 4.7-year median follow-up period. Ann Arbor stage IV and high age-adjusted international prognostic index were predictive of adverse outcome in univariate analysis. In multivariate analysis using a Cox model, only aa-IPI predicted long-term survival. While based on a limited number of cases, we suggested that radiotherapy may be useful as a consolidation modality in PB-DLBCL. We also suggested that positron emission tomography/CT scan should be interpreted with caution due to a persistent [18F]fluorodeoxyglucose [18FDG] uptake of bone lesions even after remission in some in PB-DLBCL patients. Our study based on a homogeneous cohort of PB-DLBCL patients confirmed the favorable outcome of this DLBCL variant and support the implementation of prospective clinical trials in this disease. PMID- 27118304 TI - Corrigendum: Growth of semiconducting single-wall carbon nanotubes with a narrow band-gap distribution. PMID- 27118305 TI - Imipenem-cilastatin-induced psychosis: a case report. AB - BACKGROUND: Elderly patients, in particular, have been reported to develop psychiatric side effects from antibiotics. Clarithromycin, quinolones, sulfamethoxazole-trimethoprim, isoniazid, penicillin, and cephalosporins have been reported to cause psychosis. This case report bridges a void in the medical literature with regards to the psychiatric adverse effects of imipenem cilastatin. CASE PRESENTATION: A 64-year-old Hispanic man in septic shock due to urinary tract infection was initiated on imipenem-cilastatin and mechanically ventilated, following admission to hospital. His mentation was normal for 72 hours after extubation and discontinuation of sedatives and opioids, following which he was noted to be in acute psychosis. Our patient's imipenem-cilastatin dose had been increased 24 hours prior to his violent visual and auditory hallucinations because his renal function had improved. The physical examination and laboratory tests did not reveal evidence of a new central nervous infection or endocrinopathy. His mentation improved after his antibiotic was switched to ceftriaxone, based on culture and sensitivity testing. Similar psychiatric symptoms developed 2 months later when he was treated with imipenem for a recurrent urinary tract infection. His symptoms again resolved with modification of his antibiotic regimen. CONCLUSIONS: Endocrine dysfunctions (thyroid, adrenal, and pituitary disorders) and toxic ingestions are medical disorders known to cause brief psychotic episodes. Fluoroquinolones, penicillins, and trimethoprim sulfamethoxazole are common antibiotics associated with this rare adverse effect. Several pharmacokinetic hypotheses have been proposed for this adverse effect: (1) N-methyl-D-aspartate receptor hypofunctioning, (2) sequential blockade of folic acid production, (3) inhibition of prostaglandin E2 and proinflammatory cytokine production, (4) increased central dopamine turnover, and (5) accumulation of toxic levels of the drug. Pre-existing psychopathology, relevant comorbidities, slow acetylation status, and increased permeability of the blood brain barrier have been suggested to make patients more prone to developing psychosis. According to the literature, this psychiatric manifestation resolves within 2 weeks of discontinuing the offending agent. There appears to be underreporting of the psychiatric manifestations of imipenem-cilastatin, contrary to post-marketing surveillance data. It is imperative that physicians recognize these psychiatric side effects of antibiotics, because they are a fundamental treatment option. PMID- 27118306 TI - Corrigendum to 'Intraprosthetic screw fixation increases primary fixation stability in periprosthetic fractures of the femur-A biomechanical study.' [Med. Eng. Phys. 36 (2014) 239-243]. PMID- 27118307 TI - A robust approach for ECG-based analysis of cardiopulmonary coupling. AB - Deriving respiratory signal from a surface electrocardiogram (ECG) measurement has advantage of simultaneously monitoring of cardiac and respiratory activities. ECG-based cardiopulmonary coupling (CPC) analysis estimated by heart period variability and ECG-derived respiration (EDR) shows promising applications in medical field. The aim of this paper is to provide a quantitative analysis of the ECG-based CPC, and further improve its performance. Two conventional strategies were tested to obtain EDR signal: R-S wave amplitude and area of the QRS complex. An adaptive filter was utilized to extract the common component of inter-beat interval (RRI) and EDR, generating enhanced versions of EDR signal. CPC is assessed through probing the nonlinear phase interactions between RRI series and respiratory signal. Respiratory oscillations presented in both RRI series and respiratory signals were extracted by ensemble empirical mode decomposition for coupling analysis via phase synchronization index. The results demonstrated that CPC estimated from conventional EDR series exhibits constant and proportional biases, while that estimated from enhanced EDR series is more reliable. Adaptive filtering can improve the accuracy of the ECG-based CPC estimation significantly and achieve robust CPC analysis. The improved ECG-based CPC estimation may provide additional prognostic information for both sleep medicine and autonomic function analysis. PMID- 27118308 TI - A pressure and shear sensor system for stress measurement at lower limb residuum/socket interface. AB - A sensor system for measurement of pressure and shear at the lower limb residuum/socket interface is described. The system comprises of a flexible sensor unit and a data acquisition unit with wireless data transmission capability. Static and dynamic performance of the sensor system was characterised using a mechanical test machine. The static calibration results suggest that the developed sensor system presents high linearity (linearity error <= 3.8%) and resolution (0.9 kPa for pressure and 0.2 kPa for shear). Dynamic characterisation of the sensor system shows hysteresis error of approximately 15% for pressure and 8% for shear. Subsequently, a pilot amputee walking test was conducted. Three sensors were placed at the residuum/socket interface of a knee disarticulation amputee and simultaneous measurements were obtained during pilot amputee walking test. The pressure and shear peak values as well as their temporal profiles are presented and discussed. In particular, peak pressure and shear of approximately 58 kPa and 27 kPa, respectively, were recorded. Their temporal profiles also provide dynamic coupling information at this critical residuum/socket interface. These preliminary amputee test results suggest strong potential of the developed sensor system for exploitation as an assistive technology to facilitate socket design, socket fit and effective monitoring of lower limb residuum health. PMID- 27118309 TI - Calprotectin could be a potential biomarker for acute appendicitis. AB - BACKGROUND: Acute appendicitis is a common cause for a visit to the emergency department and appendectomy represents the most common emergency procedure in surgery. The rate of negative appendectomy however has remained high despite modern diagnostic apparatus. Therefore, there is need for a better preoperative screening of patients with suspected appendicitis. Calprotectin represents a predominant protein in the cytosol of neutrophil granulocytes and has been extensively investigated with regard to bowel pathologies. This study investigates the expression of calprotectin in the lumen of the vermiform appendix of patients undergoing appendectomy for suspected appendicitis. METHODS: Appendix specimens from patients undergoing emergency appendectomy for suspected acute appendicitis were examined. Acute appendicitis was confirmed on histopathology. The qualitative expression of calprotectin in the vermiform appendix specimens was analyzed using specific calprotectin antibodies. RESULTS: Vermiform appendix specimens from 52 patients (22 female and 30 male) including 11 with uncomplicated and 41 with complicated appendicitis were analyzed. Strong immunostainings were achieved with calprotectin antibody in the lumen of all specimens irrespective of the extent of appendicitis. Immunostaining was negative in the uninflamed appendix. CONCLUSIONS: High calprotectin activity could be demonstrated within the lumen of vermiform appendix specimens following appendectomy for acute appendicitis. The high luminal accumulation of calprotectin-carrying cells could be interpreted as an invitation to study the expression of calprotectin in stool as a new diagnostic aid in patients with suspected appendicitis. PMID- 27118310 TI - Tau mutant A152T, a risk factor for FTD/PSP, induces neuronal dysfunction and reduced lifespan independently of aggregation in a C. elegans Tauopathy model. AB - BACKGROUND: A certain number of mutations in the Microtubule-Associated Protein Tau (MAPT) gene have been identified in individuals with high risk to develop neurodegenerative diseases, collectively called tauopathies. The mutation A152TMAPT was recently identified in patients diagnosed with frontotemporal spectrum disorders, including Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), Corticobasal Degeneration (CBD), and Alzheimer disease (AD). The A152TMAPT mutation is unusual since it lies within the N terminal region of Tau protein, far outside the repeat domain that is responsible for physiological Tau-microtubule interactions and pathological Tau aggregation. How A152TMAPT causes neurodegeneration remains elusive. RESULTS: To understand the pathological consequences of this mutation, here we present a new Caenorhabditis elegans model expressing the mutant A152TMAPT in neurons. While expression of full-length wild-type human tau (Tau(wt), 2N4R) in C. elegans neurons induces a progressive mild uncoordinated locomotion in a dose-dependent manner, mutant tau (Tau(A152T), 2N4R) induces a severe paralysis accompanied by acute neuronal dysfunction. Mutant Tau(A152T) worms display morphological changes in neurons reminiscent of neuronal aging and a shortened life-span. Moreover, mutant A152T overexpressing neurons show mislocalization of pre-synaptic proteins as well as distorted mitochondrial distribution and trafficking. Strikingly, mutant tau-transgenic worms do not accumulate insoluble tau aggregates, although soluble oligomeric tau was detected. In addition, the full-length A152T-tau remains in a pathological conformation that accounts for its toxicity. Moreover, the N-terminal region of tau is not toxic per se, despite the fact that it harbours the A152T mutation, but requires the C-terminal region including the repeat domain to move into the neuronal processes in order to execute the pathology. CONCLUSION: In summary, we show that the mutant Tau(A152T) induces neuronal dysfunction, morphological alterations in neurons akin to aging phenotype and reduced life-span independently of aggregation. This comprehensive description of the pathology due to Tau(A152T) opens up multiple possibilities to identify cellular targets involved in the Tau-dependent pathology for a potential therapeutic intervention. PMID- 27118311 TI - History of malaria treatment as a predictor of subsequent subclinical parasitaemia: a cross-sectional survey and malaria case records from three villages in Pailin, western Cambodia. AB - BACKGROUND: Treatment of the sub-clinical reservoir of malaria, which may maintain transmission, could be an important component of elimination strategies. The reliable detection of asymptomatic infections with low levels of parasitaemia requires high-volume quantitative polymerase chain reaction (uPCR), which is impractical to conduct on a large scale. It is unknown to what extent sub clinical parasitaemias originate from recent or older clinical episodes. This study explored the association between clinical history of malaria and subsequent sub-clinical parasitaemia. METHODS: In June 2013 a cross-sectional survey was conducted in three villages in Pailin, western Cambodia. Demographic and epidemiological data and blood samples were collected. Blood was tested for malaria by high-volume qPCR. Positive samples were analysed by nested PCR to determine the Plasmodium species. To identify previous episodes of malaria, case records were collected from village malaria workers and local health facilities and linked to study participants. RESULTS: Among 1343 participants, 40/122 (32.8 %) with a history of clinical malaria were parasitaemic during the cross sectional survey, compared to 172/1221 (14.1 %) without this history (p < 0.001). Among the 212 parasitaemic participants in the survey, 40 (18.9 %) had a history of clinical malaria, compared to 87 out of 1131 (7.7 %) parasite-negative participants; p < 0.001, adjusted OR 3.3 (95 % CI; 2.1-5.1). A history of Plasmodium vivax was associated with sub-clinical P. vivax parasitaemia in the survey (p < 0.001), but this association was not seen with Plasmodium falciparum (p = 0.253); only three participants had both P. falciparum parasites in the survey and a clinical history of P. falciparum. CONCLUSIONS: A clinical episode of vivax malaria was associated with subsequent sub-clinical parasitaemia. Treatment of P. vivax with artemisinin-based combination therapy without primaquine often resulted in recurrent episodes. Targeting individuals with a history of clinical malaria will be insufficient to eliminate the sub-clinical reservoir as they constitute a minority of parasitaemias. PMID- 27118312 TI - A staged decompression of right ventricle allows growth of right ventricle and subsequent biventricular repair in patients with pulmonary atresia and intact ventricular septum. AB - OBJECTIVES: To achieve the growth of right-sided heart structures, our choice of the first palliation for patients with pulmonary atresia and intact ventricular septum (PA-IVS) includes a modified Blalock-Taussig shunt (BTS) with pulmonary valvotomy. We sought to analyse the impact of the first palliation on the growth of right-sided heart structures and factors associated with a choice of definitive surgical procedure. METHODS: Fifty patients with PA-IVS who underwent a staged surgical approach from 1991 to 2012 were retrospectively reviewed. RESULTS: Right ventricular (RV)-coronary artery fistulas were seen in 42% of patients at the time of birth. All 50 patients had a modified BTS with pulmonary valvotomy. Six patients died after the first palliation or inter-stage. Thirty patients achieved a biventricular repair (BVR group), 6 patients had a 1 + 1/2 ventricular repair (1 + 1/2V group) and 5 patients had a Fontan completion (Fontan group). After modified BTS with pulmonary valvotomy, tricuspid valve z score did not increase in any of the group (BVR: pre -2.79 vs post -2.24, 1 + 1/2V: pre -5.25 vs post -6.69, Fontan: pre -6.82 vs post -7.94). Normalized RV end-diastolic volume increased only in BVR group after modified BTS with pulmonary valvotomy (BVR: pre 32% vs post 64%, 1 + 1/2V: pre 43% vs post 42%, Fontan: pre 29% vs post 32%). Major RV-coronary artery fistula was a strong factor with proceeding single-ventricle palliation [BVR: 4/30 (13%) patients, 1 + 1/2V: 1/6 (17%) and Fontan: 4/5 (80%)]. CONCLUSIONS: Tricuspid valve growth was not obtained by modified BTS with pulmonary valvotomy; therefore, tricuspid valve size at birth appeared to be a predictor for achieving BVR. Proportionate RV growth was seen only in patients who achieved BVR. However, RV growth was not seen in patients having 1 + 1/2 ventricular repair. Major RV-coronary artery fistula was a strong predictor for proceeding single-ventricle palliation. PMID- 27118313 TI - Comparison between off- and on-pump coronary artery bypass grafting: long-term results of a real-world registry. AB - OBJECTIVES: The aim of this study was to compare 5-year rates of overall death, cardiac-related death, myocardial infarction, repeat revascularization, stroke and new occurrence of postoperative renal failure in a large cohort of patients with coronary disease, treated with on- or off-pump coronary artery bypass grafting (CABG). METHODS: Two propensity score-matched cohorts, each of 560 patients, undergoing isolated surgical coronary revascularization at the regional public and private centres of Emilia-Romagna region (Italy) over the period 1 January 2003 - 31 December 2013, were used to compare long-term outcomes of on pump CABG (6711 patients) and off-pump CABG (597 patients). RESULTS: The matched on-pump group received significantly more bypass grafts than the matched off-pump group (2.4 +/- 1.1 vs 1.6 +/- 0.9, P < 0.0001). The on-pump group reported statistically significant lower cardiac-related mortality. There was a trend towards higher overall mortality and the need for repeat revascularization procedures in the off-pump group. No difference was found for myocardial infarction, stroke or new occurrence of postoperative renal failure between groups in the follow-up. The multivariate analysis of significant predictors of mortality in the overall population confirmed that the off-pump revascularization strategy was an independent predictor of death at long-term follow-up. On-pump CABG reported significantly better results in terms of mortality in the subgroups of patients with a depressed left ventricular ejection fraction and in patients with three-vessel disease. CONCLUSIONS: In patients undergoing elective isolated CABG, on-pump strategy conferred a long-term survival advantage compared with off pump strategy, particularly for patients with more extensive coronary disease. No benefits were found in terms of reduction of postoperative morbidity with the off pump strategy. On-pump surgery should be the preferred revascularization technique, and off-pump surgery reserved for patients for whom the perioperative risk of cardiopulmonary bypass is greater than the risk of a less complete coronary revascularization. PMID- 27118314 TI - The anaerobic linalool metabolism in Thauera linaloolentis 47 Lol. AB - BACKGROUND: The betaproteobacterium Thauera linaloolentis 47Lol(T) was isolated on the tertiary monoterpene alcohol (R,S)-linalool as sole carbon and energy source under denitrifying conditions. Growth experiments indicated the formation of geraniol and geranial. Thus, a 3,1-hydroxyl-Delta(1)-Delta(2)-mutase (linalool isomerase) activity may initiate the degradation, followed by enzymes of the acyclic terpene utilization (Atu) and leucine/isovalerate utilization (Liu) pathways that were extensively studied in Pseudomonas spp. growing on citronellol or geraniol. RESULTS: A transposon mutagenesis yielded 39 transconjugants that could not grow anaerobically on linalool and nitrate in liquid medium. The deficiencies were apparently based on gene functions required to overcome the toxicity of linalool, but not due to inactivation of genes in the degradation pathway. Growing cultures formed geraniol and geranial transiently, but also geranic acid. Analysis of expressed proteins detected several enzymes of the Atu and Liu pathways. The draft genome of T. linaloolentis 47Lol(T) had atu and liu genes with homology to those of Pseudomonas spp.. CONCLUSION: The in comparison to monoterpenes larger toxicity of monoterpene alcohols is defeated by several modifications of the cellular structure and metabolism in Thauera linaloolentis 47Lol(T). The acyclic terpene utilization pathway is used in T. linaloolentis 47Lol(T) during growth on (R,S)-linalool and nitrate under anoxic conditions. This is the first experimental verification of an active Atu pathway outside of the genus Pseudomonas. PMID- 27118315 TI - Effects of chewing rate and reactive hyperemia on blood flow in denture supporting mucosa during simulated chewing. AB - PURPOSE: We examined how chewing rate and the extent of reactive hyperemia affect the blood flow in denture-supporting mucosa during chewing. METHODS: The left palatal mucosa was loaded under conditions of simulated chewing or simulated clenching for 30s, and the blood flow during loading was recorded. We compared the relative blood flow during loading under conditions that recreated different chewing rates by combining duration of chewing cycle (DCC) and occlusal time (OT): fast chewing group, typical chewing group, slow chewing group and clenching group. The relationship between relative blood flow during simulated chewing and the extent of reactive hyperemia was also analyzed. RESULTS: When comparing the different chewing rate, the relative blood flow was highest in fast chewing rate, followed by typical chewing rate and slow chewing rate. Accordingly, we suggest that fast chewing increases the blood flow more than typical chewing or slow chewing. There was a significant correlation between the amount of blood flow during simulated chewing and the extent of reactive hyperemia. CONCLUSIONS: Within the limitations of this study, we concluded that slow chewing induced less blood flow than typical or fast chewing in denture-supporting mucosa and that people with less reactive hyperemia had less blood flow in denture-supporting mucosa during chewing. PMID- 27118317 TI - NHS England misses cancer referral targets again. PMID- 27118316 TI - Soluble Guanylate Cyclase Stimulators and Activators: Novel Therapies for Pulmonary Vascular Disease or a Different Method of Increasing cGMP? AB - Pulmonary arterial hypertension (PAH) is a progressively worsening disorder characterized by increased pulmonary vascular resistance leading to increased afterload, right ventricular hypertrophy, and ultimately right heart failure and death. Current pharmacologic treatments primarily act to reduce pulmonary vascular resistance (PVR) and provide some benefit but do not cure PAH. Canonical vasodilator therapy involving the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP pathway has demonstrated efficacy, but in pathologic states, endothelial dysfunction within the pulmonary vasculature leads to the reduced synthesis and bioavailability of NO. Acting downstream of NO, sGC stimulators and activators restore the endogenous functions of NO and exploit the positive effects of sGC stimulation on various organ systems, including the heart. Riociguat (BAY 63-2521) is the first agent in a class of sGC stimulators to receive FDA approval for the treatment of PAH and chronic thromboembolic hypertension (CTEPH). Riociguat has demonstrated significant benefit as assessed by 6MWD, PVR, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, time to clinical worsening, World Health Organization (WHO) functional class, and other quality of life measures in clinical trials as a monotherapy and in combination with endothelin receptor antagonists or non-intravenous prostanoids. Riociguat is the first FDA-approved treatment option for inoperable or persistent CTEPH and adds a new effective drug to available treatment options for pulmonary hypertension (PH). The question of whether riociguat is superior to other available treatment options is unanswered at the present time and requires further study. PMID- 27118318 TI - Thyroid cancer subtype downgraded to non-cancer. PMID- 27118319 TI - A prognostic model for survival after salvage treatment with FLAG-Ida +/- gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia. AB - The combination of fludarabine, cytarabine, idarubicin, and granulocyte colony stimulating factor (FLAG-Ida) is widely used in relapsed/refractory acute myeloid leukaemia (AML). We retrospectively analysed the results of 259 adult AML patients treated as first salvage with FLAG-Ida or FLAG-Ida plus Gentuzumab Ozogamicin (FLAGO-Ida) of the Programa Espanol de Tratamientos en Hematologia (PETHEMA) database, developing a prognostic score system of survival in this setting (SALFLAGE score). Overall, 221 patients received FLAG-Ida and 38 FLAGO Ida; 92 were older than 60 years. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 51%, with 9% of induction deaths. Three covariates were associated with lower CR/CRi: high-risk cytogenetics and t(8;21) at diagnosis, no previous allogeneic stem cell transplantation (allo-SCT) and relapse-free interval <1 year. Allo-SCT was performed in second CR in 60 patients (23%). The median overall survival (OS) of the entire cohort was 0.7 years, with 22% OS at 5-years. Four independent variables were used to construct the score: cytogenetics, FLT3-internal tandem duplication, length of relapse-free interval and previous allo-SCT. Using this stratification system, three groups were defined: favourable (26% of patients), intermediate (29%) and poor-risk (45%), with an expected 5-year OS of 52%, 26% and 7%, respectively. The SALFLAGE score discriminated a subset of patients with an acceptable long-term outcome using FLAG-Ida/FLAGO-Ida regimen. The results of this retrospective analysis should be validated in independent external cohorts. PMID- 27118320 TI - Countercurrent assisted quantitative recovery of metabolites from plant associated natural deep eutectic solvents. AB - NAtural Deep Eutectic Solvents (NADES) are chemically simple but physiologically important plant constituents that exhibit unique solubilizing properties of other metabolites, including bioactive constituents. The high polarity of NADES introduces a challenge in the ability of conventional solid-support based chromatography to recover potential bioactive metabolites. This complicates the systematic explanation of the NADES' functions in botanical extracts. The present study utilizes countercurrent separation (CCS) methodology to overcome the recovery challenge. To demonstrate its feasibility, Glucose-Choline chloride Water (GCWat, 2:5:5, mole/mole) served as a model NADES, and four widely used marker flavonoids with different polarities (rutin, quercetin, kaempferol, and daidzein) were chosen as model target analytes. In order to prepare GCWat with high consistency, a water drying study was performed. The unique capabilities of the recently introduced CherryOne system, offering volumetric phase metering, were used to monitor the CCS operations. The collected fractions were analyzed using UHPLC and NMR/quantitative NMR. CCS was able to recover the analytes from the NADES matrix with quantitative recoveries of 95.7%, 94.6%, 97.0%, and 96.7% for rutin, quercetin, kaempferol, and daidzein respectively. The CCS strategy enables recovery of target metabolites from NADES-containing crude extracts as well as from other chemical mixtures, and moreover offers a means of using NADES as environmentally friendly extraction solvents. PMID- 27118321 TI - Lignans and triterpenoids from Vitex negundo var. heterophylla and their biological evaluation. AB - Three new phenylnaphthalene-type lignans, vitexnegheteroins E-G (1-3), and a new polyoxygenated ursane-type triterpene, vitexnegheteroin H (9), were isolated from the seeds of Vitex negundo var. heterophylla, together with ten known compounds. Their structures were established on the basis of extensive 1D and 2D NMR experiments, as well as their mass spectroscopic data. The absolute configurations of compounds 1 and 2 were determined by comparing their experimental ECD spectra with that calculated by the time-dependent density functional theory (TDDFT) method. The isolates were evaluated for their cytotoxicities against three human cancer cell lines, inhibitory activities on lipopolysaccharide-induced NO production in murine microglial BV-2 cells, and antioxidant activities for ABTS radical scavenging. PMID- 27118322 TI - New steroidal saponins from the rhizomes of Paris delavayi and their cytotoxicity. AB - Four new furostanol saponins, named padelaosides C-F (1-4), together with four known spirostanol saponins 5-8 were isolated from the rhizomes of Paris delavayi Franchet. Their structures were elucidated on the basis of extensive spectroscopic analysis and chemical evidences. The discovery of the new compounds 1-4 extended the diversity and complexity of this furostanol saponin family. The cytotoxicity of all the saponins was evaluated for their cytotoxicity against human glioblastoma U87MG and human hepatocellular carcinoma Hep-G2 cell lines. The known spirostanol saponins 7 and 8 exhibited notable cytotoxicity against the two tumor cell lines with IC50 values of 1.13 and 3.42MUM, respectively, while the new furostanol saponins 3 and 4 showed moderate cytotoxicity with IC50 values of 15.28 to 16.98MUM. PMID- 27118323 TI - Oxidative stress controlling agents are effective for small intestinal injuries induced by non-steroidal anti-inflammatory drugs. AB - BACKGROUND AND AIM: Video-capsule endoscopy (VCE) has shown that intestinal ulcers are common in non-steroidal anti-inflammatory drugs (NSAIDs) users, although the mechanisms and management have not been clearly defined. To explore the contribution of oxidative stress and potential of anti-oxidants for NSAIDs induced intestinal ulcers, we assessed human serum oxidative stress balance and the effect of anti-oxidants using a mouse model. METHODS: A total of 30 NSAIDs users (17 aspirin and 13 non-aspirin users) received VCE. Serum reactive oxygen metabolite (d-ROM) and antioxidative OXY-adsorbent test (OXY) were measured. The indomethacin (IND)-induced mouse intestinal ulcer model was used to assess the effect of anti-oxidants. Eight-week-old mice were divided into four groups; control diet and diet including IND (N group), IND and L-carnitine (NC group), and IND and vitamin E (NE group). RESULTS: Serum OXY levels among non-aspirin users were lower in the mucosal injuries positive group than the negative group (P < 0.05). In the mouse models, the degree of mucosal injuries was lower in NC and NE than N (P < 0.01). Serum d-ROM levels were lower in NC and NE than N (P < 0.01), and OXY levels were higher in NC than N and NE (P < 0.01). The degeneration of intestinal mitochondria was mild in NC and NE. The serum KC/CXCL 1 level and hepatic expression of the anti-oxidant molecule Gpx4 were lower in NC than N. CONCLUSIONS: Non-aspirin NSAID-induced intestinal ulcers are related to decreased anti-oxidative stress function. Anti-oxidants, especially L-carnitine, are good candidates for intestinal ulcers. PMID- 27118324 TI - Amos B Smith, III: chemist, collaborator and mentor. PMID- 27118325 TI - Professor Amos B Smith, III. PMID- 27118326 TI - The first total synthesis and the second- or third-generation approach. PMID- 27118327 TI - A novel block of plant virus movement genes. AB - Hibiscus green spot virus (HGSV) is a recently discovered and so far poorly characterized bacilliform plant virus with a positive-stranded RNA genome consisting of three RNA species. Here, we demonstrate that the proteins encoded by the ORF2 and ORF3 in HGSV RNA2 are necessary and sufficient to mediate cell-to cell movement of transport-deficient Potato virus X in Nicotiana benthamiana. These two genes represent a specialized transport module called a 'binary movement block' (BMB), and ORF2 and ORF3 are termed BMB1 and BMB2 genes. In agroinfiltrated epidermal cells of N. benthamiana, green fluorescent protein (GFP)-BMB1 fusion protein was distributed diffusely in the cytoplasm and the nucleus. However, in the presence of BMB2, GFP-BMB1 was directed to cell wall adjacent elongated bodies at the cell periphery, to cell wall-embedded punctate structures co-localizing with callose deposits at plasmodesmata, and to cells adjacent to the initially transformed cell. Thus, BMB2 can mediate the transport of BMB1 to and through plasmodesmata. In general, our observations support the idea that cell-to-cell trafficking of movement proteins involves an initial delivery to membrane compartments adjacent to plasmodesmata, subsequent entry of the plasmodesmata cavity and, finally, transport to adjacent cells. This process, as an alternative to tubule-based transport, has most likely evolved independently in triple gene block (TGB), double gene block (DGB), BMB and the single gene-coded transport system. PMID- 27118329 TI - Objects but not concepts modulate the size of the attended region. AB - Here we investigated the types of stimuli that modulate the size of the attentional spotlight. In particular, it has been previously shown that conceptual cues that either directly refer to or are semantically related to particular spatial locations can shift attention to that location (known as "conceptual cueing"). For example, reading the word sun or joy can shift attention upward whereas the word boot or hostile can shift attention downward. Here, therefore, we tested whether words could modulate the size of the attended area. Across five experiments, we found that words that either directly referred to, or were abstractly associated with, particular sizes (small versus large) did not change the size of the attentional spotlight, whereas the presence of differently sized stimuli did, as evidenced by faster responses to targets when the spotlight is small than when it is large. This suggests that physical but not conceptual inducers can modulate the size of the attentional spotlight. This highlights an important difference between the regulation of spotlight size and shifts of attention, supporting the notion that they are subserved by distinct mechanisms. PMID- 27118328 TI - Novel strategies for development of hemorrhagic fever arenavirus live-attenuated vaccines. AB - INTRODUCTION: Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose significant public health problems in their endemic regions. Moreover, HF arenaviruses represent credible biodefense threats. There are not FDA-approved arenavirus vaccines and current anti-arenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. AREAS COVERED: Live-attenuated vaccines (LAV) represent the most feasible approach to control HF arenaviruses within their endemic regions. Different platforms, including recombinant viral vectors expressing LASV antigens, and the use of attenuated reassortant arenaviruses, have been used to develop LAV candidates against LASV with promising results in animal models of LASV infection, but none of them has entered a clinical trial. These vaccine efforts have been the subject of recent reviews and will not be examined in this review, which is focused on new avenues for the development of safe and effective LAV to combat HF arenaviruses. Expert commentary: The development of arenavirus reverse genetics has provided investigators with a novel powerful approach to manipulate the genomes of HF arenaviruses, which has opened new avenues for the rapid development of safe and effective LAV to combat these human pathogens. PMID- 27118330 TI - IL-6 blockade therapy for inflammatory diseases: current perspectives and future directions. AB - Interleukin-6 (IL-6) is a prototypical cytokine featuring pleiotropic and redundant activity. It is an essential factor to protect host from environmental stress and to maintain homeostasis, whereas its dysregulated, excessive or persistent production plays a pathological role in various inflammatory diseases. Then, IL-6 blockade was expected to become a novel therapeutic strategy and a humanized anti-IL-6 receptor antibody, tocilizumab was developed. Indeed, through clinical trials its efficacy and tolerable safety was proved and is now in clinical use for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis and Castleman's disease. Moreover, ongoing various clinical studies suggest that it will be widely applicable for the treatment of intractable chronic immune-mediated diseases as well as acute severe inflammatory diseases presenting with "cytokine storm". PMID- 27118331 TI - Relevance of involvement of tofacitinib in T cell subsets to clinical courses and adverse events in patients with rheumatoid arthritis. AB - Recent advance in treatment of rheumatoid arthritis (RA) has been derived by biological disease-modifying antirheumatic drugs (bDMARDs) targeting cytokines. A Jak inhibitor tofacitinib, the first drug of targeted synthetic DMARD (tsDMARD), a novel category of DMARD, shows similar efficacy profile, but different safety concerns, compared to bDMARDs. It is, therefore, essential to understand the mode of action of tofacitinib in the context of safety and efficacy. We here document the possible mechanism of tofacitinib in patiens with RA, shedding light upon a characteristic adverse event, herpes zoster. PMID- 27118332 TI - Gut to systemic immune-homeostasis mediated by innate signals. AB - To accommodate the vast antigenic exposure from both food components and commensal bacteria, the gut has evolved a naturally anti-inflammatory environment. We have recently shown that lactic acid bacteria (LAB), a major population of small intestinal microbiota and often found in fermented foods, contain a large amount of double-stranded RNA and capable of inducing interferon beta (IFN-beta) production from dendritic cells (DCs) via the Toll-like receptor 3 (TLR3) pathway. It is a significant feature of LAB and was not observed in other bacteria tested. Moreover, IFN-beta secreted in response to LAB prevented experimental colitis. These results identify TLR3 as a sensor to small intestinal commensal bacteria and contribute to anti-inflammatory mechanism. We also show that oral administration of beta-glucan enhance intestinal and systemic immune response in dectin-1-dependent manner. Thus elucidation of "gut to systemic immune-homeostasis" mediated by innate signals will be valued for the development of gut-biology and science-based food immunology, with a focus on innovation in the health and medical industries. PMID- 27118333 TI - The participations of the physicians on the diagnosis and treatments of antiphospholipid related pregnancy morbidities in Japan: from the result of nationwide survey. AB - BACKGROUND: Thromboses and pregnancy morbidities are major pathologies of antiphospholipid syndrome (APS). In general, rheumatologists or hematologists see APS thrombosis patients, and they often give advices for the treatments of APS related pregnancy morbidities, such as measurements and interpretations of antiphospholipid antibodies(aPL). OBJECTIVE: To survey the approaches of physicians in Japan to the diagnosis and treatment of aPL-associated pregnancy morbidities. METHOD: The study group on the Health and Labour Sciences Research Grants sent a questionnaire to 550 board members of the Japan College of Rheumatology and the Japanese Society on Thrombosis and Hemostasis, and analyzed the responses. RESULT: The number of valid responses was 157 (28.5%). The number of pregnant women who were diagnosed as having APS was 118.7 patients/year in 53 of 157 hospitals (33.8%). With respect to aPL measurements, 128 out of 157 hospitals (81.5%) determined one or more anticardiolipin antibodies or beta2GPI dependent anticardiolipin antibodies with one or more lupus anticoagulants; however aPL tests of only 2 hospitals (1.3%) covered all aPLs defined in the classification criteria. The obstetricians were responsible for treatments in 33.1% to 42.3% of the hospitals. The treatment methods or duration of treatments did not reach to the general consensus. CONCLUSION: The number of cases of aPL related pregnancy complications that physicians have intervened was relatively small. There are considerable patients that are not diagnosed as having the disease due to insufficient aPL examinations. There were less involvement of physicians to the diagnosis and treatment of pregnant women with aPLs. PMID- 27118334 TI - Clinical study of giant cell arteritis in our hospital. AB - OBJECTIVE: To investigate clinical and laboratory features of giant cell arteritis (GCA). METHOD: We included 24 patients (6 men, 18 women; mean age 69.8 years) in this study. GCA was diagnosed based on the American College of Rheumatology 1990 classification criteria. RESULTS: Mean serum C-reactive protein was 9.03 mg/dl. GCA was classified into three types: classic temporal arteritis type (cranial GCA, nine patients); large-vessel type, affecting the aorta and its major branches without temporal arteries (12 patients); generalized type, affecting both temporal arteries and large vessels (three patients). Swelling and tenderness of temporal arteries were recognized in temporal arteritis and generalized arteritis. Ten of these patients also had histopathologic findings of arteritis, including giant cells in biopsy specimens. Examination of HLA-class 1 expression showed that one patient with cranial GCA, three with generalized GCA, and seven with large-vessel GCA were positive for HLA-A24, and four patients with large-vessel GCA were positive for HLA-B39. One patient with cranial GCA, one with generalized GCA, and six with large-vessel GCA were positive for HLA-B52. Nine patients were positive for anti-phospholipid antibodies (seven for anti cardiolipin antibody immunoglobulin G, seven for anti-cardiolipin beta2 glycoprotein-1 antibody, one for lupus anticoagulant). CONCLUSION: Our study demonstrated that HLA-class 1 expression in GCA resembles that in Takayasu arteritis, suggesting that these two arteritis types share the same genetic background. In contrast, the difference in the prevalence of anti-phospholipid antibodies in GCA and Takayasu arteritis patients shows a difference in the characteristic aspects of these two arteritis types. PMID- 27118336 TI - Functional and mechanistic analysis of telomerase: An antitumor drug target. AB - The current research on anticancer drugs focuses on exploiting particular traits or hallmarks unique to cancer cells. Telomerase, a special reverse transcriptase, has been recognized as a common factor in most tumor cells, and in turn a distinctive characteristic with respect to non-malignant cells. This feature has made telomerase a preferred target for anticancer drug development and cancer therapy. This review aims to analyze the pharmacological function and mechanism and role of telomerase in oncogenesis; to provide fundamental knowledge for research on the structure, function, and working mechanism of telomerase; to expound the role that telomerase plays in the initiation and development of tumor and its relationship with tumor cell growth, proliferation, apoptosis, and related pathway molecules; and to display potential targets of antitumor drug for inhibiting the expression, reconstitution, and trafficking of the enzyme. We therefore summarize recent advances in potential telomerase inhibitors for antitumor including natural products, synthetic small molecules, peptides and proteins, which indicate that optimizing the delivery method and drug combination could be of help in a combinatorial drug treatment for tumor. More extensive understanding of the structure, biogenesis, and mechanism of telomerase will provide invaluable information for increasing the efficiency of rational antitumor drug design. PMID- 27118335 TI - Marked efficacy of adalimumab for secondary gastrointestinal amyloidosis accompanied with ankylosing spondylitis. AB - A 39-year-old man with seronegative rheumatoid arthritis which was refractory to methotrexate and prednisolone therapy complained of epigastralgia, melena and diarrhea. Diffuse mucosal damage was observed on endoscopic examination, and histological findings of the gastric and colonal mucosa showed AA type amyloidosis. He was diagnosed with ankylosing spondylitis (AS) on the basis of the clinical feature such as the limitation in range of motion of lumber spine, and sacroiliitis on MR imaging. Although digestive symptom ameliorated by fasting and antibiotic therapy, laboratory findings continued to reveal an elevation of serum C-reactive protein (CRP) value and arthritis worsened. However, after the initiation of the treatment with adalimumab (ADA), not only his manifestation but also serum levels of CRP became normalized promptly. As far as we could evaluated, follow-up colonoscopic examination showed normal mucosal findings and histologic examination proved that amyloid protein disappeared. Secondary gastrointestinal amyloidosis is ralely associated with AS. Therefore standard therapy is not established. This case might indicate an efficacy of ADA for secondary gastrointestinal amyloidosis accompanied with AS. PMID- 27118337 TI - Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy. AB - Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme important for many biological processes, has recently emerged as a critical regulator of viral infection. HDAC6 exerts this function either directly, via orchestrating various stages of the viral life cycle, or indirectly via modulating cytokine production by host cells. The broad influence of HDAC6 on viral pathogenesis suggests that this protein may represent an antiviral target. However, the feasibility of targeting HDAC6 and the optimal strategy by which this could be accomplished cannot simply be concluded from individual studies. The primary challenge in developing HDAC6 targeted therapies is to understand how its antiviral effect can be selectively harnessed. As a springboard for future investigations, in this review we recapitulate recent findings on the diverse roles of HDAC6 in viral infection and discuss its alluring potential as a novel antiviral target. PMID- 27118339 TI - Prevention of mother-to-child transmission of hepatitis B virus by treating mothers with high viral loads. PMID- 27118340 TI - Logical operations with single x-ray photons via dynamically-controlled nuclear resonances. AB - Photonic qubits lie at the heart of quantum information technology, often encoding information in their polarization state. So far, only low-frequency optical and infrared photons have been employed as flying qubits, as the resources that are at present easiest to control. With their essentially different way of interacting with matter, x-ray qubits would bear however relevant advantages: they are extremely robust, penetrate deep through materials, and can be focused down to few-nm waveguides, allowing unprecedented miniaturization. Also, x-rays are resonant to nuclear transitions, which are very well isolated from the environment and present long coherence times. Here, we show theoretically that x-ray polarization qubits can be dynamically controlled by nuclear Mossbauer resonances. The control knob is played by nuclear hyperfine magnetic fields, that allow via fast rotations precise processing of single x-ray quanta polarization. With such rotations, single-qubit and binary logical operations such as a destructive C-NOT gate can be implemented. PMID- 27118338 TI - State-of-the-art of regulatory dendritic cells in cancer. AB - Dendritic cells (DCs) with robust immunosuppressive activity are commonly found in the microenvironment of advanced solid tumors. These innate immune cells are generically termed regulatory DCs and include various subsets such as plasmacytoid, conventional and monocyte-derived/inflammatory populations whose normal function is subverted by tumor-derived signals. This review summarizes recent findings on the nature and function of regulatory DCs, their relationship with other myeloid subsets and unique therapeutic opportunities to abrogate malignant progression through their targeting. PMID- 27118341 TI - [Iconographic imaging (ultrasound/MRI) in prenatal evaluation of cervical cystic lymphatic malformations]. AB - OBJECTIVES: Assess imaging (ultrasound+/-MRI) in the diagnosis of cervical cystic lymphangioma. METHODS: Retrospective, descriptive study of the patients who underwent reference ultrasound screening for fetal anterior cervival masses in multidisciplinary prenatal diagnosis center of the Lille Regional University Hospital from 1997 to 2014. RESULTS: Seventeen lymphangiomas were identified. Seventy-three percent of lymphangiomas (n=12) were diagnosed in the baseline ultrasound and 85% (n=11) in MRI. An extra-cervical extension was identified in 10 (62%) with ultrasound and 11 (85%) with MRI. Main sites of mass extension objectived by ultrasound and MRI were respectively the face (4,23%/6,46%), the base of tongue (3, 18%/2, 15%) and buccal floor (3, 18%/3, 15%). Pharyngeal disease (5,38%) and mandible (4,31%) were detected by MRI and not found on ultrasound. Associated malformations detected with ultrasound were 2 (12%) urogenital malformation, 1 (6%) heart defect and 1 (6%) facial anomalies. Lymphangiomas remained stable in volume in 12 (71%) cases and disappeared before birth in 2 (12%) cases. CONCLUSION: MRI and ultrasound seem inseparable to assess and optimally manage fetal cervical masses. Detection of associated lesions seems to help in the final lymphangioma diagnosis. Most of the time, lymphangiomas seem to be stable lesion during pregnancy and a good prognosis in cases of uncomplicated cervical lymphatic mass and without pejorative extension. PMID- 27118342 TI - [Deep infiltrating endometriosis surgical management and pelvic nerves injury]. AB - OBJECTIVES: Deep pelvic endometriosis surgery may need substantial excisions, which in turn expose to risks of injury to the pelvic nerves. To limit functional complications, nerve-sparing surgical techniques have been developed but should be adapted to the specific multifocal character of endometriotic lesions. The objective was to identify the anatomical areas where the pelvic nerves are most at risk of injury during endometriotic excisions. METHODS: The Medline and Embase databases have been searched for available literature using the keywords "hypogastric nerve or hypogastric plexus [Mesh] or autonomic pathway [Mesh], anatomy, endometriosis, surgery [Mesh]". All relevant French and English publications, selected based on their available abstracts, have been reviewed. Five female adult fresh cadavers have been dissected to localize the key anatomical areas where the pelvic nerves are most at risk of injury. RESULTS: Six anatomical areas of high risk for pelvic nerves have been identified, analysed and described. Pelvic nerves can be damaged during the dissection of retrorectal space and the anterolateral rectal excision. Furthermore, before an uterosacral ligament excision, a parametrial excision, a colpectomy or a dissection of the vesico-uterine ligament, the hypogastric nerves, splanchnic nerves, inferior hypogastric plexus and its efferent pathways must be mapped out to avoid injury. The distance between the deep uterin vein and the pelvic splanchnic nerves were measured on four cadavers and varied from 2.5cm to 4cm. CONCLUSION: Six key anatomical pitfalls must be known in order to limit the functional complications of the endometriotic surgical excision. Applying nerve-sparing surgical techniques for endometriosis would lead to less urinary functional complications and a better short-term postoperative satisfaction. PMID- 27118343 TI - ? PMID- 27118344 TI - I Love You but I Cyberbully You: The Role of Hostile Sexism. AB - Cyberbullying is attracting social, political, and academic interest as the use of electronic devices such as computers and mobile phones by young people has increased dramatically. However, little is known about the factors involved in their perpetration, particularly in the context of college students' dating relationships. The aim of this study is to examine the involvement of college students in cyberbullying in the context of their dating relationships and to explore the impact of sexism on males' cyberbullying of their girlfriends. Participants are 219 undergraduate students from a university in the south of Spain. Results showed that 48.4% of participants reported having bullied their partners during the last year via mobile phone and 37.5% via Internet. Males reported a greater extent of cyberbullying of their girlfriends through both means. Regression analyses indicated that males' levels of hostile sexism are related to males' cyberbullying of their girlfriends. These findings suggest a modernization in the forms of violence toward women among college students and also expand current literature by revealing the influence of participants' hostile sexism on this type of cyber aggression against women in dating relationships. PMID- 27118346 TI - Consumer-run services research and implications for mental health care. AB - Mental health consumers/survivors developed consumer-run services (CRSs) as alternatives to disempowering professionally run services that limited participant self-determination. The objective of the CRS is to promote recovery outcomes, not to cure or prevent mental illness. Recovery outcomes pave the way to a satisfying life as defined by the individual consumer despite repetitive episodes of disorder. Recovery is a way of life, which through empowerment, hope, self-efficacy, minimisation of self-stigma, and improved social integration, may offer a path to functional improvement that may lead to a better way to manage distress and minimise the impact of illness episodes. 'Nothing about us without us' is the defining objective of the process activity that defines self-help. It is the giving of agency to participants. Without such process there is a real question as to whether an organisation is a legitimate CRS or simply a non governmental organisation run by a person who claims lived experience. In considering the effectiveness of CRSs, fidelity should be defined by the extent to which the organisation's process conveys agency. Unidirectional helping often does for people what they can do for themselves, stealing agency. The consequence of the lack of fidelity in CRSs to the origins of the self-help movement has been a general finding in multisite studies of no or little difference in outcomes attributable to the consumer service. This, from the perspective of the research summarised herein, results in the mixing of programmatic efforts, some of which enhance outcomes as they are true mutual assistance programmes and some of which degrade outcomes as they are unidirectional, hierarchical, staff-directed helping efforts making false claims to providing agency. The later CRS interventions may provoke disappointment and additional failure. The indiscriminate combining of studies produces the average: no effect. PMID- 27118345 TI - Transcriptome analysis of interactions between silkworm and cytoplasmic polyhedrosis virus. AB - Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) specifically infects silkworm midgut (MG) and multiplication occurs mainly in posterior midgut (PM). In this study, MG and fat body (FB) were extracted at 0, 3, 24, and 72 h after BmCPV infection. The total sequence reads of each sample were more than 1510000, and the mapping ratio exceeded 95.3%. Upregulated transcripts increased in MG during the infection process. Gene ontology (GO) categories showed that antioxidants were all upregulated in FB but not in MG. BGI001299, BGI014434, BGI012068, and BGI009201 were MG-specific genes with transmembrane transport function, the expression of which were induced by BmCPV. BGI001299, BGI014434, and BGI012068 expressed in entire MG and may be involved in BmCPV invasion. BGI009201 expressed only in PM and may be necessary for BmCPV proliferation. BmPGRP-S2 and BGI012452 (a putative serine protease) were induced by BmCPV and may be involved in immune defense against BmCPV. The expression level of BmCPV S1, S2, S3, S6, and S7 was high and there was no expression of S9 in MG 72 h, implying that the expression time of structural protein coding genes is earlier. These results provide insights into the mechanism of BmCPV infection and host defense. PMID- 27118347 TI - Status of the Regional Nodal Basin Remains Highly Prognostic in Melanoma Patients with In-Transit Disease. AB - BACKGROUND: The role of SLNB for in-transit (IT) melanoma is controversial. The objective of this study was to determine the rate and prognostic significance of occult nodal disease in patients undergoing surgical nodal staging for IT disease. STUDY DESIGN: We conducted a retrospective review of patients with IT melanoma from May 2005 through September 2014. Analysis was limited to patients with a first-time IT event who underwent surgical excision. Associations between clinicopathologic characteristics, patterns of recurrence, and survival were analyzed. RESULTS: A total of 261 patients treated at our center were identified and 157 met inclusion criteria, of which 135 (86%) presented with no evidence of nodal disease. At the time of surgical excision of the IT lesion, 80 (58%) clinically node-negative patients underwent observation of the nodal basin and 55 (41%) surgical nodal staging. Twenty (36%) clinically node-negative but surgically staged patients were found to have nodal disease. Distant metastasis free survival was 70.8 months for surgically staged node-negative patients, 19.2 months for surgically staged node-positive patients, 22.8 months for those staged node-negative by clinical examination only and 4.8 months for those with clinical nodal disease (p = 0.01). The regional nodal basin was the first site of failure in 14 of 66 (21%) clinically staged patients, 5 of 50 (10%) for those surgically staged, and 6 of 16 (38%) for those with clinical nodal disease. CONCLUSIONS: Patients with IT disease are at high risk for occult nodal metastasis. Because clinical staging is unreliable, SLNB should be considered. For patients with IT recurrence, the status of the regional basin is strongly prognostic and stratifies patients into low-, intermediate-, and high-risk groups. PMID- 27118348 TI - Should All Patients Be Included in Alternative Payment Models for Primary Total Hip Arthroplasty and Total Knee Arthroplasty? AB - BACKGROUND: Alternative payment models in total joint replacement incentivize cost effective health care delivery and reward reductions in length of stay (LOS), complications, and readmissions. If not adjusted for patient comorbidities, they may encourage restrictive access to health care. METHODS: We prospectively evaluated 802 consecutive primary total hip arthroplasty and total knee arthroplasty patients evaluating comorbidities associated with increased LOS and readmissions. RESULTS: During this 9-month period, 115 patients (14.3%) required hospitalization >3 days and 16 (1.99%) were readmitted within 90 days. Univariate analysis demonstrated that preoperative narcotic use, heart failure, stroke, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and liver disease were more likely to require hospitalization >3 days. In multivariate analysis, CKD and COPD were independent risk factors for LOS >3 days. A Charlson comorbidity index >5 points was associated with increased LOS and readmissions. CONCLUSION: Patients with CKD, COPD, and Charlson comorbidity index >5 points should not be included in alternative payment model for THA and TKA. PMID- 27118349 TI - Patient Optimization-Strategies That Work: Malnutrition. AB - BACKGROUND: Patient optimization is receiving increasing attention as outcomes monitoring and bundled payments have been introduced in joint arthroplasty. Optimization of nutrition is an important aspect of perioperative management. METHODS: This manuscript is a review of previously published material related to nutrition and the impact of malnutrition on surgical outcomes, with guidance for surgeons preparing patients for elective joint arthroplasty. RESULTS: Patients with optimized nutritional parameters have fewer complications, especially related to wound healing and infection. CONCLUSION: Nutritional assessment and optimization should be a part of the perioperative management of patients undergoing lower extremity arthroplasty. PMID- 27118350 TI - Magnetic Resonance Imaging Predicts Adverse Local Tissue Reaction Histologic Severity in Modular Neck Total Hip Arthroplasty. AB - BACKGROUND: The association between advanced imaging, serum metal ion levels, and histologic adverse local tissue reaction (ALTR) severity has not been previously reported for Rejuvenate modular neck femoral stems. METHODS: A cohort of 90 patients with 98 Rejuvenate modular neck femoral stems was revised by a single surgeon from July 2011 to December 2014. Before revision, patients underwent multiacquisition variable resonance image combination sequence magnetic resonance imaging (MRI), and serum cobalt and chromium ion levels were measured. Histologic samples from the revision surgery were scored for synovial lining, inflammatory infiltrate, and tissue organization as proposed by Campbell. Regression based on the generalized estimating equations approach was used to assess the univariate association between each MRI, demographic, and metal ion measure and ALTR severity while accounting for the correlation between bilateral hips. Random forest analysis was then used to determine the relative importance of MRI characteristics, demographics, and metal ion levels in predicting ALTR severity. RESULTS: Synovial thickness as measured on MRI was found to be the strongest predictor of ALTR histologic severity in a recalled modular neck femoral stem. CONCLUSION: MRI can accurately describe ALTR in modular femoral neck total hip arthroplasty. MRI characteristics, particularly maximal synovial thickness and synovitis volume, predicted histologic severity. Serum metal ion levels do not correlate with histologic severity in Rejuvenate modular neck total hip arthroplasty. PMID- 27118351 TI - Is Metal-On-Metal Total Hip Arthroplasty Associated With Neurotoxicity? AB - BACKGROUND: Isolated case reports in the literature describe systemic neurologic side effects associated with metal-on-metal (MOM) bearing surfaces, yet the incidence of these effects have not been evaluated beyond individual cases. The purpose of this study was to compare new diagnoses of these side effects described in isolated cases in large patient cohorts of MOM vs metal on polyethylene (MOP). METHODS: We queried the entire Medicare database from 2005 to 2012. Total hip arthroplasty (THA) and bearing surface were determined using International Classification of Diseases, 9th revision procedure codes. Patients with 5-year follow-up were selected. Using International Classification of Diseases, 9th revision codes, we identified new diagnoses of previously reported neurologic side effects: peripheral neuropathy, sensorineural hearing loss, visual impairment, paresthesias, tinnitus, and vertigo. Comorbidities and demographics were collected. Odds ratios, CIs, and P values were calculated. RESULTS: Overall, 29,483 MOM THAs and 23,587 age- and gender-matched MOP THAs were identified. The average Charlson Comorbidity Index was 5 for both groups. MOM and MOP patients had 26 of 30 identical prevalence of Elixhauser-measure comorbidities. There was no statistically significant difference in new diagnoses of any of the side effects at any time point between the 2 groups over 5 years. CONCLUSION: This study represents, to our knowledge, the first longitudinal analysis of systemic neurotoxicity after THA in a large cohort of patients. The results of our study suggest that on the large scale, neurologic side effects previously described do not occur as a common attributable complication. Rather, these cases may be due to individual patient hypersensitivity to metal ions. PMID- 27118352 TI - Modifying Risk Factors: Strategies That Work Diabetes Mellitus. AB - An estimated 29.1 million Americans are currently diagnosed with diabetes, and this number is expected to increase to 48.3 million Americans by 2050. Correspondingly, the present burden of diabetes among patients undergoing total joint arthroplasty is significant and rising. Diabetes as a chronic condition is a well-established risk factor for complication after total joint arthroplasty. A growing body of evidence also indicates that hyperglycemia in the perioperative period, and not the diagnosis of diabetes alone, is similarly associated with increased complication risk. As a result, a coordinated approach to preoperative screening and optimization, combined with judicious perioperative glycemic control, may present an opportunity to improve outcomes, reduce complications, and avoid complication-related costs for patients undergoing total joint arthroplasty. PMID- 27118353 TI - Evaluation of the Painful Dual Taper Modular Neck Stem Total Hip Arthroplasty: Do They All Require Revision? AB - Although dual taper modular-neck total hip arthroplasty (THA) design with additional neck-stem modularity has the potential to optimize hip biomechanical parameters by facilitating adjustments of leg length, femoral neck version and offset, there is increasing concern regarding this stem design as a result of the growing numbers of adverse local tissue reactions due to fretting and corrosion at the neck-stem taper junction. Implant factors such as taper cone angle, taper surface roughness, taper contact area, modular neck taper metallurgy, and femoral head size play important roles in influencing extent of taper corrosion. There should be a low threshold to conduct a systematic clinical evaluation of patients with dual-taper modular-neck stem THA using systematic risk stratification algorithms as early recognition and diagnosis will ensure prompt and appropriate treatment. Although specialized tests such as metal ion analysis and cross sectional imaging modalities such as metal artifact reduction sequence magnetic resonance imaging (MARS MRI) are useful in optimizing clinical decision-making, overreliance on any single investigative tool in the clinical decision-making process for revision surgery should be avoided. PMID- 27118354 TI - How Do Demographic, Surgical, Patient, and Cultural Factors Affect Pain Control After Unicompartmental Knee Arthroplasty? A Multivariable Regression Analysis. AB - BACKGROUND: Controlling pain after unicompartmental knee arthroplasty (UKA) is essential for improving patient satisfaction, minimizing complications, and early rehabilitation. There is little literature available evaluating the effect of both treatment and patient characteristics on in-hospital pain after UKA. The purpose of this study was to examine the effect of patient and treatment characteristics on in-hospital pain after UKA. This study also evaluated the role of analgesic cocktail (traditional periarticular injection cocktail "[PAI]" vs cocktail including liposomal bupivacaine "[LBUP]"). METHODS: The study sample included 442 consecutive UKA cases performed between December 2011 and August 2013. The primary outcome measures were the average Visual Analog Scale pain score and the percent of pain scores during hospitalization that were 0, that is, "no pain." Multivariable regression analyses were implemented to investigate associations between patient demographics and analgesic group with the outcomes. For the analgesic groups, the "PAI" group received injections of a cocktail including Marcaine, ketorolac, and morphine, the "LBUP" group received injections of LBUP. RESULTS: Postoperative pain was higher in females (P < .001) and younger patients (P = .002). The patient group treated with LBUP injection technique had similar overall average Visual Analog Scale pain scores to patients in the PAI group (P = .729); however, there was also a significant improvement in pain scores over time (as the study progressed) for patients in the LBUP group relative to the PAI group (P = .003), potentially indicating better outcomes with more experience with the injection technique. When compared individually by day, the LBUP group had lower pain scores from day 1 to 3 (P < .024). CONCLUSION: The results showed that in patients undergoing UKA, postoperative pain was lower in males, older patients, patients with lower body mass index, and those treated with LBUP over the study period. Understanding these associations is necessary to effectively manage pain and encourage earlier ambulation and physiotherapy after UKA. PMID- 27118355 TI - Non-invasive ventilation in paediatric critical care. AB - Non-invasive ventilation (NIV) is a well recognised and increasingly prevalent intervention in the paediatric critical care setting. In the acute setting NIV is used to provide respiratory support in a flexible manner that avoids a requirement for endotracheal intubation or tracheostomy, with the aim of avoiding the complications of invasive ventilation. This article will explore the physiological benefits, complications and epidemiology of the different modes of NIV including continuous positive airway pressure (CPAP), non-invasive positive pressure ventilation (NIPPV) and high-flow nasal cannula oxygen (HFNC). The currently available equipment and patient interfaces will be described, and the practical aspects of using NIV clinically will be explored. The current evidence for use of NIV in different clinical settings will be discussed, drawing on adult and neonatal as well as paediatric literature. PMID- 27118358 TI - Editorial: Strategies for cellular target identification of natural products. PMID- 27118357 TI - Maternal obesity and Caesarean delivery in sub-Saharan Africa. AB - OBJECTIVES: To quantify maternal obesity as a risk factor for Caesarean delivery in sub-Saharan Africa. METHODS: Multivariable logistic regression analysis using 31 nationally representative cross-sectional data sets from the Demographic and Health Surveys (DHS). RESULTS: Maternal obesity was a risk factor for Caesarean delivery in sub-Saharan Africa; a clear dose-response relationship (where the magnitude of the association increased with increasing BMI) was observable. Compared to women of optimal weight, overweight women (BMI 25-29 kg/m(2) ) were significantly more likely to deliver by Caesarean (OR: 1.54; 95% CI: 1.33, 1.78), as were obese women (30-34.9 kg/m(2) (OR: 2.39; 95%CI: 1.96-2.90); 35-39.9 kg/m(2) (OR: 2.47 95%CI: 1.78-3.43)) and morbidly obese women (BMI >=40 kg/m(2) OR: 3.85; 95% CI: 2.46-6.00). CONCLUSIONS: BMI is projected to rise substantially in sub-Saharan Africa over the next few decades and demand for Caesarean sections already exceeds available capacity. Overweight women should be advised to lose weight prior to pregnancy. Furthermore, culturally appropriate prevention strategies to discourage further population-level rises in BMI need to be designed and implemented. PMID- 27118356 TI - Management of multiple myeloma in older adults: Gaining ground with geriatric assessment. AB - Multiple myeloma increases in incidence with age. With the aging of the population, the number of cases of multiple myeloma diagnosed in older adults each year will nearly double in the next 20years. The novel therapeutic agents have significantly improved survival in older adults, but their outcomes remain poorer than in younger patients. Older adults may be more vulnerable to toxicity of therapy, resulting in decreased dose intensity and contributing to poorer outcomes. Data are beginning to emerge to aid in identifying which individuals are at greater risk for toxicity of therapy; comorbidities, functional limitations, and age over 80years are among the factors associated with greater risk. Geriatric assessment holds promise in the care of older adults with multiple myeloma, both to allow modification of treatment to prevent toxicity, and to identify vulnerabilities that may require intervention. Emerging treatments with low toxicity and attention to individualizing therapy based on geriatric assessment may aid in further improving outcomes in older adults with multiple myeloma. PMID- 27118359 TI - Clinical analysis on surgical management of type III external auditory canal cholesteatoma: a report of 12 cases. AB - OBJECTIVE: To investigate surgical management of type III EACC with lesions involving the posterior external auditory canal and mastoid. METHODS: This retrospective case review was conducted in 12 patients with type III EACC who underwent intact canal wall mastoidectomy with tympanoplasty and canal wall reconstruction with autologous cortical bone. RESULTS: During the follow-up, all patients obtained successful results on external auditory canal structures and hearing improvement, except for one patient who needed a revision operation for the fistula between the reconstructed wall and the mastoid. CONCLUSION: Intact canal wall mastoidectomy with tympanoplasty and canal wall reconstruction with autologous cortical bone was proved to be an effective and inexpensive choice for the patients with type III external auditory canal cholesteatoma (EACC) to achieve optimal outcomes. PMID- 27118360 TI - Q fever: a contemporary case series from a Belgian hospital. AB - OBJECTIVES: Q fever is a global zoonosis that can cause both acute and chronic infections in humans through aerogenic transmission. Although Q fever was discovered already 80 years ago, this infectious disease remains largely unknown. We studied a case series in a Belgian tertiary care hospital. METHODS: A laboratory and file query at our department was performed to detect patients who were newly diagnosed with Q fever from 01 January 2005 to 01 October 2014. RESULTS: In total, 10 acute Q fever and 5 chronic Q fever infections were identified. An aspecific flu-like illness was the prevailing manifestation of acute Q fever, while this was infective endocarditis in chronic Q fever cases. Noteworthy are the high percentage of myocarditis cases in the acute setting and one case of amyloidosis as a manifestation of chronic Q fever. No evolution from acute to chronic Q fever was noted; overall outcome for both acute and chronic Q fever was favourable with a 94% survival rate. DISCUSSION: Q fever is an infectious disease characterised by a variable clinical presentation. Detection requires correct assessment of the clinical picture in combination with a laboratory confirmation. Treatment and follow-up are intended to avoid a negative outcome. PMID- 27118361 TI - Development of a Solid Dispersion System for Improving the Oral Bioavailability of Resveratrol in Rats. AB - BACKGROUND AND OBJECTIVE: Resveratrol (3,4',5-trihydroxy-trans-stilbene; RES) produces a variety of pharmacological effects; however, its oral bioavailability (BA) approaches zero. In this study, grape peel extract (GPE) was incorporated into a solid dispersion delivery system to improve the solubility, dissolution and oral absorption of RES. METHODS: The dripping pill (DP) oral delivery system was developed through the hot-melt method, and the optimal formulation consisted of GPE, propylene glycol monocaprylate, poloxamer 188, polyoxyl 35 castor oil and polyethylene glycol 6000. RESULTS: The DPs enhanced the (mean +/- SD) dissolution of RES from 23.3 +/- 1.0 to 67.8 +/- 0.4 %. The pharmacokinetic profiles in the rats revealed that the DPs increased the oral BA of RES from 0.9 +/- 0.1 to 10.5 +/- 0.9 %; this represented an approximately 12-fold increase in absorption. CONCLUSIONS: Our results indicated that the DP formulation improves the dissolution and oral BA of RES. Thus, this could be an effective and practical technique for food and pharmaceutical applications. PMID- 27118362 TI - Simplifying the audit of risk factor recording and control: A report from an international study in 11 countries. AB - BACKGROUND: To simplify the assessment of the recording and control of coronary heart disease risk factors in different countries and regions. DESIGN: The SUrvey of Risk Factors (SURF) is an international clinical audit. METHODS: Data on consecutive patients with established coronary heart disease from countries in Europe, Asia and the Middle East were collected on a one-page collection sheet or electronically during routine clinic visits. Information on demographics, diagnostic category, risk factors, physical and laboratory measurements, and medications were included and key variables summarized in a Cardiovascular Health Index Score. RESULTS: Coronary heart disease patients (N = 10,186; 29% women) were enrolled from 79 centres in 11 countries. Recording of risk factors varied considerably: smoking was recorded in over 98% of subjects, while about 20% lacked data on laboratory measurements relevant to cardiovascular disease risk. Sixteen per cent of participants reported smoking, 29% were obese, and 46% had abdominal obesity. Sixty per cent of participants had blood pressure <140/90 mmHg (140/80 mmHg for diabetics), 48% had HbA1c<7%, 30% had low-density lipoprotein <1.8 mmol/l and 17% had a good cardiovascular health index score. There were substantial regional variations. Less than 3% of patients attended cardiac rehabilitation in Asia or the Middle East, compared with 45% in Europe. In Asia, 15% of patients had low-density lipoprotein cholesterol <1.8 mmol/l compared with 33% in Europe and 36% in the Middle East. Variations in medications were noted, with lower use of statins in Asia. CONCLUSIONS: SURF proved to be practical in daily practice. Results indicated poor control of risk factors with substantial variation between countries, calling for development and implementation of clinical standards of secondary prevention of coronary heart disease. PMID- 27118363 TI - Trends in overweight and obesity among rural children and adolescents from 1985 to 2014 in Shandong, China. AB - BACKGROUND: Childhood overweight and obesity has increased dramatically during the past decades, both in developing and developed countries. The present study examined the prevalent trends in overweight and obesity among rural children and adolescents over the past 29 years (1985-2014) in Shandong, China. METHODS: Data for this study were obtained from six cross-sectional surveys (1985, 1995, 2000, 2005, 2010 and 2014) of schoolchildren in Shandong Province, China. A total of 27,840 rural students aged 7-18 years were included in this study. Body mass index cut-off points recommended by the Working Group on Obesity in China (WGOC), the International Obesity Task Force (IOTF) and the World Health Organization (WHO) were used to define overweight and obesity. RESULTS: The prevalence of overweight and obesity has been increasing continually in rural areas over the past 29 years (1985-2014). Using WGOC criteria, for boys, the prevalence of overweight and obesity increased from 0.74% and 0.03% in 1985 to 16.35% and 17.20% in 2014, and for girls it increased from 1.45% and 0.12% in 1985 to 13.91% and 9.11% in 2014, respectively. A similar increasing trend was observed by IOTF and WHO criteria. CONCLUSION: The prevalence of overweight and obesity among children and adolescents in Shangdong rural areas increased rapidly between 1985 and 2014. Rural areas should not be neglected in obesity intervention, policy makers and experts should pay more attention to the new tendency. PMID- 27118364 TI - Time to rethink physical activity advice and blood pressure: A role for occupation-based interventions? PMID- 27118365 TI - Iris ultrastructure in patients with synechiae as revealed by in vivo laser scanning confocal microscopy : In vivo iris ultrastructure in patients with Synechiae by Laser Scanning Confocal Microscopy. AB - BACKGROUND: Iris plays important roles in ocular physiology and disease pathogenesis. Currently it is technically challenging to noninvasively examine the human iris ultrastructure in vivo. The purpose of the current study is to reveal human iris ultrastructure in patients with synechiae by using noninvasive in vivo laser scanning confocal microscopy (LSCM). METHODS: The ultrastructure of iris in thirty one patients, each with synechiae but transparent cornea, was examined by in vivo LSCM. RESULTS: Five characteristic iris ultrastructures was revealed in patients with synechiae by in vivo LSCM, which include: 1. tree trunk like structure; 2. tree branch/bush-like structure; 3. Fruit-like structure; 4. Epithelioid-like structure; 5. deep structure. Pigment granules can be observed as a loose structure on the top of the arborization structure. In iris-associated diseases with Tyndall's Phenomenon and keratic precipitates, the pigment particles are more likely to fall off from the arborization structure. CONCLUSIONS: The ultrastructure of iris in patients with synechiae has been visualized using in vivo LSCM. Five iris ultrastructures can be clearly observed, with some of the structures maybe disease-associated. The fall-off of the pigment particles may cause the Tyndall's Phenomenon positive. In vivo LSCM provides a non-invasive approach to observe the human iris ultrastructure under certain eye disease conditions, which sets up a foundation to visualize certain iris associated diseases in the future. PMID- 27118366 TI - [Shaken baby syndrome]. AB - The shaken baby syndrome (SBS) or shaking trauma describes the occurrence of subdural hematoma, retinal hemorrhage and diffuse injury to the brain by vigorous shaking of an infant that has a poor prognosis. Rapid cranial acceleration and deceleration leads to tearing of bridging veins, retinal hemorrhages and diffuse brain injuries. In addition to clinical symptoms, such as irritability, feeding difficulties, somnolence, apathy, seizures, apnea and temperature regulation disorders, vomiting also occurs due to increased intracranial pressure. Milder forms of SBS often go undiagnosed and the number of unreported cases (grey area) is probably much higher. Up to 20 % of patients die within days or weeks due to SBS and survivors often show cognitive deficits and clinical symptoms, such as physical disabilities, impaired hearing, impaired vision up to blindness, epilepsy and mental retardation as well as a combination of these conditions; therefore, prevention is very important. PMID- 27118367 TI - [Accident or maltreatment? Radiographic X-ray patterns in non-accidental trauma : The concept of sentinel injuries]. AB - The focus of this review article is on child abuse and the radiographic pattern of X-ray findings. The radiologist should be able to recognize typical injuries resulting from child abuse. In some cases the findings are highly specific for abuse and these include metaphyseal corner fractures of the long bones in children aged up to 24 months. In other cases the fractures are not specific but highly indicative of child abuse: rib fractures, for example can be associated with child abuse in more than 50 % of the cases; however, maltreatment is difficult to diagnose without taking the entire pattern of skeletal findings into consideration so that a radiological screening of the entire skeleton is often necessary. The concept of sentinel injuries might be helpful for deciding in which cases a complete skeletal screening should be performed. In the age group up to 24 months old a complete skeletal status (with some exceptions) is recommended if one of the three sentinel injuries of rib fractures, intracranial bleeding and abdominal trauma is present. PMID- 27118368 TI - [Child abuse from a pediatric perspective]. AB - CLINICAL ISSUE: Child abuse is the physical, sexual or emotional maltreatment, or neglect of a child or children. Child maltreatment is defined as any act or series of acts of commission or omission by a parent or other caregiver that results in harm, potential for harm, or threat of harm to a child. Child abuse can occur in a child's home, or in the organizations, schools or communities the child interacts with. There are four major categories of child abuse: neglect, physical abuse, psychological or emotional abuse, and sexual abuse. DIAGNOSTIC WORK-UP: In child abuse, establishing an early diagnosis is essential. Apart from taking a detailed history and performing a meticulous physical examination, including forensic evaluation as indicated, further diagnostic steps (imaging studies, ophthalmic examination/funduscopy, laboratory studies, etc.) may be warranted. PRACTICAL RECOMMENDATIONS: In addition to providing acute medical help, longer-term, multidisciplinary interventions have to be put in place in cases of child abuse. This article summarizes the most important facts pertinent to this subject. PMID- 27118369 TI - [Chronic sports injuries of the knee joint]. AB - Chronic sports injuries of the knee joint are common and mainly caused by repetitive (micro) trauma and exertion. Chronic insertion tendinopathies and avulsion fractures and symptoms related to entrapment, friction and impingement can be pathophysiologically distinguished in athletes. In this review, we depict the characteristic magnetic resonance imaging (MRI) findings of the most commonly occurring pathologies. PMID- 27118370 TI - Methodological considerations for researching the financial costs of family caregiving within a palliative care context. AB - BACKGROUND: The financial impact of family caregiving in a palliative care context has been identified as an issue which requires further research. However, little is known about how research should be conducted in this area. OBJECTIVE: The aim of this study was to explore the opinions of family caregivers in New Zealand regarding the need to conduct research relating to the financial costs of family caregiving and to explore their perspectives on acceptable and feasible methods of data collection. METHODS: A qualitative study design was adopted. Semistructured interviews were conducted with 30 family caregivers who were either currently caring for a person with palliative care needs or had done so in the past year. RESULTS: All participants felt that research relating to the costs of family caregiving within a palliative care context was important. There was little consensus regarding the most appropriate methods of data collection and administration. Online methods were preferred by many participants, although face to-face methods were particularly favoured by Ma-ori participants. Both questionnaires and cost diaries were felt to have strengths and weaknesses. CONCLUSIONS: Prospective longitudinal designs are likely to be most appropriate for future research, in order to capture variations in costs over time. The lack of consensus for a single preferred method makes it difficult to formulate specific recommendations regarding methods of data collection; providing participants with options for methods of completion may therefore be appropriate. PMID- 27118371 TI - Mice with Sort1 deficiency display normal cognition but elevated anxiety-like behavior. AB - Exposure to stressful life events plays a central role in the development of mood disorders in vulnerable individuals. However, the mechanisms that link mood disorders to stress are poorly understood. Brain-derived neurotrophic factor (BDNF) has long been implicated in positive regulation of depression and anxiety, while its precursor (proBDNF) recently showed an opposing effect on such mental illnesses. P75(NTR) and sortilin are co-receptors of proBDNF, however, the role of these receptors in mood regulation is not established. Here, we aimed to investigate the role of sortilin in regulating mood-related behaviors and its role in the proBDNF-mediated mood abnormality in mice. We found that sortilin was up-regulated in neocortex (by 78.3%) and hippocampus (by 111%) of chronically stressed mice as assessed by western blot analysis. These changes were associated with decreased mobility in the open field test and increased depression-like behavior in the forced swimming test. We also found that sortilin deficiency in mice resulted in hyperlocomotion in the open field test and increased anxiety like behavior in both the open field and elevated plus maze tests. No depression like behavior in the forced swimming test and no deficit in spatial cognition in the Morris water maze test were found in the Sort1-deficient mice. Moreover, the intracellular and extracellular levels of mature BDNF and proBDNF were not changed when sortilin was absent in vivo and in vitro. Finally, we found that both WT and Sort1-deficient mice injected with proBDNF in lateral ventricle displayed increased depression-like behavior in the forced swimming test but not anxiety-like behaviors in the open field and elevated plus maze tests. The present study suggests that sortilin functions as a negative regulator of mood performance and can be a therapeutic target for the treatment of mental illness. PMID- 27118372 TI - Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis. AB - The mechanisms by which sepsis triggers intensive care unit acquired weakness (ICUAW) remain unclear. We previously identified difficulty with motor unit recruitment in patients as a novel contributor to ICUAW. To study the mechanism underlying poor recruitment of motor units we used the rat cecal ligation and puncture model of sepsis. We identified striking dysfunction of alpha motor neurons during repetitive firing. Firing was more erratic, and often intermittent. Our data raised the possibility that reduced excitability of motor neurons was a significant contributor to weakness induced by sepsis. In this study we quantified the contribution of reduced motor neuron excitability and compared its magnitude to the contributions of myopathy, neuropathy and failure of neuromuscular transmission. We injected constant depolarizing current pulses (5s) into the soma of alpha motor neurons in the lumbosacral spinal cord of anesthetized rats to trigger repetitive firing. In response to constant depolarization, motor neurons in untreated control rats fired at steady and continuous firing rates and generated smooth and sustained tetanic motor unit force as expected. In contrast, following induction of sepsis, motor neurons were often unable to sustain firing throughout the 5s current injection such that force production was reduced. Even when firing, motor neurons from septic rats fired erratically and discontinuously, leading to irregular production of motor unit force. Both fast and slow type motor neurons had similar disruption of excitability. We followed rats after recovery from sepsis to determine the time course of resolution of the defect in motor neuron excitability. By one week, rats appeared to have recovered from sepsis as they had no piloerection and appeared to be in no distress. The defects in motor neuron repetitive firing were still striking at 2weeks and, although improved, were present at one month. We infer that rats suffered from weakness due to reduced motor neuron excitability for weeks after resolution of sepsis. To assess whether additional contributions from myopathy, neuropathy and defects in neuromuscular transmission contributed to the reduction in force generation, we measured whole-muscle force production in response to electrical stimulation of the muscle nerve. We found no abnormality in force generation that would suggest the presence of myopathy, neuropathy or defective neuromuscular transmission. These data suggest disruption of repetitive firing of motor neurons is an important contributor to weakness induced by sepsis in rats and raise the possibility that reduced motor neuron excitability contributes to disability that persists after resolution of sepsis. PMID- 27118373 TI - Autologous osteochondral mosaicplasty in osteochondritis dissecans of the patella in adolescents. AB - PURPOSE: Osteochondritis dissecans of the patella (OCDP) is rare in adolescents. The objective of this study was to evaluate functional results of OCDP management in adolescents with mosaicplasty and to analyze proper integration of osteochondral grafts via MRI. METHODS: This is a retrospective series of eight cases of OCDP treated by mosaicplasty. Mean age at the surgery was 15 years (range 12-17). Clinical features were represented by retropatellar pain, hydarthrosis, locking and crepitus. All patients benefited from knee radiographs as well as pre-operative MRI. Six OCDP were evaluated International Cartilage Repair Society (ICRS) grade III and two were ICRS grade IV. Mean surface of the lesion was 97.5 mm2. The pre- and post-operative assessments were conducted with scores obtained on the IKDC subjective knee evaluation form, Lysholm knee score, and Tegner activity scale. These assessments were completed by post-operative MRI. The magnetic resonance observation of cartilage repair tissue (MOCART) score was calculated from the latest MRI examination conducted after surgery. RESULTS: Mean follow-up was 28.6 months. At the latest follow-up, the mean IKDC score was 86.5, Lysholm score was 89, and Tegner activity scale score was 6.2 (pre operative scores were respectively 49.9, 53.8, and 4.5). Radiographs and MRI showed a complete integration of grafts at the latest follow-up with a satisfactory reconstruction of the joint surface. Mean MOCART score was 75/100. CONCLUSIONS: Autologous osteochondral mosaicplasty to manage OCDP in adolescents appears to be a reliable technique on the short term to restore patellar joint surface and obtain satisfactory functional results. PMID- 27118374 TI - Interspinous dynamic stabilization adjacent to fusion versus double-segment fusion for treatment of lumbar degenerative disease with a minimum follow-up of three years. AB - PURPOSE: The aim of this study was to assess the outcome of symptomatic lumbar degenerative disease treated with topping-off technique (Coflex(TM) combined with fusion) and compare two-segment fusion at mid-long term follow-up; and find out whether the topping-off technique can reduce the rate of adjacent segment degeneration (ASD) after fusion. METHODS: One hundred and fifty-four consecutive patients who received topping-off surgery (76 patients) and two-segment fusion surgery (88 patients) from March 2009 to March 2012 were studied. All patients included in the analysis had a minimum of three years of follow-up. Radiographic and clinical outcomes between the two groups were compared. A logistic regression analysis was used to analyze risk factors for developing radiographic ASD. RESULTS: Significant differences in clinical outcomes were observed between these two groups at three post-operative years (all, p < 0.05). Compared with the fusion group, the topping-off group showed preserved mobility at the Coflex(TM) level (p = 0.000), which is associated with less blood loss (p = 0.000), shorter duration of surgery (p = 0.000) and lower incidence of ASD (Chi-square test, rate topping-off vs fusion = 13.2 vs 26.1 %, p = 0.039). There were no differences in complications between the two groups. CONCLUSION: Mid-long term follow-up efficacy and safety between topping-off and fusion were similar, while topping off reduced the rate of ASD. Under strict indications, topping-off surgery is an acceptable alternative to fusion surgery for the treatment of two-segment lumbar disease. PMID- 27118375 TI - Risk factors of recompression of cemented vertebrae after kyphoplasty for osteoporotic vertebral compression fractures. AB - PURPOSE: To evaluate the risk factors correlated with loss of cemented vertebral body height after kyphoplasty in patients with osteoporotic vertebral compression fractures. METHODS: Thirty-four consecutive patients with single-level osteoporotic vertebral compression fractures who underwent kyphoplasty in the Affiliated Hospital of Jiangsu University between January 2012 and August 2014 were retrospectively analysed. Eight independent variables (age, gender, body mass index, pre-operative T-score in bone mineral density, the volume of polymethylmethacrylate injected, pre-operatively vertebral body height, the restoration of body height and the distance between polymethylmethacrylate and endplate) were assessed. The recompression of body height was the dependent variable. Multivariate linear regression analyses were used to determine the factors associated with recompression of body height. RESULTS: Multiple linear regression analyses indicated that the recompression of cemented vertebral body height was correlated with the distance between polymethylmethacrylate and endplate (P = 0.008, b' = 0.489). The final multiple linear regression model, which included only the distance between polymethylmethacrylate and endplate, resulted in a formula that accounted for 41.02 % of the recompression of body height. CONCLUSIONS: The distance between polymethylmethacrylate and endplate is an important risk factor of recompression of cemented vertebrae after kyphoplasty for patients with osteoporotic vertebral compression fractures. PMID- 27118376 TI - Causality, mosaics, and the health sciences. PMID- 27118377 TI - Characteristic of optic canal invasion in 31 consecutive cases with tuberculum sellae meningioma. AB - Optic canal invasion by tuberculum sellae meningiomas (TSMs) has been reported, but the characteristics of invasion remain unclear. This study was performed to clarify the incidence and characteristics of optic canal invasion by TSM and to determine whether optic canal invasion could be predicted preoperatively by magnetic resonance imaging (MRI). Between February 2002 and August 2014, 31 patients with TSM underwent tumor resection in our institute. In all cases, the optic canal was explored to identify any tumor invasion. We classified the characteristics of optic canal invasion from intraoperative findings. Invasion was classified into four types: type 1: no invasion; type 2: secondary invasion; type 3: partial wall invasion (two subtypes); and type 4: invasion into the supero-medial-inferior walls of the optic canal. Thirty of 31 cases showed optic canal invasion. Of these 30 cases, 9 (30 %) showed bilateral optic canal invasion. The most common finding was type 1 (23 sides). Among cases with optic canal invasion (39 sides), type 4 was the most common pattern (17 sides), followed by type 3-infero-medial (13 sides), type 2 (5 sides), and type 3-supero medial (4 sides). Blinded prediction of tumor invasion was accurate in 61 % of cases, but characteristics of tumor invasion were undeterminable from preoperative MRI. In conclusion, optic canal invasion was frequently seen in our consecutive series of TSM, characteristics of which were unpredictable preoperatively. Neurosurgeons should be aware of the high incidence and variety of optic canal invasion in planning strategies for TSM treatment. PMID- 27118378 TI - Acute carotid artery stenting in symptomatic high-grade cervical carotid artery stenosis. AB - The safety and efficacy of emergency carotid artery stenting (CAS) for patients with acute ischemic stroke resulting from internal carotid artery stenosis are not established. In this retrospective study, we evaluated outcomes for CAS performed within 2 weeks of acute ischemic stroke for 16 patients treated between December 2009 and February 2014. Cases of internal carotid artery occlusion, internal carotid dissection, or intracranial major arterial trunk occlusion were excluded. Five patients were treated with CAS during the hyperacute phase (within 24 h of stroke onset), three in the advanced phase (within 24 h of stroke-in evolution after admission), and eight in the acute phase (24 h to 2 weeks after onset). We evaluated modified Rankin scale (mRS) scores 90 days after CAS. For patients treated during the hyperacute phase without intravenous tissue-type plasminogen activator (IV-tPA), two had mRS scores of 2 and one had a score of 3. Two patients treated in the hyperacute phase with IV-tPA had scores of 5: one with symptomatic intracerebral hemorrhage and the other with acute brain swelling. For patients treated in the advanced phase, mRS scores were 1, 3, and 5; the patient with 5 had contralateral cerebral infarction. All patients treated in the acute phase had scores of 2 or lower. Patients treated with IV-tPA in advanced or acute phases had no severe post-CAS complications. CAS was effective and safe for treating ischemic stroke within 2 weeks of onset. However, IV-tPA treatment may be a risk factor for CAS treatment during the hyperacute phase. PMID- 27118379 TI - Virtual Raters for Reproducible and Objective Assessments in Radiology. AB - Volumetric measurements in radiologic images are important for monitoring tumor growth and treatment response. To make these more reproducible and objective we introduce the concept of virtual raters (VRs). A virtual rater is obtained by combining knowledge of machine-learning algorithms trained with past annotations of multiple human raters with the instantaneous rating of one human expert. Thus, he is virtually guided by several experts. To evaluate the approach we perform experiments with multi-channel magnetic resonance imaging (MRI) data sets. Next to gross tumor volume (GTV) we also investigate subcategories like edema, contrast-enhancing and non-enhancing tumor. The first data set consists of N = 71 longitudinal follow-up scans of 15 patients suffering from glioblastoma (GB). The second data set comprises N = 30 scans of low- and high-grade gliomas. For comparison we computed Pearson Correlation, Intra-class Correlation Coefficient (ICC) and Dice score. Virtual raters always lead to an improvement w.r.t. inter- and intra-rater agreement. Comparing the 2D Response Assessment in Neuro-Oncology (RANO) measurements to the volumetric measurements of the virtual raters results in one-third of the cases in a deviating rating. Hence, we believe that our approach will have an impact on the evaluation of clinical studies as well as on routine imaging diagnostics. PMID- 27118380 TI - Mental health inequalities among gay and bisexual men in England, Scotland and Wales: a large community-based cross-sectional survey. AB - Background: Sexual minorities suffer worse mental health than the sexual majority but little is known about differences in mental health within sexual minorities. We aimed to describe inequality in mental health indicators among gay and bisexual men. Methods: Using multi-channel community-based opportunistic sampling we recruited 5799 eligible men aged 16 years and over, living in England, Scotland and Wales and who were sexually attracted to other men, to a self completion Internet health survey. Mental health indicators (depression (PHQ-9), anxiety (GAD-7), suicide attempt and self-harm) were examined for independent associations across common axes of inequality (age, ethnicity, migrancy, education, income, cohabitation and living in London). Results: Mental ill-health was common: 21.3% were depressed and 17.1% anxious, while 3.0% had experienced attempted suicide and 6.5% had self-harmed within the last 12 months. All four indicators were associated with younger age, lower education and lower income. Depression was also associated with being a member of visible ethnic minorities and sexual attraction to women as well as men. Cohabiting with a male partner and living in London were protective of mental health. Conclusion: Community interventions to increase mental health among gay and bisexual men should be designed to disproportionately benefit younger men and those living on lower incomes. PMID- 27118381 TI - Considerations for management of interstitial ectopic pregnancies: two case reports. AB - BACKGROUND: Conventional treatment of interstitial pregnancies includes systemic methotrexate, direct methotrexate injection, wedge resection, or hysterectomy. We present two cases of interstitial pregnancies that were successfully managed by different minimally invasive surgical techniques. We also report the novel use of hysteroscopic urologic stone retrieval forceps in the transvaginal removal of persistent products of conception after systemic methotrexate for an interstitial pregnancy. CASE PRESENTATION: Case 1 was a 28-year-old gravida 1 white woman at 8 weeks gestation; she was diagnosed with a left interstitial pregnancy. After laparoscopic confirmation of the interstitial pregnancy, successful ultrasound guided suction dilation and curettage was performed. Case 2 was a 33-year-old gravida 3 para 1021 (one term pregnancy, no preterm pregnancies, one ectopic pregnancy and one spontaneous miscarriage, and one living child) Hispanic woman with persistent products of conception after systemic methotrexate for a left interstitial pregnancy. She underwent hysteroscopic-guided removal of the persistent products of conception, which was possible due to novel use of urologic stone retrieval forceps. CONCLUSIONS: Successful minimally invasive treatment of interstitial pregnancies may be possible in certain cases. Collaboration between different specialties continues to be important for improving minimally invasive options. PMID- 27118382 TI - A test of priority effect persistence in semi-natural grasslands through the removal of plant functional groups during community assembly. AB - BACKGROUND: It is known that during plant community assembly, the early colonizing species can affect the establishment, growth or reproductive success of later arriving species, often resulting in unpredictable assembly outcomes. These so called 'priority effects' have recently been hypothesized to work through niche-based processes, with early colonizing species either inhibiting the colonization of other species of the same niche through niche preemption, or affecting the colonization success of species of different niches through niche modification. With most work on priority effects performed in controlled, short term mesocosm experiments, we have little insight in how niche preemption and niche modification processes interact to shape the community composition of natural vegetations. In this study, we used a functional trait approach to identify potential niche-based priority effects in restored semi-natural grasslands. More specifically, we imposed two treatments that strongly altered the community's functional trait composition; removal of all graminoid species and removal of all legume species, and we compared progressing assembly with unaltered control plots. RESULTS: Our results showed that niche preemption effects can be, to a limited extent, relieved by species removal. This relief was observed for competitive grasses and herbs, but not for smaller grassland species. Although competition effects acting within functional groups (niche preemption) occurred for graminoids, there were no such effects for legumes. The removal of legumes mainly affected functionally unrelated competitive species, likely through niche modification effects of nitrogen fixation. On the other hand, and contrary to our expectations, species removal was after 4 years almost completely compensated by recolonization of the same species set, suggesting that priority effects persist after species removal, possibly through soil legacy effects. CONCLUSIONS: Our results show that both niche modification and niche preemption priority effects can act together in shaping community composition in a natural grassland system. Although small changes in species composition occurred, the removal of specific functional groups was almost completely compensated by recolonization of the same species. This suggests that once certain species get established, it might prove difficult to neutralize their effect on assembly outcome, since their imposed priority effects might act long after their removal. PMID- 27118384 TI - Nanoband array electrode as a platform for high sensitivity enzyme-based glucose biosensing. AB - We describe a novel glucose biosensor based on a nanoband array electrode design, manufactured using standard semiconductor processing techniques, and bio-modified with glucose oxidase immobilized at the nanoband electrode surface. The nanoband array architecture allows for efficient diffusion of glucose and oxygen to the electrode, resulting in a thousand-fold improvement in sensitivity and wide linear range compared to a conventional electrode. The electrode constitutes a robust and manufacturable sensing platform. PMID- 27118385 TI - The impact of low-volume uterine lavage on endometrial biopsy classification. AB - In the mare, the low-volume uterine lavage technique allows for bacterial sampling of the entire uterine lumen and is usually performed after obtaining the traditional double-guarded endometrial swab for aerobic culture and cytology and before procurement of an endometrial biopsy sample during a breeding soundness examination. The purpose of this study was to explore the potential effects of the low-volume lavage on the endometrial biopsy classification and polymorphonuclear cell (PMNs) infiltration in the context of a breeding soundness examination. Fourteen light horse mares of mixed breed, age 7 to 21 years, with known reproductive history, were included in the study, matched by age and reproductive history, and then divided into treatment and control groups. Transrectal palpation and ultrasonography, endometrial swabbing, and the first endometrial biopsy were performed in all mares. Low-volume uterine lavage was performed in the treatment group but not the control group. After either the lavage or a 15-minute rest, a second endometrial biopsy was obtained from both the control and treatment groups. Endometrial swabs and effluent from the low volume lavages were submitted for aerobic culture and sensitivity. Biopsy samples were fixed in Bouin's solution for 24 hours, processed, stained with hematoxylin and eosin, and then viewed under bright light microscopy. Additional staining with anti-neutrophil elastase antibody (ab68672) was performed for indirect immunohistochemistry. All samples were interpreted by a blinded observer. When the first (pre-uterine lavage) and second (post-uterine lavage) biopsies were compared using a mixed-effects logistic regression, there was no difference in endometrial biopsy classification (P = 0.74), presence of PMNs in blood vessels (P = 0.728), or infiltration of PMNs in the tissue (P = 0.934) between the treatment and control groups. In this study, the low-volume uterine lavage did not affect the endometrial biopsy classification. PMID- 27118383 TI - CTLA-4 polymorphisms and haplotype correlate with survival in ALL after allogeneic stem cell transplantation from related HLA-haplotype-mismatched donor. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment for patients with hematological malignancies. Disease relapse remains a major cause of transplant failure. T cell homeostasis is critical to determine the potency of the GVT effect. Recent studies have shown the association of the CTLA-4 polymorphisms with the outcome after HLA-identical sibling allogeneic HSCT. METHODS: In this study, we focused on four CTLA-4 polymorphisms, and analyzed the impact of donor genotypes and haplotypes on the conditions of 152 acute leukemia patients (ALL 83) after related HLA-haplotype- mismatched transplantation. The four SNP genotypes (-1661, -318, CT60 and +49) were determined by TaqMan SNP genotyping assays. RESULTS: ALL recipients of donors with +49 GG showed significantly lower OS (67.7 vs. 90.3 %, P = 0.015) than those with GA+AA. Multivariate analyses showed that +49 GG was an independent risk factor for OS (HR: 0.306, 95 % CI 0.111-0.842, P = 0.022) .23 ALL patients receiving mDLI showed significantly lower OS with +49 GG donor than those with GA+AA (30.0 vs. 83.1 %, P = 0.003). The haplotype analysis revealed only three haplotypes in the donor population -1661/-318/CT60/+49 i.e., ACGG, ACAA and GTGA, the frequencies were 64.1, 19.4 and 16.5 %, respectively. Donors with and without the ACGG/ACGG haplotype had the same effect on transplant outcomes as those with +49 GG and +49 GA+AA. CONCLUSION: In summary, the CTLA-4 +49 GG and the haplotype ACGG/ACGG reduced the overall survival in ALL after allo HSCT from the related HLA-haplotype-mismatched donor, knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for donor selection and individual application of immunosuppressive agents and immunotherapy. PMID- 27118386 TI - Efficacy of induction of luteolysis in superovulated cows is dependent on time of prostaglandin F2alpha analog treatment: effects on plasma progesterone and luteinizing hormone profiles. AB - The objectives were to (1) evaluate the effectiveness of induction of luteolysis in superovulated (SOV) cows at two distinct time points after embryo flushing; and (2) compare the pattern of LH release after treatment with PGF in cows with single vs. multiple ovulations. In the first experiment, Holstein cows were SOV with 400 IU of FSH following standard procedures. Uterine flushing for embryo recovery was performed 7 days after artificial insemination (Day 0), and cows were randomly allocated into two groups to receive PGF (0.5-mg sodium cloprostenol, intramascular) either immediately after flushing (Day 7 group, N = 19) or 4 days later (Day 11 group, N = 20). Time of luteolysis was determined on the basis of plasma progesterone (P4) concentrations. There was no difference (P > 0.05) in plasma P4 before treatment between Day 7 and Day 11 groups. A decline in plasma P4 was observed 48 hours after PGF treatment in both the groups (P < 0.0001). In Day 11 cows, P4 continued to decrease thereafter, whereas Day 7 animals had no further reduction in plasma P4. Luteolysis (P4 < 1 ng/mL) occurred in all Day 11 cows. In the Day 7 group, however, luteolysis failure was observed for 11 of 19 cows (57.9%). In cows without luteolysis, plasma P4 increased after the initial PGF-induced decline. The second experiment compared luteolysis in (SOV, N = 6) vs. non-SOV (control, N = 8) cows. Both groups received a single PGF treatment on Day 11 after estrus, and luteolysis was monitored daily by ovarian ultrasonography and plasma P4 measurements. In addition, plasma LH was measured in blood samples taken every 20 minutes for 1 hour during five consecutive days after treatment. A similar percentage of reduction in P4 was observed in both groups 24 hours after treatment; however, SOV cows only reached plasma P4 values similar (P > 0.05) to controls 96 hours after treatment. There was no difference in initial LH values between SOV and controls (P > 0.05). The slower decrease in plasma P4 in the SOV group prevented an increase in LH for up to 96 hours after luteolysis induction, whereas LH values increased (P < 0.05) in controls 24 hours after treatment. In conclusion, (1) luteolysis may fail or be incomplete when PGF treatment is given on the day of uterine flushing (Day 7) in SOV cows; (2) induction of luteolysis 4 days later (Day 11) is effective, but the initial high plasma P4 concentrations result in a slower slope of P4 decline to basal levels, and consequently, delayed increase in LH pulses. PMID- 27118387 TI - Establishment of superovulation procedure in Japanese field vole, Microtus montebelli. AB - Japanese field vole (Microtus montebelli) is a wild-derived rodent and have unique characteristic. Thus, these species have been expected as model animal. This study was performed to develop novel superovulation procedure for Japanese field vole. First, when 30 IU pregnant mare's serum gonadotropin (PMSG) and 30 IU human chorionic gonadotropin (hCG) were administrated 48 hours apart, females showed higher response to hCG compared with three concentrations of PMSG. Second, to effectively induce ovulation on females after vaginal opening, they were mated with vasectomized male instead of hCG administration. Average number of ovulated oocytes using PMSG mating (13.9 +/- 1.9 oocytes) was higher than PMSG-hCG (control; 6.9 +/- 2.3 oocytes) or PMSG-hCG mating (6.8 +/- 0.8 oocytes). Finally, we attempted superovulation using GnRH agonist (GnRHa). With this treatment, we speculated that GnRHa might induce endogenous luteinizing hormone releasing to cause ovulation. Such superovulation was performed with 30 IU PMSG and different concentration of 20% polyvinylpyrrolidone-GnRHa (15, 30, 45, and 60 MUg/kg). As results, average number of ovulated oocytes was highest with 30 MUg/kg GnRHa (14.5 +/- 4.1 oocytes). The numbers of ovulated oocytes of other concentrations were 5.0 +/- 1.4 (15 MUg/kg), 12.8 +/- 2.7 (45 MUg/kg), and 8.8 +/- 3.7 oocytes (60 MUg/kg). Nuclear status of most collected oocytes was the second meiotic division (range, 94.3%-100%). These superovulation procedures will be useful for development of in vitro culture systems and assisted reproductive technologies for not only Japanese field vole but also other voles. PMID- 27118388 TI - The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. AB - Antisense RNAs regulate the transcription and translation of the corresponding sense genes. Here, we report that an antisense RNA, AS-RBM15, is transcribed in the opposite direction within exon 1 of RBM15 RBM15 is a regulator of megakaryocyte (MK) differentiation and is also involved in a chromosome translocation t(1;22) in acute megakaryocytic leukemia. MK terminal differentiation is enhanced by up-regulation of AS-RBM15 expression and attenuated by AS-RBM15 knockdown. At the molecular level, AS-RBM15 enhances RBM15 protein translation in a CAP-dependent manner. The region of the antisense AS RBM15 RNA, which overlaps with the 5'UTR of RBM15, is sufficient for the up regulation of RBM15 protein translation. In addition, we find that transcription of both RBM15 and AS-RBM15 is activated by the transcription factor RUNX1 and repressed by RUNX1-ETO, a leukemic fusion protein. Therefore, AS-RBM15 is a regulator of megakaryocyte differentiation and may play a regulatory role in leukemogenesis. PMID- 27118390 TI - Clustering and genetic differentiation of the normocyte binding protein (nbpxa) of Plasmodium knowlesi clinical isolates from Peninsular Malaysia and Malaysia Borneo. AB - BACKGROUND: The zoonotic malaria parasite Plasmodium knowlesi has become an emerging threat to South East Asian countries particular in Malaysia. A recent study from Sarawak (Malaysian Borneo) discovered two distinct normocyte binding protein xa (Pknbpxa) types of P. knowlesi. In the present study, the Pknbpxa of clinical isolates from Peninsular Malaysia and Sabah (Malaysian Borneo) were investigated for the presence of Pknbpxa types and natural selection force acting on the gene. METHOD: Blood samples were collected from 47 clinical samples from Peninsular Malaysia (n = 35) and Sabah (Malaysian Borneo, n = 12) were used in the study. The Pknbpxa gene was successfully amplified and directly sequenced from 38 of the samples (n = 31, Peninsular Malaysia and n = 7, Sabah, Malaysian Borneo). The Pknbpxa sequences of P. knowlesi isolates from Sarawak (Malaysian Borneo) were retrieved from GenBank and included in the analysis. Polymorphism, genetic diversity and natural selection of Pknbpxa sequences were analysed using DNAsp v 5.10, MEGA5. Phylogentics of Pknbpxa sequences was analysed using MrBayes v3.2 and Splits Tree v4.13.1. The pairwise F ST indices were used to determine the genetic differentiation between the Pknbpxa types and was calculated using Arlequin 3.5.1.3. RESULTS: Analyses of the sequences revealed Pknbpxa dimorphism throughout Malaysia indicating co-existence of the two types (Type-1 and Type-2) of Pknbpxa. More importantly, a third type (Type 3) closely related to Type 2 Pknbpxa was also detected. This third type was found only in the isolates originating from Peninsular Malaysia. Negative natural selection was observed, suggesting functional constrains within the Pknbpxa types. CONCLUSIONS: This study revealed the existence of three Pknbpxa types in Malaysia. Types 1 and 2 were found not only in Malaysian Borneo (Sarawak and Sabah) but also in Peninsular Malaysia. A third type which was specific only to samples originating from Peninsular Malaysia was discovered. Further genetic studies with a larger sample size will be necessary to determine whether natural selection is driving this genetic differentiation and geographical separation. PMID- 27118389 TI - Management of Small Vessel Vasculitides. AB - Inflammation mediated by cells of the immune system and necrosis are the most striking features observed at the histologic level in patients with vasculitides, clinical entities classified according to pathologic findings involving different organs, to etiology, or to size of vessels involved. Small vessel vasculitides (SVV) are a peculiar group of systemic disorders electively involving small intraparenchymal arteries, arterioles, capillaries, or venules and leading to different levels of vascular obstruction, tissue ischemia and risk of infarction; they can be divided into anti-neutrophil cytoplasmic antibody-associated vasculitides and immune complex vasculitides. Despite the significant advances in understanding the whole disease process and pathophysiology of SVV, strong efforts are still needed to draft, share and spread guidelines in the therapeutic management of these protean disorders. After an accurate evaluation of different open or double-blind trials and cohort studies in this review, we analyze the actual medical tools suggested for treating granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, Henoch Schonlein purpura, cryoglobulinemic vasculitis, anti-glomerular basement membrane disease and hypocomplementemic urticarial vasculitis. PMID- 27118391 TI - Spontaneous Extensor Carpi Ulnaris Compartment Syndrome. AB - We report a case of isolated compartment syndrome within the extensor carpi ulnaris (ECU) compartment in the forearm of a 40-year-old diabetic man. Magnetic resonance imaging of his forearm showed isolated changes in the ECU muscle belly; compartment syndrome was confirmed on manometry. In view of the short history of symptoms and his diabetic status, the patient was managed conservatively. Twenty four hours after onset of the symptoms, the pain and swelling resolved and he was able to be discharged. To date, 3 cases of ECU compartment syndrome secondary to trauma have been reported. This report illustrates a case of confirmed compartment syndrome without antecedent trauma, highly unusual in terms of both its etiology and its anatomical location. PMID- 27118392 TI - Modified Extensor Pollicis Longus Rerouting Technique for Boutonniere Deformity of the Thumb in Rheumatoid Arthritis. AB - PURPOSE: To assess the outcomes of a modified extensor pollicis longus (EPL) rerouting technique for boutonniere deformity of the thumb in patients with rheumatoid arthritis. METHODS: A total of 21 thumbs in 18 patients with a mean age of 63 years were retrospectively analyzed after an average follow-up period of 3.2 years. The preoperative deformities were classified as either mild (5 thumbs) or moderate (16 thumbs). After either metacarpophalangeal (MCP) joint synovectomy or implant arthroplasty, the ulnarly dislocated EPL tendon was reduced dorsally and sutured to the dorsal base of the proximal phalanx. If the interphalangeal (IP) joint extended with manual traction on the proximal portion of the extensor pollicis brevis tendon, no further treatment was considered. If the IP joint did not extend with this maneuver, the insertion of the extensor pollicis brevis tendon was dissected and transferred to the distal portion of the EPL tendon. RESULTS: The average MCP joint extensor lag improved from 62 degrees (range, 32 degrees to 85 degrees ) before surgery to 17 degrees (range, active extension 12 degrees to extensor lag 70 degrees ) at the final follow-up (P < .05), whereas average MCP joint flexion decreased from 83 degrees (range, 52 degrees to 95 degrees ) to 68 degrees (range, 30 degrees to 90 degrees ) (P < .05). Hyperextension at the IP joint was improved from 30 degrees (range, 10 degrees to 50 degrees ) before surgery to an average extensor lag of 2 degrees (range, extensor lag 24 degrees to hyperextension 20 degrees ) at the final follow-up. The average combined MCP and IP motion did not significantly change. The boutonniere deformity was improved in 18 of 21 thumbs. The 3 failures all had moderate-stage deformity prior to treatment. CONCLUSIONS: A modified EPL rerouting technique provided satisfactory results together with a low risk of IP joint extension loss. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 27118393 TI - A chondroblastic osteosarcoma of the coronoid process mimicking a fragmented coronoid process in a dog. AB - A 6-year-old Rhodesian Ridgeback was presented with a 1.5 year history of right forelimb lameness. Clinical, radiological and computed tomographic findings suggested the presence of fragmented medial coronoid process. A subtotal coronoidectomy was performed and, due to the atypical appearance of the medial coronoid process on imaging and at surgery, histopathology of the fragments was performed which revealed chondroblastic OS. Ten months after surgery, the dog was re-presented with the same clinical signs and the radiographic changes were suggestive of a recurrence of the OS. Palliative therapy was instigated at the owner's request. Thirty months after surgery of the neoplasm, the dog was presented with dyspnea. Thoracic radiographs showed lesions consistent with lung metastases. Euthanasia was requested by the owner, who declined post-mortem examination. PMID- 27118394 TI - Genome-wide analysis of Dongxiang wild rice (Oryza rufipogon Griff.) to investigate lost/acquired genes during rice domestication. AB - BACKGROUND: It is widely accepted that cultivated rice (Oryza sativa L.) was domesticated from common wild rice (Oryza rufipogon Griff.). Compared to other studies which concentrate on rice origin, this study is to genetically elucidate the substantially phenotypic and physiological changes from wild rice to cultivated rice at the whole genome level. RESULTS: Instead of comparing two assembled genomes, this study directly compared the Dongxiang wild rice (DXWR) Illumina sequencing reads with the Nipponbare (O. sativa) complete genome without assembly of the DXWR genome. Based on the results from the comparative genomics analysis, structural variations (SVs) between DXWR and Nipponbare were determined to locate deleted genes which could have been acquired by Nipponbare during rice domestication. To overcome the limit of the SV detection, the DXWR transcriptome was also sequenced and compared with the Nipponbare transcriptome to discover the genes which could have been lost in DXWR during domestication. Both 1591 Nipponbare-acquired genes and 206 DXWR-lost transcripts were further analyzed using annotations from multiple sources. The NGS data are available in the NCBI SRA database with ID SRP070627. CONCLUSIONS: These results help better understanding the domestication from wild rice to cultivated rice at the whole genome level and provide a genomic data resource for rice genetic research or breeding. One finding confirmed transposable elements contribute greatly to the genome evolution from wild rice to cultivated rice. Another finding suggested the photophosphorylation and oxidative phosphorylation system in cultivated rice could have adapted to environmental changes simultaneously during domestication. PMID- 27118396 TI - Relationship between saccadic eye movements and formation of the Krukenberg's spindle-a CFD study. AB - In this research, a series of numerical simulations for evaluating the effects of saccadic eye movement on the aqueous humour (AH) flow field and movement of pigment particles in the anterior chamber (AC) was performed. To predict the flow field of AH in the AC, the unsteady forms of continuity, momentum balance and conservation of energy equations were solved using the dynamic mesh technique for simulating the saccadic motions. Different orientations of the human eye including horizontal, vertical and angles of 10 degrees and 20 degrees were considered. The Lagrangian particle trajectory analysis approach was used to find the trajectories of pigment particles in the eye. Particular attention was given to the relation between the saccadic eye movement and potential formation of Krukenberg's spindle in the eye. The simulation results revealed that the natural convection flow was an effective mechanism for transferring pigment particles from the iris to near the cornea. In addition, the saccadic eye movement was the dominant mechanism for deposition of pigment particles on the cornea, which could lead to the formation of Krukenberg's spindle. The effect of amplitude of saccade motion angle in addition to the orientation of the eye on the formation of Krukenberg's spindle was investigated. PMID- 27118395 TI - Mass drug administration: the importance of synchrony. AB - Mass drug administration, a strategy in which all individuals in a population are subject to treatment without individual diagnosis, has been recommended by the World Health Organization for controlling and eliminating several neglected tropical diseases, including trachoma and soil-transmitted helminths. In this article, we derive effective reproduction numbers and average post-treatment disease prevalences of a simple susceptible-infectious-susceptible epidemic model with constant, impulsive synchronized and non-synchronized drug administration strategies. In the non-synchronized model, the individuals in the population are treated at most once per period and their treatment times are uniformly distributed. Mathematically, the set of pulses for the non-synchronized model has the cardinality of the continuum. We show that synchronized and constant strategies are, respectively, the most and least effective treatments in disease control. Elimination through synchronized treatment is always possible when adequate drug efficacy and coverage are fulfilled and sustained. For a strategy with multiple rounds of synchronized treatment per period, the average post treatment prevalence is irrelevant what the time differences between treatments are, as long as there are the same number of treatments per period. PMID- 27118397 TI - Enzyme-Based Test Strips for Visual or Photographic Detection and Quantitation of Gaseous Sulfur Mustard. AB - Sulfur mustard is a chemical agent of high military and terroristic significance. No effective antidote exists, and sulfur mustard can be fairly easily produced in large quantity. Rapid field testing of sulfur mustard is highly desirable. Existing analytical devices for its detection are available but can suffer from low selectivity, laborious sample preparation, and/or the need for complex instrumentation. We describe a new kind of test strip for rapid detection of gaseous sulfur mustard that is based on its degradation by the enzyme haloalkane dehalogenase that is accompanied by a change of local pH. This change can be detected using pH indicators contained in the strips whose color changes from blue-green to yellow within 10 min. In addition to visual read-out, we also demonstrate quantitative reflectometric readout by using a conventional digital camera based on red-green-blue data acquisition. Organic haloalkanes, such as 1,2 dichloroethane, have a negligible interfering effect. The visual limit of detection is 20 MUg/L, and the one for red-green-blue read-out is as low as 3 MUg/L. The assays have good reproducibility +/-6% and +/-2% for interday assays and intraday assays, respectively. The strips can be stored for at least 6 months without loss of function. They are disposable and can be produced fairly rapidly and at low costs. Hence, they represent a promising tool for in-field detection of sulfur mustard. PMID- 27118399 TI - Altered joint tribology in osteoarthritis: Reduced lubricin synthesis due to the inflammatory process. New horizons for therapeutic approaches. AB - Osteoarthritis (OA) is the most common form of joint disease. This review aimed to consolidate the current evidence that implicates the inflammatory process in the attenuation of synovial lubrication and joint tissue homeostasis in OA. Moreover, with these findings, we propose some evidence for novel therapeutic strategies for preventing and/or treating this complex disorder. The studies reviewed support that inflammatory mediators participate in the onset and progression of OA after joint injury. The flow of pro-inflammatory cytokines following an acute injury seems to be directly associated with altered lubricating ability in the joint tissue. The latter is associated with reduced level of lubricin, one of the major joint lubricants. Future research should focus on the development of new therapies that attenuate the inflammatory process and restore lubricin synthesis and function. This approach could support joint tribology and synovial lubrication leading to improved joint function and pain relief. PMID- 27118398 TI - Suppression of REDD1 in osteoarthritis cartilage, a novel mechanism for dysregulated mTOR signaling and defective autophagy. AB - OBJECTIVE: Aging is a main risk factor for the development of osteoarthritis (OA) and the molecular mechanisms underlying the aging-related changes in articular cartilage include increased mammalian target of rapamycin (mTOR) signaling and defective autophagy. REDD1 is an endogenous inhibitor of mTOR that regulates cellular stress responses. In this study we measured REDD1 expression in normal, aged and OA cartilage and assessed REDD1 function in human and mouse articular chondrocytes. METHODS: REDD1 expression was analyzed in human and mouse articular cartilage by qPCR, western blotting, and immunohistochemistry. For functional studies, REDD1 and TXNIP knockdown or overexpression was performed in chondrocytes in the presence or absence of rapamycin and chloroquine, and mTOR signaling and autophagy were measured by western blotting. REDD1/TXNIP protein interaction was assessed by co-immunoprecipitation experiments. RESULTS: Human and mouse cartilage from normal knee joints expressed high levels of REDD1. REDD1 expression was significantly reduced in aged and OA cartilage. In cultured chondrocytes, REDD1 knockdown increased whereas REDD1 overexpression decreased mTOR signaling. In addition, REDD1 activated autophagy by an mTOR independent mechanism that involved protein/protein interaction with TXNIP. The REDD1/TXNIP complex was required for autophagy activation in chondrocytes. CONCLUSION: The present study shows that REDD1 is highly expressed in normal human articular cartilage and reduced during aging and OA. REDD1 in human chondrocytes negatively regulates mTOR activity and is essential for autophagy activation. Reduced REDD1 expression thus represents a novel mechanism for the increased mTOR activation and defective autophagy observed in OA. PMID- 27118400 TI - Communication with patient's families in the intensive care unit: Do we really meet their needs? PMID- 27118401 TI - Biochemical Basis of CO2-Related Internal Browning Disorders in Pears (Pyrus communis L. cv. Rocha) during Long-Term Storage. AB - This study aimed at understanding the biochemical basis of internal browning disorders (IBDs) in 'Rocha' pear. For this purpose, the effects of storage under normal controlled atmosphere (CA) (3 kPa of O2 + 0.5 kPa of CO2) and IBD-inducing CA (1 kPa of O2 + 10 kPa of CO2) on the antioxidant and fermentative metabolisms and polyphenol oxidase (PPO) activity and phenolics concentration were studied. The higher IBD incidence in high CO2-stored fruits was positively correlated with fermentative metabolites and negatively with ascorbate and H2O2 concentrations, and it was linked to PPO activation. These results indicate that both the antioxidant and fermentative metabolisms are involved in the occurrence of IBD in 'Rocha' pear. From the integration of the biochemical and enzymatic data, a schematic model illustrating the effects of high CO2 and low O2 in 'Rocha' pears during long-term storage was constructed. PMID- 27118402 TI - CREB engages C/EBPdelta to initiate leukemogenesis. AB - cAMP response element binding protein (CREB) is frequently overexpressed in acute myeloid leukemia (AML) and acts as a proto-oncogene; however, it is still debated whether such overactivation alone is able to induce leukemia as its pathogenetic downstream signaling is still unclear. We generated a zebrafish model overexpressing CREB in the myeloid lineage, which showed an aberrant regulation of primitive hematopoiesis, and in 79% of adult CREB-zebrafish a block of myeloid differentiation, triggering to a monocytic leukemia akin the human counterpart. Gene expression analysis of CREB-zebrafish revealed a signature of 20 differentially expressed human homologous CREB targets in common with pediatric AML. Among them, we demonstrated that CREB overexpression increased CCAAT enhancer-binding protein-delta (C/EBPdelta) levels to cause myeloid differentiation arrest, and the silencing of CREB-C/EBPdelta axis restored myeloid terminal differentiation. Then, C/EBPdelta overexpression was found to identify a subset of pediatric AML affected by a block of myeloid differentiation at monocytic stage who presented a significant higher relapse risk and the enrichment of aggressive signatures. Finally, this study unveils the aberrant activation of CREB-C/EBPdelta axis concurring to AML onset by disrupting the myeloid cell differentiation process. We provide a novel in vivo model to perform high-throughput drug screening for AML cure improvement. PMID- 27118404 TI - Frequent reconstitution of IDH2(R140Q) mutant clonal multilineage hematopoiesis following chemotherapy for acute myeloid leukemia. PMID- 27118403 TI - A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells. AB - The hypoxic bone marrow (BM) microenvironment confers growth/survival and drug resistance in multiple myeloma (MM) cells. Novel therapies targeting the MM cell in its hypoxic BM milieu may overcome drug resistance. Recent studies led to the development of a novel molecule RRx-001 with hypoxia-selective epigenetic and nitric oxide-donating properties. Here, we demonstrate that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug resistance. RRx-001 inhibits MM cell growth in the presence of BM stromal cells. RRx-001-induced apoptosis is associated with: (i) activation of caspases; (ii) release of ROS and nitrogen species; (iii) induction of DNA damage via ATM/gamma H2AX; and (iv) decrease in DNA methyltransferase (DNMT) and global methylation. RNA interference study shows a predominant role of DNMT1 in MM cell survival versus DNMT3a or DNMT3b. The deubiquitylating enzyme USP7 stimulates DNMT1 activity, and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. RRx-001 plus USP7 inhibitor P5091 triggered synergistic anti-MM activity. MM xenograft studies show that RRx-001 is well tolerated, inhibits tumor growth and enhances survival. Combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity. Our results provide the rationale for translation of RRx-001, either alone or in combination, to clinical evaluation in MM. PMID- 27118405 TI - Discovery and functional characterization of a germline, CSF2RB-activating mutation in leukemia. PMID- 27118406 TI - Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism. AB - Adaptive resistance of myeloma to proteasome inhibition represents a clinical challenge, whose biology is poorly understood. Proteasome mutations were implicated as underlying mechanism, while an alternative hypothesis based on low activation status of the unfolded protein response was recently suggested (IRE1/XBP1-low model). We generated bortezomib- and carfilzomib-adapted, highly resistant multiple myeloma cell clones (AMO-BTZ, AMO-CFZ), which we analyzed in a combined quantitative and functional proteomic approach. We demonstrate that proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition, irrespective of a proteasome mutation, and uniformly show an 'IRE1/XBP1-low' signature. Adaptation of myeloma cells to proteasome inhibitors involved quantitative changes in >600 protein species with similar patterns in AMO-BTZ and AMO-CFZ cells: proteins involved in metabolic regulation, redox homeostasis, and protein folding and destruction were upregulated, while apoptosis and transcription/translation were downregulated. The quantitatively most upregulated protein in AMO-CFZ cells was the multidrug resistance protein (MDR1) protein ABCB1, and carfilzomib resistance could be overcome by MDR1 inhibition. We propose a model where proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition owing to metabolic adaptations that favor the generation of reducing equivalents, such as NADPH, which is supported by oxidative glycolysis. Proteasome inhibitor resistance may thus be targeted by manipulating the energy and redox metabolism. PMID- 27118407 TI - Detection of circulating mast cells in advanced systemic mastocytosis. PMID- 27118408 TI - Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling. AB - Mutations in the DYNAMIN2 (DNM2) gene are frequently detected in human acute T cell lymphoblastic leukemia (T-ALL), although the mechanisms linking these mutations to disease pathogenesis remain unknown. Using an ENU-based forward genetic screen for mice with erythroid phenotypes, we identified a heterozygous mouse line carrying a mutation in the GTPase domain of Dnm2 (Dnm2V265G) that induced a microcytic anemia. In vitro assays using the V265G mutant demonstrated loss of GTPase activity and impaired endocytosis that was comparable to other DNM2 mutants identified in human T-ALL. To determine the effects of DNM2 mutations in T-ALL, we bred the Dnm2V265G mice with the Lmo2 transgenic mouse model of T-ALL. Heterozygous Dnm2 mutants lacking the Lmo2 transgene displayed normal T-cell development, and did not develop T-ALL. In contrast, compound heterozygotes displayed an accelerated onset of T-ALL compared with mice carrying the Lmo2 oncogene alone. The leukemias from these mice exhibited a more immature immunophenotype and an expansion in leukemic stem cell numbers. Mechanistically, the Dnm2 mutation impaired clathrin-mediated endocytosis of the interleukin (IL) 7 receptor resulting in increased receptor density on the surface of leukemic stem cells. These findings suggest that DNM2 mutations cooperate with T-cell oncogenes by enhancing IL-7 signalling. PMID- 27118409 TI - Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma. AB - Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability. A novel agent RA190 targets Rpn13 and inhibits proteasome function, without blocking the proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13. RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes bortezomib resistance. Anti-MM activity of RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that RA190 is well tolerated, inhibits tumor growth and prolongs survival. Combining RA190 with bortezomib, lenalidomide or pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM. PMID- 27118411 TI - A matter of life or early death in CLL: do serum immunoglobulin levels really count? PMID- 27118412 TI - Professional Competence and Teamwork in the Treatment of Patients With Acute and Critical Heart Disease. Response. PMID- 27118410 TI - Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party. AB - We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM. PMID- 27118414 TI - Accumulating Evidence for Physical Activity and Prostate Cancer Survival: Time for a Definitive Trial of Exercise Medicine? PMID- 27118415 TI - Research-to-policy translation for prevention of disordered weight and shape control behaviors: A case example targeting dietary supplements sold for weight loss and muscle building. AB - New approaches to universal eating disorders prevention and interventions targeting macro-environmental change are greatly needed, and research-to-policy translation efforts hold promise for advancing both of these goals. This paper describes as a policy-translation case example an academic-community-government partnership of the Strategic Training Initiative for the Prevention of Eating Disorders, Multi-Service Eating Disorders Association, and the office of Massachusetts Representative Kay Khan, all based in Massachusetts, USA. The partnership's research-to-policy translation project focused on dietary supplements sold for weight loss and muscle building, which have been linked with serious injury and death in consumers. Youth and people of all ages with eating disorders and body dysmorphic disorder may be especially vulnerable to use these products due to deceptive promises of fast and safe weight loss and muscle gain. The research-to-policy translation project was informed by a triggers-to-action framework to establish the evidentiary base of harm to consumers, operationalize policy solutions to mitigate harm through legislation, and generate political will to support action through legislation introduced in the Massachusetts legislature to restrict sales of weight-loss and muscle-building dietary supplements. The paper concludes with lessons learned from this unique policy translation effort for the prevention of disordered weight and shape control behaviors and offers recommendations for next steps for the field to advance research and practice for universal, macro-environmentally targeted prevention. PMID- 27118413 TI - Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1). AB - CONTEXT: We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes. OBJECTIVE: This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given. MATERIALS AND METHODS: This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations. RESULTS: From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6 MUg/L) (range: 2.3-11.2 nmol/L) and 5.3 mmol/L (range: 2.9-9.2 mmol/L) respectively. Beta-blockers (n = 18), calcium antagonists (n = 6), spironolactone and/or angiotensin blocking agents (n = 24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and >=3 vials of anti digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3 mmol/L. Digoxin concentration reduced from 3.8 to 0 nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration. CONCLUSIONS: One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities. PMID- 27118416 TI - Treatment patterns of advanced malignant melanoma (stage III-IV) - A review of current standards in Europe. AB - AIMS AND BACKGROUND: With the recent emergence of immunotherapies and novel targeted treatments for advanced and metastatic melanoma such as selective B-Raf inhibitors and checkpoint inhibitors, the treatment landscape in Europe has changed considerably. The aim of this review was to provide an overview of current treatment pathways in Europe for the treatment of advanced melanoma, unresectable stage III-IV. METHODS: A literature search of four databases was conducted to identify publications reporting on the treatment patterns of advanced and metastatic melanoma (stage III-IV) in European populations. RESULTS: Seven full-text publications and two conference abstracts reported on observational studies of melanoma treatment practices in France, Italy and the United Kingdom. Treatment patterns were identified for two time periods: 2005 2009 and 2011-2012. Common treatments reported for both periods included chemotherapy with dacarbazine, fotemustine or temozolomide. The main differences between the two periods were the introduction and prescription of immunotherapy ipilimumab and targeted therapy vemurafenib between 2011 and 2012. Across the three countries studied, the types of treatments prescribed between 2005 and 2009 were relatively similar, however, with noticeable differences in the frequency and priority of administration. CONCLUSION: Treatment practices for advanced melanoma vary markedly across different European countries and continue to evolve with the introduction of new therapies. The results of this review highlight a considerable evidence gap with regards to recent treatment patterns for advanced melanoma in Europe, especially post-2011 after the introduction of novel therapeutic agents, and more recently with the introduction of programmed cell death 1 inhibitors. PMID- 27118417 TI - Family members' narratives of lifespace: Mapping changes before and after a brain injury causing driving disruption. AB - BACKGROUND/AIM: Family members of a person with an acquired brain injury often provide transport assistance during driving disruption with potential impacts on their own travel and participation within the community. The geographic area in which people travel and conduct their activities is known as lifespace. This study aimed to describe the quantitative changes in family members' lifespace after brain injury and understand their subjective experiences through interacting with maps during narratives. METHODS: Mapping was embedded within in depth semi-structured interviews with 15 family members. Two sets of maps were generated per participant showing the number of travel locations before and after brain injury. In the interviews, participants reflected on the perceived meaning of lifespace change. Qualitative data were analysed using a narrative approach. RESULTS: Quantitative data from the mapping revealed an increase in travel locations for nine participants, a decrease for five, and no change for one participant. Data analysis revealed four typologies which complemented and enriched the quantitative data: (i) I will do everything for him or her; (ii) Trying to fit all in; (iii) We spend all our time together now; (iv) I need to also care for myself. CONCLUSIONS: The findings describe the change in family members' lifespace after taking on the driver role following acquired brain injury. This study highlights the importance of understanding both quantitative and qualitative aspects of lifespace. The subjective experiences and consequences of lifespace changes are different from the impact on individuals with health conditions. Mapping in an interview as a tool has potential clinical utility. PMID- 27118418 TI - Automated sample preparation in a microfluidic culture device for cellular metabolomics. AB - Sample pretreatment in conventional cellular metabolomics entails rigorous lysis and extraction steps which increase the duration as well as limit the consistency of these experiments. We report a biomimetic cell culture microfluidic device (MFD) which is coupled with an automated system for rapid, reproducible cell lysis using a combination of electrical and chemical mechanisms. In-channel microelectrodes were created using facile fabrication methods, enabling the application of electric fields up to 1000 V cm(-1). Using this platform, average lysing times were 7.12 s and 3.03 s for chips with no electric fields and electric fields above 200 V cm(-1), respectively. Overall, the electroporation MFDs yielded a ~10-fold improvement in lysing time over standard chemical approaches. Detection of multiple intracellular nucleotides and energy metabolites in MFD lysates was demonstrated using two different MS platforms. This work will allow for the integrated culture, automated lysis, and metabolic analysis of cells in an MFD which doubles as a biomimetic model of the vasculature. PMID- 27118419 TI - Perceived social support at different times after myocardial infarction and long term mortality risk: a prospective cohort study. AB - PURPOSE: Previous research has explored the association between social support (SS), cardiovascular disease, and mortality. Perceived SS (PSS) refers to an individual's attitude toward received SS. This study aimed to: (1) assess the association between PSS levels and long-term mortality among first myocardial infarction (MI) survivors, (2) compare the effect of PSS measured shortly after the first MI to PSS measured 10-13 years after MI, and (3) compare the prognostic role of different PSS components: family, friends, and significant others. METHODS: Patients were drawn from the longitudinal prospective Israel Study of First Acute Myocardial Infarction (ISFAMI). PSS, sociodemographic and health variables were assessed in two subcohorts during initial hospitalization from 1992 to 1993 (T1, n = 660) and in 2002-2005 (T2, n = 969). Vital status was determined through 2011. Cox regression models assessed mortality risk associated with PSS. RESULTS: By the end of follow-up, 212 (32%) of the T1 and 229 (24%) of T2 subcohorts had died. Higher PSS levels were associated with lower mortality risk at both T1 and T2 (per one standard deviation [1SD] increase hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.75-0.96; HR = 0.74, 95% CI = 0.66 0.83, respectively). These associations were attenuated on adjustment for sociodemographic and clinical variables (HR = 0.93, 95% CI = 0.80-1.07; HR = 0.88, 95% CI = 0.77-1.00, respectively). PSS from friends was significantly associated with lower mortality risk at both T1 and T2 and remained significant only at T2 after adjustment (HR = 0.85, 95% CI = 0.73-0.98). CONCLUSIONS: Higher PSS levels were significantly associated with reduced mortality risk post-MI. This should encourage clinicians to assess post-MI psychosocial status to identify high-risk patients. PMID- 27118420 TI - Impact of age and sex on the composition and abundance of the intestinal microbiota in individuals with and without enteric infections. AB - PURPOSE: The intestinal microbiome is critical for human health and preventing colonization by enteric pathogens. There are notable differences in the microbiota composition among individuals with and without enteric infections, though the impact that age and gender has on the composition and abundance of intestinal microbes is not known. METHODS: A comparative 16S rRNA gene sequencing study was performed on stool DNA from 200 patients with enteric infections and 75 healthy family members representing both sexes and multiple age groups. RESULTS: Microbial community profiles were affected by age and sex in patients with enteric infections and their healthy family members. Overall, we observed an increase in Bacteroides abundance and decrease in Escherichia abundance with age, though these differences were most apparent for patients with enteric infections. Genus Bacteroides was also higher in female communities while Escherichia predominated in males. CONCLUSIONS: Because Escherichia abundance was previously linked to symptom severity, children with enteric infections may be most susceptible to severe disease outcomes due to high and low abundance of Escherichia and Bacteroides, respectively. Future studies should focus on classifying specific differences in the microbiome using metagenomics and identifying novel methods aimed at shifting the intestinal microbiome to a healthy state. PMID- 27118421 TI - Adsorption and dissociation of H2O on the (001) surface of uranium mononitride: energetics and mechanism from first-principles investigation. AB - The interfacial interaction of uranium mononitride (UN) with water from the environment unavoidably leads to corrosion of nuclear fuels, which affects a lot of processes in the nuclear fuel cycle. In this work, the microscopic adsorption behaviors of water on the UN(001) surface as well as water dissociation and accompanying H2 formation mechanisms have been investigated on the basis of DFT+U calculations and ab initio atomistic thermodynamics. For adsorption of one H2O monomer, the predicted adsorption energies are -0.88, -2.07, and -2.07 eV for the most stable molecular, partially dissociative, and completely dissociative adsorption, respectively. According to our calculations, a water molecule dissociates into OH and H species via three pathways with small energy barriers of 0.78, 0.72, and 0.85 eV, respectively. With the aid of the neighboring H atom, H2 formation through the reaction of H* + OH* can easily occur via two pathways with energy barriers of 0.61 and 0.36 eV, respectively. The molecular adsorption of water shows a slight coverage dependence on the surface while this dependence becomes obvious for partially dissociative adsorption as the water coverage increases from 1/4 to 1 ML. In addition, based on the "ab initio atomistic thermodynamic" simulations, increasing H2O partial pressure will enhance the stability of the adsorbed system and water coverage, while increasing temperature will decrease the H2O coverage. We found that the UN(001) surface reacts easily with H2O at room temperature, leading to dissolution and corrosion of the UN fuel materials. PMID- 27118422 TI - Social choice for one: On the rationality of intertemporal decisions. AB - When faced with an intertemporal choice between a smaller short-term reward and a larger long-term prize, is opting for the latter always indicative of delay tolerance? And is delay tolerance always to be regarded as a manifestation of self-control, and thus as a rational solution to intertemporal dilemmas? I argue in favor of a negative answer to both questions, based on evidence collected in the delay discounting literature. This highlights the need for a nuanced understanding of rationality in intertemporal choice, to capture also situations in which waiting is not the optimal strategy. This paper suggests that such an understanding is fostered by adopting social choice theory as a promising framework to model intertemporal decision making. Some preliminary results of this approach are discussed, and its potential is compared with a much more studied formal model for intertemporal choice, i.e. game theory. PMID- 27118423 TI - Low-dose intensive insulin therapy in patients with Acute Coronary Syndrome accompanied by Left Ventricular Failure: audit of two UK hospitals. AB - AIMS AND OBJECTIVES: To determine whether a low-dose intravenous insulin regimen reduces blood glucose levels at a timely rate and associated side effects among patients with Acute Coronary Syndrome and Left Ventricular Failure. BACKGROUND: Induced hypoglycaemia and the associated risks have questioned the benefits of intensive insulin therapy in patients presenting with raised blood glucose levels and Acute Coronary Syndromes. Local audit data identified that patients with Acute Coronary Syndrome and Left Ventricular Failure experienced more hypoglycaemic episodes than those with Acute Coronary Syndrome alone. Consequently, a new regimen of low-dose insulin for this group was implemented and audited over 12 months. DESIGN: Audit. METHODS: Thirty-six consecutive patient notes with a diagnosis of Acute Coronary Syndrome and blood glucose of >=10 mmol/l treated with a new insulin therapy regimen were analysed. Data were extracted using a standardised form and entered into an Excel spreadsheet for analysis. RESULTS: The mean age of the sample was 70 years with 66% of subjects being men and 50% presenting with Acute Coronary Syndrome and Left Ventricular Failure. The low-dose regimen was effective in achieving normoglycaemia, (range 4 8 mmol/l) for a consecutive six-hour period. This was achieved in 72% of patients and within a median time of 13 hours. CONCLUSION: The audit suggests that a low dose insulin regimen can effectively stabilise blood glucose in patients presenting with both Acute Coronary Syndrome and Left Ventricular Failure. The importance of regularly monitoring blood sugar levels is vital and highlights the role of nurses in minimising patient risk and promoting safety. RELEVANCE TO PRACTICE: Nurses are instrumental in the safe implementation of intensive insulin guidelines. Close monitoring of patients is essential, enabling timely adjustments to treatments and ensuring patient safety. Regular audits allow nurses to evaluate care provision and continue to drive practice forward. PMID- 27118424 TI - Bilateral papilloedema in a patient with non-Hodgkin lymphoma: is there central nervous system infiltration? PMID- 27118425 TI - Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure. AB - Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability, and tissue heterogeneity limit their broad applications. Here, we developed a miniaturized spinning bioreactor (SpinOmega) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and, notably, a distinct human-specific outer radial glia cell layer. We also developed protocols for midbrain and hypothalamic organoids. Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains. ZIKV infection leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell-layer volume resembling microcephaly. Together, our brain-region-specific organoids and SpinOmega provide an accessible and versatile platform for modeling human brain development and disease and for compound testing, including potential ZIKV antiviral drugs. PMID- 27118426 TI - Immune responses induced by oligogalacturonides are differentially affected by AvrPto and loss of BAK1/BKK1 and PEPR1/PEPR2. AB - Plants possess an innate immune system capable of restricting invasion by most potential pathogens. At the cell surface, the recognition of microbe-associated molecular patterns (MAMPs) and/or damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) represents the first event for the prompt mounting of an effective immune response. Pathogens have evolved effectors that block MAMP-triggered immunity. The Pseudomonas syringae effector AvrPto abolishes immunity triggered by the peptide MAMPs flg22 and elf18, derived from the bacterial flagellin and elongation factor Tu, respectively, by inhibiting the kinase function of the corresponding receptors FLS2 and EFR, as well as their co receptors BAK1 and BKK1. Oligogalacturonides (OGs), a well-known class of DAMPs, are oligomers of alpha-1,4-linked galacturonosyl residues, released on partial degradation of the plant cell wall homogalacturonan. We show here that AvrPto affects only a subset of the OG-triggered immune responses and that, among these responses, only a subset is affected by the concomitant loss of BAK1 and BKK1. However, the antagonistic effect on auxin-related responses is not affected by either AvrPto or the loss of BAK1/BKK1. These observations reveal an unprecedented complexity among the MAMP/DAMP response cascades. We also show that the signalling system mediated by Peps, another class of DAMPs, and their receptors PEPRs, contributes to OG-activated immunity. We hypothesize that OGs are sensed through multiple and partially redundant perception/transduction complexes, some targeted by AvrPto, but not necessarily comprising BAK1 and BKK1. PMID- 27118427 TI - Association study of inflammatory genes with rheumatic heart disease in North Indian population: A multi-analytical approach. AB - Rheumatic heart disease (RHD) is an inflammatory, autoimmune disease; occurring as a consequence of group A streptococcal infection complicated by rheumatic fever (RF). An inappropriate immune response is the central signature tune to the complex pathogenesis of RHD. However, some of those infected develop RHD, and genetic host susceptibility factors are thought to play a key role in diseasedevelopment. Therefore, the present study was designed to explore the role of genetic variants in inflammatory genes in conferring risk of RHD. The study recruited total of 700 subjects, including 400 RHD patients and 300 healthy controls. We examined the associations of 8 selected polymorphisms in seven inflammatory genes: IL-6 [rs1800795G/C], IL-10 [rs1800896G/A], TNF-A [rs1800629G/A], IL-1beta [rs2853550C/T], IL-1VNTR [rs2234663], TGF-beta1 [rs1800469C/T]; [rs1982073T/C], and CTLA-4 [rs5742909C/T] with RHD risk. Genotyping for all the polymorphisms was done using PCR-ARMS/PCR/RFLP methods. Multifactor dimensionality reduction and classification and regression tree approaches were combined with logistic regression to discover high-order gene gene interactions in studiedgenes involved in RHD susceptibility.In univariate logistic regression analysis, we found significant association of variant containing genotypes (CT&TT) of TGF-beta1 869T/C [rs1982073]; [p=0.0.004 & 0.001, OR (95% CI)=1.65 (1.2-2.3) & 2.25 (1.4-3.6) respectively], variant genotype (CC) of IL-1beta -511C/T [rs2853550]; [p=0.001, OR (95% CI)=2.33 (1.4-3.8)] and IL-1 VNTR [rs2234663]; [p=0.03, OR (95% CI)=5.25 (1.2-23.4)] SNPs with RHD risk. CART analysis revealed that individuals with the combined genotypes of TGF-beta1T/C_ rs1982073 (CT/TT) and IL-1 beta_ rs2853550 (CC) had significantly higher susceptibility for RHD [p=0.0005, OR (95% CI)=5.91 (2.9-12.5)]. In MDR analysis, TGF-beta1 869T>C yielded the highest testing accuracy of 0.562. In conclusion, using multi-analytical approaches, our study revealed important role of TGF-beta1 869T/C [rs1982073] in RHD susceptibility. PMID- 27118428 TI - Dry influenza vaccines: towards a stable, effective and convenient alternative to conventional parenteral influenza vaccination. AB - Cold-chain requirements, limited stockpiling potential and the lack of potent immune responses are major challenges of parenterally formulated influenza vaccines. Decreased cold chain dependence and stockpiling can be achieved if vaccines are formulated in a dry state using suitable excipients and drying technologies. Furthermore, having the vaccine in a dry state enables the development of non-parenteral patient friendly dosage forms: microneedles for transdermal administration, tablets for oral administration, and powders for epidermal, nasal or pulmonary administration. Moreover, these administration routes have the potential to elicit an improved immune response. This review highlights the rationale for the development of dried influenza vaccines, as well as processes used for the drying and stabilization of influenza vaccines; it also compares the immunogenicity of dried influenza vaccines administered via non invasive routes with that of parenterally administered influenza vaccines. Finally, it discusses unmet needs, challenges and future developments in the field of dried influenza vaccines. PMID- 27118429 TI - Effective and selective recovery of gold and palladium ions from metal wastewater using a sulfothermophilic red alga, Galdieria sulphuraria. AB - The demand for precious metals has increased in recent years. However, low concentrations of precious metals dissolved in wastewater are yet to be recovered because of high operation costs and technical problems. The unicellular red alga, Galdieria sulphuraria, efficiently absorbs precious metals through biosorption. In this study, over 90% of gold and palladium could be selectively recovered from aqua regia-based metal wastewater by using G. sulphuraria. These metals were eluted from the cells into ammonium solutions containing 0.2M ammonium salts without other contaminating metals. The use of G. sulphuraria is an eco-friendly and cost-effective way of recovering low concentrations of gold and palladium discarded in metal wastewater. PMID- 27118430 TI - A systematic review of the effects of non-conscious regulatory processes in physical activity. AB - Physical activity theories have almost exclusively focused on conscious regulatory processes such as plans, beliefs, and expected value. The aim of this review was to aggregate the burgeoning evidence showing that physical activity is also partially determined by non-conscious processes (e.g., habits, automatic associations, priming effects). A systematic search was conducted and study characteristics, design, measures, effect size of the principle summary measures, and main conclusions of 52 studies were extracted by two independent coders. The findings support that habitual regulatory processes measured via self-report are directly associated with physical activity beyond conscious processes, and that there is likely interdependency between habit strength and intentions. Response latency measures of automatic associations with physical activity were widely disparate, precluding conclusions about specific effects. A small body of evidence demonstrated a variety of priming effects on physical activity. Overall, it is evident that physical activity is partially regulated by non-conscious processes, but there remain many unanswered questions for this area of research. Future research should refine the conceptualisation and measurement of non conscious regulatory processes and determine how to harness them to promote physical activity. PMID- 27118431 TI - Morphological Modifications in Myofibrils by Suppressing Tropomyosin 4alpha in Chicken Cardiac Myocytes. AB - Tropomyosin (TPM) localizes along F-actin and, together with troponin T (TnT) and other components, controls calcium-sensitive muscle contraction. The role of the TPM isoform (TPM4alpha) that is expressed in embryonic and adult cardiac muscle cells in chicken is poorly understood. To analyze the function of TPM4alpha in myofibrils, the effects of TPM4alpha-suppression were examined in embryonic cardiomyocytes by small interference RNA transfection. Localization of myofibril proteins such as TPM, actin, TnT, alpha-actinin, myosin and connectin was examined by immunofluorescence microscopy on day 5 when almost complete TPM4alpha suppression occurred in culture. A unique large structure was detected, consisting of an actin aggregate bulging from the actin bundle, and many curved filaments projecting from the aggregate. TPM, TnT and actin were detected on the large structure, but myosin, connectin, alpha-actinin and obvious myofibril striations were undetectable. It is possible that TPM4alpha-suppressed actin filaments are sorted and excluded at the place of the large structure. This suggests that TPM4alpha-suppression significantly affects actin filament, and that TPM4alpha plays an important role in constructing and maintaining sarcomeres and myofibrils in cardiac muscle. PMID- 27118432 TI - Cost-effectiveness analysis of antiviral therapy in patients with advanced hepatitis B virus-related hepatocellular carcinoma treated with sorafenib. AB - BACKGROUND AND AIM: Antiviral therapy has been demonstrated to significantly improve the survival in patients with advanced hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The aim of the study was to investigate the cost effectiveness of antiviral therapy in patients with advanced HBV-related HCC treated with sorafenib. METHODS: To conduct the analysis, a Markov model comprising three health states (progression-free survival, progressive disease, and death) was created. The efficacy data were derived from medical records. Cost data were collected based on the Chinese national drug prices. Utility data came from the previously published studies. One-way sensitivity analyses as well as probabilistic sensitivity analyses were performed to explore model uncertainties. RESULTS: In the base-case analysis, addition of antiviral therapy to sorafenib generated an effectiveness of 0.68 quality-adjusted life years (QALYs) at a cost of $25 026.04, while sorafenib monotherapy gained an effectiveness of 0.42 QALYs at a cost of $20 249.64. The incremental cost-effectiveness ratio (ICER) was $18 370.77/QALY for antiviral therapy group versus non-antiviral therapy group. On the other hand, the ICER between the two groups in patients with high or low HBV DNA load, with or without cirrhosis, normal or elevated alanine aminotransferase/aspartate aminotransferase were $16 613.97/QALY, $19 774.16/QALY, $14 587.66/QALY, $19 873.84/QALY, $17 947.07/QALY, and $18 785.58/QALY, respectively. CONCLUSIONS: Based on the cost-effectiveness threshold ($20 301.00/QALY in China), addition of antiviral therapy to sorafenib is considered to be a cost-effective option compared with sorafenib monotherapy in patients with advanced HBV-related HCC in China from the patient's perspective. PMID- 27118433 TI - Substantial and robust changes in microRNA transcriptome support postnatal development of the hypothalamus in rat. AB - MicroRNAs (miRNAs) modulate gene expression in male germ cells and somatic tissues of mammals on a genome-wide scale. Hundreds of miRNAs are encoded by mammalian genomes, a large fraction of which is expressed in brain. Here we have investigated the complexity and dynamics of miRNA transcriptomes that associate with neuronal network maturation of hypothalamic arcuate nucleus and median eminence (ARC/ME) in rat by analysing more than 300 miRNAs from 3-7 biological replicates at 5 postnatal time-points. The network connecting ARC/ME to other hypothalamic and extra-hypothalamic regions maturates in an environment-dependent manner. We therefore analyzed miRNA transcriptomes of progeny of dams fed either a balanced or unbalanced diet during gestation and lactation. More than 30% of the miRNAs displayed significative changes of expression between stages P8 and P14, and P21 and P28; half of the changes were greater than 3-fold. Among those miRNAs were well-known and dozens of still poorly documented miRNAs. Progeny of dams fed an unbanced diet displayed a severe growth retardation phenotype, lower levels of plasma leptin but almost identical miRNA transcriptomes. Together these data demonstrate that two substantial and robust changes in miRNA transcriptome of ARC/ME occur at a period crucial for neuronal network functional organization. PMID- 27118434 TI - Reply to Letter to the Editor. PMID- 27118435 TI - CREB regulates TNF-alpha-induced GM-CSF secretion via p38 MAPK in human lung fibroblasts. AB - BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that mediates eosinophilic differentiation, migration and survival, causing respiratory tract inflammation. GM-CSF is also known to be secreted from respiratory tract structural cells. However, the mechanisms of GM-CSF secretion have not been well established. METHODS: Human fetal lung fibroblasts and human primary asthmatic lung fibroblasts were used for the study of tumor necrosis factor alpha (TNF-alpha)-induced GM-CSF secretion. GM-CSF secretion and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative real-time reverse transcription polymerase chain reaction, respectively. Knockdown of cAMP response element-binding protein (CREB) in fibroblasts was carried out by using specific small interfering RNAs of CREB. RESULTS: Among respiratory tract structural cells, pulmonary fibroblasts exhibited increased GM CSF secretion and mRNA expression after stimulation with TNF-alpha in a concentration-dependent manner. Moreover, a p38 mitogen-activated protein kinase (MAPK) inhibitor controlled TNF-alpha-induced GM-CSF secretion, and roflumilast and rolipram, inhibitors of phosphodiesterase-4, suppressed TNF-alpha-induced GM CSF secretion. Consistent with this, forskolin also completely blocked GM-CSF secretion, and similar results were observed in response to cAMP treatment, suggesting that cAMP signaling suppressed TNF-alpha-induced GM-CSF secretion in human lung fibroblasts. Furthermore, CREB was phosphorylated through p38 MAPK but not cAMP signaling after TNF-alpha stimulation, and GM-CSF secretion was inhibited by CREB knockdown. Finally, these effects were also demonstrated in human primary lung fibroblasts in a patient with asthma. CONCLUSIONS: CREB signaled independent of cAMP signaling and was phosphorylated by p38 MAPK following TNF-alpha stimulation, playing a critical role in GM-CSF secretion in human lung fibroblasts. PMID- 27118436 TI - Eosinophil infiltration in the upper gastrointestinal tract of patients with bronchial asthma. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is related to allergic diseases such as bronchial asthma (BA), atopic dermatitis, and allergic rhinitis. The aim of this study was to examine the eosinophil infiltration in the upper gastrointestinal (GI) tract in patients with BA using esophagogastroduodenoscopy. METHODS: Patients with BA who had upper GI tract symptoms were enrolled. Patients who received systemically administered steroids were excluded. Eosinophil infiltrations in the esophagus, stomach, and duodenum were examined with regard to the endoscopic findings and pathological findings of biopsy specimens (UMIN000010132). RESULTS: Ninety patients were enrolled from October in 2012 to September in 2014. Thirty-six were male, 54 were female, and the mean age was 57.5 years. Eighty-one (90%) used inhaled corticosteroids. Fourteen patients (15.6%) had reflux esophagitis, 8 of whom had grade A and 6 had grade B. No patient with EoE was observed. One female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic gastroenteritis, but endoscopy showed only mucosal edema in the antrum. Another female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic granulomatosis with polyangiitis, and endoscopy showed erosions in the antrum and the duodenum. Three patients had eosinophil infiltration in the stomach, but none of them had severe symptoms. CONCLUSIONS: Patients with asthma who had upper gastrointestinal symptoms rarely had eosinophilic gastrointestinal disorders. Biopsy specimens are of high importance in the diagnosis of eosinophilic gastrointestinal disorders even if there is no remarkable endoscopic finding. PMID- 27118437 TI - Rem2, a member of the RGK family of small GTPases, is enriched in nuclei of the basal ganglia. AB - Rem2 is a member of the RGK subfamily of RAS small GTPases. Rem2 inhibits high voltage activated calcium channels, is involved in synaptogenesis, and regulates dendritic morphology. Rem2 is the primary RGK protein expressed in the nervous system, but to date, the precise expression patterns of this protein are unknown. In this study, we characterized Rem2 expression in the mouse nervous system. In the CNS, Rem2 mRNA was detected in all regions examined, but was enriched in the striatum. An antibody specific for Rem2 was validated using a Rem2 knockout mouse model and used to show abundant expression in striatonigral and striatopallidal medium spiny neurons but not in several interneuron populations. In the PNS, Rem2 was abundant in a subpopulation of neurons in the trigeminal and dorsal root ganglia, but was absent in sympathetic neurons of superior cervical ganglia. Under basal conditions, Rem2 was subject to post-translational phosphorylation, likely at multiple residues. Further, Rem2 mRNA and protein expression peaked at postnatal week two, which corresponds to the period of robust neuronal maturation in rodents. This study will be useful for elucidating the functions of Rem2 in basal ganglia physiology. PMID- 27118438 TI - Intraorbital foreign body: A rifle bullet removed 20 years after the accident. AB - INTRODUCTION: Trauma of the orbit and eyeball is common, but intraorbital bullet is a relatively rare event. CLINICAL CASES: The authors report the management of a patient with chorioretinitis sclopetaria secondary to a gunshot wound twenty years previously. DISCUSSION: The clinical, diagnostic and therapeutic aspects of this unusual case of intraorbital foreign body are discussed. PMID- 27118439 TI - Neck tumour. PMID- 27118440 TI - Oral habits, dental trauma, and occlusal characteristics among 4- to 12-year-old institutionalized orphan children in Riyadh, Saudi Arabia. AB - The aim of this study was to assess the oral habit practices, dental trauma, and occlusal characteristics of 4- to 12-year-old orphans living in governmental orphanages in Riyadh. This cross-sectional study was conducted in three government orphanages and three ordinary schools. All 90 orphans, residing in the orphanage, were included. Ninety schoolchildren were selected to serve as the controls. Demographic data, oral habit history, and dental trauma history were obtained through a questionnaire. All children were examined to confirm the presence of signs of oral habits, dental trauma, and associated occlusal characteristics. Pearson chi-square was used for statistical analysis. Orphans were found to have more digit sucking and oral self-mutilation habits; however, the control children were found to have more nail biting habit. Nearly 21% of the orphans had dental trauma compared to 10% of the control group. About 70% of the dental trauma affected permanent teeth among orphans, whereas, 85% affected primary teeth in the control children. Dental trauma increased as the orphans got older; however, it decreased significantly as the control children got older. Orphans were found to have more cross-bite, increased over-jet, and open-bite. Digit sucking habit was positively associated with class II molar relation, presence of posterior cross-bite, and open-bite. Orphans had increased prevalence of digit sucking habit, self-mutilation, dental trauma, and malocclusion. PMID- 27118441 TI - A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma. AB - BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX 866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX 866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. RESULTS: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study. PMID- 27118442 TI - Guidance on conducting systematic reviews/meta-analyses of pharmacoepidemiological studies of safety outcomes: the gap is now filled. AB - Until recently, no comprehensive guidance specifically on the conduction of systematic reviews and meta-analyses of pharmacoepidemiological studies of safety outcomes was available. In December 2015, the European Network of Centres for Pharmacoepidemiology and Pharamacovigilance (ENCePP), a network coordinated by the European Medicines Agency, published their 'Guidance on conducting systematic reviews and meta-analyses of completed comparative pharmacoepidemiological studies of safety outcomes', filling an important gap in the field. This paper highlights the ENCePP recommendations in terms of study identification, data extraction, study quality appraisal and analytical plan. Although the ENCePP document should not be considered as definitive, since it will likely be refined following researchers' feedback, it is expected that it will be highly influential and useful for the field, with the ultimate goal to improve and standardise the conduction and reporting of systematic reviews/meta-analyses of pharmacoepidemiological studies of safety outcomes. PMID- 27118443 TI - A systematic review of interventions to improve postpartum retention of women in PMTCT and ART care. AB - INTRODUCTION: The World Health Organization recommends lifelong antiretroviral therapy (ART) for all pregnant and breastfeeding women living with HIV. Effective transitioning from maternal and child health to ART services, and long-term retention in ART care postpartum is crucial to the successful implementation of lifelong ART for pregnant women. This systematic review aims to determine which interventions improve (1) retention within prevention of mother-to-child HIV transmission (PMTCT) programmes after birth, (2) transitioning from PMTCT to general ART programmes in the postpartum period, and (3) retention of postpartum women in general ART programmes. METHODS: We searched Medline, Embase, ISI Web of Knowledge, the regional World Health Organization databases and conference abstracts for data published between 2002 and 2015. The quality of all included studies was assessed using the GRADE criteria. RESULTS AND DISCUSSION: After screening 8324 records, we identified ten studies for inclusion in this review, all of which were from sub-Saharan Africa except for one from the United Kingdom. Two randomized trials found that phone calls and/or text messages improved early (six to ten weeks) postpartum retention in PMTCT. One cluster-randomized trial and three cohort studies found an inconsistent impact of different levels of integration between antenatal care/PMTCT and ART care on postpartum retention. The inconsistent results of the four identified studies on care integration are likely due to low study quality, and heterogeneity in intervention design and outcome measures. Several randomized trials on postpartum retention in HIV care are currently under way. CONCLUSIONS: Overall, the evidence base for interventions to improve postpartum retention in HIV care is weak. Nevertheless, there is some evidence that phone-based interventions can improve retention in PMTCT in the first one to three months postpartum. PMID- 27118444 TI - Photoassisted photoluminescence fine-tuning of gold nanodots through free radical mediated ligand-assembly. AB - In this study, we have developed a simple photoassisted ligand assembly to fine tune the photoluminescence (PL) of (11-mercaptoundecyl)-N,N,N-trimethylammonium bromide-capped gold nanodots (11-MUTAB-Au NDs). The 11-MUTAB-Au NDs (size: ca. 1.8 nm), obtained from the reaction of gold nanoparticles (ca. 3 nm) and 11 MUTAB, exhibited weak, near-infrared (NIR) PL at 700 nm with a quantum yield (QY) of 0.37% upon excitation at 365 nm. The PL QY of the Au NDs increased to 11.43% after reaction with 11-mercaptoundecanoic acid (11-MUA) for 30 min under ultraviolet (UV) light, which was accompanied by a PL wavelength shift to the green region (~520 nm). UV-light irradiation accelerates 11-MUA assembly on the 11-MUTABAu NDs (11-MUA/11-MUTAB-Au NDs) through a radical-mediated reaction. Furthermore, the PL wavelength of the 11-MUA/11-MUTAB-Au NDs can be switched to 640 nm via cysteamine under UV-light irradiation. We propose that the PL of the Au NDs with NIR and visible emissions was originally from the surface thiol-Au complexes and the Au core, respectively. These dramatically different optical properties of the Au NDs were due to variation in the surface ligands, as well as the densities and surface oxidant states of the surface Au atoms/ions. These effects can be controlled by assembling surface thiol ligands and accelerated by UV irradiation. PMID- 27118445 TI - Impact of dietary nitrate on age-related diastolic dysfunction. AB - AIMS: Diastolic dysfunction is highly prevalent, and ageing is the main contributor due to impairments in active cardiac relaxation, ventriculo-vascular stiffening, and endothelial dysfunction. Nitric oxide (NO) affects cardiovascular functions, and NO bioavailability is critically reduced with ageing. Whether replenishment of NO deficiency with dietary inorganic nitrate would offer a novel approach to reverse age-related cardiovascular alterations was not known. METHODS AND RESULTS: A dietary nitrate supplementation was applied to young (6 month) and old (20 month) wild-type mice for 8 weeks and compared with controls. High resolution ultrasound, pressure-volume catheter techniques, and isolated heart measurements were applied to assess cardiac diastolic and vascular functions. Cardiac manganese-enhanced magnetic resonance imaging was performed to study the effects of dietary nitrate on myocyte calcium handling. In aged mice with preserved systolic function, dietary nitrate supplementation improved LV diastolic function, arterial compliance, and coronary flow reserve. Mechanistically, improved cardiovascular functions were associated with an accelerated cardiomyocyte calcium handling and augmented NO/cyclic guanosine monophosphate/protein kinase G signalling, while enhanced nitrate reduction was related to age-related differences in the oral microbiome. CONCLUSION: Dietary inorganic nitrate reverses age-related LV diastolic dysfunction and improves vascular functions. Our results highlight the potential of a dietary approach in the therapy of age-related cardiovascular alterations. PMID- 27118446 TI - Gender difference in Chinese adults with post-viral olfactory disorder:a hospital based study. AB - CONCLUSIONS: This hospital-based study found a gender differences in Chinese subjects with post-viral olfactory disorder (PVOD). Women appear to face higher susceptibility to PVOD, a finding that appears to be magnified with age and duration of olfactory loss. OBJECTIVES: PVOD is one of the most common reasons for acquired olfactory dysfunction, but there is little data in Chinese populations. We analyzed Chinese subjects with PVOD in order to determine demographic risk factors and clinical features in this major population group. METHODS: Data from 143 consecutive subjects with PVOD and 117 subjects with other olfactory disorders (controls) were analyzed. This study examined age, duration, and severity of olfactory loss, and compared the differences of subjective and objective olfactory function tests between two groups, using Sniffin' Sticks, Olfactory Event Related Potential (OERP), and olfactory pathway MRI. RESULTS: There were more women in the PVOD group compared to controls (p < 0.001). Older subjects with PVOD were more likely to be women (p = 0.027), and the proportion of women with PVOD increased with the duration of olfactory loss (p = 0.032). There were no differences in the prevalence of abnormal OERP between two groups, although the female-to-male ratio was higher in the PVOD group (p = 0.041). Women with PVOD were less likely to have olfactory pathway abnormalities by MRI compared to controls (p < 0.001). PMID- 27118447 TI - Why neurology? Factors which influence career choice in neurology. AB - OBJECTIVE: To evaluate the factors which influence the decision to pursue a career in neurology. METHODS: An anonymous survey was developed using a Likert scale to rate responses. The survey was sent to adult and child neurology faculty, residents and fellows, as well as medical students applying for neurology. Descriptive statistics were used to analyse the factors of influence. Respondents were subsequently categorized into pre-neurology trainees, neurology trainees, child neurologists and adult neurologists, and differences between the groups were analysed using Pearson's chi-square test. RESULTS: One hundred and thirty-three anonymous responses were received. The respondents were neurologists across all levels of training and practice. Across all respondents, the most common factor of high importance was intellectual content of specialty, challenging diagnostic problems, type of patient encountered and interest in helping people. Responses were similar across the groups; however, the earliest trainees cited interest in helping people as most important, while those in neurology training and beyond cite intellectual content of the specialty as most important. DISCUSSION: As trainees transition from their earliest levels of clinical experience into working as residents and faculty, there is a shift in the cited important factors. Lifestyle and financial factors seem to be the least motivating across all groups. Encouragement from peers, mentors, faculty and practicing physicians is considered high influences in a smaller number of neurologists. This may present an opportunity for practicing neurologists to make connections with medical students early in their education in an effort to encourage and mentor candidates. PMID- 27118448 TI - Evaluation of surgical technique on outcomes from ruptured aneurysms of the middle cerebral artery. AB - OBJECTIVE: To determine the effect of surgical technique on outcomes from ruptured middle cerebral artery aneurysms (RMCAA). METHODS: A retrospective review was performed of patients with RMCAA, who were treated at the authors' institutions. The study compares the clipping efficacy, the postoperative CT findings as well as the clinical outcome in 87 acute operated patients. Forty patients who underwent a surgical adapted technique to the preoperative radiological findings in the last 2 1/2 years were included in Group 1, and 47 previously operated cases who underwent a standardized pterional approach with aneurysm preparation from proximal to distal were included in Group 2. RESULTS: Angiographically assessed clip efficacy confirmed aneurysm occlusion in 87.5% of the patients in Group 1 and in 70.2% for Group 2 (p < 0.05). In 13 cases (32.2%) of Group 1 versus 27 cases (57.4%) of Group 2, postoperative CT scan showed hypodense brain areas (p < 0.05). In 2 cases of Group 1 versus 8 cases of Group 2, a residual haematoma was found. Three months after bleeding, 25 cases in Group 1 showed a good recovery, 10 a moderate disability, and 5 severe disability or death. In Group 2, 26 patients showed a good recovery, 9 a moderate disability, and 12 severe disability or death. There was a difference for patients with severe disability/death between both groups (p < 0.001). CONCLUSION: Individually adapted surgical technique in patients with RMCAA improves the efficacy of aneurysm clipping and clot removal, reduces postoperative hypodense brain areas and improves the patients' outcome. PMID- 27118449 TI - Identification of novel mutations of the CLCN1 gene for myotonia congenital in China. AB - OBJECTIVES: The identification of disease-specific genetic and electrophysiological patterns for myotonia congenital (MC) could help clinicians apply in the findings of genetic studies to improve diagnosis. We examined the molecular, clinical, and histopathological characteristics of eight patients with MC. METHODS: Optimization PCR was used to exclude myotonic dystrophies and the CLCN1 gene was sequenced in patients having clinical and electrophysiological features indicative of MC. RESULTS: Genetic screening identified nine CLCN1 mutations among the eight patients, including two missense, three nonsense, two insertion, and two deletion mutations. The patients showed typical myotonia and muscle hypertrophy. In contrast to the previous studies, secondary dystonia, joint contracture, and abnormal cardiac activity were also observed. Patients with novel mutations did not show any new muscle pathology compared with established mutations. Disscussion: Molecular genetics analysis offers an accurate method for diagnosing MC. The results of this analysis should be considered alongside clinical and electrophysiological characteristics. In this study, novel mutations in CLCN1 were detected, and the spectrum of CLCN1 mutations known to be associated with MC was expanded. PMID- 27118450 TI - The concentration of cell-free DNA in video-EEG patients is dependent on the epilepsy syndrome and duration of epilepsy. AB - OBJECTIVE: Cell-free DNA (cf-DNA) is a marker of inflammation and cell death. The purpose of the present study was to analyze the role of cf-DNA as a putative biomarker in refractory epilepsy. METHODS: Baseline concentration of cf-DNA was measured in the serum of 51 carefully evaluated refractory epilepsy patients undergoing video-EEG monitoring. Epilepsy was classified based on seizure semiology, patient history, and imaging findings. Majority of the patients (47) had focal epilepsy. The association of the concentration cf-DNA with different clinical determinants was analyzed. 250 healthy individuals served as control subjects. RESULTS: The mean baseline concentration of cf-DNA was lower in patients with extra temporal lobe epilepsy (XTLE) compared to control subjects (0.72 MUg/ml vs. 0.80 MUg/ml; p = 0.001). The difference in concentration of cf DNA between patients with temporal lobe epilepsy (TLE) and control subjects was not significant. The maximum concentration of cf-DNA after baseline measurement was significantly lower in patients with duration of epilepsy >= 18 years compared to those with duration of epilepsy < 18 years (0.022 MUg/ml vs. 0.031 MUg/ml; p = 0.044). The maximum concentration of cf-DNA was higher in patients with body mass index (BMI) >= 25 compared to those with BMI < 25 (0.004 MUg/ml vs. 0.041 MUg/ml; p = 0.006). DISCUSSION: The difference in cf-DNA concentration between patients with XTLE and control subjects strengthens the previous observations of the importance of epilepsy type with regard of different biomarkers. PMID- 27118451 TI - Extracellular vesicles released by CD40/IL-4-stimulated CLL cells confer altered functional properties to CD4+ T cells. AB - The complex interplay between cancer cells, stromal cells, and immune cells in the tumor microenvironment (TME) regulates tumorigenesis and provides emerging targets for immunotherapies. Crosstalk between CD4(+) T cells and proliferating chronic lymphocytic leukemia (CLL) tumor B cells occurs within lymphoid tissue pseudofollicles, and investigating these interactions is essential to understand both disease pathogenesis and the effects of immunotherapy. Tumor-derived extracellular vesicle (EV) shedding is emerging as an important mode of intercellular communication in the TME. In order to characterize tumor EVs released in response to T-cell-derived TME signals, we performed microRNA (miRNA [miR]) profiling of EVs released from CLL cells stimulated with CD40 and interleukin-4 (IL-4). Our results reveal an enrichment of specific cellular miRNAs including miR-363 within EVs derived from CD40/IL-4-stimulated CLL cells compared with parental cell miRNA content and control EVs from unstimulated CLL cells. We demonstrate that autologous patient CD4(+) T cells internalize CLL-EVs containing miR-363 that targets the immunomodulatory molecule CD69. We further reveal that autologous CD4(+) T cells that are exposed to EVs from CD40/IL-4 stimulated CLL cells exhibit enhanced migration, immunological synapse signaling, and interactions with tumor cells. Knockdown of miR-363 in CLL cells prior to CD40/IL-4 stimulation prevented the ability of CLL-EVs to induce increased synapse signaling and confer altered functional properties to CD4(+) T cells. Taken together, these data reveal a novel role for CLL-EVs in modifying T-cell function that highlights unanticipated complexity of intercellular communication that may have implications for bidirectional CD4(+) T-cell:tumor interactions within the TME. PMID- 27118452 TI - Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. AB - Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 * 10(6) in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8(+) TCM subsets, expressing a first-generation CD19 CAR containing only the CD3zeta endodomain (CD19R:zeta). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4(+) and CD8(+) TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3zeta endodomains (CD19R:28zeta). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4(+)/CD8(+) TCM derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was <=28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749. PMID- 27118453 TI - Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients. AB - The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first- to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and >=10(-5); n = 20, 12%), and MRD positive (>=10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and >=10(-5) vs >=10( 4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249. PMID- 27118454 TI - Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience. PMID- 27118455 TI - Epididymal Cysts: Are They Associated With Infertility? AB - Scrotal sonography is commonly used for evaluation of the infertile male. While epididymal cysts are frequently observed during sonographic assessment, their presence has uncertain import. This study is a retrospective case-control sonographic and chart review comparison of infertile men and fertile volunteers to clarify the possible association of epididymal cysts and infertility. The study included 91 consecutively recruited patients from January 2012 to December 2014. The infertile group consisted patients with male factor infertility who underwent scrotal sonography ( n = 67). The fertile group consisted of men requesting vasectomy who were recruited for study involvement and consented to undergo scrotal sonography ( n = 24). The main outcome measure was infertility. The existence of epididymal cysts on scrotal sonography was the main risk factor. Predictably, the only sonographic findings associated with infertility were small testes (right: t(df = 89) = -2.52; left: t(df = 89) = -2.28, both p = .01) and the presence of a varicocele, chi2(df = 1) = 5.766 with p = .02. The infertile men were also younger and more likely to use alcohol. Of the 91 men studied, 71% demonstrated epididymal cysts (73% of infertile and 67% of fertile men). Epididymal cysts were not be associated with infertility, chi2(df = 1) = 0.362 with p = .55. This occurrence of epididymal cysts is the highest ever reported (71% of all men). While the occurrence of epididymal cysts in this cohort is unexplained, our observation that these cysts are not associated with infertility will be useful for those clinicians counseling patients observed to have these structures. PMID- 27118456 TI - Predictors of Cancer Screening Among Culturally Diverse Men. AB - Men have higher rates of all cancers and are more likely to die from cancer than women; however, men are less likely to utilize disease prevention services. African American/Black men and Hispanic men have lower cancer survival rates and are less likely to utilize health care services than non-Hispanic White men. The present study examined demographic variables (age, household income, education, marital status, race/ethnicity, health insurance status), motivators to engage in healthy eating, and motivators to engage in physical activity as predictors of culturally diverse, medically underserved men's likelihood of getting a cancer screening (a) at the present time, (b) if no cancer symptoms are present, and (c) if a doctor discovers some cancer symptoms. Analyses were conducted using data from 243 men (47.3% non-Hispanic Black, 29.5% Hispanic, 16.5% non-Hispanic White, and 6.8% "other") recruited at the Men's Health Forum in Tampa, Florida. Age, having a medical or health condition that benefits from eating healthy, and having a commitment to physical activity were significant positive predictors of the likelihood of receiving a cancer screening. Motivation to engage in physical activity because of a personal priority was a significant negative predictor of the likelihood of getting a cancer screening. The findings from this study suggest that interventions to increase cancer screenings among culturally diverse, medically underserved men should be informed at least in part by an assessment of participating men's motivators for engaging in health promoting lifestyle behaviors such as physical activity and healthy eating. PMID- 27118457 TI - Anthelmintic effect of herbicidal dinitroanilines on the nematode model Caenorhabditis elegans. AB - Dinitroanilines are known herbicides that impair the polymerization of microtubules. This study investigated the effects of oryzalin and trifluralin on the viability, morphology, and ultrastructure of different life stages of Caenorhabditis elegans. Both drugs reduced the survival of the adult population in 50% after three days of treatment with concentrations of approximately 30 MUM and 57 MUM, respectively. The development of new adults was monitored for seven days and treatment with both drugs also showed a decrease in the adult population. 25 MUM Oryzalin or trifluralin inhibited the hatching of eggs by nearly 100%. Both drugs showed remarkable larvicidal activity at 25 MUM against the larvae at first and second stages (L1-L2) and at third and fourth stages (L3 L4) after 24 h. Treatment with dinitroanilines led to incomplete egg embryo development. The oryzalin and trifluralin treatments caused the detachment of cuticular layers of adults and larvae and the formation of a large number of intracellular membrane whirls and lipid bodies in the hypodermal cells and non contractile muscles of adults. Both drugs also provoked the bagging process, which generated lesions in the uterus of the adults. In addition, trifluralin caused the detachment of certain areas of the cuticle adjacent to the hypodermis in a large number of nematodes. Our results suggest that dinitroanilines are a potentially new alternative for anthelmintic chemotherapy. PMID- 27118458 TI - Using a practical molecular capsular serotype prediction strategy to investigate Streptococcus pneumoniae serotype distribution and antimicrobial resistance in Chinese local hospitalized children. AB - BACKGROUND: China is one of ten countries with the highest prevalence rate of pneumococcal infections. However, there is limited serotype surveillance data for Streptococcus pneumoniae, especially from the community or rural regions, partly due to limited serotyping capacity because Quellung serotyping is only available in few centers in China. The aim of this study was to develop a simple, practical and economic pneumococcal serotype prediction strategy suitable for future serotype surveillance in China. METHODS: In this study, 193 S. pneumoniae isolates were collected from hospitalized children, 96.9 % of whom were < 5 years old. The cpsB sequetyping, complemented by selective and modified USA CDC sequential multiplex-PCR, was performed on all the isolates, and serotypes 6A-6D specific PCRs were done on all serogroup 6 isolates. Based on systematic analysis of available GenBank cpsB sequences, we established a more comprehensive cpsB sequence database than originally published for cpsB sequetyping. Antibiotic susceptibility of all isolates was determined using the disk diffusion or E-test assays. RESULTS: We built up a comprehensive S. pneumoniae serotype cpsB sequetyping database for all the 95 described serotypes first, and then developed a simple strategy for serotype prediction based on the improved cpsB sequetyping and selective multiplex-PCR. Using the developed serotype prediction strategy, 191 of 193 isolates were successfully "serotyped", and only two isolates were "non-serotypeable". Sixteen serotypes were identified among the 191 "serotypeable" isolates. The serotype distribution of the isolates from high to low was: 19 F (34.7 %), 23 F (17.1 %), 19A (11.9 %), 14 (7.3 %), 15B/15C (6.7 %), 6B (6.7 %), 6A (6.2 %), 9 V/9A (1.6 %); serotypes 6C, 3, 15 F/15A, 23A and 20 (each 1.1 %); serotypes 10B, 28 F/28A and 34 (each 0.5 %). The prevalence of parenteral penicillin resistance was 1.0 % in the non-meningitis isolates and 88.6 % in meningitis isolates. The total rate of multidrug resistance was 86.8 %. CONCLUSIONS: The integrated cpsB sequetyping supplemented with selective mPCR and serotypes 6A-6D specific PCRs "cocktail" strategy is practical, simple and cost effective for use in pneumococcal infection serotype surveillance in China. For hospitalized children with non-meningitis penicillin-susceptible pneumococcal infections, clinicians still can use narrow-spectrum and cheaper penicillin, using the parenteral route, rather than using broader-spectrum and more expensive antimicrobials. PMID- 27118459 TI - Au-Ag-Cu nano-alloys: tailoring of permittivity. AB - Precious metal alloys enables new possibilities to tailor materials for specific optical functions. Here we present a systematic study of the effects of a nanoscale alloying on the permittivity of Au-Ag-Cu metals at 38 different atomic mixing ratios. The permittivity was measured and analyzed numerically by applying the Drude model. X-ray diffraction (XRD) revealed the face centered cubic lattice of the alloys. Both, optical spectra and XRD results point towards an equivalent composition-dependent electron scattering behavior. Correlation between the fundamental structural parameters of alloys and the resulting optical properties is elucidated. Plasmonic properties of the Au-Ag-Cu alloy nanoparticles were investigated by numerical simulations. Guidelines for designing plasmonic response of nano- structures and their patterns are presented from the material science perspective. PMID- 27118460 TI - Visuospatial working memory influences the interaction between space and time. AB - How do representations of space inform our perception of time? In language, spatial vocabulary is frequently used to describe temporal concepts, and spatial information biases temporal perception even in non-verbal tasks. In contrast, temporal information typically exerts little, if any, influence on the perception of spatial extent. Here, we used spatial and temporal reproduction tasks, both with and without verbal and spatial dual tasks, to investigate the mechanism underlying the asymmetric relation between space and time. Specifically, we tested whether the asymmetric interference between spatial and temporal stimulus attributes arises from interference in verbal or visuospatial working memory. We found that loading visuospatial working memory, but not verbal working memory, eliminated the asymmetric pattern of interference. This suggests that the interference between spatial and temporal representations arises due to processing constraints in visuospatial working memory. These findings are discussed in terms of the load theory of attention and the relative automaticity with which spatial and temporal information is processed. PMID- 27118461 TI - Quality indicators to compare accredited independent pharmacies and accredited chain pharmacies in Thailand. AB - Background Quality indicators determine the quality of actual practice in reference to standard criteria. The Community Pharmacy Association (Thailand), with technical support from the International Pharmaceutical Federation, developed a tool for quality assessment and quality improvement at community pharmacies. This tool has passed validity and reliability tests, but has not yet had feasibility testing. Objective (1) To test whether this quality tool could be used in routine settings. (2) To compare quality scores between accredited independent and accredited chain pharmacies. Setting Accredited independent pharmacies and accredited chain pharmacies in the north eastern region of Thailand. Methods A cross sectional study was conducted in 34 accredited independent pharmacies and accredited chain pharmacies. Quality scores were assessed by observation and by interviewing the responsible pharmacists. Data were collected and analyzed by independent t-test and Mann-Whitney U test as appropriate. Results were plotted by histogram and spider chart. Main outcome measure Domain's assessable scores, possible maximum scores, mean and median of measured scores. Results Domain's assessable scores were close to domain's possible maximum scores. This meant that most indicators could be assessed in most pharmacies. The spider chart revealed that measured scores in the personnel, drug inventory and stocking, and patient satisfaction and health promotion domains of chain pharmacies were significantly higher than those of independent pharmacies (p < 0.05). There was no statistical difference between independent pharmacies and chain pharmacies in the premise and facility or dispensing and patient care domains. Conclusion Quality indicators developed by the Community Pharmacy Association (Thailand) could be used to assess quality of practice in pharmacies in routine settings. It is revealed that the quality scores of chain pharmacies were higher than those of independent pharmacies. PMID- 27118462 TI - Resource use and cost of care with biologicals in Crohn's disease in South Africa: a retrospective analysis from a payer perspective. AB - Background Crohn's disease is a relapsing remitting inflammatory disease of the gastrointestinal tract. Treatment may require expensive biological therapy in severe patients. Affordability of the high cost anti-TNF-alpha agents has raised concern although evidence suggests cost-offsets can be achieved. There is little information on the resource utilisation of Crohn's patients in low and middle income countries. Objective The objective of this study is to investigate the resource utilisation and costs associated with biologicals treatment of Crohn's disease. Setting The setting for this study is in private healthcare in South Africa from a payer perspective. Method A retrospective longitudinal analysis of an administrative claims database from a large private healthcare insurer of patients who had at least 1 year claims exposure prior to starting biologicals and 2 years follow-up thereafter. Resource utilisation and costs including total Crohn's costs, hospital admissions and surgery, out of hospital costs, biologicals and chronic medicines were analysed. Main outcome measure The primary objective was to compare the change in resource utilisation and costs for Crohn's related conditions before and after starting biological treatment. Results A cohort of 72 patients was identified with a 35% (p = 0.005) reduction in Crohn's related costs (excluding the cost of biologicals) from ZAR 55,925 (U$5369) 1 year before compared to ZAR 36,293 (U$3484) 2 years after starting biological medicines. However, inclusion of the cost of biologicals more than doubled the total costs to ZAR 150,915 (+/-91,642) U$14,488 (+/-8798) in Year 2. Significant reductions in out-of hospital Crohn's related spend was also observed. Conclusions A reduction in healthcare costs is seen following starting biologicals in patients with moderate to severe Crohn's disease. However, the high cost of biological therapy outweighs any possible savings achieved in other areas of healthcare utilisation. PMID- 27118463 TI - An Islanded Rabbit Auricular Skin Flap Model of Hyaluronic Acid Injection-Induced Embolism. AB - BACKGROUND: Hyaluronic acid (HA) injection-induced embolism is a rare but severe complication. This article is aimed to introduce an islanded rabbit auricular skin flap model of HA injection-induced embolism and to study its pathophysiological progress. METHODS: An islanded skin flap was elevated based on the proximal central auricular artery/vein. Eighteen rabbits were randomized into three groups. Ten, twenty, and forty microliters of HA were injected into the central auricular artery in each group, respectively. Flap fluorescence angiography was performed. One-way ANOVA was used to compare fluorescence area at different time points and between dose groups. Two rabbits in each group were randomly chosen for histology examination. In addition to regular HE staining, Alcian Blue staining was performed to better show the existence of HA in the vessel lumen. RESULTS: The mean calculated fluorescence area was 64.41 % on POD 1, 79.77 % on POD 3, 88.20 % on POD 5, and 92.03 % on POD 7 in 10 MUl group; 60.51 % on POD 1, 58.84 % on POD 3, 71.20 % on POD 5, and 76.54 % on POD 7 in 20 MUl group; 21.60 % on POD 1, 3.08 % on POD 3, 2.91 % on POD 5, and 7.52 % on POD 7 in 40 MUl group. In all three groups, infiltration of eosinophilic granulocytes was observed in the muscular layer of both artery and vein. CONCLUSION: Our study successfully created a rabbit auricular skin necrosis model of HA embolism, which provided a valuable animal model for further investigation of the pathophysiological progress and the efficacy of potential treatments. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27118464 TI - Neonatal diabetes caused by a homozygous KCNJ11 mutation demonstrates that tiny changes in ATP sensitivity markedly affect diabetes risk. AB - AIMS/HYPOTHESIS: The pancreatic ATP-sensitive potassium (KATP) channel plays a pivotal role in linking beta cell metabolism to insulin secretion. Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively. To date, all patients affected by neonatal diabetes due to a mutation in the pore-forming subunit of the channel (Kir6.2, KCNJ11) are heterozygous for the mutation. Here, we report the first clinical case of neonatal diabetes caused by a homozygous KCNJ11 mutation. METHODS: A male patient was diagnosed with diabetes shortly after birth. At 5 months of age, genetic testing revealed he carried a homozygous KCNJ11 mutation, G324R, (Kir6.2-G324R) and he was successfully transferred to sulfonylurea therapy (0.2 mg kg(-1) day(-1)). Neither heterozygous parent was affected. Functional properties of wild-type, heterozygous and homozygous mutant KATP channels were examined after heterologous expression in Xenopus oocytes. RESULTS: Functional studies indicated that the Kir6.2-G324R mutation reduces the channel ATP sensitivity but that the difference in ATP inhibition between homozygous and heterozygous channels is remarkably small. Nevertheless, the homozygous patient developed neonatal diabetes, whereas the heterozygous parents were, and remain, unaffected. Kir6.2-G324R channels were fully shut by the sulfonylurea tolbutamide, which explains why the patient's diabetes was well controlled by sulfonylurea therapy. CONCLUSIONS/INTERPRETATION: The data demonstrate that tiny changes in KATP channel activity can alter beta cell electrical activity and insulin secretion sufficiently to cause diabetes. They also aid our understanding of how the Kir6.2-E23K variant predisposes to type 2 diabetes. PMID- 27118465 TI - Safety, feasibility, and short-term outcomes in 588 patients undergoing minimally invasive ileal pouch-anal anastomosis: a single-institution experience. AB - PURPOSE: A laparoscopic approach to proctocolectomy and ileal pouch-anal anastomosis (IPAA) in patients with chronic ulcerative colitis and familial adenomatous polyposis has grown in popularity secondary to reports of small series demonstrating short-term patient benefits. Limited data exist in large numbers of patients undergoing laparoscopic ileal pouch-anal anastomosis (L IPAA). We aimed to analyze surgical outcomes in a large cohort of patients undergoing L-IPAA. METHODS: From a prospectively maintained surgical database, 30 day surgical outcome data were reviewed for all L-IPAA performed for chronic ulcerative colitis and familial adenomatous polyposis from 1999 to 2012. Demographics, operative approach, and operative and postoperative complications were analyzed. RESULTS: A total of 588 L-IPAA ileal pouch-anal anastomoses were performed predominantly for chronic ulcerative colitis (93.9 %). The mean age was 36.2 years, and 54.3 % were male, with a mean BMI of 24.1 kg/m(2). Three-stage operations were performed in 17.7 %. The mean operating time of the patients excluding 3-stage operation was 269.4 min. Minimally invasive techniques included hand-assist in 55 % and straight laparoscopy in 45 %. Conversion to open occurred in 8.8 %. Median length of stay was 5 days. There was no mortality. Complications occurred in 36.9 % of patients: Clavien grade I (17.5 %), grade II (72.8 %), and grade III (9.7 %). Analysis of the grouped data over time demonstrated a statistically significant reduction in operative time (p < 0.001) and an increase in the ratio of hand-assisted over straight laparoscopy (p = 0.001). CONCLUSIONS: Minimally invasive IPAA performed using either a laparoscopic or hand-assisted technique is safe, can be performed with low conversion rates, and confers beneficial perioperative outcomes. PMID- 27118466 TI - Combined endoscopic-laparoscopic treatment of a rectal pocket syndrome after sigmoid resection. PMID- 27118467 TI - Cellular Profile and Expression of Immunologic Markers in Chronic Apical Periodontitis from HIV-infected Patients Undergoing Highly Active Antiretroviral Therapy. AB - INTRODUCTION: This study tested the hypothesis that the inflammatory cell profile (CD3-, CD4-, CD8-, CD20-, and CD68-positive cells) and the expression of immunologic markers (tumor necrosis factor alpha, interferon-gamma, interleukin 6, and interleukin-18) in chronic apical periodontitis are the same between non HIV-infected patients and HIV-infected patients undergoing highly active antiretroviral therapy (HAART). METHODS: Thirty-four surgically excised chronic apical periodontitis lesions were sampled from 34 patients (17 HIV-infected and 17 non-HIV-infected). The lesions were extracted from teeth with no previous endodontic treatment. All HIV-infected patients were undergoing HAART. The specimens were submitted to histopathologic and immunohistochemical analyses by using an optical microscope. Immunoexpression was graded into 2 levels, focal to weak and moderate to strong. The chi(2), Fisher exact, and Mann-Whitney tests were used to analyze all significant differences between groups. RESULTS: Periapical cysts represented 70.6% and 52.9% of the lesions in the HIV-infected and non-HIV-infected groups, respectively; however, no statistically significant difference was observed (P = .481). There were no statistically significant differences between groups for the inflammatory cell profile and for any of the immunologic markers (P > .05). CONCLUSIONS: There are no statistically significant differences of the cellular profile and expression of immunologic markers in chronic apical periodontitis between non-HIV-infected patients and HIV infected patients undergoing HAART. PMID- 27118468 TI - In Vitro and In Vivo Toxicity Evaluation of Colloidal Silver Nanoparticles Used in Endodontic Treatments. AB - INTRODUCTION: Silver nanoparticles have been used for different purposes in dentistry, including endodontic treatments. The aim of this study was to determine the cytotoxicity of different types of silver nanoparticles on mouse fibroblast cell line L929 and the reaction of subcutaneous connective tissue of Wistar rats to these nanoparticles. METHODS: Silver nanoparticles of an average size of 5 nm were synthesized with ammonia (SNA) or polyvinylpyrrolidone (SNP). L929 was exposed to SNA and SNP (0.1-100 MUg/mL), and 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assays were performed after 6, 24, and 48 hours. Culture medium was used as the control. Sixteen rats received, individually, 3 polyethylene tubes filled with a fibrin sponge embedded in 100 MUL SNA or SNP (1 MUg/mL). A fibrin sponge with no embedding was the control. Tissue reaction was performed qualitatively and quantitatively after 7, 15, 30, and 90 days of implantation in the dorsal connective tissue of Wistar rats. RESULTS: SNA and SNP were cytotoxic to L929 in higher concentrations, with SNA significantly more toxic than SNP. SNA and SNP did not induce significant interleukin-1beta and interleukin-6 production. The release of stem cell factor by L929 increased 48 hours after the treatment with SNP at 5 MUg/mL. Histologic examination showed that the inflammatory responses caused by SNA and SNP at 1 MUg/mL were similar to the control in all experimental periods. CONCLUSIONS: It was concluded that SNA and SNP were not cytotoxic at 25 MUg/mL or lower concentrations. However, for safe clinical use, further studies establishing others points of its toxicologic profile are recommended. PMID- 27118469 TI - Fanconi anemia proteins in telomere maintenance. AB - Mammalian chromosome ends are protected by nucleoprotein structures called telomeres. Telomeres ensure genome stability by preventing chromosome termini from being recognized as DNA damage. Telomere length homeostasis is inevitable for telomere maintenance because critical shortening or over-lengthening of telomeres may lead to DNA damage response or delay in DNA replication, and hence genome instability. Due to their repetitive DNA sequence, unique architecture, bound shelterin proteins, and high propensity to form alternate/secondary DNA structures, telomeres are like common fragile sites and pose an inherent challenge to the progression of DNA replication, repair, and recombination apparatus. It is conceivable that longer the telomeres are, greater is the severity of such challenges. Recent studies have linked excessively long telomeres with increased tumorigenesis. Here we discuss telomere abnormalities in a rare recessive chromosomal instability disorder called Fanconi Anemia and the role of the Fanconi Anemia pathway in telomere biology. Reports suggest that Fanconi Anemia proteins play a role in maintaining long telomeres, including processing telomeric joint molecule intermediates. We speculate that ablation of the Fanconi Anemia pathway would lead to inadequate aberrant structural barrier resolution at excessively long telomeres, thereby causing replicative burden on the cell. PMID- 27118470 TI - Anti-platelet drugs attenuate the expansion of circulating CD14highCD16+ monocytes under pro-inflammatory conditions. AB - AIMS: Levels of circulating CD14(high)CD16(+) monocytes increase in atherosclerotic patients and are predictive of future cardiovascular events. Platelet activation has been identified as a crucial determinant in the acquisition of a CD16(+) phenotype by classical CD14(high)CD16(-) cells. We tested the hypothesis that anti-platelet drugs modulate the phenotype of circulating monocytes. METHODS AND RESULTS: Sixty healthy subjects undergoing influenza immunization were randomly assigned to either no treatment or anti platelet therapy, namely aspirin 300 mg or 75 mg daily, or clopidogrel (300 mg loading dose followed by 75 mg), for 48 h post-immunization (n = 15/group). Monocyte subsets, high-sensitivity C-reactive protein, pro-inflammatory cytokines, and P-selectin were measured at baseline and post-immunization. The CD14(high)CD16(+) monocyte cell count rose by 67.3% [interquartile range (IQR): 35.7/169.2; P = 0.0002 vs. baseline] in untreated participants. All anti-platelet regimes counteracted expansion of this monocytic subpopulation. Although no statistical differences were noted among the three treatments, aspirin 300 mg was the most efficacious compared with the untreated group (-12.5% change from baseline; IQR: -28.7/18.31; P = 0.001 vs. untreated). Similarly, the rise in P selectin (17%; IQR: -5.0/39.7; P = 0.03 vs. baseline) observed in untreated participants was abolished by all treatments, with aspirin 300 mg exerting the strongest effect (-30.7%; IQR: -58.4/-0.03; P = 0.007 vs. untreated). Changes in P-selectin levels directly correlated with changes in CD14(high)CD16(+) cell count (r = 0.5; P = 0.0002). There was a similar increase among groups in high sensitivity C-reactive protein (P < 0.03 vs. baseline levels). CONCLUSIONS: Anti platelet drugs exert an immunomodulatory action by counteracting CD14(high)CD16(+) monocyte increase under pro-inflammatory conditions, with this effect being dependent on the amplitude of P-selectin reduction. PMID- 27118471 TI - The trans-well coculture of human synovial mesenchymal stem cells with chondrocytes leads to self-organization, chondrogenic differentiation, and secretion of TGFbeta. AB - BACKGROUND: Synovial mesenchymal stem cells (SMSC) possess a high chondrogenic differentiation potential, which possibly supports natural and surgically induced healing of cartilage lesions. We hypothesized enhanced chondrogenesis of SMSC caused by the vicinity of chondrocytes (CHDR). METHODS: Human SMSC and CHDR interactions were investigated in an in-vitro trans-well monolayer coculture over a time period of up to 21 days. Protein expression was analyzed using histology, immunostaining, or enzyme-linked immunosorbent assay. Additionally, mRNA expression was assessed by quantitative PCR. RESULTS: After 7 days, phase contrast microscopy revealed cell aggregation of SMSC in coculture with CHDR. Afterwards, cells formed spheres and lost adherence. However, this phenomenon was not observed when culturing SMSC alone. Fluorescence labeling showed concurrent collagen type II expression. Addition of transforming growth factor beta (TGFbeta) to the cocultures induced SMSC aggregation in less time and with higher intensity. Additionally, alcian blue staining demonstrated enhanced glycosaminoglycan expression around SMSC aggregates after 1 and 2 weeks. Although TGFbeta mRNA was expressed in all SMSC, the protein was measured with constantly increasing levels over 21 days only in supernatants of the cocultures. Considering the enhanced mRNA levels following supplementation with TGFbeta, a positive feedback mechanism can be supposed. In line with the development of a chondrogenic phenotype, aggrecan mRNA expression increased after 7 and 14 days in the cocultures with and without TGFbeta. Coculture conditions also amplified collagen type II mRNA expression after 2 weeks without and already after 1 week with TGFbeta. There was no difference in collagen type I and type X expression between SMSC alone and the coculture with CHDR. Expression of both collagens increased following addition of TGFbeta. mRNA data correlated with the intensity of immunofluorescence staining. CONCLUSIONS: Paracrine effects of CHDR induce a chondrogenic phenotype in SMSC possibly mimicking joint homeostasis. Coculture approaches may lead to a better understanding of cellular interactions with potential implications for cartilage repair procedures. PMID- 27118474 TI - Spatial patterns of genetic diversity, community composition and occurrence of native and non-native amphipods in naturally replicated tributary streams. AB - BACKGROUND: Worldwide, natural communities are invaded by non-native species, with potentially devastating effects on the native communities. A large part of past research aimed at finding traits and characteristics of the invading species or the invaded community explaining observed invasions. Only recently, the focus shifted on the spatial patterns during invasions per se. Empirical data, however, are limited, as invasions are often unique incidences of a complex spatio temporal process. In order to identify generalities of invasion patterns, we studied 13 naturally replicated tributary streams draining into Lake Constance, and studied the occurrence of native and non-native amphipods along linear transects from the stream outlets to the upstream headwater reaches. RESULTS: We found repeated spatial patterns of community composition and the occurrence of native and non-native amphipod species across two different years. Specifically, occurrence as well as abundance of two non-native amphipod species decreased from the stream outlets at the lake site towards upstream headwater reaches. Populations of the most common native amphipod species were largest at the uppermost headwater reaches. All populations of this native species, however, showed significant signals of recent genetic bottlenecks, irrespective of the stream position and occurrence of non-native species. Contrary to our expectations, this native species also showed no longitudinal genetic differentiation within individual tributaries as postulated for headwater versus outlet populations. CONCLUSIONS: Our results indicate that invasions of river systems may overall follow predictable patterns on the level of spatial distributions and community composition. However, effects of invading organisms on the genetic diversity and genetic structure of native populations observed at larger scales may not necessarily be directly reflected at the scale of smaller tributaries. PMID- 27118475 TI - GIFT4 fusokine converts leukemic B cells into immune helper cells. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) remains incurable with standard therapy, and is characterized by excessive expansion of monoclonal abnormal mature B cells and more regulatory immune properties of T cell compartment. Thus, developing novel strategies to enhance immune function merits further investigation as a possible therapy for CLL. METHODS: We generated a fusion cytokine (fusokine) arising from the combination of human GM-CSF and IL-4 (named GIFT4). Primary CLL cells were treated with GIFT4 or GM-CSG and IL-4 in vitro. GIFT4-triggered STAT5 signaling in CLL cells was examined by Western blot. The phenotype and secretome of GIFT4-treated CLL cells (GIFT4-CLL cells), and the immune stimulatory function of GIFT4-CLL cells on autologous T cells were analyzed by flow cytometry and luminex assay. RESULTS: GIFT4-CLL up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86 and adhesion molecule CD54. GIFT4-CLL cells secreted IL-1beta, IL-6, ICAM-1 and substantial IL-2 relative to unstimulated CLL cells. GIFT4 treatment led to JAK1, JAK2 and JAK3 mediated hyper-phosphorylation of STAT5 in primary CLL cells, which is essential for GIFT4-triggered conversion of CLL cells. GIFT4-CLL cells directly propelled the expansion of autologous IFN-gamma-producing CD314(+) cytotoxic T cells in vitro, and that these could lyse autologous CLL cells. Furthermore, administration of GIFT4 protein promoted the expansion of human T cells in NOD scid IL2Rgamma(null) immune deficient mice adoptively pre-transferred with peripheral blood mononuclear cells from subjects with CLL. CONCLUSION: GIFT4 has potent capability to converts primary CLL cells into APC-like immune helper cells that initiate a T cell driven anti-CLL immune response. PMID- 27118476 TI - How important is the angle of tilt in the WHO cone bioassay? AB - BACKGROUND: The World Health Organization (WHO) cone bioassay plays an integral role in the evaluation of the efficacy of long-lasting insecticidal nets as well as insecticides used in indoor residual spraying. The test is used on a variety of treated substrates, such as pieces of bed nets, mud, cement and wood. The cone setup assumes a wide variety of angles under different settings in which it is applied. However, the guidelines provided for the performance of the assay do not specify the angle at which the test must be performed. METHODS: Laboratory colonies of Anopheles gambiae Kisumu-1 and Anopheles stephensi STI were tested in the WHO cone bioassay at four different angles (0 degrees , 45 degrees , 60 degrees and 90 degrees ) following the WHO guidelines against net pieces of Olyset Plus and Netprotect. The tests were repeated after 20 washes of the nets. Individual mosquitoes were also exposed at 0 degrees and 60 degrees and the amount of time each spent in contact with the net was recorded. RESULTS: Mosquitoes spent more time on the net at 60 degrees as compared to 0 degrees (coefficient = 45.8, 95 % CI 34.6-55.6, p < 0.001) and were more likely to die when the test was done at 45 degrees (OR 3.3, 95 % CI 1.7-6.3, p = 0.001), 60 degrees (OR 3.1, 95 % CI 1.7-5.9, p < 0.001) and 90 degrees (OR 6.0, 95 % CI 1.9-18.5, p = 0.002) as compared to 0 degrees . CONCLUSION: The angle at which the test is performed significantly affects the amount of time mosquitoes spend resting on the nets, and subsequently mortality. Angle must thus be considered as an important component in the performance of the assay and duly incorporated into the guidelines. PMID- 27118477 TI - Nucleoside-Based Ultrasensitive Fluorescent Probe for the Dual-Mode Imaging of Microviscosity in Living Cells. AB - Microviscosity changes of living cells have a far-reaching influence on diffusion and movement capacity of RNA and, more seriously, could modify RNA functions in living cells. Fluorescent rotor, whose fluorescence responds to different environmental viscosities, holds great potential for the imaging of viscosity in biosystem. Although many fluorescent rotors have been reported for viscosity, the fluorogenic rotor with ultrasensitivity for the determination of microviscosity (<10 cP) was rarely reported. Herein, we report a nucleoside-based two-photon fluorescent rotor (dABp-3) that can selectively and ultrasensitively image microviscosity in RNA region of living cells for the first time. 2' Deoxyadenosine is selected as an electron donor to permit energy transfer via the acetylenic bond to acceptor, a typical boron dipyrromethene moiety. Another highlight, dABp-3 is based on 2'-deoxyadenosine, which result in its recognition capacity for RNA. dABp-3 with ultrasensitivity provides a varied linear response to the microrange viscosity (1.8-6.0 cP) in RNA region of living cells on dual mode-two-photon ratio mode and fluorescence lifetime mode. After screening and optimization, advantageously, dABp-3 can be used to screen reticulocytes from mature blood cells of thrombosis models in vitro and in vivo because of targeting RNA, while simultaneously image microviscosity changes in these cells. So, dABp-3 as an analytical tool holds considerable promise for bioimaging and monitoring of microviscosity changes in complex biological systems. PMID- 27118478 TI - Copaifera reticulata oleoresin: Chemical characterization and antibacterial properties against oral pathogens. AB - Oral infections such as periodontitis and tooth decay are the most common diseases of humankind. Oleoresins from different copaifera species display antimicrobial and anti-inflammatory activities. Copaifera reticulata is the commonest tree of this genus and grows abundantly in several Brazilian states, such as Para, Amazonas, and Ceara. The present study has evaluated the chemical composition and antimicrobial potential of the Copaifera reticulata oleoresin (CRO) against the causative agents of tooth decay and periodontitis and has assessed the CRO cytotoxic potential. Cutting edge analytical techniques (GC-MS and LC-MS) aided the chemical characterization of CRO. Antimicrobial assays included determination of the Minimum Inhibitory Concentration (MIC), determination of the Minimum Bactericidal Concentration (MBC), determination of the Minimum Inhibitory Concentration of Biofilm (MICB50), Time Kill Assay, and Checkerboard Dilution. Conduction of XTT assays on human lung fibroblasts (GM07492-A cells) helped to examine the CRO cytotoxic potential. Chromatographic analyses revealed that the major constituents of CRO were beta-bisabolene, trans alpha-bergamotene, beta-selinene, alpha-selinene, and the terpene acids ent agathic-15-methyl ester, ent-copalic acid, and ent-polyalthic acid. MIC and MBC results ranged from 6.25 to 200 MUg/mL against the tested bacteria. The time-kill assay conducted with CRO at concentrations between 50 and 100 MUg/mL showed bactericidal activity against Fusobacterium nucleatum (ATCC 25586) and Streptococcus mitis (ATCC 49456) after 4 h, Prevotella nigrescens (ATCC 33563) after 6 h, Porphyromonas gingivalis (ATCC 33277) and Lactobacillus casei (clinical isolate) after 12 h, and Streptococcus salivarius (ATCC 25975) and Streptococcus mutans (ATCC 25175) after 18 h. The fractional inhibitory concentration indexes (FICIs) revealed antagonistic interaction for Lactobacillus casei (clinical isolate), indifferent effect for Porphyromonas gingivalis (ATCC 33277), Fusobacterium nucleatum (ATCC 25586), Prevotella nigrescens (ATCC 33563), and Streptococcus salivarius (ATCC 25975), and additive effect for Streptococcus mutans (ATCC 25175) and Streptococcus mitis (ATCC 49456). Treatment of GM07492-A cells with CRO demonstrated that concentrations up to 39 MUg/mL significantly reduced cell viability as compared to the negative control, being IC50 equal to 51.85 +/- 5.4 MUg/mL. These results indicated that CRO plays an important part in the search for novel sources of agents that can act against oral pathogens. PMID- 27118479 TI - Structural characterization of tick cement cones collected from in vivo and artificial membrane blood-fed Lone Star ticks (Amblyomma americanum). AB - The Lone Star tick, Amblyomma americanum, is endemic to the southeastern United States and capable of transmitting pathogenic diseases and causing non-pathogenic conditions. To remain firmly attached to the host, the tick secretes a proteinaceous matrix termed the cement cone which hardens around the tick's mouthparts to assist in the attachment of the tick as well as to protect the mouthparts from the host immune system. Cement cones collected from ticks on a host are commonly contaminated with host skin and hair making analysis of the cone difficult. To reduce the contamination found in the cement cone, we have adapted an artificial membrane feeding system used to feed long mouthpart ticks. Cones collected from in vivo and membrane fed ticks are analyzed to determine changes in the cone morphology. Comparisons of the cement cones using light microscopy shows similar structures and color however using scanning electron microscopy the cones have drastically different structures. The in vivo cones contain fibrils, sheets, and are heavily textured whereas cones from membrane fed ticks are remarkably smooth with no distinct structures. Analysis of the secondary protein structures using FTIR-ATR show both in vivo and membrane fed cement cones contain beta sheets but only in vivo cement cones contain helical protein structures. Additionally, proteomic analysis using LC-MS/MS identifies many proteins including glycine rich proteins, metalloproteases, and protease inhibitors. Proteomic analysis of the cones identified both secreted and non secreted tick proteins. Artificial membrane feeding is a suitable model for increased collection of cement cones for proteomic analysis however, structurally there are significant differences. PMID- 27118480 TI - Transcriptome profiling of grapevine seedless segregants during berry development reveals candidate genes associated with berry weight. AB - BACKGROUND: Berry size is considered as one of the main selection criteria in table grape breeding programs. However, this is a quantitative and polygenic trait, and its genetic determination is still poorly understood. Considering its economic importance, it is relevant to determine its genetic architecture and elucidate the mechanisms involved in its expression. To approach this issue, an RNA-Seq experiment based on Illumina platform was performed (14 libraries), including seedless segregants with contrasting phenotypes for berry weight at fruit setting (FST) and 6-8 mm berries (B68) phenological stages. RESULTS: A group of 526 differentially expressed (DE) genes were identified, by comparing seedless segregants with contrasting phenotypes for berry weight: 101 genes from the FST stage and 463 from the B68 stage. Also, we integrated differential expression, principal components analysis (PCA), correlations and network co expression analyses to characterize the transcriptome profiling observed in segregants with contrasting phenotypes for berry weight. After this, 68 DE genes were selected as candidate genes, and seven candidate genes were validated by real time-PCR, confirming their expression profiles. CONCLUSIONS: We have carried out the first transcriptome analysis focused on table grape seedless segregants with contrasting phenotypes for berry weight. Our findings contributed to the understanding of the mechanisms involved in berry weight determination. Also, this comparative transcriptome profiling revealed candidate genes for berry weight which could be evaluated as selection tools in table grape breeding programs. PMID- 27118481 TI - Cardiac Rhythm Monitoring After Acute Decompensation for Heart Failure: Results from the CARRYING ON for HF Pilot Study. AB - BACKGROUND: There's scarce evidence about cardiovascular events (CV) in patients with hospitalization for acute heart failure (HF) and no indication for immediate device implant. OBJECTIVE: The CARdiac RhYthm monitorING after acute decompensatiON for Heart Failure study was designed to assess the incidence of prespecified clinical and arrhythmic events in this patient population. METHODS: In this pilot study, 18 patients (12 (67%) male; age 72+/-10; 16 (89%) NYHA II III), who were hospitalized for HF with low left ventricular ejection fraction (LVEF) (<40%) and no immediate indication for device implant received an implantable loop recorder (ILR) before hospital discharge. Follow-up visits were scheduled at 3 and 6 months, and at every 6 months until study closure; device data were remotely reviewed monthly. CV mortality, unplanned CV hospitalization, and major arrhythmic events during follow-up were analyzed. RESULTS: During a median follow-up of 593 days, major CV occurred in 13 patients (72%); of those, 7 patients had at least 1 cardiac arrhythmic event, 2 had at least a clinical event (CV hospitalization or CV death), and 4 had both an arrhythmic and a CV event. Six (33%) patients experienced 10 major clinical events, 5 of them (50%) were HF related. During follow-up, 2 (11%) patients died due to a CV cause and 3 (16%) patients received a permanent cardiac device. CONCLUSIONS: After an acute HF hospitalization, patients with LVEF<40% and who are not readily eligible for permanent cardiac device implant have a known high incidence of major CV event. In these patients, ILR allows early detection of major cardiac arrhythmias and the ability to react appropriately in a timely manner. TRIAL REGISTRATION: ClinicalTrials.gov NCT01216670; https://clinicaltrials.gov/ct2/show/NCT01216670. PMID- 27118482 TI - Sensory and Flavor Chemistry Characteristics of Australian Beef: Influence of Intramuscular Fat, Feed, and Breed. AB - The sensory attributes and flavor chemistry of grilled beef striploins (M. longissimus lumborum, n = 42) varying widely in marbling from commercial production types typical for Southern Australia were extensively characterized. Striploins from Angus grass-fed yearlings (5.2-9.9% intramuscular fat), Angus grain-finished steers (10.2-14.9%), and Wagyu grass-fed heifers (7.8-17.5%) were evaluated. Inherent differences between samples from grass- and grain-fed Angus cattle were minimal when the intramuscular fat content was above ~5%. After adjusting for intramuscular fat, Wagyu samples had more intense flavor and higher tenderness and juiciness compared to Angus grass-fed samples. Grilled beef flavor, dairy fat, and sweetness increased with the marbling level, and sourness and astringency decreased. Tenderness and juiciness increased with the marbling level and were correlated with Warner-Bratzler peak force measurements. Trained panel sensory differences in flavor corresponded with increases in aroma volatiles and changes in nonvolatile flavor compounds. Unsaturated fatty acids with potential health benefits (vaccenic, oleic, and rumenic acids) increased with the level of marbling. PMID- 27118483 TI - Association between metabolic syndrome and 10-year risk of developing cardiovascular disease in a Nigerian population. AB - BACKGROUND: Prevalence of metabolic syndrome (MetS) and consequential cardiovascular disease (CVD) events are on the increase in Nigeria. The study aimed to identify the prevalence of 10-year CVD risk in a Nigerian population and assess its relationship with different indices of MetS. METHOD: A cross-sectional study was carried out on apparently healthy persons aged 18 years of age or older. Ten-year risk was calculated using the ATPIII/Framingham criteria. Subjects with risk score <10% were considered as having low risk, 10-20% moderate risk and >20% at high risk of developing CVD in 10 years. MetS was defined based on the Joint Scientific Statement on Harmonizing the MetS. RESULT: Of the 211 subjects, mean age was 51.3+/-17.3 years. Average risk of developing CVD in the next 10 years was 3.7+/-5.3%. Prevalence of low, moderate and high risk of developing CVD among study participants was 86.3% (95% CI 82.0-91.3%), 11.8% (95% CI 6.9-16.1%) and 1.9% (95% CI 0.0-3.8%), respectively. Prevalence of MetS was 26.7% (95% CI 21.0-33.3%). There was poor agreement between MetS and the CVD risk scores (kappa=0.209, p=0.001) CONCLUSIONS: The results showed that complementary use of MetS and CVD risk score is imperative, as there is indication of risk in individuals without MetS. Also a large proportion of the study population requires lifestyle intervention. These findings provide the evidence necessary to tailor public health interventions in this population, especially towards younger age groups. PMID- 27118485 TI - Hypertension in the frail elderly. AB - Extant data indicate that treating to lower systolic pressure confers significant advantage to younger people in general good health and to relatively healthy octogenarians. Few data exist to guide practitioners on the treatment of frail elderly hypertensives. Chronological age alone does not suffice to make useful judgments regarding therapy. The definition of frailty remains controversial. One method, use of a simple questionnaire or a test of walking speed is practical but not universally accepted. Frail subjects, while at higher risk for cardiovascular complications, seem to benefit less or not at all from antihypertensive drug treatment. Clinicians should treat robust older patients as they would younger patients because the benefits far outweigh the low risk of adverse effects. Successful antihypertensive therapy in those younger than 80 years should not be discontinued simply because that age milestone has been crossed. Treatment of frail older patients must be individualized. Some frail survivors age 80 years or older may actually fare better with elevated systolic pressures. Pending the cognitive function substudy of Systolic Blood Pressure Intervention Trial, there is little evidence that antihypertensive treatment benefits established cognitive dysfunction. Because hypertension in middle age is a good predictor of later cognitive dysfunction, the clinical approach should be one of early prevention. PMID- 27118486 TI - Symmetric ambulatory arterial stiffness index in the young. AB - The ambulatory arterial stiffness index (AASI) and the symmetric ambulatory arterial stiffness index (s-AASI) have been shown to correlate to arterial stiffness in adults. This study assesses these indices with anthropometric and blood pressure (BP) measures in children. A total of 102 children at a pediatric hypertension clinic who had ambulatory blood pressure monitoring (ABPM) done from 2009 to 2013 were included (75% males, 7-22yo, 47% hypertensive, 24% prehypertensive, and 34% white-coat hypertensives). AASI is 1 minus the regression slope of diastolic BP values on systolic BP values from a 24-hour ambulatory blood pressure monitoring. s-AASI is the symmetric regression of AASI. Obese patients had a significantly higher AASI. s-AASI correlated with systolic BP variability. In multivariable regression, BP variability independently correlated with AASI and s-AASI. s-AASI is related to systolic dipping.AASI and s AASI are highly dependent on BP variability in children. Further studies are necessary to assess their utility. PMID- 27118487 TI - Mutation analysis of the CHCHD2 gene in Chinese Han patients with Parkinson's disease. PMID- 27118488 TI - Isolated task-specific lip tremor. PMID- 27118489 TI - Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. AB - In humans, the composition of gut commensal bacteria is closely correlated with obesity. The bacteria modulate metabolites and influence host immunity. In this study, we attempted to determine whether there is a direct correlation between specific commensal bacteria and host metabolism. As mice aged, we found significantly reduced body weight and fat mass in Atg7DeltaCD11c mice when compared with Atg7f/f mice. When mice shared commensal bacteria by co-housing or feces transfer experiments, body weight and fat mass were similar in both mouse groups. By pyrosequencing analysis, Bacteroides acidifaciens (BA) was significantly increased in feces of Atg7DeltaCD11c mice compared with those of control Atg7f/f mice. Wild-type C57BL/6 (B6) mice fed with BA were significantly more likely to gain less weight and fat mass than mice fed with PBS. Of note, the expression level of peroxisome proliferator-activated receptor alpha (PPARalpha) was consistently increased in the adipose tissues of Atg7DeltaCD11c mice, B6 mice transferred with fecal microbiota of Atg7DeltaCD11c mice, and BA-fed B6 mice. Furthermore, B6 mice fed with BA showed elevated insulin levels in serum, accompanied by increased serum glucagon-like peptide-1 and decreased intestinal dipeptidyl peptidase-4. These finding suggest that BA may have potential for treatment of metabolic diseases such as diabetes and obesity. PMID- 27118490 TI - Cross-protective mucosal immunity mediated by memory Th17 cells against Streptococcus pneumoniae lung infection. AB - Pneumonia caused by Streptococcus pneumoniae (Sp) remains a leading cause of serious illness and death worldwide. Immunization with conjugated pneumococcal vaccine has lowered the colonization rate and consequently invasive diseases by inducing serotype-specific antibodies. However, many of the current pneumonia cases result from infection by serotype strains not included in the vaccine. In this study, we asked if cross-protection against lung infection by heterologous strains can be induced, and investigated the underlying immune mechanism. We found that immune mice recovered from a prior infection were protected against heterologous Sp strains in the pneumonia challenge model, as evident by accelerated bacterial clearance, reduced pathology, and apoptosis of lung epithelial cells. Sp infection in the lung induced strong T-helper type 17 (Th17) responses at the lung mucosal site. Transfer of CD4+ T cells from immune mice provided heterologous protection against pneumonia, and this protection was abrogated by interleukin-17A (IL-17A) blockade. Transfer of memory CD4+ T cells from IL-17A-knockout mice failed to provide protection. These results indicate that memory Th17 cells had a key role in providing protection against pneumonia in a serotype-independent manner and suggest the feasibility of developing a broadly protective vaccine against bacterial pneumonia by targeting mucosal Th17 T cells. PMID- 27118491 TI - A key requirement for CD300f in innate immune responses of eosinophils in colitis. AB - Eosinophils are traditionally studied in the context of type 2 immune responses. However, recent studies highlight key innate immune functions for eosinophils especially in colonic inflammation. Surprisingly, molecular pathways regulating innate immune activities of eosinophil are largely unknown. We have recently shown that the CD300f is highly expressed by colonic eosinophils. Nonetheless, the role of CD300f in governing innate immune eosinophil activities is ill defined. RNA sequencing of 162 pediatric Crohn's disease patients revealed upregulation of multiple Cd300 family members, which correlated with the presence of severe ulcerations and inflammation. Increased expression of CD300 family receptors was also observed in active ulcerative colitis (UC) and in mice following induction of experimental colitis. Specifically, the expression of CD300f was dynamically regulated in monocytes and eosinophils. Dextran sodium sulfate (DSS)-treated Cd300f-/- mice exhibit attenuated disease activity and histopathology in comparison with DSS-treated wild type (WT). Decreased disease activity in Cd300f-/- mice was accompanied with reduced inflammatory cell infiltration and nearly abolished production of pro-inflammatory cytokines. Monocyte depletion and chimeric bone marrow transfer experiments revealed a cell specific requirement for CD300f in innate immune activation of eosinophils. Collectively, we uncover a new pathway regulating innate immune activities of eosinophils, a finding with significant implications in eosinophil-associated gastrointestinal diseases. PMID- 27118492 TI - Successful treatment of scleromyxedema with melphalan and dexamethasone followed by thalidomide maintenance therapy. PMID- 27118494 TI - The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. PMID- 27118495 TI - Impact of postoperative drainage autologous blood re-transfusion on the coagulation parameters and D-dimer levels of patients after total hip arthroplasty. AB - BACKGROUND: Postoperative drainage autologous blood re-transfusion (ABT) is an important treatment method that maintains a high haemoglobin (HGB) content and obviates the need for allogeneic blood transfusion in patients after surgery. However, the safety of ABT remains controversial. OBJECTIVES AND METHODS: This study aimed to investigate the safety of postoperative drainage ABT in primary total hip arthroplasty (THA). In this randomized, controlled study, patients undergoing THA were selected and randomly divided into two groups. A device for postoperative ABT was used for the 49 patients in the ABT group, whereas conventional postoperative vacuum drainage was used for the 42 patients in the drainage blood (Drain) group without ABT. The coagulation parameters and D-dimer (DD) levels of the two groups of patients were recorded before surgery (T0) and on postoperative days one (T1), three (T2), seven (T3), and 14 (T4). RESULTS: A within-group comparison after THA showed that the postoperative fibrinogen (FIB) and DD levels were higher than those before surgery in both groups (P < 0.01). A between-group comparison showed that, at different time points, the postoperative drainage blood amount and the coagulation parameters were not significantly different between the two groups. Compared with the Drain group, the DD levels in the ABT group were significantly higher at T1, T2, and T3 (P < 0.05). CONCLUSION: Postoperative drainage ABT did not significantly impact the coagulation parameters of patients after THA. However, the DD levels after ABT significantly increased, which may affect the risk of thrombosis. PMID- 27118493 TI - Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. AB - Local and systemic treatments for cancer include surgery, radiation, chemotherapy, hormonal therapy, molecularly targeted therapies, antiangiogenic therapy, and immunotherapy. Many of these therapies can be curative in patients with early stage disease, but much less frequently is this the case when they are used to treat advanced-stage metastatic disease. In the latter setting, innate and/or acquired resistance are among the reasons for reduced responsiveness or nonresponsiveness to therapy, or for tumour relapse after an initial response. Most studies of resistance or reduced responsiveness focus on 'driver' genetic (or epigenetic) changes in the tumour-cell population. Several studies have highlighted the contribution of therapy-induced physiological changes in host tissues and cells that can reduce or even nullify the desired antitumour effects of therapy. These unwanted host effects can promote tumour-cell proliferation (repopulation) and even malignant aggressiveness. These effects occur as a result of systemic release of numerous cytokines, and mobilization of various host accessory cells, which can invade the treated tumour microenvironment. In short, the desired tumour-targeting effects of therapy (the 'yin') can be offset by a reactive host response (the 'yang'); proactively preventing or actively suppressing the latter represents a possible new approach to improving the efficacy of both local and systemic cancer therapies. PMID- 27118496 TI - Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics. AB - CONTEXT: Early onset acidosis from mitochondrial toxicity can be observed in massive acetaminophen poisoning prior to the development of hepatotoxicity. In this context, the efficacy of acetylcysteine to reverse mitochondrial toxicity remains unclear and hemodialysis may offer prompt correction of acidosis. Unfortunately, toxicokinetics of acetaminophen and acetylcysteine during extracorporeal treatments hemodialysis have seldom been described. CASE DETAILS: An 18-year-old woman presented to the emergency department 60 minutes after ingestion of 100 g of acetaminophen, and unknown amounts of ibuprofen and ethanol. Initial assessment revealed an agitated patient. Her mental status worsened and she required intubation for airway protection. Investigations showed metabolic acidosis with lactate peaking at 8.6 mmol/L. Liver and coagulation profiles remained normal. Acetaminophen concentration peaked at 981 MUg/ml (6496 MUmol/L). Pending hemodialysis, the patient received 100 g of activated charcoal and an acetylcysteine infusion at 150 mg/kg over 1 hour, followed by 12.5 mg/kg/h for 4 hours. During hemodialysis, the infusion was maintained at 12.5 mg/kg/h to compensate for expected removal before it was decreased to 6.25 mg/kg for 20 hours after hemodialysis. The patient rapidly improved during hemodialysis and was discharged 48 hours post-admission. TOXICOKINETICS: The acetaminophen elimination half-life was 5.2 hours prior to hemodialysis, 1.9-hours during hemodialysis and 3.6 hours post hemodialysis. The acetaminophen and acetylcysteine clearances by A-V gradient during hemodialysis were 160.4 ml/min and 190.3 ml/min, respectively. Hemodialysis removed a total of 20.6 g of acetaminophen and 17.9 g of acetylcysteine. CONCLUSION: This study confirms the high dialyzability of both acetaminophen and acetylcysteine. Hemodialysis appears to be a beneficial therapeutic option in cases of massive acetaminophen ingestion with coma and lactic acidosis. Additionally, these results suggest that the infusion rate of acetylcysteine must be more than double during hemodialysis to compensate for its ongoing removal and provide similar plasma concentrations to the usual acetylcysteine regimen. PMID- 27118497 TI - Facile and efficient synthesis and biological evaluation of 4-anilinoquinazoline derivatives as EGFR inhibitors. AB - Series of 4-anilinoquinazoline derivatives were conveniently and efficiently synthesized and their antitumor activities were evaluated by MTT assay in three human cancer cell lines: H1975, HepG2 and SMMC-7721. New compounds 19a-19h were designed and synthesized to seek for powerful EGFR inhibitors and to explore whether methyl group at C-2 position of quinazoline ring has a positive effect on EGFR inhibition. All the compounds of 19a-19h were found potent against all three cell lines and five compounds (19c, 19d, and 19f-19h) were found more potent against H1975 than gefitinib. SAR studies revealed that methyl group at C-2 position of quinazoline ring could significantly improve the antitumor potency of 4-anilinoquinazolines. The same conclusion was also drawn according to the results of Western blotting analysis. Among all the tested compounds, 19g exhibited extremely potent against H1975 with an IC50 value of 0.11MUM, remarkably lower than that of gefitinib (1.23MUM). The results of western blotting analysis showed that compounds 19c and 19g could notably inhibit the expression of phosphorylated EGFR, especially 19g, almost inhibited completely. PMID- 27118498 TI - [The relationship of lipid imbalance and chronic inflammation mediated by PPAR]. AB - Obesity is a serious metabolic disease that threatens patients with increasing incidence of the metabolic, cardiovascular, cancer1-3) and other associated, especially autoimmune diseases. It increases significantly the morbidity and mortality of patients and reduces quality of their life.The imbalance between lipolysis and lipogenesis results in a number of metabolic related disorders at the different regulatory levels of transcription, translation, and/or activity of enzymes. One of the extensively studied areas in regulating lipogenesis, often accompanied by inflammation, is a peroxisome proliferator activated receptors (PPARs), especially its isomer PPAR-gamma. PPAR-gamma is a ligand-activated transcription factor belonging to the family of nuclear receptors. It is mostly presented in differentiated macrophages and adipose tissue5, 6). It has an important function of adipocyte differentiation and inflammation management in terms of gene expression inhibition of pro-inflammatory cytokines. PPAR-gamma inhibition of inflammatory cytokines such as TNF-alpha may present the molecular mechanism of lipid disorders, thus contributing to the pathogenesis of various diseases, e.g. inflammation, insulin resistance and atherosclerosis, for which the lipid metabolism disorders are a common feature. Under the action of specific agonists, PPAR-gamma alter the release of signal molecules from adipose tissue, which has far-reaching metabolic consequences in other tissues. It plays an important role in the inhibition of inflammation and the development of insulin resistance. KEY WORDS: obesity inflammation PPAR-gamma cytokines. PMID- 27118499 TI - Antimicrobial, antiparasitic and anticancer properties of Hibiscus sabdariffa (L.) and its phytochemicals: in vitro and in vivo studies. AB - In the last few decades, Hibiscus sabdariffa L. (Malvaceae; H. sabdariffa) has gained much attention in research field because of its potentially useful bioactivity as well as a great safety and tolerability. For decades, microbial, parasitic and cancer diseases remain a serious threat to human health and animals as well. To treat such diseases, a search for new sources such as plants that provide various bioactive compounds useful in the treatment of several physiological conditions is urgently needed, since most of the drugs currently used in the therapy have several undesirable side effects, toxicity, and drug resistance. In this paper, we aim to present an updated overview of in vitro and in vivo studies that show the significant therapeutic properties of the crude extracts and phytochemicals derived from H. sabdariffa as antimicrobial, antiparasitic, and anticancer agents. The future directions of the use of H. sabdariffa in clinical trials will be discussed. KEY WORDS: Hibiscus sabdariffa L. antimicrobial agents cancer preventive agents antiparasitic drugs natural products. PMID- 27118500 TI - [Oral films as perspective dosage form]. AB - Oral films, namely buccal mucoadhesive films and orodispersible films represent innovative formulations for administration of a wide range of drugs. Oral films show many advantageous properties and are intended for systemic drug delivery or for local treatment of the oral mucosa. In both cases, the film represents a thin layer, which could be intended to adhere to the oral mucosa by means of mucoadhesion; or to rapid dissolution and subsequent swallowing without the need of liquid intake, in the case of orodispersible films. Main constitutive excipients are film-forming polymers, which must in the case of mucoadhesive forms remain on the mucosa within the required time interval. Oral films are currently available on the pharmaceutical market and could compete with conventional oral dosage forms in the future. KEY WORDS: oral cavity oral films buccal mucoadhesive films orodispersible films film-forming polymers. PMID- 27118501 TI - [Influence of the mesh of extrusion dies on the properties of cores intended for the preparation of pellets with controlled glucose release]. AB - Diabetes mellitus and its compensation are accompanied by serious complications. One of them is hypoglycaemia, which occurs in patients treated with insulin and/or certain peroral antidiabetics. Hypoglycaemic episodes can be prevented by a dosage form with controlled release of glucose. The pellet cores of four compositions and three different sizes corresponding to the diameter of extrusion screen mesh (0.6, 0.8, and 1.0 mm) were prepared for this purpose. The cores contain 75-80% of glucose combined with one of the following osmotically or swellable active agents: croscarmellose sodium (ADS), a mixture of microcrystalline cellulose and carmellose sodium Avicel RC 591 (RC), polyethylene glycol 6000 (PEG), and carboxymethyl starch (CMS). The cores were prepared by extrusion-spheronization and are intended for subsequent coating by a semipermeable membrane based on ethylcellulose. The aim of the work was to statistically evaluate the results of the physical evaluation of the pellets which were prepared and evaluated in previously published papers. The results are processed in the form of a meta-analysis using principle component analysis. The physical characteristics of the individual pellet sizes were different among themselves. Although the same compositions and manufacturing methods were used for all the pellets sizes, the cores produced through a 0.6 and 0.8 mm mesh screens showed similar properties while the properties of cores produced through a 1.0 mm mesh screen were rather different. KEY WORDS: hypoglycemia delayed release glucose principal component analysis PCA meta-analysis of data. PMID- 27118502 TI - Potential anticancer agent hypericin and its model compound emodin: interaction with DNA. PMID- 27118503 TI - Development of a spectrophotometric method for carmoisine determination in quality control of equipment cleaning. PMID- 27118504 TI - Thin-layer chromatography application for the standardization of Sophora flowers. PMID- 27118505 TI - A portable immunomagnetic cell capture system to accelerate culture diagnosis of bacterial infections. AB - Bacterial infections continue to be a major cause of deaths globally, particularly in resource-poor settings. In the absence of rapid and affordable diagnostic solutions, patients are mostly administered broad spectrum antibiotics leading to antibiotics resistance and poor recovery. Culture diagnosis continues to be a gold standard for diagnosis of bacterial infection, despite its long turnaround time of 24 to 48 h. We have developed a portable immunomagnetic cell capture (iMC(2)) system that allows rapid culture diagnosis of bacterial pathogens. Our approach involves the culture growth of the blood samples in broth media for 6 to 8 h, followed by immunomagnetic enrichment of the target cells using the iMC(2) device. The device comprises a disposable capture chip that has two chambers of 5 ml and 50 MUl volume connected through a channel with a manual valve. Bacterial cells bound to antibody coated magnetic nanoparticles are swept from the 5 ml sample chamber into the 50 MUl recovery chamber by moving an external magnetic field with respect to the capture chip using a linear positioner. This enables specific isolation and up to 100* enrichment of the target cells. The presence of bacteria in the recovered sample is confirmed visually using a lateral flow immunoassay. The system is demonstrated in buffer and blood samples spiked with S. typhi. The method has high sensitivity (10 CFU ml(-1)), specificity and a rapid turnaround time of less than 7 h, a significant improvement over conventional methods. PMID- 27118506 TI - Embracing an occupational perspective: Occupation-based interventions in hand therapy practice. PMID- 27118507 TI - Looking inside the pores of a MCM-41 based Mo heterogeneous styrene oxidation catalyst: an inelastic neutron scattering study. AB - Styrene oxidation mediated by a Mo-based mesoporous catalyst can yield selectively styrene oxide or benzaldehyde. Kinetic data evidenced that styrene oxide is the initial single-product formed by the catalytic Mo-mediated process. However, after some hours of reaction benzaldehyde yield rises while that of the epoxide decreases concomitantly. The mechanistic proposal pointed to a surface assisted acid-base mechanism by which styrene oxide is interconverted into benzaldehyde through over-oxidation and cleavage of the C-C bond and releases formaldehyde as well. In an attempt to gain some insight into whether this mechanistic proposal is realistic we have conducted a combined DRIFT and inelastic neutron scattering (INS) study to assess the adsorbed species at the catalyst's surface and confirm the mechanistic proposal. INS and DRIFT provided complementary insight into surface-adsorbed species by probing donor (INS) and acceptor (DRIFT) species. INS also allowed for an estimation of product selectivity by means of a Job method stressing the power of the technique. PMID- 27118508 TI - The role of lipoprotein(a) in progression of renal disease: Causality or reverse causality? PMID- 27118509 TI - Validation of the close-to-delivery prediction model for vaginal birth after cesarean delivery in a Middle Eastern cohort. AB - OBJECTIVE: To validate a prediction model for vaginal birth after cesarean (VBAC) that incorporates variables available at admission for delivery among Middle Eastern women. METHODS: The present prospective cohort study enrolled women at 37weeks of pregnancy or more with cephalic presentation who were willing to attempt a trial of labor (TOL) after a single prior low transverse cesarean delivery at Al-Jahra Hospital, Kuwait, between June 2013 and June 2014. The predicted success rate of VBAC determined via the close-to-delivery prediction model of Grobman et al. was compared between participants whose TOL was and was not successful. RESULTS: Among 203 enrolled women, 140 (69.0%) had successful VBAC. The predicted VBAC success rate was higher among women with successful TOL (82.4%+/-13.1%) than among those with failed TOL (67.7%+/-18.3%; P<0.001). There was a high positive correlation between actual and predicted success rates. For deciles of predicted success rate increasing from >30%-40% to >90%-100%, the actual success rate was 20%, 30.7%, 38.5%, 59.1%, 71.4%, 76%, and 84.5%, respectively (r=0.98, P=0.013). CONCLUSION: The close-to-delivery prediction model was found to be applicable to Middle Eastern women and might predict VBAC success rates, thereby decreasing morbidities associated with failed TOL. PMID- 27118510 TI - Usefulness of cervical magnetic resonance imaging for detecting type A acute aortic dissection with acute stroke symptoms. AB - Type A acute aortic dissection (TAAAD) sometimes presents with acute stroke-like symptoms. When intravenous tissue plasminogen activator (IV-tPA) therapy is considered for acute ischemic stroke, TAAAD must be excluded. Painless TAAAD presenting with acute stroke may be easily missed. Two cases of painless TAAAD presenting with acute stroke in which IV-tPA therapy was considered are reported. In these cases, cervical magnetic resonance angiography (MRA) was useful for detecting TAAAD, and IV-tPA therapy was canceled. The mottled high signal ("snowstorm") in the common carotid artery on cervical MRA is specific for TAAAD. We have thus named this phenomenon the "snowstorm sign" and believe it can help diagnose TAAAD. PMID- 27118511 TI - A New, Dynamic Era for Somatic Cell Nuclear Transfer? AB - Cloning animals by somatic cell nuclear transfer (SCNT) has remained an uncontrollable process for many years. High rates of embryonic losses, stillbirths, and postnatal mortality have been typical outcomes. These developmental problems arise from abnormal genomic reprogramming: the capacity of the oocyte to reset the differentiated memory of a somatic cell. However, effective reprogramming strategies are now available. These target the whole genome or single domains such as the Xist gene, and their effectiveness has been validated with the ability of experimental animals to develop to term. Thus, SCNT has become a controllable process that can be used to 'rescue' endangered species, and for biomedical research such as therapeutic cloning and the isolation of induced pluripotent stem cells (iPSCs). PMID- 27118512 TI - Symbiodinium population genetics: testing for species boundaries and analysing samples with mixed genotypes. AB - Population genetic markers are increasingly being used to study the diversity, ecology and evolution of Symbiodinium, a group of eukaryotic microbes that are often mutualistic with reef-building corals. Population genetic markers can resolve individual clones, or strains, from samples of host tissue; however, samples may comprise different species that may confound interpretations of gene flow and genetic structure. Here, we propose a method for resolving species from population genetic data using tests for genetic recombination. Assigning individuals to genetically recombining populations prior to further analyses avoids critical errors in the interpretation of gene flow and dispersal. To demonstrate the effectiveness of the approach, we first apply this method to a simulated data set. We then use the method to resolve two species of host generalist Symbiodinium that commonly co-occur in reef-building corals collected from Indo-West Pacific reefs. We demonstrate that the method is robust even when some hosts contain genotypes from two distinct species. Finally, we examine population genetic data sets from two recently published papers in Molecular Ecology. We show that each strongly supports a two species interpretation, which significantly changes the original conclusions presented in these studies. When combined with available phylogenetic and ecological evidence, the use of population genetic data offers a robust method for unambiguously delimiting morphologically cryptic species. PMID- 27118513 TI - The complement receptor 3 (CD11b/CD18) agonist Leukadherin-1 suppresses human innate inflammatory signalling. AB - Complement receptor 3 (CR3, CD11b/CD18) is a multi-functional receptor expressed predominantly on myeloid and natural killer (NK) cells. The R77H variant of CD11b, encoded by the ITGAM rs1143679 polymorphism, is associated robustly with development of the autoimmune disease systemic lupus erythematosus (SLE) and impairs CR3 function, including its regulatory role on monocyte immune signalling. The role of CR3 in NK cell function is unknown. Leukadherin-1 is a specific small-molecule CR3 agonist that has shown therapeutic promise in animal models of vascular injury and inflammation. We show that Leukadherin-1 pretreatment reduces secretion of interferon (IFN)-gamma, tumour necrosis factor (TNF) and macrophage inflammatory protein (MIP)-1beta by monokine-stimulated NK cells. It was associated with a reduction in phosphorylated signal transducer and activator of transcription (pSTAT)-5 following interleukin (IL)-12 + IL-15 stimulation (P < 0.02) and increased IL-10 secretion following IL-12 + IL-18 stimulation (P < 0.001). Leukadherin-1 pretreatment also reduces secretion of IL 1beta, IL-6 and TNF by Toll-like receptor (TLR)-2 and TLR-7/8-stimulated monocytes (P < 0.01 for all). The R77H variant did not affect NK cell response to Leukadherin-1 using ex-vivo cells from homozygous donors; nor did the variant influence CR3 expression by these cell types, in contrast to a recent report. These data extend our understanding of CR3 biology by demonstrating that activation potently modifies innate immune inflammatory signalling, including a previously undocumented role in NK cell function. We discuss the potential relevance of this to the pathogenesis of SLE. Leukadherin-1 appears to mediate its anti-inflammatory effect irrespective of the SLE-risk genotype of CR3, providing further evidence to support its evaluation of Leukadherin-1 as a potential therapeutic for autoimmune disease. PMID- 27118514 TI - Response to the 'Letter to the Editor on the Maastricht Sarcopenia Study'. PMID- 27118515 TI - Differential abundances of four forms of Binder of SPerm 1 in the seminal plasma of Bos taurus indicus bulls with different patterns of semen freezability. AB - The Binder of SPerm 1 (BSP1) protein is involved in the fertilization and semen cryopreservation processes and is described to be both beneficial and detrimental to sperm. Previously, the relationship of BSP1 with freezability events has not been completely understood. The objective of this work was to determine the differential abundance of the forms of the BSP1 protein in cryopreserved seminal plasma of Bos taurus indicus bulls with different patterns of semen freezability using proteomics. A wide cohort of adult bulls with high genetic value from an artificial insemination center was used as donors of high quality, fresh semen. Nine bulls presenting different patterns of semen freezability were selected. Two dimensional gel electrophoresis showed differential abundance in a group of seven protein spots in the frozen/thawed seminal plasma from the bulls, ranging from 15 to 17 kDa, with pI values from 4.6 to 5.8. Four of these spots were confirmed to be BSP1 using mass spectrometry, proteomics, biochemical, and computational analysis (Tukey's test at P < 0.05). The protein spot weighing 15.52 +/- 0.53 kDa with a pI value of 5.78 +/- 0.12 is highlighted by its high abundance in bulls with low semen freezability and its absence in bulls presenting high semen freezability. This is the first report showing that more than two forms of BSP1 are found in the seminal plasma of Nelore adult bulls and not all animals have a similar abundance of each BSP1 form. Different BSP1 forms may be involved in different events of fertilization and the cryopreservation process. PMID- 27118516 TI - Alteration of gene expression by zinc oxide nanoparticles or zinc sulfate in vivo and comparison with in vitro data: A harmonious case. AB - Granulosa cells (GCs) are those somatic cells closest to the female germ cell. GCs play a vital role in oocyte growth and development, and the oocyte is necessary for multiplication of a species. Zinc oxide (ZnO) nanoparticles (NPs) readily cross biologic barriers to be absorbed into biologic systems that make them promising candidates as food additives. The objective of the present investigation was to explore the impact of intact NPs on gene expression and the functional classification of altered genes in hen GCs in vivo, to compare the data from in vivo and in vitro studies, and finally to point out the adverse effects of ZnO NPs on the reproductive system. After a 24-week treatment, hen GCs were isolated and gene expression was quantified. Intact NPs were found in the ovary and other organs. Zn levels were similar in ZnO-NP-100 mg/kg- and ZnSO4-100 mg/kg-treated hen ovaries. ZnO-NP-100 mg/kg and ZnSO4-100 mg/kg regulated the expression of the same sets of genes, and they also altered the expression of different sets of genes individually. The number of genes altered by the ZnO-NP 100 mg/kg and ZnSO4-100 mg/kg treatments was different. Gene Ontology (GO) functional analysis reported that different results for the two treatments and, in Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, 12 pathways (out of the top 20 pathways) in each treatment were different. These results suggested that intact NPs and Zn(2+) had different effects on gene expression in GCs in vivo. In our recent publication, we noted that intact NPs and Zn(2+) differentially altered gene expression in GCs in vitro. However, GO functional classification and KEGG pathway enrichment analyses revealed close similarities for the changed genes in vivo and in vitro after ZnO NP treatment. Furthermore, close similarities were observed for the changed genes after ZnSO4 treatments in vivo and in vitro by GO functional classification and KEGG pathway enrichment analyses. Therefore, the effects of ZnO NPs on gene expression in vitro might represent their effects on gene expression in vivo. The results from this study and our earlier studies support previous findings indicating ZnO NPs promote adverse effects on organisms. Therefore, precautions should be taken when ZnO NPs are used as diet additives for hens because they might cause reproductive issues. PMID- 27118517 TI - Role of MicroRNA 126 in screening, diagnosis, and prognosis of diabetic patients in Egypt. AB - MicroRNAs (miRNAs), family of non-coding small RNAs, play a vital role in the regulation of blood glucose level. We aimed to investigate the relation of serum miRNA-126 expression with impaired glucose tolerance as well as type 2 diabetes mellitus (T2DM) patients with and without complications. One hundred healthy controls, eighty-six patients with IGT, and one hundred patients with T2DM were recruited in this study. Serum miRNA-126 expression was assessed by quantitative real-time polymerase chain reaction. We found a significant decrease of serum miRNA-126 expression between IGT patients as well as diabetic patients when both compared with controls and between diabetic patients compared to IGT patients. A significant decrease of serum miRNA-126 expression was detected in diabetic patients with complications compared to those without evident complications especially those with diabetic macrovascular complications and diabetic retinopathy. Serum microRNA-126 expression could be a good marker for diagnosis of IGT and T2DM as well as for monitoring the outcomes of such disease. (c) 2016 IUBMB Life, 68(6):452-458, 2016. PMID- 27118518 TI - Development of a reverse transcription loop-mediated isothermal amplification assay for the detection of vesicular stomatitis New Jersey virus: Use of rapid molecular assays to differentiate between vesicular disease viruses. AB - Vesicular stomatitis (VS) is endemic in Central America and northern regions of South America, where sporadic outbreaks in cattle and pigs can cause clinical signs that are similar to foot-and-mouth disease (FMD). There is therefore a pressing need for rapid, sensitive and specific differential diagnostic assays that are suitable for decision making in the field. RT-LAMP assays have been developed for vesicular diseases such as FMD and swine vesicular disease (SVD) but there is currently no RT-LAMP assay that can detect VS virus (VSV), nor are there any multiplex RT-LAMP assays which permit rapid discrimination between these 'look-a-like' diseases in situ. This study describes the development of a novel RT-LAMP assay for the detection of VSV focusing on the New Jersey (VSNJ) serotype, which has caused most of the recent VS cases in the Americas. This RT LAMP assay was combined in a multiplex format combining molecular lateral-flow devices for the discrimination between FMD and VS. This assay was able to detect representative VSNJV's and the limit of detection of the singleplex and multiplex VSNJV RT-LAMP assays were equivalent to laboratory based real-time RT-PCR assays. A similar multiplex RT-LAMP assay was developed to discriminate between FMDV and SVDV, showing that FMDV, SVDV and VSNJV could be reliably detected within epithelial suspensions without the need for prior RNA extraction, providing an approach that could be used as the basis for a rapid and low cost assay for differentiation of FMD from other vesicular diseases in the field. PMID- 27118519 TI - Recent advances in nontoxic Escherichia coli heat-labile toxin and its derivative adjuvants. AB - INTRODUCTION: The nontoxic heat-labile enterotoxin (LT) of Escherichia coli and the B subunit of LT (LTB) have been extensively studied as potent vaccine adjuvants. Areas covered: This review covers the area of enterotoxin based vaccine adjuvant and summarizes the development of nontoxic LT mutant (mLT) and LTB and their potency as oral, parenteral and injection adjuvants. Recent evidences indicated that the mechanism of LTB adjuvanticity was to enhance the turnover of dendritic cells (DCs) in spleen and increase DCs capacity to perform as antigen presentation cells (APCs) encountered with T cells. LTB also induces B and T cells clustering and delay/arrest in T-cell division following endocytosis or B-cell receptor (BCR) uptaking of antigen in a ganglioside-mediated manner. Expert commentary: It is pointed out that the immunogenicity of LTB (or LT) is more important than the receptor binding property (or ADP-ribosylation activity) for the adjuvanticity of LT toxoid. The immunogenicity of LTB (or LT) might confer unknown characteristics to maintain LT toxoid adjuvanticity. PMID- 27118520 TI - Health behavior change: a field just picking up speed. A comment on Ogden (2016). PMID- 27118521 TI - Biokinetics of radiocesium depuration in marine fish inhabiting the vicinity of the Fukushima Dai-ichi Nuclear Power Plant. AB - Radiocesium (134Cs and 137Cs) released from the Fukushima Dai-ichi Nuclear Power Plant (1FNPP) accident contaminated the fish inhabiting the port of 1FNPP. Radiocesium concentrations in some fishes, especially rockfish, have still remained at elevated levels, while concentrations in olive flounder have decreased in 2015 to the level which is close to the Japanese regulatory limit for seafood products (0.1 kBq kg-wet-1). In this study a dynamic food chain transfer model was applied to reconstruct radiocesium levels in olive flounder residing around the port area. As a result, the observed 137Cs concentrations in olive flounder collected from the port could be explained by the simulated values in the fish, using the seawater level records at the port entrance. The reconstructed maximum 134+137Cs concentration in olive flounder inhabiting the port area was 72 kB kg-wet-1 in July 2011 and the ecological half-life (EHL) was estimated as being 180 days during the period of 2014-2015. Short term simulation which assumed that the coastal water fish swam into the port during 1 month, demonstrated that the radiocesium level in the olive flounder may become equivalent to the depurated level in the fish which were initially contaminated. This result indicated that the increase of radiocesium levels in wandering fish is unlikely to change total radiocesium concentrations in the olive flounder. In this sense, the radiocesium levels in the olive flounder of the port area can be interpreted as being convergent in 2015, regardless of the differences in their contamination histories. On the other hand, the higher 137Cs concentrations in fat greenling, compared to the olive flounder, can be attributed to a history of exposure to the contaminated seawater and food at the inner area of the port, such as the shallow draft quay and seawall area. As a result of the reconstructed initial higher radiocesium concentration, constrained by exposure history at the inner area of the port, the depurated radiocesium concentration in fat greenling is still likely to be greater than the regulatory level in the port area in 2015. PMID- 27118522 TI - Pulmonary Resection for Metastatic Gastric Cancer. AB - BACKGROUND: Pulmonary metastasectomy has come to be recognized as an effective treatment for selected patients with some malignancies. On the other hand, the role of pulmonary metastasectomy for gastric cancer is still unknown. Metastasectomy is rarely indicated in cases of pulmonary metastasis from gastric cancer, because in most cases, the metastasis occurs in the form of lymphangitic carcinomatosis and the lesions are numerous. The purpose of this study was to determine the surgical outcomes and prognostic factors for survival after pulmonary metastasectomy. METHODS: From 1985 to 2012, 10 patients underwent pulmonary metastasectomy for gastric cancer at Saitama Cancer Center, Japan. The overall survival rate was examined by the Kaplan-Meier method and univariate analysis was carried out to identify prognostic factors. RESULTS: The overall 3 year survival rate was 30.0 %. The median follow-up period was 26.8 months (range, 6.5-96.6) after the pulmonary metastasectomy. Univariate analysis revealed an advanced pathological stage of the gastric cancer and occurrence of extrapulmonary metastasis before the pulmonary metastasectomy as unfavorable prognostic factors. CONCLUSION: Pulmonary metastasectomy should be considered in selected patients with lung metastasis from gastric cancer. An advanced pathological stage of gastric cancer and occurrence of extrapulmonary metastasis before the pulmonary metastasectomy are unfavorable prognostic factors. PMID- 27118523 TI - Gastrointestinal: Ano-popliteal fistula in Crohn's disease. PMID- 27118524 TI - Development of camelid single chain antibodies against Shiga toxin type 2 (Stx2) with therapeutic potential against Hemolytic Uremic Syndrome (HUS). AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) infections are implicated in the development of the life-threatening Hemolytic Uremic Syndrome (HUS). Despite the magnitude of the social and economic problems caused by STEC infections, no licensed vaccine or effective therapy is presently available for human use. Single chain antibodies (VHH) produced by camelids exhibit several advantages in comparison with conventional antibodies, making them promising tools for diagnosis and therapy. In the present work, the properties of a recently developed immunogen, which induces high affinity and protective antibodies against Stx type 2 (Stx2), were exploited to develop VHHs with therapeutic potential against HUS. We identified a family of VHHs against the B subunit of Stx2 (Stx2B) that neutralize Stx2 in vitro at subnanomolar concentrations. One VHH was selected and was engineered into a trivalent molecule (two copies of anti Stx2B VHH and one anti-seroalbumin VHH). The resulting molecule presented extended in vivo half-life and high therapeutic activity, as demonstrated in three different mouse models of Stx2-toxicity: a single i.v. lethal dose of Stx2, several i.v. incremental doses of Stx2 and intragastrical STEC infection. This simple antitoxin agent should offer new therapeutic options for treating STEC infections to prevent or ameliorate HUS outcome. PMID- 27118525 TI - The inter-rater reliability of the modified finger goniometer for measuring forearm rotation. AB - STUDY DESIGN: Prospective cohort study. PURPOSE OF THE STUDY: To compare the inter-rater reliability of using a modified finger goniometer (MFG) for the measurement of isolated forearm rotation for patients with distal radius fractures to the currently accepted technique for isolated forearm measurement. INTRODUCTION: The currently accepted method of forearm measurement requires the assessor to visually estimate vertical for the stationary arm and placement of the moveable arm while placing a straight edge along a curved surface. Inter rater reliability may be limited as assessors may estimate the placement of the goniometer arms differently depending on their experience, posture, and even their positioning relative to the patient. Rather than continue to place a straight edge on a round surface, we evaluate a new technique using an MFG for measuring isolated forearm rotation. METHODS: Patients with clinically healed distal radius fractures were enrolled in the study. Measurement of active forearm pronation and supination was recorded using 2 separate measurement techniques. These measurements were taken by 2 separate hand therapists with more than 10 years of clinical experience in a tertiary care setting at the beginning and end of hand therapy sessions for 3 consecutive weekly visits. Intraclass correlation coefficients (ICCs), standard error of measurement, and minimal detectable change were calculated for each technique. RESULTS: The point estimates for the MFG method demonstrated a slightly higher ICC than the standard method for pronation (0.86 vs 0.82). For supination, both measurement techniques displayed equally high pooled ICCs (0.95). The standard error of measurements for the MFG were 2.1 for pronation and 1.2 for supination compared with 2.9 (pronation) and 1.2 (supination) for the standard technique. These translate into 90% minimal detectable changes of 5 degrees and 3 degrees for the MFG pronation/supination compared with 7 degrees (pronation) and 3 degrees (supination) for the standard technique, respectively. DISCUSSION: Although the point estimates for the ICCs of the MFG method are equal or higher than the standard method, the confidence intervals for the ICCs overlap, indicating that the MFG is at least equivalent to the standard method in terms of inter-rater reliability. LEVEL OF EVIDENCE: 2b. PMID- 27118526 TI - Technology and Radiology Education-Meeting the Needs of Millennial Learners. PMID- 27118527 TI - Professional Competence and Teamwork in the Treatment of Patients With Acute and Critical Heart Disease. PMID- 27118528 TI - 3'UTR SNPs and Haplotypes in the GATA4 Gene Contribute to the Genetic Risk of Congenital Heart Disease. AB - INTRODUCTION AND OBJECTIVES: Single-nucleotide polymorphisms within a microRNA binding site can have different effects on gene expression, influencing the risk of disease. This study aimed to evaluate the association between single nucleotide polymorphisms and haplotypes in the 3'UTR of the GATA4 gene and congenital heart disease risk. METHODS: Bioinformatics algorithms were used to analyze single-nucleotide polymorphisms in putative microRNA-binding sites of GATA4 3'UTR and to calculate the difference in free energy of hybridization (DeltaFE, kcal/mol) for each wild-type vs the variant allele. RESULTS: The study population comprised 146 Caucasian patients (73 males; 6.68 +/- 7.79 years) and a 265 healthy newborn participants (147 males). The sum of all |DeltaFE| was considered to predict the biological importance of single-nucleotide polymorphisms binding more microRNAs. Next, the 4 polymorphisms (+1158C > T, +1256 A > T, +1355 G > A, +1521C > G) with the highest predicted |DeltaFEtot| (9.91, 14.85, 11.03, 21.66kcal/mol, respectively) were genotyped in a case control study (146 patients and 250 controls). Applying a correction for multiple testing only the +1158 T allele was found to be associated with a reduced risk showing significant difference between patients and controls. Haplotype analysis showed that the T-T-G-C haplotype (more uncommon in congenital heart diseases than in controls) was associated with a significantly decreased risk (P = .03), while the rare C-A-A-C haplotype, which was very uncommon in controls (0.3%) compared with the disease (2.4%), was associated with a 4-fold increased risk of disease (P = .04). CONCLUSIONS: Common variants in 3'UTR of the GATA4 gene jointly interact, affecting the congenital heart disease susceptibility, probably by altering microRNA posttranscriptional regulation. PMID- 27118529 TI - Treating posttraumatic stress disorder with MDMA-assisted psychotherapy: A preliminary meta-analysis and comparison to prolonged exposure therapy. AB - Since the wars in Iraq and Afghanistan, posttraumatic stress disorder (PTSD) has become a major area of research and development. The most widely accepted treatment for PTSD is prolonged exposure (PE) therapy, but for many patients it is intolerable or ineffective. +/-3,4-methylenedioxymethamphetamine (MDMA) assisted psychotherapy (MDMA-AP) has recently re-emerged as a new treatment option, with two clinical trials having been published and both producing promising results. However, these results have yet to be compared to existing treatments. The present paper seeks to bridge this gap in the literature. Often the statistical significance of clinical trials is overemphasized, while the magnitude of the treatment effects is overlooked. The current meta-analysis aims to provide a comparison of the cumulative effect size of the MDMA-AP studies with those of PE. Effect sizes were calculated for primary and secondary outcome measures in the MDMA-AP clinical trials and compared to those of a meta-analysis including several PE clinical trials. It was found that MDMA-AP had larger effect sizes in both clinician-observed outcomes than PE did (Hedges' g=1.17 vs. g=1.08, respectively) and patient self-report outcomes (Hedges' g=0.87 vs. g=0.77, respectively). The dropout rates of PE and MDMA-AP were also compared, revealing that MDMA-AP had a considerably lower percentage of patients dropping out than PE did. These results suggest that MDMA-AP offers a promising treatment for PTSD. PMID- 27118530 TI - Rasch analysis of the Personal Wellbeing Index. AB - PURPOSE: The Personal Wellbeing Index (PWI) is used internationally to measure subjective well-being. While numerous studies have reported on the psychometric properties of the PWI using classic test theory, the current paper provides additional psychometric evaluation using the Rasch measurement model. METHOD: The responses to the PWI items of 593 healthy adults living in Australia or Canada were analysed using Rasch analysis. Assessed were overall model fit was assessed, individual person fit and item fit, reliability, differential item functioning (DIF), unidimensionality, targeting, and response format. RESULTS: Results indicate excellent psychometric properties of the PWI, provided the religion/spirituality item is excluded. The seven-item PWI showed good model fit (overall item-trait interaction chi (2) = 70.59, df = 63, p = 0.24), excellent person separation (PSI = .89), no item or person misfit, and no DIF for country or gender, and unidimensionality was supported. In addition, only very mild disordered thresholds were observed for the 'safety' item, indicating that overall, the 11-point response format was suitable for this population. CONCLUSION: It is recommended that the religion/spirituality item not be included in the aggregated or averaged total score in Western context and that caution should be used in comparison across different groups where the eight-item version has been used. PMID- 27118531 TI - Highly sensitive SnO2 sensor via reactive laser-induced transfer. AB - Gas sensors based on tin oxide (SnO2) and palladium doped SnO2 (Pd:SnO2) active materials are fabricated by a laser printing method, i.e. reactive laser-induced forward transfer (rLIFT). Thin films from tin based metal-complex precursors are prepared by spin coating and then laser transferred with high resolution onto sensor structures. The devices fabricated by rLIFT exhibit low ppm sensitivity towards ethanol and methane as well as good stability with respect to air, moisture, and time. Promising results are obtained by applying rLIFT to transfer metal-complex precursors onto uncoated commercial gas sensors. We could show that rLIFT onto commercial sensors is possible if the sensor structures are reinforced prior to printing. The rLIFT fabricated sensors show up to 4 times higher sensitivities then the commercial sensors (with inkjet printed SnO2). In addition, the selectivity towards CH4 of the Pd:SnO2 sensors is significantly enhanced compared to the pure SnO2 sensors. Our results indicate that the reactive laser transfer technique applied here represents an important technical step for the realization of improved gas detection systems with wide-ranging applications in environmental and health monitoring control. PMID- 27118532 TI - A pediatric patient with interstitial pneumonia due to enterovirus D68. AB - Enterovirus D68 (EV-D68) infection is associated with upper and lower respiratory tract symptoms such as fever, cough, and wheezing. Pediatric patients with EV-D68 infection easily develop more severe respiratory complications compared to patients infected with other species of enterovirus, and consequently, have a higher rate of hospitalization and admission to intensive care units. Therefore, the clinical picture of respiratory complications associated with EV-D68 infection needs to be elucidated. Here, we report a 4-year-old girl of EV-D68 infection that required artificial respiration management within 24 h from the onset of cold symptoms. The patient was diagnosed with interstitial pneumonia on the basis of chest imaging findings with patchy, funicular and frosted glassy shadows, increased blood markers of surfactant protein-A, surfactant protein-D and sialylated carbohydrate antigen KL-6, and increased neutrophils and lymphocytes in the bronchoalveolar lavage. Steroids showed a remarkable effect in her treatment. Further investigations are needed to confirm the efficacy of steroids for interstitial pneumonia due to EV-D68 infection. As rapid deterioration of respiratory status is observed in EV-D68 infection, the possibility of interstitial pneumonia may be considered. PMID- 27118533 TI - Light-stimulated carrier dynamics of CuInS2/CdS heterotetrapod nanocrystals. AB - We synthesized a heterotetrapod composed of a chalcopyrite(ch)-CuInS2 core and wurtzite(w)-CdS arms and elucidated its optical properties and light-stimulated carrier dynamics using fs-laser flash photolysis. The CuInS2/CdS heterotetrapod possessed quasi-type II band alignment, which caused much longer-lived charge separation than that in the isolated CuInS2 nanocrystal. PMID- 27118534 TI - No increased heart failure risk is reported with DPP-4 inhibitors. PMID- 27118535 TI - Effect of polar intermolecular interactions on the elastic constants of bent-core nematics and the origin of the twist-bend phase. AB - A molecular theory of both elastic constants and the flexoelectric coefficients of bent-core nematic liquid crystals has been developed taking into account dipole-dipole interactions as well as polar interactions determined by the bent molecular shape. It has been shown that if polar interactions are neglected, the elastic constants are increasing monotonically with the decreasing temperature. On the other hand, dipolar interactions between bent-core molecules may result in a dramatic increase of the bend flexocoefficient. As a result, the flexoelectric contribution to the bend elastic constant increases significantly, and the bend elastic constant appears to be very small throughout the nematic range and may vanish at a certain temperature. This temperature may then be identified as a temperature of the elastic instability of the bent-core nematic phase which induces a transition into the modulated phases with bend deformations like recently reported twist-bend phase. The temperature variation of the elastic constants is qualitatively similar to the typical experimental data for bent-core nematics. PMID- 27118536 TI - On moving contact lines simulated by the single-component two-phase lattice Boltzmann method. AB - We studied moving contact lines (MCLs) simulated by the single-component two phase lattice-Boltzmann method (TP-LBM) based on the free-energy theory. In TP LBM simulations CL moves by evaporation and condensation, and they do not involve an explicit slip length. How the CL motion compares with those by other methods using a slip model is not well understood yet. By comparing the results for a benchmark problem with established analytical solutions, we found an effective slip length proportional to the interface thickness in TP-LBM simulations. Besides, it was found that a recently proposed simple method originally in the framework of LBM for binary fluids can also be applied to TP-LBM to regulate the CL motion, and this method can greatly enhance its capability to simulate realistic two-phase flows with very small slip lengths. PMID- 27118537 TI - Tracking post-infectious fatigue in clinic using routine Lab tests. AB - BACKGROUND: While biomarkers for chronic fatigue syndrome (CFS) are beginning to emerge they typically require a highly specialized clinical laboratory. We hypothesized that subsets of commonly measured laboratory markers used in combination could support the diagnosis of post-infectious CFS (PI-CFS) in adolescents following infectious mononucleosis (IM) and help determine who might develop persistence of symptoms. METHODS: Routine clinical laboratory markers were collected prospectively in 301 mono-spot positive adolescents, 4 % of whom developed CFS (n = 13). At 6, 12, and 24 months post-diagnosis with IM, 59 standard tests were performed including metabolic profiling, liver enzyme panel, hormone profiles, complete blood count (CBC), differential white blood count (WBC), salivary cortisol, and urinalysis. Classification models separating PI-CFS from controls were constructed at each time point using stepwise subset selection. RESULTS: Lower ACTH levels at 6 months post-IM diagnosis were highly predictive of CFS (AUC p = 0.02). ACTH levels in CFS overlapped with healthy controls at 12 months, but again showed a trend towards a deficiency at 24 months. Conversely, estradiol levels depart significantly from normal at 12 months only to recover at 24 months (AUC p = 0.02). Finally, relative neutrophil count showed a significant departure from normal at 24 months in CFS (AUC p = 0.01). Expression of these markers evolved differently over time between groups. CONCLUSIONS: Preliminary results suggest that serial assessment of stress and sex hormones as well as the relative proportion of innate immune cells measured using standard clinical laboratory tests may support the diagnosis of PI-CFS in adolescents with IM. PMID- 27118538 TI - Calibration of PET/CT scanners for multicenter studies on differentiated thyroid cancer with (124)I. AB - BACKGROUND: Studies on imaging of differentiated thyroid cancer (DTC) using (124)I often require a multicenter approach, as the prevalence of DTC is low. Calibration of participating scanners is required to obtain comparable quantification. As determination of a well-defined range of recovery coefficients is complicated for various reasons, a simpler approach based on the assumption that the iodine uptake is highly focal with a background that significantly lacks radioactivity might be more efficient. For each scanner, a linear conversion between known and observed activity can be derived, allowing quantification that can be traced to a common source for all scanners within one study-protocol. The aim of this paper is to outline a procedure using this approach in order to set up a multicenter calibration of PET/CT scanners for (124)I. METHODS: A cylindrical polyethylene phantom contained six 2-ml vials with reference activities of ~2, 10, 20, 100, 400, and 2000 kBq, produced by dilution from a known activity. The phantom was scanned twice on PET/CT scanners of participating centers within 1 week. For each scanner, the best proportional and linear fit between measured and known activities were derived and based on statistical analyses of the results of all scanners; it was determined which fit should be applied. In addition, a Bland-Altman analysis was done on calibrated activities with respect to reference activities to asses the relative precision of the scanners. RESULTS: Nine Philips (vendor A) and nine Siemens (vendor B) PET/CT scanners were calibrated in a time period of 3 days before and after the reference time. No significant differences were detected between the two subsequent scans on any scanner. Six fitted intercepts of vendor A were significantly different from zero, so the linear model was used. Intercepts ranged from -8 to 26 kBq and slopes ranged from 0.80 to 0.98. Bland-Altman analysis of calibrated and reference activities showed that the relative error of calibrated activities was smaller than that of uncalibrated activities. CONCLUSIONS: A simplified multicenter calibration procedure for PET/CT scans that show highly focal uptake and negligible background is feasible and results in more precise quantification. Our procedure can be used in multicenter (124)I PET scans focusing on (recurrent) DTC. PMID- 27118539 TI - Procalcitonin-guided protocol is not useful to manage antibiotic therapy in febrile neutropenia: a randomized controlled trial. AB - Febrile neutropenia (FN) requires immediate use of antibiotics (ATB), and procalcitonin (PCT) is proven to be useful in guiding antibiotic therapy in different settings. This study investigated the use of PCT as a guide for the duration of ATB in FN. A randomized controlled trial was carried out from January December 2010. A total of 62 hematological adult patients with FN were randomized, in 1:1 ratio, into two groups: (1) PCT group: length of ATB guided by institutional protocol plus PCT dynamics, and (2) control group: duration of ATB in accordance with institutional protocol. There was no difference between groups regarding the use of ATB for the first episode of fever (HR 1.14, 95 % CI 0.66 1.95, p = 0.641), with equivalent median duration of ATB therapy (PCT group 9.0 days and control group 8.0 days, p = 0.67), and median number of days without ATB (0 days, IQR 0-2 days for both groups, p = 0.96). We observed no difference in clinical cure rate (p = 0.68), infection relapse (p = 1.0), superinfection (p = 0.85), length of hospitalization (p = 0.64), and mortality at 28 days (p = 0.39) and at 90 days (p = 0.72). Considering the cut-off of 0.5 ng/ml, PCT was correlated with bacteremia (sensitivity of 51.9 % and specificity of 76.5 %). In this randomized controlled trial, adding a PCT-guided protocol to the standard recommendations did not reduce the use of antibiotics in febrile neutropenia, although no apparent harm was caused. PCT proved to be a marker of bacteremia in this setting. PMID- 27118540 TI - A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy. AB - Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104. PMID- 27118541 TI - Emerging strategies for the treatment of older patients with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is the most common acute leukemia in adults, and its incidence increases with age. Clinical outcomes in younger patients have improved over the years but, unfortunately, there is little evidence for an equivalent improvement in outcome for older patients. Approximately 50 % of older patients who are able to receive intensive chemotherapy will achieve a complete remission; however, they face a much higher relapse rate than younger patients, and survival rates for this group are low. Therefore, there is an urgent need to improve outcomes in older patients with AML. In this article, we discuss current treatment paradigms for older patients with AML including the challenges faced when determining which patients are eligible for intensive chemotherapy. We then highlight new treatments in development that may benefit this patient group. Cytotoxic agents, hypomethylating agents, molecularly targeted agents, and cell cycle kinase inhibitors are discussed, with a focus on novel agents that have achieved an advanced stage of development. Overall, the treatment of AML in older patients remains a challenge and, whenever possible, treatment should be offered in the context of clinical trials and should be planned with curative intent. PMID- 27118542 TI - Clinical significance of osteoblast precursors and osteoclast precursors in earlier diagnosis and monitoring of myeloma bone disease. AB - Bone disease is the most common complication of multiple myeloma (MM). In order to diagnose and monitor the bone damages earlier, we detected circulating osteoclast precursors (OCPs) and osteoblast precursors (OBPs) by flow cytometry, comparing with special biochemical markers, such as tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), carboxy-terminal cross-linking telopeptide of type I collagen (CTX), osteocalcin (OCN), and procollagen I amino-terminal propeptide (PINP). The results showed that the circulating OBPs in the newly diagnosed MM patients significantly decreased compared with the normal controls (7.14 vs 12.82 %, P = 0.045), while circulating OCPs in the newly diagnosed patients and remission patients were significantly increased than the normal controls (2.46 vs 0.17 %, P = 0.000; 1.87 vs 0.17 %, P = 0.000, respectively). According to X-ray, newly diagnosed patients were divided into stages A and B (without and with osteolytic lesions). Compared with the normal controls, the circulating OBPs in stages A and B reduced (12.82 vs 7.47 %, P = 0.041; 12.82 vs 7.14 %, P = 0.010, respectively), while the circulating OCPs elevated (0.17 vs 2.31 %, P=0.010; 0.17 % vs 2.71 %, P=0.001, respectively). The levels of TRACP-5b and CTX in the newly diagnosed patients were higher than the normal controls (P = 0.014, P = 0.037) and remission patients (P = 0.025, P = 0.003), and they were significantly higher in stage B than the normal controls (P = 0.015, P = 0.002). However, the PINP and OCN levels had no significant changes in different stages. In conclusion, abnormal circulating OBPs and OCPs were found earlier before X-ray in MM and still existed in remission patients, indicating that they may be novel predictive markers for early diagnosing and monitoring bone disease. PMID- 27118543 TI - Self-stigma and affiliate stigma in first-episode psychosis patients and their caregivers. AB - PURPOSE: Stigma is a major factor causing delayed help-seeking and poor treatment adherence in patients with psychotic disorders. Previous research has mostly focused on chronic samples and the impact of culturally-relevant variables on both patients' and their caregivers' stigmatization is understudied. This study aimed to examine the relationships between various forms of stigma, "face concern", and clinical characteristics in a group of Chinese first-episode psychosis (FEP) patients and their caregivers. METHODS: Forty-four Hong Kong Chinese aged 15-54 years presenting with FEP to psychiatric services and their caregivers were recruited. Assessments on self-stigma, affiliate stigma, perceived public stigma, "face concern", symptom severity and subjective quality of life (QoL) were conducted. RESULTS: Self-stigma of FEP patients was correlated with perceived public stigma, "face concern", insight and psychological health of QoL. Multiple regression analysis revealed that perceived public stigma and "face concern" independently predicted self-stigma. Mediation analysis further suggested that "face concern" partially mediated the relationship between perceived public stigma and self-stigma. Caregivers' affiliate stigma was significantly associated with higher levels of stress, and symptoms of depression and anxiety. Affiliate stigma did not correlate with perceived public stigma and "face concern". CONCLUSION: Our results indicate a critical role of perceived public stigma and fear of losing face in determining self-stigma in Chinese patients with FEP. Caregivers with greater degree of affiliate stigma experience increased stress and emotional distress. Our findings highlight the importance to examine culturally specific factors that may contribute to the development of self-stigma in first-episode populations of different ethnicities. PMID- 27118544 TI - Rationale and design of the DP-TRANSFERS project: diabetes prevention transferring findings from European research to society in Catalonia. AB - BACKGROUND: Compelling evidence has been accumulated to support the effectiveness of intensive lifestyle intervention in delaying progression to Type 2 diabetes even in people identified as being at high risk determined by the Finnish diabetes risk score. The DE-PLAN-CAT project (diabetes in Europe-prevention using lifestyle, physical activity and nutritional intervention-Catalonia) evidenced that intensive lifestyle intervention was feasible and cost-effective on a short scale in real-life primary care settings, at least over 4 years. However, transferring such lifestyle interventions to society remains the major challenge of research in the field of diabetes prevention. METHODS/DESIGN: The derived DP TRANSFERS (diabetes prevention-transferring findings from European research to society) is a large scale national programme aimed at translating a tailored lifestyle intervention to the maximum of primary care centres where feasible through a core proposal agreed with all the partners. The method is built upon a 3-step (screening, intervention and follow-up) real-life, community-wide structure on the basis of a dual intensity lifestyle intervention (basic and continuity modules) and supported by a 4-channel transfer strategy (institutional relationships, facilitators' workshops, collaborative groupware and programme WEB page). Participation will initially cover nine health departments (7 million inhabitants) through nine coordinating centres located in metropolitan (3.2 million), semi-urban (2.9 million) and rural (0.9 million) areas from which it is expected accessing 25 % of all primary care settings, equivalent to 90 associated centres (1.6-1.8 million people) with an estimate of 0.32 million participants aged 45-75 years at high risk of future development of diabetes. To ascertain sustainability, effect, satisfaction and quality of the translation programme statistical analyses will be performed from both the entire population (facilitators and participants) and a stratified representative sample obtained by collecting data from at least 920 participants. DISCUSSION: The DP-TRANSFERS will use a strategy of approach to society consistent with the impact of the disease and the fast accessibility provided by primary care settings in Catalonia. Both the widespread effect of the lifestyle intervention and the translational process itself could be assessed. PMID- 27118545 TI - Sublethal effects of acaricides and Nosema ceranae infection on immune related gene expression in honeybees. AB - Nosema ceranae is an obligate intracellular parasite and the etiologic agent of Nosemosis that affects honeybees. Beside the stress caused by this pathogen, honeybee colonies are exposed to pesticides under beekeeper intervention, such as acaricides to control Varroa mites. These compounds can accumulate at high concentrations in apicultural matrices. In this work, the effects of parasitosis/acaricide on genes involved in honeybee immunity and survival were evaluated. Nurse bees were infected with N. ceranae and/or were chronically treated with sublethal doses of coumaphos or tau-fluvalinate, the two most abundant pesticides recorded in productive hives. Our results demonstrate the following: (1) honeybee survival was not affected by any of the treatments; (2) parasite development was not altered by acaricide treatments; (3) coumaphos exposure decreased lysozyme expression; (4) N. ceranae reduced levels of vitellogenin transcripts independently of the presence of acaricides. However, combined effects among stressors on imagoes were not recorded. Sublethal doses of acaricides and their interaction with other ubiquitous parasites in colonies, extending the experimental time, are of particular interest in further research work. PMID- 27118546 TI - Impact of the Pharmacy Practice Model Initiative on Clinical Pharmacy Specialist Practice. AB - This paper describes the goals of the American Society of Health-System Pharmacists' Pharmacy Practice Model Initiative (PPMI) and its recommendations for health-system pharmacy practice transformation to meet future patient care needs and elevate the role of pharmacists as patient care providers. PPMI envisions a future in which pharmacists have greater responsibility for medication-related outcomes and technicians assume greater responsibility for product-related activities. Although the PPMI recommendations have elevated the level of practice in many settings, they also potentially affect existing clinical pharmacists, in general, and clinical pharmacy specialists, in particular. Moreover, although more consistent patient care can be achieved with an expanded team of pharmacist providers, the role of clinical pharmacy specialists must not be diminished, especially in the care of complex patients and populations. Specialist practitioners with advanced training and credentials must be available to model and train pharmacists in generalist positions, residents, and students. Indeed, specialist practitioners are often the innovators and practice leaders. Negotiation between hospitals and pharmacy schools is needed to ensure a continuing role for academic clinical pharmacists and their contributions as educators and researchers. Lessons can be applied from disciplines such as nursing and medicine, which have developed new models of care involving effective collaboration between generalists and specialists. Several different pharmacy practice models have been described to meet the PPMI goals, based on available personnel and local goals. Studies measuring the impact of these new practice models are needed. PMID- 27118547 TI - Endothelin-1 is independently associated with 180-day mortality after adjusting for body mass index. PMID- 27118548 TI - Modeling health gains and cost savings for ten dietary salt reduction targets. AB - BACKGROUND: Dietary salt reduction is included in the top five priority actions for non-communicable disease control internationally. We therefore aimed to identify health gain and cost impacts of achieving a national target for sodium reduction, along with component targets in different food groups. METHODS: We used an established dietary sodium intervention model to study 10 interventions to achieve sodium reduction targets. The 2011 New Zealand (NZ) adult population (2.3 million aged 35+ years) was simulated over the remainder of their lifetime in a Markov model with a 3 % discount rate. RESULTS: Achieving an overall 35 % reduction in dietary salt intake via implementation of mandatory maximum levels of sodium in packaged foods along with reduced sodium from fast foods/restaurant food and discretionary intake (the "full target"), was estimated to gain 235,000 QALYs over the lifetime of the cohort (95 % uncertainty interval [UI]: 176,000 to 298,000). For specific target components the range was from 122,000 QALYs gained (for the packaged foods target) down to the snack foods target (6100 QALYs; and representing a 34-48 % sodium reduction in such products). All ten target interventions studied were cost-saving, with the greatest costs saved for the mandatory "full target" at NZ$1260 million (US$820 million). There were relatively greater health gains per adult for men and for Maori (indigenous population). CONCLUSIONS: This work provides modeling-level evidence that achieving dietary sodium reduction targets (including specific food category targets) could generate large health gains and cost savings for a national health sector. Demographic groups with the highest cardiovascular disease rates stand to gain most, assisting in reducing health inequalities between sex and ethnic groups. PMID- 27118549 TI - Functional Characterization of a Novel Dactylosporangium Esterase and Its Utilization in the Asymmetric Synthesis of (R)-Methyl Mandelate. AB - One novel esterase DAEst6 was identified from the genome of Dactylosporangium aurantiacum subsp. Hamdenensis NRRL 18085. DAEst6 was further characterized to be an esterase which exhibited high resistance to high pH values. Esterase DAEst6 could resolve racemic methyl mandelate and generate (R)-methyl mandelate, one key drug intermediate, with an enantiomeric excess and a conversion of 99 and 49 %, respectively, after process optimization. The optimal working condition for the preparation of (R)-methyl mandelate through DAEst6 was found to be 10-mM racemic methyl mandelate, no organic co-solvents, pH 7.5, and 40 degrees C, for 5 h. Our work was the first report about the functional characterization of one novel Dactylosporangium esterase and the utilization of one Dactylosporangium esterase in kinetic resolution. Dactylosporangium esterases represented by DAEst6 possess great potential in the generation of valuable chiral drug intermediates and chemicals. PMID- 27118550 TI - Functional Characterization of a Novel Marine Microbial Esterase and its Utilization in the Enantioselective Preparation of (R)-Methyl 2-Chloropropionate. AB - Chiral 2-chloropropanoic acids and their ester derivatives are crucial intermediates in the synthesis of many chemicals, especially herbicides. The enzymatic synthesis of chiral 2-chloropropanoic acids and their ester derivatives by esterases was not easily achieved, because the structural difference between the two enantiomers was too small to be recognized by esterases. Herein, we report the expression and functional characterization of one novel low temperature-resistant esterase EST12-7 identified from the genome of Pseudonocardia antitumoralis SCSIO 01299 isolated from the sediments of the South China Sea. Biocatalyst EST12-7 could hydrolyze racemic methyl 2-chloropropinate and generate optically pure (R)-methyl 2-chloropropinate with high enantiomeric excess (>99 %) and conversion (>49 %) after process optimization. Notably, the addition of different surfactants and using surfactants of different concentrations in the kinetic resolution catalyzed by EST12-7 could greatly affect the enantiomeric excess and conversion rate of product (R)-methyl 2 chloropropinate. PMID- 27118551 TI - Revision for the Rapid Emergency Triage and Treatment System Adult (RETTS-A) needed? AB - The study highlights the prognostic role of patient's vital signs at presentation to the emergency department (ED): The predictive role of vital signs in ED triage has been controversially discussed probably due to a paucity of data on the value of vital signs in ED at presentation. However, the authors did not find a suitable way to adjust for the inherent influence of triage decision and medical treatment on mortality. We have discussed that ambiguity concerning the assessment of vital signs criteria in RETTS-A Red priority may threaten any association between patient acuity and fatal outcome. PMID- 27118552 TI - Immigrant disadvantage or the healthy immigrant effect? Evidence about low birth weight differences in the Czech Republic. AB - BACKGROUND: Most of the research about immigrants' birth outcomes comes from countries with high numbers of immigrants. This article provides evidence from the Czech Republic, a country with a short immigration history and a small immigrant population. Two hypotheses are tested: the immigrant disadvantage hypothesis and the healthy immigrant hypothesis. METHODS: Live singleton births in 2013-14 from the national birth register are analysed. The odds of low birth weight (LBW) among the native population and five immigrant groups are compared using logistic regression. Control variables include maternal age, parity, education and marital status, paternal immigrant status, age and education. RESULTS: All immigrant groups, except for Slovaks, showed smaller odds of LBW than native mothers. Adjusted odds ratios for non-Slovak immigrants range between 0.52 and 0.65. Furthermore, maternal immigrant status interacts with education. There is a wide educational gradient in LBW among Czech and Slovak mothers with low education representing a large disadvantage. Such pattern is not present among other ethnic groups. This makes the outcomes of Czech and Slovak mothers less favourable. Native mothers and immigrants with higher level of education show more similar outcomes. Paternal immigrant status does not have a net effect on LBW when maternal ethnicity is taken into account. CONCLUSIONS: Results provide evidence for the healthy immigrant effect. The favourable outcomes of non Slovak immigrants seem to result from a combination of two factors, health selection of immigrants and relatively high prevalence of LBW in the native population caused by adverse outcomes of mothers with low education. PMID- 27118553 TI - The effect of Scutellaria baicalensis stem-leaf flavonoids on spatial learning and memory in chronic cerebral ischemia-induced vascular dementia of rats. AB - Flavonoids have been shown to improve cognitive function and delay the dementia progression. However, the underlying mechanisms remain elusive. In the present study, we examined the effect of Scutellaria baicalensis stem-leaf total flavonoids (SSTFs) extracted from S. baicalensis Georgi on spatial learning and memory in a vascular dementia (VaD) rat model and explored its molecular mechanisms. The VaD rats were developed by permanent bilateral occlusion of the common carotid artery. Seven days after recovery, the VaD rats were treated with either 50 or 100 mg/kg of SSTF for 60 days. The spatial learning and memory was evaluated in the Morris water maze (MWM) test. The tau hyperphosphorylation and the levels of the related protein kinases or phosphatases were examined by western blot analysis. In VaD rats, SSTF treatment at 100 mg/kg significantly reduced the escape latency in training trial in MWM test. In the probe trial, SSTF treatment increased the searching time and travel distance in the target quadrant. SSTF treatment inhibited the tau phosphorylation in both cortex and hippocampus in VaD rats. Meanwhile, SSTF reduced the activity of glycogen synthase kinase 3beta and cyclin-dependent kinase 5 in VaD rats. In contrast, SSTF treatment increased the level of the protein phosphatase 2A subunit B in VaD rats. SSTF treatment significantly improved the spatial cognition in VaD rats. Our results suggest that SSTF may alleviate tau-hyperphosphorylation-induced neurotoxicity through coordinating the activity of kinases and phosphatase after a stroke. SSTF may be developed into promising novel therapeutics for VaD. PMID- 27118555 TI - College Sports Dilemma. PMID- 27118554 TI - A novel serine protease, Sep1, from Bacillus firmus DS-1 has nematicidal activity and degrades multiple intestinal-associated nematode proteins. AB - Plant-parasitic nematodes (PPNs) cause serious harm to agricultural production. Bacillus firmus shows excellent control of PPNs and has been produced as a commercial nematicide. However, its nematicidal factors and mechanisms are still unknown. In this study, we showed that B. firmus strain DS-1 has high toxicity against Meloidogyne incognita and soybean cyst nematode. We sequenced the whole genome of DS-1 and identified multiple potential virulence factors. We then focused on a peptidase S8 superfamily protein called Sep1 and demonstrated that it had toxicity against the nematodes Caenorhabditis elegans and M. incognita. The Sep1 protein exhibited serine protease activity and degraded the intestinal tissues of nematodes. Thus, the Sep1 protease of B. firmus is a novel biocontrol factor with activity against a root-knot nematode. We then used C. elegans as a model to elucidate the nematicidal mechanism of Sep1, and the results showed that Sep1 could degrade multiple intestinal and cuticle-associated proteins and destroyed host physical barriers. The knowledge gained in our study will lead to a better understanding of the mechanisms of B. firmus against PPNs and will aid in the development of novel bio-agents with increased efficacy for controlling PPNs. PMID- 27118556 TI - Compliance With Injury Prevention Measures in Youth Pitchers: Survey of Coaches in Little League of Puerto Rico. AB - BACKGROUND: Because of the problem of elbow and shoulder injuries in baseball pitchers between 9 and 14 years of age, the USA Baseball Medical & Safety Advisory Committee and the Department of Recreation and Sports in Puerto Rico developed injury prevention guidelines for pitchers. The purpose of this study was to determine the compliance of pitching coaches of 9- to 14-year-old Little League teams in Puerto Rico with the Administrative Order 2006-01 and the USA Baseball guidelines. HYPOTHESES: (1) The coaches will have a satisfactory level of compliance with the Administrative Order as well as with the USA Baseball guidelines and (2) both the level of education of the coach as well as the years of experience will correlate with the level of compliance. STUDY DESIGN: Descriptive cross-sectional study. LEVEL OF EVIDENCE: Level 5. METHODS: A self administered questionnaire was developed based on the Administrative Order and on the USA Baseball guidelines. A descriptive univariate analysis was conducted to determine the mean coach compliance with both guidelines. Pearson correlation coefficients were used to describe the correlation between the level of education and the years of experience of the coaches with the level of compliance. RESULTS: Thirty-five coaches (response rate, 78%) participated in the study. On average, the coaches complied with 70% of the Administrative Order and with 73% of the USA Baseball guidelines. No significant correlations were found. CONCLUSION: The coaches who participated in the study did not reflect a satisfactory level of compliance with the USA Baseball guidelines or with the Administrative Order. CLINICAL RELEVANCE: These findings emphasize the need for reinforcing compliance with the injury prevention guidelines and the need to provide resources and training to coaches to effectively prevent elbow and shoulder injuries in pitchers. PMID- 27118558 TI - The beta-glucosidase assay: a new diagnostic tool for necrotizing enterocolitis. Sensitivity, specificity, and predictive values. AB - We aimed to establish the utility of serum cytosolic beta-glycosidase (CBG) assay as a NEC diagnosis tool. CBG activity has been compared in 192 NEC-free (NEC(-)) and 13 NEC-affected (NEC(+)) neonates, with modified Bell's stages II/III, born at Reina Sofia University Hospital; additional blood hematology, microbiology, and biochemical parameters have been assayed. NEC(+) neonates have higher serum CBG activity, 26.4 +/- 12.4 mU/mg; 95 % CI (18.8-33.9), than NEC(-) infants, 11.0 +/- 6.6 mU/mg; 95 % CI (10.1-11.9) (p < 0.0001). The CBG cutoff value in the ROC curve, 15.6 mU/mg, discriminates NEC(+)/NEC(-) infants with 84.6 % sensitivity, 85.9 % specificity, 37.9 positive predictive value and 98.2 negative predictive value, 6.11 positive likelihood ratio and 0.18 negative likelihood ratio, 33.61 DOR, and 0.89 AUC. A combined panel [CBG + aspartate aminotransferase + C reactive protein] shows a 0.90 AUC value in multiple linear regressions. CONCLUSIONS: The serum CBG level is a good NEC diagnosis test and a novel NEC biomarker which may become a screening tool. WHAT IS KNOWN: *NEC affects ~2.5 % of infants at NICU, ~90 % of them weighing <1500 g. *NEC requires a careful differential diagnosis, being lethal if not diagnosed and treated. What is new: *CBG assay will be useful to determine infants without NEC and preventing unnecessary treatment. *CBG assay could discriminate NEC better than other gut specific sera protein biomarkers. PMID- 27118559 TI - The cohort multiple randomized controlled trial design: a valid and efficient alternative to pragmatic trials? AB - Randomized controlled trials (RCTs)-the gold standard for evaluating the effects of medical interventions-are notoriously challenging in terms of logistics, planning and costs. The cohort multiple randomized controlled trial approach is designed to facilitate randomized trials for pragmatic evaluation of (new) interventions and is a promising variation from conventional pragmatic RCTs. In this paper, we evaluate methodological challenges of conducting an RCT within a cohort. We argue that equally valid results can be obtained from trials conducted within cohorts as from pragmatic RCTs. However, whether this design is more efficient compared with conducting a pragmatic RCT depends on the amount and nature of non-compliance in the intervention arm. PMID- 27118560 TI - High body mass index and risk of exacerbations and pneumonias in individuals with chronic obstructive pulmonary disease: observational and genetic risk estimates from the Copenhagen General Population Study. AB - BACKGROUND: In the clinic, the combination of obesity and chronic obstructive pulmonary disease (COPD) has been increasing. However, whether high body mass index (BMI) affects the risk of exacerbations and pneumonias in individuals with COPD is presently unknown. Genetics can be used to assess the causal role of high BMI in exacerbations and pneumonias in individuals with COPD. We tested the hypothesis that high BMI is associated with an increased risk of exacerbations and pneumonias in individuals with COPD, both observationally and genetically. METHODS: We genotyped 93 894 individuals of Danish descent, aged 20-100 years, from the Copenhagen General Population Study, for FTO (rs9939609), MC4R (rs17782313) and TMEM18 (rs6548238), and created an allele score. A total of 10 883 individuals had spirometric COPD with forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC) < lower limit of normal (LLN). In these individuals, we observed 1453 exacerbations and 3390 pneumonias during 4.7 years of follow-up. RESULTS: For each increase in allele score, BMI was 0.28 kg/m2 [95% confidence interval (CI): 0.25-0.30) higher. Age- and sex-adjusted genetic hazard ratios (HRs) per one allele score increase in individuals with COPD were 1.13 (1.01-1.27) for exacerbations, 1.10 (1.03-1.19) for pneumonias and 1.12 (1.04 1.21) for exacerbations and/or pneumonias. Corresponding multivariable adjusted observational HRs per unit (kg/m2) BMI increase were 0.98 (0.95-1.01), 0.99 (0.96 1.03) and 0.99 (0.96-1.01), respectively. CONCLUSIONS: Genetically determined high BMI was associated with an increased risk of recurrent exacerbations and pneumonias in individuals with COPD, whereas this was not the case for observationally determined high BMI. The genetic data are compatible with the notion that high BMI leads to increased risk of exacerbations and pneumonias in individuals with COPD. PMID- 27118561 TI - Metabolomics in epidemiology: from metabolite concentrations to integrative reaction networks. AB - Metabolomics is becoming feasible for population-scale studies of human disease. In this review, we survey epidemiological studies that leverage metabolomics and multi-omics to gain insight into disease mechanisms. We outline key practical, technological and analytical limitations while also highlighting recent successes in integrating these data. The use of multi-omics to infer reaction rates is discussed as a potential future direction for metabolomics research, as a means of identifying biomarkers as well as inferring causality. Furthermore, we highlight established analysis approaches as well as simulation-based methods currently used in single- and multi-cell levels in systems biology. PMID- 27118563 TI - Concern over arsenic in infants' rice products rises after US study. PMID- 27118562 TI - Predictive coding as a model of cognition. AB - Previous work has shown that predictive coding can provide a detailed explanation of a very wide range of low-level perceptual processes. It is also widely believed that predictive coding can account for high-level, cognitive, abilities. This article provides support for this view by showing that predictive coding can simulate phenomena such as categorisation, the influence of abstract knowledge on perception, recall and reasoning about conceptual knowledge, context-dependent behavioural control, and naive physics. The particular implementation of predictive coding used here (PC/BC-DIM) has previously been used to simulate low level perceptual behaviour and the neural mechanisms that underlie them. This algorithm thus provides a single framework for modelling both perceptual and cognitive brain function. PMID- 27118564 TI - A novel e8a2 BCR-ABL1 intronic fusion through insertion of a chromosome 22 BCR gene fragment into chromosome 9 in an atypical Philadelphia (Ph) chromosome chronic myeloid leukemia patient. PMID- 27118565 TI - Platelet-to-lymphocyte ratio predicts mortality better than neutrophil-to lymphocyte ratio in hemodialysis patients. AB - PURPOSE: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were established showing the poor prognosis in some diseases, such as cardiovascular diseases and malignancies. The risk of mortality in patients with end-stage renal disease (ESRD) was higher than normal population. In this study, we aimed to investigate the relationship between NLR, PLR, and all-cause mortality in prevalent hemodialysis (HD) patients. METHODS: Eighty patients were enrolled in study. NLR and PLR obtained by dividing absolute neutrophil to absolute lymphocyte count and absolute platelet count to absolute lymphocyte count, respectively. The patients were followed prospectively for 24 months. The primary end point was all-cause mortality. RESULTS: Mean levels of neutrophil, lymphocyte, and platelet were 3904 +/- 1543/mm(3), 1442 +/- 494/mm(3), 174 +/- 56 * 10(3)/mm(3), respectively. Twenty-one patients died before the follow-up at 24 months. Median NLR and PLR were 2.52 and 130.4, respectively. All-cause mortality was higher in patients with high NLR group compared to the patients with low NLR group (18.8 vs. 7.5 %, p = 0.031) and in patients with higher PLR group compared to patients with lower PLR group (18.8 vs. 7.5 %, p = 0.022). Following adjusted Cox regression analysis, the association of mortality and high NLR was lost (p = 0.54), but the significance of the association of high PLR and mortality increased (p = 0.013). CONCLUSION: Although both NLR and PLR were associated with all-cause mortality in prevalent HD patients, only PLR could independently predict all-cause mortality in these populations. PMID- 27118566 TI - Associations of fractalkine receptor (CX3CR1) and CCR5 gene variants with hypertension, diabetes and atherosclerosis in chronic renal failure patients undergoing hemodialysis. AB - PURPOSE: We aimed to investigate the associations of fractalkine receptor (CX3CR1) V249I, T280M and CCR5-59029 A/G gene polymorphisms in chronic renal failure (CRF) subjects undergoing hemodialysis and to evaluate possible associations of these polymorphisms with hypertension (HT), diabetes mellitus (DM) and atherosclerosis (AS). METHODS: A total of 225 CRF subjects undergoing hemodialysis and 201 healthy controls were enrolled in the study. CRF subjects were divided into three major subgroups according to comorbidities including HT (n = 127), DM (n = 65) and AS (n = 33). Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The II genotype and I allele frequencies of CX3CR1 V249I polymorphism were found significantly more frequent in CRF subjects, CRF subjects with DM and CRF subjects with AS compared with controls (p < 0.05 for all comparisons). G allele frequency of CCR5 polymorphism was found significantly more prevalent in CRF subjects with DM than that of controls. Further, GG genotype and G allele frequencies of CCR5 polymorphism were significantly more prevalent in CRF subjects with AS compared with controls (p < 0.05). We also explored these polymorphisms among CRF subjects with and without following comorbidities: HT, DM, AS. We found significant association between CRF subjects with HT and without HT in terms of genotype and allele frequencies of V249I polymorphism (p < 0.05). CX3CR1 T280M polymorphism was not found significantly different in none of the comparisons. CONCLUSION: These data demonstrate possible associations between CX3CR1 V249I and CCR5-59029 A/G polymorphisms and/or HT, DM and AS in CRF subjects. PMID- 27118567 TI - Is it appropriate to conduct conventional active surveillance for Asian men with low-risk prostate cancer? PMID- 27118568 TI - Carbachol-induced signaling through Thr696-phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) in rat bladder smooth muscle cells. AB - PURPOSE: Lines of evidence suggest that Rho-associated protein kinase (ROCK) mediated myosin phosphatase-targeting subunit 1 (MYPT1) phosphorylation plays a central role in smooth muscle contraction. However, the physiological significance of MYPT1 phosphorylation at Thr696 catalyzed by ROCK in bladder smooth muscle remains controversial. We attempt to directly observe the quantitative protein expression of Rho A/ROCK and phosphorylation of MYPT1 at Thr696 after carbachol administration in rat bladder smooth muscle cells (RBMSCs). MATERIALS AND METHODS: Primary cultured smooth muscle cells were obtained from rat bladders. The effects of both concentration and time-course induced by the muscarinic agonist carbachol were investigated by assessing the expression of Rho A/ROCK and MYPT1 phosphorylation at Thr696 using Western blot. RESULTS: In the dose-course studies, carbachol showed significant increase in phosphorylation of MYPT1 at Thr696 (p-MYPT1) from concentrations of 15-100 MUM based on Western blot results (p < 0.05, ANOVA test). In the time-course studies, treatment of cells with 15 MUM of carbachol significantly enhanced the expression of p-MYPT1 from 3 to 15 h (p < 0.05, ANOVA test) and induced the expression of Rho A from 10 to 120 min (p < 0.05, ANOVA test). CONCLUSIONS: Carbachol can induce the expression of ROCK pathway, leading to MYPT1 phosphorylation at Thr696 and thereby sustained RBSMCs contraction. PMID- 27118569 TI - Lutibacter profundi sp. nov., isolated from a deep-sea hydrothermal system on the Arctic Mid-Ocean Ridge and emended description of the genus Lutibacter. AB - A bacterial strain designated LP1T was isolated from a microbial mat growing on the surface of a black smoker chimney at the Loki's Castle hydrothermal system, which is located on the Arctic Mid-Ocean Ridge. Phylogenetic analyses based on 16S rRNA gene sequences positioned strain LP1T within the family Flavobacteriaceae with Lutibacterholmesii as the closest relative (97.5 % 16S rRNA gene sequence similarity). Strain LP1T was rod-shaped, Gram-reaction negative and non-motile. It grew in a modified artificial seawater medium supplemented with tryptone and vitamins at pH 5.5-7.5 (optimum pH 6.0-6.5), within a temperature range of 13-34 degrees C (optimum 23 degrees C), and under microaerobic conditions. The most abundant fatty acids (>10 %) were iso-C15 : 0 (25.2 %) and iso-C15 : 0 3-OH (14.5 %). The genome of strain LP1T has a DNA G+C content of 29.8 mol%. Based on the results of the polyphasic characterization presented here, strain LP1T is considered to represent a novel species of the genus Lutibacter, for which the name Lutibacter profundi sp. nov. is proposed. The type strain is LP1T (=DSM 100437T =JCM 30585T). An emended description of the genus Lutibacter is also provided to fit the description of strain LP1T. PMID- 27118570 TI - Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults. AB - This single-center retrospective study aimed to report the impact of early hematopoietic and immune recoveries after a standard total body irradiation, cyclophosphamide, and fludarabine (TCF) reduced-intensity conditioning (RIC) regimen for double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT) in adults. We analyzed 47 consecutive patients older than 17 years who engrafted after a dUCB TCF allo-SCT performed between January 2006 and April 2013 in our department. Median times for neutrophil and platelet recoveries were 17 (range, 6 to 59) and 37 days (range, 0 to 164), respectively. The 3-year overall (OS) and disease-free survivals, relapse incidence, and nonrelapse mortality were 65.7%, 57.2%, 27.1%, and 19%, respectively. In multivariate analysis, higher day +30 monocyte (>=615/mm(3); hazard ratio [HR], .04; 95% confidence interval [CI], .004 to .36; P < .01) and day +42 lymphocyte (>=395/mm(3); HR, .16; 95% CI, .03 to .78; P = .02) counts were independently associated with better OS. These results suggest that early higher hematopoietic and immune recovery is predictive of survival after dUCB TCF RIC allo-SCT in adults. Factors other than granulocyte colony-stimulating factor, which was used in all cases, favoring expansion of monocytes or lymphocytes, should be tested in the future as part of the UCB transplantation procedure. PMID- 27118571 TI - Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network. AB - Allogeneic (allo) hematopoietic cell transplantation (HCT) can induce long-term remissions in chemosensitive relapsed follicular lymphoma (FL). The Blood and Marrow Transplant Clinical Trials Network conducted a multicenter phase 2 trial to examine the efficacy of alloHCT using reduced-intensity conditioning with rituximab (RTX) in multiply relapsed, chemosensitive FL. The primary endpoint was 2-year progression-free survival (PFS). The conditioning regimen consisted of fludarabine, cyclophosphamide, and high-dose RTX (FCR), in which 3 of the 4 doses of RTX were administered at a dose of 1 gm/m(2). Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus and methotrexate. Sixty-five patients were enrolled and 62 were evaluable. Median age was 55 years (range, 29 to 74). This group was heavily pretreated: 77% had received >= 3 prior regimens, 32% had received >= 5 prior regimens, and 11% had received prior autologous HCT. Donors were HLA-matched siblings (n = 33) or HLA-matched unrelated adults (n = 29). No graft failures occurred. The overall response rate after HCT was 94% with 90% in complete remission (CR), including 24 patients not in CR before alloHCT. With a median follow-up of 47 months (range, 30 to 73), 3-year PFS and overall survival rates were 71% (95% confidence interval, 58% to 81%) and 82% (95% confidence interval, 70% to 90%), respectively. Three-year cumulative incidences of relapse/progression and nonrelapse mortality were 13% and 16%, respectively. Two year cumulative incidences of grades 2 to 4 and grades 3 or 4 acute GVHD were 27% and 10%, respectively, and extensive chronic GVHD incidence was 55%. Serum RTX concentrations peaked at day +28 and remained detectable as late as 1 year in 59% of patients with available data. In conclusion, alloHCT with FCR conditioning confers high CR rates, a low incidence of relapse/progression, and excellent survival probabilities in heavily pretreated FL patients. PMID- 27118573 TI - Amyloid beta plaque: a culprit for neurodegeneration. AB - Increasing life expectancy has resulted in an increase in neurodegenerative disorders like Alzheimer's disease. None of the hypothesis proposed till date explains the exact pathobiology of the disease. It is therefore imperative to understand the underlying mechanisms. Amyloid beta (Abeta) is regarded as the main culprit and maximum therapeutic efforts are centered towards Abeta. This review will discuss about the biosynthesis, the physiological role of Abeta including the pathogenic aggregation of Abeta resulting neurodegenerative cognitive disabilities. Most studies of Alzheimer's disease have focused on the biochemical mechanisms involved in the neurodegenerative processes triggered by Abeta aggregates. Abeta is generated from mature amyloid precursor protein being metabolized by two competing pathways, alpha-secretase pathway (non-amyloidogenic pathway) and beta-secretase (amyloidogenic pathway). The physiological roles of Abeta reported in neurotrophic properties, neurogenesis, synaptic plasticity, metal ion sequestration and specificity of blood brain barrier. The neuronal injury is the result of Abeta oligomerization and it is reported that oligomerization of Abeta contributes to neurodegeneration in Alzheimer's disease. The physiological role of Abeta must be considered in the development of medications that intended to decrease its oligomerization forming plaques in a disease like Alzheimer's disease. The biosynthetic pathways for transport and accumulation of Abeta need to be ascertained as an attempt to develop future strategies for prevention of neurodegenerative disorders. PMID- 27118572 TI - Characterization and Risk Factor Analysis of Osteoporosis in a Large Cohort of Patients with Chronic Graft-versus-Host Disease. AB - The National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Consensus Project Ancillary and Supportive Care Guidelines recommend annual assessment of bone mineral density (BMD) to monitor bone health. The study of osteoporosis in patients with cGVHD has been limited to small numbers of patients, and the guidelines are based on experience with other chronic diseases and expert opinion. We hypothesized that the prevalence of osteoporosis is high in a cohort of 258 patients with moderate to severe cGVHD because of prolonged exposure to risk factors for osteoporosis after allogeneic hematopoietic stem cell transplantation. We defined osteoporosis using BMD criteria (T-score <=-2.5) at 3 anatomic sites-the femoral neck (FN), lumbar spine (LS), and total hip (TH) and characterized risk factors through univariate and multivariate analyses. We found that low body weight (FN, P < .0001; LS, P = .0002; TH, P < .0001), malnutrition (FN, P = .0002; LS, P = .03; TH, P = .0076), higher platelet count (FN, P = .0065; TH, P = .0025), higher average National Institutes of Health organ score (FN, P = .038), higher prednisone dose (LS, P = .032), lower complement component 3 (LS, P = .0073), and physical inactivity (FN, P = .01) were associated with osteoporosis in at least 1 site. T-scores were significantly lower in the FN compared with the LS or TH (P < .0001 for both). The prevalence of osteoporosis and osteopenia was high (17% and 60%, respectively), supporting current recommendations for frequent monitoring of BMD. The association of higher platelet count in patients with cGVHD and osteoporosis has not been reported previously and represents a new area of interest in the study of osteoporosis after allogeneic hematopoietic stem cell transplantation. PMID- 27118574 TI - Combinational strategies of metformin and chemotherapy in cancers. AB - Chemotherapeutic regimens are the most common treatment to inhibit tumor growth, but there is great variability in clinical responses of cancer patients; cancer cells often develop resistance to chemotherapeutics which results in tumor recurrence and further progression. Metformin, an extensively prescribed and well tolerated first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer adjuvant drug combined with chemotherapeutic drugs to improve treatment efficacy and lower doses. In this review, we summarized the molecular mechanisms underlying anticancer effects of metformin, which included insulin- and AMPK-dependent effects, selectively targeting cancer stem cells, reversing multidrug resistance, inhibition of the tumor metastasis and described the antineoplastic effects of metformin combined with chemotherapeutic agents in digestive system cancers (colorectal, gastric, hepatic and pancreatic cancer), reproductive system cancers (ovarian and endometrial cancer), prostate cancer, breast cancer, lung cancer, etc. Moreover, the clinical trials regarding metformin in combination of chemotherapeutic drugs were presented and the clinical obstacle or limitation related to the potential role of metformin in cancer treatment was also discussed in this review. PMID- 27118575 TI - Zika virus-associated Guillain-Barre syndrome: a warning for critical care physicians. PMID- 27118576 TI - Exploring self-use, attitude and interest to study complementary and alternative medicine (CAM) among final year undergraduate medical, pharmacy and nursing students in Sierra Leone: a comparative study. AB - BACKGROUND: CAM inclusion into the curricula of health training institutions, a strategy for its integration into the main stream healthcare delivery system is growing globally. Future healthcare professionals knowledge and perception of CAM are key determinants to its successful integration. Thus, the main objective of this study was to compare the use, attitude and interest to study CAM among final year undergraduate medical, pharmacy and nursing students at the College of Medicine and Allied Health Sciences University of Sierra Leone (COMAHS-USL). METHODS: A questionnaire based cross-sectional survey was carried out among final year medical, pharmacy and nursing students enrolled at the College of Medicine and Allied Health Sciences University of Sierra Leone (COMAHS-USL). Chi square, fisher exact two tailed test and Kruskal-wallis test were used to analyze data collected. RESULTS: Close to two-thirds (61 %) of all the three groups of final year students used one form of CAM or the other with pharmacy (72.7 %) and nursing (55.6 %) students being the highest and least users respectively. No significant difference was observed among the three groups. In general, final year students in all three cadres demonstrated a positive attitude toward CAM (33.80 +/- 3. 2) with medical students showing more positive attitude than pharmacy (p = 0.022) and nursing student (p = 0.008). No significant difference in attitude was observed between students in pharmacy and nursing programs (p = 0.354). More than three quarter (76.6 %) of the students in all the three groups indicated their interest in studying CAM, with preference for the subject to be taught as an elective module (81.6 %). CONCLUSION: An appreciable number of final year medical, pharmacy and nursing students at COMAHS-USL have used at least one CAM modality and demonstrated an overall positive attitude towards CAM. Interest to study CAM was also observed among most of them even though they preferred it to be taught as an elective module. PMID- 27118577 TI - The benefits of newborn screening for cystic fibrosis: The Canadian experience. AB - BACKGROUND: The impact of newborn screening (NBS) for cystic fibrosis (CF) on early indicators of long-term health was evaluated in the context of government sponsored healthcare and access to current therapies. METHODS: Using data from the Canadian CF Registry between 2008 and 2013, we compared the rates of respiratory infections and markers of nutritional status in those diagnosed through NBS to those who were diagnosed clinically within the same time period using Mann-Whitney and Fischer's exact test as appropriate. RESULTS: The study included 303 subjects, 201 in the NBS group and 102 in the non-NBS group. NBS patients were diagnosed earlier and had their first clinic visit at a younger age. Pancreatic insufficiency was less common in NBS patients. The incidence of Pseudomonas aeruginosa and Staphylococcus aureus were lower in NBS patients. After adjusting for age at clinic visit, gender, pancreatic status, and Pseudomonas aeruginosa infection status, mean z-scores for weight-for-age and height-for-age were higher in NBS patients, with no differences in BMI-for-age. CONCLUSIONS: NBS programs for CF lead to improved long-term health outcomes for the CF population. PMID- 27118578 TI - Correction to: The Role of Tensor Veli Platini muscle (TVP) and Levetor Veli Platini muscle (LVP) in the opening and closing of pharyngeal orifice of Eustachian tube. PMID- 27118581 TI - Association between clean intermittent catheterization and urinary tract infection in infants and toddlers with spina bifida. AB - INTRODUCTION: The primary goal of urologic management in children with spina bifida is to reduce the risk of urinary tract infection (UTI) and associated renal injury. While clean intermittent catheterization (CIC) has been the mainstay of treatment, recent studies have suggested that this approach is not without risk. The objective of this study was to examine the association between alternative bladder management strategies and UTI in infants and toddlers with spina bifida. METHODS: A retrospective cohort study was conducted on spina bifida patients, aged 0-3 years, seen in a multidisciplinary spinal defects clinic between 2008 and 2013. Inclusion criteria included: a primary diagnosis of meningocele, myelomeningocele, or lipomyelomeningocele. Patients were excluded if they had: <1 year of follow-up, urologic surgery prior to initial evaluation, or incomplete data for analysis. Bivariate analyses were performed using Chi-squared or Fisher's exact tests. Multivariate analyses were performed using logistic regression. RESULTS: A total of 107 patients meeting study criteria were identified. The majority of patients had lumbar lesions (74.8%) and ventriculoperitoneal (VP) shunts (72.9%). Initial bladder management was by CIC in 39.3% of patients and spontaneous voiding in 60.8% of patients. Median age at follow-up was 2.5 years. During the study period, 23.4% of patients switched from spontaneous voiding to CIC. Patients managed with CIC were more likely to have UTIs at final follow-up than those managed with voiding (35.7% vs. 18.5%; P = 0.045). Patients with vesicoureteral reflux (VUR) were also more likely to have UTIs (54.5% vs. 17.9%; P = 0.015). Patients who switched from spontaneous voiding to CIC over the study period were more likely to be evaluated with urodynamics (72.0% vs. 31.8%; P < 0.0001) than those managed with voiding alone. Patients who switched to CIC were also more likely to have VUR (16% vs. 0%; P = 0.09) and UTIs (24% vs. 15%; P = 0.06) than those managed with voiding alone; however, these differences were not statistically significant. CONCLUSIONS: In the present series, infants and toddlers with spina bifida who were initially managed with spontaneous voiding had a lower risk of UTI than those managed with CIC. Patients who switched to CIC after a period of initial observation with voiding did not have a significantly different risk of UTI compared with those managed with CIC alone. These findings suggest that early initiation of CIC may not be warranted in all infants with spina bifida. Further studies are needed to more clearly define optimal indications for initiation of CIC in these patients. PMID- 27118582 TI - Relation of perceptions of educational environment with mindfulness among Chinese medical students: a longitudinal study. AB - BACKGROUND: Perceived educational environment influences academic outcomes, such as academic achievement, students' behaviors, well-being, socio-emotional adjustment and explicit self-esteem. Mindfulness is a set of skills that are beneficial to physical and mental health. Recently, it has been increasingly discussed about its usefulness in education, but little research has explored whether mindfulness can predict perceptions of educational environment. The aim of this study was to explore Chinese medical students' perceptions of learning environment and their relationship with mindfulness. METHODS: Medical students at the Second Xiangya Hospital of Central South University (N=431) completed the Chinese version of Dundee Ready Educational Environment Measure (DREEM-C) and the Kentucky Inventory of Mindfulness Skills (KIMS-C). One year later, a subgroup of the cohort (N=231) completed the DREEM-C again. Independent-samples t-test, variance analysis, correlation analysis, and hierarchical multiple regression (HMR) were conducted. RESULTS: DREEM-C total and subscales scores were net positive, but with room for improvement. Perceptions differed in relation to gender, academic year, and age. KIMS-C scores correlated with DREEM-C scores. The predictive effect persisted 1 year later. CONCLUSIONS: Medical students had net positive perceptions about their learning environment. Higher mindfulness scores were associated with greater satisfaction with the environment and this association showed persistence. PMID- 27118583 TI - High-dose-rate interstitial brachytherapy as monotherapy in one fraction for the treatment of favorable stage prostate cancer: Toxicity and long-term biochemical results. AB - BACKGROUND: To evaluate acute and late genitourinary, the gastrointestinal toxicity and the long-term biochemical control after HDR monotherapy in one fraction (19Gy). PATIENTS AND METHODS: Between April 2008 and October 2010, 60 consecutive patients were treated with favorable clinically localized prostate cancer; the median follow-up was 72months (range 32-91). All patients received one implant and one fraction of HDR. Fraction dose was 19Gy. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 (CTAE v4.02) by the National Cancer Institute. RESULTS: No intraoperative or perioperative complications occurred. Acute toxicity grade 2 or more was not observed in any patients. No chronic toxicity, such as incontinence, late urinary retention, urethral narrowing, rectal bleeding, anal ulcer and/or rectourethral fistula has been observed after treatment. The overall survival and failure in tumor-free survival (TFS) according to Kaplan-Meier estimates was 90% (+/-5%) and 88% (+/-5%) respectively at 6years. The actuarial biochemical control was 66% (+/ 6%) at 6years. CONCLUSIONS: This protocol is feasible and very well tolerated with low genitourinary morbidity, no gastrointestinal toxicity but no the same level of LDR biochemical control at 6years. PMID- 27118584 TI - Trimming Surface Sugars Protects Histoplasma from Immune Attack. AB - Dectin-1 is an essential innate immune receptor that recognizes beta-glucans in fungal cell walls. Its importance is underscored by the mechanisms that fungal pathogens have evolved to avoid detection by this receptor. One such pathogen is Histoplasma capsulatum, and in a recent article in mBio, Rappleye's group presented data showing that yeasts of this organism secrete a beta-glucanase, Eng1, which acts to prune beta-glucans that are exposed on the fungal cell surface [A. L. Garfoot et al., mBio 7(2):e01388-15, 2016, http://dx.doi.org/10.1128/mBio.01388-15]. The trimming of these sugars reduces immune recognition through Dectin-1 and subsequent inflammatory responses, enhancing the pathogenesis of H. capsulatum. PMID- 27118585 TI - Molecular Dissection of Xyloglucan Recognition in a Prominent Human Gut Symbiont. AB - Polysaccharide utilization loci (PUL) within the genomes of resident human gut Bacteroidetes are central to the metabolism of the otherwise indigestible complex carbohydrates known as "dietary fiber." However, functional characterization of PUL lags significantly behind sequencing efforts, which limits physiological understanding of the human-bacterial symbiosis. In particular, the molecular basis of complex polysaccharide recognition, an essential prerequisite to hydrolysis by cell surface glycosidases and subsequent metabolism, is generally poorly understood. Here, we present the biochemical, structural, and reverse genetic characterization of two unique cell surface glycan-binding proteins (SGBPs) encoded by a xyloglucan utilization locus (XyGUL) from Bacteroides ovatus, which are integral to growth on this key dietary vegetable polysaccharide. Biochemical analysis reveals that these outer membrane-anchored proteins are in fact exquisitely specific for the highly branched xyloglucan (XyG) polysaccharide. The crystal structure of SGBP-A, a SusD homolog, with a bound XyG tetradecasaccharide reveals an extended carbohydrate-binding platform that primarily relies on recognition of the beta-glucan backbone. The unique, tetra-modular structure of SGBP-B is comprised of tandem Ig-like folds, with XyG binding mediated at the distal C-terminal domain. Despite displaying similar affinities for XyG, reverse-genetic analysis reveals that SGBP-B is only required for the efficient capture of smaller oligosaccharides, whereas the presence of SGBP-A is more critical than its carbohydrate-binding ability for growth on XyG. Together, these data demonstrate that SGBP-A and SGBP-B play complementary, specialized roles in carbohydrate capture by B. ovatus and elaborate a model of how vegetable xyloglucans are accessed by the Bacteroidetes IMPORTANCE: The Bacteroidetes are dominant bacteria in the human gut that are responsible for the digestion of the complex polysaccharides that constitute "dietary fiber." Although this symbiotic relationship has been appreciated for decades, little is currently known about how Bacteroidetes seek out and bind plant cell wall polysaccharides as a necessary first step in their metabolism. Here, we provide the first biochemical, crystallographic, and genetic insight into how two surface glycan-binding proteins from the complex Bacteroides ovatus xyloglucan utilization locus (XyGUL) enable recognition and uptake of this ubiquitous vegetable polysaccharide. Our combined analysis illuminates new fundamental aspects of complex polysaccharide recognition, cleavage, and import at the Bacteroidetes cell surface that may facilitate the development of prebiotics to target this phylum of gut bacteria. PMID- 27118586 TI - The Bee Microbiome: Impact on Bee Health and Model for Evolution and Ecology of Host-Microbe Interactions. AB - As pollinators, bees are cornerstones for terrestrial ecosystem stability and key components in agricultural productivity. All animals, including bees, are associated with a diverse community of microbes, commonly referred to as the microbiome. The bee microbiome is likely to be a crucial factor affecting host health. However, with the exception of a few pathogens, the impacts of most members of the bee microbiome on host health are poorly understood. Further, the evolutionary and ecological forces that shape and change the microbiome are unclear. Here, we discuss recent progress in our understanding of the bee microbiome, and we present challenges associated with its investigation. We conclude that global coordination of research efforts is needed to fully understand the complex and highly dynamic nature of the interplay between the bee microbiome, its host, and the environment. High-throughput sequencing technologies are ideal for exploring complex biological systems, including host microbe interactions. To maximize their value and to improve assessment of the factors affecting bee health, sequence data should be archived, curated, and analyzed in ways that promote the synthesis of different studies. To this end, the BeeBiome consortium aims to develop an online database which would provide reference sequences, archive metadata, and host analytical resources. The goal would be to support applied and fundamental research on bees and their associated microbes and to provide a collaborative framework for sharing primary data from different research programs, thus furthering our understanding of the bee microbiome and its impact on pollinator health. PMID- 27118587 TI - Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens. AB - Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori, KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori, we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs. IMPORTANCE: Many human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines. PMID- 27118588 TI - Murine Cytomegalovirus Exploits Olfaction To Enter New Hosts. AB - Viruses transmit via the environmental and social interactions of their hosts. Herpesviruses have colonized mammals since their earliest origins, suggesting that they exploit ancient, common pathways. Cytomegaloviruses (CMVs) are assumed to enter new hosts orally, but no site has been identified. We show by live imaging that murine CMV (MCMV) infects nasally rather than orally, both after experimental virus uptake and during natural transmission. Replication-deficient virions revealed the primary target as olfactory neurons. Local, nasal replication by wild-type MCMV was not extensive, but there was rapid systemic spread, associated with macrophage infection. A long-term, transmissible infection was then maintained in the salivary glands. The viral m131/m129 chemokine homolog, which influences tropism, promoted salivary gland colonization after nasal entry but was not required for entry per se The capacity of MCMV to transmit via olfaction, together with previous demonstrations of experimental olfactory infection by murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1), suggest that this is a common, conserved route of mammalian herpesvirus entry. IMPORTANCE: Cytomegaloviruses (CMVs) infect most mammals. Human CMV (HCMV) harms people with poor immune function and can damage the unborn fetus. It infects approximately 1% of live births. We lack a good vaccine. One problem is that how CMVs first enter new hosts remains unclear. Oral entry is often assumed, but the evidence is indirect, and no infection site is known. The difficulty of analyzing HCMV makes related animal viruses an important source of insights. Murine CMV (MCMV) infected not orally but nasally. Specifically, it targeted olfactory neurons. Viral transmission was also a nasal infection. Like HCMV, MCMV infected cells by binding to heparan, and olfactory surfaces display heparan to incoming viruses, whereas most other mucosal surfaces do not. These data establish a new understanding of CMV infections and a basis for infection control. PMID- 27118589 TI - Sequential Acquisition of Virulence and Fluoroquinolone Resistance Has Shaped the Evolution of Escherichia coli ST131. AB - Escherichia coli ST131 is the most frequently isolated fluoroquinolone-resistant (FQR) E. coli clone worldwide and a major cause of urinary tract and bloodstream infections. Although originally identified through its association with the CTX-M 15 extended-spectrum beta-lactamase resistance gene, global genomic epidemiology studies have failed to resolve the geographical and temporal origin of the ST131 ancestor. Here, we developed a framework for the reanalysis of publically available genomes from different countries and used this data set to reconstruct the evolutionary steps that led to the emergence of FQR ST131. Using Bayesian estimation, we show that point mutations in chromosomal genes that confer FQR coincide with the first clinical use of fluoroquinolone in 1986 and illustrate the impact of this pivotal event on the rapid population expansion of ST131 worldwide from an apparent origin in North America. Furthermore, we identify virulence factor acquisition events that predate the development of FQR, suggesting that the gain of virulence-associated genes followed by the tandem development of antibiotic resistance primed the successful global dissemination of ST131. IMPORTANCE: Escherichia coli sequence type 131 (ST131) is a recently emerged and globally disseminated multidrug-resistant clone frequently associated with human urinary tract and bloodstream infections. In this study, we have used two large publically available genomic data sets to define a number of critical steps in the evolution of this important pathogen. We show that resistance to fluoroquinolones, a class of broad-spectrum antibiotic used extensively in human medicine and veterinary practice, developed in ST131 soon after the introduction of these antibiotics in the United States, most likely in North America. We also mapped the acquisition of several fitness and virulence determinants by ST131 and demonstrate these events occurred prior to the development of fluoroquinolone resistance. Thus, ST131 has emerged by stealth, first acquiring genes associated with an increased capacity to cause human infection, and then gaining a resistance armory that has driven its massive population expansion across the globe. PMID- 27118590 TI - Biosynthesis of Conjugate Vaccines Using an O-Linked Glycosylation System. AB - Conjugate vaccines are known to be one of the most effective and safest types of vaccines against bacterial pathogens. Previously, vaccine biosynthesis has been performed by using N-linked glycosylation systems. However, the structural specificity of these systems for sugar substrates has hindered their application. Here, we report a novel protein glycosylation system (O-linked glycosylation via Neisseria meningitidis) that can transfer virtually any glycan to produce a conjugate vaccine. We successfully established this system in Shigella spp., avoiding the construction of an expression vector for polysaccharide synthesis. We further found that different protein substrates can be glycosylated using this system and that the O-linked glycosylation system can also effectively function in other Gram-negative bacteria, including some strains whose polysaccharide structure was not suitable for conjugation using the N-linked glycosylation system. The results from a series of animal experiments show that the conjugate vaccine produced by this O-linked glycosylation system offered a potentially protective antibody response. Furthermore, we elucidated and optimized the recognition motif, named MOOR, for the O-glycosyltransferase PglL. Finally, we demonstrated that the fusion of other peptides recognized by major histocompatibility complex class II around MOOR had no adverse effects on substrate glycosylation, suggesting that this optimized system will be useful for future vaccine development. Our results expand the glycoengineering toolbox and provide a simpler and more robust strategy for producing bioconjugate vaccines against a variety of pathogens. IMPORTANCE: Recently, the rapid development of synthetic biology has allowed bioconjugate vaccines with N-linked protein glycosylation to become a reality. However, the difficulty of reestablishing the exogenous polysaccharide synthetic pathway in Escherichia coli hinders their application. Here, we show that an O-linked protein glycosylation system from Neisseria meningitidis, which has a lower structure specificity for sugar substrates, could be engineered directly in attenuated pathogens to produce effective conjugate vaccines. To facilitate the further design of next-generation bioconjugate vaccines, we optimized a novel short motif consisting of 8 amino acids that is sufficient for glycosylation. Our results expand the application potential of O-linked protein glycosylation and demonstrate a simpler and more robust strategy for producing bioconjugate vaccines against different pathogens. In the future, bacterial antigenic polysaccharides could be attached to major histocompatibility complex binding peptides to improve immunological memory or attached to protein subunit vaccine candidates to provide double immune stimulation. PMID- 27118591 TI - Deletion of a Yci1 Domain Protein of Candida albicans Allows Homothallic Mating in MTL Heterozygous Cells. AB - It has been proposed that the ancestral fungus was mating competent and homothallic. However, many mating-competent fungi were initially classified as asexual because their mating capacity was hidden behind layers of regulation. For efficient in vitro mating, the essentially obligate diploid ascomycete pathogen Candida albicans has to change its mating type locus from heterozygous MTLa/alpha to homozygous MTLa/a or MTLalpha/alpha and then undergo an environmentally controlled epigenetic switch to the mating-competent opaque form. These requirements greatly reduce the potential for C. albicans mating. Deletion of the Yci1 domain gene OFR1 bypasses the need for C. albicans cells to change the mating type locus from heterozygous to homozygous prior to switching to the opaque form and mating and allows homothallic mating of MTL heterozygous strains. This bypass is carbon source dependent and does not occur when cells are grown on glucose. Transcriptional profiling of ofr1 mutant cells shows that in addition to regulating cell type and mating circuitry, Ofr1 is needed for proper regulation of histone and chitin biosynthesis gene expression. It appears that OFR1 is a key regulator in C. albicans and functions in part to maintain the cryptic mating phenotype of the pathogen. IMPORTANCE: Candida albicans is a human fungal pathogen with a recently discovered, highly cryptic mating ability. For efficient mating, it has to lose heterozygosity at its mating type locus. Then, MTL homozygous strains can undergo an epigenetic switch to an elongated yeast state, termed the opaque form, and become mating competent. This infrequent two-step process greatly reduces the potential for mating; few strains are MTL homozygous, and the opaque state is unstable at the temperature of the mammalian host. C. albicans has a complex mechanism for mating that appears designed to ensure that mating is infrequent. Here, we have characterized a new gene, opaque-formation regulator 1 (OFR1). Deleting the OFR1 gene allows MTL A: /alpha strains to mate efficiently with either mating type or even mate homothallically. It is possible that downregulating OFR1 in the host environment could allow mating in C. albicans by a route that does not involve MTL homozygosis. PMID- 27118593 TI - RTS,S Malaria Vaccine and Increased Mortality in Girls. PMID- 27118592 TI - Structures of Pathogenic Fungal FKBP12s Reveal Possible Self-Catalysis Function. AB - Invasive fungal infections remain difficult to treat and require novel targeting strategies. The 12-kDa FK506-binding protein (FKBP12) is a ubiquitously expressed peptidyl-prolyl isomerase with considerable homology between fungal pathogens and is thus a prime candidate for future targeting efforts to generate a panfungal strategy. Despite decades of research on FKBPs, their substrates and mechanisms of action remain unclear. Here we describe structural, biochemical, and in vivo analyses of FKBP12s from the pathogenic fungi Candida albicans, Candida glabrata, and Aspergillus fumigatus Strikingly, multiple apo A. fumigatus and C. albicans FKBP12 crystal structures revealed a symmetric, intermolecular interaction involving the deep insertion of an active-site loop proline into the active-site pocket of an adjacent subunit. Such interactions have not been observed in previous FKBP structures. This finding indicates the possibility that this is a self-substrate interaction unique to the A. fumigatus and C. albicans fungal proteins that contain this central proline. Structures obtained with the proline in the cis and trans states provide more data in support of self-catalysis. Moreover, cysteine cross-linking experiments captured the interacting dimer, supporting the idea that it forms in solution. Finally, genetic studies exploring the impact of mutations altering the central proline and an adjacent residue provide evidence that any dimeric state formed in vivo, where FKBP12 concentrations are low, is transient. Taken together, these findings suggest a unique mechanism of self-substrate regulation by fungal FKBP12s, lending further novel understanding of this protein for future drug-targeting efforts. IMPORTANCE: FKBP12 is a cis-trans peptidyl-prolyl isomerase that plays key roles in cellular protein homeostasis. FKBP12s also bind the immunosuppressive drug FK506 to inhibit the phosphatase calcineurin (CaN). CaN is required for virulence of A. fumigatus, C. albicans, C. glabrata, and other deadly fungal pathogens, marking FKBP12 and CaN as potential broad-spectrum drug targets. Here we describe structures of fungal FKBP12s. Multiple apo A. fumigatus and C. albicans FKBP12 structures reveal the insertion of a proline, conspicuously conserved in these proteins, into the active sites of adjacent molecules. This suggests that these proteins might serve as their own substrates. Cysteine disulfide trapping experiments provide support for this self-interaction and hence possible intermolecular catalysis by these enzymes. PMID- 27118595 TI - Production tolerance of additive manufactured polymeric objects for clinical applications. AB - OBJECTIVES: To determine the production tolerance of four commercially available additive manufacturing systems. METHODS: By reverse engineering annex A and B from the ISO_12836;2012, two geometrical figures relevant to dentistry was obtained. Object A specifies the measurement of an inlay-shaped object and B a multi-unit specimen to simulate a four-unit bridge model. The objects were divided into x, y and z measurements, object A was divided into a total of 16 parameters and object B was tested for 12 parameters. The objects were designed digitally and manufactured by professionals in four different additive manufacturing systems; each system produced 10 samples of each objects. RESULTS: For object A, three manufacturers presented an accuracy of <100MUm and one system showed an accuracy of <20MUm. For object B, all systems presented an accuracy of <100MUm, and most parameters were <40MUm. The standard deviation for most parameters were <40MUm. SIGNIFICANCE: The growing interest and use of intra-oral digitizing systems stresses the use of computer aided manufacturing of working models. The additive manufacturing techniques has the potential to help us in the digital workflow. Thus, it is important to have knowledge about production accuracy and tolerances. This study presents a method to test additive manufacturing units for accuracy and repeatability. PMID- 27118594 TI - Local Population Structure and Patterns of Western Hemisphere Dispersal for Coccidioides spp., the Fungal Cause of Valley Fever. AB - Coccidioidomycosis (or valley fever) is a fungal disease with high morbidity and mortality that affects tens of thousands of people each year. This infection is caused by two sibling species, Coccidioides immitis and C. posadasii, which are endemic to specific arid locales throughout the Western Hemisphere, particularly the desert southwest of the United States. Recent epidemiological and population genetic data suggest that the geographic range of coccidioidomycosis is expanding, as new endemic clusters have been identified in the state of Washington, well outside the established endemic range. The genetic mechanisms and epidemiological consequences of this expansion are unknown and require better understanding of the population structure and evolutionary history of these pathogens. Here we performed multiple phylogenetic inference and population genomics analyses of 68 new and 18 previously published genomes. The results provide evidence of substantial population structure in C. posadasii and demonstrate the presence of distinct geographic clades in central and southern Arizona as well as dispersed populations in Texas, Mexico, South America, and Central America. Although a smaller number of C. immitis strains were included in the analyses, some evidence of phylogeographic structure was also detected in this species, which has been historically limited to California and Baja, Mexico. Bayesian analyses indicated that C. posadasii is the more ancient of the two species and that Arizona contains the most diverse subpopulations. We propose a southern Arizona-northern Mexico origin for C. posadasii and describe a pathway for dispersal and distribution out of this region. IMPORTANCE: Coccidioidomycosis, or valley fever, is caused by the pathogenic fungi Coccidioides posadasii and C. immitis The fungal species and disease are primarily found in the American desert southwest, with spotted distribution throughout the Western Hemisphere. Initial molecular studies suggested a likely anthropogenic movement of C. posadasii from North America to South America. Here we comparatively analyze eighty-six genomes of the two Coccidioides species and establish local and species-wide population structures to not only clarify the earlier dispersal hypothesis but also provide evidence of likely ancestral populations and patterns of dispersal for the known subpopulations of C. posadasii. PMID- 27118597 TI - Improved animal welfare, the right technology and increased business. AB - Animal welfare is receiving increasing attention from the authorities, the public and NGOs. For this reason, the improvement of animal welfare and animal handling systems is of the utmost importance for the meat industry. Technological developments have led to more animal friendly systems that handle animals on the day of slaughter, and these developments will be even more important as consideration for animal welfare and sustainability is no longer just a trend but a licence to operate. Improvement of animal welfare also leads to a higher value of the carcasses due to higher product quality, less cut-off caused by fewer injuries, and reduced working load, which leads to increased business opportunities. Therefore, good animal welfare is good business, and the development and implementation of new technology is the way to obtain improved animal welfare. These subjects will be addressed using examples and cases from the pork and broiler production industry. PMID- 27118596 TI - Impact of healthcare-associated sepsis on mortality in critically ill infants. AB - Healthcare-associated sepsis (HAS) is a life-threatening complication in neonatal intensive care. Research into the impact of HAS on mortality adjusted for comorbidities is however limited. We conducted a historical cohort study to evaluate impact of HAS on mortality stratified by birth weight and risk factors for mortality in the HAS cohort. HAS was defined according to the National Institute of Child Health and Human Development criteria. Logistic regression was used to calculate adjusted odds of mortality. Of 5134 admissions, 342 infants developed HAS (6.7 %). Mortality in the total and HAS cohort was 5.6 and 10.5 %, respectively. The majority of HAS was caused by commensals (HAS-COM, 59.4 %) and 40.6 % by recognized pathogens (HAS-REC). Adjusted for comorbidities, "HAS-REC" is only a risk factor for mortality in newborns >1500 g (adjusted odds ratio [aOR] 2.3, confidence interval [CI] 1.1-4.9). Post-hoc analysis identified HAS REC as an independent risk factor for mortality in infants with gastrointestinal disease (aOR 4.8, CI 2.1-10.8). "Renal insufficiency," "focal intestinal perforation," and "necrotizing enterocolitis" are independent risk factors for mortality in the HAS cohort (aOR 13.5, CI 4.9-36.6; aOR 7.7, CI 1.5-39.2; aOR 2.1, CI 1.0-4.7, respectively). CONCLUSION: For very low birth weight infants (<=1500 g), several comorbidities overrule the impact of HAS on mortality. After adjustment for comorbidities, HAS-REC independently predicts in-hospital mortality in heavier infants and in those with gastrointestinal disease. WHAT IS KNOWN: * The relationship between healthcare-associated sepsis and mortality is influenced by the causative pathogen and is confounded by comorbidities. * Research on impact of healthcare-associated sepsis on mortality adjusted for comorbidities is limited as well as research on independent risk factors for mortality in neonates with sepsis. What is New: * We included a large list of comorbidities and stratified risk by birth weight in order to assess the true effect of healthcare-associated sepsis on mortality. * Risk for mortality was calculated for commensal flora and for recognized pathogens as causative micro organisms. PMID- 27118598 TI - Ontogenetic thermal tolerance and performance of ectotherms at variable temperatures. AB - Early experience and environmental conditions during ontogeny may affect organismal structure, physiology and fitness. Here, we assessed the effect of developmental acclimation to environmental thermal variability on walking speed in Drosophila melanogaster adults. Our results showed a shift in the performance curve to the right. Thus, upper and lower thermal limits exhibited developmental plasticity. Additionally, in constant and variable climatic scenarios, flies shifted to the right the optimum temperature but the maximum performance decreased only in flies reared on high temperatures and high thermal variability. Overall, we showed that environmental cues during ontogeny might help to construct phenotypic variation, which supports the hypothesis of ontogenetic dependence of thermal tolerances. PMID- 27118599 TI - Accumulation of isolevuglandin-modified protein in normal and fibrotic lung. AB - Protein lysine modification by gamma-ketoaldehyde isomers derived from arachidonic acid, termed isolevuglandins (IsoLGs), is emerging as a mechanistic link between pathogenic reactive oxygen species and disease progression. However, the questions of whether covalent modification of proteins by IsoLGs are subject to genetic regulation and the identity of IsoLG-modified proteins remain unclear. Herein we show that Nrf2 and Nox2 are key regulators of IsoLG modification in pulmonary tissue and report on the identity of proteins analyzed by LC-MS following immunoaffinity purification of IsoLG-modified proteins. Gene ontology analysis revealed that proteins in numerous cellular pathways are susceptible to IsoLG modification. Although cells tolerate basal levels of modification, exceeding them induces apoptosis. We found prominent modification in a murine model of radiation-induced pulmonary fibrosis and in idiopathic pulmonary fibrosis, two diseases considered to be promoted by gene-regulated oxidant stress. Based on these results we hypothesize that IsoLG modification is a hitherto unrecognized sequelae that contributes to radiation-induced pulmonary injury and IPF. PMID- 27118600 TI - Validity of Preoperative Clinical Findings to Identify Dental Pulp Status: A National Dental Practice-Based Research Network Study. AB - INTRODUCTION: Endodontic diagnostic tests are often used clinically to assess pulp status as a basis for the diagnosis and determination of whether root canal treatment (RCT) is indicated. Response to cold and pain on percussion are 2 common tests, yet their validity in identifying nonvital pulp in regular dental practice has not been reported. METHODS: We assessed the validity of cold and percussion tests to identify nonvital pulp in teeth requiring RCT in a dental practice setting performed by 46 general dentists and 16 endodontists in the National Dental Practice-Based Research Network. The influence of patient-, tooth , and dentist-related characteristics was investigated. Observed bleeding from the pulp chamber was the clinical reference. Sensitivity (SN), specificity (SP), overall test accuracy (TA), positive (PPV) and negative (NPV) predictive values, and likelihood and diagnostic odds ratios (LR+, LR-, dORs) were calculated for each single test and the combined cold and percussion tests. RESULTS: Seven hundred eight patient teeth were included. Cold test showed high validity to identify a nonvital pulp status (SN = 89%, SP = 80%, TA = 84%, PPV = 81%, NPV = 88%, LR+ = 4.35, LR- = 0.14, dOR = 31.4), whereas pain on percussion had lower validity (SN = 72%, SP = 41%, TA = 56%, PPV = 54%, NPV = 60%, LR+ = 1.22, LR- = 0.69, dOR = 1.78). Combining the 2 tests did not increase validity, whereas preoperative pain, medication intake, patient age and sex, and dentist training level affected test validity significantly. CONCLUSIONS: In regular dental practice, the cold test exhibits higher validity to discriminate between vital and nonvital pulp than the tooth percussion test. PMID- 27118601 TI - [Autochthonous cutaneous larva migrans in Chile. A case report]. PMID- 27118602 TI - Immunomodulatory effects of bone marrow versus adipose tissue-derived mesenchymal stromal cells on NK cells: implications in the transplantation setting. AB - INTRODUCTION: The ability of mesenchymal stromal cells (MSC) to suppress T-cell function has prompted their therapeutic use for graft-versus-host disease (GVHD) control. However, as MSC also modulate the activity of NK cells, which play an important role in graft-versus-leukemia (GVL) reaction, their administration could hamper this beneficial effect of allogeneic hematopoietic stem cell transplantation. MSC can be expanded from several sources, especially bone marrow and fat, but it is not well established if the cell source makes a difference in their immunoregulatory capacity. OBJECTIVE: The aim of this study was to compare the immunomodulatory effect of MSC derived from bone marrow (BM-CSM) or adipose tissue (AT-MSC) on NK cells, to determine whether the use of MSC from one or the other origin could be more favorable to preserve NK cell activity and, therefore, GVL. METHODS: Human NK cells were stimulated with IL-15 in the presence of BM-MSC or AT-MSC. The effect of both MSC populations on NK cell proliferation, cell cycle progression, and CD56 expression was analyzed by flow cytometry. Cytokine secretion was measured by ELISA, and cytotoxic activity was assessed by calcein release assays. RESULTS: Although both BM-MSC and AT-MSC induced a similar inhibition of NK cell proliferation, only BM-MSC decreased significantly NK cell cytotoxic activity and showed a trend for a higher reduction of IFN-gamma secretion. CONCLUSION: These results suggest that, in the context of GVHD inhibition, the use of AT-MSC rather than BM-MSC could further preserve NK cell activity and, thus, favor GVL. PMID- 27118603 TI - A complex-polarization-propagator protocol for magneto-chiral axial dichroism and birefringence dispersion. AB - A computational protocol for magneto-chiral dichroism and magneto-chiral birefringence dispersion is presented within the framework of damped response theory, also known as complex polarization propagator theory, at the level of time-dependent Hartree-Fock and time-dependent density functional theory. Magneto chiral dichroism and magneto-chiral birefringence spectra in the (resonant) frequency region below the first ionization threshold of R-methyloxirane and l alanine are presented and compared with the corresponding results obtained for both the electronic circular dichroism and the magnetic circular dichroism. The additional information content yielded by the magneto-chiral phenomena, as well as their potential experimental detectability for the selected species, is discussed. PMID- 27118604 TI - The use of intrarenal Doppler ultrasonography as predictor for positive outcome after renal artery revascularization. AB - Whether patients with renal artery stenosis should undergo therapeutic revascularization is controversial. In this retrospective study, we evaluated prognostic intrarenal Doppler ultrasound parameters that might have a predictive value for a beneficial response after renal revascularization. From January 2003 until December 2012, all renovascular interventions for renal artery stenosis were analyzed. The resistive index and the maximal systolic acceleration were determined by Doppler ultrasonography prior to intervention. Thirty-two patients who underwent a renal revascularization procedure were included: 13 combined positive responders and 19 combined non-responders. The combined positive responders had a significant lower resistive index than the combined non responders (0.5 vs. 0.6, P = 0.001) and a significant lower maximal systolic acceleration (1.0 vs. 3.8, P = 0.001) before revascularization. A prediction model (RI <= 0.5 and ACCmax <= 1.3 m/s2) was formulated to identify a subgroup that benefits from renal revascularization. This model has an expected sensitivity of 69% and specificity of 89% for improvement in renal function and/or blood pressure after revascularization. The non-invasive intrarenal Doppler ultrasound parameters resistive index and maximal systolic acceleration can be used as tools to predict improvement in renal function and/or blood pressure after revascularization of renal artery stenosis. The clinical value of this prediction model should be evaluated in a prospective trial. PMID- 27118605 TI - New entry point for C2 screw, in posterior C1-C2 fixation (Goel-Harm's technique) significantly reducing the possibility of vertebral artery injury. AB - OBJECTIVE: To reduce the chance of vertebral artery injury in posterior C1 lateral mass and C2 pedicle/pars screw-rod fixation (Goel-Harms technique ). METHOD: 49 patients, 30 males and 19 females, 12years - 82 years, underwent posterior C1-C2 fixation from February 2007 till June2013. A new entry point for the posterior C2 screw, 3mm below the midpoint of the C1-C2 joint which is directed medially and downwards into the C2 body , probably avoids the vertebral artery. As the screw now bypasses the pedicle/ pars , the chance of injuring the vertebral artery is probably reduced. RESULTS: No case of intra-operative vertebral artery injury. CONCLUSION: The new technique of C2 screw fixation allows rigid immobilization of the C1-C2 joint without significant risk of vertebral artery injury. PMID- 27118606 TI - Neuroimmunomodulation by allogeneic seminal vesicle fluid in CNS is sex independent. AB - OBJECTIVES: Thymus-arisen FoxP3 regulatory T cells (Tregs) are one of the most important immunoregulatory mechanisms in the central nervous system (CNS) and pregnancy. Multiple sclerosis (MS) is an inflammatory disease of CNS associated with a reduced frequency and/or function of Tregs. Previous works have shown that seminal vesicle fluid affects female immune system and causes expansion of Tregs pool in the female reproductive tissue upon mating. Accordingly, it has been demonstrated that intra-CSF administration of seminal vesicle fluid from Wistar rats can ameliorate clinical sign of a female Lewis rat model of experimental autoimmune encephalomyelitis (EAE), the animal model of MS. The results indicated an up-regulation of FoxP3 expression in the brain and spinal cord. However, there are sex-based differences in the CNS structure & composition, sex hormones influence immune system, and gender-based differences affect treatment response. Therefore, we decided to find out if anti-inflammatory effect of seminal vesicle fluid is sex-dependent or -independent. METHODS: EAE was induced in male Lewis rats using guinea pig spinal cord and complete Freund's adjuvant. Intra-CSF injection was done on day 7 after EAE induction and the animals were followed-up until on day 14 after EAE induction when sacrificed. Then, brain and spinal cord of the animals were isolated, total RNA was extracted, and expression of mRNA for IFN-gamma, IL-4, IL-17, and FoxP3 was determined using real-time PCR where beta actin was used as reference gene. RESULT: demonstrated that intra-CSF administration of seminal vesicle fluid from male Wistar rats ameliorated EAE in male Lewis rats and increased FoxP3 in the brain and spinal cord. CONCLUSION: This study suggests that seminal vesicle fluid from Wistar rats has anti inflammatory effect on Lewis rats in a sex-independent manner. In addition, seminal vesicle fluid from Lewis rats had not beneficial effect on EAE in male Lewis rats. This is consistent with Tregs increase in allogeneic mating. More research is required to find out the immunologic aspect of allogeneic versus syngeneic administration of seminal vesicle fluid. PMID- 27118607 TI - Deep-wound and organ-space infection after surgery for degenerative spine disease: an analysis from 2006 to 2012. AB - OBJECTIVE: To study the incidence and risk factors of deep-wound and organ-space surgical site infection (SSI) following surgery for degenerative spine disease. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program were obtained for the years 2006-2012. All adult patients over 40 years of age who underwent elective cervical or lumbar spine surgery for degenerative spine disease were identified. Rates of deep-wound and organ-space SSI were calculated for each procedure. A multivariate logistic regression analysis was conducted to identify independent risk factors for SSI development. RESULTS: A total of 36,440 patients were identified, with 7,627 patients (20.93%) undergoing cervical spine surgery and 28,813 patients (79.07%) undergoing lumbar spine surgery. The overall rate of SSI was 0.72% (n = 264); there were 189 deep wound infections (0.52%) and 75 organ-space infections (0.21%). The highest rates of SSI were for patients undergoing a posterolateral fusion of the lumbar spine (1.04%), followed by patients undergoing a posterior cervical decompression (1.02%); the lowest rates were for patients undergoing cervical disc replacement (0.00%). The multivariate analysis revealed that chronic steroid use (OR 3.66) and increasing operative time (OR 1.002) were the strongest independent risk factors for SSI development in the cervical spine, and renal morbidity (OR 3.93), hemato-oncological morbidity (OR 2.55), and chronic steroid use (2.04) were the strongest risk factors for lumbar SSI. Additionally, patients with a SSI had longer lengths of stay and higher mortality rates (0.76%) when compared to patients without a SSI (0.09%). CONCLUSION: Deep-wound and organ-space infections are severe complications in patients undergoing spine surgery. In this study of a multi-centre and prospectively collected database, the rate of SSI was 0.72%. Patients with renal disorders, chronic steroid use, hemato-oncological disease, and diabetes, among others, had significantly higher odds of SSI development. PMID- 27118608 TI - Vincristine-induced neurotoxicity: electrophysiological features in children. AB - OBJECTIVE: Neuropathy caused by vincristine toxicity can be diagnosed by electrophysiological examination. The purpose of this study is to demonstrate the electrophysiological features of vincristine toxicity. METHODS: Electrophysiological data from 25 children receiving vincristine treatment and 25 normal controls were evaluated retrospectively. Nerve conduction study (NCS) parameters were compared. Additionally amplitude and negative peak duration (NPD) of distal compound muscle action potentials (CMAP) were analysed by factor analysis. RESULTS: Distal CMAP amplitudes in the patient group were significantly lower and the distal CMAP NPDs were prolonged. There were no significant differences in other motor and sensory NCS parameters. CONCLUSION: Contrary to generally accepted sensorimotor involvement, motor NCS abnormalities are more pronounced in vincristine toxicity. The current study is the first time prolonged distal CMAP NPDs were detected and indicated in vincristine-related weakness, which may be a clue to understanding its mechanism, as well as differentiating from other situations. PMID- 27118609 TI - Altered bulbocavernosus reflex in patients with multiple system atrophy. AB - OBJECTIVES: Multiple system atrophy (MSA) is characterized by a combination of symptoms including autonomic dysfunction, parkinsonism, cerebellar ataxia, and cortico-spinal disorders. The disease can have either predominant parkinsonism or cerebellar features (MSA-P and MSA-C, respectively). The measurement of the bulbocavernosus reflex (BCR) and pudendal nerve somatosensory-evoked potentials (PSEPs) was originally developed to diagnose diabetic cystopathy and other neuropathologic diseases that share similar symptoms with MSA. We investigated the relationship between abnormalities of neurophysiological parameters and MSA, and estimated the potential value of BCR. METHODS: Fifty-one MSA patients (28 and 23 MSA-P and 23 MSA-C patients, respectively) and 30 healthy controls who were seen at the Department of Neurology were included in the study. A Keypoint EMG/EP system was used to test BCR and PSEPs, and the latencies and amplitudes were recorded for statistical analyses. RESULTS: The BCR was elicited in 78.4% patients with MSA (22/28 MSA-P, 18/23 MSA-C). Prolonged BCR latencies were found in patients with MSA compared with healthy controls (p < 0.001). BCR amplitudes were significantly lower in the MSA group than the control group (p < 0.001). PSEP P41 amplitudes were not significantly different between the MSA and control groups in males (p = 0.608) or females (p = 0.897). There were no significant differences in PSEP latencies among the MSA-P, MSA-C, and control groups (p = 1.0, p = 0.263, and p = 0.060, respectively). DISCUSSION: MSA patients exhibit prolonged BCR latencies and lower amplitudes, which provides a rough anatomical localization of nervous system lesions in MSA patients. PMID- 27118610 TI - Interleukin-21 expression in hippocampal astrocytes is enhanced following kainic acid-induced seizures. AB - OBJECTIVE: Interleukin-21 (IL-21) is a cytokine that is an important modulator of immune responses. However, its roles in epilepsy are not completely clear. Here, we investigated the expression and distribution of IL-21 in a kainic acid (KA) induced acute seizure mouse model. MATERIALS AND METHODS: Mice (n = 146) were randomly divided into an age-matched group, PBS injection group, and a KA injection group. The KA-injected mice were evaluated at 1, 3, and 24 h post injection. IL-21 mRNA and protein expression levels were measured using RT-PCR and western blotting. Immunohistochemistry and immunofluorescence staining were performed to further characterize the pattern and distribution of IL-21 expression. RESULTS: The IL-21 mRNA and protein expression levels in the hippocampal tissues of the KA-treated mice were significantly increased as early as 1 h compared with the age-matched mice and PBS-treated mice. After this time point, the expression was reduced, but it remained higher than the level in the PBS-treated mice (p < 0.01). Immunohistochemical staining showed that IL-21 expression was distributed throughout the hippocampus, including areas CA1 and CA3, the dentate gyrus and the hilus. Moreover, immunofluorescence further showed that in the hippocampi of the KA-treated mice, IL-21 was mainly expressed in GFAP positive astrocytes rather than in NeuN-positive neurons or CD11b-positive microglia. SIGNIFICANCE: Our data suggest that an increase in astrocyte-derived IL-21 expression in hippocampal subregions following KA-induced seizures may have potent regulatory effects on epileptogenesis. PMID- 27118611 TI - Quantitation of oxygen-induced hypercapnia in respiratory pump failure. AB - PURPOSE: To determine the likelihood that clinicians know carbon dioxide levels before administering supplemental oxygen to patients with neuromuscular disorders, to quantitate the effect of oxygen therapy on carbon dioxide retention, and to explore hypercapnia contributing to the need to intubate and use of continuous noninvasive ventilatory support to avert it. BASIC PROCEDURES: A retrospective chart review for patients with neuromuscular disorders intubated or having intubation averted by using continuous noninvasive ventilatory support with carbon dioxide known pre- and during oxygen administration. MAIN FINDINGS: For only 2 of 316 patients who were intubated did clinicians know carbon dioxide levels prior to administering oxygen. For four cases, intubation was averted by continuous noninvasive ventilatory support and mechanical insufflation exsufflation despite severe hypercapnia and acidosis. After initiating oxygen therapy, patients' carbon dioxide partial pressures increased 52.1+/-42.0mmHg in over as little as 20min. PRINCIPAL CONCLUSIONS: Clinicians should attempt to use continuous noninvasive ventilatory support and mechanical insufflation exsufflation rather than supplemental oxygen to normalize blood gases for neuromuscular ventilatory failure and should be prepared to intubate hypercapnic patients for whom oxygen is administered. PMID- 27118612 TI - Polymorphisms of the NS3 Proteins of Hepatitis C Virus Genotype 1b Are Associated with Liver Cirrhosis. AB - Polymorphisms of the hepatitis C virus (HCV) core protein and NS3 have been described to be associated with liver cirrhosis (LC) and/or hepatocellular carcinoma in patients with chronic hepatitis C genotype 1b (HCV 1b). Here, we determine whether there is an association between LC and polymorphisms of viral core protein and NS3 in patients in Hubei province, China. A total of 42 patients with chronic HCV 1b (21 patients with LC and 21 with chronic hepatitis [CH]) were enrolled, amino acid sequence of the core protein and N-terminus of NS3 were obtained by direct sequencing and compared with the prototype strain HCV-J. No significant difference of amino acid polymorphisms was observed between isolates from LC and CH patients in the core protein. However, in the N-terminus of NS3, amino acid polymorphisms at positions A1072T (Ala 1072 chronic Thr 1072 cirrhosis), I1074V (Ile 1074 chronic Val 1074 cirrhosis), and T1098N/I (Thr 1098 chronic Asn or Ile 1098 cirrhosis) correlated significantly with LC. These findings indicate that the polymorphisms of HCV at these sites may be the risk factors for the development of LC in patients with chronic HCV 1b. PMID- 27118613 TI - SOCS3 induces neurite differentiation and promotes neuronal cell survival. AB - Cytokines and growth factors play an important role in neuronal survival as well as cell death. The family of suppressors of cytokine signalling (SOCS) proteins, which includes SOCS1-7 and cytokine-induced suppressor (CIS), has been shown to act as negative regulators of cytokine-induced signalling. In this report, we highlight the role of SOCS3 in regulating neuronal differentiation and survival. We observed increased SOCS3 expression upon differentiation of PC12 cells as well as neural stem cells. SOCS3 overexpression upregulated differentiation of both neural stem cells and PC12 cells even in the absence of NGF, as evidenced by enhanced neurite outgrowth and upregulation of GAP43, marker associated with neurite outgrowth. siRNA-mediated silencing of SOCS3 confirmed the potential role of SOCS3 in neuritogenesis. We observed that, SOCS3-induced neurite differentiation was mediated via the PI3 kinase pathway. Another interesting observation was that SOCS3 overexpression promoted neuronal cell survival under H2 O2 -mediated stress indicating its fundamental role in cell survival. In conclusion, our results indicate that SOCS3 promotes differentiation and survival of neural cells and could be potentially useful in future therapy for treatment of neurodegenerative disorders. (c) 2016 IUBMB Life, 68(6):468-476, 2016. PMID- 27118614 TI - An exploratory international study into occupational therapy students' perceptions of professional identity. AB - BACKGROUND/AIM: The successful development and maintenance of professional identity is associated with professional development and retention in the health workforce. This paper explores students' perspectives on the ways pre-entry experiences and curricula content shape professional identity. METHODS: An online cross-sectional survey was sent to students enrolled in the final year of entry level programmes in five countries. Descriptive statistical analyses of data were completed. RESULTS: The results reflect the perceptions of 319 respondents from five countries. Respondents identified professional education (98%) and professional socialisation during placement (92%) as curricula components with the greatest influence on professional identity formation. Discipline-specific knowledge such as, occupation-focussed models and occupational science were ranked lower than these aspects of practice. The students' length of programme and level of entry-level programme did not impact on these results. CONCLUSION: When designing curricula educators need to be mindful that students perceive practice education and professional socialisation have the greatest affect on professional identity formation. The findings reinforce the need for curricula to provide students with a range of practice experiences, which allow the observation and application of occupation-based practices. It highlights a need for educators to provide university-based curricula activities, which better prepare students for a potential dissonance between explicit occupation-based curricula and observed practice education experiences. The study indicates the need for further research into the role curricula content, and in particular practice education, plays in the multidimensional formation of professional development within entry-level programmes. PMID- 27118615 TI - Use of three-dimensional printing to assess transport vectors in mandibular distraction osteogenesis. AB - It can be difficult to assess the transport vectors for mandibular distraction osteogenesis intraoperatively. Computed tomography (CT) and 3-dimensional digital reconstruction allow "on screen" assessment, but they have limitations, and errors can occur when the 2-dimensional preoperative plan is translated into the operation. We can simulate the operation and reconstruction with 3-dimensional printed models. This allows us to make cutting guides that indicate the position of the osteotomy, which can be extended to position the distractor accurately. The success of this technique relies on close communication with the prosthetic scientist. PMID- 27118616 TI - Comparison of ultrasound-guided and conventional arthrocentesis of the temporomandibular joint. AB - Arthrocentesis of the temporomandibular joint (TMJ) can be done either conventionally or under ultrasonographic guidance, and we have compared the effectiveness of the two techniques. Twenty patients who required arthrocentesis of the TMJ were randomly assigned to ultrasonographically guided (US-guided) and conservative arthrocentesis (n=10 in each group). The number of relocations of the first and second punctures, pain experienced during each procedure measured using a visual analogue scale (VAS), and the duration of the procedure were the main outcome variables. The pain score compared with the maximal interincisal mouth opening measured preoperatively, immediately after operation, at 1 week, and 1 and 3 months, were secondary outcome variables. No patient in either group developed a complication, and there was no significant difference between the two groups, except that US-guided arthrocentesis took significantly longer than the conventional technique (p=0.000). US-guided arthrocentesis of the TMJ was no more successful than the conventional technique, and took longer. Further studies with more patients are required to validate these findings. PMID- 27118617 TI - Fistula Rate after primary palatal repair with intravelarveloplasty: a retrospective three-year audit of six units (NorCleft) in the UK. AB - Our aim was to evaluate the rate of fistulation after one-stage palatal repair by intravelarveloplasty in the NorCleft Cleft Services (Scotland and Northern England), this being a primary outcome measure after repair of a cleft palate. We designed a retrospective, three-year clinical audit of six cleft units in the UK, and retrospectively reviewed the casenotes of babies with cleft palate born in 2006-2008 who were treated by intravelarveloplasty. We recorded type of cleft and procedure, including lateral relieving incisions, and our main outcome measure was the presence of a fistula behind the incisive foramen at 3 years of age, or a history of repair of a fistula. A total of 743 patients had cleft palates, but 69 (9%) were excluded (because they had not been operated on, or had not been reviewed by the age of 3 years, or their records were unavailable). A total of 626 patients had had a Sommerlad intravelarveloplasty repair, and 48 had had mixed procedures including Veau-Wardill-Kilner, Furlow, or two-stage repairs, and were not studied further. Eighty-seven (14%) who had had intravelarvoloplasty had a fistula behind the incisive foramen. There was no significant difference in age at time of repair between those who developed a fistula and those who did not (p=0.65). The fistula rate of 14% is comparable with that of Sommerlad. The fistula rate was higher in patients who had had lateral releasing incisions (58/275, 21%) or who had bilateral cleft palate (16/63, 25%). To our knowledge this is the largest review of the fistula rate in patients who had primary palatal repair using the intravelarveloplasty technique in the UK, and shows significant correlation between lateral releasing incisions and formation of a fistula, except in the unilateral cleft lip and palate group (p=0.12). PMID- 27118618 TI - Cost-effectiveness of Elective Endovascular Aneurysm Repair Versus Open Surgical Repair of Abdominal Aortic Aneurysms. AB - OBJECTIVE/BACKGROUND: The aim of this study was to estimate the lifetime cost effectiveness of endovascular aneurysm repair (EVAR) versus open surgical repair (OSR) in the Netherlands, based on recently published literature. METHODS: A model was developed to simulate a cohort of individuals (age 72 years, 87% men) with an abdominal aortic aneurysm (AAA) diameter of at least 5.5 cm and considered fit for both repairs. The model consisted of two sub-models that estimated the lifetime cost-effectiveness of EVAR versus OSR: (1) a decision tree for the first 30 post-operative days; and (2) a Markov model for the period thereafter (31 days-30 years). RESULTS: In the base case analysis, EVAR was slightly more effective (4.704 vs. 4.669 quality adjusted life years) and less expensive (?24,483 vs. ?25,595) than OSR. Improved effectiveness occurs because EVAR can reduce 30 day mortality risk, as well as the risk of events following the procedure, while lower costs are primarily due to a reduction in length of hospital stay. The cost-effectiveness of EVAR is highly dependent on the price of the EVAR device and the reduction in hospital stay, complications, and 30 day mortality. CONCLUSION: EVAR and OSR can be considered equally effective, while EVAR can be cost saving compared with OSR. EVAR can therefore be considered as a cost-effective solution for patients with AAAs. PMID- 27118620 TI - Impact of Renal Denervation on Patients With Obstructive Sleep Apnea and Resistant Hypertension - Insights From the SYMPLICITY HTN-3 Trial. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with activation of the sympathetic nervous system, and patients with this condition often experience elevated blood pressure (BP), increased BP variability, and nocturnal BP surges. METHODS AND RESULTS: The SYMPLICITY HTN-3 trial was a large prospective, randomized, blinded, sham-controlled trial of renal denervation for treatment of uncontrolled, apparently treatment-resistant hypertension. In a post hoc analysis, we examined the effect of renal denervation vs. sham control on office and ambulatory (including nocturnal) systolic BP in patients with and without OSA. 26% (94/364) of renal denervation subjects and 32% (54/171) of sham control subjects had OSA. Baseline office and nighttime systolic BP values were similar in both arms, including in subjects with and without OSA. Compared with sham control, renal denervation reduced the 6-month office systolic BP in subjects with (-17.0+/-22.4 vs. -6.3+/-26.1 mmHg, P=0.01) but not in subjects without OSA (-14.7+/-24.5 vs. -13.4+/-26.4 mmHg, P=0.64), P=0.07 for the interaction between treatment arm and OSA status. In those with sleep apnea, renal denervation was also associated with a reduction in maximum (-4.8+/-21.8 vs. 4.5+/-24.6 mmHg, P=0.03) and average peak (-5.6+/-20.4 vs. 3.2+/-22.4 mmHg, P=0.02) nighttime systolic BP. CONCLUSIONS: OSA subjects appeared to be responsive to renal denervation therapy. However, this hypothesis requires prospective testing. (Circ J 2016; 80: 1404-1412). PMID- 27118619 TI - Evolution of Computed Tomographic Characteristics of Spontaneous Isolated Superior Mesenteric Artery Dissection During Conservative Management. AB - BACKGROUND: Spontaneous isolated superior mesenteric artery (SMA) dissection is a rare condition, and its clinical and angiographic courses are poorly defined. We aimed to monitor the morphological characteristics of spontaneous isolated SMA dissection using computed tomography (CT) over 2 years of follow-up, including the recovery process via vascular remodeling, and identify the factors that affect vascular remodeling using univariate analysis. METHODS AND RESULTS: We retrospectively reviewed the medical records and morphological findings of 59 consecutive patients with spontaneous isolated SMA dissection between October 2007 and July 2014, which included 36 symptomatic and 23 asymptomatic patients. Surgical intervention with open laparotomy was required in 3 patients during the follow-up period; 41 patients who received conservative treatment were followed up over 2 years with regular CT. Complete remodeling was achieved in 16 of 25 symptomatic patients who were treated conservatively (64.0%). A patent false lumen and aneurysmal formation on an initial CT scan were identified as negative factors that affected remodeling in patients with spontaneous isolated SMA dissection. CONCLUSIONS: Conservative management of spontaneous isolated SMA dissection is associated with a good prognosis, both clinically and morphologically. Surgical intervention is only required in patients with severe intestinal ischemia or rapid aneurysmal enlargement. (Circ J 2016; 80: 1452 1459). PMID- 27118621 TI - Multicenter Cohort Study of Acute Myocardial Infarction in Korea - Interim Analysis of the Korea Acute Myocardial Infarction Registry-National Institutes of Health Registry. AB - BACKGROUND: The Korea Acute Myocardial Infarction Registry (KAMIR)-National Institutes of Health (NIH) registry has the aim of evaluating the clinical characteristics, management, and long-term outcomes of patients with acute myocardial infarction (AMI) in Korea. METHODS AND RESULTS: Patients hospitalized for AMI in 20 tertiary university hospitals in Korea have been enrolled since November 2011. The study is expected to complete the scheduled enrollment of approximately 13,000 patients in October 2015, and follow-up duration is up to 5 years for each patient. As of October 2015, an interim analysis of 13,623 subjects was performed to understand the baseline clinical profiles of the study population. The mean age was 64.1 years; 73.5% were male; and 48.2% were diagnosed with ST-segment elevation AMI. Hypertension is a leading cause of AMI in Korea (51.2%), followed by smoking (38.5%) and diabetes mellitus (28.6%). Percutaneous coronary intervention was performed in 87.4% and its success rate was very high (99.4%). In-hospital, 1-year, and 2-year mortality rates were 3.9%, 4.3%, and 8.6%, respectively. The rates of major adverse cardiac events at 1 and 2 years were 9.6% and 18.8%, respectively. CONCLUSIONS: This analysis demonstrated the clinical characteristics of Korean AMI patients in comparison with those of other countries. It is necessary to develop guidelines for Asian populations to further improve their prognosis. (Circ J 2016; 80: 1427-1436). PMID- 27118622 TI - Comparison of three methods for identifying the heelstrike transient during walking gait. AB - Impulsive, or high rate, loading contributes to cartilage degradation and is commonly identified via the heelstrike transient (HST) in the vertical ground reaction force (vGRF) during gait. Investigation of the HST may improve our understanding of knee osteoarthritis mechanical pathogenesis. However, the most appropriate method for objectively identifying the HST is unclear. Twenty-eight healthy subjects walked at a self-selected pace while vGRF data were captured. The efficacies of three HST identification methods (Radin, Hunt, and Modified Hunt) were evaluated using vGRF data lowpass filtered at three frequencies (raw/unfiltered, 75Hz, and 50Hz). Both the HST identification method and lowpass filter frequency influenced whether a HST was identified and whether a subject was classified as an "impulsive loader" (i.e. HST identified in 3 of 5 trials). The methods identified different phenomena in the vGRF, with the Radin and Modified Hunt methods identifying the HST 11-16ms following ground contact and the Hunt method identifying the HST 83-122ms following ground contact. Lowpass filtering the vGRF at 75Hz and implementing the Radin method was the most effective approach for identifying the HST. Future longitudinal observations are necessary to determine if specific HST criteria are indicative of knee osteoarthritis development and progression. PMID- 27118623 TI - Segmented beat modulation method for electrocardiogram estimation from noisy recordings. AB - Clinical utility of an electrocardiogram (ECG) affected by too high levels of noise such as baseline wanders, electrode motion artifacts, muscular artifacts and power-line interference may be jeopardized if not opportunely processed. Template-based techniques have been proposed for ECG estimation from noisy recordings, but usually they do not reproduce physiological ECG variability, which, however, provides clinically useful information on the patient's health. Thus, this study proposes the Segmented-Beat Modulation Method (SBMM) as a new template-based filtering procedure able to reproduce ECG variability, and assesses SBMM robustness to the aforementioned noises in comparison to a standard template method (STM). SBMM performs a unique ECG segmentation into QRS segment and TUP segment, and successively modulates/demodulates (by stretching or compressing) the former segments in order to adaptively adjust each estimated beat to its original morphology and duration. Consequently, SBMM estimates ECG with significantly lower estimation errors than STM when applied to recordings affected by various levels of the considered noises (SBMM: 176-232uV and 79 499uV; STM: 215-496uV and 93-1056uV, for QRS and TUP segments, respectively). Thus, SBMM is able to reproduce ECG variability and is more robust to noise than STM. PMID- 27118624 TI - Diffuse colonic metastases from primary pancreatic cancer. PMID- 27118625 TI - Rendezvous endoscopic access and treatment of esophagopleural fistula. PMID- 27118627 TI - Pancreatic cancer: Infiltrating macrophages support liver metastasis. PMID- 27118626 TI - Molecular cytology genotyping of primary and metastatic GI stromal tumors by using a custom two-gene targeted next-generation sequencing panel with therapeutic intent. AB - BACKGROUND AND AIMS: In an era of precision medicine, customized genotyping of GI stromal tumors by screening for driver mutations will become the standard of care. The fidelity of genotype concordance between paired cytology smears and surgical pathology specimens is unknown. In patients with either primary or metastatic sporadic disease, we sought to determine the frequency of KIT and PDGFRA pathogenic alterations within such specimens, imatinib sensitivity, and the concordance of pathogenic alterations between paired specimens. METHODS: DNA obtained from cytology smears from 36 patients, 24 of whom had paired surgical pathology specimens, underwent targeted next-generation sequencing by using a custom panel to evaluate somatic mutations within KIT (exon 2, 9, 10, 11, 13, 14, 15, 17, 18) and PDGFRA (exon 12, 14, 15, 18) genes. Patients with KIT and PDGRFA wild-type genes completed the Qiagen Human Comprehensive Cancer GeneRead DNAseq Targeted Array V2. RESULTS: Genotyping revealed KIT and PDGFRA mutations in 68% and 15% of patients. The wild-type population did not harbor mutations in BRAF, RAS family, SDHB, SETD2, or NF1. Imatinib sensitivity based on the oncogenic kinase mutation prevalence was estimated to be 68%. Mutational concordance between paired cytology and surgical pathology specimens was 96%. CONCLUSIONS: Our data have demonstrated the ability to stratify either primary or metastatic gastrointestinal stromal tumors by mutational subtype using a targeted next generation sequencing 2 gene mutation panel. We highlight the ability to use cytology specimens obtained via minimally invasive techniques as a surrogate to surgical specimens given the high mutational landscape concordance between paired specimens. PMID- 27118628 TI - Staphylococcus aureus: the current state of disease, pathophysiology and strategies for prevention. AB - Staphylococcus aureus is both a commensal organism and also an important opportunistic human pathogen, causing a variety of community and hospital associated pathologies, such as bacteremia-sepsis, endocarditis, pneumonia, osteomyelitis, arthritis and skin diseases. The resurgence of S. aureus during the last decade in many settings has been facilitated not only by bacterial antibiotic resistance mechanisms but also by the emergence of new S. aureus clonal types with increased expression of virulence factors and the capacity to neutralize the host immune response. Prevention of the spread of S. aureus infection relies on the use of contact precautions and adequate procedures for infection control that so far have not been fully effective. Prevention using a prophylactic vaccine would complement these processes, having the potential to bring additional, significant progress toward decreasing invasive disease due to S. aureus. PMID- 27118629 TI - A comparison of change point models with application to longitudinal lung function measurements in children with cystic fibrosis. AB - Cystic fibrosis (CF) is a hereditary lung disease characterized by loss of lung function over time. Lung function in CF is believed to decline at a higher rate during the adolescence period. It has been also hypothesized that there is a subgroup of individuals for whom lung disease remains relatively stable with only a slight decline over their lifetime. Using data from the University of Colorado CF Children's Registry, we investigate four change point models to model the decline of lung function in children and adolescents: (i) a two-component mixture random change point model, (ii) a two-component mixture-fixed change point model, (iii) a random change point model, and (iv) a fixed change point model. The models are investigated through posterior predictive simulation at the individual and population levels, and a simulation study examining the effects of model misspecification. The data support the mixed random change point model as the preferred model, with roughly 30% of adolescents experiencing a steady decline of 0.5 %FEV1 per year and 70% experiencing an increase in decline of 4.4 %FEV1 per year beginning on average at 14.6 years of age. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27118630 TI - On the limitations of permuted blocked randomization. PMID- 27118631 TI - Delayed unmasking and selection bias. PMID- 27118632 TI - Are the emergence of affective disturbances in neuropathic pain states contingent on supraspinal neuroinflammation? AB - Neuro-immune interactions contribute to the pathogenesis of neuropathic pain due to peripheral nerve injury. A large body of preclinical evidence supports the idea that the immune system acts to modulate the sensory symptoms of neuropathy at both peripheral and central nervous system sites. The potential involvement of neuro-immune interactions in the highly debilitating affective disturbances of neuropathic pain, such as depression, anhedonia, impaired cognition and reduced motivation has received little attention. This is surprising given the widely accepted view that sickness behaviour, depression, cognitive impairment and other neuropsychiatric conditions can arise from inflammatory mechanisms. Moreover, there is a set of well-described immune-to-brain transmission mechanisms that explain how peripheral inflammation can lead to supraspinal neuroinflammation. In the last 5years increasing evidence has emerged that peripheral nerve injury induces supraspinal changes in cytokine or chemokine expression and alters glial cell activity. In this systematic review, based on strong preclinical evidence, we advance the argument that the emergence of affective disturbances in neuropathic pain states are contingent on pro-inflammatory mediators in the interconnected hippocampal-medial prefrontal circuitry that subserve affective behaviours. We explore how dysregulation of inflammatory mediators in these networks may result in affective disturbances through a wide variety of neuromodulatory mechanisms. There are also promising results from clinical trials showing that anti-inflammatory agents have efficacy in the treatment of a variety of neuropsychiatric conditions including depression and appear suited to sub groups of patients with elevated pro-inflammatory profiles. Thus, although further research is required, aggressively targeting supraspinal pro-inflammatory mediators at critical time-points in appropriate clinical populations is likely to be a novel avenue to treat debilitating affective disturbances in neuropathic conditions. PMID- 27118633 TI - Neurological assessment. AB - Neurological system assessment is an important skill for the orthopaedic nurse because the nervous system has such an overlap with the musculoskeletal system. Nurses whose scope of practice includes such advanced evaluation, e.g. nurse practitioners, may conduct the examination described here but the information will also be useful for nurses caring for patients who have abnormal neurological assessment findings. Within the context of orthopaedic physical assessment, possible neurological findings are evaluated as they complement the patient's history and the examiner's findings. Specific neurological assessment is integral to diagnosis of some orthopaedic conditions such as carpal tunnel syndrome. In other situations such as crushing injury to the extremities, there is high risk of associated neurological or neurovascular injury. These patients need anticipatory examination and monitoring to prevent complications. This article describes a basic neurological assessment; emphasis is on sensory and motor findings that may overlap with an orthopaedic presentation. The orthopaedic nurse may incorporate all the testing covered here or choose those parts that further elucidate specific diagnostic questions suggested by the patient's history, general evaluation and focused musculoskeletal examination. Abnormal findings help to suggest further testing, consultation with colleagues or referral to a specialist. PMID- 27118634 TI - Waiting for Godot: Predictive factors for adjuvant treatment of patients with luminal breast cancer. PMID- 27118635 TI - Erratum: 'Atlanto-axial infection after acupuncture.'. PMID- 27118636 TI - Self-assembly of virus-like particles of rabbit hemorrhagic disease virus capsid protein expressed in Escherichia coli and their immunogenicity in rabbits. AB - In this study, virus-like particles (VLPs) derived from rabbit hemorrhagic disease virus (RHDV) were evaluated for the development of a vaccine against RHDV infection. The VP60 gene was cloned and inserted into a pSMK expression vector containing a small ubiquitin-like modifier (SUMO) tag that can promote the soluble expression of heterologous proteins in Escherichia coli cells. After expression and purification of His-SUMO-VP60 and cleavage of the SUMO tag, we found that the RHDV VP60 protein had self-assembled into VLPs with a similar shape and smaller size compared with authentic RHDV capsid. Next, the antigenicity and immunogenicity of the VLPs were examined. The results showed that RHDV-specific responses were clearly induced in rabbits and that all rabbits in the VLP group survived while those in the negative control group died within 72 h post-infection. These results suggest that VLP-based RHDV could be a promising RHDV vaccine candidate. PMID- 27118637 TI - Molecular-Counting-Free and Electrochemiluminescent Single-Molecule Immunoassay with Dual-Stabilizers-Capped CdSe Nanocrystals as Labels. AB - Biorelated single-molecule detection (SMD) has been achieved typically by imaging the redox fluorescent labels and then determining each label one by one. Herein, we demonstrated that the capping agents (i.e., mercaptopropionic acid and sodium hexametaphosphate) can facilitate the electrochemical involved hole (or electron) injecting process and improve the stability of the dual-stabilizers-capped CdSe nanocrystals (NCs), so that the CdSe NCs could be electrochemically and repeatedly inspired to excited states by giving off electrochemiluminescence (ECL) in a cyclic pattern. With the CdSe NCs as ECL label and carcinoembryonic antigen (CEA) as target molecule, a convenient single-molecule immunoassay was proposed by simply detecting the ECL intensity of the dual-stabilizers-capped CdSe NCs in a sandwich-typed immune complex. The limit of detection is 0.10 fg/mL at S/N = 3, which corresponds to about 6-8 CEA molecules in 20 MUL of serum sample. Importantly, the ECL spectra of both CdSe NCs and its conjugate with probe antigen in the immune complex were almost identical to the photoluminescence spectrum of bare CdSe NCs, indicating that all emissions were originated from the same excited species. The molecular-counting-free and ECL based SMD might be a promising alternative to the fluorescent SMD. PMID- 27118639 TI - Quantitative analysis of trace palladium contamination in solution using electrochemical X-ray fluorescence (EC-XRF). AB - The application of electrochemical X-ray fluorescence (EC-XRF), for the detection of palladium (Pd) contamination in a range of solutions containing electrochemically active compounds, present in excess and relevant to the pharmaceutical and food industries, is reported. In EC-XRF, EC is used to electrochemically pre-concentrate metal on an electrode under forced convection conditions, whilst XRF is employed to spectroscopically quantify the amount of metal deposited, which quantitatively correlates with the original metal concentration in solution. Boron doped diamond is used as the electrode due to its very wide cathodic window and the fact that B and C are non-interfering elements for XRF analysis. The effect of several parameters on the Pd XRF signal intensity are explored including: deposition potential (Edep), deposition time (tdep) and Pd(2+) concentration, [Pd(2+)]. Under high deposition potentials (Edep = -1.5 V), the Pd XRF peak intensity varies linearly with both tdep and [Pd(2+)]. Quantification of [Pd(2+)] is demonstrated in the presence of excess acetaminophen (ACM), l-ascorbic acid, caffeine and riboflavin. We show the same Pd XRF signal intensity (for [Pd(2+)] = 1.1 MUM and tdep = 325 s) is observed, i.e. same amount of Pd is deposited on the electrode surface, irrespective of whether these redox active molecules are present or absent. For tdep = 900 s we report a limit of detection for [Pd(2+)] of 3.6 ppb (34 nM). Even lower LODs are possible by increasing tdep or by optimising the X-ray source specifically for Pd. The work presented for Pd detection in the presence of ACM, achieves the required detection sensitivity stipulated by international pharmacopeia guidelines. PMID- 27118638 TI - Transcriptome signature for dampened Th2 dominance in acellular pertussis vaccine induced CD4(+) T cell responses through TLR4 ligation. AB - Current acellular pertussis (aP) vaccines promote a T helper 2 (Th2)-dominated response, while Th1/Th17 cells are protective. As our previous study showed, after adding a non-toxic TLR4 ligand, LpxL1, to the aP vaccine in mice, the Bordetella pertussis-specific Th2 response is decreased and Th1/Th17 responses are increased as measured at the cytokine protein level. However, how this shift in Th response by LpxL1 addition is regulated at the gene expression level remains unclear. Transcriptomics analysis was performed on purified CD4(+) T cells of control and vaccinated mice after in vitro restimulation with aP vaccine antigens. Multiple key factors in Th differentiation, including transcription factors, cytokines, and receptors, were identified within the differentially expressed genes. Upregulation of Th2- and downregulation of follicular helper T cell-associated genes were found in the CD4(+) T cells of both aP- and aP+LpxL1 vaccinated mice. Genes exclusively upregulated in CD4(+) T cells of aP+LpxL1 vaccinated mice included Th1 and Th17 signature cytokine genes Ifng and Il17a respectively. Overall, our study indicates that after addition of LpxL1 to the aP vaccine the Th2 component is not downregulated at the gene expression level. Rather an increase in expression of Th1- and Th17-associated genes caused the shift in Th subset outcome. PMID- 27118640 TI - A new type of power energy for accelerating chemical reactions: the nature of a microwave-driving force for accelerating chemical reactions. AB - The use of microwave (MW) irradiation to increase the rate of chemical reactions has attracted much attention recently in nearly all fields of chemistry due to substantial enhancements in reaction rates. However, the intrinsic nature of the effects of MW irradiation on chemical reactions remains unclear. Herein, the highly effective conversion of NO and decomposition of H2S via MW catalysis were investigated. The temperature was decreased by several hundred degrees centigrade. Moreover, the apparent activation energy (Ea') decreased substantially under MW irradiation. Importantly, for the first time, a model of the interactions between microwave electromagnetic waves and molecules is proposed to elucidate the intrinsic reason for the reduction in the Ea' under MW irradiation, and a formula for the quantitative estimation of the decrease in the Ea' was determined. MW irradiation energy was partially transformed to reduce the Ea', and MW irradiation is a new type of power energy for speeding up chemical reactions. The effect of MW irradiation on chemical reactions was determined. Our findings challenge both the classical view of MW irradiation as only a heating method and the controversial MW non-thermal effect and open a promising avenue for the development of novel MW catalytic reaction technology. PMID- 27118641 TI - Remapping Attention Pointers: Linking Physiology and Behavior. AB - Our eyes rapidly scan visual scenes, displacing the projection on the retina with every move. Yet these frequent retinal image shifts do not appear to hamper vision. Two recent physiological studies shed new light on the role of attention in visual processing across saccadic eye movements. PMID- 27118642 TI - Navigating the Affordance Landscape: Feedback Control as a Process Model of Behavior and Cognition. AB - We discuss how cybernetic principles of feedback control, used to explain sensorimotor behavior, can be extended to provide a foundation for understanding cognition. In particular, we describe behavior as parallel processes of competition and selection among potential action opportunities ('affordances') expressed at multiple levels of abstraction. Adaptive selection among currently available affordances is biased not only by predictions of their immediate outcomes and payoffs but also by predictions of what new affordances they will make available. This allows animals to purposively create new affordances that they can later exploit to achieve high-level goals, resulting in intentional action that links across multiple levels of control. Finally, we discuss how such a 'hierarchical affordance competition' process can be mapped to brain structure. PMID- 27118643 TI - [Nicotine Induced Lung Cancer Cells Epithelial-mesenchymal Transition ?and Promote Its Vitro Invasion Potential]. AB - BACKGROUND: Our previous study found that nicotine could induce lung cancer cell epithelial-mesenchymal transition (EMT). The aim of this study is to explore the relationship between nicotine-induced EMT and lung cancer invasion and metastasis. METHODS: Real-time PCR and Western blot were used to detect the expression changes of EMT-related markers, E-cadherin and Vimentin, in A549 lung cancer cells treated with nicotine; The transposition of beta-catenin protein expression was determined by immunofluorescence; Scratch test and Transwell invasion assay were used to detect the effects of nicotine on lung cancer cell migration and invasion. RESULTS: Nicotine can significantly down-regulate the expressional level of E-cadherin mRNA and protein of A549 cells in a manner of dose and time-dependent (P<0.01, P<0.01); Nicotine can significantly up-regulate the expressional level of Vimentin mRNA and protein of A549 cells in a manner of dose and time-dependent (P<0.01, P<0.01); Immunofluorescence results showed that beta-catenin protein was significantly transfered to nucleus; Scratch test and Transwell assay showed that Nicotine could remarkably increase the migration and invasion potential of lung cancer cells (P<0.01, P<0.01). CONCLUSIONS: Nicotine can induce cancer cells EMT, and promote the invasion and metastasis ability of lung cancer cells. PMID- 27118644 TI - [LRRC3B is Downregulated in Non-small Cell Lung Cancer and Connected with Cell Proliferation and Invasion]. AB - BACKGROUND: LRRC3B expression is downregulated in many kinds of malignant tumors and it is regarded as tumor inhibition protein. However, the expression pattern and biological effect are still unclear in non-small cell lung cancer (NSCLC). Study of human cancer microarray showed LRRC3B was downregulated in breast cancer and colorectal cancer, which declares that LRRC3B takes part in tumor formation. This study is to investigate the expression of LRRC3B in lung cancer cell lines and the influence of LRRC3B during cell proliferation, invasion and cell cycle. METHODS: The expression of LRRC3B was detected through Western blot and Realtime RT-PCR. MTT assay, colony formation assay and matrigel invasion assay were performed to explore the effect of LRRC3B on cell proliferation, invasion and cell cycle. LRRC3B siRAN was transfected in lung cancer cell line H3255, and then the effect of LRRC3B on cell proliferation, invasion and cell cycle was analyzed. RESULTS: During 4 of 9 lung cancer cell lines, the expression of LRRC3B is downregulated compared with normal epithelial cells. Cell proliferation and invasion were inhibited in A549 and H460 after LRRC3B transfected. LRRC3B suppressed the progress of cell cycle and downregulated the expression of cyclin D1 and MMP9. The activity of proliferation and invasion was promoted after LRRC3B was knocked out in H3255. CONCLUSIONS: LRRC3B expression downreguated in lung cancer cell lines and LRRC3B could inhibit lung cancer cell proliferation, invasion and cell cycle progress. LRRC3B could be a new target for lung cancer therapy.?. PMID- 27118645 TI - [First-line Chemotherapy for Extensive-disease Small Cell Lung Cancer: ?A Network Meta-analysis]. AB - BACKGROUND: Regimens that combine irinotecan or etoposide with cisplatin or carboplatin have been recommended as first-line regimen for extensive-disease small cell lung cancer (ED-SCLC). In our network meta-analysis, we synthesized the direct and indirect lines of evidence to rank the short-term efficacies of these recommended chemotherapy regimens. METHODS: We searched databases, including EMBASE, PubMed, CENTRAL and clinicaltrial.gov, for relevant randomized controlled trials (RCTs) that compared the efficacies of these treatments. A risk of bias tool was used to evaluate the quality of the included studies, whereas Stata 13.1 was used for statistical synthesis. RESULTS: Our study included 10 RCTs that involved 2,378 patients. Compared with that of the regimen that combined etoposide and carboplatin, the complete remission rate was significantly higher in the group treated with irinotecan combined with carboplatin. The efficacy of the regimen that combined irinotecan with carboplatin was significantly superior over that of the combination of etoposide and cisplatin. CONCLUSIONS: Our data presented here suggest that the effect of Irinotecan combination with Carboplatin is remarkably superior. PMID- 27118646 TI - [Analysis of the Role of PET/CT SUVmax in Prognosis and Its Correlation with ?Clinicopathological Characteristics in Resectable Lung Squamous Cell Carcinoma]. AB - BACKGROUND: Lung cancer is the leading cause of cancer death in men and women in the world, more than one-half of cases are diagnosed at a advanced stage, and the overall 5-year survival rate for lung cancer is 18%. Lung cancer is divided into non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Approximately 80%-85% of cases are NSCLC which includes three main types: adenocarcinoma (40%), squamous cell carcinoma (SCC) (20%-30%), and large cell carcinoma (10%). Although therapies that target driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking related SCC. We need pay more attention to the diagnosis and treatment of SCC. 18F-FDG positron emission tomography (PET)/computed tomography (CT) has emerged as an accurate staging modality in lung cancer diagnosis. The aim of this study is to investigate the role of maximum standardized uptake value (SUVmax) on PET CT in prognosis and its correlation with clinicopathological characteristics in resectable SCC. METHODS: One hundred and eighty-two resectable SCC patients who underwent PET/CT imaging between May 2005 and October 2014 were enrolled into this retrospectively study. All the enrolled patients had underwent pulmonary resection with mediastinal lymph node dissection without preoperative chemotherapy or radiotherapy. Survival outcomes were analyzed using the Kaplan Meier method and multivariate Cox proportional hazards model. Correlation between SUVmax and clinicopathological factors was analysed using Pearson correlation analysis and Spearman rank correlation analysis. RESULTS: The patients were divided into two groups on the basis of SUVmax 13.0 as cutoff value, and patients with SUVmax more than 13.0 had shorter median overall survival than patients less than 13.0 in univariate analysis (56 months vs 87 months; P=0.022). There was remarkable correlation between SUVmax and gender, tumor size, tumor-node metastasis (TNM) stage, neutrophil, NLR, hemoglobin (P<0.05). Multivariate Cox analysis demonstrated that SUVmax (HR=1.714, 95%CI: 1.021-2.876, P=0.042), TNM stage (HR=1.677, 95%CI: 1.231-2.284, P=0.001) were independent predictors for survival. Furthermore, univariate survival analysis showed significant difference by SUVmax in patients of stage I (P=0.045). CONCLUSIONS: SUVmax may be of importance prognostic factor independent of TNM stage, which was considerable for risk stratification in patients with TNM stage. Besides, there was correlation between SUVmax of primary tumor and clinicopathological characteristics.?. PMID- 27118647 TI - [Clinical Analysis of Icotinib on Beneficiary of ?Advanced Non-small Cell Lung Cancer with EGFR Common Mutation]. AB - BACKGROUND: Targeted therapy has become an indispensable therapy method in advanced non-small cell lung cancer (NSCLC) treatment. Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) can significantly prolong the survival of patients harboring EGFR gene mutation. Icotinb is China's first EGFR TKI with independent intellectual property rights. The aim of this study is to investigate the clinical characteristics about the beneficiary of advanced NSCLC patients with EGFR Common mutation who were treated with Icotinib. Retrospectively collect the data about beneficiary [progression-free survival (PFS)>=6 months] and analysis of the related risk factors for prognosis. METHODS: From September 1, 2011 to September 30, 2015, 231 cases of advanced NSCLC beneficiary with EGFR common mutation were enrolled for treatment with icotinib in Zhejiang Cancer Hospital. RESULTS: The one year benefit rate was 67.9% in the group treated with Icotinib as first line, and in the groupas second line or above was 53.6%, which is statisticallysignificant. The two years benefit rate was 18.7% and 9.3%, respectively. The median PFS of first line group and the second line or above was 16.7 and 12.4 months, respectively. The presence of brain metastasis (P=0.010), Prior chemotherapy (P=0.001), Eastern Cooperative Oncology Group (ECOG) score (P=0.001) were the main factors influencing the prognosis. The most common adverse were skin rashes (51 cases, 22.1%) and diarrhea (27 cases, 11.7%). CONCLUSIONS: Icotinib offers long-term clinical benefit and good tolerance for advanced NSCLC harboring EGFR gene mutation. Its advantage groups in addition to the patients with brain metastases and better ECOG score, the curative effect of patients with the first-line treatment is superior to second or further line. ?. PMID- 27118648 TI - [Macrophage Inhibitory Cytokine-1 (MIC-1) as A Biomarker for Diagnosis ?and Prognosis of Stage I-II Non-small Cell Lung Cancer]. AB - BACKGROUND: Increased macrophage inhibitory cytokine-1 (MIC-1), member of transforming growth factor-beta (TGF-beta) superfamily, was found in patients serum with epithelial tumors. Therefore, our aim was to delineate the diagnostic and prognostic value of serum MIC-1 in patients with stage I-II non-small cell lung cancer (NSCLC). METHODS: A total of 152 consecutive patients with stage I-II NSCLC were prospectively enrolled and underwent follow up after total resection of tumor. Serum MIC-1 level was detected in lung cancer patients by ELISA, 48 benign pulmonary disease patients and 105 healthy controls, and was correlated with clinical features and prognosis of patients. RESULTS: The level of MIC-1 of NSCLC patients was significantly higher than that of controls (P<0.001) and benign pulmonary disease patients (P<0.001). A threshold of 1,000 pg/mL could be used to diagnose early-stage NSCLC with 70.4% sensitivity and 99.0% specificity. The level of MIC-1 was associated with elder age (P=0.001), female (P=0.03) and T2 (P=0.022). A threshold of 1,465 pg/mL could identify patients with early poor outcome with 72.2% sensitivity and 66.1% specificity. The overall 3-year survival rate in patients with high level of MIC-1 (>=1,465 pg/mL) was significantly lower than that of patients with low MIC-1 level (77.6% vs 94.8%). Multivariable Cox regression revealed that a high level of MIC-1 was an independent risk factor for compromised overall survival (HR=3.37, 95%CI: 1.09-10.42, P=0.035). CONCLUSIONS: High level of serum MIC-1 could be served as a potential biomarker for diagnosis and poorer outcome in patients with early-stage NSCLC.?. PMID- 27118649 TI - [Clinical Study of Surgical Treatment of Non-small Cell Lung Cancer ?10 mm or Less in Diameter Under Video-assisted Thoracoscopy]. AB - BACKGROUND: The reasonable operational manner of non-small cell lung cancer (NSCLC) in early stage is in dispute. This clinical study is to investigate the operational manner of NSCLC 10 mm or less in diameter. METHODS: The clinical datas of 46 cases with NSCLC 10 mm or less in diameter were retrospectively analyzed in our hospital from July 2013 to March 2016. Thin-section computed tomography (CT) was done on all cases with 46 pulmonary nodules (5 solid nodules, 23 mGGOs and 18 pGGOs). Lobectomy, wedge resection and segmentectomy with lymph node dissection may be performed in patients according to age or heart and lung function. CT-guided Hook-wire precise localization was done on 7 cases. RESULTS: Lobectomy and systematic lymph node dissection under video-assisted thoracic surgery (VATS) were performed in patients with 23 pulmonary nodules (15 mGGOs, 4 pGGOs and 4 solid nodules ), among wich, only one patient with N2 lymph node matastasis was found. Wedge resection and selective lymph node dissection under VATS were done in patients with 5 pulmonary nodules (2 mGGOs and 3 pGGOs), and segmentectomy and selective lymph node dissection under VATS were done in patients with 4 pulmonary nodules (2 mGGOs and 2 pGGOs), among wich, no patient with lymph node matastasis was found. CT-guided Hook-wire precise localization was done successfully on 7 cases. CONCLUSIONS: Usually NSCLC with pGGO and mGGO nodules 10 mm or less in diameter has no lymph node metastasis, therefore, systematic lymph node dissection may be not necessary. Selective lymph node dissection or systematic lymph node dissection should be performed in patients with solid nodules 10 mm or less in diameter. Wedge resection and segmentectomy may be performed in patients with advanced age or lower heart and lung function. The preoperative CT-guided Hook-wire localization for pulmonary nodules particularly for GGOs is an effective and safe technique to assist VATS resection of the GGOs. PMID- 27118650 TI - [Complete Single-Utility-Port Thoracoscopic Resection of Lung Cancer ?with Single Rib Metastasis]. AB - BACKGROUND: Complete thoracoscopic surgery has advanced, and its indication has also been extended to complex procedures. The aim of this study is to investigate the feasibility of complete single-utility-port thoracoscopic lobectomy with rib resection. METHODS: A patient was diagnosed with lung cancer and single-rib metastasis. The patient received lobectomy and segment costectomy through complete single-utility-port thoracoscopic surgery. The literature was also reviewed. RESULTS: The tumor was staged at T1N1M1. The patient made an uneventful recovery and was dismissed on day 4 after surgery. At the last follow-up, the patient was alive and well, with no evidence of the disease at 18 months postoperatively. CONCLUSIONS: Highly selected cases of lung cancer with single rib metastasis are appropriate candidates for complete single-utility-port thoracoscopic resection. PMID- 27118651 TI - [Whole Brain Irradiation and Hypo-fractionation Radiotherapy for the Metastases in Non-small Cell Lung Cancer]. AB - Up to 40% non-small cell lung cancer patients developed brain metastasis during progression. Multiple brain metastases are common in non-small cell lung cancer. The prognosis of brain metastasis is poor with median survival of less than 1 year. Radio therapy for brain metastases has gradually developed from whole brain radiotherapy (WBRT) to various radiation strategies. WBRT, surgery+WBRT, stereotactic radiotherapy+WBRT or WBRT with simultaneous integrated boost (SIB), etc. have better overall survival than those untreated patients. The damage of the cognitive function from WBRT has been realized recently, however, options of radiation strategies for long expected survival patients remain controversial. This paper will discuss different WBRT strategies and treatment side effects of non-small cell lung cancer with brain metastases. PMID- 27118652 TI - [Current Research of the Roles of IL-35 in Tumor Progression]. AB - Interleukin(IL)-35 is a new member of the interleukin-12 superfamily. Since its first report in 2007, IL-35 rapidly became a research highlight in the field of immunology. Like other IL-12 superfamily members, IL-35 was a heterodimer which was composed of an alpha chain P35 and a beta chain Epstein-Barr virus induced gene 3 (EBI3). Recent research work revealed two distinct roles of IL-35. Firstly, IL-35 is highly expressed in some kinds of inflammatory diseases and autoimmune diseases and plays import roles in the pathogenesis. Secondly, IL-35 is positively expressed in some cancers and plays some roles in the process of tumor progression. Here we demonstrate the structure and the signalling of IL-35. We reviewed the the roles of IL-35 in promoting tumor progression. PMID- 27118653 TI - [Advances on Driver Mutations of Small Cell Lung Cancer]. AB - Small cell lung cancer (SCLC) is an aggressive tumor and prognosis remains dismal. Screening for the targetable driver mutations of this malignant tumor contributes to improve the therapeutic approaches and outcome. This review will report the advances on some latest driver mutations. PMID- 27118655 TI - Author's reply to Luke. PMID- 27118654 TI - Optically active red-emitting Cu nanoclusters originating from complexation and redox reaction between copper(ii) and d/l-penicillamine. AB - Despite a significant surge in the number of investigations into both optically active Au and Ag nanostructures, there is currently only limited knowledge about optically active Cu nanoclusters (CuNCs) and their potential applications. Here, we have succeeded in preparing a pair of optically active red-emitting CuNCs on the basis of complexation and redox reaction between copper(ii) and penicillamine (Pen) enantiomers, in which Pen serves as both a reducing agent and a stabilizing ligand. Significantly, the CuNCs feature unique aggregation induced emission (AIE) characteristics and therefore can serve as pH stimuli-responsive functional materials. Impressively, the ligand chirality plays a dramatic role for the creation of brightly emissive CuNCs, attributed to the conformation of racemic Pen being unfavorable for the electrostatic interaction, and thus suppressing the formation of cluster aggregates. In addition, the clusters display potential toward cytoplasmic staining and labelling due to the high photoluminescence (PL) quantum yields (QYs) and remarkable cellular uptake, in spite that no chirality dependent effects in autophagy and subcellular localization are observed in the application of chiral cluster enantiomer-based cell imaging. PMID- 27118656 TI - Macrophages and regeneration: Lessons from the heart. AB - One of the most ambitious goals in modern cardiology is to regenerate the injured myocardium. The human myocardium has poor regenerative power. Thus, significant myocardial injury results in irreversible damage, scar formation, remodeling, and dysfunction. The search for therapies that will improve myocardial regeneration needs a better understanding of the mechanisms of repair and regeneration. While the role of macrophages in inflammation, scar formation, and fibrosis are well defined, their role in myocardial regeneration is less clear. Recent reports have suggested that cardiac macrophages regulate myocardial regeneration in neonatal mice. The present review aims to describe the latest discoveries about the possible role of macrophages in myocardial regeneration. We discuss the promises and difficulties to translate the latest findings into new therapies. PMID- 27118657 TI - The Gas-Phase Photophysics of Eosin Y and its Maleimide Conjugate. AB - The use of the xanthene family of dyes as fluorescent probes in a wide range of applications has provided impetus for the studying of their photophysical properties. In particular, recent advances in gas-phase techniques such as FRET that utilize such chromophores have placed a greater importance on the characterization of these properties in the gas phase. Additionally, the use of synthetic linker chains to graft the chromophores in a site-specific manner to their target system is ubiquitous. There is, however, often limited information on how the addition of such a linker chain may affect the photophysical properties of the chromophores, which is of fundamental importance for interpretation of experimental data reliant on grafted chromophores. Here, we present data on the optical spectroscopy of different protonation states of Eosin Y, a fluorescein derivative. We compare the photophysics of Eosin Y to its maleimide conjugate, and to the thioether product of the reaction of this conjugate with cysteamine. Comparison of the mass spectra following laser irradiation shows that very different relaxation takes place upon addition of the maleimide moiety but that the photophysics of the bare chromophore are restored upon addition of cysteamine. This radical change in the photophysics is interpreted in terms of charge-transfer states, whose energy relative to the S1 < S0 transition of the chromophore is dependent on the conjugation of the maleimide moiety. We also show that the shape of the absorption band is unchanged in the gas-phase as compared to the solution-phase, showing a maximum with a shoulder toward the blue, and examination of isotope distributions of the isolated ions show that this shoulder cannot be due to the presence of dimers. Consideration of the fluorescence emission spectrum allows a tentative assignment of the shoulder to be due to a vibrational progression with a high Franck-Condon factor. PMID- 27118658 TI - Patient responses to inhaler advice given by community pharmacies: The importance of meaningfulness. AB - BACKGROUND: The value of counseling in community pharmacy depends on its ability to help patients improve their use of medicine and thereby health status, by their adherence to recommendations. Studies showing how patients respond to daily pharmacy counseling are, however, scarce. The aim of this study was therefore to investigate how patients respond to medical advice given by pharmacy staff. METHODS: A heterogeneous sample of patients who received the 'Inhaler Technique Assessment Service' (ITAS) in Denmark were interviewed, using a semi-structured schedule. Meaning condensation and theoretical analysis were conducted. RESULTS: Twenty-two patients who had received the ITAS were included in the analysis. Participants found recommendations about optimal inhalation technique meaningful and accepted these without questioning. This contrasted how they accepted advice toward their medicines, in general. Participants experienced various difficulties when trying to adhere with ITAS recommendations at home. Participants who used inhalers for a long time did not feel an improvement in disease symptoms due to having improved their inhalation technique; however, they still continued to inhale the way proposed by pharmacy staff. CONCLUSIONS: ITAS recommendations seemed important to adhere with for patients despite experiencing difficulties when doing so and secondly not feeling an immediate improvement of health. Reasons for this appear to be connected with the concept of meaningfulness. Hence, this aspect should be investigated further, as this could help staff providing adequate counseling to patients. Further, pharmacy staff should focus more on supporting patients implementing their health advice at home. PMID- 27118659 TI - Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition. AB - Mutations in TP53 gene play a pivotal role in tumorigenesis and cancer development. Here, we report that gain-of-function mutant p53 proteins inhibit the autophagic pathway favoring antiapoptotic effects as well as proliferation of pancreas and breast cancer cells. We found that mutant p53 significantly counteracts the formation of autophagic vesicles and their fusion with lysosomes throughout the repression of some key autophagy-related proteins and enzymes as BECN1 (and P-BECN1), DRAM1, ATG12, SESN1/2 and P-AMPK with the concomitant stimulation of mTOR signaling. As a paradigm of this mechanism, we show that atg12 gene repression was mediated by the recruitment of the p50 NF-kappaB/mutant p53 protein complex onto the atg12 promoter. Either mutant p53 or p50 NF-kappaB depletion downregulates atg12 gene expression. We further correlated the low expression levels of autophagic genes (atg12, becn1, sesn1, and dram1) with a reduced relapse free survival (RFS) and distant metastasis free survival (DMFS) of breast cancer patients carrying TP53 gene mutations conferring a prognostic value to this mutant p53-and autophagy-related signature. Interestingly, the mutant p53-driven mTOR stimulation sensitized cancer cells to the treatment with the mTOR inhibitor everolimus. All these results reveal a novel mechanism through which mutant p53 proteins promote cancer cell proliferation with the concomitant inhibition of autophagy. PMID- 27118660 TI - Aliskiren protecting atrial structural remodeling from rapid atrial pacing in a canine model. AB - Atrial fibrillation (AF) contributing to the increasing mortality risk is the most common disease in clinical practice. Owing to the side effects and relative inefficacy of current antiarrhythmic drugs, some research focuses on renin angiotensin-aldosterone system (RAS) for finding out the new treatment of AF. The purpose of this study is to confirm whether aliskiren as a proximal inhibitor of renin, which completely inhibits RAS, has beneficial effects on atrial structural remodeling in AF. In this study, rapid atrial pacing was induced at 500 beats per minute for 2 weeks in a canine model. A different dose of aliskiren was given orally for 2 weeks before rapid atrial pacing. HE staining and Masson's staining were used for analysis of myocardial fibrosis. TGF-beta1, signal pathways, and pro-inflammatory cytokines were shown for the mechanism of structural remodeling after the treatment of aliskiren. Serious atrial fibrosis was induced by rapid atrial pacing, followed by the elevated TGF-beta1, upregulated MEK and ERK1/2, and increased inflammatory factors. Aliskiren could apparently improve myocardial fibrosis by reducing the expression of TGF-beta1, inhibiting MEK and ERK1/2 signal pathways, and decreasing IL-18 and TLR4 in both serum and atrial tissue. In conclusion, aliskiren could prevent atrial structural remodeling from rapid atrial pacing for 2 weeks. Aliskiren may play a potential beneficial role in the treatment of AF induced by rapid atrial pacing. PMID- 27118661 TI - Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels. AB - Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff's system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, -dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, -dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg(-1)) and ruthenium red (4 and 8 mg kg(-1)) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels. PMID- 27118663 TI - Consumer perspectives of medication-related problems following discharge from hospital in Australia: a quantitative study. AB - OBJECTIVE: The aim of this study was to investigate the consumer's perspectives and experiences regarding medication related problems (MRPs) following discharge from hospital. DESIGN: A cross-sectional study was conducted using an online 80 question survey. SETTING: Survey participants were recruited through an online market research company. PARTICIPANTS: Five hundred and six participants completed the survey. Participants were included if they were aged 50 years or older, taking 5 or more prescription medicines, had been admitted to hospital with a minimum stay of 24 h, admitted to hospital within the last 4 months and discharged from hospital within the last 1 month. MAIN OUTCOME MEASURES: The survey comprised questions measuring: health literacy, health status, medication safety (measured by reported MRPs), missed dose(s), role of health professionals, health services and cost, and socio-demographic status. Descriptive and univariate statistics and logistic regression analysis was performed to examine the predictors of experiencing MRPs. RESULTS: Four main risk factors of MRPs emerged as significant: health literacy (P < 0.05), health status (P < 0.05), consumer engagement (P < 0.05) and cost of medicines (P = 0.001). Participants reporting a lack of perceived control over their medicines (OR 6.3; 95% CI: 3.4 11.8) or those who played less of a role in follow-up discussions with their healthcare professionals (OR 7.6; 95% CI: 1.3-45.7) were more likely to experience a self-reported MRP. CONCLUSIONS: This study provides insight into consumers' experiences and perceptions of self-reported MRPs following hospital discharge. Results highlight novel findings demonstrating the importance of consumer engagement in developing processes to ensure medication safety on patient discharge. PMID- 27118664 TI - How do we learn about improving health care: a call for a new epistemological paradigm. AB - PURPOSE: The field of improving health care has been achieving more significant results in outcomes at scale in recent years. This has raised legitimate questions regarding the rigor, attribution, generalizability and replicability of the results. This paper describes the issue and outlines questions to be addressed in order to develop an epistemological paradigm that responds to these questions. QUESTIONS: We need to consider the following questions: (i) Did the improvements work? (ii) Why did they work? (iii) How do we know that the results can be attributed to the changes made? (iv) How can we replicate them? (Note, the goal is not to copy what was done, but to affect factors that can yield similar results in a different context.) NEXT STEPS: Answers to these questions will help improvers find ways to increase the rigor of their improvements, attribute the results to the changes made and better understand what is context specific and what is generalizable about the improvement. PMID- 27118662 TI - Effect of tiron on remote organ injury in rats with severe acute pancreatitis induced by L-arginine. AB - Acute pancreatitis (AP) is an acute inflammatory disorder of the pancreas that can be complicated by involvement of other remote organs. Oxidative stress is known to have a crucial role in the development of pancreatic acinar damage and one of the main causes in multisystem organ failure in experimental AP. The aim of the study was to determine the effect of tiron on pancreas and remote organ damage in L-arginine (L-Arg) induced AP rat model. Thirty-two male rats were divided in random into four groups: control, tiron, L-Arg, and tiron with L-Arg. At the end of the experiment, blood samples were withdrawn for biochemical analysis. The pancreas, lung, kidney, and liver were collected for histopathological examination. Estimation of pancreatic water content was done. Analysis of pulmonary, hepatic, renal, and pancreatic lipid peroxide levels (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) were carried out. Finally, nuclear factor kappa B (NF-kappaB) and transforming growth factor beta1 (TGF-beta1) expression in pancreatic tissue was determined. Results indicated that treatment with tiron significantly decreased lipid peroxide levels and markedly increased both SOD activity and GSH level. Moreover, histopathological analysis further confirmed that administration of tiron relatively ameliorates pancreatic acinar cells and remote organ damage. Increased immunoreactivity of NF-kappaB and TGF-beta1 were reduced also by tiron treatment. These findings pointed out the protective role of the mitochondrial antioxidant, tiron against AP induced by L-Arg. PMID- 27118665 TI - The Prevalence and Incidence of Diabetes in Germany. AB - BACKGROUND: The database of the German Institute of Medical Documentation and Information makes it possible for the first time to compute statistics on diabetes for all insurees of the statutory health insurance scheme in Germany. Data from this comprehensive source are less likely to be biased by differences in the membership structures of individual insurance carriers or by the underrepresentation of persons over age 80 that is seen in most population-based studies. METHODS: International Classification of Diseases (ICD)-coded diagnosis data from the inpatient and outpatient sectors were used to define persons as having diabetes. Incidences were estimated from differences in prevalence from one year to the next and the expected mortality of persons with and without diabetes. RESULTS: A diabetes diagnosis was present in 6.4 million out of a total of 65.6 million insurees in 2009 and in 6.7 million out of 64.9 million insures in 2010. The corresponding age and sex standardized prevalences of diabetes were 9.7% in 2009 and 9.9% in 2010, respectively. The number of persons with type 2 diabetes was 4.6 million in 2009 and 4.7 million in 2010. The prevalence and incidence of type 2 diabetes rose steeply from age 50 to age 80. Peak incidence was at age 85, with 24 newly diagnosed cases of diabetes per 1000 person-years. CONCLUSION: On the basis of these data, we estimate that 5.8 million persons with type 2 diabetes are living in Germany today. The database used in this study is a valuable complement to population-based studies for monitoring the prevalence of diabetes, particularly in persons over age 80. PMID- 27118666 TI - Mental Health Problems in a School Setting in Children and Adolescents. AB - BACKGROUND: 10-20% of children and adolescents have a mental health problem of some type. Manifestations such as attention deficits, cognitive disturbances, lack of motivation, and negative mood all adversely affect scholastic development. It is often unclear what factors associated with school affect children's mental development and what preventive measures and interventions at school might be effective. METHODS: This review is based on systematic reviews, meta-analyses, and randomized and non-randomized controlled trials that were retrieved by a selective search in the PubMed, PsycInfo, and Google Scholar databases. RESULTS: The prevalence of hyperkinetic disorder is 1-6%. Its main manifestations are motor hyperactivity, an attention deficit, and impulsive behavior. Learning disorders such as dyscalculia and dyslexia affect 4-6% of children each, while 4-5% of children and adolescents suffer from depression, which is twice as prevalent in girls as in boys. Mental health problems increase the risk of repeating a grade, truancy, and dropping out of school. The risk of developing an internalizing or externalizing mental health problem can be lessened by changes in the school environment and by the implementation of evidencebased school programs. CONCLUSION: Physicians, in collaboration with school social workers and psychologists, should help teachers recognize and contend with mental health problems among the children and adolescents whom they teach, to enable the timely detection of stress factors at school and the initiation of the necessary measures and aids. In particular, the school-entrance examination and screening for risk factors at school can make a positive contribution. Evidence-based preventive programs should be implemented in schools, and beneficial changes of the school environment should be a further goal. PMID- 27118667 TI - Where Are the Advantages Mentioned? PMID- 27118668 TI - Need for Innovations. PMID- 27118669 TI - Legal Situation. PMID- 27118670 TI - Substantial Advantages for Older Primiparae. PMID- 27118671 TI - An Act of Unpredictability. PMID- 27118672 TI - In Reply. PMID- 27118673 TI - Characterization of growth and exopolysaccharide production of selected acetic acid bacteria in buckwheat sourdoughs. AB - Sourdough technology is a promising approach to improve the quality of gluten free (GF) breads. It offers replacement of currently used structure-forming commercial hydrocolloids by in situ produced exopolysaccharides (EPS). Acetic acid bacteria (AAB) can produce EPS of extremely high molecular weight, which are promising candidates for structure formation in breads. In this work, an alternative aerobic GF cereal fermentation by the levan producing AAB strains Gluconobacter albidus TMW 2.1191, Kozakia baliensis NBRC 16680 and Neoasaia chiangmaiensis NBRC 101099 was established in buckwheat doughs containing molasses as a natural source of sucrose. All three strains reached up to 109CFU/g dough at 48h and produced 16-20g/kg flour of fructans. The efficiency of EPS production was strain dependent and was additionally affected by initial molasses concentrations, inoculum sizes and dough yields, which influenced the respective bacterial growth and levan forming capabilities. G. albidus was the most competitive strain to grow in the buckwheat doughs, accordingly, the levan produced by this strain was further examined for its molecular mass and size determination. The structural analysis of levans from G. albidus in buckwheat doughs at 24 and 48h revealed the changes in particle sizes during fermentation. The ability of AAB strains to grow well and to produce high amounts of levan in situ in buckwheat-molasses doughs has opened a new possibility of using AAB doughs as a natural ingredient for quality improvement of GF baked products. PMID- 27118674 TI - Regulation of brain endothelial barrier function by microRNAs in health and neuroinflammation. AB - Brain endothelial cells constitute the major cellular element of the highly specialized blood-brain barrier (BBB) and thereby contribute to CNS homeostasis by restricting entry of circulating leukocytes and blood-borne molecules into the CNS. Therefore, compromised function of brain endothelial cells has serious consequences for BBB integrity. This has been associated with early events in the pathogenesis of several disorders that affect the CNS, such as multiple sclerosis, HIV-associated neurologic disorder, and stroke. Recent studies demonstrate that brain endothelial microRNAs play critical roles in the regulation of BBB function under normal and neuroinflammatory conditions. This review will focus on emerging evidence that indicates that brain endothelial microRNAs regulate barrier function and orchestrate various phases of the neuroinflammatory response, including endothelial activation in response to cytokines as well as restoration of inflamed endothelium into a quiescent state. In particular, we discuss novel microRNA regulatory mechanisms and their contribution to cellular interactions at the neurovascular unit that influence the overall function of the BBB in health and during neuroinflammation.-Lopez Ramirez, M. A., Reijerkerk, A., de Vries, H. E., Romero, I. A. Regulation of brain endothelial barrier function by microRNAs in health and neuroinflammation. PMID- 27118675 TI - Hydroxymethylation is uniquely distributed within term placenta, and is associated with gene expression. AB - The conversion of cytosine to 5-methylcystosine (5mC) is an important regulator of gene expression. 5mC may be enzymatically converted to 5-hydroxymethylcytosine (5hmC), with a potentially distinct regulatory function. We sought to investigate these cytosine modifications and their effect on gene expression by parallel processing of genomic DNA using bisulfite and oxidative bisulfite conversion in conjunction with RNA sequencing. Although values of 5hmC across the placental genome were generally low, we identified ~21,000 loci with consistently elevated levels of 5-hydroxymethycytosine. Absence of 5hmC was observed in CpG islands and, to a greater extent, in non-CpG island-associated regions. 5hmC was enriched within poised enhancers, and depleted within active enhancers, as defined by H3K27ac and H3K4me1 measurements. 5hmC and 5mC were significantly elevated in transcriptionally silent genes when compared with actively transcribed genes. 5hmC was positively associated with transcription in actively transcribed genes only. Our data suggest that dynamic cytosine regulation, associated with transcription, provides the most complete epigenomic landscape of the human placenta, and will be useful for future studies of the placental epigenome. Green, B. B., Houseman, E. A., Johnson, K. C., Guerin, D. J., Armstrong, D. A., Christensen, B. C., Marsit, C. J. Hydroxymethylation is uniquely distributed within term placenta, and is associated with gene expression. PMID- 27118677 TI - Antioxidative stress effect of epicatechin and catechin induced by Abeta25-35 in rats and use of the electrostatic potential and the Fukui function as a tool to elucidate specific sites of interaction. AB - Alzheimer's disease (AD) is a neurodegenerative disorder caused by the aggregation of the amyloid-beta peptide (Abeta) in senile plaques and cerebral vasculature. The Abeta25-35 fraction has shown the most toxicity; its neurotoxic mechanisms are associated with the generation of oxidative stress and reactive astrogliosis that induce neuronal death and memory impairment. Studies indicate that pharmacological treatment with flavonoids reduces the rate of AD, in particular, it has been shown that antioxidants are compounds that could interact with this peptide due to their antioxidant proprieties. In this study, experimental and computational tools were used to calculate the molecular electrostatic potential and the Fukui function with the Gaussian 09 computational program, to predict the most reactive parts of these molecules and make the complex between Abeta25-35 and two flavonoids (catechin and epicatechin) in the absolute gas-phase, where a possible interaction between them was observed. This is important for understanding the Abeta25-35-Flavonoid (A-F) interaction as a therapeutic strategy to inhibit the neurotoxic effects that this peptide causes in AD, which currently is still considered an ambiguous process. PMID- 27118678 TI - [Maternal morbidity and mortality associated with conservative management for placenta morbidly adherent (accreta) diagnosed during pregnancy. Report of 15 cases]. AB - BACKGROUND: High risk of morbidly adherent placenta increased during past years. Their management is controversial. Cesarean hysterectomy, considered the gold standard treatment by American Society, is associated with high risk of maternal morbimortality. Conservative management has been sought to reduce maternal morbidity associated with caesarean hysterectomy while maintaining fertility. It consists of leaving the placenta in place but long-term monitoring. Our main objective was to determine advantage/disadvantage of conservative management on patient with an antenatal diagnosis of placenta accreta, increta or percreta. MATERIAL AND METHODS: This retrospective study included all patients with an antenatal diagnosis of placenta accreta, increta or percreta between 2007 and 2014. Conservative treatment was systematically attempted according to our protocol. The primary outcome was defined as uterine conservation and the secondary outcome as maternal morbimortality defined as any medical or surgical condition occurring after childbirth. RESULTS: Fifteen patients (0.07 % of all living childbirths) were included. Conservative management was successful in 80 % of patients. There was no case of maternal death. Severe post-partum hemorrhage occurred in 4 patients (33.3 %) requiring uterine arteries embolization in one patient and hysterectomy in the 3 others. They underwent immediate blood transfusion of 13.5+/-4.5 average of red blood cell units. No severe septic condition occurred but 4 patients suffered from endometritis, 2.6+/-0.5 months after birth requiring intravenous antibiotics treatment in conventional hospitalization. Mean duration for spontaneous abortion of the placenta was 23.0+/-7.2 weeks. Three spontaneous pregnancies occurred in 2 patients after 19+/ 16.9 months. CONCLUSION: Conservative management seems encouraging but is associated with a non-insignificant risk of secondary complication requiring long term monitoring in conciliant patients. PMID- 27118679 TI - [Anatomic, functional and identity results after clitoris transposition]. AB - OBJECTIVES: Every year 3 millions of young women had undergone female genital mutilation. The psychological, identical and sexual consequences, as well as the treatment were described only recently. After a sociodemographic and cultural reminder, we analyze the anatomical, psychological, identital, and functional results of the reconstructive surgery. PATIENTS AND METHODS: We conducted a retrospective monocentric study. Thirty women were included in our series. All the patients operated according to the technique of Pierre Foldes were contacted again, to estimate their motivations for this surgery and study the results on femininity, anatomy, psychology and functionality of this intervention. RESULTS: Twenty-six women were able to be estimated in the long term. Their main motivation was in 77% of the cases the research for a feminine identity. We compared the pre- and postoperative results, as well as different predefined under groups. The results shown a significant improvement between the pre- and the postoperative estimation for each of the items. The patients indicate an improvement: anatomical in 96% of the cases, for identity in 88% of the cases, psychological in 96% of the cases, and for sexuality in 88% of the cases. DISCUSSION AND CONCLUSION: This technique allows an improvement for anatomy and functionality but also for physical image, well-being and feminity. PMID- 27118676 TI - CIB1: a small protein with big ambitions. AB - Calcium- and integrin-binding protein 1 (CIB1) is a small, ubiquitously expressed protein that was first identified as an intracellular binding partner of a platelet-specific alpha-integrin cytoplasmic tail. Although early studies revealed a role for CIB1 in regulating platelet integrin activity, recent studies have indicated a more diverse role for CIB1 in many different cell types and processes, including calcium signaling, migration, adhesion, proliferation, and survival. Increasing evidence also points to a novel role for CIB1 in cancer and cardiovascular disease. In addition, an array of CIB1 binding partners has been identified that provide important insight into how CIB1 may regulate these processes. Some of these binding partners include the serine/threonine kinases, p21-activated kinase 1 (PAK1), apoptosis signal-regulating kinase 1 (ASK1), and polo-like kinase 3 (PLK3). Structural and mutational studies indicate that CIB1 binds most or all of its partners via a well-defined hydrophobic cleft. Although CIB1 itself lacks known enzymatic activity, it supports the PI3K/AKT and MEK/ERK oncogenic signaling pathways, in part, by directly modulating enzymes in these pathways. In this review, we discuss our current understanding of CIB1 and key questions regarding structure and function and how this seemingly diminutive protein impacts important signaling pathways and cellular processes in human health and disease.-Leisner, T. M., Freeman, T. C., Black, J. L., Parise, L. V. CIB1: a small protein with big ambitions. PMID- 27118680 TI - Evolution of sex chromosomes prior to speciation in the dioecious Phoenix species. AB - Understanding the driving forces and molecular processes underlying dioecy and sex chromosome evolution, leading from hermaphroditism to the occurrence of male and female individuals, is of considerable interest in fundamental and applied research. The genus Phoenix, belonging to the Arecaceae family, consists uniquely of dioecious species. Phylogenetic data suggest that the genus Phoenix has diverged from a hermaphroditic ancestor which is also shared with its closest relatives. We have investigated the cessation of recombination in the sex determination region within the genus Phoenix as a whole by extending the analysis of P. dactylifera SSR sex-related loci to eight other species within the genus. Phylogenetic analysis of a date palm sex-linked PdMYB1 gene in these species has revealed that sex-linked alleles have not clustered in a species dependent way but rather in X and Y-allele clusters. Our data show that sex chromosomes evolved from a common autosomal origin before the diversification of the extant dioecious species. PMID- 27118682 TI - Peel strength and interfacial characterization of maxillofacial silicone elastomers bonded to titanium. AB - OBJECTIVES: To investigate the effect of three adhesive primers on the morphology, chemistry and peel bond strength of two maxillofacial silicone elastomers with commercially pure titanium (cpTi). METHODS: The effect of three primers (PR2:A-304 Primer/A-320 Bonding Enhancer, PR3:Super Bond, and PR4:Super Glue) on cpTi morphology and chemistry were studied by reflected light polarized microscopy (RPOLM) and reflection Fourier-transform infrared microspectroscopy (RFTIRM). For testing the bond strength between two elastomers (EL1:MDX4-4210, EL2:A-2006) and primed cpTi surfaces, a 90 degrees T peel test was performed (PBS), using as reference EL1, EL2 specimens bonded to heat-cured poly(methyl methacrylate) resin (PMMA) primed with A-330G primer (PR1). Failure modes were analyzed under a stereomicroscope, and the percentage of remaining silicone (RS%) on cpTi and PMMA were calculated by image analysis. Scanning electron microscopy/energy dispersive X-ray spectrometry (SEM/EDX) was used to investigate representative failure patterns on cpTi. Data were analyzed with Weibull analysis, ANOVA plus post hoc tests, and Pearson correlation coefficient (a=0.05). RESULTS: Thick-irregular (PR2), thin-smooth (PR3), and uniform-porous (PR4) films were identified on cpTi by RPOLM. RFTIRM revealed: a strong peak of Si-O-Si with a distribution following the outline of the image (PR2); COO-M groups developed, but unevenly distributed (PR3); and reduction in CC groups due to in situ polymerization (PR4). Following PBS, the ranking of the statistical significant differences in Weibull scale parameter (sigma0) of the EL1 group was PMMA_PR1>cpTi_PR2,cpTi_PR3>cpTi_PR4, whereas for the EL2 group cpTi_PR2>PMMA_PR1>cpTi_PR4,cpTi_PR3. For RS%, the ranking in the EL1 group was: PMMA_PR1>cpTi_PR2>cpTi_PR3>cpTi_PR4, and in the EL2 cpTi_PR2>cpTi_PR3>cpTi_PR4,PMMA_PR1. There was no statistically significant correlation between PBS and RS%, with the exception of EL1_PMMA_PR1. In all groups mixed failure modes were found by SEM/EDX. SIGNIFICANCE: Although there is evidence of bonding with cpTi, there are important differences among the primer/elastomer combination that may affect the clinical performance of these materials. PMID- 27118681 TI - LPS-induced NFkappaB enhanceosome requires TonEBP/NFAT5 without DNA binding. AB - NFkappaB is a central mediator of inflammation. Present inhibitors of NFkappaB are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NFkappaB enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NFkappaB activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NFkappaB. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NFkappaB itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NFkappaB enhanceosome offers a promising target for useful anti-inflammatory agents. PMID- 27118683 TI - Chewing efficiency and maximum bite force with different attachment systems of implant overdentures: a crossover study. AB - PURPOSE: This crossover study aimed to evaluate and compare chewing efficiency and maximum bite force (MBF) with resilient telescopic and bar attachment systems of implant overdentures in patients with atrophied mandibles. MATERIAL AND METHODS: Ten participants with severely resorbed mandibles and persistent denture problems received new maxillary and mandibular conventional dentures (control, CD). After 3 months of adaptation, two implants were inserted in canine region of the mandible. In a quasi-random method, overdentures were connected to the implants with either bar overdentures (BOD) or resilient telescopic overdentures (TOD) attachment systems. Chewing efficiency in terms of unmixed fraction (UF) was measured using chewing gum (after 5, 10, 20, 30 and 50 strokes), and MBF was measured using a bite force transducer. Measurements were performed 3 months after using each of the following prostheses: CD, BOD and TOD. RESULTS: Chewing efficiency and MBF increased significantly with BOD and TOD compared to CD. As the number of chewing cycles increased, the UF decreased. TOD recorded significant higher chewing efficiency and MBF than BOD. CONCLUSION: Resilient telescopic attachments are associated with increased chewing efficiency and MBF compared bar attachments when used to retain overdentures to the implants in patients with atrophied mandibles. PMID- 27118684 TI - Amplified fluorescence emission of bolaamphiphilic perylene-azacrown ether derivatives directed towards molecular recognition events. AB - Long-term creative approaches have been considered in the design of molecular probes to overcome the quenching effect of important dyes in an aqueous medium. Using the rational donor-acceptor based design principle, we demonstrate herein the different fluorescence states of a non-conjugated symmetrical perylene azacrown ether system in a solution, from the molecular to the aggregated states. The ethylene-spacer is exceptionally capable of fluorescence enhancement, even in the aggregated state (organic nanoparticle, ONPs, 44 nm), overcoming the quenching effect on changing the solvent from tetrahydrofuran to water. The ONPs with crown ether receptors at the surface show colloidal stability in an aqueous solution. Furthermore, an improved fluorescent state is developed via ONPs polymer (protamine, Pro) hybridization. Supramolecular interactions between the crown ring and the guanidinium group in Pro play an important role in the ONPs Pro hybrid formation. The decorated fluorescent hybrid state is finally used as a nano-probe for sensing heparin via the turn-OFF mechanism. The decoration method is further generalized by recognition of the nucleotides. Herein, we detail the bottom-up approach to the molecular design and development of the different fluorescent states of a useful probe. Most excitingly, this new approach is very general and adaptive to facile detection. PMID- 27118685 TI - An Ethnopharmacological, Phytochemical and Pharmacological Review of the Genus Meconopsis. AB - The Meconopsis plants (Chinese: ), belonging to the family Papaveraceae, have been used as traditional Tibetan medicine (TTM) for thousands of years. Meconopsis has the effects of clearing heat, reducing swelling, and easing pain, and is mainly prescribed for heat syndromes, hepatitis, pneumonia, and pain in joints. Phytochemical studies have revealed the presence of major isoquinoline alkaloids and flavonoids. Modern pharmacological research has demonstrated its antitumor, hepatoprotective, analgestic, antimicrobial, anti-oxidant, antitussive, and anti-inflammatory activities. However, resource availability, in depth in vivo pharmacological study and qualitative and quantitative analysis are still insufficient and deserve further efforts. This paper provides a comprehensive advance on the ethnopharmacological, phytochemical, and pharmacological studies of the genus, in hopes of promoting a better understanding of their medicinal values. PMID- 27118686 TI - Spectroscopic investigation of water-soluble alloyed QDs with bovine serum albumin. AB - We present here a systematic investigation on the interaction between a water soluble alloyed semiconductor quantum dot and bovine serum albumin using various spectroscopic techniques i.e. fluorescence quenching, resonance light scattering and synchronous fluorescence spectroscopy. The analysis of fluorescence spectrum and fluorescence intensity indicates that the intrinsic fluorescence of bovine serum albumin (BSA) gets quenched by both static and dynamic quenching mechanism. The Stern-Volmer quenching constants, energy transfer efficiency parameters, binding parameters and corresponding thermodynamic parameters (DeltaH0 , DeltaS0 and DeltaG0 ) have been evaluated by using van 't Hoff equation at different temperatures. A positive entropy change with a positive enthalpy change was observed suggesting that the binding process was an entropy-driven, endothermic process associated with the hydrophobic effect. The intermolecular distance (r) between donor (BSA) and acceptor (CdSeS/ZnS quantum dots) was estimated according to Forster's theory of non-radiative energy transfer. The synchronous fluorescence spectra revealed a blue shift in the emission maxima of tryptophan which is indicative of increasing hydrophobicity. Negative DeltaG0 values implied that the binding process was spontaneous. It was found that hydrophobic forces played a role in the quenching process. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27118688 TI - A pilot play-based intervention to improve the social play interactions of children with autism spectrum disorder and their typically developing playmates. AB - BACKGROUND/AIM: Occupational therapists play a key role in addressing the social difficulties of children with ASD. However, interventions are often time intensive, without outcomes generalising beyond the clinic setting. To examine the feasibility and preliminary effectiveness of an intervention to address the social play skills of children with ASD. METHODS: Participants in this multiple case study design were five children with autism spectrum disorder (ASD), five typically developing playmates and five parents of children with ASD. Two therapists and parents delivered the intervention involving clinic play sessions and home modules. Parents' treatment adherence was recorded. The Test of Playfulness was scored by a blinded rater to examine child outcomes following the intervention. Line graphs were used to examine case data. Percentage of non overlapping data (PND) was used to calculate the single-case effect size for each child. RESULTS: Parents completed 92.2% of the intervention. Children's case data showed an upwards trend from pre- to post-intervention in four of the five pairs (child with ASD and playmate). However, there was a decrease in scores from post intervention to the two-month home follow-up for all but one pair. PND indicated the intervention was effective for two children with ASD and three of their playmates, had a questionable effect on three children with ASD and no observable effect on two playmates. CONCLUSION: The intervention demonstrated preliminary feasibility and effectiveness for improving the social play skills of some children with ASD. Careful consideration is needed to identify which children with ASD and which playmates would be best suited for this intervention approach. PMID- 27118689 TI - Are Abused Women's Protective Actions Associated With Reduced Threats, Stalking, and Violence Perpetrated by Their Male Intimate Partners? AB - Victims of intimate partner violence may take various actions to protect themselves from their partner. This research examined the association between abused women's ( N = 755) protective strategies at baseline and her partner's threats, stalking, and moderate and severe violence 8 months later. Emergency domestic violence shelter and orders of protection significantly reduced subsequent abuse. Receiving medical treatment was associated with a significant increase in violence, and security devices (e.g., mace, changing locks) with an increase in stalking. Safety planning and other strategies had no statistical association with abuse at follow-up. Future research should continue to examine the efficacy of safety strategies. PMID- 27118687 TI - Smoking and Adverse Outcomes in Patients With CKD: The Study of Heart and Renal Protection (SHARP). AB - BACKGROUND: The absolute and relative importance of smoking to vascular and nonvascular outcomes in people with chronic kidney disease (CKD), as well its relevance to kidney disease progression, is uncertain. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 9,270 participants with CKD enrolled in SHARP. PREDICTOR: Baseline smoking status (current, former, and never). OUTCOMES: Vascular events, site-specific cancer, ESRD, rate of change in estimated glomerular filtration rate (eGFR), and cause-specific mortality. RESULTS: At baseline, 1,243 (13%) participants were current smokers (median consumption, 10 cigarettes/day); 3,272 (35%), former smokers; and 4,755 (51%), never smokers. Median follow-up was 4.9 years. Vascular event rates were 36% higher for current than never smokers (2,317 events; relative risk [RR], 1.36; 95% CI, 1.19-1.55), reflecting increases in both atherosclerotic (RR, 1.49; 95% CI, 1.26-1.76) and nonatherosclerotic (RR, 1.25; 95% CI, 1.05-1.50) events. Cancer was 37% higher among current smokers (632 events; RR, 1.37; 95% CI, 1.07 1.76), with the biggest RRs for lung (RR, 9.31; 95% CI, 4.37-19.83) and upper aerodigestive tract (RR, 4.87; 95% CI, 2.10-11.32) cancers. For 6,245 patients not receiving dialysis at baseline, ESRD incidence did not differ significantly between current and never smokers (2,141 events; RR, 1.02; 95% CI, 0.89-1.17), nor did estimated rate of change in eGFR (current smokers, -1.77+/-0.14 [SE]; never smokers, -1.70+/-0.07mL/min/1.73m(2) per year). All-cause mortality was 48% higher among current smokers (2,257 events; RR, 1.48; 95% CI, 1.30-1.70), with significant increases in vascular (RR, 1.35; 95% CI, 1.07-1.69) and nonvascular (RR, 1.60; 95% CI, 1.34-1.91) causes of death, especially cancer (RR, 2.32; 95% CI, 1.58-3.40) and respiratory (RR, 2.25; 95% CI, 1.51-3.35) mortality. LIMITATIONS: Smoking status not assessed during follow-up. CONCLUSIONS: In this study of patients with CKD, smoking significantly increased the risks for vascular and nonvascular morbidity and mortality, but was not associated with kidney disease progression. The associations with vascular and neoplastic disease are in keeping with those observed in the general population and are likely modifiable by cessation. PMID- 27118690 TI - Imaging of traumatic injury and impingement of anterior knee fat. AB - Fat is not just used by the body as bulk tissue. In addition to its role in storing energy and regulating hormone action, fat is used in some parts of the body for its mechanical properties. The anatomy of anterior knee fat is more complex than it appears at first sight and is capable of withstanding considerable compressive and shear stress. Specific lesions occur when such mechanical stress exceeds the physiological limits and are yet little known. Superficial fat can be the site of either acute injury by closed degloving called the Morel-Lavallee lesion or chronic injury, when subject to repeat excessive shear forces, due to more complex and less well-defined disruptions that result in pseudo-bursitis. There are three main anterior, intracapsular and extrasynovial fat pads in the knee joint, which are the infrapatellar fat pad (IFP) or Hoffa's fat pad, the quadriceps fat pad and the prefemoral fat pad. The IFP plays an important role as a mechanical shock absorber and guides the patella tendon and even the patella itself during flexion-extension movements. In response to repeated excessive stress, an inflammatory reaction and swelling of the IFP is first observed, followed by a fibrotic reaction with metaplastic transformation into fibrous, cartilaginous or bone tissue. More rarely, the two other deep fat pads (quadriceps and prefemoral) can, if subject to repeated stress, undergo similar restructuring inflammatory reactions with metaplasia resulting in tissue hardening, anterior pain and partial loss of function. PMID- 27118691 TI - Driven to extinction? The ethics of eradicating mosquitoes with gene-drive technologies. AB - Mosquito-borne diseases represent a significant global disease burden, and recent outbreaks of such diseases have led to calls to reduce mosquito populations. Furthermore, advances in 'gene-drive' technology have raised the prospect of eradicating certain species of mosquito via genetic modification. This technology has attracted a great deal of media attention, and the idea of using gene-drive technology to eradicate mosquitoes has been met with criticism in the public domain. In this paper, I shall dispel two moral objections that have been raised in the public domain against the use of gene-drive technologies to eradicate mosquitoes. The first objection invokes the concept of the 'sanctity of life' in order to claim that we should not drive an animal to extinction. In response, I follow Peter Singer in raising doubts about general appeals to the sanctity of life, and argue that neither individual mosquitoes nor mosquitoes species considered holistically are appropriately described as bearing a significant degree of moral status. The second objection claims that seeking to eradicate mosquitoes amounts to displaying unacceptable degrees of hubris. Although I argue that this objection also fails, I conclude by claiming that it raises the important point that we need to acquire more empirical data about, inter alia, the likely effects of mosquito eradication on the ecosystem, and the likelihood of gene-drive technology successfully eradicating the intended mosquito species, in order to adequately inform our moral analysis of gene-drive technologies in this context. PMID- 27118692 TI - Why I wrote my advance decision to refuse life-prolonging treatment: and why the law on sanctity of life remains problematic. AB - This paper, pursuing themes indefatigably defended in this journal and elsewhere by Professors Jenny and Celia Kitzinger, explains what led me to write my own advance decision (AD) to refuse life-prolonging treatment if I become legally incapacitated to make my own healthcare decisions for longer than 3 months and am medically assessed as very unlikely to regain such legal capacity. I attach my Advance Decision to Refuse Life Prolonging Treatment to the online version of this paper for comment advice and possible general interest. I argue that while a Supreme Court judgement in 2013, followed by a Court of Protection judgement in 2015 greatly ameliorate my earlier concerns about excessive judicial emphasis on the sanctity of life, certain current requirements in the Code of Practice to the Mental Capacity Act 2005 and in the Rules of the Court of Protection, especially Practice Direction 9E, concerning permanent vegetative state and minimally conscious state, seem clearly to contradict aspects of that Supreme Court judgement. If the logical implications of those legal requirements were thoroughly implemented medical practice would be substantially and undesirably skewed towards provision of treatments to prolong life that are unwanted, non beneficial and wasteful of healthcare resources. I urge that these legal requirements are modified to make them consistent with the Supreme Court's judgement in Aintree v James. PMID- 27118693 TI - Deus ex Machina. PMID- 27118694 TI - A duty of kindness. PMID- 27118695 TI - The NHS could do better. PMID- 27118697 TI - All health researchers should begin their training by preparing at least one systematic review. PMID- 27118696 TI - Do invitations for cervical screening provide sufficient information to enable informed choice? A cross-sectional study of invitations for publicly funded cervical screening. AB - OBJECTIVE: To investigate whether invitations for publicly funded cervical screening provide sufficient information to enable an informed choice about participation. DESIGN: Cross-sectional study using a checklist of 23 information items on benefits and harms from cervical screening and the risks related to cervical cancer. MATERIAL: Invitations to publicly funded cervical screening in 10 Scandinavian and English-speaking countries. SETTING: Ten Scandinavian and English speaking countries. PARTICIPANTS: Sixteen screening units representing 10 Scandinavian and English speaking countries. MAIN OUTCOME MEASURES: Number of information items presented in invitations for cervical screening. RESULTS: We contacted 21 coordinating units from 11 countries and 20 (95%) responded. Of these, four units did not issue invitations, but the remaining 16 coordinating units in 10 different countries supplied a sample. The invitations for cervical screening were generally information poor and contained a median of only four out of 23 information items possible (17%), ranging from 0 to 12 (0-52%). The most important harms of cancer screening, overdiagnosis and overtreatment, were typically downplayed or unmentioned. The same applied to other important harms, such as false-positive results and the psychological consequences from an abnormal test result. The majority of invitations took a paternalistic approach. While only two invitations (17%) included a pre-assigned appointment date, eight (70%) of the invitations contained strong appeals for participation. CONCLUSIONS: Invitations to cervical cancer screening were information poor and biased in favour of participation. This means that informed choice is not possible, which is in conflict with modern requirements for personal involvement in medical decisions. PMID- 27118698 TI - Surgical care practitioners in orthopaedics. PMID- 27118699 TI - Nomograms for two-dimensional echocardiography derived valvular and arterial dimensions in Caucasian children. AB - BACKGROUND: Despite recent advances, current pediatric echocardiographic nomograms for valvular and arterial dimensions remain limited. METHODS: We prospectively studied healthy Caucasian Italian children by two-dimensional (2D) echocardiography. Echocardiographic measurements for 18 valvular and arterial dimensions were performed and models were generated testing for linear, logarithmic, exponential, and square root relationships. Heteroscedasticity was accounted for by White or Breusch-Pagan test. Age, weight, height, heart rate, and body surface area (BSA) were used as independent variables in different analyses to predict the mean values of each measurement. Structured Z-scores were then computed. RESULTS: In all, 1151 subjects (age 0 days to 17 years; 45% females; BSA 0.12-2.12m2) were studied. The Haycock formula was used when presenting data as predicted values (mean+/-2 SDs) for a given BSA and within equations relating echocardiographic measurements to BSA. The predicted values and Z-score boundaries for all measurements are presented. CONCLUSIONS: We report echocardiographic nomograms for valvular and arterial dimensions derived from a large population of children. Integration of these data with those of previous reports would allow for a comprehensive coverage of pediatric 2D echocardiographic nomograms for measurement of 2D cardiac structures. PMID- 27118701 TI - Antidepressant use and cardiovascular risk: moving from emotive rhetoric towards evidence based care. PMID- 27118702 TI - Temporal and associated disorders of perception in infants born extremely preterm. PMID- 27118700 TI - Increasing delirium skills at the front door: results from a repeated survey on delirium knowledge and attitudes. AB - BACKGROUND: delirium is under-recognised in comparison to other common and serious acute disorders. A 2006 survey of UK junior doctors (not undertaking specialist training) identified poor knowledge of the diagnostic criteria and treatment of delirium. We hypothesised that increased prominence accorded to delirium in the form of national initiatives and guidelines may have had an impact on understanding among junior doctors. OBJECTIVE: we repeated a multi centre survey of knowledge of and attitudes to delirium in junior doctors (not undertaking specialist training) assessing unselected acute medical presentations (the 'medical take'). DESIGN: questionnaire-based survey in 48 acute hospitals in UK and Ireland. METHODS: we used questionnaires designed to test understanding of delirium, including prevalence, knowledge of the DSM-IV diagnostic criteria, use of specific screening tools, association with adverse outcomes and pharmacological management. RESULTS: one thousand two hundred and fifteen trainee physicians participated. Compared with the 2006 cohort, improvements were seen in 9 of 17 knowledge-based questions and overall score improved in the 2013 cohort. Nonetheless, significant deficits in knowledge, particularly for the diagnostic criteria for delirium, remained. CONCLUSIONS: despite improvements in some aspects of delirium knowledge, the diagnostic criteria for delirium remain poorly understood. Challenges remain in ensuring adequate training for junior doctors in delirium. PMID- 27118703 TI - Prolactin and cortisol mediate the maintenance of hyperosmoregulatory ionocytes in gills of Mozambique tilapia: Exploring with an improved gill incubation system. AB - Endocrine control of osmoregulation is essential for teleosts to adapt to various aquatic environments. Prolactin (PRL) is known as a fundamental endocrine factor for hyperosmoregulation in teleost fishes, acting on ionocytes in the gills to maintain ion concentrations of body fluid within narrow physiological ranges in freshwater conditions. Cortisol is also known as an osmoregulation-related steroid in teleosts; however, its precise function is still controversial. Here, we investigated more detailed effects of PRL and roles of cortisol on ionocytes of Mozambique tilapia (Oreochromis mossambicus) in freshwater, using an improved gill filament incubation system. This incubation system resulted in enhanced cell viability, as evaluated using the dead cell marker propidium iodide. PRL was shown to maintain the density of freshwater-type ionocytes in isolated gill filaments; this effect of PRL is not achieved by the activation of cell proliferation, but by the maintenance of existing ionocytes. Cortisol alone did not show any distinct effect on ionocyte density in isolated gill filaments. We also assessed effects of PRL and cortisol on relative mRNA levels of NCC2, NHE3, NKAa1a, and NKAa1b. PRL maintained relative NCC2 and NKAa1a mRNA abundance, and cortisol showed a stimulatory effect on relative NCC2 and NKAa1a mRNA levels in combination with PRL, though cortisol alone exerted no effect on these genes. An increase in NKAa1b mRNA abundance was detected in cortisol-treated groups. PRL treatment also maintained normal NCC2 localization at the apical membrane of the ionocytes. These results indicate that PRL maintains freshwater-type ionocytes, and that cortisol stimulates the function of ionocytes maintained by PRL. PMID- 27118704 TI - Maternal corticosterone deposition in avian yolk: Influence of laying order and group size in a joint-nesting, cooperatively breeding species. AB - Glucocorticoid hormones play a key role in day-to-day adjustments to fluctuating metabolic needs. These hormones also mediate physiological and behavioral responses to stressful events, allowing individuals to cope with stressors. Various environmental insults, such as a food shortages, predation attempts, and agonistic encounters often elevate plasma glucocorticoid levels in vertebrates. Because exposure to maternally-derived (via circulation or egg) glucocorticoids may be detrimental to the developing embryo, maternal stress can have negative carryover effects on offspring fitness. We examined corticosterone, the primary avian glucocorticoid, concentrations in egg yolk in a plural-breeding, joint nesting species, the smooth-billed ani (Crotophaga ani), in which females compete among themselves to lay eggs in the final incubated clutch. We investigated whether yolk corticosterone levels varied with laying order and group size. Because egg-laying competition leads to physiological and social stress that is intensified with group size and laying order, we predicted that yolk corticosterone levels should increase from the early to the late egg-laying period and from single female to multi-female groups. In this two-year field study, we found that yolk corticosterone levels of late-laid eggs within the communal clutch were higher in multi-female groups than in single female groups. Results from this study suggest that laying females experience higher levels of stress in multi-female groups and that this maternal stress influences yolk corticosterone concentrations. This study identifies a novel cost of group-living in plural-breeding cooperatively breeding birds, namely an increase in yolk corticosterone levels with group size that may result in detrimental effects on offspring development. PMID- 27118705 TI - Identification, expression analysis, and functional characterization of peptide YY in chickens (Gallus gallus domesticus). AB - Peptide YY (PYY) functions as a postprandial satiety signal in mammals. However, the genomic information and physiological roles of chicken PYY have not yet been clarified, although PYY peptide was isolated from chicken intestines in 1992. In this study, we identified a full-length complementary DNA (cDNA) sequence encoding the chicken PYY precursor. The deduced amino acid sequence of chicken PYY was completely consistent with the previously identified peptide sequence. PYY mRNA was abundantly expressed in the small intestine compared with the large intestine. PYY mRNA levels in the jejunum were significantly higher during ad libitum feeding compared with fasting, suggesting that intestinal PYY expression is altered in response to nutritional status in chicks. Intravenous administration of PYY significantly suppressed food intake in chicks. Furthermore, neuropeptide Y receptor Y2, a possible target of PYY, was expressed in various brain regions including the appetite-regulating centers in chicks. This is the first evidence that the intestinal hormone PYY may function as an anorexigenic hormone in chicks. PMID- 27118706 TI - Oleic acid induces specific alterations in the morphology, gene expression and steroid hormone production of cultured bovine granulosa cells. AB - After parturition, one of the major problems related to nutritional management that is faced by the majority of dairy cows is negative energy balance (NEB). During NEB, excessive lipid mobilization takes place and hence the levels of free fatty acids, among them oleic acid, increase in the blood, but also in the follicular fluid. This accumulation can be associated with serious metabolic and reproductive disorders. In the present study, we analyzed the effects of physiological concentrations of oleic acid on cell morphology, apoptosis, necrosis, proliferation and steroid production, and on the abundance of selected transcripts in cultured bovine granulosa cells. Increasing oleic acid concentrations induced intracellular lipid droplet accumulation, thus resulting in a foam cell-like morphology, but had no effects on apoptosis, necrosis or proliferation. Oleic acid also significantly reduced the transcript abundance of the gonadotropin hormone receptors, FSHR and LHCGR, steroidogenic genes STAR, CYP11A1, HSD3B1 and CYP19A1, the cell cycle regulator CCND2, but not of the proliferation marker PCNA. In addition, treatment increased the transcript levels of the fatty acid transporters CD36 and SLC27A1, and decreased the production of 17-beta-estradiol and progesterone. From these data it can be concluded that oleic acid specifically affects morphological and physiological features and gene expression levels thus altering the functionality of granulosa cells. Suggestively, these effects might be partly due to the reduced expression of FSHR and thus the reduced responsiveness to FSH stimulation. PMID- 27118707 TI - Environmentally relevant concentrations of nitrate increase plasma testosterone concentrations in female American alligators (Alligator mississippiensis). AB - Anthropogenic nitrogen is a ubiquitous environmental contaminant that is contributing to the degradation of freshwater, estuarine, and coastal ecosystems worldwide. The effects of environmental nitrate, a principal form of nitrogen, on the health of aquatic life is of increasing concern. We exposed female American alligators to three concentrations of nitrate (0.7, 10 and 100mg/L NO3-N) for a duration of five weeks and five months from hatch. We assessed growth, plasma sex steroid and thyroid hormone concentrations, and transcription levels of key genes involved in steroidogenesis (StAR, 3beta-HSD, and P450scc) and hepatic clearance (Cyp1a, Cyp3a). Exposure to 100mg/L NO3-N for both five weeks and five months resulted in significantly increased plasma testosterone (T) concentrations compared with alligators in the reference treatment. No differences in 17beta estradiol, progesterone, or thyroid hormones were observed, nor were there differences in alligator weight or the mRNA abundance of steroidogenic or hepatic genes. Plasma and urinary nitrate concentrations increased with increasing nitrate treatment levels, although relative plasma concentrations of nitrate were significantly lower in five month, versus five week old animals, possibly due to improved kidney function in older animals. These results indicate that environmentally relevant concentrations of nitrate can increase circulating concentrations of T in young female alligators. PMID- 27118708 TI - High-Content Screening for Quantitative Cell Biology. AB - High-content screening (HCS), which combines automated fluorescence microscopy with quantitative image analysis, allows the acquisition of unbiased multiparametric data at the single cell level. This approach has been used to address diverse biological questions and identify a plethora of quantitative phenotypes of varying complexity in numerous different model systems. Here, we describe some recent applications of HCS, ranging from the identification of genes required for specific biological processes to the characterization of genetic interactions. We review the steps involved in the design of useful biological assays and automated image analysis, and describe major challenges associated with each. Additionally, we highlight emerging technologies and future challenges, and discuss how the field of HCS might be enhanced in the future. PMID- 27118709 TI - Neuroplasticity: Effects of Physical and Cognitive activity on brain structure and function. PMID- 27118710 TI - Transpancreatic Mattress Suture with Vicryl Mesh Around the Stump During Distal Pancreatectomy: A Novel Technique for Preventing Postoperative Pancreatic Fistula. PMID- 27118711 TI - A New Procedure for the Treatment of Extrahepatic Portal Hypertension in Children: Portal Cavernoma-Rex Shunt with Interposition of Grafted Portal Vessel. PMID- 27118712 TI - Positive Nipple Margins in Nipple-Sparing Mastectomies: Rates, Management, and Oncologic Safety. AB - BACKGROUND: When a nipple margin of a nipple-sparing mastectomy (NSM) contains malignancy, current practice includes removal of the nipple or nipple areola complex (NAC). We evaluated rates and trends of positive nipple margins, subsequent management, and oncologic outcomes. STUDY DESIGN: A retrospective chart review of all NSM at our institution from 2007 to 2014 was performed. A descriptive analysis was performed of patients with positive nipple/subareolar margins. RESULTS: Among 1,326 NSM, 43 of 642 (6.7%) therapeutic and 3 of 684 (0.4%) prophylactic NSM had positive nipple margins. Nipple or NAC excision was performed for 39 of 46 (85%) positive nipple margins: 20 of 39 (51%) had nipple only and 19 of 39 (49%) had the entire NAC excised. Practice evolved to remove only the nipple and retain the areola for positive nipple margins: in 2007 to 2011, 7 of 17 (41%) underwent nipple-only excision compared with 14 of 22 (64%) in 2012 to 2014. Among 39 excised nipples/NAC, 28 (72%) contained no residual malignancy, while 8 contained ductal carcinoma in situ (DCIS), 2 had invasive lobular carcinoma, and 1 had invasive ductal carcinoma. With experience, rates of positive nipple margins for therapeutic NSM decreased from 11% (17 of 160) in 2007 to 2011 to 5.4% (26 of 482) in 2012 to 2014 (p < 0.05). At 36 month median follow-up, there were no recurrences in the nipple/NAC. CONCLUSIONS: Early results suggest that excision of the nipple with retention of the areola is a safe approach for management of a positive nipple margin after NSM. With experience, low rates of positive nipple margins are possible in therapeutic NSM. Overall risk of nipple/NAC recurrence after NSM remains extremely low. PMID- 27118713 TI - Prolonged Length of Stay after Esophageal Resection: Identifying Drivers of Increased Length of Stay Using the NSQIP Database. AB - BACKGROUND: Although influence of technical complications in association to hospital length of stay has been studied extensively in esophageal resection, nontechnical factors responsible for prolonged length of stay have not been reported. Using the NSQIP dataset, we hypothesized that we would be able to identify factors associated with prolonged length of stay after esophagectomy. STUDY DESIGN: National Surgical Quality Improvement Program data from 2005 to 2012 were reviewed for CPT codes for esophagectomy. Outlier status for length of stay was defined as >75th percentile. Logistic regression was used to predict outlier status and linear regression to discern factors contributing to longer lengths of stay. RESULTS: A total of 3,538 cases were reviewed. The 75th percentile for length of stay was 17 days. Preoperative predictors of hospital stay outliers include emergency surgery and frailty index (odds ratios = 3.7 and 3.6; p < 0.001). Deep organ space infection and progressive renal insufficiency had the highest likelihood of prolonged length of stay (odds ratios = 5.2 and 5.1; p < 0.001). Failure to wean off of ventilator in 48 hours, urinary tract infection, and pneumonia were associated with length of stay outlier (odds ratios = 3.7, 2.7, and 2.7; all p < 0.001). CONCLUSIONS: Urinary tract infection and pneumonia after esophagectomy are associated with longer hospital stays. Although meticulous surgical technique remains paramount, our study demonstrates that postoperative nontechnical complications factor into prolonged hospital stays. Focus on such factors can lead to reductions in hospital stays. PMID- 27118714 TI - Analyzing Risk Factors for Morbidity and Mortality after Lung Resection for Lung Cancer Using the NSQIP Database. AB - BACKGROUND: Our goal was to develop a predictive model that identifies how preoperative risk factors and perioperative complications lead to mortality after anatomic pulmonary resections. STUDY DESIGN: This was a retrospective cohort study. The American College of Surgeons NSQIP database was examined for all patients undergoing elective lobectomies for cancer from 2005 through 2012. Fifty eight pre- and intraoperative risk factors and 13 complications were considered for their impact on perioperative mortality within 30 days of surgery. Multivariate logistic regression and a logistic regression model using least absolute shrinkage and selection operator (LASSO) selection methods were used to identify preoperative risk factors that were significant for predicting mortality, either through or independent of complications. Only factors that were significant under both the multivariate logistic regression and LASSO-selected models were considered to be validated for the final model. RESULTS: There were 6,435 lobectomies identified. After multivariate logistic regression modeling, 28 risk factors and 5 complications were found to be predictors for mortality. This was then tested against the LASSO method. There were 7 factors shared between the LASSO and multivariate logistic regressions that predicted mortality based on comorbidity: age (p = 0.007), male sex (p = 0.011), open lobectomy (p = 0.001), preoperative dyspnea at rest (p < 0.001), preoperative dyspnea on exertion (p = 0.003), preoperative dysnatremia (serum sodium <135 mEq/L or >145 mEq/L) (p = 0.011), and preoperative anemia (p = 0.002). Of these, 3 variables predicted mortality independent of any complications: dyspnea at rest, dyspnea on exertion, and dysnatremia. CONCLUSIONS: The clinical factors that predict postoperative complications and mortality are multiple and not necessarily aligned. Efforts to improve quality after anatomic pulmonary resections should focus on mechanisms to address both types of adverse outcomes. PMID- 27118715 TI - The norepinephrine reuptake inhibitor reboxetine is more potent in treating murine narcoleptic episodes than the serotonin reuptake inhibitor escitalopram. AB - One of the major symptoms of narcolepsy is cataplexy, a sudden loss of muscle tone. Despite the advances in understanding the neuropathology of narcolepsy, cataplexy is still treated symptomatically with antidepressants. Here, we investigate in a murine narcolepsy model the hypothesis that the antidepressants specifically blocking norepinephrine reuptake are more potent in treating narcoleptic episodes than the antidepressants blocking of serotonin reuptake. Furthermore, we tested the effects of alpha1 receptor stimulation and blockade, respectively, on narcoleptic episodes. Orexin-deficient mice were treated with different doses of the norepinephrine reuptake inhibitor reboxetine, the serotonin reuptake inhibitor escitalopram, the alpha1 receptor agonist cirazoline or the alpha1 receptor antagonist prazosin. The effect of these treatments on narcoleptic episodes was tested. Additionally, potential treatment effects on locomotor activity in an open-field were tested. Reboxetine (doses >=0.55mg/kg) as well as escitalopram (doses >=3.0mg/kg) dose-dependently reduced the number of narcoleptic episodes in orexin-deficient mice. The ED50 for reboxetine (0.012mg/kg) was significantly lower than for escitalopram (0.44mg/kg). Cirazoline and prazosin did not affect narcoleptic episodes. Furthermore, cirazoline but not the other compounds reduced locomotor activity of the mice. The present study strongly supports the hypothesis that a specific blockade of norepinephrine reuptake is more potent in treating cataplexy than a specific blockade of serotonin reuptake. This argues for the development of more specific norepinephrine reuptake inhibitors for the treatment of narcolepsy. PMID- 27118716 TI - Training Rehabilitation as an Effective Treatment for Patients With Vascular Cognitive Impairment With No Dementia. AB - PURPOSE: The aim of this study was to investigate the possible therapeutic effect of cognitive training on the cognitive function of patients with vascular cognitive impairment with no dementia (VCIND). DESIGN: A randomized controlled trial. METHOD: Seventy-three cases of VCIND patients were used as subjects, of which 36 patients were subjected to routine care with systemic cognitive training and classified as the intervention group, whereas the other 37 patients were subjected to a routine care only and classified as the control group. Multidimensional neuropsychological assessments were performed 3 months before and after the intervention. FINDINGS: The patients' performance on functional tests was significantly improved after intervention (p < .05) except from Stroop Color-Word Test (p >= .05). CONCLUSIONS: After systemic cognitive training, VCIND patients showed a significant improvement in visuospatial function, memory function, language function, and attention function, whereas their execution function was partially improved. CLINICAL RELEVANCE: Despite the promising results, there is still a need to improve the support for patients affected by VCIND requiring rehabilitation. PMID- 27118717 TI - The Efficacy of Body-Oriented Yoga in Mental Disorders-A Systematic Review and Meta-Analysis AB - BACKGROUND: The efficacy of body-oriented yoga in the treatment of mental disorders has been investigated in numerous studies. This article is a systematic review and meta-analysis of the relevant publications. METHODS: All studies in which the efficacy of hatha-yoga, i.e., body-oriented yoga with asanas and pranayama, was studied in adult patients suffering from a mental disorder (as diagnosed by ICD or DSM criteria) were included in the analysis. The primary endpoint was disorder-specific symptom severity. The publications were identified by a systematic search in the PubMed, Web of Science, PsycINFO and ProQuest databases, supplemented by a search with the Google Scholar search engine and a manual search in the reference lists of meta-analyses and primary studies, as well as in specialized journals. RESULTS: 25 studies with a total of 1339 patients were included in the analysis. A large and significant effect of yoga was seen with respect to the primary endpoint (symptom severity) (Hedges' g = 0.91; 95% confidence interval [0.55; 1.28]; number needed to treat [NNT]: 2.03), with substantial heterogeneity (I2 = 69.8%) compared to untreated control groups. Small but significant effects of yoga were also seen in comparison with attention control (g = 0.39; [0.04; 0.73]; NNT: 4.55) and physical exercise (g = 0.30; [0.01; 0.59]; NNT: 5.75); no difference in efficacy was found between yoga and standard psychotherapy (g = 0.08; [-0.24; 0,40]; NNT: 21.89). In view of the relatively high risk of bias, these findings should be interpreted with caution. CONCLUSION: Body-oriented yoga with asanas and pranayama as central components is a promising complementary treatment for mental disorders and should be investigated in further high-quality studies. PMID- 27118719 TI - Proctologists Omitted. PMID- 27118718 TI - Health and Disease at Age 100. AB - BACKGROUND: Centenarian studies from around the world have shown that reaching age 100 typically involves substantial health issues. The present study adds to the existing knowledge from other countries by describing health conditions in German centenarians. METHODS: A total of 112 centenarians or their primary contacts provided information on acute and chronic health conditions and pain in the context of the Second Heidelberg Centenarian Study (mean age = 100.45 years, standard deviation [SD] = 0.47, 89% females). RESULTS: Participants showed high comorbidity, with an average of five illnesses (mean = 5.3; SD = 2.20). Health conditions with highest prevalence were sensory (vision, hearing; 94%), mobility (72%) and musculoskeletal conditions (60%). Cardiovascular conditions (57%) and urinary system ailments (55%) were also common. Pain was experienced often by 30% of the participants. Of those reporting any pain, 36% indicated pain exceeding bearable levels. CONCLUSION: German centenarians experienced a substantial number of ill nesses, dominated by sensory and mobility conditions. Cardiovascular diseases were the only potentially lethal illnesses with high prevalence. Evidence of unaddressed pain seems alarming, requiring future research. Emerging health profiles indicate that even in very advanced age, quality of life may be improved by enhanced diagnostics and optimal disease management. Mobility limitations may be addressed with preventive efforts. PMID- 27118720 TI - Broadened View. PMID- 27118721 TI - Vaginal Delivery as Leading Risk Factor. PMID- 27118722 TI - NPH Among the Potential Causes. PMID- 27118723 TI - In Reply. PMID- 27118724 TI - Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity. AB - Complementarity determining region (CDR) loop flexibility has been suggested to play an important role in the selection and binding of ligands by T cell receptors (TCRs) of the cellular immune system. However, questions remain regarding the role of loop motion in TCR binding, and crystallographic structures have raised questions about the extent to which generalizations can be made. Here we studied the flexibility of two structurally well characterized alphabeta TCRs, A6 and DMF5. We found that the two receptors utilize loop motion very differently in ligand binding and cross-reactivity. While the loops of A6 move rapidly in an uncorrelated fashion, those of DMF5 are substantially less mobile. Accordingly, the mechanisms of binding and cross-reactivity are very different between the two TCRs: whereas A6 relies on conformational selection to select and bind different ligands, DMF5 uses a more rigid, permissive architecture with greater reliance on slower motions or induced-fit. In addition to binding site flexibility, we also explored whether ligand-binding resulted in common dynamical changes in A6 and DMF5 that could contribute to TCR triggering. Although binding-linked motional changes propagated throughout both receptors, no common features were observed, suggesting that changes in nanosecond-level TCR structural dynamics do not contribute to T cell signaling. PMID- 27118726 TI - Low-temperature catalytic oxidative coupling of methane in an electric field over a Ce-W-O catalyst system. AB - We examined oxidative coupling of methane (OCM) over various Ce-W-O catalysts at 423 K in an electric field. Ce2(WO4)3/CeO2 catalyst showed high OCM activity. In a periodic operation test over Ce2(WO4)3/CeO2 catalyst, C2 selectivity exceeded 60% during three redox cycles. However, Ce2(WO4)3/CeO2 catalyst without the electric field showed low activity, even at 1073 K: CH4 Conv., 6.0%; C2 Sel., 2.1%. A synergetic effect between the Ce2(WO4)3 structure and electric field created the reactive oxygen species for selective oxidation of methane. Results of XAFS, in-situ Raman and periodic operation tests demonstrated that OCM occurred as the lattice oxygen in Ce2(WO4)3 (short W-O bonds in distorted WO4 unit) was consumed. The consumed oxygen was reproduced by a redox mechanism in the electric field. PMID- 27118725 TI - Multistep Compositional Remodeling of Supported Lipid Membranes by Interfacially Active Phosphatidylinositol Kinases. AB - The multienzyme catalytic phosphorylation of phosphatidylinositol (PI) in a supported lipid membrane platform is demonstrated for the first time. One-step treatment with PI 4-kinase IIIbeta (PI4Kbeta) yielded PI 4-phosphate (PI4P), while a multistep enzymatic cascade of PI4Kbeta followed by PIP 5-kinase produced PI-4,5-bisphosphate (PI(4,5)P2 or PIP2). By employing quartz crystal microbalance with dissipation monitoring, we were able to track membrane association of kinase enzymes for the first time as well as detect PI4P and PI(4,5)P2 generation based on subsequent antibody binding to the supported lipid bilayers. Pharmacologic inhibition of PI4Kbeta by a small molecule inhibitor was also quantitatively assessed, yielding an EC50 value that agrees well with conventional biochemical readout. Taken together, the development of a PI-containing supported membrane platform coupled with surface-sensitive measurement techniques for kinase studies opens the door to exploring the rich biochemistry and pharmacological targeting of membrane-associated phosphoinositides. PMID- 27118727 TI - Isolation and characterization of culturable seed-associated bacterial endophytes from gnotobiotically grown Marama bean seedlings. AB - Marama bean (Tylosema esculentum) is an indigenous non-nodulating legume to the arid agro-ecological parts of Southern Africa. It is a staple food for the Khoisan and Bantu people from these areas. It is intriguing how it is able to synthesize the high-protein content in the seeds since its natural habitat is nitrogen deficient. The aim of the study was to determine the presence of seed transmittable bacterial endophytes that may have growth promoting effects, which may be particularly important for the harsh conditions. Marama bean seeds were surface sterilized and gnotobiotically grown to 2 weeks old seedlings. From surface-sterilized shoots and roots, 123 distinct bacterial isolates were cultured using three media, and identified by BOX-PCR fingerprinting and sequence analyses of the 16S rRNA and nifH genes. Phylogenetic analyses of 73 putative endophytes assigned them to bacterial species from 14 genera including Proteobacteria (Rhizobium, Massilia, Kosakonia, Pseudorhodoferax, Caulobacter, Pantoea, Sphingomonas, Burkholderia, Methylobacterium), Firmicutes (Bacillus), Actinobacteria (Curtobacterium, Microbacterium) and Bacteroidetes (Mucilaginibacter, Chitinophaga). Screening for plant growth-promoting activities revealed that the isolates showed production of IAA, ACC deaminase, siderophores, endoglucanase, protease, AHLs and capacities to solubilize phosphate and fix nitrogen. This is the first report that marama bean seeds may harbor endophytes that can be cultivated from seedlings; in this community of bacteria, physiological characteristics that are potentially plant growth promoting are widespread. PMID- 27118728 TI - Impact of Type 1 Diabetes Technology on Family Members/Significant Others of People With Diabetes. AB - BACKGROUND: The aim was to explore the impact of diabetes-related technology to ensure that such devices are used in a way that returns maximum benefit from a medical and psychological perspective. METHOD: Spouses and caregivers of people with type 1 diabetes were invited to complete an online questionnaire about their experiences with diabetes technologies used by their family members. Participants were recruited via the Glu online community website. Questions explored impact on daily living, frequency and severity of hypoglycemia, and diabetes-related distress. RESULTS: In all, 100 parents/caregivers and 74 partners participated in this survey. Average (mean) duration of living with a person with type 1 diabetes was 16 years (SD = 13) for partners, with duration of diabetes for children being 4.2 +/- 3.2 years. Average duration of current therapy was 8.3 +/- 7.3 years for adults and 3.4 +/- 2.9 years for children. Of the participants, 86% partners and 82% parents/caregivers reported diabetes technology had made it easier for their family members to achieve blood glucose targets. Compared to partners, parents/caregivers reported more negative emotions (P < .001) and decreased well being (P < .001) related to their family members type 1 diabetes. Diabetes related distress was common, as was sleep disturbance associated with device alarms and fear of hypoglycemia. Reduced frequency and severity of hypoglycemia related to device use was reported by approximately half of participants. CONCLUSION: There is little doubt about the medical benefit of diabetes technologies and their uptake is increasing but some downsides were reported. Barriers to uptake of technologies lie beyond the mechanics of diabetes management. Supporting users in using diabetes technology to achieve the best possible glycemic control, in the context of their own life, is crucial. Furthermore, understanding these issues with input from the type 1 diabetes community including family members and caregivers will help innovation and design of new technology. PMID- 27118731 TI - The use of ultrasound to assess fetal growth in a guinea pig model of fetal growth restriction. AB - Fetal growth restriction (FGR) is a common and potentially severe pregnancy complication. Currently there is no treatment available. The guinea pig is an attractive model of human pregnancy as placentation is morphologically very similar between the species. Nutrient restriction of the dam creates growth restricted fetuses while leaving an intact uteroplacental circulation, vital for evaluating novel therapies for FGR. Growth-restricted fetuses were generated by feeding Dunkin Hartley guinea pig dams 70% of ad libitum intake from four weeks before and throughout pregnancy. The effect of maternal nutrient restriction (MNR) on dams and fetuses was carefully monitored, and ultrasound measurements of pups collected. There was no difference in maternal weight at conception, however by five weeks post conception MNR dams were significantly lighter ( P < 0.05). MNR resulted in significantly smaller pup size from 0.6-0.66 gestation. Ultrasound is a powerful non-invasive tool for assessing the effect of therapeutic interventions on fetal growth, allowing longitudinal measurement of fetuses. This model and method yield data applicable to the human condition without the need for animal sacrifice and will be useful in the translation of therapies for FGR into the clinic. PMID- 27118729 TI - The Quantitative Relationship Between ISO 15197 Accuracy Criteria and Mean Absolute Relative Difference (MARD) in the Evaluation of Analytical Performance of Self-Monitoring of Blood Glucose (SMBG) Systems. AB - The relationship between International Organization for Standardization (ISO) accuracy criteria and mean absolute relative difference (MARD), 2 methods for assessing the accuracy of blood glucose meters, is complex. While lower MARD values are generally better than higher MARD values, it is not possible to define a particular MARD value that ensures a blood glucose meter will satisfy the ISO accuracy criteria. The MARD value that ensures passing the ISO accuracy test can be described only as a probabilistic range. In this work, a Bayesian model is presented to represent the relationship between ISO accuracy criteria and MARD. Under the assumptions made in this work, there is nearly a 100% chance of satisfying ISO 15197:2013 accuracy requirements if the MARD value is between 3.25% and 5.25%. PMID- 27118732 TI - Authors' reply to Ninan and Millar and Abou-saleh. PMID- 27118733 TI - Patient safety took second place to research needs at NIH hospital, says report. PMID- 27118734 TI - Older people need an individualised approach to treating hypertension. PMID- 27118735 TI - Hydrogen-rich gas production via fast pyrolysis of biophysical dried sludge: Effect of particle size and moisture content on product yields and syngas composition. AB - After biophysical drying, a novel biophysical dried sludge particle was obtained. This work aims to investigate the function and effects of particle sizes and moisture contents on the fast pyrolysis of biophysical dried sludge particles. The results showed that large particles (>4 mm) favoured the oil generation with a maximum value of 19.0%, and small particles (<0.27 mm) favoured the char yield with a maximum value of 60.6%. Medium particle fractions (between 0.27 mm and 4 mm) benefited syngas production and induced higher H2 and CO emission, owing to the well-developed microstructure, enrichment of cellulose, and enhanced catalytic effects during the charring process. The introduction of proper moisture content (53.9% to 62.6%) to biophysical dried sludge was found to dramatically enhance syngas yield, hydrogen production, and carbon conversion efficiency. H2 molar concentration reached a maximum of 46.02% at a moisture content of 53.9%, which was attributed to the steam reforming and steam gasification accompanying the initial biophysical dried sludge pyrolysis. PMID- 27118736 TI - Utilisation of biomass gasification by-products for onsite energy production. AB - Small scale biomass gasification is a sector with growth and increasing applications owing to the environmental goals of the European Union and the incentivised policies of most European countries. This study addresses two aspects, which are at the centre of attention concerning the operation and development of small scale gasifiers; reuse of waste and increase of energy efficiency. Several authors have denoted that the low electrical efficiency of these systems is the main barrier for further commercial development. In addition, gasification has several by-products that have no further use and are discarded as waste. In the framework of this manuscript, a secondary reactor is introduced and modelled. The main operating principle is the utilisation of char and flue gases for further energy production. These by-products are reformed into secondary producer gas by means of a secondary reactor. In addition, a set of heat exchangers capture the waste heat and optimise the process. This case study is modelled in a MATLAB-Cantera environment. The model is non-stoichiometric and applies the Gibbs minimisation principle. The simulations show that some of the thermal energy is depleted during the process owing to the preheating of flue gases. Nonetheless, the addition of a secondary reactor results in an increase of the electrical power production efficiency and the combined heat and power (CHP) efficiency. PMID- 27118737 TI - Improvements to enforcement of multilateral environmental agreements to control international shipments of chemicals and wastes. AB - Illegal trade in hazardous waste and harmful chemicals has caused severe damage on human health and the environment, and brought big challenges to countries to meet their commitments to related multilateral environmental agreements. Synergy building, like organising law enforcement operations, is critical to address illegal trade in waste and chemicals, and further improve the effectiveness of environmental enforcement. This article discusses how and why law enforcement operations can help countries to implement chemical and waste-related multilateral environmental agreements in a more efficient and effective way. The research explores key barriers and factors for organising law enforcement operations, and recommends methods to improve law enforcement operations to address illegal trade in hazardous waste and harmful chemicals. PMID- 27118738 TI - Assessment of alternative disposal methods to reduce greenhouse gas emissions from municipal solid waste in India. AB - Open dumping, the most commonly practiced method of solid waste disposal in Indian cities, creates serious environment and economic challenges, and also contributes significantly to greenhouse gas emissions. The present article attempts to analyse and identify economically effective ways to reduce greenhouse gas emissions from municipal solid waste. The article looks at the selection of appropriate methods for the control of methane emissions. Multivariate functional models are presented, based on theoretical considerations as well as the field measurements to forecast the greenhouse gas mitigation potential for all the methodologies under consideration. Economic feasibility is tested by calculating the unit cost of waste disposal for the respective disposal process. The purpose built landfill system proposed by Yedla and Parikh has shown promise in controlling greenhouse gas and saving land. However, these studies show that aerobic composting offers the optimal method, both in terms of controlling greenhouse gas emissions and reducing costs, mainly by requiring less land than other methods. PMID- 27118739 TI - Relapsing peritonitis with Bacillus cereus in a patient on continuous ambulatory peritoneal dialysis. AB - We present a case where Bacillus cereus was determined to be the causative agent of relapsing peritonitis in a patient on continuous ambulatory peritoneal dialysis (CAPD). The patient, a 70-year-old man from the Faroe Islands, was admitted with relapsing peritonitis four times over a 3-month period. Peritoneal cultures were positive for growth of B. cereus, a rare bacterial cause of peritonitis. The cultures demonstrated susceptibility to vancomycin, and therefore the patient was treated with intraperitoneal vancomycin, intraperitoneal gentamycin and oral ciprofloxacin. As a result of the relapsing B. cereus peritonitis diagnosis and a CT scan showing contraction of the peritoneum after longstanding inflammation, the peritoneal catheter was removed and the patient converted to haemodialysis. To date, the patient has not been readmitted due to peritonitis. A lack of proper hygiene when changing the dialysis bag was the suspected source of infection with B. cereus. PMID- 27118740 TI - Incidentally discovered urachal cancer in a patient with necrotising fasciitis of the abdominal wall. PMID- 27118741 TI - Trimethylaminuria. AB - We report the case of a 9-year-old boy referred to secondary care with an unusual presentation of a fishy odour to his hands, feet, saliva and urine. Laboratory investigations including urine analysis and genetic testing confirmed the diagnosis of trimethylaminuria. The patient was referred to a geneticist and dietician, and consequently treated with dietary modification. He now has an arguably much improved quality of life. PMID- 27118742 TI - Hypophosphataemia due to FGF-23 producing B cell non-Hodgkin's lymphoma. AB - Oncogenic osteomalacia (or tumour-induced osteomalacia) is a rare paraneoplastic syndrome caused by overproduction of fibroblastic growth factor 23 (FGF-23) by tumours. Excessive production of FGF-23 can lead to severe, symptomatic hypophosphataemia. The majority of cases have been associated with benign tumours of bone or soft tissue, such as haemangiopericytomas or other neoplasms of mesenchymal origin. We present a case of a 68-year-old woman with an FGF-23 producing B cell non-Hodgkin's lymphoma. Treatment with immunochemotherapy resulted in normalisation of serum FGF-23 and phosphate levels. PMID- 27118743 TI - Rare case of eosinophilic granulomatosis with polyangiitis in two patients with alpha-1-antitrypsin deficiency (PiSZ). AB - We present two cases of eosinophilic granulomatosis with polyangiitis occurring with alpha-1-antitrypsin deficiency, both PiSZ phenotype. The simultaneous occurrence of these two conditions has seldom been described in the literature, despite evidence of an association between alpha-1-antitrypsin deficiency and other forms of vasculitis. Both patients had pulmonary involvement and reported intermittent exacerbations of vasculitic symptoms. Both patients were managed on low-dose oral steroids and azathioprine remaining well with occasional exacerbations. It is important to consider whether there is an association between eosinophilic granulomatosis with polyangiitis and alpha-1-antitrypsin deficiency, as this may lead to more severe pulmonary symptoms during exacerbations. If a genetic association between the two conditions is found, clinicians should be aware of the possible need to screen for alpha-1-antitrypsin deficiency in appropriate patients. PMID- 27118744 TI - Osteolysis of the terminal phalanges of the hand. PMID- 27118745 TI - Burning vasculitis. AB - We present the case of a 69-year-old man who was found collapsed close to a heat source and admitted to hospital for severe sepsis. He was also found to have widespread blistering and ulceration of his right leg; however, a history was unobtainable due to reduced consciousness levels. The leg lesions had the initial appearance of mixed depth burns and a management plan was made to transfer the patient to a burns unit for debridement. It was subsequently noted that the patient had a previous diagnosis of seropositive erosive rheumatoid arthritis. A biopsy of the leg lesion was performed and a diagnosis of rheumatoid vasculitis confirmed. Treatment with systemic steroids, intravenous antibiotics and intravenous immunoglobulin therapy for severe hypogammaglobulinaemia was started, and the patient was not transferred for surgical debridement. Rheumatoid vasculitis is a rare and extremely serious complication of rheumatoid arthritis that can manifest in a number of ways, occasionally mimicking other conditions. This case is essential to raise awareness of rare, severe rheumatoid vasculitis and of the potential for its misdiagnosis as a mixed depth burn. PMID- 27118746 TI - Convexity subarachnoid haemorrhage secondary to internal carotid stenosis: an indication for revascularisation. AB - With increasing prevalence due to an ageing population, carotid artery stenosis is a significant cause of stroke morbidity and mortality. The indication for revascularisation treatment in symptomatic carotid stenosis is widely documented and accepted in the scientific community. However, treatment of asymptomatic carotid stenosis remains controversial. We report a case of a 78-year-old woman who was admitted with a convexity subarachnoid haemorrhage (cSAH) secondary to an asymptomatic high-grade carotid artery stenosis. Two months later, she suffered an atherothrombotic ischaemic stroke and was referred to surgery. Transcranial Doppler studies showed impaired cerebral vasoreactivity and, after endarterectomy, the patient developed a reperfusion syndrome; both findings consisting of exhausted collaterals as the underlying mechanism. We propose that cSAH secondary to a high-grade internal carotid artery stenosis is a high risk marker for stroke, and revascularisation therapy should be considered. PMID- 27118747 TI - Newborn with severe epidermolysis bullosa: to treat or not to treat? AB - Epidermolysis bullosa (EB) is an inherited skin disease with four main subtypes that cannot be distinguished clinically at birth. All subtypes may present with widespread life-threatening blisters and fragile skin, making treatment and handling of the newborn with EB challenging. The prognosis of EB depends on the subtype, and therefore maximum treatment is necessary until the final diagnosis is known. In this case, it took 2 weeks before a final diagnosis was reached. In the meantime, we had several ethical discussions on the treatment level. The most important issues were management of pain and nutrition. For immediate pain relief, intranasal fentanyl worked best and gabapentin was successfully used for chronic pain. The feeding difficulties were handled first by a nasogastric feeding tube. Later a normal feeding bottle proved to be adequate. PMID- 27118748 TI - Severe acute kidney injury as presentation of Burkitt's lymphoma. AB - We discuss a case of acute kidney injury (AKI) at a very young age caused by primary lymphomatous renal infiltration due to Burkitt's lymphoma and analyse the literature on this rare condition. At presentation, clinical examination showed impressive bilateral nephromegaly and hypertension. Blood analysis indicated severe AKI, mild anaemia and normal serum electrolytes. There were no signs of tumour lysis syndrome. Urine sediment was normal, with neither haematuria nor proteinuria. Abdominal ultrasound demonstrated bilateral renal enlargement (+12 SD), with increased corticomedullar differentiation. MRI demonstrated the presence of a homogenous renal enlargement with features of an infiltrative lesion. Ultimately, microscopic and immunohistochemical analysis of the renal biopsy confirmed the diagnosis of Burkitt's lymphoma. Early and aggressive therapy is the key to ensure a good outcome. PMID- 27118749 TI - Ocular presentation of natural killer/T-cell lymphoma in a Caucasian man. AB - Natural killer/T-cell (NK/T-cell) lymphoma-nasal subtype, is a rare form of non Hodgkin's lymphoma, most common in South East Asia, and can have an ophthalmological presentation. This report describes a 51-year-old Caucasian man with uveitis, recurrent retinal detachment and paraneoplastic features subsequently diagnosed as NK/T-cell lymphoma. PMID- 27118750 TI - Extra-axial primary non-Hodgkin's CNS lymphoma mimicking meningioma, in a 5-year old immunocompetent child: a rare entity. AB - We describe a case of a 5-year-old immunocompetent girl who presented with features of raised intracranial pressure with left eye ptosis of 1-month duration. CT scan and MRI of the brain showed an extra-axial, intensely contrast enhancing lesion in the left temporoparieto-occipital region, consistent with meningioma. On open tissue biopsy and immunohistochemistry staining, a diagnosis of B cell non-Hodgkin's lymphoma was made. Six cycles of chemotherapy with cyclophosphamide, adriamycin, vincristine and prednisolone regimen were given and showed a good clinical outcome without any recurrence during follow-up of 5 months. PMID- 27118751 TI - Tumefactive multiple sclerosis presenting with tonic-clonic seizure. PMID- 27118752 TI - Nadroparin-induced skin necrosis: clinical manifestation of HIT-2 even in the absence of thrombocytopaenia. PMID- 27118753 TI - Acute febrile neutrophilic dermatosis associated with JAK-2 positive myeloproliferative disorder. AB - We present a case of a 77-year-old man with a history of myeloproliferative disorder. He was admitted with a 2-week history of erythaema, swelling and significant pain of the right forearm following a mechanical fall at home, which had caused a skin laceration. During his admission, he developed ongoing intermittent fever and persistently elevated C reactive protein, and total white cell count. Initially, he was treated with antibiotics for suspected cellulitis. However, symptoms continued to progress, making a suitable management plan challenging. Wound swabs, blood cultures and viral PCR did not confirm infection. A punch biopsy of a skin lesion on the forearm was performed. The histology demonstrated a dense infiltrate of neutrophils and neutrophilic debris in keeping with acute febrile neutrophilic dermatosis (Sweet's syndrome). He was treated with oral steroids and after that he had a complete resolution of symptoms. However, he required a period of rehabilitation before returning home. PMID- 27118754 TI - Dome-shaped macula in oculocutaneous albinism. PMID- 27118755 TI - Milroy's disease and scrotal lymphoedema: pathological insight. PMID- 27118756 TI - Granulomatous rosacea-like facial eruption in an elderly man: leukaemia cutis. PMID- 27118757 TI - Application of the clip method, using thread, for duodenal endoscopic mucosal resection. AB - Endoscopic mucosal resection (EMR) of a duodenal tumour is associated with a risk of loss of the resected specimen resulting from air introduction, peristaltic motion of the intestines, insertion of the retrieval device or endoscopic operation, or in cases where the specimen is too large to pass the pylorus. There is a high possibility of losing the tumour if the resected tumour is passed through the second portion of the duodenum. Retrieving a specimen after EMR is essential to obtain a pathological finding. The clip method using thread has been useful for endoscopic submucosal dissection of the oesophagus and stomach. We report the effectiveness of the clip method using thread during duodenal EMR. PMID- 27118758 TI - Detection of Neuroinflammation in a Rat Model of Subarachnoid Hemorrhage Using [18F]DPA-714 PET Imaging. AB - Subarachnoid hemorrhage (SAH) can lead to delayed cerebral ischemia, which increases the rate of morbidity and mortality. The detection of microglial activation may serve as a biomarker for the identification of patients at risk of this deleterious consequence. We assessed this hypothesis in a rat model of SAH in which the exploration of neuroinflammation related to microglial activation was correlated with the degree of bleeding. We used the rat filament model and evaluated (at 48 hours postsurgery) the intensity of neuroinflammation using positron emission tomography (PET) imaging with the 18-kDa translocator protein (TSPO) tracer [(18)F]DPA-714, quantitative autoradiography with [(3)H]PK-11195, and SAH grade by postmortem brain picture. High SAH grades were strongly and positively correlated with in vivo PET imaging of TSPO in the cortex and striatum. In addition, a positive correlation was found in the cortex in TSPO, with densities determined by imaging and autoradiographic approaches. Qualitative immunofluorescence studies indicated that overexpression of TSPO was linked to astrocytic/microglial activation. In this model, PET imaging of TSPO using [(18)F]DPA-714 appeared to be a relevant index of the degree of bleeding, indicating that this imaging method could be used in human patients to improve the management of patients with SAH. PMID- 27118759 TI - De Novo Glutamine Synthesis: Importance for the Proliferation of Glioma Cells and Potentials for Its Detection With 13N-Ammonia. AB - PURPOSE: The aim of this study was to investigate the role of de novo glutamine (Gln) synthesis in the proliferation of C6 glioma cells and its detection with (13)N-ammonia. METHODS: Chronic Gln-deprived C6 glioma (0.06C6) cells were established. The proliferation rates of C6 and 0.06C6 cells were measured under the conditions of Gln deprivation along with or without the addition of ammonia or glutamine synthetase (GS) inhibitor. (13)N-ammonia uptake was assessed in C6 cells by gamma counting and in rats with C6 and 0.06C6 xenografts by micro positron emission tomography (PET) scanning. The expression of GS in C6 cells and xenografts was assessed by Western blotting and immunohistochemistry, respectively. RESULTS: The Gln-deprived C6 cells showed decreased proliferation ability but had a significant increase in GS expression. Furthermore, we found that low concentration of ammonia was sufficient to maintain the proliferation of Gln-deprived C6 cells, and (13)N-ammonia uptake in C6 cells showed Gln-dependent decrease, whereas inhibition of GS markedly reduced the proliferation of C6 cells as well as the uptake of (13)N-ammoina. Additionally, microPET/computed tomography exhibited that subcutaneous 0.06C6 xenografts had higher (13)N-ammonia uptake and GS expression in contrast to C6 xenografts. CONCLUSION: De novo Gln synthesis through ammonia-glutamate reaction plays an important role in the proliferation of C6 cells. (13)N-ammonia can be a potential metabolic PET tracer for Gln-dependent tumors. PMID- 27118761 TI - Reflections of the changes in patent ductus arteriosus management during the last 10 years. AB - Despite a large body of scientific evidence on the management of premature infants with a patent ductus arteriosus controversy remains and neonatologists remain challenged for knowing which patient to treat, what is the most optimal timing of treatment and which treatments have a positive impact on both short term and long-term outcomes. In this review article we discuss the increased body of evidence over the past 10 years, much of which questions the role of treatment and suggests the need to reconsider how haemodynamic significance is adjudicated. In addition, we discuss novel approaches to assessment and diagnosis, and highlight areas for future investigation. PMID- 27118760 TI - MS-1 magA: Revisiting Its Efficacy as a Reporter Gene for MRI. AB - Bacterial genes involved in the biomineralization of magnetic nanoparticles in magnetotactic bacteria have recently been proposed as reporters for magnetic resonance imaging (MRI). In such systems, the expression of the bacterial genes in mammalian cells purportedly leads to greater concentrations of intracellular iron or the biomineralization of iron oxides, thus leading to an enhancement in relaxation rate that is detectable via MRI. Here, we show that the constitutive expression of the magA gene from Magnetospirillum magnetotacticum is tolerated by human embryonic kidney (HEK) cells but induces a strong toxic effect in murine mesenchymal/stromal cells and kidney-derived stem cells, severely restricting its effective use as a reporter gene for stem cells. Although it has been suggested that magA is involved in iron transport, when expressed in HEK cells, it does not affect the transcription of endogenous genes related to iron homeostasis. Furthermore, the magA-induced enhancement in iron uptake in HEK cells is insignificant, suggesting this gene is a poor reporter even for cell types that can tolerate its expression. We suggest that the use of magA for stem cells should be approached with caution, and its efficacy as a reporter gene requires a careful assessment on a cell-by-cell basis. PMID- 27118762 TI - Screening for retinopathy of prematurity: does one size fit all? PMID- 27118763 TI - Post-Encephalitic Parkinsonism and Sleep Disorder Responsive to Immunological Treatment: A Case Report. AB - We describe a 70-year-old man who, after a viral encephalitis associated with pneumonia, progressively developed a parkinsonism associated with lethargy. Encephalitis manifested with persistent hiccups, seizures and impairment of consciousness. After 2 weeks, the initial neurologic symptoms subsided and the patient progressively developed movement disorders (rigidity and bradykinesia, resistant to L-DOPA), lethargy and behavioral hypersomnia. Magnetic resonance imaging showed thalamic and hippocampal signal abnormalities, immunohistochemistry on a mouse brain substrate revealed serum autoantibodies binding to the brainstem neuropil. Polysomnographic monitoring was consistent with a very severe disruption of sleep: the sleep-wake cycle was fragmented, and the NREM-REM ultradian cycle was irregular. Intravenous immune globulin therapy resulted in the complete reversal of the movement and the sleep disorders. Our observation confirms that parkinsonism and sleep disorders may be consequences of encephalitis, that an immune-mediated pathogenesis is likely, and, consequently, that immunotherapy can be beneficial in these patients. The polysomnographic monitoring suggests that lethargia, rather than a mere hypersomnia, is the result of a combination between sleep disruption and altered motor control. PMID- 27118764 TI - Long-Term Evolution Electromagnetic Fields Exposure Modulates the Resting State EEG on Alpha and Beta Bands. AB - Long-term evolution (LTE) wireless telecommunication systems are widely used globally, which has raised a concern that exposure to electromagnetic fields (EMF) emitted from LTE devices can change human neural function. To date, few studies have been conducted on the effect of exposure to LTE EMF. Here, we evaluated the changes in electroencephalogram (EEG) due to LTE EMF exposure. An LTE EMF exposure system with a stable power emission, which was equivalent to the maximum emission from an LTE mobile phone, was used to radiate the subjects. Numerical simulations were conducted to ensure that the specific absorption rate in the subject's head was below the safety limits. Exposure to LTE EMF reduced the spectral power and the interhemispheric coherence in the alpha and beta bands of the frontal and temporal brain regions. No significant change was observed in the spectral power and the inter-hemispheric coherence in different timeslots during and after the exposure. These findings also corroborated those of our previous study using functional magnetic resonant imaging. PMID- 27118765 TI - Lance-Adams Syndrome in the Pretargeted Temperature Management Era. AB - Acute posthypoxic myoclonus portends a poor prognosis. Another form of posthypoxic myoclonus, Lance-Adams syndrome, is associated with a better outcome. Differentiating these two entities is important in prognostication and guiding further medical intervention. This can be difficult in the acute setting after hypoxic brain injury but the use of neurophysiologic studies may be helpful. In this article, we present a case of a patient who presented after pulseless electrical activity arrest, underwent targeted temperature management and subsequently developed Lance-Adams syndrome. The neurologic and electroencephalographic findings in Lance-Adams syndrome are discussed with an updated review. PMID- 27118766 TI - Methods to improve patient recruitment and retention in stroke trials. AB - BACKGROUND: The success of randomized-controlled stroke trials is dependent on the recruitment and retention of a sufficient number of patients, but fewer than half of all trials meet their target number of patients. METHODS: We performed a search and review of the literature, and conducted a survey and workshop among 56 European stroke trialists, to identify barriers, suggest methods to improve recruitment and retention, and make a priority list of interventions that merit further evaluation. RESULTS: The survey and workshop identified a number of barriers to patient recruitment and retention, from patients' incapacity to consent, to handicaps that prevent patients from participation in trial-specific follow-up. Methods to improve recruitment and retention may include simple interventions with individual participants, funding of research networks, and reimbursement of new treatments by health services only when delivered within clinical trials. The literature review revealed that few methods have been formally evaluated. The top five priorities for evaluation identified in the workshop were as follows: short and illustrated patient information leaflets, nonwritten consent, reimbursement for new interventions only within a study, and monetary incentives to institutions taking part in research (for recruitment); and involvement of patient groups, remote and central follow-up, use of mobile devices, and reminders to patients about their consent to participate (for retention). CONCLUSIONS: Many interventions have been used with the aim of improving recruitment and retention of patients in stroke studies, but only a minority has been evaluated. We have identified methods that could be tested, and propose that such evaluations may be nested within on-going clinical trials. PMID- 27118767 TI - Sensory profile and acceptability for pitanga (Eugenia uniflora L.) nectar with different sweeteners. AB - The objective of this study was to evaluate the sensory properties and acceptability of pitanga nectar samples prepared with sucrose and different sweeteners (sucralose, aspartame, stevia with 40% rebaudioside A, stevia with 95% rebaudioside A, neotame, and a 2:1 cyclamate/saccharin blend). A total of 13 assessors participated in a quantitative descriptive analysis and evaluated the samples in relation to the descriptor terms. The acceptability test was carried out by 120 fruit juice consumers. The results of the quantitative descriptive analysis of pitanga nectar showed that samples prepared with sucralose, aspartame, and the 2:1 cyclamate/saccharin blend had sensory profiles similar to that of the sample prepared with sucrose. Consumers' most accepted samples were prepared with sucrose, sucralose, aspartame, and neotame. The sweeteners that have the greatest potential to replace sucrose in pitanga nectar are sucralose and aspartame. PMID- 27118768 TI - Evaluation of a potentially probiotic non-dairy beverage developed with honey and kefir grains: Fermentation kinetics and storage study. AB - The aim of this work was to study the fermentation process of honey with kefir grains through a comprehensive understanding of its rheological properties, probiotic cell viability, instrumental color parameters and kinetic aspects in a batch bioreactor and during storage. The results showed that kefir grains were well adapted to bioreactor conditions, reaching high levels of cell viability (over 106 CFU mL-1 for total yeast and bacteria), phenolic compounds content (190 GAE/100 g) and acidification after 24 h of fermentation at 30 C. Colorimetric analysis showed that lightness (L*) and redness (a*) remained constant, while yellowness intensities (b*) decreased during fermentation time. After 35 days of storage, honey kefir beverage maintained its chemical characteristics and microbial viability as required to be classified as a probiotic product. The Ostwald-de-Waele (R2 >= 0.98) and Herschel-Bulkley (R2 >= 0.99) models can be used to predict the behavior of honey kefir beverage. The parameters analyzed in this study should be taken into account for industrial production of this novel non-dairy beverage. PMID- 27118769 TI - ERK-GluR1 phosphorylation in trigeminal spinal subnucleus caudalis neurons is involved in pain associated with dry tongue. AB - BACKGROUND: Dry mouth is known to cause severe pain in the intraoral structures, and many dry mouth patients have been suffering from intraoral pain. In development of an appropriate treatment, it is crucial to study the mechanisms underlying intraoral pain associated with dry mouth, yet the detailed mechanisms are not fully understood. To evaluate the mechanisms underlying pain related to dry mouth, the dry-tongue rat model was developed. Hence, the mechanical or heat nocifensive reflex, the phosphorylated extracellular signal-regulated kinase and phosphorylated GluR1-IR immunohistochemistries, and the single neuronal activity were examined in the trigeminal spinal subnucleus caudalis of dry-tongue rats. RESULTS: The head-withdrawal reflex threshold to mechanical, but not heat, stimulation of the tongue was significantly decreased on day 7 after tongue drying. The mechanical, but not heat, responses of trigeminal spinal subnucleus caudalis nociceptive neurons were significantly enhanced in dry-tongue rats compared to sham rats on day 7. The number of phosphorylated extracellular signal regulated kinase-immunoreactive cells was also significantly increased in the trigeminal spinal subnucleus caudalis following noxious stimulation of the tongue in dry-tongue rats compared to sham rats on day 7. The decrement of the mechanical head-withdrawal reflex threshold (HWT) was reversed during intracisternal administration of the mitogen-activated protein kinase kinase 1 inhibitor, PD98059. The trigeminal spinal subnucleus caudalis neuronal activities and the number of phosphorylated extracellular signal-regulated kinase immunoreactive cells following noxious mechanical stimulation of dried tongue were also significantly decreased following intracisternal administration of PD98059 compared to vehicle-administrated rats. Increased number of the phosphorylated GluR1-IR cells was observed in the trigeminal spinal subnucleus caudalis of dry-tongue rats, and the number of phosphorylated GluR1-IR cells was significantly reduced in PD98059-administrated rats compared to the vehicle administrated tongue-dry rats. CONCLUSIONS: These findings suggest that the pERK pGluR1 cascade is involved in central sensitization of trigeminal spinal subnucleus caudalis nociceptive neurons, thus resulting in tongue mechanical hyperalgesia associated with tongue drying. PMID- 27118770 TI - Impacts of anti-nerve growth factor antibody on pain-related behaviors and expressions of opioid receptor in spinal dorsal horn and dorsal root ganglia of rats with cancer-induced bone pain. AB - OBJECTIVE: To investigate the impacts of anti-nerve growth factor antibody on pain-related behaviors and expressions of MU-opioid receptor in spinal dorsal horn and dorsal root ganglia of rats with cancer-induced bone pain. METHODS: The rats were randomly grouped and then injected with 10 MUl of phosphate buffer saline or Walker256 tumor cells into the upper segment of left tibia. Thirteen days after the injection, the intrathecal catheterization was performed, followed by the injection of saline, anti-nerve growth factor, nerve growth factor, and naloxone twice a day. The pain ethological changes were measured at the set time points; the expression changes of MU-opioid receptor protein and mRNA in spinal dorsal horn and dorsal root ganglia were detected on the 18th day. RESULTS: After the tumor cells were injected into the tibia, hyperalgesia appeared and the expression of MU-opioid receptor protein and mRNA in spinal dorsal horn and dorsal root ganglia was increased, compared with the sham group; after intrathecally injected anti-nerve growth factor, the significant antinociceptive effects appeared, and the MU-opioid receptor expression was increased, compared with the cancer pain group; the MU-opioid receptor expressions in the other groups showed no statistical significance. The naloxone pretreatment could mostly inverse the antinociception effects of anti-nerve growth factor. CONCLUSIONS: Anti-nerve growth factor could reduce hyperalgesia in the cancer-induced bone pain rats, and the antinociceptive effects were related with the upregulation of MU-opioid receptor. PMID- 27118772 TI - Isolation of mecC MRSA in Australia. PMID- 27118771 TI - Enhanced itch elicited by capsaicin in a chronic itch model. AB - Chronic itch (pruritus) is an important clinical problem. However, the underlying molecular basis has yet to be understood. The Transient Receptor Potential Vanilloid 1 channel is a heat-sensitive cation channel expressed in primary sensory neurons and involved in both thermosensation and pain, but its role in chronic itch remains elusive. Here, we for the first time revealed an increased innervation density of Transient Receptor Potential Vanilloid 1-expressing sensory fibers in the skin afflicted with chronic itch. Further analysis indicated that this phenomenon is due to an expansion of Transient Receptor Potential Vanilloid 1-expressing sensory neurons under chronic itch conditions. As a functional correlates of this neuronal expansion, we observed an enhanced neuronal responsiveness to capsaicin under the dry skin conditions. Importantly, the neuronal hypersensitivity to capsaicin results in itch, rather than pain sensation, suggesting that the up-regulated Transient Receptor Potential Vanilloid 1 underlies the pain-to-itch switch under chronic itchy conditions. The study shows that there are different mechanisms of chronic pain and itching, and Transient Receptor Potential Vanilloid 1 plays an important role in chronic itch. PMID- 27118773 TI - Characterization of an outbreak due to CTX-M-15-producing Klebsiella pneumoniae lacking the blaOXA-48 gene belonging to clone ST405 in a neonatal unit in southern Spain. PMID- 27118774 TI - Unnatural amino acid analogues of membrane-active helical peptides with anti mycobacterial activity and improved stability. AB - OBJECTIVES: The emergence of MDR-TB, coupled with shrinking antibiotic pipelines, has increased demands for new antimicrobials with novel mechanisms of action. Antimicrobial peptides have increasingly been explored as promising alternatives to antibiotics, but their inherent poor in vivo stability remains an impediment to their clinical utility. We therefore systematically evaluated unnatural amino acid-modified peptides to design analogues with enhanced anti-mycobacterial activities. METHODS: Anti-mycobacterial activities were evaluated in vitro and intracellularly against drug-susceptible and MDR isolates of Mycobacterium tuberculosis using MIC, killing efficacy and intracellular growth inhibition studies. Toxicity profiles were assessed against mammalian cells to verify cell selectivity. Anti-mycobacterial mechanisms were investigated using microfluidic live-cell imaging with time-lapse fluorescence microscopy and confocal laser scanning microscopy. RESULTS: Unnatural amino acid incorporation was well tolerated without an appreciable effect on toxicity profiles and secondary conformations of the synthetic peptides. The modified peptides also withstood proteolytic digestion by trypsin. The all d-amino acid peptide, i(llkk)2i (II-D), displayed superior activity against all six mycobacterial strains tested, with a 4-fold increase in selectivity index as compared with the unmodified l-amino acid peptide in broth. II-D effectively reduced the intracellular bacterial burden of both drug-susceptible and MDR clinical isolates of M. tuberculosis after 4 days of treatment. Live-cell imaging studies demonstrated that II-D permeabilizes the mycobacterial membrane, while confocal microscopy revealed that II-D not only permeates the cell membrane, but also accumulates within the cytoplasm. CONCLUSIONS: Unnatural amino acid modifications not only decreased the susceptibility of peptides to proteases, but also enhanced mycobacterial selectivity. PMID- 27118775 TI - Evaluation of the K-SeT R.E.S.I.S.T. immunochromatographic assay for the rapid detection of KPC and OXA-48-like carbapenemases. PMID- 27118776 TI - Evidence from a New York City hospital of rising incidence of genetically diverse carbapenem-resistant Enterobacter cloacae and dominance of ST171, 2007-14. PMID- 27118777 TI - l-Serine potentiates fluoroquinolone activity against Escherichia coli by enhancing endogenous reactive oxygen species production. AB - BACKGROUND: The increase in multiple antimicrobial-resistant bacteria seriously threatens global public health. Novel effective strategies are urgently needed. l Serine was reported as the most effective amino acid inhibitor against bacterial growth and can sensitize Escherichia coli cells to gentamicin. It is currently unknown whether l-serine affects other type of antibiotics such as beta-lactams and fluoroquinolones. METHODS: Using E. coli, we studied the combination of l serine with diverse antibiotics against laboratory and clinical E. coli cultures and persisters. The intracellular NAD(+)/NADH level and ROS were determined using kits. Total cellular iron was determined by using a colorimetric ferrozine-based assay. RESULTS: Exogenous l-serine sensitized E. coli ATCC 25922 and clinically isolated fluoroquinolone-resistant E. coli to fluoroquinolones. This potentiation is independent of growth phase. Addition of serine increases the production of NADH. The underlying mechanism of this strategy is that the combination of serine with ofloxacin or moxifloxacin increases the NAD(+)/NADH ratio, disrupts the Fe-S clusters and increases the production of endogenous reactive oxygen species. Furthermore, we used a serine and ofloxacin or moxifloxacin combination in vitro to combat bacterial persister cells, compared with antibiotic treatment alone; combinational treatments of persister cells with antibiotics and l-serine resulted in a significantly greater decrease in cell viability. CONCLUSIONS: To our knowledge, this is the first report that l-serine can potentiate the action of ofloxacin or moxifloxacin against Gram-negative bacteria and could constitute a new strategy for the eradication of bacterial infections. PMID- 27118778 TI - Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance. AB - OBJECTIVES: Fosfomycin resistance occurs rapidly with monotherapy. This study systematically investigated bacterial killing and emergence of fosfomycin resistance with fosfomycin combinations against Pseudomonas aeruginosa. METHODS: Four clinical isolates and a reference strain of P. aeruginosa were employed. Combinations of fosfomycin plus polymyxin B, tobramycin or ciprofloxacin were examined over 24 h using time-kill studies (inocula ~10(6) cfu/mL) incorporating clinically relevant concentrations (fosfomycin, 30, 150 or 300 mg/L; polymyxin B, 0.5, 1 or 2 mg/L; tobramycin, 0.5, 1.5 or 4 mg/L; ciprofloxacin, 0.5, 1 or 2.5 mg/L). Microbiological response was examined by log changes and population analysis profiles. RESULTS: Against susceptible isolates, monotherapy produced varying degrees of initial killing followed by rapid regrowth. Fosfomycin plus polymyxin B or tobramycin produced greater initial killing (up to ~4 log10 cfu/mL) with many concentrations compared with monotherapy against fosfomycin susceptible (FOF(S)) isolates. With these combinations, synergy or additivity was observed in 54 (67%) and 49 (60%) of 81 cases (nine combinations across three isolates at three timepoints) for polymyxin B and tobramycin, respectively. Substantial improvements in killing were absent against fosfomycin-resistant (FOF(R)) isolates. For fosfomycin/ciprofloxacin combinations, synergy or additivity was observed against FOF(R) isolates in 33 of 54 (61%) cases (nine combinations across two isolates at three timepoints), while improvements in killing were largely absent against FOF(S) isolates. No combination prevented emergence of fosfomycin resistance. CONCLUSIONS: Against P. aeruginosa, fosfomycin in combination with polymyxin B or tobramycin (FOF(S) isolates) or ciprofloxacin (FOF(R) isolates) increased bacterial killing, but did not suppress emergence of fosfomycin resistance. PMID- 27118779 TI - Risk factors for the acquisition of OXA-48-producing Enterobacteriaceae in a hospital outbreak setting: a matched case-control study. AB - OBJECTIVES: In the context of a large outbreak of OXA-48-producing Enterobacteriaceae (OXA-E) in a Dutch hospital we determined risk factors for acquisition of OXA-E. PATIENTS AND METHODS: A matched case-control study was performed in which cases (culture positive for OXA-E) were matched 1:3 to controls (culture negative for OXA-E) based on hospital ward, index date (+/-1 week) and time exposed in the hospital (best match). Stratified analyses were performed for patients with OXA-E producing and not producing ESBL. Potential risk factors included age, gender, surgery and ICU admission within 30 days preceding the index date, presence of comorbidities and in-hospital antibiotic treatment within 30 days preceding the index date. Data analysis was performed using multivariable conditional logistic regression with Firth correction. RESULTS: In total, 73 cases were matched to 211 controls. In the multivariable conditional logistic regression model, male gender (OR 2.63, 95% CI 1.25-5.53), age (per year increase, OR 1.03, 95% CI 1.00-1.05) and use of fluoroquinolones within 30 days preceding the index date (OR 2.98, 95% CI 1.06-8.41) were risk factors for acquisition of OXA-E. In the stratified multivariable conditional logistic regression model, quinolone use was a risk factor for the acquisition of ESBL-producing OXA-E and surgery was a risk factor for the acquisition of non ESBL-producing OXA-E. CONCLUSIONS: During a large, hospital-wide OXA-E outbreak, male gender, age and previous use of fluoroquinolones were risk factors for acquisition of OXA-E. These findings may help in optimizing screening and isolation strategies in future OXA-E outbreaks. PMID- 27118780 TI - National surveillance of Staphylococcus epidermidis recovered from bloodstream infections in Belgian hospitals. AB - OBJECTIVES: The objectives of this study were: (i) to determine the species diversity of CoNS isolated from bloodstream infections collected during a national surveillance study; and (ii) to examine the antimicrobial resistance and genomic diversity among Staphylococcus epidermidis isolates. METHODS: Eighty CoNS were identified by MALDI-TOF. Antimicrobial resistance determination, molecular characterization of resistance and virulence genes, and molecular typing were performed for S. epidermidis isolates. RESULTS: The majority (76%) of CoNS were identified as S. epidermidis. Among these S. epidermidis, 77% were resistant to methicillin [methicillin-resistant S. epidermidis (MRSE)] and showed multiresistance to other antimicrobials. Genes implicated in resistance were erm(C), erm(A) and msr(A) for erythromycin, aacA-aphD and aadC for aminoglycosides, tet(K) for tetracycline and mupA for high-level resistance to mupirocin. Molecular typing showed that 34/40 MRSE isolates (85%) belonged to clonal complex (CC) 2 that could be subdivided into CC2-I (ST2) and CC2-II (ST5, ST59 and ST88). In contrast, methicillin-susceptible S. epidermidis displayed high genomic diversity. The majority (70%) of S. epidermidis isolates contained an icaA or arcA gene. The icaA gene was found in the CC2-I subgroup, whereas arcA was more common in methicillin-susceptible S. epidermidis. CONCLUSIONS: S. epidermidis was frequently recovered among CoNS isolated from bloodstream infections with a high proportion of MRSE being multiresistant. A large number of S. epidermidis belonged to CC2, a clone that is disseminated worldwide. More studies are needed to understand its clonal evolutionary success. PMID- 27118781 TI - Tolerance to multiple metal stressors in emerging non-typhoidal MDR Salmonella serotypes: a relevant role for copper in anaerobic conditions. AB - OBJECTIVES: Factors driving the expansion of particular MDR Salmonella serotypes/clones are not completely understood. We assessed if emergent MDR Salmonella serotypes/clones were more enriched in metal tolerance genes (e.g. to Cu/Ag) than other less frequent ones, as an additional feature to survive in environments contaminated with metals. METHODS: Metal (Cu pco/Ag,Cu sil/Hg mer/As ars/Te ter) tolerance genes screening (PCR/sequencing), MICs of CuSO4/AgNO3 (aerobiosis/anaerobiosis), genetic element characterization (S1/I-CeuI PFGE) and conjugation assays were performed in a well-characterized Salmonella collection (n = 275 isolates; 2000-14; 49 serotypes/clones). RESULTS: The sil +/- pco genes were detected in 37% of isolates from diverse serotypes, mainly in emergent Rissen/ST469 and Typhimurium/ST34 European clone (100%), which are mostly associated with pig settings where Cu is highly used. These genes were frequently co-located with merA +/- terF and/or antibiotic resistance genes in plasmids (100 270 kb; IncHI2/IncHI1/IncN/IncFIIA; mostly transferable by conjugation) or in the chromosome. Most sil +/- pco(+) isolates (77%) were MDR contrasting with sil +/- pco(-) ones (48%). The sil +/- pco(+) isolates presented significantly higher MICCuSO4 under anaerobiosis (MIC50/MIC90 = 28/32 mM) and MICAgNO3 after previous Ag contact (MIC50/MIC90 > 3 mM) than sil(-) ones (MIC50/MIC90 = 2/8 mM to CuSO4; MIC50/MIC90 = 0.125/0.16 mM to AgNO3). Use of these modified methodological approaches allowed the establishment of CuSO4/AgNO3 tolerance cut-offs to differentiate sil(+) and sil(-) isolates, here firstly proposed. CONCLUSIONS: This study demonstrates that acquisition of Cu/Ag tolerance genes (sil/pco genes) might contribute to the emergence of particular clinically relevant MDR Salmonella serotypes/clones by facilitating their survival in diverse metal contaminated settings, particularly in pig production. Assessment of control measures for the use and/or accumulation of metals in diverse environments are needed to prevent a wider expansion of such strains or the emergence of new ones. PMID- 27118782 TI - Molecular analysis of Streptococcus pyogenes macrolide resistance of paediatric isolates during a 7 year period (2007-13). AB - OBJECTIVES: The molecular characterization of paediatric group A Streptococcus (GAS) isolates regarding macrolide resistance and relevant emm types in Athens, Greece. METHODS: Pharyngeal and non-pharyngeal GAS isolates were collected during a 7 year period (2007-13) and examined for antibiotic susceptibility, macrolide resistance genes [mef(A), erm(A) and erm(B)] and relevant emm types. RESULTS: Overall, 20.4% (270/1324) of GAS isolates were resistant to macrolides. The macrolide resistance rate varied during the study period with a maximum rate observed in 2008 (29.57%) and a minimum rate observed in 2013 (10.95%) (P value for trend = 0.007). During the same period, consumption of macrolides was gradually reduced by 56.6%. No difference was observed in macrolide resistance between pharyngeal and non-pharyngeal isolates (P = 0.7). Among macrolide resistant isolates, mef(A) was detected in 87 (32.2%), erm(A) in 136 (50.4%), erm(B) in 44 (16.3%) and both mef(A) and erm(A) in 3 (1.1%) isolates. The most prevalent emm types among macrolide-resistant isolates were emm77 (31.5%), emm4 (18.1%) and emm12 (10.7%). Ten emm types (77, 4, 12, 28, 1, 22, 11, 2, 44 and 89) accounted for 90.3% of macrolide-resistant isolates. emm types 4, 22, 44 and 77 were more prevalent in macrolide-resistant compared with macrolide-susceptible isolates, whereas emm types 1, 3, 5, 6, 75 and 89 were more prevalent in macrolide-susceptible compared with macrolide-resistant isolates. CONCLUSIONS: GAS macrolide resistance remained significant in our area during the study period. A substantial decline in the resistance rate was observed in the last year of the study, which may be related to reduced consumption of macrolides. PMID- 27118783 TI - Roles of subunit NuoL in the proton pumping coupling mechanism of NADH:ubiquinone oxidoreductase (complex I) from Escherichia coli. AB - Respiratory complex I has an L-shaped structure formed by the hydrophilic arm responsible for electron transfer and the membrane arm that contains protons pumping machinery. Here, to gain mechanistic insights into the role of subunit NuoL, we investigated the effects of Mg2+, Zn2+ and the Na+/H+ antiporter inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on proton pumping activities of various isolated NuoL mutant complex I after reconstitution into Escherichia coli double knockout (DKO) membrane vesicles lacking complex I and the NADH dehydrogenase type 2. We found that Mg2+ was critical for proton pumping activity of complex I. At 2 uM Zn2+, proton pumping of the wild-type was selectively inhibited without affecting electron transfer; no inhibition in proton pumping of D178N and D400A was observed, suggesting the involvement of these residues in Zn2+ binding. Fifteen micromolar of EIPA caused up to ~40% decrease in the proton pumping activity of the wild-type, D303A and D400A/E, whereas no significant change was detected in D178N, indicating its possible involvement in the EIPA binding. Furthermore, when menaquinone-rich DKO membranes were used, the proton pumping efficiency in the wild-type was decreased significantly (~50%) compared with NuoL mutants strongly suggesting that NuoL is involved in the high efficiency pumping mechanism in complex I. PMID- 27118784 TI - Enhancing Biospecimen Knowledge Among Health Care Providers and Representatives From Community Organizations. AB - In a personalized medicine environment, it is necessary to have access to a range of biospecimens to establish optimal plans for disease diagnosis and treatment for individual patients. Cancer research is especially dependent on biospecimens for determining ideal personalized treatment for patients. Unfortunately, the vast majority of biospecimens are collected from non-Hispanic White individuals; thus, minority representation is lacking. This has negative implications for comprehensive cancer treatment. The Geographic Management of Cancer Health Disparities Program (GMaP) Region 6 implemented a series of biospecimen education seminars adapted from the Biospecimen and Biobanking module of an existing Cancer Education and Training Program. Regional GMaP partners participated in a train the-trainer webinar to familiarize themselves with the training materials. Participants trained by the trainers completed pre- and posttests to document changes in awareness, knowledge, and intention. Nine biospecimen education seminars were offered in 2013; 255 health care professionals and representatives from community organizations attended. Participants demonstrated a significant increase in knowledge, intention to donate samples, and intention to talk to patients about biospecimen sample donation. Representatives from community organizations had more improvement on knowledge scores than health care providers. Participation in a well-designed biospecimen education program may ameliorate some of the distrust of biomedical research experienced by racial/ethnic minorities and, in turn, increase needed minority representation in biospecimen collection. PMID- 27118785 TI - Long-acting Neuraminidase Inhibitor Laninamivir Octanoate as Post-exposure Prophylaxis for Influenza. AB - BACKGROUND: A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, has been proven to be effective in the treatment of influenza but not for post-exposure prophylaxis. METHODS: We conducted a double blind, multicenter, randomized, placebo-controlled study to determine if a single administration of laninamivir octanoate 40 mg was superior to placebo for post exposure prophylaxis. Eligible participants who had cohabited with an influenza patient within 48 hours of symptom onset were randomly assigned (1:1:1) to 1 of 3 groups: 40 mg of laninamivir octanoate single administration (LO-40SD), 20 mg of laninamivir octanoate once daily for 2 days (LO-20TD), or placebo. The primary efficacy endpoint was the proportion of participants who developed clinical influenza (defined as influenza virus positive, an axillary temperature >37.5 degrees C, and at least 2 symptoms) over a 10-day period. RESULTS: A total of 803 participants were enrolled, with 801 included in the primary analysis. The proportions of participants with clinical influenza were 4.5% (12/267), 4.5% (13/269), and 12.1% (32/265) in the LO-40SD, LO-20TD, and placebo groups, respectively. A single administration of laninamivir octanoate 40 mg significantly reduced the development of influenza compared with placebo (P = .001). The relative risk reductions compared with the placebo group were 62.8% and 63.1% for the LO-40SD and LO-20TD groups, respectively. The incidence of adverse events in the LO-40SD group was similar to that of the LO-20TD and placebo groups. CONCLUSIONS: A single administration of laninamivir octanoate was effective and well tolerated as post-exposure prophylaxis to prevent the development of influenza. CLINICAL TRIALS REGISTRATION: JapicCTI-142679. PMID- 27118786 TI - Use of Postexposure Prophylaxis After Occupational Exposure to Zaire ebolavirus. AB - From September 2014 to April 2015, 6 persons who had occupational exposures to Zaire ebolavirus in West Africa received investigational agent rVSV-ZEBOV or TKM 100802 for postexposure prophylaxis and were monitored in the United States. All patients experienced self-limited symptoms after postexposure prophylaxis; none developed Ebola virus disease. PMID- 27118788 TI - Systemic Reactions Caused by Bed Bug Bites. PMID- 27118787 TI - HIV Infection and Carotid Artery Intima-media Thickness: Pooled Analyses Across 5 Cohorts of the NHLBI HIV-CVD Collaborative. AB - BACKGROUND: Age and human immunodeficiency virus (HIV) treatment may affect the association of HIV infection with atherosclerosis. METHODS: We used identical carotid artery B-mode ultrasonographic methods in 5 cohorts participating in the National Heart, Lung, and Blood Institute HIV-CVD Collaborative to measure intima media thickness of the right far wall of the common carotid artery (CCA-IMT) and carotid artery bifurcation (BIF-IMT) between 2010 and 2013. Participants aged 6 75 years were either HIV infected or uninfected. Linear regression assessed associations of CCA-IMT and BIF-IMT with HIV infection and cardiovascular disease risk factors, within age and HIV treatment groups. Adjustment variables included sex, race/ethnicity, smoking, height, weight, and use of antihypertensive and lipid-lowering drugs. RESULTS: We studied 867 HIV-infected and 338 HIV-uninfected male and 696 HIV-infected and 246 HIV-uninfected female participants. Among both middle-aged (30-49 years) and older adults (50-75 years), HIV-infected participants had CCA-IMT and BIF-IMT values that were similar to or lower than those in HIV-uninfected participants. In contrast, among those aged 6-29 years, HIV infection was associated with higher CCA-IMT and BIF-IMT values. Among HIV infected participants, associations of higher systolic blood pressure and lower high-density lipoprotein cholesterol with Carotid artery intima-media thickness strengthened with age. CONCLUSIONS: The effects of HIV on carotid artery structure may differ across the lifespan, with traditional determinants of cardiovascular disease burden playing a larger role and HIV playing a lesser role in older adults than in young adults and children. PMID- 27118790 TI - Maintaining Life-saving Testing for Patients With Infectious Diseases: Infectious Diseases Society of America, American Society for Microbiology, and Pan American Society for Clinical Virology Recommendations on the Regulation of Laboratory developed Tests. AB - In 2014, the US Food and Drug Administration (FDA) proposed to regulate laboratory-developed tests (LDTs)-diagnostics designed, manufactured, and used within a single laboratory. The Infectious Diseases Society of America, the American Society for Microbiology, and the Pan American Society for Clinical Virology recognize that the FDA is committed to protecting patients. However, our societies are concerned that the proposed regulations will limit access to testing and negatively impact infectious diseases (ID) LDTs. In this joint commentary, our societies discuss why LDTs are critical for ID patient care, hospital infection control, and public health responses. We also highlight how the FDA's proposed regulation of LDTs could impair patient access to life-saving tests and stifle innovation in ID diagnostics. Finally, our societies make specific recommendations for the FDA's consideration to reduce the burden of the proposed new rules on clinical laboratories and protect patients' access to state of-the art, quality LDTs. PMID- 27118791 TI - Weekend Effect in Children With Stroke in the Nationwide Inpatient Sample. AB - BACKGROUND AND PURPOSE: Studies have demonstrated differences in clinical outcomes in adult patients with stroke admitted on weekdays versus weekends. The study's objective was to determine whether a weekend impacts clinical outcomes in children with ischemic stroke and hemorrhagic stroke. METHODS: Children aged 1 to 18 years admitted to US hospitals from 2002 to 2011 with a primary discharge diagnosis of ischemic stroke or hemorrhagic stroke were identified by International Classification of Disease, 9th Revision, codes. Logistic regression estimated odds ratios and 95% confidence intervals for in-hospital mortality and discharge to a nursing facility among children admitted on weekends (Saturday and Sunday) versus weekdays (Monday to Friday), adjusting for potential confounders. RESULTS: Of 8467 children with ischemic stroke, 28% were admitted on a weekend. Although children admitted on weekends did not have a higher in-hospital mortality rate than those admitted on weekdays (4.1% versus 3.3%; P=0.4), children admitted on weekends had a higher rate of discharge to a nursing facility (25.5% versus 18.6%; P=0.003). After adjusting for age, sex, and confounders, the odds of discharge to a nursing facility remained increased among children admitted on weekends (odds ratio, 1.5; 95% confidence interval, 1.1-1.9; P=0.006). Of 10 919 children with hemorrhagic stroke, 25.3% were admitted on a weekend. Children admitted on weekends had a higher rate of in-hospital mortality (12% versus 8%; P=0.006). After adjusting for age, sex, and confounders, the odds of in-hospital mortality remained higher among children admitted on weekends (odds ratio, 1.4; 95% confidence interval, 1.1-1.9; P=0.04). CONCLUSIONS: There seems to be a weekend effect for children with ischemic and hemorrhagic strokes. Quality improvement initiatives should examine this phenomenon prospectively. PMID- 27118792 TI - Redesigned Fall and Injury Management of Patients With Stroke. PMID- 27118794 TI - Response to Letter Regarding Article, "Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People". PMID- 27118793 TI - Impact of Guidelines on Clinical Practice: Intravenous Heparin Use for Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Since its introduction, controversy has existed about the administration of intravenous heparin for the treatment of acute ischemic stroke. We studied trends in the intravenous heparin use during a 6-year time period and the potential influence of clinical guidelines in national language on intravenous heparin administration in Korea. METHODS: On the basis of a prospective nationwide multicenter stroke registry, we collected data on patients with acute ischemic stroke who arrived within 7 days of symptom onset during the time period 2008 to 2013. We studied patient demographics, prestroke medical history, stroke characteristics, and stroke treatment. Data from a total of 23 425 patients from 12 university hospitals or regional stroke centers were analyzed. RESULTS: The administration of intravenous heparin steadily decreased throughout the study period: 9.7% in 2008, 10.9% in 2009, 9.4% in 2010, 6.0% in 2011, 4.7% in 2012, and 4.3% in 2013 (P for trend <0.001). The reduced intravenous heparin use was associated with moderate stroke severity, atrial fibrillation, and stroke of cardioembolic, other-, and undetermined etiology. In a multivariable logistic model, increase of 1 calendar year (odds ratio, 0.89; 95% confidence interval, 0.84-0.95; P<0.001) and release of clinical practice guidelines in Korean (odd ratio, 0.74; 95% confidence interval, 0.59-0.91; P<0.01) were independent factors associated with reduction in the frequency of intravenous heparin use. CONCLUSIONS: Use of intravenous heparin for acute ischemic stroke treatment has decreased in Korea, and this change may be attributable to the spread and successful implementation of regional clinical practice guidelines. PMID- 27118795 TI - Letter by Kawada Regarding Article, "Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People". PMID- 27118796 TI - Recanalization Modulates Association Between Blood Pressure and Functional Outcome in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Historical stroke cohorts reported a U- or J-shaped relationship between blood pressure (BP) and clinical outcome. However, these studies predated current revascularization strategies, disregarding the recanalization state of the affected arterial territory. We aimed to investigate the relationship between BP in the first 24 hours after ischemic stroke and clinical outcome in patients submitted to intravenous or intra-arterial recanalization treatments. METHODS: Consecutive patients with acute stroke treated with intravenous thrombolysis or intra-arterial therapies were enrolled in a retrospective cohort study. BP was measured on regular intervals throughout day and night during the first 24 hours after stroke onset. The mean systolic BP and diastolic BP during the first 24 hours post stroke were calculated. Recanalization was assessed at 6 hours by transcranial color-coded Doppler, angiography, or angio-computed tomography. Functional outcome was assessed at 3 months by modified Rankin Scale. Linear and quadratic multivariate regression models were performed to determine associations between BP and functional outcome for the whole population and recanalyzed and nonrecanalyzed patients. RESULTS: We included 674 patients; mean age was 73.28 (SD, 11.50) years. Arterial recanalization was documented in 355 (52.70%) patients. In multivariate analyses, systolic BP and diastolic BP in the first 24 hours post stroke show a J-shaped relationship with functional outcome in the total population and in the nonrecanalyzed patients. Recanalyzed patients show a linear association with functional outcome (systolic BP: odds ratio, 1.015; 95% confidence interval, 1.007-1.024; P=0.001; R(2) change=0.001; P=0.412 and diastolic BP: odds ratio, 1.019; 95% confidence interval, 1.004-1.033; P=0.012; R(2) change<0.001; P=0.635). CONCLUSIONS: Systemic BP in the first 24 hours after ischemic stroke influences 3-month clinical outcome. This association is dependent on the revascularization status. PMID- 27118797 TI - The conserved dual phosphorylation sites of the Candida albicans Hog1 protein are crucial for white-opaque switching, mating, and pheromone-stimulated cell adhesion. AB - Candida albicans is an opportunistic human pathogen capable of causing life threatening infections in immunocompromised patients. C. albicans has a unique morphological transition between white and opaque phases. These two cells differ in virulence, mating capability, biofilm formation, and host-cell interaction. Previous studies revealed that deletion of the SSK2, PBS2, or HOG1 gene resulted in 100% opaque cell formation and suppressed the mating response. Thr-174 and Tyr 176 of the Hog1 protein are important phosphoacceptors and can be activated in response to stimuli. In this study, we first demonstrated the importance of two conserved phosphorylation sites in white-opaque switching, mating, and pheromone stimulated cell adhesion. Six Hog1 point-mutated strains were generated, including nonphosphorylated strains (Hog1(T174A), Hog1(Y176F), and Hog1(T174A,Y176F)) and negatively charged phosphorylated strains (Hog1(T174D), Hog1(Y176D), and Hog1(T174D,Y176D)). Point mutation on Thr-174, Tyr-176 or in combination with the Hog1 protein in C. albicans MTL homozygous strains stimulated opaque cell formation at a frequency of 100%. Furthermore, mating projections of point-mutated strains were significantly shorter and their mating efficiencies and pheromone-stimulated cell adhesive numbers were lower than those of the wild-type. By investigating the effects of Hog1 phosphorylation in ssk1Delta and sln1Delta, we also demonstrate that the phosphorylation intensity of Hog1p is directly involved in the white-opaque switching. Taken together, the results of our study demonstrate that dual phosphorylation sites of C. albicans are crucial for white-opaque transition, sexual mating, and pheromone-induced cell adhesion. PMID- 27118798 TI - A few shared up-regulated genes may influence conidia to yeast transformation in dimorphic fungal pathogens. AB - The small number of fungi that commonly cause disease in normal people share the capacity to grow as mycelia in the soil at 25 degrees C and as yeast (or spherules) in mammals at 37 degrees C. This remarkable conversion has long been a topic of interest in medical mycology. The conidia to yeast conversion has been studied by transcription profiling in several fungal species, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Coccidioides spp., Blastomyces dermatitidis, and Talaromyces marneffei One limitation of transcriptional profiling is determining which genes are involved in the process of conversion to yeast as opposed to a result of conversion to yeast. If there are genes that are up-regulated in the yeast phase of more than one dimorphic, pathogenic fungus they might be required for conversion to yeast (or spherules). To address this issue, 24 up-regulated genes common to Coccidioides spp spherules and H. capsulatum yeasts were identified. Four homologs of these genes were also found in P. brasiliensis, B. dermatitidis or T. marneffei genes that were up regulated in yeast. 4-hydroxyphenylpurvate dioxygenase, a gene involved in tyrosine metabolism and melanin synthesis that has been shown to be required for yeast conversion, is conserved and up-regulated in yeast in all five species. Another up-regulated gene that is conserved in all five species is a MFS sugar porter. These results suggest that a minority of up-regulated yeast (or spherule) genes are conserved across species and raises the possibility that conserved up regulated genes may be of special interest for differentiation of mycelium into yeast. PMID- 27118799 TI - The ZIP family zinc transporters support the virulence of Cryptococcus neoformans. AB - Zinc is an essential element in living organisms and a cofactor for various metalloproteins. To disseminate and survive, a pathogenic microbe must obtain zinc from the host, which is an environment with extremely limited zinc availability. In this study, we investigated the roles of the ZIP family zinc transporters Zip1 and Zip2 in the human pathogenic fungus Cryptococcus neoformans Zip1 and Zip2 are homologous to Zrt1 and Zrt2 of the model fungus, Saccharomyces cerevisiae, respectively. We found that the expression of ZIP1 was regulated by the zinc concentration in the environment. Furthermore, the mutant lacking ZIP1 displayed a severe growth defect under zinc-limited conditions, while the mutant lacking ZIP2 displayed normal growth. Inductively coupled plasma-atomic emission spectroscopy analysis showed that the absence of Zip1 expression significantly reduced total cellular zinc levels relative to that in the wild type, while overexpression of Zip1 was associated with increased cellular zinc levels. These findings suggested that Zip1 plays roles in zinc uptake in C. neoformans We also constructed a Zip1-FLAG fusion protein and found, by immunofluorescence, not only that the protein was localized to the periphery implying it is a membrane transporter, but also that the protein was N-glycosylated. Furthermore, the mutant lacking ZIP1 showed attenuated virulence in a murine inhalation model of cryptococcosis and reduced survival within murine macrophages. Overall, our data suggest that Zip1 plays essential roles in zinc transport and the virulence of C. neoformans. PMID- 27118800 TI - Protein A/G-based immunochromatographic test for serodiagnosis of pythiosis in human and animal subjects from Asia and Americas. AB - Pythiosis is a life-threatening infectious disease of both humans and animals living in Asia, Americas, Africa, and parts of Australia and New Zealand. The etiologic pathogen is the fungus-like organism Pythium insidiosum The disease has high mortality and morbidity rates. Use of antifungal drugs are ineffective against P. insidiosum, leaving radical surgery the main treatment option. Prompt treatment leads to better prognosis of affected individuals, and could be achieved by early and accurate diagnosis. Since pythiosis has been increasingly reported worldwide, there is a need for a rapid, user-friendly, and efficient test that facilitates the diagnosis of the disease. This study aims to develop an immunochromatographic test (ICT), using the bacterial protein A/G, to detect anti P. insidiosum IgGs in humans and animals, and compare its diagnostic performance with the established ELISA. Eighty-five serum samples from 28 patients, 24 dogs, 12 horses, 12 rabbits, and 9 cattle with pythiosis, and 143 serum samples from 80 human and 63 animal subjects in a healthy condition, with thalassemia, or with other fungal infections, were recruited for assay evaluation. Detection specificities of ELISA and ICT were 100.0%. While the detection sensitivity of ELISA was 98.8%, that of ICT was 90.6%. Most pythiosis sera, that were falsely read negative by ICT, were weakly positive by ELISA. In conclusion, a protein A/G based ICT is a rapid, user-friendly, and efficient assay for serodiagnosis of pythiosis in humans and animals. Compared to ELISA, ICT has an equivalent detection specificity and a slightly lower detection sensitivity. PMID- 27118801 TI - Childhood histoplasmosis in Colombia: Clinical and laboratory observations of 45 patients. AB - Histoplasmosis is an important mycosis in the Americas; and in children with no immune system abnormalities, histoplasmosis is typically a self-limited process. In contrast, in children with immune problems, disease manifestations are frequently more severe and include dissemination. From 1984 to 2010, a retrospective study of paediatric patients who had been diagnosed with histoplasmosis was performed. A total of 45 pediatric cases of histoplasmosis were identified. The most important risk factor was malnutrition (37%), followed by environmental exposure (33%). The patients exhibited pulmonary infiltrates (83%), fever (76%), cough, constitutional symptoms (38%), headache (35%), and lymph node hypertrophy (33%). Concerning the clinical forms, 64% of the patients presented with the progressive disseminated form that frequently affected the central nervous system (48%). Diagnostic laboratory tests indicated that the cultures were positive for 80% of the patients, the agar gel immunodiffusion was reactive in 95%, the M band of the precipitate was more commonly observed (81%), and the complement fixation tests were reactive in 88% of the patients. The timely diagnosis of histoplasmosis is important, and for this reason, it is hoped that the results of this study will lead pediatricians toward a better understanding of this mycosis in children. PMID- 27118803 TI - Toward the identification, characterization and experimental culture of Lacazia loboi from Atlantic bottlenose dolphin (Tursiops truncatus). AB - Lobomycosis (lacaziosis) is a chronic, granulomatous, fungal infection of the skin and subcutaneous tissues of humans and dolphins. To date, the causative agent, the yeast-like organism Lacazia loboi, has not been grown in the laboratory, and there have been no recent reports describing attempts to culture the organism. As a result, studies on the efficacy of therapeutics and potential environmental reservoirs have not been conducted. Therefore, the objective of the current study was to utilize both classical and novel microbiological methods in order to stimulate growth of Lacazia cells collected from dolphin lesions. This included the experimental inoculation of novel media, cell culture, and the use of artificial skin matrices. Although unsuccessful, the methods and results of this study provide important insight into new approaches that could be utilized in future investigations of this elusive organism. PMID- 27118802 TI - The environmental source of emerging Apophysomyces variabilis infection in India. AB - The rare mucoraceous fungus, Apophysomyces species complex ranks second after Rhizopus arrhizus causing mucormycosis in India. The source of this agent in the environment is not clearly known. We conducted an environmental study to find its presence in Indian soil. The soil samples from different geographical locations were analyzed for isolation of Mucorales. Rhizopus arrhizus (24.6%) was most commonly isolated from soil, followed by Lichtheimia spp. (23.2%), Cunninghamella spp. (21.7%), Rhizopus microsporus (14%) and Apophysomyces spp. (4.5%). The isolation of Apophysomyces species complex was significantly associated with low nitrogen content of the soil. Based on sequencing of internal transcribed spacer (ITS) and 28S (D1/D2) regions of ribosomal DNA, the Apophysomyces isolates were identified as Apophysomyces variabilis with 98 to 100% similarity to type strain A. variabilis (CBS658.93). The analysis of amplified fragment length polymorphism (AFLP) fingerprinting data demonstrated genomic diversity of A. variabilis isolates with multiple clades (similarity 40-90%). The minimum inhibitory concentrations (MIC), MIC50 and MIC90 for A. variabilis isolates were 1 and 4 MUg/ml for amphotericin B, 0.25 and 0.5 MUg/ml for itraconazole, 0.125 and 0.25 MUg/ml for posaconazole, 0.06 and 0.12 MUg/ml for terbinafine, respectively. The present study revealed abundant presence of A. variabilis in Indian soil with low nitrogen content, its genetic heterogeneity and relatively high MICs for amphotericin B. PMID- 27118804 TI - In vitro activity of new azoles luliconazole and lanoconazole compared with ten other antifungal drugs against clinical dermatophyte isolates. AB - In vitro susceptibilities of 100 clinical dermatophyte isolates belonging to five species from Iran toward lanoconazole and luliconazole were compared with ten other antifungal agents including econazole, itraconazole, miconazole, fluconazole, griseofulvin, butenafine, terbinafine, caspofungin, anidulafungin and tolnaftate. MIC and MEC values were analyzed according to CLSI M38-A2 document. The isolates were previously identified to the species level using PCR RFLP on ITS rDNA region. The range of luliconazole and lanoconazole minimum inhibitory concentrations (MICs) was 0.016-0.032 and 0.063-1 MUg/ml, respectively for dermatophyte species. Luliconazole and lanoconazole revealed potent activity against all dermatophyte isolates. Anidulafungin, caspofungin, and luliconazole showed the best activity with the lowest geometric mean 0.01, 0.016, and 0.018 MUg/ml, respectively, followed by tolnaftate (0.06 MUg/ml), terbinafine (0.07 MUg/ml), itraconazole (0.183 MUg/ml), butenafine (0.188 MUg/ml), econazole (0.20 MUg/ml), lanoconazole (0.24 MUg/ml), griseofulvin (1.28 MUg/ml), miconazole (2.34 MUg/ml) and fluconazole (15.34 MUg/ml). The current study demonstrated luliconazole and lanoconazole displayed excellent activity against all dermatophyte isolates, although the majority of dermatophyte isolates showed low susceptibility to griseofulvin and very low to miconazole, and fluconazole. PMID- 27118805 TI - Cryptococcosis in non-HIV/non-transplant patients: A Brazilian case series. AB - Cryptococcosis is a classical systemic opportunistic mycosis, primarily occurring among patients with significant immunologic impairment. However, this disease could also affect patients without any recognized immunologic defects, that is, phenotypically normal patients. The medical records of 29 non-HIV/nontransplant patients with cryptococcal disease during the period 2007-2014 were retrospectively reviewed. The most common site of infection was the central nervous system (n = 25, 86.2%), followed by the pulmonary system (n = 11, 37.9%) and blood (n = 2, 6.8%). Thoracic- and brain-computed tomography demonstrated abnormalities of 81.2% (n = 13) and 62.5% (n = 15), respectively. In sum, 22% (n = 6) of the patients experienced a significant underlying condition. More than one therapeutic regimen was used in 77.8% (n = 21) of the patients. The isolates were identified as being Cryptococcus neoformans species complex (n = 4, 36.4%) and Cryptococcus gattii species complex (n = 7, 63.6%). The overall mortality was 20.7% (n = 6). Herein, we presented the first case series of cryptococcosis in this specific population in Sao Paulo City, Brazil. The incidence of cryptococcosis in our hospital has not increased in recent years, and 77.8% (n = 21) of cases had no obvious predisposing factor. However, this disease remains associated with high mortality. PMID- 27118806 TI - The epidemiology of fungemia in an infectious diseases hospital in Mexico city: A 10-year retrospective review. AB - The epidemiology of invasive fungal infections has recently changed in immunosuppressed populations as a result of HIV infection, organ transplant, chemotherapy and in elderly patients. The diagnosis of invasive fungal infections by culture is prolonged since fungi grow slowly in vitro. we wanted to estimate the frequency of fungemia diagnoses established through the Clinical Mycology Laboratory over the past 10 years; through a retrospective study; data was obtained from the laboratory patient registry in the Infectious Disease Hospital's laboratory registry of patients with a systemic fungal isolate between 2005 and 2014. One hundred and thirty two (132) systemic fungal infections were identified. They were more prevalent in males, in the age group between 20 and 59 years and in patients with a diagnosis of AIDS. The most frequently isolated agents belonged to the genus Candida and others such as Histoplasma sp., Cryptococcus sp., Aspergillus sp., and Coccidioides sp. Of all blood and bone marrow cultures received 17.9% had fungal development; of these, in 70% of cases it was through blood cultures. In general, fungal agents were not diagnostically suspected. We identified that Sixty percent (60%) of fungemias developed in AIDS patients, followed by patients with sepsis. The most common agents belonged to the genus Candida, predominantly the albicans species. They were more frequently identified by blood culture than by bone marrow culture. Invasive fungal infections have not followed a usual clinical pattern and are not easily recognizable. PMID- 27118807 TI - Astroglial Scarring and Seizures: A Cell Biological Perspective on Epilepsy. AB - Epilepsy is among the most prevalent chronic neurological diseases and affects an estimated 2.2 million people in the United States alone. About one third of patients are resistant to currently available antiepileptic drugs, which are exclusively targeting neuronal function. Yet, reactive astrocytes have emerged as potential contributors to neuronal hyperexcitability and seizures. Astrocytes react to any kind of CNS insult with a range of cellular adjustments to form a scar and protect uninjured brain regions. This process changes astrocyte physiology and can affect neuronal network function in various ways. Traumatic brain injury and stroke, both conditions that trigger astroglial scar formation, are leading causes of acquired epilepsies and surgical removal of this glial scar in patients with drug-resistant epilepsy can alleviate the seizures. This review will summarize the currently available evidence suggesting that epilepsy is not a disease of neurons alone, but that astrocytes, glial cells in the brain, can be major contributors to the disease, especially when they adopt a reactive state in response to central nervous system insult. PMID- 27118808 TI - The Anti-Allodynic Gabapentinoids: Myths, Paradoxes, and Acute Effects. AB - The gabapentinoids (pregabalin and gabapentin) are first line treatments for neuropathic pain. They exert their actions by binding to the alpha2delta accessory subunits of voltage-gated Ca2+ channels. Because these subunits interact with critical aspects of the neurotransmitter release process, gabapentinoid binding prevents transmission in nociceptive pathways. Gabapentinoids also reduce plasma membrane expression of voltage-gated Ca2+ channels but this may have little direct bearing on their therapeutic actions. In animal models of neuropathic pain, gabapentinoids exert an anti-allodynic action within 30 minutes but most of their in vitro effects are 30-fold slower, taking at least 17 hours to develop. This difference may relate to increased levels of alpha2delta expression in the injured nervous system. Thus, in situations where alpha2delta is experimentally upregulated in vitro, gabapentinoids act within minutes to interrupt trafficking of alpha2delta subunits to the plasma membrane within nerve terminals. When alpha2delta is not up-regulated, gabapentinoids act slowly to interrupt trafficking of alpha2delta protein from cell bodies to nerve terminals. This improved understanding of the mechanism of gabapentinoid action is related to their slowly developing actions in neuropathic pain patients, to the concept that different processes underlie the onset and maintenance of neuropathic pain and to the use of gabapentinoids in management of postsurgical pain. PMID- 27118809 TI - The problem of sexual imbalance and techniques of the self in the Diagnostic and Statistical Manual of Mental Disorders. AB - This article examines the problematization of sexual appetite and its imbalances in the development of the Diagnostic and Statistical Manual of Mental Disorders (DSM) in the twentieth and twenty-first centuries. The dominant strands of historiographies of sexuality have focused on historicizing sexual object choice and understanding the emergence of sexual identities. This article emphasizes the need to contextualize these histories within a broader frame of historical interest in the problematization of sexual appetite. The first part highlights how sexual object choice, as a paradigm of sexual dysfunctions, progressively receded from medical interest in the twentieth century as the clinical gaze turned to the problem of sexual appetite and its imbalances. The second part uses the example of the newly introduced Female Sexual Interest/Arousal Disorder in the DSM-5 to explore how the Manual functions as a technique for taking care of the self. I argue that the design of the Manual and associated inventories and questionnaires paved the way for their interpretation and application as techniques for self-examination. PMID- 27118810 TI - Memory as persona non grata in the work of Eugene Minkowski: a historical approach. AB - Memory is both ubiquitous and persona non grata in the work of Eugene Minkowski. Despite the relevance of memory in the works of those who influenced him, in particular Bergson, Minkowski nonetheless repeatedly overlooked its importance in his writings. To the reader of his work this fact is as much evident as unaccounted for - both by prior research and by Minkowski himself. I shall try to prove that this disregard for memory was conditio sine qua non of Minkowski's first synthesis of Bleuler and Bergson in a 1921 article, which resulted in his famous concept of loss of vital contact with reality and which he equated with schizophrenia. Moreover, this historical approach will, on the one hand, explain the fragmentary use made by Minkowski of the philosophy of Bergson and, on the other, shed light on central aspects of his Le temps vecu of 1933 that an exclusively philosophical analysis cannot reveal. PMID- 27118811 TI - A rare intravascular tumour diagnosed by endobronchial ultrasound. PMID- 27118814 TI - Benefits of smoking bans on preterm and early-term births: a natural experimental design in Switzerland. AB - BACKGROUND: Birth outcomes are relevant for future children's heath. Capitalising on a natural experimental design in Switzerland, we evaluated how regional smoking bans introduced at different time points affected birth outcomes, including preterm and early-term births. METHODOLOGY: We used birth registry data of all singleton neonates born in Switzerland (2007-2012). We developed canton specific interrupted time-series followed by random meta-analysis to evaluate the benefits of smoking bans on preterm (<37 gestational weeks) and early-term (37-38 gestational weeks) births. Heterogeneity across type of ban and contextual characteristics was explored through metaregression. A time-to-event approach was used for evaluating duration of pregnancy under the smoking bans and effects, taking into account individual maternal factors. RESULTS: We observed a decrease in the risk of preterm birth of 3.6% (95% CI, -9.3% to 2.5%), and early-term birth of 5.0% (95% CI -7.5% to -2.5%). Results showed a clear dose-response relationship. Greater risk reductions were obtained for preterm births in areas with more comprehensive bans (-6.8%; 95% CI -12.1% to 0.1%), and for pregnancies with the longest gestational time under smoking bans (HR, 0.991; 95% CI 0.984 to 0.997 per 10% increase in duration). Benefits were unequal across outcomes and characteristics of cantons and mothers. CONCLUSION: Smoking bans resulted in improved birth outcomes in Switzerland with cantons that adopted more comprehensive smoking bans achieving greater benefits. Early-term births constitute a previously ignored though important group. PMID- 27118812 TI - Systemic inflammation after critical illness: relationship with physical recovery and exploration of potential mechanisms. AB - BACKGROUND: Physical recovery following critical illness is slow, often incomplete and is resistant to rehabilitation interventions. We aimed to explore the contribution of persisting inflammation to recovery, and investigated the potential role of human cytomegalovirus (HCMV) infection in its pathogenesis. METHODS: In an a priori nested inflammatory biomarker study in a post-intensive care unit (ICU) rehabilitation trial (RECOVER; ISRCTN09412438), surviving adult ICU patients ventilated >48 h were enrolled at ICU discharge and blood sampled at ICU discharge (n=184) and 3 month follow-up (N=123). C-reactive protein (CRP), human neutrophil elastase (HNE), interleukin (IL)-1beta, IL-6, IL-8, transforming growth factor beta1 (TGFbeta1) and secretory leucocyte protease inhibitor (SLPI) were measured. HCMV IgG status was determined (previous exposure), and DNA PCR measured among seropositive patients (lytic infection). Physical outcome measures including the Rivermead Mobility Index (RMI) were measured at 3 months. RESULTS: Many patients had persisting inflammation at 3 months (CRP >3 mg/L in 59%; >10 mg/L in 28%), with proinflammatory phenotype (elevated HNE, IL-6, IL-8, SLPI; low TGFbeta1). Poorer mobility (RMI) was associated with higher CRP (beta=0.13; p<0.01) and HNE (beta=0.32; p=0.03), even after adjustment for severity of acute illness and pre-existing co-morbidity (CRP beta=0.14; p<0.01; HNE beta=0.30; p=0.04). Patients seropositive for HCMV at ICU discharge (63%) had a more proinflammatory phenotype at 3 months than seronegative patients, despite undetectable HMCV by PCR testing. CONCLUSIONS: Inflammation is prevalent after critical illness and is associated with poor physical recovery during the first 3 months post-ICU discharge. Previous HCMV exposure is associated with a proinflammatory phenotype despite the absence of detectable systemic viraemia. TRIAL REGISTRATION NUMBER: ISRCTN09412438, post results. PMID- 27118815 TI - Sensing a revolution. PMID- 27118816 TI - Biomechanics of Pharyngeal Deglutitive Function following Total Laryngectomy. AB - OBJECTIVE: Postlaryngectomy, pharyngeal weakness, and pharyngoesophageal junction (PEJ) restriction are the candidate mechanisms of dysphagia. The aims were, in laryngectomees, whether (1) hypopharyngeal propulsion is reduced and/or PEJ resistance is increased, (2) dilatation improves dysphagia, and (3) whether symptomatic improvement correlates with reduced PEJ resistance. DESIGN: Multidisciplinary cross-sectional study. SETTING: Tertiary academic hospital. SUBJECTS AND METHODS: Swallow biomechanics were assessed in 30 laryngectomees. Patients were stratified into severe dysphagia (Sydney Swallow Questionnaire >500) and mild/nil dysphagia (Sydney Swallow Questionnaire <=500). Average hypopharyngeal peak (contractile) pressure (hPP) and hypopharyngeal intrabolus pressure (hIBP) were measured from high-resolution manometry with concurrent videofluoroscopy based on barium swallows (2.5 and 10 mL). In consecutive 5 patients, measurements were repeated after dilatation. RESULTS: Dysphagia was reported by 87%, and 57% had severe and 43% had mild/nil dysphagia. hIBP increased with larger bolus volumes (P < .0001), while hPP stayed stable and PEJ diameter plateaued at 9 mm. Laryngectomees had lower hPP (110 +/- 14 vs 170 +/- 15 mm Hg; P = .0162) and higher hIBP (29 +/- 5 vs 6 +/- 5 mm Hg; P = .156) than controls. There were no differences in hPP between patient groups. However, hIBP was higher in severe than in mild/nil dysphagia (41 +/- 10 vs 13 +/- 3 mm Hg; P = .02). Predilation hIBP (R(2) = 0.97) and its decrement postdilatation (R(2) = 0.98) well predicted symptomatic improvement. CONCLUSIONS: PEJ resistance correlates better with dysphagia severity than peak pharyngeal pressure and is more sensitive to bolus sizes than PEJ diameter. Both baseline PEJ resistance and its decrement following dilatation are strong predictors of treatment outcome. PEJ resistance is vital to detect, as it is reversible and can predict the response to dilatation regimens. PMID- 27118817 TI - Effects of Continuous Positive Airway Pressure on Middle Ear Pressure and Acoustic Stapedial Reflex. AB - OBJECTIVE: This study investigated the effects of continuous positive airway pressure (CPAP) on middle ear pressure and acoustic stapedial reflex and the correlation between CPAP and middle ear pressure. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary hospitals. SUBJECTS AND METHODS: Fifty patients with obstructive sleep apnea-hypopnea syndrome were assigned to the study group, and 50 healthy volunteers were assigned to the control group. The subjects underwent standard tympanometry while wearing a CPAP device (ie, simulated CPAP treatment), which was set to 0, 5, 10, and 15 cm H2O, respectively. Tympanometry was performed before and after swallowing at each pressure of CPAP treatment. RESULTS: The mean middle ear pressures were 21.2, 22.6, 22.7, and 23.4 daPa (before swallowing) and 21.6, 42.6, 81.4, and 118.6 daPa (after swallowing) in the study group and 17.6, 18.7, 19.5, and 20.8 daPa (before swallowing) and 17.7, 44.2, 85.6, and 120.5 daPa (after swallowing) in the control group at the CPAPs of 0, 5, 10, and 15 cm H2O, respectively. While the CPAPs were at 0 and 15 cm H2O, the stapedial muscle reflex at 1.0 kHz did not have a significant difference between the 2 groups (chi(2) = 0.521, P = .470). The Pearson correlation coefficient of the CPAP pressure and the middle ear pressure after swallowing was 0.812 (P < .001). CONCLUSION: CPAP affected middle ear pressure and was directly proportional to the pressure of the CPAP. However, CPAP treatment had no significant effect on stapedial muscle reflex. PMID- 27118818 TI - Association between Magnesium Disorders and Hypocalcemia following Thyroidectomy. AB - OBJECTIVE: To identify factors associated with postoperative hypocalcemia after thyroid surgery and to understand the relationship among hypocalcemia, length of hospitalization, and costs of care. STUDY DESIGN: Retrospective database analysis. METHODS: Discharge data from the Nationwide Inpatient Sample for 620,744 patients who underwent thyroid surgery from 2001 to 2010 were analyzed through cross-tabulations and multivariate regression modeling. Hypocalcemia, length of stay, and costs were examined as dependent variables. Secondary independent variables included magnesium and phosphate metabolism disorders, vitamin D deficiency, menopause, sex, extent of surgery, malignancy, and surgeon volume. RESULTS: Hypocalcemia was reported in 6% of patients and was significantly more common for the following variables: women, age <65 years, patients from the Northeast, total thyroidectomy +/- neck dissection patients, low-volume surgical care, malignancy, recurrent laryngeal nerve injury, and patients with disorders of magnesium or phosphate metabolism (P < .001). Magnesium and phosphate disorders were present in <1% of patients. Magnesium disorders were significantly more likely for patients with hypocalcemia (7%; P < .001), and hypocalcemia was present in 52% of patients with magnesium disorders (P < .001). On multiple logistic regression analysis, the odds of hypocalcemia were greatest for patients with magnesium disorders (odds ratio, 12.71; 95% confidence interval, 8.59-18.82). This relationship was not attenuated by high volume surgical care. Hypocalcemia and magnesium disorders were both associated with increased length of stay and costs, with a greater effect for magnesium disorders than for hypocalcemia (P < .001). CONCLUSIONS: Disorders of magnesium metabolism are an independent risk factor for postthyroidectomy hypocalcemia and are associated with significantly increased costs and length of stay. PMID- 27118819 TI - Tablet Audiometry in Canada's North: A Portable and Efficient Method for Hearing Screening. AB - BACKGROUND: Access to hearing health care is limited in many parts of the world, creating a lack of prompt diagnosis, which further complicates treatment. The use of portable audiometry for hearing loss testing can improve access to diagnostics in marginalized populations. Our study objectives were twofold: (1) to determine the prevalence of hearing loss in children aged 4 to 11 years in Iqaluit, Nunavut, and (2) to test and demonstrate the use of our tablet audiometer as a portable hearing-testing device in a remote location. STUDY DESIGN: Prospective cross-sectional observational. SETTING: Remote elementary schools in 3 Canadian Northern communities. SUBJECTS AND METHODS: Tablet audiometers were used to test hearing in 218 children. Air conduction pure tones thresholds were obtained at 500, 1000, 2000, and 4000 Hz. Children with hearing loss >=30 dB in either ear were referred for audiology services. RESULTS: Tablet audiometry screening testing revealed abnormal results in 14.8% of the study participants. No significant difference in the rate of hearing loss was seen by sex; however, the rate of hearing loss decreased significantly with increasing age. The median duration of the hearing test was 5 minutes 30 seconds. CONCLUSIONS: Of the study population, 14.8% tested positive for hearing loss based on our interactive tablet audiometer. In this setting, the tablet audiometer was both time efficient and largely language independent. This type of testing is valuable for providing much-needed hearing health care for high-risk populations in rural and remote areas where audiology services are often unavailable. PMID- 27118821 TI - Irradiance Decay in Fluorescent and Light-emitting Diode-based Phototherapy Devices: A Pilot Study. AB - We set out to determine the rate of decline of irradiance for fluorescent tube (FT) and light-emitting diode (LED) phototherapy devices in resource-limited settings where routine irradiance monitoring is uncommon. Irradiance levels (MUW/cm(2)/nm) were measured weekly using BiliBlanket((r)) II Meter on three FT based and two LED-based phototherapy devices over a 19 week period. The two LED devices showed stable irradiance levels and did not require any lamp changes. The three FT-based devices showed rapid decline in irradiance, and all required three complete lamp exchanges approximately every 5-6 weeks. FT-based devices are associated with more rapid decline in irradiance to sub-therapeutic levels and require more frequent lamp changes than LED devices. Clinicians should be alert to the maintenance requirements of the phototherapy devices available in their settings to ensure efficacy of treatment. PMID- 27118820 TI - Quality of Life in Children with Hearing Impairment: Systematic Review and Meta analysis. AB - OBJECTIVE: To determine the impact of pediatric hearing loss (HL) on quality of life (QOL). DATA SOURCES: A qualified medical librarian conducted a literature search for relevant publications that evaluate QOL in school-aged children with HL. REVIEW METHODS: Studies were assessed independently by 2 reviewers for inclusion in the systematic review and meta-analysis. RESULTS: From 979 abstracts, 69 were identified as relevant; ultimately, 40 articles were included in the systematic review. This review revealed that children with HL generally report a lower QOL than their normal-hearing peers and that QOL improves after interventions. The extent of these differences is variable among studies and depends on the QOL measure. Four studies using the Pediatric Quality of Life Inventory (PedsQL) had sufficient data for inclusion in a meta-analysis. After studies were pooled, statistically and clinically significant differences in PedsQL scores were found between children with normal hearing and those with HL, specifically in the social and school domains. Statistically significant differences were also noted in total scores for children with unilateral HL and in the physical domain for children with bilateral HL as compared with those having normal hearing; however, these differences were not clinically meaningful. CONCLUSIONS: Our analysis reveals that decreased QOL in children with HL is detected in distinct domains of the PedsQL. These domains-school activities and social interactions-are especially important for development and learning. Future work should focus on these aspects of QOL when assessing HL in the pediatric population. PMID- 27118822 TI - Effect of Treatment of Premature Infants with Respiratory Distress Using Low-cost Bubble CPAP in a Rural African Hospital. AB - BACKGROUND: Kenya's neonatal mortality rate remains unacceptably high, at 22 deaths per 1000 live births, with a third of those attributable to prematurity. Respiratory distress syndrome (RDS) is the single most important cause of morbidity and mortality in the premature neonate. Continuous positive airway pressure (CPAP) is a proven modality of therapy but is rarely used in low resource settings. We report on the introduction of bubble CPAP (BCPAP), a low cost method of delivering CPAP appropriate to our setting, by comparing survival to-discharge before and after the technology was introduced. METHODS: The inpatient hospital records of all preterm infants (<37 weeks) diagnosed with RDS in the AIC Kijabe Hospital Nursery during two 18-month periods before and after the introduction of BCPAP (46 infants enrolled from 1 November 2007 to 30 April 2009 vs. 72 infants enrolled from 1 November 2009 to 30 April 2011) were reviewed. Differences in survival-to-discharge rates between the two time periods were analyzed. RESULTS: The survival-to-discharge rate was higher in Period 2 (after the introduction of BCPAP) than in Period 1 (pre-BCPAP) (85% vs. 61%, p = 0.007). Similarly, there were lower referral rates of preterm infants with RDS in Period 2 than Period 1 (4% vs. 17%, p = 0.037). CONCLUSION: BCPAP has contributed significantly to favorable outcomes for preterm infants with RDS at AIC Kijabe Hospital. The use of this simple technology should be considered and studied for expansion to all hospitals in Kenya that care for preterm infants. PMID- 27118823 TI - Use of palivizumab with other infection control measures to control respiratory syncytial virus outbreaks in neonatal care units. AB - OBJECTIVE: No guidelines exist on the use of palivizumab during outbreaks of Respiratory Syncytial Virus (RSV) in Neonatal Intensive Care Units (NICUs). We aimed to describe an outbreak of RSV in NICU settings and the role of palivizumab in controlling the outbreak. METHODS: The index case was a 30-day-old premature infant. During the outbreak, 13 cases of RSV were confirmed by RT-PCR. All infants in the NICU received palivizumab after RSV diagnosis. RESULTS: Of the 13 cases, seven were male; and the median (interquartile) of birth weight was 1585 (IQR: 1480-1705) g. All cases were premature under 34-weeks-gestation. Age at onset of disease varies between 10 and 160 days. Only four cases occurred after administering palivizumab and applying other infection control measures. CONCLUSION: During nosocomial outbreaks of RSV, administration of palivizumab to all infants in NICU appears to be rational and may help contain outbreaks. PMID- 27118824 TI - Moderate-to-Vigorous Physical Activity Among Postmenopausal Women: Discrepancies in Accelerometry-Based Cut-Points. AB - The objective of this study was to compare moderate-to-vigorous physical activity (MVPA), minutes per week (min/wk), and fulfillment of the current recommendation (150 min/wk of MVPA) based on different cut-points in postmenopausal women. The sample was composed of 233 postmenopausal women aged 59.8 +/- 6.7 years old. MVPA was measured using triaxial accelerometers. Accelerometers were initialized to collect in 60-s epochs. Participants were included if using at least 5 days. MVPA min/wk were obtained using Freedson, Troiano, Copeland, and Sasaki cut-points. Box-plot indicated large mean differences between almost all cut-points, except for Freedson and Troiano (9.3 [95% LoA: -5.6; 24.3] min/wk). The proportion of women who achieved 150 min/wk of MVPA was similar between Freedson and Troiano (31% vs. 30%). Sasaki and Copeland cut-points resulted in a greater proportion than other cut-points. We concluded that the cut-points analyzed generated different results in MVPA min/wk and low agreement when using current guidelines for MVPA pattern classification, except for the comparisons between Freedson and Troiano cut-points. PMID- 27118826 TI - News Feature: Liquid sunlight. PMID- 27118828 TI - Executive Summary: Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. AB - Evidence-based guidelines for implementation and measurement of antibiotic stewardship interventions in inpatient populations including long-term care were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. The panel included clinicians and investigators representing internal medicine, emergency medicine, microbiology, critical care, surgery, epidemiology, pharmacy, and adult and pediatric infectious diseases specialties. These recommendations address the best approaches for antibiotic stewardship programs to influence the optimal use of antibiotics. PMID- 27118830 TI - Limb Embolism in a 52-Year-Old Woman. PMID- 27118831 TI - Atlantic Meridional Overturning Circulation is stable under global warming. PMID- 27118832 TI - Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents. AB - Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target. PMID- 27118834 TI - Single-enzyme biomineralization of cadmium sulfide nanocrystals with controlled optical properties. AB - Nature has evolved several unique biomineralization strategies to direct the synthesis and growth of inorganic materials. These natural systems are complex, involving the interaction of multiple biomolecules to catalyze biomineralization and template growth. Herein we describe the first report to our knowledge of a single enzyme capable of both catalyzing mineralization in otherwise unreactive solution and of templating nanocrystal growth. A recombinant putative cystathionine gamma-lyase (smCSE) mineralizes CdS from an aqueous cadmium acetate solution via reactive H2S generation from l-cysteine and controls nanocrystal growth within the quantum confined size range. The role of enzymatic nanocrystal templating is demonstrated by substituting reactive Na2S as the sulfur source. Whereas bulk CdS is formed in the absence of the enzyme or other capping agents, nanocrystal formation is observed when smCSE is present to control the growth. This dual-function, single-enzyme, aerobic, and aqueous route to functional material synthesis demonstrates the powerful potential of engineered functional material biomineralization. PMID- 27118833 TI - Memory retrieval of inhibitory avoidance requires histamine H1 receptor activation in the hippocampus. AB - Retrieval represents a dynamic process that may require neuromodulatory signaling. Here, we report that the integrity of the brain histaminergic system is necessary for retrieval of inhibitory avoidance (IA) memory, because rats depleted of histamine through lateral ventricle injections of alpha fluoromethylhistidine (a-FMHis), a suicide inhibitor of histidine decarboxylase, displayed impaired IA memory when tested 2 d after training. a-FMHis was administered 24 h after training, when IA memory trace was already formed. Infusion of histamine in hippocampal CA1 of brain histamine-depleted rats (hence, amnesic) 10 min before the retention test restored IA memory but was ineffective when given in the basolateral amygdala (BLA) or the ventral medial prefrontal cortex (vmPFC). Intra-CA1 injections of selective H1 and H2 receptor agonists showed that histamine exerted its effect by activating the H1 receptor. Noteworthy, the H1 receptor antagonist pyrilamine disrupted IA memory retrieval in rats, thus strongly supporting an active involvement of endogenous histamine; 90 min after the retention test, c-Fos-positive neurons were significantly fewer in the CA1s of a-FMHis-treated rats that displayed amnesia compared with in the control group. We also found reduced levels of phosphorylated cAMP-responsive element binding protein (pCREB) in the CA1s of a-FMHis-treated animals compared with in controls. Increases in pCREB levels are associated with retrieval of associated memories. Targeting the histaminergic system may modify the retrieval of emotional memory; hence, histaminergic ligands might reduce dysfunctional aversive memories and improve the efficacy of exposure psychotherapies. PMID- 27118835 TI - Reply to Parker: Robust response of AMOC interdecadal variability to future intense warming. PMID- 27118836 TI - Programmable RNA-binding protein composed of repeats of a single modular unit. AB - The ability to monitor and perturb RNAs in living cells would benefit greatly from a modular protein architecture that targets unmodified RNA sequences in a programmable way. We report that the RNA-binding protein PumHD (Pumilio homology domain), which has been widely used in native and modified form for targeting RNA, can be engineered to yield a set of four canonical protein modules, each of which targets one RNA base. These modules (which we call Pumby, for Pumilio-based assembly) can be concatenated in chains of varying composition and length, to bind desired target RNAs. The specificity of such Pumby-RNA interactions was high, with undetectable binding of a Pumby chain to RNA sequences that bear three or more mismatches from the target sequence. We validate that the Pumby architecture can perform RNA-directed protein assembly and enhancement of translation of RNAs. We further demonstrate a new use of such RNA-binding proteins, measurement of RNA translation in living cells. Pumby may prove useful for many applications in the measurement, manipulation, and biotechnological utilization of unmodified RNAs in intact cells and systems. PMID- 27118838 TI - Tipping the balance toward trophoblast development. PMID- 27118837 TI - Body mass scaling of passive oxygen diffusion in endotherms and ectotherms. AB - The area and thickness of respiratory surfaces, and the constraints they impose on passive oxygen diffusion, have been linked to differences in oxygen consumption rates and/or aerobic activity levels in vertebrates. However, it remains unclear how respiratory surfaces and associated diffusion rates vary with body mass across vertebrates, particularly in relation to the body mass scaling of oxygen consumption rates. Here we address these issues by first quantifying the body mass dependence of respiratory surface area and respiratory barrier thickness for a diversity of endotherms (birds and mammals) and ectotherms (fishes, amphibians, and reptiles). Based on these findings, we then use Fick's law to predict the body mass scaling of oxygen diffusion for each group. Finally, we compare the predicted body mass dependence of oxygen diffusion to that of oxygen consumption in endotherms and ectotherms. We find that the slopes and intercepts of the relationships describing the body mass dependence of passive oxygen diffusion in these two groups are statistically indistinguishable from those describing the body mass dependence of oxygen consumption. Thus, the area and thickness of respiratory surfaces combine to match oxygen diffusion capacity to oxygen consumption rates in both air- and water-breathing vertebrates. In particular, the substantially lower oxygen consumption rates of ectotherms of a given body mass relative to those of endotherms correspond to differences in oxygen diffusion capacity. These results provide insights into the long-standing effort to understand the structural attributes of organisms that underlie the body mass scaling of oxygen consumption. PMID- 27118839 TI - Big data visualization identifies the multidimensional molecular landscape of human gliomas. AB - We show that visualizing large molecular and clinical datasets enables discovery of molecularly defined categories of highly similar patients. We generated a series of linked 2D sample similarity plots using genome-wide single nucleotide alterations (SNAs), copy number alterations (CNAs), DNA methylation, and RNA expression data. Applying this approach to the combined glioblastoma (GBM) and lower grade glioma (LGG) The Cancer Genome Atlas datasets, we find that combined CNA/SNA data divide gliomas into three highly distinct molecular groups. The mutations commonly used in clinical evaluation of these tumors are regionally distributed in these plots. One of the three groups is a mixture of GBM and LGG that shows similar methylation and survival characteristics to GBM. Altogether, our approach identifies eight molecularly defined glioma groups with distinct sequence/expression/methylation profiles. Importantly, we show that regionally clustered samples are enriched for specific drug targets. PMID- 27118840 TI - Mice carrying a human GLUD2 gene recapitulate aspects of human transcriptome and metabolome development. AB - Whereas all mammals have one glutamate dehydrogenase gene (GLUD1), humans and apes carry an additional gene (GLUD2), which encodes an enzyme with distinct biochemical properties. We inserted a bacterial artificial chromosome containing the human GLUD2 gene into mice and analyzed the resulting changes in the transcriptome and metabolome during postnatal brain development. Effects were most pronounced early postnatally, and predominantly genes involved in neuronal development were affected. Remarkably, the effects in the transgenic mice partially parallel the transcriptome and metabolome differences seen between humans and macaques analyzed. Notably, the introduction of GLUD2 did not affect glutamate levels in mice, consistent with observations in the primates. Instead, the metabolic effects of GLUD2 center on the tricarboxylic acid cycle, suggesting that GLUD2 affects carbon flux during early brain development, possibly supporting lipid biosynthesis. PMID- 27118841 TI - Another piece to the intracellular FGF/Na+ channel puzzle. PMID- 27118843 TI - Mosquito vectors of ape malarias: Another piece of the puzzle. PMID- 27118842 TI - Tobacco mosaic virus-directed reprogramming of auxin/indole acetic acid protein transcriptional responses enhances virus phloem loading. AB - Vascular phloem loading has long been recognized as an essential step in the establishment of a systemic virus infection. In this study, an interaction between the replication protein of tobacco mosaic virus (TMV) and phloem-specific auxin/indole acetic acid (Aux/IAA) transcriptional regulators was found to modulate virus phloem loading in an age-dependent manner. Promoter expression studies show that in mature tissues TMV 126/183-kDa-interacting Aux/IAAs predominantly express and accumulate within the nuclei of phloem companion cells (CCs). Furthermore, CC Aux/IAA nuclear localization is disrupted upon infection with an interacting virus. In situ analysis of virus spread shows that the inability to disrupt Aux/IAA CC nuclear localization correlates with a reduced ability to load into the vascular tissue. Subsequent systemic movement assays also demonstrate that a virus capable of disrupting Aux/IAA localization is significantly more competitive at moving out of older plant tissues than a noninteracting virus. Similarly, CC expression and overaccumulation of a degradation-resistant Aux/IAA-interacting protein was found to inhibit TMV accumulation and phloem loading selectively in flowering plants. Transcriptional expression studies demonstrate a role for Aux/IAA-interacting proteins in the regulation of salicylic and jasmonic acid host defense responses as well as virus specific movement factors, including pectin methylesterase, that are involved in regulating plasmodesmata size-exclusion limits and promoting virus cell-to-cell movement. Combined, these findings indicate that TMV directs the reprogramming of auxin-regulated gene expression within the vascular phloem of mature tissues as a means to enhance phloem loading and systemic spread. PMID- 27118844 TI - Dodecagonal quasicrystalline order in a diblock copolymer melt. AB - We report the discovery of a dodecagonal quasicrystalline state (DDQC) in a sphere (micelle) forming poly(isoprene-b-lactide) (IL) diblock copolymer melt, investigated as a function of time following rapid cooling from above the order disorder transition temperature (TODT = 66 degrees C) using small-angle X-ray scattering (SAXS) measurements. Between TODT and the order-order transition temperature TOOT = 42 degrees C, an equilibrium body-centered cubic (BCC) structure forms, whereas below TOOT the Frank-Kasper sigma phase is the stable morphology. At T < 40 degrees C the supercooled disordered state evolves into a metastable DDQC that transforms with time to the sigma phase. The times required to form the DDQC and sigma phases are strongly temperature dependent, requiring several hours and about 2 d at 35 degrees C and more than 10 and 200 d at 25 degrees C, respectively. Remarkably, the DDQC forms only from the supercooled disordered state, whereas the sigma phase grows directly when the BCC phase is cooled below TOOT and vice versa upon heating. A transition in the rapidly supercooled disordered material, from an ergodic liquid-like arrangement of particles to a nonergodic soft glassy-like solid, occurs below ~40 degrees C, coincident with the temperature associated with the formation of the DDQC. We speculate that this stiffening reflects the development of particle clusters with local tetrahedral or icosahedral symmetry that seed growth of the temporally transient DDQC state. This work highlights extraordinary opportunities to uncover the origins and stability of aperiodic order in condensed matter using model block polymers. PMID- 27118845 TI - GABAB receptor-mediated, layer-specific synaptic plasticity reorganizes gamma frequency neocortical response to stimulation. AB - Repeated presentations of sensory stimuli generate transient gamma-frequency (30 80 Hz) responses in neocortex that show plasticity in a task-dependent manner. Complex relationships between individual neuronal outputs and the mean, local field potential (population activity) accompany these changes, but little is known about the underlying mechanisms responsible. Here we show that transient stimulation of input layer 4 sufficient to generate gamma oscillations induced two different, lamina-specific plastic processes that correlated with lamina specific changes in responses to further, repeated stimulation: Unit rates and recruitment showed overall enhancement in supragranular layers and suppression in infragranular layers associated with excitatory or inhibitory synaptic potentiation onto principal cells, respectively. Both synaptic processes were critically dependent on activation of GABAB receptors and, together, appeared to temporally segregate the cortical representation. These data suggest that adaptation to repetitive sensory input dramatically alters the spatiotemporal properties of the neocortical response in a manner that may both refine and minimize cortical output simultaneously. PMID- 27118847 TI - A topologically driven glass in ring polymers. AB - The static and dynamic properties of ring polymers in concentrated solutions remains one of the last deep unsolved questions in polymer physics. At the same time, the nature of the glass transition in polymeric systems is also not well understood. In this work, we study a novel glass transition in systems made of circular polymers by exploiting the topological constraints that are conjectured to populate concentrated solutions of rings. We show that such rings strongly interpenetrate through one another, generating an extensive network of topological interactions that dramatically affects their dynamics. We show that a kinetically arrested state can be induced by randomly pinning a small fraction of the rings. This occurs well above the classical glass transition temperature at which microscopic mobility is lost. Our work both demonstrates the existence of long-lived inter-ring penetrations and realizes a novel, topologically induced, glass transition. PMID- 27118846 TI - Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. AB - The primary cilium is a cellular organelle that coordinates signaling pathways critical for cell proliferation, differentiation, survival, and homeostasis. Intraflagellar transport (IFT) plays a pivotal role in assembling primary cilia. Disruption and/or dysfunction of IFT components can cause multiple diseases, including skeletal dysplasia. However, the mechanism by which IFT regulates skeletogenesis remains elusive. Here, we show that a neural crest-specific deletion of intraflagellar transport 20 (Ift20) in mice compromises ciliogenesis and intracellular transport of collagen, which leads to osteopenia in the facial region. Whereas platelet-derived growth factor receptor alpha (PDGFRalpha) was present on the surface of primary cilia in wild-type osteoblasts, disruption of Ift20 down-regulated PDGFRalpha production, which caused suppression of PDGF-Akt signaling, resulting in decreased osteogenic proliferation and increased cell death. Although osteogenic differentiation in cranial neural crest (CNC)-derived cells occurred normally in Ift20-mutant cells, the process of mineralization was severely attenuated due to delayed secretion of type I collagen. In control osteoblasts, procollagen was easily transported from the endoplasmic reticulum (ER) to the Golgi apparatus. By contrast, despite having similar levels of collagen type 1 alpha 1 (Col1a1) expression, Ift20 mutants did not secrete procollagen because of dysfunctional ER-to-Golgi trafficking. These data suggest that in the multipotent stem cells of CNCs, IFT20 is indispensable for regulating not only ciliogenesis but also collagen intracellular trafficking. Our study introduces a unique perspective on the canonical and noncanonical functions of IFT20 in craniofacial skeletal development. PMID- 27118848 TI - Arabidopsis SAURs are critical for differential light regulation of the development of various organs. AB - During deetiolation of Arabidopsis seedlings, light promotes the expansion of cotyledons but inhibits the elongation of hypocotyls. The mechanism of this differential regulation of cell enlargement is unclear. Our organ-specific transcriptomic analysis identified 32 Small Auxin Up RNA (SAUR) genes whose transcripts were light-induced in cotyledons and/or repressed in hypocotyls. We therefore named these SAURs as lirSAURs Both overexpression and mutation analyses demonstrated that lirSAURs could promote cotyledon expansion and opening and enhance hypocotyl elongation, possibly by inhibiting phosphatase activity of D clade type 2C protein phosphatases (PP2C-Ds). Light reduced auxin levels to down regulate the expression of lirSAURs in hypocotyls. Further, phytochrome interacting factors (PIFs) were shown to directly bind the genes encoding these SAURs and differentially regulate their expression in cotyledons and hypocotyls. Together, our study demonstrates that light mediates auxin levels and PIF stability to differentially regulate the expression of lirSAURs in cotyledons and hypocotyls, and these lirSAURs further mediate the differential growth of these two organs. PMID- 27118850 TI - High impact grand mal. PMID- 27118849 TI - Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks. AB - Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-d-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca(2+) signaling involving NMDAR activation, astrocyte membrane depolarization, and L type Ca(2+) channels. Intracellular infusion of NMDARs or Ca(2+)-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocyte-dependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites. PMID- 27118851 TI - Tuberculosis and Healthcare Workers in Underresourced Settings. PMID- 27118852 TI - Protecting Our Front-liners: Occupational Tuberculosis Prevention Through Infection Control Strategies. AB - Healthcare workers (HCWs) in low- and middle-income countries with high tuberculosis prevalence are at increased risk of tuberculosis infection; however, tuberculosis infection control (TBIC) measures are often poorly implemented. The World Health Organization recommends 4 levels of TBIC: managerial (establishment and oversight of TBIC policies), administrative controls (reducing HCWs' exposure to tuberculosis), environmental controls (reducing the concentration of infectious respiratory aerosols in the air), and personal respiratory protection. This article will discuss each of these levels of TBIC, and review the available data on the implementation of each in sub-Saharan African countries. In addition, we review the attitudes and motivation of HCWs regarding TBIC measures, and the impact of stigma on infection control practices and implementation. After summarizing the challenges facing effective TBIC implementation, we will discuss possible solutions and recommendations. Last, we present a case study of how a clinic effectively addressed some of the challenges of TBIC implementation. PMID- 27118853 TI - Infection Control for Drug-Resistant Tuberculosis: Early Diagnosis and Treatment Is the Key. AB - Multidrug-resistant (MDR) tuberculosis, "Ebola with wings," is a significant threat to tuberculosis control efforts. Previous prevailing views that resistance was mainly acquired through poor treatment led to decades of focus on drug sensitive rather than drug-resistant (DR) tuberculosis, driven by the World Health Organization's directly observed therapy, short course strategy. The paradigm has shifted toward recognition that most DR tuberculosis is transmitted and that there is a need for increased efforts to control DR tuberculosis. Yet most people with DR tuberculosis are untested and untreated, driving transmission in the community and in health systems in high-burden settings. The risk of nosocomial transmission is high for patients and staff alike. Lowering transmission risk for MDR tuberculosis requires a combination approach centered on rapid identification of active tuberculosis disease and tuberculosis drug resistance, followed by rapid initiation of appropriate treatment and adherence support, complemented by universal tuberculosis infection control measures in healthcare facilities. It also requires a second paradigm shift, from the classic infection control hierarchy to a novel, decentralized approach across the continuum from early diagnosis and treatment to community awareness and support. A massive scale-up of rapid diagnosis and treatment is necessary to control the MDR tuberculosis epidemic. This will not be possible without intense efforts toward the implementation of decentralized, ambulatory models of care. Increasing political will and resources need to be accompanied by a paradigm shift. Instead of focusing on diagnosed cases, recognition that transmission is driven largely by undiagnosed, untreated cases, both in the community and in healthcare settings, is necessary. This article discusses this comprehensive approach, strategies available, and associated challenges. PMID- 27118854 TI - The Development and Piloting of Parallel Scales Measuring External and Internal HIV and Tuberculosis Stigma Among Healthcare Workers in the Free State Province, South Africa. AB - BACKGROUND: The dual burden of tuberculosis and human immunodeficiency virus (HIV) is severely impacting the South African healthcare workforce. However, the use of on-site occupational health services is hampered by stigma among the healthcare workforce. The success of stigma-reduction interventions is difficult to evaluate because of a dearth of appropriate scientific tools to measure stigma in this specific professional setting. METHODS: The current pilot study aimed to develop and test a range of scales measuring different aspects of stigma-internal and external stigma toward tuberculosis as well as HIV-in a South African healthcare setting. The study employed data of a sample of 200 staff members of a large hospital in Bloemfontein, South Africa. RESULTS: Confirmatory factor analysis produced 7 scales, displaying internal construct validity: (1) colleagues' external HIV stigma, (2) colleagues' actions against external HIV stigma, (3) respondent's external HIV stigma, (4) respondent's internal HIV stigma, (5) colleagues' external tuberculosis stigma, (6) respondent's external tuberculosis stigma, and (7) respondent's internal tuberculosis stigma. Subsequent analyses (reliability analysis, structural equation modeling) demonstrated that the scales displayed good psychometric properties in terms of reliability and external construct validity. CONCLUSIONS: The study outcomes support the use of the developed scales as a valid and reliable means to measure levels of tuberculosis- and HIV-related stigma among the healthcare workforce in a resource-limited context. Future studies should build on these findings to fine tune the instruments and apply them to larger study populations across a range of different resource-limited healthcare settings with high HIV and tuberculosis prevalence. PMID- 27118855 TI - Occupational Risk Factors for Tuberculosis Among Healthcare Workers in KwaZulu Natal, South Africa. AB - BACKGROUND: Tuberculosis is a known occupational hazard for healthcare workers (HCWs), especially in countries with a high burden of tuberculosis. It is estimated that HCWs have a 2- to 3-fold increased risk of developing tuberculosis compared with the general population. The objective of this study was to identify occupational risk factors for tuberculosis among HCWs in 3 district hospitals with specialized multidrug-resistant tuberculosis wards in KwaZulu-Natal, South Africa. METHODS: We conducted a case-control study of HCWs diagnosed with tuberculosis between January 2006 and December 2010. Cases and controls were asked to complete a self-administered questionnaire regarding potential risk factors for tuberculosis. RESULTS: Of 307 subjects selected, 145 (47%) HCWs responded to the questionnaire; 54 (37%) tuberculosis cases and 91 (63%) controls. Cases occurred more frequently among clinical staff 46% (n = 25) and support staff 35% (n = 19). Thirty-two (26% [32/125]) HCWs were known to be infected with human immunodeficiency virus (HIV), including 45% (21/54) of cases. HCWs living with HIV (odds ratio [OR], 6.35; 95% confidence interval [CI], 3.54 11.37) and those who spent time working in areas with patients (OR, 2.24; 95% CI, 1.40-3.59) had significantly greater odds of developing tuberculosis, controlling for occupation, number of wards worked in, and household crowding. CONCLUSIONS: HIV was the major independent risk factor for tuberculosis among HCWs in this sample. These findings support the need for HCWs to know their HIV status, and for HIV-infected HCWs to be offered antiretroviral therapy and isoniazid preventive therapy. Infection prevention and control should also be improved to prevent transmission of tuberculosis in healthcare settings to protect both HCWs and patients. PMID- 27118857 TI - Where Caring Is Sharing: Evolving Ethical Considerations in Tuberculosis Prevention Among Healthcare Workers. AB - In many settings, the dedication of healthcare workers (HCWs) to the treatment of tuberculosis exposes them to serious risks. Current ethical considerations related to tuberculosis prevention in HCWs involve the threat posed by comorbidities, issues of power and space, the implications of intersectoral collaborations, (de)professionalization, just remuneration, the duty to care, and involvement in research. Emerging ethical considerations include mandatory vaccination and the use of geolocalization services and information technologies. The following exploration of these various ethical considerations demonstrates that the language of ethics can fruitfully be deployed to shed new light on policies that have repercussions on the lives of HCWs in underresourced settings. The language of ethics can help responsible parties get a clearer sense of what they owe HCWs, particularly when these individuals are poorly compensated, and it shows that it is essential that HCWs' contribution be acknowledged through a shared commitment to alleviate ethically problematic aspects of the environments within which they provide care. For this reason, there is a strong case for the community of bioethicists to continue to take greater interest both in the micro level (eg, patient-provider interactions) and macro-level (eg, injustices that occur as a result of the world order) issues that put HCWs working in areas with high tuberculosis prevalence in ethically untenable positions. Ultimately, appropriate responses to the various ethical considerations explored here must vary based on the setting, but, as this article shows, they require thoughtful reflection and courageous action on the part of governments, policy makers, and managers responsible for national responses to the tuberculosis epidemic. PMID- 27118856 TI - BCG and New Preventive Tuberculosis Vaccines: Implications for Healthcare Workers. AB - Healthcare workers (HCWs) are at high risk of Mycobacterium tuberculosis (Mtb) infection and tuberculosis disease, but also play a crucial role in implementing healthcare. Preexposure tuberculosis vaccination, including revaccination with BCG, might benefit Mtb-uninfected HCWs, but most HCWs in tuberculosis-endemic countries are already sensitized to mycobacteria. A new postexposure tuberculosis vaccine offers greatest potential for protection, in the setting of repeated occupational Mtb exposure. Novel strategies for induction of mycobacteria specific resident memory T cells in the lung by aerosol administration, or induction of T cells with inherent propensity for residing in mucosal sites, such as CD1-restricted T cells and mucosa-associated innate T cells, should be explored. The need for improved protection of HCWs against tuberculosis disease is clear. However, health systems in tuberculosis-endemic countries would need significantly improved occupational health structures to implement a screening and vaccination strategy for HCWs. PMID- 27118858 TI - Exposed, but Not Protected: More Is Needed to Prevent Drug-Resistant Tuberculosis in Healthcare Workers and Students. AB - "Occupational MDR-TB" ... "XDR-TB" ... "Treatment-induced hearing loss": 3 life-changing messages imparted over the phone. Three personal accounts are shared highlighting the false belief held by many healthcare workers (HCWs) and students in low-resource settings-that they are immune to tuberculosis despite high levels of occupational tuberculosis exposure. This misconception reflects a lack of awareness of tuberculosis transmission and disease risk, compounded by the absence of accurate occupational tuberculosis estimates. As the global problem of drug-resistant (DR) tuberculosis evolves, HCWs are increasingly infected and suffer considerable morbidity and mortality from occupational DR tuberculosis disease. Similarly, healthcare students are emerging as a vulnerable and unprotected group. There is an urgent need for improved detection, vaccines, preventive therapy, treatment, and support for affected HCWs and those they care for, as well as destigmatization of all forms of tuberculosis. Finally, efforts to protect HCWs and prevent DR tuberculosis transmission by universal implementation of tuberculosis infection control measures should be prioritized. PMID- 27118859 TI - Potential pharmacokinetic effect of rifampicin on enrofloxacin in broilers: Roles of P-glycoprotein and BCRP induction by rifampicin. AB - P-glycoprotein ( P-GP: , encoding gene Abcb1) and Breast Cancer Resistance Protein ( BCRP: , encoding gene Abcg2) are transport proteins that play a major role in modulating the bioavailability of oral drugs in humans and rodents. It has been shown that rifampicin is the typical inducer of P-gp in rodents by activating the nuclear receptor. However, its effect on Abcb1, Abcg2, CYP3A, and chicken xenobiotic-sensing orphan nuclear receptor ( CXR: ) mRNA expression in broilers is poorly understood. This study explored the effect of rifampicin on mRNA expression of Abcb1, Abcg2, CYP3A37, CXR as well as its effect on the pharmacokinetics of enrofloxacin in broilers. The mRNA levels of Abcb1, Abcg2, CYP3A37, and CXR were significantly increased in the liver (except Abcg2), kidney, jejunum, and ileum (P < 0.05) but not significantly changed in the duodenum (P > 0.05) after treated with rifampicin. Further analysis revealed that the variation tendencies of Abcb1, Abcg2, and CYP3A37 expression levels were significantly correlated with CXR mRNA expression levels in liver, kidney, jejunum, and ileum. Coadministration of rifampicin significantly changed the pharmacokinetic behavior of enrofloxacin orally administered by showing clearly lower AUC0-infinity, AUC0-t, and Cmax as well as longer Tmax. The bioavailability of orally administered enrofloxacin was decreased from 72.5% to 24.8% by rifampicin. However, rifampicin did not significantly change the pharmacokinetics of enrofloxacin following intravenous administration. Our study shows that rifampicin up-regulated the small intestinal level of P-gp and BCRP and suggests that P-gp and BCRP are key factors that affected pharmacokinetic behavior of orally administered enrofloxacin by limiting its absorption from the intestine in broilers. PMID- 27118860 TI - Effects of dietary L-isoleucine on laying performance and immunomodulation of laying hens. AB - Isoleucine may be a limiting amino acid for laying hens fed diets with a lowered protein level. An experiment was conducted to examine laying performance and the immune function of laying hens provided diets varying in digestible isoleucine levels during the peak production period. A total number of 400 Lohmann Brown laying hens, 28 wk of age, were allocated to 5 dietary treatment groups, each of which included 5 replicates of 16 hens per replicate (4 cages / replicate; 80 hens / treatment). L-isoleucine was added to the experimental diet (14% CP) containing synthetic amino (methionine, lysine, threonine, tryptophan, and valine) by zero, 1.0, 2.0, 3.0, and 4.0 g/kg, corresponding to 0.54%, 0.64%, 0.74%, 0.84, and 0.94% digestible isoleucine, respectively. At the end of the experiment (wk 40), dietary isoleucine did not affect laying performance or egg quality. Serum albumin concentration increased quadratically (P < 0.05) in response to digestible dietary isoleucine at 0.74%. Serum free isoleucine and lysine increased (P < 0.05) in response to digestible dietary isoleucine at 0.74%. Digestible dietary isoleucine levels did not affect the serum concentrations of total antioxidative capability (T-AOC), total superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and CuZn-superoxide dismutase (CuZn-SOD). There was no significant (P > 0.05) response of excess digestible isoleucine level on the serum level of IgG, IgA, or IgM. In addition, dietary isoleucine levels did not affect the concentrations of secretory immunoglobulin A (sIgA), tumor necrosis factor alpha (TNFalpha), or interleukin (IL-2 and IL-6) in the ileum. Also, expressions of ileal MUC2 mRNA, sIgA mRNA, and IL-1beta mRNA were not changed (P > 0.05) by excess digestible isoleucine level. Furthermore, excess digestible isoleucine level did not change mRNA expression of ileal tight junction protein (claudin-1 and occludin). No effect occurred when isoleucine was supplemented, suggesting that it is not a limiting amino acid in the low crude protein diet on laying performance and intestinal mucosal immune. PMID- 27118861 TI - Determination of yolk contamination in liquid egg white using Raman spectroscopy. AB - Purified egg white is an important ingredient in a number of baked and confectionary foods because of its foaming properties. However, yolk contamination in amounts as low as 0.01% can impede the foaming ability of egg white. In this study, we used Raman spectroscopy to evaluate the hypothesis that yolk contamination in egg white could be detected based on its molecular optical properties. Yolk contaminated egg white samples (n = 115) with contamination levels ranging from 0% to 0.25% (on weight basis) were prepared. The samples were excited with a 785 nm laser and Raman spectra from 250 to 3,200 cm(-1) were recorded. The Raman spectra were baseline corrected using an optimized piecewise cubic interpolation on each spectrum and then normalized with a standard normal variate transformation. Samples were randomly divided into calibration (n = 77) and validation (n = 38) data sets. A partial least squares regression (PLSR) model was developed to predict yolk contamination levels, based on the Raman spectral fingerprint. Raman spectral peaks, in the spectral region of 1,080 and 1,666 cm(-1), had the largest influence on detecting yolk contamination in egg white. The PLSR model was able to correctly predict yolk contamination levels with an R(2) = 0.90 in the validation data set. These results demonstrate the capability of Raman spectroscopy for detection of yolk contamination at very low levels in egg white and present a strong case for development of an on-line system to be deployed in egg processing plants. PMID- 27118862 TI - Temperature during the last week of incubation. II. Effects on first week broiler development and performance. AB - Little is known about applying various eggshell temperatures (EST) during the last week of incubation. In particular, the effect of an EST below 37.8 degrees C during the last week of incubation is poorly investigated. Therefore, we investigated effects of EST of 35.6, 36.7, 37.8, or 38.9 degrees C applied from d of incubation (E) 15, E17, or E19 on first week broiler development and performance. A total of 2,850 first grade eggs of a 43 wk old Ross 308 broiler breeder flock were incubated at an EST of 37.8 degrees C until E15. From E15, E17, or E19 onward, eggs were incubated at an EST of 35.6, 36.7, 37.8, or 38.9 degrees C. Chick quality was determined at placement in the broiler house and organ development was measured at d 7. BW was determined at placement, d4, and d7. Feed intake (FI) was measured at d4 and d7 and G:F was calculated between placement and d4, and between d4 and d7. Chick quality at placement was higher at an EST of 35.6 degrees C compared to all other EST treatments, expressed by a longer chick length and highest prevalence of closed navels. BW d 7 was higher at an EST of 36.7 degrees C compared to all other EST treatments, which was not caused by a higher FI during the first week. A higher G:F between d 0 and d 7 was found at an EST of 36.7 degrees C compared to 35.6 and 38.9 degrees C. At d 7, a higher relative heart weight was found at an EST of 35.6 compared to 38.9 degrees C. This study indicates that an EST of 38.9 degrees C applied from E15 onward negatively affected chick quality, organ development, and G:F until d 7 compared to 37.8 degrees C. Moreover, an EST of 36.7 degrees C had a clear positive effect on chick quality, organ development, G:F, and growth performance until d 7. An EST of 35.6 degrees C resulted in equal or higher chick quality and organ weights compared to 36.7 degrees C, but this was not reflected in performance parameters. PMID- 27118863 TI - Prevalence and antibiotic resistance of Salmonella Enteritidis and Salmonella Typhimurium in raw chicken meat at retail markets in Malaysia. AB - Salmonellosis is one of the major food-borne diseases in many countries. This study was carried out to determine the occurrence of Salmonella spp., Salmonella Enteritidis, and Salmonella Typhimurium in raw chicken meat from wet markets and hypermarkets in Selangor, as well as to determine the antibiotic susceptibility profile of S. Enteritidis and S. Typhimurium. The most probable number (MPN) in combination with multiplex polymerase chain reaction (mPCR) method was used to quantify the Salmonella spp., S. Enteritidis, and S. Typhimurium in the samples. The occurrence of Salmonella spp., S. Enteritidis, and S. Typhimurium in 120 chicken meat samples were 20.80%, 6.70%, and 2.50%, respectively with estimated quantity varying from <3 to 15 MPN/g. The antibiogram testing revealed differential multi-drug resistance among S. Enteritidis and S. Typhimurium isolates. All the isolates were resistance to erythromycin, penicillin, and vancomycin whereas sensitivity was recorded for Amoxicillin/Clavulanic acid, Gentamicin, Tetracycline, and Trimethoprim. Our findings demonstrated that the retail chicken meat could be a source of multiple antimicrobial-resistance Salmonella and may constitute a public health concern in Malaysia. PMID- 27118864 TI - Copy number variation identification and analysis of the chicken genome using a 60K SNP BeadChip. AB - Copy number variation (CNV) is an important source of genetic variation in organisms and a main factor that affects phenotypic variation. A comprehensive study of chicken CNV can provide valuable information on genetic diversity and facilitate future analyses of associations between CNV and economically important traits in chickens. In the present study, an F2 full-sib chicken population (554 individuals), established from a cross between Xinghua and White Recessive Rock chickens, was used to explore CNV in the chicken genome. Genotyping was performed using a chicken 60K SNP BeadChip. A total of 1,875 CNV were detected with the PennCNV algorithm, and the average number of CNV was 3.42 per individual. The CNV were distributed across 383 independent CNV regions (CNVR) and covered 41 megabases (3.97%) of the chicken genome. Seven CNVR in 108 individuals were validated by quantitative real-time PCR, and 81 of these individuals (75%) also were detected with the PennCNV algorithm. In total, 274 CNVR (71.54%) identified in the current study were previously reported. Of these, 147 (38.38%) were reported in at least 2 studies. Additionally, 109 of the CNVR (28.46%) discovered here are novel. A total of 709 genes within or overlapping with the CNVR was retrieved. Out of the 2,742 quantitative trait loci (QTL) collected in the chicken QTL database, 43 QTL had confidence intervals overlapping with the CNVR, and 32 CNVR encompassed one or more functional genes. The functional genes located in the CNVR are likely to be the QTG that are associated with underlying economic traits. This study considerably expands our insight into the structural variation in the genome of chickens and provides an important resource for genomic variation, especially for genomic structural variation related to economic traits in chickens. PMID- 27118865 TI - Nutritional quality of eggs from hens fed distillers dried grains with solubles. AB - A feeding trial was conducted with laying hens where either 10% or 20% regular fat distiller's dried grains with solubles (R-DDGS) or low-fat DDGS (L-DDGS) were incorporated into the feed. Production parameters and the effect of DDGS on egg nutritional quality, focusing on yolk lipids, were evaluated. Neither R-DDGS nor L-DDGS at up to 20% of laying hen feeds had a statistically significant impact on hen weight gain, egg production, feed intake, feed efficiency, egg mass, or egg weight. Specific gravity was slightly lower for eggs from hens fed 10% R-DDGS or 20% L-DDGS. Eggs from layers fed DDGS had enhanced levels of tocopherols, tocotrienols, and xanthophylls in the yolk, as well as also increased yolk yellow and red color. Eggs from L-DDGS diet had higher tocopherol content, but eggs from R-DDGS diets had higher xanthophylls. Fatty acid composition in eggs was slightly altered by DDGS, but the ratio of saturated to unsaturated fatty acids was very similar. Feeding DDGS to layer hens had no effect on lecithin or cholesterol content of the eggs. Thus, inclusion of DDGS in the diet of laying hens resulted in increases of several beneficial lipophilic nutrients in egg yolks with no apparent detrimental effects. PMID- 27118866 TI - Effect of d-allulose on rheological properties of chicken breast sausage. AB - d-Allulose (Alu), a rare sugar, was applied to chicken breast sausage as a sucrose (Suc) substitute. The ratio (w/w) of Alu to Suc in sugar that was added to the sausage batter was 0/1 (A0S1), 3/7 (A3S7), 7/3 (A7S3), and 1/0 (A1S0). The total amount of Suc used was 2.5% of the weight of minced chicken breast meat. Substituting Suc with Alu did not affect water content, cooking loss, breaking stress, breaking strain, and modulus of elasticity of chicken breast sausage, but a 100% substitution with Alu caused a 10% decrease in viscosity and a 31% decrease in expressible water. A significant difference appeared in the rheological properties of elasticity, viscosity, and water-holding capacity of chicken breast sausage frozen-stored (-20 degrees C) for 90 d. Particularly, the modulus of elasticity for A1S0 chicken breast sausage was 19% higher than that of the control A0S1 chicken breast sausage, suggesting that Alu appreciably reduced the deterioration in elasticity that is caused by long-term frozen storage of sausage. The quality improvement of frozen-stored chicken breast sausage demonstrates the feasibility and benefits of the application of Alu to frozen foods. PMID- 27118867 TI - Unveiling the basis of alkaline stability of an evolved versatile peroxidase. AB - A variant of high biotechnological interest (called 2-1B) was obtained by directed evolution of the Pleurotus eryngii VP (versatile peroxidase) expressed in Saccharomyces cerevisiae [Garcia-Ruiz, Gonzalez-Perez, Ruiz-Duenas, Martinez and Alcalde (2012) Biochem. J. 441: , 487-498]. 2-1B shows seven mutations in the mature protein that resulted in improved functional expression, activity and thermostability, along with a remarkable stronger alkaline stability (it retains 60% of the initial activity after 120 h of incubation at pH 9 compared with complete inactivation of the native enzyme after only 1 h). The latter is highly demanded for biorefinery applications. In the present study we investigate the structural basis behind the enhanced alkaline stabilization of this evolved enzyme. In order to do this, several VP variants containing one or several of the mutations present in 2-1B were expressed in Escherichia coli, and their alkaline stability and biochemical properties were determined. In addition, the crystal structures of 2-1B and one of the intermediate variants were solved and carefully analysed, and molecular dynamics simulations were carried out. We concluded that the introduction of three basic residues in VP (Lys-37, Arg-39 and Arg-330) led to new connections between haem and helix B (where the distal histidine residue is located), and formation of new electrostatic interactions, that avoided the hexa-co-ordination of the haem iron. These new structural determinants stabilized the haem and its environment, helping to maintain the structural enzyme integrity (with penta-co-ordinated haem iron) under alkaline conditions. Moreover, the reinforcement of the solvent-exposed area around Gln-305 in the proximal side, prompted by the Q202L mutation, further enhanced the stability. PMID- 27118868 TI - A polybasic motif in ErbB3-binding protein 1 (EBP1) has key functions in nucleolar localization and polyphosphoinositide interaction. AB - Polyphosphoinositides (PPIns) are present in the nucleus where they participate in crucial nuclear processes, such as chromatin remodelling, transcription and mRNA processing. In a previous interactomics study, aimed to gain further insight into nuclear PPIns functions, we identified ErbB3 binding protein 1 (EBP1) as a potential nuclear PPIn-binding protein in a lipid pull-down screen. EBP1 is a ubiquitous and conserved protein, located in both the cytoplasm and nucleolus, and associated with cell proliferation and survival. In the present study, we show that EBP1 binds directly to several PPIns via two distinct PPIn-binding sites consisting of clusters of lysine residues and positioned at the N- and C termini of the protein. Using interaction mutants, we show that the C-terminal PPIn-binding motif contributes the most to the localization of EBP1 in the nucleolus. Importantly, a K372N point mutation, located within the C-terminal motif and found in endometrial tumours, is sufficient to alter the nucleolar targeting of EBP1. Our study reveals also the presence of the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110beta and its product PtdIns(3,4,5)P3 together with EBP1 in the nucleolus. Using NMR, we further demonstrate an association between EBP1 and PtdIns(3,4,5)P3 via both electrostatic and hydrophobic interactions. Taken together, these results show that EBP1 interacts directly with PPIns and associate with PtdIns(3,4,5)P3 in the nucleolus. The presence of p110beta and PtdIns(3,4,5)P3 in the nucleolus indicates their potential role in regulating nucleolar processes, at least via EBP1. PMID- 27118870 TI - FAP finds FGF21 easy to digest. AB - Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates carbohydrate and lipid metabolism. In humans, circulating FGF21 is inactivated by proteolytic cleavage of its C-terminus, thereby preventing signalling through a receptor complex. The mechanism for this cleavage event and the factors contributing to the post-translational regulation of FGF21 activity has previously been unknown. In a recent issue of the Biochemical Journal, Zhen et al. have identified fibroblast activation protein (FAP) as the endopeptidase responsible for this site-specific cleavage of human FGF21 (hFGF21), and propose that inhibition of FAP may be a therapeutic strategy to increase endogenous levels of active FGF21. PMID- 27118869 TI - SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms. AB - The role of plasma membrane transporters in cancer is receiving increasing attention in recent years. Several transporters for essential nutrients are up regulated in cancer and serve as tumour promoters. Transporters could also function as tumour suppressors. To date, four transporters belonging to the SLC gene family have been identified as tumour suppressors. SLC5A8 is a Na(+)-coupled transporter for monocarboxylates. Among its substrates are the bacterial fermentation products butyrate and propionate and the ubiquitous metabolite pyruvate. The tumour-suppressive function of this transporter relates to the ability of butyrate, propionate and pyruvate to inhibit histone deacetylases (HDAC). SLC5A8 functions as a tumour suppressor in most tissues studied thus far, and provides a molecular link to Warburg effect, a characteristic feature in most cancers. It also links colonic bacteria and dietary fibre to the host. SLC26A3 as a tumour suppressor is restricted to colon; it is a Cl(-)/HCO(-) 3 exchanger, facilitating the efflux of HCO(-) 3 The likely mechanism for the tumour suppressive function of SLC26A3 is related to intracellular pH regulation. SLC39A1 is a Zn(2+) transporter and its role in tumour suppression has been shown in prostate. Zn(2+) is present at high concentrations in normal prostate where it elicits its tumour-suppressive function. SLC22A18 is possibly an organic cation transporter, but the identity of its physiological substrates is unknown. As such, there is no information on molecular pathways responsible for the tumour suppressive function of this transporter. It is likely that additional SLC transporters will be discovered as tumour suppressors in the future. PMID- 27118871 TI - Does it matter how much physician trainees work anymore? PMID- 27118872 TI - Health-related quality of life in different stages of chronic kidney disease. AB - INTRODUCTION: Improved survival of chronic kidney disease (CKD) patients has led to an increased focus on health-related quality of life (HRQoL) for evaluating treatment effectiveness and assessing health outcomes of these patients. OBJECTIVE: To evaluate HRQoL in patients in different stages of CKD and to explore possible correlating and influencing factors. METHODS: Cross-sectional design with 200 patients from India in CKD stages 1-5 assessed for HRQoL through 36-item short-form together with biomarkers. Patients were divided into four groups according to their estimated Glomerular Filtration Rate (eGFR); group A with GFR range > 90 ml/min/1.73 m2, group B with GFR range 30-59 ml/min/1.73 m2, group C with GFR range 15-29 ml/min/1.73 m2 and group D with GFR < 15 ml/min/1.73 m2 RESULTS: HRQoL scores in all dimensions impaired progressively and significantly across renal function levels and CKD stages. A statistically significant decreasing trend in physical composite summary and mental composite summary scores was found in patients from group A to D (P< 0.001). Patients with eGFR < 30 ml/min/1.73 m2, Diabetes Mellitus, Cardio vascular disease (CVD), C reactive protein (CRP) >= 5 mg/l, Hemoglobin <= 90 g/l, erythrocyte sedimentation rate >= 20 and mean arterial pressure >= 100 mm hg had significantly lower scores on all HRQoL dimensions. Among these CRP, reduced GFR and CVD were the most important predictors of impaired HRQoL. CONCLUSION: Considering the worldwide growing prevalence of CKD and increasing importance of HRQoL in chronic diseases, improving our knowledge about HRQoL and its predictors in CKD patients is important. Assessment of HRQoL early in disease course will help to identify high risk patients in whom modifying these factors may help them lead an active and healthy life. PMID- 27118873 TI - Influence of social deprivation, overcrowding and family structure on emergency medical admission rates. AB - BACKGROUND: Patients from deprived backgrounds have a higher in-patient mortality following emergency medical admission. AIM: To evaluate the influence of Deprivation Index, overcrowding and family structure on hospital admission rates. DESIGN: Retrospective cohort study. METHODS: All emergency medical admissions from 2002 to 2013 were evaluated. Based on address, each patient was allocated to an electoral division, whose small area population statistics were available from census data. Patients were categorized by quintile of Deprivation Index, overcrowding and family structure, and these were evaluated against hospital admission rate, calculated as rate/1000 population. Univariate and multivariable risk estimates (Odds Ratios or Incidence Rate Ratios) were calculated, using logistic or zero truncated Poisson regression as appropriate. RESULTS: There were 66 861 admissions in 36 214 patients over the 12-year study period. Deprivation Index quintile independently predicted the admission rate, with rates of Q1 12.0 (95% CI 11.8-12.2), Q2 19.5 (95% CI 19.3-19.6), Q3 33.7 (95% CI 33.3-34.0), Q4 31.4 (95% CI 31.2-31.6) and Q5 38.1 (95% CI 37.7-38.5). Similarly the proportions of families with children <15 years old, was an independent predictor of the admission rate with rates of Q1 20.8 (95% CI 20.4-21.1), Q2 23.0 (95% CI 22.7 23.3), Q3 32.2 (95% CI 31.9-32.5), Q4 32.4 (95% CI 32.2-32.7) and Q5 37.2 (95% CI 36.6-37.8). The proportion of families with children >=15-years old was also predictive but quintile of overcrowding was only predictive in the univarate model. CONCLUSION: Deprivation Index and family structure strongly predict emergency medical hospital admission rates. PMID- 27118874 TI - Is Renal Impairment an Anticipated COPD Comorbidity? AB - BACKGROUND: Many studies have investigated COPD-linked comorbidities and their influence on associated outcomes, but the extent to which COPD is related to chronic renal failure is undetermined. The objective of this work was to assess the prevalence of chronic renal failure (overt or concealed) in a cohort with COPD compared with that of a control group, and to investigate the relationships of the clinical and functional data with the subjects' renal conditions. METHODS: The study was performed with 136 subjects with COPD and 104 control subjects. The subjects with COPD were divided into 2 groups according to a combined assessment. The COPD and control groups were compared in terms of clinical factors, renal function, estimated glomerular filtration rate, and spirometry data. The prevalence of the renal status types was examined in all groups, and the correlations of serum creatinine and estimated glomerular filtration rate with all of the clinical and spirometry data were examined. RESULTS: There were significant differences between both COPD groups and the controls regarding estimated glomerular filtration rate. Significantly worse renal function was observed in the COPD group, which also exhibited a greater percentage of subjects with concealed chronic renal failure. Additionally, there were significant differences in renal status among the 3 groups; the percentage of subjects with concealed chronic renal failure was significantly greater in group 2 than in both group 1 and the control group. Additionally, the percentages of subjects with concealed chronic renal failure were greater than those with overt chronic renal failure in the 3 groups. There were significant correlations of serum creatinine with COPD assessment test, exacerbations and hospitalizations, percent-of predicted FVC, percent-of-predicted FEV1/FVC, percent-of-predicted maximum mid expiratory flow, and percent-of-predicted peak expiratory flow. Moreover, there were significant correlations between estimated glomerular filtration rate and all of the clinical and spirometry data. CONCLUSIONS: Chronic renal failure should not be ignored or underestimated in patients with COPD because it frequently cannot be recognized based on serum creatinine because decreases in estimated glomerular filtration rate are more prevalent. PMID- 27118875 TI - The Severe Respiratory Insufficiency Questionnaire for Subjects With COPD With Long-Term Oxygen Therapy. AB - BACKGROUND: Respiratory insufficiency in COPD may present as hypoxic and/or hypercapnic respiratory failure treated with long-term oxygen therapy (LTOT) and/or noninvasive ventilation (NIV) with LTOT. The Severe Respiratory Insufficiency Questionnaire (SRI) is a tool for the assessment of health-related quality of life (HRQOL) in subjects receiving NIV. However, it remains unclear whether the SRI is also capable of assessing and discriminating HRQOL in subjects receiving LTOT. METHODS: Stable subjects with COPD receiving LTOT or NIV + LTOT (NIV) were prospectively recruited and completed the SRI, lung function tests, and blood gases. Confirmatory factor analysis for construct validity and internal consistency reliability were calculated. RESULTS: One hundred fifty-five subjects were included (113 LTOT, 42 NIV). The Cronbach alpha coefficient of the 7 subscales ranged between 0.69 and 0.89 (LTOT) and between 0.79 and 0.93 (NIV), respectively. In both groups, confirmatory factor analysis revealed a one-factor model for the SRI summary scale; in 5 subscales, one- or 2-factor models could be established. Group differences in the SRI subsets were all P <.05 (except for physical functioning) with higher scores in subjects receiving NIV. CONCLUSIONS: The SRI showed high reliability and validity in subjects with COPD receiving LTOT. Subjects receiving LTOT had lower SRI scores, indicating a poorer HRQOL compared with subjects with established NIV and LTOT. PMID- 27118876 TI - Adherence and Subthreshold Adherence in Sleep Apnea Subjects Receiving Positive Airway Pressure Therapy: A Retrospective Study Evaluating Differences in Adherence Versus Use. AB - BACKGROUND: Research on subthreshold compliance with positive airway pressure (PAP) therapy in sleep apnea patients may inform clinical sleep medicine practice. We retrospectively assessed compliant and subthreshold compliant sleep apnea subjects to test whether regular but fewer hours of PAP use would demonstrate clinically meaningful improvements and correlate with outcomes. METHODS: A chart review was conducted of 113 consecutive sleep apnea subjects, naive to treatment, who completed a titration study and filled a PAP therapy prescription. Objective data categorized subjects into 3 groups: compliant, subthreshold compliant, and minimal use. Outcome measures assessed changes in insomnia, sleepiness, and nocturia on average 7 months from PAP initiation. Correlation coefficients analyzed dose-response relationships between hours of use and changes in outcomes. RESULTS: Among 113 PAP attempters, 104 (92%) were current users. Among 93 users with objective data, regular (consistent) PAP users included 59 compliant and 21 subthreshold compliant, and 13 subjects were minimal users. Compliant users averaging 6.6 +/- 1.3 h/night and 42.0 +/- 12.1 h/week showed the largest outcome improvements (all P < .05) with moderate to large effects for insomnia (d = 0.94), sleepiness (d = 0.58), and nocturia (d = 0.56). Subthreshold users averaging 4.1 +/- 0.7 h/night but only 18.0 +/- 5.6 h/week showed a large effect for insomnia (d = 0.76, P = .03) and nonsignificant, small effects for sleepiness (d = 0.38) and nocturia (d = 0.22). Correlation coefficients showed a trend for decrease in insomnia (P = .08; r = .20) and a significant decrease in nocturia (P = .034; r = 0.25), each in association with hours of PAP use. CONCLUSIONS: In a clinical sample, 86% of sleep apnea subjects regularly used PAP, but adherence was 63%. Regular users showed clinical treatment effects and potential dose-response relationships, suggesting that the term use offers advantages over the term adherence. Currently, subthreshold compliance may not merit insurance coverage in many countries, an issue affecting many sleep apnea patients. PMID- 27118877 TI - Risk of Pneumocystis jirovecii pneumonia in patients with rheumatoid arthritis treated with inhibitors of tumour necrosis factor alpha: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. PMID- 27118878 TI - Comment on: Delay to diagnosis in axial spondyloarthritis: are we improving in the UK? PMID- 27118879 TI - Mirroring multiple agents: motor resonance during action observation is modulated by the number of agents. AB - Although social situations regularly involve multiple persons acting together, research on the mirror neuron system has focused on situations in which a single agent is observed. Therefore, the goal of the current study was to explore the role of the mirror mechanism in situations involving multiple agents. Specifically, we used transcranial magnetic stimulation (TMS) to investigate whether mirror activation is modulated by the number of observed agents. Based on group contagion research, we hypothesized that multiple agents would provide a stronger trigger to the motor system and would therefore produce a stronger mirror response than a single agent. Participants observed movements performed by a single hand or by two hands while TMS was applied to the primary motor cortex. The results confirmed that activation in the motor system was stronger for two hands. This suggests that input to the motor system increases as the number of agents grows. Relating back to group contagion, our study suggests that groups may be more contagious simply because their actions resonate louder. Given that the mirror mechanism has been linked to a variety of social skills, our findings additionally have important implications for the understanding of social interaction at the group level. PMID- 27118881 TI - Unified analytical expressions of the three-dimensional fundamental solutions and their derivatives for linear elastic anisotropic materials. AB - Novel unified analytical displacement and stress fundamental solutions as well as the higher order derivatives of the displacement fundamental solutions for three dimensional, generally anisotropic and linear elastic materials are presented in this paper. Adequate integral expressions for the displacement and stress fundamental solutions as well as the higher order derivatives of the displacement fundamental solutions are evaluated analytically by using the Cauchy residue theorem. The resulting explicit displacement fundamental solutions and their first and second derivatives are recast into convenient analytical forms which are valid for non-degenerate, partially degenerate, fully degenerate and nearly degenerate cases. The correctness and the accuracy of the novel unified and closed-form three-dimensional anisotropic fundamental solutions are verified by using some available analytical expressions for both transversely isotropic (non degenerate or partially degenerate) and isotropic (fully degenerate) linear elastic materials. PMID- 27118880 TI - Two tagSNPs rs352493 and rs3760908 within SIRT6 Gene Are Associated with the Severity of Coronary Artery Disease in a Chinese Han Population. AB - SIRT6 has been demonstrated to exert protective effects on endothelial cells and is closely associated with lipid metabolism, glucose metabolism, and obesity, indicating an important role in the pathogenesis and progression of coronary artery disease (CAD). Nonetheless, the biological significance of SIRT6 variants on CAD is far to be elucidated. Here we aimed to investigate the influence of SIRT6 polymorphisms on individual susceptibility and severity of CAD. Multivariate logistic regression analysis exhibited no significant association between these five polymorphisms and CAD risk in the genotype and allele frequencies. However, we found that the rs352493 polymorphism in SIRT6 exhibited a significant effect on the severity of CAD; C allele (chi(2) = 7.793, adjusted P = 0.013) and the combined CC/CT genotypes (chi(2) = 5.609, adjusted P = 0.031) presented the greater CAD severity. In addition, A allele (chi(2) = 5.208, adjusted P = 0.046) and AA (chi(2) = 4.842, adjusted P = 0.054) of rs3760908 were also associated with greater CAD severity in Chinese subjects. Our data provided the first evidence that SIRT6 tagSNPs rs352493 and rs3760908 play significant roles in the severity of CAD in Chinese Han subjects, which might be useful predictors of the severity of CAD. PMID- 27118882 TI - Dynamics, morphogenesis and convergence of evolutionary quantum Prisoner's Dilemma games on networks. AB - The authors proposed a quantum Prisoner's Dilemma (PD) game as a natural extension of the classic PD game to resolve the dilemma. Here, we establish a new Nash equilibrium principle of the game, propose the notion of convergence and discover the convergence and phase-transition phenomena of the evolutionary games on networks. We investigate the many-body extension of the game or evolutionary games in networks. For homogeneous networks, we show that entanglement guarantees a quick convergence of super cooperation, that there is a phase transition from the convergence of defection to the convergence of super cooperation, and that the threshold for the phase transitions is principally determined by the Nash equilibrium principle of the game, with an accompanying perturbation by the variations of structures of networks. For heterogeneous networks, we show that the equilibrium frequencies of super-cooperators are divergent, that entanglement guarantees emergence of super-cooperation and that there is a phase transition of the emergence with the threshold determined by the Nash equilibrium principle, accompanied by a perturbation by the variations of structures of networks. Our results explore systematically, for the first time, the dynamics, morphogenesis and convergence of evolutionary games in interacting and competing systems. PMID- 27118883 TI - Explanation of [Formula: see text] fractional quantum Hall state in bilayer graphene. AB - The commensurability condition is applied to determine the hierarchy of fractional filling of Landau levels for fractional quantum Hall effect (FQHE) in monolayer and bilayer graphene. Good agreement with experimental data is achieved. The presence of even-denominator filling fractions in the hierarchy of the FQHE in bilayer graphene is explained, including the state at [Formula: see text]. PMID- 27118884 TI - Non-singular acoustic cloak derived by the ray tracing method with rotationally symmetric transformations. AB - Recently, the ray tracing method has been used to derive the non-singular cylindrical invisibility cloaks for out-of-plane shear waves, which is impossible via the transformation method directly owing to the singular push-forward mapping. In this paper, the method is adopted to design a kind of non-singular acoustic cloak. Based on Hamilton's equations of motion, eikonal equation and pre designed ray equations, we derive several constraint equations for bulk modulus and density tensor. On the premise that the perfect matching conditions are satisfied, a series of non-singular physical profiles can be obtained by arranging the singular terms reasonably. The physical profiles derived by the ray tracing method will degenerate to the transformation-based solutions when taking the transport equation into consideration. This illuminates the essence of the newly designed cloaks that they are actually the so-called eikonal cloaks that can accurately control the paths of energy flux but with small disturbance in energy distribution along the paths. The near-perfect invisible performance has been demonstrated by the numerical ray tracing results and the pressure distribution snapshots. Finally, a kind of reduced cloak is conceived, and the good invisible performance has been measured quantitatively by the normalized scattering width. PMID- 27118885 TI - Towards a physics-based multiscale modelling of the electro-mechanical coupling in electro-active polymers. AB - Owing to the increasing number of industrial applications of electro-active polymers (EAPs), there is a growing need for electromechanical models which accurately capture their behaviour. To this end, we compare the predicted behaviour of EAPs undergoing homogeneous deformations according to three electromechanical models. The first model is a phenomenological continuum-based model composed of the mechanical Gent model and a linear relationship between the electric field and the polarization. The electrical and the mechanical responses according to the second model are based on the physical structure of the polymer chain network. The third model incorporates a neo-Hookean mechanical response and a physically motivated microstructurally based long-chains model for the electrical behaviour. In the microstructural-motivated models, the integration from the microscopic to the macroscopic levels is accomplished by the micro sphere technique. Four types of homogeneous boundary conditions are considered and the behaviours determined according to the three models are compared. For the microstructurally motivated models, these analyses are performed and compared with the widely used phenomenological model for the first time. Some of the aspects revealed in this investigation, such as the dependence of the intensity of the polarization field on the deformation, highlight the need for an in-depth investigation of the relationships between the structure and the behaviours of the EAPs at the microscopic level and their overall macroscopic response. PMID- 27118887 TI - Asymmetric bifurcation of thermally and electrically actuated functionally graded material microbeam. AB - In this paper, we investigate the symmetric snap-through buckling and the asymmetric bifurcation behaviours of an initially curved functionally graded material (FGM) microbeam subject to the electrostatic force and uniform/non uniform temperature field. The beam model is developed in the framework of Euler Bernoulli beam theory, accounting for the through-thickness power law variation of the beam material and the physical neutral plane. Based on the Galerkin decomposition method, the beam model is simplified as a 2 d.f. reduced-order model, from which the necessary snap-through and symmetry breaking criteria are derived. The results of our work reveal the significant effects of the power law index on the snap-through and symmetry breaking criteria. Our results also reveal that the non-uniform temperature field can actuate the FGM microbeam and induce the snap-through and asymmetric bifurcation behaviours. PMID- 27118886 TI - Coupling all-atom molecular dynamics simulations of ions in water with Brownian dynamics. AB - Molecular dynamics (MD) simulations of ions (K+, Na+, Ca2+ and Cl-) in aqueous solutions are investigated. Water is described using the SPC/E model. A stochastic coarse-grained description for ion behaviour is presented and parametrized using MD simulations. It is given as a system of coupled stochastic and ordinary differential equations, describing the ion position, velocity and acceleration. The stochastic coarse-grained model provides an intermediate description between all-atom MD simulations and Brownian dynamics (BD) models. It is used to develop a multiscale method which uses all-atom MD simulations in parts of the computational domain and (less detailed) BD simulations in the remainder of the domain. PMID- 27118888 TI - On the formation of Friedlander waves in a compressed-gas-driven shock tube. AB - Compressed-gas-driven shock tubes have become popular as a laboratory-scale replacement for field blast tests. The well-known initial structure of the Riemann problem eventually evolves into a shock structure thought to resemble a Friedlander wave, although this remains to be demonstrated theoretically. In this paper, we develop a semi-analytical model to predict the key characteristics of pseudo blast waves forming in a shock tube: location where the wave first forms, peak over-pressure, decay time and impulse. The approach is based on combining the solutions of the two different types of wave interactions that arise in the shock tube after the family of rarefaction waves in the Riemann solution interacts with the closed end of the tube. The results of the analytical model are verified against numerical simulations obtained with a finite volume method. The model furnishes a rational approach to relate shock tube parameters to desired blast wave characteristics, and thus constitutes a useful tool for the design of shock tubes for blast testing. PMID- 27118889 TI - Universal recovery map for approximate Markov chains. AB - A central question in quantum information theory is to determine how well lost information can be reconstructed. Crucially, the corresponding recovery operation should perform well without knowing the information to be reconstructed. In this work, we show that the quantum conditional mutual information measures the performance of such recovery operations. More precisely, we prove that the conditional mutual information I(A:C|B) of a tripartite quantum state rhoABC can be bounded from below by its distance to the closest recovered state [Formula: see text], where the C-part is reconstructed from the B-part only and the recovery map [Formula: see text] merely depends on rhoBC . One particular application of this result implies the equivalence between two different approaches to define topological order in quantum systems. PMID- 27118890 TI - Effect of time delays in an HIV virotherapy model with nonlinear incidence. AB - In this paper, we propose a mathematical model for HIV infection with delays in cell infection and virus production. The model examines a viral therapy for controlling infections through recombining HIV with a genetically modified virus. For this model, we derive two biologically insightful quantities (reproduction numbers) [Formula: see text] and [Formula: see text], and their threshold properties are discussed. When [Formula: see text], the infection-free equilibrium E0 is globally asymptotically stable. If [Formula: see text] and [Formula: see text], the single-infection equilibrium Es is globally asymptotically stable. When [Formula: see text], there occurs the double infection equilibrium Ed, and there exists a constant Rb such that Ed is asymptotically stable if [Formula: see text]. Some simulations are performed to support and complement the theoretical results. PMID- 27118891 TI - The Young's moduli of three types of carbon allotropes: a molecular mechanics model and a finite-element method. AB - The close-form expressions of the Young's moduli and the fracture stresses of cyclicgraphene, graphyne and supergraphene along their armchair and zigzag directions are derived based on a molecular mechanics model. Checking against present finite-element calculations of their Young's moduli shows that the explicit solutions are reasonable. The obtained analytical solutions should be of great help for understanding the mechanical properties of the graphene-like materials. PMID- 27118892 TI - Dynamic interfacial trapping of flexural waves in structured plates. AB - The paper presents new results on the localization and transmission of flexural waves in a structured plate containing a semi-infinite two-dimensional array of rigid pins. In particular, localized waves are identified and studied at the interface boundary between the homogeneous part of the flexural plate and the part occupied by rigid pins. A formal connection has been made with the dispersion properties of flexural Bloch waves in an infinite doubly periodic array of rigid pins. Special attention is given to regimes corresponding to standing waves of different types as well as Dirac-like points that may occur on the dispersion surfaces. A single half-grating problem, hitherto unreported in the literature, is also shown to bring interesting solutions. PMID- 27118893 TI - Theory of multi-species electrophoresis in the presence of surface conduction. AB - Electrophoresis techniques are characterized by concentration disturbances (or waves) propagating under the effect of an electric field. These techniques are usually performed in microchannels where surface conduction through the electric double layer (EDL) at channel walls is negligible compared with bulk conduction. However, when electrophoresis techniques are integrated in nanochannels, shallow microchannels or charged porous media, surface conduction can alter bulk electrophoretic transport. The existing mathematical models for electrophoretic transport in multi-species electrolytes do not account for the competing effects of surface and bulk conduction. We present a mathematical model of multi-species electrophoretic transport incorporating the effects of surface conduction on bulk ion-transport and provide a methodology to derive analytical solutions using the method of characteristics. Based on the analytical solutions, we elucidate the propagation of nonlinear concentration waves, such as shock and rarefaction waves, and provide the necessary and sufficient conditions for their existence. Our results show that the presence of surface conduction alters the propagation speed of nonlinear concentration waves and the composition of various zones. Importantly, we highlight the role of surface conduction in formation of additional shock and rarefaction waves which are otherwise not present in conventional electrophoresis. PMID- 27118894 TI - Fluorescence modulation of cadmium sulfide quantum dots by azobenzene photochromic switches. AB - We have investigated the attachment of azobenzene photochromic switches on the modified surface of cadmium sulfide (CdS) quantum dots (QDs). The modification of CdS QDs is done by varying the concentration of the capping agent (mercaptoacetic acid) and NH3 in order to control the size of the QDs. The X-ray diffraction studies revealed that the crystallite size of CdS QDs ranged from 6 to 10 nm. The azobenzene photochromic derivatives bis(4-hydroxybenzene-1-azo)4,4'(1,1' diphenylmethane) (I) and 4,4'-diazenyldibenzoic acid (II) were synthesized and attached with surface-modified CdS QDs to make fluorophore-photochrome CdS-(I) and CdS-(II) dyad assemblies. Upon UV irradiation, the photochromic compounds (I) and (II) undergo a reversible trans-cis isomerization. The photo-induced trans cis transformation helps to transfer photo-excited electrons from the conduction band of the CdS QDs to the lowest unoccupied molecular orbital of cis isomer of photochromic compounds (I) and (II). As a result, the fluorescence of CdS-(I) and CdS-(II) dyads is suppressed approximately five times compared to bare CdS QDs. The fluorescence modulation in such systems could help to design luminescent probes for bioimaging applications. PMID- 27118895 TI - A class of reduced-order models in the theory of waves and stability. AB - This paper presents a class of approximations to a type of wave field for which the dispersion relation is transcendental. The approximations have two defining characteristics: (i) they give the field shape exactly when the frequency and wavenumber lie on a grid of points in the (frequency, wavenumber) plane and (ii) the approximate dispersion relations are polynomials that pass exactly through points on this grid. Thus, the method is interpolatory in nature, but the interpolation takes place in (frequency, wavenumber) space, rather than in physical space. Full details are presented for a non-trivial example, that of antisymmetric elastic waves in a layer. The method is related to partial fraction expansions and barycentric representations of functions. An asymptotic analysis is presented, involving Stirling's approximation to the psi function, and a logarithmic correction to the polynomial dispersion relation. PMID- 27118896 TI - Second-order approximation for heat conduction: dissipation principle and free energies. AB - In the context of new models of heat conduction, the second-order approximation of Tzou's theory, derived by Quintanilla and Racke, has been studied recently by two of the present authors, where it was proved equivalent to a fading memory material. The importance of determining free energy functionals for such materials, and indeed for any material with memory, is emphasized. Because the kernel does not satisfy certain convexity restrictions that allow us to obtain various traditional free energies for materials with fading memory, it is necessary to restrict the study to the minimum and related free energies, which do not require these restrictions. Thus, the major part of this work is devoted to deriving an explicit expression for the minimum free energy. Simple modifications of this expression also give an intermediate free energy and the maximum free energy for the material. These derivations differ in certain important respects from earlier work on such free energies. PMID- 27118898 TI - Post-liquefaction reconsolidation of sand. AB - Loosely packed sand that is saturated with water can liquefy during an earthquake, potentially causing significant damage. Once the shaking is over, the excess pore water pressures that developed during the earthquake gradually dissipate, while the surface of the soil settles, in a process called post liquefaction reconsolidation. When examining reconsolidation, the soil is typically divided in liquefied and solidified parts, which are modelled separately. The aim of this paper is to show that this fragmentation is not necessary. By assuming that the hydraulic conductivity and the one-dimensional stiffness of liquefied sand have real, positive values, the equation of consolidation can be numerically solved throughout a reconsolidating layer. Predictions made in this manner show good agreement with geotechnical centrifuge experiments. It is shown that the variation of one-dimensional stiffness with effective stress and void ratio is the most crucial parameter in accurately capturing reconsolidation. PMID- 27118899 TI - Effects of weak nonlinearity on the dispersion relation and frequency band-gaps of a periodic Bernoulli-Euler beam. AB - The paper deals with analytically predicting the effects of weak nonlinearity on the dispersion relation and frequency band-gaps of a periodic Bernoulli-Euler beam performing bending oscillations. Two cases are considered: (i) large transverse deflections, where nonlinear (true) curvature, nonlinear material and nonlinear inertia owing to longitudinal motions of the beam are taken into account, and (ii) mid-plane stretching nonlinearity. A novel approach is employed, the method of varying amplitudes. As a result, the isolated as well as combined effects of the considered sources of nonlinearities are revealed. It is shown that nonlinear inertia has the most substantial impact on the dispersion relation of a non-uniform beam by removing all frequency band-gaps. Explanations of the revealed effects are suggested, and validated by experiments and numerical simulation. PMID- 27118897 TI - Aerodynamics, sensing and control of insect-scale flapping-wing flight. AB - There are nearly a million known species of flying insects and 13 000 species of flying warm-blooded vertebrates, including mammals, birds and bats. While in flight, their wings not only move forward relative to the air, they also flap up and down, plunge and sweep, so that both lift and thrust can be generated and balanced, accommodate uncertain surrounding environment, with superior flight stability and dynamics with highly varied speeds and missions. As the size of a flyer is reduced, the wing-to-body mass ratio tends to decrease as well. Furthermore, these flyers use integrated system consisting of wings to generate aerodynamic forces, muscles to move the wings, and sensing and control systems to guide and manoeuvre. In this article, recent advances in insect-scale flapping wing aerodynamics, flexible wing structures, unsteady flight environment, sensing, stability and control are reviewed with perspective offered. In particular, the special features of the low Reynolds number flyers associated with small sizes, thin and light structures, slow flight with comparable wind gust speeds, bioinspired fabrication of wing structures, neuron-based sensing and adaptive control are highlighted. PMID- 27118900 TI - A minimization principle for the description of modes associated with finite-time instabilities. AB - We introduce a minimization formulation for the determination of a finite dimensional, time-dependent, orthonormal basis that captures directions of the phase space associated with transient instabilities. While these instabilities have finite lifetime, they can play a crucial role either by altering the system dynamics through the activation of other instabilities or by creating sudden nonlinear energy transfers that lead to extreme responses. However, their essentially transient character makes their description a particularly challenging task. We develop a minimization framework that focuses on the optimal approximation of the system dynamics in the neighbourhood of the system state. This minimization formulation results in differential equations that evolve a time-dependent basis so that it optimally approximates the most unstable directions. We demonstrate the capability of the method for two families of problems: (i) linear systems, including the advection-diffusion operator in a strongly non-normal regime as well as the Orr-Sommerfeld/Squire operator, and (ii) nonlinear problems, including a low-dimensional system with transient instabilities and the vertical jet in cross-flow. We demonstrate that the time dependent subspace captures the strongly transient non-normal energy growth (in the short-time regime), while for longer times the modes capture the expected asymptotic behaviour. PMID- 27118901 TI - Fast phase randomization via two-folds. AB - A two-fold is a singular point on the discontinuity surface of a piecewise-smooth vector field, at which the vector field is tangent to the discontinuity surface on both sides. If an orbit passes through an invisible two-fold (also known as a Teixeira singularity) before settling to regular periodic motion, then the phase of that motion cannot be determined from initial conditions, and, in the presence of small noise, the asymptotic phase of a large number of sample solutions is highly random. In this paper, we show how the probability distribution of the asymptotic phase depends on the global nonlinear dynamics. We also show how the phase of a smooth oscillator can be randomized by applying a simple discontinuous control law that generates an invisible two-fold. We propose that such a control law can be used to desynchronize a collection of oscillators, and that this manner of phase randomization is fast compared with existing methods (which use fixed points as phase singularities), because there is no slowing of the dynamics near a two-fold. PMID- 27118902 TI - Refined boundary conditions on the free surface of an elastic half-space taking into account non-local effects. AB - The dynamic response of a homogeneous half-space, with a traction-free surface, is considered within the framework of non-local elasticity. The focus is on the dominant effect of the boundary layer on overall behaviour. A typical wavelength is assumed to considerably exceed the associated internal lengthscale. The leading-order long-wave approximation is shown to coincide formally with the 'local' problem for a half-space with a vertical inhomogeneity localized near the surface. Subsequent asymptotic analysis of the inhomogeneity results in an explicit correction to the classical boundary conditions on the surface. The order of the correction is greater than the order of the better-known correction to the governing differential equations. The refined boundary conditions enable us to evaluate the interior solution outside a narrow boundary layer localized near the surface. As an illustration, the effect of non-local elastic phenomena on the Rayleigh wave speed is investigated. PMID- 27118903 TI - Transient in-plane thermal transport in nanofilms with internal heating. AB - Wide applications of nanofilms in electronics necessitate an in-depth understanding of nanoscale thermal transport, which significantly deviates from Fourier's law. Great efforts have focused on the effective thermal conductivity under temperature difference, while it is still ambiguous whether the diffusion equation with an effective thermal conductivity can accurately characterize the nanoscale thermal transport with internal heating. In this work, transient in plane thermal transport in nanofilms with internal heating is studied via Monte Carlo (MC) simulations in comparison to the heat diffusion model and mechanism analyses using Fourier transform. Phonon-boundary scattering leads to larger temperature rise and slower thermal response rate when compared with the heat diffusion model based on Fourier's law. The MC simulations are also compared with the diffusion model with effective thermal conductivity. In the first case of continuous internal heating, the diffusion model with effective thermal conductivity under-predicts the temperature rise by the MC simulations at the initial heating stage, while the deviation between them gradually decreases and vanishes with time. By contrast, for the one-pulse internal heating case, the diffusion model with effective thermal conductivity under-predicts both the peak temperature rise and the cooling rate, so the deviation can always exist. PMID- 27118904 TI - Improving accuracy through density correction in guided wave tomography. AB - The accurate quantification of wall loss caused by corrosion is critical to the reliable life estimation of pipes and pressure vessels. Traditional thickness gauging by scanning a probe is slow and requires access to all points on the surface; this is impractical in many cases as corrosion often occurs where access is restricted, such as beneath supports where water collects. Guided wave tomography presents a solution to this; by transmitting guided waves through the region of interest and exploiting their dispersive nature, it is possible to build up a map of thickness. While the best results have been seen when using the fundamental modes A0 and S0 at low frequency, the complex scattering of the waves causes errors within the reconstruction. It is demonstrated that these lead to an underestimate in wall loss for A0 but an overestimate for S0. Further analysis showed that this error was related to density variation, which was proportional to thickness. It was demonstrated how this could be corrected for in the reconstructions, in many cases resulting in the near-elimination of the error across a range of defects, and greatly improving the accuracy of life estimates from guided wave tomography. PMID- 27118905 TI - Stochastic simplified modelling of abrasive waterjet footprints. AB - Abrasive micro-waterjet processing is a non-conventional machining method that can be used to manufacture complex shapes in difficult-to-cut materials. Predicting the effect of the jet on the surface for a given set of machine parameters is a key element of controlling the process. However, the noise of the process is significant, making it difficult to design reliable jet-path strategies that produce good quality parts via controlled-depth milling. The process is highly unstable and has a strong random component that can affect the quality of the workpiece, especially in the case of controlled-depth milling. This study describes a method to predict the variability of the jet footprint for different jet feed speeds. A stochastic partial differential equation is used to describe the etched surface as the jet is moved over it, assuming that the erosion process can be divided into two main components: a deterministic part that corresponds to the average erosion of the jet and a stochastic part that accounts for the noise generated at different stages of the process. The model predicts the variability of the trench profiles to within less than 8%. These advances could enable abrasive micro-waterjet technology to be a suitable technology for controlled-depth milling. PMID- 27118906 TI - Poromechanical behaviour of a surficial geological barrier during fluid injection into an underlying poroelastic storage formation. AB - A competent low permeability and chemically inert geological barrier is an essential component of any strategy for the deep geological disposal of fluidized hazardous material and greenhouse gases. While the processes of injection are important to the assessment of the sequestration potential of the storage formation, the performance of the caprock is important to the containment potential, which can be compromised by the development of cracks and other defects that might be activated during and after injection. This paper presents a mathematical modelling approach that can be used to assess the state of stress in a surficial caprock during injection of a fluid to the interior of a poroelastic storage formation. Important information related to time-dependent evolution of the stress state and displacements of the surficial caprock with injection rates, and the stress state in the storage formation can be obtained from the theoretical developments. Most importantly, numerical results illustrate the influence of poromechanics on the development of adverse stress states in the geological barrier. The results obtained from the mathematical analysis illustrate that the surface heave increases as the hydraulic conductivity of the caprock decreases, whereas the surface heave decreases as the shear modulus of the caprock increases. The results also illustrate the influence of poromechanics on the development of adverse stress states in the caprock. PMID- 27118907 TI - Deformation heterogeneity and texture in surface severe plastic deformation of copper. AB - Comprehensive understanding of thermomechanical response and microstructure evolution during surface severe plastic deformation (S2PD) is important towards establishing controllable processing frameworks. In this study, the evolution of crystallographic textures during directional surface mechanical attrition treatment on copper was studied and modelled using the visco-plastic self consistent framework. In situ high-speed imaging and digital image correlation of surface deformation in circular indentation were employed to elucidate mechanics occurring in a unit process deformation and to calibrate texture model parameters. Material response during directional surface mechanical attrition was simulated using a finite-element model coupled with the calibrated texture model. The crystallographic textures developed during S2PD were observed to be similar to those resultant from uniaxial compression. The implications of these results towards facilitating a processing-based framework to predict deformation mechanics and resulting crystallographic texture in S2PD configurations are briefly discussed. PMID- 27118908 TI - Maximum margin classifier working in a set of strings. AB - Numbers and numerical vectors account for a large portion of data. However, recently, the amount of string data generated has increased dramatically. Consequently, classifying string data is a common problem in many fields. The most widely used approach to this problem is to convert strings into numerical vectors using string kernels and subsequently apply a support vector machine that works in a numerical vector space. However, this non-one-to-one conversion involves a loss of information and makes it impossible to evaluate, using probability theory, the generalization error of a learning machine, considering that the given data to train and test the machine are strings generated according to probability laws. In this study, we approach this classification problem by constructing a classifier that works in a set of strings. To evaluate the generalization error of such a classifier theoretically, probability theory for strings is required. Therefore, we first extend a limit theorem for a consensus sequence of strings demonstrated by one of the authors and co-workers in a previous study. Using the obtained result, we then demonstrate that our learning machine classifies strings in an asymptotically optimal manner. Furthermore, we demonstrate the usefulness of our machine in practical data analysis by applying it to predicting protein-protein interactions using amino acid sequences and classifying RNAs by the secondary structure using nucleotide sequences. PMID- 27118909 TI - Characterizations of matrix and operator-valued Phi-entropies, and operator Efron Stein inequalities. AB - We derive new characterizations of the matrix Phi-entropy functionals introduced in Chen & Tropp (Chen, Tropp 2014 Electron. J. Prob.19, 1-30. (doi:10.1214/ejp.v19-2964)). These characterizations help us to better understand the properties of matrix Phi-entropies, and are a powerful tool for establishing matrix concentration inequalities for random matrices. Then, we propose an operator-valued generalization of matrix Phi-entropy functionals, and prove the subadditivity under Lowner partial ordering. Our results demonstrate that the subadditivity of operator-valued Phi-entropies is equivalent to the convexity. As an application, we derive the operator Efron-Stein inequality. PMID- 27118910 TI - Twofold orthogonal weavings on cuboids. AB - Some closed polyhedral surfaces can be completely covered by two-way, twofold (rectangular) weaving of strands of constant width. In this paper, a construction for producing all possible geometries for such weavable cuboids is proposed: a theorem on spherical octahedra is proven first that all further theory is based on. The construction method of weavable cuboids itself relies on successive truncations of an initial tetrahedron and is also extended for cases of degenerate (unbounded) polyhedra. Arguments are mainly based on the plane geometry of the development of the respective polyhedra, in connection with some of three-dimensional projective properties of the same. PMID- 27118911 TI - Radiating dispersive shock waves in non-local optical media. AB - We consider the step Riemann problem for the system of equations describing the propagation of a coherent light beam in nematic liquid crystals, which is a general system describing nonlinear wave propagation in a number of different physical applications. While the equation governing the light beam is of defocusing nonlinear Schrodinger (NLS) equation type, the dispersive shock wave (DSW) generated from this initial condition has major differences from the standard DSW solution of the defocusing NLS equation. In particular, it is found that the DSW has positive polarity and generates resonant radiation which propagates ahead of it. Remarkably, the velocity of the lead soliton of the DSW is determined by the classical shock velocity. The solution for the radiative wavetrain is obtained using the Wentzel-Kramers-Brillouin approximation. It is shown that for sufficiently small initial jumps the nematic DSW is asymptotically governed by a Korteweg-de Vries equation with the fifth-order dispersion, which explicitly shows the resonance generating the radiation ahead of the DSW. The constructed asymptotic theory is shown to be in good agreement with the results of direct numerical simulations. PMID- 27118912 TI - A time-domain Kirchhoff formula for the convective acoustic wave equation. AB - Kirchhoff's integral method allows propagated sound to be predicted, based on the pressure and its derivatives in time and space obtained on a data surface located in the linear flow region. Kirchhoff's formula for noise prediction from high speed rotors and propellers suffers from the limitation of the observer located in uniform flow, thus requiring an extension to arbitrarily moving media. This paper presents a Kirchhoff formulation for moving surfaces in a uniform moving medium of arbitrary configuration. First, the convective wave equation is derived in a moving frame, based on the generalized functions theory. The Kirchhoff formula is then obtained for moving surfaces in the time domain. The formula has a similar form to the Kirchhoff formulation for moving surfaces of Farassat and Myers, with the presence of additional terms owing to the moving medium effect. The equation explicitly accounts for the influence of mean flow and angle of attack on the radiated noise. The formula is verified by analytical cases of a monopole source located in a moving medium. PMID- 27118913 TI - Monte Carlo model for electron degradation in xenon gas. AB - We have developed a Monte Carlo model for studying the local degradation of electrons in the energy range 9-10 000 eV in xenon gas. Analytically fitted form of electron impact cross sections for elastic and various inelastic processes are fed as input data to the model. The two-dimensional numerical yield spectrum (NYS), which gives information on the number of energy loss events occurring in a particular energy interval, is obtained as the output of the model. The NYS is fitted analytically, thus obtaining the analytical yield spectrum (AYS). The AYS can be used to calculate electron fluxes, which can be further employed for the calculation of volume production rates. Using the yield spectrum, mean energy per ion pair and efficiencies of inelastic processes are calculated. The value for mean energy per ion pair for Xe is 22 eV at 10 keV. Ionization dominates for incident energies greater than 50 eV and is found to have an efficiency of approximately 65% at 10 keV. The efficiency for the excitation process is approximately 30% at 10 keV. PMID- 27118914 TI - Dynamic analysis of submerged microscale plates: the effects of acoustic radiation and viscous dissipation. AB - The aim of this paper is to study the dynamic characteristics of micromechanical rectangular plates used as sensing elements in a viscous compressible fluid. A novel modelling procedure for the plate-fluid interaction problem is developed on the basis of linearized Navier-Stokes equations and no-slip conditions. Analytical expression for the fluid-loading impedance is obtained using a double Fourier transform approach. This modelling work provides us an analytical means to study the effects of inertial loading, acoustic radiation and viscous dissipation of the fluid acting on the vibration of microplates. The numerical simulation is conducted on microplates with different boundary conditions and fluids with different viscosities. The simulation results reveal that the acoustic radiation dominates the damping mechanism of the submerged microplates. It is also proved that microplates offer better sensitivities (Q-factors) than the conventional beam type microcantilevers being mass sensing platforms in a viscous fluid environment. The frequency response features of microplates under highly viscous fluid loading are studied using the present model. The dynamics of the microplates with all edges clamped are less influenced by the highly viscous dissipation of the fluid than the microplates with other types of boundary conditions. PMID- 27118915 TI - Impact of the spatial structure of the hydraulic conductivity field on vorticity in three-dimensional flows. AB - A material fluid element within a porous medium experiences deformations due to the disordered spatial distribution of the Darcy scale velocity field, caused by the heterogeneity of hydraulic conductivity. A physical consequence of this heterogeneity is the presence of localized kinematical features such as straining, shearing and vorticity in the fluid element. These kinematical features will influence the shape of solute clouds and their fate. Studies on the deformation of material surfaces highlighted the importance of stretching and shearing, whereas vorticity received so far less attention, though it determines folding, a deformation associated with the local rotation of the velocity field. We study vorticity in a three-dimensional porous formation exploring how its fluctuations are influenced by the spatial structure of the porous media, obtained by immersing spheroidal inclusions into a matrix of constant hydraulic conductivity. By comparing porous formations with the same spatial statistics, we analyse how vorticity is affected by the different shape and arrangement of inclusions, defined as the medium 'microstructure'. We conclude that, as microstructure has a significant impact on vorticity fluctuations, the usual second-order statistical description of the conductivity field is unable to capture local deformations of the plume. PMID- 27118916 TI - The shallow shell approach to Pogorelov's problem and the breakdown of 'mirror buckling'. AB - We present a detailed asymptotic analysis of the point indentation of an unpressurized, spherical elastic shell. Previous analyses of this classic problem have assumed that for sufficiently large indentation depths, such a shell deforms by 'mirror buckling'-a portion of the shell inverts to become a spherical cap with equal but opposite curvature to the undeformed shell. The energy of deformation is then localized in a ridge in which the deformed and undeformed portions of the shell join together, commonly referred to as Pogorelov's ridge. Rather than using an energy formulation, we revisit this problem from the point of view of the shallow shell equations and perform an asymptotic analysis that exploits the largeness of the indentation depth. This reveals first that the stress profile associated with mirror buckling is singular as the indenter is approached. This consequence of point indentation means that mirror buckling must be modified to incorporate the shell's bending stiffness close to the indenter and gives rise to an intricate asymptotic structure with seven different spatial regions. This is in contrast with the three regions (mirror-buckled, ridge and undeformed) that are usually assumed and yields new insight into the large compressive hoop stress that ultimately causes the secondary buckling of the shell. PMID- 27118917 TI - Too good to be true: when overwhelming evidence fails to convince. AB - Is it possible for a large sequence of measurements or observations, which support a hypothesis, to counterintuitively decrease our confidence? Can unanimous support be too good to be true? The assumption of independence is often made in good faith; however, rarely is consideration given to whether a systemic failure has occurred. Taking this into account can cause certainty in a hypothesis to decrease as the evidence for it becomes apparently stronger. We perform a probabilistic Bayesian analysis of this effect with examples based on (i) archaeological evidence, (ii) weighing of legal evidence and (iii) cryptographic primality testing. In this paper, we investigate the effects of small error rates in a set of measurements or observations. We find that even with very low systemic failure rates, high confidence is surprisingly difficult to achieve; in particular, we find that certain analyses of cryptographically important numerical tests are highly optimistic, underestimating their false negative rate by as much as a factor of 280. PMID- 27118918 TI - Uniqueness of one-dimensional Neel wall profiles. AB - We study the domain wall structure in thin uniaxial ferromagnetic films in the presence of an in-plane applied external field in the direction normal to the easy axis. Using the reduced one-dimensional thin-film micromagnetic model, we analyse the critical points of the obtained non-local variational problem. We prove that the minimizer of the one-dimensional energy functional in the form of the Neel wall is the unique (up to translations) critical point of the energy among all monotone profiles with the same limiting behaviour at infinity. Thus, we establish uniqueness of the one-dimensional monotone Neel wall profile in the considered setting. We also obtain some uniform estimates for general one dimensional domain wall profiles. PMID- 27118919 TI - Toroidal insulating inhomogeneity in an infinite space and related problems. AB - An analytic solution for the steady-state temperature distribution in an infinite conductive medium containing an insulated toroidal inhomogeneity and subjected to remotely applied uniform heat flux is obtained. The temperature flux on the torus surface is then determined as a function of torus parameters. This result is used to calculate the resistivity contribution tensor for the toroidal inhomogeneity required to evaluate the effective conductive properties of a material containing multiple inhomogeneities of this shape. PMID- 27118920 TI - Indium phosphide nanowires and their applications in optoelectronic devices. AB - Group IIIA phosphide nanocrystalline semiconductors are of great interest among the important inorganic materials because of their large direct band gaps and fundamental physical properties. Their physical properties are exploited for various potential applications in high-speed digital circuits, microwave and optoelectronic devices. Compared to II-VI and I-VII semiconductors, the IIIA phosphides have a high degree of covalent bonding, a less ionic character and larger exciton diameters. In the present review, the work done on synthesis of III-V indium phosphide (InP) nanowires (NWs) using vapour- and solution-phase approaches has been discussed. Doping and core-shell structure formation of InP NWs and their sensitization using higher band gap semiconductor quantum dots is also reported. In the later section of this review, InP NW-polymer hybrid material is highlighted in view of its application as photodiodes. Lastly, a summary and several different perspectives on the use of InP NWs are discussed. PMID- 27118921 TI - On well-posedness of variational models of charged drops. AB - Electrified liquids are well known to be prone to a variety of interfacial instabilities that result in the onset of apparent interfacial singularities and liquid fragmentation. In the case of electrically conducting liquids, one of the basic models describing the equilibrium interfacial configurations and the onset of instability assumes the liquid to be equipotential and interprets those configurations as local minimizers of the energy consisting of the sum of the surface energy and the electrostatic energy. Here we show that, surprisingly, this classical geometric variational model is mathematically ill-posed irrespective of the degree to which the liquid is electrified. Specifically, we demonstrate that an isolated spherical droplet is never a local minimizer, no matter how small is the total charge on the droplet, as the energy can always be lowered by a smooth, arbitrarily small distortion of the droplet's surface. This is in sharp contrast to the experimental observations that a critical amount of charge is needed in order to destabilize a spherical droplet. We discuss several possible regularization mechanisms for the considered free boundary problem and argue that well-posedness can be restored by the inclusion of the entropic effects resulting in finite screening of free charges. PMID- 27118922 TI - Variational principles for stochastic soliton dynamics. AB - We develop a variational method of deriving stochastic partial differential equations whose solutions follow the flow of a stochastic vector field. As an example in one spatial dimension, we numerically simulate singular solutions (peakons) of the stochastically perturbed Camassa-Holm (CH) equation derived using this method. These numerical simulations show that peakon soliton solutions of the stochastically perturbed CH equation persist and provide an interesting laboratory for investigating the sensitivity and accuracy of adding stochasticity to finite dimensional solutions of stochastic partial differential equations. In particular, some choices of stochastic perturbations of the peakon dynamics by Wiener noise (canonical Hamiltonian stochastic deformations, CH-SD) allow peakons to interpenetrate and exchange order on the real line in overtaking collisions, although this behaviour does not occur for other choices of stochastic perturbations which preserve the Euler-Poincare structure of the CH equation (parametric stochastic deformations, P-SD), and it also does not occur for peakon solutions of the unperturbed deterministic CH equation. The discussion raises issues about the science of stochastic deformations of finite-dimensional approximations of evolutionary partial differential equation and the sensitivity of the resulting solutions to the choices made in stochastic modelling. PMID- 27118923 TI - An efficient approach for limited-data chemical species tomography and its error bounds. AB - We present a computationally efficient reconstruction method for the limited-data chemical species tomography problem that incorporates projection of the unknown gas concentration function onto a low-dimensional subspace, and regularization using prior information obtained from a simple flow model. In this context, the contribution of this work is on the analysis of the projection-induced data errors and the calculation of bounds for the overall image error incorporating the impact of projection and regularization errors as well as measurement noise. As an extension to this methodology, we present a variant algorithm that preserves the positivity of the concentration image. PMID- 27118924 TI - Assessing the robustness of spatial pattern sequences in a dryland vegetation model. AB - A particular sequence of patterns, 'gaps->labyrinth->spots', occurs with decreasing precipitation in previously reported numerical simulations of partial differential equation dryland vegetation models. These observations have led to the suggestion that this sequence of patterns can serve as an early indicator of desertification in some ecosystems. Because parameter values in the vegetation models can take on a range of plausible values, it is important to investigate whether the pattern sequence prediction is robust to variation. For a particular model, we find that a quantity calculated via bifurcation-theoretic analysis appears to serve as a proxy for the pattern sequences that occur in numerical simulations across a range of parameter values. We find in further analysis that the quantity takes on values consistent with the standard sequence in an ecologically relevant limit of the model parameter values. This suggests that the standard sequence is a robust prediction of the model, and we conclude by proposing a methodology for assessing the robustness of the standard sequence in other models and formulations. PMID- 27118925 TI - Folding and faulting of an elastic continuum. AB - Folding is a process in which bending is localized at sharp edges separated by almost undeformed elements. This process is rarely encountered in Nature, although some exceptions can be found in unusual layered rock formations (called 'chevrons') and seashell patterns (for instance Lopha cristagalli). In mechanics, the bending of a three-dimensional elastic solid is common (for example, in bulk wave propagation), but folding is usually not achieved. In this article, the route leading to folding is shown for an elastic solid obeying the couple-stress theory with an extreme anisotropy. This result is obtained with a perturbation technique, which involves the derivation of new two-dimensional Green's functions for applied concentrated force and moment. While the former perturbation reveals folding, the latter shows that a material in an extreme anisotropic state is also prone to a faulting instability, in which a displacement step of finite size emerges. Another failure mechanism, namely the formation of dilation/compaction bands, is also highlighted. Finally, a geophysical application to the mechanics of chevron formation shows how the proposed approach may explain the formation of natural structures. PMID- 27118926 TI - Formulation of the Reynolds equation on a time-dependent lubrication surface. AB - The Reynolds equation, which describes the lubrication effect arising through the interaction of two physical surfaces that are separated by a thin fluid film, is formulated with respect to a continuously evolving third surface that is described by a time-dependent curvilinear coordinate system. The proposed formulation essentially addresses lubrication mechanics at interfaces undergoing large deformations and a priori satisfies all objectivity requirements, neither of which are features of the classical Reynolds equation. As such, this formulation may be particularly suitable for non-stationary elastohydrodynamic lubrication problems associated with soft interfaces. The ability of the formulation to capture finite-deformation effects and the influence of the choice of the third surface are illustrated through analytical examples. PMID- 27118927 TI - Multi-scale modelling of rubber-like materials and soft tissues: an appraisal. AB - We survey, in a partial way, multi-scale approaches for the modelling of rubber like and soft tissues and compare them with classical macroscopic phenomenological models. Our aim is to show how it is possible to obtain practical mathematical models for the mechanical behaviour of these materials incorporating mesoscopic (network scale) information. Multi-scale approaches are crucial for the theoretical comprehension and prediction of the complex mechanical response of these materials. Moreover, such models are fundamental in the perspective of the design, through manipulation at the micro- and nano scales, of new polymeric and bioinspired materials with exceptional macroscopic properties. PMID- 27118928 TI - Combined EGFR- and notch inhibition display additive inhibitory effect on glioblastoma cell viability and glioblastoma-induced endothelial cell sprouting in vitro. AB - BACKGROUND: For Glioblastoma (GBM) patients, a number of anti-neoplastic strategies using specifically targeting drugs have been tested; however, the effects on survival have been limited. One explanation could be treatment resistance due to redundant signaling pathways, which substantiates the need for combination therapies. In GBM, both the epidermal growth factor receptor (EGFR) and the notch signaling pathways are often deregulated and linked to cellular growth, invasion and angiogenesis. Several studies have confirmed cross-talk and co-dependence of these pathways. Therefore, this study aimed at testing a combination treatment strategy using inhibitors targeting the notch and EGFR pathways. METHODS: For evaluation of cell viability a standard MTT assay was used. Western blotting (WB) and Q-RT-PCR were employed in order to assess the protein- and mRNA expression levels, respectively. In order to determine angiogenic processes, we used an endothelial spheroid sprouting assay. For assessment of secreted VEGF from GBM cells we performed a VEGF-quantikine ELISA. RESULTS: GBM cells were confirmed to express EGFR and Notch and to have the capacity to induce endothelial cell sprouting. Inhibition of EGFR and Notch signaling was achieved using either Iressa (gefitinib) or the gamma-secretase inhibitor DAPT. Our data showed that DAPT combined with Iressa treatment displayed increased inhibitory effect on cell viability and abrogated expression and activation of major pro-survival pathways. Similarly, the combinational treatment significantly increased abrogation of GBM-induced endothelial cell sprouting suggesting reduced GBM angiogenesis. CONCLUSION: This study finds that simultaneous targeting of notch and EGFR signaling leads to enhanced inhibitory effects on GBM-induced angiogenesis and cell viability, thereby stressing the importance of further evaluation of this targeting approach in a clinical setting. PMID- 27118930 TI - Patient Education. PMID- 27118929 TI - Giant right ventricular outflow tract thrombus in hereditary spherocytosis: a case report. AB - BACKGROUND: In hereditary spherocytosis with severe anemia, splenectomy is a recommended treatment. However, the spleen carries an important role both in immune function and coagulation. The increased risk of bacterial infections associated with splenectomy is well known. Recently, hypercoagulation disorders have also been linked to splenectomy through loss of regulation of platelet activity, loss of filtering function and post-splenectomy thrombocytosis. CASE PRESENTATION: A 28 year-old smoking women who had previously undergone splenectomy due to hereditary spherocytosis with a moderate thrombocytosis (platelet count 553-635*10(9)/L), presented with recurrent episodes of pulmonary embolisms. Further examination by multimodality cardiac imaging demonstrated a giant chronic thrombus in the right ventricular outflow tract, which eventually had to be surgically removed. CONCLUSIONS: The present case highlights the increased risk of severe thromboembolic complications following therapeutic splenectomy in hereditary spherocytosis, and emphasis the important role of multimodality cardiac imaging in recurrent pulmonary embolism, diagnosing a giant chronic thrombus in the right ventricular outflow tract. PMID- 27118931 TI - High-Resolution Manometry in Clinical Practice. AB - High-resolution manometry (HRM) is the primary method used to evaluate esophageal motor function. Displayed and interpreted by esophageal pressure topography (EPT), HRM/ EPT provides a detailed assessment of esophageal function that is useful in the evaluation of patients with nonobstructive dysphagia and before foregut surgery. Esophageal motility diagnoses are determined systematically by applying objective metrics of esophageal sphincter and peristaltic function to the Chicago Classification of esophageal motility disorders. This article discusses HRM study, EPT interpretation, and the translation of EPT findings into clinical practice. Examples are provided to illustrate several clinical challenges. PMID- 27118932 TI - Positioning Ultrasonography Into Clinical Practice for the Management of Crohn's Disease. AB - Over the past few years, the technical evolution of ultrasound equipment, the use of oral and intravenous contrast agents, and an increase in the expertise of operators have enhanced the role that ultrasonography plays in the assessment of the gastrointestinal tract. For patients with chronic inflammatory conditions, particularly Crohn's disease, it has been suggested that ultrasonography can be used not only for diagnostic purposes but also in disease management. These developments are reviewed in this article. PMID- 27118933 TI - Influenza and Pneumococcal Vaccination Rates in Patients With Inflammatory Bowel Disease. AB - Patients with inflammatory bowel disease (IBD) are at an increased risk for vaccine-preventable illnesses, such as pneumococcal pneumonia and influenza. We hypothesized that a patient-directed educational program would increase vaccination rates of patients with IBD. We developed a written educational form that was given to all patients over a 15-month period. The form included information about the importance of vaccination and asked patients about their vaccination status. If patients indicated that they were not vaccinated, they were offered a vaccination at the time of their visit. For influenza, the vaccination rates during 3 seasons were compared. For pneumococcal pneumonia, the vaccination rates during a 6-month period before the introduction of the educational program and the rates during the 15-month period after implementation of the intervention were compared. Our form increased the percentage of patients who reported having an influenza vaccination (23% vs 47%; P<.001) and the percentage of patients who reported having a pneumococcal pneumonia vaccination (21% vs 32%; P<.001). We concluded that a simple written educational form designed to assess vaccination status and enable providers to offer same-day influenza and pneumococcal pneumonia vaccinations resulted in a significant increase in influenza and pneumococcal pneumonia vaccination rates among patients in an IBD specialty clinic. PMID- 27118934 TI - When Should Therapy for Inflammatory Bowel Disease Be Stopped? PMID- 27118935 TI - Imaging Techniques for Hepatocellular Carcinoma. PMID- 27118936 TI - Genomics in the Early Detection of Cholangiocarcinoma. PMID- 27118937 TI - The Role of Salivary Pepsin in the Diagnosis of Reflux. PMID- 27118939 TI - Advances in Hepatitis C Virus Treatment. PMID- 27118938 TI - Use of Prophylactic Pancreatic Stents for the Prevention of Post-ERCP Pancreatitis. PMID- 27118940 TI - Endoscopic Treatment of Early Cancer of the Colon. AB - Colorectal cancer is the fourth most common cancer diagnosis worldwide and the second leading cause of cancer death. In the United States, it is estimated that in 2015 there will be 132,700 new cases of colorectal cancer (representing 8.43% of all new cancer cases) and 49,700 deaths. Colonoscopy plays a fundamental role in the prevention and management of colorectal cancer patients and is used for both the diagnosis and treatment of early colorectal cancer and its precursors. Improvements in colonoscopy preparation, new techniques of adenoma detection, and recent progress in endoscopic imaging methods are providing higher-quality results and reducing the incidence and mortality of the disease. Traditionally, colonoscopy has been used to remove precursor lesions. Invasive cancer was treated by surgical resection with or without chemoradiotherapy. During the past decade, endoscopic resection techniques have advanced, and cancers confined to the mucosal and superficial submucosal layers can now be resected via flexible endoscopes. Therefore, it is important to understand the indications and limitations of endoscopic resection, determine whether the cancer can be curatively resected, and assess the risk of lymph node metastasis, which precludes endoscopic treatment. PMID- 27118941 TI - New Direct-Acting Antiviral Therapies for Treatment of Chronic Hepatitis C Virus Infection. AB - The treatment of hepatitis C virus infection has been advancing at breakneck speeds over the past few years. This article provides an update on the newest drugs available and those currently in development, including newer-generation protease inhibitors, RNA-dependent RNA polymerase, and nonstructural component inhibitors. Also discussed in this article are the regimens developed and the genotypes they target. Treatment of cirrhotic patients and patients who have failed prior therapy is also addressed, as are special populations, such as patients with harder-to-treat genotypes, patients with HIV coinfection, patients who have undergone liver transplantation, and patients with chronic kidney disease. Future developments and economic considerations are also mentioned. PMID- 27118942 TI - Therapeutic Endoscopic Ultrasound. AB - Endoscopic ultrasound (EUS) technology has evolved dramatically over the past 20 years, from being a supplementary diagnostic aid available only in large medical centers to being a core diagnostic and therapeutic tool that is widely available. Although formal recommendations and practice guidelines have not been developed, there are considerable data supporting the use of EUS for its technical accuracy in diagnosing pancreaticobiliary and gastrointestinal pathology. Endosonography is now routine practice not only for pathologic diagnosis and tumor staging but also for drainage of cystic lesions and celiac plexus neurolysis. In this article, we cover the use of EUS in biliary and pancreatic intervention, ablative therapy, enterostomy, and vascular intervention. PMID- 27118943 TI - Defining Severity in Inflammatory Bowel Disease. PMID- 27118944 TI - Supplements and Hepatotoxicity. PMID- 27118945 TI - Proton Pump Inhibitor Nonresponders. PMID- 27118947 TI - The Obesity Epidemic. PMID- 27118946 TI - Hemostatic Powder TC-325. PMID- 27118950 TI - Gastro-Hep News. PMID- 27118948 TI - Diet and Inflammatory Bowel Disease. AB - Patients with inflammatory bowel disease (IBD) are increasingly becoming interested in nonpharmacologic approaches to managing their disease. One of the most frequently asked questions of IBD patients is what they should eat. The role of diet has become very important in the prevention and treatment of IBD. Although there is a general lack of rigorous scientific evidence that demonstrates which diet is best for certain patients, several diets-such as the low-fermentable oligosaccharide, disaccharide, monosaccharide, and polyol diet; the specific carbohydrate diet; the anti-inflammatory diet; and the Paleolithic diet-have become popular. This article discusses the diets commonly recommended to IBD patients and reviews the supporting data. PMID- 27118949 TI - Gastrointestinal Complications After Bariatric Surgery. AB - Bariatric surgery is increasingly being performed in the medically complicated obese population as convincing data continue to mount, documenting the success of surgery not only in achieving meaningful weight loss but also in correcting obesity-related illnesses. Several surgical procedures with varying degrees of success and complications are currently being performed. This article discusses the short- and long-term gastrointestinal complications for the 4 most common bariatric surgical procedures: laparoscopic adjustable gastric banding, vertical sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion with duodenal switch. PMID- 27118951 TI - Polycystic Liver Disease. PMID- 27118952 TI - Treatment of Intermediate-Stage Hepatocellular Carcinoma. PMID- 27118953 TI - Very-Early-Onset Inflammatory Bowel Disease. PMID- 27118954 TI - Lymphocytic Esophagitis. PMID- 27118955 TI - Endoscopic Approach to Reopening a Completely Obstructed Esophagus. PMID- 27118956 TI - Transitional care for the highest risk patients: findings of a randomised control study. AB - BACKGROUND: Interventions to prevent readmissions of patients at highest risk have not been rigorously evaluated. We conducted a randomised controlled trial to determine if a post-discharge transitional care programme can reduce readmissions of such patients in Singapore. METHODS: We randomised 840 patients with two or more unscheduled readmissions in the prior 90 days and Length of stay, Acuity of admission, Comorbidity of patient, Emergency department utilisation score >=10 to the intervention programme (n = 419) or control (n = 421). Patients allocated to the intervention group received post-discharge surveillance by a multidisciplinary integrated care team and early review in the clinic. The primary outcome was the proportion of patients with at least one unscheduled readmission within 30 days after discharge. RESULTS: We found no statistically significant reduction in readmissions or emergency department visits in patients on the intervention group compared to usual care. However, patients in the intervention group reported greater patient satisfaction (p < 0.001). CONCLUSION: Any beneficial effect of interventions initiated after discharge is small for high-risk patients with multiple comorbidity and complex care needs. Future transitional care interventions should focus on providing the entire cycle of care for such patients starting from time of admission to final transition to the primary care setting. TRIAL REGISTRATION: Clinicaltrials.gov, no NCT02325752. PMID- 27118957 TI - Bridging knowledge to develop an action plan for integrated care for chronic diseases in Greece. AB - The health, social and economic impact of chronic diseases is well documented in Europe. However, chronic diseases threaten relatively more the 'memorandum and peripheral' Eurozone countries (i.e., Greece, Spain, Portugal and Ireland), which were under heavy recession after the economic crisis in 2009. Especially in Greece, where the crisis was the most severe across Europe, the austerity measures affected mainly people with chronic diseases. As a result, the urgency to tackle the threat of chronic diseases in Greece by promoting public health and providing effective chronic care while flattening the rising health care expenditure is eminent. In many European countries, integrated care is seen as a means to achieve this. The aim of this paper was to support Greek health policy makers to develop an action plan from 2015 onwards, to integrate care by bridging local policy context and needs with knowledge and experience from other European countries. To achieve this aim, we adopted a conceptual framework developed by the World Health Organization on one hand to analyse the status of integrated care in Greece, and on the other to develop an action plan for reform. The action plan was based on an analysis of the Greek health care system regarding prerequisite conditions to integrate care, a clear understanding of its context and successful examples of integrated care from other European countries. This study showed that chronic diseases are poorly addressed in Greece and integrated care is in embryonic stage. Greek policy makers have to realise that this is the opportunity to make substantial reforms in chronic care. Failing to reform towards integrated care would lead to the significant risk of collapse of the Greek health care system with all associated negative consequences. The action plan provided in this paper could support policy makers to make the first serious step to face this challenge. The details and specifications of the action plan can only be decided by Greek policy makers in close cooperation with other health and social care partners. This is the appropriate time for doing so. PMID- 27118958 TI - Readiness to tackle chronicity in Spanish health care organisations: a two-year experience with the Instrumento de Evaluacion de Modelos de Atencion ante la Cronicidad/Assessment of Readiness for Chronicity in Health Care Organisations instrument. AB - INTRODUCTION: The Instrumento de Evaluacion de Modelos de Atencion ante la Cronicidad/Assessment of Readiness for Chronicity in Health Care Organisations instrument was developed to implement the conceptual framework of the Chronic Care Model in the Spanish national health system. It has been used to assess readiness to tackle chronicity in health care organisations. In this study, we use self-assessments at macro-, meso- and micro-management levels to (a) describe the two-year experience with the Instrumento de Evaluacion de Modelos de Atencion ante la Cronicidad/Assessment of Readiness for Chronicity in Health Care Organisations tool in Spain and (b) assess the validity and reliability of this instrument. METHODS: The results from 55 organisational self-assessments were included and described. In addition to that, the internal consistency, reliability and construct validity of Instrumento de Evaluacion de Modelos de Atencion ante la Cronicidad/Assessment of Readiness for Chronicity in Health Care Organisations were examined using Cronbach's alpha, the Spearman-Brown coefficient and factorial analysis. RESULTS: The obtained scores reflect opportunities for improvement in all dimensions of the instrument. Cronbach's alpha ranged between 0.90 and 0.95 and the Spearman-Brown coefficient ranged between 0.77 and 0.94. All 27 components converged in a second-order factorial solution that explained 53.8% of the total variance, with factorial saturations for the components of between 0.57 and 0.94. CONCLUSIONS: Instrumento de Evaluacion de Modelos de Atencion ante la Cronicidad/Assessment of Readiness for Chronicity in Health Care Organisations is an instrument that allows health care organisations to perform self-assessments regarding their readiness to tackle chronicity and to identify areas for improvement in chronic care. PMID- 27118960 TI - Beyond integrated care: challenges on the way towards population health management. PMID- 27118959 TI - Developing a tool for mapping adult mental health care provision in Europe: the REMAST research protocol and its contribution to better integrated care. AB - INTRODUCTION: Mental health care is a critical area to better understand integrated care and to pilot the different components of the integrated care model. However, there is an urgent need for better tools to compare and understand the context of integrated mental health care in Europe. METHOD: The REMAST tool (REFINEMENT MApping Services Tool) combines a series of standardised health service research instruments and geographical information systems (GIS) to develop local atlases of mental health care from the perspective of horizontal and vertical integrated care. It contains five main sections: (a) Population Data; (b) the Verona Socio-economic Status (SES) Index; (c) the Mental Health System Checklist; (d) the Mental Health Services Inventory using the DESDE-LTC instrument; and (e) Geographical Data. EXPECTED RESULTS: The REMAST tool facilitates context analysis in mental health by providing the comparative rates of mental health service provision according to the availability of main types of care; care placement capacity; workforce capacity; and geographical accessibility to services in the local areas in eight study areas in Austria, England, Finland, France, Italy, Norway, Romania and Spain. DISCUSSION: The outcomes of this project will facilitate cooperative work and knowledge transfer on mental health care to the different agencies involved in mental health planning and provision. This project would improve the information to users and society on the available resources for mental health care and system thinking at the local level by the different stakeholders. The techniques used in this project and the knowledge generated could eventually be transferred to the mapping of other fields of integrated care. PMID- 27118961 TI - Patient involvement in diabetes care: experiences in nine diabetes care groups. AB - INTRODUCTION: Despite the expected beneficial effects on quality of care, patient involvement in diabetes care groups, which deliver a bundled paid integrated care programme for diabetes type 2, seems to be limited. The aim of this study was to gain insight into levels and methods of patient involvement, into facilitators and barriers, and into the future preferences of care groups and patient representatives. THEORY AND METHODS: Semi-structured interviews were held with 10 representatives of care groups and 11 representatives of patient advocacy groups. An adapted version of Arnstein's ladder of citizen participation was used to define five levels of patient involvement. RESULTS: Patient involvement in care groups was mostly limited to informing and consulting patients. Higher levels, i.e., advising, co-producing and decision-making, were less frequently observed. Care groups and patient representatives perceived largely the same barriers and facilitators and had similar preferences regarding future themes and design of patient involvement. CONCLUSION: Constructive collaboration between diabetes care groups and patient representatives to enhance patient involvement in the future seems viable. Several issues such as the lack of evidence for effectiveness of patient involvement, differences in viewpoints on the role and responsibilities of care groups and perceived barriers need to be addressed. PMID- 27118962 TI - Changes in geriatric rehabilitation: a national programme to improve quality of care. The Synergy and Innovation in Geriatric Rehabilitation study. AB - OBJECTIVE: To describe changes in the health service delivery process experienced by professionals, patients and informal caregivers during implementation of a national programme to improve quality of care of geriatric rehabilitation by improving integration of health service delivery processes. STUDY SETTING: Sixteen skilled nursing facilities. STUDY DESIGN: Prospective study, comparing three consecutive cohorts. DATA COLLECTION: Professionals (elderly care physicians, physiotherapists and nursing staff) rated four domains of health service delivery at admission and at discharge of 1075 patients. In addition, these patients [median age 79 (Interquartile range 71-85) years, 63% females] and their informal caregivers rated their experiences on these domains 4 weeks after discharge. PRINCIPAL FINDINGS: During the three consecutive cohorts, professionals reported improvement on the domain team cooperation, including assessment for intensive treatment and information transfer among professionals. Fewer improvements were reported within the domains alignment with patients' needs, care coordination and care quality. Between the cohorts, according to patients (n = 521) and informal caregivers (n = 319) there were no changes in the four domains of health service delivery. CONCLUSION: This national programme resulted in small improvements in team cooperation as reported by the professionals. No effects were found on patients' and informal caregivers' perceptions of health service delivery. PMID- 27118963 TI - Measuring parents' perspective on continuity of care in children with special health care needs. AB - INTRODUCTION: Children with special health care needs are an exponentially growing population needing integrated health care programmes that involve primary, community, hospital and tertiary care services. The aims of the study are (1) to develop and validate the Special Needs Kids Questionnaire (SpeNK-Q) designed to measure parents' perspective on continuity of care for children with special health care needs and (2) to evaluate the continuity of care based on parental experiences in this population. METHODS: SpeNK-Q was derived from a previous qualitative study and was based on Haggerty's constructs of informational, management and relational continuity. Parents of preterm birth children completed the 20-item SpeNK-Q at the second or subsequent planned follow up visit after the child's hospital discharge. Principal component analysis was used to examine the structure of the instrument. RESULTS: Principal component analysis of 101 questionnaires administered allowed us to identify five factors explaining 60.2% of item variance: informational continuity; coordination of care; continuity of family-paediatrician relationship; family support; information on care plan. CONCLUSIONS AND DISCUSSION: SpeNK-Q proved to be a psychometrically promising instrument. Its utilisation could improve the identification of areas for service development, the delivery of coordinated care and support policy makers in redesigning integrated services. PMID- 27118964 TI - Integrating collaborative place-based health promotion coalitions into existing health system structures: the experience from one Australian health coalition. AB - BACKGROUND: Increasingly, place-based collaborative partnerships are being implemented to develop the capacity of communities to build supportive environments and improve population health outcomes. These place-based initiatives require cooperative and coordinated responses that can exist within social systems and integrate multiple responses. However, the dynamic interplay between co-existing systems and new ways of working makes implementation outcomes unpredictable. METHOD: We interviewed eight programme leaders, three programme teams and two advisory groups to explore the capacity of one social system to implement and normalise a collaborative integrated place-based health promotion initiative in the Logan and Beaudesert area in South East Queensland, Australia. The construct of capacity as defined in the General Theory of Implementation was used to develop a coding framework. Data were then placed into conceptually coherent groupings according to this framework until all data could be accounted for. RESULTS: Four themes defined capacity for implementation of a collaborative and integrated response; namely, the ability to (1) traverse a nested and contradictory social landscape, (2) be a responsive and 'good' community partner, (3) establish the scaffolding required to work 'in place'; and (4) build a shared meaning and engender trust. Overall, we found that the capacity of the system to embed a place-based health promotion initiative was severely limited by the absence of these features. CONCLUSION: Conflict, disruption and constant change within the context into which the place-based collaborative partnership was being implemented meant that existing relationships were constantly undermined and the capacity of the partners to develop trust-based coherent partnerships was constantly diminished. To enhance the likelihood that collaborative and integrated place-based health promotion initiatives will become established ways of working, an agreed, meaningful and clearly articulated vision and identity are required; goals must be prioritised and negotiated; and sustainable resourcing must be assured. PMID- 27118965 TI - MEG Analysis of Neural Interactions in Attention-Deficit/Hyperactivity Disorder. AB - The aim of the present study was to explore the interchannel relationships of resting-state brain activity in patients with attention-deficit/hyperactivity disorder (ADHD), one of the most common mental disorders that develop in children. Magnetoencephalographic (MEG) signals were recorded using a 148-channel whole-head magnetometer in 13 patients with ADHD (range: 8-12 years) and 14 control subjects (range: 8-13 years). Three complementary measures (coherence, phase-locking value, and Euclidean distance) were calculated in the conventional MEG frequency bands: delta, theta, alpha, beta, and gamma. Our results showed that the interactions among MEG channels are higher for ADHD patients than for control subjects in all frequency bands. Statistically significant differences were observed for short-distance values within right-anterior and central regions, especially at delta, beta, and gamma-frequency bands (p < 0.05; Mann Whitney U test with false discovery rate correction). These frequency bands also showed statistically significant differences in long-distance interactions, mainly among anterior and central regions, as well as among anterior, central, and other areas. These differences might reflect alterations during brain development in children with ADHD. Our results support the role of frontal abnormalities in ADHD pathophysiology, which may reflect a delay in cortical maturation in the frontal cortex. PMID- 27118966 TI - Support Vector Machine with Ensemble Tree Kernel for Relation Extraction. AB - Relation extraction is one of the important research topics in the field of information extraction research. To solve the problem of semantic variation in traditional semisupervised relation extraction algorithm, this paper proposes a novel semisupervised relation extraction algorithm based on ensemble learning (LXRE). The new algorithm mainly uses two kinds of support vector machine classifiers based on tree kernel for integration and integrates the strategy of constrained extension seed set. The new algorithm can weaken the inaccuracy of relation extraction, which is caused by the phenomenon of semantic variation. The numerical experimental research based on two benchmark data sets (PropBank and AIMed) shows that the LXRE algorithm proposed in the paper is superior to other two common relation extraction methods in four evaluation indexes (Precision, Recall, F-measure, and Accuracy). It indicates that the new algorithm has good relation extraction ability compared with others. PMID- 27118967 TI - Clinical Features, Diagnosis, and Treatment Strategies of Gastrointestinal Diaphragm Disease Associated with Nonsteroidal Anti-Inflammatory Drugs. AB - Background. To demonstrate the clinical features, diagnosis, and treatment of nonsteroidal anti-inflammatory drug- (NSAID-) induced diaphragm disease (DD). Methods. A literature search between January 1973 and August 2015 was undertaken. The clinical data of patients with NSAID-induced DD were recorded and analyzed. Results. 159 patients were included. The ratio of male to female was 1 : 2.3; the mean age was 65 +/- 11 years. The most common clinical manifestations were gastrointestinal bleeding and obstruction. 121 (84%) patients took traditional NSAIDs. The durations of NSAIDs use ranged from 2 to 300 months. A majority (59.7%) of DD were seen in the small bowel, were seen secondly in the colon (30.2%), and were mainly located in the ileum (57.9%) and right colon (91.7%), respectively. 80% of patients had multiple diaphragms. 41.5% of small bowel DD were diagnosed preoperatively by capsule endoscopy and/or double-balloon enteroscopy, 52.1% at laparotomy. Nearly 75% of patients underwent surgery, endoscopic balloon dilation was performed in 22 patients, and NSAIDs were withdrawn in 53 patients. Conclusions. NSAID-induced DD is relatively rare. The small bowel is most commonly involved. Preoperative diagnosis of small bowel DD is relatively difficult. Discontinuation of the NSAIDs is recommended, surgical resection is the main treatment presently, and endoscopic balloon dilation should be considered as an alternative therapy. PMID- 27118968 TI - Evolving Techniques in Pancreatic Surgery. PMID- 27118969 TI - Erosive Esophagitis in the Obese: The Effect of Ethnicity and Gender on Its Association. AB - Background. Data examining the association between obesity and erosive esophagitis (ErE) have been inconsistent, with very little known about interracial variation. Goals. To examine the association between obesity and ErE among patients of different ethnic/racial backgrounds. Methods. The study sample included 2251 patients who underwent esophagogastroduodenoscopy (EGD). The effects of body mass index (BMI) on ErE were assessed by gender and in different ethnic groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariate logistic regression analysis. Results. The prevalence of ErE was 29.4% (661/2251). Overweight and obese subjects were significantly more likely to have ErE than individuals with a normal BMI, with the highest risk seen in the morbidly obese (OR 6.26; 95% CI 3.82-10.28; p < 0.0001). Normal weight Black patients were less likely to have ErE as compared to Caucasians (OR 0.46; 95% CI 0.27-0.79; p = 0.005), while the odds ratio comparing normal weight Hispanics to normal weight Whites was not statistically significant. No effect modification was seen between BMI and race/ethnicity or BMI and gender. Significant trends were seen in each gender and ethnicity. Conclusions. The effect of BMI on ErE does not appear to vary by race/ethnicity or gender. PMID- 27118970 TI - Pituitary Morphology and Function in 43 Children with Central Diabetes Insipidus. AB - Objective. In pediatric central diabetes insipidus (CDI), etiology diagnosis and pituitary function monitoring are usually delayed. This study aimed to illustrate the importance of regular follow-up and pituitary function monitoring in pediatric CDI. Methods. The clinical, hormonal, and neuroradiological characteristics of children with CDI at diagnosis and during 1.5-2-year follow-up were collected and analyzed. Results. The study included 43 CDI patients. The mean interval between initial manifestation and diagnosis was 22.29 +/- 3.67 months (range: 2-108 months). The most common complaint was polyuria/polydipsia. Causes included Langerhans cell histiocytosis, germinoma, and craniopharyngioma in 2, 5, and 4 patients; the remaining were idiopathic. No significant changes were found during the 1.5-2 years after CDI diagnosis. Twenty-three of the 43 cases (53.5%) had >=1 anterior pituitary hormone deficiency. Isolated growth hormone deficiency was the most frequent abnormality (37.5%) and was not associated with pituitary stalk diameter. Multiple pituitary hormone deficiencies were found in 8 cases with pituitary stalk diameter > 4.5 mm. Conclusion. Diagnosis of CDI is usually delayed. CDI with a pituitary stalk diameter > 4.5 mm carries a higher risk of multiple pituitary hormone deficiencies. Long-term MRI and pituitary function follow-ups are necessary for children with idiopathic CDI. PMID- 27118971 TI - Therapeutic Outcome of Second Primary Malignancies in Patients with Well Differentiated Thyroid Cancer. AB - Background. The aims of this study were to analyze the clinical characteristics of SPM in patients with well-differentiated thyroid cancer and to determine the long-term prognosis in patients with double malignancies. Materials and Methods. We retrospectively analyzed 2,864 patients with well-differentiated thyroid cancer and a mean age of 44.0 +/- 14.4 years. Of these, 200 (7.0%) were diagnosed with SPM, 115 of which were diagnosed with metachronous SPM. Results. Of 2,864 patients, 163 (5.7%) patients died of thyroid cancer and 301 (10.5%) died of any cause by the end of the follow-up period. Multivariate analysis identified age, SPM, external radiotherapy, TNM stage, and postoperative serum Tg level to be factors independently associated with decreased survival. Of 200 patients with SPM, 74 (37.0%) died. In comparison to the anachronous and synchronous groups, the metachronous SPM group had a higher mean age; more advanced tumor, node, and metastasis stage; lower remission rate; higher postoperative radioactive iodide ((131)I) accumulated dose; a higher proportion of patients who underwent external radiotherapy; and higher thyroid cancer and total mortality rates. Conclusions. Patients with well-differentiated thyroid carcinoma and metachronous SPM had worse prognoses compared to patients without SPM. PMID- 27118972 TI - Promoter Methylation and mRNA Expression of Response Gene to Complement 32 in Breast Carcinoma. AB - Background. Response gene to complement 32 (RGC32), induced by activation of complements, has been characterized as a cell cycle regulator; however, its role in carcinogenesis is still controversial. In the present study we compared RGC32 promoter methylation patterns and mRNA expression in breast cancerous tissues and adjacent normal tissues. Materials and Methods. Sixty-three breast cancer tissues and 63 adjacent nonneoplastic tissues were included in our study. Design. Nested methylation-specific polymerase chain reaction (Nested-MSP) and quantitative PCR (qPCR) were used to determine RGC32 promoter methylation status and its mRNA expression levels, respectively. Results. RGC32 methylation pattern was not different between breast cancerous tissue and adjacent nonneoplastic tissue (OR = 2.30, 95% CI = 0.95-5.54). However, qPCR analysis displayed higher levels of RGC32 mRNA in breast cancerous tissues than in noncancerous tissues (1.073 versus 0.959; P = 0.001), irrespective of the promoter methylation status. The expression levels and promoter methylation of RGC32 were not correlated with any of patients' clinical characteristics (P > 0.05). Conclusion. Our findings confirmed upregulation of RGC32 in breast cancerous tumors, but it was not associated with promoter methylation patterns. PMID- 27118973 TI - Choice of Unmanipulated T Cell Replete Graft for Haploidentical Stem Cell Transplant and Posttransplant Cyclophosphamide in Hematologic Malignancies in Adults: Peripheral Blood or Bone Marrow-Review of Published Literature. AB - Allogeneic hematopoietic stem cell transplantation (SCT) is often the only curative option for many patients with malignant and benign hematological stem cell disorders. However, some issues are still of concern regarding finding a donor like shrinking family sizes in many societies, underrepresentation of the ethnic minorities in the registries, genetic variability for some races, and significant delays in obtaining stem cells after starting the search. So there is a considerable need to develop alternate donor stem cell sources. The rapid and near universal availability of the haploidentical donor is an advantage of the haploidentical SCT and an opportunity that is being explored currently in many centers especially using T cell replete graft and posttransplant cyclophosphamide. This is probably because it does not require expertise in graft manipulation and because of the lower costs. However, there are still lots of unanswered questions, like the effect of use of bone marrow versus peripheral blood as the source of stem cells on graft-versus-host disease, graft versus tumor, overall survival, immune reconstitution, and quality of life. Here we review the available publications on bone marrow and peripheral blood experience in the haploidentical SCT setting. PMID- 27118974 TI - A Giant Intrathoracic Malignant Schwannoma Causing Respiratory Failure in a Patient without von Recklinghausen's Disease. AB - We report an unusual case of a thoracic opacity due to a huge mediastinal malignant schwannoma which compressed the whole left lung and the mediastinum causing respiratory failure in a 73-year-old woman without von Recklinghausen's disease. Although the tumor was resected, the patient failed to wean from mechanical ventilation and died one month later because of multiple organ dysfunction syndrome. PMID- 27118976 TI - The Novel Methods for Analysis of Exosomes Released from Endothelial Cells and Endothelial Progenitor Cells. AB - Exosomes (EXs) are cell-derived vesicles that mediate cell-cell communication and could serve as biomarkers. Here we described novel methods for purification and phenotyping of EXs released from endothelial cells (ECs) and endothelial progenitor cells (EPCs) by combining microbeads and fluorescence quantum dots (Q dots(r)) techniques. EXs from the culture medium of ECs and EPCs were isolated and detected with cell-specific antibody conjugated microbeads and second antibody conjugated Q-dots by using nanoparticle tracking analysis (NTA) system. The sensitivities of the cell origin markers for ECs (CD105, CD144) and EPCs (CD34, KDR) were evaluated. The sensitivity and specificity were determined by using positive and negative markers for EXs (CD63), platelets (CD41), erythrocytes (CD235a), and microvesicles (Annexin V). Moreover, the methods were further validated in particle-free plasma and patient samples. Results showed that anti-CD105/anti-CD144 and anti-CD34/anti-KDR had the highest sensitivity and specificity for isolating and detecting EC-EXs and EPC-EXs, respectively. The methods had the overall recovery rate of over 70% and were able to detect the dynamical changes of circulating EC-EXs and EPC-EXs in acute ischemic stroke. In conclusion, we have developed sensitive and specific microbeads/Q-dots fluorescence NTA methods for EC-EX and EPC-EX isolation and detection, which will facilitate the functional study and biomarker discovery. PMID- 27118975 TI - The Therapeutic Targets of miRNA in Hepatic Cancer Stem Cells. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide malignancy and the third leading cause of cancer death in patients. Several studies demonstrated that hepatic cancer stem cells (HCSCs), also called tumor initiating cells, are involved in regulation of HCC initiation, tumor progression, metastasis development, and drug resistance. Despite the extensive research, the underlying mechanisms by which HCSCs are regulated remain still unclear. MicroRNAs (miRNAs) are able to regulate a lot of biological processes such as self-renewal and pluripotency of HCSCs, representing a new promising strategy for treatment of HCC chemotherapy-resistant tumors. In this review, we synthesize the latest findings on therapeutic regulation of HCSCs by miRNAs, in order to highlight the perspective of novel miRNA-based anticancer therapies for HCC treatment. PMID- 27118977 TI - Restoration of a Critical Mandibular Bone Defect Using Human Alveolar Bone Derived Stem Cells and Porous Nano-HA/Collagen/PLA Scaffold. AB - Periodontal bone defects occur in a wide variety of clinical situations. Adult stem cell- and biomaterial-based bone tissue regeneration are a promising alternative to natural bone grafts. Recent evidence has demonstrated that two populations of adult bone marrow mesenchymal stromal cells (BMSCs) can be distinguished based on their embryonic origins. These BMSCs are not interchangeable, as bones preferentially heal using cells that share the same embryonic origin. However, the feasibility of tissue engineering using human craniofacial BMSCs was unclear. The goal of this study was to explore human craniofacial BMSC-based therapy for the treatment of localized mandibular defects using a standardized, minimally invasive procedure. The BMSCs' identity was confirmed. Scanning electron microscopy, a cell proliferation assay, and supernatant detection indicated that the nHAC/PLA provided a suitable environment for aBMSCs. Real-time PCR and electrochemiluminescence immunoassays demonstrated that osteogenic markers were upregulated by osteogenic preinduction. Moreover, in a rabbit critical-size mandibular bone defect model, total bone formation in the nHAC/PLA + aBMSCs group was significantly higher than in the nHAC/PLA group but significantly lower than in the nHAC/PLA + preinduced aBMSCs. These findings demonstrate that this engineered bone is a valid alternative for the correction of mandibular bone defects. PMID- 27118978 TI - Evaluation of the Isoflavone Genistein as Reversible Human Monoamine Oxidase-A and -B Inhibitor. AB - Monoamine oxidases inhibitors (MAOIs) are effective therapeutic drugs for managing Parkinson's disease (PD) and depression. However, their irreversibility may lead to rare but serious side effects. As finding safer and reversible MAOIs is our target, we characterized the recombinant human (h) MAO-A and MAO-B inhibition potentials of two common natural isoflavones, genistein (GST) and daidzein (DZ) using luminescence assay. The results obtained showed that DZ exhibits partial to no inhibition of the isozymes examined while GST inhibited hMAO-B (IC50 of 6.81 MUM), and its hMAO-A inhibition was more potent than the standard deprenyl. Furthermore, the reversibility, mode of inhibition kinetics, and tyramine oxidation of GST were examined. GST was a time-independent reversible and competitive hMAO-A and hMAO-B inhibitor with a lower K i of hMAO-B (1.45 MUM) than hMAO-A (4.31 MUM). GST also inhibited hMAO-B tyramine oxidation and hydrogen peroxide production more than hMAO-A. Docking studies conducted indicated that the GST reversibility and hMAO-B selectivity of inhibition may relate to C5-OH effects on its orientation and its interactions with the threonine 201 residue of the active site. It was concluded from this study that the natural product GST has competitive and reversible MAOs inhibitions and may be recommended for further investigations as a useful therapeutic agent for Parkinson's disease. PMID- 27118979 TI - Cytotoxic Effect and TLC Bioautography-Guided Approach to Detect Health Properties of Amazonian Hedyosmum sprucei Essential Oil. AB - Bioautography has been used as rapid and easy strategy to detect and identify bioactive fractions/molecules in the never before investigated Hedyosmum sprucei Solms (Chloranthaceae) essential oil (EO). The antioxidant activity, performed through DPPH bioautographic assay and spectrophotometric evaluations (IC50 = 230 +/- 10 ug/mL), seemed to be mainly due to alpha-cadinol and alpha-muurolol. (HP)TLC bioautography, focused on antimicrobial capacities, pointed out alpha cadinol, alpha-muurolol, tau-muurolol, caryophyllene oxide, and methyleugenol as the most effective compounds against Staphylococcus aureus, considered as testing strain. Moreover, the microdilution method, assessed among a wide panel of microorganisms, revealed Listeria grayi and Staphylococcus aureus as the most sensitive among human tested strains and Clavibacter michiganensis among phytopathogens. GC-MS chemical profile showed that bioactive molecules represented only a small quantity of the whole EO: germacrene D (23.16%), beta caryophyllene (15.53%), delta-cadinene (5.50%), alpha-copaene (5.08%), and alpha phellandrene (3.48%) were the main compounds, highlighting an uncommon composition among the genus Hedyosmum. Finally, H. sprucei EO was checked for cytotoxic potential against A549 (lung cancer) and MCF-7 (breast cancer) cell lines showing promising cytotoxic effects against both cell lines after 48 h (IC50 A549 = 44.05 +/- 2.35 ug/mL; IC50 MCF-7 = 32.76 +/- 4.92 ug/mL) and 72 h (IC50 A549 = 43.55 +/- 2.80 ug/mL; IC50 MCF-7 = 33.64 +/- 0.43 ug/mL). PMID- 27118980 TI - Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats. AB - The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae) was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract. PMID- 27118981 TI - Acupoints Stimulation for Anxiety and Depression in Cancer Patients: A Quantitative Synthesis of Randomized Controlled Trials. AB - This study aims at concluding the current evidence on the therapeutic effects of acupoints stimulation for cancer patients with anxiety and depression. Randomized controlled trials using acupoints stimulation for relieving anxiety and/or depression in cancer patients were searched, and 11 studies were finally included, of which eight trials compared acupoints stimulation with standard methods of treatment/care, and acupoints stimulation showed significantly better effects in improving depression than using standard methods of treatment/care. Four studies compared true acupoints stimulation with sham methods, and no significant differences can be found between groups for either depression or anxiety, although the pooled effects still favored true intervention. For the five studies that evaluated sleep quality, the results were conflicting, with three supporting the superiority of acupoints stimulation in improving sleep quality and two demonstrating no differences across groups. Acupoints stimulation seems to be an effective approach in relieving depression and anxiety in cancer patients, and placebo effects may partially contribute to the benefits. However, the evidence is not conclusive due to the limited number of included studies and the clinical heterogeneity identified among trials. More rigorous designed randomized, sham-controlled studies are necessary in future research. PMID- 27118982 TI - Therapeutic Effects of Traditional Chinese Medicine on Spinal Cord Injury: A Promising Supplementary Treatment in Future. AB - Objective. Spinal cord injury (SCI) is a devastating neurological disorder caused by trauma. Pathophysiological events occurring after SCI include acute, subacute, and chronic phases, while complex mechanisms are comprised. As an abundant source of natural drugs, Traditional Chinese Medicine (TCM) attracts much attention in SCI treatment recently. Hence, this review provides an overview of pathophysiology of SCI and TCM application in its therapy. Methods. Information was collected from articles published in peer-reviewed journals via electronic search (PubMed, SciFinder, Google Scholar, Web of Science, and CNKI), as well as from master's dissertations, doctoral dissertations, and Chinese Pharmacopoeia. Results. Both active ingredients and herbs could exert prevention and treatment against SCI, which is linked to antioxidant, anti-inflammatory, neuroprotective, or antiapoptosis effects. The detailed information of six active natural ingredients (i.e., curcumin, resveratrol, epigallocatechin gallate, ligustrazine, quercitrin, and puerarin) and five commonly used herbs (i.e., Danshen, Ginkgo, Ginseng, Notoginseng, and Astragali Radix) was elucidated and summarized. Conclusions. As an important supplementary treatment, TCM may provide benefits in repair of injured spinal cord. With a general consensus that future clinical approaches will be diversified and a combination of multiple strategies, TCM is likely to attract greater attention in SCI treatment. PMID- 27118983 TI - Psychopathology of addiction: May a SCL-90-based five dimensions structure be applied irrespectively of the involved drug? AB - BACKGROUND: We previously found a five cluster of psychological symptoms in heroin use disorder (HUD) patients: 'worthlessness-being trapped', 'somatic symptoms', 'sensitivity-psychoticism', 'panic-anxiety', and 'violence-suicide'. We demonstrated that this aggregation is independent of the chosen treatment, of intoxication status and of the presence of psychiatric problems. METHODS: 2314 Subjects, with alcohol, heroin or cocaine dependence were assigned to one of the five clusters. Differences between patients dependent on alcohol, heroin and cocaine in the frequency of the five clusters and in their severity were analysed. The association between the secondary abuse of alcohol and cocaine and the five clusters was also considered in the subsample of HUD patients. RESULTS: We confirmed a positive association of the 'somatic symptoms' dimension with the condition of heroin versus cocaine dependence and of the 'sensitivity psychoticism' dimension with the condition of alcohol versus heroin dependence. 'Somatic symptoms' and 'panic anxiety' successfully discriminated between patients as being alcohol, heroin or cocaine dependents. Looking at the subsample of heroin dependents, no significant differences were observed. CONCLUSIONS: The available evidence coming from our results, taken as a whole, seems to support the extension of the psychopathological structure previously observed in opioid addicts to the population of alcohol and cocaine dependents. PMID- 27118984 TI - "When you give birth you will not be without your mother" A mixed methods study of advice on breastfeeding for first-time mothers in rural coastal Kenya. AB - BACKGROUND: Exclusive breastfeeding for the first 6 months of life is currently recommended by the World Health Organization, but mixed feeding earlier than this commonly occurs in rural coastal Kenya. Mothers may receive conflicting advice on breastfeeding from various sources including health workers, relatives and community members. We aimed to find out how first-time mothers learn to breastfeed, who advises them on infant feeding and what advice they obtain in case of any breastfeeding problems. METHODS: To identify advisers, a questionnaire on socio-demographic status, place of delivery, household members, education and help received on breastfeeding, breastfeeding problems, name of advisers and their relationship to the mothers was administered to 50 new first time mothers in Jaribuni, Kilifi (population approximately 18,000). Summary statistics were obtained using frequencies, medians and interquartile ranges (IQR). Focus group discussions (FGDs) were held amongst 4 groups of mothers who had answered questionnaires; 4 groups of their named advisers; and 1 group of community health workers in order to explore breastfeeding practices, problems and advice given. FGDs were analysed by thematic framework analysis. RESULTS: First-time mothers were young (median age 18, IQR 17-21, range 14-26 years) and 42 % were single. Living in extended families was the norm and married women lived with their husband's family. All had a female family member or neighbour helping with childcare in the perinatal period. The main advisers on breastfeeding were their mother or older female members of their husband's family. Married first-time mothers felt obliged to follow their mother-in-law's advice to maintain good relationships and show respect within the household. Breastfeeding problems were reported by 80 % of respondents. Nipple pain (56 %) was the most reported problem, then breast engorgement (48 %) and insufficient milk supply (38 %). Most problems were treated at home without consultation with health workers. Concerns were raised about co-sleeping, breastfeeding whilst lying down, and insufficient milk supply. Advisers would like more information on breastfeeding in order to help mothers. CONCLUSIONS: Interventions to increase knowledge of, and facilitate optimal breastfeeding practices in first-time mothers should include those family members who advise and assist with childcare around the time of delivery. PMID- 27118985 TI - Efficient multiplex mutagenesis by RNA-guided Cas9 and its use in the characterization of regulatory elements in the AGAMOUS gene. AB - BACKGROUND: The efficiency of multiplex editing in plants by the RNA-guided Cas9 system is limited by efficient introduction of its components into the genome and by their activity. The possibility of introducing large fragment deletions by RNA guided Cas9 tool provides the potential to study the function of any DNA region of interest in its 'endogenous' environment. RESULTS: Here, an RNA-guided Cas9 system was optimized to enable efficient multiplex editing in Arabidopsis thaliana. We demonstrate the flexibility of our system for knockout of multiple genes, and to generate heritable large-fragment deletions in the genome. As a proof of concept, the function of part of the second intron of the flower development gene AGAMOUS in Arabidopsis was studied by generating a Cas9-free mutant plant line in which part of this intron was removed from the genome. Further analysis revealed that deletion of this intron fragment results 40 % decrease of AGAMOUS gene expression without changing the splicing of the gene which indicates that this regulatory region functions as an activator of AGAMOUS gene expression. CONCLUSIONS: Our modified RNA-guided Cas9 system offers a versatile tool for the functional dissection of coding and non-coding DNA sequences in plants. PMID- 27118986 TI - The utility of flow sorting to identify chromosomes carrying a single copy transgene in wheat. AB - BACKGROUND: Identification of transgene insertion sites in plant genomes has practical implications for crop breeding and is a stepping stone to analyze transgene function. However, single copy sequences are not always easy to localize in large plant genomes by standard approaches. RESULTS: We employed flow cytometric chromosome sorting to determine chromosomal location of barley sucrose transporter construct in three transgenic lines of common wheat. Flow-sorted chromosomes were used as template for PCR and fluorescence in situ hybridization to identify chromosomes with transgenes. The chromosomes carrying the transgenes were then confirmed by PCR using DNA amplified from single flow-sorted chromosomes as template. CONCLUSIONS: Insertion sites of the transgene were unambiguously localized to chromosomes 4A, 7A and 5D in three wheat transgenic lines. The procedure presented in this study is applicable for localization of any single-copy sequence not only in wheat, but in any plant species where suspension of intact mitotic chromosomes suitable for flow cytometric sorting can be prepared. PMID- 27118987 TI - A Bayesian Approach for Evaluation of Determinants of Health System Efficiency Using Stochastic Frontier Analysis and Beta Regression. AB - In today's world, Public expenditures on health are one of the most important issues for governments. These increased expenditures are putting pressure on public budgets. Therefore, health policy makers have focused on the performance of their health systems and many countries have introduced reforms to improve the performance of their health systems. This study investigates the most important determinants of healthcare efficiency for OECD countries using second stage approach for Bayesian Stochastic Frontier Analysis (BSFA). There are two steps in this study. First we measure 29 OECD countries' healthcare efficiency by BSFA using the data from the OECD Health Database. At second stage, we expose the multiple relationships between the healthcare efficiency and characteristics of healthcare systems across OECD countries using Bayesian beta regression. PMID- 27118988 TI - Establishment of Relational Model of Congenital Heart Disease Markers and GO Functional Analysis of the Association between Its Serum Markers and Susceptibility Genes. AB - PURPOSE: The purpose of present study was to construct the best screening model of congenital heart disease serum markers and to provide reference for further prevention and treatment of the disease. METHODS: Documents from 2006 to 2014 were collected and meta-analysis was used for screening susceptibility genes and serum markers closely related to the diagnosis of congenital heart disease. Data of serum markers were extracted from 80 congenital heart disease patients and 80 healthy controls, respectively, and then logistic regression analysis and support vector machine were utilized to establish prediction models of serum markers and Gene Ontology (GO) functional annotation. RESULTS: Results showed that NKX2.5, GATA4, and FOG2 were susceptibility genes of congenital heart disease. CRP, BNP, and cTnI were risk factors of congenital heart disease (p < 0.05); cTnI, hs-CRP, BNP, and Lp(a) were significantly close to congenital heart disease (p < 0.01). ROC curve indicated that the accuracy rate of Lp(a) and cTnI, Lp(a) and BNP, and BNP and cTnI joint prediction was 93.4%, 87.1%, and 97.2%, respectively. But the detection accuracy rate of the markers' relational model established by support vector machine was only 85%. GO analysis suggested that NKX2.5, GATA4, and FOG2 were functionally related to Lp(a) and BNP. CONCLUSIONS: The combined markers model of BNP and cTnI had the highest accuracy rate, providing a theoretical basis for the diagnosis of congenital heart disease. PMID- 27118989 TI - Implementation of a quality improvement project on smoking cessation reduces smoking in a high risk trauma patient population. AB - BACKGROUND: Cigarette smoking causes about one of every five deaths in the U.S. each year. In 2013 the prevalence of smoking in our institution's trauma population was 26.7 %, well above the national adult average of 18.1 % according to the CDC website. As a quality improvement project we implemented a multimodality smoking cessation program in a high-risk trauma population. METHODS: All smokers with independent mental capacity admitted to our level I trauma center from 6/1/2014 until 3/31/2015 were counseled by a physician on the benefits of smoking cessation. Those who wished to quit smoking were given further counseling by a pulmonary rehabilitation nurse and offered nicotine replacement therapy (e.g. nicotine patch). A planned 30 day or later follow-up was performed to ascertain the primary endpoint of the total number of patients who quit smoking, with a secondary endpoint of reduction in the frequency of smoking, defined as at least a half pack per day reduction from their pre intervention state. RESULTS: During the 9 month study period, 1066 trauma patients were admitted with 241 (22.6 %) identified as smokers. A total of 31 patients with a mean Injury Severity Score (ISS) of 14.2 (range 1-38), mean age of 47.6 (21-71) and mean years of smoking of 27.1 (2-55), wished to stop smoking. Seven of the 31 patients, (22.5 %, 95 % confidence interval [CI] of 10-41 %) achieved self-reported smoking cessation at or beyond 30 days post discharge. An additional eight patients (25.8 %, 95 % CI 12-45 %) reported significant reduction in smoking. CONCLUSIONS: Trauma patients represent a high risk smoking population. The implementation of a smoking cessation program led to a smoking cessation rate of 22.5 % and smoking reduction in 25.8 % of all identified smokers who participated in the program. This is a relatively simple, inexpensive intervention with potentially far reaching and beneficial long-term health implications. A larger, multi-center prospective study appears warranted. LEVEL OF EVIDENCE: Therapeutic Study, Level V evidence. PMID- 27118990 TI - How to improve the clinical diagnosis of acute appendicitis in resource limited settings. AB - This article is a general review of the diagnostic tools that the clinician can use for the early diagnosis of acute appendicitis with emphasis on the Alvarado Score, and it is aimed principally to the medical practitioners in different parts of the world where the diagnostic facilities and technological resources are limited. PMID- 27118991 TI - Herb-partitioned moxibustion upregulated the expression of colonic epithelial tight junction-related proteins in Crohn's disease model rats. AB - BACKGROUND: Herb-partitioned moxibustion (HPM) at Tianshu (ST25) and Qihai (RN6) has been used to treat Crohn's disease (CD). Injury to intestinal epithelial tight junctions (TJs) is the leading cause of CD onset with under expression of TJ-related proteins such as occludin, claudin-1, and zonula occludens protein-1 (ZO-1). This study aimed to investigate whether HPM can change the permeability of the intestinal epithelial barrier by affecting the expression of colonic epithelial TJ-related proteins in vitro. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into four groups of twelve rats: normal control (NC) group; model control (MC) group; herb-partitioned moxibustion (HPM) group; and mesalazine control (MESA) group. The rats in the latter three groups were given trinitrobenzene sulfonic acid (TNBS) enemas to establish CD models. The HPM group was treated with HPM at Tianshu (ST25) and Qihai (RN6) once daily for 14 consecutive days, while the MESA group was given mesalazine solution (at the proportion of 0.018:1) by lavage twice daily for the same period. After the treatment period, the colon tissues from all groups were partly processed for macroscopic damage assessment and histological observation, and partly purified and cultured in vitro to examine the permeability of the intestinal epithelial cell barrier by trans-epithelial electrical resistance (TEER). Western blot and fluorescence quantitative polymerase chain reaction (FQ-PCR) analyses were performed to observe the expression of occludin, claudin-1, and ZO-1 proteins and mRNAs, respectively. RESULTS: In the HPM and MESA groups, the typical CD macroscopic damage, i.e., inflammatory cell infiltration in colonic mucosa and submucosa, submucosal lymphoid follicular hyperplasia, hyperemia and edema, and morphological changes were improved to different degrees in the colonic tissues (HPM, MESA vs. MC for macroscopic score of colonic damage: all P < 0.001). The decreasing tendencies were minor for colonic TEER values (HPM, MESA vs. MC: all P < 0.001), and expression of intestinal epithelial TJ-related proteins (HPM, MESA vs. MC: all P < 0.05) and mRNAs (HPM, MESA vs. MC: all P < 0.05), especially in the HPM group (HPM vs. MESA for TEER values: P < 0.001). CONCLUSIONS: HPM at Tianshu (ST25) and Qihai (RN6) upregulated the expression of occludin, claudin-1, and ZO-1 in TNBS-induced CD model rats. PMID- 27118992 TI - Depressive symptoms are associated with oxidative stress in middle-aged women: a cross-sectional study. AB - BACKGROUND: Oxidative stress is known to be a factor in various diseases. In this study, we investigated whether physical and psychological symptoms of menopause, cardiovascular parameters, body composition, and lifestyle factors are associated with oxidative stress in middle-aged women. METHODS: This cross-sectional study used baseline data collected in a previous study that examined the effects of a dietary supplement on a variety of health parameters in 95 women aged 40 to 60 years. Participants had been assessed for age, menopausal status, body composition, cardiovascular parameters, physical and psychological symptoms of menopause, and lifestyle factors. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) level, an oxidative stress marker, had also been measured. Dichotomizing 8-OHdG levels as low (<=25 ng/mg creatinine) and high (>25 ng/mg creatinine), we sought to identify the health parameters that are associated with high 8-OHdG level. RESULTS: Women with a high 8-OHdG level had lower body weight, lower body mass index, lower body fat mass, higher body temperature, scored higher for both anxiety and depression on the Hospital Anxiety and Depression Scale (HADS), and consumed more alcohol. Multiple logistic regression analysis revealed that the HADS-depression subscale (HADS-D) score was the sole independent contributor to high 8-OHdG level (adjusted odds ratio, 1.23 per point increase in HADS-D score; 95 % confidence interval, 1.06-1.45). CONCLUSION: Depressive symptom score was shown to be independently associated with high 8-OHdG level in middle-aged women, suggesting a link between mood disorder and oxidative stress. TRIAL REGISTRATION: UMIN-CTR UMIN000009353. PMID- 27118993 TI - The prevalence and risk factors of school absenteeism due to premenstrual disorders in Japanese high school students-a school-based cross-sectional study. AB - BACKGROUND: Premenstrual disorders such as premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) interfere with the daily lives of adolescents. The causes of PMS and PMDD are unknown, but lifestyle habits, such as regular exercise and taste preference are known to be associated. This study was conducted to investigate how premenstrual symptoms affect the school life in Japanese high school students and whether there was a risk factor for school absenteeism that is dependent on the types of premenstrual symptoms or lifestyle habits. METHODS: A school-based survey was conducted in Sendai, an industrial city in Japan. A total of 901 girls aged 15-19 with regular menstrual cycles were assessed using the self-reporting premenstrual symptoms questionnaire (PSQ) and questions regarding school absence, taste preference, and exercise. We classified the girls into 'no/mild PMS', 'moderate-to-severe PMS' and 'PMDD' according to the PSQ. The girls were classified into the 'absent' group if they were absent for more than 1 day per month. We used multivariate logistic analysis to examine the risk factors for school absenteeism. RESULTS: The rates of 'moderate-to severe PMS' and 'PMDD' were 9.9 and 3.1 %, respectively. A total of 107 girls (11.9 %) were classified into the 'absent' group. Significant differences were observed in the prevalence of all premenstrual symptoms (p < 0.001), 'age' (p < 0.001), 'a preference for salty food' (p = 0.001), and 'lack of regular exercise' (p = 0.03) between the 'absent' and 'non-absent' groups. Multivariate analysis revealed that premenstrual symptoms such as 'insomnia or hypersomnia' (odds ratio [OR] 2.27, 95 % confidence interval [CI]: 1.46-4.17) and 'physical symptoms' (OR 2.24, 95 % CI: 1.37-3.66), 'reduced social life activities' (OR 2.71, 95 % CI 1.31-5.59), and 'a preference for salty food' (OR 1.89, 95 % CI: 1.20-2.98) were risk factors for school absenteeism. CONCLUSIONS: One in nine Japanese female high school students were absent from school due to premenstrual symptoms. Physical premenstrual symptoms and lifestyles, such as a preference for salty food and a lack of regular exercise, were identified as risk factors for school absenteeism. PMID- 27118994 TI - Elucidation of the roles of adhE1 and adhE2 in the primary metabolism of Clostridium acetobutylicum by combining in-frame gene deletion and a quantitative system-scale approach. AB - BACKGROUND: Clostridium acetobutylicum possesses two homologous adhE genes, adhE1 and adhE2, which have been proposed to be responsible for butanol production in solventogenic and alcohologenic cultures, respectively. To investigate their contributions in detail, in-frame deletion mutants of each gene were constructed and subjected to quantitative transcriptomic (mRNA molecules/cell) and fluxomic analyses in acidogenic, solventogenic, and alcohologenic chemostat cultures. RESULTS: Under solventogenesis, compared to the control strain, only DeltaadhE1 mutant exhibited significant changes showing decreased butanol production and transcriptional expression changes in numerous genes. In particular, adhE2 was over expressed (126-fold); thus, AdhE2 can partially replace AdhE1 for butanol production (more than 30 % of the in vivo butanol flux) under solventogenesis. Under alcohologenesis, only DeltaadhE2 mutant exhibited striking changes in gene expression and metabolic fluxes, and butanol production was completely lost. Therefore, it was demonstrated that AdhE2 is essential for butanol production and thus metabolic fluxes were redirected toward butyrate formation. Under acidogenesis, metabolic fluxes were not significantly changed in both mutants except the complete loss of butanol formation in DeltaadhE2, but numerous changes in gene expression were observed. Furthermore, most of the significantly up- or down-regulated genes under this condition showed the same pattern of change in both mutants. CONCLUSIONS: This quantitative system-scale analysis confirms the proposed roles of AdhE1 and AdhE2 in butanol formation that AdhE1 is the key enzyme under solventogenesis, whereas AdhE2 is the key enzyme for butanol formation under acidogenesis and alcohologenesis. Our study also highlights the metabolic flexibility of C. acetobutylicum to genetic alterations of its primary metabolism. PMID- 27118995 TI - Foot health education provision for people with rheumatoid arthritis-an online survey of UK podiatrists' perceptions. AB - BACKGROUND: Patient education supports general disease self-management and in relation to foot problems, it is recommended as a key intervention for people with rheumatoid arthritis (RA). Further, it is known what the foot health educational (FHE) needs are in relation to their experiences of foot problems. Podiatrists are the key health professionals who provide the management of RA related foot pathology and this includes the delivery of FHE. However, we do not know what is currently provided and what podiatrists' perceptions are of this intervention. It is possible that there is a difference between what is provided and what patients need in order to maximise their foot health benefits and hence this may contribute to the persistence of foot problems and symptoms. This study primarily aims to define what UK podiatrists' perceptions of FHE are in relation to; what is delivered, how it is delivered, and the timing of its delivery, in the context of its' accessibility. The secondary aim is to identify any influence of the participants' gender, age and duration of professional qualification on their responses. METHOD: An online survey of UK HCPC registered podiatrists was used to capture quantitative data in relation to the perceived; aims, content, methods and effectiveness, timing and barriers to FHE provision to people with RA. Data was analysed to assess significant associations between the participant responses and their gender, age and duration of professional qualification. Free text comments were analysed using thematic analysis. RESULTS: 43 podiatrists across the UK completed the survey. The majority of participants stated that, they provided FHE and agreed with its overall aims. The most common methods of delivery that were perceived to be most effective were: verbal, written and website based information. The best times at which to deliver FHE were thought to be at the point of diagnosis of RA and at any available opportunity of health care delivery. The majority of participants thought they had enough knowledge and access to information resources to effectively deliver FHE, but half of the participants felt that consultation duration limited their ability to do so. Gender and duration of professional qualification influenced participants' perceptions of FHE. CONCLUSION: The importance and content of FHE for people with RA has been defined, but time limitations are seen to restrict its delivery. The development of an education needs analysis tool to facilitate efficient identification of patients FHE needs could enable timely and tailored delivery of FHE to people with RA. PMID- 27118996 TI - Photochemical synthesis and anticancer activity of barbituric acid, thiobarbituric acid, thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives. AB - 2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene} 2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines. PMID- 27118997 TI - JOCB Bulletin. PMID- 27118998 TI - Developmental phenotype in Phelan-McDermid (22q13.3 deletion) syndrome: a systematic and prospective study in 34 children. AB - BACKGROUND: Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by global developmental delay, cognitive deficits, and behaviour in the autism spectrum. Knowledge about developmental and behavioural characteristics of this rare chromosomal disorder is still limited despite a rapid growing number of diagnoses. Our aim was to study a new and relatively large cohort to further characterize the developmental phenotype of children with PMS. METHODS: We performed a descriptive study of children with a 22q13.3 deletion including SHANK3, aged 8 to 178 months, who were systematically (n = 34) and longitudinally (n = 29) assessed with standardized instruments: Bayley Scales of Infant and Toddler Development, third edition; Wechsler Preschool and Primary Scale of Intelligence, third edition; and Vineland Screener for Social and Adaptive Behavior. RESULTS: Maximal developmental functioning ranged from 34 to 52 months depending on the developmental domain. In general, children performed poorest in the domain of language and best on the domain of motor (young children) or cognitive development (older children). At the individual level, 25 % scored better for receptive and 18 % for expressive language, whereas 22 % scored better for fine and 33 % for gross motor function. Developmental quotients were higher in younger children and decreased with age for all developmental domains, with 38 % of the children showing no improvement of cognitive developmental functioning. Almost all children (33/34) had significant deficits in adaptive behaviour. Children with very small deletions, covering only the SHANK3, ACR, and RABL2B genes, had a more favourable developmental phenotype. CONCLUSIONS: Cognitive, motor, and especially language development were significantly impaired in all children with PMS but also highly variable and unpredictable. In addition, deficits in adaptive behaviour further hampered their cognitive development. Therefore, cognitive and behavioural characteristics should be evaluated and followed in each child with PMS to adapt supportive and therapeutic strategies to individual needs. Further research evaluating the relationship between deletion characteristics and the developmental phenotype is warranted to improve counselling of parents. PMID- 27118999 TI - Analysis of RET promoter CpG island methylation using methylation-specific PCR (MSP), pyrosequencing, and methylation-sensitive high-resolution melting (MS HRM): impact on stage II colon cancer patient outcome. AB - BACKGROUND: Already since the 1990s, promoter CpG island methylation markers have been considered promising diagnostic, prognostic, and predictive cancer biomarkers. However, so far, only a limited number of DNA methylation markers have been introduced into clinical practice. One reason why the vast majority of methylation markers do not translate into clinical applications is lack of independent validation of methylation markers, often caused by differences in methylation analysis techniques. We recently described RET promoter CpG island methylation as a potential prognostic marker in stage II colorectal cancer (CRC) patients of two independent series. METHODS: In the current study, we analyzed the RET promoter CpG island methylation of 241 stage II colon cancer patients by direct methylation-specific PCR (MSP), nested-MSP, pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM). All primers were designed as close as possible to the same genomic region. In order to investigate the effect of different DNA methylation assays on patient outcome, we assessed the clinical sensitivity and specificity as well as the association of RET methylation with overall survival for three and five years of follow-up. RESULTS: Using direct-MSP and nested-MSP, 12.0 % (25/209) and 29.6 % (71/240) of the patients showed RET promoter CpG island methylation. Methylation frequencies detected by pyrosequencing were related to the threshold for positivity that defined RET methylation. Methylation frequencies obtained by pyrosequencing (threshold for positivity at 20 %) and MS-HRM were 13.3 % (32/240) and 13.8 % (33/239), respectively. The pyrosequencing threshold for positivity of 20 % showed the best correlation with MS-HRM and direct-MSP results. Nested-MSP detected RET promoter CpG island methylation in deceased patients with a higher sensitivity (33.1 %) compared to direct-MSP (10.7 %), pyrosequencing (14.4 %), and MS-HRM (15.4 %). While RET methylation frequencies detected by nested-MSP, pyrosequencing, and MS-HRM varied, the prognostic effect seemed similar (HR 1.74, 95 % CI 0.97-3.15; HR 1.85, 95 % CI 0.93-3.86; HR 1.83, 95 % CI 0.92-3.65, respectively). CONCLUSIONS: Our results show that upon optimizing and aligning four RET methylation assays with regard to primer location and sensitivity, differences in methylation frequencies and clinical sensitivities are observed; however, the effect on the marker's prognostic outcome is minimal. PMID- 27119000 TI - Erythroderma. A clinical and etiological study of 103 patients. AB - BACKGROUND: Erythroderma is an uncommon and severe dermatological manifestation of a variety of diseases. It is commonly challenging to find the underlying cause. OBJECTIVE: The aim of this study was to analyze the causes of the disease in patients with erythroderma. PATIENTS AND METHODS: Data including the clinical symptoms, laboratory examinations, histopathology and follow-up information were collected from patients with erythroderma admitted to our department between 2000 and 2010. RESULTS: One-hundred and three patients diagnosed with erythroderma were identified during this period (11.9% of all hospitalized patients; hospital incidence = 9.4 cases/year). The mean age of onset was 54.4 years (range: 17-89 years) with a male:female ratio of 1.5:1. The most frequent cause of erythroderma was exacerbation of preexisting dermatoses (65.0%), including psoriasis (44.7%) and eczema (16.5%). Drugs (18.4%) and cutaneous T-cell lymphomas (11.7%) induced most of the remaining cases. No cause could be identified in four cases (3.9%). Apart from erythema and scaling, that were present in all patients, clinical findings were dominated by pruritus (97.1%), followed by edema (56.3%), fever (54.4%), palmoplantar keratoderma (50.5%), nail changes (42.7%), liver or spleen enlargement (41.7%) and lymphadenopathy (40.8%). CONCLUSIONS: Although numerous clinical features and laboratory values were abnormal, most findings were non specific. The skin biopsy yielded a positive clinical correlation in most cases. Our study had a high percentage of erythroderma secondary to preexisting skin disease and a relatively low percentage of idiopathic erythroderma. PMID- 27119001 TI - Sporadic and familial cases of aquagenic keratoderma. AB - BACKGROUND: Aquagenic keratoderma is a dermatosis characterized by transient whitish and transluscent hyperwrinkling after water exposure. The aim of the current report was to present a sporadic and familial cases of aquagenic keratoderma. OBSERVATION: Sporadic Case: A 38-year-old female patient presented with eruption in the right hand after exposure to water. The patient was placed on systemic acitretin therapy with the diagnosis of idiopathic acquired aquagenic keratoderma. No recurrence occurred during a 6-month follow-up period. Familial Cases: A 55-year-old male patient, who was engaged in fishery, presented to the outpatient clinics of the department of dermatology due to whitish vesicles in the palms of both hands. It was realized that the father, sister, and brother of the patient had similar complaints. The cases were thought to have familial aquagenic keratoderma; however acitretin therapy could not be initiated due to elevated alanine aminotransferase and triglyceride levels. Topical application of salicylic acid 10% and 10% urea containing lotions was effective but did not prevent recurrence. CONCLUSION: Systemic acitretin may be an effective agent in the treatment of aquagenic keratoderma, and topical application of 10% salicylic acid and 10% urea-containing lotion did not prevent recurrence. PMID- 27119002 TI - Stevens-Johnson syndrome in a patient with rheumatoid arthritis during long-term etanercept therapy. AB - BACKGROUND: Etanercept and other anti-TNF-alpha agents have been indicated as a therapeutic option in severe drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Etanercept has been shown to quickly reduce the detachment of the epidermis and shorten healing time. Cases of etanercept-induced severe adverse drug reactions were also described. MAIN OBSERVATIONS: A 27-year old woman with a 4-year history of etanercept and sulfasalazine treatment for rheumatoid arthritis was admitted with Stevens-Johnson syndrome. The patient received one dose of an OTC drug containing acetaminophen, phenylephrine and pheniramine two days prior to developing fist mucocutaneous symptoms. The most probable causative agent was paracetamol. Throughout the successful routine therapy of Stevens-Johnson syndrome etanercept therapy was continued. Sulfosalazin administration was stopped and administered again after recovery with no recurrence of the skin and mucosal symptoms. CONCLUSIONS: This case indicates that there is no justification for discontinuation of long-term anti TNF-alpha treatment in patients who develop Stevens- Johnson syndrome / toxic epidermal necrolysis. PMID- 27119003 TI - Photoletter to the editor: Postradiation sarcoma. AB - Postradiation sarcomas are rare and highly malignant tumors which may appear as a consequence of radiotherapy. They may originate on bone or soft tissues.We report the case of a patient who developed a malignant fibrous histiocytoma 35 years after radiotherapy for a melanoma on her right leg. PMID- 27119004 TI - Photoletter to the editor: Dermoscopy as a diagnostic aid for pruritic folliculitis of pregnancy. AB - Pruritic folliculitis of pregnancy is a noninfective dermatosis of the gestation period characterized by multiple pruritic follicular papules and/or pustules which is not uncommonly mistaken for other similar skin disorders that may occur during pregnancy. In the present article we describe the usefulness of dermoscopy as a supportive diagnostic tool in a case of pruritic folliculitis of pregnancy. The main (always present) dermoscopic clue consisted of a vellus hair in the centre of each papule/pustule. Moreover, most papules showed a central yellowish orange hue with some dotted vessels and irregular haemorrhagic spots. The detection of the aforementioned dermoscopic features might help distinguish pruritic folliculitis of pregnancy from its main differential diagnoses, mainly including microbial folliculitis, prurigo lesions, and the papular stage of pruritic urticarial papules and plaques of pregnancy, as they typically show different dermoscopic patterns. PMID- 27119005 TI - Tualang Honey Attenuates Noise Stress-Induced Memory Deficits in Aged Rats. AB - Ageing and stress exposure may lead to memory impairment while oxidative stress is thought to be one of the underlying mechanisms involved. This study aimed to investigate the potential protective effects of Tualang honey supplementation on memory performance in aged rats exposed to noise stress. Tualang honey supplementation was given orally, 200 mg/kg body weight for 28 days. Rats in the stress group were subjected to loud noise, 100 dB(A), 4 hours daily for 14 days. All rats were subjected to novel object recognition test for evaluation of memory performance. It was observed that the rats subjected to noise stress exhibited significantly lower memory performance and higher oxidative stress as evident by elevated malondialdehyde and protein carbonyl levels and reduction of antioxidant enzymes activities compared to the nonstressed rats. Tualang honey supplementation was able to improve memory performance, decrease oxidative stress levels, increase brain-derived neurotrophic factor (BDNF) concentration, decrease acetylcholinesterase activity, and enhance neuronal proliferation in the medial prefrontal cortex (mPFC) and hippocampus. In conclusion, Tualang honey protects against memory decline due to stress exposure and/or ageing via enhancement of mPFC and hippocampal morphology possibly secondary to reduction in brain oxidative stress and/or upregulation of BDNF concentration and cholinergic system. PMID- 27119006 TI - The Role of Mitochondrial Functional Proteins in ROS Production in Ischemic Heart Diseases. AB - Ischemic heart diseases (IHD) have become the leading cause of death around the world, killing more than 7 million people annually. In IHD, the blockage of coronary vessels will cause irreversible cell injury and even death. As the "powerhouse" and "apoptosis center" in cardiomyocytes, mitochondria play critical roles in IHD. Ischemia insult can reduce myocardial ATP content, resulting in energy stress and overproduction of reactive oxygen species (ROS). Thus, mitochondrial abnormality has been identified as a hallmark of multiple cardiovascular disorders. To date, many studies have suggested that these mitochondrial proteins, such as electron transport chain (ETC) complexes, uncoupling proteins (UCPs), mitochondrial dynamic proteins, translocases of outer membrane (Tom) complex, and mitochondrial permeability transition pore (MPTP), can directly or indirectly influence mitochondria-originated ROS production, consequently determining the degree of mitochondrial dysfunction and myocardial impairment. Here, the focus of this review is to summarize the present understanding of the relationship between some mitochondrial functional proteins and ROS production in IHD. PMID- 27119008 TI - Immune, Inflammatory, and Oxidative Responses in Cardiovascular Complications. PMID- 27119007 TI - Metforminium Decavanadate as a Potential Metallopharmaceutical Drug for the Treatment of Diabetes Mellitus. AB - New potential drugs based on vanadium are being developed as possible treatments for diabetes mellitus (DM) and its complications. In this regard, our working group developed metforminium decavanadate (MetfDeca), a compound with hypoglycemic and hypolipidemic properties. MetfDeca was evaluated in models of type 1 and type 2 diabetes mellitus, on male Wistar rats. Alloxan-induction was employed to produce DM1 model, while a hypercaloric-diet was employed to generate DM2 model. Two-month treatments with 3.7 MUg (2.5 MUM)/300 g/twice a week for DM2 and 7.18 MUg (4.8 MUM)/300 g/twice a week for DM1 of MetfDeca, respectively, were administered. The resulting pharmacological data showed nontoxicological effects on liver and kidney. At the same time, MetfDeca showed an improvement of carbohydrates and lipids in tissues and serum. MetfDeca treatment was better than the monotherapies with metformin for DM2 and insulin for DM1. Additionally, MetfDeca showed a protective effect on pancreatic beta cells of DM1 rats, suggesting a possible regeneration of these cells, since they recovered their insulin levels. Therefore, MetfDeca could be considered not only as an insulin mimetic agent, but also as an insulin-enhancing agent. Efforts to elucidate the mechanism of action of this compound are now in progress. PMID- 27119009 TI - The Natural Polyphenol Epigallocatechin Gallate Protects Intervertebral Disc Cells from Oxidative Stress. AB - Oxidative stress-related phenotypic changes and a decline in the number of viable cells are crucial contributors to intervertebral disc degeneration. The polyphenol epigallocatechin 3-gallate (EGCG) can interfere with painful disc degeneration by reducing inflammation, catabolism, and pain. In this study, we hypothesized that EGCG furthermore protects against senescence and/or cell death, induced by oxidative stress. Sublethal and lethal oxidative stress were induced in primary human intervertebral disc cells with H2O2 (total n = 36). Under sublethal conditions, the effects of EGCG on p53-p21 activation, proliferative capacity, and accumulation of senescence-associated beta-galactosidase were tested. Further, the effects of EGCG on mitochondria depolarization and cell viability were analyzed in lethal oxidative stress. The inhibitor LY249002 was applied to investigate the PI3K/Akt pathway. EGCG inhibited accumulation of senescence-associated beta-galactosidase but did not affect the loss of proliferative capacity, suggesting that EGCG did not fully neutralize exogenous radicals. Furthermore, EGCG increased the survival of IVD cells in lethal oxidative stress via activation of prosurvival PI3K/Akt and protection of mitochondria. We demonstrated that EGCG not only inhibits inflammation but also can enhance the survival of disc cells in oxidative stress, which makes it a suitable candidate for the development of novel therapies targeting disc degeneration. PMID- 27119012 TI - Studies using IPS cells support a possible link between ZIKA and microcephaly. AB - There is a suspected link between Brazilian babies born with microcephaly and Zika virus (ZIKV) infection. However, little is know about the brain cell targets and the mechanisms that Zika virus may cause microcephaly. A recent report demonstrated that Zika virus infection increases cell death and dysregulates cell cycle, resulting in attenuated human neural progenitor cells growth. This study fills a major gap and serves as an entry point to establish a mechanistic link between Zika infection and microcephaly. PMID- 27119011 TI - Lower Serum Caveolin-1 Is Associated with Cerebral Microbleeds in Patients with Acute Ischemic Stroke. AB - Caveolin-1 (Cav-1) plays pivotal roles in the endothelial damage following stroke. The present study aimed to investigate whether serum Cav-1 level is associated with the presence of cerebral small vessel disease (cSVD) in patients with acute ischemic stroke. To this end, 156 patients were consecutively enrolled. Cranial magnetic resonance imaging was analyzed to determine the surrogates of cSVD, including cerebral microbleeds (CMBs), silent lacunar infarcts (SLIs), and white matter hyperintensities (WMHs). After adjusting for potential confounders, patients with low Cav-1 level had a higher risk of CMBs than patients with high Cav-1 level (OR: 4.05, 95% CI: 1.77-9.30). However, there was no relationship between Cav-1 and the presence of SLIs or WMHs. When CMBs were stratified by location and number, a similar association was found in patients with deep or infratentorial CMBs (OR: 4.04, 95% CI: 1.59-10.25) and with multiple CMBs (OR: 3.18, 95% CI: 1.16-8.72). These results suggest lower serum Cav-1 levels may be associated with CMBs, especially those that are multiple and located in deep brain or infratentorial structures, in patients with acute ischemic stroke. Cav-1 may be involved in the pathophysiology of CMBs, and may act as a potential target for treating cSVD. PMID- 27119010 TI - Metabolic Syndrome Augments the Risk of Early Neurological Deterioration in Acute Ischemic Stroke Patients Independent of Inflammatory Mediators: A Hospital-Based Prospective Study. AB - BACKGROUND AND AIMS: Metabolic syndrome (MetS) has been associated with occurrence and prognosis of ischemic stroke. This study aimed to evaluate whether an association exists between MetS and early neurological deterioration (END) following acute ischemic stroke and the possible role inflammatory biomarkers play. METHODS AND RESULTS: . We conducted a prospective cohort investigation that involved 208 stroke patients within 48 hours from symptom onset. MetS was determined by the modified National Cholesterol Education Program/Adult Treatment Panel III criteria. END was defined as an increase of ?1 point in motor power or ?2 points in the total National Institutes of Health Stroke Scale (NIHSS) score within 7 days. Univariate logistic regression analysis showed that patients with MetS had a 125% increased risk of END (OR 2.25; 95% CI 1.71-4.86, P = 0.005). After adjustment for fibrinogen and high-sensitivity C-reactive protein, MetS remained significantly correlated to END (OR 2.20; 95% CI 1.10-4.04, P = 0.026) with a 77% elevated risk per additional MetS trait (OR 1.77; 95% CI 1.23-2.58, P = 0.002). CONCLUSIONS: . This study demonstrated that MetS may be a potential predictor for END after ischemic stroke, which was independent of raised inflammatory mediators. PMID- 27119013 TI - Predicting, preventing, and identifying delirium after cardiac surgery. AB - Delirium after cardiac surgery is a major problem. The exact mechanisms behind delirium are not understood. Potential pathways of delirium include neurotransmitter interference, global cognitive disorder, and neuroinflammation. Several predisposing and precipitating risk factors have been identified for postoperative delirium. The development of delirium following cardiac surgery is associated with worse outcomes in the perioperative period. Multiple interventions are being explored for the prevention and treatment of delirium. Studies investigating the potential roles of biomarkers in delirium as well as pharmacological interventions to reduce the incidence and duration of delirium are necessary to mitigate this negative outcome. PMID- 27119014 TI - Occurrence of retained placenta is preceded by an inflammatory state and alterations of energy metabolism in transition dairy cows. AB - BACKGROUND: Failure to expel fetal membranes within 24 h of calving is a pathological condition defined as retained placenta (RP). The objective of this investigation was to evaluate whether there are alterations in several selected serum variables related to innate immunity and carbohydrate and lipid metabolism that precede occurrence of RP in transition Holstein dairy cows. METHODS: One hundred multiparous Holstein dairy cows were involved in the study. Blood samples were collected from the coccygeal vein during the -8 to +4 wks around parturition, once per week before the morning feeding. Six healthy control cows (CON) and 6 cows with RP were selected and serum samples at -8, -4, time of diagnosis of disease, and +4 wks relative to parturition were used for analyses. All samples were analyzed for lactate, non-esterified fatty acids (NEFA), beta hydroxybutyrate (BHBA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA). RESULTS: Cows with RP had greater concentrations of serum lactate, IL-1, IL-6, TNF, and SAA in comparison with CON cows. Intriguingly, elevated concentrations of all five variables were observed at -8 and -4 wks before the occurrence of RP compared to healthy cows. Cows with RP also had lower DMI and milk production vs CON animals; however milk composition was not affected by RP. CONCLUSIONS: Cows with RP showed an activated innate immunity 8 wks prior to diagnosis of disease. Overall results suggest that serum IL-1, IL- 6, and TNF, and lactate can be used as screening biomarkers to indicate cows that might have health issues during the transition period. PMID- 27119015 TI - Muscle strength differences in healthy young adults with and without generalized joint hypermobility: a cross-sectional study. AB - BACKGROUND: Generalized joint hypermobility (GJH), in the absence of symptoms, is a common clinical finding. The joint instability present due to excessive musculoskeletal flexibility in hypermobile joints impairs the external force production during muscle contraction. However, whether GJH is associated with muscle weakness is unclear. This study evaluated differences in upper and lower limb muscle strengths among asymptomatic young adults with and without GJH. METHODS: One hundred six young adults (53 hypermobile, i.e. 25 male (mean age 22 +/- 1.8); 28 female (mean age 21 +/- 1.8), and 53 non-hypermobile, i.e. 25 male (mean age 19 +/- 1.06); 28 female (mean age 20 +/- 1.4) were selected using a cut off >= 4 on Beighton and Horan Joint Mobility Index. Isometric strength of elbow and knee extensors was measured using an isokinetic dynamometer. Independent sample t- tests were done to compare the muscle strengths of hypermobile and non hypermobile participants. One-way ANCOVA was applied to control the effect of height and body mass on muscle strength. RESULTS: Male hypermobile participants had significantly less strength than non-hypermobile males in the right (71.7 Nm, SD = 23.1, vs 97.6 Nm, SD = 47.4, p = 0.006*) and left (74.8 Nm, SD = 24.3, vs 97.7 Nm, SD = 45.5, p = 0.007*) elbow extensors and right knee extensors (188.7 Nm, SD = 83.3, vs 228.3 Nm, SD = 106.7, p = 0.03*). In females, both elbow extensors (right: 51.9 Nm, SD = 16.2 vs 48.8 Nm, SD = 17.8, p = 0.4; left: 48.9 Nm, SD = 17.2, vs 44.7 Nm, SD = 15.1, p = 0.2) and knee extensors (right: 161.3 Nm, SD = 74.9 vs 145.5 Nm, SD = 75.8, p = 0.3; left: 155.2 Nm, SD = 73 vs 124.3 Nm, SD = 69.6, p = 0.07) strength were not statistically different between hypermobile and non-hypermobile participants. CONCLUSION: The findings indicate that male participants with GJH have less isometric muscle strength in both elbow extensors and right knee extensors compared to non-hypermobile male participants. Female hypermobile participants did not show any significant differences in muscle strength compared to non-hypermobile female participants. PMID- 27119016 TI - Reduction in new-onset diabetes mellitus after renal transplant with erythropoietin-stimulating agents: a retrospective cohort study. AB - BACKGROUND: Studies have shown that erythropoietin-stimulating agents (ESAs) protect mice against the development of diabetes through direct effects on pancreatic beta cells. However, the effect of ESAs on the incidence of diabetes in humans has not been well studied. It is unknown whether exposure to ESAs is associated with a reduced incidence of new-onset diabetes after transplant (NODAT). OBJECTIVE: The objective of this study is to examine the relationship between ESA exposure post-renal transplant and the development of NODAT. DESIGN: We performed a single center, retrospective cohort analysis. PATIENTS: We compared patients who received a first live or deceased donor renal allograft, with any exposure to an ESA vs. those without such exposure and who developed NODAT and who did not. Patients with a prior history of diabetes mellitus or multi-organ transplant, including a second renal transplant were excluded. MEASUREMENTS AND METHODS: NODAT was defined based on the 2008 Canadian Diabetes Association criteria. Multivariate logistic regression analysis was performed to determine factors independently associated with NODAT. RESULTS: One hundred thirty-two (29 %) patients were exposed to an ESA, four of which developed NODAT compared to 128 who did not develop NODAT (p < 0.0001). Of those not exposed to an ESA, 15 % (48/319) developed NODAT. By Fisher's exact test, exposure to an ESA at any time post-transplant reduced the risk of developing NODAT; odds ratio (OR) = 0.08, 95 % confidence interval (CI) (0.018-0.352), p = 0.0008. Older age; OR = 1.41, 95 % CI (1.036-1.933), p < 0.02, higher random blood sugar at discharge; OR = 1.30, 95 % CI (1.077-1.57), p < 0.006 and deceased donor; OR 2.18 CI (1.009 4.729), p = 0.04 were associated with an increased risk of NODAT. LIMITATIONS: The limitations of this study include its retrospective nature, single center, and homogenous population; thus, generalizability of the results must be approached with caution. CONCLUSION: ESA exposure may be associated with a reduced incidence of NODAT in the post-renal transplant population. The role of ESA in preventing NODAT requires further investigation. PMID- 27119017 TI - Population genetic structure analysis and effect of inbreeding on body weights at different ages in Iranian Mehraban sheep. AB - The objective of this study was to describe the population structure and inbreeding, and to quantify their effects on weights at different ages of Mehraban sheep in Iran. The analysis was based on the pedigree information of 26990 animals and 10278 body weight records from birth to yearling age. Data and pedigree information were collected during 1994 to 2011 by the breeding station of Mehraban sheep. The population structure was analyzed using the CFC program. Inbreeding of all animals was calculated by INBUPGF90 program. All animals were grouped into three classes according to their inbreeding coefficients: the first class included non-inbred animals (F=0); and the second and third classes included inbred animals (0=0.05, respectively). The average inbreeding in Mehraban sheep was 1.69%. Founder equivalent (fe) values were estimated to be 4244, 3116 and 2965 during 1994-1999, 2000-2005 and 2006-2011, respectively. The effective population sizes (Ne) were 363, 5080 and 5740 during 1994-1999, 2000-2005 and 2006-2011, respectively. Generation interval was 2.15 years for this breed of sheep. Regression coefficients of birth weight, 3-month weight, 6-month weight and yearling weight on lamb inbreeding were estimated to be -6.34+/-0.69, -14.68+/-5.33, 48.00+/-9.43 and 98.65+/-15.65, respectively. Both positive and negative inbreeding effects were found in the current study. The utilization of a program for designed mating system, in the present flock, could be a suitable approach to keep the level of inbreeding under control. PMID- 27119018 TI - Accuracy of Intraocular Lens Power Calculation Formulas for Highly Myopic Eyes. AB - Purpose. To evaluate and compare the accuracy of different intraocular lens (IOL) power calculation formulas for eyes with an axial length (AL) greater than 26.00 mm. Methods. This study reviewed 407 eyes of 219 patients with AL longer than 26.0 mm. The refractive prediction errors of IOL power calculation formulas (SRK/T, Haigis, Holladay, Hoffer Q, and Barrett Universal II) using User Group for Laser Interference Biometry (ULIB) constants were evaluated and compared. Results. One hundred seventy-one eyes were enrolled. The Barrett Universal II formula had the lowest mean absolute error (MAE) and SRK/T and Haigis had similar MAE, and the statistical highest MAE were seen with the Holladay and Hoffer Q formulas. The interquartile range of the Barrett Universal II formula was also the lowest among all the formulas. The Barrett Universal II formulas yielded the highest percentage of eyes within +/-1.0 D and +/-0.5 D of the target refraction in this study (97.24% and 79.56%, resp.). Conclusions. Barrett Universal II formula produced the lowest predictive error and the least variable predictive error compared with the SRK/T, Haigis, Holladay, and Hoffer Q formulas. For high myopic eyes, the Barrett Universal II formula may be a more suitable choice. PMID- 27119019 TI - A Comparison of Clinical Outcomes of Dislocated Intraocular Lens Fixation between In Situ Refixation and Conventional Exchange Technique Combined with Vitrectomy. AB - Purpose. To evaluate surgical efficacy of in situ refixation technique for dislocated posterior chamber intraocular lens (PCIOL). Methods. This was a single center retrospective case series. 34 patients (34 eyes) who underwent sclera fixation for dislocated IOLs combined with vitrectomy were studied. Of 34 eyes, 17 eyes underwent IOL exchange and the other 17 eyes underwent in situ refixation. Results. Mean follow-up period was 6 months. Mean logMAR best corrected visual acuity (BCVA) was not significantly different between the groups 6 months after surgery (0.10 +/- 0.03 in the IOL exchange group and 0.10 +/- 0.05 in the refixation group; p = 0.065). Surgically induced astigmatism (SIA) was significantly lower in the refixation group (0.79 +/- 0.41) than in the IOL exchange group (1.29 +/- 0.46) (p = 0.004) at 3 months, which persisted to 6 months (1.13 +/- 0.18 in the IOL exchange group and 0.74 +/- 0.11 in the refixation group; p = 0.006). Postoperative complications occurred in 3 eyes in the IOL exchange group (17.6%) and 2 eyes in the refixation group (11.8%). However, all of the patients were well managed without additional surgery. Conclusion. The in situ refixation technique should be preferentially considered if surgery is indicated since it seemed to produce a sustained less SIA compared to IOL exchange. PMID- 27119020 TI - Chronic Neck Pain and Cervico-Craniofacial Pain Patients Express Similar Levels of Neck Pain-Related Disability, Pain Catastrophizing, and Cervical Range of Motion. AB - Background. Neck pain (NP) is strongly associated with cervico-craniofacial pain (CCFP). The primary aim of the present study was to compare the neck pain-related disability, pain catastrophizing, and cervical and mandibular ROM between patients with chronic mechanical NP and patients with CCFP, as well as asymptomatic subjects. Methods. A total of 64 participants formed three groups. All participants underwent a clinical examination evaluating the cervical range of motion and maximum mouth opening, neck disability index (NDI), and psychological factor of Pain Catastrophizing Scale (PCS). Results. There were no statistically significant differences between patients with NP and CCFP for NDI and PCS (P > 0.05). One- way ANOVA revealed significant differences for all ROM measurements. The post hoc analysis showed no statistically significant differences in cervical extension and rotation between the two patient groups (P > 0.05). The Pearson correlation analysis shows a moderate positive association between NDI and the PCS for the group of patients with NP and CCFP. Conclusion. The CCFP and NP patient groups have similar neck disability levels and limitation in cervical ROM in extension and rotation. Both groups had positively correlated the NDI with the PCS. PMID- 27119021 TI - Pain Predicts Function One Year Later: A Comparison across Pain Measures in a Rheumatoid Arthritis Sample. AB - Background. Guidance is limited on best measures and time periods to reference when measuring pain in order to predict future function. Objective. To examine how different measures of pain predict functional limitations a year later in a sample of rheumatoid arthritis patients. Methods. Logistic regression analyses were conducted using baseline and one-year data (n = 262). Pain intensity in the last 24 hours was measured on a 0-10 numerical rating scale and in the last month using an item from the Arthritis Impact Measurement Scale 2 (AIMS2). AIMS2 also provided frequency of severe pain, pain composite scores, and patient-reported limitations. Physician-rated function was also examined. Results. Composite AIMS2 pain scale performed best, predicting every functional outcome with the greatest magnitude, a one-point increase in pain score predicting 21% increased odds of limitations (combined patient and physician report). However, its constituent item-frequency of severe pain in the last month-performed nearly as well (19% increased odds). Pain intensity measures in last month and last 24 hours yielded inconsistent findings. Conclusion. Although all measures of pain predicted some functional limitations, predictive consistency varied by measure. Frequency of severe pain in the last month provided a good balance of brevity and predictive power. PMID- 27119022 TI - ct-DNA Binding and Antibacterial Activity of Octahedral Titanium (IV) Heteroleptic (Benzoylacetone and Hydroxamic Acids) Complexes. AB - Five structurally related titanium (IV) heteroleptic complexes, [TiCl2(bzac)(L(1 4))] and [TiCl3(bzac)(HL(5))]; bzac = benzoylacetonate; L(1-5) = benzohydroximate (L(1)), salicylhydroximate (L(2)), acetohydroximate (L(3)), hydroxyurea (L(4)), and N-benzoyl-N-phenyl hydroxylamine (L(5)), were used for the assessment of their antibacterial activities against ten pathogenic bacterial strains. The titanium (IV) complexes (1-5) demonstrated significant level of antibacterial properties as measured using agar well diffusion method. UV-Vis absorption spectroscopic technique was applied, to get a better insight into the nature of binding between titanium (IV) complexes with calf thymus DNA (ct-DNA). On the basis of the results of UV-Vis absorption spectroscopy, the interaction between ct-DNA and the titanium (IV) complexes is likely to occur through the same mode. Results indicated that titanium (IV) complex can bind to calf thymus DNA (ct-DNA) via an intercalative mode. The intrinsic binding constant (K b ) was calculated by absorption spectra by using Benesi-Hildebrand equation. Further, Gibbs free energy was also calculated for all the complexes. PMID- 27119023 TI - From Synthesis to Biological Impact of Pd (II) Complexes: Synthesis, Characterization, and Antimicrobial and Scavenging Activity. AB - The Pd (II) complexes with a series of halosubstituted benzylamine ligands (BLs) have been synthesized and characterized with different spectroscopic technique such as FTIR, UV/Vis, LCMS, (1)H, and (13)C NMR. Their molecular sustainability in different solvents such as DMSO, DMSO : H2O, and DMSO : PBS at physiological condition (pH 7.2) was determined by UV/Vis spectrophotometer. The in vitro antibacterial and antifungal activities of the complexes were investigated against Gram-positive and Gram-negative microbes and two different fungi indicated their significant biological potential. Additionally, their antioxidant activity has been analyzed with DPPH(*) free radical through spectrophotometric method and the result inferred them as an antioxidant. The stronger antibacterial and antioxidant activities of the synthesized complexes suggested them as a stronger antimicrobial agent. Our study advances the biological importance of palladium (II) amine complexes in the field of antimicrobial and antioxidant activities. PMID- 27119024 TI - Reducing Time to First on Scene: An Ambulance-Community First Responder Scheme. AB - The importance of early access to prehospital care has been demonstrated in many medical emergencies. This work aims to describe the potential time benefit of implementing a student Community First Responder scheme to support ambulance services in an inner-city setting in the United Kingdom. Twenty final and penultimate year medical students in the UK were trained in the "First Person on Scene" Business and Technology Education Council (BTEC) qualification. Over 12 months, they attended 89 emergency calls in an inner-city setting as Community First Responders (CFRs), alongside the West Midlands Ambulance Service, UK. At the end of this period, a qualitative survey investigated the perceived educational value of the scheme. The mean CFR response time across all calls was an average of 3 minutes and 8 seconds less than ambulance crew response times. The largest difference was to calls relating to falls (12 min). The difference varied throughout the day, peaking between 16:00 and 18:00. All questionnaire respondents stated that they felt more prepared in assessing and treating acutely unwell patients. In this paper, the authors present a symbiotic solution which has both reduced time to first on scene and provided training and experience in medical emergencies for senior medical students. PMID- 27119025 TI - Evaluation of Quality and Readability of Health Information Websites Identified through India's Major Search Engines. AB - Background. The available health information on websites should be reliable and accurate in order to make informed decisions by community. This study was done to assess the quality and readability of health information websites on World Wide Web in India. Methods. This cross-sectional study was carried out in June 2014. The key words "Health" and "Information" were used on search engines "Google" and "Yahoo." Out of 50 websites (25 from each search engines), after exclusion, 32 websites were evaluated. LIDA tool was used to assess the quality whereas the readability was assessed using Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), and SMOG. Results. Forty percent of websites (n = 13) were sponsored by government. Health On the Net Code of Conduct (HONcode) certification was present on 50% (n = 16) of websites. The mean LIDA score (74.31) was average. Only 3 websites scored high on LIDA score. Only five had readability scores at recommended sixth-grade level. Conclusion. Most health information websites had average quality especially in terms of usability and reliability and were written at high readability levels. Efforts are needed to develop the health information websites which can help general population in informed decision making. PMID- 27119026 TI - Sleep Spindles as Facilitators of Memory Formation and Learning. AB - Over the past decades important progress has been made in understanding the mechanisms of sleep spindle generation. At the same time a physiological role of sleep spindles is starting to be revealed. Behavioural studies in humans and animals have found significant correlations between the recall performance in different learning tasks and the amount of sleep spindles in the intervening sleep. Concomitant neurophysiological experiments showed a close relationship between sleep spindles and other sleep related EEG rhythms as well as a relationship between sleep spindles and synaptic plasticity. Together, there is growing evidence from several disciplines in neuroscience for a participation of sleep spindles in memory formation and learning. PMID- 27119027 TI - Neural Plasticity and Neurogenesis in Mental Disorders. PMID- 27119028 TI - The Case of the Disappearing Spindle Burst. AB - Sleep spindles are brief cortical oscillations at 10-15 Hz that occur predominantly during non-REM (quiet) sleep in adult mammals and are thought to contribute to learning and memory. Spindle bursts are phenomenologically similar to sleep spindles, but they occur predominantly in early infancy and are triggered by peripheral sensory activity (e.g., by retinal waves); accordingly, spindle bursts are thought to organize neural networks in the developing brain and establish functional links with the sensory periphery. Whereas the spontaneous retinal waves that trigger spindle bursts in visual cortex are a transient feature of early development, the myoclonic twitches that drive spindle bursts in sensorimotor cortex persist into adulthood. Moreover, twitches-and their associated spindle bursts-occur exclusively during REM (active) sleep. Curiously, despite the persistence of twitching into adulthood, twitch-related spindle bursts have not been reported in adult sensorimotor cortex. This raises the question of whether such spindle burst activity does not occur in adulthood or, alternatively, occurs but has yet to be discovered. If twitch-related spindle bursts do occur in adults, they could contribute to the calibration, maintenance, and repair of sensorimotor systems. PMID- 27119029 TI - Solid Right Ventricular Compression by Intraventricular Septum-Hematoma Induced after Percutaneous Coronary Intervention. AB - Intraventricular septum-hematoma is a rare complication following percutaneous coronary intervention (PCI). This complication may represent a challenge for accurate diagnosis and treatment. This case report is about a 60-year-old male patient being admitted with an acute coronary syndrome. Despite successful PCI with drug eluting stent implantation into the right coronary artery (RCA) the patient complained about recurrent angina pectoris according to Canadian Cardiovascular Society (CCS) class IV. Cardiac magnetic resonance imaging and transthoracic echocardiography revealed a massive 4.9 * 9.2 cm sized end diastolic septum-hematoma, which compromised right ventricular cavity. Emergent recoronary angiography ruled out further contrast extravasation from the RCA. Conservative treatment was intended after discussion in the "heart-team." The patient completely recovered with nearly complete resolution of the hematoma after 6 months. PMID- 27119030 TI - Synthetic Marijuana Induced Acute Nonischemic Left Ventricular Dysfunction. AB - Synthetic marijuana is an uptrending designer drug currently widely spread in the US. We report a case of acute deterioration of nonischemic left ventricular dysfunction after exposure to synthetic marijuana. This case illustrates the importance of history taking in cardiac patients and identifies a negative cardiovascular effect of synthetic marijuana known as K2, not yet well detected by urine toxicology screening tools. PMID- 27119031 TI - Aesthetic Surgical Approach for Bone Dehiscence Treatment by Means of Single Implant and Interdental Tissue Regeneration: A Case Report with Five Years of Follow-Up. AB - The replacement of single anterior teeth by means of endosseous implants implies the achievement of success in restoring both aesthetic and function. However, the presence of wide endoperiodontal lesions can lead to horizontal hard and soft tissues defects after tooth extraction, making it impossible to correctly place an implant in the compromised alveolar socket. Vertical augmentation procedures have been proposed to solve these clinical situations, but the amount of new regenerated bone is still not predictable. Furthermore, bone augmentation can be complicated by the presence of adjacent teeth, especially if they bring with them periodontal defects. Therefore, it is used to restore periodontal health of adjacent teeth before making any augmentation procedures and to wait a certain healing period before placing an implant in vertically augmented sites, otherwise risking to obtain a nonsatisfactory aesthetic result. All of these procedures, however, lead to an expansion of treatment time which should affect patient compliance. For this reason, this case report suggests a surgical technique to perform vertical bone augmentation at a single gap left by a central upper incisor while placing an implant and simultaneously to regenerate the periodontal attachment of an adjacent lateral incisor, without compromising the aesthetic result. PMID- 27119032 TI - Pneumomediastinum following Crystal Use: A Report of Two Cases. AB - Crystal is a synthetic substance with an increasing rate of abuse. It may cause patients to present to the emergency department because of its acute complications. We depict two cases of pneumomediastinum following inhalation of crystal. Both cases had used crystal for recreational purposes. In one case, a young man presenting to the ED with the retrosternal chest pain and neck pain was diagnosed to have pneumomediastinum and pneumopericardium. The other patient presenting with dyspnea and chest pain was shown to have collection of air within mediastinum. Both patients underwent a series of diagnostic evaluations and, after a course of observation, were discharged without a surgical intervention. Patients with chest pain following inhalation of crystal may suffer from this complication. PMID- 27119033 TI - Extra-Adrenal Myelolipoma Containing Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia: A Case Report and Review of the Literature. AB - Myelolipoma is a benign tumor consisting of mature fat interspersed with hematopoietic elements resembling bone marrow. The vast majority occurs within the adrenal glands, but several cases of extra-adrenal myelolipomas (EAMLs) have been reported. We report a case of a 64-year-old male who presented with complaint of lower abdominal discomfort. CT scan of abdomen and pelvis showed a 6 cm * 5 cm, well-circumscribed, predominantly fatty mass in the presacral region. Histological examination of the pelvic mass revealed a myelolipoma heavily infiltrated by small lymphoid cell aggregates with immunophenotypic features of small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). Review of the literature revealed that there is only one published report of SLL/CLL involving a myelolipoma, which was also an extra-adrenal myelolipoma, and, therefore, our case is the second case of a SLL/CLL involving a myelolipoma that is an extra adrenal myelolipoma. Extra-adrenal myelolipomas seem to the preferred myelolipomas for involvement by SLL/CLL. PMID- 27119034 TI - Spontaneous Knee Ankylosis through Heterotopic Ossification after Total Knee Arthroplasty. AB - This paper reports on a case of total ankylosis of the knee after a cruciate sacrificing cemented total knee arthroplasty (TKA). An 82-year-old female patient previously underwent primary TKA for osteoarthritis twenty years ago in our institution. She had recovered uneventfully and returned to her regular activities. There was no history of postsurgical trauma; however, she progressively lost knee range of motion. Radiographs revealed severe bridging heterotopic ossification. PMID- 27119035 TI - A Case of Nonunion Avulsion Fracture of the Anterior Tibial Eminence. AB - Avulsion fracture of the anterior tibial eminence is an uncommon injury. If bone union does not occur, knee extension will be limited by impingement of the avulsed fragment and knee instability will be induced by dysfunction of the anterior cruciate ligament (ACL). This report describes a 55-year-old woman who experienced an avulsion fracture of the right anterior tibial eminence during recreational skiing. Sixteen months later, she presented at our hospital with limitation of right knee extension. Plain radiography showed nonunion of the avulsion fracture region, and arthroscopy showed that the avulsed fragment impinged the femoral intercondylar notch during knee extension. The anterior region of the bony fragment was debrided arthroscopically until the knee could be extended completely. There was no subsequent instability, and the patient was able to climb a mountain 6 months after surgery. These findings indicate that arthroscopic debridement of an avulsed fragment for nonunion of an avulsion fracture of the anterior tibial eminence is a minimally invasive and effective treatment for middle-aged and elderly patients with a low level of sports activity. PMID- 27119036 TI - Thyroglossal Duct Papillary Thyroid Carcinoma and Synchronous Lingual Thyroid Atypia. AB - Thyroglossal duct and lingual thyroid ectopic lesions are exceedingly rare synchronous findings. Papillary thyroid carcinoma of these ectopic thyroid sites is well understood but still a rare finding. This case points to some management nuances in regard to ectopic thyroid screening with imaging and also shows the effectiveness of minimally invasive transoral robotic surgery for lingual thyroid. PMID- 27119037 TI - Fever, Myositis, and Paralysis: Is This Inflammatory Myopathy or Neuroinvasive Disease? AB - West Nile virus (WNV) is a mosquito-borne RNA Flavivirus which emerged in North America in 1999. Most patients present with a febrile illness but a few develop WNV neuroinvasive disease. Myopathy is an uncommon manifestation. We describe a case of a 42-year-old male from Los Angeles who presented with 8 days of fever and muscle pain. Initial physical exam was normal except for 4/5 muscle strength testing in his extremity proximal muscles. Laboratory revealed a creatine kinase of 45,000 and a urinalysis with large blood but no red blood cells, suggesting rhabdomyolysis. The patient's condition declined despite aggressive supportive care and hydration, and on hospital day #6 he developed severe altered mental status and progressed to complete right arm paralysis and 2/5 muscle strength in bilateral legs. EMG/NCS showed sensorimotor axonal polyneuropathy and the cerebrospinal fluid was positive for IgM and IgG WNV antibodies. The patient was diagnosed with WNV neuroinvasive disease, poliomyelitis (and encephalitis) type with myopathy/muscle involvement. He was treated supportively and his muscle and neurologic disease gradually improved. At 12-month follow-up his muscle enzymes had normalized and his weakness had improved to 5/5 strength in bilateral legs and 3/5 strength in the right arm. PMID- 27119038 TI - Do the Hydatid Cysts Have Unusual Localization and Dissemination Ways in the Chest Cavity? AB - We wanted to report our two cases of intrathoracic extrapulmonary hydatid cyst in pleural cavity due to its rarity. Our first case is a 24-year-old male patient who was admitted with a cystic mass lesion consistent with hydatid cyst which was incidentally detected in inferior lobe of the right lung neighboring to thoracic wall and diaphragm. Our second case is a 32-year-old male patient who was admitted with chest pain and a cystic lesion in apex of the right hemithorax and intercostal field in basal after he had been medically treated due to hydatid cyst of the dome of the liver for two years. The cysts were removed with thoracotomy. Extrapulmonary intrathoracic hydatid cysts were evaluated with regard to invasion ways and treatment indications and methods. PMID- 27119039 TI - Transurethral Unroofing of a Symptomatic Imperforate Cowper's Syringocele in an Adult Male. AB - Cystic dilatation of bulbourethral gland ducts (Cowper's gland syringocele) is a rare abnormality. The condition has been described among pediatric populations, but it is uncommon in adults. It can be asymptomatic or present with obstructive and irritative urinary symptoms. We report a case of a symptomatic imperforate Cowper's syringocele in a young patient that was successfully managed with transurethral unroofing of the cyst. PMID- 27119041 TI - Electrochemical Determination of Metronidazole in Tablet Samples Using Carbon Paste Electrode. AB - Cyclic voltammetric investigation of metronidazole at carbon paste electrode revealed an irreversible reduction peak centered at about -0.4 V. Observed peak potential shift with pH in the range 2.0 to 8.5 indicated the involvement of protons during the reduction of metronidazole, whereas the peak potential shift with scan rate in the range 10-250 mV/s confirmed the irreversibility of the reduction reaction. A better correlation coefficient for the dependence of peak current on the scan rate than on the square root of scan rate indicated an adsorption controlled kinetics. Under the optimized method and solution parameters, an excellent linearity between the reductive peak current and the concentration of metronidazole was observed in the concentration range 1.0 * 10( 6) to 5.0 * 10(-4) M with a correlation coefficient, method detection limit (based on s = 3sigma), and limit of quantification of 0.999, 2.97 * 10(-7) M and 9.91 * 10(-7) M, respectively. Good recovery results for spiked metronidazole in tablet samples and selective determination of metronidazole in tablet formulations in the presence of selected potential interferents such as rabeprazole, omeprazole, and tinidazole confirmed the potential applicability of the developed method for the determination of metronidazole in real samples like pharmaceutical tablets. PMID- 27119040 TI - Dually Diagnosed Patients with Arrests for Violent and Nonviolent Offenses: Two Year Treatment Outcomes. AB - The purpose of this study was to examine the history of arrests among dually diagnosed patients entering treatment, compare groups with different histories on use of treatment and mutual-help groups and functioning, at intake to treatment and six-month, one-year, and two-year follow-ups, and examine correlates and predictors of legal functioning at the study endpoint. At treatment intake, 9.2% of patients had no arrest history, 56.3% had been arrested for nonviolent offenses only, and 34.5% had been arrested for violent offenses. At baseline, the violent group had used the most outpatient psychiatric treatment and reported poorer functioning (psychiatric, alcohol, drug, employment, and family/social). Both arrest groups had used more inpatient/residential treatment and had more mutual-help group participation than the no-arrest group. The arrest groups had higher likelihood of substance use disorder treatment or mutual-help group participation at follow-ups. Generally, all groups were comparable on functioning at follow-ups (with baseline functioning controlled). With baseline arrest status controlled, earlier predictors of more severe legal problems at the two-year follow-up were more severe psychological, family/social, and drug problems. Findings suggest that dually diagnosed patients with a history of arrests for violent offenses may achieve comparable treatment outcomes to those of patients with milder criminal histories. PMID- 27119042 TI - A Novel Ratiometric Probe Based on Nitrogen-Doped Carbon Dots and Rhodamine B Isothiocyanate for Detection of Fe(3+) in Aqueous Solution. AB - A ratiometric probe for determining ferric ions (Fe(3+)) was developed based on nitrogen-doped carbon dots (CDs) and rhodamine B isothiocyanate (RhB), which was then applied to selective detection of Fe(3+) in PB buffer solution, lake water, and tap water. In the sensing system, FePO4 particles deposit on the surface of CDs, resulting in larger particles and surface passivation. The fluorescence (FL) intensity and the light scattering (LS) intensity of CDs can be gradually enhanced with the addition of Fe(3+), while the FL intensity of RhB remains constant. The ratiometric light intensity of CDs LS and RhB FL was quantitatively in response to Fe(3+) concentrations in a dynamic range of 0.01-1.2 MUM, with a detection limit as low as 6 nM. Other metal ions, such as Fe(2+), Al(3+), K(+), Ca(2+), and Co(2+), had no significant interference on the determination of Fe(3+). Compared with traditional probes based on single-signal probe for Fe(3+) detection, this dual-signal-based ratiometric probe exhibits a more reliable and stable response on target concentration and is characterized by easy operation in a simple fluorescence spectrophotometer. PMID- 27119043 TI - Investigation and Management of Adnexal Masses in Pregnancy. AB - Adnexal masses can be found in 0.19 to 8.8% of all pregnancies. Most masses are functional and asymptomatic and up to 70% resolve spontaneously in the second trimester. The main predictors of persistence are the size (>5 cm) and the imagiological morphocomplexity. Those that persist carry a low risk of malignancy (0 to 10%). Most malignant masses are diagnosed at early stages and more than 50% are borderline epithelial neoplasms. Ultrasound is the preferred method to stratify the risk of complications and malignancy, allowing medical approach planning. Pregnancy and some gestational disorders may modify the levels of tumor markers, whereby their interpretation during pregnancy should be cautious. Large masses are at increased risk of torsion, rupture, and dystocia. When surgery is indicated, laparoscopy is a safe technique and should ideally be carried out in the second trimester of pregnancy. PMID- 27119044 TI - Reduced Pelvic Floor Muscle Tone Predisposes to Persistence of Lower Urinary Tract Symptoms after Puerperium. AB - Pregnant primiparous women at term were enrolled in the study. ICIQ-FLUTS questionnaire was used to find out prevalence of LUTS. MOS was used to assess pelvic floor muscle strength. Women were followed up after 8-10 weeks of delivery to find out remission or persistence of these symptoms. We found that increased frequency of micturition was the most common (82%) LUTS seen in primiparous women at term. More than half (51%) of these women who complained of LUTS had a poor pelvic floor muscle tone (MOS grade 3). Out of those who had symptoms during pregnancy 11% remained symptomatic even after puerperium. Interestingly 61% of those with persistence of symptoms demonstrated a very poor pelvic floor muscle tone at term (MOS grade 2), while the remaining 39% also had a tone of only MOS grade 3. Thus women with LUTS during pregnancy should be screened for their pelvic floor muscle tone with simple MOS system which will help to predict the persistence of these symptoms later on. Women with a low score (three or less) should be triaged for regular pelvic floor muscle exercises. PMID- 27119046 TI - Review on the Eyedrop Self-Instillation Techniques and Factors Affecting These Techniques in Glaucoma Patients. AB - Objective. This study aims to evaluate eyedrop self-installation techniques and factors affecting these techniques in glaucoma patients. Methods. Researchers directly observed eyedrop instillation procedures of 66 glaucoma patients. Contact with periocular tissues and instillation onto ocular surface or conjunctival fornices were considered. Correlations of instillation patterns with patient characteristics including age, gender, intraocular pressure, cup-to-disc ratio, visual field loss, and total intake of glaucoma medication and handgrip strength score were searched. Results. The average handgrip strength in the instillation without periocular contact group was 66.4 +/- 19.7 kg, while the average handgrip strength score was 55.9 +/- 20.9 kg in the instillation with contact group. The difference between the two groups was statistically significant (p = 0.039). No statistically significant correlation was found between handgrip strength and the mean number of glaucoma medications, c/d, intraocular pressure (p > 0.05). Also there was no significant relation between mean handgrip strength score and the severity of the visual field defect (p = 0.191). Conclusion. Patients especially with severe glaucomatous damage should be adequately instructed about the proper techniques for self-instillation of eyedrops and motivated to use a proper technique. Also, it is possible to suggest that patients with a higher handgrip strength, indicating the well-being of general health, may be doing better in properly instilling glaucoma eyedrops. PMID- 27119047 TI - Does Body Mass Index in Pregnant Women Affect Laboratory Parameters in the Newborn? AB - Objective The objective of this study was to determine the effect of body mass index (BMI) during pregnancy in laboratory parameters in the serum of the three groups of pregnant women and in their newborns. Methods This prospective study is comparison between the three groups of pregnant women and their newborns categorized according to their BMI. The study included 128 pregnant women and their newborns. In this study, the concentration of blood count, iron, ferritin, and bilirubin were analyzed in the subjects. Results The pregnant women in the three groups significantly differ in the values of blood count (p < 0.001). Statistically significant difference in iron and ferritin was not found between individual three studied groups of pregnant women (p = 0.947). The newborn of the first group of pregnant women had significantly lower values of ferritin (p < 0.001), leucocytes (p < 0.001), and bilirubin (p < 0.001). Significant positive correlation between BMI of pregnant women and leucocytes, ferritin, and bilirubin of the newborn was found (p < 0.001). Conclusion In this study, the tested pregnant women do not have biochemical signs of anemia, neither do their newborns. It was noted that there was no negative correlation between individual tested biochemical parameters for anemia in pregnant women and their newborns. PMID- 27119045 TI - DNA Methylation and Chromatin Remodeling: The Blueprint of Cancer Epigenetics. AB - Epigenetics deals with the interactions between genes and the immediate cellular environment. These interactions go a long way in shaping up each and every person's individuality. Further, reversibility of epigenetic interactions may offer a dynamic control over the expression of various critical genes. Thus, tweaking the epigenetic machinery may help cause or cure diseases, especially cancer. Therefore, cancer epigenetics, especially at a molecular level, needs to be scrutinised closely, as it could potentially serve as the future pharmaceutical goldmine against neoplastic diseases. However, in view of its rapidly enlarging scope of application, it has become difficult to keep abreast of scientific information coming out of various epigenetic studies directed against cancer. Using this review, we have attempted to shed light on two of the most important mechanisms implicated in cancer, that is, DNA (deoxyribonucleic acid) methylation and histone modifications, and their place in cancer pathogenesis. Further, we have attempted to take stock of the new epigenetic drugs that have emerged onto the market as well as those in the pipeline that offer hope in mankind's fight against cancer. PMID- 27119048 TI - Diagnosing Pulmonary Embolism in Pregnancy: Are Biomarkers and Clinical Predictive Models Useful? AB - Objective The objective of this study was to evaluate whether trimester-specific D-dimer levels or the modified Wells score (MWS) is a useful risk stratification tool to exclude pregnant women at low risk of pulmonary embolism (PE) from diagnostic imaging. Study Design This is a prospective and retrospective cohort study. Pregnant women who underwent diagnostic imaging for suspected PE were prospectively enrolled. D-dimer serum levels were drawn, and a MWS was assigned. Pregnant women diagnosed with a PE before study launch who underwent diagnostic imaging and had a D-dimer level drawn were also evaluated. Results In this study, 17 patients were diagnosed with a PE and 42 patients had no PE on diagnostic imaging. Sixteen out of 17 patients with a PE versus 11 out of 42 without PE had an abnormal D-dimer level (p = 0.001). Four patients with a PE versus zero without a PE had an abnormal MWS (p = 0.005). The combination of a trimester specific D-dimer level along with the MWS was abnormal in all 17 patients with a documented PE versus 11/42 (26.2%) patients without a documented PE (p = 0.001). Conclusion A combination of trimester-specific D-dimer levels along with a MWS can be used in pregnancy to triage women into a low-risk category for PE and thereby avoid radiation exposure in a majority of pregnant patients. PMID- 27119049 TI - The Most Cited Works in Essential Tremor and Dystonia. AB - BACKGROUND: The study of the most cited works in a particular field gives an indication of the important advances, developments, and discoveries that have had the highest impact in that discipline. Our aim was to identify the most cited works in essential tremor (ET) and dystonia. METHODS: A bibliometric search was performed using the ISI Web of Science database using selected search terms for ET and dystonia for articles published from 1900 to 2015. The resulting citation counts were analyzed to identify the most cited works, and the studies were categorized. RESULTS: Using the criterion of more than 400 citations, there were four citation classics for ET and six for dystonia. The most cited studies were those on pathophysiology followed by medical treatments, clinical classification, genetic studies, surgical treatments, review articles, and epidemiology studies. A comparison of the most cited articles for ET and dystonia showed that there was a divergence, with ET and dystonia having a higher number of epidemiologic and genetic studies, respectively. Whereas the peak period for the number of publications was 2000-2004 for ET, it was 1995-1999 for dystonia. DISCUSSION: Given the large number of patients with these disorders, there appears to be an unmet need for further research advances in both areas, but particularly for ET as the most common movement disorder. PMID- 27119050 TI - Threat driven modeling framework using petri nets for e-learning system. AB - Vulnerabilities at various levels are main cause of security risks in e-learning system. This paper presents a modified threat driven modeling framework, to identify the threats after risk assessment which requires mitigation and how to mitigate those threats. To model those threat mitigations aspects oriented stochastic petri nets are used. This paper included security metrics based on vulnerabilities present in e-learning system. The Common Vulnerability Scoring System designed to provide a normalized method for rating vulnerabilities which will be used as basis in metric definitions and calculations. A case study has been also proposed which shows the need and feasibility of using aspect oriented stochastic petri net models for threat modeling which improves reliability, consistency and robustness of the e-learning system. PMID- 27119051 TI - Dynamics of almost periodic Schoener's competition model with time delays and impulses. AB - In real world, the ecological systems are usually perturbed by human exploitation activities such as planting and harvesting and so on. In order to obtain a more accurate description for such phenomenon, the impulsive differential equations play an important role. This paper is concerned with a kind of almost periodic Schoener's competition model with pure-delays and impulsive effects. By using the comparison theorem and the Lyapunov functional method of the impulsive differential equations, some sufficient conditions are obtained for the persistence and existence of a unique uniformly asymptotically stable positive almost periodic solution in a class of impulsive Schoener's competition model with pure-delays. The main results in this paper improve some results in recent years. And the method used in this paper provides a possible and effective method to study the permanence and existence of a unique uniformly asymptotically stable positive almost periodic solution of the models with impulsive perturbations in biological populations. Finally, an example and numerical simulations are given to illustrate the feasibility and effectiveness of our main results. PMID- 27119052 TI - Transformer fault diagnosis using continuous sparse autoencoder. AB - This paper proposes a novel continuous sparse autoencoder (CSAE) which can be used in unsupervised feature learning. The CSAE adds Gaussian stochastic unit into activation function to extract features of nonlinear data. In this paper, CSAE is applied to solve the problem of transformer fault recognition. Firstly, based on dissolved gas analysis method, IEC three ratios are calculated by the concentrations of dissolved gases. Then IEC three ratios data is normalized to reduce data singularity and improve training speed. Secondly, deep belief network is established by two layers of CSAE and one layer of back propagation (BP) network. Thirdly, CSAE is adopted to unsupervised training and getting features. Then BP network is used for supervised training and getting transformer fault. Finally, the experimental data from IEC TC 10 dataset aims to illustrate the effectiveness of the presented approach. Comparative experiments clearly show that CSAE can extract features from the original data, and achieve a superior correct differentiation rate on transformer fault diagnosis. PMID- 27119053 TI - A pertinent approach to solve nonlinear fuzzy integro-differential equations. AB - Fuzzy integro-differential equations is one of the important parts of fuzzy analysis theory that holds theoretical as well as applicable values in analytical dynamics and so an appropriate computational algorithm to solve them is in essence. In this article, we use parametric forms of fuzzy numbers and suggest an applicable approach for solving nonlinear fuzzy integro-differential equations using homotopy perturbation method. A clear and detailed description of the proposed method is provided. Our main objective is to illustrate that the construction of appropriate convex homotopy in a proper way leads to highly accurate solutions with less computational work. The efficiency of the approximation technique is expressed via stability and convergence analysis so as to guarantee the efficiency and performance of the methodology. Numerical examples are demonstrated to verify the convergence and it reveals the validity of the presented numerical technique. Numerical results are tabulated and examined by comparing the obtained approximate solutions with the known exact solutions. Graphical representations of the exact and acquired approximate fuzzy solutions clarify the accuracy of the approach. PMID- 27119054 TI - Vertebral body fractures of unknown origin in cancer patients receiving MDCT: reporting by radiologists and awareness by clinicians. AB - BACKGROUND: To evaluate prevalence, radiological reporting and clinical management of pathologic vertebral body fractures (VBFs) of unknown origin in cancer patients receiving computed tomography (CT) examinations. METHODS: We investigated all CT examinations (over 1 year) of male and female patients with an underlying malignancy and an increased risk of osteoporosis (age 55-79 years) for the presence of VBFs. We evaluated midline sagittal CT-reformations of the spine for prevalence, fracture type, severity and location, the accuracy and style of radiological reporting, subsequent clinical management and documentation in hospital discharge letters. RESULTS: 848 patients were investigated. We found 143 VBFs in 94 (11 %) patients. 6, 49, and 45 % were grade 1, grade 2, and grade 3 fractures, respectively, while 20, 66, and 14 % were wedge, biconcave and crush fractures, respectively. 32 (34 %) radiological reports correctly classified VBFs as fractures, 25 (27 %) reports recognized VBFs, but did not type them, and VBFs were not described in 37 (39 %) reports. In 3 (3 %) patients further clinical work-up of VBFs was performed, while only 8 (9 %) hospital discharge letters contained the information of the presence of pathologic VBFs of unknown origin. CONCLUSIONS: VBFs of unknown origin appear frequently in cancer patients, however, clinical management and documentation was found in only few cases. Moreover, especially in cancer patients consistent radiological reporting of VBFs seems important, as aetiology of VBFs could be from osteoporosis, disease progression or oncological therapy, however, reporting is still performed inconsistently. PMID- 27119055 TI - Differences in technology innovation R&D performance creation behavior between for-profit institutions and not-for-profit institutions. AB - The present study compares the performance creation behavior between for-profit institutions and not-for-profit institutions within a national technology innovation research and development (R&D) program. Based on the stepwise performance creation chain structure of typical R&D logic models, a series of successive binary logistic regression models is newly proposed. Using the models, a sample of n = 2076 completed government-sponsored R&D projects was analyzed. For each institution type, its distinctive behavior is diagnosed, and relevant implications are suggested for improving the R&D performance. PMID- 27119056 TI - Vertical transmission and reproduction rate: modeling a common strategy for two related diseases. AB - Motivated by (Goyal and Murray in PLoS One 9(10):e110143, 2014) we consider a partially age-structured model simulating the dynamic of two infectious diseases vertically transmitted almost independently with horizontal coinfection and a common age-structured vaccination strategy. We study influence of parameters on existence and uniqueness of solutions and epidemiological equilibria. Impact of vertical transmission on basic reproduction rate is also presented. PMID- 27119057 TI - Surface disinfection procedure and in vitro regeneration of grapevine (Vitis vinifera L.) axillary buds. AB - Establishment of an efficient explants surface disinfection protocol is essential for in vitro cell and tissue culture as well as germplasm conservation, such as the case of Grapevine (Vitis spp.) culture. In this research, different procedures for disinfection and regeneration of field-grown grapevine cv. 'Flame seedless' axillary buds were evaluated. The buds were disinfected using either NaOCl or allyl, benzyl, phenyl and 2-phenylethyl isothiocyanates. Two different media for shooting and four media for rooting were tested. Shoot and root development per buds were registered. The best disinfection procedure with 90 % of tissue survival involved shaking for 60 min in a solution containing 20 % Clorox with 50 drops/L Triton((r)) X-100. These tissues showed the potential to regenerate a complete plant. Plant regeneration was conducted using full strength Murashigue and Skoog (MS) medium supplemented with 8 uM benzyl aminopurine for shoot induction and multiplication, whereas rooting was obtained on half strength MS supplemented with 2 mg L(-1) of indole-3-butyric acid and 200 mg L(-1) of activated charcoal. In this work, it was designed the protocols for obtaining sterile field-grown grapevine buds and in vitro plant development. This methodology showed potential to produce vigorous and healthy plants in 5 weeks for clonal grapevine propagation. Regenerated plants were successfully established in soil. PMID- 27119058 TI - Identification of IgE-binding peptide and critical amino acids of Jatropha curcas allergen involved in allergenic response. AB - Increasing energy demand has spurred interest in the use of biofuels. Jatropha curcas (physic nut), an inedible oilseed, is a potential source of bioenergy. The seeds, however, contain allergens such as Jat c 1, a 2S albumin that can induce hypersensitivity reactions in humans and result in allergic diseases. Recent advances in identifying and characterizing plant allergens and, in particular, their immunoglobulin E (IgE)-binding epitopes have produced a wealth of information. We identified IgE-binding regions and the critical amino acids involved in the degranulation of mast cells and the release of histamine, preliminary steps for the prevention and treatment of this allergy. Four IgE binding regions were identified in the sequence of Jat c 1. We identified and demonstrated the fundamental role of two glutamic acid residues in IgE binding. The sequence LEKQLEEGEVGS produces a random loop on the most exposed part of Jat c 1. This region is important to the stimulation of the allergic response. The possibility of using this information to produce vaccines and other pharmacological agents for allergy treatment is discussed. PMID- 27119059 TI - On a bivariate spectral relaxation method for unsteady magneto-hydrodynamic flow in porous media. AB - The paper presents a significant improvement to the implementation of the spectral relaxation method (SRM) for solving nonlinear partial differential equations that arise in the modelling of fluid flow problems. Previously the SRM utilized the spectral method to discretize derivatives in space and finite differences to discretize in time. In this work we seek to improve the performance of the SRM by applying the spectral method to discretize derivatives in both space and time variables. The new approach combines the relaxation scheme of the SRM, bivariate Lagrange interpolation as well as the Chebyshev spectral collocation method. The technique is tested on a system of four nonlinear partial differential equations that model unsteady three-dimensional magneto-hydrodynamic flow and mass transfer in a porous medium. Computed solutions are compared with previously published results obtained using the SRM, the spectral quasilinearization method and the Keller-box method. There is clear evidence that the new approach produces results that as good as, if not better than published results determined using the other methods. The main advantage of the new approach is that it offers better accuracy on coarser grids which significantly improves the computational speed of the method. The technique also leads to faster convergence to the required solution. PMID- 27119060 TI - An analytical coupled technique for solving nonlinear large-amplitude oscillation of a conservative system with inertia and static non-linearity. AB - Based on a new trial function, an analytical coupled technique (a combination of homotopy perturbation method and variational method) is presented to obtain the approximate frequencies and the corresponding periodic solutions of the free vibration of a conservative oscillator having inertia and static non-linearities. In some of the previous articles, the first and second-order approximations have been determined by the same method of such nonlinear oscillator, but the trial functions have not been satisfied the initial conditions. It seemed to be a big shortcoming of those articles. The new trial function of this paper overcomes aforementioned limitation. The first-order approximation is mainly considered in this paper. The main advantage of this present paper is, the first-order approximation gives better result than other existing second-order harmonic balance methods. The present method is valid for large amplitudes of oscillation. The absolute relative error measures (first-order approximate frequency) in this paper is 0.00 % for large amplitude A = 1000, while the relative error gives two different second-order harmonic balance methods: 10.33 and 3.72 %. Thus the present method is suitable for solving the above-mentioned nonlinear oscillator. PMID- 27119061 TI - Use of polyurea from urea for coating of urea granules. AB - A new type of controlled release fertilizers coated with polyurea was prepared. The granulated urea was firstly changed into a liquid urea by heating as the coating liquid. By spraying uniformly the urea was coated with the polyurea synthesized by the reaction of isocyanates with a liquid urea. The effects of different modifiers on N release characteristics of polyurea-coated urea (PCU) were studied. The morphology and chemical structure of PCU coating materials was investigated by SEM and FTIR. We studied the nitrogen release characteristics of the PCU applied in both water and soil, and the biodegradability of PCU coating after buried in soil. The results showed that PCU reduced nitrogen release rate and exhibited excellent controlled release property. The PCU coating materials could biodegrade in soil. This indicated that the low cost PCU products from urea are expected to use in agricultural and horticultural applications. PMID- 27119063 TI - Oscillation of certain higher-order neutral partial functional differential equations. AB - In this paper, we study the oscillation of certain higher-order neutral partial functional differential equations with the Robin boundary conditions. Some oscillation criteria are established. Two examples are given to illustrate the main results in the end of this paper. PMID- 27119062 TI - Prevalence in running events and running performance of endurance runners following a vegetarian or vegan diet compared to non-vegetarian endurance runners: the NURMI Study. AB - BACKGROUND: Beneficial and detrimental effects of various vegetarian and vegan diets on the health status are well known. Considering the growing background numbers of vegetarians and vegans, the number of vegetarian and vegan runners is likely to rise, too. Therefore, the Nutrition and Running High Mileage (NURMI) Study was designed as a comparative study to investigate the prevalence of omnivores, vegetarians, and vegans in running events and to detect potential differences in running performance comparing these three subgroups. METHODS/DESIGN: The NURMI Study will be conducted in three steps following a cross-sectional design. Step 1 will determine epidemiological aspects of endurance runners (any distance) using a short standardized questionnaire. Step 2 will investigate dietary habits and running history from eligible participants (capable of running a half-marathon at least) using an extended standardized questionnaire. Step 3 will collect data after a running event on finishing time and final ranking as well as a post-race rating of perceived exertion, mood status, nutrient and fluid intake during the race. DISCUSSION: Our study will provide a major contribution to overcome the lack of data on the prevalence and running performance of vegetarian and vegan runners in endurance running events. We estimate the prevalence of vegetarians and vegans participating in a running event to be less compared to the respective proportion of vegetarians and vegans to the general population. Furthermore we will validate the subject's self assessment of their respective diet. This comparative study may identify possible effects of dietary behavior on running performance und may detect possible differences between the respective subgroups: omnivorous, vegetarian and vegan runners. Trial registration Current controlled trials, ISRCTN73074080. PMID- 27119064 TI - A novel Bronsted-Lewis acidic heteropoly organic-inorganic salt: preparation and catalysis for rosin dimerization. AB - A novel Bronsted-Lewis acidic heteropoly organic-inorganic salt has been prepared via the replacement of protons in neat phosphotungstic acid with both organic and metal cations. This hybrid catalyst, Sm0.33[TEAPS]2PW12O40, exhibited satisfactory performance in the dimerization of rosin to prepare polymerized rosin Under optimum conditions (15.0 g rosin and 5.0 g Sm0.33[TEAPS]2PW12O40 catalyst in 18.0 mL toluene at 90 degrees C for 10 h), a polymerized rosin product with a softening point of 120.1 degrees C was obtained. In addition, the Sm0.33[TEAPS]2PW12O40 catalyst maintains excellent catalytic performance over five recycles. PMID- 27119065 TI - Dynamics of a modified Leslie-Gower predator-prey model with Holling-type II schemes and a prey refuge. AB - We propose a modified Leslie-Gower predator-prey model with Holling-type II schemes and a prey refuge. The structure of equilibria and their linearized stability is investigated. By using the iterative technique and further precise analysis, sufficient conditions on the global attractivity of a positive equilibrium are obtained. Our results not only supplement but also improve some existing ones. Numerical simulations show the feasibility of our results. PMID- 27119066 TI - Impact of preoperative ultrasonography findings on the patency rate of vascular access in Japanese hemodialysis patients. AB - BACKGROUND: Although ultrasonography before a vascular access (VA) operation has become popular in recent years, benchmarks for the diameter or blood flow of arteries or veins are not defined in Japan. The objective of the present study is to analyze the relationship between preoperative US findings and the patency rate of VA in Japanese hemodialysis patients. METHODS: 139 patients with end stage kidney disease were enrolled in this study. They had been given primary radiocephalic arteriovenous fistula (AVF) from February 2009 to December 2010 at the Juntendo University Hospital and were followed up over 2 years. We defined the interval from the time of AVF creation until first access thrombosis or any intervention to maintain or restore blood flow as patency time (primary patency). We examined the correlation between the 2-year primary patency rate of VA and the diameter of the radial artery (RA), brachial artery (BA), or cephalic vein at an anastomosis presumptive region by US, the blood flow of RA or BA, as measured by US, age, gender, and primary kidney diseases. RESULTS: The average patency term was 448.6 +/- 271.3 days, with the 1-year and 2-year patency rate as 64.0 and 51.2 %, respectively. The patency rate was significantly lower in elderly patients over the age of 75 and in patients with diabetes mellitus. US findings of 2.0 mm or less in the RA diameter also resulted in a noticeably low patency rate. A multivariate analysis indicated that those factors were risk factors for early VA failure. CONCLUSIONS: Preoperative US findings of the diameter of RA may involve the patency rate of VA, making it appears that an RA of 2.0 mm or more in diameter at an anastomosis region may be more effective for the improvement in the patency rate of VA. PMID- 27119067 TI - Does pain relate with activation of quadriceps and hamstrings muscles during strengthening exercise in people with knee osteoarthritis? AB - Muscle strengthening may be difficult to achieve in knee osteoarthritis (OA) due to pain. A large knee adduction moment (KAM), representing medial relative to lateral knee load, may also relate with pain during strengthening exercise. The objective of this study was to examine relationships between knee pain status and electromyography (EMG) amplitude of knee muscles during squat and lunge exercises. We also evaluated relationships between pain and KAM during these exercises. Forty-two women with symptomatic knee OA participated. Knee pain intensity and frequency were captured with two reliable and valid questionnaires. Motion analyses of squat and lunge exercises were completed. Total average EMG amplitude across five muscles of the lower limb and average KAM were calculated from the static portion of these exercises. Multiple regression analyses examined the relationships between pain and total average EMG amplitude; and pain and average KAM during squats and lunges. Pain improved the model for KAM from the trailing leg of a lunge. Pain did not improve any other model. Overall, pain may not be a useful indicator of EMG amplitude or KAM during exercise in knee OA. PMID- 27119069 TI - Rainfall erosivity index for the Ghana Atomic Energy Commission site. AB - Rainfall erosivity is the potential ability for rainfall to cause soil loss. The purpose of this study was to estimate the rainfall erosivity index for the Ghana Atomic Energy Commission site in order to compute the surface erosion rate. Monthly rainfall data, for the period 2003-2012 were used to compute annual rainfall erosivity indices for the site, using the Modified Fournier index. Values of the annual rainfall erosivity indices ranged from 73.5 mm for 2004 to 200.4 mm for the year 2003 with a mean annual erosivity index of 129.8 mm for the period. The Pearson's Coefficient of Correlation was used to establish the relationship between annual rainfall and annual rainfall erosivity. This showed a high degree of positive relationship (r = 0.7) for the study area. The computed mean annual erosivity index revealed that the site is in the high erosion risk zone. Therefore, it is necessary to develop soil protection and management strategies to protect the soil from erosion. PMID- 27119068 TI - Incidence and prevalence of Vibrio parahaemolyticus in seafood: a systematic review and meta-analysis. AB - Vibrio parahaemolyticus is an important seafood borne human pathogen worldwide due to it occurrence, prevalence and ability to cause gastrointestinal infections. This current study aim at investigating the incidence and prevalence of V. parahaemolyticus in seafood using systematic review-meta-analysis by exploring heterogeneity among primary studies. A comprehensive systematic review and meta-analysis of peer reviewed primary studies reported between 2003 and 2015 for the occurrence and prevalence of V. parahaemolyticus in seafood was conducted using "isolation", "detection", "prevalence", "incidence", "occurrence" or "enumeration" and V. parahaemolyticus as search algorithms in Web of Science (Science Direct) and ProQuest of electronic bibliographic databases. Data extracted from the primary studies were then analyzed with fixed effect meta analysis model for effect rate to explore heterogeneity between the primary studies. Publication bias was evaluated using funnel plot. A total of 10,819 articles were retrieved from the data bases of which 48 studies met inclusion criteria. V. parahaemolyticus could only be isolated from 2761 (47.5 %) samples of 5811 seafood investigated. The result of this study shows that incidence of V. parahaemolyticus was more prevalent in oysters with overall prevalence rate of 63.4 % (95 % CI 0.592-0.674) than other seafood. Overall prevalence rate of clams was 52.9 % (95 % CI 0.490-0.568); fish 51.0 % (95 % CI 0.476-0.544); shrimps 48.3 % (95 % CI 0.454-0.512) and mussels, scallop and periwinkle: 28.0 % (95 % CI 0.255-0.307). High heterogeneity (p value <0.001; I (2) = 95.291) was observed mussel compared to oysters (I (2) = 91.024). It could be observed from this study that oysters harbor V. parahaemolyticus based on the prevalence rate than other seafood investigated. The occurrence and prevalence of V. parahaemolyticus is of public health importance, hence, more studies involving seafood such as mussels need to be investigated. PMID- 27119070 TI - Pathogenic bacteria profile and antimicrobial susceptibility patterns of ear infection at Bahir Dar Regional Health Research Laboratory Center, Ethiopia. AB - Ear infection linked with frequent antibiotic prescription, hearing impairment, severe disability and death is a public health threat in developing countries. However, there is scarcity of documented data in the study area. Therefore, this study aimed at determining bacterial etiologic agents and their antimicrobial susceptibility patterns among patients of all age groups referred to Bahir Dar Regional Health Research Laboratory Center. Retrospective data recorded on culture and antimicrobial susceptibility profile were retrieved for analysis. Pus swabs from discharging ears collected and processed for aerobic bacteria culture and susceptibility testing. Of the total 368 pus swab samples processed, 296 (80.4 %) were culture positive. Of which, 289 (97.6 %) were bacteria and 7 (2.4 %) were yeast cells. The proportion of ear infection was higher in males (92.7 %) than females (65 %) (P = 0.014). The frequency of ear infection below 21 years of age was 65.2 %. The predominant isolate was Pseudomonas aeruginosa (29.7 %) followed by Staphylococcus aureus (26.3 %) and Proteus spp. (21.9 %). High level of antimicrobial resistance rates were observed for amoxicillin/clavulanic acid, ampicillin and penicillin whereas ciprofloxacin, ceftriaxone, chloramphenicol, cotrimoxazole, gentamicin and amikacin were found effective against the isolated bacteria. Aerobic bacterial otitis media linked with high levels of resistance against amoxicillin/clavulanic acid and ampicillin is major health problem in the study area. Moreover, considerable level of oxacillin resistant S. aureus suggests the diffusion of methicillin resistant S. aureus in the community. Therefore, treatment of otitis media in the study area needs to be guided by antibiotic susceptibility testing of isolates. PMID- 27119071 TI - Potential biomarkers for esophageal cancer. AB - Esophageal cancer, which consist of esophageal adenocarcinoma and esophageal squamous cell carcinoma, is one of the most common malignant tumors in the world, especially in the south of Iran and China. To find and investigate the biomarkers in the initiation, development and progression of esophageal cancer will help us predict the prognosis of esophageal cancer patients and improve the curative effect and survival rate. Here, we reviewed the potential biomarkers of esophageal cancer in three aspects: Immunohistochemical markers, blood-based markers, miRNA markers and Gene expression profiling. All these biomarkers provided promising therapeutic targets for the diagnosis, treatment, and prognosis of esophageal cancer. PMID- 27119072 TI - Antifungal activity of the piroctone olamine in experimental intra-abdominal candidiasis. AB - This work aimed to evaluate the antifungal activity of piroctone olamine in the treatment of intra-abdominal candidiasis in an experimental model using Swiss mice. The mice (n = 6) were infected by intraperitoneal injection of 0.2 ml of C. albicans (10(7)cells/ml in saline). The animals were observed daily for clinical signs and mortality for 14 days. The treatment with piroctone olamine (0.5 mg/kg) was performed 72 h after infection by intraperitoneal administration. For comparison, a group of animals (n = 6) was treated with amphotericin B (0.5 mg/kg). The mycological diagnosis was made by collecting the liver, spleen and kidneys. Data regarding the fungal growth and mortality were analyzed statistically by Student's t test and analysis of variance (ANOVA), with level of significance set at P < 0.05. The difference in fungal growth scoring between the control group and the treatment groups (piroctone olamine and amphotericin B) was statistically significant (P < 0.05). The difference in fungal growth scoring between the treatment groups (piroctone olamine and amphotericin B) was not statistically significant (P < 0.05). PMID- 27119073 TI - Heavy metals phyto-assessment in commonly grown vegetables: water spinach (I. aquatica) and okra (A. esculentus). AB - The growth response, metal tolerance and phytoaccumulation properties of water spinach (Ipomoea aquatica) and okra (Abelmoschus esculentus) were assessed under different contaminated spiked metals: control, 50 mg Pb/kg soil, 50 mg Zn/kg soil and 50 mg Cu/kg soil. The availability of Pb, Zn and Cu metals in both soil and plants were detected using flame atomic absorption spectrometry. The concentration and accumulation of heavy metals from soil to roots and shoots (edible parts) were evaluated in terms of translocation factor, accumulation factor and tolerance index. Okra recorded the highest accumulation of Pb (80.20 mg/kg) in its root followed by Zn in roots (35.70 mg/kg) and shoots (34.80 mg/kg) of water spinach, respectively. Different accumulation trends were observed with, Pb > Zn > Cu in okra and Zn > Pb > Cu in water spinach. Significant differences (p < 0.01) of Pb, Zn and Cu accumulation were found in both water spinach and okra cultivated among tested treatments. However, only the accumulation of Pb metal in the shoots of water spinach and okra exceeded the maximum permissible levels of the national Malaysian Food Act 1983 and Food Regulations 1985 (2006) as well as the international Codex Alimentarius Commission limits. This study has shown that both water spinach and okra have good potential as Pb and Zn phytoremediators. PMID- 27119074 TI - Effects of Laminaria japonica polysaccharides on exercise endurance and oxidative stress in forced swimming mouse model. AB - BACKGROUND: Polysaccharides are the major active ingredients responsible for the bioactivities of Laminaria japonica. However, the effects of L. japonica polysaccharides (LJP) on exercise endurance and oxidative stress have never been investigated. Therefore, this study was conducted to investigate the effects of LJP on exercise endurance and oxidative stress in a forced swimming mouse model. The animals were divided into four groups, namely the control (C), LJP-75, LJP 150, and LJP-300 groups, which received physiological saline and 75, 150, and 300 mg kg(-1) LJP, respectively, by gavage once a day for 28 days. This was followed by a forced swimming test and measurements of various biochemical parameters. RESULTS: LJP increased swimming time to exhaustion, the liver and muscle glycogen content, and levels of superoxide dismutase, glutathione peroxidase, and catalase in the serum, liver, and muscle, which were accompanied by corresponding decreases in the malondialdehyde (MDA) content of the same tissues. Furthermore, decreases in blood lactic acid and serum myeloperoxidase (MPO) levels were observed. CONCLUSION: LJP enhanced exercise endurance and protected mice against exhaustive exercise-induced oxidative stress. PMID- 27119075 TI - Co-culturing bacteria and microalgae in organic carbon containing medium. AB - BACKGROUND: Microalgae frequently grow in natural environment and long-term laboratory cultures in association with bacteria. Bacteria benefit the oxygen and extracellular substances generated by microalgae, and reimburse microalgae with carbon dioxide, vitamins and so on. Such synergistic relationship has aided in establishing an efficient microalga-bacterium co-culturing mode. Obviously, the mutually beneficial relationship can be strengthened with the increase of the densities of microalgae and bacteria. However, nearly all of the early co cultures were performed under photoautotrophic conditions, thus both microalgae and bacteria were at relatively low densities. In this study, the feasibility of bacteria-microalgae co-cultured under mixotrophic conditions was studied. RESULTS: Firstly, bacteria mingled with xenic microalgae were isolated and identified based on their 16S rRNA gene sequence (16S rDNA hereafter). Then, the two most frequently found strains of Muricauda sp. were co-cultured with axenic microalga (Tetraselmis chuii, Cylindrotheca fusiformis and Nannochloropsis gaditana) in extra organic carbon containing medium. At the end of a co-culture period of 33 days, we found that the final cell density of T. chuii and C. fusiformis of various treatments was remarkably higher than that of controls (21.37-31.18 and 65.42-83.47 %, respectively); on the contrary, the growth of N. gaditana was markedly inhibited. During the co-culture of bacteria with C. fusiformis, the cell density of two strains of bacteria firstly decreased, then increased and maintained at a relatively steady level. However, the cell density of bacteria performed a sustaining downward trend when they were co-cultured with T. chuii and N. gaditana. CONCLUSIONS: Our findings proved that microalgae bacteria co-cultures under mixotrophic conditions are quite effective strategy for microalgal cultivation. PMID- 27119076 TI - Acceptability and Feasibility of Sexually Transmitted Infection Testing and Treatment among Pregnant Women in Gaborone, Botswana, 2015. AB - INTRODUCTION: Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) are curable sexually transmitted infections (STIs) that can cause adverse maternal and birth outcomes. Most countries do not conduct routine testing during antenatal care. We present data on the acceptability and feasibility of testing and treating pregnant women for STIs in an antenatal clinic in Gaborone, Botswana. MATERIALS AND METHODS: We offered CT, NG, and TV testing using self-collected vaginal swabs to eligible pregnant women. Participants received same-day test results. Those who tested positive were given treatment. RESULTS: Among the 225 women who were eligible and recruited, 200 (89%) agreed to participate. The median age of our study sample was 30 years; most were unmarried (77%), with a median gestational age of 27 weeks and a 23% HIV prevalence. All participants received their results with at least 72% (n = 143) on the same day. Thirty participants (15%) tested positive for an STI, all were treated, and 24 (80%) were treated on the same day. CONCLUSION: The acceptability of STI testing was high, and the intervention was feasible. This study provides support for continued research into STI prevalence, cost effectiveness, and the association of STIs with adverse maternal and infant outcomes. PMID- 27119077 TI - Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype. AB - Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-kappaB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies. PMID- 27119079 TI - Positive Selection and Centrality in the Yeast and Fly Protein-Protein Interaction Networks. AB - Proteins within a molecular network are expected to be subject to different selective pressures depending on their relative hierarchical positions. However, it is not obvious what genes within a network should be more likely to evolve under positive selection. On one hand, only mutations at genes with a relatively high degree of control over adaptive phenotypes (such as those encoding highly connected proteins) are expected to be "seen" by natural selection. On the other hand, a high degree of pleiotropy at these genes is expected to hinder adaptation. Previous analyses of the human protein-protein interaction network have shown that genes under long-term, recurrent positive selection (as inferred from interspecific comparisons) tend to act at the periphery of the network. It is unknown, however, whether these trends apply to other organisms. Here, we show that long-term positive selection has preferentially targeted the periphery of the yeast interactome. Conversely, in flies, genes under positive selection encode significantly more connected and central proteins. These observations are not due to covariation of genes' adaptability and centrality with confounding factors. Therefore, the distribution of proteins encoded by genes under recurrent positive selection across protein-protein interaction networks varies from one species to another. PMID- 27119078 TI - Ocular Complications of Diabetes and Therapeutic Approaches. AB - Diabetes mellitus (DM) is a metabolic disease defined by elevated blood glucose (BG). DM is a global epidemic and the prevalence is anticipated to continue to increase. The ocular complications of DM negatively impact the quality of life and carry an extremely high economic burden. While systemic control of BG can slow the ocular complications they cannot stop them, especially if clinical symptoms are already present. With the advances in biodegradable polymers, implantable ocular devices can slowly release medication to stop, and in some cases reverse, diabetic complications in the eye. In this review we discuss the ocular complications associated with DM, the treatments available with a focus on localized treatments, and what promising treatments are on the horizon. PMID- 27119080 TI - Apical External Root Resorption and Repair in Orthodontic Tooth Movement: Biological Events. AB - Some degree of external root resorption is a frequent, unpredictable, and unavoidable consequence of orthodontic tooth movement mediated by odontoclasts/cementoclasts originating from circulating precursor cells in the periodontal ligament. Its pathogenesis involves mechanical forces initiating complex interactions between signalling pathways activated by various biological agents. Resorption of cementum is regulated by mechanisms similar to those controlling osteoclastogenesis and bone resorption. Following root resorption there is repair by cellular cementum, but factors mediating the transition from resorption to repair are not clear. In this paper we review some of the biological events associated with orthodontically induced external root resorption. PMID- 27119081 TI - Subtractive Cell-SELEX Selection of DNA Aptamers Binding Specifically and Selectively to Hepatocellular Carcinoma Cells with High Metastatic Potential. AB - Relapse and metastasis are two key risk factors of hepatocellular carcinoma (HCC) prognosis; thus, it is emergent to develop an early and accurate detection method for prognostic evaluation of HCC after surgery. In this study, we sought to acquire oligonucleotide DNA aptamers that specifically bind to HCC cells with high metastatic potential. Two HCC cell lines derived from the same genetic background but with different metastatic potential were employed: MHCC97L (low metastatic properties) as subtractive targets and HCCLM9 (high metastatic properties) as screening targets. To mimic a fluid combining environment, initial DNA aptamers library was firstly labelled with magnetic nanoparticles using biotin-streptavidin system and then applied for aptamers selection. Through 10 round selection with subtractive Cell-SELEX, six aptamers, LY-1, LY-13, LY-46, LY 32, LY-27/45, and LY-7/43, display high affinity to HCCLM9 cells and do not bind to MHCC97L cells, as well as other tumor cell lines, including breast cancer, lung cancer, colon adenocarcinoma, gastric cancer, and cervical cancer, suggesting high specificity for HCCLM9 cells. Thus, the aptamers generated here will provide solid basis for identifying new diagnostic targets to detect HCC metastasis and also may provide valuable clues for developing new targeted therapeutics. PMID- 27119082 TI - Polyphenols from Chilean Propolis and Pinocembrin Reduce MMP-9 Gene Expression and Activity in Activated Macrophages. AB - Polyphenols from diverse sources have shown anti-inflammatory activity. In the context of atherosclerosis, macrophages play important roles including matrix metalloproteinases synthesis involved in degradation of matrix extracellular components affecting the atherosclerotic plaque stability. We prepared a propolis extract and pinocembrin in ethanol solution. Propolis extract was chemically characterized using LC-MS. The effect of treatments on gene expression and proteolytic activity was measured in vitro using murine macrophages activated with LPS. Cellular toxicity associated with both treatments and the vehicle was determined using MTT and apoptosis/necrosis detection assays. MMP-9 gene expression and proteolytic activity were measured using qPCR and zymography, respectively. Thirty-two compounds were identified in the propolis extract, including pinocembrin among its major components. Treatment with either ethanolic extract of propolis or pinocembrin inhibits MMP-9 gene expression in a dose dependent manner. Similarly, an inhibitory effect was observed in proteolytic activity. However, the effect showed by ethanolic extract of propolis was higher than the effect of pinocembrin, suggesting that MMP-9 inhibition results from a joint contribution between the components of the extract. These data suggest a potential role of polyphenols from Chilean propolis in the control of extracellular matrix degradation in atherosclerotic plaques. PMID- 27119083 TI - A Nested Case-Control Study of Association between Metabolome and Hypertension Risk. AB - We aimed to explore novel small metabolites that associated with hypertension risk in a population-based nested case-control study. Among 460 individuals with optimal blood pressure (<120/80 mmHg) at baseline, 55 progressed to hypertension during 5 years of follow-up. Twenty-nine cases of incident hypertension and 29 controls, matched for age, sex, and baseline systolic blood pressure, were included in this study. Serum metabolites were measured by gas chromatography tandem mass spectrometry. t-test and logistic regression analysis were applied to investigate the association between metabolites and incident hypertension. Among the 241 metabolites identified in this study, baseline levels of 26 metabolites were significantly different between hypertension and control groups. After adjusting for body mass index, smoking, and drinking, 16 out of the 26 metabolites were still associated with hypertension risk including four amino acids. Amino acids were negatively associated with risk of future hypertension, with odds ratio (OR) ranging from 0.33 to 0.53. Two of these amino acids were essential amino acids including threonine and phenylalanine. Higher level of lyxose, a fermentation product of gut microbes, was associated with higher risk of hypertension. Our study identified multiple metabolites that associated with hypertension risk. These findings implied that low amino acid levels and gut microbiome might play an important role in the pathogenesis of hypertension. PMID- 27119085 TI - Leishmania infantum Genetic Diversity and Lutzomyia longipalpis Mitochondrial Haplotypes in Brazil. AB - Leishmania infantum is the etiological agent of visceral leishmaniasis (VL) in the Americas with domestic dogs being its major reservoir hosts. The main VL vector is the sandfly Lutzomyia longipalpis, while other Lutzomyia species may play a role in disease transmission. Although the genetic structure of L. infantum populations has been widely evaluated, only a few studies have addressed this subject coupled to the genetic structure of the respective sandfly vectors. In this study, we analyzed the population structure of L. infantum in three major VL endemic areas in Brazil and associated it with Lutzomyia longipalpis geographic structure. PMID- 27119086 TI - Ocular Comorbidities and the Relationship between Eye Diseases and Systemic Disorders. PMID- 27119084 TI - Next Generation Sequencing Identifies Five Major Classes of Potentially Therapeutic Enzymes Secreted by Lucilia sericata Medical Maggots. AB - Lucilia sericata larvae are used as an alternative treatment for recalcitrant and chronic wounds. Their excretions/secretions contain molecules that facilitate tissue debridement, disinfect, or accelerate wound healing and have therefore been recognized as a potential source of novel therapeutic compounds. Among the substances present in excretions/secretions various peptidase activities promoting the wound healing processes have been detected but the peptidases responsible for these activities remain mostly unidentified. To explore these enzymes we applied next generation sequencing to analyze the transcriptomes of different maggot tissues (salivary glands, gut, and crop) associated with the production of excretions/secretions and/or with digestion as well as the rest of the larval body. As a result we obtained more than 123.8 million paired-end reads, which were assembled de novo using Trinity and Oases assemblers, yielding 41,421 contigs with an N50 contig length of 2.22 kb and a total length of 67.79 Mb. BLASTp analysis against the MEROPS database identified 1729 contigs in 577 clusters encoding five peptidase classes (serine, cysteine, aspartic, threonine, and metallopeptidases), which were assigned to 26 clans, 48 families, and 185 peptidase species. The individual enzymes were differentially expressed among maggot tissues and included peptidase activities related to the therapeutic effects of maggot excretions/secretions. PMID- 27119087 TI - Risk Factors Associated with Irreversible Airway Obstruction in Asthma: A Systematic Review and Meta-Analysis. AB - Irreversible airway obstruction (IAO) is a subtype of asthma and relates to poorer prognosis in some asthma patients. However, the prevalence and risk factors for IAO are unknown. A systematic review regarding controlled clinical studies (cohort, case-control studies) on IAO asthma in adult and/or children affected by asthma/early wheeze was performed. Eighteen papers were identified in this study. It was reported that the incidence of IAO at random effects or fixed effects in severe asthma and nonsevere asthma was 0.54 (95% CI: 0.45-0.62) and 0.16 (95% CI: 0.12-0.20), respectively. In IAO asthma, the pooled odds ratio (OR) related to smoking exposure was 2.22 (95% CI: 1.82-2.73), the OR for male, smoking, and fractional exhaled nitric oxide (FENO) was 2.22 (95% CI: 1.82-2.7), 1.79 (95% CI: 1.46-2.19), and 2.16 (95% CI: 1.05-4.43), respectively, suggesting these factors increase the risk of IAO. However, a decreased OR in IAO asthma was observed due to rhinitis (OR = 0.31, 95% CI: 0.24-0.40), atopy (OR = 0.584, 95% CI: 0.466-0.732), and atopic dermatitis (OR = 0.60, 95% CI: 0.42-0.85), indicating these factors are associated with reduced risk of IAO. IAO in asthma is associated with gender, smoking, FENO, rhinitis, atopy, and atopic dermatitis. PMID- 27119089 TI - On Vertex Covering Transversal Domination Number of Regular Graphs. AB - A simple graph G = (V, E) is said to be r-regular if each vertex of G is of degree r. The vertex covering transversal domination number gamma vct(G) is the minimum cardinality among all vertex covering transversal dominating sets of G. In this paper, we analyse this parameter on different kinds of regular graphs especially for Q n and H 3,n. Also we provide an upper bound for gamma vct of a connected cubic graph of order n >= 8. Then we try to provide a more stronger relationship between gamma and gamma vct. PMID- 27119088 TI - Combined Microencapsulated Islet Transplantation and Revascularization of Aortorenal Bypass in a Diabetic Nephropathy Rat Model. AB - OBJECTIVE: Revascularization of aortorenal bypass is a preferred technique for renal artery stenosis (RAS) in diabetic nephropathy (DN) patients. Restenosis of graft vessels also should be considered in patients lacking good control of blood glucose. In this study, we explored a combined strategy to prevent the recurrence of RAS in the DN rat model. METHODS: A model of DN was established by intraperitoneal injection of streptozotocin. Rats were divided into 4 groups: SR group, MIT group, Com group, and the untreated group. The levels of blood glucose and urine protein were measured, and changes in renal pathology were observed. The expression of monocyte chemoattractant protein-1 (MCP-1) in graft vessels was assessed by immunohistochemical staining. Histopathological staining was performed to assess the pathological changes of glomeruli and tubules. RESULTS: The levels of urine protein and the expression of MCP-1 in graft vessels were decreased after islet transplantation. The injury of glomerular basement membrane and podocytes was significantly ameliorated. CONCLUSIONS: The combined strategy of revascularization and microencapsulated islet transplantation had multiple protective effects on diabetic nephropathy, including preventing atherosclerosis in the graft vessels and alleviating injury to the glomerular filtration barrier. This combined strategy may be helpful for DN patients with RAS. PMID- 27119090 TI - The Existence of Weak D-Pullback Exponential Attractor for Nonautonomous Dynamical System. AB - First, for a process {U(t, tau)?t >= tau}, we introduce a new concept, called the weak D-pullback exponential attractor, which is a family of sets {M(t)?t <= T}, for any T ? R, satisfying the following: (i) M(t) is compact, (ii) M(t) is positively invariant, that is, U(t, tau)M(tau) ? M(t), and (iii) there exist k, l > 0 such that dist(U(t, tau)B(tau), M(t)) <= ke (-(t-tau)); that is, M(t) pullback exponential attracts B(tau). Then we give a method to obtain the existence of weak D-pullback exponential attractors for a process. As an application, we obtain the existence of weak D-pullback exponential attractor for reaction diffusion equation in H 0 (1) with exponential growth of the external force. PMID- 27119091 TI - MTO: a new journal for a maturing field. PMID- 27119092 TI - Safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding CD40 ligand in laboratory Beagles. AB - We evaluated adverse events, biodistribution and shedding of oncolytic vaccinia virus encoding CD40 ligand in two Beagles, in preparation for a phase 1 trial in canine cancer patients. Dog 1 received one dose of vaccinia virus and was euthanized 24 hours afterwards, while dog 2 received virus four times once weekly and was euthanized 7 days after that. Dogs were monitored for adverse events and underwent a detailed postmortem examination. Blood, saliva, urine, feces, and organs were collected for virus detection. Dog 1 had mild fever and lethargy while dog 2 experienced a possible seizure 5.5 hours after first virus administration. Viral DNA declined quickly in the blood after virus administration in both dogs but was still detectable 1 week later by quantitative polymerase chain reaction. Only samples taken directly after virus infusion contained infectious virus. Small amounts of viral DNA, but no infectious virus, were detected in a few saliva and urine samples. Necropsies did not reveal any relevant pathological changes and virus DNA was detected mainly in the spleen. The dogs in the study did not have cancer, and thus adverse events could be more common and viral load higher in dogs with tumors which allow viral amplification. PMID- 27119093 TI - Regression of established renal cell carcinoma in nude mice using lentivirus transduced human T cells expressing a human anti-CAIX chimeric antigen receptor. AB - Carbonic anhydrase IX (CAIX) is a tumor-associated antigen and marker of hypoxia that is overexpressed on > 90% of clear-cell type renal cell carcinoma (RCC) but not on neighboring normal kidney tissue. Here, we report on the construction of two chimeric antigen receptors (CARs) that utilize a carbonic anhydrase (CA) domain mapped, human single chain antibody (scFv G36) as a targeting moiety but differ in their capacity to provide costimulatory signaling for optimal T cell proliferation and tumor cell killing. The resulting anti-CAIX CARs were expressed on human primary T cells via lentivirus transduction. CAR-transduced T cells (CART cells) expressing second-generation G36-CD28-TCRzeta exhibited more potent in vitro antitumor effects on CAIX(+) RCC cells than first-generation G36-CD8 TCRzeta including cytotoxicity, cytokine secretion, proliferation, and clonal expansion. Adoptive G36-CD28-TCRzeta CART cell therapy combined with high-dose interleukin (IL)-2 injection also lead to superior regression of established RCC in nude mice with evidence of tumor cell apoptosis and tissue necrosis. These results suggest that the fully human G36-CD28-TCRzeta CARs should provide substantial improvements over first-generation mouse anti-CAIX CARs in clinical use through reduced human anti-mouse antibody responses against the targeting scFv and administration of lower doses of T cells during CART cell therapy of CAIX(+) RCC. PMID- 27119095 TI - Reporter gene imaging identifies intratumoral infection voids as a critical barrier to systemic oncolytic virus efficacy. AB - Systemically administered oncolytic viruses have the ability to cause tumor destruction through the expansion and coalescence of intratumoral infectious centers. Efficacy is therefore dependent upon both the density and intratumoral distribution of virus-infected cells achieved after initial virus infusion, and delivery methods are being developed to enhance these critical parameters. However, the three-dimensional (3D) mapping of intratumoral infectious centers is difficult using conventional immunohistochemical methodology, requiring painstaking 3D reconstruction of numerous sequential stained tumor sections, with no ability to study the temporal evolution of spreading infection in a single animal. We therefore developed a system using very high-resolution noninvasive in vivo micro single-photon emitted computed tomography/computed tomography (microSPECT/CT) imaging to determine the intratumoral distribution of thyroid radiotracers in tumors infected with an oncolytic virus encoding the thyroidal sodium-iodide symporter (NIS). This imaging system was used for longitudinal analysis of the density, distribution, and evolution of intratumoral infectious centers after systemic administration of oncolytic vesicular stomatitis virus in tumor-bearing mice and revealed heterogeneous delivery of virus particles both within and between tumors in animals receiving identical therapy. This study provides compelling validation of high resolution in vivo reporter gene mapping as a convenient method for serial monitoring of intratumoral virus spread that will be necessary to address critical barriers to systemic oncolytic virus efficacy such as intratumoral delivery. PMID- 27119094 TI - Potentiation of immunomodulatory antibody therapy with oncolytic viruses for treatment of cancer. AB - Identification of the immune suppressive mechanisms active within the tumor microenvironment led to development of immunotherapeutic strategies aiming to reverse the immunosuppression and to enhance the function of tumor-infiltrating lymphocytes. Of those, cancer therapy with antibodies targeting the immune costimulatory and coinhibitory receptors has demonstrated significant promise in the recent years, with multiple antibodies entering clinical testing. The responses to these agents, however, have not been universal and have not been observed in all cancer types, calling for identification of appropriate predictive biomarkers and development of combinatorial strategies. Pre-existing immune infiltration in tumors has been demonstrated to have a strong association with response to immunotherapies, with the type I interferon (IFN) pathway emerging as a key player in tumor innate immune recognition and activation of adaptive immunity. These findings provide a rationale for evaluation of strategies targeting the type I IFN pathway as a means to enhance tumor immune recognition and infiltration, which could potentially make them susceptible to therapeutics targeting the cosignaling receptors. To this end in particular, oncolytic viruses (OVs) have been demonstrated to enhance tumor recognition by the immune system through multiple mechanisms, which include upregulation of major histocompatibility complex and costimulatory molecules on cancer cells, immunogenic cell death and antigen release, and activation of the type I IFN pathway. Evidence is now emerging that combination therapies using OVs and agents targeting immune cosignaling receptors such as 4-1BB, PD-1, and CTLA-4 may work in concert to enhance antitumor immunity and therapeutic efficacy. Our evolving understanding of the interplay between OVs and the immune system demonstrates that the virus-induced antitumor immune responses can be harnessed to drive the efficacy of the agents targeting cosignaling receptors and provides a strong rationale for integration of such therapies in clinic. PMID- 27119096 TI - Combinatorial treatment with oncolytic adenovirus and helper-dependent adenovirus augments adenoviral cancer gene therapy. AB - Oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Investigators have therefore incorporated sequences into these vectors that encode immunomodulatory molecules to enhance antitumor immunity. Successful implementation of this strategy requires multiple tumor immune inhibitory mechanisms to be overcome, and insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. HDAds, however, lack replicative capacity. Since HDAds encode the adenoviral packaging signal, we hypothesized that the coadministration of Onc.Ad with HDAd would allow to be amplified and packaged during replication of Onc.Ad in transduced cancer cells. This combination could provide immunostimulation without losing oncolytic activity. We now show that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy. PMID- 27119097 TI - Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy. AB - Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer. PMID- 27119098 TI - Molecular imaging of oncolytic viral therapy. AB - Oncolytic viruses have made their mark on the cancer world as a potential therapeutic option, with the possible advantages of reduced side effects and strengthened treatment efficacy due to higher tumor selectivity. Results have been so promising, that oncolytic viral treatments have now been approved for clinical trials in several countries. However, clinical studies may benefit from the ability to noninvasively and serially identify sites of viral targeting via molecular imaging in order to provide safety, efficacy, and toxicity information. Furthermore, molecular imaging of oncolytic viral therapy may provide a more sensitive and specific diagnostic technique to detect tumor origin and, more importantly, presence of metastases. Several strategies have been investigated for molecular imaging of viral replication broadly categorized into optical and deep tissue imaging, utilizing several reporter genes encoding for fluorescence proteins, conditional enzymes, and membrane protein and transporters. Various imaging methods facilitate molecular imaging, including computer tomography, magnetic resonance imaging, positron emission tomography, single photon emission CT, gamma-scintigraphy, and photoacoustic imaging. In addition, several molecular probes are used for medical imaging, which act as targeting moieties or signaling agents. This review will explore the preclinical and clinical use of in vivo molecular imaging of replication-competent oncolytic viral therapy. PMID- 27119099 TI - Antimelanoma CTL recognizes peptides derived from an ORF transcribed from the antisense strand of the 3' untranslated region of TRIT1. AB - Noncoding regions of the genome play an important role in tumorigenesis of cancer. Using expression cloning, we have identified a cytotoxic T lymphocyte (CTL)-defined antigen that recognizes a protein sequence derived from an open reading frame transcribed from the reverse strand in the 3' untranslated region of tRNA isopentenyltransferase 1 (TRIT1). A peptide derived from this open reading frame (ORF) sequence and predicted to bind to HLA-B57, sensitized HLA B57(+) tumor cells to lysis by CTL793. The peptide also induced a CTL response in peripheral blood mononuclear cells (PBMC) of patient 793 and in two other melanoma patients. The CTL lysed peptide-pulsed HLA-B57(+) target cells and melanoma cells with endogenous antigen expression. The recognition of this antigen is not limited to HLA-B57-restricted CTLs. An HLA-A2 peptide derived from the ORF was able to induce CTLs in PBMC of 2 HLA-A2(+) patients. This study describes for the first time a CTL-defined melanoma antigen that is derived from an ORF on the reverse strand of the putative tumor suppressor gene TRIT1. This antigen has potential use as a vaccine or its ability to induce CTLs in vitro could be used as a predictive biomarker. PMID- 27119100 TI - Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity. AB - Multiple studies have indicated that in addition to direct oncolysis, virotherapy promotes an antitumor cytotoxic T cell response important for efficacy. To study this phenomenon further, we tested three syngeneic murine sarcoma models that displayed varied degrees of permissiveness to oncolytic herpes simplex virus replication and cytotoxicity in vitro, with the most permissive being comparable to some human sarcoma tumor lines. The in vivo antitumor effect ranged from no or modest response to complete tumor regression and protection from tumor rechallenge. The in vitro permissiveness to viral oncolysis was not predictive of the in vivo antitumor effect, as all three tumors showed intact interferon signaling and minimal permissiveness to virus in vivo. Tumor shrinkage was T-cell mediated with a tumor-specific antigen response required for maximal antitumor activity. Further analysis of the innate and adaptive immune microenvironment revealed potential correlates of susceptibility and resistance, including favorable and unfavorable cytokine profiles, differential composition of intratumoral myeloid cells, and baseline differences in tumor cell immunogenicity and tumor-infiltrating T-cell subsets. It is likely that a more complete understanding of the interplay between the immunologic immune microenvironment and virus infection will be necessary to fully leverage the antitumor effects of this therapeutic platform. PMID- 27119101 TI - Retargeted oncolytic adenovirus displaying a single variable domain of camelid heavy-chain-only antibody in a fiber protein. AB - Conditionally replicative adenoviruses are promising agents for oncolytic virotherapy. Various approaches have been attempted to retarget adenoviruses to tumor-specific antigens to circumvent deficiency of receptor for adenoviral binding and to provide an additional level of tumor specificity. Functional incorporation of highly specific targeting molecules into the viral capsid can potentially retarget adenoviral infection. However, conventional antibodies are not compatible with the cytoplasmic adenovirus capsid synthesis. The goal of this study was to evaluate the utility of single variable domains derived from heavy chain camelid antibodies for retargeting of adenovirus infection. We have combined transcriptional targeting using a tumor-specific promoter with transductional targeting through viral capsid incorporation of antihuman carcinoembryonic antigen single variable domains. Obtained data demonstrated that employment of a single variable domain genetically incorporated into an adenovirus fiber increased specificity of infection and efficacy of replication of single variable domain-targeted oncolytic adenovirus. The double targeting, both transcriptional through the C-X-C chemokine receptor type 4 promoter and transductional using the single variable domain, is a promising means to improve the therapeutic index for these advanced generation conditionally replicative adenoviruses. A successful strategy to transductional retargeting of oncolytic adenovirus infection has not been shown before and therefore we believe this is the first employment of transductional targeting using single variable domains derived from heavy chain camelid antibodies to enhance specificity of conditionally replicative adenoviruses. PMID- 27119102 TI - Expression of anti-VEGF antibody together with anti-EGFR or anti-FAP enhances tumor regression as a result of vaccinia virotherapy. AB - The tumor microenvironment plays an important role in tumor growth and progression. Here we demonstrate that vaccinia virus-mediated, constitutively expressed intratumoral antibodies against vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and fibroblast activation protein (FAP) significantly improved tumor regression and oncolytic virotherapy through suppression of angiogenesis, cell proliferation, and stromagenesis in virus-colonized tumors. In contrast to the tumor growth inhibition by the three tumor growth-inhibiting antibodies individually, when two of the three antibodies were expressed simultaneously by single vaccinia virus strains tumor regression was further enhanced. These findings strongly indicate that interference with the two tumor growth-stimulating mechanisms did in fact result in enhanced therapeutic efficacy in tumor xenograft models and may lead to an effective therapy in patients with cancer. PMID- 27119103 TI - Enhanced efficacy with azacytidine and oncolytic BHV-1 in a tolerized cotton rat model of breast adenocarcinoma. AB - Oncolytic viruses selectively replicate in cancer cells by exploiting biochemical differences between normal and tumor cells. Treatment with epigenetic modifiers such as 5-Azacytidine, a DNA methyltransferase inhibitor, increases the replication and cytotoxicity of oncolytic viruses in vivo and in vitro. The cotton rat is an attractive animal to study oncolytic viruses, as syngeneic models of breast adenocarcinoma and osteosarcoma are well established, and many features of primary and secondary tumor growth recapitulate human disease. Treatment of LCRT breast cancer cells with 5-Azacytidine increases bovine herpesvirus type 1 (BHV-1)-mediated cytotoxicity in vitro, with Chou-Talalay analysis indicating a very strong synergy. In vivo, BHV-1 monotherapy delayed tumor growth but did not improve survival of cotton rats with subcutaneous breast adenocarcinomas. However, combination therapy significantly decreased the incidence of secondary lesions, with enhanced tumor cell clearance and evidence of immune cell infiltration compared to BHV-1 monotherapy. Together, these results warrant further investigation of BHV-1 combination therapy with epigenetic modifiers for the treatment of breast cancer, particularly in the context of the prevention and treatment of secondary lesions. PMID- 27119104 TI - L-Asparaginase delivered by Salmonella typhimurium suppresses solid tumors. AB - Bacteria can be engineered to deliver anticancer proteins to tumors via a controlled expression system that maximizes the concentration of the therapeutic agent in the tumor. L-asparaginase (L-ASNase), which primarily converts asparagine to aspartate, is an anticancer protein used to treat acute lymphoblastic leukemia. In this study, Salmonellae were engineered to express L ASNase selectively within tumor tissues using the inducible araBAD promoter system of Escherichia coli. Antitumor efficacy of the engineered bacteria was demonstrated in vivo in solid malignancies. This result demonstrates the merit of bacteria as cancer drug delivery vehicles to administer cancer-starving proteins such as L-ASNase to be effective selectively within the microenvironment of cancer tissue. PMID- 27119105 TI - ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, and the 5-year survival rates are among the worst of the major cancers. Oncolytic herpes simplex viruses (oHSV) have the potential to make a significant impact in the targeted treatment of these patients. Here, we tested antitumor efficacy of RAMBO, an oHSV armed with the antiangiogenic Vstat120, alone and in conjunction with ATN-224, a copper chelator against HNSCC in vitro and in vivo animal models. We found that all tested HNSCC cells responded well to virus treatment and were sensitive to RAMBO-mediated oncolytic destruction. In vivo, RAMBO had a significant antiangiogenic and antitumorigenic effect. Physiologic levels of copper inhibited viral replication and HNSCC cell killing. Chelation of copper using ATN-224 treatment significantly improved serum stability of RAMBO and permitted systemic delivery in HNSCC tumor xenografts models. Furthermore, our results show that the combination of ATN-224 and RAMBO strongly inhibits lung metastases in a mouse model of HNSCC. These findings suggest that combining ATN-224 with RAMBO has potential for clinical trials in both early and advanced HNSCC patients. PMID- 27119106 TI - Intratumoral INF-gamma triggers an antiviral state in GL261 tumor cells: a major hurdle to overcome for oncolytic vaccinia virus therapy of cancer. AB - Oncolytic vaccinia virus (VACV) therapy is an alternative treatment option for glioblastoma multiforme. Here, we used a comparison of different tumor locations and different immunologic and genetic backgrounds to determine the replication efficacy and oncolytic potential of the VACV LIVP 1.1.1, an attenuated wild-type isolate of the Lister strain, in murine GL261 glioma models. With this approach, we expected to identify microenvironmental factors, which may be decisive for failure or success of oncolytic VACV therapy. We found that GL261 glioma cells implanted subcutaneously or orthotopically into Balb/c athymic, C57BL/6 athymic, or C57BL/6 wild-type mice formed individual tumors that respond to oncolytic VACV therapy with different outcomes. Surprisingly, only Balb/c athymic mice with subcutaneous tumors supported viral replication. We identified intratumoral IFN gamma expression levels that upregulate MHCII expression on GL261 cells in C57BL/6 wild-type mice associated with a non-permissive status of the tumor cells. Moreover, this IFN-gamma-induced tumor cell phenotype was reversible. PMID- 27119107 TI - Oncolytic potency of HER-2 retargeted VSV-FH hybrid viruses: the role of receptor ligand affinity. AB - The hybrid oncolytic vesicular stomatitis virus (VSV-FH) deleted for its G glycoprotein and displaying the measles virus (MV) envelope glycoproteins (hemagglutinin H and fusion F) is fusogenic, infects cells via any of the three MV receptors and has potent oncolytic activity against subcutaneous and disseminated myeloma tumors. To tailor VSV-FH as an oncolytic virus for ovarian cancer, we ablated its natural tropism and retargeted the virus by display of a single-chain antibody (scFv) with specificity to the HER-2/neu receptor. A panel of six VSVFH-alphaHER2 viruses displaying anti-HER2 scFv that bind to the same HER2 epitope but with different K d (10(-6) to 10(-11) M, VSVFH-alphaHER2#6 to #11, respectively) were rescued and characterized. A K d of at least 10(-8) M is required for infection of HER-2 positive SKOV3ip.1 cells. The higher affinity viruses (>10(-8) M) were able to infect and fuse SKOV3ip.1 cells more efficiently, inducing more extensive cytopathic effects. We next compared the antitumor potency of the viruses against SKOV3ip.1 tumor xenografts. In contrast to the saline-treated animals, one intratumoral injection of VSVFH-alphaHER2#9, #10, or #11 resulted in efficient tumor control. There was no significant difference between viruses with an affinity higher than 10(-9) M in terms of oncolytic potency. VSVFH-alphaHER2 virus may be a promising agent for the treatment of HER-2 positive malignancies. PMID- 27119108 TI - Evidence for differential viral oncolytic efficacy in an in vitro model of epithelial ovarian cancer metastasis. AB - Epithelial ovarian cancer is unique among most carcinomas in that metastasis occurs by direct dissemination of malignant cells traversing throughout the intraperitoneal fluid. Accordingly, we test new therapeutic strategies using an in vitro three-dimensional spheroid suspension culture model that mimics key steps of this metastatic process. In the present study, we sought to uncover the differential oncolytic efficacy among three different viruses-Myxoma virus, double-deleted vaccinia virus, and Maraba virus-using three ovarian cancer cell lines in our metastasis model system. Herein, we demonstrate that Maraba virus effectively infects, replicates, and kills epithelial ovarian cancer (EOC) cells in proliferating adherent cells and with slightly slower kinetics in tumor spheroids. Myxoma virus and vaccinia viruses infect and kill adherent cells to a much lesser extent than Maraba virus, and their oncolytic potential is almost completely attenuated in spheroids. Myxoma virus and vaccinia are able to infect and spread throughout spheroids, but are blocked in the final stages of the lytic cycle, and oncolytic-mediated cell killing is reactivated upon spheroid reattachment. Alternatively, Maraba virus has a remarkably reduced ability to initially enter spheroid cells, yet rapidly infects and spreads throughout spheroids generating significant cell killing effects. We show that low-density lipoprotein receptor expression in ovarian cancer spheroids is reduced and this controls efficient Maraba virus binding and entry into infected cells. Taken together, these results are the first to implicate the potential impact of differential viral oncolytic properties at key steps of ovarian cancer metastasis. PMID- 27119109 TI - Chimeric antigen receptor-engineered T cells as oncolytic virus carriers. AB - The use of engineered T cells in adoptive transfer therapies has shown significant promise in treating hematological cancers. However, successes treating solid tumors are much less prevalent. Oncolytic viruses (OVs) have the capacity to induce specific lysis of tumor cells and indirectly impact tumor growth via vascular shutdown. These viruses bear natural abilities to associate with lymphocytes upon systemic administration, but therapeutic doses must be very high in order to evade antibodies and other components of the immune system. As T cells readily circulate through the body, using these cells to deliver OVs directly to tumors may provide an ideal combination. Our studies demonstrate that loading chimeric antigen receptor-engineered T cells with low doses of virus does not impact receptor expression or function in either murine or human T cells. Engineered T cells can deposit virus onto a variety of tumor targets, which can enhance the tumoricidal activity of the combination treatment. This concept appears to be broadly applicable, as we observed similar results using murine or human T cells, loaded with either RNA or DNA viruses. Overall, loading of engineered T cells with OVs represents a novel combination therapy that may increase the efficacy of both treatments. PMID- 27119110 TI - Assessment of current virotherapeutic application schemes: "hit hard and early" versus "killing softly"? AB - Over the past two decades, a considerable amount of oncolytic vector families has entered numerous clinical trials. However, to this date, the field has not yet been able to come to a common understanding regarding the best possible ways to administer oncolytic viruses to cancer patients. This is mainly due to the fact that so far clinical trials being designed for head-to-head comparisons (such as using two different virotherapeutics originating from two distinct virus families being applied via identical routes in the same types of cancer) are still missing. Hence, there is no consent (i) on the best route of virotherapeutics administration (e.g., systemic versus intratumoral), (ii) on the virus dosages to be applied, (iii) on dosing intervals, and (iv) on the numbers of repetitive courses of virus administration. As the detailed comparison of clinical virotherapy trial regimens is time-consuming and complex, we here present an overview of current state-of-the-art virotherapeutic application schemes. Notably, our comprehensive assessment culminates in raising two rough classifications of virotherapeutic strategies, i.e., "hit hard and early" versus "killing softly". In order to find out which one of these two gross alternatives might be most successful for each and every tumor entity, we here suggest the implementation of phase 1/2 studies, which primarily aim at a repetitive sampling and analysis of tumor samples in cancer patients treated with oncolytic viruses reading out (i) virus-specific, (ii) tumor-specific as well as (iii) immunotherapeutic parameters. On this basis, a rational design of significantly improved virotherapeutic application schemes should be possible in the future. PMID- 27119111 TI - Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma. AB - Epigenetic therapies such as histone deacetylase inhibitors (HDACi) not only have the capability to decrease tumor cell proliferation and to induce tumor cell death but also to silence antiviral response genes. Here, we investigated whether the combination of an oncolytic measles vaccine virus (MeV) with the novel oral HDACi resminostat (Res), being in clinical testing in patients with hepatocellular carcinoma (HCC), results in an enhanced efficacy of this epi virotherapeutic approach compared to any of the two corresponding monotherapies. When testing a panel of human hepatoma cell lines, we found (i) a significantly improved rate of primary infections when using oncolytic MeV under concurrent treatment with resminostat, (ii) a boosted cytotoxic effect of the epi virotherapeutic combination (Res + MeV) with enhanced induction of apoptosis, and, quite importantly, (iii) an absence of any resminostat-induced impairment of MeV replication and spread. Beyond that, we could also show that (iv) resminostat, after hepatoma cell stimulation with exogenous human interferon (IFN)-beta, is able to prevent the induction of IFN-stimulated genes, such as IFIT-1. This finding outlines the possible impact of resminostat on cellular innate immunity, being instrumental in overcoming resistances to MeV-mediated viral oncolysis. Thus, our results support the onset of epi-virotherapeutic clinical trials in patients exhibiting advanced stages of HCC. PMID- 27119112 TI - Inhibition of hypoxia-inducible factor via upregulation of von Hippel-Lindau protein induces "angiogenic switch off" in a hepatoma mouse model. AB - "Angiogenic switch off" is one of the ideal therapeutic concepts in the treatment of cancer. However, the specific molecules which can induce "angiogenic switch off" in tumor have not been identified yet. In this study, we focused on von Hippel-Lindau protein (pVHL) in hepatocellular carcinoma (HCC) and investigated the effects of sulfoquinovosyl-acylpropanediol (SQAP), a novel synthetic sulfoglycolipid, for HCC. We examined mutation ratio of VHL gene in HCC using 30 HCC samples and we treated the HCC-implanted mice with SQAP. Thirty clinical samples showed no VHL genetic mutation in HCC. SQAP significantly inhibited tumor growth by inhibiting angiogenesis in a hepatoma mouse model. SQAP induced tumor "angiogenic switch off" by decreasing hypoxia-inducible factor (HIF)-1, 2alpha protein via pVHL upregulation. pVHL upregulation decreased HIFalpha protein levels through different multiple mechanisms: (i) increasing pVHL-dependent HIFalpha protein degradation; (ii) decreasing HIFalpha synthesis with decrease of NF-kappaB expression; and (iii) decrease of tumor hypoxia by vascular normalization. We confirmed these antitumor effects of SQAP by the loss-of function experiments. We found that SQAP directly bound to and inhibited transglutaminase 2. This study provides evidence that upregulation of tumor pVHL is a promising target, which can induce "angiogenic switch off" in HCC. PMID- 27119113 TI - Development of new therapy for canine mammary cancer with recombinant measles virus. AB - Oncolytic virotherapy is a promising treatment strategy for cancer. We previously generated a recombinant measles virus (rMV-SLAMblind) that selectively uses a poliovirus receptor-related 4 (PVRL4/Nectin4) receptor, but not signaling lymphocyte activation molecule (SLAM). We demonstrated that the virus exerts therapeutic effects against human breast cancer cells. Here, we examined the applicability of rMV-SLAMblind to treating canine mammary cancers (CMCs). We found that the susceptibilities of host cells to rMV-SLAMblind were dependent on canine Nectin-4 expression. Nectin-4 was detected in four of nine CMC cell lines. The rMV-SLAMblind efficiently infected those four Nectin-4-positive cell lines and was cytotoxic for three of them (CF33, CHMm, and CTBm). In vivo experiment showed that the administration of rMV-SLAMblind greatly suppressed the progression of tumors in mice xenografted with a CMC cell line (CF33). Immunohistochemistry revealed that canine Nectin-4 was expressed in 45% of canine mammary tumors, and the tumor cells derived from one clinical specimen were efficiently infected with rMV-SLAMblind. These results suggest that rMV-SLAMblind infects CMC cells and displays antitumor activity in vitro, in xenografts, and ex vivo. Therefore, oncolytic virotherapy with rMV-SLAMblind can be a novel method for treating CMCs. PMID- 27119114 TI - Design and characterization of the tumor vaccine MGN1601, allogeneic fourfold gene-modified vaccine cells combined with a TLR-9 agonist. AB - The tumor vaccine MGN1601 was designed and developed for treatment of metastatic renal cell carcinoma (mRCC). MGN1601 consists of a combination of fourfold gene modified cells with the toll-like receptor 9 agonist dSLIM, a powerful connector of innate and adaptive immunity. Vaccine cells originate from a renal cell carcinoma cell line (grown from renal cell carcinoma tissue), express a variety of known tumor-associated antigens (TAA), and are gene modified to transiently express two co-stimulatory molecules, CD80 and CD154, and two cytokines, GM-CSF and IL-7, aimed to support immune response. Proof of concept of the designed vaccine was shown in mice: The murine homologue of the vaccine efficiently (100%) prevented tumor growth when used as prophylactic vaccine in a syngeneic setting. Use of the vaccine in a therapeutic setting showed complete response in 92% of mice as well as synergistic action and necessity of the components. In addition, specific cellular and humoral immune responses in mice were found when used in an allogeneic setting. Immune response to the vaccine was also shown in mRCC patients treated with MGN1601: Peptide array analysis revealed humoral CD4-based immune response to TAA expressed on vaccine cells, including survivin, cyclin D1, and stromelysin. PMID- 27119115 TI - CD19xCD3 DART protein mediates human B-cell depletion in vivo in humanized BLT mice. AB - Novel therapeutic strategies are needed for the treatment of hematologic malignancies; and bispecific antibody-derived molecules, such as dual-affinity re targeting (DART) proteins, are being developed to redirect T cells to kill target cells expressing tumor or viral antigens. Here we present our findings of specific and systemic human B-cell depletion by a CD19xCD3 DART protein in humanized BLT mice. Administration of the CD19xCD3 DART protein resulted in a dramatic sustained depletion of human CD19(+) B cells from the peripheral blood, as well as a dramatic systemic reduction of human CD19(+) B-cell levels in all tissues (bone marrow, spleen, liver, lung) analyzed. When human CD8(+) T cells were depleted from the mice, no significant B-cell depletion was observed in response to CD19xCD3 DART protein treatment, confirming that human CD8(+) T cells are the primary effector cells in this in vivo model. These studies validate the use of BLT humanized mice for the in vivo evaluation and preclinical development of bispecific molecules that redirect human T cells to selectively deplete target cells. PMID- 27119116 TI - Oncolytic vesicular stomatitis virus expressing interferon-gamma has enhanced therapeutic activity. AB - Oncolytic viruses are known to stimulate the antitumor immune response by specifically replicating in tumor cells. This is believed to be an important aspect of the durable responses observed in some patients and the field is rapidly moving toward immunotherapy. As a further means to engage the immune system, we engineered a virus, vesicular stomatitis virus (VSV), to encode the proinflammatory cytokine interferon-gamma. We used the 4T1 mammary adenocarcinoma as well as other murine tumor models to characterize immune responses in tumor bearing animals generated by treatment with our viruses. The interferon-gamma encoding virus demonstrated greater activation of dendritic cells and drove a more profound secretion of proinflammatory cytokines compared to the parental virus. From a therapeutic point of view, the interferon-gamma virus slowed tumor growth, minimized lung tumors, and prolonged survival in several murine tumor models. The improved efficacy was lost in immunocompromized animals; hence the mechanism appears to be T-cell-mediated. Taken together, these results demonstrate the ability of oncolytic viruses to act as immune stimulators to drive antitumor immunity as well as their potential for targeted gene therapy. PMID- 27119117 TI - Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors. AB - To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass. PMID- 27119118 TI - Preclinical evaluation of VAX-IP, a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer. AB - The development of new therapies that can prevent recurrence and progression of nonmuscle invasive bladder cancer remains an unmet clinical need. The continued cost of monitoring and treatment of recurrent disease, along with its high prevalence and incidence rate, is a strain on healthcare economics worldwide. The current work describes the characterization and pharmacological evaluation of VAX IP as a novel bacterial minicell-based biopharmaceutical agent undergoing development for the treatment of nonmuscle invasive bladder cancer and other oncology indications. VAX-IP minicells selectively target two oncology-associated integrin heterodimer subtypes to deliver a unique bacterial cytolysin protein toxin, perfringolysin O, specifically to cancer cells, rapidly killing integrin expressing murine and human urothelial cell carcinoma cells with a unique tumorlytic mechanism. The in vivo pharmacological evaluation of VAX-IP minicells as a single agent administered intravesically in two clinically relevant variations of a syngeneic orthotopic model of superficial bladder cancer results in a significant survival advantage with 28.6% (P = 0.001) and 16.7% (P = 0.003) of animals surviving after early or late treatment initiation, respectively. The results of these preclinical studies warrant further nonclinical and eventual clinical investigation in underserved nonmuscle invasive bladder cancer patient populations where complete cures are achievable. PMID- 27119119 TI - A multi-antigen vaccine in combination with an immunotoxin targeting tumor associated fibroblast for treating murine melanoma. AB - A therapeutically effective cancer vaccine must generate potent antitumor immune responses and be able to overcome tolerance mechanisms mediated by the progressing tumor itself. Previous studies showed that glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) are promising immunogens for melanoma immunotherapy. In this study, we administered these three melanoma-associated antigens via lentiviral vectors (termed LV-3Ag) and found that this multi-antigen vaccine strategy markedly increased functional T-cell infiltration into tumors and generated protective and therapeutic antitumor immunity. We also engineered a novel immunotoxin, alphaFAP-PE38, capable of targeting fibroblast activation protein (FAP)-expressing fibroblasts within the tumor stroma. When combined with alphaFAP-PE38, LV-3Ag exhibited greatly enhanced antitumor effects on tumor growth in an established B16 melanoma model. The mechanism of action underlying this combination treatment likely modulates the immune suppressive tumor microenvironment and, consequently, activates cytotoxic CD8(+) T cells capable of specifically recognizing and destroying tumor cells. Taken together, these results provide a strong rationale for combining an immunotoxin with cancer vaccines for the treatment of patients with advanced cancer. PMID- 27119120 TI - Molecular network, pathway, and functional analysis of time-dependent gene changes associated with pancreatic cancer susceptibility to oncolytic vaccinia virotherapy. AB - BACKGROUND: Pancreatic cancer is a fatal disease associated with resistance to conventional therapies. This study aimed to determine changes in gene expression patterns associated with infection and susceptibility of pancreatic cancer cells to an oncolyticvaccinia virus, GLV-1h153, carrying the human sodium iodide symporter for deep tissue imaging of virotherapy. METHODS: Replication and susceptibility of pancreatic adenocarcinoma PANC-1 cells to GLV-1h153 was confirmed with replication and cytotoxicity assays. PANC-1 cells were then infected with GLV-1h153 and near-synchronous infection confirmed via flow cytometry of viral-induced green fluorescent protein (GFP) expression. Six and 24 hours after infection, three samples of each time point were harvested, and gene expression patterns assessed using HG-U133A cDNA microarray chips as compared to uninfected control. Differentially expressed genes were identified using Bioconductor LIMMA statistical analysis package. A fold change of 2.0 or above was used as a cutoff, with a P value of 0.01. The gene list was then analyzed using Ingenuity Pathways Analysis software. RESULTS: Differential gene analysis revealed a total of 12,412 up- and 11,065 downregulated genes at 6 and 24 hours postinfection with GLV-1h153 as compared to control. At 6 hours postinfection. A total of 139 genes were either up or downregulated >twofold (false discovery rate < 0.05), of which 124 were mapped by Ingenuity Pathway Analysis (IPA). By 24 hours postinfection, a total of 5,698 genes were identified and 5,563 mapped by IPA. Microarray revealed gene expression changes, with gene networks demonstrating downregulation of processes such as cell death, cell cycle, and DNA repair, and upregulation of infection mechanisms (P < 0.01). Six hours after infection, gene changes involved pathways such as HMGB-1, interleukin (IL)-2, IL 6, IL-8, janus kinase/signal tranducer and activator of transcription (JAK/STAT), interferon, and ERK 5 signaling (P < 0.01). By 24 hours, prominent pathways included P53- and Myc-induced apoptotic processes, pancreatic adenocarcinoma signaling, and phosphoinositide 3-kinase/v-akt murine thymoma vial oncogene homolog 1 (PI3/AKT) pathways. CONCLUSIONS: Our study reveals the ability to assess time-dependent changes in gene expression patterns in pancreatic cancer cells associated with infection and susceptibility to vaccinia viruses. This suggests that molecular assays may be useful to develop safer and more efficacious oncolyticvirotherapies and support the idea that these treatments may target pathways implicated in pancreatic cancer resistance to conventional therapies. PMID- 27119121 TI - Serum allergen-specific IgE, allergic rhinitis severity, and age. AB - BACKGROUND: Allergic rhinitis (AR) is characterized by an IgE-mediated reaction. Aging usually induces a progressive decline of immune system function. There is common belief that both allergic symptoms severity and serum IgE production decline during aging. OBJECTIVE: This study aimed to evaluate the possible impact of age on: i) serum allergen-specific IgE levels in a large sample of subjects, and ii) AR symptom severity in a group of mono-allergic patients. METHODS: Serum allergen-specific IgE to birch, Bet v 1, Parietaria, and Dermatophagoides pteronyssinus were measured by immunofluorometric assay (IFMA) in a sample of 8098 subjects. AR symptom severity was assessed by visual analogue scale (VAS) in a sub-group of 531 mono-allergic patients. RESULTS: The analysis of variance showed that IgE to Bet v 1, birch, and Dermatophagoides pteronyssinus significantly decreased considering the age, whereas IgE to Parietaria did not significantly decline in respect of the age. Considering the global sample of mono-allergic patients, elderly subjects (over 65 years old) tended to have lower IgE levels, but had significantly lower VAS rating, and significantly less sensitizations than adult subjects (18-65 years old). In both adult and elderly patients VAS strongly correlated with IgE values. CONCLUSIONS: Allergen-specific IgE levels tend to reduce with aging, but with differences between types of allergy. The IgE decrease is usually associated with reduced AR symptom severity. Elderly AR patients seem to have a different phenotype/endotype in comparison with adult AR ones, characterized by milder symptoms, lower IgE production, and less sensitizations. However, a close positive relationship between IgE values and VAS scores is shared by both adult and elderly AR patients, confirming the close link between allergy and symptoms that persists also in the elderly. PMID- 27119122 TI - Momentum-dependent band spin splitting in semiconducting MnO2: a density functional calculation. AB - Recently, manganese-oxide compounds have attracted considerable attention, in particular, as candidate materials for photochemical water-splitting reactions. Here, we investigate electronic states of pristine manganese dioxides (MnO2) in different crystal phases using spin-polarized density functional theory (DFT) with Hubbard U correction. Geometrical structures and band dispersions of alpha-, beta-, delta-, and lambda-MnO2 crystals with collinear magnetic [ferromagnetic (FM) and antiferromagnetic (AFM)] orders are discussed in detail. We reveal that penalty energies that arise by violating the Goodenough-Kanamori rule are important and the origin of the magnetic interactions of the MnO2 crystals is governed by the superexchange interactions of Mn-O-Mn groups. In addition, it is found that momentum-dependent band spin splitting occurs in the AFM alpha-, beta , and delta-MnO2 crystals while no spin splitting occurs in the AFM lambda-MnO2 crystal. Our results show that spin-split band dispersions stem from the different orientations of Mn-centred oxygen octahedra. Such interesting electronic states of the MnO2 crystals are unraveled by our discussion on the relationship between the effective (spin-dependent) single-electron potentials and the space-group symmetry operations that map up-spin Mn atoms onto down-spin Mn atoms. This work provides a basis to understand the relationship between the spin-dependent electronic states and the crystallography of manganese oxides. Another relationship to the recent experimental observations of the photochemical oxygen evolution of MnO2 crystals is also discussed. PMID- 27119123 TI - Formic acid as a hydrogen storage material - development of homogeneous catalysts for selective hydrogen release. AB - Formic acid (FA, HCO2H) receives considerable attention as a hydrogen storage material. In this respect, hydrogenation of CO2 to FA and dehydrogenation of FA are crucial reaction steps. In the past decade, for both reactions, several molecularly defined and nanostructured catalysts have been developed and intensively studied. From 2010 onwards, this review covers recent advancements in this area using homogeneous catalysts. In addition to the development of catalysts for H2 generation, reversible H2 storage including continuous H2 production from formic acid is highlighted. Special focus is put on recent progress in non-noble metal catalysts. PMID- 27119124 TI - Cellular processing and destinies of artificial DNA nanostructures. AB - Since many bionanotechnologies are targeted at cells, understanding how and where their interactions occur and the subsequent results of these interactions is important. Changing the intrinsic properties of DNA nanostructures and linking them with interactions presents a holistic and powerful strategy for understanding dual nanostructure-biological systems. With the recent advances in DNA nanotechnology, DNA nanostructures present a great opportunity to understand the often convoluted mass of information pertaining to nanoparticle-biological interactions due to the more precise control over their chemistry, sizes, and shapes. Coupling just some of these designs with an understanding of biological processes is both a challenge and a source of opportunities. Despite continuous advances in the field of DNA nanotechnology, the intracellular fate of DNA nanostructures has remained unclear and controversial. Because understanding its cellular processing and destiny is a necessary prelude to any rational design of exciting and innovative bionanotechnology, in this review, we will discuss and provide a comprehensive picture relevant to the intracellular processing and the fate of various DNA nanostructures which have been remained elusive for some time. We will also link the unique capabilities of DNA to some novel ideas for developing next-generation bionanotechnologies. PMID- 27119125 TI - Treatment of prosthetic joint infections due to Propionibacterium--reply. PMID- 27119126 TI - A proposed set of metrics for standardized outcome reporting in the management of low back pain--reply. PMID- 27119127 TI - Symptom-related emergency department visits and hospital admissions during ambulatory cancer treatment. AB - BACKGROUND: People with cancer experience symptoms related to the disease and treatments. Symptom distress has a negative impact on quality of life (QoL). Attending to symptoms and side effects of treatment promotes safe and effective delivery of therapies and may prevent or reduce emergency department visits (EDVs) and unplanned hospital admissions (HAs). There is limited evidence examining symptom-related EDVs or HAs (sx-EDV/HAs) and interventions in ambulatory oncology patients. OBJECTIVE: To examine factors associated with sx EDV/HAs in ambulatory oncology patients receiving chemotherapy and/or radiation. METHODS: This secondary analysis used data from a randomized controlled trial of ambulatory oncology patients (n = 663) who received the web-based Electronic Self Report Assessment - Cancer intervention (symptom self-monitoring, tailored education, and communication coaching) or usual care with symptom self-monitoring alone. Group differences were described by summary statistics and compared by t test. Factors associated with the odds of at least 1 sx-EDV/HA were modeled using logistic regression. RESULTS: 98 patients had a total of 171 sx-EDV/HAs with no difference between groups. Higher odds of at least 1 sx-EDV/HA were associated with socioeconomic and clinical factors. The multivariable model indicated that work status, education level, treatment modality, and on-treatment Symptom Distress Scale-15 scores were signifcantly associated with having at least 1 sx EDV/HA. LIMITATIONS: This is a secondary analysis not sized to determine cause and effect. The results have limited generalizability. CONCLUSION: Most patients did not experience a sx-EDV/HA. Demographic and clinical factors predicted a sx EDV/HA. PMID- 27119129 TI - Editorial. PMID- 27119128 TI - Lung Cancer and Personalized Medicine: Novel Therapies and Clinical Management. Preface. PMID- 27119130 TI - Bad presentations. PMID- 27119131 TI - A patient presenting with collapse and breathlessness. PMID- 27119132 TI - [US study. Cannabis promotes addictions but not depressions]. PMID- 27119133 TI - [Carefully assessing benefits and risks. Also vaccinate young children against "ticks"?]. PMID- 27119134 TI - [Multicenter study. Early summer meningoencephalitis: an added dose for patients with rheumatoid arthritis?]. PMID- 27119135 TI - [Familial breast cancer: radical primary prevention. "Fear is a bad counselor"]. PMID- 27119136 TI - [No change in travel for medical reasons]. PMID- 27119138 TI - [In general practice the temperature should be measured rectally]. PMID- 27119139 TI - Translating Science into Survival: Report on the Inaugural International Cancer Immunotherapy Conference. AB - The inaugural International Cancer Immunotherapy Conference, cohosted by the Cancer Research Institute (CRI), the American Association for Cancer Research (AACR), the Association for Cancer Immunotherapy (CIMT), and the European Academy of Tumor Immunology (EATI), was held in New York City on September 16-19, 2015. The conference brought together nearly 1,400 scientists, clinicians, regulators, patient advocates, and other stakeholders to discuss the latest scientific developments in cancer immunology and immunotherapy, as well as the regulatory hurdles facing new drug development. This conference report summarizes the main themes that emerged during the 4-day meeting. PMID- 27119140 TI - From the nucleus to the apoplast: building the plant's cell wall. PMID- 27119142 TI - Erratum. PMID- 27119141 TI - The pending wave of point of care molecular testing: outlook and initial observations. PMID- 27119144 TI - 63rd ORCA Congress. July 6-9, 2016, Athens, Greece: Abstracts. PMID- 27119143 TI - Left Ventricular Dilation and Pulmonary Vasodilatation after Surgical Shunt for Treatment of Pre-Sinusoidal Portal Hypertension. AB - OBJECTIVE: The aim of this study was to prospectively investigate the long-term cardiovascular and pulmonary hemodynamic effects of surgical shunt for treatment of portal hypertension (PH) due to Schistosomiasis mansoni. LOCATION: The University of Sao Paulo Medical School, Brazil; Public Practice. METHODS: Hemodynamic evaluation was performed with transesophageal Doppler and contrast enhanced echocardiography (ECHO) on twenty-eight participants with schistosomal portal hypertension. Participants were divided into two groups according to the surgical procedure used to treat their schistosomal portal hypertension within the last two years: group 1-distal splenorenal shunt (DSRS, n = 13) and group 2 esophagogastric devascularization and splenectomy (EGDS, n = 15). RESULTS: The cardiac output (5.08 +/- 0.91 L/min) and systolic volume (60.1 +/- 5.6 ml) were increased (p = 0.001) in the DSRS group. DSRS participants had a significant increase (p < 0.0001) in their left ventricular end-systolic and end-diastolic diameters as well as in their left ventricular end-diastolic and end-systolic volumes (p < 0.001) compared with the preoperative period. No statistically significant difference was found in the patients who underwent EGDS. ECHO revealed intrapulmonary vasodilatation (IPV) in 18 participants (64%), 9 DSRS and 9 EGDS (p > 0.05). CONCLUSIONS: The late increase in the cardiac output, stroke volume and left ventricular diameters demonstrated left ventricular dilatation after a distal splenorenal shunt. ECHO revealed a greater prevalence for IPV in patients with schistosomiasis than has previously been described in patients with PH from liver cirrhosis. PMID- 27119145 TI - Pumping Iron in Australia: Prevalence, Trends and Sociodemographic Correlates of Muscle Strengthening Activity Participation from a National Sample of 195,926 Adults. AB - OBJECTIVE: The current Australian Physical Activity Guidelines recommend that adults engage in regular muscle-strengthening activity (e.g. strength or resistance training). However, public health surveillance studies describing the patterns and trends of population-level muscle-strengthening activity participation are sparse. The aim of this study is to examine the prevalence, trends and sociodemographic correlates of muscle-strengthening activity participation in a national-representative sample of Australians aged 15 years and over. METHODS: Between 2001 and 2010, quarterly cross-sectional national telephone surveys were conducted as part of the Australian Sports Commission's 'Exercise, Recreation and Sport Survey'. Pooled population-weighted proportions were calculated for reporting: [i] no muscle-strengthening activity; [ii] insufficient muscle-strengthening activity, and [iii] sufficient muscle strengthening activity. Associations with sociodemographic variables were assessed using multiple logistic regression analyses. RESULTS: Out of 195,926 participants, aged 15-98 years, only 10.4% (95% CI: 10.1-10.7) and 9.3% (95% CI: 9.1-9.5) met the muscle-strengthening activity recommendations in the past two weeks and in the past year, respectively. Older adults (50+ years), and those living in socioeconomically disadvantaged, outer regional/remote areas and with lower education were less likely to report sufficient muscle-strengthening activity (p<0.001). Over the 10-year monitoring period, there was a significant increase in the prevalence of sufficient muscle-strengthening activity (6.4% to 12.0%, p-value for linear trend <0.001). CONCLUSIONS: A vast majority of Australian adults did not engage in sufficient muscle-strengthening activity. There is a need for public health strategies to support participation in muscle strengthening activity in this population. Such strategies should target older and lower educated adults, and those living in socioeconomically disadvantaged, outer regional/remote and areas. PMID- 27119148 TI - On Retinal Gene Therapy. AB - Mutations in a large number of genes cause retinal degeneration and blindness with no cure currently available. Retinal gene therapy has evolved over the last decades to become a promising new treatment paradigm for these rare disorders. This article reflects on the ideas and concepts arising from basic science towards the translation of retinal gene therapy into the clinical realm. It describes the advances and present thinking on the efficacy of current clinical trials and discusses potential roadblocks and solutions for the future of retinal gene therapy. PMID- 27119146 TI - Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation. AB - Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis. PMID- 27119147 TI - Relative Contributions of Various Cellular Mechanisms to Loss of Algae during Cnidarian Bleaching. AB - When exposed to stress such as high seawater temperature, corals and other cnidarians can bleach due to loss of symbiotic algae from the host tissue and/or loss of pigments from the algae. Although the environmental conditions that trigger bleaching are reasonably well known, its cellular and molecular mechanisms are not well understood. Previous studies have reported the occurrence of at least four different cellular mechanisms for the loss of symbiotic algae from the host tissue: in situ degradation of algae, exocytic release of algae from the host, detachment of host cells containing algae, and death of host cells containing algae. The relative contributions of these several mechanisms to bleaching remain unclear, and it is also not known whether these relative contributions change in animals subjected to different types and/or durations of stresses. In this study, we used a clonal population of the small sea anemone Aiptasia, exposed individuals to various precisely controlled stress conditions, and quantitatively assessed the several possible bleaching mechanisms in parallel. Under all stress conditions tested, except for acute cold shock at 4 degrees C, expulsion of intact algae from the host cells appeared to be by far the predominant mechanism of bleaching. During acute cold shock, in situ degradation of algae and host-cell detachment also became quantitatively significant, and the algae released under these conditions appeared to be severely damaged. PMID- 27119149 TI - Patterns of Phylogenetic Diversity of Subtropical Rainforest of the Great Sandy Region, Australia Indicate Long Term Climatic Refugia. AB - Australia's Great Sandy Region is of international significance containing two World Heritage areas and patches of rainforest growing on white sand. Previous broad-scale analysis found the Great Sandy biogeographic subregion contained a significantly more phylogenetically even subset of species than expected by chance contrasting with rainforest on white sand in Peru. This study aimed to test the patterns of rainforest diversity and relatedness at a finer scale and to investigate why we may find different patterns of phylogenetic evenness compared with rainforests on white sands in other parts of the world. This study focussed on rainforest sites within the Great Sandy and surrounding areas in South East Queensland (SEQ), Australia. We undertook field collections, expanded our three marker DNA barcode library of SEQ rainforest plants and updated the phylogeny to 95% of the SEQ rainforest flora. We sampled species composition of rainforest in fixed area plots from 100 sites. We calculated phylogenetic diversity (PD) measures as well as species richness (SR) for each rainforest community. These combined with site variables such as geology, were used to evaluate patterns and relatedness. We found that many rainforest communities in the Great Sandy area were significantly phylogenetically even at the individual site level consistent with a broader subregion analysis. Sites from adjacent areas were either not significant or were significantly phylogenetically clustered. Some results in the neighbouring areas were consistent with historic range expansions. In contrast with expectations, sites located on the oldest substrates had significantly lower phylogenetic diversity (PD). Fraser Island was once connected to mainland Australia, our results are consistent with a region geologically old enough to have continuously supported rainforest in refugia. The interface of tropical and temperate floras in part also explains the significant phylogenetic evenness and higher than expected phylogenetic diversity. PMID- 27119150 TI - HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naive and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes. AB - The use of antiretroviral therapy in HIV infected subjects prevents AIDS-related illness and delayed occurrence of death. In Panama, rollout of ART started in 1999 and national coverage has reached 62.8% since then. The objective of this study was to determine the level and patterns of acquired drug resistance mutations of clinical relevance (ADR-CRM) and surveillance drug resistance mutations (SDRMs) from 717 HIV-1 pol gene sequences obtained from 467 ARV drug experienced and 250 ARV drug-naive HIV-1 subtypes B infected subjects during 2007 2013, respectively. The overall prevalence of SDRM and of ADR-CRM during the study period was 9.2% and 87.6%, respectively. The majority of subjects with ADR CRM had a pattern of mutations that confer resistance to at least two classes of ARV inhibitors. The non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K103N and P225H were more prevalent in both ARV drug-naive and ARV drug experienced subjects. The nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V was more frequent in ARV drug-experienced individuals, while T215YFrev and M41L were more frequent in ARV drug-naive subjects. Prevalence of mutations associated to protease inhibitors (PI) was lower than 4.1% in both types of subjects. Therefore, there is a high level of resistance (>73%) to Efavirenz/Nevirapine, Lamivudine and Azidothymidine in ARV drug-experienced subjects, and an intermediate to high level of resistance (5-10%) to Efavirenz/Nevirapine in ARV drug-naive subjects. During the study period, we observed an increasing trend in the prevalence of ADR-CRM in subjects under first line schemes, but not significant changes in the prevalence of SDRM. These results reinforce the paramount importance of a national surveillance system of ADR-CRM and SDRM for national management policies of subjects living with HIV. PMID- 27119152 TI - Correction: Shaping the Growth Behaviour of Biofilms Initiated from Bacterial Aggregates. AB - [This corrects the article DOI: 10.1371/journal.pone.0149683.]. PMID- 27119151 TI - Carbonate Production by Benthic Communities on Shallow Coralgal Reefs of Abrolhos Bank, Brazil. AB - The abundance of reef builders, non-builders and the calcium carbonate produced by communities established in Calcification Accretion Units (CAUs) were determined in three Abrolhos Bank shallow reefs during the period from 2012 to 2014. In addition, the seawater temperature, the irradiance, and the amount and composition of the sediments were determined. The inner and outer reef arcs were compared. CAUs located on the inner reef shelf were under the influence of terrigenous sediments. On the outer reefs, the sediments were composed primarily of marine biogenic carbonates. The mean carbonate production in shallow reefs of Abrolhos was 579 +/- 98 g m-2 y-1. The builder community was dominated by crustose coralline algae, while the non-builder community was dominated by turf. A marine heat wave was detected during the summer of 2013-2014, and the number of consecutive days with a temperature above or below the summer mean was positively correlated with the turf cover increase. The mean carbonate production of the shallow reefs of Abrolhos Bank was greater than the estimated carbonate production measured for artificial structures on several other shallow reefs of the world. The calcimass was higher than the non-calcareous mass, suggesting that the Abrolhos reefs are still in a positive carbonate production balance. Given that marine heat waves produce an increase of turf cover on the shallow reefs of the Abrolhos, a decrease in the cover represented by reef builders and shifting carbonate production are expected in the near future. PMID- 27119153 TI - Optimized depiction of thalamic substructures with a combination of T1-MPRAGE and phase: MPRAGE. AB - OBJECTIVE: Deep brain stimulation has received increasing attention in recent years as a treatment option for many neurological diseases. The thalamic nuclei in particular are widely used as targets. The goal of the present work was to evaluate whether the combination of two known MRI techniques can lead to identification of thalamic substructures at 3 T. METHODS: In nine healthy subjects, an optimized 3D magnetization prepared rapid acquisition GRE (MPRAGE) protocol and phase data from a 3D GRE sequence were combined to form a new contrast (MPRAGE*). The depiction of 13 thalamic substructures was rated by two independent raters in the MPRAGE, phase and MPRAGE* image on a five-point scale. Inter-rater reliability was scored with a weighted Cohen's kappa. RESULTS: Inter rater reliability was good, with the average weighted kappa = 0.68. No significant difference between the depiction of the thalamic substructures between phase and MPRAGE images could be found. MPRAGE* showed a significantly better depiction of thalamic substructures in comparison to MPRAGE and phase (p < 0.001 for both cases). CONCLUSION: The combination of an optimized MPRAGE protocol with phase data to form an MPRAGE* image leads to a further improvement in the depiction of thalamic substructures, which enables the depiction of thalamic nuclei at 3 T. PMID- 27119154 TI - Two-Solvent Method Synthesis of NiO/ZnO Nanoparticles Embedded in Mesoporous SBA 15: Photocatalytic Properties Study. AB - Different loadings of NiO/ZnO nanoparticles embedded in mesoporous silica (SBA 15) were prepared via a two-solvent method with the ordered hexagonal mesoporous structure of SBA-15 kept. X-ray diffraction, transmission electron microscope, X ray photoelectron spectroscopy, diffusive reflective UV-vis spectroscopy, and N2 adsorption porosimetry were employed to characterize the nanocomposites. The results indicate that the ordered hexagonal mesoporous structure of SBA-15 is kept and the absorption band edges of the nanocomposites shift into the ultraviolet light regime. The photocatalytic activity of our samples for degradation of methylene orange was investigated under UV light irradiation, and the results show that the nanocomposites have higher photodegradation ability toward methylene orange than commercial pure P-25. The photocatalytic activity of the nanocomposites was found to be dependent on both the adsorption ability of the SBA-15 and the photocatalytic activity of NiO-ZnO nanoparticles encapsulated in SBA-15. In addition, there is an optimal loading of NiO-ZnO nanoparticles. Too high or low loading will lower the photodegradation ability of the nanocomposites. PMID- 27119155 TI - Conjugation Magnetic PAEEP-PLLA Nanoparticles with Lactoferrin as a Specific Targeting MRI Contrast Agent for Detection of Brain Glioma in Rats. AB - The diagnosis of malignant brain gliomas is largely based on magnetic resonance imaging (MRI) with contrast agents. In recent years, nano-sized contrast agents have been developed for improved MRI diagnosis. In this study, oleylamine-coated Fe3O4 magnetic nanoparticles (OAM-MNPs) were synthesized with thermal decomposition method and encapsulated in novel amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer nanoparticles. The OAM MNP-loaded PAEEP-PLLA nanoparticles (M-PAEEP-PLLA-NPs) were further conjugated with lactoferrin (Lf) for glioma tumor targeting. The Lf-conjugated M-PAEEP-PLLA NPs (Lf-M-PAEEP-PLLA-NPs) were characterized by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), thermo-gravimetric analysis (TGA), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM). The average size of OAM-MNPs, M-PAEEP-PLLA-NPs, and Lf-M PAEEP-PLLA-NPs were 8.6 +/- 0.3, 165.7 +/- 0.6, and 218.2 +/- 0.4 nm, with polydispersity index (PDI) of 0.185 +/- 0.023, 0.192 +/- 0.021, and 0.224 +/- 0.036, respectively. TEM imaging showed that OAM-MNPs were monodisperse and encapsulated in Lf-M-PAEEP-PLLA-NPs. TGA analysis showed that the content of iron oxide nanoparticles was 92.8 % in OAM-MNPs and 45.2 % in Lf-M-PAEEP-PLLA-NPs. VSM results indicated that both OAM-MNPs and Lf-M-PAEEP-PLLA-NPs were superparamagnetic, and the saturated magnetic intensity were 77.1 and 74.8 emu/g Fe. Lf-M-PAEEP-PLLA-NPs exhibited good biocompatibility in cytotoxicity assay. The high cellular uptake of Lf-M-PAEEP-PLLA-NPs in C6 cells indicated that Lf provided effective targeting for the brain tumor cells. The T 2 relaxation rate (r 2) of M-PAEEP-PLLA-NPs and Lf-M-PAEEP-PLLA-NPs were calculated to be 167.2 and 151.3 mM(-1) s(-1). In MRI on Wistar rat-bearing glioma tumor, significant contrast enhancement could clearly appear at 4 h after injection and last 48 h. Prussian blue staining of the section clearly showed the retention of Lf-M-PAEEP PLLA-NPs in tumor tissues. The results from the in vitro and in vivo MRI indicated that Lf-M-PAEEP-PLLA-NPs possessed strong, long-lasting, tumor targeting, and enhanced tumor MRI contrast ability. Lf-M-PAEEP-PLLA-NPs represent a promising nano-sized MRI contrast agent for brain glioma targeting MRI. PMID- 27119156 TI - Organo/Zn-Al LDH Nanocomposites for Cationic Dye Removal from Aqueous Media. AB - Cationic dye sorption by Zn-Al-layered double hydroxides (LDHs) modified with anionic surfactants was examined using methylene blue (MB) dye as a compound model in aqueous solutions. The modification of Zn-Al LDHs was performed by reconstruction method using dodecyl sulfate anion (DS) solutions. DS contained Zn Al LDHs were characterized by XRD, FTIR, thermogravimetric, and SEM analysis. The reconstructed organo/Zn-Al LDHs comprise the crystalline phases (DS-intercalated LDHs, hydrotalcite), and the amorphous phase. The intercalation of DS ions into the interlayer galleries and DS adsorption on the surface of the LDHs occurred causing the MB adsorption on the external and its sorption in the internal surfaces of modified LDHs. The presence of DS greatly increased the affinity of organo/Zn-Al LDHs for MB due to hydrophobic interactions between the surfactants and the dye molecules. The optical properties of sorbed MB were studied. PMID- 27119157 TI - Temperature-Dependent Nanofabrication on Silicon by Friction-Induced Selective Etching. AB - Friction-induced selective etching provides a convenient and practical way for fabricating protrusive nanostructures. A further understanding of this method is very important for establishing a controllable nanofabrication process. In this study, the effect of etching temperature on the formation of protrusive hillocks and surface properties of the etched silicon surface was investigated. It is found that the height of the hillock produced by selective etching increases with the etching temperature before the collapse of the hillock. The temperature dependent selective etching rate can be fitted well by the Arrhenius equation. The etching at higher temperature can cause rougher silicon surface with a little lower elastic modulus and hardness. The contact angle of the etched silicon surface decreases with the etching temperature. It is also noted that no obvious contamination can be detected on silicon surface after etching at different temperatures. As a result, the optimized condition for the selective etching was addressed. The present study provides a new insight into the control and application of friction-induced selective nanofabrication. PMID- 27119158 TI - Concentration Effect of Reducing Agents on Green Synthesis of Gold Nanoparticles: Size, Morphology, and Growth Mechanism. AB - Under various concentration conditions of reducing agents during the green synthesis of gold nanoparticles (AuNPs), we obtain the various geometry (morphology and size) of AuNPs that play a crucial role in their catalytic properties. Through both theoretical and experimental approaches, we studied the relationship between the concentration of reducing agent (caffeic acid) and the geometry of AuNPs. As the concentration of caffeic acid increases, the sizes of AuNPs were decreased due to the adsorption and stabilizing effect of oxidized caffeic acids (OXCAs). Thus, it turns out that optimal concentration exists for the desired geometry of AuNPs. Furthermore, we investigated the growth mechanism for the green synthesis of AuNPs. As the caffeic acid is added and adsorbed on the surface of AuNPs, the aggregation mechanism and surface free energy are changed and consequently resulted in the AuNPs of various geometry. PMID- 27119159 TI - The Integral Role of Genetic Variation in the Evolution of Outcrossing in the Caenorhabditis elegans-Serratia marcescens Host-Parasite System. AB - Outcrossing is predicted to facilitate more rapid adaptation than self fertilization as a result of genetic exchange between genetically variable individuals. Such genetic exchange may increase the efficacy of selection by breaking down Hill-Robertson interference, as well as promoting the maintenance of within-lineage genetic diversity. Experimental studies have demonstrated the selective advantage of outcrossing in novel environments. Here, we assess the specific role of genetic variation in the evolution of outcrossing. We experimentally evolved genetically variable and inbred populations of mixed mating (outcrossing and self-fertilizing) Caenorhabditis elegans nematodes under novel ecological conditions-specifically the presence of the virulent parasite Serratia marcescens. Outcrossing rates increased in genetically variable host populations evolved in the presence of the parasite, whereas parasite exposure in inbred populations resulted in reduced rates of host outcrossing. The host populations with genetic variation also exhibited increased fitness in the presence of the parasite over eight generations, whereas inbred populations did not. This increase in fitness was primarily the result of adaptation to the parasite, rather than recovery from initial inbreeding depression. Therefore, the benefits of outcrossing were only manifested in the presence of genetic variation, and outcrossing was favored over self-fertilization as a result. As predicted, the benefits of outcrossing under novel ecological conditions are a product of genetic exchange between genetically diverse lineages. PMID- 27119160 TI - Nematopsis temporariae (Gregarinasina, Apicomplexa, Alveolata) is an intracellular infectious agent of tadpole livers. AB - Amphibians are in decline as a result of habitat destruction, climate change and infectious diseases. Tadpoles are thought susceptible to infections because they are dependent on only an innate immune system (e.g. macrophages). This is because the frog adaptive immune system does not function until later stages of their life cycle. In 1920, Noller described a putative infectious agent of tadpoles named Nematopsis temporariae, which he putatively assigned to gregarine protists (Apicomplexa). Here, we identify a gregarine infection of tadpoles using both microscopy and ribosomal DNA sequencing of three different frog species (Rana temporaria, R. dalmatina, and Hyla arborea). We show that this protist lineage belongs to the subclass Gregarinasina Dufour 1828 and is regularly present in macrophages located in liver sinusoids of tadpoles, confirming the only known case of a gregarine infection of a vertebrate. PMID- 27119162 TI - Expression Levels of Human Equilibrative Nucleoside Transporter 1 and Deoxycytidine Kinase Enzyme as Prognostic Factors in Patients with Acute Myeloid Leukemia Treated with Cytarabine. AB - BACKGROUND: Cytarabine (Ara-C) is the primary drug in different treatment schemas for acute myeloid leukemia (AML) and requires the human equilibrative nucleoside transporter (hENT1) to enter cells. The deoxycytidine kinase (dCK) enzyme limits its activation rate. Therefore, decreased expression levels of these genes may influence the response rate to this drug. METHODS: AML patients without previous treatment were enrolled. The expression of hENT1 and dCK genes was analyzed using RT-PCR. Clinical parameters were registered. All patients received Ara-C + doxorubicin as an induction regimen (7 + 3 schema). Descriptive statistics were used to analyze data. Uni- and multivariate analyses were performed to determine factors that influenced response and survival. RESULTS: Twenty-eight patients were included from January 2011 until December 2012. Median age was 36.5 years. All patients had an adequate performance status (43% with ECOG 1 and 57% with ECOG 2). Cytogenetic risk was considered unfavorable in 54% of the patients. Complete response was achieved in 53.8%. Cox regression analysis showed that a higher hENT1 expression level was the only factor that influenced response and survival. CONCLUSIONS: These results highly suggest that the pharmacogenetic analyses of Ara-C influx may be decisive in AML patients. PMID- 27119161 TI - A common effect of angiotensin II and relaxin 2 on the PNT1A normal prostate epithelial cell line. AB - The prostate gland is a part of the male reproductive tract which produces both angiotensin II (Ang II) and relaxin 2 (RLN2). The present study analyzes the effect of both these peptide hormones at concentration 10(-8)M on viability, proliferation, adhesion, migration, and invasion of normal prostate epithelial cells (PNT1A). Improved survival in two- and three-dimensional cell cultures was noted as well as visual changes in colony size and structure in GeltrexTM. Stimulatory influence on cell viability of each peptide applied single was lower than in combination. Enhanced survival of PNT1A cells appears to be associated with increased BCL2/BAX messenger RNA (mRNA) expression ratio. Modulation of cell spreading and cell-extracellular matrix adhesion dynamics were also altered as an influence of tested hormone application. However, long-term Ang II and RLN2 effects may lead to an increase of normal prostate cell migration and invasion abilities. Moreover, gelatin zymography revealed that both gelatinases A and B were augmented by Ang II treatment, whereas RLN2 significantly stimulated only MMP-9 secretion. These results support the hypothesis that deregulation of locally secreted peptide hormones such as Ang II and RLN2 may take part in the development of certain cancers, including prostate cancer. Moreover, the observed ability of relaxin 2 to act as a regulator of mRNA expression levels not only LGR7 but also classic angiotensin receptors suggested that renin-angiotensin system and relaxin family peptide system are functionally linked. PMID- 27119163 TI - Relationship between left atrial appendage emptying and left atrial function using cardiac magnetic resonance in patients with atrial fibrillation: comparison with transesophageal echocardiography. AB - To compare cardiac magnetic resonance (CMR) quantifications of left atrium (LA) function and left atrial appendage (LAA) emptying depending on the presence of LA spontaneous echogenic contrast (LA-SEC) on transesophageal echocardiography (TEE) in patients with atrial fibrillation (AF). A total of 48 patients with AF underwent sequential CMR examination and TEE in preparation for catheter ablation. The CMR protocol included cine and velocity encoding (VENC) sequences for evaluation of both LA function and LAA emptying. The peak blood velocity of LAA just before left ventricle systole was defined as the LAA emptying velocity (LAA-EV). Depending on the presence of LA-SEC on TEE, patients were divided into two groups, the SEC group (n = 15) and the non-SEC group (n = 33). Mean LAA-EV was significantly greater in the non-SEC group than in the SEC group (54.5 +/- 24.8 ml/s vs. 26.0 +/- 22.6 ml/s, P < 0.01). LAA-EV had a significant positive relationship (P < 0.05) with LAA backflow velocity, as assessed using TEE. Use of an optimal LAA-EV cutoff value of 35 ml/s to predict LA-SEC yielded a sensitivity of 80.0 %, a specificity of 75.7 %, and positive and negative predictive values of 58.8 and 83.9 %, respectively. Using VENC-CMR, LAA-EV is associated with LA function and can be useful for predicting LA-SEC in patients with AF. PMID- 27119164 TI - Coronary artery calcium scores and cardiovascular risk factors in 31,545 asymptomatic Korean adults. AB - The aims of this study were to identify the distribution of coronary artery calcium score (CACS) by age group and cardiovascular (CV) risk factors and to evaluate the association between CV risk factors and CACS classification in asymptomatic adults. The study included 31,545 asymptomatic Koreans, over 20 years of age with no previous history of malignancy, proven coronary artery disease, or stroke, who underwent CACS computed tomography at the Health Promotion Center, Samsung Medical Center, between January 2005 and June 2013. Mean (+/-SD) age was 53.8 (+/-8.5) years overall, 56.1 (+/-8.3) in men, and 53.3 (+/-8.5) in women. They were classified into five groups based on their resting CACS: none (CAC = 0), minimal (0 < CAC <= 10), mild (10 < CAC <= 100), moderate (100 < CAC <= 400), and extensive (400 > CAC). Older age groups exhibited higher CACS values. The proportion of CACS classification in our study was 55.5 % with no CACS, 9.5 % with minimal CACS, 19.8 % with mild CACS, 10.8 % with moderate CACS, and 4.3 % with extensive CACS. Adjusted odds ratios (ORs) were calculated for CV risk factors to determine their association with CACS. When analyzed according to sex, in males, the adjusted OR for CACS increased with the presence of hypertension (HT), diabetes mellitus (DM), obesity, chronic kidney disease, and smoking status. While, in females, the adjusted OR for CACS increased with the presence of HT, DM, and obesity. CV risk factors appear to be significantly associated with CACS in the Korean population. PMID- 27119166 TI - Joint Cooling does not Hinder Athletic Performance during High-intensity Intermittent Exercise. AB - We examined the effects of ankle and knee joint cooling on 20-m sprint times and maximal vertical jump heights during high-intensity intermittent exercise. 21 healthy collegiate male basketball (n=14) and handball players (n=7) underwent 3 experimental sessions. Each session consisted of four 15-min quarters of high intensity intermittent exercises including various intensities of 20-m shuttle running and jumping. A 20-min bilateral joint cooling (ankle, knee, or control-no cooling: in a counterbalanced order) was applied before quarters 1 and 3. After joint cooling, no warm-up activity other than the exercise protocol was given. The 20-m sprint times and maximal vertical jump heights in each experimental session were recorded at baseline (prior to quarter-1) and during each quarter. To test joint cooling effects over time, we performed 3*5 mixed model ANOVAs. Neither ankle nor knee joint cooling changed 20-m sprint times (F8,280=1.45; p=0.18) or maximal vertical jump heights (F8,280=0.76; p=0.64). However, a trend was observed in which joint cooling immediately decreased (quarters 1 and 3) but active warm-up for approximately 20 min improved 20-min sprint times (quarters 2 and 4). Our study suggests that athletic performance such as sprinting and jumping are not altered by joint cooling applied prior to or during high intensity intermittent exercise. PMID- 27119165 TI - Assessing the Construct Validity and Internal Reliability of the Screening Tool Test Your Memory in Patients with Chronic Pain. AB - Patients with chronic pain often complain about cognitive difficulties, and since these symptoms represent an additional source of suffering and distress, evaluating the cognitive status of these patients with valid and reliable tests should be an important part of their overall assessment. Although cognitive impairment is a critical characteristic of pain, there is no specific measure designed to detect these effects in this population. The objective was to analyze the psychometric properties of the "Test Your Memory" (TYM) test in patients with chronic pain of three different origins. A cross-sectional study was carried out on 72 subjects free of pain and 254 patients suffering from different types of chronic pain: neuropathic pain (104), musculoskeletal pain (99) and fibromyalgia (51). The construct validity of the TYM was assessed using the Mini-Mental State Examination (MMSE), Hospital Anxiety and Depression Scale (HADs), Index-9 from MOS-sleep, SF-12, and through the intensity (Visual Analogical Scale) and duration of pain. An exploratory factor analysis was also performed and internal reliability was assessed using Cronbach's alpha. After adjusting for potential confounders the TYM could distinguish between pain and pain-free patients, and it was correlated with the: MMSE (0.89, p<0.001); HAD-anxiety (-0.50, p<0.001) and HAD-depression scales (-0.52, p<0.001); MOS-sleep Index-9 (-0.49, p<0.001); and the physical (0.49, p < .001) and mental components (0.55, p < .001) of SF-12. The exploratory structure of the TYM showed an 8-factor solution that explained 53% of the variance, and Cronbach's alpha was 0.66. The TYM is a valid and reliable screening instrument to assess cognitive function in chronic pain patients that will be of particular value in clinical situations. PMID- 27119198 TI - Methanol Oxidation on Pt3Sn(111) for Direct Methanol Fuel Cells: Methanol Decomposition. AB - PtSn alloy, which is a potential material for use in direct methanol fuel cells, can efficiently promote methanol oxidation and alleviate the CO poisoning problem. Herein, methanol decomposition on Pt3Sn(111) was systematically investigated using periodic density functional theory and microkinetic modeling. The geometries and energies of all of the involved species were analyzed, and the decomposition network was mapped out to elaborate the reaction mechanisms. Our results indicated that methanol and formaldehyde were weakly adsorbed, and the other derivatives (CHxOHy, x = 1-3, y = 0-1) were strongly adsorbed and preferred decomposition rather than desorption on Pt3Sn(111). The competitive methanol decomposition started with the initial O-H bond scission followed by successive C H bond scissions, (i.e., CH3OH -> CH3O -> CH2O -> CHO -> CO). The Bronsted-Evans Polanyi relations and energy barrier decomposition analyses identified the C-H and O-H bond scissions as being more competitive than the C-O bond scission. Microkinetic modeling confirmed that the vast majority of the intermediates and products from methanol decomposition would escape from the Pt3Sn(111) surface at a relatively low temperature, and the coverage of the CO residue decreased with an increase in the temperature and decrease in partial methanol pressure. PMID- 27119200 TI - Formation of the S = 1 paramagnetic centers in the bond-diluted spin-gap magnet. AB - Electron spin resonance experiment reveals that non-magnetic bond doping of the spin-gap magnet (C4H12N2)Cu2Cl6 (abbreviated PHCC) results in the formation of S = 1 paramagnetic centers that dominate low-temperature ESR response. We have followed evolution of this signal with doping impurity content and have found that the concentraion of these centers is quadratic over the impurity content. We also observe coexistence of the ESR responses from these local centers and from delocalized triplet excitations over a certain temperature range. PMID- 27119199 TI - In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation. AB - The immunological attributes of stem cell grafts play an important role in the outcome of allogeneic stem cell transplants. Currently, ex vivo manipulation techniques such as bulk T-cell depletion or positive selection of CD34(+) cells are utilized to improve the immunological attributes of grafts and minimize the potential for graft-versus-host disease (GvHD). Here, we demonstrate a novel graft engineering technique, which utilizes the immunomodulatory drug FTY720 for in vivo depletion of naive T (TN ) cells from donor G-CSF-mobilized grafts without ex vivo manipulation. We show that treatment of donor mice with FTY720 during mobilization depletes grafts of TN cells and prevents lethal GvHD following transplantation in a major mismatch setting. Importantly, both stem cells and NK cells are retained in the FTY720-treated grafts. FTY720 treatment does not negatively affect the engraftment potential of stem cells as demonstrated in our congenic transplants or the functionality of NK cells. In addition, potentially useful memory T cells may be retained in the graft. These findings suggest that FTY720 may be used to optimize the immunological attributes of G-CSF-mobilized grafts by removing potentially deleterious TN cells which can contribute to GvHD, and by retaining useful cells which can promote immunity in the recipient. PMID- 27119201 TI - A mathematics-based new penalty area in football: tackling diving. AB - A novel penalty area (PA) for football (soccer) is proposed; it is based on considering mathematically the actual scoring possibility on the 2 dimensions near the goal. It is shown that the 150-year-old rectangular area is mathematically disproportionate; this can be causing too much diving or simulation by players around the goal and also too many matches that are decided unfairly. The goal or objective is to reduce these problems - and others - with a new PA based on the proposed scoring potential measure which is in turn based on the angle towards the goal line (between posts) and the distance to the centre of this line. PMID- 27119202 TI - Colloidal Suspensions of Rodlike Nanocrystals and Magnetic Spheres under an External Magnetic Stimulus: Experiment and Molecular Dynamics Simulation. AB - Using experiments and molecular dynamics simulations, we explore magnetic field induced phase transformations in suspensions of nonmagnetic rodlike and magnetic sphere-shaped particles. We experimentally demonstrate that an external uniform magnetic field causes the formation of small, stable clusters of magnetic particles that, in turn, induce and control the orientational order of the nonmagnetic subphase. Optical birefringence was studied as a function of the magnetic field and the volume fractions of each particle type. Steric transfer of the orientational order was investigated by molecular dynamics (MD) simulations; the results are in qualitative agreement with the experimental observations. By reproducing the general experimental trends, the MD simulation offers a cohesive bottom-up interpretation of the physical behavior of such systems, and it can also be regarded as a guide for further experimental research. PMID- 27119203 TI - Counteranion-Stabilized Titanium(IV) Isopolyoxocationic Clusters Isolated from Water. AB - A novel titanium(IV) oxo cluster comprised solely of Ti, O, and H atoms, [Ti6(OMU)8(OtH2)20](8+) (Ti6) was synthesized in high yield via controlled hydrolysis and condensation of TiX4 (X = Cl, Br) in the presence of TBAX (TBA = tetrabutylammonium; X = Cl, Br) from water, while reactions of TiI4 and TBAI yielded [Ti8O12(OH2)24](8+) (Ti8). The structures and compositions of the clusters were determined by single-crystal X-ray crystallography, powder X-ray diffraction, inductively coupled plasma atomic emission spectrometry, and energy dispersive spectrometry. Ti6 is comprised of six-coordinated titanium(IV) atoms bridged with MU2-O atoms, structurally similar to a typical Lindqvist polyoxometalate. On the basis of a structural comparison of Ti6 and Ti8, density functional theory calculations, and spectroscopic analysis, it is evident that both clusters are stabilized by halide counteranions via the formation of hydrogen bonds. This study not only presents the second example of a titanium(IV) isopolyoxocationic cluster isolated from water but also suggests that counteranions are generally important for synthesizing molecular fragments of titanium oxides. PMID- 27119204 TI - Fast food versus slow food in very and extremely low-birthweight infants: speed of feeds is a little more than a gut feeling. PMID- 27119205 TI - Cyano-bridged coordination polymer hydrogel-derived Sn-Fe binary oxide nanohybrids with structural diversity: from 3D, 2D, to 2D/1D and enhanced lithium storage performance. AB - Metal oxide nanohybrids with uniform dimensions and controlled architectures possess unique compositional and structural superiorities, and thus harbor promising potential for a series of applications in energy, catalysis, and sensing systems. Herein, we propose a facile, general, and scalable cyano-bridged coordination polymer hydrogel-derived thermal-oxidation route for the construction of main-group metal and transition-metal heterometallic oxide nanohybrids with controlled constituents and architectures. The formation of Sn Fe binary oxide nanohybrids has been demonstrated as an example by using cyano bridged Sn(iv)-Fe(ii) bimetallic coordination polymer hydrogels (i.e., SnCl4 K4Fe(CN)6 cyanogels, Sn-Fe cyanogels) as precursors. The physicochemical properties of Sn-Fe cyanogels with different Sn/Fe ratios have been systematically examined, and it is found that perfect Sn-Fe cyanogels without unbridged Sn(iv) or Fe(ii) can be formed with Sn/Fe ratios from 2 : 1 to 1 : 2. More importantly, the simple adjustment of Sn/Fe ratios in the Sn-Fe cyanogel precursors can realize flexible dimensional control of the Sn-Fe binary oxide nanohybrids, and 2D/1D SnO2-Fe2O3 hierarchitectures, 2D SnO2-Fe2O3 nanosheets, and 3D SnO2-Fe2O3 networks have been synthesized using the Sn-Fe 1 : 2, Sn-Fe 1 : 1, and Sn-Fe 2 : 1 cyanogels as precursors, respectively. To demonstrate their compositional/structural superiorities and potential applications, the lithium storage utilization of the Sn-Fe binary oxide nanohybrids has been selected as an objective application, and the nanohybrids exhibit Sn/Fe ratio-dependent lithium storage performance. As a representative example, the 2D/1D SnO2-Fe2O3 hierarchitectures manifest markedly enhanced Li-storage performance in terms of reversible capacities and cycling stability in comparison with their constituent units, i.e., bare SnO2 nanosheets and Fe2O3 nanorods. The proposed cyanogel derived thermal-oxidation strategy could open up new opportunities for constructing heterometallic oxide nanohybrids, and the rationally designed metal oxide nanohybrids may find broad applications in energy, catalysis, and sensing fields by virtue of their structural and compositional features. PMID- 27119206 TI - Rebaudiosides R and S, Minor Diterpene Glycosides from the Leaves of Stevia rebaudiana. AB - Two new diterpene glycosides have been isolated from a commercial extract of the leaves of Stevia rebaudiana. Compound 1 was shown to be 13-[(2-O-beta-d glucopyranosyl-3-O-beta-d-glucopyranosyl-beta-d-xylopyranosyl)oxy]ent-kaur-16-en 19-oic acid beta-d-glucopyranosyl ester (rebaudioside R), while compound 2 was determined to be 13-[(2-O-alpha-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]ent kaur-16-en-19-oic acid 2-O-alpha-l-rhamnopyranosyl-beta-d-glucopyranosyl ester (rebaudioside S). Six additional known compounds were identified, dulcoside B, 13 [(2-O-beta-d-xylopyranosyl-beta-d-glucopyranosyl)oxy]ent-kaur-16-en-19-oic acid beta-d-glucopyranosyl ester, eugenol diglucoside, rebaudioside G, 13-[(2-O-6 deoxy-beta-d-glucopyranosyl-3-O-beta-d-glucopyranosyl-beta-d glucopyranosyl)oxy]ent-kaur-16-en-19-oic acid beta-d-glucopyranosyl ester, and rebaudioside D (3), respectively. The structures of 1 and 2 were determined based on comprehensive 1D and 2D NMR (COSY, HSQC, and HMBC) studies. A high-quality crystal of compound 3 allowed confirmation of its structure by X-ray diffraction. PMID- 27119207 TI - Flexible MgO Barrier Magnetic Tunnel Junctions. AB - Flexible MgO barrier magnetic tunnel junction (MTJ) devices are fabricated using a transfer printing process. The flexible MTJ devices yield significantly enhanced tunneling magnetoresistance of ~300% and improved abruptness of switching, as residual strain in the MTJ structure is released during the transfer process. This approach could be useful for flexible electronic systems that require high-performance memory components. PMID- 27119208 TI - Amphiphilic Graft Copolymers as a Versatile Binder for Various Electrodes of High Performance Lithium-Ion Batteries. AB - It is known that grafting one polymer onto another polymer backbone is a powerful strategy capable of combining dual benefits from each parent polymer. Thus amphiphilic graft copolymer precursors (poly(vinylidene difluoride)-graft poly(tert-butylacrylate) (PVDF-g-PtBA)) have been developed via atom transfer radical polymerization, and demonstrated its outstanding properties as a promising binder for high-performance lithium-ion battery (LIB) by using in situ pyrolytic transformation of PtBA to poly(acrylic acid) segments. In addition to its superior mechanical properties and accommodation capability of volume expansion, the Si anode with PVDF-g-PtBA exhibits the excellent charge and discharge capacities of 2672 and 2958 mAh g(-1) with the capacity retention of 84% after 50 cycles. More meaningfully, the graft copolymer binder shows good operating characteristics in both LiN0.5 M1.5 O4 cathode and neural graphite anode, respectively. By containing such diverse features, a graft copolymer loaded LiN0.5 M1.5 O4 /Si-NG full cell has been successfully achieved, which delivers energy density as high as 546 Wh kg(-1) with cycle retention of ~70% after 50 cycles (1 C). For the first time, this work sheds new light on the unique nature of the graft copolymer binders in LIB application, which will provide a practical solution for volume expansion and low efficiency problems, leading to a high-energy-density lithium-ion chemistry. PMID- 27119209 TI - Rice OVERLY TOLERANT TO SALT 1 (OTS1) SUMO protease is a positive regulator of seed germination and root development. AB - Salinity is one of the major environmental stresses affecting rice production worldwide. Improving rice salt tolerance is a critical step for sustainable food production. Posttranslational modifications of proteins greatly expand proteome diversity, increase functionality and allow quick responses to environmental stresses, all at low cost to the cell. SUMO mediated modification of substrate proteins is a highly dynamic process governed by the balance of activities of SUMO E3 ligases and deconjugating SUMO proteases. In recent years, SUMO (Small Ubiquitin like Modifier) conjugation of proteins has emerged as an influential regulator of stress signaling in the model plant Arabidopsis. However SUMOylation remain largely under studied in crop plants. We recently identified the SUMO protease gene family in rice and demonstrated a role for OsOTS1 SUMO proteases in salt stress. Interestingly, rice plants silencing OsOTS1 also show significantly reduced germination rate. Knockdown of OsOTS1 gene expression affects root growth by primarily reducing cell size rather than cell division. PMID- 27119211 TI - The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities. AB - Research has suggested that individuals who engage in self-injurious behavior may have enhanced expressions of pain, which contradicts previous assertions of blunted pain sensitivity in this population. The purpose of this study was to measure expressions of pain among young children being evaluated for autism and other neurodevelopmental disabilities. The frequency of pain-related behaviors was assessed during everyday routines using the Non-Communicating Children's Pain Checklist (NCCPC-R) for 51 children. Significant group differences between children with and without self-injury were found for the NCCPC-R total scores. The frequency and severity of self-injury, aggression, and stereotypy were also highly correlated with the total scores on the NCCPC-R. These results continue to support that individuals with self-injury may have enhanced expressions of pain. PMID- 27119210 TI - Comparing Single Case Design Overlap-Based Effect Size Metrics From Studies Examining Speech Generating Device Interventions. AB - Meaningfully synthesizing single case experimental data from intervention studies comprised of individuals with low incidence conditions and generating effect size estimates remains challenging. Seven effect size metrics were compared for single case design (SCD) data focused on teaching speech generating device use to individuals with intellectual and developmental disabilities (IDD) with moderate to profound levels of impairment. The effect size metrics included percent of data points exceeding the median (PEM), percent of nonoverlapping data (PND), improvement rate difference (IRD), percent of all nonoverlapping data (PAND), Phi, nonoverlap of all pairs (NAP), and Tau(novlap). Results showed that among the seven effect size metrics, PAND, Phi, IRD, and PND were more effective in quantifying intervention effects for the data sample (N = 285 phase or condition contrasts). Results are discussed with respect to issues concerning extracting and calculating effect sizes, visual analysis, and SCD intervention research in IDD. PMID- 27119212 TI - Contributors to Adult Sibling Relationships and Intention to Care of Siblings of Individuals With Down Syndrome. AB - The contribution of childhood sibling relationships to adult sibling relationships and intention to provide care was investigated in a sample in which one member of each dyad had Down syndrome. Thirty-nine adult siblings of an adult with Down syndrome who had participated in a study of sibling relationships in childhood/adolescence provided data about the quality of current relationships and of their intention to provide care for their brother/sister with Down syndrome in the future. Only behavior problems in the child with Down syndrome predicted warmth of the current adult relationship. Although adult sibling relationships were reported to be warm, the quality of neither the current nor the past relationship was associated with the reported intention to provide care. PMID- 27119213 TI - Stimulus Overselectivity in Autism, Down Syndrome, and Typical Development. AB - Stimulus overselectivity refers to maladaptive narrow attending that is a common learning problem among children with intellectual disabilities and frequently associated with autism. The present study contrasted overselectivity among groups of children with autism, Down syndrome, and typical development. The groups with autism and Down syndrome were matched for intellectual level, and all three groups were matched for developmental levels on tests of nonverbal reasoning and receptive vocabulary. Delayed matching-to-sample tests presented color/form compounds, printed words, photographs of faces, Mayer-Johnson Picture Communication Symbols, and unfamiliar black forms. No significant differences among groups emerged for test accuracy scores. Overselectivity was not statistically overrepresented among individuals with autism in contrast to those with Down syndrome or typically developing children. PMID- 27119215 TI - A Qualitative Analysis of Imitation Performances of Preschoolers With Down Syndrome. AB - A number of studies suggest that imitation is a characteristic strength in children with Down Syndrome (DS). The present study aims to discover whether imitation performances are qualitatively phenotypical in DS. Eight preschoolers with DS were matched on chronological, mental, language and imitation age with 8 preschoolers with intellectual disability of undifferentiated etiology (ID-UND). Imitation performances on the Preschool Imitation and Praxis Scale were videotaped for blind scoring on 30 possible errors. Children with DS made fewer production errors (synkinesias, OR 0.3 [0.1-0.7]), but more conceptual errors (substitution, OR 2.5 [1.6-3.9]) compared to children with ID-UND. This finding is in line with the view of a cognitive phenotype in DS, which is characterized by preserved visuospatial and impaired language abilities. PMID- 27119214 TI - A Spoken-Language Intervention for School-Aged Boys With Fragile X Syndrome. AB - Using a single case design, a parent-mediated spoken-language intervention was delivered to three mothers and their school-aged sons with fragile X syndrome, the leading inherited cause of intellectual disability. The intervention was embedded in the context of shared storytelling using wordless picture books and targeted three empirically derived language-support strategies. All sessions were implemented through distance videoteleconferencing. Parent education sessions were followed by 12 weekly clinician coaching and feedback sessions. Data were collected weekly during independent homework and clinician observation sessions. Relative to baseline, mothers increased their use of targeted strategies, and dyads increased the frequency and duration of story-related talking. Generalized effects of the intervention on lexical diversity and grammatical complexity were observed. Implications for practice are discussed. PMID- 27119218 TI - SAINTq: Scoring protein-protein interactions in affinity purification - mass spectrometry experiments with fragment or peptide intensity data. AB - SAINT (Significance Analysis of INTeractome) is a probabilistic method for scoring bait-prey interactions against negative controls in affinity purification - mass spectrometry (AP-MS) experiments. Our published SAINT algorithms use spectral counts or protein intensities as the input for calculating the probability of true interaction, which enables objective selection of high confidence interactions with false discovery control. With the advent of new protein quantification methods such as Data Independent Acquisition (DIA), we redeveloped the scoring method to utilize the reproducibility information embedded in the peptide or fragment intensity data as a key scoring criterion, bypassing protein intensity summarization required in the previous SAINT workflow. The new software package, SAINTq, addresses key issues in the interaction scoring based on intensity data, including treatment of missing values and selection of peptides and fragments for scoring each prey protein. We applied SAINTq to two independent DIA AP-MS data sets profiling the interactome of MEPCE and EIF4A2 and that of 14-3-3beta, and benchmarked the performance in terms of recovering previously reported literature interactions in the iRefIndex database. In both data sets, the SAINTq analysis using the fragment-level intensity data led to the most sensitive detection of literature interactions at the same level of specificity. This analysis outperforms the analysis using protein intensity data summed from fragment intensity data that is equivalent to the model in SAINTexpress. PMID- 27119219 TI - Reply letter to "Insurance claims of alleged anesthesiology malpractice in a Spanish series". PMID- 27119220 TI - Subcortical connections of the perirhinal, postrhinal, and entorhinal cortices of the rat. I. afferents. AB - In this study the subcortical afferents for the rat PER areas 35 and 36, POR, and the lateral and medial entorhinal areas (LEA and MEA) were characterized. We analyzed 33 retrograde tract-tracing experiments distributed across the five regions. For each experiment, we estimated the total numbers, percentages, and densities of labeled cells in 36 subcortical structures and nuclei distributed across septum, basal ganglia, claustrum, amygdala, olfactory structures, thalamus, and hypothalamus. We found that the complement of subcortical inputs differs across the five regions, especially the PER and POR. The PER receives input from the reuniens, suprageniculate, and medial geniculate thalamic nuclei as well as the amygdala. Overall, the subcortical inputs to the PER were consistent with a role in perception, multimodal processing, and the formation of associations that include the motivational significance of individual items and objects. Subcortical inputs to the POR were dominated by the dorsal thalamus, particularly the lateral posterior nucleus, a region implicated in visuospatial attention. The complement of subcortical inputs to the POR is consistent with a role in representing and monitoring the local spatial context. We also report that, in addition to the PER, the LEA and the medial band of the MEA also receive strong amygdala input. In contrast, subcortical input to the POR and the MEA lateral band includes much less amygdala input and is dominated by dorsal thalamic nuclei, particularly nuclei involved in spatial information processing. Thus, some subcortical inputs are consistent with the view that there is functional differentiation along the septotemporal axis of the hippocampus, but others provide considerable integration. Overall, we conclude that the patterns of subcortical inputs to the PER, POR, and the entorhinal LEA and MEA provide further evidence for functional differentiation in the medial temporal lobe. (c) 2016 Wiley Periodicals, Inc. PMID- 27119222 TI - Taking Control: The Efficacy and Durability of a Peer-Led Uncertainty Management Intervention for People Recently Diagnosed With HIV. AB - HIV creates substantial uncertainty for people infected with the virus, which subsequently affects a host of psychosocial outcomes critical to successful management of the disease. This study assessed the efficacy and durability of a theoretically driven, one-on-one peer support intervention designed to facilitate uncertainty management and enhance psychosocial functioning for patients newly diagnosed with HIV. Using a pretest-posttest control group design, 98 participants received information and training in specific communication strategies (e.g., disclosing to friends and family, eliciting social support, talking to health care providers, using the Internet to gather information, and building social networks through AIDS service organizations). Participants in the experimental group attended six 1-hour sessions, whereas control participants received standard of care for 12 months (after which they received the intervention). Over time, participants in the intervention fared significantly better regarding (a) illness uncertainty, (b) depression, and (c) satisfaction with social support than did those in the control group. Given the utility and cost-effectiveness of this intervention and the uncertainty of a multitude of medical diagnoses and disease experiences, further work is indicated to determine how this program could be expanded to other illnesses and to address related factors, such as treatment adherence and clinical outcomes. PMID- 27119221 TI - From Chemical Mutagenesis to Post-Expression Mutagenesis: A 50 Year Odyssey. AB - Site-directed (gene) mutagenesis has been the most useful method available for the conversion of one amino acid residue of a given protein into another. Until relatively recently, this strategy was limited to the twenty standard amino acids. The ongoing maturation of stop codon suppression and related technologies for unnatural amino acid incorporation has greatly expanded access to nonstandard amino acids by expanding the scope of the translational apparatus. However, the necessity for translation of genetic changes restricts the diversity of residues that may be incorporated. Herein we highlight an alternative approach, termed post-expression mutagenesis, which operates at the level of the very functional biomolecules themselves. Using the lens of retrosynthesis, we highlight prospects for new strategies in protein modification, alteration, and construction which will enable protein science to move beyond the constraints of the "translational filter" and lead to a true synthetic biology. PMID- 27119223 TI - Validity and reliability of the Chinese version of the Daily Living Self-Efficacy Scale among stroke patients. AB - The aim of this study was to examine the reliability and validity of the Chinese version of the Daily Living Self-Efficacy Scale (DLSES) in stroke patients. In total, 172 participants were recruited from a local hospital in China. The internal consistent reliability and convergent validity of the total scale and activities of daily living (ADL) and psychosocial functioning subscales were examined and factor analysis was carried out. Cronbach's alphas for the Chinese version of the DLSES, ADL subscale, and psychosocial subscale were 0.96, 0.90, and 0.95, respectively. In the factor analysis, two factors (ADL and psychosocial functioning) were extracted, explaining 84.4% of the total variance in self efficacy (chi/d.f.=2.19, root mean square error of approximation=0.08, normed fit index=0.95, comparative fit index=0.98, incremental fit index=0.98). Convergent validity was confirmed by positive relationships between the Chinese version of the DLSES and the Modified Fall Efficacy Scale (r=0.87). The ADL subscale was associated positively with the Barthel Index (r=0.74) and the psychosocial functioning subscale was associated negatively with the Functional Activities Questionnaire (r=-0.73) and Center for Epidemiologic Studies Depression Scale (r= 0.44). The Chinese version of the DLSES was shown to be a reliable and valid measure of self-efficacy in stroke patients. PMID- 27119224 TI - The effectiveness of external sensory cues in improving functional performance in individuals with Parkinson's disease: a systematic review with meta-analysis. AB - A systematic review with meta-analysis was performed to investigate the effect external sensory cued therapy on activities of daily living (ADL) performance that include walking and daily tasks such as dressing for individuals with Parkinson's disease (PD). A detailed computer-aided search of the literature was applied to MEDLINE, Cumulative Index to Nursing and Allied Health Literature, EMBASE and PubMed. Studies investigating the effects of external sensory cued therapy on ADL performance for individuals with PD in all stages of disease progression were collected. Relevant articles were critically reviewed and study results were synthesized by two independent researchers. A data-analysis method was used to extract data from selected articles. A meta-analysis was carried out for all randomized-controlled trials. Six studies with 243 individuals with PD were included in this review. All six studies yielded positive findings in favour of external sensory cues. The meta-analysis showed that external sensory cued therapy improved statistically after treatment (P=0.011) and at follow-up (P<0.001) for ADL performance. The results of this review provided evidence of an improvement in ADL performance in general in individuals with PD. It is recommended that clinicians incorporate external sensory into a training programme focused on improving daily task performance. PMID- 27119226 TI - Multiple analyses of large-scale genome-wide association study highlight new risk pathways in lumbar spine bone mineral density. AB - Osteoporosis is a common human complex disease. It is mainly characterized by low bone mineral density (BMD) and low-trauma osteoporotic fractures (OF). Until now, a large proportion of heritability has yet to be explained. The existing large scale genome-wide association studies (GWAS) provide strong support for the investigation of osteoporosis mechanisms using pathway analysis. Recent findings showed that different risk pathways may be involved in BMD in different tissues. Here, we conducted multiple pathway analyses of a large-scale lumbar spine BMD GWAS dataset (2,468,080 SNPs and 31,800 samples) using two published gene-based analysis software including ProxyGeneLD and the PLINK. Using BMD genes from ProxyGeneLD, we identified 51 significant KEGG pathways with adjusted P<0.01. Using BMD genes from PLINK, we identified 38 significant KEGG pathways with adjusted P<0.01. Interestingly, 33 pathways are shared in both methods. In summary, we not only identified the known risk pathway such as Wnt signaling, in which the top GWAS variants are significantly enriched, but also highlight some new risk pathways. Interestingly, evidence from further supports the involvement of these pathways in MBD. PMID- 27119227 TI - Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha particle emitting radionuclide in a preclinical model of human breast cancer. AB - The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer. PMID- 27119228 TI - NEDL2 regulates enteric nervous system and kidney development in its Nedd8 ligase activity-dependent manner. AB - The GDNF (Glial cell line-derived neurotrophic factor)/Ret/Akt signaling pathway is essential to the development of ENS (enteric nervous system) as well as kidney. We previously showed that the HECT-type E3 ligase NEDL2 (Nedd4-like ligase 2) is required for the ENS development by activating GDNF/Ret/Akt. However, the underlying mechanism remains unknown. Here we show that in addition to ENS, NEDL2 is also pivotal for kidney development since about 1/3 of Nedl2 deficient mice displayed postnatal unilateral or bilateral kidney hydronephrosis. Double knockout of Nedl1 and Nedl2 in mice leads to postnatal lethal within 2 weeks and the phenotypes resemble those of Nedl2 single knockout mice. Surprisingly, its close member NEDL1 is dispensable for ENS and kidney function and the reason is lack of NEDL1 expression in these systems during early development. Furthermore, biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. Intriguingly, we found that NEDL2 harbours intrinsic Nedd8 ligase activity with cysteine 1341 as the core site. NEDL2 upregulates GDNF-stimulated Akt activity dependent of its Nedd8 ligase activity but not its ubiquitin ligase activity. These findings demonstrate that NEDL2 but not NEDL1 is required for ENS and kidney development in a unique Nedd8 ligase-dependent manner. PMID- 27119229 TI - Downregulation and pro-apoptotic effect of hypoxia-inducible factor 2 alpha in hepatocellular carcinoma. AB - The role of HIF-2alpha in hepatocellular carcinoma (HCC) is unclear. The aim of the present study was to investigate the expression pattern and role of HIF 2alpha in HCC patients. Immunohistochemical staining and western blotting analyses were applied to detect the protein level of HIF-2alpha in 206 paired HCC and peritumoral tissues. Kaplan-Meier survival and Cox proportional hazard regression analyses were performed to identify risk factors for overall survival and recurrence-free survival in these patients. The function of HIF-2alpha was studied in HCC cells and in vivo models. We found that the protein levels of HIF 2alpha in HCC tissues were lower than in peritumoral tissues, and were negatively correlated with tumor size (P < 0.05). Kaplan-Meier survival and univariate analysis revealed that HCC patients with high HIF-2alpha protein levels had longer overall survival (P < 0.05). Over-expression of HIF-2alpha induced apoptosis in HCC cells and increased the levels of pro-apoptotic proteins, Bak, ZBP-89 and PDCD4, whereas the inhibition of HIF-2alpha expression achieved opposite results. The findings were confirmed in a mouse HCC xenograft model. In conclusion, our study revealed that HIF-2alpha was decreased and played an anti tumorigenic role in HCC. PMID- 27119230 TI - ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation. AB - Glioma-initiating cells possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Therefore, their elimination is an essential factor for the development of efficient therapy. Here, we report that endoplasmic reticulum (ER) stress inducer tunicamycin inhibits glioma-initiating cell self-renewal as determined by neurosphere formation assay. Moreover, tunicamycin decreases the efficiency of glioma initiating cell to initiate tumor formation. Although tunicamycin induces glioma initiating cell apoptosis, apoptosis inhibitor z-VAD-fmk only partly abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Indeed, tunicamycin reduces the expression of self-renewal regulator Sox2 at translation level. Overexpression of Sox2 obviously abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Taken together, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma initiating cell partly through reducing Sox2 translation. This finding provides a cue to potential effective treatment of glioblastoma through controlling stem cells. PMID- 27119232 TI - Impact of PI3K/AKT/mTOR pathway activation on the prognosis of patients with head and neck squamous cell carcinomas. AB - The PI3K/AKT/mTOR signaling pathway has emerged as one of the most frequently deregulated in head and neck squamous cell carcinomas (HNSCC). Numerous alterations of various upstream and downstream components have been described; however, their prognostic significance and impact on HNSCC patient survival remains to be established. This was addressed using an unbiased cohort of 93 consecutive and homogeneous surgically treated HNSCC patients and results confirmed in 432 HNSCC patients. Our findings reveal the high prevalence of S6 phosphorylation, a surrogate marker of mTORC1 activation, in HNSCC specimens (>70%) and, more importantly, demonstrate its relevance on clinical outcome. Phosphorylation of ribosomal protein S6 on either Ser235/236 or Ser240/244 was consistently and significantly correlated with favorable prognosis, although with differences depending on the tumor site. Thus, p-S6 expression was significantly correlated with better disease-specific survival specifically in the subgroup of laryngeal carcinoma patients (P< 0.001). In addition, multivariate regression models revealed p-S6 to be an inverse and independent predictor of lymph-node metastasis (P= 0.004) and distant metastasis (P= 0.006). Taken together, this study unveils an unprecedented correlation of mTOR activation with improved clinical outcome in patients with laryngeal carcinomas and uncovers the potential of p-S6 expression as a good prognostic biomarker and an inverse predictor of lymph node and distant metastases. These results should be of broad interest as immunohistochemical detection of p-S6 may help to stratify patients and guide treatment decisions. PMID- 27119234 TI - Therapeutic deferoxamine and deferiprone monitoring in beta-thalassemia patients' plasma by field-amplified sample injection and sweeping in capillary electrophoresis. AB - One CE method was established for detecting deferoxamine (DFO) and deferiprone (DFR) in plasma. For beta-thalassemia patients, DFO and DFR are major medicines to treat the iron overload caused by blood transfusion. Field-amplified sample injection combined with sweeping was used for sensitivity enhancement in CE. This method was performed on an uncoated fused-silica capillary. After liquid-liquid extraction, the plasma samples were electrokinetically injected into capillary at +10 kV for 180 s. The phosphate buffer (100 mM) containing 50 mM triethanolamine was used as the BGE (pH 6.6). Separation buffer was phosphate buffer (100 mM, pH 3.0) containing 150 mM SDS. This method showed good linearity (r >= 0.9960). Precision and accuracy were evaluated by the results of RSD and relative error of intrabatch and interbatch analyses, and all of the absolute values were less than 6.12%. The LODs (S/N = 3) were 200 ng/mL for DFO, and 25 ng/mL for DFR. The LOQ (S/N = 10) of DFO and DFR were 600 and 75 ng/mL, respectively. This method was applied for clinical applications of five beta-thalassemia patients. PMID- 27119233 TI - Expression and prognostic significance of CCL11/CCR3 in glioblastoma. AB - Glioblastoma (GBM) is the most lethal primary nervous system cancer, but due to its rarity and complexity, its pathogenesis is poorly understood. To identify potential tumorigenic factors in GBM, we screened antibody-based cytokine arrays and found that CCL11 was upregulated. We then demonstrated in vitro that both CCL11 and its receptor, CCR3, were overexpressed and promoted the proliferation, migration and invasion of cancer cells. To examine the clinical significance of CCL11/CCR3, 458 GBM samples were divided into a training cohort with 225 cases and a test cohort containing 233 cases. In the training set, immunohistochemical analysis showed overexpression of CCL11 and CCR3 were correlated with unfavorable overall survival (OS). We further developed a prognostic classifier combining CCL11 and CCR3 expression and Karnofsky performance status (KPS) for predicting one-year survival in GBM patients. Receiver operating characteristic (ROC) analysis demonstrated that this predictor achieved 90.7% sensitivity and 73.4% specificity. These results were validated with the test sample set. Our findings suggest that CCL11-CCR3 binding is involved in the progression of GBM and may prompt a novel therapeutic approach. In addition, CCL11 and CCR3 expression, combined with KPS, may be used as an accurate predictor of one-year survival in GBM patients. PMID- 27119231 TI - Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1. AB - A subset of Non-Small Cell Lung Carcinoma (NSCLC) carries chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene. ALK rearranged NSCLC are typically adenocarcinoma characterized by a solid signet ring cell pattern that is frequently associated with a metastatic phenotype. Recent reports linked the presence of ALK rearrangement to an epithelial mesenchymal transition (EMT) phenotype in NSCLC, but the extent and the mechanisms of an ALK-mediated EMT in ALK-rearranged NSCLC are largely unknown. We found that the ALK-rearranged H2228 and DFCI032, but not the H3122, cell lines displayed a mesenchymal phenotype. In these cell lines, oncogenic ALK activity dictated an EMT phenotype by directly suppressing E-cadherin and up-regulating vimentin expression, as well as expression of other genes involved in EMT. We found that the epithelial splicing regulatory protein 1 (ESRP1), a key regulator of the splicing switch during EMT, was repressed by EML4-ALK activity. The treatment of NSCLC cells with ALK tyrosine kinase inhibitors (TKIs) led to up regulation of ESRP1 and E-cadherin, thus reverting the phenotype from mesenchymal to epithelial (MET). Consistently, ESRP1 knock-down impaired E-cadherin up regulation upon ALK inhibition, whereas enforced expression of ESRP1 was sufficient to increase E-cadherin expression. These findings demonstrate an ALK oncogenic activity in the regulation of an EMT phenotype in a subset of NSCLC with potential implications for the biology of ALK-rearranged NSCLC in terms of metastatic propensity and resistance to therapy. PMID- 27119235 TI - Moonshot to Malawi. PMID- 27119236 TI - Colorectal Cancer on the Decline--Why Screening Can't Explain It All. PMID- 27119238 TI - Workplace Violence against Health Care Workers in the United States. PMID- 27119239 TI - IMAGES IN CLINICAL MEDICINE. Aortocoronary Saphenous-Vein-Graft Aneurysms. PMID- 27119240 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 13-2016. A 49-Year-Old Woman with Sudden Hemiplegia and Aphasia during a Transatlantic Flight. PMID- 27119241 TI - The CRISPR Way to Think about Duchenne's. PMID- 27119242 TI - Sofosbuvir and Velpatasvir for Patients with HCV Infection. PMID- 27119237 TI - Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. AB - BACKGROUND: Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression free survival. RESULTS: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.). PMID- 27119243 TI - Sofosbuvir and Velpatasvir for Patients with HCV Infection. PMID- 27119244 TI - Mass Drug Administration for Scabies Control. PMID- 27119245 TI - Mass Drug Administration for Scabies Control. PMID- 27119246 TI - Mass Drug Administration for Scabies Control. PMID- 27119247 TI - Transcatheter Aortic-Valve Replacement in Clinical Practice. PMID- 27119248 TI - Transcatheter Aortic-Valve Replacement in Clinical Practice. PMID- 27119249 TI - Transcatheter Aortic-Valve Replacement in Clinical Practice. PMID- 27119250 TI - Comfort Care for Patients Dying in the Hospital. PMID- 27119251 TI - Comfort Care for Patients Dying in the Hospital. PMID- 27119252 TI - Reform of Clinical Research Regulations. PMID- 27119253 TI - Reform of Clinical Research Regulations. PMID- 27119254 TI - IMAGES IN CLINICAL MEDICINE. Oral Amalgam Tattoo Mimicking Melanoma. PMID- 27119255 TI - Exploring the relationships between maternal and child metacognitions and child anxiety. AB - Research has shown that anxiety may be transmitted through verbal information pathways, for example, when parents share their anxious cognitions with their child. Less is known about the influence of parental metacognitions, that is, beliefs regarding thoughts, on child anxiety. We explored the relations between metacognitions in mothers and their children and anxiety in the children. Our study included 111 non-clinical children aged 8 to 12 years and their mothers. Children rated their metacognitions, worry and anxiety, and mothers rated their metacognitions. Results indicated agreement between maternal and child metacognitions. Maternal metacognitions were positively associated with children's anxiety symptoms and worry, and this relation was mediated by the children's metacognitions. Our results warrant further examination of the role of parental metacognitions in child anxiety. PMID- 27119256 TI - Effectiveness of cognitive behavioral therapy on health-related quality of life: An evaluation of therapies provided by trainee therapists. AB - The present study was carried out to examine the treatment effect of cognitive behavioral therapy provided by trainee therapists at a university clinic, focusing on health-related quality of life (HRQOL) optimism and symptoms. The study was conducted through a repeated measures design and included a treatment group (n = 21), which received cognitive behavioral therapy for an average of 10.7 therapy sessions and a control group (n = 14), that was put on a wait list for 8.6 weeks on average. After treatment, the treatment group improved significantly concerning general health (p = 0.028) and optimism (p = 0.027). In addition, clients improved in several areas within mental health and displayed some reduction in anxiety symptoms. Concurrently, the results also indicated some improvement within the control group, which may have been caused by the initial therapeutic contact, expectancy effects or spontaneous remission. The study concluded that cognitive behavioral therapy provided by trainee therapists may have a positive effect on areas within HRQOL and optimism. PMID- 27119257 TI - Emotion processing deficits in the different dimensions of psychometric schizotypy. AB - Schizotypy refers to a personality structure indicating "proneness" to schizophrenia. Around 10% of the general population has increased schizotypal traits, they also share other core features with schizophrenia and are thus at heightened risk for developing schizophrenia and spectrum disorders. A key aspect in schizophrenia-spectrum pathology is the impairment observed in emotion-related processes. This review summarizes findings on impairments related to central aspects of emotional processes, such as emotional disposition, alexithymia, facial affect recognition and speech prosody, in high schizotypal individuals in the general population. Although the studies in the field are not numerous, the current findings indicate that all these aspects of emotional processing are deficient in psychometric schizotypy, in accordance to the schizophrenia-spectrum literature. A disturbed frontotemporal neural network seems to be the critical link between these impairments, schizotypy and schizophrenia. The limitations of the current studies and suggestions for future research are discussed. PMID- 27119258 TI - Relationship between advanced glycation end-product accumulation and low skeletal muscle mass in Japanese men and women. AB - AIM: The present study aimed to investigate the relationship between advanced glycation end-product accumulation and skeletal muscle mass among middle-aged and older Japanese men and women. METHODS: A total of 132 participants enrolled in this cross-sectional study. Skin autofluorescence was assessed as a measure of advanced glycation-end products. Appendicular skeletal muscle mass was measured using dual-energy X-ray absorptiometry, and skeletal muscle index was calculated by dividing appendicular skeletal muscle mass by height squared. Participants were divided into two groups (low skeletal muscle index and normal skeletal muscle index) using the Asian Working Group for Sarcopenia's skeletal muscle index criteria for diagnosing sarcopenia. Multivariate logistic regression analysis and the area under the receiver operating characteristic curve were used to determine significant factors associated with low skeletal muscle index. RESULTS: Participants consisted of 70 men (mean age 57 +/- 10 years) and 62 women (mean age 60 +/- 11 years). There were 31 and 101 participants in the low and normal skeletal muscle index groups, respectively. Skin autofluorescence was significantly higher in the low skeletal muscle index group compared with the normal skeletal muscle index group (P < 0.01). Skin autofluorescence was a significant independent factor associated with low skeletal muscle index based on multivariate logistic regression analysis (odds ratio 15.7, 95% confidence interval 1.85-133.01; P = 0.012). The cut-off for skin autofluorescence was 2.45 arbitrary units, with a sensitivity of 0.75 and specificity of 0.91. CONCLUSIONS: Skin autofluorescence was an independent factor associated with low skeletal muscle index among middle-aged and older Japanese men and women. Geriatr Gerontol Int 2017; 17: 785-790. PMID- 27119259 TI - Predicting Electrophoretic Mobility of Protein-Ligand Complexes for Ligands from DNA-Encoded Libraries of Small Molecules. AB - Selection of target-binding ligands from DNA-encoded libraries of small molecules (DELSMs) is a rapidly developing approach in drug-lead discovery. Methods of kinetic capillary electrophoresis (KCE) may facilitate highly efficient homogeneous selection of ligands from DELSMs. However, KCE methods require accurate prediction of electrophoretic mobilities of protein-ligand complexes. Such prediction, in turn, requires a theory that would be applicable to DNA tags of different structures used in different DELSMs. Here we present such a theory. It utilizes a model of a globular protein connected, through a single point (small molecule), to a linear DNA tag containing a combination of alternating double-stranded and single-stranded DNA (dsDNA and ssDNA) regions of varying lengths. The theory links the unknown electrophoretic mobility of protein-DNA complex with experimentally determined electrophoretic mobilities of the protein and DNA. Mobility prediction was initially tested by using a protein interacting with 18 ligands of various combinations of dsDNA and ssDNA regions, which mimicked different DELSMs. For all studied ligands, deviation of the predicted mobility from the experimentally determined value was within 11%. Finally, the prediction was tested for two proteins and two ligands with a DNA tag identical to those of DELSM manufactured by GlaxoSmithKline. Deviation between the predicted and experimentally determined mobilities did not exceed 5%. These results confirm the accuracy and robustness of our model, which makes KCE methods one step closer to their practical use in selection of drug leads, and diagnostic probes from DELSMs. PMID- 27119260 TI - Responses of endothelial cells, smooth muscle cells, and platelets dependent on the surface topography of polytetrafluoroethylene. AB - In this study, the effect of different structures (flat, expanded, and electrospun) of polytetrafluoroethylene (PTFE) on the interactions of endothelial cells (ECs), smooth muscle cells (SMCs), and platelets was investigated. In addition, the mechanisms that govern the interactions between ECs, SMCs, and platelets with different structures of PTFE were discussed. The surface characterizations showed that the different structures of PTFE have the same surface chemistry, similar surface wettability and zeta potential, but uniquely different surface topography. The viability, proliferation, morphology, and phenotype of ECs and SMCs interacted with different structures of PTFE were investigated. Expanded PTFE (ePTFE) provided a relatively better surface for the growth of ECs. In case of SMC interactions, although all the different structures of PTFE inhibited SMC growth, a maximum inhibitory effect was observed for ePTFE. In case of platelet interactions, the electrospun PTFE provided a better surface for preventing the adhesion and activation of platelets. Thus, this study demonstrated that the responses of ECs, SMCs, and platelets strongly dependent on the surface topography of the PTFE. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2291-2304, 2016. PMID- 27119261 TI - Vector-Borne Infections in Tornado-Displaced and Owner-Relinquished Dogs in Oklahoma, USA. AB - To determine the prevalence of infection with vector-borne agents in a cross section of dogs from Oklahoma, where canine vector-borne diseases are common, blood samples were evaluated through serology and molecular analysis. Antibodies reactive to Ehrlichia spp., Rickettsia rickettsii, R. montanensis, and "R. amblyommii" were detected in 10.5% (11/105), 74.3% (78/105), 58.1% (61/105), and 55.2% (58/105) of dogs, respectively. Presence of spotted fever group Rickettsia spp. DNA was identified in 13.1% (8/61) of shelter dogs but not in any pet dogs (0/44). DNA of "R. amblyommii" was confirmed by sequencing, constituting the first report of this agent in a naturally infected dog. Antigen of Dirofilaria immitis was detected in 10.5% (11/105) and 16.2% (17/105) of samples before and after heat treatment, respectively. In total, 87.6% (92/105) of the dogs had evidence of infection with at least one vector-borne disease agent, confirming high risk of exposure to multiple vector-borne disease agents, several of which are zoonotic. PMID- 27119262 TI - Rhodium-Catalyzed Enantioselective Arylation of Aliphatic Imines. AB - Chiral rhodium(I)-catalyzed highly enantioselective arylation of aliphatic N sulfonyl aldimines with arylboronic acids has been developed. This transformation is achieved by the use of a rhodium/bis(phosphoramidite) catalyst to give enantiomerically enriched alpha-branched amines (up to 99 % ee). In addition, this system enables efficient synthesis of (+)-NPS R-568 and Cinacalcet which are calcimimetic agents. PMID- 27119267 TI - Effect of prior statin use on outcome after severe traumatic brain injury in a South-East Asian population. AB - INTRODUCTION: Traumatic brain injury (TBI) is a global concern associated with high mortality and morbidity. Costs to individuals and society are extensive due to poor recovery, long-term disability and the young age group affected. Statins have emerged as potential therapeutic agents in TBI. This study aimed to investigate the protective effect of statins in severe TBI. METHODS: This case control study included adults with severe TBI. A sliding dichotomy approach was used to dichotomize mortality at 14-days and Glasgow Outcome Score (GOS) at 6 months. Logistic regression analysis was used to calculate the odds ratios (OR) for 14-day mortality and 6-month GOS. RESULTS: Equivalent cohorts of 59 age- and sex-matched statin and non-statin users were selected, resulting in population of 118 (mean age = 70.2 years, SD = 10.3), with a median Glasgow Coma Score of 5. Statins did not reduce the likelihood of mortality at 14 days (adjusted OR = 1.23, p = 0.68) or unfavourable outcome at 6 months (adjusted OR = 1.19, p = 0.78). CONCLUSIONS: Despite increasing evidence for benefit of statins in TBI, this study in an Asian population does not support this association, demonstrating no significant improvement in outcome for statin users. Further research is required to understand the mechanisms and impact of statins in TBI. PMID- 27119268 TI - Fiber Optic Surface Plasmon Resonance-Based Biosensor Technique: Fabrication, Advancement, and Application. AB - Fiber optic-based biosensors with surface plasmon resonance (SPR) technology are advanced label-free optical biosensing methods. They have brought tremendous progress in the sensing of various chemical and biological species. This review summarizes four sensing configurations (prism, grating, waveguide, and fiber optic) with two ways, attenuated total reflection (ATR) and diffraction, to excite the surface plasmons. Meanwhile, the designs of different probes (U-bent, tapered, and other probes) are also described. Finally, four major types of biosensors, immunosensor, DNA biosensor, enzyme biosensor, and living cell biosensor, are discussed in detail for their sensing principles and applications. Future prospects of fiber optic-based SPR sensor technology are discussed. PMID- 27119269 TI - Roles of collagen Q in MuSK antibody-positive myasthenia gravis. AB - The low-density lipoprotein receptor-related protein 4 (LRP4) and the muscle specific receptor tyrosine kinase (MuSK) form a tetrameric protein complex on the postsynaptic membrane at the neuromuscular junction (NMJ). Binding of agrin to LRP4 triggers phosphorylation of MuSK. Activated MuSK drives clustering of acetylcholine receptor (AChR). Wnt ligands also directly bind to MuSK to induce AChR clustering. MuSK anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. In addition, an extracellular proteoglycan, biglycan, binds to MuSK. Anti-MuSK autoantibodies (MuSK-IgG) are observed in 5 15% of autoimmune myasthenia gravis (MG) patients. MuSK-IgG blocks both ColQ-MuSK and LRP4-MuSK interactions. MuSK-IgG, LRP4, ColQ, and biglycan bind to the immunoglobulin-like domains 1 and 4 of MuSK. Lack of the effects of cholinesterase inhibitors in MuSK-MG patients is likely due to hindrance of ColQ MuSK interaction by MuSK-IgG and subsequent deficiency of AChE observed in model mice, which, however, has not been proven in MuSK-MG patients. As ColQ enhances expression of membrane-bound MuSK, inhibition of ColQ-MuSK interaction by MuSK IgG may account for lack of AChR clusters in MuSK-MG. We thus made passive transfer models using Colq+/+ and Colq-/- mice to dissect the effect of ColQ on AChR clustering in MuSK-MG. We found that MuSK-IgG-mediated suppression of LRP4 MuSK interaction, not of ColQ-MuSK interaction, caused defective AChR clustering. We also unexpectedly observed that both MuSK-IgG and ColQ suppressed agrin/LRP4/MuSK signaling in dose-dependent manners. Quantitative comparison revealed that MuSK-IgG blocked agrin-LRP4-MuSK signaling more than ColQ. We propose that attenuation of AChR clustering in MuSK-MG is due to hindrance of LRP4-MuSK interaction in the presence of agrin by MuSK-IgG. PMID- 27119270 TI - Laser Treatment of Nongenital Verrucae: A Systematic Review. AB - IMPORTANCE: Although cutaneous warts are common lesions, full remission is not always achieved with conventional therapies. Laser modalities including carbon dioxide (CO2), erbium:yttrium-aluminum-garnet (Er:YAG), pulsed dye (PDL), and Nd:YAG have been investigated as alternative treatments for warts. OBJECTIVE: To review the use and efficacy of lasers for treating nongenital cutaneous warts. EVIDENCE REVIEW: Published randomized clinical trials (RCTs), cohort studies, case series, and case reports involving laser treatment of nongenital warts were retrieved by searching PubMed with no date limits. Quality ratings of studies were based on a modified version of the Oxford Centre for Evidence-Based Medicine scheme for rating individual studies. A higher emphasis was placed on RCTs and prospective cohort studies with large sample sizes and detailed methodology. FINDINGS: There were 35 studies published between 1989 and 2015 that comprised an aggregate of 2149 patients. Simple and recalcitrant nongenital warts treated with lasers show variable response rates (CO2 laser, 50%-100%; Er:YAG laser, 72%-100%; PDL, 47%-100%; and Nd:YAG laser, 46%-100%). Current RCTs suggest that PDL is equivalent to conventional therapies such as cryotherapy and cantharidin. Combination therapies with lasers and other agents including bleomycin, salicylic acid, and light-emitting diode have shown some success. CONCLUSIONS AND RELEVANCE: Lasers can be an effective treatment option for both simple and recalcitrant warts. The lasers most studied for this purpose are CO2, PDL, and Nd:YAG, and of these, PDL has the fewest adverse effects. Currently, use of lasers for wart treatment is limited by lack of established treatment guidelines. Future studies are needed to compare laser modalities with each other and with nonlaser treatment options, and to establish optimal treatment protocols. PMID- 27119271 TI - Mevastatin suppresses melanogenesis by lowering the levels of cyclic adenosine monophosphate and cholesterol. PMID- 27119272 TI - Supramolecular vs Electronic Structure: The Effect of the Tilt Angle of the Active Group in the Performance of a Molecular Diode. AB - It is important to understand how the supramolecular structure of molecular junctions affects their performance. Such studies are challenging because it is difficult to separate electronic effects from supramolecular structural effects because both depend on each other. Here we show that by changing the connector group that connects the active component (a ferrocene unit) of a molecular diode to the backbone (an alkyl chain), both the electronic and supramolecular structures of the junctions are modified. The connector group determines the tilt angle of the Fc unit which in turn affects the packing structure of the molecular diodes. In this case, the supramolecular structure dominates over the electronic structure of the molecular diodes, and junctions with loosely packed SAMs result in poorly performing molecular diodes, while stiff, densely packed SAMs result in well-performing molecular diodes. PMID- 27119273 TI - Secondary organic aerosol origin in an urban environment: influence of biogenic and fuel combustion precursors. AB - Source contributions of organic aerosol (OA) are still not fully understood, especially in terms of quantitative distinction between secondary OA formed from anthropogenic precursors vs. that formed from natural precursors. In order to investigate the OA origin, a field campaign was carried out in Barcelona in summer 2013, including two periods characterized by low and high traffic conditions. Volatile organic compound (VOC) concentrations were higher during the second period, especially aromatic hydrocarbons related to traffic emissions, which showed a marked daily cycle peaking during traffic rush hours, similarly to black carbon (BC) concentrations. Biogenic VOC (BVOC) concentrations showed only minor changes from the low to the high traffic period, and their intra-day variability was related to temperature and solar radiation cycles, although a decrease was observed for monoterpenes during the day. The organic carbon (OC) concentrations increased from the first to the second period, and the fraction of non-fossil OC as determined by (14)C analysis increased from 43% to 54% of the total OC. The combination of (14)C analysis and Aerosol Chemical Speciation Monitor (ACSM) OA source apportionment showed that the fossil OC was mainly secondary (>70%) except for the last sample, when the fossil secondary OC only represented 51% of the total fossil OC. The fraction of non-fossil secondary OC increased from 37% of total secondary OC for the first sample to 60% for the last sample. This enhanced formation of non-fossil secondary OA (SOA) could be attributed to the reaction of BVOC precursors with NOx emitted from road traffic (or from its nocturnal derivative nitrate that enhances night-time semi-volatile oxygenated OA (SV-OOA)), since NO2 concentrations increased from 19 to 42 MUg m( 3) from the first to the last sample. PMID- 27119274 TI - Cerebral Venous Sinus Thrombosis From a Tertiary Care Teaching Hospital in India. AB - OBJECTIVE: The prognosis of cerebral venous sinus thrombosis (CVST) may be dependent on underlying causes and magnetic resonance imaging findings. We report the clinical, laboratory, and radiologic spectrum, and outcome of consecutive patients with CVST. METHODS: Consecutive patients with CVST over the last 15 years were subjected to detailed history, clinical examination, and laboratory tests as per fixed protocol. The diagnosis of CVST was based on MR venography. The magnetic resonance imaging findings and the sinuses involved were noted. The patients were treated with low-molecular-weight heparin or unfractionated heparin for 14 days, followed by oral anticoagulation. Hospital mortality and 3-month outcome (good or poor) were recorded and correlated with various clinical and laboratory parameters. RESULTS: There were 86 patients whose median age was 30 (6 to 76) years; 47 of them were females. Headache was present in 91.9%, vomiting in 68.6%, focal weakness in 53.5%, seizure in 51.2%, and altered sensorium in 53.5%. Female-specific etiology was present in 34%, prothrombotic condition in 62.8%, infections in 19.8%, and malignancy in 2.8%; no cause could be established in 25.6% of patients. Hyperhomocystinemia was present in 45.9% of patients. Five patients died in the unfractionated heparin group. At 3 months, 77 patients were followed up, of whom 68 had complete, 3 had partial, and 6 had poor recovery. The 3-month outcome was related to Glasgow Coma Scale score and type of heparin used. CONCLUSIONS: In our study multiple prothrombotic conditions were common, and low molecular-weight heparin reduces mortality and results in good outcome. PMID- 27119275 TI - Caring for Patients With Functional Neurological Disorders: A Case-oriented Review. AB - Patients with functional neurological symptoms are commonly seen in neurological practice. They have significant disability that may not improve and their care is costly. This article will use case histories to underline the important aspects of caring for patients with functional neurological disorders, including important features of the history, examination, neurobiology, appropriate investigations, and an approach to treatment. PMID- 27119276 TI - Meningiomatosis in an AIDS Patient Receiving Highly Active Antiretroviral Therapy (HAART). AB - INTRODUCTION: Currently, AIDS is the worldwide leading cause of death among 15- to 59-year-old individuals. This trend has had particularly harsh social and economic consequences in sub-Saharan Africa, where more than half of global AIDS deaths take place. In the United States, an estimated 1.2 million people are infected with HIV. In 2012, a worldwide estimate of 1.7 million deaths due to AIDS-related causes was reported.About 10% to 12% of all AIDS patients will develop intracranial tumors. Differential diagnosis should rule out brain tumors such as central nervous system lymphoma and gliomas, as well as infectious processes such as toxoplasmosis, tuberculosis, and cryptococcosis. CASE REPORT: A 27-year-old homosexual man was referred to our care center after 2 months of disabling left frontal headache. Upon AIDS diagnosis, the patient was given abacavir (ABC), lamivudine (3TC), and efavirenz (EFV), but he discontinued the treatment after 9 months and failed to attend follow-up appointments. Three years later, the patient returned to the hospital and received ABC, 3TC, and lopinavir/ritonavir (LPV/r). On admission, computed tomographic scan reported multiple contrast-enhancing lesions compatible with meningiomas. The patient underwent uncomplicated surgical resection of the frontal basal lesion originating in the left olfactory bulb. No new neurological deficits were reported during the postoperative stay. CONCLUSIONS: According to a literature revision, it is likely that associated meningiomas are more aggressive in AIDS patients. Severe immunosuppression and the HIV-Tat protein may be involved in the pathogenesis of tumoral growth. PMID- 27119277 TI - Refractory Mononeuritis Multiplex Due to Hepatitis C Infection and Cryoglobulinemia: Efficient Response to Rituximab. AB - BACKGROUND: Mononeuritis multiplex due to hepatitis C infection and cryoglobulinemia has no specific treatment guidelines. Despite the favorable evolution of the liver disease after treatment with interferon and ribavirin, neurological symptoms might not respond very efficiently to antiviral therapy. CASE REPORT: We report the case of a 50-year-old woman, with a mononeuritis multiplex related to cryoglobulinemia and hepatitis C virus infection, who was treated with rituximab. Hepatitis C virus infection was treated successfully with interferon-alpha and ribavirin, but the neurological symptoms were still worsening until rituximab therapy. Significant improvement of paraparesis and painful hypoesthesia were evident after the fourth infusion of rituximab. However, every 6 months, the neurological symptoms relapsed and the patient was subjected to a new cycle of rituximab therapy, with the disappearing of the paraparesis and hypoesthesias. CONCLUSIONS: This case highlights the potential use of rituximab in immune-mediated neuropathies, especially the mononeuritis multiplex associated with hepatitis C infection. PMID- 27119278 TI - Cervical Artery Dissection: Spotting the Zebra Among the Horses. PMID- 27119301 TI - In this issue June 2016. PMID- 27119279 TI - Fusion of Ferredoxin and Cytochrome P450 Enables Direct Light-Driven Biosynthesis. AB - Cytochrome P450s (P450s) are key enzymes in the synthesis of bioactive natural products in plants. Efforts to harness these enzymes for in vitro and whole-cell production of natural products have been hampered by difficulties in expressing them heterologously in their active form, and their requirement for NADPH as a source of reducing power. We recently demonstrated targeting and insertion of plant P450s into the photosynthetic membrane and photosynthesis-driven, NADPH independent P450 catalytic activity mediated by the electron carrier protein ferredoxin. Here, we report the fusion of ferredoxin with P450 CYP79A1 from the model plant Sorghum bicolor, which catalyzes the initial step in the pathway leading to biosynthesis of the cyanogenic glucoside dhurrin. Fusion with ferredoxin allows CYP79A1 to obtain electrons for catalysis by interacting directly with photosystem I. Furthermore, electrons captured by the fused ferredoxin moiety are directed more effectively toward P450 catalytic activity, making the fusion better able to compete with endogenous electron sinks coupled to metabolic pathways. The P450-ferredoxin fusion enzyme obtains reducing power solely from its fused ferredoxin and outperforms unfused CYP79A1 in vivo. This demonstrates greatly enhanced electron transfer from photosystem I to CYP79A1 as a consequence of the fusion. The fusion strategy reported here therefore forms the basis for enhanced partitioning of photosynthetic reducing power toward P450 dependent biosynthesis of important natural products. PMID- 27119302 TI - Pediatric preoperative risk factors to predict postoperative ICU admission and death from a multicenter retrospective study. AB - BACKGROUND: Although some studies have investigated the potential predictors of perioperative mortality, there are few specifically for pediatrics. OBJECTIVE: The aim of the retrospective study was to analyze potential preoperative risk factors and to develop a pediatric preoperative risk prediction score (PRPS), and to predict postoperative ICU admission and the incidence of perioperative death in pediatric patients. METHODS: Patients who postoperatively admitted to ICU or died (occurred within 30 days after the surgery) from 263 607 pediatric surgical patients with age from 1 day to 14 years old in eight centers in China from October 2010 to September 2013 were retrospectively analyzed. About 5500 non-ICU admission and death patients were randomly selected from those 263 607 patients as controls for analysis comparison. Independent risk factors and a risk model were derived from these analyses, and were further assessed with the likelihood ratio test and the area under the receiver operating characteristic (ROC) curve. RESULTS: There were 1812 ICU admission or death patients but 187 patients' records are incomplete. There were 487 patients with incomplete records among 5500 controls. Collectively, data from 6626 patients were enrolled in final analyses. With multiple logistic regression analysis, age, ASA physical status, SpO2 , prematurity, and unfasted status were found to be independent predictors for critical patients. The AUC value of 0.905 indicated excellent predictive performance between critical and noncritical predictors. CONCLUSIONS: Our study revealed that age, ASA physical status, SpO2 , prematurity, and unfasted status are risk factors to predict postoperative ICU admission and death in pediatric patients. PMID- 27119303 TI - A 'Wake up' call for our specialty-time to examine the impact of production pressure on patient safety. PMID- 27119304 TI - Regional anesthesia for anterior cruciate ligament reconstruction in adolescents. PMID- 27119305 TI - Reply to Xue, Fu-Shan; Liu, Gao-Pu; Sun, Chao, regarding their comment 'Use of a 90-degree anticlockwise tube rotation to facilitate nasotracheal tube passage over the fiberscope into the trachea in pediatric patients'. PMID- 27119306 TI - Modification of the swivel adapter for intraoperative use of pediatric fiberoptic bronchoscopes. PMID- 27119307 TI - Consider an additional pressure-relief port before we abandon the use of the wall oxygen through a bronchoscope. PMID- 27119308 TI - Reply to Schmitz et al. regarding 'Ultrasound assessment of gastric volume in the fasted pediatric patient undergoing upper gastrointestinal endoscopy: development of a predictive model using endoscopically suctioned volumes'. PMID- 27119309 TI - Left Axillary Implantation of Loop Recorder versus the Traditional Left Chest Area: A Prospective Randomized Study. AB - BACKGROUND: Based upon the results of a previous small pilot study, we present the results of a prospective single-center randomized study comparing the performance of the implantable loop recorder (ILR) at two implanting sites. METHODS: A group of patients whose ILRs were implanted via a left axillary approach were compared with a group who received an ILR in the traditional left site of the chest. Follow-up (FU) was scheduled every 6 months or when symptoms occurred. All patients enrolled in the study had a complete FU from implantation to explantation. R- and P-wave amplitudes were measured at implantation and during FU. Explantation of the device was programmed at the end of service life or when ILR analysis resulted in a complete and exhaustive diagnosis. RESULTS: Sixty-three patients were enrolled (70 +/- 12 years, range: 21-92, 59% male): 31 standard and 32 with axillary access. The R-wave amplitude obtained with the new technique was comparable with that obtained with the standard procedure. The diagnostic accuracy of the ILR was comparable in the two groups. The axillary implantation procedure was slightly longer but no complications were observed. CONCLUSION: This long-term randomized study confirmed that axillary access for ILR implantation is feasible, safe, well tolerated, and reliable in terms of device performance. Moreover, it is aesthetically superior to the standard approach and carries the potential of minimizing permanent scarring after ILR extraction. PMID- 27119310 TI - The things that batter. AB - Over 20 years ago, the Australian Liberal/National Party Federal Opposition had a set of policies with which it hoped to persuade the Australian people to return it to government in the election due in 1996. This particular collection of proposed initiatives was called "The things that matter". When the then leader of the opposition, Alexander Downer (later Australia's Foreign Minister 1996-2007 and now Australian High Commissioner in London), launched the Opposition's policy on family violence (the Coalition parties, like their Labor opponents, were and are against it in principle), his introductory line was: "From the things that matter to the things that batter". Not long afterwards he lost his job as Opposition Leader, his engagement with what was and is a serious and troubling issue having been deemed too glib by half by the shapers of public opinion. PMID- 27119311 TI - Cardioprotective effect of pioglitazone in diabetic and non-diabetic rats subjected to acute myocardial infarction involves suppression of AGE-RAGE axis and inhibition of apoptosis. AB - Insulin resistance increases risk of cardiovascular diseases. This work investigated the protective effect of pioglitazone on myocardial infarction (MI) in non-diabetic and diabetic rats, focusing on its role on advanced glycated endproducts (AGEs) and cardiac apoptotic machinery. Male rats were divided into 2 experiments: experiment I and II (non-diabetic and diabetic rats) were assigned as saline, MI (isoproterenol, 85 mg/kg, daily), and MI+pioglitazone (5, 10, and 20 mg/kg). Injection of isoproterenol in diabetic rats produced greater ECG disturbances compared to non-diabetic rats. Treatment with pioglitazone (5 mg/kg) reduced the infarct size and improved some ECG findings. Pioglitazone (10 mg/kg) enhanced ECG findings, improved the histopathological picture and downregulated apoptosis in cardiac tissues. Whereas the higher dose of pioglitazone (20 mg/kg) did not improve most of the measured parameters but rather worsened some of them, such as proapoptotic markers. Importantly, a positive correlation was found between serum AGEs and cardiac AGE receptors (RAGEs) versus caspase 3 expression in the two experiments. Therefore, the current effect of pioglitazone was, at least in part, mediated through downregulation of AGE-RAGE axis and inhibition of apoptosis. Consequently, these data suggest that pioglitazone, at optimized doses, may have utility in protection from acute MI. PMID- 27119312 TI - Does Abdominal Aortic Aneurysm Screening Save Lives? PMID- 27119314 TI - Impact of specimen adequacy on the assessment of renal allograft biopsy specimens. AB - The Banff classification was introduced to achieve uniformity in the assessment of renal allograft biopsies. The primary aim of this study was to evaluate the impact of specimen adequacy on the Banff classification. All renal allograft biopsies obtained between July 2010 and June 2012 for suspicion of acute rejection were included. Pre-biopsy clinical data on suspected diagnosis and time from renal transplantation were provided to a nephropathologist who was blinded to the original pathological report. Second pathological readings were compared with the original to assess agreement stratified by specimen adequacy. Cohen's kappa test and Fisher's exact test were used for statistical analyses. Forty-nine specimens were reviewed. Among these specimens, 81.6% were classified as adequate, 6.12% as minimal, and 12.24% as unsatisfactory. The agreement analysis among the first and second readings revealed a kappa value of 0.97. Full agreement between readings was found in 75% of the adequate specimens, 66.7 and 50% for minimal and unsatisfactory specimens, respectively. There was no agreement between readings in 5% of the adequate specimens and 16.7% of the unsatisfactory specimens. For the entire sample full agreement was found in 71.4%, partial agreement in 20.4% and no agreement in 8.2% of the specimens. Statistical analysis using Fisher's exact test yielded a P value above 0.25 showing that - probably due to small sample size - the results were not statistically significant. Specimen adequacy may be a determinant of a diagnostic agreement in renal allograft specimen assessment. While additional studies including larger case numbers are required to further delineate the impact of specimen adequacy on the reliability of histopathological assessments, specimen quality must be considered during clinical decision making while dealing with biopsy reports based on minimal or unsatisfactory specimens. PMID- 27119313 TI - Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge. AB - BACKGROUND: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in clinic. METHODS: We analyzed the findings of CNV studies from a cohort referred for genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID). RESULTS: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found seven cases with more than two CNV and two with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine 9 (H3K9) methyltransferase, in a case with ASD. CONCLUSION: We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders in autism genetics clinic. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNV. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD. PMID- 27119315 TI - Insights into the Reaction Mechanism of Aromatic Ring Cleavage by Homogentisate Dioxygenase: A Quantum Mechanical/Molecular Mechanical Study. AB - To elucidate the reaction mechanism of the ring cleavage of homogentisate by homogentisate dioxygenase, quantum mechanical/molecular mechanical (QM/MM) calculations were carried out by using two systems in different protonation states of the substrate C2 hydroxyl group. When the substrate C2 hydroxyl group is ionized (the ionized pathway), the superoxo attack on the substrate is the rate-limiting step in the catalytic cycle, with a barrier of 15.9 kcal/mol. Glu396 was found to play an important role in stabilizing the bridge species and its O-O cleavage product by donating a proton via a hydrogen-bonded water molecule. When the substrate C2 hydroxyl group is not ionized (the nonionized pathway), the O-O bond cleavage of the bridge species is the rate-limiting step, with a barrier of 15.3 kcal/mol. The QM/MM-optimized geometries for the dioxygen and alkylperoxo complexes using the nonionized model (for the C2 hydroxyl group) are in agreement with the experimental crystal structures, suggesting that the C2 hydroxyl group is more likely to be nonionized. PMID- 27119316 TI - Effect of vitamin B12 deficiency on olfactory function. AB - BACKGROUND: Vitamin B12 plays a major role in the maintenance of central and peripheral nervous systems. Vitamin B12 deficiency may affect the spinal cord, brain, optic nerve, and peripheral nerve functions; however, the effect of vitamin B12 deficiency on olfactory function has not been studied, so our study aimed to investigate that. METHODS: Thirty-nine patients with low vitamin B12 levels and 34 controls were included in the study. All participants had detailed otorhinolaryngological examinations and laboratory tests. The Sniffin' Stick test was used for analysis of olfactory function. The 2 groups were compared for smell test results. Correlations of smell test results with demographic and laboratory data were investigated in the vitamin B12-deficient group. RESULTS: The threshold discrimination identification scores were (mean +/- standard deviation) 28.04 +/- 5.58 and 35.10 +/- 2.84 in the vitamin B12-deficient and control groups, respectively (p < 0.001). In the vitamin B12-deficient group, hyposmia and anosmia were evident in 56.4% and 5.1% of the patients, respectively, but no subjects in the control group had olfactory dysfunction (p < 0.001). Correlation analysis showed that age and odor identification score showed a negative correlation (p < 0.001); however, there was a positive correlation between threshold, discrimination and identification (TDI) score and vitamin B12 levels. CONCLUSION: In this study, we showed for the first time that olfactory dysfunction may be present in patients with vitamin B12 deficiency. Apart from a negative correlation of age with odor identification score, none of the other parameters studied showed correlations with olfactory dysfunction. PMID- 27119317 TI - [Not Available]. PMID- 27119318 TI - Lewis Acid and Fluoroalcohol Mediated Nucleophilic Addition to the C2 Position of Indoles. AB - Indole readily undergoes nucleophilic substitution at the C3 site, and many indole derivatives have been functionalized using this property. Indole also forms indolium, which allows electrophilic addition in acidic conditions, but current examples have been limited to intramolecular reactions. C2 site-selective nucleophilic addition to indole derivatives using fluoroalcohol and a Lewis acid was developed. PMID- 27119319 TI - Role of tumour necrosis factor-a in the regulation of T-type calcium channel current in HL-1 cells. AB - Increasing evidence indicates that inflammation contributes to the initiation and perpetuation of atrial fibrillation (AF). Although tumour necrosis factor (TNF) alpha levels are increased in patients with AF, the role of TNF-alpha in the pathogenesis of AF remains unclear. Besides L-type Ca(2+) currents (IC a,L ), T type Ca(2+) currents (IC a,T ) also plays an important role in the pathogenesis of AF. This study was designed to use the whole-cell voltage-clamp technique and biochemical assays to explore if TNF-alpha is involved in the pathogenesis of AF through regulating IC a,T in atrial myocytes. It was found that compared with sinus rhythm (SR) controls, T-type calcium channel (TCC) subunit mRNA levels were decreased, while TNF-alpha expression levels were increased, in human atrial tissue from patients with AF. In murine atrial myocyte HL-1 cells, after culturing for 24 h, 12.5, 25 and 50 ng/mL TNF-alpha significantly reduced the protein expression levels of the TCC alpha1G subunit in a concentration-dependent manner. The peak current was reduced by the application of 12.5 or 25 ng/mL TNF alpha in a concentration-dependent manner (from -15.08 +/- 1.11 pA/pF in controls to -11.89 +/- 0.83 pA/pF and -8.54 +/- 1.55 pA/pF in 12.5 or 25 ng/mL TNF-alpha group respectively). TNF-alpha application also inhibited voltage-dependent inactivation of IC a,T, shifted the inactivation curve to the left. These results suggest that TNF-alpha is involved in the pathogenesis of AF, probably via decreasing IC a,T current density in atrium-derived myocytes through impaired channel function and down-regulation of channel protein expression. This pathway thus represents a potential pathogenic mechanism in AF. PMID- 27119320 TI - The Effect of an All-Ages Bicycle Helmet Law on Bicycle-Related Trauma. AB - In 2003, Seattle implemented an all-ages bicycle helmet law; King County outside of Seattle had implemented a similar law since 1994. For the period 2000-2010, the effect of the helmet legislation on helmet use, helmet-preventable injuries, and bicycle-related fatalities was examined, comparing Seattle to the rest of King County. Data was retrieved from the Washington State Trauma Registry and the King County Medical Examiner. Results comparing the proportions of bicycle related head injuries before (2000-2002) and after (2004-2010) the law show no significant change in the proportion of bicyclists admitted to the hospital and treated for head injuries in either Seattle (37.9 vs 40.2 % p = 0.75) nor in the rest of King County (30.7 vs 31.4 %, p = 0.84) with the extension of the helmet law to Seattle in 2003. However, bicycle-related major head trauma as a proportion of all bicycle-related head trauma did decrease significantly in Seattle (83.9 vs 64.9 %, p = 0.04), while there was no significant change in King County (64.4 vs 57.6 %, p = 0.41). While the results do not show an overall decrease in head injuries, they do reveal a decrease in the severity of head injuries, as well as bicycle-related fatalities, suggesting that the helmet legislation was effective in reducing severe disability and death, contributing to injury prevention in Seattle and King County. The promotion of helmet use through an all ages helmet law is a vital preventative strategy for reducing major bicycle-related head trauma. PMID- 27119321 TI - What are the real waiting times for therapeutic management of head and neck cancer: a study in the general population in the north-west of France. AB - Head and neck cancers (HNC) have a poor prognosis and a long treatment delay may have a negative impact on this. Some studies have investigated the determinants of this delay but not in the general population and rarely taking into account socio-economic factors. A high-resolution population-based study about cancer management was conducted, using registries in the north-west of France, on HNC diagnosed between 2008 and 2010. The median time between diagnosis and multidisciplinary team meeting (DMI) (N = 1631) was 14 days (Q1: 7 to Q3: 26). The median time between diagnosis and first treatment (DTI) (N = 1519) was 35 days (Q1: 21 to Q3: 54). When the first treatment was radiotherapy, the interval was 54.5 days (Q1: 40 to Q3: 71). In multivariate analysis, DTI was associated with the type of first treatment and place of treatment. For advanced stage HNC, DTI was associated with comorbidities, topography of the cancer and socio economic status, underprivileged patients being treated later than privileged ones. Given the French governmental cancer plans which set out to coordinate care pathways via nursing coordinators and to improve the availability of radiotherapy, the waiting times observed in this study still seem long. The optimal care pathway should include adapted social management but the DTI was still longer for underprivileged patients. PMID- 27119322 TI - Collaboration Platforms in China for Translational and Clinical Research: The Partnership Between Peking University Health Science Center and the University of Michigan Medical School. AB - PROBLEM: Clinical and translational research is increasing in China, attracting faculty-to-faculty collaborations between U.S. and Chinese researchers. However, examples of successful institution-to-institution collaborations to facilitate this research are limited. The authors describe a partnership between Peking University Health Science Center (PUHSC) and the University of Michigan Medical School (UMMS) designed to enable faculty-initiated joint translational and clinical research projects. APPROACH: In 2009, UMMS leadership identified PUHSC as the most appropriate institutional partner, and the Joint Institute for Translational and Clinical Research was established in 2010. Each contributed $7 million for joint research projects in areas of mutual interest. A shared governance structure, four thematic programs (pulmonary, cardiovascular, liver, and renal diseases), three joint research-enabling cores, and processes for awarding funding have been established along with methods for collaborating and mechanisms to share data and biomaterials. OUTCOMES: As of November 2015, 52 joint faculty proposals have been submitted, and 25 have been funded. These projects have involved more than 100,000 patients in the United States and China and have generated 13 peer-reviewed publications. Pilot data have been leveraged to secure $3.3 million of U.S. extramural funding. Faculty and trainee exchanges take place regularly (including an annual symposium), and mechanisms exist to link faculty seeking collaborations. Critical determinants of success include having co-ownership at all levels with coinvestment of resources. NEXT STEPS: Each institution is committed to continuing its support with a repeat $7 million investment. Next steps include initiating studies in new clinical areas and pursuing large clinical intervention trials. PMID- 27119323 TI - Why July Matters. AB - Each July, new graduates from premedical, medical, and residency programs, along with junior and midcareer faculty, acclimatize to their changing roles. During this month, overall efficiency, quality, and patient safety may suffer, a problem dubbed the "July effect." The many transitions that occur in teaching hospitals during July are often implicated as the root cause of this problem. The question, then, of how best to improve the team-based clinical care provided in July remains important. In this Commentary, the authors outline a model that combines the team-based care paradigm with effective leadership, followership, and communication-based strategies and propose some actionable steps.A key first step to enhancing patient safety in July is improving effective leadership through use of a select group of attendings whose teaching style empowers learners within a framework of close supervision. Second, programmatic efforts to pair these leaders with good followers are needed. Senior residents in July should be selected on their ability to mentor, guide, and support interns. Third, a system of free-flowing, bidirectional communication must be nurtured to ensure optimal outcomes. Adapting strategies from the airlines (e.g., interdisciplinary conferences to discuss optimal patient care approaches; checklists for daily activities such as sign-outs; directed feedback and debriefing techniques emphasizing actionable areas for improvement) is promising and worth studying.Available data suggest that the "July effect" is real. Developing new and exploring existing approaches for allaying this phenomenon are important areas of further investigation. PMID- 27119324 TI - Caring to Care: Applying Noddings' Philosophy to Medical Education. AB - The authors argue that Nel Noddings' philosophy, "an ethic of caring," may illuminate how students learn to be caring physicians from their experience of being in a caring, reciprocal relationship with teaching faculty. In her philosophy, Noddings acknowledges two important contextual continuities: duration and space, which the authors speculate exist within longitudinal integrated clerkships. In this Perspective, the authors highlight core features of Noddings' philosophy and explore its applicability to medical education. They apply Noddings' philosophy to a subset of data from a previously published longitudinal case study to explore its "goodness of fit" with the experience of eight students in the 2012 cohort of the Columbia-Bassett longitudinal integrated clerkship. In line with Noddings' philosophy, the authors' supplementary analysis suggests that students (1) recognized caring when they talked about "being known" by teaching faculty who "cared for" and "trusted" them; (2) responded to caring by demonstrating enthusiasm, action, and responsibility toward patients; and (3) acknowledged that duration and space facilitated caring relations with teaching faculty. The authors discuss how Noddings' philosophy provides a useful conceptual framework to apply to medical education design and to future research on caring-oriented clinical training, such as longitudinal integrated clerkships. PMID- 27119325 TI - The Use of Smartphones for Health Research. AB - Because of their growing popularity and functionality, smartphones are increasingly valuable potential tools for health and medical research. Using ResearchKit, Apple's open-source platform to build applications ("apps") for smartphone research, collaborators have developed apps for researching asthma, breast cancer, cardiovascular disease, type 2 diabetes, and Parkinson disease. These research apps enhance widespread participation by removing geographical barriers to participation, provide novel ways to motivate healthy behaviors, facilitate high-frequency assessments, and enable more objective data collection. Although the studies have great potential, they also have notable limitations. These include selection bias, identity uncertainty, design limitations, retention, and privacy. As smartphone technology becomes increasingly available, researchers must recognize these factors to ensure that medical research is conducted appropriately. Despite these limitations, the future of smartphones in health research is bright. Their convenience grants unprecedented geographic freedom to researchers and participants alike and transforms the way clinical research can be conducted. PMID- 27119326 TI - Distinguishing Three Unprofessional Behavior Profiles of Medical Students Using Latent Class Analysis. AB - PURPOSE: Because unprofessional behavior of physicians is associated with unprofessional behavior in medical school, identifying unprofessional behavior in medical school is critical. Research has noted the difficulty in assessing professional behavior. Instead of identifying isolated behaviors, it could be more helpful to recognize behavioral patterns to evaluate students' professional behavior. The authors aimed to identify patterns in the unprofessional behaviors of medical students and to construct descriptions based on these patterns. METHOD: Content analysis of research articles yielded a template of unprofessional behaviors for coding student evaluation forms indicating unsatisfactory professional behavior, collected from 2012 to 2014 at the VUmc School of Medical Sciences, Amsterdam, the Netherlands. Latent class analysis was used to identify classes of students with a high chance of displaying comparable unprofessional behaviors. Teachers' feedback of prototype students was summarized to generate profile descriptions. RESULTS: A template of 109 behaviors was used to code 232 evaluation forms of 194 students (3.9% students/year). Latent class analysis identified three hypothetical classes of students: Class 1 (43%) was labeled as "Poor reliability," class 2 (20%) was labeled as "Poor reliability and poor insight," and class 3 (37%) was labeled as "Poor reliability, poor insight, and poor adaptability." CONCLUSIONS: These profiles of unprofessional behavior might help to improve the evaluation of unprofessional behavior in medical school. Further research should provide evidence for confidently accepting or rejecting the profiles as an instrument to identify which students are expected to benefit from remediation trajectories. PMID- 27119327 TI - Clinician-Educators as Dual Professionals: A Contemporary Reappraisal. AB - Physicians who teach face unique responsibilities and expectations because they must educate learners while simultaneously caring for patients. Recently this has become even more difficult as the environment for clinician-educators has been undermined by public antipathy toward both the education profession and the medicine profession.Erosion of public confidence in both professions is evidenced by three trends. First, the democratizing nature of the Internet and the availability of technical knowledge to laypeople have encroached on the domain of professional knowledge. Second, the responsibility of a professional to make decisions has been undercut by legal interpretations regarding how physicians are paid for patient care and how teachers are evaluated on performance. And finally, altruistic motivations in both professions have been called into question by external forces promoting "accountability" rather than trusting professionals to act for the best interest of their patients or students.In this climate of increasing accountability and decreasing trust for professionals, clinician educators can best serve patients and learners through transdisciplinary collaboration with professional educators. Clinician-educators should rely on professional educators for judgment and specialized knowledge in the field of education rather than embodying both professions by themselves. Health care practice has become more team oriented; health care education should do likewise to counteract the social and political trends eroding public confidence in medicine and education. Relying on collaboration with education professionals constitutes a substantial change to how clinician-educators define themselves, but it holds the best promise for medical training in the current social milieu. PMID- 27119329 TI - Early Experiences After Adopting a Quality Improvement Portfolio Into the Academic Advancement Process. AB - PROBLEM: Academic medical centers (AMCs) and their academic departments are increasingly assuming leadership in the education, science, and implementation of quality improvement (QI) and patient safety efforts. Fostering, recognizing, and promoting faculty leading these efforts is challenging using traditional academic metrics for advancement. APPROACH: The authors adapted a nationally developed QI portfolio, adopted it into their own department's advancement process in 2012, and tracked its utilization and impact over the first two years of implementation. OUTCOMES: Sixty-seven QI portfolios were submitted with 100% of faculty receiving their requested academic advancement. Women represented 60% of the submitted portfolios, while the Divisions of General Internal Medicine and Hospital Medicine accounted for 60% of the submissions. The remaining 40% were from faculty in 10 different specialty divisions. Faculty attitudes about the QI portfolio were overwhelmingly positive, with 83% agreeing that it "was an effective tool for helping to better recognize faculty contributions in QI work" and 85% agreeing that it "was an effective tool for elevating the importance of QI work in our department." NEXT STEPS: The QI portfolio was one part of a broader effort to create opportunities to recognize and support faculty involved in improvement work. Further adapting the tool to ensure that it complements rather than duplicates-other elements of the advancement process is critical for continued utilization by faculty. This will also drive desired dissemination to other departments locally and other AMCs nationally who are similarly committed to cultivating faculty career paths in systems improvement. PMID- 27119328 TI - Predictors of Primary Care Physician Practice Location in Underserved Urban or Rural Areas in the United States: A Systematic Literature Review. AB - PURPOSE: The authors conducted a systematic review of the medical literature to determine the factors most strongly associated with localizing primary care physicians (PCPs) in underserved urban or rural areas of the United States. METHOD: In November 2015, the authors searched databases (MEDLINE, ERIC, SCOPUS) and Google Scholar to identify published peer-reviewed studies that focused on PCPs and reported practice location outcomes that included U.S. underserved urban or rural areas. Studies focusing on practice intentions, nonphysicians, patient panel composition, or retention/turnover were excluded. They screened 4,130 titles and reviewed 284 full-text articles. RESULTS: Seventy-two observational or case-control studies met inclusion criteria. These were categorized into four broad themes aligned with prior literature: 19 studies focused on physician characteristics, 13 on financial factors, 20 on medical school curricula/programs, and 20 on graduate medical education (GME) programs. Studies found significant relationships between physician race/ethnicity and language and practice in underserved areas. Multiple studies demonstrated significant associations between financial factors (e.g., debt or incentives) and underserved or rural practice, independent of preexisting trainee characteristics. There was also evidence that medical school and GME programs were effective in training PCPs who locate in underserved areas. CONCLUSIONS: Both financial incentives and special training programs could be used to support trainees with the personal characteristics associated with practicing in underserved or rural areas. Expanding and replicating medical school curricula and programs proven to produce clinicians who practice in underserved urban or rural areas should be a strategic investment for medical education and future research. PMID- 27119330 TI - Helping Basic Scientists Engage With Community Partners to Enrich and Accelerate Translational Research. AB - PROBLEM: Engaging basic scientists in community-based translational research is challenging but has great potential for improving health. APPROACH: In 2009, The Rockefeller University Center for Clinical and Translational Science partnered with Clinical Directors Network, a practice-based research network (PBRN), to create a community-engaged research navigation (CEnR-Nav) program to foster research pairing basic science and community-driven scientific aims. The program is led by an academic navigator and a PBRN navigator. Through meetings and joint activities, the program facilitates basic science-community partnerships and the development and conduct of joint research protocols. OUTCOMES: From 2009-2014, 39 investigators pursued 44 preliminary projects through the CEnR-Nav program; 25 of those became 23 approved protocols and 2 substudies. They involved clinical scholar trainees, early-career physician-scientists, faculty, students, postdoctoral fellows, and others. Nineteen (of 25; 76%) identified community partners, of which 9 (47%) named them as coinvestigators. Nine (of 25; 36%) included T3-T4 translational aims. Seven (of 25; 28%) secured external funding, 11 (of 25; 44%) disseminated results through presentations or publications, and 5 (71%) of 7 projects publishing results included a community partner as a coauthor. Of projects with long-term navigator participation, 9 (of 19; 47%) incorporated T3-T4 aims and 7 (of 19; 37%) secured external funding. NEXT STEPS: The CEnR-Nav program provides a model for successfully engaging basic scientists with communities to advance and accelerate translational science. This model's durability and generalizability have not been determined, but it achieves valuable short-term goals and facilitates scientifically meaningful community academic partnerships. PMID- 27119331 TI - Parting the Clouds: Three Professionalism Frameworks in Medical Education. AB - Current controversies in medical education associated with professionalism, including disagreements about curriculum, pedagogy, and assessment, are rooted in part in the differing frameworks that are used to address professionalism. Three dominant frameworks, which have evolved in the medical education community, are described. The oldest framework is virtue based and focuses on the inner habits of the heart, the development of moral character and reasoning, plus humanistic qualities of caring and compassion: The good physician is a person of character. The second framework is behavior based, which emphasizes milestones, competencies, and measurement of observable behaviors: The good physician is a person who consistently demonstrates competence in performing patient care tasks. The third framework is identity formation, with a focus on identity development and socialization into a community of practice: The good physician integrates into his or her identity a set of values and dispositions consonant with the physician community and aspires to a professional identity reflected in the very best physicians. Although each professionalism framework is useful and valid, the field of medical education is currently engaged in several different discourses resulting in misunderstanding and differing recommendations for strategies to facilitate professionalism. In this article, the assumptions and contributions of each framework are described to provide greater insight into the nature of professionalism. By examining each discourse in detail, underlying commonalities and differences can be highlighted to assist educators in more effectively creating professionalism curricula, pedagogy, and assessment. PMID- 27119332 TI - Medical Student Perceptions of the Learning Environment: Learning Communities Are Associated With a More Positive Learning Environment in a Multi-Institutional Medical School Study. AB - PURPOSE: Many medical schools have implemented learning communities (LCs) to improve the learning environment (LE) for students. The authors conducted this study to determine whether a relationship exists between medical student perceptions of the LE and presence of LCs during the preclerkship years. METHOD: Students from 24 schools participating in the American Medical Association Learning Environment Study completed the 17-item Medical Student Learning Environment Survey (MSLES) at the end of their first and second years of medical school between 2011 and 2013. Mean total MSLES scores and individual item scores at the end of the first and second years in schools with and without LCs were compared with t tests, and effect sizes were calculated. Mixed-effects longitudinal models were used to control for student demographics and random school and student effects on the relationship between LC status and MSLES score. RESULTS: A total of 4,980 students (81% of 6,148 matriculants) from 18 schools with LCs and 6 without LCs participated. Mean [SD] MSLES scores were significantly higher in LC schools compared with non-LC schools at the end of year one (3.72 [0.44] versus 3.57 [0.43], P < .001) and year two (3.69 [0.49] versus 3.42 [0.54], P < .001). The effect size increased from 0.35 (small) at the end of year one to 0.53 (medium) at the end of year two. CONCLUSIONS: This large multi-institutional cohort study found that LCs at medical schools were associated with more positive perceptions of the LE by preclerkship students. PMID- 27119333 TI - A Hybrid Interview Model for Medical School Interviews: Combining Traditional and Multisampling Formats. AB - PROBLEM: Most medical schools have either retained a traditional admissions interview or fully adopted an innovative, multisampling format (e.g., the multiple mini-interview) despite there being advantages and disadvantages associated with each format. APPROACH: The University of Michigan Medical School (UMMS) sought to maximize the strengths associated with both interview formats after recognizing that combining the two approaches had the potential to capture additional, unique information about an applicant. In September 2014, the UMMS implemented a hybrid interview model with six, 6-minute short-form interviews highly structured scenario-based encounters-and two, 30-minute semistructured long-form interviews. Five core skills were assessed across both interview formats. OUTCOMES: Overall, applicants and admissions committee members reported favorable reactions to the hybrid model, supporting continued use of the model. The generalizability coefficients for the six-station short-form and the two interview long-form formats were estimated to be 0.470 and 0.176, respectively. Different skills were more reliably assessed by different interview formats. Scores from each format seemed to be operating independently as evidenced through moderate to low correlations (r = 0.100-0.403) for the same skills measured across different interview formats; however, after correcting for attenuation, these correlations were much higher. NEXT STEPS: This hybrid model will be revised and optimized to capture the skills most reliably assessed by each format. Future analysis will examine validity by determining whether short-form and long-form interview scores accurately measure the skills intended to be assessed. Additionally, data collected from both formats will be used to establish baselines for entering students' competencies. PMID- 27119334 TI - CaPOW! Using Problem Sets in a Capstone Course to Improve Fourth-Year Medical Students' Confidence in Self-Directed Learning. AB - PROBLEM: Despite the importance of self-directed learning (SDL) in the field of medicine, individuals are rarely taught how to perform SDL or receive feedback on it. Trainee skill in SDL is limited by difficulties with self-assessment and goal setting. APPROACH: Ninety-two graduating fourth-year medical students from Duke University School of Medicine completed an individualized learning plan (ILP) for a transition-to-residency Capstone course in spring 2015 to help foster their skills in SDL. Students completed the ILP after receiving a personalized report from a designated faculty coach detailing strengths and weaknesses on specific topics (e.g., pulmonary medicine) and clinical skills (e.g., generating a differential diagnosis). These were determined by their performance on 12 Capstone Problem Sets of the Week (CaPOWs) compared with their peers. Students used transitional-year milestones to self-assess their confidence in SDL. OUTCOMES: SDL was successfully implemented in a Capstone course through the development of required clinically oriented problem sets. Coaches provided guided feedback on students' performance to help them identify knowledge deficits. Students' self-assessment of their confidence in SDL increased following course completion. However, students often chose Capstone didactic sessions according to factors other than their CaPOW performance, including perceived relevance to planned specialty and session timing. NEXT STEPS: Future Capstone curriculum changes may further enhance SDL skills of graduating students. Students will receive increased formative feedback on their CaPOW performance and be incentivized to attend sessions in areas of personal weakness. PMID- 27119335 TI - Plasmon-enhanced nanoporous BiVO4 photoanodes for efficient photoelectrochemical water oxidation. AB - Conversion of solar irradiation into chemical fuels such as hydrogen with the use of a photoelectrochemical (PEC) cell is an attractive strategy for green energy. The promising technique of incorporating metal nanoparticles (NPs) in the photoelectrodes is being explored to enhance the performance of the photoelectrodes. In this work, we developed Au-NPs-functionalized nanoporous BiVO4 photoanodes, and utilized the plasmonic effects of Au NPs to enhance the photoresponse. The plasmonic enhancement leads to an AM 1.5 photocurrent of 5.1 +/- 0.1 mA cm(-2) at 1.23 V versus a reverse hydrogen electrode. We observed an enhancement of five times with respect to pristine BiVO4 in the photocurrent with long-term stability and high energy-conversion efficiency. The overall performance enhancement is attributed to the synergy between the nanoporous architecture of BiVO4 and the plasmonic effects of Au NPs. Our further study reveals that the commendable photoactivity arises from the different plasmonic effects and co-catalyst effects of Au NPs. PMID- 27119336 TI - Neandertal versus Modern Human Dietary Responses to Climatic Fluctuations. AB - The Neandertal lineage developed successfully throughout western Eurasia and effectively survived the harsh and severely changing environments of the alternating glacial/interglacial cycles from the middle of the Pleistocene until Marine Isotope Stage 3. Yet, towards the end of this stage, at the time of deteriorating climatic conditions that eventually led to the Last Glacial Maximum, and soon after modern humans entered western Eurasia, the Neandertals disappeared. Western Eurasia was by then exclusively occupied by modern humans. We use occlusal molar microwear texture analysis to examine aspects of diet in western Eurasian Paleolithic hominins in relation to fluctuations in food supplies that resulted from the oscillating climatic conditions of the Pleistocene. There is demonstrable evidence for differences in behavior that distinguish Upper Paleolithic humans from members of the Neandertal lineage. Specifically, whereas the Neandertals altered their diets in response to changing paleoecological conditions, the diets of Upper Paleolithic humans seem to have been less affected by slight changes in vegetation/climatic conditions but were linked to changes in their technological complexes. The results of this study also indicate differences in resource exploitation strategies between these two hominin groups. We argue that these differences in subsistence strategies, if they had already been established at the time of the first contact between these two hominin taxa, may have given modern humans an advantage over the Neandertals, and may have contributed to the persistence of our species despite habitat related changes in food availabilities associated with climate fluctuations. PMID- 27119337 TI - Differential Expression of Long Noncoding RNAs between Sperm Samples from Diabetic and Non-Diabetic Mice. AB - To investigate the potential core reproduction-related genes associated with the development of diabetes, the expression profiles of long noncoding RNA (lncRNA) and messenger RNA (mRNA) in the sperm of diabetic mice were studied. We used microarray analysis to detect the expression of lncRNAs and coding transcripts in six diabetic and six normal sperm samples, and differentially expressed lncRNAs and mRNAs were identified through Volcano Plot filtering. The function of differentially expressed mRNA was determined by pathway and gene ontology (GO) analysis, and the function of lncRNAs was studied by subgroup analysis and their physical or functional relationships with corresponding mRNAs. A total of 7721 lncRNAs and 6097 mRNAs were found to be differentially expressed between the diabetic and normal sperm groups. The diabetic sperm exhibited aberrant expression profiles for lncRNAs and mRNAs, and GO and pathway analyses showed that the functions of differentially expressed mRNAs were closely related with many processes involved in the development of diabetes. Furthermore, potential core genes that might play important roles in the pathogenesis of diabetes related low fertility were revealed by lncRNA- and mRNA-interaction studies, as well as coding-noncoding gene co-expression analysis based on the microarray expression profiles. PMID- 27119339 TI - CORR Insights((r)): Does Preadmission Cutaneous Chlorhexidine Preparation Reduce Surgical Site Infections After Total Knee Arthroplasty? PMID- 27119338 TI - Carbon Nanofiber Arrays: A Novel Tool for Microdelivery of Biomolecules to Plants. AB - Effective methods for delivering bioprobes into the cells of intact plants are essential for investigating diverse biological processes. Increasing research on trees, such as Populus spp., for bioenergy applications is driving the need for techniques that work well with tree species. This report introduces vertically aligned carbon nanofiber (VACNF) arrays as a new tool for microdelivery of labeled molecules to Populus leaf tissue and whole plants. We demonstrated that VACNFs penetrate the leaf surface to deliver sub-microliter quantities of solution containing fluorescent or radiolabeled molecules into Populus leaf cells. Importantly, VACNFs proved to be gentler than abrasion with carborundum, a common way to introduce material into leaves. Unlike carborundum, VACNFs did not disrupt cell or tissue integrity, nor did they induce production of hydrogen peroxide, a typical wound response. We show that femtomole to picomole quantities of labeled molecules (fluorescent dyes, small proteins and dextran), ranging from 0.5-500 kDa, can be introduced by VACNFs, and we demonstrate the use of the approach to track delivered probes from their site of introduction on the leaf to distal plant regions. VACNF arrays thus offer an attractive microdelivery method for the introduction of biomolecules and other probes into trees and potentially other types of plants. PMID- 27119340 TI - Emergence of Swarming Behavior: Foraging Agents Evolve Collective Motion Based on Signaling. AB - Swarming behavior is common in biology, from cell colonies to insect swarms and bird flocks. However, the conditions leading to the emergence of such behavior are still subject to research. Since Reynolds' boids, many artificial models have reproduced swarming behavior, focusing on details ranging from obstacle avoidance to the introduction of fixed leaders. This paper presents a model of evolved artificial agents, able to develop swarming using only their ability to listen to each other's signals. The model simulates a population of agents looking for a vital resource they cannot directly detect, in a 3D environment. Instead of a centralized algorithm, each agent is controlled by an artificial neural network, whose weights are encoded in a genotype and adapted by an original asynchronous genetic algorithm. The results demonstrate that agents progressively evolve the ability to use the information exchanged between each other via signaling to establish temporary leader-follower relations. These relations allow agents to form swarming patterns, emerging as a transient behavior that improves the agents' ability to forage for the resource. Once they have acquired the ability to swarm, the individuals are able to outperform the non-swarmers at finding the resource. The population hence reaches a neutral evolutionary space which leads to a genetic drift of the genotypes. This reductionist approach to signal-based swarming not only contributes to shed light on the minimal conditions for the evolution of a swarming behavior, but also more generally it exemplifies the effect communication can have on optimal search patterns in collective groups of individuals. PMID- 27119341 TI - Vascular Endothelial Cell Injury Is an Important Factor in the Development of Encapsulating Peritoneal Sclerosis in Long-Term Peritoneal Dialysis Patients. AB - BACKGROUND AND OBJECTIVES: Encapsulating peritoneal sclerosis (EPS) is a rare but serious and life-threatening complication of peritoneal dialysis (PD). However, the precise pathogenesis remains unclear; in addition, predictors and early diagnostic biomarkers for EPS have not yet to be established. METHODS: Eighty three peritoneal membrane samples taken at catheter removal were examined to identify pathological characteristics of chronic peritoneal deterioration, which promotes EPS in patients undergoing long-term PD treatment with low occurrence of peritonitis. RESULTS: According to univariable logistic regression analysis of the pathological findings, thickness of the peritoneal membrane (P = 0.045), new membrane formation score (P = 0.006), ratio of luminal diameter to vessel diameter (L/V ratio, P<0.001), presence of CD31-negative vessels (P = 0.021), fibrin deposition (P<0.001), and collagen volume fraction (P = 0.018) were associated with EPS development. In analyses of samples with and without EPS matched for PD treatment period, non-diabetes, and PD solution, univariable analysis identified L/V ratio (per 0.1 increase: odds ratio (OR) 0.44, P = 0.003) and fibrin deposition (OR 6.35, P = 0.027) as the factors associated with EPS. L/V ratio was lower in patients with fibrin exudation than in patients without fibrin exudation. CONCLUSIONS: These findings suggest that damage to vascular endothelial cells, as represented by low L/V ratio, could be a predictive finding for the development of EPS, particularly in long-term PD patients unaffected by peritonitis. PMID- 27119342 TI - Challenges in Collating Spirometry Reference Data for South-Asian Children: An Observational Study. AB - METHODS: Spirometry datasets from South-Asian children were collated from four centres in India and five within the UK. Records with transcription errors, missing values for height or spirometry, and implausible values were excluded(n = 110). RESULTS: Following exclusions, cross-sectional data were available from 8,124 children (56.3% male; 5-17 years). When compared with GLI-predicted values from White Europeans, forced expired volume in 1s (FEV1) and forced vital capacity (FVC) in South-Asian children were on average 15% lower, ranging from 4 19% between centres. By contrast, proportional reductions in FEV1 and FVC within all but two datasets meant that the FEV1/FVC ratio remained independent of ethnicity. The 'GLI-Other' equation fitted data from North India reasonably well while 'GLI-Black' equations provided a better approximation for South-Asian data than the 'GLI-White' equation. However, marked discrepancies in the mean lung function z-scores between centres especially when examined according to socio economic conditions precluded derivation of a single South-Asian GLI-adjustment. CONCLUSION: Until improved and more robust prediction equations can be derived, we recommend the use of 'GLI-Black' equations for interpreting most South-Asian data, although 'GLI-Other' may be more appropriate for North Indian data. Prospective data collection using standardised protocols to explore potential sources of variation due to socio-economic circumstances, secular changes in growth/predictors of lung function and ethnicities within the South-Asian classification are urgently required. PMID- 27119343 TI - Variation in Copy Number of Ty3/Gypsy Centromeric Retrotransposons in the Genomes of Thinopyrum intermedium and Its Diploid Progenitors. AB - Speciation and allopolyploidization in cereals may be accompanied by dramatic changes in abundance of centromeric repeated transposable elements. Here we demonstrate that the reverse transcriptase part of Ty3/gypsy centromeric retrotransposon (RT-CR) is highly conservative in the segmental hexaploid Thinopyrum intermedium (JrJvsSt) and its possible diploid progenitors Th. bessarabicum (Jb), Pseudoroegneria spicata (St) and Dasypyrum villosum (V) but the abundance of the repeats varied to a large extent. Fluorescence in situ hybridization (FISH) showed hybridization signals in centromeric region of all chromosomes in the studied species, although the intensity of the signals drastically differed. In Th. intermedium, the strongest signal of RT-CR probe was detected on the chromosomes of Jv, intermediate on Jr and faint on Js and St subgenome suggesting different abundance of RT-CR on the individual chromosomes rather than the sequence specificity of RT-CRs of the subgenomes. RT-CR quantification using real-time PCR revealed that its content per genome in Th. bessarabicum is ~ 2 times and P. spicata is ~ 1,5 times higher than in genome of D. villosum. The possible burst of Ty3/gypsy centromeric retrotransposon in Th. intermedium during allopolyploidization and its role in proper mitotic and meiotic chromosome behavior in a nascent allopolyploid is discussed. PMID- 27119344 TI - Spatial Distribution of Black Bear Incident Reports in Michigan. AB - Interactions between humans and carnivores have existed for centuries due to competition for food and space. American black bears are increasing in abundance and populations are expanding geographically in many portions of its range, including areas that are also increasing in human density, often resulting in associated increases in human-bear conflict (hereafter, bear incidents). We used public reports of bear incidents in Michigan, USA, from 2003-2011 to assess the relative contributions of ecological and anthropogenic variables in explaining the spatial distribution of bear incidents and estimated the potential risk of bear incidents. We used weighted Normalized Difference Vegetation Index mean as an index of primary productivity, region (i.e., Upper Peninsula or Lower Peninsula), primary and secondary road densities, and percentage land cover type within 6.5-km2 circular buffers around bear incidents and random points. We developed 22 a priori models and used generalized linear models and Akaike's Information Criterion (AIC) to rank models. The global model was the best compromise between model complexity and model fit (w = 0.99), with a DeltaAIC 8.99 units from the second best performing model. We found that as deciduous forest cover increased, the probability of bear incident occurrence increased. Among the measured anthropogenic variables, cultivated crops and primary roads were the most important in our AIC-best model and were both positively related to the probability of bear incident occurrence. The spatial distribution of relative bear incident risk varied markedly throughout Michigan. Forest cover fragmented with agriculture and other anthropogenic activities presents an environment that likely facilitates bear incidents. Our map can help wildlife managers identify areas of bear incident occurrence, which in turn can be used to help develop strategies aimed at reducing incidents. Researchers and wildlife managers can use similar mapping techniques to assess locations of specific conflict types or to address human impacts on endangered species. PMID- 27119345 TI - Awake, Offline Processing during Associative Learning. AB - Offline processing has been shown to strengthen memory traces and enhance learning in the absence of conscious rehearsal or awareness. Here we evaluate whether a brief, two-minute offline processing period can boost associative learning and test a memory reactivation account for these offline processing effects. After encoding paired associates, subjects either completed a distractor task for two minutes or were immediately tested for memory of the pairs in a counterbalanced, within-subjects functional magnetic resonance imaging study. Results showed that brief, awake, offline processing improves memory for associate pairs. Moreover, multi-voxel pattern analysis of the neuroimaging data suggested reactivation of encoded memory representations in dorsolateral prefrontal cortex during offline processing. These results signify the first demonstration of awake, active, offline enhancement of associative memory and suggest that such enhancement is accompanied by the offline reactivation of encoded memory representations. PMID- 27119347 TI - New Developments in Mechanical Enhancement of Colonoscopy: Cuffs, Caps and Rings. AB - BACKGROUND: Colorectal cancer (CRC) is a common cause of cancer-related deaths. Early detection of precursor lesions in the adenoma-carcinoma sequence via colonoscopy can decrease mortality from CRC. SUMMARY: In this review article, we have summarized retrospective studies, prospective single center, multicenter studies and randomized controlled trials describing the efficacy of endocuff colonoscopy (EC), cap-assisted colonoscopy (CAC) and endorings colonoscopy (ERC). Indications, techniques, outcomes, limitations and complications reported are discussed. KEY MESSAGE: Use of colonoscope with cap, cuff or rings attached to its distal tip has been shown to increase the polyp detection rate and adenoma detection rate, predominantly for the small polyps (<1 cm) and proximal colon location. Evidence is uniform for EC and ERC but not for CAC. Benefits of shorter cecum intubation time, improved cecum intubation rates and decreased pain scores during colonoscopy done with assistance of cuff or cap has potential to decrease the number of incomplete colonoscopy and increase overall patient satisfaction, thus improving follow-up. In the absence of any additional adverse events, EC, CAC and ERC have potential to enhance the benefits of colonoscopy. PMID- 27119346 TI - Lamivudine Concentration in Hair and Prediction of Virologic Failure and Drug Resistance among HIV Patients Receiving Free ART in China. AB - BACKGROUND: The assessment of adherence to antiretroviral therapy (ART) is important in order to predict treatment outcomes. Lamivudine (3TC) is one of the most widely used NRTIs in China, but its concentrations in hair and association with virologic failure and drug resistance have not been studied. METHODS: We conducted a cross-sectional survey to investigate 3TC concentrations in hair as a predictor of virologic failure and drug resistance among HIV patients receiving free ART. We also compared the capacity of hair 3TC concentrations with self reported adherence in predicting virologic responses. Hair 3TC concentrations were detected through the LC-MS/MS system. RESULTS: In patients without HIV drug resistance (HIVDR), with a threshold hair 3TC concentration of 260 ng/g, the sensitivity and specificity in predicting virologic suppression were 76.9% and 89.9%, respectively. Some factors, including CD4+ cell counts, initial treatment regimens with 3TC, and current regimens with second-line drugs, influenced the association between hair 3TC concentrations and virologic suppression. In patients who experienced virologic failure with HIVDR, with a threshold of 180 ng/g, the sensitivity and specificity were 70.0% and 74.4%, respectively. Hair 3TC concentrations had higher sensitivity and specificity in predicting virologic failure and drug resistance than self-reported adherence. CONCLUSIONS: The hair 3TC concentration was a stronger indicator than self-reported adherence in predicting virologic failure and drug resistance in HIV patients receiving free ART. PMID- 27119348 TI - Gambogic Acid Inhibits Malignant Melanoma Cell Proliferation Through Mitochondrial p66shc/ROS-p53/Bax-Mediated Apoptosis. AB - BACKGROUND/AIMS: Malignant melanoma has high metastatic potential, is highly resistant to chemotherapy, and has a poor survival rate. Gambogic acid (GA), a polyprenylated xanthone extracted from a traditional Chinese medicinal herb, has been proven to exhibit antitumor activity. The present study aimed to investigate the signaling pathways that mediated GA-induced inhibition of human malignant skin melanoma proliferation. METHODS: The study was conducted using A375 cells and the corresponding tumor transplanted in nude mice. RESULTS: Incubation of A375 cells with 1-10 MUg/ml GA decreased cell viability and increased apoptosis. GA concentration-dependently increased p66shc expression and intracellular ROS levels. GA also decreased the oxygen consumption rate and the mitochondrial membrane potential (MMP) in A375 cells. Experimental inhibition of p66shc by siRNA suppressed GA-induced increase of ROS, decrease of oxygen consumption rate, MMP and cell viability, whilst suppressing GA-induced increase of apoptosis. GA concentration-dependently upregulated p53 and Bax expression in A375 cells. GA also increased p53-TA-luciferase activity and p53-binding to Bax promoter, which was inhibited by Sip53. Experimental inhibition of p53 with Sip53 blocked GA induced decrease of the oxygen consumption rate and cell viability, and blocked the increase of apoptosis. In tumor-bearing nude mice, GA notably inhibited tumor growth, and this action was suppressed by N-acetylcysteine (NAC), a potent antioxidant, and by PFT-alpha, a p53 inhibitor. In A375 tumors transplanted in nude mice, GA increased both p66shc and p53 expression. NAC and PFT-alpha treatment did not significantly affect p66shc expression in tumors grown in mice treated with GA. In contrast, both NAC and PFT-alpha treatment inhibited GA induced p53 expression in mouse tumors. CONCLUSION: Results provided novel preclinical insights into the chemotherapeutic use of GA by highlighting the importance of p66shc/ROS-p53/Bax pathways in the antitumor effect of GA in malignant melanoma. PMID- 27119349 TI - Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes. AB - Clinically, serum level of folate has been negatively correlated to the stage and progression of liver cancer. Nevertheless, the functional consequence of folate deficiency (FD) in malignancy has not been fully investigated. Human hepatocellular carcinoma (HCC) cells (as study model) and other cancer types such as lung and glioma were cultured under folate deficient (FD) and folate complete (FD) conditions. Molecular characterization including intracellular ROS/RNS (reactive oxygen/nitrogen species), viability, colony formation, cancer stem-like cell (CSC) phenotype analyses were performed. In vivo tumorigenesis under FD and FC conditions were also examined. FD induced a significant increase in ROS and RNS, suppressing proliferative ability but inducing metastatic potential. Mesenchymal markers such as Snail, ZEB2, and Vimentin were significantly up regulated while E-cadherin down-regulated. Importantly, CSC markers such as Oct4, beta-catenin, CD133 were induced while PRRX1 decreased under FD condition. Furthermore, FD-conditioned HCC cells showed a decreased miR-22 level, leading to the increased expression of its target genes including HDAC4, ZEB2 and Oct4. Finally, xenograft mouse model demonstrated that FD diet promoted tumorigenesis and metastasis as compared to their FC counterparts. Our data provides rationales for the consideration of folate supplement as a metastasis preventive measure. PMID- 27119350 TI - Interference with mutagenic aflatoxin B1-induced checkpoints through antagonistic action of ochratoxin A in intestinal cancer cells: a molecular explanation on potential risk of crosstalk between carcinogens. AB - Foodborne aflatoxin B1 (AFB1) and ochratoxin A (OTA) cause genotoxic injury and subsequent tumor formation. As a biomarker of oncogenic stimulation by genotoxic mycotoxins, p53-triggered Mdm2 was assessed in intestinal cancer cells. AFB1 increased Mdm2 reporter expression in a dose-dependent manner. However, this was strongly antagonized by OTA treatment. As a positive transcription factor of Mdm2 expression, p53 levels were also increased by AFB1 alone and reduced by OTA. With marginal cell death responses, AFB1 induced p53-mediated S phase arrest and cell cycle-regulating target genes, which was completely suppressed by OTA. Although enterocyte-dominant CYP3A5 counteracted AFB1-induced DNA damage, expression of CYP3A5 was decreased by OTA or AFB1. Instead, OTA enhanced expression of another metabolic inactivating enzyme CYP3A4, attenuation of formation of AFB1-DNA adduct and p53-mediated cell cycle checking responses to the mutagens. Finally, the growth of intestinal cancer cells exposed to the mycotoxin mixture significantly exceeded the expected growth calculated from that of cells treated with each mycotoxin. Although AFB1-induced mutagen formation was decreased by OTA, interference with checkpoints through antagonistic action of OTA may contribute to the survival of tumor cells with deleterious mutations by genotoxic mycotoxins, potently increasing the risk of carcinogenesis. PMID- 27119351 TI - MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma. AB - Autophagy favors both cell survival and cancer suppression, and increasing evidence reveals that microRNAs (MIRs) regulate autophagy. Previously we reported that MIR126 is downregulated in malignant mesothelioma (MM). Therefore, we investigated the role of MIR126 in the regulation of cell metabolism and autophagy in MM models. We report that MIR126 induces autophagic flux in MM cells by downregulating insulin receptor substrate-1 (IRS1) and disrupting the IRS1 signaling pathway. This was specific to MM cells, and was not observed in non malignant cells of mesothelial origin or in MM cells expressing MIR126 insensitive IRS1 transcript. The MIR126 effect on autophagy in MM cells was recapitulated by IRS1 silencing, and antagonized by IRS1 overexpression or antisense MIR126 treatment. The MIR126-induced loss of IRS1 suppressed glucose uptake, leading to energy deprivation and AMPK-dependent phosphorylation of ULK1. In addition, MIR126 stimulated lipid droplet accumulation in a hypoxia-inducible factor-1alpha (HIF1alpha)-dependent manner. MIR126 also reduced pyruvate dehydrogenase kinase (PDK) and acetyl-CoA-citrate lyase (ACL) expression, leading to the accumulation of cytosolic citrate and paradoxical inhibition of pyruvate dehydrogenase (PDH) activity. Simultaneous pharmacological and genetic intervention with PDK and ACL activity phenocopied the effects of MIR126. This suggests that in MM MIR126 initiates a metabolic program leading to high autophagic flux and HIF1alpha stabilization, incompatible with tumor progression of MM. Consistently, MIR126-expressing MM cells injected into immunocompromised mice failed to progress beyond the initial stage of tumor formation, showing that increased autophagy has a protective role in MM. PMID- 27119353 TI - c-MYC inhibition impairs hypoxia response in glioblastoma multiforme. AB - The c-MYC oncoprotein is a DNA binding transcription factor that enhances the expression of many active genes. c-MYC transcriptional signatures vary according to the transcriptional program defined in each cell type during differentiation. Little is known on the involvement of c-MYC in regulation of gene expression programs that are induced by extracellular cues such as a changing microenvironment. Here we demonstrate that inhibition of c-MYC in glioblastoma multiforme cells blunts hypoxia-dependent glycolytic reprogramming and mitochondria fragmentation in hypoxia. This happens because c-MYC inhibition alters the cell transcriptional response to hypoxia and finely tunes the expression of a subset of Hypoxia Inducible Factor 1-regulated genes. We also show that genes whose expression in hypoxia is affected by c-MYC inhibition are able to distinguish the Proneural subtype of glioblastoma multiforme, thus potentially providing a molecular signature for this class of tumors that are the least tractable among glioblastomas. PMID- 27119352 TI - Altered expression pattern of circular RNAs in primary and metastatic sites of epithelial ovarian carcinoma. AB - Recently, a class of endogenous species of RNA called circular RNA (circRNA) has been shown to regulate gene expression in mammals and their role in cellular function is just beginning to be understood. To investigate the role of circRNAs in ovarian cancer, we performed paired-end RNA sequencing of primary sites, peritoneal and lymph node metastases from three patients with stage IIIC ovarian cancer. We developed an in-house computational pipeline to identify and characterize the circRNA expression from paired-end RNA-Seq libraries. This pipeline revealed thousands of circular isoforms in Epithelial Ovarian Carcinoma (EOC). These circRNAs are enriched for potentially effective miRNA seed matches. A significantly larger number of circRNAs are differentially expressed between tumor sites than mRNAs. Circular and linear expression exhibits an inverse trend for many cancer related pathways and signaling pathways like NFkB, PI3k/AKT and TGF-beta typically activated for mRNA in metastases are inhibited for circRNA expression. Further, circRNAs show a more robust expression pattern across patients than mRNA forms indicating their suitability as biomarkers in highly heterogeneous cancer transcriptomes. The consistency of circular RNA expression may offer new candidates for cancer treatment and prognosis. PMID- 27119354 TI - MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells. AB - Manganese porphyrins have been shown to be potent radioprotectors in a variety of cancer models. However, the mechanism as to how these porphyrins protect normal tissues from radiation damage still remains largely unknown. In the current study, we determine the effects of the manganese porphyrin, MnTnBuOE-2-PyP, on primary colorectal fibroblasts exposed to irradiation. We found that 2 Gy of radiation enhances the fibroblasts' ability to contract a collagen matrix, increases cell size and promotes cellular senesence. Treating fibroblasts with MnTnBuOE-2-PyP significantly inhibited radiation-induced collagen contraction, preserved cell morphology and also inhibited cellular senescence. We further showed that MnTnBuOE-2-PyP enhanced the overall viability of the fibroblasts following exposure to radiation but did not protect colorectal cancer cell viability. Specifically, MnTnBuOE-2-PyP in combination with irradiation, caused a significant decrease in tumor clonogenicity. Since locally advanced rectal cancers are treated with chemoradiation therapy followed by surgery and non metastatic anal cancers are treated with chemoradiation therapy, we also investigated the effects of MnTnBuOE-2-PyP in combination with radiation, 5 fluorouracil with and without Mitomycin C. We found that MnTnBuOE-2-PyP in combination with Mitomycin C or 5-fluorouracil further enhances those compounds' ability to suppress tumor cell growth. When MnTnBuOE-2-PyP was combined with the two chemotherapeutics and radiation, we observed the greatest reduction in tumor cell growth. Therefore, these studies indicate that MnTnBuOE-2-PyP could be used as a potent radioprotector for normal tissue, while at the same time enhancing radiation and chemotherapy treatment for rectal and anal cancers. PMID- 27119355 TI - Potential diagnostic and prognostic marker dimethylglycine dehydrogenase (DMGDH) suppresses hepatocellular carcinoma metastasis in vitro and in vivo. AB - Key metabolic enzymes regulatethe fluxes of small compounds to provide the basal substrates for cellular architecture and energy. Some of them are reported to be important carcinogenesis- and metastasis-related genes. In our work, we performed RNA-seq for50 pairs of normal-tumor of hepatocellular carcinoma (HCC) samples and found that the expression of dimethylglycine dehydrogenase (DMGDH) is decreased in HCC. The analysis of protein levels with Western blotting and immunohistochemistry also conformed our findings. It is proven to be a valuable biomarker for both diagnosis and prognosis in three independent datasets. Furthermore, we revealed that DMGDH suppresses migration, invasion and metastasis both in vitro and in vivo. By utilizing gene expression microarray for DMGDH, we identified several possible pathways altered in a DMGDH over-expressing cell line. Among these pathways, we noted that the phosphorylation of Akt-308/473 was significantly suppressed when DMGDH was over-expressed. In summary, our work reveals that DMGDH is a potential valuable biomarker for both diagnosis and prognosisfor HCC, and DMGDH gene expression suppresses metastasis through the Akt signaling pathway. PMID- 27119357 TI - [Communicative Competence in Medical Studies]. PMID- 27119358 TI - [Optimizing ADHD Treatment? Results of a Pilotstudy of the ADHD Selective Contract in Bremerhaven, Germany]. AB - BACKGROUND: The attention deficit hyperactivity disorder (ADHD) is associated with substantial impairment and psychiatric comorbidities. Thus, an optimized treatment is essential. In 2011, a new multidisciplinary treatment strategy (so called Versorgungsvertrag) was contracted for the model region of Bremerhaven, Germany. This manuscript describes the results of the feasibility testing, focusing on the effects of the Versorgungsvertrag on patients' ADHD symptoms and on the treatment satisfaction of patients' kins. MATERIAL AND METHODS: Patients with ADHD (4-17 years) were assessed at baseline and at 9 months follow-up. Kins documented the current symptomatology using the FBB-ADHS questionnaire on both occasions, and rated their satisfaction with the Versorgungsvertrag at follow-up. The FBB-ADHS gives information on the severity of the ADHD core symptoms (0=normal, 3=very noticeable). RESULTS: 69 patients (77 kins) were included. At follow-up, data from 59 patients (67 kins) were available. FBB-ADHS data of both occasions was available for 44 patients. Improvements regarding the ADHD total score (1.27 at follow-up vs. 1.59 at baseline, p=0.003) and the subdomains inattention (1.42 vs. 1.81, p=0.001) and hyperactivity (0.96 vs. 1.22, p=0.032) were documented. In the subgroup of boys (n=34), inattention (p=0.001), impulsivity (p=0.019) and the ADHD total score (p=0.002) improved, while no changes were observed in the subgroup of girls (n=10). The majority of kins (52.4 to 68.4%) rated the treatment as helpful. DISCUSSION: Our study shows improvements for the ADHD core symptoms after 9 months and a high satisfaction of kins with the treatment strategy. Due to the lack of a control group from routine care, no certain statement about the additional benefit of the treatment strategy can be made. The null effect in the subgroup of girls might be explained by the underrepresentation of girls, but the gender distribution observed in our study is commonly observed in patients with ADHD. CONCLUSION: The positive effects during the observation period should be confirmed in further studies including a control group from routine care. PMID- 27119359 TI - [Shared Decision Making (SDM) - Patient and Physician as a Team]. AB - The article provides an overview on Shared Decision Making (SDM), which is considered as the ideal form of physician-patient-interaction by many stakeholders of the health care system. SDM is distinguished from other models of physician-patient-interaction such as the paternalistic model and the information model. Besides the degree of acceptance of SDM in the general population and among physicians, barriers for its implementation will be reported. Indications for SDM as well as strategies and support material for its use in individual consultations will be discussed and illustrated by an oncological case study. Effects of SDM for patients as well as for clinicians will be highlighted. After background information on origins of SDM, its significance with regard to health policy in Germany is discussed. PMID- 27119360 TI - Decreased functional connectivity of insula-based network in young adults with internet gaming disorder. AB - The insula is a region that integrates interoception and drug urges, but little is known about its role in behavioral addiction such as internet addiction. We investigated insula-based functional connectivity in participants with internet gaming disorder (IGD) and healthy controls (HC) using resting-state functional MRI. The right and left insula subregions (posterior, ventroanterior, and dorsoanterior) were used as seed regions in a connectivity analysis. Compared with the HC group, the IGD group showed decreased functional connectivity between left posterior insula and bilateral supplementary motor area and middle cingulated cortex, between right posterior insula and right superior frontal gyrus, and decreased functional integration between insular subregions. The finding of reduced functional connectivity between the interoception and the motor/executive control regions is interpreted to reflect reduced ability to inhibit motor responses to internet gaming or diminished executive control over craving for internet gaming in IGD. The results support the hypothesis that IGD is associated with altered insula-based network, similar to substance addiction such as smoking. PMID- 27119361 TI - Sensitivity to communicative and non-communicative gestures in adolescents and adults with autism spectrum disorder: saccadic and pupillary responses. AB - Nonverbal communication using social cues, like gestures, governs a great part of our daily interactions. It has been proposed that people with autism spectrum disorder (ASD) show a deviant processing of social cues throughout their social cognitive development. However, social cues do not always convey an intention to communicate. Hence, the aim of this study was to test the sensitivity of adolescents and adults with ASD and neurotypical controls to social cues of high communicative (pointing) and low communicative values (grasping). For this purpose, we employed a spatial cueing paradigm with both Cue Types and compared saccadic reaction times (SRTs) between conditions in which the target appeared at a location which was congruent versus incongruent with the direction of the cue. Results showed that both adolescents and adults with ASD had slower SRTs for the incongruent relative to the congruent condition for both Cue Types, reflecting sensitivity to these cues. Additionally, mental effort during the processing of these social cues was assessed by means of pupil dilation. This analysis revealed that, while individuals with and without ASD required more mental effort to process incongruent compared to the congruent cues, cues with higher communicative value posed more processing load for the ASD group. These findings suggest that the perception of social gestures is intact in ASD but requires additional mental effort for gestures with higher communicative value. PMID- 27119362 TI - Neuroanatomy of the killer whale (Orcinus orca): a magnetic resonance imaging investigation of structure with insights on function and evolution. AB - The evolutionary process of adaptation to an obligatory aquatic existence dramatically modified cetacean brain structure and function. The brain of the killer whale (Orcinus orca) may be the largest of all taxa supporting a panoply of cognitive, sensory, and sensorimotor abilities. Despite this, examination of the O. orca brain has been limited in scope resulting in significant deficits in knowledge concerning its structure and function. The present study aims to describe the neural organization and potential function of the O. orca brain while linking these traits to potential evolutionary drivers. Magnetic resonance imaging was used for volumetric analysis and three-dimensional reconstruction of an in situ postmortem O. orca brain. Measurements were determined for cortical gray and cerebral white matter, subcortical nuclei, cerebellar gray and white matter, corpus callosum, hippocampi, superior and inferior colliculi, and neuroendocrine structures. With cerebral volume comprising 81.51 % of the total brain volume, this O. orca brain is one of the most corticalized mammalian brains studied to date. O. orca and other delphinoid cetaceans exhibit isometric scaling of cerebral white matter with increasing brain size, a trait that violates an otherwise evolutionarily conserved cerebral scaling law. Using comparative neurobiology, it is argued that the divergent cerebral morphology of delphinoid cetaceans compared to other mammalian taxa may have evolved in response to the sensorimotor demands of the aquatic environment. Furthermore, selective pressures associated with the evolution of echolocation and unihemispheric sleep are implicated in substructure morphology and function. This neuroanatomical dataset, heretofore absent from the literature, provides important quantitative data to test hypotheses regarding brain structure, function, and evolution within Cetacea and across Mammalia. PMID- 27119363 TI - Working memory load predicts visual search efficiency: Evidence from a novel pupillary response paradigm. AB - An observer's pupil dilates and constricts in response to variables such as ambient and focal luminance, cognitive effort, the emotional stimulus content, and working memory load. The pupil's memory load response is of particular interest, as it might be used for estimating observers' memory load while they are performing a complex task, without adding an interruptive and confounding memory test to the protocol. One important task in which working memory's involvement is still being debated is visual search, and indeed a previous experiment by Porter, Troscianko, and Gilchrist (Quarterly Journal of Experimental Psychology, 60, 211-229, 2007) analyzed observers' pupil sizes during search to study this issue. These authors found that pupil size increased over the course of the search, and they attributed this finding to accumulating working memory load. However, since the pupil response is slow and does not depend on memory load alone, this conclusion is rather speculative. In the present study, we estimated working memory load in visual search during the presentation of intermittent fixation screens, thought to induce a low, stable level of arousal and cognitive effort. Using standard visual search and control tasks, we showed that this paradigm reduces the influence of non-memory-related factors on pupil size. Furthermore, we found an early increase in working memory load to be associated with more efficient search, indicating a significant role of working memory in the search process. PMID- 27119364 TI - Individual and Neighborhood Determinants of Late HIV Diagnosis Among Latinos, Florida, 2007-2011. AB - The objective of this study was to examine individual and neighborhood determinants of late HIV diagnosis by gender and birthplace among Latinos. Florida HIV surveillance data for 2007-2011 were merged with American Community Survey data to estimate the odds of late HIV diagnosis (AIDS within 3 months of HIV diagnosis). Of 5522 HIV-positive Latinos, 26.5 % were diagnosed late. The odds ratio (OR) for late diagnosis was 1.39 times higher for males than females [95 % confidence interval (CI) 1.14-1.69]. Neighborhood-level factors associated with late diagnosis included residing in the 3 highest quartiles of neighborhood unemployment for males. The OR was 1.22 times higher for foreign- than US-born Latinos (95 % CI 1.07-1.40). Among foreign-born, residing in areas in the 2nd and 3rd quartiles of unemployment, in rural areas, and areas with <25 % Hispanic/Latino population were associated with late diagnosis. Population-based HIV testing campaigns may require tailoring to ensure that they effectively reach male Latinos in areas with high unemployment and foreign-born Latinos in rural and predominantly non-Latino areas. PMID- 27119356 TI - Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents. AB - Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL. PMID- 27119365 TI - Nitrated Fatty Acids Reverse Cigarette Smoke-Induced Alveolar Macrophage Activation and Inhibit Protease Activity via Electrophilic S-Alkylation. AB - Nitrated fatty acids (NFAs), endogenous products of nonenzymatic reactions of NO derived reactive nitrogen species with unsaturated fatty acids, exhibit substantial anti-inflammatory activities. They are both reversible electrophiles and peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, but the physiological implications of their electrophilic activity are poorly understood. We tested their effects on inflammatory and emphysema-related biomarkers in alveolar macrophages (AMs) of smoke-exposed mice. NFA (10-nitro oleic acid or 12-nitrolinoleic acid) treatment downregulated expression and activity of the inflammatory transcription factor NF-kappaB while upregulating those of PPARgamma. It also downregulated production of inflammatory cytokines and chemokines and of the protease cathepsin S (Cat S), a key mediator of emphysematous septal destruction. Cat S downregulation was accompanied by decreased AM elastolytic activity, a major mechanism of septal destruction. NFAs downregulated both Cat S expression and activity in AMs of wild-type mice, but only inhibited its activity in AMs of PPARgamma knockout mice, pointing to a PPARgamma-independent mechanism of enzyme inhibition. We hypothesized that this mechanism was electrophilic S-alkylation of target Cat S cysteines, and found that NFAs bind directly to Cat S following treatment of intact AMs and, as suggested by in silico modeling and calculation of relevant parameters, elicit S alkylation of Cys25 when incubated with purified Cat S. These results demonstrate that NFAs' electrophilic activity, in addition to their role as PPARgamma agonists, underlies their protective effects in chronic obstructive pulmonary disease (COPD) and support their therapeutic potential in this disease. PMID- 27119366 TI - Psychosocial Mechanisms Linking the Social Environment to Mental Health in African Americans. AB - Resource-poor social environments predict poor health, but the mechanisms and processes linking the social environment to psychological health and well-being remain unclear. This study explored psychosocial mediators of the association between the social environment and mental health in African American adults. African American men and women (n = 1467) completed questionnaires on the social environment, psychosocial factors (stress, depressive symptoms, and racial discrimination), and mental health. Multiple-mediator models were used to assess direct and indirect effects of the social environment on mental health. Low social status in the community (p < .001) and U.S. (p < .001) and low social support (p < .001) were associated with poor mental health. Psychosocial factors significantly jointly mediated the relationship between the social environment and mental health in multiple-mediator models. Low social status and social support were associated with greater perceived stress, depressive symptoms, and perceived racial discrimination, which were associated with poor mental health. Results suggest the relationship between the social environment and mental health is mediated by psychosocial factors and revealed potential mechanisms through which social status and social support influence the mental health of African American men and women. Findings from this study provide insight into the differential effects of stress, depression and discrimination on mental health. Ecological approaches that aim to improve the social environment and psychosocial mediators may enhance health-related quality of life and reduce health disparities in African Americans. PMID- 27119368 TI - Coronary Sinus Lead Removal: A Comparison between Active and Passive Fixation Leads. AB - BACKGROUND: Implantation of coronary sinus (CS) leads may be a difficult procedure due to different vein anatomies and a possible lead dislodgement. The mode of CS lead fixation has changed and developed in recent years. OBJECTIVES: We compared the removal procedures of active and passive fixation leads. METHODS: Between January 2009 and January 2014, 22 patients at our centre underwent CS lead removal, 6 active and 16 passive fixation leads were attempted using simple traction or lead locking devices with or without laser extraction sheaths. Data on procedural variables and success rates were collected and retrospectively analyzed. RESULTS: The mean patient age was 67.2 +/- 9.8 years, and 90.9% were male. The indication for lead removal was infection in all cases. All active fixation leads were Medtronic(r) Attain StarFixTM Model 4195 (Medtronic Inc., Minneapolis, MN, USA). The mean time from implantation for the active and passive fixation leads was 9.9 +/- 11.7 months (range 1.0-30.1) and 48.7 +/- 33.6 months (range 5.7-106.4), respectively (p = 0.012). Only 3 of 6 StarFix leads were successfully removed (50%) compared to 16 of 16 (100%) of the passive fixation CS leads (p = 0.013). No death or complications occurred during the 30-day follow up. CONCLUSION: According to our experience, removal of the Starfix active fixation CS leads had a higher procedural failure rate compared to passive. PMID- 27119369 TI - [Neurophilic urticarial dermatosis]. AB - Neurophilic urticarial dermatosis (NUD) is a new, important differential diagnosis of urticarial rashes. It is a clinical and histological response pattern that strongly correlates with systemic disease. Both autoinflammatory and autoimmune conditions can be present in patients with NUD. In this article the clinical and histological criteria of NUD, diagnostic considerations and the diseases most frequently associated with NUD are discussed. PMID- 27119370 TI - Galectin-3 in patients with chronic heart failure: association with oxidative stress, inflammation, renal dysfunction and prognosis. AB - BACKGROUND: Galectin-3 is a recently developed biomarker of fibrosis, which may play a role in cardiac remodeling and associated with both the progression and severity of heart failure (HF). METHODS: A prospective cohort study of 190 patients with documented prior myocardial infarction and chronic HF (NYHA class II-IV) was conducted. Patients were divided into 3 groups based on their NYHA functional class. Levels of galectin-3, NT-proBNP, CRP, IL-6, oxidized-LDL, extracellular superoxide dismutase (EC-SOD), 3-nitrotyrosine, SH-groups, cystatin C were determined. Follow-up period was 26 months, and all-cause mortality was determined as the primary endpoint. Statistical analysis was performed and statistical significance was set at P<0.05. RESULTS: The cytokines hs-CRP, IL-6 and markers of oxidative stress had significant positive correlation with plasma galectin-3 levels in all groups of patients. The level of galectin-3 was significantly different between the groups (P<0.05). Galectin-3 was found to be the most sensitive and specific value in determination of 26 months mortality in patients with chronic HF. Logistic regression analysis showed that age, galectin 3 and cystatin-C were associated with death during the follow up period. CONCLUSIONS: Galectin-3 levels are elevated in patients with chronic HF across all NYHA functional classes. Galectin-3 shows positive correlation with markers of oxidative stress, inflammation and kidney dysfunction. Galectin-3 levels and cystatin-C levels are independent predictors of 26-month mortality in patients with chronic HF. Patients with cystatin-C level >2800 pg/mL carry a worse prognosis. Galectin-3 level >21 ng/mL associated with increased mortality. PMID- 27119371 TI - Identification of miRNAs as Potential Biomarkers in Cerebrospinal Fluid from Amyotrophic Lateral Sclerosis Patients. AB - Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder. Since no diagnostic laboratory test exists, the identification of specific biomarkers could be fundamental in clinical practice. microRNAs (miRNAs) are considered promising biomarkers for neurodegenerative diseases. The aim of the study was to identify a CSF miRNA set that could differentiate ALS from non ALS condition. miRNA profiling in CSF from ALS patients (n = 24; eight with C9orf72 expansion) and unaffected control subjects (n = 24) by quantitative reverse transcription PCR identified fourteen deregulated miRNAs. Validation experiments confirmed eight miRNAs as significantly deregulated in ALS. No significant differences were observed between ALS patients with or without C9orf72 expansion. The receiver operator characteristic (ROC) curve analyses revealed the highest diagnostic accuracy for the upregulated miR181a-5p and the downregulated miR21-5p and miR15b-5p. The miR181a-5p/miR21-5p and miR181a 5p/miR15b-5p ratios detected ALS with 90 and 85 % sensitivity and 87 and 91 % specificity, respectively, confirming the application potential as disease biomarkers. These deregulated miRNAs are implicated in apoptotic way and provide insight into processes responsible for motor neuron degeneration. PMID- 27119372 TI - The Impact of Diabetic Neuropathy on Balance and on the Risk of Falls in Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study. AB - INTRODUCTION: Diabetic neuropathy (DN) is a prevalent complication of Type 2 Diabetes Mellitus (T2DM) with a major impact on the health of the affected patient. We hypothesized that mediated by the dysfunctionalities associated with DN's three major components: sensitive (lack of motion associated sensory), motor (impairments in movement coordination) and autonomic (the presence of postural hypotension), the presence of DN may impair the balance in the affected patients. Our study's main aim is to evaluate the possible association between the presence and severity of DN and both the balance impairment and the risk of falls in patients with T2DM. MATERIAL AND METHOD: In this cross-sectional study we enrolled, according to a consecutive-case population-based setting 198 patients with T2DM. The presence and severity of DN was evaluated using the Michigan Neuropathy Screening Instrument, a tool which allows both diagnosing and severity staging of DN. The balance impairment and the risk of falls were evaluated using four validated and standardized tools: Berg Balance Scale (BBS), Timed-up and Go test (TUG), Single Leg Stand test (SLS) and Fall Efficacy Scale (FES-I). RESULTS: The presence of DN was associated with significant decreases in the BBS score (40.5 vs. 43.7 points; p<0.001) and SLS time (9.3 vs. 10.3 seconds; p = 0.003) respectively increases in TUG time (8.9 vs. 7.6 seconds; p = 0.002) and FES-I score (38 vs. 33 points; p = 0.034). The MNSI score was reverse and significantly correlated with both BBS score (Spearman's r = -0.479; p<0.001) and SLS time (Spearman's r = -0.169; p = 0.017). In the multivariate regression model, we observed that patient's age, DN severity and depression's symptoms acted as independent, significant predictors for the risk of falls in patients with T2DM. CONCLUSIONS: The presence of DN in patients with DM is associated with impaired balance and with a consecutively increase in the risk of falls. PMID- 27119374 TI - Musculoskeletal Disorders and Agricultural Risk Factors Among Korean Farmers. AB - Farming is a strenuous occupation with various health risks, with musculoskeletal disorders (MSDs) being some of the most common. The risk factors for MSDs among Korean farmers are not well understood. Data were obtained from the Korean Farmers' Occupational Disease and Injury Survey (2012), which interviewed 16,113 participants regarding their demographic profiles, self-reported MSDs, and agricultural characteristics. Multiple logistic regression analysis was used to identify the risk factors for MSDs. Subjects reported MSDs in the neck or upper extremities (5.89%), lower extremities (19.62%), and back (26.9%). Working in animal husbandry significantly increased the risk of MSDs in the neck/upper extremities, compared with irrigation farming (odds ratio: 1.837, 95% confidence interval: 1.130-2.987). The risk of MSDs increased significantly with number of years of farming, after adjusting for age and sex (neck/upper extremities, P for trend = .0002; lower extremities, <.001; back, <.001). Agriculture type, years of farming, and ergonomic factors increased the risk of MSDs among Korean farmers. PMID- 27119375 TI - Vascularized Buccal Inversion Flap. PMID- 27119373 TI - TNFalpha/IFNgamma Mediated Intestinal Epithelial Barrier Dysfunction Is Attenuated by MicroRNA-93 Downregulation of PTK6 in Mouse Colonic Epithelial Cells. AB - Since inflammatory bowel diseases (IBD) represent significant morbidity and mortality in the US, the need for defining novel drug targets and inflammatory mechanisms would be of considerable benefit. Although protein tyrosine kinase 6 (PTK6, also known as breast tumor kinase BRK) has been primarily studied in an oncogenic context, it was noted that PTK6 null mice exhibited significantly enhanced colonic epithelial barrier function. Considering that the inflammatory functions of PTK6 have not yet been explored, we hypothesized that cytokines responsible for mediating IBD, such as TNFalpha/IFNgamma, may solicit the action of PTK6 to alter barrier function. After first assessing critical mediators of TNFalpha/IFNgamma driven epithelial barrier dysfunction, we further explored the possibility of PTK6 in this inflammatory context. In this report, we showed that PTK6 siRNA and PTK6 null young adult mouse colonic epithelial cells (YAMC) exhibited significant attenuation of TNFalpha/IFNgamma induced barrier dysfunction as measured by electric cell-substrate impedance sensing (ECIS) assay and permeability assays. In addition, PTK6 null cells transfected with PTK6 cDNA displayed restored barrier dysfunction in response to TNFalpha/IFNgamma, while the cells transfected with vector alone showed similar attenuation of barrier dysfunction. Furthermore, using subcellular fractionation and immunocytochemistry experiments, we found that PTK6 plays a role in FoxO1 nuclear accumulation leading to down-regulation of claudin-3, a tight junction protein. Moreover, we searched for relevant miRNA candidates putative for targeting PTK6 in order to identify and assess the impact of microRNA that target PTK6 with respect to TNFalpha/IFNgamma induced barrier dysfunction. Subsequently, we assayed likely targets and determined their effectiveness in attenuating PTK6 expression as well as cytokine induced barrier dysfunction. Results showed that miR-93 reduced PTK6 expression and attenuated TNFalpha/IFNgamma imposed decrease in transepithelial electrical resistance (TER), as well as excluded FoxO1 from the nucleus. Our results indicate that PTK6 may act as a novel mediator of intestinal epithelial permeability during inflammatory injury, and miR-93 may protect intestinal epithelial barrier function, at least in part, by targeting PTK6. PMID- 27119376 TI - Pressure- and flow-derived indices of coronary stenosis severity: old rivals, new allies. PMID- 27119377 TI - Three-dimensional quick response code based on inkjet printing of upconversion fluorescent nanoparticles for drug anti-counterfeiting. AB - Medicine counterfeiting is a serious issue worldwide, involving potentially devastating health repercussions. Advanced anti-counterfeit technology for drugs has therefore aroused intensive interest. However, existing anti-counterfeit technologies are associated with drawbacks such as the high cost, complex fabrication process, sophisticated operation and incapability in authenticating drug ingredients. In this contribution, we developed a smart phone recognition based upconversion fluorescent three-dimensional (3D) quick response (QR) code for tracking and anti-counterfeiting of drugs. We firstly formulated three colored inks incorporating upconversion nanoparticles with RGB (i.e., red, green and blue) emission colors. Using a modified inkjet printer, we printed a series of colors by precisely regulating the overlap of these three inks. Meanwhile, we developed a multilayer printing and splitting technology, which significantly increases the information storage capacity per unit area. As an example, we directly printed the upconversion fluorescent 3D QR code on the surface of drug capsules. The 3D QR code consisted of three different color layers with each layer encoded by information of different aspects of the drug. A smart phone APP was designed to decode the multicolor 3D QR code, providing the authenticity and related information of drugs. The developed technology possesses merits in terms of low cost, ease of operation, high throughput and high information capacity, thus holds great potential for drug anti-counterfeiting. PMID- 27119378 TI - Hierarchically constructed NiCo2S4@Ni(1-x)Co x (OH)2 core/shell nanoarrays and their application in energy storage. AB - We report a new type of core-shell heterostructure consisting of a rod-like NiCo2S4 (NCS) core and an urchin-like Ni(1-x)Co x (OH)2 (NCOH) shell via a simple hydrothermal route coupled with a facile electrodeposition. NCS nanorod arrays (NRAs) can not only act as excellent electrochemically active materials by themselves, but they can also serve as hierarchical porous scaffolds capable of fast electron conduction and ion diffusion for loading a large amount of additional active materials. Moreover, it is observed that the urchin-like NCOH nanosheets coating could bind the inner NCS nanorods together and thereby reinforce the whole structure mechanically. Meanwhile, more effective pathways for electrons are available in the NCS@NCOH hybrids than an individual NCS nanorod. Benefiting from both structural and compositional features, the NCS@NCOH electrode exhibits greatly improved electrochemical performance with high capacity (3.54 C cm(-2) at 1 mA cm(-2)) and excellent cycling stability (78% capacity retention after 4000 cycles). Moreover, a battery-type device is also fabricated by using NCS@NCOH as a positive electrode and activated carbon (AC) as a negative electrode, displaying high capacity (2.51 C cm(-2) at 2 mA cm(-2)) and good durability (88.8% capacity retention after 4000 cycles) as well. PMID- 27119379 TI - Above- and Belowground Biomass Allocation in Shrub Biomes across the Northeast Tibetan Plateau. AB - Biomass partitioning has been explored across various biomes. However, the strategies of allocation in plants still remain contentious. This study investigated allocation patterns of above- and belowground biomass at the community level, using biomass survey from the Tibetan Plateau. We explored above and belowground biomass by conducting three consecutive sampling campaigns across shrub biomes on the northeast Tibetan Plateau during 2011-2013. We then documented the above-ground biomass (AGB), below-ground biomass (BGB) and root: shoot ratio (R/S) and the relationships between R/S and environment factors using data from 201 plots surveyed from 67 sites. We further examined relationships between above-ground and below-ground biomass across various shrub types. Our results indicated that the median values of AGB, BGB, and R/S in Tibetan shrub were 1102.55, 874.91 g m-2, and 0.85, respectively. R/S showed significant trend with mean annual precipitation (MAP), while decreased with mean annual temperature (MAT). Reduced major axis analysis indicated that the slope of the log-log relationship between above- and belowground biomass revealed a significant difference from 1.0 over space, supporting the optimal hypothesis. Interestingly, the slopes of the allometric relationship between log AGB and log BGB differed significantly between alpine and desert shrub. Our findings supported the optimal theory of above- and belowground biomass partitioning in Tibetan shrub, while the isometric hypothesis for alpine shrub at the community level. PMID- 27119380 TI - Biomechanics of the Peacock's Display: How Feather Structure and Resonance Influence Multimodal Signaling. AB - Courtship displays may serve as signals of the quality of motor performance, but little is known about the underlying biomechanics that determines both their signal content and costs. Peacocks (Pavo cristatus) perform a complex, multimodal "train-rattling" display in which they court females by vibrating the iridescent feathers in their elaborate train ornament. Here we study how feather biomechanics influences the performance of this display using a combination of field recordings and laboratory experiments. Using high-speed video, we find that train-rattling peacocks stridulate their tail feathers against the train at 25.6 Hz, on average, generating a broadband, pulsating mechanical sound at that frequency. Laboratory measurements demonstrate that arrays of peacock tail and train feathers have a broad resonant peak in their vibrational spectra at the range of frequencies used for train-rattling during the display, and the motion of feathers is just as expected for feathers shaking near resonance. This indicates that peacocks are able to drive feather vibrations energetically efficiently over a relatively broad range of frequencies, enabling them to modulate the feather vibration frequency of their displays. Using our field data, we show that peacocks with longer trains use slightly higher vibration frequencies on average, even though longer train feathers are heavier and have lower resonant frequencies. Based on these results, we propose hypotheses for future studies of the function and energetics of this display that ask why its dynamic elements might attract and maintain female attention. Finally, we demonstrate how the mechanical structure of the train feathers affects the peacock's visual display by allowing the colorful iridescent eyespots-which strongly influence female mate choice-to remain nearly stationary against a dynamic iridescent background. PMID- 27119381 TI - Recovery of consciousness after 7 years in vegetative state of non-traumatic origin: A single case study. AB - PRIMARY OBJECTIVE: To report consistent recovery of consciousness to a state of severe disability in a young patient after 7 years in vegetative state due to severe acquired brain injury, with reflections on protraction of intensive care and expert follow-up for the purpose of intercepting possible, albeit infrequent, cases of late recovery of consciousness. RESEARCH DESIGN: Single case study Methods: This study describes the 9-year history of a healthy 15-year-old who suffered cerebellar haemorrhage due to rupture of an arteriovenous malformation, followed by a brief period of coma then protracted vegetative state; late stabilization of general condition with resolution of neurosurgical complications. Clinical monitoring employed scales for structured assessment of severe disability and disorders of consciousness. RESULTS: The transition from vegetative state to full consciousness occurred over a period of ~ 3 months, 7 years after onset. In the subsequent 2 years the patient has shown slow but progressive overall improvement in a framework of severe residual motor and cognitive disability. CONCLUSIONS: Cases of recovery of consciousness after periods of vegetative state exceeding 1 year are rare, but remind one that a negative prognosis decided too early may be a self-fulfilling forecast. PMID- 27119383 TI - Kinetic trapping through coalescence and the formation of patterned Ag-Cu nanoparticles. AB - In recent years, due to its inherent flexibility, magnetron-sputtering has been widely used to synthesise bi-metallic nanoparticles (NPs) via subsequent inert gas cooling and gas-phase condensation of the sputtered atomic vapour. Utilising two separate sputter targets allows for good control over composition. Simultaneously, it involves fast kinetics and non-equilibrium processes, which can trap the nascent NPs into metastable configurations. In this study, we observed such configurations in immiscible, bi-metallic Ag-Cu NPs by scanning transmission electron microscopy (S/TEM) and electron energy-loss spectroscopy (EELS), and noticed a marked difference in the shape of NPs belonging to Ag- and Cu-rich samples. We explained the formation of Janus or Ag@Cu core/shell metastable structures on the grounds of in-flight mixed NP coalescence. We utilised molecular dynamics (MD) and Monte Carlo (MC) computer simulations to demonstrate that such configurations cannot occur as a result of nanoalloy segregation. Instead, sintering at relatively low temperatures can give rise to metastable structures, which eventually can be stabilised by subsequent quenching. Furthermore, we compared the heteroepitaxial diffusivities along various surfaces of both Ag and Cu NPs, and emphasised the differences between the sintering mechanisms of Ag- and Cu-rich NP compositions: small Cu NPs deform as coherent objects on large Ag NPs, whereas small Ag NPs dissolve into large Cu NPs, with their atoms diffusing along specific directions. Taking advantage of this observation, we propose controlled NP coalescence as a method to engineer mixed NPs of a unique, patterned core@partial-shell structure, which we refer to as a "glass-float" (ukidama) structure. PMID- 27119382 TI - A Pharmacovigilance Approach for Post-Marketing in Japan Using the Japanese Adverse Drug Event Report (JADER) Database and Association Analysis. AB - BACKGROUND: Rapid dissemination of information regarding adverse drug reactions is a key aspect for improving pharmacovigilance. There is a possibility that unknown adverse drug reactions will become apparent through post-marketing administration. Currently, although there have been studies evaluating the relationships between a drug and adverse drug reactions using the JADER database which collects reported spontaneous adverse drug reactions, an efficient approach to assess the association between adverse drug reactions of drugs with the same indications as well as the influence of demographics (e.g. gender) has not been proposed. METHODS AND FINDINGS: We utilized the REAC and DEMO tables from the May 2015 version of JADER for patients taking antidepressant drugs (SSRI, SNRI, and NaSSA). We evaluated the associations using association analyses with an apriori algorithm. Support, confidence, lift, and conviction were used as indicators for associations. The highest score in adverse drug reactions for SSRI was obtained for "aspartate aminotransferase increased", "alanine aminotransferase increased", with values of 0.0059, 0.93, 135.5, and 13.9 for support, confidence, lift and conviction, respectively. For SNRI, "international normalized ratio increased", "drug interaction" were observed with 0.0064, 1.00, 71.9, and NA. For NaSSA, "anxiety", "irritability" were observed with 0.0058, 0.80, 49.9, and 4.9. For female taking SSRI, the highest support scores were observed in "twenties", "suicide attempt", whereas "thirties", "neuroleptic malignant syndrome" were observed for male. Second, for SNRI, "eighties", "inappropriate antidiuretic hormone secretion" were observed for female, whereas "interstitial lung disease" and "hepatitis fulminant" were for male. Finally, for NaSSA, "suicidal ideation" was for female, and "rhabdomyolysis" was for male. CONCLUSIONS: Different combinations of adverse drug reactions were noted between the antidepressants. In addition, the reported adverse drug reactions differed by gender. This approach using a large database for examining the associations can improve safety monitoring during the post-marketing phase. PMID- 27119384 TI - Brine Spills Associated with Unconventional Oil Development in North Dakota. AB - The rapid rise of unconventional oil production during the past decade in the Bakken region of North Dakota raises concerns related to water contamination associated with the accidental release of oil and gas wastewater to the environment. Here, we characterize the major and trace element chemistry and isotopic ratios ((87)Sr/(86)Sr, delta(18)O, delta(2)H) of surface waters (n = 29) in areas impacted by oil and gas wastewater spills in the Bakken region of North Dakota. We establish geochemical and isotopic tracers that can identify Bakken brine spills in the environment. In addition to elevated concentrations of dissolved salts (Na, Cl, Br), spill waters also consisted of elevated concentrations of other contaminants (Se, V, Pb, NH4) compared to background waters, and soil and sediment in spill sites had elevated total radium activities ((228)Ra + (226)Ra) relative to background, indicating accumulation of Ra in impacted soil and sediment. We observed that inorganic contamination associated with brine spills in North Dakota is remarkably persistent, with elevated levels of contaminants observed in spills sites up to 4 years following the spill events. PMID- 27119387 TI - Inclusion of an Anthracene-based Fluorophore within Molecular Containers: A Comparative Study of the Cucurbituril and Cyclodextrin Host Families. AB - In this paper, the binding interaction of a promising chloride channel blocker, 9 methyl anthroate (9-MA), with two different classes of molecular containers, beta cyclodextrins (beta-CD and methyl-beta-CD) and cucurbit[7]uril, having comparable cavity dimensions, has been thoroughly demonstrated via inspection of the modulation of the excited-state properties of the emissive molecule. Spectral data suggest that CB7 encapsulates the probe more efficiently in a 1:2 fashion, whereas the efficacies of beta-CDs are relatively less and the corresponding stoichiometry is 1:1. Interestingly, despite being thermodynamically much more favorable than the probe-beta-CD complexation equilibria, the fraction of probe CB7 complex formed is appreciably smaller with respect to that of probe-beta-CD complexes. This apparent inconsistency has been addressed via the proposition that since the formation of a 1:2 complex is entropically disadvantageous, it is anticipated that the activation barrier of the corresponding reaction is reasonably high, and thus only a small fraction of the reactants are able to surpass the energy barrier to form the products. This proposition has been thoroughly corroborated by fluorescence lifetime measurements at different temperatures. PMID- 27119388 TI - Using systems thinking to support clinical system transformation. AB - Purpose - The British Columbia Ministry of Health's Clinical Care Management initiative was used as a case study to better understand large-scale change (LSC) within BC's health system. Using a complex system framework, the purpose of this paper is to examine mechanisms that enable and constrain the implementation of clinical guidelines across various clinical settings. Design/methodology/approach - Researchers applied a general model of complex adaptive systems plus two specific conceptual frameworks (realist evaluation and system dynamics mapping) to define and study enablers and constraints. Focus group sessions and interviews with clinicians, executives, managers and board members were validated through an online survey. Findings - The functional themes for managing large-scale clinical change included: creating a context to prepare clinicians for health system transformation initiatives; promoting shared clinical leadership; strengthening knowledge management, strategic communications and opportunities for networking; and clearing pathways through the complexity of a multilevel, dynamic system. Research limitations/implications - The action research methodology was designed to guide continuing improvement of implementation. A sample of initiatives was selected; it was not intended to compare and contrast facilitators and barriers across all initiatives and regions. Similarly, evaluating the results or process of guideline implementation was outside the scope; the methods were designed to enable conversations at multiple levels - policy, management and practice - about how to improve implementation. The study is best seen as a case study of LSC, offering a possible model for replication by others and a tool to shape further dialogue. Practical implications - Recommended action-oriented strategies included engaging local champions; supporting local adaptation for implementation of clinical guidelines; strengthening local teams to guide implementation; reducing change fatigue; ensuring adequate resources; providing consistent communication especially for front-line care providers; and supporting local teams to demonstrate the clinical value of the guidelines to their colleagues. Originality/value - Bringing a complex systems perspective to clinical guideline implementation resulted in a clear understanding of the challenges involved in LSC. PMID- 27119389 TI - Healthcare reform in China: making sense of a policy experiment? AB - Purpose - The purpose of this paper is to explore recent healthcare reform in China. Reflecting on the current literature, the viewpoint argues that greater attention should be paid to healthcare reform in China as a public policy process, particularly one that is built on policy experimentation. Design/methodology/approach - The viewpoint argues that while recent efforts to understand the impact of reform have brought significant understanding of key issues and processes, such interest tends to focus on pragmatic concerns rather than pose wider theoretical and methodological questions about the nature and pace of reform. Findings - The authors suggest that the lens of public policy is particular relevant and insightful given what has been documented elsewhere regarding China's unique policy process characterised by "policy experimentation". The authors discuss how a policy experiment perspective can provide a useful heuristic for understanding healthcare reform in China. Originality/value - The viewpoint concludes by outlining possible applications of this approach and looks forward at the emerging research agenda in this area. PMID- 27119390 TI - Management practices in Australian healthcare: can NSW public hospitals do better? AB - Purpose - The purpose of this paper is to investigate the determinants of best management practices in an Australian state-run healthcare system, namely New South Wales (NSW), and studies the impact of a range of hospital factors in driving best management practices as a means of enhancing healthcare delivery. Design/methodology/approach - This study adapts a unique survey instrument globally tested to quantify the multi-dimensional nature of hospital management practices in 42 acute care public hospitals of NSW. The authors then analysed the role of hospital-specific characteristics in driving best management practices, namely hospital size (measured by the number of hospital beds, employees and doctors), level of skill and education, degree of hospital manager autonomy and organisational hierarchy. Findings - The findings of this study show the areas of strength and potential areas of improvement in NSW hospitals. The authors find a positive association between the adoption of better management practices and hospital size (measured by the number of hospital beds and employees), level of skills and education, degree of hospital manager autonomy and organisational hierarchy. However, hospital size as measured by the number of doctors did not have a statistically significant relationship. Practical implications - This paper is of interest to both hospital administrators, clinical doctors and healthcare policy-makers who want to improve and develop strategies for better management in the healthcare sector. Originality/value - This study provides an internationally comparable robust measure of management capability in public hospitals, and contributes to the evidence-base of management practices and performance in hospitals. PMID- 27119391 TI - Analysis of introducing e-services: a case study of Health Insurance Fund of Macedonia. AB - Purpose - Information systems play a significant role in the improving of health and healthcare, as well as in the planning and financing of health services. Fund's Information System is an essential component of the information infrastructure that allows assessment of the impact of changes in health insurance and healthcare for the population. The purpose of this paper is to give a brief overview of the affection of e-services and electronic data exchange (between Fund's information systems and other IT systems) at the quality of service for insured people and savings funds. Design/methodology/approach - The authors opted for an exploratory study using the e-services implemented in Health Insurance Fund (HIF) of Macedonia and data which were complemented by documentary analysis, including brand documents and descriptions of internal processes. In this paper is presented an analysis of the financial aspects of some e-services in HIF of Macedonia by using computer-based information systems and calculating the financial implications on insured people, companies and healthcare providers. Findings - The analysis conducted in this paper shows that the HIF's e-services would have a positive impact for the insured people, healthcare providers and companies when fulfilling their administrative obligations and exercising their rights. Originality/value - The analysis presented in this paper can serve as a valuable input for the healthcare authorities in making decisions related to introducing e-services in healthcare. These enhanced e-services will improve the quality service of the HIF. PMID- 27119392 TI - Hospital administrative characteristics and volunteer resource management practices. AB - Purpose - The purpose of this paper is to explore the links between various characteristics of hospital administration and the utilization of classes of volunteer resource management (VRM) practices. Design/methodology/approach - This paper uses original data collected via surveys of volunteer directors in 122 hospitals in five Northeastern and Southern US states. Findings - Structural equation modeling results suggest that number of paid volunteer management staff, scope of responsibility of the primary volunteer administrator, and hospital size are positively associated with increased usage of certain VRM practices. Research limitations/implications - First, the authors begin the exploration of VRM antecedents, and encourage others to continue this line of inquiry; and second, the authors assess dimensionality of practices, allowing future researchers to consider whether specific dimensions have a differential impact on key individual and organizational outcomes. Practical implications - Based on the findings of a relationship between administrative characteristics and the on-the-ground execution of VRM practice, a baseline audit comparing current practices to those VRM practices presented here might be useful in determining what next steps may be taken to focus investments in VRM that can ultimately drive practice utilization. Originality/value - The exploration of the dimensionality of volunteer management adds a novel perspective to both the academic study, and practice, of volunteer management. To the authors' knowledge, this is the first empirical categorization of VRM practices. PMID- 27119393 TI - Evaluating a physician leadership development program - a mixed methods approach. AB - Purpose - With the extent of change in healthcare today, organizations need strong physician leaders. To compensate for the lack of physician leadership education, many organizations are sending physicians to external leadership programs or developing in-house leadership programs targeted specifically to physicians. The purpose of this paper is to outline the evaluation strategy and outcomes of the inaugural year of a Physician Leadership Academy (PLA) developed and implemented at a Michigan-based regional healthcare system. Design/methodology/approach - The authors applied the theoretical framework of Kirkpatrick's four levels of evaluation and used surveys, observations, activity tracking, and interviews to evaluate the program outcomes. The authors applied grounded theory techniques to the interview data. Findings - The program met targeted outcomes across all four levels of evaluation. Interview themes focused on the significance of increasing self-awareness, building relationships, applying new skills, and building confidence. Research limitations/implications - While only one example, this study illustrates the importance of developing the evaluation strategy as part of the program design. Qualitative research methods, often lacking from learning evaluation design, uncover rich themes of impact. The study supports how a PLA program can enhance physician learning, engagement, and relationship building throughout and after the program. Physician leaders' partnership with organization development and learning professionals yield results with impact to individuals, groups, and the organization. Originality/value - Few studies provide an in-depth review of evaluation methods and outcomes of physician leadership development programs. Healthcare organizations seeking to develop similar in-house programs may benefit applying the evaluation strategy outlined in this study. PMID- 27119394 TI - The mediating effect of job stress in the relationship between work-related dimensions and career commitment. AB - Purpose - The purpose of this paper is to examine associations between career commitment, job stress, and work-related dimensions of work routinization, role clarity, social support, and promotional opportunity. Design/methodology/approach - In all, 408 employees holding supervisor or above level job positions in Sri Lanka responded to the survey. For the data analysis, structural equation modelling with maximum likelihood estimation was performed. Findings - Job stress fully mediates the relationship between role clarity and career commitment while partially mediates the relationships between work routinization, social support, and the lack of promotional opportunity and career commitment. Originality/value An investigation into relationships between work-related dimensions and career commitment holds a number of implications in the current business environment where employee commitment may be shifting from the organization to one's career. PMID- 27119395 TI - Healthcare managers' construction of the manager role in relation to the medical profession. AB - Purpose - The purpose of this paper is to explore how healthcare managers construct the manager role in relation to the medical profession in their organisations. Design/methodology/approach - In total, 18 of Sweden's 20 healthcare chief executive officers (CEOs) and 20 clinical department managers (CDMs) were interviewed about their views on management of physicians. Interviews were performed in the context of one aspect of healthcare management; i.e., management of physicians' sickness certification practice. A discourse analysis approach was used for data analysis. Findings - Few managers used a management based discourse to construct the manager role. Instead, a profession-based discourse dominated and managers frequently used the attributes "physician" or "non-physician" to categorise themselves or other managers in their managerial roles. Some managers, both CEOs and CDMs, shifted between the management- and profession-based discourses, resulting in a kind of "yes, but [...]" approach to management in the organisations. The dominating profession-based discourse served to reproduce the power and status of physicians within the organisation, thereby rendering the manager role weaker than the medical profession for both physician and non-physician managers. Research limitations/implications - Further studies are needed to explore the impact of gender, managerial level, and basic profession on how managers construct the manager role in relation to physicians. Practical implications - The results suggest that there is a need to address the organisational conditions for managers' role taking in healthcare organisations. Originality/value - Despite the general strengthening of the manager position in healthcare through political reforms during the last decades, this study shows that a profession-based discourse clearly dominated in how the managers constructed the manager role in relation to the medical profession on the workplace level in their organisations. PMID- 27119396 TI - Benefits and risks of shared services in healthcare. AB - Purpose - The purpose of this paper is to explore the experiences of staff in a large, public health service involved in transitioning support services to a shared services model. It aims to understand their perceptions of the benefits and risks arising from this change. Design/methodology/approach - Thematic analysis of qualitative data from semi-structured interviews with both service provider and customer agency staff was used to identify, analyze and report patterns of benefits and risks within data. Findings - Staff expressed the need for relevant subject-matter-experts to work within customer agencies to facilitate effective communication between the customer agency and shared services provider, reflecting observations found in out-sourcing literature. Research limitations/implications - Results point to significant challenges continuing to occur for shared services in healthcare. Risks identified suggest a more intimate relationship between clinical and support services than previously discussed. Originality/value - Previous discussion of the shared services model has not considered the skills, knowledge and ability required by staff in the customer agency. This research indicates that in the absence of such consideration, the concepts of the shared services model are weakened. PMID- 27119397 TI - Prioritizing lean management practices in public and private hospitals. AB - Purpose - The purpose of this paper is to prioritize 21 healthcare wastes in public and private hospitals of United Arab Emirates (UAE). Design/methodology/approach - Seven healthcare wastes linked with lean management are further decomposed in to sub-criteria and to deal with this complexity of multi criteria decision-making process, analytical hierarchical process (AHP) method is used in this research. Findings - AHP framework for this study resulted in a ranking of 21 healthcare wastes in public and private hospitals of UAE. It has been found that management in private healthcare systems of UAE is putting more emphasis on the inventory waste. On the other hand, over processing waste has got highest weight in public hospitals of UAE. Research limitations/implications - The future directions of this research would be to apply a lean set of tools for the value stream optimization of the prioritized key improvement areas. Practical implications - This is a contribution to the continuing research into lean management, giving practitioners and designers a practical way for measuring and implementing lean practices across health organizations. Originality/value - The contribution of this research, through successive stages of data collection, measurement analysis and refinement, is a set of reliable and valid framework that can be subsequently used in conceptualization, prioritization of the waste reduction strategies in healthcare management. PMID- 27119398 TI - Lean healthcare from a change management perspective. AB - Purpose - Lean healthcare is used in a growing number of hospitals to increase efficiency and quality of care. However, healthcare organizations encounter problems with the implementation of change initiatives due to an implementation gap: the gap between strategy and execution. From a change management perspective, the purpose of this paper is to increase scientific knowledge regarding factors that diminish the implementation gap and make the transition from the "toolbox lean" toward an actual transformation to lean healthcare. Design/methodology/approach - A cross-sectional study was executed in an operating theatre of a Dutch University Medical Centre. Transformational leadership was expected to ensure the required top-down commitment, whereas team leadership creates the required active, bottom-up behavior of employees. Furthermore, professional and functional silos and a hierarchical structure were expected to impede the workforce flexibility in adapting organizational elements and optimize the entire process flow. Findings - The correlation and regression analyses showed positive relations between the transformational leadership and team leadership styles and lean healthcare implementation. The results also indicated a strong relation between workforce flexibility and the implementation of lean healthcare. Originality/value - With the use of a recently developed change management model, the Change Competence Model, the authors suggest leadership and workforce flexibility to be part of an organization's change capacity as crucial success factor for a sustainable transformation to lean healthcare. PMID- 27119399 TI - Implementing a new governance model. AB - Purpose - The purpose of this paper is to discuss the lessons learnt from the process of implementing a new model of governance within Living Well, a New Zealand statutory mental health agency. Design/methodology/approach - It presents the findings from an organisational case study that involved qualitative interviews, meeting observations and document analysis. Archetype theory provided the analytical framework for the research enabling an analysis of both the formal structures and informal value systems that influenced the implementation of the governance model. Findings - The research found that the move to a new governance model did not proceed as planned. It highlighted the importance of staff commitment, the complexity of adopting a new philosophical approach and the undue influence of key personalities as key determining factors in the implementation process. The findings suggest that planners and managers within statutory mental health agencies need to consider the implications of any proposed governance change on existing roles and relationships, thinking strategically about how to secure professional commitment to change. Practical implications - There are ongoing pressures within statutory mental health agencies to improve the efficiency and effectiveness of organisational structures and systems. This paper has implications for how planners and managers think about the process of implementing new governance models within the statutory mental health environment in order to increase the likelihood of sustaining and embedding new approaches to service delivery. Originality/value - The paper presents insights into the process of implementing new governance models within a statutory mental health agency in New Zealand that has relevance for other jurisdictions. PMID- 27119400 TI - What's in a name? PMID- 27119401 TI - Bringing 'something more' to the bedside: the importance of clinical wisdom at end of life. PMID- 27119402 TI - Implementing a palliative approach in the intensive care unit: an oxymoron or a realistic possibility? PMID- 27119403 TI - An exploratory study of reiki experiences in women who have cancer. AB - AIMS: To explore the perceptions and experiences of reiki for women who have cancer and identify outcome measures for an intervention study. METHODS: A cross sectional qualitative study of 10 women who had received reiki after cancer treatment was conducted. Interviews were audiotaped, transcribed and coded using framework analysis. RESULTS: Key themes identified were: limited understanding of reiki prior to receiving any reiki; release of emotional strain during reiki feelings of a release of energy, a clearing of the mind from cancer, inner peace/relaxation, hope, a sense of being cared for; experience of physical sensations during reiki, such as pain relief and tingling; physical, emotional and cognitive improvements after reiki, such as improved sleep, a sense of calm and peace, reduced depression and improved self-confidence. CONCLUSION: Findings suggest that reiki could be a beneficial tool in the self-management of quality of life issues for women who have cancer. PMID- 27119404 TI - Training palliative care: a study of public and private institutions in Kenya. AB - BACKGROUND: Globally, life-threatening diseases are on the rise, indicating the need for palliative care, an approach of ensuring quality of life for the patient and his or her family. Education and training is one of the ways of ensuring staff competency in providing palliative care. AIMS: This study sought to explore challenges faced by both public and private faith-based training institutions offering palliative care. METHODS: This was a qualitative study in both public and private training institutions, which were selected randomly. Six institutions were selected for the study. One palliative care trainer in each institution was interviewed using a semi-structured interview guide. Information was recorded, transcribed and thematic analysis was done. Data were presented in the form of narration. RESULTS: Many institutions had incorporated palliative care into their curricula. However, these institutions faced challenges, including few allocated hours and few members of staff trained in palliative care. Clinical area employees were not well equipped with knowledge on palliative care. CONCLUSION: Challenges exist in both public and private institutions. Institutions should allow for more training hours in palliative care. PMID- 27119405 TI - Development of a logic model to support a network approach in delivering 24/7 children's palliative care: part one. AB - AIM: This research aimed to develop and evaluate a 24/7 symptom-management service for children with life-limiting conditions and a model for palliative care nursing. STUDY DESIGN: A combination of audit and qualitative and quantitative evaluation. SAMPLE AND SETTING: A consultant nurse-led service (n=5 clinical nurse specialists) provided care and support to children and their families, which spanned a range of settings (home, hospital, hospice) supported by a managed clinical network of consultant paediatricians (n=4) with postgraduate expertise in palliative care. METHODS: A pluralistic evaluation was conducted where the predefined service standards were audited and the predetermined service objectives were evaluated using daily diary data from the nursing team (micro), qualitative and quantitative survey data of stakeholders using the service (mezzo) and family assessment of children's palliative care (CPC) standards across the CPC network (macro). PMID- 27119406 TI - An interprofessional education programme for medical learners during a one-month palliative care rotation. AB - Interprofessional education in health care and in palliative care has been the focus of increasing attention in recent years. For health professionals to provide and deliver high-quality palliative care, collaboration and teamwork is required. Palliative care is the ideal service to introduce interprofessional teamwork to medical learners early on in their training. During a 1-month palliative care rotation in Ontario, Canada, medical learners completed a questionnaire seeking their feedback on the interprofessional team model. This article will highlight the results of the questionnaire, how the team promotes a culture of interprofessional collaborative practice, and the supportive structures that foster collaboration among professionals. PMID- 27119407 TI - Knowledge and practice of end-of-life care among nurses in a teaching hospital in Nigeria. AB - BACKGROUND: Improving end-of-life care (EoLC) has become a major goal among nurses since they have the most contact with patients and their families at this phase of life. This study examined the knowledge and practice of EoLC among nurses working at the University of Nigeria Teaching Hospital, in Enugu. METHODS: A cross-sectional descriptive research study was used. A total of 130 nurses, working in selected wards of the hospital, took part in the study, meeting the inclusion criteria. Data were obtained through a structured questionnaire, analysed using descriptive statistics and results were presented in tables and charts. RESULTS: The results showed that 123 respondents (94.6%) had knowledge of EoLC as care given to terminal state of life and or a dying person. Findings also showed the practice of EoLC with a mean score of 3.6+/-2.8 and inadequate manpower and lack of experience with the mean 2.9+/-1.6 and 2.9+/-1.5 respectively, as factors negatively influenced their practice of EoLC. CONCLUSIONS: It was recommended that workshop or seminar and advocacy on EoLC should be organised to create awareness and raise the practice of EoLC. PMID- 27119409 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 27119410 TI - Politics and palliative care: Libya. AB - Dion Smyth's review of the internet for palliative nursing. PMID- 27119417 TI - Serious Illness Conversations With Doctors: Patients Using Information Obtained From Sources Other Than Their Doctors. AB - The purpose of this study was to examine how people with serious illnesses communicate information they have acquired about their illness from the Internet and social or mass media to their doctors. Twenty-two in-depth interviews of patients with serious or life-threatening illnesses were conducted and analyzed. Street's ecological perspective of communication was used to understand the processes that influence when and how patients bring information that they obtained from external sources to their doctors. The reactions patients received from their doctors affected their future communication with them. Results indicate doctors who have a dominant communication style often discourage patients from bringing outside information to them, and in some cases this results in patients changing doctors. On the other hand, doctors who are more attentive make patients feel more comfortable about bringing outside information to them, and this leads to more meaningful and beneficial conversations. PMID- 27119411 TI - Seeing Circles and Drawing Ellipses: When Sound Biases Reproduction of Visual Motion. AB - The perception and production of biological movements is characterized by the 1/3 power law, a relation linking the curvature and the velocity of an intended action. In particular, motions are perceived and reproduced distorted when their kinematics deviate from this biological law. Whereas most studies dealing with this perceptual-motor relation focused on visual or kinaesthetic modalities in a unimodal context, in this paper we show that auditory dynamics strikingly biases visuomotor processes. Biologically consistent or inconsistent circular visual motions were used in combination with circular or elliptical auditory motions. Auditory motions were synthesized friction sounds mimicking those produced by the friction of the pen on a paper when someone is drawing. Sounds were presented diotically and the auditory motion velocity was evoked through the friction sound timbre variations without any spatial cues. Remarkably, when subjects were asked to reproduce circular visual motion while listening to sounds that evoked elliptical kinematics without seeing their hand, they drew elliptical shapes. Moreover, distortion induced by inconsistent elliptical kinematics in both visual and auditory modalities added up linearly. These results bring to light the substantial role of auditory dynamics in the visuo-motor coupling in a multisensory context. PMID- 27119418 TI - Mutagenesis of mNeptune Red-Shifts Emission Spectrum to 681-685 nm. AB - GFP-like fluorescent proteins with diverse emission wavelengths have been developed through mutagenesis, offering many possible choices in cellular and tissue imaging, such as multi-targets imaging, deep tissue imaging that require longer emission wavelength. Here, we utilized a combined approach of random mutation and structure-based rational design to develop new NIR fluorescent proteins on the basis of a far-red fluorescent protein, mNeptune (Ex/Em: 600/650 nm). We created a number of new monomeric NIR fluorescent proteins with the emission range of 681-685 nm, which exhibit the largest Stocks shifts (77-80 nm) compared to other fluorescent proteins. Among them, mNeptune681 and mNeptune684 exhibit more than 30 nm redshift in emission relative to mNeptune, owing to the major role of the extensive hydrogen-bond network around the chromophore and contributions of individual mutations to the observed redshift. Furthermore, the two variants still maintain monomeric state in solution, which is a trait crucial for their use as protein tags. In conclusion, our results suggest that there is untapped potential for developing fluorescent proteins with desired properties. PMID- 27119419 TI - Impact of dialysis requirement on outcomes in tumor lysis syndrome. AB - Tumor lysis syndrome (TLS) is a life threatening emergency due to destruction and massive release of intracellular metabolites from cancer cells often resulting in acute kidney injury (AKI), sometimes severe enough to require dialysis (AKI-D). The impact of dialysis requirement in AKI has not been explored. We utilized data from the Nationwide Inpatient Sample and using International Classification of Diseases, 9th Revision, diagnoses codes for TLS, AKI and dialysis, evaluated the incidence, risk factors and impact of AKI-D on mortality, adverse discharge and length of stay (LOS). Survey multivariable logistic regression was used to compute adjusted Odds Ratios (aOR and 95% confidence intervals (CI). An estimated 12% (2,919) of all TLS hospitalizations (n = 22 875) develop AK-D. After adjustment for confounders, AKI-D was associated with greater odds of mortality (aOR 1.98; (95% CI 1.60-2.45)), adverse discharge (aOR 1.63 (95% CI 1.19-2.24)) and longer LOS (19 vs 14.6 days; P < 0.01) compared with those without AKI-D. Further studies to evaluate the association of AKI-D on long-term outcomes in patients with TLS are needed. PMID- 27119421 TI - Cp*Co(III)-Catalyzed Dehydrative C-H Allylation of 6-Arylpurines and Aromatic Amides Using Allyl Alcohols in Fluorinated Alcohols. AB - Cp*Co(III)-catalyzed C-H allylation of various aromatic C-H bonds using allyl alcohols as allylating reagents is described. Improved reaction conditions using fluorinated alcohol solvents afforded efficient directed C-H allylation of 6 arylpurines, benzamides, and a synthetically useful Weinreb amide with good functional group compatibility. PMID- 27119420 TI - Evaluation of cognitivity, proinflammatory cytokines, and brain magnetic resonance imaging in minimal hepatic encephalopathy induced by cirrhosis and extrahepatic portal vein obstruction. AB - BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy (HE) and is characterized by deficits in neurocognitive performance without any clinical symptoms of HE. In the current study, we aim to evaluate and compare the neurocognitive, biochemical, and brain magnetic resonance (MR) imaging changes between patients with cirrhotic MHE and extrahepatic portal vein obstruction (EHPVO) MHE. METHODS: Thirty-three cirrhotic and 14 EHPVO patients were diagnosed with MHE and were included in the analysis along with 24 normal healthy volunteers. All subjects underwent MR imaging including diffusion tensor imaging and proton MR spectroscopy (1 H-MRS) followed by cognitive assessments, critical flicker frequency (CFF) measurements, quantification of blood ammonia, and serum proinflammatory cytokine levels. RESULTS: We observed abnormal neurocognitive functions and CFF measurements in both cirrhotic MHE and EHPVO MHE patients as compared with controls. Significantly increased blood ammonia, serum proinflammatory cytokines (IL-6, TNF alpha) level, mean diffusivity in multiple brain sites, 1 H-MRS derived glutamate/glutamine (Glx)/creatine (Cr), and significantly decreased 1 H-MRS derived myo-inositol/Cr were observed in both cirrhotic MHE and EHPVO MHE compared with those of controls. Choline/Cr level was significantly decreased in cirrhotic MHE as compared with controls and EHPVO MHE. CONCLUSIONS: Cirrhotic MHE showed more severe changes on mean diffusivity in multiple brain sites and inflammation as compared with EHPVO MHE. This study confirms that there are significant difference in neurocognitive, biochemical, and MR profile between cirrhotic MHE and EHPVO MHE, which may help to understand the pathophysiologies of these two types of MHE and may contribute to improve their clinical managements. PMID- 27119423 TI - Anisotropic Black Phosphorus Synaptic Device for Neuromorphic Applications. AB - The first black-phosphorus synaptic device is demonstrated, which offers intrinsic anisotropy in its synaptic characteristics directly resulting from its low crystalline symmetry. Key features of biological synapses, such as long-term plasticity with heterogeneity, including long-term potentiation/depression and spike-timing-dependent plasticity, are mimicked. This demonstration represents an important step toward introducing intrinsic heterogeneity to artificial neuromorphic systems. PMID- 27119422 TI - Lack of health maintenance examinations and risk in myeloma patients. AB - Health maintenance (HM) practices are essential to prevent illness, promote well being, and maximize health. Patients with multiple myeloma (MM) are at increased risk for cardiovascular disease and cancers, yet, research on HM practices and preventative care of MM survivors has limited report. The study comprised a descriptive, correlational, and cross-sectional online survey design. Survey of patients with MM was carried out through the International Myeloma Foundation (IMF) and the Association of Cancer Online Resources (ACOR) e-mail list services. The members of the IMF and ACOR e-mail list services were surveyed, of which 237 patients responded. The modified Medical Expenditure Preventive Survey-Preventive Care questionnaire was used; it included items that ask patients regarding their healthcare practices that relate to dental care, cancer prevention, addiction, lifestyles, sensory screening, immunizations, cardiovascular, endocrine, psychosocial, and bone health. Descriptive statistics, Pearson's chi-square, and Spearman's rho correlation coefficient were obtained. In this study, men had statistically significant inferior global health maintenance scores than women (P = 0.002). Being employed (P = 0.054) and married or partnered (P = 0.017) were significantly correlated with better health maintenance patterns among male respondents. In contrast, no statistically significant correlations between sociodemographic factors and health maintenance patterns were found in women. Patients with MM, particularly men, require continued education and close monitoring of health maintenance practices. These findings are consistent with publications looking at gender disparities in healthcare utilization in the United States. Studies show that men, in general, are less likely to seek preventative healthcare screenings. Healthcare providers must incorporate health maintenance promotion during clinic visits. PMID- 27119424 TI - Ordered and Active Nanochannel Electrode Design for High-Performance Electrochemical Actuator. AB - A novel electrochemical actuator based on polyaniline@vertically aligned carbon nanotube nanocomposite electrodes, in which the vertically aligned structure is introduced by a facilely electrochemical process. Owing to the vertically aligned nanocomposite electrode providing ordered path channel for faster ion transportation and high electrochemical capacitance for more ion accumulation, our actuator displays intriguing actuation performance including large deformation, fast-actuation speed, and excellent actuation stability. PMID- 27119425 TI - Characterizing Heterogeneity in Infiltration Rates During Managed Aquifer Recharge. AB - Infiltration rate is the key parameter that describes how water moves from the surface into a groundwater aquifer during managed aquifer recharge (MAR). Characterization of infiltration rate heterogeneity in space and time is valuable information for MAR system operation. In this study, we utilized fiber optic distributed temperature sensing (FO-DTS) observations and the phase shift of the diurnal temperature signal between two vertically co-located fiber optic cables to characterize infiltration rate spatially and temporally in a MAR basin. The FO DTS measurements revealed spatial heterogeneity of infiltration rate: approximately 78% of the recharge water infiltrated through 50% of the pond bottom on average. We also introduced a metric for quantifying how the infiltration rate in a recharge pond changes over time, which enables FO-DTS to be used as a method for monitoring MAR and informing maintenance decisions. By monitoring this metric, we found high-spatial variability in how rapidly infiltration rate changed during the test period. We attributed this variability to biological pore clogging and found a relationship between high initial infiltration rate and the most rapid pore clogging. We found a strong relationship (R2 = 0.8) between observed maximum infiltration rates and electrical resistivity measurements from electrical resistivity tomography data taken in the same basin when dry. This result shows that the combined acquisition of DTS and ERT data can improve the design and operation of a MAR pond significantly by providing the critical information needed about spatial variability in parameters controlling infiltration rates. PMID- 27119426 TI - Revascularisation of the left subclavian artery for thoracic endovascular aortic repair. AB - BACKGROUND: Controversy exists as to whether revascularisation of the left subclavian artery (LSA) confers improved outcomes in patients undergoing thoracic endovascular aortic repair (TEVAR). Even though preemptive revascularisation of the LSA has theoretical advantages, including a reduced risk of ischaemic damage to vital organs, such as the brain and the spinal cord, it is not without risks. Current practice guidelines recommend routine revascularisation of the LSA in patients undergoing elective TEVAR where achievement of a proximal seal necessitates coverage of the LSA, and in patients who have an anatomy that compromises perfusion to critical organs. However, this recommendation was based on very low-quality evidence. OBJECTIVES: To assess the comparative efficacy of routine LSA revascularisation versus either selective or no revascularisation in patients with descending thoracic aortic disease undergoing TEVAR with coverage of the LSA origin. SEARCH METHODS: The Cochrane Vascular Trials Search Co ordinator (TSC) searched the Specialised Register (June 2015). In addition, the TSC searched the Cochrane Register of Studies (CENTRAL (2015, Issue 5)).Trials databases were also searched (June 2015). SELECTION CRITERIA: We had planned to consider all randomised controlled trials (RCTs) that compared routine revascularisation of the LSA with selective or no revascularisation, in patients undergoing TEVAR. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the title and abstract of articles identified through literature searches. An independent third review author was consulted in the event of disagreement. We had planned for two review authors to independently extract data and assess the risk of bias of identified trials using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We did not identify any RCTs relevant to our review topic. Therefore, no quantitative analysis was conducted. AUTHORS' CONCLUSIONS: High quality RCT evidence for or against routine or selective revascularisation of the LSA in TEVAR is not currently available. It is not possible to draw conclusions with regard to the optimal management of LSA coverage in TEVAR, and whether routine revascularisation, which was defined as the intervention of interest in our review, confers beneficial effects, as indicated by reduced mortality, cerebrovascular events, and spinal cord ischaemia. This review highlights the need for continued research to provide RCT evidence and define the role of LSA revascularisation in the context of TEVAR with coverage of the LSA. PMID- 27119427 TI - Clinical applications of retrograde autologous priming in cardiopulmonary bypass in pediatric cardiac surgery. AB - Retrograde autologous priming (RAP) has been routinely applied in cardiac pediatric cardiopulmonary bypass (CPB). However, this technique is performed in pediatric patients weighing more than 20 kg, and research about its application in pediatric patients weighing less than 20 kg is still scarce. This study explored the clinical application of RAP in CPB in pediatric patients undergoing cardiac surgery. Sixty pediatric patients scheduled for cardiac surgery were randomly divided into control and experimental groups. The experimental group was treated with CPB using RAP, while the control group was treated with conventional CPB (priming with suspended red blood cells, plasma and albumin). The hematocrit (Hct) and lactate (Lac) levels at different perioperative time-points, mechanical ventilation time, hospitalization duration, and intraoperative and postoperative blood usage were recorded. Results showed that Hct levels at 15 min after CPB beginning (T2) and at CPB end (T3), and number of intraoperative blood transfusions were significantly lower in the experimental group (P<0.05). There were no significant differences in CPB time, aortic blocking time, T2-Lac value or T3-Lac between the two groups (P>0.05). Postoperatively, there were no significant differences in Hct (2 h after surgery), mechanical ventilation time, intensive care unit time, or postoperative blood transfusion between two groups (P>0.05). RAP can effectively reduce the hemodilution when using less or not using any banked blood, while meeting the intraoperative perfusion conditions, and decreasing the perioperative blood transfusion volume in pediatric patients. PMID- 27119428 TI - Effect of hyperbaric oxygenation on mitochondrial function of neuronal cells in the cortex of neonatal rats after hypoxic-ischemic brain damage. AB - The timing and mechanisms of protection by hyperbaric oxygenation (HBO) in hypoxic-ischemic brain damage (HIBD) have only been partially elucidated. We monitored the effect of HBO on the mitochondrial function of neuronal cells in the cerebral cortex of neonatal rats after HIBD. Neonatal Sprague-Dawley rats (total of 360 of both genders) were randomly divided into normal control, HIBD, and HIBD+HBO groups. The HBO treatment began immediately after hypoxia-ischemia (HI) and continued once a day for 7 consecutive days. Animals were euthanized 0, 2, 4, 6, and 12 h post-HI to monitor the changes in mitochondrial membrane potential (DeltaPsim) occurring soon after a single dose of HBO treatment, as well as 2, 3, 4, 5, 6, and 7 days post-HI to study DeltaPsim changes after a series of HBO treatments. Fluctuations in DeltaPsim were observed in the ipsilateral cortex in both HIBD and HIBD+HBO groups. Within 2 to 12 h after HI insult, the DeltaPsim of the HIBD and HIBD+HBO groups recovered to some extent. A secondary drop in DeltaPsim was observed in both groups during the 1-4 days post HI period, but was more severe in the HIBD+HBO group. There was a secondary recovery of DeltaPsim observed in the HIBD+HBO group, but not in the HIBD group, during the 5-7 days period after HI insult. HBO therapy may not lead to improvement of neural cell mitochondrial function in the cerebral cortex in the early stage post-HI, but may improve it in the sub-acute stage post-HI. PMID- 27119429 TI - Cocaine/levamisole-induced systemic vasculitis with retiform purpura and pauci immune glomerulonephritis. AB - Levamisole has been increasingly used as an adulterant of cocaine in recent years, emerging as a public health challenge worldwide. Levamisole-associated toxicity manifests clinically as a systemic vasculitis, consisting of cutaneous, hematological, and renal lesions, among others. Purpura retiform, cutaneous necrosis, intravascular thrombosis, neutropenia, and less commonly crescentic nephritis have been described in association with anti-neutrophil cytoplasmic antibodies (ANCAs) and other autoantibodies. Here we report the case of a 49-year old male who was a chronic cocaine user, and who presented spontaneous weight loss, arthralgia, and 3 weeks before admission purpuric skin lesions in the earlobes and in the anterior thighs. His laboratory tests on admission showed serum creatinine of 4.56 mg/dL, white blood count 3,800/MUL, hemoglobin 7.3 g/dL, urinalysis with 51 white blood cells/MUL and 960 red blood cells/MUL, and urine protein-to-creatinine ratio 1.20. Serum ANCA testing was positive (>1:320), as well as serum anti-myeloperoxidase and anti-proteinase 3 antibodies. Urine toxicology screen was positive for cocaine and levamisole, with 62.8% of cocaine, 32.2% of levamisole, and 5% of an unidentified substance. Skin and renal biopsies were diagnostic for leukocytoclastic vasculitis and pauci-immune crescentic glomerulonephritis, respectively. The patient showed a good clinical response to cocaine abstinence, and use of corticosteroids and intravenous cyclophosphamide. Last serum creatinine was 1.97 mg/dL, white blood cell count 7,420/MUL, and hemoglobin level 10.8 g/dL. In levamisole-induced systemic vasculitis, the early institution of cocaine abstinence, concomitant with the use of immunosuppressive drugs in severe cases, may prevent permanent end organ damage and associate with better clinical outcomes. PMID- 27119430 TI - A Prussian Blue/Zinc Secondary Battery with a Bio-Ionic Liquid-Water Mixture as Electrolyte. AB - The development of rechargeable zinc ion batteries with high capacity and high cycling stability is a great challenge in aqueous solution due to hydrogen evolution and dendritic growth of zinc. In this study, we present a zinc ion secondary battery, comprising a metallic zinc anode, a bio-ionic liquid-water electrolyte, and a nanostructured prussian blue analogue (PBA) cathode. Both the Zn anode and the PBA cathode exhibit good compatibility with the bio-ionic liquid water electrolyte, which enables the electrochemical deposition/dissolution of zinc at the zinc anode, and reversible insertion/extraction of Zn(2+) ions at the PBA cathode. The cell exhibits a well-defined discharge voltage plateau of ~1.1 V with a specific capacity of about 120 mAh g(-1) at a current of 10 mA g(-1) (~0.1 C). The Zn anode shows great reversibility, and dendrite-free Zn deposits were obtained after 100 deposition/dissolution cycles. The integration of an environmentally friendly PBA cathode, a nontoxic and low-cost Zn anode, and a biodegradable ionic liquid-water electrolyte provides new perspective to develop rechargeable zinc ion batteries for various applications in electric energy storage. PMID- 27119431 TI - Transcranial Sonography Findings in Depression in Association With Psychiatric and Neurologic Diseases: A Review. AB - The transcranial sonography (TCS) finding of reduced echogenicity of brainstem raphe (hypoechogenic BR) has been associated with depressive states. Here, we review the TCS studies in subjects with depressive disorders and with depression related to degenerative brain diseases, and compare the frequency and clinical correlates of hypoechogenic BR in these reports. Summarizing the data published so far, hypoechogenic BR is present in 67% (range, 37-95%) of depressed but only in 15% (5-36%) of nondepressed subjects without history of neurodegenerative disease. The finding of hypoechogenic BR in these subjects is associated with a relative risk of 3.03 (95% CI, 2.44-3.75; P < .001) of being diagnosed with depression. In patients with Parkinson's disease, hypoechogenic BR is present in 63% (35-92%) of depressed but only in 27% (10-62%) of nondepressed patients, resulting in a relative risk of 2.18 (95% CI, 1.80-2.66; P < .001) of being diagnosed with depression. Hypoechogenic BR is associated with depression in a number of neurological disorders such Huntington's disease, idiopathic Rapid Eye Movement (REM) sleep behavior disorder, myotonic dystrophies, and cerebral small vessel disease. Although some studies did not show any relationship between BR echogenicity and severity of depression, others suggest an association with higher severity of depression, or even with suicidal ideation. In one study BR hypoechogenicity was found to be associated with better responsivity to serotonin reuptake inhibitors. Further studies are warranted to compare the TCS findings of BR alteration with post-mortem histopathological findings, and with genetic variants related to cerebral serotonin metabolism. PMID- 27119432 TI - Application of the Prunus spp. Cyanide Seed Defense System onto Wheat: Reduced Insect Feeding and Field Growth Tests. AB - Many crops are ill-protected against insect pests during storage. To protect cereal grains from herbivores during storage, pesticides are often applied. While pesticides have an undoubtable functionality, increasing concerns are arising about their application. In the present study, we investigated a bioinspired cyanogenic grain coating with amygdalin as cyanogenic precursor mimicking the feeding-triggered release of hydrogen cyanide (HCN) found for example in bitter almonds. The multilayer coating consisted of biodegradable polylactic acid with individual layers containing amygdalin or beta-glucosidase which is capable of degrading amygdalin to HCN. This reaction occurred only when the layers were ruptured, e.g., by a herbivore attack. Upon feeding coated cyanogenic wheat grains to Tenebrio molitor (mealworm beetle), Rhizopertha dominica (lesser grain borer), and Plodia interpunctella (Indianmeal moth), their reproduction as well as consumption rate were significantly reduced, whereas germination ability increased compared to noncoated grains. In field experiments, we observed an initial growth delay compared to uncoated grains which became negligible at later growth stages. The here shown strategy to artificially apply a naturally occurring defense mechanisms could be expanded to other crops than wheat and has the potential to replace certain pesticides with the benefit of complete biodegradability and increased safety during storage. PMID- 27119433 TI - Diphenylalanine peptide nanotubes self-assembled on functionalized metal surfaces for potential application in drug-eluting stent. AB - This study focuses on the potential of diphenylalanine self-assembled peptide nanotubes (FF Nts) for delivery of flufenamic acid (FA) from metal implants. Self assembly of FF Nts was studied in solution and on surfaces of glass, silicone and gold substrates. FA was loaded inside the shell of FF Nts and subsequently FF/FA Nts were attached to gold surfaces. The substrate were characterized by Field Emission Scanning Electron Microscopy (FESEM), fluorescence microscopy, confocal microscopy, and UV-vis spectroscopy. Release of FA from FF Nts were investigated by immersing coated metal substrates in phosphate-buffered saline for 12 days. Self-assembly of FF in water and solvent resulted in formation of nanotubes, which efficiently loaded 98% of FA with concentration of 20 ug/mL. FESEM images confirmed successful attachment of FF/FA Nts to functionalized gold substrates. In vitro release studies indicated using FF Nts has prolonged the release rate of FA for several days. Biocompatibility studied confirmed more than 50% of the cells were alive in concentration of 250-1000 ug/mL of FF Nts thus suggesting the potential of peptide based self-assemble nanostructures as an alternate system for polymer coating in drugs eluting stents. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2280-2290, 2016. PMID- 27119434 TI - Effect of Performance Deficiencies on Graduation and Board Certification Rates: A 10-yr Multicenter Study of Anesthesiology Residents. AB - BACKGROUND: This multicenter, retrospective study was conducted to determine how resident performance deficiencies affect graduation and board certification. METHODS: Primary documents pertaining to resident performance were examined over a 10-yr period at four academic anesthesiology residencies. Residents entering training between 2000 and 2009 were included, with follow-up through February 2016. Residents receiving actions by the programs' Clinical Competency Committee were categorized by the area of deficiency and compared to peers without deficiencies. RESULTS: A total of 865 residents were studied (range: 127 to 275 per program). Of these, 215 residents received a total of 405 actions from their respective Clinical Competency Committee. Among those who received an action compared to those who did not, the proportion graduating differed (93 vs. 99%, respectively, P < 0.001), as did the proportion achieving board certification (89 vs. 99%, respectively, P < 0.001). When a single deficiency in an Essential Attribute (e.g., ethical, honest, respectful behavior; absence of impairment) was identified, the proportion graduating dropped to 55%. When more than three Accreditation Council for Graduate Medical Education Core Competencies were deficient, the proportion graduating also dropped significantly. CONCLUSIONS: Overall graduation and board certification rates were consistently high in residents with no, or isolated, deficiencies. Residents deficient in an Essential Attribute, or multiple competencies, are at high risk of not graduating or achieving board certification. More research is needed on the effectiveness and selective deployment of remediation efforts, particularly for high-risk groups. PMID- 27119435 TI - Mechanism of the Novel Prenylated Flavin-Containing Enzyme Ferulic Acid Decarboxylase Probed by Isotope Effects and Linear Free-Energy Relationships. AB - Ferulic acid decarboxylase from Saccharomyces cerevisiae catalyzes the decarboxylation of phenylacrylic acid to form styrene using a newly described prenylated flavin mononucleotide cofactor. A mechanism has been proposed, involving an unprecedented 1,3-dipolar cyclo-addition of the prenylated flavin with the alpha?beta bond of the substrate that serves to activate the substrate toward decarboxylation. We measured a combination of secondary deuterium kinetic isotope effects (KIEs) at the alpha- and beta-positions of phenylacrylic acid together with solvent deuterium KIEs. The solvent KIE is 3.3 on Vmax/KM but is close to unity on Vmax, indicating that proton transfer to the product occurs before the rate-determining step. The secondary KIEs are normal at both the alpha and beta-positions but vary in magnitude depending on whether the reaction is performed in H2O or D2O. In D2O, the enzyme catalyzed the exchange of deuterium into styrene; this reaction was dependent on the presence of bicarbonate. This observation implies that CO2 release must occur after protonation of the product. Further information was obtained from a linear free-energy analysis of the reaction through the use of a range of para- and meta-substituted phenylacrylic acids. Log(kcat/KM) for the reaction correlated well with the Hammett sigma(-) parameter with rho = -0.39 +/- 0.03; r(2) = 0.93. The negative rho value and secondary isotope effects are consistent with the rate-determining step being the formation of styrene from the prenylated flavin-product adduct through a cyclo elimination reaction. PMID- 27119436 TI - Marangoni Convection in Evaporating Organic Liquid Droplets on a Nonwetting Substrate. AB - We quantitatively characterize the flow field inside organic liquid droplets evaporating on a nonwetting substrate. A mushroom-structured surface yields the desired nonwetting behavior with methanol droplets, while use of a cooled substrate (5-15 degrees C) slows the rate of evaporation to allow quasi-static particle image velocimetry. Visualization reveals a toroidal vortex within the droplet that is characteristic of surface tension-driven flow; we demonstrate by means of a scaling analysis that this recirculating flow is Marangoni convection. The velocities in the droplet are on the order of 10-45 mm/s. Thus, unlike in the case of evaporation on wetting substrates where Marangoni convection can be ignored for the purpose of estimating the evaporation rate, advection due to the surface tension-driven flow plays a dominant role in the heat transfer within an evaporating droplet on a nonwetting substrate because of the large height-to radius aspect ratio of the droplet. We formulate a reduced-order model that includes advective transport within the droplet for prediction of organic liquid droplet evaporation on a nonwetting substrate and confirm that the predicted temperature differential across the height of the droplet matches experiments. PMID- 27119437 TI - Identification of a cis-acting element in nitrogen fixation genes recognized by CnfR in the nonheterocystous nitrogen-fixing cyanobacterium Leptolyngbya boryana. AB - The filamentous cyanobacterium Leptolyngbya boryana has the ability to fix nitrogen without any heterocysts under microoxic conditions. Previously, we identified the cnfR gene for a master transcriptional activator for nitrogen fixation (nif) genes in a 50-kb gene cluster containing nif and nif-related genes in L. boryana. We showed that CnfR activates the transcription of nif genes in response to low oxygen conditions, which allows the oxygen-vulnerable enzyme nitrogenase to function. However, the regulatory mechanism that underlies regulation by CnfR remains unknown. In this study, we identified a conserved cis acting element that is recognized by CnfR. We established a reporter system in the non-diazotrophic cyanobacterium Synechocystis sp. PCC 6803 using luciferase genes (luxAB). Reporter analysis was performed with a series of truncated and modified upstream regulatory regions of nifB and nifP. The cis-element can be divided into nine motifs I-IX, and it is located 76 bp upstream of the transcriptional start sites of nifB and nifP. Six motifs of them are essential for transcriptional activation by CnfR. This cis-acting element is conserved in the upstream regions of nif genes in all diazotrophic cyanobacteria, including Anabaena and Cyanothece, thereby suggesting that the transcriptional regulation by CnfR is widespread in nitrogen-fixing cyanobacteria. PMID- 27119438 TI - Molecular Ultrasound Imaging of alphavbeta3-Integrin Expression in Carotid Arteries of Pigs After Vessel Injury. AB - OBJECTIVES: Interventions such as balloon angioplasty can cause vascular injury leading to platelet activation, thrombus formation, and inflammatory response. This induces vascular smooth muscle cell activation and subsequent re endothelialization with expression of alphavbeta3-integrin by endothelial cells and vascular smooth muscle cell. Thus, poly-N-butylcyanoacrylate microbubbles (MBs) targeted to alphavbeta3-integrin were evaluated for monitoring vascular healing after vessel injury in pigs using molecular ultrasound imaging. MATERIALS AND METHODS: Approval for animal experiments was obtained. The binding specificity of alphavbeta3-integrin-targeted MB to human umbilical vein endothelial cells was tested with fluorescence microscopy. In vivo imaging was performed using a clinical ultrasound system and an 8-MHz probe. Six mini pigs were examined after vessel injury in the left carotid artery. The right carotid served as control. Uncoated MB, cDRG-coated MB, and alphavbeta3-integrin-specific cRGD-coated MB were injected sequentially. Bound MBs were assessed 8 minutes after injection using ultrasound replenishment analysis. Measurements were performed 2 hours, 1 and 5 weeks, and 3 and 6 months after injury. In vivo data were validated by immunohistochemistry. RESULTS: Significantly stronger binding of cRGD-MB than MB and cDRG-MB to human umbilical vein endothelial cells was found (P < 0.01). As vessel injury leads to upregulation of alphavbeta3-integrin, cRGD-MBs bound significantly stronger (P < 0.05) in injured carotid arteries than at the counter side 1 week after vessel injury and significant differences could also be observed after 5 weeks. After 3 months, alphavbeta3-integrin expression decreased to baseline and binding of cRGD-MB was comparable in both vessels. Values remained at baseline also after 6 months. CONCLUSIONS: Ultrasound imaging with RGD-MB is promising for monitoring vascular healing after vessel injury. This may open new perspectives to assess vascular damage after radiological interventions. PMID- 27119439 TI - Pharmacokinetics and Pharmacodynamics of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis. AB - The characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) properties in pediatric patients is essential in supporting the recommended dosage of canakinumab in the relevant population. Here the PK and PD properties of canakinumab-a monoclonal antibody-in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) are presented. Blood samples were obtained from 4 phase 2/3 clinical studies in patients with SJIA. Canakinumab PK properties and total interleukin (IL)-1beta kinetic properties were characterized by a population-based PK-binding model. On administration, canakinumab increased total IL-1beta complex in SJIA patients. Canakinumab clearance and volume of distribution were not impacted by age in pediatric patients after correction for the patient's body weight. The estimated serum clearance of canakinumab was 0.106 +/- 0.00689 L/day, with a corresponding volume of distribution at steady state of 3.2 L and an estimated half-life of 22 days, based on a model typical body weight of 33 kg. Body-weight-based dosing provided comparable canakinumab exposure across the age groups in patients 2 to <20 years with SJIA. In younger children, a modest increase in the turnover rate of IL-1beta was observed. Compared to other indications, IL-1beta production rate was higher and clearance was slower in patients with SJIA. Low immunogenicity incidence of 3.1% was observed, and none of the patients had neutralizing antibodies. In conclusion, the PK/PD findings further support dose selection of canakinumab in patients with SJIA. PMID- 27119440 TI - Cost-effectiveness of a nurse practitioner-family physician model of care in a nursing home: controlled before and after study. AB - AIMS: To examine the cost-effectiveness of a nurse practitioner-family physician model of care compared with family physician-only care in a Canadian nursing home. BACKGROUND: As demand for long-term care increases, alternative care models including nurse practitioners are being explored. DESIGN: Cost-effectiveness analysis using a controlled before-after design. METHODS: The study included an 18-month 'before' period (2005-2006) and a 21-month 'after' time period (2007 2009). Data were abstracted from charts from 2008-2010. We calculated incremental cost-effectiveness ratios comparing the intervention (nurse practitioner-family physician model; n = 45) to internal (n = 65), external (n = 70) and combined internal/external family physician-only control groups, measured as the change in healthcare costs divided by the change in emergency department transfers/person month. We assessed joint uncertainty around costs and effects using non parametric bootstrapping and cost-effectiveness acceptability curves. RESULTS: Point estimates of the incremental cost-effectiveness ratio demonstrated the nurse practitioner-family physician model dominated the internal and combined control groups (i.e. was associated with smaller increases in costs and emergency department transfers/person-month). Compared with the external control, the intervention resulted in a smaller increase in costs and larger increase in emergency department transfers. Using a willingness-to-pay threshold of $1000 CAD/emergency department transfer, the probability the intervention was cost effective compared with the internal, external and combined control groups was 26%, 21% and 25%. CONCLUSION: Due to uncertainty around the distribution of costs and effects, we were unable to make a definitive conclusion regarding the cost effectiveness of the nurse practitioner-family physician model; however, these results suggest benefits that could be confirmed in a larger study. PMID- 27119455 TI - Quantitative means for differentiating renal obstruction by analysing renography by compartmental modelling of renal fluid flow rate. AB - OBJECTIVE: The aim of this study was to investigate the accuracy of using a newly developed index, the ratio of urine outflow to renal pelvis volume U/V2 (1/s), in evaluating renal obstruction and determining the severity of obstruction. PATIENTS AND METHODS: A total of 42 patients' renograms (80 kidneys) were studied. Compartmental modelling was used to model the behaviour of tracers flowing through the kidney. The derived model led to the formation of the normalized urine flow rate U/V2. An analysis was carried to test the accuracy of the developed index by comparing the developed model and the clinical evaluation of renograms. The Support Vector Machine algorithm was implemented to predict the renal obstruction status. RESULTS: From the comparison performed between the index and the clinical evaluation from certified experts, it was shown that a higher value of index U/V2 indicated a normal kidney, whereas a lower value indicated an obstructed kidney. The classifier developed could provide a 100% accurate diagnosis of differentiated unobstructed kidneys (42/42) and obstructed kidney (18/18). For further classification of obstructed kidneys, the system grouped the samples into slightly obstructed cases with an accuracy of 100% (9/9) and heavily obstructed cases with an accuracy of 89% (8/9). CONCLUSION: The use of the single parameter U/V2 could produce the diagnosis of renal obstruction with a high level of accuracy. This method has the potential to be used as a benchmark to distinguish the severity level of the renal obstruction. PMID- 27119456 TI - Importance of the Dimethylamino Functionality on a Multifunctional Framework for Regulating Metals, Amyloid-beta, and Oxidative Stress in Alzheimer's Disease. AB - The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-beta (Abeta) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as a useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure-reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the Abeta sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced Abeta aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, Abeta, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents. PMID- 27119458 TI - Percutaneous Retrieval of Dislodged Left Atrial Appendage Occlusion Devices through the Transseptal Approach. AB - Percutaneous left atrial appendage (LAA) occlusion is a promising treatment option in patients with atrial fibrillation who have a high risk of embolic stroke and are not eligible for chronic oral anticoagulation therapy. This procedure, however, can induce several complications. Device embolization can result in a serious situation, requiring immediate and safe device removal. We report two cases in which dislodged LAA occlusion devices were flitting in the left atrium or entrapped in the mitral valve leaflets and were successfully retrieved through a transseptal approach without complications. PMID- 27119457 TI - ML314: A Biased Neurotensin Receptor Ligand for Methamphetamine Abuse. AB - Pharmacological treatment for methamphetamine addiction will provide important societal benefits. Neurotensin receptor NTR1 and dopamine receptor distributions coincide in brain areas regulating methamphetamine-associated reward, and neurotensin peptides produce behaviors opposing psychostimulants. Therefore, undesirable methamphetamine-associated activities should be treatable with druggable NTR1 agonists, but no such FDA-approved therapeutics exist. We address this limitation with proof-of-concept data for ML314, a small-molecule, brain penetrant, beta-arrestin biased, NTR1 agonist. ML314 attenuates amphetamine-like hyperlocomotion in dopamine transporter knockout mice, and in C57BL/6J mice it attenuates methamphetamine-induced hyperlocomotion, potentiates the psychostimulant inhibitory effects of a ghrelin antagonist, and reduces methamphetamine-associated conditioned place preference. In rats, ML314 blocks methamphetamine self-administration. ML314 acts as an allosteric enhancer of endogenous neurotensin, unmasking stoichiometric numbers of hidden NTR1 binding sites in transfected-cell membranes or mouse striatal membranes, while additionally supporting NTR1 endocytosis in cells in the absence of NT peptide. These results indicate ML314 is a viable, preclinical lead for methamphetamine abuse treatment and support an allosteric model of G protein-coupled receptor signaling. PMID- 27119459 TI - Enzymatic conjugation of multiple proteins on a DNA aptamer in a tail-specific manner. AB - Conjugation of single-strand DNA aptamers and enzymes has been of great significance in bioanalytical and biomedical applications because of the unlimited functions provided by DNA aptamer direction. Therefore, we developed efficient tailing of a DNA aptamer, with end-specific conjugation of multiple enzymes, through enzymatic catalysis. Terminal deoxynucleotidyl transferase (TdT) added multiple Z-Gln-Gly (Z-QG) moieties to the 3'-end of a DNA aptamer via the addition of Z-QG-modified deoxyuridine triphosphate (Z-QG-dUTP) and deoxynucleoside triphosphates (dNTPs). The resultant (Z-QG)m -(dN)l-aptamer, whose Z-QGs with dN spacers served as stickers for microbial transglutaminase (MTG), were crosslinked between the Z-QGs on the DNA and a substrate peptide sequence containing lysine (K), fused to a recombinant enzyme (i.e. bacterial alkaline phosphatase; BAP) by MTG. The incorporation efficiency of Z-QG moieties on the aptamer tail and the subsequent conjugation efficiency with multiple enzyme molecules were dramatically altered by the presence of dNTPs, revealing that a combination of Z-QG-dUTP/dTTP comprised the best labeling efficiency and corresponding properties during analytical performance. Thus, a novel optimized platform for designing (BAP)n -(dT)l-DNA aptamers was demonstrated for the first time in this article, offering unique opportunities for tailoring new types of covalent protein-nucleic acid conjugates in a controllable way. PMID- 27119460 TI - Dopant Enriched Nitrogen Gas Combined with Sheathless Capillary Electrophoresis Electrospray Ionization-Mass Spectrometry for Improved Sensitivity and Repeatability in Glycopeptide Analysis. AB - Over the last years, numerous strategies have been proposed to enhance both ionization efficiency and spray stability in electrospray ionization (ESI), in particular for nanospray applications. In nano-liquid chromatography-mass spectrometry (nano-LC-ESI-MS), a better ESI performance has been observed when a coaxial gas flow is added around the ESI emitter. Moreover, enrichment of the gas with an organic dopant has led to an improved desolvation and ionization efficiency with an overall enhanced sensitivity. In this study, the use of a dopant enriched nitrogen (DEN)-gas combined with sheathless capillary electrophoresis (CE)-ESI-MS was evaluated for glycopeptide analysis. Using acetonitrile as a dopant, an increased sensitivity was observed compared to conventional sheathless CE-ESI-MS. Up to 25-fold higher sensitivities for model glycopeptides were obtained, allowing for limits of detection unachieved by state of-the-art nano-LC-ESI-MS. The effect of DEN-gas on the repeatability and intermediate precision was also investigated. When compared to previously reported nano-LC-ESI-MS measurements, similar values were found for CE-ESI-MS with DEN-gas. The enhanced repeatability fosters the use of DEN-gas sheathless CE ESI-MS in protein glycosylation analysis, where precision is essential. The use of DEN-gas opens new avenues for highly sensitive sheathless CE-ESI-MS approaches in glycoproteomics research, by significantly improving sensitivity and precision. PMID- 27119461 TI - Biosurfactant production by hydrocarbon-degrading Brevibacterium and Vibrio isolates from the sea pen Pteroeides spinosum (Ellis, 1764). AB - Among filter-feeders, pennatulids are the most complex and polymorphic members of the cnidarian class Anthozoa. They display a wide distribution throughout all the oceans, constituting a significant component of the sessile megafauna from intertidal to abyssal depths. In this study, a total of 118 bacterial isolates from enrichment cultures, carried out with homogenates of the sea pen Pteroeides spinosum (Ellis, 1764), were screened for hydrocarbon utilization by using the 2,6-dichlorophenol indophenol assay. Among them, 83 hydrocarbon-oxidizing isolates were analyzed for biosurfactant production by standard screening tests (i.e., emulsifying activity, E24 detection, surface tension measurement, microplate assay). The 16S rRNA gene sequencing revealed the affiliation of the most promising isolates to the genera Brevibacterium and Vibrio. Biosurfactant production resulted strongly affected by salinity and temperature conditions, and occurred in the presence of diesel oil and/or crude oil, whereas no production was observed when isolates were grown on tetradecane. The strains resulted able to create stable emulsions, thus suggesting the production of biosurfactants. Further analyses revealed a glycolipidic nature of the biosurfactant extracted from Vibrio sp. PBN295, a genus that has been only recently reported as biosurfactant producer. Results suggest that pennatulids could represent a novel source for the isolation of hydrocarbon-oxidizing bacteria with potential in biosurfactant production. PMID- 27119463 TI - Mykologische Diagnostik im Wandel der Zeiten. PMID- 27119464 TI - Nachruf. PMID- 27119465 TI - Current options for the treatment of pathological scarring. AB - Scarring is the consequence of surgery, trauma or different skin diseases. Apart from fresh, immature scars,that transform into mature scars over the course of would healing and that do not require further treatment,linear hypertrophic scars, widespread hypertrophic scars, keloids and atrophic scars exist. Symptoms like pruritusand pain, stigmatization as well as functional and aesthetic impairments that are very disturbing for the affected patients can bethe basis for the desire for treatment. Today, a multitude of options for the treatment and prevention of scars exists. Topical agents based on silicone or onion extract, intralesional injections of cristalline glucocorticoids (oftentimes in combinationwith cryotherapy) or 5-Fluorouracil as well as ablative and nonablative laser treatment are used. Current guidelines summarize the multitude of available treatment options and the currently available datafor the treating physicians, allowing them to make clear therapy recommendations for every single scar type. Relieving patients of their discomfort and doing their aesthetic demands justice is thus possible. Apart from scar prevention becoming more and more important, the increased use of modernlaser treatment options constitutes a key point in clinical scar treatment. At the same time the attention is turned to evaluating current therapeutic options with the help of contemporary study designs so as to graduallyimprove the level of evidence in scar treatment. PMID- 27119462 TI - Distinctive molecular responses to ultraviolet radiation between keratinocytes and melanocytes. AB - Solar ultraviolet radiation (UVR) is the major risk factor for skin carcinogenesis. To gain new insights into the molecular pathways mediating UVR effects in the skin, we performed comprehensive transcriptomic analyses to identify shared and distinctive molecular responses to UVR between human keratinocytes and melanocytes. Keratinocytes and melanocytes were irradiated with varying doses of UVB (10, 20 and 30 mJ/cm(2) ) then analysed by RNA-Seq at different time points post-UVB radiation (4, 24 and 72 h). Under basal conditions, keratinocytes and melanocytes expressed similar number of genes, although they each expressed a distinctive subset of genes pertaining to their specific cellular identity. Upon UVB radiation, keratinocytes displayed a clear pattern of time- and dose-dependent changes in gene expression that was different from melanocytes. The early UVB-responsive gene set (4 h post-UVR) differed significantly from delayed UVB-responsive gene sets (24 and 72 h). We also identified multiple novel UVB signature genes including PRSS23, SERPINH1, LCE3D and CNFN, which were conserved between melanocyte and keratinocyte lines from different individuals. Taken together, our findings elucidated both common and distinctive molecular features between melanocytes and keratinocytes and uncovered novel UVB signature genes that might be utilized to predict UVB photobiological effects on the skin. PMID- 27119466 TI - Aktuelle Optionen zur Behandlung pathologischer Narben. AB - Die Entstehung von Narben ist die Konsequenz von Operationen, Traumata und verschiedenen Hautkrankheiten. Neben frischen unreifen Narben, die im Laufe der Heilung in reife Narben ubergehen und in der Regel keiner weiteren Behandlung bedurfen, existieren lineare hypertrophe Narben, flachige hypertrophe Narben, Keloide und atrophe Narben, die aufgrund von Symptomen wie Juckreiz und Schmerzen, einer Stigmatisierung, funktionellen und asthetischen Einschrankungen fur die betroffenen Patienten sehr storend und Grundlage fur einen Behandlungswunsch sein konnen. Fur die Behandlung und Pravention von Narben existiert heutzutage eine Vielzahl von Optionen. Zur Anwendung kommen konnen Externa, basierend auf Silikon oder Zwiebelextrakt, intralasionale Injektionsverfahren mit kristallinen Glukokortikoiden (haufig in Kombination mit Kryotherapie) oder 5-Fluorouracil sowie ablative und nichtablative Laserverfahren. Um die Vielfalt an Behandlungsansatzen und die aktuelle Datenlage fur die behandelnden Arzte zusammenzufassen, existieren aktuelle Leitlinien, mit deren Hilfe fur jeden einzelnen Narbentyp klare Therapieempfehlungen gegeben werden konnen. Dies erlaubt es, Patienten zu schnellerer Beschwerdefreiheit zu verhelfen und ihren asthetischen Anspruchen gerecht zu werden. Neben der immer wichtiger werdenden Narbenpravention nimmt auch der zunehmende Einsatz modernster Laserverfahren einen zentralen Stellenwert in der klinischen Narbenbehandlung ein. Zugleich liegt grobetaes Augenmerk darauf, aktuelle Therapieverfahren mit Hilfe zeitgemabetaer Studiendesigns zu evaluieren, um die Evidenz der Narbenbehandlung zunehmend zu verbessern. PMID- 27119467 TI - Laser assisted Drug Delivery: Grundlagen und Praxis. AB - Die topische Applikation von Wirkstoffen ist eine zentrale Therapieoption der Dermatologie. Allerdings mindert die effektive Barrierefunktion der Haut die Bioverfugbarkeit der meisten Externa. Fraktionierte ablative Laser stellen ein innovatives Verfahren dar, um die epidermale Barriere standardisiert, kontaktfrei zu uberwinden. Die Bioverfugbarkeit im Anschluss applizierter Externa wird im Sinne einer laser assisted drug delivery (LADD) signifikant gesteigert. Das Prinzip der LADD wird bereits in einigen Bereichen der Dermatologie erfolgreich eingesetzt. Die vorliegende Ubersichtsarbeit soll einen Uberblick uber die aktuellen aber auch perspektivischen Einsatzmoglichkeiten der LADD bieten. PMID- 27119468 TI - Laser-assisted drug delivery: mode of action and use in daily clinical practice. AB - Topical application of pharmaceutical agents is a basic principle of dermatological therapy. However, the effective barrier function of the skin significantly impairs the bioavailability of most topical drugs. Fractional ablative lasers represent an innovative strategy to overcome the epidermal barrier in a standardized, contact-free manner. The bioavailability of topical agents can be significantly enhanced using laser-assisted drug delivery (LADD). In recent years, the principle of LADD has become well established for various dermatological indications. Herein, we review the current literature on LADD and present potential future applications. PMID- 27119469 TI - Sind die klassischen Methoden zur mykologischen Diagnostik noch "State-of-the Art"? AB - Die Labordiagnose einer Pilzinfektion der Haut basiert traditionell auf dem Nativpraparat und der Anzucht des Erregers aus dem klinischen Material. Auch der dermato- histologischer Nachweis von Pilzelementen ist moglich. Diese Methoden sind, sofern sie korrekt ausgefuhrt werden, in der Regel zum Pilznachweis geeignet. Im Zuge der personalisierten Medizin und den daraus erwachsenden Aufgaben werden jedoch neue Verfahren erforderlich, welche einfach, spezifisch und schnell sind. Der zusatzliche Einsatz von DNA-basierten molekularen Methoden erhoht die Empfindlichkeit sowie die diagnostische Spezifitat und reduziert die zum Teil wochenlange Durchfuhrungszeit der konventionellen mykologischen Diagnostik auf 24 bis 48 Stunden. Im Zuge der stetigen Weiterentwicklung im Bereich der personalisierten Medizin sind einfache Analysensysteme auf PCR-Basis denkbar, die in der Hautarztpraxis eine Dermatophyten-Sofort-Diagnostik erlauben (Point-of-Care-Tests). PMID- 27119470 TI - Are the classic diagnostic methods in mycology still state of the art? AB - The diagnostic workup of cutaneous fungal infections is traditionally based on microscopic KOH preparations as well as culturing of the causative organism from sample material. Another possible option is the detection of fungal elements by dermatohistology. If performed correctly, these methods are generally suitable for the diagnosis of mycoses. However, the advent of personalized medicine and the tasks arising therefrom require new procedures marked by simplicity, specificity, and swiftness. The additional use of DNA-based molecular techniques further enhances sensitivity and diagnostic specificity, and reduces the diagnostic interval to 24-48 hours, compared to weeks required for conventional mycological methods. Given the steady evolution in the field of personalized medicine, simple analytical PCR-based systems are conceivable, which allow for instant diagnosis of dermatophytes in the dermatology office (point-of-care tests). PMID- 27119471 TI - Pressure profiles of sport compression stockings. AB - BACKGROUND: While sport compression stockings (SCS) have become increasingly popular, there is no regulatory norm as exists for medical compression stockings (MCS). The objective of this pilot study was to compare five SCS with respect to their pressure profiles ex vivo and in vivo, and in relation to German standards for MCS (RAL norm). PATIENTS AND METHODS: In vivo (10 competitive athletes; standardized procedure using the Kikuhime pressure monitor) and ex vivo (tested at the Hohenstein Institute) pressure profiles were tested for the following products: CEP Running Progressive Socks, Falke Running Energizing, Sigvaris Performance, X-Socks Speed Metal Energizer, and 2XU Compression Race Socks. RESULTS: Ex vivo ankle pressures of CEP (25.6 mmHg) and 2XU (23.2 mmHg) corresponded to class 2 MCS; that of Sigvaris (20.8 mmHg), to class 1 MCS. The remaining SCS achieved lower pressure values. The pressure gradients showed marked differences, and did not meet MCS standards. Average in vivo pressures were higher for 2XU, CEP, and Sigvaris than for Falke and X-Socks. However, in vivo values for all SCS were below those of class 1 MCS. None of the SCS showed the decreasing pressure gradient (from distal to proximal) required for MCS. CONCLUSIONS: In vivo and ex vivo pressure profiles of all SCS examined showed marked heterogeneity, and did not meet MCS standards. Consequently, the clinical and practical effects of SCS cannot be compared, either. It would therefore be desirable to establish a classification that allows for the categorization and comparison of various SCS as well as their selection based on individual preferences and needs (high vs. low pressure, progressive vs. degressive profile). PMID- 27119472 TI - Das Druckprofil von Sportkompressionsstrumpfen. AB - HINTERGRUND: Zunehmend werden Sportkompressionsstrumpfe (SKS) eingesetzt, doch fehlt eine Norm in Analogie zu medizinischen Kompressionsstrumpfen (MKS). Ziel dieser Pilotstudie war der Vergleich der Druckprofile von funf SKS ex vivo und in vivo miteinander sowie mit MKS-Normen. PATIENTEN UND METHODIK: CEP Running Progressive-Socks, Falke Running--Energizing, Sigvaris Performance, X-Socks Speed Metal-Energizer und 2XU Compression--Race-Socks wurden an zehn Leistungssportlern (standardisiert in vivo, Kikuhime--Sensor) sowie im Hohenstein Institut (ex vivo) hinsichtlich ihres Druckprofils getestet. ERGEBNISSE: Die Ex-vivo-Messungen im Fesselbereich von CEP (25,6 mmHg) und 2XU (23,2 mmHg) entsprachen der deutschen MKS-Klasse 2, von Sigvaris-SKS (20,8 mmHg) der deutschen MKS-Klasse 1. Die ubrigen SKS lagen darunter. Die ermittelten Druckprofile differierten stark und entsprachen nicht der MKS-Norm. Die In-vivo-Messungen zeigten fur drei SKS (2XU, CEP, Sigvaris) durchschnittlich einen hoheren Anpressdruck als die SKS von Falke und X-Socks. Alle SKS lagen in vivo jedoch unter der deutschen MKS-Klasse 1. Kein SKS bot den fur MKS geforderten Druckabfall vom Messpunkt B nach D. SCHLUSSFOLGERUNGEN: Die in vivo und ex vivo ermittelten SKS-Druckprofile zeigten heterogene Ergebnisse und folgten kaum den MKS-Anforderungen. Entsprechend sind auch die klinisch-praktischen Effekte von SKS nicht vergleichbar. Wunschenswert ware eine SKS-Klassifikation, die erlaubt, Produkte einzuordnen, zu vergleichen und nach konkreten Vorlieben und Bedurfnissen (hoher vs. geringer Druck, progressiver vs. degressiver Gradient) auszuwahlen. PMID- 27119473 TI - Gebrauch von Komplementarmedizin bei Patienten mit metastasierendem Melanom unter Therapie mit Ipilimumab innerhalb einer klinischen Studie. AB - HINTERGRUND UND ZIEL: In Deutschland wenden 40-90 % aller Krebspatienten Methoden der komplementaren and alternativen Medizin (KAM) an. Bis dato gibt es kein Datenmaterial zum Einsatz der KAM bei Melanompatienten. Das Ziel unserer Studie war es, Daten uber den Gebrauch, die Informationsquellen und Ziele von Patienten mit metastasierendem Melanom zu erfassen. PATIENTEN UND METHODEN: Einhundertsechsundfunfzig Patienten aus 25 Studienzentren nahmen an der DecOG-MM PAL Multibasket Studie teil. Die beteiligten Personen wurden auch gebeten, an einer Nebenstudie teilzunehmen, die ihren Gebrauch von KAM erfassen sollte. Dazu wurde wahrend der Behandlung ein standardisierter Fragebogen zu genau festgelegten Zeitpunkten ausgeteilt. ERGEBNISSE: Insgesamt gingen 55 Fragebogen von 32 (21 %) Melanompatienten ein. Von diesen gaben 17 (53 %) ein Interesse an KAM an, und sieben (22 %) machten von KAM Gebrauch. Die Hauptinformationsquellen (31 %) waren Familienmitglieder und Freunde, gefolgt von Arzten (19 %). Die Hauptgrunde fur die Anwendung von KAM waren die Starkung des Immunsystems (41 %) und des Korpers (34 %). Nahrungserganzungsmittel (Vitamine und Spurenelemente) wurden am haufigsten angewendet (28 %). FAZIT: Eine relativ hohe Anzahl an Patienten mit metastasierendem Melanom machte trotz Teilnahme an einer klinischen Studie von KAM Gebrauch. Wechselwirkungen konnten durch biologisch basierte KAM auftreten, und hier besonders bei immunmodulierenden KAM- Strategien. Um Risiken zu vermeiden, sollte die Kommunikation zwischen den Arzten und den Patienten verbessert werden. PMID- 27119474 TI - Use of complementary medicine in metastatic melanoma patients treated with ipilimumab within a clinical trial. AB - BACKGROUND AND OBJECTIVES: In Germany, 40-90 % of all cancer patients use complementary and alternative medicine (CAM). So far, no data are available on the use of CAM by melanoma patients. The objective of our study was to gather data on CAM use, sources of information, and goals of patients with metastatic melanoma. PATIENTS AND METHODS: One hundred and fifty-six patients from 25 study centers participated in the DecOG-MM-PAL-Multibasket Study. These individuals were also asked to participate in a side study addressing CAM use. A standardized CAM questionnaire was distributed at defined points during the treatment. RESULTS: Overall, 55 questionnaires from 32 (21 %) melanoma patients were received. Of those, 17 (53 %) stated an interest in CAM, and seven (22 %) actually used CAM. Family and friends were the main source of information (31 %), followed by physicians (19 %). The main reasons for using CAM were boosting the immune system (41 %) and strengthening the body (34 %). Supplements (vitamins and trace elements) were most commonly used (28 %). CONCLUSIONS: A relatively high number of metastatic melanoma patients used CAM despite their participation in a clinical trial. Interactions may be due to biologically based CAM, especially immunomodulatory CAM strategies. In order to avoid risks, communication between physicians and patients should be improved. PMID- 27119475 TI - Ungual squamous cell carcinoma in a patient with Mal de Meleda. PMID- 27119476 TI - Unguales Plattenepithelkarzinom bei einem Patienten mit Mal de Meleda. PMID- 27119477 TI - Tief penetrierender Navus an der Fubetasohle: Fallbericht und dermatoskopische Merkmale. PMID- 27119478 TI - Diagnostische Kriterien des Netherton-Syndroms in der nichtinvasiven konfokalen Laserscanmikroskopie. PMID- 27119479 TI - Diagnostic criteria of Netherton syndrome using noninvasive reflectance confocal microscopy. PMID- 27119480 TI - Primary cutaneous CD4(+) small/medium-sized T-cell lymphoma of the face: successful treatment with radiation therapy. PMID- 27119481 TI - Primares kutanes CD4(+) klein- bis mittelgrobetazelliges T-Zell-Lymphom des Gesichts: erfolgreiche Behandlung mit Strahlentherapie. PMID- 27119482 TI - Genetic basis of a solitary familial plexiform neurofibroma without verified associated neurofibromatosis. PMID- 27119483 TI - Genetische Grundlagen eines solitaren familiaren plexiformen Neurofibroms ohne verifizierte begleitende Neurofibromatose. PMID- 27119484 TI - Zusammenhang zwischen chronischem Stress und dem CRP-Spiegel bei Frauen mit Psoriasis. PMID- 27119485 TI - Relationship between chronic stress and CRP levels in women with psoriasis. PMID- 27119486 TI - Schmerzhafte Fubetaschwellung bei 41-jahriger Patientin. PMID- 27119487 TI - Painful pedal edema in a 41-year-old patient. PMID- 27119488 TI - Report on immediate irradiation of a rapidly growing sarcoma of the scalp prior to wound closure. AB - Cutaneous sarcomas are primarily treated with extensive surgery, and occasionally require adjuvant radiation therapy following complete wound healing. Thus, sarcoma surgery leads to large and deep wounds, and the initiation of adjuvant radiation therapy depends on the time required for defect closure. We present the case of a male patient with pleomorphic sarcoma of the temporal skin, which was treated with multiple wide and deep excisions, instant application of an Integra((r)) bilayer, and immediate radiation therapy prior to wound closure. The objective was to investigate the usefulness of a dermal substitute (Integra((r)) ) in accelerating the effect of adjuvant radiation therapy on scalp defects after tumor surgery. A ring-shaped skin area - at risk for recurrence - around the Integra((r)) bilayer was irradiated with a total of 59.4 Gy. No necrosis, infection, or major radiotoxicity was observed, and a subsequent split skin graft following radiation therapy remained fully vital until complete healing. In conclusion, a combined procedure consisting of sequential tumor surgery and subsequent application of a dermal substitute in conjunction with immediate initiation of adjuvant radiation therapy is, in principle, possible, and may permit innovative therapeutic options in dermatooncology and dermatosurgery. PMID- 27119494 TI - Kongresskalender 2016/2017. PMID- 27119489 TI - Bericht uber die sofortige Bestrahlung eines schnell wachsenden Sarkoms der Kopfhaut vor dem Wundverschluss. PMID- 27119495 TI - Web Alert: Microbiology in archaeology: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 27119496 TI - [Prediction and Prevention of Dropouts in Vocational Retraining]. AB - Principal objective: To verify if a psychological intervention targeting individuals with high resignation tendency prevents dropouts in vocational retraining. For individuals with high resignation tendency a high risk of dropping out was assumed under regular conditions. METHOD: Data was collected at 2 adult education institutes. At the beginning of vocational training the occupational inventory Work-related Behaviour and Experience Patterns (AVEM) was used. The questionnaire allows to classify 4 types of coping behaviour. G: healthy-ambitious, S: unambitious, A: excessively ambitious, B: resigned. Using a quasi-experimental design, the effect of resilience building was verified by comparing a treatment group with a control group. Control group was offered the usual treatment of the education institute. The treatment group was additionally offered two individual meetings and a work-related group treatment focussing on coping behaviour. RESULTS: Given a very high resignation tendency in both groups, dropping out of rehabilitation was less frequent in the treatment group. Other individuals tended to drop out more frequently, but this is not statistically significant. CONCLUSION: The study shows that work-related resilience building helps to minimize risk of dropping out of vocational rehabilitation in the case of extremely resigned coping behaviour. PMID- 27119497 TI - [Recommendations for the Stepwise Occupational Reintegration: Can the Characteristic of the Patients Explain the Differences Between the Rehabilitation Centers?]. AB - BACKGROUND: The first step to initiate a stepwise occupational reintegration (SOR) is the recommendation of the rehabilitation centers. Therefore rehabilitation centers have a significant impact on the use of SOR. There is evidence that the recommendation rate between the rehabilitation centers differs clearly. The present survey therefore analyses in detail the differences of the recommendation rate and examines which patient-related factors could explain the differences. METHODS: This study is based on analysis of routine data provided by the German pension insurance in Baden-Wurttemberg (Rehabilitationsstatistikdatenbasis 2013; RSD). In the analyses rehabilitation measures were included if they were conducted by employed patients (18-64 years) with a muscular-skeletal system disease or a disorder of the connective tissue. Logistic regression models were performed to explain the differences in the recommendation rate of the rehabilitation centers. RESULTS: The data of 134 853 rehabilitation measures out of 32 rehabilitation centers were available. The recommendation rate differed between the rehabilitation centers from 1.36-18.53%. The logistic regression analysis showed that the period of working incapacity 12 month before the rehabilitation and the working capacity on the current job were the most important predictors for the recommendation of a SOR by the rehabilitation centers. Also the rehabilitation centers themselves have an important influence. DISCUSSION: The results of this survey indicate that the characteristic of the patients is an important factor for the recommendation of SOR. Additionally the rehabilitation centers themselves have an influence on the recommendation of SOR. The results point to the fact that the rehabilitation centers use different criteria by making a recommendation. PMID- 27119498 TI - Vitamin D3 suppresses morphological evolution of the cribriform cancerous phenotype. AB - Development of cribriform morphology (CM) heralds malignant change in human colon but lack of mechanistic understanding hampers preventive therapy. This study investigated CM pathobiology in three-dimensional (3D) Caco-2 culture models of colorectal glandular architecture, assessed translational relevance and tested effects of 1,25(OH)2D3,theactive form of vitamin D. CM evolution was driven by oncogenic perturbation of the apical polarity (AP) complex comprising PTEN, CDC42 and PRKCZ (phosphatase and tensin homolog, cell division cycle 42 and protein kinase C zeta). Suppression of AP genes initiated a spatiotemporal cascade of mitotic spindle misorientation, apical membrane misalignment and aberrant epithelial configuration. Collectively, these events promoted "Swiss cheese-like" cribriform morphology (CM) comprising multiple abnormal "back to back" lumens surrounded by atypical stratified epithelium, in 3D colorectal gland models. Intestinal cancer driven purely by PTEN-deficiency in transgenic mice developed CM and in human CRC, CM associated with PTEN and PRKCZ readouts. Treatment of PTEN-deficient 3D cultures with 1,25(OH)2D3 upregulated PTEN, rapidly activated CDC42 and PRKCZ, corrected mitotic spindle alignment and suppressed CM development. Conversely, mutationally-activated KRAS blocked1,25(OH)2D3 rescue of glandular architecture. We conclude that 1,25(OH)2D3 upregulates AP signalling to reverse CM in a KRAS wild type (wt), clinically predictive CRC model system. Vitamin D could be developed as therapy to suppress inception or progression of a subset of colorectal tumors. PMID- 27119499 TI - Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/beta-catenin signaling. AB - Non-small-cell lung cancer (NSCLC) is the most prevalent malignancy worldwide given its high incidence, considerable mortality, and poor prognosis. The anti malaria compounds artemisinin (ART), dihydroartemisinin (DHA), and artesunate (ARTS) reportedly have anti-cancer potential, although the underlying mechanisms remain unclear. In this work, we used flow cytometry to show that ART, DHA, and ARTS could inhibit the proliferation of A549 and H1299 cells by arresting cell cycle in G1 phase. Meanwhile, tumor malignancy including migration, invasion, cancer stem cells, and epithelial-mesenchymal transition were also significantly suppressed by these compounds. Furthermore, ART, DHA, and ARTS remarkably decreased tumor growth in vivo. By using IWP-2, the inhibitor of Wnt/beta-catenin pathway, and Wnt5a siRNA, we found that ART, DHA, and ARTS could render tumor inhibition partially dependent on Wnt/beta-catenin inactivation. These compounds could strikingly decrease the protein level of Wnt5-a/b and simultaneously increase those of NKD2 and Axin2, ultimately resulting in beta-catenin downregulation. In summary, our findings revealed that ART, DHA, and ARTS could suppress lung-tumor progression by inhibiting Wnt/beta-catenin pathway, thereby suggesting a novel target for ART, DHA, and ARTS in cancer treatment. PMID- 27119500 TI - Proteomics and peptidomics: moving toward precision medicine in urological malignancies. AB - Urological malignancies are a major cause of morbidity and mortality worldwide. Advances in early detection, diagnosis, prognosis and prediction of treatment response can significantly improve patient care. Proteomic and peptidomic profiling studies are at the center of kidney, prostate and bladder cancer biomarker discovery and have shown great promise for improved clinical assessment. Mass spectrometry (MS) is the most widely employed method for proteomic and peptidomic analyses. A number of MS platforms have been developed to facilitate accurate identification of clinically relevant markers in various complex biological samples including tissue, urine and blood. Furthermore, protein profiling studies have been instrumental in the successful introduction of several diagnostic multimarker tests into the clinic. In this review, we will provide a brief overview of high-throughput technologies for protein and peptide based biomarker discovery. We will also examine the current state of kidney, prostate and bladder cancer biomarker research as well as review the journey toward successful clinical implementation. PMID- 27119502 TI - Identification of the microRNA networks contributing to macrophage differentiation and function. AB - Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associated alterations in expression with putative mRNA targets that are critical during differentiation of macrophages. In an effort to map the dynamic changes in the bone marrow (BM), we profiled whole BM cultures during differentiation into macrophages. We identified 112 miRNAs with expression patterns that were differentially regulated 5-fold or more during BMDM development. With TargetScan and MeSH databases, we identified 1267 transcripts involved in 30 canonical pathways linked to macrophage biology as potentially regulated by these specific 112 miRNAs. Furthermore, by employing miRanda and Ingenuity Pathways Analysis (IPA) analysis systems, we identified 18 miRNAs that are temporally linked to the expression of CSF1R, CD36, MSR1 and SCARB1; 7 miRNAs linked to the regulation of the transcription factors RUNX1 and PU.1, and 14 miRNAs target the nuclear receptor PPARalpha and PPARgamma. This novel information provides an important reference resource for further study of the functional links between miRNAs and their target mRNAs for the regulation of differentiation and function of macrophages. PMID- 27119501 TI - Circulating adiponectin levels in various malignancies: an updated meta-analysis of 107 studies. AB - Early detection of cancers is challenging for lack of specific biomarkers. Adiponectin is an adipokine predominantly derived from adipocytes and hypoadiponectinemia has been reported to associate with risk of many types of cancers. However, available evidence is controversial. Some studies show that increased adiponectin levels correlate with cancer risk. Therefore, we performed a meta-analysis of the association between circulating adiponectin levels and cancer development. A systematic search of PubMed, EMBASE, Wiley Online Library and Cochrane Library was conducted for eligible studies involving circulating adiponectin and malignancies from inception to August 8, 2015. Standard mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated by use of a random-effect model. Funnel plot and Egger's linear regression test were conducted to examine the risk of publication bias. 107 studies were included with 19,319 cases and 25,675 controls. The pooled analysis indicated that circulating adiponectin levels were lower in patients with various cancers than in controls, with a pooled SMD of -0.334 MUg/ml (95% CI, -0.465 to -0.203, P = 0.000). No evidence of publication bias was observed. Circulating high molecular weight adiponectin levels were also lower in cancer patients than in controls, with a pooled SMD of -0.502 MUg/ml (95% CI, -0.957 to -0.047, P = 0.000). This meta analysis provides further evidence that decreased adiponectin levels is associated with risk of various cancers. Hypoadiponectinemia may represent a useful biomarker for early detection of cancers. PMID- 27119503 TI - Neoadjuvant modified TPF (docetaxel, cisplatin, fluorouracil) for patients unfit to standard TPF in locally advanced head and neck squamous cell carcinoma: a study of 48 patients. AB - TPF (docetaxel, cisplatin, fluorouracil) is the standard chemotherapy used for induction in locally advanced head and neck squamous cell carcinoma (LAHNSCC). Its toxicity limits it to younger patients with good functional status and without significant comorbidity. Since modified TPF (mTPF) demonstrated higher tolerability with similar efficacy in gastric cancer, we tested this scheme on frail patients.From July 2010 to July 2014, the files of the 48 patients treated for LAHNSCC with mTPF in three French institutions were retrospectively collected.mTPF was chosen because of age>70 years, or severe denutrition, or PS>1, or severe comorbidities or after severe toxicity of standard TPF. During the first 4 cycles, 2 patients died, 14 secondary hospitalizations were required and 10 patients stopped treatment due to no lethal toxicity. Two patients died during radiotherapy.The response rate was 83% (19% complete response). With a median follow-up of 15.2 months, 4 patients died during treatment, 8 died of non head and neck cancer related disorders, 18 progressed (17 deaths) and 18 were free of disease. The median overall survival was 18.5 months (95% IC: 16.9 30.0).mTPF is effective in terms of response rate compared with the standard TPF and could become a new option in induction for frail patients with LAHNSCC. PMID- 27119505 TI - Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids. AB - Mitophagy is a critical cellular process that selectively targets damaged mitochondria for autophagosomal degradation both under baseline conditions and in response to stress preventing oxidative damage and cell death. Recent studies have linked alterations in mitochondria function and reduced autophagy with the development of age-related pathologies. However, the significance of mitochondrial autophagy in vessel wall in response to atherogenic lipid stressors is not known. In the present study, we investigated the role of mitophagy on human vascular smooth muscle cells (VSMC) apoptosis induced by oxidized low density lipoproteins (LDL). We reported for the first time that the engulfment of defective mitochondria by autophagosomes occurred in human VSMC in response to oxidized LDL. The molecular mechanism mediating mitophagy in human VSMC involved dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, accumulation of PTEN-induced putative kinase 1 (PINK1) and the recruitment of the E3 ubiquitin ligase Parkin to mitochondria. Likewise, we found increased voltage-dependent anion channel 1 (VDAC1) and mitofusin 2 (Mnf2) mitochondrial proteins ubiquitination and LC3 association to mitochondria. Using flow cytometry in the presence of lysosomal inhibitors, we showed that PINK1 and Parkin silencing impaired mitophagy flux and enhanced oxidized LDL-induced VSMC apoptosis. In addition, overexpression of PINK1 and Parkin were protective by limiting cell death. Moreover, reduced Bax levels found in VSMC-overexpressing Parkin indicated cross talk among mitophagy and mitochondrial apoptotic signalling pathways. Altogether these data demonstrate that mitophagy is a safeguard mechanism against human VSMC apoptosis induced by atherogenic stressors and highlight mitophagy as a potential target to stabilize atherosclerotic plaque. PMID- 27119506 TI - MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1. AB - Colorectal cancer (CRC) is the third most common cancer causing high mortality rates world-wide. Delineating the molecular mechanisms leading to CRC development and progression, including the role of microRNAs (miRNAs), are currently being unravelled at a rapid rate. Here, we report frequent downregulation of the microRNA miR-320 family in primary CRC tissues and cell lines. Lentiviral mediated re-expression of miR-320c (representative member of the miR-320 family) inhibited HCT116 CRC growth and migration in vitro, sensitized CRC cells to 5 Fluorouracil (5-FU), and inhibited tumor formation in SCID mice. Global gene expression analysis in CRC cells over-expressing miR-320c, combined with in silico prediction identified 84 clinically-relevant potential gene targets for miR-320 in CRC. Using a series of biochemical assays and functional validation, SOX4, FOXM1, and FOXQ1 were validated as novel gene targets for the miR-320 family. Inverse correlation between the expression of miR-320 members with SOX4, FOXM1, and FOXQ1 was observed in primary CRC patients' specimens, suggesting that these genes are likely bona fide targets for the miR-320 family. Interestingly, interrogation of the expression levels of this gene panel (SOX4, FOXM1, and FOXQ1) in The Cancer Genome Atlas (TCGA) colorectal cancer data set (319 patients) revealed significantly poor disease-free survival in patients with elevated expression of this gene panel (P-Value: 0.0058). Collectively, our data revealed a novel role for the miR-320/SOX4/FOXM1/FOXQ1 axes in promoting CRC development and progression and suggest targeting those networks as potential therapeutic strategy for CRC. PMID- 27119504 TI - Metabolic pathways regulated by TAp73 in response to oxidative stress. AB - Reactive oxygen species are involved in both physiological and pathological processes including neurodegeneration and cancer. Therefore, cells have developed scavenging mechanisms to maintain redox homeostasis under control. Tumor suppressor genes play a critical role in the regulation of antioxidant genes. Here, we investigated whether the tumor suppressor gene TAp73 is involved in the regulation of metabolic adaptations triggered in response to oxidative stress. H2O2 treatment resulted in numerous biochemical changes in both control and TAp73 knockout (TAp73-/-) mouse embryonic fibroblasts, however the extent of these changes was more pronounced in TAp73-/- cells when compared to control cells. In particular, loss of TAp73 led to alterations in glucose, nucleotide and amino acid metabolism. In addition, H2O2 treatment resulted in increased pentose phosphate pathway (PPP) activity in null mouse embryonic fibroblasts. Overall, our results suggest that in the absence of TAp73, H2O2 treatment results in an enhanced oxidative environment, and at the same time in an increased pro-anabolic phenotype. In conclusion, the metabolic profile observed reinforces the role of TAp73 as tumor suppressor and indicates that TAp73 exerts this function, at least partially, by regulation of cellular metabolism. PMID- 27119507 TI - Expression of MLL-AF4 or AF4-MLL fusions does not impact the efficiency of DNA damage repair. AB - The most frequent rearrangement of the human MLL gene fuses MLL to AF4 resulting in high-risk infant B-cell acute lymphoblastic leukemia (B-ALL). MLL fusions are also hallmark oncogenic events in secondary acute myeloid leukemia. They are a direct consequence of mis-repaired DNA double strand breaks (DNA-DSBs) due to defects in the DNA damage response associated with exposure to topoisomerase-II poisons such as etoposide. It has been suggested that MLL fusions render cells susceptible to additional chromosomal damage upon exposure to etoposide. Conversely, the genome-wide mutational landscape in MLL-rearranged infant B-ALL has been reported silent. Thus, whether MLL fusions compromise the recognition and/or repair of DNA damage remains unanswered. Here, the fusion proteins MLL-AF4 (MA4) and AF4-MLL (A4M) were CRISPR/Cas9-genome edited in the AAVS1 locus of HEK293 cells as a model to study MLL fusion-mediated DNA-DSB formation/repair. Repair kinetics of etoposide- and ionizing radiation-induced DSBs was identical in WT, MA4- and A4M-expressing cells, as revealed by flow cytometry, by immunoblot for gammaH2AX and by comet assay. Accordingly, no differences were observed between WT, MA4- and A4M-expressing cells in the presence of master proteins involved in non-homologous end-joining (NHEJ; i.e.KU86, KU70), alternative-NHEJ (Alt-NHEJ; i.e.LigIIIa, WRN and PARP1), and homologous recombination (HR, i.e.RAD51). Moreover, functional assays revealed identical NHEJ and HR efficiency irrespective of the genotype. Treatment with etoposide consistently induced cell cycle arrest in S/G2/M independent of MA4/A4M expression, revealing a proper activation of the DNA damage checkpoints. Collectively, expression of MA4 or A4M does neither influence DNA signaling nor DNA-DSB repair. PMID- 27119508 TI - Inflammatory and immune markers associated with physical frailty syndrome: findings from Singapore longitudinal aging studies. AB - Chronic systematic inflammation and reduced immune system fitness are considered potential contributing factors to the development of age-related frailty, but the underlying mechanisms are poorly defined. This exploratory study aimed to identify frailty-related inflammatory markers and immunological phenotypes in a cohort of community-dwelling adults aged >= 55 years. Frailty was assessed using two models, a Frailty Index and a categorical phenotype, and correlated with levels of circulating immune biomarkers and markers of senescence in immune cell subsets. We identified eight serological biomarkers that were associated with frailty, including sgp130, IL-2Ralpha, I-309, MCP-1, BCA-1, RANTES, leptin, and IL-6R. Frailty Index was inversely predicted by the frequency of CD3+, CD45RA+, and central memory CD4 cells, and positively predicted by the loss of CD28 expression, especially in CD8+ T cells, while frailty status was predicted by the frequency of terminal effector CD8+ T cells. In gamma/delta T cells, frailty was negatively associated with CD27, and positively associated with IFNgamma+TNFalpha secretion by gamma/delta2+ cells and IFNgamma-TNFalpha+ secretion by gamma/delta2- cells. Increased numbers of exhausted and CD38+ B cells, as well as CD14+CD16+ inflammatory monocytes, were also identified as frailty-associated phenotypes. This pilot study supports an association between inflammation, cellular immunity, and the process of frailty. These findings have significance for the early identification of frailty using circulating biomarkers prior to clinical manifestations of severe functional decline in the elderly. PMID- 27119510 TI - MicroRNA-93 inhibits ischemia-reperfusion induced cardiomyocyte apoptosis by targeting PTEN. AB - MicroRNAs have been implicated in some biological and pathological processes, including the myocardial ischemia/reperfusion (I/R) injury. Recent findings demonstrated that miR-93 might provide a potential cardioprotective effect on ischemic heart disease. This study was to investigate the role of miR-93 in I/R induced cardiomyocyte injury and the potential mechanism. In this study, we found that hypoxia/reoxygenation (H/R) dramatically increased LDH release, MDA contents, ROS generation, and endoplasmic reticulum stress (ERS)-mediated cardiomyocyte apoptosis, which were attenuated by co-transfection with miR-93 mimic. Phosphatase and tensin homolog (PTEN) was identified as the target gene of miR-93. Furthermore, miR-93 mimic significantly increased p-Akt levels under H/R, which was partially released by LY294002. In addtion, Ad-miR-93 also attenuated myocardial I/R injury in vivo, manifested by reduced LDH and CK levels, infarct area and cell apoptosis. Taken together, our findings indicates that miR-93 could protect against I/R-induced cardiomyocyte apoptosis by inhibiting PI3K/AKT/PTEN signaling. PMID- 27119509 TI - Dietary fat intake and ovarian cancer risk: a meta-analysis of epidemiological studies. AB - Observational studies assessing the association of dietary fat and risk of ovarian cancer yield discrepant results. Pertinent prospective cohort studies were identified by a PubMed search from inception to December 2015. Sixteen independent case-control and nine cohort studies on dietary fat intake were included, with approximately 900,000 subjects in total. Relative risks (RRs) with 95% confidence intervals were pooled using a random effects model. Heterogeneity, sensitivity analysis and publication bias were assessed; subgroup analysis and analysis stratified by EOC histology were conducted. The reported studies showed a significant increase of ovarian cancer risk with high consumption of total-, saturated-, and trans-fats, while serous ovarian cancer was more susceptible to dietary fat consumption than other pathological subtypes. No evidence of positive association between dietary fat intake and ovarian cancer risk was provided by cohort studies. Menopausal status, hormone replacement therapy, body mass index (BMI), and pregnancy times, modified the objective associations. In conclusion, the meta-analysis findings indicate that high consumption of total, saturated and trans-fats increase ovarian cancer risk, and different histological subtypes have different susceptibility to dietary fat. PMID- 27119511 TI - Multicentric survey on dose reduction/interruption of cancer drug therapy in 12.472 patients: indicators of suspected adverse reactions. AB - Antiblastic drugs have a high number of potential side-effects. Paradoxically, according to the National Network of Pharmacovigilance, the number of reported adverse reactions to these agents is proportionally lower than that registered for non antiblastic drugs. Critical phenomena such as treatment interruptions and significant dose reductions within the first two months of use may be indicators of adverse drug reactions. The aim of the present study was to increase our knowledge of pharmacovigilance to facilitate the actions taken to improve the risk-benefit profile of cancer drugs and, consequently, their safety. This retrospective observational survey was carried out on prescriptions from 1st January 2012 to 31st December 2012.Dose reductions of more than 10% during the first 90 days of therapy were considered as a surrogate indicator of an adverse reaction. Dose interruptions during the first 60 days of therapy were taken into consideration. Of the12,472 patients 1,248 underwent a dose reduction. The drugs that most often required a dose reduction were paclitaxel and oxaliplatin (17.4% and 17.3%, respectively), docetaxel (14.8%), carboplatin (15%), fluorouracil (10.7%) and, among oral medications, capecitabine (6.9%). Of the 1896 patients treated with the same drugs, 9.7% interrupted treatment. Patients required a lower dose reduction than that reported by other authors. Around 15% of cases underwent a 30% dose reduction within three months of starting therapy, indicating a possible adverse reaction. Constant monitoring of dose prescription and continuous training of medical and nursing staff are clearly needed to increase awareness of the importance of reporting adverse events. PMID- 27119513 TI - The Effects of Two Anesthetics, Propofol and Sevoflurane, on Liver Ischemia/Reperfusion Injury. AB - BACKGROUND: Propofol and sevoflurane are widely used in clinical anesthesia, and both have been reported to exert a protective effect in organ ischemia/reperfusion (IR). This study aims to investigate and compare the effects of propofol and sevoflurane on liver ischemia/reperfusion and the precise molecular mechanism. METHODS AND MATERIALS: Rats were randomized into four groups: the sham group, I/R group, propofol treatment group (infused with 1% propofol at 500 MUg. kg-1. min-1), and sevoflurane treatment group (infused with 3% (2 L/min) sevoflurane). The liver ischemia/reperfusion model was used to evaluate the hepatoprotective effect on ischemic injury. Liver enzyme leakage, liver cytokines and histopathological examination were used to evaluate the extent of hepatic ischemia/reperfusion injury. Oxidative stress was investigated by evaluating the levels of Malondialdehyde(MDA), Superoxide Dismutase(SOD) and NO. The terminal dexynucleotidyl transferase(TdT)-mediated dUTP nick end labeling (TUNEL) assay and western blot were applied to detect apoptosis in the ischemic liver tissue and its mechanism. RESULTS: Both propofol and sevoflurane attenuated the extent of hepatic ischemia/reperfusion injury which is evident from the hisopathological studies and alterations in liver enzymes such as AST and LDH by inhibiting Nuclear factor kappa B (NFx03BA;B) activation and subsequent alterations in inflammatory cytokines interleukin-1(IL-1), interleukin-6(IL-6), tumor necrosis factor-alpha (TNF-alpha) and increased IL10 release. Propofol exhibited a similar protective effect and a lower IL-1 release, while sevoflurane decreased TNF-alpha leakage more significantly. Meanwhile, oxidative stress was attenuated by reduced MDA and NO and elevated SOD release. The expression of antiapoptotic protein Bcl-2 and Bcl-xl were enhanced while that of apoptotic protein Bax and Bak were reduced by both propofol and sevoflurane to regulate hepatic apoptosis. In addition, propofol downregulated the phosphorylation of AKT and Bad protein, while sevoflurane downregulated the phosphorylation of p38. In addition, Both the treatments had no effect on the expression of AKT, Bad and p38. CONCLUSION: Both propofol and sevoflurane can protect the liver from ischemia/reperfusion injury by modulating the inflammatory responses reducing oxidative stress and liver apoptosis. PMID- 27119512 TI - Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma. AB - Resistance to epidermal growth factor receptor (EGFR)-targeted therapy is insufficiently understood in head and neck squamous cell carcinoma (HNSCC), entailing the lack of predictive biomarkers.Here, we studied resistance-mediating EGFR ectodomain and activating RAS mutations by next-generation sequencing (NGS) of cell lines and tumor tissue of cetuximab-naive patients (46 cases, 12 cell lines), as well as liquid biopsies taken during and after cetuximab/platinum/5 fluorouracil treatment (20 cases). Tumors of cetuximab-naive patients were unmutated, except for HRAS mutations in 4.3% of patients. Liquid biopsies revealed acquired KRAS, NRAS or HRAS mutations in more than one third of patients after cetuximab exposure. 46% of patients with on-treatment disease progression showed acquired RAS mutations, while no RAS mutations were found in the non progressive subset of patients, indicating that acquisition of RAS mutant clones correlated significantly with clinical resistance (Chi square p=0.032). The emergence of mutations preceded clinical progression in half of the patients, with a maximum time from mutation detection to clinical progression of 16 weeks.RAS mutations account for acquired resistance to EGFR-targeting in a substantial proportion of HNSCC patients, even though these tumors are rarely mutated at baseline. Liquid biopsies may be used for mutational monitoring to guide treatment decisions. PMID- 27119514 TI - Extraction of Silver by Glucose. AB - Unprecedented silver ion leaching, in the range of 0.7 ppm was seen when metallic silver was heated in water at 70 degrees C in presence of simple carbohydrates, such as glucose, making it a green method of silver extraction. Extraction was facilitated by the presence of anions, such as carbonate and phosphate. Studies confirm a two-step mechanism of silver release, first forming silver ions at the metal surface and later complexation of ionic silver with glucose; such complexes have been detected by mass spectrometry. Extraction leads to microscopic roughening of the surface making it Raman active with an enhancement factor of 5*10(8) . PMID- 27119515 TI - Perforated Peptic Ulcer Repair: Factors Predicting Conversion in Laparoscopy and Postoperative Septic Complications. AB - OBJECTIVE: The surgical treatment for perforated peptic ulcers can be safely performed laparoscopically. The aim of the study was to define simple predictive factors for conversion and septic complications. METHODS: This retrospective case control study analyzed patients treated with either laparoscopic surgery or laparotomy for perforated peptic ulcers. RESULTS: A total of 71 patients were analyzed. Laparoscopically operated patients had a shorter hospital stay (13.7 vs. 15.1 days). In an intention-to-treat analysis, patients with conversion to open surgery (analyzed as subgroup from laparoscopic approach group) showed no prolonged hospital stay (15.3 days) compared to patients with a primary open approach. Complication and mortality rates were not different between the groups. The statistical analysis identified four intraoperative risk factors for conversion: Mannheim peritonitis index (MPI) > 21 (p = 0.02), generalized peritonitis (p = 0.04), adhesions, and perforations located in a region other than the duodenal anterior wall. We found seven predictive factors for septic complications: age >70 (p = 0.02), cardiopulmonary disease (p = 0.04), ASA > 3 (p = 0.002), CRP > 100 (p = 0.005), duration of symptoms >24 h (p = 0.02), MPI > 21(p = 0.008), and generalized peritonitis (p = 0.02). CONCLUSION: Our data suggest that a primary laparoscopic approach has no disadvantages. Factors necessitating conversions emerged during the procedure inhibiting a preoperative selection. Factors suggesting imminent septic complications can be assessed preoperatively. An assessment of the proposed parameters may help optimize the management of possible septic complications. PMID- 27119517 TI - Clinicopathologic significance of HMGA2 expression's correlation with prognosis of esophageal squamous cell carcinoma after Ivor Lewis esophagectomy. AB - BACKGROUND? The main reason for the commonly poor prognosis of esophageal squamous cell carcinoma (ESCC) after surgery is the high recurrence rate. For patients at high risk of recurrence, it may be of value to seek indicators of recurrence, which would be useful for further treatment. High-mobility group A2 (HMGA2) is a small non-histone chromosomal protein, highly expressed in many epithelial tissue malignant tumors and closely correlated with the occurrence, development and prognosis of tumor. Its aberrant expression in various cancers was detected, while its expression and significance in ESCC is still unclear. METHODS? We enrolled 127 patients with ESCC who had undergone Ivor-Lewis esophagectomy. The expression profile of HMGA2 was examined by immunohistochemistry. RESULTS: The result showed that the high expression of HMGA2 correlated with a higher T stage (P=0.007), lower differentiation degree (P=0.008), lymph node metastasis (P<0.01), recurrence status (P=0.005) and TNM stage (P=0.006). The Cox regression analysis showed that the TNM stage (P=0.006), differentiation degree (P=0.003) and high HMGA2 expression (P=0.048) were independent risk factors of survival. CONCLUSIONS? Our data indicated that HMGA2 expression level associates with key clinicopathological features and could be an effective biomarker to predict the prognosis of ESCC. PMID- 27119516 TI - Clonal heterogeneity in osteogenic potential of lung cancer-associated fibroblasts: promotional effect of osteogenic progenitor cells on cancer cell migration. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) consist of heterogeneous cell population in terms of their differentiation potential. The functional differences in tumor progression between CAFs with mesenchymal stem/progenitor cells (MSCs/MPCs) characteristics and CAFs without MSCs/MPCs characteristics are not clarified. METHODS: CAFs and vascular adventitial fibroblasts (VAFs, which contain MSCs/MPCs) were isolated from nine primary lung cancers and were cultured in osteogenic or adipogenic medium to assess their multi-lineage differentiation. Next, we established nine single-cell-derived clones from the primary culture of CAFs and examined their differentiation potential. The effects of each single cell-derived clone on the proliferation and migration of lung adenocarcinoma cell line, A549, were analyzed. RESULTS: The nine samples of VAFs and CAFs showed various degrees of osteogenic differentiation. Although the VAFs displayed the ability to undergo adipogenic differentiation, all cases of the CAFs did not. CAFs clones presented varying degrees of osteogenic differentiation. Four clones displayed comparable levels of osteogenic potential with that of the VAFs, and two clones were completely negative. As compared to the CAFs clones that possessed lower osteogenic potential, CAFs clones with higher osteogenic potential did not confer proliferative activity in A549 cells. On the contrary, these clones significantly promoted the migration of A549 cells as compared to the clones with lower osteogenic potential. CONCLUSION: Our studies clearly indicate that CAFs derived from lung cancer are heterogeneous population that consists of cells with varying osteogenic potentials and that CAFs with higher osteogenic potential have a greater tumor-promoting function through the enhancement of cancer cell migration. PMID- 27119518 TI - Minimal physiologically-based pharmacokinetic (mPBPK) model for a monoclonal antibody against interleukin-6 in mice with collagen-induced arthritis. AB - Therapeutic monoclonal antibodies (mAb) targeting soluble inflammatory cytokines exert their pharmacological effects in rheumatoid arthritis through binding and neutralizing free cytokines in target tissue sites. Therefore suppression of free cytokines in such sites directly relates to the magnitude of therapeutic response. Although the interrelationships between mAb and cytokines have been examined in the systemic circulation, less is known about the interaction of mAb and cytokines in inflamed joints. In the present study, the interplay between the mAb, CNTO 345, and its target IL-6 in serum as well as ankle joint synovial fluid were characterized in collagen-induced arthritic mice. A minimal physiologically based pharmacokinetic model with target-mediated drug disposition (TMDD) features in serum and ankle joint synovial fluid was developed for the assessment of the TMDD dynamics of CNTO 345 and IL-6. Our model indicates that TMDD kinetics in ankle joints differ greatly from that in serum. The differences can be attributed to the limited tissue distribution of CNTO 345 in ankle joint synovial fluid, the significant rise of the IL-6 baseline in ankle joint synovial fluid in comparison with serum, and the relative time-scales of elimination rates between CNTO 345, free IL-6 and CNTO 345-IL-6 complex in serum and ankle joint synovial fluid. PMID- 27119519 TI - Judging the morality of utilitarian actions: How poor utilitarian accessibility makes judges irrational. AB - Is it acceptable and moral to sacrifice a few people's lives to save many others? Research on moral dilemmas in psychology, experimental philosophy, and neuropsychology has shown that respondents judge utilitarian personal moral actions (footbridge dilemma) as less appropriate than equivalent utilitarian impersonal moral actions (trolley dilemma). Accordingly, theorists (e.g., Greene et al., 2001) have argued that judgments of appropriateness in personal moral dilemmas are more emotionally salient and cognitively demanding (taking more time to be rational) than impersonal moral dilemmas. Our novel findings show an effect of psychological accessibility (driven by partial contextual information; Kahneman, 2003) on utilitarian moral behavior and response time for rational choices. Enhanced accessibility of utilitarian outcomes through comprehensive information about moral actions and consequences boosted utility maximization in moral choices, with rational choices taking less time. Moreover, our result suggests that previous results indicating emotional interference, with rational choices taking more time to make, may have been artifacts of presenting partial information. PMID- 27119520 TI - Generation, Characterization and Application of Antibodies Directed against HERV H Gag Protein in Colorectal Samples. AB - INTRODUCTION: A substantial part of the human genome originates from transposable elements, remnants of ancient retroviral infections. Roughly 8% of the human genome consists of about 400,000 LTR elements including human endogenous retrovirus (HERV) sequences. Mainly, the interplay between epigenetic and post transcriptional mechanisms is thought to silence HERV expression in most physiological contexts. Interestingly, aberrant reactivation of several HERV-H loci appears specific to colorectal carcinoma (CRC). RESULTS: The expression of HERV-H Gag proteins (Gag-H) was assessed using novel monoclonal mouse anti Gag-H antibodies. In a flow cytometry screen four antibody clones were tested on a panel of primary CRC cell lines and the most well performing ones were subsequently validated in western blot analysis. Finally, Gag-H protein expression was analyzed by immune histology on cell line cytospins and on clinical samples. There, we found a heterogeneous staining pattern with no background staining of endothelial, stromal and infiltrating immune cells but diffuse staining of the cytoplasm for positive tumor and normal crypt cells of the colonic epithelium. CONCLUSION: Taken together, the Gag-H antibody clone(s) present a valuable tool for staining of cells with colonic origin and thus form the basis for future more detailed investigations. The observed Gag-H protein staining in colonic epithelium crypt cells demands profound analyses of a potential role for Gag-H in the normal physiology of the human gut. PMID- 27119521 TI - IL12, IL10, IFNgamma and TNFalpha Expression in Human Primary Monocytes Stimulated with Bacterial Heat Shock GroEL (Hsp64) Protein. AB - Actinobacillus (Aggregatibacter) actinomycetemicomitans (Aa) is a bacterium that lives in the oral cavity and plays an important role in periodontal diseases. The effect of A.actinomycetemcomitans's heat shock family protein GroEL on host or immune cells including monocytes is quite limited. In this study, the recombinant A.actinomycetemcomitans's GroEL protein (rAaGroEL) was used as an antigen and its effects on monocytes of peripheral blood mononuclear cells (PBMCs) was investigated. To do that, PBMCs were stimulated with rAaGroEL protein at different time points (16h to 96h) and the cytokines of CD14+ monocytes were detected with intracellular cytokine staining by Flow cytometry. Data showed that AaGroEL protein has an antigenic effect on human primary monocytes. AaGroEL protein responsive CD14 monocytes stimulates the expression of IL12, IL10, IFNgamma and TNFalpha cytokines with different kinetics and expression profile. Therefore, A. actinomycetemcomitans's heat shock GroEL protein can modulate innate and adaptive immune responses and contribute to an inflammatory diseases pathology. PMID- 27119522 TI - A Moist Crevice for Word Aversion: In Semantics Not Sounds. AB - Why do people self-report an aversion to words like "moist"? The present studies represent an initial scientific exploration into the phenomenon of word aversion by investigating its prevalence and cause. Results of five experiments indicate that about 10-20% of the population is averse to the word "moist." This population often speculates that phonological properties of the word are the cause of their displeasure. However, data from the current studies point to semantic features of the word-namely, associations with disgusting bodily functions-as a more prominent source of peoples' unpleasant experience. "Moist," for averse participants, was notable for its valence and personal use, rather than imagery or arousal-a finding that was confirmed by an experiment designed to induce an aversion to the word. Analyses of individual difference measures suggest that word aversion is more prevalent among younger, more educated, and more neurotic people, and is more commonly reported by females than males. PMID- 27119524 TI - Miami Obstetrician Uses Evidence to Quell Zika Fears. PMID- 27119523 TI - The effect of atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMG-CoA), on the prevention of osteoporosis in ovariectomized rabbits. AB - Osteoporosis is a most frequent systemic skeletal disease characterized as low bone mineral density and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and fracture risk. Although several drugs such as bisphosphonates, estrogen replacement treatment, and selective estrogen receptor modulators have been used to treat osteoporosis, all these are not the ideal drugs because of insufficient curative ability and adverse side effects. Recently, atorvastatin has ordinarily been prescribed as an anti-hyperlipidemia drug, not as an anti-osteoporosis drug. However, its clinical outcome and potential treatment mechanism are still unclear. In this study, the bilateral ovariectomy of rabbits was duplicated to develop osteoporosis animal model. The effect of atorvastatin on in vivo was determined, and the functional mechanism was studied in vitro after the curative effect was explored. Atorvastatin was observed to significantly increase the mechanical parameters such as maximum load, stiffness, and energy-absorbing capacity, and it improved the microarchitecture. The anti-osteoporosis activity of atorvastatin may be the result of the promotion of differentiation of osteoblasts by inducing synthesis of vascular endothelial growth factor, bone morphogenetic protein 2 (BMP2), core binding factor alpha 1 (CBFalpha1), and inhibition of osteoclast formation through the osteoprotegerin (OPG)-receptor activator for the nuclear factor kappaB ligand (RANKL) system. Our study observations give reliable experimental evidence for clinical application of atorvastatin to treat the disorder of osteoporosis. PMID- 27119526 TI - Mindfulness-Based Cognitive Therapy and the Prevention of Depressive Relapse: Measures, Mechanisms, and Mediators. PMID- 27119527 TI - The Effectiveness of Educational Programs to Improve Recognition and Reporting of Elder Abuse and Neglect: A Systematic Review of the Literature. AB - Health professionals often lack adequate protocols or knowledge to detect, manage, and prevent elder maltreatment. This systematic review describes and evaluates existing literature on the effectiveness of educational interventions to improve health professionals' recognition and reporting of elder abuse and neglect. Fourteen articles described 22 programs ranging from brief didactics to experiential learning and targeted a variety of health and social service audiences. Most evaluations were limited to satisfaction measures. These programs may result in increased awareness, collaboration, and improved case finding. However, using the published literature to guide new program planning is constrained by lack of details and limited evaluations. PMID- 27119525 TI - Connective Auxin Transport in the Shoot Facilitates Communication between Shoot Apices. AB - The bulk polar movement of the plant signaling molecule auxin through the stem is a long-recognized but poorly understood phenomenon. Here we show that the highly polar, high conductance polar auxin transport stream (PATS) is only part of a multimodal auxin transport network in the stem. The dynamics of auxin movement through stems are inconsistent with a single polar transport regime and instead suggest widespread low conductance, less polar auxin transport in the stem, which we term connective auxin transport (CAT). The bidirectional movement of auxin between the PATS and the surrounding tissues, mediated by CAT, can explain the complex auxin transport kinetics we observe. We show that the auxin efflux carriers PIN3, PIN4, and PIN7 are major contributors to this auxin transport connectivity and that their activity is important for communication between shoot apices in the regulation of shoot branching. We propose that the PATS provides a long-range, consolidated stream of information throughout the plant, while CAT acts locally, allowing tissues to modulate and be modulated by information in the PATS. PMID- 27119528 TI - Essential Data Elements for Reporters of Elder Abuse. AB - Most states' adult or elder protective services and aging agency personnel prepare annual reports about their protective services. These reports vary by state and have different terms for the reporter of abuse. Reviewing annual reports from 46 states and the District of Columbia, 248 different terms were used for the reporter of abuse. To develop essential data elements for reporters of abuse, a literature search, a compilation of state elder abuse annual report list of abuse reporters, and a sorting exercise were conducted. Eleven terms were recommended for the different reporters of abuse, encouraging all state administrators and caseworkers to reach consensus to standardize the language. PMID- 27119529 TI - The Social Vulnerability Scale for Older Adults: An Exploratory and Confirmatory Factor Analytic Study. AB - The Social Vulnerability Scale (SVS), a 22-item informant report of vulnerability to exploitation and, in particular, financial exploitation of older adults, was administered to 266 respondents who assessed the social vulnerability of a significant other aged 50 years or over, either a person with dementia or other neurological condition (n = 116), or a healthy adult (n = 150). Exploratory factor analysis in the combined sample revealed a 15-item two-factor solution labeled gullibility and credulity. Stability in factor structure was established in an independent sample (n = 123) using confirmatory factor analysis, and sound reliability (internal consistency) and validity (known-groups) were demonstrated. The SVS15 is a potentially useful instrument for assessing older adults' vulnerability to exploitation. PMID- 27119530 TI - Relationship of Facility Characteristics and Presence of an Ombudsman to Missouri Long-Term Care Facility State Inspection Report Results. AB - This study analyzes existing data describing general facility characteristics, the presence of an ombudsman in the facility, and the number of deficiencies/violations reported for long-term care facilities in the state of Missouri. The model that predicted the rate of deficiencies/violations best was one that included the following characteristics: "contained more than 50 beds" and "considered a Skilled Nursing facility." Findings suggest that the characteristics that are significantly associated with fewer deficiencies are larger size (more than 50 beds) and being classified as Skilled Nursing. While those facilities that housed an ombudsman were found to have fewer deficiencies per bed in the general analysis, further investigation found this to be an artifact mostly due to the higher rate of ombudsmen at larger facilities. PMID- 27119531 TI - [Suicide and euthanasia : Discourse on physician-assisted suicide]. AB - Suicidal thoughts and behavior have been a part of human nature since the beginning of mankind. In his autobiographical work From my Life: Poetry and Truth Goethe summarized two important aspects: "Suicide is an event of human nature which, whatever may be said and done with respect to it, demands the sympathy of every man, and in every epoch must be discussed anew". The authors of this article aim to motivate the readership to question and analyze this complex topic and the accompanying multifaceted positions with a summarized presentation of historical aspects and the more recent political developments. PMID- 27119532 TI - [Mental disorders after mild traumatic brain injury]. AB - Mild traumatic brain injury (mTBI) is a frequent neurological disorder following a closed head injury. It is often accompanied by temporary changes of consciousness as well as cognitive, emotional and physical symptoms. These symptoms subside in the vast majority of affected persons within a few weeks; however, in recent years it has become increasingly more apparent that functionally significant long-term effects can remain after an initially diagnosed mTBI. In these cases mental disorders, such as impairment of cognitive and emotional functions as well as somatic disorders play an important role. This article presents the frequency, diagnosis, therapy and possible mechanisms of cognitive and emotional dysfunction after mTBI, including medicolegal aspects. PMID- 27119533 TI - Alterations in inflammatory biomarkers and energy intake in cancer cachexia: a prospective study in patients with inoperable pancreatic cancer. AB - Chronic systemic inflammatory response is proposed as an underlying mechanism for development of cancer cachexia. We conducted a prospective study to examine changes in inflammatory biomarkers during the disease course and the relationship between inflammatory biomarkers and cachexia in patients with inoperable pancreatic cancer. Twenty patients, median (range) age 67.5 (35-79) years, 5 females, were followed for median 5.5 (1-12) months. Cachexia was diagnosed according to the 2011 consensus-based classification system (weight loss >5 % past six months, BMI < 20 kg/m(2) and weight loss >2 %, or sarcopenia) and the modified Glasgow Prognostic score (mGPS) that combines CRP and albumin levels. Inflammatory biomarkers were measured by enzyme immunoassays. The patients had increased levels of most inflammatory biomarkers, albeit not all statistically significant, both at study entry and close to death, indicating ongoing inflammation. According to the consensus-based classification system, eleven (55 %) patients were classified as cachectic upon inclusion. They did not differ from non-cachectic patients with regard to inflammatory biomarkers or energy intake. According to the mGPS, seven (35 %) were defined as cachectic and had a higher IL 6 (p < 0.001) than the non-cachectic patients. They also had a slightly, but insignificantly longer survival than non-cachectic patients (p = 0.08). The mGPS should be considered as an additional framework for identification of cancer cachexia. PMID- 27119534 TI - Controversy and Strategies Exploration in Blocking Mother-to-Child Transmission of Hepatitis B. AB - Hepatitis B, a serious infectious disease caused by the hepatitis B virus (HBV), remains a worldwide social and public health problem. Hepatitis B has a particularly high incidence rate in the world, whereas approximately 35-50% HBV carriers are infected through vertical transmission. Even after newborn immunoprophylaxis, vertical transmission still accounts for 5-10% in China according to plenty of literature in Chinese language. For these reasons, it is important to determine how to effectively intervene in mother-to-child transmission (MTCT). To date, though, intervention methods and measures remain controversial. In order to understand the mechanism of MTCT intervention further and develop effective preventions and interventions, a comprehensive analysis and presentation on some of its more controversial issues will be given in this paper. And eventually we conclude three measures and strategies for these issues: (1) emancipate the mind and seek truth from facts to understand the controversial issues pertaining to MTCT of HBV; (2) treat the basic rules and changing characteristics of MTCT blocking process of hepatitis B with holistic medical thought dialectically and (3) further explore the interaction of genetic susceptibility and environmental factors of MTCT of hepatitis B. PMID- 27119535 TI - Generation of an Oocyte-Specific Cas9 Transgenic Mouse for Genome Editing. AB - The CRISPR/Cas9 system has been developed as an easy-handle and multiplexable approach for engineering eukaryotic genomes by zygote microinjection of Cas9 and sgRNA, while preparing Cas9 for microinjection is laborious and introducing inconsistency into the experiment. Here, we describe a modified strategy for gene targeting through using oocyte-specific Cas9 transgenic mouse. With this mouse line, we successfully achieve precise gene targeting by injection of sgRNAs only into one-cell-stage embryos. Through comprehensive analysis, we also show allele complexity and off-target mutagenesis induced by this strategy is obviously lower than Cas9 mRNA/sgRNA injection. Thus, injection of sgRNAs into oocyte-specific Cas9 transgenic mouse embryo provides a convenient, efficient and reliable approach for mouse genome editing. PMID- 27119537 TI - Protecting women's health. PMID- 27119536 TI - Real-Time Predictions of Reservoir Size and Rebound Time during Antiretroviral Therapy Interruption Trials for HIV. AB - Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients-between 40 and 150-will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two "Boston patients", recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir. PMID- 27119538 TI - Scrapping bursaries: we must learn from the past. PMID- 27119539 TI - Assessment, diagnosis and treatment of urinary incontinence in women. AB - This article gives an overview of female urinary incontinence including the symptoms, diagnosis and treatment of stress urinary incontinence and overactive bladder syndrome. It summarises recent guidelines, the role of the nurse in conservative management and when a referral for specialist care is required. It aims to encourage nurses to use all opportunities to identify women who have urinary incontinence then to assess and treat urinary incontinence effectively. All patients should receive a full continence assessment. National Institute for Health and Care Excellence guidelines recommend conservative treatments including lifestyle advice, pelvic floor exercises and bladder retraining. Nurses may need to access training from their local specialist continence nurse service to enable them to provide evidence-based care. This article concludes that equitable, integrated continence services are essential to improve the quality of care for people with continence problems. PMID- 27119540 TI - Excellence in continence care: an overview. PMID- 27119541 TI - Airway management in the hospital environment. AB - In the hospital environment, patients can deteriorate rapidly and for many different reasons. Maintaining a patient's breathing is the main priority in any emergency situation, although achieving airway control can be difficult. All health professionals need to be able to undertake airway management safely. The key is a thorough assessment to ensure first of all whether the airway is patent (open and clear) or not. This article will discuss airway management, both acute and chronic, as well as associated nursing care. PMID- 27119542 TI - Wound exudate: a survey of current understanding and clinical competency. AB - A survey was undertaken with the aim of identifying health professionals' understanding of wound exudate and their ability to assess and manage it. The survey was carried out at Wound Expo, which is a large annual event that provides generalist nurses with interactive education on the core aspects of wound care, including wound exudate. The sample comprised 223 delegates. Almost all delegates (89%) included exudate in every wound assessment, but only 20% based assessment of excess exudate on colour, viscosity and malodour, with the majority (67%) basing it on leakage and increased frequency of dressing changes. While almost all (94%) delegates said they always assess exudate colour and most (80%) that they always assess its viscosity, 18% did not understand the clinical significance of exudate colour and 29% were unable to correctly identify the characteristics of low-viscosity exudate. Furthermore, one quarter of the sample did not always take absorbency into account when selecting a wound dressing. The results indicate that exudate assessment is often subjective, and there is scope for greater use of wound exudate assessment tools and exudate descriptors. PMID- 27119543 TI - Working towards widening participation in nurse education. AB - The widening participation agenda has particular significance for worldwide nursing since it is a profession which is under increasing scrutiny in its recruitment and retention practices. Debate about this agenda within nurse education is strengthened by careful scrutiny of the research within the wider context of higher education, some of which challenges commonly held assumptions. This paper examines four areas of relevance to the UK widening participation agenda: disability, ethnicity, socioeconomic status and family responsibilities. Taken together, they indicate that nurse education operates within a particularly complex context with some important implications for the future design of pre registration programmes. These complexities should be debated in depth by educational commissioners and providers, in tandem with regulatory bodies. PMID- 27119544 TI - Education for excellence in professional nursing practice. PMID- 27119545 TI - Moving into second year: hitting the ground running. PMID- 27119546 TI - Women's health in the UK: addressing the risks and overcoming taboos. PMID- 27119547 TI - Patients' experiences of using hospital services. PMID- 27119548 TI - From staff nurse to nurse consultant. PMID- 27119549 TI - Nursing associates are not the answer. PMID- 27119550 TI - An enzyme-free catalytic DNA circuit for amplified detection of aflatoxin B1 using gold nanoparticles as colorimetric indicators. AB - An enzyme-free biosensor for the amplified detection of aflatoxin B1 has been constructed based on a catalytic DNA circuit. Three biotinylated hairpin DNA probes (H1, H2, and H3) were designed as the assembly components to construct the sensing system (triplex H1-H2-H3 product). Cascaded signal amplification capability was obtained through toehold-mediated strand displacement reactions to open the hairpins and recycle the trigger DNA. By the use of streptavidin functionalized gold nanoparticles as the signal indicators, the colorimetric readout can be observed by the naked eye. In the presence of a target, the individual nanoparticles (red) aggregate into a cross-linked network of nanoparticles (blue) via biotin-streptavidin coupling. The colorimetric assay is ultrasensitive, enabling the visual detection of trace levels of aflatoxin B1 (AFB1) as low as 10 pM without instrumentation. The calculated limit of detection (LOD) is 2 pM in terms of 3 times standard deviation over the blank response. The sensor is robust and works even when challenged with complex sample matrices such as rice samples. Our sensing platform is simple and convenient in operation, requiring only the mixing of several solutions at room temperature to achieve visible and intuitive results, and holds great promise for the point-of-use monitoring of AFB1 in environmental and food samples. PMID- 27119552 TI - Automated quantification of one-dimensional nanostructure alignment on surfaces. AB - A method for automated quantification of the alignment of one-dimensional (1D) nanostructures from microscopy imaging is presented. Nanostructure alignment metrics are formulated and shown to be able to rigorously quantify the orientational order of nanostructures within a two-dimensional domain (surface). A complementary image processing method is also presented which enables robust processing of microscopy images where overlapping nanostructures might be present. Scanning electron microscopy (SEM) images of nanowire-covered surfaces are analyzed using the presented methods and it is shown that past single parameter alignment metrics are insufficient for highly aligned domains. Through the use of multiple parameter alignment metrics, automated quantitative analysis of SEM images is shown to be possible and the alignment characteristics of different samples are able to be quantitatively compared using a similarity metric. The results of this work provide researchers in nanoscience and nanotechnology with a rigorous method for the determination of structure/property relationships, where alignment of 1D nanostructures is significant. PMID- 27119551 TI - HIPPO-Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension. AB - RATIONALE: Enhanced proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiologic components of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). OBJECTIVES: To determine the role and therapeutic relevance of HIPPO signaling in PAVSMC proliferation/apoptosis imbalance in PAH. METHODS: Primary distal PAVSMCs, lung tissue sections from unused donor (control) and idiopathic PAH lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. MEASUREMENTS AND MAIN RESULTS: Immunohistochemical and immunoblot analyses demonstrated that the HIPPO central component large tumor suppressor 1 (LATS1) is inactivated in small remodeled pulmonary arteries (PAs) and distal PAVSMCs in idiopathic PAH. Molecular- and pharmacology-based analyses revealed that LATS1 inactivation and consequent up-regulation of its reciprocal effector Yes-associated protein (Yap) were required for activation of mammalian target of rapamycin (mTOR)-Akt, accumulation of HIF1alpha, Notch3 intracellular domain and beta-catenin, deficiency of proapoptotic Bim, increased proliferation, and survival of human PAH PAVSMCs. LATS1 inactivation and up-regulation of Yap increased production and secretion of fibronectin that up-regulated integrin-linked kinase 1 (ILK1). ILK1 supported LATS1 inactivation, and its inhibition reactivated LATS1, down regulated Yap, suppressed proliferation, and promoted apoptosis in PAH, but not control PAVSMCs. PAVSM in small remodeled PAs from rats and mice with SU5416/hypoxia-induced PH showed down-regulation of LATS1 and overexpression of ILK1. Treatment of mice with selective ILK inhibitor Cpd22 at Days 22-35 of SU5416/hypoxia exposure restored LATS1 signaling and reduced established pulmonary vascular remodeling and PH. CONCLUSIONS: These data report inactivation of HIPPO/LATS1, self-supported via Yap-fibronectin-ILK1 signaling loop, as a novel mechanism of self-sustaining proliferation and apoptosis resistance of PAVSMCs in PAH and suggest a new potential target for therapeutic intervention. PMID- 27119553 TI - Metal-Organic Polyhedral Core as a Versatile Scaffold for Divergent and Convergent Star Polymer Synthesis. AB - We herein report the divergent and convergent synthesis of coordination star polymers (CSP) by using metal-organic polyhedrons (MOPs) as a multifunctional core. For the divergent route, copper-based great rhombicuboctahedral MOPs decorated with dithiobenzoate or trithioester chain transfer groups at the periphery were designed. Subsequent reversible addition-fragmentation chain transfer (RAFT) polymerization of monomers mediated by the MOPs gave star polymers, in which 24 polymeric arms were grafted from the MOP core. On the other hand, the convergent route provided identical CSP architectures by simple mixing of a macroligand and copper ions. Isophthalic acid-terminated polymers (so-called macroligands) immediately formed the corresponding CSPs through a coordination reaction with copper(II) ions. This convergent route enabled us to obtain miktoarm CSPs with tunable chain compositions through ligand mixing alone. This powerful method allows instant access to a wide variety of multicomponent star polymers that conventionally have required highly skilled and multistep syntheses. MOP-core CSPs are a new class of star polymer that can offer a design strategy for highly processable porous soft materials by using coordination nanocages as a building component. PMID- 27119554 TI - Protective effects of PARP inhibitor, PJ34, is related to down-regulation of calpain and NF-kappaB in a mouse model of TBI. AB - BACKGROUND: Poly(ADP-ribose) polymerase (PARP), calpain and nuclear factor-kappaB (NF-kappaB) are reported to participate in inflammatory reactions in pathological conditions and are involved in traumatic brain injury. The objective of this study was to investigate whether PARP participated in inflammation related to calpain and NF-kappaB in a mouse model of controlled cortical impact (CCI). MATERIALS AND METHODS: PJ34 (10 mg kg-1), a selective PARP inhibitor, was administered intraperitoneally 5 minutes and 8 hours after experimental CCI. A neurobehavioural evaluation and a histopathological analysis were then performed and the contusion volume, calpain activity and protein levels were measured in all animals. RESULTS: Treatment with PJ34 markedly reduced neurological deficits, decreased contusion volume and attenuated necrotic and apoptotic neuronal cell death 24 hours after CCI. The data showed that the cytosolic and nuclear fractions of calpain and NF-kappaB were up-regulated in the injured cortex and that these changes were reversed by PJ34. Moreover, PJ34 significantly enhanced the calpastatin and IkappaB levels and decreased the levels of inflammatory mediators. CONCLUSIONS: PARP inhibition by PJ34 suppresses the over-activation of calpain and the production of inflammatory factors that are caused by NF-kappaB activation and it improves neurological functioning, decreases the contusion volume and attenuates neuronal cell death in a mouse model of CCI. PMID- 27119556 TI - Absorption and electrochromic modulation of near-infrared light: realized by tungsten suboxide. AB - In the present study, needle-like tungsten suboxide W18O49 nanocrystals were fabricated as the optical active substance to realize the aim of optical control of near-infrared light. The W18O49 nanocrystals were selected in this regard due to their unique optical performance. As revealed by the powder absorption result, the needle-like W18O49 nanocrystals show strong and wide photoabsorption in the entire near infrared region of 780-2500 nm, from which thin films with the W18O49 nanocrystal coating thus benefits and can strongly shield off almost all near infrared irradiation, whereas transmitting the majority of visible light. To make it more tunable, the W18O49 nanocrystals were finally assembled onto an ITO glass via the layer-by-layer strategy for later electrochromic investigation. The nanostructured architectures of the W18O49 nanocrystal electrochromic films exhibit high contrast, faster switching response, higher coloration efficiencies (150 cm(2) C(-1) at 650 nm and 255 cm(2) C(-1) at 1300 nm), better long-term redox switching stability (reversibility of 98% after 500 cycles) and wide electrochromic spectrum coverage of both the visible and infrared regions. PMID- 27119555 TI - Expression of CD11c Is Associated with Unconventional Activated T Cell Subsets with High Migratory Potential. AB - CD11c is an alpha integrin classically employed to define myeloid dendritic cells. Although there is little information about CD11c expression on human T cells, mouse models have shown an association of CD11c expression with functionally relevant T cell subsets. In the context of genital tract infection, we have previously observed increased expression of CD11c in circulating T cells from mice and women. Microarray analyses of activated effector T cells expressing CD11c derived from naive mice demonstrated enrichment for natural killer (NK) associated genes. Here we find that murine CD11c+ T cells analyzed by flow cytometry display markers associated with non-conventional T cell subsets, including gammadelta T cells and invariant natural killer T (iNKT) cells. However, in women, only gammadelta T cells and CD8+ T cells were enriched within the CD11c fraction of blood and cervical tissue. These CD11c+ cells were highly activated and had greater interferon (IFN)-gamma secretory capacity than CD11c- T cells. Furthermore, circulating CD11c+ T cells were associated with the expression of multiple adhesion molecules in women, suggesting that these cells have high tissue homing potential. These data suggest that CD11c expression distinguishes a population of circulating T cells during bacterial infection with innate capacity and mucosal homing potential. PMID- 27119557 TI - Blind Flight? A New Troglobiotic Orthoclad (Diptera, Chironomidae) from the Lukina Jama - Trojama Cave in Croatia. AB - The genus Troglocladius Andersen, Baranov et Hagenlund, gen. n. is erected based on T. hajdi Andersen, Baranov et Hagenlund, sp. n. collected at 980 m depth in the Lukina jama-Trojama cave system in Croatia. Morphological features such as pale color, strongly reduced eyes and very long legs make it a typical cave animal. Surprisingly, it has also retained large wings and appears to be capable of flight which would make T. hajdi the first flying troglobiont worldwide, disproving previous beliefs that bats are the only animals capable of flying in complete darkness. Morphologically the new species does not readily fit within any described genus, but shares characteristics with genera both in the tribes "Metriocnemini" and "Orthocladiini". Bayesian molecular phylogenetic analysis using the markers COI, 18S rDNAs, 28S rDNA, CADI, and CADIV groups it with the genera Tvetenia, Cardiocladius and Eukiefferiella in the tribe "Metriocnemini". Troglocladius hajdi may be parthenogenetic, as only females were collected. The discovery confirms the position of the Dinaric arch as a highly important hotspot of subterranean biodiversity. PMID- 27119562 TI - Understanding SO2 Capture by Ionic Liquids. AB - Ionic liquids have generated interest for efficient SO2 absorption due to their low vapor pressure and versatility. In this work, a systematic investigation of the structure, thermodynamics, and dynamics of SO2 absorption by ionic liquids has been carried out through quantum chemical calculations and molecular dynamics (MD) simulations. MP2 level calculations of several ion pairs complexed with SO2 reveal its preferential interaction with the anion. Results of condensed phase MD simulations of SO2-IL mixtures manifested the essential role of both cations and anions in the solvation of SO2, where the solute is surrounded by the "cage" formed by the cations (primarily its alkyl tail) through dispersion interactions. These structural effects of gas absorption are substantiated by calculated Gibbs free energy of solvation; the dissolution is demonstrated to be enthalpy driven. The entropic loss of SO2 absorption in ionic liquids with a larger anion such as [NTf2](-) has been quantified and has been attributed to the conformational restriction of the anion imposed by its interaction with SO2. SO2 loading IL decreases its shear viscosity and enhances the electrical conductivity. This systematic study provides a molecular level understanding which can aid the design of task-specific ILs as electrolytes for efficient SO2 absorption. PMID- 27119558 TI - Tumor Content Chart-Assisted HER2/CEP17 Digital PCR Analysis of Gastric Cancer Biopsy Specimens. AB - Evaluating HER2 gene amplification is an essential component of therapeutic decision-making for advanced or metastatic gastric cancer. A simple method that is applicable to small, formalin-fixed, paraffin-embedded biopsy specimens is desirable as an adjunct to or as a substitute for currently used HER2 immunohistochemistry and in situ hybridization protocols. In this study, we developed a microfluidics-based digital PCR method for determining HER2 and chromosome 17 centromere (CEP17) copy numbers and estimating tumor content ratio (TCR). The HER2/CEP17 ratio is determined by three variables-TCR and absolute copy numbers of HER2 and CEP17-by examining tumor cells; only the ratio of the latter two can be obtained by digital PCR using the whole specimen without purifying tumor cells. TCR was determined by semi-automatic image analysis. We developed a Tumor Content chart, which is a plane of rectangular coordinates consisting of HER2/CEP17 digital PCR data and TCR that delineates amplified, non amplified, and equivocal areas. By applying this method, 44 clinical gastric cancer biopsy samples were classified as amplified (n = 13), non-amplified (n = 25), or equivocal (n = 6). By comparison, 11 samples were positive, 11 were negative, and 22 were equivocally immunohistochemistry. Thus, our novel method reduced the number of equivocal samples from 22 to 6, thereby obviating the need for confirmation by fluorescence or dual-probe in situ hybridization to < 30% of cases. Tumor content chart-assisted digital PCR analysis is also applicable to multiple sites in surgically resected tissues. These results indicate that this analysis is a useful alternative to HER2 immunohistochemistry in gastric cancers that can serve as a basis for the automated evaluation of HER2 status. PMID- 27119563 TI - An open-source computational tool to automatically quantify immunolabeled retinal ganglion cells. AB - A fully automated and robust method was developed to quantify beta-III-tubulin stained retinal ganglion cells, combining computational recognition of individual cells by CellProfiler and a machine-learning tool to teach phenotypic classification of the retinal ganglion cells by CellProfiler Analyst. In animal models of glaucoma, quantification of immunolabeled retinal ganglion cells is currently performed manually and remains time-consuming. Using this automated method, quantifications of retinal ganglion cell images were accelerated tenfold: 1800 images were counted in 3 h using our automated method, while manual counting of the same images took 72 h. This new method was validated in an established murine model of microbead-induced optic neuropathy. The use of the publicly available software and the method's user-friendly design allows this technique to be easily implemented in any laboratory. PMID- 27119564 TI - A Highly Effective Protocol for the Rapid and Consistent Induction of Digital Dermatitis in Holstein Calves. AB - Bovine Digital Dermatitis (DD) is a leading cause of lameness in dairy cattle. DD is reportedly increasing in prevalence in beef cattle feedlots of the US. The exact etiologic agent(s) responsible for the disease have yet to be determined. Multiple studies have demonstrated the presence of a variety of Treponema spp. within lesions. Attempts to reproduce clinically relevant disease using pure cultures of these organisms has failed to result in lesions that mirror the morphology and severity of naturally occurring lesions. This manuscript details the systematic development of an experimental protocol that reliably induces digital dermatitis lesions on a large enough scale to allow experimental evaluation of treatment and prevention measures. In total, 21 protocols from five experiments were evaluated on their effectiveness in inducing DD lesions in 126 Holstein calves (504 feet). The protocols varied in the type and concentration of inoculum, frequency of inoculation, duration the feet were wrapped, and type of experimental controls need to validate a successful induction. Knowledge gained in the first four experiments resulted in a final protocol capable of inducing DD lesions in 42 of 44 (95%) feet over a 28 day period. All induced lesions were macroscopically and microscopically identified as clinical DD lesions by individuals blinded to protocols. Lesions were also located at the site of inoculation in the palmer aspect of the interdigital space, and induced clinically measurable lameness in a significant portion of the calves. Collectively these results validate the model and provide a rapid and reliable means of inducing DD in large groups of calves. PMID- 27119565 TI - Clinicopathological Factors Associated with Recurrence and Prognosis after R0 Resection for Stage IV Colorectal Cancer with Peritoneal Metastasis. AB - BACKGROUND/AIMS: Peritoneal metastasis (PM) is a well-known predictor of poor prognosis. This study aims at identifying factors affecting recurrence and prognosis after R0 resection for colorectal cancer (CRC) with synchronous PM. METHODS: A multi-institutional, retrospective analysis of 172 patients with R0 surgery for CRC with PM was conducted. Clinicopathological variables were analyzed for their significance in contributing toward recurrence and prognosis. RESULTS: Lymph node (LN) metastasis was an independent factor affecting recurrence as indicated by logistic regression analyses. The following factors were independent predictors of poor prognostic using the Cox proportional hazard model: LN metastasis, no postoperative adjuvant chemotherapy, five or fewer dissected LNs, and preoperative high serum carbohydrate antigen 19-9 levels. Of the patients undergoing postoperative adjuvant chemotherapy, no significant differences were observed in recurrence rate and disease-free interval between those with intensive adjuvant chemotherapy and those with non-intensive chemotherapy. After R0 surgery for PM, 90 patients (76.3%) experienced recurrence by 18 months, and hematogenous recurrence occurred significantly more often than peritoneal recurrence. CONCLUSION: Harvesting of more than 5 LNs and administration of postoperative adjuvant chemotherapy after R0 surgery are recommended for prognosis improvement. Intensive follow-up should be performed within 18 months after R0 surgery for CRC with synchronous PM. PMID- 27119566 TI - Robert J. Suhadolnik (1925-2016). PMID- 27119567 TI - IL-27 Promotes Proliferation of Human Leukemic Cell Lines Through the MAPK/ERK Signaling Pathway and Suppresses Sensitivity to Chemotherapeutic Drugs. AB - IL-27 is a pleiotropic cytokine of the IL-6/IL-12 family with diverse biological functions. Previous in vivo studies have suggested the antitumor activities of IL 27 in animal models, whereas clinical observations indicate the link of IL-27 in tumor progression. IL-27 has recently been shown to cause inhibition of proliferation on primary leukemic cells from pediatric patients, but information on its role in human leukemic cell lines is limited. In the present study, we investigated the ability of IL-27 to regulate cell growth and survival of various human leukemic cell lines. Our results showed that in human leukemic cell lines coexpressing both IL-27R chains, IL-27Ralpha and gp130, IL-27 did not inhibit cell growth, but caused dose-dependent proliferation of the acute myeloid leukemic cell line, OCI-AML5, and the erythroleukemic cell lines, TF-1, UT-7, and UT-7/EPO. Consistent with this, IL-27 promoted cell survival and reduced TNF alpha-induced apoptosis of the leukemic cell lines. IL-27 also decreased the responsiveness of the leukemic cells to chemotherapeutic drugs, cytarabine and daunorubicin. We observed that IL-27 induced the activation of STAT1/3 and ERK1/2 in the leukemic cells. Growth stimulation by IL-27 was suppressed by the specific MEK inhibitor, U0126, indicating that IL-27-induced cell proliferation is mainly mediated through the activation of the MAPK/ERK signaling pathway. The present study is the first demonstration of the proliferative and antichemotherapeutic properties of IL-27 in human leukemic cell lines, suggesting that IL-27 can play an unfavorable role in tumor growth and can be an important determinant in the chemoresponsiveness of certain subtypes of human leukemia. PMID- 27119568 TI - Lactate Stimulates IL-4 and IL-13 Production in Activated HuT-78 T Lymphocytes Through a Process That Involves Monocarboxylate Transporters and Protein Hyperacetylation. AB - Mucosal cells of the gastrointestinal and female reproductive tract are constantly exposed to l- and d-lactate of bacterial origin. These compounds not only protect the host from pathogen colonization but also modulate the activity of mucosal immune cells, thereby playing an important role in inflammatory host responses. In this study, we demonstrated that exposure of anti-CD3/CD28 or phorbol 12-myristate 13-acetate (PMA)/ionomycin-activated HuT-78 T lymphocyte cells to 10-20 mM d-lactate significantly increased IL-4 and IL-13 production. Interestingly, the d-lactate isomer, exclusively produced locally by gut or cervicovaginal microbiota, was found to be more potent than the l-isomer. Interestingly, neither of the strong histone deacetylase inhibitors [structurally similar butyrate and suberoylanilide hydroxamic acid (SAHA)] was as effective in the stimulation of IL-13 production as d-lactate. Lactate transport through monocarboxylate transporters was required for lactate-enhanced IL-13 production in a manner that was not hydroxycarboxylic acid receptor 1-dependent. Furthermore, lactate treatment increased the acetylation of GATA-3, a critical regulator of Th1/Th2 differentiation and resulted in H3 and H4 histone hyperacetylation state, which is a characteristic feature of transcriptionally active chromatin. Both lactate isomers also enhanced IL4 and IL13 promoter-driven activity of reporter constructs in murine and human cells. Together, these findings demonstrate that a local millimolar concentration of l- or d-lactate may play an important role in the modulation of inflammation-mediated processes. PMID- 27119569 TI - Biomechanical and organisational stressors and associations with employment withdrawal among pregnant workers: evidence and implications. AB - The distribution of exposure to biomechanical and organisational job stressors (BOJS) and associations with employment withdrawal (antenatal leave, unemployment) was examined in a case-control study of 1114 pregnant workers in California. We performed descriptive and multivariate logistic and multinomial regression analyses. At pregnancy onset, 57% were exposed to one or more biomechanical stressors, including frequent bending, heavy lifting and prolonged standing. One-third were simultaneously exposed to BOJS. Exposure to biomechanical stressors declined as pregnancy progressed and cessation often (41%) coincided with employment withdrawal (antenatal leave and unemployment). In multivariate modelling, whether we adjusted for or considered organisational stressors as coincident exposures, results showed that pregnant workers exposed to biomechanical stressors had increased employment withdrawal compared to the unexposed. Work schedule accommodations moderate this association. Paid antenatal leave, available to few US women, was an important strategy for mitigating exposure to BOJS. Implications for science and policy are discussed. Practitioner Summary: This case-control study showed that exposure to biomechanical stressors decline throughout pregnancy. Antenatal leave was an important strategy used for mitigating exposure among sampled California women with access to paid benefits. Employment withdrawal among workers exposed to BJOS may be reduced by proactive administrative and engineering efforts applied early in pregnancy. PMID- 27119573 TI - Difluorocarbene Addition to Alkenes and Alkynes in Continuous Flow. AB - The first in-flow difluorocarbene generation and addition to alkenes and alkynes is reported. The application of continuous flow technology allowed for the controlled generation of difluorocarbene from TMSCF3 and a catalytic quantity of NaI. The in situ generated electrophilic carbene reacts smoothly with a broad range of alkenes and alkynes, allowing the synthesis of the corresponding difluorocyclopropanes and difluorocyclopropenes. The reaction is complete within a 10 min residence time at high reaction concentrations. With a production flow rate of 1 mmol/min, continuous flow chemistry enables scale up of this process in a green, atom-economic, and safe manner. PMID- 27119571 TI - Communication Tools for End-of-Life Decision-Making in Ambulatory Care Settings: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Patients with serious illness, and their families, state that better communication and decision-making with healthcare providers is a high priority to improve the quality of end-of-life care. Numerous communication tools to assist patients, family members, and clinicians in end-of-life decision-making have been published, but their effectiveness remains unclear. OBJECTIVES: To determine, amongst adults in ambulatory care settings, the effect of structured communication tools for end-of-life decision-making on completion of advance care planning. METHODS: We searched for relevant randomized controlled trials (RCTs) or non-randomized intervention studies in MEDLINE, EMBASE, CINAHL, ERIC, and the Cochrane Database of Randomized Controlled Trials from database inception until July 2014. Two reviewers independently screened articles for eligibility, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to evaluate the quality of evidence for each of the primary and secondary outcomes. RESULTS: Sixty-seven studies, including 46 RCTs, were found. The majority evaluated communication tools in older patients (age >50) with no specific medical condition, but many specifically evaluated populations with cancer, lung, heart, neurologic, or renal disease. Most studies compared the use of communication tools against usual care, but several compared the tools to less-intensive advance care planning tools. The use of structured communication tools increased: the frequency of advance care planning discussions/discussions about advance directives (RR 2.31, 95% CI 1.25 4.26, p = 0.007, low quality evidence) and the completion of advance directives (ADs) (RR 1.92, 95% CI 1.43-2.59, p<0.001, low quality evidence); concordance between AD preferences and subsequent medical orders for use or non-use of life supporting treatment (RR 1.19, 95% CI 1.01-1.39, p = 0.028, very low quality evidence, 1 observational study); and concordance between the care desired and care received by patients (RR 1.17, 95% CI 1.05-1.30, p = 0.004, low quality evidence, 2 RCTs). CONCLUSIONS: The use of structured communication tools may increase the frequency of discussions about and completion of advance directives, and concordance between the care desired and the care received by patients. The use of structured communication tools rather than an ad-hoc approach to end-of life decision-making should be considered, and the selection and implementation of such tools should be tailored to address local needs and context. REGISTRATION: PROSPERO CRD42014012913. PMID- 27119574 TI - Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H1 and H2 Antagonists. AB - Knowledge about the history and development of therapeutic agents holds a central position in the education and training of pharmacists and pharmacologists. Students enjoy learning about the discovery of drugs, including details about the pioneer workers involved (apothecaries, organic chemists, pharmacologists, and physiologists) and the role played by serendipity. The treatment of people suffering from allergies and the development of drugs that block the actions of histamine at H1 and H2 receptors are the subject of this review. Pharmaceutical products that block H1 receptors are widely used as prophylactic treatment for seasonal allergies that plague millions of people worldwide. The development of H2 receptor antagonists revolutionized treatment of gastric hyperacidity, the principal cause of peptic ulcers. Antihistamine research has changed focus toward the development of drugs that block the action of histamine at H3 and H4 receptors and the therapeutic potential is gradually being appreciated. PMID- 27119575 TI - Safety, pharmacokinetics, and pharmacodynamics of PD 0348292, an oral, direct factor Xa inhibitor, after single and multiple dosings in healthy subjects. AB - OBJECTIVE: The objective of this study was to evaluate PD 0348292 safety, pharmacokinetics, and pharmacodynamics in healthy subjects. METHODS: Three phase 1 studies were conducted. Studies 1001 and 1021 were single ascending-dose studies in healthy subjects randomized to oral PD 0348292 (2.5-150 and 0.1-2.5 mg, respectively) or placebo. Study 1003 was a multiple ascending-dose study in which 3 cohorts of young subjects received multiple doses of PD 0348292 (5-30 mg) every 12 hours or placebo, and 1 cohort of elderly subjects received a single dose (5 mg) of PD 0348292 or placebo. Drug plasma concentrations were measured. The effects of PD 0348292 on thrombin generation and typical coagulation measures such as prothrombin time, and international normalized ratio were evaluated. RESULTS: Single doses of PD 0348292 were well tolerated. Minor bleeding-related adverse events were observed following multiple doses of PD 0348292. PD 0348292 exposure increased less than proportionally at doses > 20 mg. Median peak concentrations occurred 3 to 4 hours following administration, and the mean terminal t1/2 value was approximately 10 hours. PD 0348292 demonstrated robust and concentration-dependent inhibition of thrombin generation, and modest and dose-related increases in typical coagulation measures. CONCLUSIONS: The safety, pharmacokinetics, and pharmacodynamics of PD 0348292 were acceptable for future clinical development. PMID- 27119576 TI - Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel ethinyl estradiol in healthy subjects. AB - LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 MUg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. PMID- 27119577 TI - Population pharmacokinetic modeling and noncompartmental analysis demonstrated bioequivalence between metformin component of metformin/vildagliptin fixed-dose combination products and metformin immediate-release tablet sourced from various countries. AB - Metformin is the first-line pharmacotherapy choice for treating type-2 diabetes mellitus, alone or in combination with other antidiabetic drugs. During the development of immediate-release (IR) metformin containing novel fixed-dose combination (FDC) products, several health-authorities require sponsors to demonstrate bioequivalence between FDC products and the country-sourced metformin for market approval. Eight bioequivalence studies that compared metformin/vildagliptin FDC product (test) to metformin IR tablet sourced from various countries (reference) were conducted. A population pharmacokinetic (PPK) analysis of pooled metformin concentration-time data was performed to evaluate whether country-sourced metformin is a significant covariate. The PPK analysis demonstrated that there was no clinically relevant effect of metformin source or race/ethnicity on metformin pharmacokinetics. Also, noncompartmental analysis conducted showed that 90%CI of geometric mean ratios of test to reference metformin formulations, calculated for maximum-concentration and exposure parameters, were within the 80%-125% criteria, indicating comparable metformin exposure regardless of the country-sourced metformin IR formulation. These results are consistent with the biopharmaceutics properties of metformin and provide scientific evidence that after assessing in vitro dissolution of novel FDC formulation, additional bioequivalence studies with multiple countries' reference products may not be required once bioequivalence is established with 1 country-sourced IR metformin formulation. PMID- 27119578 TI - Essential criteria for pharmacokinetic studies supporting bioequivalence of inhaled tiotropium bromide products. PMID- 27119579 TI - Tolerability, safety, and pharmacokinetics of the novel cathepsin A inhibitor SAR164653 in healthy subjects. AB - Cathepsin A (CathA) is a lysosomal protein where it forms a stable complex with neuraminidase and beta-galactosidase. CathA also has enzymatic activity and is involved in the degradation of many peptides. CathA was recently discovered as a target for heart failure, fostering the development of CathA inhibitors with SAR164653 as a frontrunner. The first-in-man study investigated single oral doses from 20 to 800 mg of SAR164653 followed by repeat dose studies at doses up to 800 mg in healthy young and elderly subjects. SAR164653 was safe and well tolerated at doses up to 800 mg in healthy subjects, and a maximum tolerated dose could not be determined from the study. Activity of beta-galactosidase measured in leukocytes did not show any abnormalities. The tmax was 1.0 to 2.5 hours, and the t1/2 was ~5-11 after single dosing; exposure increased less than dose proportional. Following multiple dosing, accumulation was not observed, Cmax and AUC0-24 increased in a dose-proportional manner, and t1/2 was around 14-20 hours. The novel CathA inhibitor SAR164653 was found to have a favorable safety profile in these early phase 1 studies, but further studies are required to confirm if SAR164653 is equally safe in patients undergoing long-term treatment. PMID- 27119580 TI - Bioequivalence and comparative pharmacodynamics of insulin lispro 200 U/mL relative to insulin lispro (Humalog(r)) 100 U/mL. AB - Insulin lispro 200 U/mL (IL200) is a new strength formulation of insulin lispro (Humalog(r), IL100), developed as an option for diabetic patients on higher daily mealtime insulin doses. This phase 1, open-label, 2-sequence, 4-period crossover, randomized, 8-hour euglycemic clamp study aimed to demonstrate the bioequivalence of IL200 and IL100 after subcutaneous administration of 20 U (U) to healthy subjects (n = 38). Pharmacokinetic (PK) and pharmacodynamic (PD) responses were similar in both formulations. All 90%CIs for the ratios of area under the concentration-versus-time curve from time zero to the time of the last measurable concentration (AUC0-tlast) and maximum observed drug concentration (Cmax), as well as the total glucose infused throughout the clamp (Gtot) and the maximum glucose infusion rate (Rmax), were contained within 0.80 and 1.25. Time of maximum observed drug concentration (tmax) was similar between formulations, with a median difference of 15 minutes and a 95%CI of the difference that included zero. Inter- and intrasubject variability estimates were similar for both formulations. Both formulations were well tolerated. IL200 was bioequivalent to IL100 after subcutaneous administration of 20-U single doses, and PD responses were comparable between formulation strengths. PMID- 27119581 TI - Relative bioavailability of diclofenac potassium from softgel capsule versus powder for oral solution and immediate-release tablet formulation. AB - The oral bioavailability of diclofenac potassium 50 mg administered as a soft gelatin capsule (softgel capsule), powder for oral solution (oral solution), and tablet was evaluated in a randomized, open-label, 3-period, 6-sequence crossover study in healthy adults. Plasma diclofenac concentrations were measured using a validated liquid chromatography-mass spectrometry/mass spectrometry method, and pharmacokinetic analysis was performed by noncompartmental methods. The median time to achieve peak plasma concentrations of diclofenac was 0.5, 0.25, and 0.75 hours with the softgel capsule, oral solution, and tablet formulations, respectively. The geometric mean ratio and associated 90%CI for AUCinf, and Cmax of the softgel capsule formulation relative to the oral solution formulation were 0.97 (0.95-1.00) and 0.85 (0.76-0.95), respectively. The geometric mean ratio and associated 90%CI for AUCinf and Cmax of the softgel capsule formulation relative to the tablet formulation were 1.04 (1.00-1.08) and 1.67 (1.43-1.96), respectively. In conclusion, the exposure (AUC) of diclofenac with the new diclofenac potassium softgel capsule formulation was comparable to that of the existing oral solution and tablet formulations. The peak plasma concentration of diclofenac from the new softgel capsule was 67% higher than the existing tablet formulation, whereas it was 15% lower in comparison with the oral solution formulation. PMID- 27119584 TI - Insights into mechanism of pyrido[2,3-d]pyrimidines as DYRK1A inhibitors based on molecular dynamic simulations. AB - DYRK1A is characterized by the early development and regulation of neuronal proliferation, and its over expression gives rise to neurological abnormalities. As the promising DYRK1A inhibitors, the binding mechanism between DYRK1A and pyrido[2,3-d]pyrimidines derivatives at molecular level are still veiled. In this article, it was achieved to get the structural insights into pyrido[2,3 d]pyrimidines derivatives as DYRK1A inhibitors by means of comprehensive computational approaches involving molecular docking, molecular dynamics simulation, free energy calculation, and energy decomposition analysis. The calculated energy values were highly consistent with the experimental activities. Based on the individual energy terms analysis, the van der Waals interaction was the major leading force in the DYRK1A-ligand interaction. Lys188 was the important residue that formed the hydrogen bond, which improved the inhibitory activity. Furthermore, four novel inhibitors with higher predicted activity were designed based on the obtained findings and confirmed by molecular simulations. Our study is expected to provide significant drug design strategy for the development of more promising DYRK1A inhibitors. Proteins 2016; 84:1108-1123. (c) 2016 Wiley Periodicals, Inc. PMID- 27119583 TI - The Natural History of Changes in Preferences for Life-Sustaining Treatments and Implications for Inpatient Mortality in Younger and Older Hospitalized Adults. AB - OBJECTIVES: To compare changes in preferences for life-sustaining treatments (LSTs) and subsequent mortality of younger and older inpatients. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Northern California (KPNC). PARTICIPANTS: Individuals hospitalized at 21 KPNC hospitals between 2008 and 2012 (N = 227,525). MEASUREMENTS: Participants were divided according to age (<65, 65-84, >=85). The effect of age on adding new and reversing prior LST limitations was evaluated. Survival to inpatient discharge was compared according to age group after adding new LST limitations. RESULTS: At admission, 18,254 (54.2%) of those aged 85 and older, 18,349 (20.8%) of those aged 65 to 84, and 3,258 (3.1%) of those younger than 65 had requested that the use of LST be limited. Of the 187,664 participants who initially did not request limitations on the use of LST, 15,932 (8.5%) had new LST limitations added; of the 39,861 admitted with LST limitations, 3,017 (7.6%) had these reversed. New limitations were more likely to be seen in older participants (aged 65-84, odds ratio (OR) = 2.27, 95% confidence interval (CI) = 2.16-2.39; aged >=85, OR = 6.43, 95% CI = 6.05-6.84), and reversals of prior limitations were less likely to be seen in older individuals (aged 65-84, OR = 0.73, 95% CI = 0.65-0.83; aged >=85, OR = 0.46, 95% CI = 0.41-0.53) than in those younger than 65. Survival rates to inpatient discharge were 71.7% of subjects aged 85 and older who added new limitations, 57.2% of those aged 65 to 84, and 43.4% of those younger than 65 (P < .001). CONCLUSION: Changes in preferences for LSTs were common in hospitalized individuals. Age was an important determinant of likelihood of adding new or reversing prior LST limitations. Of subjects who added LST limitations, those who were older were more likely than those who were younger to survive to hospital discharge. PMID- 27119585 TI - Age-related changes in the Brazilian woman's smile. AB - The aim of this research was to evaluate age-related changes in the smile of Brazilian women. The sample consisted of 249 Brazilian women who had not undergone previous orthodontic treatment or facial surgery. They were divided into four groups, according to age: G1 (20-29), G2 (30-39), G3 (40-49) and G4 (50 or older). Standardized front view photographs were taken while smiling and at rest. Measurements were evaluated by ANOVA and post-hoc Tukey. The Chi-square test was applied for qualitative variables. Upper lip thickness at rest and exposure of upper incisors on smiling decreased with age. Most individuals (60.9%) exhibited a medium smile. High smiles were more often seen in G1 (45%) and less frequently in G4 (18.8%), whereas the opposite occurred with the low smile, i.e., G4 (21.9%) and G1 (6.7%). Variations among the groups were observed in the transverse exposure of the teeth on smiling. In G1 and G3, there was a balance between tooth exposures, so that the teeth were exposed as far as the premolars and/or molars. Most of the women (56.3%) in G2 exposed their teeth as far as the first molars on smiling, whereas most of those (40.6%) in G4 exposed their teeth only as far as the first premolars on smiling. As age increased, there was decreased exposure of the upper incisors, decreased upper lip thickness and lower exposure of teeth vertically and transversely. PMID- 27119586 TI - Location and classification of Canalis sinuosus for cone beam computed tomography: avoiding misdiagnosis. AB - The aim of this study was to assess the presence, location and, multiplanar distance of the canalis sinuosus (CS) between the incisive foramen and the anterior maxillary alveolar ridge using cone beam computed tomography (CBCT). Therefore, 500 CBCT maxillary images obtained from male and female patients aged 20 to 80 years were selected to assist in the dental treatment. Low-quality tomographic images were discarded. All images were captured with the i-CATTM Classic tomograph and assessed using the XoranCatTM software. The axial sections were analyzed at the incisive foramen in order to verify the CS presence in laterality and location. Furthermore, linear measurements of the nasal cavity floor, buccal cortical bone, and alveolar ridge crest were made. All the collected data were statistically analyzed. Results show a variation of the CS in relation to the classification and distance of anatomical structures, but no significant difference between the right and left sides. It should be highlighted that CBCT is necessary before invasive procedures in order to preserve important anatomical structures. In conclusion, the location of the CS varies in relation to the alveolar ridge crest and buccal cortical bone, assuming that it is going to be located by the upper lateral incisor palatine. PMID- 27119587 TI - Chitosan-collagen biomembrane embedded with calcium-aluminate enhances dentinogenic potential of pulp cells. AB - The development of biomaterials capable of driving dental pulp stem cell differentiation into odontoblast-like cells able to secrete reparative dentin is the goal of current conservative dentistry. In the present investigation, a biomembrane (BM) composed of a chitosan/collagen matrix embedded with calcium aluminate microparticles was tested. The BM was produced by mixing collagen gel with a chitosan solution (2:1), and then adding bioactive calcium-aluminate cement as the mineral phase. An inert material (polystyrene) was used as the negative control. Human dental pulp cells were seeded onto the surface of certain materials, and the cytocompatibility was evaluated by cell proliferation and cell morphology, assessed after 1, 7, 14 and 28 days in culture. The odontoblastic differentiation was evaluated by measuring alkaline phosphatase (ALP) activity, total protein production, gene expression of DMP-1/DSPP and mineralized nodule deposition. The pulp cells were able to attach onto the BM surface and spread, displaying a faster proliferative rate at initial periods than that of the control cells. The BM also acted on the cells to induce more intense ALP activity, protein production at 14 days, and higher gene expression of DSPP and DMP-1 at 28 days, leading to the deposition of about five times more mineralized matrix than the cells in the control group. Therefore, the experimental biomembrane induced the differentiation of pulp cells into odontoblast-like cells featuring a highly secretory phenotype. This innovative bioactive material can drive other protocols for dental pulp exposure treatment by inducing the regeneration of dentin tissue mediated by resident cells. PMID- 27119588 TI - Antimicrobial activity and substantivity of Uncaria tomentosa in infected root canal dentin. AB - The aim of this study was to analyze the antimicrobial activity and substantivity of Uncaria tomentosa Willd DC (cat's claw, CC) in root dentin contaminated with Enterococcus faecalis. Forty-eight human premolars were contaminated with E. faecalis (ATCC 29212) and randomly divided into four groups according to the irrigant used during chemomechanical preparation (CMP): CC group: 2% CC gel; CHX group: 2% chlorhexidine digluconate gel (CHX); NaOCl group: 5.25% sodium hypochlorite (NaOCl); and SS group: sterile saline (SS). Microbiological samples were collected before (S1) and after (S2) CMP and after 7 days (S3). Colony forming units (CFU/mL) at the different sampling times and comparisons among the groups were statistically analyzed by Wilcoxon and Kruskal-Wallis tests (p < 0.05). Significant bacterial reduction was achieved in all groups after CMP (p < 0.05). Results show no significant difference between S3 and S2 (p > 0.05) in the CC and CHX groups. Bacterial load was higher in S3 than in S2 samples (p < 0.05) in the NaOCl and SS groups. Our results suggest antibacterial effect of 2% CC gel against E. faecalis in infected dentin, in addition to antibacterial substantivity of 2% CC and 2% CHX up to 7 days. PMID- 27119589 TI - Maternal Zika infection: like rubella but worse. PMID- 27119590 TI - Tuning Ice Nucleation with Supercharged Polypeptides. AB - Supercharged unfolded polypeptides (SUPs) are exploited for controlling ice nucleation via tuning the nature of charge and charge density of SUPs. The results show that positively charged SUPs facilitate ice nucleation, while negatively charged ones suppress it. Moreover, the charge density of the SUP backbone is another parameter to control it. PMID- 27119591 TI - Correction to Enzyme-Assisted Synthesis and Structural Characterization of the 3 , 8-, and 15-Glucuronides of Deoxynivalenol. PMID- 27119592 TI - Communication, Reasoning, and Planned Behaviors: Unveiling the Effect of Interactive Communication in an Anti-Smoking Social Media Campaign. AB - This study examines direct and indirect effects of interactive communication in an antismoking social media campaign. To that end, we pose a multitheoretical framework that integrates communication mediation models and the Theory of Planned Behavior. To test the theorized model, we conducted an experiment using a two-group pretest-posttest design. Participants (N = 201) were randomly assigned into two experimental conditions: "campaign message reception only" as a control group and "message reception and social interaction" as a treatment group, in which the participants contributed to the antismoking campaign by posting their own campaign ideas and information they found through mediated and interpersonal communication. The findings show that interactive communication catalyzes the participants' information searching behaviors through diverse communication channels. In turn, increased media use plays a crucial role in changing their attitudes and perceived social norms about smoking behaviors, and eventually reducing smoking intention. This study affirms that the theory of planned behavior is effective in predicting behavioral intention and demonstrates the usefulness of a multitheoretical approach in interactive campaign research on social media. PMID- 27119593 TI - Facile Assembly of Functional Upconversion Nanoparticles for Targeted Cancer Imaging and Photodynamic Therapy. AB - The treatment depth of existing photodynamic therapy (PDT) is limited because of the absorption of visible excitation light in biological tissue. It can be augmented by means of upconversion nanoparticles (UCNPs) transforming deep penetrating near-infrared (NIR) light to visible light, exciting PDT drugs. We report here a facile strategy to assemble such PDT nanocomposites functionalized for cancer targeting, based on coating of the UCNPs with a silica layer encapsulating the Rose Bengal photosensitizer and bioconjugation to antibodies through a bifunctional fusion protein consisting of a solid-binding peptide linker genetically fused to Streptococcus Protein G'. The fusion protein (Linker Protein G) mediates the functionalization of silica-coated UCNPs with cancer cell antibodies, allowing for specific target recognition and delivery. The resulting nanocomposites were shown to target cancer cells specifically, generate intracellular reactive oxygen species under 980 nm excitation, and induce NIR triggered phototoxicity to suppress cancer cell growth in vitro. PMID- 27119594 TI - 36th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2015 annual meeting. AB - The 36th Annual David W Smith Workshop on Malformations and Morphogenesis was held on August 14-19, 2015 at the Harbourtowne Conference Center in St. Michaels Maryland. The Workshop, which honors the legacy of David W Smith, brought together over 120 clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. As is the tradition of the meeting, the Workshop highlighted five themes besides mechanisms of morphogenesis: Rasopathies, Eye Malformations, Therapeutics, Prenatal Diagnosis, and Disorders of Sex Development. This Conference Report includes the abstracts presented at the 2015 Workshop. (c) 2016 Wiley Periodicals, Inc. PMID- 27119595 TI - Dual-template magnetic molecularly imprinted particles with multi-hollow structure for the detection of dicofol and chlorpyrifos-methyl. AB - In this work, a novel dual-template magnetic molecularly imprinted polymer particle for dicofol and chlorpyrifos-methyl was prepared through oil-in-water emulsifier-free emulsion technology. The resulting magnetic particles were characterized with electron microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. It was found that as-prepared particles were well-shaped spheres with multi-hollow structures and of a size around 125 MUm. Meanwhile it showed a good magnetic sensitivity. The results testified that multi-hollow magnetic molecularly imprinted polymers possessed excellent recognition capacity and fast kinetic binding behavior to the objective molecules. The maximum binding amounts toward dicofol and chlorpyrifos-methyl were 31.46 and 25.23 mg/g, respectively. The feasibility of the use of the particles as a solid-phase extraction sorbent was evaluated. Satisfactory recoveries ranging from 90.62 to 111.47 and 91.07 to 94.03% were obtained for dicofol and chlorpyrifos-methyl, respectively, spiked at three concentration levels from real samples. The Langmuir isotherm equation provided an excellent fit to the equilibrium sorption data of either dicofol or chlorpyrifos-methyl. It provided a novel way to advise dual-template magnetic molecularly imprinted polymer particles to adsorb pesticides with high selectivity. PMID- 27119596 TI - Experimental evidence for fundamental, and not realized, niche partitioning in a plant-herbivore community interaction network. AB - Patterns of niche partitioning can result from local ecological interactions (e.g. interspecific competition) occurring within a contemporary time frame (realized niche partitioning). Alternatively, they may represent the end product of historical processes acting over long time frames (fundamental niche partitioning). Niche partitioning is often detected by analysing patterns of resource use within communities, but experiments are rarely conducted to test whether patterns of non-overlapping resource use reflect realized or fundamental niche partitioning. We studied a community of restio leafhoppers from the genus Cephalelus and their host plants, the Restionaceae (restios). We used network and experimental approaches to determine whether network modularity (a measure of niche partitioning within local communities) reflects fundamental or realized niche partitioning. Using a weighted modularity index for two party networks (e.g. insect-plant), we determined whether the network of this community is modular (i.e. consists of groups of species interacting strongly, with weak interactions between groups). We also aimed to identify specific Cephalelus - restio modules (groups). Using knowledge of module membership to design experiments, we tested whether Cephalelus species from two different modules, Cephalelus uncinatus and Cephalelus pickeri, prefer and perform better on restios from their own modules vs. restios from other modules. These experiments were performed under controlled conditions, eliminating the influences of competition and predation on host choices. The Cephalelus - restio community was modular, implying niche partitioning. Cephalelus also preferred and performed better on restios from their own modules in the absence of local contemporary factors. Most niche partitioning in the investigated Cephalelus community is not caused by local interactions, and thus, host use patterns represent fundamental niches. Our findings highlight the importance of understanding local community structure in the light of processes extrinsic to the local community context. PMID- 27119597 TI - Experimental Investigation of Wetting with Magnetic Fluids. AB - Here we report the experimental results of the general wetting behavior of an oil based ferrofluid and a water-based magnetic paint droplet on a hydrophobic surface under the effect of an external magnetic field. By increasing the magnetic field in the vertical direction, the height of the oil-based ferrofluid droplet increases while the width decreases; on the contrary, under the same circumstances, the height of the water-based magnetic paint droplet decreases whereas the width increases. The wetting behavior of the oil-based ferrofluid and the water-based magnetic paint droplets is evaluated as a function of the contact angle, contact line diameter, and hysteresis curve alterations. Conclusively, a general explanation is given for the contrary behavior of both liquids, and some application processes for future implementations are introduced. PMID- 27119598 TI - Arrhythmogenic right ventricular cardiomyopathy: ECG progression over time and correlation with long-term follow-up. AB - AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease primarily affecting the right ventricle and potentially causing sudden death in young people. Our aims are to analyse the progression over time of electrocardiographic (ECG) findings and to investigate their prognostic impact. METHODS: Sixty-eight patients (69% men; age 31 +/- 19 years) with ARVC diagnosis were followed up for a mean of 17 +/- 8 years. Follow-up included baseline ECG, 24-h Holter ECG, signal-averaged ECG, stress test, echocardiography, cardiac magnetic resonance and electrophysiologic study. RESULTS: During follow-up 12 (18%) patients died: three of sudden cardiac death (SCD), four of end-stage heart failure and five of noncardiac causes. Aborted SCD occurred in 7 (10%) patients, syncope in 31 (46%), sustained ventricular tachycardia in 43 (63%), heart failure in 18 (26%), atrial fibrillation in 16 (24%) and 3 (4%) patients underwent heart transplant. Twenty-four (35%) patients had implantable cardiac defibrillator (15 and 5 of them received both appropriate and inappropriate interventions, respectively and 7 experienced device-related complications). Of the ECG parameters registered at the enrolment, left anterior fascicular block (P = 0.001), QRS duration in lead 1 (P < 0.001), Epsilon wave (P < 0.001), T wave inversion in V4-V5-V6 (P = 0.012, P = 0.001 and P = 0.006) and low QRS voltages (P = 0.001) progressed over time. At multivariate analysis Epsilon wave (odds ratio 20.9, confidence interval 95% 1.8-239.8, P = 0.015) was the only predictor of the composite endpoint of SCD, heart failure-related death or heart transplant. CONCLUSION: Apart from playing a pivotal role in ARVC diagnosis, a simple ECG feature such as Epsilon wave is a marker of poor prognosis. PMID- 27119599 TI - Time-dependent classification accuracy curve under marker-dependent sampling. AB - Evaluating the classification accuracy of a candidate biomarker signaling the onset of disease or disease status is essential for medical decision making. A good biomarker would accurately identify the patients who are likely to progress or die at a particular time in the future or who are in urgent need for active treatments. To assess the performance of a candidate biomarker, the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) are commonly used. In many cases, the standard simple random sampling (SRS) design used for biomarker validation studies is costly and inefficient. In order to improve the efficiency and reduce the cost of biomarker validation, marker dependent sampling (MDS) may be used. In a MDS design, the selection of patients to assess true survival time is dependent on the result of a biomarker assay. In this article, we introduce a nonparametric estimator for time-dependent AUC under a MDS design. The consistency and the asymptotic normality of the proposed estimator is established. Simulation shows the unbiasedness of the proposed estimator and a significant efficiency gain of the MDS design over the SRS design. PMID- 27119600 TI - Artemisia Extract Improves Insulin Sensitivity in Women With Gestational Diabetes Mellitus by Up-Regulating Adiponectin. AB - Gestational diabetes mellitus (GDM) has affected a great number of pregnant women worldwide. Artemisia extracts have been found to exhibit a potent antidiabetic effect in the treatment of type 2 diabetes mellitus. We aimed to examine the effects of Artemisia extract on insulin resistance and lipid profiles in pregnant GDM patients. Patients in their second trimester were randomly assigned to the Artemisia extract group (AE) or to a placebo group (PO). They were instructed to consume either AE or PO daily for a period of 10 weeks. Glucose and insulin profiles and adiponectin level were assessed at baseline (week 0) and after the treatment (week 10). Compared to the PO group, fasting plasma glucose, serum insulin levels, homeostasis model of assessment of insulin resistance (HOMA-IR), and beta-cell function (HOMA-B) were significantly reduced in the AE group participants. Moreover, levels of circulating adiponectin were also significantly up-regulated in the AE group, which also positively contributed to improved insulin sensitivity. Daily administration of Artemisia extract improves insulin sensitivity by up-regulating adiponectin in women with gestational diabetes mellitus. PMID- 27119601 TI - Iron quantification with susceptibility. AB - Iron is an essential trace element involved in a variety of biological mechanisms in the human body. Disturbances of iron homeostasis have been observed in several inflammatory and degenerative diseases, which have raised strong interest in non invasive iron mapping techniques. Numerous MRI techniques have been proposed so far, mostly based on the field changes induced by the magnetic properties of iron. Each of these approaches has a specific sensitivity for iron and its microstructural environment. Quantitative susceptibility mapping is the latest development and provides a direct measure of bulk susceptibility. However, field changes induced by iron are not always directly related to the concentration of iron, but rather reflect the structure of iron compounds and its cellular distribution. This review provides an overview of the most relevant iron compounds in the human body, their magnetic properties and their cellular distribution. In addition, MRI methods based on direct or indirect susceptibility changes are presented and discussed with respect to technical aspects and clinical applicability. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27119618 TI - Effect of the [Ba2BO3F]infinity Layer on the Band Gap: Synthesis, Characterization, and Theoretical Studies of BaZn2B2O6.nBa2BO3F (n = 0, 1, 2). AB - Two new zincoborate fluorides with the common formula BaZn2B2O6.nBa2BO3F (n = 1, 2) have been successfully synthesized for the relationship study between the band gaps and crystal structures in zinc-containing borate fluorides. Ba3Zn2B3O9F with n = 1 in the common formula belongs to the orthorhombic space group Pnma (No. 20), and Ba5Zn2B4O12F2 with n = 2 in the common formula crystallizes in the monoclinic space group C2/c (No. 62). They can both be seen as compounds with the n[Ba2BO3F]infinity (n = 1 or 2) layer inserted in the structure of BaZn2B2O6. UV vis-near-IR diffuse-reflectance spectra show that the band gaps of BaZn2B2O6.nBa2BO3F (n = 0, 1, 2) gradually increase with more [Ba2BO3F]infinity layers inserted. The first-principles calculation indicates that the inserted n[Ba2BO3F]infinity layers play a positive effect in increasing the band gaps of zincoborate fluorides. Furthermore, the IR spectra, thermal behaviors, and refractive indices of these compounds are also studied. PMID- 27119619 TI - An Isolated and Transient Lead Impedance Alert as the Sole Indicator of ICD System Failure. PMID- 27119620 TI - Fibroblast growth factor 21 (FGF21) therapy attenuates left ventricular dysfunction and metabolic disturbance by improving FGF21 sensitivity, cardiac mitochondrial redox homoeostasis and structural changes in pre-diabetic rats. AB - AIMS: Fibroblast growth factor 21 (FGF21) acts as a metabolic regulator and exerts cardioprotective effects. However, the effects of long-term FGF21 administration on the heart under the FGF21-resistant condition in obese, insulin resistant rats have not been investigated. We hypothesized that long-term FGF21 administration reduces FGF21 resistance and insulin resistance and attenuates cardiac dysfunction in obese, insulin-resistant rats. METHODS: Eighteen rats were fed on either a normal diet (n = 6) or a high-fat diet (HFD; n = 12) for 12 weeks. Then, rats in the HFD group were divided into two subgroups (n = 6 per subgroup) and received either the vehicle (HFV) or recombinant human FGF21 (rhFGF21, 0.1 mg kg(-1) day(-1) ; HFF) injected intraperitoneally for 28 days. The metabolic parameters, inflammation, malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, cardiac mitochondrial redox homoeostasis, cardiac mitochondrial fatty acid beta-oxidation (FAO) and anti apoptotic signalling pathways were determined. RESULTS: HFV rats had increased dyslipidaemia, insulin resistance, plasma FGF21 levels, TNF-alpha, adiponectin and MDA, depressed HRV, and impaired LV and mitochondrial function. HFV rats also had decreased cardiac Bcl-2, cardiac PGC-1alpha and CPT-1 protein expression. However, FGF21 restored metabolic parameters, decreased TNF-alpha and MDA, increased serum adiponectin, and improved HRV, cardiac mitochondrial and LV function in HFF rats. Moreover, HFF rats had increased cardiac Bcl-2, cardiac PGC 1alpha and CPT-1 protein expression. CONCLUSION: Long-term FGF21 therapy attenuates FGF21 resistance and insulin resistance and exerts cardioprotection by improving cardiometabolic regulation via activating anti-apoptotic and cardiac mitochondrial FAO signalling pathways in obese, insulin-resistant rats. PMID- 27119621 TI - Over-expression of fHbp in Arabdopsis for development of meningococcal serogroup B subunit vaccine. AB - Due to lack of commercial vaccine against the serogroup B (MenB) of Neisseria meningitides, the incidence of meningococcal disease remains high. To solve the issue, transgenic plants are used as bioreactors to produce a plant-derived fHbp subunit vaccine. In this study, the fHbp gene was optimized according to the codon usage bias of Arabidopsis thaliana, synthesized artificially, cloned into an expression vector, driven by a seed-specific promoter, and introduced into A. thaliana by Agrobacterium-mediated floral-dip transformation. Transgenic plants were identified by glufosinate selection, quickstix strips for PAT/bar tests and PCR analysis. The five plants showing higher expression of recombinant fHbp were screened through indirect ELISA. Southern blot analysis showed that the transgenic line rHF-22 had a single-copy integration and the highest expression of fHbp. Recombinant fHbp was purified from seeds of rHF-22 by nitrilotriacetic acid-mediated affinity chromatography, and the purity was 82.5%. BALB/c mice were tested for fHbp vaccine protection from lethal MenB infection, and the relative percent survival was found to be 80%. This study indicates that the recombinant fHbp produced from seeds of rHF-22 is a potential candidate for commercial MenB vaccine. It also provides a reference for safe, cheap and large-scale production of other plant-made vaccines. PMID- 27119622 TI - Mobile group II intron based gene targeting in Lactobacillus plantarum WCFS1. AB - The usage of recombinant lactic acid bacteria for delivery of therapeutic proteins to the mucosa has been emerging. In the present study, an attempt was made to engineer a thyA mutant of Lactobacillus plantarum (L. plantarum) using lactococcal group II intron Ll.LtrB for the development of biologically contained recombinant L. plantarum for prevention of calcium oxalate stone disease. The 3 kb Ll.LtrB intron donor cassettes from the source vector pACD4C was PCR amplified, ligated into pSIP series of lactobacillus vector pLp_3050sAmyA, yielding a novel vector pLpACD4C (8.6 kb). The quantitative real-time PCR experiment shows 94-fold increased expression of Ll.LtrB intron and 14-fold increased expression of ltrA gene in recombinant L. plantarum containing pLpACD4C. In order to target the thyA gene, the potential intron RNA binding sites in the thyA gene of L. plantarum was predicted with help of computer algorithm. The insertion location 188|189s of thyA gene (lowest E-0.134) was chosen and the wild type intron Ll.LtrB was PCR modified, yielding a retargeted intron of pLpACDthyA. The retargeted intron was expressed by using induction peptide (sppIP), subsequently the integration of intron in thyA gene was identified by PCR screening and finally ThyA- mutant of L. plantarum (ThyA18) was detected. In vitro growth curve result showed that in the absence of thymidine, colony forming units of mutant ThyA18 was decreased, whereas high thymidine concentration (10 MUM) supported the growth of the culture until saturation. In conclusion, ThyA- mutant of L. plantarum (ThyA18) constructed in this study will be used as a biologically contained recombinant probiotic to deliver oxalate decarboxylase into the lumen for treatment of hyperoxaluria and calcium oxalate stone deposition. PMID- 27119623 TI - Droplet Manipulation Using Acoustic Streaming Induced by a Vibrating Membrane. AB - We present a simple method for on-demand manipulation of aqueous droplets in oil. With numerical simulations and experiments, we show that a vibrating membrane can produce acoustic streaming. By making use of this vortical flow, we manage to repulse the droplets away from the membrane edges. Then, by simply aligning the membrane at 45 degrees to the flow, the droplets can be forced to follow the membrane's boundaries, thus steering them across streamlines and even between different oil types. We also characterize the repulsion and steering effect with various excitation voltages at different water and oil flow rates. The maximum steering frequency we have achieved is 165 Hz. The system is extremely robust and reliable: the same membrane can be reused after many days and with different oils and/or surfactants at the same operating frequency. PMID- 27119624 TI - Removal of Selected Metals from Wastewater Using a Constructed Wetland. AB - Removal of selected metals from municipal wastewater using a constructed wetland with a horizontal subsurface flow was studied. The objective of the work was to determine the efficiency of Cu, Zn, Ni, Co, Sr, Li, and Rb removal, and to describe the main removal mechanisms. The highest removal efficiencies were attained for zinc and copper (89.8 and 81.5%, respectively). It is apparently due to the precipitation of insoluble sulfides (ZnS, CuS) in the vegetation bed where the sulfate reduction takes place. Significantly lower removal efficiencies (43.9, 27.7, and 21.5%) were observed for Li, Sr, and Rb, respectively. Rather, low removal efficiencies were also attained for Ni and Co (39.8 and 20.9%). However, the concentrations of these metals in treated water were significantly lower compared to Cu and Zn (e.g., 2.8 +/- 0.5 and 1.7 +/- 0.3 MUg/l for Ni at the inflow and outflow from the wetland compared to 27.6 +/- 12.0 and 5.1 +/- 4.7 MUg/l obtained for Cu, respectively). The main perspective of the constructed wetland is the removal of toxic heavy metals forming insoluble compounds depositing in the wetland bed. Metal uptake occurs preferentially in wetland sediments and is closely associated with the chemism of sulfur and iron. PMID- 27119625 TI - Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers. PMID- 27119627 TI - Watching Signaling in Action: Single Molecule Studies of a Reaction Circuit Involved in Chemotaxis. PMID- 27119626 TI - Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex. AB - Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4. PMID- 27119628 TI - Reductionism Is Dead: Long Live Reductionism! Systems Modeling Needs Reductionist Experiments. PMID- 27119629 TI - Optics-Integrated Microfluidic Platforms for Biomolecular Analyses. AB - Compared with conventional optical methods, optics implemented on microfluidic chips provide small, and often much cheaper ways to interrogate biological systems from the level of single molecules up to small model organisms. The optical probing of single molecules has been used to investigate the mechanical properties of individual biological molecules; however, multiplexing of these measurements through microfluidics and nanofluidics confers many analytical advantages. Optics-integrated microfluidic systems can significantly simplify sample processing and allow a more user-friendly experience; alignments of on chip optical components are predetermined during fabrication and many purely optical techniques are passively controlled. Furthermore, sample loss from complicated preparation and fluid transfer steps can be virtually eliminated, a particularly important attribute for biological molecules at very low concentrations. Excellent fluid handling and high surface area/volume ratios also contribute to faster detection times for low abundance molecules in small sample volumes. Although integration of optical systems with classical microfluidic analysis techniques has been limited, microfluidics offers a ready platform for interrogation of biophysical properties. By exploiting the ease with which fluids and particles can be precisely and dynamically controlled in microfluidic devices, optical sensors capable of unique imaging modes, single molecule manipulation, and detection of minute changes in concentration of an analyte are possible. PMID- 27119630 TI - DNA Nanostructures on Membranes as Tools for Synthetic Biology. AB - Over the last decade, functionally designed DNA nanostructures applied to lipid membranes prompted important achievements in the fields of biophysics and synthetic biology. Taking advantage of the universal rules for self-assembly of complementary oligonucleotides, DNA has proven to be an extremely versatile biocompatible building material on the nanoscale. The possibility to chemically integrate functional groups into oligonucleotides, most notably with lipophilic anchors, enabled a widespread usage of DNA as a viable alternative to proteins with respect to functional activity on membranes. As described throughout this review, hybrid DNA-lipid nanostructures can mediate events such as vesicle docking and fusion, or selective partitioning of molecules into phase-separated membranes. Moreover, the major benefit of DNA structural constructs, such as DNA tiles and DNA origami, is the reproducibility and simplicity of their design. DNA nanotechnology can produce functional structures with subnanometer precision and allow for a tight control over their biochemical functionality, e.g., interaction partners. DNA-based membrane nanopores and origami structures able to assemble into two-dimensional networks on top of lipid bilayers are recent examples of the manifold of complex devices that can be achieved. In this review, we will shortly present some of the potentially most relevant avenues and accomplishments of membrane-anchored DNA nanostructures for investigating, engineering, and mimicking lipid membrane-related biophysical processes. PMID- 27119631 TI - A Tool for Alignment and Averaging of Sparse Fluorescence Signals in Rod-Shaped Bacteria. AB - Fluorescence microscopy studies have shown that many proteins localize to highly specific subregions within bacterial cells. Analyzing the spatial distribution of low-abundance proteins within cells is highly challenging because information obtained from multiple cells needs to be combined to provide well-defined maps of protein locations. We present (to our knowledge) a novel tool for fast, automated, and user-impartial analysis of fluorescent protein distribution across the short axis of rod-shaped bacteria. To demonstrate the strength of our approach in extracting spatial distributions and visualizing dynamic intracellular processes, we analyzed sparse fluorescence signals from single molecule time-lapse images of individual Escherichia coli cells. In principle, our tool can be used to provide information on the distribution of signal intensity across the short axis of any rod-shaped object. PMID- 27119632 TI - Markov State Models and tICA Reveal a Nonnative Folding Nucleus in Simulations of NuG2. AB - After reanalyzing simulations of NuG2-a designed mutant of protein G-generated by Lindorff-Larsen et al. with time structure-based independent components analysis and Markov state models as well as performing 1.5 ms of additional sampling on Folding@home, we found an intermediate with a register-shift in one of the beta sheets that was visited along a minor folding pathway. The minor folding pathway was initiated by the register-shifted sheet, which is composed of solely nonnative contacts, suggesting that for some peptides, nonnative contacts can lead to productive folding events. To confirm this experimentally, we suggest a mutational strategy for stabilizing the register shift, as well as an infrared experiment that could observe the nonnative folding nucleus. PMID- 27119633 TI - The Influence of Ionic Environment and Histone Tails on Columnar Order of Nucleosome Core Particles. AB - The nucleosome core particle (NCP) is the basic building block of chromatin. Nucleosome-nucleosome interactions are instrumental in chromatin compaction, and understanding NCP self-assembly is important for understanding chromatin structure and dynamics. Recombinant NCPs aggregated by multivalent cations form various ordered phases that can be studied by x-ray diffraction (small-angle x ray scattering). In this work, the effects on the supramolecular structure of aggregated NCPs due to lysine histone H4 tail acetylations, histone H2A mutations (neutralizing the acidic patch of the histone octamer), and the removal of histone tails were investigated. The formation of ordered mainly hexagonal columnar NCP phases is in agreement with earlier studies; however, the highly homogeneous recombinant NCP systems used in this work display a more compact packing. The long-range order of the NCP columnar phase was found to be abolished or reduced by acetylation of the H4 tails, acidic patch neutralization, and removal of the H3 and H2B tails. Loss of nucleosome stacking upon removal of the H3 tails in combination with other tails was observed. In the absence of the H2A tails, the formation of an unknown highly ordered phase was observed. PMID- 27119634 TI - The In Situ Tryptophan Analogue Probes the Conformational Dynamics in Asparaginase Isozymes. AB - Dynamic water solvation is crucial to protein conformational reorganization and hence to protein structure and functionality. We report here the characterization of water dynamics on the L-asparaginase structural homology isozymes L asparaginases I (AnsA) and II (AnsB), which are shown via fluorescence spectroscopy and dynamics in combination with molecular dynamics simulation to have distinct catalytic activity. By use of the tryptophan (Trp) analog probe 2,7 diaza-tryptophan ((2,7-aza)Trp), which exhibits unique water-catalyzed proton transfer properties, AnsA and AnsB are shown to have drastically different local water environments surrounding the single Trp. In AnsA, (2,7-aza)Trp exhibits prominent green N(7)-H emission resulting from water-catalyzed excited-state proton transfer. In stark contrast, the N(7)-H emission is virtually absent in AnsB, which supports a water-accessible and a water-scant environment in the proximity of Trp for AnsA and AnsB, respectively. In addition, careful analysis of the emission spectra and corresponding relaxation dynamics, together with the results of molecular dynamics simulations, led us to propose two structural states associated with the rearrangement of the hydrogen-bond network in the vicinity of Trp for the two Ans. The water molecules revealed in the proximity of the Trp residue have semiquantitative correlation with the observed emission spectral variations of (2,7-aza)Trp between AnsA and AnsB. Titration of aspartate, a competitive inhibitor of Ans, revealed an increase in N(7)-H emission intensity in AnsA but no obvious spectral changes in AnsB. The changes in the emission profiles reflect the modulation of structural states by locally confined environment and trapped-water collective motions. PMID- 27119635 TI - Disulfide Bridges: Bringing Together Frustrated Structure in a Bioactive Peptide. AB - Disulfide bridges are commonly found covalent bonds that are usually believed to maintain structural stability of proteins. Here, we investigate the influence of disulfide bridges on protein dynamics through molecular dynamics simulations on the cysteine-rich trypsin inhibitor MCoTI-II with three disulfide bridges. Correlation analysis of the reduced cyclic peptide shows that two of the three disulfide distances (Cys(11)-Cys(23) and Cys(17)-Cys(29)) are anticorrelated within ~1 MUs of bridge formation or dissolution: when the peptide is in nativelike structures and one of the distances shortens to allow bond formation, the other tends to lengthen. Simulations over longer timescales, when the denatured state is less structured, do not show the anticorrelation. We propose that the native state contains structural elements that frustrate one another's folding, and that the two bridges are critical for snapping the frustrated native structure into place. In contrast, the Cys(4)-Cys(21) bridge is predicted to form together with either of the other two bridges. Indeed, experimental chromatography and nuclear magnetic resonance data show that an engineered peptide with the Cys(4)-Cys(21) bridge deleted can still fold into its near native structure even in its noncyclic form, confirming the lesser role of the Cys(4)-Cys(21) bridge. The results highlight the importance of disulfide bridges in a small bioactive peptide to bring together frustrated structure in addition to maintaining protein structural stability. PMID- 27119636 TI - StructMap: Elastic Distance Analysis of Electron Microscopy Maps for Studying Conformational Changes. AB - Single-particle electron microscopy (EM) has been shown to be very powerful for studying structures and associated conformational changes of macromolecular complexes. In the context of analyzing conformational changes of complexes, distinct EM density maps obtained by image analysis and three-dimensional (3D) reconstruction are usually analyzed in 3D for interpretation of structural differences. However, graphic visualization of these differences based on a quantitative analysis of elastic transformations (deformations) among density maps has not been done yet due to a lack of appropriate methods. Here, we present an approach that allows such visualization. This approach is based on statistical analysis of distances among elastically aligned pairs of EM maps (one map is deformed to fit the other map), and results in visualizing EM maps as points in a lower-dimensional distance space. The distances among points in the new space can be analyzed in terms of clusters or trajectories of points related to potential conformational changes. The results of the method are shown with synthetic and experimental EM maps at different resolutions. PMID- 27119637 TI - The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes. AB - Prion diseases are a group of fatal neurodegenerative disorders that afflict mammals. Misfolded and aggregated forms of the prion protein (PrP(Sc)) have been associated with many prion diseases. A transmembrane form of PrP favored by the pathogenic mutation A116V is associated with Gerstmann-Straussler-Scheinker syndrome, but no accumulation of PrP(Sc) is detected. However, the role of the transmembrane form of PrP in pathological processes leading to neuronal death remains unclear. This study reports that the full-length mouse PrP (moPrP) significantly increases the permeability of living cells to K(+), and forms K(+)- and Ca(2+)-selective channels in lipid membranes. Importantly, the pathogenic mutation A116V greatly increases the channel-forming capability of moPrP. The channels thus formed are impermeable to sodium and chloride ions, and are blocked by blockers of voltage-gated ion channels. Hydrogen-deuterium exchange studies coupled with mass spectrometry (HDX-MS) show that upon interaction with lipid, the central hydrophobic region (109-132) of the protein is protected against exchange, making it a good candidate for inserting into the membrane and lining the channel. HDX-MS also shows a dramatic increase in the protein-lipid stoichiometry for A116V moPrP, providing a rationale for its increased channel forming capability. The results suggest that ion channel formation may be a possible mechanism of PrP-mediated neurodegeneration by the transmembrane forms of PrP. PMID- 27119638 TI - Membrane Cholesterol Modulates Superwarfarin Toxicity. AB - Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but not warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content. PMID- 27119639 TI - Selective Membrane Disruption Mechanism of an Antibacterial gamma-AApeptide Defined by EPR Spectroscopy. AB - gamma-AApeptides are a new class of antibacterial peptidomimetics that are not prone to antibiotic resistance and are highly resistant to protease degradation. It is not clear how gamma-AApeptides interact with bacterial membranes and alter lipid assembly, but such information is essential to understanding their antimicrobial activities and guiding future design of more potent and specific antimicrobial agents. Using electron paramagnetic resonance techniques, we characterized the membrane interaction and destabilizing mechanism of a lipo cyclic-gamma-AApeptide (AA1), which has broad-spectrum antibacterial activities. The analyses revealed that AA1 binding increases the membrane permeability of POPC/POPG liposomes, which mimic negatively charged bacterial membranes. AA1 binding also inhibits membrane fluidity and reduces solvent accessibility around the lipid headgroup region. Moreover, AA1 interacts strongly with POPC/POPG liposomes, inducing significant lipid lateral-ordering and membrane thinning. In contrast, minimal membrane property changes were observed upon AA1 binding for liposomes mimicking mammalian cell membranes, which consist of neutral lipids and cholesterol. Our findings suggest that AA1 interacts and disrupts bacterial membranes through a carpet-like mechanism. The results showed that the intrinsic features of gamma-AApeptides are important for their ability to disrupt bacterial membranes selectively, the implications of which extend to developing new antibacterial biomaterials. PMID- 27119640 TI - Polyunsaturated Lipids Regulate Membrane Domain Stability by Tuning Membrane Order. AB - The plasma membrane (PM) serves as the functional interface between a cell and its environment, hosting extracellular signal transduction and nutrient transport among a variety of other processes. To support this extensive functionality, PMs are organized into lateral domains, including ordered, lipid-driven assemblies termed lipid rafts. Although the general requirements for ordered domain formation are well established, how these domains are regulated by cell endogenous mechanisms or exogenous perturbations has not been widely addressed. In this context, an intriguing possibility is that dietary fats can incorporate into membrane lipids to regulate the properties and physiology of raft domains. Here, we investigate the effects of polyunsaturated fats on the organization of membrane domains across a spectrum of membrane models, including computer simulations, synthetic lipid membranes, and intact PMs isolated from mammalian cells. We observe that the omega-3 polyunsaturated fatty acid docosahexaenoic acid is robustly incorporated into membrane lipids, and this incorporation leads to significant remodeling of the PM lipidome. Across model systems, docosahexaenoic acid-containing lipids enhance the stability of ordered raft domains by increasing the order difference between them and coexisting nonraft domains. The relationship between interdomain order disparity and the stability of phase separation holds for a spectrum of different perturbations, including manipulation of cholesterol levels and high concentrations of exogenous amphiphiles, suggesting it as a general feature of the organization of biological membranes. These results demonstrate that polyunsaturated fats affect the composition and organization of biological membranes, suggesting a potential mechanism for the extensive effects of dietary fat on health and disease. PMID- 27119642 TI - The Influence of Lipid Bilayer Physicochemical Properties on Gramicidin A Conformer Preferences. AB - The conformational preferences adopted by gramicidin A (GA) dimers inserted into phospholipid bilayers are reported as a function of the bilayer cholesterol content, temperature, and incubation time. Through use of vesicle capture-freeze drying methodology, GA dimers were captured in lipid bilayers and the conformational preferences of the complex were analyzed using ion mobility-mass spectrometry. Perturbations that affect the physicochemical interactions in the lipid bilayer such as cholesterol incorporation, temperature, and incubation time directly alter the conformer preferences of the complex. Regardless of bilayer cholesterol concentration, the antiparallel double helix (ADH) conformation was observed to be most abundant for GA dimers in bilayers composed of lipids with 12 to 22 carbon acyl chains. Incorporation of cholesterol into lipid bilayers yields increased bilayer thickness and rigidity, and an increased abundance of parallel double helix (PDH) and single-stranded head-to-head (SSHH) dimers were observed. Bilayers prepared using 1,2-dilauroyl-sn-glycero-3-phosphocholine, a lipid with 12 carbon acyl chains, yielded a nascent conformer that decreased in abundance as a function of bilayer cholesterol content. High resolution ion mobility-mass spectrometry data revealed two peaks in the ADH region suggesting that ADH populations are composed of two distinct conformers. The conformer preferences of GA dimers from 1,2-distearoyl-sn-glycero-3-phosphocholine bilayers were significantly different for samples incubated at 4 degrees C vs. 60 degrees C; increased cholesterol content yielded more PDH and SSHH at 60 degrees C. The addition of cholesterol as well as incubating samples of 1,2-distearoyl-sn glycero-3-phosphocholine at 60 degrees C for 24-72 h yielded an increase in PDH and SSHH abundance. PMID- 27119641 TI - Regulation of PI3K by PKC and MARCKS: Single-Molecule Analysis of a Reconstituted Signaling Pathway. AB - In chemotaxing ameboid cells, a complex leading-edge signaling circuit forms on the cytoplasmic leaflet of the plasma membrane and directs both actin and membrane remodeling to propel the leading edge up an attractant gradient. This leading-edge circuit includes a putative amplification module in which Ca(2+) protein kinase C (Ca(2+)-PKC) is hypothesized to phosphorylate myristoylated alanine-rich C kinase substrate (MARCKS) and release phosphatidylinositol-4,5 bisphosphate (PIP2), thereby stimulating production of the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3) by the lipid kinase phosphoinositide-3-kinase (PI3K). We investigated this hypothesized Ca(2+)-PKC MARCKS-PIP2-PI3K-PIP3 amplification module and tested its key predictions using single-molecule fluorescence to measure the surface densities and activities of its protein components. Our findings demonstrate that together Ca(2+)-PKC and the PIP2-binding peptide of MARCKS modulate the level of free PIP2, which serves as both a docking target and substrate lipid for PI3K. In the off state of the amplification module, the MARCKS peptide sequesters PIP2 and thereby inhibits PI3K binding to the membrane. In the on state, Ca(2+)-PKC phosphorylation of the MARCKS peptide reverses the PIP2 sequestration, thereby releasing multiple PIP2 molecules that recruit multiple active PI3K molecules to the membrane surface. These findings 1) show that the Ca(2+)-PKC-MARCKS-PIP2-PI3K-PIP3 system functions as an activation module in vitro, 2) reveal the molecular mechanism of activation, 3) are consistent with available in vivo data, and 4) yield additional predictions that are testable in live cells. More broadly, the Ca(2+) PKC-stimulated release of free PIP2 may well regulate the membrane association of other PIP2-binding proteins, and the findings illustrate the power of single molecule analysis to elucidate key dynamic and mechanistic features of multiprotein signaling pathways on membrane surfaces. PMID- 27119643 TI - Extracting Subcellular Fibrillar Alignment with Error Estimation: Application to Microtubules. AB - The order and orientation of cortical microtubule (CMT) arrays and their dynamics play an essential role in plant morphogenesis. To extract detailed CMT alignment structures in an objective, local, and accurate way, we propose an error-based extraction method that applies to general fluorescence intensity data on three dimensional cell surfaces. Building on previous techniques to quantify alignments, our method can determine the statistical error for specific local regions, or the minimal scales of local regions for a desired accuracy goal. After validating our method with synthetic images with known alignments, we demonstrate the ability of our method to quantify subcellular CMT alignments on images with microtubules marked with green fluorescent protein in various cell types. Our method could also be applied to detect alignment structures in other fibrillar elements, such as actin filaments, cellulose, and collagen. PMID- 27119644 TI - Active Traction Force Response to Long-Term Cyclic Stretch Is Dependent on Cell Pre-stress. AB - Mechanical stimulation is recognized as a potent modulator of cellular behaviors such as proliferation, differentiation, and extracellular matrix assembly. However, the study of how cell-generated traction force changes in response to stretch is generally limited to short-term stimulation. The goal of this work is to determine how cells actively alter their traction force in response to long term physiological cyclic stretch as a function of cell pre-stress. We have developed, to our knowledge, a novel method to assess traction force after long term (24 h) uniaxial or biaxial cyclic stretch under conditions of high cell pre stress with culture on stiff (7.5 kPa) polyacrylamide gels (with or without transforming growth factor beta1 (TGF-beta1)) and low pre-stress by treating with blebbistatin or culture on soft gels (0.6 kPa). In response to equibiaxial stretch, valvular interstitial cells on stiff substrates decreased their traction force (from 300 nN to 100 nN) and spread area (from 3000 to 2100 MUm(2)). With uniaxial stretch, the cells had similar decreases in traction force and area and reoriented perpendicular to the stretch. TGF-beta1-treated valvular interstitial cells had higher pre-stress (1100 nN) and exhibited a larger drop in traction force with uniaxial stretch, but the percentage changes in force and area with stretch were similar to the non-TGF-beta1-treated group. Cells with inhibited myosin II motors increased traction force (from 41 nN to 63 nN) and slightly reoriented toward the stretch direction. In contrast, cells cultured on soft gels increased their traction force significantly, from 15 nN to 45 nN, doubled their spread area, elongated from an initially rounded morphology, and reoriented perpendicular to the uniaxial stretch. Contractile-moment measurements provided results consistent with total traction force measurements. The combined results indicate that the change in traction force in response to external cyclic stretch is dependent upon the initial cell pre-stress. This finding is consistent with depolymerization of initially high-tension actin stress fibers, and reinforcement of an initially low-tension actin cytoskeleton. PMID- 27119645 TI - Imaging Extracellular Matrix Remodeling In Vitro by Diffusion-Sensitive Optical Coherence Tomography. AB - The mammary gland extracellular matrix (ECM) is comprised of biopolymers, primarily collagen I, that are created and maintained by stromal fibroblasts. ECM remodeling by fibroblasts results in changes in ECM fiber spacing (pores) that have been shown to play a critical role in the aggressiveness of breast cancer. However, minimally invasive methods to measure the spatial distribution of ECM pore areas within tissues and in vitro 3D culture models are currently lacking. We introduce diffusion-sensitive optical coherence tomography (DS-OCT) to image the nanoscale porosity of ECM by sensing weakly constrained diffusion of gold nanorods (GNRs). DS-OCT combines the principles of low-coherence interferometry and heterodyne dynamic light scattering. By collecting co- and cross-polarized light backscattered from GNRs within tissue culture, the ensemble-averaged translational self-diffusion rate, DT, of GNRs is resolved within ~3 coherence volumes (10 * 5 MUm, x * z). As GNRs are slowed by intermittent collisions with ECM fibers, DT is sensitive to ECM porosity on the size scale of their hydrodynamic diameter (~46 nm). Here, we validate the utility of DS-OCT using pure collagen I gels and 3D mammary fibroblast cultures seeded in collagen/Matrigel, and associate differences in artificial ECM pore areas with gel concentration and cell seed density. Across all samples, DT was highly correlated with pore area obtained by scanning electron microscopy (R(2) = 0.968). We also demonstrate that DS-OCT can accurately map the spatial heterogeneity of layered samples. Importantly, DS-OCT of 3D mammary fibroblast cultures revealed the impact of fibroblast remodeling, where the spatial heterogeneity of matrix porosity was found to increase with cell density. This provides an unprecedented view into nanoscale changes in artificial ECM porosity over effective pore diameters ranging from ~43 to 360 nm using a micron-scale optical imaging technique. In combination with the topical deposition of GNRs, the minimally invasive nature of DS-OCT makes this a promising technology for studying tissue remodeling processes. PMID- 27119646 TI - Computational Study of Thrombus Formation and Clotting Factor Effects under Venous Flow Conditions. AB - A comprehensive understanding of thrombus formation as a physicochemical process that has evolved to protect the integrity of the human vasculature is critical to our ability to predict and control pathological states caused by a malfunctioning blood coagulation system. Despite numerous investigations, the spatial and temporal details of thrombus growth as a multicomponent process are not fully understood. Here, we used computational modeling to investigate the temporal changes in the spatial distributions of the key enzymatic (i.e., thrombin) and structural (i.e., platelets and fibrin) components within a growing thrombus. Moreover, we investigated the interplay between clot structure and its mechanical properties, such as hydraulic resistance to flow. Our model relied on the coupling of computational fluid dynamics and biochemical kinetics, and was validated using flow-chamber data from a previous experimental study. The model allowed us to identify the distinct patterns characterizing the spatial distributions of thrombin, platelets, and fibrin accumulating within a thrombus. Our modeling results suggested that under the simulated conditions, thrombin kinetics was determined predominantly by prothrombinase. Furthermore, our simulations showed that thrombus resistance imparted by fibrin was ~30-fold higher than that imparted by platelets. Yet, thrombus-mediated bloodflow occlusion was driven primarily by the platelet deposition process, because the height of the platelet accumulation domain was approximately twice that of the fibrin accumulation domain. Fibrinogen supplementation in normal blood resulted in a nonlinear increase in thrombus resistance, and for a supplemented fibrinogen level of 48%, the thrombus resistance increased by ~2.7-fold. Finally, our model predicted that restoring the normal levels of clotting factors II, IX, and X while simultaneously restoring fibrinogen (to 88% of its normal level) in diluted blood can restore fibrin generation to ~78% of its normal level and hence improve clot formation under dilution. PMID- 27119647 TI - Regulators of Metastasis Modulate the Migratory Response to Cell Contact under Spatial Confinement. AB - The breast tumor microenvironment (TMEN) is a unique niche where protein fibers help to promote invasion and metastasis. Cells migrating along these fibers are constantly interacting with each other. How cells respond to these interactions has important implications. Cancer cells that circumnavigate or slide around other cells on protein fibers take a less tortuous path out of the primary tumor; conversely, cells that turn back upon encountering other cells invade less efficiently. The contact response of migrating cancer cells in a fibrillar TMEN is poorly understood. Here, using high-aspect ratio micropatterns as a model fibrillar platform, we show that metastatic cells overcome spatial constraints to slide effectively on narrow fiber-like dimensions, whereas nontransformed MCF-10A mammary epithelial cells require much wider micropatterns to achieve moderate levels of sliding. Downregulating the cell-cell adhesion protein, E-cadherin, enables MCF-10A cells to slide on narrower micropatterns; meanwhile, introducing exogenous E-cadherin in metastatic MDA-MB-231 cells increases the micropattern dimension at which they slide. We propose the characteristic fibrillar dimension (CFD) at which effective sliding is achieved as a metric of sliding ability under spatial confinement. Using this metric, we show that metastasis-promoting genetic perturbations enhance cell sliding and reduce CFD. Activation of ErbB2 combined with downregulation of the tumor suppressor and cell polarity regulator, PARD3, reduced the CFD, in agreement with their cooperative role in inducing metastasis in vivo. The CFD was further reduced by a combination of ErbB2 activation and transforming growth factor beta stimulation, which is known to enhance invasive behavior. These findings demonstrate that sliding is a quantitative property and a decrease in CFD is an effective metric to understand how multiple genetic hits interact to change cell behavior in fibrillar environments. This quantitative framework sheds insights into how genetic perturbations conspire with fibrillar maturation in the TMEN to drive the invasive behavior of cancer cells. PMID- 27119649 TI - Molecular Basis of S100A1 Activation at Saturating and Subsaturating Calcium Concentrations. PMID- 27119648 TI - Multisite Phosphorylation Modulates the T Cell Receptor zeta-Chain Potency but not the Switchlike Response. AB - Multisite phosphorylation is ubiquitous in cellular signaling and is thought to provide signaling proteins with additional regulatory mechanisms. Indeed, mathematical models have revealed a large number of mechanisms by which multisite phosphorylation can produce switchlike responses. The T cell antigen receptor (TCR) is a multisubunit receptor on the surface of T cells that is a prototypical multisite substrate as it contains 20 sites that are distributed on 10 conserved immunoreceptor tyrosine-based activation motifs (ITAMs). The TCR zeta-chain is a homodimer subunit that contains six ITAMs (12 sites) and exhibits a number of properties that are predicted to be sufficient for a switchlike response. We have used cellular reconstitution to systematically study multisite phosphorylation of the TCR zeta-chain. We find that multisite phosphorylation proceeds by a nonsequential random mechanism, and find no evidence that multiple ITAMs modulate a switchlike response but do find that they alter receptor potency and maximum phosphorylation. Modulation of receptor potency can be explained by a reduction in molecular entropy of the disordered zeta-chain upon phosphorylation. We further find that the tyrosine kinase ZAP-70 increases receptor potency but does not modulate the switchlike response. In contrast to other multisite proteins, where phosphorylations act in strong concert to modulate protein function, we suggest that the multiple ITAMs on the TCR function mainly to amplify subsequent signaling. PMID- 27119650 TI - Coexistence facilitates interspecific biofilm formation in complex microbial communities. AB - Social interactions in which bacteria respond to one another by modifying their phenotype are central determinants of microbial communities. It is known that interspecific interactions influence the biofilm phenotype of bacteria; a phenotype that is central to the fitness of bacteria. However, the underlying role of fundamental ecological factors, specifically coexistence and phylogenetic history, in biofilm formation remains unclear. This study examines how social interactions affect biofilm formation in multi-species co-cultures from five diverse environments. We found prevalence of increased biofilm formation among co cultured bacteria that have coexisted in their original environment. Conversely, when randomly co-culturing bacteria across these five consortia, we found less biofilm induction and a prevalence of biofilm reduction. Reduction in biofilm formation was even more predominant when co-culturing bacteria from environments where long-term coexistence was unlikely to have occurred. Phylogenetic diversity was not found to be a strong underlying factor but a relation between biofilm induction and phylogenetic history was found. The data indicates that biofilm reduction is typically correlated with an increase in planktonic cell numbers, thus implying a behavioral response rather than mere growth competition. Our findings suggest that an increase in biofilm formation is a common adaptive response to long-term coexistence. PMID- 27119651 TI - Unusually Stable Triazine-based Organic Superstructures. AB - Solid-state reactions have been rapidly gaining popularity in organic chemistry owing to their simplicity, efficiency, and selectivity compared to liquid-phase reactions. Herein, we describe the formation of superstructures through the solid state reaction of an organic single-crystal. The superstructure of 5,5',5'' (1,3,5-triazine-2,4,6-triyl)triisophthalonitrile (TIPN) can be formed by cyclotrimerization of 1,3,5-tricyanobenzene (TCB) single crystals. The TIPN superstructure was confirmed by single crystal X-ray diffraction and visualized by transmission electron microscopy. The superstructure has hexagonally packed 1 dimensional (1D) channels along the crystal axis. Furthermore, the superstructure arises from interdigitated nitrile interactions in the crystal lattice, and thus has electron-beam tolerance and very high thermal stability. PMID- 27119652 TI - Down-Regulation of Store-Operated Ca2+ Entry and Na+ Ca2+ Exchange in MCF-7 Breast Cancer Cells by Pharmacological JAK3 Inhibition. AB - BACKGROUND/AIMS: Oscillations of cytosolic Ca2+ activity ([Ca2+]i) participate in the orchestration of tumor cell proliferation. [Ca2+]i could be increased by intracellular Ca2+ release followed by store-operated Ca2+-entry (SOCE). [Ca2+]i could be decreased by Ca2+ extrusion via Na+/Ca2+ exchange. Mechanisms accomplishing SOCE include the pore-forming ion channel unit Orai1 and its regulator STIM1, Na+/Ca2+ exchanger isoforms include NCX1. In MCF-7 breast carcinoma cells Orai1 and NCX1 have previously been shown to be modified by pharmacological inhibition of Janus activated kinase JAK2. The present study explored whether SOCE and Na+/Ca2+ exchange are similarly sensitive to pharmacological JAK3 inhibition. METHODS: MCF-7 breast carcinoma cells were studied in the absence and presence of the JAK3 inhibitor WHI-P154 (22 uM). [Ca2+]i was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 uM), and Na+/Ca2+ exchanger activity from increase of [Ca2+]i following extracellular Na+ removal. Transcript levels were quantified with RT-PCR. RESULTS: Addition of ATP (100 uM) was followed by a rapid increase of [Ca2+]i, which was significantly blunted by WHI P154. Thapsigargin-induced intracellular Ca2+ release was not appreciably influenced by WHI-P154. Subsequent SOCE was, however, significantly blunted by WHI-P154. WHI-P154 further significantly decreased Orai1 transcript levels. The increase of [Ca2+]i following extracellular Na+-removal and the NCX1 transcript levels were similarly decreased by WHI-P154. CONCLUSIONS: The JAK3 inhibitor WHI P154 decreases both, Orai1 and NCX1 transcript levels and thus impairs SOCE and Na+/Ca2+ exchange. PMID- 27119654 TI - Can the angle between optic nerves indicate whether optic chiasm is prefixed, normofixed or postfixed? An anatomical study with radiologic and neurosurgical implications. AB - PURPOSE: The objective of this study was to measure the angle (Interneural angle, INA) between intracranial segments of optic nerves (ISON), and to look for any relation between it and the relative anteroposterior location (RAPL) of the optic chiasm (OC)-viz. prefixed, normofixed and postfixed. METHODS: The sample comprised of 100 autopsy specimens from South Indian population. INA was measured using software-aided processing of digital photographs. Length of the ISON was measured on each side using Vernier calipers. RAPL of the OC was noted during dissection. These were analysed with statistical methods. RESULTS: RAPL of OC was found to be prefixed in 24 %, normofixed in 65 % and postfixed in 11 %. The INA had an overall mean of 69.9 degrees (SD 9.29 degrees ). ANOVA confirmed statistically significant difference in INA among different groups; the corresponding mean value for the group was as follows: 79.61 degrees (prefixed), 68.10 degrees (normofixed) and 59.48 degrees (postfixed). ROC curve was plotted for the use of various 'cut off' values of INA to 'diagnose' prefixed OC; an INA >=71.4 degrees was seen to diagnostically correlate with prefixed OC with 83.3 % sensitivity and 75 % specificity. CONCLUSIONS: The INA is wider when OC is prefixed, intermediate when normofixed and narrowed when postfixed. This observation throws light on the possibility of using INA as a marker of RAPL of OC. As INA can be measured in axial MRI sections, it can be used in differentiation of the cases with prefixed OC from others during pre-operative work up for pituitary surgeries and to identify individuals 'at risk' during subfrontal approach for pituitary lesions. PMID- 27119653 TI - Biologically distinct subsets of nevi. AB - Melanocytic nevi (MN) encompass a range of benign tumors with varying microscopic and macroscopic features. Their development is a multifactorial process under genetic and environmental influences. The clinical importance of MN lies in distinguishing them from melanoma and in recognizing their associations with melanoma risk and cancer syndromes. Historically, the distinction between the different types of MN, as well as between MN and melanoma, was based on clinical history, gross morphology, and histopathological features. While histopathology with clinical correlation remains the gold standard for differentiating and diagnosing melanocytic lesions, in some cases, this may not be possible. The use of dermoscopy has allowed for the assessment of subsurface skin structures and has contributed to the clinical evaluation and classification of MN. Genetic profiling, while still in its early stages, has the greatest potential to refine the classification of MN by clarifying their developmental processes, biological behaviors, and relationships to melanoma. Here we review the most salient clinical, dermoscopic, histopathological, and genetic features of different MN subgroups. PMID- 27119655 TI - Neck Circumference Positively Related with Central Obesity and Overweight in Turkish University Students: A Preliminary Study. AB - AIM: According to the World Health Organization, central obesity is increasing alarmingly worldwide. Neck circumference is a relatively new method of differentiating between normal and abnormal fat distribution. The aim of this study is to determine the association between neck circumference and central obesity in young Turkish male and female university students. METHODS: A community of university students based cross-sectional study was conducted on 319 males and 838 females and investigated the association between neck circumference and other anthropometric variables by gender. RESULTS: In male subjects, the neck circumference revealed a positive correlation with the body mass index (r=0.684, p<0.01), waist circumference (r=0.686, p<0.01) and waist/hip ratio (r=0.534, p<0.01). Similarly, in female subjects neck circumference revealed a positive correlation with the body mass index (r=0.482, p<0.01), waist circumference (r=0.479, p<0.01) and waist/hip ratio (r=0.246, p<0.01). CONCLUSION: Our study has demonstrated that the positive correlation between neck circumference, which is a simple and fast anthropometric measurement, and visceral obesity, is also applicable to university students. PMID- 27119656 TI - Expression of concern: Sequences enhancing cassava mosaic disease symptoms occur in the cassava genome and are associated with South African cassava mosaic virus infection by A. T. Maredza, F. Allie, G. Plata, M. E. C. Rey. PMID- 27119657 TI - Detection and validation of one stable fiber strength QTL on c9 in tetraploid cotton. AB - Fiber strength is an essential trait of fiber property in cotton, and it is quantitatively inherited. Identification of stable quantitative trait loci (QTL) contributing to fiber strength would provide the key basis for marker-assisted selection (MAS) in cotton breeding. In this study, four interspecific hybridization populations were established with a common G. barbadense parent Pima 90-53 and two G. hirsutum parents (CCRI 8 and Handan 208), each of which had fiber strength characteristic. Based on the phenotypic data of fiber strength from seven environments, a stable QTL, qFS-c9-1, was detected and validated on c9 in a marker interval between SSR markers NAU2395 and NAU1092. The QTL explaining 14.4-17.9 % of the phenotypic variation was firstly detected in two populations (CCRI 8 * Pima 90-53, BC1F1 and BC1F2) and its derived lines in four environments. And it accounting for 12.1-14.8 % of the phenotypic variation was further confirmed in two populations (Handan 208 * Pima 90-53, BC1F1, and F2) under one environment. In silico mapping using three sequenced cotton genomes indicated that homologous genes, anchored by NAU2395 and NAU1092, were aligned to the G. arboreum genome within a physical distance between 81.10 Mbps and 87.07 Mbps. In that interval, several genes were confirmed in literatures to associate with fiber development. Among these genes, seven genes were further selected for an expression analysis through fiber development transcriptome database, revealing unique expression patterns across different stages of fiber development between CCRI 8 and Pima 90-53. The genes underlying qFS-c9-1 were favorable to fine mapping and cloning. The current study results provided valuable evidence for mapping stable QTL of fiber strength utilizing multiple populations and environments, as well as map-based cloning the candidate gene underlying the QTL for future prospective research directions. PMID- 27119658 TI - Neighborhood Frequency Effect in Chinese Word Recognition: Evidence from Naming and Lexical Decision. AB - Neighborhood frequency is a crucial variable to know the nature of word recognition. Different from alphabetic scripts, neighborhood frequency in Chinese is usually confounded by component character frequency and neighborhood size. Three experiments were designed to explore the role of the neighborhood frequency effect in Chinese and the stimuli were all two-character words. This effect was evaluated on targets with- and without-higher frequency neighbors with neighborhood size matched. Among the experiments, the patterns of the leading character frequency effect and word frequency effect in the naming and lexical decision tasks were compared. The results implied an inhibitory neighborhood frequency effect in Chinese word recognition. Accordingly, a possible cognitive mechanism of the neighborhood frequency effect was thus proposed. PMID- 27119660 TI - [Then a low pulse rate is usually harmless]. PMID- 27119659 TI - Kin-Aggregations Explain Chaotic Genetic Patchiness, a Commonly Observed Genetic Pattern, in a Marine Fish. AB - The phenomenon of chaotic genetic patchiness is a pattern commonly seen in marine organisms, particularly those with demersal adults and pelagic larvae. This pattern is usually associated with sweepstakes recruitment and variable reproductive success. Here we investigate the biological underpinnings of this pattern in a species of marine goby Coryphopterus personatus. We find that populations of this species show tell-tale signs of chaotic genetic patchiness including: small, but significant, differences in genetic structure over short distances; a non-equilibrium or "chaotic" pattern of differentiation among locations in space; and within locus, within population deviations from the expectations of Hardy-Weinberg equilibrium (HWE). We show that despite having a pelagic larval stage, and a wide distribution across Caribbean coral reefs, this species forms groups of highly related individuals at small spatial scales (<10 metres). These spatially clustered family groups cause the observed deviations from HWE and local population differentiation, a finding that is rarely demonstrated, but could be more common than previously thought. PMID- 27119663 TI - [More premature births in high fine particle dust exposure]. PMID- 27119664 TI - [Without my doctor I say nothing about the error]. PMID- 27119665 TI - [Overweight and fatigued into hypertension]. PMID- 27119666 TI - [What led to the terrible deed?]. PMID- 27119667 TI - [Does pornography access lead to sex offenses?]. PMID- 27119668 TI - [New combination heals still more patients in an even shorter period of time]. PMID- 27119669 TI - [Allergy related rarities in the erotic tension field]. PMID- 27119670 TI - ["Without knowledge of the illness one could believe in miracles!"]. PMID- 27119671 TI - [How do you manage muscle pain?"]. PMID- 27119672 TI - [In most cases conservative therapy is enough]. PMID- 27119673 TI - [Following fractures chronic pain is more frequent]. PMID- 27119674 TI - [What do the guidelines say?]. PMID- 27119675 TI - [Dual platelet inhibition - for how long?]. PMID- 27119676 TI - [Medicinal herbs and warm wraps to control recurrent cystitis]. PMID- 27119677 TI - [Are vaccinations ineffective during cortisone treatment?]. PMID- 27119678 TI - [Staying neurologically alert]. PMID- 27119679 TI - [Referral for arthroscopy becomes more tricky]. PMID- 27119680 TI - [Prevention pads your fee reserve]. PMID- 27119681 TI - [The pension bee is spontaneously provided for]. PMID- 27119682 TI - [Varicose veins? Operate!!]. PMID- 27119683 TI - [Physician network in the large city with perspective]. PMID- 27119684 TI - [Hand-in-hand with nursing]. PMID- 27119686 TI - [You may send your non-physician assistant on a vaccination tour]. PMID- 27119687 TI - [Telematics does not function this way]. PMID- 27119688 TI - [Strong position thanks to certified continuing education]. PMID- 27119689 TI - [Gluten sensitivity is real]. PMID- 27119690 TI - [Calculi not formed in the gallbladder this time]. PMID- 27119691 TI - [Good report for terminal palliative sedation]. PMID- 27119692 TI - [A rare dislocation after a fall]. PMID- 27119693 TI - [After the first stroke, acetylsalicylic acid is no longer enough]. PMID- 27119694 TI - [A 6 year old child with eyelash lice]. PMID- 27119695 TI - [Healthy microbiome - healthy person?]. PMID- 27119696 TI - [Overweight increases cancer incidence worldwide]. PMID- 27119697 TI - [Cullen sign of the abdomen refers to the pancreas]. PMID- 27119698 TI - [Is cognition impaired due to vitamin B 12 deficiency?]. PMID- 27119699 TI - [Always worthwhile--a look to the patient's hands]. PMID- 27119700 TI - [Thyroid nodules--Indication for surgery?]. PMID- 27119701 TI - [Death from fentanyl: Causative and preventive approaches in Bavaria]. PMID- 27119702 TI - [Reduced pain perception in bulimia]. PMID- 27119703 TI - [Emergency checklist: red lower leg and fever--suspected erysipelas]. PMID- 27119704 TI - [Gastrointestinal stromal tumors (GIST)--literature review]. PMID- 27119705 TI - [Trichobacteriosis palmellina]. PMID- 27119706 TI - [Great patient satisfaction with DuoResp Spiromax in routine inhalation therapy]. PMID- 27119707 TI - [Fear of severe bleeding mostly not justified]. PMID- 27119708 TI - [Degludec/liraglutide] fixed combination as a therapy alternative]. PMID- 27119709 TI - [Severe refractory eosinophilic asthma]. PMID- 27119710 TI - [The cardiovascular outcome is critical]. PMID- 27119711 TI - [Long-term treatment controls progression]. PMID- 27119712 TI - [Phytotherapy special distillate evaluated]. PMID- 27119713 TI - [In therapy there are many hurdles to overcome]. PMID- 27119714 TI - [Improving prevention and after-care]. PMID- 27119715 TI - [Greater involvement is required]. PMID- 27119716 TI - [Pain Care Award 2016]. PMID- 27119717 TI - [What is the cause of watery bloody diarrhea? It has no connection with the Arabia trip]. PMID- 27119718 TI - Bayesian State-Space Modelling of Conventional Acoustic Tracking Provides Accurate Descriptors of Home Range Behavior in a Small-Bodied Coastal Fish Species. AB - State-space models (SSM) are increasingly applied in studies involving biotelemetry-generated positional data because they are able to estimate movement parameters from positions that are unobserved or have been observed with non negligible observational error. Popular telemetry systems in marine coastal fish consist of arrays of omnidirectional acoustic receivers, which generate a multivariate time-series of detection events across the tracking period. Here we report a novel Bayesian fitting of a SSM application that couples mechanistic movement properties within a home range (a specific case of random walk weighted by an Ornstein-Uhlenbeck process) with a model of observational error typical for data obtained from acoustic receiver arrays. We explored the performance and accuracy of the approach through simulation modelling and extensive sensitivity analyses of the effects of various configurations of movement properties and time steps among positions. Model results show an accurate and unbiased estimation of the movement parameters, and in most cases the simulated movement parameters were properly retrieved. Only in extreme situations (when fast swimming speeds are combined with pooling the number of detections over long time-steps) the model produced some bias that needs to be accounted for in field applications. Our method was subsequently applied to real acoustic tracking data collected from a small marine coastal fish species, the pearly razorfish, Xyrichtys novacula. The Bayesian SSM we present here constitutes an alternative for those used to the Bayesian way of reasoning. Our Bayesian SSM can be easily adapted and generalized to any species, thereby allowing studies in freely roaming animals on the ecological and evolutionary consequences of home ranges and territory establishment, both in fishes and in other taxa. PMID- 27119719 TI - Nonfasting for Routine Lipid Testing: From Evidence to Action. PMID- 27119720 TI - Autonomous Visual Navigation of an Indoor Environment Using a Parsimonious, Insect Inspired Familiarity Algorithm. AB - The navigation of bees and ants from hive to food and back has captivated people for more than a century. Recently, the Navigation by Scene Familiarity Hypothesis (NSFH) has been proposed as a parsimonious approach that is congruent with the limited neural elements of these insects' brains. In the NSFH approach, an agent completes an initial training excursion, storing images along the way. To retrace the path, the agent scans the area and compares the current scenes to those previously experienced. By turning and moving to minimize the pixel-by-pixel differences between encountered and stored scenes, the agent is guided along the path without having memorized the sequence. An important premise of the NSFH is that the visual information of the environment is adequate to guide navigation without aliasing. Here we demonstrate that an image landscape of an indoor setting possesses ample navigational information. We produced a visual landscape of our laboratory and part of the adjoining corridor consisting of 2816 panoramic snapshots arranged in a grid at 12.7-cm centers. We show that pixel-by-pixel comparisons of these images yield robust translational and rotational visual information. We also produced a simple algorithm that tracks previously experienced routes within our lab based on an insect-inspired scene familiarity approach and demonstrate that adequate visual information exists for an agent to retrace complex training routes, including those where the path's end is not visible from its origin. We used this landscape to systematically test the interplay of sensor morphology, angles of inspection, and similarity threshold with the recapitulation performance of the agent. Finally, we compared the relative information content and chance of aliasing within our visually rich laboratory landscape to scenes acquired from indoor corridors with more repetitive scenery. PMID- 27119721 TI - Promising 2-Pronged Approach to Genetic Basis of Bipolar Disorder. PMID- 27119722 TI - Relaxation Techniques for Trauma. AB - Physiological symptoms of posttraumatic stress disorder (PTSD) manifest as increased arousal and reactivity seen as anger outburst, irritability, reckless behavior with no concern for consequences, hypervigilance, sleep disturbance, and problems with focus (American Psychiatric Association, 2013 ). In seeking the most beneficial treatment for PTSD, consideration must be given to the anxiety response. Relaxation techniques are shown to help address the physiological manifestations of prolonged stress. The techniques addressed by the authors in this article include mindfulness, deep breathing, yoga, and meditation. By utilizing these techniques traditional therapies can be complemented. In addition, those who are averse to the traditional evidence-based practices or for those who have tried traditional therapies without success; these alternative interventions may assist in lessening physiological manifestations of PTSD. Future research studies assessing the benefits of these treatment modalities are warranted to provide empirical evidence to support the efficacy of these treatments. PMID- 27119723 TI - Morphological study of efficacy of clarithromycin-loaded nanocarriers for treatment of biofilm infection disease. AB - In this study, we developed a drug delivery system (DDS) using polymeric nanocarriers for the treatment of biofilm infection disease. Clarithromycin (CAM) encapsulated and chitosan (CS) modified polymeric nanoparticles (NPs) were prepared using a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(r)) (Sol) and poly-(DL-lactide-co-glycolide), respectively. To understand the availability of the prepared NPs, we made morphological observations of the antibacterial activity derived from the NPs toward the bacterial cells within the biofilm using scanning electron microscopy and transmission electron microscopy measurements. These results revealed different antibacterial activities for the two types of drug carriers. In the case of CAM-encapsulated + CS-modified Sol micelles treatment, NPs can exert their antibacterial activity not only by the surfactant, CAM and CS effects but also by intrusion into the bacterial cells. Thereby, CAM-encapsulated + CS modified Sol micelles had a higher antibacterial activity. The morphological information is useful to design suitable NPs for the treatment against biofilm infections. PMID- 27119724 TI - The Unfolded Protein Response in Homeostasis and Modulation of Mammalian Immune Cells. AB - The endoplasmic reticulum (ER) plays important roles in eukaryotic protein folding and lipid biosynthesis. Several exogenous and endogenous cellular sources of stress can perturb ER homeostasis leading to the accumulation of unfolded proteins in the lumen. Unfolded protein accumulation triggers a signal transduction cascade known as the unfolded protein response (UPR), an adaptive mechanism which aims to protect cells from protein aggregates and to restore ER functions. Further to this protective mechanism, in immune cells, UPR molecular effectors have been shown to participate in a wide range of biological processes such as cell differentiation, survival and immunoglobulin and cytokine production. Recent findings also highlight the involvement of the UPR machinery in the maturational program and antigen presentation capacities of dendritic cells. UPR is therefore a key element in immune system homeostasis with direct implications on both adaptive and innate immune responses. The present review summarizes the knowledge on the emerging roles of UPR signaling cascades in mammalian immune cells as well as the consequences of their dysregulation in relation to the pathogenesis of several diseases. PMID- 27119725 TI - Structural and Molecular Mechanism of CdpR Involved in Quorum-Sensing and Bacterial Virulence in Pseudomonas aeruginosa. AB - Although quorum-sensing (QS) systems are important regulators of virulence gene expression in the opportunistic human pathogen Pseudomonas aeruginosa, their detailed regulatory mechanisms have not been fully characterized. Here, we show that deletion of PA2588 resulted in increased production of pyocyanin and biofilm, as well as enhanced pathogenicity in a mouse model. To gain insights into the function of PA2588, we performed a ChIP-seq assay and identified 28 targets of PA2588, including the intergenic region between PA2588 and pqsH, which encodes the key synthase of Pseudomonas quinolone signal (PQS). Though the C terminal domain was similar to DNA-binding regions of other AraC family members, structural studies revealed that PA2588 has a novel fold at the N-terminal region (NTR), and its C-terminal HTH (helix-turn-helix) domain is also unique in DNA recognition. We also demonstrated that the adaptor protein ClpS, an essential regulator of ATP-dependent protease ClpAP, directly interacted with PA2588 before delivering CdpR to ClpAP for degradation. We named PA2588 as CdpR (ClpAP degradation and pathogenicity Regulator). Moreover, deletion of clpP or clpS/clpA promotes bacterial survival in a mouse model of acute pneumonia infection. Taken together, this study uncovered that CdpR is an important QS regulator, which can interact with the ClpAS-P system to regulate the expression of virulence factors and pathogenicity. PMID- 27119726 TI - Probing the structures of gold-aluminum alloy clusters AuxAly(-): a joint experimental and theoretical study. AB - Besides the size and structure, compositions can also dramatically affect the properties of alloy nanoclusters. Due to the added degrees of freedom, determination of the global minimum structures for multi-component nanoclusters poses even greater challenges, both experimentally and theoretically. Here we report a systematic and joint experimental/theoretical study of a series of gold aluminum alloy clusters, AuxAly(-) (x + y = 7,8), with various compositions (x = 1-3; y = 4-7). Well-resolved photoelectron spectra have been obtained for these clusters at different photon energies. Basin-hopping global searches, coupled with density functional theory calculations, are used to identify low-lying structures of the bimetallic clusters. By comparing computed electronic densities of states of the low-lying isomers with the experimental photoelectron spectra, the global minima are determined. It is found that for y >= 6 there is a strong tendency to form the magic-number square bi-pyramid motif of Al6(-) in the AuxAly(-) clusters, suggesting that the Al-Al interaction dominates the Au-Au interaction in the mixed clusters. A closely related trend is that for x > 1, the gold atoms tend to be separated by Al atoms unless only the magic-number Al6(-) square bi-pyramid motif is present, suggesting that in the small-sized mixed clusters, Al and Au components do not completely mix with one another. Overall, the Al component appears to play a more dominant role due to the high robustness of the magic-number Al6(-) square bi-pyramid motif, whereas the Au component tends to be either "adsorbed" onto the Al6(-) square bi-pyramid motif if y >= 6, or stays away from one another if x < y < 6. PMID- 27119727 TI - Segmentation of peritumoral oedema offers a valuable radiological feature of cerebral metastasis. AB - OBJECTIVE: Peritumoral oedema (PTO) is commonly observed on MRI in malignant brain tumours including brain metastasis (bMET) and glioblastoma multiforme (GBM). This study aimed to differentiate bMET from GBM by comparing the volume ratio of PTO to tumour lesion (Rvol). METHODS: 56 patients with solitary bMET or GBM were enrolled, and MRI was analyzed by a semi-automatic methodology based on MATLAB (Mathworks, Natick, MA). The PTO volume (Voedema) was segmented for quantification using T2 fluid-attenuated inversion-recovery images, while the tumour volume was quantified with enhanced T1 images. The quantitative volume of the tumour, PTO and the ratio of PTO to tumour were interpreted using SPSS((r)) (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) by considering different locations and pathologies. RESULTS: The tumour volumes of supratentorial GBM, supratentorial bMET (supra-bMET) and infratentorial bMET were 32.22 +/- 21.9, 18.45 +/- 17.28 and 11.40 +/- 5.63 ml, respectively. The corresponding Voedema were 44.08 +/- 25.84, 73.20 +/- 40.35 and 23.74 +/- 7.78 ml, respectively. The Voedema difference between supratentorial and infratentorial lesions is significant (p-value = 0.002). Supra-bMET has a smaller tumour volume (p-value = 0.032), but a larger PTO (p-value = 0.007). The ratio of Voedema to the tumour volume in bMET is statistically higher than that in GBM (p value = 0.015). The cut-off ratio for identifying bMET from GBM is 3.9, with a specificity and sensitivity of 90.0% and 68.8%, respectively. CONCLUSION: Segmentation is an efficient method to quantify irregular PTO. bMET possesses more extensive oedema with smaller tumour volume than does GBM. The Rvol is a valuable index to distinguish bMET from GBM. ADVANCES IN KNOWLEDGE: This study presents a new method for the quantitation of PTO to differentiate bMET from GBM. PMID- 27119728 TI - Effect of diosgenin, a steroidal sapogenin, on the rat skeletal system. AB - Diosgenin is a steroidal sapogenin present in fenugreek and Dioscorea spp. as glycosides (saponins). Diosgenin has already been reported to inhibit osteoclastogenesis and to stimulate osteogenic activity of osteoblastic cells in vitro, and to exert some antiosteoporotic effects in rats in vivo. The aim of the present study was to investigate the effects of diosgenin administration on the skeletal system of rats with normal estrogen level and with estrogen deficiency induced by bilateral ovariectomy. The experiments were carried out on 3-month-old non-ovariectomized and ovariectomized Wistar rats, divided into control rats and rats receiving diosgenin (50 mg/kg p.o. daily) for 4 weeks. Serum bone turnover markers, bone mass and mineralization, histomorphometric parameters and mechanical properties were studied. Diosgenin improved some investigated parameters in both non-ovariectomized and ovariectomized rats, in which estrogen deficiency induced osteoporotic changes. Diosgenin increased compact bone formation and probably inhibited cancellous bone resorption, which led to improvement of mechanical properties of compact and cancellous bone. In conclusion, this in vivo study demonstrated that diosgenin may be one of sparse compounds increasing bone formation. PMID- 27119729 TI - Association and polymorphism study of seven candidate genes with reproductive traits in three pig breeds in Hungary. AB - Seven genes (BF, EGF, ESR, FSHB, H2AFZ, LEP and PRLP) were studied as candidate gene influencing eleven reproduction traits (interval between litters (IBL), percent of litter (PL), number of litters (NL), number of piglets born dead (NBD), number of piglet born alive (NBA), total number born (TNB), mean of born alive (MBA), mean of born dead (MBD), mean of born total (MBT), mean of piglets at 21 days of age (M21D) and growth rate (GR) in three pig breeds (Hungarian Large White (HLW), Duroc and Pietrain) by PCR-RFLP. Based on the observed vs. expected genotypes frequencies populations across loci were in Hardy-Weinberg equilibrium (P>0.05). In case HLW breed ESR and FSHbeta genes were in disequilibrium. Association study suggested that only EGF gene showed significant influence on the trait NBA and TNB. The AA genotype are preferable for sows, associated with higher NBA and TNB. The longest IBL, and the highest NL is associated with AB and AA genotype of EGF gene. IBL is significantly shorter in case of pigs with AB and AA alleles than BB alleles of PRLP genes. Selection for these SNPs could improve the reproductivity in the studied breeds. PMID- 27119731 TI - [Nonsmoker protection works]. PMID- 27119730 TI - Revelation of Influencing Factors in Overall Codon Usage Bias of Equine Influenza Viruses. AB - Equine influenza viruses (EIVs) of H3N8 subtype are culprits of severe acute respiratory infections in horses, and are still responsible for significant outbreaks worldwide. Adaptability of influenza viruses to a particular host is significantly influenced by their codon usage preference, due to an absolute dependence on the host cellular machinery for their replication. In the present study, we analyzed genome-wide codon usage patterns in 92 EIV strains, including both H3N8 and H7N7 subtypes by computing several codon usage indices and applying multivariate statistical methods. Relative synonymous codon usage (RSCU) analysis disclosed bias of preferred synonymous codons towards A/U-ended codons. The overall codon usage bias in EIVs was slightly lower, and mainly affected by the nucleotide compositional constraints as inferred from the RSCU and effective number of codon (ENc) analysis. Our data suggested that codon usage pattern in EIVs is governed by the interplay of mutation pressure, natural selection from its hosts and undefined factors. The H7N7 subtype was found less fit to its host (horse) in comparison to H3N8, by possessing higher codon bias, lower mutation pressure and much less adaptation to tRNA pool of equine cells. To the best of our knowledge, this is the first report describing the codon usage analysis of the complete genomes of EIVs. The outcome of our study is likely to enhance our understanding of factors involved in viral adaptation, evolution, and fitness towards their hosts. PMID- 27119732 TI - A Versatile Method for the Preparation of Ferroelectric Supramolecular Materials via Radical End-Functionalization of Vinylidene Fluoride Oligomers. AB - A synthetic method for the end-functionalization of vinylidene fluoride oligomers (OVDF) via a radical reaction between terminal olefins and I-OVDF is described. The method shows a wide substrate scope and excellent conversions, and permits the preparation of different disc-shaped cores such as benzene-1,3,5 tricarboxamides (BTAs), perylenes bisimide (PBI), and phthalocyanines (Pc) bearing three to eight ferroelectric oligomers at their periphery. The formation, purity, OVDF conformation, and morphology of the final adducts has been assessed by a combination of techniques, such as NMR, size exclusion chromatography, differential scanning calorimetry, polarized optical microscopy, and atomic force microscopy. Finally, PBI-OVDF and Pc-OVDF materials show ferroelectric hysteresis behavior together with high remnant polarizations, with values as high as Pr ~ 37 mC/m(2) for Pc-OVDF. This work demonstrates the potential of preparing a new set of ferroelectric materials simply by attaching OVDF oligomers to different small molecules. The use of carefully chosen small molecules paves the way to new functional materials in which ferroelectricity and electrical conductivity or light-harvesting properties coexist in a single compound. PMID- 27119733 TI - Systematic review of physiotherapy interventions to improve gross motor capacity and performance in children and adolescents with an acquired brain injury. AB - AIM: To systematically review the efficacy of physiotherapy interventions to improve gross motor capacity, performance and societal participation in children aged 5-17 years with an acquired brain injury (ABI). METHODS: Randomized and non randomized controlled trials, cohort, case series, case-control and case studies were included and classified according to grades of evidence. Methodological quality of studies was assessed using the Downs and Black (D&B) scale and quantitative data was analysed using effect sizes. RESULTS: Two home-based studies investigated functional strength training (one randomized controlled trial, n = 20, level 2b, D&B = 16/32 and one non-randomized self-control study, n = 19, level 4, D&B = 15/32). Four studies evaluated virtual reality including: one pilot study, n = 50, level 4, D&B = 22/32; one single-subject, non concurrent, randomized multiple baseline study, n = 3, level 4, D&B = 15/32; one case series study, n = 2, level 4, D&B = 15/32; one case study, n = 1, level 4, D&B = 15/32. Effect sizes for the randomized controlled trial ranged between 0.30 1.29 for the Functional Reach and Timed Up and Go outcome measures. CONCLUSION: There is preliminary evidence to support the efficacy of physiotherapy interventions to improve gross motor outcomes in children with an ABI. Both functional strength training and virtual-reality based therapy are potential treatment options for clinicians to prescribe in either home or clinical settings. PMID- 27119734 TI - Downregulated ECRG4 is correlated with lymph node metastasis and predicts poor outcome for nasopharyngeal carcinoma patients. AB - OBJECTIVE: Esophageal cancer-related gene 4 (ECRG4) is a new candidate tumor suppressor gene. In this retrospective study, we evaluated ECRG4 protein expression in patients with nasopharyngeal carcinoma (NPC) under curative treatment and examined its association with pathological features and clinical outcomes as a possible biomarker for diagnosis and prognosis of NPC. METHODS: We enrolled 122 patients with a first diagnosis between January 2001 and December 2003. Tumor tissue and control tissue from biopsies underwent immunohistochemical staining for ECRG4. ECRG4 expression was analyzed by clinicopathological variables. After Kaplan-Meier survival analysis, we used Cox proportional hazards regression to estimate the predictive effect of ECRG4 expression on overall survival. RESULTS: ECRG4 protein level was lower in NPC than control tissue (P < 0.01). It was inversely related to node status (P < 0.001) and clinical stage (P = 0.027). ECRG4 expression was associated with overall survival, and downregulated ECRG4 expression was an independent prognostic factor of poor survival (hazard ratio = 0.677, 95 % confidence interval 0.463-0.989, P = 0.044). CONCLUSIONS: A significant NPC patients showed downregulated ECRG4 expression, which is correlated with lymph node metastasis. The marker could be an independent prognostic factor for NPC patients. The precise function of ECRG4 in the progression of NPC, especially for lymphatic metastasis, deserves further investigation, which would bring a new target for personalized therapy. PMID- 27119735 TI - Caspase-1 Activation Protects Lung Endothelial Barrier Function during Infection Induced Stress. AB - Dysregulated activation of the inflammasome-caspase-1-IL-1beta axis elicits damaging hyperinflammation during critical illnesses, such as pneumonia and sepsis. However, in critical illness models of Salmonella infection, burn, or shock, caspase-1 inhibition worsens outcomes. These paradoxical effects suggest that caspase-1 drives novel protective responses. Whether the protective effects of caspase-1 activation involve canonical immune cell and/or nonimmune cell responses is unknown. The objective of this study was to test the hypothesis that, in addition to its recognized proinflammatory function, caspase-1 initiates protective stress responses in nonimmune cells. In vivo, lung epithelial and endothelial barrier function and inflammation were assessed in mice infected with Pseudomonas aeruginosa in the presence or absence of a caspase-1 inhibitor. Lung endothelial barrier function was assessed ex vivo in isolated, perfused rat lungs infected with P. aeruginosa in the presence or absence of a caspase-1 inhibitor. Endothelial barrier function during P. aeruginosa infection was assessed in vitro in cultured rat wild-type pulmonary microvascular endothelial cells (PMVECs) or recombinant PMVECs engineered to decrease caspase-1 expression. We demonstrated in vivo that caspase-1 inhibition in P. aeruginosa-infected mice ameliorated hyperinflammation, but, counterintuitively, increased pulmonary edema. Ex vivo, caspase-1 inhibition increased pulmonary permeability in P. aeruginosa-infected isolated rat lungs. To uncouple caspase-1 from its canonical inflammatory role, we used cultured rat PMVECs in vitro and discovered that genetic knockdown of caspase-1 accelerated P. aeruginosa-induced barrier disruption. In conclusion, caspase-1 is a sentinel stress-response regulator that initiates proinflammatory responses and also initiates novel response(s) to protect PMVEC barrier function during pneumonia. PMID- 27119736 TI - Chemical-Induced Read-Through at Premature Termination Codons Determined by a Rapid Dual-Fluorescence System Based on S. cerevisiae. AB - Nonsense mutations generate in-frame stop codons in mRNA leading to a premature arrest of translation. Functional consequences of premature termination codons (PTCs) include the synthesis of truncated proteins with loss of protein function causing severe inherited or acquired diseases. A therapeutic approach has been recently developed that is based on the use of chemical agents with the ability to suppress PTCs (read-through) restoring the synthesis of a functional full length protein. Research interest for compounds able to induce read-through requires an efficient high throughput large scale screening system. We present a rapid, sensitive and quantitative method based on a dual-fluorescence reporter expressed in the yeast Saccharomyces cerevisiae to monitor and quantitate read through at PTCs. We have shown that our novel system works equally well in detecting read-through at all three PTCs UGA, UAG and UAA. PMID- 27119737 TI - 3D position determination in monolithic crystals coupled to SiPMs for PET. AB - The interest in using continuous monolithic crystals in positron emission tomography (PET) has grown in the last years. Coupled to silicon photomultipliers (SiPMs), the detector can combine high sensitivity and high resolution, the two main factors to be maximized in a positron emission tomograph. In this work, the position determination capability of a detector comprised of a [Formula: see text] mm(3) LYSO crystal coupled to an [Formula: see text]-pixel array of SiPMs is evaluated. The 3D interaction position of gamma-rays is estimated using an analytical model of the light distribution including reflections on the facets of the crystal. Monte Carlo simulations have been performed to evaluate different crystal reflectors and geometries. The method has been characterized and applied to different cases. Intrinsic resolution obtained with the position estimation method used in this work, applied to experimental data, achieves sub-millimetre resolution values. Average resolution over the detector surface for 5 mm thick crystal is ~0.9 mm FWHM and ~1.2 mm FWHM for 10 mm thick crystal. Depth of interaction resolution is close to 2 mm FWHM in both cases, while the FWTM is ~5.3 mm for 5 mm thick crystal and ~9.6 mm for 10 mm thick crystal. PMID- 27119738 TI - Evaluation of different diagnostic methods of American Cutaneous Leishmaniasis in the Brazilian Amazon. AB - Epidemiological studies have been conducted to better understand the dynamics of American Cutaneous Leishmaniasis (ACL) in the Amazon region where distinct species of Leishmania circulate. In endemic areas, the optimal diagnosis must be made in the earlier clinical presentation to avoid the complications of chronic disease. The scarcity of financial support, laboratory infrastructure and trained persons are the major obstacles in this reality. This paper describes the result of performing different diagnostic methods for ACL in Amazonas State between the years 2010 and 2011. The tests used were the intradermal skin test (Montenegro's skin test), ELISA (Enzyme-Linked Immunosorbent Assay), direct examination, culture isolation and identification of Leishmania species. A total of 38 suspected human cases of ACL were diagnosed by different methods, of which 71.0% (n = 27) were positive by direct examination, 75.6% (n = 28) had positivity in the culture isolates and, of these, 54.0% (n = 19) had infection with Leishmania (Viannia) guyanensis. The positivity of the intradermal skin test with the leishmanin solution was observed in 77.0% of cases analyzed and the serology with detection of IgG and IgM showed the presence of antibodies in 100% of exams realized results, showing variation in the titles of antibodies. The success of Leishmaniasis treatment depends on an effective and early diagnosis. Parasitological diagnosis is highly specific, but sensitivity is subject to variation because the tissue distribution of parasites generally is not homogeneous and depends on the specie of parasite. Moreover, parasitological tests require invasive procedures and depend on restrictive conditions for the collection of biological sample, which limit their use in large-scale for epidemiological studies. ELISA has been the most widely used serological method for the diagnosis of Visceral Leishmaniasis (VL) as it is easy to perform and has a low cost. However, flaws in specificity are observed in the diagnosis of cutaneous leishmaniasis. Actually the diagnosis needs to be done as an associated methods depending on the question to be solved. PMID- 27119739 TI - De Novo Adult Transcriptomes of Two European Brittle Stars: Spotlight on Opsin Based Photoreception. AB - Next generation sequencing (NGS) technology allows to obtain a deeper and more complete view of transcriptomes. For non-model or emerging model marine organisms, NGS technologies offer a great opportunity for rapid access to genetic information. In this study, paired-end Illumina HiSeqTM technology has been employed to analyse transcriptomes from the arm tissues of two European brittle star species, Amphiura filiformis and Ophiopsila aranea. About 48 million Illumina reads were generated and 136,387 total unigenes were predicted from A. filiformis arm tissues. For O. aranea arm tissues, about 47 million reads were generated and 123,324 total unigenes were obtained. Twenty-four percent of the total unigenes from A. filiformis show significant matches with sequences present in reference online databases, whereas, for O. aranea, this percentage amounts to 23%. In both species, around 50% of the predicted annotated unigenes were significantly similar to transcripts from the purple sea urchin, the closest species to date that has undergone complete genome sequencing and annotation. GO, COG and KEGG analyses were performed on predicted brittle star unigenes. We focused our analyses on the phototransduction actors involved in light perception. Firstly, two new echinoderm opsins were identified in O. aranea: one rhabdomeric opsin (homologous to vertebrate melanopsin) and one RGR opsin. The RGR-opsin is supposed to be involved in retinal regeneration while the r-opsin is suspected to play a role in visual-like behaviour. Secondly, potential phototransduction actors were identified in both transcriptomes using the fly (rhabdomeric) and mammal (ciliary) classical phototransduction pathways as references. Finally, the sensitivity of O.aranea to monochromatic light was investigated to complement data available for A. filiformis. The presence of microlens-like structures at the surface of dorsal arm plate of O. aranea could potentially explain phototactic behaviour differences between the two species. The results confirm (i) the ability of these brittle stars to perceive light using opsin-based photoreception, (ii) suggest the co-occurrence of both rhabdomeric and ciliary photoreceptors, and (iii) emphasise the complexity of light perception in this echinoderm class. PMID- 27119740 TI - Finite Element Analysis of Foot and Ankle Impact Injury: Risk Evaluation of Calcaneus and Talus Fracture. AB - INTRODUCTION: Foot and ankle impact injury is common in geriatric trauma and often leads to fracture of rearfoot, including calcaneus and talus. The objective of this study was to assess the influence of foot impact on the risk of calcaneus and talus fracture via finite element analysis. METHODS: A three-dimensional finite element model of foot and ankle was constructed based on magnetic resonance images of a female aged 28. The foot sustained a 7-kg passive impact through a foot plate. The simulated impact velocities were from 2.0 to 7.0 m/s with 1.0 m/s interval. RESULTS: At 5.0 m/s impact velocity, the maximum von Mises stress of the trabecular calcaneus and talus were 3.21MPa and 2.41MPa respectively, while that of the Tresca stress were 3.46MPa and 2.55MPa. About 94% and 84% of the trabecular calcaneus and talus exceeded the shear yielding stress, while 21.7% and 18.3% yielded the compressive stress. The peak stresses were distributed around the talocalcaneal articulation and the calcaneal tuberosity inferiorly, which corresponded to the common fracture sites. CONCLUSIONS: The prediction in this study showed that axial compressive impact at 5.0 m/s could produce considerable yielding of trabecular bone in both calcaneus and talus, dominantly by shear and compounded with compression that predispose the rearfoot in the risk of fracture. This study suggested the injury pattern and fracture mode of high energy trauma that provides insights in injury prevention and fracture management. PMID- 27119741 TI - Frequency of Cry1F Non-Recessive Resistance Alleles in North Carolina Field Populations of Spodoptera frugiperda (Lepidoptera: Noctuidae). AB - Fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a target species of transgenic corn (Zea mays L.) that expresses single and pyramided Bacillus thuringiensis (Bt) toxin. In 2014, S. frugiperda were collected from a light trap in North Carolina, and a total of 212 F1/F2 isofemale lines of S. frugiperda were screened for resistance to Bt and non-Bt corn. All of the 212 isolines were susceptible to corn tissue expressing Cry1A.105 + Cry2Ab, Cry1F + Cry1A.105 + Cry2Ab, and Cry1F + Cry1Ab + Vip3Aa20. Growth rate bioassays were performed to isolate non-recessive Bt resistance alleles. Seven individuals out of the 212 isofemale lines carried major non-recessive alleles conferring resistance to Cry1F. A pooled colony was created from the seven individuals. This colony was 151.21 times more resistant to Cry1F than a known-susceptible population and was also resistant to Cry1A.105, but was not resistant to Cry2Ab and Vip3Aa20. The results demonstrate that field populations of S. frugiperda collected from North Carolina are generally susceptible to Cry1F, but that some individuals carry resistant alleles. The data generated in this study can be used as baseline data for resistance monitoring. PMID- 27119742 TI - Anatomical Knowledge for the Infra-Pyloric Vein Preservation during the Laparoscopy-Assisted Pylorus-Preserving Gastrectomy. AB - BACKGROUND: Fine anatomical knowledge enables us to use safer laparoscopy assisted pylorus-preserving gastrectomy (LAPPG). Detailed anatomical knowledge of the infra-pyloric vein (IPV) remains obscure. In this study, the aim was to classify the IPV vessel flow. METHODS: From April 2009 to November 2012, 43 patients with clinical T1 gastric cancer underwent LAPPG with preservation of IPV. Operative videos were retrospectively reviewed, and an anatomical classification of IPV was proposed. RESULTS: The IPV flow came into the right gastro-epiploic vein (RGEV) and/or the anterior superior pancreaticoduodenal vein (ASPDV). The IPV anatomical flow pattern was classified according to the following 4 types: Type I, the IPV more than 2 flow into RGEV; Type IIa, only 1 IPV into RGEV without into ASPDV; Type IIb, one IPV flow into RGEV and one flow into ASPDV; Type III, IPV only into ASPDV. The proportion of each type was 39.5% (17/43) in Type I, 30.2% (13/43) in Type IIa, 14% (6/43) in Type IIb, and 16.3% (7/43) in Type III. CONCLUSIONS: The anatomical flow pattern of the IPV was described. It would be beneficial to improve the anatomical knowledge of the IPV for more elaborate and safer lymph node dissection during laparoscopic gastrectomy. PMID- 27119743 TI - Access to Awareness for Faces during Continuous Flash Suppression Is Not Modulated by Affective Knowledge. AB - It is a controversially debated topic whether stimuli can be analyzed up to the semantic level when they are suppressed from visual awareness during continuous flash suppression (CFS). Here, we investigated whether affective knowledge, i.e., affective biographical information about faces, influences the time it takes for initially invisible faces with neutral expressions to overcome suppression and break into consciousness. To test this, we used negative, positive, and neutral famous faces as well as initially unfamiliar faces, which were associated with negative, positive or neutral biographical information. Affective knowledge influenced ratings of facial expressions, corroborating recent evidence and indicating the success of our affective learning paradigm. Furthermore, we replicated shorter suppression durations for upright than for inverted faces, demonstrating the suitability of our CFS paradigm. However, affective biographical information did not modulate suppression durations for newly learned faces, and even though suppression durations for famous faces were influenced by affective knowledge, these effects did not differ between upright and inverted faces, indicating that they might have been due to low-level visual differences. Thus, we did not obtain unequivocal evidence for genuine influences of affective biographical information on access to visual awareness for faces during CFS. PMID- 27119744 TI - Transcriptome Analysis of Piperlongumine-Treated Human Pancreatic Cancer Cells Reveals Involvement of Oxidative Stress and Endoplasmic Reticulum Stress Pathways. AB - Piperlongumine (PL), an alkaloid obtained from long peppers, displays antitumorigenic properties for a variety of human cell- and animal-based models. The aim of this study was to identify the underlying molecular mechanisms for PL anticancer effects on human pancreatic cancer cells. RNA sequencing (RNA-seq) was used to identify the effects of PL on the transcriptome of MIA PaCa-2 human pancreatic cancer cells. PL treatment of pancreatic cancer cells resulted in differential expression of 683 mRNA transcripts with known protein functions, 351 of which were upregulated and 332 of which were downregulated compared to control treated cells. Transcripts associated with oxidative stress, endoplasmic reticulum (ER) stress, and unfolded protein response pathways were significantly overexpressed with PL treatment. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to validate the RNA-seq results, which included upregulation of HO-1, IRE1alpha, cytochrome c, and ASNS. The results provide key insight into the mechanisms by which PL alters cancer cell physiology and identify that activation of oxidative stress and ER stress pathways is a critical avenue for PL anticancer effects. PMID- 27119749 TI - Diagnostic criteria for adrenal venous sampling. AB - PURPOSE OF REVIEW: Primary aldosteronism accounts for 3 to 5% of all hypertension cases. Unilateral aldosterone hypersecretion can be treated with adrenalectomy. Guidelines for primary aldosteronism management recommend adrenal vein sampling (AVS) to ascertain unilateral primary aldosteronism before surgery. Many different protocols are used to perform AVS and for the interpretation of its results, but without hard evidence of why one should be given preference. Experts have proposed recommendations to guide clinical practice and the grounds for future research to address this situation. RECENT FINDINGS: Proper patient preparation is a prerequisite for interpretable results. New trends are emerging to improve adequate cannulation of adrenal veins including: training of a limited number of dedicated radiologists, contrast computed tomography of adrenal veins before or during AVS, and rapid assays to measure cortisol concentrations during AVS. Cosyntropin stimulation is performed in several centers to avoid the variability of cortisol secretion during AVS, but whether this improves diagnostic performance is unknown. SUMMARY: Better markers of adequate catheter placement are currently under investigation, including other adrenal steroids and metanephrines. Innovative strategies for interpreting partially failed AVS are also being developed. Other approaches to ascertain primary aldosteronism subtype will be necessary because of limited patient access to AVS. PMID- 27119750 TI - Novel targeted therapies in adrenocortical carcinoma. AB - PURPOSE OF REVIEW: Adrenocortical carcinoma is a rare cancer, but one that carries a poor prognosis due to its aggressive nature and unresponsiveness to conventional chemotherapeutic strategies. Over the past 12 years, there has been renewed interest in developing new therapies for this cancer, including identifying key signaling nodes responsible for cell proliferation. RECENT FINDINGS: Clinical trials of tyrosine kinase inhibitors as monotherapy have generally been disappointing, although the identification of exceptional responders may lead to the identification of targeted therapies that may produce responses in subsets of patients. Agents targeted to the Wnt signaling pathway, a known player in adrenal carcinogenesis, have been developed, although they have not yet been used specifically for adrenal cancer. There is current excitement about inhibitors of acetyl-coA cholesterol acetyl transferase 1, an enzyme required for intracellular cholesterol handling, although trials are still underway. Tools to target other proteins such as Steroidogenic Factor 1 and mechanistic target of rapamycin have been developed and are moving towards clinical application. SUMMARY: Progress is being made in the fight against adrenocortical carcinoma with the identification of new therapeutic targets and new means by which to attack them. Continued improvement in the prognosis for patients with adrenal cancer is expected as this research continues. PMID- 27119751 TI - Immunohistochemistry of the adrenal in primary aldosteronism. AB - PURPOSE OF REVIEW: Primary aldosteronism is a major cause of hypertension; aldosterone-producing adenomas (APA) cause about half of primary aldosteronism; idiopathic hyperplasia of adrenal glomerulosa cells are responsible for the rest. A surprising variety of mutations have recently been identified in ion channels and pumps in a significant number of APA. The present review addresses histological and molecular aspects of APA and the surrounding adrenal. RECENT FINDINGS: Specific antibodies against the CYP11B2 and CYP11B1 enzymes, the last enzyme in aldosterone and cortisol synthesis, respectively, allow for the first time study of the steroidogenic capabilities of cells within the APA and adjacent adrenal. Cells expressing CYP11B2 may be scattered and/or in clusters throughout the normal adrenal zona glomerulosa. APA differ widely in the number of cells expressing CYP11B2; some did not express it at all, but were surrounded by cells, some in clusters or micronodules, that expressed CYP11B2. Some APAs also comprised cells expressing both CYP11B1 and CYP17A1. In some samples, analysis of the tissue adjacent to APA detected ion channel and pump mutations heretofore associated only with APA. SUMMARY: APAs have a complex structure and expression of steroidogenic enzymes. PMID- 27119752 TI - Current advances in intratumoral androgen metabolism in castration-resistant prostate cancer. AB - PURPOSE OF REVIEW: Androgen deprivation therapy is a cornerstone in the treatment of advanced prostate cancer and has extended the lives of countless patients. Unfortunately, many of these patients eventually succumb to metastatic castration resistant prostate cancer (mCRPC). The efficacy of abiraterone acetate (AA, Zytiga) and enzalutamide (Enza, Xtandi) in the mCRPC setting prove that these tumors remain androgen-driven. We review recent studies that have shown that intratumoral androgen biosynthesis plays a significant role in the ever-evolving mCRPC tumor and we discuss the therapeutic implications of these findings. RECENT FINDINGS: A novel abiraterone metabolite, 17-(pyridin-3-yl)androsta-4,16-dien-3 one (D4A), possesses robust antitumor activity in rodent models via the inhibition of androgen biosynthetic enzymes and antagonism of the androgen receptor. The TMPRSS2 : ERG fusion drives aldo-keto reductase 1C3 (AKR1C3) expression and activity to facilitate androgen biosynthesis and activate the androgen receptor in prostate cancer. Intracrine androgen formation and AKR1C3 expression and activity have been found to confer resistance to enzalutamide. SUMMARY: These studies highlight the significant role that intratumoral androgen biosynthesis plays in the mCRPC tumor. The therapeutic implications include the inhibition of AKR1C3 in tumors that become resistant to current drugs such as abiraterone acetate or Enza and the potential administration of D4A as an mCRPC therapeutic. PMID- 27119753 TI - Tumoral Vitamin D Synthesis by CYP27B1 1-alpha-Hydroxylase Delays Mammary Tumor Progression in the PyMT-MMTV Mouse Model and Its Action Involves NF-kappaB Modulation. AB - Biologically active vitamin D (1,25-dihydroxycholecalciferol or 1,25(OH)2D) is synthetized from inactive prohormone 25-hydroxycholecalciferol (25(OH)D) by the enzyme CYP27B1 1-alpha-hydroxylase in kidney and several extrarenal tissues including breast. Although the development of breast cancer has been linked to inadequate vitamin D status, the importance of bioactive vitamin D production within tumors themselves is not fully understood. To investigate the role of tumoral vitamin D production in mammary epithelial cell progression to breast cancer, we conducted a Cre-loxP-mediated Cyp27b1 gene ablation in the mammary epithelium of the polyoma middle T antigen-mouse mammary tumor virus (PyMT-MMTV) mouse breast cancer model. Targeted ablation of Cyp27b1 was accompanied by significant acceleration in initiation of spontaneous mammary tumorigenesis. In vivo, cell proliferation, angiogenesis, cell cycle progression, and survival markers were up-regulated in tumors by Cyp27b1 ablation, and apoptosis was decreased. AK thymoma (AKT) phosphorylation and expression of several components of nuclear factor kappaB (NF-kappaB), integrin, and signal transducer and activator of transcription 3 (STAT3) signaling pathways were increased in Cyp27b1 ablated tumors compared with nonablated controls. In vitro, 1,25(OH)2D treatment induced a strong antiproliferative action on tumor cells from both ablated and nonablated mice, accompanied by rapid disappearance of NF-kappaB p65 from the nucleus and segregation in the cytoplasm. In contrast, treatment with the metabolic precursor 25(OH)D was only effective against cells from nonablated mice. 25(OH)D did not inhibit growth of Cyp27b1-ablated cells, and their nuclear NF-kappaB p65 remained abundant. Our findings demonstrate that in-tumor CYP27B1 1 alpha-hydroxylase activity plays a crucial role in controlling early oncogene mediated mammary carcinogenesis events, at least in part by modulating tumoral cell NF-kappaB p65 nuclear translocation. PMID- 27119754 TI - A de novo 10p11.23-p12.1 deletion recapitulates the phenotype observed in WAC mutations and strengthens the role of WAC in intellectual disability and behavior disorders. AB - Chromosomal microarray analysis has become a powerful diagnostic tool in the investigation of patients with intellectual disability leading to the discovery of dosage sensitive genes implicated in the manifestation of various genomic disorders. Interstitial deletions of the short arm of chromosome 10 represent rare genetic abnormalities, especially those encompassing the chromosomal region 10p11-p12. To date, only 10 postnatal cases with microdeletion of this region have been described, and all patients shared a common phenotype, including intellectual disability, abnormal behavior, distinct dysmorphic features, visual impairment, and cardiac malformations. WAC was suggested to be the main candidate gene for intellectual disability associated with 10 p11-p12 deletion syndrome. Here, we describe a new case of de novo 10p11.23-p12.1 microdeletion in a patient with intellectual disability, abnormal behavior, and distinct dysmorphic features. Our observation allows us to redefine the smallest region of overlap among patients reported so far, with a size of 80 Kb and which contains only the WAC gene. These findings strengthen the hypothesis that haploinsufficency of WAC gene might be likely responsible for intellectual disability and behavior disorders. Our data also led us to propose a clinical pathway for patients with this recognizable genetic syndrome depending on the facial dysmorphisms. (c) 2016 Wiley Periodicals, Inc. PMID- 27119755 TI - A hybrid model of support vector regression with genetic algorithm for forecasting adsorption of malachite green onto multi-walled carbon nanotubes: central composite design optimization. AB - The aim of this work is the study of the predictive ability of a hybrid model of support vector regression with genetic algorithm optimization (GA-SVR) for the adsorption of malachite green (MG) onto multi-walled carbon nanotubes (MWCNTs). Various factors were investigated by central composite design and optimum conditions was set as: pH 8, 0.018 g MWCNTs, 8 mg L(-1) dye mixed with 50 mL solution thoroughly for 10 min. The Langmuir, Freundlich, Temkin and D-R isothermal models are applied to fitting the experimental data, and the data was well explained by the Langmuir model with a maximum adsorption capacity of 62.11 80.64 mg g(-1) in a short time at 25 degrees C. Kinetic studies at various adsorbent dosages and the initial MG concentration show that maximum MG removal was achieved within 10 min of the start of every experiment under most conditions. The adsorption obeys the pseudo-second-order rate equation in addition to the intraparticle diffusion model. The optimal parameters (C of 0.2509, sigma(2) of 0.1288 and epsilon of 0.2018) for the SVR model were obtained based on the GA. For the testing data set, MSE values of 0.0034 and the coefficient of determination (R(2)) values of 0.9195 were achieved. PMID- 27119756 TI - The Impact of Body Dissatisfaction on Distressing Sexual Difficulties Among Men and Women: the Mediator Role of Cognitive Distraction. AB - Research has demonstrated a negative impact of cognitive distraction on sexual activity, and body dissatisfaction has been associated with less satisfying and fewer sexual activities. In the current study we examined the extent to which cognitive distraction, based on body appearance and sexual performance, mediated the impact of body dissatisfaction on sexual difficulties among women and men. A sample of 493 women (Mage = 30.61) and 595 men (Mage = 37.90) completed an online survey. Women reported significantly higher levels of distressing sexual difficulties, significantly more body dissatisfaction, and greater cognitive distraction based on appearance than men. In contrast, men reported higher cognitive distraction based on performance than women. A path analysis model indicated that, for men, only cognitive distraction based on performance mediated the effects of body dissatisfaction on distressing sexual difficulties, and the mediation was only partial as body dissatisfaction had a significant direct effect on distressing sexual difficulties. In contrast, among women, both appearance-based cognitive distraction and performance-based cognitive distraction fully mediated the effects of body dissatisfaction on distressing sexual difficulties. PMID- 27119757 TI - The effect of swimming on oral health status: competitive versus non-competitive athletes. AB - Young swimmers are particularly susceptible to the onset of oral diseases. Objective To evaluate the oral health status in young competitive and non competitive swimmers, involving an assessment of salivary cariogenic bacteria and secretory IgA (S-IgA) concentration. Material and Methods Before training sessions (T1), 54 competitive and 69 non-competitive swimmers had the following parameters assessed: decayed, missing, and filled teeth (DMFT), Plaque Index (PlI), and Gingival Index (GI). At T1 and after training sessions (T2), stimulated saliva was collected and microbiological and immunological analyses were performed. Results Competitive swimmers trained 2.02+/-0.09 hours 5 times a week, while non-competitive swimmers trained 2.03+/-0.18 hours a week. A total of 14.7% of competitive swimmers suffered dental trauma related to sports. Only 11.76% of the competitive swimmers took a daily dose of fluoride, against 32.65% of non-competitive swimmers (p=0.029). Neither group followed an established diet or presented statistically significant differences in terms of nutritional supplement drink and chocolate intake. There were statistically significant differences in terms of oral hygiene. No significant difference in clinical indexes (DMFT, PlI, and GI) was present. S. mutans was harbored by 18.6% of competitive and the 32.2% of non-competitive swimmers. S. sobrinus was detected in 22.03% of competitive and 91.6% of non-competitive swimmers (p<0.05). S. sanguinis was found only in the saliva of competitive swimmers. The average S-IgA of competitive swimmers decreased significantly at T2 (p<0.05). The pool water had a daily average pH of 7.22. Conclusions Microbial markers, immune status and sporting characteristics are important for establishing guidelines for management of training load in order to minimize physical stress and the risk of oral infection. PMID- 27119758 TI - Effect of cantilever length and alloy framework on the stress distribution in peri-implant area of cantilevered implant-supported fixed partial dentures. AB - Because many mechanical variables are present in the oral cavity, the proper load transfer between the prosthesis and the bone is important for treatment planning and for the longevity of the implant-supported fixed partial denture. Objectives To verify the stress generated on the peri-implant area of cantilevered implant supported fixed partial dentures and the potential effects of such variable. Material and Methods A U-shaped polyurethane model simulating the mandibular bone containing two implants (O 3.75 mm) was used. Six groups were formed according to the alloy's framework (CoCr or PdAg) and the point of load application (5 mm, 10 mm and 15 mm of cantilever arm). A 300 N load was applied in pre-determined reference points. The tension generated on the mesial, lingual, distal and buccal sides of the peri-implant regions was assessed using strain gauges. Results Two way ANOVA and Tukey statistical tests were applied showing significant differences (p<0.05) between the groups. Pearson correlation test (p<0.05) was applied showing positive correlations between the increase of the cantilever arm and the deformation of the peri-implant area. Conclusions This report demonstrated the CoCr alloy shows larger compression values compared to the PdAg alloy for the same distances of cantilever. The point of load application influences the deformation on the peri-implant area, increasing in accordance with the increase of the lever arm. PMID- 27119759 TI - Solubility and bacterial sealing ability of MTA and root-end filling materials. AB - Objective To evaluate solubility and sealing ability of Mineral Trioxide Aggregate (MTA) and root-end filling materials. Material and Methods The materials evaluated were: MTA, Calcium Silicate Cement with zirconium oxide (CSC/ZrO2), and zinc oxide/eugenol (ZOE). Solubility test was performed according to ANSI/ADA. The difference between initial and final mass of the materials was analyzed after immersion in distilled water for 7 and 30 days. Retrograde cavities in human teeth with single straight root canal were performed by using ultrasonic tip CVD 9.5107-8. The cavities were filled with the evaluated materials to evaluate sealing ability using the bacterial leakage test with Enterococcus faecalis. Bacterial leakage was evaluated every 24 hours for six weeks observing the turbidity of Brain Heart infusion (BHI) medium in contact with root apex. Data were submitted to ANOVA followed by Tukey tests (solubility), and Kruskal-Wallis and Dunn tests (sealing ability) at a 5% significance level. Results For the 7-day period, ZOE presented highest solubility when compared with the other groups (p<0.05). For the 30-day period, no difference was observed among the materials. Lower bacterial leakage was observed for MTA and CSC/ZrO2, and both presented better results than ZOE (p<0.05). Conclusion MTA and CSC/ZrO2 presented better bacterial sealing capacity, which may be related to lower initial solubility observed for these materials in relation to ZOE. PMID- 27119760 TI - In vivo model for microbial invasion of tooth root dentinal tubules. AB - Objective Bacterial penetration of dentinal tubules via exposed dentine can lead to root caries and promote infections of the pulp and root canal system. The aim of this work was to develop a new experimental model for studying bacterial invasion of dentinal tubules within the human oral cavity. Material and Methods Sections of human root dentine were mounted into lower oral appliances that were worn by four human subjects for 15 d. Roots were then fixed, sectioned, stained and examined microscopically for evidence of bacterial invasion. Levels of invasion were expressed as Tubule Invasion Factor (TIF). DNA was extracted from root samples, subjected to polymerase chain reaction amplification of 16S rRNA genes, and invading bacteria were identified by comparison of sequences with GenBank database. Results All root dentine samples with patent tubules showed evidence of bacterial cell invasion (TIF value range from 5.7 to 9.0) to depths of 200 mm or more. A spectrum of Gram-positive and Gram-negative cell morphotypes were visualized, and molecular typing identified species of Granulicatella, Streptococcus, Klebsiella, Enterobacter, Acinetobacter, and Pseudomonas as dentinal tubule residents. Conclusion A novel in vivo model is described, which provides for human root dentine to be efficiently infected by oral microorganisms. A range of bacteria were able to initially invade dentinal tubules within exposed dentine. The model will be useful for testing the effectiveness of antiseptics, irrigants, and potential tubule occluding agents in preventing bacterial invasion of dentine. PMID- 27119761 TI - Evaluation of temperature increase during in-office bleaching. AB - The use of light sources in the bleaching process reduces the time required and promotes satisfactory results. However, these light sources can cause an increase in the pulp temperature. Objective The purpose of the present study was to measure the increase in intrapulpal temperature induced by different light activated bleaching procedures with and without the use of a bleaching gel. Material and Methods A human maxillary central incisor was sectioned 2 mm below the cementoenamel junction. A K-type thermocouple probe was introduced into the pulp chamber. A 35% hydrogen peroxide bleaching gel was applied to the vestibular tooth surface. The light units used were a conventional halogen, a hybrid light (only LED and LED/Laser), a high intensity LED, and a green LED light. Temperature increase values were compared by two-way ANOVA and Tukey's tests (p<0.05). Results There were statistically significant differences in temperature increases between the different light sources used and between the same light sources with and without the use of a bleaching gel. The presence of a bleaching gel generated an increase in intra-pulpal temperature in groups activated with halogen light, hybrid light, and high intensity LED. Compared to the other light sources, the conventional halogen lamp applied over the bleaching gel induced a significant increase in temperature (3.83+/-0.41 degrees C). The green LED unit with and without gel application did not produce any significant intrapulpal temperature variations. Conclusion In the present study, the conventional halogen lamp caused the highest increase in intrapulpal temperature, and the green LED caused the least. There was an increase in temperature with all lights tested and the maximum temperature remained below the critical level (5.5 degrees C). The addition of a bleaching gel led to a higher increase in intrapulpal temperatures. PMID- 27119762 TI - Detection of cfxA2, cfxA3, and cfxA6 genes in beta-lactamase producing oral anaerobes. AB - Purpose The aim of this study was to identify beta-lactamase-producing oral anaerobic bacteria and screen them for the presence of cfxA and BlaTEM genes that are responsible for beta-lactamase production and resistance to beta-lactam antibiotics. Material and Methods Periodontal pocket debris samples were collected from 48 patients with chronic periodontitis and anaerobically cultured on blood agar plates with and without beta-lactam antibiotics. Presumptive beta lactamase-producing isolates were evaluated for definite beta-lactamase production using the nitrocefin slide method and identified using the API Rapid 32A system. Antimicrobial susceptibility was performed using disc diffusion and microbroth dilution tests as described by CLSI Methods. Isolates were screened for the presence of the beta-lactamase-TEM (BlaTEM) and beta-lactamase-cfxA genes using Polymerase Chain Reaction (PCR). Amplified PCR products were sequenced and the cfxA gene was characterized using Genbank databases. Results Seventy five percent of patients carried two species of beta-lactamase-producing anaerobic bacteria that comprised 9.4% of the total number of cultivable bacteria. Fifty one percent of beta-lactamase-producing strains mainly Prevotella, Porphyromonas, and Bacteroides carried the cfxA gene, whereas none of them carried blaTEM. Further characterization of the cfxA gene showed that 76.7% of these strains carried the cfxA2 gene, 14% carried cfxA3, and 9.3% carried cfxA6. The cfxA6 gene was present in three Prevotella spp. and in one Porphyromonas spp. Strains containing cfxA genes (56%) were resistant to the beta-lactam antibiotics. Conclusion This study indicates that there is a high prevalence of the cfxA gene in beta-lactamase-producing anaerobic oral bacteria, which may lead to drug resistance and treatment failure. PMID- 27119763 TI - Sealing ability of MTA, CPM, and MBPc as root-end filling materials: a bacterial leakage study. AB - Objectives To evaluate the sealing ability of three root-end filling materials (white MTA, CPM, and MBPc) using an Enterococcus faecalis leakage model. Material and Methods Seventy single-root extracted human teeth were instrumented and root ends were resected to prepare 3 mm depth cavities. Root-end preparations were filled with white MTA, CPM, and MBPc cements. Enterococcus faecalis was coronally introduced and the apical portion was immersed in BHI culture medium with phenol red indicator. The bacterial leakage was monitored every 24 h for 4 weeks. The statistical analysis was performed using the Wilcoxon-Gehan test (p<0.05). Results All cements showed bacterial leakage after 24 hours, except for the negative control group. The MBPc showed significantly less bacterial leakage compared with the MTA group (p<0.05). No significant differences were found between the CPM and the other groups. Conclusions The epoxy resin-based cement MBPc had lower bacterial leakage compared with the calcium silicate-based cements MTA and CPM. PMID- 27119764 TI - Combined effects of melatonin and FGF-2 on mouse preosteoblast behavior within interconnected porous hydroxyapatite ceramics - in vitro analysis. AB - Objective Biocompatible materials such as interconnected porous hydroxyapatite ceramics (IP-CHA) loaded with osteogenic cells and bioactive agents are part of an evolving concept for overcoming craniofacial defects by use of artificial bone tissue regeneration. Amongst the bioactive agents, melatonin (MEL) and basic fibroblast growth factor (FGF-2) have been independently reported to induce osteoblastic activity. The present in vitro study was undertaken to examine the relationship between these two bioactive agents and their combinatory effects on osteoblastic activity and mineralization in vitro. Material and Methods Mouse preosteoblast cells (MC3T3-E1) were seeded and cultured within cylindrical type of IP-CHA block (o 4x7 mm) by vacuum-assisted method. The IP-CHA/MC3T3 composites were subjected to FGF-2 and/or MEL. The proliferation assay, alkaline phosphatase enzyme activity (ALP), mRNA expressions of late bone markers, namely Osteocalcin (OCN) and Osteopontin (OPN), and Alizarin Red staining were examined over a period of 7 days. Results FGF-2 mainly enhanced the proliferation of MC3T3-E1 cells within the IP-CHA constructs. MEL mainly induced the mRNA expression of late bone markers (OCN and OPN) and showed increased ALP activity of MC3T3 cells cultured within IP-CHA construct. Moreover, the combination of FGF-2 and MEL showed increased osteogenic activity within the IP-CHA construct in terms of cell proliferation, upregulated expressions of OCN and OPN, increased ALP activity and mineralization with Alizarin Red. The synergy of the proliferative potential of FGF-2 and the differentiation potential of MEL showed increased osteogenic activity in MC3T3-E1 cells cultured within IP-CHA constructs. Conclusion These findings indicate that the combination of FGF-2 and MEL may be utilized with biocompatible materials to attain augmented osteogenic activity and mineralization. PMID- 27119765 TI - Effects of a buried magnetic field on cranial bone reconstruction in rats. AB - The understanding of bone repair phenomena is a fundamental part of dentistry and maxillofacial surgery. Objective The present study aimed to evaluate the influence of buried magnetic field stimulation on bone repair in rat calvaria after reconstruction with autogenous bone grafts, synthetic powdered hydroxyapatite, or allogeneic cartilage grafts, with or without exposure to magnetic stimulation. Material and Methods Ninety male Wistar rats were divided into 18 groups of five animals each. Critical bone defects were created in the rats' calvaria and immediately reconstructed with autogenous bone, powdered synthetic hydroxyapatite or allogeneic cartilage. Magnetic implants were also placed in half the animals. Rats were euthanized for analysis at 15, 30, and 60 postoperative days. Histomorphometric analyses of the quantity of bone repair were performed at all times. Results These analyses showed significant group by postoperative time interactions (p=0.008). Among the rats subjected to autogenous bone reconstruction, those exposed to magnetic stimulation had higher bone fill percentages than those without magnetic implants. Results also showed that the quality of bone repair remained higher in the former group as compared to the latter at 60 postoperative days. Conclusions After 60 postoperative days, bone repair was greater in the group treated with autogenous bone grafts and exposed to a magnetic field, and bone repair was most pronounced in animals treated with autogenous bone grafts, followed by those treated with powdered synthetic hydroxyapatite and allogeneic cartilage grafts. PMID- 27119766 TI - Evaluation of an experimental rat model for comparative studies of bleaching agents. AB - Dental materials in general are tested in different animal models prior to the clinical use in humans, except for bleaching agents. Objectives To evaluate an experimental rat model for comparative studies of bleaching agents, by investigating the influence of different concentrations and application times of H2O2 gel in the pulp tissue during in-office bleaching of rats' vital teeth. Material and Methods The right and left maxillary molars of 50 Wistar rats were bleached with 20% and 35% H2O2 gels, respectively, for 5, 10, 15, 30, or 45 min (n=10 rats/group). Ten animals were untreated (control). The rats were killed after 2 or 30 days, and the maxillae were examined by light microscopy. Inflammation was evaluated through histomorphometric analysis with inflammatory cell count in the coronal and radicular thirds of the pulp. Fibroblasts were also counted. Scores were attributed to odontoblastic layer and vascular changes. Tertiary dentin area and pulp chamber central area were measured histomorphometrically. Data were compared by analysis of variance and Kruskal Wallis test (p<0.05). Results After 2 days, the amount of inflammatory cells increased in the coronal pulp occlusal third up to the 15-min application groups of each bleaching gel. In the groups exposed to each concentration for 30 and 45 min, the number of inflammatory cells decreased along with the appearance of necrotic areas. After 30 days, reduction on the pulp chamber central area and enlargement of the tertiary dentin area were observed, without the detection of inflammation areas. Conclusion The rat model of extracoronal bleaching showed to be adequate for studies of bleaching protocols, as it was possible to observe alterations in the pulp tissues and tooth structure caused by different concentrations and application periods of bleaching agents. PMID- 27119768 TI - Alignment of threat, effort, and perceived success in North American conservation translocations. AB - The use of conservation translocations to mitigate human effects on biodiversity is increasing, but how these efforts are allocated remains unclear. Based on a comprehensive literature review and online author survey, we sought to determine the goals of translocation efforts, whether they focus on species and regions with high threat and likelihood of perceived success, and how success might be improved. We systematically searched the ISI Web of Knowledge and Academic Search Complete databases to determine the species and regions of conservation translocations and found 1863 articles on conservation translocations in the United States, Canada, Mexico, Central America, and Caribbean published from 1974 to 2013. We questioned 330 relevant authors to determine the motivation for translocations, how translocations were evaluated, and obstacles encountered. Conservation translocations in North America were geographically widespread (in 21 countries), increased in frequency over time for all animal classes (from 1 in 1974 to 84 in 2013), and included 279 different species. Reintroductions and reinforcements were more common in the United States than in Canada and Mexico, Central America, or the Caribbean, and their prevalence was correlated with the number of species at risk at national and state or provincial levels. Translocated species had a higher threat status at state and provincial levels than globally (International Union for Conservation of Nature Red List categorization), suggesting that translocations may have been motivated by regional priorities rather than global risk. Our survey of authors was consistent with these results; most translocations were requested, supported, or funded by government agencies and downlisting species at national or state or provincial levels was the main goal. Nonetheless, downlisting was the least reported measure of success, whereas survival and reproduction of translocated individuals were the most reported. Reported barriers to success included biological factors such as animal mortality and nonbiological factors, such as financial constraints, which were less often considered in the selection of release sites. Our review thus highlights discrepancies between project goals and evaluation criteria and between risk factors considered and obstacles encountered, indicating room to further optimize translocation projects. PMID- 27119767 TI - Association of three putative periodontal pathogens with chronic periodontitis in Brazilian subjects. AB - Objective The aim of this study was to evaluate the association of Porphyromonas endodontalis, Filifactor alocis and Dialister pneumosintes with the occurrence of periodontitis. Material and Methods Thirty subjects with chronic periodontitis (ChP) and 10 with periodontal health (PH) were included in the study. Nine subgingival biofilm samples were collected as follows: i) PH group - from the mesial/buccal aspect of each tooth in two randomly chosen contralateral quadrants; ii) ChP group - from three sites in each of the following probing depth (PD) categories: shallow (<=3 mm), moderate (4-6 mm) and deep (>=7 mm). Checkerboard DNA-DNA hybridization was used to analyze the samples. Results We found the three species evaluated in a higher percentage of sites and at higher levels in the group with ChP than in the PH group (p<0.05, Mann-Whitney test). We also observed these differences when the samples from sites with PD<=4 mm or >=5 mm of subjects with ChP were compared with those from subjects with PH (p<0.05, Mann-Whitney test). In addition, the prevalence and levels of D. pneumosintes, and especially of F. alocis were very low in healthy subjects (0.12x105 and 0.01x105, respectively). Conclusion F. alocis and D. pneumosintes might be associated with the etiology of ChP, and their role in the onset and progression of this infection should be further investigated. The role of P. endodontalis was less evident, since this species was found in relatively high levels and prevalence in the PH group. PMID- 27119769 TI - A perfect storm: Tumor lysis syndrome with rasburicase-induced methemoglobinemia in a G6PD deficient adult. PMID- 27119770 TI - Enhanced Cellular Uptake of Bowl-like Microcapsules. AB - Among several properties of colloidal particles, shape is emerging as an important parameter for tailoring the interactions between particles and cells. In this study, bowl-like multilayer microcapsules were prepared by osmotic induced invagination of their spherical counterparts in a concentrated polyelectrolyte solution. The internalization behaviors of bowl-like and spherical microcapsules were compared by coincubation with smooth muscle cells (SMCs) and macrophages. The bowl-like capsules tended to attach onto the cell membranes from the bend side and could be enwrapped by the membranes of SMCs, leading to a faster uptake rate and larger accumulation inside cells than those of their spherical counterparts. These results are important for understanding the shape-dependent internalization behavior, providing useful guidance for further materials design especially in biomedical applications. PMID- 27119771 TI - The histopathologic effects of L-carnitine in Sodium Taurocholate Induced Severe Pancreatitis Model. AB - OBJECTIVE: To evaluate the histopathologic effects of L-carnitine (LC) in an experimental severe pancreatitis (SP) model induced with sodium taurocholate (STC). SUMMARY OF BACKGROUND DATA: LC is an amino acid-like molecule that plays an active role in transporting fatty acids and producing Acetyl CoA in mitochondrial matrix for beta-oxidation to provide energy which is needed for metabolism. It has ameliorative effects on cell injury demonstrated in many studies. The present study focuses on evaluating histopathologic effects of LC in an experimental SP model. METHODS: This experimental study in rats was conducted at the Experimental Animal Research Laboratory of the Faculty of Medicine of Inonu University, Malatya, Turkey. Thirty-two Spraque-dawley male rats were divided into 4 groups in a randomized fashion: control (C) group, L-carnitine (LC) group, pancreatitis (P) group, pancreatitis and L-carnitine (P+LC) group. Pancreatitis was induced by a retrograde pancreatic duct injection of 4% sodium taurocholate and L-carnitine was administered 200 mg/kg/day in treatment group. Rats were euthanized with cardiac puncture under anesthesia at 48th hour of the experiment for biochemical and histopathological examination. RESULTS: In (P+LC) group, the histopathological findings of the pancreatitis were markedly reduced. Acinar cell degeneration was rarely seen. Interlobular and intralobular inflammation and edema was generally mild. The pancreatic damage score of (P+LC) group was significantly lower than that of the (P) group (p<0.05). CONCLUSION: This study revealed that l-carnitine has a significant histopathologic protective effect on acinar cell degeneration in STC-induced SP model in rats. PMID- 27119772 TI - Analysis of a Social Work-Based Model of Transitional Care to Reduce Hospital Readmissions: Preliminary Data. AB - Efforts to reduce readmissions after hospital discharge are increasingly being made to better identify and address social and logistical needs in addition to attending to posthospital clinical challenges. A transitional care model based in the social work professional skill set may be well matched to assess and address social and logistical needs during the posthospital transitional care period. The effect of a social work-based transitional care intervention on all-cause 30-day readmission rates for Medicare fee-for-service (FFS) beneficiaries discharged from an urban medical center was analyzed. Analyses revealed a 20% relative reduction in readmissions for 1,546 Medicare FFS discharges to home, with or without home care (a 4.5% absolute rate reduction). This model may be of interest to entities that are accountable for the care of individuals with complex social needs, such as dually eligible individuals (those eligible for Medicare and Medicaid) and adults who are newly eligible for Medicaid coverage. PMID- 27119773 TI - Female infidelity is constrained by El Nino conditions in a long-lived bird. AB - Explaining the remarkable variation in socially monogamous females' extrapair (EP) behaviour revealed by decades of molecular paternity testing remains an important challenge. One hypothesis proposes that restrictive environmental conditions (e.g. extreme weather, food scarcity) limit females' resources and increase EP behaviour costs, forcing females to reduce EP reproductive behaviours. For the first time, we tested this hypothesis by directly quantifying within-pair and EP behaviours rather than inferring behaviour from paternity. We evaluated whether warmer sea surface temperatures depress total pre-laying reproductive behaviours, and particularly EP behaviours, in socially paired female blue-footed boobies (Sula nebouxii). Warm waters in the Eastern Pacific are associated with El Nino Southern Oscillation and lead to decreased food availability and reproductive success in this and other marine predators. With warmer waters, females decreased their neighbourhood attendance, total copulation frequency and laying probability, suggesting that they contend with restricted resources by prioritizing self-maintenance and committing less to reproduction, sometimes abandoning the attempt altogether. Females were also less likely to participate in EP courtship and copulations, but when they did, rates of these behaviours were unaffected by water temperature. Females' neighbourhood attendance, total copulation frequency and EP courtship probability responded to temperature differences at the between-season scale, and neighbourhood attendance and EP copulation probability were affected by within-season fluctuations. Path analysis indicated that decreased EP participation was not attributable to reduced female time available for EP activities. Together, our results suggest that immediate time and energy constraints were not the main factors limiting females' infidelity. Our study shows that El Nino conditions depress female boobies' EP participation and total reproductive activity. In addition to increasing general self-maintenance and reproductive costs, warm waters may increase costs specific to EP behaviours including divorce, reduced male parental care, or pathogen exposure. Our results suggest that female boobies strategically refrained from EP behaviours to avoid these or other longer-term costs, rather than being compelled by immediate constraints. This study demonstrates that current environmental conditions affect females' mating decisions, contributing to variation in EP behaviours, even in a long-lived, iteroparous species that can buffer against temporary adversity. PMID- 27119774 TI - Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with Azadienes: Assembly of Functionalized Quinolines. AB - A base promoted, protection-free, and regioselective synthesis of highly functionalized quinolines via [4 + 2] cycloaddition of azadienes (generated in situ from o-aminobenzyl alcohol) with internal alkynes has been discovered. The reaction tolerates a wide variety of functional groups which has been successfully extended with diynes, (2-aminopyridin-3-yl)methanol, and 1,4 bis(phenylethynyl)benzene to afford (Z)-phenyl-2-styrylquinolines, phenylnaphthyridine, and alkyne-substituted quinolines, respectively. The proposed mechanism and significant role of the solvent were well supported by isolating the azadiene intermediate and deuterium-labeling studies. PMID- 27119775 TI - Wafer-Scale, Homogeneous MoS2 Layers on Plastic Substrates for Flexible Visible Light Photodetectors. AB - An appropriate solution is suggested for synthesizing wafer-scale, continuous, and stoichiometric MoS2 layers with spatial homogeneity at the low temperature of 450 degrees C. It is also demonstrated that the MoS2 -based visible-light photodetector arrays are both fabricated on 4 inch SiO2 /Si wafer and polyimide films, revealing 100% active devices with a narrow photocurrent distribution and excellent mechanical durability. PMID- 27119776 TI - Mitochondrial DNA Variation and Heteroplasmy in Monozygotic Twins Clinically Discordant for Multiple Sclerosis. AB - We examined the debated link between mitochondrial DNA (mtDNA) variation and multiple sclerosis (MS) using 49 monozygotic (MZ) twin pairs clinically discordant for MS, which enables to associate de novo mtDNA variants, skewed heteroplasmy, and mtDNA copy number with MS manifestation. Ultra-deep sequencing of blood-derived mtDNA revealed 25 heteroplasmic variants with potentially pathogenic features in 18 pairs. All variants were pair-specific and had low and/or similar heteroplasmy levels in both cotwins. In one pair, a confirmed pathogenic variant (m.11778G>A, heteroplasmy ~50%) associated with Leber hereditary optic neuropathy was detected. Detailed diagnostic investigation revealed subclinical MS signs in the prior nondiseased cotwin. Moreover, neither mtDNA deletions nor copy-number variations were involved. Furthermore, the majority of heteroplasmic variants were shared among MZ twins and exhibited more similar heteroplasmy levels in the same tissue of MZ twins as compared with different tissues of the same individual. Heteroplasmy levels were also more similar within MZ twins compared with nonidentical siblings. Our analysis excludes mtDNA variation as a major driver of the discordant clinical manifestation of MS in MZ twins, and provides valuable insights into the occurrence and distribution of heteroplasmic variants within MZ twins and nonidentical siblings, and across different tissues. PMID- 27119790 TI - Implantable Cardioverter Defibrillator Outcomes in Pediatric and Congenital Heart Disease: Time to System Revision. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) are intended to prevent sudden cardiac death yet also impose a risk of morbidity. This study describes the outcomes of ICDs in a pediatric and congenital heart disease (CHD) population from a single center. METHODS: Retrospective cohort study of all patients with an ICD followed at the University of Michigan Congenital Heart Center from 2005-2013. The primary outcome was ICD system revision for any reason excluding routine generator change for battery depletion. RESULTS: There were 191 ICD systems in 131 patients, including 57 with CHD, 24 with hypertrophic cardiomyopathy, and 45 with structurally normal hearts. Median age was 16 years at initial implant. Total follow-up was 850 patient-years; median 4.9 years/patient. There were 43 (33%) patients who required 60 ICD revisions; 70 revisions/1,000 patient-years of follow-up. Revisions included 25 lead extractions with replacement, 21 lead additions, five lead repositions, and four full system revisions. Kaplan-Meier (K-M) median time to appropriate shock was similar to the median time to system revision. K-M time to system revision was significantly affected by recalled lead performance. CONCLUSIONS: The need for ICD system revision is high in this pediatric and CHD population and occurs at a rate similar to the rate of receiving appropriate therapy. These results highlight the need for judicious implant criteria and improved device longevity. PMID- 27119791 TI - Long-Lived Charge Transfer Excited States in HBC-Polypyridyl Complex Hybrids. AB - The synthesis of two bipyridine-hexa-peri-hexabenzocoronene (bpy-HBC) ligands functionalized with either (t)Bu or C12H25 and their Re(I) tricarbonyl chloride complexes are reported and their electronic properties investigated using spectroscopic and computational methods. The metal complexes show unusual properties, and we observed the formation of a long-lived excited state using time-resolved infrared spectroscopy. Depending on the solvent, this appears to be of the form Rebpy(*-)HBC(*+) or a bpy-centered pi,pi* state. TD-DFT calculations support the donor-acceptor charge transfer character of these systems, in which HBC is the donor and bpy is the acceptor. The ground state optical properties are dominated by the HBC chromophore with additional distinct transitions of the complexes, one associated with MLCT 450 nm (epsilon > 17 000 L mol(-1) cm(-1)) and another with a HBC/metal to bpy charge transfer, termed the MLLCT band (373 nm, epsilon = 66 000 L mol(-1) cm(-1)). These assignments are also supported by resonance Raman spectroscopy. PMID- 27119792 TI - A systematic review of the surgical techniques for the treatment of internal nasal valve collapse: where do we stand? AB - BACKGROUND: A myriad of interventions have been described to address the restoration or preservation of the internal nasal valve, the narrowest portion of nasal airway. OBJECTIVE OF REVIEW: To review systematically available knowledge and evidence about management options of the collapse of the internal nasal valve area. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: A MEDLINE, EMBASE, Cochrane Library and CENTRAL database search, followed by extensive hand searching for the identification of relevant studies. EVALUATION METHOD: Review of all English-language studies addressing the treatment of the internal nasal valve collapse. RESULTS: Fifty-three studies were eventually identified and systematically reviewed. The majority (50 of 53) of the included articles are graded as level IV evidence and only one randomised trial was identified. The included randomised study reported no significant difference in improvement between the intervention group (autospreader flap) and placebo arms. The majority of the included studies presented in this systematic review provide level IV evidence concerning the optimal approach for cases of nasal valve collapse. Current research is driven more by reports of techniques than patient outcomes. CONCLUSIONS: Proper evaluation and identification of the cause of the internal nasal valve collapse is paramount prior to selection of the preferred surgical solution. The three-dimensional construction of the nasal valve implies that many pathologies cannot be restored by a single solution. Treatment approaches should be directed at specific involved sites. Present systematic review of the literature revealed that the available evidence is based on low-level studies and focuses more on the description of various surgical techniques rather than on patient-reported outcome measures. Future studies are needed, including homogenous patient groups, comparing different surgical techniques and incorporating patient-reported outcome measures. PMID- 27119793 TI - Characterization of clear cell renal cell carcinoma with diffusion kurtosis imaging: correlation between diffusion kurtosis parameters and tumor cellularity. AB - The aim of this study was to evaluate the role of diffusion kurtosis imaging (DKI) in the characterization of clear cell renal cell carcinoma (ccRCC) and to correlate DKI parameters with tumor cellularity. Fifty-nine patients with pathologically diagnosed ccRCCs were evaluated by DKI on a 3-T scanner. Regions of interest were drawn on the maps of the mean diffusion coefficient (MD) and mean diffusion kurtosis (MK). All ccRCCs were histologically graded according to the Fuhrman classification system. Tumor cellularity was measured by the nuclear to-cytoplasm (N/C) ratio and the number of tumor cell nuclei (NTCN). ccRCCs were classified as grade 1 (n = 23), grade 2 (n = 24), grade 3 (n = 10) and grade 4 (n = 3). Both MD and MK could readily discriminate between normal renal parenchyma and ccRCCs (p < 0.001), and receiver operating characteristic (ROC) curve analysis showed that MK exhibited a better performance with an area under the ROC curve of 0.874 and sensitivity/specificity of 68.33%/100% (p < 0.001). Further, MD and MK were significantly different between grade 1 and grades 3 and 4 (p = 0.01, p < 0.001) and between grade 2 and grades 3 and 4 (p = 0.015, p < 0.005), respectively. However, no significant difference was found between grade 1 and grade 2 (p > 0.05) for both MD and MK. With regard to NTCN, no significant difference was found between any two grades (p > 0.05), and the N/C ratio changed significantly with grade (p < 0.01, between any two grades). Negative correlations were found between MK and MD (r = -0.56, p < 0.001), and between MD and N/C ratio (r = -0.36, p < 0.005), whereas MK and the N/C ratio were positively correlated (r = 0.45, p = 0.003). DKI could quantitatively characterize ccRCC with different grades by probing non-Gaussian diffusion properties related to changes in the tumor microenvironment or tissue complexities in the tumor. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27119794 TI - Leadership Transitions. PMID- 27119795 TI - NCF @ Work! PMID- 27119796 TI - Etc. PMID- 27119797 TI - Embracing Servant Leadership. PMID- 27119798 TI - Practicing Transformational Leadership. PMID- 27119799 TI - Nursing in the Church. PMID- 27119800 TI - Student TXT. PMID- 27119801 TI - More With Less. PMID- 27119802 TI - Teen Depression and Suicide, A SILENT CRISIS. AB - Adolescent depression is a serious problem affecting 10.7% of all teens and 29.9% of high school students; 17% of high school students have contemplated suicide. Yet, depression in teens is often unrecognized. This article relays the tragic death of a 17-year-old, along with symptoms of depression and suicide in adolescents; DSM-5 criteria for depression; treatments including protective factors, psychotherapy, and medications; and imparts interventions for addressing this huge but silent crisis. PMID- 27119804 TI - Nursing's Critical Role in the Shifting Landscape of Mental Health. AB - By 2020, mental and substance use disorders will surpass all physical diseases as a major cause of disability in the United States. Four key actions are proposed in which healthcare systems and nurses--the largest group of providers--can leverage nursing to address the biggest public health challenge the United States and many other nations face. Faith community nurses and faith congregations have particular opportunities to address this overwhelming need. PMID- 27119803 TI - Church Member Support Benefits Psychological Well-Being of Pregnant African American Women. AB - Depression during pregnancy is common, and pregnant African American (AA) women are more likely to experience depressive symptoms compared with pregnant non Hispanic white women. This study explored AA women's experience of church attendance, church member support, depressive symptoms, and psychological well being at 15-25 weeks' gestation. Nurses need to be aware of the importance of church support and encourage clergy and church members to be supportive of pregnant women. PMID- 27119805 TI - EMPLOYEE SPIRITUAL CARE: Supporting Those Who Care for Others. AB - In order to provide whole-person care for patients and families, Loma Linda University Health recognizes the importance of supporting employee wholeness. The Employee Spiritual Care department helps create and support an environment that nurtures the spiritual health and wholeness of employees, and provides employees tools and knowledge about providing whole-person care to patients and colleagues. PMID- 27119806 TI - NURSE EDUCATOR PERCEPTIONS OF FAITH-BASED ORGANIZATIONS FOR SERVICE-LEARNING. AB - Knowledge about service-learning for nursing students in faith-based organizations (FBOs) is limited. This descriptive study explored the perceptions of nurse educators about using FBOs for service-learning clinical sites. Participants (N = 112) relayed specific benefits and barriers to using FBOs for service-learning clinical experiences. Recommendations are made for effective school-FBO partnerships. PMID- 27119807 TI - GUIDELINES FOR APPROPRIATELY USING Scripture at the Bedside. AB - The losses patients experience are spiritual, as well as physical, events. Christian nurses are ideally situated to integrate calming biblical truths into dialogue with patients and family members when appropriate. This article discusses how Scripture can be used at the bedside with patients or families who want this type of spiritual care. Examples are presented from the author's nursing practice. PMID- 27119808 TI - A Transitional Care Model Using Faith Community Nurses. AB - The Medicare mandatory readmission reduction program has hospitals scrambling to reduce 30-day readmissions. A Faith Community Nurse (FCN) Transitional Care Model was developed from systematic literature review of predictive factors of readmission and pre- and postdischarge interventions that decrease readmission. The model presents specific FCN care that occurs pre- and posthospital discharge to support the patient in transitioning from one level of care to another, move toward wholistic health, and avoid unnecessary readmission. PMID- 27119809 TI - How Do I Learn About Poetry? PMID- 27119810 TI - How Do We Prepare for Emergency Spiritual Care? PMID- 27119812 TI - The Power of Words. PMID- 27119811 TI - JOY:Ten Minutes to Describe the Essence of Nursing. PMID- 27119813 TI - Resources. PMID- 27119814 TI - PulseBeats. PMID- 27119815 TI - Developing Global Nurse Influencers. AB - How can universities create engaged citizens and global leaders? Each year, a select group of advanced practice nursing students at Baylor University Louise Herrington School of Nursing travel to Africa for a month-long clinical mission experience. Students work alongside local and missionary healthcare providers in a comprehensive Christian outreach to the community at a high-volume clinic. Creating rich learning experiences in a global setting in significant and sustainable ways is difficult, but intentionally focusing on what we are called to do and who we serve provides ballast for faculty and students. The success of the trip in preparing students to be global influencers is evident by the work graduates elect to do around the world, following graduation. PMID- 27119816 TI - Teaching and Practicing Caring in the Classroom: Students' Responses to a Self Awareness Intervention in Psychiatric-Mental Health Nursing. AB - The purpose of this study was to test the assumption that caring could be taught by nurse educators in the classroom environment and that learning to be self aware in a mindful state would facilitate students to listen more closely to their inner spirit, which would affect caring behaviors. A convenience sample of 238 students in the Psychiatric-Mental Health Nursing course in a baccalaureate program was obtained from 2007 to 2011. At the beginning of each class and throughout the semester, self-awareness was explained to the students, a reflection statement was read, and students were asked to take two minutes of quiet time, with their eyes closed. At the end of each semester, an author composed Self-Awareness Questionnaire and Measurement Scale was administered to consenting students to assess whether self-awareness led to caring behaviors. Students' responses were analyzed using descriptive statistics. Findings were positive and supported the assumption that self-awareness and silence positively affected caring behaviors in nursing students in their psychiatric nursing rotation. PMID- 27119817 TI - Teen Depression and Suicide: A Silent Crisis. PMID- 27119818 TI - A Transitional Care Model Using Faith Community Nurses. PMID- 27119819 TI - Synergetic mechanism and enantioseparation of aromatic beta-amino acids by biphasic chiral high-speed counter-current chromatography. AB - A biphasic chiral recognition system based on chiral ligand exchange with Cu(II) N-n-dodecyl-L-proline and hydroxypropyl-beta-cyclodextrin as an additive was developed to enantioseparate aromatic beta-amino acids by high-speed counter current chromatography. The biphasic chiral recognition system was established with an n-butanol/water (1:1, v/v) solvent system by adding N-n-dodecyl-L-proline and Cu(II) ions to the organic phase and hydroxypropyl-beta-cyclodextrin to the aqueous phase. Several separation parameters, such as temperature, pH value, and chiral selector concentration, were systematically investigated by enantioselective liquid-liquid extraction. Under the optimal separation conditions, 54.5 mg of (R,S)-beta-phenylalanine and 74.3 mg of (R,S)-beta-3,4 dimethoxyphenylalanine were baseline enantioseparated. More importantly, the synergistic enantiorecognition mechanism, based on the Cu(II)-N-n-dodecyl-L proline and hydroxypropyl-beta-cyclodextrin, was discussed for the first time. PMID- 27119820 TI - The effects of weight loss after sleeve gastrectomy on left ventricular systolic function in men versus women. AB - PURPOSE: To evaluate and compare the effects of weight lost after sleeve gastrectomy on left ventricular (LV) systolic function using both two-dimensional speckle tracking (2D-STE) and three-dimensional echocardiography (3DE) in men versus women. METHODS: In 53 obese patients referred for sleeve gastrectomy, 2D STE and 3DE were performed prior to and 6 months after surgery. RESULTS: The study included 53 obese patients (62.3% female; mean age 36.8 +/- 10.7 years). Six months after surgery, all patients demonstrated a significant decrease in body mass index, body weight, blood pressure, heart rate, LV end-diastolic dimension, myocardial wall thickness, LV mass, LV mass index, LV mass/height(2.7) , LV end-diastolic volume, LV end-systolic volume, and stroke volume as well as an increase in SV index and ejection fraction. There was no significant difference in measured variables between men and women at baseline or postsurgery, except for baseline LV end-diastolic dimension, and baseline and after surgery LV mass, LV mass index, and LV mass/height(2.7) , which were all significantly higher in men. CONCLUSIONS: Sleeve gastrectomy improves LV systolic function and contributes to reverse LV remodeling in both genders. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:492-499, 2016. PMID- 27119822 TI - Understanding why we age and how: Evolutionary biology meets different model organisms and multi-level omics: Meeting report on "Comparative Biology of Aging," Roscoff, October 12-16, 2015. AB - The conference explored an extraordinary diversity of aging strategies in organisms ranging from short-lived species to "immortal" animals and plants. Research on the biological processes of aging is at the brink of a revolution with respect to our understanding of its underlying mechanisms as well as our ability to prevent and cure a wide variety of age-related pathologies. PMID- 27119821 TI - Development of a MALDI MS-based platform for early detection of acute kidney injury. AB - PURPOSE: Septic acute kidney injury (AKI) is associated with poor outcome. This can partly be attributed to delayed diagnosis and incomplete understanding of the underlying pathophysiology. Our aim was to develop an early predictive test for AKI based on the analysis of urinary peptide biomarkers by MALDI-MS. EXPERIMENTAL DESIGN: Urine samples from 95 patients with sepsis were analyzed by MALDI-MS. Marker search and multimarker model establishment were performed using the peptide profiles from 17 patients with existing or within the next 5 days developing AKI and 17 with no change in renal function. Replicates of urine sample pools from the AKI and non-AKI patient groups and normal controls were also included to select the analytically most robust AKI markers. RESULTS: Thirty nine urinary peptides were selected by cross-validated variable selection to generate a support vector machine multidimensional AKI classifier. Prognostic performance of the AKI classifier on an independent validation set including the remaining 61 patients of the study population (17 controls and 44 cases) was good with an area under the receiver operating characteristics curve of 0.82 and a sensitivity and specificity of 86% and 76%, respectively. CONCLUSION AND CLINICAL RELEVANCE: A urinary peptide marker model detects onset of AKI with acceptable accuracy in septic patients. Such a platform can eventually be transferred to the clinic as fast MALDI-MS test format. PMID- 27119823 TI - Viruses, Artificial Viruses and Virus-Based Structures for Biomedical Applications. AB - Nanobiomaterials such as virus particles and artificial virus particles offer tremendous opportunities to develop new biomedical applications such as drug- or gene-delivery, imaging and sensing but also improve understanding of biological mechanisms. Recent advances within the field of virus-based systems give insights in how to mimic viral structures and virus assembly processes as well as understanding biodistribution, cell/tissue targeting, controlled and triggered disassembly or release and circulation times. All these factors are of high importance for virus-based functional systems. This review illustrates advances in mimicking and enhancing or controlling these aspects to a high degree toward delivery and imaging applications. PMID- 27119824 TI - OSR1 and SPAK Sensitivity of Large-Conductance Ca2+ Activated K+ Channel. AB - BACKGROUND/AIMS: The oxidative stress-responsive kinase 1 (OSR1) and the serine/threonine kinases SPAK (SPS1-related proline/alanine-rich kinase) are under the control of WNK (with-no-K [Lys]) kinases. OSR1 and SPAK participate in diverse functions including cell volume regulation and neuronal excitability. Cell volume and neuronal excitation are further modified by the large conductance Ca2+-activated K+ channels (maxi K+ channel or BK channels). An influence of OSR1 and/or SPAK on BK channel activity has, however, never been shown. The present study thus explored whether OSR1 and/or SPAK modify the activity of BK channels. METHODS: cRNA encoding the Ca2+ insensitive BK channel mutant BKM513I+x0394;899 903 was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding wild-type OSR1 or wild-type SPAK, constitutively active T185EOSR1, catalytically inactive D164AOSR1, constitutively active T233ESPAK or catalytically inactive D212ASPAK. K+ channel activity was measured utilizing dual electrode voltage clamp. RESULTS: BK channel activity in BKM513I+x0394;899-903 expressing oocytes was significantly decreased by co-expression of OSR1 or SPAK. The effect of wild-type OSR1/SPAK was mimicked by T185EOSR1 and T233ESPAK, but not by D164AOSR1 or D212ASPAK. CONCLUSIONS: OSR1 and SPAK suppress BK channels, an effect possibly contributing to cell volume regulation and neuroexcitability. PMID- 27119826 TI - Single nucleotide polymorphisms of miR-149 gene rs2292832 contributes to the risk of hepatocellular carcinoma, but not overall cancer: a meta-analysis. AB - BACKGROUND: Single nucleotide polymorphism in miRNAs can alter its expression, thus lead to the development of cancers. Numerous studies have explored the association between miR-149 gene rs2292832 polymorphism and hepatocellular carcinoma risk, but the results remains inconsistent. So, we performed this pooled analyses in order to get a precise result. METHODS: Odds ratios (OR) with 95% confidence intervals (CI), calculated by STATA software, were used to determine whether miR-149 gene rs2292832 polymorphism contributes to the risk of Hepatocellular carcinoma. A comprehensive literature search was conducted on Medline (mainly PubMed), Cochrane Library database, Web of science and the China National Knowledge Internet (CNKI) up to March 22, 2016. RESULTS: A total of 20 studies including 8,201 cases and 9,294 controls were included in this meta analysis. Four of 20 studies related to the hepatocellular carcinoma risk. When all the eligible studies were pooled into this meta-analysis, a significant association between miR-149 gene rs2292832 polymorphism and hepatocellular carcinoma risk was found. While no association was found between this gene polymorphism and overall cancer risk. CONCLUSIONS: Our meta-analysis supports that the miR-149 gene rs2292832 polymorphism contributed to the risk of hepatocellular carcinoma from currently available evidence. However, a study with a larger sample size is needed to further evaluate gene-environment interaction on MiR-149 gene rs2292832 polymorphism and hepatocellular carcinoma risk. PMID- 27119825 TI - Distinctive Effects of Cytochalasin B in Chick Primary Myoblasts and Fibroblasts. AB - Actin-based structures play fundamental roles in cellular functions. However it remains controversial how cells cope with the absence of F-actin structures. This report focuses on short- and long-term effects of cytochalasin B (CB) on actin complexes in fibroblasts and myoblasts. Thirty min of CB treatment dispersed subplasma actin cortices, lamellipodia, ruffled membranes, stress fibers and adhesion plaques into actin patches in fibroblasts and muscle cells. In contrast, 72 hrs CB treatment showed distinct morphological effects. Fibroblasts became giant multinucleated-finger shaped with 5 to 10 protrusions, 3-8 MUm in width, and >200 MUm in length. They lacked cortical actin, stress fibers, adhesion plaques and ruffled membranes but contained immense lamelliopodia with abnormal adhesion plaque protein complexes. Muscle cells transformed into multinucleated globular-shaped but contained normal I-Z-I and A-bands, indicating that CB did not interfere with the assembly of myofibrils. Within 30 min after CB removal, finger-shaped fibroblasts returned to their original shape and actin-containing structures rapidly reappeared, whereas muscle cells respond slowly to form elongated myotubes following CB washout. The capacity to grow, complete several nuclear cycles, assemble intermediate filaments and microtubules without a morphologically recognizable actin cytoskeleton raises interesting issues related to the role of the actin compartments in eukaryotic cells. PMID- 27119827 TI - A RARE CASE OF RIGHT DIAPHRAGM AGENESIS. AB - Diaphragmatic agenesis is the most extreme and rare form of congenital diaphragmatic maldevelopment and therefore diagnosis of it are only few in literature, especially in children. It may be unilateral or bilateral. Frequently, diaphragmatic agenesis is accompanied with diaphragmatic hernia, when through a congenital defect of the diaphragm liver, intestine and other viscera herniate into the chest. Diagnostics typically are made early in infancy and is generally associated with other genetic anomalies, especially aneuploidy syndromes. It is associated with a high mortality, if not treated in infancy. However, according to published literature only a few patients have survived till adulthood. In this report, we describe the case of a 63 years old male patient who admitted in a hospital with small bowel intussusception because of strangulated intestinal obstruction and peritonitis. While surgical operation and revision of abdominal cavity, partial right-sided agenesis of the diaphragm was revealed. Two operations were performed on a patient; one because of strangulated intestinal obstruction and accompanied peritonitis and the second, because of stitch insufficiency after 5 days from the first surgical operation. Taking into account the heavy overall status of the patient, diaphragm plastic was not performed and its performance postponed for future. PMID- 27119828 TI - INCIDENCE OF TUBERCULOSIS AMONG HIV/HCV CO-INFECTED PATIENTS RECEIVING HEPATITIS C TREATMENT WITH PEGYLATED INTERFERON AND RIBAVIRIN IN GEORGIA. AB - Treatment of hepatitis C is necessary for ensuring higher life expectancy among HIV/HCV co-infected patients. However antiviral treatment for chronic HCV infection with Pegylated interferon (PEG-IFN) and Ribavirin (RBV) is associated with a variety of side effects. In Georgia up to 22% of HIV-infected patients were found to have active Tuberculosis (TB) and 22.4 to 32.6% had latent TB. The objective of this study was to describe the characteristics and clinical outcomes of tuberculosis in HIV/HCV co-infected patients receiving hepatitis C treatment with pegylated interferon and ribavirin and calculate incidence rate of TB. A retrospective study was conducted among HIV/HCV co-infected patients receiving antiviral treatment for chronic HCV infection at the Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia from December 2011 to May, 2015. A total of 420 HIV/HCV co-infected patients received HCV therapy with PEG-IFN and RBV during study period. Six of 420 patients developed TB while receiving PEG IFN + RBV therapy. These patients were on Antiretroviral treatment. Baseline HIV RNA load was <34 copies/ml and CD4+ cell counts >350 cells/mm3. No opportunistic infections were observed in all cases. Three of 6 patients had a previous positive tuberculin skin test (TST) result and had completed isoniazid chemoprophylaxis several years before TB diagnosis. In 2 patients TST was not performed. Only one patient had experienced a previous episode of TB and had completed the anti-TB therapy 1 year before hepatitis C treatment. In all patients TB was diagnosed during the PEG IFN + RBV therapy. Hepatitis C treatment was immediately stopped in all patients. The incidence rate of TB was 1.4 cases per 100 person-years (95% CI=0.58-2.97). Our study emphasizes the necessity of screening for latent TB prior to the initiation of chronic hepatitis C treatment with PEG IFN and RBV. PMID- 27119829 TI - COMBINATION THERAPY EFFECTIVENESS OF EZETIMIBE AND ATORVASTATIN IN PATIENTS WITH ACUTE CORONARY SYNDROME. AB - Atorvastatin reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe (EZE) , a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. We conducted a 16-week one center, prospective, randomized, and open-label clinical trial, involving 323 patients who had been hospitalized for an acute coronary syndrome within the preceding 14 days. They were received atorvastatin 20 mg during 28 days and after that 292 patients, who had LDL cholesterol levels>=1.81 mmol/L, were randomized to ezetimibe 10 mg/day co-administered with atorvastatin therapy (EZE+Statin) or doubling their current atorvastatin dose. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (>=30 days after randomization), or nonfatal stroke. At 16 weeks, the mean LDL cholesterol level during the study was 1.60 mmol per liter in the atorvastatine-ezetimibe group, as compared with 1.91 mmol per liter in the atorvastatin-monotherapy group (p<0.001). The Kaplan-Meier survival rate at 16 weeks were 88 .1 % in the atorvastatin-ezetimibe group and 77.0 % in the atorvastatin monotherapy group (absolute risk reduction, 11.1 percentage points; hazard ratio, 2.099 ; 95% confidence interval, 1.165 to 3.781; p=0.014). Patients receiving ezetimibe and statin were more likely to achieve target LDL-C after 16 weeks compared to patients doubling their statin dose. When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Ezetimibe/statin combination therapy was well tolerated among this patients, without safety concerns. PMID- 27119830 TI - ASSOCIATION OF DEPRESSION WITH HOSPITAL LENGTH OF STAY IN PATIENTS WITH ACUTE CORONARY SYNDROME. AB - Psychosocial risk factors are known to have a negative impact on coronary disease morbidity and mortality. The aim of our study was to establish contribution of depression on hospital length of stay in patients with acute coronary events. Depression screening was performed in the Chapidze Center, Tbilisi Georgia. Main inclusion criteria in the study were acute coronary events - non-ST elevation myocardial infarction or unstable angina. The total nomber of participants was 84. A binary logistic regression was used in order to assess contribution of depression on prolonged hospital stay. The mean age for both genders was 59.2 (10.2) years. Most patients had coronary risk factors. Higher BDI score was found in elderly patients, females, and in those with systolic dysfunction as well as in whom revascularization was not performed. In binary logistic regression model myocardial infarction and depression were found to be significant contributors of prolonged hospital stay. Depressive symptoms contribute independently to prolongation of hospital stay in patients with non-STEMI. PMID- 27119831 TI - EFFECTS OF VITAMIN D ANALOGS ON ERYTHROPOIESIS-STIMULATING AGENT DASAGE AND SECONDARY ANEMIA IN HEMODIALYSIS PATIENTS. AB - To investigate the effects of Vitamin D Analogs, paricalcitol and alphacalcidol, on hemoglobin levels and erythropoietin-stimulating agents' dosage in hemodialysis patients with chronic renal failure. A total of 310 patients under hemodialysis treatment for chronic renal failure were included in this retrospective multicenter study. Data on serum parathormone and hemoglobin levels, erythropoietin-stimulating agents' doses, C-reactive protein, calcium and phosphate levels were collected from medical records to comparatively evaluate paricalcitol, alphacalcidol and no treatment groups. Apart from significantly higher levels for hematocrit in patients treated with paricalcitol compared to pre-treatment values (32.3(3.8) vs. 34.1(3.1) p=0.007), pre-treatment and post treatment values for biochemical parameters were similar in paricalcitol and alphacalcidol groups including ESA dose. A significant increase in parathormone levels (p=0.000 for each) while a significant decrease in calcium (p=0.003 and 0.040, respectively), Hb (p=0.001 and 0.009, respectively) and hematocrit (p=0.001 and 0.021, respectively) levels were determined in paricalcitol and alphacalcidol treated patients compared with untreated patients. Also, phosphate levels in alphacalcidol treated patients were significantly higher (p=0.018) than untreated patients. Our findings revealed insufficient suppression of parathormone levels and there of lower hemoglobin and hematocrit levels, but similar ESA dosage among CRF patients treated with Vitamin D analogs compared with untreated patients. PMID- 27119832 TI - [PREVALENCE OF MODIFIABLE RISK FACTORS OF CHRONIC NON INFECTION DISEASES AMONG URBAN AND RURAL RESIDENTS OF KARAGANDA REGION]. AB - The study aimed to investigate prevalence of modifiable risk factors of chronic non infection diseases among urban and rural residents in Karaganda region. The cross-sectional screening study of 1453 respondents' age 18 to 65 among the urban and rural population of the Karaganda region: 672 urban and 781 rural adult residents were included into the study. The screening stage included conducting survey using international questionnaires, anthropometry, arterial blood pressure, fasting plasma glucose and total cholesterol measurement. According study results the most common risk factors among residents of Saran town and Osakarovsky area included: hypercholesterolemia (46,2 % and 36,9 %, respectively), arterial hypertension (39,3 % and 32,2 %, respectively) and smoking (26,3 % and 19,5 % respectively). Frequency of active and passive smoking, hypertension, hypercholesterolemia, obesity and alcohol abuse 1.2-2.0 times higher compared in urban population in comparison rural population. These differences gave possibility to identify special groups need to management preventive targeted measures. PMID- 27119833 TI - [FATAL DIAGNOSIS AND THE HORIZON OF HUMAN LIFE (REVIEW)]. AB - The majority of widespread cancers on the stage of clinical manifestation is incurable and therapy is only for the purpose of life extension. So, it isn't surprising that most of people realize the word "cancer" as a verdict. A man himself doesn't believe in his own death and doesn't realize the fact that "Death is an appropriate phenomenon, but not punishment". Facing the death causes existential crisis. The understanding of inevitable fact of death arouses short, but desperate fight against it, which is, in most cases accompanied by anxiety. Some fundamental changes in phsychoemotional status take place within the young patients (knowing the diagnosis), which help an individual move into a new stage of actions with forming new values and aims. All these give conditions for better adaptation of an individual with phsychic traumas. So, the research of a person's emotional situation, facing the death, will help to indentify the necessity of prophylactic pharmacotherapy with anxiolytics and to overcome both the negative associations with death and the fear connected with it (preserving life horizon). PMID- 27119834 TI - SHOCK-WAVE THERAPY APPLICATION IN CLINICAL PRACTICE (REVIEW). AB - The article presents literature review on the use of extracorporeal shock-wave therapy in physiotherapeutic practice. The basic mechanisms of shock waves influence on the organism are spotlighted. Studies proving high efficacy of the method in treatment of wide variety of inflammatory diseases and traumatic genesis are presented. The data on comparative assessment of shock-wave therapy efficacy, and results of researches on possibility of extracorporeal shock-wave therapy effect potentiating in combination with other therapeutic methods are reflected. Recent years, the range of indications for shock-wave therapy application had been significantly widened. However, further study of the method is still relevant because mechanisms of action of the factor are studied insufficiently; methods of therapy parameters selection (energy flux density, number of pulses per treatment, duration of a course) are either advisory or empirical. PMID- 27119835 TI - MAIN TRENDS IN ACCESS TO PRIMARY HEALTH CARE FOR ADOLESCENTS IN GEORGIA. AB - This study identifies barriers to accessing primary health care among youth in Georgia to inform strategies for improving the appropriateness, quality and usage of primary health care services. The quantitative survey was conducted throughout Georgia among 1000 adolescents 11-19 years of age via interview. Multi stage probability sampling was used to administer questionnaires in the schools, universities and in the streets between March-May 2014 and September-October 2014. Young people in Georgia identified a range of problems in accessing primary health services. By far the most important issues were preventive checkups, geographical access, cost of care, and perceptions about the quality of care. The majority of respondents (78.4%) declared that they do not visit family doctor when well, and 81.9% said that no information was provided about reproductive health issues. Most (77.3%) stated that their family doctor had never talked about health promotion or life style risk factors. Access to health care is still problematic in the villages; and in some areas young people must travel more than 30 minutes by public transport. Limited access in rural areas compared to urban areas was statistically significant (p<0.05). As our survey data shows, most adolescents do not visit a health provider annually, obviating opportunities to integrate prevention into clinical encounters. Because repeated contacts with a primary care provider may occur over several years, clinicians should ideally have multiple opportunities to screen and counsel an adolescent patient for risky health behaviors. However, young people report that there is little screening or discussion about healthy lifestyles. The biggest health challenge for young people in Georgia is overcoming barriers (socioeconomic, geographic, trust, and perceived competence) to visit a doctor for regular preventive checkups and to get health behavior advice from health professional. Addressing the health and development needs of adolescents requires a comprehensive and timely response, and interventions can be incorporated in many programs supported young population of Georgia. PMID- 27119836 TI - [ANTIBIOTIC SENSITIVITY/RESISTANCY OF MICROBIAL STRAINS, ISOLATED FROM PUERPERAS, NEWBORNS AND SAMPLES OF MATERNITY WARD ENVIRONMENT]. AB - In this article, there are given data of microorganisms sensitivity/resistancy investigation, to different groups of antibiotics. Microorganisms where isolated from puerperas, newborns and samples of maternity ward environment. Investigation was performed in L.T.D. "Imedis Clinica". Detection of microorganisms sensitivity/resistancy to antibiotics was performed by use of two methods: method of disc diffusion and serial dilution on solid breeding substratum. It was determined that gram positive, as well as gram negative microorganisms had sufficiently high level of resistancy to some penicillines, aminoglycosides, macrolides. Some species of gram negative microorganisms had resistancy to lincomicin in 100% of cases. High level of sensitivity was revealed to such antibiotics as amicalin, amoxiclav, cefepim, ciprofloxacin. Gram negative microorganisms had high level of sensitivity to imipenem-cilastatin and meropenem. Performed investigation confirms necessity of microbiological monitoring in different clinics, because it is one of the most significant components of infection control. It gives opportunity to perform exact antibiotic prophylaxis and if necessary - rational antibiotic therapy. PMID- 27119837 TI - MEMANTINE ATTENUATES THE OKADAIC ACID INDUCED SHORT-TERM SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS IN RATS. AB - In the present study, the possible beneficial effect of memantine on the Okadaic Acid (OA) induced spatial short-term memory impairment was examined in spatial alternation task, and the neuroprotective potential of memantine on OA-induced structural changes in the hippocampus was evaluated by Nissl staining. OA was dissolved in artificial cerebrospinal fluid (aCSF) and injected intracerebroventriculary (ICV) 200 ng in a volume of 10 MUl bilaterally. Vehicle control received aCSF ICV bilaterally. Control and OA injected rats were divided into 2 subgroups injected i.p. with saline or memantine (5 mg/kg). Memantine or saline were given daily for 13 days starting from the day of OA injection. Behavioral study showed that bilateral ICV microinjection of OA induced impairment in spatial short-term memory. Nissl staining in the present study showed that the ICV microinjection of OA significantly decreased the number of surviving pyramidal neurons in the CA1 region of the hippocampus. Chronic administration of memantine effectively attenuated OA induced spatial short-term memory impairment and the OA-induced neuropathological changes in the hippocampus. Therefore, ICV injection of OA can be used as an experimental model to study mechanisms of neurodegeneration and define novel therapeutics targets for AD pathology. PMID- 27119838 TI - BEHAVIORAL CHARACTERISTICS OF RATS ON VARIOUS HIERARCHICAL LEVEL CAUSED BY ACUTE INFORMATIONAL STRESS. AB - The aim of our research was to study behavioral indices of rats standing on various hierarchical level in the conditions of acute informational stress as well as their resistance to stress taking into account their social status. The Animal's behavior has been studied in conflict and agonist conditions against the background of high food and thirst motivation. After determination of hierarchical relations the stressing procedure of two active avoidance reactions was performed simultaneously during one trial (14 days). During the experiment, behavioral indices of rats induced by stressing procedure were registered. We used "open field" test in order to assess animals' emotional state. The studies performed by us demonstrated behavioral characteristics of animals standing on various hierarchical level. The obtained results showed that after stressing all the animals of the group under stressogenic influence of equal strength, behavior of rats did nor reliably differ in conflict situations. Dominants standing on high hierarchical level remained active in both conflict situations. The impact of stress on their behavior was less detected. Dominant animal maintained its hierarchical status. Submissive rats were more greatly influenced by stress. The obtained results confirmed that dominant animals were characterized with more comprehensively developed self-regulating mechanisms of brain. PMID- 27119839 TI - [ANALYSIS OF THE ASSOCIATION BETWEEN THR83ALA POLYMORPHISM OF MATRIX GLA-PROTEIN GENE AND LOWER EXTREMITY ARTERIAL CALCIFICATION]. AB - Lower extremity arterial calcification (AC) is a common pathological process that has independent significance in the pathogenesis of many cardiovascular diseases. There is evidence that development of AC associated with Thr83Ala polymorphism of matrix GLA-protein gene. The objective of this study was to examine the association between Thr83Ala polymorphism of matrix Cla protein (MGP) gene and AC in male and female subjects of the Ukrainian population. 40 AC and 40 healthy controls were recruited to the study. MGP exon 4 Thr83Ala polymorphism (rs 4236) was examined using the polymerase chain reaction with subsequent restriction fragment length polymorphism analysis. The obtained data show that the substitution of threonin by alanine at position 83 in a molecule of MGP can affect its functional characteristics and anticalcinogenic properties. The distribution of homozygous carriers of a major allelic variant, and heterozygous and homozygous minor allele variants of Thr83Ala polymorphism in patients with AC was 40,0%, 47,5%, and 12,5% respectively. The corresponding distribution of variants in the control group was 32,5%, 42,5% and 25,0% (p=0,352 by chi2 -test). In women who are carriers of Ala/Ala-variant, CA occurs more rarely than in men with the same genotype (p=0,036 by chi2 -test). The substitution of threonine by alanine due to MGP exon 4 Thr83Ala polymorphism is related to a decrease in the likelihood of CA in female persons in the Ukrainian population. PMID- 27119840 TI - [ROLE OF SLC2A9 AND ABCG2 GENE POLYMORPHISMS IN ORIGIN OF HYPERURICEMIA AND GOUT]. AB - The polymorphisms V253I, Q126X, Q141K of SLC2A9 and ABCG2 genes were characterized. GCA i GTC haplotypes of Q126X and Q141K variants can be predictors of gout. The relationship of these polymorphisms with hyperuricaemia according to gender, metabolic syndrome components, with the response to allopurinol was analyzed. It has been established that Q141K polymorphism can directly modulate BCRP-mediated allopurinol and oxypurinol efflux, the K allele is associated with a lower reduction in serum uric acid in response to allopurinol treatment. PMID- 27119841 TI - THE STUDY OF THE IMMUNE CORRECTIVE PROPERTIES OF GREEK WALNUT (JUGLANS REGIA L.) SEPTA ON THE EXPERIMENTAL MODEL OF LEUKOPENIA. AB - From the positive effects of the drugs prepared from various parts of walnut described for a wide variety of diseases, their antitumor effect is remarkable. This feature can be used for treatment of leukopenia caused by radiotherapy and/or chemotherapy. Therefore, to study the immunocorrective properties of Greek walnut, the walnut septa were selected, aqueous extract of which has been studied on experimental model of leukopenia in white mice caused by a single injection of cyclophosphamide. The material of the study were the blood and bone marrow smears from intact and tested adult mice stained by Giemsa's dye. The quantity of leukocytes in peripheral blood were determined by the counting chamber under the light microscope with standard protocol. Cloud-point extraction, HPLC analysis and UV-visible spectrophotometry were used to study the composition of the walnut septa extract. It has been established that the Greek walnut septa extract has the correction ability of suppressed myelopoiesis in white mice caused by injection of cyclophosphamide. The blood formula normalization process by the mentioned extract is provided by the fast increasing in number of immature (band neutrophil) and mature neutrophils in the peripheral blood. It was shown that walnut septa extract stimulates the division, differentiation and maturation of blast forms of myeloid as well as lymphoid line in the bone marrow of mice with leukopenia. Cloud-point extraction and liquid-chromatographic analysis revealed the presence of hydrophilic and hydrophobic components in the walnuts septum extract. PMID- 27119842 TI - ACCURATE DIAGNOSIS OF THYROID NODULES: A REVIEW OF DIAGNOSTIC DILEMMAS ON THYROID FINE-NEEDLE ASPIRATION BIOPSIES. AB - FNA biopsy is well known method for the first step evaluation of thyroid nodules, it is the "gold standard" for diagnosis and surgical approach of nodular goiter. Despite the high sensitivity and specificity of the method there are grey zone in the diagnosis of thyroid nodules, mainly due to the heterogeneous group of Bethesda category AUS/FLUS. There are also some difficulties in diagnosis of PTC, especially FVPTC, even on histologic sections. The limited studies exist that specifically address details of cytologic features associated with cytohistologic discrepancy. Cell-block is very helpful in the diagnosis of papillary thyroid carcinoma and the carcinoma of undefined category; as the papillary configuration and nuclear features were more obvious, also immunocytochemical markers are applicable for ancillary studies. The BRAF mutation detection, which is associated with papillary microcarcinomas and cancer, can be yield for preoperative diagnosis, as well as for prognostic marker and as therapeutic target for farther management. PMID- 27119843 TI - [ULTRASTRUCTURAL ORGANIZATION OF CELLULAR ELEMENTS AND INTERCELLULAR CONNECTIONS IN STATOCYSTS OF TERRESTRIAL PULMONARY SNAIL H. LUCORUM]. AB - The organ of mollusc equilibrium - statocyst appears to be the analogue of acoustic-vestibular system in vertebrate animals. In terrestrial pulmonary snail the epithelial lining of statocyst cavity is created by two types of the cells - a small amount of large cells, provided with kinocilia of sensitive cells and considerably a large number of small supporting or inserted cells, covered with the microvilli. By means of transmission and scanning electron microscopy the ultrastructure and intercellular connections of these cells were studied. The sensitive cells have in a certain way structured cytoplasm, which consists of three layers: ectoplasm, granular layer and hyaloplasm. Myelin-like bodies having the granular, vesicular and drop-like formations in the centre appear to be the special structure of the cytoplasm. In the cytoplasm there are areas, saturated with electron dense glycogen granules. On the electronograms sometimes it is observed how the pinocytic vesicles in the supporting cells are created from the diverticulum of plasmatic membrane of sensitive cells. The boundary areas of plasmatic membrane of adjacent cells (sensitive cells with supporting or supporting cells with the support) are also characterized by the presence of specialized contacts, which are analogous to desmosomes in the epithelial tissues, as well as by the existence of cellular desmosomes, interdigitations. Numerous lacunas have been revealed in the intercellular space, which are connected by the thin tubules and ducts resulting in the formation of a complicated configuration of extensive system of communicating with each other lacunae, which have the exit in statocyst cavity. PMID- 27119844 TI - [MORPHOLOGICAL FEATURES OF RAT MUCOUS MEMBRANE OF THE TONGUE EARLY AFFECTED BY ACRYLIC RESIN MONOMER]. AB - Base materials, made on the basis of various derivatives of acrylic and methacrylic acids, have been widely used in prosthetic dentistry. Free monomer, affecting the tissues of prosthetic bed and the whole body, is always found in dentures. Therefore, study of the effect of acrylic resins' monomer on mucous membrane of the tongue is crucial. Rat tongue is very similar to human tongue, and this fact has become the basis for selecting these animals to be involved into the experiment. The paper presents the findings related to the effect of "Ftoraks" base acrylic resin monomer on the state of rat mucous membrane of the tongue and its regeneration. The microscopy has found that the greatest changes in the mucous membrane of the tongue occur on day 3 and 7 day after applying the monomer and are of erosive and inflammatory nature. Regeneration of tongue epithelium slows down. PMID- 27119845 TI - [CLINICAL AND EPIDEMIOLOGICAL CHARACTERISTICS OF MYELODYSPLASTIC SYNDROMES IN ADULTS]. AB - The myelodysplastic syndromes (MDS) are a distinct group of clonal disorders of hematopoietic stem or progenitor cells characterized by ineffective hematopoiesis and peripheral cytopenias. The data on the epidemiology of MDS in Russia are absent.The aim of the study was to evaluate the incidence of MDS in adults, to evaluate methods of diagnosis confirmation and choice of therapy in the system of Moscow Health Care.The observational study included adult patients with newly diagnosed MDS in 2010. Two hundred and one adult patients (male - 110, female - 118) were registered. Median age at diagnosis was 71.5 years (range, 23.9-93.7). The incidence rate of MDS was 2.0 cases per 100.000 persons per year in the general adult population. All patients divided into 5 groups depending on the type of first-line therapy: 69 patients treated withepoetin alfa or beta; 20 - lowdose Ara-C; 12 - hypomethylating agents; 60 - symptomatic (red cell transfusion for low-risk MDS) and 38 - palliative care (elderly and weakened high risk patients). Two patients with 5q- syndrome treated with lenalidomide. With a median follow-up for survivors 46 months 4-year overall survival (OS) for all patients was 34.8+/-13.4% (median 24.3 months). The incidence of MDS in Moscow, Russia is 1.5-2 times lower than in Europe and the United States. Current standards of survey under the mandatory health insurance does not provide for molecular and cytogenetic assays, which is one of the factors limiting the diagnostic potential. PMID- 27119846 TI - Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug. AB - PURPOSE: To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption. METHODS: IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, and prior information about typical and between subject variability of GI pH and transit times. Data were analysed using the population modelling approach as implemented in NONMEM. RESULTS: Dissolution kinetics were described using first order models. The in vivo pharmacokinetics of itraconazole was described with a 2-compartment model with 4-transit absorption compartments. Pharmacokinetic profiles for fasted itraconazole periods were described based on the in vitro dissolution model, in vivo disposition model, and the prior information on GI pH and transit times. The IVIVC model indicated that drug dissolution in the fed state required an additional pH-independent dissolution pathway. The IVIVC models were presented in a 'Shiny' application. CONCLUSION: An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure. PMID- 27119847 TI - Oscillating from Neurosecretion to Multitasking Dopamine Neurons. AB - In this issue of Cell Reports, Stagkourakis et al. (2016) report that oscillating hypothalamic TIDA neurons, previously thought to be simple neurosecretory neurons controlling pituitary prolactin secretion, control dopamine output via autoregulatory mechanisms and thus could potentially regulate other physiologically important hypothalamic neuronal circuits. PMID- 27119848 TI - Retraction Notice to: Maternal dazap2 Regulates Germ Granules by Counteracting Dynein in Zebrafish Primordial Germ Cells. PMID- 27119850 TI - The Value of Long-Term Stream Invertebrate Data Collected by Citizen Scientists. AB - The purpose of this investigation was to systematically examine the variability associated with temporally-oriented invertebrate data collected by citizen scientists and consider the value of such data for use in stream management. Variability in invertebrate data was estimated for three sources of variation: sampling, within-reach spatial and long-term temporal. Long-term temporal data were also evaluated using ordinations and an Index of Biotic Integrity (IBI). Through two separate investigations over an 11-year study period, participants collected more than 400 within-reach samples during 44 sampling events at three streams in the western United States. Within-reach invertebrate abundance coefficient of variation (CV) ranged from 0.44-0.50 with approximately 62% of the observed variation strictly due to sampling. Long-term temporal CV ranged from 0.31-0.36 with 27-30% of the observed variation in invertebrate abundance related to climate conditions (El Nino strength) and sampling year. Ordinations showed that citizen-generated assemblage data could reliably detect differences between study streams and seasons. IBI scores were significantly different between streams but not seasons. The findings of this study suggest that citizen data would likely detect a change in mean invertebrate density greater than 50% and would also be useful for monitoring changes in assemblage. The information presented here will help stream managers interpret and evaluate changes to the stream invertebrate community detected by citizen-based programs. PMID- 27119853 TI - [What is growing from the nose?]. PMID- 27119849 TI - An Improved microRNA Annotation of the Canine Genome. AB - The domestic dog, Canis familiaris, is a valuable model for studying human diseases. The publication of the latest Canine genome build and annotation, CanFam3.1 provides an opportunity to enhance our understanding of gene regulation across tissues in the dog model system. In this study, we used the latest dog genome assembly and small RNA sequencing data from 9 different dog tissues to predict novel miRNAs in the dog genome, as well as to annotate conserved miRNAs from the miRBase database that were missing from the current dog annotation. We used both miRCat and miRDeep2 algorithms to computationally predict miRNA loci. The resulting, putative hairpin sequences were analysed in order to discard false positives, based on predicted secondary structures and patterns of small RNA read alignments. Results were further divided into high and low confidence miRNAs, using the same criteria. We generated tissue specific expression profiles for the resulting set of 811 loci: 720 conserved miRNAs, (207 of which had not been previously annotated in the dog genome) and 91 novel miRNA loci. Comparative analyses revealed 8 putative homologues of some novel miRNA in ferret, and one in microbat. All miRNAs were also classified into the genic and intergenic categories, based on the Ensembl RefSeq gene annotation for CanFam3.1. This additionally allowed us to identify four previously undescribed MiRtrons among our total set of miRNAs. We additionally annotated piRNAs, using proTRAC on the same input data. We thus identified 263 putative clusters, most of which (211 clusters) were found to be expressed in testis. Our results represent an important improvement of the dog genome annotation, paving the way to further research on the evolution of gene regulation, as well as on the contribution of post-transcriptional regulation to pathological conditions. PMID- 27119854 TI - [Breast cancer? Then also the risk for thyroid cancer is increased]. PMID- 27119855 TI - [Breast reconstruction with autologous fatty tissue does not promote cancer recurrence]. PMID- 27119856 TI - [Suspected Zika virus infection: who should be tested?]. PMID- 27119857 TI - [What you can advise for cancer patients]. PMID- 27119858 TI - [When sports becomes addictive]. PMID- 27119859 TI - [Calculated insanity]. PMID- 27119860 TI - [NOAK in atrial fibrillation and renal failure]. PMID- 27119861 TI - [Conservative anticoagulation]. PMID- 27119862 TI - [Dealing with palpitations safely by number!]. PMID- 27119863 TI - [What do the guidelines say?]. PMID- 27119864 TI - [Patient with fibromyalgia - which therapy is sensible?]. PMID- 27119865 TI - [Borreliosis diagnosis: what is sensible, what is nonsense?]. PMID- 27119866 TI - [Poorly managed diabetes promotes tooth loss]. PMID- 27119867 TI - [Does faith help or harm?]. PMID- 27119868 TI - [Brain aneurysm: score reveals the urgency for an operation]. PMID- 27119869 TI - [How long does clipping hold in the brain?]. PMID- 27119870 TI - [For the house call the no. 01415 is often appropriate]. PMID- 27119871 TI - [Complicated number combination with elderly patients]. PMID- 27119872 TI - [Fun in life: defying cancer with sildenafil]. PMID- 27119873 TI - [With this simple trick all problems falling asleep are passe]. PMID- 27119874 TI - [A city person becomes an enthusiastic rural physician]. PMID- 27119875 TI - [GOP 03230 is also possible for chronic disease patients]. PMID- 27119876 TI - [Will there be a breakthrough in 2016?]. PMID- 27119877 TI - [Promoting graduate education - but never influencing it]. PMID- 27119878 TI - [Not Available]. PMID- 27119879 TI - [Not Available]. PMID- 27119880 TI - [The distended abdomen is a tension pneumoperitoneum]. PMID- 27119881 TI - [Not Available]. PMID- 27119882 TI - [What is pressing there to the outside?]. PMID- 27119883 TI - [Not Available]. PMID- 27119884 TI - [Not Available]. PMID- 27119885 TI - [Colonic polyp--defusing the time bomb]. PMID- 27119886 TI - [Screening colonoscopy--a success story]. PMID- 27119887 TI - [Diagnosis and endoscopic treatment of early colorectal cancer]. PMID- 27119888 TI - [Sudden painful backache due to a (minor) traumatic injury]. PMID- 27119889 TI - [When the nose is itchy]. PMID- 27119890 TI - [Infectious diseases in refugees and their minors arriving in Germany--what the GP needs to know]. PMID- 27119891 TI - [Early diagnosis, early care--"Fr1da" screening of children for type 1 diabetes]. PMID- 27119892 TI - [Preventive medicine: With or without a spoonful of sugar]. PMID- 27119893 TI - [Digital adherence support relieves the physician]. PMID- 27119894 TI - [Early diagnosis and therapy improve prognosis]. PMID- 27119895 TI - [Online portal simplifies the initiation in basal supported oral therapy]. PMID- 27119896 TI - [Iodine supply in Germany is not adequate]. PMID- 27119897 TI - [Nocturnal leg cramps in adults]. PMID- 27119898 TI - [High chance of healing for opiate dependent patients]. PMID- 27119899 TI - Oral Communications. PMID- 27119910 TI - Synthesis of (-)-Cannabimovone and Structural Reassignment of Anhydrocannabimovone through Gold(I)-Catalyzed Cycloisomerization. AB - The first total synthesis of cannabimovone from Cannabis sativa and anhydrocannabimovone was achieved by means of a highly stereoselective gold(I) catalyzed cycloisomerization. The results led to reassignment of the structure of anhydrocannabimovone. PMID- 27119911 TI - Dual-Pedicle Flap for Unilateral Autologous Breast Reconstruction Revisited: Evolution and Optimization of Flap Design over 15 Years. AB - BACKGROUND: In thin patients or when a significant amount of skin is needed, use of the entire abdomen to reconstruct a single breast may be necessary. In this article, the authors present their 15-year experience in dual-pedicle flap evolution and optimization of flap design. METHODS: A retrospective review was conducted of all bipedicle flaps performed from 2000 to 2015. RESULTS: Overall, 57 patients (mean age, 49.2 years; mean body mass index, 26.2 kg/m) underwent dual-pedicle flap reconstruction of a unilateral mastectomy defect. Thirteen patients had a history of smoking, 30 patients had previously undergone irradiation, and 21 patients underwent immediate reconstruction. Eleven bipedicle flaps were performed with a pedicle transverse rectus abdominis musculocutaneous (TRAM) flap coupled to a free TRAM (n = 4), muscle-sparing TRAM (n = 4), or deep inferior epigastric artery perforator (DIEP) (n = 3) flap, and all were performed from 2000 to 2007. The thoracodorsal vessels (n = 8) were used more frequently earlier in the study period with the internal mammary vessels, whereas the antegrade/retrograde internal mammary vessels were used in the remaining patients, except for three patients in whom the internal mammary vessels and an internal mammary vessel perforator were used. Over the study period, there was an increase in the use of DIEP and superficial inferior epigastric artery flaps and the internal mammary vessels as recipients. Complications included delayed wound healing (n = 6), abdominal bulge (n = 2), cellulitis (n = 4), seroma (n = 3), and fat necrosis (n = 4). There was one partial flap loss where the superficial inferior epigastric artery portion of the dual-pedicle flap was lost. CONCLUSIONS: Dual-pedicle free flaps can be performed safely and reliably. Use of DIEP flaps maximizes pedicle length, and the internal mammary vessels can be used reliably in an antegrade and retrograde fashion to perfuse both components of the dual-pedicle flap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27119912 TI - Discussion: Dual-Pedicle Flap for Unilateral Autologous Breast Reconstruction Revisited: Evolution and Optimization of Flap Design over 15 Years. PMID- 27119913 TI - The Transverse Musculocutaneous Gracilis Free Flap: Virtual Animation-Assisted Dissection and Application in Breast Reconstruction. AB - The transverse musculocutaneous gracilis free flap is a valuable choice for autologous tissue, unilateral or bilateral breast reconstruction. This procedure is an excellent and customized option for immediate or delayed breast reconstruction in patients with small to moderate size breasts. Few descriptions of flap dissection and breast mound shaping are available. In this first educational video, the authors report the original dissection of the transverse musculocutaneous gracilis free flap used for breast reconstruction. Virtual animations insist on surgical key points and relevant details of the harvesting of the flap. PMID- 27119914 TI - The Blood Supply of the Breast Revisited. AB - BACKGROUND: Many surgeons are under the impression that the blood supply is clearly defined in textbooks. Unfortunately, the majority of textbooks supply inadequate information and illustrations can be misleading in many instances. None of the textbooks describe a segmental pattern of blood supply when in actual fact a basic segmental pattern does exist. The reason for inadequate information is the perpetuation of facts since the work of the pioneers Cooper and Manchot from one textbook to another. A paucity of research studies thereafter and the fact that the results of some of these studies did not find their way into textbooks is another contributing factor. METHODS: The findings of research studies since the descriptions by Cooper and Manchot are analyzed and compared in an effort to find common ground and its clinical implication. RESULTS: Researchers concurred on the main sources of blood supply; these are internal thoracic, lateral thoracic, anterior intercostal, and acromiothoracic (thoracoacromial) arteries. However, the different research studies showed considerable variation in the branches from the main sources to supply the nipple areola complex. CONCLUSIONS: Even though the locations of the main sources of blood supply are constant, partial or complete absence of branches from the main sources does occur and therefore the blood supply to the nipple-areola complex is unpredictable. Cognizance of the basic segmental pattern and the variations resulting from embryologic development will be helpful for the surgeon to use or adapt a technique to minimize the risk of nipple necrosis. PMID- 27119915 TI - Discussion: The Blood Supply of the Breast Revisited. PMID- 27119916 TI - Three-Dimensional Topographic Surface Changes in Response to Compartmental Volumization of the Medial Cheek: Defining a Malar Augmentation Zone. AB - BACKGROUND: Given the widespread use of facial fillers and recent identification of distinct facial fat compartments, a better understanding of three-dimensional surface changes in response to volume augmentation is needed. Advances in three dimensional imaging technology now afford an opportunity to elucidate these morphologic changes for the first time. METHODS: A cadaver study was undertaken in which volumization of the deep medial cheek compartment was performed at intervals up to 4 cc (n = 4). Three-dimensional photographs were taken after each injection to analyze the topographic surface changes, which the authors define as the "augmentation zone." Perimeter, diameter, and projection were studied. The arcus marginalis of the inferior orbit consistently represented a fixed boundary of the augmentation zone, and additional cadavers underwent similar volumization following surgical release of this portion of the arcus marginalis (n = 4). Repeated three-dimensional computer analysis was performed comparing the augmentation zone with and without arcus marginalis release. RESULTS: Volumization of the deep medial cheek led to unique topographic changes of the malar region defined by distinct boundaries. Interestingly, the cephalic border of the augmentation zone was consistently noted to be at the level of the arcus marginalis in all specimens. When surgical release of the arcus marginalis was performed, the cephalic border of the augmentation zone was no longer restricted. CONCLUSIONS: Using advances in three-dimensional photography and computer analysis, the authors demonstrate characteristic surface anatomy changes in response to volume augmentation of facial compartments. This novel concept of the augmentation zone can be applied to volumization of other distinct facial regions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27119918 TI - A Quantitative Analysis of OnabotulinumtoxinA, AbobotulinumtoxinA, and IncobotulinumtoxinA: A Randomized, Double-Blind, Prospective Clinical Trial of Comparative Dynamic Strain Reduction. AB - BACKGROUND: U.S. Food and Drug Administration-approved formulations of botulinum toxin include onabotulinumtoxinA (Botox; Allergan, Inc., Irvine, Calif.), abobotulinumtoxinA (Dysport; Galderma Pharma S.A., Lausanne, Switzerland), and incobotulinumtoxinA (Xeomin; Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany). This study uses digital image correlation to compare dynamic strain reduction between available neurotoxins. METHODS: Seventy-three treatment-naive female patients aged were randomized to injection with onabotulinumtoxinA (20 units), abobotulinumtoxinA (60 units), or incobotulinumtoxinA (20 units) in the glabella. Imaging was conducted at 4, 14, and 90 days after injection. Change in average dynamic strain of the glabella was compared using ANOVA. RESULTS: At day 4, there was a 42.1 percent strain reduction in the onabotulinumtoxinA group, a 39.4 percent strain reduction in the abobotulinumtoxinA group, and a 19.8 percent strain reduction in the incobotulinumtoxinA group (onabotulinumtoxinA versus abobotulinumtoxinA, p = 0.77; onabotulinumtoxinA versus incobotulinumtoxinA, p = 0.02; and abobotulinumtoxinA versus incobotulinumtoxinA, p = 0.04). At day 14, there was a 66.1 percent strain reduction in the onabotulinumtoxinA group, a 51.4 percent strain reduction in the abobotulinumtoxinA group, and a 42.8 percent strain reduction in the incobotulinumtoxinA group (onabotulinumtoxinA versus abobotulinumtoxinA, p = 0.14; onabotulinumtoxinA versus incobotulinumtoxinA, p = 0.02; and abobotulinumtoxinA versus incobotulinumtoxinA, p = 0.36). At day 90, there was a 43.5 percent strain reduction in the onabotulinumtoxinA group, a 38.4 percent strain reduction in the abobotulinumtoxinA group, and a 25.3 percent strain reduction in the incobotulinumtoxinA group (onabotulinumtoxinA versus abobotulinumtoxinA, p = 0.66; onabotulinumtoxinA versus incobotulinumtoxinA, p = 0.12; and abobotulinumtoxinA versus incobotulinumtoxinA, p = 0.24). CONCLUSIONS: Using digital image correlation, the tested neuromodulators do not have equivalent strain reduction in the glabella at the doses used. These results confirm assertions of noninterchangeability. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 27119917 TI - Global Aesthetics Consensus: Hyaluronic Acid Fillers and Botulinum Toxin Type A Recommendations for Combined Treatment and Optimizing Outcomes in Diverse Patient Populations. AB - BACKGROUND: Combination of fillers and botulinum toxin for aesthetic applications is increasingly popular. Patient demographics continue to diversify, and include an expanding population receiving maintenance treatments over decades. METHODS: A multinational panel of plastic surgeons and dermatologists convened the Global Aesthetics Consensus Group to develop updated guidelines with a worldwide perspective for hyaluronic acid fillers and botulinum toxin. This publication considers strategies for combined treatments, and how patient diversity influences treatment planning and outcomes. RESULTS: Global Aesthetics Consensus Group recommendations reflect increased use of combined treatments in the lower and upper face, and some midface regions. A fully patient-tailored approach considers physiologic and chronologic age, ethnically associated facial morphotypes, and aesthetic ideals based on sex and culture. Lower toxin dosing, to modulate rather than paralyze muscles, is indicated where volume deficits influence muscular activity. Combination of toxin with fillers is appropriate for several indications addressed previously with toxin alone. New scientific data regarding hyaluronic acid fillers foster an evidence-based approach to selection of products and injection techniques. Focus on aesthetic units, rather than isolated rhytides, optimizes results from toxin and fillers. It also informs longitudinal treatment planning, and analysis of toxin nonresponders. CONCLUSIONS: The emerging objective of injectable treatment is facial harmonization rather than rejuvenation. Combined treatment is now a standard of care. Its use will increase further as we refine the concept that aspects of aging are intimately related, and that successful treatment entails identifying and addressing the primary causes of each. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27119919 TI - Management of the Postbariatric Medial Thigh Deformity. AB - BACKGROUND: Thigh contour deformities-in particular, those of the medial thighs are a common concern for many individuals seeking body contouring. Despite the frequency of this concern, some plastic surgeons have often been reluctant to embrace the medial thigh-lift procedure because of the risk for significant complications and relatively poor results. The authors' approach to medial thigh contouring is to address the variables outside of the medial thighs affecting the medial thighs before considering a medial thigh-lift procedure with a vertical component. In this article, the authors review the senior author's (J.F.C.) experience of 350 vertical medial thigh lifts in the weight-loss patient. METHODS: The charts of 350 consecutive individuals who had undergone vertical medial thigh lifts were reviewed for complications and other variables. The procedures were all performed by the senior author between February of 2000 and February of 2014. The preoperative markings, current surgical technique, and postoperative care are described. RESULTS: There were 326 women and 24 men in the study, with an average age of 43 years. The overall complication rate was 45.14 percent. Skin dehiscence and seroma formation were the most frequent complications, at 31.14 percent and 18.18 percent, respectively. The vast majority of patients were pleased with the aesthetic and functional results of their surgery. CONCLUSION: The medial thigh deformities of the weight-loss patient are effectively addressed by a vertical medial thigh lift when the variables adjacent to the medial thighs are first treated by a body lift. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27119920 TI - Interventions to Decrease Postoperative Edema and Ecchymosis after Rhinoplasty: A Systematic Review of the Literature. AB - BACKGROUND: Today, minimally invasive procedures are becoming more popular because of the fast recovery. Rhinoplasty is a common facial plastic surgery procedure that can be associated with significant postoperative morbidities, especially periorbital edema and ecchymosis. The aim of this review is to summarize the results of published literature that studied interventions that decrease postoperative edema and ecchymosis after rhinoplasty, and provide evidence-based strategies for surgeons to incorporate into practice. METHODS: A systematic review of the PubMed, Scopus, and EMBASE databases was performed to investigate interventions studied to decrease postoperative edema and ecchymosis after rhinoplasty. After inclusion and exclusion criteria were applied, articles were grouped into one of the following categories: corticosteroids, other medications and herbal supplements, interventions to decrease intraoperative bleeding, other postoperative interventions, and surgical techniques. RESULTS: A total of 50 articles were included for review. Fourteen articles studied corticosteroids exclusively, whereas another 10 articles reviewed other medications and herbal supplements. Nine articles evaluated methods to decrease intraoperative bleeding during rhinoplasty, and four articles studied postoperative interventions to decrease edema and ecchymosis. Thirteen articles studied various surgical techniques to decrease postoperative morbidities. CONCLUSIONS: There was a consensus within the literature that steroids, intraoperative hypotension, intraoperative cooling, and head elevation postoperatively decrease postoperative edema and ecchymosis, whereas nasal packing and periosteal elevation before osteotomy increased these postoperative morbidities. Studies of herbal supplements may be incorporated into practice with minimal risk to the patient. More studies must be performed before recommending an external or internal approach to lateral osteotomy. PMID- 27119921 TI - Discussion: Interventions to Decrease Postoperative Edema and Ecchymosis after Rhinoplasty: A Systematic Review of the Literature. PMID- 27119922 TI - Promotion of Osteogenesis and Angiogenesis in Vascularized Tissue-Engineered Bone Using Osteogenic Matrix Cell Sheets. AB - BACKGROUND: The regeneration of large, poorly vascularized bone defects remains a significant challenge. Although vascularized bone grafts promote osteogenesis, the required tissue harvesting causes problematic donor-site morbidity. Artificial bone substitutes are promising alternatives for regenerative medicine applications, but the incorporation of suitable cells and/or growth factors is necessary for their successful clinical application. The inclusion of vascular bundles can further enhance the bone-forming capability of bone substitutes by promoting tissue neovascularization. Little is known about how neovascularization occurs and how new bone extends within vascularized tissue-engineered bone, because no previous studies have used tissue-engineered bone to treat large, poorly vascularized defects. METHODS: In this study, the authors developed a novel vascularized tissue-engineered bone scaffold composed of osteogenic matrix cell sheets wrapped around vascular bundles within beta-tricalcium phosphate ceramics. RESULTS: Four weeks after subcutaneous transplantation in rats, making use of the femoral vascular bundle, vascularized tissue-engineered bone demonstrated more angiogenesis and higher osteogenic potential than the controls. After vascularized tissue-engineered bone implantation, abundant vascularization and new bone formation were observed radially from the vascular bundle, with increased mRNA expression of alkaline phosphatase, bone morphogenetic protein-2, osteocalcin, and vascular endothelial growth factor-A. CONCLUSION: This novel method for preparing vascularized tissue-engineered bone scaffolds may promote the regeneration of large bone defects, particularly where vascularization has been compromised. PMID- 27119923 TI - Wound Healing and Angiogenesis through Combined Use of a Vascularized Tissue Flap and Adipose-Derived Stem Cells in a Rat Hindlimb Irradiated Ischemia Model. AB - BACKGROUND: Treatment of critical limb ischemia is sometimes difficult because of the patient's condition, and some novel approaches are needed. METHODS: The hindlimbs of Sprague-Dawley rats, after 20-Gy x-ray irradiation and surgical occlusion, were divided into four groups: with a superficial fascial flap, 5.0 * 10 adipose-derived stromal/stem cells, and both combined. The rats were tested for laser tissue blood flow, immunohistologic blood vessel density, and foot paw punch hole wound healing. Green fluorescent protein-tagged Sprague-Dawley rats were used for further investigation by cell tracking for 2 weeks. RESULTS: Laser tissue blood flow demonstrated a significant increase in the combined treatment of flap and adipose-derived stem cells at both 1 and 2 weeks. There were no significant differences between the treatment groups treated with flaps alone and those treated with adipose-derived stem cells alone. Wound healing was significantly increased following combined treatment at 1 week, and there was no wound by 2 weeks except for the no-flap and no-adipose-derived stem cell group. The number of vessels depicted by von Willebrand factor showed a significant increase in the combined treatment group, at both 1 week and 2 weeks. In the cell tracking group, at 2 weeks, the green fluorescent protein-tagged adipose-derived stem cells were significantly more positive in the no-flap group than in the flap group. CONCLUSIONS: Adipose-derived stem cells may be a potent cell source in irradiated and occluded limbs by enhancing tissue blood flow and blood vessel density. Adipose-derived stem cells may play an important role in some difficult ischemic conditions in terms of wound healing. PMID- 27119924 TI - Collagen and Fractionated Platelet-Rich Plasma Scaffold for Dermal Regeneration. AB - BACKGROUND: Current options for in vivo regeneration of dermal tissue remain limited. The purpose of this study was to engineer a unique scaffold capable of recruiting dermal stem cells from adjacent tissue, thus circumventing the need to seed the scaffolds with stem cells before implantation, leading to skin regeneration. METHODS: A hydrogel scaffold was created through combination of type I collagen along with fractionated platelet-rich plasma. This was compared to a control hydrogel consisting of type I collagen and fetal bovine serum. Hydrogels were cultured with fresh human skin tissue and incubated with supplemental media. Gels were digested weekly for cellular content as examined by flow cytometry at the 4- and 8-week time points. The fractionated platelet-rich plasma and collagen gels were then implanted onto full-thickness skin defects on the backs of rats and compared to wounds healing by secondary intention. Wound area was evaluated for epithelialization and neovascularization. RESULTS: Platelet-rich plasma fractionation increased platelet-derived growth factors. In contrast to collagen scaffolds, fractionated platelet-rich plasma-supplemented scaffolds recruited more dermal-derived stem cells from fresh skin tissue compared with collagen hydrogels at the 4- and 8-week time points. Furthermore, fractionated platelet-rich plasma-supplemented hydrogels accelerated wound healing, angiogenesis, and hair and sweat gland formation, ultimately regenerating a dermis-like tissue. CONCLUSIONS: Generation of hydrogels with fractionated platelet-rich plasma was able to improve cellular recruitment and growth and differentiation of dermal-derived stem cells, leading to hair growth and sweat gland formation. This provides a novel approach to regenerate skin for treating large defects. PMID- 27119925 TI - Inequalities in Specialist Hand Surgeon Distribution across the United States. AB - BACKGROUND: Unequal access to hospital specialists for emergency care is an issue in the United States. The authors sought to describe the geographic distribution of specialist hand surgeons and associated factors in the United States. METHODS: Geographic distributions of surgeons holding a Subspecialty Certificate in Surgery of the Hand and hand surgery fellowship positions were identified from the American Board of Medical Specialties Database and the literature (2013), respectively. State-level population and per capita income were ascertained using U.S. Census data. Variations in hand trauma admissions were determined using Healthcare Cost and Utilization Project national/state inpatient databases. Risk adjusted generalized linear models were used to assess independent association between hand surgeon density and hand trauma admission density, fellowship position density, and per capita income. RESULTS: Among 2019 specialist hand surgeons identified, 72.1 percent were orthopedic surgeons, 18.3 percent were plastic surgeons, and 9.6 percent were general surgeons. There were 157 hand surgery fellowship positions nationwide. There were 149,295 annual hand trauma admissions. The national density of specialist hand surgeons and density of trauma admission were 0.6 and 47.6, respectively. The density of specialist hand surgeons varied significantly between states. State-level variations in density of surgeons were independent and significantly associated with median per capita income (p < 0.001) and with density of fellowships (p = 0.014). CONCLUSIONS: Specialist hand surgeons are distributed unevenly across the United States. State level analyses suggest that states with lower per capita incomes may be particularly underserved, which may contribute to regional disparities in access to emergency hand trauma care. PMID- 27119926 TI - Anthropometric Outcomes following Fronto-Orbital Advancement for Metopic Synostosis. AB - BACKGROUND: The authors' purpose is to present changes in anthropometric fronto orbital dimensions after surgical correction of metopic synostosis. METHODS: The authors retrospectively analyzed craniometric dimensions in older patients with metopic synostosis corrected by fronto-orbital advancement performed by the senior author (J.B.M.). Preoperative and postoperative linear measures (frontal breadth, cranial width, and intercanthal distance) were taken by direct anthropometry. Interdacryon distance and width of the bandeau were also recorded intraoperatively, before and after widening. Follow-up anthropometric values were compared to age- and sex-matched normative data and standard (z) scores were calculated. RESULTS: Sixteen patients met the inclusion criteria. Syndromic diagnosis was documented in five of 16 patients. Average age at the last postoperative evaluation was 8.9 +/- 3.8 years (range, 4 to 16 years). Mean frontal width z-scores decreased postoperatively from 0.82 to -0.32 (p = 0.007), indicating diminished growth in this dimension. The last measured frontal width strongly correlated with the breadth of the bandeau after surgical correction but not with preoperative values. Postoperative mean cranial width diminished significantly to a more normal value. Mean intercanthal distance was normal preoperatively and remained so but was significantly greater in syndromic than in nonsyndromic cases. CONCLUSIONS: Frontal growth rate is diminished in the coronal plane after fronto-orbital advancement. The authors recommend primary techniques to overcorrect the width of the bandeau and frontal region, including zygomaticosphenoid osteotomies and interpositional cranial bone grafts to advance/widen the lateral orbital rim. Continued evaluation is required to assess whether overcorrection results in normal frontotemporal shape and breadth at skeletal maturity. PMID- 27119927 TI - Objective Assessment of the Interfrontal Angle for Severity Grading and Operative Decision-Making in Metopic Synostosis. AB - BACKGROUND: The purpose of this study was to evaluate the utility of a previously validated interfrontal angle for classification of severity of metopic synostosis and as an aid to operative decision-making. METHODS: An expert panel was asked to study 30 cases ranging from minor to severe metopic synostosis. Based on computed tomographic images of the skull and clinical photographs, they classified the severity of trigonocephaly (1 = normal, 2 = mild, 3 = moderate, and 4 = severe) and management (0 = nonoperative and 1 = operative). The severity scores and management reported by experts were then pooled and matched with the interfrontal angle computed from each respective computed tomographic scan. A threshold was identified at which most experts agree on operative management. RESULTS: Expert severity scores were higher for more acute interfrontal angles. There was a high concordance at the extremes of classifications, severe (4) and normal (1) (p < 0.0001); however, between interfrontal angles of 114.3 and 136.1 degrees, there exists a "gray zone," with severe discordance in expert rankings. An operative threshold of 118.2 degrees was identified, with the interfrontal angle able to predict the expert panel's decision to proceed with surgery 87.6 percent of the time. CONCLUSIONS: The interfrontal angle has been previously validated as a simple, accurate, and reproducible means for diagnosing trigonocephaly, but must be obtained from computed tomographic data. In this article, the authors demonstrate that the interfrontal angle can be used to further characterize the severity of trigonocephaly. It also correlated with expert decision-making for operative versus nonoperative management. This tool may be used as an adjunct to clinical decision-making when the decision to proceed with surgery may not be straightforward. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, V. PMID- 27119928 TI - Age at the Time of Surgery and Maintenance of Head Size in Nonsyndromic Sagittal Craniosynostosis. AB - BACKGROUND: Repair of nonsyndromic sagittal craniosynostosis should durably improve intracranial volume and cranial index. The optimal timing of surgery is not known. The authors previously reported reoperation in patients aged younger than 6 months at primary repair. METHODS: Patients undergoing primary reconstruction for sagittal craniosynostosis before age 1 year between 2005 and 2013 at Oregon Health & Science University underwent retrospective computed tomographic determination of cranial index and intracranial volume preoperatively and 2 years postoperatively and head circumference measurements until age 6 years. RESULTS: Fifty-six patients undergoing operation before their first birthday were studied in two groups: those younger than 6 months [34 (61 percent)] and those aged 6 months or older at the time of operation. Head circumference percentile increased immediately after surgery but decreased at 1 and 2 years after surgery, significantly more so in patients younger than 6 months (p < 0.015 at 1 year; p < 0.011 at 2-year follow-up). Mean 2-year postoperative cranial index was significantly increased in both groups (p < 0.001), which did not differ preoperatively (younger than 6 months, 76.5; 6 months or older, 78.0) or 2 years postoperatively (younger than 6 months, 88.4; 6 months or older, 87.1; p = not significant). Intracranial volume increased in all patients from before surgery to 2 years postoperatively and was higher in the patients aged 6 months or older (p < 0.001). CONCLUSION: Cranial reconstruction for nonsyndromic sagittal craniosynostosis improved cranial index equally in all patients but increased head circumference and intracranial volume significantly more in patients who underwent surgical reconstruction at age 6 months or older. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27119929 TI - Discussion: Age at the Time of Surgery and Maintenance of Head Size in Nonsyndromic Sagittal Craniosynostosis. PMID- 27119930 TI - Total Face, Eyelids, Ears, Scalp, and Skeletal Subunit Transplant Cadaver Simulation: The Culmination of Aesthetic, Craniofacial, and Microsurgery Principles. AB - BACKGROUND: The application of aesthetic, craniofacial, and microsurgical principles in the execution of face transplantation may improve outcomes. Optimal soft-tissue face transplantation can be achieved by incorporating subunit facial skeletal replacement and subsequent tissue resuspension. The purpose of this study was to establish a reconstructive solution for a full face and scalp burn and to evaluate outcome precision and consistency. METHODS: Seven mock face transplants (14 cadavers) were completed in the span of 1 year. Components of the vascularized composite allograft included the eyelids, nose, lips, facial muscles, oral mucosa, total scalp, and ears; and skeletal subunits of the zygoma, nasal bone, and genial segment. Virtual surgical planning was used for osteotomy selection, and to evaluate postoperative precision of hard- and soft-tissue elements. RESULTS: Each transplant experience decreased each subsequent transplant surgical time. Prefabricated cutting guides facilitated a faster dissection of both donor and recipient tissue, requiring minimal alteration to the allograft for proper fixation of bony segments during inset. Regardless of donor-to-recipient size discrepancy, ample soft tissue was available to achieve tension-free allograft inset. Differences between virtual transplant simulation and posttransplant measurements were minimal or insignificant, supporting replicable and precise outcomes. CONCLUSIONS: This facial transplant model was designed to optimize reconstruction of extensive soft-tissue defects of the craniofacial region representative of electrical, thermal, and chemical burns, by incorporating skeletal subunits within the allograft. The implementation of aesthetic, craniofacial, and microsurgical principles and computer-assisted technology improves surgical precision, decreases operative time, and may optimize function. PMID- 27119931 TI - Comparison of Single and Double Venous Anastomoses in Head and Neck Oncologic Reconstruction Using Free Flaps: A Meta-Analysis. AB - BACKGROUND: Venous insufficiency is the main cause of failure and surgical revision in free flap surgery. Achieving a double venous anastomosis is frequently proposed to improve flap drainage. However, this procedure remains controversial. The authors evaluated, through a meta-analysis, the benefit of double venous anastomoses in the venous thrombosis, surgical revision, and failure rates of free flaps in head and neck oncologic reconstruction. METHODS: A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria in the MEDLINE, PubMed Central, Cochrane Library, and EMBASE databases. Statistical heterogeneity evaluation and then fixed effects and random effects models were used. RESULTS: Sixteen articles were included involving 3684 flaps. The overall success rate was 96.15 percent. The authors reported a failure rate of 1.51 percent in the group with two anastomoses versus 5.03 percent in the group with single anastomoses (OR, 0.64; 95 percent CI, 0.277 to 1.522; p = 0.320). The authors found a venous thrombosis rate of 2.74 percent in the group with two anastomoses versus 4.54 percent in the group with single anastomoses (OR, 0.535; 95 percent CI, 0.334 to 0.858; p = 0.009). There were also more surgical revisions in the single venous anastomoses group, 11.87 percent versus 6.04 percent (OR, 0.474; 95 percent CI, 0.349 to 0.643; p < 0.001). CONCLUSIONS: This meta-analysis supports that performing a double venous anastomosis confers protective effects in venous thrombosis and surgical revision, thus reducing free flap failure. The authors recommend the achievement of double venous anastomosis whenever it is feasible in head and neck oncologic reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27119932 TI - Discussion: Comparison of Single and Double Venous Anastomoses in Head and Neck Oncologic Reconstruction Using Free Flaps: A Meta-Analysis. PMID- 27119933 TI - A Novel Surgical Approach to Chronic Temporal Headaches. AB - The targets for the surgical treatment of temporal headaches are the zygomaticotemporal branch of the trigeminal nerve and the auriculotemporal nerve. The former is often accessed by means of an endoscopic brow approach or potentially by laterally extending a transpalpebral incision. An established surgical approach, the Gillies incision, was modified to access the zygomaticotemporal nerve, as it was felt to combine the advantages of the traditional techniques. Nineteen patients underwent zygomaticotemporal nerve decompression and neuroplasty or neurectomy and muscle implantation using this surgical approach. A 3.5-cm incision was made behind the anterior, temporal hairline and the zygomaticotemporal branch of the trigeminal nerve was approached directly, remaining superficial to the deep temporal fascia. Each patient was assessed preoperatively and postoperatively with regard to the frequency, duration, and severity of their symptoms to calculate a Migraine Headache Index score. All evaluations were performed at least 1 year postoperatively. The mean preoperative Migraine Headache Index score was 131.7 and the mean postoperative score was 52 (p < 0.0001). There were no surgical complications. There appeared to be no differences between those patients that had decompression and neuroplasty versus those that underwent neurectomy and implantation, as both groups experienced significant reductions in Migraine Headache Index scores following the procedure. The anterior temporal approach to the zygomaticotemporal nerve is both safe and effective. The advantages of this approach include a hidden scar, the ability to directly manipulate the nerve for transection or preservation, and access to the auriculotemporal nerve through the same incision. PMID- 27119934 TI - Discussion: Three-Dimensional Computed Tomographic Angiography Study of the Interperforator Flow of the Lower Leg. PMID- 27119935 TI - Making Master Surgeons Out of Trainees: Part I. Teaching Surgical Judgment. AB - The training of competent and ethical plastic surgery residents has become more difficult, as surgeons face increasing clinical and research demands, concern for medicolegal liability, and pressure to increase efficiency to decrease health care expenditures. The resulting variation in operative experience among plastic surgery trainees exemplifies the need for educational reform to accommodate change. Although the Accreditation Council for Graduate Medical Education has mandated a transition to competency-based training, and state-of-the-art technologies in surgical simulation are being developed to improve operative skills, the construction of a system to teach and assess operative judgment is deficient and should be thoughtfully created and implemented. Established educational methods and curriculums can be used in this effort and include apprenticeship operative teaching, surgical simulation, morbidity and mortality conferences, and resident clinics. The first step in this effort is to require trainees to make decisions, communicating their judgments and recommendations using language that demonstrates clear thinking and thoughtful analysis. For faculty, this means carving out dedicated preoperative teaching time in addition to efficient use of intraoperative time and sharing of postoperative outcomes. For programs, this means developing metrics to evaluate progress and build procedure-specific simulations. The goal should be not just to settle for training safe and ethical surgeons but to produce masterful surgeons with mature judgment. PMID- 27119936 TI - Head and Neck Vascular Anomalies: A Practical Case-Based Approach. PMID- 27119937 TI - Lymphedema: Presentation, Diagnosis, and Treatment. PMID- 27119938 TI - Volumetric Planning Using Computed Tomographic Angiography Improves Clinical Outcomes in DIEP Flap Breast Reconstruction. AB - BACKGROUND: The present study evaluated outcomes of deep inferior epigastric perforator (DIEP) flap breast reconstruction using volumetric planning-which is preoperative planning based on volumetric data of the breast and flap estimated from computed tomographic angiography. METHODS: A prospective review of three patient cohorts undergoing DIEP flap breast reconstruction from June of 2009 to February of 2015 was performed. Cohort 1 comprised 48 cases in which no volumetric planning was used. Cohort 2 included the next 101 consecutive cases undergoing breast reconstruction according to an algorithm based on volumetric planning. Cohort 3 consisted of the next 109 consecutive cases using a modified algorithm. The inset rate (weight ratio of the inset flap to harvested flap) was estimated during volumetric planning, and specific surgical strategies, such as incorporating multiple perforators, conducting venous augmentation (cohort 2), or harvesting bipedicled flaps (cohort 3), were used with reference to it. Rates of perfusion-related complications were compared. RESULTS: All but one flap survived completely. Fat necrosis occurred in 9.7 percent. Overall, the perfusion-related complication rate was 22.9 percent of cohort 1, 10.9 percent in cohort 2, and 5.6 percent in cohort 3 (p = 0.006). The fat necrosis rates were 19.1, 9.9, and 5.6 percent in cohorts 1, 2, and 3, respectively (p = 0.032). A multivariate analysis demonstrated that volumetric planning had independent benefits for preventing perfusion-related complications (p = 0.003). CONCLUSION: The authors' results suggest that volumetric planning can facilitate elaborate planning and reduce perfusion-related complications, enabling reliable breast reconstruction using DIEP flaps. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27119939 TI - Discussion: Volumetric Planning Using Computed Tomographic Angiography Improves Clinical Outcomes in DIEP Flap Breast Reconstruction. PMID- 27119940 TI - The Efficacy of Intense Pulsed Light Therapy in Postoperative Recovery from Eyelid Surgery. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of postoperative intense pulsed light therapy on patients who undergo bilateral eyelid surgery. METHODS: Patients presenting over a 3-month period for bilateral eyelid surgery were asked to participate in an institutional review board approved study. Intense pulsed light therapy was administered three times to the same randomly assigned side on postoperative days 1 to 2, 5 to 7, and 10 to 12. Sham light therapy was administered to the contralateral side. Patient surveys and physician ratings were obtained based on photographic evaluation of ecchymosis, edema, and erythema. Three physicians, including the senior author (A.E.W.), submitted ratings, and these ratings were assessed for interobserver reliability. RESULTS: Twenty-eight patients who underwent bilateral eyelid surgery followed by intense pulsed light therapy were enrolled. The mean age of the patients was 66 years (range, 44 to 81 years). Eighty-six percent of patients were female. The change in ratings between postoperative days 1 to 2 and 10 to 12, in the treatment and control groups, was statistically significant for severity of bruising by both patient and physician assessment and for color of bruising only by patient assessment. The interobserver reliability reached the greatest agreement in the ecchymosis category at each time point for the treatment group. CONCLUSION: In a series of patients who underwent eyelid surgery, intense pulsed light therapy decreased the degree of ecchymosis compared with sham treatment in postoperative eyelid surgery patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 27119941 TI - Perioperative Corneal Abrasion: Updated Guidelines for Prevention and Management. AB - Corneal abrasion is the most common ocular complication in surgery. Treatment requires pain control, antimicrobial prophylaxis, and close monitoring. Pain improves significantly after 24 hours and should be resolved by 48 hours. Persistent, worsening, or new symptoms warrant immediate specialist consultation. The authors review the pathophysiology of perioperative corneal abrasion, and propose updated evidence-based guidelines for improved patient care. PMID- 27119942 TI - External Volume Expansion in Irradiated Tissue: Effects on the Recipient Site. AB - BACKGROUND: External volume expansion prepares recipient sites to improve outcomes of fat grafting. For patients receiving radiotherapy after mastectomy, results with external volume expansion vary, and the relationship between radiotherapy and expansion remains unexplored. Thus, the authors developed a new translational model to investigate the effects in chronic skin fibrosis after radiation exposure. METHODS: Twenty-four SKH1-E mice received 50 Gy of beta radiation to each flank and were monitored until fibrosis developed (8 weeks). External volume expansion was then applied at -25 mmHg to one side for 6 hours for 5 days. The opposite side served as the control. Perfusion changes were assessed with hyperspectral imaging. Mice were euthanized at 5 (n = 12) and 15 days (n = 12) after the last expansion application. Tissue samples were analyzed with immunohistochemistry for CD31 and Ki67, Masson trichrome for skin thickness, and picrosirius red to analyze collagen composition. RESULTS: All animals developed skin fibrosis 8 weeks after radiotherapy and became hypoperfused based on hyperspectral imaging. Expansion induced edema on treated sides after stimulation. Perfusion was decreased by 13 percent on the expansion side (p < 0.001) compared with the control side for 5 days after stimulation. Perfusion returned to control-side levels by day 15. Dermal vasculature increased 38 percent by day 15 (p < 0.01) in expansion versus control. No difference was found in collagen composition. CONCLUSIONS: External volume expansion temporarily reduces perfusion, likely because of transient ischemia or edema. Together with mechanotransduction, these effects encourage a proangiogenic and proliferative environment in fibrotic tissue after radiotherapy in the authors' mouse model. Further studies are needed to assess these changes in fat graft retention. PMID- 27119943 TI - Increased Osteoid Formation in BMP-2-Loaded Silk-Based Screws. AB - BACKGROUND: Resorbable osteosynthesis systems are used to treat craniofacial fractures. However, conventional synthetic polyester materials are potentially associated with inflammatory reaction and negative host response and may result in incomplete bone remodeling. The authors have developed a resorbable silk fibroin-based osteosynthesis system and propose that silk screws loaded with bone morphogenetic protein-2 (BMP-2) may exhibit biocompatibility and promote bone remodeling. METHODS: Resorbable silk screws were prepared and loaded with BMP-2. The BMP-2-loaded and nonloaded silk screws were inserted into the distal femora in 15 Sprague-Dawley rats by self-tapping, similar to conventional metal systems. Animals were euthanized after 1, 3, and 6 months. The femora were explanted at the designated time points, dissected for histologic evaluation, and compared regarding osteoid formation and inflammatory response. RESULTS: Increasing organization of newly formed bone tissue was observed over time in both groups. No appreciable difference in inflammation was noted between the BMP-2-loaded and nonloaded silk screws. Notably, mineralized collagen around the periphery of the screw appears to be greatest and more organized in the BMP-2-loaded samples. There was greater recruitment of osteoclasts and osteoblasts around the perimeter of the BMP-2-loaded screws at 3 and 6 months. CONCLUSIONS: The BMP-2-loaded silk based fixation device in this study exhibited characteristics comparable to the current nonloaded silk screws with regard to integration and biocompatibility. However, functionalization of silk screws with BMP-2 appeared to allow for more organized collagen and osteoid deposition after 3 and 6 months and may increase the potential of successful remodeling. PMID- 27119944 TI - An Algorithmic Approach to the Surgical Treatment of Chronic Ischemia of the Hand: A Systematic Review of the Literature. AB - BACKGROUND: Chronic ischemia of the hand can lead to intractable pain, cold intolerance, and digital necrosis, affecting up to 4.8 percent of patients undergoing vascular surgery. Treatment of patients suffering from chronic hand ischemia, in particular, the subset of patients with a nonreconstructible distal arterial tree, can be a significant challenge for hand surgeons. The purpose of this systematic review is to analyze the outcomes of surgical therapies in an effort to define the efficacy of each intervention. The authors also revisit the treatment algorithm for nontraumatic chronic hand ischemia. METHODS: A systematic search of the literature published since 1990 in the PubMed/MEDLINE database was performed using keywords. Articles were eligible if they described clinical studies of human patients with nontraumatic chronic hand ischemia who underwent sympathectomy, arterial bypass, or venous arterialization. Pain improvement, wound healing, and new ulcerations were primary outcome measures. Primary patency rates and limb salvage data were also collected as primary outcome measures in the bypass and arterialization study arms. RESULTS: For sympathectomy, arterial bypass, and venous arterialization, pain relief was achieved in 89, 100, and 100 percent of patients, respectively; whereas wound healing occurred in 74, 93, and 75 percent, respectively. Postoperative ulcerations were 0, 3, and 8 percent, respectively. No secondary amputations were reported in these 33 studies. Complication rates were moderately high (2.1 to 30.8 percent). CONCLUSION: This systematic review confirms that sympathectomy, arterial bypass, and venous arterialization are efficacious treatments, and allows for an algorithmic approach to the surgical treatment of chronic hand ischemia. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27119945 TI - An Algorithm for Managing Syndromic Craniosynostosis Using Posterior Vault Distraction Osteogenesis. AB - BACKGROUND: The authors hypothesize that early posterior vault distraction osteogenesis safely confers considerable cranial vault remodeling, sufficient to enable fronto-orbital advancement to be delayed to a later age, with improved outcomes. METHODS: The authors conducted a retrospective cohort study of children with syndromic craniosynostosis treated before (2003 to 2008) or after (2009 to 2014) implementation of posterior vault distraction osteogenesis. RESULTS: Sixty children with syndromic craniosynostosis presented during the study period. Forty met inclusion criteria with care continuity and complete records: 22 before and 18 after implementation of posterior vault distraction osteogenesis. Only 11 patients (61 percent) who underwent initial posterior vault distraction osteogenesis required frontal advancement, at a mean follow-up of 4.0 years of age, compared with 22 patients (100 percent) before implementation of posterior vault distraction osteogenesis. Kaplan-Meier survival analysis indicated significant delay of first fronto-orbital advancement in the posterior vault distraction osteogenesis cohort compared with the pre-posterior vault distraction osteogenesis cohort (p = 0.011). Comparing treatment in the first 5 years of life among posterior vault distraction osteogenesis versus non-posterior vault distraction osteogenesis subcohorts of patients older than 5 years, there were significantly fewer fronto-orbital advancements performed (0.6 versus 1.5 per patient; p = 0.023). CONCLUSION: Using early posterior vault distraction osteogenesis for patients with syndromic craniosynostosis significantly reduces the average number of fronto-orbital advancement procedures in the first 5 years of life, delays initial fronto-orbital advancement, and is likely to reduce the total number of major craniofacial procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27119946 TI - Discussion: An Algorithm for Managing Syndromic Craniosynostosis Using Posterior Vault Distraction Osteogenesis. PMID- 27119947 TI - Total Face, Eyelids, Ears, Scalp, and Skeletal Subunit Transplant Research Procurement: A Translational Simulation Model. AB - BACKGROUND: Cadaveric face transplant models are routinely used for technical allograft design, perfusion assessment, and transplant simulation but are associated with substantial limitations. The purpose of this study was to describe the experience of implementing a translational donor research facial procurement and solid organ allograft recovery model. METHODS: Institutional review board approval was obtained, and a 49-year-old, brain-dead donor was identified for facial vascularized composite allograft research procurement. The family generously consented to donation of solid organs and the total face, eyelids, ears, scalp, and skeletal subunit allograft. RESULTS: The successful sequence of computed tomographic scanning, fabrication and postprocessing of patient-specific cutting guides, tracheostomy placement, preoperative fluorescent angiography, silicone mask facial impression, donor facial allograft recovery, postprocurement fluorescent angiography, and successful recovery of kidneys and liver occurred without any donor instability. Preservation of the bilateral external carotid arteries, facial arteries, occipital arteries, and bilateral thyrolinguofacial and internal jugular veins provided reliable and robust perfusion to the entirety of the allograft. Total time of facial procurement was 10 hours 57 minutes. CONCLUSIONS: Essential to clinical face transplant outcomes is the preparedness of the institution, multidisciplinary face transplant team, organ procurement organization, and solid organ transplant colleagues. A translational facial research procurement and solid organ recovery model serves as an educational experience to modify processes and address procedural, anatomical, and logistical concerns for institutions developing a clinical face transplantation program. This methodical approach best simulates the stressors and challenges that can be expected during clinical face transplantation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27119948 TI - A Novel Approach to Surgical Markings Based on a Topographic Map and a Projected Three-Dimensional Image. AB - Surgical markings play a crucial role in the planning of plastic surgery procedures. However, despite their importance, they are often imprecise. For instance, when assessing patients in need of autologous fat grafting, surgeons often base markings on estimations of where volume deficiency exists and how much volume will correct the deficiency. In this article, the authors describe a novel approach to lipostructure, guided by a computer-based roadmap. A digital three dimensional topographic surgical map is created using three-dimensional photography and analytic software and then projected as an image onto the patient in the operating room. This unique concept can be applied to most soft-tissue procedures in plastic surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 27119949 TI - Correction of Pectus Excavatum by Custom-Made Silicone Implants: Contribution of Computer-Aided Design Reconstruction. A 20-Year Experience and 401 Cases. AB - BACKGROUND: In the absence of demonstrable functional impairment, pectus excavatum is merely a congenital deformity, albeit with a marked psychological impact. Many patients do not wish to undergo thoracic remodeling operations, which are invasive and do not clearly result in respiratory or cardiac improvement. METHODS: From 1993 to 2015, the authors designed 401 custom-made silicone implants to treat funnel chests. Before 2007, implants were made from plaster chest molds. Beginning in 2007, three-dimensional reconstructions were made from computed tomographic scans by computer-aided design. The authors prospectively recorded all assessments and follow-up data since 1993. Preoperative and postoperative photographs of two random groups of 50 patients were analyzed, in a blinded manner, by two surgeons independently. Intraoperative and postoperative complications, clinical outcomes, patient satisfaction, and quality of life were evaluated. RESULTS: One infection and three hematomas were recorded. Periprosthetic seroma was evident in all cases. Patients rated the cosmetic outcomes of computer-aided design implants significantly higher than those of the earlier implants made using plaster molds (p = 0.030). Malformations were better corrected in the computer-aided design group (86 percent) than in the plaster group (72 percent) (p = 0.038). Patient satisfaction was higher in the former group (p = 0.011). Medical Outcomes Study 36-Item Short-Form Health Survey scores revealed significant improvements, both socially and emotionally. CONCLUSIONS: Correction of pectus excavatum using a computer-aided design silicone implant fulfils aesthetic and psychological demands. The technique is simple and reliable and yields high-quality results. In the medium term, the approach may render invasive techniques obsolete. These operations remain risky and of doubtful functional utility. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 27119950 TI - Current Applications of Facial Volumization with Fillers. AB - LEARNING OBJECTIVES: After reading this article and watching the accompanying videos, the participant should be able to: 1. Assess patients seeking facial volumization and correlate volume deficiencies anatomically. 2. Identify appropriate fillers based on rheologic properties and anatomical needs. 3. Recognize poor candidates for facial volumization. 4. Recognize and treat filler related side effects and complications. SUMMARY: Facial volumization is widely applied for minimally invasive facial rejuvenation both as a solitary means and in conjunction with surgical correction. Appropriate facial volumization is dependent on patient characteristics, consistent longitudinal anatomical changes, and qualities of fillers available. In this article, anatomical changes seen with aging are illustrated, appropriate techniques for facial volumization are described in the setting of correct filler selection, and potential complications are addressed. PMID- 27119951 TI - Big Data and Machine Learning in Plastic Surgery: A New Frontier in Surgical Innovation. AB - Medical decision-making is increasingly based on quantifiable data. From the moment patients come into contact with the health care system, their entire medical history is recorded electronically. Whether a patient is in the operating room or on the hospital ward, technological advancement has facilitated the expedient and reliable measurement of clinically relevant health metrics, all in an effort to guide care and ensure the best possible clinical outcomes. However, as the volume and complexity of biomedical data grow, it becomes challenging to effectively process "big data" using conventional techniques. Physicians and scientists must be prepared to look beyond classic methods of data processing to extract clinically relevant information. The purpose of this article is to introduce the modern plastic surgeon to machine learning and computational interpretation of large data sets. What is machine learning? Machine learning, a subfield of artificial intelligence, can address clinically relevant problems in several domains of plastic surgery, including burn surgery; microsurgery; and craniofacial, peripheral nerve, and aesthetic surgery. This article provides a brief introduction to current research and suggests future projects that will allow plastic surgeons to explore this new frontier of surgical science. PMID- 27119952 TI - Scarpa Fascia Preservation in Abdominoplasty: Does It Preserve the Lymphatics? PMID- 27119953 TI - An Electrostatic Funnel in the GABA-Binding Pathway. AB - The gamma-aminobutyric acid type A receptor (GABAA-R) is a major inhibitory neuroreceptor that is activated by the binding of GABA. The structure of the GABAA-R is well characterized, and many of the binding site residues have been identified. However, most of these residues are obscured behind the C-loop that acts as a cover to the binding site. Thus, the mechanism by which the GABA molecule recognizes the binding site, and the pathway it takes to enter the binding site are both unclear. Through the completion and detailed analysis of 100 short, unbiased, independent molecular dynamics simulations, we have investigated this phenomenon of GABA entering the binding site. In each system, GABA was placed quasi-randomly near the binding site of a GABAA-R homology model, and atomistic simulations were carried out to observe the behavior of the GABA molecules. GABA fully entered the binding site in 19 of the 100 simulations. The pathway taken by these molecules was consistent and non-random; the GABA molecules approach the binding site from below, before passing up behind the C loop and into the binding site. This binding pathway is driven by long-range electrostatic interactions, whereby the electrostatic field acts as a 'funnel' that sweeps the GABA molecules towards the binding site, at which point more specific atomic interactions take over. These findings define a nuanced mechanism whereby the GABAA-R uses the general zwitterionic features of the GABA molecule to identify a potential ligand some 2 nm away from the binding site. PMID- 27119955 TI - [Focal therapy is also not chamomile tea : Comment on Apfelbeck et al.: "Focal therapy of prostate cancer in Germany"]. PMID- 27119954 TI - Transcriptional Regulation of the beta-Type Carbonic Anhydrase Gene bca by RamA in Corynebacterium glutamicum. AB - Carbonic anhydrase catalyzes the reversible hydration of carbon dioxide to bicarbonate and maintains the balance of CO2/HCO3- in the intracellular environment, specifically for carboxylation/decarboxylation reactions. In Corynebacterium glutamicum, two putative genes, namely the bca (cg2954) and gca (cg0155) genes, coding for beta-type and gamma-type carbonic anhydrase, respectively, have been identified. We here analyze the transcriptional organization of these genes. The transcriptional start site (TSS) of the bca gene was shown to be the first nucleotide "A" of its putative translational start codon (ATG) and thus, bca codes for a leaderless transcript. The TSS of the gca gene was identified as an "A" residue located at position -20 relative to the first nucleotide of the annotated translational start codon of the cg0154 gene, which is located immediately upstream of gca. Comparative expression analysis revealed carbon source-dependent regulation of the bca gene, with 1.5- to 2-fold lower promoter activity in cells grown on acetate as compared to glucose as sole carbon source. Based on higher expression of bca in a mutant deficient of the regulator of acetate metabolism RamA as compared to the wild-type of C. glutamicum and based on the binding of His-tagged RamA protein to the bca promoter region, we here present evidence that RamA negatively regulates expression of bca in C. glutamicum. Functional characterization of a gca deletion mutant of C. glutamicum revealed the same growth characteristics of C. glutamicum ?gca as that of wild-type C. glutamicum and no effect on expression of the bca gene. PMID- 27119956 TI - [Organ-sparing treatment of bladder cancer]. AB - BACKGROUND: Muscle invasive bladder cancer is a frequent disease in Germany. The accepted therapy of choice is radical cystectomy. Due to comorbidities, radical removal of the bladder is often associated with increased perioperative morbidity; therefore alternatives to a radical procedure should be offered. OBJECTIVES: Overview and description of focal therapeutic concepts in muscle invasive bladder cancer to provide therapeutic alternatives for radical organ removal. MATERIALS AND METHODS: Database research, analysis and discussion of clinical trials presenting therapeutic concepts for focal therapy in muscle invasive bladder cancer. RESULTS: High-energy shock waves, high-intensity focused ultrasound and laser therapy are experimental concepts for muscle invasive bladder cancer. Transurethral resection and radiotherapy in combination with chemotherapy, where appropriate, are available as focal therapy in bladder cancer. CONCLUSIONS: Cystectomy is the accepted therapy for muscle invasive bladder cancer. Several therapeutic procedures are available as focal therapy. In selected cases, focal therapy can offer an alternative therapy in muscle invasive bladder cancer. PMID- 27119958 TI - [Side effect management of tyrosine kinase inhibitors in urology : Fatigue and hypothyroidism]. AB - Not only has the use of tyrosine kinase inhibitors (TKI) for the treatment of metastatic renal cell carcinomas (mRCC) changed the therapeutic options for this disease significantly, but with the occurrence of typical side effects this therapy also poses a challenge for the treating physician. Fatigue und hypothyroidism are two common side effects of TKI therapy that can often appear simultaneously. By reducing the patients' quality of life these side effects often lead to a discontinuation of therapy. With this review we want to give the treating physician an overview of the classification and the specific treatment of TKI-induced fatigue and hypothyroidism in order to maximize patients' compliance and the therapeutic efficacy of TKI therapy. PMID- 27119957 TI - [Focal therapy for small renal masses : Observation, ablation or surgery]. AB - BACKGROUND: The rising incidence of renal cell carcinoma, its more frequent early detection (stage T1a) and the increasing prevalence of chronic renal failure with higher morbidity and shorter life expectancy underscore the need for multimodal focal nephron-sparing therapy. DISCUSSION: During the past decade, the gold standard shifted from radical to partial nephrectomy. Depending on the surgeon's experience, the patient's constitution and the tumor's location, the intervention can be performed laparoscopically with the corresponding advantages of lower invasiveness. A treatment alternative can be advantageous for selected patients with high morbidity and/or an increased risk of complications associated with anesthesia or surgery. Corresponding risk stratification necessitates previous confirmation of the small renal mass (cT1a) by histological examination of biopsy samples. Active surveillance represents a controlled delay in the initiation of treatment. RESULTS: Percutaneous radiofrequency ablation (RFA) and laparoscopic cryoablation are currently the most common treatment alternatives, although there are limitations particularly for renal tumors located centrally near the hilum. More recent ablation procedures such as high intensity focused ultrasound (HIFU), irreversible electroporation, microwave ablation, percutaneous stereotactic ablative radiotherapy and high-dose brachytherapy have high potential in some cases but are currently regarded as experimental for the treatment of renal cell carcinoma. PMID- 27119959 TI - [Focal therapy for penile cancer]. AB - BACKGROUND: Focal therapies for superficial penile cancer are today important treatments since organ preservation in penile cancer has a much higher priority than it used to. Because a local recurrence does not substantially influence long term tumour-specific survival, a slightly higher risk of local recurrence is accepted in favour of maximum organ sparing. THERAPY: Topical chemotherapy and laser ablation can be used for carcinoma in situ, while laser ablation and surgical options are used for Ta/T1 tumours. Radiotherapeutic options can be used, but carry a much higher rate of local complications and lower local control rates. PMID- 27119960 TI - [Renaissance of immuno-oncology for urological tumors : Current status]. AB - With the advent of immune checkpoint inhibitors, immunotherapy has gained new importance in oncology. Current research is focused on the cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) immune checkpoints. The CTLA4 antibody ipilimumab (melanoma) as well as the PD-1 antibodies nivolumab (melanoma, non-small cell lung cancer and renal cell carcinoma) and pembrolizumab (melanoma) are approved for the treatment of metastatic disease in Europe. Immune checkpoint inhibitors (re)activate the immune system against cancer cells and appear to be more effective than current standards for many tumors. The toxicity profile is favorable but involves new so called immune-related side effects, which need to be recognized and treated in time. Immune checkpoint inhibitors are also currently being tested in uro oncology in phase 3 trials relevant for approval status. Based on this it is to be expected that immune checkpoint inhibitors will become a new standard (as monotherapy or as part of combination therapy) in the early lines of therapy in the near future and replace the previous standard therapies, particularly for metastasized renal cell carcinoma and urothelial cancer. PMID- 27119961 TI - [Emphysematous cystitis]. AB - Emphysematous cystitis is a rare disease with a high mortality rate. Generally elderly women with diabetes mellitus are affected. Diagnosis is made radiologically using plain abdominal X-ray or computed tomography. The therapy includes urine drainage, antibiotic treatment and hyperglycaemic control to avoid progress of the infection and the development of complications. In the current report we present a case of a 79-year-old woman with uncontrolled diabetes mellitus and an incidental diagnosis of emphysematous cystitis. PMID- 27119962 TI - [Bladder-sparing therapy as an alternative to cystectomy : Commentary on organ sparing therapy in bladder cancer]. PMID- 27119963 TI - Quantitative Evaluation of Filter Aided Sample Preparation (FASP) and Multienzyme Digestion FASP Protocols. AB - Filter aided sample preparation (FASP) and related methods gain increasing popularity for proteomic sample preparation. Nevertheless, the originally published FASP method has been criticized by several authors, who reported low digestion performance. In this work, we re-evaluate FASP and the related multienzyme digestion (MED) FASP method. We use different types of animal tissues and cultured cells and test the performance of the method under various conditions. We analyze the protein to peptide conversion by assessing the yield of peptides, frequency of peptides with missed cleavage sites, and the reproducibility of FASP. We identify conditions allowing efficient protein processing with high peptide yields and demonstrate advantages of the two step digestion strategy over single step digestion with trypsin. In addition, we show that FASP outperforms in-solution cleavage strategies. Our results clearly demonstrate that the performance of digestion varies between different types of samples. We show that MED FASP in combination with the total protein approach provides highly reproducible protein abundance values. The presented data can be used as a guide for optimization of sample processing. PMID- 27119964 TI - Comparing clinical and demographic characteristics of people with mental illness in hospital- and community-based residential rehabilitation units in Queensland. AB - Objective The aim of the present study was to examine care pathways and characteristics of mental health consumers participating in both hospital- and community-based residential rehabilitation programs. Methods An audit of consumers (n=240) in all publicly funded residential rehabilitation units in Queensland was performed on the same day in 2013. Data collection focused on demographic characteristics, clinical information and measures of consumer functioning. Results Significant differences emerged for consumers in community- and hospital-based services with regard to age, length of stay, functioning, Mental Health Act status, guardianship status, family contact and risk of violence. Consumers in hospital-based programs have more severe and complex problems. Conclusions Consumers in residential rehabilitation units have high levels of disability, poor physical health and high levels of vulnerability. Nonetheless, it is likely that a sizeable proportion of consumers occupying rehabilitation beds in Queensland could be discharged if more 'step-down' options to move patients on were available. What is known about the topic? A small subgroup of people with severe and complex mental health problems is likely to require time in a residential rehabilitation program. This group is characterised by failure to respond to treatment, severe negative symptoms and some degree of cognitive impairment. What does this paper add? Patients currently occupying residential rehabilitation beds in Queensland have high levels of disability, poor physical health and high levels of vulnerability. Patients in hospital-based programs are more severely disabled than those in community-based programs. What are the implications for practitioners? It is likely that a sizeable proportion of patients occupying rehabilitation beds in Queensland could be discharged if more 'step-down' options were available. Future planning initiatives need to focus on developing a greater array of community support options to facilitate the discharge of people from residential services. PMID- 27119965 TI - Liposomal Bupivacaine Injection Technique in Total Knee Arthroplasty. AB - Liposomal bupivacaine has gained popularity for pain control after total knee arthroplasty (TKA), yet its true efficacy remains unproven. We compared the efficacy of two different periarticular injection (PAI) techniques for liposomal bupivacaine with a conventional PAI control group. This retrospective cohort study compared consecutive patients undergoing TKA with a manufacturer recommended, optimized injection technique for liposomal bupivacaine, a traditional injection technique for liposomal bupivacaine, and a conventional PAI of ropivacaine, morphine, and epinephrine. The optimized technique utilized a smaller gauge needle and more injection sites. Self-reported pain scores, rescue opioids, and side effects were compared. There were 41 patients in the liposomal bupivacaine optimized injection group, 60 in the liposomal bupivacaine traditional injection group, and 184 in the conventional PAI control group. PAI liposomal bupivacaine delivered via manufacturer-recommended technique offered no benefit over PAI ropivacaine, morphine, and epinephrine. Mean pain scores and the proportions reporting no or mild pain, time to first opioid, and amount of opioids consumed were not better with PAI liposomal bupivacaine compared with PAI ropivacaine, morphine, and epinephrine. The use of the manufacturer-recommended technique for PAI of liposomal bupivacaine does not offer benefit over a conventional, less expensive PAI during TKA. PMID- 27119966 TI - Optimizing Graft Placement in Anterior Cruciate Ligament Reconstruction: A Finite Element Analysis. AB - Femoral anterior cruciate ligament (ACL) graft malposition may lead to clinical instability and graft failure. The purpose of this study was to evaluate the effect of ACL graft placement on global knee biomechanics using finite element (FE) analysis. An established nonlinear contact FE model was used to evaluate 25 distinct tunnel loci representing primary ACL reconstructions; knee flexion and a simulated Lachman maneuver was used to assess knee joint laxity, meniscal stress, in situ graft loading, and peak articular cartilage contact pressure for each of the tunnel positions. Increased anterior tibial translation during Lachman testing was observed when the femoral graft was moved from anterior, anterior/inferior, and posterior/inferior relative to the anatomic footprint. Cartilage contact pressure and meniscal stresses increased with anterior graft placement. Peak stresses in the ACL grafts increased with significant posterior and inferior placement (5-7.5 mm) from the anatomic location. Global joint biomechanics are lease favorable with anterior graft placement. Excessive posterior/inferior placement (> 5 mm) may subject grafts to increased pressures. PMID- 27119967 TI - Diagnosis and Treatment of Anterior Tibial Plateau Fracture-Dislocation: A Case Series and Literature Review. AB - Anterior tibial plateau fracture is fairly common. This study was aimed at introducing a type of severe anterior tibial plateau fracture (anterior tibial plateau fracture-dislocation) and evaluating its clinical characteristics and treatment strategies. In this study, 18 patients with severe anterior tibial plateau fracture (study group) were enrolled between November 2006 and August 2014, and their data were compared with those of 21 patients treated for normal Schatzker type VI tibial plateau fracture (control group) between January 2010 and August 2014. At the last follow-up, bony union had been achieved in both groups. The incidence of ligament injury was higher in the case of anterior tibial plateau fracture than control group. The average range of motion in the study group was 0.56 to 109 degrees, while that in the control group was 1.81 to 117 degrees. The average Hospital for Special Surgery scores and Lysholm scores in the study group were significantly lower than those in the control group. Further, the incidence of postoperative complications and reduction loss were higher for anterior tibial plateau fracture cases than for normal Schatzker type VI fracture. Our findings also showed a significantly higher rate (22.2%) of popliteal artery injury in the study group than in the control group. Anterior tibial plateau fracture-dislocation is a special type of Schatzker type VI fracture with very low incidence and most commonly characterized by the anterior subsidence of the tibial component, irreducible dislocation of the knee joint, and varying degrees of neurovascular and knee-joint peripheral ligaments injuries, as well as high incidence of complications during fixation surgery. The treatment of anterior tibial plateau fracture-dislocation is challenging even for experienced surgeons. PMID- 27119968 TI - Efficacy of Mindfulness-Based Cognitive Therapy in Prevention of Depressive Relapse: An Individual Patient Data Meta-analysis From Randomized Trials. AB - IMPORTANCE: Relapse prevention in recurrent depression is a significant public health problem, and antidepressants are the current first-line treatment approach. Identifying an equally efficacious nonpharmacological intervention would be an important development. OBJECTIVE: To conduct a meta-analysis on individual patient data to examine the efficacy of mindfulness-based cognitive therapy (MBCT) compared with usual care and other active treatments, including antidepressants, in treating those with recurrent depression. DATA SOURCES: English-language studies published or accepted for publication in peer-reviewed journals identified from EMBASE, PubMed/Medline, PsycINFO, Web of Science, Scopus, and the Cochrane Controlled Trials Register from the first available year to November 22, 2014. Searches were conducted from November 2010 to November 2014. STUDY SELECTION: Randomized trials of manualized MBCT for relapse prevention in recurrent depression in full or partial remission that compared MBCT with at least 1 non-MBCT treatment, including usual care. DATA EXTRACTION AND SYNTHESIS: This was an update to a previous meta-analysis. We screened 2555 new records after removing duplicates. Abstracts were screened for full-text extraction (S.S.) and checked by another researcher (T.D.). There were no disagreements. Of the original 2555 studies, 766 were evaluated against full study inclusion criteria, and we acquired full text for 8. Of these, 4 studies were excluded, and the remaining 4 were combined with the 6 studies identified from the previous meta-analysis, yielding 10 studies for qualitative synthesis. Full patient data were not available for 1 of these studies, resulting in 9 studies with individual patient data, which were included in the quantitative synthesis. RESULTS: Of the 1258 patients included, the mean (SD) age was 47.1 (11.9) years, and 944 (75.0%) were female. A 2-stage random effects approach showed that patients receiving MBCT had a reduced risk of depressive relapse within a 60-week follow-up period compared with those who did not receive MBCT (hazard ratio, 0.69; 95% CI, 0.58-0.82). Furthermore, comparisons with active treatments suggest a reduced risk of depressive relapse within a 60-week follow up period (hazard ratio, 0.79; 95% CI, 0.64-0.97). Using a 1-stage approach, sociodemographic (ie, age, sex, education, and relationship status) and psychiatric (ie, age at onset and number of previous episodes of depression) variables showed no statistically significant interaction with MBCT treatment. However, there was some evidence to suggest that a greater severity of depressive symptoms prior to treatment was associated with a larger effect of MBCT compared with other treatments. CONCLUSIONS AND RELEVANCE: Mindfulness-based cognitive therapy appears efficacious as a treatment for relapse prevention for those with recurrent depression, particularly those with more pronounced residual symptoms. Recommendations are made concerning how future trials can address remaining uncertainties and improve the rigor of the field. PMID- 27119969 TI - Method for Attaining Caraway Seed Oil Fractions with Different Composition. AB - Caraway (Carum carvi L.) is a medicinal and aromatic plant; its seeds (fruits) are used as spice and they contain essential oils. We hypothesized that by collecting caraway oil at different time points during the extraction process, we could obtain oil fractions with distinct chemical composition. A hydrodistillation time (HDT) study was conducted to test the hypothesis. The caraway seed oil fractions were collected at eight different HDT (at 0 - 2, 2 - 7, 7 - 15, 15 - 30, 30 - 45, 45 - 75, 75 - 105, and 105 - 135 min). Additionally, a non-stop HD for 135 min was conducted as a control. Most of the oil was eluted early in the HD process. The non-stop HDT treatment yielded 2.76% oil by weight. Of the 24 essential oil constituents, limonene (77 - 19% of the total oil) and carvone (20 - 79%) were the major ones. Other constituents included myrcene (0.72 - 0.16%), trans-carveol (0.07 - 0.39%), and beta-caryophyllene (0.07 - 0.24%). Caraway seed oil with higher concentration of limonene can be obtained by sampling oil fractions early in HD process; conversely, oil with high concentration of carvone can be obtained by excluding the fractions eluted early in the HD process. We demonstrated a method of obtaining caraway seed oil fractions with various and unique composition. These novel oil fractions with unique composition are not commercially available and could have much wider potential uses, and also target different markets compared to the typical caraway essential oil. PMID- 27119971 TI - Any route for melanoblasts to colonize the skin! AB - Melanocytes arise from the fourth embryonic layer, the neural crest. They emerge from the roof plate of the neural tube and migrate throughout the body. In mammals, these cells have the capacity to migrate in any type of environment and use various pathways and mechanisms to colonize the skin and hair, and for their maintenance throughout the life of the animal. PMID- 27119970 TI - Pyomelanin-producing Pseudomonas aeruginosa selected during chronic infections have a large chromosomal deletion which confers resistance to pyocins. AB - When bacterial lineages make the transition from free-living to permanent association with hosts, they can undergo massive gene losses, for which the selective forces within host tissues are unknown. We identified here melanogenic clinical isolates of Pseudomonas aeruginosa with large chromosomal deletions (66 to 270 kbp) and characterized them to investigate how they were selected. When compared with their wild-type parents, melanogenic mutants (i) exhibited a lower fitness in growth conditions found in human tissues, such as hyperosmolarity and presence of aminoglycoside antibiotics, (ii) narrowed their metabolic spectrum with a growth disadvantage with particular carbon sources, including aromatic amino acids and acyclic terpenes, suggesting a reduction of metabolic flexibility. Despite an impaired fitness in rich media, melanogenic mutants can inhibit their wild-type parents and compete with them in coculture. Surprisingly, melanogenic mutants became highly resistant to two intraspecific toxins, the S pyocins AP41 and S1. Our results suggest that pyocins produced within a population of infecting P. aeruginosa may have selected for bacterial mutants that underwent massive gene losses and that were adapted to the life in diverse bacterial communities in the human host. Intraspecific interactions may therefore be an important factor driving the continuing evolution of pathogens during host infections. PMID- 27119972 TI - Atypical white matter microstructure in left-handed individuals. AB - Information regarding anatomical connectivity in the human brain can be gathered using diffusion tensor imaging (DTI). Fractional anisotropy (FA) is the most commonly derived value, and reflects how strongly directional are the underlying tracts. Differences in FA are thus associated with differences in the underlying microstructure of the brain. The relationships between these differences in microstructure and functional differences in corresponding regions have also been examined. Previous studies have found an effect of handedness on functional lateralization in the brain and corresponding microstructural differences. Here, using tract-based spatial statistics to analyse DTI-derived FA values, we further investigated the structural white matter architecture in the brains of right- and left-handed males. We found significantly higher FA values for left-handed, relatively to right-handed, individuals, in all major lobes, and in the corpus callosum. In support of previous suggestions, we find that there is a difference in the microstructure of white matter in left- and right-handed males that could underpin reduced lateralization of function in left-handed individuals. PMID- 27119973 TI - Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium. AB - Rhinovirus (RV), which causes exacerbation in patients with chronic airway diseases, readily infects injured airway epithelium and has been reported to delay wound closure. In this study, we examined the effects of RV on cell repolarization and differentiation in a model of injured/regenerating airway epithelium (polarized, undifferentiated cells). RV causes only a transient barrier disruption in a model of normal (mucociliary-differentiated) airway epithelium. However, in the injury/regeneration model, RV prolongs barrier dysfunction and alters the differentiation of cells. The prolonged barrier dysfunction caused by RV was not a result of excessive cell death but was instead associated with epithelial-to-mesenchymal transition (EMT)-like features, such as reduced expression of the apicolateral junction and polarity complex proteins, E cadherin, occludin, ZO-1, claudins 1 and 4, and Crumbs3 and increased expression of vimentin, a mesenchymal cell marker. The expression of Snail, a transcriptional repressor of tight and adherence junctions, was also up-regulated in RV-infected injured/regenerating airway epithelium, and inhibition of Snail reversed RV-induced EMT-like features. In addition, compared with sham-infected cells, the RV-infected injured/regenerating airway epithelium showed more goblet cells and fewer ciliated cells. Inhibition of epithelial growth factor receptor promoted repolarization of cells by inhibiting Snail and enhancing expression of E-cadherin, occludin, and Crumbs3 proteins, reduced the number of goblet cells, and increased the number of ciliated cells. Together, these results suggest that RV not only disrupts barrier function, but also interferes with normal renewal of injured/regenerating airway epithelium by inducing EMT-like features and subsequent goblet cell hyperplasia. PMID- 27119974 TI - Convolution-based estimation of organ dose in tube current modulated CT. AB - Estimating organ dose for clinical patients requires accurate modeling of the patient anatomy and the dose field of the CT exam. The modeling of patient anatomy can be achieved using a library of representative computational phantoms (Samei et al 2014 Pediatr. Radiol. 44 460-7). The modeling of the dose field can be challenging for CT exams performed with a tube current modulation (TCM) technique. The purpose of this work was to effectively model the dose field for TCM exams using a convolution-based method. A framework was further proposed for prospective and retrospective organ dose estimation in clinical practice. The study included 60 adult patients (age range: 18-70 years, weight range: 60-180 kg). Patient-specific computational phantoms were generated based on patient CT image datasets. A previously validated Monte Carlo simulation program was used to model a clinical CT scanner (SOMATOM Definition Flash, Siemens Healthcare, Forchheim, Germany). A practical strategy was developed to achieve real-time organ dose estimation for a given clinical patient. CTDIvol-normalized organ dose coefficients ([Formula: see text]) under constant tube current were estimated and modeled as a function of patient size. Each clinical patient in the library was optimally matched to another computational phantom to obtain a representation of organ location/distribution. The patient organ distribution was convolved with a dose distribution profile to generate [Formula: see text] values that quantified the regional dose field for each organ. The organ dose was estimated by multiplying [Formula: see text] with the organ dose coefficients ([Formula: see text]). To validate the accuracy of this dose estimation technique, the organ dose of the original clinical patient was estimated using Monte Carlo program with TCM profiles explicitly modeled. The discrepancy between the estimated organ dose and dose simulated using TCM Monte Carlo program was quantified. We further compared the convolution-based organ dose estimation method with two other strategies with different approaches of quantifying the irradiation field. The proposed convolution-based estimation method showed good accuracy with the organ dose simulated using the TCM Monte Carlo simulation. The average percentage error (normalized by CTDIvol) was generally within 10% across all organs and modulation profiles, except for organs located in the pelvic and shoulder regions. This study developed an improved method that accurately quantifies the irradiation field under TCM scans. The results suggested that organ dose could be estimated in real-time both prospectively (with the localizer information only) and retrospectively (with acquired CT data). PMID- 27119975 TI - Surface-confined fluorescence enhancement of Au nanoclusters anchoring to a two dimensional ultrathin nanosheet toward bioimaging. AB - Gold nanoclusters (Au NCs) as ultrasmall fluorescent nanomaterials possess discrete electronic energy and unique physicochemical properties, but suffer from relatively low quantum yield (QY) which severely affects their application in displays and imaging. To solve this conundrum and obtain highly-efficient fluorescent emission, 2D exfoliated layered double hydroxide (ELDH) nanosheets were employed to localize Au NCs with a density as high as 5.44 * 10(13) cm(-2), by virtue of the surface confinement effect of ELDH. Both experimental studies and computational simulations testify that the excited electrons of Au NCs are strongly confined by MgAl-ELDH nanosheets, which results in a largely promoted QY as well as prolonged fluorescence lifetime (both ~7 times enhancement). In addition, the as-fabricated Au NC/ELDH hybrid material exhibits excellent imaging properties with good stability and biocompatibility in the intracellular environment. Therefore, this work provides a facile strategy to achieve highly luminescent Au NCs via surface-confined emission enhancement imposed by ultrathin inorganic nanosheets, which can be potentially used in bio-imaging and cell labelling. PMID- 27119976 TI - Narrative skills of children treated for brain tumours: The impact of tumour and treatment related variables on microstructure and macrostructure. AB - OBJECTIVE: The narrative skills of children with brain tumours were examined. Influence of tumour location, radiotherapy, time post-treatment and presence of hydrocephalus was also investigated, as well as associations between narrative and language abilities. METHOD: Seventeen children (aged 5;6-14;11) treated for brain tumour and their matched controls completed a narrative assessment and comprehensive language testing. Audio recorded narratives were analysed for microstructure and macrostructure elements. Between-group comparisons were conducted. Narrative elements were explored in association with tumour and treatment-related variables. Correlation analysis examined relationships between narrative scores and language test performance. RESULTS: While significant differences were not found between two groups of children across narrative elements, sub-group comparisons revealed marginal differences in macrostructure related to tumour location and hydrocephalus. Children treated with methods other than radiotherapy showed a significant increase in number of mazes in their narratives compared to children who received radiotherapy. Strong positive correlations also existed between narrative elements and language performance. CONCLUSION: Preliminary findings highlight the importance of investigating narrative abilities as part of a comprehensive language assessment. Macrostructure should be routinely examined where children are diagnosed with either posterior fossa tumour or hydrocephalus or have undergone surgery and/or chemotherapy for brain tumour. PMID- 27119978 TI - Psychological Trauma and LGBT Caregivers: A Conceptual Framework to Guide Practice. AB - LGBT adults face unique risk factors such as social isolation, discrimination, and victimization, and occasionally th ey engage in detrimental behaviors like high alcohol and drug use and risky sexual activity that negatively impacts psychological/physical health. These risks can affect their overall health and stress the relationship with an older caregiver/recipient-partner following exposure to acute medical event. The experience of an acute medical event among a LGBT caregiving partner can result in psychological trauma. In this article the authors present a conceptual framework involving stress process theory, life course theory, and family systems perspective to understand the effect of stressors on LGBT caregiving partners. Implications for social work practice include assessing, coordinating care, counseling and negotiating services at micro level, engaging family-centered approaches to support positive transition to caregiving role at mezzo level, and advocating for policy and cultural shifts to supports and diminish stigma of this group. PMID- 27119977 TI - Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD. AB - Allogeneic hematopoietic stem cell transplantation is a curable treatment for hematological diseases. Graft-versus-host disease (GVHD) causes morbidity and mortality after HSCT. Methotrexate (MTX) is used for GVHD prophylaxis, but its appropriate dose remains unclear. In the present study, we compared the efficacy and toxicity of 15-10-10 MTX (day +1: 15 mg/m(2); days +3 and +6: 10 mg/m(2)) with 10-7-7 MTX (day +1: 10 mg/m(2); day +3 and +6: 7 mg/m(2)) in combination with tacrolimus. The cumulative incidence rates of grades II-IV acute GVHD, grades III-IV acute GVHD and chronic GVHD in the 15-10-10 MTX and 10-7-7 MTX groups did not differ to a statistically significant extent. The median time for neutrophil engraftment in the 15-10-10 MTX group was 16 days (range, 11-31 days), while that in the 10-7-7 group was 15 days (range, 12-19 days) (P = 0.024). Moreover, the median time for platelet recovery was significantly shorter in the 10-7-7 MTX group (22 days; range, 13-49 days) than that in the 15-10-10 MTX group (27 days; range, 9-405 days) (P = 0.027). The duration of oral mucositis was significantly shorter in the patients who received a reduced dose of MTX (median, 4.5 vs 13.0 days; P = 0.013). In conclusion, GVHD prophylaxis with a reduced dose of MTX was associated with earlier engraftment and earlier recovery from mucositis in comparison to a standard dose of MTX, without affecting the incidence of GVHD. PMID- 27119980 TI - Solar Inactivation of Enterococci and Escherichia coli in Natural Waters: Effects of Water Absorbance and Depth. AB - The decay of sewage-sourced Escherichia coli and enterococci was measured at multiple depths in a freshwater marsh, a brackish water lagoon, and a marine site, all located in California. The marine site had very clear water, while the waters from the marsh and lagoon contained colored dissolved organic matter that not only blocked light but also produced reactive oxygen species. First order decay rate constants of both enterococci and E. coli were between 1 and 2 d(-1) under low light conditions and as high as 6 d(-1) under high light conditions. First order decay rate constants were well correlated to the daily average UVB light intensity corrected for light screening incorporating water absorbance and depth, suggesting endogenous photoinactivation is a major pathway for bacterial decay. Additional laboratory experiments demonstrated the presence of colored dissolved organic matter in marsh water enhanced photoinactivation of a laboratory strain of Enterococcus faecalis, but depressed photoinactivation of sewage-sourced enterococci and E. coli after correcting for UVB light screening, suggesting that although the exogenous indirect photoinactivation mechanism may be active against Ent. faecalis, it is not for the sewage-source organisms. A simple linear regression model based on UVB light intensity appears to be a useful tool for predicting inactivation rate constants in natural waters of any depth and absorbance. PMID- 27119979 TI - Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70. AB - HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner. PMID- 27119981 TI - Immune responses to modified live virus vaccines developed from classical or highly pathogenic PRRSV following challenge with a highly pathogenic PRRSV strain. AB - Modified live virus vaccines (MLVs) are used on swine farms to control porcine reproductive and respiratory syndrome virus (PRRSV). MLVs from classical PRRSV (C PRRSV) provide some protection against emergent highly pathogenic PRRSV (HP PRRSV). This study characterized the protective efficacy and immune response to MLVs from C-PRRSV (CH-1R) or HP-PRRSV (HuN4-F112) in a challenge using HP-PRRSV (HuN4). The outcomes were clinical signs of disease, pathological changes in the thymus and lungs, viremia, and humoral and cellular immune responses. CH-1R provided some protection against challenge with HuN4, while HuN4-F112 was protective in the HuN4 challenge. Compared to unvaccinated piglets, the vaccinated piglets had milder symptoms and fewer pathological changes in the lung and thymus. Piglets vaccinated with HuN4-F112 had higher antibody titers and lower viral loads than piglets vaccinated with CH-1R post challenge. The differences in outcome between the MLVs suggested that underlying differences in the immune responses might warrant further study. PMID- 27119982 TI - Sympathetic neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals. AB - This review will highlight recently discovered mechanisms underlying sympathetic nervous system (SNS) regulation of the immune system in hematopoiesis, thermogenesis, and inflammation. This work in mammals illuminates potential mechanisms by which the nervous and immune systems may interact in invertebrate and early vertebrate species and allow diverse organisms to thrive under varying and extreme conditions and ultimately improve survival. PMID- 27119983 TI - Combined Molecular Dynamics Simulations and Experimental Studies of the Structure and Dynamics of Poly-Amido-Saccharides. AB - Poly-amido-saccharides (PAS) are carbohydrate-based, enantiopure synthetic polymers in which sugar repeat units are joined by amide linkages. This unique and relatively rigid pyranose backbone contributes to their defined helical secondary structure and remarkable chemical properties. Glucose- (glc-) and galactose- (gal-) PAS 10-mer structures are synthesized and investigated with molecular dynamics (MD) simulations and experimental measurements. Quantum mechanical DFT energy minimization calculations, as well as experimental observables including circular dichroism, (1)H,(13)C-HSQC, and (1)H,(1)H-NOESY 2D NMR studies, validated the all-atom simulation models produced using a modified CHARMM force field. Water radial distribution functions show distinct differences in the glc- and gal-PAS systems that correlate well with observed differences in solubility between gal-PASs and glc-PASs. The computational analysis and MD simulations are in good agreement with experimental results, validating the proposed models as reliable representations of novel glc- and gal-PASs. PMID- 27119984 TI - Genetic Variants in SDC3 Gene are Significantly Associated with Growth Traits in Two Chinese Beef Cattle Breeds. AB - Identification of the genes and polymorphisms underlying quantitative traits, and understanding these genes and polymorphisms affect economic growth traits, are important for successful marker-assisted selection and more efficient management strategies in commercial cattle (Bos taurus) population. Syndecan-3 (SDC3), a member of the syndecan family of type I transmembrane heparan sulfate proteoglycans is a novel regulator of feeding behavior and body weight. The aim of this study is to examine the association of the SDC3 polymorphism with growth traits in Chinese Jiaxian and Qinchuan cattle breeds (). Four single nucleotide polymorphisms (SNPs: 1-4) were detected in 555 cows from three Chinese native cattle breeds by means of sequencing pooled DNA samples and polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) methods. We found one SNP (g.28362A > G) in intron and three SNPs (g.30742T > G, g.30821C > T and 33418 A > G) in exons. The statistical analyses indicated that these SNPs of SDC3 gene were associated with bovine body height, body length, chest circumference, and circumference of cannon bone (P < 0.05). The mutant-type variant was superior for growth traits; the heterozygote was associated with higher growth traits compared to wild-type homozygote. Our result confirms the polymorphisms in the SDC3 gene are associated with growth traits that may be used for marker-assisted selection in beef cattle breeding programs. PMID- 27119985 TI - Efficacy and Safety of Benralizumab, a Monoclonal Antibody against IL-5Ralpha, in Uncontrolled Eosinophilic Asthma. AB - Nonresponders to maximal guideline-based therapies of asthma account for most of the morbidity, mortality, and economic burden of the disease. Because eosinophils are key effector cells in asthmatic airway inflammation, blocking IL-5, the main cytokine responsible for its survival and activation, seems to be a rational strategy. While previous monoclonal antibodies against the IL-5 ligand resulted in inconsistent improvements in asthma outcomes, benralizumab has shown promise. Benralizumab is a monoclonal antibody against IL-5 receptor, and has an enhanced antibody dependent cell-mediated cytotoxicity function. In this article, we review the theoretical advantages of benralizumab compared to previous compounds, as well as current status of the clinical development of benralizumab in asthma. Lastly, we briefly discuss the potential role of benralizumab in chronic obstructive pulmonary disease. PMID- 27119986 TI - Pattern Selection in Network of Coupled Multi-Scroll Attractors. AB - Multi-scroll chaotic attractor makes the oscillator become more complex in dynamic behaviors. The collective behaviors of coupled oscillators with multi scroll attractors are investigated in the regular network in two-dimensional array, which the local kinetics is described by an improved Chua circuit. A feasible scheme of negative feedback with diversity is imposed on the network to stabilize the spatial patterns. Firstly, the Chua circuit is improved by replacing the nonlinear term with Sine function to generate infinite aquariums so that multi-scroll chaotic attractors could be generated under appropriate parameters, which could be detected by calculating the Lyapunov exponent in the parameter region. Furthermore, negative feedback with different gains (D1, D2) is imposed on the local square center area A2 and outer area A1 of the network, it is found that spiral wave, target wave could be developed in the network under appropriate feedback gain with diversity and size of controlled area. Particularly, homogeneous state could be reached after synchronization by selecting appropriate feedback gain and controlled size in the network. Finally, the distribution for statistical factors of synchronization is calculated in the two-parameter space to understand the transition of pattern region. It is found that developed spiral waves, target waves often are associated with smaller factor of synchronization. These results show that emergence of sustained spiral wave and continuous target wave could be effective for further suppression of spatiotemporal chaos in network by generating stable pacemaker completely. PMID- 27119987 TI - Super-Dispersive Off-Axis Meta-Lenses for Compact High Resolution Spectroscopy. AB - Metasurfaces have opened a new frontier in the miniaturization of optical technology by allowing exceptional control over the wavefront. Here, we demonstrate off-axis meta-lenses that simultaneously focus and disperse light of different wavelengths with unprecedented spectral resolution. They are designed based on the geometric phase via rotated silicon nanofins and can focus light at angles as large as 80 degrees . Due to the large angle focusing, these meta lenses have superdispersive characteristics (0.27 nm/mrad) that make them capable of resolving wavelength differences as small as 200 pm in the telecom region. In addition, by stitching several meta-lenses together, we maintain a high spectral resolution for a wider wavelength range. The meta-lenses have measured efficiencies as high as 90% in the wavelength range of 1.1 to 1.6 MUm. The planar and compact configuration together with high spectral resolution of these meta lenses has significant potential for emerging portable/wearable optics technology. PMID- 27119988 TI - Influenza Seasonality in the Tropics and Subtropics - When to Vaccinate? AB - BACKGROUND: The timing of the biannual WHO influenza vaccine composition selection and production cycle has been historically directed to the influenza seasonality patterns in the temperate regions of the northern and southern hemispheres. Influenza activity, however, is poorly understood in the tropics with multiple peaks and identifiable year-round activity. The evidence-base needed to take informed decisions on vaccination timing and vaccine formulation is often lacking for the tropics and subtropics. This paper aims to assess influenza seasonality in the tropics and subtropics. It explores geographical grouping of countries into vaccination zones based on optimal timing of influenza vaccination. METHODS: Influenza seasonality was assessed by different analytic approaches (weekly proportion of positive cases, time series analysis, etc.) using FluNet and national surveillance data. In case of discordance in the seasonality assessment, consensus was built through discussions with in-country experts. Countries with similar onset periods of their primary influenza season were grouped into geographical zones. RESULTS: The number and period of peak activity was ascertained for 70 of the 138 countries in the tropics and subtropics. Thirty-seven countries had one and seventeen countries had two distinct peaks. Countries near the equator had secondary peaks or even identifiable year-round activity. The main influenza season in most of South America and Asia started between April and June. The start of the main season varied widely in Africa (October and December in northern Africa, April and June in Southern Africa and a mixed pattern in tropical Africa). Eight "influenza vaccination zones" (two each in America and Asia, and four in Africa and Middle East) were defined with recommendations for vaccination timing and vaccine formulation. The main limitation of our study is that FluNet and national surveillance data may lack the granularity to detect sub-national variability in seasonality patterns. CONCLUSION: Distinct influenza seasonality patterns, though complex, could be ascertained for most countries in the tropics and subtropics using national surveillance data. It may be possible to group countries into zones based on similar recommendations for vaccine timing and formulation. PMID- 27119990 TI - Viewing of Internet-Based Sexually Explicit Media as a Risk Factor for Condomless Anal Sex among Men Who Have Sex with Men in Four U.S. Cities. AB - The last decade has seen a dramatic increase in the availability of sexually explicit media (SEM) on the Internet. Men who have sex with men (MSM) report near universal use of SEM. However, this widespread use of SEM among MSM may contribute to more condomless anal sex. To examine the association of viewing SEM on the Internet and the number of condomless anal sex encounters among MSM, in 2012, an online survey was conducted of 265 MSM from New York, Philadelphia, Baltimore, or Washington D.C. who reported viewing SEM online in the past 3 months. Analyses were performed using negative binomial regression. Nearly all men reported viewing SEM featuring anal sex with (91%) or without (92%) condoms in the past 3 months. Neither viewing more hours of SEM per week or compulsively viewing SEM were associated with more condomless anal sex encounters. Rather, viewing a greater proportion of SEM containing condomless anal sex was associated with engaging in more condomless anal encounters (IRR = 1.25), while viewing a greater proportion of SEM containing anal sex where condoms were used was associated with fewer condomless anal sex encounters (IRR = 0.62). MSM reported that viewing SEM caused changes in their sexual fantasies, desires, and behaviors. These findings provide important insights for health policy and the design of interventions addressing SEM and condomless sex among MSM. The findings suggest that condom use by SEM performers may benefit not only actor health, but also have health implications for SEM viewers. PMID- 27119991 TI - Tumor Regression and Patterns of Distant Metastasis of T1-T2 Nasopharyngeal Carcinoma with Intensity-Modulated Radiotherapy. AB - PURPOSE: To study tumor regression and failure patterns in T1-T2 non-metastatic nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT). METHODS: A retrospective analysis of 139 nasopharyngeal carcinoma patients treated with IMRT between January 2005 and December 2010 in our center was performed. According to the AJCC staging system, all primary lesions were attributed to T1 and T2. The prescription doses were 66 Gy at 30 fractions to gross tumor volume of the nasopharynx and the positive neck nodes, 60 Gy to high risk clinical target volume and 54 Gy to low-risk clinical target volume. Patients staged III, IV A/B or II (lymph node measured 4 cm or more in diameter) received platinum-based chemotherapy. RESULTS: By the end of radiotherapy, 7.2% (10/139), 23.7% (33/139), and 9.4% (13/139) of patients had residual lesions in the nasopharynx, cervical lymph nodes and retropharyngeal lymph nodes, respectively. The majority of patients had complete remission within 6 months of radiotherapy completion. Five months after IMRT, three patients with residual tumors in the cervical lymph nodes underwent surgery. Among these patients, two patients had positive pathological findings, and one patient had negative findings. With a median follow-up of 59 months, the 5-year overall survival, local control, regional control and distant metastasis-free rates were 87.8%, 96.7%, 94.9% and 89.1%, respectively. Fifteen patients developed distant metastases, representing the primary failure pattern. CONCLUSIONS: Most residual lesions that persisted after IMRT vanished completely in six months. Considering the potential damage to normal structures, clinicians should be cautious when considering the use of boost irradiation after radiotherapy. Distant metastasis was the primary cause of treatment failure, which was significantly higher in N2 3 patients than in N0-1. Additional studies to better understand distant metastases are needed. PMID- 27119992 TI - Retrocolic or Antecolic Roux-en-Y Reconstruction after Distal Gastrectomy: Which Is More Effective in the Prevention of Postoperative Gastroesophageal Reflux Disease. AB - BACKGROUND: It is unclear which reconstructive route (retrocolic or antecolic) is more effective in preventing postoperative gastroesophageal reflux disease (GERD) in Roux-en-Y reconstruction following distal gastrectomy. METHODS: Eighty-one eligible patients (retrocolic, n = 39; antecolic, n = 42) underwent endoscopies before surgery and 1 year after surgery to evaluate reflux esophagitis according to the Los Angeles classifications. The relative anatomical position of gastrojejunostomy to the cardia was measured by CT imaging. RESULTS: The proportion of patients with reflux esophagitis was also significantly higher in the antecolic group than in the retrocolic group (38.1 vs. 10.3%, p = 0.005). Multivariate analysis revealed that antecolic reconstruction and body mass index (BMI) were independent risk factors for reflux esophagitis. The relative position of gastrojejunostomy to the cardia in the antecolic group was shifted to the left laterally (59.0 vs. 28.8 degree, p < 0.001) and ventrally (65.4 vs. 39.8 degree, p < 0.001) than in the retrocolic group. There was a positive correlation between BMI and left lateral and ventral shifts of gastrojejunostomy in the antecolic group. CONCLUSION: Retrocolic reconstruction may be superior to antecolic reconstruction in preventing postoperative GERD, especially in obese patients. The left lateral and ventral shifts of gastrojejunostomy after antecolic reconstruction may aggravate the occurrence of GERD. PMID- 27119994 TI - pi Activation of Alkynes in Homogeneous and Heterogeneous Gold Catalysis. AB - The activation of alkynes toward nucleophilic attack upon coordination to gold based catalysts (neutral and positively charged gold clusters and gold complexes commonly used in homogeneous catalysis) is investigated to elucidate the role of the sigma donation and pi back-donation components of the Au-C bond (where we consider ethyne as prototype substrate). Charge displacement (CD) analysis is used to obtain a well-defined measure of sigma donation and pi back-donation and to find out how the corresponding charge flows affect the electron density at the electrophilic carbon undergoing the nucleophilic attack. This information is used to rationalize the activity of a series of catalysts in the nucleophilic attack step of a model hydroamination reaction. For the first time, the components of the Dewar-Chatt-Duncanson model, donation and back-donation, are put in quantitative correlation with the kinetic parameters of a chemical reaction. PMID- 27119993 TI - Fibrin Sealants in Dura Sealing: A Systematic Literature Review. AB - BACKGROUND: Fibrin sealants are widely used in neurosurgery to seal the suture line, provide watertight closure, and prevent cerebrospinal fluid leaks. The aim of this systematic review is to summarize the current efficacy and safety literature of fibrin sealants in dura sealing and the prevention/treatment of cerebrospinal fluid leaks. METHODS: A comprehensive electronic literature search was run in the following databases: Cochrane Database of Systematic Reviews, Cochrane Central Resister of Controlled Trials, clinicaltrials.gov, MEDLINE/PubMed, and EMBASE. Titles and abstracts of potential articles of interest were reviewed independently by 3 of the authors. RESULTS: A total of 1006 database records and additional records were identified. After screening for duplicates and relevance, a total of 78 articles were assessed by the investigators for eligibility. Thirty-eight were excluded and the full-text of 40 articles were included in the qualitative synthesis. Seven of these included only safety data and were included in the safety assessment. The remaining 33 articles included findings from 32 studies that enrolled a total of 2935 patients who were exposed to fibrin sealant. Among these 33 studies there were only 3 randomized controlled trials, with the remaining being prospective cohort analysis, case controlled studies, prospective or retrospective case series. One randomized controlled trial, with 89 patients exposed to fibrin sealant, found a greater rate of intraoperative watertight dura closure in the fibrin sealant group than the control group (92.1% versus 38.0%, p<0.001); however, post-operative cerebrospinal fluid leakage occurred in more fibrin sealant than control patients (6.7% versus 2.0%, p>0.05). Other clinical trials evaluated the effect of fibrin sealant in the postoperative prevention of cerebrospinal fluid leaks. These were generally lower level evidence studies (ie, not prospective, randomized, controlled trials) that were not designed or powered to demonstrate a significant advantage to fibrin sealant use. Two small case series studies evaluated the effect of fibrin sealants in persistent cerebrospinal fluid leak treatment, but did not establish firm efficacy conclusions. Specific adverse reports where fibrin sealants were used for dura sealing were limited, with only 8 cases reported in neurosurgical procedures since 1987 and most reporting only a speculative relationship/association with fibrin sealant exposure. CONCLUSIONS: A major finding of this systematic literature review is that there is a paucity of randomized studies that have evaluated the effectiveness and safety of fibrin sealants in providing intraoperative watertight dura closure and post-operative cerebrospinal fluid leakage. Among the limited studies available, evidence from a single randomized, controlled trial indicates that fibrin sealants provide a higher rate of intraoperative watertight closure of the dura suture line than control, albeit with a higher rate of postoperative cerebrospinal fluid leakage. Evidence from non-randomized, controlled trials suggests that fibrin sealants may be effective in preventing cerebrospinal fluid leaks with an acceptable safety profile. There is a substantial need for randomized, controlled clinical trials or well-designed prospective observational trials where the conduct of a randomized trial is not feasible to fully assess the impact of fibrin sealant utilization on the rates of intraoperative dura closure, postoperative cerebrospinal leakage, and safety. PMID- 27120000 TI - Urinary incontinence in multiple sclerosis: prevalence, severity and impact on patients' quality of life. AB - BACKGROUND AND PURPOSE: Lower urinary tract symptoms (LUTS) including frequent urination, nocturia and urge urinary incontinence negatively impact quality of life. This project aimed at characterizing the prevalence and severity of urinary incontinence in multiple sclerosis (MS) patients and its association with demographic and clinical features. METHODS: In all, 403 consecutive clinically stable MS patients answered the International Consultation on Incontinence Questionnaire (ICIQ) and the Patient Perception of Bladder Condition (PPBC) questionnaire. Demographic and clinical parameters including the Expanded Disability Status Scale (EDSS) were collected. Statistical analyses were performed using univariate and multivariate linear regression models. RESULTS: Females represented 72%, relapsing-remitting patients 82%. The mean (SD) disease duration and EDSS were 11.8 (8.6) years and 3.1 (1.9) respectively. Approximately 35% of patients reported urine incontinence. ICIQ scores were positively associated with EDSS, female gender, presence of LUTS therapies and absence of disease modifying treatments (P < 0.001). PPBC scores were positively associated with EDSS and the presence of LUTS therapies (P < 0.001). DISCUSSION: Urinary incontinence is frequent in MS, prevailing in more disabled and female patients. Currently available LUTS therapies appear insufficient in the treatment of this symptom. The negative impact of urinary incontinence on quality of life is high and requires more attention in clinical management and research. PMID- 27120001 TI - Using mouse and zebrafish models to understand the etiology of developmental defects in Cornelia de Lange Syndrome. AB - Cornelia de Lange Syndrome (CdLS) is a multisystem birth defects disorder that affects every tissue and organ system in the body. Understanding the factors that contribute to the origins, prevalence, and severity of these developmental defects provides the most direct approach for developing screens and potential treatments for individuals with CdLS. Since the majority of cases of CdLS are caused by haploinsufficiency for NIPBL (Nipped-B-like, which encodes a cohesin associated protein), we have developed mouse and zebrafish models of CdLS by using molecular genetic tools to create Nipbl-deficient mice and zebrafish (Nipbl(+/-) mice, zebrafish nipbl morphants). Studies of these vertebrate animal models have yielded novel insights into the developmental etiology and genes/gene pathways that contribute to CdLS-associated birth defects, particularly defects of the gut, heart, craniofacial structures, nervous system, and limbs. Studies of these mouse and zebrafish CdLS models have helped clarify how deficiency for NIPBL, a protein that associates with cohesin and other transcriptional regulators in the nucleus, affects processes important to the emergence of the structural and physiological birth defects observed in CdLS: NIPBL exerts chromosome position-specific effects on gene expression; it influences long-range interactions between different regulatory elements of genes; and it regulates combinatorial and synergistic actions of genes in developing tissues. Our current understanding is that CdLS should be considered as not only a cohesinopathy, but also a "transcriptomopathy," that is, a disease whose underlying etiology is the global dysregulation of gene expression throughout the organism. (c) 2016 Wiley Periodicals, Inc. PMID- 27120002 TI - Toxoplasma gondii infection and schizophrenia: an inter-kingdom communication perspective. AB - PURPOSE OF REVIEW: The apicomplexan protozoan Toxoplasma gondii has a striking predilection for infecting the central nervous system and has been suggested as a risk factor for schizophrenia. Here, we address some of the mechanisms by which T. gondii achieves this by manipulating signaling pathways of the host brain cells. RECENT FINDINGS: Recent years have brought notable progress in the understanding of how the opportunistic parasite T. gondii establishes a successful infection in mammalian brain by secreting effector molecules that manipulate multiple cell functions. Many pathways involved in this inter-kingdom signaling, such as dopaminergic, GABAergic and kynurenine pathways, also have key roles in the development of schizophrenia. More understanding of T. gondii-brain cell interaction holds the key to unlocking the mystery of T. gondii-mediated schizophrenia pathogenesis. SUMMARY: T. gondii usurps a variety of host signaling pathways to ensure physiological adaptation, evasion of host immune defense systems, and efficient replication. A detailed knowledge of T. gondii signaling molecules involved in this cross-kingdom communication with host brain cells will probably provide novel means of pharmacologically manipulating host cellular pathways to promote efficient elimination of the parasite and may permit the development of new schizophrenia-modifying therapeutics. PMID- 27120003 TI - Prolonged exposure to arsenic in UK private water supplies: toenail, hair and drinking water concentrations. AB - Chronic exposure to arsenic (As) in drinking water is an established cause of cancer and other adverse health effects. Arsenic concentrations >10 MUg L(-1) were previously measured in 5% of private water supplies (PWS) in Cornwall, UK. The present study investigated prolongued exposure to As by measuring biomarkers in hair and toenail samples from 212 volunteers and repeated measurements of As in drinking water from 127 households served by PWS. Strong positive Pearson correlations (rp = 0.95) indicated stability of water As concentrations over the time period investigated (up to 31 months). Drinking water As concentrations were positively correlated with toenail (rp = 0.53) and hair (rp = 0.38) As concentrations - indicative of prolonged exposure. Analysis of washing procedure solutions provided strong evidence of the effective removal of exogenous As from toenail samples. Significantly higher As concentrations were measured in hair samples from males and smokers and As concentrations in toenails were negatively associated with age. A positive association between seafood consumption and toenail As and a negative association between home-grown vegetable consumption and hair As was observed for volunteers exposed to <1 As MUg L(-1) in drinking water. These findings have important implications regarding the interpretation of toenail and hair biomarkers. Substantial variation in biomarker As concentrations remained unaccounted for, with soil and dust exposure as possible explanations. PMID- 27120004 TI - Nicotine Deprivation Produces Deficits in Pain Perception that are Moderately Attenuated by Caffeine Consumption. AB - During withdrawal, nicotine users experience aversive withdrawal symptoms, such as increased nociceptive processing, which may be responsible for subsequent use. Smokers often consume more caffeine than non-smokers and the combined effects of these two psychoactive drugs result in an enhanced analgesic effect of nicotine. We examined the effects of caffeine (via coffee consumption) and nicotine withdrawal on pain perception in minimally deprived smokers and non-smokers. Pain threshold and pain tolerance were assessed using a radiant heat stimulus before and 30 minutes after caffeine consumption. Nicotine deprivation (2 hrs) produced increases in pain threshold and decreases in pain tolerance representative of hyperalgesia. When smokers are nicotine deprived, caffeine consumption diminished baseline elevations in pain threshold, but had no effect on pain tolerance. These data suggest that caffeine consumption can dampen deficits in sensory discrimination related to pain during nicotine deprivation by reducing pain threshold to levels representative of non-smoking controls. PMID- 27120005 TI - Participating in a Culture of Consent May Be Associated With Lower Rape Supportive Beliefs. AB - With the recent national focus on rates of sexual violence, many interventions have been proposed, including those that focus on affirmative consent (e.g., "Yes Means Yes" campaign). The goal of the present study was to test whether individuals within a subculture with long-standing norms of affirmative consent the bondage and discipline/dominance and submission/sadism and masochism (BDSM) community-report lower rape-supportive attitudes compared to individuals not from within this subculture. BDSM practitioner participants, adult participants from Amazon's Mechanical Turk (MTurk), and college student participants completed measures of hostile sexism, benevolent sexism, rape myth acceptance, victim blaming, expectation of sexual aggression, and acceptance of sexual aggression. BDSM practitioners reported significantly lower levels of benevolent sexism, rape myth acceptance, and victim blaming than did college undergraduates and adult MTurk workers. BDSM practitioners did not differ significantly from college undergraduates or adult MTurk workers on measures of hostile sexism, expectations of sexual aggression, or acceptance of sexual aggression. Limitations and implications are discussed. PMID- 27120006 TI - Respiratory syncytial virus seasonality in Brazil: implications for the immunisation policy for at-risk populations. AB - Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for respiratory diseases among children under 5 years old. The aim of this study was to analyse RSV seasonality in the five distinct regions of Brazil using time series analysis (wavelet and Fourier series) of the following indicators: monthly positivity of the immunofluorescence reaction for RSV identified by virologic surveillance system, and rate of hospitalisations per bronchiolitis and pneumonia due to RSV in children under 5 years old (codes CID 10 J12.1, J20.5, J21.0 and J21.9). A total of 12,501 samples with 11.6% positivity for RSV (95% confidence interval 11 - 12.2), varying between 7.1 and 21.4% in the five Brazilian regions, was analysed. A strong trend for annual cycles with a stable stationary pattern in the five regions was identified through wavelet analysis of the indicators. The timing of RSV activity by Fourier analysis was similar between the two indicators analysed and showed regional differences. This study reinforces the importance of adjusting the immunisation period for high risk population with the monoclonal antibody palivizumab taking into account regional differences in seasonality of RSV. PMID- 27120007 TI - Phylogenetic analyses of chikungunya virus among travelers in Rio de Janeiro, Brazil, 2014-2015. AB - Chikungunya virus (CHIKV) is a mosquito-borne pathogen that emerged in Brazil by late 2014. In the country, two CHIKV foci characterized by the East/Central/South Africa and Asian genotypes, were established in North and Northeast regions. We characterized, by phylogenetic analyses of full and partial genomes, CHIKV from Rio de Janeiro state (2014-2015). These CHIKV strains belong to the Asian genotype, which is the determinant of the current Northern Brazilian focus, even though the genome sequence presents particular single nucleotide variations. This study provides the first genetic characterisation of CHIKV in Rio de Janeiro and highlights the potential impact of human mobility in the spread of an arthropod borne virus. PMID- 27120008 TI - Dr. William Francis (Bill) Morgan (1952-2015). PMID- 27120009 TI - Clinical characteristics, beliefs, and coping strategies among older patients with overactive bladder. AB - AIMS: To describe clinical characteristics and assess beliefs and coping strategies in older patients with overactive bladder (OAB) attending urology and gynecology clinics in Spain. METHODS: This non-interventional, multicenter, cross sectional study collected demographic and clinical details from individuals aged >=60 years with a diagnosis of OAB and score >=3 on the Patient Perception of Intensity of Urgency Scale. Symptoms were assessed using the Bladder Control Self Assessment Questionnaire (B-SAQ) and Health-Related Quality of Life (HRQoL) rated using a simple visual analogue scale. Coping strategies and OAB beliefs were assessed using two specially designed questionnaires. RESULTS: Patients (n = 786) reported a mean (+/-SD) of 4.9 +/- 2.9 urinary urgency episodes and 2.9 +/- 2.3 urgency urinary incontinence (UUI) episodes per 24 hr. Mean times since diagnosis and symptom onset were 18 +/- 34 and 38 +/- 46 months, respectively. B-SAQ symptom and bother scores were 7.5 +/- 2.3 and 8.3 +/- 2.5, respectively. Most patients (92%) reported worse HRQoL after symptom onset. Approximately, 50% of patients considered their symptoms normal for their age/gender and most (71.5%) expected symptoms to worsen with age/time. However, 80% believed that symptoms would improve with treatment. For coping strategies, 81% of patients changed their urinary frequency, 71% controlled fluid intake, and 64% used pads. Use of coping strategies was associated with UI severity. CONCLUSIONS: Many older individuals view their OAB symptoms as a normal feature of age, which may delay diagnosis. Reduced HRQoL and adoption of coping strategies are also common. The results support the need for improved patient education, earlier recognition, and effective intervention in the older OAB population. Neurourol. Urodynam. 36:774 779, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27120010 TI - Fully Solution-Processed and Foldable Metal-Oxide Thin-Film Transistor. AB - Flexible and foldable thin-film transistors (TFTs) have been widely studied with the objective of achieving high-performance and low-cost flexible TFTs for next generation displays. In this study, we introduced the fabrication of foldable TFT devices with excellent mechanical stability, high transparency, and high performance by a fully solution process including PI, YOx, In2O3, SWCNTs, IL-PVP, and Ag NWs. The fabricated fully solution-processed TFTs showed a higher transmittance above 86% in the visible range. Additionally, the charge-carrier mobility and Ion/Ioff ratio of them were 7.12 +/- 0.43 cm(2)/V.s and 5.53 +/- 0.82 * 10(5) at a 3 V low voltage operating, respectively. In particular, the fully solution-processed TFTs showed good electrical characteristics under tensile strain with 1 mm bending and even extreme folding up to a strain of 26.79%. Due to the good compatibility of each component layer, it maintained the charge-carrier mobility over 79% of initial devices after 5,000 cycles of folding test in both the parallel and perpendicular direction with a bending radius of 1 mm. These results show the potential of the fully solution-processed TFTs as flexible TFTs for a next generation devices because of the robust mechanical flexibility, transparency, and high electrical performance of it. PMID- 27120011 TI - Failure pattern and survival after breast conserving therapy. Long-term results of the Danish Breast Cancer Group (DBCG) 89 TM cohort. AB - Based on the results from the DBCG 82 trial, breast conserving therapy (BCT) has been implemented as standard in Denmark since 1989, and today constitutes more than 70% of the primary treatment. Our aim was to evaluate the implementation of BCT as a routine procedure in patients treated according to the DBCG 89 program and compare recurrence pattern and survival both overall and when separated in age groups, with the results from the randomized DBCG 82 TM trial. MATERIAL AND METHODS: A total of 1847 patients treated between 1989 and 1999 were included in a retrospective population-based cohort study. Data from the DBCG database were completed via search through the Danish Pathology Data Bank and medical records. RESULTS: Median follow-up time was 17 years. At 20 years the cumulative incidences of local recurrence (LR) and disease-specific mortality (DSM) were 15.3% and 25.8%, respectively. Twenty-year overall survival (OS) and recurrence free survival were 63.7% and 43.1%, respectively. Subdivided by age groups cumulative incidences at 20 years were LR: 18.9%, 10.5% and 12.4%, and DSM: 28.9%, 18.9% and 28.4% in young (<=45 years), middle-aged (46-55 years) and older (>=56 years) women, respectively. In an adjusted analysis age maintained a significant and independent effect on both LR and DSM. CONCLUSION: The DBCG 82 TM program was successfully implemented. The women treated with BCT in the DBCG 89 program displayed equal failure pattern and improved survival in comparison with women from the DBCG 82 TM protocol. Occurrence of first failure and mortality varied with age; demonstrated by increased risk of LR, DM and DSM in the young patients and increased risk of DM and DSM in the older patients, compared to the middle-aged patients. PMID- 27120012 TI - Novel materials based on DNA-CTMA and lanthanide (Ce(3+) , Pr(3+) ). AB - New, deoxyribonucleic acid (DNA) based compounds, functionalized with hexadecyltrimethylammonium chloride (CTMA) and lanthanide hydroxide nanoparticles were synthesized. The spectral measurements suggest that between the DNA-CTMA complex and the lanthanide (III) ions a chemical interaction takes place. The obtained materials exhibit an improved fluorescence efficiency, showing a potential interest for application in photonics, and more particularly, in light emitting devices. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 613-617, 2016. PMID- 27120013 TI - The effects of food web structure on ecosystem function exceeds those of precipitation. AB - Ecosystems are being stressed by climate change, but few studies have tested food web responses to changes in precipitation patterns and the consequences to ecosystem function. Fewer still have considered whether results from one geographic region can be applied to other regions, given the degree of community change over large biogeographic gradients. We assembled, in one field site, three types of macroinvertebrate communities within water-filled bromeliads. Two represented food webs containing both a fast filter feeder-microbial and slow detritivore energy channels found in Costa Rica and Puerto Rico, and one represented the structurally simpler food webs in French Guiana, which only contained the fast filter feeder-microbial channel. We manipulated the amount and distribution of rain entering bromeliads and examined how food web structure mediated ecosystem responses to changes in the quantity and temporal distribution of precipitation. Food web structure affected the survival of functional groups in general and ecosystem functions such as decomposition and the production of fine particulate organic matter. Ecosystem processes were more affected by decreased precipitation than were the abundance of micro-organisms and metazoans. In our experiments, the sensitivity of the ecosystem to precipitation change was primarily revealed in the food web dominated by the single filter feeder microbial channel because other top-down and bottom-up processes were weak or absent. Our results show stronger effects of food web structure than precipitation change per se on the functioning of bromeliad ecosystems. Consequently, we predict that ecosystem function in bromeliads throughout the Americas will be more sensitive to changes in the distribution of species, rather than to the direct effects caused by changes in precipitation. PMID- 27120015 TI - Highly Chemo- and Regioselective Construction of Spirocarbocycles by a Pd(0) Catalyzed Dearomatization of Phenol-Based Biaryls with 1,3-Dienes. AB - A novel Pd(0)-catalyzed intermolecular carbocyclization of phenol-derived biaryls with 1,3-dienes has been implemented through a sequence of oxidative addition to the C-I bond, regioselective olefin insertion, and allylative dearomatization. This method provides a broad range of attractive spirocyclic compounds bearing two contiguous tertiary/quaternary carbon centers in good yields with excellent chemoselectivity and regioselectivity. Moreover, preliminary results indicate that asymmetric control of this process is feasible with chiral ligands. PMID- 27120014 TI - Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments. AB - Recent studies have demonstrated that subtype-selective GABAA receptor modulators are able to relax precontracted human airway smooth muscle ex vivo and reduce airway hyper-responsiveness in mice upon aerosol administration. Our goal in this study was to investigate systemic administration of subtype-selective GABAA receptor modulators to alleviate bronchoconstriction in a mouse model of asthma. Expression of GABAA receptor subunits was identified in mouse lungs, and the effects of alpha4-subunit-selective GABAAR modulators, XHE-III-74EE and its metabolite XHE-III-74A, were investigated in a murine model of asthma (ovalbumin sensitized and challenged BALB/c mice). We observed that chronic treatment with XHE-III-74EE significantly reduced airway hyper-responsiveness. In addition, acute treatment with XHE-III-74A but not XHE-III-74EE decreased airway eosinophilia. Immune suppressive activity was also shown in activated human T cells with a reduction in IL-2 expression and intracellular calcium concentrations [Ca(2+)]i in the presence of GABA or XHE-III-74A, whereas XHE-III 74EE showed only partial reduction of [Ca(2+)]i and no inhibition of IL-2 secretion. However, both compounds significantly relaxed precontracted tracheal rings ex vivo. Overall, we conclude that the systemic delivery of a alpha4 subunit-selective GABAAR modulator shows good potential for a novel asthma therapy; however, the pharmacokinetic properties of this class of drug candidates have to be improved to enable better beneficial systemic pharmacodynamic effects. PMID- 27120016 TI - Vitamin B12 Phosphate Conjugation and Its Effect on Binding to the Human B12 Binding Proteins Intrinsic Factor and Haptocorrin. AB - The binding of vitamin B12 derivatives to human B12 transporter proteins is strongly influenced by the type and site of modification of the cobalamin original structure. We have prepared the first cobalamin derivative modified at the phosphate moiety. The reaction conditions were fully optimized and its limitations examined. The resulting derivatives, particularly those bearing terminal alkyne and azide groups, were isolated and used in copper-catalyzed alkyne-azide cycloaddition reactions (CuAAC). Their sensitivity towards light revealed their potential as photocleavable molecules. The binding abilities of selected derivatives were examined and compared with cyanocobalamin. The interaction of the alkylated derivatives with haptocorrin was less affected than the interaction with intrinsic factor. Furthermore, the configuration of the phosphate moiety was irrelevant to the binding process. PMID- 27120017 TI - Hyaluronan Hydrogels for a Biomimetic Spongiosa Layer of Tissue Engineered Heart Valve Scaffolds. AB - Advanced tissue engineered heart valves must be constructed from multiple materials to better mimic the heterogeneity found in the native valve. The trilayered structure of aortic valves provides the ability to open and close consistently over a full human lifetime, with each layer performing specific mechanical functions. The middle spongiosa layer consists primarily of proteoglycans and glycosaminoglycans, providing lubrication and dampening functions as the valve leaflet flexes open and closed. In this study, hyaluronan hydrogels were tuned to perform the mechanical functions of the spongiosa layer, provide a biomimetic scaffold in which valve cells were encapsulated in 3D for tissue engineering applications, and gain insight into how valve cells maintain hyaluronan homeostasis within heart valves. Expression of the HAS1 isoform of hyaluronan synthase was significantly higher in hyaluronan hydrogels compared to blank-slate poly(ethylene glycol) diacrylate (PEGDA) hydrogels. Hyaluronidase and matrix metalloproteinase enzyme activity was similar between hyaluronan and PEGDA hydrogels, even though these scaffold materials were each specifically susceptible to degradation by different enzyme types. KIAA1199 was expressed by valve cells and may play a role in the regulation of hyaluronan in heart valves. Cross-linked hyaluronan hydrogels maintained healthy phenotype of valve cells in 3D culture and were tuned to approximate the mechanical properties of the valve spongiosa layer. Therefore, hyaluronan can be used as an appropriate material for the spongiosa layer of a proposed laminate tissue engineered heart valve scaffold. PMID- 27120018 TI - Gain-of-Function Mutations in RARB Cause Intellectual Disability with Progressive Motor Impairment. AB - Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans. PMID- 27120033 TI - Exercise and Arrhythmias: A Double-Edged Sword. AB - Ample evidence indicates that moderate regular exercise is beneficial for both normal individuals and patients with cardiovascular (CV) disease. However, intense and strenuous exercise in individuals with evident or occult underlying CV abnormalities may have adverse effects with provocation and exacerbation of arrhythmias that may lead to life-threatening situations. Both of these aspects of exercise-induced effects are herein reviewed. PMID- 27120034 TI - Outcomes in endoscopic sinus surgery: olfaction, nose scale and quality of life in a prospective cohort study. AB - OBJECTIVES: To determine the efficacy of endoscopic sinus surgery (ESS) on olfactory function in chronic rhinosinusitis patients with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) and to compare the nasal obstruction and symptom evaluation (NOSE) scale before and after surgery. DESIGN: A prospective cohort study SETTING: Royal National Throat and Nose and Ear Hospital, London UK. PARTICIPANTS: One hundred and thirteen patients with CRS; 60 CRSwNP and 53 CRSsNP. OUTCOME MEASUREMENTS: Olfaction was measured using both the University of Pennsylvania Smell Investigation Test (UPSIT) and the 'sense of smell' visual analogue scale (VAS). The NOSE scale, the sinonasal outcome test (SNOT 22) and the Lund-Kennedy (LK) surgeon reported scores were also measured pre- and postoperatively at 6 months. RESULTS: The UPSIT psychophysical measurement significantly improved following ESS in the CRSwNP subgroup as did the patients perceived VAS sense of smell. However, in the CRSsNP subgroup, the improved VAS and UPSIT measurements were not significant. The NOSE, SNOT 22 and LK scores all improved significantly. The olfactory improvement as measured by the UPSIT correlated to the SNOT-22, but a correlation between the NOSE score and UPSIT was not found. CONCLUSIONS: Endoscopic sinus surgery significantly improved the patient's perceived and measured sense of smell in the CRSwNP subgroup which is the most surgically responsive CRS subgroup. Additionally, improved olfaction in the CRSwNP subgroup is most likely to improve the patient's quality of life. Endoscopic sinus surgery significantly improved the NOSE scale in both CRS subgroups at 6 months following surgery. PMID- 27120035 TI - Validation of a semi-automatic co-registration of MRI scans in patients with brain tumors during treatment follow-up. AB - There is an expanding research interest in high-grade gliomas because of their significant population burden and poor survival despite the extensive standard multimodal treatment. One of the obstacles is the lack of individualized monitoring of tumor characteristics and treatment response before, during and after treatment. We have developed a two-stage semi-automatic method to co register MRI scans at different time points before and after surgical and adjuvant treatment of high-grade gliomas. This two-stage co-registration includes a linear co-registration of the semi-automatically derived mask of the preoperative contrast-enhancing area or postoperative resection cavity, brain contour and ventricles between different time points. The resulting transformation matrix was then applied in a non-linear manner to co-register conventional contrast-enhanced T1 -weighted images. Targeted registration errors were calculated and compared with linear and non-linear co-registered images. Targeted registration errors were smaller for the semi-automatic non-linear co registration compared with both the non-linear and linear co-registered images. This was further visualized using a three-dimensional structural similarity method. The semi-automatic non-linear co-registration allowed for optimal correction of the variable brain shift at different time points as evaluated by the minimal targeted registration error. This proposed method allows for the accurate evaluation of the treatment response, essential for the growing research area of brain tumor imaging and treatment response evaluation in large sets of patients. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27120036 TI - Oxygen Uptake Attenuation at Ventilatory Threshold in Men With Coronary Artery Disease. AB - PURPOSE: Maximal oxygen uptake ((Equation is included in full-text article.)O2) and ventilatory threshold (VT) are widely used to assess cardiorespiratory fitness in healthy people, as well as in patients with various clinical conditions. The aim of this study was to determine whether an attenuation of (Equation is included in full-text article.)O2 occurs above the VT in patients with stable coronary artery disease. METHODS: A total of 33 male patients participating in an outpatient cardiac rehabilitation/secondary prevention program underwent maximal incremental cycle ergometry at increasing pedaling cadences up to the limit of tolerance. Ventilatory gas-exchange variables were measured breath by breath while work rate was recorded continuously. Ventilatory threshold was determined by a dual linear regression model (V-slope analysis). RESULTS: Four patients were excluded from the analysis because they were unable to pedal at the increasing cadences required by the protocol. The remaining 29 patients successfully completed the test without complications or evidence of significant ST segment depression. The slope of the (Equation is included in full text article.)O2/work rate relationship above the VT decreased significantly ( 44.6% on average) in 23 of the 26 patients in which VT was able to be determined. (Equation is included in full-text article.)O2 at the start of (Equation is included in full-text article.)O2 attenuation ((Equation is included in full-text article.)O2att) and at VT were highly correlated and in strong agreement (1637 +/ 451 mL/min vs 1650 +/- 473 mL/min, r = 0.96, P < .01). CONCLUSIONS: (Equation is included in full-text article.)O2att does occur and coincides with the VT in the majority of patients tested with stable coronary artery disease. PMID- 27120037 TI - Health-Related Quality of Life Improves Similarly in Patients With and Without Type 2 Diabetes After Cardiac Rehabilitation. AB - PURPOSE: Cardiovascular disease is the leading cause of death in the United States and results in substantial healthcare expenditures. Health-related quality of life (HRQoL) is an important aspect in long-term recovery for patients with cardiovascular disease. As such, improvement in HRQoL is a relevant outcome for determining cardiovascular rehabilitation (CR) program efficacy. Increasingly, diabetic patients are participating in CR and face additional challenges to HRQoL, yet there is a lack of research addressing program efficacy in this population. This study tested the hypothesis that CR would effect a favorable change in HRQoL for both diabetic (D; n = 37) and nondiabetic (N-D; n = 58) patients. Furthermore, we tested the hypothesis that the D group would demonstrate a greater overall change compared with the N-D group. METHODS: In this retrospective study, we reviewed the charts of 95 patients who completed a CR program and collected HRQoL measures using the COOP questionnaire, where lower scores indicate higher HRQoL. RESULTS: After CR, COOP scores for both the N-D improved (pre: 20.39 +/- 0.79 vs post: 16.06 +/- 0.75; P < .05) and D (pre: 20.92 +/- 0.88 vs post: 15.84 +/- 0.80; P < .05). HRQoL was not different between groups at the start of the program (P = .88) or at the end (P = .58), and thus, the improvement in HRQoL was not different between groups (P = .44). CONCLUSIONS: These results suggest that D and N-D patients do not differ in their HRQoL at the start or end of CR, and that the 2 groups show similar improvements from attending the program. Larger sample studies are needed to confirm these findings. PMID- 27120038 TI - Physiological Profile and Limitations in Exercise in Idiopathic Pulmonary Fibrosis. AB - PURPOSE: This study aimed to describe the physiological profile and limiting factors during exercise among patients with idiopathic pulmonary fibrosis. METHODS: A descriptive study involving 34 patients with idiopathic pulmonary fibrosis (22 men) aged 68 +/- 8 years was conducted. All patients completed a pulmonary function test, cardiopulmonary exercise test, Doppler echocardiography, 6-minute walk test, and modified Medical Research Council dyspnea evaluation. RESULTS: Approximately 38% of patients (range, 15%-71%) presented with coexisting comorbidities including pulmonary hypertension and emphysema. Modified Medical Research Council grades 0-2 and 3-4 were assigned to 68% and 32% of patients, respectively. Median values for forced vital capacity and diffusion capacity for carbon monoxide percent (%) predicted were 68 (95% CI, 63-76) and 51 (95% CI, 46 55), respectively. Left ventricular systolic function was normal. Aerobic capacity ((Equation is included in full-text article.)O2peak = 13.4 mL/kg/min [95% CI, 12.6-14.9]; 62% predicted [95% CI, 56-67]) was moderately reduced with the presence of abnormalities in pulmonary gas exchange and desaturation, circulatory impairments, inefficient ventilation, and skeletal muscle dysfunction. Functional capacity was normal (6-minute walk test distance = 505 m [95% CI, 435-522]; 99% predicted [95% CI, 91-108]). CONCLUSIONS: The physiological profile demonstrated the presence of comorbidities in approximately 38% of patients with idiopathic pulmonary fibrosis and a moderate level of dyspnea. Resting cardiopulmonary function showed moderate pulmonary restriction and severe impairments in diffusion capacity with normal left ventricular systolic function. Multifactorial limitations for a moderately diminished aerobic capacity were revealed during the cardiopulmonary exercise test, although functional capacity was normal. These results emphasize the significance of a meticulous evaluation, including the cardiopulmonary exercise test for an accurate exercise tolerance evaluation, to aid in the diagnosis and prognosis and for developing effective targeted treatments. PMID- 27120039 TI - Prevalence, Reasons for Use, and Risk Perception of Electronic Cigarettes Among Post-Acute Coronary Syndrome Smokers. AB - PURPOSE: The use of electronic cigarettes (e-cigarettes) has risen dramatically in recent years. However, there are currently no published data on the use of e cigarettes among cardiac patients. The current study reports on the prevalence, reasons for use, and perceived risks of e-cigarettes among patients with post acute coronary syndrome (ACS). The relationship between e-cigarette use and post ACS tobacco smoking cessation is also explored. METHODS: Participants were drawn from a randomized trial of smoking cessation treatments following hospitalization for ACS. The current study focused on 49 participants who completed e-cigarette questions at 24 weeks post-ACS. RESULTS: Of the 49 of participants, 51.0% reported ever use of an e-cigarette and 26.5% reported using an e-cigarette at some time during the 24 weeks post-ACS. Ever use and post-ACS use were both significantly associated with lower rates of abstinence from tobacco cigarettes. Participants perceived e-cigarettes as less harmful to cardiac health than tobacco use and Chantix (varenicline), and similarly harmful as nicotine replacement therapy. Participant perceived likelihood of experiencing a heart attack in the next year was 34.6% if they were to regularly use only e cigarettes, significantly lower than the perceived risk of recurrence if they were to regularly smoke only tobacco cigarettes (56.2%) and significantly higher than the perceived risk of recurrence if they were to use no nicotine (15.2%). CONCLUSIONS: A significant minority of patients are using e-cigarettes post-ACS. Providers should be prepared to discuss potential discrepancies between patient beliefs about the safety of e-cigarettes and the current state of the science. PMID- 27120040 TI - Evolving Role of Exercise Testing in Contemporary Cardiac Rehabilitation. AB - Symptom-limited (maximal) exercise testing before cardiac rehabilitation (CR) was once an unambiguous standard of care. In particular, it served as an important screen for residual ischemia and instability before initiating a progressive exercise training regimen. However, improved revascularization and therapy for coronary heart disease has led many clinicians to downplay this application of exercise testing, especially because such testing is also a potential encumbrance to CR enrollment (delaying ease and efficiency of enrollment after procedures and hospitalizations) and patient burden (eg, added costs, logistic hassle, and anxiety). Nonetheless, exercise testing has enduring value for CR, especially because it reveals dynamic physiological responses as well as ischemia, arrhythmias, and symptoms pertinent to exercise prescription and training and to overall stability and prognosis. Moreover, as indications for CR have expanded, the value of exercise testing and functional assessment is more relevant than ever in the growing population of eligible patients, including those with heart failure, valvular heart disease, and posttransplantation, especially as current patients also tend to be more clinically complex, with advanced ages, multimorbidity, frailty, and obesity. This review focuses on the appropriate use of exercise testing in the CR setting. Graded exercise tests, cardiopulmonary exercise tests, submaximal walking tests, and other functional assessments (strength, frailty) for CR are discussed. PMID- 27120041 TI - Percutaneous ultrasound-guided core needle biopsy of solid pancreatic masses: Results in 250 patients. AB - BACKGROUND: To determine the diagnostic accuracy and complications of percutaneous sonographic (US)-guided core needle-needle biopsy in the diagnosis of solid pancreatic masses. METHODS: Cases of US-guided percutaneous core needle biopsy of solid pancreatic masses performed in our department between July 2009 and June 2015 were analyzed retrospectively. The demographic data, lesions' size and location, pathology results, accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and complications of the biopsies were determined. RESULTS: A total of 250 patients (150 males, 100 females; age range, 16-88 years; mean age, 64.3 +/- 12.1 years) were included in the study. The overall diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of all 250 biopsies were 94.8%, 94.3%, 97.2%, 99.5%, and 75%, respectively, and changed to 98.4%, 99%, 94.7%, 99%, and 94.7%, respectively, after the biopsy was repeated in 12 patients. Four (1.6%) major complications, including a pseudoaneurysm of the gastroduodenal artery, and three cases of acute pancreatitis, and one (0.4%) minor complication (a vaso vagal syncope), were observed. There was no biopsy-related death. CONCLUSIONS: US guided percutaneous core needle biopsy is a safe and highly effective method with acceptable complication rates in the diagnosis of solid pancreatic masses. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:470-473, 2016. PMID- 27120042 TI - Analysis of forchlorfenuron and thidiazuron in fruits and vegetables by surface enhanced Raman spectroscopy after selective solid-phase extraction with modified beta-cyclodextrin. AB - beta-Cyclodextrin and its derivatives can selectively bind to various organic molecules in its cavity and provide good applications in sample preparation. Surface-enhanced Raman spectroscopy is a sensitive technique and has received increasing attention in the last decade. Herein, 3,5-dimethyl phenyl carbamoylated beta-cyclodextrin bonded silica gel was used as a ssorbent in solid phase extraction to selectively enrich forchlorfenuron and thidiazuron followed by determination with surface-enhanced Raman spectroscopy. It showed excellent selectivity for forchlorfenuron and thidiazuron and the adsorption capacities were 40.0 and 30.0 MUg/g, respectively. A rapid and sensitive method based on the modified beta-cyclodextrin solid-phase extraction coupled with surface-enhanced Raman spectroscopy was developed. The linear ranges were 30.0-300.0 MUg/L for forchlorfenuron and thidiazuron at 1005 and 640 cm(-1) , respectively. Both of the limits of detection were 15.0 MUg/L, which were significantly lower than the maximum permitted by the National Standard. The recoveries of forchlorfenuron and thidiazuron were 78.9-87.9% for the spiked grape, kiwi, cucumber and tomato, with relative standard deviations of 8.1-13.2%. The results show that this method is sensitive, selective, and relatively time saving, and has great potential in the analysis of trace amounts of plant growth regulators in fruits and vegetables. PMID- 27120043 TI - SERS and integrative imaging upon internalization of quantum dots into human oral epithelial cells. AB - CdTe quantum dots (QDs) are widely used in bio-applications due to their size and highly efficient optical properties. However internalization mechanisms thereof for the variety of freshly extracted, not cultivated human cells and their specific molecular interactions remains an open topic for discussion. In this study, we assess the internalization mechanism of CdTe quantum dots (3.3 nm) capped with thioglycolic acid using non cultivated oral epithelial cells obtained from healthy donors. Naked gold nanoparticles (40 nm) were successfully used as nanosensors for surface-enhanced Raman spectroscopy to efficiently identify characteristic Raman peaks, providing new evidence indicating that the first interactions of these QDs with epithelial cells occurred preferentially with aromatic rings and amine groups of amino acid residues and glycans from trans membrane proteins and cytoskeleton. Using an integrative combination of advanced imaging techniques, including ultra-high resolution SEM, high resolution STEM coupled with EDX spectroscopy together with the results obtained by Raman spectroscopy, it was determined that thioglycolic acid capped CdTe QDs are efficiently internalized into freshly extracted oral epithelial cells only by facilitated diffusion, distributed into cytoplasm and even within the cell nucleus in three minutes. PMID- 27120046 TI - Clinical Connections. PMID- 27120044 TI - Analysis of Amblyomma sculptum haplotypes in an area endemic for Brazilian spotted fever. AB - Amblyomma sculptum (Ixodida: Ixodidae) Berlese, 1888, a member of the Amblyomma cajennense complex, is the major vector of Brazilian spotted fever (BSF) in southeastern Brazil. In this study, the genetic diversity of A. sculptum populations in the state of Rio de Janeiro (RJ), Brazil, was investigated because genetic variability in tick populations may be related to vector competence. Samples of A. sculptum from 19 municipalities in 7 regions of RJ were subjected to DNA extraction, amplification and sequencing of D-loop, cytochrome oxidase II and 12S rDNA mitochondrial genes. These sequences were used to map the genetic diversity of this tick. Amblyomma sculptum populations are genetically diverse in RJ, especially in the South Centre and Highland regions. Few unique haplotypes were observed in all populations, and the majority of genetic variation found was among ticks within each population. Phylogenetic reconstruction reinforced the assumption that all the haplotypes identified in RJ belong to A. sculptum. However, some RJ haplotypes are closer to A. sculptum from Argentina than to A. sculptum from elsewhere in Brazil. In RJ, A. sculptum has high genetic diversity, although little genetic differentiation. Observations also indicated a high level of gene flow among the studied populations and no evidence of population structure according to region in RJ. PMID- 27120047 TI - MiR-4282 suppresses proliferation and mobility of human colorectal carcinoma cells by targeting semaphorin 3E. AB - BACKGROUND: MicroRNAs play an important role in cancer development. Deregulation of microRNAs can lead to tumorigenesis. Class 3 semaphorin, semaphorin 3E (Sema3E), has been shown to be implicated in tumor growth and metastasis. The role of miR-4282 in regulating colorectal carcinoma and its correlation to Sema3E remain uncertain. METHODS: Real-time quantitative reverse transcription polymerase chain reaction was used to detect the levels of miR-4282 and Sema3E in colorectal carcinoma cells and colorectal tumor tissues. Sema3E protein level in cell lines and human tissues was analyzed by western blot Transient transfections of miR-4282 inhibitor or mimics were conducted to silence or overexpress miR 4282. Sema3E siRNA was transfected to knockdown Sema3E in tumor cell lines. MTT assay was employed to measure colorectal tumor cell growth. Migration and invasion of the cells were examined by trans-well assays. Luciferase reporter assays were performed to confirm miR-4282 targeted at Sema3E. RESULTS: In the present study, reduced miR-4282 expression was observed in the colorectal carcinoma cell lines and human carcinoma tissues in comparison with normal human colon cells (P<0.05) or matched non-tumor tissues (P<0.05), whereas, Sema3E was up-regulated in colorectal carcinoma cells lines (P<0.05) and human colorectal tumor tissues (P<0.05). MiR-4282 was then reduced by the inhibitor and overexpressed by its mimics transfection. It was found that miR-4282 inhibition promoted cell growth, migration and invasion (P<0.05) of HT29 and HCT116 colorectal carcinoma cells while miR-4282 overexpression suppressed cell growth and mobility (P<0.05). Sema3E was predicted as a target of miR-4282 in miRDB database. We found that miR-4282 overexpression significantly reduced luciferase activity of pRL-Sema3E-3'-UTR (P<0.05), but failed to alter the activity of pRL sema3E-3'-UTR-mutation. Also, miR4282 overexpression suppressed Sema3E expression in the colorectal carcinoma cell lines. To further confirm the role of Sema3E suppression in the function of the colorectal carcinoma cells by miR-4282, HT29 and HCT116 cells were transfected with Sema3E siRNA. We found that cell growth, migration and invasion of HT29 and HCT116 cells were dramatically inhibited by Sema3E knockdown (P<0.05). CONCLUSIONS: Our findings suggested that miR-4282 is a tumor suppressor in colorectal carcinoma cells and exerted its inhibitory effect on the tumor cells through targeting Sema3E by inhibiting Sema3E translation or enhancing Sema3E mRNA degradation. Thus, manipulation of miR-4282 and interfere with Sema3E might represent a potential target for the treatment of colorectal cancer. PMID- 27120048 TI - Detection of hTERT mRNA in peripheral blood and its implication for diagnosis of early stage postoperative endometrial cancer micrometastasis. AB - BACKGROUND: The aim of this study was to examine the expression of human telomerase reverse transcriptase (hTERT) in peripheral blood of endometrial cancer (EC) patients before and after surgery, and explore its clinical implication for diagnosis of early stage postoperative EC micrometastases. METHODS: Fluorescence quantitative polymerase chain reaction (FQ-PCR) was used to determine the expression level of hTERT mRNA in peripheral blood of 40 healthy controls, 40 patients with benign uterine diseases, and 56 EC patients before and after surgery. All data were analyzed using SPSS Statistics v.17.0 software. RESULTS: hTERT mRNA in peripheral blood was positive in 57.1% of EC patients (32/56), which is significantly higher compared to 0.0% (0/40) in healthy controls (chi2=34.286, P=0.000) and 5.0% (2/40) in patients with benign uterine diseases (chi2=27.736, P=0.000). The 32 EC patients with positive hTERT mRNA expression included 16 cases of stage I~II, and 16 cases of stage III~IV. The relative expression level of hTERT mRNA is -4.0000+/-0.2401 for stage I~II, and 2.7107+/-0.1253 for stage III~IV. The relative expression level of hTERT mRNA was significantly higher in EC patients with at higher pathological stages (t= 14.398, P=0.000). hTERT mRNA positive expression rates in peripheral blood of EC patients before and after surgery were 57.1% (32/56) and 85.7% (48/56), respectively, which is significantly different (chi2=11.200, P=0.001). CONCLUSIONS: hTERT can be used as a marker for diagnosis of endometrial cancer micrometastasis via blood, and therefore has important value in choosing postoperative adjunctive therapy for early stage endometrial cancer. PMID- 27120049 TI - Spin Crossover in Fe(II)-M(II) Cyanoheterobimetallic Frameworks (M = Ni, Pd, Pt) with 2-Substituted Pyrazines. AB - Discovery of spin-crossover (SCO) behavior in the family of Fe(II)-based Hofmann clathrates has led to a "new rush" in the field of bistable molecular materials. To date this class of SCO complexes is represented by several dozens of individual compounds, and areas of their potential application steadily increase. Starting from Fe(2+), square planar tetracyanometalates M(II)(CN)4(2-) (M(II) = Ni, Pd, Pt) and 2-substituted pyrazines Xpz (X = Cl, Me, I) as coligands we obtained a series of nine new Hofmann clathrate-like coordination frameworks. X ray diffraction reveals that in these complexes Fe(II) ion has a pseudo octahedral coordination environment supported by four MU4-tetracyanometallates forming its equatorial coordination environment. Depending on the nature of X and M, axial positions are occupied by two 2X-pyrazines (X = Cl and M(II) = Ni (1), Pd (2), Pt (3); X = Me and M(II) = Ni (4), Pd (5)) or one 2X-pyrazine and one water molecule (X = I and M(II) = Ni (7), Pd (8), Pt (9)), or, alternatively, two distinct Fe(II) positions with either two pyrazines or two water molecules (X = Me and M(II) = Pt (6)) are observed. Temperature behavior of magnetic susceptibility indicates that all compounds bearing FeN6 units (1-6) display cooperative spin transition, while Fe(II) ions in N5O or N4O2 surrounding are high spin (HS). Structural changes in the nearest Fe(II) environment upon low spin (LS) to HS transition, which include ca. 10% Fe-N distance increase, lead to the cell expansion. Mossbauer spectroscopy is used to characterize the spin state of all HS, LS, and intermediate phases of 1-9 (see abstract figure). Effects of a pyrazine substituent and M(II) nature on the hyperfine parameters in both spin states are established. PMID- 27120050 TI - Prevalent Diabetes Mellitus: Mortality and Management in Norwegian Heart Failure Outpatients. AB - OBJECTIVES: Heart failure (HF) patients with diabetes mellitus experience poor prognosis. We assessed the independent predictive effect of prevalent diabetes mellitus on all-cause mortality in HF outpatients. Furthermore, we investigated if optimized HF medication differed in diabetic versus nondiabetic patients. METHODS: From 6,289 patients included in the Norwegian HF registry during 2000 2012, 724 diabetic HF outpatients were propensity-score-matched with nondiabetic HF outpatients (1:1), based on 21 measured baseline variables. Baseline characteristics, measured comorbidities and medication were balanced in the matched sample. RESULTS: Diabetes was not an independent predictor of all-cause mortality in the propensity-matched analyses (hazard ratio 1.041; 95% confidence interval 0.875-1.240). No interactions were found between the prognostic impact of diabetes and the strata renal function, systolic function or etiology of chronic HF. Diabetic HF outpatients were independently prescribed higher doses of beta-blockers and loop diuretics (both p < 0.001) and were more prone to receive statins (p = 0.003) than nondiabetics. CONCLUSIONS: Prevalent diabetes mellitus was not an independent predictor of all-cause mortality in HF outpatients. Explanations other than tight glycemic control should be assessed to improve the prognosis of diabetic HF outpatients. The more intensive, optimized HF medication for diabetic HF outpatients may, to a certain degree, explain our results. PMID- 27120051 TI - Direct and Indirect Effects of Five Factor Personality and Gender on Depressive Symptoms Mediated by Perceived Stress. AB - This study was designed to investigate associations among five factor personality traits, perceived stress, and depressive symptoms and to examine the roles of personality and perceived stress in the relationship between gender and depressive symptoms. The participants (N = 3,950) were part of a cohort study for health screening and examination at the Kangbuk Samsung Hospital. Personality was measured with the Revised NEO Personality Inventory (NEO-PI-R). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). Perceived stress level was evaluated with a self-reported stress questionnaire developed for the Korea National Health and Nutrition Examination Survey. A higher degree of neuroticism and lower degrees of extraversion, agreeableness, and conscientiousness were significantly associated with greater perceived stress and depressive symptoms. Neuroticism and extraversion had significant direct and indirect effects (via stress as a mediator) on depressive symptoms in both genders. Agreeableness and conscientiousness had indirect effects on depression symptoms in both genders. Multiple mediation models were used to examine the mediational roles of each personality factor and perceived stress in the link between gender and depressive symptoms. Four of the personality factors (except openness) were significant mediators, along with stress, on the relationship between gender and depressive symptoms. Our findings suggest that the links between personality factors and depressive symptoms are mediated by perceived stress. As such, personality is an important factor to consider when examining the link between gender and depression. PMID- 27120052 TI - Development of a fluorescent transgenic zebrafish biosensor for sensing aquatic heavy metal pollution. AB - We report a transgenic zebrafish (Danio rerio) designed to respond to heavy metals using a metal-responsive promoter linked to a fluorescent reporter gene (DsRed2). The metallothionein MT-Ia1 promoter containing metal-responsive elements was derived from the Asian green mussel, Perna viridis. The promoter is known to be induced by a broad spectrum of heavy metals. The promoter-reporter cassette cloned into the Tol2 transposon vector was microinjected into zebrafish embryos that were then reared to maturity. A transgene integration rate of 28 % was observed. The confirmed transgenics were mated with wild-type counterparts, and pools of F1 embryos were exposed to sub-lethal doses of Cd(2+), Cu(2+), Hg(2+), Pb(2+) and Zn(2+). The red fluorescence response of zebrafish embryos was observed 8 h post- exposure to these sub-lethal doses of heavy metals using a fluorescence microscope. Reporter expression estimated by real-time PCR revealed eightfold, sixfold and twofold increase on exposure to highest concentrations of Hg(2+), Cd(2+) and Cu(2+), while Pb(2+) and Zn(2+) had no effect. This biosensor could be a first-level screening method for confirming aquatic heavy metal bio toxicity to eukaryotes. PMID- 27120053 TI - Ultrasonic-Assisted Extraction of Raspberry Seed Oil and Evaluation of Its Physicochemical Properties, Fatty Acid Compositions and Antioxidant Activities. AB - Ultrasonic-assisted extraction was employed for highly efficient separation of aroma oil from raspberry seeds. A central composite design with two variables and five levels was employed and effects of process variables of sonication time and extraction temperature on oil recovery and quality were investigated. Optimal conditions predicted by response surface methodology were sonication time of 37 min and extraction temperature of 54 degrees C. Specifically, ultrasonic-assisted extraction (UAE) was able to provide a higher content of beneficial unsaturated fatty acids, whereas conventional Soxhlet extraction (SE) resulted in a higher amount of saturated fatty acids. Moreover, raspberry seed oil contained abundant amounts of edible linoleic acid and linolenic acid, which suggest raspberry seeds could be valuable edible sources of natural gamma-linolenic acid products. In comparison with SE, UAE exerted higher free radical scavenging capacities. In addition, UAE significantly blocked H2O2-induced intracellular reactive oxygen species (ROS) generation. PMID- 27120054 TI - An Original Stepwise Multilevel Logistic Regression Analysis of Discriminatory Accuracy: The Case of Neighbourhoods and Health. AB - BACKGROUND AND AIM: Many multilevel logistic regression analyses of "neighbourhood and health" focus on interpreting measures of associations (e.g., odds ratio, OR). In contrast, multilevel analysis of variance is rarely considered. We propose an original stepwise analytical approach that distinguishes between "specific" (measures of association) and "general" (measures of variance) contextual effects. Performing two empirical examples we illustrate the methodology, interpret the results and discuss the implications of this kind of analysis in public health. METHODS: We analyse 43,291 individuals residing in 218 neighbourhoods in the city of Malmo, Sweden in 2006. We study two individual outcomes (psychotropic drug use and choice of private vs. public general practitioner, GP) for which the relative importance of neighbourhood as a source of individual variation differs substantially. In Step 1 of the analysis, we evaluate the OR and the area under the receiver operating characteristic (AUC) curve for individual-level covariates (i.e., age, sex and individual low income). In Step 2, we assess general contextual effects using the AUC. Finally, in Step 3 the OR for a specific neighbourhood characteristic (i.e., neighbourhood income) is interpreted jointly with the proportional change in variance (i.e., PCV) and the proportion of ORs in the opposite direction (POOR) statistics. RESULTS: For both outcomes, information on individual characteristics (Step 1) provide a low discriminatory accuracy (AUC = 0.616 for psychotropic drugs; = 0.600 for choosing a private GP). Accounting for neighbourhood of residence (Step 2) only improved the AUC for choosing a private GP (+0.295 units). High neighbourhood income (Step 3) was strongly associated to choosing a private GP (OR = 3.50) but the PCV was only 11% and the POOR 33%. CONCLUSION: Applying an innovative stepwise multilevel analysis, we observed that, in Malmo, the neighbourhood context per se had a negligible influence on individual use of psychotropic drugs, but appears to strongly condition individual choice of a private GP. However, the latter was only modestly explained by the socioeconomic circumstances of the neighbourhoods. Our analyses are based on real data and provide useful information for understanding neighbourhood level influences in general and on individual use of psychotropic drugs and choice of GP in particular. However, our primary aim is to illustrate how to perform and interpret a multilevel analysis of individual heterogeneity in social epidemiology and public health. Our study shows that neighbourhood "effects" are not properly quantified by reporting differences between neighbourhood averages but rather by measuring the share of the individual heterogeneity that exists at the neighbourhood level. PMID- 27120055 TI - Adalimumab for Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Evidence-based studies are increasingly being focused on evaluating the efficacy and safety of adalimumab (ADA) for moderately to severely active ulcerative colitis (UC). However, the dosage pattern of ADA for UC management is still not clear. OBJECTIVE: A meta-analysis was conducted to evaluate the efficacy and safety of different ADA dosage regimens for moderately to severely active UC. METHODS: The Medline, EMBASE, ISI Web of Knowledge, and Cochrane databases were searched from their inception to January 2015. Randomized controlled trials (RCTs) comparing ADA with placebo were eligible for initial inclusion. The efficacy and side effects were evaluated for ADA 160/80 (ADA 160/80 mg at weeks 0/2 and then 40 mg at weeks 4 and 6), and ADA 80/40 (ADA 80/40 mg at weeks 0/2 and then 40 mg at weeks 4 and 6) induction therapy, with ADA 40 mg every other week (EOW) for maintenance therapy of 52 weeks. The pooled risk ratio (RR) and its 95 % confidence interval (CI) were calculated. RESULTS: Three RCTs were included. All of the studies were considered to have a low risk of bias. ADA 160/80 was more effective than placebo for induction of clinical remission (RR 1.62, 95 % CI 1.15-2.29), clinical response (RR 1.37, 95 % CI 1.19 1.59), mucosal healing (RR 1.27, 95 % CI 1.08-1.50), and inflammatory bowel disease questionnaire (IBDQ) response (RR 1.22, 95 % CI 1.05-1.43) and did not increase adverse events (RR 1.10, 95 % CI 0.95-1.27). Compared with placebo, ADA 80/40 did not show significant differences for induction of clinical remission and clinical response and did not increase adverse events. ADA 40 mg EOW was superior to placebo in maintaining clinical remission (RR 2.38, 95 % CI 1.57 3.59), clinical response (RR 1.69, 95 % CI 1.29-2.21), mucosal healing (RR 1.69, 95 % CI 1.26-2.28), and IBDQ response (RR 1.73, 95 % CI 1.28-2.34). Compared with placebo, ADA 40 mg EOW increased adverse events (RR 1.28, 95 % CI 1.06-1.54). CONCLUSION: ADA 160/80 was a safe and effective treatment for induction management of moderately to severely active UC, but the benefits of ADA 80/40 application were limited. ADA 40 mg EOW was effective for maintenance management of UC. Additional well designed RCTs are needed to confirm these results. PMID- 27120056 TI - Variability Over Time of Preoperative Sagittal Alignment Parameters: Radiographic and Clinical Considerations. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To evaluate preoperative variability in radiographic sagittal parameters in adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: In ASD surgical planning, deformity magnitude is determined from preoperative radiographs. There are no studies evaluating the clinical relevance and timing to repeat radiographs during interval clinic visits and timing to repeat radiograph for preoperative planning. METHODS: A total of 139 patients with ASD with minimum two preoperative full-body spine x-rays were included. Cervical, thoracic, lumbar, pelvic, and hip/knee sagittal alignment parameters were analyzed using dedicated spine measurement software. Patients were grouped by time intervals between x-rays: A: 8 weeks or lesser, B: 10 to 20 weeks, and C: 21 weeks or more. Changes in sagittal parameters were correlated to age and deformity magnitude (T1 pelvic angle or pelvic tilt [PT] >20 degrees ). RESULTS: The cohort had mean age 59 years, mean body mass index 27, 30% men, 95 patients with no prior spine surgery, and 44 patients at minimum 9 months since prior spine surgery. There were 25 patients in group A, 38 in B, and 71 in C. All radiographic measures showed good time-based consistency at intervals less than 21 weeks (groups A and B). Group C had significant increases in PT (1.5 degrees ) and hip extension (2.1 degrees ) (P < 0.05). These changes were greater in group C patients with previous surgery (PT 3.7 degrees ; P < 0.006, hip extension 3.2 degrees ; P < 0.025). Greater interval changes in parameters were also associated with higher magnitudes of deformity and younger patient ages. CONCLUSION: All sagittal radiographic parameters were statistically consistent at intervals of less than 21 weeks. In patients with more than 21 weeks between interval x-rays, change in PT was greater than the standard error of measurement for patients with prior surgery or severe deformity. Consideration should be made to obtain new x rays for patients with ASD when the interval between clinical visits exceeds 5 months. LEVEL OF EVIDENCE: 4. PMID- 27120057 TI - Prevalence, Concomitance, and Distribution of Ossification of the Spinal Ligaments: Results of Whole Spine CT Scans in 1500 Japanese Patients. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To investigate the prevalence, concomitance, and distribution of various types of ossification of the spinal ligaments in healthy subjects using computed tomography (CT). SUMMARY OF BACKGROUND DATA: CT has better diagnostic accuracy for ossification of the spinal ligaments compared to plain radiography. Currently there is no study that examines the prevalence of ossification of the spinal ligaments using whole spine CT scans. METHODS: One thousand five hundred Japanese patients (888 men and 612 women) who underwent positron emission tomography and CT (PETCT) in a private health check center between 2006 and 2013 were included. This PETCT was performed on self-paying participants as a preventive cancer screen. Existence of ossification of the posterior longitudinal ligament (OPLL), ligamentum flavum (OLF), anterior longitudinal ligament (OALL), diffuse idiopathic skeletal hyperostosis (DISH), and nuchal ligament (ONL) was examined. RESULTS: The prevalence of spinal ligament ossifications was found to be 6.3% in cervical OPLL (8.3% in men and 3.4% in women), 23% in ONL (33% in men and 8.8% in women), 1.6% in thoracic OPLL (1.4% in men and 2.0% in women), 12% in thoracic OLF (15% in men and 7.7% in women), 37% in thoracolumbar OALL (45% in men and 26% in women), and 12% in DISH (16% in men and 6.2% in women). Thirteen percent of patients with cervical OPLL had thoracic OPLL, 34% of cervical OPLL had thoracic OLF, 45% of cervical OPLL had ONL, and 36% of cervical OPLL had DISH. The most common level was C5 for cervical OPLL, T1/2 for thoracic OPLL, T11 for thoracic OLF, and T8/9 for OALL. CONCLUSION: Accurate prevalence of various types of ossification of the spinal ligaments evaluated by CT was revealed. High concomitance was observed in each classification of spinal ligament ossification. LEVEL OF EVIDENCE: 3. PMID- 27120058 TI - Biomechanical Role of the C1 Lateral Mass Screws in Occipitoatlantoaxial Fixation: A Finite Element Analysis. AB - STUDY DESIGN: Finite element analysis. OBJECTIVE: To determine and compare the construct stability of occipitoatlantoaxial (C0-C1-C2) fixation provided by occipital plate, rod, and screw fixation with or without C1 lateral mass screw (C1LMS). SUMMARY OF BACKGROUND DATA: Occipitoatlantoaxial fixation techniques use C2 pedicle screw (C2PS) with and without C1LMS that are then incorporated into occipital plate fixation points using occipital screw. There has, however, been no consensus about the standard occiput to C2 fixation in literature and few reports exist about the effects of additional intervening rigid C1LMS on the biomechanics. The role of biomechanics of the addition of C1LMS in occipitoatlantoaxial fixation for fusion is not known. METHODS: A nonlinear finite element model (FEM) of the intact upper cervical spine had been developed and validated. Then an FEM of an unstable model treated with occipital plate combined with C2PS and C1LMS fixation (C1LMS + C2PS + plate), was compared to that with C2PS fixation (C2PS + plate). Vertical load of 50 N was applied on the C0, to simulate head weight and 1.5 Nm torque was applied to the C0 to simulate flexion, extension, lateral bending, and axial rotation. RESULTS: Compared with C2PS + plate, the C1LMS + C2PS + plate reduced the range of motion of C0-C2 segment by 3.0%, 35.4%, 29.2%, and 56.9% in flexion, extension, lateral bending, and axial rotation, respectively, and it also led to lower occipital screw and superior rod stresses in all loading conditions. CONCLUSION: The addition of supplemental C1LMS to occiput-C2 fixation not only enhances greater stability, especially during axial rotation, but also has the capability of distributing the stress evenly and reduces the risk of construct failure because of occipital screw pullout and rod fracture. Therefore, this method may be important to elderly patients with osteopenia or osteoporosis and it may promote a high occipitoatlantoaxial fusion rate. LEVEL OF EVIDENCE: N/A. PMID- 27120059 TI - Routine Use of Intraoperative Neuromonitoring During ACDFs for the Treatment of Spondylotic Myelopathy and Radiculopathy Is Questionable: A Review of 15,395 Cases. AB - STUDY DESIGN: A retrospective database study. OBJECTIVE: The goal of this study was to (1) evaluate the trends in the use of intraoperative neuromonitoring (ION) for anterior cervical discectomy and fusion (ACDF) surgery in the United States and (2) assess the incidence of neurological injuries after ACDFs with and without ION. SUMMARY OF BACKGROUND DATA: Somatosensory-evoked potentials (SSEPs) and motor-evoked potentials (MEPs) are the commonly used ION modalities for ACDFs. Controversy exists on the routine use of ION for ACDFs and there is limited literature on national practice patterns of its use. METHODS: A retrospective review was performed using the PearlDiver Patient Record Database to identify cases of spondylotic myelopathy and radiculopathy that underwent ACDF from 2007 to 2014. The type of ION modality used and the rates of neurological injury after surgery were assessed. RESULTS: During the study period, 15,395 patients underwent an ACDF. Overall, ION was used in 2627 (17.1%) of these cases. There was a decrease in the use of ION for ACDFs from 22.8% in 2007 to 4.3% use in 2014 (P < 0.0001). The ION modalities used for these ACDFs were quite variable: SSEPs only (48.7%), MMEPs only (5.3%), and combined SSEPs and MMEPs (46.1%). Neurological injuries occurred in 0.23% and 0.27% of patients with and without ION, respectively (P = 0.84). Younger age was associated with a higher utility of ION (<45: 20.3%, 45-54: 19.3%, 55-64: 16.6%, 65-74: 14.3%, and >75: 13.6%, P < 0.0001). Significant regional variability was observed in the utility of ION for ACDFs across the country (West; 21.9%, Midwest; 12.9% (P < 0.0001). CONCLUSION: There has been a significant decrease in the use of ION for ACDFs. Furthermore, there was significant age and regional variability in the use of ION for ACDFs. Use of ION does not further prevent the rate of postoperative neurological complications for ACDFs as compared with the cases without ION. The utility of routine ION for ACDFs is questionable. LEVEL OF EVIDENCE: 3. PMID- 27120060 TI - Granulocyte Colony-Stimulating Factor Improves Motor Function in Rats Developing Compression Myelopathy. AB - STUDY DESIGN: Basic animal research. OBJECTIVE: The effects of granulocyte colony stimulating factor (G-CSF) were assessed in a rat chronic spinal cord compression model to explore the potential of G-CSF as a pharmacological treatment for cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: G-CSF is a hematopoietic cytokine used clinically to treat neutropenia. Recently, neuroprotective effects of G-CSF have been reported in spinal cord disorders. METHODS: To introduce the chronic cervical cord compression, thin polyurethane sheets were implanted under C5-C6 laminae of rats and gradually expanded by absorbing water. This model reproduces delayed compressive myelopathy of the cervical spine. In sham operations, the sheets were immediately removed. G-CSF (15 MUg/kg) or normal saline (NS) was administered subcutaneously 5 days a week. Experimental groups were sham operation given NS; cord compression given NS; and cord compression given G-CSF. To assess motor functions, rotarod performance, and grip strength were measured. Twenty-six weeks after surgery, cervical spinal cords were examined histopathologically. In the prevention experiment, G-CSF or NS administration was started immediately after surgery. In the treatment experiment, their administration was started 8 weeks after surgery. In another experiment, in three groups in the prevention experiment, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining was performed to assess apoptotic cell death at 8 weeks after surgery. RESULTS: In the prevention experiment, administration of G-CSF preserved the motor functions and motor neurons throughout the 26 weeks, and significantly decreased the number of apoptotic cells at 8 weeks. In the treatment experiment, G-CSF administration from 8 weeks after surgery markedly restored the motor function temporarily to a level equal to the sham group. CONCLUSION: G-CSF prevents the decline in motor functions and preserves motor neurons in the rat chronic cord compression model. G-CSF also improves motor function in the progressive phase of compression myelopathy. LEVEL OF EVIDENCE: N/A. PMID- 27120061 TI - Readmission Rates, Reasons, and Risk Factors Following Anterior Cervical Fusion for Cervical Spondylosis in Patients Above 65 Years of Age. AB - STUDY DESIGN: A retrospective database review. OBJECTIVE: The aim of this study was to determine readmission reasons and rates following primary, elective anterior cervical spinal fusion surgery for cervical spondylosis and determine risk factors predicting increased risk of 30-day readmission in an exclusively elderly population. SUMMARY OF BACKGROUND DATA: In the United States, there were almost 190,000 cervical spine procedures in 2009. Many cervical spine surgery patients are elderly, a demographic increasingly requiring surgery for degenerative cervical spine pathology. Unfortunately, this patient population is poorly studied, particularly concerning readmission rates. METHODS: Medicare data from 2005 to 2012 were queried for elderly patients (65-84 years) who underwent primary one to two and >=three-level anterior cervical spine fusion surgeries for cervical spondylosis. Forty-five thousand two hundred eighty-four patients treated with one to two-level and 12,103 patients with >=three-level anterior cervical fusion (ACF) were identified and included in two study cohorts. Reasons for and rates of readmission were determined within 30 days, 90 days, and one year postoperatively. Risk factors for medical, surgical, and all 30-day readmissions were also determined, selecting from various comorbidities, demographics, and surgical variables. RESULTS: Readmission rates of 1.0% to 1.4%, 2.7% to 3.6%, and 13.2% to 14.1% were observed within 30 days, 90 days, and one year. Within 30 days, over 30% of patients from both study cohorts were readmitted for surgical reasons. Of surgical reasons for 30-day readmission, hematoma/seroma diagnoses were the most frequent (11.4%-15.4% of all readmissions). Male gender, diabetes mellitus, chronic pulmonary disease, obesity, and smoking history were all found to be predictive of all-cause readmissions. CONCLUSION: Unplanned 30-day readmission rates following primary, elective ACF in elderly patients is low and often due to medical reasons. Frequent surgical reasons for 30-day readmission include hematoma/seroma formation. Male gender and various comorbid diagnoses are significant predictors of all-cause readmissions within 30 days. LEVEL OF EVIDENCE: 3. PMID- 27120063 TI - K-line (-) in the Neck-Flexed Position in Patients With Ossification of the Posterior Longitudinal Ligament Is a Risk Factor for Poor Clinical Outcome After Cervical Laminoplasty. AB - STUDY DESIGN: Retrospective study comparing postoperative clinical outcomes after cervical laminoplasty between K-line (-) ossification of the posterior longitudinal ligament (OPLL) and K-line (+) OPLL in the neck-flexed position. OBJECTIVE: To investigate postoperative outcomes using Japanese Orthopedic Association (JOA) scores, and grip-and-release (GR) and foot-tap (FT) test scores after laminoplasty in patients with K-line (-) OPLL in the neck-flexed position. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty has been reported to lead to poor outcomes in K-line (-) OPLL and good outcomes in K-line (+) OPLL. The cervical spine, however, continues moving in the extension and flexion direction after laminoplasty. METHODS: Patients with cervical myelopathy were divided into K-line (+) and (-) in the neck-flexed position. We compared postoperative outcomes after cervical laminoplasty using recovery rate, as assessed by the JOA score and degree of improvement in the six JOA score items, and performance, as assessed by GR and (FT) tests, between patients with K-line (+) OPLL (n = 18) and K-line (-) OPLL (n = 23) in the neck-flexed position. RESULTS: Recovery rate of JOA score (23.8%) of patients in the K-line (-) group was significantly lower (P = 0.028) than that (46.3%) of K-line (+) group in the neck-flexed position. In the K-line (+) group, significant improvements were seen in all JOA-score items except bladder function; however, in the K-line (-) group, improvements were seen only in upper- and the lower-extremity sensory functions. In the K-line (+) group, mean GR and FT tests significantly improved, but in the K-line (-) group, only mean FT test significantly improved. CONCLUSION: The K-line (-) OPLL in the neck-flexed position is a risk factor for poor clinical outcome after cervical laminoplasty. LEVEL OF EVIDENCE: 4. PMID- 27120064 TI - Pharmacokinetic comparison of different flubendazole formulations in pigs: A further contribution to its development as a macrofilaricide molecule. AB - Despite the well established ivermectin activity against microfilaria, the success of human filariasis control programmes requires the use of a macrofilaricide compound. Different in vivo trials suggest that flubendazole (FLBZ), an anthelmintic benzimidazole compound, is a highly efficacious and potent macrofilaricide. However, since serious injection site reactions were reported in humans after the subcutaneous FLBZ administration, the search for alternative pharmaceutical strategies to improve the systemic availability of FLBZ has acquired special relevance both in human and veterinary medicine. The goal of the current experimental work was to compare the pharmacokinetic plasma behavior of FLBZ, and its metabolites, formulated as either an aqueous hydroxypropyl- beta -cyclodextrin-solution (HPBCD), an aqueous carboxymethyl cellulose-suspension (CMC) or a Tween 80-based formulation, in pigs. Animals were allocated into three groups and treated (2 mg/kg) with FLBZ formulated as either a HPBCD-solution (oral), CMC-suspension (oral) or Tween 80-based formulation (subcutaneous). Only trace amounts of FLBZ parent drug and its reduced metabolite were measured after administration of the different FLBZ formulations in pigs. The hydrolyzed FLBZ (H-FLBZ) metabolite was the main analyte recovered in the bloodstream in pigs treated with the three experimental FLBZ formulations. The oral administration of the HPBCD-solution accounted for significantly higher (P < 0.05) Cmax and AUC (23.1 +/- 4.4 MUg h/mL) values for the main metabolite (H FLBZ), compared with those observed for the oral CMC-suspension (AUC = 3.5 +/- 1.0 MUg h/mL) and injectable Tween 80-based formulation (AUC: 7.5 +/- 1.7 MUg h/mL). The oral administration of the HPBCD-solution significantly improved the poor absorption pattern (indirectly assessed as the H-FLBZ plasma concentrations) observed after the oral administration of the FLBZ-CMC suspension or the subcutaneous injection of the Tween 80 FLBZ formulation to pigs. Overall, the work reported here indicates that FLBZ pharmacokinetic behavior can be markedly changed by the pharmaceutical formulation. PMID- 27120065 TI - Therapeutic effects of acetylspiramycin and garlicin on cryptosporidiosis among drug users. AB - Cryptosporidiosis affects humans of all ages, particularly malnourished children and those with compromised immune systems such as HIV/AIDS. This study investigated the therapeutic effects of acetylspiramycin and garlicin on Cryptosporidium infection in institutionalized male drug users receiving rehabilitative treatment. Examination of stool specimens from 903 drug users via modified acid-fast bacilli staining resulted in 172 positive cases. Among them 151 subjects consented to participate in a randomized trial of acetylspiramycin and garlicin in four groups: acetylspiramycin plus garlicin, acetylspiramycin only, garlicin only, and placebo control. The cryptosporidiosis rate was higher in younger subjects with longer drug use history than subjects who are older with shorter history of drug use. After two segments of treatments, 76.2% of the cases achieved negative test results, with the four groups achieving the rates of 92.1%, 76.7%, 72.2%, and 61.8%, respectively (chi(2) = 9.517, P = 0.023). These results indicate clinical potential of garlicin in conjunction with acetylspiramycin in treating cryptosporidiosis. PMID- 27120066 TI - Sesquiterpene lactone containing extracts from two cultivars of forage chicory (Cichorium intybus) show distinctive chemical profiles and in vitro activity against Ostertagia ostertagi. AB - The study investigated direct anthelmintic effects of sesquiterpene lactones (SL) containing extracts from forage chicory against free-living and parasitic stages of Ostertagia ostertagi. Freeze-dried leaves from chicory cultivars 'Spadona' and 'Puna II' were extracted using methanol/water. Total SL were further fractionated by solid-phase extraction and resulting extracts were characterised by high performance liquid chromatography (HPLC). O. ostertagi eggs from faeces of mono infected calves were hatched and L1 were used in a larval feeding inhibition assay (LFIA), while cultured L3 were used in a larval exsheathment inhibition assay (LEIA). Adult worms were immediately recovered after slaughter and used for motility inhibition assays (AMIA). Electron microscopy (EM) was performed on adult O. ostertagi exposed to 1000 MUg extract mL(-1) of both chicory cultivars. In all assays, decreasing concentrations of SL-containing extracts in PBS (1% DMSO) were tested in replicates with 1% DMSO in PBS as negative controls. HPLC demonstrated similar concentrations of most SL in both extracts. However, Spadona extract contained significantly higher concentrations of 11, 13-dihydro-8 deoxylactucin (P = 0.01), while Puna II-extract had increased levels of 11, 13 dihydrolactucin (P < 0.0001). In the LFIA, both extracts reduced larval feeding at increasing concentrations, but Spadona-extract showed higher potency confirmed by significantly lower EC50 (P < 0.0001). In the LEIA, neither of the two extracts interfered with the exsheathment of L3 (P > 0.05). In the AMIA, both SL containing extracts induced a dose-dependent effect but Spadona-extract showed greater activity and exerted faster worm paralysis than Puna II-extract with significantly lower EC50 (P < 0.0001). No cuticular damage was observed by EM in worms exposed to any of the extracts. We have demonstrated that SL-containing extracts from forage chicory can inhibit feeding of free-living larvae and exert direct effects against parasitic stages of O. ostertagi. Our results may contribute to the identification of natural anti-parasitic compounds and to interpret the in vivo anthelmintic effects of forage chicory. PMID- 27120067 TI - Histone deacetylase enzymes as drug targets for the control of the sheep blowfly, Lucilia cuprina. AB - The Australian sheep blowfly, Lucilia cuprina, is an ecto-parasite that causes significant economic losses in the sheep industry. Emerging resistance to insecticides used to protect sheep from this parasite is driving the search for new drugs that act via different mechanisms. Inhibitors of histone deacetylases (HDACs), enzymes essential for regulating eukaryotic gene transcription, are prospective new insecticides based on their capacity to kill human parasites. The blowfly genome was found here to contain five HDAC genes corresponding to human HDACs 1, 3, 4, 6 and 11. The catalytic domains of blowfly HDACs 1 and 3 have high sequence identity with corresponding human and other Dipteran insect HDACs (Musca domestica and Drosophila melanogaster). On the other hand, HDACs 4, 6 and 11 from the blowfly and the other Dipteran species showed up to 53% difference in catalytic domain amino acids from corresponding human sequences, suggesting the possibility of developing HDAC inhibitors specific for insects as desired for a commercial insecticide. Differences in transcription patterns for different blowfly HDACs through the life cycle, and between the sexes of adult flies, suggest different functions in regulating gene transcription within this organism and possibly different vulnerabilities. Data that supports HDACs as possible new insecticide targets is the finding that trichostatin A and suberoylanilide hydroxamic acid retarded growth of early instar blowfly larvae in vitro, and reduced the pupation rate. Trichostatin A was 8-fold less potent than the commercial insecticide cyromazine in inhibiting larval growth. Our results support further development of inhibitors of blowfly HDACs with selectivity over human and other mammalian HDACs as a new class of prospective insecticides for sheep blowfly. PMID- 27120068 TI - Selection for anthelmintic resistant Teladorsagia circumcincta in pre-weaned lambs by treating their dams with long-acting moxidectin injection. AB - Administration of long-acting anthelmintics to pregnant ewes prior to lambing is a common practice in New Zealand. Today, most of these products contain macrocyclic lactone (ML) actives, which because of their lipophilic nature, are detectable in the milk of treated animals and in the plasma of their suckling offspring. This study was conducted to confirm the transfer of ML actives to lambs in the ewe's milk, and to assess whether this could result in selection for ML resistant nematodes in the lamb. Ninety, twin bearing Romney ewes were treated before lambing with a long-acting injectable formulation of moxidectin, a 100-day controlled release capsule (CRC) containing abamectin and albendazole, or remained untreated. After lambing, seven ewes from each treatment group were selected for uniformity of lambing date and, along with their twin lambs, relocated indoors. At intervals, all ewes and lambs were bled, and samples of ewe's milk were collected, for determination of drug concentrations. Commencing 4 weeks after birth all lambs were dosed weekly with 250 infective larvae (L3) of either an ML-susceptible or -resistant isolate of Teladorsagia circumcinta. At 12 weeks of age all lambs were slaughtered and their abomasa recovered for worm counts. Moxidectin was detected in the plasma of moxidectin-treated ewes until about 50 days after treatment and in their lambs until about day 60. Abamectin was detected in the plasma of CRC-treated ewes until the last sample on day 80 and in the plasma of their lambs until about day 60. Both actives were detectable in milk of treated ewes until day 80 after treatment. Establishment of resistant L3 was not different between the treatment groups but treatment of ewes with moxidectin reduced establishment of susceptible L3 by 70%, confirming the potential of drug transfer in milk to screen for ML-resistance in the suckling lamb. PMID- 27120069 TI - Development and application of a sensitive, phenotypic, high-throughput image based assay to identify compound activity against Trypanosoma cruzi amastigotes. AB - We have developed a high content 384-well, image-based assay to estimate the effect of compound treatment on Trypanosoma cruzi amastigotes in 3T3 fibroblasts. In the same well, the effect of compound activity on host cells can also be determined, as an initial indicator of cytotoxicity. This assay has been used to identify active compounds from an in-house library of compounds with either known biological activity or that are FDA approved, and separately, from the Medicines for Malaria Venture Malaria Box collection. Active compounds were screened against T. cruzi trypomastigotes, utilising an assay developed with the viability dye resazurin. Twelve compounds with reconfirmed solid sample activity, with IC50 values of less than 10 MUM and selectivity indices to T. cruzi amastigotes over 3T3 host cells of between >22 and 319 times were identified from these libraries. As 3T3 cells are contact inhibited, with limited proliferation in the assay, selective compounds of interest were profiled in a separate assay to estimate the viability of compound treated, replicating HEK293 cells. Selective compounds that were not previously reported in the literature were further profiled by extending the incubation time against amastigote infected 3T3 cells to determine if there were residual amastigotes post-treatment, important for the consideration of the exposure time required for further biological characterisation. The assay development process and the suitability of identified compounds as hit molecules for Chagas disease research are discussed. PMID- 27120070 TI - Institutional Delivery and Satisfaction among Indigenous and Poor Women in Guatemala, Mexico, and Panama. AB - Indigenous women in Mesoamerica experience disproportionately high maternal mortality rates and are less likely to have institutional deliveries. Identifying correlates of institutional delivery, and satisfaction with institutional deliveries, may help improve facility utilization and health outcomes in this population. We used baseline surveys from the Salud Mesoamerica Initiative to analyze data from 10,895 indigenous and non-indigenous women in Guatemala and Mexico (Chiapas State) and indigenous women in Panama. We created multivariable Poisson regression models for indigenous (Guatemala, Mexico, Panama) and non indigenous (Guatemala, Mexico) women to identify correlates of institutional delivery and satisfaction. Compared to their non-indigenous peers, indigenous women were substantially less likely to have an institutional delivery (15.2% vs. 41.5% in Guatemala (P<0.001), 29.1% vs. 73.9% in Mexico (P<0.001), and 70.3% among indigenous Panamanian women). Indigenous women who had at least one antenatal care visit were more than 90% more likely to have an institutional delivery (adjusted risk ratio (aRR) = 1.94, 95% confidence interval (CI): 1.44 2.61), compared to those who had no visits. Indigenous women who were advised to give birth in a health facility (aRR = 1.46, 95% CI: 1.18-1.81), primiparous (aRR = 1.44, 95% CI: 1.24-1.68), informed that she should have a Caesarean section (aRR = 1.41, 95% CI: 1.21-1.63), and had a secondary or higher level of education (aRR = 1.36, 95% CI: 1.04-1.79) also had substantially higher likelihoods of institutional delivery. Satisfaction among indigenous women was associated with being able to be accompanied by a community health worker (aRR = 1.15, 95% CI: 1.05-1.26) and facility staff speaking an indigenous language (aRR = 1.10, 95% CI: 1.02-1.19). Additional effort should be exerted to increase utilization of birthing facilities by indigenous and poor women in the region. Improving access to antenatal care and opportunities for higher-level education may increase institutional delivery rates, and providing culturally adapted services may improve satisfaction. PMID- 27120071 TI - Parkinsonism and dementia are negative prognostic factors for the outcome of subdural hematoma. AB - To determine, among a population with subdural hematoma (SH), whether patients affected by neurodegenerative disorders (parkinsonism and dementia) have a worse clinical outcome. We reviewed the data of patients diagnosed with fall-related SH discharged from the Departments of Neurology/Stroke unit, Neurosurgery, Intensive Care Unit at Brotzu General Hospital (Cagliari, Italy) between January 2010 and December 2013. Patients with severe traumatisms, evidence of spontaneous intracerebral bleeding or aged less than 50 were excluded. 332 patients were selected: 69 with a neurodegenerative parkinsonism or dementia (N-group), 217 with history of chronic non-neurological medical conditions with significant disability, previous falls and/or balance problems (NND-group) and 46 with a history of "minor" chronic non-neurological disorder. (NN-group). The clinical status at admission and discharge was assessed by modified Rankin Scale (mRS). The time-span between trauma and hospital admission was also calculated. At hospital admission we found a significantly longer delay in SH's diagnosis (chi (2) test p < 0.001) and a worse mRS score (Kruskal Wallis p < 0.001) in the N group compared to both NN and NND-groups. During hospital stay we observed the lack of significant variation in mRS score in N-group (Wilcoxon test p = 0.86), in contrast with NN and NND-groups who significantly improved (Wilcoxon test p < 0.001). Our results demonstrate that the consequences of SH are more severe in the N-group compared to NN and NND-groups. The longer interval between trauma and hospital admittance plays a critical role in worsening the outcome of patients with parkinsonism and dementia compared to subjects without neurodegenerative disorders. PMID- 27120072 TI - Association of post stroke depression with social factors, insomnia, and neurological status in Chinese elderly population. AB - The purpose of this study was to investigate the association of post stroke depression (PSD) with social factors, insomnia, and neurological status among elderly Chinese patients with ischemic stroke. Six hundred and eight patients over 60 years of age, who had suffered from a first episode of ischemic stroke within 7 days, were enrolled into the study. They were divided into PSD and non PSD groups according to the Self-rating Depression Scale (SDS) scores. The association of PSD with social factors, insomnia, and neurological status was analyzed using multivariable logistic regression analysis. Compared with the patients who did not develop PSD, those with PSD reported adverse life events more frequently, and more subjects with PSD lived alone, had left carotid artery infarction and cortical infarction (P < 0.05), history of insomnia, and high National Institute of Health Stroke Scale (NIHSS) scores and low Barthel Index (BI) scores (P < 0.01). The multivariable logistic regression analysis showed that the occurrence of PSD was associated with a history of insomnia (HR = 1.59, 95 % CI 1.12-2.36, P < 0.01), NIHSS scores (HR = 2.45, 95 % CI 1.42-3.91, P < 0.01) and BI scores (HR = 2.56, 95 % CI 1.39-4.25, P < 0.01). Insomnia and the degree of neurological deficit were associated with PSD in an elderly population of Chinese people. PMID- 27120073 TI - Effect of varus and valgus alignment on implant loading after proximal femur fracture fixation. AB - INTRODUCTION: More than 10 % of proximal femur fractures repaired with either a sliding hip screw and side plate (SHS-P) or a sliding hip screw and intramedullary nail (SHS-IMN) demonstrate varus malreduction. The purpose of this study was to compare the effect of varus or valgus loading on comminuted intertrochanteric fractures repaired with SHS-P or SHS-IMN constructs. METHODS: Unstable intertrochanteric fractures with segmental comminution were generated in 12 cadaver proximal femurs, six of which were fixed with an SHS-P and six with an SHS-IMN. Both implants had a strain gauge at the lag screw-nail-plate interface to assess implant load bearing. The load on the implants was measured with the specimens in neutral position and at 5 degrees , 10 degrees , and 15 degrees of varus and valgus. RESULTS: Loads on both SHS-IMN and SHS-P constructs were significantly increased when loading the implants in varus and significantly decreased when loading the implants in valgus. Unlike the SHS-IMN, the SHS-P trended toward increased load bearing at 15 degrees varus (159.1 vs. 118.5 %, P = .065) and trended toward less load bearing at 15 degrees valgus (42.3 vs. 59.8 %, P = .06). CONCLUSIONS: Regardless of implant choice, avoiding varus loading on the fixation construct reduces the load on the implant. SHS-P constructs may be more affected by varus or valgus malalignment than SHS-IMN constructs. PMID- 27120074 TI - Evaluating the performance of the quick CSF method in detecting contrast sensitivity function changes. AB - The contrast sensitivity function (CSF) has shown promise as a functional vision endpoint for monitoring the changes in functional vision that accompany eye disease or its treatment. However, detecting CSF changes with precision and efficiency at both the individual and group levels is very challenging. By exploiting the Bayesian foundation of the quick CSF method (Lesmes, Lu, Baek, & Albright, 2010), we developed and evaluated metrics for detecting CSF changes at both the individual and group levels. A 10-letter identification task was used to assess the systematic changes in the CSF measured in three luminance conditions in 112 naive normal observers. The data from the large sample allowed us to estimate the test-retest reliability of the quick CSF procedure and evaluate its performance in detecting CSF changes at both the individual and group levels. The test-retest reliability reached 0.974 with 50 trials. In 50 trials, the quick CSF method can detect a medium 0.30 log unit area under log CSF change with 94.0% accuracy at the individual observer level. At the group level, a power analysis based on the empirical distribution of CSF changes from the large sample showed that a very small area under log CSF change (0.025 log unit) could be detected by the quick CSF method with 112 observers and 50 trials. These results make it plausible to apply the method to monitor the progression of visual diseases or treatment effects on individual patients and greatly reduce the time, sample size, and costs in clinical trials at the group level. PMID- 27120075 TI - Potential role for microfluctuations as a temporal directional cue to accommodation. AB - The goal was to revisit an important, yet unproven notion that accommodative microfluctuations facilitate the determination of direction (sign) of abrupt focus changes in the stimulus to accommodation. We contaminated the potential temporal cues from natural accommodative microfluctuations by presenting uncorrelated external (screen) temporal defocus noise that combined with the retinal image effects of natural microfluctuations. A polychromatic Maltese spoke pattern thus either modulated defocus at a combination of two temporal frequencies (on-screen noise condition) or was static (control condition). The on screen conditions were combined with step changes in optical vergence that were randomized in direction and magnitude. Five subjects monocularly viewed stimuli through a Badal optical system in a Maxwellian view. An artificial 4-mm aperture was imaged at the entrance pupil of the eye. Wavefront aberrations were measured dynamically at 50 Hz using a custom Shack-Hartmann aberrometer. Dynamic changes in the Zernike defocus term with step changes in optical vergence were analyzed. We calculated the percentage of correct directional responses for 1, 2, and 3 D accommodative and disaccommodative step stimuli using preset criteria for latency, velocity, and persistence of the response. The on-screen noise condition reduced the percent-correct responses compared to the static stimulus, suggesting that this manipulation affected the detectability of the sign of the accommodative stimulus. Several possible reasons and implications of this result are discussed. PMID- 27120076 TI - Three-Way-Switchable (Right/Left/OFF) Selective Reflection of Circularly Polarized Light on Solid Thin Films of Helical Polymer Blends. AB - Two poly(quinoxaline-2,3-diyl) copolymers bearing miscibility-enhancing 8 chlorooctyloxy and (S)-2-methylbutoxy or n-butoxy side chains were synthesized. After annealing in CHCl3 vapor, a polymer-blend film of these copolymers exhibited selective reflection of right-handed circularly polarized light (CPL) in the visible region. The handedness of the CPL reflected was completely inverted upon annealing of the film in THF vapor. Annealing in n-hexane vapor resulted in the phase separation of the polymer blend, which turned the selective reflection off. This three-way-switchable reflection, that is, reflection of right-handed or left-handed CPL, together with an OFF state, could be observed visually through right- and left-handed CPL filters. PMID- 27120078 TI - pH-Sensitive Polymeric Nanoparticles Modulate Autophagic Effect via Lysosome Impairment. AB - In drug delivery systems, pH-sensitive polymers are commonly used as drug carriers, and significant efforts have been devoted to the aspects of controlled delivery and release of drugs. However, few studies address the possible autophagic effects on cells. Here, for the first time, using a fluorescent autophagy-reporting cell line, this study evaluates the autophagy-induced capabilities of four types of pH-sensitive polymeric nanoparticles (NPs) with different physical properties, including size, surface modification, and pH sensitivity. Based on experimental results, this study concludes that pH sensitivity is one of the most important factors in autophagy induction. In addition, this study finds that variation of concentration of NPs could cause different autophagic effect, i.e., low concentration of NPs induces autophagy in an mTOR-dependent manner, but high dose of NPs leads to autophagic cell death. Identification of this tunable autophagic effect offers a novel strategy for enhancing therapeutic effect in cancer therapy through modulation of autophagy. PMID- 27120077 TI - Exome Sequencing of Familial Bipolar Disorder. AB - IMPORTANCE: Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing. OBJECTIVE: To utilize a combined family-based and case-control approach to exome sequencing in BD using multiplex families as an initial discovery strategy, followed by association testing in a large case-control meta-analysis. DESIGN, SETTING, AND PARTICIPANTS: We performed exome sequencing of 36 affected members with BD from 8 multiplex families and tested rare, segregating variants in 3 independent case-control samples consisting of 3541 BD cases and 4774 controls. MAIN OUTCOMES AND MEASURES: We used penalized logistic regression and 1-sided gene-burden analyses to test for association of rare, segregating damaging variants with BD. Permutation-based analyses were performed to test for overall enrichment with previously identified gene sets. RESULTS: We found 84 rare (frequency <1%), segregating variants that were bioinformatically predicted to be damaging. These variants were found in 82 genes that were enriched for gene sets previously identified in de novo studies of autism (19 observed vs. 10.9 expected, P = .0066) and schizophrenia (11 observed vs. 5.1 expected, P = .0062) and for targets of the fragile X mental retardation protein (FMRP) pathway (10 observed vs. 4.4 expected, P = .0076). The case-control meta-analyses yielded 19 genes that were nominally associated with BD based either on individual variants or a gene-burden approach. Although no gene was individually significant after correction for multiple testing, this group of genes continued to show evidence for significant enrichment of de novo autism genes (6 observed vs 2.6 expected, P = .028). CONCLUSIONS AND RELEVANCE: Our results are consistent with the presence of prominent locus and allelic heterogeneity in BD and suggest that very large samples will be required to definitively identify individual rare variants or genes conferring risk for this disorder. However, we also identify significant associations with gene sets composed of previously discovered de novo variants in autism and schizophrenia, as well as targets of the FRMP pathway, providing preliminary support for the overlap of potential autism and schizophrenia risk genes with rare, segregating variants in families with BD. PMID- 27120079 TI - Factors affecting turnover intentions among public hospital doctors in a middle level city in central China. AB - Objective The aim of the present study was to explore prominent factors affecting turnover intentions among public hospital doctors in urban areas, particularly in Xiangyang City, Hubei Province, a middle-level city in central China. Methods Questionnaires were used to collect data from 284 public hospital doctors. Pearson's Chi-squared was used to assess whether sociodemographic and other factors were related to the turnover intentions of public hospital doctors. Binary logistic regression was performed to determine the significant factors that influence turnover intentions. Results The analysis revealed that 28.2% of public hospital doctors intended to leave the hospital where they were currently employed. Dissatisfaction with working conditions and hospital management processes, as well as work pressures, were significant factors contributing to the turnover intentions of public hospital doctors. Conclusion Research into turnover intentions indicates that public hospital doctors surveyed in urban China give greater weight to their professional environment and career development rather than salary in their employment decisions. What is known about the topic? Turnover of medical staff is a concern to hospital administrators because it is costly and detrimental to organisational performance and quality of care. Most studies have focused on the effects of individual and organisational factors on nurses' intentions to leave their employment. Income dissatisfaction was one of the determining factors of turnover intentions in previous studies. What does this paper add? The satisfaction of public hospital doctors with regard to income is not a determining factor of turnover intentions. In contrast with findings of previous studies, the doctors in public hospitals in urban China in the present study gave greater weight to their professional environment and career development in their employment decisions. What are the implications for practitioners? The findings suggest that health service managers and policy makers should pay greater attention to the factors affecting public hospital doctors' turnover intentions. This study will be useful for optimising public hospital management and minimising the turnover of doctors in China. PMID- 27120080 TI - A multiplayer game: species of Clostridium, Acinetobacter, and Pseudomonas are responsible for the persistence of antibiotic resistance genes in manure-treated soils. AB - Antibiotics are routinely used in modern livestock farming. The manure from medicated animals is used for the fertilization of arable crops, which in turn leads to the accumulation of antibiotic resistance genes (ARGs) in the environment. This is a potentially serious public health issue, yet the identities of the bacterial taxa involved in ARG persistence are as yet undetermined. Using soil-manure microcosm experiments, we investigated the relationship between (i) the persistence of diverse ARGs and (ii) the dynamics of bacterial community members. We were able to identify, for the first time, the bacterial taxa involved in ARG enrichment in manured soils. They were gut associated Clostridium species, and environmental species of Acinetobacter and Pseudomonas genera, all of them closely related to important nosocomial pathogens. Our data provide new clues on the routes by which ARGs may spread from farms to medical clinics. PMID- 27120081 TI - The Evolution of Quorum Sensing as a Mechanism to Infer Kinship. AB - Bacteria regulate many phenotypes via quorum sensing systems. Quorum sensing is typically thought to evolve because the regulated cooperative phenotypes are only beneficial at certain cell densities. However, quorum sensing systems are also threatened by non-cooperative "cheaters" that may exploit quorum-sensing regulated cooperation, which begs the question of how quorum sensing systems are maintained in nature. Here we study the evolution of quorum sensing using an individual-based model that captures the natural ecology and population structuring of microbial communities. We first recapitulate the two existing observations on quorum sensing evolution: density-dependent benefits favor quorum sensing but competition and cheating will destabilize it. We then model quorum sensing in a dense community like a biofilm, which reveals a novel benefit to quorum sensing that is intrinsically evolutionarily stable. In these communities, competing microbial genotypes gradually segregate over time leading to positive correlation between density and genetic similarity between neighboring cells (relatedness). This enables quorum sensing to track genetic relatedness and ensures that costly cooperative traits are only activated once a cell is safely surrounded by clonemates. We hypothesize that under similar natural conditions, the benefits of quorum sensing will not result from an assessment of density but from the ability to infer kinship. PMID- 27120083 TI - Infusion Rate Dependent Pharmacokinetics of Bendamustine with Altered Formation of gamma-hydroxybendamustine (M3) Metabolite Following 30- and 60-min Infusion of Bendamustine in Rats. AB - Bendamustine is an alkylating agent administered as 1 h intravenous infusion in the clinic for the treatment of malignant haematological cancers. The aim of the study was to evaluate the pharmacokinetics of bendamustine and its key cytochrome P 450 (CYP) 1A2 mediated gamma-hydroxybendamustine (M3) metabolite after 30- and 60-min intravenous infusion of bendamustine in rats. 2 groups were assigned to receive bendamustine either as 30- or 60-min infusion and doses were normalized to 15 mg/kg for the sake of statistical evaluation. Serial pharmacokinetic samples were collected and were analysed for the circulatory levels of bendamustine and its M3 metabolite. Standard pharmacokinetic parameters were generated for bendamustine and its M3 metabolite. Regardless of the intravenous regimens, Cmax coincided with end of infusion for both bendamustine and its M3 metabolite. Immediately after stoppage of infusion, a rapid decline in the plasma levels occurred for both bendamustine and M3 metabolite. The Cmax and AUC0 infinity parameters for bendamustine after 60-min infusion were 1.90 and 1.34 fold higher; while CL was lower by 1.32-fold as compared to the 30-min infusion. In contrast, the Cmax and AUC0-infinity after 30-min infusion for the M3 metabolite was 2.15- and 2.78-fold greater; while CL was 2.32-fold lower when compared to the 60-min infusion. However, T1/2 and Vz values were similar between the 2 intravenous treatments for bendamustine or the M3 metabolite. The data unequivocally confirmed the existence of differential pharmacokinetics of bendamustine and its M3 metabolite as the function of the duration of intravenous infusion. PMID- 27120082 TI - Effect of atorvastatin on the incidence of acute kidney injury following valvular heart surgery: a randomized, placebo-controlled trial. AB - PURPOSE: Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have the potential to reduce acute kidney injury (AKI) after cardiac surgery through their pleiotropic properties. Here we studied the preventive effect of atorvastatin on AKI after valvular heart surgery. METHODS: Two-hundred statin-naive patients were randomly allocated to receive either statin or placebo. Atorvastatin was administered orally to the statin group according to a dosage schedule (80 mg single dose on the evening prior to surgery; 40 mg on the morning of surgery; three further doses of 40 mg on the evenings of postoperative days 0, 1, and 2). AKI incidence was assessed during the first 48 postoperative hours on the basis of Acute Kidney Injury Network criteria. RESULTS: The incidence of AKI was similar in the statin and control groups (21 vs. 26 %, respectively, p = 0.404). Biomarkers of renal injury including plasma neutrophil gelatinase-associated lipocalin and interleukin-18 were also similar between the groups. The statin group required significantly less norepinephrine and vasopressin during surgery, and fewer patients in the statin group required vasopressin. There were no significant differences in postoperative outcomes. CONCLUSIONS: Acute perioperative statin treatment was not associated with a lower incidence of AKI or improved clinical outcome in patients undergoing valvular heart surgery. (ClinicalTrials.gov NCT01909739). PMID- 27120084 TI - Ascorbic Acid Attenuates Hyperoxia-Compromised Host Defense against Pulmonary Bacterial Infection. AB - Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial infections, causing ventilator associated pneumonia. The phagocytic activity of macrophages is impaired by hyperoxia-induced increases in the levels of reactive oxygen species (ROS) and extracellular high-mobility group box protein B1 (HMGB1). Ascorbic acid (AA), an essential nutrient and antioxidant, has been shown to be beneficial in various animal models of ROS-mediated diseases. The aim of this study was to determine whether AA could attenuate hyperoxia-compromised host defense and improve macrophage functions against bacterial infections. C57BL/6 male mice were exposed to hyperoxia (>=98% O2, 48 h), followed by intratracheal inoculation with Pseudomonas aeruginosa, and simultaneous intraperitoneal administration of AA. AA (50 mg/kg) significantly improved bacterial clearance in the lungs and airways, and significantly reduced HMGB1 accumulation in the airways. The incubation of RAW 264.7 cells (a macrophage-like cell line) with AA (0-1,000 MUM) before hyperoxic exposure (95% O2) stabilized the phagocytic activity of macrophages in a concentration-dependent manner. The AA-enhanced macrophage function was associated with significantly decreased production of intracellular ROS and accumulation of extracellular HMGB1. These data suggest that AA supplementation can prevent or attenuate the development of ventilator-associated pneumonia in patients receiving oxygen support. PMID- 27120085 TI - Comparison of Cherenkov excited fluorescence and phosphorescence molecular sensing from tissue with external beam irradiation. AB - Ionizing radiation delivered by a medical linear accelerator (LINAC) generates Cherenkov emission within the treated tissue. A fraction of this light, in the 600-900 nm wavelength region, propagates through centimeters of tissue and can be used to excite optical probes in vivo, enabling molecular sensing of tissue analytes. The success of isolating the emission signal from this Cherenkov excitation background is dependent on key factors such as: (i) the Stokes shift of the probe spectra; (ii) the excited state lifetime; (iii) the probe concentration; (iv) the depth below the tissue surface; and (v) the radiation dose used. Previous studies have exclusively focused on imaging phosphorescent dyes, rather than fluorescent dyes. However there are only a few biologically important phosphorescent dyes and yet in comparison there are thousands of biologically relevant fluorescent dyes. So in this study the focus was a study of efficacy of Cherenkov-excited luminescence using fluorescent commercial near infrared probes, IRDye 680RD, IRDye 700DX, and IRDye 800CW, and comparing them to the well characterized phosphorescent probe Oxyphor PtG4, an oxygen sensitive dye. Each probe was excited by Cherenkov light from a 6 MV external radiation beam, and measured in continuous wave or time-gated modes. The detection was performed by spectrally resolving the luminescence signals, and measuring them with spectrometer-based separation on an ICCD detector. The results demonstrate that IRDye 700DX and PtG4 allowed for the maximal signal to noise ratio. In the case of the phosphorescent probe, PtG4, with emission decays on the microsecond (MUs) time scale, time-gated acquisition was possible, and it allowed for higher efficacy in terms of the probe concentration and detection depth. Phantoms containing the probe at 5 mm depth could be detected at concentrations down to the nanoMolar range, and at depths into the tissue simulating phantom near 3 cm. In vivo studies showed that 5 nmol of dye was readily detected with radiation doses less than 5 cGy. Since concentration, radiation dose and depth each contribute to the level of the detected signal, it may be possible to improve any of these parameters at expense of the others. This paradigm of nanoMolar sensitivity for optical reporters in vivo introduces the concept of molecular sensing of tumors during therapy or diagnostically with biologically relevant concentrations of fluorescent reporters. PMID- 27120086 TI - Single-molecule detection at high concentrations with optical aperture nanoantennas. AB - Single-molecule detection has become an indispensable technology in life science, and medical research. In order to get meaningful information on many biological processes, single-molecule analysis is required in micro-molar concentrations. At such high concentrations, it is very challenging to isolate a single molecule with conventional diffraction-limited optics. Recently, optical aperture nanoantennas (OANs) have emerged as a powerful tool to enhance the single molecule detection under a physiological environment. The OANs, which consist of nano-scale apertures on a metallic film, have the following unique properties: (1) nanoscale light confinement; (2) enhanced fluorescence emission; (3) tunable radiation pattern; (4) reduced background noise; and (5) massive parallel detection. This review presents the fundamentals, recent developments and future perspectives in this emerging field. PMID- 27120087 TI - Release of Escherichia coli from Foreshore Sand and Pore Water during Intensified Wave Conditions at a Recreational Beach. AB - Foreshore beach sands and pore water may act as a reservoir and nonpoint source of fecal indicator bacteria (FIB) to surface waters. This paper presents data collected at a fine sand beach on Lake Huron, Canada over three field events. The data show that foreshore sand erosion as wave height increases results in elevated Escherichia coli concentrations in surface water, as well as depletion of E. coli from the foreshore sand and pore water. E. coli initially attached to foreshore sand rather than initially residing in the pore water was found to be the main contributor to elevated surface water concentrations. Surface water E. coli concentrations were a function of not only wave height (and associated sand erosion) but also the time elapsed since a preceding period of high wave intensity. This finding is important for statistical regression models used to predict beach advisories. While calculations suggest that foreshore sand erosion may be the dominant mechanism for releasing E. coli to surface water during intensified wave conditions at a fine sand beach, comparative characterization of the E. coli distribution at a coarse sand-cobble beach suggests that interstitial pore water flow and discharge may be more important for coarser sand beaches. PMID- 27120088 TI - Initiator Control of Conjugated Polymer Topology in Ring-Opening Alkyne Metathesis Polymerization. AB - Molybdenum carbyne complexes [RC=Mo(OC(CH3)(CF3)2)3] featuring a mesityl (R = Mes) or an ethyl (R = Et) substituent initiate the living ring-opening alkyne metathesis polymerization of the strained cyclic alkyne, 5,6,11,12 tetradehydrobenzo[a,e][8]annulene, to yield fully conjugated poly(o-phenylene ethynylene). The difference in the steric demand of the polymer end-group (Mes vs Et) transferred during the initiation step determines the topology of the resulting polymer chain. While [MesC=Mo(OC(CH3)(CF3)2)3] exclusively yields linear poly(o-phenylene ethynylene), polymerization initiated by [EtC=Mo(OC(CH3)(CF3)2)3] results in cyclic polymers ranging in size from n = 5 to 20 monomer units. Kinetic studies reveal that the propagating species emerging from [EtC=Mo(OC(CH3)(CF3)2)3] undergoes a highly selective intramolecular backbiting into the butynyl end-group. PMID- 27120089 TI - The differentiation of amniotic fluid stem cells into sweat glandlike cells is enhanced by the presence of Sonic hedgehog in the conditioned medium. AB - After patients suffer severe full-thickness burn injuries, the current treatments cannot lead to the complete self-regeneration of the sweat gland structure and function. Therefore, it is important to identify new methods for acquiring sufficient functional sweat gland cells to restore skin function. In this study, we induced CD117+ human amniotic fluid stem (hAFS) cells to differentiate into sweat glandlike (hAFS-SG) cells based on the use of conditioned medium (CM) from the human sweat gland (hSG) cells. Real-time PCR and immunofluorescent staining were used to confirm the expression of the sweat gland-related genes Ectodysplasin-A (EDA), Ectodysplasin-A receptor (EDAR), keratin 8 (K8) and carcino-embryonic antigen (CEA). Transmission electron microscopy analysis shows that microvilli, the cellular structures that are typical for hSG cells, can also be observed on the membrane of the hAFS-SG cells. Our test for the calcium response to acetylcholine (Ach) proved that hAFS-SG cells have the potential to respond to Ach in a manner similar to normal sweat glands. A three-dimensional culture is an effective approach that stimulates the hAFS-SG cells to form tubular structures and drives hAFS-SG cells to mature into higher stage. We also found that epidermal growth factor enhances the efficiency of differentiation and that Sonic hedgehog is an important factor of the CM that influences sweat gland differentiation. Our study provides the basis for further investigations into novel methods of inducing stem cells to differentiate into sweat glandlike cells. PMID- 27120090 TI - Preparation and Characterization of Minoxidil Loaded Nanostructured Lipid Carriers. AB - Nanostructured lipid carriers (NLCs) are interesting delivery systems for enhancing the penetration of an active substance through the skin after topical administration. The present paper described the development of a novel NLCs for minoxidil (MXD) topical delivery. Stearic acid and oleic acid that showed the highest solubility for MXD were selected as solid lipid and liquid lipid, respectively, and the NLCs were prepared by hot high pressure homogenization method. The minoxidil loaded NLCs prepared accordingly to the optimal formulation exhibited spherical shape with a mean diameter of 281.4 +/- 7.4 nm, polydispersity of 0.207 +/- 0.009, zeta potential of -32.90 +/- 1.23 mV, drug entrapment efficiency of 92.48 +/- 0.31%, and drug loading of 13.85 +/- 0.47%. Storage stability studies demonstrated that the particle size and entrapment efficiency of the MXD-NLCs were not changed during 3 months both at 4 degrees C and room temperature. Moreover, the release of MXD from the NLCs was faster than drug release from SLNs. In vitro skin permeability test demonstrated that MXD NLCs had a more pronounced permeation and retention profile than MXD-SLNs. Furthermore, no erythema was observed after administration of MXD-NLCs. All these results indicated that the developed MXD-NLCs could be a promising and effective nanocarrier for topical delivery of MXD. PMID- 27120091 TI - Advances in Pretransplant Donor-Specific Antibody Testing in Solid Organ Transplantation: From Bench to Bedside. AB - Immunological risk stratification has a central role in determining both the feasibility of solid organ transplantation and the type (and amount) of induction and maintenance immunosuppressive therapy. Currently there is poor consensus on how to exactly estimate the global immunological risk, and most transplant centers adopt complicated internal guidelines for risk stratification. Here we systematically review published evidences that should drive appropriateness in risk stratification, focusing on donor-specific antibodies against HLA and other antigens. PMID- 27120093 TI - Singlet Halophenylcarbenes as Strong Hydrogen-Bond Acceptors. AB - Chlorophenylcarbene and fluorophenylcarbene were generated in water-doped argon matrices at cryogenic temperatures by photolysis of the corresponding matrix isolated diazirines. When diffusion of H2O in solid argon was induced by annealing of the matrices at temperatures above 20 K, hydrogen-bonded complexes between the carbenes and water were formed. UV photolysis of these complexes resulted in the formation of benzaldehyde and hydrogen halides HX. The same products were obtained after photolysis of the diazirines in amorphous water ice. Obviously, the primary insertion product of the carbenes into H-OH is unstable under these conditions, and benzaldehyde is formed via secondary photolysis. The stable primary photochemical insertion product of chlorophenylcarbene into an O-H bond was observed in the reaction of the carbene with methanol. PMID- 27120092 TI - No Evidence for Disease History as a Risk Factor for Narcolepsy after A(H1N1)pdm09 Vaccination. AB - OBJECTIVES: To investigate disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy. METHODS: Case-control study in Sweden. Cases included persons referred for a Multiple Sleep Latency Test between 2009 and 2010, identified through diagnostic sleep centres and confirmed through independent review of medical charts. Controls, selected from the total population register, were matched to cases on age, gender, MSLT-referral date and county of residence. Disease history (prescriptions and diagnoses) and vaccination history was collected through telephone interviews and population-based healthcare registers. Conditional logistic regression was used to investigate disease history before A(H1N1)pdm09 vaccination as a risk-factor for narcolepsy. RESULTS: In total, 72 narcolepsy cases and 251 controls were included (range 3-69 years mean19-years). Risk of narcolepsy was increased in individuals with a disease history of nervous system disorders (OR range = 3.6-8.8) and mental and behavioural disorders (OR = 3.8, 95% CI 1.6-8.8) before referral. In a second analysis of vaccinated individuals only, nearly all initial associations were no longer statistically significant and effect sizes were smaller (OR range = 1.3-2.6). A significant effect for antibiotics (OR = 0.4, 95% CI 0.2-0.8) and a marginally significant effect for nervous system disorders was observed. In a third case-only analysis, comparing cases referred before vaccination to those referred after; prescriptions for nervous system disorders (OR = 26.0 95% CI 4.0-170.2) and ADHD (OR = 35.3 95% CI 3.4-369.9) were statistically significant during the vaccination period, suggesting initial associations were due to confounding by indication. CONCLUSION: The findings of this study do not support disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy. PMID- 27120094 TI - Picky eating: Associations with child eating characteristics and food intake. AB - Food rejection behaviors such as picky eating are of concern for many parents and attempts to increase healthy food intake can cause distress at mealtimes. An important limitation in most of the picky eating studies is that they cover few characteristics of picky eating behaviors and use limited measures of food intake. The objective of this study was to explore the associations between picky eating, child eating characteristics, and food intake among toddlers 12-47.9 months old (n = 2371) using data from the 2008 Feeding Infants and Toddlers Study (FITS). Logistic regression was used to examine associations between demographic and feeding characteristics and picky eater status. Differences in food group intake between picky and non-picky eaters were analyzed. Picky eaters were more likely to be neophobic, texture resistant, and to eat only favorite foods, In addition, the parents of picky eaters tend to offer new food a greater number of times than those of non-picky eaters before deciding that the child does not like it. Picky eaters showed significant lower intakes of eggs, burritos/tacos/enchiladas/nachos and sandwiches than non-picky eaters. Picky eaters consumed fewer vegetables from the "other vegetables" category and less raw vegetables than non-picky eaters. Neophobia, eating only favorite foods and difficulties with texture are all important characteristics of picky eaters which need to be integrated in studies measuring picky eating behaviors. Food intake of picky eaters differs only slightly from non-picky eaters. Because picky eating is a major parental concern, feeding strategies and advice related to the relevant characteristics of picky eating behavior need to be developed and assessed for their effectiveness. PMID- 27120095 TI - The role of expectations in the effect of food cue exposure on intake. AB - Pre-exposure to food cues has often been shown to increase food intake, especially in restrained eaters. This study investigated the role of expectations in the effect of such pre-exposure on food intake. A sample of 88 undergraduate women was exposed to visual food cues (photos of grapes and chocolate-chip cookies). In a 2 * 2 * 2 design, participants were explicitly told to expect that they would be tasting and rating either grapes or chocolate-chip cookies. Participants subsequently completed an ostensible taste test, in which they tasted and rated either grapes or cookies, such that half were given the food that they had been led to expect and the other half were given the other food. Participants' restraint status (restrained versus unrestrained) was based on their scores on the Revised Restraint Scale (Herman & Polivy, 1980). A significant interaction between expected food and restraint status was found. When participants were led to expect that they would be tasting grapes, restrained and unrestrained eaters did not differ in their subsequent consumption (of either grapes or cookies). However, when participants were led to expect that they would be tasting cookies, restrained eaters ate significantly less (of both grapes and cookies) than did unrestrained eaters, even though craving ratings were similarly elevated for both restrained and unrestrained eaters. The findings are consistent with counteractive control theory in that restrained eaters who expected to eat a high caloric food may have been able to activate their dieting goal, thereby limiting their food intake. The findings further point to an important role for expectations in the understanding and regulation of food intake in restrained eaters. PMID- 27120096 TI - Erectile Dysfunction in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Outcomes from a Multi-Center Study and Risk Factor Analysis in a Single Center. AB - The aim of this study was to investigate the prevalence of erectile dysfunction (ED) in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and explore the influence of UPOINT domains, National Institutes of Health-CP symptom index (NIH-CPSI) and other factors on ED prevalence. This was a prospective study of consecutive patients with CP/CPPS seen at 11 tertiary hospitals during January-July 2014. ED was diagnosed as a score of<21 on the International Index of Erectile Function (IIEF-5). Patients from one center were evaluated by the UPOINT system and NIH-CPSI. Each patient was assessed using clinical examination, asocio-demographic questionnaire, the Patient Health Questionnaire (PHQ), the Pain Catastrophizing Scale (PCS), NIH-CPSI and IIEF 5.1406 patients from 11 centers (mean age, 32.18 years; range 18-60 years) were enrolled. ED was found in 638/1406 patients (45.4%), and was categorized as mild in 291(45.6%), moderate in 297(46.6%) and severe in50(7.7%). 192 patients from one center(mean age,31.3 years; range 18-57 years) were further studied.IIEF-5 score correlated negatively with NIH-CPSI(r = 0.251), PHQ (r = 0.355) and PCS (r = 0.322)scores (P<0.001).PHQ score correlated positively with NIH-CPSI (r = 0.586) and PCS(r = 0.662) scores (P<0.001).NIH-CPSI, PHQ, PCS and IIEF-5 scores did not differ significantly between class IIIA and IIIB CP/CPPS. Multivariate logistic regression showed that UPOINT psychological (P) domain and NIH-CPSI symptom severity were independent risk factors for ED in CP/CPPS. It is concluded that psychological factors and symptom severity are independent risk factors for ED in CP/CPPS. PMID- 27120097 TI - An Investigation of the Immediate Effect of Static Stretching on the Morphology and Stiffness of Achilles Tendon in Dominant and Non-Dominant Legs. AB - AIMS: This study was undertaken to investigate the immediate effect of static stretching on normal Achilles tendon morphology and stiffness, and the different effect on dominant and non-dominant legs; and to evaluate inter-operator and intra-operator reliability of using shear-wave elastography in measuring Achilles tendon stiffness. METHODS: 20 healthy subjects (13 males, 7 females) were included in the study. Thickness, cross-sectional area and stiffness of Achilles tendons in both legs were measured before and after 5-min static stretching using grey-scale ultrasound and shear-wave elastography. Inter-operator and intra operator reliability of tendon stiffness measurements of six operators were evaluated. RESULTS: Result showed that there was no significant change in the thickness and cross-sectional area of Achilles tendon after static stretching in both dominant and non-dominant legs (p > 0.05). Tendon stiffness showed a significant increase in non-dominant leg (p < 0.05) but not in dominant leg (p > 0.05). The inter-operator reliability of shear-wave elastography measurements was 0.749 and the intra-operator reliability ranged from 0.751 to 0.941. CONCLUSION: Shear-wave elastography is a useful and non-invasive imaging tool to assess the immediate stiffness change of Achilles tendon in response to static stretching with high intra-operator and inter-operator reliability. PMID- 27120098 TI - Exfoliated MoS2 in Water without Additives. AB - Many solution processing methods of exfoliation of layered materials have been studied during the last few years; most of them are based on organic solvents or rely on surfactants and other funtionalization agents. Pure water should be an ideal solvent, however, it is generally believed, based on solubility theories that stable dispersions of water could not be achieved and systematic studies are lacking. Here we describe the use of water as a solvent and the stabilization process involved therein. We introduce an exfoliation method of molybdenum disulfide (MoS2) in pure water at high concentration (i.e., 0.14 +/- 0.01 g L-1). This was achieved by thinning the bulk MoS2 by mechanical exfoliation between sand papers and dispersing it by liquid exfoliation through probe sonication in water. We observed thin MoS2 nanosheets in water characterized by TEM, AFM and SEM images. The dimensions of the nanosheets were around 200 nm, the same range obtained in organic solvents. Electrophoretic mobility measurements indicated that electrical charges may be responsible for the stabilization of the dispersions. A probability decay equation was proposed to compare the stability of these dispersions with the ones reported in the literature. Water can be used as a solvent to disperse nanosheets and although the stability of the dispersions may not be as high as in organic solvents, the present method could be employed for a number of applications where the dispersions can be produced on site and organic solvents are not desirable. PMID- 27120099 TI - Evolution of the Epidural Treatment of Sciatica Provides Excellent Historic Review with Incomplete Modern Evidence. PMID- 27120100 TI - Comparative Phylogeography Reveals Cryptic Diversity and Repeated Patterns of Cladogenesis for Amphibians and Reptiles in Northwestern Ecuador. AB - Comparative phylogeography allow us to understand how shared historical circumstances have shaped the formation of lineages, by examining a broad spectrum of co-distributed populations of different taxa. However, these types of studies are scarce in the Neotropics, a region that is characterized by high diversity, complex geology, and poorly understood biogeography. Here, we investigate the diversification patterns of five lineages of amphibians and reptiles, co-distributed across the Choco and Andes ecoregions in northwestern Ecuador. Mitochondrial DNA and occurrence records were used to determine the degree of geographic genetic divergence within species. Our results highlight congruent patterns of parapatric speciation and common geographical barriers for distantly related taxa. These comparisons indicate similar biological and demographic characteristics for the included clades, and reveal the existence of two new species of Pristimantis previously subsumed under P. walkeri, which we describe herein. Our data supports the hypothesis that widely distributed Chocoan taxa may generally experience their greatest opportunities for isolation and parapatric speciation across thermal elevational gradients. Finally, our study provides critical information to predict which unstudied lineages may harbor cryptic diversity, and how geology and climate are likely to have shaped their evolutionary history. PMID- 27120101 TI - Wafer-Scale and Wrinkle-Free Epitaxial Growth of Single-Orientated Multilayer Hexagonal Boron Nitride on Sapphire. AB - Large-scale growth of high-quality hexagonal boron nitride has been a challenge in two-dimensional-material-based electronics. Herein, we present wafer-scale and wrinkle-free epitaxial growth of multilayer hexagonal boron nitride on a sapphire substrate by using high-temperature and low-pressure chemical vapor deposition. Microscopic and spectroscopic investigations and theoretical calculations reveal that synthesized hexagonal boron nitride has a single rotational orientation with AA' stacking order. A facile method for transferring hexagonal boron nitride onto other target substrates was developed, which provides the opportunity for using hexagonal boron nitride as a substrate in practical electronic circuits. A graphene field effect transistor fabricated on our hexagonal boron nitride sheets shows clear quantum oscillation and highly improved carrier mobility because the ultraflatness of the hexagonal boron nitride surface can reduce the substrate induced degradation of the carrier mobility of two-dimensional materials. PMID- 27120102 TI - Sleep quantity and quality is not compromised during planned burn shifts of less than 12 h. AB - Planned burning is a preventative strategy aimed at decreasing fuel loads to reduce the severity of future wildfire events. During planned burn operations, firefighters can work long shifts. Furthermore, remote burning locations may require firefighters to sleep away from home between shifts. The existing evidence surrounding firefighters' sleep during such operations is exclusively anecdotal. The aims of the study were to describe firefighters' sleep during planned burn operations and evaluate the impact of the key operational factors (shift start time, shift length and sleeping location) that may contribute to inadequate sleep. Thirty-three salaried firefighters were recruited from Australia's fire agencies and sleep was measured objectively using wrist actigraphy for four weeks. All variables were examined in two conditions: (1) burn days, and (2) non-burn days. Time in bed, total sleep time, sleep latency and sleep efficiency were evaluated objectively. Subjective reports of pre- and post-sleep fatigue, sleep location, sleep quality, sleep quantity, number of times woken and sleep timing were also recorded. Analyses revealed no differences in measures of sleep quantity and quality when comparing non-burn and burn days. Total sleep time was less when planned burn shifts were >12 h. However, on burn days, work shift start time as well as sleeping location did not impact firefighters' sleep quantity. Self-reported levels of pre- and post-sleep fatigue were greater on burn days compared to non-burn days. These findings indicate that sleep quantity and quality are not compromised during planned burn operations <12 h in duration. PMID- 27120104 TI - Highlights in migraine electrophysiology: are controversies just reflecting disease heterogeneity? AB - PURPOSE OF REVIEW: In migraine, the brain is 'hyperresponsive', which refers to a deficit of habituation to repeated sensory stimuli between attacks. This deficit normalizes in peri-ictal and ictal phases. A decreased cortical preactivation of thalamo-cortical origin and an impaired intracortical inhibition are probably involved in its pathophysiology. RECENT FINDINGS: The reality of a habituation deficit of visual evoked potentials, a neurophysiological 'hallmark' of interictal migraine, has been questioned. Blinding may be an issue, but some genetic, environmental, or behavioural differences could also exist between populations. A habituation deficit is found interictally in other sensory modalities, and strongly depends on the time of the recordings within the migraine cycle. An impaired thalamocortical drive is demonstrated in interictal phase, and normalizes in ictal phase as well as in chronic migraine, where a strength enhancement of primary cortical activation is observed. An interictal dysexcitability, of subcortical or primary cortical origin, is suggested by magnetic stimulation. These phenomena could occur in varying degrees depending on patients and on the migraine cycle, and account for the heterogeneity of electrophysiological results. SUMMARY: Finding a reliable electrophysiological biomarker for such a multifaceted and cycling disease as migraine is still a challenge. A better standardization of protocols would be worthwhile. PMID- 27120103 TI - The Role of Psychoeducation in Trauma Recovery: Recommendations for Content and Delivery. AB - Providing trauma psychoeducation remains a highly popular intervention despite the fact that little remains known about how effective such information provision is for improving participant outcomes. In this article the author outlines recommendations that can be identified from available research on how to provide psychoeducation for trauma recovery. The author also describes suggested content areas and material to include in this psychoeducation, highlighting the importance of conducting trauma psychoeducation in a culturally-sensitive, human centered, and relationship-focused manner which emphasizes the value of building resiliency in response to trauma. PMID- 27120106 TI - Infant formula with galacto-oligosaccharides (OM55N) stimulates the growth of indigenous bifidobacteria in healthy term infants. AB - The objective of the study was to investigate whether an infant formula supplemented with galacto-oligosaccharides (GOS; OM55N) was able to stimulate the growth of indigenous bifidobacteria and to establish microbiota similar to that of breastfed infants. A randomised, double-blind, placebo-controlled trial was performed using 35 healthy term infants (31-54 days of age; 42+/-6 days) to determine whether infant formula with 0.3 g/dl GOS (OM55N) stimulated the growth of bifidobacteria in the infants' guts. At the trial onset and 2 weeks after, the infants' faecal samples were examined for microbiota composition (bacterial abundance and alpha-diversity) and faecal characteristics. Among the 35 infants, 5 were withdrawn and 8 were excluded from the final evaluation before breaking the blinding since the indigenous bifidobacteria were not detected at the trial onset. After 2 weeks, the abundance of Bifidobacteriaceae was significantly increased in the GOS feeding group compared to the control (+11.6+/-24.1% vs 3.9+/-13.0%; P=0.043). The Shannon index, which accounts for both abundance and evenness of the present species, was significantly decreased with GOS supplementation (-0.1+/-0.4 vs +0.4+/-0.4; P=0.014). Faecal characteristics such as pH and organic acids were similar in both groups, with no statistical differences. No adverse side effects related to the formula consumption were reported. Although the concentration of GOS was relatively low, the infant formula with GOS increased the abundance of bifidobacteria and resulted in a reduced alpha-diversity of the microbiota. PMID- 27120107 TI - Evaluation of Stump Pressure in Three Types of Appendectomy: Harmonic Scalpel, LigaSure, and Conventional Technique. AB - INTRODUCTION AND OBJECTIVE: Appendectomy is one of the most common operations carried out by general surgeons. The recent introduction of the alternative energy-based devices in surgery and their use in the laparoscopic appendectomy shortened the duration of operations, but these devices are used generally for meso dissection. These devices did not receive wide acceptance among surgeons as there is not enough evidence confirming their use in appendicular lumen operations. Our objective in this study was to test the safety of three types of appendectomy. MATERIALS AND METHODS: Twenty-four cases with right hemicolectomy or subtotal colectomy were enrolled into this study. The patients were distributed in three groups. After the colectomy specimen was removed, in Group 1 conventional appendectomy (it was dissected with mesoappendiceal fixation and with electro cauterization) was performed in the operating room, the appendicular stump was ligated with a silk suture; in Group 2 appendectomy was performed with LigaSureTM and the stump was closed also with LigaSure; in Group 3 appendectomy was performed with Harmonic ScalpelTM and the stump was closed also with Harmonic Scalpel. Stump opening pressures were measured in all patients in the groups. RESULTS: Three groups were compared in terms of age, gender, concomitant diseases, clinical diagnosis, previous operations, pathological findings, and applied maximum pressure levels. No statistical difference was detected among the groups. CONCLUSION: Appendectomies carried out with LigaSure and Harmonic Scalpel are as safe as appendectomies carried out with the conventional methods. PMID- 27120108 TI - Multiple sclerosis and risk of attempted and completed suicide - a cohort study. AB - BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. The relation between education level and suicidality has not been investigated in MS patients. Our objective was to estimate attempted suicide and completed suicide risks amongst MS patients. METHODS: A total of 29 617 Swedish MS patients were identified through the Swedish Patient Register and matched with 296 164 people without MS from the general population. Cox regression analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education and calendar period. RESULTS: The adjusted HR for attempted suicide amongst MS patients is 2.18 (95% CI 1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (95% CI 1.53-2.30). In both groups women are at higher risk of attempting suicide, whilst men are at higher risk of completing suicide. Education level is inversely associated with completed suicide amongst the non-MS cohort (0.68, 0.51-0.91), but not amongst MS patients (1.10, 0.60 2.04). CONCLUSION: Multiple sclerosis patients are at higher risk of both attempted and completed suicide. No evidence was found of an inverse association between educational level and risk of completed suicide amongst MS patients. PMID- 27120109 TI - Genetic enhancement of limb defects in a mouse model of Cornelia de Lange syndrome. AB - Cornelia de Lange Syndrome (CdLS) is characterized by a wide variety of structural and functional abnormalities in almost every organ system of the body. CdLS is now known to be caused by mutations that disrupt the function of the cohesin complex or its regulators, and studies of animal models and cell lines tell us that the effect of these mutations is to produce subtle yet pervasive dysregulation of gene expression. With many hundreds of mostly small gene expression changes occurring in every cell type and tissue, identifying the etiology of any particular birth defect is very challenging. Here we focus on limb abnormalities, which are commonly seen in CdLS. In the limb buds of the Nipbl-haploinsufficient mouse (Nipbl(+/-) mouse), a model for the most common form of CdLS, modest gene expression changes are observed in several candidate pathways whose disruption is known to cause limb abnormalities, yet the limbs of Nipbl(+/-) mice develop relatively normally. We hypothesized that further impairment of candidate pathways might produce limb defects similar to those seen in CdLS, and performed genetic experiments to test this. Focusing on Sonic hedgehog (Shh), Bone morphogenetic protein (Bmp), and Hox gene pathways, we show that decreasing Bmp or Hox function (but not Shh function) enhances polydactyly in Nipbl(+/-) mice, and in some cases produces novel skeletal phenotypes. However, frank limb reductions, as are seen in a subset of individuals with CdLS, do not occur, suggesting that additional signaling and/or gene regulatory pathways are involved in producing such dramatic changes. (c) 2016 Wiley Periodicals, Inc. PMID- 27120110 TI - Lipid dynamics in zebrafish embryonic development observed by DESI-MS imaging and nanoelectrospray-MS. AB - The zebrafish Danio rerio is a model vertebrate organism for understanding biological mechanisms. Recent studies have explored using zebrafish as a model for lipid-related diseases, for in vivo fish bioassays, and for embryonic toxicity experiments. Mass spectrometry (MS) and MS imaging are established tools for lipid profiling and spatial mapping of biomolecules and offer rapid, sensitive, and simple analytical protocols for zebrafish analysis. When ambient ionization techniques are used, ions are generated in native environmental conditions, requiring neither sample preparation nor separation of molecules prior to MS. We used two direct MS techniques to describe the dynamics of the lipid profile during zebrafish embryonic development from 0 to 96 hours post fertilization and to explore these analytical approaches as molecular diagnostic assays. Desorption electrospray ionization (DESI) MS imaging followed by nanoelectrospray (nESI) MS and tandem MS (MS/MS) were used in positive and negative ion modes, allowing the detection of a large variety of phosphatidylglycerols, phosphatidylcholines, phosphatidylinositols, free fatty acids, triacylglycerols, ubiquinone, squalene, and other lipids, and revealed information on the spatial distributions of lipids within the embryo and on lipid molecular structure. Differences were observed in the relative ion abundances of free fatty acids, triacylglycerols, and ubiquinone - essentially localized to the yolk - across developmental stages, whereas no relevant differences were found in the distribution of complex membrane glycerophospholipids, indicating conserved lipid constitution. Embryos exposed to trichloroethylene for 72 hours exhibited an altered lipid profile, indicating the potential utility of this technique for testing the effects of environmental contaminants. PMID- 27120111 TI - Review: Mechanochemistry of the kinesin-1 ATPase. AB - Kinesins are P-loop NTPases that can do mechanical work. Like small G-proteins, to which they are related, kinesins execute a program of active site conformational changes that cleaves the terminal phosphate from an NTP substrate. But unlike small G-proteins, kinesins can amplify and harness these conformational changes in order to exert force. In this short review I summarize current ideas about how the kinesin active site works and outline how the active site chemistry is coupled to the larger-scale structural cycle of the kinesin motor domain. Focusing largely on kinesin-1, the best-studied kinesin, I discuss how the active site switch machinery of kinesin cycles between three distinct states, how docking of the neck linker stabilizes two of these states, and how tension-sensitive and position-sensitive neck linker docking may modulate both the hydrolysis step of ATP turnover and the trapping of product ADP in the active site. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 476-482, 2016. PMID- 27120112 TI - Crystal Structure of Human E-Cadherin-EC1EC2 in Complex with a Peptidomimetic Competitive Inhibitor of Cadherin Homophilic Interaction. AB - Cadherins are transmembrane cell adhesion proteins whose aberrant expression often correlates with cancer development and proliferation. We report the crystal structure of an E-cadherin extracellular fragment in complex with a peptidomimetic compound that was previously shown to partially inhibit cadherin homophilic adhesion. The structure reveals an unexpected binding mode and allows the identification of a druggable cadherin interface, thus paving the way to a future structure-guided design of cell adhesion inhibitors against cadherin expressing solid tumors. PMID- 27120113 TI - A Hyper-Heuristic Ensemble Method for Static Job-Shop Scheduling. AB - We describe a new hyper-heuristic method NELLI-GP for solving job-shop scheduling problems (JSSP) that evolves an ensemble of heuristics. The ensemble adopts a divide-and-conquer approach in which each heuristic solves a unique subset of the instance set considered. NELLI-GP extends an existing ensemble method called NELLI by introducing a novel heuristic generator that evolves heuristics composed of linear sequences of dispatching rules: each rule is represented using a tree structure and is itself evolved. Following a training period, the ensemble is shown to outperform both existing dispatching rules and a standard genetic programming algorithm on a large set of new test instances. In addition, it obtains superior results on a set of 210 benchmark problems from the literature when compared to two state-of-the-art hyper-heuristic approaches. Further analysis of the relationship between heuristics in the evolved ensemble and the instances each solves provides new insights into features that might describe similar instances. PMID- 27120114 TI - Gray Box Optimization for Mk Landscapes (NK Landscapes and MAX-kSAT). AB - This article investigates Gray Box Optimization for pseudo-Boolean optimization problems composed of M subfunctions, where each subfunction accepts at most k variables. We will refer to these as Mk Landscapes. In Gray Box Optimization, the optimizer is given access to the set of M subfunctions. We prove Gray Box Optimization can efficiently compute hyperplane averages to solve non-deceptive problems in [Formula: see text] time. Bounded separable problems are also solved in [Formula: see text] time. As a result, Gray Box Optimization is able to solve many commonly used problems from the evolutional computation literature in [Formula: see text] evaluations. We also introduce a more general class of Mk Landscapes that can be solved using dynamic programming and discuss properties of these functions. For certain type of problems Gray Box Optimization makes it possible to enumerate all local optima faster than brute force methods. We also provide evidence that randomly generated test problems are far less structured than those found in real-world problems. PMID- 27120115 TI - Sexually Experienced Adolescents' Thoughts About Sexual Pleasure. AB - Little research on adolescents has examined developmentally normative facets of sexuality that are not obviously linked to physical health. The purpose of this secondary data analysis was to qualitatively analyze adolescents' thoughts about and experiences with sexual pleasure. The study sample consisted of 56 sexually experienced, ethnically diverse, predominantly female adolescents who were participating in a Web-based intervention to promote healthy sexual decision making. Comments on one message board, "Sexual Pleasure: Does It Matter to You?," provided an opportunity to examine adolescents' thoughts about and experiences with sexual pleasure, as well as their communication with partners about that topic. Adolescents' comments demonstrated that they experience difficulties with pleasure in their sexual relationships. Adolescents generally believed that men are more likely than women to feel pleasure due to differences that include biology, understanding of one's body, and control over partnered sexual behavior. Adolescents defined inequality of received pleasure differently and discussed contexts in which inequality may be acceptable. Adolescents expressed motivation to communicate with partners about sexual pleasure. However, their statements suggested they often lack the skills to do so. Future prevention and intervention programs should equip adolescents with skills to communicate with partners about sexual pleasure. PMID- 27120116 TI - Vitelliform dystrophies: Prevalence in Olmsted County, Minnesota, United States. AB - BACKGROUND: Vitelliform dystrophies are a group of macular degenerative diseases characterized by round yellow lesions in the macula. While often idiopathic, vitelliform dystrophies include inherited maculopathies such as Best disease and some cases of pattern dystrophy. The prevalence of vitelliform dystrophies in the United States has not been reported. This study examined the prevalence of vitelliform dystrophies in Olmsted County, Minnesota. MATERIALS AND METHODS: The Rochester Epidemiology Project database was used to identify all cases of vitelliform or pattern dystrophy in Olmsted County from 1 January 2000-31 December 2014. RESULTS: Overall, 27 patients had true vitelliform lesions, indicating a prevalence of 1 in 5500. Of these, two had genetically confirmed Best disease, and an additional five to seven carried a diagnosis of Best disease, which chart reviews confirmed as probable cases; 18-20 patients had adult-onset vitelliform macular dystrophy. The prevalence of Best disease was 1 in 16,500 to 1 in 21,000. Adult-onset vitelliform macular dystrophy was found in 1 in 7400 to 1 in 8200. CONCLUSIONS: Vitelliform dystrophies affect 1 in 5500 individuals in Olmsted County. While the values in this study provide good estimates for the prevalence of Best disease versus adult-onset vitelliform macular dystrophy, the results are limited by dependence on diagnoses made by other ophthalmologists and underutilization of genetic testing. Thus, these diseases should be thought of as at least as prevalent as reported here. As therapies for Best disease and other macular degenerative diseases are quickly becoming a reality, genetic testing should be employed as the gold standard for diagnosis of these diseases. PMID- 27120117 TI - Inhibitory RNA Aptamers of Tau Oligomerization and Their Neuroprotective Roles against Proteotoxic Stress. AB - Tau is a cytosolic protein that functions in the assembly and stabilization of axonal microtubule networks. Its oligomerization may be the rate-limiting step of insoluble aggregate formation, which is a neuropathological hallmark of Alzheimer's disease (AD) and a number of other tauopathies. Recent evidence indicates that soluble tau oligomers are the toxic species for tau-mediated pathology during AD progression. Herein, we describe novel RNA aptamers that target human tau and were identified through an in vitro selection process. These aptamers significantly inhibited the oligomerization propensity of tau both in vitro and in cultured cell models of tauopathy without affecting the half-life of tau. Tauopathy model cells treated with the aptamers were less sensitized to proteotoxic stress induced by tau overexpression. Moreover, the tau aptamers significantly alleviated synthetic tau oligomer-mediated neurotoxicity and dendritic spine loss in primary hippocampal neurons. Thus, our study demonstrates that delaying tau assembly with RNA aptamers is an effective strategy for protecting cells under various neurodegenerative stresses originating from pathogenic tau oligomerization. PMID- 27120119 TI - We Send Thrombosed AV Accesses to the Operating Room. AB - A thrombosed dialysis access can be declotted either through an open surgical procedure or a percutaneous one. In choosing how the access should be managed, a nephrologist should balance the experience and outcomes of local providers to ensure the efficient and safe salvage of the vascular access. Percutaneous procedures often offer less disruption to the schedule of the patient and dialysis clinic, give more information about the central vasculature, are less invasive, and ultimately are preferred. Nephrologist should encourage local vascular surgeons and interventional radiologists to become proficient in these procedures to avoid unnecessary open cases. PMID- 27120120 TI - Gastric Outlet Obstruction. PMID- 27120118 TI - Protein synthetic machinery and mRNA in regenerating tips of spinal cord axons in lamprey. AB - Polyribosomes, mRNA, and other elements of translational machinery have been reported in peripheral nerves and in elongating injured axons of sensory neurons in vitro, primarily in growth cones. Evidence for involvement of local protein synthesis in regenerating central nervous system (CNS) axons is less extensive. We monitored regeneration of back-labeled lamprey spinal axons after spinal cord transection and detected mRNA in axon tips by in situ hybridization and microaspiration of their axoplasm. Poly(A)+mRNA was present in the axon tips, and was more abundant in actively regenerating tips than in static or retracting ones. Target-specific polymerase chain reaction (PCR) and in situ hybridization revealed plentiful mRNA for the low molecular neurofilament subunit and beta tubulin, but very little for beta-actin, consistent with the morphology of their tips, which lack filopodia and lamellipodia. Electron microscopy showed ribosomes/polyribosomes in the distal parts of axon tips and in association with vesicle-like membranes, primarily in the tip. In one instance, there were structures with the appearance of rough endoplasmic reticulum. Immunohistochemistry showed patches of ribosomal protein S6 positivity in a similar distribution. The results suggest that local protein synthesis might be involved in the mechanism of axon regeneration in the lamprey spinal cord. J. Comp. Neurol. 524:3614-3640, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27120127 TI - Mutations in GAS8, a Gene Encoding a Nexin-Dynein Regulatory Complex Subunit, Cause Primary Ciliary Dyskinesia with Axonemal Disorganization. AB - Primary ciliary dyskinesia (PCD) is an autosomal recessive disease characterized by chronic respiratory infections of the upper and lower airways, hypofertility, and, in approximately half of the cases, situs inversus. This complex phenotype results from defects in motile cilia and sperm flagella. Among the numerous genes involved in PCD, very few-including CCDC39 and CCDC40-carry mutations that lead to a disorganization of ciliary axonemes with microtubule misalignment. Focusing on this particular phenotype, we identified bi-allelic loss-of-function mutations in GAS8, a gene that encodes a subunit of the nexin-dynein regulatory complex (N DRC) orthologous to DRC4 of the flagellated alga Chlamydomonas reinhardtii. Unlike the majority of PCD patients, individuals with GAS8 mutations have motile cilia, which, as documented by high-speed videomicroscopy, display a subtle beating pattern defect characterized by slightly reduced bending amplitude. Immunofluorescence studies performed on patients' respiratory cilia revealed that GAS8 is not required for the proper expression of CCDC39 and CCDC40. Rather, mutations in GAS8 affect the subcellular localization of another N-DRC subunit called DRC3. Overall, this study, which identifies GAS8 as a PCD gene, unveils the key importance of the corresponding protein in N-DRC integrity and in the proper alignment of axonemal microtubules in humans. PMID- 27120128 TI - Ansalactams B-D Illustrate Further Biosynthetic Plasticity within the Ansamycin Pathway. AB - Further chemical investigation of a marine-derived bacterium of the genus Streptomyces has led to the isolation of ansalactams B-D (1-3) along with the previously reported metabolite ansalactam A (4). Ansalactams B-D are significantly modified ansamycins, representing three new carbon skeletons and further illustrating the biosynthetic plasticity of the ansalactam class. Unlike ansalactam A, ansalactams B and D are penta- and hexacyclic metabolites, while ansalactam C illustrates an open polyene chain with a terminal carboxylic acid. PMID- 27120129 TI - Prediction of multiple organ dysfunction syndrome complicating acute myocardial infarction on the basis of comorbidities on admission. AB - BACKGROUND: Acute myocardial infarction (AMI) can be complicated by multiple organ dysfunction syndrome (MODS), but the exact influence of MODS on AMI remains unclear. METHODS: This was a retrospective study of 6674 Chinese patients with AMI. The impact of MODS was assessed using the Cox proportional hazard model. Using the occurrence of MODS as the outcome, a prediction model was developed using the factors identified by logistic regression analysis and analyzed using receiving operator characteristic curves. RESULTS: Of 6674 patients with AMI, 83 (1.2%) progressed to MODS. MODS independently predicted the risk of 30-day in hospital mortality [hazard ratio, 2.3; 95% confidence interval (95% CI), 1.7-3.2; P<0.001]. Advanced age [odds ratio (OR), 2.76; 95% CI, 1.26-6.03; P=0.011 for age 65-74 years; OR, 4.85; 95% CI, 2.96-7.93; P<0.001 for age >=75 years), pneumonia (OR, 4.27; 95% CI, 2.68-6.81; P<0.001), and chronic renal failure (OR, 2.09; 95% CI, 1.09-4.01; P=0.027) were associated independently with MODS. The area under the receiving operator characteristic curve for the predictive model was 0.802, indicating a good predictive value. CONCLUSION: MODS can predict the worst severity of AMI. Using common clinical variables, it is possible to identify patients with AMI who are at high risk of MODS. Additional studies are necessary to confirm this model. PMID- 27120130 TI - Testicular microlithiasis: Correlation with doppler sonography of testicular arteries and sperm function. AB - PURPOSE: To determine the prevalence of testicular microlithiasis and its correlation with Doppler parameters of testicular arteries and sperm function. METHODS: Reports of 1,200 consecutive scrotal sonographic examinations performed at our hospital were reviewed. Patients diagnosed with testicular microlithiasis were recalled for detailed scrotal sonographic examination, including Doppler sonography and sperm function. The same examinations were performed in an age matched control group and the findings compared. RESULTS: Testicular microlithiasis was found in 64 cases (5.3%). Doppler sonography showed mean resistance index, Vmax, and Vmin of 61.1 +/- 9.3%, 18.2 +/- 4.7 cm/s, and 7.7 +/- 2.3 cm/s, respectively, in the testicular microlithiasis group versus 62.4 +/- 10.4%, 18.4 +/- 5.7 cm/s, and 7.3 +/- 2.4 cm/s, respectively, in the control group (p = 0.49, 0.84 and 0.35, respectively). Sperm function tests demonstrated sperm count, motility, and normal morphology (normal oval head) of 29.6 +/- 20.4 * 10(6) /mL, 35.3 +/- 16.2%, and 44.4 +/- 12%, respectively, in patients with testicular microlithiasis versus 54.3 +/- 22.4 * 10(6) /mL, 50.2% +/- 14.4%, and 66.4 +/- 11.6% in control subjects (p < 0.02). CONCLUSIONS: Prevalence of testicular microlithiasis of 5.3% in Jordanian patients is similar to what has been reported in the literature. Testicular microlithiasis does not have a significant effect on Doppler parameters of testicular arteries. The apparent impairment of sperm function in patients with testicular microlithiasis warrants further studies. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:474-479, 2016. PMID- 27120131 TI - Highly Crystalline Nanoparticle Suspensions for Low-Temperature Processing of TiO2 Thin Films. AB - In this work, we present preparation and stabilization methods for highly crystalline TiO2 nanoparticle suspensions for the successful deposition of transparent, photocatalytically active TiO2 thin films toward the degradation of organic pollutants by a low temperature deposition method. A proof-of-concept is provided wherein stable, aqueous TiO2 suspensions are deposited on glass substrates. Even if the processing temperature is lowered to 150-200 degrees C, the subsequent heat treatment provides transparent and photocatalytically active titania thin layers. Because all precursor solutions are water-based, this method provides an energy-efficient, sustainable, and environmentally friendly synthesis route. The high load in crystalline titania particles obtained after microwave heating opens up the possibility to produce thin coatings by low temperature processing, as a conventional crystallization procedure is in this case superfluous. The impact of the precursor chemistry in Ti(4+)-peroxo solutions, containing imino-diacetic acid as a complexing ligand and different bases to promote complexation was studied as a function of pH, reaction time and temperature. The nanocrystal formation was followed in terms of colloidal stability, crystallinity and particle size. Combined data from Raman and infrared spectroscopy, confirmed that stable titanium precursors could be obtained at pH levels ranging from 2 to 11. A maximum amount of 50.7% crystallinity was achieved, which is one of the highest reported amounts of anatase nanoparticles that are suspendable in stable aqueous titania suspensions. Decoloring of methylene blue solutions by precipitated nanosized powders from the TiO2 suspensions proves their photocatalytic properties toward degradation of organic materials, a key requisite for further processing. This synthesis method proves that the deposition of highly crystalline anatase suspensions is a valid route for the production of photocatalytically active, transparent films on heat sensitive substrates such as polymers. PMID- 27120132 TI - Atomic-scale characterization of the equilibrium beta phase in Mg-Nd-Y alloy by means of HAADF-STEM. AB - The beta phase in Mg-Nd-Y alloy, which forms during isothermal ageing, is proved to be Mg41 Nd5 by energy-dispersive X-ray spectroscopy (EDS) results as compositional evidence and by atomic-scaled high angle annular dark field scanning transmission electron microscopy (HAADF-STEM) direct images from [001]beta , [111-]beta, and [3-11]beta as structural evidence. SCANNING 38:743 746, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27120133 TI - Flow-modulated targeted signal enhancement for volatile organic compounds. AB - Comprehensive two-dimensional gas chromatography is a technique that is becoming more widespread within the analytical community, especially in the separation of complex mixtures. Modulation in comprehensive two-dimensional gas chromatography can be achieved by manipulating temperature or flow and offers many advantages such as increased separation power, but one underutilized advantage is increased detectability due to the reduction of peak width from the use of a modulator. A flow modulator was used to selectively target analytes for increased detectability with a standard flame ionization detector operated at 100 Hz, without the need for cryogens or advanced modulation software. By the collection of the entire peak volume followed by peak transfer rather than further separation, an increase of 12 times in peak height and detectability was realized for the analytes tested using an internal loop modulator configuration. An external loop flow modulator configuration allowed for more volatile analytes (with k < 5), and demonstrated an analyte detectability enhancement factor of at least 6. The collection loop size can be readily increased with an external loop configuration to accommodate for these naturally broader peaks. This novel flow modulated targeted signal enhancement approach was applied to industrially significant analyses like the analysis of methanol in a hydrocarbon streams. Methanol was detected at 7 ppb with a conventional flame ionization detector and without the need for pre-concentration. PMID- 27120134 TI - Fundamentals and Catalytic Applications of CeO2-Based Materials. AB - Cerium dioxide (CeO2, ceria) is becoming an ubiquitous constituent in catalytic systems for a variety of applications. 2016 sees the 40(th) anniversary since ceria was first employed by Ford Motor Company as an oxygen storage component in car converters, to become in the years since its inception an irreplaceable component in three-way catalysts (TWCs). Apart from this well-established use, ceria is looming as a catalyst component for a wide range of catalytic applications. For some of these, such as fuel cells, CeO2-based materials have almost reached the market stage, while for some other catalytic reactions, such as reforming processes, photocatalysis, water-gas shift reaction, thermochemical water splitting, and organic reactions, ceria is emerging as a unique material, holding great promise for future market breakthroughs. While much knowledge about the fundamental characteristics of CeO2-based materials has already been acquired, new characterization techniques and powerful theoretical methods are deepening our understanding of these materials, helping us to predict their behavior and application potential. This review has a wide view on all those aspects related to ceria which promise to produce an important impact on our life, encompassing fundamental knowledge of CeO2 and its properties, characterization toolbox, emerging features, theoretical studies, and all the catalytic applications, organized by their degree of establishment on the market. PMID- 27120135 TI - How Do Light and Intermittent Smokers Differ from Heavy Smokers in Young Adulthood: The Role of Smoking Restraint Strategies. AB - Light and intermittent smoking has become a prevalent pattern of use among young adults. Little is known about which factors differentiate light and intermittent smokers (LITS) from heavy smokers (HS) in young adulthood. In this study, we compare young adult LITS with HS with regard to demographic- and smoking-related variables, self-control abilities, and concrete strategies of smoking restraint. The data were collected as part of an Ecological Momentary Assessment (EMA) study with 137 German young adult smokers (M Age = 21.1 years, 46.0% female; 76 HS [>=10 cigarettes/day] and 61 LITS [<=5 cigarettes/day]). Participants were recruited over the Internet and completed a baseline questionnaire online. Several variables differentiated LITS and HS in a multiple logistic regression analysis: LITS reported fewer smoking friends (p < .001) and a higher self efficacy to resist smoking (p < .01). Further, LITS smoking status was associated with reporting a past quit attempt (p < .05) and the use of smoking restraint strategies (counting, limiting, and purposefully not smoking cigarettes; p < .05). Notably, nicotine dependence and trait self-control abilities did not differentiate between LITS and HS. Our results point to the role of smoking restraint strategies and self-monitoring of smoking to limit the daily number of cigarettes smoked. PMID- 27120136 TI - Trabeculectomy With Moorfields Conjunctival Closure Technique Offers Safety Without Astigmatism Induction. AB - PURPOSE: To evaluate the safety profile and possible change in corneal astigmatism following trabeculectomy with a fornix-based conjunctival flap which is closed with 4 corneal groove-embedded sutures. MATERIALS AND METHODS: Patients scheduled for a primary trabeculectomy were included in this single center, prospective trial between February and April 2013. Refractive status was assessed with an automated refractokeratometer preoperatively and at months 1, 3, 6, and 18 postoperatively, together with clinical assessment of intraocular pressure, visual acuity, postoperative complications, and medication use. Preoperative and postoperative variables were compared using paired samples t tests and vector analysis for corneal astigmatism change was performed. RESULTS: Forty-four eyes of 44 patients were included. Vector analysis showed a transient significant with the-rule shift in astigmatism without influence on spherical equivalent. Visual acuity was transiently reduced in the first month but recovered to preoperative values with no need to change optical correction. Two patients developed postoperative wound leakage, which was successfully treated with a bandage corneoscleral contact lens. CONCLUSIONS: Trabeculectomy with a fornix-based conjunctival flap closed by 4 corneal groove-embedded sutures results in a low complication rate. This safe suturing technique induces a transient shift of with the-rule astigmatism, reverting to the preoperative values within 3 months of surgery. Adjustments to refractive correction are recommended to be postponed until after this period. PMID- 27120137 TI - Tuning the Protein-Induced Absorption Shifts of Retinal in Engineered Rhodopsin Mimics. AB - Rational design of light-capturing properties requires understanding the molecular and electronic structure of chromophores in their native chemical or biological environment. We employ here large-scale quantum chemical calculations to study the light-capturing properties of retinal in recently designed human cellular retinol binding protein II (hCRBPII) variants (Wang et al. Science, 2012, 338, 1340-1343). Our calculations show that these proteins absorb across a large part of the visible spectrum by combined polarization and electrostatic effects. These effects stabilize the ground or excited state energy levels of the retinal by perturbing the Schiff-base or beta-ionone moieties of the chromophore, which in turn modulates the amount of charge transfer within the molecule. Based on the predicted tuning principles, we design putative in silico mutations that further shift the absorption properties of retinal in hCRBPII towards the ultraviolet and infrared regions of the spectrum. PMID- 27120138 TI - Conversion of Xylose to Furfuryl Alcohol and 2-Methylfuran in a Continuous Fixed Bed Reactor. AB - An efficient process was designed for the synthesis of furfuryl alcohol and 2 methylfuran from xylose using a continuous fixed-bed reactor over a catalyst combining Hbeta zeolite and Cu/ZnO/Al2 O3 in gamma-butyrolactone (GBL)/water as solvent. The cooperative effect of Hbeta zeolite and GBL facilitated the dehydration of xylose and enhanced largely the furfural yield. The production of furfuryl alcohol and 2-methylfuran can be simply tuned by changing the hydrogenation temperature for furfural over the Cu/ZnO/Al2 O3 catalyst. The yield for furfuryl alcohol reached 87.2 % at 150 degrees C whereas a yield of 86.8 % was achieved for 2-methylfuran at 190 degrees C. PMID- 27120139 TI - Unusual presentation: Concurrent IgA deficiency and idiopathic pulmonary hemosiderosis. AB - Idiopathic pulmonary hemosiderosis (IPH) is a rare disorder that should be considered in the differential diagnosis of patients with hemoptysis, recurrent alveolar hemorrhage, dyspnea and iron deficiency anemia (IDA). The frequent association of autoimmune disorders with IPH and a favorable response to steroids suggest the presence of an underlying immune disorder. Here we present a case of a patient with cough, fever, and cyanosis who was also diagnosed with IPH and concurrent selective immunoglobulin A deficiency. This presentation is a unique presentation because of the co-occurrence of these two disorders. Pediatr Pulmonol. 2016;51:E34-E36. (c) 2016 Wiley Periodicals, Inc. PMID- 27120154 TI - New Frontiers in Language Evolution and Development. AB - This article introduces the Special Issue and its focus on research in language evolution with emphasis on theory as well as computational and robotic modeling. A key theme is based on the growth of evolutionary developmental biology or evo devo. The Special Issue consists of 13 articles organized in two sections: A) Theoretical foundations and B) Modeling and simulation studies. All the papers are interdisciplinary in nature, encompassing work in biological and linguistic foundations for the study of language evolution as well as a variety of computational and robotic modeling efforts shedding light on how language may be developed and may have evolved. PMID- 27120155 TI - Distinguishing immunoglobulin G4-related disease from its pancreatobiliary mimics: Are we there now? PMID- 27120156 TI - A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. AB - Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 - 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission. PMID- 27120158 TI - Iron(III)-catalysed carbonyl-olefin metathesis. AB - The olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon-carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries. These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism. While the corresponding carbonyl-olefin metathesis reaction can also be used to construct carbon-carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl-olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl-olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis. PMID- 27120159 TI - Resolved atomic lines reveal outflows in two ultraluminous X-ray sources. AB - Ultraluminous X-ray sources are extragalactic, off-nucleus, point sources in galaxies, and have X-ray luminosities in excess of 3 * 10(39) ergs per second. They are thought to be powered by accretion onto a compact object. Possible explanations include accretion onto neutron stars with strong magnetic fields, onto stellar-mass black holes (of up to 20 solar masses) at or in excess of the classical Eddington limit, or onto intermediate-mass black holes (10(3)-10(5) solar masses). The lack of sufficient energy resolution in previous analyses has prevented an unambiguous identification of any emission or absorption lines in the X-ray band, thereby precluding a detailed analysis of the accretion flow. Here we report the presence of X-ray emission lines arising from highly ionized iron, oxygen and neon with a cumulative significance in excess of five standard deviations, together with blueshifted (about 0.2 times light velocity) absorption lines of similar significance, in the high-resolution X-ray spectra of the ultraluminous X-ray sources NGC 1313 X-1 and NGC 5408 X-1. The blueshifted absorption lines must occur in a fast-outflowing gas, whereas the emission lines originate in slow-moving gas around the source. We conclude that the compact object in each source is surrounded by powerful winds with an outflow velocity of about 0.2 times that of light, as predicted by models of accreting supermassive black holes and hyper-accreting stellar-mass black holes. PMID- 27120157 TI - Molecular mechanism of APC/C activation by mitotic phosphorylation. AB - In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase. The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1 mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas phosphorylation of Cdh1 prevents its association with the APC/C. Since both coactivators associate with the APC/C through their common C-box and Ile-Arg tail motifs, the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20) rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our results reveal the mechanism for the regulation of mitotic APC/C by phosphorylation and provide a rationale for the development of selective inhibitors of this state. PMID- 27120160 TI - Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. AB - The bacterial CRISPR/Cas9 system allows sequence-specific gene editing in many organisms and holds promise as a tool to generate models of human diseases, for example, in human pluripotent stem cells. CRISPR/Cas9 introduces targeted double stranded breaks (DSBs) with high efficiency, which are typically repaired by non homologous end-joining (NHEJ) resulting in nonspecific insertions, deletions or other mutations (indels). DSBs may also be repaired by homology-directed repair (HDR) using a DNA repair template, such as an introduced single-stranded oligo DNA nucleotide (ssODN), allowing knock-in of specific mutations. Although CRISPR/Cas9 is used extensively to engineer gene knockouts through NHEJ, editing by HDR remains inefficient and can be corrupted by additional indels, preventing its widespread use for modelling genetic disorders through introducing disease associated mutations. Furthermore, targeted mutational knock-in at single alleles to model diseases caused by heterozygous mutations has not been reported. Here we describe a CRISPR/Cas9-based genome-editing framework that allows selective introduction of mono- and bi-allelic sequence changes with high efficiency and accuracy. We show that HDR accuracy is increased dramatically by incorporating silent CRISPR/Cas-blocking mutations along with pathogenic mutations, and establish a method termed 'CORRECT' for scarless genome editing. By characterizing and exploiting a stereotyped inverse relationship between a mutation's incorporation rate and its distance to the DSB, we achieve predictable control of zygosity. Homozygous introduction requires a guide RNA targeting close to the intended mutation, whereas heterozygous introduction can be accomplished by distance-dependent suboptimal mutation incorporation or by use of mixed repair templates. Using this approach, we generated human induced pluripotent stem cells with heterozygous and homozygous dominant early onset Alzheimer's disease-causing mutations in amyloid precursor protein (APP(Swe)) and presenilin 1 (PSEN1(M146V)) and derived cortical neurons, which displayed genotype-dependent disease associated phenotypes. Our findings enable efficient introduction of specific sequence changes with CRISPR/Cas9, facilitating study of human disease. PMID- 27120161 TI - Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. PMID- 27120162 TI - Topology of ON and OFF inputs in visual cortex enables an invariant columnar architecture. AB - Circuits in the visual cortex integrate the information derived from separate ON (light-responsive) and OFF (dark-responsive) pathways to construct orderly columnar representations of stimulus orientation and visual space. How this transformation is achieved to meet the specific topographic constraints of each representation remains unclear. Here we report several novel features of ON-OFF convergence visualized by mapping the receptive fields of layer 2/3 neurons in the tree shrew (Tupaia belangeri) visual cortex using two-photon imaging of GCaMP6 calcium signals. We show that the spatially separate ON and OFF subfields of simple cells in layer 2/3 exhibit topologically distinct relationships with the maps of visual space and orientation preference. The centres of OFF subfields for neurons in a given region of cortex are confined to a compact region of visual space and display a smooth visuotopic progression. By contrast, the centres of the ON subfields are distributed over a wider region of visual space, display substantial visuotopic scatter, and have an orientation-specific displacement consistent with orientation preference map structure. As a result, cortical columns exhibit an invariant aggregate receptive field structure: an OFF dominated central region flanked by ON-dominated subfields. This distinct arrangement of ON and OFF inputs enables continuity in the mapping of both orientation and visual space and the generation of a columnar map of absolute spatial phase. PMID- 27120163 TI - FGF8 and SHH substitute for anterior-posterior tissue interactions to induce limb regeneration. AB - In salamanders, grafting of a left limb blastema onto a right limb stump yields regeneration of three limbs, the normal limb and two 'supernumerary' limbs. This experiment and other research have shown that the juxtaposition of anterior and posterior limb tissue plus innervation are necessary and sufficient to induce complete limb regeneration in salamanders. However, the cellular and molecular basis of the requirement for anterior-posterior tissue interactions were unknown. Here we have clarified the molecular basis of the requirement for both anterior and posterior tissue during limb regeneration and supernumerary limb formation in axolotls (Ambystoma mexicanum). We show that the two tissues provide complementary cross-inductive signals that are required for limb outgrowth. A blastema composed solely of anterior tissue normally regresses rather than forming a limb, but activation of hedgehog (HH) signalling was sufficient to drive regeneration of an anterior blastema to completion owing to its ability to maintain fibroblast growth factor (FGF) expression, the key signalling activity responsible for blastema outgrowth. In blastemas composed solely of posterior tissue, HH signalling was not sufficient to drive regeneration; however, ectopic expression of FGF8 together with endogenous HH signalling was sufficient. In axolotls, FGF8 is expressed only in the anterior mesenchyme and maintenance of its expression depends on sonic hedgehog (SHH) signalling from posterior tissue. Together, our findings identify key anteriorly and posteriorly localized signals that promote limb regeneration and show that these single factors are sufficient to drive non-regenerating blastemas to complete regeneration with full elaboration of skeletal elements. PMID- 27120164 TI - Principles underlying sensory map topography in primary visual cortex. AB - The primary visual cortex contains a detailed map of the visual scene, which is represented according to multiple stimulus dimensions including spatial location, ocular dominance and stimulus orientation. The maps for spatial location and ocular dominance arise from the spatial arrangement of thalamic afferent axons in the cortex. However, the origins of the other maps remain unclear. Here we show that the cortical maps for orientation, direction and retinal disparity in the cat (Felis catus) are all strongly related to the organization of the map for spatial location of light (ON) and dark (OFF) stimuli, an organization that we show is OFF-dominated, OFF-centric and runs orthogonal to ocular dominance columns. Because this ON-OFF organization originates from the clustering of ON and OFF thalamic afferents in the visual cortex, we conclude that all main features of visual cortical topography, including orientation, direction and retinal disparity, follow a common organizing principle that arranges thalamic axons with similar retinotopy and ON-OFF polarity in neighbouring cortical regions. PMID- 27120165 TI - Immunology: Mum's microbes boost baby's immunity. PMID- 27120166 TI - Bioengineering: Evolved to overcome Bt-toxin resistance. PMID- 27120168 TI - Regeneration: Limb regrowth takes two. PMID- 27120167 TI - Continuous evolution of Bacillus thuringiensis toxins overcomes insect resistance. AB - The Bacillus thuringiensis delta-endotoxins (Bt toxins) are widely used insecticidal proteins in engineered crops that provide agricultural, economic, and environmental benefits. The development of insect resistance to Bt toxins endangers their long-term effectiveness. Here we have developed a phage-assisted continuous evolution selection that rapidly evolves high-affinity protein-protein interactions, and applied this system to evolve variants of the Bt toxin Cry1Ac that bind a cadherin-like receptor from the insect pest Trichoplusia ni (TnCAD) that is not natively bound by wild-type Cry1Ac. The resulting evolved Cry1Ac variants bind TnCAD with high affinity (dissociation constant Kd = 11-41 nM), kill TnCAD-expressing insect cells that are not susceptible to wild-type Cry1Ac, and kill Cry1Ac-resistant T. ni insects up to 335-fold more potently than wild type Cry1Ac. Our findings establish that the evolution of Bt toxins with novel insect cell receptor affinity can overcome insect Bt toxin resistance and confer lethality approaching that of the wild-type Bt toxin against non-resistant insects. PMID- 27120170 TI - In vitro volatile organic compound profiling using GC*GC-TOFMS to differentiate bacteria associated with lung infections: a proof-of-concept study. AB - Chronic pulmonary infections are the principal cause of morbidity and mortality in individuals with cystic fibrosis (CF). Due to the polymicrobial nature of these infections, the identification of the particular bacterial species responsible is an essential step in diagnosis and treatment. Current diagnostic procedures are time-consuming, and can also be expensive, invasive and unpleasant in the absence of spontaneously expectorated sputum. The development of a rapid, non-invasive methodology capable of diagnosing and monitoring early bacterial infection is desired. Future visions of real-time, in situ diagnosis via exhaled breath testing rely on the differentiation of bacteria based on their volatile metabolites. The objective of this proof-of-concept study was to investigate whether a range of CF-associated bacterial species (i.e. Pseudomonas aeruginosa, Burkholderia cenocepacia, Haemophilus influenzae, Stenotrophomonas maltophilia, Streptococcus pneumoniae and Streptococcus milleri) could be differentiated based on their in vitro volatile metabolomic profiles. Headspace samples were collected using solid phase microextraction (SPME), analyzed using comprehensive two dimensional gas chromatography-time-of-flight mass spectrometry (GC*GC-TOFMS) and evaluated using principal component analysis (PCA) in order to assess the multivariate structure of the data. Although it was not possible to effectively differentiate all six bacteria using this method, the results revealed that the presence of a particular pattern of VOCs (rather than a single VOC biomarker) is necessary for bacterial species identification. The particular pattern of VOCs was found to be dependent upon the bacterial growth phase (e.g. logarithmic versus stationary) and sample storage conditions (e.g. short-term versus long term storage at -18 degrees C). Future studies of CF-associated bacteria and exhaled breath condensate will benefit from the approaches presented in this study and further facilitate the production of diagnostic tools for the early detection of bacterial lung infections. PMID- 27120171 TI - Problems, Pitfalls and Encouraging Information on Patients with Diabetes and Heart Failure. PMID- 27120169 TI - Susceptibility tensor imaging (STI) of the brain. AB - Susceptibility tensor imaging (STI) is a recently developed MRI technique that allows quantitative determination of orientation-independent magnetic susceptibility parameters from the dependence of gradient echo signal phase on the orientation of biological tissues with respect to the main magnetic field. By modeling the magnetic susceptibility of each voxel as a symmetric rank-2 tensor, individual magnetic susceptibility tensor elements as well as the mean magnetic susceptibility and magnetic susceptibility anisotropy can be determined for brain tissues that would still show orientation dependence after conventional scalar based quantitative susceptibility mapping to remove such dependence. Similar to diffusion tensor imaging, STI allows mapping of brain white matter fiber orientations and reconstruction of 3D white matter pathways using the principal eigenvectors of the susceptibility tensor. In contrast to diffusion anisotropy, the main determinant factor of the susceptibility anisotropy in brain white matter is myelin. Another unique feature of the susceptibility anisotropy of white matter is its sensitivity to gadolinium-based contrast agents. Mechanistically, MRI-observed susceptibility anisotropy is mainly attributed to the highly ordered lipid molecules in the myelin sheath. STI provides a consistent interpretation of the dependence of phase and susceptibility on orientation at multiple scales. This article reviews the key experimental findings and physical theories that led to the development of STI, its practical implementations, and its applications for brain research. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27120172 TI - Single center experience of aortic bypass graft for aortic arch obstruction in children. AB - The purpose of this study is to access the outcomes of aortic bypass graft placement in children. This is a retrospective review of all children having aortic bypass graft placement for aortic arch obstruction for the first time between 1982 and 2013 at a single institution. The actuarial survival and the freedom from aortic arch reoperation were calculated and compared between the groups. Seventy consecutive children underwent aortic bypass graft placements. The median age and body weight at the operation were 14 days and 3.6 kg. There were 7 early deaths, 6 late deaths, and 7 heart transplants during the median follow-up of 10.8 years (0.0-31.5 years). The actuarial transplant free survival was 64.7 % at 20 years and the freedom from aortic arch reoperation was 50.5 % at 10 years. Between the children younger than 1 year old and older than 1 year old, there were significant differences in actuarial transplant free survival (56.4 vs. 100 % at 15 years, p = 0.0042) and in the freedom from aortic arch reoperation (18.7 vs. 100 % at 10 years, p < 0.001). The children who received aortic bypass graft larger than 16 mm in size had no aortic arch reoperation at 15 years. The aortic bypass graft placement for aortic arch obstruction can be done with low mortality and morbidity for children who can receive bypass graft larger than 16 mm in size. However, it should be avoided for the neonates and infants except selected situations. PMID- 27120173 TI - Outcomes of plasma exchange for severe dilated cardiomyopathy in children. AB - Antimyocardial autoantibodies are a cause of dilated cardiomyopathy (DCM). Immunoabsorption therapy for eliminating autoantibodies can improve cardiac function in adult DCM. The purpose of this study was to investigate the indication and efficacy of plasma exchange in children with DCM and their outcomes. We performed a single-center, retrospective study in children with DCM who had received plasma exchange (PE). Six patients in various degrees of heart failure (three patients in acute exacerbation phase, one patient in early phase, and two patients in chronic phase) received PE. The effects of first PE were that the left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class were transiently increased in five of six patients (83 %) and in four of five patients (80 %), respectively. The median duration of improved cardiac function after first PE was 8 months. PE was performed a total of two times in two patients and three times in one patient. The effect of repeated PE was attenuated when compared with first PE. Improved LVEF and NYHA functional class were observed in two of four courses (50 %) and in one of four courses (25 %), respectively. The median duration of improved cardiac function was 1 month. PE can transiently improve cardiac function and clinical symptoms of DCM in children. PE may be an additional therapeutic option in children with refractory DCM. However, PE should only be considered as a bridge to ventricular assist device implantation or heart transplantation. PMID- 27120174 TI - Inter-Hospital Variability of Postoperative Pain after Tonsillectomy: Prospective Registry-Based Multicentre Cohort Study. AB - OBJECTIVES: Although tonsillectomy is one of the most frequent and painful surgeries, the association between baseline and process parameters and postoperative pain are not fully understood. METHODS: A multicentre prospective cohort study using a web-based registry enrolled 1,527 women and 1,008 men aged 4 to 85 years from 52 German hospitals between 2006 and 2015. Maximal pain (MP) score the first day after surgery on a numeric rating scale (NRS) from 0 (no pain) to 10 (MP) was the main outcome parameter. RESULTS: The mean maximal pain score was 5.8+/-2.2 (median 6). Multivariable analysis revealed that female gender (Odds ratio [OR] = 1.33; 95% confidence interval [CI] = 1.12 to 1.56; p = 0.001), age <20 years (OR = 1.56; CI = 1.27 to 1.91; p<0.0001), no pain counselling (OR = 1.78; CI = 1.370 to 2.316; p<0.001), chronic pain (OR = 1.34; CI = 1.107 to 1.64; p = 0.004), and receiving opioids in recovery room (OR = 1.89; CI = 1.55 to 2.325; p<0.001) or on ward (OR = 1.79; CI = 1.42 to 2.27; p<0.001) were independently associated with higher experienced maximal postoperative pain (greater the median of 6). The effect of age on pain was not linear. Maximal pain increased in underage patients to a peak at the age of 18 to 20 years. From the age of >=20 years on, maximal pain after tonsillectomy continuously decreased. Even after adjustment to all statistically important baseline and process parameters, there was substantial variability of maximal pain between hospitals with a heterogeneity variance of 0.31. CONCLUSION: Many patients seem to receive insufficient or ineffective analgesia after tonsillectomy. Further research should address if populations at risk of higher postoperative pain such as females, younger patients or those with preexisting pain might profit from a special pain management protocol. Beyond classical demographical and process parameters the large variability between different hospitals is striking and indicates the existence of other unknown factors influencing postoperative pain after tonsillectomy. PMID- 27120175 TI - Potency of extracts from selected Egyptian plants as inducers of the Nrf2 dependent chemopreventive enzyme NQO1. AB - Medicinal plants from the Egyptian Sinai Peninsula are widely used in traditional Bedouin medicine to treat a range of conditions including cancer, and as such are a promising resource for novel anti-cancer compounds. To achieve scientific justification of traditional use and/or to recommend the use of those plants as medicinal herbs for cancer chemoprevention, a group of 11 Sinai plants of different species that belong to 3 families (Asteraceae, Lamiaceae, and Euphorbiaceae) were biologically screened for cancer preventive activity using the chemoprevention marker enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1). Among the fractions assayed, a solvent extract from Pulicaria incisa had potent NQO1 inducing activity. Further analysis of the mechanism of induction revealed the concentration-dependent stabilization of the transcription factor NF-E2 p45 related factor 2 (Nrf2) and a coordinate upregulation of the Nrf2-dependent enzymes NQO1, heme oxygenase 1 and glutathione S-transferase-Pi. These results establish P. incisa as a promising target for future phytochemical characterization for cancer preventive components. PMID- 27120176 TI - The cytotoxic and tyrosine kinase inhibitory properties of C21 steroids and iridoids from the tubers of Alocasia cucullata. AB - Ten steroids and iridoids were isolated from the tubers of Alocasia cucullata (Lour.) G. Don. Among them, alocasgenin A (1) and alocasgenoside B-C (2-3) were new compounds and the aglycone of compound 1, obtained from the acid hydrolysis of 1, was named alocasgenol (1a). Also, for the first time, tenacigenin B (4), 17beta-tenacigenin-B (5), 3-O-6-deoxy-3-O-methyl-beta-D-allopyranosyl-(1->4)-beta D-oleandropyranosyl-tenacigenin C (6), marsdenoside A-B (7-8) and tenacigenoside A-B (9-10) were isolated from the genus Alocasia. The chemical structures were elucidated by the extensive analysis of spectral data and compared with the literature. By evaluation of the cytotoxic and tyrosine kinase inhibition, compounds 1-10, 1a and compound 2 showed significant growth inhibition against two tumour cell lines, MGC-803 and HT-29, while compounds 1, 1a, 3, 6 and 8 presented moderate inhibition. Furthermore, compound 2 had the inhibitory property against the enzyme activity biochemically. PMID- 27120177 TI - Population Pharmacokinetics of Prednisolone in Relation to Clinical Outcome in Children With Nephrotic Syndrome. AB - BACKGROUND: The relapse frequency in children with nephrotic syndrome (NS) is highly variable despite standardized prednisolone treatment regimens. Existing evidence on the relationship between prednisolone pharmacokinetics (PK) and clinical response in children with NS is scarce and limited. The aim of this study was to develop a pediatric popPK model for prednisolone based on our previous model based on healthy adults using salivary measurements in children with NS and to correlate clinical outcome with between-subject variability in prednisolone exposure. METHODS: The pharmacokinetics of prednisolone in a well defined, prospective cohort consisting of 104 children with NS while in remission was determined. Pharmacokinetic parameters were analyzed in relation to relapse patterns and side effects. Noninvasive salivary prednisolone measurements were performed using a sparse sampling strategy. A population pharmacokinetic approach was used to derive individual estimates of apparent clearance (CL/F) and apparent volume of distribution (V/F) from the salivary concentration-time curve, followed by calculation of the area under the curve (AUC) of free prednisolone. The individual free serum prednisolone exposure from prednisolone in saliva was derived from the salivary concentration-time curves. Genetic polymorphisms of CYP3A4, CYP3A5, ABCB1, NR1L2, and POR were explored in relation to between subject variability of CL/F. RESULTS: Moderate interindividual variability was found for CL/F (CV, 44.7%). Unexplained random between-subject variability (eta) of CL/F was lower in patients carrying 1 or 2 ABCB1 3435C>T alleles compared to wild type: median -0.04 (interquartile range, -0.17 to 0.21) and 0.00 (-0.11 to 0.16) versus 0.17 (-0.08 to 0.47), P = 0.046. Exposure to free prednisolone was not associated with frequent relapses or adverse effects. CONCLUSIONS: This study provides evidence for the possibility of prednisolone drug monitoring through salivary measurements and this may be of particular usefulness in pediatric patients. However, the observed variability in prednisolone exposure, in the therapeutic dose range studied, is not considered to be a major determinant of clinical outcome in children with NS. PMID- 27120178 TI - Comparison of Three Assays to Quantify Infliximab, Adalimumab, and Etanercept Serum Concentrations. AB - BACKGROUND: To optimize treatment of inflammatory diseases, interest in the measurement of anti-tumor necrosis factor alpha (anti-TNFalpha) serum drug concentrations is increasing. Preferably, assays for the detection of these drugs should be compared using the same reference material. In this study, 2 commercially available enzyme-linked immunosorbent assays (ELISAs) and a commercially available bioassay for the determination of anti-TNFalpha drugs are compared. METHODS: Serum samples from infliximab-, adalimumab-, and etanercept treated patients, control samples from ustekinumab-treated patients, and healthy donors were obtained. ELISAs manufactured by Sanquin and Theradiag and the iLite reporter gene-based bioassay from Biomonitor were compared. RESULTS: Sanquin, Theradiag, and iLite assays concordantly (100%) detected infliximab, adalimumab, and etanercept in the relevant patient groups. The Sanquin ELISAs specifically detected the anti-TNFalpha drug they were designed for, whereas the Theradiag and iLite showed cross-reactivity with other anti-TNFalpha drugs. Ustekinumab was not detected in any of the assays. Sanquin, Theradiag, and iLite exhibited linear quantitative correlation for all drug concentration assays. However, there were statistically significant quantitative differences in measured concentrations. CONCLUSIONS: All 3 commercially available assays seem suitable for therapeutic drug monitoring of anti-TNFalpha drugs, allowing sensitive and comparable detection of infliximab, adalimumab, and etanercept concentrations, however with differences in specificity and recovery. PMID- 27120179 TI - Novelty, Challenge, and Practice: The Impact of Intensive Language Learning on Attentional Functions. AB - We investigated the impact of a short intensive language course on attentional functions. We examined 33 participants of a one-week Scottish Gaelic course and compared them to 34 controls: 16 active controls who participated in courses of comparable duration and intensity but not involving foreign language learning and 18 passive controls who followed their usual routines. Participants completed auditory tests of attentional inhibition and switching. There was no difference between the groups in any measures at the beginning of the course. At the end of the course, a significant improvement in attention switching was observed in the language group (p < .001) but not the control group (p = .127), independent of the age of participants (18-78 years). Half of the language participants (n = 17) were retested nine months after their course. All those who practiced Gaelic 5 hours or more per week improved from their baseline performance. In contrast, those who practiced 4 hours or fewer showed an inconsistent pattern: some improved while others stayed the same or deteriorated. Our results suggest that even a short period of intensive language learning can modulate attentional functions and that all age groups can benefit from this effect. Moreover, these short-term effects can be maintained through continuous practice. PMID- 27120180 TI - A Retrospective Study of Patients with Psoriasis Treated with Biologics: Relation to Body Mass Index and Gender. PMID- 27120181 TI - Evaluation of Liver Ischemia-Reperfusion Injury in Rabbits Using a Nanoscale Ultrasound Contrast Agent Targeting ICAM-1. AB - OBJECTIVE: To assess the feasibility of ultrasound molecular imaging in the early diagnosis of liver ischemia-reperfusion injury (IRI) using a nanoscale contrast agent targeting anti-intracellular adhesion molecule-1 (anti-ICAM-1). METHODS: The targeted nanobubbles containing anti-ICAM-1 antibody were prepared using the avidin-biotin binding method. Human hepatic sinusoidal endothelial cells (HHSECs) were cultured at the circumstances of hypoxia/reoxygenation (H/R) and low temperature. The rabbit liver IRI model (I/R group) was established using the Pringle's maneuver. The time-intensity curve of the liver contrast ultrasonographic images was plotted and the peak intensity, time to peak, and time of duration were calculated. RESULTS: The size of the targeted nanobubbles were 148.15 +/- 39.75 nm and the concentration was 3.6-7.4 * 109/ml, and bound well with the H/R HHSECs. Animal contrast enhanced ultrasound images showed that the peak intensity and time of duration of the targeted nanobubbles were significantly higher than that of common nanobubbles in the I/R group, and the peak intensity and time of duration of the targeted nanobubbles in the I/R group were also significantly higher than that in the SO group. CONCLUSION: The targeted nanobubbles have small particle size, stable characteristic, and good targeting ability, which can assess hepatic ischemia-reperfusion injury specifically, noninvasively, and quantitatively at the molecular level. PMID- 27120182 TI - Perispinal Delivery of CNS Drugs. AB - Perispinal injection is a novel emerging method of drug delivery to the central nervous system (CNS). Physiological barriers prevent macromolecules from efficiently penetrating into the CNS after systemic administration. Perispinal injection is designed to use the cerebrospinal venous system (CSVS) to enhance delivery of drugs to the CNS. It delivers a substance into the anatomic area posterior to the ligamentum flavum, an anatomic region drained by the external vertebral venous plexus (EVVP), a division of the CSVS. Blood within the EVVP communicates with the deeper venous plexuses of the CSVS. The anatomical basis for this method originates in the detailed studies of the CSVS published in 1819 by the French anatomist Gilbert Breschet. By the turn of the century, Breschet's findings were nearly forgotten, until rediscovered by American anatomist Oscar Batson in 1940. Batson confirmed the unique, linear, bidirectional and retrograde flow of blood between the spinal and cerebral divisions of the CSVS, made possible by the absence of venous valves. Recently, additional supporting evidence was discovered in the publications of American neurologist Corning. Analysis suggests that Corning's famous first use of cocaine for spinal anesthesia in 1885 was in fact based on Breschet's anatomical findings, and accomplished by perispinal injection. The therapeutic potential of perispinal injection for CNS disorders is highlighted by the rapid neurological improvement in patients with otherwise intractable neuroinflammatory disorders that may ensue following perispinal etanercept administration. Perispinal delivery merits intense investigation as a new method of enhanced delivery of macromolecules to the CNS and related structures. PMID- 27120183 TI - Highly Sensitive Detection of Melamine Using a One-Step Sample Treatment Combined with a Portable Ag Nanostructure Array SERS Sensor. AB - There is an urgent need for rapid and reliable methods able to detect melamine in animal feed. In this study, a quick, simple, and sensitive method for the determination of melamine content in animal feed was developed using surface enhanced Raman spectroscopy on fabricated Ag nanorod (AgNR) array substrates with a one-step sample extraction procedure. The AgNR array substrates washed by HNO3 solvent (10-7 M) and methanol and showed the good stability within 6 months. The Raman shift at ?nu = 682 cm-1 was used as the characteristic melamine peak in the calculations. Sufficient linearity was obtained in the 2-200 MUg.g-1 range (R2 = 0.926). The limits of detection and quantification were 0.9 and 2 MUg.g-1, respectively. The recovery rates were 89.7-93.3%, with coefficients of variation below 2.02%. The method showed good accuracy compared with the tradition GC-MS analysis. This new protocol only need 2 min to fininsh the detection which could be developed for rapid onsite screening of melamine contamination in quality control and market surveillance applications. PMID- 27120184 TI - Palladium-Catalyzed Asymmetric Benzylic Alkylation of Active Methylene Compounds with alpha-Naphthylbenzyl Carbonates and Pivalates. AB - A Pd/(R)-H8 -BINAP-catalyzed asymmetric benzylic alkylation of active methylene compounds has been developed. The reaction proceeds without the use of an external base, and the starting racemic diarylmethyl carbonates are converted into the optically active coupling products which contain the benzylic chiral stereocenter by a dynamic kinetic asymmetric transformation (DYKAT). Additionally, with suitable carbonates bases, the same palladium catalysis allows the corresponding pivalates to be adopted in the same DYKAT process. PMID- 27120185 TI - Emergence of reticuloendotheliosis virus in pigeons in Guangdong Province, Southern China. AB - Reticuloendotheliosis virus (REV), an important immunosuppressive pathogen, has many hosts, including chickens, ducks, geese, turkeys, and wild birds. Clinically, REV may lead to increased susceptibility to other pathogens, resulting in serious tissue damage (especially tumors) and the death of its host. In this study, we encountered a disease outbreak resulting in a large number of deaths of pigeons in Guangdong Province, Southern China. Histopathological analysis revealed apparent tumor-like lesions in multiple organs of pigeons. PCR assays for detection of tumor-associated pathogens (REV, avian leukosis virus, and Marek's disease virus) in poultry revealed the presence of REV sequences only. Moreover, fowlpox virus (FPV) with an insertion of REV long terminal repeat (LTR) sequences was also considered, but it was excluded using a specific PCR assay. To gain more genetic information, two full-length REV genome sequences were determined and found to have the highest nucleotide sequence similarity (99.9 %) and the closest genetic relationship to a vaccine strain (MD-2) and had a more distant genetic relationship (94.3 %) to a duck-origin strain (ATCC VR775). To confirm the presence of REVs in pigeons, specific-pathogen-free (SPF) chickens and healthy pigeons were inoculated with microfiltered tumor tissue homogenates and were found to be susceptible to infection with REV. To our knowledge, this is the first report of REV in pigeons, and the data suggest that pigeons may be the natural host of REV. PMID- 27120186 TI - Variations in Training of Surgical Oncologists: Proposal for a Global Curriculum. AB - BACKGROUND: The global cancer burden is predicted to rise significantly over the next few decades. While there are several barriers to providing optimal cancer care on the global stage, some are related to the absence of an adequately trained workforce. This could be attributed in part to the significant global variations in the training of surgical oncology professionals. There are currently no published data mapping the training pathways for surgical oncologists for all countries in the world. The aims of this descriptive article are to report on the training paradigms in surgical oncology for all countries in the world, and to correlate the influence of economic standing on these training paradigms. MATERIALS AND METHODS: The training paradigms for all countries in the world were analyzed and categorized on the basis of the six World Health Organization geographic regions and economic standing stratified by the Human Development Index. RESULTS: Data on the training paradigms were obtained for 174 countries from a total of 211 (82 %). We noted extremely significant and concerning variations in the length, availability and structure of training paradigms depending on the geographic region and economic standing. CONCLUSIONS: The results of our study demonstrated significant global variations in the training paradigms of surgical oncologists. These variations call for a global curriculum which has been developed by the Society of Surgical Oncology and the European Society of Surgical Oncology. It is hoped that this curriculum will serve a role in streamlining education to tackle the rising global cancer burden. (c) 2016 Society of Surgical Oncology and the European Society of Surgical Oncology. Published by SpringerNature. All rights reserved. PMID- 27120187 TI - Global Curriculum in Surgical Oncology. AB - BACKGROUND: The significant global variations in surgical oncology training paradigms can have a detrimental effect on tackling the rising global cancer burden. While some variations in training are essential to account for the differences in types of cancer and biology, the fundamental principles of providing care to a cancer patient remain the same. The development of a global curriculum in surgical oncology with incorporated essential standards could be very useful in building an adequately trained surgical oncology workforce, which in turn could help in tackling the rising global cancer burden. MATERIALS AND METHODS: The leaders of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in surgical oncology. RESULTS: A global curriculum in surgical oncology was developed to incorporate the required domains considered to be essential in training a surgical oncologist. The curriculum was constructed in a modular fashion to permit flexibility to suit the needs of the different regions of the world. Similarly, recognizing the various sociocultural, financial and cultural influences across the world, the proposed curriculum is aspirational and not mandatory in intent. CONCLUSIONS: A global curriculum was developed which may be considered as a foundational scaffolding for training surgical oncologists worldwide. It is envisioned that this initial global curriculum will provide a flexible and modular scaffolding that can be tailored by individual countries or regions to train surgical oncologists in a way that is appropriate for practice in their local environment. (c) 2016 Society of Surgical Oncology and the European Society of Surgical Oncology. Published by SpringerNature. All rights reserved. PMID- 27120188 TI - Association of Vitamin B12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults: A Longitudinal Population-Based Study. AB - IMPORTANCE: Vitamin B12, folate, and sulfur amino acids may be modifiable risk factors for structural brain changes that precede clinical dementia. OBJECTIVE: To investigate the association of circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids with the rate of total brain volume loss and the change in white matter hyperintensity volume as measured by fluid-attenuated inversion recovery in older adults. DESIGN, SETTING, AND PARTICIPANTS: The magnetic resonance imaging subsample of the Swedish National Study on Aging and Care in Kungsholmen, a population-based longitudinal study in Stockholm, Sweden, was conducted in 501 participants aged 60 years or older who were free of dementia at baseline. A total of 299 participants underwent repeated structural brain magnetic resonance imaging scans from September 17, 2001, to December 17, 2009. MAIN OUTCOMES AND MEASURES: The rate of brain tissue volume loss and the progression of total white matter hyperintensity volume. RESULTS: In the multi adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, beta (SE) was 0.048 (0.013) for vitamin B12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (beta [SE] per 1-SD increase, -0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140 mm Hg (beta [SE] per 1 SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids. CONCLUSIONS AND RELEVANCE: This study suggests that both vitamin B12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B12 supplementation on slowing brain aging in older adults. PMID- 27120189 TI - MEDYAN: Mechanochemical Simulations of Contraction and Polarity Alignment in Actomyosin Networks. AB - Active matter systems, and in particular the cell cytoskeleton, exhibit complex mechanochemical dynamics that are still not well understood. While prior computational models of cytoskeletal dynamics have lead to many conceptual insights, an important niche still needs to be filled with a high-resolution structural modeling framework, which includes a minimally-complete set of cytoskeletal chemistries, stochastically treats reaction and diffusion processes in three spatial dimensions, accurately and efficiently describes mechanical deformations of the filamentous network under stresses generated by molecular motors, and deeply couples mechanics and chemistry at high spatial resolution. To address this need, we propose a novel reactive coarse-grained force field, as well as a publicly available software package, named the Mechanochemical Dynamics of Active Networks (MEDYAN), for simulating active network evolution and dynamics (available at www.medyan.org). This model can be used to study the non-linear, far from equilibrium processes in active matter systems, in particular, comprised of interacting semi-flexible polymers embedded in a solution with complex reaction-diffusion processes. In this work, we applied MEDYAN to investigate a contractile actomyosin network consisting of actin filaments, alpha-actinin cross linking proteins, and non-muscle myosin IIA mini-filaments. We found that these systems undergo a switch-like transition in simulations from a random network to ordered, bundled structures when cross-linker concentration is increased above a threshold value, inducing contraction driven by myosin II mini-filaments. Our simulations also show how myosin II mini-filaments, in tandem with cross-linkers, can produce a range of actin filament polarity distributions and alignment, which is crucially dependent on the rate of actin filament turnover and the actin filament's resulting super-diffusive behavior in the actomyosin-cross-linker system. We discuss the biological implications of these findings for the arc formation in lamellipodium-to-lamellum architectural remodeling. Lastly, our simulations produce force-dependent accumulation of myosin II, which is thought to be responsible for their mechanosensation ability, also spontaneously generating myosin II concentration gradients in the solution phase of the simulation volume. PMID- 27120190 TI - Resorbable screw and sheath versus resorbable interference screw and staples for ACL reconstruction: a comparison of two tibial fixation methods. AB - PURPOSE: The anterior cruciate ligament (ACL) reconstruction is one of the most performed and successful orthopaedic procedures. The results are considered independent by the choice of the graft and the fixation devices. A growing interest on resorbable non-metallic fixation devices versus standard metallic fixation devices has been noted over recent years with few clinical experiences reported in the literature. The aim of this study is to compare the clinical and radiological outcomes of patients undergoing ACL reconstruction using autologous hamstring tendons with tibial fixation by a centrally placed resorbable screw and sheath to a combination of an eccentrically placed resorbable interference screw and supplementary staple fixation. METHODS: Ninety patients undergoing an isolated, single-bundle, primary ACL reconstruction with autologous hamstring tendons, using the same femoral fixation, were randomized to a tibial fixation with a centrally placed resorbable screw and sheath, BioIntrafix (group A), or an eccentrically placed resorbable interference screw, BioRCI, and two non resorbable staples (group B). The latter has represented for many years our standard fixation method. Clinical evaluations (KOOS, IKDC, KT-2000TM side-to side difference) and radiological analyses were conducted in both groups with a minimum follow-up of 2 years. RESULTS: We assisted in a satisfactory pain relief and functional improvements, without significant clinical and radiological differences in both groups. No further surgery was needed in patients with the screw/sheath tibial fixation. Seven patients with the screw/staples tibial fixation needed the surgical removal of the fixation devices due to pes anserinus irritation or local infection years after the index operation. Other parameters such as the tunnel enlargement were not statistically different in the two groups. CONCLUSIONS: Good clinical and radiological outcomes of ACL reconstruction by a screw/sheath tibial fixation have been reported showing comparable results with respect to screw/staples fixation. There were no failures associated with loss of fixation with either of tibial fixation methods. A fewer number of surgical removals of tibial devices were also recorded in patients treated by the screw/sheath fixation system, related to the absence of local intolerance or infection compared to subjects with a standard tibial fixation. PMID- 27120191 TI - Regenerative approaches for the treatment of early OA. AB - The diagnosis and the prompt treatment of early osteoarthritis (OA) represent vital steps for delaying the onset and progression of fully blown OA, which is the most common form of arthritis, involving more than 10 % of the world's population older than 60 years of age. Nonsurgical treatments such as physiotherapy, anti-inflammatory medications, and other disease-modifying drugs all have modest and short-lasting effect. In this context, the biological approaches have recently gained more and more attention. Growth factors, blood derivatives, such as platelet concentrates, and mesenchymal adult stem cells, either expanded or freshly isolated, are advocated amongst the most promising tool for the treatment of OA, especially in the early phases. Primarily targeted towards focal cartilage defects, these biological agents have indeed recently showed promising results to relieve pain and reduce inflammation in patients with more advanced OA as well, with the final aim to halt the progression of the disease and the need for joint replacement. However, despite of a number of satisfactory in vitro and pre-clinical studies, the evidences are still limited to support their clinical efficacy in OA setting. PMID- 27120192 TI - PSI kinematic versus non-PSI mechanical alignment in total knee arthroplasty: a prospective, randomized study. AB - PURPOSE: Kinematic alignment in TKA is supposed to restore function by aligning the components to the premorbid flexion-extension axis instead of altering the joint line and natural kinematic axes of the knee. The purpose of this study was to compare mechanically aligned TKA to kinematic alignment. METHODS: In this study, 200 patients underwent TKA and were randomly assigned to 2 groups: 100 TKAs were performed using kinematic alignment with custom-made cutting guides in order to complete cruciate-retaining TKA; the other 100 patients underwent TKA that was manually performed using mechanical alignment. The WOMAC and combined Knee Society Score (KSS), as well as radiological alignment, were determined as outcome parameters at the 12-month endpoint. RESULTS: WOMAC and KSS significantly improved in both groups. There was a significant difference in both scores between groups in favour of kinematic alignment. Although the kinematic alignment group demonstrated significantly better overall results, more outliers with poor outcomes were also seen in this group. A correlation between post-operative alignment deviation from the initial plan and poor outcomes was also noted. The most important finding of this study is that applying kinematic alignment in TKA achieves comparable results to mechanical alignment in TKA. This study also shows that restoring the premorbid flexion-extension axis of the knee joint leads to better overall functional results. CONCLUSION: Kinematic alignment is a favourable technique for TKA. CLINICAL RELEVANCE: The kinematic alignment idea might be a considerable alternative to mechanical alignment in the future. LEVEL OF EVIDENCE: II. PMID- 27120193 TI - Early osteoarthritis of the patellofemoral joint. AB - Patellofemoral joint cartilage lesions are associated with a variety of clinical situations including blunt trauma, lateral patella dislocations, or as a secondary development in the setting of abnormal joint loading. There is a need for more clarity on how to best address these lesions. Most specifically, when is it necessary to surgically treat these lesions of the patella and trochlea and which technique to use? This review will focus on the spectrum of patellofemoral disease/injury and their treatment strategies, with special emphasis on cartilage damage and early osteoarthritis. Chapter sections will review the most common scenarios of cartilage damage in the patellofemoral joint, with an attempt to summarize current treatment, their outcomes, remaining challenges and unanswered questions. PMID- 27120194 TI - No difference in terms of radiostereometric analysis between fixed- and mobile bearing total knee arthroplasty: a randomized, single-blind, controlled trial. AB - PURPOSE: A concern that arises with any new prosthesis is whether it will achieve satisfactory long-term implant stability. The gold standard of assessing the quality of fixation in a new or relatively new implant is to undertake a randomized controlled trial using radiostereometric analysis. It was hypothesized that both mobile-bearing total knee arthroplasty and fixed-bearing total knee arthroplasty have comparable migration patterns at 2-year follow-up. This study investigated two types of cemented total knee arthroplasty, the mobile- or fixed bearing variant from the same family with use of radiostereometric analysis. METHODS: This prospective, patient-blinded, randomized, controlled trial was designed to investigate early migration of the tibia component after two years of follow-up with use of radiostereometric analysis. A total of 50 patients were randomized to receive a mobile- or fixed-bearing TKA from the same family. Patients were evaluated during 2-year follow-up, including radiostereometric analysis, physical and clinical examination and patient reported outcome measures (PROMs). RESULTS: At two-year follow-up, the mean (+/-SD) maximum total point motion (MTPM) in the fixed-bearing group was 0.82 (+/-1.16) versus 0.92 mm (+/ 0.64) in the mobile-bearing group (p = n.s) with the largest migration seen during the first 6 weeks (0.45 +/- 0.32 vs. 0.54 +/- 0.30). The clinical outcome and PROMs significantly improved within each group, not between both groups. CONCLUSIONS: Measuring early micromotion is useful for predicting clinical loosening that can lead to revision. The results of this study demonstrate that early migration of the mobile-bearing is similar to that of the fixed-bearing component at two years and was mainly seen in the first weeks after implantation. LEVEL OF EVIDENCE: Randomized, single-blind, controlled trial, Level I. PMID- 27120195 TI - Multiphoton Microscopy of Nonfluorescent Nanoparticles In Vitro and In Vivo. AB - Nanotechnology holds great promise for a plethora of potential applications. The interaction of engineered nanomaterials with living cells, tissues, and organisms is, however, only partly understood. Microscopic investigations of nano-bio interactions are mostly performed with a few model nanoparticles (NPs) which are easy to visualize, such as fluorescent quantum dots. Here the possibility to visualize nonfluorescent NPs with multiphoton excitation is investigated. Signals from silver (Ag), titanium dioxide (TiO2 ), and silica (SiO2 ) NPs in nonbiological environments are characterized to determine signal dependency on excitation wavelength and intensity as well as their signal stability over time. Ag NPs generate plasmon-induced luminescence decaying over time. TiO2 NPs induce photoluminescent signals of variable intensities and in addition strong third harmonic generation (THG). Optimal settings for microscopic detection are determined and then applied for visualization of these two particle types in living cells, in murine muscle tissue, and in the murine blood stream. Silica NPs produce a THG signal, but in living cells it cannot be discriminated sufficiently from endogenous cellular structures. It is concluded that multiphoton excitation is a viable option for studies of nano-bio interactions not only for fluorescent but also for some types of nonfluorescent NPs. PMID- 27120196 TI - Hydroxylations of trichothecene rings in the biosynthesis of Fusarium trichothecenes: evolution of alternative pathways in the nivalenol chemotype. AB - Fusarium sporotrichioides genes FsTri11, FsTri13, and FsTri1 encode cytochrome P450 monooxygenases (CYPs) responsible for hydroxylations at C-15, C-4, and C-8 of the trichothecene skeleton, respectively. However, the corresponding genes of nivalenol (NIV)-chemotype Fusarium graminearum remain to be functionally elucidated. In this study, we characterized the roles of these CYPs in NIV biosynthesis. Analyses of the metabolites of the F. graminearum Fgtri11- mutant, a disruptant of FgTri11 encoding isotrichodermin (ITD) C-15 hydroxylase, revealed a small amount of NIV-type trichothecenes suggesting that an alternative C-15 hydroxylase partially complemented FgTRI11p. In contrast, the C-7/C-8 hydroxylations depended solely on FgTRI1p, as suggested by the metabolite profiles of the Fgtri11- Fgtri1- double gene disruptant. Disruption of FgTri1 in both the wild-type and Fgtri13- mutant backgrounds revealed that FgTRI13p exhibits marginal activity toward calonectrin (CAL) and that it was the only C-4 hydroxylase. In addition, feeding experiments demonstrated that the C-4 hydroxylation of a 7-hydroxytrichothecene lacking C-8 ketone was extremely limited. The marginal activity of FgTRI13p toward CAL was advantageous for the C 7/C-8 hydroxylation steps in NIV biosynthesis, as transformation of a C-4 oxygenated trichothecene lacking C-7/C-8 modifications into NIV-type trichothecenes was quite inefficient. The significance of hydroxylation steps in the evolution of Fusarium trichothecenes is discussed. PMID- 27120197 TI - A Modeling Comparison of Mercury Deposition from Current Anthropogenic Mercury Emission Inventories. AB - Human activities have altered the biogeochemical cycle of mercury (Hg) since precolonial times, and anthropogenic activities will continue to perturb the natural cycle of Hg. Current estimates suggest the atmospheric burden is three to five times greater than precolonial times. Hg in the upper ocean is estimated to have doubled over the same period. The Minamata convention seeks to reduce the impact human activities have on Hg releases to the environment. A number of the Articles in the Convention concern the development of detailed inventories for Hg emissions and releases. Using the global Hg chemical transport model, ECHMERIT, the influence of the anthropogenic emission inventory (AMAP/UNEP, EDGAR, STREETS) on global Hg deposition patterns has been investigated. The results suggest that anthropogenic Hg emissions contribute 20-25% to present-day Hg deposition, and roughly two-thirds of primary anthropogenic Hg is deposited to the world's oceans. Anthropogenic Hg deposition is significant in the North Pacific, Mediterranean and Arctic. The results indicate immediate reductions in Hg emissions would produce benefits in the short term, as well as in the long term. The most impacted regions would be suitable to assess changes in Hg deposition resulting from implementation of the Minamata convention. PMID- 27120198 TI - Computational fluid dynamics for the assessment of upper airway changes in skeletal Class III patients treated with mandibular setback surgery. AB - OBJECTIVE: To analyze and compare pharyngeal airflow characteristics pre- and post-mandibular setback surgery in patients with Class III skeletal dysplasia using cone beam computed tomography (CBCT) and computational fluid dynamics (CFD). MATERIALS AND METHODS: Records of 29 patients who had received orthodontic treatment along with mandibular setback surgery were obtained. CBCT scans were obtained at three time points: T1 (before surgery), T2 (average of 6 months after surgery), and T3 (average of 1 year after surgery). Digitized pharyngeal airway models were generated from these scans. CFD was used to simulate and characterize pharyngeal airflow. RESULTS: Mean airway volume was significantly reduced from 35,490.324 mm3 at T1 to 24,387.369 mm3 at T2 and 25,069.459 mm3 at T3. Significant increase in mean negative pressure was noted from 3.110 Pa at T1 to 6.116 Pa at T2 and 6.295 Pa at T3. There was a statistically significant negative correlation between the change in airway volume and the change in pressure drop at both the T2 and T3 time points. There was a statistically significant negative correlation between the amount of mandibular setback and change in pressure drop at the T2 time point. CONCLUSIONS: Following mandibular setback surgery, pharyngeal airway volume was decreased and relative mean negative pressure was increased, implying an increased effort required from a patient for maintaining constant pharyngeal airflow. Thus, high-risk patients undergoing a large amount of mandibular setback surgery should be evaluated for obstructive sleep apnea and the proposed treatment plan be revised based on the risk for potential airway compromise. PMID- 27120199 TI - Lactobacillus acidophilus K301 Inhibits Atherogenesis via Induction of 24 (S), 25 Epoxycholesterol-Mediated ABCA1 and ABCG1 Production and Cholesterol Efflux in Macrophages. AB - Lactobacillus acidophilus species are well-known probiotics with the beneficial activity of regulating cholesterol levels. In this study, we showed that L. acidophilus K301 reduced the level of cholesterol through reverse transport in macrophages. L. acidophilus K301 upregulated the mRNA and protein levels of genes such as ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) under the control of liver X receptor (LXR), resulting in increased apoA-I-dependent cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. L. acidophilus K301 induced both ABCA1 and ABCG1 through the endogenous LXR agonist 24(S), 25-epoxcycholesterol, which is synthesized by intracellular cholesterol synthetic pathways. In vivo studies using L. acidophilus K301-treated ApoE-/- mice showed reduced accumulation of lipoproteins in the arterial lumen. The inhibitory effects of L. acidophilus K301 on accumulation of lipoprotein in atherosclerotic plaques were mediated by the induction of squalene reductase (SQLE) and oxidosqualene cyclase (OSC) and resulted in ABCA1-mediated cholesterol efflux. Taken together, our findings revealed that Lactobacillus acidophilus K301 regulates the expression of genes related to cholesterol reverse transport via the induction of endogenous LXR agonist, suggesting the therapeutic potential of Lactobacillus acidophilus K301 as an anti-atherosclerotic agent. PMID- 27120200 TI - Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D. AB - BACKGROUND: Type 2C and 2D limb girdle muscular dystrophies (LGMD) are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio respiratory events and mortality in LGMD 2C and 2D. METHODS: We reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax), cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke) and mortality as outcomes of interest for the present analysis. RESULTS: A total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24-38]. At baseline, median pulmonary vital capacity (VC) was 31% of predicted value [20 40]. Median maximal inspiratory pressure (MIP) was 31 cmH2O [IQR 20.25-39.75]. Median maximal expiratory pressure (MEP) was 30 cm H2O [20-36]. Median left ventricular ejection fraction (LVEF) was 55% [45-64] with 38% of patients with LVEF <50%. Over a median follow-up of 6 years, we observed 38% respiratory events, 14% cardiac events and 20% mortality. Among baseline characteristics, LVEF and left ventricular end diastolic diameter (LVEDD) were associated with mortality, whilst respiratory parameters (VC, MIP, MEP) and the need for home mechanical ventilation (HMV) were associated with respiratory events. CONCLUSION: In our cohort of severely respiratory impaired type 2C and 2D LGMD, respiratory morbidity was high. Cardiac dysfunction was frequent in particular in LGMD 2C and had an impact on long-term mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT02501083. PMID- 27120201 TI - Relative Performance of Non-Local Cultivars and Local, Wild Populations of Switchgrass (Panicum virgatum) in Competition Experiments. AB - The possibility of increased invasiveness in cultivated varieties of native perennial species is a question of interest in biofuel risk assessment. Competitive success is a key factor in the fitness and invasive potential of perennial plants, and thus the large-scale release of high-yielding biomass cultivars warrants empirical comparisons with local conspecifics in the presence of competitors. We evaluated the performance of non-local cultivars and local wild biotypes of the tallgrass species Panicum virgatum L. (switchgrass) in competition experiments during two growing seasons in Ohio and Iowa. At each location, we measured growth and reproductive traits (plant height, tiller number, flowering time, aboveground biomass, and seed production) of four non locally sourced cultivars and two locally collected wild biotypes. Plants were grown in common garden experiments under three types of competition, referred to as none, moderate (with Schizachyrium scoparium), and high (with Bromus inermis). In both states, the two "lowland" cultivars grew taller, flowered later, and produced between 2x and 7.5x more biomass and between 3x and 34x more seeds per plant than local wild biotypes, while the other two cultivars were comparable to wild biotypes in these traits. Competition did not affect relative differences among biotypes, with the exception of shoot number, which was more similar among biotypes under high competition. Insights into functional differences between cultivars and wild biotypes are crucial for developing biomass crops while mitigating the potential for invasiveness. Here, two of the four cultivars generally performed better than wild biotypes, indicating that these biotypes may pose more of a risk in terms of their ability to establish vigorous feral populations in new regions outside of their area of origin. Our results support an ongoing assessment of switchgrass cultivars developed for large-scale planting for biofuels. PMID- 27120202 TI - Pleistocene Hominins as a Resource for Carnivores: A c. 500,000-Year-Old Human Femur Bearing Tooth-Marks in North Africa (Thomas Quarry I, Morocco). AB - In many Middle Pleistocene sites, the co-occurrence of hominins with carnivores, who both contributed to faunal accumulations, suggests competition for resources as well as for living spaces. Despite this, there is very little evidence of direct interaction between them to-date. Recently, a human femoral diaphysis has been recognized in South-West of Casablanca (Morocco), in the locality called Thomas Quarry I. This site is famous for its Middle Pleistocene fossil hominins considered representatives of Homo rhodesiensis. The bone was discovered in Unit 4 of the Grotte a Hominides (GH), dated to c. 500 ky and was associated with Acheulean artefacts and a rich mammalian fauna. Anatomically, it fits well within the group of known early Middle Pleistocene Homo, but its chief point of interest is that the diaphyseal ends display numerous tooth marks showing that it had been consumed shortly after death by a large carnivore, probably a hyena. This bone represents the first evidence of consumption of human remains by carnivores in the cave. Whether predated or scavenged, this chewed femur indicates that humans were a resource for carnivores, underlining their close relationships during the Middle Pleistocene in Atlantic Morocco. PMID- 27120203 TI - Author's Reply to the Letter of Manchikanti and Hirsch, Entitled 'Evolution of the Epidural Treatment of Sciatica Provides Excellent Historic Review with Incomplete Modern Evidence'. PMID- 27120204 TI - Anatomical Involvement of the Subventricular Zone Predicts Poor Survival Outcome in Low-Grade Astrocytomas. AB - The subventricular zone (SVZ) has been implicated in the origination, development, and biological behavior of gliomas. Tumor-SVZ contact is also postulated to be a poor prognostic factor in glioblastomas. We aimed to evaluate the prognostic consequence of the anatomical involvement of low-grade gliomas with the SVZ. To that end, we reviewed 143 patients with diffuse astrocytomas, and tumor lesions were manually delineated on magnetic resonance images. We initially investigated the prognostic role of SVZ contact in all patients. Additionally, we investigated the influence of the anatomical proximity of the tumor lesion centroids to the SVZ in the SVZ-involved patient cohorts, as well as location within the SVZ. We found SVZ contact with tumors to be a significant prognostic factor of overall survival in all patients with diffuse astrocytomas (p = 0.027). In the SVZ-involved cohort, a shorter distance from the tumor centroid to the SVZ (<=30 mm) correlated with shorter overall survival (p = 0.022) on univariate analysis. However, there was no significant difference in overall survival with respect to the SVZ region involved with the tumor (p = 0.930). Multivariate analysis showed that a shorter distance between the tumor centroid and the SVZ (p = 0.039) was significantly associated with poor overall survival in SVZ-involved patients. Hence, this study helps establish the prognostic role of the anatomical interaction of tumors with the SVZ in low-grade astrocytomas. PMID- 27120205 TI - Fluorescent non-conjugated polymer dots for targeted cell imaging. AB - Through the chemical crosslinking of the sub-fluorophore, linear non-conjugated polymers can possess strong photoluminescence (PL), which is a very important fluorescence behavior and the non-conjugated polymer dots (PDs) are efficient bio fluorophores for bio-based applications. Herein, the new type of non-conjugated polyethyleneimine (PEI) PDs was further modified by targeting molecules (folic acid) for a new generation of bio-fluorophores. The free folic acid can quench the PL of PDs by energy transfer, while the conjugated folic acid@PDs (FA@PDs) can still maintain their PL properties to a certain degree. The FA@PDs also possess lower toxicity compared with free PDs, which is possibly due to blocking of the amino groups. Moreover, we investigated the targeted bioimaging applications of the FA@PDs, which gave a very important direction for application of these types of materials. PMID- 27120206 TI - Proteome of equine oviducal fluid: effects of ovulation and pregnancy. AB - The equine oviduct plays a pivotal role in providing the optimal microenvironment for early embryonic development, but little is known about the protein composition of the oviducal fluid in the horse. The aim of the present study was to provide a large-scale identification of proteins in equine oviducal fluid and to determine the effects of ovulation and pregnancy. Four days after ovulation, the oviducts ipsilateral and contralateral to the ovulation side were collected from five pregnant and five non-pregnant mares. Identification and relative quantification of proteins in the oviducal fluid of the four groups was achieved by isobaric tags for relative and absolute quantification (iTRAQ) labelling and HPLC-tandem mass spectrometry. The presence of an embryo in the ipsilateral oviducal fluid of pregnant mares induced upregulation of 11 and downregulation of two proteins compared with the contralateral side, and upregulation of 19 proteins compared with the ipsilateral side of non-pregnant mares. Several of these upregulated proteins are related to early pregnancy in other species. The present study represents the first high-throughput identification of proteins in the oviducal fluid of the mare. The results support the hypothesis that the equine embryo interacts with the oviduct, affecting the maternal secretion pattern of proteins involved in pregnancy-related pathways. PMID- 27120207 TI - Aromatic Cyanoalkylation through Double C-H Activation Mediated by Ni(III). AB - Herein we report an atom- and step-economic aromatic cyanoalkylation reaction that employs nitriles as building blocks and proceeds through Csp(2)-H and Csp(3) H bond activation steps mediated by Ni(III). In addition to cyanomethylation with MeCN, regioselective alpha-cyanoalkylation was observed with various nitrile substrates to generate secondary and tertiary nitriles. Importantly, to the best of our knowledge these are the first examples of C-H bond activation reactions occurring at a Ni(III) center, which may exhibit different reactivity and selectivity profiles than those corresponding to analogous Ni(II) centers. These studies provide guiding principles to design catalytic C-H activation and functionalization reactions involving high-valent Ni species. PMID- 27120208 TI - [Pulmonary hypertension 2016: classification, diagnosis, therapy]. PMID- 27120210 TI - [Stroke from the Perspective of Neurologists (Part 1): Update in the Acute Diagnosis]. AB - Stroke care is rapidly changing. The next three "Praxis" editions will give you an update and the neurological perspective of stroke including acute diagnosis, acute therapy and secondary prevention. The first article focuses on diagnostic procedures in the acute stage. In spite of the tremendous progress stroke remains frequent and the major cause of adult-onset disability. The pathophysiological correlate is the cerebral ischemia or the cerebral bleeding, which are in most reason responsible for persistent disability and high health care and social costs. The shortest work-up to the right diagnoses and the favored therapies can save life and improve quality of daily living. The rapid clinical and radiological identification of the target groups which benefit is essential. In the last years several randomized controlled studies show new medical evidence. PMID- 27120211 TI - [Pediatric Abdominal Pain - Harmless or Harmful?]. AB - Abdominal pain is a very common pediatric complaint. In the majority of cases there is no life-threatening pathology behind this symptom, but a functional disease. However, all-day activities of children and adolescents are often limited, frequent absences from school, and general physician/ pediatrician office visits with often unnecessary diagnostic and therapies are registered. Once an organic etiology of the abdominal pain is excluded by a thoroughly medical history taking and physical examination, the first steps for a successful alleviation of the pain is the reassurance of the patients and their family that there is no life-threatening pathology. There is evidence that cognitive behavioral therapy may be useful in improving pain and disability outcome in the short term. There is no evidence for pharmacological, dietetic, or complementary intervention in the treatment of chronic functional abdominal pain. PMID- 27120212 TI - [How to Manage Polypharmacy in the Elderly]. AB - Polypharmacy is accentuated in our fast-growing population. Polypharmacy is associated with adverse drug reactions, interactions, non-compliance, and increased risk of geriatric syndroms (falls, incontinence, malnutrition, cognitive impairment, delirium). There is a dilemma between clinical practice guidelines and pragmatism in the treatment of elderly patients in the last ten years of life. Reducing polypharmacy is a challenge and we present some instruments for reducing polypharmacy. PMID- 27120213 TI - [What is the Optimal Nutrition for Humans?]. AB - As practitioners, we are faced in practice daily with the question about the optimal diet. Nevertheless, nutrition covers only a very small part of our medical training. A look back in the history of man shows that the human body was set to a predominantly plant-based diet for millions of years. With the introduction of factory farming and industrial food processing several hundred years ago, the current Western diet has been consisting to a large extent of animal products, leading to a number of chronic diseases such as hypertension, hypercholesterolemia, coronary heart disease, vascular dementia, diabetes, and to an increase of cancer. Many of these diseases are preventable, some even reversible when resorting to a whole-foods plant-based diet. This review work is intended to provide the practitioner with the necessary knowledge and the scientific facts. PMID- 27120214 TI - [The Mysterious Paresis]. AB - Internal jugular central venous line placement is a standardized and common clinical procedure. However, even the most skillful physician may face complications. Careful patient evaluation and detailed vascular anatomical knowledge can minimize the risk of iatrogenic injuries. Following a strict protocol in case of unsuccessful attempts of venous puncture helps to improve patient outcome. In this case report, we present a patient who suffered an unusual injury. Further, we discuss current treatment options for pseudoaneurysms. PMID- 27120215 TI - [Nearly a third of all assistant physicians have depression or depressive symptoms]. PMID- 27120216 TI - [Testosterone is not a miracle cure for elderly men]. PMID- 27120218 TI - [ORL19. A rare swelling at the base of the tongue]. PMID- 27120219 TI - [Insights into diversity]. PMID- 27120220 TI - Repurposing Synechocystis PCC6803 UirS-UirR as a UV-Violet/Green Photoreversible Transcriptional Regulatory Tool in E. coli. AB - We have previously engineered green/red and red/far red photoreversible E. coli phytochrome and cyanobacteriochrome (CBCR) two-component systems (TCSs) and utilized them to program tailor-made gene expression signals for gene circuit characterization. Here, we transport the UV-violet/green photoreversible CBCR TCS UirS-UirR from Synechocystis PCC6803 to E. coli. We demonstrate that the promoter of the small RNA csiR1, previously shown to be activated by inorganic carbon stress, is a UirS-UirR output. Additionally, in contrast to a recently proposed sequestration model, we show that the sensor histidine kinase UirS phosphorylates the response regulator UirR to activate PcsiR1 transcription in response to UV violet light. Finally, we measure changes in UirS-UirR output minutes after a change in light input and exploit these rapid dynamics to program a challenging gene expression signal with high predictability. UirS-UirR is the first engineered transcriptional regulatory tool activated exclusively by UV-violet light, and the most blue shifted photoreversible transcriptional regulatory tool. PMID- 27120221 TI - One-step synthesis of amino-functionalized ultrasmall near infrared-emitting persistent luminescent nanoparticles for in vitro and in vivo bioimaging. AB - Near infrared (NIR)-emitting persistent luminescent nanoparticles (NPLNPs) have attracted much attention in bioimaging because they can provide long-term in vivo imaging with a high signal-to-noise ratio (SNR). However, conventional NPLNPs with large particle sizes that lack modifiable surface groups suffer from many serious limitations in bioimaging. Herein, we report a one-step synthesis of amino-functionalized ZnGa2O4:Cr,Eu nanoparticles (ZGO) that have an ultrasmall size, where ethylenediamine served as the reactant to fabricate the ZGO as well as the surfactant ligand to control the nanocrystal size and form surface amino groups. The ZGO exhibited a narrow particle size distribution, a bright NIR emission and a long afterglow luminescence. In addition, due to the excellent conjugation ability of the surface amino groups, the ZGO can be easily conjugated with many bio-functional molecules, which has been successfully utilized to realize in vitro and in vivo imaging. More importantly, the ZGO achieved re excitation imaging using 650 nm and 808 nm NIR light in situ, which is advantageous for long-term and higher SNR bioimaging. PMID- 27120222 TI - Interaction Between Helminths and Toll-Like Receptors: Possibilities and Potentials for Asthma Therapy. AB - Toll-like receptors (TLRs) are essential components of the innate immune system. They play an important role in the pathogenesis of allergic diseases, especially asthma. Since TLRs significantly orchestrate innate and adaptive immune response, their manipulation has widely been considered as a potential approach to control asthma symptoms. It is well established that helminths have immunoregulatory effects on host immune responses, especially innate immunity. They release bioactive molecules such as excretory-secretory (ES) products manipulating TLRs expression and signaling. Thus, given the promising results derived from preclinical studies, harnessing helminth-derived molecules affecting TLRs can be considered as a potential biological therapy for allergic diseases. Prospectively, the data that are available at present suggest that, in the near future, it is possible that helminth antigens will offer new therapeutic strategies and druggable targets for fighting allergic diseases. This review describes the interactions between helminths and TLRs and discusses the potential possibilities for asthma therapy. In this opinion paper, the authors aimed to review the updated literatures on the interplay between helminths, TLRs, and asthma with a view to proposing helminth-based asthma therapy. PMID- 27120223 TI - Ventricular fibrillation: triggers, mechanisms and therapies. AB - Ventricular fibrillation (VF) is a common, life-threatening arrhythmia responsible for significant morbidity and mortality. Due to challenges in safely mapping VF, a comprehensive understanding of its mechanisms remains elusive. Recent findings have provided new insights into mechanisms that sustain early VF. Notably, the central role of electrical rotors and catheter-based ablation of VF rotor substrate have been recently reported. In this article, we will review data regarding four stages of VF: initiation, transition, maintenance and evolution. We will discuss the particular mechanisms for each stage and therapies targeting these mechanisms. We also examine inherited arrhythmia syndromes, including the mechanisms and therapies specific to each. We hope that the overview of VF outlined in this work will assist other investigators in designing future therapies to interrupt this life-threatening arrhythmia. PMID- 27120251 TI - FLG mutations in the East Asian atopic dermatitis patients: genetic and clinical implication. PMID- 27120252 TI - Effects of a single-dose preemptive pregabalin on acute and chronic pain after inguinal hernia repair with mesh under spinal anaesthesia: A randomised controlled trial. PMID- 27120254 TI - Comparison of Learning Curves for Major and Minor Laparoscopic Liver Resection. AB - BACKGROUND: Because laparoscopic liver resection (LLR) has a steep learning curve, analyzing experience is important for trainees. Several authors have described the learning curve of LLR, without comparing the learning curves between major and minor LLR. METHODS: Perioperative data were retrieved from the medical records of 170 consecutive patients who underwent LLR by a single surgeon at a tertiary hospital. Learning curves were generated and compared between major and minor LLR using cumulative sum control charts and the moving average. RESULTS: Major and minor LLR was performed in 96 and 74 patients, respectively. The learning curves showed a steady state after case 50 for major LLR. Because of discordant results in minor LLR, subgroup analyses were performed, showing competency in LLR after cases 25 and 35 for left lateral sectionectomy and tumorectomy, respectively. Transfused red blood cell volume (0.6 versus 2.2 packs, P < .001) decreased after achievement of competence in major LLR. Blood loss exceeding 500 mL (odds ratio 2.395, 95% confidence interval 1.096-5.233, P = .028) was independently associated with LLR failure. CONCLUSIONS: The number of cases required to accomplish LLR differed according to the extent of resection. Extensive blood loss was independently associated with LLR failure. PMID- 27120253 TI - Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome. AB - HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5' and 3' UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558-10G>A, that causes an aberrant splice product and a mutation in the 3'UTR, c.*559C>T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway. PMID- 27120255 TI - Chronic stress alters the expression levels of longevity-related genes in the rat hippocampus. AB - The molecular mechanisms underlying the negative effects of psychological stress on cellular stress during aging and neurodegenerative diseases are poorly understood. The main objective of this study was to test the effect of chronic psychological stress, and the consequent increase of circulating glucocorticoids, on several hippocampal genes involved in longevity. Sirtuin-1, p53, thioredoxin interacting protein, and heat shock protein 70 were studied at the mRNA and protein levels in stressed and non-stressed animals. Stress treatment for 10 days decreased sirtuin-1 and heat shock protein 70 levels, but increased levels of p53, thioredoxin-interacting protein and the NADPH oxidase enzyme. Examination of protein expression following two months of stress treatment indicated that sirtuin-1 remained depressed. In contrast, an increase was observed for thioredoxin-interacting protein, heat shock protein 70, p53 and the NADPH oxidase enzyme. The effect of stress was reversed by mifepristone, a glucocorticoid receptor antagonist. These data suggest that chronic stress could contribute to aging in the hippocampus. PMID- 27120256 TI - Risk of Recurrence After Surviving Severe Sepsis: A Matched Cohort Study. AB - OBJECTIVES: To examine the risk of recurrence in adults who survived first episode severe sepsis for at least 3 months. DESIGN: A matched cohort study. SETTING: Inpatient claims data from Taiwan's National Health Insurance Research Database. SUBJECTS: We analyzed 10,818 adults who survived first-episode severe sepsis without recurrence for at least 3 months in 2000 (SS group; mean age, 62.7 yr; men, 54.7%) and a group of age/sex-matched (1:1) population controls who had no prior history of severe sepsis. All subjects were followed from the study entry to the occurrence of end-point, death, or until December 31, 2008, whichever date came first. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary end-point was severe sepsis that occurred after January 1, 2001 (the study entry). Relative risk of the end-point was assessed using competing risk regression model. During the follow-up period, severe sepsis and death occurred in 35.0% and 26.5% of SS group and in 4.3% and 18.6% of controls, respectively, representing a covariate-adjusted sub-hazard ratio of 8.89 (95% CI, 8.04-9.83) for the risk of recurrence. In stratified analysis by patient characteristics, the sub-hazard ratios ranged from 7.74 in rural area residents to 23.17 in young adults. In subgroup analysis by first-episode infection sites in SS group, the sub-hazard ratios ranged from 4.82 in intra-abdominal infection to 9.99 in urinary tract infection. CONCLUSIONS: Risk of recurrence after surviving severe sepsis is substantial regardless of patient characteristics or infection sites. Further research is necessary to find underlying mechanisms for the high risk of recurrence in these patients. PMID- 27120257 TI - Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa. AB - The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent degradation of the CFTR. We describe here the development of a series of potent and selective Cif inhibitors by structure-based drug design. Initial screening revealed 1a (KB2115), a thyroid hormone analog, as a lead compound with low micromolar potency. Structural requirements for potency were systematically probed, and interactions between Cif and 1a were characterized by X-ray crystallography. On the basis of these data, new compounds were designed to yield additional hydrogen bonding with residues of the Cif active site. From this effort, three compounds were identified that are 10-fold more potent toward Cif than our first-generation inhibitors and have no detectable thyroid hormone-like activity. These inhibitors will be useful tools to study the pathological role of Cif and have the potential for clinical application. PMID- 27120258 TI - DNA methylation in Parkinson's disease. AB - Epigenetic processes control the embryonic development into multicellular organisms and determine the functional differences of genetically identical cells and individuals. They are also involved in a variety of complex functions such as learning and memory consolidation and have been implicated in aging processes. Beyond the actual genetic information encoded in the DNA sequence, epigenetic modifications in particular DNA methylation and various histone modifications shape the chromatin into a transcriptional permissive or repressive state. DNA methylation patterns are altered by environmental conditions and can be carried forward through mitosis and meiosis. Hence, DNA methylation probably mediates complex environment-gene interactions, determines individual disease characteristics, and contributes to effects and side effects of drugs. In addition to classic monogenic epigenetic diseases, i.e., Prader-Willi and Rett syndrome, recent data point to an epigenetic component also in apparent sporadic neuro-psychiatric disorders and increasing evidence suggests a role for altered DNA methylation in Parkinson's disease. Epigenetic alterations, DNA methylation in particular, may account for the yet unexplained individual susceptibility and the variability in the course of Parkinson's disease and could provide hints toward the development of novel therapeutic targets. Parkinson's disease (PD) is conceptualized as a consequence of genetic variants and environment-gene interactions on a background of age-related changes. Epigenetic modifications have been implicated in aging and can be altered by environment stimuli. The review explores the possibility of an epigenetic component in PD, focusing on DNA methylation. Methylation of alpha-synuclein (SNCA) and microtubule-associated protein tau gene appear to be of particular importance and epigenome-wide methylation studies point to several additional candidate genes which may contribute to the individual susceptibility toward PD. This article is part of a special issue on Parkinson disease. PMID- 27120259 TI - The Public Health Crisis in Emergency General Surgery: Who Will Pay the Price and Bear the Burden? PMID- 27120260 TI - Characterization of limb differences in children with Cornelia de Lange Syndrome. AB - Cornelia de Lange syndrome (CdLS) is a well-described multisystem developmental disorder characterized by dysmorphic facial features, growth and behavioral deficits, and cardiac, gastrointestinal, and limb anomalies. The limb defects seen in CdLS can be mild, with small feet or hands only, or can be severe, with variable deficiency defects involving primarily the ulnar structures and ranging from mild hypoplasia of the fifth digit to complete absence of the forearm. Interestingly, the upper limbs are typically much more involved than the lower extremities that generally manifest with small feet and 2-3 syndactyly of the toes and shortened fourth metatarsal. The upper limbs often manifest asymmetric involvement. The limb findings in our cohort of 378 individuals with CdLS demonstrate a consistent pattern of laterality and symmetry involvement (with increased severity of right-sided limb in individuals with asymmetric limb defects) and a correlation of more significant limb defects with an increased risk of other structural anomalies, and more severe behavioral outcomes. Additionally, we found that individuals with mutations in NIPBL were most likely to have limb defects compared to mutations in other genes with nonsense, exonic deletion, and frameshift mutations being most prevalent in those with limb defects. Characterization of the limb differences in children with CdLS may provide a tool to assist in genetic counseling and determining prognosis. This paper will review the limb involvement in a large cohort of individuals with CdLS assessing the correlation with molecular etiologies, symmetry, additional structural birth defects, and cognitive outcomes. (c) 2016 Wiley Periodicals, Inc. PMID- 27120261 TI - Prognostic significance of pulsatile tinnitus in cervical artery dissection. AB - BACKGROUND AND PURPOSE: Our aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. METHODS: All CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0-1. RESULTS: Sixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22 12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79-0.86), Horner syndrome (OR 1.95, 95% CI 1.16-3.29) and vessel occlusion (OR 0.62, 95% CI 0.40-0.94) and to non-significant predictors age, sex, pain and location of CeAD. CONCLUSION: The presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome. PMID- 27120262 TI - Al-Anon newcomers: benefits of continuing attendance for six months. AB - BACKGROUND: Al-Anon Family Groups, a 12-step mutual-help program for people concerned about another person's drinking, is the most widely used form of help by Concerned Others. OBJECTIVES: This longitudinal study examined newcomers' outcomes of attending Al-Anon. Aims were to better understand early gains from Al Anon to inform efforts in the professional community to facilitate concerned others' attendance of and engagement in Al-Anon. METHODS: We compared two groups of Al-Anon newcomers who completed surveys at baseline and 6 months later: those who discontinued attendance by the 6-month follow-up (N = 133), and those who were still attending Al-Anon meetings (N = 97); baseline characteristics were controlled in these comparisons. RESULTS: Newcomers who sustained participation in Al-Anon over the first 6 months of attendance were more likely than those who discontinued participation during the same period to report gains in a variety of domains, such as learning how to handle problems due to the drinker, and increased well-being and functioning, including reduced verbal or physical abuse victimization. Newcomers to Al-Anon reported more personal gains than drinker related gains. The most frequent drinker gain was a better relationship with the Concerned Other; attendees were more likely to report this, as well as daily, in person contact with the drinker. CONCLUSION: Al-Anon participation may facilitate ongoing interaction between Concerned Others and drinkers, and help Concerned Others function and feel better. Thus, short-term participation may be beneficial. Health-care professionals should consider providing referrals to Al Anon and monitoring early attendance. PMID- 27120263 TI - Spectrally Selective Photocapacitance Modulation in Plasmonic Nanochannels for Infrared Imaging. AB - The optical response of subwavelength plasmonic structures can be used to monitor minute changes in their physical, chemical, and biological environments with high performance for sensing. The optical response in the far field is governed by the near-field properties of plasmon resonances. Sharp, tunable resonances can be obtained by controlling the shape of the structure and by using resonant cavities. However, microintegration of plasmonic structures on chips is difficult because of the readout in the far field. As such, structures that form an electrical microcircuit and directly monitor the near-field variation would be more desirable. Here, we report on an electronically readable photocapacitor based on a plasmonic nanochannel structure with high spectral resolution and a large modulation capability. The structure consists of metallic U-cavities and semiconductor channels, which are used to focus and confine light at the semiconductor-metal interfaces. At these interfaces, light is efficiently converted into photocarriers that change the electrical impedance of the structure. The capacitance modulation of the structure in response to light produces a light-to-dark contrast ratio larger than 10(3). A reflectance spectrum with a bandwidth of 16 nm and a 6% modulation depth is detected using a reactance variation of 3 kOmega with the same bandwidth. This photocapacitor design offers a practical means of monitoring changes induced by the near field and thus could be deployed in pixel arrays of image sensors for miniaturized spectroscopic applications. PMID- 27120264 TI - Substance abuse in early adolescents and HIV preventive behaviors: findings from a school-based cross-sectional survey for the period from 2009 to 2013, Bangkok Thailand. AB - This study is first of its kind in Bangkok, and is a five-year (2009-2013) cross sectional web-based survey to examine HIV preventive behaviors related to substance abuse among adolescents (N = 16,913). The questionnaire was self administered. Logistic regression was used to analyze the data. The relationship between different types of substance abuse with risky and preventive behaviors was assessed. Male participants reported more substance abuse as compared to females. The risk behaviors observed among the substance abusers include increased sexual experience, multiple sex partners, no use of condoms, and injection drug use. The preventive behaviors include having a high self-risk assessment, going for HIV testing (highest in methamphetamine users), and screening for sexually transmitted infection. Logistic regression suggests that risky behaviors (e.g., sexual experience, injection drug use) are more common in substance abusers. Adolescents are clearly at a high risk. Behavioral preventive measures are needed to reduce or delay premature substance exposure to prevent a wide range of health problems and risks such as HIV and AIDS, injection drug use and unprotected sex. PMID- 27120265 TI - Ncx3 gene ablation impairs oligodendrocyte precursor response and increases susceptibility to experimental autoimmune encephalomyelitis. AB - The Na(+) /Ca(2+) exchanger NCX3, recently identified as a myelin membrane component, is involved in the regulation of [Ca(2+) ]i during oligodendrocyte maturation. Here NCX3 involvement was studied in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Western blotting and quantitative colocalization studies performed in wild-type ncx3(+/+) mice at different stages of EAE disease showed that NCX3 protein was intensely upregulated during the chronic stage, where it was intensely coexpressed with the oligodendrocyte precursor cells (OPC) marker NG2 and the premyelinating marker CNPase. Moreover, MOG35-55 -immunized mice lacking the ncx3 gene displayed not only a reduced diameter of axons and an intact myelin ring number but also a dramatic decrease in OPC and pre-myelinating cells in the white matter of the spinal cord when compared with ncx3(+/+) . Accordingly, ncx3(-/-) and ncx3(+/-) mutants developed early onset of EAE and more severe clinical symptoms. Interestingly, cytofluorimetric analysis revealed that during the peak stage of the disease, the number of immune T-cell subsets in ncx3(-/-) mice, was not statistically different from that measured in ncx3(+/+) . Our findings demonstrate that knocking-out NCX3 impairs oligodendrocyte response and worsens clinical symptoms in EAE without altering the immune T-cell population. GLIA 2016;64:1124-1137. PMID- 27120267 TI - Synthesis Toward and Stereochemical Assignment of Clathsterol: Exploring Diverse Strategies to Polyoxygenated Sterols. AB - Herein we describe a synthesis of the trisulfate derivative of clathsterol (1), a marine sterol endowed with impressive structural features and moderate inhibitory activity against HIV-1 reverse transcriptase. By synthesizing two possible isomers of the side chain, the stereochemistry of 1 is assigned. In creating chiral side chains from steroidal lactone, our strategies, including an addition/reduction procedure to give C22R-OH, an epoxide-opening reaction, and a [3.3]-rearrangement to induce the generation of C24S-Et and C24R-Et respectively, are highly flexible and complementary to each other. PMID- 27120266 TI - Periprosthetic tibial bone mineral density changes after total knee arthroplasty. AB - Background and purpose - Total knee arthroplasty (TKA) may cause postoperative periprosthetic bone loss due to stress shielding. Bone also adapts to mechanical alterations such as correction of malalignment. We investigated medium-term changes in bone mineral density (BMD) in tibial periprosthetic bone after TKA. Patients and methods - 86 TKA patients were prospectively measured with dual energy X-ray absorptiometry (DXA), the baseline measurement being within 1 week after TKA and the follow-up measurements being at 3 and 6 months, and at 1, 2, 4, and 7 years postoperatively. Long standing radiographs were taken and clinical evaluation was done with the American Knee Society (AKS) score. Results - The baseline BMD of the medial tibial metaphyseal region of interest (ROI) was higher in the varus aligned knees (25%; p < 0.001). Medial metaphyseal BMD decreased in subjects with preoperatively varus aligned knees (13%, p < 0.001) and in those with preoperatively valgus aligned knees (12%, p = 0.02) between the baseline and 7-year measurements. No statistically significant changes in BMD were detected in lateral metaphyseal ROIs. No implant failures or revision surgery due to tibial problems occurred. Interpretation - Tibial metaphyseal periprosthetic bone is remodeled after TKA due to mechanical axis correction, resulting in more balanced bone stock below the tibial tray. The diaphyseal BMD remains unchanged after the initial drop, within 3-6 months. This remodeling process was related to good component survival, as there were no implant failures or revision operations due to tibial problems in this medium-term follow-up. PMID- 27120268 TI - Unusually Huge Charge Storage Capacity of Mn3O4-Graphene Nanocomposite Achieved by Incorporation of Inorganic Nanosheets. AB - Remarkable improvement in electrode performance of Mn3O4-graphene nanocomposites for lithium ion batteries can be obtained by incorporation of a small amount of exfoliated layered MnO2 or RuO2 nanosheets. The metal oxide nanosheet incorporated Mn3O4-reduced graphene oxide (rGO) nanocomposites are synthesized via growth of Mn3O4 nanocrystals in the mesoporous networks of rGO and MnO2/RuO2 2D nanosheets. Incorporation of metal oxide nanosheets is highly effective in optimizing porous composite structure and charge transport properties, resulting in a remarkable increase of discharge capacity of Mn3O4-rGO nanocomposite with significant improvement of cyclability and rate performance. The observed enormous discharge capacity of synthesized Mn3O4-rGO-MnO2 nanocomposite (~1600 mA.h.g(-1) for the 100th cycle) is the highest value among reported data for Mn3O4-rGO nanocomposite. Despite much lower electrical conductivity of MnO2 than RuO2, the MnO2-incorporated nanocomposite at optimal composition (2.5 wt %) shows even larger discharge capacities with comparable rate characteristics compared with the RuO2-incorporated homologue. This finding underscores that the electrode performance of the resulting nanosheet-incorporated nanocomposite is strongly dependent on its pore and composite structures rather than on the intrinsic electrical conductivity of the additive nanosheet. The present study clearly demonstrates that, regardless of electrical conductivity, incorporation of metal oxide 2D nanosheet is an effective way to efficiently optimize the electrode functionality of graphene-based nanocomposites. PMID- 27120269 TI - Ureteral Papilla Implantation as a Technique for Neoureterocystostomy in Cats Undergoing Renal Transplantation: 30 Cases. AB - OBJECTIVE: To describe the clinical outcome of donor and recipient cats undergoing ureteral papilla harvest and implantation as a technique for neoureterocystostomy in clinical kidney transplant. STUDY DESIGN: Retrospective case series. ANIMALS: Donor (n=31) and recipient (n=30) cats that underwent kidney harvest and transplantation using ureteral papilla implantation technique for neoureterocystostomy. METHODS: Medical records for donor and recipient cats presented to the University of Wisconsin Veterinary Teaching Hospital from January 2003 to December 2014 were reviewed. Data recorded included complete blood count, serum chemistry panel, surgical technique, diagnostic imaging results, short- and long-term complications, and anesthetic survival. RESULTS: All 30 recipients recovered from anesthesia. Four died within 24 hours and 26 survived to hospital discharge. Serum creatinine was within the reference interval by 72 hours in 22/26 cats (85%). Complications related to the ureteral papilla implantation technique were seen in only 1 cat (3%). Uroabdomen diagnosed on day 3 ultimately resolved over the following 24 hours without surgical intervention. All 31 donor cats survived to discharge. Four donors (13%) experienced mild, transiently increased serum creatinine. CONCLUSION: Ureteral papilla implantation is a viable technique for neoureterocystostomy in cats undergoing kidney transplantation. Proposed benefits for the recipient include a less technically challenging anastomosis, decreased risk of ureteral obstruction at the anastomosis site, and reduced risk of leakage compared to previous reports. Benefits for recipients should be weighed against risks to donors, including a more complex ureteral harvest, increased surgical time, and potential injury or obstruction of the contralateral ureteral papilla. PMID- 27120270 TI - Systematic Review of Outcome Measures Reported in Clinical Canine Osteoarthritis Research. AB - OBJECTIVE: To record and categorize the outcome measures used in dogs with naturally occurring osteoarthritis (OA) by systematically reviewing the peer reviewed publications on OA in dogs. STUDY DESIGN: Systematic literature review. STUDY POPULATION: Peer reviewed literature on canine OA. METHODS: A computer based bibliographic search was performed on PubMed and CAB Abstracts in August 2013 to find peer reviewed publications relevant to canine OA. Inclusion and exclusion criteria were applied. The outcome measures reported within each publication were recorded and categorized for comparison. Adequately described outcome measures were assessed for uniqueness and evidence of prior validation. RESULTS: Of 3,697 publications identified and screened, 117 were deemed eligible for inclusion. Within eligible publications, outcome measures were used 618 times (median of 4 outcome measures per publication). Outcomes measured were divided into 5 groups containing 65 categories. The most frequently assessed outcomes were lameness assessment with no stated gait/mixed gaits (66 outcomes), radiography (58), and lameness single gait/lateral motion (55). Of 618 outcome measures reported, 491 were assessed for uniqueness and 348 (71%) were unique to a single publication. Ten outcome measures were reported to have been validated. CONCLUSION: Many outcome measures have been used to assess canine OA. There is no consensus on which are the most useful outcomes or by which method they should be assessed. There is a pressing need for agreement on outcomes reporting in canine OA and for validation of outcome measures used for these assessments. Until consensus is reached, we recommend at least one validated outcome measure be used in every clinical study. PMID- 27120271 TI - Antibacterial Efficacy of Several Surgical Hand Preparation Products Used by Veterinary Students. AB - OBJECTIVE: To compare the antibacterial efficacy of different surgical hand antisepsis protocols used by veterinary students. STUDY DESIGN: Prospective, randomized, controlled study. STUDY POPULATION: Third year veterinary students (n=45). METHODS: The participants were randomly assigned to 4 of the following 12 hand preparation product/time combinations: nonabrasive hand scrub method with 4% chlorhexidine gluconate (CH); hand rub with a mixture of 30% 1-propanol and 45% 2 propanol solution (MPS), 70% 2-propanol solution (IPS), or 61% ethanol solution with 1% chlorhexidine gluconate (ES/CH), with a contact time of 1.5, 3, or 5 minutes. Antibacterial efficacy was assessed after surgical hand preparation and at the end of surgery. Log reductions of total bacterial colony forming unit (CFU)/mL and positive aerobic culture rates were compared using multivariable analysis of variance and multivariable logistic regression, respectively. RESULTS: After surgical hand preparation, CH and ES/CH provided significantly higher log CFU reduction and lower positive culture rate for Gram-positive and spore-forming bacteria compared to MPS and IPS. Increase in contact time did not provide significant improvement in bacterial reduction. At the end of surgery, ES/CH provided significantly higher log CFU reduction compared to IPS and lower positive culture rate for Gram-positive bacteria compared to CH, MPS, and IPS. Increase in contact time significantly improved log CFU reduction in ES/CH and MPS groups. CONCLUSION: In our population of veterinary students ES/CH hand rubs or CH scrubs were more effective in reducing bacterial CFU during surgical hand preparation than MPS or IPS. PMID- 27120272 TI - Reconstruction of a Complicated Orbital Depression Fracture with Medial Wall and Globe Repositioning in a Horse: A Collaboration Across Disciplines and Specialties. AB - OBJECTIVE: To report the surgical reconstruction of a complicated orbital depression fracture in a horse with emphasis on medial wall and globe repositioning. STUDY DESIGN: Clinical report. ANIMALS: A 6 year old Irish Sport Horse gelding. METHODS: The eventer presented with acute, severe orbital trauma and globe displacement. After initial elevation of the depression fractures of the facial bones and reconstruction of the orbit, the globe was recessed secondary to displacement of the medial wall and floor of the orbit within the conchofrontal sinus. A three-dimensional model of the fracture configuration was used for presurgical planning to reposition the globe. During a subsequent surgical procedure, a resorbable plate was placed in the floor of the orbit and the medial orbital wall and globe were repositioned using a sinoscopic approach and stabilized with the placement of tissue expanders within the conchofrontal sinus. The tissue expanders were subsequently removed after 3 weeks under standing sedation. RESULTS: The right globe was successfully repositioned in a more correct anatomical orientation and the horse resumed work 3 months postoperatively, and successfully competed at its previous level 5 months postoperatively. No visual deficits have been reported by the owners. CONCLUSION: Efforts to restore the medial wall and/or floor of the orbit with concurrent globe repositioning should be considered in horses with severe orbital depression fractures that result in abnormal globe position. PMID- 27120273 TI - Arthroscopic Removal of Large Extensor Process Fragments in 18 Friesian Horses: Long-Term Clinical Outcome and Radiological Follow-Up of the Distal Interphalangeal Joint. AB - OBJECTIVE: Report long-term clinical and radiological follow-up in horses after removal of large extensor process fragments occupying >25% of the joint surface of the distal interphalangeal joint (DIJ). STUDY DESIGN: Retrospective case series. ANIMALS: Friesian horses (n=18) that underwent arthroscopic removal of a large extensor process fragment. METHODS: Arthroscopic examination of the DIJ was performed in dorsal recumbency with the affected foot in extension using routine portals. Visualization of the fragment was improved using motorized synovial resectors. A dissection plane between the common digital extensor tendon and the extensor process fragment was created using sharp lever instruments, in some cases aided by motorized burrs and radiofrequency ligament dissection. The fragment was removed piecemeal using Ferris-Smith rongeurs. Medical records, preoperative and postoperative radiographs, and owner surveys were reviewed for case details and outcome. RESULTS: The technique described allowed removal of the large fragment in all 18 horses. Of the 17 horses where long-term clinical follow up was available, 14 were used as intended and 3 kept some degree of lameness. The angle between the remodeled extensor process and the dorsal surface of the distal phalanx was increased and subchondral bone remodeling at the fragment bed was noted on postoperative lateromedial radiographs. CONCLUSION: Arthroscopic removal is a good treatment option for horses with large extensor process fragmentation with a good long-term outcome. Remodeling of the remaining extensor process and the subchondral new bone formation in the fragment bed can occur with functional recovery. PMID- 27120274 TI - Letter to the Editor. PMID- 27120275 TI - Keep It Complicated. PMID- 27120276 TI - Home. PMID- 27120277 TI - Collecting New Data on Disability Health Inequities. PMID- 27120278 TI - "Isn't that euthanasia?". PMID- 27120279 TI - Why Bioethics Has a Race Problem. PMID- 27120280 TI - Emergence of a Discipline? Growth in U.S. Postsecondary Bioethics Degrees. PMID- 27120282 TI - Conscience, Courage, and "Consent". PMID- 27120281 TI - Reframing Conscientious Care: Providing Abortion Care When Law and Conscience Collide. AB - Much of the debate on conscience has addressed the ethics of refusal: the rights of providers to refuse to perform procedures to which they object and the interests of the patients who might be harmed by their refusals. But conscience can also be a positive force, grounding decision about offering care. PMID- 27120283 TI - When Policy Produces Moral Distress: Reclaiming Conscience. PMID- 27120287 TI - There Are All Kinds of Rights. PMID- 27120288 TI - Mental shortcuts. PMID- 27120290 TI - Computational design and fabrication of core-shell magnetic molecularly imprinted polymer for dispersive micro-solid-phase extraction coupled with high-performance liquid chromatography for the determination of rhodamine 6G. AB - A novel core-shell magnetic nano-adsorbent with surface molecularly imprinted polymer coating was fabricated and then applied to dispersive micro-solid-phase extraction followed by determination of rhodamine 6G using high-performance liquid chromatography. The molecularly imprinted polymer coating was prepared by copolymerization of dopamine and m-aminophenylboronic acid (functional monomers), in the presence of rhodamine 6G (template). The selection of the suitable functional monomers was based on the interaction between different monomers and the template using the density functional theory. The ratios of the monomers to template were further optimized by an OA9 (3(4) ) orthogonal array design. The binding performances of the adsorbent were evaluated by static, kinetic, and selective adsorption experiments. The results reveal that the adsorbent possesses remarkable affinity and binding specificity for rhodamine 6G because of the enhanced Lewis acid-base interaction between the B(SH) embedded in the imprinted cavities and the template. The nano-adsorbent was successfully applied to dispersive micro-solid-phase extraction coupled to high-performance liquid chromatography for the trace determination of rhodamine 6G in samples with a detection limit of 2.7 nmol/L. Spiked recoveries ranged from 93.0-99.1, 89.5 92.7, and 86.9-105% in river water, matrimony vine and paprika samples, respectively, with relative standard deviations of less than 4.3%. PMID- 27120291 TI - Management of Spasticity in Moderate and Severe Traumatic Brain Injury: Evaluation of Clinical Practice Guidelines. AB - INTRODUCTION: Moderate to severe traumatic brain injury (TBI) can result in development of spasticity, which adversely affects function and quality of life. Given the foundation of optimal clinical practice is use of the best available evidence, we aimed to identify, describe, and evaluate methodological quality of evidence-based spasticity clinical practice guidelines (CPGs). METHODS: A comprehensive search for CPGs encompassed electronic databases and online sources. Eligible CPGs were evaluated using the validated Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. RESULTS: Five CPGs were eligible for review; 2 were specific to acquired brain injury and 1 to TBI. The 3 brain injury-specific CPGs contained 423 recommendations overall, but only 8 spasticity recommendations. On the basis of AGREE appraisals, all CPGs performed well in the areas of reporting scope and purpose; clearly presenting recommendations; including various stakeholders in the CPG development process; and reporting conflict of interest. However, only one CPG performed adequately on describing facilitators and barriers to implementation, advice, and tools on how to implement recommendations and provision of audit criteria. Intraclass correlation coefficient (ICC) for agreement between raters showed high agreement (ICC > 0.80) for most guidelines. CONCLUSION: Given the unique etiological features and treatment challenges associated with managing spasticity after TBI, more TBI-specific spasticity CPGs are required. These should incorporate information on the facilitators and barriers to implementation, advice on implementing recommendations, and audit criteria. PMID- 27120292 TI - The Effects of (-)-OSU6162 on Chronic Fatigue in Patients With Traumatic Brain Injury: A Randomized Controlled Trial. AB - OBJECTIVE: To examine the effects of the monoaminergic stabilizer (-)-OSU6162 on mental fatigue in patients with traumatic brain injury. SETTING: Single-center Neurorehabilitation Clinic. DESIGN: Randomized, double-blind, placebo-controlled trial. PARTICIPANTS: Sixty-four subjects with traumatic brain injury were randomized to treatment (n = 33) and placebo (n = 31). MAIN MEASURES: The effects of (-)-OSU6162 at a dose of 15 mg twice a day were evaluated using self assessment scales and neuropsychological tests measuring mental fatigue. RESULTS: No difference between groups was observed on any scale at baseline. At follow-up, both groups showed significant improvement on the Fatigue Severity Scale and the Mental Fatigue Scale (both Ps < .01). Similarly, the performance of both groups increased significantly on many neuropsychological tests. However, no significant between-group difference in changes on these scales was observed before or after adjustment for confounders except for one neuropsychological test favoring the control group. Sensitivity analyses showed significantly greater changes in levels of prolactin and folic acid and heart rate (all Ps < .05) in the treatment group. The mean plasma concentration after 4 weeks of treatment was 0.14 (range, 0.01-0.32) uM, which was lower than expected. INTERPRETATION: Treatment with (-) OSU6162 had no significant effect on mental fatigue in patients with traumatic brain injury compared with placebo. PMID- 27120289 TI - Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis. AB - The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis. PMID- 27120293 TI - Traumatic Brain Injury, Sleep, and Mental Health: A Longitudinal Study of Air Force Personnel Pre- and Postdeployment to Iraq. AB - OBJECTIVE: We investigated the complex relationships between traumatic brain injury (TBI), sleep, and mental health problems longitudinally among US service members (SMs) pre- and postdeployment to Iraq. PARTICIPANTS: One hundred sixty eight SMs enrolled in a 4-week Air Force Basic Combat Convoy Course predeployment. DESIGN: Self-report data were collected at the beginning and end of training and then at 1, 3, 6, and 12 months postdeployment. Regression analyses were implemented, and participants were categorized into 4 groups based on TBI history for further statistical analysis. RESULTS: Positive TBI history was associated with greater symptoms of insomnia and posttraumatic stress predeployment and persistence of insomnia symptoms, posttraumatic stress, and depression postdeployment. Positive TBI history and posttraumatic stress served as risk factors for head injury in Iraq, and SMs who reported a head injury during deployment also endorsed greater posttraumatic stress postdeployment than those without head injury. SMs with positive TBI history who also reported a new TBI in Iraq endorsed the greatest sleep and mental health problems across the study period. CONCLUSIONS: This study provides valuable information regarding temporal relationships between TBI, sleep, and mental health problems among a combat military population. Findings have important implications from both prevention and clinical perspectives. PMID- 27120295 TI - A Paired Comparison of Initial and Recurrent Concussions Sustained by US High School Athletes Within a Single Athletic Season. AB - OBJECTIVE: To compare initial and recurrent concussions regarding average number of days between concussions, acute concussion symptoms and symptom resolution time, and return to play time. SETTING/PARTICIPANTS: High school athletes sustaining multiple concussions linked within sport seasons drawn from a large sports injury surveillance study. DESIGN: Retrospective analysis of longitudinal surveillance data. MEASURES: Number of days between concussions, number of symptoms endorsed, specific symptoms endorsed, symptom resolution time, return to play time. RESULTS: Median time between initial and recurrent concussions was 21 days (interquartile range = 10-43 days). Loss of consciousness, the only significant symptom difference, occurred more frequently in recurrent (6.8%) than initial (1.7%) concussions (P = .04). No significant difference was found in the number of symptoms (P = .84) or symptom resolution time (P = .74). Recurrent concussions kept athletes from play longer than initial concussions (P < .0001); 26.6% of recurrent concussions were season ending. CONCLUSIONS: We found that athletes' initial and recurrent concussions had similar symptom presentations and resolution time. Despite these similarities, athletes were restricted from returning to play for longer periods following a recurrent concussion, indicating clinicians are managing recurrent concussions more conservatively. It is probable that concussion recognition and management are superior now compared with when previous studies were published, possibly improving recurrent concussion outcomes. PMID- 27120294 TI - Aerobic Exercise for Adolescents With Prolonged Symptoms After Mild Traumatic Brain Injury: An Exploratory Randomized Clinical Trial. AB - OBJECTIVE: To describe the methodology and report primary outcomes of an exploratory randomized clinical trial (RCT) of aerobic training for management of prolonged symptoms after a mild traumatic brain injury (mTBI) in adolescents. SETTING: Outpatient research setting. PARTICIPANTS: Thirty adolescents between the ages of 12 and 17 years who sustained a mTBI and had between 4 and 16 weeks of persistent symptoms. DESIGN: Partially blinded, pilot RCT of subsymptom exacerbation aerobic training compared with a full-body stretching program. MAIN MEASURES: The primary outcome was postinjury symptom improvement assessed by the adolescent's self-reported Post-Concussion Symptom Inventory (PCSI) repeated for at least 6 weeks of the intervention. Parent-reported PCSI and adherence are also described. RESULTS: Twenty-two percent of eligible participants enrolled in the trial. Repeated-measures analysis of variance via mixed-models analysis demonstrated a significant group * time interaction with self-reported PCSI ratings, indicating a greater rate of improvement in the subsymptom exacerbation aerobic training group than in the full-body stretching group (F = 4.11, P = .044). Adherence to the home exercise programs was lower in the subsymptom exacerbation aerobic training group compared with the full-body stretching group (mean [SD] times per week = 4.42 [1.95] vs 5.85 [1.37], P < .0001) over the duration of the study. CONCLUSION: Findings from this exploratory RCT suggest subsymptom exacerbation aerobic training is potentially beneficial for adolescents with persistent symptoms after an mTBI. These findings and other recent research support the potential benefit of active rehabilitation programs for adolescents with persistent symptoms after an mTBI. Larger replication studies are needed to verify findings and improve generalizability. Future work should focus on determining the optimal type, timing, and intensity of active rehabilitation programs and characteristics of individuals most likely to benefit. PMID- 27120296 TI - Intrauterine Inflammation and Maternal Exposure to Ambient PM2.5 during Preconception and Specific Periods of Pregnancy: The Boston Birth Cohort. AB - BACKGROUND: Prenatal exposure to ambient PM2.5, (i.e., fine particulate matter, aerodynamic diameter <= 2.5 MUm) has been associated with preterm birth and low birth weight. The association between prenatal PM2.5 exposure and intrauterine inflammation (IUI), an important risk factor for preterm birth and neurodevelopmental outcomes, has not been evaluated. OBJECTIVES: We aimed to investigate the association between maternal exposure to PM2.5 and IUI in the Boston Birth Cohort, a predominantly urban low-income minority population. METHODS: This analysis included 5,059 mother-infant pairs in the Boston Birth Cohort. IUI was assessed based on intrapartum fever and placenta pathology. PM2.5 exposure was assigned using data from the U.S. EPA's Air Quality System. Odds ratios (OR) and 95% confidence intervals (CI) quantified the association of maternal PM2.5 exposure during preconception and various periods of pregnancy with IUI. RESULTS: Comparing the highest with the lowest PM2.5 exposure quartiles, the multi-adjusted association with IUI was significant for all exposure periods considered, including 3 months before conception (OR = 1.52; 95% CI: 1.22, 1.89), first trimester (OR = 1.93; 95% CI: 1.55, 2.40), second trimester (OR = 1.67; 95% CI: 1.35, 2.08), third trimester (OR = 1.53; 95% CI: 1.24, 1.90), and whole pregnancy (OR = 1.92; 95% CI: 1.55, 2.37). CONCLUSIONS: Despite relatively low exposures, our results suggest a monotonic positive relationship between PM2.5 exposure during preconception and pregnancy and IUI. IUI may be a sensitive biomarker for assessing early biological effect of PM2.5 exposure on the developing fetus. CITATION: Nachman RM, Mao G, Zhang X, Hong X, Chen Z, Soria CS, He H, Wang G, Caruso D, Pearson C, Biswal S, Zuckerman B, Wills Karp M, Wang X. 2016. Intrauterine inflammation and maternal exposure to ambient PM2.5 during preconception and specific periods of pregnancy: the Boston Birth Cohort. Environ Health Perspect 124:1608-1615; http://dx.doi.org/10.1289/EHP243. PMID- 27120297 TI - Huckel's Rule of Aromaticity Categorizes Aromatic closo Boron Hydride Clusters. AB - A direct connection is established between three-dimensional aromatic closo boron hydride clusters and planar aromatic [n]annulenes for medium and large boron clusters. In particular, the results prove the existence of a link between the two-dimensional Huckel rule, as followed by aromatic [n]annulenes, and Wade Mingos' rule of three-dimensional aromaticity, as applied to the aromatic [Bn Hn ](2-) closo boron hydride clusters. The closo boron hydride clusters can be categorized into different series, according to the n value of the Huckel (4 n+2) pi rule. The distinct categories studied in this work correspond to n=1, 2, and 3. Each category increases in geometrical difficulty but, more importantly, it is possible to associate each category with the number of pentagonal layers in the structure perpendicular to the main axis. Category 1 has one pentagonal layer, category 2 has two, and category 3 has three. PMID- 27120298 TI - Carbon Cathodes in Rechargeable Lithium-Oxygen Batteries Based on Double-Lithium Salt Electrolytes. AB - The use of carbon materials as air electrodes in lithium-oxygen (Li-O2 ) batteries is known to be advantageous owing to their good conductivity and because they offer sites suitable for the reversible electrode reactions. However, the exact influence of carbon materials on the electrochemical performance of Li-O2 batteries is not clear. In this study the electrochemical performance of four different types of carbon materials (multiwalled carbon nanotubes (MWCNTs), CMK-3, graphene nanosheets (GNSs), and Ketjen Black (KB)) as air electrodes is examined. We find that a Li-O2 cell based on an electrode of multiwalled carbon nanotubes (MWCNTs) demonstrates good rate performance and cycle stability, when using LiNO3 -LiTFSI/DMSO as electrolyte. Li-O2 cells based on such MWCNT electrodes, with a cut-off capacity of 1000 mAh g(-1) at 500 mA g( 1) , can undergo around 90 cycles without obvious losses of capacity. Even when the discharge depth is increased to 2000 mA h g(-1) , stable cycling is maintained for 45 cycles at a charge potential below 4.0 V. PMID- 27120311 TI - Low genome content diversity of marine planktonic Thaumarchaeota. AB - Members of Thaumarchaeota are responsible for much of the ammonia oxidation occurring in the ocean. Recent studies showed that marine Thaumarchaeota have versatile metabolic capabilities, but sequencing additional genomes has not significantly increased the gene content ascribed to this group. We used the assembly-free dN pipeline software in combination with phylogenetic analyses to interrogate shotgun metagenomic data sets to gain a better understanding of the genomic diversity of Thaumarchaeota populations. The program confidently assigned ~3,000 paired-end reads to Thaumarchaeota, independent of homologies to any known Thaumarchaeota genome sequence. Only 2% of these reads potentially harbor new genes that were absent from the genome of 'Candidatus Nitrosopumilus maritimus' str. SCM1, even though this strain was isolated from a marine aquarium rather than directly from the ocean. One of these novel genes encode proteins associated with the CRISPR/Cas system, Cas1, suggesting that phage defense through CRISPR may be also present in planktonic Thaumarchaeota lineages. Our results suggest that marine Thaumarchaeota populations have very low diversity in genome content, which is corroborated using computer simulation analyses of two bacterial lineages with known genome content diversity. PMID- 27120312 TI - Opposite-sex social bonding in wild Assamese macaques. AB - In large multimale-multifemale primate groups, individual adult males and females may form close social relationships that extend beyond the mating context, a surprising finding for polygynandrous mammals. The patterns of these associations can be relatively stable across time. Here we investigate whether dyadic social relationships between the sexes transcend mere association in wild Assamese macaques and may be characterized as strong, equitable, and stable affiliative relationships or social bonds. We collected >9,000 hr of focal animal data on adult males and females from two groups of wild Assamese macaques (Macaca assamensis) at Phu Khieo Wildlife Sanctuary, Thailand. Using dyadic composite sociality indices, we found male-female affiliative relationships to be highly differentiated. The stronger the relationships were, the more likely partners were to reciprocate grooming and the more stable were the relationships. In addition, the strongest dyadic relationships remained stable over multiple years as long as both partners remained in the group. These results indicate that in a polygynous species particular males and females form strong, equitable, and enduring affiliative relationships qualitatively similar to the same-sex bonds described for female baboons and male chimpanzees. Am. J. Primatol. 78:872-882, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27120313 TI - Comprehensive Energetic Scale for Quantitatively Estimating the Fluorinating Potential of N-F Reagents in Electrophilic Fluorinations. AB - Quantitative knowledge of the fluorinating strength of electrophilic N-F reagents is of crucial importance for rational design and optimization of novel reagents and new reactions. Herein, we report the first systematic computation of fluorinating potentials of 130 electrophilic N-F reagents in two commonly used solvents dichloromethane and acetonitrile in terms of the N-F bond heterolysis energies as expressed by the fluorine plus detachment (FPD) values. The calculated FPD scales of 130 N-F reagents cover a range from 112.3 to 290.4 kcal mol(-1) and 110.9 to 278.4 kcal mol(-1) in dichloromethane and acetonitrile, respectively. This comprehensive FPD database provides a valuable quantitative guide for studying the influence of structural variation on the fluorinating strength of the N-F reagents, opening a door to the rational design of novel reagents with appropriate fluorinating strength for specific purposes. It is demonstrated that the FPD values can reproduce the reactivity order for electrophilic N-F reagents better than other parameters. PMID- 27120314 TI - Will the Australian Government's response to its 'National Ice Taskforce' deliver more treatment as promised? PMID- 27120315 TI - Determination of the vibrational contribution to the entropy change at the martensitic transformation in Ni-Mn-Sn metamagnetic shape memory alloys: a combined approach of time-of-flight neutron spectroscopy and ab initio calculations. AB - The different contributions to the entropy change linked to the austenite martensitic transition in a Ni-Mn-Sn metamagnetic shape memory alloy have been determined by combining different experimental techniques. The vibrational contribution has been inferred from the vibrational density of states of both the martensitic and austenite phases. This has been accomplished by combining time-of flight neutron scattering measurements and ab initio calculations. Further, the electronic part of the entropy change has also been calculated. Since the martensitic transformation takes place between two paramagnetic phases, the magnetic contribution can be neglected and the entropy change can be reduced to the sum of two terms: vibrational and electronic. The obtained value of the vibrational contribution ([Formula: see text]) nearly provides the total entropy change measured by calorimetry ([Formula: see text]), the difference being the electronic contribution within the experimental error. PMID- 27120316 TI - Impact of Liver and Whole-Body Diffusion-Weighted MRI for Neuroendocrine Tumors on Patient Management: A Pilot Study. AB - BACKGROUND: Computed tomography scan is the current standard cross-sectional imaging modality for neuroendocrine tumor (NET) workup. Diffusion-weighted magnetic resonance imaging (DW-MRI) has proven to be more sensitive than standard sequences to diagnose liver metastases; whole-body DW-MRI may be more sensitive than whole-body MRI. Clinical implications have not yet been assessed. Thus, we evaluated radiological and clinical contributions of liver and whole-body DW-MRI to manage NETs. METHODS: Twenty-five abnormal liver and 22 abnormal whole-body standard MRIs were first analyzed retrospectively. MR images were then reanalyzed after adding DW sequences. The standard of reference for metastasis confirmation was a combination of radiological follow-up and histological proof. Clinical impact was defined as MRI changes of liver invasion (unilobar to bilobar and/or <50 to >50% of liver) or therapeutic management changes made during a dedicated multidisciplinary meeting after whole-body MRI. RESULTS: Thirty-two patients with mainly small intestine NETs (24/32) were studied. Adding DW to standard liver MRI yielded additional findings for 45% of the patients with 1.78 times more new lesions, mainly infracentimetric; it induced a management change for 18% of the patients. DW sequences added to whole-body MRI yielded additional findings for 71% of the patients, with 1.72 times more lesions, mainly infracentimetric, and induced a change in management for 19% of the patients. CONCLUSION: Adding DW sequences to standard MRI revealed additional metastases and led to modifications of patient management. Prospective studies are needed to confirm these results. PMID- 27120318 TI - The use of angiography in pediatric blunt abdominal trauma patients. AB - BACKGROUND: Angiography is a common treatment used in adults with blunt abdominal trauma and/or severe pelvic fractures. The Committee on Trauma of the American College of Surgeons has recently advocated for this resource to be urgently available at pediatric trauma centers; however, its usefulness in the pediatric setting is unclear. The purpose of this study was to determine the incidence of angiography in the treatment of blunt abdominal trauma among injured children. METHODS: An analysis was performed using an established public use data set of children (younger than 18 years) treated at 20 participating trauma centers for blunt torso trauma through the Pediatric Emergency Care Applied Research Network. Patients who underwent angiography of the abdomen or pelvis were identified and analyzed. RESULTS: Of the 12,044 children evaluated for blunt abdominal trauma included within the data set, 973 sustained abdominopelvic injuries. Of these, only 26 (3%) underwent angiography. The median age was 14 years, 65% were males, with a mortality rate of 19%. Overall, 29 angiographic procedures were performed: 21 abdominal, 8 pelvic, with 3 patients undergoing both abdominal and pelvic. Eleven patients underwent embolization of a bleeding vessel, all of which were related to the spleen. No hepatic, renal, or pelvic vessels required embolization. The median time to angiography from emergency department evaluation was 7.3 hours. In addition to angiography, 50% also required surgical intervention, of which 31% underwent a laparotomy. Thirty-five percent of these patients required blood product transfusion, and 42% were admitted to the intensive care unit. CONCLUSION: The emergent use of angiography with embolization is uncommon in pediatric patients with blunt abdominal injuries. The requirement that pediatric trauma centers have access to interventional radiology within 30 minutes may be unnecessary. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV. PMID- 27120317 TI - Underage drinking, brief interventions, and trauma patients: Are they really special? AB - BACKGROUND: While the relationship between underage drinking and injury has been well established, few studies have examined whether presenting for an acute injury moderates the efficacy of a brief intervention (BI) on alcohol misuse. METHODS: Patients (aged 14-20 years) in the emergency department screening positive for risky drinking (Alcohol Use Disorders Identification Test Consumption score) completed a baseline assessment, were randomized to conditions (a standalone computer-delivered BI [n = 277], a therapist-delivered BI [n = 278], or a control condition [n = 281]), and completed a 3-month follow-up. This secondary analysis of Project U-Connect examined regression models (controlling for baseline values) to examine the main effects of injury and the interaction effects of injury by BI condition on alcohol consumption and consequences. RESULTS: Among 836 youth enrolled in the randomized controlled trial (mean age, 18.6 years; 51.6% were male; 79.4% were white), 303 (36.2%) had a primary complaint of intentional or unintentional injury. At baseline, injured patients were more likely to be male (p < 0.001) and have higher alcohol consumption (p < 0.01), but were less likely to misuse prescription drugs (p = 0.02) than those presenting for medical reasons. Regression models (controlling for baseline values) demonstrated that injury presentation predicted greater alcohol consumption prior to a BI. The computer BI was more effective at reducing alcohol consequences among those presenting with injury than those presenting for other reasons. Injury did not affect the efficacy of the computer BI on alcohol consumption, and injury did not affect the efficacy of the therapist BI on alcohol outcomes. CONCLUSIONS: A therapist or computer BI reduced alcohol consumption and consequences among risky drinkers regardless of reason for emergency department presentation highlighting the opportunity to reach a broad array of youth. Although the therapist BI was not moderated by injury presentation, the computer BI was particularly effective at reducing alcohol consequences among those presenting with injury at 3-month follow-up. LEVEL OF EVIDENCE: Therapeutic/care management study, level III. PMID- 27120319 TI - Adipose tissue location and contribution to postinjury hypercoagulability. AB - OBJECTIVES: Obesity is associated with a hypercoagulable state at baseline and following injury. The anatomic location of adipose deposition may influence the type of thrombotic event, with visceral adipose tissue (VAT) associated with arterial thrombosis and subcutaneous adipose tissue (SAT) predisposing to venous thrombosis. We sought to determine whether adipose tissue amount and location correlated with measures of coagulation. METHODS: All adult Level I trauma activations at our institution between January 2013 and August 2014 who underwent admission abdominal computed tomography scan and had admission rotational thromboelastometry measurements were included. Patients were excluded for history of anticoagulant use and known coagulopathy/hypercoagulable state. Admission computed tomography was used to obtain cross-sectional VAT and SAT areas at the umbilicus utilizing a novel software system; VAT and SAT measurements were associated with markers of coagulation utilizing Spearman correlation and stepwise linear regression with significance set at p < 0.05. RESULTS: Two hundred forty-two patients met inclusion and exclusion criteria. Sixty-nine percent of patients sustained blunt injury, 79% were male, mean age was 40 years, 25% were obese or morbidly obese, and mean Injury Severity Scale score was 17. Seventeen percent of patients had acute deep venous thrombosis or pulmonary embolism during hospitalization. Neither SAT nor VAT correlated with prothrombin time, international normalized ratio, or partial thromboplastin time. Subcutaneous adipose tissue correlated positively with platelet count. Visceral adipose tissue and SAT correlated negatively with clot formation time and positively with TEM fibrinogen, alpha angle, maximum clot firmness, and lysis at 30 minutes; stronger correlations and greater significance were seen between SAT and these measures except for lysis at 30 minutes. Stepwise linear regression confirmed significant relationships between SAT and clot formation time, AA, and maximum clot firmness; VAT showed a significant relationship with TEM fibrinogen. CONCLUSIONS: Increased adipose tissue correlates with relative hypercoagulability following trauma. Subcutaneous adipose tissue shows a stronger relationship with functional measures of coagulation, suggesting that SAT may be associated with hemorrhage resistance and hypercoagulability after injury. LEVEL OF EVIDENCE: Prognostic study, level IV. PMID- 27120320 TI - Team of Teams or Team of Rivals. PMID- 27120322 TI - Suction evacuation of hemothorax: A prospective study. AB - BACKGROUND: Although tube thoracostomy is a common procedure after thoracic trauma, incomplete evacuation of fluid places the patient at risk for retained hemothorax. As little as 300 to 500 cm of blood may result in the need for an additional thoracostomy tube or, in more severe cases, lung entrapment and empyema. We hypothesized that suction evacuation of the thoracic cavity before tube placement would decrease the incidence of late complications. METHODS: Patients requiring tube thoracostomy within 96 hours of admission were prospectively identified and underwent suction evacuation of the pleural space (SEPS) before tube placement. These patients were compared to historical controls without suction evacuation. Demographics, admission vital signs, laboratory values, details of chest tube placement, and outcomes were collected on all patients. Multivariable logistic regression was used to compare outcomes between groups. RESULTS: A total of 199 patients were identified, consisting of 100 retrospective controls and 99 SEPS patients. There were no differences in age, sex, admission injury severity score or chest abbreviated injury score, admission laboratory values or vital signs, or hospital length of stay. Mean (SD) volume of hemothorax in SEPS patients was 220 (297) cm; with only 48% having a volume greater than 100 cm at the time of tube placement. Three patients developed empyema, and 19 demonstrated retained blood; there was no difference between SEPS and control patients. Suction evacuation of the pleural space was significantly protective against recurrent pneumothorax after chest tube removal (odds ratio, 0.332; 95% confidence interval, 0.148-0.745). CONCLUSION: Preemptive suction evacuation of the thoracic cavity did not have a significant impact on subsequent development of retained hemothorax or empyema. Suction evacuation of the pleural space significantly decreased incidence of recurrent pneumothorax after thoracostomy removal. Although the mechanism is unclear, such a benefit may make this simple procedure worthwhile. A larger sample size is required for validation and to determine if preemptive thoracic evacuation has a clinical benefit. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 27120323 TI - Initial safety and feasibility of cold-stored uncrossmatched whole blood transfusion in civilian trauma patients. AB - BACKGROUND: The transfusion of cold-stored uncrossmatched whole blood (WB) has not been extensively used in civilian trauma resuscitation. This report details the initial experience with the safety and feasibility of using WB in this setting after a change of practice at a Level 1 trauma center was instituted. METHODS: Up to two units of uncrossmatched group O positive WB that was leukoreduced using a platelet-sparing filter from male donors were transfused to male trauma patients with hypotension secondary to bleeding. Hemolytic marker haptoglobin and reports of transfusion reactions in these patients were followed. Additionally, transfusion volumes and outcomes were compared to a historical cohort of male trauma patients who received at least one red blood cell (RBC) unit, but not WB, during the first 24 hours of admission. RESULTS: There were 47 WB patients who were transfused with a mean (SD) of 1.74 (0.61) WB units. The median haptoglobin concentration on post-WB transfusion Day 1 was 25.1 (9.3) mg/dL in 7 of 30 non-group O recipients. No adverse reactions in temporal relation to the WB transfusions were reported. There were 145 male historical control patients identified who were resuscitated with component therapy; the median volume of incompatible plasma transfused to the WB versus component therapy group was not significantly different (1,000 vs. 800 mL, respectively; p = 0.38); the mean plasma:RBC (0.99 [0.47] vs. 0.77 [ 0.73], respectively; p = 0.006) and platelet:RBC (0.72 [0.40] vs. 0.51 [0.734], respectively; p < 0.0001) ratios were significantly higher in the WB group. CONCLUSION: Transfusion of two units of cold-stored uncrossmatched WB is feasible and seems to be safe in civilian trauma resuscitation. Determining the efficacy of WB with regard to reducing the number of blood products transfused in the first 24 hours or improving recipient survival will require a larger randomized trial. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 27120324 TI - Evaluation of role 2 (R2) medical resources in the Afghanistan combat theater: Initial review of the joint trauma system R2 registry. AB - BACKGROUND: A Role 2 registry (R2R) was developed in 2008 by the US Joint Trauma System (JTS). The purpose of this project was to undertake a preliminary review of the R2R to understand combat trauma epidemiology and related interventions at these facilities to guide training and optimal use of forward surgical capability in the future. METHODS: A retrospective review of available JTS R2R records; the registry is a convenience sample entered voluntarily by members of the R2 units. Patients were classified according to basic demographics, affiliation, region where treatment was provided, mechanism of injury, type of injury, time and method of transport from point of injury (POI) to R2 facility, interventions at R2, and survival. Analysis included trauma patients aged >=18 years or older wounded in year 2008 to 2014, and treated in Afghanistan. RESULTS: A total of 15,404 patients wounded and treated in R2 were included in the R2R from February 2008 to September 2014; 12,849 patients met inclusion criteria. The predominant patient affiliations included US Forces, 4,676 (36.4%); Afghan Forces, 4,549 (35.4%); and Afghan civilians, 2,178 (17.0%). Overall, battle injuries predominated (9,792 [76.2%]). Type of injury included penetrating, 7,665 (59.7%); blunt, 4,026 (31.3%); and other, 633 (4.9%). Primary mechanism of injury included explosion, 5,320 (41.4%); gunshot wounds, 3,082 (24.0%); and crash, 1,209 (9.4%). Of 12,849 patients who arrived at R2, 167 (1.3%) were dead; of 12,682 patients who were alive upon arrival, 342 (2.7%) died at R2. CONCLUSION: This evaluation of the R2R describes the patient profiles of and common injuries treated in a sample of R2 facilities in Afghanistan. Ongoing and detailed analysis of R2R information may provide evidence-based guidance to military planners and medical leaders to best prepare teams and allocate R2 resources in future operations. Given the limitations of the data set, conclusions must be interpreted in context of other available data and analyses, not in isolation. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 27120325 TI - Influences of limited resuscitation with plasma or plasma protein solutions on hemostasis and survival of rabbits with noncompressible hemorrhage. AB - BACKGROUND: Plasma infusion with or without red blood cells is the current military standard of care for prehospital resuscitation of combat casualties. We examined possible advantages of early and limited resuscitation with fresh plasma compared with a single plasma protein or crystalloid solutions in an uncontrolled hemorrhage model in rabbits. METHODS: Anesthetized spontaneously breathing rabbits (3.3 +/- 0.1 kg) were instrumented and subjected to a splenic uncontrolled hemorrhage. Rabbits in shock were resuscitated at 15 minutes with Plasma-Lyte (PAL; 30 mL/kg), PAL + fibrinogen (PAL + F; 30 mL + 100 mg/kg), fresh rabbit plasma (15 mL/kg), or 25% albumin (ALB; 5 mL/kg) solution, all given in two bolus intravenous injections (15 minutes apart) to achieve a mean arterial pressure of 65 mm Hg, n = 8 to 9/group. Animals were monitored for 2 hours or until death, and blood loss was measured. Blood samples and tissues were collected and analyzed. RESULTS: There were no differences among groups in baseline measures and their initial bleeding volume at 15 minutes. At 60 minutes after injury, mean arterial pressure was higher with ALB than with crystalloids (PAL or PAL + F), but shock indices were not different despite the large differences in resuscitation volumes. Fibrinogen addition to PAL only increased clot strength. Plasma resuscitation increased survival rate (75%) without significant improvement in coagulation measures. Albumin administration replenished total plasma protein and increased survival rate to 100% (p < .05 vs. crystalloids). No histological adverse events were identified in the vital organs. CONCLUSIONS: Fibrinogen administration added to a compatible crystalloid did not improve hemostatic outcomes. Plasma resuscitation increased survival rate; however, its effects did not differ from those obtained with 25% ALB at one third of the volume. The ALB advantage was consistent with our previous findings in which 5% ALB was used at a volume equal to plasma. The benefit of plasma for resuscitation may be mostly due to its ALB content rather than its coagulation proteins. PMID- 27120326 TI - Managing the surge in demand for blood following mass casualty events: Early automatic restocking may preserve red cell supply. AB - BACKGROUND: Traumatic hemorrhage is a leading preventable cause of mortality following mass casualty events (MCEs). Improving outcomes requires adequate in hospital provision of high-volume red blood cell (RBC) transfusions. This study investigated strategies for optimizing RBC provision to casualties in MCEs using simulation modeling. METHODS: A computerized simulation model of a UK major trauma center (TC) transfusion system was developed. The model used input data from past MCEs and civilian and military trauma registries. We simulated the effect of varying on-shelf RBC stock hold and the timing of externally restocking RBC supplies on TC treatment capacity across increasing loads of priority one (P1) and two (P2) casualties from an event. RESULTS: Thirty-five thousand simulations were performed. A casualty load of 20 P1s and P2s under standard TC RBC stock conditions left 35% (95% confidence interval, 32-38%) of P1s and 7% (4 10%) of P2s inadequately treated for hemorrhage. Additionally, exhaustion of type O emergency RBC stocks (a surrogate for reaching surge capacity) occurred in a median of 10 hours (IQR, 5 to >12 hours). Doubling casualty load increased this to 60% (57-63%) and 30% (26-34%), respectively, with capacity reached in 2 hours (1-3 hours). The model identified a minimum requirement of 12 U of on-shelf RBCs per P1/P2 casualty received to prevent surge capacity being reached. Restocking supplies in an MCE versus greater permanent on-shelf RBC stock holds was considered at increasing hourly intervals. T-test analysis showed no difference between stock hold versus supply restocking with regard to overall outcomes for MCEs up to 80 P1s and P2s in size (p < 0.05), provided the restock occurred within 6 hours. CONCLUSION: Even limited-sized MCEs threaten to overwhelm TC transfusion systems. An early-automated push approach to restocking RBCs initiated by central suppliers can produce equivocal outcomes compared with holding excess stock permanently at TCs. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 27120327 TI - Tube thoracostomy: Increased angle of insertion is associated with complications. AB - INTRODUCTION: Tube thoracostomy (TT), considered a routine procedure, has significant complications. Current recommendations for placement rely on surface anatomy. There is no information to guide operators regarding angle of insertion relative to chest wall. We aim to determine if angle of insertion is associated with complications of TT. METHODS: We performed a retrospective review of adult trauma patients who necessitated TT at a Level I trauma center over a 2-year period (January 2012 to December 2013). Tube thoracostomies performed intraoperatively or using radiological guidance were excluded. Thoracic anteroposterior or posteroanterior radiographs were reviewed to determine the angle of insertion of TT relative to the thoracic wall. A previously validated classification method was used to categorize complications. Descriptive and univariate statistics were used to compare angle of insertion and complicated versus uncomplicated TT. RESULTS: Review identified 154 patients who underwent a total of 246 TT placed for emergent trauma. All patients had a postprocedural chest x-ray. We identified 90 complications (37%) over the study period. One hundred forty-four of the TTs reviewed had an angle of insertion less than 45 degrees of which there were 27 complications (19%). One hundred two of the TTs had an angle greater than 45 degrees and 63 complications (62%); p < 0.0001. CONCLUSIONS: Tube thoracostomy insertion is inherently dangerous. Placement of TT using a higher angle of insertion greater than 45 degrees is associated with increased complications. Further prospective studies quantifying TT angle of insertion on outcomes are needed. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 27120328 TI - Initial Research on Postoperative Management of Tetralogy of Fallot with Major Aortopulmonary Collaterals. AB - OBJECTIVES: Tetralogy of Fallot (TOF) with major aortopulmonary collaterals (MAPCA) is a well-known but always severe congenital heart disease. This study was designed to explore proper management after radical correction of TOF with MAPCA based on a hierarchical approach. METHODS: The following data were collected from 39 patients planned to undergo radical correction of TOF: age, weight, number of aortopulmonary collaterals, total lumen diameter and collateral diameter-to-body weight ratio, transcatheter occlusion and cardiac catheterization findings, mechanical ventilation time, and ICU monitoring time. The patients were divided into 4 groups by collateral diameter-to-body weight ratio as follows: <0.200 mm/kg (group 1), 0.200-0.500 mm/kg (group 2), >0.500 mm/kg (group 3), and no MAPCA (group 4). Data analysis was performed using IBM SPSS Statistics software for Mac version 22.0 (SPSS Inc., Chicago, Ill., USA) with logistic regression and Fisher's exact test. RESULTS: Most of the patients recovered well after radical correction; postoperative complications occurred in 12 patients and included bloody sputum, low cardiac output syndrome, and severe pulmonary infection that led to tracheotomy. By prolonging the mechanical ventilation time of the patients with postoperative complications, the conditions in 3 patients were improved. However, in the remaining patients, the condition worsened until transcatheter occlusions were performed. Transcatheter occlusion was performed in all 7 patients in group 3 (100%). Only 2 of the 8 patients in group 2 required transcatheter occlusion (25%), and none of the 9 patients in group 1 required transcatheter occlusion (0%). Only 1 patient (group 3) died after radical correction. The transcatheter occlusion results showed a strong association with the total lumen diameter and the collateral diameter-to-body weight ratio (p < 0.05) but no obvious association with age, weight, or the number of aortopulmonary collaterals (p > 0.05). CONCLUSIONS: Postoperative management of patients with TOF and MAPCA has great significance. To reduce the morbidity and mortality, transcatheter coil embolization or surgical ligation should be performed in patients with a collateral diameter-to-body weight ratio of at least 0.500 mm/kg. In patients with values between approximately 0.200 and 0.500 mm/kg, prolongation of mechanical ventilation should have priority over transcatheter occlusion, and for patients with values below 0.200 mm/kg no additional treatment is needed. PMID- 27120329 TI - Effects of chronic carotid baroreceptor activation on arterial stiffness in severe heart failure. AB - BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by activation of the sympathetic nervous system and increased arterial stiffness, leading to an impaired ventricular-vascular coupling. Baroreflex activation therapy (BAT) has been shown to reduce muscle sympathetic nerve activity (MSNA) and improve clinical status of patients with HFrEF. The purpose of this investigation was to determine the effects of BAT on arterial stiffness in HFrEF. METHODS AND RESULTS: MSNA, clinical variables, and parameters of central blood pressure (BP) and arterial stiffness were collected in 18 NYHA Class III HFrEF patients, nine receiving BAT and nine continuing with optimal medical management alone. Patients were followed for 3 months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3 months, BAT did not improve central BP and arterial stiffness despite a significant amelioration of MSNA, NYHA class, Minnesota living with heart failure questionnaire score, number of heart failure medications and six minute walking distance. The control group exhibited no significant changes in all the measured variables. CONCLUSIONS: Despite significant reductions in MSNA and clinical improvement, BAT does not appear to chronically modify arterial stiffness within this HFrEF cohort. Additional study is required to determine if this result applies to the HFrEF population as a whole. PMID- 27120330 TI - Atorvastatin treatment and LDL cholesterol target attainment in patients at very high cardiovascular risk. AB - The use of atorvastatin is rapidly increasing among statins since the introduction of generics. However, only limited data are available on its current use and the effectiveness outside of randomised trials. The aim of the study was to assess low-density lipoprotein (LDL-C) levels in ambulatory patients at very high cardiovascular risk on atorvastatin therapy in physician's offices. A total of 2625 high-risk patients on atorvastatin were included into this cross sectional study by 539 office-based physicians between June and December 2014. 47.0 % of the patients had documented coronary heart disease (CHD), 25.1 % type 2 diabetes mellitus (DM), and 27.9 % CHD plus concomitant DM. The mean age was 66.1 +/- 10.8 years, 62.1 % were male. Atorvastatin at the dose of 10, 20, 40 and 80 mg/day was administered in 15.6, 45.7, 33.9, and 4.8 % of the patients, respectively. The treatment duration was 92.6 +/- 109.6 weeks. The mean atorvastatin dose at therapy start was 24.8 +/- 15.2 mg/day and at time of documentation 27.9 +/- 15.8 mg/day. Low-density lipoprotein cholesterol (LDL-C) <70 mg/dL was achieved by 10.5 % of the total cohort (7.5 % in DM, 9.3 % in CHD, and 15.2 % in CHD + DM). In contrast, according to physicians' subjective assessment, 62.7 % of patients (with small differences between groups) had reached their individual LDL-C target. In summary, higher doses of atorvastatin are not frequently used in clinical practice. The LDL-C target level <70 mg/dL as recommended by current guidelines is achieved only in a minority of atorvastatin treated patients at very high cardiovascular risk. PMID- 27120331 TI - Hospital Utilisation in Indigenous and Non-Indigenous Infants under 12 Months of Age in Western Australia, Prospective Population Based Data Linkage Study. AB - BACKGROUND: Indigenous infants (infants aged under 12 months) have the highest hospital admission and emergency department presentation risks in Australia. However, there have been no recent reports comparing hospital utilisation between Indigenous and non-Indigenous infants. METHODS: Our primary objective was to use a large prospective population-based linked dataset to assess the risk of all cause hospital admission and emergency department presentation in Indigenous compared to non-Indigenous infants in Western Australia (WA). Secondary objectives were to assess the effect of socio-economic status (Index of Relative Socio-Economic Disadvantage [IRSD]) on hospital utilisation and to understand the causes of hospital utilisation. FINDINGS: There were 3,382 (5.4%) Indigenous and 59,583 (94.6%) non-Indigenous live births in WA from 1 January 2010 to 31 December 2011. Indigenous infants had a greater risk of hospital admission (adjusted odds ratio [aOR] 1.90, 95% confidence interval [95% CI] 1.77-2.04, p = <0.001) and emergency department presentation (aOR 2.15, 95% CI 1.98-2.33, p = <0.001) compared to non-Indigenous infants. Fifty nine percent (59.0%) of admissions in Indigenous children were classified as preventable compared to 31.2% of admissions in non-Indigenous infants (aOR 2.12, 95% CI 1.88-2.39). The risk of hospital admission in the most disadvantaged (IRSD 1) infants in the total cohort (35.7%) was similar to the risk in the least disadvantaged (IRSD 5) infants (30.6%) (aOR 1.04, 95% CI 0.96-1.13, p = 0.356). INTERPRETATION: WA Indigenous infants have much higher hospital utilisation than non Indigenous infants. WA health services should prioritise Indigenous infants regardless of their socio economic status or where they live. PMID- 27120332 TI - Structural Defects of Laminin beta3 N-terminus Underlie Junctional Epidermolysis Bullosa with Altered Granulation Tissue Response. AB - Mutations in the laminin-332 (alpha3Abeta3gamma2) genes cause junctional epidermolysis bullosa (JEB), a recessively inherited disease characterized by blistering and altered wound repair. In addition, specific mutations that affect the N-terminus of the alpha3A chain cause a JEB-related non-blistering condition characterized by chronic production of granulation tissue, suggesting a critical role of this region in epithelial-mesenchymal communication. We report here a 9 year-old patient with JEB with a few long-standing skin ulcers with prominent granulation tissue in the absence of active blistering. He bears a homozygous missense mutation, p.Gly254Asp, within the first laminin epidermal growth factor like (LE) repeat of the beta3 short arm. We show that p.Gly254Asp causes mis folding of the LE motif, leading to reduced secretion of laminin-332 and structural alterations of the cutaneous basement membrane zone. These findings demonstrate, in a patient in vivo, that the beta3 short arm is also involved in the outcome of the granulation tissue response. PMID- 27120333 TI - Habit Discontinuity, Self-Activation, and the Diminishing Influence of Context Change: Evidence from the UK Understanding Society Survey. AB - Repeated behaviours in stable contexts can become automatic habits. Habits are resistant to information-based techniques to change behaviour, but are contextually cued, so a change in behaviour context (e.g., location) weakens habit strength and can facilitate greater consideration of the behaviour. This idea was demonstrated in previous work, whereby people with strong environmental attitudes have lower car use, but only after recently moving home. We examine the habit discontinuity hypothesis by analysing the Understanding Society dataset with 18,053 individuals representative of the UK population, measuring time since moving home, travel mode to work, and strength of environmental attitudes. Results support previous findings where car use is significantly lower among those with stronger environmental views (but only after recently moving home), and in addition, demonstrate a trend where this effects decays as the time since moving home increases. We discuss results in light of moving into a new home being a potential 'window of opportunity' to promote pro-environmental behaviours. PMID- 27120334 TI - Vibronic Coupling Explains the Different Shape of Electronic Circular Dichroism and of Circularly Polarized Luminescence Spectra of Hexahelicenes. AB - We present the simulation of the absorption (ABS), electronic circular dichroism (ECD), emission (EMI), and circularly polarized luminescence (CPL) spectra for the weak electronic transition between the ground (S0) and the lowest excited state (S1) of hexahelicene, 2-methylhexahelicene, 2-bromohexahelicene, and 5 azahexahelicene. Vibronic contributions have been computed at zero Kelvin and at room temperature in harmonic approximation including Duschinsky effects and accounting for both Franck-Condon and Herzberg-Teller contributions. Our results nicely capture the effects of the different substituents on the experimental spectra. They also show that HT effects dominate the shape of ECD and CPL spectra where they even induce changes of signs; HT effects are also relevant in ABS and EMI, tuning the relative intensities of the different vibronic bands. HT effects are the main reason for the differences in the line shapes of ABS and ECD and of EMI and CPL spectra and for the mirror-symmetry breaking between ABS and EMI and between ECD and CPL spectra. In order to check the robustness of our results, given also that few examples of calculations of vibronic CPL spectra exist, we adopted both adiabatic and vertical approaches to define the model potential energy surfaces of the (S0) and the (S1) states; moreover we expanded the electric and magnetic dipole transition moments around both the S0 and S1 equilibrium geometries. PMID- 27120336 TI - Advanced High-Voltage Aqueous Lithium-Ion Battery Enabled by "Water-in-Bisalt" Electrolyte. AB - A new super-concentrated aqueous electrolyte is proposed by introducing a second lithium salt. The resultant ultra-high concentration of 28 m led to more effective formation of a protective interphase on the anode along with further suppression of water activities at both anode and cathode surfaces. The improved electrochemical stability allows the use of TiO2 as the anode material, and a 2.5 V aqueous Li-ion cell based on LiMn2 O4 and carbon-coated TiO2 delivered the unprecedented energy density of 100 Wh kg(-1) for rechargeable aqueous Li-ion cells, along with excellent cycling stability and high coulombic efficiency. It has been demonstrated that the introduction of a second salts into the "water-in salt" electrolyte further pushed the energy densities of aqueous Li-ion cells closer to those of the state-of-the-art Li-ion batteries. PMID- 27120335 TI - Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech. AB - Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1 q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS. PMID- 27120337 TI - Purple Crusted Nodules in a Patient With End-stage Liver Disease. PMID- 27120338 TI - A Framework for Instrument Development of a Choice Experiment: An Application to Type 2 Diabetes. AB - OBJECTIVE: Choice experiments are increasingly used to obtain patient preference information for regulatory benefit-risk assessments. Despite the importance of instrument design, there remains a paucity of literature applying good research principles. We applied a novel framework for instrument development of a choice experiment to measure type 2 diabetes mellitus treatment preferences. METHODS: Applying the framework, we used evidence synthesis, expert consultation, stakeholder engagement, pretest interviews, and pilot testing to develop a best worst scaling (BWS) and discrete choice experiment (DCE). We synthesized attributes from published DCEs for type 2 diabetes, consulted clinical experts, engaged a national advisory board, conducted local cognitive interviews, and pilot tested a national survey. RESULTS: From published DCEs (n = 17), ten attribute categories were extracted with cost (n = 11) having the highest relative attribute importance (RAI) (range 6-10). Clinical consultation and stakeholder engagement identified six attributes for inclusion. Cognitive pretesting with local diabetes patients (n = 25) ensured comprehension of the choice experiment. Pilot testing with patients from a national sample (n = 50) identified nausea as most important (RAI for DCE: 10 [95 % CI 8.5-11.5]; RAI for BWS: 10 [95 % CI 8.9-11.1]). The developed choice experiment contained five attributes (A1c decrease, blood glucose stability, low blood glucose, nausea, additional medicine, and cost). CONCLUSION: The framework for instrument development of a choice experiment included five stages of development and incorporated multiple stakeholder perspectives. Further comparisons of instrument development approaches are needed to identify best practices. To facilitate comparisons, researchers need to be encouraged to publish or discuss their instrument development strategies and findings. PMID- 27120340 TI - Quantitative Control of Pore Size of Mesoporous Carbon Nanospheres through the Self-Assembly of Diblock Copolymer Micelles in Solution. AB - This paper reports facile synthesis of nitrogen-doped mesoporous carbon nanospheres (MCNSs) with average diameters of around 300 nm and well-controlled pore sizes ranging from 8 to 38 nm, by employing polystyrene-b-poly(ethylene oxide) (PS-b-PEO) diblocks with different PS block lengths as the soft templates and dopamine as the carbon-rich precursor. For the first time, a linear equation is achieved for the quantitative control of the average pore size of MCNSs by simply adjusting a block length of diblock copolymer. The resultant MCNSs possess high surface areas of up to 450 m(2) g(-1) and nitrogen doping contents of up to ~3 wt%. As electrode materials of supercapacitors, the MCNSs exhibit excellent electrochemical performance with high specific capacitances of up to 350 F g(-1) at 0.1 A g(-1) , superior rate capability, and cycling stability. Interestingly, the specific capacitance of the MCNSs reduces linearly with increasing pore size, whereas the normalized capacitance by specific surface area remains invariable. This represents a new spectrum of the relationship between electrochemical capacitance and pore size (>5 nm) for porous carbons, which makes a complement to the existing spectra focusing on pore diameters of <5 nm. PMID- 27120339 TI - Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate. AB - The T-box transcription factor TBX18 is essential to mesenchymal cell differentiation in several tissues and Tbx18 loss-of-function results in dramatic organ malformations and perinatal lethality. Here we demonstrate for the first time that Tbx18 is required for the normal development of periductal smooth muscle stromal cells in prostate, particularly in the anterior lobe, with a clear impact on prostate health in adult mice. Prostate abnormalities are only subtly apparent in Tbx18 mutants at birth; to examine postnatal prostate development we utilized a relatively long-lived hypomorphic mutant and a novel conditional Tbx18 allele. Similar to the ureter, cells that fail to express Tbx18 do not condense normally into smooth muscle cells of the periductal prostatic stroma. However, in contrast to ureter, the periductal stromal cells in mutant prostate assume a hypertrophic, myofibroblastic state and the adjacent epithelium becomes grossly disorganized. To identify molecular events preceding the onset of this pathology, we compared gene expression in the urogenital sinus (UGS), from which the prostate develops, in Tbx18-null and wild type littermates at two embryonic stages. Genes that regulate cell proliferation, smooth muscle differentiation, prostate epithelium development, and inflammatory response were significantly dysregulated in the mutant urogenital sinus around the time that Tbx18 is first expressed in the wild type UGS, suggesting a direct role in regulating those genes. Together, these results argue that Tbx18 is essential to the differentiation and maintenance of the prostate periurethral mesenchyme and that it indirectly regulates epithelial differentiation through control of stromal epithelial signaling. PMID- 27120341 TI - Acute cocoa flavanol supplementation improves muscle macro- and microvascular but not anabolic responses to amino acids in older men. AB - The anabolic effects of nutrition on skeletal muscle may depend on adequate skeletal muscle perfusion, which is impaired in older people. Cocoa flavanols have been shown to improve flow-mediated dilation, an established measure of endothelial function. However, their effect on muscle microvascular blood flow is currently unknown. Therefore, the objective of this study was to explore links between the consumption of cocoa flavanols, muscle microvascular blood flow, and muscle protein synthesis (MPS) in response to nutrition in older men. To achieve this objective, leg blood flow (LBF), muscle microvascular blood volume (MBV), and MPS were measured under postabsorptive and postprandial (intravenous Glamin (Fresenius Kabi, Germany), dextrose to sustain glucose ~7.5 mmol.L(-1)) conditions in 20 older men. Ten of these men were studied with no cocoa flavanol intervention and a further 10 were studied with the addition of 350 mg of cocoa flavanols at the same time that nutrition began. Leg (femoral artery) blood flow was measured by Doppler ultrasound, muscle MBV by contrast-enhanced ultrasound using Definity (Lantheus Medical Imaging, Mass., USA) perflutren contrast agent and MPS using [1, 2-(13)C2]leucine tracer techniques. Our results show that although older individuals do not show an increase in LBF or MBV in response to feeding, these absent responses are apparent when cocoa flavanols are given acutely with nutrition. However, this restoration in vascular responsiveness is not associated with improved MPS responses to nutrition. We conclude that acute cocoa flavanol supplementation improves muscle macro- and microvascular responses to nutrition, independently of modifying muscle protein anabolism. PMID- 27120342 TI - Impact of replacing regular chocolate milk with the reduced-sugar option on milk consumption in elementary schools in Saskatoon, Canada. AB - Excess sugar consumption in children has led to the removal of chocolate milk from some schools. Lower-sugar formulations, if accepted, would provide the benefits of milk consumption. In a cross-over trial, milk consumption was measured in 8 schools over 6 weeks in 2 phases: phase 1 provided standard 1% chocolate milk and plain 2% milk choices for the first 3 weeks, and phase 2 provided reduced-sugar 1% chocolate milk and plain 2% milk for the next 3 weeks. Milk selection and milk wasted were measured by sex and grade (1-8). Children chose chocolate milk more often than white milk in both phases (phase 1, 8.93% +/ 0.75% vs. 0.87% +/- 0.11% (p < 0.001), and phase 2, 5.76% +/- 0.29% vs. 0.78% +/ 0.14% (p < 0.001), respectively). Fewer children chose reduced-sugar chocolate milk in phase 2 (p < 0.001). A greater percentage of younger students (grades 1 4) than older students (grades 5-8) purchased milk in both phases (phase 1, 11.10% +/- 0.81% vs. 8.36% +/- 0.74%, p = 0.020, and phase 2, 8.47% +/- 0.43% vs. 4.62% +/- 0.40%, p < 0.001, respectively); older children drank more milk at lunch. Schoolchildren preferred chocolate milk over plain milk even when a reduced-sugar formula was offered; however, switching to reduced-sugar chocolate milk led to a decrease in the number of students choosing milk. Longer-duration studies are required to determine if students would purchase reduced-sugar chocolate milk at the same rate as they would purchase regular chocolate milk. PMID- 27120343 TI - Low-Symmetrical Zinc(II) Benzonaphthoporphyrazine Sensitizers for Light Harvesting in Near-IR Region of Dye-Sensitized Solar Cells. AB - Two ring-expanded naphthalocyanine-based sensitizers NcS1 and NcS2 have been designed and synthesized to harvest near-IR light energy in dye-sensitized solar cells. Low-symmetrical "push-pull" structures of NcS1 and NcS2 enable the red shift of absorption spectrum as well as the defined Q-band splitting. The zinc benzonaphthoporphyrazine sensitizer NcS1 possessing one carboxylic acid and six 2,6-diisopropylphenoxy units showed a PCE value of 3.2% when used as a light harvesting dye on a TiO2 electrode under one sun condition. The NcS1 cell showed a broad photoresponse at wavelengths from 600 to 850 nm. PMID- 27120344 TI - Parasites Sustain and Enhance RNA-Like Replicators through Spatial Self Organisation. AB - In a prebiotic RNA world, parasitic behaviour may be favoured because template dependent replication happens in trans, thus being altruistic. Spatially extended systems are known to reduce harmful effects of parasites. Here we present a spatial system to show that evolution of replication is (indirectly) enhanced by strong parasites, and we characterise the phase transition that leads to this mode of evolution. Building on the insights of this analysis, we identify two scenarios, namely periodic disruptions and longer replication time-span, in which speciation occurs and an evolved parasite-like lineage enables the evolutionary increase of replication rates in replicators. Finally, we show that parasites co evolving with replicators are selected to become weaker, i.e. worse templates for replication when the duration of replication is increased. We conclude that parasites may not be considered a problem for evolution in a prebiotic system, but a degree of freedom that can be exploited by evolution to enhance the evolvability of replicators, by means of emergent levels of selection. PMID- 27120346 TI - Which technique to choose in the high-tech era of minimal-access rectal cancer surgery? PMID- 27120345 TI - Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: a systematic review and meta-analysis. AB - The aim of this review is to compare the efficacy and safety of denosumab over other treatments for osteoporosis. The results of this study suggest that the safety of denosumab and its efficacy in reducing fractures is not significantly different from bisphosphonates. Denosumab was, however, more effective in increasing bone mineral density. INTRODUCTION: This study was conducted to compare the efficacy and safety of denosumab over other pharmacological treatments for osteoporosis in individuals at risk of fracture. METHODS: Randomised controlled trials comparing denosumab with another pharmacological treatment for osteoporosis were searched in MEDLINE, EMBASE and CENTRAL. Identified articles were screened by two independent reviewers and assessed for inclusion. Data from included studies were extracted and meta-analyses were conducted using random effects models. RESULTS: Nine studies including a total of 4890 postmenopausal women were identified. The follow-up period varied from 12 to 24 months. In all studies except one, the comparator treatment was a bisphosphonate. There was no statistically significant difference between patients receiving denosumab and those receiving a bisphosphonate in terms of fracture risk (RR[95 % CI] = 1.15 [0.84-1.58]), adverse events (RR[95 % CI] = 0.99 [0.96-1.02]) or deaths (OR[95 % CI] = 0.58 [0.12-2.71]). Withdrawals due to adverse events were less frequent in denosumab than in other treatment groups but the difference did not reach statistical significance (OR[95 % CI] = 0.68 [0.45 1.04]). The percent change in bone mineral density at the total hip, lumbar spine, femoral neck and one-third radius was significantly higher in participants who received denosumab (e.g. mean difference [95 % CI] at the total hip: 1.06 [0.86-1.25]). CONCLUSIONS: These results suggest that, after 12 to 24 months, the safety and efficacy of denosumab for reducing fracture risk is not significantly different from bisphosphonates despite higher gains in bone mineral density. In a clinical setting, denosumab may demonstrate greater effectiveness. PMID- 27120347 TI - Comment on Makino et al. and observations on spatial modeling. PMID- 27120348 TI - Expression of Tight Junction Proteins and Cadherin 17 in the Small Intestine of Young Goats Offered a Reduced N and/or Ca Diet. AB - Diets fed to ruminants should contain nitrogen (N) as low as possible to reduce feed costs and environmental pollution. Though possessing effective N-recycling mechanisms to maintain the N supply for rumen microbial protein synthesis and hence protein supply for the host, an N reduction caused substantial changes in calcium (Ca) and phosphate homeostasis in young goats including decreased intestinal transepithelial Ca absorption as reported for monogastric species. In contrast to the transcellular component of transepithelial Ca transport, the paracellular route has not been investigated in young goats. Therefore, the aim of the present study was to characterise the effects of dietary N and/or Ca reduction on paracellular transport mechanisms in young goats. Electrophysiological properties of intestinal epithelia were investigated by Ussing chamber experiments. The expression of tight junction (TJ) and adherens junction (AJ) proteins in intestinal epithelia were examined on mRNA level by qPCR and on protein level by western blot analysis. Dietary N reduction led to a segment specific increase in tissue conductances in the proximal jejunum which might be linked to concomitantly decreased expression of cadherin 17 mRNA. Expression of occludin (OCLN) and zonula occludens protein 1 was increased in mid jejunal epithelia of N reduced fed goats on mRNA and partly on protein level. Reduced dietary Ca supply resulted in a segment specific increase in claudin 2 and claudin 12 expression and decreased the expression of OCLN which might have been mediated at least in part by calcitriol. These data show that dietary N as well as Ca reduction affected expression of TJ and AJ proteins in a segment specific manner in young goats and may thus be involved in modulation of paracellular Ca permeability. PMID- 27120351 TI - Intimate partner violence and condom negotiation efficacy among gay and bisexual men in Atlanta. AB - Background: The experience of intimate partner violence (IPV) has been shown to decrease condom negotiation efficacy among women; however, studies of this association among gay and bisexual men (GBM) are lacking. Methods: A venue recruited sample of 745 GBM was recruited in Atlanta, GA, USA in 2012-13. Participants self-completed a survey including questions on recent (previous 12 month) experience and perpetration of IPV using the IPV-GBM Scale. Multivariate regression analysis examined the association between reporting low condom negotiation efficacy with the respondent's most recent sex partner (19.2% of respondents) and recent experience of IPV with the same or another partner. Results: Nearly half the sample (49.1%) reported recent receipt of IPV, although prevalence varied considerably across the forms of IPV. GBM who reported recent IPV experience were significantly less likely to report having felt able to negotiate condom use. Conclusions: These findings suggest that IPV may be a significant risk factor for HIV acquisition and transmission among GBM. PMID- 27120349 TI - Psychotic Experiences and Working Memory: A Population-Based Study Using Signal Detection Analysis. AB - Psychotic Experiences (PEs) during adolescence index increased risk for psychotic disorders and schizophrenia in adult life. Working memory (WM) deficits are a core feature of these disorders. Our objective was to examine the relationship between PEs and WM in a general population sample of young people in a case control study. 4744 individuals of age 17-18 from Bristol and surrounding areas (UK) were analyzed in a cross-sectional study nested within the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. The dependent variable was PEs, assessed using the semi-structured Psychosis-Like Symptom Interview (PLIKSi). The independent variable was performance on a computerized numerical n back working memory task. Signal-Detection Theory indices, including standardized hits rate, false alarms rate, discriminability index (d') and response bias (c) from 2-Back and 3-Back tasks were calculated. 3576 and 3527 individuals had complete data for 2-Back and 3-Back respectively. Suspected/definite PEs prevalence was 7.9% (N = 374). Strongest evidence of association was seen between PEs and false alarms on the 2-Back, (odds ratio (OR) = 1.17 [95% confidence intervals (CI) 1.01, 1.35]) and 3-back (OR = 1.35 [1.18, 1.54]) and with c (OR = 1.59 [1.09, 2.34]), and lower d' (OR = 0.76 [0.65, 0.89]), on the 3-Back. Adjustment for several potential confounders, including general IQ, drug exposure and different psycho-social factors, and subsequent multiple imputation of missing data did not materially alter the results. WM is impaired in young people with PEs in the general population. False alarms, rather than poor accuracy, are more closely related to PEs. Such impairment is consistent with different neuropsychological models of psychosis focusing on signal-to-noise discrimination, probabilistic reasoning and impaired reality monitoring as a basis of psychotic symptoms. PMID- 27120350 TI - Epidemiology of Mental Health Attendances at Emergency Departments: Systematic Review and Meta-Analysis. AB - BACKGROUND: The characteristics of Emergency Department (ED) attendances due to mental or behavioural health disorders need to be described to enable appropriate development of services. We aimed to describe the epidemiology of mental health related ED attendances within health care systems free at the point of access, including clinical reason for presentation, previous service use, and patient sociodemographic characteristics. METHOD: Systematic review and meta-analysis of observational studies describing ED attendances by patients with common mental health conditions. FINDINGS: 18 studies from seven countries met eligibility criteria. Patients attending due to mental or behavioural health disorders accounted for 4% of ED attendances; a third were due to self-harm or suicidal ideation. 58.1% of attendees had a history of psychiatric illness and up to 58% were admitted. The majority of studies were single site and of low quality so results must be interpreted cautiously. CONCLUSIONS: Prevalence studies of mental health-related ED attendances are required to enable the development of services to meet specific needs. PMID- 27120352 TI - Characterization of a C3 Deoxygenation Pathway Reveals a Key Branch Point in Aminoglycoside Biosynthesis. AB - Apramycin is a clinically interesting aminoglycoside antibiotic (AGA) containing a highly unique bicyclic octose moiety, and this octose is deoxygenated at the C3 position. Although the biosynthetic pathways for most 2-deoxystreptamine containing AGAs have been well characterized, the pathway for apramycin biosynthesis, including the C3 deoxygenation process, has long remained unknown. Here we report detailed investigation of apramycin biosynthesis by a series of genetic, biochemical and bioinformatical studies. We show that AprD4 is a novel radical S-adenosyl-l-methionine (SAM) enzyme, which uses a noncanonical CX3CX3C motif for binding of a [4Fe-4S] cluster and catalyzes the dehydration of paromamine, a pseudodisaccharide intermediate in apramycin biosynthesis. We also show that AprD3 is an NADPH-dependent reductase that catalyzes the reduction of the dehydrated product from AprD4-catalyzed reaction to generate lividamine, a C3' deoxygenated product of paromamine. AprD4 and AprD3 do not form a tight catalytic complex, as shown by protein complex immunoprecipitation and other assays. The AprD4/AprD3 enzyme system acts on different pseudodisaccharide substrates but does not catalyze the deoxygenation of oxyapramycin, an apramycin analogue containing a C3 hydroxyl group on the octose moiety, suggesting that oxyapramycin and apramycin are partitioned into two parallel pathways at an early biosynthetic stage. Functional dissection of the C6 dehydrogenase AprQ shows the crosstalk between different AGA biosynthetic gene clusters from the apramycin producer Streptomyces tenebrarius, and reveals the remarkable catalytic versatility of AprQ. Our study highlights the intriguing chemistry in apramycin biosynthesis and nature's ingenuity in combinatorial biosynthesis of natural products. PMID- 27120353 TI - Palladium catalysed meta-C-H functionalization reactions. AB - The directing group assisted site selective C-H functionalization approach is having a continuous impact in the field of natural product synthesis, drug discovery and material sciences. While ortho-selective C-H functionalization has been studied extensively, meta-selective C-H functionalization has been less explored. Recent studies have highlighted the efficacy of palladium as a catalyst in activating the meta-C-H bond of arenes. Notably, the introduction of a novel palladium catalysed directing template based approach to activate the remote meta position has created a revolutionary impact towards seeking a solution to this long standing challenge. In this review we summarize recent advances in palladium catalysed meta-C-H functionalization that have helped in creating a new outlook towards modern organic synthesis. PMID- 27120354 TI - Functional Relevance of Relative Maintenance of Maximal Eccentric Quadriceps Torque in Healthy Old Adults. AB - BACKGROUND: Old referenced to young adults show a relative maintenance of maximal eccentric (RELM) compared to concentric muscle torque: ~76 and ~59%, respectively. However, it is unknown if RELM affords functional benefits in old adults. OBJECTIVE: We examined if there is specificity between the two types of peak quadriceps torque (i.e., concentric and eccentric) and timed gait performance measured during level, ramp, and stair walking and if gait performance was higher in old adults with high versus low RELM. METHODS: We measured peak concentric and eccentric quadriceps torque at 60 and 120 degrees /s and timed gait at habitual and safe-fast speeds in healthy young (age 22.7 years, n = 24) and old (age 70.0 years, n = 21) adults. RESULTS: Comparable to previous studies, RELM was 21%, but instead of the anticipated specificity, we found that concentric compared with eccentric torque was more strongly associated with gait performance than eccentric torque, independently of walking direction and age (R2 = 0.16: eccentric vs. descending gaits; R2 = 0.17: eccentric vs. ascending gaits; R2 = 0.45: concentric vs. descending gaits; R2 = 0.56: concentric vs. ascending gaits, n = 45, all p < 0.01). Furthermore, old adults (n = 10) with ~30% greater than normal levels of RELM (n = 11) ambulated at similar velocities measured on level and inclined surfaces. CONCLUSION: Normal and 30% above normal levels of RELM do not seem to increase or predict healthy old adults' gait performance on level and inclined surfaces. Future work should examine if RELM is associated with a heightened performance in other measures of neuromuscular function, such as gait biomechanics, muscle activation, as well as rate and control of voluntary force development in old adults with high or low mobility. PMID- 27120355 TI - Differential Expression of Inflammatory Cytokines and Stress Genes in Male and Female Mice in Response to a Lipopolysaccharide Challenge. AB - BACKGROUND: Sex plays a key role in an individual's immune response against pathogenic challenges such that females fare better when infected with certain pathogens. It is thought that sex hormones impact gene expression in immune cells and lead to sexually dimorphic responses to pathogens. We predicted that, in the presence of E. coli gram-negative lipopolysaccharide (LPS), there would be a sexually dimorphic response in proinflammatory cytokine production and acute phase stress gene expression and that these responses might vary among different mouse strains and times in a pattern opposite to that of body temperature associated with LPS-induced shock. MATERIALS AND METHODS: Interleukin-6 (IL-6), macrophage inflammatory protein-Ibeta (MIP-1beta), tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) as well as beta-fibrinogen (Fgb) and metallothionein-1 (Mt-1) mRNA expression were measured at four time points (0, 2, 4 and 7 hours) after injection of E. coli LPS in mice from three inbred strains. RESULTS: Statistical analysis using analyses of variance (ANOVAs) showed that the levels of the all six traits changed over time, generally peaking at 2 hours after LPS injection. Mt-1, Fgb, and IL-6 showed differences among strains, although these were time-specific. Sexual dimorphism was seen for Fgb and IL6, and was most pronounced at the latest time period (7 hours) where male levels exceeded those for females. Trends for all six cytokine/gene expression traits were negatively correlated with those for body temperatures. DISCUSSION: The higher levels of expression of Fgb and IL6 in males compared with females are consistent with the greater vulnerability of males to infection and subsequent inflammation. Temperature appears to be a useful proxy for mortality in endotoxic shock, but sexual dimorphism in cytokine and stress gene expression levels may persist after an LPS challenge even if temperatures in the two sexes are similar and have begun to stabilize. PMID- 27120356 TI - Correction: Comparison of O-Antigen Gene Clusters of All O-Serogroups of Escherichia coli and Proposal for Adopting a New Nomenclature for O-Typing. AB - [This corrects the article DOI: 10.1371/journal.pone.0147434.]. PMID- 27120358 TI - Corrigendum. PMID- 27120357 TI - Incremental Prognostic Value of ADC Histogram Analysis over MGMT Promoter Methylation Status in Patients with Glioblastoma. AB - Purpose To investigate the incremental prognostic value of apparent diffusion coefficient (ADC) histogram analysis over oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in patients with glioblastoma and the correlation between ADC parameters and MGMT status. Materials and Methods This retrospective study was approved by institutional review board, and informed consent was waived. A total of 112 patients with glioblastoma were divided into training (74 patients) and test (38 patients) sets. Overall survival (OS) and progression-free survival (PFS) was analyzed with ADC parameters, MGMT status, and other clinical factors. Multivariate Cox regression models with and without ADC parameters were constructed. Model performance was assessed with c index and receiver operating characteristic curve analyses for 12- and 16-month OS and 12-month PFS in the training set and validated in the test set. ADC parameters were compared according to MGMT status for the entire cohort. Results By using ADC parameters, the c indices and diagnostic accuracies for 12- and 16-month OS and 12-month PFS in the models showed significant improvement, with the exception of c indices in the models for PFS (P < .05 for all) in the training set. In the test set, the diagnostic accuracy was improved by using ADC parameters and was significant, with the 25th and 50th percentiles of ADC for 16-month OS (P = .040 and P = .047) and the 25th percentile of ADC for 12-month PFS (P = .026). No significant correlation was found between ADC parameters and MGMT status. Conclusion ADC histogram analysis had incremental prognostic value over MGMT promoter methylation status in patients with glioblastoma. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 27120359 TI - Controlling the ripple density and heights: a new way to improve the electrical performance of CVD-grown graphene. AB - We report a new way to enhance the electrical performances of large area CVD grown graphene through controlling the ripple density and heights after transfer onto SiO2/Si substrates by employing different cooling rates during fabrication. We find that graphene films prepared with a high cooling rate have reduced ripple density and heights and improved electrical characteristics such as higher electron/hole mobilities as well as reduced sheet resistance. The corresponding Raman analysis also shows a significant decrease of the defects when a higher cooling rate is employed. We suggest a model that explains the improved morphology of the graphene film obtained with higher cooling rates. From these points of view, we can suggest a new pathway toward a relatively lower density and heights of ripples in order to reduce the flexural phonon-electron scattering effect, leading to higher lateral carrier mobilities. PMID- 27120360 TI - Chlamydia pneumoniae, and mycoplasma pneumoniae: Are they related to severe asthma in childhood? AB - BACKGROUND: Mycoplasma pneumoniae and Chlamydia pneumoniae are frequent agents of acute respiratory diseases and they have been recognized as infectious triggers of asthma. OBJECTIVE: To determine the frequency of these triggers and their relationship to severe asthma. METHODS: 82 patients were enrolled in a prospective cross-sectional study from January 2007 to March 2013 and they were divided into three study groups: Group 1: 27 children with severe asthma, Group 2: 29 children with stable asthma and Group 3: 26 children which was the control group. Serological tests included IgG and IgM for both C. pneumoniae and M. pneumoniae. RESULTS: Average age +/- SD was 10.9 +/- 2.5 for Group 1; 10.1 +/- 2.9 for Group 2 and 9.9+/- 1.9 for Group 3 (p = 0.4). M. pneumoniae IgM was observed in 6/27 (22.2%) in Group 1, 2/29 (6.9%) in Group 2 and 0/26 in the Control Group (p = 0,01). C.pneumoniae IgM was present in 7/26 (26.9%) in Group 1, 2/29 (6.9%) in Group 2 and 0/26 in Group 3 (p = 0.005). No significant difference was observed between Group 2 and Group 3. M. pneumoniae IgG was observed in 7/27 (25.9%) in Group 1, 4/29 (13.7%) in Group 2 and 0/26 in the Control Group (p < 0,05). C.pneumoniae IgG was present in 8/26 (30.7%) in Group 1, 5/29 (17.2%) in Group 2 and 0/26 in Group 3 (p < 0,05). CONCLUSIONS: M. pneumoniae and C. pneumoniae may play a role in the development of severe asthma. PMID- 27120361 TI - The Continuous Challenge of Characterizing the Foodborne Pathogen Listeria monocytogenes. AB - Listeria monocytogenes is an important foodborne pathogen commonly isolated from food processing environments and food products. This organism can multiply at refrigeration temperatures, form biofilms on different materials and under various conditions, resist a range of environmental stresses, and contaminate food products by cross-contamination. L. monocytogenes is recognized as the causative agent of listeriosis, a serious disease that affects mainly individuals from high-risk groups, such as pregnant women, newborns, the elderly, and immunocompromised individuals. Listeriosis can be considered a disease that has emerged along with changing eating habits and large-scale industrial food processing. This disease causes losses of billions of dollars every year with recalls of contaminated foods and patient medical treatment expenses. In addition to the immune status of the host and the infecting dose, the virulence potential of each strain is crucial for the development of disease symptoms. While many isolates are naturally virulent, other isolates are avirulent and unable to cause disease; this may vary according to the presence of molecular determinants associated with virulence. In the last decade, the characterization of genetic profiles through the use of molecular methods has helped track and demonstrate the genetic diversity among L. monocytogenes isolates obtained from various sources. The purposes of this review were to summarize the main methods used for isolation, identification, and typing of L. monocytogenes and also describe its most relevant virulence characteristics. PMID- 27120388 TI - Comparison of the yield from two faecal immunochemical tests at identical cutoff concentrations - a randomized trial in Latvia. AB - OBJECTIVE: We have compared the performance of two faecal immunochemical tests (FIT) in an average-risk population. MATERIALS AND METHODS: Altogether, 10 000 individuals aged 50-74 were selected randomly from the population of Latvia in 2011 and assigned randomly either to OC-Sensor or to FOB Gold single-time testing. Positivity of the test, frequency of colonic lesions, number needed to screen (NNscreen) and scope for the detection of an advanced neoplasm (cancer and advanced adenoma) were compared between the tests using the same cutoff concentrations in ug/g faeces. Confidence intervals (CIs) at 95% were calculated. RESULTS: Positivity with the cutoff set at 10 ug/g faeces was 12.8% (95% CI: 11.4 14.2) for FOB Gold and 8.3% (95% CI: 7.2-9.4) for OC-Sensor (P<0.001). Positivity was higher in men and the older age groups. Colonoscopy compliance was 55.5%. There was no significant difference between the two tests at comparable cutoff concentrations in ug/g, colonoscopy attendance rate or colonoscopy results. For advanced neoplasm detection, there was no significant difference in number needed to scope and NNscreen at a cutoff of 10 ug/g faeces; however, lower NNscreen was required to detect advanced neoplasms with the FOB Gold test at increased cutoff concentrations. CONCLUSION: Different quantitative FIT systems may report different positivity rate at identical cutoff concentrations, which has to be considered when implementing the use of FIT in national screening programmes. PMID- 27120389 TI - Early pancreatic carcinogenesis - risk factors, early symptoms, and the impact of antidiabetic drugs. AB - Risk factors (long-term diabetes, obesity) and early symptoms (new-onset diabetes, loss of weight, or persistent low body mass) are the initial symptoms of pancreatic carcinogenesis. They may be influenced by antidiabetic drugs and their correct evaluation is a prerequisite for early diagnosis of pancreatic cancer (PC). We review the risk factors, early symptoms, and the impact of antidiabetic drugs on early pancreatic carcinogenesis. The main source of data was the database Medline/PubMed and abstracts of international congresses (DDW, UEGW). The risk factors and early symptoms are integral components of the familial PC surveillance and sporadic PC screening. Preventive programs should always be include multistep and multidisciplinary procedures. The correct evaluation of antidiabetic drugs and their interactions with other components of pancreatic carcinogenesis may influence the early diagnosis of PC. PMID- 27120390 TI - Three Novel Heterozygous Point Mutations of NR3C1 Causing Glucocorticoid Resistance. AB - Generalized glucocorticoid resistance is associated with glucocorticoid receptor (GR; NR3C1) mutations. Three novel heterozygous missense NR3C1 mutations (R477S, Y478C, and L672P) were identified in patients presenting with adrenal incidentalomas, glucocorticoid excess without Cushing syndrome. Dexamethasone (DXM) binding studies demonstrated that the affinity of GRR477S and GRY478C mutants, located in the DNA-binding domain (DBD) of GR, was similar to wild-type GR (Kd = 2-3 nM). In contrast, GRL672P mutant, located in the ligand-binding domain (LBD) of GR, was unable to bind glucocorticoids and was more sensitive to protein degradation. GR subcellular distribution revealed a marked decrease in DXM-induced nuclear translocation of GRR477S and GRY478C mutants, whereas GRL672P remained exclusively cytoplasmic. Chromatin immunoprecipitation demonstrated impaired recruitment of DBD mutants onto the regulatory sequence of FKBP5. Transactivation assays disclosed the lack of transcriptional activity of GRR477S and GRL672P , whereas GRY478C had a reduced transactivation capacity. Three dimensional modeling indicated that R477S lost two essential hydrogen bonds with DNA, Y478C resulted in altered interaction with surrounding amino-acids, destabilizing DBD, whereas L672P altered the H8 helix folding, leading to unstructured LBD. This study identifies novel NR3C1 mutations with their molecular consequences on altered GR signaling and suggests that genetic screening of NR3C1 should be conducted in patients with subclinical hypercorticism. PMID- 27120391 TI - An Aqueous Rechargeable Zn//Co3 O4 Battery with High Energy Density and Good Cycling Behavior. AB - An aqueous rechargeable Zn//Co3 O4 battery is demonstrated with Zn@carbon fibers and Co3 O4 @Ni foam as the negative and positive electrodes, respectively, using an electrolyte of 1 m KOH and 10 * 10(-3) m Zn(Ac)2 . It can operate at a cell voltage as high as 1.78 V with an energy density of 241 W h kg(-1) and presents excellent cycling. The battery is also assembled into a flexible shape, which can be applied in flexible or wearable devices requiring high energy. PMID- 27120392 TI - Cytotoxic activity of aeroplysinin-1 against colon cancer cells by promoting beta catenin degradation. AB - An aberrant accumulation of beta-catenin in intestinal epithelial cells is relevant to the development and progression of colon cancer and is thus a potential target for the development of therapeutics for this malignancy. Here, we used cell-based natural compound screening with genetically engineered HEK293 reporter cells to identify aeroplysinin-1, a brominated tyrosine derivative originated from marine sponges, as an inhibitor of Wnt/beta-catenin signaling. Aeroplysinin-1 suppressed the beta-catenin response transcription that was activated by Wnt3a-conditioned medium or 6-bromoindirubin-3'-oxime (an inhibitor of glycogen synthase kinase-3beta) by promoting the proteasomal degradation of intracellular beta-catenin. Consistently, aeroplysinin-1 decreased the amount of intracellular beta-catenin and repressed the expression of beta-catenin/T-cell factor-dependent genes, thereby inhibiting the proliferation of colon cancer cells. In addition, apoptosis was elicited by aeroplysinin-1, as indicated by the increase in the population of Annexin V-FITC stained cells and caspase-3/7 activities in DLD-1 colon cancer cells. These findings indicate that aeroplysinin 1 exerts its antiproliferative activity by attenuating Wnt/beta-catenin signaling and may have potential as a chemopreventive agent for human colon cancer. PMID- 27120393 TI - Pomegranate peel extract polyphenols induced apoptosis in human hepatoma cells by mitochondrial pathway. AB - This study was aimed to investigate the influence of pomegranate peel polyphenols (PPPs) on the proliferation and apoptosis of HepG2 cells (a kind of human hepatoma cells) and the related mechanism. The inverted fluorescence microscope and the flow cytometer (FCM) were used to test the changes of the cellular morphology, cell cycle, apoptosis, reactive oxygen species (ROS) and mitochondrial transmembrane potential (Deltapsim). The kit was used to measure the activities of caspase-3/9, and Western Blot was used to detect the expressions of apoptosis-associated proteins including p53, Bcl-2/Bax, Cyt-c and PARP. The results showed that the cells cycle of HepG2 arrested at the S-phase by PPPs and the amount of the early apoptotic cells and ROS level were increased obviously, the level of Cyt-c and the activity of Caspase-3/9 markedly were also increased by PPPs, as well as the ratio of Bax/Bcl-2 and the protein expressions of P53. It was concluded that PPPs could inhibit the growth of HepG2 cells by blocking the cell cycle and inducing the mitochondrial apoptotic pathway in a dose-dependent manner. PMID- 27120394 TI - H2S-Donating Doxorubicins May Overcome Cardiotoxicity and Multidrug Resistance. AB - Doxorubicin (DOXO) is one of the most effective antineoplastic agents in clinical practice. Its use is limited by acute and chronic side effects, in particular by its cardiotoxicity and by the rapid development of resistance to it. As part of a program aimed at developing new DOXO derivatives endowed with reduced cardiotoxicity, and active against DOXO-resistant tumor cells, a series of H2S releasing DOXOs (H2S-DOXOs) were obtained by combining DOXO with appropriate H2S donor substructures. The resulting compounds were studied on H9c2 cardiomyocytes and in DOXO-sensitive U-2OS osteosarcoma cells, as well as in related cell variants with increasing degrees of DOXO-resistance. Differently from DOXO, most of the products were not toxic at 5 MUM concentration on H9c2 cells. A few of them triggered high activity on the cancer cells. H2S-DOXOs 10 and 11 emerged as the most interesting members of the series. The capacity of 10 to impair Pgp transporter is also discussed. PMID- 27120395 TI - Long-Term Outcomes of Laparoscopic Bean Vaginoplasty (Modified Vecchietti Procedure) for Mayer-Rokitansky-Kuster-Hauser Syndrome. AB - OBJECTIVE: The objective of our study is to evaluate the long-term results of laparoscopic bean vaginoplasty (LBV), which we previously described. MATERIALS AND METHODS: From April 2002 to September 2013, 62 patients, who were diagnosed with Mayer-Rokitansky-Kuster-Hauser Syndrome and underwent LBV in Cukurova University School of Medicine Department of Obstetrics and Gynecology were included in the study. Operative data, complication rates, vaginal length, and sexuality of patients during the follow-up period were evaluated. Sexuality of the patients were evaluated using the Female Sexual Function Index (FSFI) questionnaire. The FSFI scores were compared with age-matched 65 healthy control subjects. RESULTS: Mean age of patients in case and control groups were 23.9 +/- 5.1 (18-32) and 25.1 +/- 4.2 (18-31), respectively (P = .69). Median length of follow-up after surgery was 48 months (24-144 months). No complications occurred during the operations. No vaginal adhesions occurred during the follow-up periods. Median vaginal length during the last follow-up was 7 cm (6-9 cm). FSFI scores were similar with the control group. CONCLUSION: LBV is a successful modification of Vecchietti procedure, without any reported complication. However, the procedure should still be compared with the other methods in randomized trials. PMID- 27120396 TI - Text2Quit: an analysis of participant engagement in the mobile smoking cessation program. AB - BACKGROUND: Text2Quit, an interactive text-messaging program aimed at smoking cessation, has been shown to increase quit rates, but engagement has not been thoroughly explored. Understanding the program features associated with engagement and behavior change is integral for effective program design. OBJECTIVES: This study explored participants' interaction with the Text2Quit text messaging program and associations between engagement and smoking cessation. METHODS: The study included the 262 participants who received the Text2Quit intervention. Self-reported engagement measures, primarily usage of Text2Quit keywords and survey responses, were collected through computer records of participant use. Demographic variables and self-reported smoking abstinence were recorded in surveys at baseline and 6-month assessment. RESULTS: The majority of participants (73%) maintained their subscription during the 6-month intervention. On average, participants received 210.51 text messages, 23.75 emails, and logged into the web portal 1.94 times. Being female was predictive of engagement with the program (beta = 15.39). Program engagement, measured by the keyword PLEDGE (p = .002) and the Smokefree Status at 7 Days survey (p < .001) were associated with 6-month abstinence; use of keywords SMOKED (p < .001), RELAPSE (p = .007), and STOP (p = .023) were inversely related to abstinence. While abstainers (N = 83, 31%) stayed enrolled longer and engaged with the program more frequently, program "dose" was not predictive of smoking cessation. CONCLUSIONS: Using interactive tools such as pledges and reporting on smoking status were predictive of cessation. Further study of program features is required to understand how to optimally design text messaging programs. PMID- 27120397 TI - Restraining reactive oxygen species in Listeria monocytogenes promotes the apoptosis of glial cells. AB - OBJECTIVES: Listeria monocytogenes is a facultative anaerobic foodborne pathogen that can traverse the blood-brain barrier and cause brain infection. L. monocytogenes infection induces host cell apoptosis in several cell types. In this study, we investigated the apoptosis of human glioma cell line U251 invaded by L. monocytogenes and evaluated the function of bacterial reactive oxygen species (ROS) during infection. METHODS: Bacterial ROS level was reduced by carrying out treatment with N-acetyl cysteine (NAC) and diphenyleneiodonium chloride (DPI). After infection, the apoptosis of U251 cells was examined by flow cytometry assay and propidium iodide staining. RESULTS: DPI and NAC efficiently decreased ROS level in L. monocytogenes without affecting bacterial growth. Moreover, the apoptosis of glial cells was enhanced upon invasion of DPI- and NAC pretreated L. monocytogenes. DISCUSSION: Results indicate that the apoptosis of glial cells can be induced by L. monocytogenes, and that the inhibition of bacterial ROS increases the apoptosis of host cells. PMID- 27120398 TI - Over-vibration induced blood perfusion and vascular permeability changes may lead to vocal edema. AB - OBJECTIVES/HYPOTHESIS: To observe blood perfusion and vascular permeability changes under varying vibration frequency exposures. STUDY DESIGN: Animal model. METHODS: Blood perfusion was measured using laser Doppler flowmetry in eight rabbit auricular vessels (four rabbits) under nonvibration, and 62.5-Hz/1-mm, 125 Hz/1-mm, and 250-Hz/0.5-mm vibration frequency/amplitude exposures. Another 12 rabbits were randomly divided into vibration only and vibration with histamine groups. After 3 hours of continuous 125-Hz, 1-mm amplitude vibration of the auricle, vascular permeability was analyzed by absorbance of Evans blue-albumin complex. RESULTS: Significantly lower blood perfusion was observed in the vibration group, compared with no vibration exposure controls. Blood perfusion decreased 29 +/- 16% as the vibration frequency was increased from 62.5 Hz to 125 Hz with the vibration amplitude constant at 1 mm. When the frequency was increased from 125 Hz to 250 Hz, while the amplitude was decreased from 1 mm to 0.5 mm, blood flow perfusion further decreased 29 +/- 29%, and the decline tendency in blood perfusion showed no significant difference (P = .992). Meanwhile, in the vibration with histamine group, vascular permeability of the vibrated ears increased significantly compared to the nonvibrated ears (P = .005). CONCLUSIONS: Overvibration of the vocal folds due to voice overuse or abuse may significantly reduce blood perfusion, and increase vascular permeability in the vocal fold in inflammatory situations, which may lead to the formation of vocal edema. LEVEL OF EVIDENCE: NA Laryngoscope, 127:148-152, 2017. PMID- 27120400 TI - Response of duplex Cr(N)/S and Cr(C)/S coatings on 316L stainless steel to tribocorrosion in 0.89% NaCl solution under plastic contact conditions. AB - Two duplex coatings, Cr(N)/S and Cr(C)/S, were deposited on 316 L stainless steel by magnetron sputtering. The effectiveness of these duplex coatings in improving the tribocorrosion behavior of medical alloys under elastic contact conditions has been demonstrated in a recent publication. The present work focused on the response of these duplex coatings to tribocorrosion under plastic contact conditions. Tribocorrosion tests were conducted in 0.89% NaCl solution at 37 degrees C at an initial contact pressure of 740 MPa and under unidirectional sliding conditions for sliding duration up to 24 h. The results showed that during sliding in the corrosive solution, the duplex coatings were plastically deformed into the substrate to a depth about 1 MUm. The Cr(C)/S duplex coating had sufficient ductility to accommodate the deformation without cracking, such that it was worn through gradually, leading to the gradual increase in open circuit potential (OCP) and coefficient of friction (COF). On the other hand, the Cr(N)/S duplex coating suffered from cracking at all tested potentials, leading to coating blistering after prolonged sliding at OCP and stable pit formation in the substrate beneath the coating at applied anodic potentials. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1503-1513, 2017. PMID- 27120401 TI - Strain-Induced Electronic Structure Changes in Stacked van der Waals Heterostructures. AB - Vertically stacked van der Waals heterostructures composed of compositionally different two-dimensional atomic layers give rise to interesting properties due to substantial interactions between the layers. However, these interactions can be easily obscured by the twisting of atomic layers or cross-contamination introduced by transfer processes, rendering their experimental demonstration challenging. Here, we explore the electronic structure and its strain dependence of stacked MoSe2/WSe2 heterostructures directly synthesized by chemical vapor deposition, which unambiguously reveal strong electronic coupling between the atomic layers. The direct and indirect band gaps (1.48 and 1.28 eV) of the heterostructures are measured to be lower than the band gaps of individual MoSe2 (1.50 eV) and WSe2 (1.60 eV) layers. Photoluminescence measurements further show that both the direct and indirect band gaps undergo redshifts with applied tensile strain to the heterostructures, with the change of the indirect gap being particularly more sensitive to strain. This demonstration of strain engineering in van der Waals heterostructures opens a new route toward fabricating flexible electronics. PMID- 27120402 TI - Helper and cytotoxic T-cell subsets (Th1, Th2, Tc1, and Tc2) in benign and malignant salivary gland tumors. AB - OBJECTIVE: The objective of this study was to explore the prevalence of T helper type 1 (Th1; CD4(+) IFN-gamma (+) ) and Th2 (CD4(+) IL-4(+) ) cells, as well as cytotoxic T cell type 1 (Tc1; CD8(+) IFN-gamma(+) ) and Tc2 cells (CD8(+) IL-4(+) ) in peripheral blood of the patients with salivary gland tumors (SGTs). SUBJECTS AND METHODS: Thirty new patients with SGTs and 15 healthy controls were recruited. After intracellular cytokine staining, data acquisition and analysis were performed by flow cytometry. RESULTS: The mean percentages of Th1 and Tc1 cells, as well as the ratios of Th1/Th2 and Tc1/Tc2, were observed to be significantly lower in patients with malignant SGTs in comparison with controls. Furthermore, the geometric mean fluorescent intensity (geometric MFI, representing the cytokine expression intensity) for IL-4 production by Th2 and Tc2 lymphocytes was significantly higher in patients with malignant tumors than controls. Positive correlations were observed between the mean percentage of Tc2 cells with Th2 cells, and with the tumor size in patients with benign and malignant tumors, respectively. CONCLUSION: The findings suggest that the imbalance of Th1/Th2 and Tc1/Tc2 ratios, as well as the increase in the expression of IL-4 by Th2 and Tc2 lymphocytes, may contribute to the pathogenesis of SGTs, especially in malignant cases. PMID- 27120403 TI - Validating subject-specific RF and thermal simulations in the calf muscle using MR-based temperature measurements. AB - PURPOSE: Ongoing discussions occur to translate the safety restrictions on MR scanners from specific absorption rate (SAR) to thermal dose. Therefore, this research focuses on the accuracy of thermal simulations in human subjects during an MR exam, which is fundamental information in that debate. METHODS: Radiofrequency (RF) heating experiments were performed on the calves of 13 healthy subjects using a dedicated transmit-receive coil while monitoring the temperature with proton resonance frequency shift (PRFS) thermometry. Subject specific models and one generic model were used for electromagnetic and thermal simulations using Pennes' bioheat equation, with the blood equilibration constant equaling zero. The simulations were subsequently compared with the experimental results. RESULTS: The mean B1+ equaled 15 uT in the center slice of all volunteers, and 95% of the voxels had errors smaller than 2.8 uT between the simulation and measurement. The intersubject variation in RF power to achieve the required B1+ was 11%. The resulting intersubject variation in median temperature rise was 14%. Thermal simulations underestimated the median temperature increase on average, with 34% in subject-specific models and 28% in the generic model. CONCLUSIONS: Although thermal measures are directly coupled to tissue damage and therefore suitable for RF safety assessment, insecurities in the applied thermal modeling limit their estimation accuracy. Magn Reson Med 77:1691-1700, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27120404 TI - "On Water" Organocatalyzed [4 + 2] Cycloaddition of Enones and Nitro Dienes for the Enantioselective Synthesis of Densely Substituted Cyclohexanones. AB - An "on water" hydroquinine-based primary amine-benzoic acid organocatalyst system was found to be best suited to produce 3,4,5-trisubstituted cyclohexanones with a nitro group in the 4-position from enones and nitro dienes under ambient conditions in good yield, with good diastereoselectivity, and with excellent enantioselectivity. An appreciable rate enhancement by water was observed compared to organic solvents. Mechanistic analysis of the reaction suggests that it followed an endo [4 + 2] cycloaddition with enamine of enone as diene and nitro diene as dienophile. PMID- 27120405 TI - Predicting Venous Thromboembolism in Pediatric Trauma Patients. PMID- 27120406 TI - Integrated Photoelectrolysis of Water Implemented On Organic Metal Halide Perovskite Photoelectrode. AB - Herein we report on integrated photoelectrolysis of water employing organic metal halide (OMH) perovskite material. Generic OMH perovskite material and device architecture are highly susceptible to degradation by moisture and water. We found that decomposition of perovskite devices proceeds by water ingress through pinholes in upper layers and is strongly affected by applied bias/light and electrolyte pH. It was also found that a pinhole-free hole transport layer (HTL) could significantly enhance the stability of the perovskite photoelectrode, thereby extending the photoelectrode lifetime to several tens of minutes, which is an unprecedented record-long operation. Furthermore, a carbon nanotube (CNT)/polymer composite layer was developed that can effectively protect the underlying perovskite layer from electrolyte molecules. PMID- 27120407 TI - Prevalence and associated factors of behavioral intention for risk compensation following voluntary medical male circumcision among male sexually transmitted diseases patients in China. AB - Risk compensation was an important concern of voluntary medical male circumcision (VMMC) promotion campaigns. No study investigated risk compensation following VMMC among male sexually transmitted diseases patients (MSTDP). A cross-sectional survey interviewed 308 uncircumcised MSTDP in Shenzhen, China. 26.9% of them intended to perform at least one of the five types of risk compensation behaviors following VMMC. In the summary stepwise model, provision of incorrect response to HIV/sexually transmitted diseases knowledge items (multivariate odds ratios (ORm) = 2.30), genital herpes infection (ORm = 3.19), Risk Reduction Score for Unprotected Sex, and Negative Condom Attitudes Scale (ORm = 1.13) were significantly associated with behavioral intention to perform at least one type of risk compensation behavior following VMMC. The results provided a framework for developing related interventions. Prevention of risk compensation should be an essential component of VMMC promotion for all MSTDP, irrespective of their intention for VMMC. PMID- 27120408 TI - Randomized clinical trial comparing self-gripping mesh with a standard polypropylene mesh for open inguinal hernia repair. AB - BACKGROUND: The introduction of mesh for open inguinal hernia repair has reduced the rate of recurrence, allowing research to focus on prevention of postoperative pain. In an effort to reduce chronic pain, a semiresorbable, lighter and self gripping mesh was developed. METHODS: A double-blind randomized clinical trial was conducted comparing the self-gripping mesh with a standard polypropylene mesh repair. Patients over 18 years of age undergoing open primary hernia repair were included. Pain was measured on a six-point verbal rating scale (VRS) and a 150-mm visual analogue scale (VAS). Postoperative pain reduction from baseline pain (DeltaVAS), complications and return to work/hobbies were studied. Data were collected at baseline, 3 weeks, 3 months and 1 year after surgery (primary outcome). RESULTS: A total of 363 patients were analysed. Median age was 59 (range 19-88) years. Baseline VRS and VAS scores were similar for the two groups. There was no difference in VRS scores at 1-year follow-up. Duration of surgery was significantly shorter with the self-gripping mesh (mean 40 min versus 49 min for standard mesh repair; P < 0.001). At 3 weeks, DeltaVAS in patients receiving the self-gripping mesh was significantly larger (-10.6 versus -5.0 respectively; P = 0.049) and less subjective discomfort was reported (P = 0.016). Complication rates, return to work and recurrence rates were similar, although there were more recurrences in the self-gripping mesh group (5.5 versus 2.2 per cent; P = 0.103). CONCLUSION: A self-gripping mesh for hernia repair may result in less pain in the early postoperative phase but chronic postherniorraphy pain is not affected. Recurrence rates may be a potential disadvantage. REGISTRATION NUMBER: NTR1212 (http://www.trialregister.nl). PMID- 27120409 TI - In vitro culture of Mesocestoides corti metacestodes and isolation of immunomodulatory excretory-secretory products. AB - Cestode-mediated diseases hold the interesting feature of persisting metacestode larvae dwelling within the host tissues, in the midst of the immune response. Excretory-secretory (ES) products of the metacestode larval stage modulate the host immune response and modify the outcome of the disease. Therefore, isolation and analysis of axenic metacestode ES products are crucial to study their properties. Here, we report the development of a system for long-term in vitro cultivation of the metacestode of the parasitic cestode Mesocestoides corti (syn. Mesocestoides vogae). Although feeder cells and host serum supported the early growth of the parasite, long-term survival was not dependent on host serum or host-derived factors enabling the collection of parasite released products in serum-free medium. Functionally, these axenic ES products recapitulated M. corti tetrathyridia's ability to inhibit LPS-driven IL-12p70 secretion by dendritic cells. Thus, our new axenic culture system will simplify the identification and characterization of M. corti-derived immunomodulatory factors that will indirectly enable the identification and characterization of corresponding factors in the metacestode larvae of medically relevant cestodes such as Echinococcus multilocularis that are not yet amenable to serum-free cultivation. PMID- 27120410 TI - Stage dependent expression and tumor suppressive function of FAM134B (JK1) in colon cancer. AB - The aims of the present study are to investigate sub-cellular location, differential expression in different cancer stages and functional role of FAM134B in colon cancer development. FAM134B expression was studied and quantified at protein and mRNA levels in cell lines using immunocytochemistry, Western blot and real-time PCR. In vitro functional assays and an in vivo xenotransplantation mouse models were used to investigate the molecular role of FAM134B in cancer cell biology in response to FAM134B silencing with shRNA lentiviral particles. FAM134B protein was noted in both cytoplasm and nuclei of cancer cells. In cancer cells derived from stage IV colon cancer, FAM134B expression was remarkably reduced when compared to non-cancer colon cells and cancer cells derived from stage II colon cancer. FAM134B knockdown significantly (P < 0.05) increased the proliferation of colon cancer cells following lentiviral transfection. Furthermore, FAM134B suppression significantly increased (34-52%; P < 0.05) the clonogenic capacity, wound healing potential of and increases the proportion of cells performing DNA synthesis (P < 0.01). Xenotransplantation model showed that larger and higher-grade tumors were formed in mice receiving FAM134B knockdown cells. To conclude, expression analysis, in vitro and in vivo indicated that FAM134B acts as a cancer suppressor gene in colon cancer. (c) 2016 Wiley Periodicals, Inc. PMID- 27120411 TI - Electrospinning of magnetic cellulose tris-(4-methylbenzoate) microparticles for enantioselective adsorption of racemic drug. AB - In this work, we introduce electrospinning to prepare magnetic enantioselective material for the first time. Multianalytical tools were used to characterize the resulted magnetic cellulose tris-(4-methylbenzoate) particles including transmission electron microscopy, SEM, FTIR spectroscopy, thermogravimetric analysis, X-ray diffractometer. Under the optimum conditions, the resulted particles were well-shaped sphere with a diameter range of 800 nm to 2 MUm and high magnetic sensitivity. The enantioselectivity of the adsorbents was evaluated using racemic ibuprofen as a model drug; an e.e. value of -4.78% (where e.e. is enantiomeric excess) was achieved in a single adsorption stage. We hope that our finding provides an efficient and economical procedure for the preparation of magnetic enantioselective materials with high selectivity and reproducibility. PMID- 27120412 TI - How Natural Evaporation Temporally Self-Tunes an Oscillating Sessile Droplet To Resonate at Different Modes. AB - We report the dynamics and underlying physics of evaporation driven transitions and autotuning of oscillation modes in sessile droplets subject to substrate perturbations. We have shown that evaporation controls temporal transition of the oscillation mode with a spatially downward shift of nodes (surface locations with zero displacement) toward the three-phase contact line. We have explained the physical mechanism using two parameters: the first quantifies evaporation driven tuning for resonance detection, and the second parameter characterizes mode lifetime which is found to be governed by evaporation dynamics. It is desirable to achieve autotuning of the oscillation modes in sessile droplets that essentially self-evolves in a spatiotemporal manner with continued evaporation. The insights suggest control of mode resonances is possible, which in turn will allow precision manipulations at droplet scale crucial for many applications such as surface patterning and others. PMID- 27120413 TI - Magnetic solid-phase extraction for determination of the total malachite green, gentian violet and leucomalachite green, leucogentian violet in aquaculture water by high-performance liquid chromatography with fluorescence detection. AB - In this study, magnetic multi-walled carbon nanotube nanoparticles were synthesized and used as the adsorbent for the sums of malachite green, gentian violet and leucomalachite green, leucogentian violet in aquaculture water samples followed by high performance liquid chromatography with fluorescence detection. This method was based on in situ reduction of chromic malachite green, gentian violet to colorless leucomalachite green, leucogentian violet with potassium borohydride, respectively. The obtained adsorbent combines the advantages of carbon nanotubes and Fe3 O4 nanoparticles in one material for separation and preconcentration of the reductive dyes in aqueous media. The structure and properties of the prepared nanoparticles were characterized by transmission and scanning electron microscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy. The main parameters affecting the adsorption recoveries were investigated and optimized, including reducing agent concentration, type and amount of sorbent, sample pH, and eluting conditions. Under the optimum conditions, the limits of detection in this method were 0.22 and 0.09 ng/mL for malachite green and gentian violet, respectively. Product recoveries ranged from 87.0 to 92.8% with relative standard deviations from 4.6 to 5.9%. The results indicate that the sorbent is a suitable material for the removal and concentration of triphenylmethane dyes from polluted environmental samples. PMID- 27120415 TI - Pyrene-Bridged Boron Subphthalocyanine Dimers: Combination of Planar and Bowl Shaped pi-Conjugated Systems for Creating Uniquely Curved pi-Conjugated Systems. AB - Pyrene-bridged boron subphthalocyanine dimers were synthesized from a mixed condensation reaction of 2,7-di-tert-butyl-4,5,9,10-tetracyanopyrene and tetrafluorophthalonitrile, and their syn and anti isomers arising from the result of connecting two bowl-shaped boron subphthalocyanine molecules were successfully separated. Expansion of the conjugated system of boron subphthalocyanine through a pyrene bridge caused a redshift of the Q band absorption relative to the parent pyrene-fused monomer, whereas combining the curved pi-conjugation of boron subphthalocyanine with the planar pi-conjugation of pyrene enabled facile embracement of C60 molecules, owing to the enhanced concave-convex pi-pi stacking interactions. PMID- 27120416 TI - Catalytic Synthesis of 3-Thioindoles Using Bunte Salts as Sulfur Sources under Metal-Free Conditions. AB - An efficient catalytic method for the synthesis of 3-thioindoles has been successfully developed, which uses odorless, stable, readily available crystalline Bunte salts as the sulfenylating agents, iodine as nonmetallic catalyst, and DMSO as both the oxidant and solvent. This method is practical and environmentally benign in terms of sulfur sources, catalyst, and solvent. The catalytic reaction is selective at the C3 position of indoles and compatible with a wide range of substrates, giving the desired products in good to excellent yields. PMID- 27120414 TI - Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria. AB - Riboswitches and attenuators are cis-regulatory RNA elements, most of which control bacterial gene expression via metabolite-mediated, premature transcription termination. We developed an unbiased experimental approach for genome-wide discovery of such ribo-regulators in bacteria. We also devised an experimental platform that quantitatively measures the in vivo activity of all such regulators in parallel and enables rapid screening for ribo-regulators that respond to metabolites of choice. Using this approach, we detected numerous antibiotic-responsive ribo-regulators that control antibiotic resistance genes in pathogens and in the human microbiome. Studying one such regulator in Listeria monocytogenes revealed an attenuation mechanism mediated by antibiotic-stalled ribosomes. Our results expose broad roles for conditional termination in regulating antibiotic resistance and provide a tool for discovering riboswitches and attenuators that respond to previously unknown ligands. PMID- 27120417 TI - The effects of host age and spatial location on bacterial community composition in the English Oak tree (Quercus robur). AB - Drivers of bacterial community assemblages associated with plants are diverse and include biotic factors, such as competitors and host traits, and abiotic factors, including environmental conditions and dispersal mechanisms. We examine the roles of spatial distribution and host size, as an approximation for age, in shaping the microbiome associated with Quercus robur woody tissue using culture independent 16S rRNA gene amplicon sequencing. In addition to providing a baseline survey of the Q. robur microbiome, we screened for the pathogen of acute oak decline. Our results suggest that age is a predictor of bacterial community composition, demonstrating a surprising negative correlation between tree age and alpha diversity. We find no signature of dispersal limitation within the Wytham Woods plot sampled. Together, these results provide evidence for niche-based hypotheses of community assembly and the importance of tree age in bacterial community structure, as well as highlighting that caution must be applied when diagnosing dysbiosis in a long-lived plant host. PMID- 27120418 TI - Introduction. PMID- 27120419 TI - Validating the proposed ICD-11 domains. AB - AIM: The ICD-11 Personality Disorders Committee has proposed five personality domains: Detached, Anankastic, Negative Affective, Dissocial and Disinhibited. We attempted to validate these proposed domains in a large sample of patients with major depression. METHODS: Participants from five treatment studies received a SCID assessment interview to assess DSM-5 personality disorder symptoms. Personality disorder symptoms were assigned to the five proposed domains. Confirmatory factor analysis in an exploratory framework was used to test the hypothesized domain structure. RESULTS: A total of 606 patients were included in the analysis. A series of models were tested on the data set. The best fitting model produced five domains. Three domains detached, anankastic and negative affective were similar to the ICD-11 proposed domains. The Disinhibited domain did not emerge as a distinct factor but loaded onto a single Dissocial/Disinhibited factor. The model was improved by adding a separate Antisocial domain. The remaining domain incorporating borderline, histrionic and narcissistic symptoms is tentatively labelled Borderline to retain continuity with clinical practice and research. CONCLUSIONS: The proposed ICD-11 personality disorder domains were partially validated. We have five domains currently labelled Detached, Anankastic, Negative Emotional, Antisocial and Borderline. The sample studied limits the generalizability of our findings. In particular, the broad domain we have called Borderline requires further study. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27120420 TI - Dimensions of dependence and their influence on the outcome of cognitive behaviour therapy for health anxiety: randomized controlled trial. AB - BACKGROUND: The personality trait of dependence is common in health-seeking behaviour. We therefore examined its impact in a large randomized controlled trial of psychological treatment for health anxiety. AIMS: To test whether dependent personality traits were positive or negative in determining the outcome of an adapted form of cognitive behaviour therapy for health anxiety (CBT-HA) over the course of 5 years and whether dependent personality dysfunction could be viewed dimensionally in a similar way to the new ICD-11 diagnostic system for general personality disorder. METHOD: Dependent personality dysfunction was assessed using a self-rated questionnaire, the Dependent Personality Questionnaire, at baseline in a randomized controlled trial of 444 patients from medical clinics with pathological health anxiety treated with a modified form of CBT-HA or standard treatment in the medical clinics, with assessment on five occasions over 5 years. Dependent personality dysfunction was assessed using four severity groups. RESULTS: Patients with mild and moderate dependent personality disorder treated with CBT-HA showed the greatest reduction in health anxiety compared with standard care, and those with no dependent dysfunction showed the least benefit. Patients with higher dependent traits received significantly more treatment sessions (8.6) than those with low trait levels (5.4) (p < 0.01). CONCLUSION: The results suggest that patients treated with cognitive behaviour therapy for health anxiety respond better if they have moderate dependent personality. The reasons for this may be related to better adherence to psychological treatment and greater negative effects of frequent reassurance and excessive consultation in those treated in standard care. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27120422 TI - The future is now: Personality disorder and the ICD-11. PMID- 27120421 TI - Schedule for personality assessment from notes and documents (SPAN-DOC): Preliminary validation, links to the ICD-11 classification of personality disorder, and use in eating disorders. AB - BACKGROUND: The underlying core of personality is insufficiently assessed by any single instrument. This has led to the development of instruments adapted for written records in the assessment of personality disorder. AIMS: To test the construct validity and inter-rater reliability of a new personality assessment method. METHOD: This study (four parts) assessed the construct validity of the Schedule for Personality Assessment from Notes and Documents (SPAN-DOC), a dimensional assessment from clinical records. We examined inter-rater reliability using case vignettes (Part 1) and convergent validity in three ways: by comparison with NEO Five-Factor Inventory in 130 Korean patients (Part 2), with agreed ICD-11 personality severity levels in two populations (Part 3) and determining its use in assessing the personality status in 90 British patients with eating disorders (Part 4). RESULTS: Internal consistency (alpha = .90) and inter-rater reliability (intraclass correlation coefficient >= .88) were satisfactory. Each factor in the five-factor model of personality was correlated with conceptually valid SPAN-DOC variables. The SPAN-DOC domain traits in those with eating disorders were categorized into 3 clusters: self-aggrandisement, emotionally unstable, and anxious/dependent. CONCLUSIONS: This study provides preliminary support for the usefulness of SPAN-DOC in the assessment of personality disorder. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27120423 TI - The ICD-11 proposals and field trials. PMID- 27120424 TI - Toward a firmer foundation for ICD-11: On the conceptualization and assessment of personality pathology. PMID- 27120425 TI - Reflections of the reconceptualization of ICD-11. Empirical and practical considerations. PMID- 27120426 TI - Constructing a short form of the hierarchical personality inventory for children (HiPIC): the HiPIC-30. AB - Children's personality traits are invaluable predictors of concurrent and later mental and physical health. Several validated longer inventories for assessing the widely recognized Five-Factor Model of personality in children are available, but short forms are scarce. This study aimed at constructing a 30-item form of the 144-item Hierarchical Personality Inventory for Children (HiPIC) (Mervielde & De Fruyt, ). Participants were 1543 children aged 6-12 years (sample 1) and 3895 children aged 8 years (sample 2). Sample 1 completed the full HiPIC, from which we constructed the HiPIC-30, and the Child Behaviour Checklist (Achenbach, ). Sample 2 completed the HiPIC-30. The HiPIC-30 personality domains correlated over r = .90 with the full HiPIC domains, had good Cronbach's alphas and correlated similarly with CBCL behaviour problems and gender as the full HiPIC. The factor structures of the HiPIC-30 were convergent across samples, but the imagination factor was not clear-cut. We conclude that the HiPIC-30 is a reliable and valid questionnaire for the Five-Factor personality traits in children. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27120427 TI - Assessment of retinal arteriolar morphology by noninvasive methods: the philosopher's stone? PMID- 27120428 TI - Can we predict outcome by noninvasive assessment of renal haemodynamics in hypertension? The role of renal resistive index. PMID- 27120429 TI - Global longitudinal strain: a novel hallmark of cardiac risk in arterial hypertension. PMID- 27120430 TI - Comparing the therapeutic merits of angiotensin receptor blockers. PMID- 27120431 TI - Relationship between aortic root size and glomerular filtration rate in hypertensive patients. PMID- 27120432 TI - Reply. PMID- 27120433 TI - Proteins Take up Water Before Unfolding. AB - Proteins perform specific biological functions that strongly depend on their three-dimensional structure. This three-dimensional structure, i.e. the way the protein folds, is strongly determined by the interaction between the protein and the water solvent. We study the dynamics of water in aqueous solutions of several globular proteins at different degrees of urea-induced unfolding, using polarization-resolved femtosecond infrared spectroscopy. We observe that a fraction of the water molecules is strongly slowed down by their interaction with the protein surface. By monitoring the slow water fraction we can directly probe the amount of water-exposed protein surface. We find that at mild denaturing conditions, the water-exposed surface increases by almost 50%, while the secondary structure is still intact. This finding indicates that protein unfolding starts with the protein structure becoming less tight, thereby allowing water to enter. PMID- 27120434 TI - A Precision Ethylene-Styrene Copolymer with High Styrene Content from Ring Opening Metathesis Polymerization of 4-Phenylcyclopentene. AB - Ring-opening metathesis polymerization of 4-phenylcyclopentene is investigated for the first time under various conditions. Thermodynamic analysis reveals a polymerization enthalpy and entropy sufficient for high molar mass and conversions at lower temperatures. In one example, neat polymerization using Hoveyda-Grubbs second generation catalyst at -15 degrees C yields 81% conversion to poly(4-phenylcyclopentene) (P4PCP) with a number average molar mass of 151 kg mol(-1) and dispersity of 1.77. Quantitative homogeneous hydrogenation of P4PCP results in a precision ethylene-styrene copolymer (H2 -P4PCP) with a phenyl branch at every fifth carbon along the backbone. This equates to a perfectly alternating trimethylene-styrene sequence with 71.2% w/w styrene content that is inaccessible through molecular catalyst copolymerization strategies. Differential scanning calorimetry confirms P4PCP and H2 -P4PCP are amorphous materials with similar glass transition temperatures (Tg ) of 17 +/- 2 degrees C. Both materials present well-defined styrenic analogs for application in specialty materials or composites where lower softening temperatures may be desired. PMID- 27120435 TI - Iron-refractory iron deficiency anemia (IRIDA) cases with 2 novel TMPRSS6 mutations. AB - Iron-refractory iron deficiency anemia (IRIDA) is a rarely diagnosed autosomal recessive disorder that presents with hypochromic, microcytic anemia due to mutations in TMPRSS6, which encodes matriptase-2. Contrary to classical iron deficiency anemia, serum hepcidin levels are found to be elevated in this disorder. Here, we report 5 cases from 4 unrelated families with inadequate response to iron therapy, who were consequently diagnosed as IRIDA. The mean age of the cases at diagnosis was 5.0 years (range: 0.7-11.3 years). All cases were either homozygous or compound heterozygous for missense or frameshift mutations in the TMPRSS6 gene, 2 of the mutations being novel (Cys410Ser and Leu689Pro). IRIDA should be considered in patients with findings of iron deficiency anemia unresponsive to oral iron therapy, whose serum ferritin levels are found normal or elevated. PMID- 27120437 TI - Cardiac Tamponade Physiology Secondary to Tense Ascites. AB - Cardiac tamponade is a common and often life-threatening process, which is typically associated with a pericardial effusion or, in rare cases, with a large pleural effusion. Theoretically, as reported in only a single prior case, it can be caused by extrinsic compression from tense ascites. We present a case in which dynamic inferior wall collapse was secondary to increased abdominal pressure from tense ascites. This phenomenon may be more common than previously diagnosed, especially in patients with liver disease. These patients often develop frequent ascites and present with clinical signs and symptoms similar to cardiac tamponade (tachycardia, hypotension and dyspnea). Presently, no formal practice guidelines exist regarding cardiac imaging for these patients. A high index of suspicion is required for timely diagnosis and management. PMID- 27120436 TI - Metastatic Gastroesophageal Adenocarcinoma Patients Treated with Systemic Therapy Followed by Consolidative Local Therapy: A Nomogram Associated with Long-Term Survivors. AB - OBJECTIVE: Patients with metastatic gastroesophageal adenocarcinoma (MGEAC) have a poor but heterogeneous clinical course. Some patients have an unusually favorable outcome. We sought to identify clinical variables associated with more favorable outcomes. METHODS: Of 246 patients with MGEAC, we identified 64 who received systemic therapy and eventually received local consolidation therapy. Univariate and multivariate Cox regression models were used, and a nomogram was developed. RESULTS: Of these 64 patients, 61% had received consolidation chemoradiation (CRT) with doses of 50-55 Gy and 78% did not undergo surgery. The median follow-up time of survivors was 3.9 years, and the median overall survival (OS) from CRT start was 1.5 years (95% CI, 1.2-2.2). Surgery (as local consolidation) was an independent prognosticator for longer OS in the multivariate analysis (p = 0.02). The 5-year OS rate was 25% (SE = 6%). The contributors to the nomogram were longer duration of systemic therapy before CRT and the type of local therapy. CONCLUSIONS: Our data suggest that a subset of patients with MGEAC have an excellent prognosis (OS >5 years). However, these patients need to be identified during their clinical course so that local consolidation (CRT, surgery, or both) may be offered. PMID- 27120438 TI - Balancing Accuracy and Cost of Confinement Simulations by Interpolation and Extrapolation of Confinement Energies. AB - Improvements to the confinement method for the calculation of conformational free energy differences are presented. By taking advantage of phase space overlap between simulations at different frequencies, significant gains in accuracy and speed are reached. The optimal frequency spacing for the simulations is obtained from extrapolations of the confinement energy, and relaxation time analysis is used to determine time steps, simulation lengths, and friction coefficients. At postprocessing, interpolation of confinement energies is used to significantly reduce discretization errors in the calculation of conformational free energies. The efficiency of this protocol is illustrated by applications to alanine n peptides and lactoferricin. For the alanine-n-peptide, errors were reduced between 2- and 10-fold and sampling times between 8- and 67-fold, while for lactoferricin the long sampling times at low frequencies were reduced 10-100 fold. PMID- 27120439 TI - Different evolutionary pathways from B4 to B1 phase in AlN and InN: metadynamics investigations. AB - Pressure-induced B4-B1 phase transitions of AlN and InN at ambient temperature are systematically investigated using density functional-based metadynamics simulations. A homogeneous deformation path, which is energetically favorable, is through a hexagonal structure for AlN, and through a tetragonal structure for InN. Furthermore, the dynamical stability, instead of the mechanical stability, is crucial to determining the phase-transition paths: the intermediate hexagonal structure can remain stable, whereas the tetragonal structure is always unstable. The B4 phase always shows the direct band gap before the occurrence of structure transition, while the band gap of stable intermediate hexagonal phase is indirect for AlN. Finally, the band gap of the ultimate cubic phase is direct for AlN and indirect for InN, due to the strong p-d repulsion at the R point. PMID- 27120440 TI - [Prevalence of rheumatoid arthritis in Germany based on health insurance data : Regional differences and first results of the PROCLAIR study]. AB - BACKGROUND: Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease with a prevalence of up to 1 % in the adult population. OBJECTIVE: This study describes the prevalence of RA diagnoses in outpatient health insurance claims data, based on different case definitions and stratified by age, sex and region of residence. METHODS: Based on data from a nationwide statutory health insurance fund (BARMER GEK) from the year 2013, a cross-sectional study of insurants aged 18 years or older was conducted. The following case definitions were applied: A) a diagnosis of seropositive rheumatoid arthritis (M05) or other rheumatoid arthritis (M06) according to the international classification of diseases 10 German modification (ICD-10-GM) in at least two quarterly periods of the year 2013, B) case definition A plus determination of C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) at least once, C) case definition B plus specific drug therapy and D) case definition A plus treatment by a rheumatologist. Raw as well as age and sex-standardized prevalences were calculated and stratified according to the federal state. RESULTS: The study population consisted of 7,155,315 insurants of whom 60.2 % were female. Overall, RA prevalences for the respective case definitions were 1.62 % (A), 1.11 % (B), 0.94 % (C) and 0.64 % (D). When standardized to the German population the prevalences were 1.38 % (A), 0.95 % (B), 0.81 % (C) and 0.55 % (D). The proportion of women was approximately 80 % for all case definitions. Prevalences increased with age, peaking in the age group 70-79 years old and showing the highest values in eastern and the lowest in southern Germany for raw as well as standardized measures. CONCLUSION: Regional differences in the prevalence of RA diagnoses in health insurance claims data were observed independent of age, sex and case definition. The expected prevalence according to the results of international studies was best achieved when case definitions with CRP or ESR were considered. PMID- 27120441 TI - Regulatory networks in evolution. PMID- 27120442 TI - Intolerable secretion and diabetes in tolerant transgenic mice, revisited. AB - A new mouse model linking diabetes, insulin secretion and autoimmunity with a high-fat diet supports a shared mechanism for type 1 (T1D) and type 2 (T2D) diabetes. In this model, the protein secretion system of insulin-producing pancreatic beta cells is stressed, leading to increased beta cell apoptosis and diabetes via reduced levels of the transcription factor GLIS3, a pathogenic pathway that can be mimicked by a high-fat diet. PMID- 27120443 TI - Fat eggs shape offspring health. AB - How maternal diet influences offspring metabolism is unclear, as it is difficult to distinguish between the effects of the in utero environment and epigenetic factors contributed by the oocyte. In a mouse model of high-fat diet, a new study teases apart these mechanisms by using in vitro fertilization and shows that susceptibility of offspring to metabolic disorder can likely be attributed to epigenetic inheritance via the oocyte. PMID- 27120444 TI - Connecting the regulatory genome. AB - Determining how the evolving genome-wide map of distal regulatory elements is connected with target genes has remained a significant challenge, despite progress in understanding chromatin architecture and regulation. A new study presents a computational approach for predicting distal element-gene interactions. PMID- 27120445 TI - International regulatory needs for development of an IATA for non-genotoxic carcinogenic chemical substances. AB - Although regulatory requirements for carcinogenicity testing of chemicals vary according to product sector and regulatory jurisdiction, the standard approach starts with a battery of genotoxicity tests. If any of the in vivo genotoxicity tests are positive, a lifetime rodent cancer bioassay may be requested, which allows the detection of non-genotoxic carcinogens (NGTxC). However, under most chemical regulations the cancer bioassay is rarely requested, specific requests to obtain information on non-genotoxic mechanisms of carcinogenicity are few, and there are no OECD approved screening methods. When the in vitro genotoxicity battery is negative, usually no further carcinogenicity testing is requested. Consequently NGTxC might remain unidentified and therefore the risks they may pose to human health will not be managed. In contrast to genotoxic carcinogens NGTxCact through a large variety of specific mechanisms, and a panel of tests covering multiple biological traits will be needed. The development of an Integrated Approach to Testing and Assessment (IATA) of NGTxC could assist regulatory decision makers. We examine what NGTxC are and discuss chemical regulatory requirements and limitations. With a strong drive to reduce animal testing and costs in mind, it is essential that proper and robust alternatives for animal testing (3Rs) methods for addressing non-genotoxic modes of action are developed and used. Therefore relevant in vitro mechanisms and assays are described and tentatively organized in levels of information, indicating both a possible structure of the future IATA for NGTxC and associated OECD Test Guideline development priorities. PMID- 27120446 TI - Surgeon-Level Variation in Postoperative Complications. AB - BACKGROUND: Variation in surgical outcomes is often attributed to patient comorbidities and the severity of underlying disease, but little is known about the extent of variation in outcomes by surgeon and the surgeon factors that are associated with quality. METHODS: Using the Maryland Health Services Cost Review Commission database, we evaluated risk-adjusted postoperative events by surgeon. Operations studied were elective laparoscopic and open colectomy procedures for colon cancer performed over a 2-year period (July 2012-September 2014). Postoperative events were defined using the Agency for Healthcare Research and Quality Patient Safety Indicators. Surgeons performing fewer than ten procedures during the study period were excluded. Logistic regression and post-estimation were used to calculate an observed-to-expected (O/E) ratio of postoperative complications for each surgeon, adjusting for patient and surgeon characteristics. RESULTS: A total of 2525 patients underwent an elective colectomy during the study period by 276 surgeons at 44 hospitals. Postoperative complications varied more by surgeon (range 0 to 30.0 %) than by hospital (range 0 to 18.2 %). Surgeon-level use of laparoscopic surgery to perform colectomy ranged from 0 to 100 %. After risk adjustment with patient factors, surgeon experience, surgeon medical school, surgeon gender, and annual surgeon colectomy volume were not associated with postoperative complications. Surgeon use of laparoscopy was the strongest predictor of lower complications (vs fourth quartile of surgeons, first quartile OR = 0.47 (0.26-0.85); second quartile OR = 0.41 (0.22-0.73); and third quartile OR = 0.84 (0.52-1.36). CONCLUSIONS: Quality metrics in health care have been measured at the hospital level, but a greater quality improvement potential exists at the surgeon level. Awareness of this variation could better inform patients undergoing elective surgery and their referring physicians. PMID- 27120447 TI - National Trends in Short-term Outcomes Following Non-emergent Surgery for Diverticular Disease. AB - INTRODUCTION: Elective surgery for diverticulitis has evolved over the last decade. We aimed to evaluate the impact of changing practice patterns on postoperative outcomes. We hypothesized that the increased use of laparoscopy, and other management changes, would correlate with a decrease in postoperative complications. METHODS: Patients undergoing non-emergent surgery for diverticulitis from 2005 to 2013 were selected from the National Surgical Quality Improvement Program (NSQIP) database. We compared patient demographics, comorbidities, and operative approach by year of operation using chi-square tests and investigated temporal trends in postoperative outcomes using univariate, trend, and multivariate analyses. RESULTS: The analytic cohort, which included 29,893 patients, had increasing rates of obesity, advanced age, and higher American Society of Anesthesiologists (ASA) class over the study period. The use of laparoscopy increased significantly from 48 % in 2005/2006 to 70 % in 2013 (p < 0.001), while the rate of stoma creation remained unchanged (10-12 %, p = 0.072). The absolute risk of any postoperative complication decreased by 5.8 % over the study period, driven primarily by a reduction in infectious complications. Year of operation was a significant independent predictor of fewer complications for 2011-2013. CONCLUSION: Despite a trend towards increasing patient complexity, there has been a decline in postoperative morbidity following non-emergent surgery for diverticulitis. This trend coincides with the steadily increasing use of laparoscopy in this population. PMID- 27120448 TI - Impact of Mucinous Histology on the Prognosis of Stage I-III Adenocarcinomas of the Appendix: a Population-Based, Propensity Score-Matched Analysis. AB - BACKGROUND: Whereas the poor prognosis of signet ring cell adenocarcinomas of the appendix is well known, the significance of mucinous histology remains unclear. The aim of this population-based study was to evaluate if mucinous histology is an independent prognostic factor in appendiceal adenocarcinomas. METHODS: Patients with stage I-III adenocarcinoma of the appendix who underwent surgery between 2004 and 2012 were identified in the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and cancer-specific survival (CSS) were assessed using risk-adjusted Cox proportional hazards regression models and propensity score methods. RESULTS: Overall, 980 patients with appendix cancer were included, of which 449 (45.8 %) had a mucinous histology. In an unadjusted analysis, the 5-year OS and CSS in patients with a mucinous adenocarcinoma (MC) was 76.8 % (95 % confidence interval (95 %CI): 72.1-81.7 %) and 81.0 % (95 %CI: 76.6-85.6 %), respectively, compared with 70.0 % (95 %CI: 65.1-75.3 %) and 76.2 % (95 %CI: 71.5-81.2 %) in patients with non-mucinous adenocarcinoma (NMC) (P = 0.082 and P = 0.368). In multivariable analysis, no impact on survival was observed for OS (HR = 1.22, 95 %CI: 0.89-1.68, P = 0.208) and CSS (HR = 1.21, 95 %CI: 0.84-1.74, P = 0.296). After propensity score matching, nearly identical survival rates were observed (OS: HR = 1.03, 95 %CI: 0.71-1.49, P = 0.881 and CSS: HR = 1.05, 95 %CI: 0.70-1.59, P = 0.803). CONCLUSIONS: The present population-based, propensity score matched analysis shows that mucinous histology does not affect survival in stage I-III appendiceal adenocarcinoma patients. Therefore, the same treatment strategies can be applied for patients with NMC and MC of the appendix. PMID- 27120449 TI - Role of Rilpivirine and Etravirine in Efavirenz and Nevirapine-Based Regimens Failure in a Resource-Limited Country: A Cross- Sectional Study. AB - INTRODUCTION: Etravirine(ETR) can be used for patients who have failed NNRTI based regimen. In Thailand, ETR is approximately 45 times more expensive than rilpivirine(RPV). However, there are no data of RPV use in NNRTI failure. Therefore, we assessed the susceptibility and mutation patterns of first line NNRTI failure and the possibility of using RPV compared to ETV in patients who have failed efavirenz(EFV)- and nevirapine(NVP)-based regimens. METHODS: Clinical samples with confirmed virological failure from EFV- or NVP-based regimens were retrospectively analyzed. Resistance-associated mutations (RAMs) were interpreted by IAS-USA Drug Resistance Mutations. Susceptibility of ETR and RPV were interpreted by DUET, Monogram scoring system, and Stanford University HIV Drug Resistance Database. RESULTS: 1,279 and 528 patients failed EFV- and NVP-based regimens, respectively. Y181C was the most common NVP-associated RAM (54.3% vs. 14.7%, p<0.01). K103N was the most common EFV-associated RAM (56.5% vs. 19.1%, P<0.01). The results from all three scoring systems were concordant. 165(11.1%) and 161(10.9%) patients who failed NVP-based regimen were susceptible to ETR and RPV, respectively (p = 0.85). 195 (32.2%) and 191 (31.6%) patients who failed EFV based regimen, were susceptible to ETR and RPV, respectively (p = 0.79). The susceptibility of ETV and RPV in EFV failure was significantly higher than NVP failure (p<0.01). CONCLUSION: The mutation patterns for ETR and RPV were similar but 32% and 11% of patients who failed EFV and NVP -based regimen, respectivly were susceptible to RPV. This finding suggests that RPV can be used as the alternative antiretroviral agent in patients who have failed EFV-based regimen. PMID- 27120450 TI - Addressing Loss of Efficiency Due to Misclassification Error in Enriched Clinical Trials for the Evaluation of Targeted Therapies Based on the Cox Proportional Hazards Model. AB - A key feature of precision medicine is that it takes individual variability at the genetic or molecular level into account in determining the best treatment for patients diagnosed with diseases detected by recently developed novel biotechnologies. The enrichment design is an efficient design that enrolls only the patients testing positive for specific molecular targets and randomly assigns them for the targeted treatment or the concurrent control. However there is no diagnostic device with perfect accuracy and precision for detecting molecular targets. In particular, the positive predictive value (PPV) can be quite low for rare diseases with low prevalence. Under the enrichment design, some patients testing positive for specific molecular targets may not have the molecular targets. The efficacy of the targeted therapy may be underestimated in the patients that actually do have the molecular targets. To address the loss of efficiency due to misclassification error, we apply the discrete mixture modeling for time-to-event data proposed by Eng and Hanlon [8] to develop an inferential procedure, based on the Cox proportional hazard model, for treatment effects of the targeted treatment effect for the true-positive patients with the molecular targets. Our proposed procedure incorporates both inaccuracy of diagnostic devices and uncertainty of estimated accuracy measures. We employed the expectation-maximization algorithm in conjunction with the bootstrap technique for estimation of the hazard ratio and its estimated variance. We report the results of simulation studies which empirically investigated the performance of the proposed method. Our proposed method is illustrated by a numerical example. PMID- 27120451 TI - Antibody-Mediated Rejection in a Blood Group A-Transgenic Mouse Model of ABO Incompatible Heart Transplantation. AB - BACKGROUND: ABO-incompatible (ABOi) organ transplantation is performed owing to unremitting donor shortages. Defining mechanisms of antibody-mediated rejection, accommodation, and tolerance of ABOi grafts is limited by lack of a suitable animal model. We report generation and characterization of a murine model to enable study of immunobiology in the setting of ABOi transplantation. METHODS: Transgenesis of a construct containing human A1- and H-transferases under control of the ICAM-2 promoter was performed in C57BL/6 (B6) mice. A-transgenic (A-Tg) mice were assessed for A-antigen expression by histology and flow cytometry. B6 wild-type (WT) mice were sensitized with blood group A-human erythrocytes; others received passive anti-A monoclonal antibody and complement after heart transplant. Serum anti-A antibodies were assessed by hemagglutination. "A-into-O" transplantation (major histocompatibility complex syngeneic) was modeled by transplanting hearts from A-Tg mice into sensitized or nonsensitized WT mice. Antibody-mediated rejection was assessed by morphology/immunohistochemistry. RESULTS: A-Tg mice expressed A-antigen on vascular endothelium and other cells including erythrocytes. Antibody-mediated rejection was evident in 15/17 A-Tg grafts in sensitized WT recipients (median titer, 1:512), with 2 showing hyperacute rejection and rapid cessation of graft pulsation. Hyperacute rejection was observed in 8/8 A-Tg grafts after passive transfer of anti-A antibody and complement into nonsensitized recipients. Antibody-mediated rejection was not observed in A-Tg grafts transplanted into nonsensitized mice. CONCLUSIONS: A-Tg heart grafts transplanted into WT mice with abundant anti-A antibody manifests characteristic features of antibody-mediated rejection. These findings demonstrate an effective murine model to facilitate study of immunologic features of ABOi transplantation and to improve potential diagnostic and therapeutic strategies. PMID- 27120452 TI - Diagnostic Contribution of Donor-Specific Antibody Characteristics to Uncover Late Silent Antibody-Mediated Rejection-Results of a Cross-Sectional Screening Study. AB - BACKGROUND: Circulating donor-specific antibodies (DSA) detected on bead arrays may not inevitably indicate ongoing antibody-mediated rejection (AMR). Here, we investigated whether detection of complement-fixation, in parallel to IgG mean fluorescence intensity (MFI), allows for improved prediction of AMR. METHODS: Our study included 86 DSA+ kidney transplant recipients subjected to protocol biopsy, who were identified upon cross-sectional antibody screening of 741 recipients with stable graft function at 6 months or longer after transplantation. IgG MFI was analyzed after elimination of prozone effect, and complement-fixation was determined using C1q, C4d, or C3d assays. RESULTS: Among DSA+ study patients, 44 recipients (51%) had AMR, 24 of them showing C4d-positive rejection. Although DSA number or HLA class specificity were not different, patients with AMR or C4d + AMR showed significantly higher IgG, C1q, and C3d DSA MFI than nonrejecting or C4d-negative patients, respectively. Overall, the predictive value of DSA characteristics was moderate, whereby the highest accuracy was computed for peak IgG MFI (AMR, 0.73; C4d + AMR, 0.71). Combined analysis of antibody characteristics in multivariate models did not improve AMR prediction. CONCLUSIONS: We estimate a 50% prevalence of silent AMR in DSA+ long-term recipients and conclude that assessment of IgG MFI may add predictive accuracy, without an independent diagnostic advantage of detecting complement-fixation. PMID- 27120453 TI - The International Liver Transplant Society Guideline on Living Liver Donation. AB - The following guideline represents the position of the International Liver Transplantation Society (ILTS) on key preoperative, operative, and postoperative aspects surrounding living liver donation. These recommendations were developed from experts in the field from around the world. The authors conducted an analysis of the National Library of Medicine indexed literature on "living donor liver transplantation" [Medline search] using Grading of Recommendations Assessment, Development and Evaluation methodology. Writing was guided by the ILTS Policy on the Development and Use of Practice Guidelines (www.ilts.org). ILTS members, and many more nonmembers, were invited to comment. Recommendations have been based on information available at the time of final submission (March 2016). The lack of randomized controlled trials in this field to date is acknowledged and is reflected in the grading of evidence. Intended for use by physicians, these recommendations support specific approaches to the diagnostic, therapeutic, and preventive aspects of care. PMID- 27120457 TI - Rosuvastatin Attenuates CD40L-Induced Downregulation of Extracellular Matrix Production in Human Aortic Smooth Muscle Cells via TRAF6-JNK-NF-kappaB Pathway. AB - CD40L and statins exhibit pro-inflammatory and anti-inflammatory effects, respectively. They are both pleiotropic and can regulate extracellular matrix (ECM) degeneration in an atherosclerotic plaque. Statins can decrease both the CD40 expression and the resulting inflammation. However, the effects of CD40L and stains on atherosclerotic plaque ECM production and the underlying mechanisms are not well established. Moreover, prolyl-4-hydroxylase alpha1 (P4Halpha1) is involved in collagen synthesis but its correlations with CD40L and statins are unknown. In the present study, CD40L suppressed P4Halpha1 expression in human aortic smooth muscle cells (HASMCs) in a dose- and time-dependent manner, with insignificant changes in MMP2 expression and negative enzymatic activity of MMP9. CD40L increased TRAF6 expression, JNK phosphorylation, NF-kappaB nuclear translocation as well as DNA binding. Furthermore, silencing TRAF6, JNK or NF kappaB genes abolished CD40L-induced suppression of P4Halpha1. Lower NF-kappaB nuclear import rates were observed when JNK or TRAF6 silenced HASMCs were stimulated with CD40L compared to HASMCs with active JNK or TRAF6. Together, these results indicate that CD40L suppresses P4Halpha1 expression in HASMCs by activating the TRAF6-JNK- NF-kappaB pathway. We also found that rosuvastatin inhibits CD40L-induced activation of the TRAF6-JNK- NF-kappaB pathway, thereby significantly rescuing the CD40L stimulated P4Halpha1 inhibition. The results from this study will help find potential targets for stabilizing vulnerable atherosclerotic plaques. PMID- 27120459 TI - Mutational analysis of hepatitis B virus pre-S1 (9-24) fusogenic peptide. AB - A hollow nanoparticle known as a bio-nanocapsule (BNC) consisting of hepatitis B virus (HBV) envelope L protein and liposome (LP) can encapsulate drugs and genes and thereby deliver them in vitro and in vivo to human hepatic tissues, specifically by utilizing the HBV-derived infection machinery. Recently, we identified a low pH-dependent fusogenic domain at the N-terminal part of the pre S1 region of the HBV L protein (amino acid residues 9 to 24; NPLGFFPDHQLDPAFG), which shows membrane destabilizing activity (i.e., membrane fusion, membrane disruption, and payload release) upon interaction with target LPs. In this study, instead of BNC and HBV, we generated LPs displaying a mutated form of the pre-S1 (9-24) peptide, and performed a membrane disruption assay using target LPs containing pyranine (fluorophore) and p-xylene-bis (N-pyridinium bromide) (DPX) as a quencher. The membrane disruption activity was found to correlate with the hydrophobicity of the whole structure, while the peptide retained a random-coil structure even under low pH condition. One large hydrophobic cluster (I) and one small hydrophobic cluster (II) residing in the peptide would be connected by the protonation of residues D16 and D20, and thereby exhibit strong membrane disruption activity in a low pH-dependent manner. Furthermore, the introduction of a positively charged residue enhanced the activity significantly, suggesting that a sole positively charged residue (H17) may be important for the interaction with target LPs by electrostatic interaction. Collectively, these results suggest that the pre-S1 (9-24) peptide may be involved in the endosomal escape of the BNC's payloads, as well as in the HBV uncoating process. PMID- 27120458 TI - Validation of Metabolic Alterations in Microscale Cell Culture Lysates Using Hydrophilic Interaction Liquid Chromatography (HILIC)-Tandem Mass Spectrometry Based Metabolomics. AB - By standard convention, in order to increase the efficacy of metabolite detection from cell culture lysates, metabolite extracts from a large quantity of cells are utilized for multiple reaction monitoring-based metabolomic studies. Metabolomics from a small number of cell extracts offers a potential economical alternative to increased cell numbers, in turn increasing the utility of cell culture-based metabolomics. However, the effect of reduced cell numbers on targeted metabolomic profiling is relatively unstudied. Considering the limited knowledge available of the feasibility and accuracy of microscale cell culture metabolomics, the present study analyzes differences in metabolomic profiles of different cell numbers of three pancreatic cancer cell lines. Specifically, it examines the effects of reduced cell numbers on metabolite profiles by obtaining extracts either directly from microscale culture plates or through serial dilution of increased numbers of cellular metabolite extracts. Our results indicate reduced cell numbers only modestly affect the number of metabolites detected (93% of metabolites detected in cell numbers as low as 104 cells and 97% for 105 cells), independent of the method used to obtain the cells. However, metabolite peak intensities were differentially affected by the reduced cell numbers, with some peak intensities inversely proportional to the cell numbers. To help eliminate such potential inverse relationships, peak intensities for increased cell numbers were excluded from the comparative analysis. Overall, metabolite profiles from microscale culture plates were observed to differ from the serial dilution samples, which may be attributable to the medium-to-cell-number ratios. Finally, findings identify perturbations in metabolomic profiling for cellular extracts from reduced cell numbers, which offer future applications in microscale metabolomic evaluations. PMID- 27120460 TI - Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening. AB - Peptidyl prolyl cis/trans isomerization by Pin1 regulates various oncogenic signals during cancer progression, and its inhibition through multiple approaches has established Pin1 as a therapeutic target. However, lack of simplified screening systems has limited the discovery of potent Pin1 inhibitors. We utilized phosphorylation-dependent binding of Pin1 to its specific substrate to develop a screening system for Pin1 inhibitors. Using this system, we screened a chemical library, and identified a novel selenium derivative as Pin1 inhibitor. Based on structure-activity guided chemical synthesis, we developed more potent Pin1 inhibitors that inhibited cancer cell proliferation. PMID- 27120461 TI - Structural and biochemical characterization of the Bacillus cereus 3 hydroxyisobutyrate dehydrogenase. AB - The 3-hydroxyisobutyrate dehydrogenase (HIBADH) family catalyzes the NAD(+)- or NADP(+)-dependent oxidation of various beta-hydroxyacid substrates into their cognate semialdehydes for diverse metabolic pathways. Because HIBADH group members exhibit different substrate specificities, the substrate-recognition mode of each enzyme should be individually characterized. In the current study, we report the biochemical and structural analysis of a HIBADH group enzyme from Bacillus cereus (bcHIBADH). bcHIBADH mediates a dehydrogenation reaction on S-3 hydroxyisobutyrate substrate with high catalytic efficiency in an NAD(+) dependent manner; it also oxidizes l-serine and 3-hydroxypropionate with lower activity. bcHIBADH consists of two domains and is further assembled into a functional dimer rather than a tetramer that has been commonly observed in other prokaryotic HIBADH group members. In the bcHIBADH structure, the interdomain cleft forms a putative active site and simultaneously accommodates both an NAD(+) cofactor and a substrate mimic. Our structure-based comparative analysis highlights structural motifs that are important in the cofactor and substrate recognition of the HIBADH group. PMID- 27120462 TI - Non-Straub type actin from molluscan catch muscle. AB - We have developed a method of obtaining natural actin from smooth muscles of the bivalves on the example of the Srenomytilus grayanus catch muscle. The muscles were previously rigorized to prevent a loss of thin filaments during homogenization and washings. Thin filaments were isolated with a low ionic strength solution in the presence of ATP and sodium pyrophosphate. Surface proteins of thin filaments-tropomyosin, troponin, calponin and some minor actin binding proteins-were dissociated from actin filaments by increasing the ionic strength to 0.6 M KCL. Natural fibrillar actin obtained in that way depolymerizes easily in low ionic strength solutions commonly used for the extraction of Straub type actin from acetone powder. Purification of natural actin was carried out by the polymerization-depolymerization cycle. The content of inactivated actin remaining in the supernatant is much less than at a similar purification of Straub-type actin. A comparative investigation was performed between the natural mussel actin and the Straub-type rabbit skeletal actin in terms of the key properties of actin: polymerization, activation of Mg-ATPase activity of myosin, and the electron-microscopic structure of actin polymers. PMID- 27120464 TI - Flavobacterium panacisoli sp. nov., isolated from soil of a ginseng field. AB - A novel bacterial strain, designated DCY70(T), was isolated from soil of a ginseng field in Republic of Korea and was characterized in order to determine its taxonomic position. The strain was Gram-reaction negative, yellow-pigmented, rod-shaped and catalase- and oxidase-positive. Based on the 16S rRNA gene sequence similarity, strain DCY70(T) was shown to belong to the genus Flavobacterium, most closely related to Flavobacterium oncorhynchi 631-08(T) (98.4 %), Flavobacterium plurextorum 1126-1H-08(T) (97.9 %), Flavobacterium chilense LM-09-Fp(T) (97.9 %) and Flavobacterium chungangense CJ(T) (97.7 %). The chemotaxonomic characteristics showed only menaquinone-6 (MK-6), iso-C15:0, iso C15:0 3OH, iso-C17:0 3OH and summed feature 3 as major cellular fatty acids. Polar lipids were phosphatidylethanolamine (PE), two unidentified aminolipids, four unidentified polar lipids and one unidentified phospholipid. The DNA G+C content was 34.9 mol%. Based on the phylogenetic, phenotypic and genotypic data, a novel species, Flavobacterium panacisoli sp. nov., is proposed (=KCTC 32393(T) = JCM 19162(T)). PMID- 27120463 TI - A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects. AB - Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway. PMID- 27120465 TI - VennPainter: A Tool for the Comparison and Identification of Candidate Genes Based on Venn Diagrams. AB - VennPainter is a program for depicting unique and shared sets of genes lists and generating Venn diagrams, by using the Qt C++ framework. The software produces Classic Venn, Edwards' Venn and Nested Venn diagrams and allows for eight sets in a graph mode and 31 sets in data processing mode only. In comparison, previous programs produce Classic Venn and Edwards' Venn diagrams and allow for a maximum of six sets. The software incorporates user-friendly features and works in Windows, Linux and Mac OS. Its graphical interface does not require a user to have programing skills. Users can modify diagram content for up to eight datasets because of the Scalable Vector Graphics output. VennPainter can provide output results in vertical, horizontal and matrix formats, which facilitates sharing datasets as required for further identification of candidate genes. Users can obtain gene lists from shared sets by clicking the numbers on the diagram. Thus, VennPainter is an easy-to-use, highly efficient, cross-platform and powerful program that provides a more comprehensive tool for identifying candidate genes and visualizing the relationships among genes or gene families in comparative analysis. PMID- 27120466 TI - Rare case of double atrial septum, an incidentally detected anomaly. PMID- 27120467 TI - Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer. AB - Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted therapy for breast cancer (BC). However, the treatment of triple-negative BC (TNBC) that lack estrogen receptor expression or HER2 amplification remains a major challenge. We previously discovered that approximately two-thirds of TNBCs express vitamin D receptor (VDR) and/or androgen receptor (AR) and hypothesized that TNBCs co-expressing AR and VDR (HR2 av TNBC) could be treated by targeting both of these hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different BC lines and identified 2 HR2-av TNBC lines and examined the changes in their phenotype, viability, and proliferation after VDR and AR-targeted treatment. Treatment of BC cell lines with VDR or AR agonists inhibited cell viability in a receptor-dependent manner, and their combination appeared to inhibit cell viability additively. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, high aldehyde dehydrogenase activity, and CSC markers. Surprisingly, we found that AR antagonists inhibited proliferation of most BC cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In summary, AR/VDR-targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor-dependent manner and can be combined with chemotherapy. PMID- 27120468 TI - Racial differences in receipt of adjuvant hormonal therapy among Medicaid enrollees in South Carolina diagnosed with breast cancer. AB - Several factors contribute to the pervasive Black-White disparity in breast cancer mortality in the U.S., such as tumor biology, access to care, and treatments received including adjuvant hormonal therapy (AHT), which significantly improves survival for hormone receptor-positive breast cancers (HR+). We analyzed South Carolina Central Cancer Registry-Medicaid linked data to determine if, in an equal access health care system, racial differences in the receipt of AHT exist. We evaluated 494 study-eligible, Black (n = 255) and White women (n = 269) who were under 65 years old and diagnosed with stages I-III, HR+ breast cancers between 2004 and 2007. Bivariate and multivariate analyses were conducted to assess receipt of >=1 AHT prescriptions at any point in time following (ever-use) or within 12 months of (early-use) breast cancer diagnosis. Seventy-two percent of the participants were ever-users (70 % Black, 74 % White) and 68 % were early-users (65 % Black, 71 % White) of AHT. Neither ever-use (adjusted OR (AOR) = 0.75, 95 % CI 0.48-1.17) nor early-use (AOR = 0.70, 95 % CI 0.46-1.06) of AHT differed by race. However, receipt of other breast cancer specific treatments was independently associated with ever-use and early-use of AHT [ever-use: receipt of surgery (AOR = 2.15, 95 % CI 1.35-3.44); chemotherapy (AOR = 1.97, 95 % CI 1.22-3.20); radiation (AOR = 2.33, 95 % CI 1.50-3.63); early use: receipt of surgery (AOR = 2.03, 95 % CI 1.30-3.17); chemotherapy (AOR = 1.90, 95 % CI 1.20-3.03); radiation (AOR = 1.73, 95 % CI 1.14-2.63)]. No racial variations in use of AHT among women with HR+ breast cancers insured by Medicaid in South Carolina were identified, but overall rates of AHT use by these women is low. Strategies to improve overall use of AHT should include targeting breast cancer patients who do not receive adjuvant chemotherapy and/or radiation. PMID- 27120469 TI - The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study. AB - Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them-and perhaps also the other dipeptides-as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity. PMID- 27120470 TI - Complementary Hand Responses Occur in Both Peri- and Extrapersonal Space. AB - Human beings have a strong tendency to imitate. Evidence from motor priming paradigms suggests that people automatically tend to imitate observed actions such as hand gestures by performing mirror-congruent movements (e.g., lifting one's right finger upon observing a left finger movement; from a mirror perspective). Many observed actions however, do not require mirror-congruent responses but afford complementary (fitting) responses instead (e.g., handing over a cup; shaking hands). Crucially, whereas mirror-congruent responses don't require physical interaction with another person, complementary actions often do. Given that most experiments studying motor priming have used stimuli devoid of contextual information, this space or interaction-dependency of complementary responses has not yet been assessed. To address this issue, we let participants perform a task in which they had to mirror or complement a hand gesture (fist or open hand) performed by an actor depicted either within or outside of reach. In three studies, we observed faster reaction times and less response errors for complementary relative to mirrored hand movements in response to open hand gestures (i.e., 'hand-shaking') irrespective of the perceived interpersonal distance of the actor. This complementary effect could not be accounted for by a low-level spatial cueing effect. These results demonstrate that humans have a strong and automatic tendency to respond by performing complementary actions. In addition, our findings underline the limitations of manipulations of space in modulating effects of motor priming and the perception of affordances. PMID- 27120471 TI - Obesity and Aging in Humans and Nonhuman Primates: A Mini-Review. AB - The prevalence of obesity in the US is increasing exponentially across gender, age and ethnic groups. Obesity and a long-term hypercaloric diet result in what appears to be accelerated aging, often leading to a multi-systemic deterioration known as the metabolic syndrome. Due to their physiological similarity to humans as well as comparable rates of spontaneous obesity and diabetes mellitus, nonhuman primates provide a useful translational model for the human condition. They allow for an in vivo study of disease progression, interaction of comorbidities, and novel interventions. However, defining obesity in aged humans and nonhuman primates is difficult as the physiological changes that occur with aging are not accounted for using our current systems (BMI - body mass index and BCS - body condition score). Nonetheless, nonhuman primate studies have greatly contributed to our understanding of obesity and metabolic dysfunction and should continue to play a large role in translational research. Here, methods for defining obesity and metabolic syndrome in humans and nonhuman primates are described along with the prevalence and effects of these conditions. PMID- 27120473 TI - Emergence of Cooperative Long-Term Market Loyalty in Double Auction Markets. AB - Loyal buyer-seller relationships can arise by design, e.g. when a seller tailors a product to a specific market niche to accomplish the best possible returns, and buyers respond to the dedicated efforts the seller makes to meet their needs. We ask whether it is possible, instead, for loyalty to arise spontaneously, and in particular as a consequence of repeated interaction and co-adaptation among the agents in a market. We devise a stylized model of double auction markets and adaptive traders that incorporates these features. Traders choose where to trade (which market) and how to trade (to buy or to sell) based on their previous experience. We find that when the typical scale of market returns (or, at fixed scale of returns, the intensity of choice) become higher than some threshold, the preferred state of the system is segregated: both buyers and sellers are segmented into subgroups that are persistently loyal to one market over another. We characterize the segregated state analytically in the limit of large markets: it is stabilized by some agents acting cooperatively to enable trade, and provides higher rewards than its unsegregated counterpart both for individual traders and the population as a whole. PMID- 27120472 TI - Epidemiology of Acute Gastroenteritis Outbreaks Caused by Human Calicivirus (Norovirus and Sapovirus) in Catalonia: A Two Year Prospective Study, 2010-2011. AB - BACKGROUND: The epidemiology of cases of acute gastroenteritis (AGE) of viral etiology is a relevant public health issue. Due to underreporting, the study of outbreaks is an accepted approach to investigate their epidemiology. The objective of this study was to investigate the epidemiological characteristics of AGE outbreaks due to norovirus (NoV) and sapovirus (SV) in Catalonia. MATERIAL AND METHODS: Prospective study of AGE outbreaks of possible viral etiology notified during two years in Catalonia. NoV and SV were detected by real time reverse transcription polymerase (RT-PCR). RESULTS: A total of 101 outbreaks were registered affecting a total of 2756 persons and 12 hospitalizations (hospitalization rate: 0.8x1,000,000 persons-year); 49.5% of outbreaks were foodborne, 45.5% person to person and 5% waterborne. The distribution of outbreaks according to the setting showed a predominance of catering services (39.6%), nursing homes and long term care facilities (26.8%) and schools (11.9%). The median number of cases per outbreak was 17 (range 2-191). The total Incidence rate (IR) was 18.3 per 100,000 persons-years (95%CI: 17.6-19.0). The highest IR was in persons aged >=65 years (43.6x100,000 (95% CI: 41.0-46.2)) (p<0.001). A total of 1065 samples were analyzed with a positivity rate of 60.8%. 98% of positive samples were NoV (GII 56.3%; GI 4.2%; GII+GI 4.2%; non- typable 33.0%). SV was identified in two person-to-person transmission outbreaks in children. CONCLUSIONS: These results confirm the relevance of viral AGE outbreaks, both foodborne and person-to-person, especially in institutionalized persons. SV should be taken into account when investigating viral AGE outbreaks. PMID- 27120474 TI - Center Variation in the Delivery of Indicated Late Preterm Births. AB - Objective Evidence for optimal timing of delivery for some pregnancy complications at late preterm gestation is limited. The purpose of this study was to identify center variation of indicated late preterm births. Study design We performed an analysis of singleton late preterm and term births from a large U.S. retrospective obstetrical cohort. Births associated with spontaneous preterm labor, major congenital anomalies, chorioamnionitis, and emergency cesarean were excluded. We used modified Poisson fixed effects logistic regression with interaction terms to assess center variation of indicated late preterm births associated with four medical/obstetric comorbidities after adjusting for socio demographics, comorbidities, and hospital/provider characteristics. Results We identified 150,055 births from 16 hospitals; 9,218 were indicated late preterm births. We found wide variation of indicated late preterm births across hospitals. The extent of center variation was greater for births associated with preterm premature rupture of membranes (risk ratio [RR] across sites: 0.45-3.05), hypertensive disorders of pregnancy (RR across sites: 0.36-1.27), and placenta previa/abruption (RR across sites: 0.48-1.82). We found less center variation for births associated with diabetes (RR across sites: 0.65-1.39). Conclusion Practice variation in the management of indicated late preterm deliveries might be a source of preventable late preterm birth. PMID- 27120475 TI - Vaginal Fluid Inflammatory Biomarkers and the Risk of Adverse Neonatal Outcomes in Women with PPROM. AB - Objective The purpose of this study was to evaluate the predictive value of vaginal fluid biomarkers for chorioamnionitis and adverse perinatal outcomes in women with preterm premature rupture of membranes (PPROM). Methods We recruited women with PPROM, without clinical chorioamnionitis, between 22 and 36 weeks' gestation. Vaginal fluid was collected on admission for the measurement of metalloproteinase-8 (MMP-8), interleukin-6 (IL-6), lactate, and glucose concentration. Placental pathology and neonatal charts were reviewed. Primary outcomes were histological chorioamnionitis and adverse neonatal neurological outcomes (intraventricular hemorrhage grade 2 or 3, periventricular leukomalacia, or hypoxic/ischemic encephalopathy). Linear regression analyses were used to adjust for gestational age at PPROM. Results Twenty-seven women were recruited at a mean gestational age of 31.6 +/- 3.1 weeks, including 25 (93%) with successful collection of vaginal fluid sample. Histological chorioamnionitis and adverse neonatal neurological outcomes were observed in nine (33%) and four (15%) cases, respectively. In univariate analysis, MMP-8, IL-6, glucose, and lactate concentrations in vaginal fluid were associated with the risk of chorioamnionitis but not anymore after adjustment for gestational age at PPROM. MMP-8 concentration was the only biomarker associated with adverse neurological outcome, and it remained significant after adjustment for gestational age at PPROM (p = 0.02). Conclusion Vaginal fluid inflammatory biomarkers at admission for PPROM could predict adverse perinatal outcomes. PMID- 27120476 TI - Association between Hemoglobin Levels in the First 3 Days of Life and Bronchopulmonary Dysplasia in Preterm Infants. AB - Objective The objective of this study was to determine the association between hemoglobin (Hb) levels in the first 3 days of life and bronchopulmonary dysplasia (BPD) in preterm infants. Study Design The study population comprises 147 neonates with a gestational age (GA) of less than 32 weeks who were admitted to BaYi Children's Hospital Affiliated to Beijing Military General Hospital from January 2014 to May 2015. Hb levels in the first 3 days of life, maternal and infant characteristics, were recorded and then analyzed. Results BPD patients had a lower GA and birth weight than non-BPD patients. Rates of surfactant use, use of early inhalation hormone, days of mechanical ventilation > 2 weeks, and patent ductus arteriosus in BPD patients were higher and have a significant difference. Number of transfusions was higher in BPD patients. Lower Hb levels in the first 3 days of life were also observed in BPD patients. A cutoff value of Hb levels was determined as 155.5 g/L. Hb <= 155 g/L in the first 3 days of life was a significant risk factor for BPD. Conclusion Our study demonstrated that lower Hb levels in the first 3 days of life may increase the risk of developing BPD in preterm infants. PMID- 27120477 TI - Do Obese Women Receive the Necessary Interventions to Achieve Vaginal Birth after Cesarean? AB - Objective We aimed to determine if obese women undergoing trial of labor after cesarean (TOLAC) were more likely to undergo repeat cesarean for arrest disorders prior to active labor, and whether this was due to decreased use of standard interventions to achieve vaginal birth. Study Design This was a secondary analysis of a prospective registry. Women undergoing TOLAC with one prior cesarean and a singleton, term gestation who had a repeat cesarean for an arrest disorder were included. The primary outcome was repeat cesarean prior to active labor (cervical dilation < 6 cm). Obese (body mass index >=30 kg/m(2)) and nonobese women were compared. Multivariable logistic regression was used to estimate the association between obesity and repeat cesarean prior to active labor. Clinical interventions were compared between groups using t-test and chi (2) test. Results Among 2,098 women undergoing TOLAC, 1,454 (69%) were obese. Obese women were more likely to undergo repeat cesarean for an arrest disorder prior to active labor (odds ratio, 1.4; 95% confidence interval, 1.1-1.7) despite being allowed longer labors and receiving higher maximum doses of oxytocin for a longer duration than nonobese women. Conclusion Obese women were more likely to undergo repeat cesarean prior to active labor despite more clinical interventions to achieve vaginal birth. PMID- 27120479 TI - First Trimester Hemoglobin A1c Prediction of Gestational Diabetes. AB - Objective The objective of this study is to examine whether a first trimester hemoglobin A1c (A1C) of 5.7 to 6.4% predicts an abnormal second trimester oral glucose tolerance test (OGTT). Methods We conducted a retrospective cohort study of all women screened with A1C through 13 (6/7) weeks' gestation between January 1, 2011, and December 31, 2012. Prediabetic women (A1C of 5.7-6.4%) were compared with women with a normal first trimester A1C (< 5.7%). The primary outcome was an abnormal 2-hour, 75-g OGTT as defined by the International Association of Diabetes and Pregnancy Study Groups. Results There were 2,812 women who met inclusion criteria of whom 6.7% (n = 189) were prediabetic. Women with prediabetes were more likely to have gestational diabetes mellitus (GDM) even after adjusting for potential confounders (29.1 vs. 13.7%; adjusted relative risk, 1.48; 95% confidence interval, 1.15-1.89). There were no statistically significant differences in secondary outcomes except that women with prediabetes had less excessive gestational weight gain. A prediabetic-range A1C in the first trimester was associated with a 13% sensitivity and a 94% specificity for predicting GDM Conclusion Although women with prediabetes by first trimester A1C are significantly more likely to have GDM, the low sensitivity of an A1C in this range renders it a poor test to identify women who will develop GDM. PMID- 27120478 TI - Is Mid-trimester Insulin Resistance Predictive of Subsequent Puerperal Infection? A Secondary Analysis of Randomized Trial Data. AB - Objective The objective of this study was to examine whether there is an association between insulin resistance and subsequent development of puerperal infection by measuring insulin resistance in the mid-trimester using the homeostasis model assessment (HOMA:IR). Methods Secondary analysis of low-risk nulliparas enrolled in a multicenter preeclampsia prevention trial. HOMA:IR was measured on fasting plasma glucose and insulin concentrations among low-risk nulliparas between 22 and 26 weeks' gestation. Median HOMA:IR was compared between women who did and did not develop puerperal infection using Wilcoxon rank sum test. Logistic regression was used to control for potential confounders. Results Of 1,180 women with fasting glucose and insulin available, 121 (10.3%) had a puerperal infection. Median HOMA:IR was higher among those with subsequent puerperal infection (4.3 [interquartile, IQR: 2.2-20.5] vs. 2.6 [IQR: 1.5-6.7], p < 0.0001). After controlling for potentially confounding variables HOMA:IR was only marginally associated with an increased risk of development of puerperal infection, adjusted odds ratio: 1.01 (95% confidence interval: 1.00-1.02; p = 0.04) per unit increase. Elevated HOMA:IR performed poorly as a predictor of puerperal infection, with a positive predictive value of 15% and a negative predictive value of 92%. Conclusion Though associated with an increased risk of puerperal infection, insulin resistance, measured by HOMA:IR, is not a clinically useful predictor of puerperal infection. PMID- 27120480 TI - Provider Awareness, Understanding and Use of NICHD Neonatal Research Network Outcomes Estimator. AB - Introduction Our aim was to survey clinicians to assess awareness and utilization of the NICHD Neonatal Research Network outcomes estimator, which allows clinicians to use multiple factors to better estimate the likelihood that intensive care will benefit the delivered neonate. Study Design The survey tool included a list of questions regarding the estimator. We collected responses from various medical personnel assessing awareness, frequency of use, knowledge of estimator, and information regarding the database. Results There were a total of 141 participants. Forty-two percent reported awareness of the estimator and of those, 75% had visited the Web site. Eighty-two percent of those visiting the site had actually used the estimator. Maternal-fetal medicine (MFM) physicians versus generalists were more likely to have heard of the estimator (75 vs. 32%). Obstetrics and gynecology residents had similar familiarity with the estimator as attending generalists. Of those having used the tool, 25% knew the correct variables, with only 19% knowing the outcomes. Interestingly, a majority of users misunderstood database components. Conclusion A majority of clinicians, and a fourth of MFM physicians, who care for patients with threatened preterm birth are either unaware or have limited understanding of the estimator, offering a potential area of improvement in the counseling of such at-risk patients. PMID- 27120481 TI - Early Postpartum Glucose Testing in Women with Gestational Diabetes Mellitus. AB - Objective Given that most women with gestational diabetes mellitus (GDM) never undergo the recommended 6 to 12 weeks postpartum glucose tolerance test (GTT), we assessed the feasibility of performing GTTs on postpartum day 2. Study Design Women with abnormal postpartum day 2 results were similar to women with normal postpartum day 2 results except that more women with abnormal results required medicine to treat their GDM (Table 1). [corrected]. We assessed the feasibility of this GTT and compared the results to the standard of care GTT at 6 to 12 weeks postpartum. We also evaluated maternal and pregnancy characteristics of women who return for 6 to 12 weeks GTTs compared with those lost to follow-up. Results In this study, 98 of 106 participants (92%) completed the postpartum day 2 GTT; 59% had normal glucose values at that time. Only 49 women returned at 6 to 12 weeks postpartum. Among women who had testing at both time points, the 2 days postpartum GTT were 100% sensitive and 94% specific for diabetes mellitus but less sensitive and specific for milder forms of abnormal glucose. Women who did not return for testing at 6 to 12 weeks postpartum were more likely to have less education, have Medicaid, and to have GDM previously (Table 2). [corrected]. Conclusion Performing GTTs on postpartum day 2 is feasible and should be further investigated as an alternative postpartum testing regimen in GDM. PMID- 27120482 TI - Surfactant Treatment Threshold during NCPAP for the Treatment of Preterm Infants with Respiratory Distress Syndrome. AB - Although surfactant is the most studied drug in the preterm infant, the best criteria for treatment of preterm infants with respiratory distress syndrome (RDS) with surfactant have been not extensively investigated. We assessed the criteria used for deciding the rescue surfactant treatment of preterm infants with RDS in combination with nasal continuous positive airway pressure as reported by the main recent randomized controlled trials. We evaluated 10 studies and found that the criteria chosen for administering selective surfactant were very heterogeneous, different types and doses of surfactant were used, and this limits their applicability in the clinical practice. In conclusion, although current data seem to suggest that low threshold is better than high threshold, additional studies are necessary to identify the most effective criteria for selective surfactant treatment of preterm infants with RDS. PMID- 27120483 TI - A Coordination Chemistry Approach for Lithium-Ion Batteries: The Coexistence of Metal and Ligand Redox Activities in a One-Dimensional Metal-Organic Material. AB - We demonstrate herein the use of a one-dimensional metal-organic material as a new type of electrode material for lithium-ion batteries (LIBs) in place of the classic porous three-dimensional materials, which are subject to the size of the channel for lithium-ion diffusion and blocking of the windows of the framework by organic solvents during the charging and discharging processes. Introducing a one dimensional coordination compound can keep organic active substances insoluble in the electrolyte during the charging and discharging processes, providing a facile and general new system for further studies. The results show that both the aromatic ligand and the metal center can participate in lithium storage simultaneously, illustrating a new energy storage mechanism that has been well characterized by X-ray photoelectron spectroscopy, electron paramagnetic resonance spectroscopy, and cyclic voltammetry. In addition, the fact that the one-dimensional chains are linked by weak hydrogen bonds rather than strong pi-pi stacking interactions or covalent bonds is beneficial for the release of capacity entirely without the negative effect of burying the active sites. PMID- 27120484 TI - Psoriasis, Type 2 Diabetes Mellitus, and Obesity: Weighing the Evidence. PMID- 27120485 TI - Alteration of steric hindrance modulates glutathione resistance and cytotoxicity of three structurally related Ru(II)-p-cymene complexes. AB - The effect of steric hindrance on reactivity towards biomolecules while designing Ru(II)-eta(6)-p-cymene based anticancer agents seems to be an important parameter in improving the activity and inducing resistance against glutathione (GSH) deactivation. Herein we present the structure, hydrolysis, anticancer activity and the effect of steric hindrance on deactivation by glutathione for three complexes, [Ru(II)(eta(6)-p-cym)(L1)(Cl)](PF6) (1), [Ru(II)(eta(6)-p cym)(L2)(Cl)](PF6) (2) and [Ru(II)(eta(6)-p-cym)(L3)(Cl)](PF6) (3). The ligands L1-L3 are Schiff bases which show increasing substitution in a benzene ring, such that two ortho hydrogens are replaced by -methyl in 2 and by -isopropyl in 3. The cytotoxicity results strongly suggest that controlling the rate of hydrolysis through tuning of steric hindrance may be a feasible pathway to derive GSH resistant anticancer agents. The cellular studies show that all the three complexes show good blood compatibility (haemolysis <3%) and induce cellular death through caspase activation via the mitochondrial pathway. They have anti angiogenic activity and prevent the healing of treated cells. PMID- 27120486 TI - Dibenzothiophene Catabolism Proceeds via a Flavin-N5-oxide Intermediate. AB - The dibenzothiophene catabolic pathway converts dibenzothiophene to 2 hydroxybiphenyl and sulfite. The third step of the pathway, involving the conversion of dibenzothiophene sulfone to 2-(2-hydroxyphenyl)-benzenesulfinic acid, is catalyzed by a unique flavoenzyme DszA. Mechanistic studies on this reaction suggest that the C2 hydroperoxide of dibenzothiophene sulfone reacts with flavin to form a flavin-N5-oxide. The intermediacy of the flavin-N5-oxide was confirmed by LC-MS analysis, a co-elution experiment with chemically synthesized FMN-N5-oxide and (18)O2 labeling studies. PMID- 27120487 TI - Toward High-Performance Top-Gate Ultrathin HfS2 Field-Effect Transistors by Interface Engineering. AB - Top-gate HfS2 field-effect transistors (FETs) with 5 nm HfO2 as dielectrics are successfully demonstrated, with on/off ratio of 10(5) and subthreshold swing of 95 mV dec(-1) . Moreover, due to the self-functionalization of HfS2 , uniform and ultrathin HfO2 film free of pinhole-like defects could be deposited on HfS2 , which is dramatically different from other transition metal dichalcogenide FETs. PMID- 27120488 TI - A biological study establishing the endotoxin limit of biomaterials for bone regeneration in cranial and femoral implantation of rats. AB - The purpose of this study was to accurately quantify the risk of endotoxin contamination in biomaterials for bone regeneration in order to establish the acceptable endotoxin limit. Collagen sheets containing varying amounts of purified endotoxin from Escherichia coli and dried, heat-killed E. coli or Staphylococcus aureus cells were implanted into cranial or femoral defects in rats. These defects were artificially prepared to a size of 5 * 5 mm or a diameter of 1 mm, respectively. The degree of osteoanagenesis was assessed by soft X-ray radiography and histopathology at 1 and 4 weeks after implantation. The collagen sheet containing the dried E. coli cells showed a dose-dependent delay in cranial and/or femoral osteoanagenesis at endotoxin activities of more than 33.6 EU/mg, at which no inflammatory response was observed. In contrast, no such observation occurred with the collagen sheet containing S. aureus cells. These results suggest that endotoxins may affect the process of osteoanagenesis. Additionally, the no-observed-adverse-effect level was 9.6 EU/mg, corresponding to 255 EU/kg body weight in rats. Interestingly, no delay in osteoanagenesis was induced by the implantation of collagen sheets containing purified endotoxin at any dose tested. This suggested that pure endotoxin implanted into tissues having poor circulation of bodily fluids without bleeding may not be recognized as a foreign substance and may not induce a significant biological response. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1514 1524, 2017. PMID- 27120490 TI - Single-Plasmid-Based System for Efficient Noncanonical Amino Acid Mutagenesis in Cultured Mammalian Cells. AB - We describe a new expression system for efficient non-canonical amino acid mutagenesis in cultured mammalian cells by using the pyrrolysine tRNA synthetase/tRNACUA (Pyl) pair. A significant improvement in the incorporation of non-canonical amino acids into proteins was obtained by combining all the required genetic components into a single and compact vector that can be efficiently delivered to different mammalian cell lines by conventional transfection reagents. PMID- 27120489 TI - Long-term effects of in utero and lactational exposure to butyl paraben in female rats. AB - Parabens are used as preservatives in cosmetic, pharmaceutical, and food industries, and are frequently detected as contaminants in human fluids and tissues. The endocrine disrupting effects of parabens in female rodents include uterotrophic response, steroidogenesis impairment, and ovarian disturbances. The objective of this study was to determine the effects of maternal butyl paraben (BP) exposure on female sexual development. Pregnant Wistar rats were treated subcutaneously with either corn oil or BP at doses of 10, 100, or 200 mg/kg, from gestational day (GD) 12 until GD 20 for female foetal gonad evaluation, and from GD 12 until the end of lactation to evaluate sexual parameters on the female offspring. Immature female rats were also used in the uterotrophic assay to evaluate the possible estrogenic action of parabens. Our results revealed that, in this experimental protocol, BP did not show estrogenic activity at the doses used and did not impair sexual development and fertility capacity in the female rats, but impaired sexual behavior. We conclude that brain sexual development may be more sensitive to BP effects and we speculate that doses higher than 100 mg/kg (the male lowest observed adverse effect level (LOAEL) for rodent reproductive parameters) would be necessary to promote damages in the female reproduction, regarding the same protocol of exposure. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 776-788, 2017. PMID- 27120491 TI - Visual Acuity after Retinal Gene Therapy for Choroideremia. PMID- 27120492 TI - Dependence on Prescription Opioids. AB - BACKGROUND: The incidence of initial prescriptions of opioids for chronic non cancer pain rose by 37% in Germany from 2000 to 2010. Prescribing practice does not always conform with the recommendations of current guidelines. In the USA, 8 12% of patients with chronic non-cancer pain are opioid-dependent. METHODS: This review is based on publications retrieved by a selective PubMed search and on the German S3 guideline on the long-term use of opioids in non-cancer pain. RESULTS: Patients must be informed and counseled about the effects and risks of opioids before these drugs are prescribed. All opioid prescriptions for patients with chronic non-cancer pain should be regularly reviewed. The risk of abuse is high in young adults (odds ratio [OR] = 6.74) and in those with a history of substance abuse (OR = 2.34). Any unusual medication-related behavior, e.g., loss of prescriptions or increasing the dose without prior discussion with the physician, calls for further assessment by the physician in conversation with the patient. Urine testing for drugs and their metabolites is helpful as well. The goal of treatment of opioid abuse is opioid abstinence by gradual reduction of the dose. If this is not possible on an outpatient basis, hospitalization for drug withdrawal or substitution-based addiction therapy can be offered. CONCLUSION: Physicians who know the indications and risks of opioid therapy and the typical behavior of drug-dependent patients will be better able to identify patients at risk and to prevent dependence. Studies on the prevalence of opioid abuse and dependence in German patients with chronic pain can help provide better estimates of the current extent and implications of this problem in Germany. PMID- 27120493 TI - The Prevalence is Only Estimated. PMID- 27120494 TI - Seropositivity Needs to Be Critically Considered. PMID- 27120495 TI - In Reply. PMID- 27120496 TI - Acute Lumbar Back Pain. AB - BACKGROUND: Back pain has many causes. In Germany, about 70% of adults have at least one episode of back pain per year. METHODS: This review is based on a selective literature search and on the German National Disease Management Guideline for Low Back Pain. RESULTS: The physician taking the history from a patient with back pain should ask about the nature, onset, course, localization, and radiation of the pain and its dependence on physical activity and/or emotional stress. In the differential diagnosis, neurologic deficits and any "red flags" suggesting dangerous conditions such as spinal fracture, bacterial infection, and tumors must be ruled out. If no specific cause of the pain can be identified, no imaging studies are indicated on initial presentation. The treatment of acute, nonspecific low back pain focuses on pain relief and functional improvement. Adequate patient education and counseling are essential. Exercise therapy is no more effective than the continuation of normal daily activities. Restriction of activity, including bed rest, is of no benefit and merely prolongs recovery and the resumption of normal activity. Further diagnostic testing is indicated if there is any suspicion of a fracture, infection, or tumor. CONCLUSION: After dangerous conditions have been ruled out, low back pain can be pragmatically classified as either nonspecific or specific. More research is needed so that the diagnostic assessment and individualized treatment of acute lower back pain can be further refined. PMID- 27120498 TI - Correlation of serum sHLA-G levels with cyst stage in patients with cystic echinococcosis: is it an immune evasion strategy? AB - Patients with cystic echinococcosis (CE) can harbour cysts for years or even decades, apparently without effect of the immune system on the metacestode. Although several immune evasion mechanisms by echinococcal cysts have been described, it is unclear whether the human leucocyte antigen (HLA) system plays a role in the susceptibility or resistance to CE in humans. HLA-G molecules are known to exert a suppressive action on dendritic cells maturation and on natural killer (NK) cells functions, therefore hampering T-cell responses and NK cytolysis. HLA-G plays an important role in immune tolerance, is involved in foetus and in allotransplant tolerance, and may be involved in tumoral and viral immune evasion. In this study, we assessed the presence and levels of soluble HLA G (sHLA-G) in patients with CE using a commercial ELISA kit to determine whether host's HLA-G may have a role in the course of human CE. PMID- 27120497 TI - Bisphenol A causes reproductive toxicity, decreases dnmt1 transcription, and reduces global DNA methylation in breeding zebrafish (Danio rerio). AB - Bisphenol A (BPA) is a commercially important high production chemical widely used in epoxy resins and polycarbonate plastics, and is ubiquitous in the environment. Previous studies demonstrated that BPA activates estrogenic signaling pathways associated with adverse effects on reproduction in vertebrates and that exposure can induce epigenetic changes. We aimed to investigate the reproductive effects of BPA in a fish model and to document its mechanisms of toxicity. We exposed breeding groups of zebrafish (Danio rerio) to 0.01, 0.1, and 1 mg/L BPA for 15 d. We observed a significant increase in egg production, together with a reduced rate of fertilization in fish exposed to 1 mg/L BPA, associated with significant alterations in the transcription of genes involved in reproductive function and epigenetic processes in both liver and gonad tissue at concentrations representing hotspots of environmental contamination (0.1 mg/L) and above. Of note, we observed reduced expression of DNA methyltransferase 1 (dnmt1) at environmentally relevant concentrations of BPA, along with a significant reduction in global DNA methylation, in testes and ovaries following exposure to 1 mg/L BPA. Our findings demonstrate that BPA disrupts reproductive processes in zebrafish, likely via estrogenic mechanisms, and that environmentally relevant concentrations of BPA are associated with altered transcription of key enzymes involved in DNA methylation maintenance. These findings provide evidence of the mechanisms of action of BPA in a model vertebrate and advocate for its reduction in the environment. PMID- 27120499 TI - Cancer drug related cardiotoxicity during breast cancer treatment. AB - INTRODUCTION: Breast cancer (BC) is the most common cancer in women. Although therapeutic armamentarium like chemotherapy, endocrine and target agents have increased survival, cardiovascular side effects have been observed. A comprehensive risk assessment, early detection and management of cardiac adverse events is therefore needed. AREAS COVERED: In this review we focus on cardiotoxicity data deriving from Phase III randomized trials, systematic reviews and meta-analysis in BC patients. We provide insight into advances that have been made in the molecular mechanisms, clinical presentation and management of such adverse event. EXPERT OPINION: Despite the large number of data from Phase III trials about cardiac events incidence, there are poor evidences for detection, monitoring and management of cardiotoxicity during BC treatment. Future cardiotoxicity-oriented clinical cancer research can help to predict the risk of cardiac adverse events and improve patients' outcome. Multidisciplinary approach as well as integration of blood biomarkers with imaging will be desirable. PMID- 27120500 TI - HIV-free survival at 12-24 months in breastfed infants of HIV-infected women on antiretroviral treatment. AB - OBJECTIVE: To provide estimates of HIV-free survival at 12-24 months in breastfed children by maternal ART (6 months or lifelong) to inform WHO HIV and Infant Feeding guidelines. METHODS: Eighteen studies published 2005-2015 were included in a systematic literature review (1295 papers identified, 156 abstracts screened, 55 full texts); papers were analysed by narrative synthesis and meta analysis of HIV-free survival by maternal ART regimen in a random effects model. We also grouped studies by feeding modality. Study quality was assessed using a modified Newcastle-Ottawa Scale (NOS) and GRADE. RESULTS: The pooled estimates for 12-month HIV-free survival were 89.8% (95% confidence interval, CI: 86.5%, 93.2%) for infants of mothers on ART for 6 months post-natally (six studies) and 91.4% (95% CI 87.5%, 95.4%) for infants of mothers on lifelong ART (three studies). Eighteen-month HIV-free survival estimates were 89.0% (95% CI 83.9%, 94.2%) with 6 months ART (five studies) and 96.1% (95% CI 92.8%, 99.0%) with lifelong ART (three studies). Twenty-four-month HIV-free survival for infants whose mothers were on ART to 6 months post-natally (two studies) was 89.2% (95% CI 79.9%, 98.5%). Heterogeneity was considerable throughout. In four studies, HIV free survival in breastfed infants ranged from 87% (95% CI 78%, 92%) to 96% (95% CI 91%, 98%) and in formula-fed infants from 67% (95% CI 35.5%, 87.9%) to 97.6% (95% CI 93.0%, 98.2%). CONCLUSION: Our results highlight the importance of breastfeeding for infant survival and of ART in reducing the risk of mother-to child HIV transmission and support the WHO recommendation to initiate ART for life immediately after HIV diagnosis. PMID- 27120501 TI - Hot Off the Press: Do Emergency Department-based Predischarge Educational Interventions for Adult Asthma Patients Improve Outcomes? PMID- 27120503 TI - Driven Translocation of Polynucleotides Through an Aerolysin Nanopore. AB - Aerolysin has been used as a biological nanopore for studying peptides, proteins, and oligosaccharides in the past two decades. Here, we report that wild-type aerolysin could be utilized for polynucleotide analysis. Driven a short polynucleotide of four nucleotides length through aerolysin occludes nearly 50% amplitude of the open pore current. Furthermore, the result of total internal reflection fluorescence measurement provides direct evidence for the driven translocation of single polynucleotide through aerolysin. PMID- 27120502 TI - Implementation and uptake of the Conexiones y Opciones en la Argentina intervention: feasibility and acceptability. AB - Challenging HIV-infected patients, those neither adherent nor actively engaged in care, represent an important opportunity for intervention if the HIV epidemic is to be contained. This pilot study assessed the feasibility and acceptability of an adapted patient adherence intervention and a motivational interview-based provider intervention in urban Buenos Aires, Argentina, in order to optimize health benefits in challenging HIV-infected patients. To maximize implementation and uptake of both strategies, interventions were adapted to the local setting. Qualitative data and a short quantitative assessment from patients, staff, fellows, residents and physicians (n = 84) were examined to establish the feasibility and acceptability of offering patient and provider evidence-based interventions in both public and private health-care settings. Results identified key themes on provision of information, use of specialized communication techniques and group support in the utilization of the interventions. Both providers (n = 12) and patients (n = 120) endorsed the acceptability and value of the interventions, and the feasibility of their delivery. Findings support the use of both intervention modalities with challenging patients in diverse urban health-care settings. PMID- 27120504 TI - Seizing opportunities for change at the operational level. AB - Purpose - This paper presents a method for handling everyday opportunities for improvement, led by floor staff in healthcare institutions. More than 400,000 incidents and accidents were recorded in Quebec healthcare institutions in 2013. The burden of treatment falls on hospital floor staff. The purpose of this paper is to raise the visibility of this problem and support staff better in their efforts to handle opportunities for improvement. Design/methodology/approach - Based on issues identified in the literature, which have been found to exist in various organizations, the method involved reviewing practices in the field, proposing a solution, and testing it to assess its relevance and limitations. The method was tested in partnership with the Centre Hospitalier de l'Universite de Montreal, in the internal medicine unit at Hotel-Dieu campus. The test lasted three months. Indicators from this test have been compared to results in the literature. Findings - The proposed method presents a 68 per cent increase in ideas generated per person and per week compared to the reference study. The mean time for closing actions was about 41 per cent better (lower) than in the reference case. Research limitations/implications - The test lasted 15 weeks; a longer test is needed to collect more data. Practical implications - The first practical implication of this study was the creation of a method allowing employees to seize opportunities for improvement in their daily work. The application of this method revealed: first, the operational nature of the proposal (empowerment of the work team); second, the operationalization of continuous improvement (71 per cent of ideas were finalized while the initiative was monitored); third, the smooth operation of the mechanism for facilitating continuous improvement (organization of weekly meetings and team participation in these meetings in 90 per cent of cases); and fourth, a shared feeling that intra- and inter-team communication had been strengthened. Originality/value - The main value of this paper is that it proposes a simple problem-solving process that gives employees an opportunity to improve their daily work. The originality of this paper resides in comparing results to a standard case and observing an improvement. This paper proposes a new problem-solving structure and tests it scientifically. PMID- 27120505 TI - Measuring quality in community based housing support - the QPC-H instrument. AB - Purpose - The purpose of this paper is to test the psychometric properties and dimensionality of the instrument Quality in Psychiatric Care-Housing (QPC-H) and briefly describe the residents' perception of quality of housing support. Design/methodology/approach - A sample of 174 residents from 22 housing support services in nine Swedish municipalities participated in the study. Confirmatory factor analysis (CFA) revealed that the QPC-H consisted of six dimensions and had a factor structure largely corresponding to that found among other instruments in the Quality in Psychiatric Care (QPC) family of instruments. Findings - CFA revealed that the QPC-H consisted of six dimensions and had a factor structure largely corresponding to that found among other instruments in the QPC family of instruments. The internal consistency of the factors was acceptable except in the case of secure and secluded environment, probably due to few numbers of items. With this exception, the QPC-H shows adequate psychometric properties. Social implications - The residents' ratings of quality of housing service were generally high; the highest rating was for secluded environment and the lowest for participation. This dimension would thus seem to indicate an important area for improvement. Originality/value - The QPC-H includes important aspects of residents' assessment of quality of housing service and offers a simple and inexpensive way to evaluate housing support services from the residents' perspective. PMID- 27120506 TI - Reduced time from diagnosis to stone-free status in patients with ureteral calculi. AB - Purpose - The purpose of this paper is to describe an improvement project and its effects on decreasing the time from diagnosis to treatment for patients with kidney stones and to reduce the negative effects related to untreated stones at one hospital in western Sweden. Design/methodology/approach - A quantitative descriptive study based on Nolan's improvement model was used. The quality improvement effects were evaluated using statistical process control. Findings - Extracorporeal shock wave lithotripsy treatment's positive effects within 48 hours were described as efficiency (decreased waiting time) from diagnosis to treatment, even if a re-treatment was necessary. The results also showed a reduction in the usage of percutaneous nephropyelostomies as a treatment option. Research limitations/implications - This study includes data from one department at one hospital in one country. Comparative data include the time from acute radiological examination to final treatment but not total re-treatments, complications or time to up following radiological examination. However, the study was performed over one year and analyzed data from medical records in a systematic way. Practical implications - This study may inspire measuring and developing routines from diagnosis to treatment for patients who are transferred within different departments at one hospital. Social implications - By measuring the working process, resource use within a healthcare organization could be visualized. Planning and co-operation at different managerial levels are key factors for success when improvement projects are performed. Originality/value - Studies in improvement projects considering ureteral or kidney stones are generally lacking; thus, this study is important for improving the care of patients with this diagnose. PMID- 27120507 TI - Measuring healthcare productivity - from unit to system level. AB - Purpose - Healthcare productivity is a growing issue in most Western countries where healthcare expenditure is rapidly increasing. Therefore, accurate productivity metrics are essential to avoid sub-optimization within a healthcare system. The purpose of this paper is to focus on healthcare production system productivity measurement. Design/methodology/approach - Traditionally, healthcare productivity has been studied and measured independently at the unit, organization and system level. Suggesting that productivity measurement should be done in different levels, while simultaneously linking productivity measurement to incentives, this study presents the challenges of productivity measurement at the different levels. The study introduces different methods to measure productivity in healthcare. In addition, it provides background information on the methods used to measure productivity and the parameters used in these methods. A pilot investigation of productivity measurement is used to illustrate the challenges of measurement, to test the developed measures and to prove the practical information for managers. Findings - The study introduces different approaches and methods to measure productivity in healthcare. Practical implications - A pilot investigation of productivity measurement is used to illustrate the challenges of measurement, to test the developed measures and to prove the practical benefits for managers. Originality/value - The authors focus on the measurement of the whole healthcare production system and try to avoid sub optimization. Additionally considering an individual patient approach, productivity measurement is examined at the unit level, the organizational level and the system level. PMID- 27120508 TI - Measuring patient-perceived hospital service quality: a conceptual framework. AB - Purpose - Although measuring healthcare service quality is not a new phenomenon, the instruments used to measure are timeworn. With the shift in focus to patient centric processes in hospitals and recognizing healthcare to be different compared to other services, service quality measurement needs to be tuned specifically to healthcare. The purpose of this paper is to design a conceptual framework for measuring patient perceived hospital service quality (HSQ), based on existing service quality literature. Design/methodology/approach - Using HSQ theories, expanding existing healthcare service models and literature, a conceptual framework is proposed to measure HSQ. The paper outlines patient perceived service quality dimensions. Findings - An instrument for measuring HSQ dimensions is developed and compared with other service quality measuring instruments. The latest dimensions are in line with previous studies, but a relationship dimension is added. Practical implications - The framework empowers managers to assess healthcare quality in corporate, public and teaching hospitals. Originality/value - The paper helps academics and practitioners to assess HSQ from a patient perspective. PMID- 27120509 TI - Measuring patient satisfaction in complex continuing care/rehabilitation care. AB - Purpose - The purpose of this paper is to develop a psychometrically validated survey to assess satisfaction in complex continuing care (CCC)/rehabilitation patients. Design/methodology/approach - A paper or computer-based survey was administered to 252 CCC/rehabilitation patients (i.e. post-acute hospital care setting for people who require ongoing care before returning home) across two hospitals in Toronto, Ontario, Canada. Findings - Using factor analysis, five domains were identified with loadings above 0.4 for all but one item. Behavioral intention and information/communication showed the lowest patient satisfaction, while patient centredness the highest. Each domain correlated positively and significantly predicted overall satisfaction, with quality and safety showing the strongest predictive power and the healing environment the weakest. Gender made a significant contribution to predicting overall satisfaction, but age did not. Research limitations/implications - Results provide evidence of the survey's psychometric properties. Owing to a small sample, supplemental testing with a larger patient group is required to confirm the five-factor structure and to assess test-retest reliability. Originality/value - Improving the health system requires integrating patient perspectives. The patient experience, however, will vary depending on the population being served. This is the first psychometrically validated survey specific to a smaller specialty patient group receiving care at a CCC/rehabilitation facility in Canada. PMID- 27120510 TI - Healthcare quality maturity assessment model based on quality drivers. AB - Purpose - Healthcare providers differ in their readiness and maturity levels regarding quality and quality management systems applications. The purpose of this paper is to serve as a useful quantitative quality maturity-level assessment tool for healthcare organizations. Design/methodology/approach - The model proposes five quality maturity levels (chaotic, primitive, structured, mature and proficient) based on six quality drivers: top management, people, operations, culture, quality focus and accreditation. Findings - Healthcare managers can apply the model to identify the status quo, quality shortcomings and evaluating ongoing progress. Practical implications - The model has been incorporated in an interactive Excel worksheet that visually displays the quality maturity-level risk meter. The tool has been applied successfully to local hospitals. Originality/value - The proposed six quality driver scales appear to measure healthcare provider maturity levels on a single quality meter. PMID- 27120511 TI - Monitoring operating room turnaround time: a retrospective analysis. AB - Purpose - Operating room (OR) turnaround time is a key process indicator for hospital business management: delays lead to a reduced surgical interventions per day with a consequent increase in costs and decrease in efficiency. The purpose of this paper is to increase understanding by assessing the process' steady-state behaviour and identifying changes that indicate either improvement or deterioration in quality. Design/methodology/approach - With this purpose, the authors retrospectively applied Shewhart control charts and exponentially weighted moving average control charts to data extracted from an hospital information system. Findings - The results showed that statistical process control is able to identify steady-state behaviour process and to detect positive or negative changes in process performance. In particular the authors detected a deterioration in the process performance coinciding with the change in the operating room patient transfer staff. Practical implications - This study showed that statistical quality control is a valuable tool for monitoring performance indicators. Currently, hospital managers are designing an OR dashboard which also includes the control charts. Originality/value - The paper highlights the control chart application to organizational indicators allowing an objective OR system performance assessment. PMID- 27120512 TI - Responsive Biomaterials: Advances in Materials Based on Shape-Memory Polymers. AB - Shape-memory polymers (SMPs) are morphologically responsive materials with potential for a variety of biomedical applications, particularly as devices for minimally invasive surgery and the delivery of therapeutics and cells for tissue engineering. A brief introduction to SMPs is followed by a discussion of the current progress toward the development of SMP-based biomaterials for clinically relevant biomedical applications. PMID- 27120517 TI - Gallium plasmonic nanoparticles for label-free DNA and single nucleotide polymorphism sensing. AB - A label-free DNA and single nucleotide polymorphism (SNP) sensing method is described. It is based on the use of the pseudodielectric function of gallium plasmonic nanoparticles (GaNPs) deposited on Si (100) substrates under reversal of the polarization handedness condition. Under this condition, the pseudodielectric function is extremely sensitive to changes in the surrounding medium of the nanoparticle surface providing an excellent sensing platform competitive to conventional surface plasmon resonance. DNA sensing has been carried out by immobilizing a thiolated capture probe sequence from Helicobacter pylori onto GaNP/Si substrates; complementary target sequences of Helicobacter pylori can be quantified over the range of 10 pM to 3.0 nM with a detection limit of 6.0 pM and a linear correlation coefficient of R(2) = 0.990. The selectivity of the device allows the detection of a single nucleotide polymorphism (SNP) in a specific sequence of Helicobacter pylori, without the need for a hybridization suppressor in solution such as formamide. Furthermore, it also allows the detection of this sequence in the presence of other pathogens, such as Escherichia coli in the sample. The broad applicability of the system was demonstrated by the detection of a specific gene mutation directly associated with cystic fibrosis in large genomic DNA isolated from blood cells. PMID- 27120519 TI - Observation of Switchable Photoresponse of a Monolayer WSe2-MoS2 Lateral Heterostructure via Photocurrent Spectral Atomic Force Microscopic Imaging. AB - In the pursuit of two-dimensional (2D) materials beyond graphene, enormous advances have been made in exploring the exciting and useful properties of transition metal dichalcogenides (TMDCs), such as a permanent band gap in the visible range and the transition from indirect to direct band gap due to 2D quantum confinement, and their potential for a wide range of device applications. In particular, recent success in the synthesis of seamless monolayer lateral heterostructures of different TMDCs via chemical vapor deposition methods has provided an effective solution to producing an in-plane p-n junction, which is a critical component in electronic and optoelectronic device applications. However, spatial variation of the electronic and optoelectonic properties of the synthesized heterojunction crystals throughout the homogeneous as well as the lateral junction region and the charge carrier transport behavior at their nanoscale junctions with metals remain unaddressed. In this work, we use photocurrent spectral atomic force microscopy to image the current and photocurrent generated between a biased PtIr tip and a monolayer WSe2-MoS2 lateral heterostructure. Current measurements in the dark in both forward and reverse bias reveal an opposite characteristic diode behavior for WSe2 and MoS2, owing to the formation of a Schottky barrier of dissimilar properties. Notably, by changing the polarity and magnitude of the tip voltage applied, pixels that show the photoresponse of the heterostructure are observed to be selectively switched on and off, allowing for the realization of a hyper-resolution array of the switchable photodiode pixels. This experimental approach has significant implications toward the development of novel optoelectronic technologies for regioselective photodetection and imaging at nanoscale resolutions. Comparative 2D Fourier analysis of physical height and current images shows high spatial frequency variations in substrate/MoS2 (or WSe2) contact that exceed the frequencies imposed by the underlying substrates. These results should provide important insights in the design and understanding of electronic and optoelectronic devices based on quantum confined atomically thin 2D lateral heterostructures. PMID- 27120518 TI - Cerebral metabolic rate of oxygen (CMRO2 ) mapping with hyperventilation challenge using quantitative susceptibility mapping (QSM). AB - PURPOSE: Our objective was to demonstrate the feasibility of using hyperventilation as an efficient vasoconstrictive challenge and prior knowledge as denoising constraints for cerebral metabolic rate of oxygen (CMRO2 ) mapping based upon quantitative susceptibility mapping (QSM). METHODS: Three-dimensional (3D) multi-echo gradient echo and arterial spin labeling imaging were performed to calculate QSM and perfusion maps before and after a hyperventilation challenge in 11 healthy subjects. For comparison, this was repeated using a caffeine challenge. Whole-brain CMRO2 and oxygen extraction fraction (OEF) maps were computed using constrained optimization. Hyperventilation scans were repeated to measure reproducibility. Regional agreement of CMRO2 and OEF maps was analyzed within the cortical gray matter (CGM) using t-test and Bland-Altman plots. RESULTS: Hyperventilation challenge eliminates the 30-min waiting time needed for caffeine to exert its vasoconstrictive effects. Mean CMRO2 (in umol/100g/min) obtained in CGM using the caffeine and repeated hyperventilation scans were 149 +/- 16, 153 +/- 19, and 150 +/- 20, respectively. This corresponded to an OEF of 33.6 +/- 3.4%, 32.3 +/- 3.2%, and 34.1 +/- 3.8% at baseline state and 39.8 +/- 4.8%, 43.6 +/- 6.2%, and 42.8 +/- 6.8% at challenged state, respectively. Hyperventilation scans produced a good agreement of CMRO2 and OEF values. CONCLUSIONS: Hyperventilation is a feasible, reproducible, and efficient vasoconstrictive challenge for QSM-based quantitative CMRO2 mapping. Magn Reson Med 77:1762-1773, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27120520 TI - The starship children's hospital tonsillectomy: A further 10 years of experience. AB - OBJECTIVES/HYPOTHESIS: Tonsillectomy as a day-stay procedure remains controversial, although it is an established procedure in New Zealand. We reviewed our last 10 years' experience. METHODS: A prospective audit was used to determine unplanned conversion from day-stay to overnight hospital admission rates and the incidence of postoperative complications. RESULTS: There were 5,400 tonsillectomies performed over the 10-year study period (January 2004-January 2015); 71% as outpatients. The unplanned conversion rate to overnight stay was 0.4%. The median age of day-stay patients was 6.5 years (range 13 months-15 years) compared with those admitted for overnight stay (5 years; range 8 months 15 years). The primary postoperative bleed rate was 0.5% (confidence interval [CI] 0.3%-0.7%), and the combined primary and secondary posttonsillectomy bleed rate was 4.3% (CI 3.8%-5.0%). The rate of patients returning with postoperative complications within 1 month of surgery was 6.3% (CI 5.6%-7.0%). CONCLUSION: Day stay tonsillectomy in the pediatric population is safe when performed using the described guidelines in a facility with appropriate resources. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:E416-E420, 2016. PMID- 27120521 TI - Short-Coupled Ventricular Fibrillation. PMID- 27120522 TI - Circulating Galectin-3 Levels Are Increased in Patients with Ischemic Heart Disease, but Are Not Influenced by Acute Myocardial Infarction. AB - OBJECTIVES: Galectin-3 (Gal-3) is involved in cardiac inflammation and fibrosis, and is in use as a biomarker that indicates increased risk in heart failure. This study examined the relationship between Gal-3 levels and acute and old myocardial infarction (MI) in patients assessed by cardiac magnetic resonance (CMR) imaging. METHODS: Group 1 consisted of 38 patients with ST-elevation MI and single-vessel disease treated with primary percutaneous coronary intervention (PCI). Group 2 consisted of 52 patients with prior complicated MI. Twenty-two controls were included. CMR was performed in group 1 at 2 days, 1 week, 2 months and 1 year following PCI and in group 2 at >4 years after MI. RESULTS: Median Gal-3 was elevated in patients compared with controls, group 1: 11.93 ng/ml (IQR 6.34 17.52, p = 0.03), group 2: 12.96 (IQR 6.33-19.29, p = 0.03) and controls: 10.16 (IQR 5.59-14.73). Gal-3 levels did not change during acute MI, and there was no relationship between Gal-3 and infarct size, troponin-T, high-sensitivity C reactive protein, left-ventricular (LV) volumes or LV ejection fraction (LVEF) in group 1. In group 2, Gal-3 correlated modestly with MI size (r = 0.28, p < 0.05), LV end-diastolic volume index (r = 0.40, p < 0.01), LV end-systolic volume index (r = 0.43, p < 0.01) and LVEF (r = -0.39, p < 0.01). CONCLUSION: There was no relationship between Gal-3 levels and acute ischemic myocardial injury. A significant, modest relationship between Gal-3 levels, MI size and LV remodeling was only found in patients with old MI. PMID- 27120551 TI - Biomechanical Properties of the Internal Limiting Membrane after Intravitreal Ocriplasmin Treatment. AB - PURPOSE: To assess the stiffness of the human internal limiting membrane (ILM) and evaluate potential changes of mechanical properties following intravitreal ocriplasmin injection for vitreomacular traction. METHODS: This is an interventional comparative case series of 12 surgically excised ILM specimens consecutively obtained from 9 eyes of 9 patients after unsuccessful pharmacologic vitreolysis with ocriplasmin. During the same time period, 16 specimens from 13 other eyes without ocriplasmin treatment were harvested during vitrectomy and served as controls. All patients presented with macular holes or vitreomacular traction and underwent vitrectomy with ILM peeling either with or without brilliant blue (BB) staining. All specimens were analyzed using atomic force microscopy with scan regions of 25 * 25 MUm. In all specimens, both the retinal side and vitreal side of the ILM were analyzed. RESULTS: Atomic force microscopy revealed no significant differences in elasticity of ILM specimens removed from eyes with or without ocriplasmin treatment. Undulated areas of the retinal side presented stiffer than the vitreal side of the ILM. Topographical mapping of both the vitreal and retinal side of the ILM showed no apparent alteration of the morphology in ocriplasmin-treated eyes compared to untreated eyes. Staining with BB resulted in an increase of tissue stiffness. CONCLUSIONS: Intravitreal injection of ocriplasmin does not change biomechanical properties of the human ILM. There is no evidence of a potential enzymatic effect of ocriplasmin interfering with the stiffness of this basement membrane. PMID- 27120553 TI - Predicting Venous Thromboembolism in Pediatric Trauma Patients-Reply. PMID- 27120552 TI - Screening for co-occurring conditions in adults with autism spectrum disorder using the strengths and difficulties questionnaire: A pilot study. AB - Adolescents and adults with autism spectrum disorder (ASD) are at elevated risk of co-occurring mental health problems. These are often undiagnosed, can cause significant impairment, and place a very high burden on family and carers. Detecting co-occurring disorders is extremely important. However, there is no validated screening tool for this purpose. The aim of this pilot study is to test the utility of the strengths and difficulties questionnaire (SDQ) to screen for co-occurring emotional disorders and hyperactivity in adolescents and adults with ASD. The SDQ was completed by 126 parents and 98 individuals with ASD (in 79 cases both parent and self-report were available from the same families). Inter rater reliability, test-retest stability, internal consistency, and construct validity were examined. SDQ subscales were also compared to clinically utilized measures of emotional disorders and hyperactivity to establish the ability to predict risk of disorder. Inter-rater reliability (r = 0.42), test-retest stability (r = 0.64), internal consistency (alpha = 0.52-0.81) and construct validity (r = 0.42-0.57) for the SDQ subscales were comparable to general population samples. Parent- and self-report SDQ subscales were significantly associated with measures of anxiety, depression and hyperactivity (62-74% correctly classified). Parent-report performed significantly better than self report; adults with ASD under-reported difficulties. The SDQ shows promise as a simple and efficient way to screen for emotional disorders and hyperactivity in adolescents and adults with ASD that could help reduce the impact of these disorders on individuals and their families. However, further more systematic attempts at validation are warranted. Autism Res 2016, 9: 1353-1363. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27120554 TI - Isoflurane rescue therapy for bronchospasm reduces intracranial pressure in a patient with traumatic brain injury. AB - PRIMARY OBJECTIVE: To assess the unusual use of a volatile anaesthetic for treatment of life-threatening bronchospasm in a patient with traumatic brain injury (TBI). RESEARCH DESIGN: Case report. METHODS AND PROCEDURES: This study presents a previously healthy 30-year-old man with severe TBI and bronchospasm induced acute hypercapnia. He was treated with inhaled isoflurane in combination with monitoring of intracranial pressure (ICP) and regional cerebral blood flow (rCBF). RESULTS: Three-day-long isoflurane treatment resolved drug-refractory bronchospasm, decreased airway pressure and improved gas exchange, even at a low end-tidal concentration (0.3-0.5 vol%). Although rCBF was increased by 18 ml min( 1) 100 g(-1) during isoflurane treatment, there was a significant decrease in ICP (21 (SD = 3) mmHg, 9 (SD = 5) mmHg, 2 (SD = 3) mmHg; during pre-treatment, treatment and post-treatment, respectively; p < 0.001). Improved autoregulation due to lower partial pressure of carbon dioxide, restoration of carbon dioxide reactivity, isoflurane-induced regional differences in rCBF and improved microcirculation may have been responsible for the prompt and long-lasting normalization of ICP. The patient had no TBI-related disability at 6 months post injury. CONCLUSIONS: Isoflurane at a low dose can be an effective and safe treatment option for drug-refractory bronchospasm in a patient with traumatic intracranial hypertension, provided that multimodality neuromonitoring is used. PMID- 27120555 TI - Self management interventions for type 2 diabetes in adult people with severe mental illness. AB - BACKGROUND: People with severe mental illness are twice as likely to develop type 2 diabetes as those without severe mental illness. Treatment guidelines for type 2 diabetes recommend that structured education should be integrated into routine care and should be offered to all. However, for people with severe mental illness, physical health may be a low priority, and motivation to change may be limited. These additional challenges mean that the findings reported in previous systematic reviews of diabetes self management interventions may not be generalised to those with severe mental illness, and that tailored approaches to effective diabetes education may be required for this population. OBJECTIVES: To assess the effects of diabetes self management interventions specifically tailored for people with type 2 diabetes and severe mental illness. SEARCH METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the International Clinical Trials Registry Platform (ICTRP) Search Portal, ClinicalTrials.gov and grey literature. The date of the last search of all databases was 07 March 2016. SELECTION CRITERIA: Randomised controlled trials of diabetes self management interventions for people with type 2 diabetes and severe mental illness. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text articles, extracted data and conducted the risk of bias assessment. We used a taxonomy of behaviour change techniques and the framework for behaviour change theory to describe the theoretical basis of the interventions and active ingredients. We used the GRADE method (Grades of Recommendation, Assessment, Development and Evaluation Working Group) to assess trials for overall quality of evidence. MAIN RESULTS: We included one randomised controlled trial involving 64 participants with schizophrenia or schizoaffective disorder. The average age of participants was 54 years; participants had been living with type 2 diabetes for on average nine years, and with their psychiatric diagnosis since they were on average 28 years of age. Investigators evaluated the 24-week Diabetes Awareness and Rehabilitation Training (DART) programme in comparison with usual care plus information (UCI). Follow-up after trial completion was six months. Risk of bias was mostly unclear but was high for selective reporting. Trial authors did not report on diabetes-related complications, all-cause mortality, adverse events, health-related quality of life nor socioeconomic effects. Twelve months of data on self care behaviours as measured by total energy expenditure showed a mean of 2148 kcal for DART and 1496 kcal for UCI (52 participants; very low-quality evidence), indicating no substantial improvement. The intervention did not have a substantial effect on glycosylated haemoglobin A1c (HbA1c) at 6 or 12 months of follow-up (12-month HbA1c data 7.9% for DART vs 6.9% for UCI; 52 participants; very low-quality evidence). Researchers noted small improvements in body mass index immediately after the intervention was provided and at six months, along with improved weight post intervention. Diabetes knowledge and self efficacy improved immediately following receipt of the intervention, and knowledge also at six months. The intervention did not improve blood pressure. AUTHORS' CONCLUSIONS: Evidence is insufficient to show whether type 2 diabetes self management interventions for people with severe mental illness are effective in improving outcomes. Researchers must conduct additional trials to establish efficacy, and to identify the active ingredients in these interventions and the people most likely to benefit from them. PMID- 27120556 TI - Ontogeny of tool use: how do toddlers use hammers? AB - Hammering with a hand tool appears early in life. Skillful hammering involves accommodating movements to properties of the hammer, orienting the hammer's head to the item to be struck, and maintaining stable posture during forceful action with the arm(s). We aimed to characterize development of these abilities in young children (12, 18, and 24 months old). Children struck at a peg with a hammer held in the hand or a hammer attached to a handle. Children struck more frequently with a hard hammer surface than a soft one, and more frequently (although less accurately) with handled hammers than with non-handled hammers. Developmental differences were evident in accuracy, number of strikes, and kinematic parameters, especially with the handled object. Children's ability to use objects for forceful and accurate percussion changed measurably over the second year, in tandem with improving postural stability and greater motion of the elbow. PMID- 27120557 TI - Further Insight into the Definite Morphology and Formation Mechanism of Mesoporous Silica KCC-1. AB - The unique three-dimensional pore structure of KCC-1 has attracted significant attention and has proven to be different compared to other conventional mesoporous silica such as the MCM-41 family, SBA-15, or even MSN nanoparticles. In this research, we carefully examine the morphology of KCC-1 to define more appropriate nomenclature. We also propose a formation mechanism of KCC-1 based on our experimental evidence. Herein, the KCC-1 morphology was interpreted mainly on the basis of compiling all observation and information taken from SEM and TEM images. Further analysis on TEM images was carried out. The gray value intensity profile was derived from TEM images in order to determine the specific pattern of this unique morphology that is found to be clearly different from that of other types of porous spherical-like morphologies. On the basis of these results, the KCC-1 morphology would be more appropriately reclassified as bicontinuous concentric lamellar morphology. Some physical characteristics such as the origin of emulsion, electrical conductivity, and the local structure of water molecules in the KCC-1 emulsion were disclosed to reveal the formation mechanism of KCC-1. The origin of the KCC-1 emulsion was characterized by the observation of the Tyndall effect, conductometry to determine the critical micelle concentration, and Raman spectroscopy. In addition, the morphological evolution study during KCC 1 synthesis completes the portrait of the formation of mesoporous silica KCC-1. PMID- 27120558 TI - Quantitation of low molecular weight sugars by chemical derivatization-liquid chromatography/multiple reaction monitoring/mass spectrometry. AB - A new method for the separation and quantitation of 13 mono- and disaccharides has been developed by chemical derivatization/ultra-HPLC/negative-ion ESI multiple-reaction monitoring MS. 3-Nitrophenylhydrazine (at 50 degrees C for 60 min) was shown to be able to quantitatively derivatize low-molecular weight (LMW) reducing sugars. The nonreducing sugar, sucrose, was not derivatized. A pentafluorophenyl-bonded phase column was used for the chromatographic separation of the derivatized sugars. This method exhibits femtomole-level sensitivity, high precision (CVs of <= 4.6%) and high accuracy for the quantitation of LMW sugars in wine. Excellent linearity (R(2) >= 0.9993) and linear ranges of ~500-fold for disaccharides and ~1000-4000-fold for monosaccharides were achieved. With internal calibration ((13) C-labeled internal standards), recoveries were between 93.6% +/- 1.6% (xylose) and 104.8% +/- 5.2% (glucose). With external calibration, recoveries ranged from 82.5% +/- 0.8% (ribulose) to 105.2% +/- 2.1% (xylulose). Quantitation of sugars in two red wines and two white wines was performed using this method; quantitation of the central carbon metabolism-related carboxylic acids and tartaric acid was carried out using a previously established derivatization procedure with 3-nitrophenylhydrazine as well. The results showed that these two classes of compounds-both of which have important organoleptic properties-had different compositions in red and white wines. PMID- 27120559 TI - Efficient Spectral Diffusion at the Air/Water Interface Revealed by Femtosecond Time-Resolved Heterodyne-Detected Vibrational Sum Frequency Generation Spectroscopy. AB - Femtosecond vibrational dynamics at the air/water interface is investigated by time-resolved heterodyne-detected vibrational sum frequency generation (TR-HD VSFG) spectroscopy and molecular dynamics (MD) simulation. The low- and high frequency sides of the hydrogen-bonded (HB) OH stretch band at the interface are selectively excited with special attention to the bandwidth and energy of the pump pulses. Narrow bleach is observed immediately after excitation of the high frequency side of the HB OH band at ~3500 cm(-1), compared to the broad bleach observed with excitation of the low-frequency side at ~3300 cm(-1). However, the time-resolved spectra observed with the two different excitations become very similar at 0.5 ps and almost indistinguishable by 1.0 ps. This reveals that efficient spectral diffusion occurs regardless of the difference of the pump frequency. The experimental observations are well-reproduced by complementary MD simulation. There is no experimental and theoretical evidence that supports extraordinary slow dynamics in the high-frequency side of the HB OH band, which was reported before. PMID- 27120561 TI - Stereotype Threat Alters the Subjective Experience of Memory. AB - There is now evidence that negative age-related stereotypes about memory reduce older adults' memory performance, and inflate age differences in this domain. Here, we examine whether stereotype threat may also influence the basic feeling that one is more or less able to remember. Using the Remember/Know paradigm, we demonstrated that stereotype threat conducted older adults to a greater feeling of familiarity with events, while failing to retrieve any contextual detail. This finding indicates that stereotype threat alters older adults' subjective experience of memory, and strengthens our understanding of the mechanisms underlying stereotype threat effects. PMID- 27120562 TI - A Strong Validation of the Crosswise Model Using Experimentally-Induced Cheating Behavior. AB - We constructed an online cheating paradigm that could be used to validate the Crosswise Model ( Yu, Tian, & Tang, 2008 ), a promising indirect questioning technique designed to control for socially desirable responding on sensitive questions. Participants qualified for a reward only if they could identify the target words from three anagrams, one of which was virtually unsolvable as shown on a pretest. Of the 664 participants, 15.5% overreported their performance and were categorized as cheaters. When participants were asked to report whether they had cheated, a conventional direct question resulted in a substantial underestimate (5.1%) of the known prevalence of cheaters. Using a CWM question resulted in a more accurate estimate (13.0%). This result shows that the CWM can be used to control for socially desirable responding and provides estimates that are much closer to the known prevalence of a sensitive personal attribute than those obtained using a direct question. PMID- 27120563 TI - Self-Prioritization Beyond Perception. AB - Recently, Sui, He, and Humphreys (2012) introduced a new paradigm to measure perceptual self-prioritization processes. It seems that arbitrarily tagging shapes to self-relevant words (I, my, me, and so on) leads to speeded verification times when matching self-relevant word shape pairings (e.g., me - triangle) as compared to non-self-relevant word shape pairings (e.g., stranger - circle). In order to analyze the level at which self-prioritization takes place we analyzed whether the self-prioritization effect is due to a tagging of the self-relevant label and the particular associated shape or due to a tagging of the self with an abstract concept. In two experiments participants showed standard self-prioritization effects with varying stimulus features or different exemplars of a particular stimulus-category suggesting that self-prioritization also works at a conceptual level. PMID- 27120564 TI - C-di-GMP regulates the expression of lapA and bcs operons via FleQ in Pseudomonas putida KT2440. AB - Cyclic diguanylate (c-di-GMP) positively modulates the production of biofilm matrix components from the transcriptional to the post-translational level in a variety of bacterial species. However, mechanisms by which it regulates these opponents in Pseudomonas putida KT2440 remain unclear. Here we show that c-di-GMP regulates the adhesin LapA, LapF and exopolysaccharides Bcs, Pea at transcriptional level. Transcriptional regulator FleQ is required for the modulation of lapA and bcs expression by c-di-GMP, but seems not to be necessary for that of lapF and pea. We also found that fleQ mutant of P. putida was defective in biofilm formation and had smooth colony morphology. Transcription assay indicates that FleQ acts as an activator of lapA, but a repressor of bcs. In vitro experiments show that FleQ binds to lapA and bcs promoter DNA. The binding to lapA promoter was slightly promoted by c-di-GMP, while binding to bcs promoter was inhibited by c-di-GMP. Our results show that c-di-GMP regulates the expression of lapA and bcs operons via FleQ in P. putida. PMID- 27120565 TI - The relationship between burnout symptoms and Type D personality among health care professionals in Turkey. AB - The aim of this study was to investigate the relationship between burnout and Type D personality in health care professionals. The study randomly included 120 health care professionals (73 nurses, 47 doctors). Sociodemographic data form, Maslach Burnout Inventory, and Type D Personality Scale were applied to each participant; 38.3% of the health care professionals (n = 46) had the Type D personality. Emotional exhaustion and depersonalization of health care professionals with Type D personality were higher than of those without Type D personality (p = .006 and p = .005). Stepwise regression analysis indicated that Type D personality was a predictor of emotional exhaustion and depersonalization (p = .005 and p = .001, respectively). Our results suggest that Type D personality is associated with higher burnout levels. PMID- 27120560 TI - The fine-tuning of proteolytic pathways in Alzheimer's disease. AB - Several integrated proteolytic systems contribute to the maintenance of cellular homeostasis through the continuous removal of misfolded, aggregated or oxidized proteins and damaged organelles. Among these systems, the proteasome and autophagy play the major role in protein quality control, which is a fundamental issue in non-proliferative cells such as neurons. Disturbances in the functionality of these two pathways are frequently observed in neurodegenerative diseases, like Alzheimer's disease, and reflect the accumulation of protease resistant, deleterious protein aggregates. In this review, we explored the sophisticated crosstalk between the ubiquitin-proteasome system and autophagy in the removal of the harmful structures that characterize Alzheimer's disease neurons. We also dissected the role of the numerous shuttle factors and chaperones that, directly or indirectly interacting with ubiquitin and LC3, are used for cargo selection and delivery to one pathway or the other. PMID- 27120567 TI - Anti-infliximab Antibodies with Neutralizing Capacity in Patients with Inflammatory Bowel Disease: Distinct Clinical Implications Revealed by a Novel Assay. AB - BACKGROUND: About 60% of infliximab (IFX)-treated patients develop antidrug antibodies (ADA), although their clinical significance remains disputed. The aim of this study was to develop an assay for assessing ADA-neutralizing potential, and clinical significance. METHODS: An immune assay was devised in which the inhibition of IFX binding to plated-tumor necrosis factor in the presence of patient sera or controls, was assessed and defined as IFX-tumor necrosis factor binding reduction ratio (ITBR). The assay was compared to a bioassay in which tumor necrosis factor-alpha-induced interleukin-8 secretion from HT-29 cells was assessed after addition of IFX to ADA-containing sera or control sera. RESULTS: Both assays detected neutralizing antibodies in 39 of 44 ADA-positive sera. The median ITBR was 3.66 (mean 4.9 +/- 3.2) in 29 ADA-positive patients with loss of response (LOR), and 1.3 (mean 1.9 +/- 1.3) in 15 patients without LOR (P = 0.001). ADA titers in both groups were similar (median 9.5 and 10.2 MUg/mL, respectively P = 0.74). Using an ITBR of 1.65, the sensitivity for LOR detection was 86.2% and the specificity was 66.7%. (positive predictive value 83%; negative predictive value 71.4%; P = 0.001). When early ADA-IFX-sera from IFX-treated patients with or without subsequent LOR were compared, the median ITBRs were 1.1 and 0.57, respectively (P = 0.028). CONCLUSIONS: Detection of neutralizing antibody activity was superior to antibody quantization by enzyme-linked immunosorbent assay with respect to correlation with clinical LOR, and for prediction of subsequent LOR. These findings may assist in optimizing infliximab therapy in patients with inflammatory bowel disease. PMID- 27120569 TI - Function and Ventilation of Large and Small Airways in Children and Adolescents with Inflammatory Bowel Disease. AB - BACKGROUND: Extraintestinal manifestations are common among patients with inflammatory bowel disease (IBD), whereas pulmonary involvement is considered rare. However, chronic lung diseases begin with subclinical changes of the small airways and often originate in childhood. Pulmonary involvement, particularly of the small airways, can be assessed using novel inert gas washout tests. METHODS: In this prospective, single-center study, 30 children and adolescents (mean age, 14 years; SD, +/-2.6; 13 boys) with IBD (mean disease duration, 3.2 years; SD, +/ 2.8), and 32 healthy age-matched controls, performed nitrogen multiple-breath washout, double-tracer gas single-breath washout, and diffusion capacity for carbon monoxide. Patients with IBD additionally performed spirometry, plethysmography, and measurement of exhaled nitric oxide. RESULTS: Patients with IBD demonstrated no abnormalities in classical lung function tests. There was no difference between active disease and remission. The lung clearance index, a very sensitive indicator for small airway function, did not differ between patients with IBD and healthy controls (mean difference [95% confidence interval] -0.01 [ 0.28 to 0.25]). Specific markers for peripheral lung ventilation (Sacin and Scond) were also within the normal range (0.002 [-0.003 to 0.008] and -0.002 [ 0.020 to 0.015], respectively). No association was found between measures of lung function and IBD subtype, clinical disease activity scores, laboratory values, treatment modalities, or disease duration. CONCLUSIONS: In our cohort of pediatric and adolescent patients with IBD without respiratory symptoms, there was no evidence of significant lung disease on extensive screening testing. General screening of asymptomatic patients therefore appears unnecessary and is not recommended in this population. PMID- 27120568 TI - Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation. AB - BACKGROUND: Dairy products may be involved in the etiology of inflammatory bowel disease by modulating gut microbiota and immune responses, but data from epidemiological studies examining this relationship are limited. We investigated the association between prediagnostic intake of these foods and dietary calcium, and the subsequent development of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: In total, 401,326 participants were enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. At recruitment, consumption of total and specific dairy products (milk, yogurt, and cheese) and dietary calcium was measured using validated food frequency questionnaires. Cases developing incident CD (n = 110) or UC (n = 244) during follow-up were matched with 4 controls. Conditional logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for total energy intake and smoking. RESULTS: Compared with the lowest quartile, the ORs for the highest quartile of total dairy products and dietary calcium intake were 0.61 (95% CI, 0.32-1.19, p trend = 0.19) and 0.63 (95% CI, 0.28-1.42, p trend = 0.23) for CD, and 0.80 (95% CI, 0.50-1.30, p trend = 0.40) and 0.81 (95% CI, 0.49-1.34, p trend = 0.60) for UC, respectively. Compared with nonconsumers, individuals consuming milk had significantly reduced odds of CD (OR 0.30, 95% CI, 0.13-0.65) and nonsignificantly reduced odds of UC (OR 0.85, 95% CI, 0.49-1.47). CONCLUSIONS: Milk consumption may be associated with a decreased risk of developing CD, although a clear dose-response relationship was not established. Further studies are warranted to confirm this possible protective effect. PMID- 27120570 TI - Use of Complementary and Alternative Medicine for Inflammatory Bowel Disease Is Associated with Worse Adherence to Conventional Therapy: The COMPLIANT Study. AB - BACKGROUND: Complementary and alternative medicine (CAM) use is highly prevalent among inflammatory bowel disease (IBD patients). We assessed whether its use, both for IBD and for general health, influenced adherence to conventional medications. METHODS: We enrolled 392 IBD subjects in a prospective cohort study and categorized them as CAM nonusers (38%) and those who used CAM for general health (CAM-GEN, 41%) and for IBD (CAM-IBD, 21%). Their self-reported adherence was measured using the 4-item Morisky Adherence Scale during a median follow-up period of 6.8 months. RESULTS: CAM-IBD users were less likely to be adherent to medical therapy than CAM nonusers and CAM-GEN users (70% vs. 84% and 81%, respectively, P < 0.05). Nearly all subjects who were nonadherent reported that it was unintentional (97%), and this did not vary use of CAM. After adjusting for confounders, the adjusted odds ratio for adherence among CAM-IBD relative to CAM nonuser was 0.47 (95% CI, 0.22-0.96). CAM-GEN demonstrated similar adherence to CAM nonusers (adjusted odds ratio, 0.85; 95% CI, 0.44-1.66). CAM-IBD was also less likely than CAM nonusers and CAM-GEN to have improvement in their adherence scores during follow-up (14% vs. 33% and 34%, respectively, P < 0.01). The adjusted odds ratio for improved adherence in CAM-IBD compared with CAM nonusers and CAM-GEN were 0.32 (95% CI, 0.15-0.69) and 0.34 (95% CI, 0.16-0.72), respectively. CONCLUSIONS: CAM-IBD, but not CAM-GEN, was associated with lower adherence to IBD medical therapy. A third of CAM nonusers and CAM-GEN improved adherence during the observation period, suggesting a Hawthorne effect. PMID- 27120572 TI - Cytomegalovirus Viral Load in the Colon and Risk of Colectomy in Hospitalized Patients With Inflammatory Bowel Diseases. PMID- 27120573 TI - The Complement System and Inflammatory Bowel Disease. PMID- 27120574 TI - TEMPO-Mediated Aza-Diels-Alder Reaction: Synthesis of Tetrahydropyridazines Using Ketohydrazones and Olefins. AB - A novel, facile, and efficient method for the synthesis of tetrahydropyridazines by a one-pot tandem reaction of easily accessible ketohydrazones and olefins in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) has been successfully developed. The reaction involves the initial generation of azoalkenes from direct oxidative dehydrogenation of ketohydrazones using TEMPO as the commercially available oxidant, followed by a subsequent aza-Diels-Alder reaction with olefins. PMID- 27120571 TI - Epidemiology, Diagnosis, and Management of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease. AB - Clostridium difficile infection (CDI) is a major source of morbidity and mortality for the U.S. health care system and frequently complicates the course of inflammatory bowel disease (IBD). Patients with IBD are more likely to be colonized with C. difficile and develop active infection than the general population. They are also more likely to have severe CDI and develop subsequent complications such as IBD flare, colectomy, or death. Even after successful initial treatment and recovery, recurrent CDI is common. Management of CDI in IBD is fraught with diagnostic and therapeutic challenges because the clinical presentations of CDI and IBD flare have considerable overlap. Fecal microbiota transplantation can be successful in curing recurrent CDI when other treatments have failed, but may also trigger IBD flare and this warrants caution. New experimental treatments including vaccines, monoclonal antibodies, and nontoxigenic strains of C. difficile offer promise but are not yet available for clinicians. A better understanding of the complex relationship between the gut microbiota, CDI, and IBD is needed. PMID- 27120575 TI - JNK signaling mediates wing form polymorphism in brown planthoppers (Nilaparvata lugens). AB - Wing polyphenism is considered to be an adaptive trade-off between migration (long winged forms) and reproduction (short winged forms), determined by various environmental conditions. The c-Jun NH2-terminal kinase (JNK) is crucial for the regulation of the activity of a number of transcription factors, and is activated under stress and environmental fluctuations where it functions in maintaining cell viability and proliferation. We used RNA interference and a pharmacological inhibitor of JNK to test the role of JNK signaling in regulating the wing dimorphism of the brown planthopper, Nilaparvata lugens. Silencing NlJNK increased the proportion of short winged female adults, reminiscent of the effect of silencing inhibitory components of the insulin-signaling pathway, such as NlAkt. However, silencing of the JNK-activated transcription factors NlJun and NlFos did not change the wing form ratio significantly, indicating that NlJNK may not act through NlJun and NlFos in mediating this process. In summary, JNK signaling may play a role in determining wing polymorphism in N. lugens females. PMID- 27120576 TI - Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds. AB - We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned alpha to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles. PMID- 27120578 TI - A 5-year prospective study on single immediate implants in the aesthetic zone. AB - AIM: There is a paucity of long-term data on soft tissue aesthetics of single immediate implants. The objective of this study was to evaluate the 5-year clinical and aesthetic outcome of this treatment concept. MATERIALS AND METHODS: Twenty-two periodontally healthy patients (12 men, 10 women; mean age 50) with low risk for aesthetic complications (thick gingival biotype, intact buccal bone wall, both neighbouring teeth present) were consecutively treated with a single immediate implant in the aesthetic zone (15-25). Flapless surgery was performed and the gap between the implant and buccal bone wall was systematically filled with bovine bone particles. Implants were immediately non-functionally loaded with a screw-retained provisional crown. Cases demonstrating major alveolar process changes and/or advanced mid-facial recession (>1 mm) at 3 months were additionally treated with a connective tissue graft (CTG). Permanent crowns were installed at 6 months. The clinical and aesthetic results at 5 years were compared to those obtained at 1 year. RESULTS: Seventeen patients attended the 5 year re-assessment, of whom five had been treated with a CTG for early aesthetic complications. There was one early implant failure and one complication after 1 year (porcelain chipping). Mean marginal bone loss was 0.12 mm at 1 year and 0.19 mm at 5 years (p = 0.595) with the moment of implant installation as baseline. Papilla height increased between 1 and 5 years (p <= 0.007), whereas mid-facial contour (p = 0.005) and alveolar process deficiency (p = 0.008) deteriorated. Mean mid-facial recession was on average 0.28 mm (SD 0.48) at 1 year and 0.53 mm (SD 0.53) at 5 years (p = 0.072) with the preoperative status as baseline. Three implants demonstrated advanced mid-facial recession (>1 mm) at 5 years. All three were in a central incisor position and none had been treated with a CTG. Thus, 8/17 implants showed aesthetic complications (five early and three late aesthetic complications). Implants in a lateral incisor position showed stable soft tissue levels. The pink aesthetic score was on average 12.15 at 1 year and 11.18 at 5 years (p = 0.030). CONCLUSION: Single immediate implants showed high implant survival and limited marginal bone loss in the long term. However, mid-facial recession, mid-facial contour and alveolar process deficiency deteriorated after 1 year. With an aesthetic complication rate of 8/17 in well-selected patients who had been treated by experienced clinicians, type I placement may not be recommended for daily practice. PMID- 27120577 TI - IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. AB - Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor rather than host-derived IL-33 induced the enhanced recruitment of CD11b+ GR1+ and CD11b+ F4/80+ myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. (c) 2016 Wiley Periodicals, Inc. PMID- 27120579 TI - Evaluation of Refractive Errors and Ocular Biometric Outcomes after Intravitreal Bevacizumab for Retinopathy of Prematurity. AB - PURPOSE: To assess ocular biometric outcomes following intravitreal bevacizumab (IVB) monotherapy for retinopathy of prematurity (ROP) and compare these results with those of laser photocoagulated infants and with the ones with spontaneously regressed ROP. MATERIALS AND METHODS: Premature infants including those who underwent IVB monotherapy (Group 1) or laser photocoagulation (Group 2) for ROP and infants with spontaneously regressed ROP (Group 3) were recruited for the study. Refractive errors and ocular biometric parameters (Axial length [AL], anterior chamber depth [ACD], and lens thickness [LT]) were measured at adjusted 1 year of age in all subjects. RESULTS: There was no significant difference of spherical equivalent (SE) value between the groups (P = 0.781). The incidence of high myopia was 7.4% in Group 1 and 12.7% in Group 2 (P = 0.081). No infants exhibited high myopia in Group 3. LT was greater in Group 2 when compared to Group 1 and Group 3 (P = 0.011). Lower SE was significantly correlated to longer AL in Group 1 (r = -0.656, P = 0.015). There was a significant positive correlation between SE and ACD values in Group 2 (r = 0.391, P = 0.005). CONCLUSION: The study showed no significant difference of SE between the groups. High myopia was only present among the treated infants either with IVB or laser. Infants who received laser treatment significantly had thicker lenses. PMID- 27120581 TI - Ion-Pairing Assemblies Based on Pentacyano-Substituted Cyclopentadienide as a pi Electronic Anion. AB - Pentacyanocyclopentadienide (PCCp(-) ), a stable pi-electronic anion, provided various ion-pairing assemblies in combination with various cations. PCCp(-) based assemblies exist as single crystals and mesophases owing to interionic interactions with pi-electronic and aliphatic cations with a variety of geometries, substituents, and electronic structures. Single-crystal X-ray analysis revealed that PCCp(-) formed cation-dependent arrangements with contributions from charge-by-charge and charge-segregated assembly modes for ion pairs with pi-electronic and aliphatic cations, respectively. Furthermore, some aliphatic cations gave dimension-controlled organized structures with PCCp(-) , as observed in the mesophases, for which synchrotron XRD analysis suggested the formation of charge-segregated modes. Noncontact evaluation of conductivity for (C12 H25 )3 MeN(+) ?PCCp(-) films revealed potential hole-transporting properties, yielding a local-scale hole mobility of 0.4 cm(2) V(-1) s(-1) at semiconductor-insulator interfaces. PMID- 27120580 TI - An Indel Polymorphism in the MtnA 3' Untranslated Region Is Associated with Gene Expression Variation and Local Adaptation in Drosophila melanogaster. AB - Insertions and deletions (indels) are a major source of genetic variation within species and may result in functional changes to coding or regulatory sequences. In this study we report that an indel polymorphism in the 3' untranslated region (UTR) of the metallothionein gene MtnA is associated with gene expression variation in natural populations of Drosophila melanogaster. A derived allele of MtnA with a 49-bp deletion in the 3' UTR segregates at high frequency in populations outside of sub-Saharan Africa. The frequency of the deletion increases with latitude across multiple continents and approaches 100% in northern Europe. Flies with the deletion have more than 4-fold higher MtnA expression than flies with the ancestral sequence. Using reporter gene constructs in transgenic flies, we show that the 3' UTR deletion significantly contributes to the observed expression difference. Population genetic analyses uncovered signatures of a selective sweep in the MtnA region within populations from northern Europe. We also find that the 3' UTR deletion is associated with increased oxidative stress tolerance. These results suggest that the 3' UTR deletion has been a target of selection for its ability to confer increased levels of MtnA expression in northern European populations, likely due to a local adaptive advantage of increased oxidative stress tolerance. PMID- 27120582 TI - Physical properties and electronic band structure of noncentrosymmetric Th7Co3 superconductor. AB - The physical properties of the noncentrosymmetric superconductor Th7Co3 have been investigated by means of ac-magnetic susceptibility, magnetization, specific heat, electrical resistivity, magnetoresistance and Hall effect measurements. From these data it is established that Th7Co3 is a dirty type-II superconductor with [Formula: see text] K, [Formula: see text] and moderate electron-phonon coupling [Formula: see text]. Some evidences for anisotropic superconducting gap are found, including e.g. reduced specific heat jump ([Formula: see text]) at T c, diminished superconducting energy gap ([Formula: see text]) as compared to the BCS values, power law field dependence of the Sommerfeld coefficient at 0.4 K ([Formula: see text]), and a concave curvature of the [Formula: see text] line. The magnitudes of the thermodynamic critical field and the energy gap are consistent with mean-squared anisotropy parameter [Formula: see text]. The electronic specific heat in the superconducting state is reasonably fitted to an oblate spheroidal gap model. Calculations of scalar relativistic and fully relativistic electronic band structures reveal considerable differences in the degenerate structure, resulting from asymmetric spin-orbit coupling (ASOC). A large splitting energy of spin-up spin-down bands at the Fermi level E F, [Formula: see text] meV is observed and a sizeable ratio [Formula: see text] could classify the studied compound into the class of noncentrosymmetric superconductors with strong ASOC. The noncentrosymmetry of the crystal structure and the atomic relativistic effects are both responsible for an importance of ASOC in Th7Co3. The calculated results for the density of states show a Van Hove singularity just below E F and dominant role of the 6d electrons of Th to the superconductivity. PMID- 27120583 TI - Synthesis and Anti-Influenza Activity of Pyridine, Pyridazine, and Pyrimidine C Nucleosides as Favipiravir (T-705) Analogues. AB - Influenza viruses are responsible for seasonal epidemics and occasional pandemics which cause significant morbidity and mortality. Despite available vaccines, only partial protection is achieved. Currently, there are two classes of widely approved anti-influenza drugs: M2 ion channel blockers and neuraminidase inhibitors. However, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action. Favipiravir (T-705), a broad-spectrum antiviral agent, has shown potent anti-influenza activity in cell-based assays, and its riboside (2) triphosphate inhibited influenza polymerase. In one of our approaches to treat influenza infection, we designed, prepared, and tested a series of C-nucleoside analogues, which have an analogy to 2 and were expected to act by a similar antiviral mechanism as favipiravir. Compound 3c of this report exhibited potent inhibition of influenza virus replication in MDCK cells, and its triphosphate was a substrate of and demonstrated inhibitory activity against influenza A polymerase. Metabolites of 3c are also presented. PMID- 27120584 TI - Novel cationic coating agent for protein separation by capillary electrophoresis(?). AB - A novel positively charged surfactant N-dodecyl-N,N-dimethyl-(1,2-propandiol) ammonium chloride was used for the dynamic coating of the inner wall of a silica capillary. This paper covers the evaluation of dynamic coating and study of the influence of the analysis conditions for the magnitude and direction of electroosmotic flow as well as for the effective and selective separation of chosen proteins (ribonuclease A, cytochrome c, lysozyme, and myoglobin). The concentration of 0.1 mM of N-dodecyl-N,N-dimethyl-(1,2-propandiol) ammonium chloride enabled the reversal of the electro-osmotic flow, however, to separate basic as well as neutral proteins the higher concentration of the studied surfactant was necessary. The final conditions for the separation of studied proteins were set at 100 mM sodium acetate pH 5.5 with 10.0 mM of the studied surfactant. The results were also compared with those of two commercially available cationic surfactants, cetyltrimethylammonium bromide and dodecyltrimethylammonium bromide. Additionally, the developed method for protein separation was applied for the determination of lysozyme in a cheese sample. The limits of detection and quantification of lysozyme were 0.9 and 3.0 mg/L, respectively. The mean concentration of lysozyme found in the cheese sample was 167.3 +/- 10.3 mg/kg. PMID- 27120585 TI - Breast Cancer Stem Cell Culture and Enrichment Using Poly(epsilon-Caprolactone) Scaffolds. AB - The cancer stem cell (CSC) population displays self-renewal capabilities, resistance to conventional therapies, and a tendency to post-treatment recurrence. Increasing knowledge about CSCs' phenotype and functions is needed to investigate new therapeutic strategies against the CSC population. Here, poly(epsilon-caprolactone) (PCL), a biocompatible polymer free of toxic dye, has been used to fabricate scaffolds, solid structures suitable for 3D cancer cell culture. It has been reported that scaffold cell culture enhances the CSCs population. A RepRap BCN3D+ printer and 3 mm PCL wire were used to fabricate circular scaffolds. PCL design and fabrication parameters were first determined and then optimized considering several measurable variables of the resulting scaffolds. MCF7 breast carcinoma cell line was used to assess scaffolds adequacy for 3D cell culture. To evaluate CSC enrichment, the Mammosphere Forming Index (MFI) was performed in 2D and 3D MCF7 cultures. Results showed that the 60 degrees scaffolds were more suitable for 3D culture than the 45 degrees and 90 degrees ones. Moreover, 3D culture experiments, in adherent and non-adherent conditions, showed a significant increase in MFI compared to 2D cultures (control). Thus, 3D cell culture with PCL scaffolds could be useful to improve cancer cell culture and enrich the CSCs population. PMID- 27120586 TI - Bifunctional Phosphorus Dendrimers and Their Properties. AB - Dendrimers are hyperbranched and monodisperse macromolecules, generally considered as a special class of polymers, but synthesized step-by-step. Most dendrimers have a uniform structure, with a single type of terminal function. However, it is often desirable to have at least two different functional groups. This review will discuss the case of bifunctional phosphorus-containing dendrimers, and the consequences for their properties. Besides the terminal functions, dendritic structures may have also a function at the core, or linked off-center to the core, or at the core of dendrons (dendritic wedges). Association of two dendrons having different terminal functions leads to Janus dendrimers (two faces). The internal structure can also possess functional groups on one layer, or linked to one layer, or on several layers. Finally, there are several ways to have two types of terminal functions, besides the case of Janus dendrimers: either each terminal function bears two functions sequentially, or two different functions are linked to each terminal branching point. Examples of each type of structure will be given in this review, as well as practical uses of such sophisticated structures in the fields of fluorescence, catalysis, nanomaterials and biology. PMID- 27120587 TI - Correction: Popp, J., et al. Biofuels and Their Co-Products as Livestock Feed: Global Economic and Environmental Implications. Molecules 2016, 21, 285. PMID- 27120588 TI - 3,5,6,7,8,3',4'-Heptamethoxyflavone, a Citrus Flavonoid, Ameliorates Corticosterone-Induced Depression-like Behavior and Restores Brain-Derived Neurotrophic Factor Expression, Neurogenesis, and Neuroplasticity in the Hippocampus. AB - We previously reported that the citrus flavonoid 3,5,6,7,8,3',4' heptamethoxyflavone (HMF) increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of a transient global ischemia mouse model. Since the BDNF hypothesis of depression postulates that a reduction in BDNF is directly involved in the pathophysiology of depression, we evaluated the anti depressive effects of HMF in mice with subcutaneously administered corticosterone at a dose of 20 mg/kg/day for 25 days. We demonstrated that the HMF treatment ameliorated (1) corticosterone-induced body weight loss, (2) corticosterone induced depression-like behavior, and (3) corticosterone-induced reductions in BDNF production in the hippocampus. We also showed that the HMF treatment restored (4) corticosterone-induced reductions in neurogenesis in the dentate gyrus subgranular zone and (5) corticosterone-induced reductions in the expression levels of phosphorylated calcium-calmodulin-dependent protein kinase II and extracellular signal-regulated kinase1/2. These results suggest that HMF exerts its effects as an anti-depressant drug by inducing the expression of BDNF. PMID- 27120589 TI - Selenium in Cattle: A Review. AB - This review article examines the role of selenium (Se) and the effects of Se supplementation especially in the bovine species. Selenium is an important trace element in cattle. Some of its roles include the participation in the antioxidant defense the cattle farms. The nutritional requirements of Se in cattle are estimated at 100 MUg/kg DM (dry matter) for beef cattle and at 300 MUg/kg DM for dairy cows. The rations high in fermentable carbohydrates, nitrates, sulfates, calcium or hydrogen cyanide negatively influence the organism's use of the selenium contained in the diet. The Se supplementation may reduce the incidence of metritis and ovarian cysts during the postpartum period. The increase in fertility when adding Se is attributed to the reduction of the embryonic death during the first month of gestation. A use of organic Se in feed would provide a better transfer of Se in calves relative to mineral Se supplementation. The addition of Se yeasts in the foodstuffs of cows significantly increases the Se content and the percentage of polyunsaturated fatty acids (PUFA) in milk compared to the addition of sodium selenite. The enzyme 5-iodothyronine deiodinase is a seleno-dependent selenoprotein. It is one of the last proteins to be affected in the event of Se deficiency. This delay in response could explain the fact that several studies did not show the effect of Se supplementation on growth and weight gain of calves. Enrichment of Se in the diet did not significantly affect the slaughter weight and carcass yield of bulls. The impact and results of Se supplementation in cattle depend on physiological stage, Se status of animals, type and content of Se and types of Se administration. Further studies in Se supplementation should investigate the speciation of Se in food and yeasts, as well as understanding their metabolism and absorption. This constitute a path to exploit in order to explain certain different effects of Se. PMID- 27120590 TI - Highly Efficient Reproducible Perovskite Solar Cells Prepared by Low-Temperature Processing. AB - In this work, we describe the role of the different layers in perovskite solar cells to achieve reproducible, ~16% efficient perovskite solar cells. We used a planar device architecture with PEDOT: PSS on the bottom, followed by the perovskite layer and an evaporated C60 layer before deposition of the top electrode. No high temperature annealing step is needed, which also allows processing on flexible plastic substrates. Only the optimization of all of these layers leads to highly efficient and reproducible results. In this work, we describe the effects of different processing conditions, especially the influence of the C60 top layer on the device performance. PMID- 27120591 TI - Crystallization of Esomeprazole Magnesium Water/Butanol Solvate. AB - The molecular structure of esomeprazole magnesium derivative in the solid-state is reported for the first time, along with a simplified crystallization pathway. The structure was determined using the single crystal X-ray diffraction technique to reveal the bonding relationships between esomeprazole heteroatoms and magnesium. The esomeprazole crystallization process was carried out in 1-butanol and water was utilized as anti-solvent. The product proved to be esomeprazole magnesium tetrahydrate with two 1-butanol molecules that crystallized in P63 space group, in a hexagonal unit cell. Complete characterization of a sample after drying was conducted by the use of powder X-ray diffraction (PXRD), 1H nuclear magnetic resonance (NMR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectroscopy (IR), and dynamic vapor sorption (DVS). Investigation by 1H-NMR and TGA has shown that the solvent content in the dried sample consists of two water molecules and 0.3 butanol molecules per esomeprazole magnesium molecule. This is different from the single crystal X-ray diffraction results and can be attributed to the loss of some water and 1-butanol molecules stabilized by intermolecular interactions. The title compound, after drying, is a true solvate in terms of water; conversely, 1 butanol fills the voids of the crystal lattice in non-stoichiometric amounts. PMID- 27120592 TI - The Unusual Acid-Accumulating Behavior during Ripening of Cherimoya (Annona cherimola Mill.) is Linked to Changes in Transcription and Enzyme Activity Related to Citric and Malic Acid Metabolism. AB - Cherimoya (Annona cherimola Mill.) is a subtropical fruit characterized by a significant increase in organic acid levels during ripening, making it an interesting model for studying the relationship between acidity and fruit flavor. In this work, we focused on understanding the balance between the concentration of organic acids and the gene expression and activity of enzymes involved in the synthesis and degradation of these metabolites during the development and ripening of cherimoya cv. "Concha Lisa". Our results showed an early accumulation of citric acid and other changes associated with the accumulation of transcripts encoding citrate catabolism enzymes. During ripening, a 2-fold increase in malic acid and a 6-fold increase in citric acid were detected. By comparing the contents of these compounds with gene expression and enzymatic activity levels, we determined that cytoplasmic NAD-dependent malate dehydrogenase (cyNAD-MDH) and mitochondrial citrate synthase (mCS) play important regulatory roles in the malic and citric acid biosynthetic pathways. PMID- 27120593 TI - Neuroprotective Effects of Biochanin A against beta-Amyloid-Induced Neurotoxicity in PC12 Cells via a Mitochondrial-Dependent Apoptosis Pathway. AB - Alzheimer's disease is considered one of the major neurodegenerative diseases and is characterized by the production of beta-amyloid (Abeta) proteins and progressive loss of neurons. Biochanin A, a phytoestrogen compound found mainly in Trifolium pratense, was used in the present study as a potential alternative to estrogen replacement therapy via the investigation of its neuroprotective effects against Abeta25-35-induced toxicity, as well as of its potential mechanisms of action in PC12 cells. Exposure of these cells to the Abeta25-35 protein significantly increased cell viability loss and apoptosis. However, the effects induced by Abeta25-35 were markedly reversed in the present of biochanin A. Pretreatment with biochanin A attenuated the cytotoxic effect of the Abeta25 35 protein by decreasing viability loss, LDH release, and caspase activity in cells. Moreover, we found that expression of cytochrome c and Puma were reduced, alongside with the restoration of Bcl-2/Bax and Bcl-xL/Bax ratio in the presence of biochanin A, which led to a decrease in the apoptotic rate. These data demonstrate that mitochondria are involved in the protective effect of biochanin A against Abeta25-35 and that this drug attenuated Abeta25-35-induced PC12 cell injury and apoptosis by preventing mitochondrial dysfunction. Thus, biochanin A might raise a possibility as a potential therapeutic agent for Alzheimer's disease and other related neurodegenerative diseases. PMID- 27120594 TI - Piperlongumine Suppresses Proliferation of Human Oral Squamous Cell Carcinoma through Cell Cycle Arrest, Apoptosis and Senescence. AB - Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum L., in human OSCC cells. The effects of PL on cell proliferation, the cell cycle, apoptosis, senescence and reactive oxygen species (ROS) levels in human OSCC cells were investigated. PL effectively inhibited cell growth, caused cell cycle arrest and induced apoptosis and senescence in OSCC cells. Moreover, PL-mediated anti-human OSCC behavior was inhibited by an ROS scavenger N-acetyl-l-cysteine (NAC) treatment, suggesting that regulation of ROS was involved in the mechanism of the anticancer activity of PL. These findings suggest that PL suppresses tumor growth by regulating the cell cycle and inducing apoptosis and senescence and is a potential chemotherapy agent for human OSCC cells. PMID- 27120595 TI - TNFSF15 Inhibits Blood Retinal Barrier Breakdown Induced by Diabetes. AB - Tumor necrosis factor superfamily 15 (TNFSF15) is an endogenous neovascularization inhibitor and an important negative regulator of vascular homeostasis. This study aimed to explore the potential role of TNFSF15 in diabetic retinopathy. Vitreous TNFSF15 and VEGF levels in proliferative diabetic retinopathy (PDR) patients were detected by ELISA. Retinal expression of TNFSF15 and the content of tight junction proteins (TJPs) in rats were detected by immunohistochemistry and Western blot, respectively. The blood retinal barrier (BRB) permeability was evaluated using Evans Blue (EB) dye. The TNFSF15/VEGF ratio was decreased in the vitreous fluid of patients with PDR relative to the controls, even though the expression levels of TNFSF15 were higher. TNFSF15 was dramatically decreased one month later after diabetes induction (p < 0.001), and then increased three months later and thereafter. TNFSF15 treatment significantly protected the BRB in the diabetic animals. Diabetes decreased TJPs levels in the retina, and these changes were inhibited by TNFSF15 treatment. Moreover, TNFSF15 decreased activation of VEGF both in mRNA and protein levels caused by diabetes. These results indicate that TNFSF15 is an important inhibitor in the progression of DR and suggest that the regulation of TNFSF15 shows promise for the development of diabetic retinopathy treatment strategies. PMID- 27120597 TI - Glycated Albumin versus Glycated Hemoglobin as a Glycemic Indicator in Diabetic Patients on Peritoneal Dialysis. AB - Compared with glycated hemoglobin (HbA1c), glycated albumin (GA) is superior in estimating glycemic control in diabetic patients on hemodialysis (HD). However, the better index for assessment of glycemic control in diabetic patients on peritoneal dialysis (PD) and the impact of protein loss on GA are unknown. Twenty diabetic patients on HD were matched by age, sex, and baseline postprandial plasma glucose (PG) levels to 20 PD patients. PG, HbA1c, GA, and serum albumin levels were measured for six months. Protein loss in PD patients was estimated by measuring the protein concentration in the peritoneal dialysate and by 24 h urine collection. Although PG and HbA1c did not differ significantly between the groups, the PD group had significantly lower GA (17.8% versus 20.8%, p < 0.001) and GA/HbA1c ratio (2.95% versus 3.45%, p < 0.0001) than the HD group. Although the PG level correlated significantly with the GA levels in both groups, it was not correlated with the HbA1c levels in both groups. HbA1c level was negatively associated with erythropoiesis-stimulating agent (ESA) dose in both groups, whereas GA was not significantly associated with serum albumin, hemoglobin concentration, ESA dose, and protein loss. Multiple regression analysis identified GA as the only independent factor associated with PG in PD patients. Our results suggested that GA was not significantly associated with protein loss, hemoglobin, serum albumin, and ESA dose. Although GA might underestimate glycemic status, it provided a significantly better measure for estimating glycemic control than HbA1c, even in PD patients. PMID- 27120598 TI - The Opposite Effect of Metal Ions on Short-/Long-Range Water Structure: A Multiple Characterization Study. AB - Inorganic electrolyte solutions are very important in our society as they dominate many biochemical and geochemical processes. Herein, an in-depth study was performed to illustrate the ion-induced effect on water structure by coupling NMR, viscometer, Raman and Molecular Dynamic (MD) simulations. The NMR coefficient (BNMR) and diffusion coefficient (D) from NMR, and viscosity coefficient (Bvis) from a viscometer all proved that dissolved metal ions are capable of enhancing the association degree of adjacent water molecules, and the impact on water structure decreased in the order of Cr(3+) > Fe(3+) > Cu(2+) > Zn(2+). This regularity was further evidenced by Raman analysis; however, the deconvoluted Raman spectrum indicated the decrease in high association water with salt concentration and the increase in low association water before 200 mmol.L( 1). By virtue of MD simulations, the opposite changing manner proved to be the result of the opposite effect on short-/long-range water structure induced by metal ions. Our results may help to explain specific protein denaturation induced by metal ions. PMID- 27120599 TI - Secure and Cost-Effective Distributed Aggregation for Mobile Sensor Networks. AB - Secure data aggregation (SDA) schemes are widely used in distributed applications, such as mobile sensor networks, to reduce communication cost, prolong the network life cycle and provide security. However, most SDA are only suited for a single type of statistics (i.e., summation-based or comparison-based statistics) and are not applicable to obtaining multiple statistic results. Most SDA are also inefficient for dynamic networks. This paper presents multi functional secure data aggregation (MFSDA), in which the mapping step and coding step are introduced to provide value-preserving and order-preserving and, later, to enable arbitrary statistics support in the same query. MFSDA is suited for dynamic networks because these active nodes can be counted directly from aggregation data. The proposed scheme is tolerant to many types of attacks. The network load of the proposed scheme is balanced, and no significant bottleneck exists. The MFSDA includes two versions: MFSDA-I and MFSDA-II. The first one can obtain accurate results, while the second one is a more generalized version that can significantly reduce network traffic at the expense of less accuracy loss. PMID- 27120600 TI - VitiCanopy: A Free Computer App to Estimate Canopy Vigor and Porosity for Grapevine. AB - Leaf area index (LAI) and plant area index (PAI) are common and important biophysical parameters used to estimate agronomical variables such as canopy growth, light interception and water requirements of plants and trees. LAI can be either measured directly using destructive methods or indirectly using dedicated and expensive instrumentation, both of which require a high level of know-how to operate equipment, handle data and interpret results. Recently, a novel smartphone and tablet PC application, VitiCanopy, has been developed by a group of researchers from the University of Adelaide and the University of Melbourne, to estimate grapevine canopy size (LAI and PAI), canopy porosity, canopy cover and clumping index. VitiCanopy uses the front in-built camera and GPS capabilities of smartphones and tablet PCs to automatically implement image analysis algorithms on upward-looking digital images of canopies and calculates relevant canopy architecture parameters. Results from the use of VitiCanopy on grapevines correlated well with traditional methods to measure/estimate LAI and PAI. Like other indirect methods, VitiCanopy does not distinguish between leaf and non-leaf material but it was demonstrated that the non-leaf material could be extracted from the results, if needed, to increase accuracy. VitiCanopy is an accurate, user-friendly and free alternative to current techniques used by scientists and viticultural practitioners to assess the dynamics of LAI, PAI and canopy architecture in vineyards, and has the potential to be adapted for use on other plants. PMID- 27120596 TI - New Is Old, and Old Is New: Recent Advances in Antibiotic-Based, Antibiotic-Free and Ethnomedical Treatments against Methicillin-Resistant Staphylococcus aureus Wound Infections. AB - Staphylococcus aureus is the most common pathogen of wound infections. Thus far, methicillin-resistant S. aureus (MRSA) has become the major causative agent in wound infections, especially for nosocomial infections. MRSA infections are seldom eradicated by routine antimicrobial therapies. More concerning, some strains have become resistant to the newest antibiotics of last resort. Furthermore, horizontal transfer of a polymyxin resistance gene, mcr-1, has been identified in Enterobacteriaceae, by which resistance to the last group of antibiotics will likely spread rapidly. The worst-case scenario, "a return to the pre-antibiotic era", is likely in sight. A perpetual goal for antibiotic research is the discovery of an antibiotic that lacks resistance potential, such as the recent discovery of teixobactin. However, when considering the issue from an ecological and evolutionary standpoint, it is evident that it is insufficient to solve the antibiotic dilemma through the use of antibiotics themselves. In this review, we summarized recent advances in antibiotic-based, antibiotic-free and ethnomedical treatments against MRSA wound infections to identify new clues to solve the antibiotic dilemma. One potential solution is to use ethnomedical drugs topically. Some ethnomedical drugs have been demonstrated to be effective antimicrobials against MRSA. A decline in antibiotic resistance can therefore be expected, as has been demonstrated when antibiotic-free treatments were used to limit the use of antibiotics. It is also anticipated that these drugs will have low resistance potential, although there is only minimal evidence to support this claim to date. More clinical trials and animal tests should be conducted on this topic. PMID- 27120601 TI - HybridPLAY: A New Technology to Foster Outdoors Physical Activity, Verbal Communication and Teamwork. AB - This paper presents HybridPLAY, a novel technology composed of a sensor and mobile-based video games that transforms urban playgrounds into game scenarios. With this technology we aim to stimulate physical activity and playful learning by creating an entertaining environment in which users can actively participate and collaborate. HybridPLAY is different from other existing technologies that enhance playgrounds, as it is not integrated in them but can be attached to the different elements of the playgrounds, making its use more ubiquitous (i.e., not restricted to the playgrounds). HybridPLAY was born in 2007 as an artistic concept, and evolved after different phases of research and testing by almost 2000 users around the world (in workshops, artistic events, conferences, etc.). Here, we present the temporal evolution of HybridPLAY with the different versions of the sensors and the video games, and a detailed technical description of the sensors and the way interactions are produced. We also present the outcomes after the evaluation by users at different events and workshops. We believe that HybridPLAY has great potential to contribute to increased physical activity in kids, and also to improve the learning process and monitoring at school centres by letting users create the content of the apps, leading to new narratives and fostering creativity. PMID- 27120603 TI - Color-Space-Based Visual-MIMO for V2X Communication. AB - In this paper, we analyze the applicability of color-space-based, color independent visual-MIMO for V2X. We aim to achieve a visual-MIMO scheme that can maintain the original color and brightness while performing seamless communication. We consider two scenarios of GCM based visual-MIMO for V2X. One is a multipath transmission using visual-MIMO networking and the other is multi-node V2X communication. In the scenario of multipath transmission, we analyze the channel capacity numerically and we illustrate the significance of networking information such as distance, reference color (symbol), and multiplexing diversity mode transitions. In addition, in the V2X scenario of multiple access, we may achieve the simultaneous multiple access communication without node interferences by dividing the communication area using image processing. Finally, through numerical simulation, we show the superior SER performance of the visual MIMO scheme compared with LED-PD communication and show the numerical result of the GCM based visual-MIMO channel capacity versus distance. PMID- 27120602 TI - Sensor Monitoring of Physical Activity to Improve Glucose Management in Diabetic Patients: A Review. AB - Diabetic individuals need to tightly control their blood glucose concentration. Several methods have been developed for this purpose, such as the finger-prick or continuous glucose monitoring systems (CGMs). However, these methods present the disadvantage of being invasive. Moreover, CGMs have limited accuracy, notably to detect hypoglycemia. It is also known that physical exercise, and even daily activity, disrupt glucose dynamics and can generate problems with blood glucose regulation during and after exercise. In order to deal with these challenges, devices for monitoring patients' physical activity are currently under development. This review focuses on non-invasive sensors using physiological parameters related to physical exercise that were used to improve glucose monitoring in type 1 diabetes (T1DM) patients. These devices are promising for diabetes management. Indeed they permit to estimate glucose concentration either based solely on physical activity parameters or in conjunction with CGM or non invasive CGM (NI-CGM) systems. In these last cases, the vital signals are used to modulate glucose estimations provided by the CGM and NI-CGM devices. Finally, this review indicates possible limitations of these new biosensors and outlines directions for future technologic developments. PMID- 27120604 TI - Electromyographic Patterns during Golf Swing: Activation Sequence Profiling and Prediction of Shot Effectiveness. AB - This study analyzes muscle activity, recorded in an eight-channel electromyographic (EMG) signal stream, during the golf swing using a 7-iron club and exploits information extracted from EMG dynamics to predict the success of the resulting shot. Muscles of the arm and shoulder on both the left and right sides, namely flexor carpi radialis, extensor digitorum communis, rhomboideus and trapezius, are considered for 15 golf players (~5 shots each). The method using Gaussian filtering is outlined for EMG onset time estimation in each channel and activation sequence profiling. Shots of each player revealed a persistent pattern of muscle activation. Profiles were plotted and insights with respect to player effectiveness were provided. Inspection of EMG dynamics revealed a pair of highest peaks in each channel as the hallmark of golf swing, and a custom application of peak detection for automatic extraction of swing segment was introduced. Various EMG features, encompassing 22 feature sets, were constructed. Feature sets were used individually and also in decision-level fusion for the prediction of shot effectiveness. The prediction of the target attribute, such as club head speed or ball carry distance, was investigated using random forest as the learner in detection and regression tasks. Detection evaluates the personal effectiveness of a shot with respect to the player-specific average, whereas regression estimates the value of target attribute, using EMG features as predictors. Fusion after decision optimization provided the best results: the equal error rate in detection was 24.3% for the speed and 31.7% for the distance; the mean absolute percentage error in regression was 3.2% for the speed and 6.4% for the distance. Proposed EMG feature sets were found to be useful, especially when used in combination. Rankings of feature sets indicated statistics for muscle activity in both the left and right body sides, correlation-based analysis of EMG dynamics and features derived from the properties of two highest peaks as important predictors of personal shot effectiveness. Activation sequence profiles helped in analyzing muscle orchestration during golf shot, exposing a specific avalanche pattern, but data from more players are needed for stronger conclusions. Results demonstrate that information arising from an EMG signal stream is useful for predicting golf shot success, in terms of club head speed and ball carry distance, with acceptable accuracy. Surface EMG data, collected with a goal to automatically evaluate golf player's performance, enables wearable computing in the field of ambient intelligence and has potential to enhance exercising of a long carry distance drive. PMID- 27120606 TI - Healthcare4VideoStorm: Making Smart Decisions Based on Storm Metrics. AB - Storm-based stream processing is widely used for real-time large-scale distributed processing. Knowing the run-time status and ensuring performance is critical to providing expected dependability for some applications, e.g., continuous video processing for security surveillance. The existing scheduling strategies' granularity is too coarse to have good performance, and mainly considers network resources without computing resources while scheduling. In this paper, we propose Healthcare4Storm, a framework that finds Storm insights based on Storm metrics to gain knowledge from the health status of an application, finally ending up with smart scheduling decisions. It takes into account both network and computing resources and conducts scheduling at a fine-grained level using tuples instead of topologies. The comprehensive evaluation shows that the proposed framework has good performance and can improve the dependability of the Storm-based applications. PMID- 27120605 TI - Unsupervised Event Characterization and Detection in Multichannel Signals: An EEG application. AB - In this paper, we propose a new unsupervised method to automatically characterize and detect events in multichannel signals. This method is used to identify artifacts in electroencephalogram (EEG) recordings of brain activity. The proposed algorithm has been evaluated and compared with a supervised method. To this end an example of the performance of the algorithm to detect artifacts is shown. The results show that although both methods obtain similar classification, the proposed method allows detecting events without training data and can also be applied in signals whose events are unknown a priori. Furthermore, the proposed method provides an optimal window whereby an optimal detection and characterization of events is found. The detection of events can be applied in real-time. PMID- 27120607 TI - Remote Evaluation of Rotational Velocity Using a Quadrant Photo-Detector and a DSC Algorithm. AB - This paper presents an approach to remotely evaluate the rotational velocity of a measured object by using a quadrant photo-detector and a differential subtraction correlation (DSC) algorithm. The rotational velocity of a rotating object is determined by two temporal-delay numbers at the minima of two DSCs that are derived from the four output signals of the quadrant photo-detector, and the sign of the calculated rotational velocity directly represents the rotational direction. The DSC algorithm does not require any multiplication operations. Experimental calculations were performed to confirm the proposed evaluation method. The calculated rotational velocity, including its amplitude and direction, showed good agreement with the given one, which had an amplitude error of ~0.3%, and had over 1100 times the efficiency of the traditional cross correlation method in the case of data number N > 4800. The confirmations have shown that the remote evaluation of rotational velocity can be done without any circular division disk, and that it has much fewer error sources, making it simple, accurate and effective for remotely evaluating rotational velocity. PMID- 27120608 TI - Perceived Indoor Environment and Occupants' Comfort in European "Modern" Office Buildings: The OFFICAIR Study. AB - Indoor environmental conditions (thermal, noise, light, and indoor air quality) may affect workers' comfort, and consequently their health and well-being, as well as their productivity. This study aimed to assess the relations between perceived indoor environment and occupants' comfort, and to examine the modifying effects of both personal and building characteristics. Within the framework of the European project OFFICAIR, a questionnaire survey was administered to 7441 workers in 167 "modern" office buildings in eight European countries (Finland, France, Greece, Hungary, Italy, The Netherlands, Portugal, and Spain). Occupants assessed indoor environmental quality (IEQ) using both crude IEQ items (satisfaction with thermal comfort, noise, light, and indoor air quality), and detailed items related to indoor environmental parameters (e.g., too hot/cold temperature, humid/dry air, noise inside/outside, natural/artificial light, odor) of their office environment. Ordinal logistic regression analyses were performed to assess the relations between perceived IEQ and occupants' comfort. The highest association with occupants' overall comfort was found for "noise", followed by "air quality", "light" and "thermal" satisfaction. Analysis of detailed parameters revealed that "noise inside the buildings" was highly associated with occupants' overall comfort. "Layout of the offices" was the next parameter highly associated with overall comfort. The relations between IEQ and comfort differed by personal characteristics (gender, age, and the Effort Reward Imbalance index), and building characteristics (office type and building's location). Workplace design should take into account both occupant and the building characteristics in order to provide healthier and more comfortable conditions to their occupants. PMID- 27120609 TI - The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis. AB - There is a largely divergent body of literature regarding the relationship between Epstein-Barr virus (EBV) infection and brain inflammation in multiple sclerosis (MS). Here, we tested MS patients during relapse (n = 11) and in remission (n = 19) in addition to n = 22 healthy controls to study the correlation between the EBV- and brain-specific B cell response in the blood by enzyme-linked immunospot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). Cytomegalovirus (CMV) was used as a control antigen tested in n = 16 MS patients during relapse and in n = 35 patients in remission. Over the course of the study, n = 16 patients were untreated, while n = 33 patients received immunomodulatory therapy. The data show that there was a moderate correlation between the frequencies of EBV- and brain-reactive B cells in MS patients in remission. In addition we could detect a correlation between the B cell response to EBV and disease activity. There was no evidence of an EBV reactivation. Interestingly, there was also a correlation between the frequencies of CMV- and brain-specific B cells in MS patients experiencing an acute relapse and an elevated B cell response to CMV was associated with higher disease activity. The trend remained when excluding seronegative subjects but was non-significant. These data underline that viral infections might impact the immunopathology of MS, but the exact link between the two entities remains subject of controversy. PMID- 27120611 TI - Development of a Triple-Color Pseudovirion-Based Assay to Detect Neutralizing Antibodies against Human Papillomavirus. AB - Pseudovirion-based neutralization assay is considered the gold standard method for evaluating the immune response to human papillomavirus (HPV) vaccines. In this study, we developed a multicolor neutralization assay to simultaneously detect the neutralizing antibodies against different HPV types. FluoroSpot was used to interpret the fluorescent protein expression instead of flow cytometry. The results of FluoroSpot and flow cytometry showed good consistency, with R2 > 0.98 for the log-transformed IC50 values. Regardless of the reporter color, the single-, dual-, and triple-color neutralization assays reported identical results for the same samples. In low-titer samples from naturally HPV-infected individuals, there was strong agreement between the single- and triple-color assays, with kappa scores of 0.92, 0.89, and 0.96 for HPV16, HPV18, and HPV58, respectively. Good reproducibility was observed for the triple-color assay, with coefficients of variation of 2.0%-41.5% within the assays and 8.3%-36.2% between the assays. Three triple-color systems, HPV16-18-58, HPV6-33-45, and HPV11-31-52, were developed that could evaluate the immunogenicity of a nonavalent vaccine in three rounds of the assay. With the advantages of an easy-to-use procedure and less sample consumption, the multiple-color assay is more suitable than classical assays for large sero-epidemiological studies and clinical trials and is more amenable to automation. PMID- 27120610 TI - Glutamic Acid Residues in HIV-1 p6 Regulate Virus Budding and Membrane Association of Gag. AB - The HIV-1 Gag p6 protein regulates the final abscission step of nascent virions from the cell membrane by the action of its two late (L-) domains, which recruit Tsg101 and ALIX, components of the ESCRT system. Even though p6 consists of only 52 amino acids, it is encoded by one of the most polymorphic regions of the HIV-1 gag gene and undergoes various posttranslational modifications including sumoylation, ubiquitination, and phosphorylation. In addition, it mediates the incorporation of the HIV-1 accessory protein Vpr into budding virions. Despite its small size, p6 exhibits an unusually high charge density. In this study, we show that mutation of the conserved glutamic acids within p6 increases the membrane association of Pr55 Gag followed by enhanced polyubiquitination and MHC I antigen presentation of Gag-derived epitopes, possibly due to prolonged exposure to membrane bound E3 ligases. The replication capacity of the total glutamic acid mutant E0A was almost completely impaired, which was accompanied by defective virus release that could not be rescued by ALIX overexpression. Altogether, our data indicate that the glutamic acids within p6 contribute to the late steps of viral replication and may contribute to the interaction of Gag with the plasma membrane. PMID- 27120612 TI - Association between Dietary Patterns and the Risk of Hypertension among Chinese: A Cross-Sectional Study. AB - Epidemiological studies of different dietary patterns and the risk of hypertension among a middle-aged Chinese population remain extremely scare. Thus, the aim of this study was to identify dietary patterns and investigate the relationship between dietary patterns and the risk of hypertension among Chinese adults aged 45-60 years. The present cross-sectional study includes 2560 participants who reported their dietary intake using a validated food frequency questionnaire (FFQ). Dietary patterns were identified using factor analysis. Anthropometric measurements were obtained using standardized procedures. We used log-binomial regression analysis to examine the associations between dietary patterns and hypertension risk. Four major dietary patterns were identified and labeled as traditional Chinese, animal food, western fast-food, and high-salt patterns. After adjusting for potential confounders, participants in the highest quartile of animal food pattern scores had a greater prevalence ratio (PR) for hypertension (PR = 1.26; 95% confidence interval (CI): 1.064-1.727; p < 0.05) in comparison to those from the lowest quartile. Compared with the lowest quartile of high-salt pattern, the highest quartile had a higher prevalence ratio for hypertension (PR = 1.12; 95% CI: 1.013-1.635; p < 0.05). CONCLUSIONS: Our findings indicated that animal food and high-salt patterns were associated with increased risk of hypertension, while traditional Chinese and western fast-food patterns were not associated with the risk of hypertension. Further prospective studies are warranted to confirm these findings. PMID- 27120613 TI - Literature Review and Meta-Analysis on Micronutrient Fortified Condiments and Noodles: Reduction of Anemia in Children and Adults. PMID- 27120614 TI - The Association between Sweet Taste Function, Anthropometry, and Dietary Intake in Adults. AB - Variation in ability to detect, recognize, and perceive sweetness may influence food consumption, and eventually chronic nutrition-related conditions such as overweight and obesity. The aim of this study was to investigate the associations between sweet taste function, anthropometry, and dietary intake in adults. Participants' (n = 60; mean age in years = 26, SD = +/-7.8) sweet taste function for a range of sweeteners (glucose, fructose, sucrose, sucralose, erythritol, and Rebaudioside A) was assessed by measuring detection and recognition thresholds and sweetness intensity. Height, weight, and waist circumference were also measured, and participants also completed a Food Frequency Questionnaire. There was large inter-individual variation in detection, recognition and sweetness intensity measures. Pearson's correlation coefficient revealed no robust correlations between measures of sweet taste function, anthropometry, and dietary intake, with the exception of suprathreshold intensity, which was moderately correlated with total energy intake (r = 0.23-0.40). One-way analysis of variance revealed no significant differences between the most and least sensitive participants in terms of BMI, waist circumference, and dietary intake for all measures of sweet taste function and sweeteners (all p > 0.01). When stratified into BMI categories, there were no significant differences in any measure of sweet taste function between the normal weight and overweight/obese participants (all p > 0.01). Results show that that sweet taste function is not associated with anthropometry and sweetness intensity measures are the most appropriate measure when assessing links between sweet taste and food consumption. PMID- 27120615 TI - Cocoa Diet Prevents Antibody Synthesis and Modifies Lymph Node Composition and Functionality in a Rat Oral Sensitization Model. AB - Cocoa powder, a rich source of polyphenols, has shown immunomodulatory properties in both the intestinal and systemic immune compartments of rats. The aim of the current study was to establish the effect of a cocoa diet in a rat oral sensitization model and also to gain insight into the mesenteric lymph nodes (MLN) activities induced by this diet. To achieve this, three-week-old Lewis rats were fed either a standard diet or a diet with 10% cocoa and were orally sensitized with ovalbumin (OVA) and with cholera toxin as a mucosal adjuvant. Specific antibodies were quantified, and lymphocyte composition, gene expression, and cytokine release were established in MLN. The development of anti-OVA antibodies was almost totally prevented in cocoa-fed rats. In addition, this diet increased the proportion of TCRgammadelta+ and CD103+CD8+ cells and decreased the proportion of CD62L+CD4+ and CD62L+CD8+ cells in MLN, whereas it upregulated the gene expression of OX40L, CD11c, and IL-1beta and downregulated the gene expression of IL-17alpha. In conclusion, the cocoa diet induced tolerance in an oral sensitization model accompanied by changes in MLN that could contribute to this effect, suggesting its potential implication in the prevention of food allergies. PMID- 27120616 TI - Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Alleviates Doxorubicin-Induced Depressive-Like Behaviors and Neurotoxicity in Rats: Involvement of Oxidative Stress and Neuroinflammation. AB - Doxorubicin (DOX) is a chemotherapeutic agent widely used in human malignancies. Its long-term use can cause neurobiological side-effects associated with depression. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), the essential fatty acids found in fish oil, possess neuroprotecitve and antidepressant activities. Thus, the aim of this study was to explore the potential protective effects of omega-3 PUFAs against DOX-induced behavioral changes and neurotoxicity. omega-3 PUFAs were given daily by gavage (1.5 g/kg) over three weeks starting seven days before DOX administration (2.5 mg/kg). Open-field test (OFT) and forced swimming test (FST) were conducted to assess exploratory activity and despair behavior, respectively. Our data showed that omega-3 PUFAs supplementation significantly mitigated the behavioral changes induced by DOX. omega-3 PUFAs pretreatment also alleviated the DOX-induced neural apoptosis. Meanwhile, omega-3 PUFAs treatment ameliorated DOX-induced oxidative stress in the prefrontal cortex and hippocampus. Additionally, gene expression of pro inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha, and the protein levels of NF-kappaB and iNOS were significantly increased in brain tissues of DOX treated group, whereas omega-3 PUFAs supplementation significantly attenuated DOX induced neuroinflammation. In conclusion, omega-3 PUFAs can effectively protect against DOX-induced depressive-like behaviors, and the mechanisms underlying the neuroprotective effect are potentially associated with its anti-oxidant, anti inflammatory, and anti-apoptotic properties. PMID- 27120617 TI - Dietary Capsaicin Protects Cardiometabolic Organs from Dysfunction. AB - Chili peppers have a long history of use for flavoring, coloring, and preserving food, as well as for medical purposes. The increased use of chili peppers in food is very popular worldwide. Capsaicin is the major pungent bioactivator in chili peppers. The beneficial effects of capsaicin on cardiovascular function and metabolic regulation have been validated in experimental and population studies. The receptor for capsaicin is called the transient receptor potential vanilloid subtype 1 (TRPV1). TRPV1 is ubiquitously distributed in the brain, sensory nerves, dorsal root ganglia, bladder, gut, and blood vessels. Activation of TRPV1 leads to increased intracellular calcium signaling and, subsequently, various physiological effects. TRPV1 is well known for its prominent roles in inflammation, oxidation stress, and pain sensation. Recently, TRPV1 was found to play critical roles in cardiovascular function and metabolic homeostasis. Experimental studies demonstrated that activation of TRPV1 by capsaicin could ameliorate obesity, diabetes, and hypertension. Additionally, TRPV1 activation preserved the function of cardiometabolic organs. Furthermore, population studies also confirmed the beneficial effects of capsaicin on human health. The habitual consumption of spicy foods was inversely associated with both total and certain causes of specific mortality after adjustment for other known or potential risk factors. The enjoyment of spicy flavors in food was associated with a lower prevalence of obesity, type 2 diabetes, and cardiovascular diseases. These results suggest that capsaicin and TRPV1 may be potential targets for the management of cardiometabolic vascular diseases and their related target organs dysfunction. PMID- 27120618 TI - The Octyl Ester of Ginsenoside Rh2 Induces Lysosomal Membrane Permeabilization via Bax Translocation. AB - Ginsenoside Rh2 is a potential pharmacologically active metabolite of ginseng. Previously, we have reported that an octyl ester derivative of ginsenoside Rh2 (Rh2-O), has been confirmed to possess higher bioavailability and anticancer effect than Rh2 in vitro. In order to better assess the possibility that Rh2-O could be used as an anticancer compound, the underlying mechanism was investigated in this study. The present results revealed that lysosomal destabilization was involved in the early stage of cell apoptosis in HepG2 cells induced by Rh2-O. Rh2-O could induce an early lysosomal membrane permeabilization with the release of lysosomal protease cathepsins to the cytosol in HepG2 cells. The Cat B inhibitor (leu) and Cat D inhibitor (pepA) inhibited Rh2-O-induced HepG2 apoptosis as well as tBid production and Deltaphim depolarization, indicating that lysosomal permeabilization occurred upstream of mitochondrial dysfunction. In addition, Rh2-O induced a significant increase in the protein levels of DRAM1 and Bax (p < 0.05) in lysosomes of HepG2 cells. Knockdown of Bax partially inhibited Rh2-O-induced Cat D release from lysosomes. Thus it was concluded that Rh2-O induced apoptosis of HepG2 cells through activation of the lysosomal-mitochondrial apoptotic pathway involving the translocation of Bax to the lysosome. PMID- 27120619 TI - A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions. AB - Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs' function that have underscored the importance of these proteins in physiological and pathological processes over the years. PMID- 27120620 TI - Dynamic Duo-The Salmonella Cytolethal Distending Toxin Combines ADP Ribosyltransferase and Nuclease Activities in a Novel Form of the Cytolethal Distending Toxin. AB - The cytolethal distending toxin (CDT) is a well characterized bacterial genotoxin encoded by several Gram-negative bacteria, including Salmonella enterica (S. enterica). The CDT produced by Salmonella (S-CDT) differs from the CDT produced by other bacteria, as it utilizes subunits with homology to the pertussis and subtilase toxins, in place of the traditional CdtA and CdtC subunits. Previously, S-CDT was thought to be a unique virulence factor of S. enterica subspecies enterica serotype Typhi, lending to its classification as the "typhoid toxin." Recently, this important virulence factor has been identified and characterized in multiple nontyphoidal Salmonella (NTS) serotypes as well. The significance of S-CDT in salmonellosis with regards to the: (i) distribution of S-CDT encoding genes among NTS serotypes, (ii) contributions to pathogenicity, (iii) regulation of S-CDT expression, and (iv) the public health implication of S-CDT as it relates to disease severity, are reviewed here. PMID- 27120622 TI - A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy. AB - ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient. PMID- 27120621 TI - Role of Intermediate Filaments in Vesicular Traffic. AB - Intermediate filaments are an important component of the cellular cytoskeleton. The first established role attributed to intermediate filaments was the mechanical support to cells. However, it is now clear that intermediate filaments have many different roles affecting a variety of other biological functions, such as the organization of microtubules and microfilaments, the regulation of nuclear structure and activity, the control of cell cycle and the regulation of signal transduction pathways. Furthermore, a number of intermediate filament proteins have been involved in the acquisition of tumorigenic properties. Over the last years, a strong involvement of intermediate filament proteins in the regulation of several aspects of intracellular trafficking has strongly emerged. Here, we review the functions of intermediate filaments proteins focusing mainly on the recent knowledge gained from the discovery that intermediate filaments associate with key proteins of the vesicular membrane transport machinery. In particular, we analyze the current understanding of the contribution of intermediate filaments to the endocytic pathway. PMID- 27120624 TI - Basing Turkey Lighting Programs on Broiler Research: A Good Idea? A Comparison of 18 Daylength Effects on Broiler and Turkey Welfare. AB - Daylength used as a management tool has powerful implications on the welfare of both broilers and turkeys. Near-constant light results in many detrimental impacts, including lack of behavioural rhythms and circadian melatonin rhythms. Both are suggestive that sleep fragmentation could result in birds reared on long photoperiods, which can lead to the same negative health and physiological responses as total sleep deprivation. An indirect comparison of the welfare implications of graded levels of daylength on broilers and turkeys clearly indicate that long daylengths depress welfare by increasing mortality, reducing mobility, increasing ocular pathologies and changing behaviour in both species. Furthermore, long daylengths change melatonin secretion patterns and eliminate behavioural and melatonin circadian rhythms, which were measured in broilers in these works. However, feather pecking in turkeys was reduced when birds were exposed to long daylengths. Exactly how much darkness should be included in a management program to maximize welfare will depend on the species, the age of marketing, and in turkeys, bird gender. PMID- 27120623 TI - Pheromone Autodetection: Evidence and Implications. AB - Olfactory communication research with insects utilizing sex pheromones has focused on the effects of pheromones on signal receivers. Early pheromone detection studies using the silkworm moth, Bombyx mori L., and Saturniids led to the assumption that emitters, especially females, are unable to detect their own pheromone. Pheromone anosmia, i.e., the inability of females to detect their conspecific sex pheromone, was often assumed, and initially little attention was paid to female behaviors that may result from autodetection, i.e., the ability of females to detect their sex pheromone. Detection of conspecific pheromone plumes from nearby females may provide information to improve chances of mating success and progeny survival. Since the first documented example in 1972, numerous occurrences of autodetection have been observed and verified in field and laboratory studies. We summarize here a significant portion of research relating to autodetection. Electrophysiological and behavioral investigations, as well as expression patterns of proteins involved in pheromone autodetection are included. We discuss problems inherent in defining a boundary between sex and aggregation pheromones considering the occurrence of autodetection, and summarize hypothesized selection pressures favoring autodetection. Importance of including autodetection studies in future work is emphasized by complications arising from a lack of knowledge combined with expanding the use of pheromones in agriculture. PMID- 27120625 TI - Cecil: A Moment or a Movement? Analysis of Media Coverage of the Death of a Lion, Panthera leo. AB - The killing of a satellite-tagged male lion by a trophy hunter in Zimbabwe in July 2015 provoked an unprecedented media reaction. We analyse the global media response to the trophy hunting of the lion, nicknamed "Cecil", a study animal in a long-term project run by Oxford University's Wildlife Conservation Research Unit (WildCRU). We collaborated with a media-monitoring company to investigate the development of the media coverage spatially and temporally. Relevant articles were identified using a Boolean search for the terms Cecil AND lion in 127 languages. Stories about Cecil the Lion in the editorial media increased from approximately 15 per day to nearly 12,000 at its peak, and mentions of Cecil the Lion in social media reached 87,533 at its peak. We found that, while there were clear regional differences in the level of media saturation of the Cecil story, the patterns of the development of the coverage of this story were remarkably similar across the globe, and that there was no evidence of a lag between the social media and the editorial media. Further, all the main social media platforms appeared to react in synchrony. This story appears to have spread synchronously across media channels and geographically across the globe over the span of about two days. For lion conservation in particular, and perhaps for wildlife conservation more generally, we speculate that the atmosphere may have been changed significantly. We consider the possible reasons why this incident provoked a reaction unprecedented in the conservation sector. PMID- 27120626 TI - Treatment of Established Status Epilepticus. AB - Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non convulsive ESE. PMID- 27120628 TI - Accurate Measurement of the in vivo Ammonium Concentration in Saccharomyces cerevisiae. AB - Ammonium (NH4+) is the most common N-source for yeast fermentations, and N limitation is frequently applied to reduce growth and increase product yields. While there is significant molecular knowledge on NH4+ transport and assimilation, there have been few attempts to measure the in vivo concentration of this metabolite. In this article, we present a sensitive and accurate analytical method to quantify the in vivo intracellular ammonium concentration in Saccharomyces cerevisiae based on standard rapid sampling and metabolomics techniques. The method validation experiments required the development of a proper sample processing protocol to minimize ammonium production/consumption during biomass extraction by assessing the impact of amino acid degradation-an element that is often overlooked. The resulting cold chloroform metabolite extraction method, together with quantification using ultra high performance liquid chromatography-isotope dilution mass spectrometry (UHPLC-IDMS), was not only more sensitive than most of the existing methods but also more accurate than methods that use electrodes, enzymatic reactions, or boiling water or boiling ethanol biomass extraction because it minimized ammonium consumption/production during sampling processing and interference from other metabolites in the quantification of intracellular ammonium. Finally, our validation experiments showed that other metabolites such as pyruvate or 2-oxoglutarate (alphaKG) need to be extracted with cold chloroform to avoid measurements being biased by the degradation of other metabolites (e.g., amino acids). PMID- 27120627 TI - Current-Induced Transistor Sensorics with Electrogenic Cells. AB - The concepts of transistor recording of electroactive cells are considered, when the response is determined by a current-induced voltage in the electrolyte due to cellular activity. The relationship to traditional transistor recording, with an interface-induced response due to interactions with the open gate oxide, is addressed. For the geometry of a cell-substrate junction, the theory of a planar core-coat conductor is described with a one-compartment approximation. The fast electrical relaxation of the junction and the slow change of ion concentrations are pointed out. On that basis, various recording situations are considered and documented by experiments. For voltage-gated ion channels under voltage clamp, the effects of a changing extracellular ion concentration and the enhancement/depletion of ion conductances in the adherent membrane are addressed. Inhomogeneous ion conductances are crucial for transistor recording of neuronal action potentials. For a propagating action potential, the effects of an axon substrate junction and the surrounding volume conductor are distinguished. Finally, a receptor-transistor-sensor is described, where the inhomogeneity of a ligand-activated ion conductance is achieved by diffusion of the agonist and inactivation of the conductance. Problems with regard to a development of reliable biosensors are mentioned. PMID- 27120629 TI - Surface-to-surface biofilm transfer: a quick and reliable startup strategy for mixed culture microbial fuel cells. AB - The startup of microbial fuel cells (MFCs) is known to be prone to failure or result in erratic performance impeding the research. The aim of this study was to advise a quick launch strategy for laboratory-scale MFCs that ensures steady operation performance in a short period of time. Different startup strategies were investigated and compared with membraneless single chamber MFCs. A direct surface-to-surface biofilm transfer (BFT) in an operating MFC proved to be the most efficient method. It provided steady power densities of 163 +/- 13 mWm(-2) 4 days after inoculation compared to 58 +/- 15 mWm(-2) after 30 days following a conventional inoculation approach. The in situ BFT eliminates the need for microbial acclimation during startup and reduces performance fluctuations caused by shifts in microbial biodiversity. Anaerobic pretreatment of the substrate and addition of suspended enzymes from an operating MFC into the new MFC proved to have a beneficial effect on startup and subsequent operation. Polarization methods were applied to characterize the startup phase and the steady state operation in terms of power densities, internal resistance and power overshoot during biofilm maturation. Applying this method a well-working MFC can be multiplied into an array of identically performing MFCs. PMID- 27120630 TI - Treatment of natural rubber processing wastewater using a combination system of a two-stage up-flow anaerobic sludge blanket and down-flow hanging sponge system. AB - A pilot-scale experiment of natural rubber processing wastewater treatment was conducted using a combination system consisting of a two-stage up-flow anaerobic sludge blanket (UASB) and a down-flow hanging sponge (DHS) reactor for more than 10 months. The system achieved a chemical oxygen demand (COD) removal efficiency of 95.7% +/- 1.3% at an organic loading rate of 0.8 kg COD/(m(3).d). Bacterial activity measurement of retained sludge from the UASB showed that sulfate reducing bacteria (SRB), especially hydrogen-utilizing SRB, possessed high activity compared with methane-producing bacteria (MPB). Conversely, the acetate utilizing activity of MPB was superior to SRB in the second stage of the reactor. The two-stage UASB-DHS system can reduce power consumption by 95% and excess sludge by 98%. In addition, it is possible to prevent emissions of greenhouse gases (GHG), such as methane, using this system. Furthermore, recovered methane from the two-stage UASB can completely cover the electricity needs for the operation of the two-stage UASB-DHS system, accounting for approximately 15% of the electricity used in the natural rubber manufacturing process. PMID- 27120631 TI - Development of a simplified urban water balance model (WABILA). AB - During the last decade, water sensitive urban design (WSUD) has become more and more accepted. However, there is not any simple tool or option available to evaluate the influence of these measures on the local water balance. To counteract the impact of new settlements, planners focus on mitigating increases in runoff through installation of infiltration systems. This leads to an increasing non-natural groundwater recharge and decreased evapotranspiration. Simple software tools which evaluate or simulate the effect of WSUD on the local water balance are still needed. The authors developed a tool named WABILA (Wasserbilanz) that could support planners for optimal WSUD. WABILA is an easy-to use planning tool that is based on simplified regression functions for established measures and land covers. Results show that WSUD has to be site specific, based on climate conditions and the natural water balance. PMID- 27120632 TI - Absorption and decomposition of ozone in a three-phase split-rectangular airlift reactor under ultrasonic irradiation. AB - Ozone absorption was investigated in a three-phase split-rectangular airlift reactor under ultrasonic irradiation using gamma-Al2O3 as catalyst. The reactor consisted of a square column (50 * 50 mm) with the height of 120 mm, divided into a riser and a downcomer by a baffle, 50 mm in width, 4 mm in thickness and 50 mm in total height. An absorption kinetic model was proposed to determine the volumetric mass transfer coefficient of ozone kLaA. The results showed that kLaA increased from 0.409 to 0.712 min(-1) as power density rose from 27.2 to 100.3 W L(-1), comparing with 0.242 min(-1) in the absence of ultrasonic irradiation. The increase in gas flow rate and catalyst loading also favored the increase of kLaA. The degassing effect due to ultrasonic irradiation could be ignored in the ozone absorption process. PMID- 27120633 TI - Copper-spent activated carbon as a heterogeneous peroxydisulfate catalyst for the degradation of Acid Orange 7 in an electrochemical reactor. AB - The exhausted activated carbon generated from the adsorption of heavy metal wastewater needs further treatment/disposal. In this study, a new application of copper-spent activated carbon (Cu-AC) was proposed. Cu-AC was used to activate peroxydisulfate (PDS) for the decolorization of Acid Orange 7 (AO7) and electrical current was introduced to enhance the process. The decolorization followed a pseudo-first-order kinetic pattern well (R(2) > 0.95). 92.4% of color removal at 60 min and 38.3% of total organic carbon removal at 180 min were achieved when initial pH value was 9.0, current density was 16 mA/cm(2), PDS concentration was 5 mM and Cu-AC dosage was 0.25 g/L. The radical scavengers including methanol, tert-butanol and phenol, as well as electron paramagnetic resonance test, were employed to investigate the oxidizing species responsible for AO7 decolorization. The stability of Cu-AC was confirmed by three recycle experiments. PMID- 27120634 TI - Application of forward osmosis membrane technology for oil sands process-affected water desalination. AB - The extraction process used to obtain bitumen from the oil sands produces large volumes of oil sands process-affected water (OSPW). As a newly emerging desalination technology, forward osmosis (FO) has shown great promise in saving electrical power requirements, increasing water recovery, and minimizing brine discharge. With the support of this funding, a FO system was constructed using a cellulose triacetate FO membrane to test the feasibility of OSPW desalination and contaminant removal. The FO systems were optimized using different types and concentrations of draw solution. The FO system using 4 M NH4HCO3 as a draw solution achieved 85% water recovery from OSPW, and 80 to 100% contaminant rejection for most metals and ions. A water backwash cleaning method was applied to clean the fouled membrane, and the cleaned membrane achieved 77% water recovery, a performance comparable to that of new FO membranes. This suggests that the membrane fouling was reversible. The FO system developed in this project provides a novel and energy efficient strategy to remediate the tailings waters generated by oil sands bitumen extraction and processing. PMID- 27120635 TI - Virulence determinants and production of extracellular enzymes in Enterococcus spp. from surface water sources. AB - Virulence factors in Enterococcus may be indicative of potential pathogenicity. The aim of this study was to determine the relationship between the presence of clinically relevant virulence genes, in Enterococcus spp. from environmental water, and their in vitro expression. One hundred and twenty-four Enterococcus isolates (seven species), from five surface water systems in the North West Province, South Africa, were screened for the presence of asa1, cylA, esp, gelE and hyl using polymerase chain reaction. The expression of cylA, hyl and gelE was determined by phenotypic assessments. Sixty-five percent of the isolates were positive for one virulence gene and 13% for two or more. Most frequently detected genes were gelE (32%) and cylA (28%). Enterococcal surface protein was absent in all isolates screened. The presence of virulence genes was correlated with their extracellular enzyme production. The results show that a large percentage of these environmental Enterococcus spp. possess virulence factors that could be expressed in vitro. This is a cause for concern and could have implications for individuals using this water for recreational and cultural purposes. Further investigation is required into the sources of these potential pathogenic Enterococcus isolates and measures to minimize their presence in water sources. PMID- 27120636 TI - Comparative study on toxicity evaluation of anaerobically treated parboiled rice manufacturing wastewater through fish bioassay. AB - Short term aquatic bioassay has been developed into a useful tool in water quality management. These tests give information on comparative toxicity of several compounds. The objective of this study was to evaluate the acute toxicity of raw and anaerobically treated effluents of the parboiled rice manufacturing industry. The acute toxicity test was carried out by using the fish Lebistes reticulatus under laboratory conditions. LC50 values for 24, 48, 72 and 96 hours ranged between 4.6 and 7.0% for the raw parboiled rice manufacturing wastewater. Two anaerobic fixed film fixed bed reactors and two different media matrices, i.e. UV stabilized Biopac media and Fugino spirals, were used for the treatment of parboiled rice mill wastewater. Effluents from these two reactors depicted LC50 values in the range of 68-88% and 62-78% for Biopac and Fugino spiral packed reactors, respectively. From the results, it is evident that anaerobically treated effluents from Biopac packed reactor is marginally better than Fugino spiral packed reactor. Results subjected to statistical evaluation depicted regression coefficient of more than 0.9 indicating good correlation between the mortality and effluent concentration. PMID- 27120637 TI - Nested-PCR and TaqMan real-time quantitative PCR assays for human adenoviruses in environmental waters. AB - Human adenovirus (HAdV) infections can occur throughout the year. Cases of HAdV associated respiratory disease have been more common in the late winter, spring, and early summer. In this study, to provide viral pollution data for further epidemiological studies and governmental actions, the presence of HAdV in the aquatic environment was quantitatively surveyed in the summer. This study was conducted to compare the efficiencies of nested-PCR (polymerase chain reaction) and qPCR (quantitative PCR) for detecting HAdV in environmental waters. A total of 73 water samples were collected from Puzi River in Taiwan and subjected to virus concentration methods. In the results, qPCR had much better efficiency for specifying the pathogen in river sample. HAdV41 was detected most frequently in the river water sample (10.9%). The estimated HAdV concentrations ranged between 6.75 * 10(2) and 2.04 * 10(9) genome copies/L. Significant difference was also found in heterotrophic plate counts, conductivity, water temperature, and water turbidity between presence/absence of HAdV. HAdV in the Puzi River may pose a significant health risk. PMID- 27120638 TI - Contributions to the design of rainwater harvesting systems in buildings with green roofs in a Mediterranean climate. AB - Green roofs (GRs) are becoming a trend in urban areas, favouring thermal performance of buildings, promoting removal of atmospheric pollutants, and acting as possible water collection spots. Rainwater harvesting systems in buildings can also contribute to the management of stormwater runoff reducing flood peaks. These technologies should be enhanced in Mediterranean countries where water scarcity is increasing and the occurrence of extreme events is becoming very significant, as a result of climate change. An extensive pilot GR with three aromatic plant species, Satureja montana, Thymus caespititius and Thymus pseudolanuginosus, designed to study several parameters affecting rainwater runoff, has been in operation for 12 months. Physico-chemical analyses of roof water runoff (turbidity, pH, conductivity, NH4(+), NO3(-), PO4(3-), chemical oxygen demand) have shown that water was of sufficient quality for non-potable uses in buildings, such as toilet flushing. An innovative approach allowed for the development of an expression to predict a 'monthly runoff coefficient' of the GR system. This parameter is essential when planning and designing GRs combined with rainwater harvesting systems in a Mediterranean climate. This study is a contribution to improving the basis for the design of rainwater harvesting systems in buildings with extensive GRs under a Mediterranean climate. PMID- 27120639 TI - Start-up performance of Anammox process in a fixed bed reactor (FBR) filled with honeycomb-like polypropylene carriers. AB - Novel honeycomb-like carriers, made of polypropylene, were applied to enhance biomass retention capacity so as to improve Anammox start-up performance in a fixed bed reactor (FBR). The reactor was operated for 3 months. On day 45, Anammox activity appeared. After 61 days' operation, the removal efficiencies of ammonium and nitrite were both over 91% based on 70 mg N L(-1) of the influent ammonium and influent nitrite, indicating that a remarkable Anammox activity was attained. A final specific Anammox activity of 0.12 g NH4(+)-N gVSS(-1) d(-1) was reached (VSS: volatile suspended solids). The FBR showed a good capacity for resisting shock loading and was more able to resist shock loading of nitrogen concentration than resist hydraulic shock loading. Phylogenetic analysis showed that Candidatus Brocadia anammoxidans' and Candidatus Kuenenia stuttgartiensis' were detected in the mature biofilm, and Candidatus Brocadia anammoxidans' was the dominant Anammox strain. Candidatus Kuenenia stuttgartiensis' played a positive role in the reactor performance, as it could consumed nitrite quickly and efficiently so as to avoid an adverse effect of temporary nitrite accumulation. The results showed that the honeycomb-like carriers were suitable for start-up of Anammox. PMID- 27120640 TI - Removal of Pb(2+) and Fe(3+) from water using N-TiO2 blended copolymer grafted asymmetric membranes. AB - The aim of this study was to evaluate the photo-catalytic properties of nitrogen doped titanium dioxide nano-particles supported on polymer membranes in the photo reduction of Fe(3+) and Pb(2+) from synthetic wastewater. The morphology of the prepared N-TiO2 nanoparticles was evaluated using transmission electron microscopy. Successful grafting of methacrylic acid side chains onto poly(vinylidene difluoride) (PVDF) backbone was confirmed by Fourier-transform infrared spectroscopy. The photo-catalytic asymmetric membranes were prepared through the dry-wet phase inversion technique. The asymmetric morphology was evaluated using scanning electron microscopy. The highest Fe(3+) photo-reduction efficiency (76.2%) was achieved in 6 hours using 1% N-TiO2-PMAA-g-PVDF/PAN (PMAA: poly(methacrylic acid); PAN: poly(acrylonitrile)) asymmetric membrane under solar irradiation. Increasing the photo-catalyst loading to 3% was found to negatively impact the photo-reduction of Fe(3+). Very high photo-reduction efficiencies were observed in the photo-reduction of Pb(2+) using 1% N-TiO2-PAN, 1% N-TiO2-PMAA-g PVDF/PAN and 1% N-TiO2-PVDF membranes (90.5%, 88.9% and 86.9%, respectively) under similar conditions. Increasing the photo-catalyst loading to 3% N-TiO2 was observed to slightly increase the photo-reduction efficiency in the removal of Pb(2+) unlike in the case of Fe(3+). The best support material for the N-TiO2 photo-catalyst was PMAA-g-PVDF/PAN. PMID- 27120641 TI - Effect of sodium salt on anaerobic digestion of kitchen waste. AB - The effect of different sodium salt concentration on anaerobic digestion of kitchen waste was investigated. The methane production performance, the corresponding methane production model and sodium salt inhibition model were studied, and the degradation efficiency was analyzed. With the increase of sodium salt concentration, the methane yield and the maximal methane production rate decreased along with the increase of lag phase time. The highest methane yield of 594 mL/g-VSadded (VS: volatile solids) was found with no sodium salt addition while the lowest was obtained with addition of 16 g/L NaCl. The declines of the methane yield were negligible when the sodium salt concentration was below 8 g/L, which corresponded to <10% inhibiting efficiency. In contrast, a sharp decrease of methane yield was observed with addition of >8 g/L NaCl (causing 17-80% inhibition). Five kinds of regression models were developed to describe the sodium salt inhibition efficiency, and the cubic regression model of y = 0.508 + 2.401x - 0.369x(2) + 0.033x(3) showed the best fitting. The volatile fatty acids/ethanol gradually accumulated along with the increase of the sodium salt concentration, and the volatile solid removal efficiency represented a gradual decline accordingly. It is recommended that the sodium salt concentration in the anaerobic digesters should be controlled below 8 g/L in order to avoid intense methane inhibition. PMID- 27120642 TI - Heterogeneous photodegradation of methylene blue with iron and tea or coffee polyphenols in aqueous solutions. AB - Recently, we developed two new Fenton catalysts using iron (Fe) and spent tea leaves or coffee grounds as raw material. In this study, Fe-to-tea or Fe-to coffee polyphenol complexes were successfully tested as heterogeneous photo Fenton catalysts. The photodegradation efficiency of methylene blue solutions with Fe-to-polyphenol complexes was higher than that of homogeneous iron salts in the photo-Fenton process. Furthermore, the tested Fe-to-polyphenol complexes could be reused by simply adding H2O2 to the solutions. After three sequential additions of H2O2, the conventional catalysts FeCl2.4H2O and FeCl3 removed only 16.6% and 53.6% of the dye, while the catalysts made using spent coffee grounds and tea leaves removed 94.4% and 96.0% of the dye, respectively. These results showed that the complexes formed between Fe and chlorogenic acid, caffeic acid, gallic acid and catechin, which are the main polyphenols in tea and coffee, can be used to improve the photo-Fenton process. PMID- 27120643 TI - Isolation and growth kinetics of a novel phenol-degrading bacterium Microbacterium oxydans from the sediment of Taihu Lake (China). AB - Seven phylogenetically diverse phenol-degrading bacterial strains designated as P1 to P7 were isolated from the industry-effluent dump sites of an industrial area near Taihu Lake, China. Through the 16S rDNA sequence analysis, these strains were widely distributed among five different genera: Rhodococcus (P1), Pseudomonas (P2-P4), Acinetobacter (P5), Alcaligenes (P6), and Microbacterium (P7). All seven isolates were capable of growing with phenol as the sole carbon source. Strain P7 was found to be a novel phenol-degrading strain by detailed morphological, physiological and biochemical characteristic analysis as well as the 16S rDNA sequence analyses, and was named Microbacterium oxydans LY1 (M. oxydans LY1 in its short form). Degradation experiments of phenol at various initial concentrations (20-1,000 mg/L) revealed that phenol is an inhibitory substrate to M. oxydans LY1. In a batch culture experiment, more than 95% of the phenol (500 mg/L) was degraded by M. oxydans LY1 at 30 degrees C, pH 7.0 and 120 rpm within 88 h. Phenol concentration higher than 200 mg/L was found to inhibit the bacterial growth. The growth kinetics correlated well with the Haldane model with MUmax (maximum specific cell growth rate) = 0.243 h(-1), Ks (saturation constant) = 25.7 mg/L, and Ki (self-inhibition constant) = 156.3 mg/L. This is the first report of the ability of M. oxydans to degrade phenol, and the results could provide important information for bioremediation of phenol-contaminated environments. PMID- 27120644 TI - Study on an effective industrial waste-based adsorbent for the adsorptive removal of phosphorus from wastewater: equilibrium and kinetics studies. AB - In this work, an effective adsorbent for removing phosphate from aqueous solution was developed from modifying industrial waste--lithium silica fume (LSF). The characterization of LSF before and after modification was investigated using an N2 adsorption-desorption technique (Brunauer-Emmett-Teller, BET), scanning electron microscopy (SEM) and X-ray diffraction (XRD). Studies were conducted to investigate the effect of adsorbent dose, initial solution pH, contact time, phosphate concentration, and temperature on phosphate removal using this novel adsorbent. The specific surface area for modified LSF (LLSF) is 24.4024 m(2)/g, improved 69.8% compared with unmodified LSF. XRD result suggests that the lanthanum phosphate complex was formed on the surface of LLSF. The maximum phosphate adsorption capacity was 24.096 mg P/g for LLSF, and phosphate removal was favored in the pH range of 3-8. The kinetic data fitted pseudo-second-order kinetic equation, intra-particle diffusion was not the only rate controlling step. The adsorption isotherm results illustrated that the Langmuir model provided the best fit for the equilibrium data. The change in free energy (?G(0)), enthalpy (?H(0)) and entropy (?S(0)) revealed that the adsorption of phosphate on LLSF was spontaneous and endothermic. It was concluded that by modifying with lanthanum, LSF can be turned to be a highly efficient adsorbent in phosphate removal. PMID- 27120645 TI - Continuous treatment of flotation collector wastewater using a membrane bioreactor. AB - Aniline aerofloat (DDA) is a widely used material in China and has become a main pollutant in floatation wastewater. In this study, a membrane reactor (MBR) was constructed to continuously treat simulated wastewater contaminated with DDA. The study investigated the hydraulic retention time (HRT) and the impact of influent DDA concentration on MBR performance, and analyzed intermediates from the DDA biodegradation pathway and activated sludge transfer pathway. The results showed that a 3 h HRT was an efficient and economical time period for MBR to remove 95 +/- 5 mg/L DDA from the simulated wastewater; the chemical oxygen demand reduction rate was 89.9%. DDA concentration negatively impacted MBR performance. MBR performance fluctuated slightly when HRT was 3 h, dissolved oxygen ranged from 4.8 to 5.3 mg/L, pH was between 6.5 and 7.0, and DDA concentrations were at 95 +/- 5 mg/L DDA. The transfer pathway in the activated sludge of DDA was through soluble microbial products, loosely bound extracellular polymeric substances, tightly bound extracellular polymeric substances, and finally cell biodegradation. DDA initially degraded to aniline; the aniline was further biodegraded to other organic compounds and was finally mineralized through the tricarboxylic acid cycle. This study offers a new continuous biological treatment technology to address DDA. PMID- 27120646 TI - Preparation of a novel positively charged nanofiltration composite membrane incorporated with silver nanoparticles for pharmaceuticals and personal care product rejection and antibacterial properties. AB - A novel positively charged N-[(2-hydroxy-3-trimethylammonium)propyl] chloride chitosan (HTCC)-Ag/polyethersulfone (PES) composite nanofiltration membrane was easily prepared by coating the active layer, HTCC, onto PES as the support through epichlorohydrin as the cross-linking reagent and nano-Ag particles as the introduced inorganic components. Scanning election microscopy, X-ray photoelectron spectroscopy, atomic force microscopy, and X-ray diffraction were employed to characterize the morphology of the resultant membranes, of which the molecular weight cut-off was about 941 Da. At 25 degrees C, the pure water permeability is 16.27 L/h.m(2).MPa. Our results showed that the rejection of pharmaceuticals and personal care products (PPCPs) followed the sequence: atenolol > carbamazepine > ibuprofen, confirming that the membranes were positively charged. The antibacterial properties of the membranes were compared to elucidate the existence of Ag nanoparticles which help to improve antibacterial activity against Gram-negative Escherichia coli (DH5alpha, Rosetta) and Gram-positive Bacillus subtilis. The inhibition zone diameters of HTCC-Ag/PES membranes towards E. coli DH5alpha, E. coli Rosetta and Bacillus subtilis were 17.77, 16.18, and 15.44 mm, respectively. It was found that HTCC-Ag/PES membrane has a better antibacterial activity against E. coli than against Bacillus subtilis, especially for E. coli DH5alpha. PMID- 27120647 TI - Structure changes and water filtration properties of electrospun polyamide nanofibre membranes. AB - Nanofibre membranes are studied extensively in water treatment. Inappropriate storage, however, could alter their performance, e.g. regarding water filtration. This shows the need for investigating this effect in more detail so as to offer a solution for long-term behaviour and stability. In this study, polyamide nanofibre membranes were treated under different conditions, simulating the diverse storage conditions and to simulate their use in water filtration systems. Under all these different settings, nanofibre properties (scanning electron microscope pictures, dimensional changes, tensile strength) and water filtration performance (clean water permeability (CWP), bacterial removal) were investigated. The results demonstrate that, as soon as the dimensional change of a membrane is >2%, the CWP, tensile strength and bacterial removal significantly decrease. These dimensional changes occurred when the membrane became dry after it had been in contact with water. As such, it is important to keep the membrane either in dry or in wet conditions to store its unique properties. When heat treated, the membrane had a higher tensile strength and kept its morphology and characteristics better during storage. PMID- 27120648 TI - Facile synthesis of TiO2-RGO composite with enhanced performance for the photocatalytic mineralization of organic pollutants. AB - Current research reports the synthesis of reduced graphene oxide (RGO)-TiO2 nanocomposite by in-situ redox method and graphene oxide by modified hummers method. The ratio of RGO and TiO2 in the composite was optimized to show best photocatalytic activity for the degradation of targeted pollutants. Optimized (1:10) RGO-TiO2 nanocomposite was characterized by various techniques viz. X-ray diffraction (XRD), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Brunauer-Emmett-Teller surface area (BET), Raman and diffuse reflectance spectroscopy (DRS) technique confirming successful formation of nanocomposite. XRD results confirm the presence of anatase phase in RGO-TiO2. Uniform dispersion of TiO2 nanoparticles on RGO could be seen from TEM images. The obtained results of (1:10) RGO-TiO2 showed five-fold and two-fold enhancement for the visible light and UV light, respectively, for the photocatalytic mineralization of methylene blue dye as compared to commercial Aeroxide P25 TiO2. The excellent photocatalytic mineralization activity of (1:10) RGO-TiO2 could be attributed to the enhanced surface area of composite as well as to its good electron sink capability. (1:10) RGO-TiO2 could be recycled easily and was found to be equally efficient even after the fourth cycle for the photocatalytic mineralization of methylene blue dye. The non-selectivity of synthesized composite was checked by the mineralization studies of oxalic acid. PMID- 27120649 TI - Hybrid wavelet-support vector machine approach for modelling rainfall-runoff process. AB - Because of the importance of water resources management, the need for accurate modeling of the rainfall-runoff process has rapidly grown in the past decades. Recently, the support vector machine (SVM) approach has been used by hydrologists for rainfall-runoff modeling and the other fields of hydrology. Similar to the other artificial intelligence models, such as artificial neural network (ANN) and adaptive neural fuzzy inference system, the SVM model is based on the autoregressive properties. In this paper, the wavelet analysis was linked to the SVM model concept for modeling the rainfall-runoff process of Aghchai and Eel River watersheds. In this way, the main time series of two variables, rainfall and runoff, were decomposed to multiple frequent time series by wavelet theory; then, these time series were imposed as input data on the SVM model in order to predict the runoff discharge one day ahead. The obtained results show that the wavelet SVM model can predict both short- and long-term runoff discharges by considering the seasonality effects. Also, the proposed hybrid model is relatively more appropriate than classical autoregressive ones such as ANN and SVM because it uses the multi-scale time series of rainfall and runoff data in the modeling process. PMID- 27120650 TI - Arsenic removal from water using a novel amorphous adsorbent developed from coal fly ash. AB - A novel effective adsorbent of alumina/silica oxide hydrate (ASOH) for arsenic removal was developed through simple chemical reactions using coal fly ash. The iron-modified ASOH with enhancing adsorption activity was further developed from raw fly ash based on the in situ technique. The adsorbents were characterized by X-ray diffraction, Fourier transform infrared spectrometry, scanning electron micrograph, laser particle size and Brunauer-Emmet-Teller surface area. The results show that the adsorbents are in amorphous and porous structure, the surface areas of which are 8-12 times that of the raw ash. The acidic hydrothermal treatment acts an important role in the formation of the amorphous structure of ASOH rather than zeolite crystal. A series of adsorption experiments for arsenic on them were studied. ASOH can achieve a high removal efficiency for arsenic of 96.4% from water, which is more than 2.5 times that of the raw ash. Iron-modified ASOH can enhance the removal efficiency to reach 99.8% due to the in situ loading of iron (Fe). The condition of synthesis pH = 2-4 is better for iron-modified ASOH to adsorb arsenic from water. PMID- 27120651 TI - Optimisation of bioflocculant production by a biofilm forming microorganism from poultry slaughterhouse wastewater for use in poultry wastewater treatment. AB - Poultry slaughterhouse wastewater contains nutrients that are sufficient for microbial growth; moreover, the wastewater has microorganisms which can be harnessed to perform specific functions. Additionally, these microorganisms can grow either in planktonic (free floating) mode or sessile (attached) mode. This study focused on the optimisation of bioflocculant production by quantifying flocculation activity, determined using kaolin clay (4 g/L), by isolates prevalent in poultry slaughterhouse wastewater. Subsequent to their identification and characterisation, six bacterial strains were initially isolated from the poultry wastewater. Although all the isolated microorganisms produced bioflocculants under different conditions, i.e. pH and temperature, the strain that produced bioflocculants with a higher flocculation activity was isolate BF-3, a Comamonas sp., achieving a flocculation activity of 93.8% at 32.9 degrees C and pH 6.5. Fourier transform infrared spectroscopy (FTIR) analysis of the bioflocculant of the isolate, showed the presence of hydroxyl, carboxyl, alkane and amine functional groups, an indication that the bioflocculant was a protein constituent. PMID- 27120652 TI - The effect of microbubbles on gas-liquid mass transfer coefficient and degradation rate of COD in wastewater treatment. AB - A commonly used aeration device at present has the disadvantages of low mass transfer rate because the generated bubbles are several millimeters in diameter which are much bigger than microbubbles. Therefore, the effect of a microbubble on gas-liquid mass transfer and wastewater treatment process was investigated. To evaluate the effect of each bubble type, the volumetric mass transfer coefficients for microbubbles and conventional bubbles were determined. The volumetric mass transfer coefficient was 0.02905 s(-1) and 0.02191 s(-1) at a gas flow rate of 0.67 L min(-1) in tap water for microbubbles and conventional bubbles, respectively. The degradation rate of simulated municipal wastewater was also investigated, using aerobic activated sludge and ozone. Compared with the conventional bubble generator, the chemical oxygen demand (COD) removal rate was 2.04, 5.9, 3.26 times higher than those of the conventional bubble contactor at the same initial COD concentration of COD 200 mg L(-1), 400 mg L(-1), and 600 mg L(-1), while aerobic activated sludge was used. For the ozonation process, the rate of COD removal using microbubble generator was 2.38, 2.51, 2.89 times of those of the conventional bubble generator. Based on the results, the effect of initial COD concentration on the specific COD degradation rate were discussed in different systems. Thus, the results revealed that microbubbles could enhance mass transfer in wastewater treatment and be an effective method to improve the degradation of wastewater. PMID- 27120653 TI - Comparison of multi-enzyme and thermophilic bacteria on the hydrolysis of mariculture organic waste (MOW). AB - Mariculture organic waste (MOW) is rich in organic matter, which is a potential energy resource for anaerobic digestion. In order to enhance the anaerobic fermentation, the MOW was hydrolyzed by multi-enzyme and thermophilic bacteria. It was advantageous for soluble chemical oxygen demand (SCOD) release at MOW concentrations of 6 and 10 g/L with multi-enzyme and thermophilic bacteria pretreatments. For multi-enzyme, the hydrolysis was not obvious at substrate concentrations of 1 and 3 g/L, and the protein and carbohydrate increased with hydrolysis time at substrate concentrations of 6 and 10 g/L. For thermophilic bacteria, the carbohydrate was first released at 2-4 h and then consumed, and the protein increased with hydrolysis time. The optimal enzyme hydrolysis for MOW was determined by measuring the changes of SCOD, protein, carbohydrate, ammonia and total phosphorus, and comparing with acid and alkaline pretreatments. PMID- 27120654 TI - Design of a generalized predictive controller for a biological wastewater treatment plant. AB - This paper presents a generalized predictive control (GPC) technique to regulate the activated sludge process found in a bioreactor used in wastewater treatment. The control strategy can track dissolved oxygen setpoint changes quickly, adapting to the system uncertainties and disturbances. Tests occur on an Activated Sludge Model No. 1 benchmark of an activated sludge process. A T filter added to the GPC framework results in an effective control strategy in the presence of coloured measurement noise. This work also suggests how a constraint on the measured variable can be added as a penalty term to the GPC framework which leads to improved control of the dissolved oxygen concentration in the presence of dynamic input disturbance. PMID- 27120655 TI - Enhanced decolorization of dyes by an iron modified clay and thermodynamic parameters. AB - The sorption processes of red 5 (R5) and yellow 5 (Y5) dyes by iron modified and sodium bentonite in aqueous solutions was evaluated. The modified clay was prepared, conditioned and characterized. The sodium clay did not remove any of either dye. The sorption kinetics and isotherms of R5 and Y5 dyes by iron modified clay were determined. The maximum removal percentages achieved were 97% and 98% for R5 and Y5, respectively, and a contact time of 72 h; the experimental data were best adjusted to Ho model. The isotherms of both dyes were best adjusted to the Langmuir model and the maximum adsorption capacities of the modified clay were 11.26 mg/g and 5.28 mg/g for R5 and Y5, respectively. These results indicate that adsorption processes have a high probability to be described as chemisorption on a homogeneous material. Temperature range between 283 and 213 K does not affect the adsorption of Y5 by the iron modified clay, but the adsorption process of R5 was affected, and the thermodynamic parameters could be calculated, which indicate a chemisorption mechanism. PMID- 27120656 TI - Removal of pharmaceutical residues using ozonation as intermediate process step at Linkoping WWTP, Sweden. AB - Pilot tests as basis for the design, implementation and operation of a future full-scale oxidation plant completing the existing sewage treatment in Linkoping, Sweden, were performed. Using an ozonation step between bio-sedimentation and post-denitrification processes, the primary goal was the removal of the highest priority substances to effluent water levels that will not cause adverse effects in the recipient considering the natural dilution. The study included initial emission screenings, dose control trials, treatment performance studies and eco toxicity studies. At an ozone dose of 5 mg O3/L, most substances could be removed. Ecotoxicological tests showed no negative effect for the tested ozone doses. High levels of oxygen into the denitrification could be rapidly reduced in the biology. The number of bacteria in the treated water could be significantly reduced even at relatively low ozone doses. Based on these results, the planning for the full-scale implementation of the treatment system was initiated in 2015. PMID- 27120657 TI - Hard coal as a potential low-cost adsorbent for removal of 4-chlorophenol from water. AB - The potential use of raw hard coals as low-cost adsorbents for the removal of 4 chlorophenol (4-CP) from aqueous solutions was examined. The effect of experimental parameters such as the pH and salt presence was evaluated. The kinetic studies showed the equilibrium time was found to be 2 h for all of the adsorbents and that the adsorption process followed the pseudo-second order kinetic model. The adsorption isotherms of the 4-CP on the hard coals were fitted to the Langmuir, Freundlich, Langmuir-Freundlich, Sips and Redlich-Peterson equations. Based on the results obtained, hard coals appear to be a promising adsorbent for the removal of some hazardous water pollutants, like 4-CP and related compounds. PMID- 27120658 TI - Treatment of petrochemical secondary effluent by an up-flow biological aerated filter (BAF). AB - In this study, petrochemical secondary effluent was treated by a 55 cm diameter pilot-scale biological aerated filter (BAF) with a media depth of 220 cm. Volcanic rock grains were filled as the BAF media. Median removal efficiency of chemical oxygen demand (COD) and ammonia nitrogen (NH3-N) was 29.35 and 57.98%, respectively. Moreover, the removal profile of the COD, NH3-N, total nitrogen and total organic carbon demonstrated that the filter height of 140 cm made up to 90% of the total removal efficiency of the final effluent. By gas chromatography-mass spectrometry, removal efficiencies of 2-chloromethyl-1,3-dioxolane, and benzonitrile, indene and naphthalene were obtained, ranging from 30.12 to 63.01%. The biomass and microbial activity of the microorganisms on the filter media were in general reduced with increasing filter height, which is consistent with the removal profile of the contaminants. The detected genera Defluviicoccus, Betaproteobacteria_unclassified and the Blastocatella constituted 1.86-6.75% of the identified gene, enhancing the COD and nitrogen removal in BAF for treating petrochemical secondary effluent. PMID- 27120676 TI - Bicarbonate Values for Healthy Residents Living in Cities Above 1500 Meters of Altitude: A Theoretical Model and Systematic Review. AB - Ramirez-Sandoval, Juan C., Maria F. Castilla-Peon, Jose Gotes-Palazuelos, Juan C. Vazquez-Garcia, Michael P. Wagner, Carlos A. Merelo-Arias, Olynka Vega-Vega, Rodolfo Rincon-Pedrero, and Ricardo Correa-Rotter. Bicarbonate values for healthy residents living in cities above 1500 m of altitude: a theoretical model and systematic review. High Alt Med Biol. 17:85-92, 2016.-Plasma bicarbonate (HCO3( )) concentration is the main value used to assess the metabolic component of the acid-base status. There is limited information regarding plasma HCO3(-) values adjusted for altitude for people living in cities at high altitude defined as 1500 m (4921 ft) or more above sea level. Our aim was to estimate the plasma HCO3(-) concentration in residents of cities at these altitudes using a theoretical model and compare these values with HCO3(-) values found on a systematic review, and with those venous CO2 values obtained in a sample of 633 healthy individuals living at an altitude of 2240 m (7350 ft). We calculated the PCO2 using linear regression models and calculated plasma HCO3(-) according to the Henderson-Hasselbalch equation. Results show that HCO3(-) concentration falls as the altitude of the cities increase. For each 1000 m of altitude above sea level, HCO3(-) decreases to 0.55 and 1.5 mEq/L in subjects living at sea level with acute exposure to altitude and in subjects acclimatized to altitude, respectively. Estimated HCO3(-) values from the theoretical model were not different to HCO3(-) values found in publications of a systematic review or with venous total CO2 measurements in our sample. Altitude has to be taken into consideration in the calculation of HCO3(-) concentrations in cities above 1500 m to avoid an overdiagnosis of acid-base disorders in a given individual. PMID- 27120677 TI - Effect of Interparticle Interactions on Agglomeration and Sedimentation Rates of Colloidal Silica Microspheres. PMID- 27120678 TI - A Purple Cupredoxin from Nitrosopumilus maritimus Containing a Mononuclear Type 1 Copper Center with an Open Binding Site. AB - Mononuclear cupredoxin proteins usually contain a coordinately saturated type 1 copper (T1Cu) center and function exclusively as electron carriers. Here we report a cupredoxin isolated from the nitrifying archaeon Nitrosopumilus maritimus SCM1, called Nmar1307, that contains a T1Cu center with an open binding site containing water. It displays a deep purple color due to strong absorptions around 413 nm (1880 M(-1) cm(-1)) and 558 nm (2290 M(-1) cm(-1)) in the UV-vis electronic spectrum. EPR studies suggest the protein contains two Cu(II) species of nearly equal population, one nearly axial, with hyperfine constant A? = 98 * 10(-4) cm(-1), and another more rhombic, with a smaller A? value of 69 * 10(-4) cm(-1). The X-ray crystal structure at 1.6 A resolution confirms that it contains a Cu atom coordinated by two His and one Cys in a trigonal plane, with an axial H2O at 2.25 A. Both UV-vis absorption and EPR spectroscopic studies suggest that the Nmar1307 can oxidize NO to nitrite, an activity that is attributable to the high reduction potential (354 mV vs SHE) of the copper site. These results suggest that mononuclear cupredoxins can have a wide range of structural features, including an open binding site containing water, making this class of proteins even more versatile. PMID- 27120679 TI - Trehalose-Based Glassy Matrices as an Effective Tool to Trap Short-Lived Intermediates in the Nitric Oxide Dioxygenation (NOD) Reaction of Hemoglobin. AB - The very rapid nitric oxide dioxygenation (NOD) reaction of nitric oxide (NO) with the oxygen bound to the ferrous derivatives of hemeproteins such as hemoglobin and myoglobin to yield nitrate and the ferric derivate (met) of the hemeprotein is of considerable physiological and biomedical importance. The mechanism for this reaction has been elusive due to the rapidity of the reaction. This article describes a method based both on using trehalose-derived glassy matrices to control the reaction of NO with oxyhemoglobin through both a temperature and glass-dependent modulation of the protein dynamics and a novel method of generating NO within the glassy matrix. The results support models in which there is a very rapid formation of an intermediate that immediately decays into an initial nonequilibrium population of high and low ferric nitrate that on a slower time scale relaxed to an easily dissociated equilibrium form of the ferric nitrate derivative of hemoglobin. PMID- 27120680 TI - A CIEF-LIF method for simultaneous analysis of multiple protein kinases and screening of inhibitors. AB - Here, a CIEF-LIF method for multiple protein kinase simultaneous analysis and inhibitors throughput screening with fast rate and low cost is presented. Comparing with CZE, CIEF-LIF exhibited great focusing ability and high separation efficiency for substrate and phosphorylated peptides, and is applicable for multiple kinases simultaneous analysis regardless of their substrate peptides compositions and charge statuses. Thus, highly sensitive analysis for cyclic adenosine 3', 5'-monophosphate-dependent protein kinase (PKA) and cyclin dependent kinase 1 (CDK1) was achieved in CIEF-LIF analysis with detection sensitivity up to 1.25 mU/MUL and 0.4 mU/MUL, respectively, two magnitudes higher than that of CZE and comparable with that in nanomaterials or green fluorescent protein-based kinase assay. Moreover, the inhibition effect of inhibitors on multiple kinases could be simultaneously readout in a single electrophoretic run, with half maximal inhibitory concentration of H-89 for PKA and Ro-3306 for CDK1 calculated as 37.0 and 35.9 nM, respectively, consistent with literatures reported. The CIEF-LIF also exhibited strong anti-interference ability in human breast cancer cell lysates analysis and simulators such as forskolin and 3 isobutyl-1-methylxantine assessment. Therefore, CIEF-LIF is desirable for future biological application and clinical diagnostics and drug discovery. PMID- 27120682 TI - Excitons Racing Against the Clock. PMID- 27120681 TI - Aripiprazole for the Treatment of Antipsychotic-Induced Hyperprolactinemia in an Adolescent Boy. PMID- 27120683 TI - Artifacts in Absorption Measurements of Organometal Halide Perovskite Materials: What Are the Real Spectra? AB - Organometal halide (OMH) perovskites have attracted lots of attention over the last several years due to their very promising performance as the materials for solar cells and light-emitting devices. Photophysical processes in these hybrid organic-inorganic semiconductors are still heavily debated. To know precise absorption spectra is absolutely necessary for quantitative understanding of the fundamental properties of OMH perovskites. We show that to measure the absorption of perovskite materials correctly is a difficult task which could be easily overlooked by the community. Many of the published absorption spectra exhibit a characteristic step-like featureless shape due to light scattering, high optical density of individual perovskite crystals and poor coverage of the substrate. We show how to recognize these artifacts, to avoid them, and to use absorption spectra of films for estimation of the surface coverage ratio. PMID- 27120684 TI - Reconstruction of the Disassembly Pathway of an Icosahedral Viral Capsid and Shape Determination of Two Successive Intermediates. AB - Viral capsids derived from an icosahedral plant virus widely used in physical and nanotechnological investigations were fully dissociated into dimers by a rapid change of pH. The process was probed in vitro at high spatiotemporal resolution by time-resolved small-angle X-ray scattering using a high brilliance synchrotron source. A powerful custom-made global fitting algorithm allowed us to reconstruct the most likely pathway parametrized by a set of stoichiometric coefficients and to determine the shape of two successive intermediates by ab initio calculations. None of these two unexpected intermediates was previously identified in self assembly experiments, which suggests that the disassembly pathway is not a mirror image of the assembly pathway. These findings shed new light on the mechanisms and the reversibility of the assembly/disassembly of natural and synthetic virus based systems. They also demonstrate that both the structure and dynamics of an increasing number of intermediate species become accessible to experiments. PMID- 27120685 TI - Antagonism between Spin-Orbit Coupling and Steric Effects Causes Anomalous Band Gap Evolution in the Perovskite Photovoltaic Materials CH3NH3Sn1-xPbxI3. AB - Halide perovskite solar cells are a recent ground-breaking development achieving power conversion efficiencies exceeding 18%. This has become possible owing to the remarkable properties of the AMX3 perovskites, which exhibit unique semiconducting properties. The most efficient solar cells utilize the CH3NH3PbI3 perovskite whose band gap, Eg, is 1.55 eV. Even higher efficiencies are anticipated, however, if the band gap of the perovskite can be pushed deeper in the near-infrared region, as in the case of CH3NH3SnI3 (Eg = 1.3 eV). A remarkable way to improve further comes from the CH3NH3Sn1-xPbxI3 solid solution, which displays an anomalous trend in the evolution of the band gap with the compositions approaching x = 0.5 displaying lower band gaps (Eg ~ 1.1 eV) than that of the lowest of the end member, CH3NH3SnI3. Here we use first-principles calculations to show that the competition between the spin-orbit coupling (SOC) and the lattice distortion is responsible for the anomalous behavior of the band gap in CH3NH3Sn1-xPbxI3. SOC causes a linear reduction as x increases, while the lattice distortion causes a nonlinear increase due to a composition-induced phase transition near x = 0.5. Our results suggest that electronic structure engineering can have a crucial role in optimizing the photovoltaic performance. PMID- 27120686 TI - Size and Energy Level Tuning of Quantum Dot Solids via a Hybrid Ligand Complex. AB - The performance of quantum dots (QDs) in optoelectronic devices suffers as a result of sub-bandgap states induced by the large fraction of atoms on the surface of QDs. Recent progress in passivating these surface states with thiol ligands and halide ions has led to competitive efficiencies. Here, we apply a hybrid ligand mixture to passivate PbSe QD sub-bandgap tail states via a low temperature, solid-state ligand exchange. We show that this ligand mixture allows tuning of the energy levels and the physical QD size in the solid state during film formation. We hereby present a novel, postsynthetic path to tune the properties of QD films. PMID- 27120687 TI - Direct Oil Recovery from Saturated Carbon Nanotube Sponges. AB - Oil adsorption by porous materials is a major strategy for water purification and industrial spill cleanup; it is of great interest if the adsorbed oil can be safely recovered from those porous media. Here, direct oil recovery from fully saturated bulk carbon nanotube (CNT) sponges by displacing oil with water in controlled manner is shown. Surfactant-assisted electrocapillary imbibition is adopted to drive aqueous electrolyte into the sponge and extrude organic oil out continuously at low potentials (up to -1.2 V). More than 95 wt % of oil adsorbed within the sponge can be recovered, via a single electrocapillary process. Recovery of different oils with a wide range of viscosities is demonstrated, and the remaining CNT sponge can be reused with similar recovery capacity. A direct and efficient method is provided to recover oil from CNT sponges by water imbibition, which has many potential environmental and energy applications. PMID- 27120688 TI - Human Peritoneal Mesothelial Cells Display Phagocytic and Antigen-Presenting Functions to Contribute to Intraperitoneal Immunity. AB - Mesothelial cells lining the peritoneal cavity are strategically positioned to respond to and counter intraperitoneal infections, cancer cells, and other challenges. We have investigated human peritoneal mesothelial cells (HPMCs) for phagocytic activity, expression of surface Major Histocompatibility Complex (MHC) class II and accessory molecules involved in antigen presentation, and the ability to present recall antigens to T cells. Phagocytosis of dextran, latex beads, and Escherichia coli was observed by flow cytometry, and internalization was visualized using confocal and electron microscopy. Flow cytometry and/or cellular enzyme-linked immunosorbent assay showed constitutive expression of ICAM 1, LFA-3, and B7-1, but not B7-2 or MHC class II. Interferon-gamma induced MHC II and ICAM-1 expression in a dose- and time-dependent manner. Importantly, HPMCs induced autologous CD3 T-lymphocyte proliferation (H incorporation) after pulse with recall antigen. Human peritoneal mesothelial cells equipped with phagocytic and antigen-presenting machinery are anticipated to have an integral role in intraperitoneal immune surveillance. PMID- 27120689 TI - Synthesis of PEGylated Ferrocene Nanoconjugates as the Radiosensitizer of Cancer Cells. AB - Radiation is one of the most widely used methods for cancer diagnosis and therapy. Herein, we report a new type of radiation sensitizer (Fc-PEG) by a facile one-step reaction of conjugating the hydrophilic PEG chain with hydrophobic ferrocene molecule. The chemical composition and structure of Fc-PEG have been thoroughly characterized by FT-IR, NMR, GPC, and MALDI-TOF mass spectrometry. This Fc-PEG conjugate could self-assemble in aqueous solution into spherical aggregates, and it was found that the exposure to 4 Gy of X-ray radiation have little influence on the shape and size of these aggregates. After the chemical bonding with PEG chains, the uptake level of Fe element could be enhanced via the formation of aggregates. The live/dead, CCK-8, as well as apoptosis assays, indicated that the death of cancer cells can be obviously increased by X-ray radiation after the incubation of these Fc-based nanoconjugates, which might be served as the radiation sensitizer toward cancer cells. We suggest that this radiosensitizing effect comes from the enhancement of reactive oxygen specimen (ROS) level as denoted by both flow cytometric and fluorescence microscopic analysis. The enhanced radiation sensitivity of cancer cells is contributed by the synergic effect of Fe-induced radiation-sensitizing and the increased uptake of nanoconjugates after polymeric grafting. PMID- 27120690 TI - A TiS2 nanosheet enhanced fluorescence polarization biosensor for ultra-sensitive detection of biomolecules. AB - Development of new strategies for the sensitive and selective detection of ultra low concentrations of specific cancer markers is of great importance for assessing cancer therapeutics due to its crucial role in early clinical diagnoses and biomedical applications. In this work, we have developed two types of fluorescence polarization (FP) amplification assay strategies for the detection of biomolecules by using TiS2 as a FP enhancer and Zn(2+)-dependent self hydrolyzing deoxyribozymes as catalysts to realize enzyme-catalyzed target recycling signal amplification. One approach is based on the terminal protection of small-molecule-linked DNA, in which biomolecular binding to small molecules in DNA-small-molecule chimeras can protect the conjugated DNA from degradation by exonuclease I (Exo I); the other approach is based on the terminal protection of biomolecular bound aptamer DNA, in which biomolecules directly bound to the single strand aptamer DNA can protect the ssDNA from degradation by Exo I. We select folate receptor (FR) and thrombin (Tb) as model analytes to verify the current concept. It is shown that under optimized conditions, our strategies exhibit high sensitivity and selectivity for the quantification of FR and Tb with low detection limits (0.003 ng mL(-1) and 0.01 pM, respectively). Additionally, this strategy is a simple "mix and detect" approach, and does not require any separation steps. This biosensor is also utilized in the analysis of real biological samples, the results agree well with those obtained by the enzyme linked immunosorbent assay (ELISA). PMID- 27120691 TI - A fast chemical exchange saturation transfer imaging scheme based on single-shot spatiotemporal encoding. AB - PURPOSE: To design a new approach that can not only keep the spatial and temporal resolution but also have better built-in immunity to magnetic field inhomogeneity and chemical shift effects than the single-shot echo planar imaging (EPI) for chemical exchange saturation transfer (CEST) MRI. METHOD: The single-shot spatiotemporally encoded (SPEN) MRI sequence was combined with a continuous wave saturation pulse for fast CEST MRI (CEST-SPEN MRI). The resulting images were super-resolved reconstructed by a hybrid method that solves the l1 norm minimization together with total variation (TV) regularization. Partial Lorentzian fitting was used to analyze the subsequent Z-spectra. RESULTS: Experimental results of a creatine phantom and in vivo tumor rat brains show that CEST-SPEN MRI has good capability in providing CEST-based and NOE-based contrast images. CONCLUSIONS: Compared with CEST-EPI, CEST-SPEN MRI has better immunity to magnetic field inhomogeneity and provides better contrast images within identical acquisition time, especially under an identical inhomogeneous field. Magn Reson Med 77:1786-1796, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27120692 TI - Diamond Quantum Devices in Biology. AB - The currently available techniques for molecular imaging capable of reaching atomic resolution are limited to low temperatures, vacuum conditions, or large amounts of sample. Quantum sensors based on the spin-dependent photoluminescence of nitrogen-vacancy (NV) centers in diamond offer great potential to achieve single-molecule detection with atomic resolution under ambient conditions. Diamond nanoparticles could also be prepared with implanted NV centers, thereby generating unique nanosensors that are able to traffic into living biological systems. Therefore, this technique might provide unprecedented access and insight into the structure and function of individual biomolecules under physiological conditions as well as observation of biological processes down to the quantum level with atomic resolution. The theory of diamond quantum sensors and the current developments from their preparation to sensing techniques have been critically discussed in this Minireview. PMID- 27120693 TI - An Advanced Tool To Interrogate BRD9. AB - Selective inhibitors of bromodomain-containing protein 9 (BRD9) may have therapeutic potential in the treatment of human malignancies and inflammatory diseases. A selective small molecule inhibitor that is well tolerated and has proper pharmacokinetic properties is required to explore the function of BRD9 in diseases. BI-9564 (2) is a cell permeable and noncytotoxic BRD9 inhibitor provided to the scientific community to explore BRD9 biology and determine its potential as a drug target. PMID- 27120694 TI - Viral protein suppresses oxidative burst and salicylic acid-dependent autophagy and facilitates bacterial growth on virus-infected plants. AB - Virus interactions with plant silencing and innate immunity pathways can potentially alter the susceptibility of virus-infected plants to secondary infections with nonviral pathogens. We found that Arabidopsis plants infected with Cauliflower mosaic virus (CaMV) or transgenic for CaMV silencing suppressor P6 exhibit increased susceptibility to Pseudomonas syringae pv. tomato (Pst) and allow robust growth of the Pst mutant hrcC-, which cannot deploy effectors to suppress innate immunity. The impaired antibacterial defense correlated with the suppressed oxidative burst, reduced accumulation of the defense hormone salicylic acid (SA) and diminished SA-dependent autophagy. The viral protein domain required for suppression of these plant defense responses is dispensable for silencing suppression but essential for binding and activation of the plant target-of-rapamycin (TOR) kinase which, in its active state, blocks cellular autophagy and promotes CaMV translation. Our findings imply that CaMV P6 is a versatile viral effector suppressing both silencing and innate immunity. P6 mediated suppression of oxidative burst and SA-dependent autophagy may predispose CaMV-infected plants to bacterial infection. PMID- 27120697 TI - Activation of 7-Silanorbornadienes by N-Heterocyclic Carbenes: A Selective Way to N-Heterocyclic-Carbene-Stabilized Silylenes. AB - The synthesis of hydridosilylenes Ter(H)Si: 3a (Ter: 2,6-bis(2,4,6 trimethylphenyl)phenyl) and Ter*(H)Si: 3b (Ter*: 2,6-bis(2,4,6-triiso propylphenyl)phenyl) stabilized by the N-heterocyclic carbene (NHC) ImMe4 is reported. The synthesis of stabilized hydridosilylenes 3 was accomplished by a previously unknown NHC-induced fragmentation of silanorbornadiene derivatives. Structural studies of the stabilized silylenes 3 and of its Fe(CO)4 complex 12 accompanied by a theoretical analysis of their bonding situation indicate that stabilized silylenes such as 3 can be regarded as neutral silyl anion equivalents. A computational investigation of the reaction course indicate a virtual one-step reaction between the NHC and the silanorbornadiene. A theoretical assessment of the scope and limitations of this reaction suggests that it is general and can be used also for the synthesis of other carbene analogues such as germylenes and phosphinidenes. PMID- 27120695 TI - Separase Is Required for Homolog and Sister Disjunction during Drosophila melanogaster Male Meiosis, but Not for Biorientation of Sister Centromeres. AB - Spatially controlled release of sister chromatid cohesion during progression through the meiotic divisions is of paramount importance for error-free chromosome segregation during meiosis. Cohesion is mediated by the cohesin protein complex and cleavage of one of its subunits by the endoprotease separase removes cohesin first from chromosome arms during exit from meiosis I and later from the pericentromeric region during exit from meiosis II. At the onset of the meiotic divisions, cohesin has also been proposed to be present within the centromeric region for the unification of sister centromeres into a single functional entity, allowing bipolar orientation of paired homologs within the meiosis I spindle. Separase-mediated removal of centromeric cohesin during exit from meiosis I might explain sister centromere individualization which is essential for subsequent biorientation of sister centromeres during meiosis II. To characterize a potential involvement of separase in sister centromere individualization before meiosis II, we have studied meiosis in Drosophila melanogaster males where homologs are not paired in the canonical manner. Meiosis does not include meiotic recombination and synaptonemal complex formation in these males. Instead, an alternative homolog conjunction system keeps homologous chromosomes in pairs. Using independent strategies for spermatocyte-specific depletion of separase complex subunits in combination with time-lapse imaging, we demonstrate that separase is required for the inactivation of this alternative conjunction at anaphase I onset. Mutations that abolish alternative homolog conjunction therefore result in random segregation of univalents during meiosis I also after separase depletion. Interestingly, these univalents become bioriented during meiosis II, suggesting that sister centromere individualization before meiosis II does not require separase. PMID- 27120696 TI - BIDIRECTIONAL PROSPECTIVE ASSOCIATIONS OF METABOLIC SYNDROME COMPONENTS WITH DEPRESSION, ANXIETY, AND ANTIDEPRESSANT USE. AB - BACKGROUND: Metabolic syndrome components-waist circumference, high-density lipoprotein cholesterol (HDL-C), triglycerides, systolic blood pressure and fasting glucose-are cross-sectionally associated with depression and anxiety with differing strength. Few studies examine the relationships over time or whether antidepressants have independent effects. METHODS: Participants were from the Netherlands Study of Depression and Anxiety (NESDA; N = 2,776; 18-65 years; 66% female). At baseline, 2- and 6-year follow-up, participants completed diagnostic interviews, depression and anxiety symptom inventories, antidepressant use assessment, and measurements of the five metabolic syndrome components. Data were analyzed for the consistency of associations between psychopathology indicators and metabolic syndrome components across the three assessment waves, and whether psychopathology or antidepressant use at one assessment predicts metabolic dysregulation at the next and vice versa. RESULTS: Consistently across waves, psychopathology was associated with generally poorer values of metabolic syndrome components, particularly waist circumference and triglycerides. Stronger associations were observed for psychopathology symptom severity than diagnosis. Antidepressant use was independently associated with higher waist circumference, triglycerides and number of metabolic syndrome abnormalities, and lower HDL-C. Symptom severity and antidepressant use were associated with subsequently increased number of abnormalities, waist circumference, and glucose after 2 but not 4 years. Conversely, there was little evidence that metabolic syndrome components were associated with subsequent psychopathology outcomes. CONCLUSIONS: Symptom severity and antidepressant use were independently associated with metabolic dysregulation consistently over time and also had negative consequences for short-term metabolic health. This is of concern given the chronicity of depression and anxiety and prevalence of antidepressant treatment. PMID- 27120698 TI - Is It Necessary to Achieve a Complete Box Isolation in the Case of Frequent Esophageal Temperature Rises? Feasibility of Shifting to a Partial Box Isolation Strategy for Patients With Non-Paroxysmal Atrial Fibrillation. AB - INTRODUCTION: There are some cases with frequent luminal esophageal temperature (LET) rises despite titrating the radiofrequency energy while creating a linear lesion for the Box isolation of atrial fibrillation (AF). Little is known about the feasibility of redesigning the ablation lines for a modified Box isolation strategy to prevent fatal esophageal injury in those cases. METHODS AND RESULTS: Two hundred and seventeen patients who underwent a Box isolation of non paroxysmal AF were evaluated. We divided them into 2 groups, patients in whom a box lesion set of the entire posterior left atrium had been achieved (complete Box isolation [CBI]; n = 157) and those in whom 2 additional peri-esophageal vertical lines were created at both the right and left ends of the esophagus, and those areas were left with an incomplete isolation when frequent rapid LET rises above 39.0 degrees C were observed while creating the floor line (partial Box isolation [PBI]; n = 60). During 20.1 +/- 13.9 months of follow-up, the arrhythmia-free rates were 54.1% in the CBI group versus 48.3% in the PBI group (P = 0.62). In the second session, a complete Box isolation was highly achieved even in the PBI group (94.3% vs. 83.3%, respectively; P = 0.17) and after 2 procedures, the arrhythmia-free rates increased to 75.2% vs. 68.3%, respectively (P = 0.34). There was no symptomatic esophageal injury in the PBI group. CONCLUSION: In the case of frequent LET rises while creating the linear lesions for the Box isolation strategy for non-paroxysmal AF, shifting to the PBI strategy was feasible. PMID- 27120699 TI - Binder-Free and Carbon-Free 3D Porous Air Electrode for Li-O2 Batteries with High Efficiency, High Capacity, and Long Life. AB - Pt-Gd alloy polycrystalline thin film is deposited on 3D nickel foam by pulsed laser deposition method serving as a whole binder/carbon-free air electrode, showing great catalytic activity enhancement as an efficient bifunctional catalyst for the oxygen reduction and evolution reactions in lithium oxygen batteries. The porous structure can facilitate rapid O2 and electrolyte diffusion, as well as forming a continuous conductive network throughout the whole energy conversion process. It shows a favorable cycle performance in the full discharge/charge model, owing to the high catalytic activity of the Pt-Gd alloy composite and 3D porous nickel foam structure. Specially, excellent cycling performance under capacity limited mode is also demonstrated, in which the terminal discharge voltage is higher than 2.5 V and the terminal charge voltage is lower than 3.7 V after 100 cycles at a current density of 0.1 mA cm(-2) . Therefore, this electrocatalyst is a promising bifunctional electrocatalyst for lithium oxygen batteries and this depositing high-efficient electrocatalyst on porous substrate with polycrystalline thin film by pulsed laser deposition is also a promising technique in the future lithium oxygen batteries research. PMID- 27120701 TI - Stochastic Processes in Electrochemistry. AB - Stochastic behavior becomes an increasingly dominant characteristic of electrochemical systems as we probe them on the smallest scales. Advances in the tools and techniques of nanoelectrochemistry dictate that stochastic phenomena will become more widely manifest in the future. In this Perspective, we outline the conceptual tools that are required to analyze and understand this behavior. We draw on examples from several specific electrochemical systems where important information is encoded in, and can be derived from, apparently random signals. This Perspective attempts to serve as an accessible introduction to understanding stochastic phenomena in electrochemical systems and outlines why they cannot be understood with conventional macroscopic descriptions. PMID- 27120700 TI - Successful implementation of outpatient parenteral antimicrobial therapy at a medical respite facility for homeless patients. AB - BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) is a safe way to administer intravenous (IV) antimicrobial therapy to patients with the potential to decrease hospital length of stay (LOS). Often, homeless patients with complex infections, who could otherwise be treated as an outpatient, remain in the hospital for the duration of IV antibiotic treatment. Injection drug use (IDU) is a barrier to OPAT. OBJECTIVE: To evaluate our experience with administering OPAT to homeless patients at a medical respite facility and determine if patients could complete a successful course of antibiotics. DESIGN: Using retrospective chart review, demographics, diagnosis, and comorbidities including mental illness, current IDU, and remote IDU (>3 months ago) were recorded. Surgical, microbiologic, and antimicrobial therapy including route (IV or oral), duration of therapy, and adverse events were abstracted. PARTICIPANTS: Homeless patients >18 years old who received OPAT at medical respite after discharge, no exclusions. MAIN MEASUREMENTS: Primary outcome was successful completion of OPAT at medical respite. Secondary outcome was successful antimicrobial course completion for a specific diagnosis. RESULTS: Forty-six (87%) patients successfully completed a defined course of antibiotic therapy. Thirty-four (64%) patients were successfully treated with OPAT at medical respite. Readmission rate was 30%. The average length of OPAT was 22 days. The cost savings to our institution (using $1500/day inpatient cost) was $25,000 per episode of OPAT. CONCLUSIONS: OPAT can be successful in a supervised medical respite setting for homeless patients with the help of a multidisciplinary team, and can decrease inpatient LOS resulting in cost savings. Journal of Hospital Medicine 2016;11:531 535. (c) 2016 Society of Hospital Medicine. PMID- 27120702 TI - Anisotropic Dissociation of pi-pi Stacking and Flipping-Motion-Induced Crystal Jumping in Alkylacridones and Their Dicyanomethylene Derivatives. AB - Ethylacridone (1 b) and dicyanomethylenated acridones 2 a,b,d showed crystal jumping activity upon heating. This is the first example of thermosalient behavior in a simple aromatic ketone and its derivatives. A systematic investigation of the jumping behavior of derivatives with different alkyl chains by variable-temperature X-ray crystal-structure analyses revealed the mechanism of this phenomenon. Anisotropic dissociation of pi stacking in a dimer was important for inducing crystal jumping in 1 b, whereas the collective fluctuation/flipping motion of a dicyanomethylene unit induced crystal jumping in 2. PMID- 27120703 TI - Insights into the pharmacokinetic properties of antitubercular drugs. AB - INTRODUCTION: The furiously advancing cases of multidrug-resistant tuberculosis (TB) along with the recent emergence of total drug resistant TB and TB-AIDS comorbidity present an increased threat to global public health. Knowledge of pharmacokinetic properties helps in selecting an appropriate anti-TB dosage regimen to achieve optimal results in patients. AREAS COVERED: This article provides a brief compilation of the information available regarding published pharmacokinetic data for anti-TB drugs and may act as a single window for investigators/medical practitioners in this field. The information regarding absorption, tissue distribution, elimination and pharmacokinetic interactions of the first- and second-line anti-TB drugs and candidate drugs under clinical trials is discussed. EXPERT OPINION: Pharmacokinetic properties such as poor absorption, too short biological half-life, extensive first-pass metabolism, drug food and drug-drug related interactions are not attractive for prospective anti TB drugs and significantly contribute to treatment failure and further resistance. The long duration, monotonous and multidrug treatment plan leads to poor patient compliance and resulted in a greater occurrence of anti-TB drug resistance worldwide. Few new agents, which are in development phase, are considering the aspect of shortening duration of the treatment regimen and provide a boost in therapy that is sorely needed. PMID- 27120704 TI - Nitric Oxide Inhibitory Meroterpenoids from the Fungus Penicillium purpurogenum MHZ 111. AB - Five new meroterpenoids, purpurogenolides A-E (1-5), and four known metabolites (6-9) were isolated from the solid substrate fermentation cultures of the fungus Penicillium purpurogenum MHz 111. The structures of the new meroterpenoids were elucidated by analysis of spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS). The absolute configurations of 1 and 5 were determined by single-crystal X-ray crystallographic analysis, and those of 2-4 were elucidated on the basis of experimental and calculated electronic circular dichroism spectra. Compounds 2-4 and 6 showed inhibition of nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells with IC50 values of 0.8-30.0 MUM. PMID- 27120705 TI - alpha-Tocopherol supplementation and the oxidative stress, homocysteine, and antioxidants in lead exposure. AB - To investigate whether alpha-tocopherol supplementation in workers exposed to lead would reduce the oxidative stress intensity and decrease homocysteine level, the examined population was randomly divided into two groups. Workers in the first group (n = 49, reference group) were not administered any drugs. Workers in the second group (n = 34) were administered orally alpha-tocopherol, 200 mg per day for 12 weeks. The level of alpha-tocopherol significantly increased compared to the baseline and the reference group. The level of thiol groups significantly increased compared to the reference group. However, the levels of malondialdehyde and homocysteine did not significantly change. Animal studies suggest the ability of alpha-tocopherol administration to reverse adverse health effects of lead exposure, such as oxidative stress; however, the results of this study on humans do not confirm these protective effects. PMID- 27120706 TI - Relative importance of advective flow versus environmental gradient in shaping aquatic ammonium oxidizers near the Three Gorges Dam of the Yangtze River, China. AB - Construction of a dam in a large river alters its hydrodynamic condition and geochemical gradient, but the effect of such anthropogenic activity on microbial ecology remains poorly understood. To assess this effect, we investigated the relative importance of advective flow versus environmental condition in shaping ammonia oxidizing bacteria (AOB) and archaea (AOA) community from 110 km upstream to the Three Gorges Dam (TGD) of the Yangtze River, China. Water physicochemical conditions, including turbidity, conductivity, redox state and nutrient level, were fairly constant from 110 to 45 km upstream of the TGD, but significantly oscillated near the dam. AOB and AOA in the Yangtze River were dominated by Nitrosospira- and Nitrosopumilus-affiliated clusters, respectively, and these compositions were invariant throughout the sampled 110 km flow path, suggesting that AOB and AOA communities in the river were largely transported from upstream by advection with minor local and transient inputs from surrounding soils and tributaries. However, the abundance of AOB and AOA was influenced by local geochemical conditions, possibly via the growth/decay mechanisms. The source of AOB in the Yangtze River appeared to be derived from soil near the headwater, but its abundance was enhanced during downstream transport, likely due to survival and growth. PMID- 27120707 TI - A lysin to kill. AB - An enzyme produced by a bacteriophage can enter human cells and kill intracellular Streptococcus pyogenes. PMID- 27120708 TI - Association between posterior teeth occlusion and functional dependence among older adults in nursing homes in Japan. AB - AIM: To examine whether posterior teeth occlusion is associated with functional dependence regardless of the number of natural teeth among Japanese nursing home residents. METHODS: The present cross-sectional study included 234 residents aged >60 years from eight nursing homes in Aso City, Japan. Functional dependence in basic activities of daily living was measured using the Barthel Index, and the primary outcome was independence for essential personal care (Barthel Index >= 60 points). Posterior teeth occlusion was assessed by a dentist using the total number of functional tooth units, depending on the number and location of the remaining natural and artificial teeth on implant-supported, fixed, and removable prostheses. Logistic regression models were used to assess univariate and multivariate associations between the total number of functional tooth units and independence for essential personal care. Models were sequentially adjusted for the number of natural teeth, demographic characteristics, socioeconomic status, health behaviors and comorbidities. RESULTS: Independence for essential personal care was found in 14.1% of participants. Greater total numbers of functional tooth units were significantly associated with greater odds of independence for essential personal care (odds ratio 1.12; 95% confidence interval 1.01-1.24). The association remained significant after adjustment for the number of natural teeth and other possible confounders (odds ratio 1.14, 95% confidence interval 1.01 1.29). CONCLUSIONS: Posterior teeth occlusion was independently associated with functional dependence among nursing home older residents in Japan. The maintenance and restoration of posterior teeth occlusion might be preventive factors against late-life functional decline. Geriatr Gerontol Int 2017; 17: 622 627. PMID- 27120709 TI - Ecological succession of the microbial communities of an air-conditioning cooling coil in the tropics. AB - Air-conditioning systems harbor microorganisms, potentially spreading them to indoor environments. While air and surfaces in air-conditioning systems are periodically sampled as potential sources of indoor microbes, little is known about the dynamics of cooling coil-associated communities and their effect on the downstream airflow. Here, we conducted a 4-week time series sampling to characterize the succession of an air-conditioning duct and cooling coil after cleaning. Using an universal primer pair targeting hypervariable regions of the 16S/18S ribosomal RNA, we observed a community succession for the condensed water, with the most abundant airborne taxon Agaricomycetes fungi dominating the initial phase and Sphingomonas bacteria becoming the most prevalent taxa toward the end of the experiment. Duplicate air samples collected upstream and downstream of the coil suggest that the system does not act as ecological filter or source/sink for specific microbial taxa during the duration of the experiment. PMID- 27120710 TI - An investigation of the influence of patient-related factors and comedications on lamotrigine clearance in patients with epilepsy. AB - Lamotrigine (LTG) is one of the most widely used antiepileptic drugs. Confusion still exists in the literature as to the relative influence of age, body weight, and concomitant drug therapy on LTG pharmacokinetics. So, the objective of this study is to evaluate the influence of patient-related factors and comedication on LTG apparent oral clearance (CL/F). A therapeutic drug-monitoring database was used to identify steady-state plasma LTG concentrations in 210 patients. LTG CL/F values were calculated for each patient according to the equation CL/F (L/h per kg) = LTG daily dose (mg/kg)/Css (steady state concentration) (mg/L) * 24 h. A linear-regression model was used to assess the influence of gender, dose, age, and body weight in LTG CL/F. The influence of comedication on LTG CL/F was investigated by applying the Bonferroni post-test. The lowest LTG CL/F was found in patients comedicated with valproate (VPA) (mean, 0.0183 L/h per kg), followed by patients receiving VPA + enzyme inducers (0.0271 L/h per kg), patients on LTG monotherapy (0.0298 L/h per kg) and patients comedicated with enzyme inducers (0.056 L/h per kg) LTG CL/F correlated significantly with LTG dose (P < 0.01), but showed no significant relationship with gender, weight, and age. LTG CL/F is influenced by the type of antiepileptic comedication. The correlation with dose may be a spurious finding related to the fact that physicians, in adjusting dosage according to clinical response, are more likely to use larger doses in patients with high clearance values. PMID- 27120711 TI - The scientific foundations and associated injury risks of early soccer specialisation. AB - Early specialisation is characterised by formal participation in a single sport at the exclusion of others. Limited data are available to support this approach in the development of soccer players who attain elite status later in life. Of growing concern is the associated increased risk of injury and suggestions that single sport specialisation is a risk factor independent of age, growth, biological maturation and training volumes. In the United Kingdom, elite soccer organisations have recently adopted an early sport specialisation approach following the introduction of the Elite Player Performance Plan. A key tenet of this programme is increased opportunities for training through a marked rise in the specified on-pitch hours per week. The accumulation of high training hours may be less of a relevant marker for success, and the impact of such a significant increase in training volume for young athletes who are experiencing a range of growth and maturational processes is currently unknown. This critical commentary includes an evidence-based discussion of the effectiveness of early sport specialisation and the potential injury risks associated with such programmes placing a specific focus on elite male youth soccer players. Available data indicate that modifications to the existing Elite Player Performance Plan framework could enhance players' development and reduce injury risk. Proposed alterations include reduced volume of soccer-specific training at key stages of growth and maturation and guidelines for the provision of a greater variety of physical activities that are integrated within other programme components. PMID- 27120712 TI - Use of National Burden to Define Operative Emergency General Surgery. AB - IMPORTANCE: Emergency general surgery (EGS) represents 11% of surgical admissions and 50% of surgical mortality in the United States. However, there is currently no established definition of the EGS procedures. OBJECTIVE: To define a set of procedures accounting for at least 80% of the national burden of operative EGS. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was conducted using data from the 2008-2011 National Inpatient Sample. Adults (age, >=18 years) with primary EGS diagnoses consistent with the American Association for the Surgery of Trauma definition, admitted urgently or emergently, who underwent an operative procedure within 2 days of admission were included in the analyses. Procedures were ranked to account for national mortality and complication burden. Among ranked procedures, contributions to total EGS frequency, mortality, and hospital costs were assessed. The data query and analysis were performed between November 15, 2015, and February 16, 2016. MAIN OUTCOMES AND MEASURES: Overall procedure frequency, in-hospital mortality, major complications, and inpatient costs calculated per 3-digit International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes. RESULTS: The study identified 421 476 patient encounters associated with operative EGS, weighted to represent 2.1 million nationally over the 4-year study period. The overall mortality rate was 1.23% (95% CI, 1.18%-1.28%), the complication rate was 15.0% (95% CI, 14.6% 15.3%), and mean cost per admission was $13 241 (95% CI, $12 957-$13 525). After ranking the 35 procedure groups by contribution to EGS mortality and morbidity burden, a final set of 7 operative EGS procedures were identified, which collectively accounted for 80.0% of procedures, 80.3% of deaths, 78.9% of complications, and 80.2% of inpatient costs nationwide. These 7 procedures included partial colectomy, small-bowel resection, cholecystectomy, operative management of peptic ulcer disease, lysis of peritoneal adhesions, appendectomy, and laparotomy. CONCLUSIONS AND RELEVANCE: Only 7 procedures account for most admissions, deaths, complications, and inpatient costs attributable to the 512 079 EGS procedures performed in the United States each year. National quality benchmarks and cost reduction efforts should focus on these common, complicated, and costly EGS procedures. PMID- 27120714 TI - Toward Wearable Cooling Devices: Highly Flexible Electrocaloric Ba0.67 Sr0.33 TiO3 Nanowire Arrays. AB - Flexible lead-free ferroelectric ceramic nanowire arrays exhibit a unique combination of features that can contribute to the realization of wearable cooling devices, including an outstanding electrocaloric effect at low fields, high efficiency, bendability and stretchability, and robustness against mechanical deformations. Thermodynamic and phase-field simulations are carried out to validate their superior electrocaloric effect in comparison to thin films. PMID- 27120713 TI - Comparative top down proteomics of peripheral blood mononuclear cells from kidney transplant recipients with normal kidney biopsies or acute rejection. AB - Recent studies utilizing transcriptomics, metabolomics, and bottom up proteomics have identified molecular signatures of kidney allograft pathology. Although these results make significant progress toward non-invasive differential diagnostics of dysfunction of a transplanted kidney, they provide little information on the intact, often modified, protein molecules present during progression of this pathology. Because intact proteins underpin diverse biological processes, measuring the relative abundance of their modified forms promises to advance mechanistic understanding, and might provide a new class of biomarker candidates. Here, we used top down proteomics to inventory the modified forms of whole proteins in peripheral blood mononuclear cells (PBMCs) taken at the time of kidney biopsy for 40 kidney allograft recipients either with healthy transplants or those suffering acute rejection. Supported by gas-phase fragmentation of whole protein ions during tandem mass spectrometry, we identified 344 proteins mapping to 2905 distinct molecular forms (proteoforms). Using an initial implementation of a label-free approach to quantitative top down proteomics, we obtained evidence suggesting relative abundance changes in 111 proteoforms between the two patient groups. Collectively, our work is the first to catalog intact protein molecules in PBMCs and suggests differentially abundant proteoforms for further analysis. PMID- 27120715 TI - Narrow QRS Tachycardia with Spontaneous Switch. What Is the Mechanism? PMID- 27120717 TI - Structural and Thermodynamic Properties of the Cm(III) Ion Solvated by Water and Methanol. AB - The geometric and electronic structures of the 9-coordinate Cm(3+) ion solvated with both water and methanol are systematically investigated in the gas phase at each possible solvent-shell composition and configuration using density functional theory and second-order Moller-Plesset perturbation theory. Ab initio molecular dynamics simulations are employed to assess the effects of second and third solvent shells on the gas-phase structure. The ion-solvent dissociation energy for methanol is greater than that of water, potentially because of increased charge donation to the ion made possible by the electron-rich methyl group. Further, the ion-solvent dissociation energy and the ion-solvent distance are shown to be dependent on the solvent-shell composition. This has implications for solvent exchange, which is generally the rate-limiting step in complexation reactions utilized in the separation of curium from complex metal mixtures that derive from the advanced nuclear fuel cycle. PMID- 27120718 TI - The Psychobiology of Authentic and Simulated Dissociative Personality States: The Full Monty. AB - The etiology of dissociative identity disorder (DID) remains a topic of debate. Proponents of the fantasy model and the trauma model of DID have both called for more empirical research. To this end, the current study presents new and extended data analyses of a previously published H2O positron emission tomography imaging study. This study included 29 subjects: 11 patients with DID and 10 high- and 8 low-fantasy-prone DID-simulating mentally healthy control subjects. All subjects underwent an autobiographical memory script-driven (neutral and trauma related) imagery paradigm in 2 (simulated) dissociative personality states (neutral and trauma related). Psychobiological and psychophysiological data were obtained. Results of the new post-hoc tests on the psychophysiological responses support the trauma model. New results of the brain imaging data did not support the fantasy model. This study extends previously published results by offering important new supporting data for the trauma model of DID. PMID- 27120719 TI - Psychological Strains and Suicidal Intent: An Empirical Study to Relate the 2 Psychopathological Variables. AB - Psychological strains are hypothesized to precede a suicidal intent that may lead to suicide, where psychological strains can be considered a function of social structure embedded with negative life events. This study aimed to test the potential relationship between psychological strains and suicidal intent in Chinese rural suicide attempters. Data regarding medically serious suicide attempters (N = 791) were gathered from county-level emergency rooms in randomly selected counties in rural China (15-54 years of age). Face-to-face interview data were obtained with semistructured instruments. Results showed that the strain variables interacted with gender in predicting degree of suicide intent in Chinese rural suicide attempters. Specifically, aspiration strain and coping strain were associated with suicide intent in Chinese male suicide attempters, whereas value strain was associated with suicide intent in Chinese female suicide attempters. This study supported the strain hypothesis in Chinese rural suicide attempters. PMID- 27120720 TI - Jack Kerouac Revisited: "Madness" in On the Road Between Stigma and Glorification. AB - On the Road is a classic American novel that appeared at a time of great political, cultural, and psychiatric upheaval. Published almost 60 years ago, it still exerts great influence. We propose that the affirmative approach toward "madness" in the novel can enlighten our understanding of alternative perceptions of mental illness. The novel is analyzed with quantifying and narrative methods focusing on the concept of madness, which is a prominent theme in the novel. Stigma and glorification of madness can be found throughout the text. The positive sides and the pitfalls of an overly positive attitude toward mental illness and minority group members are discussed, including benevolent discrimination, recovery, and positive psychiatry. PMID- 27120716 TI - Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells. AB - Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or "allergic" immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT "browning," and systemic insulin sensitivity, protecting against obesity induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis. PMID- 27120721 TI - [Actual questions about the prevention of venous thromboembolism in cancer patients receiving chemotherapy]. AB - Cancer patients have a 2-7 fold increased risk of venous thromboembolism compared with the general population and, since 1990, this is associated with significant morbidity and mortality. This review summarizes the current knowledge on venous thromboembolism and cancer. Notably, the risk of venous thromboembolism varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of venous thromboembolism than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors, cytokines and growth factors may directly and indirectly enhance venous thromboembolism. Chemotherapy produces ~6,5 fold increase in venous thromboembolism incidence in cancer patients compared to the general population. Prevention of this complication is challenging. The authors review the development of guidelines concerning venous thromboembolism prevention in hospitalized and also in ambulatory cancer patients treated with chemotherapy. Current guidelines recommend the use of low-molecular-weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent venous thromboembolism in cancer patients. PMID- 27120722 TI - [Developments in suture techniques of hand flexor tendon injuries during the last fifteen years]. AB - In the reconstruction of hand flexor tendon injuries it is fundamental to select the best suture technique, which makes possible early, active postoperative mobilization and achievement of the best results. The author reviews the development of suture techniques of the flexor tendon injuries during the last fifteen years, and discusses experimental tendon reconstruction results as well as clinical outcomes. The author describes the importance of different tendon suture materials, the significance of the pulley system of the fingers, the stretching between the sutured tendon ends by tendon sutures and, finally, the importance of the moving course in the reconstructed tendon. He states, that the wide-range adoption of the discussed modern tendon sutures would be necessary for better postoperative results. PMID- 27120723 TI - [In silico diabetology]. AB - INTRODUCTION: Simulation models can contribute substantially to our understanding and ability to control the dynamic processes underlying impaired glucose metabolism in diabetic patients. AIM: The aim of this paper is to outline a new comprehensive, physiologically-based dynamic model of glucose homeostasis incorporating up-to-date quantitative knowledge about glucose metabolism and its control by insulin and glucagon. METHOD: The model is composed of three submodels for glucose, insulin, and glucagon. RESULTS: The glucose submodel specifies the dynamics of glucose absorption following meals, hepatic glucose production and uptake, peripheral glucose uptake, kidney excretion, and insulin-independent uptake of glucose in the brain and red blood cells. The insulin submodel includes equations for insulin absorption, pancreatic insulin release and insulin clearance. The glucagon model specifies the hormone secretion and elimination kinetics. Algebraic equations are used to specify (i) how the hormones affect glucose production and utilisation in various compartments such as liver, muscle and fat tissues, and (ii) how glucose levels modify insulin and glucagon release from the pancreas. Setting the values of various model parameters is used to generate virtual individual patients. CONCLUSIONS: The model allows the simulation of 24-hour blood glucose profiles for both insulin-dependent non insulin dependent diabetic patients. PMID- 27120724 TI - [Synovial sarcoma. Case report]. AB - In 2013 there were 94,770 new cancer patients reported in Hungary. Synovial sarcoma accounts for 0.05-0.1% of all cancers and, therefore its incidence is predicted to be 47-94 patients/year in Hungary. The authors report the history of a 18-year-old man who was operated on a right upper abdominal wall tumor with R1 resection. During the next 5 months the tumor grew up to 8 cm in largest diameter. Histology revealed monophasic synovial sarcoma. Immunohistochemistry showed bcl2, focal CD99 and high molecular weight cytokeratin positivity, while smooth muscle actin, S100 and CD34 immunostainings were negative. Becose of this reoperation was not possible, curative six cycles of doxorubicine and ifosfamide with granulocyte colony stimulating factor support and 60 Gy radiotherapy was given to the tumor bed. After these treatments computed tomography scan was negative and the patient attended regular imaging every 3 months. At the age of 20 years the patient developed two neoplastic lesions in the surgical scar measuring 10 mm and 45 * 10 mm in size. R0 resection, partial rib resection and abdominal wall reconstruction were performed. Histology confirmed residual monophasic synovial sarcoma. Radiotherapy was not given because of a risk of intestinal wall perforation. Staging positron emission tomography-computed tomography proved to be negative. At the age of 22 years magnetic resonance imaging scans indicated no tumor recurrence, but after one month a rapidly growing tumorous lesion was found on ultrasound in the surgical scar measuring 20 * 20 * 12 mm in size. Cytology confirmed local recurrence and fluorescence in situ hibridization indicated t(x;18). R0 exstirpation and partial mesh resection were performed and histology showed the same monophasic synovial sarcoma. Because of the presence of vascular invasion and a close resection margin (1 mm) the patient underwent 3 cycles of adjuvant chemotherapy (doxorubicine and ifosfamide) with granulocyte colony stimulating factor support and 3 cycles of ifosfamide. After 2 years follow up at the age of 24 years, imaging studies did not reveal any local or distant recurrence. PMID- 27120725 TI - [Criticism of physicians by Johannes Gregorius Macer Szepsius (1530-after 1579)]. AB - Humanist author J. G. Macer Szepsius (1530-after 1579) born in Szepsi, Upper Hungary (today Slovakia, Moldava and Bodvou) lived in Krakow and was a typical author of Latin occasional poetry. In a part of his work De vera gloria libellus (Booklet on the true glory) published in 1562 he deals with certain professions and criticizes them. Physicians are described as being garrulus (loquacious), mendicus (beggar), and having a big belly due to a luxury. The Physician doesn't read books, is lazy and not characterized by his knowledge, but rather by ignorance, arrogance and pride. Physicians prescribe medications without knowing their effects. Such a criticism is surprising, because Macer Szepsius was probably closely related to medicine. PMID- 27120727 TI - Synthesis and Photophysical Properties of a 13,13'-Bibenzo[b]perylenyl Derivative as a pi-Extended 1,1'-Binaphthyl Analog. AB - A 13,13'-bibenzo[b]perylenyl derivative-an axially chiral pi-extended compound in which two perylene subunits fused to 1,1'-binaphthyl scaffold-has been synthesized from 1,8-dibromophenanthrene using an anionic cyclodehydrogenation reaction in the presence of potassium metal as the key step. The pair of enantiomers can be separated by chiral high-performance liquid chromatography (HPLC), which showed a strong circular dichroism (CD) (Deltaepsilon = 330 M(-1) cm(-1) at 449 nm, |gCD| = 5.8 * 10(-3) at 453 nm), high fluorescence quantum yield (Phif = 64%), and strong circular polarized luminescence (CPL) (|gCPL| = 5 * 10(-3) at 454 nm) in solution phase. PMID- 27120728 TI - microRNA-25 Inhibits Cell Apoptosis of Human Gastric Adenocarcinoma Cell Line AGS via Regulating CCNE1 and MYC. AB - BACKGROUND Gastric carcinoma is the second leading cause of cancer death. microRNAs play vital roles in regulating expression of related oncogenes. microRNA-25 (miR-25) has been found to be up-regulated in gastric carcinoma. However, its roles in affecting cell apoptosis of gastric carcinoma and the related mechanism remain elusive. This study aimed to uncover the influences of miR-25 on gastric carcinoma cell apoptosis and the possible functional mechanisms involved. MATERIAL AND METHODS Human gastric adenocarcinoma cell line AGS was used and transfected with lentivirus containing miR-25-specifc inhibitor sponge or expression vector to analyze the effects of miR-25. RESULTS miR-25 had higher expression in AGS than in human gastric epithelial cell line GES-1 (P<0.01). Inhibition of miR-25 by its sponge in AGS cells resulted in suppressed cell viability (P<0.01) and promoted cell apoptosis (P<0.01), while overexpression of miR-25 abrogated these effects (P<0.01 and P<0.05), indicating that miR-25 can promote cell viability and inhibit cell apoptosis in AGS cells. Expression analysis of related factors by Western blot showed that inhibiting miR-25 led to the up-regulation of F-box and WD repeat domain-containing 7 (FBXW7, P<0.01) and the down-regulation of FBXW7 substrates, cyclin E1 (CCNE1, P<0.01), and v-myc avian myelocytomatosis viral oncogene homolog (MYC, P<0.001). CONCLUSIONS These results indicate that miR-25 has anti-apoptosis roles in AGS cells, possibly via inhibiting FBXW7 and thus promoting oncogenes, such as CCNE1 and MYC. This study provides basic evidence for using miR-25 as a possible therapeutic target in treating gastric carcinoma. PMID- 27120729 TI - LAPAROSCOPIC RESECTION OF GASTROINTESTINAL STROMAL TUMORS (GIST). AB - BACKGROUND: Gastrointestinal mesenchymal or stromal tumors (GIST) are lesions originated on digestive tract walls, which are treated by surgical resection. Several laparoscopic techniques, from gastrectomies to segmental resections, have been used successfully. AIM: Describe a single center experience on laparoscopic GIST resection. METHOD: Charts of 15 operated patients were retrospectively reviewed. Thirteen had gastric lesions, of which ten were sub epithelial, ranging from 2-8 cm; and three were pure exofitic growing lesions. The remaining two patients had small bowel lesions. Surgical laparoscopic treatment consisted of two distal gastrectomies, 11 wedge gastric resections and two segmental enterectomies. Mechanical suture was used in the majority of patients except on six, which underwent resection and closure using manual absorbable sutures. There were no conversions to open technique. RESULTS: Mean operative time was 1h 29 min+/-92 (40-420 min). Average lenght of hospital stay was three days (2-6 days). There were no leaks, postoperative bleeding or need for reintervention. Mean postoperative follow-up was 38+/-17 months (6-60 months). Three patients underwent adjuvant Imatinib treatment, one for recurrence five months postoperatively and two for tumors with moderate risk for recurrence . CONCLUSION: Laparoscopic GIST resection, not only for small lesions but also for tumors above 5 cm, is safe and acceptable technique. PMID- 27120730 TI - THE PANC 3 SCORE PREDICTING SEVERITY OF ACUTE PANCREATITIS. AB - BACKGROUND: About 20% of cases of acute pancreatitis progress to a severe form, leading to high mortality rates. Several studies suggested methods to identify patients that will progress more severely. However, most studies present problems when used on daily practice. OBJECTIVE: To assess the efficacy of the PANC 3 score to predict acute pancreatitis severity and its relation to clinical outcome. METHODS: Acute pancreatitis patients were assessed as to sex, age, body mass index (BMI), etiology of pancreatitis, intensive care need, length of stay, length of stay in intensive care unit and mortality. The PANC 3 score was determined within the first 24 hours after diagnosis and compared to acute pancreatitis grade of the Revised Atlanta classification. RESULTS: Out of 64 patients diagnosed with acute pancreatitis, 58 met the inclusion criteria. The PANC 3 score was positive in five cases (8.6%), pancreatitis progressed to a severe form in 10 cases (17.2%) and five patients (8.6%) died. Patients with a positive score and severe pancreatitis required intensive care more often, and stayed for a longer period in intensive care units. The PANC 3 score showed sensitivity of 50%, specificity of 100%, accuracy of 91.4%, positive predictive value of 100% and negative predictive value of 90.6% in prediction of severe acute pancreatitis. CONCLUSION: The PANC 3 score is useful to assess acute pancreatitis because it is easy and quick to use, has high specificity, high accuracy and high predictive value in prediction of severe acute pancreatitis. PMID- 27120731 TI - I BRAZILIAN CONSENSUS ON MULTIMODAL TREATMENT OF COLORECTAL LIVER METASTASES. MODULE 2: APPROACH TO RESECTABLE METASTASES. AB - BACKGROUND: Liver metastases of colorectal cancer are frequent and potentially fatal event in the evolution of patients. AIM: In the second module of this consensus, management of resectable liver metastases was discussed. METHOD: Concept of synchronous and metachronous metastases was determined, and both scenarius were discussed separately according its prognostic and therapeutic peculiarities. RESULTS: Special attention was given to the missing metastases due to systemic preoperative treatment response, with emphasis in strategies to avoid its reccurrence and how to manage disappeared lesions. CONCLUSION: Were presented validated ressectional strategies, to be taken into account in clinical practice. PMID- 27120732 TI - IMPLEMENTATION AND VALIDATION OF STATISTICAL TESTS IN RESEARCH'S SOFTWARE HELPING DATA COLLECTION AND PROTOCOLS ANALYSIS IN SURGERY. AB - BACKGROUND: The use of information technology is often applied in healthcare. With regard to scientific research, the SINPE(c) - Integrated Electronic Protocols was created as a tool to support researchers, offering clinical data standardization. By the time, SINPE(c) lacked statistical tests obtained by automatic analysis. AIM: Add to SINPE(c) features for automatic realization of the main statistical methods used in medicine . METHODS: The study was divided into four topics: check the interest of users towards the implementation of the tests; search the frequency of their use in health care; carry out the implementation; and validate the results with researchers and their protocols. It was applied in a group of users of this software in their thesis in the strict sensu master and doctorate degrees in one postgraduate program in surgery. To assess the reliability of the statistics was compared the data obtained both automatically by SINPE(c) as manually held by a professional in statistics with experience with this type of study. RESULTS: There was concern for the use of automatic statistical tests, with good acceptance. The chi-square, Mann-Whitney, Fisher and t-Student were considered as tests frequently used by participants in medical studies. These methods have been implemented and thereafter approved as expected. CONCLUSION: The incorporation of the automatic SINPE PMID- 27120733 TI - THE LARGEST WESTERN EXPERIENCE WITH HEPATOPANCREATODUODENECTOMY: LESSONS LEARNED WITH 35 CASES. AB - BACKGROUND: Hepatopancreatoduodenectomy is one of the most complex abdominal operations mainly indicated in advanced biliary carcinoma. AIM: To present 10 year experience performing this operation in advanced malignant tumors. METHODS: This is a retrospective descriptive study. From 2004 to 2014, 35 hepatopancreatoduodenectomies were performed in three different institutions. The most common indication was advanced biliary carcinoma in 24 patients (68.5%). RESULTS: Eighteen patients had gallbladder cancer, eight Klatskin tumors, five neuroendocrine tumors with liver metastasis, one colorectal metastasis invading the pancreatic head, one intraductal papillary mucinous neoplasm with liver metastasis, one gastric cancer recurrence with liver involvement and one ocular melanoma with pancreatic head and right liver lobe metastasis. All patients were submitted to pancreatoduodenectomy with a liver resection as follows: eight right trisectionectomies, five right lobectomies, four left lobectomies, 18 central lobectomies (IVb, V and VIII). The overall mortality was 34.2% (12/35) and the overall morbidity rate was 97.4%. CONCLUSION: Very high mortality is seen when major liver resection is performed with pancreatoduodenectomy, including right lobectomy and trisectionectomy. Liver failure in combination with a pancreatic leak is invariably lethal. Efforts to ensure a remnant liver over 40-50% of the total liver volume are the key to obtain patient survival. PMID- 27120734 TI - COMPARATIVE STUDY ON LIVER TRANSPLANTATION WITH AND WITHOUT HEPATOCELLULAR CARCINOMA WITH CIRRHOSIS: ANALYSIS OF MELD, WAITING TIME AND SURVIVAL. AB - BACKGROUND: Liver transplantation is the usual treatment for hepatocellular carcinoma. AIM: To analyze the MELD score, waiting time and three month and one year survival for liver transplantation in cirrhotic patients affected by hepatocellular carcinoma or not. METHODS: This was a retrospective, observational and analytical study of 93 patients submitted to liver transplantation. RESULTS: There were 28 hepatocellular carcinoma and 65 non-hepatocellular carcinoma patients with no differences related to age and sex distribution. The main causes of cirrhosis on hepatocellular carcinoma were hepatitis C virus (57.1%) and hepatitis B virus (28.5%), more frequent than non-hepatocellular carcinoma patients, which presented 27.7% and 4.6% respectively. The physiological and exception MELD score on hepatocellular carcinoma were 11.9 and 22.3 points. On non-hepatocellular carcinoma, it was 19.4 points, higher than the physiological MELD and lower than the exception MELD on hepatocellular carcinoma. The waiting time for transplantation was 96.2 days for neoplasia, shorter than the waiting time for non-neoplasia patients, which was 165.6 days. Three month and one year survival were 85.7% and 78.6% for neoplasia patients, similar to non-neoplasia, which were 77% and 75.4%. CONCLUSION: Hepatocellular carcinoma patients presented lower physiological MELD score, higher exception MELD score and shorter waiting time for transplantation when compared to non-hepatocellular carcinoma patients. Three month and one year survival were the same between the groups. PMID- 27120735 TI - COMPARATIVE ANALYSIS OF PREOPERATIVE ULTRASONOGRAPHY REPORTS WITH INTRAOPERATIVE SURGICAL FINDINGS IN CHOLELITHIASIS. AB - BACKGROUND: Laparoscopic cholecystectomy is widely used for cholelithiasis. Abdominal ultrasonography often precedes this operation and can prove diagnosis, as well as helps in showing possible complications during the perioperative period. AIM: Evaluate the description of variables of gallbladder and bile ducts present in reports of preoperative abdominal ultrasonography in cholelithiasis comparing with surgical findings. METHODS: Were studied 91 patients who underwent elective laparoscopic cholecystectomy with previous abdominal ultrasonography. Variables such as identification and amount of gallstones involved were evaluated, both in preoperative ultrasonography and during surgery to evaluate sensitivity, specificity, concordance and positive and negative predictive values. RESULTS: The reports did not mention diameter of vesicular light (98.9%), organ distension (62.6%), gallstone sizes (58.2%), wall thickness (41.8%) and evaluation of the common bile duct (39.6%). Ultrasound had high values for sensitivity, consistency and positive predictive value for identifying the presence/absence of gallstones: 98.8%, 96.7% and 97.8% respectively. As for the amount of stones, ultrasonography showed agreement in 82.7%, negative predictive value in 89.1% and specificity in 87.7%, with lower values for sensitivity (68.2%) and positive predictive value (65.2%). CONCLUSIONS: The ultrasound reports were flawed in standardization. Significant percentage of them did not have variables that could predict perioperative complications and surgical conversion. PMID- 27120736 TI - ACUTE APENDICITIS IN LIVER TRANSPLANT RECIPIENTS. AB - BACKGROUND: Appendicitis is a common cause of emergency surgery that in the population undergoing organ transplantation presents a rare incidence due to late diagnosis and treatment. AIM: To report the occurrence of acute appendicitis in a cohort of liver transplant recipients. METHODS: Retrospective analysis in a period of 12 years among 925 liver transplants, in witch five cases of acute appendicitis were encountered. RESULTS: Appendicitis occurred between three and 46 months after liver transplantation. The age ranged between 15 and 58 years. There were three men and two women. The clinical presentations varied, but not discordant from those found in non-transplanted patients. Pain was a symptom found in all patients, in two cases well located in the right iliac fossa (40%). Two patients had symptoms characteristic of peritoneal irritation (40%) and one patient had abdominal distention (20%). All patients were submitted to laparotomies. In 20% there were no complications. In 80% was performed appendectomy complicated by suppuration (40%) or perforation (40%). Superficial infection of the surgical site occurred in two patients, requiring clinical management. The hospital stay ranged from 48 h to 45 days. CONCLUSION: Acute appendicitis after liver transplantation is a rare event being associated with a high rate of drilling, due to delays in diagnosis and therapy, and an increase in hospital stay. PMID- 27120737 TI - CORRELATION BETWEEN PRE AND POSTOPERATIVE UPPER DIGESTIVE ENDOSCOPY IN PATIENTS WHO UNDERWENT ROUX-EN-Y GASTROJEJUNAL BYPASS. AB - BACKGROUND: Bariatric operations have variable range of complications and postoperative benefits. Gastroesophageal reflux is considered potential factor that may result in damage to the esophageal mucosa and this subject is quite controversial in the literature. AIM: To evaluate patients who underwent to Roux en-Y gastrojejunal bypass correlating epidemiologic and endoscopic findings in pre and postoperative periods. METHOD: A retrospective, paired study which evaluated 110 patients. Inclusion criteria were formal indication for bariatric surgery and patients with pre and postoperative endoscopy. Exclusion criteria were previous bariatric surgery, patients subjected to other types of bariatric surgery and those who had no pre or postoperative upper digestive endoscopy. The epidemiological variables were: sex, age, body mass index, type 2 diabetes mellitus or impaired glucose tolerance, and preoperative dyslipidemia. RESULTS: The preoperative upper endoscopy was normal in 26.4% of the patients. Among endoscopic alterations, the hiatus hernia was the most prevalent followed by non erosive gastritis. The postoperative upper endoscopy was normal in 40.9% and stenosis was the most prevalent followed by marginal ulcer. Correlation on pre and postoperative endoscopies, was found 100% reduction of hiatal hernias and 88% of esophagitis. There was no statistical significance in relationship to anastomotic stenosis with preoperative other variables. Conclusions . There was significant decrease in postoperative hiatus hernia, erosive esophagitis, non erosive esophagitis, erosive gastritis and non-erosive gastritis with the operation. Stenosis of the gastrojejunostomy anastomosis was the most prevalent postoperative complication with no correlation with preoperative variables. PMID- 27120738 TI - IMPACT OF DEFICIENT NUTRITION IN BONE MASS AFTER BARIATRIC SURGERY. AB - BACKGROUND: Essential nutrients are considered for the prevention of the bone loss that occurs after bariatric surgery. AIM: Evaluate nutrients involved in bone metabolism, and relate to serum concentrations of calcium, vitamin D, and parathyroid hormone, and the use of supplements and sun exposure on the bone mass of patients who had undergone gastric bypass surgery. METHODS: An observational study, with patients who had undergone the surgery 12 or more months previously, operated group (OG), compared to a control group (CG). RESULTS: Were included 56 in OG and 27 in the CG. The mean age was 36.4+/-8.5 years. The individuals in the OG, compared to CG, consumed inadequate amounts of protein and daily calcium. The OG had a higher prevalence of low sun exposure, lower levels of 25OH Vitamin D (21.3+/-10.9 vs. 32.1+/-11.8 ng/dl), and increased serum levels of parathyroid hormone (68.1+/-32.9 vs. 39.9+/-11.9 pg/ml, p<0.001). Secondary hyperparathyroidism was present only in the OG (41.7%). The mean lumbar spine bone mineral density was lower in the OG. Four individuals from the OG had low bone mineral density for chronological age, and no one from the CG. CONCLUSION: The dietary components that affect bone mass in patients undergoing bariatric surgery were inadequate. The supplementation was insufficient and the sun exposure was low. These changes were accompanied by secondary hyperparathyroidism and a high prevalence of low bone mass in lumbar spine in these subjects. PMID- 27120739 TI - SPEECH THERAPY INTERVENTION IN MORBIDLY OBESE UNDERGOING FOBI-CAPELL GASTROPLASTY METHOD. AB - BACKGROUND: The rehabilitation of complications related to oral feeding, resulting from gastroplasty is the competence of the speech therapist, to intervene in mastication and swallowing functions, aiming at quality of life. AIM: Check in the postoperative period the efficiency of stimulation, independent judges in readiness for re-introduction of solid food in morbidly obese undergoing gastroplasty. METHOD: Cross-sectional study of descriptive and quantitative evaluated mastication and quality of life of 70 morbidly obese patients undergoing gastroplasty, and a group of 35 obese suffered speech therapy. RESULTS: In the evaluation of mastication for group 1 (pre and post speech therapy), the results show that, except for the lack of chewing, the other variables, such as food court, type of mastication, mastication rhythm, jaw movements, bolus size, excessive mastication and fluid intake, demonstrate statistical insignificance. In evaluating the quality of life when compared groups 1 and 2, the results from the questionnaire on quality of life in dysphagia (SWAL-QoL - Quality of Life in Swallowing) total and 11 domains assessed in the questionnaire, were statistically significant. With these results, the group 2 presented unfavorable conditions for quality of life. CONCLUSION: The stimulation protocol, independent judges in readiness for re introduction of solid food of these patients in the postoperative period, applied in these conditions of the study, was not the distinguishing factor of the rehabilitation process for the observed period. PMID- 27120740 TI - END-TO-END VERSUS END-TO-SIDE ANASTOMOSIS IN THE TREATMENT OF ESOPHAGEAL ATRESIA OR TRACHEO-ESOPHAGEAL FISTULA. AB - BACKGROUND: Dehiscence of esophageal anastomosis is frequent and there are still controversies which type of anastomosis is preferred to diminish its incidence . AIM: To compare end-to-end anastomosis versus end-to-side anastomosis in terms of anastomotic leakage, esophageal stricture and gastroesophageal reflux symptom. METHODS: This study was carried out for two year starting from 2012. End-to-side and end-to-side anastomosis were compared in terms of anastomotic leakage, esophageal stricture, gastroesophageal reflux symptom, length of surgery and pack cell infusion. RESULTS: Respectively to end-to-end and end-to-side anastomosis, duration of surgery was 127.63+/-13.393 minutes and 130.29+/-10.727 minutes (p=0.353); esophageal stricture was noted in two (5.9%) and eight (21.1%) cases (p=0.09); gastroesophageal reflux disease was detected in six (15.8%) and three (8.8%) cases (p=0.485); anastomotic leakage was found in five (13.2%) and one (2.9%) cases (p=0.203); duration of neonatal intensive care unit admission was significantly shorter in end-to-end (11.05+/-2.438 day) compared to end-to-side anastomosis (13.88+/-2.306 day) (p<0.0001). CONCLUSION: There were no significant differences between end-to-end and end-to-side anastomosis except for length of neonatal intensive care unit admission which was significantly shorter in end-to end anastomosis group. PMID- 27120741 TI - SURGICAL GASTROSTOMY BASED ON ENDOSCOPIC CONCEPTS. AB - BACKGROUND: Until the early 1980s, Stamm technique was considered standard method to gastrostomy. After description of the endoscopic technique, due to its efficiency and speed, quickly became the method of choice for long-term enteral access. AIM: Describe a technique that combines direct view of the stomach from open surgery with the simplicity and less traumatic endoscopic gastrostomy method. METHOD: In patient supine under spinal anesthesia the technique stars with small epigastric incision to pull up the stomach. A 3 mm incision in the left hypochondrium is made to pass needle puncture to guidewire passage. The stomach is drilled, guidewire is seizured, connection to catheter and percutaneous approach is made with traction of the stomach to the abdominal wall. Purse suture on the anterior gastric wall is not needed. RESULTS: Twenty-eight patients underwent gastrostomy using endoscopy devices; six had local minor complications without the need for re-intervention; there was no death. CONCLUSION: The surgical gastrostomy with minimal incision in the stomach to pull off the catheter using endoscopic gastrostomy devices, proved to be safe, easy to perform, less traumatic, quick, simple and elegant. PMID- 27120742 TI - MINILAPAROSCOPIC APPENDECTOMY. AB - BACKGROUND: Minilaparoscopy is considered one of the minimally invasive options available for acute appendicitis treatment, although not always employed in less complexity public health services. AIM: Report surgical outcomes of minilaparoscopy use in acute appendicitis treatment. METHOD: The study included 21 patients undergoing minilaparoscopic appendectomy with instrumental of 3 mm. The following variables were analyzed: sex, age, body mass index, stage of appendicitis, surgical time, hospital stay, surgical complications, conversion rate to conventional laparoscopy or laparotomy, pain after surgery and aesthetic result. RESULTS: Twelve men and nine women underwent minilaparoscopic appendectomy. The average age was 27,8 years, the mean BMI was 24,8 kg/m2. The operative time ranged from 33 to 160 min and the average of hospital stay was three days. Among the 21 patients, 20 reported mild pain or no pain in the first postoperative day. The aesthetic result was considered "satisfactory" and "very satisfactory" by 95% of the patients. CONCLUSIONS: The minilaparoscopy is viable technique for treating acute appendicitis with a satisfactory recovery. It combines the benefits of minimally invasive procedures with results similar to conventional techniques. PMID- 27120743 TI - ON VASCULAR STENOSIS, RESTENOSIS AND MANNOSE BINDING LECTIN. AB - Mannose binding lectin is a lectin instrumental in the innate immunity. It recognizes carbohydrate patterns found on the surface of a large number of pathogenic micro-organisms, activating the complement system. However, this protein seems to increase the tissue damage after ischemia. In this paper is reviewed some aspects of harmful role of the mannose binding lectin in ischemia/reperfusion injury. PMID- 27120744 TI - MAIN CONTROVERSIES IN THE NONOPERATIVE MANAGEMENT OF BLUNT SPLENIC INJURIES. AB - INTRODUCTION: The nonoperative management of traumatic spleen injuries is the modality of choice in patients with blunt abdominal trauma and hemodynamic stability. However, there are still questions about the treatment indication in some groups of patients, as well as its follow-up. AIM: Update knowledge about the spleen injury. METHOD: Was performed review of the literature on the nonoperative management of blunt injuries of the spleen in databases: Cochrane Library, Medline and SciELO. Were evaluated articles in English and Portuguese, between 1955 and 2014, using the headings "splenic injury, nonoperative management and blunt abdominal trauma". RESULTS: Were selected 35 articles. Most of them were recommendation grade B and C. CONCLUSION: The spleen traumatic injuries are frequent and its nonoperative management is a worldwide trend. The available literature does not explain all aspects on treatment. The authors developed a systematization of care based on the best available scientific evidence to better treat this condition. PMID- 27120745 TI - GASTRIC STUMP CANCER AFTER GASTRECTOMY BY GASTRODUODENAL PEPTIC ULCER. PMID- 27120746 TI - SURGICAL TREATMENT OF FISH IMPACTED IN THE UPPER ESOPHAGUS. PMID- 27120747 TI - NEISSERIA MENINGITIDIS PERITONITIS SEROTYPE C: CASE REPORT. PMID- 27120748 TI - WILKIE'S SYNDROME: A RARE CAUSE OF INTESTINAL OBSTRUCTION. PMID- 27120749 TI - Tofacitinib Citrate for Refractory Cutaneous Dermatomyositis: An Alternative Treatment. PMID- 27120770 TI - ToxCast EPA in Vitro to in Vivo Challenge: Insight into the Rank-I Model. AB - The ToxCast EPA challenge was managed by TopCoder in Spring 2014. The goal of the challenge was to develop a model to predict the lowest effect level (LEL) concentration based on in vitro measurements and calculated in silico descriptors. This article summarizes the computational steps used to develop the Rank-I model, which calculated the lowest prediction error for the secret test data set of the challenge. The model was developed using the publicly available Online CHEmical database and Modeling environment (OCHEM), and it is freely available at http://ochem.eu/article/68104 . Surprisingly, this model does not use any in vitro measurements. The logic of the decision steps used to develop the model and the reason to skip inclusion of in vitro measurements is described. We also show that inclusion of in vitro assays would not improve the accuracy of the model. PMID- 27120772 TI - Movement disorders and motor impairments following repeated head trauma: A systematic review of the literature 1990-2015. AB - BACKGROUND: There is increasing attention on the long-term sequelae following multiple concussions and traumatic brain injury (TBI) in later life. The majority of the research has focused on long-term cognitive impairments and behavioural changes. Despite being researched and reported, long-term motor dysfunction and movement disorders as a consequence of concussions and TBI have not received due consideration. REVIEW: This study used a systematic review and qualitative analysis that focused on two key areas: (1) identified movement disorders in individuals with a reported history of repeated concussions or repeated mild-to moderate TBIs; and (2) identified motor impairments in individuals with a history of repeated concussions or repeated mild-to-moderate TBIs. Fourteen studies investigating long-term movement disorders or motor impairments as a result of repeated concussions or TBI met the selection criteria. Study ratings were moderate-to-high; therefore, evidence was strong enough to conclude that repeated concussions or repeated mild/moderate TBIs did affect the motor system. CONCLUSION: The evidence in this systematic review highlights the need for future studies to include motor outcomes along with cognitive and behavioural outcomes when assessing the long-term effects of repeated concussions or repeated mild/moderate TBIs. PMID- 27120771 TI - Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations. AB - BACKGROUND: Three pregnancies with male offspring in one family were complicated by severe polyhydramnios and prematurity. One fetus died; the other two had transient massive salt-wasting and polyuria reminiscent of antenatal Bartter's syndrome. METHODS: To uncover the molecular cause of this possibly X-linked disease, we performed whole-exome sequencing of DNA from two members of the index family and targeted gene analysis of other members of this family and of six additional families with affected male fetuses. We also evaluated a series of women with idiopathic polyhydramnios who were pregnant with male fetuses. We performed immunohistochemical analysis, knockdown and overexpression experiments, and protein-protein interaction studies. RESULTS: We identified a mutation in MAGED2 in each of the 13 infants in our analysis who had transient antenatal Bartter's syndrome. MAGED2 encodes melanoma-associated antigen D2 (MAGE-D2) and maps to the X chromosome. We also identified two different MAGED2 mutations in two families with idiopathic polyhydramnios. Four patients died perinatally, and 11 survived. The initial presentation was more severe than in known types of antenatal Bartter's syndrome, as reflected by an earlier onset of polyhydramnios and labor. All symptoms disappeared spontaneously during follow-up in the infants who survived. We showed that MAGE-D2 affects the expression and function of the sodium chloride cotransporters NKCC2 and NCC (key components of salt reabsorption in the distal renal tubule), possibly through adenylate cyclase and cyclic AMP signaling and a cytoplasmic heat-shock protein. CONCLUSIONS: We found that MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter's syndrome. MAGE-D2 is essential for fetal renal salt reabsorption, amniotic fluid homeostasis, and the maintenance of pregnancy. (Funded by the University of Groningen and others.). PMID- 27120773 TI - Tunable White Fluorescent Copper Gallium Sulfide Quantum Dots Enabled by Mn Doping. AB - Fluorescence of semiconductor quantum dots (QDs) can be tuned by engineering the band gap via size and composition control and further doping them with impurity ions. Targeting on highly bright white-emissive I-III-VI -type copper gallium sulfide (Cu-Ga-S, CGS) host QDs with the entire visible spectral coverage of blue to red, herein, Mn(2+) ion doping, through surface adsorption and lattice diffusion is fulfilled. Upon doping a distinct Mn emission from (4)T1-(6)A1 transition successfully appears in white photoluminescence (PL) of undoped CGS/ZnS core/shell QDs and with varying Mn concentration a systematic white spectral evolution of CGS:Mn/ZnS QDs is achievable with high PL quantum yield retained. The origins of white PL of CGS:Mn/ZnS QDs that is well decomposed into three emission bands are appropriately assigned. The resulting single-phased, doped QDs are then employed as near-UV-to-white down converters for the fabrication of white light-emitting diodes (LEDs). Electroluminescent properties of white QD-LEDs depending on Mn concentration of CGS:Mn/ZnS QDs and forward current are also discussed in detail. PMID- 27120774 TI - Editorial in this issue. PMID- 27120775 TI - Editorial. PMID- 27120776 TI - Difference of opinion - Which is the best treatment on a 2 cm complete endophitic tumor on the posterior side of the left kidney? Opinion: Cryoablation. PMID- 27120777 TI - Difference of opinion - Which is the best treatment on a 2 cm complete endophitic tumor on the posterior side of the left kidney? Opinion: Robotic partial nephrectomy. PMID- 27120778 TI - Male fertility potential alteration in rheumatic diseases: a systematic review. AB - BACKGROUND: Improved targeted therapies for rheumatic diseases were developed recently resulting in a better prognosis for affected patients. Nowadays, patients are living longer and with improved quality of life, including fertility potential. These patients are affected by impaired reproductive function and the causes are often multifactorial related to particularities of each disease. This review highlights how rheumatic diseases and their management affect testicular function and male fertility. MATERIALS AND METHODS: A systematic review of literature of all published data after 1970 was conducted. Data was collected about fertility abnormalities in male patients with systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, ankylosing spondylitis, Behcet disease and gout. Two independent researchers carried out the search in online databases. RESULTS: A total of 19 articles were included addressing the following diseases: 7 systemic lupus erythematosus, 6 Behcet disease, 4 ankylosing spondylitis, 2 rheumatoid arthritis, 2 dermatomyositis and one gout. Systemic lupus erythematosus clearly affects gonadal function impairing spermatogenesis mainly due to antisperm antibodies and cyclophosphamide therapy. Behcet disease, gout and ankylosing spondylitis patients, including those under anti-TNF therapy in the latter disease, do not seem to have reduced fertility whereas in dermatomyositis, the fertility potential is hampered by disease activity and by alkylating agents. Data regarding rheumatoid arthritis is scarce, gonadal dysfunction observed as consequence of disease activity and antisperm antibodies. CONCLUSIONS: Reduced fertility potential is not uncommon. Its frequency and severity vary among the different rheumatic diseases. Permanent infertility is rare and often associated with alkylating agent therapy. PMID- 27120779 TI - Three-dimensional reconstructive kidney volume analyses according to the endophytic degree of tumors during open partial or radical nephrectomy. AB - OBJECTIVES: To investigate the renal function outcomes and contralateral kidney volume change measured by using a 3-dimensional reconstructive method after open partial nephrectomy (PN) or open radical nephrectomy (RN) according to the endophytic degree of tumors. MATERIALS AND METHODS: We included 214 PN and 220 RN patients. According to the endophytic degree of the tumors, we divided patients into 3 groups. Patients were assessed for renal function and kidney volume change both preoperatively and postoperatively at 6 months. Kidney volume was calculated by using personal computer-based software. Subgroup analyses was performed for tumor >4cm. RESULTS: Larger and complex tumors were more frequent in the RN group than PN group. Among patients with exophytic and mild endophytic tumors, the mean postoperative renal function was well preserved in PN group and the mean contralateral kidney volume significantly increased in the RN compared to the PN group (PN, 145.55 to 149.98mL; 3.0% versus RN, 143.93 to 169.64mL;17.9% p=0.006). However, in fully endophytic tumors, compensatory hypertrophy of the contralateral kidney was similar between PN and RN (PN, 138.16 to 159.64mL; 15.5% versus RN, 138.65 to 168.04mL; 21.2% p=0.416) and renal functional outcomes were similar between both groups. These results were also confirmed in tumors >4cm in size. CONCLUSIONS: In fully endophytic tumors, especially large tumors, the postoperative renal function and contralateral kidney volume were similar; therefore, we should consider RN preferentially as surgical option for these tumors. PMID- 27120780 TI - Stiffness-controlled three-dimensional collagen scaffolds for differentiation of human Wharton's jelly mesenchymal stem cells into cardiac progenitor cells. AB - Stem cell-based regenerative therapy has emerged as a promising treatment for myocardial infarction. The aim of this study is to develop stiffness-controlled collagen scaffolds to allow proliferation and differentiation of mesenchymal stem cell (MSCs) into cardiac progenitor cells. In this study transforming growth factor beta2 (TGF-beta2), was used to induce stem cell differentiation into cardiac lineage cells. Collagen scaffolds were cross-linked with cross-linkers, 1 Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), and N-Hydroxysuccinimide (NHS). The results showed that collagen scaffolds cross-linked with 25/50 and 50/50 of EDC mM/NHS mM cross-linkers exhibited little difference in shape and size, the scaffold cross-linked with 50/50 of cross-linkers demonstrated better interconnectivity and higher Young's modulus (31.8 kPa) than the other (15.4 kPa). SEM observation showed that MSCs could grow inside the scaffolds and interact with collagen scaffolds. Furthermore, greater viability and cardiac lineage differentiation were achieved in MSCs cultured on stiffer scaffolds. The results suggest that three-dimensional type I collagen scaffolds with suitable cross-linking to adjust for stiffness can affect MSC fate and direct the differentiation of MSCs into cardiac progenitor cells with/without TGF-beta2. These stiffness-controlled collagen scaffolds hold great potential as carriers for delivering MSCs differentiated cardiac progenitor cells into infracted hearts. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2234 2242, 2016. PMID- 27120781 TI - In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems. AB - Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions. PMID- 27120782 TI - p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma. AB - p75NTR, a member of TNF receptor family, is the low affinity receptor common to several mature neurotrophins and the high affinity receptor for pro neurotrophins. Brain-Derived Neurotrophic Factor (BDNF), a member of neurotrophin family has been described to play an important role in development and progression of several cancers, through its binding to a high affinity tyrosine kinase receptor B (TrkB) and/or p75NTR. However, the functions of these two receptors in renal cell carcinoma (RCC) have never been investigated. An overexpression of p75NTR, pro-BDNF, and to a lesser extent for TrkB and sortilin, was detected by immunohistochemistry in a cohort of 83 clear cell RCC tumors. p75NTR, mainly expressed in tumor tissues, was significantly associated with higher Fuhrman grade in multivariate analysis. In two derived-RCC lines, 786-O and ACHN cells, we demonstrated that pro-BDNF induced cell survival and migration, through p75NTR as provided by p75NTR RNA silencing or blocking anti p75NTR antibody. This mechanism is independent of TrkB activation as demonstrated by k252a, a tyrosine kinase inhibitor for Trk neurotrophin receptors. Taken together, these data highlight for the first time an important role for p75NTR in renal cancer and indicate a putative novel target therapy in RCC. PMID- 27120783 TI - CYB5R1 links epithelial-mesenchymal transition and poor prognosis in colorectal cancer. AB - Colorectal cancers show significant tumor cell heterogeneity within the same core genetic background. Epithelial-mesenchymal transition (EMT) is an important functional aspect of this heterogeneity and hallmark of colorectal cancer progression. Here, we identify CYB5R1, an enzyme involved in oxidative stress protection and drug metabolism, as an indicator of EMT in colon cancer. We demonstrate high CYB5R1 expression in colorectal cancer cells undergoing EMT at the infiltrative tumor edge and reveal an extraordinarily strong association of CYB5R1 expression with two core EMT gene expression signatures in a large independent colon cancer data set from The Cancer Genome Atlas (TCGA). Furthermore, we demonstrate that CYB5R1 is required for an infiltrative tumor cell phenotype, and robustly linked with poor prognosis in colorectal cancer. Our findings have important implications for colon cancer cells undergoing EMT and may be exploited for diagnostic and therapeutic purposes. PMID- 27120784 TI - Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma. AB - The miR-145-5p, which induces TP53-dependent apoptosis, is down-regulated in several tumors, including hepatocellular carcinomas (HCCs), but some HCCs show physiological expression of this miR. Here we demonstrate that in HCC cells carrying wild-type TP53 the steady activation of the miR-145 signaling selects clones resistant to apoptosis via up-regulation of the oncogenic miR-483-3p. Expression of the miR-145-5p and of the miR-483-3p correlated negatively in non neoplastic liver (n=41; rho=-0.342, P=0.028), but positively in HCCs (n=21; rho=0.791, P<0.0001), which we hypothesized to be due to impaired glucose metabolism in HCCs versus normal liver. In fact, when liver cancer cells were grown in low glucose, miR-145-5p lowered miR-483-3p expression, allowing apoptosis, whereas when cells were grown in high glucose the levels of miR-483-3p increased, reducing the apoptotic rate. This indicates that depending on glucose availability the miR-145-5p has double effects on the miR-483-3p, either inhibitory or stimulatory. Moreover, resistance to apoptosis in clones overexpressing both miR-145-5p and miR-483-3p was abrogated by silencing the miR 483-3p. Our data highlight a novel mechanism of resistance to apoptosis in liver cancer cells harbouring wild type TP53 and suggest a potential role of miR-145-5p and miR-483-3p as druggable targets in a subset of HCCs. PMID- 27120785 TI - Reduction in expression of the benign AR transcriptome is a hallmark of localised prostate cancer progression. AB - BACKGROUND: Despite the importance of androgen receptor (AR) signalling to prostate cancer development, little is known about how this signalling pathway changes with increasing grade and stage of the disease. OBJECTIVE: To explore changes in the normal AR transcriptome in localised prostate cancer, and its relation to adverse pathological features and disease recurrence. DESIGN: Publically accessible human prostate cancer expression arrays as well as RNA sequencing data from the prostate TCGA. Tumour associated PSA and PSAD were calculated for a large cohort of men (n=1108) undergoing prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed a meta-analysis of the expression of an androgen-regulated gene set across datasets using Oncomine. Differential expression of selected genes in the prostate TCGA database was probed using the edgeR Bioconductor package. Changes in tumour PSA density with stage and grade were assessed by Student's t-test, and its association with biochemical recurrence explored by Kaplan-Meier curves and Cox regression. RESULTS: Meta-analysis revealed a systematic decline in the expression of a previously identified benign prostate androgen-regulated gene set with increasing tumour grade, reaching significance in nine of 25 genes tested despite increasing AR expression. These results were confirmed in a large independent dataset from the TCGA. At the protein level, when serum PSA was corrected for tumour volume, significantly lower levels were observed with increasing tumour grade and stage, and predicted disease recurrence. CONCLUSIONS: Lower PSA secretion-per-tumour volume is associated with increasing grade and stage of prostate cancer, has prognostic relevance, and reflects a systematic perturbation of androgen signalling. PMID- 27120786 TI - IDH-1R132H mutation status in diffuse glioma patients: implications for classification. AB - WHO2007 grading of diffuse gliomas in adults is well-established. However, IDH mutations make classification of gliomas according to the WHO2007 edition controversial. Here, we characterized IDH-1R132H mut status in a cohort of 670 adult patients with different WHO2007 grades of diffuse glioma. Patient characteristics, clinical data and prognoses were obtained from medical records. Patients with IDH-1R132H mut were younger and had better clinical outcomes than those without mutations. Differences in age among patients with astrocytomas of different WHO2007 grades were eliminated after patients were grouped based on IDH 1R132H status. IDH-1R132H mut was present more often in patients with lower Ki-67 and MGMT protein levels and higher mutant p53 levels. Ki-67 was also strongly associated with WHO2007 grade independently of IDH-1R132H mut status. Moreover, patients with Ki-67<30 survived longer than those with Ki-67>=30, regardless of IDH-1R132H mut status. Patients in the IDH-1R132H mut group with lower MGMT protein levels also had better clinical outcomes than those in other groups. Our results indicate that to better treat gliomas, IDH mutation status should be included when determining WHO2007 grade in glioma patients. PMID- 27120787 TI - The development and validation of a CT-based radiomics signature for the preoperative discrimination of stage I-II and stage III-IV colorectal cancer. AB - OBJECTIVES: To investigative the predictive ability of radiomics signature for preoperative staging (I-IIvs.III-IV) of primary colorectal cancer (CRC). METHODS: This study consisted of 494 consecutive patients (training dataset: n=286; validation cohort, n=208) with stage I-IV CRC. A radiomics signature was generated using LASSO logistic regression model. Association between radiomics signature and CRC staging was explored. The classification performance of the radiomics signature was explored with respect to the receiver operating characteristics(ROC) curve. RESULTS: The 16-feature-based radiomics signature was an independent predictor for staging of CRC, which could successfully categorize CRC into stage I-II and III-IV (p <0.0001) in training and validation dataset. The median of radiomics signature of stage III-IV was higher than stage I-II in the training and validation dataset. As for the classification performance of the radiomics signature in CRC staging, the AUC was 0.792(95%CI:0.741-0.853) with sensitivity of 0.629 and specificity of 0.874. The signature in the validation dataset obtained an AUC of 0.708(95%CI:0.698-0.718) with sensitivity of 0.611 and specificity of 0.680. CONCLUSIONS: A radiomics signature was developed and validated to be a significant predictor for discrimination of stage I-II from III IV CRC, which may serve as a complementary tool for the preoperative tumor staging in CRC. PMID- 27120788 TI - Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis. AB - The matrix metalloprotease ADAMTS1 (A Disintegrin And Metalloprotease with ThromboSpondin repeats 1) has been involved in tumorigenesis although its contributions appeared ambiguous. To understand the multifaceted actions of this protease, it is still required a deeper knowledge of its implication in heterogeneous tumor-stroma interactions. Using a syngeneic B16F1 melanoma model in wild type and ADAMTS1 knockout mice we found distinct stroma versus tumor functions for this protease. Genetic deletion of ADAMTS1 in the host microenvironment resulted in a drastic decrease of tumor growth and metastasis. However, the downregulation of tumor ADAMTS1 did not uncover relevant effects. Reduced tumors in ADAMTS1 KO mice displayed a paradoxical increase in vascular density and vascular-related genes; a detailed characterization revealed an impaired vasculature, along with a minor infiltration of macrophages. In addition, ex-vivo assays supported a chief role for ADAMTS1 in vascular sprouting, and melanoma xenografts showed a relevant induction of its expression in stroma compartments. These findings provide the first genetic evidence that supports the pro-tumorigenic role of stromal ADAMTS1. PMID- 27120789 TI - The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer. AB - Breast cancer is the leading cause of cancer-associated deaths in women worldwide. Clinical biomarkers give information on disease progression and identify relevant biological pathways. A confounding factor that uncouples markers from disease outcome is the ability of tumor cells to mutate and evade clinical intervention. Therefore, we focussed on apoptotic genes that modulate tumor regression. Using gene and tissue microarray analyses, we identified an association of Bcl-2 interacting killer (Bik) with poor breast cancer prognosis. Bik prognostic ability was independent of Estrogen Receptor/Progesterone Receptor and Her2 status. Additionally, Bik was independent of anti-apoptotic Bcl-2, Bcl xL, Mcl-1 and Bcl-w suggesting a complex mechanism of tumor promotion identified by Bik high tumors. Bik also stimulates autophagy, which can contribute to enhanced tumor fitness. We found a significant association between the autophagy marker ATG5 and Bik. Combined high expression level of ATG5 and Bik was a stronger predictor of outcome than either alone. Thus, our study identifies Bik as a novel, independent prognostic biomarker for poor outcomes in breast cancer and suggests that Bik-mediated autophagy contributes to disease recurrence. PMID- 27120790 TI - Mesothelin's minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane. AB - TRAIL has been extensively explored as a cancer drug based on its tumor-selective activity profile but it is incapable per se of discriminating between death receptors expressed by normal host cells and transformed cancer cells. Furthermore, it is well documented that surface tethering substantially increases its biologic activity. We have previously reported on Meso-TR3, a constitutive TRAIL trimer targeted to the biomarker MUC16 (CA125), in which the entire ectodomain of human mesothelin was genetically fused to the TR3 platform, facilitating attachment to the cancer cells via the MUC16 receptor. Here, we designed a truncation variant, in which the minimal 64 amino acid MUC16 binding domain of mesothelin was incorporated into TR3. It turned out that the dual domain biologic Meso64-TR3 retained its high MUC16 affinity and bound to the cancer cells quickly, independent of the TR3/death receptor interaction. Furthermore, it was substantially more potent than Meso-TR3 and TR3 in vitro and in a preclinical xenograft model of MUC16-dependent ovarian cancer. Phenotypically, Meso64-TR3 is more closely related to non-targeted TR3, evident by indistinguishable activity profiles on MUC16-deficient cancers and similar thermal stability characteristics. Overall, Meso64-TR3 represents a fully human, MUC16-targetd TRAIL-based biologic, ideally suited for exploring preclinical and clinical evaluation studies in MUC16-dependent malignancies. PMID- 27120791 TI - Palmitoylated claudin7 captured in glycolipid-enriched membrane microdomains promotes metastasis via associated transmembrane and cytosolic molecules. AB - In epithelial cells claudin7 (cld7) is a major component of tight junctions, but is also recovered from glycolipid-enriched membrane microdomains (GEM). In tumor cells, too, cld7 exists in two stages. Only GEM-located cld7, which is palmitoylated, promotes metastasis. Searching for the underlying mechanism(s) revealed the following.The metastatic capacity of the rat pancreatic adenocarcinoma cell line ASML is lost by a knockdown (kd) of cld7 and is not regained by rescuing cld7 with a mutated palmitoylation site (cld7mPalm). ASML cld7kd and ASML-cld7mPalm cells show reduced motility and invasiveness. This is due to cld7, but not cld7mPalm associating with alpha6beta4, ezrin, uPAR and MMP14, which jointly support motility and invasion. Palmitoylated cld7 also is engaged in drug resistance by repressing Pten, allowing activation of the antiapoptotic PI3K/Akt pathway. An association of cld7mPalm with the major Pten phosphorylating kinases does not restore apoptosis resistance as phosphorylated Pten is not guided towards GEM to compete with non-phosphorylated Pten. The pathway whereby palmitoylated cld7 supports expression of several EMT genes and nuclear translocation of EMT transcription factors remains to be unraveled. An association with Notch, reduced in ASML-cld7mPalm cells, might be the starting point. Finally, GEM-located, palmitoylated cld7 associates with several components of vesicle transport machineries engaged in exosome biogenesis.Taken together, prerequisites for cld7 acting as a cancer-initiating cell marker are GEM location and palmitoylation, which support a multitude of associations and integration into exosomes. The latter suggests palmitoylated cld7 contributing to message transfer via exosomes. PMID- 27120792 TI - Identification of lipid-phosphatidylserine (PS) as the target of unbiasedly selected cancer specific peptide-peptoid hybrid PPS1. AB - Phosphatidylserine (PS) is an anionic phospholipid maintained on the inner leaflet of the cell membrane and is externalized in malignant cells. We previously launched a careful unbiased selection targeting biomolecules (e.g. protein, lipid or carbohydrate) distinct to cancer cells by exploiting HCC4017 lung cancer and HBEC30KT normal epithelial cells derived from the same patient, identifying HCC4017 specific peptide-peptoid hybrid PPS1. In this current study, we identified PS as the target of PPS1. We validated direct PPS1 binding to PS using ELISA-like assays, lipid dot blot and liposome based binding assays. In addition, PPS1 recognized other negatively charged and cancer specific lipids such as phosphatidic acid, phosphatidylinositol and phosphatidylglycerol. PPS1 did not bind to neutral lipids such as phosphatidylethanolamine found in cancer and phosphatidylcholine and sphingomyelin found in normal cells. Further we found that the dimeric version of PPS1 (PPS1D1) displayed strong cytotoxicity towards lung cancer cell lines that externalize PS, but not normal cells. PPS1D1 showed potent single agent anti-tumor activity and enhanced the efficacy of docetaxel in mice bearing H460 lung cancer xenografts. Since PS and anionic phospholipid externalization is common across many cancer types, PPS1 may be an alternative to overcome limitations of protein targeted agents. PMID- 27120793 TI - Downregulation of miRNA-638 promotes angiogenesis and growth of hepatocellular carcinoma by targeting VEGF. AB - The expression and function of microRNA-638 (miR-638) in hepatocellular carcinoma (HCC) remained unknown. Using the miRNA target prediction tools, we predicted that the vascular endothelial growth factor (VEGF) might be a direct target of miR-638. The aim of this study was to test the hypothesis that downregulation of miRNA-638 promotes angiogenesis and growth of HCC by targeting the VEGF signaling pathway. We found that miR-638 was significantly downregulated in HCC cells and clinical HCC specimens, and miR-638 levels were inversely correlated with tumor size, portal vein invasion and poor prognosis. Overexpression of miR-638 inhibited the processes of tumor angiogenesis in vitro and in vivo. The xenograft mouse model experiments showed miR-638 repressed tumor growth of HCC in vivo. Using a luciferase reporter assay, we identified VEGF as a direct target of miR 638. Subsequent investigation revealed that miR-638 expression was inversely correlated with VEGF expression in human HCC samples. Taken together, these results suggested that miR-638 is a novel therapeutic target for HCC and overexpression of miR-638 could suppress angiogenesis and tumor growth of HCC by inhibiting VEGF signaling. PMID- 27120794 TI - miR-675-5p enhances tumorigenesis and metastasis of esophageal squamous cell carcinoma by targeting REPS2. AB - Recently H19 has been demonstrated to be up-regulated in esophageal squamous cell carcinoma (ESCC) and shown to be the precursor of miR-675 that encodes miR-675-5p conservatively. miR-675 is overexpressed in many human cancers; however, the function of miR-675-5p is largely unknown in ESCC. In this study, we found that miR-675-5p expression was significantly increased in ESCC tissues and cell lines and related with ESCC progression and poor prognosis. We also showed here that down-regulation of miR-675-5p in ESCC cells dramatically induced cell G1 arrest and reduced cell proliferation, colony formation, migration and invasion in vitro as well as tumorigenesis and tumor metastasis in vivo. We subsequently identified that REPS2 was a target gene of miR-675-5p. We found that inhibition of miR-675 5p up-regulated the expression of REPS2, inhibited RalBP1/RAC1/CDC42 signaling pathway. Inversely, interference of REPS2 abrogated the effect induced by miR-675 5p inhibition, which resembled the function of miR-675-5p up-regulation. Taken together, our findings suggested that miR-675-5p might play an oncogenic role in ESCC through RalBP1/RAC1/CDC42 signaling pathway by inhibiting REPS2 and might serve as a valuable prognostic biomarker and therapeutic target for ESCC patients. PMID- 27120797 TI - Prelithiation of Nanostructured Sulfur Cathode by an "On-Sheet" Solid-State Reaction. AB - A novel "on-sheet" solid-state chemical reaction method is designed to fabricate a nanostructured Li2 S-reduced graphene oxide (rGO) cathode using a semi sacrificial sulfur-graphene oxide template. The as-fabricated Li2 S-rGO nanocomposite shows a superior electrochemical performance, e.g., high utilization of Li2 S active materials (86.3 wt%), long cell life (1000 cycles), and excellent rate ability. PMID- 27120796 TI - Prognostic significance of programmed death-1 and programmed death-ligand 1 expression in patients with esophageal squamous cell carcinoma. AB - AIMS: To evaluate the expression of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) and their clinical and prognostic significance in primary esophageal squamous cell carcinoma (ESCC). RESULTS: The expression rate of PD-1 and PD-L1 in ESCC was 33.5% (117/349) and 41.4% (222/536), respectively. PD-L1 expression differed significantly by tumor location, grade, lymph node metastases, and disease stage (P < 0.05). Moreover, its expression was associated with the disease free survival (DFS). Patients with positive PD-L1 expression had reduced risk for disease relapse compared to those without PD-L1 expression (Hazard ratio [HR] = 0.75, 95% confidence interval [CI]: 0.56-1.00, P = 0.048). Kaplan-Meier curves showed the similar result, P = 0.047. However, there was no significant correlation between PD-1 expression and clinicopathological factors or outcome in ESCC (P > 0.05). METHODS: The expression of PD-1 and PD-L1 was assessed by immunohistochemistry on tissue microarrays from 536 primary ESCC who underwent surgery during January 2008 and April 2012 in Zhejiang Cancer Hospital. Chi-square test and Cox proportional hazards regression were employed to analyze the associations between their expressions and clinicopathological variables and survival. CONCLUSIONS: Our results suggested that PD-L1 could be a favorable indicator of prognosis in ESCC. PMID- 27120795 TI - Novel diagnostic and prognostic classifiers for prostate cancer identified by genome-wide microRNA profiling. AB - PURPOSE: This study investigates the diagnostic and prognostic biomarker potential of miRNAs in prostate cancer (PC). RESULTS: We identified several new deregulated miRNAs between non-malignant (NM) and PC tissue samples and between more/less aggressive PC subgroups. We also developed and validated a novel 13 miRNA diagnostic classifier with high sensitivity and specificity for PC. Finally, we trained a new 3-miRNA prognostic classifier (miR-185-5p+miR-221 3p+miR-326) that predicted time to biochemical recurrence (BCR) independently of routine clinicopathological variables in a training radical prostatectomy (RP) cohort (n = 126) as well as in two independent validation cohorts (n = 110 and n = 99). EXPERIMENTAL DESIGN: After RT-qPCR-based profiling of 752 miRNAs in 13 NM and 134 PC tissue samples (cohort 1), we selected 93 top candidate diagnostic/prognostic miRNAs for validation in two independent patient sets (cohort 2: 19 NM and 138 PC; cohort 3: 28 NM and 113 PC samples). Diagnostic potential was assessed by ROC curve analysis and prognostic potential by Kaplan Meier, uni- and multivariate Cox regression analyses. BCR after RP was used as endpoint. CONCLUSIONS: This is the first report of a miRNA signature with significant independent prognostic value demonstrated in three PC patient cohorts. PMID- 27120798 TI - Bioactive Dihydro-beta-agarofuran Sesquiterpenoids from the Australian Rainforest Plant Maytenus bilocularis. AB - Chemical investigations of the CH2Cl2 extract obtained from the leaves of the Australian rainforest tree Maytenus bilocularis afforded three new dihydro-beta agarofurans, bilocularins A-C (1-3), and six known congeners, namely, celastrine A (4), 1alpha,6beta,8alpha-triacetoxy-9alpha-benzoyloxydihydro-beta-agarofuran (5), 1alpha,6beta-diacetoxy-9alpha-benzoyloxy-8alpha-hydroxydihydro-beta agarofuran (6), Ejap-10 (11), 1alpha,6beta-diacetoxy-9beta-benzoyloxydihydro-beta agarofuran (12), and Ejap-2 (13). The major compound 1 was used in semisynthetic studies to afford four ester derivatives (7-10). The chemical structures of 1-3 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configurations of bilocularins A (1) and B (2) were determined by single-crystal X-ray diffraction analysis. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP; none of the compounds were active. However, several compounds showed similar potency to the drug efflux pump inhibitor verapamil in reversing the drug resistance of the human leukemia CEM/VCR R cell line. In addition, similar to verapamil, compound 5 was found to inhibit leucine uptake in LNCaP cells (IC50 = 15.5 MUM), which was more potent than the leucine analogue 2-aminobicyclo[2.2.1]heptane-2-carbocyclic acid. This is the first report of secondary metabolites from Maytenus bilocularis. PMID- 27120799 TI - Usefulness of chair stand time as a surrogate of gait speed in diagnosing sarcopenia. AB - AIM: Determining gait speed as a measure of physical performance is recommended in diagnosing sarcopenia. Gait speed measurements require a certain amount of space (e.g. a 6-m course), and might not be feasible in clinical settings or heath checkup examination sites. We developed a formula to estimate chair stand time based on gait speed, and examined the validity (sensitivity and specificity) of using the estimated chair stand time cut-off point as a surrogate for the recommended gait speed cut-off point. METHODS: Chair stand time was defined as the time it took to stand up from a standard chair five times. Gait speed was calculated from the time required for participants to walk a 6-m course at their usual pace. RESULTS: Simple regression analysis showed a significant negative relationship between chair stand time and gait speed (P < 0.0001), and the estimated formula was derived as follows: five times chair stand time = -8.41 * gait speed + 20.0 (R2 = 0.34). Therefore, the chair stand time cut-off point was estimated to be 13.3 s by inserting the recommended gait speed cut-off of 0.8 m/s in the above formula. Rounding off to make its use simpler, the estimated chair stand time cut-off was 13 s. The sensitivity and specificity of the estimated chair stand time cut off were 0.75 and 0.94, respectively. CONCLUSIONS: Chair stand time might be useful as a surrogate of gait speed when screening for sarcopenia. Geriatr Gerontol Int 2017; 17: 659-661. PMID- 27120800 TI - How cells kill a "killer" messenger. AB - Establishing a link between the nonsense-mediated decay pathway and a gene associated with programmed cell death could explain why this pathway is essential in most, but not all, eukaryotes. PMID- 27120801 TI - Quasistatic Metamaterials: Magnetic Coupling Enhancement by Effective Space Cancellation. AB - A novel and broadly applicable way to increase magnetic coupling between distant circuits in the quasistatic regime is introduced. It is shown how the use of magnetic metamaterials enhances the magnetic coupling between emitting and receiving coils. Results are experimentally demonstrated by measuring a boost on the efficiency of the wireless transmission of power between distant circuits. PMID- 27120802 TI - Association of Psoriasis With the Risk for Type 2 Diabetes Mellitus and Obesity. AB - IMPORTANCE: Psoriasis has been shown to be associated with overweight and type 2 diabetes mellitus. The genetic association is unclear. OBJECTIVE: To examine the association among psoriasis, type 2 diabetes mellitus, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in twins. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, population-based twin study included 34 781 Danish twins, 20 to 71 years of age. Data from a questionnaire on psoriasis was validated against hospital discharge diagnoses of psoriasis and compared with hospital discharge diagnoses of type 2 diabetes mellitus and self-reported BMI. Data were collected in the spring of 2002. Data were analyzed from January 1 to October 31, 2014. MAIN OUTCOMES AND MEASURES: Crude and adjusted odds ratios (ORs) were calculated for psoriasis in relation to type 2 diabetes mellitus, increasing BMI, and obesity in the whole population of twins and in 449 psoriasis-discordant twins. Variance component analysis was used to measure genetic and nongenetic effects on the associations. RESULTS: Among the 34 781 questionnaire respondents, 33 588 with complete data were included in the study (15 443 men [46.0%]; 18 145 women [54.0%]; mean [SD] age, 44.5 [7.6] years). After multivariable adjustment, a significant association was found between psoriasis and type 2 diabetes mellitus (odds ratio [OR], 1.53; 95% CI, 1.03-2.27; P = .04) and between psoriasis and increasing BMI (OR, 1.81; 95% CI, 1.28-2.55; P = .001 in individuals with a BMI>35.0). Among psoriasis-discordant twin pairs, the association between psoriasis and obesity was diluted in monozygotic twins (OR, 1.43; 95% CI, 0.50-4.07; P = .50) relative to dizygotic twins (OR, 2.13; 95% CI, 1.03-4.39; P = .04). Variance decomposition showed that additive genetic factors accounted for 68% (95% CI, 60%-75%) of the variance in the susceptibility to psoriasis, for 73% (95% CI, 58%-83%) of the variance in susceptibility to type 2 diabetes mellitus, and for 74% (95% CI, 72%-76%) of the variance in BMI. The genetic correlation between psoriasis and type 2 diabetes mellitus was 0.13 (-0.06 to 0.31; P = .17); between psoriasis and BMI, 0.12 (0.08 to 0.19; P < .001). The environmental correlation between psoriasis and type 2 diabetes mellitus was 0.10 (-0.71 to 0.17; P = .63); between psoriasis and BMI, 0.05 (-0.14 to 0.04; P = .44). CONCLUSIONS AND RELEVANCE: This study determines the contribution of genetic and environmental factors to the interaction between obesity, type 2 diabetes mellitus, and psoriasis. Psoriasis, type 2 diabetes mellitus, and obesity are also strongly associated in adults after taking key confounding factors, such as sex, age, and smoking, into account. Results indicate a common genetic etiology for psoriasis and obesity. PMID- 27120803 TI - Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay. AB - Conventional cytotoxic therapies for synovial sarcoma provide limited benefit. Drugs specifically targeting the product of its driver translocation are currently unavailable, in part because the SS18-SSX oncoprotein functions via aberrant interactions within multiprotein complexes. Proximity ligation assay is a recently-developed method that assesses protein-protein interactions in situ. Here we report use of the proximity ligation assay to confirm the oncogenic association of SS18-SSX with its co-factor TLE1 in multiple human synovial sarcoma cell lines and in surgically-excised human tumor tissue. SS18-SSX/TLE1 interactions are disrupted by class I HDAC inhibitors and novel small molecule inhibitors. This assay can be applied in a high-throughput format for drug discovery in fusion-oncoprotein associated cancers where key effector partners are known. PMID- 27120804 TI - Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF. AB - Cell migration is a process crucial for a variety of biological events, such as morphogenesis and wound healing. Several reports have described the possible regulation of cell migration by autophagy; however, this remains controversial. We here demonstrate that mouse embryonic fibroblasts (MEFs) lacking autophagy protein 5 (Atg5), an essential molecule of autophagy, moved faster than wild-type (WT) MEFs. Similar results were obtained for MEFs lacking Atg7 and unc-51-like kinase 1 (Ulk1), which are molecules required for autophagy. This phenotype was also observed in Atg7-deficient macrophages. WT MEFs moved by mesenchymal-type migration, whereas Atg5 knockout (KO) MEFs moved by amoeba-like migration. This difference was thought to be mediated by the level of RhoA activity, because Atg5 KO MEFs had higher RhoA activity, and treatment with a RhoA inhibitor altered Atg5 KO MEF migration from the amoeba type to the mesenchymal type. Autophagic regulation of RhoA activity was dependent on GEF-H1, a member of the RhoA family of guanine nucleotide exchange factors. In WT MEFs, GEF-H1 directly bound to p62 and was degraded by autophagy, resulting in low RhoA activity. In contrast, the loss of autophagy increased GEF-H1 levels and thereby activated RhoA, which caused cells to move by amoeba-like migration. This amoeba-like migration was cancelled by the silencing of GEF-H1. These results indicate that autophagy plays a role in the regulation of migration by degrading GEF-H1. PMID- 27120805 TI - Immunomodulatory role of bitter melon extract in inhibition of head and neck squamous cell carcinoma growth. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and leading cause of cancer related mortality worldwide. Despite the advancement in treatment procedures the overall survival rate of patients has not considerably enhanced in the past few decades. Therefore, new strategies to achieve a favorable response for the improvement in the prognosis of HNSCC are urgently needed. In this study, we examined the role of bitter melon extract (BME) in HNSCC tumor microenvironment. Mouse head and neck cancer (SCCVII) cells were subcutaneously injected into the flanks of syngeneic mice. We observed that oral gavage of BME significantly inhibits the tumor growth in mice as compared to control group. Further study suggested that BME inhibits cell proliferation as evident from low expression of proliferating cell nuclear antigen (PCNA) and c Myc in the tumors of BME fed mice as compared to that of control group. We next investigated the role of BME as an immunomodulator in HNSCC model. Forkhead box protein P3+ (FoxP3+) T cells suppress tumor immunity. Our data suggested that BME treatment decreases the infiltrating regulatory T (Treg) cells by inhibiting FoxP3+ populations in the tumors and in spleens. Additionally, BME treatment reduces Th17 cell population in the tumor. However, BME treatment did not alter Th1 and Th2 cell populations. Together, our findings offer a new insight into how bitter melon extract inhibits head and neck tumor growth by modulating cell proliferation and Treg populations, with implications for how to control tumor infiltrating lymphocytes and tumor progression. PMID- 27120806 TI - Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110alpha inhibition. AB - The PIM family of proteins encodes serine/threonine kinases with important roles in protein synthesis and cancer cell metabolism. In glioblastoma (GBM) cell lines, siRNA-mediated knockdown of PIM kinases or pharmacological inhibition of PIM kinases by SGI-1776 or AZD-1208 results in reduced phosphorylation of classic PIM effectors and also elements of the PI3K/mTOR pathway, suggesting interplay between PIM and mTOR signals in GBM cells. Combination of PIM kinase inhibitors with BYL-719, an inhibitor specific for the PI3K catalytic isoform p110alpha, results in enhanced antineoplastic effects in GBM cells. Additionally, pharmacologic inhibition of PIM kinases impairs growth of patient-derived glioma sphere cells, suggesting an important role for PIM kinases in cancer stem cell (CSC) function and survival. Such effects are further enhanced by concomitant inhibition of PIM kinase and p110alpha activities. Altogether these findings suggest that pharmacological PIM targeting in combination with PI3K inhibition may provide a unique therapeutic approach for the treatment of heterogeneous tumors containing populations of therapy-resistant CSCs in GBM. PMID- 27120808 TI - Long-term outcomes of imatinib in patients with FIP1L1/ PDGFRA associated chronic eosinophilic leukemia: experience of a single center in China. AB - BACKGROUND: The FIP1L1/PDGFRA (F/P) fusion gene is the most common clonal genetic abnormality of chronic eosinophilic leukemia (CEL). Tyrosine kinase inhibitors (TKI), such as imatinib, have been demonstrated to be effective therapies for F/P mutated disease. The aim of this study was to analyze the treatment response and long term prognosis in patients with F/P mutated CEL. METHODS: The clinical features and treatment responses of 33 consecutive patients with F/P mutated CEL between August 2006 and October 2014 were analyzed. The 33 cases received imatinib therapy at an initial dose of 100 mg/day (30 patients) or 200 mg/day (3 patients); the maintenance dose depended on the response condition and patient willingness. Through the follow up, the molecular responses were regularly monitored. RESULTS: With a median follow up of 64 months, 94% of the 33 patients with F/P mutated CEL achieved a complete hematologic remission (CHR), and 97% achieved a complete molecular remission (CMR) after a median of 3 (1.5-12) months. Twenty-four cases received maintenance therapy, with a median CMR duration of 43 (5-88) months. Imatinib therapy was discontinued in 8 cases, including 4 cases who experienced relapse, and 4 patients who maintained CHR or CMR after discontinuing therapy with a median time of 47 (2-74) months. One case exhibited primary resistance with a PDGFRA T674I mutation. CONCLUSIONS: F/P mutated CEL has an excellent long-term prognosis following imatinib therapy. A 100 mg daily dose of imatinib is sufficient to induce remission, and a single 100 mg weekly dose maintains a durable remission. A subgroup of patients may maintain a durable remission after discontinuing therapy with a CMR. PMID- 27120807 TI - Inflammatory indexes as predictors of prognosis and bevacizumab efficacy in patients with metastatic colorectal cancer. AB - BACKGROUND: To investigate the role of pre-treatment inflammatory indexes (II) as predictors of prognosis and treatment efficacy in patients with metastatic colorectal cancer mCRC randomized onto the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT) with or without bevacizumab (Bev). RESULTS: In the overall population, PFS and OS were higher in patients with low SII (p = .015 and .002, respectively), low NLR (p = .0001 and <.0001, respectively) and low PLR (p = .004 and .008, respectively). Patients with low NLR in the CT plus Bev arm had a higher PFS than those treated with CT alone (HR = 0.69, p = .021). PATIENTS AND METHODS: Two hundred and eighty-nine patients were considered for this study, 141 receiving CT plus Bev and 148 receiving CT alone. The pre-treatment systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were evaluated to identify a potential correlation with progression-free (PFS) and overall survival (OS) in both the overall population and the 2 treatment arms. CONCLUSION: Our results indicate that II, in particular NLR, are good prognostic and predictive markers for mCRC patients who are candidates for CT plus Bev. PMID- 27120809 TI - Hyaluronic acid-conjugated liposome nanoparticles for targeted delivery to CD44 overexpressing glioblastoma cells. AB - Glioblastoma Multiforme (GBM) is a highly prevalent and deadly brain malignancy characterized by poor prognosis and restricted disease management potential. Despite the success of nanocarrier systems to improve drug/gene therapy for cancer, active targeting specificity remains a major hurdle for GBM. Additionally, since the brain is a multi-cell type organ, there is a critical need to develop an approach to distinguish between GBM cells and healthy brain cells for safe and successful treatment. In this report, we have incorporated hyaluronic acid (HA) as an active targeting ligand for GBM. To do so, we employed HA conjugated liposomes (HALNPs) to study the uptake pathway in key cells in the brain including primary astrocytes, microglia, and human GBM cells. We observed that the HALNPs specifically target GBM cells over other brain cells due to higher expression of CD44 in tumor cells. Furthermore, CD44 driven HALNP uptake into GBM cells resulted in lysosomal evasion and increased efficacy of Doxorubicin, a model anti-neoplastic agent, while the astrocytes and microglia cells exhibited extensive HALNP-lysosome co-localization and decreased antineoplastic potency. In summary, novel CD44 targeted lipid based nanocarriers appear to be proficient in mediating site-specific delivery of drugs via CD44 receptors in GBM cells, with an improved therapeutic margin and safety. PMID- 27120810 TI - A meta-analysis of MSI frequency and race in colorectal cancer. AB - PURPOSE: African Americans (AA) are at a higher risk of colorectal cancer (CRC) and some studies report a higher frequency of microsatellite instability (MSI) in this population while others report lower frequency compared to Caucasians. AIM: To determine and evaluate the association of race and clinical factors with MSI frequency through meta- analysis. METHODS: Twenty-two studies out of 15,105 (1997 2015) were evaluated after a search in different literature databases, using keywords "colorectal cancer, microsatellite instability, African Americans, Caucasians and Hispanics". We used random effect meta-analysis to calculate the MSI frequency in all studies as well as in African American and Caucasian samples. Meta-regression analysis was used to assess the univariate effect of race, gender, age, tumor location and stage on MSI frequency. RESULTS: The overall MSI frequency among CRCs was 17% (95%CI: 15%-19%, I2=91%). In studies with available race data, The MSI rate among AAs, Hispanics and Caucasians were 12%, 12% and 14% respectively and was not significantly different. Sub-group analysis of studies with racial information indicates MSI OR of 0.78 for AAs compared to Caucasians. CONCLUSION: CRCs demonstrate an overall MSI frequency of 17%. MSI frequency differences between AAs and Caucasians were not pronounced, suggesting that other factors contribute to the racial disparity. The methodological approaches and biological sources of the variation seen in MSI frequency between different studies need to be further investigated. PMID- 27120813 TI - Puzzles in bonding and spectroscopy: the case of dicarbon. AB - The unstable molecule C2 has been of interest since its identification as the source of the "Swan band" features observable in the spectra offlames, carbon arcs, white dwarf stars, and comets, and it continues to serve as a focal point for experimental and theoretical discovery. Recent spectroscopic work has identified a quintet state of the molecule for the first time, while new insights into the bond order of C2 in its ground state have been provided by sophisticated computational methods based on valence bond theory. This article gives a review of spectroscopic and computational work on C2 including both historical background and the most recent discoveries. PMID- 27120811 TI - MiR-17-5p regulates cell proliferation and migration by targeting transforming growth factor-beta receptor 2 in gastric cancer. AB - TGFBR2 serves as an initial regulator of the TGF-beta signaling pathway, and loss or reduction of its expression leads to uncontrolled cell growth and invasion. TGFBR2 plays a crucial role in the carcinogenesis and malignant process of gastric cancer, but the mechanism remains unclear. In this study, we found that TGFBR2 protein levels were consistently upregulated in gastric cancer tissues, whereas TGFBR2 mRNA levels varied among these tissues, indicating that a post transcriptional mechanism is involved in the regulation of TGFBR2. MiRNAs are known to regulate gene expression at the post-transcriptional level. Therefore, we performed bioinformatics analyses to search for miRNAs potentially targeting TGFBR2. MiR-17-5p was found to bind to the 3'UTR of TGFBR2 mRNA, and further validation of this specific binding was performed through a reporter assay. An inverse correlation between miR-17-5p and TGFBR2 protein was observed in gastric cancer tissues. Cell studies revealed that miR-17-5p negatively regulated TGFBR2 expression by directly binding to the 3'UTR of TGFBR2 mRNA, thereby promoting cell growth and migration. We also validated the role of TGFBR2 using siRNA and an overexpression plasmid. The results of our study suggest a novel regulatory network in gastric cancer mediated by miR-17-5p and TGFBR2 and may indicate that TGFBR2 could serve as a new therapeutic target in gastric cancer. PMID- 27120814 TI - Concepts and relevance of genome-wide association studies. AB - Genome-wide association study (GWAS) technology has been a primary method for identifying the genes responsible for diseases and other traits for the past 10 years. Over 2,000 human GWAS reports now appear in the scientific journals. The technology is continuing to improve, and has recently become accessible to researchers studying a wide variety of animals, plants and model organisms. Here, we present an overview of GWAS concepts: the underlying biology, the origins of the method, and the primary components of a GWAS experiment. PMID- 27120815 TI - Animal welfare: a social networks perspective. AB - Social network theory provides a useful tool to study complex social relationships in animals. The possibility to look beyond dyadic interactions by considering whole networks of social relationships allows researchers the opportunity to study social groups in more natural ways. As such, network-based analyses provide an informative way to investigate the factors influencing the social environment of group-living animals, and so has direct application to animal welfare. For example, animal groups in captivity are frequently disrupted by separations, reintroductions and/or mixing with unfamiliar individuals and this can lead to social stress and associated aggression. Social network analysis ofanimal groups can help identify the underlying causes of these socially-derived animal welfare concerns. In this review we discuss how this approach can be applied, and how it could be used to identify potential interventions and solutions in the area of animal welfare. PMID- 27120812 TI - Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle. AB - The Warburg effect is a metabolic hallmark of cancer cells; cancer cells, unlike normal cells, exclusively activate glycolysis, even in the presence of enough oxygen. On the other hand, intratumoral heterogeneity is currently of interest in cancer research, including that involving cancer stem cells (CSCs). In the present study, we attempted to gain an understanding of metabolism in CSCs that is distinct from that in non-CSCs. After forming spheroids from the OVTOKO (ovarian clear cell adenocarcinoma) and SiHa (cervical squamous cell carcinoma) cell lines, the metabolites of these cells were compared with the metabolites of cancer cells that were cultured in adherent plates. A principle components analysis clearly divided their metabolic features. Amino acids that participate in tricarboxylic acid (TCA) cycle reactions, such as serine and glutamine, were significantly increased in the spheroids. Indeed, spheroids from each cell line contained more total adenylates than did their corresponding cells in adherent cultures. This study demonstrated that cancer metabolism is not limited to aerobic glycolysis (i.e. the Warburg effect), but is flexible and context dependent. In addition, activation of TCA cycles was suggested to be a metabolic feature of CSCs that was distinct from non-CSCs. The amino acid metabolic pathways discussed here are already considered as targets for cancer therapy, and they are additionally proposed as potential targets for CSC treatment. PMID- 27120816 TI - Rosemary, the beneficial chemistry of a garden herb. AB - The major natural products that are present in the garden herb, rosemary (Rosmarinus officinalis) including the mono di- and triterpenoid, flavonoid and phenolic constituents together with their biological activity as anti-microbial, anti-oxidant, anti-inflammatory, memory-enhancing and tumour-inhibitory agents, are reviewed. PMID- 27120818 TI - The 2015 Paris Climate Change Conference: COP21. PMID- 27120817 TI - Antibiotic resistance and antibiotic alternatives: looking towards the future. PMID- 27120819 TI - RECENT ADVANCES IN SCIENCE--ORGANIC CHEMISTRY. PMID- 27120820 TI - Foreword. The merging of ethnomedicine and ethno-ethics. PMID- 27120821 TI - [ETHNOMEDICAL ETHICS WITH REGARD TO PATIENT PLURIVOCALITY: BETWEEN AUTONOMY AND HETERONOMY]. AB - BACKGROUND: In a contemporary multicultural context that stimulates new dynamics within the plural health systems, the universality of the patient autonomy principle is questioned. Wishing to contribute to the discussion on the topic, this article presents a reflection drawn from a case study in an integrative health care (IHC) clinic. This type of organization, polarizing a variety of care traditions, is an exceptional social laboratory for the analysis of the convergence of values and ethical principles, marked by various cultural foundations. METHODOLOGY: The combination of different data collection methods (semi-structured interviews, participant observation during interprofessional meetings, recorded clinical meetings) permitted the detailed analysis of patients' therapeutic itineraries in a Quebec IHC clinic that grouped practitioners of biomedical, alternative and traditional approaches. The interpretive conceptual framework illustrates the occasionally contradictory intersection of different cultural foundations influencing patient and practitioner explanatory models (EM) and semantic networks (SN). RESULTS: Data analysis highlights a dissonance between a liberal and Cartesian conception of the individual, responsible for the management of his or her health, and some Taoist premises of traditional Chinese medicine (TCM), prioritizing the benefit of the person to his or her self-determination. The monitoring of therapeutic patient itineraries emphasized a phenomenon of EM plurivocality, proposing that individuals can use different voices and embody different characters, autonomous or heteronomous, depending on the context in which they describe their illness. The exploration of the heterogeneity of patients' SNs illustrates that it is possible for the same person to both need to be taken by the hand and desire autonomy. CONCLUSION: Stressing the influence of certain cultural foundations on differential prioritization of patient autonomy principle, this article offers a reflection on the development of narrative ethnomedical ethics respecting the idiosyncrasies and plurivocality of the person. PMID- 27120822 TI - BETWEEN REASON, SCIENCE AND CULTURE: BIOMEDICAL DECISION-MAKING. AB - Over the last decade, we have extensively examined clinical practice in the context of sociocultural, religious and ethnic diversity. Stemming mainly from data collected amongst physicians we reflect, in this paper, upon the norms and values which guide decision-making processes in tertiary pediatric hospital contexts. Clinical ethics is portrayed a neutral guide between competing choices and obligations of hospital units, healthcare professionals, and families, when there is a conflict or divergence in the perspectives concerning the progression of the clinical trajectory. We will chart the sharing/non-sharing of different voices in critical decision-making pathways of maternal-child hospital care. How do "universal" ethical principles accommodate the diversity of perspectives anchored within the ensemble of cultural, social, and religious institutions? Similarly to the image of cosmopolitan urban communities, health care settings are defined by a multiplicity of values brought forth by families and health care professionals from diverse backgrounds. Attempting to seize these logics entails a better grasp of the delicate relationship between the individual and the collective, between personal values and instituted norms, between majorities and minorities. PMID- 27120823 TI - [ETHICAL PRINCIPALS AND A POSTERIORI JUSTIFICATIONS]. AB - It is difficult to conceive that the human being, while being the same everywhere, could be cared for in such different ways in other societies. Anthropologists acknowledge that the diversity of cultures implies a diversity of moral values, thus that in a multicultural society the individual could draw upon different moral frames to justify the peculiarities of her/his demand of care. But how could we determine what is the moral frame that catalyzes behaviour while all we can record are a posteriori justifications of actions? In most multicultural societies where several moralframes coexist, there is an implicit hierarchy between ethical systems derived from a hierarchy of power which falsifies these a posteriori justifications. Moreover anthropologists often fail to acknowledge that individual behaviour does not always reflect individual values, but is more often the result of negotiations between the moralframes available in society and her/his own desires and personal experience. This is certainly due to the difficulty to account for a dynamic and complex interplay of moral values that cannot be analysed as a system. The impact of individual experience on the way individuals give or receive care could also be only weakly linked to a moral system even when this reference comes up explicitly in the a posteriori justifications. PMID- 27120825 TI - (ETHNO-)MEDICAL ETHICS IN GLOBALIZING CHINA: TRACING LOCAL KNOWLEDGE AND ADAPTATION OF BIOMEDICINE. AB - Encounters between several bodies of therapeutic knowledge have led to a restructuring of the entire health system, including a transformation in medical ethics. Defining "new ethics" with both Chinese and international characteristics, is part of the ongoing knowledge production process: plural health ideas, practices and medical sciences develop within the broader framework of social and economic transition. Such transition simultaneously reveals and encourages China's influence and position in an era of globalization including in the technical and knowledge production domains. Re-alignments in medical ethics in Reform China (post-1979) highlight a rather under-explored aspect of medical plurality enabling these ethics to be used as an analytical lens to provide information about social and political issues. In this article, two sets of ethical principles, one from Late Imperial China (Late Ming Era), the other from post-Mao China (1980s), are detailed and analysed. They were selected as case studies mainly because they reflected at the time of their emergence an on-going radical change in society in the realm of health and medicine. Therefore both sets unveil the process of legitimizing a "Chinese medicine" in a context of epistemological shift: such a process takes various conceptual and practicalforms framed along the lines of the current dominant ideological system and constrained by socio-economic and political factors. Finally, issues relative to research ethics, bioethics and the New Health Reform guidelines raised in the 2000s, which represents also a significant historical turn for China, are discussed. Drawn from the overall discussion throughout the text, several concluding remarks contribute to advocate for "win-win" encounters--from the East to the West and from the South to the South, and for more implementable transnational/global ethics designing. PMID- 27120824 TI - [ETHICAL CONDUCT FOR RESEARCH INVOLVING INDIGENOUS PEOPLE IN FRANCE: A COMMENT OF THE CNRS ETHICS COMMITTEE OPINION ON THE IMPERATIVE OF FAIRNESS IN THE RELATIONSHIP BETWEEN RESEARCHERS AND INDIGENOUS PEOPLES]. AB - Historically, scientific research and colonization process have maintained very close ties. In order to frame research involving indigenous peoples and to avoid situations of abuse, some States have developed very detailed ethicalframeworks. In France, there are no ethicalframework comparable to those observed in particular in Anglo-Saxon countries like Canada. Extensive discussions were conducted by the Ethics Committee of the CNRS leading to the adoption of an opinion of a high quality but which appears largely unknown and under-exploited. This opinion deals with "the delicate question of the rights of local and indigenous populations during the research projected conducted with their support in developed and developing countries (DCs)". In this paper, we propose to analyze how this opinion can be considered remarkable because it recognizes the current challenges of research projects involving indigenous people, but also because of his recommendations. We still see that the scope of its recommendations is however limited so far although some encouraging experiences like the recent adoption of the CRIOBE centre code of ethics in French Polynesia can be observed. PMID- 27120826 TI - [THE FORMS OF DELIBERATION INVOLVED IN THE FIELD OF BIOETHICS: TECHNIQUE DELIBERATION AND ETHICS DELIBERATION]. AB - In this article the author examines the formulation of the problem of new technologies with their ethical limits and legal. To do this, in a first it is d'assess the contribuitions of the two most important contemporary philosophers who have treated this subject: Jurgen Habermas and Ronald Dworkin, while trying to put them into dialog with the one who has been one of the founders of l'classic ethics: Aristotle. Then, it tries to answer the question of how could we understand this notion that Dworkin nome "moral dislocation" between the random and the choice or well, as the appointed Habermas, "l'extension of the contingency". Finally, we questioned how the Aristotelian distinction between the technical deliberation and deliberative ethical-moral can contribute to a better understanding of the questions on the decisions and choices that will make the moral agents (such as patients or the judges), as well as those relating to the type of deliberation technique chosen by the doctor or by the health professional. PMID- 27120827 TI - [BETWEEN USAGE AND POLEMIC, AN ARGUMENT IN FAVOUR OF CLARIFYING THE TERMINOLOGY FOR PREIMPLANTATION GENETIC DIAGNOSIS]. AB - Over 30 years ago, preimplantation genetic diagnosis (PGD) was developed to help couples at risk of transmitting a serious genetic disease to their offspring. Today, the range of medical and non-medical uses of PGD has expanded considerably and some raise much controversy. This is the case, for example, with In-Vitro Fertilization to select embryos as 'saviour siblings' or to screen for susceptibility and predisposition to late onset diseases or conditions of variable penetrance. The situation is even more problematic in the case of sex selection or selection of traits that are culturally valued or discredited (such as deafness, behavioral traits, or height). The debate surrounding PGD has been employing terms to describe these particular uses that have contributed to a focus on the negative effects, thus preventing a distinction between the abuses and the benefits of this reproductive technology. In this context, this paper proposes a terminological clarification that would allow distinguishing medical and non-medical use and, therefore, the issues relevant to each. A more accurate and less generic nomenclature could prevent a conflation of different levels of ethical, clinical and social issues under the single term 'PGD'. For the vast majority of medical uses, we propose to keep: 'preimplantation genetic diagnosis (PGD)', which emphasizes that it is a genetic diagnosis. For non-medical uses, we suggest: 'preimplantation genetic trait selection (PGTS)'. PMID- 27120828 TI - On Theriac to Piso, Attributed to Galen. PMID- 27120830 TI - Maintaining a Careful Balance. PMID- 27120829 TI - Translating The Language of Mission. PMID- 27120831 TI - Reflections of A Rabbi Mission Leader. PMID- 27120832 TI - Cultivating an Inheritance. Mission Integration in a Rapidly Changing Health Ministry. PMID- 27120833 TI - Exploring Formation With Other Organizations. PMID- 27120834 TI - Ministry Identity and the Work of Mission Integration. Ascension's Story of Insight and Implementation. PMID- 27120835 TI - Mission Integration and Workplace Spirituality. PMID- 27120837 TI - Mission Integration in Long-Term Care Settings. Four Mission Leaders Discuss the Advantages, Differences and Challenges. PMID- 27120836 TI - The Value of Mutual Inculturation. PMID- 27120838 TI - Ensuring the Values in Value-Based Payments. PMID- 27120839 TI - Bible Interpretation Speaks Mission Integration at Every Turn. PMID- 27120840 TI - The Role of Evaluation In Leadership Formation. PMID- 27120841 TI - The Disconnect between Public Health and Health Care. PMID- 27120842 TI - New Opportunities To Grow PACE. An Expression of Leadership in the Catholic Health Ministry. PMID- 27120843 TI - CATHOLIC HEALTH CARE AND THE JUBILEE OF MERCY. PMID- 27120844 TI - A HOLY YEAR ABOUT DEMONSTRATING MERCY. PMID- 27120845 TI - CATHOLIC HOSPITALS ADDRESS SUBSTANCE ABUSE. PMID- 27120846 TI - MISSION INTEGRATION IN AN INTERNATIONAL CONTEXT. PMID- 27120847 TI - TECH PREDICTIONS. Safety, consistency & control are the EMS buzzwords for 2016. PMID- 27120849 TI - THAT'S HOT. Recommendations for the safety & transport of burn victims. PMID- 27120848 TI - LEADING OTHERS. Competencies for current & aspiring leaders. PMID- 27120850 TI - FULL ATTENTION. Don't differentiate from the differential diagnosis. PMID- 27120851 TI - QUALITY OF VIEW. Video laryngoscopy improves intubation success rate. PMID- 27120852 TI - WHAT'S NEW & WHY. Important changes in the 2015 AHA Guidelines Update. PMID- 27120853 TI - OPIOID CRISIS. Prehospital naloxone administration for opioid-related emergencies. PMID- 27120854 TI - KEEPING COOL? Prehospital targeted temperature management in cardiac arrest patients. PMID- 27120855 TI - BEYOND THE LIMIT. Why we shouldn't terminate resuscitations after 20 minutes. PMID- 27120856 TI - REVISING PROTOCOLS. A back-to-basics training approach to comply with the AHA Guidelines Update. PMID- 27120857 TI - ANTIDYSRHYTHMIC AGENTS. Managing prehospital stable v tach. PMID- 27120858 TI - TICKING TIME BOMB. How aortic aneurysms become aortic catastrophes. PMID- 27120859 TI - DOWN UNDER. Street doc sheds light on EMS culture in Australia. PMID- 27120860 TI - 89th President of APS. PMID- 27120861 TI - Studying Both Sexes: A New Frontier for Discovery. PMID- 27120862 TI - Jane F. Reckelhoff Biography. PMID- 27120863 TI - Switching Gears After Graduate School: From Applied Human Physiology to Basic Science. PMID- 27120864 TI - NIH to End All Chimpanzee Research. PMID- 27120865 TI - WHO Says Ketamine Should Not Be Placed Under International Control. PMID- 27120866 TI - NIH to End Research Targeted by PETA. PMID- 27120867 TI - In Memoriam: Aubrey E. Taylor (1933-2015). PMID- 27120868 TI - [Definition and clinic of the allergic rhinitis]. AB - The allergic rhinitis is the most common immune disorder with a lifetime prevalence of 24% and one of the most common chronic diseases at all--with tendency to rise. It occurs in childhood and influences the patients' social life, school performance and labour productivity. Furthermore the allergic rhinitis is accompanied by a lot of comorbidities, including conjunctivitis, asthma bronchiale, food allergy, neurodermatitis and sinusitis. For example the risk for asthma is 3.2-fold higher for adults with allergic rhinitis than for healthy people. PMID- 27120869 TI - [Diagnostic methods of allergic rhinitis]. AB - The diagnosis of allergic rhinitis is based on a typical history with allergic symptoms and the results of diagnostic tests which are directed in vivo and in vitro on the detection of free or cell bound IgE antibodies. However, the detection of specific IgE antibodies does not imply the presence of clinical relevance, yet merely indicates the presence of a specific sensitization. PMID- 27120870 TI - [Therapy of allergic rhinitis]. AB - If the avoidance of the provoking allergen is insufficient or not possible, medical treatment can be tried. Therapeutics of the first choice for the treatment of the seasonal and persistent allergic rhinitis are antihistamines and topical glucocorticoids. Chromones are less effective so they should only be used for adults with a special indication, for example during pregnancy. Beside the avoidance of the allergen the immunotherapy is the only causal treatment of allergic diseases. PMID- 27120871 TI - [Not Available]. PMID- 27120872 TI - [Dengue fever--not just a tropical infectious disease]. AB - Dengue fever is a viral disease that is transmitted primarily by Aedes mosquitoes, i. e., A. aegypti and A. albopictus. Other species are rarely involved. The disease is caused by dengue virus, an enveloped RNA virus which belongs to the family of flaviviridae. Although most infections are asymptomatic, in 20 to 30 percentages all cases infections are accompanied with high fever and other influenza-like signs of illness. Serious medical conditions with lethal complications also occur. During the last decades, the incidence of dengue fever rose sharply in many tropical and subtropical countries. In some of these regions, dengue is one of the leading causes of death in children. In Europe, since a few years a strong clustering of dengue fever cases has been registered in travelers returning from certain tropical or subtropical regions. Recently, autochthonous outbreaks have been observed on the Atlantic island of Madeira and in a few other regions of South Europe. Treatment of dengue fever is supportive and symptomatic, a specific therapy does not exist. For prevention of disease, vector control is of crucial importance. PMID- 27120873 TI - [The calcium debate--strong bones at the expense of cardiovascular health?]. AB - Ensuring an adequate intake of calcium--by means of supplements, if necessary--is a well-established approach in prevention and therapy of osteoporosis. However, in the meantime concerns have been voiced doubting the safety of calcium supplements. The discussion commenced when a new evaluation of the Auckland calcium intervention study revealed a higher rate of myocardial infarction after administration of calcium, compared to placebo. Two meta-analyses on the cardiovascular risk of calcium supplements supported these findings. Nevertheless, these results are still discussed contentiously. Doubts were increased by the fact that neither a reevaluation of the WHI calcium vitamin D study, nor a current meta-analysis could identify calcium as a cardiovascular risk factor. Against this background the present article analyses the controversial data with respect to the well-known "Hill-criteria" of causality, including consistency of data, magnitude of association, dose-response relationship and biological plausibility. PMID- 27120874 TI - [Not Available]. PMID- 27120875 TI - THE INTERNET OF CARING THINGS. PMID- 27120876 TI - EHRs Can Facilitate Nutrition Management. PMID- 27120877 TI - An Interdisciplinary Approach To Dysphagia. PMID- 27120878 TI - Tech Solutions Need To Focus On Simplicity, Service. PMID- 27120879 TI - Scanning The IT Horizon In Long Term, Post-Acute Care. PMID- 27120880 TI - Preface. Social Networking & New Technologies. PMID- 27120881 TI - Youth Perspectives on Social Media and Technology. PMID- 27120882 TI - Cross-Cultural and Cross-Platform Differences in Youths' Social Networking Site Behavior. PMID- 27120883 TI - Sex and Social Media: New Avenues for Hookups and New Opportunities for Interventions. PMID- 27120884 TI - Online Pro-Eating Disorder (Pro-ED) Activity. PMID- 27120885 TI - Cyberbullying and Online Harassment in Adolescents. PMID- 27120886 TI - Sex Online: Pornography, Sexual Solicitation, and Sexting. PMID- 27120887 TI - Legal Risks of Online Adolescent Communication. PMID- 27120888 TI - Problematic Internet Use During Adolescence and Young Adulthood. PMID- 27120889 TI - Adolescent Social Media Use: The Role of the Pediatric Practitioner and the Healthy Internet Use Model. PMID- 27120890 TI - Adolescent Mobile Phone Use and Mobile Phone-Based Health Promotion. AB - The past 20 years of mobile technology has shifted the ways in which young people communicate and network with one another. Mobile phone use is prevalent among adolescents and therefore is an ideal form of communication for tailored health care. This is especially so given the dramatic uptake in use of mobile technologies in this age group. Technology developments have also altered how physicians and public health interventionists communicate with adolescents for prevention messages. Rapidly changing technology has made the study of how best to communicate with youth a challenge because research can scarcely keep up with advances in the technology. However, best practices from behavior change and communication theories remain a foundation for future intervention directions and how we might best meet the health promotion needs of adolescents. PMID- 27120891 TI - Media Matter: But "Old" Media May Matter More Than "New" Media. PMID- 27120892 TI - Social Media and Mental Health in Adolescent and Young Adult Populations. PMID- 27120893 TI - The Role of Media on Adolescent Substance Use: Implications for Patient Visits. PMID- 27120894 TI - Adolescent Health and the Electronic Health Record: Can It Be a Social Media Tool for Quality Adolescent Care? PMID- 27120895 TI - Physician Blogging for Parent Health Education. PMID- 27120896 TI - [A critical review of applied criminology]. AB - By reporting on a recent decision of the Regional Court (LG) of Marburg (Germany) calling attention to applied criminology, a concept still insufficiently considered in the administration of criminal justice, the paper argues that professional action in the execution of the sentence represents nothing else but applied criminology. Based on this assumption, the paper discusses practical diagnosis and correctional planning. Beyond that, the paper deals with the future of criminology. In the opinion of the author an important aspect for the future of criminology will be if it will be able to remain in touch with the world in which we live, as an independent empirical science. Applied criminology and its methodology constitute the link between science and practice. PMID- 27120897 TI - [Carbon monoxide poisoning by a heating system]. AB - A case of accidental carbon monoxide poisoning in several occupants of two neighboring residential buildings in Hamburg-Harburg (Germany) caused by a defective gas central heating system is described. Because of leaks in one of the residential buildings and the directly adjacent wall of the neighboring house, the gas could spread and accumulated in both residential buildings, which resulted in a highly dangerous situation. Exposure to the toxic gas caused mild to severe intoxication in 15 persons. Three victims died still at the site of the accident. Measures to protect the occupants were taken only with a great delay. As symptoms were unspecific, it was not realized that the various alarms given by persons involved in the accident were related to the same cause. In order to take appropriate measures in time it is indispensible to recognize, assess and check potential risks, which can be done by using carbon monoxide warning devices and performing immediate COHb measurements with special pulse oximeters on site. Moreover, the COHb content in the blood should be routinely determined in all patients admitted to an emergency department with unspecific symptoms. PMID- 27120898 TI - [Surprisingly old skeleton found at Bornheim-Uedorf (Rhein-Sieg-Kreis)--Research results in forensic medicine, anthropology and archaeology]. AB - On April 15th 2014, human skeletal remains were found during digging activities for constructing a new building at Bornheim-Uedorf (Rhein-Sieg-Kreis) near the river Rhine (about 20 meters) in a pit measuring 10 by 10 meters and having a depth of about 150 cm. The skeletal remains were preserved quite well considering the fact that they were located so near to the Rhine, although several skeletal parts were missing. The preserved skeletal remains comprised some skull fragments (including two ear bones of the right side), right scapula, both humeri, left ulna, left radius, left metacarpal bone 2, right metacarpal bones 1, 3 and 4, rib fragments, three thoracic vertebrae, all lumbar vertebrae, one sacral vertebra, pelvis fragments, left femur, proximal part of the left tibial diaphysis, right tibia and diaphysis of both fibulae. The anthropological analysis revealed that the skeletal remains belonged to a 20-to-30-year-old presumably male individual with a body height of about 163 to 173 cm (depending on the formula used for body height estimation). Evidence of intense physical activity and traumatological findings could not be detected on the preserved bones. Periosteal reactions on the bone surface caused by nonspecific bacterial infection were found on the right humerus close to the elbow and on both tibiae, especially the left one. Besides the skeletal remains, metal fragments were recovered--among them an arrowhead, which was typologically classified as an early medieval finding (6th to 7th century). Radiocarbon dating of a bone sample revealed an age of 1561 +/- 19 a BP corresponding to a calibrated age of 436 to 540 AD (1 sigma). So, the archaeological classification of the recovered skeleton into the early medieval period was verified. Amongst the human remains, there was also a metatarsal bone of cattle with cut marks. The animal bone as well as the metal fragments indicated that the find was part of an early medieval burial with typical grave goods. PMID- 27120899 TI - [Homicides committed by women in the area served by the Munich Institute of Legal Medicine]. AB - According to crime statistics only a small percentage of intentional killings are committed by women. Female emancipation has not changed this finding. In spite of numerous studies in the field of psychiatry and social criminology there are few systematic investigations analyzing homicides committed by women under medico legal aspects. The presented data include 127 homicides committed by female offenders, which were assessed at the Munich Institute of Legal Medicine between 1990 and 2010. The results of the evaluation are presented with regard to the type of offence, the motive, the means and method used to commit the offence and the sentence imposed. PMID- 27120900 TI - [Fatal explosion injuries from blasting a cigarette machine]. AB - In the last few years, a growing number of cases have been reported in Germany in which vending machines have been blasted by criminals to get at the money. Thus, it was only a question of time for the first fatalities to occur as a consequence of such careless explosions. We report on the death of a 16-year-old boy who died after triggering an explosion by spraying a deodorant into the coin slot of a cigarette machine. Death was caused by severe craniocerebral trauma due to tertiary blast-related injuries when the front plate of the machine hit the victim's cerebral and facial skull. PMID- 27120901 TI - [Not Available]. PMID- 27120902 TI - [Not Available]. PMID- 27120904 TI - [Not Available]. AB - Although most people consider gambling as a recreational activity, some individuals lose control and enter into a spiral of compulsive gambling with dramatic consequences. The many similarities with substance addiction have led psychiatrists to redefine pathological gambling as a behavioural addiction. A number of neurobiological hypotheses originating from this framework have been tested in the past ten years, in particular using neuroimaging. Similarly to substance addiction, a number of observations indicate a central role for dopamine in pathological gambling. However the underlying mechanism seems to be different and is still poorly understood. Neuropsychological studies have shown decision-making deficits in pathological gamblers, accompanied by a lack of inhibition and cognitive flexibility. This disruption of so-called "executive functions" is typical of frontal lobe dysfunction. Finally, functional MRI studies have revealed abnormal reactivity within the brain regions of the " reward system ", including the striatum and ventro-medial prefrontal cortex. These regions are over-activated by gambling cues, and under-activated by monetary gains. However, the scarcity and heterogeneity of brain imaging studies currently hinders the development of a coherent neurobiological model of pathological gambling. Further replications and diversification of approaches will be needed in the coming years in order to produce such a model that will have the ability to inform prevention and treatment strategies. PMID- 27120903 TI - [Not Available]. AB - Although dopamine replacement therapy has been used in Parkinson's disease since the 1960s, it is only recently that behavioral disorders associated with these drugs have been described. Gathered under the term "behavioral addiction", they include impulse control disorders, dopamine dysregulation syndrome (DDS), and punding. Whereas addiction per se occurs almost exclusively with levodopa, impulse control disorders appear preferentially during dopamine agonist therapy. The prevalence of these disorders is estimated to be 10-17% in Parkinson's disease, a rate far higher than in the general population. Behavioral addiction in Parkinson's disease is thus a major public health problem, notably because of its familial, social, economic and legal implications. Preventive measures, and dopaminergic drug dose reduction, are currently the best strategies for managing these disorders. PMID- 27120905 TI - [Not Available]. AB - Indications of assist devices concern (a) patients with severe/endstage heart failure on waiting list for heart transplantation a bridge to transplant"; (b) " Bridge to recovery" for patients at imminent risk of death due to acute cardiac failure; (c) "Destination therapy" with chronic implantation due to the imbalance between needs and scarcity of cardiac donors. Classical criteria of implantation correspond to severe heart failure resistant to available therapies. In order to avoid too advanced situations, many investigators recommend to discuss assist devices in patients who are dependent on inotropic support or in whom a progressive increase in inotrope doses is needed to maintain an adequate hemodynamic status. Choice of devices includes pneumatic paracorporeal/intracorporeal machines or electromechanical devices. In case of right and left cardiac failure, biventricular assist devices are needed. A significant reduction in death while on waiting list for heart transplant has resulted from technological progresses in assist devices. However; the benefit/risk must be evaluated individually, taking into consideration contraindications and complications such as thrombosis, bleeding, stroke or infection. PMID- 27120906 TI - [Not Available]. PMID- 27120907 TI - [Not Available]. AB - The World Health Organization defines Quality of life (QOL) as an individual's perception of their position in lfe in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. During chronic heart failure several factors contribute to the alteration of QOL: congestion, dyspnea, fatigue, sleep disturbances, anxiety, depression, side effects of medications, impacts on personal life and disruption of social interactions which can modify patients' social roles, life situation and ability to travel. NYHA class, exercise tolerance represent physician-reported patient well-being parameters but do not actually assess alterations expressed by the patient. There are several specific instruments to better evaluate QOL: they can be generic (self-assessment of general well-being), health related QOL (SF36), specific to diseases (Minnesota Living With Heart Failure Questionnaire) or domain specific (anxiety, depression). Impact of ACE inhibitors, angiotensin 2 antagonists, and beta-blockers are small while that of cardiac resynchronization and multidisciplinary management programmes are more efficient. In advanced heart failure when patient recognize equal importance between improvement in QOL and gain in survival, left ventricle assist devices (LVAD) significantly improve QOL at early (3 months) and long-term (2 years) follow up. LVADs allow the rapid return of the patients at home and genuine autonomy in the context of a personalized care plan supervised by the referring centre. Beneficial effects are close to those of heart transplantation but still are limited by the need of taking care of their equipment. PMID- 27120908 TI - [Not Available]. AB - Idiopathic pulmonary fibrosis usually develops after 60 years of age, especially in men, leading to progressive exercise dyspnea. Median survival is about 3 years after diagnosis. This disease emerged in the middle of the last century and is linked to smoking. Mutations of genes encoding surfactant proteins and the telomerase complex may occasionally be present. International diagnostic criteria based on histopathology and computed tomography (CT) define the diagnosis as definite, probable or possible. Recent treatments (pirfenidone and nintedanib) have proven beneficial. Therapeutic advances warrant earlier diagnosis, based on Velcro crackles on pulmonary auscultation or interstitial opacities on CT screening for lung cancer. PMID- 27120909 TI - [Not Available]. AB - In France, the number of students admitted to the second year of medical studies is limited (numerus clausus) by law. In 1971 this limit was first based according to hospital training capacity and subsequently 1979 it has been based on demographic trends. An objective of 250 physicians per 100 000 inhabitants seemed reasonable and required 6 000 students to be trained each year. In 1979, it was decided to restrict the number of students temporarily because of a likely demographic slump after the year 2000. These steps were introduced progressively, in order not to unfairly treat a particular student class. The numerus clausus is also modulated geographically to take into account differences in medical density, as most students set up in the region where they did their medical studies. It is logical to practice preselection for admission to medical school, yet in France every baccalaureat holder can enrol any medical school, and students are totally opposed to preselection. This is why selection takes place at the end of the first year. In the late 1980s, the numerus clausus should have been increased by the health and education ministries, but this was in fact done only ten years later. Estimates of medical demography are complicated by three factors. First, many physicians from European Union member states (mainly Belgium and Romania) practice in France. Second, some students not admitted to the second year of medical studies go to learn medicine in aforeign country before returning to sit the French national examination at the end of the sixth year. Third, public hospitals hire foreign physicians from outside the EU (mainly Algeria and Morocco), who then stay in France permanently. Thus, EU-level decisions are needed to harmonize the medical numerus clausus across member states. The hiring of physicians from non EU countries by French hospitals should be more tightly controlled. PMID- 27120910 TI - [Not Available]. PMID- 27120911 TI - [Not Available]. AB - Important preventive measures carried out in the herds of domestic animals have found improving the health status of farms, particularly for contagious diseases subject to mandatory declaration and accompanying drastic but necessary eradication measures in infected flocks. However it is more difficult to apply these same biosecurity measures on wildlife that may have been contaminated or not by domestic animals. The growing number of emerging infectious diseases of wildlife may reflect increased vigilance, but most often the result of a change in the ecology of the host, the causative agent or both. So, wildlife may be reservoirs of pathogens that can infect domestic herds again but mostly for the majority of them contaminating humans. This is the case, for example, of West Nile virus (WNV), avian influenza virus, rabies virus, Nipah virus, diseases transmitted by ticks, tuberculosis, brucellosis, hepatitis E or some parasitic zoonoses. PMID- 27120912 TI - [Not Available]. AB - More than 1 240 species of bats are known; many of them are insectivorous, others are frugivorous and some american species are haematophagous. More than 100 diferent viruses are associated with these mammals, particularly Rhabdoviridae (Lyssavirus like rabies virus), Paramyxoviridae (like Nipah and Hendra viruses), Filoviridae (Ebola and Marburg viruses) and Coronavirida (viruses causing SARS and MERS). These infections are usually asymptomatic in bats but the mechanism of this tolerance is not yet understood. For those viruses, bats are efficient reservoirs and disseminators. So, they represent a significative risk for human and animal public health, that justifies to set up surveillance of bat-associated viruses and research programs about the particular immunity mechanisms of bats. PMID- 27120913 TI - [Not Available]. AB - Among human parasites, some are also hosted by wild animals which can play a role in their transmission. Different rodents are well known as reservoirs of cutaneous leishmaniasis or of multilocular echinococcosis. But some other groups as fish, can also carry parasites; herrings causes anisakiasis in North Europe, but fresh water fishes do the same for Diphyllobothrium in alpine lakes. Human cases of trichinellosis are rare in countries where veterinary control of pig and horse meat is strict, but cases still occurr with boar meat. All together, the incidence in developped countries is limited, but reducing the prevention would induce re-emergencies of public health importance. PMID- 27120914 TI - [Not Available]. AB - Exotic and pocket pets are becoming more and more popular in developed countries. These animals can carry zoonotic pathogens and young children and elderly people as well as immunocompromised persons are at highest risk to contract severe or even lethal infections. Despite the small number of such incidents or outbreaks compared to the large number of exotic and pocket pets owned by households, risk of infection still exist. Basic hygienic rules and a regular veterinary and medical check-up should be apply regularly to reduce such a risk. PMID- 27120915 TI - A Vision for Healthcare Leadership Excellence. PMID- 27120916 TI - AN INTERVIEW WITH ACHE's 2016-2017 Chairman. PMID- 27120917 TI - Advancing a Total-Systems Approach to Patient Safety. 3 Award-Winning Health Systems Share Their Initiatives. PMID- 27120919 TI - Use a Problem-Solving Lens. PMID- 27120918 TI - Radically Redesigning Patient Safety. PMID- 27120920 TI - 5 Strategies for a Successful Career Handoff. PMID- 27120921 TI - Price Transparency Is Not Enough. Indecipherable billing statements are indefensible. PMID- 27120922 TI - A Blueprint for Superior Customer Care. PMID- 27120923 TI - The Power of Partnership. PMID- 27120924 TI - Drug Prices: A Policy Puzzle. PMID- 27120925 TI - The Ever-Changing CEO. PMID- 27120926 TI - Boards' Practices Evolving. PMID- 27120927 TI - Improving the Health of Populations. PMID- 27120928 TI - Leading Change With Grit and Resiliency. PMID- 27120930 TI - [Not Available]. AB - Because of the significant costs related to the treatment of end-stage kidney disease by dialysis, Belgian Health Care Authorities proposed in June 2009 an early multidisciplinary care of the chronic kidney disease (CKD) in a so-called clinical pathway (CP). Working on the hypothesis that inclusion into a CP could result in reduced morbidity and mortality and delayed admission on dialysis, we initiated a retrospective cohort study on dialyzed patients for whom a prior CKD diagnosis was made between June 1, 2009 and August 31, 2013 in the Nephrology Dept of Erasme Hospital. The exposed patient group was defined as enrolled patients into a CP (n = 25), the control patients were free of any CP (n = 25). Survival analyses were performed to search for an association between the inclusion into a CP and the time period needed to reach dialysis, but also to find a possible impact of CP on mortality and risk of hospitalization. The present study showed that CKD-CP significantly delayed the time of dialysis initiation (HR = 0.48 [0.27-0.87]; p = 0.015) but also reduced mortality (HR = 0.10 [0.02-0.53]; p = 0.007) and hospitalization risk (HR = 0.30 [0.11-0.83]; p = 0.020) after starting dialysis. These data suggest the benefit of a multidisciplinary care of CKD patients. However, a larger scale study is necessary to confirm these results. PMID- 27120931 TI - [Not Available]. AB - This is the clinical history of a term baby born at home who presents a severe hyperbilirubinemia. The medical monitoring was assessed by a private midwife according to parental choice. On the third day of life, the newborn presented an icterus and was exposed to natural daylight in the familial greenhouse under the midwife recommandations. On that day, no laboratory test precised the bilirubin level. On the fifth day, a blood sampling revealed a very high blood bilirubinemia (31 mg/dl or 527 mmol/L), the baby is refered to our NICU and underwent an exchange transfusion. The radiological assessment report structural abnomalies in basal ganglia seen on both MRI and transfontannellar echography. These lesions are known to be responsible of cerebral palsy and hearing loos. The neurophysiologic investigations showed background abnormaly and depression. The extensive blood sampling excluded haemolysis. The clinical examination brought out neurologic impairement and weight loos in this exclusively breastfed baby. This clinical case point out the increasing risk of home Kernicterius as hospital stays diminish and homebirth enthousiasm rise up. The present clinical situation vouches for an adaptation of care giving to both mother and child at home in order to avoid this severe illness. PMID- 27120932 TI - [Not Available]. AB - Gamma Knife treatments of arteriovenous malformations (AVM) are performed for about 40 years. This article presents the results of 123 patients treated for a brain AVM at the Gamma Knife Center ULB-Hopital Erasme. Radiosurgical treatment is proposed following multidisciplinary discussion of the best therapeutic strategy based on specific parameters of the AVM. Gamma Knife irradiation was achieved for an AVM residue after endovascular embolization for 84% of patients, after microsurgery for 7% of patients, or after previous radiosurgical irradiation for 6% of patients. The whole volume of the nidus was irradiated in a single session for all patients. A mean margin dose of 22.3 Gy was delivered to the nidus, which had a mean volume of 3.3 cc. The maximum dose ranged from 30 Gy to 50 Gy (mean 44.1 Gy). All patients were prospectively followed after treatment with serial angio-MR and/or conventional angiography. A retrospective analysis shows complete obliteration of the AVM for 109 patients (89%) after 6 to 52 months (mean 32 months). For 14 patients the nidus was only partially obliterated from the radiosurgical procedure; for 9 patients a second irradiation was performed with subsequent complete occlusion of the AVM in all cases. So, 118 of 123 patients (96%) irradiated by Gamma Knife in 1 or 2 sessions were cured. Four patients bled after irradiation and before complete occlusion of the AVM, with neurological deficit for 2 patients. Transient neurological symptoms develop after treatment for 12 patients (10%), associated with postradic edema treated with corticoids. Permanent neurological worsening occurred in 5 patients (4%). Gamma Knife treatment of cerebral arteriovenous malformations is a highly efficient and low-risk therapy when used by a multidisciplinary team. PMID- 27120933 TI - [Not Available]. AB - In Belgium and around the world, the weight-control surgery has grown significantly since the beginning of the 21st century. The principal argument in favour of this type of surgery is the expected reduction of the obesity associated morbidities. However, the expectatif reduction of mortality associated with this kind of surgery is based on a low level of evidence. Besides the mechanical complications, there are a number of health-related problems associated with the post-operative metabolic changes. Authors of the present article have observed four cases presenting with serious affections consecutive to bariatric interventions and reviewed the literature. The most frequent consequence of bariatric surgery is anaemia (15%), which is either due to iron or cyanocobalamine deficiency, followed by neuropathies, bone mineral loss, substance abuse or postprandial hypoglycaemia syndrome. Rare but severe complications are Wernicke's encephalopathy, fulminant hepatitis or hyperoxaluric tubular disease. The prevention, diagnosis and management of these new diseases are becoming a major public health concern. PMID- 27120934 TI - [Not Available]. AB - The implementation of preventive devices is always a difficult task to anticipate. It is also difficult to verify the adequacy of resources used to the needs. For this purpose, the Belgian Red Cross created the computer tool collecting administrative information, diagnostic codes, destination of the patient, triage, level of emergency as well as kinetics of admission to the preventive care station. Data analysis in the various types of events confirms the usefulness of prevention devices. Although it can be improved, the tool is reliable and permits a great extent the adaptative means to the needs. PMID- 27120935 TI - [Not Available]. AB - Male breast cancer is a rare disease, accounting for less than 1% of all breast cancer cases. It is often diagnosed late, at a more advanced stage than its female counterpart. Therefore, it is more commonly treated with mastectomy. In early stages, a conservative treatment associating lumpectomy, sentinel lymph node (SLN) biopsy and whole-breast external beam radiotherapy (EBRT) is possible and has been described. Recently, intra-operative radiation therapy (IORT) has been assessed as an alternative to EBRT in selected female breast cancer cases. Its use has never been described in male patients. In this article, we present the case of a 56 years old man treated with lumpectomy with the excision of the nipple-areola complex, SLN biopsy, and IORT with electron beams (IOERT), for early breast cancer disease. This case demonstrates that the IORT technique is feasible on men with early breast cancer (pT1N0). PMID- 27120936 TI - [Not Available]. AB - We report the case of a 35 year old man, who first presented diffuse muscle pain and then joint pain, especially in the lumbar and right knee level. The diagnosis of gonococcal septicemia is done through positive blood cultures in the absence of genital signs. PMID- 27120937 TI - [Not Available]. PMID- 27120938 TI - [Not Available]. AB - Medicine owes many to Hippocrate, but pneumology traces its origin back to antiquity, from Mesopotamia to ancient Rome. Regarding prehistory: if viscera of this period have not been kept, some bones were. Since Neanderthals, it is then possible to study osteoarticular pathologies (often chronic arthrosis). But no evidence of tuberculosis was found (all thoracic kyphosis are not tuberculosis). Tuberculosis probably appears during the Neolithic age, because of high concentration of population. In ancient times, pneumology was of course not a real medical specialty. However, respiratory illness already constituted a big part of antique medical practice. The purpose of the physician in antiquity was to establish a diagnosis, a prognostic and to propose a treatment. Prognostic revealed to be of great importance in ancient times, since therapeutic efficacy was limited. Contemporary physicians often neglect this part of their practice. In ancient times, physicians also tried to gradually eliminate magic-religious aspects in taking care of the patients. This review will propose a journey from Mesopotamia to ancient Egypt (and its medical papyrus). Very few sources are available concerning medicine in pre-Columbian cultures. However, it is well known that shamans had, besides their religious competences, a great pharmacopoeia. Because of these very few sources, this topic will not be added to this article. Little is known in Europa about chinese medicine before the Jesuit mission in China during the 17th and 18th centuries. Yet, chinese medicine grew in parallel with European's one. Some relevant elements of this medicine will hereafter be shown. PMID- 27120939 TI - [Not Available]. PMID- 27120940 TI - Relationship between water compartments, body composition assessed by bioelectrical impedance analysis and blood pressure in school children. AB - BACKGROUND: Electrical bioimpedance analysis (BIA) is becoming more widely used in clinical practice as a method of body composition analysis. In healthy children blood pressure (BP) changes with age, body mass and height. Until now the relation between water compartments and BP in healthy children has not been evaluated. The aim of this study was to evaluate the relationship between body composition as well as water compartments (measured by electrical bioimpedance) and BP. METHODS: The study was performed in 72 children (32 girls and 40 boys) aged: 6-7 and 12-13 years. BIA measurements were taken using Nutriguard Data Input device with Bianostic electrodes and following parameters were calculated: total body water (TBW), lean body mass (LBM), fat mass (FM), intra- and extracellular water (ICW, ECW) and phase angle alpha. BP was measured twice using the oscillometric method. RESULTS: Elevated BP > 95th percentile for gender, age and height were observed in 9 children. A significant correlation between systolic (S)BP and TBW (R = 0.4023, p < 0.001), LBM (R = 0.3600, p = 0.002), FM (R = 0.4725, p < 0.001), ECW (R = 0.4598, p < 0.001) and body mass index (BMI) (R = 0.4089, p < 0.001) was found. Furthermore, diastolic (D)BP significantly correlated with TBW (R = 0.3056, p = 0.011), LBM (R = 0.2783, p = 0.021), FM (R = 0.3956, p < 0.001), ECW (R = 0.3869, p = 0.001) and BMI (R = 0.3550, p = 0.002). In the studied group malnutrition (weight < 3rd percentile) was found in 8 children and 2 had obesity (BMI > 95th percentile). Growth disorders were found in 6 children (5 of them being undernourished). CONCLUSIONS: In the studied children SBP and DBP correlated with water compartments, lean body and fat masses derived from BIA. The problem of unrecognized hypertension and malnutrition in children and adolescents is still underestimated in the Polish population. PMID- 27120941 TI - Assessment of ovarian reserve in patients with ovarian endometriosis following laparoscopic enucleation of a cyst accompanied by CO2 laser ablation or electroablation. AB - INTRODUCTION: Endometriosis affects about 5-15% of women in the reproductive period. One of the most important complications of pelvic endometriosis is infertility. OBJECTIVE: The assessment of ovarian endometriosis therapy with the use of combined laparoscopic techniques (cyst enucleation with electroablation/CO2 laser ablation) and their influence on the preservation of the ovarian reserve. MATERIALS AND METHOD: Fifty-eight patients aged 19-40 with diagnosed ovarian endometriosis underwent pre-surgical assessment of their ovarian reserve consisting of antral follicle count (AFC), basal ovarian volume (BOV) and FSH level. Twenty-four patients underwent laparoscopic enucleation of the cyst with CO2 laser ablation and thirty-four patients had enucleation with successive electroablation. The ovarian reserve of the patients was reassessed during follow-up assessments three and six months after surgery. RESULTS: In neither group was there a statistically significant decrease of AFC after three or six months. Additionally, in the group that underwent enucleation with electroablation, a significant drop in FSH level was observed after three months. This group was characterized by a statistically significant decrease in BOV at the three- and six-month follow-up assessments. 17% patients had ovarian relapses visible in the ultrasound scan at the six month follow-up assessment. In the group of patients who underwent enucleation with CO2 laser ablation, BOV had not changed significantly, while a high rate of ovarian relapses (39%) was observed. CONCLUSIONS: The lack of significant changes in AFC level after the surgeries suggests an initial positive evaluation of both techniques in the context of ovarian reserve preservation. The detrimental BOV decrease after enucleation with electroablation and high relapse rate after enucleation after CO2 laser ablation shows that further research is needed in order to optimize the laparoscopic techniques of endometriosis therapy. PMID- 27120942 TI - [The impact of the type of anesthesia on postoperative pain after surgical correction of hallux valgus deformity]. AB - BACKGROUND: Different kind of anesthesia are used in hallux valgus surgery e.g general and spinal anesthesia, peripheral blocks (sciatic, femoral, ankle), patient controlled analgesia (PCA), multimodal anesthesia and preemptive local anesthesia. The type of anesthesia can play a key role in postoperative pain control. The aim of the study was to compare the effectiveness of different types of anesthesia in reduction of postoperative pain. MATERIAL AND METHODS: In the years 2009-2015,260 hallux valgus surgeries were performed using chevron, scarf, Mitchell-Kramer or Kramer method. Depending on the kind of anesthesia, patients were assigned to one of the five groups: group A--general, group B--spinal, group C--general with local preemptive, group D--spinal with local preemptive, group E- sciatic (popliteal) block. The level of postoperative pain intensity was measured using a visual analogue scale (VAS) in 2, 4, 8, 12, 16, 24, 48 and 72 hours after surgery. Regardless of the type of anesthesia each patient received three doses of 1000 mg paracetamol, two doses of 100 mg ketoprofen and at the request 7.5 mg morphine sulphate intravenously. During discharge from the hospital followed a day after surgery each patient received a prescription for 325 mg paracetamol + 37.5 mg tramadol hydrochloride . All adverse effects of anesthesia and drugs were reported. RESULTS: During the first 24 hours average pain intensity measured by VAS was increased in group A compared to others (p < 0.05). Between 8 and 24 hours, a similar relationship was observed in group B compared to C, D and E (p < 0.05). At the second and third day after surgery the differences in VAS were not statistically significant. In groups C, D and E we observed decreased use of 7.5 mg morphine sulphate on demand and 325 mg paracetamol + 37.5 mg tramadol hydrochloride. In two patients of group A and one in group B dizziness and nausea after use of 325 mg paracetamol + 37.5 mg of tramadol hydrochloride were noted. Two patients in group B and one of group D had incident of bradycardia. Three patients of group A and C had nausea and vomiting. We did not observe side effects of injected solution of local anesthetics. CONCLUSIONS: Preemptive local anesthetic infiltration combined with general or spinal anesthesia and sciatic (popliteal) block are more effective than isolated general and spinal anesthesia in reducing the level of postoperative pain after hallux valgus surgery. They are also associated with decreased number of complications and reduction of applied analgesics. PMID- 27120943 TI - [Clinical characteristic of patients with acute kidney injury complicated severe cardio-vascular diseases]. AB - INTRODUCTION: Patients with cardiovascular diseases are a group of increased risk of acute kidney injury (AKI). Mortality in this group of patients with AKI, especially treated in intensive care units, is very high. The aim of this study was to evaluate the clinical characteristic of patients with AKI complicated severe cardiovascular diseases. MATERIAL AND METHODS: Retrospective evaluation of 246 questionnaire of patients with AKI in the course of severe cardiovascular diseases treated in the wards of nephrological profile from the malopolska and podkarpackie voivodships in the years 2000-2011 was performed. RESULTS: The group of patients consisted of 157 men and 89 women, with mean age 67.9 +/- 14.8 years. The most common cause of AKI were: acute decompensated heart failure--24 (9.8%), chronic decompensated heart failure--94 (38.2%), cardiac arrest--29 (11.8%), myocardial infarction--48 (19.5%), CABG--12 (4.9%), cardiac valve implantation- 14 (5.7), heart transplantation--4 (1.6%) and aortic aneurysm--21 (8.5%). Age distribution of patients with AKI revealed that most numerous group had 71-80 years. The most of patients (95.9%) with AKI were treated with hemodialysis. The mortality rate in the study group was very high (69.5%). Recovery of renal function was observed in 39 (27.3%) of patients. Signs of kidney disease before AKI was noted in 116 (47.2%) of patients. CONCLUSIONS: Patients with severe cardiovascular complications and AKI had high mortality rate instead of performed hemodialysis treatment. PMID- 27120944 TI - [Brief measure to assess patient perception of self-influence on the disease course-version for hemodialysis]. AB - INTRODUCTION: Self-influence on the disease course has a significant impact on coping with disease and adherence to medical recommendations. AIM: Elaboration of a brief scale for screening of patient perception of self-influence on the course of disease among hemodialysis, which could be used during usual medical practice. METHODS: In the first stage of the study, based on a group focus interview with 6 hemodialysis (mean age 65.2 +/- 14.8 year)--5 women (83%) and 1 men (17%), mean time of dialysis 43.8 +/- 38 months, a list of 51 characteristics of patients with low (LP) and high perception (HP) of self-influence on the curse of disease, was constructed. In the second stage 99 patients (mean age 66.1 +/- 14.7 year)- 51 men (52%) and 48 women (48%), mean time of dialysis 48.7 +/- 48.1 months, assessed scale reliability. They were selected by their nephrologists to groups with LP and HP. Based on the results 11 items had the strongest power of discrimination of those two groups. 15 (13.2%) hemodialysis refused to participate at this part of study. In a third step 70 (mean age 68 +/- 13.3 year) patients--40 men (57.1%) and 30 women (42.9%), mean time of dialysis 48.1 +/- 45.6 months, assessed validity of the tool. RESULTS: The reliability alfa Cronbach = 0.9 and validity tau-Kendall = 0.6. CONCLUSIONS: Scale has a very high reliability and satisfactory validity. It can be used for those of hemodialysis who have problems with adherence to medical recommendations or have difficulty in contact with the medical staff or other patients. PMID- 27120945 TI - [Effect of pre-surgical stress on recovery of patients undergoing hip replacement procedures]. AB - The aim of this study was to assess the effect of emotional stress experienced by patients prior to surgery on the process of post-surgical recovery. The study covered 50 hospitalised patients (31 women and 19 men) who underwent hip replacement procedures. The research relied on STAI-X1 anxiety questionnaire, as well as a specially prepared survey and the analysis of medical documentation. The results of the study suggest that fears most frequently listed by patients include fear of pain and anaesthesia, as well as anxieties related to the possibility of medical complications and the need to rely on a stranger. A positive statistical correlation was found between the level of emotional stress and the occurrence of psychological and care problems in the first three days following the surgery (unfounded anxieties, self-removal of drainage, ports or dressing). In addition, a statistically significant relation was found between the emotional stress level before the surgery and the number of times the patient's blood pressure exceeded 140/90 mmHg (p = 0.0408), as well as his or her consumption of analgesics (p = 0.0033), sedatives (p = 0.0340) and soporific drugs (p = 0.0273) in postoperative period. PMID- 27120946 TI - [Paraneoplastic endocrine syndromes]. AB - Among the most interesting manifestations of neoplasms is the production of functional peptides and hormones that may induce unique clinical syndromes. It has become obvious in the last decades that a wide range of endocrine tumors secrete hormones not normally associated with the tissue in which the neoplasm arises. The resultant syndromes, some of which resemble other endocrine entities, can be the first clinical manifestation of malignant disease or a harbinger of cancer recurrence. The development of these disorders does not necessarily correlate with cancer stage or unfavorable prognosis. Early recognition of paraneoplastic endocrine syndromes is clinically important as it might lead to the detection of underlying malignancy and might prevent delay in treatment. Because paraneoplastic endocrine syndromes often cause considerable morbidity and mortality, effective treatment can improve patient quality and length of life. The aim of this study was to review the most common and the most specific paraneoplastic syndromes associated with the presence of ectopic hormone production. We emphasize the importance of considering the ectopic hormone production in the differential diagnosis of various endocrine entities. PMID- 27120947 TI - [Cardiac syndrome X--epidemiology, diagnostics, ethiopatoghenesis, prognosis, treatment and latest guidelines]. AB - Since first performed coronary angiography it was noticed that many patients with chest pain, abnormal rest electrocardiogram and positive stress test have normal result of coronary angiogram. The cause of this wasn't known. For the first time this disorder was named cardiac syndrome X by Harvey Kemp in 1973. In the new 2013 European Society of Cardiology guidelines regarding diagnosis and treatment of stable coronary artery disease, term cardiac syndrome X was substituted by "angina with normal coronary arteries". This article elaborates epidemiology, diagnostics, ethiopatoghenesis, prognosis and treatment of patients with diagnosis of term cardiac syndrome X in the light of the latest studies and guidelines. PMID- 27120948 TI - [The rare case of osteonecrosis of the jaws in a patient treated with bisphosphonates for osteoporosis]. AB - Bisphosphonates are used primarily in patients with bone metastases and osteoporosis One of the local complications, less well-known to doctors, associated with the use of bisphosphonates is osteonecrosis of the jaw (Biophosphatate Related osteonecrosis of the jaw--BRONJ). It affects approximately 1-10% of patients and may cause diagnostic difficulties because of its similarity to a primary focus in the bone. This issue can be encountered by the doctors of various specialties who use bisphosphonates. The purpose of this study is to present a case of the patient with BRONJ symptoms following the administration of bisphosphonate therapy, which can occur in the doctors practice. Concluding, maintaining good health of the oral cavity before starting the therapy reduces the incidence of BROKJ. Before starting bisphosphonate therapy, all patients should be referred to dental consultation to assess the potential foci of infection in the mouth. PMID- 27120949 TI - [Computed tomography imaging in ureteropelvic junction obstruction--case report]. AB - Ureteropelvic junction obstruction (UPJO) is defined as an impedance in the normal flow of urine from the renal pelvis into the proximal ureter. This leads to an increase urine pressure in the pelvicalyceal system and as a consequence cause hydronephrosis and damage of renal parenchyma. Presence of anomalous vessels crossing the ureter (crossing vessels) is one of the many reasons of UPJ obstruction. We report a case of 32-year-old female patient with chronic abdominal pain and recurrent episodes of pyelonephritis in the past. Contrast enhanced URO-CT was performed in order to determine the cause of complaints. This examination revealed right pelvicalyceal system dilatation and ipsilateral UPJ obstruction. After urological consultation patient was qualified for surgery, which aimed to decompress right pelvicalyceal system by changing anatomical conditions between the ureter and presumably crossing vessels. We demonstrate in the described case the value of contrast enhanced computed tomography URO-CT) in the diagnostic process of UPJ pathology. A multitude of information that we obtain from URO-CT examination allows the surgeon to reveal the cause of abnormal urine flow and choose the optimal operating method to minimize the risk of adverse events (such as intraoperative bleeding from mutilated crossing vessels). PMID- 27120950 TI - [Medical support of the Armed Forces of the Russian Federation: results of activity and tasks for 2016]. AB - The author gives an analysis of activity of the medical service of the Armed Forces in 2015 concerning development of normative legal basis for the military health care, improvement of the level of operational and mobilization readiness of subunits of army group, and military-medical institutions, improvement of effectiveness of treatment and evacuation measures, health resort treatment, medical stuff training optimization, sanitary-and-epidemiologic support, material and technical support improvement, adoption of advanced scientific achievements focusing on medical care delivery to army group, active development and increase in medical information systems, telehealth. system. The author gives data characterizing state and level of development of medical service of the Armed Forces and its dynamics. Main tasks and parameters of development of the service in 2016 and up to 2020 are formulated. PMID- 27120951 TI - [Modern state and prospects of development of medical-and-psychological support of military servicemen of the Armed Forces of the Russian Federation]. AB - The authors analysed state and prospects of medical-and-psychological support of military servicemen, which is supposed to consider as a complex of measures aimed at monitoring of professional psychological health, professional-and psychological expertise, psychophysiological and pharmacological, correction, and medical-and-psychological rehabilitation. Organisation and maintaince of the above mentioned measures should be carried out by specialists of medical--and psychological support groups and medical-and-psychological correction. PMID- 27120952 TI - [Pecularities of organisation and health care delivery to military servicemen under conditions of mid- and high mountains]. AB - The authors present an analysis of adverse climatic factors mid- and high mountains, which have a significant negative impact on fighting facility and capacity for work in military servicemen that may cause an acute mountain sickness and severe complications (high altitude pulmonary edema and high altitude cerebral edema). Complicated mechanisms of organism disorder are shown. Sophisticated medical and tactical factors of mountain theatre of war, defining the nature of actions of troops, require special approaches to organisation of medical support. One of the major tasks of the medical service and the commanders is the timely prevention of health disorders troops in mountainous terrain. PMID- 27120953 TI - [Corrrelation between blood pressure levels in patients with glaucoma (Literature review)]. AB - The problem of correlation between blood pressure levels and intraocular pressure is one of the most talked about. Both, Russian and foreign literature, reflects the heterogeneity of views on the impact of blood pressure changes into the level of intraocular. pressure. At the same time it underestimated the role of systemic cardiovascular changes in the deterioration of visual function in case of primary open-angle glaucoma. Numerous data demonstrate the role of additional factors than average blood pressure levels in advance of glaucoma. More and more researchers tend to assess not only intraocular pressure, but also perfusion pressure as a risk predictor of advance of glaucoma. Correlation between blood pressure level and intraocular pressure has a particular relevance due to the significant improvement of the range of cardiovascular drugs that can affect on intraocular pressure indictors. A number of literature data confirm the need to research variations in blood pressure levels during the day and types of therapy that patients receive. PMID- 27120954 TI - [Hygienic characteristics of daily ration, designed for military servicemen doing call-up military service]. AB - The article gives the hygienic characteristics of the daily diet of soldiers doing call-up military service. The object of study--military servicemen aged 18 22 years doing call-up military service. The material of the study data was obtained from a continuous cross-sectional study of dietary intake among military personnel. Investigation pointed out that consumption of nutrients and energy value of the surveyed military personnel was broadly in accordance with recommended physiological requirements for nutrients and energy for this age group. However; despite the adequacy of energy supply, showed signs of imbalance on the nutrients of rations provided in the military establishment. Structure of consumption of products is not in full compliance with the existing recommendations of the Kazakh academy of Nutrition. PMID- 27120955 TI - [Medical Service of the Lithuanian Armed Forces]. AB - The article is a brief description of the current state of Lithuanian Armed Forces medical service and is based on the study of the open access foreign sources. At the beginning, the general information about Lithuania, its Armed Forces, and their, medical service is presented. Then the medical service particular features are described, with more detail, namely, the organization of the inpatient and outpatient treatment, medical supply, scientific research, combat medicine, medical staff education and training, medical service personnel income. PMID- 27120956 TI - [Military-medical academy celebrates the 60th anniversary]. AB - The first field therapy department in our country was established in the S.M.Kirov Military Medical Academy in November, 1955. The new department was established by merging of academical Department's of military toxicology, nuclear weapon and field therapy course, taught in Hospital Therapy Department. The new department was imposed as teaching and research center of organizational issues of field therapy, pathology and clinic of radiation injuries and injuries due to chemical agents. Scientific researches were also conducted on the same direction. Department was headed by outstanding field therapist such as Ivanosvky B.D., Zakrzhevsky E.B., Gembitsky E.V., Alexeev G.I., Shishmarev Yu.N, Sosukin A.E. Since 2010 the head of department is Khalimov Yu.Sh. Over the last 60 years of its activity department has became a scientific and academic center on field therapy, alma mater of specialists on clinical radiology, clinical toxicology, military professional pathology, and organization of therapeutic medicine for the Armed Forces of the Russian Federation and other foreign countries. Department became famous as in our country as outside. Today department answers neccessary requirements for scientific-and-research work and successful training and professional improvement of the army and navy physicians. PMID- 27120957 TI - [From Leonardo Da Vinci to present days; from the history of antiplague costume]. AB - As a prototype of the antiplague costume can be considered a special clothing, which physicians in medieval Europe wear for protection in plague nidus. Inventor of the first antiplague costume is considered to be a French doctor Charles de Lorme (1619). Much later, in 1878, a Russian professor Pashutin V V offered to use a costume, which looked like a hermetically sealed "bag" with a special breathing device aimed at protection of medical staff. Later, professor O.I. Dogel's respirator became well-known (1889). At the beginning of 20th century as part of the antiplague costume was used a charcoal filter mask, invented by Zelinsky N.D. Requirements to order the use of modern means of individual protection when working in nidus of especially dangerous infections identified sanitary-epidemiological rules, which reflect issues of laboratory workers working and protective clothing, respiratory protection, and view, especially operation, the procedure of putting on, removing and disinfecting antiplague costumes, pneumocostumes, pneumohelmets, isolation suits, gas-protection boxes, etc. PMID- 27120958 TI - [Children's department and child care institutions of the Central military, hospital of People's commissariat during the Great Patriotic War]. AB - The article presents historical data about paediatric health care delivery and escort of children of the Command of the Red Army during their evacuation from Moscow in 1941. Data on foundation of kindergartens of People's commissariat in 1942-1943, their support and foundation of children's department in the hospital is given. Special subdivision governed by the head of child care institutions of the hospital was formed for managing child care institutions. PMID- 27120959 TI - State Prescription Drug and Opioid Abuse Task Force Releases Findings and Recommendations. PMID- 27120961 TI - Credit Report and Interest Questions. PMID- 27120962 TI - Communication and Its Role in Team Building. PMID- 27120960 TI - The Choosing Wisely Initiative. PMID- 27120963 TI - HIPAA Compliance: Know Your Potential Vulnerabilities. PMID- 27120964 TI - Ameloblastoma of the Anterior Mandible: Comprehensive Patient Management. PMID- 27120965 TI - ACCESS TO CARE: WHY I'M A MISSION OF MERCY VOLUNTEER. PMID- 27120966 TI - When Is It Time to Hang Up the Handpiece? PMID- 27120967 TI - Student Loan Strategies for New Dentists. PMID- 27120969 TI - Yielding and flow of cellulose microfibril dispersions in the presence of a charged polymer. AB - The shear flow of microfibrillated cellulose dispersions is still not wholly understood as a consequence of their multi-length-scale heterogeneity. We added carboxymethyl cellulose, a charged polymer, that makes cellulose microfibril dispersions more homogeneous at the submicron and macro scales. We then compared the yielding and flow behavior of these dispersions to that of typical thixotropic yield-stress fluids. Despite the apparent homogeneity of the dispersions, their flow velocity profiles in cone-plate geometry, as measured by rheo-MRI velocimetry, differ strongly from those observed for typical thixotropic model systems: the viscosity across the gap is not uniform, despite a flat stress field across the gap. We describe these velocity profiles with a nonlocal model, and attribute the non-locality to persistent micron-scale structural heterogeneity. PMID- 27120968 TI - Stunting coexisting with overweight in 2.0-4.9-year-old Indonesian children: prevalence, trends and associated risk factors from repeated cross-sectional surveys. AB - OBJECTIVE: The persistence of undernutrition, along with overweight and obesity, constitute the double burden of malnutrition. The present study aimed to: (i) describe the prevalence and trends of concurrent stunting and overweight in Indonesian children; (ii) identify potentially associated risk factors; and (iii) determine whether stunted children are at greater risk of overweight compared with those of healthy height. DESIGN: A secondary data analysis of children aged 2.0-4.9 years in four cross-sectional studies of the Indonesian Family Life Survey. Children's height and BMI Z-scores were calculated based on the WHO Child Growth Standards (2006). We defined 'concurrent stunting and overweight' as height-for-age Z-score +1. Multivariate generalised linear latent and mixed models were used to determine associated risk factors. SETTING: Thirteen out of twenty-seven provinces in Indonesia. SUBJECTS: Children (n 4101) from four waves of the Indonesian Family Life Survey (1993-2007). RESULTS: There were inconsistent trends in the prevalence of concurrent stunting and overweight from waves 1 to 4. Children were more likely to be stunted and overweight when they were in the youngest age group (2.0-2.9 years), were weaned after the age of 6 months, had short-statured mothers or lived in rural areas. Stunted children were significantly more likely to be overweight than healthy-height children (OR>1) but did not differ significantly different across each wave (OR=1.34-2.01). CONCLUSIONS: Concurrent stunting and overweight occurs in Indonesian children aged 2.0-4.9 years. Current policies and programmes need to be tailored for the management of this phenomenon. PMID- 27120970 TI - Identification of potential biomarkers for post-traumatic complications released after trauma-hemorrhage from murine Kupffer cells and its investigation in lung and liver. AB - CONTEXT: Early diagnosis of complications after severe trauma by specific biomarkers remains difficult. OBJECTIVE: Identify potential new biomarkers for early diagnosis of post-traumatic complications. MATERIAL AND METHODS: Mice underwent pressure-controlled hemorrhage or sham procedure. Four hours later, genome-wide expression of isolated Kupffer cells was compared with controls using Affymetrix-Genechip-Expression-Analysis and real-time-PCR. RESULTS: Expression analysis and real-time-PCR revealed a significant increase of gene expression of Cxcl10, Il4ra, Csf2rb2, Lcn2, and Gbp5. CONCLUSION: Cxcl10, Il4ra, Csf2rb2, Lcn2, and Gbp5 might represent new biomarkers for early diagnosis of post-traumatic complications, if they are linked to the development of post-traumatic complications. PMID- 27120971 TI - A silicon carbide nanowire field effect transistor for DNA detection. AB - This work reports on the label-free electrical detection of DNA molecules for the first time, using silicon carbide (SiC) as a novel material for the realization of nanowire field effect transistors (NWFETs). SiC is a promising semiconductor for this application due to its specific characteristics such as chemical inertness and biocompatibility. Non-intentionally n-doped SiC NWs are first grown using a bottom-up vapor-liquid-solid (VLS) mechanism, leading to the NWs exhibiting needle-shaped morphology, with a length of approximately 2 MUm and a diameter ranging from 25 to 60 nm. Then, the SiC NWFETs are fabricated and functionalized with DNA molecule probes via covalent coupling using an amino terminated organosilane. The drain current versus drain voltage (I d-V d) characteristics obtained after the DNA grafting and hybridization are reported from the comparative and simultaneous measurements carried out on the SiC NWFETs, used either as sensors or references. As a representative result, the current of the sensor is lowered by 22% after probe DNA grafting and by 7% after target DNA hybridization, while the current of the reference does not vary by more than +/ 0.6%. The current decrease confirms the field effect induced by the negative charges of the DNA molecules. Moreover, the selectivity, reproducibility, reversibility and stability of the studied devices are emphasized by de hybridization, non-complementary hybridization and re-hybridization experiments. This first proof of concept opens the way for future developments using SiC-NW based sensors. PMID- 27120972 TI - Discovery of a potential lead compound for treating leprosy with dapsone resistance mutation in M. leprae folP1. AB - Dapsone resistance is a serious impediment to the implementation of the present leprosy control strategies. In the recent past, many studies have been undertaken to address the antibiotic activity and binding pattern of dapsone against both native and mutant (Pro55Leu) folP1. Yet, there is no well-developed structural basis for understanding drug action and there is dire need for new antibacterial therapies. In the present study, molecular simulation techniques were employed alongside experimental strategies to address and overcome the mechanism of dapsone resistance. In essence, we report the identification of small molecule compounds to effectively and specifically inhibit the growth of M. leprae through targeting dihydropteroate synthase, encoded by folP1 which is involved in folic acid synthesis. Initially, ADME and toxicity studies were employed to screen the lead compounds, using dapsone as standard drug. Subsequently, molecular docking was employed to understand the binding efficiency of dapsone and its lead compounds against folP1. Further, the activity of the screened lead molecule was studied by means of molecular dynamics simulation techniques. Furthermore, we synthesized 4-(2-fluorophenylsulfonyl)benzenamine, using (2-fluorophenyl)boronic acid and 4-aminobenzenesulfonyl chloride, and the compound structure was confirmed by (1)H NMR and (13)C NMR spectroscopic techniques. Most importantly, the antibacterial activity of the compound was also examined and compared against dapsone. Overall, the result from our analysis suggested that CID21480113 (4-(2 fluorophenylsulfonyl)benzenamine) could be developed into a promising lead compound and could be effective in treating dapsone resistant leprosy cases. PMID- 27120973 TI - Spontaneously ruptured hepatic cyst treated with laparoscopic deroofing and cystobiliary communication closure: A case report. AB - The rupture of a nonparasitic hepatic cyst with biliary communication is rare. We report the case of a patient with a hepatic cyst with biliary communication that spontaneously ruptured and was successfully treated by laparoscopic deroofing and closure of the communication. A 61-year-old woman presented at our hospital with a chief complaint of right upper abdominal pain. Enhanced abdominal CT showed a collapsed hepatic cyst and fluid collection. Drip infusion CT cholangiography showed contrast medium pooling in the collapsed cyst. Therefore, hepatic cyst rupture with biliary communication was diagnosed, and laparoscopic deroofing and closure of the communication were performed. The postoperative course was uneventful, and the patient was discharged on postoperative day 6. In cases of hepatic cyst rupture, even in the presence of biliary communication, laparoscopic deroofing and closure of the communication should be recommended as the first choice treatment. PMID- 27120975 TI - Generation of siRNA Nanosheets for Efficient RNA Interference. AB - After the discovery of small interference RNA (siRNA), nanostructured siRNA delivery systems have been introduced to achieve an efficient regulation of the target gene expression. Here we report a new siRNA-generating two dimensional nanostructure in a formation of nanosized sheet. Inspired by tunable mechanical and functional properties of the previously reported RNA membrane, siRNA nanosized sheets (siRNA-NS) with multiple Dicer cleavage sites were prepared. The siRNA-NS has two dimensional structure, providing a large surface area for Dicer to cleave the siRNA-NS for the generation of functional siRNAs. Furthermore, downregulation of the cellular target gene expression was achieved by delivery of siRNA-NS without chemical modification of RNA strands or conjugation to other substances. PMID- 27120976 TI - Identification of effective exciton-exciton annihilation in squaraine-squaraine copolymers. AB - Ultrafast time-resolved transient absorption spectroscopy is able to monitor the fate of the excited state population in molecular aggregates or polymers. Due to many competing decay processes, the identification of exciton-exciton annihilation (EEA) is difficult. Here, we use a microscopic model to describe exciton annihilation processes in squaraine-squaraine copolymers. Transient absorption time traces measured at different laser powers exhibit an unusual time dependence. The analysis points towards dynamics taking place on three time scales. Immediately after laser-excitation a localization of excitons takes place within the femtosecond time-regime. This is followed by exciton-exciton annihilation which is responsible for a fast decay of the exciton population. At later times, excitations being localized on units which are not directly connected remain so that diffusion dominates the dynamics and leads to a slower decay. We thus provide evidence for EEA tracked by time-resolved spectroscopy which has not been reported that clearly before. PMID- 27120974 TI - Complete genomes of Hairstreak butterflies, their speciation, and nucleo mitochondrial incongruence. AB - Comparison of complete genomes of closely related species enables research on speciation and how phenotype is determined by genotype. Lepidoptera, an insect order of 150,000 species with diverse phenotypes, is well-suited for such comparative genomics studies if new genomes, which cover additional Lepidoptera families are acquired. We report a 729 Mbp genome assembly of the Calycopis cecrops, the first genome from the family Lycaenidae and the largest available Lepidoptera genome. As detritivore, Calycopis shows expansion in detoxification and digestion enzymes. We further obtained complete genomes of 8 Calycopis specimens: 3 C. cecrops and 5 C. isobeon, including a dry specimen stored in the museum for 30 years. The two species differ subtly in phenotype and cannot be differentiated by mitochondrial DNA. However, nuclear genomes revealed a deep split between them. Genes that can clearly separate the two species (speciation hotspots) mostly pertain to circadian clock, mating behavior, transcription regulation, development and cytoskeleton. The speciation hotspots and their function significantly overlap with those we previously found in Pterourus, suggesting common speciation mechanisms in these butterflies. PMID- 27120977 TI - BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer. AB - Paclitaxel in combination with carboplatin improves survival among patients with susceptible ovarian cancers, but no strategy has been established against resistant ovarian cancers. BAG3 (Bcl-2-associated athanogene 3) is one of six BAG family proteins, which are involved in such cellular processes as proliferation, migration and apoptosis. In addition, expression of BAG3 with Mcl-1, a Bcl-2 family protein, reportedly associates with resistance to chemotherapy. Our aim in this study was to evaluate the functional role of BAG3 and Mcl-1 in ovarian cancer chemoresistance and explore possible new targets for treatment. We found that combined expression of BAG3 and Mcl-1 was significantly associated with a poor prognosis in ovarian cancer patients. In vitro, BAG3 knockdown in ES2 clear ovarian cancer cells significantly increased the efficacy of paclitaxel in combination with the Mcl-1 antagonist MIM1, with or without the Bcl-2 family antagonist ABT737. Moreover, BAG3 was found to positively regulate Mcl-1 levels by binding to and inhibiting USP9X. Our data show that BAG3 and Mcl-1 are key mediators of resistance to chemotherapy in ovarian cancer. In BAG3 knockdown ES2 clear ovarian cancer cells, combination with ABT737 and MIM1 enhanced the efficacy of paclitaxel. These results suggest that inhibiting BAG3 in addition to anti-apoptotic Bcl-2 family proteins may be a useful therapeutic strategy for the treatment of chemoresistant ovarian cancers. PMID- 27120978 TI - Physiological and Behavioral Effects of Exposure to Environmentally Relevant Concentrations of Prednisolone During Zebrafish (Danio rerio) Embryogenesis. AB - The presence of synthetic glucocorticoids within the aquatic environment has been highlighted as a potential environmental concern as they may mimic the role of endogenous glucocorticoids during vertebrate ontogeny. Prednisolone is a commonly prescribed synthetic glucocorticoid which has been repeatedly detected in the environment. This study investigated the impact of environmentally relevant concentrations of prednisolone (0.1, 1, and 10 MUg/L) during zebrafish embryogenesis using physiological and behavioral end points which are known to be mediated by endogenous glucocorticoids. The frequency of spontaneous muscle contractions (24 hpf) was significantly reduced by prednisolone and 0.1 MUg/L increased the distance embryos swam in response to a mechanosensory stimulus (48 hpf). The percentage of embryos hatched significantly increased following prednisolone treatment (1 and 10 MUg/L), while growth and mortality were unaffected. The onset of heart contraction was differentially affected by prednisolone while heart rate and oxygen consumption both increased significantly throughout embryogenesis. No substantial effect on the axial musculature was observed. Morphological changes to the lower jaw were detected at 96 hpf in response to 1 MUg/L of prednisolone. Several parameters of swim behavior were also significantly affected. Environmentally relevant concentrations of prednisolone therefore alter early zebrafish ontogeny and significantly affect embryo behavior. PMID- 27120979 TI - Characterization of a new HLA-DRB1 allele: DRB1*14:172. AB - DRB1*14:172 homologous to DRB1*14:01 has been found with a variation in 314 A > G. PMID- 27120980 TI - Mechanical properties and osteogenic potential of hydroxyapatite-PLGA-collagen biomaterial for bone regeneration. AB - A bone graft is a complicated structure that provides mechanical support and biological signals that regulate bone growth, reconstruction, and repair. A single-component material is inadequate to provide a suitable combination of structural support and biological stimuli to promote bone regeneration. Multicomponent composite biomaterials lack adequate bonding among the components to prevent phase separation after implantation. We have previously developed a novel multistep polymerization and fabrication process to construct a nano hydroxyapatite-poly(D,L-lactide-co-glycolide)-collagen biomaterial (abbreviated nHAP-PLGA-collagen) with the components covalently bonded to each other. In the present study, the mechanical properties and osteogenic potential of nHAP-PLGA collagen are characterized to assess the material's suitability to support bone regeneration. nHAP-PLGA-collagen films exhibit tensile strength very close to that of human cancellous bone. Human mesenchymal stem cells (hMSCs) are viable on 2D nHAP-PLGA-collagen films with a sevenfold increase in cell population after 7 days of culture. Over 5 weeks of culture, hMSCs deposit matrix and mineral consistent with osteogenic differentiation and bone formation. As a result of matrix deposition, nHAP-PLGA-collagen films cultured with hMSCs exhibit 48% higher tensile strength and fivefold higher moduli compared to nHAP-PLGA-collagen films without cells. More interestingly, secretion of matrix and minerals by differentiated hMSCs cultured on the nHAP-PLGA-collagen films for 5 weeks mitigates the loss of mechanical strength that accompanies PLGA hydrolysis. PMID- 27120981 TI - A unique PE_PGRS protein inhibiting host cell cytosolic defenses and sustaining full virulence of Mycobacterium marinum in multiple hosts. AB - Despite intense research, PE_PGRS proteins still represent an intriguing aspect of mycobacterial pathogenesis. These cell surface proteins influence virulence in several pathogenic species, but their diverse and exact functions remain unclear. Herein, we focussed on a PE_PGRS member from Mycobacterium marinum, MMAR_0242, characterized by an extended and unique C-terminal domain. We demonstrate that an M. marinum mutant carrying a transposon insertion in MMAR_0242 is highly impaired in its ability to replicate in macrophages and amoebae, because of its inability to inhibit lysosomal fusion. As a consequence, this mutant failed to survive intracellularly as evidenced by a reduced number of cytosolic actin tail-forming bacteria and by quantitative electron microscopy, which mainly localized MMAR_0242::Tn within membrane-defined vacuoles. Functional complementation studies indicated that the C-terminus, but not the N-terminal PE_PGRS domain, is required for intracellular growth/survival. In line with these findings, disruption of MMAR_0242 resulted in a highly attenuated virulence phenotype in zebrafish embryos, characterized by restricted bacterial loads and a failure to produce granulomas. Furthermore, expression of MMAR_0242 in Mycobacterium smegmatis, a non-pathogenic species naturally deficient in PE_PGRS production, resulted in increased survival in amoebae with enhanced cytotoxic cell death and increased survival in infected mice with splenomegaly. Overall, these results indicate that MMAR_0242 is required for full virulence of M. marinum and sufficient to confer pathogenic properties to M. smegmatis. PMID- 27120983 TI - The intersection of autism spectrum disorder and intellectual disability. PMID- 27120982 TI - Dynamic functional connectivity reveals altered variability in functional connectivity among patients with major depressive disorder. AB - Resting-state fMRI (RS-fMRI) has become a useful tool to investigate the connectivity structure of mental health disorders. In the case of major depressive disorder (MDD), recent studies regarding the RS-fMRI have found abnormal connectivity in several regions of the brain, particularly in the default mode network (DMN). Thus, the relevance of the DMN to self-referential thoughts and ruminations has made the use of the resting-state approach particularly important for MDD. The majority of such research has relied on the grand averaged functional connectivity measures based on the temporal correlations between the BOLD time series of various brain regions. We, in our study, investigated the variations in the functional connectivity over time at global and local level using RS-fMRI BOLD time series of 27 MDD patients and 27 healthy control subjects. We found that global synchronization and temporal stability were significantly increased in the MDD patients. Furthermore, the participants with MDD showed significantly increased overall average (static) functional connectivity (sFC) but decreased variability of functional connectivity (vFC) within specific networks. Static FC increased to predominance among the regions pertaining to the default mode network (DMN), while the decreased variability of FC was observed in the connections between the DMN and the frontoparietal network. Hum Brain Mapp 37:2918-2930, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27120984 TI - Individual, parent and social-environmental correlates of caregiving experiences among parents of adults with autism spectrum disorder. AB - INTRODUCTION: Compared to parents of adults with other types of disabilities, parents of adults with autism spectrum disorder (ASD) experience worse well being. Thus, it is crucial to identify the individual, parent and social environmental correlates of caregiving experiences among parents of adults with ASD. METHOD: For this study, 130 parents of adults with ASD responded to a survey about caregiving satisfaction, self-efficacy and burden. RESULTS: Greater future planning and community involvement related to more caregiving satisfaction and increased caregiving self-efficacy, respectively. Less choicemaking of the adult with ASD related to greater caregiving satisfaction and self-efficacy. Maladaptive behaviours and poor health of the adult with ASD related to greater caregiving burden. CONCLUSIONS: Implications for policymakers, practitioners and future research are discussed. PMID- 27120985 TI - South African families raising children with autism spectrum disorders: relationship between family routines, cognitive appraisal and family quality of life. AB - BACKGROUND: The purpose of this study was to investigate the relationship between family routines, cognitive appraisal of the impact of autism spectrum disorders (ASD) on the family and family quality of life (FQOL) in families raising children with ASD in South Africa. METHODS: A sample of 180 families of young children with ASD who were receiving disability-related services in the Gauteng province of South Africa completed a self-administered survey. Structural equation modelling was used to examine the direct relationship between the regularity of family routines and FQOL, and the mediating effect of cognitive appraisal on this relationship. RESULTS: The results suggested a direct, positive relationship between the regularity of family routines and families' satisfaction with their FQOL. Furthermore, cognitive appraisal of the impact of ASD on the family mediated this relationship in a partial manner. CONCLUSION: A higher frequency of regular family routines was strongly associated with a higher satisfaction level of FQOL. Also, cognitive appraisal of the impact of ASD acted as a mechanism through which the regularity of family routines influenced FQOL. We discuss the research and clinical implications of these findings. PMID- 27120986 TI - Functional severity and Latino ethnicity in specialty services for children with autism spectrum disorder. AB - BACKGROUND: Children with autism spectrum disorder (ASD) experience a range of severity levels characterised as levels of support they need for everyday functioning. By this definition, greater levels of severity should warrant greater use of services and supports among children with ASD. In previous studies, Latino children with ASD in the USA have been shown to have lower access to diagnosis and treatment services than White children. However, none have examined service use in relation to severity. In this study, we examined whether there are ethnic disparities between Latino and White children with ASD in specialty autism-related services, and whether functional severity moderates the relationship between ethnicity and receipt of autism services. METHODS: We used data from the Survey of Pathways to Diagnosis and Services, a supplement to the National Survey of Children with Special Health Care Needs and analysed four specialty services commonly used by children with ASD, adjusting for demographic variables. RESULTS: We found that Latino children with ASD who had severe limitations received fewer specialty autism-related services than White children with similarly severe conditions. These disparities were evident despite the fact that the sample of Latino children in these data were more privileged than the general US Latino population. CONCLUSION: Assertive policy initiatives are needed to address these disparities and ensure that these highly vulnerable children with severe functional limitations receive appropriate services and supports. PMID- 27120987 TI - Examining the social participation of children and adolescents with Intellectual Disabilities and Autism Spectrum Disorder in relation to peers. AB - BACKGROUND: Participation in social and physical activities has a number of benefits for children with or without disabilities. However, individuals with disabilities are often excluded from taking part in social activities. Most of the research on activity participation has focused on adults or youth with milder disabilities. However, children and adolescents with severe and complex needs, including those with autism, are often excluded from this type of research because of their complexities and level of functioning. Thus, we examined the social participation and friendships of children and adolescents with severe developmental disabilities, with and without autism, compared with peers without developmental disabilities. METHODS: We compared the activity participation and friendships of typically developing children (n = 210), children with an intellectual disability (ID only; n = 186), and children with autism spectrum disorder plus intellectual disability (ID + ASD; n = 232) between the ages of 3 and 19 years. Parents of these children completed a survey, which included questions about their children's participation in six activities, and the number and quality of their children's friendships. RESULTS: Children and adolescents with ID only and ID + ASD were reported to participate in significantly fewer activities and to participate much less frequently than typically developing peers. Those with ID only and ID + ASD were reported to have fewer friends and poorer quality of friendships. In addition, those with ID + ASD participated even less frequently in some activities and had fewer friends relative to those with ID only. CONCLUSION: It is important to find ways to increase the social and activity participation of children and adolescents with ID only and ID + ASD. Future research should examine the barriers to such participation and factors that impact social participation in this population. PMID- 27120988 TI - Intervention effects on spoken-language outcomes for children with autism: a systematic review and meta-analysis. AB - BACKGROUND: Although spoken-language deficits are not core to an autism spectrum disorder (ASD) diagnosis, many children with ASD do present with delays in this area. Previous meta-analyses have assessed the effects of intervention on reducing autism symptomatology, but have not determined if intervention improves spoken language. This analysis examines the effects of early interventions on spoken-language in children with ASD. METHOD: A systematic review of 1756 studies of children with ASD who participated in early intervention resulted in the inclusion of 26 studies in the current review. These studies included 1738 participants with ASD who were, on average, 3.3 years old (SD = 0.91). RESULTS: This random-effects meta-analysis of spoken-language outcomes for children with ASD who received early intervention as compared with usual treatments yielded a significant overall mean effect size of g = 0.26 (CI = 0.11 to 0.42). On average, children with ASD significantly increased their use of spoken-language following experimental early interventions. Treatments delivered simultaneously by a clinician and a parent resulted in greater gains in spoken-language than treatments delivered by a clinician or parent only. No other participant or study characteristics predicted individual-study effect sizes. CONCLUSIONS: Early intervention improves spoken-language outcomes for children with ASD, and the largest effects are found when both parent and clinician implement the intervention. Recommendations for practice include adding systematic parent training to interventions for spoken language to potentially improve outcomes. Future research should report standard language measures as well as child (cognitive ability and socio-economic status) and intervention characteristics to improve evidence related to the effects of interventions on spoken communication in children with ASD. PMID- 27120989 TI - The proportion of minimally verbal children with autism spectrum disorder in a community-based early intervention programme. AB - BACKGROUND: Estimates of the proportion of children with autism spectrum disorder (ASD) who are minimally verbal vary from 25%to 35%. However, there is a lack of consensus in defining minimally verbal and few detailed reports of communication outcomes for these children following intervention. The aim of this study was to explore how minimally verbal children have been defined and to document the proportion of minimally verbal children in a group of children with ASD receiving a community based early intervention programme. METHOD: A longitudinal cohort design was used to examine the proportion of children who met criteria for minimally verbal in 246 children with ASD when they entered and exited an early intervention programme. RESULTS: Overall, 26.3% of the children in this study exited the programme using 'fewer than five spontaneous and functional words' and 36.4% exited not using 'two word phrases' as indicated by direct assessment. However, our findings were mixed depending on measures and definitions used, with parent report indicating that as many as 29.4% of children were not 'naming at least three objects' consistently, and 43.3% not using 'phrases with a noun and verb' consistently at exit. More than half of the children who entered the programme with minimal speech exited the programme with a similar language profile. A small percentage of children (1.2%-4.7%) regressed in their language level over time. CONCLUSIONS: Despite advances in early intervention, and access to services at a younger age, around a quarter of individuals with ASD in this study exited early intervention with significant communication needs. Our findings are considered in relation to the literature and clinical implications, and future research directions are discussed. PMID- 27120990 TI - Consonant differentiation mediates the discrepancy between non-verbal and verbal abilities in children with ASD. AB - BACKGROUND: Many children with autism spectrum disorder (ASD) demonstrate verbal communication disorders reflected in lower verbal than non-verbal abilities. The present study examined the extent to which this discrepancy is associated with atypical speech sound differentiation. METHODS: Differences in the amplitude of auditory event-related potentials elicited by contrasting consonant-vowel syllables during a passive listening paradigm were used to assess speech sound differentiation in 24 children with ASD and 18 chronological age-matched children with typical development (TD), M age 6.90 years (SD = 1.39). RESULTS: Results revealed that compared with TD peers, children with ASD showed reduced consonant differentiation in the 84- to 308-ms period. Brain responses indexing consonant differentiation were negatively related to the degree of discrepancy in non verbal and verbal abilities and mediated the relationship between diagnostic group membership and the greater discrepancy. CONCLUSIONS: We discuss the theoretical and clinical implications of the brain's response to speech sound contrasts possibly explaining the greater non-verbal versus language ability in children with ASD compared with that in typically developing children. PMID- 27120991 TI - Assessment of cognition and language in the early diagnosis of autism spectrum disorder: usefulness of the Bayley Scales of infant and toddler development, third edition. AB - BACKGROUND: The aim of this study was to test the usefulness of the Cognitive and Language scales Bayley-III in the early assessment of cognitive and language functions in the context of an autism spectrum disorder (ASD) diagnosis. This paper focuses on the application of the Bayley-III and studies the predictive value of the test result in children with ASD with different levels of verbal ability. METHOD: A sample of 135 children (121 boys, 14 girls) with a confirmed ASD diagnosis at age 4 years were assessed with the Bayley-III before 42 months of age (m = 36.49, s = 4.46) and later with other rating scales of different psychological and psycholinguistic functions as part of a longitudinal study [McCarthy Scales of Children's Abilities (MSCA) (n = 48, 90% boys), Kaufman Assessment Battery for Children (K-ABC) (n = 38, 87% boys) or Illinois Test of Psycholinguistic Abilities (ITPA) (n = 44, 89% boys)]. Age assessment in months: MSCA (m = 48.80, s = 3.33), K-ABC (m = 51.80, s = 7.17) and ITPA (m = 54.48, s = 3.34). RESULTS: Lower scores on the cognitive and language Bayley-III scales before 3.5 years of age predicted lower cognitive and oral language levels at 4 years of age. A significant correlation was found between the Cognitive Bayley III Scale and the General Cognitive MSCA Scale, and with the Compound K-ABC Mental Processing. An association between the nonverbal cognitive level and oral language level acquired at 4 years of age was found. CONCLUSIONS: The Bayley-III is a useful instrument in cognitive and language assessment of ASD. PMID- 27120992 TI - Screening for ASD in adults with ID-moving toward a standard using the DiBAS-R and the ACL. AB - BACKGROUND: Identification of Autism Spectrum Disorder (ASD) in persons with intellectual disability (ID) is challenging but essential to allow adequate treatment to be given. This study examines whether the combination of two ASD screening instruments specifically developed for persons with ID, namely, the Diagnostic Behavioral Assessment for ASD-Revised (DiBAS-R) and the Autism Checklist (ACL), improves diagnostic accuracy when used in combination compared to the application of the single instrument. METHOD: A clinical sample of adults with ID who are suspected of having ASD (N =148) was assessed using two ID specific screening scales (DiBAS-R and ACL). The diagnostic validity of the single instruments and of their combination was assessed. RESULTS: While both instruments showed acceptable diagnostic validity when applied alone (DiBAS R/ACL: sensitivity: 75%/91%; specificity: 75%/75%; overall agreement: 75%/83%), specificity increased when two positive screening results were used (88%), and sensitivity increased (95%) when at least one positive screening result was used. CONCLUSIONS: Different combinations of the ASD screening instruments DiBAS-R and ACL lead to improvements in sensitivity and specificity. The complementary use of the ACL in addition to the sole use of the DiBAS-R improves overall accuracy. PMID- 27120993 TI - Possible paradoxical occurrence of inflammatory arthritis in patients with psoriasis treated with biologics: findings in the Biobadaderm cohort. PMID- 27120994 TI - Revealing heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys. AB - The heterogeneous nucleation of primary Si and eutectic Si can be attributed to the presence of AlP. Although P, in the form of AlP particles, is usually observed in the centre of primary Si, there is still a lack of detailed investigations on the distribution of P within primary Si and eutectic Si in hypereutectic Al-Si alloys at the atomic scale. Here, we report an atomic-scale experimental investigation on the distribution of P in hypereutectic Al-Si alloys. P, in the form of AlP particles, was observed in the centre of primary Si. However, no significant amount of P was detected within primary Si, eutectic Si and the Al matrix. Instead, P was observed at the interface between the Al matrix and eutectic Si, strongly indicating that P, in the form of AlP particles (or AlP 'patch' dependent on the P concentration), may have nucleated on the surface of the Al matrix and thereby enhanced the heterogeneous nucleation of eutectic Si. The present investigation reveals some novel insights into heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al Si alloys and can be used to further develop heterogeneous nucleation mechanisms based on adsorption. PMID- 27120996 TI - New Evidence on What Works in Effective Public Reporting. AB - OBJECTIVE: To describe the current state of the public reporting field and provide guidance to public report producers based on the evidence. PRINCIPAL FINDINGS: Public reports should address the questions and priorities that consumers actually have; present information credibly and in a way that is understood by the intended audience; reach the intended audience; and enable consumers to act on the information. CONCLUSIONS: Public reports have advanced greatly in recent years, but there remains much room for improvement. Report producers should continually evaluate their reports and apply the latest evidence to maximize their usefulness and impact. PMID- 27120997 TI - The Establishment of Adult Reference Intervals on Fructosamine in Beijing. AB - BACKGROUND: Fructosamine (FRA) is widely used for diabetes monitor and control as a glycemic marker, especially in patients in whom the measurement of HbA1c may be biased or even unreliable. However, the FRA reference intervals based on Asian population features still keep seldom reported. The objective of this study was to establish the adult FRA reference intervals in Beijing, China. METHODS: A total of 1,497 healthy subjects were separated into three groups by gender and age. Subsequently, FRA levels in the collected serum samples from the reference individuals were tested by automatic chemical analyzer. The obtained data were statistically analyzed with SPSS. RESULTS: The serum FRA level in female group was slightly higher than that in male group without statistical significance. Meanwhile, further analysis indicated that the FRA level gradually increased along with the growth of the age. Compared with the age 20-45 group (248.83 +/- 17.64 MUmol/l) or the age 46-65 group (251.95 +/- 19.63 MUmol/l), the FRA level of the age >65 group (264.63+/- 23.05 MUmol/l) was statistically significantly increased (P < 0.01). To better analyze the difference, the age 20-45 group and the age 46-65 group were combined into an age 20-65 group (249.88 +/-18.39 MUmol/l). In comparison to the age >65 group, the FRA level of age 20-65 group was significantly decreased (P <0.01). CONCLUSION: A novel FRA reference interval of the local healthy population in Beijing was established. The data demonstrated that there was no gender difference in FRA level, however, which was significantly increased in elder persons. PMID- 27120998 TI - Identification of a Potential Regulatory Variant for Colorectal Cancer Risk Mapping to 3p21.31 in Chinese Population. AB - Genome-wide association studies (GWAS) have established chromosome 3p21.31 as a susceptibility locus for colorectal cancer (CRC) that lacks replication and exploration in the Chinese population. We searched potentially functional single nucleotide polymorphisms (SNPs) in the linkage disequilibrium (LD) block of 3p21.31 with chromatin immunoprecipitation-sequencing (ChIP-seq) data of histone modification, and tested their association with CRC via a case-control study involving 767 cases and 1397 controls in stage 1 and 528 cases and 678 controls in stage 2. In addition to the tag SNP rs8180040 (odds ratio (OR) = 0.875, 95% confidence interval (95% CI) = 0.793-0.966, P = 0.008, P-FDR (false discovery rate) = 0.040), rs1076394 presented consistently significant associations with CRC risk at both stages with OR = 0.850 (95% CI = 0.771-0.938, P = 0.001, P-FDR = 0.005) under the additive model in combined analyses. Supported by the analyses of data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), it was suggested that rs1076394 served as an expression Quantitative Trait Loci (eQTL) for gene CCDC12 and NME6, while NME6's expression was obviously higher in CRC tissues. Using biofeature information such as ChIP-seq and RNA sequencing (RNA-seq) data might help researchers to interpret GWAS results and locate functional variants for diseases in the post-GWAS era. PMID- 27120999 TI - Failed pneumoperitoneum for laparoscopic surgery following autologous Deep Inferior Epigastric Perforator (DIEP) flap breast reconstruction: a case report. AB - BACKGROUND: Laparoscopic abdominal surgery may prove difficult in patients who have undergone previous abdominal procedures. No reports in the medical literature have presented an aborted laparoscopic procedure for failed pneumoperitoneum following autologous flap-based breast reconstruction. CASE PRESENTATION: A 55-year-old woman presented with recurrent invasive lobular carcinoma of the right breast as well as a history of ductal carcinoma in situ of the left breast. The patient desired to proceed with bilateral skin- and nipple sparing mastectomies with right axillary lymph node biopsy, followed by immediate bilateral autologous deep inferior epigastric perforator (DIEP) flap-based breast reconstruction. Preoperatively, a computerized tomography angiogram was obtained for reconstructive preparation, which revealed a left adrenal mass. Ensuing work up diagnosed a pheochromocytoma. Given the concern for breast cancer progression, the patient elected to proceed first with breast cancer surgery and reconstruction prior to addressing the adrenal tumor. Subsequently, 3 months later the patient was brought to the operating room for a laparoscopic left adrenalectomy for the pheochromocytoma. With complete pharmacologic abdominal relaxation, the abdomen proved too tight to accommodate sufficient pneumoperitoneum and the laparoscopy was aborted. The patient was evaluated in the outpatient setting for assessment of abdominal wall compliance at regular intervals. Five months later, the patient was taken back to the operating room where pneumoperitoneum was established without difficulty and the laparoscopic left adrenalectomy was performed without complications. CONCLUSION: Pneumoperitoneum for laparoscopic surgery subsequent to autologous DIEP flap based breast reconstruction may prove difficult as a result of loss of abdominal wall compliance. Prior to performing laparoscopy in such patients, surgeons should consider the details of the patient's previous reconstructive procedure and assess potential risk factors for difficulty with insufflation. Lastly, careful abdominal examination should be performed to indicate whether laparoscopy for elective procedures should be delayed until abdominal wall compliance normalizes. PMID- 27121000 TI - The Life Science Exchange: a case study of a sectoral and sub-sectoral knowledge exchange programme. AB - BACKGROUND: Local and national governments have implemented sector-specific policies to support economic development through innovation, entrepreneurship and knowledge exchange. Supported by the Welsh Government through the European Regional Development Fund, The Life Science Exchange(r) project was created with the aim to increase interaction between stakeholders, to develop more effective knowledge exchange mechanisms, and to stimulate the formation and maintenance of long-term collaborative relationships within the Welsh life sciences ecosystem. The Life Science Exchange allowed participants to interact with other stakeholder communities (clinical, academic, business, governmental), exchange perspectives and discover new opportunities. METHODS: Six sub-sector focus groups comprising over 200 senior stakeholders from academia, industry, the Welsh Government and National Health Service were established. Over 18 months, each focus group provided input to inform healthcare innovation policy and knowledge mapping exercises of their respective sub-sectors. Collaborative projects identified during the focus groups and stakeholder engagement were further developed through sandpit events and bespoke support. RESULTS: Each sub-sector focus group produced a report outlining the significant strengths and opportunities in their respective areas of focus, made recommendations to overcome any 'system failures', and identified the stakeholder groups which needed to take action. A second outcome was a stakeholder-driven knowledge mapping exercise for each area of focus. Finally, the sandpit events and bespoke support resulted in participants generating more than L1.66 million in grant funding and inward investment. This article outlines four separate outcomes from the Life Science Exchange programme. CONCLUSIONS: The Life Science Exchange process has resulted in a multitude of collaborations, projects, inward investment opportunities and special interest group formations, in addition to securing over ten times its own costs in funding for Wales. The Life Science Exchange model is a simple and straightforward mechanism for a regional or national government to adapt and implement in order to improve innovation, skills, networks and knowledge exchange. PMID- 27121001 TI - Serological survey of Coxiella burnetii at the wildlife-livestock interface in the Eastern Pyrenees, Spain. AB - BACKGROUND: Coxiella burnetii is a zoonotic bacterium that infects a wide range of animal species and causes the disease Q fever. Both wild and domestic ruminants may be relevant in the epidemiology of C. burnetii infection. In order to investigate the significance of the ruminant host community in the alpine and subalpine ecosystems of the Eastern Pyrenees, Northeastern Spain, in the epidemiology of Q fever, a serological survey was performed on samples from 599 wild and 353 sympatric domestic ruminants. RESULTS: Specific antibodies against C. burnetii were detected with a commercial enzyme-linked immunosorbent assay (ELISA). Domestic sheep showed the highest prevalence (12.7 %, CI 95 % 8.6-16.9), followed by European mouflon (Ovis orientalis musimon) with a 6.8 % prevalence (CI 95 % 1.6-12.1), red deer (Cervus elaphus) with 2.4 % (CI 95 % 0-5.6), and cattle with a prevalence of 1.1 % (CI 95 % 0-3.2). No positive domestic goats, fallow deer (Dama dama), roe deer (Capreolus capreolus) and Southern chamois (Rupicapra pyrenaica) were detected. Sheep flock prevalence was 75 % (nine of the 12 sheep flocks sampled were positive, within-flock prevalence ranging from 11.1 to 25.0 %), whereas cattle herd prevalence was 11.1 % (one out of the nine cattle herds sampled was positive, within-herd prevalence of 10.0 %. CONCLUSIONS: Both domestic and wild ruminants from the alpine and subalpine ecosystems of the Eastern Pyrenees were exposed to C. burnetii. The higher seroprevalence in sheep and its relative abundance suggest that this species may have a major contribution to the ecology of C. burnetii. Conversely, wild ruminants do not seem to represent a relevant host community for C. burnetii maintenance in the Eastern Pyrenees. PMID- 27121002 TI - Tellurium-Assisted Epitaxial Growth of Large-Area, Highly Crystalline ReS2 Atomic Layers on Mica Substrate. AB - Anisotropic 2D layered material rhenium disulfide (ReS2 ) with high crystal quality and uniform monolayer thickness is synthesized by using tellurium assisted epitaxial growth on mica substrate. Benefit from the lower eutectic temperature of rhenium-tellurium binary eutectic, ReS2 can grow from rhenium (melting point at 3180 degrees C) and sulfur precursors in the temperature range of 460-900 degrees C with high efficiency. PMID- 27121003 TI - Rapid Light-Triggered Drug Release in Liposomes Containing Small Amounts of Unsaturated and Porphyrin-Phospholipids. AB - Prompt membrane permeabilization is a requisite for liposomes designed for local stimuli-induced intravascular release of therapeutic payloads. Incorporation of a small amount (i.e., 5 molar percent) of an unsaturated phospholipid, such as dioleoylphosphatidylcholine (DOPC), accelerates near infrared (NIR) light triggered doxorubicin release in porphyrin-phospholipid (PoP) liposomes by an order of magnitude. In physiological conditions in vitro, the loaded drug can be released in a minute under NIR irradiation, while liposomes maintain serum stability otherwise. This enables rapid laser-induced drug release using remarkably low amounts of PoP (i.e., 0.3 molar percent). Light-triggered drug release occurs concomitantly with DOPC and cholesterol oxidation, as detected by mass spectrometry. In the presence of an oxygen scavenger or an antioxidant, light-triggered drug release is inhibited, suggesting that the mechanism is related to singlet oxygen mediated oxidization of unsaturated lipids. Despite the irreversible modification of lipid composition, DOPC-containing PoP liposome permeabilization is transient. Human pancreatic xenograft growth in mice is significantly delayed with a single chemophototherapy treatment following intravenous administration of 6 mg kg(-1) doxorubicin, loaded in liposomes containing small amounts of DOPC and PoP. PMID- 27121004 TI - An essential malaria protein defines the architecture of blood-stage and transmission-stage parasites. AB - Blood-stage replication of the human malaria parasite Plasmodium falciparum occurs via schizogony, wherein daughter parasites are formed by a specialized cytokinesis known as segmentation. Here we identify a parasite protein, which we name P. falciparum Merozoite Organizing Protein (PfMOP), as essential for cytokinesis of blood-stage parasites. We show that, following PfMOP knockdown, parasites undergo incomplete segmentation resulting in a residual agglomerate of partially divided cells. While organelles develop normally, the structural scaffold of daughter parasites, the inner membrane complex (IMC), fails to form in this agglomerate causing flawed segmentation. In PfMOP-deficient gametocytes, the IMC formation defect causes maturation arrest with aberrant morphology and death. Our results provide insight into the mechanisms of replication and maturation of malaria parasites. PMID- 27121006 TI - Transplantation of ovarian granulosa-like cells derived from human induced pluripotent stem cells for the treatment of murine premature ovarian failure. AB - Premature ovarian failure (POF) is a common cause of female infertility, for which there are currently no ideal treatments or medications. Furthermore, apoptosis of ovarian granulosa cells (OGCs) is an important mechanism underlying the decline in ovarian reserve and function. In the present study, several cellular growth factors and hormones were used to induce the differentiation of human induced pluripotent stem cells (iPSCs) into ovarian granulosa-like cells (OGLCs) in vitro. Immunohistochemical staining demonstrated that OGLCs derived from iPSCs strongly expressed granulosa cell markers, including anti-Mullerian hormone, inhibin alpha, inhibin beta and follicle-stimulating hormone receptor, but did not express stem cell markers, including octamer-binding transcription factor 4, SRY (sex determining region Y)-box 2, Nanog and stage-specific embryonic antigen-4 12 days post-induction. In addition, a mouse model of POF was generated by cyclophosphamide treatment. Subsequently, iPSC-derived OGLCs were transplanted into the POF mice (OGLCs-iPSCs-POF group) in vivo. Results indicated that, compared with the control group (POF mice treated with phosphate-buffered saline), the growth state of OGLCs was markedly improved, and mature follicles could be detected in the ovarian tissue of the OGLCs-iPSCs-POF group. Immunohistochemical staining demonstrated that iPSC-derived OGLCs transplanted into POF mice not only exhibited substantial growth in murine ovarian tissues, but also strongly expressed OGC markers. Furthermore, enzyme-linked immunosorbent assays indicated that the levels of the hormone estradiol in peripheral blood samples were significantly enhanced following transplantation of iPSC-derived OGLCs into POF mice. Furthermore, ovarian tissue weight was significantly higher in the OGLCs-iPSCs-POF group compared with in the control group, and the number of atretic follicles in OGLCs-iPSCs-POF mice was significantly reduced, as compared with in the control mice. These results suggest that OGLCs derived from human iPSCs may not only effectively enhance OGC growth and repair damaged ovarian tissue, but may also maintain the ovarian tissue niche, promoting follicular development and maturation in a mouse model of POF. PMID- 27121005 TI - MiR-210 promotes sensory hair cell formation in the organ of corti. AB - BACKGROUND: Hearing loss is the most common sensory defect afflicting several hundred million people worldwide. In most cases, regardless of the original cause, hearing loss is related to the degeneration and death of hair cells and their associated spiral ganglion neurons. Despite this knowledge, relatively few studies have reported regeneration of the auditory system. Significant gaps remain in our understanding of the molecular mechanisms underpinning auditory function, including the factors required for sensory cell regeneration. Recently, the identification of transcriptional activators and repressors of hair cell fate has been augmented by the discovery of microRNAs (miRNAs) associated with hearing loss. As miRNAs are central players of differentiation and cell fate, identification of miRNAs and their gene targets may reveal new pathways for hair cell regeneration, thereby providing new avenues for the treatment of hearing loss. RESULTS: In order to identify new genetic elements enabling regeneration of inner ear sensory hair cells, next-generation miRNA sequencing (miRSeq) was used to identify the most prominent miRNAs expressed in the mouse embryonic inner ear cell line UB/OC-1 during differentiation towards a hair cell like phenotype. Based on these miRSeq results eight most differentially expressed miRNAs were selected for further characterization. In UB/OC-1, miR-210 silencing in vitro resulted in hair cell marker expression, whereas ectopic expression of miR-210 resulted in new hair cell formation in cochlear explants. Using a lineage tracing mouse model, transdifferentiation of supporting epithelial cells was identified as the likely mechanism for this new hair cell formation. Potential miR-210 targets were predicted in silico and validated experimentally using a miR-trap approach. CONCLUSION: MiRSeq followed by ex vivo validation revealed miR-210 as a novel factor driving transdifferentiation of supporting epithelial cells to sensory hair cells suggesting that miR-210 might be a potential new factor for hearing loss therapy. In addition, identification of inner ear pathways regulated by miR-210 identified potential new drug targets for the treatment of hearing loss. PMID- 27121007 TI - Pipelle for Pregnancy (PIP): study protocols for three randomised controlled trials. AB - BACKGROUND: The success rate of infertility treatments remains modest. Endometrial injury has been suggested as an intervention to increase the probability of pregnancy in women undergoing assisted reproductive technologies such as in vitro fertilisation (IVF). The majority of studies and systematic reviews have reported that endometrial injury improves the outcomes of IVF, intrauterine insemination and natural conception; however, the size and quality of the studies are poor. The low quality of the available evidence questions the presence of any real beneficial effect, and the applicability of the intervention in different populations remains unclear. METHODS/DESIGN: The PIP trials are three multi-centre, randomised controlled trials designed to test three separate hypotheses: whether endometrial injury increases the probability of live birth in women or couples 1) who are undergoing autologous embryo transfer as part of an IVF cycle (PIP-IVF), 2) with unexplained infertility who are attempting to conceive naturally (PIP-UE) and 3) with subfertility related to polycystic ovarian syndrome (PCOS) who are on ovulation induction medication and attempting to conceive (PIP-PCOS). Participants will be randomised to either undergo endometrial injury by endometrial pipelle biopsy or to: * no intervention (PIP IVF), or * a sham procedure (PIP-PCOS and PIP-UE). In PIP-IVF, endometrial injury will be carried out between day three of the cycle prior to the IVF cycle, and day three of the IVF cycle. In PIP-UE and PIP-PCOS, endometrial injury or a sham procedure will be undertaken between days 1-12 of a menstrual cycle or ovulation induction cycle respectively. Participants in PIP-UE and PIP-PCOS will then be followed for three cycles during which time they will attempt to conceive from sexual intercourse. To ensure allocation concealment, randomisation will be carried out using a web-based system or sequentially numbered, opaque, sealed envelopes. The primary outcome is live birth. Secondary outcomes include ongoing pregnancy, clinical pregnancy and miscarriage. The required sample sizes for the PIP studies have been estimated at 840 (PIP-IVF), 350 (PIP-UE) and 280 (PIP PCOS). Primary analysis will be as per intention-to-treat principles. DISCUSSION: The PIP trials are designed to address the gaps in the utility of endometrial scratching as a treatment for subfertility in three different populations. If the beneficial effect of this intervention can be confirmed in these settings, endometrial scratching will provide a cost-effective method for helping women and couples to conceive. TRIAL REGISTRATIONS: PIP-IVF ACTRN12614000626662 registered 13/6/2014; PIP-PCOS ACTRN12614000657628 registered 24/6/2014; PIP-UE ACTRN12614000656639 registered 24/6/2014. The trials are ongoing. PMID- 27121009 TI - Rod-shaped and fluorine-substituted hydroxyapatite free of molecular immunopotentiators stimulates anti-cancer immunity in vivo. AB - Herein, rod-shaped and fluorine-substituted hydroxyapatite nanoparticles (FHA) were synthesized using a facile hydrothermal method. The rod-shaped FHA significantly increased the cellular uptake of a model antigen by bone marrow dentritic cells in vitro, improved antigen presentation in vivo, stimulated immune-related cytokine secretion in vitro and ex vivo, and enhanced the anti cancer immunity in vivo. PMID- 27121008 TI - Genome-wide association studies of drought-related metabolic changes in maize using an enlarged SNP panel. AB - KEY MESSAGE: Genetic determinants of metabolites related to drought tolerance in maize. Water deficit or drought is one of the most serious abiotic stresses of plant development and greatly reduces crop production, and the plant's response to this deficit leads to many metabolic changes. To dissect the genetic basis of these metabolic traits in maize, we performed a genome-wide association analysis of drought-related traits using 156,599 SNPs in 318 maize inbred lines. In total, 123 significant SNP/trait associations (P <= 6.39E-6) involving 63 loci were identified for related metabolic and physiological traits in multiple tissues and different environments under two irrigation conditions. Of the 63, 23 loci demonstrated a significant interaction effect between QTL and water status, indicating that these metabolite-associated loci were probably related to drought stress tolerance. To evaluate the potential utility of metabolite-associated loci applied in hybrid maize breeding, we assembled two groups of hybrid entries with high or low drought tolerance and measured the metabolic and physiological traits. In the hybrid pools, a set of 10 metabolite-associated loci identified in leaf and ear were validated as responsive to drought stress. The favorable alleles of these ten loci were significantly enriched in hybrids with high drought tolerance, which jointly explained almost 18.4 % of the variation in drought tolerance using a multivariate logistic regression model. These results provide clues to understanding the genetic basis of metabolic and physiological changes related to drought tolerance, potentially facilitating the genetic improvement of varieties with high drought tolerance in maize breeding programs. PMID- 27121010 TI - A pulse-chase strategy for EdU labelling assay is able to rapidly quantify cell division orientation. AB - Measurement of the direction of cell division is an important, yet difficult, task to analyse how a plant organ acquires its final shape from an initially small group of cells. We introduce a method that rapidly and easily quantifies cell division direction and is applicable to all plant species. A pulse-chase strategy for 5-ethynyl-2'-deoxyuridine (EdU) labelling assay was established and was shown to be successful for leaves of Arabidopsis thaliana (Arabidopsis) and Juncus prismatocarpus. By optimization of the pulse and chase periods, most of the signals obtained were sets of daughter nuclei. For Arabidopsis, the optimal time was a 45-min pulse and a 7-h chase. For J. prismatocarpus, the optimal time was a 2-h pulse and a 13.5-h chase. The positions of the daughter nuclei were used to quantify cell division direction in the Arabidopsis leaf primordia. Overall, cell division along the proximal-distal axis was more frequent than along the medial-lateral axis. In petiole, major vein, minor vein and margin areas, the major cell division direction seemed to be coincident with the direction of auxin flow. The advantages of our method over the few methods used previously are discussed. We anticipate that it will provide opportunities to study plant development in the near future. PMID- 27121011 TI - Simvastatin ameliorates ventricular remodeling via the TGF-beta1 signaling pathway in rats following myocardial infarction. AB - Statins are widely used in patients with cardiovascular diseases. A considerable number of previous studies revealed that the intracellular signaling of transforming growth factor (TGF)-beta1 mediated the development of cardiomyocyte hypertrophy and interstitial fibrosis. However, whether statins can ameliorate ventricular remodeling in post-myocardial infarction via the TGF-beta1 signaling pathway remains to be rigorously tested. The left anterior descending artery was ligated to induce a rat model of myocardial infarction. The rat model of myocardial infarction was treated with simvastatin through gastric gavage (10, 20 or 40 mg kg-1.d-1). All rats were sacrificed on day 28 after the myocardial infarction operation. The results revealed that simvastatin significantly improved the hemodynamic indexes, left ventricular mass index, the myocardial tissue structure, the cardiomyocyte cross-sectional area and the collagen volume fraction, and also showed that the levels of TGF-beta1, TGF-activated kinase (TAK)1 and drosophila mothers against decapentaplegic (Smad)3 were significantly reduced following treatment with simvastatin, while the levels of Smad7 in the simvastatin treatment groups were markedly increased. The results of the present study suggested that statins ameliorated ventricular remodeling in post myocardial infarction rats via the TGF-beta1 signaling pathway, which provided a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system. PMID- 27121012 TI - The Use of Acute Peritoneal Dialysis in Critically Ill Newborns. AB - BACKGROUND To evaluate the efficacy, complications, and mortality rate of acute peritoneal dialysis (APD) in critically ill newborns. MATERIAL AND METHODS The study included 31 newborns treated in our center between May 2012 and December 2014. RESULTS The mean birth weight, duration of peritoneal dialysis, and gestational age of the patients were determined as 2155.2 +/- 032.2 g (580-3900 g), 4 days (1-20 days), and 34 weeks (24-40 weeks), respectively. The main reasons for APD were sepsis (35.5%), postoperative cardiac surgery (16%), hypoxic ischemic encephalopathy (13%), salting of the newborn (9.7%), congenital metabolic disorders (6.1%), congenital renal diseases (6.5%), nonimmune hydrops fetalis (6.5%), and acute kidney injury (AKI) due to severe dehydration (3.2%). APD-related complications were observed in 48.4% of the patients. The complications encountered were catheter leakages in nine patients, catheter obstruction in three patients, peritonitis in two patients, and intestinal perforation in one patient. The general mortality rate was 54.8%, however, the mortality rate in premature newborns was 81.3%. CONCLUSIONS APD can be an effective, simple, safe, and important therapy for renal replacement in many neonatal diseases and it can be an appropriate treatment, where necessary, for newborns. Although it may cause some complications, they are not common. However, it should be used carefully, especially in premature newborns who are vulnerable and have a high mortality risk. The recommendation of APD therapy in such cases needs to be verified by further studies in larger patient populations. PMID- 27121013 TI - Targeting clinically-relevant metallo-beta-lactamases: from high-throughput docking to broad-spectrum inhibitors. AB - Metallo-beta-lactamases (MBLs) represent one of the most important and widespread mechanisms of resistance to beta-lactam antibiotics (including the life-saving carbapenems), against which no clinically useful inhibitors are currently available. We report herein a structure-based high-throughput docking (HTD) campaign on three clinically-relevant acquired MBLs (IMP-1, NDM-1 and VIM-2). The initial hit NF1810 (1) was optimized providing the broad-spectrum inhibitor 3i, which is able to potentiate the in vitro activity of cefoxitin on a VIM-2 producing E. coli strain. PMID- 27121015 TI - Toxicity of 3,5,6-trichloro-2-pyridinol tested at multiple stages of zebrafish (Danio rerio) development. AB - Organophosphate compounds (OP) are widely used throughout the world for pest control. 3,5,6-Trichloro-2-pyridinol (TCP) is a primary metabolite of two OP compounds namely CP and triclopyr. This study is carried out to know whether a metabolite of parent compound is doing well or harm to biota. The potential effect of TCP was evaluated on development as destabilization of any events transpiring during embryogenesis could be deleterious. To determine this, 4-hpf zebrafish embryos were exposed to five concentrations of TCP (200, 400, 600, 800, 1000 MUg/L) or 99.5 % acetone (solvent control). Different early life-stage parameters were observed at four different developmental stages, 24, 48, 72 and 96 hpf. TCP-treated embryo/larvae showed increased mortality, delay in hatching time and decrease in percentage of hatched embryos. Reduction in heartbeat rate, blood flow and body and eye pigmentation was noticed in a dose-dependent manner. Pericardial and yolk sac edema were most severe malformations caused by TCP. Along with this crooked spine/notochord, tail deformation was noticed in hatched and unhatched embryos. The malformations observed provide a good starting point for examination of the molecular mechanisms that are affected during development by TCP. Results gain significance as TCP, which is a breakdown product, appears to be more toxic during development compared to parent compound, CP (our earlier publication). PMID- 27121014 TI - Crocin protects human embryonic kidney cells (HEK293) from alpha- and beta Zearalenol-induced ER stress and apoptosis. AB - alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL) are the major metabolites of Zearalenone (ZEN) and are known to induce many toxic effects. In the present study, we investigated the involvement of endoplasmic reticulum (ER) stress in alpha- and beta-ZOL-mediated toxicity in human kidney cells (HEK293) and evaluated the effect of a common dietary compound Crocin (CRO), from saffron. We show that alpha- and beta-ZOL treatment induces ER stress as evidenced by the upregulation of the 78 kDa glucose-regulated protein (GRP78) and the Growth arrest and DNA damage-inducible protein (GADD34). Activation of the ER stress response is associated with activation of the mitochondrial pathway of apoptosis. This apoptotic process is characterized by an increase in ROS generation and lipid peroxidation, a loss of mitochondrial transmembrane potential (DeltaPsim) and activation of caspases. We also demonstrate that the antioxidant properties of CRO help to prevent ER stress and reduce alpha- and beta-ZOL-induced apoptosis in HEK293 cells. Our results suggest that saffron consumption might be helpful to prevent alpha- and beta-ZOL-induced ER stress and toxicity. PMID- 27121016 TI - Effect of photosynthetically elevated pH on performance of surface flow constructed wetland planted with Phragmites australis. AB - Combination of emergent and submerged plants has been proved to be able to enhance pollutant removal efficiency of surface flow-constructed wetland (SFCW) during winter. However, intensive photosynthesis of submerged plants during summer would cause pH increase, which may have adverse effects on emergent plants. In this study, nitrogen transformation of lab-scale SFCW under pH gradient of 7.5, 8.5, 9.5 and 10.5 was systematically investigated. The results showed that total nitrogen (TN) removal efficiency decreased from 76.3 +/- 0.04 to 51.8 +/- 0.04 % when pH increased from 7.5 to 10.5, which was mainly attributed to plant assimilation decay and inhibition of microbe activities (i.e., nitrite-oxidizing bacteria and denitrifiers). Besides, the highest sediment adsorption in SFCW was observed at pH of 8.5. In general, the combination of submerged and emergent plants is feasible for most of the year, but precaution should be taken to mitigate the negative effect of high alkaline conditions when pH rises to above 8.5 in midsummer. PMID- 27121017 TI - Immobilization of Pb and Cu in polluted soil by superphosphate, multi-walled carbon nanotube, rice straw and its derived biochar. AB - Lead (Pb) and copper (Cu) contamination in croplands pose severe health hazards and environmental concerns throughout soil-food chain transfer. In the present study, BCR, TCLP, CaCl2, and SBET techniques were employed to evaluate the simultaneous effectiveness of rice straw (RS) and its derived biochar (BC), multiwall carbon nanotube (MWCNT), and single superphosphate (SSP) to immobilize the Pb and Cu in co-contaminated soil. The BCR sequential extraction results suggested that with increasing BC and SSP amount, the acid-soluble fractions decreased while oxidizable and residual proportions of Pb and Cu were increased significantly. Compared to SSP, the application of BC amendment substantially modified partitioning of Cu from easily exchangeable phase to less bioavailable residual bound fraction. The immobilized Pb and Cu were mainly transformed to reducible forms. The TCLP and CaCl2-extracted Pb and Cu were reduced significantly by the addition of BC compared to RS and MWCNT, whereas the bio accessibility of Pb significantly reduced with RS addition. SSP showed better results for Pb immobilization while marginal for Cu in co-contaminated soil. Overall, the addition of BC offered the best results and could be effective in both Pb and Cu immobilization thereby reducing their mobility and bioavailability in the co-contaminated soil. PMID- 27121018 TI - Trichostatin A potentiates genistein-induced apoptosis and reverses EMT in HEp2 cells. AB - Genistein and trichostatin A (TSA) are two chemotherapeutic compounds with antitumor effects in different types of cancer cell. However, the effects of genistein and TSA on the HEp-2 laryngeal cancer cell line remain to be fully elucidated. In the present study, it was found that genistein and TSA inhibited cell growth and cell migration, and promoted apoptosis in the HEp-2 laryngeal cancer cell line. The HEp-2 cells were treated with genistein, TSA or the two compounds in combination. Cell proliferation and apoptosis were measured using an MTT assay, Annexin V/propidium iodide staining and a TUNEL assay. Cell invasion was determined using a Matrigel-based Transwell assay. Western blotting was used to examine the activation of the Akt pathway and the expression levels of pro-or anti-apoptotic proteins. Treatment with either genistein or TSA alone mildly inhibited cell viability, growth and invasion, and induced the apoptosis of the laryngeal cancer cells, whereas more marked effects were observed in the cells treated with the combination of the two compounds. In addition, genistein reversed endothelial growth factor-induced epithelial-mesenchymal transition (EMT) in the HEp-2 cells, the effect of which were was further increased by joint application with TSA. Treatment of the HEp-2 cells with genistein and TSA led to a significant reduction in the phosphorylation of Akt and activation of its downstream target, and resulted in peroxisome proliferator-activated receptor gamma cleavage, increased expression of B cell lymphoma-2 (Bcl-2)-associated X protein and reduced the expression of Bcl-2. In conclusion, the present study demonstrated that, with the involvement of TSA, genistein exhibited substantial advantages in inhibiting laryngeal carcinoma cell growth, invasion and EMT, and induced apoptosis, compared with genistein treatment alone, which occurred through the regulation of Akt activation and the apoptotic pathway. PMID- 27121019 TI - Static magnetic field controls cell cycle in cultured human glioblastoma cells. AB - Magnetic field has been widely used in clinical diagnostics or for clinical treatment and is an important biomedical technology. Glioblastoma multiforme U87 and U251 are models of a fast growing malignant cancer. We focused on cellular level drafting of these cell lines as a time-dependent effect indicator of static magnetic fields (2000 +/- 600 Gauss) by using their fast-growing properties. Cell viability showed a significant decrease (p < 0.01). The results coincided with the occurrence of apoptotic signals or protein expression of cyclin B1 and cyclin dependent kinase 1 in a non-apoptotic manner. Cdk1 was decreased in proportion to ankyrin G and cyclin B1 (Chi-square test, p = 0.0366). Our findings suggest that static magnetic stimulation creates a specific cyto-proliferative pattern, rather than producing randomized growth impairment. PMID- 27121020 TI - Identification of vitamin D sensitive pathways during lung development. AB - BACKGROUND: We have previously shown that vitamin D deficiency has a detrimental impact on lung development. In this study, we aimed to identify the mechanisms linking vitamin D with lung development using a mouse model of dietary manipulation. METHODS: Female offspring were euthanized at different time-points; embryonic day (E)14.5, E17.5 or postnatal day (P)7. Lung tissue was collected for mass spectrometry-based proteomic analysis. Label-free quantitation was used to identify the differentially expressed proteins and ELISA confirmed the expression of selected proteins. Lungs from separate groups of mice were fixed and processed for stereological assessment of lung structure. RESULTS: No differences in protein expression between vitamin D deficient and replete mice were detected at E14.5 and E17.5, whereas 66 proteins were differentially expressed in P7 lungs. The expression of pulmonary surfactant-associated protein B (SP-B) and peroxiredoxin 5 (PRDX5) were reduced in P7 lungs of vitamin D deficient mice, while the production of collagen type Iota alpha 1 (COL1A1) was higher in lungs of vitamin D deficient mice. There were no differences in lung volume, parenchymal volume, volume of airspaces or surface area of airspaces between vitamin D deficient and vitamin D replete mice across three time-points. CONCLUSIONS: The difference in protein expression during the early postnatal time point suggests that vitamin D deficiency may induce alterations of lung structure and function in later life during alveolarization stage through impaired pulmonary surfactant production and anti-oxidative stress ability as well as enhanced collagen synthesis. These data provided a plausible mechanism linking maternal vitamin D deficiency with altered postnatal lung function. PMID- 27121022 TI - Erratum to: Spontaneous inward currents reflecting oscillatory activation of Na+/Ca2+ exchangers in human embryonic stem cell-derived cardiomyocytes. PMID- 27121021 TI - Increased risk of allergic rhinitis among children delivered by cesarean section: a cross-sectional study nested in a birth cohort. AB - BACKGROUND: Few studies have evaluated the association between delivery by cesarean section (CS) and asthma, allergic rhinitis and chronic rhinitis and whether this association is different in children with and without a family history of asthma. This study aims to investigate whether children born by CS have a higher chance to develop asthma, allergic rhinitis and chronic rhinitis and to evaluate the influence of parental history of asthma on these associations. METHODS: This is a cross-sectional study of 672 children nested in a birth cohort evaluated at 6-years of age. Asthma and chronic/allergic rhinitis were identified by means of the mother's responses to the ISAAC questionnaire. The association between CS, asthma, chronic rhinitis and allergic rhinitis was evaluated by multivariable logistic regression. The evidence of effect modification of parental history of asthma on the association CS and outcomes was examined by introducing interactions terms in the logistic regression models adjusting for confounders. RESULTS: Asthma was not associated with birth by CS irrespective of parental history of asthma (odds ratio (OR) 1.03; 95 % CI 0.61 1.74). Chronic rhinitis and allergic rhinitis were both significantly associated with birth by CS but only in the subgroup of children with by parental history of asthma (OR 1.56; 95 % CI 1.04-2.34) and (OR 1.60; 95 % CI 1.01-2.55) respectively, after adjustment for confounders. The parental history of asthma was a effect modifier in the association between CS, chronic rhinitis and allergic rhinitis (p for effect modification = 0.10 and 0.02, respectively). CONCLUSION: CS increases the risk of chronic rhinitis and allergic rhinitis in children at 6 years of age with parental history of asthma. Health professionals must be alerted with regard to the increased risk of allergic rhinitis and made aware this is another reason to avoid unnecessary CS. PMID- 27121023 TI - Recurrent genetic defects in classical Hodgkin lymphoma cell lines. AB - Genetic analysis of classical Hodgkin lymphoma (cHL) has been hampered by the paucity of Hodgkin cells in biopsies and their poor growth in vitro. However, a wealth of information has been obtained from cHL cell lines. Here we report results of whole-exome sequencing and karyotypic analysis of five cHL cell lines. Four genes with potentially pathogenic single nucleotide variants (SNV) were detected in three cell lines. SNV were also detected in seventeen HL-related genes and three mitosis-related genes. Copy number variants were detected in four HL-related genes in all five cell lines. Given the high degree of aneuploidy in HL, mitosis-related genes were screened for defects. One mitotic gene (NCAPD2) was amplified in all five HL cell lines, and two genes (FAM190A, PLK4) were amplified in four cell lines. These results suggest that genomic instability of HL may be due to defects in genes involved in chromosome duplication and segregation. PMID- 27121024 TI - On the lack of evolutionary continuity between prebiotic peptides and extant enzymes. AB - The significance of experiments that claim to simulate the properties of prebiotic small peptides and polypeptides as models of the polymers that may have preceded proteins is critically addressed. As discussed here, most of these experiments are based only on a small number of a larger set of amino acids that may have been present in the prebiotic environment, supported by both experimental simulations and the repertoire of organic compounds reported in carbonaceous chondrites. Model experiments with small peptides may offer some insights into the processes that contributed to generate the chemical environment leading to the emergence of informational oligomers, but not to the origin of proteins. The large body of circumstantial evidence indicating that catalytic RNA played a key role in the origin of protein synthesis during the early stages of cellular evolution implies that the emergence of the genetic code and of protein biosynthesis are no longer synonymous with the origin of life. Hence, reports on the abiotic synthesis of small catalytic peptides under potential prebiotic conditions do not provide information on the origin of triplet encoded protein biosynthesis, but in some cases may serve as models to understand the properties of the earliest proteins. PMID- 27121025 TI - Implications of edoxaban in the prevention and treatment of thromboembolic complications in clinical practice. AB - Edoxaban is a once-daily oral inhibitor of factor Xa, currently indicated to reduce the risk of stroke or systemic embolism in nonvalvular atrial fibrillation patients and for the treatment and prevention of venous thromboembolism (EMA, FDA and Japan). The ENGAGE AF-TIMI 48 and the Hokusai-VTE trials demonstrated that edoxaban was at least as effective as warfarin for the prevention of stroke or systemic embolism in nonvalvular atrial fibrillation patients, as well as for the prevention and treatment of venous thromboembolism, but with a lesser risk of bleeding in both cases. In addition, it seems a cost-effective strategy for the management of this population. In this review, the implications of the most recent available evidence about edoxaban in clinical practice will be updated. PMID- 27121026 TI - General practitioners' attitudes towards electronic prescribing and the use of the national prescription centre. AB - RATIONALE, AIMS AND OBJECTIVES: The purpose of this study was to assess general practitioners' (GP) experience of an electronic prescription (e-prescription) system and the use of a national prescription centre. METHODS: A web-based survey with 29 structured questions and 8 open-ended questions was used. The technology acceptance model was used to explain first users' use of e-prescribing technology. GPs (n = 269) in two different primary health care organizations, which implemented the e-prescribing module as the first of its kind in Finland. RESULTS: Of the 269 GPs, 69 (26%) completed the survey. E-prescribing had influenced GP work and their management of patients' medication positively. Electronic health records and e-prescribing increased GPs' flexibility at work. There was a notable improvement in the management of prescription of narcotics with the introduction of e-prescribing. Issues with the e-prescribing system software delayed data processing and produced negative experience as users were forced to browse through too many pages to write a prescription. CONCLUSIONS: E prescribing has improved GP's patient medication management, meeting Finland's national objectives. E-prescriptions not only reinforce the process of writing, transmitting and checking the authenticity of prescriptions but also make it mandatory for all key prescription information to be present for transmission. The perceived usefulness of e-prescribing by GPs could lead to more widespread adoption of the technology. Making e-prescribing more user friendly requires reforming work processes, which in turn would enhance the effectiveness of GP work. PMID- 27121027 TI - Total Synthesis of Rubriflordilactone B. AB - Taking advantage of a 6pi electrocyclization-aromatization strategy, we accomplished the first and asymmetric total synthesis of rubriflordilactone B, a heptacyclic Schisandraceae bisnortriterpenoid featuring a tetrasubstituted arene moiety. The left-hand fragment was accessed through a chiral-pool-based route, and linked to the right-hand fragment by a Sonogashira coupling. The cis geometry of the electrocyclization substrates was established by hydrogenation or hydrosilylation of the alkyne. An electrocyclization-aromatization sequence finally built the multisubstituted arene. The hydrosilylation approach was of significant advantage in terms of reaction scale, reproducibility, and intermediate stability. The structure of synthetic rubriflordilactone B was validated by X-ray crystallographic analysis, and found to be consistent with that reported for the authentic natural product based on an independent X-ray crystallographic analysis. However, obvious differences in the NMR spectra of the synthetic and authentic samples suggest that the authentic samples subjected to X ray crystallography and NMR spectroscopy were two different compounds. PMID- 27121028 TI - Balancing placebo and nocebo effects during electromyography in children. PMID- 27121030 TI - Isolated polycystic disease of pancreas. PMID- 27121029 TI - Interaction between V-ATPase B2 and (Pro) renin Receptors in Promoting the progression of Renal Tubulointerstitial Fibrosis. AB - To investigate the levels of (Pro) renin receptor [(P) RR], alpha-smooth muscle actin (alpha-SMA), fibronectin (FN), and vacuolar H(+)-ATPase (V-ATPase) subunits (B2, E, and c) in rat unilateral ureteral obstruction (UUO) models and rat proximal tubular epithelial cells (NRK-52E) treated with prorenin to elucidate the role of V-ATPase in these processes by activating the (P) RR. UUO significantly upregulated (P) RR, V-ATPase subunits, alpha-SMA and FN expression in tubulointerstitium or tubular epithelial cells. A marked colocalization of (P) RR and the B2 subunit was also observed. Prorenin treatment upregulated alpha SMA, FN, (P) RR, and V-ATPase subunits and activity in NRK52E cell in a dose- and time-dependent manner. The V-ATPase inhibitor bafilomycin A1 partially blocked prorenin-induced (P) RR, FN, and alpha-SMA expression. Co-immunoprecipitate and immunofluorescence results demonstrated that the V-ATPase B2 subunit bound to the (P) RR, which was upregulated after prorenin stimulation. Either siRNA-mediated (P) RR or B2 subunit knockdown partially reduced V-ATPase activity and attenuated prorenin-induced FN and alpha-SMA expression. From the data we can assume that activation of (P) RR and V-ATPase may play an important role in tubulointerstitial fibrosis with possible involvement of interaction of V-ATPase B2 subunit and (P)RR. PMID- 27121031 TI - A Glycine soja methionine sulfoxide reductase B5a interacts with the Ca(2+) /CAM binding kinase GsCBRLK and activates ROS signaling under carbonate alkaline stress. AB - Although research has extensively illustrated the molecular basis of plant responses to salt and high-pH stresses, knowledge on carbonate alkaline stress is poor and the specific responsive mechanism remains elusive. We have previously characterized a Glycine soja Ca(2+) /CAM-dependent kinase GsCBRLK that could increase salt tolerance. Here, we characterize a methionine sulfoxide reductase (MSR) B protein GsMSRB5a as a GsCBRLK interactor by using Y2H and BiFc assays. Further analyses showed that the N-terminal variable domain of GsCBRLK contributed to the GsMSRB5a interaction. Y2H assays also revealed the interaction specificity of GsCBRLK with the wild soybean MSRB subfamily proteins, and determined that the BoxI/BoxII-containing regions within GsMSRBs were responsible for their interaction. Furthermore, we also illustrated that the N-terminal basic regions in GsMSRBs functioned as transit peptides, which targeted themselves into chloroplasts and thereby prevented their interaction with GsCBRLK. Nevertheless, deletion of these regions allowed them to localize on the plasma membrane (PM) and interact with GsCBRLK. In addition, we also showed that GsMSRB5a and GsCBRLK displayed overlapping tissue expression specificity and coincident expression patterns under carbonate alkaline stress. Phenotypic experiments demonstrated that GsMSRB5a and GsCBRLK overexpression in Arabidopsis enhanced carbonate alkaline stress tolerance. Further investigations elucidated that GsMSRB5a and GsCBRLK inhibited reactive oxygen species (ROS) accumulation by modifying the expression of ROS signaling, biosynthesis and scavenging genes. Summarily, our results demonstrated that GsCBRLK and GsMSRB5a interacted with each other, and activated ROS signaling under carbonate alkaline stress. PMID- 27121032 TI - 293 cells express both epithelial as well as mesenchymal cell adhesion molecules. AB - The 293 cell line, used extensively in various types of studies due to the ease with which these cells can be transfected, was thought to be derived by the transformation of primary cultures of human embryonic kidney cells with sheared adenovirus type 5 DNA. Although the 293 cells were assumed to originate from epithelial cells, the exact origin of these cells remains unknown. Previous attempts to characterize these cells combined immunostaining, immunoblot analysis and microarray analysis to demonstrate that 293 cells express neurofilament subunits, alpha-internexin, and several other proteins typically found in neurons. These findings raised the possibility that the 293 cell line may have originated from human neuronal lineage cells. Contrary to this suggestion, in this study, we found that the 293 cells expressed N-cadherin and vimentin, which are marker proteins expressed in mesenchymal cells. Furthermore, the 293 cells also expressed E-cadherin, cytokeratins 5/8 and desmoglein 2, which are epithelial cell markers. When the cells, primarily cultured from the kidneys of Clawn miniature swine and passaged 10-15 generations [termed porcine kidney epithelial (PKE) cells] were examined, they were found to be positive for the expression of both mesenchymal and epithelial markers. Thus, transformation by adenovirus was not necessary for the cells to express N-cadherin. Occludin and zonula occludens (ZO)-1, two components of tight junctions in epithelial and endothelial cells, were detected in the 293 and the PKE cells. Thus, the findings of the present study demonstrate that 293 cells retain several characteristics of epithelial cells. PMID- 27121033 TI - Ligation of the mesovarium in dogs with a self-locking implant of a resorbable polyglycolic based co-polymer: a study of feasibility and comparison to suture ligation. AB - BACKGROUND: Ligation of the mesovarium in female dogs may be cumbersome with risk of complications and is associated with intense noxious stimuli. A resorbable implant, a self-locking loop designed for surgery, was developed as an alternative to traditional ligation. The study aimed to test the feasibility of ligating the canine ovarian pedicle with the implant and to compare its performance to traditional suture ligation. RESULTS: In total 45 intact female dogs destined for elective ovariohysterectomy and adoption were included. In 21 dogs the new resorbable implant was used to ligate the mesovarium, and in 24 control dogs traditional suture was used with one encircling ligature. Mean weight of implant dogs was 10.7 +/- 5.6 kg (range 3.5-22.0), and mean weight of control dogs was 12.8 +/- 6.4 kg, (range 4.1-27.0). The body weight of dogs did not differ between groups (P = 0.25). In total, 42 ovarian pedicles were successfully ligated with the implant. In one control dog, intraoperative haemorrhage from the left ovarian pedicle was diagnosed. The mesovarium was re ligated and haemostasis was confirmed. All dogs recovered uneventfully. The ligation time of the mesovarium was significantly shortened (P = 0.02) by using the self-locking implant versus a single ligature (3'28'' +/- 1'05'' and 5'29'' +/- 3'54'', respectively). Total duration of surgery differed between the groups (P = 0.02) with a shortened duration of surgery when using the self-locking implant (15'56'' +/- 2'47'' and 20'39'' +/- 8'58'', study group versus control group, respectively). In both groups, duration of surgery and time required to ligate the ovarian pedicle were longer in larger dogs than smaller dogs. CONCLUSION: The results of this feasibility study suggested the implant can be used to ligate the canine mesovarium. Compared with traditional suture ligation, the results suggested that time to ligate the ovarian pedicle and duration of surgery were significantly reduced with the implant. More time was required to perform surgeries in larger dogs. PMID- 27121034 TI - Cytopathological features of villous adenoma of the urinary bladder in urine: A rare case report. AB - Villous adenoma of the urinary bladder is a rare tumor that histologically mimics its enteric counterpart. Patients with an isolated villous adenoma have an excellent prognosis, but associated adenocarcinomas can frequently be identified in them as well. There is no literature that discusses the cytopathologic features of villous adenoma. Here we report a case which was diagnosed as villous adenoma histologically, which has been followed up with urine cytology. In urine cytology, many mucin producing cells are recognized. Few cell clusters show glandular formation or arrangement along the basement membrane. When glandular cells with columnar mucin-filled goblet cells are seen in urine cytology, the presence of a primary glandular lesion of the urinary bladder, such as villous adenoma, should be considered possible. Diagn. Cytopathol. 2016;44:632-635. (c) 2016 Wiley Periodicals, Inc. PMID- 27121036 TI - Aortic root compression during transcatheter pulmonary valve replacement. AB - OBJECTIVES: To describe the incidence of aortic root compression (ARC) during transcatheter pulmonary valve replacement (TPVR). BACKGROUND: ARC can occur during balloon sizing of the right ventricular outflow tract (RVOT) or during coronary compression testing (BS/CCT) prior to TPVR, causing aortic valve dysfunction and/or root distortion with or without coronary compression. This has limited the use of TPVR in patients with native RVOTs, including those with a transannular patch (TAP). The characteristics of this patient cohort have not previously been described. METHODS: A retrospective review was performed of all patients with congenital heart disease who presented for TPVR at UCLA from 2010 to 2015. ARC characteristics during BS/CCT were noted for all relevant cases. RESULTS: Inclusion criteria were met by 174 patients. ARC occurred in 16 patients (9%), of whom 14 had Tetralogy of Fallot with a native/TAP RVOT (14/42, 33%, of all native/TAP patients). Five ARC patients also had concomitant coronary artery compression. Isolated coronary compression occurred in six patients. Two patients underwent successful TPVR despite ARC by implanting the valves in the distal RVOT. One patient required surgical PVR and Sapien valve explantation after TPVR caused severe ARC. CONCLUSIONS: The majority of cases of ARC occur in patients with native/TAP RVOTs. ARC during BS/CCT may identify those at risk for ARC following TPVR. While ARC is a real phenomenon, it is unclear if it can be accurately predicted, what its clinical significance will be and how it is best avoided. Further studies are necessary to answer these questions. (c) 2016 Wiley Periodicals, Inc. PMID- 27121037 TI - Impact of timing and cycles of systemic chemotherapy on survival outcome of colorectal liver metastases patients treated by percutaneous microwave ablation. AB - PURPOSE: The aim of this retrospective study is to determine the optimal timing and number of cycles of systemic chemotherapy in patients with colorectal liver metastases (CLM) treated by ultrasound-guided percutaneous microwave ablation (PMWA). MATERIALS AND METHODS: In total 199 patients with 318 CLM, median number of tumours one per patient and median maximum size of tumours 3.0 cm, treated by PMWA combined with or without systemic chemotherapy were included in our study. Chemotherapy was administered pre-ablatively in 148 of those patients (74.4%), and post-ablatively in 142 (73.6%). Chemotherapy regimens included FOLFOX/XELOX, FOLFIRI/XELIRI, and sequential monotherapy. Prognostic factors were evaluated by univariate and multivariate analyses, using log-rank test and Cox proportional hazards model, respectively. RESULTS: The estimated 5-year rates of progression free survival (PFS) and overall survival (OS) were 10.1% and 27.9%, respectively. The number of CLM (P = 0.003), maximum size of CLM (P < 0.001) and topography (P = 0.030) were independent prognostic factors for PFS of patients with CLM while age (P = 0.002), maximum size of CLM (P = 0.006) and post-ablative chemotherapy (P = 0.046) for OS. In further analysis, CLM patients receiving more than six cycles of post-ablative chemotherapy had significantly better OS (P = 0.015) than those without post-ablative chemotherapy. CONCLUSION: This study revealed chemotherapy administered after (more than six cycles) PMWA improved the OS of CLM patents. And, PMWA was a safe procedure in view of the absence of procedure related death and low rate of major complications. PMID- 27121038 TI - Cloning and characterization of the serotonin N-acetyltransferase-2 gene (SNAT2) in rice (Oryza sativa). AB - The penultimate enzyme in melatonin synthesis is serotonin N-acetyltransferase (SNAT), which exists as a single copy in mammals and plants. Our recent studies of the Arabidopsis snat-knockout mutant and SNAT RNAi rice (Oryza sativa) plants predicted the presence of at least one other SNAT isogene in plants; that is, the snat-knockout mutant of Arabidopsis and the SNAT RNAi rice plants still produced melatonin, even in the absence or the suppression of SNAT expression. Here, we report a molecular cloning of an SNAT isogene (OsSNAT2) from rice. The mature amino acid sequences of SNAT proteins indicated that OsSNAT2 and OsSNAT1 proteins had 39% identity values and 60% similarity. The Km and Vmax values of the purified recombinant OsSNAT2 were 371 MUm and 4700 pmol/min/mg protein, respectively; the enzyme's optimal activity temperature was 45 degrees C. Confocal microscopy showed that the OsSNAT2 protein was localized to both the cytoplasm and chloroplasts. The in vitro enzyme activity of OsSNAT2 was severely inhibited by melatonin, but the activities of sheep SNAT (OaSNAT) and rice OsSNAT1 proteins were not. The enzyme activity of OsSNAT2 was threefold higher than that of OsSNAT1, but 232-fold lower than that of OaSNAT. The OsSNAT1 and OsSNAT2 transcripts were similarly suppressed in rice leaves during the melatonin induction after cadmium treatment. Phylogenetic analyses indicated that OsSNAT1 and OsSNAT2 are distantly related, suggesting that they evolved independently from Cyanobacteria prior to the endosymbiosis event. PMID- 27121039 TI - Total hip arthroplasty after hip fracture. PMID- 27121040 TI - Professionalism of physicians at a major teaching hospital during the Fukushima nuclear disaster. AB - It poses a serious problem if physicians leave a hospital without having a replacement or without permission. A huge earthquake followed by a devastating tsunami seriously damaged the Fukushima-Daiichi nuclear power plant. This disaster overwhelmed a major teaching hospital in the local area and many hospital employees, including some resident physicians, left the premises. Since the threat of severe radiation exposure poses a potentially greater lifetime risk to younger individuals, letting the young resident physicians leave the hospital was not only allowed, it was actually recommended by many attending physicians and hospital administrators. The hospital administrator was required to make the difficult decision of whether to make all efforts to provide the highest level of medical care, including keeping all of the physicians on the premises, or to evacuate the resident physicians in order to preserve their health and their potential future contributions to healthcare. Consideration and compassion needed to be provided to all people, regardless of the reason they wanted to leave. From an ethical perspective, the roles of performance under these complex circumstances should be understood and embraced by us as individuals, professionals, supervisors and society as a whole. PMID- 27121041 TI - Nutmeg oil alleviates chronic inflammatory pain through inhibition of COX-2 expression and substance P release in vivo. AB - BACKGROUND: Chronic pain, or sometimes referred to as persistent pain, reduces the life quality of patients who are suffering from chronic diseases such as inflammatory diseases, cancer and diabetes. Hence, herbal medicines draw many attentions and have been shown effective in the treatment or relief of pain. METHODS AND RESULTS: Here in this study, we used the CFA-injected rats as a sustainable pain model to test the anti-inflammatory and analgesic effect of nutmeg oil, a spice flavor additive to beverages and baked goods produced from the seed of Myristica fragrans tree. CONCLUSIONS: We have demonstrated that nutmeg oil could potentially alleviate the CFA-injection induced joint swelling, mechanical allodynia and heat hyperanalgesia of rats through inhibition of COX-2 expression and blood substance P level, which made it possible for nutmeg oil to be a potential chronic pain reliever. PMID- 27121042 TI - Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi. AB - UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1. Results of this characterization support a model in which UBIAD1 continuously cycles between the ER and medial-trans Golgi of isoprenoid replete cells. Upon sensing a decline of GGpp in ER membranes, UBIAD1 becomes trapped in the organelle where it inhibits reductase degradation. Mutant forms of UBIAD1 associated with Schnyder corneal dystrophy (SCD), a human eye disease characterized by corneal accumulation of cholesterol, are sequestered in the ER and block reductase degradation. Collectively, these findings disclose a novel sensing mechanism that allows for stringent metabolic control of intracellular trafficking of UBIAD1, which directly modulates reductase degradation and becomes disrupted in SCD. PMID- 27121043 TI - Sampling the Body Odor of Primates: Cotton Swabs Sample Semivolatiles Rather Than Volatiles. AB - We assessed the suitability of a frequently used sampling method employing cotton swabs for collecting animal body odor for gas chromatography-mass spectrometry (GC-MS) analysis of volatile organic compounds (VOCs). Our method validation showed that both sampling material and sampling protocols affect the outcome of the analyses. Thus, among the tested protocols swabs of pure viscose baked before use and extracted with hexane had the least blank interferences in GC-MS analysis. Most critical for the recovery of VOCs was the handling time: the significant recovery losses of volatiles experienced with this sampling procedure suggest that a rapid processing of such samples is required. In a second part, we used swab sampling to sample the body odor of rhesus macaques (Macaca mulatta), which lack scent glands. First results after GC-MS analysis of the samples collected from these nonhuman primates emphasize that proper analytical performance is an indispensable prerequisite for successful automated data evaluation of the complex GC-MS profiles. Moreover, the retention times and the nature of the identified chemical compounds in our samples suggest that the use of swabs is generally more appropriate for collecting semivolatile rather than VOCs. PMID- 27121044 TI - Approach to the Management of Pediatric-Onset Anti-N-Methyl-d-Aspartate (Anti NMDA) Receptor Encephalitis: A Case Series. AB - Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is a treatable cause of autoimmune encephalitis. It remains unclear if the natural history of this disease is altered by choice of acute therapy or the employment of chronic immunotherapy. Chart review was undertaken for pediatric patients diagnosed with anti-NMDA receptor encephalitis. Data obtained included patient demographics, disease manifestations, treatment course, and clinical outcomes. Ten patients with anti-NMDA receptor encephalitis were identified. All patients were treated with immunotherapy in the acute period, and all patients experienced good recovery. Neurologic relapse did not occur in any patient. All patients received varied forms of chronic immunosuppression to prevent relapses. Complications of chronic immunotherapy occurred in 50% of patients. The benefits of chronic immunotherapy and the duration of use should be carefully weighed against the risks. Complications from immunotherapy are not uncommon and can be serious. Clinical trials assessing the benefit of long-term immunotherapy in this population are needed. PMID- 27121045 TI - Electronic Dietary Intake Assessment (e-DIA): relative validity of a mobile phone application to measure intake of food groups. AB - Automation of dietary assessment can reduce limitations of established methodologies, by alleviating participant and researcher burden. Designed as a research tool, the electronic Dietary Intake Assessment (e-DIA) is a food record in mobile phone application format. The present study aimed to examine the relative validity of the e-DIA with the 24-h recall method to estimate intake of food groups. A sample of eighty university students aged 19-24 years recorded 5 d of e-DIA and 3 d of recall within this 5-d period. The three matching days of dietary data were used for analysis. Food intake data were disaggregated and apportioned to one of eight food groups. Median intakes of food groups were similar between the methods, and strong correlations were found (mean: 0.79, range: 0.69-0.88). Cross-classification by tertiles produced a high level of exact agreement (mean: 71 %, range: 65-75 %), and weighted kappa values were moderate to good (range: 0.54-0.71). Although mean differences (e-DIA-recall) were small (range: -13 to 23 g), limits of agreement (LOA) were relatively large (e.g. for vegetables, mean difference: -4 g, LOA: -159 to 151 g). The Bland Altman plots showed robust agreement, with minimum bias. This analysis supports the use of e-DIA as an alternative to the repeated 24-h recall method for ranking individuals' food group intake. PMID- 27121046 TI - rno-miR-665 targets BCL2L1 (Bcl-xl) and increases vulnerability to propofol in developing astrocytes. AB - Propofol exerts a cytotoxic influence over immature neurocytes. Our previous study revealed that clinically relevant doses of propofol accelerated apoptosis of primary cultured astrocytes of developing rodent brains via rno-miR-665 regulation. However, the role of rno-miR-665 during the growth spurt of neonatal rodent brains in vivo is still uncertain. Post-natal day 7 (P7) rats received a single injection of propofol 30 mg/kg intraperitoneally (i.p.), and neuroapoptosis of hippocampal astrocytes was analyzed by immunofluorescence and scanning electron microscopy. The differential expression of rno-miR-665, BCL2L1 (Bcl-xl), and cleaved caspase 3 (CC3) was surveyed by qRT-PCR and western blotting. In addition, the utility of A-1155463, a highly potent and BCL2L1 selective antagonist, was aimed to assess the contribution of BCL2L1 for neuroglial survival. Following the intraventricular injection of lentivirus rno miR-665, neuroprotection was detected by 5-point scale measurement. The single dose of propofol 30 mg/kg triggered dose-dependent apoptosis of developing hippocampal astrocytes. Meanwhile, propofol triggered both rno-miR-665 and CC3, and depressed BCL2L1, which was predicted as one target gene of rno-miR-665. Combination treatment with A-1155463 and propofol induced lower mRNA and protein levels of BCL2L1 and more CC3 activation than propofol treatment alone in vivo. The lentivirus-mediated knockdown of rno-miR-665 elevated BCL2L1 and attenuated CC3 levels, whereas up-regulation of rno-miR-665 suppressed BCL2L1 and induced CC3 expression in vivo. More importantly, rno-miR-665 antagomir infusion improved neurological outcomes of pups receiving propofol during the brain growth spurt. Rno-miR-665, providing a potential target for alternative therapeutics for pediatric anesthesia, is susceptible to propofol by negatively targeting antiapoptotic BCL2L1. Relatively little is known about the association between exposure of astrocytes to brief propofol anaesthesia and risk for impairment. Here, it revealed that propofol-related neurotoxicity of neonatal astrocytes was under rno-miR-665 regulation during the brain growth spurt. Rno-miR-665 might act as a clinically alternative therapeutic target for treatment of neurological disorders in peadiatric anesthesia or sedation with propofol in future. PMID- 27121048 TI - 2015 Research Forum Poster Session and Competition: Finalists and Posters. PMID- 27121047 TI - Dynamics of histone H2A, H4 and HS1ph during spermatogenesis with a focus on chromatin condensation and maturity of spermatozoa. AB - Histones and histone phosphorylation play vital roles during animal spermatogenesis and spermatozoa maturation. The dynamic distribution of histones H2A and H4 and phosphorylated H2A and H4 at serine 1 (HS1ph) was explored in mammalian and Decapoda germ cells, with a special focus on the distribution of H2A, H4 and HS1ph between mouse condensed spermatozoa chromatin and crab non condensed spermatozoa chromatin. The distribution of histone marks was also analysed in mature spermatozoa with different chromatin structures. Histone H2A and H4 marks were closely associated with the relatively loose chromatin structure in crab spermatozoa. The significant decrease in the HS1ph signal during spermatogenesis suggests that eliminating most of these epigenetic marks in the nucleusis closely associated with spermatozoa maturity. PMID- 27121049 TI - Gold nanocluster sensitized TiO2 nanotube arrays for visible-light driven photoelectrocatalytic removal of antibiotic tetracycline. AB - It is of technical interest to develop low-cost, high-quality and scalable photosensitizers that could efficiently harvest visible light. Here we design an efficient photoelectrocatalyst by integrating a recently developed gold nanocluster (AuNC, as a photosensitizer) into two types of highly ordered TiO2 nanotube arrays (TNAs, as substrates to host the photosensitizers). The TNA electrodes used in this study are a short TNA (~0.5 um in length, synthesized by the anodic oxidation in an aqueous hydrofluoric (HF) acid solution) and a long TNA (~4.5 um in length, synthesized by the anodic oxidation in a fluorinated ethylene glycol (EG) solution). A number of characterization techniques (e.g., FESEM, XRD and XPS) were applied to study the as-synthesized nanocomposites. In particular, diffuse reflectance spectroscopy and photochemical measurements suggest that the AuNC-coated TNA electrodes have successfully extended visible light absorption and improved their photochemical performance. Compared with the blank TNAs, the as-designed nanocomposites exhibit an evidently enhanced photoelectrocatalytic performance towards tetracycline (an emerging antibiotic contaminant in aquatic environment) decomposition, where the removal efficiency increases from 65% to 81% for AuNC/long-TNA and from 46% to 73% for AuNC/short TNA electrodes, respectively. The improved performance is largely attributed to the photo-electro-chemical synergetic effect. The photochemical performance of the as-designed nanocomposites could be further improved by fine tuning the size, composition, and surface of the AuNC-based photosensitizers. PMID- 27121050 TI - UBAP2 negatively regulates the invasion of hepatocellular carcinoma cell by ubiquitinating and degradating Annexin A2. AB - The ubiquitin-dependent proteasomal degradation of proteins controls signaling and cellular survival. In this study, we found that ubiquitin associated protein 2 (UBAP2) was significantly downregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent normal tissues. Furthermore, higher expression of UBAP2 in cancer tissues was correlated with good prognosis in HCC patients. Knockdown of UBAP2 significantly enhanced the invasion and proliferation of HCC cells in vitro and promoted tumor growth in vivo, while enforced expression of UBAP2 impaired the aggressive ability and tumor growth of HCC cells. Mechanistically, UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination, and then inhibited HCC progression. Collectively, UBAP2 appears as a novel marker for predicting prognosis and a therapeutic target for HCC. PMID- 27121051 TI - B7-H3 as a promising target for cytotoxicity T cell in human cancer therapy. AB - Targeting B7-H3 over-expressed tumor cells with anti-B7-H3 monoclonal antibodies inhibits tumor growth. Here we demonstrated the expression of B7 family homologue 3 (B7-H3) in a wide range of human tumor cells and further investigated whether B7-H3 could be served as a target for T-cell mediated immunotherapy against human cancers. The specific cytotoxic activity of activated T cell (ATC) armed with a novel anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) against tumor cell was evaluated in vitro and in vivo. In contrast with unarmed ATC, an increase in cytotoxic activity of B7-H3Bi-armed ATC against tumor cells was observed at effector/target (E/T) ratios of 5:1, 10:1, and 20:1. Moreover, B7-H3Bi-armed ATC secreted more IFN-gamma, TNF-alpha and IL-2 than unarmed ATC. Infusion of B7-H3Bi armed ATC inhibited tumor growth in severe combined immunodeficiency (SCID) xenograft models, along with a significant survival benefit. Therefore, treatment with novel B7-H3Bi-armed ATC will be a promising strategy for current cancer immunotherapy. PMID- 27121052 TI - Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling. AB - The binding of hepatocyte growth factor (HGF) to its receptor MET activates a signaling cascade that promotes cell survival, proliferation, cell scattering, migration and invasion of malignant cells. HGF is secreted by cancer cells or by tumor-associated fibroblasts as pro-HGF, an inactive precursor. A key step in the regulation of HGF/MET signaling is proteolytic processing of pro-HGF to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA).We developed SRI 31215, a small molecule that acts as a triplex inhibitor of matriptase, hepsin and HGFA and mimics the activity of HAI-1/2, endogenous inhibitors of HGF activation. We demonstrated that SRI 31215 inhibits fibroblast-induced MET activation, epithelial-mesenchymal transition and migration of cancer cells. SRI 31215 overcomes primary resistance to cetuximab and gefitinib in HGF-producing colon cancer cells and prevents fibroblast mediated resistance to EGFR inhibitors. Thus, SRI 31215 blocks signaling between cancer cells and fibroblasts and inhibits the tumor-promoting activity of cancer associated fibroblasts.Aberrant HGF/MET signaling supports cell survival, proliferation, angiogenesis, invasion and metastatic spread of cancer cells, establishing HGF and MET as valid therapeutic targets. Our data demonstrate that inhibitors of HGF activation, such as SRI 31215, merit investigation as potential therapeutics in tumors that are addicted to HGF/MET signaling. The findings reported here also indicate that inhibitors of HGF activation overcome primary and acquired resistance to anti-EGFR therapy, providing a rationale for concurrent inhibition of EGFR and HGF to prevent therapeutic resistance and to improve the outcome of cancer patients. PMID- 27121053 TI - Reduced expression of CD109 in tumor-associated endothelial cells promotes tumor progression by paracrine interleukin-8 in hepatocellular carcinoma. AB - Tumor-associated endothelial cells (TEC) directly facilitate tumor progression, but little is known about the mechanisms. We investigated the function of CD109 in TEC and its clinical significance in hepatocellular carcinoma (HCC). The correlation between CD109 expressed on tumor vessels and the prognosis after surgical resection of HCC was studied. The effect of human umbilical vein endothelial cells (HUVEC) with different CD109 expression on hepatoma cell proliferation, migration, and invasion was compared in co-culture assay. Associated key factors were screened by human cytokine antibody array and validated thereafter. HUVEC with different CD109 expression were co-implanted with HCCLM3 or HepG2 cells in nude mice to investigate the effect of CD109 expression on tumor growth and metastasis. Reduced expression of CD109 on tumor vessels was associated with large tumor size, microvascular invasion, and advanced tumor stage. CD109 was an independent risk factor for disease-free survival (P = 0.001) after curative resection of HCC. CD109 knockdown in HUVEC promoted hepatoma cell proliferation, migration, and invasion. Interleukin-8 (IL 8) was a key tumor-promoting factor secreted from CD109 knockdown HUVEC. CD109 knockdown upregulated IL-8 expression through activation of TGF-beta/Akt/NF kappaB pathway in HUVEC. Co-implantation with CD109 knockdown HUVEC accelerated tumor growth and metastasis in mice models. In conclusion, CD109 expression on tumor vessels is a potential prognostic marker for HCC, and its reduced expression on TEC promoted tumor progression by paracrine IL-8. PMID- 27121054 TI - Nomogram based on systemic inflammatory response markers predicting the survival of patients with resectable gastric cancer after D2 gastrectomy. AB - This study aimed to construct a nomogram to predict survival of patients with resectable gastric cancer (RGC) based on both clinicopathology characteristics and systemic inflammatory response markers (SIRMs). Of 3,452 RGC patients after D2 gastrectomy at the Sun Yat-sen University Cancer Center, 1058 patients who met the inclusion criterion were analyzed. The patients operated on from January 1, 2005 to December 31, 2009 were assigned to the training set (817 patients) to establish a nomogram, and the rest (241 patients) were selected as validation set. Based on the training set, seven independent risk factors were selected in the nomogram. The calibration curves for probability of 1-year, 3-year and 5-year overall survival (OS) showed satisfactory accordance between nomogram prediction and actual observation. When the metastatic lymph node stage (mLNS) is replaced by metastasis lymph node ratio (mLNR) in validation set, the C-index in predicting OS rise from 0.77 to 0.79, higher than that of 7th American Joint Committee on Cancer 7th (AJCC) staging system (0.70; p<0.001). In conclusions, the proposed nomogram which including mLNR and routine detected SIRMs resulted in optimal survival prediction for RGC patients after D2 gastrectomy. PMID- 27121055 TI - Knockdown of CMTM3 promotes metastasis of gastric cancer via the STAT3/Twist1/EMT signaling pathway. AB - CMTM3 (CKLF-like MARVEL transmembrane domain containing 3) possesses tumor suppressor properties in multiple types of malignancies. Restoration of CMTM3 significantly inhibits the metastasis of gastric cancer, and its expression level is correlated with prognosis. However, the physiological effects and the mechanism of CMTM3 remain unknown. Here, we suppress CMTM3 expression by shRNA to explore its endogenous effects and its mechanism of action in gastric cancer. Stable knockdown of CMTM3 promotes cell migration, invasion and tumor metastasis, increases MMP2 expression and enhances MMP2 activity. CMTM3 inhibits EMT along with the upregulation of E-cadherin and the downregulation of N-cadherin, Vimentin and Twist1. It has no obvious effects on Zeb1 and Snail. CMTM3 suppresses the phosphorylation of STAT3 but not Akt. More importantly, the EMT phenotype and cell migration induced by CMTM3 knockdown can be reversed by the Jak2/STAT3 inhibitor JSI-124 or by siRNA against STAT3 or Twist1. Overall, this study demonstrates that knockdown of CMTM3 promotes the metastasis of gastric cancer through the STAT3/Twist1/EMT pathway. PMID- 27121056 TI - Targeting of Chk2 as a countermeasure to dose-limiting toxicity triggered by topoisomerase-II (TOP2) poisons. AB - The DNA damage response (DDR) gene cell cycle checkpoint kinase 2 (Chk2) triggers programmed cell death and lethal radiation-induced toxicity in mice in vivo. However, it is not well established to what extent targeting of Chk2 may protect from dose-limiting toxicities (DLT) inflicted by mainstay cancer chemotherapy. We screened different classes of chemotherapy in wild type and Chk2-deficient cells. Here we show that loss of Chk2 protect from cell death in vitro and lethal toxicity in vivo following treatment with topoisomerase II (TOP2)-inhibitors whereas no such protection was observed following treatment with topoisomerase I (TOP1) inhibitors. Furthermore, through combined in silico and functional screens of the Diversity Set II (NCI/NTP) chemical library we identified the carbanilide derivative NSC105171, also known as ptu-23, as a novel Chk2 inhibitor (Chk2i). Indeed, NSC105171 can be administered safely to mice to countermeasure etoposide induced toxicity. Incorporation of Chk2i into chemotherapy protocols employing TOP2-inhibitors may be an effective strategy to prevent DLT's without interfering with treatment. PMID- 27121057 TI - Calcium influx-mediated translocation of m-calpain induces Ku80 cleavage and enhances the Ku80-related DNA repair pathway. AB - Proteomic analysis of ionomycin-treated and untreated mammary epithelial MCF10A cells elucidated differences in Ku80 cleavage. Ku80, a subunit of the Ku protein complex, is an initiator of the non-homologous, end-joining (NHEJ), double-strand breaks (DSBs) repair pathway. The nuclear Ku80 was cleaved in a calcium concentration-dependent manner by m-calpain but not by m-calpain. The cleavage of nuclear Ku80 at its alpha/beta domain was validated by Western blotting analysis using flag-tagged expression vectors of truncated versions of Ku80 and a flag antibody and was confirmed in m-calpain knock-down cells and in vitro cell-free evaluation with recombinant proteins of calpains, Ku70, and Ku80. In addition, the cleaved Ku80 still formed a Ku heterodimer and promoted DNA DSB repair activity. Taken together, these findings indicate that translocated m-calpain enhances the NHEJ pathway through the cleavage of Ku80. Based on the present study, m-calpain in DNA repair pathways might be a novel anticancer drug target, or its mechanism might be a possible route for resistance acquisition of DNA damage-inducing chemotherapeutics. PMID- 27121058 TI - Deciphering the role of nuclear and cytoplasmic IKKalpha in skin cancer. AB - Nonmelanoma skin cancers (NMSC) are the most common human malignancies. IKKalpha is an essential protein for skin development and is also involved in the genesis and progression of NMSC, through mechanisms not fully understood. While different studies show that IKKalpha protects against skin cancer, others indicate that it promotes NMSC. To resolve this controversy we have generated two models of transgenic mice expressing the IKKalpha protein in the nucleus (N-IKKalpha mice) or the cytoplasm (C-IKKalpha mice) of keratinocytes. Chemical skin carcinogenesis experiments show that tumors developed by both types of transgenic mice exhibit histological and molecular characteristics that make them more prone to progression and invasion than those developed by Control mice. However, the mechanisms through which IKKalpha promotes skin tumors are different depending on its subcellular localization; while IKKalpha of cytoplasmic localization increases EGFR, MMP-9 and VEGF-A activities in tumors, nuclear IKKalpha causes tumor progression through regulation of c-Myc, Maspin and Integrin-alpha6 expression. Additionally, we have found that N-IKKalpha skin tumors mimic the characteristics associated to aggressive human skin tumors with high risk to metastasize. Our results show that IKKalpha has different non-overlapping roles in the nucleus or cytoplasm of keratinocytes, and provide new targets for intervention in human NMSC progression. PMID- 27121059 TI - RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells. AB - The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells. PMID- 27121060 TI - Collaboration between tumor-specific CD4+ T cells and B cells in anti-cancer immunity. AB - The role of B cells and antibodies in anti-tumor immunity is controversial, with both positive and negative effects reported in animal models and clinical studies. We developed a murine B16.F10 melanoma model to study the effects of collaboration between tumor-specific CD4+ T cells and B cells on tumor control. By incorporating T cell receptor transgenic T cells and B cell receptor isotype switching B cells, we were able to track the responses of tumor-reactive T and B cells and the development of anti-tumor antibodies in vivo. In the presence of tumor-specific B cells, the number of tumor-reactive CD4+ T cells was reduced in lymphoid tissues and the tumor itself, and this correlated with poor tumor control. B cells had little effect on the Th1 bias of the CD4+ T cell response, and the number of induced FoxP3+ regulatory cells (iTregs) generated from within the original naive CD4+ T cell inoculum was unrelated to the degree of B cell expansion. In response to CD4+ T cell help, B cells produced a range of isotype switched anti-tumor antibodies, principally IgG1, IgG2a/c and IgG2b. In the absence of CD4+ T cells, B cells responded to agonistic anti-CD40 administration by switching to production of IgG2a/c and, to a lesser extent, IgG1, IgG3, IgA and IgE, which reduced the number of lung metastases after i.v. tumor inoculation but had no effect on the growth of subcutaneous tumors. PMID- 27121061 TI - Differential expression of major histocompatibility complex class I in subtypes of breast cancer is associated with estrogen receptor and interferon signaling. AB - Tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC) have a strong prognostic and predictive significance. However, the mechanism of TIL influx in TNBC is unclear. Expression of major histocompatibility complex class I (MHC I) on the tumor cell is essential for the effective killing of tumor by cytotoxic TILs. In our current study, human leukocyte antigen (HLA) expression was inversely correlated with estrogen receptor (ER) expression in normal and cancerous breast tissue and positively correlated with TILs in breast cancer. The ER score was inversely correlated with TILs in breast cancer. HLA-A and CD8B gene expression was negatively correlated with ESR1 and positively correlated with interferon-associated gene expression in The Cancer Genome Atlas (TCGA) data. Negative correlation between ESR1 and HLA and positive correlation between interferon-associated and HLA gene expression were also confirmed in Cancer Cell Line Encyclopedia (CCLE) data. Taken together, our data suggest that a lower expression of HLA in luminal-type tumors might be associated with low level of TILs in those tumors. Further investigation of the mechanism of higher HLA expression and TIL influx in TNBC may help to boost the host immune response. PMID- 27121063 TI - USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment. AB - Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States. Most endometrial cancer cases are diagnosed at an early stage and have good prognosis. Unfortunately a subset of patients with early stage and low grade disease experience recurrence for reasons that remain unclear. Recurrence is often accompanied by chemoresistance and high mortality.Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis. DUBs have been shown to be upregulated in a number of human cancers and their aberrant activity has been linked to cancer progression, initiation and onset of chemoresistance. Thus, selective inhibition of DUBs has been proposed as a targeted therapy for cancer treatment.This study suggests the DUB USP14 as a promising biomarker for stratifying endometrial cancer patients at diagnosis based on their risk of recurrence. Further USP14 is expressed along with the marker of proliferation Ki67 in endometrial cancer cells in situ. Lastly, pharmacological targeting of USP14 with the FDA approved small-molecule inhibitor VLX1570, decreases cell viability in chemotherapy resistant endometrial cancer cells with a mechanism consistent with cell cycle arrest and caspase-3 mediated apoptosis. PMID- 27121064 TI - GP73-regulated oncolytic adenoviruses possess potent killing effect on human liver cancer stem-like cells. AB - Cancer stem cells (CSCs), also known as tumor-initiating cells, are highly metastatic, chemo-resistant and tumorigenic, and are critical for cancer development, maintenance and recurrence. Oncolytic adenovirus could targetedly kill CSCs and has been acted as a promising anticancer agent. Currently, a novel GP73-regulated oncolytic adenovirus GD55 was constructed to specifically treat liver cancer and exhibited obvious cytotoxicity effect. However, there remains to be confirmed that whether GD55 could effectively eliminate liver CSCs. We first utilized the suspension culture to enrich the liver CSCs-like cells, which acquires the properties of liver CSCs in self-renewal, differentiation, quiescence, chemo-resistance and tumorigenicity. The results indicated that GD55 elicited more significant cytotoxicity and stronger oncolytic effect in liver CSC like cells compared to common oncolytic virus ZD55. Additionally, GD55 possessed the greater efficacy in suppressing the growth of implanted tumors derived from liver CSC-like cells than ZD55. Furthermore, GD55 induced remarkable apoptosis of liver CSC-like cells in vitro and in vivo, and inhibited the propogation of cells and angiogenesis in xenograft tumor tissues. Thus, GD55 may virtually represent an attractive therapeutic agent for targeting liver CSCs to achieve better clinical outcomes for HCC patients. PMID- 27121062 TI - Myosins as fundamental components during tumorigenesis: diverse and indispensable. AB - Myosin is a kind of actin-based motor protein. As the crucial functions of myosin during tumorigenesis have become increasingly apparent, the profile of myosin in the field of cancer research has also been growing. Eighteen distinct classes of myosins have been discovered in the past twenty years and constitute a diverse superfamily. Various myosins share similar structures. They all convert energy from ATP hydrolysis to exert mechanical stress upon interactions with microfilaments. Ongoing research is increasingly suggesting that at least seven kinds of myosins participate in the formation and development of cancer. Myosins play essential roles in cytokinesis failure, chromosomal and centrosomal amplification, multipolar spindle formation and DNA microsatellite instability. These are all prerequisites of tumor formation. Subsequently, myosins activate various processes of tumor invasion and metastasis development including cell migration, adhesion, protrusion formation, loss of cell polarity and suppression of apoptosis. In this review, we summarize the current understanding of the roles of myosins during tumorigenesis and discuss the factors and mechanisms which may regulate myosins in tumor progression. Furthermore, we put forward a completely new concept of "chromomyosin" to demonstrate the pivotal functions of myosins during karyokinesis and how this acts to optimize the functions of the members of the myosin superfamily. PMID- 27121065 TI - Wip1 suppresses ovarian cancer metastasis through the ATM/AKT/Snail mediated signaling. AB - Inactivation of p53 greatly contributes to serous ovarian cancer, while the role of the wild-type p53 induced phosphatase 1 (Wip1) is quite unclear. In this study, by silencing or overexpression of Wip1, we found that Wip1 suppressed ovarian cancer cell invasion, migration, epithelial to mesenchymal transition (EMT), and ovarian cancer metastasis in xenograft animal models. Mechanistic studies showed that Wip1 may block ovarian cancer metastasis through inhibition of Snail and p-Akt expression because silencing or overexpression of Wip1 either upregulated or downregulated the expression of Snail and p-Akt (Ser 473), while further knockdown of Snail by shRNA or inhibition of p-Akt by a chemical compound attenuated cell invasion, migration and EMT in Wip1 silencing cells. We also found that the phosphorylation of Akt at Ser 473 might be mediated through p-ATM (Ser 1981). Thus, Wip1 may suppress ovarian cancer metastasis through negative regulation of p-ATM, p-Akt, and Snail, which was also evidenced in the limited clinical specimens. Therefore, our data may provide a novel therapeutic indication for serous ovarian cancer based on the uncovered mechanism associated with the precise function of Wip1 independent of p53. PMID- 27121066 TI - HIF-1alpha activates hypoxia-induced BCL-9 expression in human colorectal cancer cells. AB - B-cell CLL/lymphoma 9 protein (BCL-9), a multi-functional co-factor in Wnt signaling, induced carcinogenesis as well as promoting tumor progression, metastasis and chemo-resistance in colorectal cancer (CRC). However, the mechanisms for increased BCL-9 expression in CRC were not well understood. Here, we report that hypoxia, a hallmark of solid tumors, induced BCL-9 mRNA expression in human CRC cells. Analysis of BCL-9 promoter revealed two functional hypoxia responsive elements (HRE-B and HRE-C) that can be specifically bound with and be transactivated by hypoxia inducible factors (HIF) -1alpha but not HIF-2alpha. Consistently, ectopic expression of HIF-1alpha but not HIF-2alpha transcriptionally induced BCL-9 expression levels in cells. Knockdown of endogenous HIF-1alpha but not HIF-2alpha by siRNA largely abolished the induction of HIF by hypoxia. Furthermore, there was a strong association of HIF-1alpha expression with BCL-9 expression in human CRC specimens. In summary, results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1alpha, which could be an important underlying mechanism for increased BCL-9 expression in CRC. PMID- 27121067 TI - The role of histological subtype in hormone receptor positive metastatic breast cancer: similar survival but different therapeutic approaches. AB - INTRODUCTION: This study describes the differences between the two largest histological breast cancer subtypes (invasive ductal carcinoma (IDC) and invasive (mixed) lobular carcinoma (ILC) with respect to patient and tumor characteristics, treatment-choices and outcome in metastatic breast cancer. RESULTS: Patients with ILC were older at diagnosis of primary breast cancer and had more often initial bone metastasis (46.5% versus 34.8%, P = 0.01) and less often multiple metastatic sites compared to IDC (23.7% versus 30.9%, P = 0.11). Six months after diagnosis of metastatic breast cancer, 28.1% of patients with ILC and 39.8% of patients with IDC had received chemotherapy with a longer median time to first chemotherapy for those with ILC (P = 0.001). After six months 84.8% of patients with ILC had received endocrine therapy versus 72.5% of patients with IDC (P = 0.0001). Median overall survival was 29 months for ILC and 25 months for IDC (P = 0.53). MATERIALS AND METHODS: We included 437 patients with hormone receptor-positive IDC and 131 patients with hormone receptor-positive ILC, all diagnosed with metastatic breast cancer between 2007-2009, irrespective of date of the primary diagnosis. Patient and tumor characteristics and data on treatment and outcome were collected. Survival curves were obtained using the Kaplan-Meier method. CONCLUSIONS: Treatment strategies of hormone receptor-positive metastatic breast cancer were remarkably different for patients with ILC and IDC. Further research is required to understand tumor behavior and treatment-choices in real life. PMID- 27121068 TI - Etiology of molar incisor hypomineralization - A systematic review. AB - OBJECTIVES: Molar incisor hypomineralization (MIH) is a common developmental dental defect of permanent teeth, which can increase the risk of dental caries, infection and hospitalization. The etiology is currently unclear although prenatal or early childhood health factors are suspected. The aim of this systematic review was to assess the strength of evidence linking etiological factors with MIH. METHODS: A systematic search was conducted using the Medline and Embase electronic databases for studies investigating environmental etiological factors of MIH. Two reviewers assessed the eligibility of studies. The level of evidence and bias was determined for all eligible studies according to Australian National Health and Medical Research Council guidelines for systematic reviews of etiology and the Newcastle-Ottawa Scale. RESULTS: From a total of 2254 studies identified through electronic and hand searching, 28 were eligible for inclusion. Twenty-five of these investigated MIH and three investigated a related condition in primary teeth, hypomineralized second primary molars (HSPM), and these were analysed separately. A limited number of studies reported significant associations between MIH and pre- and perinatal factors such as maternal illness and medication use in pregnancy, prematurity and birth complications. Early childhood illness was implicated as an etiological factor in MIH in several studies, in particular fever, asthma and pneumonia. The studies investigating HSPM revealed an association with maternal alcohol consumption, infantile fever and ethnicity. However, the validity of these findings is impaired by study design, lack of adjustment for confounders, lack of detail and consistency of exposures investigated and poor reporting. CONCLUSIONS: Childhood illness is likely to be associated with MIH. Further prospective studies of the etiology of MIH/HSPM are needed. PMID- 27121069 TI - The analysis of estrogen receptor-alpha positive breast cancer stem-like cells unveils a high expression of the serpin proteinase inhibitor PI-9: Possible regulatory mechanisms. AB - Breast cancer stem cells seem to play important roles in breast tumor recurrence and endocrine therapy resistance, although the underlying mechanisms have not been well established. Moreover, in some tumor systems the immunosurveillance failure against cancer cells has been related to the presence of the granzyme B inhibitor PI-9. This study explored the status of PI-9 in tumorspheres isolated from estrogen receptor-alpha positive (ERalpha+) breast cancer MCF7 cells. Studies were performed in tertiary tumorspheres which possess high levels of stemness markers (Nanog, Oct3/4 and Sox2) and self-renewal ability. The exposure to estrogens (17-beta estradiol and genistein) increased the number and sizes of tumorspheres, promoting cell proliferation as demonstrated by the increase in the proliferating cell nuclear antigen (PCNA). The study of the three isoforms (66, 46 and 36 kDa) of ERalpha disclosed that tertiary tumorspheres exhibit a marked increase in ERalpha36, while the level of ERalpha66, which is highly expressed in MCF7 cells, declines. Although it is known that PI-9 is a transcriptional target of ERalpha66, surprisingly in tertiary tumorspheres, despite the reduced level of ERalpha66, the protein and mRNA content of PI-9 is higher than in MCF7 cells. Treatment with estrogens further increased PI-9 level while decreased that of ERalpha66 isoform thus excluding the involvement of this receptor isoform in the event. Moreover, our studies also provided evidence that tertiary tumorspheres express elevated levels of CXCR4 and phospho-p38, suggesting that the high PI-9 content might be ascribed to the activation of the proliferative CXCR4/phospho p38 axis. Taken together, these events could supply a selective advantage to breast cancer stem cells by interfering with immunosurveillance systems and open up the avenue to new possible targets for breast cancer treatment. PMID- 27121070 TI - Optimizing Water Transport through Graphene-Based Membranes: Insights from Nonequilibrium Molecular Dynamics. AB - Recent experimental results suggest that stacked layers of graphene oxide exhibit strong selective permeability to water. To construe this observation, the transport mechanism of water permeating through a membrane consisting of layered graphene sheets is investigated via nonequilibrium and equilibrium molecular dynamics simulations. The effect of sheet geometry is studied by changing the offset between the entrance and exit slits of the membrane. The simulation results reveal that the permeability is not solely dominated by entrance effects; the path traversed by water molecules has a considerable impact on the permeability. We show that contrary to speculation in the literature, water molecules do not pass through the membrane as a hydrogen-bonded chain; instead, they form well-mixed fluid regions confined between the graphene sheets. The results of the present work are used to provide guidelines for the development of graphene and graphene oxide membranes for desalination and solvent separation. PMID- 27121071 TI - The effect of amifostine on lung ischaemia-reperfusion injury in rats. AB - OBJECTIVES: Lung ischaemia-reperfusion injury (LIRI) frequently occurs after lung transplantation or cardiac surgery with cardiopulmonary bypass, thus increasing postoperative morbidity and mortality. As LIRI is associated with the release of reactive oxygen species and a subsequent inflammatory reaction, we tested whether amifostine, a thiol and free radical scavenger, has a beneficial effect on LIRI. METHODS: A total number of 72 Wistar rats were subjected to LIRI with or without a single or double dose of amifostine (100 mg/kg, intraperitoneally). Experimental induction of LIRI was performed by clamping either the left lung hilum or the pulmonary artery alone for 60 min, followed by 90 min of reperfusion. Control groups consisted of LIRI and NaCl, a sham group and a no intervention group (baseline). At the end of the experiments, the left lung was analysed by quantitative RT-PCR of inflammatory marker gene expression, western blot of activated nuclear factor-kappaB (NF-kappaB) and light and electron microscopy. RESULTS: In placebo and amifostine groups, the expression levels of pro-inflammatory markers were increased significantly and to a similar extent independent of the type of ischaemia induction. In contrast, amifostine reduced the activation of NF-kappaB in comparison with placebo. This effect was present independent of the type of ischaemia or the application of a single or double dose of amifostine. However, oedema formation, blood-gas barrier damage and inflammatory reaction were similar in all amifostine or placebo LIRI groups. CONCLUSIONS: Despite a significant reduction in NF-kappaB activation, amifostine failed to decrease the inflammatory response and structural changes induced by LIRI in this experimental setting. PMID- 27121072 TI - An unusual complication: aortic graft perforation by a fractured rib after type B aortic dissection. AB - Aortic injury caused by the penetration of a fractured rib is rare, but aortic graft penetration is even less common. This is a case report describing perforation of a Dacron aortic graft by the sharp margin of a displaced rib, which occurred after a thoracotomy. This case illustrates the importance of fixing fractured ribs. PMID- 27121073 TI - Gelsolin Promotes Radioresistance in Non-Small Cell Lung Cancer Cells Through Activation of Phosphoinositide 3-Kinase/Akt Signaling. AB - Gelsolin is an actin-binding protein and acts as an important regulator of cell survival. This study aimed to determine the function of gelsolin in the radioresistance of non-small cell lung cancer cells. We examined the expression of gelsolin in radioresistant A549 and H460 cells and their parental cells. The effects of gelsolin overexpression and knockdown on the clonogenic survival and apoptosis of non-small cell lung cancer cells after irradiation were studied. The involvement of phosphoinositide 3-kinase/Akt signaling in the action of gelsolin was checked. We found that gelsolin was significantly upregulated in radioresistant A549 and H460 cells. Overexpression of gelsolin significantly ( P < .05) increased the number of colonies from irradiated A549 and H460 cells compared to transfection of empty vector. In contrast, knockdown of gelsolin significantly ( P < .05) suppressed colony formation after irradiation. Gelsolin overexpressing cells displayed reduced apoptosis in response to irradiation, which was coupled with decreased levels of cleaved caspase-3 and poly adenosine diphosphate-ribose polymerase. Ectopic expression of gelsolin significantly ( P < .05) enhanced the phosphorylation of Akt compared to nontransfected cells. Pretreatment with the phosphoinositide 3-kinase inhibitor LY294002 (20 MUmol/L) significantly decreased clonogenic survival and enhanced apoptosis in gelsolin overexpressing A549 and H460 cells after irradiation. Taken together, gelsolin upregulation promotes radioresistance in non-small cell lung cancer cells, at least partially, through activation of phosphoinositide 3-kinase/Akt signaling. PMID- 27121075 TI - Comment on 'Parametrization of Stillinger-Weber potential based on a valence force field model: application to single-layer MoS2 and black phosphorus'. AB - We compare the simplified valence-force model for single-layer black phosphorus with the original model and recent ab initio results. Using an analytic approach and numerical calculations we find that the simplified model yields Young's moduli that are smaller compared to the original model and are almost a factor of two smaller than ab initio results. Moreover, the Poisson ratios are an order of magnitude smaller than values found in the literature. PMID- 27121074 TI - Mechanistic and Technical Challenges in Studying the Human Microbiome and Cancer Epidemiology. AB - This article reviews the significance of the microbiome in cancer epidemiology, mechanistic and technical challenges in the field, and characterization of the microbiome in different tumor types to identify biomarkers of risk, progression, and prognosis. Publications on the microbiome and cancer epidemiology were reviewed to analyze sample collection and processing, microbiome taxa characterization by 16S ribosomal RNA sequencing, and microbiome metabolite characterization (metabotyping) by nuclear magnetic resonance and mass spectrometry. The analysis identified methodology types, research design, sample types, and issues in integrating data from different platforms. Aerodigestive cancer epidemiology studies conducted by different groups demonstrated the significance of microbiome information in developing approaches to improve health. Challenges exist in sample preparation and processing (eg, standardization of methods for collection and analysis). These challenges relate to technology, data integration from "omics" studies, inherent bias in primer selection during 16S ribosomal RNA sequencing, the need for large consortia with well-characterized biospecimens, cause and effect issues, resilience of microbiota to exposure events (requires longitudinal studies), and expanding studies for fungal and viral diversity (most studies used bacterial 16S ribosomal RNA sequencing for microbiota characterization). Despite these challenges, microbiome and cancer epidemiology studies are significant and may facilitate cancer risk assessment, diagnosis, and prognosis. In the future, clinical trials likely will use microbiota modifications to improve the efficacy of existing treatments. PMID- 27121076 TI - Asiatic acid attenuates renin-angiotensin system activation and improves vascular function in high-carbohydrate, high-fat diet fed rats. AB - BACKGROUND: In the rat model of high carbohydrate, high fat (HCHF) diet-induced metabolic syndrome (MS), previous studies have found that asiatic acid has an antihypertensive effect. In this study, we investigated effects of asiatic acid on vascular structure, vascular function and renin-angiotensin system (RAS) in HCHF diet-induced MS rats. METHODS: Male Sprague-Dawley rats were divided into three treatment groups for the 15 week study: a control group fed a normal diet, a MS group fed HCHF diet plus 15 % fructose in their drinking water for 15 weeks, and an asiatic acid treated group that received a HCHF diet plus fructose for 15 weeks and also received orally administered asiatic acid (20 mg/kg BW/day) for the final 3 weeks. Vascular structure and function were investigated. AT1 receptor expression in aortic tissues and eNOS protein expression in the mesenteric arteries were detected. The levels of serum angiotensin (Ang) II, angiotensin converting enzyme (ACE) and plasma norepinephrine (NE) were measured. The differences among treatment groups were analyzed by one-way analysis of variance (ANOVA) followed by post-hoc Bonferroni tests. RESULTS: At the end of the study, all rats fed a HCHF diet exhibited signs of MS including, hypertension, dyslipidemia and insulin resistance. Vascular remodeling in large and small arteries, overexpression of AT1 receptor, and high levels of serum Ang II and ACE were also observed in MS group (p < 0.05). Contractile responses to sympathetic nerve stimulation were enhanced relating to high plasma NE level in MS rats (p < 0.05). The response to exogenous NE was not changed in the mesenteric bed. Vasorelaxation responses to acetylcholine were blunted in thoracic aorta and mesenteric beds, which is consistent with downregulation of eNOS expression in MS rats (p < 0.05). Restoration of metabolic alterations, hemodynamic changes, RAS and sympathetic overactivity, increased plasma NE, endothelium dysfunction, and downregulation of eNOS expression was observed in the asiatic acid treated group (p < 0.05). However, asiatic acid failed to alleviate vascular remodeling in MS rats. CONCLUSION: Our findings suggest that the observed antihypertensive effect of asiatic acid in MS rats might be related to its ability to alleviate RAS overactivity and improve vascular function with restoration of sympathetic overactivity. PMID- 27121077 TI - Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy. AB - BACKGROUND: Trimetazidine, as an anti-ischemic and antioxidant agent, has been demonstrated to have many cardioprotective effects. However, whether early administration of trimetazidine has an effect on diabetic cardiomyopathy and the mechanisms underlying the effect have not yet been elucidated. METHODS: We established a type 2 DCM rat model by high-fat diet and low-dose streptozotocin. Rats were separated into different groups: control, diabetes, and diabetes + trimetazidine (n = 6, each). Cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored. RESULTS: Rats with type 2 DCM showed severe insulin resistance, left ventricular dysfunction, increased cardiomyocyte apoptosis, and reduced cardiac autophagy. Collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) ratio were significantly higher in the diabetic group than the control group. We found that trimetazidine treatment ameliorated metabolic disturbance and insulin resistance, reduced cardiomyocyte apoptosis, and restored cardiac autophagy. CVF and PVCA/LA ratio were also lower in the diabetes + trimetazidine group than the diabetic group (CVF, 4.75 +/- 0.52 % vs. 11.04 +/- 1.67 %, p < 0.05; PVCA/LA, 8.37 +/- 0.51 vs. 17.97 +/- 2.66, p < 0.05). Furthermore, trimetazidine inhibited phosphorylation of ERK and P38 MAPK to reduce myocardial fibrosis. Inhibited phosphorylation of AMPK was restored and the interaction between Bcl-2 and Beclin1 was enhanced in diabetes + trimetazidine group, resulting in the initiation of autophagy and alleviation of apoptosis. CONCLUSIONS: Early administration of trimetazidine could ameliorate diabetic cardiomyopathy by inhibiting myocardial fibrosis and cardiomyocyte apoptosis and enhancing autophagy. Therefore, trimetazidine may be a good choice in the prevention of diabetic cardiomyopathy if applied at the early stage of diabetes. PMID- 27121079 TI - MicroRNA-451 protects against cardiomyocyte anoxia/reoxygenation injury by inhibiting high mobility group box 1 expression. AB - High mobility group box 1 (HMGB1) protein serves an important role in myocardial ischemia/reperfusion (I/R) injury. MicroRNAs (miRNAs) are a group of small non coding RNAs that regulate numerous signaling pathways involved in myocardial I/R injury. The present study aimed to investigate whether miR-451 protects against cardiomyocyte anoxia/reoxygenation (A/R) injury by attenuating HMGB1 expression. Neonatal rat ventricular cardiomyocytes were prepared and then subjected to A/R injury. The effect of upregulation or downregulation of miR-451 on cell viability, apoptosis, superoxide dismutase (SOD) activity, and the expression of cleaved-caspase-3 and HMGB1 were measured accordingly. A luciferase assay was performed to further confirm whether miR-451 can directly recognize the 3' untranslated region of HMGB1 in HEK293 cells. The expression of miR-451 was significantly decreased in the cardiomyocytes during A/R, and upregulation of miR 451 led to increased miR-451 expression (P<0.05). Upregulation of miR-451 significantly attenuated the loss of cardiomyocyte viability (P<0.05) and increased the intracellular levels of SOD during A/R (P<0.05). Furthermore, upregulation of miR-451 significantly decreased the apoptosis of cardiomyocytes during A/R (P<0.05). The HMGB1 mRNA and protein expression levels were significantly downregulated in the Ad-miR-451 group compared with those in the A/R group (P<0.05). In addition, upregulation of miR-451 reduced its translocation from the nucleus to the cytoplasm. The luciferase assay confirmed that HMGB1 mRNA is a direct target of miR-451 in cardiomyocytes. In conclusion, the present study suggested that upregulation of miR-451 could protect against A/R-induced cardiomyocyte injury by inhibiting HMGB1 expression. PMID- 27121080 TI - The Whiteley Index-6: An Examination of Measurement Invariance Among Self Identifying Black, Latino, and White Respondents in Primary Care. AB - Brief measures that are comparable across disparate groups are particularly likely to be useful in primary care settings. Prior research has supported a six item short form of the Whiteley Index (WI), a commonly used measure of health anxiety, among English-speaking respondents. This study examined the measurement invariance of the WI-6 among Black ( n = 183), Latino ( n = 173), and White ( n = 177) respondents seeking treatment at a U.S. community health center. Results supported a bifactor model of the WI-6 among the composite sample ( N = 533), suggesting the presence of a general factor and two domain-specific factors. Results supported the incremental validity of one of the domain-specific factors in accounting for unique variance in somatic symptom severity scores beyond the general factor. Multiple-groups confirmatory factor analysis supported the configural, metric, ands scalar invariance of the bifactor WI-6 model across the three groups of respondents. Results provide support for the measurement invariance of the WI-6 among Black, Latino, and White respondents. The potential use of the WI-6 in primary care, and broader, settings is discussed. PMID- 27121078 TI - Down-regulation of p21-activated serine/threonine kinase 1 is involved in loss of mesencephalic dopamine neurons. AB - BACKGROUND: Although the roles of p21-activated serine/threonine kinase 1 (PAK1) have been reported in some neurodegenerative diseases, details regarding neurodegeneration are still limited. Hence, we tried to determine the role of PAK1 and molecular mechanisms of neuronal death involved in neurodegeneration. RESULTS: Expression of a dominant-negative form of PAK1 (PAK1(H83,86L, K229R), PAK1-DN) decreased the cell viability and increased cell death induced by oxidative stress. Indeed, oxidative stress decreased the phosphorylation of PAK1 in neuroblastoma cells, cultured dopamine (DA) neurons, or rat midbrains. PAK1-DN reduced the level of Bcl-2 protein, through an ubiquitin/proteasome-dependent mechanism. The level of Bcl-2 may be regulated by PAK1-ERK signaling and/or PAK1, directly. Conversely, expression of an active form of PAK1 (PAK1(T423E), PAK1-CA) could recover both loss of DA neurons in the substantia nigra (SN) and behavioral defects in a 6-OHDA-induced hemiparkinsonian rat model. CONCLUSIONS: Our data suggest that the oxidative stress-induced down-regulation of PAK1 activity could be involved in the loss of mesencephalic DA neurons through modulation of neuronal death, suggesting a novel role of PAK1 as a molecular determinant and mechanisms in the pathogenesis of Parkinson's disease. PMID- 27121081 TI - Diagnostic Accuracy, Sensitivity, and Specificity of Executive Function Tests in Moderate Traumatic Brain Injury in Ghana. AB - The sociocultural differences between Western and sub-Saharan African countries make it imperative to standardize neuropsychological tests in the latter. However, Western-normed tests are frequently administered in sub-Saharan Africa because of challenges hampering standardization efforts. Yet a salient topical issue in the cross-cultural neuropsychology literature relates to the utility of Western-normed neuropsychological tests in minority groups, non-Caucasians, and by extension Ghanaians. Consequently, this study investigates the diagnostic accuracy, sensitivity, and specificity of executive function (EF) tests (The Stroop Test, Trail Making Test, and Controlled Oral Word Association Test), and a Revised Quick Cognitive Screening Test (RQCST) in a sample of 50 patients diagnosed with moderate traumatic brain injury and 50 healthy controls in Ghana. The EF test scores showed good diagnostic accuracy, with area under the curve (AUC) values of the Trail Making Test scores ranging from .746 to .902. With respect to the Stroop Test scores, the AUC values ranged from .793 to .898, while Controlled Oral Word Association Test had AUC value of .787. The RQCST scores discriminated between the groups, with AUC values ranging from .674 to .912. The AUC values of composite EF score and a neuropsychological score created from EF and RQCST scores were .936 and. 942, respectively. Additionally, the Stroop Test, Trail Making Test, EF composite score, and RQCST scores showed good to excellent sensitivities and specificities. In general, this study has shown that commonly used EF tests in Western countries have diagnostic accuracy, sensitivity, and specificity when administered in Ghanaian samples. The findings and implications of the study are discussed. PMID- 27121082 TI - Visceral States Call for Visceral Measures: Verbal Overshadowing of Hunger Ratings Across Assessment Modalities. AB - We introduce a nonverbal "visceral" measure of hunger (i.e., squeezing a handheld dynamometer) and provide the first evidence of verbal overshadowing effects in this visceral domain. We presented 106 participants with popcorn and recorded their hunger levels in one of three conditions: (1) first report hunger using a traditional self-report rating scale (i.e., verbal measure) and then indicate hunger by squeezing a dynamometer (i.e., nonverbal measure), (2) first indicate hunger nonverbally and then indicate hunger verbally, or (3) indicate hunger only nonverbally. As hypothesized, nonverbal measures of hunger predicted subsequent eating behavior when they were uncontaminated by verbal measures-either because they preceded verbal measures of hunger or because they were the sole measure of hunger. Moreover, nonverbal measures of hunger were a better predictor of eating behavior than verbal measures. Implications of the study for communicating embodied experiences in a way that escapes the confines of symbolic representations are discussed. PMID- 27121083 TI - Transcriptomic analysis of a classical model of carbon catabolite regulation in Streptomyces coelicolor. AB - BACKGROUND: In the genus Streptomyces, one of the most remarkable control mechanisms of physiological processes is carbon catabolite repression (CCR). This mechanism regulates the expression of genes involved in the uptake and utilization of alternative carbon sources. CCR also affects the synthesis of secondary metabolites and morphological differentiation. Even when the outcome effect of CCR in different bacteria is the same, their essential mechanisms can be quite different. In several streptomycetes glucose kinase (Glk) represents the main glucose phosphorylating enzyme and has been regarded as a regulatory protein in CCR. To evaluate the paradigmatic model proposed for CCR in Streptomyces, a high-density microarray approach was applied to Streptomyces coelicolor M145, under repressed and non-repressed conditions. The transcriptomic study was extended to assess the ScGlk role in this model by comparing the transcriptomic profile of S. coelicolor M145 with that of a ?glk mutant derived from the wild type strain, complemented with a heterologous glk gene from Zymomonas mobilis (Zmglk), insensitive to CCR but able to grow in glucose (ScoZm strain). RESULTS: Microarray experiments revealed that glucose influenced the expression of 651 genes. Interestingly, even when the ScGlk protein does not have DNA binding domains and the glycolytic flux was restored by a heterologous glucokinase, the ScGlk replacement modified the expression of 134 genes. From these, 91 were also affected by glucose while 43 appeared to be under the control of ScGlk. This work identified the expression of S. coelicolor genes involved in primary metabolism that were influenced by glucose and/or ScGlk. Aside from describing the metabolic pathways influenced by glucose and/or ScGlk, several unexplored transcriptional regulators involved in the CCR mechanism were disclosed. CONCLUSIONS: The transcriptome of a classical model of CCR was studied in S. coelicolor to differentiate between the effects due to glucose or ScGlk in this regulatory mechanism. Glucose elicited important metabolic and transcriptional changes in this microorganism. While its entry and flow through glycolysis and pentose phosphate pathway were stimulated, the gluconeogenesis was inhibited. Glucose also triggered the CCR by repressing transporter systems and the transcription of enzymes required for secondary carbon sources utilization. Our results confirm and update the agar model of the CCR in Streptomyces and its dependence on the ScGlk per se. Surprisingly, the expected regulatory function of ScGlk was not found to be as global as thought before (only 43 out of 779 genes were affected), although may be accompanied or coordinated by other transcriptional regulators. Aside from describing the metabolic pathways influenced by glucose and/or ScGlk, several unexplored transcriptional regulators involved in the CCR mechanism were disclosed. These findings offer new opportunities to study and understand the CCR in S. coelicolor by increasing the number of known glucose and ScGlk -regulated pathways and a new set of putative regulatory proteins possibly involved or controlling the CCR. PMID- 27121084 TI - Imaging large-scale cellular activity in spinal cord of freely behaving mice. AB - Sensory information from mechanoreceptors and nociceptors in the skin plays key roles in adaptive and protective motor behaviours. To date, very little is known about how this information is encoded by spinal cord cell types and their activity patterns, particularly under freely behaving conditions. To enable stable measurement of neuronal and glial cell activity in behaving mice, we have developed fluorescence imaging approaches based on two- and miniaturized one photon microscopy. We show that distinct cutaneous stimuli activate overlapping ensembles of dorsal horn neurons, and that stimulus type and intensity is encoded at the single-cell level. In contrast, astrocytes show large-scale coordinated calcium responses to intense but not weak sensory inputs. Sensory-evoked activity is potently suppressed by anaesthesia. By revealing the cellular and computational logic of spinal cord networks under behaving conditions, our approach holds promise for better understanding of healthy and aberrant spinal cord processes. PMID- 27121085 TI - Enterovirus D68 Infections Associated with Severe Respiratory Illness in Elderly Patients and Emergence of a Novel Clade in Hong Kong. AB - Despite the recent emergence of enterovirus D68 (EV-D68), its clinical impact on adult population is less well defined. To better define the epidemiology of EV D68, 6,800 nasopharyngeal aspirates (NPAs) from 2010-2014 were subject to EV-D68 detection by RT-PCR and sequencing of 5'UTR and partial VP1. EV-D68 was detected in 30 (0.44%) NPAs from 22 children and 8 adults/elderlies. Sixteen patients (including five elderly) (53%) had pneumonia and 13 (43%) patients were complicated by small airway disease exacerbation. Phylogenetic analysis of VP1, 2C and 3D regions showed four distinct lineages of EV-D68, clade A1, A2, B1 and B3, with adults/elderlies exclusively infected by clade A2. The potentially new clade, B3, has emerged in 2014, while strains closely related to recently emerged B1 strains in the United States were also detected as early as 2011 in Hong Kong. The four lineages possessed distinct aa sequence patterns in BC and DE loops. Amino acid residues 97 and 140, within BC and DE-surface loops of VP1 respectively, were under potential positive selection. EV-D68 infections in Hong Kong usually peak in spring/summer, though with a delayed autumn/winter peak in 2011. This report suggests that EV-D68 may cause severe respiratory illness in adults/elderlies with underlying co-morbidities. PMID- 27121086 TI - High prevalence of vaterite in sagittal otoliths causes hearing impairment in farmed fish. AB - The rapid growth of aquaculture raises questions about the welfare status of mass produced species. Sagittal otoliths are primary hearing structures in the inner ear of all teleost (bony) fishes and are normally composed of aragonite, though abnormal vaterite replacement is sometimes seen in the wild. We provide the first widespread evaluation of the prevalence of vaterite in otoliths, showing that farmed fish have levels of vaterite replacement over 10 times higher than wild fish, regardless of species. We confirm this observation with extensive sampling of wild and farmed Atlantic salmon in Norway, the world's largest producer, and verify that vateritic otoliths are common in farmed salmon worldwide. Using a mechanistic model of otolith oscillation in response to sound, we demonstrate that average levels of vaterite replacement result in a 28-50% loss of otolith functionality across most of a salmonid's known hearing range and throughout its life cycle. The underlying cause(s) of vaterite formation remain unknown, but the prevalence of hearing impairment in farmed fish has important implications for animal welfare, the survival of escapees and their effects on wild populations, and the efficacy of restocking programs based on captive-bred fish. PMID- 27121087 TI - Hepatitis B virus genome replication triggers toll-like receptor 3-dependent interferon responses in the absence of hepatitis B surface antigen. AB - The hepatitis B virus (HBV) has been described as stealth virus subverting immune responses initially upon infection. Impaired toll-like receptor signaling by the HBV surface antigen (HBsAg) attenuates immune responses to facilitate chronic infection. This implies that HBV replication may trigger host innate immune responses in the absence of HBsAg. Here we tested this hypothesis, using highly replicative transgenic mouse models. An HBV replication-dependent expression of antiviral genes was exclusively induced in HBsAg-deficient mice. These interferon responses attributed to toll-like receptor 3 (TLR3)-activated Kupffer and liver sinusoidal endothelial cells and further controlled the HBV genome replication. However, activation of TLR3 with exogenous ligands indicated additional HBs independent immune evasion events. Our data demonstrate that in the absence of HBsAg, hepatic HBV replication leads to Tlr3-dependent interferon responses in non-parenchymal liver cells. We hypothesize that HBsAg is a major HBV-mediated evasion mechanism controlling endogenous antiviral responses in the liver. Eradication of HBsAg as a therapeutic goal might facilitate the induction of endogenous antiviral immune responses in patients chronically infected with HBV. PMID- 27121089 TI - Sustainable Sulfur-rich Copolymer/Graphene Composite as Lithium-Sulfur Battery Cathode with Excellent Electrochemical Performance. AB - A sulfur-rich copolymer, poly(S-r-C-a) has been synthesized via a sustainable route, showing the utility of two major industrial wastes- elemental sulfur (petroleum waste) and cardanol (agro waste), to explore its potential as cathode material for Li-S batteries. The sulfur-rich copolymer exhibited a reduction in the active material dissolution into the electrolyte and a low self-discharge rate behavior during the rest time compared to an elemental sulfur cathode, indicating the chemical confinement of sulfur units. The presence of organosulfur moieties in copolymer suppress the irreversible deposition of end-discharge products on electrode surfaces and thus improve the electrochemical performances of Li-S batteries. This sulfur copolymer offered a reversible capacity of 892 mA h g(-1) at 2nd cycle and maintained the capacity of 528 mA h g(-1) after 50 cycles at 200 mA g(-1). Reduced graphene oxide (rGO) prepared via a sustainable route was used as a conductive filler to extract the better electrochemical performances from this sulfur copolymer. Such sustainable origin batteries prepared via economically viable showed an improved specific capacity of ~975 mA h g(-1) after 100 cycles at 200 mA g(-1) current rate with capacity fading of 0.15% per cycle and maintained a stable performance over 500 cycles at 2000 mA g( 1). PMID- 27121088 TI - CXCL12/CXCR4 axis regulates neovascularization and lymphangiogenesis in sutured corneas in mice. AB - The present study aimed to determine the plausible functional role of chemokine (C-X-C motif) ligand 12 (CXCL12/chemokine (C-X-C motif) receptor 4 (CXCR4) in inflammatory corneal hemangiogenesis and lymphangiogenesis in vivo. Corneal hemangiogenesis and lymphangiogenesis were induced by placing an 11-0 nylon suture in an intrastromal position. The expression levels of the vascular endothelial growth factor (VEGF) family, CXCL12 and CXCR4 in the corneas were investigated in the corneas using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. Corneal hemangiogenic and lymphangiogenic responses were assessed by immunofluorescence using specific antibodies against cluster of differentiation 31 and lymphatic vessel endothelial hyaluronan receptor-1. Subconjunctival injection of AMD3100 to the sutured corneas was also performed. CXCL12/CXCR4 mRNA and protein expression levels increased markedly in suture-induced corneal neovascularization (CNV) and decreased with AMD3100 treatment. Hemangiogenesis and lymphangiogenesis were captured in images using immunofluorescence and were shown to be markedly increased with suture placement and reduced with AMD3100 treatment. VEGF-A/VEGFR 1 and VEGF-C/VEGFR-3 mRNA expression levels were upregulated in the suture placement and control groups, whereas the expression levels of all the factors were downregulated in the AMD3100 treatment group. The results from the present study demonstrated that CXCL12/CXCR4 interactions regulate hemangiogenesis and lymphangiogenesis in suture-induced CNV. AMD3100 may be a novel therapeutic target for the prevention of blindness. PMID- 27121090 TI - Online CBT life skills programme for low mood and anxiety: study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Low mood is a common mental health problem with significant health consequences. Studies have shown that cognitive behavioural therapy (CBT) is an effective treatment for low mood and anxiety when delivered one-to-one by an expert practitioner. However, access to this talking therapy is often limited and waiting lists can be long, although a range of low-intensity interventions that can increase access to services are available. These include guided self-help materials delivered via books, classes and online packages. This project aims to pilot a randomized controlled trial of an online CBT-based life skills course with community-based individuals experiencing low mood and anxiety. METHODS: Individuals with elevated symptoms of depression will be recruited directly from the community via online and newspaper advertisements. Participants will be remotely randomized to receive either immediate access or delayed access to the Living Life to the Full guided online CBT-based life skills package, with telephone or email support provided whilst they use the online intervention. The primary end point will be at 3 months post-randomization, at which point the delayed-access group will be offered the intervention. Levels of depression, anxiety, social functioning and satisfaction will be assessed. DISCUSSION: This pilot study will test the trial design, and ability to recruit and deliver the intervention. Drop-out rates will be assessed and the completion and acceptability of the package will be investigated. The study will also inform a sample size power calculation for a subsequent substantive randomized controlled trial. TRIAL REGISTRATION: ISRCTN ISRCTN12890709. PMID- 27121091 TI - Tumor suppressor miR-149-5p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma. AB - Several studies have recently explored the role of microRNAs (miRNAs, miRs) in the tumorigenesis of various types of cancer. miRNAs have been reported to be involved in numerous cell processes, including cell apoptosis, proliferation and migration, thus suggesting that miRNAs may have an important role in cancer progression. Downregulation of miR-149-5p has been detected in RCC tissues by microarray profiling; however, its expression and function in RCC has yet to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction was performed to detect the expression levels of miR-149-5p in RCC tissues and paired normal tissues. In order to determine whether miR-149-5p was able to regulate cell proliferation, apoptosis or migration, 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometric and wound healing assays were conducted. The results demonstrated that miR-149-5p was significantly downregulated in RCC tissues compared with in normal tissues (P<0.05). The restoration of miR-149-5p expression using synthetic mimics suppressed cell proliferation and migration, and promoted cell apoptosis. These results indicated that miR-149-5p may act as a tumor suppressor in RCC. The present study is the first, to the best of our knowledge, to identify miR-149-5p as a tumor suppressor in RCC. Future studies will be focused on the potential role of miR-149-5p as a biomarker for the early detection and prognostic prediction of RCC, and as a therapeutic target in RCC. In addition, further exploration regarding the pathways underlying the effects of miR-149-5p in RCC is required. PMID- 27121092 TI - Maternal and fetal human leukocyte antigen class Ia and II alleles in severe preeclampsia and eclampsia. AB - A line of investigations indicate that genes in the human leukocyte antigen (HLA) complex are involved in a successful acceptance of the semiallogeneic fetus during pregnancy. In this study, associations between specific HLA class Ia (HLA A and -B) and class II (HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) alleles and the risk of developing severe preeclampsia/eclampsia were investigated in a detailed and large-scale study. In total, 259 women diagnosed with severe preeclampsia or eclampsia and 260 matched control women with no preeclampsia, together with their neonates, were included in the study. HLA genotyping for mothers and neonates was performed using next-generation sequencing. The HLA-DPB1*04:01:01G allele was significantly more frequent (Pc=0.044) among women diagnosed with severe preeclampsia/eclampsia compared with controls, and the DQA1*01:02:01G allele frequency was significantly lower (Pc=0.042) among newborns born by women with severe preeclampsia/eclampsia compared with controls. In mothers with severe preeclampsia/eclampsia, homozygosity was significantly more common compared with controls at the HLA-DPB1 locus (Pc=0.0028). Although the current large study shows some positive results, more studies, also with a functional focus, are needed to further clarify a possible role of the classical HLA genes in preeclampsia. PMID- 27121093 TI - Ophthalmic statistics note 9: parametric versus non-parametric methods for data analysis. PMID- 27121094 TI - Computer-aided design and three-dimensional printing in the manufacturing of an ocular prosthesis. AB - : Restoring the facial appearance in acquired anophthalmos entails precision fitting of a customised ocular prosthesis. The fabrication is an artisanal process, and is primarily based on an impression of the anophthalmic cavity. This is usually achieved by the impression-moulding method, which, however, may introduce errors, resulting in a poorly fitted prosthesis. We developed a new method in the manufacturing of a customised ocular prosthesis based on computer aided design and computer-aided manufacturing. An ocular prosthesis, based on a three-dimensional (3D) printed impression-free mould of the anophthalmic cavity, was successfully fitted in a 68-year-old male. To the best of our knowledge, this is the first case of a customised ocular prosthesis designed with the aid of 3D printing. TRIAL REGISTRATION NUMBER: B322201628407, Pre-results. PMID- 27121095 TI - Endoresection of large uveal melanomas: clinical results in a consecutive series of 200 cases. AB - BACKGROUND: To report eye salvaging rate, visual acuity (VA), local recurrences, complications and the potential benefit of adjuvant brachytherapy after endoresection of large uveal melanomas. METHODS: 200 patients were included in this retrospective study. They were treated from March 1999 to December 2010 with preoperative stereotactic gamma knife radiosurgery followed by endoresection and adjuvant brachytherapy in most cases. RESULTS: A total of 200 patients were included in this study (113 male, 87 female). Mean tumour height was 9.4 mm and the largest basal diameter ranged from 6.3 to 20 mm. The median follow-up time was 32.3 months. In 13.4% the eye was retained with a VA of 20/50 or better, in 33.6% VA was ranging from 20/400 to 20/50 and 53% had a VA of less than 20/400. In almost 90% of the cases the eye was preserved at the final visit. In 15.5% additional major surgery was required. In terms of survival 15.5% of our patients developed liver metastases during follow-up and died. Local tumour recurrence was observed in 10 out of 200 patients (5%) and was mainly treated with enucleation. The use of an adjuvant ruthenium-106 plaque did not lower the recurrence or enucleation rate significantly. CONCLUSIONS: Eyes with a large uveal melanoma can be preserved by stereotactic radiotherapy followed by endoresection with the chance to obtain useful vision in approximately half of the cases. Adjuvant brachytherapy has no beneficial effect except a reduction of the frequency for major revision surgery. PMID- 27121096 TI - Changes in the nutritional status of children and adolescents in Shandong, China. AB - OBJECTIVE: Nutritional status during childhood plays an important role in the human life cycle. The present study examined the prevalence trends in different grades of nutritional status (thinness, normal weight, overweight and obesity) among children and adolescents in Shandong, China. DESIGN: Data for the study were obtained from six cross-sectional surveys of schoolchildren carried out in 1985, 1995, 2000, 2005, 2010 and 2014. Height and weight of all children were measured; BMI was calculated from their height and weight. International BMI cut offs were used to define thinness, overweight and obesity. SETTING: Shandong Province, China. SUBJECTS: A total of 56 045 students aged 7-18 years were included in the current analysis. RESULTS: In the past 29 years, the prevalence of thinness decreased from 18.22 % and 23.45 % in 1985 to 7.18 % and 9.49 % in 2014 for boys and girls, respectively. Conversely, the prevalence of combined overweight and obesity increased from 1.79 % and 1.66 % in 1985 to 31.12 % and 20.11 % in 2014 for boys and girls, respectively. CONCLUSIONS: The nutritional profile of Shandong children and adolescents had an obvious change over the past 29 years. Special attention should be paid to controlling the rapid rise of childhood overweight and obesity. PMID- 27121097 TI - The source of circulating selenoprotein S and its association with type 2 diabetes mellitus and atherosclerosis: a preliminary study. AB - BACKGROUND: Selenoprotein S (SelS) is a transmembrane protein that is expressed in the liver, skeletal muscle, adipose tissue, pancreatic islets, kidney, and blood vessels. In addition to its transmembrane localization, SelS is also secreted from hepatoma HepG2 cells (but not L6 skeletal muscle cells, 3T3-L1 adipocytes, Min6 pancreatic beta cells and human embryonic kidney 293 cells) and has been detected in the serum of some human subjects, with a detection rate of 31.1 %. These findings prove that serum SelS is secreted by hepatocytes. However, whether vascularly expressed SelS can be secreted has not been reported. Transmembrane SelS has been suggested to play different roles in the pathogenesis and progression of diabetes mellitus (DM) and atherosclerosis (AS), but the association of secreted SelS with DM and macroangiopathy remains unclear. RESEARCH DESIGN AND METHODS: Supernatants were collected from human umbilical vein endothelial cells (HUVECs), human aortic vascular smooth muscle cells (HA/VSMCs) and human hepatoma HepG2 cells that were untransfected or transfected with the indicated plasmid and concentrated for western blotting. Serum samples were collected from 158 human subjects with or without type 2 DM (T2DM) and/or AS. Serum SelS levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Secreted SelS was only detected in the supernatants of hepatoma HepG2 cells. The SelS detection rate among the 158 human serum samples was 100 %, and the average SelS level was 64.81 ng/dl. The serum SelS level in the isolated DM subjects was lower than the level in the healthy control subjects (52.66 +/- 20.53 vs 70.40 +/- 21.38 ng/dl). The serum SelS levels in the DM complicated with SAS subjects (67.73 +/- 21.41 ng/dl) and AS subjects (71.69 +/- 27.00 ng/dl) were significantly increased compared with the serum SelS level in the isolated DM subjects. There was a positive interaction effect between T2DM and AS on the serum SelS level (P = 0.002). Spearman correlation analysis showed that the serum SelS level was negatively correlated with fasting plasma glucose. CONCLUSIONS: Vascular endothelial and vascular smooth muscle cells could not secrete SelS. Serum SelS was primarily secreted by hepatocytes. SelS was universally detected in human serum samples, and the serum SelS level was associated with T2DM and its macrovascular complications. Thus, regulating liver and serum SelS levels might become a new strategy for the prevention and treatment of DM and its macrovascular complications. PMID- 27121099 TI - A phased antenna array for surface plasmons. AB - Surface plasmon polaritons are electromagnetic waves that propagate tightly bound to metal surfaces. The concentration of the electromagnetic field at the surface as well as the short wavelength of surface plasmons enable sensitive detection methods and miniaturization of optics. We present an optical frequency plasmonic analog to the phased antenna array as it is well known in radar technology and radio astronomy. Individual holes in a thick gold film act as dipolar emitters of surface plasmon polaritons whose phase is controlled individually using a digital spatial light modulator. We show experimentally, using a phase sensitive near field microscope, that this optical system allows accurate directional emission of surface waves. This compact and flexible method allows for dynamically shaping the propagation of plasmons and holds promise for nanophotonic applications employing propagating surface plasmons. PMID- 27121098 TI - Obsessive-compulsive and posttraumatic stress symptoms among civilian survivors of war. AB - BACKGROUND: Several psychological sequelae have been identified in civilian war survivors. However, little is known about the prevalence of obsessive-compulsive symptoms and their relationship to trauma in this population. METHOD: Fifty-one adult civilian survivors of the Kosovo War (28 males) who had immigrated to Switzerland completed the Revised Obsessive-Compulsive Inventory Scale, the Posttraumatic Stress Diagnostic Scale and the Hopkins Symptom Checklist. Data were analysed using multiple regression analyses. RESULTS: Overall, 35 and 39% of the sample scored above the cut-offs for likely obsessive-compulsive disorder and posttraumatic stress disorder, respectively. Participants with high levels of posttraumatic stress symptoms were significantly more likely to have obsessive compulsive symptoms, and vice versa. In multiple regression analysis, gender and severity of posttraumatic stress symptoms were predictors of obsessive-compulsive symptoms, whereas number of traumatic life event types and depressive symptoms were not. CONCLUSION: Given the small sample size, the results of this study need to be interpreted cautiously. Nevertheless, a surprisingly high number of participants in our study suffered from both obsessive-compulsive and posttraumatic stress symptoms, with obsessive-compulsive symptoms tending to be more pronounced in women. It remains, therefore, critical to specifically assess both obsessive-compulsive and posttraumatic stress symptoms in civilian war survivors, and to provide persons afflicted with appropriate mental health care. PMID- 27121100 TI - Dynamic self-assembly of microscale rotors and swimmers. AB - Biological systems often involve the self-assembly of basic components into complex and functioning structures. Artificial systems that mimic such processes can provide a well-controlled setting to explore the principles involved and also synthesize useful micromachines. Our experiments show that immotile, but active, components self-assemble into two types of structure that exhibit the fundamental forms of motility: translation and rotation. Specifically, micron-scale metallic rods are designed to induce extensile surface flows in the presence of a chemical fuel; these rods interact with each other and pair up to form either a swimmer or a rotor. Such pairs can transition reversibly between these two configurations, leading to kinetics reminiscent of bacterial run-and-tumble motion. PMID- 27121101 TI - Biorelevant reactions of the potential anti-tumor agent vanadocene dichloride. AB - The interaction of the potential anti-tumor agent vanadocene dichloride ([Cp2VCl2] or VDC) with some relevant bioligands of the cytosol such as proteins (Hb), amino acids (glycine and histidine), NADH derivatives (NADH, NADPH, NAD(+) and NADP(+)), reductants (GSH and ascorbic acid), phosphates (HPO4(2-), P2O7(4-), cAMP, AMP, ADP and ATP) and carboxylate derivatives (lactate) and its uptake by red blood cells were studied. The results indicated that [Cp2VCl2] transforms at physiological pH into [Cp2V(OH)2] and that only HPO4(2-), P2O7(4-), lactate, ATP and ADP form mixed species with the [Cp2V](2+) moiety replacing the two hydroxide ions. EPR and electronic absorption spectroscopy, agarose gel electrophoresis and spin trapping measurements allow excluding any direct interaction and/or intercalation with DNA and the formation of reactive oxygen species (ROS) in Fenton-like reactions. Uptake experiments by erythrocytes suggested that VDC crosses the membrane and enters inside the cells, whereas 'bare' V(IV) transforms into V(IV)O species with loss of the two cyclopentadienyl rings. This transformation in the cellular environment could be related to the mechanism of action of VDC. PMID- 27121102 TI - miR-133a enhances the sensitivity of Hep-2 cells and vincristine-resistant Hep-2v cells to cisplatin by downregulating ATP7B expression. AB - The expression levels of the copper transporter P-type adenosine triphosphatase (ATP7B) are known correlate with tumor cell sensitivity to cisplatin. However, the mechanisms underlying cisplatin resistance remained poorly understood. Therefore, in the present study, we treated Hep-2 cells and in-house-developed vincristine-resistant Hep-2v cells with 50, 100, or 200 uM cisplatin and assessed cell viability after 24 or 48 h. Hep-2v cells were shown to be resistant to 50 200 uM cisplatin. Furthermore, using immunofluorescence staining and western blot analysis, we noted that ATP7B, but not copper-transporting ATPase 1 (ATP7A), expression was significantly increased in Hep-2v cells, and this increase was maintained at a higher level compared with Hep-2 cells. As ATP7B is a target of microRNA 133a (miR-133a), the ability of miR-133a to influence cisplatin sensitivity in Hep-2v cells was then assessed by CCK-8 assay. We noted that miR 133a expression was lower in both Hep-2 and Hep-2v cells compared with epithelial NP69 cells. Following treatment with 50 uM cisplatin, in Hep-2v cells expressing exogenous miR-133a we noted reduced ATP7B expression, and these cells had a significantly lower survival rate compared with the control. The present study demonstrates that miR-133a enhances the sensitivity of multidrug-resistant Hep-2v cells to cisplatin by downregulating ATP7B expression. PMID- 27121103 TI - Silver-mediated direct trifluoromethoxylation of alpha-diazo esters via the ( )OCF3 anion. AB - Silver-mediated direct trifluoromethoxylation of alpha-diazo esters and ketosteroid was disclosed. The reactions of alkyl alpha-diazo arylacetates with AgOCF3 or CF3SO2OCF3/AgF at -30 to 10 degrees C under a N2 atmosphere provided alpha-trifluoromethoxyl arylacetates in up to 90% yield, while alkyl alpha-diazo vinylacetates reacting with CF3SO2OCF3/AgF or AgOCF3 afforded gamma trifluoromethoxyl alpha,beta-unsaturated esters in up to 94% yield. The alpha diazo ketosteroid was also trifluoromethoxylated under the standard reaction conditions. This protocol allows for an effective and convenient access to a large number of synthetic building blocks, which are promising in the development of new functional OCF3-molecules. PMID- 27121104 TI - Energy redistribution dynamics in triarylamine-triarylborane containing hexaarylbenzenes. AB - Two hexaarylbenzenes (HAB) 1 and 2 each decorated by three triarylamines (TAA) as electron donors and three triarylboranes (TAB) as electron acceptors in a symmetric (1) and asymmetric (2) fashion as well as one model compound (3) with only one donor-acceptor pair were investigated by ultrafast transient absorption and fluorescence upconversion spectroscopy. Fluorescence anisotropy measurements revealed energy redistribution between localised, partly relaxed CT-states of the HABs 1 and 2 induced by dipole-dipole interaction with energy transfer time constants of ca. 3 ps. These results manifest symmetry breaking in the formally symmetric HAB 1 upon photoexcitation. PMID- 27121106 TI - Assessing chemistry schemes and constraints in air quality models used to predict ozone in London against the detailed Master Chemical Mechanism. AB - Air pollution is the environmental factor with the greatest impact on human health in Europe. Understanding the key processes driving air quality across the relevant spatial scales, especially during pollution exceedances and episodes, is essential to provide effective predictions for both policymakers and the public. It is particularly important for policy regulators to understand the drivers of local air quality that can be regulated by national policies versus the contribution from regional pollution transported from mainland Europe or elsewhere. One of the main objectives of the Coupled Urban and Regional processes: Effects on AIR quality (CUREAIR) project is to determine local and regional contributions to ozone events. A detailed zero-dimensional (0-D) box model run with the Master Chemical Mechanism (MCMv3.2) is used as the benchmark model against which the less explicit chemistry mechanisms of the Generic Reaction Set (GRS) and the Common Representative Intermediates (CRIv2-R5) schemes are evaluated. GRS and CRI are used by the Atmospheric Dispersion Modelling System (ADMS-Urban) and the regional chemistry transport model EMEP4UK, respectively. The MCM model uses a near-explicit chemical scheme for the oxidation of volatile organic compounds (VOCs) and is constrained to observations of VOCs, NOx, CO, HONO (nitrous acid), photolysis frequencies and meteorological parameters measured during the ClearfLo (Clean Air for London) campaign. The sensitivity of the less explicit chemistry schemes to different model inputs has been investigated: Constraining GRS to the total VOC observed during ClearfLo as opposed to VOC derived from ADMS-Urban dispersion calculations, including emissions and background concentrations, led to a significant increase (674% during winter) in modelled ozone. The inclusion of HONO chemistry in this mechanism, particularly during wintertime when other radical sources are limited, led to substantial increases in the ozone levels predicted (223%). When the GRS and CRIv2-R5 schemes are run with the equivalent model constraints to the MCM, they are able to reproduce the level of ozone predicted by the near-explicit MCM to within 40% and 20% respectively for the majority of the time. An exception to this trend was observed during pollution episodes experienced in the summer, when anticyclonic conditions favoured increased temperatures and elevated O3. The in situ O3 predicted by the MCM was heavily influenced by biogenic VOCs during these conditions and the low GRS [O3] : MCM [O3] ratio (and low CRIv2-R5 [O3] : MCM [O3] ratio) demonstrates that these less explicit schemes under-represent the full O3 creation potential of these VOCs. To fully assess the influence of the in situ O3 generated from local emissions versus O3 generated upwind of London and advected in, the time since emission (and, hence, how far the real atmosphere is from steady state) must be determined. From estimates of the mean transport time determined from the NOx : NOy ratio observed at North Kensington during the summer and comparison of the O3 predicted by the MCM model after this time, ~60% of the median observed [O3] could be generated from local emissions. During the warmer conditions experienced during the easterly flows, however, the observed [O3] may be even more heavily influenced by London's emissions. PMID- 27121107 TI - South African clinical practice guidelines quality measured with complex and rapid appraisal instruments. AB - BACKGROUND: Critically appraising the quality of clinical practice guidelines (CPGs) is an essential element of evidence implementation. Critical appraisal considers the quality of CPG construction and reporting processes, and the credibility of the body of evidence underpinning recommendations. To date, the focus on CPG critical appraisal has come from researchers and evaluators, using complex appraisal instruments. Rapid critical appraisal is a relatively new approach for CPGs, which targets busy end-users such as service managers and clinicians. This paper compares the findings of two critical appraisal instruments: a rapid instrument (iCAHE) and a complex instrument (AGREE II). They were applied independently to 16 purposively-sampled, heterogeneous South African CPGs, written for eleven primary health care conditions/health areas. Overall scores, and scores in the two instruments' common domains Scope and Purpose, Stakeholder involvement, Underlying evidence/Rigour of Development, Clarity), were compared using Pearson r correlations and intraclass correlation coefficients. CPGs with differences of 10 % or greater between scores were identified and reasons sought for such differences. The time taken to apply the instruments was recorded. RESULTS: Both instruments identified the generally poor quality of the included CPGs, particularly in Rigour of Development. Correlation and agreement between instrument scores was moderate, and there were no overall significant score differences. Large differences in scores for some CPGs could be explained by differences in instrument construction and focus, and CPG construction. The iCAHE instrument was demonstrably quicker to use than the AGREE II instrument. CONCLUSIONS: Either instrument could be used with confidence to assess the quality of CPGs. The choice of appraisal instrument depends on the needs and time of end-users. Having an alternative (rapid) critical appraisal tool will potentially encourage busy end-users to identify and use good quality CPGs to inform practice decisions. PMID- 27121108 TI - Current Approaches and Future Perspectives for In Vivo Clonal Tracking of Hematopoietic Cells. AB - Over the past years, clonal tracking has gained the center stage as a unique technology capable to unveil population dynamics and hierarchical relationships in vivo. We here highlighted the main open questions related to the in vivo clonal behavior of hematopoietic cells with a particular focus on hematopoietic stem and progenitor cells and T cells as main targets of cell- and gene therapies. We walked through the current methods applied for tracing in vivo dynamics and functions of hematopoietic cells in animal models and we described the results of early studies conducted on humans. We specifically focused our attention on the recent use of retroviral/lentiviral vector Integration Site (IS) analyses to follow stably marked clones and their progeny in vivo. We showed how this molecular tracking method can be successfully employed in human studies to unveil the clonal behavior of hematopoietic cells, describing pioneering works conducted on samples from gene therapy treated patients. Clonal tracking through IS identification still comes with a complex wet-experimental protocol and technical/analytical constraints. In this regard, we reviewed the features of the available computational tools for the identification and quantification of ISs and we highlighted the potential future improvements of IS-based tracking, as this technology is becoming a major source of information on in vivo fate and survival of engineered cells in humans. PMID- 27121109 TI - Restriction Factors Against Recombinant Adeno-associated Virus Vectormediated Gene Transfer in Dystrophin-deficient Muscles. AB - Despite the unprecedented beneficial effects of rAAV gene therapy in animal models of Duchenne muscular dystrophy (DMD), the need to inject large amounts of vector in vivo to improve phenotype raises obvious biosafety concerns. While rAAV vectors generally exhibit a good safety profile, specific pathological phenotypes such as those observed in dystrophin-deficient muscles may promote immunotoxic/genotoxic effects. Increasing the therapeutic index of rAAV in DMD muscles by reducing the effective dose could be a pivotal means of ensuring efficient clinical translation. This requires a comprehensive understanding of the rAAV transduction process, which is almost always studied in non-pathological tissues or in vitro. In this review, we focus on the molecular fate of rAAV after injection, and how the individual stages of transduction could be affected in the context of DMD. PMID- 27121110 TI - Rhus verniciflua Stokes (RVS) and butein induce apoptosis of paclitaxel-resistant SKOV-3/PAX ovarian cancer cells through inhibition of AKT phosphorylation. AB - BACKGROUND: Rhus verniciflua Stokes (RVS) belongs to the Anacardiaceae family and traditionally used for cancer treatment. RVS and butein, a major compound of RVS, were known to induce apoptosis via AKT inhibition in cancer cells. Thus, in this study, we investigated the effect of RVS and its derivative compounds (fisetin, quercetin, butein) on cell death in SKOV-3/PAX cells. METHODS: The 80 % ethanol extract of RVS and its derivative compounds (fisetin, quercetin, butein) were prepared. The cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) colorimetric assay. Apoptotic cells were detected by staining with propidium iodide (PI) and Annexin V-fluorescein isothiocyanate/7-aminoactinomycin D (Annexin V-FITC/7-AAD). The expression level of intracellular signaling related-proteins in apoptosis and growth were measured by western blot assay. RESULTS: We found that RVS and butein suppressed the growth of SKOV-3/PAX cells in a dose-dependent manner. We also found that RVS and butein produced the cleavage of caspase-9, -8, -3, and PARP. Similarly, sub-G1 phase and Annexin V-FITC positive cells were increased by RVS and butein. Moreover, RVS and butein significantly reduced AKT phosphorylation in SKOV-3/PAX cells. PI3K inhibitor LY294002 caused PARP cleavage supporting our finding. CONCLUSION: Our data clearly indicate that RVS and butein induce apoptosis of SKOV-3/PAX cells through inhibition of AKT activation. RVS and butein could be useful compounds for the treatment for paclitaxel resistant-ovarian cancer. PMID- 27121111 TI - An exploration of the views of paramedics regarding airway management. AB - BACKGROUND: Paramedics are a skilled group of clinicians with expertise in airway management. Our research group has completed a trial comparing supraglottic airway devices with tracheal intubation during out of hospital cardiac arrest. This is a contentious topic amongst paramedics in the United Kingdom (UK). We explored the customs and beliefs of UK paramedics in relation to airway management, and whether tracheal intubation contributes to and sustains paramedic professional identity. METHODS: The study took place within South Western Ambulance Service NHS Foundation Trust. We used a qualitative approach, conducting interviews and focus groups with paramedics. The themes arising from interviews were discussed in focus groups, developing a deeper understanding and providing insight and recommendations for future research and policy. Purposive sampling accounted for differing training and for participation in the main trial. There were 17interviews and five focus groups with a further 17 participants. Data saturation was achieved. RESULTS: Four domains were identified. Pride - The ability to use a life-saving skill in austere conditions. Utility - Different training routes and experience have led to different attitudes towards airway management. Inconsistent expectations - Paramedics felt that there were different perceptions of their abilities amongst hospital staff and the general public. Professionalization - Debate over airway management is not founded on good evidence. CONCLUSION: We have demonstrated that UK paramedics have a wide range of views regarding airway management, and that these are based on evidence and experience rather than dogma. Airway management contributes to paramedics' professional identity, but is not reliant on this. PMID- 27121112 TI - Genetic aberrations in small B-cell lymphomas and leukemias: molecular pathology, clinical relevance and therapeutic targets. AB - Small B-cell lymphomas and leukemias (SBCLs) are a clinically, morphologically, immunophenotypically and genetically heterogeneous group of clonal lymphoid neoplasms, including entities such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL) and hairy cell leukemia (HCL). The pathogenesis of some of these lymphoid malignancies is characterized by distinct translocations, for example t(11;14) in the majority of cases of MCL and t(14;18) in most cases of FL, whereas other entities are associated with a variety of recurrent but nonspecific numeric chromosomal abnormalities, as exemplified by del(13q14), del(11q22), and +12 in CLL, and yet others such as LPL and HCL that lack recurrent or specific cytogenetic aberrations. The recent surge in next generation sequencing (NGS) technology has shed more light on the genetic landscape of SBCLs through characterization of numerous driver mutations including SF3B1 and NOTCH1 in CLL, ATM and CCND1 in MCL, KMT2D and EPHA7 in FL, MYD88 (L265P) in LPL, KLF2 and NOTCH2 in splenic MZL (SMZL) and BRAF (V600E) in HCL. The identification of distinct genetic lesions not only provides greater insight into the molecular pathogenesis of these disorders but also identifies potential valuable biomarkers for prognostic stratification, as well as specific targets for directed therapy. This review discusses the well-established and recently identified molecular lesions underlying the pathogenesis of SBCLs, highlights their clinical relevance and summarizes novel targeted therapies. PMID- 27121113 TI - Computational Study of Oxygen Diffusion along a[100] Dislocations in the Perovskite Oxide SrTiO3. AB - We used classical molecular-dynamics simulations to study the atomistic structure of, and the diffusion of oxygen ions along, the periodic array of edge dislocations comprising a symmetrical 6.0 degrees [100] tilt grain boundary in SrTiO3. The results indicate that, at elevated temperatures, the two types of dislocation core (TiO2-type and SrO-type) that make up the boundary are stable and that oxygen-deficient cores maintain their dissociated structures. They also confirm that oxygen vacancies prefer to reside at the cores rather than in the bulk. Tracer diffusion coefficients of oxygen were obtained for oxygen-deficient bulk and grain-boundary simulation cells at temperatures in the range of 1000 <= T/K <= 2300. Calculated values of the oxygen-vacancy diffusion coefficient for the bulk phase agree extremely well with published experimental data. Tracer diffusion coefficients obtained for the grain-boundary cell are, in comparison to those for the bulk, lower in magnitude and have a higher activation enthalpy, indicating that, relative to the bulk, the migration of oxygen ions along a[100] dislocation cores in SrTiO3 is hindered. These results provide further support for the decoupled model of filament formation in resistively switching SrTiO3. PMID- 27121114 TI - Validation of T2* in-line analysis for tissue iron quantification at 1.5 T. AB - BACKGROUND: There is a need for improved worldwide access to tissue iron quantification using T2* cardiovascular magnetic resonance (CMR). One route to facilitate this would be simple in-line T2* analysis widely available on MR scanners. We therefore compared our clinically validated and established T2* method at Royal Brompton Hospital (RBH T2*) against a novel work-in-progress (WIP) sequence with in-line T2* measurement from Siemens (WIP T2*). METHODS: Healthy volunteers (n = 22) and patients with iron overload (n = 78) were recruited (53 males, median age 34 years). A 1.5 T study (Magnetom Avanto, Siemens) was performed on all subjects. The same mid-ventricular short axis cardiac slice and transaxial slice through the liver were used to acquire both RBH T2* images and WIP T2* maps for each participant. Cardiac white blood (WB) and black blood (BB) sequences were acquired. Intraobserver, interobserver and interstudy reproducibility were measured on the same data from a subset of 20 participants. RESULTS: Liver T2* values ranged from 0.8 to 35.7 ms (median 5.1 ms) and cardiac T2* values from 6.0 to 52.3 ms (median 31 ms). The coefficient of variance (CoV) values for direct comparison of T2* values by RBH and WIP were 6.1 7.8 % across techniques. Accurate delineation of the septum was difficult on some WIP T2* maps due to artefacts. The inability to manually correct for noise by truncation of erroneous later echo times led to some overestimation of T2* using WIP T2* compared with the RBH T2*. Reproducibility CoV results for RBH T2* ranged from 1.5 to 5.7 % which were better than the reproducibility of WIP T2* values of 4.1-16.6 %. CONCLUSIONS: Iron estimation using the T2* CMR sequence in combination with Siemens' in-line data processing is generally satisfactory and may help facilitate global access to tissue iron assessment. The current automated T2* map technique is less good for tissue iron assessment with noisy data at low T2* values. PMID- 27121115 TI - A high-selenium lentil dietary intervention in Bangladesh to counteract arsenic toxicity: study protocol for a randomized controlled trial. AB - BACKGROUND: Millions of people worldwide are exposed to dangerous levels of arsenic (above the WHO water standard of 10 ppb) in drinking water and food. Lack of nutritious foods exacerbates the adverse health effects of arsenic poisoning. The micronutrient selenium is a known antagonist to arsenic, promoting the excretion of arsenic from the body. Studies are in progress examining the potential of using selenium supplement pills to counteract arsenic toxicity. We are planning a clinical trial to test whether high-selenium lentils, as a whole food solution, can improve the health of arsenic-exposed Bangladeshi villagers. METHODS/DESIGN: A total of 400 participants (about 80 families) will be divided into two groups via computer-generated block randomization. Eligibility criteria are age (>=14) years) and arsenic concentration in the household tube well (>=100 ppb). In this double-blind study, one group will eat high-selenium lentils grown in western Canada; the other will consume low-selenium lentils grown in Idaho, USA. Each participant will consume 65 g of lentils each day for 6 months. At the onset, midterm, and end of the trial, blood, urine and stool, plus hair (day 1 and at 6 months only) samples will be collected and a health examination conducted including assessment of acute lung inflammation, body mass and height, and blood pressure. The major outcome will be arsenic excretion in urine and feces, as well as arsenic deposition in hair and morbidity outcomes as assessed by a biweekly questionnaire. Secondary outcomes include antioxidant status, lipid profile, lung inflammation status, and blood pressure. DISCUSSION: Selenium pills as a treatment for arsenic exposure are costly and inconvenient, whereas a whole food approach to lower the toxic burden of arsenic may be a practical remedy for Bangladeshi people while efforts to provide safe drinking water are continuing. If high-selenium lentils prove to be effective in counteracting arsenic toxicity, agronomic partnerships between Canada and Bangladesh will work to improve the selenium content of the Bangladeshi-grown lentil crops. Results will be presented to the community to promote informed food choices, which may include increasing selenium in their diet. TRIAL REGISTRATION: ClinicalTrials.gov NCT02429921. PMID- 27121116 TI - Synthetic lepidocrocite for phosphorous removal from reclaimed water: optimization using convex optimization method and successive adsorption in fixed bed column. AB - The batch and column experimental studies on the adsorption of phosphate onto synthetic lepidocrocite from reclaimed water are presented. A second-order polynomial model in the batch study is successfully applied to describe phosphate immobilization performance using the response surface methodology. The model proposed is further linked with the convex optimization method to determine the optimal variables for maximum phosphate uptake since convex method is a global optimization method. Consequently, under optimal parameters determined as pH of 3.88, an initial P concentration of 0.66 mg/L, and a dosage of 0.15 g, the corresponding phosphate removal efficiency can reach up to 97.4%. Adsorption behavior is further revealed by X-ray photoelectron spectroscopy observation and FTIR spectra. A comparative column study indicates that co-existing competing anions in artificial reclaimed water do not significantly interfere with P adsorption under the neutral condition. The experimental results highlight that synthetic lepidocrocite is an excellent absorbent for sustainable P removal from reclaimed water. PMID- 27121117 TI - Development and validation of a smartphone-based digits-in-noise hearing test in South African English. AB - OBJECTIVE: The objective of this study was to develop and validate a smartphone based digits-in-noise hearing test for South African English. DESIGN: Single digits (0-9) were recorded and spoken by a first language English female speaker. Level corrections were applied to create a set of homogeneous digits with steep speech recognition functions. A smartphone application was created to utilize 120 digit-triplets in noise as test material. An adaptive test procedure determined the speech reception threshold (SRT). Experiments were performed to determine headphones effects on the SRT and to establish normative data. STUDY SAMPLE: Participants consisted of 40 normal-hearing subjects with thresholds <=15 dB across the frequency spectrum (250-8000 Hz) and 186 subjects with normal-hearing in both ears, or normal-hearing in the better ear. RESULTS: The results show steep speech recognition functions with a slope of 20%/dB for digit-triplets presented in noise using the smartphone application. The results of five headphone types indicate that the smartphone-based hearing test is reliable and can be conducted using standard Android smartphone headphones or clinical headphones. CONCLUSION: A digits-in-noise hearing test was developed and validated for South Africa. The mean SRT and speech recognition functions correspond to previous developed telephone-based digits-in-noise tests. PMID- 27121118 TI - Predictors of folate status among pregnant Japanese women: the Hokkaido Study on Environment and Children's Health, 2002-2012. AB - The International Clearinghouse for Birth Defects, Surveillance and Research reports a rise in the prevalence rate of spina bifida in Japan. We determined first-trimester folate status of Hokkaido women and identified potential predictors. Participants were 15 266 pregnant women of the Hokkaido Study on Environment and Children's Health Cohort. Data were extracted from self-reported questionnaires and biochemical assay results. Demographic determinants of low folate status were younger maternal age (adjusted OR (AOR) 1.48; 95 % CI 1.32, 1.66), lower educational level (AOR 1.27; 95 % CI 1.17, 1.39) and lower annual income (AOR 1.11; 95 % CI 1.01, 1.22). Plasma cotinine concentrations of 1.19 65.21 nmol/l increased the risk of low folate status (AOR 1.20; 95 % CI 1.10, 1.31) and concentrations >65.21 nmol/l further increased the risk (AOR 1.91; 95 % CI 1.70, 2.14). The most favourable predictor was use of folic acid (FA) supplements (AOR 0.19; 95 % CI 0.17, 0.22). Certain socio-demographic factors influence folate status among pregnant Japanese women. Modifiable negative and positive predictors were active and passive tobacco smoking and use of FA supplements. Avoiding both active and passive tobacco smoking and using FA supplements could improve the folate status of Japanese women. PMID- 27121120 TI - Solar-light photocatalytic disinfection using crystalline/amorphous low energy bandgap reduced TiO2. AB - A generation of reactive oxygen species (ROS) from TiO2 under solar light has been long sought since the ROS can disinfect organic pollutants. We found that newly developed crystalline/amorphous reduced TiO2 (rTiO2) that has low energy bandgap can effectively generate ROS under solar light and successfully remove a bloom of algae. The preparation of rTiO2 is a one-pot and mass productive solution-process reduction using lithium-ethylene diamine (Li-EDA) at room temperature. Interestingly only the rutile phase of TiO2 crystal was reduced, while the anatase phase even in case of both anatase/rutile phased TiO2 was not reduced. Only reduced TiO2 materials can generate ROS under solar light, which was confirmed by electron spin resonance. Among the three different types of Li EDA treated TiO2 (anatase, rutile and both phased TiO2), the both phased rTiO2 showed the best performance to produce ROS. The generated ROS effectively removed the common green algae Chlamydomonas. This is the first report on algae degradation under solar light, proving the feasibility of commercially available products for disinfection. PMID- 27121119 TI - Comparative expression profiling reveals a role of the root apoplast in local phosphate response. AB - BACKGROUND: Plant adaptation to limited phosphate availability comprises a wide range of responses to conserve and remobilize internal phosphate sources and to enhance phosphate acquisition. Vigorous restructuring of root system architecture provides a developmental strategy for topsoil exploration and phosphate scavenging. Changes in external phosphate availability are locally sensed at root tips and adjust root growth by modulating cell expansion and cell division. The functionally interacting Arabidopsis genes, LOW PHOSPHATE RESPONSE 1 and 2 (LPR1/LPR2) and PHOSPHATE DEFICIENCY RESPONSE 2 (PDR2), are key components of root phosphate sensing. We recently demonstrated that the LOW PHOSPHATE RESPONSE 1 - PHOSPHATE DEFICIENCY RESPONSE 2 (LPR1-PDR2) module mediates apoplastic deposition of ferric iron (Fe(3+)) in the growing root tip during phosphate limitation. Iron deposition coincides with sites of reactive oxygen species generation and triggers cell wall thickening and callose accumulation, which interfere with cell-to-cell communication and inhibit root growth. RESULTS: We took advantage of the opposite phosphate-conditional root phenotype of the phosphate deficiency response 2 mutant (hypersensitive) and low phosphate response 1 and 2 double mutant (insensitive) to investigate the phosphate dependent regulation of gene and protein expression in roots using genome-wide transcriptome and proteome analysis. We observed an overrepresentation of genes and proteins that are involved in the regulation of iron homeostasis, cell wall remodeling and reactive oxygen species formation, and we highlight a number of candidate genes with a potential function in root adaptation to limited phosphate availability. Our experiments reveal that FERRIC REDUCTASE DEFECTIVE 3 mediated, apoplastic iron redistribution, but not intracellular iron uptake and iron storage, triggers phosphate-dependent root growth modulation. We further highlight expressional changes of several cell wall-modifying enzymes and provide evidence for adjustment of the pectin network at sites of iron accumulation in the root. CONCLUSION: Our study reveals new aspects of the elaborate interplay between phosphate starvation responses and changes in iron homeostasis. The results emphasize the importance of apoplastic iron redistribution to mediate phosphate-dependent root growth adjustment and suggest an important role for citrate in phosphate-dependent apoplastic iron transport. We further demonstrate that root growth modulation correlates with an altered expression of cell wall modifying enzymes and changes in the pectin network of the phosphate-deprived root tip, supporting the hypothesis that pectins are involved in iron binding and/or phosphate mobilization. PMID- 27121121 TI - Self-assembled Biodegradable Nanoparticles and Polysaccharides as Biomimetic ECM Nanostructures for the Synergistic effect of RGD and BMP-2 on Bone Formation. AB - Producing biomimetic extracellular matrix (ECM) is an effective approach to improve biocompatibility of medical devices. In this study, biomimetic ECM nanostructures are constructed through layer-by-layer self-assembling positively charged chitosan (Chi), negatively charged oxidized sodium alginate (OAlg), and positively charged bovine serum albumin (BSA)-based nanoparticles. The BSA-based nanoparticles in the self-assembled films not only result in porous nanostructures similar to natural ECM, but also preserve the activity and realize the sustained release of Bone morphogenetic protein-2 (BMP-2). The results of bone marrow stem cells (BMSCs) culture demonstrate that the penta-peptide glycine arginine-glycine-aspartate-serine (GRGDS) grafted Chi/OAlg films favor cell adhesion and proliferation. GRGDS and BMP-2 in biomimetic ECM nanostructures synergistically promote BMSC functions and new bone formation. The RGD and BMP incorporated biomimetic ECM coatings could be applied on a variety of biomedical devices to improve the bioactivity and biocompatibility. PMID- 27121122 TI - Risk factors of malaria in children under the age of five years old in Uganda. AB - BACKGROUND: Malaria is the leading cause of morbidity in Uganda with 90-95 % of the population at risk and it contributing to approximately 13 % of under-five mortality. The aim of this study was to investigate the relationship between the malaria status of children under the age of 5 years old in Uganda and selected socio-economic, demographic and environmental factors, as well as to identify significant risk factors associated with malaria. METHODS: This study made use of data collected from the 2014 Malaria Indicator Survey conducted in Uganda. Two test procedures for malaria in children under the age of 5 years old were carried out. Due to the complex survey design, a generalized linear mixed model was used to test for associations between several independent variables and the response variable, which was whether a child tested positive or negative for malaria according to the microscopy test. RESULTS: The sample in this study was made up of 4939 children. Of those children, 974 tested positive for malaria, resulting in an observed malaria prevalence of 19.7 %. The socio-economic factors closely related to the risk of malaria were main floor material, main wall material and availability of electricity in the household. The event of indoor residual spraying (IRS) significantly reduced a child's risk of malaria. An older child was associated with a higher risk of malaria, however their risk decreased with an increase in cluster altitude and an increase in their caregiver's education level. CONCLUSION: Although there has been a significant increase in the use of mosquito nets since the previous Malaria Indicator Survey done in 2009, particularly in the use of insecticide-treated nets (ITNs) and long-lasting insecticidal nets (LLINs), these control measures alone may not be sufficient. IRS will be a key strategy in reaching the malaria goals set by the government of Uganda. Supplementing these control measures with education of appropriate and consistent use of ITNs and LLINs, as well as education of practicing safe living habits, such as reducing outdoor activities during peak biting hours of a mosquito, can go a long way in aiding the reduction of the burden of malaria in Uganda. PMID- 27121123 TI - Safety voice for ergonomics (SAVE) project: protocol for a workplace cluster randomized controlled trial to reduce musculoskeletal disorders in masonry apprentices. AB - BACKGROUND: Masons have the highest rate of overexertion injuries among all construction trades and rank second for occupational back injuries in the United States. Identified ergonomic solutions are the primary method of reducing exposure to risk factors associated with musculoskeletal disorders. However, many construction workers lack knowledge about these solutions, as well as basic ergonomic principles. Construction apprentices, as they embark on their careers, are greatly in need of ergonomics training to minimize the cumulative exposure that leads to musculoskeletal disorders. Apprentices receive safety training; however, ergonomics training is often limited or non-existent. In addition, apprenticeship programs often lack "soft skills" training on how to appropriately respond to work environments and practices that are unsafe. The SAVE program - SAfety Voice for Ergonomics - strives to integrate evidence-based health and safety training strategies into masonry apprenticeship skills training to teach ergonomics, problem solving, and speaking up to communicate solutions that reduce musculoskeletal injury risk. The central hypothesis is that the combination of ergonomics training and safety voice promotion will be more effective than no training or either ergonomics training alone or safety voice training alone. METHODS/DESIGN: Following the development and pilot testing of the SAVE intervention, SAVE will be evaluated in a cluster-randomized controlled trial at 12 masonry training centers across the U.S. Clusters of apprentices within centers will be assigned at random to one of four intervention groups (n = 24 per group): (1) ergonomics training only, (2) safety voice training only, (3) combined ergonomics and safety voice training, or (4) control group with no additional training intervention. Outcomes assessed at baseline, at the conclusion of training, and then at six and 12 months post training will include: musculoskeletal symptoms, general health perceptions, knowledge of ergonomic and safety voice principles, and perception and attitudes about ergonomic and safety voice issues. DISCUSSION: Masons continue to have a high rate of musculoskeletal disorders. The trade has an expected increase of 40 % in the number of workers by 2020. Therefore, a vetted intervention for apprentices entering the trade, such as SAVE, could reduce the burden of musculoskeletal disorders currently plaguing the trade. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02676635 , 2 February 2016. PMID- 27121125 TI - Reply to the Comment on 'Parametrization of Stillinger-Weber potential based on valence force field model: application to single-layer MoS2 and black phosphorus'. AB - This is a reply to the comment by Midtvedt and Croy on our article 2015 Nanotechnology 26 315706. PMID- 27121124 TI - A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma. AB - Cancer stem cells (CSCs) were reported to be involved in resistance to chemo/radiation therapy. We previously reported that CD13 was both a marker of CSCs and a candidate therapeutic target in HCC. In the present study, we explored the antitumor effect of a combined therapy, where ubenimex, a CD13 inhibitor, was combined with conventional anticancer drugs, fluorouracil (5-FU), cisplatin (CDDP), doxorubicin (DXR) and sorafenib (SOR), and we elucidated the mechanism of these combination therapies. We evaluated changes in the expression of CD13 before and after treatment with anticancer drugs and with or without ubenimex in the human HCC cell lines HuH7 and PLC/PRF/5. The interactions between the anticancer drugs and ubenimex were determined with isobologram analyses. We analyzed cell cycle, apoptosis, and intracellular reactive oxygen species (ROS) levels to explore the mechanisms of the combination therapies. In both cell lines, the expression of CD13 increased after a 72-h exposure to each anticancer drug alone (p<0.05), and the expression of CD13 decreased with ubenimex administration (p<0.05). Isobologram analyses indicated that ubenimex had synergistic effects with 5-FU, CDDP and DXR, and an additive effect with SOR. Cell cycle analyses showed that ubenimex decreased the proportion of cells in G0/G1. Ubenimex enhanced the effects of 5-FU, CDDP and DXR by increasing apoptosis and intracellular ROS levels. In combination therapies, ubenimex synergistically enhanced the antitumor effects of 5-FU, CDDP and DXR on cell cycle regulation and apoptosis induction in HCC cell lines. The effects of ubenimex were due to increased intracellular ROS levels. PMID- 27121126 TI - Photoinactivation of Eight Health-Relevant Bacterial Species: Determining the Importance of the Exogenous Indirect Mechanism. AB - It is presently unknown to what extent the endogenous direct, endogenous indirect, and exogenous indirect mechanisms contribute to bacterial photoinactivation in natural surface waters. In this study, we investigated the importance of the exogenous indirect mechanism by conducting photoinactivation experiments with eight health-relevant bacterial species (Bacteroides thetaiotaomicron, Campylobacter jejuni, Enterococcus faecalis, Escherichia coli K12, E. coli O157:H7, Salmonella enterica serovar Typhimurium LT2, Staphylococcus aureus, and Streptococcus bovis). We used three synthetic photosensitizers (methylene blue, rose bengal, and nitrite) and two model natural photosensitizers (Suwannee River natural organic matter and dissolved organic matter isolated from a wastewater treatment wetland) that generated singlet oxygen and hydroxyl radical. B. thetaiotaomicron had larger first order rate constants than all other organisms under all conditions tested. The presence of the synthetic photosensitizers generally enhanced photoinactivation of Gram-positive facultative anaerobes (Ent. faecalis, Staph. aureus, and Strep. bovis). Among Gram-negative bacteria, only methylene blue with E. coli K12 and rose bengal with C. jejuni showed an enhancing effect. The presence of model natural photosensitizers either reduced or did not affect photoinactivation rate constants. Our findings highlight the importance of the cellular membrane and photosensitizer properties in modulating the contribution of the exogenous indirect mechanism to the overall bacterial photoinactivation. PMID- 27121127 TI - Silicon nanocrystal-noble metal hybrid nanoparticles. AB - We report a novel and facile self-limiting synthesis route of silicon nanocrystal (Si NC)-based colloidally stable semiconductor-metal (gold, silver and platinum) hybrid nanoparticles (NPs). For the formation of hybrid NPs, we employ ligand free colloidal Si NCs with heavily boron (B) and phosphorus (P) doped shells. By simply mixing B and P codoped colloidal Si NCs with metal salts, hybrid NPs consisting of metal cores and Si NC shells are spontaneously formed. We demonstrate the synthesis of highly uniform and size controllable hybrid NPs. It is shown that codoped Si NCs act as a reducing agent for metal salts and also as a protecting layer to stop metal NP growth. The process is thus self-limiting. The development of a variety of Si NC-based hybrid NPs is a promising first step for the design of biocompatible multifunctional NPs with broad material choices for biosensing, bioimaging and solar energy conversion. PMID- 27121128 TI - Soluble urokinase plasminogen activator receptor informs on the progression course after multiple injuries. AB - PURPOSE: The purpose of this study is to study the use of soluble urokinase plasminogen activator receptor (suPAR) for the prognosis of multiple organ dysfunction (MOF) after multiple traumas. METHODS: Serum suPAR was measured within the first 24 h after multiple injuries in 85 patients. Measurements were repeated after 4 d or at sepsis onset. RESULTS: Odds ratio for trauma-associated MOF was 4.09 (p: 0.026) with admission suPAR greater than 8 ng/ml. More than 40% increases of suPAR were associated with odds ratio 9.33 (p: 0.047) for severe sepsis. CONCLUSIONS: suPAR is a useful surrogate biomarker for development of MOF and severe sepsis after multiple traumas. PMID- 27121129 TI - A new hand-held optical reflectometer to measure enamel erosion: correlation with surface hardness and calcium release. AB - In the present study, the surface reflection intensity (SRI) was measured from enamel with different induced erosion degrees using a hand-held pen-size reflectometer (Hand-Held) and a Table-Top reflectometer. To validate the Hand Held reflectometer, we correlated its optical signals with the change of surface microhardness (SMH), and amount of calcium released from the enamel samples during erosion. We used 124 tooth enamel specimens that were exposed to an erosive challenge of either 1, 2, 4, 6, 8, or 10 minutes. SRI and SMH were measured before and after the erosive challenge and we also measured the amount of calcium released to the citric acid. Relative SRI loss (rSRIloss) and relative SMH loss (rSMHloss) were calculated. rSRIloss from the Hand-Held and the Table Top reflectometers were similar and significantly correlated to rSMHloss and calcium release. The regression analyses showed a significant association between rSRIloss from both reflectometers and rSMHloss and calcium, showing that both reflectometers can be used to measure erosive demineralization of enamel. The Hand-Held reflectometer is capable of assessing in vitro erosion, correlating to other commonly used methods. It is small, easy to handle and provides fast measurement, being a possible candidate to measure erosion in clinical studies. PMID- 27121130 TI - Fluoroscopy pulse rate reduction during diagnostic and therapeutic imaging in the cardiac catheterization laboratory: An evaluation of radiation dose, procedure complications and outcomes. AB - OBJECTIVES: To evaluate radiation reduction by reducing fluoroscopy pulse rate in diagnostic cardiac catheterizations and percutaneous coronary interventions (PCI) as well as outcomes at 30 days and six months. BACKGROUND: Radiation exposure to the public at large has increased dramatically over the past three decades, and the cardiac catheterization laboratory is a large contributor. Fluoroscopy pulse rate is one way to decrease radiation exposure. METHODS: Fluoroscopy pulse rate was reduced from 10 pulses/sec (p/s) to 7.5 p/s as part of an internal quality improvement project. A retrospective analysis of all cardiac catheterizations was performed, evaluating Air KERMA at the interventional reference point (Ka, r ), Air KERMA area product (PKA ), procedural complications and major adverse cardiac events at 30 days and 6 months. RESULTS: In diagnostic catheterization median PKA (uGy.m2 ) and Ka,r (mGy) were significantly reduced (PKA - 5,613.3 vs. 4,400, P < 0.001; Ka,r - 703.0 vs. 621.0, P = 0.041). In PCI, median PKA and Ka,r were further reduced (PKA - 13,481.6 vs. 10,648.0, P < 0.001; Ka,r - 1787.0 vs. 1,459.0, P = 0.002). There was no difference in complications, fluoroscopy time or number of stents placed. There was no difference in MACE after adjustment for number of STEMIs. CONCLUSIONS: Reducing fluoroscopy pulse rates to 7.5 from 10 is an effective way to reduce patient radiation exposure across meaningful dose indices. A pulse rate of 7.5 p/s is safe, with no difference in complications or outcomes. A fluoroscopy pulse rate of 7.5 p/s should be given strong consideration for a new standard. (c) 2016 Wiley Periodicals, Inc. PMID- 27121131 TI - Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis. AB - Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia induced tumor cell migration, invasion and metastasis. PMID- 27121133 TI - Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp(3) )-H and C(sp(2) )-H under Rhodium(III) Catalysis. AB - Previous direct C-H nitrogenation suffered from simple amidation/amination with limited atom-economy and is mostly limited to C(sp(2) )-H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp(2) )-H and C(sp(3) )-H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species. PMID- 27121132 TI - Type I collagen aging impairs discoidin domain receptor 2-mediated tumor cell growth suppression. AB - Tumor cells are confronted to a type I collagen rich environment which regulates cell proliferation and invasion. Biological aging has been associated with structural changes of type I collagen. Here, we address the effect of collagen aging on cell proliferation in a three-dimensional context (3D).We provide evidence for an inhibitory effect of adult collagen, but not of the old one, on proliferation of human fibrosarcoma HT-1080 cells. This effect involves both the activation of the tyrosine kinase Discoidin Domain Receptor 2 (DDR2) and the tyrosine phosphatase SHP-2. DDR2 and SHP-2 were less activated in old collagen. DDR2 inhibition decreased SHP-2 phosphorylation in adult collagen and increased cell proliferation to a level similar to that observed in old collagen.In the presence of old collagen, a high level of JAK2 and ERK1/2 phosphorylation was observed while expression of the cell cycle negative regulator p21CIP1 was decreased. Inhibition of DDR2 kinase function also led to an increase in ERK1/2 phosphorylation and a decrease in p21CIP1 expression. Similar signaling profile was observed when DDR2 was inhibited in adult collagen. Altogether, these data suggest that biological collagen aging could increase tumor cell proliferation by reducingthe activation of the key matrix sensor DDR2. PMID- 27121134 TI - Surface-active ionic liquids in micellar catalysis: impact of anion selection on reaction rates in nucleophilic substitutions. AB - A series of surface-active ionic liquids based on the 1-dodecyl-3 methylimidazolium cation and different anions such as halides and alkylsulfates was synthesized. The aggregation behavior of these ionic liquids in water was characterized by surface tension, conductivity measurements and UV-Vis spectroscopy in order to determine the critical micelle concentration (CMC) and to provide aggregation parameters. The determination of surface activity and aggregation properties of amphiphilic ionic liquids was accompanied by SAXS studies on selected surface-active ionic liquids. The application of these surface-active ionic liquids with different anions was tested in nucleophilic substitution reactions for the degradation of organophosphorus compounds. Kinetic studies via UV-Vis spectrophotometry showed a strong acceleration of the reaction in the micellar system compared to pure water. In addition, an influence of the anion was observed, resulting in a correlation between the anion binding to the micelle and the reaction rate constants, indicating that the careful choice of the surface-active ionic liquid can considerably affect the outcome of reactions. PMID- 27121135 TI - Bioinspired Synthesis of All-in-One Organic-Inorganic Hybrid Nanoflowers Combined with a Handheld pH Meter for On-Site Detection of Food Pathogen. AB - With a mild elaborately bioinspired one-pot process, Con A-GOx-CaHPO4 nanoflowers are prepared. Employing the as-prepared all-in-one hybrid nanoflowers as signal tags, a simple but potentially powerful amplification biosensing technology for the detection of food pathogen with excellent simplicity, portability, sensitivity, and adaptability is achieved. PMID- 27121136 TI - Adenovirus encoding XAF-1 and TNF-alpha in the same open reading frame efficiently inhibits hepatocellular cancer cells. AB - X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF-1), a tumor suppressor, is downregulated in most human malignant tumors. However, the tumor suppressive role of XAF-1 in hepatocellular carcinoma (HCC) and its therapeutic value require further elucidation. The present study examined the expression of XAF-1 at the mRNA and protein level in the HCC and paired peritumor tissue specimens, as well as in HCC cell lines and a normal liver cell line. A recombinant adenovirus which co-expressed XAF-1 and TNF-alpha was then constructed, and its effects on the proliferation and colony formation ability of the MHCC97H HCC cell line were assessed using apoptosis induction, flow cytometry, trypan blue staining assay and a clonogenic assay. The results demonstrated that the expression of XAF-1 was significantly reduced in HCC tissues compared with that in their matched peritumor specimens, and a significant correlation with the tumor size, stage and tumor - nodes - metastasis stage was identified. The reduced levels of XAF-1 were further confirmed the HCC cell lines MHCC97L, HepG2 and MHCC97H compared with those in the L02 normal liver cell line. The recombinant adenovirus Ad-XAF-1&TNF-alpha, which co-expressed XAF 1 and TNF-alpha, was shown to efficiently express the two proteins at the mRNA and protein level. Furthermore, infection with Ad-XAF-1&TNF-alpha synergistically induced apoptosis, reduced the proliferation and colony formation ability of MHCC97L cells to a significantly greater extent than overexpression of XAF-1 or TNF-alpha individually. To the best of our knowledge, the present study was the first to construct an adenovirus which co-expressed XAF-1 and TNF-alpha in the same open reading frame and expressed them proportionally. As Ad-XAF-1&TNF-alpha inhibited HCC cells with enhanced efficiency, it may be applicable for the treatment of HCC. PMID- 27121138 TI - Behavior of Bilayer Leaflets in Asymmetric Model Membranes: Atomistic Simulation Studies. AB - Spatial organization within lipid bilayers is an important feature for a range of biological processes. Leaflet compositional asymmetry and lateral lipid organization are just two of the ways in which membrane structure appears to be more complex than initially postulated by the fluid mosaic model. This raises the question of how the phase behavior in one bilayer leaflet may affect the apposing leaflet and how one begins to construct asymmetric model systems to investigate these interleaflet interactions. Here we report on all-atom molecular dynamics simulations (a total of 4.1 MUs) of symmetric and asymmetric bilayer systems composed of liquid-ordered (Lo) or liquid-disordered (Ld) leaflets, based on the nanodomain-forming POPC/DSPC/cholesterol system. We begin by analyzing an asymmetric bilayer with leaflets derived from simulations of symmetric Lo and Ld bilayers. In this system, we observe that the properties of the Lo and Ld leaflets are similar to those of the Lo and Ld leaflets in corresponding symmetric systems. However, it is not obvious that mixing the equilibrium structures of their symmetric counterparts is the most appropriate way to construct asymmetric bilayers nor that these structures will manifest interleaflet couplings that lead to domain registry/antiregistry. We therefore constructed and simulated four additional asymmetric bilayer systems by systematically adding or removing lipids in the Ld leaflet to mimic potential density fluctuations. We find that the number of lipids in the Ld leaflet affects its own properties, as well as those of the apposing Lo leaflet. Collectively, the simulations reveal the presence of weak acyl chain interdigitation across bilayer leaflets, suggesting that interdigitation alone does not contribute significantly to the interleaflet coupling in nonphase-separated bilayers of this chemical composition. However, the properties of both leaflets appear to be sensitive to changes in in-plane lipid packing, possibly providing a mechanism for interleaflet coupling by modulating local density and/or curvature fluctuations. PMID- 27121137 TI - High-resolution analytical imaging and electron holography of magnetite particles in amyloid cores of Alzheimer's disease. AB - Abnormal accumulation of brain metals is a key feature of Alzheimer's disease (AD). Formation of amyloid-beta plaque cores (APC) is related to interactions with biometals, especially Fe, Cu and Zn, but their particular structural associations and roles remain unclear. Using an integrative set of advanced transmission electron microscopy (TEM) techniques, including spherical aberration corrected scanning transmission electron microscopy (Cs-STEM), nano-beam electron diffraction, electron holography and analytical spectroscopy techniques (EDX and EELS), we demonstrate that Fe in APC is present as iron oxide (Fe3O4) magnetite nanoparticles. Here we show that Fe was accumulated primarily as nanostructured particles within APC, whereas Cu and Zn were distributed through the amyloid fibers. Remarkably, these highly organized crystalline magnetite nanostructures directly bound into fibrillar Abeta showed characteristic superparamagnetic responses with saturated magnetization with circular contours, as observed for the first time by off-axis electron holography of nanometer scale particles. PMID- 27121139 TI - Aggregatibacter actinomycetemcomitans outer membrane protein 29 (Omp29) induces TGF-beta-regulated apoptosis signal in human gingival epithelial cells via fibronectin/integrinbeta1/FAK cascade. AB - Gingival junctional epithelial cell apoptosis caused by periodontopathic bacteria exacerbates periodontitis. This pathological apoptosis is involved in the activation of transforming growth factor beta (TGF-beta). However, the molecular mechanisms by which microbes induce the activation of TGF-beta remain unclear. We previously reported that Aggregatibacter actinomycetemcomitans (Aa) activated TGF beta receptor (TGF-betaR)/smad2 signalling to induce epithelial cell apoptosis, even though Aa cannot bind to TGF-betaR. Additionally, outer membrane protein 29 kDa (Omp29), a member of the Aa Omps family, can induce actin rearrangements via focal adhesion kinase (FAK) signalling, which also plays a role in the activation of TGF-beta by cooperating with integrin. Accordingly, we hypothesized that Omp29 induced actin rearrangements via FAK activity would enhance the activation of TGF beta, leading to gingival epithelial cell apoptosis in vitro. By using human gingival epithelial cell line OBA9, we found that Omp29 activated TGF-betaR/smad2 signalling and decreased active TGF-beta protein levels in the extracellular matrix (ECM) of cell culture, suggesting the transactivation of TGF-betaR. Inhibition of actin rearrangements by cytochalasin D or blebbistatin and knockdown of FAK or integrinbeta1 expression by siRNA transfection attenuated TGF betaR/smad2 signalling activity and reduction of TGF-beta levels in the ECM caused by Omp29. Furthermore, Omp29 bound to fibronectin (Fn) to induce its aggregation on integrinbeta1, which is associated with TGF-beta signalling activity. All the chemical inhibitors and siRNAs tested blocked Omp29-induced OBA9 cells apoptosis. These results suggest that Omp29 binds to Fn in order to facilitate Fn/integrinbeta1/FAK signalling-dependent TGF-beta release from the ECM, thereby inducing gingival epithelial cell apoptosis via TGF-betaR/smad2 pathway. PMID- 27121140 TI - Biological Variation and Reference Change Value Data for Serum Neuron-Specific Enolase in a Turkish Population. AB - BACKGROUND: Neuron-specific enolase (NSE) is a recognized biomarker for the assessment of cerebral injury in neurological disorders. This study aims to report a definitive assessment of the biological variation (BV) components of this biomarker, including within-subject BV (CVI), between-subject BV (CVG), index of individuality (II), and reference change value (RCV), in a cohort of Turkish participants using an experimental protocol. METHODS: Six blood specimens were collected from each of the 13 apparently healthy volunteers (seven women, six men; ranging in age from 23 to 36) on the same day, every 2 weeks for 2 months. Serum specimens were stored at -20 degrees C until analysis. Neuron specific enolase levels were evaluated in serum samples using an electrochemiluminescence (ECLIA) immunoassay kit with a Roche Cobas e 411 auto analyser. ANOVA test was used to calculate the variations. RESULTS: The CVI and CVG for NSE were 21.5% and 28.8%, respectively. Analytical variation (CVA) was calculated as 10.2%. Additionally, II and RCV were calculated as 0.74 and 66% (95% confident interval, CI), respectively. CONCLUSION: As the performance index (PI) was found to be less than 2 (PI = 0.95), it is concluded that the NSE measurements have a desirable performance for analytical imprecision. Since the II was found to be less than 1 (II: 0.74), the reference values will be of little use. Thus, RCV would provide better information for deciding whether a significant change has occurred. PMID- 27121146 TI - The influence of maternal nutrition on expression of genes responsible for adipogenesis and myogenesis in the bovine fetus. AB - The objective of this study was to determine whether altered maternal energy supply during mid-gestation results in differences in muscle histology or genes regulating fetal adipose and muscle development. In total, 22 Angus cross-bred heifers (BW=527.73+/-8.3 kg) were assigned randomly to the three dietary treatments providing 146% (HIGH; n=7), 87% (INT; n=7) or 72% (LOW; n=8) of the energy requirements for heifers from day 85 to day 180 of gestation. Fetuses were removed via cesarean section at day 180 of gestation and longissimus muscle (LM) and subcutaneous fat were collected and prepared for analysis of gene expression. Samples from the LM and semitendinosus (ST) were evaluated for muscle fiber diameter, area and number. The right hind limb was dissected and analyzed to determine compositional analysis. Fetal growth and muscle histology characteristics of the LM and ST were similar among treatments. Preadipocyte factor-1 expression was up-regulated in fetal LM (P<0.05) of HIGH fetuses as compared with INT, whereas LOW fetuses showed increased CCAAT/enhancer-binding protein-beta (C/EBP-beta) expression in LM as compared with INT (P<0.05). Peroxisome proliferator-activated receptor gammaand C/EBP-alpha did not differ as a result of dietary treatment in LM or subcutaneous fat samples. There was a tendency for increased expression of fatty acid synthase in LM of LOW fetuses as compared with INT (P<0.10). Myogenin was more highly expressed (P<0.05) in LM of the LOW fetuses, whereas MU-calpain expression was increased in the HIGH treatment compared with INT. A tendency for increased expression of IGF-II was observed for both LOW and HIGH fetuses compared with INT (P<0.10). Expression of stearoyl-CoA desaturase, myoblast determination protein 1, myogenic factor 5, myogenic regulatory factor-4, m-calpain, calpastatin, IGF-I and myostatin was similar between treatments. Collectively, these results suggest that fetal growth characteristics are not affected by the level of maternal nutritional manipulation imposed in this study during mid-gestation. However, differences in expression of fetal genes regulating adipose and muscle tissue growth and development could lead to differences in postnatal composition and warrants further investigation. PMID- 27121147 TI - The influence of social challenges when implementing information systems in a Swedish health-care organisation. AB - AIM: To describe and obtain a deeper understanding of social challenges and their influence on the implementation process when implementing Information systems in a Swedish health-care organisation. BACKGROUND: Despite positive effects when implementing Information systems in health-care organisations, there are difficulties in the implementation process. Nurses' experiences of being neglected have been dismissed as reasons for setbacks in implementation. METHODS: An Institutional Ethnography design was used. A deductive content analysis was made influenced by empirically identified social challenges of power, professional identity and encounters. An abstraction was made of the analysis. RESULTS: Nineteen nurses at macro, meso and micro levels were interviewed in focus groups. Organisational levels are lost in different ways in how to control the reformation, how to introduce Information systems as reformation strategies and in how to translate new tools and assumptions that do not fit traditional ways of working in shaping professional identities. CONCLUSION AND IMPLICATION FOR NURSE MANAGEMENT: Different focus may affect the reformation of health-care organisations and implementation and knowledge processes. An implementation climate is needed where the system standards fit the values of the users. Nursing management needs to be visionary, engaged and work with risk factors in order to reform the hierarchical health-care organisation. PMID- 27121149 TI - Implementing Data Definition Consistency for Emergency Department Operations Benchmarking and Research. AB - OBJECTIVES: The objective was to obtain a commitment to adopt a common set of definitions for emergency department (ED) demographic, clinical process, and performance metrics among the ED Benchmarking Alliance (EDBA), ED Operations Study Group (EDOSG), and Academy of Academic Administrators of Emergency Medicine (AAAEM) by 2017. METHODS: A retrospective cross-sectional analysis of available data from three ED operations benchmarking organizations supported a negotiation to use a set of common metrics with identical definitions. During a 1.5-day meeting-structured according to social change theories of information exchange, self-interest, and interdependence-common definitions were identified and negotiated using the EDBA's published definitions as a start for discussion. Methods of process analysis theory were used in the 8 weeks following the meeting to achieve official consensus on definitions. These two lists were submitted to the organizations' leadership for implementation approval. RESULTS: A total of 374 unique measures were identified, of which 57 (15%) were shared by at least two organizations. Fourteen (4%) were common to all three organizations. In addition to agreement on definitions for the 14 measures used by all three organizations, agreement was reached on universal definitions for 17 of the 57 measures shared by at least two organizations. The negotiation outcome was a list of 31 measures with universal definitions to be adopted by each organization by 2017. CONCLUSION: The use of negotiation, social change, and process analysis theories achieved the adoption of universal definitions among the EDBA, EDOSG, and AAAEM. This will impact performance benchmarking for nearly half of US EDs. It initiates a formal commitment to utilize standardized metrics, and it transitions consistency in reporting ED operations metrics from consensus to implementation. This work advances our ability to more accurately characterize variation in ED care delivery models, resource utilization, and performance. In addition, it permits future aggregation of these three data sets, thus facilitating the creation of more robust ED operations research data sets unified by a universal language. Negotiation, social change, and process analysis principles can be used to advance the adoption of additional definitions. PMID- 27121148 TI - Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) neuropathology is associated with neuroinflammation, but there are few useful biomarkers. Mutant variants of triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to late-onset AD and other neurodegenerative disorders. TREM2, a microglial receptor, is involved in innate immunity. A cleaved fragment, soluble TREM2 (sTREM2), is present in the cerebrospinal fluid (CSF). METHODS: We developed and used a novel enzyme-linked immunosorbent assay to investigate the potential value of CSF sTREM2 as an AD biomarker in two independent cohorts: an AD/mild cognitive impairment (MCI)/control cohort (n = 100) and an AD/control cohort (n = 50). RESULTS: We found no significant difference in sTREM2 levels between groups of controls and patients with AD or MCI. However, among all controls there was a positive correlation between sTREM2 and age (Spearman rho = 0.50; p < 0.001; n = 75). In the AD/MCI/control cohort, CSF sTREM2 correlated positively with total Tau (T-tau) (Spearman rho 0.57; p < 0.001; n = 50), phosphorylated Tau (P-tau) (Spearman rho 0.63; p < 0.001; n = 50) and amyloid beta1-42 (Abeta42) (Spearman rho 0.35; p = 0.01; n = 50) in control subjects. Among controls with a CSF Abeta42 above a cut-off value (700 pg/ml) in this cohort, the positive correlation between sTREM2 and Abeta42 was stronger (Spearman rho = 0.44; p = 0.002; n = 46). CONCLUSIONS: sTREM2 in CSF correlates with aging in controls, and with the neurodegenerative markers CSF T-tau/P-tau among controls who are negative for AD CSF core biomarkers Abeta42, T-tau or P tau. PMID- 27121150 TI - Effect of Photoinduced Size Changes on Protein Refolding and Transport Abilities of Soft Nanotubes. AB - Self-assembly of azobenzene-modified amphiphiles (Glyn Azo, n=1-3) in water at room temperature in the presence of a protein produced nanotubes with the protein encapsulated in the channels. The Gly2 Azo nanotubes (7 nm internal diameter [i.d.]) promoted refolding of some encapsulated proteins, whereas the Gly3 Azo nanotubes (13 nm i.d.) promoted protein aggregation. Although the 20 nm i.d. channels of the Gly1 Azo nanotubes were too large to influence the encapsulated proteins, narrowing of the i.d. to 1 nm by trans-to-cis photoisomerization of the azobenzene units of the Gly1 Azo monomers packed in the solid bilayer membranes led to a squeezing out of the proteins into the bulk solution and simultaneously enhanced their refolding ratios. In contrast, photoinduced transformation of the Gly2 Azo nanotubes to short nanorings (<40 nm) with a large i.d. (28 nm) provided no further refolding assistance. We thus demonstrate that pertubation by the solid bilayer membrane wall of the nanotubes is important to accelerate refolding of the denatured proteins during their transport in the narrow nanotube channels. PMID- 27121151 TI - Glass-on-Glass Fabrication of Bottle-Shaped Tunable Microlasers and their Applications. AB - We describe a novel method for making microbottle-shaped lasers by using a CO2 laser to melt Er:Yb glass onto silica microcapillaries or fibres. This is realised by the fact that the two glasses have different melting points. The CO2 laser power is controlled to flow the doped glass around the silica cylinder. In the case of a capillary, the resulting geometry is a hollow, microbottle-shaped resonator. This is a simple method for fabricating a number of glass whispering gallery mode (WGM) lasers with a wide range of sizes on a single, micron-scale structure. The Er:Yb doped glass outer layer is pumped at 980 nm via a tapered optical fibre and WGM lasing is recorded around 1535 nm. This structure facilitates a new way to thermo-optically tune the microlaser modes by passing gas through the capillary. The cooling effect of the gas flow shifts the WGMs towards shorter wavelengths and thermal tuning of the lasing modes over 70 GHz is achieved. Results are fitted using the theory of hot wire anemometry, allowing the flow rate to be calibrated with a flow sensitivity as high as 72 GHz/sccm. Strain tuning of the microlaser modes by up to 60 GHz is also demonstrated. PMID- 27121152 TI - BAP1 Immunostain and CDKN2A (p16) FISH Analysis: Clinical Applicability for the Diagnosis of Malignant Mesothelioma in Effusions. AB - BACKGROUND: Loss of BAP1 by immunohistochemistry (IHC) and CDKN2A(p16) deletion by fluorescence in situ hybridization (FISH) have been proposed to distinguish malignant mesothelioma (MM) from atypical reactive mesothelial proliferations (ARMP) in effusions but it is uncertain whether both tests are needed routinely. METHODS: Paraffin embedded blocks from 67 effusions (32 MM, 35 ARMP) were evaluated with BAP1 IHC. 38 of them (17 MM, 21 ARMP) were also analyzed with CDKN2A (p16) FISH. Criteria for MM were absence of BAP1 nuclear staining in >50% of atypical mesothelial cells in the presence of a positive internal control, and/or CDKN2A(p16) homozygous or hemizygous deletion pattern in >15% or >41.5% of atypical mesothelial cells, respectively. Sensitivity (SS), specificity (SP), positive, and negative predictive values (PPV, NPV) for MM were calculated. RESULTS: 17 of 32 MM were correctly diagnosed by IHC (SS 53.1%, SP 85.7%, PPV 77.3%, NPV 64.3% for MM). In the subset of 38 cases studied by IHC and FISH, the SS, SP, PPV, and NPV of IHC for MM were 41.2, 81.0, 63.6, and 63.0%, respectively. 7 of 17 MM were diagnosed by FISH (SS 41.2%, SP 100%, PPV 100%, NPV 67.7% for MM). CONCLUSION: BAP1 IHC and CDKN2A(p16) FISH yield similar sensitivities for MM in paired samples but FISH has a higher specificity. To diagnose effusions with atypical mesothelial cells, use of both tests is optimal. However, BAP1 IHC alone may be sufficient to diagnose MM when clinical, imaging, and cytological findings strongly suggest MM. Diagn. Cytopathol. 2016. (c) 2016 Wiley Periodicals, Inc. Diagn. Cytopathol. 2016;44:599-606. (c) 2016 Wiley Periodicals, Inc. PMID- 27121153 TI - Feasibility of laparoscopic surgery for complex Crohn's disease of the small intestine. AB - BACKGROUND: The laparoscopic approach for complex Crohn's disease (CD), which involves abscess formation, fistula formation, and recurrent CD, is controversial. The aim of this study was to investigate the feasibility and safety of the laparoscopic approach for complex CD. METHODS: Fifty-six patients who had undergone surgery for CD of the small bowel from January 2007 to August 2014 were divided into two groups: the laparoscopic approach for complex CD group (LC group, n = 31) and the laparoscopic approach for simple CD group (LS group, n = 25). The preoperative data and surgical outcomes of the LC group were compared with those of the LS groups. RESULTS: There were no significant differences in preoperative data and operating time between the two groups. Blood loss was not significantly different between the LC and LS groups. The incision length was longer in the LC group than the LS group (P = 0.004). The incidence of severe postoperative complications in the LC group was higher than in the LS group (P = 0.026). The length of postoperative stay was similar in the LC and LS groups. CONCLUSIONS: The laparoscopic approach for complex CD is feasible and provides good cosmesis that is comparable to that offered by simple CD. PMID- 27121154 TI - DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells. AB - Promoter DNA methylation is a key epigenetic mechanism for stable gene silencing, but is correlated with expression when located in gene bodies. Maintenance and de novo DNA methylation by catalytically active DNA methyltransferases (DNMT1 and DNMT3A/B) require accessory proteins such as UHRF1 and DNMT3L. DNMT3B isoforms are widely expressed, although some do not have active catalytic domains and their expression can be altered during cell development and tumourigenesis, questioning their biological roles. Here, we show that DNMT3B isoforms stimulate gene body methylation and re-methylation after methylation-inhibitor treatment. This occurs independently of the isoforms' catalytic activity, demonstrating a similar functional role to the accessory protein DNMT3L, which is only expressed in undifferentiated cells and recruits DNMT3A to initiate DNA methylation. This unexpected role for DNMT3B suggests that it might substitute for the absent accessory protein DNMT3L to recruit DNMT3A in somatic cells. PMID- 27121155 TI - Lentinan mitigates therarubicin-induced myelosuppression by activating bone marrow-derived macrophages in an MAPK/NF-kappaB-dependent manner. AB - Bone marrow (BM) suppression (also known as myelosuppression) is the most common and most severe side-effect of therarubicin (THP) and thereby limits the clinical application of this anticancer agent. Lentinan (LNT), a glucan extracted from dried shiitake mushrooms (Lentinula edodes), exhibits a variety of pharmacological activities. The objectives of the present study were to determine the effect of LNT on the myelosuppression of THP-treated mice and to examine the pharmacological mechanism of these effects. In vivo experiments indicated that non-cytotoxic levels of LNT strongly increased blood myeloperoxidase (MPO) activity; improved BM structural injuries; increased the numbers of leukocytes and neutrophils in the blood and BM; elevated the blood levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF); and reduced the self-healing period in THP-treated mice. In vitro experiments indicated that LNT increased the viability of BM-derived macrophages (BMDMs) in a time- and dose dependent manner without toxic side-effects and markedly increased the release of G-CSF, GM-CSF and M-CSF by BMDMs. Further analyses revealed that LNT activated the NF-kappaB and MAPK signalling pathways and promoted the nuclear import of p65 and that BAY 11-7082 (a specific inhibitor of NF-kappaB) suppressed the release of G-CSF, GM-CSF and M-CSF. Furthermore, we found that U0126, SB203580 and SP600125 (specific inhibitors of ERK, p38 and JNK, respectively) markedly inhibited the IKK/IkappaB/NF-kappaB-dependent release of G-CSF, GM-CSF and M-CSF. In conclusion, LNT induces the production of G-CSF, GM-CSF and M-CSF by activating the MAPK/NF-kappaB signalling pathway in BM cells, thereby mitigating THP-induced myelosuppression. PMID- 27121157 TI - Peer review and Publons - enhancements for the reviewer. PMID- 27121158 TI - GPs views and understanding of PSA testing, screening and early detection; survey. AB - BACKGROUND: There is currently no national prostate cancer screening programme in the UK. However, patients 50 years and older are entitled to a prostate specific antigen (PSA) test, if informed on the advantages and disadvantages of testing and their risk of cancer. The Prostate Cancer Risk Management Programme (PCRMP) provides this guidance. AIM: The aim of this study was to access GPs' views and understanding of PSA testing, prostate cancer screening and early detection. METHOD: A total of 708 questionnaires were returned by GPs across two English regions in 2013 and the GP questionnaire responses were quantitatively analysed. RESULTS: In the 699 completed questionnaires, the majority of GPs were well informed about PSA testing, screening and early detection. Only 32% used guidelines for referral, 14% knew all age-specific PSA referral levels, 71% that Black men have a higher prostate cancer risk than White men (22% correctly answered threefold increase) and 82% that family history is a risk factor. A further 78% thought electronic prompts during consultation would encourage PCRMP guideline usage and 75% had never been offered a PSA test and prostate cancer educational course, of which 73% would like to attend a course. Only 23% were aware of the latest PSA screening evidence and 94% would like an update. CONCLUSIONS: Participating GPs seem to be well informed but need more information and tools to help follow recommended guidance. In particular, increased awareness of PCRMP guidelines especially by automated methods, further educational courses and evidence updates would be beneficial. PMID- 27121156 TI - Present and future roles of FDG-PET/CT imaging in the management of lung cancer. AB - Integrated positron emission tomography/computed tomography (PET/CT) using 2 [(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) has emerged as a powerful tool for combined metabolic and anatomic evaluation in clinical oncologic imaging. This review discusses the utility of (18)F-FDG PET/CT as a tool for managing patients with lung cancer. We discuss different patient management stages, including diagnosis, initial staging, therapy planning, early treatment response assessment, re-staging, and prognosis. PMID- 27121159 TI - Aerobic training and l-arginine supplementation promotes rat heart and hindleg muscles arteriogenesis after myocardial infarction. AB - Arteriogenesis is a main defense mechanism to prevent heart and local tissues dysfunction in occlusive artery disease. TGF-beta and angiostatin have a pivotal role in arteriogenesis. We tested the hypothesis that aerobic training and l arginine supplementation promotes cardiac and skeletal muscles arteriogenesis after myocardial infarction (MI) parallel to upregulation of TGF-beta and downregulation of angiostatin. For this purpose, 4 weeks after LAD occlusion, 50 male Wistar rats were randomly distributed into five groups: (1) sham surgery without MI (sham, n = 10), (2) control-MI (Con-MI, n = 10), (3) l-arginine-MI (La MI, n = 10), (4) exercise training-MI (Ex-MI, n = 10), and (5) exercise and l arginine-MI (Ex + La-MI). Exercise training groups running on a treadmill for 10 weeks with moderate intensity. Rats in the l-arginine-treated groups drank water containing 4 % l-arginine. Arteriolar density with different diameters (11-25, 26 50, 51-75, and 76-150 MUm), TGF-beta, and angiostatin gene expression were measured in cardiac (area at risk) and skeletal (soleus and gastrocnemius) muscles. Smaller arterioles decreased in cardiac after MI. Aerobic training and l arginine increased the number of cardiac arterioles with 11-25 and 26-50 MUm diameters parallel to TGF-beta overexpression. In gastrocnemius muscle, the number of arterioles/mm(2) was only increased in the 11 to 25 MUm in response to training with and without l-arginine parallel to angiostatin downregulation. Soleus arteriolar density with different size was not different between experimental groups. Results showed that 10 weeks aerobic exercise training and l arginine supplementation promotes arteriogenesis of heart and gastrocnemius muscles parallel to overexpression of TGF-beta and downregulation of angiostatin in MI rats. PMID- 27121160 TI - B-cell-activating factor is elevated in serum of patients with myasthenia gravis. AB - INTRODUCTION: Myasthenia gravis (MG) is a B-cell-mediated autoimmune disease. B cell-activating factor (BAFF) is a major factor in B-cell development and activation. In this study we investigated serum BAFF levels in MG patients. METHODS: We compared the serum BAFF levels of 20 MG patients with gender-matched healthy controls. We assayed serum concentrations of BAFF and anti-acetylcholine receptor antibody (AChR) titers. RESULTS: Serum BAFF levels of MG patients with AChR antibodies were significantly higher than those of healthy controls. A significant positive correlation was observed between serum BAFF levels and anti AChR antibody titers. BAFF values did not correlate with disease severity. CONCLUSIONS: BAFF may play a major role in the pathogenesis of MG, and it may provide a potential target for therapy in patients with MG. Muscle Nerve 54: 1030 1033, 2016. PMID- 27121161 TI - Analysis of SLC4A11, ZEB1, LOXHD1, COL8A2 and TCF4 gene sequences in a multi generational family with late-onset Fuchs corneal dystrophy. AB - The aim of the present study was to determine the genetic basis of a multi generational family with late-onset (LO) Fuchs corneal dystrophy (FCD). Five FCD causal genes [solute carrier family 4, sodium borate transporter, member 11 (SLC4A11), zinc finger E-box binding homeobox 1 (ZEB1), lipoxygenase homology domains 1 (LOXHD1), collagen, type VIII, alpha 2 (COL8A2) and transcription factor 4 (TCF4)], previously reported to be implicated in the pathogenesis of FCD, were screened. A total of 27 variants [including 22 known single nucleotide polymorphisms (SNPs) from the Single Nucleotide Polymorphism Database (dbSNP) and 5 variants absent from dbSNP] were detected in this FCD pedigree across the SLC4A11, ZEB1, LOXHD1 and COL8A2 genes as follows: i) 22 known SNPs from dbSNP, including 3 coding (p.R161R, p.S213S and p.T833T) and 11 non-coding variants of SLC4A11, 2 intronic SNPs of ZEB1 from dbSNP (rs220057 and rs220060), 1 intronic SNP of LOXHD1 from dbSNP (rs16939650), and 5 SNPs of COL8A2 from dbSNP (p.A35A, p.R155Q, p.L335L, p.G495G and p.T502M); and ii) 5 variants that have not been previously reported in FCD patients and that are absent from dbSNP were identified across the ZEB1 and LOXHD1 genes; these included 3 continuous indels located at the junction of the 5'-UTR and the adjacent exon 1 of ZEB1 [Indel 1 (c.-86_-53delins gggaggggtggaggcggaggggtGGGGGGGAAGG); Indel 2 (c.-52_ 46delinsGGGAGGG); and Indel 3 (c.-45_-42delinsAGGG)], and 2 intronic variants of LOXHD1 (c.5332-126C>T and c.1809+155G>A). Apart from one intronic SNP of SLC4A11 from dbSNP (rs372201212), the pathologic consequence of which is uncertain, and 2 intron variants of LOXHD1 (c.5332-126C>T and c.1809+155G>A); the variants likely represent examples of de novo mutations. Neither of the other 24 variants provided strong evidence of pathogenesis in this FCD pedigree. An analysis of 7 SNPs in TCF4 from dbSNP, which have been associated with LO FCD in different populations, revealed that these 7 SNPs were not associated with FCD in this specific pedigree. A genome-wide linkage scan to search for linkage to one of the previously described FCD loci or to identify a novel locus for FCD will need to be performed in this FCD pedigree. Our observation, nevertheless, expands the knowledge of the genetic status of patients with FCD. PMID- 27121162 TI - Constitutive photomorphogenesis protein 1 (COP1) and COP9 signalosome, evolutionarily conserved photomorphogenic proteins as possible targets of melatonin. AB - The ubiquitin proteasome system has been proposed as a possible mechanism involved in the multiple actions of melatonin. COP1 (constitutive photomorphogenesis protein 1), a RING finger-type ubiquitin E3 ligase formerly identified in Arabidopsis, is a central switch for the transition from plant growth underground in darkness (etiolation) to growth under light exposure (photomorphogenesis). In darkness, COP1 binds to photomorphogenic transcription factors driving its degradation via the 26S proteasome; blue light, detected by cryptochromes, and red and far-red light detected by phytochromes, negatively regulate COP1. Homologues of plant COP1 containing all the structural features present in Arabidopsis as well as E3 ubiquitin ligase activity have been identified in mice and humans. Substrates for mammalian (m) COP1 include p53, AP 1 and c-Jun, p27(Kip1) , ETV1, MVP, 14-3-3sigma, C/EBPalpha, MTA1, PEA3, ACC, TORC2 and FOXO1. This mCOP1 target suggests functions related to tumorigenesis, gluconeogenesis, and lipid metabolism. The role of mCOP1 in tumorigenesis (either as a tumor promoter or tumor suppressor), as well as in glucose metabolism (inhibition of gluconeogenesis) and lipid metabolism (inhibition of fatty acid synthesis), has been previously demonstrated. COP1, along with numerous other ubiquitin ligases, is regulated by the COP9 signalosome; this protein complex is associated with the oxidative stress sensor Keap1 and the deubiquitinase USP15. The objective of this review was to provide new information on the possible role of COP1 and COP9 as melatonin targets. The hypothesis is based on common functional aspects of melatonin and COP1 and COP9, including their dependence on light, regulation of the metabolism, and their control of tumor growth. PMID- 27121164 TI - The role of attainment value, academic self-efficacy, and message frame in the appraisal of value-promoting messages. AB - BACKGROUND: Prior to high-stakes examinations, teachers may use value-promoting messages (VPMs) to communicate to students the value and importance of their forthcoming examinations in the hope that they will adopt adaptive learning and study behaviours. These messages can focus on achieving success (gain-framed) or avoiding failure (loss-framed). AIMS: This study examined how secondary school students appraised hypothetical gain- and loss-framed VPMs, and how these appraisals differed according to self-reported levels of attainment value (AV) and academic self-efficacy (ASE). SAMPLES: In total, 539 secondary school students (284 male, 255 female, mean age 14.8 years) were participated in this study. METHODS: Participants completed self-report measures of AV and ASE and appraised hypothetical VPMs as challenging, threatening, or irrelevant (disregard). Participants were randomly assigned to a gain- or loss-framed condition. RESULTS: A challenge appraisal was greater in students with higher AV and ASE. A threat appraisal was greater in students with higher AV and lower ASE. A disregard appraisal was higher in students with lower AV. Message frame did not interact with AV or ASE in the appraisal of VPMs as challenging, threatening, or irrelevant. CONCLUSIONS: Educational practitioners should consider the characteristics of their students before using VPMs. In particular, they may not be effective for students high in AV and low in ASE. They are likely to be ineffective for students low in AV. PMID- 27121163 TI - Negative role of TAK1 in marginal zone B-cell development incidental to NF-kappaB noncanonical pathway activation. AB - The transcription factor nuclear factor-kappaB (NF-kappaB) signaling pathway is crucial in B-cell physiology. One key molecule regulating this pathway is the serine/threonine kinase TAK1 (MAP3K7). TAK1 is responsible for positive feedback mechanisms in B-cell receptor signaling that serve as an NF-kappaB activation threshold. This study aimed to better understand the correlation between TAK1 mediated signaling and B-cell development and humoral immune responses. Here we showed that a B-cell conditional deletion of TAK1 using mb1-cre resulted in a dramatic elimination of the humoral immune response, consistent with the absence of the B-1 B-cell subset. When monitoring the self-reactive B-cell system (the immunoglobulin hen egg lysozyme/soluble hen egg lysozyme double-transgenic mouse model), we found that TAK1-deficient B cells exhibited an enhanced susceptibility to cell death that might explain the disappearance of the B1 subset. In contrast, these mice gained numerous marginal zone (MZ) B cells. We consequently examined the basal and B-cell receptor-induced activity of NF-kappaB2 that is reported to regulate MZ B-cell development, and demonstrated that the activity of NF-kappaB2 increased in TAK1-deficient B cells. Thus, our results present a novel in vivo function, the negative role of TAK1 in MZ B-cell development that is likely associated with NF-kappaB2 activation. PMID- 27121165 TI - Does chlortetracycline ointment aid healing of a traumatic tympanic membrane perforation? PMID- 27121166 TI - Erratum. PMID- 27121167 TI - Sequential changes of endoplasmic reticulum stress and apoptosis in myocardial fibrosis of diabetes mellitus-induced rats. AB - The endoplasmic reticulum (ER) is an organelle in which proteins form their appropriate structures. However, several of these proteins become unfolded or misfolded when exposed to stimuli, including hyperglycemia, oxidative stress, ischemia, disturbance of calcium homeostasis and overexpression of abnormal proteins, which activates ER stress and the unfolded protein response (UPR). To date, investigations have demonstrated that ER stress is important in diabetic myocardial fibrosis by inducing cardiac cell apoptosis. Therefore, in the present study, the polymerase chain reaction, western blotting analysis and tissue staining were performed to identify the changes in UPR signaling proteins and apoptotic proteins in diabetic rats at different time points, and to determine whether the myocardial fibrosis is associated with ER-stress-mediated apoptosis using a diabetes mellitus (DM) rat model. It was found that the upregulation of ER stress markers and apoptotic molecules developed over time. It was also demonstrated that anti-apoptotic markers and proapoptotic markers were activated early following model establishment, and then decreased in months 4 and 5. The changes in myocardial fibrosis were found to accelerate in a time-dependent manner with apoptosis in the DM rats. PMID- 27121168 TI - Prospective study on microangiopathy in type 2 diabetic foot ulcer. AB - AIMS/HYPOTHESIS: We investigated the significance of microangiopathy in the development of foot ulcer, which is still disputed. METHODS: We assessed microangiopathy by histological analysis of the capillary ultrastructure using transmission electron microscopy and capillary density and arteriolar morphology in paraffin-embedded sections from the skin of type 2 diabetic patients: 30 neuroischaemic patients (Isc) revascularised with peripheral angioplasty and 30 neuropathic patients (Neu) with foot ulcer, compared with ten non-diabetic volunteers. RESULTS: In the diabetic patients, capillaries in the dermal papillary layer were fewer (-22.2%, 159 +/- 43 vs 205 +/- 52 mm(2) in non diabetic volunteers, p < 0.01). They also showed detrimental remodelling, with a 2.2-fold increase in capillary basement membrane thickness (3.44 +/- 1.19 vs 1.53 +/- 0.34 MUm in non-diabetic volunteers, p < 0.001) and a 57.7% decrease in lumen area (14.6 +/- 11.1 vs 34.7 +/- 27.5 MUm(2), p < 0.001). No differences were observed between the diabetic Isc or Neu patients. Isc were more prone to develop arteriolar occlusion than Neu (16.8 +/- 6.9% vs 6.7 +/- 3.7%, respectively, p < 0.001). No patient had been amputated at 30 days and healing time was significantly longer in Isc (180 +/- 120 vs 64 +/- 50 days in Neu, p < 0.001). CONCLUSIONS/INTERPRETATION: Capillary microangiopathy is present in equal measure in neuroischaemic and neuropathic diabetic foot skin. The predominance of arteriolar occlusions with neuroischaemia indicated the existence of an additional 'small vessel disease' that did not affect an effective revascularisation and did not worsen the prognosis of major amputations but slowed the healing process of the neuroischaemic foot ulcer. TRIAL REGISTRATION: ClinicalTrials.gov NCT02610036. PMID- 27121169 TI - Histopathological alterations, biochemical responses and acetylcholinesterase levels in Clarias gariepinus as biomarkers of exposure to organophosphates pesticides. AB - Organophosphate pesticides, commonly used in large scale farming, have been found to be major contaminants in aquatic environment. Clarias gariepinus was exposed to acute and sublethal concentrations of phostoxin and DD Force to evaluate single and joint action toxicity of the organophosphates. Effects of phostoxin and DD force on antioxidant enzymes, fish organs and acetylcholinesterase levels in fingerlings and juveniles of C. gariepinus were also investigated. The lethal concentrations (96 h LC50) for phostoxin and DD Force were 0.631 and 1.759 mg/l, respectively. The results obtained from the bioassay showed that phostoxin was 2.8* more toxic than DD Force after exposure of C. gariepinus. Joint action toxicity evaluations of phostoxin and DD Force showed that the interaction between the chemicals was synergistic (RTU >1). The biochemical responses in the exposed fish differed significantly (P < 0.05) from the control fish. The result of acetylcholinesterase study revealed significant difference between acetylcholinesterase levels in the exposed fish and control, with reduction in the acetylcholineterase level in fish exposed to sublethal concentrations of phostoxin and DD Force. Haematological studies revealed an increase in WBC, RBC, PCV and platelets in the exposed fish. Histopathology of the gills showed shortened primary lamellae, loss of secondary lamellae and loss of ceratobrachial bones. In the acute toxicity studies, respiratory stress, erratic swimming and instant death of fish were observed in the exposed fish. This study reveals that changes in histopathology and acetylcholinesterase level are good biomarkers and can be successfully used to detect exposure to organophosphates pesticides in fish. PMID- 27121171 TI - Estimation of Discriminative Feature Subset Using Community Modularity. AB - Feature selection (FS) is an important preprocessing step in machine learning and data mining. In this paper, a new feature subset evaluation method is proposed by constructing a sample graph (SG) in different k-features and applying community modularity to select highly informative features as a group. However, these features may not be relevant as an individual. Furthermore, relevant in dependency rather than irrelevant redundancy among the selected features is effectively measured with the community modularity Q value of the sample graph in the k-features. An efficient FS method called k-features sample graph feature selection is presented. A key property of this approach is that the discriminative cues of a feature subset with the maximum relevant in-dependency among features can be accurately determined. This community modularity-based method is then verified with the theory of k-means cluster. Compared with other state-of-the-art methods, the proposed approach is more effective, as verified by the results of several experiments. PMID- 27121170 TI - Objective assessment of mastication predominance in healthy dentate subjects and patients with unilateral posterior missing teeth. AB - We aimed to investigate mastication predominance in healthy dentate individuals and patients with unilateral posterior missing teeth using objective and subjective methods. The sample comprised 50 healthy dentate individuals (healthy dentate group) and 30 patients with unilateral posterior missing teeth (partially edentulous group). Subjects were asked to freely chew three kinds of test foods (peanuts, beef jerky and chewing gum). Electromyographic activity of the bilateral masseter muscles was recorded. The chewing side (right side or left side) was judged by the level of root mean square electromyographic amplitude. Mastication predominance was then objectively assessed using the mastication predominant score and the mastication predominant index. Self-awareness of mastication predominance was evaluated using a modified visual analogue scale. Mastication predominance scores of the healthy dentate and partially edentulous groups for each test food were analysed. There was a significant difference in the distribution of the mastication predominant index between the two groups (P < 0.05). The mastication predominant score was weakly correlated with self awareness of mastication predominance in the healthy dentate group, whereas strong correlation was observed in the partially edentulous group (P < 0.05). The results suggest that the individuals with missing unilateral posterior teeth exhibited greater mastication predominance and were more aware of mastication predominance than healthy dentate individuals. Our findings suggest that an objective evaluation of mastication predominance is more precise than a subjective method. PMID- 27121172 TI - Auxin-mediated lamina growth in tomato leaves is restricted by two parallel mechanisms. AB - In the development of tomato compound leaves, local auxin maxima points, separated by the expression of the Aux/IAA protein SlIAA9/ENTIRE (E), direct the formation of discrete leaflets along the leaf margin. The local auxin maxima promote leaflet initiation, while E acts between leaflets to inhibit auxin response and lamina growth, enabling leaflet separation. Here, we show that a group of auxin response factors (ARFs), which are targeted by miR160, antagonizes auxin response and lamina growth in conjunction with E. In wild-type leaf primordia, the miR160-targeted ARFs SlARF10A and SlARF17 are expressed in leaflets, and SlmiR160 is expressed in provascular tissues. Leaf overexpression of the miR160-targeted ARFs SlARF10A, SlARF10B or SlARF17, led to reduced lamina and increased leaf complexity, and suppressed auxin response in young leaves. In agreement, leaf overexpression of miR160 resulted in simplified leaves due to ectopic lamina growth between leaflets, reminiscent of e leaves. Genetic interactions suggest that E and miR160-targeted ARFs act partially redundantly but are both required for local inhibition of lamina growth between initiating leaflets. These results show that different types of auxin signal antagonists act cooperatively to ensure leaflet separation in tomato leaf margins. PMID- 27121174 TI - Effect of indoleamine 2,3-dioxygenase expressed by foetal fibroblasts on melanoma cells. PMID- 27121176 TI - A randomized side-by-side study comparing alexandrite laser at different pulse durations for port wine stains. AB - BACKGROUND AND OBJECTIVES: Pulsed dye laser (PDL) represents the gold-standard treatment for port wine stains (PWS). However, approximately 20% of patients are poor responders and yield unsatisfactory end-results. The Alexandrite (Alex) laser may be a therapeutic alternative for selected PWS subgroups, but optimal laser parameters are not known. The aim of this study was to assess clinical PWS clearance and safety of Alex laser at a range of pulse durations. MATERIALS AND METHODS: Sixteen individuals (14 previously PDL-treated) with deep red (n = 4), purple macular (n = 5) and purple hypertrophic (n = 7) PWS were included. Four side-by-side test areas were marked within each lesion. Three test areas were randomized to Alex laser at pulse durations of 3, 5, or 10 ms (8 mm spot, DCD 60/40), while the fourth was untreated. The lowest effective fluence to create purpura within the entire test spot was titrated and applied to intervention areas. Standardized clinical photographs were taken prior to, immediately after laser exposure and at 6-8 weeks follow up. Clinical PWS clearance and laser related side effects were assessed using clinical photos. RESULTS: Alex laser at 3, 5, and 10 ms pulse durations demonstrated significant clearance compared to untreated controls (P < 0.001). Three milli second pulse duration exhibited improved clearance versus 5 ms (P = 0.016) and 10 ms (P = 0.004), while no difference between five and 10 ms was shown (P = 0.063). Though not significant, good responders (>50% clearance) were more likely to have purple hypertrophic PWS (5/7) compared to purple macular (2/5) and deep red lesions (1/4). Eight laser exposed test areas (17%) developed hypopigmented atrophic scarring. Side effects tended to be more frequently observed with 5 ms (n = 4) and 10 ms (n = 3) versus 3 ms pulse duration (n = 1). Correspondingly, 3 ms was associated with a superior (n = 6) or comparable (n = 10) overall cosmetic appearance for all individuals. CONCLUSION: Alex laser at 3 ms pulse duration offers superior clinical clearance and safety compared to 5 and 10 ms, and seems best suited for purple hypertrophic PWS. Treatment should be restricted to experienced personnel due to a particularly narrow therapeutic window. Lasers Surg. Med. 49:97-103, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27121177 TI - pulSED: pulsed sonoelectrodeposition of fractal nanoplatinum for enhancing amperometric biosensor performance. AB - For the first time, we combine pulsed electrodeposition with out-of-phase pulsed sonication for controlled synthesis of fractal nanoplatinum structures as the transducer layer in electrochemical sensing. We develop and test this technique, called bimodal pulsed sonoelectrodeposition (pulSED), as a simple approach for creating highly conductive transducer nanometals for use in sensing and biosensing. We first compared the efficiency of pulSED nanoplatinum to other pulsed electrodeposition techniques, and then explored the effect of duty cycle and plating time on electroactive surface area and nanoparticle size/morphology. The developed pulSED nanoplatinum displayed fractal features with a relatively homogenous size distribution (26.31 +/- 1.3 nm) and extremely high electroactive surface (0.28 +/- 0.04 cm(2)) relative to other electroplating techniques (up to one order of magnitude higher). A high duty cycle (900 mHz) promotes formation of stable nanostructures (including fractal nanostructures) and reduces amorphous structure formation due to bubble cavitation and enhanced mass transport of metal ions to the electrode surface. To demonstrate the applicability of the pulSED technique, non-enzymatic and enzymatic sensors were developed for measuring hydrogen peroxide and glucose. The sensitivity for non-enzymatic peroxide sensing (3335 +/- 305 MUA cm(-2) mM(-1)), non-enzymatic glucose sensing (73 +/- 14 MUA cm(-2) mM(-1)) and enzymatic glucose biosensing (155 +/- 25 MUA cm(-2) mM(-1)) was higher than, or similar to, other nanomaterial-mediated amperometric sensors reported in the literature. The pulSED technique is a one pot method for tunable synthesis of nanometal structures as a transducer layer in electrochemical sensing and biosensing that requires no precursors or capping agents, and can be carried out at room temperature with inexpensive hardware. PMID- 27121178 TI - Descriptive review of tuberculosis surveillance systems across the circumpolar regions. AB - BACKGROUND: Tuberculosis is highly prevalent in many Arctic areas. Members of the International Circumpolar Surveillance Tuberculosis (ICS-TB) Working Group collaborate to increase knowledge about tuberculosis in Arctic regions. OBJECTIVE: To establish baseline knowledge of tuberculosis surveillance systems used by ICS-TB member jurisdictions. DESIGN: Three questionnaires were developed to reflect the different surveillance levels (local, regional and national); all 3 were forwarded to the official representative of each of the 15 ICS-TB member jurisdictions in 2013. Respondents self-identified the level of surveillance conducted in their region and completed the applicable questionnaire. Information collected included surveillance system objectives, case definitions, data collection methodology, storage and dissemination. RESULTS: Thirteen ICS-TB jurisdictions [Canada (Labrador, Northwest Territories, Nunavik, Nunavut, Yukon), Finland, Greenland, Norway, Sweden, Russian Federation (Arkhangelsk, Khanty Mansiysk Autonomous Okrug, Yakutia (Sakha Republic), United States (Alaska)] voluntarily completed the survey - representing 2 local, 7 regional and 4 national levels. Tuberculosis reporting is mandatory in all jurisdictions, and case definitions are comparable across regions. The common objectives across systems are to detect outbreaks, and inform the evaluation/planning of public health programmes and policies. All jurisdictions collect data on confirmed active tuberculosis cases and treatment outcomes; 11 collect contact tracing results. Faxing of standardized case reporting forms is the most common reporting method. Similar core data elements are collected; 8 regions report genotyping results. Data are stored using customized programmes (n=7) and commercial software (n=6). Nine jurisdictions provide monthly, bi-annual or annual reports to principally government and/or scientific/medical audiences. CONCLUSION: This review successfully establishes baseline knowledge on similarities and differences among circumpolar tuberculosis surveillance systems. The similarity in case definitions will allow for description of the epidemiology of TB based on surveillance data in circumpolar regions, further study of tuberculosis trends across regions, and recommendation of best practices to improve surveillance activities. PMID- 27121179 TI - Etiquette for medical students' email communication with faculty members: a single-institution study. AB - BACKGROUND: Email is widely used as a means of communication between faculty members and students in medical education because of its practical and educational advantages. However, because of the distinctive nature of medical education, students' inappropriate email etiquette may adversely affect their learning as well as faculty members' perception of them. Little data on medical students' competency in professional email writing is available; therefore, this study explored the strengths and weaknesses of medical students' email etiquette and factors that contribute to professional email writing. METHODS: A total of 210 emails from four faculty members at Seoul National University College of Medicine were collected. An evaluation criteria and a scoring rubric were developed based on the various email-writing guidelines. The rubric comprised 10 items, including nine items for evaluation related to the email components and one item for the assessment of global impression of politeness. Three evaluators independently assessed all emails according to the criteria. RESULTS: Students were identified as being 61.0% male and 52.8% were in the undergraduate-entry program. The sum of each component score was 62.21 out of 100 and the mean value for global impression was 2.6 out of 4. The results demonstrated that students' email etiquettes remained low-to-mediocre for most criteria, except for readability and honorifics. Three criteria, salutation (r=0.668), closing (r=0.653), and sign-off (r=0.646), showed a strong positive correlation with the global impression of politeness. Whether a student entered a graduate-entry program or an undergraduate-entry program significantly contributed to professional email writing after other variables were controlled. CONCLUSIONS: Although students in the graduate-entry program demonstrated a relatively superior level of email etiquette, the majority of medical students did not write emails professionally. Educating all medical students in email etiquette may well contribute to the improvement of student-faculty relationships as well as their email writing. PMID- 27121180 TI - Antioxidant properties of formula derived Maillard reaction products in colons of intrauterine growth restricted pigs. AB - OBJECTIVE: the present study has been conducted to evaluate the impact of the consumption of high MRP formula on changes in the microbiota and the oxidative status, during development, in the colons of intrauterine growth restricted (IUGR) juvenile pigs. METHODS: over a 3-week period, fifteen-day old piglets received formula with two different heat treatments. A formula heated at high temperature (HHF, n = 8) and another one heated at a low temperature (LHF, n = 8). After weaning, animals were fed, ad libitum, a solid diet until postnatal day 54 (PND54). The diversity and composition of the major microbiota were analyzed by CE SSCP and qPCR at postnatal day 36 (PND36) and PND54. Protein oxidation levels, glutathione peroxidase (GPX) activity, catalase (CAT), manganese dependent superoxide dismutase (Mn SOD), NFkappaB and inducible nitric oxide synthase (iNOS) gene expression were measured in the colon at the juvenile stage (PND54). RESULTS: HHF resulted in a significant decrease in bacterial diversity in the colon at PND36. An increase in the total count of Bifidobacteria, Lactobacillus, Bacteroidetes and Enterobacteria, without major changes in total microbiota was evidenced by qPCR, suggesting qualitative changes in the bacterial population of the HHF group. The imbalance of microbiota observed at PND36 was significantly modified at PND54, when animals received a solid diet. Colon GPX activity (p < 0.05) and gene expression of CAT and iNOS were significantly (p < 0.05) upregulated in the HHF group. No differences in the total protein oxidation and carbonyl score were found in the HHF group. Colon redox enzyme gene expression and pro-inflammatory factor NFkappaB negatively correlated (p < 0.05) with the bacterial population, suggesting the involvement of certain phyla in controlling the oxidative status of the IUGR piglets, fed on the high AGE formula. CONCLUSION: during development, consuming a high load MRP formula was associated with a major modification in the diversity and composition of the microbiota. The onset of an IUGR adaptive oxidant defense mechanism was found to counteract the oxidative stress induced by the presence of MRPs in formula. PMID- 27121181 TI - Can the parasitoid Necremnus tutae (Hymenoptera: Eulophidae) improve existing biological control of the tomato leafminer Tuta aboluta (Lepidoptera: Gelechiidae)? AB - Necremnus tutae is native to the Mediterranean region where it has been observed in greenhouses parasitizing the invasive Tuta absoluta on tomato. The objective of the present study was to determine whether augmentative releases of N. tutae can improve existing biological control of T. absoluta based on predation by Nesidicoris tenuis. Two experiments were carried out, of which the first evaluated different N. tutae release rates (1 and 2 N. tutae m-2 week-1). The parasitoid reduced plant and fruit damage, especially at the higher rate. However, such reduction was considered insufficient given the large numbers of parasitoids needed and still unacceptable level of fruit damage. The second experiment focused on combining the most efficient rate of N. tutae of those evaluated during the first experiment, with the pre- and post-planting release of N. tenuis and supplemental additions of Ephestia kuehniella eggs. Addition of N. tutae decreased leaf damage by T. absoluta regardless the release method for N. tenuis, but the pre-plant release of N. tenuis alone was sufficient to prevent fruit damage by T. absoluta. This suggested that the addition of N. tutae may not be necessary to obtain satisfactory control of T. absoluta following pre-plant application of N. tenuis, although different options for using N. tutae in commercial crops may still be possible. PMID- 27121182 TI - Effects of Carbon Allotrope Interface on the Photoactivity of Rutile One Dimensional (1D) TiO2 Coated with Anatase TiO2 and Sensitized with CdS Nanocrystals. AB - The assembly of a large-bandgap one-dimensional (1D) oxide-conductive carbon chalcogenide nanocomposite and its surface, optical, and photoelectrochemical properties are presented. Microscopy, surface analysis, and optical spectroscopy results are reported to provide insights into the assembly of the nanostructure. We have investigated (i) how the various carbon allotropes (C60), reduced graphene oxide (RGO), carbon nanotubes (CNTs), and graphene quantum dots (GQDs) can be integrated at the interface of the 1D TiO2 and zero-dimensional (0D) CdS nanocrystals; (ii) the carbon allotrope and CdS loading effects; (iii) the impact of the carbon allotrope presence on 0D CdS nanocrystals; and (iv) how they promote light absorbance. Subsequently, the functioning of the integrated nanostructured assembly in a photoelectrochemical cell has been systematically investigated. These studies include (i) chronoamperometry, (ii) impedance measurements or EIS, and (iii) linear sweep voltammetry. The results indicate that the presence of a GQD interface shows the most enhancement in the photoelectrochemical properties. The optimized photocurrent values were respectively noted to be 2.8, 2.2, 1.9, and 1.6 mA/cm(2), indicating JGQD > JRGO > JCNT > Jfullerene. Furthermore, the annealing conditions have indicated that ammonia treatment leads to an increase in the photoelectrochemical responses when using any form of the carbon allotropes. PMID- 27121183 TI - Incidence and outcome of cardiac injury in patients with severe head trauma. AB - BACKGROUND: Although cardiac injury has been reported in patients with various neurological conditions, few data report cardiac injury in patients with traumatic brain injury (TBI). The aim of this work is to report the incidence of cardiac injury in patients with TBI and its impact on patient outcome. METHODS: A prospective observational study was conducted on a cohort of 50 patients with severe TBI. Only patients with isolated severe TBI defined as Glascow coma scale (GCS) < 8 were included in the study. Acute physiology and chronic health evaluation (APACHE) II score, GCS, hemodynamic data, serum Troponin I, electrocardiogram (ECG), and echocardiographic examination, and patients' outcome were recorded. A neurogenic cardiac injury score (NCIS) was calculated for all patients (rising troponin = 1, abnormal echocardiography = 1, hypotension = 1). Univariate and multivariate analyses for risk factors for mortality were done for all risk factors. RESULTS AND DISCUSSION: Fifty patients were included; age was 31 +/- 12, APACHE II was 21 +/- 5, and male patients were 45 (90 %). Troponin I was elevated in 27 (54 %) patients, abnormal echocardiography and hypotension were documented in 14 (28 %) and 16 (32 %) patients, respectively. The in hospital mortality was 36 %. Risk factors for mortality by univariate analysis were age, GCS, APACHE II score, serum troponin level, NCIS, and hypotension. However, in multivariate analysis, the only two independent risk factors for mortality were APACHE II score (OR = 1.25, 95 % confidence interval: 1.02-1.54, P = 0.03) and NCIS score (OR = 8.38, 95 % confidence interval: 1.44-48.74, P = 0.018). CONCLUSIONS: Cardiac injury is common in patients with TBI and is associated with increased mortality. The association of high NCIS and poor outcome in these patients warrants a further larger study. PMID- 27121184 TI - Identification and functional analysis of the HvD14 gene involved in strigolactone signaling in Hordeum vulgare. AB - In this study, the barley HvD14 gene encoding alpha/beta hydrolase, which is involved in strigolactone (SL) signaling, was identified. Bioinformatics analysis revealed that the identified gene is an orthologue of the D14, AtD14 and PhDAD2 genes that have been described in rice, Arabidopsis thaliana and petunia, respectively. Using TILLING strategy, an hvd14.d mutant that carried the G725A transition, located in the second exon, was identified. This mutation led to the substitution of a highly conserved glycine-193 to glutamic acid in the conserved fragment of the alpha/beta hydrolase domain of the HvD14 protein. The plants that carry the hvd14.d allele were semi-dwarf and produced a higher number of tillers in comparison to the wild-type (WT) parent cultivar. Additionally, the root architecture of mutant plants was affected: the total length of the seminal roots was significantly reduced, and the density of the lateral roots was higher than in the WT. Plants with the hvd14.d allele were insensitive to treatment with GR24, which is the synthetic analogue of SL. Analysis of the indole-3-acetic acid (IAA) concentration in the lateral buds showed no differences between the WT and mutant plants. By contrast, the WT seedlings treated with GR24 developed a lower number of tillers, longer primary roots with a reduced number of lateral roots and had an increased concentration of IAA in lateral buds. This paper describes the first barley SL mutant and shows the potential functions of SLs in barley growth and development. PMID- 27121186 TI - New Therapeutic Applications of Phosphodiesterase 5 Inhibitors (PDE5-Is). AB - BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). In addition to this, sildenafil and tadalafil, have also been approved for the treatment of pulmonary arterial hypertension. Due to its expression and localization in many tissues, PDE5 and its regulation has been reported to be involved in several other diseases. OBJECTIVE: We aim to provide an updated overview of the emerging therapeutic applications of PDE5-Is besides ED, taking into account the latest ongoing research reports. METHODS: We searched online databases (Pubmed, Reaxys, Scopus) to lay the bases for an accurate, quality criteria-based literature update. We focused our attention on most recent research reports, in particular when supported by pre-clinical and clinical data. RESULTS: The regulation of PDE5 may influence pathological conditions such as, among the others, heart failure, cystic fibrosis, cancer, CNS-related diseases, diabetes and dysfunctions affecting male urinary/reproductive system. CONCLUSION: Sildenafil, vardenafil, tadalafil and the other chemical entities considered PDE5-Is showed overall positive results and significant improvements in the studied disease, thus some discordant results, in particular when comparing pre-clinical and clinical data, have to be pointed out, suggesting that further insights are needed especially to assess the exact molecular pathway underlying. PMID- 27121185 TI - Affect school and script analysis versus basic body awareness therapy in the treatment of psychological symptoms in patients with diabetes and high HbA1c concentrations: two study protocols for two randomized controlled trials. AB - BACKGROUND: Depression is linked with alexithymia, anxiety, high HbA1c concentrations, disturbances of cortisol secretion, increased prevalence of diabetes complications and all-cause mortality. The psycho-educational method 'affect school with script analysis' and the mind-body therapy 'basic body awareness treatment' will be trialled in patients with diabetes, high HbA1c concentrations and psychological symptoms. The primary outcome measure is change in symptoms of depression. Secondary outcome measures are changes in HbA1c concentrations, midnight salivary cortisol concentration, symptoms of alexithymia, anxiety, self-image measures, use of antidepressants, incidence of diabetes complications and mortality. METHODS: Two studies will be performed. Study I is an open-labeled parallel-group study with a two-arm randomized controlled trial design. Patients are randomized to either affect school with script analysis or to basic body awareness treatment. According to power calculations, 64 persons are required in each intervention arm at the last follow up session. Patients with type 1 or type 2 diabetes were recruited from one hospital diabetes outpatient clinic in 2009. The trial will be completed in 2016. Study II is a multicentre open-labeled parallel-group three-arm randomized controlled trial. Patients will be randomized to affect school with script analysis, to basic body awareness treatment, or to treatment as usual. Power calculations show that 70 persons are required in each arm at the last follow-up session. Patients with type 2 diabetes will be recruited from primary care. This study will start in 2016 and finish in 2023. For both studies, the inclusion criteria are: HbA1c concentration >=62.5 mmol/mol; depression, alexithymia, anxiety or a negative self-image; age 18-59 years; and diabetes duration >=1 year. The exclusion criteria are pregnancy, severe comorbidities, cognitive deficiencies or inadequate Swedish. Depression, anxiety, alexithymia and self image are assessed using self-report instruments. HbA1c concentration, midnight salivary cortisol concentration, blood pressure, serum lipid concentrations and anthropometrics are measured. Data are collected from computerized medical records and the Swedish national diabetes and causes of death registers. DISCUSSION: Whether the "affect school with script analysis" will reduce psychological symptoms, increase emotional awareness and improve diabetes related factors will be tried, and compared to "basic body awareness treatment" and treatment as usual. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01714986. PMID- 27121187 TI - The Importance of Melatonin and Mitochondria Interaction in Mood Disorders and Schizophrenia: A Current Assessment. AB - Mitochondria play a critical role in regulating cellular functions, such as redox signaling, calcium homeostasis, and apoptosis. Also, mitochondria are crucial for neurogenesis and neuronal functions. Melatonin is an indole analog hormone, which is generally produced by the pineal gland. It plays a vital role in circadian rhythm and act as a powerful antioxidant by scavenging free radicals, immunomodulators, and anticancer agents. Schizophrenia and mood disorders are the two major psychiatric disorders. Disturbances of sleep and circadian rhythms are well-known symptoms of schizophrenia and mood disorders (bipolar disorder, major depression). Since melatonin has a regulator effect on circadian rhythm and sleep quality, it has a close interaction with schizophrenia and mood disorders. Herein, we aimed to summarize the effects of melatonin on mitochondrial activity in schizophrenia and mood disorders. PMID- 27121188 TI - Current Progresses and Trends in the Development of Progesterone Receptor Modulators. AB - The progesterone receptor (PR) is a ligand-activated steroid receptor in the nuclear receptor (NR) superfamily of transcription factor. Besides gynecological and obstetrical indications, the involvement/mechanism of PR in many other diseases, such as oncology, neurology, immunology, etc. has been revealed and studied in recent decades. Therapeutic agents that selectively activate or inhibit PR have been developed. PR agonists have generally been used in oral contraception and postmenopausal hormone replacement therapy (HRT), typically in combination with estrogens. PR antagonists and selective PR modulators (SPRMs) can be useful therapies for hormone dependent breast and prostate cancers, nonmalignant chronic conditions such as fibroids, and endometriosis. This review provides an overview and detailed discussions about the recent development of chemical structures of the PR ligands, their structural characteristics (particularly those contributing to their activity and selectivity), in vitro/in vivo studies and clinical trial outcomes, and the synthetic methodologies. PMID- 27121189 TI - Impact of Macrophages in Atherosclerosis. AB - Atherosclerosis is driven by inflammation, with a strong involvement of innate immunity, and involves an expansion of the arterial intima, a normally small area composed of several cell types including smooth muscle cells, lipids, monocytes, macrophages, dendritic cells, and extracellular matrix. Macrophages derived from recruited monocytes are predominant innate immune cells that play crucial roles in the formation of atherosclerotic lesions. Human atherosclerotic plaques have shown that macrophage subsets within a plaque might be more useful for explaining plaque phenotype than just simply giving the total number of macrophages. Therefore, recognizing the roles of macrophage subsets in atherosclerotic plaque formation, progression, and regression would be most helpful for identification of novel strategies to stabilize, or attenuate atherosclerotic lesions. This review discusses the impact of macrophage subsets and their roles in atherosclerosis. PMID- 27121190 TI - Juvenile idiopathic arthritis-associated uveitis. AB - Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management. PMID- 27121191 TI - Cancer stem cells are underestimated by standard experimental methods in clear cell renal cell carcinoma. AB - Rare cancer stem cells (CSC) are proposed to be responsible for tumour propagation and re-initiation and are functionally defined by identifying tumour initiating cells (TICs) using the xenotransplantation limiting dilution assay (LDA). While TICs in clear cell renal cell carcinoma (ccRCC) appeared rare in NOD/SCID/IL2Rgamma(-/-) (NSG) mice, xenografts formed more efficiently from small tumour fragments, indicating the LDA underestimated ccRCC TIC frequency. Mechanistic interrogation of the LDA identified multiple steps that influence ccRCC TIC quantitation. For example, tissue disaggregation destroys most ccRCC cells, common assays significantly overestimate tumour cell viability, and microenvironmental supplementation with human extracellular factors or pharmacological inhibition of anoikis increase clonogenicity and tumourigenicity of ccRCC cell lines and primary tumour cells. Identification of these previously uncharacterized concerns that cumulatively lead to substantial underestimation of TICs in ccRCC provides a framework for development of more accurate TIC assays in the future, both for this disease and for other cancers. PMID- 27121192 TI - Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt. AB - Cancer metabolism is characterized by an accelerated glycolytic rate facing reduced activity of oxidative phosphorylation. This "Warburg effect" represents a standard to diagnose and monitor tumor aggressiveness with (18)F fluorodeoxyglucose whose uptake is currently regarded as an accurate index of total glucose consumption. Studying cancer metabolic response to respiratory chain inhibition by metformin, we repeatedly observed a reduction of tracer uptake facing a marked increase in glucose consumption. This puzzling discordance brought us to discover that (18)F-fluorodeoxyglucose preferentially accumulates within endoplasmic reticulum by exploiting the catalytic function of hexose-6 phosphate-dehydrogenase. Silencing enzyme expression and activity decreased both tracer uptake and glucose consumption, caused severe energy depletion and decreased NADPH content without altering mitochondrial function. These data document the existence of an unknown glucose metabolism triggered by hexose-6 phosphate-dehydrogenase within endoplasmic reticulum of cancer cells. Besides its basic relevance, this finding can improve clinical cancer diagnosis and might represent potential target for therapy. PMID- 27121194 TI - Comprehensive evaluation and validation of targeted next-generation sequencing performance in two clinical laboratories. AB - Next-generation sequencing (NGS) has led to breakthroughs for genetic and genomic analyses and personalized medicine approaches for many diseases. More and more clinical laboratories are using NGS as a genetic screening tool for providing mutation information that is used to select the best treatment regimens for cancer patients. However, several obstacles prevent the routine implementation of NGS technology into the clinical molecular diagnosis setting: the sophisticated sample preparation process, high cost, time-consuming data analyses, as well as the reproducibility and accuracy of interpretation. To systematically evaluate the performance and quality of targeted NGS cancer panel analyses in clinical laboratories, we performed three different tests: i) laboratory-to-laboratory accuracy test, ii) intra-laboratory precision validation, and iii) limit of detection test, using formalin-fixed, paraffin-embedded cancer tissue specimens, cell lines and mutation positive DNA. A laboratory-to-laboratory accuracy test performed using 51 samples showed 100% sensitivity and 99.97% specificity. For the intra-laboratory precision test, 100% reproducibility was observed. For the limit of detection test, KRAS mutations from samples diluted from 70 to 2% of mutant allele frequencies were detected correctly. We believe that the present study demonstrated the feasibility of clinical implementation of a targeted NGS cancer panel analysis for personalized medicine. PMID- 27121193 TI - Tolerance of citrus plants to the combination of high temperatures and drought is associated to the increase in transpiration modulated by a reduction in abscisic acid levels. AB - BACKGROUND: In natural environments, several adverse environmental conditions occur simultaneously constituting a unique stress factor. In this work, physiological parameters and the hormonal regulation of Carrizo citrange and Cleopatra mandarin, two citrus genotypes, in response to the combined action of high temperatures and water deprivation were studied. The objective was to characterize particular responses to the stress combination. RESULTS: Experiments indicated that Carrizo citrange is more tolerant to the stress combination than Cleopatra mandarin. Furthermore, an experimental design spanning 24 h stress duration, heat stress applied alone induced higher stomatal conductance and transpiration in both genotypes whereas combined water deprivation partially counteracted this response. Comparing both genotypes, Carrizo citrange showed higher phostosystem-II efficiency and lower oxidative damage than Cleopatra mandarin. Hormonal profiling in leaves revealed that salicylic acid (SA) accumulated in response to individual stresses but to a higher extent in samples subjected to the combination of heat and drought (showing an additive response). SA accumulation correlated with the up-regulation of pathogenesis-related gene 2 (CsPR2), as a downstream response. On the contrary, abscisic acid (ABA) accumulation was higher in water-stressed plants followed by that observed in plants under stress combination. ABA signaling in these plants was confirmed by the expression of responsive to ABA-related gene 18 (CsRAB18). Modulation of ABA levels was likely carried out by the induction of 9-neoxanthin cis epoxicarotenoid dioxygenase (CsNCED) and ABA 8'-hydroxylase (CsCYP707A) while conversion to ABA-glycosyl ester (ABAGE) was a less prominent process despite the strong induction of ABA O-glycosyl transferase (CsAOG). CONCLUSIONS: Cleopatra mandarin is more susceptible to the combination of high temperatures and water deprivation than Carrizo citrange. This is likely a result of a higher transpiration rate in Carrizo that could allow a more efficient cooling of leaf surface ensuring optimal CO2 intake. Hence, SA induction in Cleopatra was not sufficient to protect PSII from photoinhibition, resulting in higher malondialdehyde (MDA) build-up. Inhibition of ABA accumulation during heat stress and combined stresses was achieved primarily through the up-regulation of CsCYP707A leading to phaseic acid (PA) and dehydrophaseic acid (DPA) production. To sum up, data indicate that specific physiological responses to the combination of heat and drought exist in citrus. In addition, these responses are differently modulated depending on the particular stress tolerance of citrus genotypes. PMID- 27121195 TI - Outcome of penile prosthesis implantation: are malleable prostheses an appropriate treatment option in patients with erectile dysfunction caused by prior radical surgery? AB - The aim of our study was to evaluate the outcome of penile prosthesis implantation in patients with various comorbidities as a cause of erectile dysfunction (ED). The data of 181 patients who underwent surgery between 1998 and 2012 in two centers were evaluated. The mean age of the patients was 52.2 years (range: 31-71 years). The study group contained 162 patients (89.5%) with malleable prostheses and 19 (10.5%) with inflatable implants. All patients were re-evaluated 1 month later to assess prosthesis function and complications, and further re-examinations were performed if needed. Satisfaction was defined as having satisfactory intercourse and happiness with the device in general. The follow-up period was at least 12 months for each patient. The postoperative complication rate was 32% (n = 58). The number of complications with inflatable and malleable prostheses was 7 (3.9%) and 51 (28.1%), respectively. Overall, 21 prostheses (11.6%) had to be removed because of various complications and patient dissatisfaction. Patients with prior radical surgery had higher extraction rates (lambda = 14.606, P < 0.05, Chi-square test). The main reasons for removal were erosion (n = 11; 6.1%) and infection (n = 3; 2.1%). With respect to satisfaction during intercourse, we found that 104 (57.5%) patients described themselves as very satisfied with the prosthesis, while 21 (11.6%) were unsatisfied. The high explantation rate in patients with prior surgery was remarkable in our study. Our results revealed that a malleable prosthesis should not be the preferred type of implant for patients with prior surgery. PMID- 27121196 TI - Heterogeneous malaria transmission in long-term Afghan refugee populations: a cross-sectional study in five refugee camps in northern Pakistan. AB - BACKGROUND: Afghan refugees in northern Pakistan have been resident for over 30 years and current information on malaria in this population is sparse. Understanding malaria risk and distribution in refugee camps is important for effective management both in camps and on return to Afghanistan. METHODS: Cross sectional malariometric surveys were conducted in five Afghan refugee camps to determine infection and exposure to both Plasmodium falciparum and Plasmodium vivax. Factors associated with malaria infection and exposure were analysed using logistic regression, and spatial heterogeneity within camps was investigated with SatScan. RESULTS: In this low-transmission setting, prevalence of infection in the five camps ranged from 0-0.2 to 0.4-9 % by rapid diagnostic test and 0-1.39 and 5-15 % by polymerase chain reaction for P. falciparum and P. vivax, respectively. Prevalence of anti-malarial antibodies to P. falciparum antigens was 3-11 and 17-45 % for P. vivax antigens. Significant foci of P. vivax infection and exposure were detected in three of the five camps. Hotspots of P. falciparum were also detected in three camps, only one of which also showed evidence of P. vivax hotspots. CONCLUSIONS: There is low and spatially heterogeneous malaria transmission in the refugee camps in northern Pakistan. Understanding malaria risk in refugee camps is important so the malaria risk faced by these populations in the camps and upon their return to Afghanistan can be effectively managed. PMID- 27121198 TI - Biomarkers of exposure, effect, and susceptibility in workers exposed to chloronitrobenzenes. AB - Biomonitoring methods were applied to workers exposed to high levels of chloronitrobenzenes. The external dose, internal dose, biologically effective dose, and biological effects were determined. Individual susceptibility was assessed by analyzing genetic polymorphisms of glutathione S-transferases M1, P1 and T1, and N-acetyltransferases 1 and 2. When the markers of exposure and susceptibility were compared with the frequency of chromosomal aberrations, clinical blood and urine parameters, and health effects typical of chloronitrobenzenes exposure, only a few of the comparisons were statistically significant. A statistically significantly higher frequency of chromosomal aberrations was detected in workers with a high level of hemoglobin-adducts. PMID- 27121197 TI - Point-of-sale cigarette marketing and smoking-induced deprivation in smokers: results from a population-based survey. AB - BACKGROUND: Strict restrictions on outdoor cigarette marketing have resulted in increasing concentration of cigarette marketing at the point-of-sale (POS). The association between POS cigarette marketing and smoking-induced deprivation (SID) has never been studied. The aim of this study was to examine this association and how it is mediated by cravings to smoke, urges to buy cigarettes, and unplanned purchases of cigarettes. METHODS: Data from a telephone survey of 939 smokers were collected in Omaha, Nebraska. POS cigarette marketing was measured by asking respondents three questions about noticing pack displays, advertisements, and promotions such as cigarette price discounts within their respective neighborhoods. SID was measured with the following question: "In the last six months, has there been a time when the money you spent on cigarettes resulted in not having enough money for household essentials such as food? [yes/no]" We used structural equation modeling to examine the study aim. RESULTS: There was overwhelming evidence for an association between higher levels of POS cigarette marketing and a higher probability of SID (p < 0.001). This association was partly mediated by cravings to smoke, urges to buy cigarettes, and unplanned purchases of cigarettes during a visit to a neighborhood store (p < 0.001). CONCLUSION: Given that POS cigarette marketing is associated with a higher probability of experiencing SID, policies that ban POS cigarette marketing might help some smokers afford essentials household items such as food more easily and thus have better standards of living. PMID- 27121199 TI - A novel maneuver to facilitate retrograde wire externalization during retrograde chronic total occlusion percutaneous coronary intervention. AB - BACKGROUND: Although the retrograde approach has improved the success rate and procedural efficiency of chronic total occlusion (CTO) percutaneous coronary intervention (PCI), it can still be challenging and time-consuming. We introduce a novel technique that aims to facilitate the critical step of retrograde wire externalization during reverse controlled antegrade and retrograde tracking and dissection (CART), which we named DRAFT (Deflate, Retract and Advance into the Fenestration Technique). MATERIALS AND METHODS: DRAFT is performed by simultaneous retraction of the deflating antegrade balloon (after inflation in the subintimal space) and advancement of the retrograde looped wire in the same plane through the transient fenestrations created by reverse CART, in order to cross through the fenestrated dissection flap before its collapse. The retrograde wire is then quickly and easily advanced into the antegrade guiding catheter. RESULTS: DRAFT was used in 11 patients (8 with right coronary artery and 3 with left anterior descending artery CTOs). Several different guidewires were used, since this technique does not need any specific wire to be performed. DRAFT was successful in all cases, after at most five attempts. CTO PCI was then completed as per standard retrograde practice. No complications occurred. CONCLUSIONS: DRAFT is a versatile approach that allows easy and quick re-entry of the retrograde wire into the true lumen during reverse CART. It can be performed with a variety of guidewires and is feasible both in the left and right coronary arteries. (c) 2016 Wiley Periodicals, Inc. PMID- 27121200 TI - In-situ Liquid Phase Epitaxy: Another Strategy to Synthesize Heterostructured Core-shell Composites. AB - Core-shell Nb2O5/TiO2 composite with hierarchical heterostructure is successfully synthesized In-situ by a facile template-free and acid-free solvothermal method based on the mechanism of liquid phase epitaxy. The chemical circumstance change induced by the alcoholysis of NbCl5 is utilized tactically to trigger core-shell assembling In-situ. The tentative mechanism for the self-assembling of core-shell structure and hierarchical structure is explored. The microstructure and morphology changes during synthesis process are investigated systematically by using X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy and transmission electron microscopy. The dramatic alcoholysis of NbCl5 has been demonstrated to be the fundamental factor for the formation of the spherical core, which changes the acid circumstance of the solution and induces the co-precipitation of TiO2. The homogeneous co-existence of Nb2O5/TiO2 in the core and the co-existence of Nb/Ti ions in the reaction solution facilitate the In-situ nucleation and epitaxial growth of the crystalline shell with the same composition as the core. In-situ liquid phase epitaxy can offer a different strategy for the core-shell assembling for oxide materials. PMID- 27121201 TI - A Macrocyclic Fluorophore Dimer with Flexible Linkers: Bright Excimer Emission with a Long Fluorescence Lifetime. AB - Bright fluorescent molecules with long fluorescence lifetimes are important for the development of lifetime-based fluorescence imaging techniques. Herein, a molecular design is described for simultaneously attaining long fluorescence lifetime (tau) and high brightness (PhiF *E) in a system that features macrocyclic dimerization of fluorescent pi-conjugated skeletons with flexible linkers. An alkylene-linked macrocyclic dimer of bis(thienylethynyl)anthracene was found to show excimer emission with a long fluorescence lifetime (tau~19 ns) in solution, while maintaining high brightness. A comparison with various relevant derivatives revealed that the macrocyclic structure and the length of the alkylene chains play crucial roles in attaining these properties. In vitro time-gated imaging experiments were conducted as a proof-of-principle for the superiority of this macrocyclic fluorophore relative to the commercial fluorescent dye Alexa Fluor 488. PMID- 27121202 TI - Unravelling the effect of anchoring groups on the ground and excited state properties of pyrene using computational and spectroscopic methods. AB - Anchoring groups play an important role in dye sensitized solar cells (DSCs). In order to acquire a suitable anchoring group for DSCs, a deeper understanding of the effect of anchoring groups on the ground and excited state properties of the dye is significant. In this context, various anchoring group connected pyrene derivatives are successfully synthesized and well characterized by using (1)H, (13)C-NMR, FT-IR and EI-MS spectrometry. The anchoring groups employed are carboxylic acid, malonic acid, acrylic acid, malononitrile, cyanoacrylic acid, rhodanine and rhodanine-3-acetic acid. The optimized geometries, HOMO-LUMO energy gap, light harvesting efficiency (LHE) and electronic absorption spectra of these dyes are studied by using density functional theory (DFT) calculations. The results show that pyrene connected with anchoring groups with weak electron pulling strength (PC, PAC and PMC) has a larger HOMO-LUMO energy gap, whereas that connected with anchoring groups with strong electron pulling strength (PCC, PMN, PR and PRA) has a reduced HOMO-LUMO energy gap. These molecules with a reduced energy gap are primarily preferred for DSC applications. Moreover, P, PC, PAC and PMC molecules undergo pi->pi* transition, whereas PCC, PMN, PR and PRA molecules show significant charge transfer along with pi->pi* transition. UV visible absorption spectral studies on these dyes reveal that connecting various anchoring groups with different electron pulling abilities enables the pyrene chromophore to absorb in the longer wavelength region. Notably, an efficient bathochromic shift is observed for PCC, PMN, PR and PRA molecules in both electronic absorption and fluorescence spectral measurements, which suggests that the excitation is delocalized throughout the entire pi-system of the molecules. Both theoretical and spectral studies reveal that dyes with an ICT character (PCC, PMN, PR and PRA) are suitable for dye sensitized solar cell applications. PMID- 27121203 TI - Linking Subcellular Disturbance to Physiological Behavior and Toxicity Induced by Quantum Dots in Caenorhabditis elegans. AB - The wide-ranging applications of fluorescent semiconductor quantum dots (QDs) have triggered increasing concerns about their biosafety. Most QD-related toxicity studies focus on the subcellular processes in cultured cells or global physiological effects on whole animals. However, it is unclear how QDs affect subcellular processes in living organisms, or how the subcellular disturbance contributes to the overall toxicity. Here the behavior and toxicity of QDs of three different sizes in Caenorhabditis elegans (C. elegans) are systematically investigated at both the systemic and the subcellular level. Specifically, clear size-dependent distribution and toxicity of the QDs in the digestive tract are observed. Short-term exposure of QDs leads to acute toxicity on C. elegans, yet incurring no lasting, irreversible damage. In contrast, chronic exposure of QDs severely inhibits development and shortens lifespan. Subcellular analysis reveals that endocytosis and nutrition storage are disrupted by QDs, which likely accounts for the severe deterioration in growth and longevity. This work reveals that QDs invasion disrupts key subcellular processes in living organisms, and may cause permanent damage to the tissues and organs over long-term retention. The findings provide invaluable information for safety evaluations of QD-based applications and offer new opportunities for design of novel nontoxic nanoprobes. PMID- 27121204 TI - AURKA induces EMT by regulating histone modification through Wnt/beta-catenin and PI3K/Akt signaling pathway in gastric cancer. AB - Gastric cancer, a highly invasive and aggressive malignancy, is the third leading cause of death from cancer worldwide. Genetic association studies have successfully revealed several important genes consistently associated with gastric cancer to date. However, these robust gastric cancer-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. In the present study, we performed an alternative approach, a gene expression-based genome-wide association study (eGWAS) across 13 independent microarray experiments (including 251 gastric cancer cases and 428 controls), to identify top candidates (p<0.00001). Additionally, we conducted gene ontology analysis, pathway analysis and network analysis and identified aurora kinase A (AURKA) as our candidate. We observed that MLN8237, which is a specific inhibitor of AURKA, decreased the beta-catenin and the phosphorylation of Akt1 and GSK 3beta, as well as blocked the Akt and Wnt signaling pathways. Furthermore, MLN8237 arrested the cells in the G2/M phase. The activity of Wnt and Akt signaling pathways affected the level of histone methylation significantly, and we supposed that MLN8237 affected the level of histone methylation through these two signaling pathways. Additionally, the treatment of MLN8237 influenced the level of H3K4 me1/2/3 and H3K27 me1/2/3. Chip data on cell lines suggested that MLN8237 increases the level of H3K27 me3 on the promoter of Twist and inhibits EMT (epithelial-mesenchymal transition). In summary, AURKA is a potential therapeutic target in gastric cancer and induces EMT through histone methylation. PMID- 27121205 TI - In vitro functional characterization of prostaglandin-endoperoxide synthase 2 during chondrocyte hypertrophic differentiation. AB - Cyclooxygenase 2 (Cox-2) has been implicated an essential role during bone repair, but the mechanisms remain elusive. Bone repair healing is known to include processes similar to endochondral ossification. In this study, we investigated the in vitro effect of Cox-2 on Col10a1 expression and chondrocyte hypertrophy, two critical components of endochondral ossification. Using quantitative RT-PCR, we detected increased mRNA levels of Cox-2 and Col10a1 in hypertrophic MCT cells, while cells treated with Cox-2 inhibitor, NS398, showed decreased mRNA and protein levels of Cox-2 and Col10a1. Increased Cox-2 also correlated with significantly upregulated Col10a1 in hypertrophic ATDC5 cells, whereas inhibition of Cox-2 significantly decreased Col10a1 expression. We further generated a Cox-2-expressing ATDC5 stable cell line. Compared with the controls, Cox-2 over-expression significantly increased Col10a1 as early as day 7 of continuous culturing, but not at days 14 and 21. Enhanced Alp staining was also observed in day 7 stable cell line. Correspondingly, we detected significantly increased levels of Runx2, Alp, Bcl-2, Bax, Col1a1, Osterix, and Bsp in day 7 stable line. Most of these genes have been associated with chondrocyte maturation and apoptosis. Together, our results support that Cox-2 promotes Col10a1 expression and chondrocyte hypertrophy in vitro, possibly through upregulation of Runx2 and other relevant transcription factors. PMID- 27121206 TI - Efficacy of adjuvant chemotherapy for non-small cell lung cancer assessed by metastatic potential associated with ACTN4. AB - Although several clinical trials have demonstrated the benefits of platinum combined adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC), predictive biomarkers for the efficacy of such therapy have not yet been identified. Selection of patients with high metastatic ability in the early stage of non-small cell lung cancer (NSCLC) has the potential to predict clinical benefit of adjuvant chemotherapy (ADJ).In order to develop a predictive biomarker for efficacy of ADJ, we reanalyzed patient data using a public database enrolled by JBR.10, which was a clinical trial to probe the clinical benefits of ADJ in stage-IB/II patients with NSCLC. The patients who were enrolled by JBR.10 were classified into 2 subgroups according to expression of the ACTN4 transcript: ACTN4 positive (ACTN4 (+)) and ACTN4 negative (ACTN4 (-)). In the ACTN4 (+) group, overall survival (OS) was significantly higher in the ADJ subgroup compared with the observation subgroup (OBS), indicating a significant survival benefit of ADJ. However, no difference in OS was found between ADJ and OBS groups in ACTN4 (-). Although ACTN4 expression level did not correlate with the chemosensitivity of cancer cell lines for cytotoxic drugs, the metastatic potential of A549 lung adenocarcinoma cells was significantly reduced by ACTN4 shRNA in in vitro assays and in an animal transplantation model. The clinical and preclinical data suggested that ACTN4 is a potential predictive biomarker for efficacy of ADJ in stage-IB/II patients with NSCLC, by reflecting the metastatic potential of tumor cells. PMID- 27121207 TI - SSRI use and clinical outcomes in epithelial ovarian cancer. AB - Selective serotonin reuptake inhibitor (SSRI) use is common among ovarian cancer patients. We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. Cox proportional hazards models were used for multivariate analysis. SSRI use was associated with decreased time to disease recurrence (HR 1.3, CI 1.0-1.6, p=0.03), but not overall survival (HR 1.1, CI 0.9-1.3, p=0.56). Compared to normal ovarian cells, most OCCs had elevated 5-HT2A receptor mRNA expression (up to 1600 fold greater expression). Clonogenic survival increased in cells treated with 10 uM (1.6 fold, p<0.001) and 20uM (1.9 fold, p=0.018) 5-HT. Mice receiving 5-HT injections had increases in tumor weight (p=0.07) and nodules (p=0.08) with increased Ki67 expression. Injections with sertraline doubled mean tumor weight in mice (p=0.16). 5-HT and sertraline both increased Ki67 expression in mouse tumors (p < 0.001).Patients using SSRIs had significantly decreased time to disease progression. It is possible that SSRIs alter serotonin levels in the tumor microenvironment, resulting in activation of proliferation pathways. Further characterization of serotonergic pathways in ovarian cancer is recommended to demonstrate safety of these medications. PMID- 27121208 TI - Botulinum neurotoxin type C protease induces apoptosis in differentiated human neuroblastoma cells. AB - Neuroblastomas constitute a major cause of cancer-related deaths in young children. In recent years, a number of translation-inhibiting enzymes have been evaluated for killing neuroblastoma cells. Here we investigated the potential vulnerability of human neuroblastoma cells to protease activity derived from botulinum neurotoxin type C. We show that following retinoic acid treatment, human neuroblastoma cells, SiMa and SH-SY5Y, acquire a neuronal phenotype evidenced by axonal growth and expression of neuronal markers. Botulinum neurotoxin type C which cleaves neuron-specific SNAP25 and syntaxin1 caused apoptotic death only in differentiated neuroblastoma cells. Direct comparison of translation-inhibiting enzymes and the type C botulinum protease revealed one order higher cytotoxic potency of the latter suggesting a novel neuroblastoma targeting pathway. Our mechanistic insights revealed that loss of ubiquitous SNAP23 due to differentiation coupled to SNAP25 cleavage due to botulinum activity may underlie the apoptotic death of human neuroblastoma cells. PMID- 27121210 TI - MicroRNA-143 targets CD44 to inhibit breast cancer progression and stem cell-like properties. AB - CD44 is closely linked to breast cancer progression; however, the regulatory functions of microRNAs (miRs) in breast cancer have yet to be fully elucidated. In order to investigate the regulation of CD44 by miRs in breast cancer, the present study isolated CD44+ and CD44- breast cancer cells by flow cytometry, revealing that CD44+ cells were enriched in transplanted compared with those in primary breast cancers, and that their proliferation and stem-cell sphere formation ability were enhanced. A miRNA array assay indicated that miR-143 expression in CD44+ breast cancer cells was lower than that in CD44- cells. Furthermore, miR-143 was decreased in breast cancer tissues and cell lines compared with that in normal tissues and cells. Restoration of miR-143 expression in CD44+ breast cancer cells inhibited their proliferation and sphere formation. A luciferase reporter assay demonstrated that miR-143 directly tartgeted the 3' untranslated region of CD44. In addition, miR-143 inhibited metastasis-associated features in breast cancer and reduced tumor growth in a mouse model of breast cancer. In conclusion, the results of the present study demonstrated that miR-143 inhibited the progression and stem-cell properties of breast cancer cells by targeting CD44. PMID- 27121211 TI - Quentin Young. PMID- 27121209 TI - Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium). AB - BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Patients and methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P<0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders. Conclusions: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163). PMID- 27121212 TI - Low level off-road vehicle (ORV) traffic negatively impacts macroinvertebrate assemblages at sandy beaches in south-western Australia. AB - Off-road vehicle use is arguably one of the most environmentally damaging human activities undertaken on sandy beaches worldwide. Existing studies focused on areas of high traffic volumes have demonstrated significantly lower abundance, diversity and species richness of fauna in zones where traffic is concentrated. The impact of lower traffic volumes is unknown. This study aimed to investigate the impacts of relatively low-level vehicle traffic on sandy beach fauna by sampling invertebrate communities at eight beaches located in south-western Australia. We found that even low-level vehicle traffic negatively impacts the physical beach environment, and consequently, the ability of many species to survive in this habitat in the face of this disturbance. Compaction, rutting and displacement of the sand matrix were observed over a large area, resulting in significant decreases in species diversity and density, and measurable shifts in community structure on beaches that experienced off-road vehicle traffic. Communities at impact sites did not display seasonal recovery as traffic was not significantly different between seasons. Given a choice between either reducing traffic volumes, or excluding ORV traffic from beaches, our results suggest that the latter would be more appropriate when the retention of ecological integrity is the objective. PMID- 27121214 TI - Age-Adjusted Glycated Albumin at Diagnosis is more Correlated with the Product of Age and Plasma Glucose than Plasma Glucose Alone in Patients with Neonatal Diabetes Mellitus. AB - BACKGROUND: We previously showed that glycated albumin (GA) is a useful glycemic control indicator in patients with neonatal diabetes mellitus (NDM), and that age adjusted GA (Aa-GA) can reflect more accurately glycemic control status. Here, we investigated whether the age at diagnosis influences Aa-GA at diagnosis of NDM. METHODS: Eight patients with NDM whose GA was measured at diagnosis (age at diagnosis: 39 +/- 18 days; GA: 31.3 +/- 7.6%; Aa-GA: 47.1 +/- 10.3%; plasma glucose: 525 +/- 194 mg/dl) were included. Aa-GA was calculated as follows: Aa-GA = GA * 14.0/[1.77 * log-age (days) + 6.65]. Correlations of GA or Aa-GA at diagnosis with its logarithmically transformed age in days (log-age), plasma glucose, and their product were investigated. RESULTS: GA at diagnosis was not significantly correlated with log-age or plasma glucose. On the other hand, Aa-GA at diagnosis was significantly positively correlated with plasma glucose (R = 0.75, P = 0.031) and was more strongly positively correlated with the product of plasma glucose and log-age (R = 0.82, P = 0.012) although it was not correlated with log-age. CONCLUSION: Aa-GA at diagnosis is influenced by both age in days and plasma glucose. This finding is likely to show the aspect that age in days is almost equal to diabetes duration because glycemic control indicators including GA reflect the weighted mean of plasma glucose. PMID- 27121215 TI - Effectiveness and safety of recombinant human bone morphogenetic protein-2 for adults with lumbar spine pseudarthrosis following spinal fusion surgery: A systematic review. AB - OBJECTIVES: We performed a systematic review of the literature to determine the safety and efficacy of bone morphogenetic protein (BMP) compared with bone graft when used specifically for revision spinal fusion surgery secondary to pseudarthrosis. METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched using defined search terms. The primary outcome measure was spinal fusion, assessed as success or failure in accordance with radiograph, MRI or CT scan review at 24-month follow-up. The secondary outcome measure was time to fusion. RESULTS: A total of six studies (three prospective and three retrospective) reporting on the use of BMP2 met the inclusion criteria (203 patients). Of these, four provided a comparison of BMP2 and bone graft whereas the other two solely investigated the use of BMP2. The primary outcome was seen in 92.3% (108/117) of patients following surgery with BMP2. Although none of the studies showed superiority of BMP2 to bone graft for fusion, its use was associated with a statistically quicker time to achieving fusion. BMP2 did not appear to increase the risk of complication. CONCLUSION: The use of BMP2 is both safe and effective within the revision setting, ideally in cases where bone graft is unavailable or undesirable. Further research is required to define its optimum role.Cite this article: Mr P. Bodalia. Effectiveness and safety of recombinant human bone morphogenetic protein-2 for adults with lumbar spine pseudarthrosis following spinal fusion surgery: A systematic review. Bone Joint Res 2016;5:145 152. DOI: 10.1302/2046-3758.54.2000418. PMID- 27121216 TI - Insights Into Intimate Partner Violence in Pregnancy: Findings From a Cross Sectional Study in Two States in Nigeria. AB - A household survey and focus group discussions examined the frequency and risk factors for physical intimate partner violence (IPV) during pregnancy in two Nigerian states. Some 22% of women in Cross River and 9% in Bauchi reported IPV in their last pregnancy. The risk was higher in communities where more women reported IPV in the past year and lower among less poor women with more educated partners. Women were more likely to experience IPV in pregnancy if they had an income and decided how to spend it. Efforts to reduce IPV in pregnancy should involve communities as well as individuals. PMID- 27121217 TI - Regulatory and Scientific Aspects of Drug-Drug Interaction Studies. PMID- 27121213 TI - Rational bases for the use of the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer patients. AB - The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumor, nodes, metastasis (TNM) classification system based on tumor features is used for prognosis estimation and treatment recommendations in most cancers. However, the clinical outcome can vary significantly among patients within the same tumor stage and TNM classification does not predict response to therapy. Therefore, many efforts have been focused on the identification of new markers. Multiple tumor cell-based approaches have been proposed but very few have been translated into the clinic. The recent demonstration of the essential role of the immune system in tumor progression has allowed great advances in the understanding of this complex disease and in the design of novel therapies. The analysis of the immune infiltrate by imaging techniques in large patient cohorts highlighted the prognostic impact of the in situ immune cell infiltrate in tumors. Moreover, the characterization of the immune infiltrates (e.g. type, density, distribution within the tumor, phenotype, activation status) in patients treated with checkpoint-blockade strategies could provide information to predict the disease outcome. In colorectal cancer, we have developed a prognostic score ('Immunoscore') that takes into account the distribution of the density of both CD3(+) lymphocytes and CD8(+) cytotoxic T cells in the tumor core and the invasive margin that could outperform TNM staging. Currently, an international retrospective study is under way to validate the Immunoscore prognostic performance in patients with colon cancer. The use of Immunoscore in clinical practice could improve the patients' prognostic assessment and therapeutic management. PMID- 27121218 TI - Sublingual Flumazenil for the Residual Effects of Hypnotics: Zolpidem and Brotizolam. AB - Residual morning drowsiness is a frequent side effect of hypnotics. This study examined the safety and efficacy of sublingual Flumazenil in reversing the residual hypnotic effect. A double-blind, placebo-controlled, randomized crossover study with 20 healthy subjects who slept for 1.5 hours following sleep induction was conducted. Upon awakening, they underwent neurocognitive tests including immediate word recall test (iWRT), Digit Symbol Substitution Test (DSST), and mood/performance questionnaires. They were then treated by Flumazenil or placebo and were reevaluated after 20 and 60 minutes. A week later, the same procedures were performed (placebo/Flumazenil accordingly). All 20 volunteers completed the study. Flumazenil was superior to placebo by 59% to 93% (P < .05 .001) in improving performance in the various neurocognitive tasks. Subjects reported a significant improvement in vigilance with Flumazenil, both at 20 minutes and 60 minutes. iWRT improved with Flumazenil vs placebo at 20 minutes (4.2 +/- 0.8 vs 1.3 +/- 0.9 words, P < .005) and 60 minutes (5.4 +/- 1.1 vs 1.2 +/- 1.2 words, P < .02). Sublingual administration of Flumazenil is safe and effective in reversing the hypnotic effects of Zolpidem and Brotizolam. This may offer a comprehensive and safer treatment for insomniac patients. PMID- 27121219 TI - Comparative Sirolimus Pharmacokinetics After Single-Dose Administration of Two Prototype 0.5-mg Tablets in Healthy Volunteers. AB - Availability of a lower dose tablet would add to the dosing flexibility of currently available 1- and 2-mg sirolimus tablets for optimal concentrations and patient compliance. A randomized, 3-period crossover study was conducted in 30 fasting healthy volunteers (29 men, aged 31 +/- 8 years, weight 79 +/- 12 kg). Subjects were given 5 mg of sirolimus, either as doses of the 0.5-mg nonshellac core prototype, 0.5-mg shellac-core prototype, or approved 1-mg tablet. Whole blood samples were collected at selected time points for 144 hours after dosing and analyzed using LC/MS/MS assay. Noncompartmental pharmacokinetic analysis was performed, followed by bioequivalence assessment. Twenty-four subjects completed all dosing periods, and no formulation-associated adverse events were reported. Ratios of maximum plasma concentration (Cmax ), area under the concentration-time curve to the last measured concentration (AUCT ), and area under the concentration-time curve from time 0 to infinity (AUC) for the nonshellac-core prototype compared with the 1-mg tablet were within the 80% to 125% range dictated by bioequivalence conventions. Similar results were observed when comparing the ratios of AUCT and AUC for the shellac-core prototype, while 90% confidence interval of the ratio of Cmax values was 105% to 129%. Within the context of clinical equivalence standards established by a phase 3 study comparing liquid to tablet formulations, it was concluded that both prototypes were clinically bioequivalent to the reference formulation. PMID- 27121220 TI - A Thorough QT Study of Teduglutide in Healthy Subjects. AB - Teduglutide, an analog of the endogenous hormone glucagon-like peptide-2, is currently being developed for the treatment of short bowel syndrome. This study investigated the potential effects of teduglutide on cardiac conduction and repolarization. Seventy-two healthy volunteers underwent 4 treatment periods in randomized order with a single subcutaneous injection of placebo, 5 and 20 mg teduglutide, and a single oral 400-mg dose of moxifloxacin. The primary variable to investigate the effect on cardiac repolarization was the difference between QTcF after administration versus predose. The observed upper bounds of the 95% one-sided confidence intervals were 3.0 ms (5 mg) and 4.5 ms (20 mg). Arithmetic mean curves of QTcF intervals over time of both doses of teduglutide and of placebo were almost superposable. Assay sensitivity for the positive control moxifloxacin was shown. In conclusion, teduglutide at intended therapeutic and supratherapeutic doses had no effect on cardiac repolarization. No safety concerns were identified. Treatment with teduglutide was well tolerated. PMID- 27121221 TI - Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan and Warfarin in Healthy Subjects. AB - PURPOSE: Tolvaptan, a nonpeptide V2 receptor antagonist approved in Japan and in the United States, is likely to be co-administered with warfarin in patients with heart failure (HF). Therefore, the effect of tolvaptan on warfarin pharmacokinetics, pharmacodynamics, and protein binding was evaluated. METHODS: An open-label, randomized, 2-period crossover trial was conducted involving healthy subjects (N = 24) administered 25 mg warfarin sodium on day 4 of a 13-day regimen of either 60 mg once daily tolvaptan or matching placebo. Blood samples were taken over 240 hours postdose for analysis of tolvaptan, R- and S-warfarin, and 7- and 10-hydroxywarfarin concentrations and for the measurement of activated partial thromboplastin time, prothrombin time, and international normalized ratio. RESULTS: For S-warfarin, the geometric mean ratios (warfarin+tolvaptan/warfarin alone; 90% confidence interval) for maximum plasma concentration (Cmax ) and area under the concentration-time curve from time 0 to infinity (AUCinfinity ) were 1.09 (1.05, 1.12) and 1.09 (1.04, 1.13), respectively. Corresponding ratios for R-warfarin were 1.06 (1.02, 1.09) and 1.05 (1.01, 1.11), respectively. No changes were observed in 7- or 10-hydroxywarfarin Cmax or AUCinfinity values, prothrombin time, activated partial thromboplastin time, and international normalized ratio. The protein binding of racemic warfarin and tolvaptan was not significantly altered by the presence of the other compound. CONCLUSION: Warfarin doses do not need to be altered when co administered with tolvaptan. PMID- 27121222 TI - Polymerization of a Photocleavable Monomer Using Visible Light. AB - The polymerization of the photocleavable monomer, o-nitrobenzyl methacrylate (NBMA), is investigated using photoinduced electron/energy transfer reversible addition-fragmentation chain transfer polymerization. The polymerizations under visible red (lambda max = 635 nm, 0.7 mW cm(-2) ) and yellow (lambda max = 560 nm, 9.7 mW cm(-2) ) light are performed and demonstrate rational evidence of a controlled/living radical polymerization process. Well-defined poly(o-nitrobenzyl methacrylate) (PNBMA) homopolymers with good control over the molecular weight and polymer dispersity are successfully synthesized by varying the irradiation time and/or targeted degree of polymerization. Chain extension of a poly(oligo(ethylene glycol) methyl ether methacrylate) macro-chain transfer agent with NBMA is carried out to fabricate photocleavable amphiphilic block copolymers (BCP). Finally, these self-assembled BCP rapidly dissemble under UV light suggesting the photoresponsive character of NBMA is not altered during the polymerization under yellow or red light. Such photoresponsive polymers can be potentially used for the remote-controlled delivery of therapeutic compounds. PMID- 27121223 TI - Brazilian Twin Registry: A Bright Future for Twin Studies/Twin Research: Twin Study of Alcohol Consumption and Mortality; Oxygen Uptake in Adolescent Twins/In the News: Superfecundated Twins In Vietnam; Adolescent Twin Relations; Twin and Triplet Co-Workers; A Special Twin Ultrasound; Monozygotic Twins With Different Skin Color; Identical Twin Returns from Space. AB - The establishment of the Brazilian Twin Registry for the study of genetic, social, and cultural influences on behavior is one of eleven newly funded projects in the Department of Psychology at the University of Sao Paulo. These 11 interrelated projects form the core of the university's Center for Applied Research on Well-Being and Human Behavior. An overview of the planned twin research and activities to date is presented. Next, two recent twin studies are reviewed, one on the relationship between alcohol consumption and mortality, and the other on factors affecting maximal oxygen uptake. Twins cited in the media include the first identified superfecundated twins in Vietnam, adolescent twin relations, twins and triplets who work together, monozygotic twins with different skin tones and a co-twin control study that addresses the effects of space travel. PMID- 27121224 TI - Neurofeedback Against Binge Eating: A Randomized Controlled Trial in a Female Subclinical Threshold Sample. AB - Brain-directed treatment techniques, such as neurofeedback, have recently been proposed as adjuncts in the treatment of eating disorders to improve therapeutic outcomes. In line with this recommendation, a cue exposure EEG-neurofeedback protocol was developed. The present study aimed at the evaluation of the specific efficacy of neurofeedback to reduce subjective binge eating in a female subthreshold sample. A total of 75 subjects were randomized to EEG-neurofeedback, mental imagery with a comparable treatment set-up or a waitlist group. At post treatment, only EEG-neurofeedback led to a reduced frequency of binge eating (p = .015, g = 0.65). The effects remained stable to a 3-month follow-up. EEG neurofeedback further showed particular beneficial effects on perceived stress and dietary self-efficacy. Differences in outcomes did not arise from divergent treatment expectations. Because EEG-neurofeedback showed a specific efficacy, it may be a promising brain-directed approach that should be tested as a treatment adjunct in clinical groups with binge eating. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27121225 TI - Employing Core-Shell Quantum Dots as Triplet Sensitizers for Photon Upconversion. AB - A new family of surface-functionalized CdSe/ZnS core-shell quantum dots (csQD) has been developed, which work as triplet sensitizers for triplet-triplet annihilation-based photon upconversion (TTA-UC). The surface modification of csQD with acceptor molecules plays a key role in the efficient relay of the excited energy of csQD to emitter molecules in the bulk solution, where the generated emitter triplets undergo triplet-triplet annihilation that leads to photon upconversion. Interestingly, improved UC properties were achieved with the core shell QDs compared with core-only CdSe QDs (cQD). The threshold excitation intensity, which is defined as the necessary irradiance to achieve efficient TTA process, decreases by more than a factor of four. Furthermore, the total UC quantum yield is enhanced more than 50-fold. These enhancements should be derived from better optical properties of csQD, in which the non-radiative surface recombination sites are passivated by the shell layer with wider bandgap. PMID- 27121227 TI - Clinical trials for stem cell transplantation: when are they needed? AB - In recent years, both stem cell research and the clinical application of these promising cells have increased rapidly. About 1000 clinical trials using stem cells have to date been performed globally. More importantly, more than 10 stem cell-based products have been approved in some countries. With the rapid growth of stem cell applications, some countries have used clinical trials as a tool to diminish the rate of clinical stem cell applications. However, the point at which stem cell clinical trials are essential remains unclear. This commentary discusses when stem cell clinical trials are essential for stem cell transplantation therapies. PMID- 27121226 TI - Experimental evidence of coherent transport. AB - Coherent transport phenomena are difficult to observe due to several sources of decoherence. For instance, in the electronic transport through quantum devices the thermal smearing and dephasing, the latter induced by inelastic scattering by phonons or impurities, destroy phase coherence. In other wave systems, the temperature and dephasing may not destroy the coherence and can then be used to observe the underlying wave behaviour of the coherent phenomena. Here, we observe coherent transmission of mechanical waves through a two-dimensional elastic Sinai billiard with two waveguides. The flexural-wave transmission, performed by non contact means, shows the quantization when a new mode becomes open. These measurements agree with the theoretical predictions of the simplest model highlighting the universal character of the transmission fluctuations. PMID- 27121229 TI - Moving the mean with feedback: insights from behavioural science. PMID- 27121230 TI - Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations. AB - EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small molecules such as gefitinib has been used for inhibiting EGFR with good initial responses; however, drug resistance is common when using a mono-targeting strategy. At present, KRAS remains an undruggable target. As such, the development of new drugs targeting the downstream of KRAS and EGFR and their crosstalk pathways is critically needed to effectively treat NSCLC. The present study aimed to elucidate the anticancer effects of PI3K (BKM120) and MEK (PD1056309) inhibitors on NSCLC cell lines with KRAS or EGFR mutations. Inhibition of the EGFR and KRAS downstream P13K pathway using BKM120 significantly inhibited the growth of NSCLC cell lines with either EGFR or KRAS mutations. In addition, significant cell cycle arrest and induction of apoptosis were observed following BKM120 treatment. Notably, although the A549 and H358 NSCLC cell lines harbor the same KRAS mutation, A549 cells were less sensitive than H358 cells in the response to BKM120 treatment. Similarly, PC-9 and H1650 cells harbor the same EGFR mutation, however, H1650 was less sensitive to BKM120. Different sensitivity between NSCLC cell lines with the same oncogenic mutation suggests that multiple crosstalk pathways exit. Combined usage of BKM120 and PD1056309 synergistically enhanced apoptosis in the A549 cells and mildly enhanced apoptosis in the H1650 and H358 cells, suggesting the crosstalk of the MEK pathway with the P13K/Akt pathways in these cell lines. Overall, our findings suggest that inhibition of EGFR and KRAS downstream with a P13K/Akt inhibitor could be useful for treating NSCLC. However, for NSCLC exhibiting crosstalk with other survival pathways, such as the MEK pathway, combination treatment is required. PMID- 27121232 TI - In Memory of Dr. James J. Mezhir, June 28, 1973-February 3, 2016. PMID- 27121231 TI - A benzenediamine derivate FC-99 attenuates lupus nephritis in MRL/lpr mice via inhibiting myeloid dendritic cell-secreted BAFF. AB - Myeloid dendritic cells (DCs) can produce B-cell-activating factor (BAFF) that modulates survival and differentiation of B cells and plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Toll-like receptor 4 (TLR4) signaling has important functions in the process of BAFF production. Our previous study showed that a benzenediamine derivate FC-99 possesses anti-inflammation activity and directly interacts with interleukin-1 receptor-associated kinase 4 (IRAK4), which was a pivotal molecule in TLR4 signaling. In this study, we demonstrated that FC-99 attenuated lupus nephritis in the MRL/lpr mice. FC-99 also decreased the levels of total immunoglobulin G (IgG), total IgG2a and IgM in sera, as well as the activation of B cells in the spleens of MRL/lpr mice. Moreover, FC-99 inhibited abnormal activation of myeloid DCs in spleens and reduced the levels of BAFF in sera, spleens, and kidneys of MRL/lpr mice. Furthermore, upon TLR4 stimulation with lipopolysaccharide in vitro, FC-99 inhibited IRAK4 phosphorylation, as well as the activation and BAFF production in murine bone marrow-derived DCs. These data indicate that FC-99 attenuates lupus nephritis in MRL/lpr mice via inhibiting DC-secreted BAFF, suggesting that FC-99 may be a potential therapeutic candidate for the treatment of SLE. PMID- 27121233 TI - Assessing Trends in Palliative Surgery for Extrahepatic Biliary Malignancies: A 15-Year Multicenter Study. AB - INTRODUCTION: Extrahepatic biliary malignancies are often diagnosed at an advanced stage. We compared patients with unresectable perihilar cholangiocarcinoma (PHCC) and gallbladder cancer (GBC) who underwent a palliative procedure versus an aborted laparotomy. METHODS: Seven hundred seventy-seven patients who underwent surgery for PHCC or GBC between 2000 and 2014 were identified. Uni- and multivariable analyses were performed to identify factors associated with outcome. RESULTS: Utilization of preoperative imaging increased over time (CT use, 80.1 % pre-2009 vs. 90 % post-2009) (p < 0.001). The proportion of the patients undergoing curative-intent resection also increased (2000-2004, 67.0 % vs. 2005-2009, 74.5 % vs. 2010-2014, 78.8 %; p = 0.001). The planned surgery was aborted in 106 (13.7 %) patients and 94 (12.1 %) had a palliative procedure. A higher incidence of postoperative complications (19.2 vs. 3.8 %, p = 0.001) including deep surgical site infections (8.3 vs. 1.1 %), bleeding (4.8 vs. 0 %), bile leak (6.0 vs. 0 %) and longer length of stay (7 vs. 4.5 days) were observed among the patients who underwent a palliative surgical procedure versus an aborted non-therapeutic, non-palliative laparotomy (all p < 0.05). OS was comparable among the patients who underwent a palliative procedure (8.7 months) versus an aborted laparotomy (7.8 months) (p = 0.23). CONCLUSION: Increased use of advanced imaging modalities was accompanied by increased curative-intent surgery. Compared with patients in whom surgery was aborted, patients who underwent surgical palliation demonstrated an increased incidence of postoperative morbidity with comparable survival. PMID- 27121235 TI - Fusidic acid betamethasone lipid cream. AB - Bacterial infections of the skin and soft tissues are frequent disorders. They can be primitive infections (e.g. impetigo, folliculitis) or secondary infections complicating other diseases, particularly atopic dermatitis. The most common aetiologic agent is Staphylococcus aureus. Topical antibiotic therapy may be sufficient in many instances to control these infections. Fusidic acid is an antibiotic used topically on the skin which is very active against S. aureus, including methicillin-resistant strains, and other Gram-positive bacteria. Resistance rates to fusidic acid are stably low. A fusidic acid and betamethasone formulation in a lipid-enriched cream (lipid cream) has been recently developed in order to provide effective antibacterial and anti-inflammatory activities in conjunction with a powerful emollient and moisturising effect. This preparation may be especially useful in patients with atopic-infected eczema. PMID- 27121234 TI - Impact of Perioperative Phosphorus and Glucose Levels on Liver Regeneration and Long-term Outcomes after Major Liver Resection. AB - INTRODUCTION: The impact of phosphorus as well as glycemic alterations on liver regeneration has not been directly examined. We sought to determine the impact of phosphorus and glucose on liver regeneration after major hepatectomy. METHODS: Early and late liver regeneration index was defined as the relative increase of liver volume (RLV) within 2[(RLV2m-RLVp)/RLVp] and 7 months[(RLV7m-RLVp)/RLVp] following surgery. The association of perioperative metabolic factors, liver regeneration, and outcomes was assessed. RESULTS: On postoperative day 2, 50 (52.6 %) patients had a low phosphorus level (<=2.4 mg/dl), while 45 (47.4 %) had a normal/high phosphorus level (>2.4 mg/dl). Despite comparable clinicopathologic characteristics (all P > 0.05) and RLV/TLV at surgery (P = 0.84), regeneration index within 2 months was lower in the normal/high phosphorus group (P = 0.01) with these patients having increased risk for postoperative liver failure (P = 0.01). The inhibition of liver regeneration persisted at 7 months (P = 0.007) and was associated with a worse survival (P = 0.02). Preoperative hypoglycemia was associated only with a lower early regeneration index (P = 0.02). CONCLUSIONS: Normal/high phosphorus was associated with inhibition of early and late liver regeneration, as well as with an increased risk of liver failure and worse long term outcomes. Immediate preoperative hypoglycemia was associated with a lower early volumetric gain. Metabolic factors may represent early indicators of liver failure that could identify patients at increased risk for worse outcomes. PMID- 27121236 TI - ACMT Position Statement: Guidance for the Use of Intravenous Lipid Emulsion. PMID- 27121237 TI - Melatonin Concentrations and Antioxidative Capacity of Human Breast Milk According to Gestational Age and the Time of Day. AB - BACKGROUND: While changes in the composition of breast milk throughout the lactation period are well known, little is known about the antioxidative capacity of breast milk and its regulation as a function of time of day. OBJECTIVE: The aim of this study was to evaluate the antioxidative capacity in breast milk and its regulation by time of day. METHODS: Melatonin, superoxide dismutase (SOD), glutathione peroxidase 3 (Gpx3) concentrations, and the total antioxidative capacity (TAOC) were analyzed in 105 breast milk samples and 12 maternal serum samples from 21 healthy nursing mothers. RESULTS: Comparison between daytime breast milk (collected from 1000-2200 h) and nighttime breast milk (collected from 2200-1000 h) revealed significantly higher concentrations of melatonin and Gpx3 in nighttime milk (melatonin: 1.5 pg/mL [1.0-2.1] day vs 7.3 pg/mL [3.8 13.6] night, median [quartiles], with an estimated mean night-to-day ratio of 5.2 [3.9, 7.1], P < .001; Gpx3: 1436 ng/mL [765-2060] day vs 1800 ng/mL [1242-2297] night, night-to-day difference 192.1 [0.6, 383.7], P = .049). Subgroup analysis showed that melatonin had a circadian rhythm in both preterm and term milk, with a significantly higher nighttime concentration ( P < .001), while antioxidant enzymes had a circadian rhythm only in preterm milk, with a significantly higher nighttime concentration for Gpx3 and a significant higher daytime concentration for SOD and TAOC ( P = .041 and P = .049, respectively). We found no significant correlation between the concentration of melatonin and the concentration of SOD, Gpx3, or TAOC. Moreover, there were no significant correlations observed between gestational age and the concentration of melatonin and antioxidant enzymes. CONCLUSION: Because of its higher melatonin and Gpx3 content, future research is needed to determine if preterm nighttime milk ought to be the first choice in the feeding of high-risk preterm infants. PMID- 27121238 TI - A Multifaceted Approach to Revitalizing the Baby-Friendly Hospital Initiative in Croatia. AB - The Baby-Friendly Hospital Initiative (BFHI) was launched in Croatia in 1993. By 1998, 15 of 34 maternity facilities were designated "Baby-Friendly." Introduction of hospital bags, violating the International Code of the Marketing of Breastmilk Substitutes, led to a standstill in the BFHI. The aim of this article is to describe the successful reintroduction of the BFHI in Croatia between 2007 and 2015. After hospital bags were abolished in 2007, UNICEF Croatia undertook an assessment of BFHI implementation. All maternity facilities were invited by UNICEF and the Ministry of Health to join the renewed BFHI. UNICEF materials were translated and training for trainers, assessors, coordinators, and hospital staff held. By June 2015, 30 of 32 (94%) maternity facilities, providing care to 89% of newborns, were Baby-Friendly. Nine maternity hospitals have been renovated and 2 new hospitals have been built. Exclusive breastfeeding rates have risen 16% at 0 to 2 months (from 51% in 2007 to 67% in 2014) and 14% at 3 to 5 months (from 32% in 2007 to 46% in 2014). Fourteen "Breastfeeding-Friendly" primary care practices have been designated, 166 breastfeeding support groups are in operation, criteria for Mother-Friendly care are being piloted in 2 maternity facilities, and "Ten Steps in the Neonatal Intensive Care Unit" are being introduced. The BFHI provides an excellent opportunity for revitalizing breastfeeding protection, promotion, and support in all settings. Recognition and support of the BFHI by the Croatian government was crucial for implementing the BFHI, whereas the marketing practices of the breast milk substitutes industry are an ongoing challenge. PMID- 27121239 TI - Labor Epidural Analgesia and Breastfeeding: A Systematic Review. AB - Despite widespread use of epidural analgesia during labor, no consensus has been reached among obstetric and anesthesia providers regarding its effects on breastfeeding. The purpose of this review was to examine the relationship between labor epidural analgesia and breastfeeding in the immediate postpartum period. PubMed, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature were searched for articles published in 1990 or thereafter, using the search term breastfeeding combined with epidural, labor epidural analgesia, labor analgesia, or epidural analgesia Of 117 articles, 23 described empirical studies specific to labor epidural analgesia and measured a breastfeeding outcome. Results were conflicting: 12 studies showed negative associations between epidural analgesia and breastfeeding success, 10 studies showed no effect, and 1 study showed a positive association. Most studies were observational. Of 3 randomized controlled studies, randomization methods were inadequate in 2 and not evaluable in 1. Other limitations were related to small sample size or inadequate study power; variation and lack of information regarding type and dosage of analgesia or use of other intrapartum interventions; differences in timing, definition, and method of assessing breastfeeding success; or failure to consider factors such as mothers' intention to breastfeed, social support, siblings, or the mother's need to return to work or school. It is also unclear to what extent results are mediated through effects on infant neurobehavior, maternal fever, oxytocin release, duration of labor, and need for instrumental delivery. Clinician awareness of factors affecting breastfeeding can help identify women at risk for breastfeeding difficulties in order to target support and resources effectively. PMID- 27121240 TI - Melatonin inhibits tumorigenicity of glioblastoma stem-like cells via the AKT EZH2-STAT3 signaling axis. AB - Glioblastoma stem-like cells (GSCs) displaying self-renewing and tumor propagating capacity play a particularly important role in maintaining tumor growth, therapeutic resistance, and tumor recurrence. Therefore, new therapeutic strategies focusing on impairing GSC maintenance are urgently needed. Here, we used GSCs isolated from surgical specimens from patients with glioblastoma multiforme (GBM) to study the roles and underlying mechanisms associated with melatonin in GSC biology. The results showed that melatonin directly targeted glioma tumor cells by altering GSC biology and inhibiting GSC proliferation. Additionally, melatonin altered profile of transcription factors to inhibit tumor initiation and propagation. Furthermore, EZH2 S21 phosphorylation and EZH2-STAT3 interaction in GSCs were impaired following melatonin treatment. These results suggested that melatonin attenuated multiple key signals involved in GSC self renewal and survival, and further supported melatonin as a promising GBM therapeutic. PMID- 27121242 TI - Parent perceptions of an adapted evidence-based practice for toddlers with autism in a community setting. AB - Although data from parent-implemented Naturalistic Developmental Behavioral Interventions have shown positive effects on decreasing core symptoms of autism, there has been limited examination of the effectiveness of Naturalistic Developmental Behavioral Interventions in community settings. In addition, parent perspectives of their involvement in parent-implemented early intervention programs have not been well studied. Using both qualitative and quantitative data to examine parent perspectives and the perceived feasibility of parent training by community providers, 13 families were followed as they received training in the Naturalistic Developmental Behavioral Intervention, Project ImPACT. Data indicate that parent training by community providers is feasible and well received, and parents find value in participating in intervention and perceive benefit for their children. Recommendations for adaptation of program elements and future research are discussed. PMID- 27121241 TI - Antioxidant effects of hydroxysafflor yellow A and acetyl-11-keto-beta-boswellic acid in combination on isoproterenol-induced myocardial injury in rats. AB - Oxidative stress plays an important role in the initiation and development of myocardial injury (MI). The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is considered to be a potential target for cardioprotection in MI. Acetyl-11-keto-beta-boswellic acid (AKBA) is the major organic acid component extracted from Boswellia serrata Roxb. ex Colebr. Hydroxysafflor yellow A (HSYA) is the principal active constituent of Carthamus tinctorius L. In the present study, we aimed to investigate the cardioprotective effects of HSYA and AKBA in combination in vivo and in vitro, as well as the underlying mechanisms responsible for these effects. For this purpose, MI was produced in Sprague Dawley rats by subcutaneous injection with isoproterenol. To model ischemic-like conditions in vitro, H9C2 cells were subjected to oxygen-glucose deprivation (OGD). The levels of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA) as well as superoxide dismutase (SOD) activity were examined as well as apoptotic cell death. Mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential (DeltaPsim or MMP) were measured using MitoSOX Red and 5,5',6,6'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) dye. The expression of PGC-1alpha and Nrf2 was quantified by western blot analysis and immunohistochemistry. HSYA and AKBA prevented myocardial pathological changes, significantly reduced the blood levels of CK-MB and LDH, and decreased apoptotic cell death. They significantly increased the expression of PGC-1alpha and Nrf2, and the activity of the antioxidant enzyme SOD and also decreased the levels of MDA and ROS. Moreover, the reduction in MMP was partly prevented by HSYA and AKBA. Taken together, these findings elucidate the underlying mechanisms through which HSYA and AKBA protect against MI. Additionally, HSYA and AKBA appear to act synergistically in order to exert cardioprotective effects. PMID- 27121243 TI - A cross-cultural exploration of the everyday social participation of individuals with autism spectrum disorders in Australia and Taiwan: An experience sampling study. AB - Individuals with an autism spectrum disorder commonly have limited social participation. This study aimed to examine the similarities and differences of everyday participation among males and females with autism spectrum disorder in Australia and Taiwan, using an experience sampling methodology. A total of 14 Australians (4 males, aged 16-43 years) and 16 Taiwanese (12 males, aged 19-45 years) with autism spectrum disorder who are cognitively able were asked to carry a device which prompted them seven times per day for 7 days, to record everyday participation: where they were, what they were doing, and who they were with. Multilevel analyses were used to identify the relationships between everyday participation and associated factors including gender, country of residence, clinical severity of autism spectrum disorder, and social anxiety. The results showed that Taiwanese participants were more likely to stay at home than Australian participants. However, female participants were more likely to engage in social situations than males. Furthermore, participants with fewer autism spectrum disorder symptoms and those with higher levels of social anxiety were less likely to engage in social interactions. This study sheds light on ways that culture and gender affect social participation and highlights the relationship of social anxiety to social participation. The findings have implications for interventions for social participation. PMID- 27121244 TI - Predicting social and communicative ability in school-age children with autism spectrum disorder: A pilot study of the Social Attribution Task, Multiple Choice. AB - The Social Attribution Task, Multiple Choice is introduced as a measure of implicit social cognitive ability in children, addressing a key challenge in quantification of social cognitive function in autism spectrum disorder, whereby individuals can often be successful in explicit social scenarios, despite marked social adaptive deficits. The 19-question Social Attribution Task, Multiple Choice, which presents ambiguous stimuli meant to elicit social attribution, was administered to children with autism spectrum disorder (N = 23) and to age matched and verbal IQ-matched typically developing children (N = 57). The Social Attribution Task, Multiple Choice performance differed between autism spectrum disorder and typically developing groups, with typically developing children performing significantly better than children with autism spectrum disorder. The Social Attribution Task, Multiple Choice scores were positively correlated with age (r = 0.474) while being independent from verbal IQ (r = 0.236). The Social Attribution Task, Multiple Choice was strongly correlated with Vineland Adaptive Behavior Scales Communication (r = 0.464) and Socialization (r = 0.482) scores, but not with Daily Living Skills scores (r = 0.116), suggesting that the implicit social cognitive ability underlying performance on the Social Attribution Task, Multiple Choice is associated with real-life social adaptive function. PMID- 27121246 TI - Mass-forming type 1 autoimmune pancreatitis mimicking pancreatic cancer. AB - We reported three cases of mass-forming type 1 autoimmune pancreatitis (AIP) that were preoperatively suspected to be pancreatic cancer, and reviewed their clinicopathological features. Radiological findings in the patients revealed hypoattenuating masses in the early phase or a stricture of the main pancreatic duct with upstream dilatation, which was consistent with the diagnosis of pancreatic cancer. Histopathologically, the lesions were well demarcated and met all diagnostic criteria for immunoglobulin G4 (IgG4)-related AIP, including the presence of periductal lymphoplasmacytic infiltration, obliterative phlebitis, storiform fibrosis and abundant IgG4-positive plasma cells. However, the adjacent uninvolved pancreatic duct and lobular structures were well preserved. And in all patients, none or some of the aforementioned characteristics were observed. We suggest that some cases of focal AIP may progress to more severe grades and exhibit mass formation, although remaining localized. These focal cases of AIP are difficult to distinguish from pancreatic cancer. To our knowledge, this report is the first to present a histopathological comparison of mass-forming AIP with the adjacent uninvolved pancreatic tissues. PMID- 27121245 TI - Myasthenia gravis induced by nivolumab therapy in a patient with non-small-cell lung cancer. PMID- 27121248 TI - Deactivation of the left dorsolateral prefrontal cortex in Prader-Willi syndrome after meal consumption. AB - BACKGROUND/OBJECTIVES: Prader-Willi syndrome (PWS) is a type of human genetic obesity that may give us information regarding the physiology of non-syndromic obesity. The objective of this study was to investigate the functional correlates of hunger and satiety in individuals with PWS in comparison with healthy controls with obesity, hypothesizing that we would see significant differences in activation in the left dorsolateral prefrontal cortex (DLPFC) based on prior findings. SUBJECTS/METHODS: This study compared the central effects of food consumption in nine individuals with PWS (7 men, 2 women; body fat 35.3+/-10.0%) and seven controls (7 men; body fat 28.8+/-7.6%), matched for percentage body fat. H2(15)O-PET (positron emission tomography) scans were performed before and after consumption of a standardized liquid meal to obtain quantitative measures of regional cerebral blood flow (rCBF), a marker of neuronal activity. RESULTS: Compared with obese controls, PWS showed altered (P<0.05 family-wise error cluster-level corrected; voxelwise P<0.001) rCBF before and after meal consumption in multiple brain regions. There was a significant differential rCBF response within the left DLPFC after meal ingestion with decreases in DLPFC rCBF in PWS; in controls, DLPFC rCBF tended to remain unchanged. In more liberal analyses (P<0.05 family-wise error cluster-level corrected; voxelwise P<0.005), rCBF of the right orbitofrontal cortex (OFC) increased in PWS and decreased in controls. In PWS, DeltarCBF of the right OFC was associated with changes in appetite ratings. CONCLUSIONS: The pathophysiology of eating behavior in PWS is characterized by a paradoxical meal-induced deactivation of the left DLPFC and activation in the right OFC, brain regions implicated in the central regulation of eating behavior. PMID- 27121249 TI - The differential effect of socio-economic status, birth weight and gender on body mass index in Australian Aboriginal Children. AB - BACKGROUND: Adult Aboriginal Australians have 1.5-fold higher risk of obesity, but the trajectory of body mass index (BMI) through childhood and adolescence and the contribution of socio-economic factors remain unclear. Our objective was to determine the changes in BMI in Australian Aboriginal children relative to non Aboriginal children as they move through adolescence into young adulthood, and to identify risk factors for higher BMI. METHODS: A prospective cohort study of Aboriginal and non-Aboriginal school children commenced in 2002 across 15 different screening areas across urban, regional and remote New South Wales, Australia. Socio-economic status was recorded at study enrolment and participants' BMI was measured every 2 years. We fitted a series of mixed linear regression models adjusting for age, birth weight and socio-economic status for boys and girls. RESULTS: In all, 3418 (1949 Aboriginal) participants were screened over a total of 11 387 participant years of follow-up. The prevalence of obesity was higher among Aboriginal children from mean age 11 years at baseline (11.6 vs 7.6%) to 16 years at 8 years follow-up (18.6 vs 12.3%). The mean BMI increased with age and was significantly higher among Aboriginal girls compared with non-Aboriginal girls (P<0.01). Girls born of low birth weight had a lower BMI than girls born of normal birth weight (P<0.001). Socio-economic status and low birth weight had a differential effect on BMI for Aboriginal boys compared with non-Aboriginal boys (P for interaction=0.01). Aboriginal boys of highest socio-economic status, unlike those of lower socio-economic status, had a higher BMI compared with non-Aboriginal boys. Non-Aboriginal boys of low birth weight were heavier than Aboriginal boys. CONCLUSIONS: Socio-economic status and birth weight have differential effects on BMI among Aboriginal boys, and Aboriginal girls had a higher mean BMI than non-Aboriginal girls through childhood and adolescence. Intervention programs need to recognise the differential risk for obesity for Aboriginal and non-Aboriginal boys and girls to maximise their impact. PMID- 27121247 TI - Relationship of prediagnostic body mass index with survival after colorectal cancer: Stage-specific associations. AB - Higher body mass index (BMI) is a well-established risk factor for colorectal cancer (CRC), but is inconsistently associated with CRC survival. In 6 prospective studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), 2,249 non-Hispanic white CRC cases were followed for a median 4.5 years after diagnosis, during which 777 died, 554 from CRC-related causes. Associations between prediagnosis BMI and survival (overall and CRC specific) were evaluated using Cox regression models adjusted for age at diagnosis, sex, study and smoking status (current/former/never). The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (p-interaction = 0.03) and CRC-specific mortality (p interaction = 0.04). Compared to normal BMI (18.5-24.9 kg/m(2) ), overweight (BMI 25.0-29.9) was associated with increased mortality among those with Stage I disease, and decreased mortality among those with Stages II-IV disease. Similarly, obesity (BMI >=30) was associated with increased mortality among those with Stages I-II disease, and decreased mortality among those with Stages III-IV disease. These results suggest the relationship between BMI and survival after CRC diagnosis differs by stage at diagnosis, and may emphasize the importance of adequate metabolic reserves for colorectal cancer survival in patients with late stage disease. PMID- 27121250 TI - Sex-specific associations of birth weight with measures of adiposity in mid-to late adulthood: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND/OBJECTIVES: To investigate sex-specific associations of birth weight with body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) in mid-to-late adulthood. SUBJECTS/METHODS: ELSA-Brasil is a multicenter cohort study of adults aged 35-74 years affiliated with universities or research institutions of six capital cities in Brazil. After exclusions, we investigated 11 636 participants. Socio-demographic factors and birth weight were obtained by interview. All anthropometry was directly measured at baseline. We categorized birth weight as low (?2.5 kg); normal (2.5-4 kg) and high (?4 kg). We performed analysis of covariance (ANCOVA) for continuous outcomes and ordinal logistic regression for categorical adiposity outcomes. We examined interaction on the multiplicative scale by sex and by race. RESULTS: High birth weight uniformly predicted greater overall and central obesity in men and women. However, low (vs normal) birth weight, in ANCOVA models adjusted for participant age, family income, race, education, maternal education, and maternal and paternal history of diabetes, was associated with lower BMI, WC and WHR means for men, but not for women (Pinteraction=0.01, <0.0001 and <0.0001, respectively). In similarly adjusted ordinal logistic regression models, odds of obesity (odds ratio (OR)=0.65, 0.46-0.90) and of being in the high (vs low) tertile of WC (OR=0.66, 0.50-0.87) and of WHR (OR=0.79, 0.60-1.03) were lower for low (vs normal) birth weight men, but trended higher (BMI: OR=1.18, 0.92-1.51; WC: OR=1.21, 0.97-1.53; WHR: OR=1.44, 1.15-1.82) for low (vs normal) birth weight women. CONCLUSIONS: In this Brazilian sample of middle-aged and elderly adults who have lived through a rapid nutritional transition, low birth weight was associated with adult adiposity in a sex-specific manner. In men, low birth weight was associated with lower overall and central adult adiposity, while in women low birth weight was generally associated with greater central adiposity. PMID- 27121251 TI - miR-200a regulates Rheb-mediated amelioration of insulin resistance after duodenal-jejunal bypass. AB - OBJECTIVES: Duodenal-jejunal bypass (DJB) surgery can induce the rapid and durable remission of diabetes. Recent studies indicate that ameliorated hepatic insulin resistance and improved insulin signaling might contribute to the diabetic control observed after DJB. Ras homolog enriched in brain (Rheb) is reported to have an important role in insulin pathway, and some microRNAs (miRNAs) have been found to regulate Rheb. This study was conducted to investigate the effects of DJB on hepatic insulin resistance and the effects of miRNA-200a, a Rheb-targeting miRNA, on the development of DJB-induced amelioration in hepatic insulin resistance. SUBJECTS: We investigated hepatic insulin signaling change and mapped the hepatic miRNAome involved in a rat model of DJB. We studied the effects of miR-200a on Rheb signaling pathway in buffalo rat liver cell lines. Liver tissues were studied and glucose tolerance tests were conducted in DJB rats injected with lentivirus encoding miR-200a inhibitor and diabetic rats injected with miR-200a mimic. RESULTS: Rheb is a potential target of miR-200a. Transfection with an miR-200a inhibitor increased Rheb protein levels and enhanced the feedback action on insulin receptor substrate-dependent insulin signaling, whereas transfection with an miR-200a mimic produced the opposite effects. A luciferase assay confirmed that miR-200a bind to the 3'UTR (untranslated regions) of Rheb. Global downregulation of miR-200a in DJB rats showed impaired insulin sensitivity whereas upregulation of miR-200a in diabetic rats showed amelioration of diabetes. CONCLUSIONS: A novel mechanism was identified, in which miR-200a regulates the Rheb-mediated amelioration of insulin resistance in DJB. The findings suggest miR-200a should be further explored as a potential target for the treatment of diabetes. PMID- 27121252 TI - Established BMI-associated genetic variants and their prospective associations with BMI and other cardiometabolic traits: the GLACIER Study. AB - BACKGROUND: Recent cross-sectional genome-wide scans have reported associations of 97 independent loci with body mass index (BMI). In 3541 middle-aged adult participants from the GLACIER Study, we tested whether these loci are associated with 10-year changes in BMI and other cardiometabolic traits (fasting and 2-h glucose, triglycerides, total cholesterol, and systolic and diastolic blood pressures). METHODS: A BMI-specific genetic risk score (GRS) was calculated by summing the BMI-associated effect alleles at each locus. Trait-specific cardiometabolic GRSs comprised only the loci that show nominal association (P?0.10) with the respective trait in the original cross-sectional study. In longitudinal genetic association analyses, the second visit trait measure (assessed ~10 years after baseline) was used as the dependent variable and the models were adjusted for the baseline measure of the outcome trait, age, age(2), fasting time (for glucose and lipid traits), sex, follow-up time and population substructure. RESULTS: The BMI-specific GRS was associated with increased BMI at follow-up (beta=0.014 kg m(-2) per allele per 10-year follow-up, s.e.=0.006, P=0.019) as were three loci (PARK2 rs13191362, P=0.005; C6orf106 rs205262, P=0.043; and C9orf93 rs4740619, P=0.01). Although not withstanding Bonferroni correction, a handful of single-nucleotide polymorphisms was nominally associated with changes in blood pressure, glucose and lipid levels. CONCLUSIONS: Collectively, established BMI-associated loci convey modest but statistically significant time-dependent associations with long-term changes in BMI, suggesting a role for effect modification by factors that change with time in this population. PMID- 27121253 TI - Reduced circulating levels of sTWEAK are associated with NAFLD and may affect hepatocyte triglyceride accumulation. AB - CONTEXT: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is strongly associated with obesity, dyslipidaemia and altered glucose regulation. Previous data demonstrated that low circulating levels of tumour necrosis factor weak inducer of apoptosis (sTWEAK) were associated with obesity, diabetes and insulin resistance, all traits associated with an increased risk of NALFD. Circulating sTWEAK levels are expected to be reduced in the presence of NAFLD. OBJECTIVE: We aimed to explore the relationship between NAFLD and circulating sTWEAK levels in obese patients, and to evaluate the effect of sTWEAK on hepatocyte triglyceride accumulation.Design setting and patients:This is an observational case-control study performed in n=112 severely obese patients evaluated for NAFLD by abdominal ultrasound and n=32 non-obese patients without steatosis. Serum sTWEAK concentrations were measured by ELISA. Multivariable analyses were performed to determine the independent predictors of NAFLD. We analysed TWEAK and Fn14 protein expression in liver biopsies by western blotting and immunohistochemistry. An immortalized primary human hepatocyte cell line (HHL) was used to evaluate the effect of sTWEAK on triglyceride accumulation. RESULTS: We observed a reduction in serum circulating sTWEAK concentrations with the presence of liver steatosis. On multivariable analysis, lower sTWEAK concentrations were independently associated with the presence of NAFLD (odds ratio (OR)=0.023; 95% confidence interval: 0.001-0.579; P<0.022). In human hepatocytes, sTWEAK administration reduced fat accumulation as demonstrated by the reduction in palmitic acid-induced accumulation of triglyceride and the decreased expression of cluster of differentiation 36 (CD36) and perilipin 1 and 2 (PLIN1 and PLIN2) genes. CONCLUSIONS: Decreased sTWEAK concentrations are independently associated with the presence of NAFLD. This is concordant with the observation that TWEAK reduces lipid accumulation in human liver cells. PMID- 27121254 TI - Childhood body mass index and height and risk of histologic subtypes of endometrial cancer. AB - BACKGROUND: Endometrial cancer risk factors include adult obesity and taller stature, but the influence of size earlier in life is incompletely understood. We examined whether childhood body mass index (BMI; kg m(-2)) and height were associated with histologic subtypes of endometrial cancer. METHODS: From the Copenhagen School Health Records Register, 155 505 girls born 1930-1989 with measured weights and heights from 7 to 13 years were linked to health registers. BMI and height were transformed to age-specific z-scores. Hazard ratios (HRs) and 95% confidence intervals were estimated by Cox regressions. RESULTS: A total of 1020 endometrial cancers were recorded. BMI was non-linearly associated with all endometrial cancers, oestrogen-dependent cancers and the subtype of endometrioid adenocarcinomas; associations were statistically significant and positive above a z-score=0 and non-significant below zero. Compared with a 7-year-old girl with a BMI z-score=0, an equally tall girl who was 3.6 kg heavier (BMI z-score=1.5) had a hazard ratio=1.53 (95% confidence interval: 1.29-1.82) for endometrioid adenocarcinoma. BMI was not associated with non-oestrogen-dependent cancers, except at the oldest childhood ages. Height at all ages was statistically significant and positively associated with all endometrial cancers, except non oestrogen-dependent cancers. At 7 years, per ~5.2 cm (1 z-score), the risk of endometrioid adenocarcinoma was 1.18 (95% confidence interval: 1.09-1.28). Among non-users of unopposed oestrogens, associations between BMI and endometrioid adenocarcinoma strengthened, but no effects on height associations were observed. CONCLUSIONS: Endometrial carcinogenesis is linked to early-life body size, suggesting that childhood BMI and height may be useful indicators for the risk of later development of endometrial cancer and might aid in the early prevention of obesity-related endometrial cancers. PMID- 27121256 TI - Party on wheels: mobile party spaces in the Norwegian high school graduation celebration. AB - Research on partying and nightlife often emphasizes commercial control while overlooking participants' creativity and agency. Due to their age, appearance and transgressive partying, participants in the Norwegian high school graduation celebration have limited access to bars and pubs in the ordinary night-time economy. To create alternative party spaces under their own control they utilize the spatial opportunities offered by automobility. Groups of students get together many years in advance and buy old buses which they refurbish to become rolling nightclubs that enable them to 'transcend space' through partying while on the move. These mobile party spaces provide a material and symbolic centre of communion and a tight space for physical assembly that enhances the production of intense positive emotions. In a cat-and-mouse game with the police, the buses provide a sense of nomadic autonomy, and enable participants to drink heavily for days on end. The study examines how youth may creatively zone their own party spaces within the context of automobility and how these mobile spaces again shape the partying that goes on within them. While this party practice opens up for autonomy, creativity and social transgressions reminiscent of liminal phases or carnivals, at a deeper level participants clearly reproduce class-based differences and exaggerate conventional practices and symbols. PMID- 27121255 TI - Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis and hepatic fibrosis in LDLR-/ .Leiden mice. AB - BACKGROUND/OBJECTIVES: Non-alcoholic steatohepatitis (NASH) is a serious liver condition, closely associated with obesity and insulin resistance. Recent studies have suggested an important role for inflammasome/caspase-1 in the development of NASH, but the potential therapeutic value of caspase-1 inhibition remains unclear. Therefore, we aimed to investigate the effects of caspase-1 inhibition in the ongoing disease process, to mimic the clinical setting. SUBJECTS/METHODS: To investigate effects of caspase-1 inhibition under therapeutic conditions, male LDLR-/-.Leiden mice were fed a high-fat diet (HFD) for 9 weeks to induce a pre diabetic state before start of treatment. Mice were then continued on HFD for another 12 weeks, without (HFD) or with (HFD-YVAD) treatment with the caspase-1 inhibitor Ac-YVAD-cmk (40 mg kg(-1) per day). RESULTS: Nine weeks of HFD feeding resulted in an obese phenotype, with obesity-associated hypertriglyceridemia, hypercholesterolemia, hyperglycemia and hyperinsulinemia. Treatment with Ac-YVAD cmk did not affect further body weight gain or dyslipidemia, but did attenuate further progression of insulin resistance. Histopathological analysis of livers clearly demonstrated prevention of NASH development in HFD-YVAD mice: livers were less steatotic and neutrophil infiltration was strongly reduced. In addition, caspase-1 inhibition had a profound effect on hepatic fibrosis, as assessed by histological quantification of collagen staining and gene expression analysis of fibrosis-associated genes Col1a1, Acta2 and Tnfa. CONCLUSIONS: Intervention with a caspase-1 inhibitor attenuated the development of NASH, liver fibrosis and insulin resistance. Our data support the importance of inflammasome/caspase-1 in the development of NASH and demonstrate that therapeutic intervention in the already ongoing disease process is feasible. PMID- 27121257 TI - Helminth fauna of chiropterans in Amazonia: biological interactions between parasite and host. AB - Amazonia, the largest Brazilian biome, is one of the most diverse biomes around the world. Considering the Brazilian chiropteran species, 120 out of known 167 species are registered in Para state, with 10 endemic species. Despite the high diversity of bats in Amazonia, studies on their parasites, especially on helminths, are scarce. Therefore, the present study aims to study the helminth fauna of different bats from the Para state, Amazon biome, determine the descriptors of infection, and evaluate the host-parasite interactions, as well as evaluate differences in ecological indexes in accordance with the feeding guilds. The study was developed on 67 bats of 21 species captured in several areas of the Para state. The animals were identified, divided into feeding guilds, and necropsied. The parasites obtained were identified and quantified. A total of 182 parasites were found in 20.89 % of the studied bats, representing nine species, as follows: Anenterotrema eduardocaballeroi, Anenterotrema liliputianum, Ochoterenatrema caballeroi, Tricholeiperia sp., Parahistiostrongylus octacanthus, Litomosoides guiterasi, Litomosoides brasiliensis, Capillariinae gen. sp., and Hymenolepididae gen. sp. Also, the results indicated that there was no impact of parasitism on host body condition and no relationship between sex and parasite intensity. In relation to the feeding guilds, the omnivores showed higher prevalence and mean intensity. Animals from regions closer to the equator tend to have greater richness in parasite species, but the present study revealed low diversity and richness in species. In conclusion, the ecological pattern observed for other animal groups, in which higher parasitic diversity are registered in lower latitudes, is not applicable to chiropterans from the study area. PMID- 27121258 TI - Microsatellite polymorphism in the P1 promoter region of the IGF-1 gene is associated with endometrial cancer. AB - Endometrial carcinoma (EC) is the most common type of gynecological malignancy. Studies have demonstrated that the insulin growth factor (IGF) pathway is implicated in the development of endometrial tumors and that the serum levels of IGF-1 are affected by estrogen. Most EC cells with high microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the IGF 1 gene. The present study investigated the CA repeat polymorphism in the P1 promoter region of the IGF-1 gene among Caucasian females with endometrial hyperplasia, EC and healthy control subjects, whose blood serum and surgical tissue specimens were analyzed. Differences or correlations between the analyzed parameters [serum levels of IGF-1 and IGF binding protein (IGFBP)-1 and IGFBP-3 as well as estrogens among the polymorphisms] were verified using the chi2, Mann Whitney U, Kruskal-Wallis or Spearman's rank correlation tests. A PCR amplification and DNA sequencing analysis was used for identification of (CA)n repeats in the P1 region of IGF-1. ELISA was used to determine the blood serum levels of IGF-1, IGFBP-1, IGFBP-3 and estrogens. Furthermore, IGF-1 was assessed in endometrial tissues by immunohistochemical analysis. The present study indicated no statistically significant differences between serum levels of IGF-1, IGFBP-1, IGFBP-3 and estrone, estriol and estradiol in the control and study groups. A significant correlation was identified between the IGF-1 levels and estrone levels in the MSI-H polymorphism (r=-0.41, P=0.012) as well as a highly negative correlation between IGF-1 levels and the estradiol levels in the MSI-H polymorphism (r=-0.6, P=0.002). Genotypes without the 19 CA allele were predominantly found in EC. Furthermore, statistical analysis indicated that the number of IGF-1-expressing cells was significantly elevated in MSI-H type 18-20 (P=0.0072), MSI-L type 19-20 (P=0.025) and microsatellite-stable MSS type 19-19 (P=0.024) compared with those in the MSI-H 20-20 genotype. The present study suggested that it is rather likely that the polymorphisms in the IGF-1 promoter are associated with EC in Caucasian females with regard to its development. In the present study, polymorphisms of the IGF-1 promoter may have been introduced during the genesis of EC and contributed to it by leading to aberrant expression of IGF-1. PMID- 27121259 TI - Wellbeing, mental health knowledge and caregiving experiences of siblings of people with psychosis, compared to their peers and parents: an exploratory study. AB - PURPOSE: The wellbeing and caregiving experiences of family carers supporting people with psychosis has garnered increasing interest. Evidence indicates that the burden of caregiving can adversely impact on parents' wellbeing, few studies have investigated whether this is also the case for siblings, who often take on caregiving responsibilities. This exploratory study investigated the wellbeing, mental health knowledge, and appraisals of caregiving in siblings of individuals with psychosis. METHOD: Using a cross-sectional design, 90 siblings completed three validated questionnaires: Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), Mental Health Knowledge Schedule (MAKS), and Experience of Caregiving Inventory (ECI). Data obtained were compared to general population norms and parent-carers' scores. Multi-variable regression analyses were conducted to examine relationships between questionnaire scores and demographic characteristics including age, sex, birth order, marital status, accommodation and educational level. RESULTS: Siblings, especially sisters, had significantly poorer mental wellbeing, compared to normative scores. Conversely, they had better mental health knowledge. Siblings and parent-carers had comparable high levels of negative appraisals of caregiving experiences, but siblings reported more satisfaction with personal experiences and relationships. Education level was a significant predictor for better mental health knowledge; there were no other relationships between siblings' demographic factors and outcomes. CONCLUSION: Study findings suggest that siblings have overlapping as well as distinct needs, compared to parent-carers. Further research is required to better understand siblings' experiences so as to inform development of targeted interventions that enhance wellbeing and caregiving capacity. PMID- 27121260 TI - Strategy and software for the statistical spatial analysis of 3D intracellular distributions. AB - The localization of proteins in specific domains or compartments in the 3D cellular space is essential for many fundamental processes in eukaryotic cells. Deciphering spatial organization principles within cells is a challenging task, in particular because of the large morphological variations between individual cells. We present here an approach for normalizing variations in cell morphology and for statistically analyzing spatial distributions of intracellular compartments from collections of 3D images. The method relies on the processing and analysis of 3D geometrical models that are generated from image stacks and that are used to build representations at progressively increasing levels of integration, ultimately revealing statistical significant traits of spatial distributions. To make this methodology widely available to end-users, we implemented our algorithmic pipeline into a user-friendly, multi-platform, and freely available software. To validate our approach, we generated 3D statistical maps of endomembrane compartments at subcellular resolution within an average epidermal root cell from collections of image stacks. This revealed unsuspected polar distribution patterns of organelles that were not detectable in individual images. By reversing the classical 'measure-then-average' paradigm, one major benefit of the proposed strategy is the production and display of statistical 3D representations of spatial organizations, thus fully preserving the spatial dimension of image data and at the same time allowing their integration over individual observations. The approach and software are generic and should be of general interest for experimental and modeling studies of spatial organizations at multiple scales (subcellular, cellular, tissular) in biological systems. PMID- 27121261 TI - PTIR: Predicted Tomato Interactome Resource. AB - Protein-protein interactions (PPIs) are involved in almost all biological processes and form the basis of the entire interactomics systems of living organisms. Identification and characterization of these interactions are fundamental to elucidating the molecular mechanisms of signal transduction and metabolic pathways at both the cellular and systemic levels. Although a number of experimental and computational studies have been performed on model organisms, the studies exploring and investigating PPIs in tomatoes remain lacking. Here, we developed a Predicted Tomato Interactome Resource (PTIR), based on experimentally determined orthologous interactions in six model organisms. The reliability of individual PPIs was also evaluated by shared gene ontology (GO) terms, co evolution, co-expression, co-localization and available domain-domain interactions (DDIs). Currently, the PTIR covers 357,946 non-redundant PPIs among 10,626 proteins, including 12,291 high-confidence, 226,553 medium-confidence, and 119,102 low-confidence interactions. These interactions are expected to cover 30.6% of the entire tomato proteome and possess a reasonable distribution. In addition, ten randomly selected PPIs were verified using yeast two-hybrid (Y2H) screening or a bimolecular fluorescence complementation (BiFC) assay. The PTIR was constructed and implemented as a dedicated database and is available at http://bdg.hfut.edu.cn/ptir/index.html without registration. PMID- 27121263 TI - Studying the effect of Zn-substitution on the magnetic and hyperthermic properties of cobalt ferrite nanoparticles. AB - The possibility to finely control nanostructured cubic ferrites (M(II)Fe2O4) paves the way to design materials with the desired magnetic properties for specific applications. However, the strict and complex interrelation among the chemical composition, size, polydispersity, shape and surface coating renders their correlation with the magnetic properties not trivial to predict. In this context, this work aims to discuss the magnetic properties and the heating abilities of Zn-substituted cobalt ferrite nanoparticles with different zinc contents (ZnxCo1-xFe2O4 with 0 < x < 0.6), specifically prepared with similar particle sizes (~7 nm) and size distributions having the crystallite size (~6 nm) and capping agent amount of 15%. All samples have high saturation magnetisation (Ms) values at 5 K (>100 emu g(-1)). The increase in the zinc content up to x = 0.46 in the structure has resulted in an increase of the saturation magnetisation (Ms) at 5 K. High Ms values have also been revealed at room temperature (~90 emu g(-1)) for both CoFe2O4 and Zn0.30Co0.70Fe2O4 samples and their heating ability has been tested. Despite a similar saturation magnetisation, the specific absorption rate value for the cobalt ferrite is three times higher than the Zn substituted one. DC magnetometry results were not sufficient to justify these data, the experimental conditions of SAR and static measurements being quite different. The synergic combination of DC with AC magnetometry and (57)Fe Mossbauer spectroscopy represents a powerful tool to get new insights into the design of suitable heat mediators for magnetic fluid hyperthermia. PMID- 27121262 TI - Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment. AB - AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles. RESULTS: Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95-1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. CONCLUSIONS: In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment. PMID- 27121264 TI - Galanin 3 receptor-deficient mice show no alteration in the oxazolone-induced contact dermatitis phenotype. AB - Allergic contact dermatitis (ACD) is an inflammatory skin disease induced by allergen exposure and characterized by erythema, oedema and immune cell infiltration. The sensory peptide galanin (GAL) and its three receptors (GAL1-3 ) are involved in regulating inflammation. As GAL and its receptors are expressed in human and murine skin and GAL expression is increased in oxazolone-induced contact allergy, it could play a role in dermatitis. As GAL reduces neurogenic plasma extravasation in the mouse skin via GAL3 activation, the role of GAL3 in the oxazolone-induced dermatitis model was explored. Following topical challenge with oxazolone, GAL3 gene-deficient mice showed a trend towards reduced ear thickness. Plasma extravasation and neutrophil infiltration increased considerably upon oxazolone challenge in both GAL3 knockout animals and wild-type controls without any observable effect of the gene deletion. We conclude that a lack of GAL3 does not influence oxazolone-induced ACD. PMID- 27121269 TI - 2D wax-printed paper substrates with extended solvent supply capabilities allow enhanced ion signal in paper spray ionization. AB - Paper-based microfluidic channels were created from solid wax printing, and the resultant 2D wax-printed paper substrates were used for paper spray (PS) mass spectrometry (MS) analysis of small organic compounds. Controlling fluid flow at the tip of the wax-printed paper triangles enabled the use of lower spray voltages (0.5-1 kV) and extended signal lifetime (10 minutes) in PS-MS. High sensitivity (sub ng mL(-1) levels) and quantitation precision (<10% RSD) have been achieved in the analysis of illicit drugs in 4 MUL of raw urine (fresh and dry), as well as corrosion inhibitors and pesticides in water samples. The reported study encourages the future development of disposable 3D microfluidic paper-based analytical devices, which function with simple operation but capable of on-chip analyte detection by MS; such a device can replace the traditional complex laboratory procedures for MS analysis to enable on-site in situ sampling with portable mass spectrometers. PMID- 27121270 TI - Extended charge accumulation in ruthenium-4H-imidazole-based black absorbers: a theoretical design concept. AB - A theoretical-guided design concept aiming to achieve highly efficient unidirectional charge transfer and multi-charge separation upon successive photoexcitation for light-harvesting dyes in the scope of supramolecular photocatalysts is presented. Four 4H-imidazole-ruthenium(ii) complexes incorporating a biimidazole-based electron-donating ligand sphere have been designed based on the well-known 4H-imidazole-ruthenium(ii) polypyridyl dyes. The quantum chemical evaluation, performed at the density functional and time dependent density functional level of theory, revealed extraordinary unidirectional charge transfer bands from the near-infrared to the ultraviolet region of the absorption spectrum upon multi-photoexcitation. Spectro electrochemical simulations modeling photoexcited intermediates determined the outstanding multi-electron storage capacity for this novel class of black dyes. These remarkable photochemical and photophysical properties are found to be preserved upon site-specific protonation rendering 4H-imidazole-ruthenium(ii) biimidazole dyes ideal for light-harvesting applications in the field of solar energy conversion. PMID- 27121268 TI - On-body calibration and measurements using personal radiofrequency exposimeters in indoor diffuse and specular environments. AB - For the first time, response of personal exposimeters (PEMs) is studied under diffuse field exposure in indoor environments. To this aim, both numerical simulations, using finite-difference time-domain method, and calibration measurements were performed in the range of 880-5875 MHz covering 10 frequency bands in Belgium. Two PEMs were mounted on the body of a human male subject and calibrated on-body in an anechoic chamber (non-diffuse) and a reverberation chamber (RC) (diffuse fields). This was motivated by the fact that electromagnetic waves in indoor environments have both specular and diffuse components. Both calibrations show that PEMs underestimate actual incident electromagnetic fields. This can be compensated by using an on-body response. Moreover, it is shown that these responses are different in anechoic chamber and RC. Therefore, it is advised to use an on-body calibration in an RC in future indoor PEM measurements where diffuse fields are present. Using the response averaged over two PEMs reduced measurement uncertainty compared to single PEMs. Following the calibration, measurements in a realistic indoor environment were done for wireless fidelity (WiFi-5G) band. Measured power density values are maximally 8.9 mW/m(2) and 165.8 MUW/m(2) on average. These satisfy reference levels issued by the International Commission on Non-Ionizing Radiation Protection in 1998. Power density values obtained by applying on-body calibration in RC are higher than values obtained from no body calibration (only PEMs) and on body calibration in anechoic room, by factors of 7.55 and 2.21, respectively. Bioelectromagnetics. 37:298-309, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27121266 TI - Gamma-Linolenic Acid Suppresses NF-kappaBeta Signaling via CD36 in the Lipopolysaccharide-Induced Inflammatory Response in Primary Goat Mammary Gland Epithelial Cells. AB - Gamma-linolenic acid (GLA) and linoleic acid (LA), which are both n-6 unsaturated fatty acids, play vital roles in lipopolysaccharide (LPS)-induced inflammation. The multi-functional protein scavenger receptor CD36 has also been shown to participate in inflammation. However, the molecular mechanisms underlying the interactions between CD36 and GLA or LA in LPS-induced inflammation remain unclear. We used small interfering RNA and adenoviral systems to manipulate CD36 expression in primary goat mammary gland epithelial cells (pGMECs), and the results showed that nuclear factor kappa B (NF-kappaB) levels were significantly decreased by CD36 receptor signaling following treatment with GLA but not LA. GLA inhibited NF-kappaB activation in LPS-induced pGMECs. However, silencing CD36 or deleting its fatty acid-binding domain blocked the anti-inflammatory effects of GLA, resulting in an increase in NF-kappaB activation and disrupting its localization during LPS-induced inflammation. The activity of the cytokines IL 1beta, IL-6, and TNF-alpha, which act downstream of NF-kappaB, was also modulated when CD34 expression was manipulated by the addition of GLA in LPS-induced pGMECs. Our data suggest that GLA, but not LA, may interact with the CD36 fatty acid-binding domain to regulate the activation and localization of NF-kappaB in LPS-induced pGMECs. PMID- 27121271 TI - Living with constipation--older people's experiences and strategies with constipation before and during hospitalization. AB - BACKGROUND: Constipation is a common problem among older people. This study aimed to explore how older patients experience constipation and which strategies they used in handling the condition before and during hospitalization. METHODS: A qualitative exploratory research design was used. Fourteen semi-structured interviews were conducted with patients (61-91 years of age) during hospitalization. Data were analyzed by using content analysis. RESULTS: Themes concerning experiences were Bodily signs and symptoms of constipation; the participants described severe pain during constipation, as well as pronounced relief after bowel movements, Impact on well-being and social activities; being constipated negatively impacted their mood and limited social activities, Striving for bowel balance; the participants experienced an ongoing strive for balancing between constipation and diarrhea. Themes related to strategies were Struggling to find a solution; they were aware of different strategies to prevent and treat constipation, though the most common solution described was the use of laxatives, Wait and see; the participants were awaiting to take action until they experienced constipation symptoms, Constipation is a private problem being challenged during hospitalization; constipation was considered a private issue rarely discussed with health-care professionals. CONCLUSION: This study illuminates the need for health-care professionals to be attentive to this issue and initiate the conversation with patients in order to advise on the management of constipation. PMID- 27121272 TI - Salacia chinensis L. extract ameliorates abnormal glucose metabolism and improves the bone strength and accumulation of AGEs in type 1 diabetic rats. AB - Although extracts of the roots and stems of Salacia chinensis have been used in folk medicines for chronic diseases such as rheumatism, irregular menstruation, asthma and diabetes mellitus, little is known about the mechanism by which Salacia chinensis extract (SCE) ameliorates these diseases. To clarify whether SCE ameliorates the progression of lifestyle-related diseases, the inhibitory effect of SCE on the formation of advanced glycation end products (AGEs) was analyzed in a rat model of streptozotocin-induced diabetes. Although the oral administration of SCE did not ameliorate the diabetes-induced decrease in body weight, it ameliorated the increase in glycoalbumin levels in diabetic rats. An analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) demonstrated that the levels of N(epsilon)-(carboxymethyl)lysine (CML) were highest in the femurs and that they increased by the induction of diabetes. The administration of SCE also ameliorated the decreased femur strength and the accumulation of CML. Furthermore, when all of the carbohydrates in the chow of diabetic rats were replaced with free glucose, the administration of SCE significantly ameliorated a diabetes-induced increase in glycoalbumin and decrease in serum creatinine level and body weight. This study provides evidence to support that SCE ameliorates diabetes-induced abnormalities by improving the uptake of glucose by various organs. PMID- 27121273 TI - Grape seed proanthocyanidin extracts prevent hyperglycemia-induced monocyte adhesion to aortic endothelial cells and ameliorates vascular inflammation in high-carbohydrate/high-fat diet and streptozotocin-induced diabetic rats. AB - The role of grape seed proanthocyanidin extracts (GSPE) in the prevention of diabetic vascular inflammation and monocyte-endothelial cell interactions has not been examined. We used high-carbohydrate/high-fat diet and streptozotocin to induce diabetes and treated with GSPE (125, 250 and 500 mg/kg) for 24 weeks. Inflammatory response and intima-media thickness (IMT) in aortic root were observed by hematoxylin-eosin (H&E) staining. The receptor of advanced glycation end products (RAGE) expression of aortic root was assayed by immunohistochemistry. Isolation of rat aortic endothelial cell (RAEC) was used to ex vivo monocyte adhesion assay. In this study, inflammatory response and IMT were significantly increased in diabetic rats compared to non-diabetic rats, which can be reversed by GSPE (p < 0.05). Advanced glycation end products (AGEs) and RAGE in diabetic rats were significantly higher than in non-diabetic animals, but were effectively lowered by 500 mg/kg GSPE for 24 weeks (p < 0.05). There was a greater binding of WEHI 78/24 cells to RAEC isolated from diabetic rats as compared with normal rats, which can be normalized by GSPE. The concentrations of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in RAEC cell supernatant and serum of diabetic rats were greater than those in the normal rats. This study provided evidence that GSPE may be an effective agent to protect vasculature from diabetes-caused inflammation and endothelial dysfunction. PMID- 27121274 TI - Sex-biased response in activity to light sources with different spectral composition in geometrid moths with flightless females (Lepidoptera: Geometridae). AB - Geometrid moths occurring in late autumn and early spring in temperate forest habitats are often harmful defoliators of deciduous stands. Their populations can cause locally cyclic outbreaks and thus preventive monitoring actions have been developed, mainly based on pheromone attraction of males. Females are mostly flightless with reduced or lost wings and reduced senses associated with flying. Males are standard flyers with well-developed eyes and must be able to deal with rapidly changing light conditions during their activity. Although such differences indicate sex-biased differences in reactions to light, this has been insufficiently tested. In conditions of an experimental arena and using light emitting diodes, we tested the different reactions of the sexes for nine species to precisely defined short segments of the electromagnetic spectrum in the range 360-660 nm. Across all species, males preferred shorter wavelengths up to 500 nm, while females were nonselective and generally less active. The sexes differed by eye size and body mass, with males having significantly larger eyes and lower body mass. Between brachypterous and apterous females, the former had larger eye size, while body mass differences were statistically insignificant. There were differences between the sexes in move-to-light reactions and changes in eye size and body mass in line with wing reduction. While males preferred a relatively distinct range of shorter wavelengths, a method of attraction to lights with distinct narrow spectra could be used markedly to enhance the established methods of forest pest monitoring, either alone or in combination with chemical male attraction. PMID- 27121275 TI - Identification of MAC1: A Small Molecule That Rescues Spindle Bipolarity in Monastrol-Treated Cells. AB - The genetic integrity of each organism is intimately tied to the correct segregation of its genome during mitosis. Insights into the underlying mechanisms are fundamental for both basic research and the development of novel strategies to treat mitosis-relevant diseases such as cancer. Due to their fast mode of action, small molecules are invaluable tools to dissect mitosis. Yet, there is a great demand for novel antimitotic compounds. We performed a chemical genetic suppression screen to identify compounds that restore spindle bipolarity in cells treated with Monastrol, an inhibitor of the mitotic kinesin Eg5. We identified one compound-MAC1-that rescued spindle bipolarity in cells lacking Eg5 activity. Mechanistically, MAC1 induces the formation of additional microtubule nucleation centers, which allows kinesin Kif15-dependent bipolar spindle assembly in the absence of Eg5 activity. Thus, our chemical genetic suppression screen revealed novel unexpected insights into the mechanism of spindle assembly in mammalian cells. PMID- 27121276 TI - Predictors of medical school clerkship performance: a multispecialty longitudinal analysis of standardized examination scores and clinical assessments. AB - BACKGROUND: Evidence suggests that poor performance on standardized tests before and early in medical school is associated with poor performance on standardized tests later in medical school and beyond. This study aimed to explore relationships between standardized examination scores (before and during medical school) with test and clinical performance across all core clinical clerkships. METHODS: We evaluated characteristics of 435 students at Mayo Medical School (MMS) who matriculated 2000-2009 and for whom undergraduate grade point average, medical college aptitude test (MCAT), medical school standardized tests (United States Medical Licensing Examination [USMLE] 1 and 2; National Board of Medical Examiners [NBME] subject examination), and faculty assessments were available. We assessed the correlation between scores and assessments and determined USMLE 1 cutoffs predictive of poor performance (<=10th percentile) on the NBME examinations. We also compared the mean faculty assessment scores of MMS students vs visiting students, and for the NBME, we determined the percentage of MMS students who scored at or below the tenth percentile of first-time national examinees. RESULTS: MCAT scores correlated robustly with USMLE 1 and 2, and USMLE 1 and 2 independently predicted NBME scores in all clerkships. USMLE 1 cutoffs corresponding to poor NBME performance ranged from 220 to 223. USMLE 1 scores were similar among MMS and visiting students. For most academic years and clerkships, NBME scores were similar for MMS students vs all first-time examinees. CONCLUSIONS: MCAT, USMLE 1 and 2, and subsequent clinical performance parameters were correlated with NBME scores across all core clerkships. Even more interestingly, faculty assessments correlated with NBME scores, affirming patient care as examination preparation. USMLE 1 scores identified students at risk of poor performance on NBME subject examinations, facilitating and supporting implementation of remediation before the clinical years. MMS students were representative of medical students across the nation. PMID- 27121277 TI - Coping With Strain (CWS) course - its effects on depressive symptoms: A four-year longitudinal randomized controlled trial. AB - The Coping With Strain (CWS) course is a modification of the Coping With Depression (CWD) course. CWD is by far the most studied psycho-educational intervention to reduce and prevent depression, but CWD has never been tested in a randomized controlled trial in the workplace. This study seeks to examine the extent to which CWS, on a short-term and a long-term basis, reduces depressive symptoms in employees. After advertising at workplaces, 119 employees were randomized into Intervention Group I (IG1), which immediately participated in CWS, or Intervention Group II (IG2), which functioned as a control group for six months until its participation in CWS. The follow up period lasted for four years in both IG1 and IG2. Linear mixed models were fitted to the data. Depressive symptoms were significantly reduced during the course. The reduction of depressive symptoms was maintained over a period of four years in both IG1 and IG2, although there is a slight increase towards the end of the follow-up period. CWS is effective in reducing depressive symptoms among employees. The effects are long lasting and may be maintained over a period of four years. PMID- 27121278 TI - Effect of electrode position on azo dye removal in an up-flow hybrid anaerobic digestion reactor with built-in bioelectrochemical system. AB - In this study, two modes of hybrid anaerobic digestion (AD) bioreactor with built in BESs (electrodes installed in liquid phase (R1) and sludge phase (R2)) were tested for identifying the effect of electrodes position on azo dye wastewater treatment. Alizarin yellow R (AYR) was used as a model dye. Decolorization efficiency of R1 was 90.41 +/- 6.20% at influent loading rate of 800 g-AYR/ m(3).d, which was 39% higher than that of R2. The contribution of bioelectrochemical reduction to AYR decolorization (16.23 +/- 1.86% for R1 versus 22.24 +/- 2.14% for R2) implied that although azo dye was mainly removed in sludge zone, BES further improved the effluent quality, especially for R1 where electrodes were installed in liquid phase. The microbial communities in the electrode biofilms (dominant by Enterobacter) and sludge (dominant by Enterococcus) were well distinguished in R1, but they were similar in R2. These results suggest that electrodes installed in liquid phase in the anaerobic hybrid system are more efficient than that in sludge phase for azo dye removal, which give great inspirations for the application of AD-BES hybrid process for various refractory wastewaters treatment. PMID- 27121279 TI - The impact of occupational hazards and traumatic events among Belgian emergency physicians. AB - BACKGROUND: Emergency Physicians (EPs) are regularly confronted with work related traumatic events and hectic work conditions. Several studies mention a high incidence of post-traumatic stress disorder (PTSD) and psychosomatic complaints in EP. The main objective of this study is to examine the contribution of demographics, traumatic events, life events, the occurrence of occupational hazards and social support to post-traumatic stress symptoms (PTSS), psychological distress, fatigue, somatic complaints and job satisfaction in Emergency Physicians. METHODS: For this study questionnaires were distributed to Belgian Emergency Physicians, These include, as determinants socio-demographic characteristics, traumatic events, life events, the occurrence of physical hazards, occurrences of violence, occurrence of situations that increase the risk of burnout and social support by supervisors and colleagues (LQWQ-Med), and as outcomes PTSS (IES), psychological distress (BSI), somatic complaints (PHQ 15), perceived fatigue (CIS20 R) and job satisfaction (LQWQ-MD). The response rate was 52.3 %. Hierarchical multiple regression analysis was performed to examine the association between the determinants and each of the outcomes. RESULTS: Emergency Physicians are particularly vulnerable to post-traumatic and chronic stress consequences due to repetitive exposure to work related traumatic incidents such as serious injuries or death of a child/adolescent. One out of three Emergency Physicians met sub-clinical levels of anxiety and 14.5 % met a clinical level of PTSD, short for Post-Traumatic Stress Disorder. Levels of fatigue were high but not directly related to traumatic events and occupational hazards. Social support from colleagues was found to have a beneficial effect on these complaints. Job satisfaction seems to have a protective factor. All of these not only affect the Emergency Physicians themselves, but can also have an adverse impact on patient care. DISCUSSION: EPs are, according to our and other studies, confronted on a regular basis with significant, potentially traumatizing work related events. There is a higher perception of traumatic events in older Eps. We find out that 36 % of the EPs find dealing with sudden death of a young person and traumatic accident/disease involving a young person the most traumatic experience during their work activity. Three quarter of these EPs have children of their own. The results of the study show that frequency of exposure to traumatic (work) events contributes next to occurrence of situations that increase the risk of burnout to the explanation of variance in posttraumatic stress and psychological distress. The novelty of this study is that it explores the effect of specific determinants of PTSS, psychological distress, fatigue, somatic complaints and job satisfaction in Emergency Physicians. Especially occurrence of situations that increase the risk of burnout seems to have a major impact on all outcomes including job satisfaction, while occurrence of violence contributes especially to psychological distress and perceived fatigue. Lack of social support is a well known predictor of occupational stress in emergency care workers. In contrast however, good social support of colleagues at work, as we found in our study, can facilitate the recovery process after confrontation with traumatic events and occupational hazards. CONCLUSION: Emergency Physicians are particularly vulnerable to post-traumatic stress and chronic stress consequences due to repetitive exposure to work related traumatic events. Training in dealing with violence and situations that can increase the risk of burnout can reduce detrimental consequences in emergency physicians. In addition, it is suggested that emergency units are screened systematically on determinants of burnout, in view of interventions. Finally, creating a supportive work environment and training the medical staff in supportive skills with backup by experts may also reduce adverse consequences of confrontation with traumatic work events. PMID- 27121280 TI - Elemental mapping of Neuromelanin organelles of human Substantia Nigra: correlative ultrastructural and chemical analysis by analytical transmission electron microscopy and nano-secondary ion mass spectrometry. AB - Neuromelanin (NM) is a compound which highly accumulates mainly in catecholamine neurons of the substantia nigra (SN), and is contained in organelles (NM containing organelles) with lipid bodies and proteins. These neurons selectively degenerate in Parkinson's disease and NM can play either a protective or toxic role. NM-containing organelles of SN were investigated by Analytical Electron Microscopy (AEM) and Nano-Secondary Ion Mass Spectrometry (NanoSIMS) within human tissue sections with respect to ultrastructure and elemental composition. Within the NM-containing organelle, the single NM granules and lipid bodies had sizes of about 200-600 nm. Energy-Dispersive X-ray microanalysis spectra of the NM granules and lipid bodies were acquired with 100 nm beam diameter in AEM, NanoSIMS yielded elemental maps with a lateral resolution of about 150 nm. AEM yielded the quantitative elemental composition of NM granules and bound metals, e.g., iron with a mole fraction of about 0.15 atomic percent. Chemical analyses by AEM and NanoSIMS were consistent at the subcellular level so that nanoSIMS measurements have been quantitated. In NM granules of SN from healthy subjects, a significant amount of S, Fe, and Cu was found. In lipid bodies an amount of P consistent with the presence of phospholipids was measured. The improved detection limits of nanoSIMS offer new possibilities for chemical mapping, high sensitivity trace element detection, and reduced acquisition times. Variations between individual NM granules can now be investigated effectively and quantitatively by NanoSIMS mapping Cu and Fe. This should yield new insight into the changes in chemical composition of NM pigments during healthy aging and disease. Neuromelanin-containing organelles of dopamine neurons in normal human substantia nigra were investigated by analytical electron mircoscopy and secondary ion mass spectroscopy (NanoSIMS) yielding the ultrastructure and elemental composition. In neuromelanin granules a significant amount of S, Fe and Cu was found. In lipid bodies an amount of P consistent with the presence of phospholipids was measured. The improved sensitivity of NanoSIMS shows differences in chemical composition between individual neuromelanin granules and allows to study chemical changes of neuromelanin organelles during aging and disease. PMID- 27121281 TI - Formulation of venlafaxine for once daily administration using polymeric material hybrids. AB - OBJECTIVE: Controlled release venlafaxine for once daily administration. METHODS: Drug resin complexation followed by polymer encapsulation. A 4(1).2(1) factorial design was used to study the effect of polymer type and core: coat ratio on the release profile and kinetics. Polymer combinations were tried for optimisation adapting the desIMNCility function. The optimised formula was tested in rabbits against commercial extended release capsules. RESULTS: Poly-epsilon-caprolactone, poly(d, l-lactide-co-glycolide) ester and poly(d, l-lactide) ester polymers were more efficient in lowering the release rate and the initial burst release than Eudragit((r))RS100. Encapsulation at 1:1 ratio ensured complete coats and drug release sustainment. Formula prepared using 50:50 PLA/Eudragit at 1:1 ratio sustained the drug release up to 24 h with low burst release. This formula had higher venlafaxine absorption in rabbits compared to the commercial capsules. CONCLUSIONS: The optimised formula is superior to the available once-daily trials regarding enhanced bioavailability, dosage form versatility and ease of scaling up. PMID- 27121282 TI - A qualitative exploration of trial-related terminology in a study involving Deaf British Sign Language users. AB - BACKGROUND: Internationally, few clinical trials have involved Deaf people who use a signed language and none have involved BSL (British Sign Language) users. Appropriate terminology in BSL for key concepts in clinical trials that are relevant to recruitment and participant information materials, to support informed consent, do not exist. Barriers to conceptual understanding of trial participation and sources of misunderstanding relevant to the Deaf community are undocumented. METHODS: A qualitative, community participatory exploration of trial terminology including conceptual understanding of 'randomisation', 'trial', 'informed choice' and 'consent' was facilitated in BSL involving 19 participants in five focus groups. Data were video-recorded and analysed in source language (BSL) using a phenomenological approach. RESULTS AND DISCUSSION: Six necessary conditions for developing trial information to support comprehension were identified. These included: developing appropriate expressions and terminology from a community basis, rather than testing out previously derived translations from a different language; paying attention to language-specific features which support best means of expression (in the case of BSL expectations of specificity, verb directionality, handshape); bilingual influences on comprehension; deliberate orientation of information to avoid misunderstanding not just to promote accessibility; sensitivity to barriers to discussion about intelligibility of information that are cultural and social in origin, rather than linguistic; the importance of using contemporary language-in-use, rather than jargon-free or plain language, to support meaningful understanding. CONCLUSIONS: The study reinforces the ethical imperative to ensure trial participants who are Deaf are provided with optimum resources to understand the implications of participation and to make an informed choice. Results are relevant to the development of trial information in other signed languages as well as in spoken/written languages when participants' language use is different from the dominant language of the country. PMID- 27121283 TI - A novel type 2 diabetes risk allele increases the promoter activity of the muscle specific small ankyrin 1 gene. AB - Genome-wide association studies have identified Ankyrin-1 (ANK1) as a common type 2 diabetes (T2D) susceptibility locus. However, the underlying causal variants and functional mechanisms remain unknown. We screened for 8 tag single nucleotide polymorphisms (SNPs) in ANK1 between 2 case-control studies. Genotype analysis revealed significant associations of 3 SNPs, rs508419 (first identified here), rs515071, and rs516946 with T2D (P < 0.001). These SNPs were in linkage disequilibrium (r(2) > 0.80); subsequent analysis indicated that the CCC haplotype associated with increased T2D susceptibility (OR 1.447, P < 0.001). Further mapping showed that rs508419 resides in the muscle-specific ANK1 gene promoter. Allele-specific mRNA and protein level measurements confirmed association of the C allele with increased small ANK1 (sAnk1) expression in human skeletal muscle (P = 0.018 and P < 0.001, respectively). Luciferase assays showed increased rs508419-C allele transcriptional activity in murine skeletal muscle C2C12 myoblasts, and electrophoretic mobility-shift assays demonstrated altered rs508419 DNA-protein complex formation. Glucose uptake was decreased with excess sAnk1 expression upon insulin stimulation. Thus, the ANK1 rs508419-C T2D-risk allele alters DNA-protein complex binding leading to increased promoter activity and sAnk1 expression; thus, increased sAnk1 expression in skeletal muscle might contribute to T2D susceptibility. PMID- 27121284 TI - Vitamin D levels in children with familial Mediterranean fever. AB - BACKGROUND: This study aimed to determine whether vitamin D deficiency is more common in children with familial Mediterranean fever (FMF) than in healthy individuals. METHODS: The study group consisted of 100 patients diagnosed with FMF and 50 healthy children. Serum baseline 25-hydroxyvitamin D levels and other related parameters were evaluated. RESULTS: The mean (standard deviation [SD]) vitamin D levels in patients with FMF and healthy controls were 24.78 (8.35) and 28.70 (11.70) ng/mL, respectively. Patients with FMF had significantly decreased vitamin D levels compared with those in healthy controls (P = 0.039). Vitamin D levels were similar in patients with FMF with different MEFV mutations (P = 0.633). Age was significantly correlated with vitamin D levels (r = -0.235, P = 0.019). In addition, a negative correlation between parathyroid hormone and vitamin D levels was detected (rs = -0.382, P < 0.0001). CONCLUSION: This study demonstrated that vitamin D levels are lower in children with FMF than in healthy controls. We speculate that vitamin D levels should be carefully examined, and nutritional supplementation may be required in patients with FMF. Further studies with larger patient populations are needed to confirm the frequency of vitamin D deficiency in patients with FMF. PMID- 27121285 TI - The Role of Oxidative Stress in Methamphetamine-induced Toxicity and Sources of Variation in the Design of Animal Studies. AB - BACKGROUND: The prevalence of methamphetamine (MA) use has increased in recent years. In order to assess how this drug produces its effects, both clinical and preclinical studies have recently begun to focus on oxidative stress as an important biochemical mechanism in mediating these effects. OBJECTIVE: The purpose of this review is to illustrate the variation in the design of preclinical studies investigating MA exposure on oxidative stress parameters in animal models. METHOD: The experimental variables investigated and summarised include MA drug treatment, measurements of oxidative stress and antioxidant treatments that ameliorate the harmful effects of MA. RESULTS: These preclinical studies differ greatly in their experimental design with respect to the dose of MA (ranging between 0.25 and 20 mg/kg), the dosing regime (acute, binge or chronic), the time of measurement of oxidative stress (0.5 h to 2 wks after last MA administration), the antioxidant system targeted and finally the use of antioxidants including the route of administration (i.p. or p.o.), the frequency of exposure and the time of exposure (preventative or therapeutic). CONCLUSION: The findings in this paper suggest that there is a large diversity among these studies and so the interpretation of these results is challenging. For this reason, the development of guidelines and how best to assess oxidative stress in animal models may be beneficial. The use of these simple recommendations mean that results will be more comparable between laboratories and that future results generated will give us a greater understanding of the contribution of this important biochemical mechanism and its implications for the clinical scenario. PMID- 27121286 TI - Faecal short-chain fatty acids - a diagnostic biomarker for irritable bowel syndrome? AB - BACKGROUND: The diagnosis of irritable bowel syndrome (IBS) relies on symptom based criteria. A valid and reliable biomarker that could confirm the diagnosis is desirable. This study evaluated the properties of faecal short-chain fatty acids (SCFA) as diagnostic biomarkers for IBS. METHODS: Twenty-five subjects with IBS and 25 controls were included in this explanatory case-control study. Stool samples were analysed for SCFA (acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid) with gas chromatography and reported as mmol/l and molar%. In the search for the best way to distinguish between subjects with and without IBS, the total amount and the amount of each of the SCFA were measured, and the proportions and differences between the SCFA were calculated. RESULTS: In the IBS and control group, the mean age was 46.2 (SD 12.9) and 49.2 (SD 14.6), and the number of females was 13/25 (52 %) and 15/25 (60 %) respectively. The difference between propionic and butyric acid (mmol/l) had the best diagnostic properties, the area under the Receiver Operating Characteristic curve was 0.89 (95 % CI: 0.80-0.98) (p < 0.001). With a cut-off value > 0.015 mmol/l indicating IBS, the sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio were 92 %, 72 %, 3.29, 0.11 and 29.6 respectively. Similar diagnostic properties were shown for all the IBS subgroups. CONCLUSIONS: The study indicated that faecal SCFA could be a non invasive, valid and reliable biomarker for the differentiation of healthy subjects from subjects with IBS. PMID- 27121287 TI - Assessing students' perceptions of the effects of a new Canadian longitudinal pre clerkship family medicine experience. AB - BACKGROUND: Despite the implementation of longitudinal community-based pre clerkship courses in several Canadian medical schools, there is a paucity of data assessing students' views regarding their experiences. The present study sought to measure students' perceived effects of the new Longitudinal Family Medicine Experience (LFME) course at McGill University. METHODS: A 34-item questionnaire called the 'LFME Survey (Student Version)' was created, and all first-year medical students completed it online. RESULTS: The participation rate was 64% (N = 120). Eight factors were identified in the factor analysis performed: overall satisfaction, satisfaction with preceptor, knowledge, affective learning, clinical skills, teaching/feedback, professional identity/professionalism and attitude toward primary care. Factor composite scores were above 4.5/7,indicating that students had positive perceptions of the LFME. Students felt that the LFME was a valuable educational experience and that their preceptors were good role models. The course improved students' confidence, reinforced their commitment to being a physician and increased their positive attitude toward primary care. INTERPRETATION: Along with similar pre-clerkship courses, the LFME provides a valuable context for developing students' clinical skills, providing real-world cases, teaching patient-centred care and improving attitudes toward primary care. The LFME Survey appears to be a promising and innovative tool that deserves further validation. PMID- 27121288 TI - Improved estimation of the cardiac global function using combined long and short axis MRI images of the heart. AB - BACKGROUND: Estimating the left ventricular (LV) volumes at the different cardiac phases is necessary for evaluating the cardiac global function. In cardiac magnetic resonance imaging, accurate estimation of the LV volumes requires the processing a relatively large number of parallel short-axis cross-sectional images of the LV (typically from 9 to 12). Nevertheless, it is inevitable sometimes to estimate the volume from a small number of cross-sectional images, which can lead to a significant reduction of the volume estimation accuracy. This usually encountered when a number of cross-sectional images are excluded from analysis due to patient motion artifacts. In some other cases, the number of image acquisitions is reduced to accommodate patients who cannot withstand long scan times or multiple breath-holds. Therefore, it is required to improve the accuracy of estimating the LV volume from a reduced number of acquisitions. METHODS: In this work, we propose a method for accurately estimating the LV volume from a small number of images. The method combines short-axis (SAX) and long axis (LAX) cross sectional views of the heart to accurately estimate the LV volumes. In this method, the LV is divided into a set of consecutive chunks and a simple geometric model is then used to calculate the volume of each chunk. Validation and performance evaluation of the proposed method is achieved using real MRI datasets (25 patients) in addition to CT-based phantoms of human hearts. RESULTS: The results show a better performance of the proposed method relative to the other available techniques. It is shown that, at the same number of cross sectional images, the volume calculation error is significantly lower than that of current methods. In addition, the experiments show that the results of the proposed model are reproducible despite variable orientations of the imaged cross sections. CONCLUSION: A new method for calculating the LV volume from a set of SAX and LAX MR images has been developed. The proposed method is based on fusing the SAX and LAX segmented contours to accurately estimate the LV volume from a small number of images. The method was tested using simulated and real MRI datasets and the results showed improved accuracy of estimating the LV volume from small number of images. PMID- 27121290 TI - Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition. AB - The epidermal growth factor (EGFR) pathway is frequently activated in glioblastoma but the clinical efficacy of EGFR inhibitors in malignant glioma has been disappointing. The reasons for the failure of the mechanisms of resistance of these inhibitors are unclear, but may involve factors of the tumor microenvironment such as limited glucose availability and hypoxia. It was therefore examined whether glucose and oxygen influenced the response of glioma cells to EGFR inhibition. Decreased levels of glucose and oxygen led to resistance against the EGFR inhibitor PD153035, whereas high glucose amounts and normoxia sensitised glioma cells towards the inhibitor. Low levels of glucose and oxygen stimulated AMP-activated kinase (AMPK) in glioma cells. 2DG, an inhibitor of glycolysis, and the AMPK activator A769662 reduced glucose consumption, induced phosphorylation of AMPK and mimicked the effects of low glucose availability on the toxicity of PD153035. Similarly, 2DG reduced toxicity of imatinib in K562 leukemia cells. In contrast, inhibition of AMPK by compound C or by short-hairpin (sh)-mediated gene suppression increased cell death induced by the EGFR inhibitor and reverted the protective effects of 2DG and A769662. In conclusion, cytotoxicity of EGFR inhibition can be diminished by AMPK activation in glioma cells. These results may provide one explanation for the low activity of EGFR inhibitors in clinical trials and suggest antagonism of AMPK or of AMPK regulated metabolic alterations as a promising approach to enhance their therapeutic efficacy. PMID- 27121289 TI - Modelling the impact of alcohol consumption on cardiovascular disease mortality for comparative risk assessments: an overview. AB - BACKGROUND: Although alcohol consumption has long been considered as a risk factor for chronic disease, the relationship to cardiovascular disease (CVD) is complex and involves at least two dimensions: average volume of alcohol consumption and patterns of drinking. The objective of this contribution was to estimate the burden of CVD mortality caused by alcohol consumption. METHODS: Risk assessment modelling with alcohol-attributable CVD mortality as primary outcome. The mortality burden of ischaemic heart disease (IHD) and ischaemic stroke (IS) attributable to alcohol consumption was estimated using attributable-fraction methodology. Relative Risk (RR) data for IHD and IS were obtained from the most comprehensive meta-analyses (except for Russia and surrounding countries where alcohol RR data were obtained from a large cohort study). Age-group specific RRs were calculated, based on large studies. Data on mortality were obtained from the World Health Organization's Global Health Estimates and alcohol consumption data were obtained from the Global Information System on Alcohol and Health. Risk of former drinkers was modelled taking into account global differences in the prevalence of sick quitters among former drinkers. Alcohol-attributable mortality estimates for all other CVD causes except IHD and IS were obtained from the 2014 Global Status Report on Alcohol and Health. RESULTS: An estimated 780,381 CVD deaths (441,893 and 338,490 CVD deaths among men and women respectively) were attributable to alcohol consumption globally in 2012, accounting for 1.4 % of all deaths and 26.6 % of all alcohol-attributable deaths. This is in contrast to the previously estimated 1,128,273 CVD deaths attributable to alcohol consumption globally, and represents a decrease of 30.8 % in alcohol-attributable CVD mortality and of 10.6 % in the global burden of all alcohol-attributable deaths. CONCLUSIONS: When the most comprehensive and recent systematic reviews and meta analyses are taken as bases, the net impact of alcohol consumption on CVD is lower than previously estimated. PMID- 27121291 TI - Diagnostic yield of EBUS-TBNA for lymphoma and review of the literature. AB - AIM: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA), which enables cytological examination of mediastinal lymph node (LN) aspiration samples, is a safe and minimally invasive method for diagnosis and staging of lung cancer and diagnosis of diseases affecting mediastinal LNs. In this study, we investigated the yield of EBUS-TBNA for diagnosis of lymphoma and reviewed the literature since the British Thoracic Society (BTS) guidelines were published. MATERIALS AND METHODS: We retrospectively evaluated our database for patients who underwent EBUS between March 2011 and December 2014. One hundred eighty-nine patients with isolated mediastinal lymphadenopathy were included in the study. Patients with other causes of lymphadenopathy, such as lung cancer or extrathoracic malignancy, and those with pulmonary lesions accompanying mediastinal lymphadenopathy were excluded from the study. Patients with final diagnosed lymphoma were included in the study on the basis of a history of lymphoma or newly evaluated mediastinal lymphadenopathy. The sensitivity and negative predictive value (NPV) of EBUS-TBNA were calculated. RESULTS: There were 13 patients with the final diagnosis of lymphoma. Eleven of them were new diagnoses and 2 patients were known chronic lymphocytic leukemia (CLL), and underwent EBUS-TBNA for determination of recurrence. Twelve EBUS-TBNA procedures were performed for suspected new cases. Three (25%) were diagnostic, 2 (16.7%) were suspicious for lymphoma and underwent further interventions for definite diagnosis, and 7 (58.3%) were false negative. All 3 patients diagnosed with EBUS TBNA were non-Hodgkin lymphoma (NHL). None of the Hodgkin lymphoma (HL) cases could be diagnosed with EBUS-TBNA. The overall diagnostic sensitivity and NPV of EBUS-TBNA in detecting lymphoma was 65% and 96.1%, respectively. For the newly diagnosed lymphoma cases, EBUS-TBNA had a sensitivity of 61.1%. CONCLUSION: In conclusion, we believe that since the publication of the BTS guidelines, the value of EBUS-TBNA in the diagnosis of lymphoma still remains controversial. EBUS TBNA can be the first diagnostic modality in diagnosis of recurrent lymphomas. However, for suspected new cases, especially for HL, the diagnostic yield of EBUS TBNA is low and negative results do not exclude lymphoma. Further interventions such as mediastinoscopy should be performed for high-suspicion patients. PMID- 27121293 TI - George Alberti: Laid back, iconoclastic, irreverent. PMID- 27121292 TI - Contribution of cell block obtained by endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of malignant diseases and sarcoidosis. AB - AIM: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a safe and minimally invasive procedure that can be performed in outpatient settings. Several studies have demonstrated the usefulness of EBUS-TBNA in the diagnosis of sarcoidosis and malignant diseases. This study focused on the role of cell block (CB) analysis in determining the diagnostic yield of EBUS-TBNA in malignant diseases and sarcoidosis. MATERIALS AND METHODS: The study was conducted at a training and research hospital. Records of patients who underwent EBUS-TBNA between March 2011 and December 2014 for diagnosed sarcoidosis or malignancy were retrospectively analyzed. Results of all EBUS-TBNA smears and CB were separately evaluated to determine the diagnostic value of each. RESULTS: There were 84 sarcoidosis and 179 malignancy patients. In the malignancy group, CB contributed to cancer diagnosis in 15 (8.3%) patients and subclassification in 19 (10.6%) patients. In the sarcoidosis group, for 45.2% of patients (38/84), smears were not diagnostic but CB showed granulomatous inflammation. CONCLUSION: CB significantly increases the diagnostic yield of EBUS-TBNA for sarcoidosis. In our study, in the malignancy group the diagnostic yield was low but it was helpful for subclassification, especially for adenocarcinoma. PMID- 27121295 TI - Preventing injuries in professional football: thinking bigger and working together. PMID- 27121294 TI - Metabolomic patterns associated to QTc interval in shiftworkers: an explorative analysis. AB - OBJECTIVES: (1)H NMR-metabolomic approach was used to investigate QTc interval correlation with plasma metabolic profiles in shiftworkers. METHODS: Socio demographic data, electrocardiographic QTc interval and plasma metabolic profiles from 32 male shiftworkers, were correlated by multivariate regression analysis. RESULTS: We found a positive correlation between QTc interval values, body mass index, glycemia and lactate level and a negative correlation between QTc interval and both pyroglutamate and 3-hydroxybutyrate plasma level. CONCLUSIONS: Our analysis provides evidence of the association between clinical, metabolic profiles and QTc interval values. This could be used to identify markers of early effects and/or susceptibility in shiftworkers. PMID- 27121296 TI - Compressive Broad-Band Hyperspectral Sum Frequency Generation Microscopy to Study Functionalized Surfaces. AB - A broad-band sum frequency generation microscope has been developed for the study of molecular monolayers on surfaces. Because sum frequency generation is a vibrational spectroscopy based on a second-order optical process, it is uniquely sensitive to detecting a molecule's vibrational fingerprints specifically at interfaces. In this microscope, a structured illumination beam generated by a spatial light modulator is used to irradiate the sample with a series of sparsifying pseudorandom patterns. The spectra associated with each pattern are then input into a reconstruction algorithm to compressively recover the full hyperspectral image cube. As a proof-of-principle, this system performed molecule specific imaging of a microcontact-printed self-assembled monolayer of alkanethiolate on copper. This hyperspectral compressive imaging effectively recovered both spatial and spectral surface features with compression greater than 80%, meaning more than a 5-fold decrease in acquisition time compared to traditional methods. PMID- 27121297 TI - Pain tolerance predicts human social network size. AB - Personal social network size exhibits considerable variation in the human population and is associated with both physical and mental health status. Much of this inter-individual variation in human sociality remains unexplained from a biological perspective. According to the brain opioid theory of social attachment, binding of the neuropeptide beta-endorphin to MU-opioid receptors in the central nervous system (CNS) is a key neurochemical mechanism involved in social bonding, particularly amongst primates. We hypothesise that a positive association exists between activity of the MU-opioid system and the number of social relationships that an individual maintains. Given the powerful analgesic properties of beta-endorphin, we tested this hypothesis using pain tolerance as an assay for activation of the endogenous MU-opioid system. We show that a simple measure of pain tolerance correlates with social network size in humans. Our results are in line with previous studies suggesting that MU-opioid receptor signalling has been elaborated beyond its basic function of pain modulation to play an important role in managing our social encounters. The neuroplasticity of the MU-opioid system is of future research interest, especially with respect to psychiatric disorders associated with symptoms of social withdrawal and anhedonia, both of which are strongly modulated by endogenous opioids. PMID- 27121299 TI - Cutaneous Chromatophoromas in Captive Snakes. AB - Chromatophoromas are neoplasms arising from pigment-bearing cells (chromatophores) of the dermis. While isolated cases have been reported in the literature, the prevalence and biological behavior of chromatophoromas in snakes are unknown. Forty-two chromatophoromas were identified among 4663 submissions (0.9%) to a private diagnostic laboratory in a 16-year period. The most commonly affected snakes were colubrids (23 cases, 55%) and vipers (8 cases, 19%). The San Francisco garter snake was the most commonly affected species (6 cases; 14% of all affected snake species and 3.7% of all garter snake submissions). No sex predilection was found. The age of 28 snakes ranged from 5 to 27 years. Single cutaneous chromatophoromas were most commonly observed and presented as pigmented cutaneous masses or plaques along any body segment. Euthanasia or death due to progressive neoplastic disease or metastasis was reported in 8 (19%) and 4 (10%) cases, respectively. The survival time of 4 animals ranged from 4 to 36 months. Microscopically, xanthophoromas, iridophoromas, melanocytic neoplasms, and mixed chromatophoromas were identified, with melanocytic neoplasms being most common. Microscopic examination alone was generally sufficient for the diagnosis of chromatophoroma, but immunohistochemistry for S-100 and PNL-2 may be helpful for diagnosing poorly pigmented cases. Moderate to marked nuclear atypia appears to be consistently present in cutaneous chromatophoromas with a high risk of metastasis, while mitotic count, lymphatic invasion, the level of infiltration, and the degree of pigmentation or ulceration were not reliable predictors of metastasis. PMID- 27121298 TI - The C-terminal domain of Clostridium perfringens alpha toxin as a vaccine candidate against bovine necrohemorrhagic enteritis. AB - Bovine necrohemorrhagic enteritis is caused by Clostridium perfringens and leads to sudden death. Alpha toxin, together with perfringolysin O, has been identified as the principal toxin involved in the pathogenesis. We assessed the potential of alpha toxin as a vaccine antigen. Using an intestinal loop model in calves, we investigated the protection afforded by antisera raised against native alpha toxin or its non-toxic C-terminal fragment against C. perfringens-induced intestinal necrosis. Immunization of calves with either of the vaccine preparations induced a strong antibody response. The resulting antisera were able to neutralize the alpha toxin activity and the C. perfringens-induced endothelial cytotoxicity in vitro. The antisera raised against the native toxin had a stronger neutralizing activity than those against the C-terminal fragment. However, antibodies against alpha toxin alone were not sufficient to completely neutralize the C. perfringens-induced necrosis in the intestinal loop model. The development of a multivalent vaccine combining the C-terminal fragment of alpha toxin with other C. perfringens virulence factors might be necessary for complete protection against bovine necrohemorrhagic enteritis. PMID- 27121300 TI - Measuring the Elasticity of Poly-l-Proline Helices with Terahertz Spectroscopy. AB - The rigidity of poly-l-proline is an important contributor to the stability of many protein secondary structures, where it has been shown to strongly influence bulk flexibility. The experimental Young's moduli of two known poly-l-proline helical forms, right-handed all-cis (Form I) and left-handed all-trans (Form II), were determined in the crystalline state by using an approach that combines terahertz time-domain spectroscopy, X-ray diffraction, and solid-state density functional theory. Contrary to expectations, the helices were found to be considerably less rigid than many other natural and synthetic polymers, as well as differing greatly from each other, with Young's moduli of 4.9 and 9.6 GPa for Forms I and II, respectively. PMID- 27121301 TI - Quantitative determination of 15 bioactive triterpenoid saponins in different parts of Acanthopanax henryi by HPLC with charged aerosol detection and confirmation by LC-ESI-TOF-MS. AB - Triterpenoid saponins are difficult to analyze using high-performance liquid chromatography coupled to UV/vis spectrophotometry due to their lack of chromophores. This study describes the first analytical method for the determination of 15 triterpenoid saponins from the leaves, stems, root bark, and fruits of Acanthopanax henryi, using a high-performance liquid chromatography with charged aerosol detection coupled with electrospray ionization mass spectrometry method. The separation was carried out on a Kinetex XB-C18 column with an acetonitrile/water gradient as the mobile phase, followed by charged aerosol detection. The operating conditions of charged aerosol detection were set at 24 kPa for nitrogen pressure and 100 pA for the detection range. Liquid chromatography with electrospray ionization mass spectrometry is described for the identification of compounds in plant samples. The electrospray ionization mass spectrometry method involved the use of the [M + Na](+) and [M + NH4 ](+) ions for compounds 1-15 in the positive ion mode with an extracted ion chromatogram. The developed method was fully validated in terms of linearity, sensitivity, precision, repeatability, and recovery, then subsequently applied to evaluate the quality of A. henryi. PMID- 27121303 TI - Production of interleukin-4 in CD133+ cervical cancer stem cells promotes resistance to apoptosis and initiates tumor growth. AB - The cancer stem cell (CSC) theory suggests that cancer growth and invasion is dictated by the small population of CSCs within the heterogenous tumor. The aim of the present study was to elucidate the cause for chemotherapy failure and the resistance of CSCs to apoptosis. A total of ~2.3% cluster of differentiation (CD)133+ cancer stem-like side population (SP) cells were identified in cases of uterine cervical cancer. These CD133+ SP cells were found to potently initiate tumor growth and invasion, as they exhibit transcriptional upregulation of stemness genes, including octamer-binding transcription factor-4, B-cell-specific Moloney murine leukemia virus insertion site-1, epithelial cell adhesion molecule, (sex determining region Y)-box 2, Nestin and anti-apoptotic B cell lymphoma-2. In addition, the CD133+ SP cells showed resistance to multi-drug treatment and apoptosis. The present study further showed that the secretion of interleukin-4 (IL-4) in CD133+ cervical cancer SP cells promoted cell proliferation and prevented the SP cells from apoptosis. Following the neutralization of IL-4 with anti-IL-4 antibody, the CD133+ SP cells were more sensitive to drug treatment and apoptosis. Therefore, the data obtained in the present study suggested that the autocrine secretion of IL-4 promotes increased survival and resistance to cell death in CSCs. PMID- 27121302 TI - Task-related functional connectivity of the caudate mediates the association between trait mindfulness and implicit learning in older adults. AB - Accumulating evidence shows a positive relationship between mindfulness and explicit cognitive functioning, i.e., that which occurs with conscious intent and awareness. However, recent evidence suggests that there may be a negative relationship between mindfulness and implicit types of learning, or those that occur without conscious awareness or intent. Here we examined the neural mechanisms underlying the recently reported negative relationship between dispositional mindfulness and implicit probabilistic sequence learning in both younger and older adults. We tested the hypothesis that the relationship is mediated by communication, or functional connectivity, of brain regions once traditionally considered to be central to dissociable learning systems: the caudate, medial temporal lobe (MTL), and prefrontal cortex (PFC). We first replicated the negative relationship between mindfulness and implicit learning in a sample of healthy older adults (60-90 years old) who completed three event related runs of an implicit sequence learning task. Then, using a seed-based connectivity approach, we identified task-related connectivity associated with individual differences in both learning and mindfulness. The main finding was that caudate-MTL connectivity (bilaterally) was positively correlated with learning and negatively correlated with mindfulness. Further, the strength of task-related connectivity between these regions mediated the negative relationship between mindfulness and learning. This pattern of results was limited to the older adults. Thus, at least in healthy older adults, the functional communication between two interactive learning-relevant systems can account for the relationship between mindfulness and implicit probabilistic sequence learning. PMID- 27121304 TI - MicroRNA-223 Attenuates Hypoxia-induced Vascular Remodeling by Targeting RhoB/MLC2 in Pulmonary Arterial Smooth Muscle Cells. AB - There is growing evidence that microRNAs are implicated in pulmonary arterial hypertension (PAH), but underlying mechanisms remain elusive. Here, we identified that miR-223 was significantly downregulated in chronically hypoxic mouse and rat lungs, as well as in pulmonary artery and pulmonary artery smooth muscle cells (PASMC) exposed to hypoxia. Knockdown of miR-223 increased PASMC proliferation. In contrast, miR-223 overexpression abrogated cell proliferation, migration and stress fiber formation. Administering miR-223 agomir in vivo antagonized hypoxia induced increase in pulmonary artery pressure and distal arteriole muscularization. RhoB, which was increased by hypoxia, was identified as one of the targets of miR-223. Overexpressed miR-223 suppressed RhoB and inhibited the consequent phosphorylation of myosin phosphatase target subunit (MYPT1) and the expression of myosin light chain of myosin II (MLC2), which was identified as another target of miR-223. Furthermore, serum miR-223 levels were decreased in female patients with PAH associated with congenital heart disease. Our study provides the first evidence that miR-223 can regulate PASMC proliferation, migration, and actomyosin reorganization through its novel targets, RhoB and MLC2, resulting in vascular remodeling and the development of PAH. It also highlights miR-223 as a potential circulating biomarker and a small molecule drug for diagnosis and treatment of PAH. PMID- 27121306 TI - TriGuardTM HDH embolic deflection device for cerebral protection during transcatheter aortic valve replacement. AB - OBJECTIVES: This study aims to evaluate the safety and performance of the new embolic deflection device TriGuardTMHDH in patients undergoing TAVR. BACKGROUND: Transcatheter aortic valve replacement (TAVR) is associated with a high incidence of new cerebral ischemic lesions. The use of an embolic protection device may reduce the frequency of TAVR-related embolic events. METHODS: This prospective, single arm feasibility pilot study included 14 patients with severe symptomatic aortic stenosis scheduled for TAVR. Cerebral diffusion weighted magnetic resonance imaging (DWI) was planned in all patients one day before and at day 4 (+/-2) after the procedure. Major adverse cerebral and cardiac events (MACCEs) were recorded for all patients. Primary endpoints of this study were I) device performance success defined as coverage of the aortic arch takeoffs throughout the entire TAVR procedure and II) MACCE occurrence. Secondary endpoints included the number and the volume of new cerebral ischemic lesions on DWI. RESULTS: Thirteen patients underwent transfemoral TAVR and one patient a transapical procedure. Edwards SAPIEN valve prosthesis was implanted in 8 (57%) patients and Medtronic CoreValve prosthesis in the remaining 6 (43%). Predefined performance success of the TriGuardTMHDH device was achieved in 9 (64%) patients. The composite endpoint MACCE occurred in none of the patients. Post-procedural DWI was performed in 11 patients. Comparing the DWI of these patients to a historical control group showed no reduction in number [median 5.5 vs. 5.0, P = 0.857], however there was a significant reduction in mean lesion volume per patient [median 13.8 vs. 25.1, P = 0.049]. CONCLUSION: This study showed the feasibility and safety of using the TriGuardTMHDH for cerebral protection during TAVR. This device did not decrease the number of post-procedural new cerebral DWI lesions, however its use showed decreased lesion volume as compared to unprotected TAVR. (c) 2016 Wiley Periodicals, Inc. PMID- 27121305 TI - Pathophysiology and management of multivalvular disease. AB - Multivalvular disease (MVD) is common among patients with valvular disease, and has a complex pathophysiology dependent on the specific combination of valve lesions. Diagnosis is challenging because several echocardiographic methods commonly used for the assessment of stenosis or regurgitation have been validated only in patients with single-valve disease. Decisions about the timing and type of treatment should be made by a multidisciplinary heart valve team, on a case-by case basis. Several factors should be considered, including the severity and consequences of the MVD, the patient's life expectancy and comorbidities, the surgical risk associated with combined valve procedures, the long-term risk of morbidity and mortality associated with multiple valve prostheses, and the likelihood and risk of reoperation. The introduction of transcatheter valve therapies into clinical practice has provided new treatment options for patients with MVD, and decision-making algorithms on how to combine surgical and percutaneous treatment options are evolving rapidly. In this Review, we discuss the pathophysiology, diagnosis, and treatment of MVD, focusing on the combinations of valve pathologies that are most often encountered in clinical practice. PMID- 27121307 TI - Proteomic mapping of p53 immunogenicity in pancreatic, ovarian, and breast cancers. AB - PURPOSE: Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53-specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation status and epitope specificity. EXPERIMENTAL DESIGN: IgG p53 autoantibodies (p53-AAb), were quantified in 412 serum samples using a programmable ELISA assay from patients with serous ovarian, pancreatic adenocarcinoma, and breast cancer. To determine if patients generated mutation-specific autoantibodies we designed a panel of the most relevant 51 p53 point mutant proteins, to be displayed on custom programmable protein microarrays. To determine the epitope specificity we displayed 12 overlapping tiling fragments and 38 N- and C-terminal deletions spanning the length of the wild-type p53 protein. RESULTS: We detected p53-AAb with sensitivities of 58.8% (ovarian), 22% (pancreatic), 32% (triple negative breast cancer), and 10.2% (HER2+ breast cancer) at 94% specificity. Sera with p53 AAb contained broadly reactive autoantibodies to 51 displayed p53 mutant proteins, demonstrating a polyclonal response to common epitopes. All p53-AAb displayed broad polyclonal immune response to both continuous and discontinuous epitopes at the N- and C-terminus as well as the DNA-binding domain. CONCLUSION AND CLINICAL RELEVANCE: In this comprehensive analysis, mutations in tumor p53 induce strong, polyclonal autoantibodies with broadly reactive epitope specificity. PMID- 27121308 TI - Charting a Key Competency Domain: Understanding Resident Physician Interprofessional Collaboration (IPC) Skills. AB - BACKGROUND: Interprofessional collaboration (IPC) is essential for quality care. Understanding residents' level of competence is a critical first step to designing targeted curricula and workplace learning activities. In this needs assessment, we measured residents' IPC competence using specifically designed Objective Structured Clinical Exam (OSCE) cases and surveyed residents regarding training needs. METHODS: We developed three cases to capture IPC competence in the context of physician-nurse collaboration. A trained actor played the role of the nurse (Standardized Nurse - SN). The Interprofessional Education Collaborative (IPEC) framework was used to create a ten-item behaviorally anchored IPC performance checklist (scored on a three-point scale: done, partially done, well done) measuring four generic domains: values/ethics; roles/responsibilities; interprofessional communication; and teamwork. Specific skills required for each scenario were also assessed, including teamwork communication (SBAR and CUS) and patient-care-focused tasks. In addition to evaluating IPC skills, the SN assessed communication, history-taking and physical exam skills. IPC scores were computed as percent of items rated well done in each domain (Cronbach's alpha > 0.77). Analyses include item frequencies, comparison of mean domain scores, correlation between IPC and other skills, and content analysis of SN comments and resident training needs. RESULTS: One hundred and seventy-eight residents (of 199 total) completed an IPC case and results are reported for the 162 who participated in our medical education research registry. IPC domain scores were: Roles/responsibilities mean = 37 % well done (SD 37 %); Values/ethics mean = 49 % (SD 40 %); Interprofessional communication mean = 27 % (SD 36 %); Teamwork mean = 47 % (SD 29 %). IPC was not significantly correlated with other core clinical skills. SNs' comments focused on respect and IPC as a distinct skill set. Residents described needs for greater clarification of roles and more workplace-based opportunities structured to support interprofessional education/learning. CONCLUSIONS: The IPC cases and competence checklist are a practical method for conducting needs assessments and evaluating IPC training/curriculum that provides rich and actionable data at both the individual and program levels. PMID- 27121309 TI - Hepatitis B virus X protein amplifies TGF-beta promotion on HCC motility through down-regulating PPM1a. AB - Over-activation of transforming growth factor-beta (TGF-beta) signaling pathway promotes cell migration and invasion in hepatocellular carcinoma (HCC). The Hepatitis B virus X protein (HBx) is involved in the enhancement of TGF-beta signaling pathway in HCC while the mechanism remains unclear. Protein phosphatase magnesium dependent 1A (PPM1a) functions as a phosphatase essential for terminating the TGF-beta signaling pathway by dephosphorylating p-Smad2/3. In this study, we found that HBx dose-dependently downregulated PPM1a protein level in the presence of TGF-beta, while having no effect on its mRNA level. Further study showed that HBx increased the ubiquitination of PPM1a and accelerated its proteasomal degradation. Restoration of PPM1a almost completely abrogated HBx mediated promotion on HCC migration and invasion. This involvement of PPM1a in HBx-related HCC was further confirmed with immunohistochemical analysis in HCC tissue. Compared with paired pericarcinous tissue, HCC tissue showed decreased PPM1a level. Besides, PPM1a level is negatively correlated with HBx expression. Taken together, our present study suggests that HBx-induced degradation of PPM1a is a novel mechanism for over-activation of TGF-beta pathway in HCC development, which might provide potential candidates for clinical diagnosis and treatment. PMID- 27121310 TI - NRAS germline variant G138R and multiple rare somatic mutations on APC in colorectal cancer patients in Taiwan by next generation sequencing. AB - Colorectal cancer (CRC) arises from mutations in a subset of genes. We investigated the germline and somatic mutation spectrum of patients with CRC in Taiwan by using the AmpliSeq Cancer Hotspot Panel V2. Fifty paired freshly frozen stage 0-IV CRC tumors and adjacent normal tissue were collected. Blood DNA from 20 healthy donors were used for comparison of germline mutations. Variants were identified using an ion-torrent personal genomic machine and subsequently confirmed by Sanger sequencing or pyrosequencing. Five nonsynonymous germline variants on 4 cancer susceptible genes, CDH1, APC, MLH1, and NRAS, were observed in 6 patients with CRC (12%). Among them, oncogene NRAS G138R variant was identified as having a predicted damaging effect on protein function, which has never been reported by other laboratories. CDH1 T340A variants were presented in 3 patients. The germline variants in the cancer patients differed completely from those found in asymptomatic controls. Furthermore, a total of 56 COSMIC and 21 novel somatic variants distributed in 20 genes were detected in 44 (88%) of the CRC samples. High inter- and intra-tumor heterogeneity levels were observed. Nine rare variants located in the beta-catenin binding region of the APC gene were discovered, 7 of which could cause amino acid frameshift and might have a pathogenic effect. In conclusion, panel-based mutation detection by using a high throughput sequencing platform can elucidate race-dependent cancer genomes. This approach facilitates identifying individuals at high risk and aiding the recognition of novel mutations as targets for drug development. PMID- 27121311 TI - Triterpenoid herbal saponins enhance beneficial bacteria, decrease sulfate reducing bacteria, modulate inflammatory intestinal microenvironment and exert cancer preventive effects in ApcMin/+ mice. AB - Saponins derived from medicinal plants have raised considerable interest for their preventive roles in various diseases. Here, we investigated the impacts of triterpenoid saponins isolated from Gynostemma pentaphyllum (GpS) on gut microbiome, mucosal environment, and the preventive effect on tumor growth. Six week old ApcMin/+ mice and their wild-type littermates were fed either with vehicle or GpS daily for the duration of 8 weeks. The fecal microbiome was analyzed by enterobacterial repetitive intergenic consensus (ERIC)-PCR and 16S rRNA gene pyrosequencing. Study showed that GpS treatment significantly reduced the number of intestinal polyps in a preventive mode. More importantly, GpS feeding strikingly reduced the sulfate-reducing bacteria lineage, which are known to produce hydrogen sulfide and contribute to damage the intestinal epithelium or even promote cancer progression. Meanwhile, GpS also boosted the beneficial microbes. In the gut barrier of the ApcMin/+ mice, GpS treatment increased Paneth and goblet cells, up-regulated E-cadherin and down-regulated N-cadherin. In addition, GpS decreased the pro-oncogenic beta-catenin, p-Src and the p-STAT3. Furthermore, GpS might also improve the inflamed gut epithelium of the ApcMin/+ mice by upregulating the anti-inflammatory cytokine IL-4, while downregulating pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-18. Intriguingly, GpS markedly stimulated M2 and suppressed M1 macrophage markers, indicating that GpS altered mucosal cytokine profile in favor of the M1 to M2 macrophages switching, facilitating intestinal tissue repair. In conclusion, GpS might reverse the host's inflammatory phenotype by increasing beneficial bacteria, decreasing sulfate-reducing bacteria, and alleviating intestinal inflammatory gut environment, which might contribute to its cancer preventive effects. PMID- 27121313 TI - Correlational study on mitochondrial DNA mutations as potential risk factors in breast cancer. AB - The presented study performed an mtDNA genome-wide association analysis to screen the peripheral blood of breast cancer patients for high-risk germline mutations. Unlike previous studies, which have used breast tissue in analyzing somatic mutations, we looked for germline mutations in our study, since they are better predictors of breast cancer in high-risk groups, facilitate early, non-invasive diagnoses of breast cancer and may provide a broader spectrum of therapeutic options. The data comprised 22 samples of healthy group and 83 samples from breast cancer patients. The sequencing data showed 170 mtDNA mutations in the healthy group and 393 mtDNA mutations in the disease group. Of these, 283 mtDNA mutations (88 in the healthy group and 232 in the disease group) had never been reported in the literature. Moreover, correlation analysis indicated there was a significant difference in 32 mtDNA mutations. According to our relative risk analysis of these 32 mtDNA mutations, 27 of the total had odds ratio values (ORs) of less than 1, meaning that these mutations have a potentially protective role to play in breast cancer. The remaining 5 mtDNA mutations, RNR2-2463 indelA, COX1 6296 C>A, COX1-6298 indelT, ATP6-8860 A>G, and ND5-13327 indelA, whose ORs were 8.050, 4.464, 4.464, 5.254 and 4.853, respectively, were regarded as risk factors of increased breast cancer. The five mutations identified here may serve as novel indicators of breast cancer and may have future therapeutic applications. In addition, the use of peripheral blood samples was procedurally simple and could be applied as a non-invasive diagnostic technique. PMID- 27121312 TI - miR186 suppresses prostate cancer progression by targeting Twist1. AB - Prostate cancer (PCa) is the second leading cause of cancer-related deaths in north American men, and most its related deaths are due to advanced and metastatic PCa. However, the molecular mechanisms underlying PCa progression are still unclear. Here we use a pair of prostate cell lines P69/M12, which have the same genetic background and the highly metastatic cell line M12 is a subline derived from P69, to identify the pathogenesis of PCa. We find that a key miRNA- miR186 is significantly reduced in M12 compared to that in P69. Further, we validate that miR186 is also downregulated in human PCa specimens, most significantly in the metastatic patient specimens. The low miR186 expression is correlated with poor patient survival. Through knockdown or overexpression of miR186 in PCa cell lines, we discover that miR186 strongly inhibits cell motility, invasive, soft-agar colony formation, 3D culture growth and vasculogenic mimicry (VM) formation capacity, as well as the epithelial-to mesenchymal transition (EMT) process by downregulation of its target Twist1. Moreover, the inverse relationship between the expression levels of miR186 and Twist1 is confirmed in vivo tumor metastasis experiment and clinical specimens. Taken together, our findings demonstrate an important role of miR186/Twist1 axis in the regulation of PCa progression, suggesting a potential application of miR186/Twist1 in PCa treatment. PMID- 27121314 TI - Mitochondrial transplantation attenuates hypoxic pulmonary vasoconstriction. AB - Hypoxia triggers pulmonary vasoconstriction, however induces relaxation of systemic arteries such as femoral arteries. Mitochondria are functionally and structurally heterogeneous between different cell types. The aim of this study was to reveal whether mitochondrial heterogeneity controls the distinct responses of pulmonary versus systemic artery smooth muscle cells to hypoxia. Intact mitochondria were transplanted into Sprague-Dawley rat pulmonary artery smooth muscle cells in culture and pulmonary arteries in vitro. Mitochondria retained functional after transplantation. The cross transplantation of mitochondria between pulmonary and femoral artery smooth muscle cells reversed acute hypoxia induced alterations in cell membrane potential, [Ca2+]i signaling in smooth muscle cells and constriction or relaxation of arteries. Furthermore, the high or low amount of reactive oxygen species generation from mitochondria and their divergent (dis-)abilities in activating extracellular Ca2+-sensing receptor in smooth muscle cells were found to cause cell membrane potential depolarization, [Ca2+]i elevation and constriction of pulmonary arteries versus cell membrane potential hyperpolarization, [Ca2+]i decline and relaxation of femoral arteries in response to hypoxia, respectively. Our findings suggest that mitochondria necessarily determine the behaviors of vascular smooth muscle cells in response to hypoxia. PMID- 27121315 TI - CDX2 increases SLC7A7 expression and proliferation of pig intestinal epithelial cells. AB - Nutrient absorption mediated by nutrient transporters expressed in the intestinal epithelium supplies substrates to support intestinal processes, including epithelial cell proliferation. We evaluated the role of Caudal type homeobox 2 (CDX2), an intestine-specific transcription factor, in the proliferation of pig intestinal epithelial cells (IPEC-1) and searched for novel intestinal nutrient transporter genes activated by CDX2. Our cloned pig CDX2 cDNA contains a "homeobox" DNA binding motif, suggesting it is a transcriptional activator. CDX2 overexpression in IPEC-1 cells increased cell proliferation, the percentage of cells in S/G2 phase, and the abundance of transcripts of the cell cycle-related genes Cyclin A2; Cyclin B; Cyclin D2; proliferating cell nuclear antigen; and cell cycle cyclin-dependent kinases 1, 2 and 4, as well as the predicted CDX2 target genes SLC1A1, SLC5A1 and SLC7A7. In addition, luciferase reporter and chromatin immunoprecipitation assays revealed that CDX2 binds directly to the SLC7A7 promoter. This is the first report of CDX2 function in pig intestinal epithelial cells and identifies SLC7A7 as a novel CDX2 target gene. Our findings show that nutrient transporters are activated during CDX2-induced proliferation of normal intestinal epithelial cells. PMID- 27121316 TI - Epigenetic modification of miR-141 regulates SKA2 by an endogenous 'sponge' HOTAIR in glioma. AB - Aberrant expression of miR-141 has recently implicated in the occurrence and development of various types of malignant tumors. However whether the involvement of miR-141 in the pathogenesis of glioma remains unknown. Here, we showed that miR-141 was markedly downregulated in glioma tissues and cell lines compared with normal brain tissues, and its expression correlated with the pathological grading. Enforced expression of miR-141 in glioma cells significantly inhibited cell proliferation, migration and invasion, whereas knockdown of miR-141 exerted opposite effect. Mechanistic investigations revealed that HOTAIR might act as an endogenous 'sponge' of miR-141, thereby regulating the derepression of SKA2. Further, we explored the molecular mechanism by which miR-141 expression was regulated, and found that the miR-141 promoter was hypermethylated and that promoter methylation of miR-141 was mediated by DNMT1 in glioma cells. Finally, both overexpression of miR-141 and knockdown of HOTAIR in a mouse model of human glioma resulted in significant reduction of tumor growth in vivo. Collectively, these results suggest that epigenetic modification of miR-141 and the interaction of ceRNA regulatory network will provide a new approach for therapeutics against glioma. PMID- 27121317 TI - The role of histamine in opening blood-tumor barrier. AB - Blood-tumor barrier (BTB) reduce the permeability for drugs into tumor tissues. We found that histamine might serve as an essential regulator of BTB function. Further, we aim to determine the role of H2 receptor expression in BTB permeability, and elucidate the underlying mechanisms thereof. Transmission electron microscopy showed that histamine disrupted the integrity of tight junctions (TJ) and increased the number of pinosomes in the cytoplasm. Horseradish peroxidase (HRP) and trans-endothelial resistance detection (TEER) assays revealed that histamine could open BTB and this action was inhibited by cimetidine. Western blot and immunofluorescence assays showed that histamine decreased the expression of tight junction proteins zonula occluden-1(ZO-1), occludin, and claudin-5. Further, quantitative RT-PCR assay showed that the expression of H2 receptor could represent and predicted histamine-induced BTB permeability. In conclusion, histamine opened BTB by down-regulating the TJ associated proteins. The levels of H2 receptor expression was correlated with the histamine-induced BTB permeability. PMID- 27121318 TI - Chemolipiodolization with or without embolization in transcatheter arterial chemoembolization combined with radiofrequency ablation for hepatocellular carcinoma-propensity score matching analysis. AB - To retrospectively compare the outcome of chemolipiodolization with or without embolization in transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) in Patients with hepatocellular carcinoma (HCC) within the Milan criteria. From August 2002 to December 2014, 112 patients (median age, 56.7 years; age range, 22-80 years; 97 men, 15 women) underwent TACE with gelatin sponge particle embolization, and 125 patients (median age, 56.6 years; age range, 23-82 years; 109 men, 16 women) underwent TACE without embolization. RFA was performed within 2 weeks after the TACE. Cumulative overall survival (OS) and disease-free survival (DFS) rates were compared before and after propensity score matching. Before matching, the 1-, 3-, and 5-year OS rate were 96%, 80%, and 62% for embolization group and 94%, 76%, and 59% for non embolization group . The 1-, 3-, and 5-year DFS rate were 77%, 38%, and 30% for embolization group and 75%, 35%, and 26% for non-embolization group. After matching, the 1-, 3-, and 5-year OS rate were 97%, 82%, and 62% for embolization group and 92%, 74%, and 56% for non-embolization group. The 1-, 3-, and 5-year DFS rate were 79%, 36%, and 30% for embolization group and 74%, 33%, and 26% for non-embolization group. There were no significant difference in OS and DFS rates between the two groups before matching (P =0.999 and P =0.654) and after matching (P =0.951 and P =0.670). In conclusion, embolization in TACE combined with RFA could not improve the survival for patients with HCC within the Milan criteria. PMID- 27121319 TI - TET1 inhibits gastric cancer growth and metastasis by PTEN demethylation and re expression. AB - Ten-Eleven Translocation 1 (TET1) is a member of ten eleven translocation enzymes, which convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5 hmC). TET1 can promote CpG islands demethylation in specific genes and often absent in various cancers. Herein, we found that TET1 expression and 5-hmC content were low in gastric tumors compared to its adjacent non-tumor tissues. Cell proliferation, migration and invasion were enhanced upon TET1 knockdown in gastric cancer cells in vitro. This phenomenon was confirmed by an animal xeongraft model. We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands. TET1 knockdown activated AKT and FAK pathways, which were suppressed by PTEN. The activation of AKT and FAK facilitated tumor migration, invasion and accelerated cell growth. In conclusion, we found a novel mechanism that TET1 suppresses tumor cell growth, migration and invasion through demethylation of CpG island in PTEN promoter by increasing 5-hmC content. The re-expressed PTEN subsequently down regulates AKT and FAK activity. PMID- 27121320 TI - Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma. AB - Glioblastoma is the most frequent malignant brain tumor. Even with aggressive treatment, prognosis for patients is poor. One characteristic of glioblastoma cells is its intrinsic resistance to apoptosis. Therefore, drugs that induce alternative cell deaths could be interesting to evaluate as alternative therapeutic candidates for glioblastoma. Salinomycin (SLM) was identified through a chemical screening as a promising anticancer drug, but its mechanism of cell death remains unclear. In the present work we set out to elucidate how SLM causes cell death in glioblastoma cell lines (both established cell lines and brain tumor stem cell lines), aiming to find a potential antitumor candidate. In addition, we sought to determine the mechanism of action of SLM so that this mechanism can be can be exploited in the fight against cancer. Our data showed that SLM induces a potent endoplasmic reticulum (ER) stress followed by the trigger of the unfolded protein response (UPR) and an aberrant autophagic flux that culminated in necrosis due to mitochondria and lysosomal alterations. Of importance, the aberrant autophagic flux was orchestrated by the production of Reactive Oxygen Species (ROS). Alleviation of ROS production restored the autophagic flux. Altogether our data suggest that in our system the oxidative stress blocks the autophagic flux through lipid oxidation. Importantly, oxidative stress could be instructing the type of cell death in SLM-treated cells, suggesting that cell death modality is a dynamic concept which depends on the cellular stresses and the cellular mechanism activated. PMID- 27121321 TI - Systematic review with network meta-analysis: Comparative efficacy of oral nucleos(t)ide analogues for the prevention of chemotherapy-induced hepatitis B virus reactivation. AB - OBJECTIVES: Currently, no consensus exists regarding the optimal oral prophylactic regimens for hepatitis B surface antigen seropositive patients undergoing chemotherapy. We aimed to compare the efficacy of oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of chemotherapy-induced hepatitis B virus (HBV) reactivation and its related morbidity and mortality in patients with chronic HBV (CHB) infection. RESULTS: Fifty-two eligible articles consisting of 3892 participants were included. For HBV reactivation, prophylactic treatment with NAs were all significantly superior to no prophylaxis, with odds ratio (OR) from 0.00 (95% confidence interval [CI] 0.00~0.04) for the most effective intervention (tenofovir) to 0.10 (95% CI 0.06~0.14) for the least effective intervention (lamivudine). For secondary outcomes, prophylaxis with NAs also significantly outperformed observation. The results suggested that entecavir reduced the risk of HBV related hepatitis (predicted probability, 83%), HBV related death (68%) and all causes of hepatitis (97%) most efficaciously. It ranked second in decreasing all causes of death (34%). MATERIALS AND METHODS: PubMed, Embase and Cochrane Library database were searched for controlled trials up to March 31, 2015. Primary outcome was the incidence of HBV reactivation. Secondary outcomes included the incidence of HBV-related hepatitis and death, all causes of hepatitis and death. Network meta-analysis combined direct and indirect evidence to estimate ORs for the clinical outcomes. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment based on clinical outcomes. CONCLUSIONS: Available evidence suggests that prophylatic therapy with tenofovir and entecavir may be the most potent interventions in prevention of HBV reactivation and HBV-related morbidity and mortality for CHB infection patients undergoing chemotherapy. PMID- 27121322 TI - A functional variant at miRNA-122 binding site in IL-1a 3' UTR predicts risk of recurrence in patients with oropharyngeal cancer. AB - IL-1a, an important regulator of immune and inflammation responses, has been implicated in cancer development and prognosis. An insertion (Ins)/deletion (Del) polymorphism (IL-1a rs3783553) in the 3' UTR of IL-1a may disrupt a binding site for miRNA-122 and may affect its transcription level. Thus, this polymorphism may cause interindividual variation in immune and inflammation responses and thus may lead to different susceptibility to treatment response and prognosis of such patients. We evaluated the association of IL-1a rs3783553 polymorphism with risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP) in a cohort of 1008 patients. Log-rank test and univariate and multivariable Cox models were used to evaluate associations. Compared with patients with Del/Del homozygous genotype, the patients with Ins/Del+Ins/Ins variant genotypes had worse disease free survival (log-rank P < 0.0001) and increased risk of SCCOP recurrence (HR, 2.4, 95% CI, 1.7-3.3) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, the patients with Ins/Del+Ins/Ins variant genotypes of the IL-1a polymorphism had worse disease-free survival (log-rank P < 0.0001) and much higher recurrence risk than those with Del/Del homozygous genotype of this polymorphism (HR, 16.3, 95% CI, 5.0-52.7). Our findings suggest that IL-1a rs3783553 polymorphism may modulate the risk of SCCOP recurrence in patients, particularly for patients with HPV16-positive tumors. However, larger studies are needed to validate these results. PMID- 27121323 TI - Gene expression in normal-appearing tissue adjacent to prostate cancers are predictive of clinical outcome: evidence for a biologically meaningful field effect. AB - PURPOSE: We evaluated gene expression in histologically normal-appearing tissue (NT) adjacent to prostate tumor in radical prostatectomy specimens, assessing for biological significance based on prediction of clinical recurrence (cR - metastatic disease or local recurrence). RESULTS: A total of 410 evaluable patients had paired tumor and NT. Forty-six genes, representing diverse biological pathways (androgen signaling, stromal response, stress response, cellular organization, proliferation, cell adhesion, and chromatin remodeling) were associated with cR in NT (FDR < 20%), of which 39 concordantly predicted cR in tumor (FDR < 20%). Overall GPS and its stromal response and androgen-signaling gene group components also significantly predicted time to cR in NT (RM-corrected HR/20 units = 1.25; 95% CI: 1.01-1.56; P = 0.024). EXPERIMENTAL DESIGN: Expression of 732 genes was measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) separately in tumor and adjacent NT specimens from 127 patients with and 374 without cR following radical prostatectomy for T1/T2 prostate cancer. A 17-gene expression signature (Genomic Prostate Score [GPS]), previously validated to predict aggressive prostate cancer when measured in tumor tissue, was also assessed using pre-specified genes and algorithms. Analysis used Cox proportional hazards models, Storey's false discovery rate (FDR) control, and regression to the mean (RM) correction. CONCLUSIONS: Gene expression profiles, including GPS, from NT adjacent to tumor can predict prostate cancer outcome. These findings suggest that there is a biologically significant field effect in primary prostate cancer that is a marker for aggressive disease. PMID- 27121324 TI - Silencing of long non-coding RNA ANRIL inhibits the development of multidrug resistance in gastric cancer cells. AB - The development of multidrug resistance (MDR) is a crucial cause of therapy failure in gastric cancer, which results in disease recurrence and metastasis. Long non-coding RNAs (lncRNAs) have been proven to be critical in carcinogenesis and metastasis of gastric cancer. However, little is known about the roles of ANRIL (antisense non-coding RNA in the INK4 locus) in gastric cancer MDR. The aim of our study is to identify the biological function of ANRIL in gastric cancer MDR. In our results, ANRIL was highly expressed in gastric cancer tissues of cisplatin-resistant and 5-fluorouracil (5-FU)-resistant patients, and the same upregulation trends were observed in cisplatin-resistant cells (BGC823/DDP) and 5 FU-resistant cells (BGC823/5-FU). In addition, BGC823/DDP and BGC823/5-FU cells transfected with ANRIL siRNA and treated with cisplatin or 5-FU, respectively, exhibited significant lower survival rate, decreased invasion capability, and high percentage of apoptotic tumor cells. The influence of ANRIL knockdown on MDR was assessed by measuring IC50 of BGC823/DDP and BGC823/5-FU cells to cisplatin and 5-FU, the result showed that silencing ANRIL decreased the IC50 values in gastric cancer cells. Moreover, qRT-PCR and western blotting revealed that ANRIL knockdown decreased the expression of MDR1 and MRP1, both of which are MDR related genes; regression analysis showed that the expression of ANRIL positively correlated with the expression of MDR1 and MRP1, resprectively In summary, knockdown of lncRNA ANRIL in gastric cancer cells inhibits the development of MDR, suggesting an efficacious target for reversing MDR in gastric cancer therapy. PMID- 27121325 TI - Different flowering response to various fruit loads in apple cultivars correlates with degree of transcript reaccumulation of a TFL1-encoding gene. AB - In many perennial fruit trees, flowering in the year following a year with heavy fruit load can be quite limited. This biennial cycle of fruiting, termed alternate bearing, was described 170 years ago in apple (Malus domestica). Apple inflorescences are mainly found on short branches (spurs). Bourse shoots (BS) develop from the leaf axils of the spur. BS apices may terminate ~100 days after flowering, with formation of next year's inflorescences. We sought to determine how developing fruit on the spur prevents the adjacent BS apex from forming an inflorescence. The presence of adjacent fruit correlated with reaccumulation of transcript encoding a potential flowering inhibitor, MdTFL1-2, in BS apices prior to inflorescence initiation. BS apices without adjacent fruit that did not flower due to late fruitlet removal, neighbouring fruit on the tree, or leaf removal, also reaccumulated the MdTFL1-2 transcript. Fruit load and gibberellin (GA) application had similar effects on the expression of MdTFL1-2 and genes involved in GA biosynthesis and metabolism. Some apple cultivars are less prone to alternate bearing. We show that the response of a BS apex to different numbers of adjacent fruit differs among cultivars in both MdTFL1-2 accumulation and return flowering. These results provide a working model for the further study of alternate bearing, and help clarify the need for cultivar-specific approaches to reach stable fruit production. PMID- 27121326 TI - Role of Aif1 in regulation of cell death under environmental stress in Candida albicans. AB - Apoptosis-inducing factor (AIF) is a conserved flavoprotein localized in the mitochondria, inducing apoptosis after translocation into the nucleus. However, its role in the important fungal pathogen, Candida albicans, remains to be investigated. In this study, we find that the C. albicans AIF protein Aif1, similar to its homologues in other organisms, is localized at the mitochondria and translocated into the nucleus under apoptosis-inducing conditions. Moreover, deletion of AIF1 causes attenuated apoptosis in this pathogen under apoptosis inducing conditions, such as the treatment of 2 mm H2 O2 , 10 mm acetic acid or 0.08 mg/l caspofungin, and its overexpression enhances this process. Interestingly, treatment with high levels of these agents leads to reversed sensitivity of aif1Delta/Delta and the overexpression strain AIF1ov. In addition, the virulence of C. albicans is not affected by deletion or overexpression of AIF1. Hence, C. albicans Aif1, as a mitochondria-localized protein, plays a dual role in the regulation of cell death under different concentrations of the stress caused agents. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121327 TI - Claudin-7 indirectly regulates the integrin/FAK signaling pathway in human colon cancer tissue. AB - The claudin family of proteins is integral to the structure and function of tight junctions. The role of claudin-7 (Cldn-7, CLDN7) in regulating the integrin/focal adhesion kinase (FAK)/ERK signaling pathway remains poorly understood. Therefore, we investigated differences in gene expression, primarily focusing on CLDN7 and integrin/FAK/ERK signaling pathway genes, between colon cancer and adjacent normal tissues. Quantitative real-time reverse transcription-PCR and immunohistochemistry were utilized to verify the results of mRNA and protein expression, respectively. In silico analysis was used to predict co-regulation between Cldn-7 and integrin/FAK/ERK signaling pathway components, and the STRING database was used to analyze protein-protein interaction pairs among these proteins. Meta-analysis of expression microarrays in The Cancer Genome Atlas (TCGA) database was used to identify significant correlations between Cldn-7 and components of predicted genes in the integrin/FAK/ERK signaling pathway. Our results showed marked cancer stage-specific decreases in the protein expression of Cldn-7, Gelsolin, MAPK1 and MAPK3 in colon cancer samples, and the observed changes for all proteins except Cldn-7 were in agreement with changes in the corresponding mRNA levels. Cldn-7 might indirectly regulate MAPK3 via KRT8 due to KRT8 co-expression with MAPK3 or CLDN7. Our bioinformatics methods supported the hypothesis that Cldn-7 does not directly regulate any genes in the integrin/FAK/ERK signaling pathway. These factors may participate in a common network that regulates cancer progression in which the MAPK pathway serves as the central node. PMID- 27121328 TI - Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon? AB - Although recent studies have often revealed the presence of multilocus imprinting disturbance (MLID) at differentially methylated regions (DMRs) in patients with imprinting disorders (IDs), most patients exhibit clinical features of the original ID only. Here we report a Japanese female patient with Beckwith Wiedemann syndrome and pseudohypoparathyroidism type Ib. Molecular studies revealed marked methylation defects (MDs) at the Kv-DMR and the GNAS-DMRs and variable MDs at four additional DMRs, in the absence of a mutation in ZFP57, NLRP2, NLRP7, KHDC3L and NLRP5. It is likely that the MDs at the Kv-DMR and the GNAS-DMRs were sufficient to cause clinically recognizable IDs, whereas the remaining MDs were insufficient to result in clinical consequences or took place at DMRs with no disease-causing imprinted gene(s). The development of MLID and the two IDs of this patient may be due to a mutation in a hitherto unknown gene for MLID, or to a reduced amount of DNA methyltransferase-1 (DNMT1) available for the methylation maintenance of DMRs because of the consumption of DNMT1 by the maintenance of X-inactivation. In support of the latter possibility, such co existence of two IDs has primarily been identified in female patients, and MLID has predominantly been identified as loss of methylations. PMID- 27121329 TI - Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. AB - Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066 11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow up. PMID- 27121330 TI - Moonlighting transcriptional activation function of a fungal sulfur metabolism enzyme. AB - Moonlighting proteins, including metabolic enzymes acting as transcription factors (TF), are present in a variety of organisms but have not been described in higher fungi so far. In a previous genome-wide analysis of the TF repertoire of the plant-symbiotic fungus Tuber melanosporum, we identified various enzymes, including the sulfur-assimilation enzyme phosphoadenosine-phosphosulfate reductase (PAPS-red), as potential transcriptional activators. A functional analysis performed in the yeast Saccharomyces cerevisiae, now demonstrates that a specific variant of this enzyme, PAPS-red A, localizes to the nucleus and is capable of transcriptional activation. TF moonlighting, which is not present in the other enzyme variant (PAPS-red B) encoded by the T. melanosporum genome, relies on a transplantable C-terminal polypeptide containing an alternating hydrophobic/hydrophilic amino acid motif. A similar moonlighting activity was demonstrated for six additional proteins, suggesting that multitasking is a relatively frequent event. PAPS-red A is sulfur-state-responsive and highly expressed, especially in fruitbodies, and likely acts as a recruiter of transcription components involved in S-metabolism gene network activation. PAPS red B, instead, is expressed at low levels and localizes to a highly methylated and silenced region of the genome, hinting at an evolutionary mechanism based on gene duplication, followed by epigenetic silencing of this non-moonlighting gene variant. PMID- 27121331 TI - Self-Reports of Increased Prospective and Retrospective Memory Problems in Adults with Developmental Dyslexia. AB - Short-term and working memory problems in dyslexia are well-documented, but other memory domains have received little empirical scrutiny, despite some evidence to suggest that they might be impaired. Prospective memory is memory for delayed intentions, whilst retrospective memory relates to memory for personally experienced past events. To gain an understanding of subjective everyday memory experience, a self-report measure designed to tap prospective and retrospective memory was administered to 28 adults with dyslexia and 26 IQ-matched adults without dyslexia. Adults with dyslexia reported experiencing significantly more frequent problems with memory than the adults without dyslexia. Group differences were found across seven out of the eight questionnaire scales. Further to these analyses, the participants' own ratings were compared with proxy ratings provided by close associates. The perception of poorer memory abilities in the participants did not differ between respondent types. The self-reported difficulties are, thus, unlikely to be the result of lowered self-esteem or metacognitive awareness. More frequent difficulties with both types of memory would seem, therefore, to be experienced by adults with dyslexia in everyday life. Further laboratory-based research is recommended to explore both memory domains in dyslexia and to identify the cognitive mechanisms by which these problems occur. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121334 TI - Drug Interaction Studies With CYP3A Substrates: How Much Inhibitor Pre-exposure Is Needed? PMID- 27121332 TI - The association between low blood lead levels and the prevalence of prehypertension among nonhypertensive adults in Korea. AB - OBJECTIVES: Low-level lead exposure has been associated with increases in blood pressure (BP) and impairment of the cardiovascular system. Prehypertension is not categorized as a disease currently; however, individuals with untreated prehypertension are known to be at increased risk of progression to hypertension and mortality caused by cardiovascular disease. We investigated the association between blood lead levels below the threshold for the harmful effects of lead and the prevalence of prehypertension in Korean adults. METHODS: A total of 8,493 participants (3,945 men and 4,548 women) were included in the current analysis, using data from the fourth, fifth, and sixth Korean National Health and Nutrition Examination Survey (KNHANES) in 2007-2013. Blood analysis, self-report questionnaires, and physical examinations were used to assess blood lead levels, BP, and medical history. Odds ratios (OR) and 95% confidence intervals (95% CI) for prehypertension were calculated using multiple logistic regression models. RESULTS: Compared to the first quartile (Q1) blood lead level (0.206-1.539 MUg/dl), the ORs (95% CI) were 1.24 (1.04-1.48) in Q2, (1.540-2.056 MUg/dl), 1.27 (1.06-1.52) in Q3, (2.057-2.716 MUg/dl), and 1.30 (1.07-1.60) in Q4 (2.717-24.532 MUg/dl) for the prevalence of prehypertension after adjusting for age, sex, morbidity status, socioeconomic status, and health behavioral variables. CONCLUSIONS: Our large, cross-sectional, nationwide study revealed that blood lead levels below the threshold for the harmful effects of lead were significantly associated with prehypertension. Am. J. Hum. Biol. 28:729-735, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27121335 TI - Pharmacokinetics, Safety, and Tolerability Following the Administration of a Single Dose of a Combination Tablet Containing Sumatriptan and Naproxen Sodium in Adolescent Patients With Migraine and in Healthy Adult Volunteers. AB - OBJECTIVE: The objective was to compare the pharmacokinetics of sumatriptan and naproxen in adolescent migraineurs and healthy adults after administration of sumatriptan/naproxen sodium combination tablets. DESIGN: The design was an open label, randomized, parallel group study. Adolescent migraineurs (12-17 years) and healthy adults received 1 dose of sumatriptan/naproxen: 10 mg/60 mg, 30 mg/180 mg, or 85 mg/500 mg. Pharmacokinetic and safety assessments were conducted. RESULTS: Sumatriptan achieved Cmax rapidly (median tmax : 0.8-1.5 hours for adolescents, 0.5-2.0 hours for adults); elimination was also rapid (geometric mean t1/2 : <2 hours for adolescents, 1.9-2.4 hours for adults). Compared with sumatriptan, naproxen was absorbed and eliminated more slowly (median tmax : 1.0 4.0 hours for adolescents, 1.0-3.0 hours for adults; geometric mean t1/2 : 13.4 16.3 hours for adolescents, 14.3-16.6 hours for adults). Sumatriptan Cmax and AUC were similar for adolescents and adults for the 85 mg/500 mg dose; exposure for the 2 lower doses showed slight differences (not significant). Naproxen Cmax and AUC were comparable between the 2 groups at all doses. Increases in sumatriptan Cmax and AUC were dose proportional; for naproxen, slightly less than proportional. The tablets were generally well tolerated. CONCLUSION: Sumatriptan and naproxen pharmacokinetics were not dissimilar between adolescent migraineurs and healthy adults. PMID- 27121336 TI - A Single-Dose Bioequivalence and Food Effect Study With Aprepitant and Fosaprepitant Dimeglumine in Healthy Young Adult Subjects. AB - Fosaprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1 ) receptor antagonist. Intravenous (IV) fosaprepitant and oral aprepitant are used in combination with other antiemetics to prevent chemotherapy-induced nausea and vomiting. This randomized, phase 1 study was designed to assess the aprepitant area under the curve (AUC0 infinity ) equivalence of a single, oral 165-mg or 185-mg dose of aprepitant to a single 150-mg fosaprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165-mg and 185-mg aprepitant doses. Plasma samples were analyzed for aprepitant, and linear mixed-effects models were applied to natural log-transformed aprepitant AUC data. A 2 one-sided tests procedure was used to evaluate bioequivalence; the adjusted P values for the AUC0-infinity of both oral doses versus the IV dose were < .05, supporting the hypothesis that each single, oral dose of aprepitant is equivalent to the AUC0-infinity of a single IV infusion of fosaprepitant. Food effect results suggest that dose adjustment would not be necessary with a single oral dose of aprepitant. Single-dose administration of oral 165 mg and 185 mg aprepitant and IV 150 mg fosaprepitant was generally well tolerated. PMID- 27121338 TI - Pharmacokinetics and Bioequivalence Evaluation of 2 Cefadroxil Suspensions in Healthy Egyptian Male Volunteers. AB - The objective of this study was to evaluate the bioavailability of 2 brands of cefadroxil monohydrate suspensions, Curisafe (500 mg cefadroxil monohydrate/5 mL; test) relative to Duricef (500 mg cefadroxil monohydrate/5 mL; reference). This in vivo study was conducted according to a single-center, randomized, single dose, laboratory-blinded, 2-period, 2-sequence, crossover design with a washout period of 1 week. Under fasting conditions, 24 healthy Egyptian adult male volunteers were randomly allocated to receive a single dose of either test or reference product. Blood samples were collected at specified time intervals, and plasma was analyzed for cefadroxil concentration using a validated high performance liquid chromatography assay method. The pharmacokinetic parameters Cmax , AUC0-t , AUC0-infinity , tmax , Ke , and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio Cmax , AUC0-t , and AUCt-infinity of the test product over those of reference were within the acceptable range (0.8-1.25) for bioequivalence. On the basis of these results, the 2 cefadroxil formulations are considered bioequivalent. PMID- 27121337 TI - Absorption, Metabolism, and Excretion of [(14) C]-Tivozanib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Healthy Male Participants: A Phase I, Open-Label, Mass-Balance Study. AB - OBJECTIVE: To evaluate the absorption, metabolism, and excretion of tivozanib, a new investigational drug for renal cell carcinoma and solid malignancies. METHODS: Eight healthy male participants received a single 1.5-mg (~160 MUCi) dose of oral [(14) C]-tivozanib. Whole blood, serum, urine, and feces were evaluated up to 28 days postdose for pharmacokinetics, radioanalysis, and metabolites. Adverse events were recorded throughout the study. RESULTS: [(14) C] tivozanib concentration peaked at 10.9 +/- 5.84 hours. The mean serum half-life for [(14) C]-tivozanib was 89.3 +/- 23.5 hours. The maximum concentration and area under the curve for [(14) C]-tivozanib were 12.1 +/- 5.67 ng/mL and 1084 +/- 417.0 ng.h/mL, respectively. Mean recovery of total radioactivity was 91.0% +/- 11.0%; 79.3% +/- 8.82% of the radioactivity was recovered in feces both as unchanged tivozanib and metabolites. In the urine, 11.8% +/- 4.59% was recovered only as metabolites. No unchanged tivozanib was found in the urine. CONCLUSION: Tivozanib had a long half-life with no major circulating metabolite, was well tolerated as a single dose, and was primarily eliminated via feces with no unchanged tivozanib found in urine. These pharmacokinetic data of [(14) C] tivozanib are consistent with previous studies of unlabeled tivozanib. PMID- 27121339 TI - COD capture: a feasible option towards energy self-sufficient domestic wastewater treatment. AB - Although the activated sludge process, one of the most remarkable engineering inventions in the 20(th) century, has made significant contribution to wastewater reclamation in the past 100 years, its high energy consumption is posing a serious impact and challenge on the current wastewater industry worldwide and is also inevitably linked to the issue of global climate change. In this study, we argued that substantial improvement in the energy efficiency might be no longer achievable through further optimization of the activated sludge process. Instead, we should devote more effort to the development or the adoption of novel treatment configurations and emerging technologies. Of which an example is A-B process which can significantly improve the energy recovery potential at A-stage, while markedly reduces energy consumption at B-stage. Various configurations of A B process with energy analysis are thus discussed. It appears highly possible to achieve an overall energy gain in WWTPs with A-B process as a core. PMID- 27121340 TI - Self-harm in nurses: prevalence and correlates. AB - AIMS: The aim of this study was to examine the weighed prevalence of self-harm and its correlates among Hong Kong nurses. BACKGROUND: Recent epidemiological data suggest that the weighted prevalence of past-year suicidality among Hong Kong nurses was found to be 14.9%. Deliberate self-harm was a significant correlate of suicidality. Nonetheless, there are few population-based studies exploring the prevalence of self-harm and its correlates among medical occupational groups in Asia. DESIGN: The study uses a cross-sectional survey design. METHOD: Data were collected in Hong Kong over a four-week period from October-November 2013. Statistical methods, including binary and multivariate logistic regression models, were used to examine the weighted prevalence of self harm and its associated factors in nurses. RESULTS: A total of 850 nurses participated in the study. Seventy-nine participants (9.3%) reported self-harm in the past year. Nurses aged between 25-44 were at especially high risk of self harm. Female nurses reported self-harm more than male nurses. The most common forms of self-harm were self-cutting, striking oneself and poisoning oneself. Clinical experience, chronic illness, relationship crises with family members, a family history of self-harm, smoking, symptoms of stress and psychiatric disorder were significantly associated with nurses' self-harm. The positive correlation between psychiatric disorder and self-harm was confirmed. CONCLUSIONS: There is a need for a raft of self-harm prevention strategies, including a continuous monitoring system in the healthcare setting detecting and managing the risks of self-harm in nurses as part of the ordinary provision for their well-being. PMID- 27121341 TI - Two-photon light-sheet nanoscopy by fluorescence fluctuation correlation analysis. AB - Advances in light-sheet microscopy have enabled the fast three-dimensional (3D) imaging of live cells and bulk specimens with low photodamage and phototoxicity. Combining light-sheet illumination with super-resolution imaging is expected to resolve subcellular structures. Actually, such kind of super-resolution light sheet microscopy was recently demonstrated using a single-molecule localization algorithm. However, the imaging depth and temporal resolution of this method are limited owing to the requirements of precise single molecule localization and reconstruction. In this work, we present two-photon super-resolution light-sheet imaging via stochastic optical fluctuation imaging (2PLS-SOFI), which acquires high spatiotemporal resolution and excellent optical sectioning ability. 2PLS SOFI is based on non-linear excitation of fluctuation/blinking probes using our recently developed fast two-photon three-axis digital scanned light-sheet microscope (2P3A-DSLM), which enables both deep penetration and thin sheet of light. Overall, 2PLS-SOFI demonstrates up to 3-fold spatial resolution enhancement compared with conventional two-photon light-sheet (2PLS) microscopy and about 40-fold temporal resolution enhancement compared with individual molecule localization-selective plane illumination microscopy (IML-SPIM). Therefore, 2PLS-SOFI is promising for 3D long-term, deep-tissue imaging with high spatiotemporal resolution. PMID- 27121342 TI - Indirect co-culture of vascular smooth muscle cells with bone marrow mesenchymal stem cells inhibits vascular calcification and downregulates the Wnt signaling pathways. AB - Vascular calcification (VC) is widely considered to be a crucial clinical indicator of cardiovascular disease. Recently, certain properties of mesenchymal stem cells (MSCs) have been hypothesized to have potential in treating cardiovascular diseases. However, their effect on the initiation and progression of VC remains controversial. The present study aimed to investigate whether MSCs indirectly mediate VC and their impact on the Wnt signaling pathways. A Transwell system was selected to establish the indirect co-culture environment, and hence, vascular smooth muscle cells (VSMCs) were indirectly co-cultured in the presence or absence of MSCs at a ratio of 1:1. Osteogenic medium (OS) was added to imitate a calcifying environment. Fourteen days later, VSMCs in the lower layers of the Transwell plates were harvested. Alkaline phosphatase activity and calcium nodules were markedly increased in calcific VSMCs induced by OS. However, these parameters were significantly decreased in VSMCs by indirectly co-culturing with MSCs in the same medium. Furthermore, the messenger RNA expression levels of osteopontin and osteoprotegerin were notably increased in VSMCs cultured in OS, but reduced by indirect interaction with MSCs. In addition, the activities of canonical and noncanonical Wnt ligands, wingless-type MMTV integration site family, number 5A (Wnt5a), receptor tyrosine kinase-like orphan receptor 2 (Ror2) and beta-catenin, which are important in the process of VC, were downregulated by indirect contact with MSCs in OS. Thus, indirect co-culture with MSCs inhibits VC and downregulates the Wnt signaling pathways. PMID- 27121343 TI - An examination of the regulatory mechanism of Pxdn mutation-induced eye disorders using microarray analysis. AB - The present study aimed to identify biomarkers for peroxidasin (Pxdn) mutation induced eye disorders and study the underlying mechanisms involved in this process. The microarray dataset GSE49704 was used, which encompasses 4 mouse samples from embryos with Pxdn mutation and 4 samples from normal tissues. After data preprocessing, the differentially expressed genes (DEGs) between Pxdn mutation and normal tissues were identified using the t-test in the limma package, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed based on the STRING database, and the transcriptional regulatory (TR) network was established using the GeneCodis database. Subsequently, the overlapping DEGs with high degrees in two networks were identified, as well as the sub-network extracted from the TR network. In total, 121 (75 upregulated and 46 downregulated) DEGs were identified, and these DEGs play important roles in biological processes (BPs), including neuron development and differentiation. A PPI network containing 25 nodes such as actin, alpha 1, skeletal muscle (Acta1) and troponin C type 2 (fast) (Tnnc2), and a TR network including 120 nodes were built. By comparing the two networks, seven crucial genes which overlapped were identified, including cyclin-dependent kinase inhibitor 1B (Cdkn1b), Acta1 and troponin T type 3 (Tnnt3). In the sub-network, Cdkn1b was predicted as the target of miRNAs such as mmu-miR-24 and transcription factors (TFs) including forkhead box O4 (FOXO4) and activating enhancer binding protein 4 (AP4). Thus, we suggest that seven crucial genes, including Cdkn1b, Acta1 and Tnnt3, play important roles in the progression of eye disorders such as glaucoma. We suggest that Cdkn1b exert its effects via the inhibition of proliferation and is mediated by mmu-miR-24 and targeted by the TFs FOXO4 and AP4. PMID- 27121344 TI - Balloon kyphoplasty versus percutaneous vertebroplasty for treatment of osteoporotic vertebral compression fractures (OVCFs). AB - The study investigated whether kyphoplasty (KP) was superior to vertebroplasty (VP) in treating patients with osteoporotic vertebral compression fractures (OVCFs). KP may be superior to VP for treating patients with OVCFs based on long term VAS and ODI but not short-term VAS. Further large-scale trials are needed to verify these findings due to potential risk of selection bias. INTRODUCTION: This study aimed to assess whether KP was superior to VP in treating patients with OVCFs. METHODS: The Medline, Embase, and Cochrane databases and references within articles and proceedings of major meetings were systematically searched. Eligible studies included patients with OVCFs who received either KP or VP. Standard mean differences (SMDs) and relative risks (RRs) were used as measures of efficacy and safety in a random-effects model. RESULTS: Eleven studies enrolling 869 patients with OVCFs were identified as eligible for final analysis. Compared with VP, KP was associated with significant improvements in long-term (SMD, -0.70; 95 % confidence interval [CI]: -1.30, -0.10; P = 0.023) visual analog scale (VAS); short-term (SMD, -1.50; 95 % CI: -2.94, -0.07; P = 0.040) and long-term (SMD, 1.03; 95 % CI: -1.88, -0.18; P = 0.017) Oswestry Disability Indexes (ODIs); short term (SMD, -0.74; 95 % CI: -1.42, -0.06; P = 0.032) and long-term (SMD, -0.71; 95 % CI: -1.19, -0.23; P = 0.004) kyphosis angles; and vertebral body height (SMD, 1.56; 95 % CI: 0.62, 2.49; P = 0.001) and anterior vertebral body height (SMD, 3.04; 95 % CI: 0.53, 5.56; P = 0.018). KP was also associated with a significantly longer operation time (SMD, 0.73; 95 % CI: 0.26, 1.19; P = 0.002) and a lower risk of cement extravasation (RR, 0.68; 95 % CI: 0.48, 0.96; P = 0.030) compared with VP. No significant differences were found in the short-term VAS, posterior vertebral body height, and adjacent-level fractures. CONCLUSION: Acknowledging some risk of selection bias, KP displayed a significantly better performance compared with VP only in one of the two primary endpoints, that is, for ODI but not for short-term VAS. Further randomized studies are required to confirm these results. PMID- 27121345 TI - Clinical cone beam computed tomography compared to high-resolution peripheral computed tomography in the assessment of distal radius bone. AB - Clinical cone beam computed tomography (CBCT) was compared to high-resolution peripheral quantitative computed tomography (HR-pQCT) for the assessment of ex vivo radii. Strong correlations were found for geometry, volumetric density, and trabecular structure. Using CBCT, bone architecture assessment was feasible but compared to HR-pQCT, trabecular parameters were overestimated whereas cortical ones were underestimated. INTRODUCTION: HR-pQCT is the most widely used technique to assess bone microarchitecture in vivo. Yet, this technology has been only applicable at peripheral sites, in only few research centers. Clinical CBCT is more widely available but quantitative assessment of the bone structure is usually not performed. We aimed to compare the assessment of bone structure with CBCT (NewTom 5G, QR, Verona, Italy) and HR-pQCT (XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland). METHODS: Twenty-four distal radius specimens were scanned with these two devices with a reconstructed voxel size of 75 MUm for Newtom 5G and 82 MUm for XtremeCT, respectively. A rescaling-registration scheme was used to define the common volume of interest. Cortical and trabecular compartments were separated using a semiautomated double contouring method. Density and microstructure were assessed with the HR-pQCT software on both modality images. RESULTS: Strong correlations were found for geometry parameters (r = 0.98-0.99), volumetric density (r = 0.91-0.99), and trabecular structure (r = 0.94-0.99), all p < 0.001. Correlations were lower for cortical microstructure (r = 0.80-0.89), p < 0.001. However, absolute differences were observed between modalities for all parameters, with an overestimation of the trabecular structure (trabecular number, 1.62 +/- 0.37 vs. 1.47 +/- 0.36 mm(-1)) and an underestimation of the cortical microstructure (cortical porosity, 3.3 +/- 1.3 vs. 4.4 +/- 1.4 %) assessed on CBCT images compared to HR-pQCT images. CONCLUSIONS: Clinical CBCT devices are able to analyze large portions of distal bones with good spatial resolution and limited irradiation. However, compared to dedicated HR-pQCT, the assessment of microarchitecture by NewTom 5G dental CBCT showed some discrepancies, for density measurements mainly. Further technical developments are required to reach optimal assessment of bone characteristics. PMID- 27121346 TI - Risk factors for recurrence in patients with papillary thyroid carcinoma undergoing modified radical neck dissection. AB - BACKGROUND: This study evaluated the impact of lymph node-related factors on the risk of and site of recurrence in patients who had papillary thyroid carcinoma with lymph node metastasis in the lateral compartment (classified as pN1b). METHODS: Patients underwent total thyroidectomy with unilateral modified radical neck dissection for classical papillary thyroid carcinoma. Risk factors for recurrence were evaluated according to the pattern of recurrence. RESULTS: A total of 324 patients were included in the study. The median follow-up was 63 (range 14-181) months. Recurrence was detected in 47 patients (14.5 per cent). In the multivariable analysis, a maximum diameter of metastatic lymph nodes larger than 2.0 cm (hazard ratio (HR) 1.15, 95 per cent c.i. 1.06 to 1.25; P = 0.033) and a central compartment metastatic lymph node ratio of more than 0.42 (HR 3.35, 1.65 to 6.79; P < 0.001) were identified as independent risk factors for locoregional recurrence. Age 45 years or older (HR 5.69, 1.24 to 26.12; P = 0.025) and extranodal extension of metastasis (HR 12.71, 1.64 to 98.25; P = 0.015) were risk factors for distant metastasis. In subgroup analysis of locoregional recurrence, several lymph node-related factors affected the risk of recurrence according to the specific site of metastasis. CONCLUSION: Lymph node related factors are of importance for the risk of recurrence in patients with classical papillary thyroid carcinoma classified as pN1b. PMID- 27121347 TI - Comparison of Three Different Commercial Kits for the Human Papilloma Virus Genotyping. AB - BACKGROUND: High-risk type human papilloma virus (HPV) is the most important cause of cervical cancer. Recently, real-time polymerase chain reaction and reverse blot hybridization assay-based HPV DNA genotyping kits are developed. So, we compared the performances of different three HPV genotyping kits using different analytical principles and methods. METHODS: Two hundred positive and 100 negative cervical swab specimens were used. DNA was extracted and all samples were tested by the MolecuTech REBA HPV-ID, Anyplex II HPV28 Detection, and HPVDNAChip. Direct sequencing was performed as a reference method for confirming high-risk HPV genotypes 16, 18, 45, 52, and 58. RESULTS: Although high-level agreement results were observed in negative samples, three kits showed decreased interassay agreement as screening setting in positive samples. Comparing the genotyping results, three assays showed acceptable sensitivity and specificity for the detection of HPV 16 and 18. Otherwise, various sensitivities showed in the detection of HPV 45, 52, and 58. CONCLUSIONS: The three assays had dissimilar performance of HPV screening capacity and exhibited moderate level of concordance in HPV genotyping. These discrepant results were unavoidable due to difference in type-specific analytical sensitivity and lack of standardization; therefore, we suggested that the efforts to standardization of HPV genotyping kits and adjusting analytical sensitivity would be important for the best clinical performance. PMID- 27121348 TI - Rasch analysis of the Pediatric Evaluation of Disability Inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy. AB - INTRODUCTION: In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). METHODS: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. RESULTS: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. CONCLUSIONS: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016. PMID- 27121349 TI - Ovine fetal mesenchymal stem cell differentiation to cardiomyocytes, effects of co-culture, role of small molecules; reversine and 5-azacytidine. AB - The aim of the present study was to investigate the effect of small molecules: Reversine and 5-azacytidine (5-AC), in an indirect co-culture condition with the cardiac fibroblasts as well as non co-culture condition, in order to explore the effect of such molecules in the process of differentiation of the ovine bone marrow mesenchymal stem cells (BM-MSCs) towards cardiomyocytes. Surface antigens of the isolated cells were analysed using flow-cytometry. In addition, following to three passages cells were examined for their differentiation capacity into osteocytes and adipose cells, in order to ensure the mesenchymal origin of the stem cells. Six types of treatments were carried out in the present investigation, such that, in the first treatment BM-MSCs were cultured for 28 days as control group; the second treatment was composed of culturing ovine fetal cardiac fibroblasts on inserts, aiming to use these inserts for culturing plates which were seeded with BM-MSCs (Chamber group). As the third treatment, BM-MSCs were supplemented with 10-MUM 5-AC and incubated for 48 h. The fourth treatment was composed of supplementing BM-MSCs with the 600-nM reversine, incubated for 48 h, and subsequently the incubation was further extended for another 48 h in the presence of 5-AC. The fifth treatment was composed of supplementing the chamber group with 10-MUM 5-AC and incubation for 48 h, and the last or the sixth treatment was such that chamber group was supplemented with 600-nM reversine and an incubation period of 48 h. Following to the incubation, medium was replaced with 10-MUM 5-AC and further incubated for another round of 48 h. In all treatments, following to addition of the small molecules incubations were carried out for 28 days; same as controls. Expression of cardiac alpha-actinin was analysed by immunocytochemistry. BM-MSCs have shown to express CD44 and CD166 along with a weak expression of the CD90, CD34, in addition to CD45. Multilineage differentiation has indicated that BM-MSCs could differentiate into adipose and osteocytes cells as well. In the treatment 4 it was observed that FGF signalling involved genes and all cardiac-related genes (ANP, MYH6 and Troponin I) were significantly expressed, except connexin 43 compared to other treatments. All treatments received small molecules, either alone or as a co-culture were seen to express sarcomeric alpha-actinin. This finding was partially supported by immunocytochemistry. These results validate that reversine and 5-AC have an effect on ovine BM-MSC differentiation into cardiomyocytes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121350 TI - A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus. AB - The natural resistance of Mycobacterium abscessus to most commonly available antibiotics seriously limits chemotherapeutic treatment options, which is particularly challenging for cystic fibrosis patients infected with this rapid growing mycobacterium. New drugs with novel molecular targets are urgently needed against this emerging pathogen. However, the discovery of such new chemotypes has not been appropriately performed. Here, we demonstrate the utility of a phenotypic screen for bactericidal compounds against M. abscessus using a library of compounds previously validated for activity against M. tuberculosis. We identified a new piperidinol-based molecule, PIPD1, exhibiting potent activity against clinical M. abscessus strains in vitro and in infected macrophages. Treatment of infected zebrafish with PIPD1 correlated with increased embryo survival and decreased bacterial burden. Whole genome analysis of M. abscessus strains resistant to PIPD1 identified several mutations in MAB_4508, encoding a protein homologous to MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis was unaffected, PIPD1 strongly inhibited the transport of trehalose monomycolate, thereby abrogating mycolylation of arabinogalactan. Mapping the mutations conferring resistance to PIPD1 on a MAB_4508 tridimensional homology model defined a potential PIPD1-binding pocket. Our data emphasize a yet unexploited chemical structure class against M. abscessus infections with promising translational development possibilities. PMID- 27121351 TI - Communicating with parents of obese children: which channels are most effective? AB - BACKGROUND: One of the strategies proven most successful in curbing rising rates of childhood obesity involves targeting parents as agents of change. Prior studies have focused on what messages to communicate, but few have investigated how they should be communicated. OBJECTIVE: To identify the channels most effective for communicating with parents of overweight and obese children and understand whether their use of parenting information sources differs from others in the community. DESIGN/SETTING: This study utilizes data from the Longitudinal Study of Australian Children (LSAC). Families were included if weight and height information was available for parents and children at three data collection points: Waves 1, 2 and 4 (collected 2004, 2006 and 2010, respectively, n = 5107). ANALYSIS: A priori and a posteriori segmentation methods identified groups of parents that were similar in the sources used to obtain information about parenting, and examined whether some segments were more likely to have obese children. RESULTS: Four segments were identified that differed in their information source use: the 'personal networks', 'books', 'official sources' and 'mixed approach' segments. The 'official sources' and 'mixed approach' segments were most likely to have obese children, and they used doctors, government/community organizations and friends to obtain information on parenting. These segments were also less educated and had lower employment. CONCLUSIONS: Messages are most likely to reach families with obese children if communicated through doctors, government publications and community organizations. Further, messages targeting social groupings of parents will leverage the power of advice from friends, which is another valuable information source for this group. PMID- 27121352 TI - Color Afterimages in Autistic Adults. AB - It has been suggested that attenuated adaptation to visual stimuli in autism is the result of atypical perceptual priors (e.g., Pellicano and Burr in Trends Cogn Sci 16(10):504-510, 2012. doi: 10.1016/j.tics.2012.08.009 ). This study investigated adaptation to color in autistic adults, measuring both strength of afterimage and the influence of top-down knowledge. We found no difference in color afterimage strength between autistic and typical adults. Effects of top down knowledge on afterimage intensity shown by Lupyan (Acta Psychol 161:117-130, 2015. doi: 10.1016/j.actpsy.2015.08.006 ) were not replicated for either group. This study finds intact color adaptation in autistic adults. This is in contrast to findings of attenuated adaptation to faces and numerosity in autistic children. Future research should investigate the possibility of developmental differences in adaptation and further examine top-down effects on adaptation. PMID- 27121354 TI - Both initial red cell distribution width (RDW) and change in RDW during heart failure hospitalization are associated with length of hospital stay and 30-day outcomes. AB - INTRODUCTION: We examined the predictive ability of red cell distribution width (RDW) and the change in RDW during hospitalization (DeltaRDW) for length of stay (LOS) and 30-day outcomes after heart failure (HF) inpatient stay. METHODS: Electronic query of Intermountain Healthcare medical records identified patients (N = 6414) with a primary diagnosis of HF who were discharged between 2004 and 2013, had RDW measured within 24 h after admission, and had RDW tested at least once more during the same hospitalization. DeltaRDW was defined as the last RDW within 24 h prior to discharge minus the first RDW. RESULTS: Median LOS by initial RDW quartiles was Q1: 3.0, Q2: 3.1, Q3: 3.7, and Q4: 4.0 days (P trend<0.001), and by DeltaRDW quartiles was Q1: 4.1, Q2: 3.4, Q3: 3.6, and Q4: 4.7 days (P-trend<0.001). Both initial RDW (16.8 +/- 2.8% vs. 16.3 +/- 2.7%, P < 0.001) and DeltaRDW (0.21 +/- 1.09% vs. 0.14 +/- 1.04%, P = 0.039) predicted 30 day readmission vs. no readmit. For 30-day decedents vs. survivors, initial RDW was 17.3 +/- 3.0% vs. 16.3 +/- 2.6% (P < 0.001), while DeltaRDW was +0.20 +/- 1.14% vs. +0.14 +/- 1.04% (P = 0.15). CONCLUSIONS: Greater initial RDW and DeltaRDW during HF hospitalization were associated with 30-day mortality, longer LOS, and 30-day all-cause readmission, suggesting both DeltaRDW and initial RDW may aid in personalizing prognosis and treatment. PMID- 27121353 TI - Variant-specific persistence of infections with human papillomavirus Types 31, 33, 45, 56 and 58 and risk of cervical intraepithelial neoplasia. AB - In our previous study of the etiologic role of oncogenic human papillomavirus (HPV) types other than HPV16 and 18, we observed a significantly higher risk of cervical intraepithelial neoplasia Grades 2-3 (CIN2/3) associated with certain lineages of HPV types 31/33/45/56/58 [called high-risk (HR) variants] compared with non-HR variants. This study was to examine whether these intra-type variants differ in persistence of the infection and persistence-associated risk of CIN2/3. Study subjects were women who had any of HPV types 31/33/45/56/58 newly detected during a 2-year follow-up with 6-month intervals. For each type, the first positive sample was used for variant characterization. The association of reverting-to-negativity with group of the variants and CIN2/3 with length of positivity was assessed using discrete Cox regression and logistic regression, respectively. Of the 598 newly detected, type-specific HPV infections, 312 became undetectable during follow-up. Infections with HR, compared with non-HR, variants were marginally more likely to become negative [adjusted hazard ratio = 1.3; 95% confidence interval (CI), 0.9-1.8]. The adjusted odds ratio associating with the development of CIN2/3 was 3.0 (95% CI, 1.2-7.4) for persistent infections with HR variants for 6 months and 10.0 (95% CI, 3.8-38.0) for persistent infections with HR variants for 12-18 months as compared with the first positive detection of HR variants. Among women with non-HR variants, there were no appreciable differences in risk of CIN2/3 by length of positivity. Findings suggest that the lineage associated risk of CIN2/3 was not mediated through a prolonged persistent infection, but oncogenic heterogeneity of the variants. PMID- 27121355 TI - Clinical significance of IPF% measurement in diagnosing thrombocytopenic disorders: distinguishing primary immune thrombocytopenia from other disorders. PMID- 27121356 TI - C11orf95-RELA fusion present in a primary intracranial extra-axial ependymoma: Report of a case with literature review. AB - Ependymomas are gliomas that recapitulate the ependymal cells microscopically and ultrastructurally. They commonly occur along the ventricular surfaces and central canal of the brain and spinal cord. Intracranial extra-axial ependymoma (IEAE) is a rare entity and is commonly misdiagnosed clinically and radiologically as a meningioma. The histogenesis of such IEAEs is obscure. A novel recurrent oncogenic fusion involving the C11orf95 and RELA genes was recently described in supratentorial ependymomas. A 9-year-old girl presented with a dural based parafalcine mass that, in addition to exhibiting classical immunohistochemical features of an ependymoma, also demonstrated C11orf95-RELA fusion, characteristic of supratentorial ependymomas. We suggest that IEAEs share their histogenesis with their intra-axial counterparts, arising either from dural extension of subcortical, subependymal rests or directly from ectopic dural rests. PMID- 27121357 TI - Perfluorooctyl bromide traces self-assembled with polymeric nanovesicles for blood pool ultrasound imaging. AB - A novel perfluorooctyl bromide (PFOB)-loaded nanovesicle with a size of about 500 nm was prepared by self-assembly of an amphiphilic block copolymer, poly(ethylene oxide)-b-poly(d,l-lactic acid) (PEG-PDLLA), for blood pool ultrasound imaging. The excellent compatibility of PFOB with the hydrophobic PDLLA block makes PFOB uniformly distribute and integrate well within the nanovesicle shell. In theory, both the compressibility and shell density of the nanovesicle as ultrasound scatterers are enhanced, resulting in much higher echo intensity compared to the other PFOB nanoparticles. In vitro and in vivo imaging results illustrate that these polymeric nanovesicles with extremely low content of PFOB show quite a good contrast-enhancing effect even if highly diluted in blood. Therefore this PFOB loaded polymeric nanovesicle is anticipated to be applicable as an ultrasound contrast agent for normal angiography and specific imaging of capillary-abundant organs or tissues (e.g. tumors). PMID- 27121358 TI - Role of psychological factors in burning mouth syndrome: A systematic review and meta-analysis. AB - Background Burning mouth syndrome (BMS) is a chronic medical condition characterised by hot, painful sensations in the lips, oral mucosa, and/or tongue mucosa. On examination, these appear healthy, and organic causes for the pain cannot be found. Several studies have yielded scant evidence of the involvement of psychological and/or psychopathological factors, and several have outlined a model for the classification of BMS. Aim This review aims to provide a systematic review of research examining the psychological, psychiatric, and/or personality factors linked to BMS. Findings Fourteen controlled studies conducted between 2000 and the present were selected based on stringent inclusion/exclusion criteria. All studies but one reported at least some evidence for the involvement of psychological factors in BMS. Anxiety and depression were the most common and the most frequently studied psychopathological disorders among BMS patients. Discussion and conclusion Anxiety and depression play critical roles in this condition. Evidence on the role of personality characteristics of BMS patients has also been produced by a few studies. Further studies on the role of specific psychological factors in BMS are warranted, but the importance of a multidisciplinary approach (medical and psychological) to BMS is no matter of discussion. PMID- 27121359 TI - The use of oxygen in cluster headache treatment worldwide - a survey of the International Headache Society (IHS). AB - Background Oxygen is recommended for the treatment of acute cluster headache attacks. However, it is not available worldwide. Methods The International Headache Society performed a survey among its national member societies on the availability and the restrictions for oxygen in the treatment of cluster headache. Results Oxygen is reimbursed in 50% of all countries responding ( n = 22). There are additional restrictions in the reimbursement of the facial mask and with respect to age. Conclusion Oxygen for the treatment of cluster headache attack is not reimbursed worldwide. Headache societies should pressure national/public health authorities to reimburse oxygen for cluster headache in all countries. PMID- 27121361 TI - Excellence in Certification-The ABOMS. PMID- 27121362 TI - Concise total synthesis of (+/-)-serotobenine. AB - A concise total synthesis of (+/-)-serotobenine via a strategy inspired by the biosynthetic hypothesis for this alkaloid was accomplished. The indolofuran core was constructed by an iron-catalyzed intermolecular oxidative radical cross coupling reaction developed by our group. PMID- 27121363 TI - Implementation of the Tobacco-Free Campus Policy on College Campuses: Evidence From a Survey of College Students in Beijing. AB - OBJECTIVE: China issued a nationwide "Tobacco-Free Campus" Policy (TFCP) in January 2014, but it is unclear how well it was implemented across China's 2138 college campuses. We conducted an Internet survey of Beijing college students to evaluate the implementation of the TFCP in Beijing. METHODS: An Internet survey of 711 students from 37 colleges in Beijing was conducted in May 2015. Respondents reported on secondhand smoking (SHS) exposure on campus, knowledge on and actions taken against SHS, and tobacco marketing exposure on campus. RESULTS: Almost 90% of respondents were exposed to SHS on campus at least once in the past month. Approximately 37% of nonsmokers and 61% of smokers reported seeing a teacher smoking, and the majority of both smokers and nonsmokers reported seeing a classmate smoking in campus buildings. The likelihood and location of SHS exposure depend on the participant's demographics and own smoking behavior. Nonsmokers were more likely to be aware of the health risk of SHS than smokers. Although most participants were aware of the harms, only 13% and 9% tried to stop their last SHS exposure indoors and outdoors, respectively. Forty-seven students from 14 colleges noticed tobacco marketing activities on campus. CONCLUSIONS: The TFCP on Chinese college campuses was only partially enforced, particularly with regard to SHS. IMPLICATIONS: On January 29, 2014, the Chinese Ministry of Education issued the TFCP. A major barrier to effective tobacco control in China is the difficulty in implementing policies issued by the central government. At this point, it is unclear whether the TFCP was successfully implemented on China's college campuses. Major tobacco use monitoring efforts do not include college students. The present research describes the current tobacco control environment on Beijing's college campuses 15 months after the TFCP took effect. To our knowledge, this is the first paper in the English literature on tobacco environment and exposure (rather than a prevalence survey) of college students in China. PMID- 27121366 TI - Rh(iii)-catalyzed chemoselective C-H functionalizations of tertiary aniline N oxides with alkynes. AB - In this work, we report novel Rh(iii)-catalyzed chemoselective functionalizations of tertiary aniline N-oxides with alkynes, including annulation via the sequential C(sp(2))-H and C(sp(3))-N activation for the formation of N alkylindoles and an O-atom transfer (OAT) process for the synthesis of acetophenones. PMID- 27121364 TI - Strongyloidiasis in Latin American immigrants: a pilot study. AB - The United States of America (USA) has the largest international population of any nation in the world. Immigrants from Latin American countries, where intestinal parasites are endemic, comprise more than half of this population. This study aims to determine the prevalence of strongyloidiasis, a potentially deadly parasitic infection, in foreign-born individuals. We conducted a cross sectional study in Washington, DC, to determine the seroprevalence of Strongyloides stercoralis infection using an NIE-ELISA IgG antibody assay. Multi parallel quantitative real-time polymerase chain reaction (qPCR) was performed in stool samples of NIE-ELISA-positive patients to investigate possible polyparasitism. The NIE-ELISA assay detected an S. stercoralis prevalence of 4.2% in a group of 119 volunteers. Combining NIE-ELISA and qPCR detected a parasite prevalence of 5.0%. Our results underscore the relevance of systematic testing for gastrointestinal parasites in individuals from endemic regions. It also makes a case for a survey in the USA to identify immigrants' risk for strongyloidiasis and other gastrointestinal parasitic infections. PMID- 27121367 TI - Imaging live cells at high spatiotemporal resolution for lab-on-a-chip applications. AB - Conventional optical imaging techniques are limited by the diffraction limit and difficult-to-image biomolecular and sub-cellular processes in living specimens. Novel optical imaging techniques are constantly evolving with the desire to innovate an imaging tool that is capable of seeing sub-cellular processes in a biological system, especially in three dimensions (3D) over time, i.e. 4D imaging. For fluorescence imaging on live cells, the trade-offs among imaging depth, spatial resolution, temporal resolution and photo-damage are constrained based on the limited photons of the emitters. The fundamental solution to solve this dilemma is to enlarge the photon bank such as the development of photostable and bright fluorophores, leading to the innovation in optical imaging techniques such as super-resolution microscopy and light sheet microscopy. With the synergy of microfluidic technology that is capable of manipulating biological cells and controlling their microenvironments to mimic in vivo physiological environments, studies of sub-cellular processes in various biological systems can be simplified and investigated systematically. In this review, we provide an overview of current state-of-the-art super-resolution and 3D live cell imaging techniques and their lab-on-a-chip applications, and finally discuss future research trends in new and breakthrough research areas of live specimen 4D imaging in controlled 3D microenvironments. PMID- 27121368 TI - The effect of preexisting anti-carrier immunity on subsequent responses to CRM197 or Qb-VLP conjugate vaccines. AB - CONTEXT: Certain antigens, such as haptens (small molecules), short peptides, and carbohydrates (e.g. bacterial polysaccharides) are non- or poorly immunogenic unless conjugated to a carrier molecule that provides a structural scaffold for antigen presentation as well as T cell help required for B-cell activation and maturation. However, the carriers themselves are immunogenic and resulting carrier-specific immune responses may impact the immunogenicity of other conjugate vaccines using the same carrier that are administered subsequently. OBJECTIVE: Herein, using two different carriers (cross-reactive material 197, CRM and Qb-VLP), we examined in mice the impact that preexisting anti-carrier antibodies (Ab) had on subsequent immune responses to conjugates with either the same or a different carrier. METHOD: For this purpose, we used two nicotine hapten conjugates (NIC7-CRM or NIC-Qb), two IgE peptide conjugates (Y-CRM or Y Qb), and a pneumococcal polysaccharide conjugate (Prevnar 13((r))). RESULTS: Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier, with the exception of Prevnar 13(r) where anti-polysaccharide responses were similar to those in animals without preexisting anti-carrier Ab. CONCLUSION: Collectively, the data suggest that the relative sizes of the antigen and carrier, as well as the conjugation density for a given conjugate impact the extent of anti-carrier suppression. All animals developed anti-carrier responses with repeat vaccination and the differences in Ab titer between groups with and without preexisting anti-carrier responses became less apparent; however, anti-carrier effects were more durable for Ab function. PMID- 27121369 TI - Disgust exposure and explicit emotional appraisal enhance the LPP in response to disgusted facial expressions. AB - The influence of prior exposure to disgusting imagery and the conscious appraisal of facial expressions were examined in an event-related potential (ERP) experiment. Participants were exposed to either a disgust or a control manipulation and then presented with emotional and neutral expressions. An assessment of the gender of the face was required during half the blocks and an affective assessment of the emotion in the other half. The emotion-related early posterior negativity (EPN) and late positive potential (LPP) ERP components were examined for disgust and neutral stimuli. Results indicated that the EPN was enhanced for disgusted over neutral expressions. Prior disgust exposure modulated the middle phase of the LPP in response to disgusted but not neutral expressions, but only when the emotion of the face was explicitly evaluated. The late LPP was enhanced independently of stimuli when an emotional decision was made. Results demonstrated that exposure to disgusting imagery can affect the subsequent processing of disgusted facial expressions when the emotion is under conscious appraisal. PMID- 27121370 TI - Metal contact effect on the performance and scaling behavior of carbon nanotube thin film transistors. AB - Metal-tube contact is known to play an important role in carbon nanotube field effect transistors (CNT-FETs) which are fabricated on individual CNTs. Less attention has been paid to the contact effect in network type carbon nanotube thin film transistors (CNT-TFTs). In this study, we demonstrate that contact plays an even more important role in CNT-TFTs than in CNT-FETs. Although the Schottky barrier height at the metal-tube contact can be tuned by the work function of the metal, similar to the case in CNT-FETs, the contact resistance (Rc) forms a much higher proportion of the total resistance in CNT-TFTs. Interestingly, the contact resistivity was found to increase with channel length, which is a consequence of the percolating nature of the transport in CNT films, and this behavior does not exist in CNT-FETs and normal 2D Ohmic conductors. Electrical transport in CNT-TFTs has been predicted to scale with channel length by stick percolation theory. However, the scaling behavior is also impacted, or even covered up by the effect of Rc. Once the contact effect is excluded, the covered scaling behavior can be revealed correctly. A possible way of reducing Rc in CNT-TFTs was proposed. We believe the findings in this paper will strengthen our understanding of CNT-TFTs, and even accelerate the commercialization of CNT TFT technology. PMID- 27121371 TI - Prescribing patterns of dental practitioners in Australia from 2001 to 2012. Antimicrobials. AB - BACKGROUND: The development of antibiotic resistance by bacteria is of global concern. Inappropriate prescribing has the potential to exacerbate this issue. We aimed to examine the patterns of prescribing of antimicrobial medicines by dental practitioners in Australia from 2001 to 2012. METHODS: Data were collected from Medicare Australia on prescriptions from dental practitioners dispensed to concessional beneficiaries between 2001 and 2012. We examined patterns of use over time. RESULTS: There was an overall increase in number of prescriptions and in dispensed use (standardized by dose and population) of antibiotics and antifungals for the concessional population over the 12-year period. The use of dentally prescribed antibiotics increased 50%. Amoxicillin was the most commonly prescribed antibiotic accounting for 66% of all prescriptions in 2012. Generally, there was preferential prescribing of the highest dose formulations. The use of the two antifungals increased 30% over the study period with a preference for amphotericin B (74%) rather than nystatin. CONCLUSIONS: These data show a concerning increase in prescribing of antibiotics and antifungals by dentists in Australia. It would appear that Australian dentists may not be prescribing these medicines appropriately; however, further research is needed to understand prescribing behaviours and decision-making by dentists. PMID- 27121373 TI - The development and evaluation of the Finnish digit triplet test. AB - OBJECTIVES: The aim of the study was to develop a reliable and easily accessible screening test for primary detection of hearing impairment. METHODS: Digits 0-9 were used to form quasirandom digit triplets. First, digit specific intelligibility functions and speech recognition thresholds (SRTs) were determined. To homogenize the test material digits with steep intelligibility function slopes were chosen and level correction up to +/-2 dB were applied to the digits as needed. Evaluation measurements were performed to check for systematic differences in intelligibility between the test lists and to obtain normative reference function for normal-hearing listeners. RESULTS: The mean SRT and the final slope of the test lists were -10.8 +/- 0.1 dB signal-to-noise ratio (SNR) and 21.7 +/- 1.8%/dB, respectively (measurements at constant level; inter list variability). The mean SRT and slope of the test subjects were -10.8 +/- 0.5 dB SNR and 23.4 +/- 5.2%/dB (measurements at constant level; inter-subject variability). The mean SRT for normal-hearing young adults for a single adaptive measurement is -9.8 +/- 0.9 dB SNR. CONCLUSION: The Finnish digit triplet test is the first self-screening hearing test in the Finnish language. It was developed according to current standards, and it provides reliable and internationally comparable speech intelligibility measurements. PMID- 27121372 TI - Identification of a Potent and Broad-Spectrum Hepatitis C Virus Fusion Inhibitory Peptide from the E2 Stem Domain. AB - Hepatitis C virus (HCV) envelope proteins E1 and E2 play an essential role in virus entry. However, the fusion mechanisms of HCV remain largely unclear, hampering the development of efficient fusion inhibitors. Here, we developed two cell-based membrane fusion models that allow for screening a peptide library covering the full-length E1 and E2 amino acid sequences. A peptide from the E2 stem domain, named E27, was found to possess the ability to block E1E2-mediated cell-cell fusion and inhibit cell entry of HCV pseudoparticles and infection of cell culture-derived HCV at nanomolar concentrations. E27 demonstrated broad spectrum inhibition of the major genotypes 1 to 6. A time-of-addition experiment revealed that E27 predominantly functions in the late steps during HCV entry, without influencing the expression and localization of HCV co-receptors. Moreover, we demonstrated that E27 interfered with hetero-dimerization of ectopically expressed E1E2 in cells, and mutational analysis suggested that E27 might target a conserved region in E1. Taken together, our findings provide a novel candidate as well as a strategy for developing potent and broad-spectrum HCV fusion inhibitors, which may complement the current direct-acting antiviral medications for chronic hepatitis C, and shed light on the mechanism of HCV membrane fusion. PMID- 27121374 TI - Attitudes towards assisted dying are influenced by question wording and order: a survey experiment. AB - BACKGROUND: Surveys on attitudes towards assisted dying play an important role in informing public debate, policy and legislation. Unfortunately, surveys are often designed with insufficient attention to framing effects; that is, effects on the respondents' stated attitudes caused by question wording and context. The purpose of this study was to demonstrate and measure such framing effects. METHODS: Survey experiment in which an eight-question survey on attitudes towards assisted dying was distributed to Norwegian citizens through a web-based panel. Two variations of question wording as well as two variations of question order were employed. Respondents were randomized to receive one of four questionnaire versions. RESULTS: Three thousand and fifty responses were received. There were moderate to large question wording and question order effects. A majority of Norwegian citizens favour the legalization of assisted dying for patients with terminal or chronic disease. CONCLUSIONS: Stakeholders in the assisted dying debate need to acknowledge potential framing effects, and accordingly should interpret survey results with caution. The same holds for researchers who conduct attitude surveys in the field of bioethics. PMID- 27121375 TI - The orphan nuclear receptor NR4A2 is part of a p53-microRNA-34 network. AB - Nuclear receptor subfamily 4 group A member 2 (NR4A2) is an orphan nuclear receptor that is over-expressed in cancer and promotes cell proliferation, migration, transformation, and chemoresistance. Increased expression and function of NR4A2 have been attributed to various signaling pathways, but little is known about microRNA (miRNA) regulation of NR4A2 in cancer. To investigate the posttranscriptional regulation of NR4A2, we used a 3' untranslated region (UTR) reporter screen and identified miR-34 as a putative regulator of NR4A2. By using computer predictions, we identified and confirmed an miRNA recognition element in the 3' UTR of NR4A2 that was responsible for miR-34-mediated suppression. We next demonstrated that overexpression of exogenous miR-34 or activation of the p53 pathway, which regulates endogenous miR-34 expression, decreased NR4A2 expression. Consistent with previous reports, overexpression of NR4A2 blocked the induction of p53 target genes, including mir-34a. This was a phenotypic effect, as NR4A2 overexpression could rescue cells from p53-induced inhibition of proliferation. In summary, our results are the first characterization of a cancer related miRNA capable of regulating NR4A2 and suggest a network and possible feedback mechanism involving p53, miR-34, and NR4A2. PMID- 27121376 TI - Coma of unknown origin in the emergency department: implementation of an in-house management routine. AB - BACKGROUND: Coma of unknown origin is an emergency caused by a variety of possibly life-threatening pathologies. Although lethality is high, there are currently no generally accepted management guidelines. METHODS: We implemented a new interdisciplinary standard operating procedure (SOP) for patients presenting with non-traumatic coma of unknown origin. It includes a new in-house triage process, a new alert call, a new composition of the clinical response team and a new management algorithm (altogether termed "coma alarm"). It is triggered by two simple criteria to be checked with out-of-hospital emergency response teams before the patient arrives. A neurologist in collaboration with an internal specialist leads the in-hospital team. Collaboration with anaesthesiology, trauma surgery and neurosurgery is organised along structured pathways that include standardised laboratory tests and imaging. Patients were prospectively enrolled. We calculated response times as well as sensitivity and false positive rates, thus proportions of over- and undertriaged patients, as quality measures for the implementation in the SOP. RESULTS: During 24 months after implementation, we identified 325 eligible patients. Sensitivity was 60 % initially (months 1-4), then fluctuated between 84 and 94 % (months 5-24). Overtriage never exceeded 15 % and undertriage could be kept low at a maximum of 11 % after a learning period. We achieved a median door-to-CT time of 20 minutes. 85 % of patients needed subsequent ICU treatment, 40 % of which required specialised neuro-ICUs. DISCUSSION: Our results indicate that our new simple in-house triage criteria may be sufficient to identify eligible patients before arrival. We aimed at ensuring the fastest possible proceedings given high portions of underlying time-sensitive neurological and medical pathologies while using all available resources as purposefully as possible. CONCLUSIONS: Our SOP may provide an appropriate tool for efficient management of patients with non-traumatic coma. Our results justify the assignment of the initial diagnostic workup to neurologists and internal specialists in collaboration with anaesthesiologists. PMID- 27121377 TI - Erratum to: CASPER plus (CollAborative care in screen-positive EldeRs with major depressive disorder): study protocol for a randomised controlled trial. PMID- 27121380 TI - Physiological targets for the treatment of diabetic encephalopathy. AB - BACKGROUND: Diabetes mellitus is a chronic degenerative disease responsible for hyperglycemic episodes through insulin secretion deficiency or cellular resistance. Clinical diagnosis in diabetic patients established that this disease affects the CNS, damaging the brain and impairing cognition, and thus establishing a clinical diabetic condition named diabetic encephalopathy. Despite the physiological mechanisms responsible for the development diabetic encephalopathy are still unclear, an excessive formation of reactive oxygen species, an alteration of acetylcholinesterase activity, and a reduction of growth factor levels, may be related with the pathogenesis of this condition. Pharmacological treatments with natural compounds have been proven useful to treat and cure a wide variety of diseases through their antioxidant actions. METHODS: This study built a compendium of chemical compounds used for the treatment of diabetic encephalopathy demonstrating the most important physiological targets that future drugs should aim for, reviewing them. RESULTS: As previously suspected, antioxidants and acetylcholinesterase inhibitors were useful to prevent memory loss in streptozotocin-induced animals. In addition, growth factors showed an improvement of memory in diabetic rodents. Most studies focused on antioxidant compounds despite cross studies researched both antioxidants and acetylcholinesterase activities. CONCLUSION: Therefore, it could be suggested that future studies regarding treatments for diabetic encephalopathy should focus on the antioxidant profile and acetylcholinesterase, since they seem to play pivotal roles in cognitive impairment in diabetes. No less important, studies with growth factors are also important physiological targets for treating the diabetic encephalopathy. PMID- 27121379 TI - Quantification of maceration changes using post mortem MRI in fetuses. AB - BACKGROUND: Post mortem imaging is playing an increasingly important role in perinatal autopsy, and correct interpretation of imaging changes is paramount. This is particularly important following intra-uterine fetal death, where there may be fetal maceration. The aim of this study was to investigate whether any changes seen on a whole body fetal post mortem magnetic resonance imaging (PMMR) correspond to maceration at conventional autopsy. METHODS: We performed pre autopsy PMMR in 75 fetuses using a 1.5 Tesla Siemens Avanto MR scanner (Erlangen, Germany). PMMR images were reported blinded to the clinical history and autopsy data using a numerical severity scale (0 = no maceration changes to 2 = severe maceration changes) for 6 different visceral organs (total 12). The degree of maceration at autopsy was categorized according to severity on a numerical scale (1 = no maceration to 4 = severe maceration). We also generated quantitative maps to measure the liver and lung T2. RESULTS: The mean PMMR maceration score correlated well with the autopsy maceration score (R(2) = 0.93). A PMMR score of >=4.5 had a sensitivity of 91%, specificity of 64%, for detecting moderate or severe maceration at autopsy. Liver and lung T2 were increased in fetuses with maceration scores of 3-4 in comparison to those with 1-2 (liver p = 0.03, lung p = 0.02). CONCLUSIONS: There was a good correlation between PMMR maceration score and the extent of maceration seen at conventional autopsy. This score may be useful in interpretation of fetal PMMR. PMID- 27121378 TI - Role of transient receptor potential ankyrin 1 channels in Alzheimer's disease. AB - BACKGROUND: Transient receptor potential ankyrin 1 (TRPA1) channel plays an important role in pain and inflammation. However, little is known about the significance of the TRPA1 channel in the pathophysiology of Alzheimer's disease (AD). METHODS: Wild-type (WT), TRPA1(-/-), amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) mice, the mouse model of AD, and APP/PS1 Tg/TRPA1(-/-) mice were used to examine the role of TRPA1 in pathogenesis of AD. Western blot was used for protein expression; immunohistochemistry was used for histological examination. The mouse behaviors were evaluated by locomotion, nesting building, Y-maze and Morris water maze tests; levels of interleukin (IL)-1beta, IL-4, IL-6 and IL-10 and the activities of protein phosphatase 2B (PP2B), NF-kappaB and nuclear factor of activated T cells (NFAT) were measured by conventional assay kits; Fluo-8 NW calcium (Ca(2+)) assay kit was used for the measurement of intracellular Ca(2+) level in primary astrocytes and HEK293 cells. RESULTS: The protein expression of TRPA1 channels was higher in brains, mainly astrocytes of the hippocampus, from APP/PS1 Tg mice than WT mice. Ablation of TRPA1-channel function in APP/PS1 Tg mice alleviated behavioral dysfunction, Abeta plaque deposition and pro-inflammatory cytokine production but increased astrogliosis in brain lesions. TRPA1 channels were activated and Ca(2+) influx was elicited in both astrocytes and TRPA1-transfected HEK293 cells treated with fibrilized Abeta1-42; these were abrogated by pharmacological inhibition of TRPA1 channel activity, disruption of TRPA1 channel function or removal of extracellular Ca(2+). Inhibition of TRPA1 channel activity exacerbated Abeta1-42 induced astrogliosis but inhibited Abeta1-42-increased PP2B activation, the production of pro-inflammatory cytokines and activities of transcriptional factors NF-kappaB and NFAT in astrocytes and in APP/PS1 Tg mice. Pharmacological inhibition of PP2B activity diminished the fibrilized Abeta1-42-induced production of pro-inflammatory cytokines, activation of NF-kappaB and NFAT and astrogliosis in astrocytes. CONCLUSIONS: TRPA1 - Ca(2+) - PP2B signaling may play a crucial role in regulating astrocyte-derived inflammation and pathogenesis of AD. PMID- 27121381 TI - Schiff Bases of Benzothiazol-2-ylamine and Thiazolo[5,4-b] pyridin-2-ylamine as Anticonvulsants: Synthesis, Characterization and Toxicity Profiling. AB - BACKGROUND: Schiff bases have a broad spectrum of biological activities like antiinflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic and so forth. Thus, after a thorough perusal of literature, it was decided to conjugate benzothiazol-2 ylamine/thiazolo [5, 4-b] pyridin-2-ylamine with aromatic and heteroaromatic aldehydes to get a series of Schiff bases. OBJECTIVE: Synthesis, characterization, in-silico toxicity profiling and anticonvulsant activity of the Schiff bases of Benzothiazol-2-ylamine and Thiazolo [5, 4-b] pyridin-2-ylamine. METHOD: Aniline/4-aminopyridine was converted to the corresponding thiourea derivatives, which were cyclized to obtain benzothiazol-2-ylamine/thiazolo [5, 4 b] pyridin-2-ylamine. Finally, these were condensed with various aromatic and heteroaromatic aldehydes to obtain Schiff bases of benzothiazol-2-ylamine and thiazolo [5, 4-b] pyridin-2-ylamine. The synthesized compounds were characterized and screened for their anticonvulsant activity using maximal electroshock (MES) test and isoniazid (INH) induced convulsions test. In-silico toxicity profiling of all the synthesized compounds was done through "Lazar" and "Osiris" properties explorer. RESULTS: Majority of the compounds were more potent against MES induced convulsions than INH induced convulsions. Schiff bases of benzothiazol-2-ylamine were more effective than thiazolo [5, 4-b] pyridin-2-ylamine against MES induced convulsions. The compound benzothiazol-2-yl-(1H-indol-2-ylmethylene)-amine (VI) was the most potent member of the series against both types of convulsions. CONCLUSION: Compound VI exhibited the most significant activity profile in both the models. The compounds did not exhibit any carcinogenicity or acute toxicity in the in-silico studies. Thus, it may be concluded that the Schiff bases of benzothiazol-2-ylamine exhibit the potential to be promising and non-toxic anticonvulsant agents. PMID- 27121383 TI - Statistical colour models: an automated digital image analysis method for quantification of histological biomarkers. AB - BACKGROUND: Colour is the most important feature used in quantitative immunohistochemistry (IHC) image analysis; IHC is used to provide information relating to aetiology and to confirm malignancy. METHODS: Statistical modelling is a technique widely used for colour detection in computer vision. We have developed a statistical model of colour detection applicable to detection of stain colour in digital IHC images. Model was first trained by massive colour pixels collected semi-automatically. To speed up the training and detection processes, we removed luminance channel, Y channel of YCbCr colour space and chose 128 histogram bins which is the optimal number. A maximum likelihood classifier is used to classify pixels in digital slides into positively or negatively stained pixels automatically. The model-based tool was developed within ImageJ to quantify targets identified using IHC and histochemistry. RESULTS: The purpose of evaluation was to compare the computer model with human evaluation. Several large datasets were prepared and obtained from human oesophageal cancer, colon cancer and liver cirrhosis with different colour stains. Experimental results have demonstrated the model-based tool achieves more accurate results than colour deconvolution and CMYK model in the detection of brown colour, and is comparable to colour deconvolution in the detection of pink colour. We have also demostrated the proposed model has little inter-dataset variations. CONCLUSIONS: A robust and effective statistical model is introduced in this paper. The model-based interactive tool in ImageJ, which can create a visual representation of the statistical model and detect a specified colour automatically, is easy to use and available freely at http://rsb.info.nih.gov/ij/plugins/ihc-toolbox/index.html . Testing to the tool by different users showed only minor inter-observer variations in results. PMID- 27121382 TI - Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model. AB - Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing P<0.0001. The apparent AUC of the epidemiological model was 0.75 (95% CI 0.73-0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79-0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added. PMID- 27121384 TI - Additional Layers of Violence: The Intersections of Gender and Disability in the Violence Experiences of Women With Physical Disabilities in South Africa. AB - South Africa has unprecedented levels of violence and many South African women are exposed to violence during their lifetime. This article explores how gender and disability intersect in women's experiences of violence during their lifetime. Repeat in-depth qualitative interviews with 30 physically disabled women in Cape Town reveal that women with physical disabilities are exposed to various forms of violence, and shows how their impairments shape their violence experiences. The most common forms of violence women with disabilities experience are psychological violence, financial abuse, neglect, and deprivation, with disability stigma playing a central role and contributing to how women with disabilities are exploited and dehumanized. Constructions of women as asexual shape their sexual relationships and experiences of sexual violence. This article identifies that women with disabilities are more at risk and experience additional layers of violence than women without disabilities. These additional risks and layers of violence need to be recognized and inform interventions to prevent and respond to violence against women with disabilities in the country. Prevention of violence against women with physical disabilities in South Africa needs to address the role of disability stigma that shapes the types of violence they experience, change gender norms, and create accessible and safe environments and economic empowerment opportunities. PMID- 27121385 TI - Responding to Intimate Partner Violence: Challenges Faced Among Service Providers in Northern Communities. AB - The current study examined the needs of women experiencing intimate partner violence (IPV) in a profiled northern community in Saskatchewan, Canada. A focus group was conducted with eight knowledgeable and experienced service providers to gain an increased understanding of the needs of women IPV survivors in northern regions of Canada. The discussion was guided by the question of "What do you see as the needs of women coming through your services with regard to intimate partner violence?" Qualitative analyses highlighted important findings pertaining to the unique needs of women experiencing IPV and the challenges service providers face in northern regions. Suggestions for improvement among resources and services were discussed. The findings will enhance the ability of government representatives and community service providers to decipher the effectiveness of support services and resources for women living in geographically diverse areas. PMID- 27121386 TI - Interpersonal Sexual Objectification Experiences: Psychological and Social Well Being Consequences for Women. AB - Sexual objectification as a form of sexist discrimination accounts for the higher prevalence of psychological problems among women. More specifically, sexual objectification manifests itself in different ways with different intensities, in turn affecting women's psychological well-being differently. On one hand, experiences of body evaluation are more subtle and work by perpetuating sexist attitudes among women themselves. On the other hand, more explicit forms of sexual objectification (unwanted explicit sexual advances) are linked to higher levels of anxiety and lower levels of self-esteem. The first study, on a sample of 343 Spanish women, aims to analyze the consequences of different forms of sexual objectification on women's psychological well-being and the effect of sexism and enjoyment of objectification on these consequences. The second study, on a sample of 144 Spanish women, focuses on analyzing the ideological variables that have an effect on response to acts of sexist discrimination. Both studies reveal the significance of the more subtle experiences of sexual objectification as a mechanism that plays a part in keeping women in a subordinate position, where they end up feeling that this process is positive or pleasing. PMID- 27121387 TI - A Nationwide Evaluation of Services Provided to Domestic Violence Survivors at Shelters in Bosnia-Herzegovina. AB - The shelter movement in Bosnia-Herzegovina was born out of a tradition of assisting survivors of gender-based violence in the early 1990s during the Bosnian conflict. To date, nine shelters are in existence providing emergency shelter and services to survivors. Little is known about these shelters, or the clients these shelters serve. The purpose of this study is to examine what services are provided to domestic violence survivors by shelters in Bosnia Herzegovina and who these survivors are. A total of 43 service providers from all existing shelters within the country were surveyed about shelter characteristics, client demographics, and services provided. Findings revealed that the typical Bosnian shelter had been in operation for 11 years and had assisted 64 survivors in the previous year; the majority of whom were married females with minor children who had sought shelter services before. Core services were provided by the majority of shelters, including crisis services, legal and medical advocacy, counseling, and community education. While services were provided to a diverse group of survivors (e.g., children, elderly women, victims of human trafficking), shelters were less likely to be available for male and lesbian, gay, bisexual, and transgender survivors. Implications from these findings, as well as limitations and suggestions for further research, are discussed. PMID- 27121388 TI - Seasonal variations and shared latrine cleaning practices in the slums of Kampala city, Uganda. AB - BACKGROUND: The effect of seasons on health outcomes is a reflection on the status of public health and the state of development in a given society. Evidence shows that in Sub-Saharan Africa, most infectious diseases flourish during the wet months of the year; while human activities in a context of constrained choices in life exacerbate the effects of seasons on human health. The paper argues that, the wet season and when human activities are at their peak, sanitation is most dire poor slum populations. METHODS: A shared latrine cleaning observation was undertaken over a period of 6 months in the slums of Kampala city. Data was collected through facility observations, user group meetings, Focus group discussions and, key informant interviews. The photos of the observed sanitation facilities were taken and assessed for facility cleanliness or dirt. Shared latrine pictures, observations, Focus Group Discussion, community meetings and key informant interviews were analysed and subjected to an analysis over the wet, dry and human activity cycles before a facility was categorised as either 'dirty' or 'clean'. RESULTS: Human activity cycles also referred to as socio economic seasons were, school days, holidays, weekends and market days. These have been called 'impure' seasons, while the 'pure' seasons were the wet and dry months: improved and unimproved facilities were negatively affected by the wet seasons and the peak seasons of human activity. Wet seasons were associated with, mud and stagnant water, flooding pits and a repugnant smell from the latrine cubicle which made cleaning difficult. During the dry season, latrines became relatively cleaner than during the wet season. The presence of many child(ren) users during school days as well as the influx of market goers for the roadside weekly markets compromised the cleaning outcomes for these shared sanitation facilities. CONCLUSION: Shared latrine cleaning in slums is impacted by seasonal variations related to weather conditions and human activity. The wet seasons made the already bad sanitation situation worse. The seasonal fluctuations in the state of shared slum sanitation relate to a wider malaise in the population and an implied capacity deficit among urban authorities. Poor sanitation in slums is part of a broader urban mismanagement conundrum pointing towards the urgent need for multiple interventions aimed at improving the general urban living conditions well beyond sanitation. PMID- 27121394 TI - Assessing blood platelets as RNA biomarker source for prostate cancer. AB - CONTEXT: Blood platelets may offer as RNA biomarker source for cancer as recently described for an oncogenic transcript in glioma patients and for PCA3 in prostate cancer (PCa) patients. OBJECTIVE: Here, we elaborated on this aspect for PCa. MATERIALS AND METHODS: PCA3 and other PCa-associated RNA markers were measured in platelets of PCa patients (cases) and healthy subjects (controls) in comparison to PCa cell lines by relative quantitative RT-PCR. RESULTS: The RNA markers displayed heterogeneous expression patterns in cell lines and platelets, however, without significant differences between cases and controls. DISCUSSION AND CONCLUSION: The data do not support platelets as a profitable RNA source for early detection of PCa. Nonetheless, certain PCa-derived RNA markers in platelets may merit further investigation as potential prognostic biomarkers for PCa. PMID- 27121395 TI - Enantioselective CuH-Catalyzed Reductive Coupling of Aryl Alkenes and Activated Carboxylic Acids. AB - A new method for the enantioselective reductive coupling of aryl alkenes with activated carboxylic acid derivatives via copper hydride catalysis is described. Dual catalytic cycles are proposed, with a relatively fast enantioselective hydroacylation cycle followed by a slower diastereoselective ketone reduction cycle. Symmetrical aryl carboxyclic anhydrides provide access to enantioenriched alpha-substituted ketones or alcohols with excellent stereoselectivity and functional group tolerance. PMID- 27121397 TI - Total Syntheses of Periconiasins A-E. AB - The first and collective total syntheses of periconiasins A-E, a group of naturally occurring cytochalasans, were achieved by a series of rationally designed or bioinspired transformations. Salient features of the syntheses include a tandem aldol condensation/Grob fragmentation to assemble the linear polyketide-amino acid hybrid precursor, a Diels-Alder macrocylization to construct the 9/6/5 tricyclic core of periconiasins A-C, and a transannular carbonyl-ene reaction to forge the polycyclic framework of periconiasins D and E. PMID- 27121396 TI - Up-regulation of FGFBP1 signaling contributes to miR-146a-induced angiogenesis in human umbilical vein endothelial cells. AB - Recent microRNA expression profiling studies have documented an up-regulation of miR-146a in several angiogenesis models. However, the underlying molecular mechanism of miR-146a in the angiogenic activity of endothelial cells has not been clearly elucidated. The present study was aimed to evaluate whether miR-146a promotes angiogenesis in HUVECs by increasing FGFBP1 expression via directly targeting CREB3L1. miR-146a was over expressed in HUVECs via lentiviral-miR-146a. Expression profiling analysis found miR-146a over expression resulted in up regulation of angiogenesis and cytokine activity associated genes including FGF2. Further a combination of bioinformatics and experimental analyses demonstrated the CREB3L1 as a bona fide functional target of miR-146a during angiogenesis. Moreover, CREB3L1 inhibited luciferase expression from FGFBP1 promoter containing only CRE elements. Furthermore, CREB3L1 inhibited FGFBP1 expression by binding to two CRE-like sites located at approximately -1780-1777 and -868-865 bp relative to the FGFBP1 transcription start site. Additionally, ectopic expression of CREB3L1 decreased miR-146a-induced FGF2 secretion. These findings indicate that the miR-146a-CREB3L1-FGFBP1 signaling axis plays an important role in the regulation of angiogenesis in HUVECs and provides a potential therapeutic target for anti-angiogenic therapeutics. PMID- 27121398 TI - Dysregulation of mprF and dltABCD expression among daptomycin-non-susceptible MRSA clinical isolates. AB - BACKGROUND: In small series or individual reports, SNPs within the mprF ORF and dysregulation of its expression in Staphylococcus aureus have been linked to daptomycin resistance (DAP-R) via a proposed gain-in-function mechanism. Similarly, dysregulation of dltABCD has also been associated with DAP-R. METHODS: Using 22 well-characterized, isogenic daptomycin-susceptible (DAP-S)/DAP-R clinical MRSA strain pairs, we assessed potential relationships of the DAP-R phenotype with: (i) regulation of mprF transcription; (ii) regulation of dltABCD transcription; (iii) expression of the two-component regulatory system, graRS (upstream regulator for both mprF and dltABCD transcription); (iv) SNPs within the graRS promoter or its ORF; and (v) altered mprF transcription and lysyl phosphatidylglycerol (L-PG) synthesis. RESULTS: Enhanced expression of mprF occurred with SNPs in highly distinct and well-chronicled MprF domain 'hot spots' and rarely occurred without such mutations. Increased expression and/or dysregulation of mprF and dltABCD were not uncommon in DAP-R strains, occurring in 27% of strains for each gene. In these latter strains, neither graRS expression profiles nor polymorphic sequences within the graRS promoter or ORF could be significantly linked to altered transcription of mprF or dlt. CONCLUSIONS: Although graRS can co-regulate mprF and dltABCD expression, loci outside of this regulon appear to be involved in dysregulation of these latter two genes and the DAP-R phenotype. Finally, DAP-R strains exhibiting significantly altered mprF transcription profiles produced significantly increased levels of L-PG. PMID- 27121399 TI - Tert-butyl benzoquinone: mechanism of biofilm eradication and potential for use as a topical antibiofilm agent. AB - OBJECTIVES: Tert-butyl benzoquinone (TBBQ) is the oxidation product of tert-butyl hydroquinone (TBHQ), an antimicrobial food additive with >40 years of safe use. TBBQ displays potent activity against Staphylococcus aureus biofilms in vitro. Here, we report on studies to further explore the action of TBBQ on staphylococcal biofilms, and provide a preliminary preclinical assessment of its potential for use as a topical treatment for staphylococcal infections involving a biofilm component. METHODS: The antibacterial properties of TBBQ were assessed against staphylococci growing in planktonic culture and as biofilms in the Calgary Biofilm Device. Established assays were employed to measure the effects of TBBQ on biofilm structure and bacterial membranes, and to assess resistance potential. A living-skin equivalent was used to evaluate the effects of TBBQ on human skin. RESULTS: TBBQ eradicated biofilms of S. aureus and other staphylococcal species at concentrations <=64 mg/L. In contrast to other redox active agents exhibiting activity against biofilms, TBBQ did not cause substantial destructuring of the biofilm matrix; instead, the antibiofilm activity of the compound was attributed to its ability to kill slow- and non growing cells via membrane perturbation. TBBQ acted synergistically with gentamicin, did not damage a living-skin equivalent following topical application and exhibited low resistance potential. CONCLUSIONS: The ability of TBBQ to eradicate biofilms appears to result from its ability to kill bacteria regardless of growth state. Preliminary evaluation suggests that TBBQ represents a promising candidate for development as a topical antibiofilm agent. PMID- 27121400 TI - What prevents the intravenous to oral antibiotic switch? A qualitative study of hospital doctors' accounts of what influences their clinical practice. AB - OBJECTIVES: Escalating antimicrobial resistance worldwide necessitates urgent optimization of antimicrobial prescribing to preserve antibiotics for future generations. Early intravenous (iv) to oral switch campaigns are one strategy that hospital-based antimicrobial stewardship programmes can incorporate to minimize inappropriate antibiotic use. Yet, iv antibiotics continue to be offered for longer than is clinically indicated, increasing hospital length of stay, increasing costs and placing patients at risk (e.g. cannula-related infections). This study aims to identify why this inappropriate prescribing trend continues. METHODS: Twenty doctors (9 females and 11 males) working at a teaching hospital in north-east England participated in semi-structured interviews about their experiences of antibiotic use. NVivo10 software was used to conduct a thematic content analysis of the full interview transcripts driven by the framework approach. Results are reported according to COREQ guidelines. RESULTS: Decisions around the choice of iv over oral antibiotics were influenced by three key issues: (i) consumerism, i.e. participants were concerned about the risk of litigation or complaints if patient expectations were not met; (ii) hierarchy of the medical team structure limited opportunities for de-escalation of antibiotics; and (iii) iv antibiotics were perceived as more potent and having significant mythical qualities, which participants acknowledged were not necessarily evidence based. CONCLUSIONS: The iv to oral switch interventions should tailor strategies to demystify iv versus oral antibiotic efficacy, engage consumers around the negative effects of iv antibiotic overuse and examine strategies to streamline team decision-making. Addressing these issues has the potential to reduce inappropriate antibiotic use and resistance. PMID- 27121402 TI - Real-time PCR for detection of plasmid-mediated polymyxin resistance (mcr-1) from cultured bacteria and stools. AB - OBJECTIVES: The aim of the study was to develop a simple assay for rapid detection of the mcr-1 gene, recently identified as a source of plasmid-mediated acquired resistance to polymyxins in Enterobacteriaceae. METHODS: A SYBR Green based real-time PCR assay was designed for detection of the mcr-1 gene. This assay was applied to cultured bacteria and to spiked human and cattle stools. RESULTS: The mcr-1 gene could be detected with a lower limit of 10(2) cultured bacteria. This test was highly sensitive and specific, and generated no false positive results. The assay was also conclusive when applied to stools spiked with mcr-1-positive Escherichia coli. CONCLUSIONS: This simple, rapid, sensitive and specific assay will be useful for rapid screening of this resistance trait in both human medicine and veterinary medicine. PMID- 27121401 TI - Voriconazole pharmacokinetics following HSCT: results from the BMT CTN 0101 trial. AB - BACKGROUND: Voriconazole is a first-line agent for the prevention and treatment of a number of invasive fungal diseases. Relatively little is known about the relationship between drug exposure and the prevention of invasive fungal infections. PATIENTS AND METHODS: A pharmacokinetic-pharmacodynamic substudy was performed as part of the BMT CTN 0101 trial, which was a randomized clinical trial comparing voriconazole with fluconazole for the prevention of invasive fungal infections in HSCT recipients. A previously described population pharmacokinetic model was used to calculate the maximum a posteriori Bayesian estimates for 187 patients. Drug exposure in each patient was quantified in terms of the average AUC and average trough concentrations. The relationship between drug exposure and the probability of breakthrough infection was investigated using logistic regression. AUC and trough concentrations in patients with and without breakthrough infection were compared. RESULTS: Pharmacokinetic data from each patient were readily described using the maximum a posteriori Bayesian estimates. There were only five patients that had a breakthrough infection while receiving voriconazole in the first 100 days post-HSCT. For these patients, there was no statistically significant relationship between the average AUC or average trough concentration and the probability of breakthrough infection [OR (95% CI) 1.026 (0.956-1.102) and 1.108 (0.475-2.581), respectively]. P value for these estimates was 0.474 and 0.813, respectively. CONCLUSIONS: Given the very small number of proven/probable infections, it was difficult to identify any differences in drug exposure in HSCT recipients with and without breakthrough fungal infections. PMID- 27121403 TI - Mark Porter interview: the government will realise its mistake. PMID- 27121404 TI - Magnetic metal-organic framework MIL-100(Fe) microspheres for the magnetic solid phase extraction of trace polycyclic aromatic hydrocarbons from water samples. AB - In this work, a magnetic metal-organic framework designated as MIL-100(Fe) was prepared and applied as a magnetic solid-phase extraction sorbent for the determination of trace polycyclic aromatic hydrocarbons in environmental water samples by coupling with high-performance liquid chromatography and fluorescence detection. The magnetic microspheres exhibited large surface areas and high extraction ability, making them excellent candidates as sorbents for enrichment of trace polycyclic aromatic hydrocarbons. Under the optimized experimental conditions, good sensitivity levels were achieved with low detection limits ranging from 32 to 2110 pg/mL and good linearities with correlation coefficients higher than 0.9990 for the investigated 13 polycyclic aromatic hydrocarbons. The proposed method has been validated in the analysis of real water samples with mean recoveries in the range of 81.4-126.9% at four spiked levels and the relative standard deviations in the range of 1.3-17.0%. The magnetic MIL-100(Fe) microspheres were stable enough for 150 extractions without a significant loss of extraction performance. PMID- 27121405 TI - Clinical application of computed tomography-guided (125)I seed interstitial implantation for head and neck cancer patients with unmanageable cervical lymph node metastases. AB - BACKGROUND: To assess clinical application of computed tomography (CT)-guided (125)I seed implantation for patients who cannot endure or unwillingly receive repeated surgery, chemotherapy, or radiotherapy for unmanageable cervical lymph node metastases in head and neck cancer (HNC). METHODS: Thirty-one consecutive patients received CT-guided (125)I seed implantation between February 2010 and December 2013. To evaluate the clinical efficiency, karnofsky performance score (KPS), numeric rating scale (NRS), and tumor volume at 3-, and 6-month post implantation were compared with pre-implantation, along with local control rate (LCR), overall survival rate (OSR), and complications at 3, 6 months, 1, and 2 years. RESULTS: The tumor volume was obviously decreased at 3-, and 6-month post implantation (21.23 +/- 8.83 versus 9.19 +/- 7.52 cm(2); 21.23 +/- 8.83 versus 6.42 +/- 9.79 cm(2); P < 0.05) compared with pre-implantation. The NRS was statistically reduced (3.06 +/- 1.06 versus 7.77 +/- 0.92; 2.39 +/- 1.15 versus 7.77 +/- 0.92; P < 0.05), while KPS was significantly improved (83.18 +/- 5.97 versus 73.60 +/- 7.90; 82.86 +/- 5.43 versus 73.60 +/- 7.90; P < 0.05) postoperatively at 3 and 6 months, respectively. The LCR at 3, 6 months, 1, and 2 years was 96.30, 83.87, 64.51, and 45.16%, respectively. The OSR was 100, 100, 67.74, and 45.16%, respectively. Three cases experienced grade I and two had grade II acute radiation toxicity. CONCLUSIONS: CT-guided seed implantation may be feasible and safe for HNC patients whose neck nodes are not manageable by routine strategies with fewer complications, higher LCR, and significant pain relief. PMID- 27121406 TI - Systematic and Specific Treatment of Patients with Enteroatmospheric Fistulas: From Initial Conservative Treatment to Definitive Surgery. AB - INTRODUCTION: The open abdomen is a widespread therapeutic resource; however, it is also a source of complications, of which the enteroatmospheric fistulas (EAFs) pose one of the greatest problems. The objective of this study was to describe the implemented strategy for handling enteroatmospheric fistulas, and secondarily, to analyze the differential results based on a change in the conservative local treatment specifically designed for the stated complication. MATERIALS AND METHODS: From March 2002 to March 2014, patients treated for EAF were retrospectively analyzed. They were divided into 2 groups: Group 1 (G1: 2002 - 2007), treated with an occlusive vacuum device (SIVACO), similar to that used for other enterocutaneous fistulas, and Group 2 (G2: 2008 - 2014), covered in a specific modality for EAF. Results of conservative and surgical treatment were described and then the two groups were statistically compared. RESULTS: Study participants comprised 62 patients. Twelve cases (19.4%) healed with conservative treatment. This was statistically related with a baseline albumin level >3 g/dL, single lesions with no visible mucosa and baseline output <700 mL/d. In G1, the output fall was higher, while G2 required fewer wound dressing changes and enteral nutrition was feasible in a significantly higher number of patients. Forty-seven patients underwent reconstructive surgery. The mortality-associated variables were preoperative hypoalbuminemia and 2 or more anastomoses. Overall mortality was 8% (5 patients). In the multivariate model, only initial output (<700 mL/d) was an independent predictor for spontaneous closure, whereas 2 or more anastomoses and hypoalbuminemia were negative independent predictors. CONCLUSION: Systematic management of enteroatmospheric fistulas, following a rigorous protocol and a two-step specific treatment, resulted in a practical approach and yielded good results in healing and mortality. PMID- 27121407 TI - Percutaneous Pedicle Screw Fixation Technique in the Thoracic and Lumbar Spine Tips and Tricks. AB - The need for spinal fixation in patients who cannot tolerate classical open surgery has led in recent years to the development of minimally invasive approaches. The use of percutaneous pedicle screw fixation offers several advantages, such as less blood loss and postoperative pain due to blunt separation of the muscles with reduction of soft tissue dissection. Medical records and demographic information, diagnosis, and preoperative pain levels of 63 patients who underwent percutaneous minimally invasive thoracolumbar spine stabilization using the Illico(r) Fixation System (Alphatec Spine, Carlsbad, California) were analysed: a total of 344 screws were implanted. Preoperative and postoperative clinical assessment of the patients were based on a visual analogue scale. Because percutaneous techniques do not allow gross visualization of the vertebra and erroneous placement of the screw may be high in the initial cases, we discuss the techniques for a safe implantation of pedicle screws using a single or double intraoperative fluoroscopy. We report tips and tricks for technical challenges including fixation in osteoporotic patients, percutaneous insertion of long rods, compression/distraction using multiaxial screws turning into monoaxial, and use of minimally invasive retractror for interbody fusion. Recently, indications for minimally invasive percutaneous fixation have expanded and my results support that it may be considered a safe and effective option for the treatment of degenerative and traumatic thoracolumbar spinal diseases. PMID- 27121408 TI - Laparoscopic Psoas Hitch Double Ureteral Re-implantation in the Duplex Urinary System for Treatment of Ureterovaginal Fistula. AB - INTRODUCTION: Although laparoscopy is widely established for ablative urologic procedures, pelvic reconstructive procedures are still mostly performed by open surgery. As urologists continue to introduce advanced laparoscopic skills to reconstructive urologic procedures, we present our experience with a laparoscopic psoas hitch double ureteral re-implantation in a patient with an ureterovaginal fistula and an ipsilateral duplex urinary system. MATERIALS AND METHODS: A 42 year-old patient presented with continuous involuntary urine loss from the vagina after an abdominal hysterectomy. A double modified Lich-Gregoir ureteral re implantation with a psoas hitch was performed, using a 4-port laparoscopic approach. RESULTS: There were no post-operative complications and the cystography at post-operative day 14 revealed good positioning of the psoas hitch, with no leak or reflux. At three-months follow-up, the patient is completely dry and asymptomatic. CONCLUSION: Laparoscopic ureteroneocystostomy with psoas hitch for the treatment of lesions of the distal ureter is a possible, safe, and effective way to resolve a complex urologic situation with minimally invasive surgery. Laparoscopy is becoming the standard approach to urologic pelvic reconstructive procedures, even in the most complex cases. PMID- 27121409 TI - "See-and-Treat" Hysteroscopy in the Management of Endometrial Polyps. AB - Endometrial polyps (EPs) are a common cause of abnormal uterine bleeding (AUB) in perimenopausal and postmenopausal women and are typically suggested by a screening transvaginal ultrasound. In addition, the increasing use of pelvic imaging often discloses asymptomatic EPs. In the past, saline infusion sonography (SIS) has been advocated in order to triage patients to undergo a blind curettage or a diagnostic or operative hysteroscopy. The introduction of small diameter hysteroscopes and resectoscopes-often no larger than a SIS catheter-now allows most women with abnormal ultrasound findings to undergo a single-stage "see-and treat" hysteroscopy for the management of endometrial polyps. In order to provide optimal management of endometrial polyps, however, a variety of known and unknown factors must be considered prior to "see-and-treat" hysteroscopy. For a woman wishing to preserve or enhance her fertility, hysteroscopic polypectomy-with care to avoid collateral endometrial damage-remains the standard of care. However, the literature reveals three issues that are important to address. First, that many premalignant and malignant lesions are found at the polyp base. Second, that there is a significant recurrence risk following simple polypectomy; this is especially true in tamoxifen-treated women. Third, that polypectomy alone is often insufficient for the satisfactory management of AUB. By offering a variety of options to women undergoing hysteroscopic polypectomy-including partial or total endomyometrial resection-the author addresses many of the limitations of traditional polypectomy. Moreover, the use of small diameter hysteroscopes and resectoscopes allow these procedures to be performed as a single stage "see-and treat" hysteroscopy in the comfort and safety of an office-based setting. PMID- 27121410 TI - Grafting of Expanded Mesenchymal Stem Cells without Associated Procedure in a Healed Case of Ulna Pseudarthrosis: A Case Report. AB - BACKGROUND: The surgical management of pseudoarthrosis is often a challenge. The use of mesenchymal multipotent cells expanded and manipulated in the laboratory is an interesting treatment of pseudoarthrosis, because they can lead to differentiation into osteocytes and thus the formation of bone tissue. CASE DESCRIPTION: We present a case of a 47-years-old man with isolate ulna fracture, treated with plate and screws and evolved in non-union. The patient underwent an expanded stem cells graft on the site of non-union with a small incision of approximately 3cm, without changing the synthesis system. After one year, the X ray showed a complete fracture consolidation. DISCUSSION: In our opinion, this case is interesting because it highlights the cellular action that is the only healing factor; it is an important demonstration of the biological action of expanded mesenchymal stem cells (MSCs). CONCLUSION: To validate the use of MSCs, it is necessary to perform comparative studies for age, sex, general condition, location, and mechanism of injury as a further clinical validation of the efficiency of this cell line. PMID- 27121411 TI - Single-Use Instrumentation Technologies in Knee Arthroplasty: State of the Art. AB - The surgical site contamination and the resulting periprosthetic infections are an important cause of morbidity and socio-economic impact. In total knee arthroplasty, the single-use instrumentation is developed to simplify the surgical procedure, reduce the chance of instrument contamination, improve the operating room efficiency, and reduce overall costs (low cost of instrument washing and sterilization as well as personnel management). Surgical single-use instrumentations on the market are complete with all you need for the surgical procedure-cutting guides, conventional or PSI (patient-specific instrumentation), femoral cutting block, re-cutting block, trials components, alignment rods, inserts, and impactors. In recent years, PSI (patient-specific instrumentation) was introduced. It decreases operative time and blood loss without violating the intramedullary canal. It also allows the surgeon to preoperatively plan the patient's component size, position, and alignment. We reported an average of 30 minutes saved for each surgical procedure, a saving of 60? for each surgical tray. Moreover, we avoided surgery cancellation or delay due to un-sterile, missing, or dysfunctional instruments. We think that this technology is the first step in developing implants that are entirely customized for each patient, and we believe that it will have a more relevant role in knee surgery in the future. PMID- 27121412 TI - Giant Schwannoma of the Saphenous Nerve in The Distal Thigh: A Case Report. AB - CASE: Schwannomas are benign nerve myelin sheath tumors that can occur anywhere in the peripheral nervous system. It is very rare for Schwannomas to become malignant, but surgery is still the principal treatment to eliminate symptoms and to correctly diagnosis the tumor. We report an interesting case of a schwannoma of the saphenous nerve at the distal third of the posteromedial thigh: the patient complained of muscle weakness at left lower limb and vague anteromedial knee pain, mimicking a meniscal tear. Magnetic resonance images of the thigh showed a well-defined and oval mass lesion measuring 8.5 cm x 4.5 cm. Before investigating for a possible meniscal tear, we decided to remove the mass from the thigh, because we felt that it could itself be the cause of the mild pain complained about by the patient. Post-surgery, histological analysis conducted confirmed that this was a benign schwannoma. DISCUSSION: Schwannomas generally can be asymptomatic or present as a mass. The clinical presentation of this rare tumor makes the diagnosis difficult. CONCLUSION: This reported case is particularly interesting because of the rarity of the lesion localization along the course of the saphenous nerve. The combination of the location, and especially the large size of the tumor, led us to believe that there is a correlation with the particular clinical presentation. PMID- 27121413 TI - Is There An Ideal Stump Closure Technique In Laparoscopic Appendectomy? AB - BACKGROUND: There is no standard routine closure technique in the management of appendiceal stump. Therefore, the ideal method should be determined based on the condition of the radix of the appendix. AIM: The aim of this study was to evaluate appendiceal stump closure methods in patients undergoing laparoscopic appendectomy due to acute appendicitis. MATERIALS AND METHODS: The retrospective study included 196 patients who underwent laparoscopic appendectomy due to the diagnosis of acute appendicitis at Gazipasa State Hospital, Golhisar State Hospital, and Isparta State Hospital between 2009 and 2013. The methods performed for the closure of the appendiceal stump included stapler closure technique (Group I), ENDOLOOP(r) (Johnson & Johnson Inc., New Brunswick, New Jersey) technique (Group II), Hem-o-lok(r) (Teleflex(r), Limerick, Pennsylvania) clip (Group III), and handmade endo-loop technique (Group IV). The groups were compared in terms of duration of surgery, length of hospital stay, postoperative pain, complication rates, and cost of treatment. RESULTS: No significant difference was observed among the groups in terms of patient characteristics. In eight patients, laparoscopic appendectomy was converted to open surgery due to various reasons. Mean length of hospital stay was two days in all of the groups that underwent laparoscopic appendectomy. No significant difference was found among the groups in terms of duration of surgery, complications, and postoperative analgesic requirement, but a significant difference was observed in terms of the cost of treatment. CONCLUSIONS: We suggest that the handmade endo loop technique is a safe, applicable, and cost-effective method to be used in the closure of appendiceal stump. PMID- 27121414 TI - Critical role of oncogenic KRAS in pancreatic cancer (Review). AB - Pancreatic cancer is a human malignancy with one of the highest mortality rates and little progress has been achieved in its treatment in recent decades. Further improvement to the understanding of the biological and molecular mechanisms underlying the initiation and development of pancreatic ductal adenocarcinoma (PDAC) is required. Previous studies using genetically engineered mouse models have demonstrated that oncogenic GTPase KRas (KRAS) mutation is involved in the formation of pancreatic intraepithelial neoplasia and promotes the progression of PDAC. However, attempts to target KRAS directly by pharmacological inhibition have been unsuccessful. This has resulted in increased efforts to identify pharmacological targets and nodes associated with the mutated KRAS. The present review discusses the recent progress and prospects of KRAS signaling in pancreatic cancer. PMID- 27121415 TI - 4D-QSAR investigation and pharmacophore identification of pyrrolo[2,1 c][1,4]benzodiazepines using electron conformational-genetic algorithm method. AB - In this paper, we present the results of pharmacophore identification and bioactivity prediction for pyrrolo[2,1-c][1,4]benzodiazepine derivatives using the electron conformational-genetic algorithm (EC-GA) method as 4D-QSAR analysis. Using the data obtained from quantum chemical calculations at PM3/HF level, the electron conformational matrices of congruity (ECMC) were constructed by EMRE software. The ECMC of the lowest energy conformer of the compound with the highest activity was chosen as the template and compared with the ECMCs of the lowest energy conformer of the other compounds within given tolerances to reveal the electron conformational submatrix of activity (ECSA, i.e. pharmacophore) by ECSP software. A descriptor pool was generated taking into account the obtained pharmacophore. To predict the theoretical activity and select the best subset of variables affecting bioactivities, the nonlinear least square regression method and genetic algorithm were performed. For four types of activity including the GI50, TGI, LC50 and IC50 of the pyrrolo[2,1-c][1,4] benzodiazepine series, the r(2)train, r(2)test and q(2) values were 0.858, 0.810, 0.771; 0.853, 0.848, 0.787; 0.703, 0.787, 0.600; and 0.776, 0.722, 0.687, respectively. PMID- 27121416 TI - Gallstones. AB - Gallstones grow inside the gallbladder or biliary tract. These stones can be asymptomatic or symptomatic; only gallstones with symptoms or complications are defined as gallstone disease. Based on their composition, gallstones are classified into cholesterol gallstones, which represent the predominant entity, and bilirubin ('pigment') stones. Black pigment stones can be caused by chronic haemolysis; brown pigment stones typically develop in obstructed and infected bile ducts. For treatment, localization of the gallstones in the biliary tract is more relevant than composition. Overall, up to 20% of adults develop gallstones and >20% of those develop symptoms or complications. Risk factors for gallstones are female sex, age, pregnancy, physical inactivity, obesity and overnutrition. Factors involved in metabolic syndrome increase the risk of developing gallstones and form the basis of primary prevention by lifestyle changes. Common mutations in the hepatic cholesterol transporter ABCG8 confer most of the genetic risk of developing gallstones, which accounts for ~25% of the total risk. Diagnosis is mainly based on clinical symptoms, abdominal ultrasonography and liver biochemistry tests. Symptoms often precede the onset of the three common and potentially life-threatening complications of gallstones (acute cholecystitis, acute cholangitis and biliary pancreatitis). Although our knowledge on the genetics and pathophysiology of gallstones has expanded recently, current treatment algorithms remain predominantly invasive and are based on surgery. Hence, our future efforts should focus on novel preventive strategies to overcome the onset of gallstones in at-risk patients in particular, but also in the population in general. PMID- 27121417 TI - Assessment of economic instruments for countries with low municipal waste management performance: An approach based on the analytic hierarchy process. AB - Economic instruments provide significant potential for countries with low municipal waste management performance in decreasing landfill rates and increasing recycling rates for municipal waste. In this research, strengths and weaknesses of landfill tax, pay-as-you-throw charging systems, deposit-refund systems and extended producer responsibility schemes are compared, focusing on conditions in countries with low waste management performance. In order to prioritise instruments for implementation in these countries, the analytic hierarchy process is applied using results of a literature review as input for the comparison. The assessment reveals that pay-as-you-throw is the most preferable instrument when utility-related criteria are regarded (wb = 0.35; analytic hierarchy process distributive mode; absolute comparison) mainly owing to its waste prevention effect, closely followed by landfill tax (wb = 0.32). Deposit-refund systems (wb = 0.17) and extended producer responsibility (wb = 0.16) rank third and fourth, with marginal differences owing to their similar nature. When cost-related criteria are additionally included in the comparison, landfill tax seems to provide the highest utility-cost ratio. Data from literature concerning cost (contrary to utility-related criteria) is currently not sufficiently available for a robust ranking according to the utility-cost ratio. In general, the analytic hierarchy process is seen as a suitable method for assessing economic instruments in waste management. Independent from the chosen analytic hierarchy process mode, results provide valuable indications for policy-makers on the application of economic instruments, as well as on their specific strengths and weaknesses. Nevertheless, the instruments need to be put in the country-specific context along with the results of this analytic hierarchy process application before practical decisions are made. PMID- 27121418 TI - Concentration dependence of luminescence efficiency of Dy3+ ions in strontium zinc phosphate glasses mixed with Pb3 O4. AB - In this work we synthesized SrO-ZnO-P2 O5 glasses mixed with Pb3 O4 (heavy metal oxide) and doped with different amounts of Dy2 O3 (0.1 to 1.0 mol%). Subsequently their emission and decay characteristics were investigated as a function of Dy2 O3 concentration. The emission spectra exhibited three principal emission bands in the visible region corresponding to 4 F9/2 -> 6 H15/2 (482 nm), 6 H13/2 (574 nm) and 6 H11/2 (663 nm) transitions. With increase in the concentration of Dy2 O3 (upto 0.8 mol%) a considerable increase in the intensity of these bands was observed and, for further increase, quenching of photoluminescence (PL) output was observed. Using emission spectra, various radiative parameters were evaluated and all these parameters were found to increase with increase in Dy2 O3 concentration. The Y/B integral emission intensity ratio of Dy3+ ions evaluated from these spectra exhibited a decreasing trend with increase in the Dy2 O3 concentration up to 0.8 mol%. Quenching of luminescence observed in the case of the glasses doped with 1.0 mol% is attributed to clustering of Dy3+ ions. The quantitative analysis of these results together with infra-red (IR) spectral studies indicated that 0.8 mol% is the optimum concentration of Dy3+ ions needed to achieve maximum luminescence efficiency. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121419 TI - Disordered 3 D Multi-layer Graphene Anode Material from CO2 for Sodium-Ion Batteries. AB - We report the application of disordered 3 D multi-layer graphene, synthesized directly from CO2 gas through a reaction with Li at 550 degrees C, as an anode for Na-ion batteries (SIBs) toward a sustainable and greener future. The material exhibited a reversible capacity of ~190 mA h g(-1) with a Coulombic efficiency of 98.5 % at a current density of 15 mA g(-1) . The discharge capacity at higher potentials (>0.2 V vs. Na/Na(+) ) is ascribed to Na-ion adsorption at defect sites, whereas the capacity at low potentials (<0.2 V) is ascribed to intercalation between graphene sheets through electrochemical characterization, Raman spectroscopy, and small-angle X-ray scattering experiments. The disordered multi-layer graphene electrode demonstrated a great rate capability and cyclability. This novel approach to synthesize disordered 3 D multi-layer graphene from CO2 gas makes it attractive not only as an anode material for SIBs but also to mitigate CO2 emission. PMID- 27121420 TI - Overexpression of WNT5B promotes COLO 205 cell migration and invasion through the JNK signaling pathway. AB - WNT5B is a member of the WNT family that has been reported to be overexpressed in a variety of cancer cell lines and tissues, including colorectal cancer (CRC). However, the potential roles of WNT5B in tumorigenesis have not been reported. In the present study, the WNT5B gene was transfected into CRC cells and generated a COLO 205 cell line with stable overexpression of WNT5B. MTT, wound healing and Transwell assays showed that overexpression of WNT5B significantly increased cell proliferation, migration and invasion capacities of the COLO 205 cells in vitro. Meanwhile, western blotting demonstrated that cells with stable expression of WNT5B showed increased protein expression levels and activities of matrix metalloproteinase (MMP) 2 and MMP 9. In addition, we also observed activation of the WNT/JNK signaling pathway in WNT5B-overexpressing cells. Subsequently, c-jun NH2-terminal kinase (JNK) was knocked down by RNA interference in the WNT5B overexpressing COLO 205 cells. Knockdown of JNK significantly reduced the migratory capacity of the COLO 205 cells and decreased protein expression levels and activities of MMP 2 and 9 in vitro. In conclusion, our findings suggest that WNT5B may play an important role in the tumorigenesis of CRC. PMID- 27121421 TI - HSP90 canonical content organizes a molecular scaffold mechanism to progress flowering. AB - Highly interactive signaling processes constitute a set of parameters intertwining in a continuum mode to shape body formation and development. A sophisticated gene network is required to integrate environmental and endogenous cues in order to modulate flowering. However, the molecular mechanisms that coordinate the circuitries of flowering genes remain unclear. Here using complemented experimental approaches, we uncover the decisive and essential role of HEAT SHOCK PROTEIN 90 (HSP90) in restraining developmental noise to an acceptable limit. Localized depletion of HSP90 mRNAs in the shoot apex resulted in low penetrance of vegetative-to-reproductive phase transition and completely abolished flower formation. Extreme variation in expression of flowering genes was also observed in HSP90 mRNA-depleted transformed plants. Transient heat-shock treatments moderately increased HSP90 mRNA levels and rescued flower arrest. The offspring had a low, nevertheless noticeable failure to promote transition from vegetative into the reproductive phase and showed flower morphological heterogeneity. In floral tissues a moderate variation in HSP90 transcript levels and in the expression of flowering genes was detected. Key flowering proteins comprised clientele of the molecular chaperone demonstrating that the HSP90 is essential during vegetative-to-reproductive phase transition and flower development. Our results uncover that HSP90 consolidates a molecular scaffold able to arrange and organize flowering gene network and protein circuitry, and effectively counterbalance the extent to which developmental noise perturbs phenotypic traits. PMID- 27121422 TI - Neuroscience-based Nomenclature (NbN) for Clinical Psychopharmacology and Neuroscience. PMID- 27121423 TI - Staging Models in Bipolar Disorder: A Systematic Review of the Literature. AB - Bipolar disorder is manifested as severe dysregulation of mood with recurrent manic and major depressive episodes. It is associated with psychiatric and medical comorbidities, inadequate response to currently available pharmacological agents and a progressively deteriorating course in many patients. The index episode is often depressive in nature, while the first manic or hypomanic episode may occur several years later in the course of the disorder causing delay in diagnosis and use of inappropriate treatment strategies. Staging has been used to great advantage in other branches of medicine like cardiology and oncology. There is growing realization that major mental disorders are fundamentally progressive, with simpler treatment requirements and better prognosis during initial stages of the illness. Defining these conditions into clinically applicable stages not only helps in better understanding the trajectory of a particular disorder, but also assists in management. Patients with a chronic, recalcitrant condition like bipolar disorder are likely to greatly benefit from this approach. If the illness is correctly identified early in its course, proper treatment can be instigated arresting progression to latter phases which are associated with myriad complications in the biopsychosocial realm. With these considerations, a search of the MEDLINE data base was conducted to seek out literature pertaining to staging models in bipolar disorder. A thorough scrutiny of the existing research work revealed that a number of investigators have endeavored to stage define bipolar disorder. This paper outlines staging proposals for bipolar disorder which have the greatest supporting evidence in the literature. PMID- 27121425 TI - The Ratio of 2nd to 4th Digit Length in Korean Alcohol-dependent Patients. AB - OBJECTIVE: The ratio of 2nd to 4th digit length (2D:4D) is a sexually dimorphic trait. Men have a relatively shorter second digit than fourth digit. This ratio is thought to be influenced by higher prenatal testosterone level or greater sensitivity to androgen. The purpose of this study is to investigate the relationship between alcohol dependence and 2D:4D in a Korean sample and whether 2D:4D can be a biologic marker in alcohol dependence. METHODS: In this study, we recruited 87 male patients with alcohol dependence from the alcohol center of one psychiatric hospital and 52 healthy male volunteers who were all employees in the same hospital as controls. We captured images of the right and left hands of patients and controls using a scanner and extracted data with a graphics program. We measured the 2D:4D of each hand and compared the alcohol dependence group with the control group. We analyzed these ratios using an independent-samples t-test. RESULTS: The mean 2D:4D of patients was 0.934 (right hand) and 0.942 (left hand), while the mean 2D:4D of controls was 0.956 (right hand) and 0.958 (left hand). Values for both hands were significantly lower for patients than controls (p<0.001, right hand; p=0.004, left hand). CONCLUSION: Patients who are alcohol dependent have a significantly lower 2D:4D than controls, similar to the results of previous studies, which suggest that a higher prenatal testosterone level in the gonadal period is related to alcoholism. Furthermore, 2D:4D is a possible predictive marker of alcohol dependence. PMID- 27121426 TI - Adjunctive Low-frequency Repetitive Transcranial Magnetic Stimulation over the Right Dorsolateral Prefrontal Cortex in Patients with Treatment-resistant Obsessive-compulsive Disorder: A Randomized Controlled Trial. AB - OBJECTIVE: The ratio of 2nd to 4th digit length (2D:4D) is a sexually dimorphic trait. Men have a relatively shorter second digit than fourth digit. This ratio is thought to be influenced by higher prenatal testosterone level or greater sensitivity to androgen. The purpose of this study is to investigate the relationship between alcohol dependence and 2D:4D in a Korean sample and whether 2D:4D can be a biologic marker in alcohol dependence. OBJECTIVE: The present study aimed to evaluate the efficacy of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex (DLPFC) for the treatment of obsessive-compulsive disorder (OCD). METHODS: Twenty-seven patients with treatment resistant OCD were randomly assigned to 3 week either active (n=14) or sham (n=13) rTMS. The active rTMS parameters consisted of 1 Hz, 20-minute trains (1,200 pulses/day) at 100% of the resting motor threshold (MT). OCD symptoms, mood, and anxiety were assessed at baseline and every week throughout the treatment period. RESULTS: A repeated-measures analysis of variance (ANOVA) was used to evaluate changes on the Yale-Brown Obsessive Compulsive Scale (YBOCS). Our results revealed a significant reduction in YBOCS scores in the active group compared with the sham group after 3 weeks. Similarly, a repeated-measures ANOVA revealed significant effect of time and time*group interaction on scores on the Hamilton Depression Rating Scale and the Clinical Global Impression-Severity scale. There were no reports of any serious adverse effects following the active and sham rTMS treatments. CONCLUSION: LF rTMS over the right DLPFC appeared to be superior to sham rTMS for relieving OCD symptoms and depression in patients with treatment-resistant OCD. Further trials with larger sample sizes should be conducted to confirm the present findings. PMID- 27121427 TI - Early Improvement in One Week Predicts the Treatment Response to Escitalopram in Patients with Social Anxiety Disorder: A Preliminary Study. AB - OBJECTIVE: Social anxiety disorder (SAD) shows relatively delayed responses to pharmacotherapy when compared to other anxiety disorders. Therefore, more effective early therapeutic decisions can be made if the therapeutic response is predictable as early as possible. We studied whether the therapeutic response at 12 weeks is predictable based on the early improvement with escitalopram at 1 week. METHODS: The subjects were 28 outpatients diagnosed with SAD. The subjects took 10-20 mg/day of escitalopram. The results of the Liebowitz social anxiety scale (LSAS), Hamilton anxiety rating scale, and Montgomery-Asberg depression rating scale were evaluated at 0, 1, 4, 8, and 12 weeks of treatment. Early improvement was defined as a >=10% reduction in the LSAS total at 1 week of treatment, and endpoint response was defined as a >=35% reduction in the LSAS total score. The correlation between clinical characteristics and therapeutic responses was analyzed by simple linear regression. The correlation between early improvement responses and endpoint responses was analyzed by multivariate logistic regression analysis and receiver operating characteristic curves. RESULTS: When we adjusted the influence of a >=35% reduction in the LSAS total endpoint score on a >=10% reduction of the LSAS total score at 1 week of treatment for the patients' age, the early improvement group at 1 week of treatment was expected to show stronger endpoint responses compared to the group with no early improvement. CONCLUSION: The results suggest that a >=10% reduction in the LSAS total score in a week can predict endpoint treatment response. PMID- 27121428 TI - Heart Rate Variability and the Efficacy of Biofeedback in Heroin Users with Depressive Symptoms. AB - OBJECTIVE: Low heart rate variability (HRV) has been confirmed in heroin users, but the effects of heart-rate-variability-biofeedback in heroin users remain unknown. This study examined (1) correlations between depression and HRV indices; (2) group differences in HRV indices among a heroin-user group, a group with major depressive disorder but no heroin use, and healthy controls; and (3) the effects of heart-rate-variability-biofeedback on depressive symptoms, HRV indices, and respiratory rates within the heroin group. METHODS: All participants completed a depression questionnaire and underwent electrocardiogram measurements, and group differences in baseline HRV indices were examined. The heroin group underwent electrocardiogram and respiration rate measurements at baseline, during a depressive condition, and during a happiness condition, before and after which they took part in the heart-rate-variability-biofeedback program. The effects of heart-rate-variability-biofeedback on depressive symptoms, HRV indices, and respiration rates were examined. RESULTS: There was a negative correlation between depression and high frequency of HRV, and a positive correlation between depression and low frequency to high frequency ratio of HRV. The heroin group had a lower overall and high frequency of HRV, and a higher low frequency/high frequency ratio than healthy controls. The heart-rate-variability biofeedback intervention increased HRV indices and decreased respiratory rates from pre-intervention to post-intervention. CONCLUSION: Reduced parasympathetic and increased sympathetic activations were found in heroin users. Heart-rate variability- biofeedback was an effective non-pharmacological intervention to restore autonomic balance. PMID- 27121424 TI - The Microbiome and Mental Health: Looking Back, Moving Forward with Lessons from Allergic Diseases. AB - Relationships between gastrointestinal viscera and human emotions have been documented by virtually all medical traditions known to date. The focus on this relationship has waxed and waned through the centuries, with noted surges in interest driven by cultural forces. Here we explore some of this history and the emerging trends in experimental and clinical research. In particular, we pay specific attention to how the hygiene hypothesis and emerging research on traditional dietary patterns has helped re-ignite interest in the use of microbes to support mental health. At present, the application of microbes and their structural parts as a means to positively influence mental health is an area filled with promise. However, there are many limitations within this new paradigm shift in neuropsychiatry. Impediments that could block translation of encouraging experimental studies include environmental forces that work toward dysbiosis, perhaps none more important than westernized dietary patterns. On the other hand, it is likely that specific dietary choices may amplify the value of future microbial-based therapeutics. Pre-clinical and clinical research involving microbiota and allergic disorders has predated recent work in psychiatry, an early start that provides valuable lessons. The microbiome is intimately connected to diet, nutrition, and other lifestyle variables; microbial-based psychopharmacology will need to consider this contextual application, otherwise the ceiling of clinical expectations will likely need to be lowered. PMID- 27121429 TI - The Efficacy and Safety of Clonazepam in Patients with Anxiety Disorder Taking Newer Antidepressants: A Multicenter Naturalistic Study. AB - OBJECTIVE: This study compared the efficacy and tolerability of clonazepam with other benzodiazepines in patients with anxiety disorders. METHODS: Inclusion criteria were as follows: age >20 years, diagnosis of anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition, text revision (DSM-IV-TR) criteria, taking only one type of antidepressant, and prescribed one of three oral benzodiazepines (alprazolam, clonazepam, or lorazepam). At baseline and week 6, clinical benefit was evaluated using the Clinical Global Impression-Severity Scale (CGI-S), Clinical Global Impression Anxiety Scale (CGI-anxiety), and Clinical Global Impression-Sleep Scale (CGI sleep). RESULTS: Among 180 patients, no differences in demographic characteristics among the three benzodiazepine groups were noted. After six weeks of treatment, all benzodiazepine groups showed significant improvements in CGI-S, CGI-anxiety, and CGI-sleep scores (p<0.001). There were no differences in mean changes in CGI-S, CGI-anxiety and CGI-sleep among the three benzodiazepine groups. The incidence of side effects was significantly lower in the clonazepam group than with the other benzodiazepines. The incidences of adverse events for the clonazepam, alprazolam, and lorazepam groups were 26.7% (n=20), 48.4% (n=31), and 43.9% (n=18), respectively. CONCLUSION: The present study suggests that clonazepam is as efficacious as other benzodiazepines for the treatment of various anxiety disorders. Furthermore, the safety profile of clonazepam was superior to the other benzodiazepines in this study. PMID- 27121430 TI - The Effect of Single Dose Methylphenidate on Neurometabolites according to COMT Gene Val158Met Polymorphism in the Patient with Attention Deficit Hyperactivity Disorder: A Study Using Magnetic Resonance Spectroscopy. AB - OBJECTIVE: Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Thus, the present study aimed to determine the effects of a single dose of methylphenidate (Mph) on neurometabolite levels according to polymorphisms of the catechol-O-methyltransferase (COMT) gene. METHODS: This study evaluated the neurometabolite levels including N acetylaspartate (NAA), creatine (Cr), and choline (Cho) of ADHD patients, before and after treatment with Mph (10 mg) according to the presence of COMT polymorphisms. The spectra were obtained from the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), cerebellum, and striatum. RESULTS: The NAA levels of the val/val and val genotype carriers (val/val and val/met genotypes) increased in the DLPFC and ACC, respectively, following Mph treatment. The NAA/Cr ratio was lower in the DLPFC of val carriers than in the met/met genotype carriers prior to Mph administration. The Cho levels of the val/met genotype and val carriers increased in the striatum following Mph treatment. Following Mph treatment, the Cr levels of the met/met genotype carriers were higher than those of the val/met genotype and val carriers. Additionally, after Mph treatment, there was a significant increase in Cr levels in the DLPFC of the met/met genotype carriers but a significant decrease in such levels in the striatum of val/val genotype carriers. CONCLUSION: These findings suggest that polymorphisms of the COMT gene can account for individual differences in neurochemical responses to Mph among ADHD patients. Therefore, further studies are needed to fully characterize the effects of the Val158met polymorphism of the COMT gene on treatment outcomes in patients with ADHD. PMID- 27121431 TI - Expected Emotional Usefulness and Emotional Preference in Individuals with Major Depressive Disorder. AB - OBJECTIVE: Previous studies indicate that emotion regulation problems in major depressive disorder (MDD) may be caused by difficulties in preferring useful emotions according to their goals. We investigated expected emotional usefulness and emotional preference in individuals with MDD (MDDs) and healthy controls (HCs). METHODS: Participants were given an interpersonal scenario with two different goals (confrontation and collaboration) and rated their willingness to participate in emotion-provoking activities and the expected usefulness of a particular emotion. RESULTS: MDDs were similar to HCs in expected emotional usefulness but showed different patterns of emotional preference. HCs preferred happiness to negative emotions across goals whereas MDDs did not show such pattern. In addition, HCs displayed goal-appropriate preferences whereas MDDs did not prefer certain emotions for specific goals. CONCLUSION: Although MDDs seemed to understand how useful an emotion can be, they did not show preference for goal appropriate emotions. Interventions should address why MDDs have difficulty engaging in goal-appropriate emotions despite having full knowledge of the utility of emotions in achieving goals. PMID- 27121432 TI - Heritability and Familiality of Temperament and Character Dimensions in Korean Families with Schizophrenic Linkage Disequilibrium. AB - OBJECTIVE: Categorical syndromes such as schizophrenia may represent complexes of many continuous psychological structural phenotypes along several dimensions of personality development/degeneration. The present study investigated the heritability and familiality of personality dimensions in Korean families with schizophrenic linkage disequilibrium (LD). METHODS: We recruited 179 probands (with schizophrenia) as well as, whenever possible, their parents and siblings. We used the Temperament and Character Inventory (TCI) to measure personality and symptomatic dimensions. The heritability of personality dimensions in a total of 472 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). To measure familiality, we compared the personality dimensions of family members with those of 336 healthy unrelated controls using analysis of variance (ANOVA) analysis. RESULTS: Three of the seven TCI variables were significantly heritable and were included in subsequent analyses. The three groups (control, unaffected first-degree relative, case) were found to significantly differ from one another, with the expected order of average group scores, for all heritable dimensions. CONCLUSION: Despite several study limitations with respect to family recruitment and phenotyping, our results show that aberrations in several personality dimensions related to genetic-environment coactions or interactions may underlie the complexity of the schizophrenic syndrome. PMID- 27121433 TI - Risperidone-induced Gingival Bleeding in a Pediatric Case: A Dose-dependent Side Effect. AB - There are several case reports on risperidone-related bleeding; however, to our knowledge, there is no report about gingival bleeding associated with risperidone in the literature. We presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg/day, and subsided after decreasing the dose to 0.25 mg/day, suggesting a dose-dependent side-effect. The bleeding side effect of risperidone might be caused by several mechanisms, including 5 hydroxytryptamine 2A receptor antagonism. Although bleeding associated with risperidone is rarely reported, clinicians should be aware of this side effect. PMID- 27121434 TI - Late Onset Agranulocytosis with Clozapine Associated with HLA DR4 Responding to Treatment with Granulocyte Colony-stimulating Factor: A Case Report and Review of Literature. AB - Agranulocytosis as a side effect of clozapine has been reported to be associated with initial phases of treatment, i.e., first six months. Agranulocytosis with clozapine during the initial phases of treatment has been linked to genetic vulnerability in the form of variations in the human leukocyte-antigen haplotypes. However, there is limited literature on late onset agranulocytosis with clozapine and this has very rarely been linked to human leukocyte-antigen haplotypes vulnerability. In this report we review the existing data on late onset agranulocytosis with clozapine and describe the case of a young man, who developed agranulocytosis with clozapine after 35 months of treatment and was found to have genetic vulnerability in form of being positive for HLA DR4. This case highlights underlying autoimmune immune mechanism in clozapine-induced agranulocytosis and the need for frequent blood count monitoring on clozapine even after the initial 6 months of starting treatment especially in patients with genetic vulnerability to develop this condition. PMID- 27121435 TI - Successful Management of Tardive Dyskinesia with Quetiapine and Clonazepam in a Patient of Schizophrenia with Type 2 Diabetes Mellitus. AB - Tardive dyskinesia is one of the most significant side effects of antipsychotic medications. Antipsychotic treated schizophrenia patients with diabetes mellitus are more likely to develop tardive dyskinesia than those without diabetes. Clozapine is probably best supported for management of tardive dyskinesia. But clozapine has been strongly linked to hyperglycaemia and impaired glucose tolerance, so it is not preferred in patients with diabetes mellitus. We present a case of 35-year-old male with a diagnosis of schizophrenia and type 2 diabetes mellitus with tardive dyskinesia, who was successfully treated with quetiapine and clonazepam. PMID- 27121436 TI - Acute Dystonia Following a Switch in Treatment from Atomoxetine to Low-dose Aripiprazole. AB - The present report describes the cases of a 17-year-old male patient and a 13 year-old female patient who developed acute dystonia following the administration of low-dose aripiprazole (5 mg/day) after the cessation of atomoxetine treatment. Although aripiprazole-induced dystonia has been previously reported in the literature, it is rare, and most of these cases were associated with doses higher than 5 mg/day. Furthermore, both of the patients in the present study discontinued atomoxetine prior to the initiation of aripiprazole treatment; thus, this report also discussed the possible mechanisms underlying the manifestation of dystonia from the perspective of neurotransmitter activity. PMID- 27121437 TI - Use of Clozapine for Borderline Personality Disorder: A Case Report. AB - Patients with borderline personality disorder (BPD) show significant impairment in functioning, particularly in the interpersonal and social domains. Prior reports suggest that clozapine may be effective in the management of BPD. We present the case of a patient with BPD who experienced persistent suicidal ideation and was treated with clozapine at a state psychiatric hospital. After treatment failure with other psychotropic medications, clozapine medication was initiated; not only did suicidal ideation cease, but social and professional functioning also greatly improved to the point of no longer requiring intensive levels of observation or restrictive procedures. Clozapine appears to be efficacious in the management of suicide attempts and self-injurious behavior. Moreover, it appears to be promising as a therapeutic measure for ameliorating the global functioning of patients with severe BPD. Larger, randomized, blinded, and controlled prospective studies are needed to confirm these findings and to determine optimal dosage. PMID- 27121438 TI - An Unusual, Paradoxical Arousal with Alprazolam in a Dependant User. PMID- 27121439 TI - Facile Synthesis of Smart Nanocontainers as Key Components for Construction of Self-Healing Coating with Superhydrophobic Surfaces. AB - SiO2-imidazoline nanocomposites (SiO2-IMI) owning high loading capacity of corrosion inhibitor, 1-hexadecyl-3-methylimidazolium bromide (HMID), and a special acid/alkali dual-stimuli-accelerated release property have been synthesized via a one-step modified Stober method. SiO2-IMI were uniformly distributed into the hydrophobic SiO2 sol to construct "host"-"guest" feedback active coating with a superhydrophobic surface (SiO2-IMI@SHSC) on aluminium alloy, AA2024, by dip-coating technique. SiO2-IMI as "guest" components have good compatibility with "host" sol-gel coating, and more importantly, once localized corrosion occurs on the surface of AA2024, SiO2-IMI can simultaneously respond to the increase in environmental pH around corrosive micro-cathodic regions and decrease in pH near micro-anodic regions, promptly releasing HMID to form a compact molecular film on the damaged surface, inhibiting corrosion spread and executing a self-healing function. The scanning vibrating electrode technique (SVET) was applied to illustrate the suppression process of cathodic/anodic corrosion activities. Furthermore, benefiting from the superhydrophobic surface, SiO2-IMI@SHSC remained its protective ability after immersion in 0.5 M NaCl solution for 35 days, which is far superior to the conventional sol-gel coating with the same coating thickness. The facile fabrication method of SiO2-IMI simplifies the construction procedure of SiO2-IMI@SHSC, which have great potential to replace non-environmental chromate conversion coatings for practical use. PMID- 27121440 TI - The Potential Application of Raw Cadmium Sulfide Nanoparticles as CT Photographic Developer. AB - With the development of science and technology, new applications about nanoparticles should be explored to achieve full-scale knowledge. Therefore, in this work, the toxicity and potential application of raw cadmium sulfide nanoparticles (CdS) in vivo were further studied through ICP-OES and CTs. Surprisingly, CdS exhibited an excellent photographic property, except for finding the accumulation of CdS in the lungs, liver, spleen, and kidney with a strong dependence on time; it is also found that there were a significant uptake in the pancreas for an obvious CT imaging. And the following investigations showed that the raw CdS could damage the tissues accumulating nanoparticles. Through this work, it can be seen that the raw CdS being modified might be an excellent photographic developer for detecting cancers or other diseases. PMID- 27121441 TI - Yeast and mould dynamics in Caciofiore della Sibilla cheese coagulated with an aqueous extract of Carlina acanthifolia All. AB - Caciofiore della Sibilla is a speciality ewes' milk cheese traditionally manufactured in a foothill area of the Marche region (Central Italy) with a crude extract of fresh young leaves of Carlina acanthifolia All. subsp. acanthifolia as a coagulating agent. The fungal dynamics and diversity of this speciality cheese were investigated throughout the manufacturing and 20-day ripening process, using a combined PCR-DGGE approach. The fungal biota of a control ewes' milk cheese, manufactured with the same batch of milk coagulated with a commercial animal rennet, was also monitored by PCR-DGGE, in order to investigate the contribution of the peculiar vegetable coagulant to the fungal diversity and dynamics of the cheese. Based on the overall results collected, the raw milk and the dairy environment represented the main sources of fungal contamination, with a marginal or null contribution of thistle rennet to the fungal diversity and dynamics of Caciofiore della Sibilla cheese. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121442 TI - Hypertension: What are the self-care and health-care-seeking behaviours in women over time? AB - The aim of this study was to estimate the prevalence and incidence of hypertension in women, and describe their self-care and health-seeking behaviours. This research was conducted as part of the Australian Longitudinal Study on Women's Health, a study comprising a nationally representative sample of Australian women in three age groups. The focus of this research is 14 099 women born in 1946-1951, who have been surveyed six times (1996-2010). Student t-tests were used to compare women who did or did not have hypertension by their health care utilization. Longitudinal analyses were conducted using a Poisson generalized estimating equation model. The incidence of hypertension among this cohort during 1996 to 2010 ranged from 400 to 597 participants per survey, resulting in an increase in prevalence of hypertension from 20.9% in 1996 to 41.3% in 2010. For all survey periods, women with hypertension had a significantly higher average number of visits to doctors and allied health practitioners compared with women without hypertension (P<0.005). The use of complementary medicine (practitioners and self-prescribed treatments) by women with hypertension was significantly lower compared to women without hypertension (P<0.005). Over time, conventional health-care utilization was higher for women with hypertension compared with women without hypertension (adjusted RR=1.18; 95% CI: 1.14, 1.22; P<0.0001). Our findings show that women with hypertension are using a range of conventional and complementary and alternative medicine: with hypertensive women using more conventional medicine and less complementary and alternative medicine than non-hypertensive women. As such, health-care providers should communicate with their patients regarding their use of complementary and alternative medicine in their efforts to provide safe, effective and coordinate care. PMID- 27121443 TI - Dietary patterns, nutrition knowledge and lifestyle: associations with blood pressure in a sample of Australian adults (the Food BP study). AB - This study examined the association between dietary patterns, nutrition knowledge and lifestyle with blood pressure (BP) in a sample of Australian adults. Adults with normal and high BP were included in a cross-sectional study. Dietary intake data was collected using a Food Frequency Questionnaire. Nutrition knowledge and lifestyle surveys were included in the questionnaire. Dietary patterns were extracted using factor analysis followed by cluster analysis. Associations were analysed using logistic regression. Four hundred and seven participants were included. Three dietary patterns were identified: Western; Snack and alcohol; and Balanced. Participants with high BP had a higher intake of Western and a lower intake of Balanced dietary pattern. A significant and higher frequency of discretionary foods and oils consumption, as well as lower nutrition knowledge score and activity frequency, were observed in the high BP group. Regression analysis indicated that the intake of Western and Snack and alcohol dietary patterns increases the likelihood of having high BP by 2.40 (95% confidence interval (CI): 1.28-4.49) and 2.76 (95% CI: 1.52-5.00), respectively, when nutrition knowledge and lifestyle were controlled for as moderator variables. The likelihood of high BP was not associated with nutrition knowledge, but increased with physical inactivity. This study indicates that poor dietary patterns and inactivity are associated with increases in the likelihood of high BP, and the association is not influenced by nutrition knowledge. These findings indicate the importance of developing public health strategies with an emphasis on improving the dietary patterns of individuals to prevent and control high BP in Australian adults. PMID- 27121444 TI - Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. AB - Angiotensin-converting enzyme 2 (ACE2), a newly discovered member of renin angiotensin-aldosterone system, counterbalances the actions of angiotensin converting enzyme. The objective of our study was to assess the association between rs2106809 polymorphism in ACE2 gene and the blood pressure response to ACE inhibitors in untreated hypertensive patients. After a 2-week, double-blind placebo run-in period, either benazepril or imidapril was administered for 6 weeks to 497 patients with mild to moderate essential hypertension. The achieved changes in BP were analyzed for their association with genotypes at ACE2 gene loci. In female hypertensive patients, the genotype frequency of ACE2 rs2106809 was 36.7%, 45.2% and 18.1% for CC, CT and TT genotypes, respectively. After 6 weeks of treatment, the reductions in diastolic blood pressure were significantly greater in female patients carrying the CC or CT genotype compared with those carrying the TT genotype (9.62+/-6.83 or 10.2+/-7.2 versus 6.81+/-6.31 mm Hg, respectively; P=0.045, analysis of variance (ANOVA)). Moreover, the reductions in mean arterial pressure were significantly greater in female patients carrying the CC or CT genotype compared with those carrying the TT genotype (12.1+/-7.5 or 12.0+/-7.9 versus 8.38+/-6.83 mm Hg, respectively; P=0.035, ANOVA). In male hypertensive patients, the genotype frequency of ACE2 rs2106809 was 58.1% and 41.9% for C and T genotypes, respectively. However, no association could be observed in males. We conclude that ACE2 rs2106809 is an important predictive factor of the response to antihypertensive treatment with ACE inhibitors in Chinese female hypertensive patients. PMID- 27121445 TI - Central blood pressure assessment using oscillometry is feasible for everyday clinical practice. AB - The benefit of the central systolic blood pressure (cSBP) has already been recognized, but its general measurement in the everyday routine is still limited mainly because available established non-invasive assessment devices are not suitable for everyday use. In this study, we investigated the performance of an oscillometric device Tel-O-GRAPH for cSBP assessment in terms of suitability for everyday clinical use. One hundred and three patients were prospectively included. cSBP was computed by Tel-O-GRAPH compared with Sphygmocor using applanation tonometry. There was a good agreement between Tel-O-GRAPH and Sphygmocor for cSBP (mean difference+/-s.d.: -0.3+/-6.7 mm Hg; Pearson's R=0.95; P<0.0001). Recorded cSBP values in the supine vs seated position and for the experienced vs non-experienced user did not significantly differ (mean cSBPsupine 122.1+/-13.9 mm Hg vs cSBPseated 120.7+/-15.7 mmHg; cSBPnon-experienced 120.6+/ 20.5 mm Hg and cSBPexperienced 119.2+/-19.9 mm Hg). The mean difference of cSBP between supine and seated positions was 1.5+/-6.8 and -1.4+/-5.0 mm Hg between experienced and non-experienced users. This study showed good accuracy in assessing cSBP with an oscillometric BP measurement device Tel-O-GRAPH compared with a Sphygmocor. Furthermore, the calculation of cSBP by Tel-O-GRAPH appears to be easy and can be done during the routine brachial BP measurement. Computed cSBP values seem to remain reliable independently of the patient body position and experience of the operator. Consequently, the easiness of utilization and reliability of the device may open the opportunity for its extended use in everyday clinical practice, as well as reliable alternative for clinical studies, making complex applanation tonometry dispensable. PMID- 27121446 TI - Epitaxial growth and magnetic properties of ultraviolet transparent Ga2O3/(Ga1 xFex)2O3 multilayer thin films. AB - Multilayer thin films based on the ferromagnetic and ultraviolet transparent semiconductors may be interesting because their magnetic/electronic/photonic properties can be manipulated by the high energy photons. Herein, the Ga2O3/(Ga1 xFex)2O3 multilayer epitaxial thin films were obtained by alternating depositing of wide band gap Ga2O3 layer and Fe ultrathin layer due to inter diffusion between two layers at high temperature using the laser molecular beam epitaxy technique. The multilayer films exhibits a preferred growth orientation of crystal plane, and the crystal lattice expands as Fe replaces Ga site. Fe ions with a mixed valence of Fe(2+) and Fe(3+) are stratified distributed in the film and exhibit obvious agglomerated areas. The multilayer films only show a sharp absorption edge at about 250 nm, indicating a high transparency for ultraviolet light. What's more, the Ga2O3/(Ga1-xFex)2O3 multilayer epitaxial thin films also exhibits room temperature ferromagnetism deriving from the Fe doping Ga2O3. PMID- 27121447 TI - The Use of Preoperative Psychological Evaluations to Predict Spinal Cord Stimulation Success: Our Experience and a Review of the Literature. AB - BACKGROUND: Pre-operative psychological assessment is commonly used to assess patients for spinal cord stimulation (SCS). Though often times mandated by insurance, its value is frequently questioned. METHODS: We review the literature on the predictive value of psychological testing prior to SCS and retrospectively examine our prospective database of SCS patients. We examine associations of Minnesota Multiphasic Personality Inventory (MMPI), Beck Depression Inventory (BDI), and Pain Catastrophizing Scale (PCS) findings and outcomes on the visual analog scale (VAS), McGill Pain Questionnaire - Short Form (MPQ), and Oswestry Disability Index (ODI) at 6 and 12 months post-implantation. RESULTS: The nine studies examining psychological predictors of SCS outcomes collectively showed that substance abuse or feelings of demoralization or less joy correlated with worse outcomes. Though not statistically significant, our data show that at one year follow-up, patients without psychiatric disorders improved 1.5 times as much on ODI and 2.4 times as much on PCS as compared to patients with psychiatric disorders. Further, depressed patients concurrently treated with anti-depressants had greater improvement in BDI than non-medicated depressed patients (p = 0.009). We develop a tool for pain psychologists based on the existing literature to aid in identifying possible concerns and treating these patients peri-operatively. DISCUSSION: The predictive value of psychological testing depends on which psychiatric factors are used and which outcomes are measured. The predictive capacity of psychological indications can be used to holistically treat patients, specifically to recommend psychiatric medication and consulting to supplement SCS treatment as needed. PMID- 27121448 TI - Simultaneous Determination of Arsenic, Cadmium, Mercury, and Lead in Raw Ingredients, Nutritional Products, and Infant Formula by Inductively Coupled Plasma Mass Spectrometry: Single-Laboratory Validation. AB - A method was developed for the determination of As, Cd, Hg, and Pb in raw ingredients, nutritional products, and infant formula using inductively coupled plasma mass spectrometry (ICP-MS). Three raw ingredients (acid casein, maltodextrin, skim milk powder) and three standard reference materials [NIST 1548a (Typical Diet), NIST 1577c (Bovine Liver), NIST SRM 1568b (Rice Flour)] obtained from the National Institute of Standards and Technology were analyzed by two analysts using two ICP-MS instruments in different laboratories. NIST SRM 1568b was used as the control sample. All protocol validation parameters (intermediate precision, accuracy, linearity, quantitation limit, specificity, and robustness) were met. The overall precision (n = 8) for analyte concentrations (2.5-300 ng/g) ranged from 2 to 14% RSD. Spike recoveries ranged from 88 to109% for spike levels between 25 and 200%. The overall average concentration of As, Cd, Hg, and Pb measured in all three NIST SRMs were within the certified value ranges. Good linearity (correlation coefficient (r) = 0.9995 or better) was obtained for all analytes. Control chart results for 8 independent days showed that the method is robust (precision values of 10% and all points within +/-3 sigma were obtained). Excellent specificity was also demonstrated when the analytes were measured in the presence of high concentrations of the other concomitants. PMID- 27121449 TI - Automated quantification of abdominal adiposity by magnetic resonance imaging. AB - OBJECTIVES: To develop a fully-automated algorithm to process axial magnetic resonance imaging (MRI) slices for quantifying abdominal visceral, subcutaneous and total adipose tissues, i.e., VAT, SAT, and TAT, without human intervention or prior knowledge. MATERIALS AND METHODS: Fat regions in single MRI slice or sequence (20 slices) were identified with image processing techniques including region-growing, inhomogeneity correction, fuzzy c-means clustering, and active contours segmentation. The MR images of 85 subjects (60 males and 25 females), whose body mass index (BMI) values ranged from 19.96 to 40.35 kg/m2 , were analyzed using the fully-automated algorithm-the automatic method developed in the research and the widely used semi-automated software (sliceOmatic(r) Tomovision, Inc.)-the reference method. RESULTS: The proposed automated method showed good performance against the reference method to quantify adipose tissues in both single umbilical slice and MRI sequence. The square of the Pearson correlation coefficients (R2 ) based on the results generated from the two methods for VAT/SAT/TAT were 0.977/0.998/0.997 for single slice data and 0.995/0.999/0.999 for volumetric data. The intra-class correlation of visceral adipose tissue (VAT) between the three operators was 0.939 in the reference method, which was improved to 0.999 in the automatic method. The adipose tissue measurements in the slice at Lumbar 3 vertebra have the highest correlation with the total fat volumes across the entire abdomen. CONCLUSION: The fully-automated algorithm presented in the paper provides an accurate and reliable assessment of abdominal fat without human intervention. Am. J. Hum. Biol. 28:757-766, 2016. (c) 2016Wiley Periodicals, Inc. PMID- 27121450 TI - Topical application of the Wnt/beta-catenin activator methyl vanillate increases hair count and hair mass index in women with androgenetic alopecia. AB - BACKGROUND: Activation of the WNT/beta-catenin pathway has emerged as a potential therapeutic target in androgenetic alopecia (AGA). Methyl vanillate (MV) - a safe plant-derived ingredient - has been recently shown to activate the WNT/beta catenin signaling. Objectives Two distinct substudies were conducted. First, we designed a 6-month, uncontrolled, open-label clinical study to investigate whether topically applied MV may increase hair count and hair mass index (HMI) in female AGA. Second, we conducted a molecular study on the effect of MV on WNT10B mRNA expression in scalp biopsies of women with AGA. METHODS: A total of 20 Caucasian women (age range: 25-57 years) with AGA (Sinclair grade 1-2) were included. The research product was an alcohol-free formulation supplied in the form of a spray containing 0.2% MV as the active ingredient. RESULTS: In the clinical study, hair count and HMI were found to increase at 6 months by 6% (P < 0.01) and 12% (P < 0.001), respectively, compared with baseline. No participant discontinued treatment due to adverse effects, and the overall patient satisfaction was good. At the molecular level, the topical application of the research product resulted in a 32% increase in WNT10B mRNA expression levels in the temporal scalp area (P < 0.001). CONCLUSION: Our pilot data suggest that topical MV can increase hair count and HMI by inducing WNT10B expression in the scalp, potentially serving as a novel treatment strategy for female AGA. PMID- 27121451 TI - Mouse models of human disease: An evolutionary perspective. AB - The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Nonetheless, mice and humans have evolved in and become adapted to different environments and so, despite their phylogenetic relatedness, they have become very different organisms. Mice often respond to experimental interventions in ways that differ strikingly from humans. Mice are invaluable for studying biological processes that have been conserved during the evolution of the rodent and primate lineages and for investigating the developmental mechanisms by which the conserved mammalian genome gives rise to a variety of different species. Mice are less reliable as models of human disease, however, because the networks linking genes to disease are likely to differ between the two species. The use of mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans. PMID- 27121453 TI - Explaining Some Journal Requirements. PMID- 27121452 TI - The early history and emergence of molecular functions and modular scale-free network behavior. AB - The formation of protein structural domains requires that biochemical functions, defined by conserved amino acid sequence motifs, be embedded into a structural scaffold. Here we trace domain history onto a bipartite network of elementary functional loop sequences and domain structures defined at the fold superfamily level of SCOP classification. The resulting 'elementary functionome' network and its loop motif and structural domain graph projections create evolutionary 'waterfalls' describing the emergence of primordial functions. Waterfalls reveal how ancient loops are shared by domain structures in two initial waves of functional innovation that involve founder 'p-loop' and 'winged helix' domain structures. They also uncover a dynamics of modular motif embedding in domain structures that is ongoing, which transfers 'preferential' cooption properties of ancient loops to emerging domains. Remarkably, we find that the emergence of molecular functions induces hierarchical modularity and power law behavior in network evolution as the network of motifs and structures expand metabolic pathways and translation. PMID- 27121454 TI - Summary of Pharmacokinetics and Tissue Distribution of a Broad-Spectrum Fluoroquinolone, JNJ-Q2. AB - This article summarizes key pharmacokinetic properties of JNJ-Q2, a broad spectrum fluoroquinolone, being developed for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Two randomized placebo-controlled studies and one open-label study are presented: single and multiple ascending-dose studies evaluating intravenous (IV) and oral pharmacokinetics, absolute bioavailability accumulation, and lung penetration. Fifty-seven participants received JNJ-Q2, which was safe and well tolerated. The half-life was 13 to 20 hours, clearance (CLtot ) was 4.41 to 6.22 L/h, volume of distribution (Vd ) was 86 to 148 L, renal clearance (CLren ) was 0.58 L/h, and the fraction excreted in urine (%Fe) was 12%. Accumulation ratio was 1.63, and absolute bioavailability was 0.65. The lung penetration study demonstrated substantial concentration of JNJ-Q2 in epithelial lining fluid and alveolar macrophages with ratios to free plasma of 50.6 and 156.9, respectively, at 6 hours postdose. JNJ-Q2 doses under consideration for future clinical trials are 150 mg for IV and 250-mg tablets for oral administration. PMID- 27121455 TI - Asenapine Safety, Tolerability, and Pharmacokinetics After Single and Multiple Doses in Healthy Volunteers. AB - This double-blind, placebo-controlled, randomized study is the first in healthy volunteers to describe the safety, tolerability, and pharmacokinetics of sublingual asenapine at therapeutic dosages. After a 2-day placebo run-in phase, healthy male volunteers received placebo or asenapine escalated to dosages of 3, 5, 10, or 15 mg bid. Another group received single doses (2 and 5 mg) 1 week apart. Serial blood samples were obtained for pharmacokinetic analysis. The single asenapine doses and multiple bid doses up to 10 mg were well tolerated. The most frequent treatment-emergent adverse events were somnolence, oral paresthesia, fatigue, headache, dizziness, and dyspnea. Clinically relevant abnormalities or trends in laboratory and vital signs measures, physical examinations, or electrocardiograms were not observed. Asenapine was rapidly absorbed, with a tmax of ~1 hour, and was biphasically eliminated with a terminal elimination half-life of 20 to 30 hours. In the range of 3 to 10 mg bid, increases in plasma concentrations were less than dose proportional. Asenapine appears to be well tolerated at single doses up to 5 mg and multiple doses up to 10 mg bid and can be administered to healthy volunteers in clinical pharmacology studies using the dosing regimens described. PMID- 27121456 TI - Vancomycin: Predictive Performance of a Population Pharmacokinetic Model and Optimal Dose in Neonates and Young Infants. AB - INTRODUCTION: Model evaluation is an important issue in population pharmacokinetic analyses. The objectives were to evaluate the predictive performance of previously published pediatric population pharmacokinetic models for vancomycin in a new data set and to propose an optimal dose to obtain a vancomycin concentration target. METHODS: External evaluation was conducted for all the published models of vancomycin in neonates and young infants with a new data set of 70 patients. Bias and accuracy were calculated. Advanced analyses were performed to evaluate the predictive performance of the best model. This population pharmacokinetic analysis was performed to simulate doses of vancomycin according to the appropriate target concentration. RESULTS: All models gave almost the same results, except 2 that were not acceptable. Nevertheless, the model described by Oudin et al presented the best results with a bias and accuracy of 4.0% and 27.8%, respectively. Simulations showed that the maintenance dose should be adjusted more precisely to each neonate based on his or her weight and serum creatinine value. CONCLUSION: Simulations have allowed the authors to describe new dosage schedules, and a chart was created to help clinicians to adapt dosage of vancomycin. Because of pharmacokinetic variability, vancomycin still requires therapeutic drug monitoring. PMID- 27121457 TI - A Randomized, Open-Label, 3-Way Crossover Study to Demonstrate Bioequivalence of Sildenafil Powder for Oral Suspension With Tablets Used Commercially and in Clinical Studies for the Treatment of Pulmonary Arterial Hypertension. AB - Sildenafil citrate (Revatio) is approved for pediatric pulmonary arterial hypertension (PAH) in the European Union. A new pediatric formulation, 10 mg/mL sildenafil citrate powder for oral suspension (POS), was developed for pediatric PAH patients. Bioequivalence among the POS suspension (20 mg), the Revatio 20-mg commercial tablet, and the sildenafil citrate 2 * 10-mg clinical trial tablets was assessed. In this randomized, open-label study, 42 healthy adult volunteers received the 3 different sildenafil treatments, each in a single 20-mg oral dose, using a 3-way crossover design. Blood samples were collected at predefined times and analyzed for sildenafil plasma concentrations. Natural log-transformed sildenafil pharmacokinetic parameters (Cmax , AUClast , and AUCinfinity ) were evaluated for bioequivalence using a mixed-effects model. Results were used to estimate relative bioavailability and construct 90% confidence intervals (CIs). Bioequivalence was concluded if the 90% CIs for Cmax , AUClast , and AUCinfinity were wholly contained within 80% to 125%. All 90% CIs for the ratios of adjusted geometric means of Cmax , AUClast , and AUCinfinity were within 80% to 125%, the prespecified bioequivalence criteria. All 3 formulations were well tolerated. In conclusion, the POS suspension, the commercial 20-mg Revatio tablet, and the 10 mg sildenafil tablets were all bioequivalent to one another when given at the equal doses. PMID- 27121458 TI - Impact of Clinical Response on Different Approved Doses in Japan and the United States. AB - The pharmaceutical industry has increasingly aimed to achieve efficient strategies for simultaneous international and worldwide development of medicines, and there has been a growing need to understand ethnic differences in drug evaluation. Japan is one of the unique countries in which substantial domestic clinical data are required for dose selection as well as for marketing authorization. However, it appears challenging to accumulate a large amount of data in a single country in the recent shift to international drug development. To gain a better understanding of the influence of ethnic factors, the dosages of the products approved in Japan during 2003-2010 were reviewed, and differences in clinical responses between Japan and the United States were evaluated using a modeling approach. Of new medicines (new molecular entities) approved in Japan, 39 products (28.1%) have been approved at a different dose level compared with the United States, of which 13 products have considerable difference, twice or greater. Of those 13 products, only 2 were suggested to have a different clinical response, although limited data availability should be taken into careful consideration. Further investigation is recommended to establish new approaches for appropriate dose selection and thereby increase the efficiency of international drug development. PMID- 27121459 TI - The Effect of Food on Cysteamine Bitartrate Absorption in Healthy Participants. AB - OBJECTIVES: Treatment with cysteamine reduces the rate of progression to end stage kidney disease in cystinosis. Although food is often taken with cysteamine to reduce associated gastrointestinal symptoms, this may alter the bioavailability of cysteamine. METHODS: This is a prospective, randomized, 3 treatment study to determine the effects of fasting and high-fat/calorie and high protein meals on cysteamine absorption in healthy adult controls. On 3 separate days, serial plasma cysteamine levels were measured after cysteamine bitartrate 500 mg was ingested while fasting and also 30 minutes after high-fat/calorie and high-protein diets. Gastrointestinal (GI) symptoms were also monitored. RESULTS: Eight participants (5 men) were enrolled. Cysteamine absorption, as measured by area under the cysteamine concentration-time curve (AUC0-infinity ) while fasted and following high-fat/calorie and high-protein meals, was 3618 +/- 372 min.MUM, 2799 +/- 405 min.MUM (P = .04 vs fasted), and 2457 +/- 353 min.MUM (P = .005), respectively, and the mean Cmax values for participants were 26.3 +/- 3.5 MUM, 22.4 +/- 5.6 MUM (P = .16 vs fasted), and 17.2 +/- 2.6 MUM (P = .036 vs fasted), respectively. Mild GI symptoms were reported in 3 participants. CONCLUSIONS: Cysteamine absorption may be decreased by 30% when taken with food as compared with the fasting state. Food causes wide variation in tmax and Cmax for cysteamine. PMID- 27121461 TI - Excitatory effect of norepinephrine on neurons in the inferior vestibular nucleus and the underlying receptor mechanism. AB - The central noradrenergic system, originating mainly from the locus coeruleus in the brainstem, plays an important role in many physiological functions, including arousal and attention, learning and memory, anxiety, and nociception. However, little is known about the roles of norepinephrine (NE) in somatic motor control. Therefore, using extracellular recordings on rat brainstem slices and quantitative real-time RT-PCR, we investigate the effect and mechanisms of NE on neuronal activity in the inferior vestibular nucleus (IVN), the largest nucleus in the vestibular nuclear complex, which holds an important position in integration of information signals controlling body posture. Here, we report that NE elicits an excitatory response on IVN neurons in a concentration-dependent manner. Activation of alpha1 - and beta2 -adrenergic receptors (ARs) induces an increase in firing rate of IVN neurons, whereas activation of alpha2 -ARs evokes a decrease in firing rate of IVN neurons. Therefore, the excitation induced by NE on IVN neurons is a summation of the excitatory components mediated by coactivation of alpha1 - and beta2 -ARs and the inhibitory component induced by alpha2 -ARs. Accordingly, alpha1 -, alpha2 -, and beta2 -AR mRNAs are expressed in the IVN. Although beta1 -AR mRNAs are also detected, they are not involved in the direct electrophysiological effect of NE on IVN neurons. All these results demonstrate that NE directly regulates the activity of IVN neurons via alpha1 -, alpha2 -, and beta2 -ARs and suggest that the central noradrenergic system may actively participate in IVN-mediated vestibular reflexes and postural control. (c) 2016 Wiley Periodicals, Inc. PMID- 27121462 TI - TRIM59 is upregulated and promotes cell proliferation and migration in human osteosarcoma. AB - Osteosarcoma is a prevalent type of cancer and has a high metastatic ability, particularly for metastasis to the lungs. Effective treatment strategies have improved, however, the detailed molecular mechanism underlying the onset of this malignancy remains to be fully elucidated. The current study investigated the role of the tripartite motif (TRIM) family protein TRIM59 in osteosarcoma growth and metastasis. It was identified that TRIM59 was overexpressed in clinical osteosarcoma tissues and cultured osteosarcoma cell lines. In addition, the MTT assay demonstrated that in U2OS and MG63 cells, knockdown of TRIM59 by specific siRNA inhibited proliferation, whereas overexpression of TRIM59 promoted cell proliferation. Furthermore, overexpression of TRIM59 significantly increased the U2OS cell migrative and invasive abilities in a Transwell chamber assay. In addition, TRIM59 was able to negatively regulate the protein levels of P53 without significantly affecting the mRNA levels in U2OS and MG63 cells. These data suggest the oncogenic abilities of TRIM59 in osteosarcoma, which promote osteosarcoma cell proliferation, migration and invasion. PMID- 27121463 TI - Dysprosium electrodeposition from a hexaalkylguanidinium-based ionic liquid. AB - The rare-earth element dysprosium (Dy) is an important additive that increases the magnetocrystalline anisotropy of neodymium magnets and additionally prevents from demagnetizing at high temperatures. Therefore, it is one of the most important elements for high-tech industries and is mainly used in permanent magnetic applications, for example in electric vehicles, industrial motors and direct-drive wind turbines. In an effort to develop a more efficient electrochemical technique for depositing Dy on Nd-magnets in contrast to commonly used costly physical vapor deposition, we investigated the electrochemical behavior of dysprosium(iii) trifluoromethanesulfonate in a custom-made guanidinium-based room-temperature ionic liquid (RTIL). We first examined the electrodeposition of Dy on an Au(111) model electrode. The investigation was carried out by means of cyclic voltammetry (CV) and X-ray photoelectron spectroscopy (XPS). The initial stages of metal deposition were followed by in situ scanning tunneling microscopy (STM). CV measurements revealed a large cathodic reduction peak, which corresponds to the growth of monoatomic high islands, based on STM images taken during the initial stages of deposition. XPS identified these deposited islands as dysprosium. A similar reduction peak was also observed on an Nd-Fe-B substrate, and positively identified as deposited Dy using XPS. Finally, we varied the concentration of the Dy precursor, electrolyte flow and temperature during Dy deposition and demonstrated that each of these parameters could be used to increase the thickness of the Dy deposit, suggesting that these parameters could be tuned simultaneously in a temperature-controlled flow cell to enhance the thickness of the Dy layer. PMID- 27121464 TI - Three-dimensional printing and the surgeon. PMID- 27121465 TI - Association between flood and the morbidity of bacillary dysentery in Zibo City, China: a symmetric bidirectional case-crossover study. AB - This study examined the relationship between daily morbidity of bacillary dysentery and flood in 2007 in Zibo City, China, using a symmetric bidirectional case-crossover study. Odds ratios (ORs) and 95 % confidence intervals (CIs) on the basis of multivariate model and stratified analysis at different lagged days were calculated to estimate the risk of flood on bacillary dysentery. A total of 902 notified bacillary dysentery cases were identified during the study period. The median of case distribution was 7-year-old and biased to children. Multivariable analysis showed that flood was associated with an increased risk of bacillary dysentery, with the largest OR of 1.849 (95 % CI 1.229-2.780) at 2-day lag. Gender-specific analysis showed that there was a significant association between flood and bacillary dysentery among males only (ORs >1 from lag 1 to lag 5), with the strongest lagged effect at 2-day lag (OR = 2.820, 95 % CI 1.629 4.881), and the result of age-specific indicated that youngsters had a slightly larger risk to develop flood-related bacillary dysentery than older people at one shorter lagged day (OR = 2.000, 95 % CI 1.128-3.546 in youngsters at lag 2; OR = 1.879, 95 % CI 1.069-3.305 in older people at lag 3). Our study has confirmed that there is a positive association between flood and the risk of bacillary dysentery in selected study area. Males and youngsters may be the vulnerable and high-risk populations to develop the flood-related bacillary dysentery. Results from this study will provide recommendations to make available strategies for government to deal with negative health outcomes due to floods. PMID- 27121466 TI - The long distance transport of airborne Ambrosia pollen to the UK and the Netherlands from Central and south Europe. AB - The invasive alien species Ambrosia artemisiifolia (common or short ragweed) is increasing its range in Europe. In the UK and the Netherlands, airborne concentrations of Ambrosia pollen are usually low. However, more than 30 Ambrosia pollen grains per cubic metre of air (above the level capable to trigger allergic symptoms) were recorded in Leicester (UK) and Leiden (NL) on 4 and 5 September 2014. The aims of this study were to determine whether the highly allergenic Ambrosia pollen recorded during the episode could be the result of long distance transport, to identify the potential sources of these pollen grains and to describe the conditions that facilitated this possible long distance transport. Airborne Ambrosia pollen data were collected at 10 sites in Europe. Back trajectory and atmospheric dispersion calculations were performed using HYSPLIT_4. Back trajectories calculated at Leicester and Leiden show that higher altitude air masses (1500 m) originated from source areas on the Pannonian Plain and Ukraine. During the episode, air masses veered to the west and passed over the Rhone Valley. Dispersion calculations showed that the atmospheric conditions were suitable for Ambrosia pollen released from the Pannonian Plain and the Rhone Valley to reach the higher levels and enter the airstream moving to northwest Europe where they were deposited at ground level and recorded by monitoring sites. The study indicates that the Ambrosia pollen grains recorded during the episode in Leicester and Leiden were probably not produced by local sources but transported long distances from potential source regions in east Europe, i.e. the Pannonian Plain and Ukraine, as well as the Rhone Valley in France. PMID- 27121467 TI - Public health risks of prolonged fine particle events associated with stagnation and air quality index based on fine particle matter with a diameter <2.5 MUm in the Kaoping region of Taiwan. AB - The increasing frequency of droughts in tropical and sub-tropical areas since 1970 due to climate change requires a better understanding of the relationship between public health and long-duration fine particle events (FPE; defined as a day with an average PM2.5 >= 35.5 MUg/m3) associated with rainfall and wind speed. In the Kaoping region of Taiwan, 94.46 % of the daily average PM2.5 in winter exceeds the limit established by 2005 World Health Organization (WHO) guidelines. This study investigated the differences in winter weather characteristics and health effects between non-FPE and FPE days, and the performance of air quality indexes on FPE days. Z-statistics for one-tailed tests, multiplicative decomposition models, logarithmic regression, and product moment correlations were used for the analysis. The results indicate that mean wind speeds, rainfall hours, and air temperature were significantly decreased on FPE days. Daily mean PM2.5 concentrations were positively correlated to the duration of FPE days. The duration of FPE days was positively related to the length of drought (r = 0.97, P < 0.05). The number of respiratory admissions was positively correlated with the FPE duration (r 2 = 0.60). The age groups >15 years experienced the largest average reduction in asthma admissions on lag-days. Compared to the pollutant standard index (PSI) and revised air quality index (RAQI), the PM2.5 index is more representative and sensitive to changes in PM2.5 concentrations. PMID- 27121468 TI - Two types of interneurons in the mouse lateral geniculate nucleus are characterized by different h-current density. AB - Although hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels and the corresponding h-current (Ih) have been shown to fundamentally shape the activity pattern in the thalamocortical network, little is known about their function in local circuit GABAergic interneurons (IN) of the dorsal part of the lateral geniculate nucleus (dLGN). By combining electrophysiological, molecular biological, immunohistochemical and cluster analysis, we characterized the properties of Ih and the expression profile of HCN channels in IN. Passive and active electrophysiological properties of IN differed. Two subclasses of IN were resolved by unsupervised cluster analysis. Small cells were characterized by depolarized resting membrane potentials (RMP), stronger anomalous rectification, higher firing frequency of faster action potentials (APs), appearance of rebound bursting, and higher Ih current density compared to the large IN. The depolarization exerted by sustained HCN channel activity facilitated neuronal firing. In addition to cyclic nucleotides, Ih in IN was modulated by PIP2 probably based on the abundant expression of the HCN3 isoform. Furthermore, only IN with larger cell diameters expressed neuronal nitric oxide synthase (nNOS). It is discussed that Ih in IN is modulated by neurotransmitters present in the thalamus and that the specific properties of Ih in these cells closely reflect their modulatory options. PMID- 27121469 TI - Expert consensus on an in vitro approach to assess pulmonary fibrogenic potential of aerosolized nanomaterials. AB - The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their potential to induce adverse lung effects following inhalation has lead to much interest in better understanding the hazard associated with these nanomaterials (NMs). While the current regulatory requirement for substances of concern, such as MWCNTs, in many jurisdictions is a 90-day rodent inhalation test, the monetary, ethical, and scientific concerns associated with this test led an international expert group to convene in Washington, DC, USA, to discuss alternative approaches to evaluate the inhalation toxicity of MWCNTs. Pulmonary fibrosis was identified as a key adverse outcome linked to MWCNT exposure, and recommendations were made on the design of an in vitro assay that is predictive of the fibrotic potential of MWCNTs. While fibrosis takes weeks or months to develop in vivo, an in vitro test system may more rapidly predict fibrogenic potential by monitoring pro-fibrotic mediators (e.g., cytokines and growth factors). Therefore, the workshop discussions focused on the necessary specifications related to the development and evaluation of such an in vitro system. Recommendations were made for designing a system using lung-relevant cells co-cultured at the air-liquid interface to assess the pro-fibrogenic potential of aerosolized MWCNTs, while considering human-relevant dosimetry and NM life cycle transformations. The workshop discussions provided the fundamental design components of an air-liquid interface in vitro test system that will be subsequently expanded to the development of an alternative testing strategy to predict pulmonary toxicity and to generate data that will enable effective risk assessment of NMs. PMID- 27121470 TI - Clonal hematopoiesis in acquired aplastic anemia. AB - Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ~50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1 Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA. PMID- 27121471 TI - Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies. AB - The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers. PMID- 27121472 TI - Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. AB - Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy. PMID- 27121473 TI - Candidate driver genes involved in genome maintenance and DNA repair in Sezary syndrome. AB - Sezary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array-based copy number analyses of CD4(+) tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop-gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1 were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2 defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQ were found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-kappaB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1 and ATM genes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-kappaB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment. PMID- 27121474 TI - Systematic review and meta-analysis of iron therapy in anaemic adults without chronic kidney disease: updated and abridged Cochrane review. AB - AIMS: Anaemia is increasingly recognized as having an independent impact upon patient outcomes in cardiac disease. The role of novel iron therapies to treat anaemia is increasing. This systematic review and meta-analysis assesses the efficacy and safety of iron therapies for the treatment of adults with anaemia. METHODS AND RESULTS: Electronic databases and search engines were searched as per Cochrane methodology. Randomized controlled trials (RCTs) of iron vs. inactive control or placebo, as well as alternative formulations, doses, and routes in anaemic adults without chronic kidney disease or in the peri-partum period were eligible. The primary outcome of interest was mortality at 1 year. Secondary outcomes were blood transfusion, haemoglobin levels, quality of life, serious adverse events, and length of hospital stay. A total of 64 RCTs (including five studies of heart failure patients) comprising 9004 participants were included. None of the studies was at a low risk of bias. There were no statistically significant differences in mortality between iron and inactive control. Both oral and parenteral iron significantly reduced the proportion of patients requiring blood transfusion compared with inactive control [risk ratio (RR) 0.66, 95% confidence interval (CI) 0.48-0.90; and RR 0.84, 95% CI 0.73-0.97, respectively]. Haemoglobin was increased more by both oral and parenteral iron compared with inactive control [mean difference (MD) 0.91 g/dL, 95% CI 0.48 to 1.35; and MD 1.04, 95% CI 0.52 to 1.57, respectively], and parenteral iron demonstrated a greater increase when compared with oral iron (MD 0.53 g/dL, 95% CI 0.31-0.75). In all comparisons, there were no differences in the results comparing patients with and without heart failure. CONCLUSION: Both oral and parenteral iron are shown to decrease the proportion of people who require blood transfusion and increase haemoglobin levels, without any benefit on mortality. Further trials at a low risk of bias, powered to measure clinically significant endpoints, are still required. PMID- 27121475 TI - Two-color widefield fluorescence microendoscopy enables multiplexed molecular imaging in the alveolar space of human lung tissue. AB - We demonstrate a fast two-color widefield fluorescence microendoscopy system capable of simultaneously detecting several disease targets in intact human ex vivo lung tissue. We characterize the system for light throughput from the excitation light emitting diodes, fluorescence collection efficiency, and chromatic focal shifts. We demonstrate the effectiveness of the instrument by imaging bacteria (Pseudomonas aeruginosa) in ex vivo human lung tissue. We describe a mechanism of bacterial detection through the fiber bundle that uses blinking effects of bacteria as they move in front of the fiber core providing detection of objects smaller than the fiber core and cladding (~3 MUm ~3 MUm ). This effectively increases the measured spatial resolution of 4 MUm 4 MUm . We show simultaneous imaging of neutrophils, monocytes, and fungus (Aspergillus fumigatus) in ex vivo human lung tissue. The instrument has 10 nM and 50 nM sensitivity for fluorescein and Cy5 solutions, respectively. Lung tissue autofluorescence remains visible at up to 200 fps camera acquisition rate. The optical system lends itself to clinical translation due to high-fluorescence sensitivity, simplicity, and the ability to multiplex several pathological molecular imaging targets simultaneously. PMID- 27121476 TI - Efficient simulations of tubulin-driven axonal growth. AB - This work concerns efficient and reliable numerical simulations of the dynamic behaviour of a moving-boundary model for tubulin-driven axonal growth. The model is nonlinear and consists of a coupled set of a partial differential equation (PDE) and two ordinary differential equations. The PDE is defined on a computational domain with a moving boundary, which is part of the solution. Numerical simulations based on standard explicit time-stepping methods are too time consuming due to the small time steps required for numerical stability. On the other hand standard implicit schemes are too complex due to the nonlinear equations that needs to be solved in each step. Instead, we propose to use the Peaceman-Rachford splitting scheme combined with temporal and spatial scalings of the model. Simulations based on this scheme have shown to be efficient, accurate, and reliable which makes it possible to evaluate the model, e.g. its dependency on biological and physical model parameters. These evaluations show among other things that the initial axon growth is very fast, that the active transport is the dominant reason over diffusion for the growth velocity, and that the polymerization rate in the growth cone does not affect the final axon length. PMID- 27121477 TI - Culture and sensory response to visual stimuli. AB - This study investigated the influence of culture on people's sensory responses, such as smell, taste, sound and touch to visual stimuli. The sensory feelings of university students from four countries (Japan, South Korea, Britain and France) to six images were evaluated. The images combined real and abstract objects and were presented on a notebook computer. Overall, 280 participants (144 men and 136 women; n = 70/country) were included in the statistical analysis. The chi-square independence analysis showed differences and similarities in the sensory responses across countries. Most differences were detected in smell and taste, whereas few variations were observed for sound responses. Large variations in the response were observed for the abstract coral and butterfly images, but few differences were detected in response to the real leaf image. These variations in response were mostly found in the British and Japanese participants. PMID- 27121478 TI - Ethno-Cultural Considerations in Cardiac Patients' Medication Adherence. AB - We aimed to develop an in-depth understanding about factors that influence cardiac medication adherence among South Asian, Chinese, and European White cardiac patients. Sixty-four patients were purposively sampled from an ongoing study cohort. Interviews were audio-recorded and transcribed for analyses. Physicians' culturally sensitive communication and patients' motivation to live a symptom-free and longer life enhanced adherence. European Whites were motivated to enhance personal well-being and enjoy family life. South Asians' medication adherence was influenced by the desire to fulfill the will of God and family responsibilities. The Chinese were motivated to avoid pain, illness, and death, and to obey a health care provider. The South Asians and Chinese wanted to ultimately reduce medication use. Previous positive experiences, family support, and establishing a routine also influenced medication adherence. Deterrents to adherence were essentially the reverse of the motivators/facilitators. This analysis represents an essential first step forward in developing ethno culturally tailored interventions to optimize adherence. PMID- 27121479 TI - Systematic review with network meta-analysis: comparative effectiveness and safety of strategies for preventing NSAID-associated gastrointestinal toxicity. AB - BACKGROUND: Many strategies are used to prevent nonsteroidal anti-inflammatory drug (NSAID)-associated gastrointestinal toxicity, but the comparative effectiveness remains unclear. AIM: To evaluate the comparative effectiveness of clinical strategies for preventing gastrointestinal toxicity induced by NSAIDs. METHODS: MEDLINE, EMBASE and the Cochrane Library (from their inception to May 2015) were searched for randomised controlled trials comparing the risk of gastrointestinal adverse events in patients taking nonselective NSAIDs, selective cyclooxygenase(COX)-2 inhibitors or nonselective NSAIDs/COX-2 inhibitors plus gastroprotective agents [proton pump inhibitors (PPIs), histamine-2 receptor antagonists, misoprostol]. Both pairwise meta-analysis and Bayesian network meta analysis were performed. RESULTS: Analyses were based on 82 trials including 125 053 participants. Network meta-analysis demonstrated that selective COX-2 inhibitors + PPIs [Risk ratio (RR), 95% Credible Interval (CrI): ulcer complications 0.07, 0.02-0.18], selective COX-2 inhibitors (RR, 95% CrI: ulcer complications 0.25, 0.15- 0.38; symptomatic ulcer 0.12, 0.04-0.30), nonselective NSAIDs + PPIs (RR, 95% CrI: ulcer complications 0.28, 0.18-0.41; symptomatic ulcer 0.11, 0.04-0.23), nonselective NSAIDs + misoprostol (RR, 95% CrI: ulcer complications 0.47, 0.24-0.81; symptomatic ulcer 0.41, 0.13-1.00) were associated with significantly lower risk of clinical gastrointestinal events compared with nonselective NSAIDs. For all effectiveness endpoints, selective COX-2 inhibitors + PPIs was associated with the lowest absolute event probability and the highest rank, followed by selective COX-2 inhibitors and thirdly by nonselective NSAIDs + PPIs. CONCLUSION: The combination of selective COX-2 inhibitors plus PPIs provides the best gastrointestinal protection, followed by selective COX-2 inhibitors, and thirdly by nonselective NSAIDs plus PPIs. PMID- 27121481 TI - Individual placement and support, supported education in young people with mental illness: an exploratory feasibility study. AB - AIM: This study aimed to evaluate the feasibility and effectiveness of adapting individual placement and support (IPS) to education for young people presenting to a tertiary mental health service who wished to re-engage with or be supported in their education. METHODS: The study was an uncontrolled trial. Twenty young people with severe mental illness were recruited and worked with an educational specialist providing adapted IPS for education (IPSed). Demographic, educational and symptom measures were collected at baseline. Educational outcome was collected at the end of the 6-month intervention. Data presented are descriptive. RESULTS: Individual placement and support for education was found to be feasible with 95% of the participants successfully completing the intervention. Eighteen of the 19 who participated through to the conclusion of the intervention achieved positive educational outcomes. CONCLUSIONS: It is well established that education is the foundation of career, but many people with mental illness drop out of their education with the onset of illness in adolescence or early adulthood. There has been a dearth of interventions to reconnect people with mental illness to secondary education and training. This study demonstrates that it is feasible to adapt IPS to focus exclusively on education at the outset of illness. Further larger studies are needed to confirm these results and create an evidence base for implementation of IPSed in routine practice for the treatment of early stage mental illness. PMID- 27121484 TI - Evaluation of the Efficacy and Robustness of a Second Generation Implantable Stimulator in a Patient With Hemiplegia During 20 Years of Functional Electrical Stimulation of the Common Peroneal Nerve. AB - We evaluated the efficacy and robustness of a second generation implantable stimulator for correcting drop foot (DF) in a patient with left-sided hemiplegia over 20 years of functional electrical stimulation (FES) of the common peroneal nerve (CPN). Dorsal flexion and eversion of the affected foot was partially restored by FES of the superficial region of the CPN innervating mostly the tibialis anterior (TA) and partly peroneus longus (PL) and peroneus brevis (PB) muscles. The reasons for implant failure during the long-term follow-up assessment were analyzed and resolving procedures were identified. The stimulator had an average failure rate of once every three years, due to repetitive mechanical load on the lead wires of its internal and/or external unit, and had to be serviced once per year to replace the heel switch integrated into the shoe sole. FES-associated mechanical trauma to the CPN elicited a thickening of the connective tissue around the CPN and a slightly compromised conduction velocity of the CPN. FES of the CPN, with the second generation implantable stimulator, improved gait parameters of the affected leg during the 20 years period. Long term, daily FES enables a functional and reliable recruitment of nerve fibers, thus providing a sufficient dorsal flexion and optimal eversion of the affected foot to sustain unassisted, almost normal gait. Therefore, the presented implant is suitable for very long-term FES of the CPN. PMID- 27121483 TI - Evolved plasmid-host interactions reduce plasmid interference cost. AB - Antibiotic selection drives adaptation of antibiotic resistance plasmids to new bacterial hosts, but the molecular mechanisms are still poorly understood. We previously showed that a broad-host-range plasmid was poorly maintained in Shewanella oneidensis, but rapidly adapted through mutations in the replication initiation gene trfA1. Here we examined if these mutations reduced the fitness cost of TrfA1, and whether this was due to changes in interaction with the host's DNA helicase DnaB. The strains expressing evolved TrfA1 variants showed a higher growth rate than those expressing ancestral TrfA1. The evolved TrfA1 variants showed a lower affinity to the helicase than ancestral TrfA1 and were no longer able to activate the helicase at the oriV without host DnaA. Moreover, persistence of the ancestral plasmid was increased upon overexpression of DnaB. Finally, the evolved TrfA1 variants generated higher plasmid copy numbers than ancestral TrfA1. The findings suggest that ancestral plasmid instability can at least partly be explained by titration of DnaB by TrfA1. Thus under antibiotic selection resistance plasmids can adapt to a novel bacterial host through partial loss of function mutations that simultaneously increase plasmid copy number and decrease unfavorably high affinity to one of the hosts' essential proteins. PMID- 27121482 TI - Molecular mechanisms of cell death in intervertebral disc degeneration (Review). AB - Intervertebral discs (IVDs) are complex structures that consist of three parts, namely, nucleus pulposus, annulus fibrosus and cartilage endplates. With aging, IVDs gradually degenerate as a consequence of many factors, such as microenvironment changes and cell death. Human clinical trial and animal model studies have documented that cell death, particularly apoptosis and autophagy, significantly contribute to IVD degeneration. The mechanisms underlying this phenomenon include the activation of apoptotic pathways and the regulation of autophagy in response to nutrient deprivation and multiple stresses. In this review, we briefly summarize recent progress in understanding the function and regulation of apoptosis and autophagy signaling pathways. In particular, we focus on studies that reveal the functional mechanisms of these pathways in IVD degeneration. PMID- 27121485 TI - Formation of fibroblastic reticular network in the brain after infection with neurovirulent murine coronavirus. AB - cl-2 virus is an extremely neurovirulent murine coronavirus. However, during the initial phase of infection between 12 and 24 h post-inoculation (hpi), the viral antigens are detected only in the meninges, followed by viral spread into the ventricular wall before invasion into the brain parenchyma, indicating that the viruses employ a passage between the meninges and ventricular wall as an entry route into the brain parenchyma. At 48 hpi, the passage was found to be constructed by ER-TR7 antigen (ERag)-positive fibers (ERfibs) associated with laminin and collagen III between the fourth ventricle and meninges at the cerebellopontine angle. The construct of the fibers mimics the reticular fibers of the fibroblastic reticular network, which comprises a conduit system in the lymphoid organs. In the meninges, ERfibs together with collagen fibers, lining in a striped pattern, made up a pile of thin sheets. In the brain parenchyma, mature ERfibs associated with laminin were found around blood vessels. Besides mature ERfibs, immature Erfibs without associations with other extracellular matrix components like laminin and collagen appeared after infection, suggesting that the CNS creates a unique conduit system for immune communication triggered by viral invasion. PMID- 27121486 TI - Relationship between XspI Site Polymorphisms of LDL-R Gene and Serum IL-2 and IL 10 in Patients with Hypercholesterolemia. AB - BACKGROUND: Relationship has been identified in sporadic reports between polymorphisms and hypercholesterolemia. However, the relationship between inflammatory cytokines and polymorphism of low-density lipoprotein receptor (LDL R) gene in hypercholesterolemia is unclear. This study aimed to explore the relationship and significance between polymorphisms of LDL-R gene and serum Interleukin-2 (IL-2), IL-10 in patients with hypercholesterolemia. METHODS: PCR RFLP and direct DNA sequencing assay were employed to determine polymorphism of LDL-R gene in 900 patients with hypercholesterolemia and 400 healthy cases. ELISA was applied to assay serum concentration of IL-2 and IL-10. Blood lipid indexes were tested in all cases. RESULTS: Compared with the healthy controls, level of IL-2 increased significantly, while IL-10 decreased significantly (P < 0.05). Correlation analysis showed that IL-2 was positively correlated with total cholesterol (TC), LDL-c, and genotype (r = 0.542, 0.410, 0.598, P < 0.05) and negatively correlated with HDL-c (r = -0.352, P < 0.05). Negative relationship also was found between TC, LDL-c, genotype, and IL-10 (r = -0.452, -0.390, 0.613, P < 0.05), and positive correlation between HDL-c and IL-10 (r = 0.398, P < 0.05). Multiple linear regression showed that genotypes and TC were independent factors affecting the levels of IL-2 and IL-10 (P < 0.05). CONCLUSION: IL-2 and IL-10 were related to gene polymorphisms of LDL-R, which might be involved in the development and progress of hypercholesterolemia. PMID- 27121487 TI - Influence of temporal variation and host condition on helminth abundance in the lizard Tropidurus hispidus from north-eastern Brazil. AB - Ecological characteristics and environmental variation influence both host species composition and parasite abundance. Abiotic factors such as rainfall and temperature can improve parasite development and increase its reproduction rate. The comparison of these assemblages between different environments may give us a more refined analysis of how environment affects the variation of helminth parasite abundance. The aim of the present study was to evaluate how temporal variation, host size, sex and reproduction affect helminth abundance in the Tropidurus hispidus lizard in Caatinga, Restinga and Atlantic Forest environments. Overall, larger-sized lizards showed higher helminth abundance. We found a monthly variation in the helminth species abundance in all studied areas. In the Caatinga area, monoxenic and heteroxenic parasites were related to the rainy season and to the reproductive period of lizards. In Restinga, monoxenic and heteroxenic helminth species were more abundant during the driest months. In the Atlantic Forest, the rainy and host reproductive season occurred continuously throughout the year, so parasite abundance was relatively constant. Nevertheless, heteroxenic species were more abundant in this area. The present results showed that the temporal variation, body size, sex, reproductive period and habitat type influence the abundance and composition of helminth species in T. hispidus. PMID- 27121489 TI - ent-Abietane diterpenoids with anti-neuroinflammatory activity from the rare Chloranthaceae plant Chloranthus oldhamii. AB - Twelve new ent-abietane diterpenoids, chlorabietins A-L (), were isolated from the roots of Chloranthus oldhamii. Their structures and absolute configurations were determined by extensive spectroscopic analyses, X-ray diffraction, and experimental/calculated electronic circular dichroism (ECD) spectroscopy. Among the new isolates, chlorabietins D () and E () are the first two naturally occurring 8-spiro-fused 9,10-seco-ent-abietanes containing an unexpected cis fused A/B ring system. Chlorabietin F () is a rare chinane-type diterpenoid featuring a hitherto unknown C-ring cleavage between C-13 and C-14, which might be derived from a common precursor of the above spiro-diterpenoid epimers and , and their biosynthetic relationships are briefly discussed. Meanwhile, chlorabietin I () is the first representative of the abietane-type diterpenoids possessing a tetrahydrofurano function bridging C-6 and C-19. Chlorabietins B (), C (), F (), and G () showed anti-neuroinflammatory effects by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine BV-2 microglial cells, with IC50 values ranging from 16.4 to 33.8 MUM. PMID- 27121490 TI - New insights into the modification mechanism of Li-rich Li1.2Mn0.6Ni0.2O2 coated by Li2ZrO3. AB - Lithium-rich Mn-based layered cathode materials have attracted wide attention due to their high specific capacity for lithium-ion batteries. However, some critical issues i.e. poor rate capability and voltage fade have limited their practical applications. Herein, we propose a synchronous lithiation strategy to coat Li rich Li1.2Mn0.6Ni0.2O2 (LMNO) with a thin layer of Li(+)-conductive Li2ZrO3. The obtained syn-Li2ZrO3@LMNO integrates the advantages of the Li2ZrO3 coating and Zr(4+) doping, and shows a much higher rate capability and cycling stability than those of the counterpart post-Li2ZrO3@LMNO fabricated by a post-coating method. More importantly, the average voltage of syn-Li2ZrO3@LMNO has been enhanced by 0.15 V and the voltage decay has also been mitigated. New insights into the synergetic modification mechanism of the Li2ZrO3 coating and Zr(4+) doping have been proposed. The coating layer of Li(+)-conductive Li2ZrO3 alleviates the surface side reactions, suppresses the transition metal dissolution and enhances the Li-ion conductivity. Meanwhile, the doping and incorporation of Zr(4+) into the host structure accompanied by the Li2ZrO3 coating expands the interplanar spacing and decreases Li/Ni mixing which facilitates Li(+) diffusion. In addition, the integration of the Li2ZrO3 coating and Zr(4+) doping also further enhances the layered structure stability and mitigates the voltage fade during lithiation/delithiation cycles. Moreover, the proposed synchronous lithiation coating route avoids the duplicated high-temperature calcinations and can also be widely used to modify some other cathode materials. PMID- 27121491 TI - Deboronative cyanation of potassium alkyltrifluoroborates via photoredox catalysis. AB - A photoredox catalytic method was developed for the direct cyanation of alkyltrifluoroborates. This reaction provides a new and useful transformation of the easily available alkyltrifluoroborates. The photocatalytic reaction can tolerate a variety of functional groups with mild reaction conditions. Mechanistic investigations are consistent with the present reaction following a radical pathway. PMID- 27121492 TI - Cepharanthine induces apoptosis through the mitochondria/caspase pathway in murine dendritic cells. AB - CONTEXT: Cepharanthine (CEP) is a biscoclaurine amphipathic alkaloid isolated from the plant Stephania cepharantha Hayata. Although the effects of CEP on several types of cells have been investigated, those on dendritic cells (DCs) are poorly understood. OBJECTIVE: To investigate the effect of CEP on the induction of apoptosis in murine DCs. MATERIALS AND METHODS: The induction of Annexin V/propidium iodide-positive cells and permeability of mitochondrial membrane potential were evaluated in DCs treated with CEP. Cell-associated caspase activity and DNA fragmentation were analyzed by Dual Sensor: MitoCaspTM and agarose gel electrophoresis, respectively. RESULTS: The number of dead cells was increased by CEP treatment at concentrations more than 10 MUg/ml. Flow cytometric analysis revealed that the cell death was found to be apoptosis, CEP treatment reduced mitochondrial membrane potential and upregulated the level of cleaved caspases, including caspase-9 and caspase-3/7, in a dose-dependent fashion. Furthermore, DNA fragmentation was observed in CEP-treated DCs. CONCLUSION: CEP is capable of inducing apoptosis and may be a potential agent against DC-mediated and allergic diseases. PMID- 27121493 TI - Children's perceptions of emotion regulation strategy effectiveness: links with attachment security. AB - Six- and nine-year-old children (N = 97) heard illustrated stories evoking anger in a story character and provided evaluations of the effectiveness of eight anger regulation strategies. Half the stories involved the child's mother as social partner and the other half involved a peer. Attachment security was assessed via the Security Scale. Children reported greater effectiveness for seeking support from adults and peers in the peer context than the mother context, but perceived venting as more effective with mothers. Children with higher security scores were more likely to endorse problem solving and less likely to endorse aggression in both social contexts than those with lower security scores. Early evidence for gender differences was found in that boys endorsed the effectiveness of distraction while girls endorsed venting their emotion. PMID- 27121494 TI - Violent media and hostile appraisals: A meta-analytic review. AB - Hostile people tend to view the world as a hostile place. Although there are individual differences in hostile world-views, situational factors can also play a role. For example, scenes of violence in the mass media might influence people to view the world as a hostile place. This meta-analysis aggregates, for the first time, all studies that have investigated the link between exposure to violent media and hostile appraisals (e.g., perceiving the ambiguous actions by others as aggressive actions). This meta-analysis included 37 independent studies involving 10,410 participants. The results showed a "small" to "moderate" sized average correlation between exposure to violent media and hostile appraisals (r+ = .20, 95%CI = .14, .26). Significant correlations were found in experimental, cross-sectional, and longitudinal studies, indicating a triangulation of evidence. Effects were not correlated with participant gender. Effects were also stable over time. However, the link between exposure to violent media and hostile appraisals was positively related to age, perhaps because violent media can have cumulative effects over time. There was no evidence of publication bias. The findings from this meta-analysis are consistent with the General Aggression Model (e.g., Anderson, & Bushman, 2002; Annual Review of Psychology 53:27-51). These results compliment those from previous meta-analyses showing that violent media can increase aggressive thoughts, angry feelings, physiological arousal, and aggressive behavior. These findings also have practical significance, because people who view the world in a hostile manner are more likely to behave aggressively themselves. Aggr. Behav. 42:605-613, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27121495 TI - Using physiologically based models for clinical translation: predictive modelling, data interpretation or something in-between? AB - Heart disease continues to be a significant clinical problem in Western society. Predictive models and simulations that integrate physiological understanding with patient information derived from clinical data have huge potential to contribute to improving our understanding of both the progression and treatment of heart disease. In particular they provide the potential to improve patient selection and optimisation of cardiovascular interventions across a range of pathologies. Currently a significant proportion of this potential is still to be realised. In this paper we discuss the opportunities and challenges associated with this realisation. Reviewing the successful elements of model translation for biophysically based models and the emerging supporting technologies, we propose three distinct modes of clinical translation. Finally we outline the challenges ahead that will be fundamental to overcome if the ultimate goal of fully personalised clinical cardiac care is to be achieved. PMID- 27121497 TI - oVEMPs and cVEMPs in patients with 'clinically certain' Meniere's disease. AB - OBJECTIVE: To measure ocular vestibular-evoked myogenic potentials (oVEMPs) and cervical vestibular-evoked myogenic potentials (cVEMPS) in Meniere's disease patients with confirmed cochlear hydrops and in the normal ears of volunteers. METHODS: oVEMPs and cVEMPs were measured in 18 patients with a symptomatic diagnosis of Meniere's disease and tone burst electrocochleographic confirmation of hydrops, and in the ears of 22 volunteers. RESULTS: Threshold measures: For cVEMP: no significant differences between Meniere's ears and controls; for oVEMP: significantly elevated thresholds in affected ears of Meniere's ears compared with their unaffected ears, but not with controls. Latency measures: cVEMP N1 peaks were significantly prolonged compared with the left and right ears of controls, but not with the non-affected ear. Amplitude measures: cVEMP P1N1 and N1P2 measures were significantly reduced compared with the right ear of controls, but not with the non-affected ear; For oVEMP, N2P2 amplitudes were significantly reduced compared with both ears of controls but not with the non-affected ear. CONCLUSION: Abnormalities of oVEMPs and cVEMPs were found in 18 Meniere's disease patients who had an independent confirmation of cochlear hydrops. The overlap of the results from Meniere's patients compared with normal controls limits the use of VEMP abnormalities as a sole reliable diagnostic test for Meniere's disease. PMID- 27121496 TI - Exploring the Association between Serum BDNF and Attempted Suicide. AB - Suicide is a leading cause of death and a significant public health concern. Brain-derived neurotrophic factor (BDNF), a protein important to nervous system function, has been implicated in psychiatric disorders and suicidal behaviour. We investigated the association between serum levels of BDNF and attempted suicide in a sample of 281 participants using a case-control study design. Participants were recruited from clinical and community settings between March 2011 and November 2014. Cases (individuals who had attempted suicide) (n = 84) were matched on sex and age (within five years) to both psychiatric controls (n = 104) and community controls (n = 93) with no history of suicide attempts. We collected fasting blood samples, socio-demographic information, physical measurements, and detailed descriptions of suicide attempts. We used linear regression analysis to determine the association between BDNF level (dependent variable) and attempted suicide (key exposure variable), adjusting for age, sex, body mass index, current smoking status, and antidepressant use. 250 participants were included in this analysis. In the linear regression model, attempted suicide was not significantly associated with BDNF level (beta = 0.28, SE = 1.20, P = 0.82). Our findings suggest that no significant association exists between attempted suicide and BDNF level. However, the findings need to be replicated in a larger cohort study. PMID- 27121498 TI - Detection and quantification of water-based aerosols using active open-path FTIR. AB - Aerosols have a leading role in many eco-systems and knowledge of their properties is critical for many applications. This study suggests using active Open-Path Fourier Transform Infra-Red (OP-FTIR) spectroscopy for quantifying water droplets and solutes load in the atmosphere. The OP-FTIR was used to measure water droplets, with and without solutes, in a 20 m spray tunnel. Three sets of spraying experiments generated different hydrosols clouds: (1) tap water only, (2) aqueous ammonium sulfate (0.25-3.6%wt) and (3) aqueous ethylene glycol (0.47-2.38%wt). Experiment (1) yielded a linear relationship between the shift of the extinction spectrum baseline and the water load in the line-of-sight (LOS) (R(2) = 0.984). Experiment (2) also yielded a linear relationship between the integrated extinction in the range of 880-1150 cm(-1) and the ammonium sulfate load in the LOS (R(2) = 0.972). For the semi-volatile ethylene glycol (experiment 3), present in the gas and condense phases, quantification was much more complex and two spectral approaches were developed: (1) according to the linear relationship from the first experiment (determination error of 8%), and (2) inverse modeling (determination error of 57%). This work demonstrates the potential of the OP-FTIR for detecting clouds of water-based aerosols and for quantifying water droplets and solutes at relatively low concentrations. PMID- 27121499 TI - Ladhani SN, et al (Clin Infect Dis 2015; 61:1637-44). PMID- 27121500 TI - Process evaluation of discharge planning implementation in healthcare using normalization process theory. AB - BACKGROUND: Discharge planning is a care process that aims to secure the transfer of care for the patient at transition from home to the hospital and back home. Information exchange and collaboration between care providers are essential, but deficits are common. A wide range of initiatives to improve the discharge planning process have been developed and implemented for the past three decades. However, there are still high rates of reported medical errors and adverse events related to failures in the discharge planning. Using theoretical frameworks such as Normalization Process Theory (NPT) can support evaluations of complex interventions and processes in healthcare. The aim of this study was to explore the embedding and integration of the DPP from the perspective of registered nurses, district nurses and homecare organizers. METHODS: The study design was explorative, using the NPT as a framework to explore the embedding and integration of the DPP. Data consisted of written documentation from; workshops with staff, registered adverse events and system failures, web based survey and individual interviews with staff. RESULTS: Using the NPT as a framework to explore the embedding and integration of discharge planning after 10 years in use showed that the staff had reached a consensus of opinion of what the process was (coherence) and how they evaluated the process (reflexive monitoring). However, they had not reached a consensus of opinion of who performed the process (cognitive participation) and how it was performed (collective action). This could be interpreted as the process had not become normalized in daily practice. CONCLUSION: The result shows necessity to observe the implementation of old practices to better understand the needs of new ones before developing and implementing new practices or supportive tools within healthcare to reach the aim of development and to accomplish sustainable implementation. The NPT offers a generalizable framework for analysis, which can explain and shape the implementation process of old practices, before further development of new practices or supportive tools. PMID- 27121501 TI - Effect of prehospital notification on acute stroke care: a multicenter study. AB - BACKGROUND: The sooner thrombolytic therapy is given to acute ischemic stroke patients, the better the outcome. Prehospital notification may shorten the time between hospital arrival and brain computed tomography (door-to-CT) and the door to-needle (DTN) time. This study investigated the effect of prehospital notification on acute stroke care in an urban city in Taiwan. METHODS: This retrospective observational study utilized a prospectively collected dataset from patients treated at 9 hospitals and the emergency medical service (EMS) system in Taipei City from September 1, 2012 to December 31, 2014. During the study period, prehospital notification was performed by emergency medical technicians if the patient met the following criteria: (1) positive Cincinnati Prehospital Stroke Scale (CPSS), (2) symptom onset within 3 h, and (3) a sugar pinprick test result >= 60 mg/dL. The demographics, final diagnoses, and data associated with stroke for all patients in the prenotification group and for patients diagnosed with acute stroke within 3 h of symptoms onset were prospectively recorded in the stroke registry. The primary outcome was door-to-CT time and the secondary outcome was DTN time. The sensitivity and positive predictive value (PPV) of prehospital notifications and the association between the volume of patients receiving thrombolytic therapy at individual hospitals and DTN time were also evaluated. RESULTS: There were 928 patients who presented <= 3 h from stroke onset. Among them, 727 (78.3 %) patients were in the prenotification group; of these, more were male, smokers, and presented with severe symptoms, and fewer had a history of prior stroke or cardiac diseases compared to patients in the non prenotification group. The median door-to-CT time was significantly shorter in the prenotification group than among the non-prenotification group (13 versus 19 min, p < 0.001). Prenotification was associated with shorter DTN time (63 versus 68 min, p = 0.138). The sensitivity and PPV of prenotification of stroke were 78.3 % and 78.2 %, respectively. The DTN time demonstrated a significant and highly negative association with the volume of patients receiving thrombolytic therapy (Spearman's correlation coefficient -0.90, p < 0.001). DISCUSSION: In our study, we found prehospital notification was associated with faster door-to-CT scan and shorter DTN time in patients presenting within 3 hours of symptom onset. Such a close collaboration between hospitals and the EMS system gives citizens an in-time emergency care network. Our study revealed that, like in other countries, prehospital notification for stroke patients improved in-hospital stroke care in Taiwan. Our study showed that the sensitivity and PPV of prenotification decisions according to our CPSS-based criteria was comparable with those in other studies. Our study also found that DTN time was shorter in the hospital that treated a greater volume of patients with thrombolytic therapy. A multicenter collaboration program is needed to help those hospitals with relatively lower stroke patient volume to set up interventions that have been proven to improve stroke care. CONCLUSIONS: Prehospital notification of stroke can significantly shorten door-to-CT time and improve acute stroke care in Taiwan. PMID- 27121502 TI - Rhodnius prolixus and R. robustus (Hemiptera: Reduviidae) nymphs show different locomotor patterns on an automated recording system. AB - BACKGROUND: Circadian rhythms of triatomines, vectors of the etiological agent Trypanosoma cruzi responsible for Chagas disease, have been extensively studied in adults of the two most epidemiologically relevant vector species, Rhodnius prolixus and Triatoma infestans. However, little attention has been dedicated to the activity patterns in earlier developmental stages, even though triatomine nymphs are equally capable of transmitting T. cruzi to humans. Because circadian rhythms may differ even between closely related species, studies that focus on this behavioral trait can also be used to shed light on the taxonomy of controversial taxa, which becomes especially relevant regarding vector species. METHODS: We compared the daily locomotor activity patterns of second- and third instar nymphs of Rhodnius prolixus and Rhodnius robustus in order to unveil possible behavioral differences between these cryptic species. Mitochondrial and nuclear markers were sequenced to confirm species identification. RESULTS: Nymphs of both species had a bimodal pattern of locomotion and similar daily activity patterns, but R. prolixus is more active under light/dark cycles and depicts a more pronounced activity rhythm under constant darkness conditions. CONCLUSIONS: We describe the implementation of an often-used automated method for the recording of individual locomotor activity to differentiate sibling species of Rhodnius with distinct epidemiological relevance. The higher levels of activity observed in the nymphs of R. prolixus could potentially contribute to increased vector capacity. PMID- 27121503 TI - The NF-kappaB subunit RelB regulates the migration and invasion abilities and the radio-sensitivity of prostate cancer cells. AB - NF-kappaB subunits play important roles in carcinogenesis of a variety of human malignancies and response to cancer therapy; however, the contribution of an individual subunit has not been thoroughly defined. Constitutive activation of the canonical NF-kappaB subunit is a critical event in prostate carcinogenesis. Recent findings point out that RelB, which contributes to the non-canonical NF kappaB activity, functions importantly in the prostate cancer progression. Here, we investigated systemically the functional roles of RelB in prostate cancer and examine its significance as a therapeutic target. Targeting RelB using short hairpin RNA approach in androgen-independent DU145 prostate cancer cells interfered with various biological behaviors of cells. We observed that RelB knockdown inhibited prostate cancer cell growth, migration, and invasion, and enhanced proteasome inhibitor sensitivity. The altered expression of anti apoptotic gene Bcl-2 played critical roles in regulating both spontaneous and radiation-induced apoptosis in the presence of RelB knockdown. For the first time, we showed that RelB knockdown significantly attenuated the migration and invasion of DU145 prostate cancer cells, due to the reduction of integrin beta-1. Collectively, we provided evidence that RelB functioned as an oncogene in prostate cancer. Developing a RelB-targeted therapeutic intervention, is valuable in treating advanced, metastatic prostate cancer. PMID- 27121504 TI - Monoclonal antibodies for differentiating infections of three serological-related tospoviruses prevalent in Southwestern China. AB - BACKGROUND: The thrips-borne tospoviruses Calla lily chlorotic spot virus (CCSV), Tomato zonate spot virus (TZSV) and a new species provisionally named Tomato necrotic spot associated virus (TNSaV) infect similar crops in southwestern China. The symptoms exhibiting on virus-infected crops are similar, which is difficult for distinguishing virus species by symptomatology. The sequences of nucleocapsid proteins (NPs) of CCSV, TNSaV and TZSV share high degrees of amino acid identity with each other, and their serological relationship was currently demonstrated from the responses of the previously reported monoclonal antibodies (MAbs) against the NP of CCSV (MAb-CCSV-NP) and the nonstructural NSs protein of Watermelon silver mottle virus (WSMoV) (MAb-WNSs). Therefore, the production of virus-specific antibodies for identification of CCSV, TNSaV and TZSV is demanded to improve field surveys. METHODS: The NP of TZSV-13YV639 isolated from Crinum asiaticum in Yunnan Province, China was bacterially expressed and purified for producing MAbs. Indirect enzyme-linked immunosorbent assay (ELISA) and immunoblotting were conducted to test the serological response of MAbs to 18 tospovirus species. Additionally, the virus-specific primers were designed to verify the identity of CCSV, TNSaV and TZSV in one-step reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Two MAbs, denoted MAb-TZSV-NP(S15) and MAb-TZSV-NP(S18), were screened for test. MAb-TZSV-NP(S15) reacted with CCSV and TZSV while MAb-TZSV-NP(S18) reacted specifically to TZSV in both indirect ELISA and immunoblotting. Both MAbs can be used to detect TZSV in field-collected plant samples. The epitope of MAb-TZSV-NP(S18) was further identified consisting of amino acids 78-86 (HKIVASGAD) of the TZSV-13YV639 NP that is a highly conserved region among known TZSV isolates but is distinct from TNSaV and TZSV. CONCLUSIONS: In this study, two MAbs targeting to different portions of the TZSV NP were obtained. Unlike MAb-CCSV-NP reacted with TNSaV as well as CCSV and TZSV, both TZSV MAbs can be used to differentiate CCSV, TNSaV and TZSV. The identity of CCSV, TNSaV and TZSV was proven by individual virus-specific primer pairs to indicate the correctness of serological responses. We also proposed an serological detection platform using MAb-CCSV-NP, MAb-TZSV-NP(S15) and MAb-TZSV NP(S18) to allow researchers and quarantine staff to efficiently diagnose the infections of CCSV, TNSaV and TZSV in China and other countries. PMID- 27121505 TI - Incremental cost-utility of sevelamer relative to calcium carbonate for treatment of hyperphosphatemia among pre-dialysis chronic kidney disease patients. AB - BACKGROUND: Sevelamer is an alternative to calcium carbonate for the treatment of hyperphosphatemia among non-dialysis dependent patients with chronic kidney disease (CKD). Although some studies show that it may reduce mortality and delay the onset of dialysis when compared to calcium carbonate, it is also significantly more expensive. Prior studies looking at the incremental cost effectiveness of sevelamer versus calcium carbonate in pre-dialysis patients are based on data from a single clinical trial. The goal of our study is to use a wider range of clinical data to achieve a more contemporary and robust cost effectiveness analysis. METHODS: We used a Markov model to estimate the lifetime costs and quality-adjusted life years (QALYs) gained for treatment with sevelamer versus calcium carbonate. The model simulated transitions among three health states (CKD not requiring dialysis, end-stage renal disease, and death). Data on transition probabilities and utilities were obtained from the published literature. Costs were calculated from a third party payer perspective and included medication, hospitalization, and dialysis. Sensitivity analyses were also run to encompass a wide range of assumptions about the dose, costs, and effectiveness of sevelamer. RESULTS: Over a lifetime, the average cost per patient treated with sevelamer is S$180,724. The estimated cost for patients treated with calcium carbonate is S$152,988. A patient treated with sevelamer gains, on average, 6.34 QALYs relative to no treatment, whereas a patient taking calcium carbonate gains 5.81 QALYs. Therefore, sevelamer produces an incremental cost-effectiveness ratio (ICER) of S$51,756 per QALY gained relative to calcium carbonate. CONCLUSION: Based on established benchmarks for cost-effectiveness, sevelamer is cost effective relative to calcium carbonate for the treatment of hyperphosphatemia among patients with chronic kidney disease initially not on dialysis. PMID- 27121506 TI - Comparison of molecular detection methods for pertussis in children during a state-wide outbreak. AB - A state-wide pertussis outbreak occurred in Washington during the winter-spring months of 2012, concurrent with respiratory viral season. We compared performance characteristics of a laboratory-developed pertussis PCR (LD-PCR for Bordetella pertussis, Bordetella parapertussis, and Bordetella holmesii) and rapid multiplex PCR (RM-PCR) for respiratory viruses (FilmArrayTM, BioFire, B. pertussis data unblinded following FDA approval post outbreak). We analyzed three cohorts of patients using physician testing orders as a proxy for clinical suspicion for pertussis or respiratory viruses: Cohort 1, tested by LD-PCR for pertussis pathogens only by nasopharyngeal swab; Cohort 2, by RM-PCR for respiratory viruses only by mid-nasal turbinate swab; and Cohort 3, by both methods. B. pertussis was detected in a total of 25 of the 490 patients in Cohort 3 in which LD-PCR detected 20/25 (80 %) cases and the RM-PCR detected 24/25 (96 %; p = 0.2). Pertussis pathogens were detected in 21/584 (3.6 %) of samples from Cohort 1 where clinicians had a relatively strong suspicion for pertussis. In contrast, B. pertussis was detected in only 4/3071 (0.1 %) specimens from Cohort 2 where suspicion for pertussis was lower (p < 0.001 for comparison with Cohort 1). In summary, the two laboratory methods were comparable for the detection of B. pertussis. PMID- 27121507 TI - Neurotrophic and Neuroprotective Effects of Muscle Contraction. AB - BACKGROUND: Physical activity has been shown to be associated with reduced risk of coronary heart disease but the same effect seems to be produced in neurological diseases. OBJECTIVE: In this review, we focused on the interplay between physical activity and some neurological conditions (Stroke, dementia, epilepsy, headache, Parkinson' s disease, amyotrophic lateral sclerosis, multiple sclerosis, insomnia, depression and anxiety) with the aim of describing the potential role of physical activity in the prevention of such diseases and the physiological mechanisms involved in these processes. RESULTS: Despite a growing body of evidence which reveals that physical activity is able to reduce the frequency of neurological diseases, directly or indirectly by enhancing cardiovascular conditions, further studies are necessary to better characterize which type of exercise is useful for each condition. CONCLUSION: Physical activity could represent an additional approach to fight against such diseases. PMID- 27121509 TI - Antiretroviral pre-exposure prophylaxis: A new opportunity to slow HIV spread in India. PMID- 27121510 TI - Breaking dogma for future therapy using stem cell - Where we have reached? PMID- 27121511 TI - Understanding complexity of Fanconi anaemia. PMID- 27121512 TI - Immune based therapy for melanoma. AB - A few years ago therapeutic options in advanced melanoma were very limited and the prognosis was somber. Although recent progresses are far from providing a cure for advanced melanoma, yet these have kindled new hopes and searching for a cure does not seem unreasonable. Seven new medicines have been authorized in various regions of the world in the recent past in the therapy of advanced melanoma, over half of them acting by mechanisms involving the immune system of the host. The anti-CTLA-4 (cytotoxic T lymphocyte associated protein-4) ipilimumab has been followed by anti-PD1 (programmed death1) inhibitors, more effective and safer. Very recently, the first oncolytic immunotherapy, talimogene laherparepvec (T-VEC) has been authorized for placing on the market and a variety of combinations of the new therapies are currently being evaluated or considered. Besides, a plethora of other molecules and approaches, especially monoclonal antibodies, are in the preliminary phases of clinical investigation and are likely to bring new benefits for the treatment of this potentially fatal form of cancer. PMID- 27121513 TI - Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers. AB - Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3 K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies. PMID- 27121514 TI - Epidemiology of childhood overweight & obesity in India: A systematic review. AB - BACKGROUND & OBJECTIVES: Childhood obesity is a known precursor to obesity and other non-communicable diseases (NCDs) in adulthood. However, the magnitude of the problem among children and adolescents in India is unclear due to paucity of well-conducted nationwide studies and lack of uniformity in the cut-points used to define childhood overweight and obesity. Hence an attempt was made to review the data on trends in childhood overweight and obesity reported from India during 1981 to 2013. METHODS: Literature search was done in various scientific public domains from the last three decades using key words such as childhood and adolescent obesity, overweight, prevalence, trends, etc. Additional studies were also identified through cross-references and websites of official agencies. RESULTS: Prevalence data from 52 studies conducted in 16 of the 28 States in India were included in analysis. The median value for the combined prevalence of childhood and adolescent obesity showed that it was higher in north, compared to south India. The pooled data after 2010 estimated a combined prevalence of 19.3 per cent of childhood overweight and obesity which was a significant increase from the earlier prevalence of 16.3 per cent reported in 2001-2005. INTERPRETATION & CONCLUSIONS: Our review shows that overweight and obesity rates in children and adolescents are increasing not just among the higher socio economic groups but also in the lower income groups where underweight still remains a major concern. PMID- 27121515 TI - Hair & skin derived progenitor cells: In search of a candidate cell for regenerative medicine. AB - BACKGROUND & OBJECTIVES: Skin is an established tissue source for cell based therapy. The hair follicle has been introduced later as a tissue source for cell based therapy. The ease of tissue harvest and multipotent nature of the resident stem cells in skin and hair follicle has promoted basic and clinical research in this area. This study was conducted to evaluate skin stem cells (SSCs) and hair follicle stem cells (HFSCs) as candidate cells appropriate for neuronal and melanocyte lineage differentiation. METHODS: In this study, SSCs and hair follicle stem cells (HFSCs) were expanded in vitro by explant culture method and were compared in terms of proliferative potential and stemness; differentiation potential into melanocytes and neuronal lineage. RESULTS: SSCs were found to be more proliferative in comparison to HFSCs, however, telomerase activity was more in HFSCs in comparison to SSCs. Capacity to differentiate into two lineages of ectoderm origin (neuronal and melanocyte) was found to be different. HFSCs cells showed more propensities towards melanocyte lineage, whereas SSCs were more inclined towards neuronal lineage. INTERPRETATION & CONCLUSIONS: The study showed that SSCs had differential advantage over the HFSCs for neuronal cell differentiation, whereas, the HFSCs were better source for melanocytic differentiation. PMID- 27121516 TI - Investigation of FANCA gene in Fanconi anaemia patients in Iran. AB - BACKGROUND & OBJECTIVES: Fanconi anaemia (FA) is a syndrome with a predisposition to bone marrow failure, congenital anomalies and malignancies. It is characterized by cellular hypersensitivity to cross-linking agents such as mitomycin C (MMC). In the present study, a new approach was selected to investigate FANCA (Fanconi anaemia complementation group A) gene in patients clinically diagnosed with cellular hypersensitivity to DNA cross-linking agent MMC. METHODS: Chromosomal breakage analysis was performed to prove the diagnosis of Fanconi anaemia in 318 families. Of these, 70 families had a positive result. Forty families agreed to molecular genetic testing. In total, there were 27 patients with unknown complementary types. Genomic DNA was extracted and total RNA was isolated from fresh whole blood of the patients. The first-strand cDNA was synthesized and the cDNA of each patient was then tested with 21 pairs of overlapping primers. High resolution melting curve analysis was used to screen FANCA, and LinReg software version 1.7 was utilized for analysis of expression. RESULTS: In total, six sequence alterations were identified, which included two stop codons, two frames-shift mutations, one large deletion and one amino acid exchange. FANCA expression was downregulated in patients who had sequence alterations. INTERPRETATION & CONCLUSIONS: The results of the present study show that high resolution melting (HRM) curve analysis may be useful in the detection of sequence alteration. It is simpler and more cost-effective than the multiplex ligation-dependent probe amplification (MLPA) procedure. PMID- 27121517 TI - Clinical & radiological evaluation of atherosclerotic changes in carotid & coronary arteries in asymptomatic & clinically symptomatic individuals as a tool for pre-symptomatic diagnosis of cardiovascular disease. AB - BACKGROUND & OBJECTIVES: An increase in prevalence of atherosclerosis has been noted worldwide with reports of higher incidence of atherosclerotic vascular changes in Asian Indians. There is a need to measure vascular atherosclerotic changes and provide objective parameter to predict cardiac and cerebrovascular adverse events. Atherosclerotic changes in carotids and coronaries are generally accepted as an association. We attempted in this study to relate intimal-luminal changes in carotid arteries to luminal changes in coronary arteries. Our study presents results of high resolution ultra sonographic (HRUS) evaluation of intimal-medial-thickness (IMT) in carotid with luminal changes in coronaries on multidetector-CT (MDCT) in clinically asymptomatic and symptomatic individuals. METHODS: In this prospective study, HRUS examination of the carotid bifurcation was performed in 151 individuals to measure IMT in asymptomatic and symptomatic groups. Assessments of coronary arteries of the same group of patients were evaluated by MDCT within a week interval. IMT changes were associated with age, sex, predisposing factors, calcium burden of coronaries and structural atherosclerotic changes in coronary arteries. RESULTS: A linear association of IMT was observed with increasing age. IMT of 0.5-0.69 mm was noted in 50 per cent of patients between 51-56 yr with higher number of symptomatic patients in this group. Linear increases in coronary vascular changes were noted with increasing IMT thickness. Changes were more prevalent in diabetic, hypertensive, treadmill test (TMT) positive and clinically symptomatic patients. INTERPRETATION & CONCLUSIONS: Age-related progression of atherosclerosis was evident in internal carotid arteries. Significant association was observed in the IMT thickness of right common carotid (RCC) and coronary disease in symptomatic group; whereas IMT of left common carotid and internal carotid arteries did not show any association. RCC IMT between 0.5-0.7mm showed maximal association with significant symptomatic narrowing of coronary arteries. Patients with IMT beyond 0.7mm had no association with symptoms. PMID- 27121518 TI - Impaired systemic vascular reactivity & raised high-sensitivity C reactive protein levels in chronic obstructive pulmonary disease. AB - BACKGROUND & OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is characterized by slowly progressive airflow limitaion, chronic lung inflammation and associated systemic manifestations. The objective of this preliminary study was to investigate the levels of high sensitivity C reactive protein (hs CRP) and tumour necrosis factor-alpha (TNF-alpha) as markers of systemic inflammation and assessment of systemic vascular reactivity that may play an important role in development of cardiovascular disease in COPD patients. METHODS: Systemic vascular reactivity was assessed non-invasively by measuring peripheral pulse waveform changes during reactive hyperemia (RH) in 16 COPD patients and 14 controls by photoplethysmography technique (PPG). Parameters measured were pulse wave amplitude (PWA), slope and pulse transit time (PTT). Tumour necrosis factor alpha (TNF-alpha) and hs CRP were measured as markers of inflammation. RESULTS: PWA during the 1 st , 2 nd and 3 rd minutes post release of occlusion were significantly higher than the baseline means in controls, whereas in the patient group there was no significant change in the PWA during any of the observed time periods following release of occlusion, in comparison to the baseline means. Similar results were observed in slope values for patients and controls. Maximum percentage change in PWA during RH with reference to baseline was significantly lower in patients as compared to controls (26.78+/-20.19 vs 57.20+/-19.80%, p<0.001). Maximum percentage change in slope during RH with reference to baseline was significantly lower in patients as compared to controls (19.77+/-10.73 vs 39.25+/-13.49%, P<0.001). A vascular tone response as represented by PTT was also impaired in the 3 rd minute of RH as compared to baseline mean values in COPD patients only. INTERPRETATION & CONCLUSIONS: Our findings showed raised hs CRP levels and impaired systemic vascular reactivity in COPD patients. Whether these may increase the risk of cardiovascular disease in COPD patients need to be confirmed in future studies with large sample size and appropriate study design. PMID- 27121519 TI - Quantitative & qualitative analysis of endothelial cells of donor cornea before & after penetrating keratoplasty in different pathological conditions. AB - BACKGROUND & OBJECTIVES: Endothelial cells of the donor cornea are known to be affected quantitatively and qualitatively in different pathological conditions after penetrating keratoplasty (PK) and this has direct effect on the clarity of vision obtained after PK. This study was undertaken to analyze the qualitative and quantitative changes in donor endothelial cells before and after PK in different pathological conditions. METHODS: A prospective investigational analysis of 100 consecutive donor corneas used for penetrating keratoplasty between June 2006 and June 2008, was conducted. The patients were evaluated on the first day, at the end of first week, first month, third and six months and one year. RESULTS: A decrease was observed in endothelial cell count in all pathological conditions. After one year of follow up the loss was 33.1 per cent in corneal opacity, 45.9 per cent in acute infective keratitis (AIK), 58.5 per cent in regrafts, 28.5 per cent in pseudophakic bullous keratopathy (PBK), 37 per cent in descemetocele, 27 per cent in keratoconus and 35.5 per cent in aphakic bullous keratopathy (ABK) cases. INTERPRETATION & CONCLUSIONS: The endothelial cell loss was highest in regraft cases which was significant (P<0.05), while the least endothelial cell loss was seen in keratoconus cases. The cell loss was associated with increase in coefficient of variation (CV), i.e. polymegathism and pleomorphism. Inspite of this polymegathism and pleomorphism, the clarity of the graft was maintained. PMID- 27121521 TI - Measles & rubella outbreaks in Maharashtra State, India. AB - BACKGROUND & OBJECTIVES: Under the outbreak-based measles surveillance in Maharashtra State the National Institute of Virology at Pune receives 3-5 serum samples from each outbreak and samples from the local hospitals in Pune for laboratory diagnosis. This report describes one year data on the measles and rubella serology, virus isolation and genotyping. METHODS: Maharashtra State Health Agencies investigated 98 suspected outbreaks between January-December 2013 in the 20 districts. Altogether, 491 serum samples were received from 20 districts and 126 suspected cases from local hospitals. Samples were tested for the measles and rubella IgM antibodies by commercial enzyme immunoassay (EIA). To understand the diagnostic utility, a subset of serum samples (n=53) was tested by measles focus reduction neutralization test (FRNT). Further, 37 throat swabs and 32 urine specimens were tested by measles reverse transcription (RT)-PCR and positive products were sequenced. Virus isolation was performed in Vero hSLAM cells. RESULTS: Of the 98 suspected measles outbreaks, 61 were confirmed as measles, 12 as rubella and 21 confirmed as the mixed outbreaks. Four outbreaks remained unconfirmed. Of the 126 cases from the local hospitals, 91 were confirmed for measles and three for rubella. Overall, 93.6 per cent (383/409) confirmed measles cases were in the age group of 0-15 yr. Measles virus was detected in 18 of 38 specimens obtained from the suspected cases. Sequencing of PCR products revealed circulation of D4 (n=9) and D8 (n=9) strains. Four measles viruses (three D4 & one D8) were isolated. INTERPRETATION & CONCLUSIONS: Altogether, 94 measles and rubella outbreaks were confirmed in 2013 in the State of Maharasthra indicating the necessity to increase measles vaccine coverage in the State. PMID- 27121520 TI - Perioperative time course of matrix metalloproteinase-9 (MMP-9), its tissue inhibitor TIMP-1 & S100B protein in carotid surgery. AB - BACKGROUND & OBJECTIVES: Ischaemic stroke is a life burdening disease for which carotid endarterectomy (CEA) is considered a gold standard intervention. Pro inflammatory markers like matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) and S-100 Beta (S100B) may have a role in the early inflammation and cognitive decline following CEA. This study was aimed to describe the perioperative time courses and correlations between of MMP-9, TIMP-1 and S100B following CEA. METHODS: Fifty four patients scheduled for CEA were enrolled. Blood samples were collected at four time points, T 1 : preoperative, T 2 : 60 min after cross-clamp release, T 3 : first postoperative morning, T 4 : third postoperative morning. Twenty atherosclerotic patients were included as controls. Plasma MMP-9, TIMP-1 and S100B levels were estimated by ELISA. RESULTS: TIMP-1 was decreased significantly in the CEA group (P<0.01). Plasma MMP-9 was elevated and remained elevated from T 1-4 in the CEA group (P<0.05) with a marked elevation in T 3 compared to T 1 (P<0.05). MMP-9/TIMP-1 was elevated in the CEA group and increased further by T 2 and T 3 (P<0.05). S100B was elevated on T 2 and decreased on T 3-4 compared to T 1 . INTERPRETATION & CONCLUSIONS: Our study provides information on the dynamic changes of MMP-9-TIMP-1 system and S100B in the perioperative period. Preoperative reduction of TIMP-1 might be predictive for shunt requirement but future studies are required for verification. PMID- 27121522 TI - An alternative strategy to generate coding sequence of macrophage migration inhibitory factor-2 of Wuchereria bancrofti. AB - BACKGROUND & OBJECTIVES: Different developmental stages of Wuchereria bancrofti, the major causal organism of lymphatic filariasis (LF), are difficult to obtain. Beside this limitation, to obtain complete coding sequence (CDS) of a gene one has to isolate mRNA and perform subsequent cDNA synthesis which is laborious and not successful at times. In this study, an alternative strategy employing polymerase chain reaction (PCR) was optimized and validated, to generate CDS of Macrophage migration Inhibitory Factor-2 (wbMIF-2), a gene expressed in the transition stage between L3 to L4. METHODS: The genomic DNA of W. bancrofti microfilariae was extracted and used to amplify the full length wbMIF-2 gene (4.275 kb). This amplified product was used as a template for amplifying the exons separately, using the overlapping primers, which were then assembled through another round of PCR. RESULTS: A simple strategy was developed based on PCR, which is used routinely in molecular biology laboratories. The amplified CDS of 363 bp of wbMIF-2 generated using genomic DNA splicing technique was devoid of any intronic sequence. INTERPRETATION & CONCLUSIONS: The cDNA of wbMIF-2 gene was successfully amplified from genomic DNA of microfilarial stage of W. bancrofti thus circumventing the use of inaccessible L3-L4 transitional stage of this parasite. This strategy is useful for generating CDS of genes from parasites that have restricted availability. PMID- 27121524 TI - Adherence to anti-retroviral drugs. PMID- 27121523 TI - Compromised zinc status of experimental rats as a consequence of prolonged iron & calcium supplementation. AB - BACKGROUND & OBJECTIVES: Iron supplementation is usually given to pregnant and lactating women who may also have marginal deficiency of zinc. The negative impact of supplemental iron and calcium on zinc status is a cause of concern. The present investigation was undertaken to examine the effect of inclusion of iron and calcium in the diet at supplementary levels on zinc status of experimental rats. METHODS: Groups of experimental rats were maintained on diets supplemented with iron (Molar ratio - Zn:Fe 1:30) and calcium (Molar ratio - Zn:Ca 1:667) both individually and in combination for six weeks. Zinc status of these rats was assessed by determining zinc concentration in circulation and in organs, and the activities of zinc containing enzymes in serum and liver. RESULTS: The zinc status of experimental rats receiving supplemental levels of iron and calcium was significantly compromised. Zinc concentration in serum, kidney, spleen and liver was reduced significantly by both these minerals. Six weeks of supplementation of iron and calcium individually, significantly reduced the activity of liver and serum superoxide dismutase and alkaline phosphatase. Activity of liver alcohol dehydrogenase was lowered in calcium supplemented group and in calcium + iron supplemented group, while that of carbonic anhydrase was significantly reduced by iron, calcium and their combination. INTERPRETATION & CONCLUSIONS: Supplemental levels of iron and calcium, both individually and in combination, significantly compromised the zinc status of experimental rats. This negative effect of these two minerals was more prominent when these were supplemented for a period of six weeks. PMID- 27121525 TI - Authors' response. PMID- 27121526 TI - Drug-induced diseases (DIDs). PMID- 27121527 TI - Authors' response. PMID- 27121528 TI - Uncommon presentation of a less common tumour. PMID- 27121529 TI - Primary testicular plasmablastic lymphoma: unique case in a 30 year old. PMID- 27121530 TI - Iron Supplementation Affects Hematologic Biomarker Concentrations and Pregnancy Outcomes among Iron-Deficient Tanzanian Women. AB - BACKGROUND: Iron deficiency is a highly prevalent micronutrient abnormality and the most common cause of anemia globally, worsening the burden of adverse pregnancy and child outcomes. OBJECTIVE: We sought to evaluate the response of hematologic biomarkers to iron supplementation and to examine the predictors of the response to iron supplementation among iron-deficient pregnant women. METHODS: We identified 600 iron-deficient (serum ferritin <=12 MUg/L) pregnant women, aged 18-45 y, presenting to 2 antenatal clinics in Dar es Salaam, Tanzania using rapid ferritin screening tests, and prospectively followed them through delivery and postpartum. All women received 60 mg Fe and 0.25 mg folate daily from enrollment until delivery. Proportions meeting the thresholds representing deficient hematologic status including hemoglobin <110 g/L, ferritin <=12 MUg/L, serum soluble transferrin receptor (sTfR) >4.4 mg/L, zinc protoporphyrin (ZPP) >70 mmol/L, or hepcidin <=13.3 MUg/L at baseline and delivery were assessed. The prospective change in biomarker concentration and the influence of baseline hematologic status on the change in biomarker concentrations were assessed. Regression models were estimated to assess the relation of change in biomarker concentrations and pregnancy outcomes. RESULTS: There was significant improvement in maternal biomarker concentrations between baseline and delivery, with increases in the concentrations of hemoglobin (mean difference: 15.2 g/L; 95% CI: 13.2, 17.2 g/L), serum ferritin (51.6 MUg/L; 95% CI: 49.5, 58.8 MUg/L), and serum hepcidin (14.0 MUg/L; 95% CI: 12.4, 15.6 MUg/L) and decreases in sTfR (-1.7 mg/L; 95% CI: -2.0, -1.3 mg/L) and ZPP (-17.8 mmol/L; 95% CI: -32.1, 3.5 mmol/L). The proportions of participants with low hemoglobin, ferritin, and hepcidin were 73%, 93%, and 99%, respectively, at baseline and 34%, 12%, and 46%, respectively, at delivery. The improvements in biomarker concentrations were significantly greater among participants with poor hematologic status at baseline - up to 12.1 g/L and 14.5 MUg/L for hemoglobin and ferritin concentrations, respectively. For every 10 g/L increase in hemoglobin concentration, there was a 24% reduced risk of perinatal mortality (RR = 0.76; 95% CI: 0.59, 0.99) and a 23% reduced risk of early infant mortality (RR = 0.77; 95% CI: 0.60, 0.99). The risk of anemia at delivery despite supplementation was predicted by baseline anemia (RR = 2.11; 95% CI: 1.39, 3.18) and improvements in ferritin concentration were more likely to be observed in participants who took iron supplements for up to 90 d (RR = 1.41; 95% CI: 1.13, 1.76). CONCLUSION: Iron supplementation decreases the risk of maternal anemia and increases the likelihood of infant survival among iron-deficient Tanzanian pregnant women. Interventions to promote increased duration and adherence to iron supplements may also provide greater health benefits. PMID- 27121531 TI - Multivitamin Use and the Risk of Cardiovascular Disease in Men. AB - BACKGROUND: Although multivitamins are widely used by US adults, few prospective studies have investigated their association with the long- and short-term risks of cardiovascular disease (CVD). OBJECTIVE: The aim of this study was to investigate how multivitamin use is associated with the risk of CVD in initially healthy men at baseline. METHODS: We studied 18,530 male physicians aged >=40 y from the Physicians' Health Study I cohort who were free of CVD and cancer at baseline (1982). All men provided a wide range of self-reported lifestyle and clinical factors plus intake of selected foods and dietary supplements. Cox proportional hazards models were used to calculate multivariable-adjusted HRs (95% CIs). RESULTS: During a mean follow-up of 12.2 y (total of 225,287 person years), there were 1697 incident cases of major CVD (defined as nonfatal myocardial infarction, nonfatal stroke, and CVD death). In multivariable-adjusted analyses, no significant associations were observed among baseline multivitamin users compared with nonusers for the risk of major CVD events (HR: 0.94; 95% CI: 0.84, 1.05), whereas a self-reported duration of >=20 y at baseline was associated with lower risk (HR: 0.56; 95% CI: 0.35, 0.90; P-trend = 0.05). Baseline multivitamin use was also significantly inversely associated with the risk of cardiac revascularization (HR: 0.86; 95% CI: 0.75, 0.98). Baseline use of multivitamins was not significantly associated with other CVD endpoints. CONCLUSION: In this long-term prospective study in initially healthy men, multivitamin use for >=20 y was associated with a lower risk of major CVD events. PMID- 27121533 TI - Systemic redox imbalance in stable chronic obstructive pulmonary disease. AB - CONTEXT: Increased oxidative burden is found in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To assess the association of ceruloplasmin, albumin, bilirubin, transferrin, thiols and malondialdehyde (MDA) with stable COPD. MATERIALS AND METHODS: Oxidative stress markers measured in 106 COPD patients and 45 healthy subjects were evaluated. RESULTS: Higher ceruloplasmin and MDA, and lower albumin, transferrin and thiols in COPD patients were found. Ceruloplasmin was the strongest single predictor of COPD. The model combining ceruloplasmin, albumin and thiols improved their individual diagnostic performances. CONCLUSIONS: Diagnostic characteristics of ceruloplasmin, albumin, transferrin, thiols and MDA suggest their potential value as additional tools in disease diagnosis. PMID- 27121532 TI - Plasma Riboflavin and Vitamin B-6, but Not Homocysteine, Folate, or Vitamin B-12, Are Inversely Associated with Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition-Varese Cohort. AB - BACKGROUND: One-carbon metabolism-important for DNA stability and integrity-may play a role in breast carcinogenesis. However, epidemiologic studies addressing this issue have yielded inconsistent results. OBJECTIVE: We prospectively investigated associations between breast cancer and plasma folate, riboflavin, vitamin B-6, vitamin B-12, and homocysteine in women recruited to the Varese (Italy) cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: We performed a nested case-control study on women aged 35-65 y at recruitment with a median body mass index of 25.3 kg/m(2) who gave blood samples in 1987-1992 and again in 1993-1998. Breast cancer cases identified by 31 December 2009 were individually matched to controls. RRs of breast cancer (and subtypes defined by hormone receptor status) with 95% CIs were estimated by unconditional logistic regression, controlling for matching factors and breast cancer risk factors. RESULTS: After a median of 14.9 y, 276 breast cancer cases were identified and matched to 276 controls. Increasing plasma vitamin B-6 was associated with decreased risk of overall (RR: 0.78; 95% CI: 0.63, 0.96 for 1-SD increase), premenopausal (RR: 0.66; 95% CI: 0.48, 0.92 for 1-SD increase), estrogen receptor-positive (RR: 0.79; 95% CI: 0.63, 1.00 for 1-SD increase), and progesterone receptor-positive (RR: 0.72; 95% CI: 0.55, 0.95 for 1-SD increase) breast cancers. Increased plasma vitamin B-6 was also associated with decreased breast cancer risk in alcohol consumers (>=7 g/d) compared with consumption of <7 g/d or nonconsumption (RR: 0.71; 95% CI: 0.51, 0.99). High plasma riboflavin was associated with significantly lower risk in premenopausal women (RR: 0.45; 95% CI: 0.21, 0.94; highest compared with the lowest quartile, P trend = 0.021). Plasma homocysteine, folate, and vitamin B-12 were not associated with breast cancer risk. CONCLUSIONS: High plasma vitamin B-6 and riboflavin may lower breast cancer risk, especially in premenopausal women. Additional research is necessary to further explore these associations. PMID- 27121534 TI - Conductance Quantization at Zero Magnetic Field in InSb Nanowires. AB - Ballistic electron transport is a key requirement for existence of a topological phase transition in proximitized InSb nanowires. However, measurements of quantized conductance as direct evidence of ballistic transport have so far been obscured due to the increased chance of backscattering in one-dimensional nanowires. We show that by improving the nanowire-metal interface as well as the dielectric environment we can consistently achieve conductance quantization at zero magnetic field. Additionally we study the contribution of orbital effects to the sub-band dispersion for different orientation of the magnetic field, observing a near-degeneracy between the second and third sub-bands. PMID- 27121535 TI - Rapid analysis of six trace trichlorophenols in seawater by magnetic micro-solid phase extraction and liquid chromatography with tandem mass spectrometry. AB - A new facile, rapid, inexpensive, and sensitive method for the analysis of six trace trichlorophenols in seawater samples was developed by magnetic micro-solid phase extraction coupled to liquid chromatography with tandem mass spectrometry. Core-shell covalently functionalized ferroferric oxide coated with aminated silicon dioxide and decorated with multiwalled carbon nanotubes was applied as an adsorbent to perform the extraction process. The effect of factors including solution pH, contact time, adsorbent amount, and ionic strength were investigated in detail. The obtained results revealed that the proposed adsorbent was a highly effective and low-cost magnetic micro-solid-phase extraction material for the enrichment of 2,3,4-trichlorophenol, 2,3,5-trichlorophenol, 2,3,6 trichlorophenol, 2,4,5-trichlorophenol, 2,4,6-trichlorophenol, and 3,4,5 trichlorophenol from seawater. Under the optimized conditions, the recoveries ranged from 88.0 to 99.5% at the three spiking levels, the limits of detection and the limits of quantification were 0.002 and 0.007 MUg/L for the six trichlorophenols, respectively. The intra- and interday relative standard deviations were 2.0-6.7 and 4.5-8.9%, respectively. The calibration curves showed a good linearity in the range of 0.02-5.0 MUg/L. The routine run analyses showed that the developed method was fast, simple, accurate, solvent-saving and high resolution, and it was suitable for the determination of trace trichlorophenols in seawater. PMID- 27121536 TI - An Air-Stable Semiconducting Polymer Containing Dithieno[3,2-b:2',3'-d]arsole. AB - Arsole-containing conjugated polymers are a practically unexplored class of materials despite the high interest in their phosphole analogues. Herein we report the synthesis of the first dithieno[3,2-b;2',3'-d]arsole derivative, and demonstrate that it is stable to ambient oxidation in its +3 oxidation state. A soluble copolymer is obtained by a palladium-catalyzed Stille polymerization and demonstrated to be a p-type semiconductor with promising hole mobility, which was evaluated by field-effect transistor measurements. PMID- 27121538 TI - Zn/Cd ratios and cadmium isotope evidence for the classification of lead-zinc deposits. AB - Lead-zinc deposits are often difficult to classify because clear criteria are lacking. In recent years, new tools, such as Cd and Zn isotopes, have been used to better understand the ore-formation processes and to classify Pb-Zn deposits. Herein, we investigate Cd concentrations, Cd isotope systematics and Zn/Cd ratios in sphalerite from nine Pb-Zn deposits divided into high-temperature systems (e.g., porphyry), low-temperature systems (e.g., Mississippi Valley type [MVT]) and exhalative systems (e.g., sedimentary exhalative [SEDEX]). Our results showed little evidence of fractionation in the high-temperature systems. In the low temperature systems, Cd concentrations were the highest, but were also highly variable, a result consistent with the higher fractionation of Cd at low temperatures. The delta(114/110)Cd values in low-temperature systems were enriched in heavier isotopes (mean of 0.32 +/- 0.310/00). Exhalative systems had the lowest Cd concentrations, with a mean delta(114/110)Cd value of 0.12 +/- 0.500/00. We thus conclude that different ore-formation systems result in different characteristic Cd concentrations and fraction levels and that low temperature processes lead to the most significant fractionation of Cd. Therefore, Cd distribution and isotopic studies can support better understanding of the geochemistry of ore-formation processes and the classification of Pb-Zn deposits. PMID- 27121537 TI - Identification of TLR2 and TLR4-induced microRNAs in human mesenchymal stem cells and their possible roles in regulating TLR signals. AB - Toll-like receptors (TLRs) are expressed in human bone marrow-derived mesenchymal stromal cells (BM-MSCs), and the activation of TLRs is important in proliferation, differentiation, migration and hematopoiesis-supporting functions of BM-MSCs. However, the molecular mechanisms underlying these processes remain to be elucidated. MicroRNAs (miRNAs) are involved in various biological functions by mediating mRNA degradation or inhibiting translation of target genes. The present study aimed to identify whether TLRs regulate the expression of miRNAs in BM-MSCs and elucidate the regulatory roles of miRNAs. Illumina high-throughput sequencing was used to profile miRNAs expressed in BM-MSCs stimulated with TLR2 agonist, PAM3CSK4 (PM) or TLR4 agonist, lipopolysaccharides (LPS). A marked expression change upon PM or LPS treatment was observed for 164 known miRNAs and six novel miRNAs that were identified. The expression of six novel miRNAs and 40 randomly selected known miRNAs was further validated by reverse transcription quantitative polymerase chain reaction. In addition, bioinformatic methods were used to predict the potential target genes of the abundant known miRNAs. The gene ontology analysis demonstrated that predicted targets were enriched in the regulation of signal transduction, cellular processes and macromolecule metabolic processes. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that these potential targets were involved in numerous important pathways, predominantly including mitogen-activated protein kinase, phosphatidylinositol 4,5-bisphosphate 3-kinase-Akt, neurotrophin and cancer-associated signaling pathways. The present study aimed to identify the global expression change of miRNAs in BM-MSCs stimulated with LPS and PM, providing the opportunity to further elucidate the roles of miRNAs in mediating TLR signals to regulate the functions of BM-MSCs. PMID- 27121540 TI - Specialised services "swallow up" increasing share of NHS budget. PMID- 27121539 TI - Design of a randomized controlled trial of extended-release naltrexone versus daily buprenorphine-naloxone for opioid dependence in Norway (NTX-SBX). AB - BACKGROUND: Current guidelines for opioid dependence recommend daily maintenance of physical dependence with methadone or buprenorphine, and discourage abstinence due to the high risk of relapse and overdose. Extended-release formulations of the opioid antagonist naltrexone (XR-NTX) block heroin and other opioid agonists competitively for around 4 weeks per administration. XR-NTX thus enables opioid users to experience abstinence from opioid agonists with greatly reduced risk of overdose compared to medication-free abstinence. While XR-NTX has shown promise compared to placebo and daily naltrexone tablets, there is limited information on long-term safety and its performance compared to daily maintenance treatment. METHODS/DESIGN: In this five-hospital RCT with long-term follow-up, we aim to recruit n = 180 patients in treatment for opioid dependence and allocate them in an open, randomized manner (1:1) to receive either 4-week XR-NTX or daily buprenorphine-naloxone (BP-NLX) for the duration of 12 weeks. Allocation is open label due to the risk of overdose during attempts to self-unmask allocation using heroin. Urine drug tests are scheduled every week with follow-up visits & assessment every 4 weeks. Primary outcomes are abstinence from illicit opioids in urine drug tests and self-report, as well as retention in treatment. Secondary outcomes include other substance use, injecting behavior, drug craving, mental health, quality of life, treatment satisfaction, abstinence motivation, opioid agonist effect rating, insomnia, and pain. Observation is continued for another 36 weeks in order to assess longer-term safety, adherence and effectiveness. The study is an investigator-initiated trial, funded by public grants and approved by an Independent Ethical Committee (the Regional Ethical Committee for Research South-East B # 2011/1320) and the Norwegian Medicines Agency. DISCUSSION: Despite minor implementation problems, the protocol appears sufficiently robust to generate results of high interest to patients, clinicians and policy makers. TRIAL REGISTRATION: Clinicaltrials.gov # NCT01717963 , first registered: Oct 28, 2012. Protocol version # 3C, June 12th 2012. PMID- 27121541 TI - Resting Metabolic Rate Is Positively Correlated with Parental Care Behavior in a Dwarf Hamster. AB - Endotherms maintain high and constant body temperatures through the production and maintenance of metabolic heat. Defining the evolutionary history of these thermal adaptations and the selective factors responsible for the evolution of endothermy despite its high metabolic costs have been elusive and controversial topics in evolutionary biology. In this sense, several models have been proposed to explain the evolution of endothermy. Among them, the parental care model explains the increase in resting metabolic rate (RMR) by the action of natural selection favoring parental care. Thus, a positive relationship between parental care behavior and RMR is predicted. However, there appears to be no or little previous work experimentally testing this relationship. In the study presented here, RMR was increased through l-tyrosine injections and parental care behavior was measured. This treatment allowed us to test the relationship between RMR level and parental care behavior in a dwarf hamster. It was found that increased RMR enhanced male parental care. Specifically, male latency time, or the time until contacting and picking up their pups, decreased when RMR increased. This study demonstrates the positive relationship between RMR and the allocation of resources to parental care. This study supports the main assumption of Kotejas's parental care model and accepts Koteja's proposed explanation for the evolution of endothermy as a plausible hypothesis. PMID- 27121542 TI - Analysis of gemini pollen 3 mutant suggests a broad function of AUGMIN in microtubule organization during sexual reproduction in Arabidopsis. AB - In flowering plants, male gametes arise via meiosis of diploid pollen mother cells followed by two rounds of mitotic division. Haploid microspores undergo polar nuclear migration and asymmetric division at pollen mitosis I to segregate the male germline, followed by division of the germ cell to generate a pair of sperm cells. We previously reported two gemini pollen (gem) mutants that produced twin-celled pollen arising from polarity and cytokinesis defects at pollen mitosis I in Arabidopsis. Here, we report an independent mutant, gem3, with a similar division phenotype and severe genetic transmission defects through pollen. Cytological analyses revealed that gem3 disrupts cell division during male meiosis, at pollen mitosis I and during female gametophyte development. We show that gem3 is a hypomorphic allele (aug6-1) of AUGMIN subunit 6, encoding a conserved component in the augmin complex, which mediates microtubule (MT) dependent MT nucleation in acentrosomal cells. We show that MT arrays are disturbed in gem3/aug6-1 during male meiosis and pollen mitosis I using fluorescent MT-markers. Our results demonstrate a broad role for the augmin complex in MT organization during sexual reproduction, and highlight gem3/aug6-1 mutants as a valuable tool for the investigation of augmin-dependent MT nucleation and dynamics in plant cells. PMID- 27121544 TI - Gallstones. PMID- 27121543 TI - Investigation of binding properties of dicationic styrylimidazo[1,2-a]pyridinium dyes to human serum albumin by spectroscopic techniques. AB - The binding interaction between two dicationic styrylimidazo[1,2-a]pyridinium dyes and human serum albumin (HSA) was investigated at physiological conditions using fluorescence, UV-vis absorption, and circular dichroism (CD) spectroscopies. Analysis of the fluorescence titration data at different temperatures suggested that the fluorescence quenching mechanism of HSA by these dyes was static. The calculated thermodynamic parameters (DeltaG degrees , DeltaH degrees and DeltaS degrees ) indicated that hydrogen bonding and van der Waals forces played a major role in the formation of the dye-HSA complex. Binding distances (r) between dyes and HSA were calculated according to Forster's non radiative energy transfer theory. Studies of conformational changes of HSA using CD measurements indicate that the alpha-helical content of the protein decreased upon binding of the dyes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121545 TI - Telephone based cognitive-behavioral screening for frontotemporal changes in patients with amyotrophic lateral sclerosis (ALS). AB - Our objective was to establish a valid and reliable battery of measures to evaluate frontotemporal dementia (FTD) in patients with ALS over the telephone. Thirty-one subjects were administered either in-person or by telephone-based screening followed by the opposite mode of testing two weeks later, using a modified version of the UCSF Cognitive Screening Battery. Equivalence testing was performed for in-person and telephone based tests. The standard ALS Cognitive Behavioral Screen (ALS-CBS) showed statistical equivalence at the 5% significance level compared to a revised phone version of the ALS-CBS. In addition, the Controlled Oral Word Association Test (COWAT) and Center for Neurologic Study Lability Scale (CNS-LS) were also found to be equivalent at the 5% and 10% significance level, respectively. Similarly, the Mini-Mental State Examination (MMSE) and the well-established Telephone Interview for Cognitive Status (TICS) were also statistically equivalent. Equivalence could not be claimed for the ALS Frontal Behavioral Inventory (ALS-FBI) caregiver interview and the Written Verbal Fluency Index (WVFI). In conclusion, our study suggests that telephone-based versions of the ALS-CBS, COWAT, and CNS-LS may offer clinicians valid tools to detect frontotemporal changes in the ALS population. Development of telephone based cognitive testing for ALS could become an integral resource for population based research in the future. PMID- 27121547 TI - A quasi-steady aerodynamic model for flapping flight with improved adaptability. AB - An improved quasi-steady aerodynamic model for flapping wings in hover has been developed. The purpose of this model is to yield rapid predictions of lift generation and efficiency during the design phase of flapping wing micro air vehicles. While most existing models are tailored for a specific flow condition, the present model is applicable over a wider range of Reynolds number and Rossby number. The effects of wing aspect ratio and taper ratio are also considered. The model was validated by comparing against numerical simulations and experimental measurements. Wings with different geometries undergoing distinct kinematics at varying flow conditions were tested during validation. Generally, model predictions of mean force coefficients were within 10% of numerical simulation results, while the deviations in power coefficients could be up to 15%. The deviation is partly due to the model not taking into consideration the initial shedding of the leading-edge vortex and wing-wake interaction which are difficult to account under quasi-steady assumption. The accuracy of this model is comparable to other models in literature, which had to be specifically designed or tuned to a narrow range of operation. In contrast, the present model has the advantage of being applicable over a wider range of flow conditions without prior tuning or calibration, which makes it a useful tool for preliminary performance evaluations. PMID- 27121548 TI - Public Health Education in India - Reforms or Revolution? PMID- 27121546 TI - The role of JAM-B in cancer and cancer metastasis (Review). AB - The junctional adhesion molecule B (JAM-B) is a multifunctional transmembrane protein, which belongs to the immunoglobulin superfamily (IgSF). JAM-B is localized to cell-cell contacts and enriched at cell junctions in epithelial and endothelial cells, as well as on the surface of erythrocytes, leukocytes, and platelets. Recent research in this field has shown that JAM-B plays an important role in numerous cellular processes, such as tight junction assembly, spermatogenesis, regulation of paracellular permeability, leukocytic transmigration, angiogenesis, tumor metastasis and cell proliferation. This study provides a new research direction for the diagnosis and treatment of relevant diseases. In this review, we briefly focus on what is currently known about the structure, function, and mechanism of JAM-B, with particular emphasis on cancer. PMID- 27121551 TI - Poor agreement between diagnostic tests for latent tuberculosis infection among HIV-infected persons in Hong Kong. AB - BACKGROUND AND OBJECTIVE: The tuberculin skin test (TST), T-Spot.TB (T-Spot) and QuantiFERON-TB Gold-In Tube (QFT) were compared in diagnosing latent tuberculosis infection (LTBI) among human immunodeficiency virus (HIV)-infected persons. METHODS: Human immunodeficiency virus-infected persons without previous history of tuberculosis or LTBI were simultaneously tested by TST, T-Spot and QFT annually and followed up for tuberculosis. RESULTS: Among 110 HIV-infected subjects with 85% previous TST screening coverage, 75% on anti-retroviral therapy, well-preserved median CD4 count (414/MUL) and low median viral load (<75/MUL), baseline TST, T-Spot and QFT were positive in 5.5%, 5.6% and 4.9%, respectively, with almost complete discordance of positive results. Among 91 (83%), 66 (60%) and 26 (24%) subjects successfully undergoing the first, second and third annual retesting, TST, T-Spot and QFT were, respectively, positive in 11/123 (8.9%), 13/173 (7.5%) and 21/182 (11.5%) on retesting, with similar discordance of positive results. There was no significant association with the concurrent CD4 count or viral load. Conversion occurred in 11/123 (8.9%), 8/160 (5.0%) and 18/168 (10.7%) of TST, T-Spot and QFT, respectively, and none was associated with changes in CD4 count or viral load. More than half of the positive T-SPOT and QFT results reverted to negative on follow-up. None of these tests picked up the single case of culture-confirmed tuberculosis observed after 798 person-years of follow-up. CONCLUSION: Major discordance in positive results, high reversion rates and low tuberculosis incidence among test-positive subjects cast serious doubt on the utility of the currently available LTBI tests in the annual screening of HIV-infected persons in an intermediate tuberculosis burden area. PMID- 27121550 TI - The estrogenicity of methylparaben and ethylparaben at doses close to the acceptable daily intake in immature Sprague-Dawley rats. AB - The estrogenicity of parabens at human exposure levels has become a focus of concern due to the debate over whether the estrogenicity of parabens is strong enough to play a role in the increased incidence of breast cancer. In this study, the uterotrophic activities of methylparaben (MP) and ethylparaben (EP) at doses close to the acceptable daily intake as allocated by JECFA were demonstrated in immature Sprague-Dawley rats by intragastric administration, and up-regulations of estrogen-responsive biomarker genes were found in uteri of the rats by quantitative real-time RT-PCR (Q-RT-PCR). At the same time, the urinary concentrations of MP and EP, as measured by gas chromatography-mass spectrometry (GC-MS) in rats that received the same doses of MP and EP, were found to be near the high urinary levels reported in human populations in recent years. These results show the in vivo estrogenicity of MP and EP at human exposure levels, and indicate that populations exposed to large amounts of MP and EP may have a high burden of estrogenicity-related diseases. In addition, a molecular docking simulation showed interaction between the parabens and the agonist-binding pocket of human estrogen receptor alpha (hERalpha). PMID- 27121554 TI - Into the Second Year. PMID- 27121553 TI - Identification of ZCCHC8 as fusion partner of ROS1 in a case of congenital glioblastoma multiforme with a t(6;12)(q21;q24.3). AB - Congenital gliobastoma multiforme (GBM) is rare and little is known about the molecular defects underlying the initiation and progression of this tumor type. We present a case of congenital GBM analyzed by conventional cytogenetics, fluorescence in situ hybridization, array comparative genomic hybridization and next generation sequencing. On cytogenetic analysis we detected a reciprocal translocation t(6;12)(q21;q24.3). By sequencing, the translocation was shown to form a fusion between the 5' region of ZCCHC8 and the 3' region of ROS1. RT-PCR analyses confirmed the existence of an in-frame fusion transcript with ZCCHC8 exons 1-3 joined to ROS1 exons 36-43. In addition to the ZCCHC8-ROS1 fusion, we detected a deletion in the short arm of chromosome 9, including homozygous loss of the CDKN2A/2B locus in 9p21.3 and heterozygous deletion of the HAUS6 gene in 9p22.1. The latter encodes a protein involved in faithful chromosome segregation by regulating microtubule nucleation and its deletion might be associated with the marked subclonal changes of ploidy observed in the tumor. This report adds the ZCCHC8-ROS1 fusion as oncogenic driver in GBM and supports the role of ROS1 activation in the pathogenesis of a subset of GBM. (c) 2016 Wiley Periodicals, Inc. PMID- 27121555 TI - Tolerability and Pulmonary Pharmacodynamic Effects During Treatment Initiation of Once-Daily Oral Fingolimod in Subjects With Moderate Asthma. AB - Fingolimod, a first-in-class sphingosine 1-phosphate receptor modulator, is the first approved oral therapy for relapsing multiple sclerosis (MS). While treatment initiation of clinical dose of fingolimod (0.5 mg) does not affect pulmonary function, supra-therapeutic doses (>=5.0 mg) increased airway resistance. The aim of this double-blind, placebo-controlled, parallel group, 10 day study was to measure the effect of fingolimod on pulmonary function in otherwise healthy patients with moderate asthma. Subjects (n = 36) were randomized into four cohorts that received either fingolimod 0.5, 1.25, 2.5 mg, or placebo once daily for 10 days. Subjects in placebo and fingolimod 0.5 mg groups did not differ in FEV1 AUEC0-6 h , FEF25-75% AUEC0-6 h , or in short acting beta (beta) 2 agonists (SABA, rescue bronchodilator) use. Subjects on higher doses of fingolimod showed a mild reduction in FEV1 AUEC0-6 h and FEF25 75% AUEC0-6 h and a significant sixfold increase in SABA use versus placebo. One subject had moderately severe, acute exacerbation of asthma after receiving the first dose of fingolimod 1.25 mg that quickly responded to inhaled SABA. The observed safety profile was consistent with previous reports. These results provide reassurance that moderately asthmatic MS individuals can start on fingolimod 0.5 mg therapy with minimal effects on pulmonary function and SABA use. PMID- 27121552 TI - Triple-acting Lytic Enzyme Treatment of Drug-Resistant and Intracellular Staphylococcus aureus. AB - Multi-drug resistant bacteria are a persistent problem in modern health care, food safety and animal health. There is a need for new antimicrobials to replace over used conventional antibiotics. Here we describe engineered triple-acting staphylolytic peptidoglycan hydrolases wherein three unique antimicrobial activities from two parental proteins are combined into a single fusion protein. This effectively reduces the incidence of resistant strain development. The fusion protein reduced colonization by Staphylococcus aureus in a rat nasal colonization model, surpassing the efficacy of either parental protein. Modification of a triple-acting lytic construct with a protein transduction domain significantly enhanced both biofilm eradication and the ability to kill intracellular S. aureus as demonstrated in cultured mammary epithelial cells and in a mouse model of staphylococcal mastitis. Interestingly, the protein transduction domain was not necessary for reducing the intracellular pathogens in cultured osteoblasts or in two mouse models of osteomyelitis, highlighting the vagaries of exactly how protein transduction domains facilitate protein uptake. Bacterial cell wall degrading enzyme antimicrobials can be engineered to enhance their value as potent therapeutics. PMID- 27121556 TI - Effects of Trastuzumab Emtansine (T-DM1) on QT Interval and Safety of Pertuzumab Plus T-DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. AB - Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in development for human epidermal growth factor receptor 2 (HER2)-positive cancer. Drugs in development are generally tested for their effects on QT interval, prolongation of which is associated with the potentially fatal arrhythmia torsades de pointes. In addition, an association between left ventricular dysfunction and other HER2 directed agents has been documented. This multicenter, phase 2 study, TDM4688g, assessed the safety and pharmacokinetic characteristics of T-DM1 (3.6 mg/kg every 3 weeks) in patients with previously treated HER2-positive metastatic breast cancer, and the safety of pertuzumab plus T-DM1, an anti-HER2 extracellular domain antibody, in patients with early disease progression on T-DM1 alone. The primary end point was the change in QTc interval from baseline to each postbaseline time point, adjusted for heart rate using Fridericia's correction. T DM1 had no clinically relevant effect on QTc interval. The observed upper limit of the one-sided 95% confidence interval was below the 10-millisecond threshold of safety concern. The safety and efficacy of single-agent T-DM1 was consistent with that observed in previous studies. Pertuzumab plus T-DM1 was generally well tolerated with no new safety signals. These results support further investigation of T-DM1 as a single agent and with pertuzumab. PMID- 27121557 TI - Pharmacokinetic Studies in Healthy Subjects for the Development of an Extended Release Tablet Formulation of Guaifenesin: A 505(b)(2) New Drug Application Approval. AB - Guaifenesin is an expectorant used to improve mucociliary clearance (MCC) and relieve chest congestion from upper respiratory tract infections. Immediate release (IR) guaifenesin requires dosing every 4 hours to maintain efficacy because of the drug's short half-life. Extended-release (ER) guaifenesin has been developed to prolong efficacy and reduce dosing frequency. As part of the 505(b)(2) new drug application (NDA), the pharmacokinetics (PK) of an ER bi-layer tablet formulation of guaifenesin (Mucinex(r)) and bioequivalence to an over-the counter (OTC) monograph IR formulation were evaluated in healthy subjects. In one study, subjects received 1,200 mg ER guaifenesin every 12 hours or 400 mg IR guaifenesin every 4 hours for 6 days. Steady-state exposures were equivalent between the two products, as demonstrated by AUC and Cmax . In another study, subjects received a single dose of 600 mg (fasted) or 1,200 mg (fasted or fed) ER bi-layer tablet formulations. AUC and Cmax were equivalent between both states for the 1,200 mg ER dose. However, Tmax of 1,200 mg ER guaifenesin was later in the fed than the fasted state. ER guaifenesin is bioequivalent to corresponding OTC monograph doses of IR guaifenesin. ER guaifenesin offers a convenient 12-hour dosing alternative to 4-hour dosing of IR guaifenesin. PMID- 27121558 TI - Bioavailability of Clindamycin From a New Clindamycin Phosphate 1.2%-Benzoyl Peroxide 3% Combination Gel. AB - A new topical fixed-dose combination product containing clindamycin (1%, formulated as 1.2% clindamycin phosphate, CLNP 1.2%) with low strength (3%) benzoyl peroxide (BPO) in a methylparaben-free gel vehicle (CLNP 1.2%-BPO 3%-MPF) has been developed for the treatment of acne. The objective of this study was to determine the relative bioavailability of clindamycin and clindamycin sulfoxide from CLNP 1.2%-BPO 3%-MPF compared with clindamycin phosphate 1.2%-BPO 5% in a methylparaben-preserved gel vehicle (CLNP 1.2%-BPO 5%-MP) and clindamycin phosphate 1.2%-BPO 5% in a methylparaben-free gel vehicle (CLNP 1.2%-BPO 5%-MPF), and to determine whether exposure is affected by BPO concentration (3% vs. 5%) when applied topically. Seventy-two subjects with moderate-severe acne were randomized to receive CLNP 1.2%-BPO 3%-MPF, CLNP 1.2%-BPO 5%-MP, or CLNP 1.2%-BPO 5%-MPF in a 5-day, open-label, and parallel-group study. Cmax and AUC values for clindamycin were highest for CLNP 1.2%-BPO 5%-MP, followed by CLNP 1.2%-BPO 3% MPF and CLNP 1.2%-BPO 5%-MPF, but differences were not statistically significant. Systemic exposure to clindamycin and clindamycin sulfoxide was low and comparable between the formulations. Results indicate that differences in BPO concentration do not influence clindamycin bioavailability. PMID- 27121559 TI - Liposomal Amphotericin B for the Treatment of Cryptococcal Meningitis in HIV/AIDS Patients in India-A Pilot Pharmacokinetic Study. AB - The liposomal formulation of amphotericin B greatly reduces side effects like nephrotoxicity. The present pilot study describes the pharmacokinetic characteristics of liposomal Amp B given to eight patients of cryptococcal meningitis with HIV/AIDS at a dose of 1 and 3 mg/kg/day. We observed that the pharmacokinetic parameters namely AUC, Cmax , CL, Vd, and half-life were not proportionate with 1 and 3 mg/kg/day dose of FungiosmeTM. With 1 and 3 mg/kg/day dose the mean Cmax was found to be 626.54 +/- 39.26 and 1049.90 +/- 742.75 ng/mL, respectively. In conclusion, liposomal Amp B was observed to be safe and efficacious in the treatment of cryptococcal meningitis in HIV/AIDS patients, however, a pharmacokinetics study with larger cohort of patients of cryptococcal meningitis in HIV AIDS is warranted. PMID- 27121560 TI - A Randomized Phase I Evaluation of CTP-499, a Novel Deuterium-Containing Drug Candidate for Diabetic Nephropathy. AB - To determine maximum tolerated dose and food effect for CTP-499, a novel agent being studied for the treatment of diabetic kidney disease. CTP-499 has demonstrated anti-inflammatory, anti-fibrotic and anti-oxidative activities in vitro as well as anti-inflammatory and renoprotective effects in a diabetic nephropathy (DN) model. Two studies were performed. Study 1 was a single-dose escalation study with 600, 1200, 1800, and 2400 mg doses of controlled-release (CR) CTP-499 and a 400 mg immediate release dose to aid in the development of prototype formulations of CTP-499. Study 2 was a food-effect study. Plasma concentrations of CTP-499 and its metabolites were measured to determine pharmacokinetic parameters in each study. Safety was assessed to determine tolerability. Doses up to and including 1800 mg were well tolerated. Cmax was either equivalent (CTP-499) or slightly lower (metabolites) for the fed condition, while overall exposure was equivalent (CTP-499) or slightly higher (metabolites) for the fed condition. The range of tolerated doses of CTP-499 and the effects of food on exposure were identified, contributing to selection of the dose for Phase II development. PMID- 27121561 TI - Influence of CYP3A5 6986A > G and ABCB1 3435C > T Polymorphisms on Adverse Events Associated With Tacrolimus in Jordanian Pediatric Renal Transplant Patients. AB - The aim of the study is to investigate the influence of ABCB1(3435) and CYP3A5(6986) polymorphisms, tacrolimus troughs and clinical factors on the time of adverse events associated with tacrolimus in pediatric kidney transplant patients. Clinical data, adverse events, tacrolimus troughs, corresponding doses, ABCB1 3435C > T and CYP3A5 6986A > G genotypes were collected from 38 pediatric kidney transplant patients in a retrospective study for over 2 years post transplant. We used a marginal Cox proportional hazard model to evaluate the influence of clinical factors and single nucleotide polymorphisms (SNPs) on tacrolimus-associated adverse events. CYP3A5 genotype, the Bayesian predicted tacrolimus concentrations, hematocrit and mean corpuscular volume are significant risk factors of adverse events over a 2-year-period. CYP3A5*1 genotype was associated with 36% relative risk of CYP3A5*3/*3 genotype. In the 9-month period, the additional factor, ABCB1 3435TT genotype, was shown to be associated with 38% relative risk of the CC and CT genotypes. For graft loss, acute and chronic rejection, only tacrolimus concentration and hematocrit, but not CYP3A5 or ABCB1 polymorphisms, are important factors influencing their occurrences. PMID- 27121562 TI - Absolute Bioavailability and Effect of Food on the Disposition of Safinamide Immediate Release Tablets in Healthy Adult Subjects. AB - The objectives of this study were to establish the basic intravenous (IV) single dose PK of safinamide and its major human metabolites, the absolute bioavailability (BA) and food effect on safinamide tablets. Fourteen healthy adult male and female subjects received 50 mg safinamide single-dose treatments according to a randomized, 3-period, 2-sequence crossover design: immediate release (IR) tablets, administered after an overnight fast and after a standardized high-fat, high-calorie breakfast, and IV solution, administered over 30 minutes. Treatments were separated by wash-out intervals of at least 17 days. Serial blood samples were collected for 240 hours postdosing to evaluate safinamide parent drug and metabolite concentrations for the determination of PK parameters. The absolute BA of safinamide 50 mg IR tablets was high, with geoMean AUC0-infinity ratios of about 95% (90% CI: 90-99%) indicating that safinamide is virtually completely absorbed after oral administration. Safinamide IR tablets did not display a food effect on exposure parameters; both 90% CIs for the ratios fed/fasted of AUC0-infinity and Cmax were entirely within the bioequivalence acceptance margins of 80-125%. Only tmax was delayed by about 30% in the fed state. Oral and IV safinamide 50 mg single-dose administrations were generally well tolerated. PMID- 27121563 TI - The Influence of Multiple-Dose Vorapaxar, an Oral PAR-1 Receptor Antagonist, on the Single-Dose Pharmacokinetics and Pharmacodynamics of Digoxin. AB - Vorapaxar is a novel orally active thrombin receptor antagonist selective for the PAR-1 receptor. This open-label, single-center, fixed-sequence, 2-period, 2 treatment study assessed the pharmacokinetics and pharmacodynamics of single-dose digoxin in the presence/absence of multiple-dose vorapaxar. Eighteen healthy adult subjects received two treatments in a fixed sequence separated by >=8-day washout: (A) digoxin 0.5 mg (Day 1); (B) vorapaxar 2.5 mg/day Days 1-6 and single dose vorapaxar 40 mg administered with single-dose digoxin 0.5 mg Day 7. The geometric mean ratio (%; GMR) for the two treatments (digoxin alone and digoxin plus vorapaxar) and 90% confidence intervals (CIs) for and AUCtf and Cmax of digoxin were calculated. Pharmacodynamics of digoxin was assessed by measuring changes in electrocardiogram (ECG) parameters. The GMR (90% CIs) estimates for digoxin AUCtf and Cmax were 105% (91, 121) and 154% (130, 181), respectively. Except for differences in peak plasma concentrations, the pharmacokinetics of digoxin were similar between the two treatments. Coadministration of vorapaxar plus digoxin had no effect on digoxin Tmax or ECG parameters. The results of this study suggest that the coadministration of vorapaxar and digoxin is unlikely to cause a clinically significant drug-drug interaction. PMID- 27121564 TI - ERRATUM. PMID- 27121565 TI - Myelodysplastic syndrome associated with acquired beta thalassemia: "BTMDS". PMID- 27121567 TI - Expression and clinical significance of aquaglyceroporins in human hepatocellular carcinoma. AB - Aquaglyceroporins (AQPs) are a subset of the aquaporin family, and are permeable to water and glycerol. The aim of the present study was to determine the expression and clinical significance of three AQPs, AQP3, 7 and 9 in hepatocellular carcinoma (HCC). Fresh HCC and adjacent non-tumorous liver tissues were collected from 68 patients diagnosed with HCC. The expression levels of AQP3, 7 and 9 were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemical analysis. The association between the expression of AQPs and clinicopathological parameters of HCC were investigated. Compared with non-tumorous liver tissue, HCC tissues exhibited a significant (P<0.05) increase in the expression of AQP3 and a concomitant reduction in the expression levels of AQP7 and AQP9, at both the mRNA and protein levels. Immunohistochemistry revealed that AQP9 was dominantly localized on the plasma membrane of hepatocytes, while AQP3 and AQP7 exhibited a predominantly cytoplasmic and nuclear distribution. High expression of AQP3 was significantly (P<0.05) associated with low expression levels of AQP7 and AQP9. High expression of AQP3 was correlated with tumor grade (P=0.017), tumor stage (P=0.010) and lymphatic metastasis (P=0.031). Low expression of AQP7 was correlated with tumor grade (P=0.043). AQP3 was upregulated, and AQP7 and AQP9 were downregulated in HCC. A high expression of AQP3 and low expression of AQP7 was significantly associated with the aggressive features of HCC. PMID- 27121569 TI - Outcome improvement of patients with heart failure and reduced ejection fraction: has it ended in the new millennium? PMID- 27121568 TI - A PARP1-ERK2 synergism is required for the induction of LTP. AB - Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene expression and LTP generation in hippocampal CA3-CA1-connections. Moreover, a predominant binding of PARP1 to single-strand DNA breaks, occluding its Erk binding sites, suppressed IEG expression and prevented the generation of LTP. These findings outline a PARP1-dependent mechanism required for LTP generation, which may be implicated in long-term memory acquisition and in its deterioration in senescence. PMID- 27121570 TI - Discrepancy between long-term and previously published analysis for osteonecrosis of the jaw under denosumab. PMID- 27121571 TI - Immunohistochemical localization of cocaine- and amphetamine-regulated transcript peptide (CARTp) in the brain of the pigeon (Columba livia) and zebra finch (Taeniopygia guttata). AB - Cocaine- and amphetamine-regulated transcript peptides (CARTp) are neuropeptides that act as neurotransmitters in the brain of vertebrates. The expression of CARTp has been characterized in teleosts, amphibians, and several mammalian species, but comparative data in reptiles and birds are nonexistent. In this study, we show the distribution of immunoreactivity against CART peptides (CARTp ir) in the brains of two bird species: the pigeon (Columba livia) and zebra finch (Taeniopygia guttata). We found CARTp-ir cells and terminals in the brains of both, but no major differences between the two species. As in mammals, teleost fish, and amphibians, CARTp-ir terminals and cells were abundant in subpallial regions, particularly the striatum and nucleus accumbens. We also found CARTp-ir cells and terminals in the hypothalamus, and a large number of CARTp-ir terminals in the substantia nigra, ventral tegmental area, periaqueductal gray, parabrachial nucleus, and dorsal vagal complex. However, in contrast to other vertebrates, CARTp-ir was not found in the olfactory bulb. In addition there was almost no CARTp-ir in the pallium or the hippocampal formation, and little CARTp ir in the cerebellum. The conserved expression of CARTp in the subpallium, hypothalamus, and dorsal vagal complex of birds suggests that some of the functions of CARTp, such as regulation of food intake and interactions with the social control network and mesolimbic reward system, are conserved among vertebrates. J. Comp. Neurol. 524:3747-3773, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27121572 TI - Microbial pathogen quality criteria of rendered products. AB - The North American rendering industry processes approximately 24 million metric tons (Mt) of raw materials and produces more than 8 million Mt of rendered products. More than 85 % of rendered products produced annually in the USA are used for producing animal feed. Pathogen contamination in rendered products is an important and topical issue. Although elevated temperatures (115-140 degrees C) for 40-90 min during the standard rendering processes are mathematically sufficient to completely destroy commonly found pathogens, the presence of pathogens in rendered products has nevertheless been reported. Increased concern over the risk of microbial contamination in rendered products may require additional safeguards for producing pathogen-free rendered products. This study provides an overview of rendered products, existing microbial pathogen quality criteria of rendered products (MPQCR), limitations, and the scope of improving the MPQCR. PMID- 27121573 TI - Relationship between mycoparasites lifestyles and biocontrol behaviors against Fusarium spp. and mycotoxins production. AB - Global food security research is seeking eco-friendly solutions to control mycotoxins in grain infected by fungi (molds). In particular, mycotoxigenic Fusarium spp. outbreak is a chronic threat for cereal grain production, human, and animal health. In this review paper, we discuss up-to-date biological control strategies in applying mycoparasites as biological control agents (BCA) to prevent plant diseases in crops and mycotoxins in grain, food, and feed. The aim is to increase food safety and to minimize economic losses due to the reduced grain yield and quality. However, recent papers indicate that the study of the BCA specialists with biotrophic lifestyle lags behind our understanding of the BCA generalists with necrotrophic lifestyle. We examine critical behavioral traits of the two BCA groups of mycoparasites. The goal is to highlight their major characteristics in the context of future research towards an efficient biocontrol strategy against mycotoxin-producing Fusarium species. The emphasis is put on biocontrol of Fusarium graminearum, F. avenaceum, and F. culmorum causing Fusarium head blight (FHB) in cereals and their mycotoxins. PMID- 27121574 TI - Tactile length contraction as Bayesian inference. AB - To perceive, the brain must interpret stimulus-evoked neural activity. This is challenging: The stochastic nature of the neural response renders its interpretation inherently uncertain. Perception would be optimized if the brain used Bayesian inference to interpret inputs in light of expectations derived from experience. Bayesian inference would improve perception on average but cause illusions when stimuli violate expectation. Intriguingly, tactile, auditory, and visual perception are all prone to length contraction illusions, characterized by the dramatic underestimation of the distance between punctate stimuli delivered in rapid succession; the origin of these illusions has been mysterious. We previously proposed that length contraction illusions occur because the brain interprets punctate stimulus sequences using Bayesian inference with a low velocity expectation. A novel prediction of our Bayesian observer model is that length contraction should intensify if stimuli are made more difficult to localize. Here we report a tactile psychophysical study that tested this prediction. Twenty humans compared two distances on the forearm: a fixed reference distance defined by two taps with 1-s temporal separation and an adjustable comparison distance defined by two taps with temporal separation t <= 1 s. We observed significant length contraction: As t was decreased, participants perceived the two distances as equal only when the comparison distance was made progressively greater than the reference distance. Furthermore, the use of weaker taps significantly enhanced participants' length contraction. These findings confirm the model's predictions, supporting the view that the spatiotemporal percept is a best estimate resulting from a Bayesian inference process. PMID- 27121575 TI - Elucidating the neural circuitry underlying planning of internally-guided voluntary action. AB - In an attempt to elucidate the neural circuitry of planning of internally guided voluntary action, Ariani et al. (2015) used a delayed-movement design and multivariate pattern analysis of functional MRI data and found areas decoding internally elicited action plans, stimulus-elicited action plans, and both types of plans. In interpreting their results in the context of a heuristic decision model of voluntary action, encompassing "what" action to perform, "when" to perform it, and "whether" to perform it at all, we highlight at least some neural dissociation of these components. More to that, we note that the exact neural circuitry of each component might vary depending on the performed action type, and finally, we underscore the importance of understanding the temporal specifics of such circuitries to further elucidate how they are involved and interact during voluntary action planning. PMID- 27121576 TI - Synchronized gamma-frequency inhibition in neocortex depends on excitatory inhibitory interactions but not electrical synapses. AB - Synaptic inhibition plays a crucial role in the precise timing of spiking activity in the cerebral cortex. Synchronized, rhythmic inhibitory activity in the gamma (30-80 Hz) range is thought to be especially important for the active, information-processing neocortex, but the circuit mechanisms that give rise to synchronized inhibition are uncertain. In particular, the relative contributions of reciprocal inhibitory connections, excitatory-inhibitory interactions, and electrical synapses to precise spike synchrony among inhibitory interneurons are not well understood. Here we describe experiments on mouse barrel cortex in vitro as it spontaneously generates slow (<1 Hz) oscillations (Up and Down states). During Up states, inhibitory postsynaptic currents (IPSCs) are generated at gamma frequencies and are more synchronized than excitatory postsynaptic currents (EPSCs) among neighboring pyramidal cells. Furthermore, spikes in homotypic pairs of interneurons are more synchronized than in pairs of pyramidal cells. Comparing connexin36 knockout and wild-type animals, we found that electrical synapses make a minimal contribution to synchronized inhibition during Up states. Estimations of the delays between EPSCs and IPSCs in single pyramidal cells showed that excitation often preceded inhibition by a few milliseconds. Finally, tonic optogenetic activation of different interneuron subtypes in the absence of excitation led to only weak synchrony of IPSCs in pairs of pyramidal neurons. Our results suggest that phasic excitatory inputs are indispensable for synchronized spiking in inhibitory interneurons during Up states and that electrical synapses play a minimal role. PMID- 27121577 TI - A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons. AB - The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182-187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41-51, 1986). Kalluri et al. (J Neurophysiol 104: 2034-2051, 2010) proposed that regularity is controlled by the density of low-voltage activated potassium currents (IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium (gNa), low voltage-activated potassium (gKL), and high-voltage-activated potassium (gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking. PMID- 27121578 TI - CaMKII mediates stimulus specificity in early odor preference learning in rats. AB - After naturalistic odor preference training, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) was rapidly phosphorylated in the olfactory bulb, specifically in the odor encoding regions of the glomerular layer and external plexiform layer. Intrabulbar CaMKII antagonist experiments revealed that CaMKII supports short- and long-term preference memory formation. With bulbar PKA activation as the unconditioned stimulus odor preferences could be induced despite CaMKII blockade, but now odor specificity was lost, with odor preference generalizing to an untrained odor. Odor-specific learning was associated with increased membrane associated AMPA receptors, while nonspecific odor preference was not. Thus CaMKII activation provides a tag to confer stimulus specificity as well as supporting natural odor preference learning. PMID- 27121579 TI - Hypothesis: Hughlings Jackson and presynaptic inhibition: is there a big picture? AB - Presynaptic inhibition is a very powerful inhibitory mechanism and, despite many detailed studies, its purpose is still only partially understood. One accepted function is that, by reducing afferent inflow to the spinal cord and brainstem, the tonic level of presynaptic inhibition prevents sensory systems from being overloaded. A corollary of this function is that much of the incoming sensory data from peripheral receptors must be redundant, and this conclusion is reinforced by observations on patients with sensory neuropathies or congenital obstetric palsy in whom normal sensation may be preserved despite loss of sensory fibers. The modulation of incoming signals by presynaptic inhibition has a further function in operating a "gate" in the dorsal horn, thereby determining whether peripheral stimuli are likely to be perceived as painful. On the motor side, the finding that even minimal voluntary movement of a single toe is associated with widespread inhibition in the lumbosacral cord points to another function for presynaptic inhibition: to prevent reflex perturbations from interfering with motor commands. This last function, together with the normal suppression of muscle and cutaneous reflex activity at rest, is consistent with Hughlings Jackson's concept of evolving neural hierarchies, with each level inhibiting the one below it. PMID- 27121580 TI - Target size matters: target errors contribute to the generalization of implicit visuomotor learning. AB - The process of sensorimotor adaptation is considered to be driven by errors. While sensory prediction errors, defined as the difference between the planned and the actual movement of the cursor, drive implicit learning processes, target errors (e.g., the distance of the cursor from the target) are thought to drive explicit learning mechanisms. This distinction was mainly studied in the context of arm reaching tasks where the position and the size of the target were constant. We hypothesize that in a dynamic reaching environment, where subjects have to hit moving targets and the targets' dynamic characteristics affect task success, implicit processes will benefit from target errors as well. We examine the effect of target errors on learning of an unnoticed perturbation during unconstrained reaching movements. Subjects played a Pong game, in which they had to hit a moving ball by moving a paddle controlled by their hand. During the game, the movement of the paddle was gradually rotated with respect to the hand, reaching a final rotation of 25 degrees . Subjects were assigned to one of two groups: The high-target error group played the Pong with a small ball, and the low-target error group played with a big ball. Before and after the Pong game, subjects performed open-loop reaching movements toward static targets with no visual feedback. While both groups adapted to the rotation, the postrotation reaching movements were directionally biased only in the small-ball group. This result provides evidence that implicit adaptation is sensitive to target errors. PMID- 27121581 TI - Influence of cortical synaptic input on striatal neuronal dendritic arborization and sensitivity to excitotoxicity in corticostriatal coculture. AB - Corticostriatal cocultures are utilized to recapitulate the cortex-striatum connection in vitro as a convenient model to investigate the development, function, and regulation of synapses formed between cortical and striatal neurons. However, optimization of this dissociated neuronal system to more closely reproduce in vivo circuits has not yet been explored. We studied the effect of varying the plating ratio of cortical to striatal neurons on striatal spiny projection neuron (SPN) characteristics in primary neuronal cocultures. Despite the large difference in cortical-striatal neuron ratio (1:1 vs. 1:3) at day of plating, by 18 days in vitro the difference became modest (~25% lower cortical-striatal neuron ratio in 1:3 cocultures) and the neuronal density was lower in the 1:3 cocultures, indicating enhanced loss of striatal SPNs. Comparing SPNs in cocultures plated at a 1:1 vs. 1:3 ratio, we found that resting membrane potential, input resistance, current injection-induced action potential firing rates, and input-output curves were similar in the two conditions. However, SPNs in the cocultures plated at the lower cortical ratio exhibited reduced membrane capacitance along with significantly shorter total dendritic length, decreased dendritic complexity, and fewer excitatory synapses, consistent with their trend toward reduced miniature excitatory postsynaptic current frequency. Strikingly, the proportion of NMDA receptors found extrasynaptically in recordings from SPNs was significantly higher in the less cortical coculture. Consistently, SPNs in cocultures with reduced cortical input showed decreased basal pro-survival signaling through cAMP response element binding protein and enhanced sensitivity to NMDA-induced apoptosis. Altogether, our study indicates that abundance of cortical input regulates SPN dendritic arborization and survival/death signaling. PMID- 27121582 TI - Granule cell excitability regulates gamma and beta oscillations in a model of the olfactory bulb dendrodendritic microcircuit. AB - Odors evoke gamma (40-100 Hz) and beta (20-30 Hz) oscillations in the local field potential (LFP) of the mammalian olfactory bulb (OB). Gamma (and possibly beta) oscillations arise from interactions in the dendrodendritic microcircuit between excitatory mitral cells (MCs) and inhibitory granule cells (GCs). When cortical descending inputs to the OB are blocked, beta oscillations are extinguished whereas gamma oscillations become larger. Much of this centrifugal input targets inhibitory interneurons in the GC layer and regulates the excitability of GCs, which suggests a causal link between the emergence of beta oscillations and GC excitability. We investigate the effect that GC excitability has on network oscillations in a computational model of the MC-GC dendrodendritic network with Ca(2+)-dependent graded inhibition. Results from our model suggest that when GC excitability is low, the graded inhibitory current mediated by NMDA channels and voltage-dependent Ca(2+) channels (VDCCs) is also low, allowing MC populations to fire in the gamma frequency range. When GC excitability is increased, the activation of NMDA receptors and other VDCCs is also increased, allowing the slow decay time constants of these channels to sustain beta-frequency oscillations. Our model argues that Ca(2+) flow through VDCCs alone could sustain beta oscillations and that the switch between gamma and beta oscillations can be triggered by an increase in the excitability state of a subpopulation of GCs. PMID- 27121583 TI - Frequency-specific insight into short-term memory capacity. AB - The digit span is one of the most widely used memory tests in clinical and experimental neuropsychology for reliably measuring short-term memory capacity. In the forward version, sequences of digits of increasing length have to be reproduced in the order in which they are presented, whereas in the backward version items must be reproduced in the reversed order. Here, we assessed whether transcranial alternating current stimulation (tACS) increases the memory span for digits of young and midlife adults. Imperceptibly weak electrical currents in the alpha (10 Hz), beta (20 Hz), theta (5 Hz), and gamma (40 Hz) range, as well as a sham stimulation, were delivered over the left posterior parietal cortex, a cortical region thought to sustain maintenance processes in short-term memory through oscillatory brain activity in the beta range. We showed a frequency specific effect of beta-tACS that robustly increased the forward memory span of young, but not middle-aged, healthy individuals. The effect correlated with age: the younger the subjects, the greater the benefit arising from parietal beta stimulation. Our results provide evidence of a short-term memory capacity improvement in young adults by online frequency-specific tACS application. PMID- 27121585 TI - Taste coding of complex naturalistic taste stimuli and traditional taste stimuli in the parabrachial pons of the awake, freely licking rat. AB - Several studies have shown that taste-responsive cells in the brainstem taste nuclei of rodents respond to sensory qualities other than gustation. Such data suggest that cells in the classical gustatory brainstem may be better tuned to respond to stimuli that engage multiple sensory modalities than to stimuli that are purely gustatory. Here, we test this idea by recording the electrophysiological responses to complex, naturalistic stimuli in single neurons in the parabrachial pons (PbN, the second neural relay in the central gustatory pathway) in awake, freely licking rats. Following electrode implantation and recovery, we presented both prototypical and naturalistic taste stimuli and recorded the responses in the PbN. Prototypical taste stimuli (NaCl, sucrose, citric acid, and caffeine) and naturalistic stimuli (clam juice, grape juice, lemon juice, and coffee) were matched for taste quality and intensity (concentration). Umami (monosodium glutamate + inosine monophosphate) and fat (diluted heavy cream) were also tested. PbN neurons responded to naturalistic stimuli as much or more than to prototypical taste stimuli. Furthermore, they convey more information about naturalistic stimuli than about prototypical ones. Moreover, multidimensional scaling analyses showed that across unit responses to naturalistic stimuli were more widely separated than responses to prototypical taste stimuli. Interestingly, cream evoked a robust and widespread response in PbN cells. Collectively, these data suggest that natural foods are more potent stimulators of PbN cells than purely gustatory stimuli. Probing PbN cells with pure taste stimuli may underestimate the response repertoire of these cells. PMID- 27121584 TI - Auditory Golgi cells are interconnected predominantly by electrical synapses. AB - The mossy fiber-granule cell-parallel fiber system conveys proprioceptive and corollary discharge information to principal cells in cerebellum-like systems. In the dorsal cochlear nucleus (DCN), Golgi cells inhibit granule cells and thus regulate information transfer along the mossy fiber-granule cell-parallel fiber pathway. Whereas excitatory synaptic inputs to Golgi cells are well understood, inhibitory and electrical synaptic inputs to Golgi cells have not been examined. Using paired recordings in a mouse brain slice preparation, we find that Golgi cells of the cochlear nucleus reliably form electrical synapses onto one another. Golgi cells were only rarely electrically coupled to superficial stellate cells, which form a separate network of electrically coupled interneurons in the DCN. Spikelets had a biphasic effect on the excitability of postjunctional Golgi cells, with a brief excitatory phase and a prolonged inhibitory phase due to the propagation of the prejunctional afterhyperpolarization through gap junctions. Golgi cells and stellate cells made weak inhibitory chemical synapses onto Golgi cells with low probability. Electrical synapses are therefore the predominant form of synaptic communication between auditory Golgi cells. We propose that electrical synapses between Golgi cells may function to regulate the synchrony of Golgi cell firing when electrically coupled Golgi cells receive temporally correlated excitatory synaptic input. PMID- 27121586 TI - Simultaneous determination of paeoniflorin from total glucosides of paeony in Sprague-Dawley rats and spontaneously hypertensive rats by high-performance liquid chromatography-tandem mass spectrometry: in vivo and in vitro studies. AB - Paeoniflorin is a well-known monoterpene glucoside in the herbal drug that exhibits a number of biological activities. The pharmacokinetic characteristics of paeoniflorin from total glucosides of paeony in spontaneously hypertensive rats (SHR) are still unclear. It is essential to investigate the in vivo and in vitro pharmacokinetic differences of paeoniflorin from total glucosides of paeony in Sprague-Dawley (SD) and SHR. The in vivo pharmacokinetic data were analyzed using DAS 2.0 software and the in vitro metabolic characteristics were measured using rat hepatic microsomes. The concentration of paeoniflorin in biological samples was determined using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry method, which showed good precision and stability. The plasma concentration-time profiles of paeoniflorin following oral administration of total glucosides of paeony showed a single peak and there were significant differences in the mean values of AUC(0-t) , AUC(0-infinity) , CLz /F and Tmax between SD and SHR (p < 0.05). The metabolic rate of paeoniflorin from total glucosides of paeony was slower in SHR than in SD rats (p < 0.05). The results might be useful in further applications of paeoniflorin and total glucosides of paeony. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121587 TI - Relocation potentiates obesity and cardiovascular risk: A case-control study on relocatees from the Three Gorges area. PMID- 27121589 TI - Effects of nitrogen on the apoptosis of and changes in gene expression in human lymphoma U937 cells exposed to argon-based cold atmospheric pressure plasma. AB - Cold atmospheric pressure plasma (CAP) is known as a source of biologically active agents, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). In the present study, we examined the effects of nitrogen (N2) on the apoptosis of and changes in gene expression in human lymphoma U937 cells exposed to argon (Ar)-CAP. Enormous amounts of hydroxyl (.OH) radicals in aqueous solution were produced using Ar-CAP generated using a 20 kHz low frequency at 18 kV with a flow rate of 2 l/min. The increase in the levels of .OH radicals was significantly attenuated by the addition of N2 to Ar gas. On the other hand, the level of total nitrate/nitrite in the supernatant was significantly elevated in the Ar + N2-CAP-exposed U937 cells. When the cells were exposed to Ar-CAP, a significant increase in apoptosis was observed, whereas apoptosis was markedly decreased in the cells exposed to Ar + N2-CAP. Microarray and pathway analyses revealed that a newly identified gene network containing a number of heat shock proteins (HSPs), anti-apoptotic genes, was mainly associated with the biological function of the prevention of apoptosis. Quantitative PCR revealed that the expression levels of HSPs were significantly elevated in the cells exposed to Ar + N2-CAP than those exposed to Ar-CAP. These results indicate that N2 gas in Ar CAP modifies the ratio of ROS to RNS, and suppresses the apoptosis induced by Ar CAP. The modulation of gaseous conditions in CAP may thus prove to be useful for future clinical applications, such as for switching from a sterilizing mode to cytocidal effect for cancer cells. PMID- 27121591 TI - Sparse data bias: a problem hiding in plain sight. PMID- 27121590 TI - Sparse (13)C labelling for solid-state NMR studies of P. pastoris expressed eukaryotic seven-transmembrane proteins. AB - We demonstrate a novel sparse (13)C labelling approach for methylotrophic yeast P. pastoris expression system, towards solid-state NMR studies of eukaryotic membrane proteins. The labelling scheme was achieved by co-utilizing natural abundance methanol and specifically (13)C labelled glycerol as carbon sources in the expression medium. This strategy improves the spectral resolution by 1.5 fold, displays site-specific labelling patterns, and has advantages for collecting long-range distance restraints for structure determination of large eukaryotic membrane proteins by solid-state NMR. PMID- 27121592 TI - Impact of Therapeutic Plasma Exchange on Hemodynamic Parameters in Medical Intensive Care Unit Patients: An Observational Study. AB - Therapeutic plasma exchange (TPE) is an extracorporeal treatment with reported beneficial as well as detrimental effects on circulation. However, there is a lack of data using advanced hemodynamic monitoring during TPE. Therefore, we investigated the effects of TPE on hemodynamic parameters derived from transpulmonary thermodilution (TPTD) as well as the risk for transfusion-related acute lung injury (TRALI). We compared hemodynamic parameters obtained before and after a total of 30 sessions of TPE treatment in 10 intensive care unit patients. Among standard hemodynamic parameters, heart rate (P < 0.012) and systolic blood pressure (P < 0.008) significantly increase, whereas neither mean arterial pressure nor diastolic blood pressure was altered after TPE. The TPTD-derived cardiac function parameters, cardiac index (CI; P = 0.035), cardiac power index (CPI; P = 0.008), global ejection fraction (GEF; P = 0.002), and stroke volume index (SVI; P = 0.014), were significantly higher after TPE. Furthermore, systemic vascular index significantly increased (P < 0.042). Among the cardiac preload parameters, central venous pressure was significantly lower after TPE (P < 0.001), while the global end-diastolic volume index (GEDVI) did not change. Contractility marker dPmax did not change. Finally, TPE application did not significantly alter the pulmonary hydration and permeability parameters, extravascular lung water index (EVLWI) and pulmonary vascular permeability index. Vasopressor dose was not statistically significantly altered. Considering increases in SVI, CI, GEF, and CPI and stable values for GEDVI, EVLWI, and dPmax, our data do not give any hint for hemodynamic impairment or TRALI. PMID- 27121593 TI - An eight-year-old boy with parieto-occipital mass presenting with headache and seizure. PMID- 27121594 TI - Langerhans Cell Histiocytosis of the Maxillary Sinus. PMID- 27121595 TI - KCa 3.1-a microglial target ready for drug repurposing? AB - Over the past decade, glial cells have attracted attention for harboring unexploited targets for drug discovery. Several glial targets have attracted de novo drug discovery programs, as highlighted in this GLIA Special Issue. Drug repurposing, which has the objective of utilizing existing drugs as well as abandoned, failed, or not yet pursued clinical development candidates for new indications, might provide a faster opportunity to bring drugs for glial targets to patients with unmet needs. Here, we review the potential of the intermediate conductance calcium-activated potassium channels KCa 3.1 as the target for such a repurposing effort. We discuss the data on KCa 3.1 expression on microglia in vitro and in vivo and review the relevant literature on the two KCa 3.1 inhibitors TRAM-34 and Senicapoc. Finally, we provide an outlook of what it might take to harness the potential of KCa 3.1 as a bona fide microglial drug target. GLIA 2016;64:1733-1741. PMID- 27121597 TI - Androgens regulate scarless repair of the endometrial "wound" in a mouse model of menstruation. AB - The human endometrium undergoes regular cycles of synchronous tissue shedding (wounding) and repair that occur during menstruation before estrogen-dependent regeneration. Endometrial repair is normally both rapid and scarless. Androgens regulate cutaneous wound healing, but their role in endometrial repair is unknown. We used a murine model of simulated menses; mice were treated with a single dose of the nonaromatizable androgen dihydrotestosterone (DHT; 200 ug/mouse) to coincide with initiation of tissue breakdown. DHT altered the duration of vaginal bleeding and delayed restoration of the luminal epithelium. Analysis of uterine mRNAs 24 h after administration of DHT identified significant changes in metalloproteinases (Mmp3 and -9; P < 0.01), a snail family member (Snai3; P < 0.001), and osteopontin (Spp1; P < 0.001). Chromatin immunoprecipitation analysis identified putative androgen receptor (AR) binding sites in the proximal promoters of Mmp9, Snai3, and Spp1. Striking spatial and temporal changes in immunoexpression of matrix metalloproteinase (MMP) 3/9 and caspase 3 were detected after DHT treatment. These data represent a paradigm shift in our understanding of the role of androgens in endometrial repair and suggest that androgens may have direct impacts on endometrial tissue integrity. These studies provide evidence that the AR is a potential target for drug therapy to treat conditions associated with aberrant endometrial repair processes. Cousins, F. L., Kirkwood, P. M., Murray, A. A., Collins, F., Gibson, D. A., Saunders, P. T. K. Androgens regulate scarless repair of the endometrial "wound" in a mouse model of menstruation. PMID- 27121596 TI - Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. AB - Inflammation in arterial walls leads to coronary artery disease (CAD). Because specialized proresolving lipid mediators (SPMs; lipoxins, resolvins, and protectins) stimulate resolution of inflammation in animal models, we tested whether n-3 fatty acids impact SPM profiles in patients with CAD and promote clot remodeling. Six patients with stable CAD were randomly assigned to either treatment with daily 3.36 g Lovaza for 1 yr or without. Targeted lipid mediator metabololipidomics showed that both groups had absence of resolvin D1 (RvD1), RvD2, RvD3, RvD5 and resolvin E1-all of which are present in healthy patients. Those not taking Lovaza had an absence of aspirin-triggered resolvin D3 (AT-RvD3) and aspirin-triggered lipoxin B4 (AT-LXB4). Lovaza treatment restored AT-RvD3 and AT-LXB4 and gave levels of RvD6 and aspirin-triggered protectin D1 (AT-PD1) twice as high (resolvin E2 ~5 fold) as well as lower prostaglandins. Principal component analysis indicated positive relationships for patients with CAD who were receiving Lovaza with increased AT-RvD3, RvD6, AT-PD1, and AT-LXB4 SPMs identified in Lovaza-treated patients with CAD enhanced ~50% at 1 nM macrophage uptake of blood clots. These results indicate that patients with CAD have lower levels and/or absence of specific SPMs that were restored with Lovaza; these SPMs promote macrophage phagocytosis of blood clots. Together, they suggest that low vascular SPMs may enable progression of chronic vascular inflammation predisposing to coronary atherosclerosis and to thrombosis.-Elajami, T. K., Colas, R. A., Dalli, J., Chiang, N., Serhan, C. N., Welty, F. K. Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. PMID- 27121598 TI - Anti-tumour necrosis factor therapy is associated with certain subtypes of chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis has many risk factors; however, the effect of anti-tumour necrosis factor therapy has not been investigated in depth. Our experience points to a detrimental clinical effect in overall prevalence of chronic rhinosinusitis, despite its benefit in certain subtypes. METHOD: A telephone survey was performed to parallel the findings of the Global Allergy and Asthma European Network chronic rhinosinusitis screening survey. This was itself based on the widely recognised European Position Paper on Rhinosinusitis and Nasal Polyps criteria. RESULTS: A total of 120 patients responded to the survey. The prevalence of chronic rhinosinusitis in the anti-tumour necrosis factor therapy population was 20 per cent (95 per cent confidence interval = 12.84 27.16). When compared using a chi-square test, for a two-by-two contingency table, this finding was significant against the prevalence recorded in the normal population. CONCLUSION: This is the first observational study indicating increased prevalence of chronic rhinosinusitis in patients treated with anti tumour necrosis factor therapy. These clinical findings require investigation in greater depth to clarify the nature of pathologies currently diagnosed and treated as chronic rhinosinusitis. PMID- 27121600 TI - Effects of chain flexibility on the properties of DNA hydrogels. AB - The effect of chain rigidity on the mechanic properties of DNA hydrogels was studied. Counterintuitively, the hydrogel formed by mainly flexible chains exhibited better stability, stretchability, and much mechanical properties than the hydrogel containing only rigid chains. Calculations showed that the crosslinking ratio in the hydrogel formed by flexible chains was about twice that of the hydrogel formed by rigid chains under the same conditions. We attributed this to the ease of conformational adjustment of flexible chains. Incorporation of 25% rigid chains further improved the performance of DNA hydrogel by shrinking the pore size and tuning its distribution. PMID- 27121601 TI - Omalizumab (anti-IgE) therapy in the asthma-COPD overlap syndrome (ACOS) and its effects on circulating cytokine levels. AB - CONTEXT: The term "asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome" (ACOS) has been applied to the condition, in which a person has clinical features of both asthma and COPD. METHODS: The patients (N = 10) were presented to our clinic with low lung function, limited reversibility of airway obstruction, hyperinflation, abnormal body composition, dyspnea and episodic wheezing. Based on the clinical and laboratory findings, the patients were diagnosed with ACOS. Patients' serum IL-2 (sIL-2), sIL-4 sIL-6, sIL-10, sIL-17, sTNF-alpha and sIFN-gamma levels were investigated as an apoptotic marker and a marker for inflammation. RESULTS: Having undergone omalizumab treatment and a long-term (12 months) later, patients had a decreased IgE, fractional exhaled nitric oxide concentrations (FENO), eosinophil, neutrophils, macrophages, eosinophil cationic peptide (ECP) and sIL-4 levels. CONCLUSION: To our knowledge, this is the first documentation of omalizumab use in ACOS. We demonstrated decreased IL-4, allergic pulmonary symptoms (dyspnea, wheezing, bronchial hyper responsiveness) and migraine attacks in the patients. PMID- 27121602 TI - Late reactions in food-allergic children and adolescents after double-blind, placebo-controlled food challenges. AB - The time during which children are observed following a double-blind, placebo controlled food challenge (DBPCFC) varies in clinical practice. There are little data on late reactions (LRs) following DBPCFCs. Therefore, we determined the prevalence, severity and clinical characteristics of late reactions in food allergic children and adolescents after DBPCFC, and ascertained which factors are associated with, and may predict, LRs. Logistic regression analyses were performed to investigate which factors were associated with LRs and to develop the association and prediction models. A total of 1142 children underwent DBPCFCs (child-test combinations). Of these 1142 child-test combinations, 400 reported LRs following the DBPCFC. LRs in food-allergic children after DBPCFC are poorly predictable and are generally not severe. All LRs, including those on the placebo day, are more frequently reported in younger children. Children who do not experience severe immediate reactions may be safely discharged home 2 h after a DBPCFC. PMID- 27121604 TI - Risk factors of mastectomy skin flap necrosis in immediate breast reconstruction using low abdominal flaps. AB - BACKGROUND: The purpose of this study was to determine the risk factors associated with mastectomy skin flap necrosis during immediate reconstruction with TRAM or DIEP flaps. METHODS: This study reviewed 1116 cases of immediate breast reconstruction over 10 years. Patients ranged in age from 29-76 years (average = 45.1 years), and had an average follow-up period of 65.6 months. Thirteen factors (age, BMI (body mass index), smoking habits, diabetes ptosis grade, midclavicle-to-nipple distance, neoadjuvant chemotherapy, free or pedicled flap, mastectomy method, surgeon, stage, axillary dissection, mastectomy weight) known to be associated with mastectomy flap necrosis were retrospectively analysed. The odds ratios of the risk factors were calculated using logistic regression analyses. RESULTS: Mastectomy skin flap necrosis occurred in 247 cases (22.1%). Univariate regression analysis showed that the odds ratio of age, BMI, ptosis grade, midclavicle-to-nipple distance, free flap, mastectomy method, surgeon, stage, and mastectomy weight were significant and the odds ratios determined using multivariate analysis were significant for mastectomy method, surgeon, and mastectomy weight. CONCLUSION: During breast reconstruction using abdominal tissue, the independent risk factors that affect mastectomy skin flap necrosis include the mastectomy method, surgeon, and the weight of the mastectomy specimen. Awareness of the impact of each risk factor will lead to the modification and individualisation of surgical techniques and continually improve outcomes. PMID- 27121605 TI - Barrier Modification of Metal-contact on Silicon by Sub-2 nm Platinum Nanoparticles and Thin Dielectrics. AB - We report metal/p-Si contact barrier modification through the introduction of either "isolated" or "nonisolated" tilted-target-sputtered sub-2 nm platinum nanoparticles (Pt NPs) in combination with either a 0.98 nm Atomic Layer Deposited Al2O3 or a 1.6 nm chemically grown SiO2 dielectric layer, or both. Here, we study the role of these Pt NP's size dependent properties, i.e., the Pt NP-metal surface dipole, the Coulomb blockade and quantum confinement effect in determining the degree of Fermi level depinning observed at the studied metal/p Si interfaces. By varying only the embedded Pt NP size and its areal density, the nature of the contact can also be modulated to be either Schottky or Ohmic upon utilizing the same gate metal. 0.74 nm Pt NPs with an areal density of 1.1 * 10(13) cm(-2) show ~382 times higher current densities compared to the control sample embedded with similarly sized Pt NPs with ~1.6 times lower areal densities. We further demonstrate that both Schottky (Ti/p-Si) and poor Ohmic (Au/p-Si) contact can be modulated into a good Ohmic contact with current density of 18.7 +/- 0.6 A/cm(2) and 10.4 +/- 0.4 A/cm(2), respectively, showing ~18 and ~30 times improvement. A perfect forward/reverse current ratio of 1.041 is achieved for these low doped p-Si samples. PMID- 27121603 TI - Distinct cytoprotective roles of pyruvate and ATP by glucose metabolism on epithelial necroptosis and crypt proliferation in ischaemic gut. AB - KEY POINTS: Intestinal ischaemia causes epithelial death and crypt dysfunction, leading to barrier defects and gut bacteria-derived septic complications. Enteral glucose protects against ischaemic injury; however, the roles played by glucose metabolites such as pyruvate and ATP on epithelial death and crypt dysfunction remain elusive. A novel form of necrotic death that involves the assembly and phosphorylation of receptor interacting protein kinase 1/3 complex was found in ischaemic enterocytes. Pyruvate suppressed epithelial cell death in an ATP independent manner and failed to maintain crypt function. Conversely, replenishment of ATP partly restored crypt proliferation but had no effect on epithelial necroptosis in ischaemic gut. Our data argue against the traditional view of ATP as the main cytoprotective factor by glucose metabolism, and indicate a novel anti-necroptotic role of glycolytic pyruvate under ischaemic stress. ABSTRACT: Mesenteric ischaemia/reperfusion induces epithelial death in both forms of apoptosis and necrosis, leading to villus denudation and gut barrier damage. It remains unclear whether programmed cell necrosis [i.e. receptor-interacting protein kinase (RIP)-dependent necroptosis] is involved in ischaemic injury. Previous studies have demonstrated that enteral glucose uptake by sodium-glucose transporter 1 ameliorated ischaemia/reperfusion-induced epithelial injury, partly via anti-apoptotic signalling and maintenance of crypt proliferation. Glucose metabolism is generally assumed to be cytoprotective; however, the roles played by glucose metabolites (e.g. pyruvate and ATP) on epithelial cell death and crypt dysfunction remain elusive. The present study aimed to investigate the cytoprotective effects exerted by distinct glycolytic metabolites in ischaemic gut. Wistar rats subjected to mesenteric ischaemia were enterally instilled glucose, pyruvate or liposomal ATP. The results showed that intestinal ischaemia caused RIP1-dependent epithelial necroptosis and villus destruction accompanied by a reduction in crypt proliferation. Enteral glucose uptake decreased epithelial cell death and increased crypt proliferation, and ameliorated mucosal histological damage. Instillation of cell-permeable pyruvate suppressed epithelial cell death in an ATP-independent manner and improved the villus morphology but failed to maintain crypt function. Conversely, the administration of liposomal ATP partly restored crypt proliferation but did not reduce epithelial necroptosis and histopathological injury. Lastly, glucose and pyruvate attenuated mucosal-to-serosal macromolecular flux and prevented enteric bacterial translocation upon blood reperfusion. In conclusion, glucose metabolites protect against ischaemic injury through distinct modes and sites, including inhibition of epithelial necroptosis by pyruvate and the promotion of crypt proliferation by ATP. PMID- 27121606 TI - What do patients and the public know about clinical practice guidelines and what do they want from them? A qualitative study. AB - BACKGROUND: Guideline producers are increasingly producing versions of guidelines for the public. The aim of this study was to explore what patients and the public understand about the purpose and production of clinical guidelines, and what they want from clinical guidelines to support their healthcare decisions. METHODS: Participants were purposively selected to represent a range of the likely users of patient versions of guidelines, including individuals with health conditions (diabetes and depression), general members of the public, health communication professionals and a group of young people. Participants were asked about their awareness and understanding of clinical guidelines and presented with scenario recommendations, or draft materials from patient guidelines to prompt discussion. Each discussion was facilitated by one or two researchers. All focus groups were recorded and transcribed prior to analysis. Data were analysed using framework analysis. RESULTS: We ran nine focus groups involving 62 individuals, supplemented by four interviews with people experiencing homelessness. Eight groups were held in Scotland, one in England. The four interviews were held in Scotland. The framework analysis yielded five themes: access and awareness; what patients want to know; properties of guidelines; presenting evidence; and format. Awareness of guidelines was low. Participants emphasised the need for information that enables them to choose between treatment options, including harms. They would like help with this from healthcare professionals, especially general practitioners. Participants differed in their support for the inclusion of numerical information and graphs. CONCLUSIONS: Members of the public want information to help them choose between treatments, including information on harms, particularly to support shared decisions with health professionals. Presenting numerical information is a challenge and layered approaches that present information in stages may be helpful. Ignoring the themes identified in this study is likely to lead to materials that fail to support public and patient healthcare decision making. PMID- 27121607 TI - Effect of private versus emergency medical systems transportation in trauma patients in a mostly physician based system- a retrospective multicenter study based on the TraumaRegister DGU(r). AB - BACKGROUND: The effects of private transportation (PT) to definitive trauma care in comparison to transportation using Emergency Medical Services (EMS) have so far been addressed by a few studies, with some of them finding a beneficial effect on survival. The aim of the current study was to investigate epidemiology, pre- and in-hospital times as well as outcomes in patients after PT as compared to EMS recorded in the TraumaRegister DGU(r). METHODS: All patients in the database of the TraumaRegister DGU(r) (TR-DGU) from participating European trauma centers treated in 2009 to 2013 with available data on the mode of transportation, ISS >= 4 and ICU treatment were included in the study. Epidemiological data, pre- and in-hospital times were analysed. Outcomes were analysed after adjustment for RISC-II scores. RESULTS: 76,512 patients were included in the study, of which 1,085 (1.4 %) were private transports. Distribution of ages and trauma mechanisms showed a markedly different pattern following PT, with more children < 15 years treated following PT (3.3 % EMS vs. 9.6 for PT) and more elderly patients of 65 years or older (26.6 vs 32.4 %). Private transportation to trauma care was by far more frequent in Level 2 and 3 hospitals (41.2 % in EMS group vs 73.7 %). Median pre-hospital times were also reduced following PT (59 min for EMS vs. 46 for PT). In-hospital time in the trauma room (66 for EMS vs. 103 min for PT) and time to diagnostics were prolonged following PT. Outcome analysis after adjustment for RISC-II scores showed a survival benefit of PT over EMS transport (SMR for EMS 1.07 95 % CI 1.05 1.09; for PT 0.85 95 % CI 0.62-1.08). DISCUSSION: The current study shows a distinct pattern concerning epidemiology and mechanism of injury following PT. PT accelerates the median pre-hospital times, but prolongs time to diagnostic measures and time in the trauma room. CONCLUSIONS: In this distinct collective, PT seemed to lead to a small benefit in terms of mortality, which may reflect pre hospital times, pre-hospital interventions or other confounders. PMID- 27121608 TI - Core informatics competencies for clinical and translational scientists: what do our customers and collaborators need to know? AB - Since the inception of the Clinical and Translational Science Award (CTSA) program in 2006, leaders in education across CTSA sites have been developing and updating core competencies for Clinical and Translational Science (CTS) trainees. By 2009, 14 competency domains, including biomedical informatics, had been identified and published. Since that time, the evolution of the CTSA program, changes in the practice of CTS, the rapid adoption of electronic health records (EHRs), the growth of biomedical informatics, the explosion of big data, and the realization that some of the competencies had proven to be difficult to apply in practice have made it clear that the competencies should be updated. This paper describes the process undertaken and puts forth a new set of competencies that has been recently endorsed by the Clinical Research Informatics Workgroup of AMIA. In addition to providing context and background for the current version of the competencies, we hope this will serve as a model for revision of competencies over time. PMID- 27121610 TI - Development and usage of wiki-based software for point-of-care emergency medical information. AB - OBJECTIVE: To describe the creation and evaluate the usage of the first medical wiki linked to dedicated mobile applications. METHODS: With the support of multiple current and past contributors, we developed an emergency medicine wiki linked to offline mobile applications (WikEM) in 2009. First deployment was at the Harbor-UCLA Medical Center emergency medicine residency program, with the wiki later opened to public use. To evaluate the project, we performed a post hoc analysis of system use and surveyed 8 years of current and past residents. Outcomes included website and application analytics, as well as survey analysis by composite response categories. RESULTS: Over the 6-year period of this project, the wiki grew to over 7250 pages and 45 500 edits. The website receives more than 85 000 user sessions per month, with over 150 million page views to date. There have been over 200 000 installs of the mobile applications, progressing to produce over 5000 mobile sessions daily. Of potential survey respondents, 87.7% (107) completed the Internet-based survey. Among those who contributed to the wiki, 74.6% reported that it benefited their understanding of core emergency medicine content. Of program graduates, the vast majority reported use of the wiki as a resource after residency (93.8%) along with improvement in clinical efficiency (89.7%). Residents reported higher use and a more favorable opinion of wiki usefulness compared to graduates (P < .001). CONCLUSIONS: A wiki paired with mobile applications is beneficial for resident education and useful in post-residency clinical practice. PMID- 27121609 TI - Will they participate? Predicting patients' response to clinical trial invitations in a pediatric emergency department. AB - OBJECTIVE: (1) To develop an automated algorithm to predict a patient's response (ie, if the patient agrees or declines) before he/she is approached for a clinical trial invitation; (2) to assess the algorithm performance and the predictors on real-world patient recruitment data for a diverse set of clinical trials in a pediatric emergency department; and (3) to identify directions for future studies in predicting patients' participation response. MATERIALS AND METHODS: We collected 3345 patients' response to trial invitations on 18 clinical trials at one center that were actively enrolling patients between January 1, 2010 and December 31, 2012. In parallel, we retrospectively extracted demographic, socioeconomic, and clinical predictors from multiple sources to represent the patients' profiles. Leveraging machine learning methodology, the automated algorithms predicted participation response for individual patients and identified influential features associated with their decision-making. The performance was validated on the collection of actual patient response, where precision, recall, F-measure, and area under the ROC curve were assessed. RESULTS: Compared to the random response predictor that simulated the current practice, the machine learning algorithms achieved significantly better performance (Precision/Recall/F-measure/area under the ROC curve: 70.82%/92.02%/80.04%/72.78% on 10-fold cross validation and 71.52%/92.68%/80.74%/75.74% on the test set). By analyzing the significant features output by the algorithms, the study confirmed several literature findings and identified challenges that could be mitigated to optimize recruitment. CONCLUSION: By exploiting predictive variables from multiple sources, we demonstrated that machine learning algorithms have great potential in improving the effectiveness of the recruitment process by automatically predicting patients' participation response to trial invitations. PMID- 27121611 TI - Development and implementation of a multitiered health informatics curriculum in a college of pharmacy. AB - Standards requiring education in informatics in pharmacy curricula were introduced in the last 10 years by the Accreditation Council for Pharmacy Education. Mirroring difficulties faced by other health professions educators, implementation of these requirements remains fragmented and somewhat limited across colleges of pharmacy in the US. Clinical practice and workforce metrics underline a pronounced need for clinicians with varying competencies in health informatics. In response to these challenges, a multitiered health informatics curriculum was developed and implemented at a college of pharmacy in the Southeast. The multitiered approach is structured to ensure that graduating pharmacists possess core competencies in health informatics, while providing specialized and advanced training opportunities for pharmacy students, health professions students, and working professionals interested in a career path in informatics. The approach described herein offers institutions, administrators, faculty, residents, and students an adaptable model for selected or comprehensive adoption and integration of a multitiered health informatics curriculum. PMID- 27121612 TI - Text mining for precision medicine: automating disease-mutation relationship extraction from biomedical literature. AB - OBJECTIVE: Identifying disease-mutation relationships is a significant challenge in the advancement of precision medicine. The aim of this work is to design a tool that automates the extraction of disease-related mutations from biomedical text to advance database curation for the support of precision medicine. MATERIALS AND METHODS: We developed a machine-learning (ML) based method to automatically identify the mutations mentioned in the biomedical literature related to a particular disease. In order to predict a relationship between the mutation and the target disease, several features, such as statistical features, distance features, and sentiment features, were constructed. Our ML model was trained with a pre-labeled dataset consisting of manually curated information about mutation-disease associations. The model was subsequently used to extract disease-related mutations from larger biomedical literature corpora. RESULTS: The performance of the proposed approach was assessed using a benchmarking dataset. Results show that our proposed approach gains significant improvement over the previous state of the art and obtains F-measures of 0.880 and 0.845 for prostate and breast cancer mutations, respectively. DISCUSSION: To demonstrate its utility, we applied our approach to all abstracts in PubMed for 3 diseases (including a non-cancer disease). The mutations extracted were then manually validated against human-curated databases. The validation results show that the proposed approach is useful in a real-world setting to extract uncurated disease mutations from the biomedical literature. CONCLUSIONS: The proposed approach improves the state of the art for mutation-disease extraction from text. It is scalable and generalizable to identify mutations for any disease at a PubMed scale. PMID- 27121613 TI - Pre-immune state induced by chicken interferon gamma inhibits the replication of H1N1 human and H9N2 avian influenza viruses in chicken embryo fibroblasts. AB - BACKGROUND: Interferon gamma (IFN-gamma), an immunoregulatory cytokine, is known to control many microbial infections. In a previous study, chicken interferon gamma (chIFN-gamma) was found to be up-regulated following avian influenza virus (AIV) infection in specific pathogen-free chickens. We aimed to investigate whether the pre-immune state induced by chIFN-gamma could generate an antiviral response against influenza virus. METHODS: We generated a chIFN-gamma-expressing plasmid and transfected it into chicken embryo fibroblasts (CEFs) and then infected the cells with human origin H1N1 or avian origin H9N2 influenza viruses. Viral titers of culture medium were evaluated in MDCK cell and the viral RNA and IFN-stimulated genes (ISGs) were then quantified by real-time reverse transcriptase polymerase. To further evaluate the role of the antiviral effect of chIFN-gamma by using a backward approach, synthetic small interfering RNAs (siRNA) targeting chIFN-gamma were used to suppress chIFN-gamma. RESULTS: The chIFN-gamma-stimulated CEFs inhibited the replication of viral RNA (vRNA) and showed a mild decrease in the infectious virus load released in the culture medium. Compared to the mock-transfected control, the messenger RNA (mRNA) levels of type I IFNs and IFN-stimulated genes were up-regulated in the cells expressing chIFN-gamma. After treatment with the siRNA, we detected a higher expression of viral genes than that observed in the mock-transfected control. CONCLUSIONS: Our results suggest that apart from the important role played by chIFN-gamma in the antiviral state generated against influenza virus infection, the pre-immune state induced by chIFN-gamma can be helpful in mitigating the propagation of influenza virus. PMID- 27121614 TI - Caesarean section following induction of labour in uncomplicated first births- a population-based cross-sectional analysis of 42,950 births. AB - BACKGROUND: The impact of elective induction of labour at term on the increasing caesarean section (CS) rate is unclear. A Cochrane Systematic Review that concluded that elective induction was associated with a reduction in CS was based on trials that mostly reflect outdated obstetric care, or were flawed. The findings of other studies vary widely in the magnitude and direction of the relationship between elective induction and CS. This inconsistency may be due to the heterogeneity in the methods used to induce or augment labour, such that the relationship with CS is not constant across methods. METHODS: Using validated, routinely-collected data on all births in Victoria in 2000-2005, all singleton, cephalic, first births following uncomplicated pregnancies at 37-40 completed weeks' gestation ('standard primiparae') were identified (n = 42,950). As well as comparing induced with non-induced labour, method of birth was compared between those women experiencing spontaneous labour without augmentation, and women undergoing each method of augmentation or induction using adjusted multinomial logistic regression. Proportions, chi-square tests, adjusted Relative Risk Ratios (aRRR) and 95% confidence intervals are presented. RESULTS: Ten percent of "standard primiparae" had labour induced for no apparent medical indication. Women whose labour was induced were significantly more likely than those who laboured spontaneously to have a CS (26.5 and 12.5% respectively (OR 2.54, 95% CI 2.4, 2.7, p < 0.001). After adjustment for maternal age, epidural analgesia, birthweight, gestation, and public/private admission status, each method of induction or augmentation remained associated with a significant increase in the risk of CS (adjusted ORs range 1.48 to 4.13, p-values all <0.0001). Perinatal death did not differ by onset of labour. CONCLUSION: Induction of labour in medically uncomplicated nulliparous women at term carries a more than doubling of risk of emergency CS, compared with spontaneous labour, with no impact on perinatal mortality. All methods of induction and augmentation of labour were associated with an increase in the rate of CS. Women included in this study had no apparent medical indication for induction of labour or any complication of pregnancy, so the increase in CS was not due to identifiable underlying risk factors. These results suggest that, in the absence of direction from well designed, contemporary RCTs, minimising unindicated inductions before 41 weeks' gestation has the potential to reduce the rate of CS. PMID- 27121615 TI - Implications of construction method and spatial scale on measures of the built environment. AB - BACKGROUND: Research surrounding the built environment (BE) and health has resulted in inconsistent findings. Experts have identified the need to examine methodological choices, such as development and testing of BE indices at varying spatial scales. We sought to examine the impact of construction method and spatial scale on seven measures of the BE using data collected at two time points. METHODS: The Children's Environmental Health Initiative conducted parcel level assessments of 57 BE variables in Durham, NC (parcel N = 30,319). Based on a priori defined variable groupings, we constructed seven mutually exclusive BE domains (housing damage, property disorder, territoriality, vacancy, public nuisances, crime, and tenancy). Domain-based indices were developed according to four different index construction methods that differentially account for number of parcels and parcel area. Indices were constructed at the census block level and two alternative spatial scales that better depict the larger neighborhood context experienced by local residents: the primary adjacency community and secondary adjacency community. Spearman's rank correlation was used to assess if indices and relationships among indices were preserved across methods. RESULTS: Territoriality, public nuisances, and tenancy were weakly to moderately preserved across methods at the block level while all other indices were well preserved. Except for the relationships between public nuisances and crime or tenancy, and crime and housing damage or territoriality, relationships among indices were poorly preserved across methods. The number of indices affected by construction method increased as spatial scale increased, while the impact of construction method on relationships among indices varied according to spatial scale. CONCLUSIONS: We found that the impact of construction method on BE measures was index and spatial scale specific. Operationalizing and developing BE measures using alternative methods at varying spatial scales before connecting to health outcomes allows researchers to better understand how methodological decisions may affect associations between health outcomes and BE measures. To ensure that associations between the BE and health outcomes are not artifacts of methodological decisions, researchers would be well-advised to conduct sensitivity analysis using different construction methods. This approach may lead to more robust results regarding the BE and health outcomes. PMID- 27121616 TI - The prevalence of intraspinal anomalies in infantile and juvenile patients with "presumed idiopathic" scoliosis: a MRI-based analysis of 504 patients. AB - BACKGROUND: Though several studies have reported the incidence of intraspinal neural axis abnormalities in infantile and juvenile "presumed idiopathic" scoliosis, there has been a varying prevalence ranging from 11.1 to 26.0% based on a limited sample size. Therefore, such inconclusive findings have resulted in some questions on the MRI-associated role in the management of these patients. We aimed to investigate the prevalence and distribution of intraspinal anomalies in the infantile and juvenile patients with "presumed idiopathic" scoliosis and to explore the radiographic and clinical indicators with large sample size. METHODS: A total of 504 infantile and juvenile patients diagnosed with "presumed idiopathic" scoliosis were examined for potentially-existing neural axis abnormalities by MRI. Patients were grouped into two cohorts according to the presence of neural axis abnormalities. Radiographic parameters including curve magnitude, curve pattern, location of apex, degree of thoracic kyphosis, and span of curve were recorded and compared between the two groups. The prevalence of the neural abnormalities between the infantile-age group and juvenile-age group was also compared. The student t test was used to evaluate the differences of continuous variables and the chi-square test was used to evaluate the difference of categorical variables. Fisher exact test was applied to detect the difference of the rate of intraspinal anomalies between the "infantile idiopathic scoliosis" and "juvenile idiopathic scoliosis" group. RESULTS: Involving the spinal cord, 94 patients (18.7%) were found to have a neural abnormality: Arnold-Chiari malformation alone in 43 patients, Arnold-Chiari malformation combined with syringomyelia in 18 patients, isolated syringomyelia in 13 patients, diastematomyelia in six patients, tethered cord combined with diastematomyelia in six patients, tethered cord alone in four patients, and other uncommon intraspinal abnormalities in the remaining four patients. Totally Arnold-Chiari malformation with or without syringomyelia accounted for 64.8% (61/94) among all these abnormalities. Male gender, left thoracic curve and right lumbar curve were found to be significantly associated with the presence of neural axis abnormalities on MRI. CONCLUSIONS: The incidence of neural axis abnormalities in the presumed IIS and JIS was 18.7%. Thus a routine MRI evaluation appears warranted for those "presumed idiopathic" scoliosis patients if aged less than 10 years, being male or having left thoracic or right lumbar curve. PMID- 27121617 TI - Role of golden jackals (Canis aureus) as natural reservoirs of Dirofilaria spp. in Romania. AB - BACKGROUND: Dirofilaria immitis and Dirofilaria repens are mosquito-transmitted zoonotic nematodes, causing heartworm disease and skin lesions, respectively, in carnivores. In Europe, the domestic dog is apparently the main definitive host, but patent infections occur also in other species of carnivores. The rapid spread of the golden jackals (Canis aureus) throughout Europe opens a question of involvement of this species in the sylvatic cycle of pathogens in the colonised territories, including Dirofilaria spp. METHODS: Between January 2014 and May 2015, 54 golden jackals from 18 localities in Romania were examined by full necropsy for the presence of adult filarioid nematodes and blood samples from all animals were screened for the presence of microfilariae of D. immitis, D. repens and Acanthocheilonema reconditum by multiplex PCR DNA amplification. RESULTS: Nematodes morphologically identified as D. immitis were found in 18.52% of the animals, originating from the southern part of Romania. No D. repens or A. reconditum were found at necropsy. The molecular prevalence in blood samples from the same animals was 9.26% for D. immitis and 1.85% for D. repens. All samples were negative by PCR for A. reconditum. CONCLUSION: The relatively high prevalence of Dirofilaria spp. infections in golden jackals from Romania together with the increasing density of the jackal populations highlight their potential role in the transmission of these zoonotic parasites and in the maintenance of natural disease foci. PMID- 27121618 TI - The effects of magnetic fields exposure on relative permittivity of saline solutions measured by a high resolution SPR system. AB - A measurement system for the relative permittivity of a physiological solution under 50 Hz magnetic fields (MF) is presented. It is based on a phase-sensitive surface plasmon resonance (SPR) system. Relative permittivity was analyzed for different solute concentrations of sodium chloride under various MF exposure parameters. We found that MF exposure at 0.2-4.0 mT step-wise decreased significantly the SPR phase signal of a 0.9% sodium chloride solution while 0.1 mT of MF exposure did not. The decreases in the SPR phase signal depended on the duration of MF exposure, and the signal reached a plateau after 15 min of exposure. Interestingly, the decreased SPR phase signal showed a gradual increase and approached the background level when the exposure was drawn off. In addition, we found that the response of the sodium chloride solution to MF also depended on its concentration. In brief, the relative permittivity of sodium chloride in solutions appears to be practically affected by 50 Hz MF exposure. Our data indicates that the relative permittivity of the saline solution influenced by MF exposure should be considered when investigating the biological effects of MF exposure on organisms in experimental study. PMID- 27121619 TI - 5'-AMP-Activated Protein Kinase Regulates Papillary (TPC-1 and BCPAP) Thyroid Cancer Cell Survival, Migration, Invasion, and Epithelial-to-Mesenchymal Transition. AB - BACKGROUND: Differentiated thyroid carcinomas (DTC) are associated with a good prognosis and a high survival rate. However, tumor recurrence occurs in approximately 20-30% of DTC patients, reinforcing the importance of identifying new molecular targets for cancer management. It has been shown that the 5'-AMP activated protein kinase (AMPK) is over-activated in papillary thyroid cancer (PTC). This study aimed to investigate the effects of 5-aminoimidazole-4 carboxamide-ribonucleoside (AICAR), an AMPK activator, on various aspects of thyroid cancer cell behavior, including cell survival, apoptosis, migration, invasion, and epithelial-to-mesenchymal transition (EMT), in the human thyroid cancer cell lines BCPAP and TPC-1. METHODS: BCPAP and TPC-1 cells were cultivated in Dulbecco's modified Eagle's medium, and the non-tumor-derived cell line Nthy ORI was grown in RPMI. Cells were treated or not with AICAR for different periods of time. The cell growth rate, cell cycle phase, apoptosis, cell migration, and invasion were analyzed using transwell inserts, and EMT was quantified by the expression of mesenchymal and epithelial markers. RESULTS: AMPK is activated in thyroid cancer cell lines, and AICAR treatment further increased AMPK phosphorylation. After 48 hours of AICAR treatment, the percentage of cells in the G2/M phase decreased, and a G0/G1-phase arrest was induced in both cell lines. AMPK activation effectively induced apoptosis in the BCPAP and TPC-1 cancer cell lines, while no apoptosis induction was observed in Nthy-ORI cells. AICAR also reduced the migration of Nthy-ORI and BCPAP cells by 30% and approximately 60% in TPC-1 cells. AICAR had no effect on cell invasion in Nthy ORI and TPC-1 cells, but a significant reduction of cell invasion was observed in BCPAP cells. AICAR induced a significant reduction of N-cadherin and no changes in the expression of vimentin or TCF/Zeb1 protein in BCPAP cells. No differences in the expression of EMT markers were found in the AICAR-treated Nthy-ORI cells. A remarkable reduction of vimentin, TCF/Zeb1, and N-cadherin protein expression was detected in the TPC-1 cells. CONCLUSIONS: Increased activation of AMPK in PTC cell lines leads to a strong antitumor response, as measured by the inhibition of cell proliferation, cell migration, and induction of cell death. AMPK activation also reverses EMT in TPC-1 cells. PMID- 27121620 TI - PCSK9 Association With Lipoprotein(a). AB - RATIONALE: Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B. Proprotein convertase subtilisin/kexin type 9 (PCSK9) selectively binds low-density lipoprotein; we hypothesized that it can also be associated with Lp(a) in plasma. OBJECTIVE: Characterize the association of PCSK9 and Lp(a) in 39 subjects with high Lp(a) levels (range 39-320 mg/dL) and in transgenic mice expressing either human apo(a) only or human Lp(a) (via coexpression of human apo(a) and human apolipoprotein B). METHODS AND RESULTS: We show that PCSK9 is physically associated with Lp(a) in vivo using 3 different approaches: (1) analysis of Lp(a) fractions isolated by ultracentrifugation; (2) immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (3) ELISA quantification of Lp(a)-associated PCSK9. Plasma PCSK9 levels correlated with Lp(a) levels, but not with the number of kringle IV-2 repeats. PCSK9 did not bind to apo(a) only, and the association of PCSK9 with Lp(a) was not affected by the loss of the apo(a) region responsible for binding oxidized phospholipids. Preferential association of PCSK9 with Lp(a) versus low-density lipoprotein (1.7-fold increase) was seen in subjects with high Lp(a) and normal low-density lipoprotein. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels. CONCLUSIONS: Our results show, for the first time, that plasma PCSK9 is found in association with Lp(a) particles in humans with high Lp(a) levels and in mice carrying human Lp(a). Lp(a)-bound PCSK9 may be pursued as a biomarker for cardiovascular risk. PMID- 27121622 TI - A Comprehensive Approach for the Ergonomic Evaluation of 13 Emergency and Transport Ventilators. AB - BACKGROUND: Mechanical ventilation is an important part of emergency medicine and is frequently used for transportation. Human errors during ventilator settings are frequent and may be associated with high morbidity/mortality. The aim of the study was to provide a complete ergonomic evaluation of emergency and transport ventilators, taking into account objective and subjective human-machine interface assessments and individual mental work load. METHODS: We performed a prospective bench ergonomic evaluation of 13 emergency and transport ventilators, using standardized conditions and a global methodological approach. The study was performed in an evaluation laboratory dedicated to respiratory care, and 12 emergency physicians unfamiliar with the tested devices were included in the evaluation. The ventilators were classified into 3 categories (simple, sophisticated, and ICU-like). Objective chronometric evaluations were conducted considering 9 tasks, and subjective evaluations were performed (ease of use, willingness to use, and user-friendliness of monitoring) using Likert scales. Mental work load evaluation was performed using the NASA Task Load Index scale. RESULTS: Overall task failure rate represented 4% of all attempts. Setting modifications, ventilation mode changes, and powering down durations were different between simple and other emergency and transport ventilator categories (P < .005). There was no difference between ventilator categories for the ease of use and user-friendliness of the monitoring. In contrast, the willingness to use was lower for simple devices, compared with sophisticated and ICU-like emergency and transport ventilators (2.9 +/- 1.4 vs 3.9 +/- 1.2, P = .002 and 4.3 +/- 1, P < .001). No differences were observed between devices regarding the mental work load, except for several specific devices in the sophisticated category. CONCLUSIONS: A comprehensive ergonomic evaluation provides valuable information while investigating operational friendliness in emergency and transport ventilators. The choice of a device not only depends on its technical characteristics but should take into account its clinical operational setting and ergonomics in order to decrease mental work load. Sophisticated emergency and transport ventilators should only be used by clinicians who demonstrate expertise in mechanical ventilation. PMID- 27121621 TI - Cardiac Fibro-Adipocyte Progenitors Express Desmosome Proteins and Preferentially Differentiate to Adipocytes Upon Deletion of the Desmoplakin Gene. AB - RATIONALE: Mutations in desmosome proteins cause arrhythmogenic cardiomyopathy (AC), a disease characterized by excess myocardial fibroadipocytes. Cellular origin(s) of fibroadipocytes in AC is unknown. OBJECTIVE: To identify the cellular origin of adipocytes in AC. METHODS AND RESULTS: Human and mouse cardiac cells were depleted from myocytes and flow sorted to isolate cells expressing platelet-derived growth factor receptor-alpha and exclude those expressing other lineage and fibroblast markers (CD32, CD11B, CD45, Lys76, Ly(-6c) and Ly(6c), thymocyte differentiation antigen 1, and discoidin domain receptor 2). The PDGFRA(pos):Lin(neg):THY1(neg):DDR2(neg) cells were bipotential as the majority expressed collagen 1 alpha-1, a fibroblast marker, and a subset CCAAT/enhancer binding protein alpha, a major adipogenic transcription factor, and therefore, they were referred to as fibroadipocyte progenitors (FAPs). FAPs expressed desmosome proteins, including desmoplakin, predominantly in the adipogenic but not fibrogenic subsets. Conditional heterozygous deletion of Dsp in mice using Pdgfra-Cre deleter led to increased fibroadipogenesis in the heart and mild cardiac dysfunction. Genetic fate mapping tagged 41.4+/-4.1% of the cardiac adipocytes in the Pdgfra-Cre:Eyfp:Dsp(W/F) mice, indicating an origin from FAPs. FAPs isolated from the Pdgfra-Cre:Eyfp:Dsp(W/F) mouse hearts showed enhanced differentiation to adipocytes. Mechanistically, deletion of Dsp was associated with suppressed canonical Wnt signaling and enhanced adipogenesis. In contrast, activation of the canonical Wnt signaling rescued adipogenesis in a dose dependent manner. CONCLUSIONS: A subset of cardiac FAPs, identified by the PDGFRA(pos):Lin(neg):THY1(neg):DDR2(neg) signature, expresses desmosome proteins and differentiates to adipocytes in AC through a Wnt-dependent mechanism. The findings expand the cellular spectrum of AC, commonly recognized as a disease of cardiac myocytes, to include nonmyocyte cells in the heart. PMID- 27121623 TI - What's Next After ARDS: Long-Term Outcomes. AB - ARDS is a life-threatening organ failure due to several pulmonary and extrapulmonary injuries with an incidence between 5 and 60 cases/100,000 persons/y. Patients with ARDS have non-cardiogenic pulmonary edema and dyspnea often requiring invasive mechanical ventilation and intensive care admission. Although the short-term mortality rate has significantly decreased in the last decade, mainly due to the widespread application of lung-protective ventilation and better general support, long-term outcomes are still unsatisfactory. Besides simply evaluating the outcome at hospital discharge, several recent studies have assessed the health-related quality of life, neuropsychological disability, radiological findings, and pulmonary dysfunction up to 5 y. This paper reviews the literature regarding the long-term outcomes in patients with ARDS. PMID- 27121624 TI - Is Exercise-Induced Bronchoconstriction Exercise-Induced Asthma? PMID- 27121625 TI - A New Era for Ribavirin Aerosols to Treat Respiratory Syncitial Virus Infections in Immunocompromised Patients? PMID- 27121626 TI - Should We Nebulize Hypertonic Saline Prophylactically in Our Pediatric Intubated Patients? PMID- 27121627 TI - CPAP Devices for Emergency Prehospital Use: Looking Inside of It. PMID- 27121628 TI - CPAP Devices for Emergency Prehospital Use: Looking Inside of It-Reply. PMID- 27121629 TI - PEEP and Mechanical Ventilation: We Are Warned, We Cannot Ignore. PMID- 27121630 TI - PEEP and Mechanical Ventilation: We Are Warned, We Cannot Ignore-Reply. PMID- 27121632 TI - Editor's Commentary. PMID- 27121631 TI - Transcutaneous Carbon Dioxide in the Management of Noninvasive Ventilation. PMID- 27121633 TI - Effect of coenzyme A on outer hair cells in cisplatin ototoxicity: functional and ultrastructural study. AB - The aim of this study was to use functional and morphological analyses to evaluate the protective effect of coenzyme A (CoA) in cisplatin-induced toxicity in outer hair cells (OHC). Three groups of 8 guinea pigs were used: control (group I), cisplatin-treated (group II) and cisplatin + CoA-treated (group III). In groups II and III, a single ototoxic dose of cisplatin (10 mg/kg) was injected intraperitoneally. Group III was co-treated with CoA (900 MUg/kg per day for 7 consecutive days). Electrocochleography (ECoG) recordings were made before and after the 7-day treatment period in all groups. After ECoG on day 7, all animals were anesthetized and the cochleae were removed and fixed for ultrastructural analysis. Cell damage in OHC was observed with transmission electron microscopy. Cisplatin induced a significant increase in auditory thresholds (p<0.001) compared to group I (control). In contrast, group III (cisplatin + CoA) had significantly reduced thresholds (p<0.001) compared to the group treated with cisplatin alone (group II).We found no significant differences between the control group and animals co-treated with cisplatin and CoA. The electron microscopy findings in OHC were consistent with these results. Ultrastructural analysis of OHC in group II showed morphological indications of necrosis, i.e. cytoplasmic swelling and vacuolation, and mitochondrial swelling. In group III the cell morphology of OHC was preserved, with ultrastructural characteristics similar to the control group. In conclusion, co-treatment with cisplatin with CoA inhibited antineoplastic-induced cytotoxicity in OHC in a guinea pig model. PMID- 27121634 TI - A service evaluation of self-referral to military mental health teams. AB - BACKGROUND: The UK military runs a comprehensive mental health service ordinarily accessed via primary care referrals. AIMS: To evaluate the feasibility of self referral to mental health services within a military environment. METHODS: Three pilot sites were identified; one from each service (Royal Navy, Army, Air Force). Socio-demographic information included age, rank, service and career duration. Clinical data included prior contact with general practitioner (GP), provisional diagnosis and assessment outcome. RESULTS: Of the 57 self-referrals, 69% (n = 39) had not previously accessed primary care for their current difficulties. After their mental health assessment, 47 (82%) were found to have a formal mental health problem and 41 (72%) were offered a further mental health clinician appointment. The data compared favourably with a large military mental health department that reported 87% of primary care referrals had a formal mental health condition. CONCLUSIONS: The majority of self-referrals had formal mental health conditions for which they had not previously sought help from primary care; most were offered further clinical input. This supports the view that self-referral may be a useful option to encourage military personnel to seek professional care over and above the usual route of accessing care through their GP. PMID- 27121635 TI - Tuberculin and QuantiFERON-TB-Gold tests for latent tuberculosis: a meta analysis. AB - BACKGROUND: Up to now, there has been no universal consensus on the agreement between the tuberculin skin test (TST) and the QuantiFERON-TB-Gold test (QFT) in the detection of latent tuberculosis infection (LTBI) among high-risk populations. AIMS: To estimate the agreement between TST and QFT among health care workers (HCWs). METHODS: A meta-analysis in which all major electronic databases, including Medline, Scopus, Web of Sciences and Ovid, were searched until June 2014. All cross-sectional and cohort studies addressing the agreement between TST and the QFT were included. The extracted data were analysed and the results were reported using random effect models. RESULTS: The overall kappa statistic between TST and the QFT was 0.27 [95% confidence interval (CI) 0.22, 0.32] and the adjusted kappa statistic for prevalence and bias was 0.41 (95% CI 0.32, 0.50). The kappa for subjects with and without bacillus Calmette-Guerin (BCG) vaccination was 0.27 (95% CI 0.18, 0.36) and 0.31 (95% CI 0.15, 0.46) respectively. The figures were 0.30 (95% CI 0.16, 0.43) and 0.82 (95% CI 0.74, 0.90) for prevalence-adjusted and bias-adjusted kappa, respectively. CONCLUSIONS: The overall agreement between TST and QFT in the detection of LTBI among HCWs was poor. After adjusting for the prevalence and bias indices, kappa statistics reached fair agreement. The utility of each of these two tests is dependent on the prevalence and burden of tuberculosis as well as the BCG vaccination status. PMID- 27121636 TI - Using a nasoseptal flap for the reconstruction of osteoradionecrosis in nasopharyngeal carcinoma: a case report. AB - BACKGROUND: Osteoradionecrosis (ORN) is a challenging complication in patients with postirradiated nasopharyngeal carcinoma (NPC). The aim of this study was to evaluate the usage of a nasoseptal flap (NSF) after endoscopic sequestrectomy to reconstruct resultant skull base defects for the treatment of ORN. CASE PRESENTATION: We present our experience on the adaption of an NSF as a reconstruction method for bony clival defects after endoscopic sequestrectomy in patients with postirradiated NPC. We propose that by which the patient may be offered better and prompt surgical results in the more adequate coverage of a vascularized flap for the exposed defect and attenuate the hypoxic and inflammatory process among the NPC patients suffering from postirradiation ORN. CONCLUSIONS: To our knowledge, NSF use in such an indication has not been previously reported. Consequently, we advocate its utility for the management of patients with postirradiated skull base ORN in NPC in the future. PMID- 27121637 TI - Oral verrucous carcinoma: From multifactorial etiology to diverse treatment regimens (Review). AB - Oral verrucous carcinoma (OVC) is a verrucous variant of oral squamous cell carcinoma (OSCC), which accounts for 2-12% of all oral carcinomas with a 5-year survival rate of only approximately 50%. Enormous effort has been dedicated to this cancer, and the past decades have witnessed significant advances in relevant diagnostic and therapeutic approaches. Currently, there exist three challenges from primary sub-fields of research and clinical practice of the cancer, namely multifactorial etiology, complex molecular mechanism, and deficient treatment. This study reviews the existing literature on the cancer, encompassing its etiology, clinical manifestations and pathology, molecular mechanism, diagnosis and differential diagnosis, and treatment. For improved treatment of OVC, multifactorial etiology analysis, incorporation of effective biomarkers for mechanism illustration, and integration of multidisciplinary modalities are expounded, in an attempt to resolve the challenges and to provide a useful guide for future research in the field. PMID- 27121638 TI - Structure-Odor Activity Studies on Monoterpenoid Mercaptans Synthesized by Changing the Structural Motifs of the Key Food Odorant 1-p-Menthene-8-thiol. AB - 1-p-Menthene-8-thiol (1) has been discovered as the key odorant in grapefruit juice several decades ago and contributes to the overall odor of the fruit with an extremely low odor threshold of 0.000034 ng/L in air. This value is among the lowest odor thresholds ever reported for a food odorant. To check whether modifications in the structure of 1 would lead to changes in odor threshold and odor quality, 34 mercapto-containing p-menthane and 1-p-menthene derivatives as well as several aromatic and open-chain mercapto monoterpenoids were synthesized. Eighteen of them are reported for the first time in the literature, and their odor thresholds and odor qualities as well as analytical data are supplied. A comparison of the sensory data with those of 1 showed that hydrogenation of the double bond led to a clear increase in the odor threshold. Furthermore, moving the mercapto group into the ring always resulted in higher odor thresholds compared to thiols with a mercapto group in the side chains. Although all tertiary thiols always exhibited low odor thresholds, none of the 31 compounds reached the extremely low threshold of 1. Also, none of the synthesized mercapto monoterpenoids showed a similar odor quality resembling grapefruit. Although the saturated and aromatic analogues exhibited similar scents as 1, the aromas of the majority of the other compounds were described as sulfury, rubber-like, burned, soapy, or even mushroom-like. NMR and MS data as well as retention indices of the 23 newly reported sulfur-containing compounds might aid in future research to identify terpene-derived mercaptans possibly present in trace levels in foods. PMID- 27121639 TI - Monitoring of the tumor response to nano-graphene oxide-mediated photothermal/photodynamic therapy by diffusion-weighted and BOLD MRI. AB - Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities. Because each modality has its own set of advantages and limitations, there has been interest in developing methods that can co-deliver the two regimens for enhanced tumor treatment. Among the efforts, nano-graphene oxide-mediated phototherapies have recently attracted much attention. Nano graphene oxide has a broad absorbance spectrum and can be loaded with photosensitizers, such as chlorin e6, with high efficiency. Chlorin e6-loaded and PEGylated nano-graphene (GO-PEG-Ce6) can be excited at 660 nm, 808 nm, or both, to induce PDT, PTT, or PDT/PTT combination. Despite the potential of the treatments, there is a lack of a diagnostic tool which can monitor their therapeutic response in a non-invasive and prognostic manner; such an ability is urgently needed for the transformation and translation of the technologies. In this study, we performed diffusion-weighted and blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) after GO-PEG-Ce6-mediated PTT, PDT, or PTT/PDT. We found that after efficient PTT, there is a significant increase of the tumor apparent diffusion coefficient (ADC) value in diffusion-weighted imaging (DWI) maps; meanwhile, an efficient PDT led to an increase of in BOLD images. In both the cases, the amplitude of the increase was correlated with the treatment outcomes. More interestingly, a synergistic treatment efficacy was observed when the PTT/PDT combination was applied, and the combination was associated with a greater ADC and increase than when either modality was used alone. In particular, the PTT/PDT condition that induced the most dramatic short term increase of the ADC value (>70%) caused the most effective tumor control in the long-run, with 60% of the treated animals being tumor-free after 60 days. These results suggest the great promise of the combination of DWI and BOLD MRI as a tool for accurate monitoring and prognosis of phototherapies, which is of great value to the future developments of the methodologies. PMID- 27121640 TI - microRNA signatures in peripheral blood fail to detect acute cellular rejection after liver transplantation. AB - OBJECTIVE: We investigated whether microRNA signatures in whole blood samples are associated with acute cellular rejection (ACR) after liver transplantation. MATERIALS AND METHODS: Blood samples were collected using Paxgene technology and analyzed by microarrays and quantitative real-time polymerase chain reaction (qRT PCR). RESULTS: microRNA signatures failed to distinguish between 19 patients with ACR and 16 controls. Let-7b-5p and let-7c were upregulated in a subgroup of patients with ACR during the 6th and 7th postoperative days but failed in an independent validation of 20 patients. CONCLUSION: microRNA signatures in whole blood processed by Paxgene technology are not suited for the detection of ACR after liver transplantation. PMID- 27121641 TI - Defining occult injuries of the distal forearm and wrist in children. AB - PURPOSE: The nonspecific terms "wrist sprain" and "suspected occult bony injury" are frequently documented as diagnoses in occult paediatric wrist injuries. To date, however, no one has accurately defined their true underlying pathology. The primary objective of this study was to identify the true pathoanatomy of occult acute paediatric wrist injuries. Our secondary objective was to compare our findings with existing adult data in order to determine any population differences that might be clinically relevant. METHODS: We performed a single centre retrospective case series evaluating MRI findings in acute paediatric wrist injuries presenting to the hand injury unit between 2011 and 2014. All patients underwent standardised radiographs of the wrist and, where clinically indicated, of the scaphoid. Where no bony anomaly was identified, MRI scanning was offered. Cohen's kappa coefficient was used to calculate the agreement between clinical and MRI diagnosis. RESULTS: 57 patients met the final inclusion criteria. Occult fractures and bony contusions comprised the majority of the pathologies, at 36.5 and 35.0 %, respectively. There were no cases of isolated soft-tissue injury. MRI effected management change in 35.1 % of cases. Paediatric wrists demonstrated differences in injury pattern and distribution when compared to an adult population. CONCLUSION: This study defines for the first time the true pathology of occult paediatric wrist injuries. The current definition of a wrist sprain was not applicable to a single case and therefore appears to be inappropriate for use in the paediatric population. A precise knowledge of the likely pathology facilitates accurate information delivery whilst reducing parental uncertainty and treatment variation. PMID- 27121642 TI - Three-dimensional block-based restoration integrated with wide-field fluorescence microscopy for the investigation of thick specimens with spatially variant refractive index. AB - Development of a block-based restoration (BBR) method that addresses spatially variant (SV) imaging in wide-field fluorescence microscopy of thick samples is presented. The BBR method is based on a block-based imaging model, which approximates SV imaging using an efficient orthonormal basis decomposition of multiple SV point-spread functions computed at block vertices. The effect of reducing the number of blocks needed to account for SV imaging on the restoration accuracy was investigated with simulations using a numerical lung tissue phantom relevant to biological studies. Results show that reducing the number of blocks by 82% and 98% resulted in a 19% and 27% reduction in restoration accuracy, respectively, thereby establishing a reasonable tradeoff between computational resources and accuracy. Comparison of the BBR method to existing methods (deconvolution) that do not account for SV imaging demonstrates a 90% improvement in restoration accuracy. BBR results from synthetic and experimental images of a controlled test sample with SV refractive index (RI) show consistency, providing a validation of the BBR approach. In this study, information from DIC and fluorescence images was combined to identify regions with changing RI within the imaging volume. The BBR method provides a first step toward computationally tractable reconstruction of images from thick samples. PMID- 27121643 TI - Quantifying Nanomolar Protein Concentrations Using Designed DNA Carriers and Solid-State Nanopores. AB - Designed "DNA carriers" have been proposed as a new method for nanopore based specific protein detection. In this system, target protein molecules bind to a long DNA strand at a defined position creating a second level transient current drop against the background DNA translocation. Here, we demonstrate the ability of this system to quantify protein concentrations in the nanomolar range. After incubation with target protein at different concentrations, the fraction of DNA translocations showing a secondary current spike allows for the quantification of the corresponding protein concentration. For our proof-of-principle experiments we use two standard binding systems, biotin-streptavidin and digoxigenin antidigoxigenin, that allow for measurements of the concentration down to the low nanomolar range. The results demonstrate the potential for a novel quantitative and specific protein detection scheme using the DNA carrier method. PMID- 27121644 TI - Salmon-coloured lesions mimicking conjunctival papillae: an unusual presentation of unilateral conjunctival lymphoma in a young man. PMID- 27121645 TI - Altered immune response of immature dendritic cells following dengue virus infection in the presence of specific antibodies. AB - Dengue virus (DENV) replication is known to prevent maturation of infected dendritic cells (DCs) thereby impeding the development of adequate immunity. During secondary DENV infection, dengue-specific antibodies can suppress DENV replication in immature DCs (immDCs), however how dengue-antibody complexes (DENV IC) influence the phenotype of DCs remains elusive. Here, we evaluated the maturation state and cytokine profile of immDCs exposed to DENV-ICs. Indeed, DENV infection of immDCs in the absence of antibodies was hallmarked by blunted upregulation of CD83, CD86 and the major histocompatibility complex molecule HLA DR. In contrast, DENV infection in the presence of neutralizing antibodies triggered full DC maturation and induced a balanced inflammatory cytokine response. Moreover, DENV infection under non-neutralizing conditions prompted upregulation of CD83 and CD86 but not HLA-DR, and triggered production of pro inflammatory cytokines. The effect of DENV-IC was found to be dependent on the engagement of FcgammaRIIa. Altogether, our data show that the presence of DENV-IC alters the phenotype and cytokine profile of DCs. PMID- 27121646 TI - Three-dimensional polymer scaffolds for enhanced differentiation of human mesenchymal stem cells to hepatocyte-like cells: a comparative study. AB - Stem cell-based tissue engineering has emerged as a promising avenue for the treatment of liver diseases and as drug metabolism and toxicity models in drug discovery and development. The in vitro simulation of a micro-environmental niche for hepatic differentiation remains elusive, due to lack of information about crucial factors for the stem cell niche. For generation of functional hepatocytes, an in vivo three-dimensional (3D) micro-environment and architecture should be reproduced. Towards this, we fabricated three scaffolds as dextran gelatin (DG1), chitosan-hyaluronic acid (CH1) and gelatin-vinyl acetate (GEVAC). Hepatic differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) was induced by culturing hUC-MSCs on these scaffolds. The scaffolds support hepatic differentiation by mimicking the native extracellular matrix (ECM) micro-environment and architecture to facilitate 3D cell-cell and cell matrix interactions. The expression of hepatic markers, glycogen storage, urea production, albumin secretion and cytochrome P450 (CYP450) activity indicated the hepatic differentiation of hUC-MSCs. The differentiated hUC-MSCs on the 3D scaffolds formed hepatospheroids (3D hepatocyte aggregates), as illustrated by scanning electron microscopy (SEM), confocal microscopy and cytoskeleton organization. It was observed that the 3D scaffolds supported improved cell morphology, expression of hepatic markers and metabolic activities, as compared to Matrigel-coated plates. To the best of our knowledge, this is the first report demonstrating the use of a well-characterized scaffold (GEVAC) for enhanced differentiation of hUC-MSCs to hepatocyte-like cells (HLCs). Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121647 TI - RNA-directed DNA methylation efficiency depends on trigger and target sequence identity. AB - RNA-directed DNA methylation (RdDM) in plants has been extensively studied, but the RNA molecules guiding the RdDM machinery to their targets are still to be characterized. It is unclear whether these molecules require full complementarity with their target. In this study, we have generated Nicotiana tabacum (Nt) plants carrying an infectious tomato apical stunt viroid (TASVd) transgene (Nt-TASVd) and a non-infectious potato spindle tuber viroid (PSTVd) transgene (Nt-SB2). The two viroid sequences exhibit 81% sequence identity. Nt-TASVd and Nt-SB2 plants were genetically crossed. In the progeny plants (Nt-SB2/TASVd), deep sequencing of small RNAs (sRNAs) showed that TASVd infection was associated with the accumulation of abundant small interfering RNAs (siRNAs) that mapped along the entire TASVd but only partially matched the SB2 transgene. TASVd siRNAs efficiently targeted SB2 RNA for degradation, but no transitivity was detectable. Bisulfite sequencing in the Nt-SB2/TASVd plants revealed that the TASVd transgene was targeted for dense cis-RdDM along its entire sequence. In the same plants, the SB2 transgene was targeted for trans-RdDM. The SB2 methylation pattern, however, was weak and heterogeneous, pointing to a positive correlation between trigger-target sequence identity and RdDM efficiency. Importantly, trans-RdDM on SB2 was also detected at sites where no homologous siRNAs were detected. Our data indicate that RdDM efficiency depends on the trigger-target sequence identity, and is not restricted to siRNA occupancy. These findings support recent data suggesting that RNAs with sizes longer than 24 nt (>24-nt RNAs) trigger RdDM. PMID- 27121648 TI - Macrophages: Dissolving cholesterol to unclog arteries. PMID- 27121649 TI - Tissue repair: Biological scaffolds modulate immune cells. PMID- 27121650 TI - T cell responses: Metabolic pathways take sides. PMID- 27121653 TI - Engineering Stacks of V-Shaped Polyaromatic Compounds with Alkyl Chains for Enhanced Emission in the Solid State. AB - A V-shaped bisanthracene derivative with three butyl groups formed two types of emissive solids that display bluish green and blue fluorescence (PhiF =72 and 32 %, respectively), depending on the preparation conditions. The crystal and powder X-ray analyses reveal that the highly emissive solid adopts a head-to-head arrangement with discrete stacks of the anthracene moieties, whereas the moderately emissive solid adopts a head-to-tail arrangement without the stacks. The obtained molecular arrangements are transformed by thermal stimuli accompanying the change in fluorescence. Furthermore, large enhancements of dye emissions (12-45-fold) through highly efficient host-guest energy transfer were achieved in the solid state by adding minute amounts of various fluorescent dyes (e.g. rubrene and Nile red) to the V-shaped compound. PMID- 27121654 TI - Halloysite-based dopamine-imprinted polymer for selective protein capture. AB - We describe a facile, general, and highly efficient approach to obtain polydopamine-coated molecularly imprinted polymer based on halloysite nanotubes for bovine serum albumin. The method combined surface molecular imprinting and one-step immobilized template technique. Hierarchically structured polymer was prepared in physiological conditions adopting dopamine as functional monomer. A thin layer of polydopamine can be coated on the surface of amino-modified halloysite nanotubes by self-polymerization, and the thickness of the imprinted shells can be controlled by the mass ratio of matrix and dopamine. The polymer was characterized by Fourier transform infrared spectrometry, transmission electron microscopy, and thermogravimetric analysis. The prepared material showed high binding capacity (45.4 mg/g) and specific recognition behavior toward the template protein. In addition, stability and regeneration analyses indicated that the imprinted polymer exhibited excellent reusability (relative standard deviation < 9% for batch-to-batch evaluation). Therefore, the developed polymer is effective for protein recognition and separation. PMID- 27121652 TI - Emerging insights into natural killer cells in human peripheral tissues. AB - Natural killer (NK) cells have long been considered to be a homogenous population of innate lymphocytes with limited phenotypic and functional diversity. However, recent findings have revealed that these cells comprise a large number of distinct populations with diverse characteristics. Some of these characteristics may relate to their developmental origin, and others represent differences in differentiation that are influenced by factors such as tissue localization and imprints by viral infections. In this Review, we provide a comprehensive overview of the emerging knowledge about the development, differentiation and function of human NK cell populations, with a particular focus on NK cells in peripheral tissues. PMID- 27121655 TI - Extending the duration of hypothermia does not further improve white matter protection after ischemia in term-equivalent fetal sheep. AB - A major challenge in modern neonatal care is to further improve outcomes after therapeutic hypothermia for hypoxic ischemic encephalopathy. In this study we tested whether extending the duration of cooling might reduce white matter damage. Term-equivalent fetal sheep (0.85 gestation) received either sham ischemia followed by normothermia (n = 8) or 30 minutes of bilateral carotid artery occlusion followed by three days of normothermia (n = 8), three days of hypothermia (n = 8) or five days of hypothermia (n = 8) started three hours after ischemia. Histology was assessed 7 days after ischemia. Ischemia was associated with loss of myelin basic protein (MBP) and Olig-2 positive oligodendrocytes and increased Iba-1-positive microglia compared to sham controls (p < 0.05). Three days and five days of hypothermia were associated with a similar, partial improvement in MBP and numbers of oligodendrocytes compared to ischemia normothermia (p < 0.05). Both hypothermia groups had reduced microglial activation compared to ischemia-normothermia (p < 0.05). In the ischemia-five-day hypothermia group, but not ischemia-three-day, numbers of microglia remained higher than in sham controls (p < 0.05). In conclusion, delayed cerebral hypothermia partially protected white matter after global cerebral ischemia in fetal sheep. Extending cooling from 3 to 5 days did not further improve outcomes, and may be associated with greater numbers of residual microglia. PMID- 27121651 TI - MicroRNAs as regulatory elements in immune system logic. AB - MicroRNAs (miRNAs) are crucial post-transcriptional regulators of haematopoietic cell fate decisions. They act by negatively regulating the expression of key immune development genes, thus contributing important logic elements to the regulatory circuitry. Deletion studies have made it increasingly apparent that they confer robustness to immune cell development, especially under conditions of environmental stress such as infectious challenge and ageing. Aberrant expression of certain miRNAs can lead to pathological consequences, such as autoimmunity and haematological cancers. In this Review, we discuss the mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output, first at the level of haematopoietic stem cells, then in innate and adaptive immune cells. We then discuss the pathological consequences of dysregulation of these miRNAs. PMID- 27121657 TI - Impact of end-stage renal disease on psychological status and quality of life. AB - BACKGROUND: The aim of this study was to assess depression, anxiety, and quality of life (QOL) in a cohort of children and adolescents with end-stage renal disease (ESRD), to compare these findings with healthy controls, and to evaluate the association between these psychological symptoms, QOL, and clinical variables related to ESRD. METHODS: Thirty-two children and adolescents 8-18 years of age were enrolled in the study. The sociodemographic data were evaluated. Questionnaires were used to evaluate the psychological status and QOL of the patients and healthy controls. RESULTS: There was a significant difference in mean depression score, which was significantly higher for the ESRD patients. Mean state anxiety score was significantly lower for ESRD patients than for controls. Regarding QOL score, there were significant differences between the ESRD patients and control groups for both child-rated and parent-rated QOL scores, which were significantly lower for ESRD patients. Trait anxiety was a negative predictor of all subscales of the Pediatric Quality of Life Inventory 4. CONCLUSIONS: End stage renal disease was related to significant morbidity and poorer QOL. The assessment and enhancement of QOL and comorbid psychiatric disorders in ESRD should be a part of disease management. PMID- 27121656 TI - Body composition estimation using skinfolds in children with and without health conditions affecting growth and body composition. AB - BACKGROUND: Body composition prediction equations using skinfolds are useful alternatives to advanced techniques, but their utility across diverse paediatric populations is unknown. AIM: To evaluate published and new prediction equations across diverse samples of children with health conditions affecting growth and body composition. SUBJECTS AND METHODS: Anthropometric and dual-energy X-ray absorptiometry (DXA) body composition measures were obtained in children with Down syndrome (n = 59), Crohn disease (n = 128), steroid-sensitive nephrotic syndrome (n = 67) and a healthy reference group (n = 835). Published body composition equations were evaluated. New equations were developed for ages 3-21 years using the healthy reference sample and validated in other groups and national survey data. RESULTS: Fat mass (FM), fat-free mass (FFM) and percentage body fat (%BF) from published equations were highly correlated with DXA-derived measures (r = 0.71-0.98), but with poor agreement (mean difference = 2.4 kg, -1.9 kg and 6.3% for FM, FFM and %BF). New equations produced similar correlations (r = 0.85-1.0) with improved agreement for the reference group (0.2 kg, 0.4 kg and 0.0% for FM, FFM and %BF, respectively) and in sub-groups. CONCLUSIONS: New body composition prediction equations show excellent agreement with DXA and improve body composition estimation in healthy children and those with selected conditions affecting growth. PMID- 27121658 TI - Effects of ophiopogonin B on the proliferation and apoptosis of SGC-7901 human gastric cancer cells. AB - Ophiopogonin B (OP-B) is a bioactive component of Radix Ophiopogon japonicus, which is often used in traditional Chinese medicine to treat cancer. The present study aimed to investigate the antitumor activity of OP-B in gastric cancer. Cell Counting kit-8, flow cytometry with Annexin V-fluorescein isothiocyanate, Hoechst staining, mitochondrial membrane potential (MMP) detection, and reactive oxygen species (ROS) assay were used to detect the biological function of SGC-7901 gastric cancer cells. The results demonstrated that high concentrations of OP-B (5, 10 and 20 umol/l) exerted potent antiproliferative effects on SGC-7901 cells in a dose-dependent manner. Furthermore, apoptotic rates were increased and cell morphology was altered following treatment with OP-B. In addition, OP-B-induced apoptosis of SGC-7901 cells was associated with loss of MMP and increased ROS generation. Western blotting indicated that treatment with OP-B increased the protein expression levels of caspase-3 and B-cell lymphoma 2 (Bcl-2)-associated X protein, whereas the expression levels of Bcl-2 and the phosphorylation levels of extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinases 1/2 were decreased. These results suggest that OP-B may be considered a potential inhibitor of gastric cancer progression, and may be used as an alternative compound for its treatment. PMID- 27121659 TI - Factors associated with graft survival and endothelial cell density after Descemet's stripping automated endothelial keratoplasty. AB - Postoperative endothelial cell loss leads to graft failure after corneal transplantation, and is one of the important issues for long-term prognosis. The objective of this study was to identify clinical factors affecting graft survival and postoperative endothelial cell density (ECD) after Descemet's stripping automated endothelial keratoplasty (DSAEK). A total of 198 consecutive Japanese patients (225 eyes) who underwent DSAEK were analysed using Cox proportional hazard regression and multiple linear regression models. The candidate factors included recipient age; gender; diagnosis; pre-existing iris damage state, scored based on its severity; the number of previous intraocular surgeries; graft ECD; graft diameter; simultaneous cataract surgery; surgeons experience; intraoperative iris damage; postoperative rebubbling; and graft rejection. Eyes with higher pre-existing iris damage score and more number of previous intraocular surgery had a significantly higher risk of graft failure (HR = 8.53; P < 0.0001, and HR = 2.66; P = 0.026, respectively). Higher pre-existing iris damage score, lower graft ECD, and smaller graft diameter were identified as significant predisposing factors for lower postoperative ECD. The results show that iris damage status before DSAEK may be clinically useful in predicting the postoperative course. Avoiding intraoperative iris damage, especially in eyes with low ECD can change the prognosis of future DSAEK. PMID- 27121660 TI - Rapid fabrication of poly(DL-lactide) nanofiber scaffolds with tunable degradation for tissue engineering applications by air-brushing. AB - Polymer nanofiber based materials have been widely investigated for use as tissue engineering scaffolds. While promising, these materials are typically fabricated through techniques that require significant time or cost. Here we report a rapid and cost effective air-brushing method for fabricating nanofiber scaffolds using a simple handheld apparatus, compressed air, and a polymer solution. Air-brushing also facilities control over the scaffold degradation rate without adversely impacting architecture. This was accomplished through a one step blending process of high (M w ~ 100 000 g mol(-1)) and low (M w ~ 25 000 g mol(-1)) molecular weight poly(DL-lactide) (PDLLA) polymers at various ratios (100:0, 70:30 and 50:50). Through this approach, we were able to control fiber scaffold degradation rate while maintaining similar fiber morphology, scaffold porosity, and bulk mechanical properties across all of the tested compositions. The impact of altered degradation rates was biologically evaluated in human bone marrow stromal cell (hBMSC) cultures for up to 16 days and demonstrated degradation rate dependence of both total DNA concentration and gene regulation. PMID- 27121661 TI - 20(S)-ginsenoside Rh2 inhibits the proliferation and induces the apoptosis of KG 1a cells through the Wnt/beta-catenin signaling pathway. AB - Previous research has shown that total saponins of Panax ginseng (TSPG) and other ginsenoside monomers inhibit the proliferation of leukemia cells. However, the effect has not been compared among them. Cell viability was determined by Cell Counting Kit-8 assay, and ultra-structural characteristics were observed under transmission electron microscopy. Cell cycle distribution and apoptosis were determined by flow cytometry (FCM). Real-time fluorescence quantitative-PCR, western blotting and immunofluorescence were used to measure the expression of beta-catenin, TCF4, cyclin D1 and NF-kappaBp65. beta-catenin/TCF4 target gene transcription were observed by ChIP-PCR assay. We found that 20(S)-ginsenoside Rh2 [(S)Rh2] inhibited the proliferation of KG-1a cells more efficiently than the other monomers. Moreover, (S)Rh2 arrested KG-1a cells in the G0/G1 phase and induced apoptosis. In addition, the levels of beta-catenin, TCF4, cyclin D1 mRNA and protein were decreased. The ChIP-PCR showed that (S)Rh2 downregulated the transcription of beta-catenin/TCF4 target genes, such as cyclin D1 and c-myc. These results indicated that (S)Rh2 induced cell cycle arrest and apoptosis through the Wnt/beta-catenin signaling pathway, demonstrating its potential as a chemotherapeutic agent for leukemia therapy. PMID- 27121662 TI - Satisfaction With a Family-Focused Intervention for Mild Cognitive Impairment Dyads. AB - PURPOSE: This article describes satisfaction that persons with mild cognitive impairment (PwMCI) and their caregivers had with the Daily Enhancement of Meaningful Activity (DEMA) intervention. METHODS: This randomized controlled pilot study compared satisfaction (usefulness, ease of use, and acceptability) with DEMA (n = 17 dyads) to an information support (IS) control group (n = 19 dyads). Six biweekly sessions (two in person and four by telephone) were delivered by trained nurses. Data analysis included descriptive statistics, independent-sample t tests, and content analysis. FINDINGS: PwMCI receiving DEMA rated their satisfaction significantly higher (p = .033) than did the control group; there was no difference in satisfaction between caregivers across groups. Qualitative interview data supported the usefulness, ease of use, and acceptability of DEMA for both PwMCI and caregivers. CONCLUSIONS: Results documented PwMCI's satisfaction with DEMA as implemented by nurses to support PwMCI-caregiver dyads' engagement in meaningful activity. DEMA may need revision to increase satisfaction for caregivers. CLINICAL RELEVANCE: The DEMA intervention was evaluated as useful, easy to use, and acceptable to PwMCI and their caregivers based on positive mean ratings. The study findings provide preliminary support of DEMA as a means to improve quality of life by helping to support patient and caregiver engagement in meaningful activities and problem solving. PMID- 27121663 TI - Patients with rosacea have increased risk of dementia. AB - OBJECTIVE: Rosacea is a common chronic inflammatory skin disorder where upregulation of matrix metalloproteinases (MMPs) and antimicrobial peptides (AMPs) is observed. Notably, inflammation, MMPs, and AMPs are also involved in the etiopathogenesis of neurodegenerative disorders including certain forms of dementia such as Alzheimer disease (AD). Based on several clinical observations, we investigated the association between rosacea and dementia, including AD in Danish registers. METHODS: All Danish citizens aged >=18 years between January 1, 1997 and December 31, 2012 were linked at the individual level through administrative registers. Cox regression was used to calculate unadjusted and adjusted hazard ratios (HRs). RESULTS: The study comprised a total of 5,591,718 individuals, including 82,439 patients with rosacea. A total of 99,040 individuals developed dementia (any form) in the study period, of whom 29,193 were diagnosed with AD. The adjusted HRs of dementia and AD were 1.07 (95% confidence interval [CI] = 1.01-1.14), and 1.25 (95% CI = 1.14-1.37), respectively, in patients with rosacea. Stratified by sex, the HRs of AD were 1.28 (95% CI = 1.15-1.45) and 1.16 (95% CI = 1.00-1.35) in women and men, respectively. When results were stratified by age at study entry, the risk of AD was only significantly increased in individuals >=60 years old (adjusted HR = 1.20, 95% CI = 1.08-1.32). When analyses were limited to patients with a hospital dermatologist diagnosis of rosacea only, the adjusted HRs of dementia and AD were 1.42 (95% CI = 1.17-1.72) and 1.92 (95% CI = 1.44-2.58), respectively. INTERPRETATION: Rosacea is significantly associated with dementia, particularly AD. Increased focus on symptoms of cognitive dysfunction in older patients with rosacea may be relevant. Ann Neurol 2016;79:921-928. PMID- 27121664 TI - The Seventy-Kilogram Fantasy. PMID- 27121665 TI - Model-Supported Development of CS-8635: A Fixed-Dose Combination of Olmesartan, Amlodipine, and Hydrochlorothiazide. AB - CS-8635, a fixed-dose triple combination of olmesartan, amlodipine, and hydrochlorothiazide, was developed to address the growing need for additional blood pressure (BP) reduction in patients not controlled with dual-combination therapies. Prior to Phase III, modeling and simulation (M&S) was conducted to estimate the additional BP lowering effect of CS-8635 compared to the respective dual combinations. The Phase III study evaluated CS-8635 BP lowering effects only at the highest dose strength among the five dose strengths to be developed. Post trial M&S was performed using an integrated dataset from three Phase III programs; CS-8635 plus two prior dual combinations. M&S robustly estimated and described the BP lowering effects of CS-8635 evaluated in a clinical setting. Furthermore, M&S evaluated BP lowering effects of the additional four dose strengths not studied. In summary, M&S aided the development of the clinical study and full characterization of the BP lowering effects of CS-8635 across intermediate doses. PMID- 27121666 TI - Effect of Multiple-Dose Diltiazem on the Pharmacokinetics of the Renin Inhibitor ACT-077825. AB - This open-label, randomized study evaluated the effects of steady-state diltiazem on the pharmacokinetic, safety, and tolerability profile of a single dose of the novel renin inhibitor ACT-077825. Twelve healthy Caucasian male subjects (20-50 years) received in treatment sequence A, a single dose of 100 mg ACT-077825 (Days 1 and 17), and oral diltiazem 300 mg once daily (Days 14-26). In treatment sequence B, subjects received a single dose of 100 mg ACT-077825 (Days 4 and 22) and oral diltiazem 300 mg once daily (Days 1-13). ACT-077825 alone and combined with diltiazem was generally well tolerated. On average, the systemic exposure to ACT-077825 was higher in the presence of diltiazem. For AUC0-infinity and t1/2 , the upper limit of the 90% confidence interval (CI) of the geometric mean ratios was outside the study-specific 0.5-2.0 equivalence boundaries, that is, 1.92 (90% CI: 1.30, 2.83) and 1.58 (90% CI: 1.22, 2.04), respectively. In conclusion, diltiazem markedly affected the pharmacokinetics of ACT-077825, probably via inhibition of CYP3A4 activity, without changing its safety and tolerability profile in healthy male subjects. Whether such an interaction will require for therapeutic dose adjustment of ACT-077825 co-administered with diltiazem has to be assessed once the dose-response relationship of ACT-077825 in hypertensive patients is determined. PMID- 27121667 TI - Pharmacokinetics and Safety of Migalastat HCl and Effects on Agalsidase Activity in Healthy Volunteers. AB - Migalastat HCl is an investigational, oral treatment for Fabry disease, an X linked lysosomal storage disorder. Four Phase 1 studies were conducted to determine the pharmacokinetics, pharmacodynamics, safety, and tolerability of migalastat. Healthy volunteers (N = 124), 18-55 years old, received migalastat HCl single (25 mg-2000 mg) or twice-daily doses (50 mg, 150 mg) for 7 days in a double-blind, placebo-controlled fashion. Migalastat pharmacokinetics were dose proportional (AUCinfinity range: 1129-72 838 ng h/mL, Cmax range: 200.5-13 844 ng/mL, t1/2 3-4 hours). Steady state was achieved by Day 7. Up to 67% of the dose was excreted as unchanged drug in urine. Increased alpha-Gal A activity was dose related. No abnormal cardiac effects, including prolonged QTc intervals, were observed. The pharmacokinetics of migalastat were well characterized in these Phase 1 studies conducted healthy volunteers. The 150 mg dose of migalastat HCl administered BID for 7 days was generally safe and well tolerated. A TQT study demonstrated lack of a positive signal at therapeutic and supra-therapeutic doses. Increases in alpha-Gal A enzyme activity for the 150 mg dose observed in healthy subjects suggested a successful proof of mechanism for further investigations. PMID- 27121668 TI - Clinical Safety, Pharmacokinetics, and Pharmacodynamics of the 11beta Hydroxysteroid Dehydrogenase Type 1 Inhibitor ABT-384 in Healthy Volunteers and Elderly Adults. AB - ABT-384 is a potent and selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (HSD-1), the enzyme that regenerates cortisol in several tissues. Two clinical studies of ABT-384 were undertaken to assess its safety, pharmacokinetics, target engagement, and pharmacologic effects in healthy subjects. Single doses from 1 to 240 mg, and multiple doses from 1 to 100 mg once daily for 7-14 days, were administered to healthy adults. Multiple doses from 10 to 100 mg once daily for 21 days were administered to elderly subjects. A total of 103 subjects received at least 1 dose of ABT-384. A maximum-tolerated dose was not defined in either study. The pharmacokinetic profiles of ABT-384 and its active metabolite support once daily dosing. Analysis of urine cortisol metabolites demonstrated full hepatic HSD-1 inhibition with regimens from 1 mg daily, and confirmed in vitro target selectivity. Pharmacologic effects included increases of adrenocorticotrophic hormone levels, cortisol production and androgen and estradiol levels. ABT-384 has a wide therapeutic index relative to full hepatic target engagement which is relevant for indications such as diabetes and metabolic syndrome. Its therapeutic index for other potential indications such as Alzheimer's disease remains to be established. PMID- 27121669 TI - Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose Dependent Glucosuria in Healthy Subjects. AB - Empagliflozin is an orally available, selective inhibitor of sodium glucose cotransporter 2. In this study, single oral doses of empagliflozin from 0.5 to 800 mg were not associated with any clinically significant safety concerns in healthy male volunteers. The incidence of adverse events (AEs) was similar in subjects receiving placebo (22.2%) or empagliflozin (25.0%) in the single rising dose part of the study and after 50 mg empagliflozin under fed (28.6%) or fasted (28.6%) conditions. The most frequent AE was headache. No clinically relevant changes in laboratory or electrocardiogram (ECG) measurements were observed. Single oral doses of empagliflozin were rapidly absorbed, reaching peak levels after 1.0-2.1 hours. Increases in empagliflozin exposure were roughly dose proportional and a dose-dependent increase in urinary glucose excretion was observed for empagliflozin doses up to 100 mg. After ingestion of 50 mg empagliflozin in conjunction with a high-fat, high-calorie meal, no clinically relevant changes in exposure were found, indicating that empagliflozin can be administered independent of food. Empagliflozin up to 800 mg did not generate clinically significant safety concerns in healthy male subjects. The pharmacokinetic properties of empagliflozin support once daily administration independent of food. PMID- 27121670 TI - A Population Pharmacokinetic Analysis of Fimasartan, a Selective Angiotensin II Receptor Antagonist, in Healthy Caucasian Subjects and Korean Patients With Hypertension. AB - A population pharmacokinetic (PK) model of fimasartan, a selective angiotensin II receptor antagonist, was developed and significant covariates for its PK parameters were identified using 1438 plasma concentrations from 69 subjects (aged 19-64 years, weighing 43.5-95.3 kg), enrolled in 2 phase I studies (n = 42, 96.4% Caucasian) and a phase II study (n = 27, Korean hypertensive patients). The nonlinear mixed-effects analysis method by NONMEM was used, and the final model was qualified using sensitivity analysis, bootstrapping, and visual predictive checks. A two-compartment open linear PK model with mixed zero- and lagged first order absorption best described observed plasma fimasartan concentrations. The typical value of the apparent clearance of fimasartan for those weighing 70 kg with total bilirubin of 0.7 mg/dL was 176 L/h (95% confidence interval: 163-189 L/h), and its interindividual and interoccasion variability as coefficient of variation was 26.9% (20.5-31.6%) and 10.5% (6.3-15.5%), respectively. Simulation of steady state concentrations indicated body weight was the most influential covariate on the exposure of fimasartan (i.e., lower level in heavier subjects). The population PK model of fimasartan should be refined as more studies are conducted in various clinical conditions. PMID- 27121671 TI - Pharmacokinetics and Bioequivalence Evaluation of 2 Loxoprofen Tablets in Healthy Egyptian Male Volunteers. AB - The objective of this study was to assess the in vitro dissolution and to evaluate the bioavailability of two brands of Loxoprofen sodium dihydrate tablets. Loxoprofen tablets (68.1 mg loxoprofen sodium dihydrate equivalent to 60 mg loxoprofen; test) relative to Roxonin tablets (68.1 mg loxoprofen sodium dihydrate equivalent to 60 mg loxoprofen; reference). In vitro study was adopted to determine and compare the dissolution behavior of both products. In vivo study was conducted according to a single-center, randomized, single-dose, and laboratory-blinded, 2-period, 2-sequence, crossover design with a washout period of 1 week. Under fasting conditions, 24 healthy Egyptian adult male volunteers were randomly allocated to receive a single dose of either test or reference product. Blood samples were collected at specified time intervals, and plasma was analyzed for loxoprofen concentrations using a validated high-performance liquid chromatography assay method. The pharmacokinetic parameters Cmax , AUC0-t , AUC0 infinity , tmax , and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio Cmax , AUC0-t , and AUCt infinity of the test product over those of reference were within the acceptable range (0.8-1.25) for bioequivalence. On the basis of these results, the two loxoprofen formulations are considered bioequivalent. PMID- 27121672 TI - Pharmacokinetic Studies of Cysteamine Bitartrate Delayed-Release. AB - A twice-daily microsphere formulation of cysteamine bitartrate has been developed for cystinosis and other potential applications. To date, there are no published pharmacokinetic data for cysteamine bitartrate delayed-release in healthy adults. Three randomized open-label, crossover studies to determine the effects of fasting, high fat, and carbohydrate meals on the bioavailability of cysteamine bitartrate delayed-release (600 mg) administered in capsule or sprinkle form to healthy adults. Adverse events were monitored. Fifty-eight adults were studied. Cysteamine absorption (AUC0-24 hours ) was the same for capsule and sprinkle forms during all meal/fasting states. The AUC0-24 hours for capsules while fasted, 30 and 120 minutes before a carbohydrate meal and during a high fat meal were 6,313 +/- 329, 4,616 +/- 878, 6,691 +/- 669, 2,572 +/- 295 minutes * uM, respectively, and the mean Cmax values were 29.4 +/- 1.7, 20.7 +/- 4.9, 31.6 +/- 3.0, and 10.9 +/- 1.7 uM, respectively. The mean Tmax following fasting and high fat meal were about 3 and 6 hours, respectively. Minor transient GI adverse events occurred. Cysteamine bitartrate delayed-release capsule and sprinkle forms are bioequivalent and optimal absorption occurs during fasting state. High fat diet reduces drug absorption, increases the Tmax and should be avoided at the time of drug ingestion. Cysteamine bitartrate delayed-release (RP103) is best ingested >30 minutes before a carbohydrate-rich meal. PMID- 27121673 TI - Pharmacokinetic Profile of Orally Administered Scyllo-Inositol (Elnd005) in Plasma, Cerebrospinal Fluid and Brain, and Corresponding Effect on Amyloid-Beta in Healthy Subjects. AB - ELND005 (scyllo-inositol), an endogenous inositol stereoisomer, is being investigated as an oral treatment for Alzheimer's disease (AD). Pharmacokinetics of ELND005 in plasma, cerebrospinal fluid (CSF), and brain was characterized in healthy young subjects. Eight men received 2000 mg ELND005 every 12 hours for 10 days. Plasma and CSF samples were collected at predetermined time points; ELND005 and amyloid-beta (Abeta) fragments were measured by validated bioanalytical methods. Brain ELND005 levels, estimated by (1) H Magnetic Resonance Spectroscopy (MRS) scans were obtained from gray/white matter voxels at baseline and Day 8. ELND005 was well-tolerated during the study. During the apparent steady state, ELND005 plasma levels rapidly peaked at 39.8 ug/mL and decreased to an average trough concentration of 10.6 ug/mL at the end of the 12-hour dosing regimen. In contrast, CSF drug levels slowly peaked at 13.7 ug/mL and remained near the same level with average trough concentrations of 12.4 ug/mL. At Day 8, Brain ELND005 concentrations increased by 58-76% compared to baseline levels. The CSF concentrations achieved in this study were similar to those associated with efficacy in transgenic models of AD. No changes were detected in plasma and CSF levels of Abeta fragments. PMID- 27121674 TI - Pitavastatin Concentrations Are Not Increased by CYP3A4 Inhibitor Itraconazole in Healthy Subjects. AB - Itraconazole is a synthetic triazole antifungal agent which is known to be a potent inhibitor of cytochrome P450 (CYP) 3A4, and may cause drug-drug interactions with the many drugs metabolized by this route, including some statins. In this study, the influence of concomitant administration of a single oral dose of pitavastatin with itraconazole at steady state was investigated to determine the potential for pharmacokinetic interaction and any effects on safety. Eighteen subjects were enrolled into the study. The AUC and Cmax of pitavastatin alone were 138 ng h/mL and 63.8 ng/mL, and pitavastatin with itraconazole were 106 ng h/mL and 49.5 ng/mL, respectively. Comparison of the 90% confidence interval of the geometric mean ratio of AUC0-t and Cmax against a standard reference of 0.80-1.25 demonstrated that the lower limit was breached for both pitavastatin and its lactone metabolite (0.71-0.84 and 0.69-0.88 for AUC0-t and Cmax , respectively, for pitavastatin, 0.86-0.97 and 0.76-0.86 for AUC0-t and Cmax , respectively, for pitavastatin lactone). The safety and tolerability of pitavastatin was not affected by co-administration with itraconazole. This study suggests that pitavastatin is not a CYP3A4 substrate in humans. PMID- 27121675 TI - Outcome measures evaluating hand function in children with bilateral cerebral palsy: a systematic review. AB - AIM: To review outcome measures used to evaluate hand function, with emphasis on manual capacity and performance, in children with bilateral cerebral palsy (CP), to describe the content and measurement properties of such measures, and to investigate the quality of the studies that have examined these properties. METHOD: Embase, MEDLINE, PubMed, and CINAHL were searched. The COSMIN-criteria (COnsensus-based Standards for the selection of health Measurement INstruments) were used to assess the quality of studies and the Terwee criteria were used to assess the result of the studies. RESULTS: Five hand function measures were identified from 16 papers. The strongest level of evidence for aspects of validity and reliability was found for the Melbourne Assessment 2, assessing unimanual capacity, and for the questionnaire ABILHAND-Kids, assessing perceived manual ability in daily activities. However, evidence for the responsiveness of these measures is missing. INTERPRETATION: Further high-quality studies providing evidence for responsiveness, as well as for additional aspects of validity and reliability of the Melbourne Assessment 2 and the ABILHAND-Kids, are needed. Furthermore, there is a need to develop appropriate outcome measures evaluating how children with bilateral CP use their hands when handling objects in bimanual tasks. PMID- 27121676 TI - mglur6b:EGFP Transgenic zebrafish suggest novel functions of metabotropic glutamate signaling in retina and other brain regions. AB - Metabotropic glutamate receptors (mGluRs) are mainly known for regulating excitability of neurons. However, mGluR6 at the photoreceptor-ON bipolar cell synapse mediates sign inversion through glutamatergic inhibition. Although this is currently the only confirmed function of mGluR6, other functions have been suggested. Here we present Tg(mglur6b:EGFP)zh1, a new transgenic zebrafish line recapitulating endogenous expression of one of the two mglur6 paralogs in zebrafish. Investigating transgene as well as endogenous mglur6b expression within the zebrafish retina indicates that EGFP and mglur6b mRNA are not only expressed in bipolar cells, but also in a subset of ganglion and amacrine cells. The amacrine cells labeled in Tg(mglur6b:EGFP)zh1 constitute a novel cholinergic, non-GABAergic, non-starburst amacrine cell type described for the first time in teleost fishes. Apart from the retina, we found transgene expression in subsets of periventricular neurons of the hypothalamus, Purkinje cells of the cerebellum, various cell types of the optic tectum, and mitral/ruffed cells of the olfactory bulb. These findings suggest novel functions of mGluR6 besides sign inversion at ON bipolar cell dendrites, opening up the possibility that inhibitory glutamatergic signaling may be more prevalent than currently thought. J. Comp. Neurol. 524:2363-2378, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27121677 TI - Diamondoid-functionalized gold nanogaps as sensors for natural, mutated, and epigenetically modified DNA nucleotides. AB - Modified tiny hydrogen-terminated diamond structures, known as diamondoids, show a high efficiency in sensing DNA molecules. These diamond cages, as recently proposed, could offer functionalization possibilities for gold junction electrodes. In this investigation, we report on diamondoid-functionalized electrodes, showing that such a device would have a high potential in sensing and sequencing DNA. The smallest diamondoid including an amine modification was chosen for the functionalization. Here, we report on the quantum tunneling signals across diamondoid-functionalized Au(111) electrodes. Our work is based on quantum-transport calculations and predicts the expected signals arising from different DNA units within the break junctions. Different gating voltages are proposed in order to tune the sensitivity of the functionalized electrodes with respect to specific nucleotides. The relation of this sensitivity to the coupling or decoupling of the electrodes is discussed. Our results also shed light on the sensing capability of such a device in distinguishing the DNA nucleotides, in their natural and mutated forms. PMID- 27121678 TI - Association between mitochondrial DNA haplogroup and myelodysplastic syndromes. AB - Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non-Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS-R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population-based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. (c) 2016 Wiley Periodicals, Inc. PMID- 27121679 TI - Roles of SHARP1 in thyroid cancer. AB - SHARP1 is a basic helix-loop-helix transcription factor involved in various cellular processes, including proliferation and differentiation. The present study assessed the role of SHARP1 in the progression and invasion of thyroid cancer. PCR and western blot analysis demonstrated that in thyroid cancer tissues, SHARP1 was significantly downregulated at the mRNA and protein level compared with that in normal tissues. Furthermore, SHARP1 was downregulated in the TT and TPC-1 thyroid cancer cell lines compared with a normal thyroid cell line, while it was upregulated in other thyroid cancer cell lines. Overexpression of SHARP1 in TT and TPC-1 cells significantly inhibited the cell viability, migration and invasion in vitro. Furthermore, the protein and mRNA levels of HIF 1alpha were found to be decreased in TT and TPC-1 cells following forced overexpression of SHARP1. In addition, silencing of HIF-1alpha reduced the viability, migration and invasion of TT and TPC-1 cells. In conclusion, the present study indicated that SHARP1 acts as a tumor suppressor in thyroid cancer and that its downregulation may contribute to the proliferation, migration and invasion of thyroid cancer cells through mechanisms possibly involving HIF 1alpha, suggesting that SHARP1 may be an important therapeutic target for the treatment of thyroid cancer. PMID- 27121680 TI - Corrigendum: TET-catalyzed 5-hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer. PMID- 27121682 TI - Screening for grades of frailty using electronic health records: where do we go from here? PMID- 27121683 TI - Exercise for reducing fear of falling in older people living in the community: Cochrane systematic review and meta-analysis. AB - OBJECTIVE: to determine the effect of exercise interventions on fear of falling in community-living people aged >=65. DESIGN: systematic review and meta analysis. Bibliographic databases, trial registers and other sources were searched for randomised or quasi-randomised trials. Data were independently extracted by pairs of reviewers using a standard form. RESULTS: thirty trials (2,878 participants) reported 36 interventions (Tai Chi and yoga (n = 9); balance training (n = 19); strength and resistance training (n = 8)). The risk of bias was low in few trials. Most studies were from high-income countries (Australia = 8, USA = 7). Intervention periods (<12 weeks = 22; 13-26 weeks = 7; >26 weeks = 7) and exercise frequency (1-3 times/week = 32; >=4 times/week = 4) varied between studies. Fear of falling was measured by single-item questions (7) and scales measuring falls efficacy (14), balance confidence (9) and concern or worry about falling (2). Meta-analyses showed a small to moderate effect of exercise interventions on reducing fear of falling immediately post-intervention (standardised mean difference (SMD) 0.37, 95% CI 0.18, 0.56; 24 studies; low quality evidence). There was a small, but not statistically significant effect in the longer term (<6 months (SMD 0.17, 95% CI -0.05, 0.38 (four studies) and >=6 months post-intervention SMD 0.20, 95% CI -0.01, 0.41 (three studies)). CONCLUSIONS: exercise interventions probably reduce fear of falling to a small to moderate degree immediately post-intervention in community-living older people. The high risk of bias in most included trials suggests findings should be interpreted with caution. High-quality trials are needed to strengthen the evidence base in this area. PMID- 27121684 TI - Serum chloride in heart failure: a salty prognosis. PMID- 27121686 TI - Electrochemical de-alloying in two dimensions: role of the local atomic environment. AB - We investigate by in situ scanning tunnelling microscopy (STM) the potential dependence of the electrochemical dealloying of NiPd monoatomic layers electrodeposited on Au(111). The dealloying process is achieved by Ni selective dissolution and was studied as a function of NiPd composition: for an alloy with a Ni content >=70%, quasi-complete Ni dissolution is achieved at a potential of 0.9 VMSE whereas for a Ni content <70%, Ni dissolution at the same potential drastically slows down after the removal of small amounts of Ni. The alloy morphology at this "passivation state" is characterized by the presence of holes in the alloy monolayer with evidence for the Pd enrichment at the hole edges. These findings are confirmed by Monte Carlo simulations. Further Ni dissolution at passivation was achieved by applying more positive potentials which depend on the alloy composition. These results allowed us to determine the correlation between the Ni dissolution onset potential and the local Pd content. PMID- 27121685 TI - New endoscopic classification of cascade stomach, a risk factor for reflux esophagitis. AB - BACKGROUND: We recently demonstrated that cascade stomach detected by barium studies was correlated with upper gastrointestinal symptoms. We developed a new endoscopic classification of cascade stomach and examined its relationship with reflux esophagitis. METHODS: Study 1: the classification (grades 0-3) was based on detecting a ridge that runs from the cardia toward the anterior wall crossing the greater curvature. Inter-observer variation was evaluated by kappa statistics when ten experienced endoscopists used this classification three times each. Study 2: in 710 consecutive subjects (500 men and 210 women) undergoing endoscopic screening, the grade of cascade stomach and incidence of reflux esophagitis were compared. RESULTS: In study 1, the kappa values at the third assessment were 0.85, 0.58, 0.50, and 0.78 for each grade, respectively, while overall agreement was 0.68. In study 2, the incidence of reflux esophagitis in men was 20 % in grade 0, 17 % in grade 1, 25 % in grade 2, and 30 % in grade 3, showing significant differences. Among women, the incidence of reflux esophagitis in each grade was 9, 3, 6, and 35 %, respectively, also showing significant differences. Multivariate analysis showed that independent risk factors for reflux esophagitis were cascade stomach (odds ratio = 2.20), body mass index, and hiatus hernia in men, as well as cascade stomach (odds ratio = 9.01) and smoking tobacco in women. CONCLUSIONS: This endoscopic classification of cascade stomach showed acceptable inter-observer variation. Cascade stomach is a risk factor for reflux esophagitis. PMID- 27121687 TI - Role of time delay on intracellular calcium dynamics driven by non-Gaussian noises. AB - Effect of time delay (tau) on intracellular calcium dynamics with non-Gaussian noises in transmission processes of intracellular Ca(2+) is studied by means of second-order stochastic Runge-Kutta type algorithm. By simulating and analyzing time series, normalized autocorrelation function, and characteristic correlation time of cytosolic and calcium store's Ca(2+) concentration, the results exhibit: (i) intracellular calcium dynamics's time coherence disappears and stability strengthens as tau -> 0.1s; (ii) for the case of tau < 0.1s, the normalized autocorrelation functions of cytosolic and calcium store's Ca(2+) concentration show damped motion when tau is very short, but they trend to a level line as tau > 0.1s, and for the case of tau > 0.1s, they show different variation as tau increases, the former changes from underdamped motion to a level line, but the latter changes from damped motion to underdamped motion; and (iii) at the moderate value of time delay, reverse resonance occurs both in cytosol and calcium store. PMID- 27121690 TI - Effect of adjuvant lithium on thyroxine (T4) concentration after radioactive iodine therapy. AB - PURPOSE: To study the effect of adjuvant lithium on serum thyroxine (T4) concentrations in patients treated with radioactive iodine (RAI) therapy in our environment. METHODS: This was a prospective simple randomized comparative, experimental cohort study of patients with hyperthyroidism referred for RAI ablation therapy in the two main academic hospitals in Johannesburg between February 2014 and September 2015. RESULTS: Amongst the 163 participants in the final analysis, 75 received RAI alone and 88 received RAI with lithium. The difference in mean T4 concentrations at 3 months between the RAI-only group (17.67 pmol/l) and the RAI with lithium group (11.55 pmol/l) was significant with a small effect size (U = 2328.5, Z = -2.700, p = 0.007, r = 0.01). Significant decreases in T4 concentrations were observed as early as 1 month after RAI (p = 0.0001) in the RAI with lithium group, but in the RAI-only group, significant decreases in T4 concentrations were observed only at 3 months after RAI therapy (p = 0.000). Women and patients with Graves' disease who received RAI with adjuvant lithium also showed significant decreases in T4 concentrations at 1 month (p = 0.002 and p = 0.003, respectively). CONCLUSION: Adjuvant lithium leads to an earlier and better response to RAI therapy with lower T4 concentrations that are achieved earlier. This earlier response and decrease in T4 concentrations were noted in patients with Graves' disease and nodular goitre, and in women with hyperthyroidism who received adjuvant lithium therapy. PMID- 27121689 TI - Radium-223 dichloride in clinical practice: a review. AB - The onset of skeletal metastases is typical of advanced-stage prostate cancer and requires a multidisciplinary approach to alleviate bone pain and try to delay disease progression. The current therapeutic armamentarium includes conventional analgesics, chemotherapeutic agents, immunotherapy, androgen-deprivation therapy, osteoclast inhibitors (bisphosphonates, denosumab), surgical interventions, external-beam radiotherapy and radionuclide metabolic therapy. Many studies in recent decades have demonstrated the efficacy of various radiopharmaceuticals, including strontium-89 and samarium-153, for palliation of pain from diffuse skeletal metastases, but no significant benefit in terms of disease progression and overall survival has been shown. The therapeutic landscape of metastatic skeletal cancer significantly changed after the introduction of radium-223, the first bone-homing radiopharmaceutical with disease-modifying properties. In this paper we extensively review the literature on the use of radium-223 dichloride in metastatic castration-resistant prostate cancer. PMID- 27121691 TI - 18F-fluorocholine versus 18F-fluorodeoxyglucose for PET/CT imaging in patients with suspected relapsing or progressive multiple myeloma: a pilot study. AB - PURPOSE: Hybrid positron emission tomography/computed tomography (PET/CT) has now become available, as well as whole-body, low-dose multidetector row computed tomography (MDCT) or magnetic resonance imaging (MRI). The radioactive glucose analogue 18F-fluorodeoxyglucose (FDG) is the most widely used tracer but has a relatively low sensitivity in detecting multiple myeloma (MM). We compared FDG with a more recent metabolic tracer, 18F-fluorocholine (FCH), for the detection of MM lesions at time of disease relapse or progression. METHODS: We analyzed the results of FDG and FCH imaging in 21 MM patients undergoing PET/CT for suspected relapsing or progressive MM. For each patient and each tracer, an on-site reader and a masked reader independently determined the number of intraosseous and extraosseous foci of tracer and the intensity of uptake as measured by their SUVmax and the corresponding target/non-target ratio (T/NT). RESULTS: In the skeleton of 21 patients, no foci were found for two cases, uncountable foci were observed in four patients, including some mismatched FCH/FDG foci. In the 15 patients with countable bone foci, the on-site reader detected 72 FDG foci vs. 127 FCH foci (+76 %), whereas the masked reader detected 69 FDG foci vs. 121 FCH foci (+75 %), both differences being significant. Interobserver agreement on the total number of bone foci was very high, with a kappa coefficient of 0.81 for FDG and 0.89 for FCH. Measurement of uptake in the matched foci that took up both tracers revealed a significantly higher median SUVmax and T/NT for FCH vs. FDG. Almost all unmatched foci were FCH-positive FDG-negative (57/59 = 97 % on-site and 56/60 = 93 % on masked reading); they were more frequently observed than matched foci in the head and neck region. CONCLUSIONS: These findings suggest that PET/CT performed for suspected relapsing or progressive MM would reveal more lesions when using FCH rather than FDG. PMID- 27121692 TI - Diffuse bone metastases on (68)Ga-PSMA PET-CT in a patient with prostate cancer and normal bone scan. AB - A 75-year-old patient was diagnosed with a Gleason 9 prostate carcinoma. His PSA level was 50.4 ng/ml. Routine bone scintigraphy was negative for metastasis (a). Due to the high tumour grading and relatively high PSA level, (68)Ga-PSMA PET-CT was ordered to rule out distant metastases. This scan showed numerous skeletal lesions with high tracer accumulation as sign of diffuse osseous metastases (b). On low-dose CT there were no signs of sclerosis (c). (68)Ga-PSMA PET-CT also showed high uptake in the prostate and in para-iliac and para-aortal lymph nodes, without lymph node enlargement. No bone biopsy was obtained to confirm the metastases. Due to this result, the treatment plan was changed to systemic therapy, instead of local therapy. PMID- 27121688 TI - European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. AB - Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life. PMID- 27121693 TI - Insights into enzyme point mutation effect by molecular simulation: phenylethylamine oxidation catalyzed by monoamine oxidase A. AB - The I335Y point mutation effect on the kinetics of phenylethylamine decomposition catalyzed by monoamine oxidase A was elucidated by means of molecular simulation. The established empirical valence bond methodology was used in conjunction with the free energy perturbation sampling technique and a classical force field representing the state of reactants and products. The methodology allows for the simulation of chemical reactions, in the present case the breaking of the alpha-C H bond in a phenylethylamine substrate and the subsequent hydrogen transfer to the flavin cofactor, resulting in the formation of the N-H bond on flavin. The empirical parameters were calibrated against the experimental data for the simulated reaction in a wild type protein and then used for the calculation of the reaction free energy profile in the I335Y mutant. In very good agreement with the measured kinetic data, mutation increases the free energy barrier for the rate limiting step by slightly more than 1 kcal mol(-1) and consequently decreases the rate constant by about an order of magnitude. The magnitude of the computed effect slightly varies with simulation settings, but always remains in reasonable agreement with the experiment. Analysis of trajectories reveals a major change in the interaction between phenyl rings of the substrate and the neighboring Phe352 residue upon the I335Y mutation due to the increased local polarity, leading to an attenuated quadrupole interaction between the rings and destabilization of the transition state. Additionally, the increased local polarity in the mutant allows for a larger number of water molecules to be present near the active site, effectively shielding the catalytic effect of the enzyme and contributing to the increased barrier. PMID- 27121694 TI - Erratum to: The Elements Steering Pathogenesis in IgG-Mediated Alloimmune Diseases. PMID- 27121696 TI - Micafungin and a case of polymorphic ventricular tachycardia. AB - WHAT IS KNOWN AND OBJECTIVE: Although echinocandins are relatively safe antifungal drugs, cardiovascular toxicity is an emerging adverse event. This report reviews those side effects and describes a case of polymorphic ventricular tachycardia suggestive of torsades de pointes with micafungin. CASE DESCRIPTION: The patient was on micafungin for oesophageal candidiasis due to drug-drug interactions with fluconazole and amiodarone. WHAT IS NEW AND CONCLUSION: This is the first known case of polymorphic ventricular tachycardia with micafungin as the possible cause. Clinicians should be aware of this potential adverse event and monitor patients receiving concomitant drugs that can prolong QT interval. PMID- 27121695 TI - High expression of DDX20 enhances the proliferation and metastatic potential of prostate cancer cells through the NF-kappaB pathway. AB - DEAD (Asp-Glu-Ala-Asp) box polypeptide 20 (DDX20), a member of the DEAD box protein family, encodes an RNA helicase. Previous research has revealed that DDX20 may act as a tumor suppressor in hepatocellular carcinoma and as a tumor promoter in breast cancer. These conflicting reports prompted us to explore the role of DDX20 in prostate cancer (PCa). To gain insight into the functions of DDX20 in PCa, we examined DDX20 expression patterns in a PCa tissue microarray with 99 PCa tissue samples. The results of immunohistochemical staining revealed that DDX20 expression is frequently upregulated in PCa tissues compared with that in the adjacent tissues and further clinicopathological analysis showed that the expression level of DDX20 closely correlates with tumor size, TNM stage (positive correlation) and patient prognosis (negative correlation). Both gain-of- and loss of-function assays were performed in vitro; the overexpression of DDX20 enhanced the proliferation and metastatic potential of cancer cells and this was examined by performing a cell counting kit-8 (CCK-8) assay, wound healing assay and Transwell migration assay. Furthermore, we found that there is a positive correlation between the expression of matrix metallopeptidase 9 (MMP9) and DDX20 expression. These findings led us to examine whether DDX20 may exert effects through the NF-kappaB pathway. Luciferase reporter assays suggested that DDX20 altered the activity of NF-kappaB. Taken together, these findings show that DDX20 may promote the progression of PCa through the NF-kappaB pathway. PMID- 27121697 TI - Effect of the oral iron chelator deferiprone in diabetic nephropathy rats. AB - BACKGROUND: The aim of the present study was to investigate the effects of the iron chelator deferiprone in diabetic nephropathy (DN) rats and the mechanisms involved. METHODS: Thirty-two male Wistar rats (180-220 g, 6 weeks old) were randomly divided into a control group, a DN group and two DN groups treated with either 50 or 100 mg/kg per day deferiprone. The DN group was established by feeding of a high-carbohydrate-fat diet and injection of 35 mg/kg streptozotocin into the vena caudalis. The duration of deferiprone treatment was 20 weeks. Histopathological changes were detected by hematoxylin-eosin and Masson staining, as well as transmission electron microscopy. Levels of nuclear factor (NF) kappaB, monocyte chemotactic protein (MCP)-1, matrix metalloproteinase (MMP)-9, tissue-specific inhibitor of metalloproteinase (TIMP)-1, cyclo-oxygenase (COX)-2, and nitrotyrosine were determined in kidney tissues using reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. RESULTS: Histopathological observations showed that deferiprone treatment alleviated inflammation infiltrates and collagenous fibrosis in DN rats. Results from RT-PCR and western blotting indicated that deferiprone inhibited the expression of NF-kappaB, MCP-1, COX-2, and nitrotyrosine, which were overexpressed in DN rats. Immunohistochemistry showed that the mechanism of deferiprone action may involve regulation of MMP-9 and TIMP-1. Decreased MMP-9 expression and increased TIMP-1 expression in DN rats were significantly promoted and inhibited by deferiprone, respectively. CONCLUSION: Iron chelation by oral deferiprone has a renoprotective effect in DN rats by relieving oxidative stress, inflammation, and fibrosis, which is related to the cytokines NF-kappaB, MCP-1, MMP-9, TIMP-1, COX-2, and nitrotyrosine. PMID- 27121698 TI - Significance of epithelial cell clusters in pseudomyxoma peritonei. AB - BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterised by distension of the peritoneum by jelly-like ascites. Cytological evaluation of peritoneal fluid is often an initial diagnostic test for possible ovarian and/or appendiceal primary tumours. AIMS AND OBJECTIVES: The present work was conducted to study the usefulness of peritoneal fluid cytomorphology in the early diagnosis of PMP and to evaluate the significance of the presence of epithelial cell (EC) clusters and their prognostic implications. MATERIALS AND METHODS: We evaluated the detailed cytological features of 21 cases of PMP retrospectively. Both conventional and liquid-based cytology smears of peritoneal fluid were reviewed, cytological features were compared with histological findings and cases were classified into disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). RESULTS: In our study, the common causes of PMP were primary gastrointestinal malignancies (appendix and colorectal, 57.14%), followed by primary ovarian mucinous neoplasms (28.57%) and synchronous ovarian and appendicular tumours (14.28%). Thick mucinous material was present in all cases (100%). ECs were present in 18 of 21 (85.17%) patients, with mild nuclear atypia in the majority of cases. Histiocytes, mesothelial cells and fibroblast-like, spindle-shaped cells with entrapped mucin were also noted in the background. The cases of PMCA showed greater numbers of EC clusters in cytology smears and these patients had recurrent episodes of PMP. CONCLUSION: On cytomorphology, high-grade tumours were more cellular and frequently showed EC clusters with moderate to severe atypia, prominent nucleoli and mitosis, and were more prone to PMCA. PMID- 27121699 TI - Acute effects of different types of aerobic exercise on endothelial function and arterial stiffness. AB - BACKGROUND: Chronic aerobic exercise training is associated with improved endothelial function and arterial stiffness and favourable long-term cardiovascular effects. DESIGN: We investigated the acute effects of continuous moderate intensity aerobic exercise (CAE) and high intensity interval aerobic exercise (hIAE) on endothelial function and arterial stiffness in healthy participants. METHODS: Twenty healthy men were recruited to this cross-over study. They participated in two exercise sessions: (a) CAE, volume at 50% of maximum aerobic work for 30 minutes; and (b) hIAE, interval maximum aerobic work for 30 minutes. Endothelial function was evaluated by flow-mediated dilation in the brachial artery. The carotid femoral pulse wave velocity and the femoral dorsalis pedis pulse wave velocity were measured as indices of central aortic and peripheral arterial stiffness. Measurements were carried out before and immediately after each exercise session. RESULTS: There was no statistically significant difference in the baseline measurements before CAE and hIAE with respect to flow-mediated dilation, the carotid femoral pulse wave velocity and the femoral dorsalis pedis pulse wave velocity (p = NS). Both CAE and hIAE significantly improved the flow-mediated dilation compared with baseline (p < 0.001). Similarly, the femoral dorsalis pedis pulse wave velocity was improved after CAE and hIAE (p < 0.005), whereas the carotid femoral pulse wave velocity was not significantly affected (p = NS). CONCLUSION: Both CAE and hIAE can favourably affect endothelial function, suggesting another cardioprotective effect of acute exercise. These types of aerobic exercise have a different impact on the central and peripheral arterial stiffness. PMID- 27121700 TI - NICE approves innovative treatment for moderate to severe heart failure. PMID- 27121701 TI - Glial cells as drug targets: What does it take? AB - The last two decades have brought a significant increase in our understanding of glial biology and glial contribution to CNS disease. Yet, despite the fact that glial cells make up the majority of CNS cells, no drug specifically targeting glial cells is on the market. Given the long development times of CNS drugs, on average over 12 years, this is not completely surprising. However, there is increasing interest from academia and industry to exploit glial targets to develop drugs for the benefit of patients with currently limited or no therapeutic options. CNS drug development has a high attrition rate and has encountered many challenges. It seems unlikely that developing drugs against glial targets would be any less demanding. However, the knowledge generated in traditional CNS drug discovery teaches valuable lessons, which could enable the glial community to accelerate the cycle time from basic discovery to drug development. In this review we will discuss steps necessary to bring a "glial target idea" to a clinical development program. GLIA 2016;64:1742-1754. PMID- 27121702 TI - Single Pass Albumin Dialysis-A Dose-Finding Study to Define Optimal Albumin Concentration and Dialysate Flow. AB - Several artificial liver support concepts have been evaluated both in vitro and clinically. Single pass albumin dialysis (SPAD) has shown to be one of the most simple approaches for removing albumin-bound toxins and water-soluble substances. Being faced with acute liver failure (ALF) in everyday practice encouraged our attempt to define the optimal conditions for SPAD more precisely in a standardized experimental setup. Albumin concentration was adjusted to either 1%, 2%, 3%, or 4%, while the flow rate of the dialysate was kept constant at a speed of 700 mL/h. The flow rate of the dialysate was altered between 350, 500, 700, and 1000 mL/h, whereas the albumin concentration was continuously kept at 3%. This study revealed that the detoxification of albumin-bound substances could be improved by increasing the concentration of albumin in the dialysate with an optimum at 3%. A further increase of the albumin concentration to 4% did not lead to a significant increase in detoxification. Furthermore, we observed a gradual increase of the detoxification efficiency for albumin-bound substances, from 350 mL/h to 700 mL/h (for bilirubin) or 1000 mL/h (for bile acids) of dialysate flow. Water-soluble toxins (ammonia, creatinine, urea, uric acid) were removed almost completely, regardless of albumin concentration or flow rate. In conclusion, this study confirmed that SPAD is effective in eliminating albumin-bound as well as water-soluble toxins using a simulation of ALF. Furthermore, this project was successful in evaluating the most effective combination of albumin concentration (3%) and dialysate flow (700 mL/h-1000 mL/h) in SPAD for the first time. PMID- 27121703 TI - Consistency of the Health of the Nation Outcome Scales (HoNOS) at inpatient-to community transition. AB - OBJECTIVES: The Health of the Nation Outcome Scales (HoNOS) are mandated outcome measures in many mental-health jurisdictions. When HoNOS are used in different care settings, it is important to assess if setting specific bias exists. This article examines the consistency of HoNOS in a sample of psychiatric patients transitioned from acute inpatient care and community centres. SETTING: A regional mental health service with both acute and community facilities. PARTICIPANTS: 111 psychiatric patients were transferred from inpatient care to community care from 2012 to 2014. Their HoNOS scores were extracted from a clinical database; Each inpatient-discharge assessment was followed by a community-intake assessment, with the median period between assessments being 4 days (range 0-14). Assessor experience and professional background were recorded. PRIMARY AND SECONDARY OUTCOME MEASURES: The difference of HoNOS at inpatient-discharge and community intake were assessed with Pearson correlation, Cohen's kappa and effect size. RESULTS: Inpatient-discharge HoNOS was on average lower than community-intake HoNOS. The average HoNOS was 8.05 at discharge (median 7, range 1-22), and 12.16 at intake (median 12, range 1-25), an average increase of 4.11 (SD 6.97). Pearson correlation between two total scores was 0.073 (95% CI -0.095 to 0.238) and Cohen's kappa was 0.02 (95% CI -0.02 to 0.06). Differences did not appear to depend on assessor experience or professional background. CONCLUSIONS: Systematic change in the HoNOS occurs at inpatient-to-community transition. Some caution should be exercised in making direct comparisons between inpatient HoNOS and community HoNOS scores. PMID- 27121704 TI - Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews. AB - OBJECTIVE: To summarise existing systematic reviews that assess the effects of non-pharmacological, pharmacological and alternative therapies on activities of daily living (ADL) function in people with dementia. DESIGN: Overview of systematic reviews. METHODS: A systematic search in the Cochrane Database of Systematic Reviews, DARE, Medline, EMBASE and PsycInfo in April 2015. Systematic reviews of randomised controlled trials conducted in people with Alzheimer's disease or dementia measuring the impact on ADL function were included. Methodological quality of the systematic reviews was independently assessed by two authors using the AMSTAR tool. The quality of evidence of the primary studies for each intervention was assessed using GRADE. RESULTS: A total of 23 systematic reviews were included in the overview. The quality of the reviews varied; however most (65%) scored 8/11 or more on the AMSTAR tool, indicating high quality. Interventions that were reported to be effective in minimising decline in ADL function were: exercise (6 studies, 289 participants, standardised mean difference (SMD) 0.68, 95% CI 0.08 to 1.27; GRADE: low), dyadic interventions (8 studies, 988 participants, SMD 0.37, 95% CI 0.05 to 0.69; GRADE: low) acetylcholinesterase inhibitors and memantine (12 studies, 4661 participants, donepezil 10 mg SMD 0.18, 95% CI 0.03 to 0.32; GRADE: moderate), selegiline (7 studies, 810 participants, SMD 0.27, 95% CI 0.13 to 0.41; GRADE: low), huperzine A (2 studies, 70 participants, SMD 1.48, 95% CI 0.95 to 2.02; GRADE: very low) and Ginkgo biloba (7 studies, 2530 participants, SMD 0.36, 95% CI 0.28 to 0.44; GRADE: very low). CONCLUSIONS: Healthcare professionals should ensure that people with dementia are encouraged to exercise and that primary carers are trained and supported to provide safe and effective care for the person with dementia. Acetylcholinesterase inhibitors or memantine should be trialled unless contraindicated. TRIAL REGISTRATION NUMBER: CRD42015020179. PMID- 27121705 TI - Are higher blood mercury levels associated with dry eye symptoms in adult Koreans? A population-based cross-sectional study. AB - OBJECTIVES: The purpose of this study was to investigate whether blood mercury concentrations associated with the presence of dry eye symptoms in a nationally representative Korean population. METHODS: Population-based prospective cross sectional study using the heavy metal data set of the 2010-2012 Korean National Health and Nutrition Examination Survey (KNHANES). A total of 4761 adult Koreans were the eligible population in this study. Of the 7162 survey participants, 2401 were excluded because they were <19 years of age, there were missing data in the heavy metal data set, or they had diabetes, rheumatoid arthritis, thyroid disease, asthma, depression and/or under-the-eye surgery. Blood mercury levels were measured on the day the participants completed a questionnaire regarding the presence of dry eye symptoms (persistent dryness or eye irritation). The population was divided into low and high groups by median level (4.26 and 2.89 ug/L for males and females, respectively). RESULTS: Self-reported dry eye symptoms were present in 13.0% of the cohort. Participants with dry eye symptoms were significantly more likely to have blood mercury levels exceeding the median than those without dry eye symptoms (45.7% vs 51.7%, p=0.021). Logistic regression analysis showed that, after adjusting for age, gender, education, total household income, smoking status, heavy alcohol use, sleep time, perceived stress status, total cholesterol levels and atopy history, dry eye symptoms were significantly associated with blood mercury levels that exceeded the median (reference: lower mercury group; OR, 1.324; 95% CI 1.059 to 1.655; p<0.05). CONCLUSIONS: High blood mercury levels were associated with dry eye symptoms in a nationally representative Korean population. PMID- 27121706 TI - Investigation of bias in meta-analyses due to selective inclusion of trial effect estimates: empirical study. AB - OBJECTIVE: To explore whether systematic reviewers selectively include trial effect estimates in meta-analyses when multiple are available, and what impact this may have on meta-analytic effects. DESIGN: Cross-sectional study. DATA SOURCES: We randomly selected systematic reviews of interventions from 2 clinical specialties published between January 2010 and 2012. The first presented meta analysis of a continuous outcome in each review was selected (index meta analysis), and all trial effect estimates that were eligible for inclusion in the meta-analysis (eg, from multiple scales or time points) were extracted from trial reports. ANALYSIS: We calculated a statistic (the Potential Bias Index (PBI)) to quantify and test for evidence of selective inclusion. The PBI ranges from 0 to 1; values above or below 0.5 are suggestive of selective inclusion of effect estimates more or less favourable to the intervention, respectively. The impact of any potential selective inclusion was investigated by comparing the index meta analytic standardised mean difference (SMD) to the median of a randomly constructed distribution of meta-analytic SMDs (representing the meta-analytic SMD expected when there is no selective inclusion). RESULTS: 31 reviews (250 trials) were included. The estimated PBI was 0.57 (95% CI 0.50 to 0.63), suggesting that trial effect estimates that were more favourable to the intervention were included in meta-analyses slightly more often than expected under a process consistent with random selection; however, the 95% CI included the null hypothesis of no selective inclusion. Any potential selective inclusion did not have an important impact on the meta-analytic effects. CONCLUSION: There was no clear evidence that selective inclusion of trial effect estimates occurred in this sample of meta-analyses. Further research on selective inclusion in other clinical specialties is needed. To enable readers to assess the risk of selective inclusion bias, we recommend that systematic reviewers report the methods used to select effect estimates to include in meta-analyses. PMID- 27121707 TI - Current evidence for the effectiveness of heated and humidified high flow nasal cannula supportive therapy in adult patients with respiratory failure. AB - High flow nasal cannula (HFNC) supportive therapy has emerged as a safe, useful therapy in patients with respiratory failure, improving oxygenation and comfort. Recently several clinical trials have analyzed the effectiveness of HFNC therapy in different clinical situations and have reported promising results. Here we review the current knowledge about HFNC therapy, from its mechanisms of action to its effects on outcomes in different clinical situations. PMID- 27121708 TI - The influence of grandmothers on breastfeeding rates: a systematic review. AB - BACKGROUND: Exclusive breastfeeding for the first six months of an infant's life has enormous potential to reduce mortality and morbidity. The older generation, particularly the infant's grandmothers, play a central role in various aspects of pregnancy and child rearing decision-making within the family unit. This is particularly true in low- and middle-income countries where older women are seen as owners of traditional knowledge. Despite this, most health programs target the individual person most directly involved in the target behaviour--usually new mothers--without a commensurate understanding of who else influences those decisions. In this systematic review we aim to quantify the impact of the grandmother on influencing a mother's breastfeeding practices. METHODS: We conducted a systematic review using Web of Science, Scopus, and Medline databases using search terms for grandmother and breastfeeding. Eligible studies reported on the duration of exclusive breastfeeding and included estimates of effect of a grandmother's influence including whether or not the grandmother lived with the infant's family, the grandmother's education, and the grandmother's attitudes towards and prior experience with breastfeeding. RESULTS: We identified 568 articles and, after review, 13 articles were assessed as meeting the selection criteria. They were conducted in both developed and developing countries and included cross-sectional surveys, prospective cohort studies and one randomised controlled trial. Eight studies examined the effects of attitudes or experiences of older generations with respect to breastfeeding and five of the eight found a significant positive impact on breastfeeding when grandmothers of the infants had had their own breastfeeding experience or were positively inclined towards breastfeeding, resulting in effects of between 1.6 to 12.4 times more likely to exclusively breastfeed or refrain from introducing solid foods. A Chinese study however found that highly educated grandmothers were associated with decreased exclusive breastfeeding. The majority of the studies were assessed to be of weak or moderate quality. CONCLUSIONS: This review found evidence that demonstrates that grandmothers have the capacity to influence exclusive breastfeeding. Programs that seek to influence exclusive breastfeeding should include grandmothers in their interventions to achieve maximum impact. PMID- 27121709 TI - Deep-fried oil consumption in rats impairs glycerolipid metabolism, gut histology and microbiota structure. AB - BACKGROUND: Deep frying in oil is a popular cooking method around the world. However, the safety of deep-fried edible oil, which is ingested with fried food, is a concern, because the oil is exposed continuously to be re-used at a high temperature, leading to a number of well-known chemical reactions. Thus, this study investigates the changes in energy metabolism, colon histology and gut microbiota in rats following deep-fried oil consumption and explores the mechanisms involved in above alterations. METHODS: Deep-fried oil was prepared following a published method. Adult male Wistar rats were randomly divided into three groups (n = 8/group). Group 1: basal diet without extra oil consumption (control group); Group 2: basal diet supplemented with non-heated canola oil (NEO group); Group 3: basal diet supplemented with deep-fried canola oil (DFEO group). One point five milliliters (1.5 mL) of non-heated or heated oil were fed by oral gavage using a feeding needle once daily for 6 consecutive weeks. Effect of DFEO on rats body weight, KEGG pathway regarding lipids metabolism, gut histology and gut microbiota were analyzed using techniques of RNA sequencing, HiSeq Illumina sequencing platform, etc. RESULTS: Among the three groups, DFEO diet resulted in a lowest rat body weight. Metabolic pathway analysis showed 13 significantly enriched KEGG pathways in Control versus NEO group, and the majority of these were linked to carbohydrate, lipid and amino acid metabolisms. Comparison of NEO group versus DFEO group, highlighted significantly enriched functional pathways were mainly associated with chronic diseases. Among them, only one metabolism pathway (i.e. glycerolipid metabolism pathway) was found to be significantly enriched, indicating that inhibition of this metabolism pathway (glycerolipid metabolism) may be a response to the reduction in energy metabolism in the rats of DFEO group. Related gene analysis indicated that the down-regulation of Lpin1 seems to be highly associated with the inhibition of glycerolipid metabolism pathway. Histological analysis of gastrointestinal tract demonstrated several changes induced by DFEO on intestinal mucosa with associated destruction of endocrine tissue and the evidence of inflammation. Microbiota data showed that rats in DFEO group had the lowest proportion of Prevotella and the highest proportion of Bacteroides among the three groups. In particular, rats in DFEO group were characterized with higher presence of Allobaculum (Firmicutes), but not in control and NEO groups. CONCLUSION: This study investigated the negative effect of DFEO on health, in which DFEO could impair glycerolipid metabolism, destroy gut histological structure and unbalance microbiota profile. More importantly, this is the first attempt to reveal the mechanism involved in these changes, which may provide the guideline for designing health diet. PMID- 27121711 TI - Development and Validation of a Novel LC-MS/MS Opioid Confirmation Assay: Evaluation of beta-glucuronidase Enzymes and Sample Cleanup Methods. AB - With the rise in the use and misuse of prescription opioids, there is an increasing need for the confirmed identification of opioid analgesics in toxicology laboratories. The goals of this study were to (i) systematically evaluate the hydrolysis efficiency of four beta-glucuronidase enzymes under optimized condition; (ii) evaluate compound recovery, matrix effects and precision of three protein precipitation plates and (iii) develop and validate a qualitative liquid-chromatography mass spectrometry (LC-MS/MS) assay to identify 13 opioids in urine. A recombinant beta-glucuronidase exhibited the best overall hydrolysis efficiency for seven opioid glucuronide conjugates compared with beta glucuronidase from red abalone, Escherichia coli and Patella vulgata One of the protein precipitation plates tested exhibited overall better recovery of the opioids and lower ion suppression compared with the other two plates. An ESI positive mode LC-MS/MS assay for qualitative opioid analysis was developed and validated. Linearity, LOD, precision, matrix effect, recovery, carryover and interference of the method were evaluated. Sixty-two patient samples were analyzed by both a legacy GC-MS opioid method and the LC-MS/MS method, and 22 samples were analyzed by the LC-MS/MS and an LC-MS/MS reference method. The results of the comparisons showed good concordance. Overall, we described an efficient sample preparation procedure for a sensitive qualitative opioid confirmation assay in urine. PMID- 27121710 TI - Magnesium sulfate treatment for juvenile ferrets following induction of hydrocephalus with kaolin. AB - BACKGROUND: Previous work with 3-week hydrocephalic rats showed that white matter damage could be reduced by the calcium channel antagonist magnesium sulfate (MgSO4). We hypothesized that MgSO4 therapy would improve outcomes in ferrets with hydrocephalus induced with kaolin at 15 days. METHODS: MRI was performed at 29 days to assess ventricle size and stratify ferrets to treatment conditions. Beginning at 31 days age, they were treated daily for 14 days with MgSO4 (9 mM/kg/day) or sham saline therapy, and then imaged again before sacrifice. Behavior was examined thrice weekly. Histological and biochemical ELISA and myelin enzyme activity assays were performed at 46 days age. RESULTS: Hydrocephalic ferrets exhibited some differences in weight and behavior between treatment groups. Those receiving MgSO4 weighed less, were more lethargic, and displayed reduced activity compared to those receiving saline injections. Hydrocephalic ferrets developed ventriculomegaly, which was not modified by MgSO4 treatment. Histological examination showed destruction of periventricular white matter. Glial fibrillary acidic protein content, myelin basic protein content, and myelin enzyme activity did not differ significantly between treatment groups. CONCLUSION: The hydrocephalus-associated disturbances in juvenile ferret brains are not ameliorated by MgSO4 treatment, and lethargy is a significant side effect. PMID- 27121713 TI - Development of Amino Acid-Based Radiopharmaceuticals for Tumor Imaging. AB - Amino acids (AAs) are important nutrients for proliferating tumor cells, and amino acid transport is generally increased in many malignant tumor cells. So far, as a complementary category to 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG), radiolabeled amino acids that target the upregulated level of amino acid transport have been successfully employed for tumor imaging for decades, thanks to their better differentiation between tumor lesions and inflammation. This review summarizes the development of various radiolabeled amino acid analogues for tumor imaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET) and introduces the basic data related to this area, such as the biological basis, chemical structure, radiolabeling, preclinical evaluation and clinical application. In addition, current status and future prospects of this class of imaging agents are discussed in this review. PMID- 27121714 TI - Beyond the Selective Inhibition of Histone Deacetylase 6. AB - Histone deacetylase 6 (HDAC6) catalyses the removal of acetyl groups from the lysine residues of a series of non-histone proteins, e.g., alpha-tubulin, Hsp90 and cortactin. HDAC6 is a unique deacetylase enzyme that is related to various processes that may be important in oncological, immunological and neurological fields, which makes the study of selective inhibitors extremely important to understand the function of this enzyme and to validate HDAC6 as a drug target through the development of clinical candidates. Therefore, this review describes the structure-activity and structureselectivity relationships of HDAC6 inhibitors, which were divided into two main classes, bulky and lipophilic cap groups and inhibitors with phenyl linkers. PMID- 27121715 TI - Synthesis and Antinociception Activities of Some Novel Derivatives of Phencyclidine with Substituted Aminobenzothiazoles. AB - BACKGROUND: Phencyclidine (PCP) as well as the analogues has indicated several pharmacological behaviors like analgesic, anticonvulsant, antianxiety, antidepressant depending on the dose and species examined. They interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or both. OBJECTIVE: Due to analgesic properties of aminobenzothiazoles family, piperidine ring of PCP was replaced with electron-donating and electron-withdrawing substituted aminobenzothiazoles (1-4) for obtaining new analogues (II-V) with more analgesic activities. METHODS: Synthesis of new compounds (II-V) and measuring the acute and chronic pain properties of them were carried out through applying tail immersion &formalin tests on mice and the outcomes compared with control & PCP groups at dosage of 10 mg/kg. RESULTS: III & V with substituted methoxy and methyl-aminobenzothiazoles indicated better activity to lessen acute and chronic (thermal and chemical) pains compared with unsubstituted & phencyclidine animal groups. CONCLUSION: Methoxy and methyl-aminobenzothiazole derivatives" of phencyclidine revealed more analgesic activities compared with other groups which may concern to close affinity for DA uptake blocking as well as NMDA receptors in this family. PMID- 27121716 TI - Recent Developments in Chimeric NSAIDs as Anticancer Agents: Teaching an Old Dog a New Trick. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the widely used medications all over the world, indicated for pain, fever, and inflammation. It is now well established that inflammation and cancer are closely linked with each other. Inflammatory mediators, like cyclooxygenase (COX), vascular endothelial growth factor (VEGF), tumor growth factor (TGF), fibroblast growth factor (FGF), chemokines, and cytokines and related genes, such as inhibitor of nuclear factor kappa B kinase (IKK) and nuclear factor-kappa B (NF-kappaB) have been shown to be up-regulated in various cancers. Till date, numerous anticancer agents of different classes have been discovered to treat and eradicate various forms of cancer; though, limitations like cytotoxicity to normal cells and acquired tumor resistance restrict the scope of present cancer therapeutics. NSAIDs have shown to decrease the incidence, recurrence, and proliferation of various cancers, viz. colon, breast, lung, and pancreatic, etc. Therefore, the developing agents, such as NO-and H2S-releasing NSAIDs, NSAID-metal complexes, natural product NSAID conjugates, phospho-NSAIDs, and various other NSAIDs derivatives represent the next generation therapeutics to treat both inflammation and cancer. PMID- 27121717 TI - Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes. AB - Genomic sequencing of several dermatophyte species has revealed that they show small differences in genetic content and genome organization, although each fungus has adapted to specific niches. Thus, it seemed relevant to compare gene expression between species. Here, we examined the transcription modulation of three ATP-binding cassette (ABC) transporter genes (pdr1, mdr2 and mdr4), which code for membrane transporter proteins in four species of Trichophyton ; T. interdigitale, T. rubrum, T. tonsurans and T. equinum . These fungal species were challenged with sub-lethal doses of griseofulvin, itraconazole, terbinafine and amphotericin B. A mutant strain of T. interdigitale, Deltamdr2, was also analysed for the modulation of pdr1 and mdr4 genes to evaluate the possible functional interaction among these three genes. Disruption of the mdr2 gene resulted in the accumulation of high levels of mdr4 transcripts when challenged with griseofulvin, suggesting that the mdr4 gene is compensating for the inactivation of mdr2 by providing resistance to this antifungal. Although the three ABC transporter genes have high homology between the four dermatophytes analysed, it is likely that they have specific functions, suggesting that the action of each drug is dependent on other factors inherent to each species. Our data suggest that these ABC transporter genes act synergistically in dermatophytes, and they may compensate for one another when challenged with antifungal drugs. This may be an important cause of therapeutic failure when treating fungal infections. PMID- 27121718 TI - Minimally Invasive Stereotactical Radio-ablation of Adrenal Metastases as an Alternative to Surgery. AB - PURPOSE: The purpose of this study was to study the clinical outcome for patients with metastases of the adrenal gland treated with stereotactic body radiation therapy. MATERIALS AND METHODS: Forty-six patients were studied retrospectively. The dose prescription was 40 Gy in four fractions. Dosimetric analysis was performed using the dose volume histograms while clinical outcome was assessed using actuarial analysis with determination of the overall survival (OS) and local control (LC) rates. RESULTS: The planning objectives were met for all patients. With a median follow-up period of 7.6 months, at the last follow-up 42 patients (91.3%) were alive and four had died because of distant progression. The actuarial mean OS was 28.5+/-1.6 months, the median was not reached. One-year and 2-year OS were 87.6+/-6.1%. None of the risk factors was significant in univariate analysis. Actuarial mean LC was 14.6+/-1.8 months (95% confidence interval [CI], 11.0 to 18.2) and median LC was 14.5+/-2.0 months (95% CI, 10.5 to 18.5). One-year and 2-year LC were 65.5+/-11.9% and 40.7+/-15.8%, respectively. A mild profile of toxicity was observed in the cohort of patients. Forty patients (86.9%) showed no complication (grade 0); two patients reported asthenia, six patients (13.1%) reported either pain, nausea, or vomiting. Of these six patients, five patients (10.9%) were scored as grade 1 toxicity while one patient (2.2%) was scored as grade 2. CONCLUSION: Stereotactic body radiation therapy treatment provided an adequate clinical response in the management of adrenal gland metastases. PMID- 27121719 TI - Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort. AB - PURPOSE: Ipilimumab improves survival in advanced melanoma patients. However, the efficacy and safety of ipilimumab has not been evaluated in Asian melanoma patients with a high frequency of mucosal and acral melanoma subtypes. MATERIALS AND METHODS: Advanced melanoma patients treated with 3 mg/kg ipilimumab in a Korean multicenter named-patient program (NPP) were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes. RESULTS: A total of 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR (>= 5) were independent poor prognostic factors by multivariate analysis. CONCLUSION: In the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared to Western patients, regardless of subtypes. All subtypes should benefit from ipilimumab with consideration of performance status, liver metastasis, and NLR. PMID- 27121720 TI - Use of a High-Throughput Genotyping Platform (OncoMap) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer. AB - PURPOSE: Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RAS Mutational analysis using a high throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. MATERIALS AND METHODS: Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. RESULTS: The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). CONCLUSION: Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment. PMID- 27121721 TI - Rare Incidence of ROS1 Rearrangement in Cholangiocarcinoma. AB - PURPOSE: The recent discovery and characterization of an oncogenic ROS1 gene rearrangement has raised significant interest because small molecule inhibitors are effective in these tumors. The aim of this study was to determine frequency and clinicopathological features associated with ROS1 rearrangement in patients with cholangiocarcinoma (CCA). MATERIALS AND METHODS: A total of 261 patients who underwent surgery for CCA between October 1997 and August 2013 were identified from an international, multi-institutional database. ROS1 rearrangement was evaluated by break-apart fluorescence in situ hybridization using tissue microarrays of these patients. RESULTS: Of 261 CCA evaluated, three cases (1.1%) showed ROS1 rearrangement by fluorescence in situ hybridization (FISH), all of which were derived from intrahepatic origin. ROS1 protein expression was observed in 38 samples (19.1%). Significantly larger tumor size was observed in ROS1 immunohistochemistry (IHC)-negative patients compared with ROS1 IHC-positive patients. ROS1 FISH-positive patients had a single tumor with a median size of 4 cm and well-to-moderate differentiation. Overall, there was no difference in terms of baseline characteristics, overall survival, and recurrence-free survival between ROS1-positive and -negative patients. CONCLUSION: ROS1 rearrangement was detected in 1.1% of CCA patients. Although rare, conduct of clinical trials using ROS1 inhibitors in these genetically unique patients is warranted. PMID- 27121722 TI - Clinical Features of Male Breast Cancer: Experiences from Seven Institutions Over 20 Years. AB - PURPOSE: Breast cancer treatment has progressed significantly over the past 20 years. However, knowledge regarding male breast cancer (MBC) is sparse because of its rarity. This study is an investigation of the clinicopathologic features, treatments, and clinical outcomes of MBC. MATERIALS AND METHODS: Clinical records of 59 MBC patients diagnosed during 1995-2014 from seven institutions in Korea were reviewed retrospectively. RESULTS: Over a 20-year period, MBC patients accounted for 0.98% among total breast cancer patients, and increased every 5 years. The median age of MBC patientswas 66 years (range, 24 to 87 years). Forty three patients (73%) complained of a palpable breast mass initially. The median symptom duration was 5 months (range, 1 to 36 months). Mastectomy was performed in 96% of the patients. The most frequent histology was infiltrating ductal carcinoma (75%). Ninety-one percent of tumors (38/43) were estrogen receptor positive, and 28% (11/40) showed epidermal growth factor receptor 2 (HER-2) overexpression. After curative surgery, 42% of patients (19/45) received adjuvant chemotherapy; 77% (27/35) received hormone therapy. Five out of ten patients with HER-2 overexpressing tumors did not receive adjuvant anti-HER-2 therapy, while two out of four patients with HER-2 overexpressing tumors received palliative trastuzumab for recurrent and metastatic disease. Letrozole was used for one patient in the palliative setting. The median overall survival durations were 7.2 years (range, 0.6 to 17.0 years) in patients with localized disease and 2.9 years (range, 0.6 to 4.3 years) in those with recurrent or metastatic disease. CONCLUSION: Anti-HER-2 and hormonal therapy, except tamoxifen, have been underutilized in Korean MBC patients compared to female breast cancer patients. With the development of precision medicine, active treatment with targeted agents should be applied. Further investigation of the unique pathobiology of MBC is clinically warranted. PMID- 27121723 TI - Informational role self-efficacy: a validation in interprofessional collaboration contexts involving healthcare service and project teams. AB - BACKGROUND: Healthcare professionals perform knowledge-intensive work in very specialized disciplines. Across the professional divide, collaboration becomes increasingly difficult. For effective teamwork and collaboration to occur, it is considered necessary for individuals to believe in their ability to draw on their expertise and provide what others need to perform their job well. To date, however, no instruments exist to measure such a construct. METHODS: A two-study design is used to test the psychometric properties, factor structure and incremental validity of a five-item questionnaire measuring informational role self-efficacy. RESULTS: Based on parallel analysis and exploratory factor analysis, Study 1 shows a robust and reliable one-dimensional construct. Study 2 cross-validates this factor structure using confirmatory factor analysis. Study 2 also shows that informational role self-efficacy predicts proactive teamwork behaviors over and above goal similarity, interdependence, coordination and intra team trust. CONCLUSIONS: The instrument can be used in research to assess an individual's capability beliefs in communicating his/her informational characteristics that are pertinent to the task performance of others. The construct is also shown to have value in team-building exercises. PMID- 27121724 TI - Elementary School-Based Obesity Intervention Using an Educational Curriculum. AB - BACKGROUND: Pediatric obesity is a significant public health problem with a prevalence of 16.9% among US children. School-based obesity interventions show promise for reducing adiposity in elementary age children. This pilot study evaluated the impact of the Let's Go! 5-2-1-0 pediatric obesity intervention program in an elementary school setting. METHODS: This was a cluster randomized controlled field trial comprising 8 classrooms of second- and third-grade children. The impact of implementation of a standardized 5-2-1-0 curriculum was evaluated in the classrooms by looking at health behavior (self-reported fruit and vegetable and sugar-containing beverage intake, and screen time), physical activity (steps measured by pedometer), and body mass index (BMI). Half of the classrooms were given 5-2-1-0 teaching over a 4-month period. RESULTS: There was no statistical difference in improvement of healthy habits, BMI, or physical activity in the intervention group compared with the control group. CONCLUSIONS: The 5-2-1-0 intervention used in this study was feasible. There was no significant change in healthy habits, likely due to the small number of participants in the study. The intervention and control sites were in different classrooms and there could be factors such as teacher enthusiasm, socioeconomic factors, and individual traits affecting habits. Future studies could use pre- and post-intervention quizzes to assess healthy habits knowledge retention, involving the environments the child participates in outside of school, using research-grade pedometers or accelerometers for measuring activity data collection, and recruiting larger samples to ensure adequate statistical power. PMID- 27121725 TI - Predictors of the patient-centered outcomes of surgical carpal tunnel release - a prospective cohort study. AB - BACKGROUND: Carpal tunnel syndrome (CTS) causes a substantial burden of disease in society. While CTS can be resolved by surgical carpal tunnel release, it still remains unclear as to what degree outcomes depend on patients' characteristics. This study assesses patient-centered outcomes after surgical carpal tunnel release in a large outpatient clinic in Germany. METHODS: Patients with CTS were recruited prospectively between August 1st and December 31st, 2013. We assessed socio-demographic and psychological factors as well as nerve conduction velocities at baseline (before the surgery) and at three and six months after surgery. We analyzed the improvement of patient-centered outcomes (symptoms and function of the affected hand as well as measures of well-being and subjective quality of life) at the two follow-up time points and investigated if socio demographic characteristics and CTS-related variables predict the success of the surgery with respect to nerve conduction velocities and patient-centered outcomes by means of analysis of covariance (ANCOVA). Factors influencing the duration of sick leave were investigated by means of Cox regression. RESULTS: The study sample consisted of 71 CTS cases. Surgical carpal tunnel release generally improved nerve conduction velocity and patient-centered outcomes. Regarding the former, the improvement was proportional to the severity score at baseline. The presence of muscular atrophy in the thenar area at baseline displayed medium size effects for the patient-centered outcomes. Other socio-demographic characteristics and CTS-related variables did not have a strong predictive effect on the improvement of nerve conduction velocity and patient-centered outcomes. CONCLUSIONS: There is a significant improvement of clinical and subjective outcomes after CTS surgery in the outpatient sector. The improvement is largely independent of socio-demographic and clinical characteristics of the patients. PMID- 27121727 TI - Surgical Site Infections Following Pediatric Ambulatory Surgery: An Epidemiologic Analysis. AB - OBJECTIVE To identify surgical site infection (SSI) rates following pediatric ambulatory surgery, SSI outcomes and risk factors, and sensitivity and specificity of SSI administrative billing codes. DESIGN Retrospective chart review of pediatric ambulatory surgeries with International Classification of Disease, Ninth Revision (ICD-9) codes for SSI, and a systematic random sampling of 5% of surgeries without SSI ICD-9 codes, all adjudicated for SSI on the basis of an ambulatory-adapted National Healthcare Safety Network definition. SETTING Urban pediatric tertiary care center April 1, 2009-March 31, 2014. METHODS SSI rates and sensitivity and specificity of ICD-9 codes were estimated using sampling design, and risk factors were analyzed in case-rest of cohort, and case control, designs. RESULTS In 15,448 pediatric ambulatory surgeries, 34 patients had ICD-9 codes for SSI and 25 met the adapted National Healthcare Safety Network criteria. One additional SSI was identified with systematic random sampling. The SSI rate following pediatric ambulatory surgery was 2.9 per 1,000 surgeries (95% CI, 1.2-6.9). Otolaryngology surgeries demonstrated significantly lower SSI rates compared with endocrine (P=.001), integumentary (P=.001), male genital (P<.0001), and respiratory (P=.01) surgeries. Almost half of patients with an SSI were admitted, 88% received antibiotics, and 15% returned to the operating room. No risk factors were associated with SSI. The sensitivity of ICD-9 codes for SSI following ambulatory surgery was 55.31% (95% CI, 12.69%-91.33%) and specificity was 99.94% (99.89%-99.97%). CONCLUSIONS SSI following pediatric ambulatory surgery occurs at an appreciable rate and conveys morbidity on children. Infect Control Hosp Epidemiol 2016;37:931-938. PMID- 27121728 TI - The pharmacokinetics of transdermal flunixin meglumine in Holstein calves. AB - This study describes the pharmacokinetics of topical and intravenous (IV) flunixin meglumine in Holstein calves. Eight male Holsteins calves, aged 6 to 8 weeks, were administered flunixin at a dose of 2.2 mg/kg intravenously. Following a 10-day washout period, calves were dosed with flunixin at 3.33 mg/kg topically (transdermal). Blood samples were collected at predetermined times from 0 to 48 h for the intravenous portions and 0 to 72 h following topical dosing. Plasma drug concentrations were determined using liquid chromatography with mass spectroscopy. Pharmacokinetic analysis was completed using noncompartmental methods. The mean bioavailability of topical flunixin was calculated to be 48%. The mean AUC for flunixin was determined to be 13.9 h * ug/mL for IV administration and 10.1 h * ug/mL for topical administration. The mean half-life for topical flunixin was 6.42 h and 4.99 h for the intravenous route. The Cmax following topical application of flunixin was 1.17 MUg/mL. The time to maximum concentration was 2.14 h. Mean residence time (MRT) following IV injection was 4.38 h and 8.36 h after topical administration. In conclusion, flunixin when administered as a topical preparation is rapidly absorbed and has longer half life compared to IV administration. PMID- 27121729 TI - Detection of DNA viruses in prostate cancer. AB - We tested prostatic secretions from men with and without prostate cancer (13 cases and 13 matched controls) or prostatitis (18 cases and 18 matched controls) with metagenomic sequencing. A large number (>200) of viral reads was only detected among four prostate cancer cases (1 patient each positive for Merkel cell polyomavirus, JC polyomavirus and Human Papillomavirus types 89 or 40, respectively). Lower numbers of reads from a large variety of viruses were detected in all patient groups. Our knowledge of the biology of the prostate may be furthered by the fact that DNA viruses are commonly shed from the prostate and can be readily detected by metagenomic sequencing of expressed prostate secretions. PMID- 27121730 TI - Youth sports specialization and musculoskeletal injury: a systematic review of the literature. AB - OBJECTIVES: Early sports specialization is being seen with increasing frequency in children and adolescents in an attempt to achieve elite performance status. This phenomenon has attracted negative medical and lay media attention due, in part, to the possibility of an increased risk of acute and overuse injuries. The purpose of this study was to systematically review available research on youth sport specialization and musculoskeletal injury. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for studies evaluating sports specialization and injury rates in participants under age 18. Inclusion criteria were: (1) youth patient population (defined as <18 years of age), (2) peer-reviewed investigation of association(s) between sports specialization and incidence of injury, and (3) original research article (rather than a review, case report, or meta-analysis). Exclusion criteria were: (1) reliance on surrogate measure(s) of sports specialization (eg. hours of participation), (2) language other than English, and (3) not a clinically-based study. Rates of sport specialization, acute and overuse injuries, and frequency of organized training regimens were recorded. RESULTS: Three studies met final inclusion and exclusion criteria. Of these studies two were retrospective cohort studies and one was a case-control study. All three studies reported an increased risk of overuse injures (OR range: 1.27 4.0; P < 0.05) which varied by sport and anatomic pathology. One study noted an increased rate of withdrawal from tennis matches (OR = 1.55, P < 0.05) in athletes who participated only in tennis compared to multisport athletes who competed in tennis. Based on the consistency of the results from included studies, the strength of recommendation grade for the current evidence against early sports specialization is "B" (recommendation based on limited-quality patient-oriented evidence). CONCLUSIONS: The primary evidence that currently exists with regard to early sport specialization is scarce, retrospective, and shows only modest associations between early sports specialization and overuse injury. Further prospective research is needed to more definitively determine if early sports specialization in children is associated with increased injury risk. LEVEL OF EVIDENCE: Systematic Review, Level III. PMID- 27121731 TI - 6,6'-Bieckol suppresses inflammatory responses by down-regulating nuclear factor kappaB activation via Akt, JNK, and p38 MAPK in LPS-stimulated microglial cells. AB - OBJECTIVE: Microglial activation has been implicated in many neurological disorders for its inflammatory and neurotrophic effects. In this study, we investigated the pharmaceutical properties of 6,6'-bieckol on the regulation of nuclear factor-kappaB (NF-kappaB) activation responsible to the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 using lipopolysaccharide (LPS)-stimulated BV2 and murine primary microglial cells. Meterials and methods: The levels of nitric oxide (NO), prostaglandin E2 (PGE)2, and pro-inflammatory cytokines were measured by Griess assay and enzyme-linked immunosorbent assay. The levels of iNOS, COX-2, mitogen-activated protein kinases (MAPKs), and Akt were measured using Western blot. Nuclear translocation and transcriptional activation of NF-kappaB were determined by immunofluorescence and reporter gene assay, respectively. RESULTS: We found that 6,6'-bieckol decreased the expression of iNOS and COX-2 as well as pro-inflammatory cytokines in LPS stimulated BV2 and primary microglial cells in a dose-dependent manner. 6,6' Bieckol inhibited activation of NF-kappaB by preventing the degradation of inhibitor kappaB (IkappaB)-alpha and led to prevent the nuclear translocation of NF-kappaB/p65 subunit. Moreover, 6,6'-bieckol inhibited the phosphorylation of Akt, JNK, and p38 MAPK. DISCUSSION AND CONCLUSION: These results indicate that the anti-inflammatory effect of 6,6'-bieckol on LPS-stimulated microglial cells is mainly regulated by the inhibition of IkappaB-alpha/NF-kappaB and JNK/p38 MAPK/Akt pathways, supporting biochemical characteristics of the compound for therapeutic agent against neuroinflammatory diseases caused by microglial activation. PMID- 27121732 TI - Thermoresponsive physical hydrogels of poly(lactic acid)/poly(ethylene glycol) stereoblock copolymers tuned by stereostructure and hydrophobic block sequence. AB - CBABC-type poly(lactic acid) (PLA)/poly(ethylene glycol) (PEG) pentablock copolymers composed of a central PEG block (A) and enantiomeric poly(l-lactic acid) (PLLA, B), poly(d-lactic acid) (PDLA, C) blocks were synthesized. Such pentablock copolymers form physical hydrogels at high concentrations in an aqueous solution, which stem from the aggregation and physical bridging of copolymer micelles. These gels are thermoresponsive and turn into sols upon heating. Physical gelation, gel-to-sol transition, crystalline state, microstructure, rheological behavior, biodegradation, and drug release behavior of PLA/PEG pentablock copolymers and their gels were investigated; they were also compared with PLA-PEG-PLA triblock copolymers containing the isotactic PLLA or atactic poly(d,l-lactide) (PDLLA) endblocks and PLLA-PEG-PLLA/PDLA-PEG-PDLA enantiomeric mixtures. PLA hydrophobic domains in pentablock copolymer gels changed from a homocrystalline to stereocomplexed structure as the PLLA/PDLA block length ratio approached 1/1. The gel of symmetric pentablock copolymer exhibited a wider gelation region, higher gel-to-sol transition temperature, higher hydrophobic domain crystallinity, larger intermicellar distance, higher storage modulus, and slower degradation and drug release rate compared to those of the asymmetric PLA/PEG pentablock copolymers or triblock copolymers. SAXS results indicated that the PLLA/PDLA blocks stereocomplexation in pentablock copolymers facilitated the intermicellar aggregation and bridging. Cylindrical ordered structures were observed in all the gels formed from the PLA/PEG pentablock and triblock copolymers. The stereocomplexation degree and intermicellar distance of the pentablock copolymer gels increased with heating. PMID- 27121733 TI - Differential roles of hypoxia and innate immunity in juvenile and adult dermatomyositis. AB - Dermatomyositis (DM) can occur in both adults and juveniles with considerable clinical differences. The links between immune-mediated mechanisms and vasculopathy with respect to development of perifascicular pathology are incompletely understood. We investigated skeletal muscle from newly diagnosed, treatment-naive juvenile (jDM) and adult dermatomyositis (aDM) patients focusing on hypoxia-related pathomechanisms, vessel pathology, and immune mechanisms especially in the perifascicular region. Therefore, we assessed the skeletal muscle biopsies from 21 aDM, and 15 jDM patients by immunohistochemistry and electron microscopy. Transcriptional analyses of genes involved in hypoxia, as well as in innate and adaptive immunity were performed by quantitative Polymerase chain reaction (qPCR) of whole tissue cross sections including perifascicular muscle fibers.Through these analysis, we found that basic features of DM, like perifascicular atrophy and inflammatory infiltrates, were present at similar levels in jDM and aDM patients. However, jDM was characterized by predominantly hypoxia-driven pathology in perifascicular small fibers and by macrophages expressing markers of hypoxia. A more pronounced regional loss of capillaries, but no relevant activation of type-1 Interferon (IFN)-associated pathways was noted. Conversely, in aDM, IFN-related genes were expressed at significantly elevated levels, and Interferon-stimulated gene (ISG)15 was strongly positive in small perifascicular fibers whereas hypoxia-related mechanisms did not play a significant role.In our study we could provide new molecular data suggesting a conspicuous pathophysiological 'dichotomy' between jDM and aDM: In jDM, perifascicular atrophy is tightly linked to hypoxia-related pathology, and poorly to innate immunity. In aDM, perifascicular atrophy is prominently associated with molecules driving innate immunity, while hypoxia-related mechanisms seem to be less relevant. PMID- 27121735 TI - Attributes and outcomes of end stage liver disease as compared with other noncancer patients admitted to a geriatric palliative care unit. AB - BACKGROUND: End stage liver disease (ESLD) is increasingly more prevalent as a noncancer disease to manage in palliative care. Because of the clear lack of a "terminal phase" in ESLD, palliative care is often initiated only when death is perceived as being imminent. Palliative care units (PCUs) serve as an option for continued care for patients living with ESLD and are a limited resource, often not able to accommodate longer patient admissions. Concerns have been raised that ESLD patients may be admitted late in their disease course, not allowing for equitable access to such a service because of a perceived longer length of stay (LOS). The aim of this study is to better characterize the illness experience of patients with ESLD on a geriatric PCU comparing ESLD patients and other noncancer patients in terms of admission PPS, estimated prognosis and LOS. METHODS: This was a single-center retrospective chart review of all noncancer patients admitted to Baycrest Health Sciences Palliative Care Unit (PCU) in Toronto, Canada over a four-year period. We measured the association between demographic data, estimated prognosis, Palliative Performance Score (PPS), and LOS between patients with ESLD and other noncancer diagnoses. RESULTS: There were 235 patients with noncancer diagnoses admitted to the PCU during the study period, of which 19% had ESLD. Patients with ESLD were both significantly younger (P<0.001) and were admitted with a significantly higher PPS (P<0.001) than patients with other noncancer diagnoses. Estimated prognoses for patients with ESLD compared to other noncancer patients were similar. There were no significant difference in LOS between patients with ESLD and other noncancer patients (P=0.18), although there was a non-significant trend towards a shorter LOS for patients with ESLD. There was no significance in disposition (P=0.30); the vast majority of patients with ESLD and other noncancer diagnoses died on the PCU. CONCLUSIONS: Patients with ESLD were younger and had a higher PPS score with no significant difference in estimated prognosis, LOS, or disposition when compared to other noncancer patients. Our findings suggest that patients with ESLD have a short LOS on the PCU with a unique illness experience compared to other noncancer patients. PMID- 27121736 TI - Inter-rater reliability in performance status assessment among health care professionals: a systematic review. AB - BACKGROUND: Studies have reported that performance status (PS) is a good prognostic indicator in patients with advanced cancer. However, different health care professionals (HCPs) could grade PS differently. The purpose of this review is to investigate the PS scores evaluated by different HCPs as reported in the literature. METHODS: A literature search was conducted in Ovid MEDLINE and OLDMEDLINE from 1946 to Present (July 5, 2015), Embase Classic and Embase from 1947 to 2015 Week 26, and Cochrane Central Register of Controlled Trials up to May 2015. Information of interest was whether there was a difference of PS assessment between HCPs. Other statistical information provided to assess the agreement in ratings, such as Cohen's kappa coefficient, Krippendorff's alpha coefficient, Spearman Rank Coefficient, and Kendall's correlation, was noted. RESULTS: Of the fifteen articles, eleven compared PS assessments between HCPs of different disciplines, one between the attending and resident physician, two between similarly-specialized physicians, and one between two unspecified specialty physicians. Three studies reported a lack of agreement (kappa =0.19 0.26; Krippendorff's alpha =0.61-0.63), four reported moderate inter-rater reliability (kappa =0.31-0.72), two reported mixed reliability, and six reported strong reliability (kappa =0.91-0.92; Spearman rank correlation =0.6-1.0; Kendall's correlation =0.75-0.82). Four studies reported that Karnofsky performance status (KPS) had better inter-rater reliability than both the Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the palliative performance scale (PPS). CONCLUSIONS: The existing literature cites both good and bad inter-rater reliability of PS scores. It is difficult to conclude which HCPs' PS assessments are more accurate. PMID- 27121734 TI - Non-infectious Pulmonary Diseases and HIV. AB - Pulmonary complications remain among the most frequent causes of morbidity and mortality for individuals with HIV despite the advent of antiretroviral therapy (ART) and improvement in its efficacy and availability. The prevalence of non infectious pulmonary diseases is rising in this population, reflecting both an increase in smoking and the independent risk associated with HIV. The unique mechanisms of pulmonary disease in these patients remain poorly understood, and direct effects of HIV, genetic predisposition, inflammatory pathways, and co infections have all been implicated. Lung cancer, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension are the most prevalent non-infectious pulmonary diseases in persons with HIV, and the risk of each of these diseases is higher among HIV-infected (HIV+) persons than in the general population. This review discusses the latest advances in the literature on these important complications of HIV infection. PMID- 27121737 TI - The impact of psychosocial intervention on survival in cancer: a meta-analysis. AB - BACKGROUND: The impact of psychosocial interventions on survival remains controversial in patients with cancer. A meta-analysis of the recent literature was conducted to evaluate the potential survival benefit associated with psychosocial interventions for cancer patients. METHODS: MEDLINE, EMBASE, and Cochrane Central were searched from January 2004 to May 2015 for all randomized controlled trials (RCTs) that compared survival outcomes between cancer patients receiving a psychosocial intervention and those receiving other, or no interventions. Endpoints included one-, two-, and four-year overall survival. Subgroup analyses were performed to compare group-versus individually-delivered interventions, and to assess breast cancer-only trials. RESULTS: Of 5,080 identified articles, thirteen trials were included for analysis. There was a significant survival benefit for the intervention group at one year [risk ratio (RR) =0.82; 95% confidence interval (CI), 0.67-1.00; P=0.04] and two years (RR =0.86; 95% CI, 0.78-0.95; P=0.003). However, no significant difference was detected at four years (RR =0.94; 95% CI, 0.85-1.04; P=0.24). Among patients with breast cancer, there was a significant survival benefit of psychosocial interventions at one year (RR =0.59; 95% CI, 0.42-0.82; P=0.002), but no difference at two years (RR =0.82; 95% CI, 0.67-1.02; P=0.07) or four years (RR =0.95; 95% CI, 0.73-1.23; P=0.68). Group-delivered interventions had a significant survival benefit favouring the intervention group at one year (RR =0.57; 95% CI, 0.41-0.79; P=0.0008), but no difference at two years (RR =0.84; 95% CI, 0.68-1.02; P=0.08) or four years (RR =0.94; 95% CI, 0.75-1.20; P=0.64). Individually-delivered interventions had no significant survival benefit at one year (RR =0.92; 95% CI, 0.79-1.08; P=0.32), two years (RR =0.87; 95% CI, 0.75 1.00; P=0.05), or four years (RR =0.93; 95% CI, 0.84-1.04; P=0.21). CONCLUSIONS: For the main analysis and group-delivered treatments, psychosocial interventions demonstrated only short-term improvements in survival. Individually-delivered interventions failed to show any survival benefit. Future studies with longer follow-up are warranted to investigate long-term survival outcomes. PMID- 27121738 TI - Urinary cytokines/chemokines pattern in patients with painful bone metastases undergoing external beam radiotherapy experiencing pain flare. AB - BACKGROUND: External beam radiotherapy (EBRT) is a mainstay for treatment of painful bone metastases. Transient worsening of pain ("pain flare") occurs in 40% of patients. We investigated the pathophysiology of pain flare through assessment of changes in urinary cytokines/chemokines in patients receiving EBRT for painful bone metastases. METHODS: Urine samples were collected from patients receiving a single 8 Gy fraction for painful bone metastases preparation, day 1 or 2 and on an additional day between days 3 to 5 post radiation. Patients completed a standardized pain and analgesic use diary daily for 10 days following radiation. Patients were deemed to have pain flare if they had a two-point increase from baseline worst pain on 0-10 scale and no decrease in analgesic intake or a 25% increase in analgesic intake with no decrease in worst pain. The Millipore Milliplex 42-Plex Cyto-kine/Chemokine KitTM was used to measure urinary levels of a panel of cytokines/chemokines. RESULTS: Forty-six patients consented to the study of which 28 were evaluable (complete urine and diary data), and 83/84 urine samples were available for analysis. Pain flare was experienced by 11 patients (39%). The following cytokines/chemokines were detectable in at least 50% of the patients: EGF, fractalkine, GRO, IL-4, IL-8, interferon gamma induced protein 10 (IP-10), MCP-1, macrophage derived chemokine (MDC), PDGF-AA, sIL-2Ra, TGF-Alpha, VEGF. Comparing patients with or without pain flare EGF, fractalkine, GRO, IL-8, IP-10, MCP-1, MDC, sIL-2Ra, and TGF-alpha increased following radiation in both groups. Patients with pain flare have significant lower levels on IL-8, IP-10, and MDC over time. No specific time trend was noticed. CONCLUSIONS: Patients who experience pain flare appear to have a different pattern in urinary cytokine/chemokine levels than patients without pain flare. A larger study is required to confirm the possible role of cytokines/chemokines in predisposition to and/or the cause of pain flare following radiation to painful bone metastases. PMID- 27121739 TI - Radiological changes on CT after stereotactic body radiation therapy to non-spine bone metastases: a descriptive series. AB - BACKGROUND: In recent years, stereotactic body radiation therapy (SBRT) has become increasingly used for the management of non-spine bone metastases. Few studies have examined the radiological changes in bone metastases after treatment with SBRT and there is no consensus about what constitutes radiologic response to therapy. This article describes various changes on CT after SBRT to non-spine bone metastases in eight selected cases. METHODS: A retrospective review was conducted for patients treated with SBRT to non-spine bone metastases between November 2011 and April 2014 at Sunnybrook Health Sciences Centre. A musculoskeletal radiologist identified eight illustrative cases of interest and provided a description of the findings. RESULTS: Different radiological changes following SBRT were described, including: remineralization of lytic bone metastases, demineralization of sclerotic bone metastases, pathologic fracture, size progression and response in different lesions, as well as lung fibrosis after SBRT to a rib metastasis. CONCLUSIONS: We reviewed the radiological images of eight selected cases after SBRT to nonspine bone metastases and a number of characteristic findings were highlighted. We recommend future studies to correlate radiologic changes with clinical outcomes including pain relief, toxicity and long-term local control. PMID- 27121740 TI - Manipulating the Hippo-Yap signal cascade in stem cells for heart regeneration. AB - The Hippo-Yap pathway was originally recognized as a crucial signal cascade controlling organ size, and more recently identified as an important component involved in the regulation of cardiomyocyte survival, proliferation, and regeneration. Negative stress responses can activate mammalian sterile 20-like kinase 1 (Mst1) to suppress protective autophagy and promote cardiomyocyte apoptosis via phosphorylation and inhibition of Bcl-xL. Moreover, decreased Yap activity and nuclear entry will decrease upon Mst1 activation, ultimately suppressing cardiomyocytes proliferation and regeneration. Based on these observations, there are potential therapeutic opportunities in cardiac structural and functional regeneration post myocardium infarction to be gained by manipulation of the Hippo-Yap signal cascade. This review will summarize the main components of the Hippo-Yap pathway and their molecular biological functions. It will then highlight the role of these signal modules in the acquisition of stem cell pluripotency, cardiogenic differentiation, cardiomyocyte proliferation and maturation, and mitochondrial biogenesis in cardiac stem cells. Finally, it will discuss the potential for future studies of Hippo-Yap pathway using induced pluripotent stem cell (iPSC) technology. PMID- 27121741 TI - Illness understanding in patients with advanced lung cancer: curse or blessing? AB - Early palliative care (EPC) should be introduced from the start of the treatment of patients with advanced lung cancer. Unfortunately, this is often not integrated in daily oncologic care. This letter wants to emphasize the importance of offering a holistic approach, meaning EPC to optimize quality of life (QoL). Illness understanding is important because patients with better understanding of their disease choose more often for symptom control and less for an aggressive treatment at the end of life. This illness understanding should be achieved during communication with the treating oncologist. Based on the limited available literature about illness understanding, it seems that an EPC program is necessary when breaking bad news, in order to maintain or improve QoL in patients. PMID- 27121742 TI - Stereotactic radiosurgery/stereotactic body radiation therapy-reflection on the last decade's achievements and future directions. AB - Stereotactic radiosurgery (SRS) and its extracranial first cousin, stereotactic body radiation therapy (SBRT) have become increasingly important in the palliative treatment of cancer patients over the past decade. Appropriately designed and adequately powered clinical trials have in many clinical scenarios amply justified the time, effort, and expense associated with the development and delivery of these highly conformal and complex radiation treatment plans. Ongoing trials are anticipated to provide further confirmatory documentation of the benefits that have been readily observed by caregivers, patients, and their families. It may be predicted that future directions for palliative radiosurgery will include simplification, through greater automation, of the detailed steps that are still required for safe treatment, and thereby increase the chances for patients to receive these advanced palliative interventions at local institutions, from local caregivers. PMID- 27121743 TI - Extremely rare presentation of soft tissue metastasis from carcinoma breast as a massive swelling of upper extremity. AB - Soft tissue metastasis from any primary malignancy is considered very rare and a breast carcinoma metastasizing to soft tissue is still rarer. To the best of our knowledge, carcinoma breast with soft tissue metastasis to upper extremity is very uncommon with only six cases been reported in world literature till date and our case is the seventh such case in an 80-year-old female, previously treated for carcinoma right breast 15 years ago. The patient presented with progressive painful massive swelling of right upper arm measuring 21 cm * 17 cm, of 2 months duration. Histopathological examination of the swelling showed metastatic deposits from a poorly differentiated adenocarcinoma. Further immunohistochemical (IHC) analysis revealed tumor cells staining positive for estrogen and progesterone receptors while negative for HER 2-Nu, desmin, epithelial membrane antigen, CK7 and thyroid transcription factor-1 (TTF-1), suggestive of metastasis from a primary breast carcinoma. Only few case series and isolated cases reports have been published regarding any primary malignancy or breast carcinoma metastasizing to soft tissues. A thorough review of literature also reveals that our case is the largest soft tissue metastatic swelling from breast carcinoma ever reported. We hereby present this case with review of literature to highlight its extreme rarity, unusual presentation, clinicopathological characteristics and its overall prognosis. PMID- 27121744 TI - A case report of bone metastases from appendiceal adenocarcinoma and a review of literature. AB - Appendiceal adenocarcinoma (AA) is a rare cancer, accounting for less than 0.5% of all gastrointestinal cancers. As such, there is still debate surrounding both the nature of the disease and the roles of different treatment modalities in the care of this patient population. Metastases of AA, particularly distant metastases, have not been explored extensively in literature. As survival in optimally treated cases of AA continues to improve, clinicians may encounter previously unrealized complications of this disease or unlikely metastases at a higher frequency. We reported the rare case of a 50-year-old male with recurrent mucinous AA who developed painful pelvic bone metastases. To palliate his symptoms, the patient underwent 30 Gy of external beam radiation treatment (EBRT) in 10 fractions to the pelvis. The patient achieved a good pain response after completion of EBRT, with elimination of analgesic use one month post-treatment. This case demonstrates successful palliative management of bone metastases from a primary mucinous AA. Although there is a lack of evidence-based guidelines specific to the treatment of AA, there are a variety of therapies available [e.g., chemotherapy, cytoreductive surgery (CRS), radiation, etc.]. The use of these treatments is largely determined by prognostic factors. PMID- 27121745 TI - The impact of performance status, psychosocial interventions, and early palliative care on overall survival. PMID- 27121746 TI - Evaluation of safety climate and employee injury rates in healthcare. AB - OBJECTIVES: Safety climates that support safety-related behaviour are associated with fewer work-related injuries, and prior research in industry suggests that safety knowledge and motivation are strongly related to safety performance behaviours; this relationship is not well studied in healthcare settings. METHODS: We performed analyses of survey results from a Veterans Health Administration (VHA) Safety Barometer employee perception survey, conducted among VHA employees in 2012. The employee perception survey assessed 6 safety programme categories, including management participation, supervisor participation, employee participation, safety support activities, safety support climate and organisational climate. We examined the relationship between safety climate from the survey results on VHA employee injury and illness rates. RESULTS: Among VHA facilities in the VA New England Healthcare System, work-related injury rate was significantly and inversely related to overall employee perception of safety climate, and all 6 safety programme categories, including employee perception of employee participation, management participation, organisational climate, supervisor participation, safety support activities and safety support climate. CONCLUSIONS: Positive employee perceptions of safety climate in VHA facilities are associated with lower work-related injury and illness rates. Employee perception of employee participation, management participation, organisational climate, supervisor participation, safety support activities and safety support climate were all associated with lower work-related injury rates. Future implications include fostering a robust safety climate for patients and healthcare workers to reduce healthcare worker injuries. PMID- 27121747 TI - Coordinated process of polarized growth in filamentous fungi. AB - Filamentous fungi are extremely polarized organisms, exhibiting continuous growth at their hyphal tips. The hyphal form is related to their pathogenicity in animals and plants, and their high secretion ability for biotechnology. Polarized growth requires a sequential supply of proteins and lipids to the hyphal tip. This transport is managed by vesicle trafficking via the actin and microtubule cytoskeleton. Therefore, the arrangement of the cytoskeleton is a crucial step to establish and maintain the cell polarity. This review summarizes recent findings unraveling the mechanism of polarized growth with special emphasis on the role of actin and microtubule cytoskeleton and polarity marker proteins. Rapid insertions of membranes via highly active exocytosis at hyphal tips could quickly dilute the accumulated polarity marker proteins. Recent findings by a super-resolution microscopy indicate that filamentous fungal cells maintain their polarity at the tips by repeating transient assembly and disassembly of polarity sites. PMID- 27121748 TI - Berberine induces mitochondrial apoptosis of EBV-transformed B cells through p53 mediated regulation of XAF1 and GADD45alpha. AB - Berberine exhibits antiproliferative or cytotoxic effects against various cancers. ROS and wild-type p53 play a critical role in berberine-induced cytotoxic effects. In this study, we investigated the correlation between XAF1 and functional p53 in EBV-transformed B cells or cancerous B cells after treatment with berberine. Berberine decreased cell viability and induced apoptosis through a mitochondria-dependent pathway in EBV-transformed B cells and cancerous B cells, but not in normal peripheral blood mononuclear cells. Activated p53 and its downstream targets XAF1 and GADD45alpha interacted with PUMA, Bax, and Bim in mitochondria after treatment with berberine. Blocking phosphorylation of p38/JNK MAPK and treatment with PFT-alpha, a selective p53 inhibitor, effectively prevented apoptosis and the upregulation of phosphorylated p53, XAF1, and GADD45alpha. NAC, a ROS scavenger, also suppressed berberine induced mitochondria disruption and the whole apoptotic process via restoration of p53-related proteins and proapoptotic Bcl-2 family proteins. Taken together, our results suggest that ROS generation might be a predisposing event in berberine-induced mitochondrial apoptosis in EBV-transformed B cells through the upregulation of XAF1 and GADD45alpha expression by MAPK and functional p53. PMID- 27121749 TI - Cancer associated proteins in blood plasma: Determining normal variation. AB - Protein biomarkers have the potential to improve diagnosis, stratification of patients into treatment cohorts, follow disease progression and treatment response. One distinct group of potential biomarkers comprises proteins which have been linked to cancer, known as cancer associated proteins (CAPs). We determined the normal variation of 86 CAPs in 72 individual plasma samples collected from ten individuals using SRM mass spectrometry. Samples were collected weekly during 5 weeks from ten volunteers and over one day at nine fixed time points from three volunteers. We determined the degree of the normal variation depending on interpersonal variation, variation due to time of day, and variation over weeks and observed that the variation dependent on the time of day appeared to be the most important. Subdivision of the proteins resulted in two predominant protein groups containing 21 proteins with relatively high variation in all three factors (day, week and individual), and 22 proteins with relatively low variation in all factors. We present a strategy for prioritizing biomarker candidates for future studies based on stratification over their normal variation and have made all data publicly available. Our findings can be used to improve selection of biomarker candidates in future studies and to determine which proteins are most suitable depending on study design. PMID- 27121750 TI - Olefin hydrosilylation catalyzed by cationic nickel(ii) allyl complexes: a non innocent allyl ligand-assisted mechanism. AB - The arene-supported cationic nickel allyl complexes serve as good catalysts for olefin hydrosilylation at room temperature. Detailed mechanistic studies based on experiments and DFT calculations support the novel mechanism, which includes the facile Si-H bond cleavage and Si-C bond formation, assisted by a non-innocent allyl ligand. PMID- 27121751 TI - 5'-(E)-Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of siRNA-GalNAc Conjugates. AB - Small interfering RNA (siRNA)-mediated silencing requires siRNA loading into the RNA-induced silencing complex (RISC). Presence of 5'-phosphate (5'-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Phosphorylation of exogenous duplex siRNAs is thought to be accomplished by cytosolic Clp1 kinase. However, although extensive chemical modifications are essential for siRNA-GalNAc conjugate activity, they can significantly impair Clp1 kinase activity. Here, we further elucidated the effect of 5'-P on the activity of siRNA GalNAc conjugates. Our results demonstrate that a subset of sequences benefit from the presence of exogenous 5'-P. For those that do, incorporation of 5'-(E) vinylphosphonate (5'-VP), a metabolically stable phosphate mimic, results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability. PMID- 27121752 TI - Solanum pennellii backcross inbred lines (BILs) link small genomic bins with tomato traits. AB - We present a resource for fine mapping of traits derived from the wild tomato species Solanum pennellii (LA0716). The population of backcross inbred lines (BILs) is composed of 446 lines derived after a few generations of backcrosses of the wild species with cultivated tomato (cultivar M82; LA3475), followed by more than seven generations of self-pollination. The BILs were genotyped using the 10K SOL-CAP single nucleotide polymorphism (SNP) -Chip, and 3700 polymorphic markers were used to map recombination break points relative to the physical map of Solanum lycopersicum. The BILs carry, on average, 2.7 introgressions per line, with a mean introgression length of 11.7 Mbp. Whereas the classic 76 introgression lines (ILs) partitioned the genome into 106 mapping bins, the BILs generated 633 bins, thereby enhancing the mapping resolution of traits derived from the wild species. We demonstrate the power of the BILs for rapid fine mapping of simple and complex traits derived from the wild tomato species. PMID- 27121753 TI - Dietary levels of protein and free amino acids affect pancreatic proteases activities, amino acids transporters expression and serum amino acid concentrations in starter pigs. AB - The dietary contents of crude protein and free amino acids (AA) may affect the protein digestion and AA absorption in pigs. Trypsin and chymotrypsin activities, AA serum concentrations and expression of AA transporters in the small intestine of pigs fed a low protein, AA-supplemented (19.2%, LPAA) or a high protein (28.1%, HP), wheat-soybean meal diet were measured in two 14-d trials. The LPAA diet contained free L-Lys, L-Thr, DL-Met, L-Leu, L-Ile, L-Val, L-His, L-Trp and L Phe. All pigs were fed the same amount of feed (890 and 800 g/d for trial 1 and 2 respectively). In trial 1, samples of mucosa (duodenum, jejunum and ileum) and digesta (duodenum and jejunum) were collected from 14 pigs (17.2 +/- 0.4 kg); in trial 2, blood samples were collected from 12 pigs (12.7 +/- 0.3 kg). The trypsin and chymotrypsin activities in both intestinal segments were higher in pigs fed the HP diet (p < 0.01). Trypsin activity was higher in jejunum than in duodenum regardless the dietary treatment (p < 0.05). Pigs fed the LPAA diet expressed more b0,+ AT in duodenum, B0 AT1 in ileum (p < 0.05), and tended to express more y+ LAT1 in duodenum (p = 0.10). In pigs fed the LPAA diet, the expression of b0,+ AT was higher in duodenum than in jejunum and ileum (p < 0.01), but no difference was observed in pigs fed the HP diet. Ileum had the lowest b0,+ AT expression regardless the diet. The serum concentrations of Lys, Thr and Met were higher in LPAA pigs while serum Arg was higher in HP pigs (p < 0.05). Serum concentrations of AA appear to reflect the AA absorption. In conclusion, these data indicate that the dietary protein contents affect the extent of protein digestion and that supplemental free AA may influence the intestinal site of AA release and absorption, which may impact their availability for growth of young pigs. PMID- 27121754 TI - Dexamethasone-induced catatonia in a patient with multiple myeloma. AB - Catatonia is a complex neuropsychiatric syndrome, caused by different underlying metabolic, neurologic, psychiatric and toxic conditions. Although catatonia is often associated with psychiatric disorders such as schizophrenia or depression, in about 20 to 39% of the patients a somatic illness is found. Unfortunately, this diagnosis is often missed although catatonia is characterized by a specific symptom complex. We report a case of acute catatonia with psychotic features in a patient with multiple myeloma (MM), caused by systemic use of dexamethasone. Physicians should be aware of possible psychiatric side effects when prescribing high doses of dexamethasone. Further, MM patients on corticosteroids should be closely monitored for mild psychological and/or psychiatric symptoms since they may be predictive for the onset of catatonia. PMID- 27121755 TI - Corticosteroids for managing tuberculous meningitis. AB - BACKGROUND: Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is associated with high death rates and with disability in people who survive. Corticosteroids have been used as an adjunct to antituberculous drugs to treat people with tuberculous meningitis, but their role has been controversial. OBJECTIVES: To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register up to the 18 March 2016; CENTRAL; MEDLINE; EMBASE; LILACS; and Current Controlled Trials. We also contacted researchers and organizations working in the field, and checked reference lists. SELECTION CRITERIA: Randomized controlled trials that compared corticosteroid plus antituberculous treatment with antituberculous treatment alone in people with clinically diagnosed tuberculous meningitis and included death or disability as outcome measures. DATA COLLECTION AND ANALYSIS: We independently assessed search results and methodological quality, and extracted data from the included trials. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs) and used a fixed-effect model. We performed an intention-to-treat analysis, where we included all participants randomized to treatment in the denominator. This analysis assumes that all participants who were lost to follow-up have good outcomes. We carried out a sensitivity analysis to explore the impact of the missing data. MAIN RESULTS: Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria.At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337 participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no effect on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1314 participants, low quality evidence). There was no difference between groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia, and liver dysfunction.One trial followed up participants for five years. The effect on death was no longer apparent at this time-point (RR 0.93, 95% CI 0.78 to 1.12; one trial, 545 participants, moderate quality evidence); and there was no difference in disabling neurological deficit detected (RR 0.91, 95% CI 0.49 to 1.69; one trial, 545 participants, low quality evidence).One trial included human immunodeficiency virus (HIV)-positive people. The stratified analysis by HIV status in this trial showed no heterogeneity, with point estimates for death (RR 0.90, 95% CI 0.67 to 1.20; one trial, 98 participants) and disability (RR 1.23, 95% CI 0.08 to 19.07; one trial, 98 participants) similar to HIV-negative participants in the same trial. AUTHORS' CONCLUSIONS: Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term.Corticosteroids may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit, but this outcome is less common than death, and the CI for the relative effect includes possible harm. However, this small possible harm is unlikely to be quantitatively important when compared to the reduction in mortality.The number of HIV-positive people included in the review is small, so we are not sure if the benefits in terms of reduced mortality are preserved in this group of patients. PMID- 27121758 TI - Green Tea and Glycine Modulate the Activity of Metalloproteinases and Collagen in the Tendinitis of the Myotendinous Junction of the Achilles Tendon. AB - The myotendinous junction (MTJ) is the weakest element in the muscle-tendon unit of the heel, and thus the most susceptible to injuries. The scarcity of adequate treatments means that tendinitis is a major concern to athletes and other groups who depend on their physical fitness, although green tea and glycine have both been shown to have beneficial effects on the inflammation. The present study investigated the remodeling effects of green tea and glycine in the MTJ of rats with tendinitis. For this, male Wistar rats were divided into five groups: animals without tendinitis and animals with tendinitis; animals with tendinitis supplied with green tea; animals with tendinitis supplied with a glycine diet; animals with tendinitis supplied with a green tea and glycine diet. Tendinitis was induced and the treatment with green tea (700 mg/kg/day) and a 5% glycine diet lasted 7 days. The treatments regulated the activity of metalloproteinases (MMP)-2, -8, and -9, and induced the synthesis of type I collagen, glycosaminoglycans, and non-collagenous proteins. Changes were also noted in the compaction of the collagen molecules and the amount of tenocytes. When combined, green tea and glycine modulated the inflammatory process and induced the synthesis of the elements involved in the post-lesion recovery of the tissue. The data from the MTJ were different when compared with results already published using the whole Achilles tendon. These data indicate that each region of the inflamed tendon can exhibit different responses during the treatment and therefore, modify its extracellular matrix components to facilitate recovery and repair. Anat Rec, 299:918-928, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27121756 TI - Lipidomic analysis of epidermal lipids: a tool to predict progression of inflammatory skin disease in humans. AB - INTRODUCTION: Lipidomics is the large-scale profiling and characterization of lipid species in a biological system using mass spectrometry. The skin barrier is mainly comprised of corneocytes and a lipid-enriched extracellular matrix. The major skin lipids are ceramides, cholesterol and free fatty acids (FFA). Lipid compositions are altered in inflammatory skin disorders with disrupted skin barrier such as atopic dermatitis (AD). AREAS COVERED: Here we discuss some of the recent applications of lipidomics in human skin biology and in inflammatory skin diseases such as AD, psoriasis and Netherton syndrome. We also review applications of lipidomics in human skin equivalent and in pre-clinical animal models of skin diseases to gain insight into the pathogenesis of the skin disease. Expert commentary: Skin lipidomics analysis could be a fast, reliable and noninvasive tool to characterize the skin lipid profile and to monitor the progression of inflammatory skin diseases such as AD. PMID- 27121757 TI - Calcium/calmodulin-dependent kinase II and nitric oxide synthase 1-dependent modulation of ryanodine receptors during beta-adrenergic stimulation is restricted to the dyadic cleft. AB - KEY POINTS: The dyadic cleft, where coupled ryanodine receptors (RyRs) reside, is thought to serve as a microdomain for local signalling, as supported by distinct modulation of coupled RyRs dependent on Ca2+ /calmodulin-dependent kinase II (CaMKII) activation during high-frequency stimulation. Sympathetic stimulation through beta-adrenergic receptors activates an integrated signalling cascade, enhancing Ca2+ cycling and is at least partially mediated through CaMKII. Here we report that CaMKII activation during beta-adrenergic signalling is restricted to the dyadic cleft, where it enhances activity of coupled RyRs thereby contributing to the increase in diastolic events. Nitric oxide synthase 1 equally participates in the local modulation of coupled RyRs. In contrast, the increase in the Ca2+ content of the sarcoplasmic reticulum and related increase in the amplitude of the Ca2+ transient are primarily protein kinase A-dependent. The present data extend the concept of microdomain signalling in the dyadic cleft and give perspectives for selective modulation of RyR subpopulations and diastolic events. ABSTRACT: In cardiac myocytes, beta-adrenergic stimulation enhances Ca2+ cycling through an integrated signalling cascade modulating L-type Ca2+ channels (LTCCs), phospholamban and ryanodine receptors (RyRs). Ca2+ /calmodulin-dependent kinase II (CaMKII) and nitric oxide synthase 1 (NOS1) are proposed as prime mediators for increasing RyR open probability. We investigate whether this pathway is confined to the high Ca2+ microdomain of the dyadic cleft and thus to coupled RyRs. Pig ventricular myocytes are studied under whole-cell voltage-clamp and confocal line-scan imaging with Fluo-4 as a [Ca2+ ]i indicator. Following conditioning depolarizing pulses, spontaneous RyR activity is recorded as Ca2+ sparks, which are assigned to coupled and non-coupled RyR clusters. Isoproterenol (ISO) (10 nm) increases Ca2+ spark frequency in both populations of RyRs. However, CaMKII inhibition reduces spark frequency in coupled RyRs only; NOS1 inhibition mimics the effect of CaMKII inhibition. Moreover, ISO induces the repetitive activation of coupled RyR clusters through CaMKII activation. Immunostaining shows high levels of CaMKII phosphorylation at the dyadic cleft. CaMKII inhibition reduces ICaL and local Ca2+ transients during depolarizing steps but has only modest effects on amplitude or relaxation of the global Ca2+ transient. In contrast, protein kinase A (PKA) inhibition reduces spark frequency in all RyRs concurrently with a reduction of sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude and relaxation. In conclusion, CaMKII activation during beta-adrenergic stimulation is restricted to the dyadic cleft microdomain, enhancing LTCC-triggered local Ca2+ release as well as spontaneous diastolic Ca2+ release whilst PKA is the major pathway increasing global Ca2+ cycling. Selective CaMKII inhibition may reduce potentially arrhythmogenic release without negative inotropy. PMID- 27121759 TI - Osteoarthritis: Molecular imaging detects activated macrophages. PMID- 27121760 TI - Colletotrichum species associated with jute (Corchorus capsularis L.) anthracnose in southeastern China. AB - Anthracnose, caused by the Colletotrichum species of fungi, is one of the most serious diseases affecting jute in China. The disease causes chlorotic regions with black brown sunken necrotic pits on the surfaces of stems. In late stages of disease, plants undergo defoliation, dieback and blight, which make anthracnose a major threat to jute fiber production and quality in China. In this study, 7 strains of Colletotrichum fungi were isolated from diseased jute stems from Zhejiang, Fujian, Guangxi, and Henan plantations in China. Multi-locus sequence (ACT, TUB2, CAL, GS, GAPDH and ITS) analysis coupled with morphological assessment revealed that C. fructicola, C. siamense and C. corchorum-capsularis sp. nov. were associated with jute anthracnose in southeastern China. C. fructicola and C. siamense were previously not associated with jute anthracnose. C. corchorum-capsularis is a new species formally described here. Pathogenicity tests confirmed that all species can infect jute, causing anthracnose, however the virulence of the 3 species differed. This report is the first associating these three species with jute disease worldwide and is the first description of the pathogens responsible for jute anthracnose in China. PMID- 27121761 TI - Malaria: can we mention the e-word yet? PMID- 27121763 TI - Polarized light interaction with tissues. AB - This tutorial-review introduces the fundamentals of polarized light interaction with biological tissues and presents some of the recent key polarization optical methods that have made possible the quantitative studies essential for biomedical diagnostics. Tissue structures and the corresponding models showing linear and circular birefringence, dichroism, and chirality are analyzed. As the basis for a quantitative description of the interaction of polarized light with tissues, the theory of polarization transfer in a random medium is used. This theory employs the modified transfer equation for Stokes parameters to predict the polarization properties of single- and multiple-scattered optical fields. The near-order of scatterers in tissues is accounted for to provide an adequate description of tissue polarization properties. Biomedical diagnostic techniques based on polarized light detection, including polarization imaging and spectroscopy, amplitude and intensity light scattering matrix measurements, and polarization sensitive optical coherence tomography are described. Examples of biomedical applications of these techniques for early diagnostics of cataracts, detection of precancer, and prediction of skin disease are presented. The substantial reduction of light scattering multiplicity at tissue optical clearing that leads to a lesser influence of scattering on the measured intrinsic polarization properties of the tissue and allows for more precise quantification of these properties is demonstrated. PMID- 27121762 TI - Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation. AB - Gene loci that are hypermethylated and repressed in embryonic (ESCs) but hypomethylated and expressed in trophoblast (TSCs) stem cells are very rare and may have particularly important roles in early developmental cell fate decisions, as previously shown for Elf5. Here, we assessed another member of this small group of genes, Placenta Expressed Transcript 1 (Plet1), for its function in establishing trophoblast lineage identity and modulating trophoblast differentiation. We find that Plet1 is tightly repressed by DNA methylation in ESCs but expressed on the cell surface of TSCs and trophoblast giant cells. In hypomethylated ESCs that are prone to acquire some trophoblast characteristics, Plet1 is required to confer a trophoblast-specific gene expression pattern, including up-regulation of Elf5. Plet1 displays an unusual biphasic expression profile during TSC differentiation and thus may be pivotal in balancing trophoblast self-renewal and differentiation. Furthermore, overexpression and CRISPR/Cas9-mediated knockout in TSCs showed that high Plet1 levels favour differentiation towards the trophoblast giant cell lineage, whereas lack of Plet1 preferentially induces syncytiotrophoblast formation. Thus, the endogenous dynamics of Plet1 expression establish important patterning cues within the trophoblast compartment by promoting differentiation towards the syncytiotrophoblast or giant cell pathway in Plet1-low and Plet1-high cells, respectively. PMID- 27121764 TI - Inhaled loxapine for the urgent treatment of acute agitation associated with schizophrenia or bipolar disorder. AB - BACKGROUND: Acute agitation is a serious complication of schizophrenia and bipolar disorder, which may escalate quickly to aggressive behavior. Rapid treatment is therefore important to calm and stabilize the patient, reducing the potential for harm to the patient and others, and allowing further assessment. Current guidelines suggest that where pharmacologic intervention is indicated, medication should preferably be non-invasive, should have a rapid onset and should control aggressive behavior in the short term without compromising the physician-patient relationship in the long term. OBJECTIVES: This article presents an overview of a new inhaled formulation of the established antipsychotic loxapine, which aims to provide a more rapidly acting agent for the treatment of acute agitation without the disadvantages of intramuscular or intravenous injection. DISCUSSION: Inhaled loxapine is rapidly absorbed with intravenous-like pharmacokinetics, with a time to maximum plasma concentration of 2 minutes and a plasma half-life of approximately 6 hours. In phase III studies, loxapine reduced agitation within 10 minutes of inhalation; agitation was decreased at all subsequent assessments during a 24-hour evaluation period. Inhaled loxapine was generally well tolerated with no undue sedation. The most common adverse events were dysgeusia, mild sedation, and dizziness. Inhaled loxapine is contraindicated in patients with asthma, COPD or other pulmonary disease associated with bronchospasm. CONCLUSIONS: Inhaled loxapine rapidly reduces acute agitation in patients with schizophrenia or bipolar disorder and is generally well tolerated. The non-invasive route of delivery respects the patient's autonomy, reducing the perception of coercion or forced medication. Inhaled loxapine is therefore an effective and appropriate option for use in the emergency setting in patients with acute agitation. PMID- 27121765 TI - Hepatitis C virus core protein regulates OCT4 expression and promotes cell cycle progression in hepatocellular carcinoma. AB - Hepatitis C virus (HCV) core protein plays an important role in the development of hepatocellular carcinoma. octamer-binding protein 4 (OCT4) is critically essential for the pluripotency and self-renewal of embryonic stem cells. Abnormal expression of OCT4 has been detected in several human solid tumors. However, the relationship between HCV core and OCT4 remains uncertain. In the present study, we found that HCV core is capable of upregulating OCT4 expression. The effect of HCV core-induced OCT4 overexpression was abolished by RNAi-mediated scilencing of HCV core. In addition, HCV core-induced OCT4 overexpression resulted in enhanced cell proliferation and cell cycle progression. Inhibition of OCT4 reduced the CCND1 expression and induced G0/G1 cell cycle arrest. Furthermore, OCT4 protein directly binds to CCND1 promoter and transactivates CCND1. These findings suggest that HCV core protein regulates OCT4 expression and promotes cell cycle progression in hepatocellular carcinoma providing new insight into the mechanism of hepatocarcinogenesis by HCV infection. PMID- 27121766 TI - Formation of beta Polymorphs in Milk Fats with Large Differences in Triacylglycerol Profiles. AB - In this study, we characterized the polymorphism of milk fat (MF) with various TAG compositions during isothermal crystallization at 20 degrees C. TAG composition of MF from seven individual cows was determined using GC-FID and MALDI-TOF MS, and MF polymorphism was studied using X-ray diffraction. Results showed that TAG profile determines the polymorphic behavior of MF. Saturated TAG with carbon numbers 34-38 promoted the formation of alpha polymorphs, whereas unsaturated TAG with 52-54 promoted the formation of the beta polymorphs. Furthermore, MFs with unsaturated fatty acid profiles were increased in unsaturated TAG with 52-54 carbons. The presence of MF crystals in the beta polymorph has been controversial over the years as most authors mainly find MF crystals in the alpha and beta' form. In our work, we showed that the beta polymorph is formed in MF on the basis of its TAG composition. PMID- 27121767 TI - Evaluation of the genetic parameters for 10 common and five new ESS core autosomal STR loci in seven major geographic regions and the largest metropolitan province of Turkey. AB - BACKGROUND: Situated at the crossroads of Asia, Middle East and Europe, Turkey has an ethnically diverse population of over 78 milllion people. AIM: To investigate the population genetics and potential differences in the autosomal short tandem repeat (STR) polymorphisms across all the major geographic regions and largest metropolitan province of Turkey within the context of the Near Eastern/European genetic landscape. SUBJECTS AND METHODS: Samples from a total of 5299 unrelated individuals were analysed at 10 common [D2S1338, D3S1358, D8S1179, D16S539, D18S51, D19S433, D21S11, FGA, TH01, vWA] and five new European Standard Set (ESS) core autosomal STR loci [D1S1656, D2S441, D10S1248, D12S391, D22S1045]. RESULTS: Allele frequencies, statistical parameters of forensic interest and population differentiation tests were calculated for nine population datasets corresponding to the seven major geographic regions, the largest metropolitan province, and a combined dataset for the entire country. Cumulative results confirmed the presence of significant differences among these nine autosomal datasets themselves and with those from the nearby populations, therefore justifying the differential use of these separate datasets on a case-by-case basis in forensic investigations. CONCLUSION: This collection of autosomal STR population datasets comprises the largest and most comprehensive of its kind from Turkey so far. PMID- 27121768 TI - Green Catalytic Process for Cyclic Carbonate Synthesis from Carbon Dioxide under Mild Conditions. AB - As a renewable and abundant C1 resource possessing multiple attractive characteristics, such as low cost, nontoxicity, non-flammability, and easy accessibility, CO2 conversion into value-added chemicals and fuels can contribute to green chemistry and sustainable development. Since CO2 is a thermodynamically inert molecule, the activation of CO2 is pivotal for its effective conversion. In this regard, the formation of a transition-metal CO2 complex through direct coordination is one of the most powerful ways to induce the inert CO2 molecule to undergo chemical reactions. To date, numerous processes have been developed for efficient synthesis of cyclic carbonates from CO2 . On the basis of mechanistic understanding, we have developed efficient metal catalysts and green processes, including heterogeneous catalysis, and metal-free systems, such as ionic liquids, for cyclic carbonate synthesis. The big challenge is to develop catalysts that promote the reaction under low pressure (preferably at 1 bar). In this context, bifunctional catalysis is capable of synergistic activation of both the substrate and CO2 molecule, and thus, could render CO2 conversion smoothly under mild conditions. Alternatively, converting CO2 derivatives, that is, the captured CO2 as an activated species, would more easily take place at low pressure in comparison with gaseous CO2 . The aim of this Personal Account is to summarize versatile catalytic processes for cyclic carbonate synthesis from CO2 , including epoxide/CO2 coupling reaction, carboxylation of 1,2-diol with CO2 , oxidative cyclization of olefins with CO2 , condensation of vicinal halohydrin with CO2 , carboxylative cyclization of propargyl alcohols with CO2 , and conversion of the CO2 derivatives. PMID- 27121769 TI - Recellularized human dermis for testing gene electrotransfer ex vivo. AB - Gene electrotransfer (GET) is a proven and valuable tool for in vivo gene delivery to a variety of tissues such as skin, cardiac muscle, skeletal muscle, and tumors, with controllable gene delivery and expression levels. Optimizing gene expression is a challenging hurdle in preclinical studies, particularly for skin indications, due to differences in electrical conductivity of animal compared to human dermis. Therefore, the goal of this study was to develop an ex vivo model for GET using recellularized human dermis to more closely mimic human skin. Decellularized human dermis (DermACELL((r))) was cultured with human dermal fibroblasts and keratinocytes for 4 weeks. After one week of fibroblast culture, fibroblasts infiltrated and dispersed throughout the dermis. Air-liquid interface culture led to epithelial cell proliferation, stratification and terminal differentiation with distinct basal, spinous, granular and cornified strata. Firefly luciferase expression kinetics were evaluated after GET of recellularized constructs for testing gene delivery parameters to skin in vitro. Elevated luciferase expression persisted up to a week following GET compared to controls without electrotransfer. In summary, recellularized dermis structurally and functionally resembled native human skin in tissue histological organization and homeostasis, proving an effective 3D human skin model for preclinical gene delivery studies. PMID- 27121770 TI - Genome-wide identification of target genes for miR-204 and miR-211 identifies their proliferation stimulatory role in breast cancer cells. AB - MiR-204 and miR-211 (miR-204/211) share the same seed site sequence, targeting many of the same genes. Their role in cancer development remains controversial, as both cell proliferative and suppressive effects have been identified. This study aimed to address the relationship between the two structurally similar microRNAs (miRs) by examining their target genes in depth as well as to reveal their contribution in breast cancer cells. Genome-wide pathway analysis with the dysregulated genes after overexpression of either of the two miRs in MCF-7 breast cancer cell identified the "Cancer"- and "Cell signaling"-related pathway as the top pathway for miR-204 and miR-211, respectively. The majority of the target genes for both miRs notably comprised ones that have been characterized to drive cells anti-tumorigenic. Accordingly, the miRs induced the proliferation of MCF-7 and MDA-MB-231 cells, judged by cell proliferation as well as colony forming assay. Tumor suppressors, MX1 and TXNIP, were proven to be direct targets of the miRs. In addition, a high association was observed between miR-204 and miR-211 expression in breast cancer tissue. Our results indicate that miR-204/211 serve to increase cell proliferation at least in MCF-7 and MDA-MB-231 breast cancer cells by downregulating tumor suppressor genes. PMID- 27121772 TI - Differences in autonomic neural activity during exercise between the second and third trimesters of pregnancy. AB - AIM: To test the hypothesis that autonomic neural activity in pregnant women during exercise varies according to gestational age. METHODS: This cross sectional study involved 20 healthy women in their second (n = 13) or third (n = 7) trimester of pregnancy. Incremental cardiopulmonary exercise testing was performed with an electromagnetic cycle ergometer. Heart rate variability was analyzed by frequency analysis software. RESULTS: The low-frequency to high frequency (LF/HF) ratio, an indicator of the sympathetic nervous system, was significantly higher in third trimester than in second trimester subjects (P < 0.05) at 1, 2, and 3 min of incremental exercise testing. In contrast, the HF/total power ratio, an indicator of rapidly acting parasympathetic activity, was significantly higher in second trimester than in third trimester subjects (P < 0.05) at 2 and 3 min. In addition, a negative correlation was found between gestational age and the 'accumulation half-time' of the LH/HF ratio, the time point at which the sum of the LF/HF ratio reached 50% of that accumulated in the total 6 min of exercise testing (r = -0.49, P = 0.028). CONCLUSIONS: The autonomic response to exercise in pregnant women differs between the second and third trimesters. These differences should be considered when prescribing exercise to pregnant women. PMID- 27121771 TI - Chronic effects of soft drink consumption on the health state of Wistar rats: A biochemical, genetic and histopathological study. AB - The present study was performed to examine the effects of chronic soft drink consumption (SDC) on oxidative stress, biochemical alterations, gene biomarkers and histopathology of bone, liver and kidney. Free drinking water of adult male Wistar rats was substituted with three different soft drinks: Coca-Cola, Pepsi and 7-Up, for three consecutive months. The serum and organs were collected for examining the biochemical parameters associated with bone, liver and kidney functions. Semi-quantitative reverse transcription polymerase chain reaction was used to observe the changes in the expression of genes in the liver and kidney, which are associated with oxidative stress resistance. Histopathological investigations were performed to determine the changes in bone, liver and kidney tissues using hematoxylin and eosin stains. SDC affected liver, kidney and bone function biomarkers. Soft drinks increased oxidative stress, which is represented by an increase in malondialdehyde and a decrease in antioxidant levels. SDC affected serum mineral levels, particularly calcium and phosphorus. Soft drinks downregulated the expression levels of glutathione-S-transferase and super oxide dismutase in the liver compared with that of control rats. Rats administered Coca Cola exhibited a hepatic decrease in the mRNA expression of alpha2-macroglobulin compared with rats administered Pepsi and 7-Up. On the other hand, SDC increased the mRNA expression of alpha1-acid glycoprotein. The present renal studies revealed that Coca-Cola increased the mRNA expression levels of desmin, angiotensinogen and angiotensinogen receptor compared with the other groups, together with mild congestion in renal histopathology. Deleterious histopathological changes were reported predominantly in the bone and liver of the Coca-Cola and Pepsi groups. In conclusion, a very strict caution must be considered with SDC due to the increase in oxidative stress biomarkers and disruption in the expression of certain genes associated with the bio-vital function of both the liver and kidney. PMID- 27121773 TI - A comparison of head motion and prefrontal haemodynamics during upright and recumbent cycling exercise. AB - The aim of this observational study was to compare head motion and prefrontal haemodynamics during exercise using three commercial cycling ergometers. Participants (n = 12) completed an incremental exercise test to exhaustion during upright, recumbent and semi-recumbent cycling. Head motion (using accelerometry), physiological data (oxygen uptake, end-tidal carbon dioxide [PET CO2 ] and heart rate) and changes in prefrontal haemodynamics (oxygenation, deoxygenation and blood volume using near infrared spectroscopy [NIRS]) were recorded. Despite no difference in oxygen uptake and heart rate, head motion was higher and PET CO2 was lower during upright cycling at maximal exercise (P<0.05). Analyses of covariance (covariates: head motion P>0.05; PET CO2 , P<0.01) revealed that prefrontal oxygenation was higher during semi-recumbent than recumbent cycling and deoxygenation and blood volume were higher during upright than recumbent and semi-recumbent cycling (respectively; P<0.05). This work highlights the robustness of the utility of NIRS to head motion and describes the potential postural effects upon the prefrontal haemodynamic response during upright and recumbent cycling exercise. PMID- 27121774 TI - Clinical presentation and spectrum of neuroimaging findings in newborn infants with incontinentia pigmenti. AB - AIM: To report on the neurological presentation and neuroimaging findings in newborn infants with incontinentia pigmenti. METHOD: The clinical and neurological course including neuroimaging and follow-up data of eight newborn infants with the neurological phenotype of incontinentia pigmenti were retrospectively reviewed. RESULTS: While the clinical picture was polymorphic, the neurological manifestations were defined as encephalopathic and comprised lethargy and seizures in all but one of the infants. Magnetic resonance imaging (MRI) abnormalities were predominantly in the white matter. Diffusion-weighted imaging (DWI) was obtained during the acute phase in seven of the eight infants, showing restricted diffusion in the deep and subcortical white matter but also in the corpus callosum, basal ganglia, thalami, cerebellum, and cerebral peduncles. Susceptibility-weighted imaging (SWI), performed in five infants, showed a variable amount of signal loss, mainly in the white matter, within areas of restricted diffusion. Extensive MRI abnormalities in newborn infants were followed by abnormal neurodevelopment, with significant motor, cognitive, and/or visual problems. INTERPRETATION: To assess the extent of central nervous system involvement, MRI is recommended in the clinical evaluation of infants with incontinentia pigmenti. They have a characteristic pattern of brain lesions seen on MRI, best recognized using DWI and SWI in the acute neonatal phase, which allow the identification of and distinction between ischaemic and haemorrhagic lesions. PMID- 27121775 TI - Titanium oxide nanotube arrays for high light extraction efficiency of GaN-based vertical light-emitting diodes. AB - TiO2 nanotube (NT) arrays were fabricated on the surface of n-GaN through a liquid-phase conversion process using ZnO nanorods (NRs) as a template for high efficiency InGaN/GaN multiple quantum well (MQW) vertical light-emitting diodes (VLEDs). The optical output power of the VLEDs with TiO2 NTs was remarkably enhanced by 23% and 189% at an injection current of 350 mA compared to those of VLEDs with ZnO NRs and planar VLEDs, respectively. The large enhancement in optical output is attributed to a synergistic effect of efficient light injection from the n-GaN layer of the VLED to TiO2 NTs because of the well-matched refractive indices and superior light extraction into air at the end of the TiO2 NTs. Light propagation along various configurations of TiO2 NTs on the VLEDs was investigated using finite-difference time domain simulations and the results indicated that the wall thickness of the TiO2 NTs should be maintained close to 20 nm for superior light extraction from the VLEDs. PMID- 27121776 TI - Reply. PMID- 27121777 TI - Erosive and osteoarthritic structural progression in early rheumatoid arthritis. AB - OBJECTIVES: To investigate factors associated with joint damage in early RA, and how comorbid OA might influence patient assessment and outcomes. METHODS: Baseline radiographs of hands and feet from 512 participants in the Early RA Network cohort, and after 3 (+/-1) years, 166 of those participants yielded complete scores for RA [erosions, joint space narrowing (JSN)] and OA [JSN, osteophytes (OST)] using validated atlases. DAS28-P is the proportion of DAS28 attributed to patient-reported factors. Adjusted odds ratios were calculated using logistic regression. RESULTS: OA was common at baseline in early RA (40% hand and 48% foot) and associated with RA radiographic score. Higher baseline RA scores were associated with increasing age and ESR, and lower DAS28-P. OST scores were associated with higher age. DAS28 and patient-reported outcomes improved, whereas RA and OA radiographic scores deteriorated by follow-up. Erosive progression was predicted by higher baseline erosions, female gender, better mental health and lower DAS28-P. Hand OST progression was predicted by baseline OST scores. Inflammatory disease activity was associated with erosive, but not with OA progression. Baseline hand OA predicted worse physical function at follow up, but radiographic progression did not explain changes in patient-reported outcomes. CONCLUSION: OA is a common comorbidity that might confound radiographic and clinical assessment, but does not fully explain erosive progression or patient-reported outcomes in early RA. Early RA management should address psychosocial factors and comorbidities, as well as joint inflammation. PMID- 27121778 TI - Rituximab in the treatment of inflammatory myopathies: a review. AB - Several uncontrolled studies have encouraged the use of rituximab (RTX) in patients with myositis. Unfortunately, the first placebo-phase trial to assess the efficacy of RTX in refractory myositis did not show a significant difference between the two treatment groups, and doubts have been expressed about its study design. In this review we present an up-to-date overview of the reported experiences of RTX therapy in myositis. A PubMed search was performed to find all the available cases of refractory myositis patients treated with RTX up to July 2015. The following terms were assessed: inflammatory myopathies OR anti synthetase syndrome OR polymyositis OR dermatomyositis AND RTX. A total of 48 studies were included. We identified 458 patients with myositis treated with RTX. We found a rate of response to RTX of 78.3%. RTX can play a role in the management of patients with myositis, at least in those with positive myositis specific autoantibodies. PMID- 27121780 TI - Development of Clinical Pharmacology in India: Perspective of a Young Researcher. PMID- 27121779 TI - Neutrophils from patients with SAPHO syndrome show no signs of aberrant NADPH oxidase-dependent production of intracellular reactive oxygen species. AB - OBJECTIVE: We aimed to investigate if aberrant intracellular production of NADPH oxidase-derived reactive oxygen species (ROS) in neutrophils is a disease mechanism in the autoinflammatory disease SAPHO syndrome, characterized by synovitis, acne, pustulosis, hyperostosis and osteitis, as has previously been suggested based on a family with SAPHO syndrome-like disease. METHODS: Neutrophil function was explored in a cohort of four patients with SAPHO syndrome, two of whom were sampled during both inflammatory and non-inflammatory phase. Intracellular neutrophil ROS production was determined by luminol-amplified chemiluminescence in response to phorbol myristate acetate. RESULTS: Cells from all patients produced normal amounts of ROS, both intra- and extracellularly, when compared with internal controls as well as with a large collection of healthy controls assayed in the laboratory over time (showing an extensive inter personal variability in a normal population). Further, intracellular production of ROS increased during the inflammatory phase. Neutrophil activation markers were comparable between patients and controls. CONCLUSION: Dysfunctional generation of intracellular ROS in neutrophils is not a generalizable feature in SAPHO syndrome. Secondly, serum amyloid A appears to be a more sensitive inflammatory marker than CRP during improvement and relapses in SAPHO syndrome. PMID- 27121781 TI - Pharmacokinetics of Irinotecan With and Without Panitumumab Coadministration in Patients With Metastatic Colorectal Cancer. AB - This study examined the effects of panitumumab, a human monoclonal antibody against epidermal growth factor receptor (EGFR), on irinotecan pharmacokinetics. This phase I, open-label, multicenter, single-arm study enrolled patients with metastatic colorectal cancer (mCRC) without prior exposure to an EGFR inhibitor. In cycle 1, patients received irinotecan (180 mg/m(2) intravenously [IV]) on day 1 and panitumumab (6 mg/kg IV) on Day 4. In cycle 2 (2 weeks after cycle 1 panitumumab administration) and subsequent every-2-week cycles, patients received panitumumab followed immediately by irinotecan until disease progression or intolerability. Primary and secondary endpoints included Cmax and AUC of irinotecan after irinotecan infusion in cycles 1 and 2, and adverse events, respectively. Nineteen of 27 treated patients were eligible for pharmacokinetic analysis. Pharmacokinetic profiles of irinotecan with or without panitumumab coadministration were nearly identical. The 90% confidence intervals for ratios of geometric means for irinotecan Cmax and AUC with or without panitumumab were within the 80-125% interval, indicating that panitumumab had no apparent effects on irinotecan pharmacokinetics. Adverse events were as expected for irinotecan plus panitumumab combination therapy. PMID- 27121782 TI - Safety, Pharmacokinetics, and Pharmacodynamic Effects of a Selective TGR5 Agonist, SB-756050, in Type 2 Diabetes. AB - TGR5 is a bile acid receptor and a potential target for the treatment of type 2 diabetes (T2D). We report here the safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in patients with T2D. Fifty-one subjects were randomized to receive either placebo or one of four doses of SB 756050 for 6 days. A single 100 mg dose of sitagliptin was co-administered on Day 6 to all subjects. SB-756050 was well-tolerated; it was readily absorbed, exhibited nonlinear pharmacokinetics with a less than dose-proportional increase in plasma exposure above 100 mg, and demonstrated no significant changes in exposure when co-administered with sitagliptin. SB-756050 demonstrated highly variable pharmacodynamic effects both within dose groups and between doses, with increases in glucose seen at the two lowest doses and no reduction in glucose seen at the two highest doses. The glucose effects of SB-756050 + sitagliptin were comparable to those of sitagliptin alone, even though gut hormone plasma profiles were different. This study was registered at ClinicalTrials.gov (NCT00733577). PMID- 27121783 TI - Effect of Food, Antacid, and Age on the Pharmacokinetics of the Oral Thrombin Receptor Antagonist Vorapaxar (SCH 530348) in Healthy Volunteers. AB - This randomized, open-label, parallel group study examined the effects of food, antacid, and age on the pharmacokinetics of vorapaxar. In total, 101 subjects were enrolled including 83 young adults (18-45 years) and 18 elderly subjects (>65 years). Subjects received single-dose vorapaxar 40 mg after a 10-hour fast (young and elderly) or with extra-strength antacid, food, or 1 or 2 hours after food (young only). Vorapaxar 40 mg was rapidly absorbed after a fast (median Tmax : 1 hour). Administration with food or 1 or 2 hours post-meal modestly increased vorapaxar mean area under the curve (AUC) and Cmax and prolonged median Tmax by 1 hour. Concomitant food modestly increased vorapaxar AUC from time zero to infinity [AUC(I)] and Cmax 43% and 31%, respectively. Antacid modestly decreased vorapaxar AUC(I) by 15% and Cmax by 38%, and increased median Tmax by 1 hour. Vorapaxar AUC(I) and Cmax were 41% and 29% higher, respectively, in elderly versus young subjects. Concomitant food and older age were associated with modest increases, and antacid was associated with a small decrease in vorapaxar exposure, which are not expected to affect the drug's safety or efficacy. PMID- 27121784 TI - Therapeutic Equivalence of Ursodeoxycholic Acid Tablets and Ursodeoxycholic Acid Capsules for the Treatment of Primary Biliary Cirrhosis. PMID- 27121786 TI - Pharmacokinetics of Teneligliptin in Subjects With Renal Impairment. AB - The pharmacokinetics of teneligliptin was compared in renally impaired and healthy subjects. Subjects were assigned to one of four groups of eight subjects, according to the stage of disease [mild, moderate, severe or end stage renal disease (ESRD)], while matched healthy subjects were allocated to one of two reference groups. Mild, moderate and severe renal impairment had no effect on maximum plasma concentration (Cmax ) following a single oral dose of 20 mg teneligliptin, as defined in the FDA guideline. AUC0-infinity was increased in all groups relative to the reference group but this was unrelated to the degree of renal impairment. Mean plasma protein binding was <80% in all groups. Overall, teneligliptin was well tolerated by subjects with renal impairment or ESRD. Dialysis is not expected to affect the efficacy or safety of teneligliptin. These results indicate that dose adjustment may not be needed when teneligliptin is administered to subjects with mild, moderate or severe renal impairment or ESRD. PMID- 27121785 TI - Impact of Tesamorelin, a Growth Hormone-Releasing Factor (GRF) Analogue, on the Pharmacokinetics of Simvastatin and Ritonavir in Healthy Volunteers. AB - The potential impact of tesamorelin on CYP3A activity was investigated by examining its effect on the pharmacokinetics of simvastatin and ritonavir. In two randomized, two-way crossover studies, subjects were administered 2 mg tesamorelin on Days 1-7 with 80 mg simvastatin or 100 mg ritonavir co administered on Day 6 (Treatment A), and a single dose of simvastatin or ritonavir alone on Day 6 (Treatment B). Pharmacokinetic samples were collected on Day 6 to measure simvastatin, ritonavir and tesamorelin plasma concentrations. For simvastatin, A/B ratios of least squares geometric means and corresponding 90% confidence intervals (CIs) for AUC0-t , AUC0-inf and Cmax were contained within the usual no effect range of 80-125%. For ritonavir, ratios and 90% CIs for AUCs were within this acceptance range, but the lower CI for Cmax was 74.8%, suggesting a decreased rate of exposure. However, since the A/B ratios for AUCs and Cmax parameters were approximately 90%, these were minor decreases and no dose adjustment of ritonavir is required in the presence of tesamorelin. These studies showed that the impact of tesamorelin on CYP3A activity appears to be minimal, if any. Either medication may be co-administered with tesamorelin in patients without changing their original dosing regimen. PMID- 27121787 TI - Evaluation of the Pharmacokinetic Interaction Between the beta3 -Adrenoceptor Agonist Mirabegron and the Muscarinic Receptor Antagonist Solifenacin In Healthy Subjects. AB - Mirabegron, a selective beta3 -adrenoceptor agonist, is approved for the treatment of overactive bladder (OAB). Solifenacin is a muscarinic receptor antagonist widely used in the treatment of OAB. This open-label, 1-sequence, 2 arm study investigated whether any pharmacokinetic interaction exists between mirabegron and solifenacin. In arm 1, 21 healthy men and women received 10 mg solifenacin succinate alone and in combination with mirabegron 100 mg qd. In arm 2, 20 healthy men and women received 100 mg mirabegron alone and in combination with solifenacin succinate 10 mg qd. Plasma samples were collected and tolerability was assessed. Following coadministration of mirabegron and solifenacin in arm 1, solifenacin geometric mean ratios (90% confidence interval [CI]) for Cmax and AUCinf were 1.23 (1.15, 1.31) and 1.26 (1.17, 1.35), respectively, compared with solifenacin alone, with a 1.07-fold increase in mean t1/2 . In arm 2, mirabegron ratios (90% CI) for Cmax and AUCinf were 0.99 (0.78, 1.26) and 1.15 (1.01, 1.30), respectively, for the combination relative to mirabegron alone, with an increase in mean tmax of approximately 1 hour. Mirabegron or solifenacin alone or in combination was generally well tolerated. PMID- 27121788 TI - Dose Linearity of Glimepiride in Healthy Human Egyptian Volunteers. AB - The present study was adopted to evaluate the pharmacokinetics and dose linearity of glimepiride after administration of single oral doses of 1-6 mg glimepiride in an open-label, five-way crossover study. Twenty-four healthy male Egyptian volunteers were given 1, 2, 3, 4, and 6 mg of glimepiride on five occasions, and blood samples were collected over 24 hours. Plasma glimepiride concentrations were assayed by a validated reversed-phase high-performance liquid chromatography method with UV detection and the data were evaluated by non-compartmental methods to determine pharmacokinetic parameters. The mean elimination half-lives (t1/2 ) did not vary with the dose. The peak plasma levels (Cmax ) and area under the plasma level versus time curve (AUC) data showed dose-proportional response. The time to peak plasma concentration (tmax ), mean residence time, oral clearance (Cl/F) and apparent volume of distribution (Vd /F) were all similar regardless of the administered dose (P > .05). The 90% confidence intervals of the ratios of dose-adjusted log transformed values of Cmax , AUC0-t , AUC0-infinity , t1/2 , and tmax fell within the range of 80-125%. These findings suggest that glimepiride disposition is linear over the dose range studied healthy human Egyptian volunteers. PMID- 27121789 TI - Investigation of Pharmacodynamic and Pharmacokinetic Interactions Between Rivaroxaban and Enoxaparin in Healthy Male Subjects. AB - Rivaroxaban, an oral, direct factor Xa inhibitor, is currently used in clinical practice for the prevention and treatment of thromboembolic disorders. This single-center, three-way crossover study was designed to investigate the pharmacodynamic effects of rivaroxaban (10 mg) and enoxaparin (40 mg) alone and in combination as well as the influence of enoxaparin on the pharmacokinetics of rivaroxaban in healthy male subjects. When given alone, both drugs exhibited similar, rapid anti-factor Xa activity. Combined administration resulted in an increase of ~50% in anti-factor Xa activity and a lesser increase in activated partial thromboplastin time, compared with either drug alone. Enoxaparin had no additional effect on prolongation of the prothrombin time induced by rivaroxaban and did not affect the pharmacokinetic parameters of rivaroxaban. The results showed that rivaroxaban (10 mg) and enoxaparin (40 mg) had a similar and rapid onset of action, as indicated by the similar anti-factor Xa activity-time curves, suggesting that both drugs have a similar duration of pharmacological activity at the factor X site. Co-administration of rivaroxaban and enoxaparin is associated with enhanced pharmacodynamic effects. PMID- 27121790 TI - Glycerol Phenylbutyrate in Patients With Cirrhosis and Episodic Hepatic Encephalopathy: A Pilot Study of Safety and Effect on Venous Ammonia Concentration. AB - Glycerol tri-(4-phenylbutyrate) (glycerol phenylbutyrate, GPB, HPN-100) mediates waste nitrogen excretion through conjugation with glutamine to form phenylacetylglutamine which is excreted in urine. This pilot study was performed to assess tolerability and effect on venous ammonia concentration in patients with cirrhosis and hepatic encephalopathy (HE). Patients underwent one week of 6 mL (6.6 g) twice daily (BID). GPB dosing followed by 3 weeks of 9 mL (9.9 g) BID dosing and underwent repeated blood sampling for ammonia concentration and pharmacokinetics. Fifteen patients were enrolled. Ammonia concentrations were lowest after overnight fast and increased post-prandially. Fasting ammonia concentrations were lower on GPB compared to baseline, with a decrease on the eighth day of 6 mL BID dosing to 45.4 (27.9) umol/L (ULN ~48 umol/L) (P < .05). Nine milliliters BID yielded similar lowering but was associated with more adverse events and higher phenylacetate (PAA) plasma concentrations (PAA Cmax of 144 [125] vs. 292 [224] ug/mL on 6 and 9 mL, respectively). GPB dosed at 6 mL BID lowered fasting ammonia levels in cirrhotic patients with HE as compared with baseline, was better tolerated than 9 mL BID, and is appropriate for further evaluation in patients with cirrhosis and episodic HE. PMID- 27121791 TI - A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray. AB - Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain. A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers. The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed. Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day. In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies. PMID- 27121792 TI - RNA-seq Identification of RACGAP1 as a Metastatic Driver in Uterine Carcinosarcoma. AB - PURPOSE: Uterine carcinosarcoma is a rare aggressive malignancy frequently presenting at advanced stage of disease with extrauterine metastases. Median survival is less than 2 years due to high relapse rates after surgery and poor response to chemotherapy or radiotherapy. The goal of this study was to identify novel therapeutic targets. EXPERIMENTAL DESIGN: We applied RNA-seq analysis to prospectively collected uterine carcinosarcoma tumor samples from patients undergoing primary surgical resection and for comparison, normal endometrial tissues from postmenopausal women undergoing hysterectomy for benign indications. Functional assays were done in primary carcinosarcoma cell lines developed from patients and in established cell lines, as well as a cell line-derived xenograft model. Validation was done by analysis of an independent cohort of patients with uterine carcinosarcoma from The Cancer Genome Atlas (TCGA). RESULTS: Rac GTPase activating protein 1 (RACGAP1) was identified to be highly upregulated in uterine carcinosarcoma. Functional assays showed that RACGAP1 mediates motility and invasion via regulation of STAT3 phosphorylation and survivin expression. RACGAP1 depletion or survivin inhibition abrogated motility and invasiveness of carcinosarcoma cells, while RACGAP1 overexpression conferred invasiveness to endometrial adenocarcinoma cells. In the TCGA cohort, RACGAP1 expression correlated with survivin expression and extrauterine spread of disease. CONCLUSIONS: The RACGAP1-STAT3-survivin signaling pathway is required for the invasive phenotype of uterine carcinosarcoma and is a newly identified therapeutic target in this lethal disease. Clin Cancer Res; 22(18); 4676-86. (c)2016 AACR. PMID- 27121793 TI - WRN Promoter CpG Island Hypermethylation Does Not Predict More Favorable Outcomes for Patients with Metastatic Colorectal Cancer Treated with Irinotecan-Based Therapy. AB - PURPOSE: WRN promoter CpG island hypermethylation in colorectal cancer has been reported to increase sensitivity to irinotecan-based therapies. We aimed to characterize methylation of the WRN promoter, determine the effect of WRN promoter hypermethylation upon expression, and validate a previous report that WRN promoter hypermethylation predicts improved outcomes for patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based therapy. EXPERIMENTAL DESIGN: WRN methylation status was assessed using methylation specific PCR and bisulfite sequencing assays. WRN expression was determined using qRT-PCR and Western blotting. WRN methylation status was correlated with overall survival (OS) and progression-free survival (PFS) in 183 patients with mCRC. Among these patients, 90 received capecitabine monotherapy as first-line therapy, and 93 received capecitabine plus irinotecan (CAPIRI) therapy as part of the CAIRO phase III clinical trial. RESULTS: WRN mRNA and WRN protein expression levels were low in colorectal cancer cell lines and in primary colorectal cancer and were largely independent of WRN methylation status. Patients with methylated WRN colorectal cancer had a shorter OS compared with patients who had unmethylated WRN colorectal cancer (HR = 1.6; 95% confidence interval [CI], 1.2 2.2; P = 0.003). Patients with unmethylated WRN showed a significantly longer PFS when treated with CAPIRI compared with capecitabine alone (HR = 0.48; 95% CI, 0.32-0.70; P = 0.0001). In contrast, patients did not benefit from adding irinotecan to capecitabine when WRN was methylated (HR = 1.1; 95% CI, 0.69-1.77; P = 0.7). CONCLUSIONS: WRN expression is largely independent of WRN promoter hypermethylation in colorectal cancer. Moreover, we could not validate the previous finding that WRN promoter hypermethylation predicts improved clinical outcomes of mCRC treated with irinotecan-based therapy and found instead the opposite result. Clin Cancer Res; 22(18); 4612-22. (c)2016 AACR. PMID- 27121794 TI - Screening and identification of DNA aptamers toward Schistosoma japonicum eggs via SELEX. AB - Schistosomiasis is a major parasitic disease caused by blood flukes of the genus Schistosoma. Several million people all over the world are estimated to suffer from severe morbidity as a consequence of schistosomiasis. The worm's eggs, which cause the symptoms of schistosomiasis, are generally used to diagnose the disease. In this study, we employed egg-based systematic evolution of ligands by exponential enrichment (egg-SELEX) and identified a panel of ssDNA aptamers specifically binding to eggs derived from S. japonicum. Among these, two aptamers LC6 and LC15 exhibited strong binding to and specific recognition of S. japonicum eggs, but not eggs from Fasciolopsis buski, Enterobius, Ascaris or Clonorchis sinensis. Furthermore, tissue imaging results revealed that LC15 could recognize S. japonicum eggs laid in liver tissues with a detection ratio of 80.5%. Collectively, therefore, we obtained useful aptamers specifically recognizing S. japonicum eggs, which will facilitate the development of an effective tool for both schistosomiasis diagnosis and drug delivery. PMID- 27121795 TI - Meta-analysis of population-based studies comparing risk of cerebrovascular accident associated with first- and second-generation antipsychotic prescribing in dementia. AB - BACKGROUND: Second-generation antipsychotics (SGAs) are often prescribed in the treatment of Behavioral and Psychological Symptoms of Dementia (BPSD), however, their use has been discouraged in light of clinical trials suggesting that they cause an increased risk of cerebrovascular accidents (CVAs). OBJECTIVE: Aim of the study was to assess relative risk of CVA in dementia patients prescribed SGA rather than first-generation antipsychotics (FGAs), through meta-analysis of population-based studies. METHODS: A literature search was conducted using several relevant databases. Five studies were included in the review and data were pooled to conduct meta-analysis using the inverse variance method. RESULTS: A total of 79,910 patients were treated with SGAs and 1287 cases of CVA were reported. Of 48,135 patients treated with FGAs, a total of 511 cases of CVA were reported. The relative risk of CVA was 1.02 (95% CI 0.56-1.84) for the SGA group. There was no significant difference in the risk of stroke (p = 0.96) between groups, but significant heterogeneity was found among the results of included studies (p < 0.001). CONCLUSION: Meta-analysis of population-based data suggested that the use of SGAs as opposed to FGAs to control BPSD is not associated with significantly increased risk of CVA. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121796 TI - Fish diversity in the Rio de la Plata and adjacent waters: an overview of environmental influences on its spatial and temporal structure. AB - The fish diversity and the main environmental factors affecting the spatial distribution of species, life history stages and community structure in the Rio de la Plata (RdP) and adjacent waters are reviewed and analysed, with emphasis on the functional guild classification. The functional guild classification indicated that most species in the RdP were marine stragglers, zoobenthivores and oviparous species, although the biomass was dominated by estuarine species. Salinity had a stronger influence than temperature on the spatial pattern for all life stages, shallower and fresher waters are the preferred habitats of neonates and juveniles. During the breeding season (spring-summer), adults showed an intrusion into the inner part of RdP or to its adjacent nearshore waters from the offshore waters for spawning or mating, respectively. Variations in river discharge and wind patterns greatly affected the spatial extent of estuarine water, which ultimately influenced the domain of the main life-history stages (juveniles or adults) for both marine and estuarine fishes, as well as species and fish assemblage composition. The strong environmental gradient restricts some species and life-history stages to a particular section and defines three main fish assemblage areas. The composition of the fish assemblage is indicative of the recruitment of freshwater and marine species to the estuary in opposite ways, determined by the vertical stratification. Seasonal changes in the species composition were related to migration as a result of salinity and temperature variations and reproductive migrations to spawning and mating areas. This overview reveals that the RdP is under environmental variations that are likely to produce modifications to fish distribution and abundance that affect its fisheries. This context plus fish stock declines and changes in exploitation patterns could amplify the magnitude of the variations in the fisheries resources availability and affect the sustainability of fishing communities. PMID- 27121797 TI - P-selectin increases angiotensin II-induced cardiac inflammation and fibrosis via platelet activation. AB - Platelet activation is important in hypertension-induced cardiac inflammation and fibrosis. P-selectin expression significantly (P<0.05) increases when platelets are activated during hypertension. Although P-selectin recruits leukocytes to sites of inflammation, the role of P-selectin in cardiac inflammation and fibrosis remains to be elucidated. The present study aimed to investigate whether platelet-derived P-selectin promotes hypertensive cardiac inflammation and fibrosis. P-selectin knockout (P-sel KO) mice and wild-type (WT) C57BL/6 littermates were infused with angiotensin II (Ang II) at 1,500 ng/kg/min for 7 days and then cross-transplanted with platelets originating from either WT or P sel KO mice. P-selectin expression was increased in the myocardium and plasma of hypertensive mice, and the P-sel KO mice exhibited significantly (P<0.05) reduced cardiac fibrosis. The fibrotic areas were markedly smaller in the hearts of P-sel KO mice compared with WT mice, as assessed by Masson's trichrome staining. In addition, alpha-smooth muscle actin and transforming growth factor beta1 (TGF beta1) expression levels were decreased in the P-sel KO mice, as assessed by immunohistochemistry. Following platelet transplantation into P-sel KO mice, the number of Mac-2 (galectin-3)- and TGF-beta1-positive cells was increased in mice that received WT platelets compared with those that received P-sel KO platelets, and the mRNA expression levels of collagen I and TGF-beta1 were also increased. The results from the present study suggest that activated platelets secrete P selectin to promote cardiac inflammation and fibrosis in Ang II-induced hypertension. PMID- 27121798 TI - Erosive tooth wear status of institutionalized alcoholic patients under rehabilitation therapy in the north of Portugal. AB - OBJECTIVES: The objective of the study was to determine the erosive tooth wear (ETW) status of institutionalized patients for alcohol misuse rehabilitation therapy in the north of Portugal. MATERIAL AND METHODS: Descriptive, analytical, and cross-sectional study, conducted on 277 individuals (83.4 % men) with an average age of 43.6 +/- 8.4 years, institutionalized at Instituto da Droga e Toxicodependencia-Delegacao Regional Norte (IDT-Norte). ETW prevalence and severity were assessed by Eccles and Jenkins index. Multivariate logistic regression was used to identify ETW risk factors. Subjects with ETW risk identification according to biological and behavioral exposure were determined in the study. RESULTS: ETW prevalence was 98.6 %. In the cohort, 51.3 % showed localized ETW lesions, 40.1 % generalized ETW lesions, and 7.2 % enamel ETW lesions, more frequently localized in maxilla. From the examined dental surfaces (n = 15,598), 11,493 had erosive wear lesions: 92.4 % (95 % CI 91.7-93.1 %) of all occlusal surfaces, 71.9 % (95 % CI 70.7-73.1 %) of all palatal/lingual, and 56.7 % (95 % CI 55.4-58.1 %) of all buccal surfaces. Buccal and lingual surfaces showed 43.2 and 41.8 % enamel erosive wear lesions; occlusal surfaces had 43.4 % localized erosive wear lesions in dentin. The main ETW risk factors were as follows: age, gastroesophageal reflux disease over 1 year, daily intake of alcohol >=240 g (grams), and intra-oral location in anterior region; 46.2 % of the participants had erosive risk by exposure to biological and behavioral factors. CONCLUSIONS: The ETW status showed high values for disease prevalence and severity, mainly located in the maxilla, and high frequency of erosive wear lesions at occlusal, buccal, and lingual surfaces, resulting from simultaneous exposure to several risk factors. CLINICAL IMPLICATIONS: For ETW differential diagnosis, the association of both clinical and biological/nutritional/behavioral risk factors should be done for each studied population. PMID- 27121800 TI - Renal denervation in patients with heart failure with preserved ejection fraction: end of the beginning? PMID- 27121799 TI - Screening of efficient siRNA carriers in a library of surface-engineered dendrimers. AB - Polymers are widely used as non-viral carriers for siRNA delivery, but concern has also arisen in their limited efficacy and inherent toxicity. Whilst many of previous efforts have been documented towards improving the performance of polymers via chemical modifications, the structure-activity relationships (SAR) of these ligand-modified polymers are not well understood. To address this issue, we systemically prepared a library of surface-engineered dendrimers (>300) as the screening pool to discover efficient siRNA carriers. The modified ligands include alkyls and fluoroalkyls, amino acids, benzene derivatives and heterocyclic compounds. Gene silencing results showed that the lead material shows excellent efficacy even in hard-to-transfect cells such as mesenchymal stem cells. The SAR studies revealed that ligands containing appropriate hydrophobicity, or ligands with both hydrophobic and functional atoms/groups are essential for polymers to achive efficient knockdown efficacy. A second-generation library designed based on the above principles further confirms the proposed design criteria. The results enable the future rational design of potent siRNA carriers. PMID- 27121801 TI - Anticipating artificial intelligence. PMID- 27121802 TI - On a downer. PMID- 27121803 TI - Biden time. PMID- 27121804 TI - Speak up about subtle sexism in science. PMID- 27121815 TI - Devastating wheat fungus appears in Asia for first time. PMID- 27121816 TI - AI talent grab sparks excitement and concern. PMID- 27121817 TI - Scientists worry as cancer moonshots multiply. PMID- 27121818 TI - Researchers push for personalized tumour vaccines. PMID- 27121819 TI - Europe plans giant billion-euro quantum technologies project. PMID- 27121820 TI - Correction. PMID- 27121821 TI - AstraZeneca launches project to sequence 2 million genomes. PMID- 27121822 TI - Killer landslides: The lasting legacy of Nepal's quake. PMID- 27121823 TI - The quiet revolutionary: How the co-discovery of CRISPR explosively changed Emmanuelle Charpentier's life. PMID- 27121824 TI - Seven chemical separations to change the world. PMID- 27121825 TI - Correction. PMID- 27121829 TI - Air corridors: Ventilating Beijing cannot fix pollution. PMID- 27121830 TI - Palaeontology: Benefits of trade in amber fossils. PMID- 27121831 TI - Correspondence: Tell us the end of the story. PMID- 27121832 TI - Government: Anti-science wave sweeps Poland. PMID- 27121833 TI - Portugal: Postdoc rights need not hurt productivity. PMID- 27121834 TI - R. McNeill Alexander (1934-2016). PMID- 27121835 TI - Materials science: Cracks help membranes to stay hydrated. PMID- 27121837 TI - Mathematical physics: Glitches in time. PMID- 27121838 TI - Correction. PMID- 27121839 TI - Natural speech reveals the semantic maps that tile human cerebral cortex. AB - The meaning of language is represented in regions of the cerebral cortex collectively known as the 'semantic system'. However, little of the semantic system has been mapped comprehensively, and the semantic selectivity of most regions is unknown. Here we systematically map semantic selectivity across the cortex using voxel-wise modelling of functional MRI (fMRI) data collected while subjects listened to hours of narrative stories. We show that the semantic system is organized into intricate patterns that seem to be consistent across individuals. We then use a novel generative model to create a detailed semantic atlas. Our results suggest that most areas within the semantic system represent information about specific semantic domains, or groups of related concepts, and our atlas shows which domains are represented in each area. This study demonstrates that data-driven methods--commonplace in studies of human neuroanatomy and functional connectivity--provide a powerful and efficient means for mapping functional representations in the brain. PMID- 27121840 TI - Dynamics from noisy data with extreme timing uncertainty. AB - Imperfect knowledge of the times at which 'snapshots' of a system are recorded degrades our ability to recover dynamical information, and can scramble the sequence of events. In X-ray free-electron lasers, for example, the uncertainty- the so-called timing jitter--between the arrival of an optical trigger ('pump') pulse and a probing X-ray pulse can exceed the length of the X-ray pulse by up to two orders of magnitude, marring the otherwise precise time-resolution capabilities of this class of instruments. The widespread notion that little dynamical information is available on timescales shorter than the timing uncertainty has led to various hardware schemes to reduce timing uncertainty. These schemes are expensive, tend to be specific to one experimental approach and cannot be used when the record was created under ill-defined or uncontrolled conditions such as during geological events. Here we present a data-analytical approach, based on singular-value decomposition and nonlinear Laplacian spectral analysis, that can recover the history and dynamics of a system from a dense collection of noisy snapshots spanning a sufficiently large multiple of the timing uncertainty. The power of the algorithm is demonstrated by extracting the underlying dynamics on the few-femtosecond timescale from noisy experimental X ray free-electron laser data recorded with 300-femtosecond timing uncertainty. Using a noisy dataset from a pump-probe experiment on the Coulomb explosion of nitrogen molecules, our analysis reveals vibrational wave-packets consisting of components with periods as short as 15 femtoseconds, as well as more rapid changes, which have yet to be fully explored. Our approach can potentially be applied whenever dynamical or historical information is tainted by timing uncertainty. PMID- 27121841 TI - Nanocrack-regulated self-humidifying membranes. AB - The regulation of water content in polymeric membranes is important in a number of applications, such as reverse electrodialysis and proton-exchange fuel-cell membranes. External thermal and water management systems add both mass and size to systems, and so intrinsic mechanisms of retaining water and maintaining ionic transport in such membranes are particularly important for applications where small system size is important. For example, in proton-exchange membrane fuel cells, where water retention in the membrane is crucial for efficient transport of hydrated ions, by operating the cells at higher temperatures without external humidification, the membrane is self-humidified with water generated by electrochemical reactions. Here we report an alternative solution that does not rely on external regulation of water supply or high temperatures. Water content in hydrocarbon polymer membranes is regulated through nanometre-scale cracks ('nanocracks') in a hydrophobic surface coating. These cracks work as nanoscale valves to retard water desorption and to maintain ion conductivity in the membrane on dehumidification. Hydrocarbon fuel-cell membranes with surface nanocrack coatings operated at intermediate temperatures show improved electrochemical performance, and coated reverse-electrodialysis membranes show enhanced ionic selectivity with low bulk resistance. PMID- 27121842 TI - Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells. AB - Umbilical cord blood-derived haematopoietic stem cells (HSCs) are essential for many life-saving regenerative therapies. However, despite their advantages for transplantation, their clinical use is restricted because HSCs in cord blood are found only in small numbers. Small molecules that enhance haematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified, but in many cases their mechanisms of action or the nature of the pathways they impinge on are poorly understood. A greater understanding of the molecular circuitry that underpins the self-renewal of human HSCs will facilitate the development of targeted strategies that expand HSCs for regenerative therapies. Whereas transcription factor networks have been shown to influence the self-renewal and lineage decisions of human HSCs, the post-transcriptional mechanisms that guide HSC fate have not been closely investigated. Here we show that overexpression of the RNA-binding protein Musashi-2 (MSI2) induces multiple pro-self-renewal phenotypes, including a 17-fold increase in short-term repopulating cells and a net 23-fold ex vivo expansion of long-term repopulating HSCs. By performing a global analysis of MSI2-RNA interactions, we show that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signalling through post-transcriptional downregulation of canonical AHR pathway components in cord blood HSPCs. Our study gives mechanistic insight into RNA networks controlled by RNA-binding proteins that underlie self-renewal and provides evidence that manipulating such networks ex vivo can enhance the regenerative potential of human HSCs. PMID- 27121844 TI - Negative impact of waiting time for primary total knee arthroplasty on satisfaction and patient-reported outcome. AB - PURPOSE: The primary objective of this study was to evaluate the influence of the time on waiting list for total knee arthroplasty (TKA) on the post-operative satisfaction and patient-reported outcomes. METHODS: This was a prospective observational study of 192 patients followed for one year. Patients were pre and post-operatively assessed with the 12-item Short-Form, reduced Western Ontario MacMaster University, and Knee Society scores. In addition, the Hospital Anxiety and Depression scale was used at time of admission, and patient satisfaction on a five point Likert scale at one post-operative year. Univariate and multivariate analyses were performed. RESULTS: Patients waiting longer than six months had significantly worse pre-operative anxiety score as well as post-operative SF12 (both physical and mental) and KSS-function scores compared to those with a waiting time shorter than six months. Dissatisfaction rate was also higher in patients waiting longer than six months, and it was mainly influenced by pre operative anxiety and depression. CONCLUSIONS: Waiting time longer than six months negatively influenced post-operative satisfaction and patient-related outcome at one year after TKA. These findings may have important clinical implications regarding the prioritization of patients on wait lists or for optimization of treatment while patients wait for surgery related to the management of the mental health and anxiety in order to reduce post-operative dissatisfaction and improve patient-reported outcomes. PMID- 27121845 TI - Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability. AB - Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software. The families showed heterogeneity and novel mutations in three different genes known to be associated with intellectual disability. These mutations were not found in 514 ethnically matched control chromosomes. p.G410C in WWOX, p.H530Y in RARS2, and p.I69F in C10orf2 are novel changes that affect protein function and could give new insights into the development and function of the central nervous system. PMID- 27121846 TI - Probiotics in management of hepatic encephalopathy. AB - Gut microflora leads to production of ammonia and endotoxins which play important role in the pathogenesis of hepatic encephalopathy (HE). There is relationship between HE and absorption of nitrogenous substances from the intestines. Probiotics play a role in treatment of HE by causing alterations in gut flora by decreasing the counts of pathogen bacteria, intestinal mucosal acidification, decrease in production and absorption of ammonia, alterations in permeability of gut, decreased endotoxin levels and changes in production of short chain fatty acids. Role of gut microbiota using prebiotics, probiotics and synbiotics have been evaluated in the management of minimal hepatic encephalopathy (MHE), overt HE and prevention of HE. Many studies have shown efficacy of probiotics in reduction of blood ammonia levels, treatment of MHE and prevention of HE. However these trials have problems like inclusion of small number of patients, short treatment durations, variability in HE/MHE related outcomes utilized and high bias risk, errors of systematic and random types. Systematic reviews also have shown different results with one systematic review showing clinical benefits whereas another concluded that probiotics do not have any role in treatment of MHE or HE. Also practical questions on optimal dose, ideal combination of organisms, and duration of treatment and persistence of benefits on long term follow-up are still to be clarified. At present, there are no recommendations for use of probiotics in patients with HE. PMID- 27121847 TI - Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. AB - BACKGROUND: Prostate cancer (PCa) diagnosis is challenging because efforts for effective, timely treatment of men with significant cancer typically result in over-diagnosis and repeat biopsies. The presence or absence of epigenetic aberrations, more specifically DNA-methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies has resulted in an increased negative predictive value (NPV) of ~90% and thus could lead to a reduction of unnecessary repeat biopsies. Here, it is investigated whether, in methylation positive men, DNA-methylation intensities could help to identify those men harboring high-grade (Gleason score >=7) PCa, resulting in an improved positive predictive value. METHODS: Two cohorts, consisting of men with histopathologically negative index biopsies, followed by a positive or negative repeat biopsy, were combined. EpiScore, a methylation intensity algorithm was developed in methylation-positive men, using area under the curve of the receiver operating characteristic as metric for performance. Next, a risk score was developed combining EpiScore with traditional clinical risk factors to further improve the identification of high-grade (Gleason Score >=7) cancer. RESULTS: Compared to other risk factors, detection of DNA-methylation in histopathologically negative biopsies was the most significant and important predictor of high-grade cancer, resulting in a NPV of 96%. In methylation positive men, EpiScore was significantly higher for those with high-grade cancer detected upon repeat biopsy, compared to those with either no or low-grade cancer. The risk score resulted in further improvement of patient risk stratification and was a significantly better predictor compared to currently used metrics as PSA and the prostate cancer prevention trial (PCPT) risk calculator (RC). A decision curve analysis indicated strong clinical utility for the risk score as decision-making tool for repeat biopsy. CONCLUSIONS: Low DNA methylation levels in PCa-negative biopsies led to a NPV of 96% for high-grade cancer. The risk score, comprising DNA-methylation intensity and traditional clinical risk factors, improved the identification of men with high-grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA. The risk score could help to identify patients with histopathologically negative biopsies harboring high-grade PCa. Prostate 76:1078-1087, 2016. (c) 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc. PMID- 27121848 TI - A potential role for zinc transporter 7 in testosterone synthesis in mouse Leydig tumor cells. AB - Previous studies have demonstrated that zinc (Zn) is an essential trace element which is involved in male reproduction. The zinc transporter (ZnT) family, SLC30a, is involved in the maintenance of Zn homeostasis and in mediating intracellular signaling events; however, relatively little is known regarding the effect of ZnTs on testosterone synthesis. Thus, in the present study, we aimed to determine the effect of Zn transporter 7 (ZnT7) on testosterone synthesis in male CD-1 mice and mouse Leydig cells. The findings of the present study revealed that the concentrations of Zn in the testes and Leydig cells were significantly lower in mice fed a Zn-deficient diet compared with the control mice fed a Zn-adequate diet. In addition, ZnT7 was principally expressed and colocalized with steroidogenic acute regulatory protein (StAR) in the Leydig cells of male CD-1 mice. ZnT7 expression was downregulated in the mice fed a Zn-deficient diet, which led to decreases in the expression of the enzymes involved in testosterone synthesis namely cholesterol side-chain cleavage enzyme (P450scc) and 3beta hydroxysteroid dehydrogenase/D5-D4 isomerase (3beta-HSD) as well as decreased serum testosterone levels. These results suggested that Znt7 may be involved in testosterone synthesis in the mouse testes. To examine this hypothesis, we used the mouse Leydig tumor cell line (MLTC-1 cell line) in which the ZnT7 gene had been silenced, in order to gauge the impact of changes in ZnT7 expression on testosterone secretion and the enzymes involved in testosterone synthesis. The results demonstrated that ZnT7 gene silencing downregulated the expression of StAR, P450scc and 3beta-HSD as well as progesterone concentrations in the human chorionic gonadotrophin (hCG)-stimulated MLTC-1 cells. Taken together, these findings reveal that ZnT7 may play an important role in the regulation of testosterone synthesis by modulating steroidogenic enzymes, and may represent a therapeutic target in testosterone deficiency. PMID- 27121850 TI - Randomized Controlled Trial of Social Media: Effect of Increased Intensity of the Intervention. AB - BACKGROUND: A prior randomized controlled trial of social media exposure at Circulation determined that social media did not increase 30-day page views. Whether insufficient social media intensity contributed to these results is uncertain. METHODS AND RESULTS: Original article manuscripts were randomized to social media exposure compared with no social media exposure (control) at Circulation beginning in January 2015. Social media exposure consisted of Facebook and Twitter posts on the journal's accounts. To increase social media intensity, a larger base of followers was built using advertising and organic growth, and posts were presented in triplicate and boosted on Facebook and retweeted on Twitter. The primary outcome was 30-day page views. Stopping rules were established at the point that 50% of the manuscripts were randomized and had 30-day follow-up to compare groups on 30-day page views. The trial was stopped for futility on September 26, 2015. Overall, 74 manuscripts were randomized to receive social media exposure, and 78 manuscripts were randomized to the control arm. The intervention and control arms were similar based on article type (P=0.85), geographic location of the corresponding author (P=0.33), and whether the manuscript had an editorial (P=0.80). Median number of 30-day page views was 499.5 in the social media arm and 450.5 in the control arm; there was no evidence of a treatment effect (P=0.38). There were no statistically significant interactions of treatment by manuscript type (P=0.86), by corresponding author (P=0.35), by trimester of publication date (P=0.34), or by editorial status (P=0.79). CONCLUSIONS: A more intensive social media strategy did not result in increased 30-day page views of original research. PMID- 27121849 TI - Ribonuclease (RNase) Prolongs Survival of Grafts in Experimental Heart Transplantation. AB - BACKGROUND: Cell damage, tissue and vascular injury are associated with the exposure and release of intracellular components such as RNA, which promote inflammatory reactions and thrombosis. Based on the counteracting anti inflammatory and cardioprotective functions of ribonuclease A (RNase A) in this context, its role in an experimental model of heart transplantation in rats was studied. METHODS AND RESULTS: Inbred BN/OrlRj rat cardiac allografts were heterotopically transplanted into inbred LEW/OrlRj rats. Recipients were intravenously treated every other day with saline or bovine pancreatic RNase A (50 MUg/kg). Toxic side effects were not found (macroscopically and histologically). Heart tissue flow cytometry and quantitative morphological analyses of explanted hearts at postoperative day 1 or postoperative day 4 showed reduced leukocyte infiltration, edema, and thrombus formation in RNase A-treated rats. In allogeneic mixed lymphocyte reactions, RNase A decreased the proliferation of effector T cells. RNase A treatment of rats resulted in prolonged median graft survival up to 10.5 days (interquartile range 1.8) compared to 6.5 days (interquartile range 1.0) in saline treatment (P=0.001). Treatment of rats with a new generated (recombinant) human pancreatic RNase 1 prolonged median graft survival similarly, unlike treatment with (recombinant) inactive human RNase 1 (each 50 MUg/kg IV every other day, 11.0 days, interquartile range 0.3, versus 8.0 days, interquartile range 0.5, P=0.007). CONCLUSIONS: Upon heart transplantation, RNase administration appears to present a promising and safe drug to counteract ischemia/reperfusion injury and graft rejection. Furthermore, RNase treatment may be considered in situations of critical reperfusion after percutaneous coronary interventions or in cardiac surgery using the heart-lung machine. PMID- 27121851 TI - Immunotherapy tablet helps control asthma in people with house dust mite allergy. PMID- 27121852 TI - Computational analyses of type 2 diabetes-associated loci identified by genome wide association studies. AB - BACKGROUND: Genome-wide association studies (GWAS) of type 2 diabetes (T2D) have discovered a number of loci that contribute to susceptibility to the disease. Future challenges include elucidation of functional mechanisms through which these GWAS-identified loci modulate T2D disease risk. The aim of the present study was to comprehensively characterize T2D associated single nucleotide polymorphisms (SNPs) and genes through computational approaches. METHODS: Computational biology approaches used in the present study included comparative genomic analyses and functional annotation using GWAS3D and RegulomeDB, investigation of the effects of T2D-associated SNPs on miRNA binding and protein phosphorylation, and gene ontology, pathway enrichment, protein-protein interaction (PPI) networks and functional module analysis of T2D-associated genes from previously published GWAS. RESULTS: Computational analysis identified a number of T2D GWAS-associated SNPs that were located at protein binding sites, including CCCTC-binding factor (CTCF), E1A binding protein p300 (EP300), hepatocyte nuclear factor 4alpha (HNF4A), transcription factor 7 like 2 (TCF7L2), forkhead box A1 (FOXA1) and A2 (FOXA2), and potentially affected the binding of miRNAs and protein phosphorylation. Pathway enrichment analysis confirmed two well-known maturity onset diabetes of the young and T2D pathways, whereas PPI network analysis identified highly interconnected "hub" genes, such as TCF7L2, melatonin receptor 1B (MTNR1B), and solute carrier family 30 (zinc transporter), member 8 (SLC30A8), that created two tight subnetworks. CONCLUSIONS: The results provide objectives and clues for future experimental studies and further insights into the molecular pathogenesis of T2D. PMID- 27121853 TI - Enhancing resolution of free-flow zone electrophoresis via a simple sheath-flow sample injection. AB - In this work, a simple and novel sheath-flow sample injection method (SFSIM) is introduced to reduce the band broadening of free-flow zone electrophoresis separation in newly developed self-balance free-flow electrophoresis instrument. A needle injector was placed in the center of the separation inlet, into which the BGE and sample solution were pumped simultaneously. BGE formed sheath flow outside the sample stream, resulting in less band broadening related to hydrodynamics and electrodynamics. Hemoglobin and C-phycocyanin were successfully separated by the proposed method in contrast to the poor separation of free-flow electrophoresis with the traditional injection method without sheath flow. About 3.75 times resolution enhancement could be achieved by sheath-flow sample injection method. PMID- 27121854 TI - Definition, evaluation, and management of brain relaxation during craniotomy. AB - The term 'brain relaxation' is routinely used to describe the size and firmness of the brain tissue during craniotomy. The status of brain relaxation is an important aspect of neuroanaesthesia practice and is relevant to the operating conditions, retraction injury, and likely patient outcomes. Brain relaxation is determined by the relationship between the volume of the intracranial contents and the capacity of the intracranial space (i.e. a content-space relationship). It is a concept related to, but distinct from, intracranial pressure. The evaluation of brain relaxation should be standardized to facilitate clinical communication and research collaboration. Both advantageous and disadvantageous effects of the various interventions for brain relaxation should be taken into account in patient care. The outcomes that matter the most to patients should be emphasized in defining, evaluating, and managing brain relaxation. To date, brain relaxation has not been reviewed specifically, and the aim of this manuscript is to discuss the current approaches to the definition, evaluation, and management of brain relaxation, knowledge gaps, and targets for future research. PMID- 27121855 TI - Association between alpha-fetoprotein and metabolic syndrome in a Chinese asymptomatic population: a cross-sectional study. AB - BACKGROUND: Metabolic syndrome is closely associated with an increased risk for fatty liver disease morbidity and mortality. Recently, studies have reported that participants with fatty liver disease have higher serum alpha-fetoprotein levels than those without. We investigated the association between alpha-fetoprotein levels and the prevalence of metabolic syndrome in a Chinese asymptomatic population. METHODS: A cross-sectional study was performed with 7,755 participants who underwent individual health examinations. Clinical and anthropometric parameters were collected and serum alpha-fetoprotein levels and other clinical and laboratory parameters were measured. Logistic regression analysis was used to examine associations between alpha-fetoprotein and metabolic syndrome. RESULTS: Participants with metabolic syndrome had significantly higher (p < 0.001) alpha-fetoprotein levels than those without, though all alpha fetoprotein levels were within the reference interval. The association between the components of metabolic syndrome (central obesity, elevated blood pressure, elevated triglycerides, reduced high-density lipoprotein cholesterol, and elevated fasting plasma glucose) and alpha-fetoprotein levels was evaluated. Alpha-fetoprotein levels in the elevated triglycerides, reduced high-density lipoprotein cholesterol, and elevated fasting plasma glucose groups were significantly different (p=0.002, p < 0.001, p=0.020) compared with alpha fetoprotein in the normal triglycerides, high-density lipoprotein cholesterol, and fasting plasma glucose groups. Logistic regression analyses showed an association between alpha-fetoprotein levels and increased risk for metabolic syndrome, the presence of reduced high-density lipoprotein cholesterol, and elevated fasting plasma glucose, but not with obesity, elevated blood pressure, or triglycerides. CONCLUSIONS: These results suggest a significant association between alpha-fetoprotein and metabolic syndrome. PMID- 27121856 TI - A1 -Adenosine receptor activation has biphasic roles in development of acute kidney injury at 4 and 24 h of reperfusion following ischaemia in rats. AB - NEW FINDINGS: What is the central question of this study? A1 -Adenosine receptor (A1 AR) blockade before renal ischaemia aggravated kidney injury after 24 h reperfusion in several studies, whereas we previously observed a renoprotective effect of A1 AR blockade during a 4 h reperfusion period. What are the underlying mechanisms for this biphasic effect of pretreatment with an A1 AR antagonist at 4 and 24 h reperfusion? What is main finding and its importance? A1 -Adenosine receptor blockade protects the kidney against ischaemia-induced injury during the early hours of reperfusion by attenuating the reduction in renal blood flow and lowering energy expenditure, whereas its inflammatory effects gradually dominate over 24 h reperfusion to intensify kidney injury. We previously reported that selective blockade of the A1 -adenosine receptor (A1 AR) with an antagonist, 8 cyclopentyl-1,3-dipropylxanthine (DPCPX), had protective effects on renal ischaemia-induced structural and functional disruption during a 4 h reperfusion period. In contrast, several studies demonstrated that endogenous and exogenous A1 AR activation before renal ischaemia had a renoprotective role 24 h after reperfusion, through mechanisms that reduced inflammation, necrosis and apoptosis. In this study, we investigated potential mechanisms underlying this biphasic action of A1 AR in renal ischaemia-reperfusion injury. Anaesthetized male Sprague-Dawley rats underwent 30 min of bilateral renal ischaemia, and biphasic effects of pretreatment with DPCPX at 4 and 24 h reperfusion were studied on the kidney injury. Pretreatment with DPCPX attenuated at 4 h but augmented at 24 h reperfusion the renal ischaemia-induced histological damage, reductions in creatinine clearance, urea excretion and free-water reabsorption, and increases in bicarbonate excretion and tissue malondialdehyde. The DPCPX increased tumour necrosis factor-alpha expression and migration of lymphocytes in the postischaemic kidney at both time points, but with a different pattern; lymphocytes mostly aggregated in cortical periarterial spaces at 4 h reperfusion but had infiltrated into the interstitium at 24 h reperfusion. In conclusion, A1 AR activation contributes to ischaemia-induced acute kidney injury during the early hours of reperfusion by causing a greater reduction in renal haemodynamics and by elevating tubular energy expenditure, which overcome its anti-inflammatory effect. However, its anti-inflammatory actions are exerted by reducing lymphocyte infiltration and cytokine production that begins to dominate from 4 to 24 h of reperfusion, which is reflected in attenuation of renal structural and functional disruption. PMID- 27121857 TI - Comparison of birth certificates and hospital-based birth data on pregnancy complications in Los Angeles and Orange County, California. AB - BACKGROUND: The incidence of both gestational diabetes mellitus and preeclampsia is on the rise; however, these pregnancy complications may not be systematically reported. This study aimed to examine differences in reporting of preeclampsia and gestational diabetes between hospital records and birth certificate data, and to determine if such differences vary by maternal socioeconomic status indicators. METHODS: We obtained over 70,000 birth records from 2001 to 2006 from the perinatal research database of the Memorial Care system, a network of four hospitals in Los Angeles and Orange Counties, California. Memorial birth records were matched to corresponding state birth certificate records and analyzed to determine differential rates of reporting of preeclampsia and diabetes. Additionally, the influence of maternal socioeconomic factors on the reported incidence of such adverse pregnancy outcomes was analyzed. Socioeconomic factors of interest included maternal education levels, race, and type of health insurance (private or public). RESULTS: It was found that the birth certificate data significantly underreported the incidence of both preeclampsia (1.38% vs. 3.13%) and diabetes (1.97% vs. 5.56%) when compared to Memorial data. For both outcomes of interest, the degree of underreporting was significantly higher among women with lower education levels, among Hispanic women compared to Non-Hispanic White women, and among women with public health insurance. CONCLUSION: The Memorial Care database is a more reliable source of information than birth certificate data for analyzing the incidence of preeclampsia and diabetes among women in Los Angeles and Orange Counties, especially for subpopulations of lower socioeconomic status. PMID- 27121859 TI - NeuroRehabilitation. PMID- 27121858 TI - High CHI3L1 expression is associated with glioma patient survival. AB - BACKGROUND: Survival of glioma patients with the same tumor histology and grade can vary significantly, and some low-grade gliomas transform to a more malignant phenotype. There is a need of molecular signatures, which are better predictors of the patient diagnosis, outcome of treatment, and prognosis than the diagnosis provided by histopathology. We propose CHI3L1 mRNA expression as a prognostic biomarker for patients with glioma. METHODS: We measured CHI3L1 expression with quantitative real time-polymerase chain reaction (qRT-PCR) in the cohort of 98 patients with different grade glioma: 10 grade I pylocytic astrocytomas, 30 grade II diffuse astrocytomas, 20 grade III anaplastic astrocytomas, and 38 grade IV astrocytomas (glioblastomas). Statistical analyses were conducted to investigate the association between CHI3L1 mRNA expression levels and patient clinical variables. RESULTS: We demonstrated that mRNA expression of CHI3L1 was evidently higher in glioblastoma than in lower grade glioma tissues. We evaluated correlations between CHI3L1 expression, clinicopathological characteristics, and the outcomes of the patients. Patients with high CHI3L1 expression had a shorter overall survival (p < 0.001). CONCLUSIONS: Findings presented in our study showed that increased mRNA level of CHI3L1 could be associated with the progression of astrocytoma and poor patient survival not only for glioblastoma, but for lower grade astrocytoma tumors as well. Further investigation will be required to evaluate CHI3L1 value as a molecular marker for astrocytoma prognoses and for novel treatment strategies against all grade astrocytomas. PMID- 27121860 TI - Cephalosporins inhibit human metallo beta-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo. AB - Bacterial metallo-beta-lactamases (MBLs) are involved in resistance to beta lactam antibiotics including cephalosporins. Human SNM1A and SNM1B are MBL superfamily exonucleases that play a key role in the repair of DNA interstrand cross-links, which are induced by antitumour chemotherapeutics, and are therefore targets for cancer chemosensitization. We report that cephalosporins are competitive inhibitors of SNM1A and SNM1B exonuclease activity; both the intact beta-lactam and their hydrolysed products are active. This discovery provides a lead for the development of potent and selective SNM1A and SNM1B inhibitors. PMID- 27121862 TI - Behavioural improvement in a minimally conscious state after caloric vestibular stimulation: evidence from two single case studies. AB - OBJECTIVE: To investigate whether caloric vestibular stimulation, a non-invasive form of neuro-modulation, alters the level of awareness in people residing in a minimally conscious state. DESIGN: Single-case ( n = 2), prospective, controlled (ABAB) efficacy study. SETTING: Tertiary, neuro-rehabilitation inpatient ward within a university hospital. PARTICIPANTS: Two individuals in a minimally conscious state. INTERVENTION: Left ear caloric vestibular stimulation was performed in two four/five-week blocks interleaved with two four/five-week blocks of sham stimulation. Session duration and frequency gradually increased within each block from once per day for 10 minutes (Week 1) to once per day for 20 minutes (Week 2) to 20 minutes twice per day in the remaining weeks. MEASURES: Wessex Head Injury Matrix, JFK Coma Recovery Scale - Revised. RESULTS: Both participants' Wessex Head Injury Matrix scores indicated a transition from involuntary (i.e. mechanical vocalization) to voluntary (i.e. gesture making, selective responses to family members) behaviour that was time-locked to the onset of active stimulation. In one participant, this improvement persisted for at least four weeks after active stimulation, while in the other it diminished two weeks after stimulation. Allied, although less dramatic, changes were seen on the arousal and auditory subscales of the JFK Coma Recovery Scale - Revised. CONCLUSION: The data provide the first evidence that vestibular stimulation may help improve outcome in a low awareness state, although further studies are needed to replicate effect and determine longer-term benefit. PMID- 27121861 TI - Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection. AB - BACKGROUND: Recurrent Clostridium difficile infection (CDI) remains problematic, with up to 30 % of individuals diagnosed with primary CDI experiencing at least one episode of recurrence. The success of microbial-based therapeutics, such as fecal microbiota transplantation, for the treatment of recurrent CDI underscores the importance of restoring the microbiota. However, few studies have looked at the microbial factors that contribute to the development of recurrent disease. Here we compare microbial changes over time in patients with or without recurrence to identify microbial signatures associated with the development of recurrence. METHODS: We used 16S rRNA-encoding gene sequence analysis to compare the fecal microbiota of 93 patients with recurrent and nonrecurrent CDI, sampled longitudinally. Cross-group and intra-individual differences in microbial community diversity and similarity were compared prior to the development of recurrent disease and over time. RESULTS: Samples from these patient groups exhibited variable community profiles, clustering into four distinct community groups. Cross-group comparison of the index sample collected from patients that did or did not develop recurrence revealed differences in diversity and community structure (analysis of molecular variance, p < 0.05). Intra-individual comparisons of the microbiota were more informative and samples from recurrent patients were less likely to recover in diversity (Chi-square test, p < 0.005), exhibiting less community similarity overall (Kruskal-Wallis test, p < 0.05). Interestingly, patients with severe disease harbored a significantly less diverse community, a trend that was observed across both nonrecurrent and recurrent patient groups (Wilcoxon test, p < 0.05). CONCLUSIONS: To date, this study represents one of the largest studies focused on the relationship between predictive signals from the gut microbiota and the development of recurrent CDI. Our data demonstrate that specific microbiota-derived characteristics associate with disease severity and recurrence and that future studies could incorporate these characteristics into predictive models. PMID- 27121863 TI - Psychometric properties of the Behavioural Outcomes of Anxiety questionnaire in stroke patients with aphasia. AB - OBJECTIVE: To evaluate the psychometric properties of an observational, carer completed anxiety screen for aphasic stroke patients. DESIGN: Phase 1: A cross sectional questionnaire design to establish psychometric properties. Phase 2: A randomized longitudinal design with treatment and control to evaluate sensitivity to change and repeatability/reliability. SUBJECTS: Phase 1: 111 patient-carer dyads were recruited through stroke charities: patient mean age 69.7(10. 7), 6.2(5. 2) years since stroke, 76 male; carer mean age 64.7(12. 2), 27 male. Phase 2. A subsample of 50 dyads (29 completed). MEASURES: All patients completed the Tension Rating Circles and the Frenchay Aphasia Screening Test. Carers completed the Behavioural Outcomes of Anxiety questionnaire, observational versions of the Hospital Anxiety and Depression Scale (HADS-A) and the Generalised Anxiety Disorder-7, and a feedback questionnaire. INTERVENTION: Phase 2: 25 dyads were offered relaxation training and 25 acted as controls. RESULTS: The Behavioural Outcomes of Anxiety questionnaire correlated .77 with the HADS-A and Cronbach's Alpha was .82 demonstrating validity and internal consistency. Using HADS-A cut off > 7 as criterion the area under the curve was 0.90 and at cut-off of > 16 sensitivity (0.85) and specificity (0.85) were both good. Scores declined significantly more in a group given anxiety training ( n = 12) than in a control group ( n = 17), demonstrating sensitivity to change and construct validity. Two week repeatability/reliability was .92. Feedback suggested the scale was acceptable. CONCLUSIONS: The Behavioural Outcomes of Anxiety questionnaire shows promise as an anxiety screen for stroke patients with aphasia and is sensitive to change. Further analysis of dimensionality and discriminant validity is needed. PMID- 27121864 TI - Proof of concept for inhibiting metastasis: circulating tumor cell-triggered localized release of anticancer agent via a structure-switching aptamer. AB - Existing drug delivery systems were not suitable for killing cells in the circulatory system specifically. Herein, we developed a novel localized drug delivery strategy, in which the release of anticancer agents was specifically triggered by circulating tumor cells. Meanwhile, damage to non-target cells was avoided. PMID- 27121865 TI - A Pilot Study of Tailored Cognitive-Behavioral Resilience Training for Trauma Survivors With Subthreshold Distress. AB - This pilot study evaluated the feasibility, acceptability, and preliminary effectiveness of tailored cognitive-behavioral resilience training (TCBRT) for trauma-exposed individuals with a variety of subsyndromal psychological symptoms. TCBRT is a brief, flexible intervention that allows individuals to select the areas they wish to target using common cognitive-behavioral change principles. There were 14 individuals (78.6% female) who were recruited from a major medical center and enrolled in the 5-session intervention. There were 12 (85.7%) who completed all TCBRT sessions, and 2 (14.3%) who dropped out after 3 sessions. All participants reported that they received benefit from, were engaged in, and were satisfied with the intervention. Of the 12 with postintervention data, 5 of the participants demonstrated reliable increases in resilience and 6 demonstrated reliable decreases in anxiety. These improvements appeared to be maintained at 2 month follow-up; of the 11 participants with follow-up data, 5 demonstrated reliable increases in resilience and 6 demonstrated reliable decreases in anxiety. Our findings suggested that TCRBT was acceptable to trauma-exposed individuals with varying types of subthreshold distress. PMID- 27121866 TI - Retraction Note: Peripheral blood mono-nuclear cells implantation in patients with peripheral arterial disease: a pilot study for clinical and biochemical outcome of neoangiogenesis. PMID- 27121867 TI - Management of pulmonary nodules according to the 2015 British Thoracic Society guidelines. Key messages for clinical practice. AB - The British Thoracic Society guideline on the investigation and management of pulmonary nodules is based on a comprehensive and systematic review of the literature on pulmonary nodules. Recent evidence has suggested that significant changes to existing guidelines are necessary. The use of 2 malignancy prediction calculators to better characterize the risk of malignancy was firmly supported by evidence, as were the recommendations for a higher nodule size threshold for follow-up (>=5 mm or >=80 mm3) and a reduction of the follow-up period to 1 year for solid pulmonary nodules. Although caution is required where there is a history of cancer, both of these recommendations will reduce the number of follow up computed tomographies, thereby improving cost-effectiveness and pressure on imaging services. Recent evidence has also confirmed the superiority of volumetry as the preferred measurement method and clarified the management of nodules with extended volume-doubling times. Acknowledging the good prognosis of subsolid nodules, there are recommendations for less aggressive options in their management. The guidelines recommend ordinal scale reporting for positron emission tomography-computed tomography to facilitate incorporation into risk models. There are recommendations on when biopsy is most helpful, the threshold for treatment without histological confirmation, and surgical and nonsurgical treatment. The guideline also provides evidence-based recommendations about the information that people need and that should be provided for them. The complexity of managing pulmonary nodules is made more accessible by 4 management algorithms. In the real world, it is surprising how easy these are to follow and how they seem to follow an intuitive approach. PMID- 27121868 TI - Mechanisms of extracellular S0 globule production and degradation in Chlorobaculumtepidum via dynamic cell-globule interactions. AB - The Chlorobiales are anoxygenic phototrophs that produce solid, extracellular elemental sulfur globules as an intermediate step in the oxidation of sulfide to sulfate. These organisms must export sulfur while preventing cell encrustation during S0 globule formation; during globule degradation they must find and mobilize the sulfur for intracellular oxidation to sulfate. To understand how the Chlorobiales address these challenges, we characterized the spatial relationships and physical dynamics of Chlorobaculum tepidum cells and S0 globules by light and electron microscopy. Cba. tepidum commonly formed globules at a distance from cells. Soluble polysulfides detected during globule production may allow for remote nucleation of globules. Polysulfides were also detected during globule degradation, probably produced as an intermediate of sulfur oxidation by attached cells. Polysulfides could feed unattached cells, which made up over 80% of the population and had comparable growth rates to attached cells. Given that S0 is formed remotely from cells, there is a question as to how cells are able to move toward S0 in order to attach. Time-lapse microscopy shows that Cba. tepidum is in fact capable of twitching motility, a finding supported by the presence of genes encoding type IV pili. Our results show how Cba. tepidum is able to avoid mineral encrustation and benefit from globule degradation even when not attached. In the environment, Cba. tepidum may also benefit from soluble sulfur species produced by other sulfur-oxidizing or sulfur-reducing bacteria as these organisms interact with its biogenic S0 globules. PMID- 27121869 TI - Co-creation of an ICT-supported cancer rehabilitation application for resected lung cancer survivors: design and evaluation. AB - BACKGROUND: Lung cancer (LC) patients experience high symptom burden and significant decline of physical fitness and quality of life following lung resection. Good quality of survivorship care post-surgery is essential to optimize recovery and prevent unscheduled healthcare use. The use of Information and Communication Technology (ICT) can improve post-surgery care, as it enables frequent monitoring of health status in daily life, provides timely and personalized feedback to patients and professionals, and improves accessibility to rehabilitation programs. Despite its promises, implementation of telehealthcare applications is challenging, often hampered by non-acceptance of the developed service by its end-users. A promising approach is to involve the end-users early and continuously during the developmental process through a so called user-centred design approach. The aim of this article is to report on this process of co-creation and evaluation of a multimodal ICT-supported cancer rehabilitation program with and for lung cancer patients treated with lung resection and their healthcare professionals (HCPs). METHODS: A user-centered design approach was used. Through semi-structured interviews (n = 10 LC patients and 6 HCPs), focus groups (n = 5 HCPs), and scenarios (n = 5 HCPs), user needs and requirements were elicited. Semi-structured interviews and the System Usability Scale (SUS) were used to evaluate usability of the telehealthcare application with 7 LC patients and 10 HCPs. RESULTS: The developed application consists of: 1) self-monitoring of symptoms and physical activity using on-body sensors and a smartphone, and 2) a web based physical exercise program. 71 % of LC patients and 78 % of HCPs were willing to use the application as part of lung cancer treatment. Accessibility of data via electronic patient records was essential for HCPs. LC patients regarded a positive attitude of the HCP towards the application essential. Overall, the usability (SUS median score = 70, range 35-95) was rated acceptable. CONCLUSIONS: A telehealthcare application that facilitates symptom monitoring and physical fitness training is considered a useful tool to further improve recovery following surgery of resected lung cancer (LC) patients. Involvement of end users in the design process appears to be necessary to optimize chances of adoption, compliance and implementation of telemedicine. PMID- 27121870 TI - Cholesterol Point-of-Care Testing for Community Pharmacies: A Review of the Current Literature. AB - OBJECTIVE: To summarize the literature on cholesterol point-of-care tests (POCTs). This article would serve as a resource to assist community pharmacists in developing cholesterol point-of-care (POC) pharmacy services. DATA SOURCES: A literature search was performed in MEDLINE Ovid, PubMed, EMBASE, and Cochrane database using the following medical subject headings (MeSH) terms: point-of-care test, cholesterol, blood chemical analysis, rapid testing, collaborative practice, community pharmacy, and ambulatory care. Additional resources including device manufacturer web sites were summarized to supplement the current literature. STUDY SELECTION AND DATA EXTRACTION: All human research articles, review articles, meta-analyses, and abstracts published in English through September 1, 2014, were considered. DATA SYNTHESIS: A total of 36 articles were applicable for review. Information was divided into the following categories to be summarized: devices, pharmacists' impact, and operational cost for the pharmacy. CONCLUSIONS: The current literature suggests that POCTs in community pharmacies assist with patient outcomes by providing screenings and referring patients with dyslipidemia for further evaluation. The majority of studies on cholesterol POC devices focused on accuracy, revealing the need for further studies to develop best practices and practice models with successful reimbursement. Accuracy, device specifications, required supplies, and patient preference should be considered when selecting a POC device for purchase. PMID- 27121871 TI - ALS-linked misfolded SOD1 species have divergent impacts on mitochondria. AB - Approximately 20 % of familial Amyotrophic Lateral Sclerosis (ALS) is caused by mutations in superoxide dismutase (SOD1), which leads to misfolding of the SOD1 protein, resulting in a toxic gain of function. Several conformation-restricted antibodies have been generated that specifically recognize misfolded SOD1 protein, and have been used as therapeutics in pre-clinical models. Misfolded SOD1 selectively associates with spinal cord mitochondria in SOD1 rodent models. Using the SOD1(G93A) rat model, we find that SOD1 conformational specific antibodies AMF7-63 and DSE2-3H1 labeled a fibrillar network concentrated in the anterior horn; while A5C3, B8H10, C4F6 and D3H5 labeled motor neurons as well as puncta in the neuropil. There is a time-dependent accumulation of misfolded SOD1 at the surface of spinal cord mitochondria with AMF7-63-labeled mitochondria having increased volume in contrast to a mitochondrial subset labeled with B8H10. In spinal cord homogenates and isolated mitochondria, AMF7-63, DSE2-3H1 and B8H10 detect misfolded SOD1 aggregates. SOD1 that lacks its metal cofactors has an increased affinity for naive mitochondria and misfolded SOD1 antibodies B8H10 and DSE2-3H1 readily detect demetalated mutant and wild-type SOD1. Together, these data suggest that multiple non-native species of misfolded SOD1 may exist, some of which are associated with mitochondrial damage. Conformational antibodies are invaluable tools to identify and characterize the variation in misfolded SOD1 species with regards to biochemical characteristics and toxicity. This information is highly relevant to the further development of these reagents as therapeutics. PMID- 27121872 TI - Are Females at Greater Risk for Revision Surgery After Hip Resurfacing Arthroplasty With the Articular Surface Replacement Prosthesis? AB - BACKGROUND: Female patients undergoing hip resurfacing arthroplasties may be at greater risk of revision surgery than males, but it is unclear whether this is related to sex or other factors. We focused our analysis on data from a prospective multicenter cohort study monitoring the ASR(TM) hip resurfacing arthroplasty prosthesis on the potential association of sex on patient-reported outcome measures (PROMs), metal ion levels, revision surgery, and presence of adverse local tissue reaction. As thousands of patients with the ASR(TM) prosthesis are still undergoing followup it is critical to optimize the protocol for monitoring these patients. QUESTIONS/PURPOSES: We wished (1) to assess the associations between sex and implant survival, and adverse local tissue reaction; and (2) to report the differences between sexes in metal ion levels and patient reported outcome measures. METHODS: One thousand two hundred fifty-two patients (1390 hips) who underwent hip resurfacing arthroplasty with implantation of the ASR(TM) prosthesis from April 2003 to July 2010 were eligible for enrollment in a multicenter followup study of the ASR(TM) Hip Resurfacing System after the voluntary recall of this device was initiated by DePuy in 2010. Nine hundred seventy patients (1098 hips) were enrolled at a mean of 7 years after surgery, with a mean followup of 2 years (range, 1-3.5 years). Nine hundred fifty-eight patients (1084 hips) met the inclusion criteria: ability to provide informed consent, complete PROMs, and continued routine followup. A subset of patients (150 patients, 171 hips), who all were from one center, with annual metal artifact reduction sequence MRI were analyzed. Ninety-three percent of patients from this center had routine MRI performed. The EuroQoL (EQ-5D), Harris hip score (HHS), University of California Los Angeles (UCLA) activity score, VAS pain, radiographs, patient and surgery details, and blood cobalt and chromium levels were obtained. Cox regression analysis was conducted to identify factors associated with implant survival, using any revision as the end point, and presence of adverse local tissue reaction. RESULTS: In patients who had unilateral surgery, the only variable found to be associated with revision surgery was HHS (hazard ratio [HR], 0.96; 95% CI, 0.94-0.97; p < 0.001). In patients who had bilateral surgery, only HHS (HR, 0.93; 95% CI, 0.90-0.97; p < 0.001) and cobalt level (HR, 1.02; 95% CI, 1.01-1.03; p < 0.001) were associated with risk for revision. In patients with metal artifact reduction sequence MRI, the only variable found to be associated with presence of adverse local tissue reaction was cobalt level (HR, 1.06; 95% CI, 1.02-1.10; p = 0.001). Cobalt and chromium concentrations were greater in female patients than in male patients (cobalt, median 1.89 versus median 1.12 parts per billion [ppb], p < 0.001; chromium, median 2.03 versus median 1.17 ppb, p < 0.001). Slight differences were observed between males and females in HHS (males median 96 versus females median 94, p < 0.001) and UCLA scores (median 8 versus median 6, p < 0.001); however, there was no difference between sexes for VAS pain (median 0.5 versus median 0.5, p = 0.405). Differences were identified between males and females in the distribution of EQ-5D scores, yet the medians were the same (median 1.0 versus median 1.0, p < 0.001). CONCLUSIONS: Male and female patients who had hip resurfacing arthroplasty with implantation of the ASR(TM) prosthesis should be followed with equal vigilance as both are at similar risk of revision surgery and adverse local tissue reaction. Metal ion levels and HHS should be obtained at followup to monitor for risk of revision and as a screening tool for MRI. Further research is necessary to evaluate if these relationships persist in patients with other metal-on-metal prostheses. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 27121873 TI - Rotational Acetabular Osteotomy for Pre- and Early Osteoarthritis Secondary to Dysplasia Provides Durable Results at 20 Years. AB - BACKGROUND: Hip dysplasia is a common cause of secondary osteoarthritis (OA). Periacetabular osteotomy or rotational acetabular osteotomy has been used as joint-preserving procedures. However, only a few reports of long-term results with these operations have been reported. QUESTIONS/PURPOSES: (1) Would satisfactory clinical and radiographic outcomes be maintained at a mean duration of 20 years after rotational acetabular osteotomy for pre- and early-stage OA; and (2) could we identify risk factors for radiographic progression of OA? METHODS: Between 1987 and 2001, we treated 159 patients (173 hips) with rotational acetabular osteotomies for the diagnosis of pre-OA or early-stage OA according to the technique of Ninomiya and Tagawa. During that period, our general indications for this approach were age younger than 60 years, center-edge angle less than 20 degrees , and improved femoral head coverage and joint congruency on preoperative AP plain radiographs of the hip in abduction; we did not use this approach when joint congruency was not improved or no widening of the joint space was noted on preoperative AP plain radiographs of the hip in abduction. Of those patients, 21 patients with pre-OA (followup rate: 84% [27 hips]) and 110 patients in the early-stage group (followup rate: 82% [118 hips]) were available at a minimum of 15 years for a total patient group of 131 (followup rate: 82% [145 hips]). The mean age at the time of surgery was 22 years in the pre-OA group and 38 years in the early-stage group. The mean followup was 21 years in the pre-OA group and 20 years in the early-stage group. Clinical evaluation was performed with the Merle d'Aubigne and Postel rating scale, and radiographic analyses included measurements of the center-edge angle, acetabular roof angle, and head lateralization index on preoperative and postoperative AP radiographs of the pelvis. Postoperative joint congruency was also evaluated. The cumulative probabilities of radiographic signs of OA progression were estimated with use of the Kaplan-Meier product-limited method and parametric survivorship analysis using the Cox proportional-hazards model was used to determine risk factors for radiographic OA progression. RESULTS: The mean clinical score improved very slightly, from 15 (SD, 0.8) to 18 (SD, 1.1) (95% confidence interval [CI], -2.9 to -2.0; p < 0.001) in the pre-OA group and from 15 (SD, 1.0) to 16 (SD, 2.1) (95% CI, -2.0 to -1.2; p < 0.001) in the early-stage group at followup. Fourteen patients (15 hips) including one pre-OA patient (one hip) and 13 early-stage patients (14 hips) experienced worsening of their Merle d'Aubigne and Postel score, from a mean of 15 (SD, 0.9) to 12 (SD, 1.6) (95% CI, 1.8-3.3; p < 0.001). Eight patients (nine hips) with early-stage OA preoperatively underwent total hip arthroplasty at a mean duration after rotational acetabular osteotomy of 20 (SD, 2.5) years. Radiographic indices were improved after surgery in both groups. Radiographic progression of OA occurred in 24 patients (25 hips). Kaplan Meier survivorship analysis, with radiographic signs of progression of OA as the endpoint, predicted survival of 96% (95% CI, 89%-100%) at 10 years and 20 years in the pre-OA group. For the early-stage group, we found survivorship of 89% (95% CI, 83%-95%) at 10 years and 78% (95% CI, 69%-87%) at 20 years. We identified two factors associated with poor outcome: fair (rather than excellent and good) postoperative joint congruency (hazard ratio, 12.1; 95% CI, 3.8-39; p < 0.001) and age older than 46 years at the time of surgery (hazard ratio, 4.6; 95% CI, 1.9-11; p < 0.01). CONCLUSIONS: Rotational acetabular osteotomy is an effective surgical procedure for symptomatic dysplastic hips in pre- and early-stage OA, and it prevented radiographic OA progression and maintained hip function at a mean 20 years after surgery. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 27121874 TI - Nasopharyngeal carcinoma-past lessons and a glimpse into the future. PMID- 27121875 TI - Genetic susceptibility to the endemic form of NPC. AB - Nasopharyngeal carcinoma (NPC) is a malignancy with remarkably high prevalence in East Asia. Lines of evidence have suggested the involvement of genetic lesions in the etiology of NPC, together with the contributions of Epstein-Barr virus infection and environmental exposures. Linkage and association studies, either based on candidate genes or genome-wide levels, have been conducted to dissect the genetic variants that contribute to NPC risk. This review summarizes the current findings of genetic susceptibility to NPC, and points out some future challenges on discovery of other risk variants to explain the missing heritability of NPC. PMID- 27121876 TI - Genetic and epigenetic landscape of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a unique epithelial malignancy that shows a remarkable geographical and ethic distribution. Multiple factors including predisposing genetic factors, environmental carcinogens, and Epstein-Barr virus (EBV) infection contribute to the accumulation of genetic and epigenetic alterations leading to NPC development. Emerging technologies now allow us to detailedly characterize and understand cancer genomes. Genome-wide studies show that typically NPC tumors are characterized as having comparatively low mutation rates, widespread hypermethylation, and frequent copy number alterations and chromosome abnormalities. In this review, we provide an updated overview of the genetic and epigenetic aberrations that likely drive nasopharyngeal tumor development and progression. We integrate the previous knowledge and novel findings from whole-exome sequencing (WES) and methylome studies in NPC, and further discuss the potential use of these findings to identify biomarkers for NPC diagnosis and prognosis. PMID- 27121877 TI - MicroRNAs in nasopharyngeal carcinoma. AB - It is becoming increasingly evident that aberrantly expressed microRNAs (miRNAs) are responsible for a number of disease processes, including cancer initiation and progression. miRNAs have been implicated as key players in numerous neoplasms, including nasopharyngeal carcinoma (NPC). Functionally, deregulation of miRNAs that act either as tumour suppressors or oncogenes results in numerous cancer-associated phenomena, including changes in proliferation, migration, and cell survival. Furthermore, miRNA expression has been associated with chemoresistant or radioresistant phenotypes; highlighting the importance of miRNAs in mediating oncogenic processes. Prognostic and predictive miRNA signatures have been defined for a variety of cancer types, including NPC, whereby these signatures offer a potentially important clinical tool for assessing the disease state, as well as predicting treatment response and clinical outcome. Therefore, further examination and validation of miRNAs that are deregulated in NPC will provide insight into the fundamental drivers of this disease, which will aid in the identification of novel targeted treatments. This review summarizes recent advances in the study of miRNAs in NPC, with specific discussion on the role of miRNAs in NPC pathogenesis and the potential utility of miRNAs as prognostic biomarkers. Our increasing understanding of the role of miRNAs in NPC tumorigenesis and their application as novel biomarkers will undoubtedly prove useful in the stratification of future patients into clinically relevant treatment classifications, thereby improving and personalizing disease management. PMID- 27121878 TI - Clinical utility of circulating Epstein-Barr virus DNA analysis for the management of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is one of the commonest cancers in Southern China. The carcinogenesis is closely associated with Epstein-Barr virus (EBV) infection. In endemic regions with high incidence of NPC, EBV genome can be detected in virtually all NPC tumor tissues. Over the last decade, circulating cell-free EBV DNA has been developed as a tumor marker for NPC. Plasma EBV DNA analysis using real-time PCR has been shown to be useful for early detection, prognostication and monitoring of treatment response of NPC. In this review, the clinical applications of EBV DNA analysis in the management of NPC would be discussed. PMID- 27121879 TI - Evolution of the Chinese staging system for nasopharyngeal carcinoma. AB - The clinical treatment of nasopharyngeal carcinoma (NPC) in China started in 1940s is based on our own clinical staging system. In 1965, we established the first TNM staging system for NPC. Advances in technology and therapy led to continuous updates in clinical staging. Currently, the Chinese staging system of 2008 is commonly used in China. Compared with the 7th edition of the American Joint Committee on Cancer (AJCC) staging system, which is widely used internationally, the N classification was based on magnetic resonance imaging (MRI) as well as the lymph node criteria of the Radiation Therapy Oncology Group (RTOG) consensus guidelines. However, several studies showed that these two staging systems were associated with limitations. Additional international studies from different cancer centers are needed to improve and evolve a universally accepted staging system for NPC. PMID- 27121880 TI - Clinical trials in nasopharyngeal carcinoma-past, present and future. AB - Nasopharyngeal carcinoma (NPC) has an age-adjusted incidence for both sexes with greater frequency in some endemic regions, especially the southern China. Genetic, ethnic, environmental factors and Epstein-Barr virus (EBV) infection might take part in the cause of the disease. Based on the understanding and research progresses, we have had a further step among the diagnosis and prognosis of the disease. Meanwhile, a numerous clinical trials aiming to pick out the most suitable therapeutic choice are carried on from past till now. The purpose of this review is to summarize therapeutic approaches from past RCTs, introduce hot topics at present, and explore the development trend in the future. Applying appropriate combining procedures of radiotherapy and chemotherapy with developments in gene therapy and immunotherapy, the outcomes in the future might be widely improved. PMID- 27121882 TI - Immunotherapy for nasopharyngeal cancer-a review. AB - Nasopharyngeal carcinoma (NPC) is associated with the Epstein-Barr virus (EBV) and characterized by peritumoral immune infiltrate. Advanced NPC has high lethality. Immunotherapy directed against EBV antigen targets has been previously explored in clinical trials, and is likely to be validated as an important target in NPC as randomized data emerges in the future. Cancer vaccines and adoptive T cell therapy have been explored in the clinic, with the latter showing the greatest success. Recent advances in gene sequencing technology now allow personalized tumor epitope mapping, whilst the advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis offers the opportunity to activate adaptive T cell response in vivo. Anti-PD1 antibodies have shown promising activity in early phase clinical trials, and randomized studies against chemotherapy are underway. As immunotherapy is incorporated into standard treatment paradigms, issues of optimal combinations with targeting agents, immune adjuvants, and sequence with chemotherapy and radiation therapy will need to be addressed. Effective strategies to increase tumor antigenicity, improve immunological memory and reduce immune escape, will need to be developed to improve treatment outcomes. Here we present a brief history of the evolution of immunotherapy in NPC, and highlight key concepts relevant to its further development in the clinic. PMID- 27121881 TI - Advances in systemic treatment for nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a unique disease endemic in Asia. It is etiologically linked to the Epstein-Barr virus and is both radio- and chemo sensitive. While radiotherapy (RT) remains the primary treatment modality with high cure rates for early stage disease, systemic treatment forms an important integral component in the treatment of NPC, both in the non-metastatic as well as palliative setting. Presently, standard therapy in locally advanced NPC comprises conventional cytotoxic chemotherapy administered concurrently during RT. The role of induction chemotherapy and adjuvant chemotherapy remain to be well-defined. Further research strategies in non-metastatic disease will require better identification of patients with high risk disease, and determining the optimal sequence and combination of chemotherapeutic regimens. In metastatic disease, whilst chemotherapy remains the mainstay of care, resistance inevitably develops. Development of molecularly targeted therapies has not yielded much success to date, and further research has been focused on development of EBV-targeted strategies such as vaccination or administration of cytotoxic T-cells directed towards EBV, as well as evaluation of immune checkpoint inhibition approaches. PMID- 27121883 TI - Therapeutic vaccination strategies to treat nasopharyngeal carcinoma. AB - Epstein-Barr virus (EBV) infects most people worldwide. EBV has oncogenic potential and is strongly associated with several lymphomas and carcinomas, including nasopharyngeal carcinoma (NPC), that together total 200,000 cases of cancer each year. All EBV-associated cancers express viral proteins that allow highly selective immunotherapeutic targeting of the malignant cells. A number of therapeutic EBV vaccines have been tested in clinical trials with evidence of immune boosting and clinical responses in NPC patients. Therapeutic vaccination could be used after adoptive T-cell transfer to increase and sustain the number of infused T-cells or combined with immunotherapies acting at different stages of the cancer immunity cycle to increase efficacy. The therapeutic EBV vaccines tested to date have been well tolerated with minimal off-target toxicity. A safe therapeutic vaccine that was also able to be mass produced could, in principle, be used to vaccinate large numbers of patients after first line therapy to reduce recurrence. PMID- 27121884 TI - Clinical significance of hypoxia in nasopharyngeal carcinoma with a focus on existing and novel hypoxia molecular imaging. AB - Locally advanced nasopharyngeal carcinoma (NPC) is still associated with significant locoregional failure and poor overall survival (OS) after chemoradiation. The maximal therapeutic effect of conventional chemotherapy combined with radiation may have been reached and there is a clinical need to identify additional adverse prognostic factors that could be targeted therapeutically. Hypoxia, a known prognostic factor in head and neck cancers is an attractive target in NPC with various treatment strategies available such as hypoxic cell sensitisers/cytotoxins and increasing intratumoral oxygen delivery, to overcome the poorer outcomes associated with this phenotype. Thus, we aim to review the clinical significance of hypoxia as well as the current and future of molecular hypoxia imaging in NPC. PMID- 27121885 TI - Proton therapy for nasopharyngeal carcinoma. AB - The treatment of nasopharyngeal carcinoma (NPC) has traditionally included a multimodality approach including radiotherapy (RT) and systemic chemotherapy. RT has long been favored as the mainstay of local treatment for disease in this challenging anatomic location owing to the morbidity of extensive surgical resection in the nasopharynx. However, NPC presents a unique treatment challenge for radiation oncologists because such tumors typically involve complex anatomic structures near several critical organ structures such as the brainstem, spinal cord, temporal lobes, salivary glands, cochleae, oral cavity, mandible and optic structures. Thus, radiation is not without toxicity, and critical organs in these areas clearly benefit from the use of conformal and precise treatment delivery. The unique physical properties of proton radiotherapy (PRT) make it especially well-suited for treating tumors in this anatomically complex area and offer promising potential for acute and chronic toxicity reduction while maintaining excellent disease control. PMID- 27121886 TI - Reirradiation of locally recurrent nasopharyngeal cancer: history, advances, and promises for the future. AB - Local or locoregional recurrence of nasopharyngeal carcinoma (NPC) after high dose radiotherapy remains a significant clinical problem. This is especially important in regions of the world in which NPC is endemic, such as Southern China. In this review, we briefly present the evolution in the definitive treatment of NPC, but focus more so on the historical and contemporary treatment approaches and outcomes utilized in the recurrent setting. Specifically, we highlight the various treatment strategies (repeat surgery, brachytherapy, conventional re-irradiation, SRS/SBRT, and salvage IMRT), and their technical, physical and biological limitations. Special attention is given towards salvage IMRT, as this is becoming the standard of care for locally recurrent NPC. Further, it is the most commonly indicated modality, since it can be used to treat larger tumors and more extensive disease stages, which represent the majority of recurrent cases. Predictive and prognostic factors for the efficacy of repeat treatment are discussed as well. The toxicities brought about by repeat radiotherapy courses are also highlighted, with an emphasis on their impact on mortality and quality of life, which underscore the difficulty that this clinical entity presents. Lastly, the rationale for particle radiation therapy, which is potentially safer and more efficacious, for the treatment of locally recurrent NPC is presented. PMID- 27121887 TI - The International Atomic Energy Agency global initiatives on nasopharyngeal cancer treatment. AB - Since its establishment in 1957, the International Atomic Energy Agency (IAEA) has striven to promote global access to reliable and affordable radiotherapy, with much of its latest focus being in developing countries. While nasopharyngeal cancer (NPC) is highly curable by radiotherapy with excellent outcomes in developed countries, the outcomes in low- and middle-income countries (LMICs) are disappointing. Although the reasons for this are complex and multifactorial, improving the accessibility and quality of radiotherapy in these countries is fundamental. With concerted effort from experts and advocates around the world, ongoing initiatives are supported by the IAEA to combat the challenges in LMICs. PMID- 27121888 TI - Korean perspectives of nasopharynx cancer management. AB - Though Korea is located in non-endemic region of Epstein-Barr virus (EBV) infection and the incidence rate of nasopharynx cancer (NPCa) is very low, some clinical and histologic characteristics are similar to those in EBV endemic regions. Korean Radiation Oncology Group (KROG) established a database of NPCa patients and a few informative studies were performed, which mostly have conformed to those from the previously reports by others. Large variation in intensity modulated RT (IMRT) detail was recognized and the key principles at Samsung Medical Center are introduced. Based on the current understandings of Korean perspective, further refinement aiming at improved clinical outcomes would be anticipated through large scale prospective clinical trials. PMID- 27121889 TI - Nasopharyngeal carcinoma-some closing remarks. PMID- 27121890 TI - Maternal and infant correlates of maternal feeding beliefs and practices in a multi-ethnic Asian population: the GUSTO (Growing Up in Singapore Towards healthy Outcomes) study. AB - OBJECTIVE: Little is known about the influences of maternal and infant correlates on maternal feeding beliefs and practices in the first 2 years of life, despite its important role in early obesogenic eating behaviours and weight gain. DESIGN: Cross-sectional study using demographic data of mothers and infants obtained at 26-28 weeks of gestation, and postnatally from birth to 15 months, respectively. The Infant Feeding Questionnaire was administered at 15 months postpartum. The associations between maternal and infant characteristics with seven maternal feeding beliefs and practices subscales were evaluated using multivariate linear regression analysis. SETTING: Data obtained from the Singapore GUSTO (Growing Up in Singapore Towards healthy Outcomes) mother-offspring birth cohort. SUBJECTS: Mothers and infants (n 1237). RESULTS: Among other maternal correlates such as age, education, BMI, income and milk feeding practices, ethnicity was a consistent factor associated with six subscales, including concern about infant overeating/undereating and weight status, concern and awareness about infants' hunger and satiety cues, social interaction during feeding and feeding an infant on schedule. Similarly, among infant correlates such as gender and birth order, infant body size gain (reflected by BMI Z-score change from 0 to 15 months) was significantly associated with all subscales except feeding an infant on schedule. Overall, maternal correlates had greater influence on all subscales compared with infant correlates except for the maternal concern about infant undereating or becoming underweight subscale. CONCLUSIONS: The present study highlights that maternal feeding beliefs and practices can be influenced by both maternal correlates and infant correlates at 15 months of age. PMID- 27121891 TI - Development and Patient Satisfaction of a New Telemedicine Service for Pain Management at Massachusetts General Hospital to the Island of Martha's Vineyard. AB - OBJECTIVE: Patients in remote areas lack access to specialist care and pain management services. In order to provide pain management care to patients remote from our center, we created a telemedicine pain clinic (telepain) at Massachusetts General Hospital (MGH) in Boston, MA to extend services to the Island of Martha's Vineyard. DESIGN: Over 13 months, 238 telepain video clinic evaluations were conducted. A pain physician visited the island 1-2 days per month and performed 121 interventions. Given the novelty of telemedicine clinics, we surveyed patients to gauge satisfaction and identify perceived weaknesses in our approach that could be addressed. Forty-nine consecutive patients answered a 14-question, 5-point balanced Likert-scale survey with 1 (no, definitely not) being most negative and 5 (yes, definitely) being most positive. SETTING: Patients on Martha's Vineyard referred for pain management consultation services via telemedicine. PATIENTS: Forty-nine consecutive patients evaluated via telemedicine. INTERVENTIONS: Likert-scale survey administered. MEASURES: Questions measured patient impressions of video-based visits with their doctor, convenience of the visit, concerns about privacy, and whether they would recommend such a visit, among other items. RESULTS: Mean respondent scores for each question were >4.3 indicating a favorable impression of the telepain clinic experience. Lowest mean scores were found when respondents were asked to compare the care they received by telepain versus an in-person visit, or whether they were able to develop a friendly relationship with the doctor. CONCLUSIONS: The results suggest an overall positive reception of telepain by patients, yet highlight the challenge of building a patient-physician relationship remotely. PMID- 27121892 TI - Elimination of cetirizine following administration of multiple doses to exercised thoroughbred horses. AB - Cetirizine is an antihistamine used in performance horses for the treatment of hypersensitivity reactions and as such a withdrawal time is necessary prior to competition. The objective of the current study was to describe the disposition and elimination of cetirizine following oral administration in order to provide additional serum concentration data upon which appropriate regulatory recommendations can be established. Nine exercised thoroughbred horses were administered 0.4 mg/kg of cetirizine orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum cetirizine concentrations were determined and selected pharmacokinetic parameters determined. The serum elimination half-life was 5.83 +/- 0.841 h. Average serum cetirizine concentrations were still above the LOQ of the assay (0.05 ng/mL) at 48 h (final sample collected) postadministration of the final dose. PMID- 27121893 TI - Kesterite Cu2Zn(Sn,Ge)(S,Se)4 thin film with controlled Ge-doping for photovoltaic application. AB - Cu2ZnSn(S,Se)4 (CZTSSe) semiconductors have been a focus of extensive research effort owing to low-toxicity, high abundance and low material cost. Yet, the CZTSSe thin film solar cell has a low open-circuit voltage value that presents challenges. Herein, using GeSe2 as a new Ge source material, we have achieved a wider band gap CZTSSe-based semiconductor absorber layer with its band-gap controlled by adjusting the ratio of SnS2 : GeSe2 used. In addition, the Cu2Zn(Sn,Ge)(S,Se)4 thin films were prepared with optimal Ge doping (30%) and solar cells were fabricated to attain a respectable power conversion efficiency of 4.8% under 1.5 AM with an active area of 0.19 cm(2) without an anti-reflection layer. PMID- 27121896 TI - Living with cancer: challenges across the lifespan. PMID- 27121894 TI - High-sensitivity intravascular photoacoustic imaging of lipid-laden plaque with a collinear catheter design. AB - A highly sensitive catheter probe is critical to catheter-based intravascular photoacoustic imaging. Here, we present a photoacoustic catheter probe design on the basis of collinear alignment of the incident optical wave and the photoacoustically generated sound wave within a miniature catheter housing for the first time. Such collinear catheter design with an outer diameter of 1.6 mm provided highly efficient overlap between optical and acoustic waves over an imaging depth of >6 mm in D2O medium. Intravascular photoacoustic imaging of lipid-laden atherosclerotic plaque and perivascular fat was demonstrated, where a lab-built 500 Hz optical parametric oscillator outputting nanosecond optical pulses at a wavelength of 1.7 MUm was used for overtone excitation of C-H bonds. In addition to intravascular imaging, the presented catheter design will benefit other photoacoustic applications such as needle-based intramuscular imaging. PMID- 27121897 TI - Parenthood in young cancer survivors is more than a combination of motivation and capacity. PMID- 27121898 TI - Implementation and feasibility of an adapted two-stage visual inspection with acetic acid/cryotherapy-based cervical cancer screening programme for HIV infected women in Addis Ababa, Ethiopia. PMID- 27121899 TI - An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance. AB - Pharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process. Here we used a publicly available warfarin dosing calculator (www.warfarindosing.org) to create an expanded gene-based warfarin dosing table, the CPMC-WD table that includes nine genetic variants in CYP2C9, VKORC1, and CYP4F2. Using two datasets, a European American cohort (EUA, n=73) and the Quebec Warfarin Cohort (QWC, n=769), we show that the CPMC-WD table more accurately predicts therapeutic dose than the FDA table (51 % vs 33 %, respectively, in the EUA, McNemar's two-sided p=0.02; 52 % vs 37 % in the QWC, p<1*10(-6)). It also outperforms both the standard of care 5 mg/day dosing (51 % vs 34 % in the EUA, p=0.04; 52 % vs 31 % in the QWC, p<1*10( 6)) as well as a clinical-only algorithm (51 % vs 38 % in the EUA, trend p=0.11; 52 % vs 45 % in the QWC, p=0.003). This table offers a valuable update to the PGx dosing guideline in the drug label. PMID- 27121901 TI - Effects of highly concentrated hyaluronic acid filler on nasolabial fold correction: A 24-month extension study. AB - BACKGROUND: A previous 6-month study using a more highly concentrated novel hyaluronic acid (HA) filler, PP-501-B, found nasolabial fold (NLF) improvements with increased tolerability. OBJECTIVE: We investigated the long-term efficacy, durability and safety of PP-501-B in the correction of NLFs. METHODS: Subjects completing the initial six-month study were enrolled in this 24-month, randomized, multicenter, double-blind, split-face, extension study. The injection areas and treatment procedures were identical to those of the initial study: each subject was injected with PP-501-B in one NLF and with Restylane Perlane (Q-med) in the contralateral NLF. We reassessed wrinkle improvement using the five-point Wrinkle Severity Rating Scale (WSRS) and changes in the Global Aesthetic Improvement Scale at 12, 18 and 24 months after the initial treatment. RESULTS: Of the 81 patients enrolled, 72 completed the study. The WSRS score significantly decreased from baseline throughout the follow-up period after retreatment with both fillers. There was no significant difference in the WSRS scores between the two fillers at 24 months. Both fillers were well tolerated with no severe complications or adverse reactions. CONCLUSION: The new HA filler PP-501-B is safe and effective in the long term for the correction of moderate-to-severe NLFs, even after a second treatment. PMID- 27121900 TI - DISC1 is a coordinator of intracellular trafficking to shape neuronal development and connectivity. AB - The long, asymmetric and specialised architecture of neuronal processes necessitates a properly regulated transport network of molecular motors and cytoskeletal tracks. This allows appropriate distribution of cargo for correct formation and activity of the synapse, and thus normal neuronal communication. This communication is impaired in psychiatric disease, and ongoing studies have proposed that Disrupted in schizophrenia 1 (DISC1) is an important genetic risk factor for these disorders. The mechanisms by which DISC1 dysfunction might increase propensity to psychiatric disease are not completely understood; however, an emerging theme is that DISC1 can function as a key regulator of neuronal intracellular trafficking. Transport of a wide range of potential cargoes - including mRNAs, neurotransmitter receptors, vesicles and mitochondria can be modulated by DISC1, and therefore is susceptible to DISC1 dysfunction. This theme highlights the importance of understanding precisely how DISC1 can regulate intracellular trafficking, and suggests that a novel approach to the treatment of psychiatric disorders could be provided by targeting this protein and the trafficking machinery with which it interacts. PMID- 27121902 TI - Infiltration of F98 glioma cells in Fischer rat brain is temporary stimulated by radiation. AB - PURPOSE: Irradiation of brain stimulates the expression of inflammatory mediators, some of which can modify the ability of cancer cells to infiltrate the brain. In the present study, the time window during which this stimulation occurs was determined. MATERIALS AND METHODS: Brain of Fischer rat was irradiated (15 Gy) and expression of pro-inflammatory mediators IL-1beta, IL-6 and TNF-alpha was measured from 4 h to 20 days post-irradiation. Level of the matrix metalloproteinase 2 (MMP-2) and prostaglandin E2 (PGE2) which can favor cancer cell infiltration were also measured. The F98 glioma cells were implanted either during (4 h post-irradiation) or after (10 days post-irradiation) the pro inflammatory phase. Infiltration distance of F98 cells in brain parenchyma and the median survival time of the animals were determined. RESULTS: Expression of IL-1beta, IL-6 and TNF-alpha was significantly increased in the irradiated brains with a peak at 4 h post-irradiation. Implantation of F98 glioma cells 4 h post irradiation reduced the median survival time of Fischer rats to 18 days, compared to 25 days when the F98 were implanted in non-irradiated brain. Irradiation of the brain increased the distance of infiltration of F98 cells and was associated with increased levels of MMP-2 and PGE2. Conversely, F98 cells implanted 10 days post-irradiation have infiltrated the brain over a shorter distance and the median survival time of rats was increased to 35 days. CONCLUSIONS: Cancer recurrence is frequently observed in GBM patients. A better understanding of the inflammatory response observed in irradiated brain could contribute to develop new therapeutic modalities to further increase the efficiency of radiotherapy. PMID- 27121903 TI - The isoflavone daidzein directly affects porcine ovarian cell functions and modifies the effect of follicle-stimulating hormone. AB - The key biological active molecule of soya is the isoflavone daidzein, which possesses phytoestrogenic activity. The direct effect of soya and daidzein on ovarian cell functions is not known. This study examined the effect of daidzein on basic porcine ovarian granulosa cell functions and the response to follicle stimulating hormone (FSH). We studied the effects of daidzein (0, 1, 10 and 100 MUm), FSH (0, 0.01, 0.1, 1 IU/ml) and combinations of FSH (0, 0.01, 0.1, 1 IU/ml) + daidzein (50 MUm) on proliferation, apoptosis and hormone release from cultured porcine ovarian granulosa cells and ovarian follicles. The expression of a proliferation-related peptide (PCNA) and an apoptosis-related peptide (Bax) was analysed using immunocytochemistry. The release of progesterone (P4) and testosterone (T) was detected using EIA. Leptin output was analysed using RIA. Daidzein administration increased granulosa cell proliferation, apoptosis and T and leptin release but inhibited P4 output. Daidzein also increased T release and decreased P4 release from cultured ovarian follicles. Follicle-stimulating hormone stimulated granulosa cell proliferation, apoptosis and P4, T and leptin release. The addition of daidzein promoted FSH-stimulated apoptosis (but not proliferation) but suppressed FSH-stimulated P4, T and leptin release. Our observations of FSH action confirm previous data on the stimulatory effect of FSH on ovarian cell proliferation, apoptosis and steroidogenesis and demonstrate for the first time the involvement of FSH in the upregulation of ovarian leptin release. Our observations of daidzein effects demonstrated for the first time that this soya isoflavone affected basic ovarian cell functions (proliferation, apoptosis and hormones release) and modified the effects of FSH. Daidzein promoted FSH action on ovarian cell proliferation and apoptosis and suppressed, and even inverted, FSH action on hormone release. The direct action of daidzein on basic ovarian cell functions and the ability of these cells to respond to FSH indicate the potential influence of soya-containing diets on female reproductive processes via direct action on the ovary. PMID- 27121904 TI - Quantification of dopaminergic neuron differentiation and neurotoxicity via a genetic reporter. AB - Human pluripotent stem cells provide a powerful human-genome based system for modeling human diseases in vitro and for potentially identifying novel treatments. Directed differentiation of pluripotent stem cells produces many specific cell types including dopaminergic neurons. Here, we generated a genetic reporter assay in pluripotent stem cells using newly-developed genome editing technologies in order to monitor differentiation efficiency and compare dopaminergic neuron survival under different conditions. We show that insertion of a luciferase reporter gene into the endogenous tyrosine hydroxylase (TH) locus enables rapid and easy quantification of dopaminergic neurons in cell culture throughout the entire differentiation process. Moreover, we demonstrate that the cellular assay is effective in assessing neuron response to different cytotoxic chemicals and is able to be scaled for high throughput applications. These results suggest that stem cell-derived terminal cell types can provide an alternative to traditional immortal cell lines or primary cells as a quantitative cellular model for toxin evaluation and drug discovery. PMID- 27121905 TI - Purification and characterization of 4-N-trimethylamino-1-butanol dehydrogenase from Fusarium merismoides var. acetilereum. AB - From investigation of 60 filamentous fungi, we identified Fusarium merismoides var. acetilereum, which uses 4-N-trimethylamino-1-butanol (TMA-butanol) as the sole source of carbon and nitrogen. The fungus produced NAD(+)-dependent TMA butanol dehydrogenase (DH) when it was cultivated in medium containing TMA butanol. The enzyme showed molecular mass of 40 kDa by SDS-PAGE and 160 kDa by gel filtration, suggesting that it is a homotetramer. TMA-butanol DH is stable at pH 7.5-9.0. It exhibits moderate stability with respect to temperature (up to 30 degrees C). Additionally, it has optimum activity at 45 degrees C and at pH 9.5. The enzyme has broad specificity to various alkyl alcohols and amino alkyl alcohols, and the carbon chains of which are longer than butanol. Moreover, the activity is strongly inhibited by oxidizing agents, carbonyl and thiol modulators, and chelating agents. This report is the first study examining TMA butanol DH from eukaryotic microbes. PMID- 27121906 TI - Ectopic extramammary Paget's disease on the left hypochondrium. PMID- 27121907 TI - Midwife-led continuity models versus other models of care for childbearing women. AB - BACKGROUND: Midwives are primary providers of care for childbearing women around the world. However, there is a lack of synthesised information to establish whether there are differences in morbidity and mortality, effectiveness and psychosocial outcomes between midwife-led continuity models and other models of care. OBJECTIVES: To compare midwife-led continuity models of care with other models of care for childbearing women and their infants. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (25 January 2016) and reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished trials in which pregnant women are randomly allocated to midwife-led continuity models of care or other models of care during pregnancy and birth. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included 15 trials involving 17,674 women. We assessed the quality of the trial evidence for all primary outcomes (i.e. regional analgesia (epidural/spinal), caesarean birth, instrumental vaginal birth (forceps/vacuum), spontaneous vaginal birth, intact perineum, preterm birth (less than 37 weeks) and all fetal loss before and after 24 weeks plus neonatal death using the GRADE methodology: all primary outcomes were graded as of high quality.For the primary outcomes, women who had midwife-led continuity models of care were less likely to experience regional analgesia (average risk ratio (RR) 0.85, 95% confidence interval (CI) 0.78 to 0.92; participants = 17,674; studies = 14; high quality), instrumental vaginal birth (average RR 0.90, 95% CI 0.83 to 0.97; participants = 17,501; studies = 13; high quality), preterm birth less than 37 weeks (average RR 0.76, 95% CI 0.64 to 0.91; participants = 13,238; studies = eight; high quality) and less all fetal loss before and after 24 weeks plus neonatal death (average RR 0.84, 95% CI 0.71 to 0.99; participants = 17,561; studies = 13; high quality evidence). Women who had midwife-led continuity models of care were more likely to experience spontaneous vaginal birth (average RR 1.05, 95% CI 1.03 to 1.07; participants = 16,687; studies = 12; high quality). There were no differences between groups for caesarean births or intact perineum.For the secondary outcomes, women who had midwife-led continuity models of care were less likely to experience amniotomy (average RR 0.80, 95% CI 0.66 to 0.98; participants = 3253; studies = four), episiotomy (average RR 0.84, 95% CI 0.77 to 0.92; participants = 17,674; studies = 14) and fetal loss less than 24 weeks and neonatal death (average RR 0.81, 95% CI 0.67 to 0.98; participants = 15,645; studies = 11). Women who had midwife-led continuity models of care were more likely to experience no intrapartum analgesia/anaesthesia (average RR 1.21, 95% CI 1.06 to 1.37; participants = 10,499; studies = seven), have a longer mean length of labour (hours) (mean difference (MD) 0.50, 95% CI 0.27 to 0.74; participants = 3328; studies = three) and more likely to be attended at birth by a known midwife (average RR 7.04, 95% CI 4.48 to 11.08; participants = 6917; studies = seven). There were no differences between groups for fetal loss equal to/after 24 weeks and neonatal death, induction of labour, antenatal hospitalisation, antepartum haemorrhage, augmentation/artificial oxytocin during labour, opiate analgesia, perineal laceration requiring suturing, postpartum haemorrhage, breastfeeding initiation, low birthweight infant, five-minute Apgar score less than or equal to seven, neonatal convulsions, admission of infant to special care or neonatal intensive care unit(s) or in mean length of neonatal hospital stay (days).Due to a lack of consistency in measuring women's satisfaction and assessing the cost of various maternity models, these outcomes were reported narratively. The majority of included studies reported a higher rate of maternal satisfaction in midwife led continuity models of care. Similarly, there was a trend towards a cost-saving effect for midwife-led continuity care compared to other care models. AUTHORS' CONCLUSIONS: This review suggests that women who received midwife-led continuity models of care were less likely to experience intervention and more likely to be satisfied with their care with at least comparable adverse outcomes for women or their infants than women who received other models of care.Further research is needed to explore findings of fewer preterm births and fewer fetal deaths less than 24 weeks, and all fetal loss/neonatal death associated with midwife-led continuity models of care. PMID- 27121908 TI - Alternative splicing enhances transcriptome complexity in desiccating seeds. AB - Before being dispersed in the environment, mature seeds need to be dehydrated. The survival of seeds after dispersal depends on their low hydration in combination with high desiccation tolerance. These characteristics are established during seed maturation. Some key seed maturation genes have been reported to be regulated by alternative splicing (AS). However, so far AS was described only for single genes and a comprehensive analysis of AS during seed maturation has been lacking. We investigated gene expression and AS during Arabidopsis thaliana seed development at a global level, before and after desiccation. Bioinformatics tools were developed to identify differentially spliced regions within genes. Our data suggest the importance and shows the peculiar features of AS during seed desiccation. We identified AS in 34% of genes that are expressed at both timepoints before and after desiccation. Most of these AS transcript variants had not been found before in other tissues. Among the AS genes some seed master regulators could be found. Interestingly, 6% of all expressed transcripts were not transcriptionally regulated during desiccation, but only modified by AS. We propose that AS should be more routinely taken into account in the analysis of transcriptomic data to prevent overlooking potentially important regulators. PMID- 27121909 TI - Older peoples' experiences of living in a residential aged care facility in Australia. AB - AIM: The objectives of the study were to investigate the lived experience of older people in residential aged care facilities (RACFs) in Australia, to explore their perceptions of their lives in RACFs and how care might be improved. METHODS: This qualitative study used a phenomenological approach to explore the lived experience of older persons in RACFs across two Australian states. In-depth interviews regarding independence, dignity, autonomy, communication and relationships were conducted with 18 participants. The interviews were audiotaped, transcribed and thematically analysed. RESULTS: Three themes emerged reflecting the reality of RACF life for these participants: (i) loss of autonomy, dignity and control; (ii) valuing important relationships; and (iii) resigned acceptance. CONCLUSION: Older people were not included in decision-making and found it difficult to maintain their autonomy and dignity, and forge meaningful relationships. They traded their independence and dignity for the safety and assistance they needed; however, they accepted this trade-off with stoicism and remained positive. PMID- 27121910 TI - Histone deacetylase inhibitor givinostat: the small-molecule with promising activity against therapeutically challenging haematological malignancies. AB - Histone acetyl transferases and histone deacetylases (HDACs) are counteracting epigenetic enzymes regulating the turnover of histone acetylation thereby regulating transcriptional events in a precise manner. Deregulation of histone acetylation caused by aberrant expression of HDACs plays a key role in tumour onset and progression making these enzymes as candidate targets for anticancer drugs and therapy. Small-molecules namely histone deacetylase inhibitors (HDACi) modulating the biological function of HDACs have shown multiple biological effects including differentiation, cell cycle arrest and apoptosis in tumour models. HDACi in general have been described in plethora of reviews with respect to various cancers. However, no review article is available describing thoroughly the role of inhibitor givinostat (ITF2357 or [6-(diethylaminomethyl) naphthalen-2 yl] methyl N-[4-(hydroxycarbamoyl) phenyl] carbamate) in haematological malignancies. Thus, the present review explores the intricate role of novel inhibitor givinostat in the defined malignancies including multiple myeloma, acute myelogenous leukaemia, Hodgkin's and non-Hodgkin's lymphoma apart from myeloproliferative neoplasms. The distinct molecular mechanisms triggered by this small-molecule inhibitor in these cancers to exert cytotoxic effect have also been dealt with. The article also highlights the combination strategy that can be used for enhancing the therapeutic efficiency of this inhibitor in the upcoming future. PMID- 27121912 TI - Speeding up pyrogenicity testing: Identification of suitable cell components and readout parameters for an accelerated monocyte activation test (MAT). AB - Pyrogen testing represents a crucial safety measure for parental drugs and medical devices, especially in direct contact with blood or liquor. The European Pharmacopoeia regulates these quality control measures for parenterals. Since 2010, the monocyte activation test (MAT) has been an accepted pyrogen test that can be performed with different human monocytic cell sources: whole blood, isolated monocytic cells or monocytic cell lines with IL1beta, IL6, or TNFalpha as readout cytokines. In the present study, we examined the three different cell sources and cytokine readout parameters with the scope of accelerating the assay time. We could show that despite all cell types being able to detect pyrogens, primary cells were more sensitive than the monocytic cell line. Quantitative real time PCR revealed IL6 mRNA transcripts having the largest change in Ct-values upon LPS-stimulation compared to IL1beta and TNFalpha, but quantification was unreliable. IL6 protein secretion from whole blood or peripheral blood mononuclear cells (PBMC) was also best suited for an accelerated assay with a larger linear range and higher signal-to-noise ratios upon LPS-stimulation. The unique combination with propan-2-ol or a temperature increase could additionally increase the cytokine production for earlier detection in PBMC. The increased incubation temperature could finally increase not only responses to lipopolysaccharides (LPS) but also other pyrogens by up to 13-fold. Therefore, pyrogen detection can be accelerated considerably by using isolated primary blood cells with an increased incubation temperature and IL6 as readout. These results could expedite assay time and thus help to promote further acceptance of the MAT. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121911 TI - Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes. AB - Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and nociception. Among these genes, Asic1 showed heightened mRNA expression, coherent with RCF mice's respiratory hypersensitivity to CO2 and altered nociception. Functional enrichment and mRNA transcript analyses yielded a consistent picture of enhancement for several genes affecting chemoception, neurodevelopment, and emotionality. Particularly, results with Asic1 support recent human findings with panic and CO2 responses, and provide new perspectives on how early adversities and genes interplay to affect key components of panic and related disorders. PMID- 27121913 TI - Usefulness of a fluorescence visualization system for the detection of oral precancerous and early cancerous lesions. AB - Early detection of precancerous and early cancerous lesions could greatly reduce both the mortality and morbidity of oral cancer. The objective of this study was to analyze a fluorescence visualization (FV) system for the detection of precancerous and early cancerous lesions in rat tongue carcinogenesis and human oral cancerous lesions using for the first time a 4NQO rat model and human tissue. Based on the results from the rat tongue carcinogenesis model, under direct FV, the normal oral mucosa emitted various shades of pale green autofluorescence. In the precancerous and early cancerous cases, the lesion appeared as an irregular dark area. Histological examination of the lesions showed that the VELscope system had a sensitivity of 95% and specificity of 100% in discriminating normal mucosa from dysplasia/carcinoma in situ (CIS) or invasive carcinoma. The proliferating cell nuclear antigen (PCNA) protein level was gradually increased with progression of carcinogenic transformation. Furthermore, the results of PCNA and FV loss (FVL) were correlated. Next, results from 17 patients were also presented. Histological examination of the lesions showed that the VELscope system had a sensitivity of 95% and specificity of 100% in discriminating normal mucosa from severe dysplasia/CIS or invasive carcinoma. There were no normal epithelium cells in any of the FVL regions. Furthermore, to clarify the usefulness of FV compared to vital staining with iodine, we investigated the surgical margins of early oral squamous cell carcinoma (OSCC) tissues and compared the FVL and iodine unstained area (IU). The percentage of various types of dysplasia were almost equal when comparing the FVL and IU. These results suggest that this direct FV device has the potential for simple, cost effective screening, detection and margin determination of oral precancerous and early cancerous lesions. PMID- 27121914 TI - Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. AB - Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a natural anticoagulant deficiency. Contrary, additive risk of factor V Leiden (FVL) or prothrombin-G20210A (PT) mutation is modest. Women with a FVL/PT mutation as single risk factor can use COCs if alternatives are not tolerated. SUMMARY: Background Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), which is shown to be more pronounced in women with hereditary thrombophilia. Currently, WHO recommendations state that COC-use in women with hereditary thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden and prothrombin-G20210A mutation) is associated with an unacceptable health risk. Objective To perform a meta-analysis evaluating the additional risk of VTE in COC users with thrombophilia. Methods The MEDLINE and EMBASE databases were searched on 10 February 2015 for potential eligible studies. A distinction was made between 'mild' (factor V Leiden and prothrombin-G20210A mutation) and 'severe' thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). Results We identified 12 case-control and three cohort studies. In COC-users, mild and severe thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95% confidence interval [CI], 4.21 8.23) and 7-fold (RR, 7.15; 95% CI, 2.93-17.45), respectively. The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). Conclusion These results support discouraging COC-use in women with severe hereditary thrombophilia. By contrast, additive VTE risk of mild thrombophilia is modest. When no other risk factors are present, (e.g. family history) COCs can be offered to these women when reliable alternative contraceptives are not tolerated. PMID- 27121915 TI - Detection and adequacy evaluation of erythrocyte glutathione transferase on levels of circulating toxins in hemodialysis patients. AB - To explore detection and adequacy evaluation of erythrocyte glutathione S transferase (GST) on levels of circulating toxins in hemodialysis patients in Qinhuangdao region in China, this study divided 84 cases of long-term, end-stage hemodialysis patients into 2 groups: one group of 33 cases of adequate hemodialysis (spKt/V >= 1.3) and another group of 51 cases of inadequate hemodialysis (spKt/V < 1.3), according to the urea index value of the unit chamber model (spKt/V). Another 50 cases of subjects found healthy by a physical examination were taken as the control group, and the differences in the related clinical and biochemical indexes of the 3 groups were compared and analyzed. The levels of GST, creatinine, high sensitivity C-reactive protein (hs-CRP), transferrin saturation (TSAT), parathyroid hormone (PTH), interleukin-2,6,8 (IL 2,6,8) and tumor necrosis factor-a (TNF-a) in the hemodialysis group were significantly higher than those in the control group (P < 0.05), and GST, IL-2, 6, 8, and TNF-a levels in the inadequate hemodialysis group were significantly higher than in the adequate hemodialysis group (P < 0.05). Pearson's relevant analysis showed that the levels of GST and spKt/V, IL-2, IL-6, IL-8, and TNF-a have a positive correlation (P < 0.05), and they have no correlation with levels of creatinine, hs-CRP, TSAT, and PHT (P > 0.05). There were 23 patients with levels of spKt/V >= 1.3 after adjusting the dialysis solution for 51 cases of inadequate hemodialysis patients, and the GST level after the adjustment was significantly lower than that before the adjustment, but still higher than that in the adequate dialysis group. This concludes that the maintenance of hemodialysis in patients has certain relevance on spKt/V and associated inflammatory factors. Through the study, it can be determined that GST can effectively respond to adequate hemodialysis, which has a guiding significance on adjusting the blood dialysis solution in clinical practice. PMID- 27121916 TI - Comparison of social functioning in community-living older individuals with schizophrenia and bipolar disorder: a catchment area-based study. AB - OBJECTIVE: Preserved social functioning is of utmost importance for older individuals living in the community to maintain independency. However, in patients with schizophrenia or bipolar disorder, it remains unclear which factors influence social functioning in later life. METHODS: In a catchment area-based study in Amsterdam, The Netherlands, 120 older (>60 years) community-living patients with schizophrenia (n = 73) and with bipolar disorder (n = 47) were included. Clinical interviews on social functioning and psychometric measurements were applied. RESULTS: Patients with schizophrenia scored lower on all social measures (social functioning, social participation, network size, availability of confidants) compared with their peers with bipolar disorder. In patients with schizophrenia, lower social functioning was associated with having more negative symptoms and depressive symptoms. Age of onset was also associated with social functioning in schizophrenia, with higher scores in very late-onset schizophrenia like psychosis. Unfavourable social functioning in patients with bipolar disorder was associated with lower cognitive functioning. Furthermore, in both groups, social functioning was not related to age, having offspring or the presence of a partner. CONCLUSIONS: In community-living older patients, schizophrenia has a more disruptive effect on social functioning than bipolar disorder, except in those with a very late-onset schizophrenia-like psychosis. Minimizing residual depressive symptoms and optimizing cognitive functioning may be targets for improving social functioning and independent-living in older patients with severe mental illness. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27121917 TI - Surface-induced spin state locking of the [Fe(H2B(pz)2)2(bipy)] spin crossover complex. AB - Temperature- and coverage-dependent studies of the Au(1 1 1)-supported spin crossover Fe(II) complex (SCO) of the type [Fe(H2B(pz)2)2(bipy)] with a suite of surface-sensitive spectroscopy and microscopy tools show that the substrate inhibits thermally induced transitions of the molecular spin state, so that both high-spin and low-spin states are preserved far beyond the spin transition temperature of free molecules. Scanning tunneling microscopy confirms that [Fe(H2B(pz)2)2(bipy)] grows as ordered, molecular bilayer islands at sub monolayer coverage and as disordered film at higher coverage. The temperature dependence of the electronic structure suggest that the SCO films exhibit a mixture of spin states at room temperature, but upon cooling below the spin crossover transition the film spin state is best described as a mix of high-spin and low-spin state molecules of a ratio that is constant. This locking of the spin state is most likely the result of a substrate-induced conformational change of the interfacial molecules, but it is estimated that also the intra-atomic electron-electron Coulomb correlation energy, or Hubbard correlation energy U, could be an additional contributing factor. PMID- 27121918 TI - Effect of different levels of nitrogen on rhizosphere bacterial community structure in intensive monoculture of greenhouse lettuce. AB - Pyrosequencing-based analyses revealed significant effects among low (N50), medium (N80), and high (N100) fertilization on community composition involving a long-term monoculture of lettuce in a greenhouse in both summer and winter. The non-fertilized control (CK) treatment was characterized by a higher relative abundance of Actinobacteria, Acidobacteria, and Chloroflexi; however, the average abundance of Firmicutes typically increased in summer, and the relative abundance of Bacteroidetes increased in winter in the N-fertilized treatments. Principle component analysis showed that the distribution of the microbial community was separated by a N gradient with N80 and N100 in the same group in the summer samples, while CK and N50 were in the same group in the winter samples, with the other N-level treatments existing independently. Redundancy analysis revealed that available N, NO3(-)-N, and NH4(+)-N, were the main environmental factors affecting the distribution of the bacterial community. Correlation analysis showed that nitrogen affected the shifts of microbial communities by strongly driving the shifts of Firmicutes, Bacteroidetes, and Proteobacteria in summer samples, and Bacteroidetes, Actinobacteria, and Acidobacteria in winter samples. The study demonstrates a novel example of rhizosphere bacterial diversity and the main factors influencing rizosphere microbial community in continuous vegetable cropping within an intensive greenhouse ecosystem. PMID- 27121919 TI - Quantitative analysis of gene expression in fixed colorectal carcinoma samples as a method for biomarker validation. AB - Biomarkers have been described as the future of oncology. Modern proteomics provide an invaluable tool for the near-whole proteome screening for proteins expressed differently in neoplastic vs. healthy tissues. However, in order to select the most promising biomarkers, an independent method of validation is required. The aim of the current study was to propose a methodology for the validation of biomarkers. Due to material availability the majority of large scale biomarker studies are performed using formalin-fixed paraffin-embedded (FFPE) tissues, therefore these were selected for use in the current study. A total of 10 genes were selected from what have been previously described as the most promising candidate biomarkers, and the expression levels were analyzed with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using calibrator normalized relative quantification with the efficiency correction. For 6/10 analyzed genes, the results were consistent with the proteomic data; for the remaining four genes, the results were inconclusive. The upregulation of karyopherin alpha 2 (KPNA2) and chromosome segregation 1-like (CSE1L) in colorectal carcinoma, in addition to downregulation of chloride channel accessory 1 (CLCA1), fatty acid binding protein 1 (FABP1), sodium channel, voltage gated, type VII alpha subunit (SCN7A) and solute carrier family 26 (anion exchanger), member 3 (SLC26A3) was confirmed. With the combined use of proteomic and genetic tools, it was reported, for the first time to the best of our knowledge, that SCN7A was downregulated in colorectal carcinoma at mRNA and protein levels. It had been previously suggested that the remaining five genes served an important role in colorectal carcinogenesis, however the current study provided strong evidence to support their use as biomarkers. Thus, it was concluded that combination of RT-qPCR with proteomics offers a powerful methodology for biomarker identification, which can be used to analyze FFPE samples. PMID- 27121920 TI - A review of 111 anaesthetic patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - INTRODUCTION: Cytoreductive surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC) is the treatment of choice for selected patients with peritoneal carcinomatosis, a previously lethal condition with dismal survival rates. METHODS: We reviewed CRS and HIPEC procedures performed at our centre from January 1997 to December 2012, focusing on perioperative events and anaesthetic implications. RESULTS: In total, 111 patients underwent 113 procedures. Mean age of the patients was 51.7 (range 14-74) years and 84.1% were women. Mean duration of surgery was 9 hours 10 minutes +/- 2 hours 56 minutes. Most tumours were ovarian or colorectal in origin, and the mean peritoneal cancer index (PCI) score was 14.3 +/- 8.9. Mean estimated blood loss was 1,481 +/- 1,064 mL. Mean total intravenous fluids and blood products administered was 8,498 +/- 3,941 mL. Postoperatively, 79.5% of the patients needed intensive care, as 75.2% of the 113 procedures required interval extubation. Patients with lower PCI scores were more likely to be extubated immediately after surgery (p < 0.05). 80.0% of patients had coagulopathy postoperatively, and this was associated with longer HIPEC duration (p < 0.05). Median lengths of intensive care unit and hospital stays were two days and 14 days, respectively. Longer duration of surgery significantly correlated with longer hospitalisation. Prolonged hospitalisation was due to nosocomial pneumonia, pleural effusions, respiratory failure, sepsis, surgical complications (such as anastomotic or wound dehiscence), and intra-abdominal infections. CONCLUSION: The CRS and HIPEC technique is a major surgery with significant morbidity, as highlighted by the perioperative concerns observed in our study. PMID- 27121921 TI - A randomised, double-blinded clinical study on the efficacy of multimedia presentation using an iPad for patient education of postoperative hip surgery patients in a public hospital in Singapore. AB - INTRODUCTION: This study compared patient satisfaction and recall of physiotherapy patient education among patients who had undergone hip surgery, with information presented via an iPad versus a standard paper booklet. METHODS: Patients who had undergone hip surgery joined and completed this single-centre study, which utilised a randomised parallel group design. They were randomly allocated to either Group A (received information on hip surgery physiotherapy via an iPad) or Group B (received the same information via a paper booklet). The participants were blinded to the intervention received by the other group and the testers were blinded to the intervention received by the participants. The interventions were carried out during the patients' first four postoperative physiotherapy sessions. The outcome measures were recorded using pre-validated questionnaires. RESULTS: A total of 42 participants (mean age 70 +/- 12 years) were recruited. After the intervention, patients in both groups had improved recall of the information presented during patient education. However, the patients in Group A had a significantly better recall score than those in Group B (4.0 points higher, p < 0.001). The level of patient satisfaction was also significantly higher in Group A than in Group B (8.5 points higher, p < 0.001). CONCLUSION: While the use of an iPad and a paper booklet both had positive outcomes for patient recall and satisfaction, the use of an iPad was found to be more effective at improving patient satisfaction and recall of physiotherapy patient education in the present study. PMID- 27121922 TI - Knowledge of diabetes mellitus and safe practices during Ramadan fasting among Muslim patients with diabetes mellitus in Singapore. AB - INTRODUCTION: This study aimed to explore the level of knowledge of Muslim patients with diabetes mellitus (DM) regarding DM and the self-management of DM when fasting during Ramadan. METHODS: Muslim patients with DM attending the Diabetes Centre of Singapore General Hospital, Singapore, were surveyed on their knowledge of DM and self-management of DM when fasting during Ramadan. Data on patient demographics, DM history and management of DM during the previous Ramadan was also collected. RESULTS: A total of 92 patients (34 male, 58 female) were surveyed. The mean age of the patients was 53.4 +/- 13.3 years. The patients were either Malay (91.3%) or Indian (8.7%), and most (66.3%) had at least a secondary school education. Most (89.1%) had Type 2 DM. The mean duration of DM was 8.7 +/- 5.1 years and mean pre-Ramadan haemoglobin A1c was 8.4% +/- 1.8%. DM treatment consisted of insulin therapy (37.0%), oral glucose-lowering drugs (35.9%) and combined therapy (22.8%). The mean DM knowledge score was 58.8% for general knowledge and 75.9% for fasting knowledge. During the previous Ramadan, although 71.4% of the patients consulted their physicians, 37.3% did not monitor their blood glucose levels and 47.0% had hypoglycaemic episodes. Among those who had hypoglycaemia, 10.8% continued to fast. CONCLUSION: Unsafe self-management practices were observed among DM patients who fasted during Ramadan. Efforts should be made to bridge the gap between knowledge of DM and self-management of DM. PMID- 27121924 TI - Controversial issues in the early identification of atypical language development in young children. PMID- 27121923 TI - Effects of Novel Finishing and Polishing Systems on Surface Roughness and Morphology of Nanocomposites. AB - OBJECTIVES: The purpose of this in vitro study was to evaluate the effects of different finishing/polishing techniques on the surface roughness of nanocomposites after thermocycling aging. MATERIALS AND METHODS: Five contemporary resin-based composites (Clearfil Majesty ES-2, Filtek Z550, Estelite?Quick, Zenit, Filtek Z250) were tested. For each resin-based composite, 50 disc-shaped specimens were prepared and groups were divided into five subgroups according to the finishing/polishing methods (n = 10): control, finishing/polishing brush, finishing/polishing disc, and two different finishing/polishing wheels. Before and after aging, the surface roughness of specimens was measured. For each treatment method two samples were analyzed using a scanning electron microscope. Two-way analysis of variance and paired samples t tests were used to evaluate the data and the means were compared by Bonferroni tests (p <= 0.05). RESULTS: Before aging, the Filtek Z250 resin with the Mylar strip group showed the lowest surface roughness (Ra) value (0.13 +/- 0.03 um, p < 0.05) and the Clearfil Majesty ES 2 resin with Occlubrush finishing/polishing system showed the highest (0.7 +/- 0.13 um, p < 0.05). After aging, the Clearfil Majesty ES 2 resin with the Mylar strip group showed the highest surface roughness (Ra) value (0.96 +/- 0.4 um) and the Clearfil Majesty ES 2 resin with the Sof-Lex aluminum oxide disc finishing/polishing system showed the lowest surface roughness (Ra) value (0.25 +/- 0.06 um, p < 0.05). CONCLUSIONS: Composite type and finishing/polishing method significantly affected the surface roughness of composites before and after thermocycling aging. CLINICAL SIGNIFICANCE: There were significant interactions between finishing/polishing methods and composite types for surface roughness. The results give clinicians some flexibility in choosing appropriate finishing/polishing techniques for each resin composite material. (J Esthet Restor Dent 28:247-261, 2016). PMID- 27121925 TI - Citrus Tachibana Leaf Extract Mitigates Symptoms of Food Allergy by Inhibiting Th2-Associated Responses. AB - Although the incidence of food allergy continues to rise, there have been no effective therapeutic strategies. Citrus fruits contain a number of bioactive flavonoids with immune-regulatory functions. The objective of this study was to determine whether Citrus tachibana (fruit body with peel, leaves, and branch) can protect against the development of food allergy and the mechanism behind it, and to identify the active compound(s) responsible. We found that C. tachibana leaf extract (CLE) mitigated ovalbumin (OVA)-induced food allergy symptoms including increased rectal temperature, diarrhea, and anaphylaxis. This mitigation was likely due to CLE-mediated decreases in cytokine release from T-helper 2 cells (Th2 cells) in mesenteric lymph nodes. Moreover, higher levels of CLE attenuated systemic Th2 cell-mediated responses in mouse splenocytes sensitized with OVA+Alum. This was evidenced by CLE-mediated reductions in Th2 cytokine release, including interleukin (IL)-4, IL-5, and IL-13, but not the Th1 cytokines IL-12 and interferon (IFN)-gamma, which was attributable to decreased gene expression levels. We also identified kaempferol as the most potent compound for reducing Th2-associated responses in splenocytes. The findings of this study suggest that CLE suppresses Th2-cell-mediated immune responses, contributing to alleviation of food allergy symptoms, and that kaempferol is a flavonoid with potential antiallergenic activity that targets Th2 cell-induced responses. PMID- 27121926 TI - Sessile multidroplets and salt droplets under high tangential electric fields. AB - Understanding the interaction behaviors between sessile droplets under imposed high voltages is very important in many practical situations, e.g., microfluidic devices and the degradation/aging problems of outdoor high-power applications. In the present work, the droplet coalescence, the discharge activity and the surface thermal distribution response between sessile multidroplets and chloride salt droplets under high tangential electric fields have been investigated with infrared thermography, high-speed photography and pulse current measurement. Obvious polarity effects on the discharge path direction and the temperature change in the droplets in the initial stage after discharge initiation were observed due to the anodic dissolution of metal ions from the electrode. In the case of sessile aligned multidroplets, the discharge path direction could affect the location of initial droplet coalescence. The smaller unmerged droplet would be drained into the merged large droplet as a result from the pressure difference inside the droplets rather than the asymmetric temperature change due to discharge. The discharge inception voltages and the temperature variations for two salt droplets closely correlated with the ionization degree of the salt, as well as the interfacial electrochemical reactions near the electrodes. Mechanisms of these observed phenomena were discussed. PMID- 27121927 TI - Twin-Arginine Protein Translocation. AB - Twin-arginine protein translocation systems (Tat) translocate fully folded and co factor-containing proteins across biological membranes. In this review, we focus on the Tat pathway of Gram-positive bacteria. The minimal Tat pathway is composed of two components, namely a TatA and TatC pair, which are often complemented with additional TatA-like proteins. We provide overviews of our current understanding of Tat pathway composition and mechanistic aspects related to Tat-dependent cargo protein translocation. This includes Tat pathway flexibility, requirements for the correct folding and incorporation of co-factors in cargo proteins and the functions of known cargo proteins. Tat pathways of several Gram-positive bacteria are discussed in detail, with emphasis on the Tat pathway of Bacillus subtilis. We discuss both shared and unique features of the different Gram-positive bacterial Tat pathways. Lastly, we highlight topics for future research on Tat, including the development of this protein transport pathway for the biotechnological secretion of high-value proteins and its potential applicability as an antimicrobial drug target in pathogens. PMID- 27121928 TI - Primary lateral sclerosis and hereditary spastic paraplegia in sporadic patients. An important distinction in descriptive studies. PMID- 27121929 TI - Native myocardial T1 mapping in pulmonary hypertension: correlations with cardiac function and hemodynamics. AB - OBJECTIVES: To analyze alterations in left ventricular (LV) myocardial T1 times in patients with pulmonary hypertension (PH) and to investigate their associations with ventricular function, mass, geometry and hemodynamics. METHODS: Fifty-eight patients with suspected PH underwent right heart catheterization (RHC) and 3T cardiac magnetic resonance imaging. Ventricular function, geometry and mass were derived from cine real-time short-axis images. Myocardial T1 maps were acquired by a prototype modified Look-Locker inversion-recovery sequence in short-axis orientations. LV global, segmental and ventricular insertion point (VIP) T1 times were evaluated manually and corrected for blood T1. RESULTS: Septal, lateral, global and VIP T1 times were significantly higher in PH than in non-PH subjects (septal, 1249 +/- 58 ms vs. 1186 +/- 33 ms, p < 0.0001; lateral, 1190 +/- 45 ms vs. 1150 +/- 33 ms, p = 0.0003; global, 1220 +/- 52 ms vs. 1171 +/ 29 ms, p < 0.0001; VIP, 1298 +/- 78 ms vs. 1193 +/- 31 ms, p < 0.0001). In PH, LV eccentricity index was the strongest linear predictor of VIP T1 (r = 0.72). Septal, lateral and global T1 showed strong correlations with VIP T1 (r = 0.81, r = 0.59 and r = 0.75, respectively). CONCLUSIONS: In patients with PH, T1 times in VIPs and in the entire LV myocardium are elevated. LV eccentricity strongly correlates with VIP T1 time, which in turn is strongly associated with T1 time changes in the entire LV myocardium. KEY POINTS: * Native T1 mapping detects left ventricular myocardial alterations in pulmonary hypertension * In pulmonary hypertension, native T1 times at ventricular insertion points are increased * These T1 times correlate strongly with left ventricular eccentricity * In pulmonary hypertension, global and segmental myocardial T1 times are increased * Global, segmental and ventricular insertion point T1 times are strongly correlated. PMID- 27121930 TI - Assessment and treatment planning of lateral intracranial dural arteriovenous fistulas in 3 T MRI and DSA: A detailed analysis under consideration of time resolved imaging of contrast kinetics (TRICKS) and ce-MRA sequences. AB - OBJECTIVES: The current gold standard in the assessment of lateral intracranial dural arteriovenous fistulas (LDAVF) is digital subtraction angiography (DSA). However, magnetic resonance imaging (MRI) is a non-invasive emerging tool for the evaluation of such lesions. The aim of our study was to compare the DSA to our 3 T MR-imaging protocol including a highly spatial resolved (ce-MRA) and a temporal resolved ("time-resolved imaging of contrast kinetics", TRICKS) contrast-enhanced MR angiography to evaluate if solely DSA can remain the gold-standard imaging modality for the treatment planning of LDAVF. METHODS: We retrospectively reviewed matched pairs of DSA and 3 T MRI examinations of 24 patients with LDAVF (03/2008-04/2014) by the same list of relevant criteria for an endovascular LDAVF treatment planning. In particular, we determined intermodality agreement for the Cognard classification, the identifeication of arterial feeders, and the detailed assessment of each venous drainage pattern. RESULTS: Intermodality agreement for the Cognard classification was excellent (K = 1.0). Whereas MRI failed in identifying small arterial feeders, it was superior to the DSA in the assessment of the sinus and the venous drainage pattern. CONCLUSIONS: The combination of MRI and DSA is the new gold standard in LDAVF treatment planning. KEY POINTS: * DSA is superior to the MRI in detecting LDAVF arterial feeders. * MRI excellently evaluates the venous side of an LDAVF. * MRI can replace DSA in initial diagnosis and monitoring of LDAVF. * MRI and DSA combined are the new gold standard in LDAVF treatment planning. PMID- 27121933 TI - Hepatic Clearance of Drugs in Patients With Renal Insufficiency. PMID- 27121931 TI - Partial meniscectomy is associated with increased risk of incident radiographic osteoarthritis and worsening cartilage damage in the following year. AB - OBJECTIVES: To assess whether partial meniscectomy is associated with increased risk of radiographic osteoarthritis (ROA) and worsening cartilage damage in the following year. METHODS: We studied 355 knees from the Osteoarthritis Initiative that developed ROA (Kellgren-Lawrence grade >= 2), which were matched with control knees. The MR images were assessed using the semi-quantitative MOAKS system. Conditional logistic regression was applied to estimate risk of incident ROA. Logistic regression was used to assess the risk of worsening cartilage damage in knees with partial meniscectomy that developed ROA. RESULTS: In the group with incident ROA, 4.4 % underwent partial meniscectomy during the year prior to the case-defining visit, compared with none of the knees that did not develop ROA. All (n = 31) knees that had partial meniscectomy and 58.9 % (n = 165) of the knees with prevalent meniscal damage developed ROA (OR = 2.51, 95 % CI [1.73, 3.64]). In knees that developed ROA, partial meniscectomy was associated with an increased risk of worsening cartilage damage (OR = 4.51, 95 % CI [1.53, 13.33]). CONCLUSIONS: The probability of having had partial meniscectomy was higher in knees that developed ROA. When looking only at knees that developed ROA, partial meniscectomy was associated with greater risk of worsening cartilage damage. KEY POINTS: * Partial meniscectomy is a controversial treatment option for degenerative meniscal tears. * Partial meniscectomy is strongly associated with incident osteoarthritis within 1 year. * Partial meniscectomy is associated with increased risk of worsening cartilage damage. PMID- 27121932 TI - Prognostic value of preoperative intratumoral FDG uptake heterogeneity in patients with epithelial ovarian cancer. AB - OBJECTIVES: To investigate the prognostic value of intratumoral FDG uptake heterogeneity (IFH) derived from PET/CT in patients with epithelial ovarian cancer (EOC). METHODS: We retrospectively reviewed patients with pathologically proven epithelial ovarian cancer who underwent preoperative 18F-FDG PET/CT scans. PET/CT parameters such as maximum and average standardized uptake values (SUVmax and SUVavg), sum of all metabolic tumour volume (MTV), cumulative total lesion glycolysis (TLG) and IFH were assessed. Regression analyses were used to identify clinicopathological and imaging variables associated with disease-free survival (DFS). RESULTS: Clinicopathological data were reviewed for 61 eligible patients. The median duration of DFS was 13 months (range, 6-26 months), and 18 (29.5 %) patients experienced recurrence. High IFH values were associated with tumour recurrence (P = 0.005, hazard ratio 4.504, 95 % CI 1.572-12.902). The Kaplan Meier survival graphs showed that DFS significantly differed in groups categorized based on IFH (P = 0.002, log-rank test). Moreover, there were significant differences in DFS (P = 0.009) and IFH (P = 0.040) between patients with and without recurrence. CONCLUSIONS: Preoperative IFH measured by 18F-FDG PET/CT was significantly associated with EOC recurrence. FDG-based heterogeneity could be a useful and potential predicator of EOC recurrence before treatment. KEY POINTS: * Preoperative IFH was significantly associated with recurrence of EOC * Disease-free survival significantly differed in groups categorized by IFH * FDG-based heterogeneity could be a potential predicator of EOC recurrence before treatment. PMID- 27121934 TI - Effect of Vortioxetine on Cardiac Repolarization in Healthy Adult Male Subjects: Results of a Thorough QT/QTc Study. AB - This double-blind, randomized, placebo- and positive-controlled, parallel-group study evaluated the effect of vortioxetine (Lu AA21004), an investigational multimodal antidepressant, on QT interval in accordance with current guidelines of the International Conference on Harmonisation (ICH-E14). A total of 340 healthy men were randomized to receive 1 of 4 treatments for 14 days: (1) vortioxetine 10 mg once daily (QD), (2) vortioxetine 40 mg QD, (3) placebo QD, or (4) placebo QD on Days 1 through 13 followed by a single dose of moxifloxacin 400 mg (positive control). The primary endpoint was the largest time-matched, baseline-adjusted least-squares (LS) mean difference for the individual-corrected QT interval (QTcNi [linear]) between vortioxetine and placebo. Alternative QT correction formulas (i.e., Fredericia [QTcF], Bazett [QTcB], Framingham [QTcFm], and QTcNi [nonlinear]) were used as secondary endpoints. The upper bound of the 2 sided 90% confidence interval around the LS mean difference from placebo for baseline-adjusted QTcNi (linear), QTcF, QTcB, QTcFm, and QTcNi (nonlinear) did not exceed 10 ms at any time point after multiple doses of vortioxetine 10 mg (therapeutic) or 40 mg (supratherapeutic). Overall, the study results indicate that vortioxetine is unlikely to affect cardiac repolarization in healthy subjects. PMID- 27121935 TI - The Absence of a Clinically Significant Effect of Food on the Single Dose Pharmacokinetics of Vorapaxar, a PAR-1 Antagonist, in Healthy Adult Subjects. AB - In this open-label, randomized, 2-period crossover study, 16 healthy subjects received a single oral 2.5-mg dose of vorapaxar in the fed (i.e., standardized high-fat breakfast) and fasted (i.e., an overnight fast) state with a 6-week washout. Plasma samples for vorapaxar assay were obtained pre-dose and up to 72 hours post-dose. Least squares (LS) geometric mean AUC0-72 hr and Cmax were analyzed by ANOVA. If 90% confidence intervals (CI) for the geometric mean ratios (GMRs; fed/fasted) of AUC0-72 hr and Cmax were within the 50-200% range, then food was deemed not to have a clinically important effect. The LS geometric mean (90% CI) AUC0-72 hr and Cmax of vorapaxar in the fasted state were 314 (284-348) ng hr/mL and 23.4 (20.7-26.4) ng/mL, respectively. The GMRs (fed/fasted) and 90% CIs for AUC0-72 hr and Cmax were 96.9 (92.2-102) and 79.1 (67.6-92.5), respectively. Vorapaxar was generally safe and well tolerated in the presence and absence of food. Concomitant food decreased the rate (i.e., 21% reduction in Cmax and 45-min delay in Tmax ) with no effect on the extent of vorapaxar absorption when administered as a single 2.5-mg dose. Thus, vorapaxar can be administered without regard to food. PMID- 27121936 TI - Pharmacokinetics of the NS3 Protease Inhibitor, Asunaprevir (ASV, BMS-650032), in Phase I Studies in Subjects With or Without Chronic Hepatitis C. AB - Asunaprevir (BMS-650032, ASV) is a potent, selective hepatitis C virus (HCV) NS3 protease inhibitor in clinical evaluation for chronic hepatitis C treatment. ASV pharmacokinetics were evaluated in four single- and multiple-ascending-dose studies in healthy subjects or subjects with HCV genotype 1 infection and in human mass balance and food-effect studies. Median Tmax was 2-4 hours. Although T1/2 was 14-23 hours, oral clearance was high (302-668 L/h at doses >=100 mg). Steady state was achieved by Day 7. The ASV dose-exposure relationship was disproportionate at doses <200 mg but largely proportional for Cmax and AUC at clinically relevant doses of 200-600 mg (capsule). Following multiple doses, the accumulation index for AUC[TAU] and Cmin was lower at doses >=200 mg, suggestive of possible auto-induction. ASV exposure increased when administered as a solution (vs. suspension) or with a high-fat meal; the effect was greater for Cmax than AUC, suggesting a saturable first-pass process, the mechanism of which remains to be defined. The apparent complexities of ASV pharmacokinetics will be further explored; nevertheless, data from these studies and antiviral activity in phase 2a/2b studies support further development. Clinical studies are ongoing with ASV in combination with other antivirals. PMID- 27121937 TI - Clinical Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Darexaban, an Oral Direct Factor Xa Inhibitor, in Healthy Elderly Japanese Subjects. AB - The clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban after single and multiple once-daily doses of 60, 120, and 240 mg in healthy elderly Japanese subjects were assessed. Following oral administration, darexaban was rapidly and extensively metabolized to darexaban glucuronide, which is an active glucuronide metabolite. Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose-dependently after both single and repeated doses. Cumulative urinary excretion of darexaban glucuronide up to 24 hours after repeated doses ranged from 28.59% to 36.50%. PT INR, aPTT, and FXa activity were prolonged or decreased dose-dependently after both single and repeated doses of darexaban. The time-profile of pharamcodynamic parameters closely followed the time-concentration profile of darexaban glucuronide. Five adverse events occurred in the present study (4: darexaban [16.7%]; 1: placebo [8.3%]), all of which were mild in severity and required no treatment. PMID- 27121938 TI - Effects of Esomeprazole on the Pharmacokinetics of Lapatinib in Breast Cancer Patients. AB - The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate. PMID- 27121940 TI - Bioavailability and Safety of the Factor Xa Inhibitor Edoxaban and the Effects of Quinidine in Healthy Subjects. AB - BACKGROUND: Edoxaban is an oral, once-daily, direct factor Xa inhibitor under investigation for stroke prevention in patients with atrial fibrillation and for treatment and secondary prevention of venous thromboembolism. This study evaluated edoxaban absolute bioavailability and effects of the P-glycoprotein inhibitor quinidine on edoxaban pharmacokinetics after intravenous edoxaban administration. METHODS: Healthy volunteers received three treatments in a randomized sequence: single oral 60-mg edoxaban dose, single intravenous 30-mg edoxaban dose, and concomitant single intravenous 30-mg edoxaban dose with quinidine 300 mg every 8 hours for 4 days. The primary objective was to determine absolute bioavailability of edoxaban. Secondary objectives included pharmacokinetics and pharmacodynamics of edoxaban after oral or intravenous administration, quinidine effect on intravenous edoxaban pharmacokinetics, and safety. RESULTS: Thirty-six subjects were randomized; five discontinued (three for adverse events [AEs]). Edoxaban oral absolute bioavailability was 61.8%. With concomitant quinidine, total edoxaban exposure increased ~35% and total clearance decreased ~25%. Coagulation parameters increased after edoxaban administration in most subjects, but returned to baseline within 24 hours postdose. No deaths, serious AEs, or bleeding-related AEs occurred. CONCLUSIONS: Absolute bioavailability of edoxaban in healthy volunteers was established (61.8%). Edoxaban, administered orally or intravenously, appeared to be safe and well tolerated. PMID- 27121939 TI - Bioavailability, Pharmacokinetics, and Safety of Belimumab Administered Subcutaneously in Healthy Subjects. AB - This Phase 1 study evaluated the absolute bioavailability, pharmacokinetics (PK), tolerability, and safety of belimumab 200 mg/mL administered subcutaneously (SC) to healthy subjects as a single dose and as multiple doses up to 240 mg. In all, 118 subjects (age range 18-55 years; body weight 51-115 kg) were enrolled. Seventy-eight subjects received a single dose of belimumab 240 mg intravenously, or 2 * 120, 1 * 240, or 1 * 200 mg SC. Forty subjects received 4 weekly injections of belimumab 2 * 120 or 1 * 200 mg SC. Randomization was stratified by weight (<75 kg vs. >=75 kg) and injection site (abdomen vs. thigh). Following single belimumab SC doses, bioavailability was 74-82%, indicating that belimumab SC was well absorbed, and bioavailability was similar among the three SC groups. Following 4 weekly belimumab SC doses, bioavailability was similar to that following single SC administration. Four subjects had persistent positive immune responses; neutralizing antibodies in these subjects were not detected and there was no apparent impact on PK. Belimumab was generally well tolerated after single and multiple SC dosing, and 200 mg SC weekly dosing is expected to provide an exposure similar to 10 mg/kg intravenously every 28 days. PMID- 27121941 TI - Differential Pharmacokinetics of Ganitumab in Patients With Metastatic Pancreatic Cancer Versus Other Advanced Solid Cancers. AB - Ganitumab is an investigational, fully human monoclonal antibody antagonist of the insulin-like growth factor-1 receptor (IGF1R) that has shown trends towards improved progression-free survival and overall survival in a phase 2 pancreatic cancer clinical trial. To characterize ganitumab pharmacokinetics (PK) and identify factors affecting PK, ganitumab serum concentration data from three clinical trials were analyzed. The PK of ganitumab as monotherapy and in combination with gemcitabine in patients with pancreatic or non-pancreatic cancer were assessed with a non-linear mixed-effect model. We found that ganitumab exhibited linear and time-invariant kinetics. A two-compartment model adequately described data over a dose range of 1-20 mg/kg with good predictive capability. Typical clearance and central volume of distribution values were 1.7- and 1.3 fold higher, respectively, in patients with pancreatic cancer than in patients with other advanced solid cancers, resulting in lower ganitumab exposure. Covariate analysis was used to evaluate effects of cancer type, gemcitabine coadministration, clinical study, demographics, and laboratory values on ganitumab PK. Pancreatic cancer type was the most significant covariate on clearance along with weight, albumin, and serum creatinine. Gemcitabine coadministration did not affect ganitumab clearance. Thus, disease state can significantly affect PK and should be considered when selecting the clinically effective dose. PMID- 27121942 TI - GCG100649, A Novel Cyclooxygenase-2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase I/II: Preliminary Dose-Exposure Relationships to Define Clinical Development Strategies. AB - CG100649, proposed as a dual inhibitor of cyclooxygenase (COX)-2 and carbonic anhydrase (CA)-I/-II, is long-lived in plasma and whole blood. The mean +/- SD half-lives were 131 +/- 19 and 127 +/- 33 hours, respectively, after administration of oral single doses of 2 or 8 mg CG100649 to healthy volunteers. The whole blood to plasma concentration ratio (78 +/- 23) for CG100649 is linear over the dosing interval reflecting a biodistribution pattern consistent with other strong CA-inhibitors (e.g., acetazolamide, methazolamide). A one compartment model with first order absorption and elimination described CG100649 concentration-time profiles well. Estimates (%relative SD) between plasma and whole blood were in agreement for the absorption rate constant, 1.54 (58.6) and 1.43 (28.0) hour(-1) , respectively, but considerably different for clearance, 3.29 (10.4) and 0.04 (7.7) L/h/70 kg, and for volume of distribution, 559 (6.7) and 7.6 (2.4) L/70 kg, respectively. The extent to which these unique PK characteristics of CG100649 discriminate it from other COX-2 inhibitors will be the subject of future investigation. PMID- 27121943 TI - Single-Dose Pharmacokinetics of the CCR9 Receptor Antagonist Vercirnon in Healthy US and Japanese Subjects. AB - Two randomized, single-dose, crossover studies were carried out to assess different formulations and doses of the CCR9 receptor antagonist vercirnon in healthy subjects. US study (n = 24): a five-period crossover study in healthy US subjects to assess the bioavailability of four new GlaxoSmithKline formulations compared with a "reference" formulation. Each subject received a single 500 mg dose of each of the five vercirnon formulations in a fed state. Primary pharmacokinetic (PK) endpoints were maximum plasma concentration, (Cmax ), and exposure as assessed by area under the curve (AUC). There was no significant difference in PK parameters and bioavailability between the formulations tested. Japanese study (n = 30): a four-period crossover study in healthy Japanese male subjects to assess PK and dose proportionality following single, ascending, oral doses of 250, 500, and 1,000 mg vercirnon under fasted and fed conditions. Vercirnon Cmax and AUC parameters in the fasted state increased in a less than dose proportional manner and were on average 20% higher in fed subjects compared with fasted subjects. Overall, these results support the premise that vercirnon has similar PK/safety profiles within US and Japanese populations. There was no evidence to preclude the use of the new vercirnon formulation in future studies. PMID- 27121944 TI - Pharmacokinetics of a Single 150-mg Intravenous Infusion of Fosaprepitant: Effects of Concentration and Infusion Time in Healthy Japanese Men. AB - PURPOSE: Fosaprepitant dimeglumine (Proemend(r) for Injection; formerly ONO-7847) is a phosphorylated prodrug that is rapidly converted to aprepitant, an oral selective neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced nausea and vomiting. This Phase 1 study evaluated the pharmacokinetics, safety, and tolerability of fosaprepitant after a single intravenous dose in healthy Japanese men. METHODS: All fosaprepitant- or placebo treated subjects were assessed for the occurrence of adverse events. RESULTS: Ninety subjects were randomized into treatment and placebo groups. The plasma fosaprepitant concentrations generally reached steady state by 15 minutes after the start of infusion. Although the maximum concentration was proportional to the infusion time, no clinically important pharmacokinetic differences were noted in the cohorts examined. Most adverse events observed in this study were associated with infusion site reactions, which tended toward a higher incidence with shorter infusion times. These events were mild in severity. CONCLUSIONS: These findings demonstrate that fosaprepitant at different concentrations and over different infusion times has a pharmacokinetic and safety profile that is comparable to the intravenous dose previously established as efficacious and well tolerated. The dosing flexibility afforded by the single-dose fosaprepitant formulation should lead to greater convenience for patients and health care providers. PMID- 27121945 TI - Structural modeling of the phycobilisome core and its association with the photosystems. AB - The phycobilisome (PBS) is a major light-harvesting complex in cyanobacteria and red algae. To obtain the detailed structure of the hemidiscoidal PBS core composed of allophycocyanin (APC) and minor polypeptide components, we analyzed all nine available 3D structures of APCs from different photosynthetic species and found several variants of crystal packing that potentially correspond to PBS core organization. Combination of face-to-face APC trimer crystal packing with back-to-back APC hexamer packing suggests two variants of the tricylindrical PBS core. To choose one of these structures, a computational model of the PBS core complex and photosystem II (PSII) dimer with minimized distance between the terminal PBS emitters and neighboring antenna chlorophylls was built. In the selected model, the distance between two types of pigments does not exceed 37 A corresponding to the Forster mechanism of energy transfer. We also propose a model of PBS and photosystem I (PSI) monomer interaction showing a possibility of supercomplex formation and direct energy transfer from the PBS to PSI. PMID- 27121946 TI - Tetrandrine suppresses beta-glucan-induced macrophage activation via inhibiting NF-kappaB, ERK and STAT3 signaling pathways. AB - Macrophages are important in inflammation through the production of various proinflammatory mediators. beta-glucan is a polymer of glucose, which is produced by numerous different organisms, including fungi, and acts as a trigger for the induction of inflammatory responses. Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the Chinese herb Radix Stephania tetrandra, has been demonstrated to modulate inflammatory responses. In the present study, it was investigated whether TET affects the inflammatory reaction induced by beta-glucan in murine and human macrophages. It was demonstrated that beta-glucan induced the activation of nuclear factor (NF)-kappaB and markedly increased the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1beta) in macrophages. Treatment with TET resulted in downregulation of phosphorylated NF kappaB p65 and reduction of the production of TNF-alpha and IL-1beta. In addition, the phosphorylation of ERK and STAT3 was decreased by TET in activated macrophages. Furthermore, it was demonstrated that the inhibitory effects of TET on beta-glucan-induced macrophage activation was not due to its cytotoxic action. Conclusively, these results indicate that TET can decrease the inflammatory responses mediated by beta-glucan in macrophages. Thus, TET may serve as an effective tool for the treatment of beta-glucan-associated inflammatory diseases. PMID- 27121949 TI - Bitter dispute leads junior doctors to take unprecedented action. PMID- 27121947 TI - Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. AB - Polycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue. The structure and binding studies suggest a mechanism for the oncogenic inhibition of H3K27M. The structure also reveals how binding of repressive marks, like H3K27me3, to the EED subunit of the complex leads to enhancement of the catalytic efficiency of the SET domain and thus the propagation of this repressive histone modification. PMID- 27121948 TI - Elevations in serum anti-flagellin and anti-LPS Igs are related to growth faltering in young Tanzanian children. AB - BACKGROUND: Antibodies to LPS and flagellin have been described as indirect measures of increased gastrointestinal permeability and may be markers of environmental enteric dysfunction (EED), which is a condition associated with poor child growth. OBJECTIVE: We assessed whether LPS- and flagellin-specific immunoglobulin (Ig) concentrations were associated with poor growth in young Tanzanian children at risk of EED. DESIGN: Blood samples were obtained from 590 children at 6 wk, 6 mo, and 12 mo of age. Serum LPS- and flagellin-specific Ig concentrations (IgA and IgG) were measured with the use of an ELISA. Growth was measured on a monthly basis for 18 mo. RESULTS: Anti-LPS and anti-flagellin IgA and IgG concentrations increased over the first year of life and were higher than concentrations (measured at 9 mo of age) in healthy controls. Children with anti flagellin IgA, anti-LPS IgA, anti-flagellin IgG, and anti-LPS IgG concentrations in the highest quartile at 6 wk of age were 2.02 (95% CI: 1.11, 3.67), 1.84 (95% CI: 1.03, 3.27), 1.94 (95% CI: 1.04, 3.62), and 2.31 (95% CI: 1.25, 4.27) times, respectively, more likely to become underweight (weight-for-age z score <-2) after adjustment for covariates (P-trend < 0.05) than were children with Ig concentrations in the lowest quartile. Children with increased concentrations of anti-flagellin IgA were also more likely to become wasted; however, there was no association between any of the markers and subsequent stunting. CONCLUSION: Serologic measures of increased intestinal permeability to bacterial components are associated with subsequent poor growth and could help identify children who may benefit most from preventive interventions. This trial was registered at clinicaltrials.gov as NCT00421668. PMID- 27121950 TI - CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq. AB - Single-cell transcriptomics requires a method that is sensitive, accurate, and reproducible. Here, we present CEL-Seq2, a modified version of our CEL-Seq method, with threefold higher sensitivity, lower costs, and less hands-on time. We implemented CEL-Seq2 on Fluidigm's C1 system, providing its first single-cell, on-chip barcoding method, and we detected gene expression changes accompanying the progression through the cell cycle in mouse fibroblast cells. We also compare with Smart-Seq to demonstrate CEL-Seq2's increased sensitivity relative to other available methods. Collectively, the improvements make CEL-Seq2 uniquely suited to single-cell RNA-Seq analysis in terms of economics, resolution, and ease of use. PMID- 27121951 TI - Li-Assisted Low-Temperature Phase Transitions in Solution-Processed Indium Oxide Films for High-Performance Thin Film Transistor. AB - Lithium (Li)-assisted indium oxide (In2O3) thin films with ordered structures were prepared on solution-processed zirconium oxide (ZrO2) gate dielectrics by spin-casting and thermally annealing hydrated indium nitrate solutions with different Li nitrate loadings. It was found that the Li-assisted In precursor films on ZrO2 dielectrics could form crystalline structures even at processing temperatures (T) below 200 degrees C. Different In oxidation states were observed in the Li-doped films, and the development of such states was significantly affected by both temperature and the mol% of Li cations, [Li(+)]/([In(3+)] + [Li(+)]), in the precursor solutions. Upon annealing the Li assisted precursor films below 200 degrees C, metastable indium hydroxide and/or indium oxyhydroxide phases were formed. These phases were subsequently transformed into crystalline In2O3 nanostructures after thermal dehydration and oxidation. Finally, an In2O3 film doped with 13.5 mol% Li(+) and annealed at 250 degrees C for 1 h exhibited the highest electron mobility of 60 cm(2) V(-1) s(-1) and an on/off current ratio above 10(8) when utilized in a thin film transistor. PMID- 27121954 TI - Leg defect reconstruction with double hatchet flaps: report of eight cases. PMID- 27121953 TI - High prevalence of herpes simplex virus (HSV)- type 2 co-infection among HIV positive women in Ukraine, but no increased HIV mother-to-child transmission risk. AB - BACKGROUND: Over 3500 HIV-positive women give birth annually in Ukraine, a setting with high prevalence of sexually transmitted infections. Herpes simplex virus Type 2 (HSV-2) co-infection may increase HIV mother-to-child transmission (MTCT) risk. We explored factors associated with HSV-2 seropositivity among HIV positive women in Ukraine, and its impact on HIV MTCT. METHODS: Data on 1513 HIV positive women enrolled in the Ukraine European Collaborative Study from 2007 to 2012 were analysed. Poisson and logistic regression models respectively were fit to investigate factors associated with HSV-2 seropositivity and HIV MTCT. RESULTS: Median maternal age was 27 years (IQR 24-31), 53% (796/1513) had been diagnosed with HIV during their most recent pregnancy and 20% had a history of injecting drugs. Median antenatal CD4 count was 430 cells/mm(3) (IQR 290-580). Ninety-six percent had received antiretroviral therapy antenatally. HSV-2 seroprevalence was 68% (1026/1513). In adjusted analyses, factors associated with HSV-2 antibodies were history of pregnancy termination (APR 1.30 (95% CI 1.18 1.43) for >= 2 vs. 0), having an HIV-positive partner (APR 1.15 (95% CI 1.05 1.26) vs partner's HIV status unknown) and HCV seropositivity (APR 1.23 (95 % CI 1.13-1.35)). The overall HIV MTCT rate was 2.80% (95% CI 1.98-3.84); no increased HIV MTCT risk was detected among HSV-2 seropositive women after adjusting for known risk factors (AOR 1.43 (95% CI 0.54-3.77). CONCLUSION: No increased risk of HIV MTCT was detected among the 68% of HIV-positive women with antibodies to HSV 2, in this population with an overall HIV MTCT rate of 2.8%. Markers of ongoing sexual risk among HIV-positive HSV-2 seronegative women indicate the importance of interventions to prevent primary HSV-2 infection during pregnancy in this high risk group. PMID- 27121955 TI - Risk factors and negative consequences of patient's delay for penile carcinoma. AB - BACKGROUND: Delayed first medical consultation (patient's delay) is quite common in cases of penile carcinoma (PC), but its reasons and impacts remain unclear. We conducted this study to ascertain risk factors resulting in delayed treatment seeking and evaluate its influence on prognosis. METHODS: From 2004 to 2010 at 4 centers, 254 patients were enrolled into this study from 262 consecutive PC cases. Patients' sexual performance was investigated using the International Index of Erectile Function (IIEF)-15 at the sixth-month end after treatment. Data for prognostic analyses was obtained via a 5-year follow-up. RESULTS: A multivariate model ascertained 4 risk factors (single, living in rural areas, heavy drinking alcohol, and aspecific initial symptoms) and 1 protective factor (history of condyloma) significantly associated with patient's delay. Delay >3 months led to significant risks for adverse clinical characteristics, low penis sparing rate, and poor sexual function restoration. Although patient's delay was not found to impact on postoperative relapses and 5-year overall survival (OS), patients with delay >6 months had significantly inferior 2-year OS. CONCLUSIONS: Single, living in rural areas, heavy drinking alcohol, and aspecific initial symptoms are significant risk factors of PC associated with patient's delay. Delay >3 months will lead to significantly inferior clinical consequences. Minimizing patient's delay is the key to avoid amputation and retain superior sexual potency. Improving patient education on initial symptoms of PC is necessary in men of >40 years old. PMID- 27121957 TI - Separation and detection of amino acid metabolites of Escherichia coli in microbial fuel cell with CE. AB - In this work, CE-LIF was employed to investigate the amino acid metabolites produced by Escherichia coli (E. coli) in microbial fuel cell (MFC). Two peptides, l-carnosine and l-alanyl-glycine, together with six amino acids, cystine, alanine, lysine, methionine, tyrosine, arginine were separated and detected in advance by a CE-LIF system coupled with a homemade spontaneous injection device. The injection device was devised to alleviate the effect of electrical discrimination for analytes during sample injection. All analytes could be completely separated within 8 min with detection limits of 20-300 nmol/L. Then this method was applied to analyze the substrate solution containing amino acid metabolites produced by E. coli. l-carnosine, l-alanyl-glycine, and cystine were used as the carbon, nitrogen, and sulfur source for the E. coli culture in the MFC to investigate the amino acid metabolites during metabolism. Two MFCs were used to compare the activity of metabolism of the bacteria. In the sample collected at the running time 200 h of MFC, the amino acid methionine was discovered as the metabolite with the concentrations 23.3 MUg/L. PMID- 27121956 TI - Efficacy of vancomycin-releasing biodegradable poly(lactide-co-glycolide) antibiotics beads for treatment of experimental bone infection due to Staphylococcus aureus. AB - BACKGROUND: Clinical experience and animal studies have suggested that positron emission tomography (PET) using fluorine-18-labeled fluorodeoxyglucose ((18)F FDG) may be promising for imaging of bone infections. In this study, we aimed to establish the accuracy of (18)F-FDG PET scanning for monitoring the response to poly(lactide-co-glycolide) (PLGA) vancomycin beads for treatment of bone infection. METHODS: PLGA was mixed with vancomycin and hot-compress molded to form antibiotic beads. In vitro, elution assays and bacterial inhibition tests were employed to characterize the released antibiotics. In vivo, cylindrical cavities were made in six adult male New Zealand white rabbits, and Staphylococcus aureus or saline was injected into the cavity to create a bone infection. After 2 weeks, the infection was confirmed by bacterial cultures, and the defect was filled with PLGA vancomycin beads. The treatment response was monitored by (18)F-FDG PET. RESULTS: The biodegradable beads released high concentrations of vancomycin (well above the breakpoint sensitivity concentration) for treatment of bone infection. In bacterial inhibition tests, the diameter of the sample inhibition zone ranged from 6.5 to 10 mm, which was equivalent to 12.5-100 % relative activity. (18)F-FDG PET results showed that uncomplicated bone healing was associated with a temporary increase in (18)F-FDG uptake at 2 weeks, with return to near baseline at 6 weeks. In the infected animals, localized infection resulted in intense continuous uptake of (18)F-FDG, which was higher than that in uncomplicated healing bones. Bone infection was confirmed with positive bacterial cultures. In vancomycin-treated animals, data showed rapidly decreasing amounts of (18)F-FDG uptake after treatment. CONCLUSIONS: In vitro and in vivo analyses showed that the use of biodegradable PLGA vancomycin beads successfully eradicated S. aureus infection in damaged bone. PMID- 27121958 TI - Gestational Diabetes Mellitus:current knowledge and unmet needs. AB - Gestational diabetes mellitus (GDM) is a global health concern, not only because its prevalence is high and on the increase, but also because of the potential implications for the health of mothers and their offspring. Unfortunately, there is considerable controversy in the literature surrounding the diagnosis and treatment of GDM, as well as the possible long-term consequences for the offspring. As a result, worldwide there is a lack of uniformly accepted diagnostic criteria and the advice regarding the treatment of GDM, including diet, insulin therapy, and the use of oral blood glucose-lowering agents, is highly variable. In this review we provide an overview of the important issues in the field of GDM, including diagnostic criteria, different treatment regimens available, and the long-term consequences of GDM in the offspring. PMID- 27121959 TI - Polymorphisms in STAT4 are not associated with treatment response and spontaneous clearance of hepatitis C virus in europeans. PMID- 27121961 TI - Anticonvulsant Activity of Enantiomeric N-trans-Cinnamoyl Derivatives of 2 Aminopropan-1-ols and 2-Aminobutan-1-ols. AB - Epilepsy, one of the most frequent neurological disorders, is still insufficiently treated in about 30% of patients. As a consequence, identification of novel anticonvulsant agents is an important issue in medicinal chemistry. In the present article we report synthesis, physicochemical, and pharmacological evaluation of N-trans-cinnamoyl derivatives of R and S-2-aminopropan-1-ol, as well as R and S-2-aminobutan-1-ol. The structures were confirmed by spectroscopy and for derivatives of 2-aminopropan-1-ols the configuration was evaluated by means of crystallography. The investigated compounds were tested in rodent models of seizures: maximal electroshock (MES) and subcutaneous pentetrazol test (scPTZ), and also in a rodent model of epileptogenesis: pilocarpine-induced status prevention. Additionally, derivatives of 2-aminopropan-1-ols were tested in benzodiazepine-resistant electrographic status epilepticus rat model as well as in vitro for inhibition of isoenzymes of cytochrome P450. All of the tested compounds showed promising anticonvulsant activity in MES. For R(-)-(2E)-N-(1 hydroxypropan-2-yl)-3-phenylprop-2-enamide pharmacological parameters were found as follows: ED50 = 76.7 (68.2-81.3) mg/kg (MES, mice i.p., time = 0.5 h), ED50 = 127.2 (102.1-157.9) mg/kg (scPTZ, mice i.p., time = 0.25 h), TD50 = 208.3 (151.4-230.6) mg/kg (rotarod, mice i.p., time = 0.25 h). Evaluation in pilocarpine status prevention proved that all of the reported compounds reduced spontaneous seizure activity and act as antiepileptogenic agents. Both enantiomers of 2-aminopropan-1-ols did not influence cytochrome P450 isoenzymes activity in vitro and are likely not to interact with CYP substrates in vivo. Chirality 28:482-488, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27121960 TI - Serotonin in the solitary tract nucleus shortens the laryngeal chemoreflex in anaesthetized neonatal rats. AB - What is the central question of this study? Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who died of SIDS. Therefore, we tested the hypothesis that serotonin in the nucleus of the solitary tract (NTS) would shorten reflex apnoea. What is the main finding and its importance? Serotonin microinjected into the NTS shortened the apnoea and respiratory inhibition associated with the laryngeal chemoreflex. Moreover, this effect was achieved through a 5-HT3 receptor. This is a new insight that is likely to be relevant to the pathogenesis of SIDS. The laryngeal chemoreflex (LCR), an airway-protective reflex that causes apnoea and bradycardia, has long been suspected as an initiating event in the sudden infant death syndrome. Serotonin (5-HT) and 5-HT receptors may be deficient in the brainstems of babies who die of sudden infant death syndrome, and 5-HT seems to be important in terminating apnoeas directly or in causing arousals or as part of the process of autoresuscitation. We hypothesized that 5-HT in the brainstem would limit the duration of the LCR. We studied anaesthetized rat pups between 7 and 21 days of age and made microinjections into the cisterna magna or into the nucleus of the solitary tract (NTS). Focal, bilateral microinjections of 5-HT into the caudal NTS significantly shortened the LCR. The 5-HT1a receptor antagonist, WAY 100635, did not affect the LCR consistently, nor did a 5-HT2 receptor antagonist, ketanserin, alter the duration of the LCR. The 5-HT3 specific agonist, 1-(3-chlorophenyl)-biguanide, microinjected bilaterally into the caudal NTS significantly shortened the LCR. Thus, endogenous 5-HT released within the NTS may curtail the respiratory depression that is part of the LCR, and serotonergic shortening of the LCR may be attributed to activation of 5-HT3 receptors within the NTS. 5-HT3 receptors are expressed presynaptically on C fibre afferents of the superior laryngeal nerve, and serotonergic shortening of the LCR may be mediated presynaptically by enhanced activation of inhibitory interneurons within the NTS. PMID- 27121962 TI - Associations Between Arthritis and Change in Physical Function in U.S. Retirees. AB - BACKGROUND: The aims of this study were to determine among retirees: the associations of arthritis with limitations in physical functions, and whether these associations changed differently with age for those with arthritis versus without arthritis. METHODS: We identified retirees from the Health and Retirement Study, a nationally representative longitudinal panel study of U.S. adults >=51 years old. We calculated incidence density ratios (IDRs) using Poisson regression modeling with generalized estimating equations to estimate the associations between arthritis and limitations in four physical function measures (large muscle tasks, mobility, activities of daily living, and instrumental activities of daily living) adjusting for age, sex, race/ethnicity, marital status, education, total household income, depression, obesity, smoking, chronic conditions, physical activity, and cohort status. We examined interaction effects between arthritis and age to determine if the rate of change in physical function differed by arthritis status across age. RESULTS: Over 8 years (2004-2012), significantly more retirees with arthritis had limitations with large muscle tasks (IDR 2.1: 95% confidence interval 1.6, 2.8), mobility (IDR 1.6: 1.2, 2.2), activities of daily living (IDR 2.2: 1.0, 4.7), and instrumental activities of daily living (IDR 3.7: 1.9, 7.4) than retirees without arthritis. Retirees with arthritis did not develop limitations in mobility, activities of daily living, and instrumental activities of daily living at a different rate as they aged compared to those without arthritis. CONCLUSIONS: Arthritis was associated with a greater prevalence of physical function limitations. Preventing limitations caused by arthritis is a key strategy to prevent disability in retirees. PMID- 27121963 TI - Construction and analysis of protein-protein interaction networks based on proteomics data of prostate cancer. AB - Currently, using human prostate cancer (PCa) tissue samples to conduct proteomics research has generated a large amount of data; however, only a very small amount has been thoroughly investigated. In this study, we manually carried out the mining of the full text of proteomics literature that involved comparisons between PCa and normal or benign tissue and identified 41 differentially expressed proteins verified or reported more than 2 times from different research studies. We regarded these proteins as seed proteins to construct a protein protein interaction (PPI) network. The extended network included one giant network, which consisted of 1,264 nodes connected via 1,744 edges, and 3 small separate components. The backbone network was then constructed, which was derived from key nodes and the subnetwork consisting of the shortest path between seed proteins. Topological analyses of these networks were conducted to identify proteins essential for the genesis of PCa. Solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4) had the highest closeness centrality located in the center of each network, and the highest betweenness centrality and largest degree in the backbone network. Tubulin, beta 2C (TUBB2C) had the largest degree in the giant network and subnetwork. In addition, using module analysis of the whole PPI network, we obtained a densely connected region. Functional annotation indicated that the Ras protein signal transduction biological process, mitogen-activated protein kinase (MAPK), neurotrophin and the gonadotropin releasing hormone (GnRH) signaling pathway may play an important role in the genesis and development of PCa. Further investigation of the SLC2A4, TUBB2C proteins, and these biological processes and pathways may therefore provide a potential target for the diagnosis and treatment of PCa. PMID- 27121964 TI - Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. AB - BACKGROUND: Bacteremia, or bloodstream infection (BSI), is a leading cause of death among patients with certain types of cancer. A previous study reported that intestinal domination, defined as occupation of at least 30 % of the microbiota by a single bacterial taxon, is associated with BSI in patients undergoing allo HSCT. However, the impact of the intestinal microbiome before treatment initiation on the risk of subsequent BSI remains unclear. Our objective was to characterize the fecal microbiome collected before treatment to identify microbes that predict the risk of BSI. METHODS: We sampled 28 patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic stem cell transplantation (HSCT) prior to administration of chemotherapy and characterized 16S ribosomal RNA genes using high-throughput DNA sequencing. We quantified bacterial taxa and used techniques from machine learning to identify microbial biomarkers that predicted subsequent BSI. RESULTS: We found that patients who developed subsequent BSI exhibited decreased overall diversity and decreased abundance of taxa including Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella. Using machine-learning methods, we developed a BSI risk index capable of predicting BSI incidence with a sensitivity of 90 % at a specificity of 90 % based only on the pretreatment fecal microbiome. CONCLUSIONS: These results suggest that the gut microbiota can identify high-risk patients before HSCT and that manipulation of the gut microbiota for prevention of BSI in high-risk patients may be a useful direction for future research. This approach may inspire the development of similar microbiome-based diagnostic and prognostic models in other diseases. PMID- 27121965 TI - ITD assembler: an algorithm for internal tandem duplication discovery from short read sequencing data. AB - BACKGROUND: Detection of tandem duplication within coding exons, referred to as internal tandem duplication (ITD), remains challenging due to inefficiencies in alignment of ITD-containing reads to the reference genome. There is a critical need to develop efficient methods to recover these important mutational events. RESULTS: In this paper we introduce ITD Assembler, a novel approach that rapidly evaluates all unmapped and partially mapped reads from whole exome NGS data using a De Bruijn graphs approach to select reads that harbor cycles of appropriate length, followed by assembly using overlap-layout-consensus. We tested ITD Assembler on The Cancer Genome Atlas AML dataset as a truth set. ITD Assembler identified the highest percentage of reported FLT3-ITDs when compared to other ITD detection algorithms, and discovered additional ITDs in FLT3, KIT, CEBPA, WT1 and other genes. Evidence of polymorphic ITDs in 54 genes were also found. Novel ITDs were validated by analyzing the corresponding RNA sequencing data. CONCLUSIONS: ITD Assembler is a very sensitive tool which can detect partial, large and complex tandem duplications. This study highlights the need to more effectively look for ITD's in other cancers and Mendelian diseases. PMID- 27121966 TI - Terrace Aware Data Structure for Phylogenomic Inference from Supermatrices. AB - In phylogenomics the analysis of concatenated gene alignments, the so-called supermatrix, is commonly accompanied by the assumption of partition models. Under such models each gene, or more generally partition, is allowed to evolve under its own evolutionary model. Although partition models provide a more comprehensive analysis of supermatrices, missing data may hamper the tree search algorithms due to the existence of phylogenetic (partial) terraces. Here, we introduce the phylogenetic terrace aware (PTA) data structure for the efficient analysis under partition models. In the presence of missing data PTA exploits (partial) terraces and induced partition trees to save computation time. We show that an implementation of PTA in IQ-TREE leads to a substantial speedup of up to 4.5 and 8 times compared with the standard IQ-TREE and RAxML implementations, respectively. PTA is generally applicable to all types of partition models and common topological rearrangements thus can be employed by all phylogenomic inference software. PMID- 27121967 TI - Retraction Note: Observational study: daily treatment with a new compound "tradamixina" plus serenoa repens for two months improved the lower urinary tract symptoms. PMID- 27121968 TI - 18F-FDG-PET and CT fusion imaging in a differential diagnosis of residual intracardiac masses after removal of implantable cardioverter defibrillator due to endocarditis. PMID- 27121969 TI - Integrating care for frequent users of emergency departments: implementation evaluation of a brief multi-organizational intensive case management intervention. AB - BACKGROUND: Addressing the needs of frequent users of emergency departments (EDs) is a health system priority in many jurisdictions. This study describes stakeholder perspectives on the implementation of a multi-organizational brief intervention designed to support integration and continuity of care for frequent ED users with mental health and addictions problems, focusing on perceived barriers and facilitators to early implementation in a large urban centre. METHODS: Coordinating Access to Care from Hospital Emergency Departments (CATCH ED) is a brief case management intervention bridging hospital, primary and community care for frequent ED users experiencing mental illness and addictions. To examine barriers and facilitators to early implementation of this multi organizational intervention, between July and October 2012, 47 stakeholders, including direct service providers, managers and administrators participated in 32 semi-structured qualitative interviews and one focus group exploring their experience with the intervention and factors that helped or hindered successful early implementation. Qualitative data were analyzed using thematic analysis. RESULTS: Stakeholders valued the intervention and its potential to support continuity of care for this population. Service delivery system factors, including organizational capacity and a history of collaborative relationships across the healthcare continuum, and support system factors, such as training and supervision, emerged as key facilitators of program implementation. Operational challenges included early low program referral rates, management of a multi organizational initiative, variable adherence to the model among participating organizations, and scant access to specialty psychiatric resources. Factors contributing to these challenges included lack of dedicated staff in the ED and limited local system capacity to support this population, and insufficient training and technical assistance available to participating organizations. CONCLUSIONS: A multi-organizational brief intervention is an acceptable model to support integration of hospital, primary and community care for frequent ED users. The study highlights the importance of early implementation evaluation to identify potential solutions to implementation barriers that may be applicable to many jurisdictions. PMID- 27121970 TI - Developmental delay in a Streptomyces venezuelae glgE null mutant is associated with the accumulation of alpha-maltose 1-phosphate. AB - The GlgE pathway is thought to be responsible for the conversion of trehalose into a glycogen-like alpha-glucan polymer in bacteria. Trehalose is first converted to maltose, which is phosphorylated by maltose kinase Pep2 to give alpha-maltose 1-phosphate. This is the donor substrate of the maltosyl transferase GlgE that is known to extend alpha-1,4-linked maltooligosaccharides, which are thought to be branched with alpha-1,6 linkages. The genome of Streptomyces venezuelae contains all the genes coding for the GlgE pathway enzymes but none of those of related pathways, including glgC and glgA of the glycogen pathway. This provides an opportunity to study the GlgE pathway in isolation. The genes of the GlgE pathway were upregulated at the onset of sporulation, consistent with the known timing of alpha-glucan deposition. A constructed DeltaglgE null mutant strain was viable but showed a delayed developmental phenotype when grown on maltose, giving less cell mass and delayed sporulation. Pre-spore cells and spores of the mutant were frequently double the length of those of the wild-type, implying impaired cross-wall formation, and spores showed reduced tolerance to stress. The mutant accumulated alpha-maltose 1 phosphate and maltose but no alpha-glucan. Therefore, the GlgE pathway is necessary and sufficient for polymer biosynthesis. Growth of the DeltaglgE mutant on galactose and that of a Deltapep2 mutant on maltose were analysed. In both cases, neither accumulation of alpha-maltose 1-phosphate/alpha-glucan nor a developmental delay was observed. Thus, high levels of alpha-maltose 1-phosphate are responsible for the developmental phenotype of the DeltaglgE mutant, rather than the lack of alpha-glucan. PMID- 27121971 TI - Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy. AB - Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients. PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology. PMID- 27121972 TI - Fructose-rich diet induces gender-specific changes in expression of the renin angiotensin system in rat heart and upregulates the ACE/AT1R axis in the male rat aorta. AB - INTRODUCTION: The cardiovascular renin-angiotensin system (RAS) could be affected by gender and dietary regime. We hypothesized that male rats will be more susceptible to activation of RAS in the heart and aorta, as a response to a fructose-rich diet (FRD). MATERIALS AND METHODS: Both male and female Wistar rats were given a 10% (w/v) fructose solution for 9 weeks. We measured the biochemical parameters, blood pressure (BP) and heart rate. We used Western blot and real time polymerase chain reaction (PCR) to quantify protein and gene expression. RESULTS: In the male rats, the FRD elevated BP and expression of cardiac angiotensin-converting enzyme (ACE), while the expression of angiotensin converting enzyme 2 (ACE2) and angiotensin II Type 2 receptor (AT2R) were significantly decreased. In female rats, there were no changes in cardiac RAS expression due to FRD. Furthermore, the ACE/AT1R axis was overexpressed in the FRD male rats' aortae, while only AT1R was upregulated in the FRD female rats' aortae. ACE2 expression remained unchanged in the aortae of both genders receiving the FRD. CONCLUSIONS: The FRD induced gender-specific changes in the expression of the RAS in the heart and aortae of male rats. Further investigations are required in order to get a comprehensive understanding of the underlying mechanisms of gender-specific fructose-induced cardiovascular pathologies. PMID- 27121973 TI - Roles of Copper in Hepatocarcinogenesis via the Activation of Hypoxia-Inducible Factor-1alpha. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is involved in the pathogenesis of hepatocellular carcinoma (HCC). However, the roles of trace elements in the activation of HIF-1alpha during hepatocarcinogenesis have been unclear. We investigated whether copper (Cu) and zinc (Zn) participated in the activation of HIF-1alpha in the process of hepatocarcinogenesis or not. Nine patients with chronic hepatitis (CH), five with liver cirrhosis (LC), 12 with HCC, and nine normal healthy controls were enrolled in this study. Their serum HIF-1alpha, Cu, and Zn levels were determined in the enrolled patients. Hepatic HIF-1alpha expression was evaluated, using an immunohistochemical procedure. The HCC patients had significantly higher serum HIF-1alpha levels than the CH patients (6.47 +/- 1.57 vs. 5.09 +/- 1.22 ng/ml, p = 0.0344). The serum Cu level in the HCC patients was also significantly higher than those in the CH and LC patients (137 +/- 24 vs. 107 +/- 15 MUg/dl, 114 +/- 24 MUg/dl). Interestingly, a positive correlation was observed between serum HIF-1alpha and Cu levels in the enrolled patients (r = 0.425, p = 0.0137). In contrast, no significant differences in serum Zn levels were present between the HCC patients and the CH or LC patients. The serum HIF-1alpha was not positively correlated with the serum Zn level in the enrolled patients, either. Immunohistochemical analysis revealed that two of the five HCC patients had HIF-1alpha expression in the tumor tissues, whereas none of CH and LC had hepatic HIF-1alpha expression in the liver tissues. These data suggest that the activation of HIF-1alpha derived from a Cu accumulation in the liver may cause hepatocarcinogenesis. PMID- 27121974 TI - Thiol Oxidation by Diamide Leads to Dopaminergic Degeneration and Parkinsonism Phenotype in Mice: A Model for Parkinson's Disease. AB - AIMS: This study investigates the role of thiol homeostasis disruption in Parkinson's disease (PD) pathogenesis using a novel animal model. A single unilateral administration of the thiol oxidant, diamide (1.45 MUmol) into substantia nigra (SN) of mice leads to locomotor deficits and degeneration of dopaminergic (DA) neurons in SN pars compacta (SNpc). RESULTS: Diamide-injected mice showed hemiparkinsonian behavior, measured as spontaneous contralateral body rotations, poor grip strength, and impaired locomotion on a rotarod. We observed a significant loss of DA neurons in ipsilateral but not contralateral SNpc and their striatal fibers. This was accompanied by increased Fluoro-Jade C-positive cells and a loss of NeuN-positive neurons, indicative of neurodegeneration. Importantly, diamide injection led to alpha-synuclein aggregation in ipsilateral SNpc, a hallmark of PD pathology not often seen in animal models of PD. On investigating putative mechanism(s) involved, we observed a loss of glutathione, which is essential for maintaining protein thiol homeostasis (PTH). Concomitantly, the redox-sensitive ASK1-p38 mitogen-activated protein kinase (MAPK) death signaling pathway was activated in the ipsilateral but not contralateral ventral midbrain through dissociation of ASK1-Trx1 complex. In Neuro-2a cells, diamide activated ASK1-p38 cascade through Trx1 oxidation, leading to cell death, which was abolished by ASK1 knockdown. INNOVATION: Since diamide selectively disrupts PTH, DA neurons appear to be vulnerable to such perturbations and even a single insult with a thiol oxidant can result in long lasting degeneration. CONCLUSION: Identification of the role of PTH dysregulation in neurodegeneration, especially in early PD, not only facilitates an understanding of novel regulatory features of molecular signaling cascades but also may aid in developing disease-modifying strategies for PD. Antioxid. Redox Signal. 25, 252-267. PMID- 27121975 TI - Tuning Soft Ionization Strength for Organic Mass Spectrometry. AB - Besides the progress of new mass spectrometer technologies, the investigation and development of soft ionization sources play an important key role for analytical sciences. Since the dielectric barrier discharge ionization (DBDI) is identified as two temporally separated events, a selective prevention of the coincident plasma can lead to improved ionization strength. Although a DBDI is known as a soft ionization source, a modulation of the high-voltage amplitude and duty cycle can lead to optimized ionization strength. This is an advantage to cover different types of analytes. PMID- 27121976 TI - Cuticular Defects in Oryza sativa ATP-binding Cassette Transporter G31 Mutant Plants Cause Dwarfism, Elevated Defense Responses and Pathogen Resistance. AB - The cuticle covers the surface of the polysaccharide cell wall of leaf epidermal cells and forms an essential diffusion barrier between plant and environment. Homologs of the ATP-binding cassette (ABC) transporter AtABCG32/HvABCG31 clade are necessary for the formation of a functional cuticle in both monocots and dicots. Here we characterize the osabcg31 knockout mutant and hairpin RNA interference (RNAi)-down-regulated OsABCG31 plant lines having reduced plant growth and a permeable cuticle. The reduced content of cutin in leaves and structural alterations in the cuticle and at the cuticle-cell wall interface in plants compromised in OsABCG31 expression explain the cuticle permeability. Effects of modifications of the cuticle on plant-microbe interactions were evaluated. The cuticular alterations in OsABCG31-compromised plants did not cause deficiencies in germination of the spores or the formation of appressoria of Magnaporthe oryzae on the leaf surface, but a strong reduction of infection structures inside the plant. Genes involved in pathogen resistance were constitutively up-regulated in OsABCG31-compromised plants, thus being a possible cause of the resistance to M. oryzae and the dwarf growth phenotype. The findings show that in rice an abnormal cuticle formation may affect the signaling of plant growth and defense. PMID- 27121977 TI - A pilot study of a nurse-delivered cognitive behavioral therapy intervention (Ziphamandla) for adherence and depression in HIV in South Africa. AB - Depression is prevalent among people living with HIV in South Africa and interferes with adherence to antiretroviral therapy. This study evaluated a nurse delivered, cognitive behavioral therapy intervention for adherence and depression among antiretroviral therapy users with depression in South Africa ( n = 14). Primary outcomes were depression, antiretroviral therapy adherence, feasibility, and acceptability. Findings support robust improvements in mood through a 3-month follow up. Antiretroviral therapy adherence was maintained during the intervention period. Participant retention supports acceptability; however, modest provider fidelity despite intensive supervision warrants additional attention to feasibility. Future effectiveness research is needed to evaluate this nurse-delivered cognitive behavioral therapy intervention for adherence and depression in this context. PMID- 27121978 TI - Brief report: Self-compassion, physical health and the mediating role of health promoting behaviours. AB - To test the hypothesis that self-compassion predicts better physical health and that this is partially mediated through health-promoting behaviours, 147 adults completed self-report measures of self-compassion, health-promoting behaviours and physical health. Self-compassion and health-promoting behaviours were negatively associated with physical symptom scores. Self-compassion was positively associated with health-promoting behaviours. A bootstrapped mediation model confirmed a significant direct effect of self-compassion on physical health through health-promoting behaviours ( R2 = 0.13, b = -8.98, p = 0.015), which was partially mediated through health-promoting behaviours ( R2 = 0.06, b = -3.16, 95 per cent confidence interval [-6.78, -0.86]). Findings underscore the potential health-promoting benefits of self-compassion. PMID- 27121979 TI - Factors associated with nutritional outcomes in the mother-child dyad: a population-based cross-sectional study. AB - OBJECTIVE: To estimate factors associated with double burden of nutritional outcomes in the mother-child dyad at the household level (child stunting and/or maternal overweight). DESIGN: Cross-sectional study using the Brazilian Demographic and Health Survey. Nutritional outcomes were: mother with normal weight and child with normal height; overweight mother and child with normal height; mother with normal weight and short-stature child; and overweight mother and child with short stature (double burden). The child was classified as short when height-for-age Z-score was <-2 and the mother as overweight when BMI was >=25.00 kg/m2. Socio-economic status, environment, social vulnerability, maternal characteristics and the child's food intake were the exposure factors. The hierarchical approach for multinomial logistic regression modelling was used to assess the associations. SETTING: National Demographic and Health Survey of Children and Women conducted in Brazil, 2006-2007. SUBJECTS: Mother-child dyads (n 3676). RESULTS: After adjustments, lower maternal educational level (OR=3.53; 95 % CI 1.33, 9.33) and inadequate household (non-masonry house; OR=2.54; 95 % CI 1.39, 4.66) were associated with the double burden of malnutrition. Mother's short stature (OR=3.41; 95 % CI 1.76, 6.61), child's vegetable intake on less than or equal to 4 d/week (OR=2.21; 95 % CI 1.03, 4.75) and inadequate household (non-masonry house; OR=2.29; 95 % CI 1.36, 3.87) were associated with child's short stature. The lack of breast-feeding (OR=2.00; 95 % CI 1.07, 3.72) was associated with maternal overweight. CONCLUSIONS: The present findings contribute to establishing strategies promoting health and healthy diets, by considering the growth deficit and overweight/obesity concomitantly. PMID- 27121980 TI - Pharmacokinetic and pharmacodynamic evaluations of a 10 mg/kg enrofloxacin intramuscular administration in bearded dragons (Pogona vitticeps): a preliminary assessment. AB - Enrofloxacin (E) is commonly used in veterinary medicine. It is necessary to perform pharmacokinetic/dynamic studies to minimize the selection of resistant mutants of bacteria and extend the efficacy of antimicrobial agents. Eight healthy adult Pogona vitticeps were assigned into two groups of equal size and treated with a single intramuscular injection of E at 10 mg/kg. Blood samples were withdrawn at different scheduled times for each group, and rectal swabs were collected. E and ciprofloxacin (active metabolite) blood concentrations were quantified by an HPLC validated method, while the in vitro antimicrobial susceptibility was evaluated by the Kirby-Bauer disc diffusion susceptibility test. The pharmacokinetic profiles of E gave similar pharmacokinetic parameters irrespective of the collection time schedule. Bacteria isolation showed the presence of both E. coli, Salmonella enterica subspecies enterica and subspecies 3a, Proteus spp., and Pseudomonas spp. The majority of isolated colonies were sensitive to E, but the treatment did not reduce the number of bacteria in faeces. Results suggest that E is able to reach blood concentrations high enough to kill susceptible bacteria (MIC < 0.9 MUg/mL), but at the same time does not significantly affect intestinal bacteria. PMID- 27121981 TI - GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway. AB - Hepatic steatosis is strongly linked to insulin resistance and type 2 diabetes. GPR40 is a G protein-coupled receptor mediating free fatty acid-induced insulin secretion and thus plays a beneficial role in the improvement of diabetes. However, the impact of GPR40 agonist on hepatic steatosis still remains to be elucidated. In the present study, we found that activation of GPR40 by its agonist GW9508 attenuated Liver X receptor (LXR)-induced hepatic lipid accumulation. Activation of LXR in the livers of C57BL/6 mice fed a high cholesterol diet and in HepG2 cells stimulated by chemical agonist caused increased expression of its target lipogenic genes and subsequent lipid accumulation. All these effects of LXR were dramatically downregulated after GW9508 supplementation. Moreover, GPR40 activation was accompanied by upregulation of AMPK pathway, whereas the inhibitive effect of GPR40 on the lipogenic gene expression was largely abrogated by AMPK knockdown. Taken together, our results demonstrated that GW9508 exerts a beneficial effect to ameliorate LXR-induced hepatic steatosis through regulation of AMPK signaling pathway. PMID- 27121982 TI - Coupling carbon dioxide reduction with water oxidation in nanoscale photocatalytic assemblies. AB - The reduction of carbon dioxide by water with sunlight in an artificial system offers an opportunity for utilizing non-arable land for generating renewable transportation fuels to replace fossil resources. Because of the very large scale required for the impact on fuel consumption, the scalability of artificial photosystems is of key importance. Closing the photosynthetic cycle of carbon dioxide reduction and water oxidation on the nanoscale addresses major barriers for scalability as well as high efficiency, such as resistance losses inherent to ion transport over macroscale distances, loss of charge and other efficiency degrading processes, or excessive need for the balance of system components, to mention a few. For the conversion of carbon dioxide to six-electron or even more highly reduced liquid fuel products, introduction of a proton conducting, gas impermeable separation membrane is critical. This article reviews recent progress in the development of light absorber-catalyst assemblies for the reduction and oxidation half reactions with focus on well defined polynuclear structures, and on novel approaches for optimizing electron transfer among the molecular or nanoparticulate components. Studies by time-resolved optical and infrared spectroscopy for the understanding of charge transfer processes between the chromophore and the catalyst, and of the mechanism of water oxidation at metal oxide nanocatalysts through direct observation of surface reaction intermediates are discussed. All-inorganic polynuclear units for reducing carbon dioxide by water at the nanoscale are introduced, and progress towards core-shell nanotube assemblies for completing the photosynthetic cycle under membrane separation is described. PMID- 27121983 TI - A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding. AB - Cardiac surgery with cardiopulmonary bypass (CPB) is associated with blood loss and post-surgery thrombotic complications. The process of thrombin generation is disturbed during surgery with CPB because of haemodilution, coagulation factor consumption and heparin administration. We aimed to investigate the changes in thrombin generation during cardiac surgery and its underlying pro- and anticoagulant processes, and to explore the clinical consequences of these changes using in silico experimentation. Plasma was obtained from 29 patients undergoing surgery with CPB before heparinisation, after heparinisation, after haemodilution, and after protamine administration. Thrombin generation was measured and prothrombin conversion and thrombin inactivation were quantified. In silico experimentation was used to investigate the reaction of patients to the administration of procoagulant factors and/or anticoagulant factors. Surgery with CPB causes significant coagulation factor consumption and a reduction of thrombin generation. The total amount of prothrombin converted and the rate of prothrombin conversion decreased during surgery. As the surgery progressed, the relative contribution of alpha2-macroglobulin-dependent thrombin inhibition increased, at the expense of antithrombin-dependent inhibition. In silico restoration of post surgical prothrombin conversion to pre-surgical levels increased thrombin generation excessively, whereas co-administration of antithrombin resulted in the normalisation of post-surgical thrombin generation. Thrombin generation is reduced during surgery with cardiopulmonary bypass because of a balance shift between prothrombin conversion and thrombin inactivation. According to in silico predictions of thrombin generation, this new balance increases the risk of thrombotic complications with prothrombin complex concentrate administration, but not if antithrombin is co-administered. PMID- 27121984 TI - Programmable bioelectronics in a stimuli-encoded 3D graphene interface. AB - The ability to program and mimic the dynamic microenvironment of living organisms is a crucial step towards the engineering of advanced bioelectronics. Here, we report for the first time a design for programmable bioelectronics, with 'built in' switchable and tunable bio-catalytic performance that responds simultaneously to appropriate stimuli. The designed bio-electrodes comprise light and temperature responsive compartments, which allow the building of Boolean logic gates (i.e."OR" and "AND") based on enzymatic communications to deliver logic operations. PMID- 27121985 TI - Funding for change: New Zealand pharmacists' views on, and experiences of, the community pharmacy services agreement. AB - OBJECTIVE: To explore pharmacist's views on the shift in ethos, funding and service delivery model introduced through the New Zealand's Community Pharmacy Services Agreement (CPSA). METHODS: A purposive sampling approach drew pharmacists from a matrix who were then contacted via telephone and invited to be interviewed. Semistructured interviews were conducted face-to-face with community pharmacists (n = 17) across urban and rural New Zealand. An interview schedule exploring 12 subject areas was used to facilitate discussion and determine pharmacist's views and understanding of the CPSA. The interviews were recorded and transcribed verbatim and a general inductive approach was taken to identifying emergent themes. KEY FINDINGS: Key themes that emerged were: pharmacists supported the philosophy behind the CPSA, pharmacists understanding of the CPSA, implementing CPSA-related services, perceived impact on patient outcomes and future sustainability of the CPSA. Overall, pharmacists supported the alignment of funding with patient-centred services, but pharmacy owners reported difficulty understanding the funding model, resulting in uncertainty over income. Several pharmacists believed the quality of care offered had not changed, while others found their attitudes towards care had evolved. All pharmacists communicated an increase in their workload and many perceived the sustainability of the CPSA to be linked to its ability to financially sustain community pharmacies. CONCLUSIONS: The majority of pharmacists believed in the philosophy of the CPSA, but expressed concerns over funding, workload and benefits for patients. Future research is required to determine generalisability of these findings, investigate patient perspectives and assess the effect of the CPSA on patient outcomes. PMID- 27121986 TI - Development of 3-dimensional time-dependent density functional theory and its application to gas diffusion in nanoporous materials. AB - I developed a novel time-dependent density functional theory (TDDFT) and applied it to complicated 3-dimensional systems for the first time. Superior to conventional TDDFT, the diffusion coefficient is modeled as a function of density profile, which is self-determined by the entropy scaling rule instead using an input parameter. The theory was employed to mimic gas diffusion in a nanoporous material. The TDDFT prediction on the transport diffusivity was reasonable compared to simulations. Moreover, the time-dependent density profiles gave an insight into the microscopic mechanism of the diffusion process. PMID- 27121987 TI - Cerebrovascular disorders caused by hyperfibrinogenaemia. AB - KEY POINTS: Hyperfibrinogenaemia (HFg) results in vascular remodelling, and fibrinogen (Fg) and amyloid beta (Abeta) complex formation is a hallmark of Alzheimer's disease. However, the interconnection of these effects, their mechanisms and implications in cerebrovascular diseases are not known. Using a mouse model of HFg, we showed that at an elevated blood level, Fg increases cerebrovascular permeability via mainly caveolar protein transcytosis. This enhances deposition of Fg in subendothelial matrix and interstitium making the immobilized Fg a readily accessible substrate for binding Abeta and cellular prion protein (PrPC ), the protein that is thought to have a greater effect on memory than Abeta. We showed that enhanced formation of Fg-Abeta and Fg-PrPC complexes are associated with reduction in short-term memory. The present study delineates a new mechanistic pathway for vasculo-neuronal dysfunctions found in inflammatory cardiovascular and cerebrovascular diseases associated with an elevated blood level of Fg. ABSTRACT: Many cardiovascular diseases are associated with inflammation and as such are accompanied by an increased blood level of fibrinogen (Fg). Besides its well-known prothrombotic effects Fg seems to have other destructive roles in developing microvascular dysfunction that include changes in vascular reactivity and permeability. Increased permeability of brain microvessels has the most profound effects as it may lead to cerebrovascular remodelling and result in memory reduction. The goal of the present study was to define mechanisms of cerebrovascular permeability and associated reduction in memory induced by elevated blood content of Fg. Genetically modified, transgenic hyperfibrinogenic (HFg) mice were used to study cerebrovascular transcellular and paracellular permeability in vivo. The extent of caveolar formation and the role of caveolin-1 signalling were evaluated by immunohistochemistry (IHC) and Western blot (WB) analysis in brain samples from experimental animals. Formation of Fg complexes with amyloid beta (Abeta) and with cellular prion protein (PrPC ) were also assessed with IHC and WB analysis. Short-term memory of mice was assessed by novel object recognition and Y-maze tests. Caveolar protein transcytosis was found to have a prevailing role in overall increased cerebrovascular permeability in HFg mice. These results were associated with enhanced formation of caveolae. Increased formation of Fg-PrPC and Fg-Abeta complexes were correlated with reduction in short-term memory in HFg mice. Using the model of hyperfibrinogenaemia, the present study shows a novel mechanistic pathway of inflammation-induced and Fg-mediated reduction in short-term memory. PMID- 27121988 TI - Barrels XXVIII take the Windy City by storm. AB - The 28th annual Barrels meeting was held prior to the Society for Neuroscience meeting in October 2015 at the Northwestern University School of Law in Chicago, Illinois. The meeting brought together researchers focused on the rodent sensorimotor system. The meeting focused on modern techniques to decipher cortical circuits, social interactions among rodents, and decision-making. The meeting allowed investigators to share their work via short talks, poster presentations, and a data blitz. PMID- 27121989 TI - Consequences of point mutations in melanoma-associated antigen 4 (MAGE-A4) protein: Insights from structural and biophysical studies. AB - The Melanoma-Associated Antigen A4 (MAGE-A4) protein is a target for cancer therapy. The function of this protein is not well understood. We report the first comprehensive study on key cancer-associated MAGE-A4 mutations and provide analysis on the consequences of these mutations on the structure, folding and stability of the protein. Based on Nuclear Magnetic Resonance and Circular Dichroism, these mutations had no significant effects on the structure and the folding of the protein. Some mutations affected the thermal stability of the protein remarkably. Native mass spectrometry of wild-type MAGE-A4 showed a broad charge state distribution suggestive of a structurally dynamic protein. Significant intensity was found in relatively low charge states, indicative of a predominantly globular form and some population in more extended states. The latter is supported by Ion Mobility measurements. The MAGE-A4 mutants exhibited similar features. These novel molecular insights shed further light on better understanding of these proteins, which are implicated in a wide range of human cancers. PMID- 27121990 TI - Engineering analysis of the high-density heterotrophic cultivation of mung bean sprouts. AB - This study investigated the heterotrophic growth behavior of mung beans cultivated in an individual bed under water supply. The fresh weight of mung beans in the bed was estimated, and changes in temperature, and oxygen and carbon dioxide concentrations were recorded during the cultivation period. The specific growth rate, oxygen uptake rate, and carbon dioxide evolution rate, based on the fresh weight in the bed, were calculated. Growth under heterotrophic cultivation can be classified into the following three stages. Reductions in specific oxygen uptake rate, specific carbon dioxide evolution rate, and specific energy production rate corresponded to that of specific growth rate. Indicators of biological activity related to oxygen and carbon dioxide were evaluated quantitatively for beds under high-density heterotrophic cultivation. Moreover, the results obtained from this study successfully demonstrate that there is a relationship between the growth of mung beans and indicators of biological activity. PMID- 27121991 TI - Therapeutic uses for Angiotensin-(1-7). AB - INTRODUCTION: Angiotensin-(1-7) is a key component of the Renin-Angiotensin System, which can counter-regulate several deleterious effects caused by angiotensin II. Due to the potential for therapeutic use, several of its actions are specifically described in patents. AREAS COVERED: In this review, the authors describe a plethora of therapeutic uses for Angiotensin-(1-7), claimed and supported by experimental evidence in patent documents and applications. EXPERT OPINION: The clinical potential of Angiotensin-(1-7) as a therapeutic agent to treat several pathologies is evidenced by the variety of patents and clinical trials involving this peptide. Cancer treatment is one of the most advanced therapeutic areas, but clinical studies are also available in several other areas, such as cardiovascular, hematological, transplantation, surgical and medical procedures. PMID- 27121992 TI - Identification of MBF2 family genes in Bombyx mori and their expression in different tissues and stages and in response to Bacillus bombysepticus infection and starvation. AB - The Multiprotein bridge factor 2 (MBF2) gene was first identified as a co activator involved in BmFTZ-F1-mediated activation of the Fushi tarazu gene. Herein, nine homologous genes of MBF2 gene are identified. Evolutionary analysis showed that this gene family is insect-specific and that the family members are closely related to response to pathogens (REPAT) genes. Tissue distribution analysis revealed that these genes could be expressed in a tissue-specific manner. Developmental profiles analysis showed that the MBF2 gene family members were highly expressed in the different stages. Analysis of the expression patterns of nine MBF2 family genes showed that Bacillus bombysepticus treatment induced the up-regulation of several MBF2 family genes, including MBF2-4, -7, -9, -8. Furthermore, we found the MBF2 family genes were modulated by starvation and the expression of these genes recovered upon re-feeding, except for MBF2-5, -9. These findings suggested roles for these proteins in insect defense against pathogens and nutrient metabolism, which has an important guiding significance for designing pest control strategies. PMID- 27121993 TI - Unsupervised Estimation of Mouse Sleep Scores and Dynamics Using a Graphical Model of Electrophysiological Measurements. AB - The proportion, number of bouts, and mean bout duration of different vigilance states (Wake, NREM, REM) are useful indices of dynamics in experimental sleep research. These metrics are estimated by first scoring state, sometimes using an algorithm, based on electrophysiological measurements such as the electroencephalogram (EEG) and electromyogram (EMG), and computing their values from the score sequence. Isolated errors in the scores can lead to large discrepancies in the estimated sleep metrics. But most algorithms score sleep by classifying the state from EEG/EMG features independently in each time epoch without considering the dynamics across epochs, which could provide contextual information. The objective here is to improve estimation of sleep metrics by fitting a probabilistic dynamical model to mouse EEG/EMG data and then predicting the metrics from the model parameters. Hidden Markov models (HMMs) with multivariate Gaussian observations and Markov state transitions were fitted to unlabeled 24-h EEG/EMG feature time series from 20 mice to model transitions between the latent vigilance states; a similar model with unbiased transition probabilities served as a reference. Sleep metrics predicted from the HMM parameters did not deviate significantly from manual estimates except for rapid eye movement sleep (REM) ([Formula: see text]; Wilcoxon signed-rank test). Changes in value from Light to Dark conditions correlated well with manually estimated differences (Spearman's rho 0.43-0.84) except for REM. HMMs also scored vigilance state with over 90% accuracy. HMMs of EEG/EMG features can therefore characterize sleep dynamics from EEG/EMG measurements, a prerequisite for characterizing the effects of perturbation in sleep monitoring and control applications. PMID- 27121994 TI - An EEG-Based Fatigue Detection and Mitigation System. AB - Research has indicated that fatigue is a critical factor in cognitive lapses because it negatively affects an individual's internal state, which is then manifested physiologically. This study explores neurophysiological changes, measured by electroencephalogram (EEG), due to fatigue. This study further demonstrates the feasibility of an online closed-loop EEG-based fatigue detection and mitigation system that detects physiological change and can thereby prevent fatigue-related cognitive lapses. More importantly, this work compares the efficacy of fatigue detection and mitigation between the EEG-based and a nonEEG based random method. Twelve healthy subjects participated in a sustained attention driving experiment. Each participant's EEG signal was monitored continuously and a warning was delivered in real-time to participants once the EEG signature of fatigue was detected. Study results indicate suppression of the alpha- and theta-power of an occipital component and improved behavioral performance following a warning signal; these findings are in line with those in previous studies. However, study results also showed reduced warning efficacy (i.e. increased response times (RTs) to lane deviations) accompanied by increased alpha-power due to the fluctuation of warnings over time. Furthermore, a comparison of EEG-based and nonEEG-based random approaches clearly demonstrated the necessity of adaptive fatigue-mitigation systems, based on a subject's cognitive level, to deliver warnings. Analytical results clearly demonstrate and validate the efficacy of this online closed-loop EEG-based fatigue detection and mitigation mechanism to identify cognitive lapses that may lead to catastrophic incidents in countless operational environments. PMID- 27121995 TI - Learning Topologies with the Growing Neural Forest. AB - In this work, a novel self-organizing model called growing neural forest (GNF) is presented. It is based on the growing neural gas (GNG), which learns a general graph with no special provisions for datasets with separated clusters. On the contrary, the proposed GNF learns a set of trees so that each tree represents a connected cluster of data. High dimensional datasets often contain large empty regions among clusters, so this proposal is better suited to them than other self organizing models because it represents these separated clusters as connected components made of neurons. Experimental results are reported which show the self organization capabilities of the model. Moreover, its suitability for unsupervised clustering and foreground detection applications is demonstrated. In particular, the GNF is shown to correctly discover the connected component structure of some datasets. Moreover, it outperforms some well-known foreground detectors both in quantitative and qualitative terms. PMID- 27121996 TI - Adding Emulsified Isoflurane to Cardioplegia Solution Produces Cardiac Protection in a Dog Cardiopulmonary Bypass Model. AB - This study investigated whether caridoplegia solution with Emulsified Isoflurane (EI) could improve cardiaoprotection in a dog CPB model of great similarity to clinical settings. Adult dogs were randomly assigned to receive one of the following cardioplegia solutions: St. Thomas with EI (group ST+EI), St. Thomas with 30% Intralipid (group ST+EL) and St. Thomas alone (group ST). The aorta was cross-clamped for two hours followed by reperfusion for another two hours, during which cardiac output was measured and dosages of positive inotropic agent to maintain normal hemodynamics were recorded. Serum level of cardiac troponin I (cTnI) and CK-MB were measured. Deletion of cardiac mitochondrial DNA was examined at the end of reperfusion. Compared with ST, ST+EI decreased the requirement of dopamine support while animals receiving ST+EI had a significantly larger cardiac output. ST+EI reduced post-CPB release of cTnI and CK-MB. Mitochondrial DNA loss was observed in only one of the tested animals from group ST+EI while it was seen in all the tested animals from group ST+EL and ST. Addition of emulsified isoflurane into cardioplegia solution protects against myocardial ischemia reperfusion injury. This protective effect might be mediated by preserving mitochondrial ultrastructure and DNA integrity. PMID- 27121997 TI - Australian Rheumatology Association in conjunction with Rheumatology Health Professionals Association, 57th Annual Scientific Meeting, 30 April-4 May 2016, Darwin, NT, Australia. PMID- 27121998 TI - Pilomatricoma presenting with localized alopecia. PMID- 27121999 TI - PTEN inhibition preserves trigeminal nucleus caudalis neuron activation through tyrosine phosphorylation of the NR2B subunit at Tyr1472 of the NMDA receptor in a rat model of recurrent migraine. AB - OBJECTIVE: Activation of the trigeminal nucleus caudalis is believed to be involved in the pathomechanism of migraine. Evidence suggests that N-methyl-d aspartate receptor subtype 2B tyrosine phosphorylation, originating from the trigeminal nucleus caudalis neuron dysfunction, might be a triggering mechanism for recurrent migraine. Phosphatase and tensin homolog is thought to have a neuroprotective effect in various neurologic diseases by regulating N-methyl-d aspartate receptor subtype 2B or tyrosine phosphorylation. Thus, the aim of this study was to explore whether the recombinant adenovirus AdR-siPTEN attenuates neuron activation in the trigeminal nucleus caudalis in a rat model of recurrent migraine. METHODS: Adenovirus-expressing siPTEN or RFP was independently injected into the spinal trigeminal nucleus of the rat model suffering from recurrent migraine by inflammatory soup stimulation the superior sagittal sinus of rats. Seven days later, tactile sensory testing was performed to detect the tactile threshold. Immunofluorescence, Immunohistochemistry, and western blot assay were done to measure PTEN, NR2B, NR2B-pTyr1472, and c-Fos levels in the trigeminal nucleus caudalis of recurrent migraine rats. RESULTS: A significant increase (p < 0.05) in neuron c-Fos content, an indicator of neuron activation, was detected in the trigeminal nucleus caudalis in a rat model of recurrent migraine. However, neuron activation in the trigeminal nucleus caudalis was attenuated by pretreatment with AdR-siPTEN. Moreover, the attenuated effect was potentially mediated by tyrosine phosphorylation of the NR2B-p1472 tyrosine site in the trigeminal nucleus caudalis, as seen in rat brain slices. CONCLUSION: These results suggest that, phosphatase and tensin homolog might be a novel and promising candidate for future treatment or prophylaxis of recurrent migraine by attenuating neuron activation in the trigeminal nucleus caudalis. PMID- 27122000 TI - Pieter Cullis: an outstanding lipid biophysicist, drug delivery scientist, educator, and entrepreneur. AB - There are much said about Pieter Cullis in this special volume honoring him. He was the pioneer to study the role of hexagonal HII phase in membrane fusion and the one who applied this concept for the design of lipid nanoparticles. He was also the first to utilize remote loading techniques for the delivery of amphipathic bases. At the same time, he is a tremendous entrepreneur and an excellent mentor. He is, without doubt, an exceptional scientist and set us an excellent model to follow. PMID- 27122002 TI - Myricetin suppresses p21-activated kinase 1 in human breast cancer MCF-7 cells through downstream signaling of the beta-catenin pathway. AB - As a main active compound in the bark of waxberry (Myrica rubra), myricetin is a macrocyclic diarylheptanoid, and can trigger the apoptosis of HeLa and PC3 cells. The aim of the present study was to elucidate the anticancer effect of myricetin on human breast cancer MCF-7 cells and to explore the possible mechanisms of action. MCF-7 cells were treated with different concentrations of myricetin (0-80 uM) for 12, 24 and 48 h. In the present study, we found that myricetin suppressed the cell viability of the MCF-7 cells at least partly through the induction of apoptosis as determined by MTT assay and flow cytometry. Western blot analysis revealed that myricetin effectively suppressed the protein expression of p21 activated kinase 1 (PAK1), MEK and phosphorylated extracellular mitogen-activated protein kinase (ERK1/2). In addition, treatment of myricetin activated glycogen synthase kinase-3beta (GSK3beta) and Bax protein expression, and inhibited beta catenin/cyclin D1/proliferating cell nuclear antigen (PCNA)/survivin and promoted caspase-3 activity in the MCF-7 cells. These results demonstrated that myricetin suppressed the cell viability of human breast cancer MCF-7 cells through PAK1/MEK/ERK/GSK3beta/beta-catenin/cyclin D1/PCNA/survivin/Bax-caspase-3 signaling. PMID- 27122001 TI - Saffron with resistance exercise improves diabetic parameters through the GLUT4/AMPK pathway in-vitro and in-vivo. AB - Saffron is consumed as food and medicine to treat several illnesses. This study elucidates the saffron effectiveness on diabetic parameters in-vitro and combined with resistance exercise in-vivo. The antioxidant properties of saffron was examined. Insulin secretion and glucose uptake were examined by cultured RIN-5F and L6 myotubes cells. The expressions of GLUT2, GLUT4, and AMPKalpha were determined by Western blot. Diabetic and non-diabetic male rats were divided into: control, training, extract treatment, training + extract treatment and metformin. The exercise and 40 mg/kg/day saffron treatments were carried out for six weeks. The antioxidant capacity of saffron was higher compare to positive control (P < 0.01). High dose of saffron stimulated insulin release in RIN-5F cells and improved glucose uptake in L6 myotubes. GLUT4 and AMPKalpha expressions increased in both doses of saffron (P < 0.01), whereas GLUT2 not changed (p > 0.05). Serum glucose, cholesterol, triglyceride, low-density lipoprotein, very low-density lipoprotein, insulin resistance, and glycated hemoglobin levels decreased in treated rats compared to untreated (p < 0.01). However, no significant differences were observed in the high-density lipoprotein, insulin, adiponectin, and leptin concentration levels in all groups (p > 0.05). The findings suggest that saffron consuming alongside exercise could improve diabetic parameters through redox-mediated mechanisms and GLUT4/AMPK pathway to entrap glucose uptake. PMID- 27122003 TI - Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia. AB - Essentials Two groups recently reported GFI1B as a novel causative gene for congenital macrothrombocytopenia. We performed functional analysis of a novel GFI1B mutation and previous mutations. An immunofluorescence analysis of the platelet CD34 expression can be useful as a screening test. Mutant-transduced megakaryocytes produced enlarged proplatelet tips which were reduced in number. SUMMARY: Background GFI1B is an essential transcription factor for megakaryocyte and erythrocyte development. Two groups have recently identified GFI1B as a novel causative gene for congenital macrothrombocytopenia associated with alpha-granule deficiency. Methods We performed whole exome sequencing and identified a novel GFI1B p.G272fsX274 mutation in a family with macrothrombocytopenia, and a decreased number of platelet alpha-granules and abnormally shaped red blood cells. p.G272fsX274 and the previous two mutations all predicted disruption of an essential DNA-binding domain in GFI1B. We therefore performed functional studies to characterize the biochemical and biological effects of these three patient derived mutations. Results An immunofluorescence analysis revealed decreased thrombospondin-1 and increased CD34 expression in platelets from our patient. Consistent with the previous studies, the three patient-derived mutants were unable to repress the expression of the reporter gene and had a dominant-negative effect over wild-type GFI1B. In addition, the three mutations abolished recognition of a consensus-binding site in gel shift assays. Furthermore, transduction of mouse fetal liver-derived megakaryocytes with the three GFI1B mutants resulted in the production of abnormally large proplatelet tips, which were reduced in number. Conclusions Our study provides further proof of concept that GFI1B is an essential protein for the normal development of the megakaryocyte lineage. PMID- 27122004 TI - Genetic and environmental factors associated with delirium severity in older adults with dementia. AB - OBJECTIVE: To determine (1) whether delirium severity was associated with Apolipoprotein E (APOE) genotype status and occupational complexity, a measure of cognitive reserve, in individuals with delirium superimposed on dementia; and (2) whether decline in delirium severity was associated with these same factors over a post-acute care (PAC) stay. METHODS: Control group data (n = 142) from a completed randomized clinical trial were used to address the aims of the study. Delirium severity was calculated by combining items from the Confusion Assessment Method and the Montreal Cognitive Assessment. APOE epsilon4 carriers versus non carriers were considered. Occupational complexity, a measure of cognitive reserve, was derived from the Lifetime of Experiences Questionnaire. Covariates examined included age, gender, education, Clinical Dementia Rating Scale, and the Charlson comorbidity score. Data were nested (i.e., days nested within persons) and analyzed using multilevel models. RESULTS: The presence of an APOE epsilon4 allele and higher Clinical Dementia Rating Scale were associated with greater delirium severity at baseline. The presence of an APOE epsilon4 allele was also associated with greater delirium severity averaged across the PAC stay. Occupational complexity was not associated with baseline delirium severity or average daily delirium severity; however, individuals with low occupational complexity showed a significant decreased in delirium severity during the course of their PAC stay. CONCLUSIONS: Individual differences, including genetic factors and level of cognitive reserve, contribute to the severity of delirium in older adults with dementia. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27122005 TI - Estimating times of extinction in the fossil record. AB - Because the fossil record is incomplete, the last fossil of a taxon is a biased estimate of its true time of extinction. Numerous methods have been developed in the palaeontology literature for estimating the true time of extinction using ages of fossil specimens. These methods, which typically give a confidence interval for estimating the true time of extinction, differ in the assumptions they make and the nature and amount of data they require. We review the literature on such methods and make some recommendations for future directions. PMID- 27122006 TI - Long-term effect of yolk carotenoid levels on testis size in a precocial bird. AB - Conditions experienced during prenatal development can have long-lasting organizational effects on offspring. Maternal carotenoids deposited in the eggs of birds and other oviparous species play an important role during fast embryonic growth and chick development through their antioxidant properties. However, the long-term consequences of variation in maternal carotenoid transfer for the offspring have seldom been considered. Since plasma carotenoid levels at adulthood are known to influence testis size and yolk carotenoid levels influence the ability to extract carotenoids later in life, we hypothesized that maternally transmitted carotenoids might influence gonad size at adulthood. Here, we showed that male Japanese quail (Coturnix japonica) originating from a carotenoid enriched egg had smaller testes than control individuals at adulthood. This result shows that yolk carotenoids have long-term organizational effects. In addition, given that carotenoid intake at sexual maturity increases sperm quality and that a decreased testis size is associated with a lower sperm production, we propose that carotenoid exposure during embryo development might influence a trade-off between ejaculate size and sperm quality. PMID- 27122007 TI - Stay tuned: active amplification tunes tree cricket ears to track temperature dependent song frequency. AB - Tree cricket males produce tonal songs, used for mate attraction and male-male interactions. Active mechanics tunes hearing to conspecific song frequency. However, tree cricket song frequency increases with temperature, presenting a problem for tuned listeners. We show that the actively amplified frequency increases with temperature, thus shifting mechanical and neuronal auditory tuning to maintain a match with conspecific song frequency. Active auditory processes are known from several taxa, but their adaptive function has rarely been demonstrated. We show that tree crickets harness active processes to ensure that auditory tuning remains matched to conspecific song frequency, despite changing environmental conditions and signal characteristics. Adaptive tuning allows tree crickets to selectively detect potential mates or rivals over large distances and is likely to bestow a strong selective advantage by reducing mate-finding effort and facilitating intermale interactions. PMID- 27122008 TI - Pollinator shifts drive petal epidermal evolution on the Macaronesian Islands bird-flowered species. AB - Pollinator shifts are considered to drive floral trait evolution, yet little is still known about the modifications of petal epidermal surface at a biogeographic region scale. Here we investigated how independent shifts from insects to passerine birds in the Macaronesian Islands consistently modified this floral trait (i.e. absence of papillate cells). Using current phylogenies and extensive evidence from field observations, we selected a total of 81 plant species and subspecies for petal microscopy and comparative analysis, including 19 of the 23 insular species pollinated by opportunistic passerine birds (Macaronesian bird flowered element). Species relying on passerine birds as the most effective pollinators (bird-pollinated) independently evolved at least five times and in all instances associated with a loss of papillate cells, whereas species with a mixed pollination system (birds plus insects and/or other vertebrates) evolved at least five times in Macaronesia and papillate cells were lost in only 25% of these transitions. Our findings suggest that petal micromorphology is a labile trait during pollinator shifts and that papillate cells tend to be absent on those species where pollinators have limited mechanical interaction with flowers, including opportunistic passerine birds that forage by hovering or from the ground. PMID- 27122009 TI - Intra-specific variability of hindlimb length in the palmate newt: an indicator of population isolation induced by habitat fragmentation? AB - Habitat fragmentation is one of the main drivers of global amphibian decline. Anthropogenic landscape elements can act as barriers, hindering the dispersal that is essential for maintaining gene flow between populations. Dispersal ability can be influenced by locomotor performance, which in turn can depend on morphological traits, such as hindlimb length (HLL) in amphibians. Here, we tested relationships between HLL and environmental variables--road types, forests and agricultural lands--among 35 sub-populations of palmate newts (Lissotriton helveticus) in southwestern France. We expected roads to select for short-legged newts due to a higher mortality of more mobile individuals (long-legged newts) when crossing roads. Accordingly, short-legged newts were found in the vicinity of roads, whereas long-legged newts were found closer to forests and in ponds close geographically to another water body. HLL in newts was hence influenced by habitat types in a heterogeneous landscape, and could therefore be used as an indicator of population isolation in a meta-population system. PMID- 27122010 TI - Genetic variation in male-induced harm in Drosophila melanogaster. AB - In Drosophila melanogaster, prolonged exposure to males reduces the longevity and fecundity of females. This harm arises from the effects of male courtship behaviours and the toxic side effects of the accessory gland proteins (Acps) in their seminal fluids. Here, we examine the relationship between male exposure and its harmful effect on the lifetime fitness of his mates, and quantify the genetic basis for this variation. We found significant additive genetic variation in the magnitude of harm that males impose on females by exposing females to males from a variety of hemiclonal backgrounds for either a brief or prolonged period of time and measuring their fecundity, a meaningful fitness index. Furthermore, we discovered a strong negative correlation between the magnitude of harm and the short-term effects of male exposure on female fitness. We discuss the evolutionary significance of these results with regards to potential life-history trade-offs in females, and its relationship to male body size. PMID- 27122011 TI - Tree diversity reduces pest damage in mature forests across Europe. AB - Forest pest damage is expected to increase with global change. Tree diversity could mitigate this impact, but unambiguous demonstration of the diversity resistance relationship is lacking in semi-natural mature forests. We used a network of 208 forest plots sampled along two orthogonal gradients of increasing tree species richness and latitudes to assess total tree defoliation in Europe. We found a positive relationship between tree species richness and resistance to insect herbivores: overall damage to broadleaved species significantly decreased with the number of tree species in mature forests. This pattern of associational resistance was frequently observed across tree species and countries, irrespective of their climate. These findings confirm the greater potential of mixed forests to face future biotic disturbances in a changing world. PMID- 27122012 TI - Income and Cognitive Stimulation: A Reanalysis of the Minnesota Family Investment Program. AB - Correlational research suggests that parents engage in more cognitive stimulation with their children when their income increases as reported by Votruba-Drzal (Journal of Marriage and Family 65:341-355, 2003). The present study uses data from an evaluation of the Minnesota Family Investment Program (MFIP), a welfare program that allows families to combine their work payments with their welfare benefits. We used the dataset in order to assess the causal impact of income on how often mothers engage their young children (N = 69) in cognitively stimulating activities. Results indicated that single mothers, who were long-term welfare recipients and received the financial benefits of the MFIP without employment training services, engaged in more cognitively stimulating activities with their children, relative to mothers who received traditional Aid to Families with Dependent Children. Contrary to expectations, an increase in income did not appear to cause the increase in cognitive stimulation. Rather, a reduction in work hours, without a drastic loss of income, appeared to cause the increase in cognitive stimulation. Implications for future work and policy are discussed. PMID- 27122013 TI - Understanding particle size and distance driven competition of interparticle interactions and effective single-particle anisotropy. AB - Magnetic response of single-domain nanoparticles (NPs) in concentrated systems is strongly affected by mutual interparticle interactions. However, particle proximity significantly influences single-particle effective anisotropy. To solve which of these two phenomena plays a dominant role in the magnetic response of real NP systems, systematic study on samples with well-defined parameters is required. In our work, we prepared a series of nanocomposites constituted of highly-crystalline and well-isolated CoFe2O4 NPs embedded in an amorphous SiO2 matrix using a single-molecule precursor method. This preparation method enabled us to reach a wide interval of particle size and concentration. We observed that the characteristic parameters of the single-domain state (coercivity, blocking temperature) and dipole-dipole interaction energy ([Formula: see text]) scaled with each other and increased with increasing [Formula: see text], where d XRD was the NP diameter and r was the interparticle distance. Our results are in excellent agreement with Monte-Carlo simulations of the particle growth. Moreover, we demonstrated that the contribution of [Formula: see text] acting as an additional energetic barrier to the superspin reversal or as an average static field did not sufficiently explain how the concentrated NP systems responded to an external magnetic field. Alternations in the blocking temperature and coercivity of our NP systems accounted for reformed relaxations of the NP superspins and modified effective anisotropy energy of the interacting NPs. Therefore, the concept of modified NP effective anisotropy explains the magnetic response of our concentrated NP systems better than the concept of the energy barrier influenced by interparticle interactions. PMID- 27122014 TI - Homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy. AB - Febrile-induced neurodegenerative diseases are a heterogeneous group of genetic disorders most commonly inborn errors of metabolism that result in irreversible damage involving the central nervous system. Here, we report on five siblings of consanguineous family who developed normally for the first 6-12 months of life then presented with a severe leukoencephalopathy following a trivial febrile illness. Using homozygosity mapping followed by whole exome sequencing, we identified a homozygous c. 281C>A mutation in the APOA1BP gene resulting in substitution of a highly conserved alanine residue with aspartic acid (p.Ala94Asp). APOA1BP encodes for epimerase that catalyzes the R to S epimerization of NAD(P)XH, a crucial step in the dehydration of these toxic metabolites accumulating during cellular metabolism. This is the first report of a defect in the nicotinamide nucleotide repair system in humans. PMID- 27122015 TI - Epigenetic assimilation in the aging human brain. AB - BACKGROUND: Epigenetic drift progressively increases variation in DNA modification profiles of aging cells, but the finale of such divergence remains elusive. In this study, we explored the dynamics of DNA modification and transcription in the later stages of human life. RESULTS: We find that brain tissues of older individuals (>75 years) become more similar to each other, both epigenetically and transcriptionally, compared with younger individuals. Inter individual epigenetic assimilation is concurrent with increasing similarity between the cerebral cortex and the cerebellum, which points to potential brain cell dedifferentiation. DNA modification analysis of twins affected with Alzheimer's disease reveals a potential for accelerated epigenetic assimilation in neurodegenerative disease. We also observe loss of boundaries and merging of neighboring DNA modification and transcriptomic domains over time. CONCLUSIONS: Age-dependent epigenetic divergence, paradoxically, changes to convergence in the later stages of life. The newly described phenomena of epigenetic assimilation and tissue dedifferentiation may help us better understand the molecular mechanisms of aging and the origins of diseases for which age is a risk factor. PMID- 27122016 TI - The epidemiology of childhood brain injury in the state of Selangor and Federal Territory of Kuala Lumpur, Malaysia. AB - BACKGROUND: There are limited studies describing the epidemiology of childhood brain injury, especially in developing countries. This study analyses data from the Malaysian National Trauma Database (NTrD) registry to estimate the incidence of childhood brain injury among various demographic groups within the state of Selangor and Federal Territory of Kuala Lumpur. METHODS: This study analysed all traumatic brain injury cases for children ages 0-19 included in the 2010 NTrD report. RESULTS: A total of 5,836 paediatric patients were admitted to emergency departments (ED) of reporting hospitals for trauma. Of these, 742 patients (12.7 %) suffered from brain injuries. Among those with brain injuries, the mortality rate was 11.9 and 71.2 % were aged between 15 and 19. Traffic accidents were the most common mode of injury (95.4 %). Out of the total for traffic accidents, 80.2 % of brain injuries were incurred in motorcycle accidents. Severity of injury was higher among males and patients who were transferred or referred to the reporting centres from other clinics. Glasgow Coma Scale (GCS) total score and type of admission were found to be statistically significant, chi (2) (5, N = 178) = 66.53, p < 0.001, in predicting patient outcomes. According to this analysis, the overall rate of childhood brain injury for this one year period was 32 per 100,000 children while the incidence of significant (moderate to severe) brain injury was approximately 8 per 100,000 children. CONCLUSIONS: This study provides an overview of traumatic brain injury rates among children within the most populous region of Malaysia. Most brain injuries occurred among older male children, with traffic, specifically motorcycle-related, accidents being the main mode of injury. These findings point to risk factors that could be targeted for future injury prevention programs. PMID- 27122017 TI - Surgically treated solitary giant gluteal and retroperitoneal neurofibroma: a case report. AB - BACKGROUND: Giant neurofibromas in patients with neurofibromatosis type 1 involve multiple regions and are often difficult to surgically extirpate. However, surgical intervention is the most effective means for improving quality of life. The case reported herein is unique in that it involves a giant neurofibroma, involving the patient's peritoneal and pelvic cavities, retroperitoneal space, and buttock, which was causing compressive displacement of abdominal and pelvic organs. A challenging surgical intervention was required to accomplish near-total resection to relieve organ compression while preserving visceral and genitoanal function. CASE PRESENTATION: The case reported is of a patient presenting with a solitary giant retroperitoneal neurofibroma that threatened to obliterate both peritoneal and pelvic cavities and protruded conspicuously into the right gluteal region. The enormous dumbbell-shaped mass was surgically removed in three parts. Postoperative pathology studies confirmed a diagnosis of neurofibroma. Follow-up computed tomography images taken three months postoperatively revealed residual tumor in the perianal region. The patient's quality of life had measurably improved on follow-up at eight months. CONCLUSIONS: Surgical intervention in such extraordinary circumstances of a giant neurofibroma causing compressive displacement of critical organs reduces tumor burden, restores appearance and function of patient's body and internal organs, and improves the patient's quality of life. PMID- 27122018 TI - Quantification of cephalomedullary nail fit in the femur using 3D computer modelling: a comparison between 1.0 and 1.5m bow designs. AB - BACKGROUND: The radius of curvature (ROC) misfit of cephalomedullary nails during anterograde nailing can lead to complications such as distal anterior cortical encroachment. This study quantified the anatomical fit of a new nail with 1.0-m ROC (TFN-ADVANCED(TM) Proximal Femoral Nailing System [TFNA]) compared with a nail with 1.5-m ROC (Gamma3 Long Nail R1.5 [Gamma3]). METHODS: We generated 63 three-dimensional models (48 female, 45 right femur) representing the cortical surfaces of the femora (31 Caucasian, 28 Japanese, and 4 Thai). The mean age of the specimens was 77 years (+/-8.1), and the mean height was 158.5 cm (+/-9.6). Utilizing a customized software tool, nail fit was determined from the total surface area of nail protrusion from the inner cortex surface and maximum distance of nail protrusion in the axial plane; the position of the distal nail tip within the canal was also determined. RESULTS: Overall, TFNA had both a significantly smaller mean total surface area of nail protrusion (915.8 vs. 1181.6 mm(2); P < 0.05) and a mean maximum distance of nail protrusion in the axial plane (1.9 vs. 2.1 mm; P = 0.007) when compared with Gamma3. The mean total surface area of nail protrusion was significantly smaller with TFNA versus Gamma3 in both the Caucasian (P = 0.0009) and Asian (Japanese and Thai) samples (P = 0.000002); the mean maximum distance of TFNA protrusion was significantly smaller in Asians (P = 0.04), but not in Caucasians (P = 0.08). Most tip positions for both nail types were anterior, but TFNA had a higher number of center positions than Gamma3 (13 vs. 7) and a shift from the far anterior cortex to the center of the medullary canal (overall and in Caucasians). In Asians, the most prominent position was far anterior for both nails. CONCLUSIONS: The 1.0-m ROC TFNA nail resulted in better fit than the 1.5-m ROC Gamma3 nail. Clinical trials and case studies should be conducted in the future to verify if these findings would also result in clinical improvements. PMID- 27122019 TI - A man with severe abdominal pain. PMID- 27122020 TI - ImiRP: a computational approach to microRNA target site mutation. AB - BACKGROUND: MicroRNAs (miRNAs) are small ~22 nucleotide non-coding RNAs that function as post-transcriptional regulators of messenger RNA (mRNA) through base pairing to 6-8 nucleotide long target sites, usually located within the mRNA 3' untranslated region. A common approach to validate and probe microRNA-mRNA interactions is to mutate predicted target sites within the mRNA and determine whether it affects miRNA-mediated activity. The introduction of miRNA target site mutations, however, is potentially problematic as it may generate new, "illegitimate sites" target sites for other miRNAs, which may affect the experimental outcome. While it is possible to manually generate and check single miRNA target site mutations, this process can be time consuming, and becomes particularly onerous and error prone when multiple sites are to be mutated simultaneously. We have developed a modular Java-based system called ImiRP (Illegitimate miRNA Predictor) to solve this problem and to facilitate miRNA target site mutagenesis. RESULTS: The ImiRP interface allows users to input a sequence of interest, specify the locations of multiple predicted target sites to mutate, and set parameters such as species, mutation strategy, and disallowed illegitimate target site types. As mutant sequences are generated, ImiRP utilizes the miRBase high confidence miRNA dataset to identify illegitimate target sites in each mutant sequence by comparing target site predictions between input and mutant sequences. ImiRP then assembles a final mutant sequence in which all specified target sites have been mutated. CONCLUSIONS: ImiRP is a mutation generator program that enables selective disruption of specified miRNA target sites while ensuring predicted target sites for other miRNAs are not inadvertently created. ImiRP supports mutagenesis of single and multiple miRNA target sites within a given sequence, including sites that overlap. This software will be particularly useful for studies looking at microRNA cooperativity, where mutagenesis of multiple microRNA target sites may be desired. The software is available at imirp.org and is available open source for download through GitHub ( https://github.com/imirp ). PMID- 27122022 TI - The Basis of Structure/Function Claims of Nutraceuticals. AB - In the United States, as in most of the world, there are large numbers of nutraceuticals that are sold and which people take to boost their immune response. There are, in addition, almost an equal number of products sold to reduce allergies. However, very few consumers, and indeed physicians, are aware of what a structure/function claim is. Structure/function claims are labeling claims that can be used to describe the potential effects of a dietary ingredient or similar substance on the structure or function of the human body. This category of claims was created by legislation contained in the Dietary Supplement Health and Education Act. The intent was to supply consumers with reasonably substantiated information that would allow them to make educated choices about their diet and health. They were not intended to have the same weight and substantiation as the claims made for conventional prescription pharmaceuticals. Rather, they were proposed to fill the gap between consumer desire for over-the counter supplements and foods, and rigorous and generally more potent and potentially "toxic" prescription medications. The legally mandated disclaimer, stating that the U.S. Food and Drug Administration has not evaluated the structure/function claim, often leads to misinterpretation. While there should be a biologic premise underlying the claim, there is not an absolute requirement for a conventional rigorous placebo-controlled dose response trial. While this may not be the clinical standard that a typical scientific oriented society might desire, it reflects the attempts of the FDA to find common grounds and to allow consumers to use products that are generally considered as safe based on historical use and biologic comparisons. The logic of, indeed need for, structure/function claims is straightforward; however, of equal importance is that nutraceuticals should be properly labeled, have accuracy in their ingredients, be free of contamination, be safe, and have a reasonable body of data that supports their efficacy. PMID- 27122021 TI - Bradykinin: Inflammatory Product of the Coagulation System. AB - Episodic and recurrent local cutaneous or mucosal swelling are key features of angioedema. The vasoactive agents histamine and bradykinin are highly implicated as mediators of these swelling attacks. It is challenging to assess the contribution of bradykinin to the clinical expression of angioedema, as accurate biomarkers for the generation of this vasoactive peptide are still lacking. In this review, we will describe the mechanisms that are responsible for bradykinin production in hereditary angioedema (HAE) and the central role that the coagulation factor XII (FXII) plays in it. Evidently, several plasma parameters of coagulation change during attacks of HAE and may prove valuable biomarkers for disease activity. We propose that these changes are secondary to vascular leakage, rather than a direct consequence of FXII activation. Furthermore, biomarkers for fibrinolytic system activation (i.e. plasminogen activation) also change during attacks of HAE. These changes may reflect triggering of the bradykinin-forming mechanisms by plasmin. Finally, multiple lines of evidence suggest that neutrophil activation and mast-cell activation are functionally linked to bradykinin production. We put forward the paradigm that FXII functions as a 'sensor molecule' to detect conditions that require bradykinin release via crosstalk with cell-derived enzymes. Understanding the mechanisms that drive bradykinin generation may help to identify angioedema patients that have bradykinin-mediated disease and could benefit from a targeted treatment. PMID- 27122023 TI - Using ultra-sensitive next generation sequencing to dissect DNA damage-induced mutagenesis. AB - Next generation sequencing (NGS) technologies have dramatically improved studies in biology and biomedical science. However, no optimal NGS approach is available to conveniently analyze low frequency mutations caused by DNA damage treatments. Here, by developing an exquisite ultra-sensitive NGS (USNGS) platform "EasyMF" and incorporating it with a widely used supF shuttle vector-based mutagenesis system, we can conveniently dissect roles of lesion bypass polymerases in damage induced mutagenesis. In this improved mutagenesis analysis pipeline, the initial steps are the same as in the supF mutation assay, involving damaging the pSP189 plasmid followed by its transfection into human 293T cells to allow replication to occur. Then "EasyMF" is employed to replace downstream MBM7070 bacterial transformation and other steps for analyzing damage-induced mutation frequencies and spectra. This pipeline was validated by using UV damaged plasmid after its replication in lesion bypass polymerase-deficient 293T cells. The increased throughput and reduced cost of this system will allow us to conveniently screen regulators of translesion DNA synthesis pathway and monitor environmental genotoxic substances, which can ultimately provide insight into the mechanisms of genome stability and mutagenesis. PMID- 27122024 TI - Exploring the Origins and Development of the Visual Number Form Area: A Functionally Specialized and Domain-Specific Region for the Processing of Number Symbols? PMID- 27122025 TI - Task-Related Dynamic Division of Labor Between Anterior Temporal and Lateral Occipital Cortices in Representing Object Size. AB - Object size is represented by functionally distinct sectors along the ventral visual pathway. The early visual cortex encodes objects' sensory-retinal size. Subsequently, the occipitotemporal cortex computes objects' canonical size based on statistical regularities of visual features. Although the neurocomputation of size has been studied in a "bottom-up" sensory-driven framework, little is known about how perceptual size information is transformed into conceptual knowledge and how this computation is modulated by "top-down" goal-driven signals. Using continuous theta burst stimulation, we demonstrated that behavioral goal shapes the neurocognitive network underpinning object size. We manipulated the congruency of perceptual versus conceptual object size, which provides a robust behavioral probe reflecting implicit size knowledge. Neurostimulation was targeted at the lateral occipital cortex (LOC), a key region for object perception, or the anterior temporal lobe (ATL), a "hub" of supramodal conceptual processing. We observed striking contextual modulation of the neurocognitive architecture: when human participants judged perceptual size, the congruency effect was significantly attenuated by LOC stimulation but stayed resilient to ATL stimulation. By contrast, when they judged conceptual size, both LOC and ATL stimulation eradicated the otherwise robust effect. Our findings demonstrate disparate functional profiles of the LOC and ATL, providing the first evidence of a malleable network adaptively altering its division of labor with top-down states. The LOC, regardless of task demand, automatically represents "bottom-up" statistical regularities of visual conformation (reflecting typical object size), whereas the ATL contributes to this computation when the context requires semantically based linkage of visual attributes to object recognition. SIGNIFICANCE STATEMENT: In the present study, we provide compelling evidence that the "top-down" cognitive state of an observer changes the dynamic interaction between different subregions of the ventral temporal cortex. Using inhibitory neurostimulation combined with a novel paradigm, we demonstrate a flexible division of labor in the neurocognitive architecture that underpins size knowledge: the lateral occipital cortex codes perceptually based aspects (statistical visual configuration of small/large objects), whereas the anterior temporal lobe represents semantically based aspects (object identity), with their involvement interactively weighted by task demand. The interactive nature of the ventral temporal cortex highlights how top-down modulation constrains and shapes neural representations in the visual system. PMID- 27122026 TI - Cohesion and Joint Speech: Right Hemisphere Contributions to Synchronized Vocal Production. AB - Synchronized behavior (chanting, singing, praying, dancing) is found in all human cultures and is central to religious, military, and political activities, which require people to act collaboratively and cohesively; however, we know little about the neural underpinnings of many kinds of synchronous behavior (e.g., vocal behavior) or its role in establishing and maintaining group cohesion. In the present study, we measured neural activity using fMRI while participants spoke simultaneously with another person. We manipulated whether the couple spoke the same sentence (allowing synchrony) or different sentences (preventing synchrony), and also whether the voice the participant heard was "live" (allowing rich reciprocal interaction) or prerecorded (with no such mutual influence). Synchronous speech was associated with increased activity in posterior and anterior auditory fields. When, and only when, participants spoke with a partner who was both synchronous and "live," we observed a lack of the suppression of auditory cortex, which is commonly seen as a neural correlate of speech production. Instead, auditory cortex responded as though it were processing another talker's speech. Our results suggest that detecting synchrony leads to a change in the perceptual consequences of one's own actions: they are processed as though they were other-, rather than self-produced. This may contribute to our understanding of synchronized behavior as a group-bonding tool. SIGNIFICANCE STATEMENT: Synchronized human behavior, such as chanting, dancing, and singing, are cultural universals with functional significance: these activities increase group cohesion and cause participants to like each other and behave more prosocially toward each other. Here we use fMRI brain imaging to investigate the neural basis of one common form of cohesive synchronized behavior: joint speaking (e.g., the synchronous speech seen in chants, prayers, pledges). Results showed that joint speech recruits additional right hemisphere regions outside the classic speech production network. Additionally, we found that a neural marker of self-produced speech, suppression of sensory cortices, did not occur during joint synchronized speech, suggesting that joint synchronized behavior may alter self other distinctions in sensory processing. PMID- 27122027 TI - TMEM184b Promotes Axon Degeneration and Neuromuscular Junction Maintenance. AB - Complex nervous systems achieve proper connectivity during development and must maintain these connections throughout life. The processes of axon and synaptic maintenance and axon degeneration after injury are jointly controlled by a number of proteins within neurons, including ubiquitin ligases and mitogen activated protein kinases. However, our understanding of these molecular cascades is incomplete. Here we describe the phenotype resulting from mutation of TMEM184b, a protein identified in a screen for axon degeneration mediators. TMEM184b is highly expressed in the mouse nervous system and is found in recycling endosomes in neuronal cell bodies and axons. Disruption of TMEM184b expression results in prolonged maintenance of peripheral axons following nerve injury, demonstrating a role for TMEM184b in axon degeneration. In contrast to this protective phenotype in axons, uninjured mutant mice have anatomical and functional impairments in the peripheral nervous system. Loss of TMEM184b causes swellings at neuromuscular junctions that become more numerous with age, demonstrating that TMEM184b is critical for the maintenance of synaptic architecture. These swellings contain abnormal multivesicular structures similar to those seen in patients with neurodegenerative disorders. Mutant animals also show abnormal sensory terminal morphology. TMEM184b mutant animals are deficient on the inverted screen test, illustrating a role for TMEM184b in sensory-motor function. Overall, we have identified an important function for TMEM184b in peripheral nerve terminal structure, function, and the axon degeneration pathway. SIGNIFICANCE STATEMENT: Our work has identified both neuroprotective and neurodegenerative roles for a previously undescribed protein, TMEM184b. TMEM184b mutation causes delayed axon degeneration following peripheral nerve injury, indicating that it participates in the degeneration process. Simultaneously, TMEM184b mutation causes progressive structural abnormalities at neuromuscular synapses and swellings within sensory terminals, and animals with this mutation display profound weakness. Thus, TMEM184b is necessary for normal peripheral nerve terminal morphology and maintenance. Loss of TMEM184b results in accumulation of autophagosomal structures in vivo, fitting with emerging studies that have linked autophagy disruption and neurological disease. Our work recognizes TMEM184b as a new player in the maintenance of the nervous system. PMID- 27122028 TI - Targeted Epigenetic Remodeling of the Cdk5 Gene in Nucleus Accumbens Regulates Cocaine- and Stress-Evoked Behavior. AB - Recent studies have implicated epigenetic remodeling in brain reward regions following psychostimulant or stress exposure. It has only recently become possible to target a given type of epigenetic remodeling to a single gene of interest, and to probe the functional relevance of such regulation to neuropsychiatric disease. We sought to examine the role of histone modifications at the murine Cdk5 (cyclin-dependent kinase 5) locus, given growing evidence of Cdk5 expression in nucleus accumbens (NAc) influencing reward-related behaviors. Viral-mediated delivery of engineered zinc finger proteins (ZFP) targeted histone H3 lysine 9/14 acetylation (H3K9/14ac), a transcriptionally active mark, or histone H3 lysine 9 dimethylation (H3K9me2), which is associated with transcriptional repression, specifically to the Cdk5 locus in NAc in vivo We found that Cdk5-ZFP transcription factors are sufficient to bidirectionally regulate Cdk5 gene expression via enrichment of their respective histone modifications. We examined the behavioral consequences of this epigenetic remodeling and found that Cdk5-targeted H3K9/14ac increased cocaine-induced locomotor behavior, as well as resilience to social stress. Conversely, Cdk5 targeted H3K9me2 attenuated both cocaine-induced locomotor behavior and conditioned place preference, but had no effect on stress-induced social avoidance behavior. The current study provides evidence for the causal role of Cdk5 epigenetic remodeling in NAc in Cdk5 gene expression and in the control of reward and stress responses. Moreover, these data are especially compelling given that previous work demonstrated opposite behavioral phenotypes compared with those reported here upon Cdk5 overexpression or knockdown, demonstrating the importance of targeted epigenetic remodeling tools for studying more subtle molecular changes that contribute to neuropsychiatric disease. SIGNIFICANCE STATEMENT: Addiction and depression are highly heritable diseases, yet it has been difficult to identify gene sequence variations that underlie this heritability. Gene regulation via epigenetic remodeling is an additional mechanism contributing to the neurobiological basis of drug and stress exposure. In particular, epigenetic regulation of the Cdk5 gene alters responses to cocaine and stress in mouse and rat models. In this study, we used a novel technology, zinc-finger engineered transcription factors, to remodel histone proteins specifically at the Cdk5 gene. We found that this is sufficient to regulate the expression of Cdk5 and results in altered behavioral responses to cocaine and social stress. These data provide compelling evidence of the significance of epigenetic regulation in the neurobiological basis of reward- and stress-related neuropsychiatric disease. PMID- 27122029 TI - Oligodendrogliopathy in Multiple Sclerosis: Low Glycolytic Metabolic Rate Promotes Oligodendrocyte Survival. AB - Multiple sclerosis (MS) lesions feature demyelination with limited remyelination. A distinct injury phenotype of MS lesions features dying back of oligodendrocyte (OL) terminal processes, a response that destabilizes myelin/axon interactions. This oligodendrogliopathy has been linked with local metabolic stress, similar to the penumbra of ischemic/hypoxic states. Here, we developed an in vitro oligodendrogliopathy model using human CNS-derived OLs and related this injury response to their distinct bioenergetic properties. We determined the energy utilization properties of adult human surgically derived OLs cultured under either optimal or metabolic stress conditions, deprivation of growth factors, and glucose and/or hypoxia using a Seahorse extracellular flux analyzer. Baseline studies were also performed on OL progenitor cells derived from the same tissue and postnatal rat-derived cells. Under basal conditions, adult human OLs were less metabolically active than their progenitors and both were less active than the rat cells. Human OLs and progenitors both used aerobic glycolysis for the majority of ATP production, a process that contributes to protein and lipid production necessary for myelin biosynthesis. Under stress conditions that induce significant process retraction with only marginal cell death, human OLs exhibited a significant reduction in overall energy utilization, particularly in glycolytic ATP production. The stress-induced reduction of glycolytic ATP production by the human OLs would exacerbate myelin process withdrawal while favoring cell survival, providing a potential basis for the oligodendrogliopathy observed in MS. The glycolytic pathway is a potential therapeutic target to promote myelin maintenance and enhance repair in MS. SIGNIFICANCE STATEMENT: The neurologic deficits that characterize multiple sclerosis (MS) reflect disruption of myelin (demyelination) within the CNS and failure of repair (remyelination). We define distinct energy utilization properties of human adult brain-derived oligodendrocytes and oligodendrocyte progenitor cells under conditions of metabolic stress that model the initial relapsing and subsequent progressive phases of MS. The observed changes in energy utilization affect both cell survival and myelination capacity. These processes may be amenable to therapeutic interventions to limit the extent of cumulative tissue injury and to promote repair in MS. PMID- 27122030 TI - Clinically Anxious Individuals Show Disrupted Feedback between Inferior Frontal Gyrus and Prefrontal-Limbic Control Circuit. AB - Clinical anxiety is associated with generalization of conditioned fear, in which innocuous stimuli elicit alarm. Using Pavlovian fear conditioning (electric shock), we quantify generalization as the degree to which subjects' neurobiological responses track perceptual similarity gradients to a conditioned stimulus. Previous studies show that the ventromedial prefrontal cortex (vmPFC) inversely and ventral tegmental area directly track the gradient of perceptual similarity to the conditioned stimulus in healthy individuals, whereas clinically anxious individuals fail to discriminate. Here, we extend this work by identifying specific functional roles within the prefrontal-limbic circuit. We analyzed fMRI time-series acquired from 57 human subjects during a fear generalization task using entropic measures of circuit-wide regulation and feedback (power spectrum scale invariance/autocorrelation), in combination with structural (diffusion MRI-probabilistic tractography) and functional (stochastic dynamic causal modeling) measures of prefrontal-limbic connectivity within the circuit. Group comparison and correlations with anxiety severity across 57 subjects revealed dysregulatory dynamic signatures within the inferior frontal gyrus (IFG), which our prior work has linked to impaired feedback within the circuit. Bayesian model selection then identified a fully connected prefrontal limbic model comprising the IFG, vmPFC, and amygdala. Dysregulatory IFG dynamics were associated with weaker reciprocal excitatory connectivity between the IFG and the vmPFC. The vmPFC exhibited inhibitory influence on the amygdala. Our current results, combined with our previous work across a threat-perception spectrum of 137 subjects and a meta-analysis of 366 fMRI studies, dissociate distinct roles for three prefrontal-limbic regions, wherein the IFG provides evaluation of stimulus meaning, which then informs the vmPFC in inhibiting the amygdala. SIGNIFICANCE STATEMENT: Affective neuroscience has generally treated prefrontal regions (orbitofrontal cortex, dorsolateral prefrontal cortex, inferior frontal gyrus, ventromedial prefrontal cortex) equivalently as inhibitory components of the prefrontal-limbic system. Yet research across the anxiety spectrum suggests that the inferior frontal gyrus may have a more complex role in emotion regulation, as this region shows abnormal function in disorders of both hyperarousal and hypoarousal. Using entropic measures of circuit-wide regulation and feedback, in combination with measures of structural and functional connectivity, we dissociate distinct roles for three prefrontal-limbic regions, wherein the inferior frontal gyrus provides evaluation of stimulus meaning, which then informs the ventromedial prefrontal cortex in inhibiting the amygdala. This reconfiguration coheres with studies of conceptual disambiguation also implicating the inferior frontal gyrus. PMID- 27122031 TI - Decoding the Charitable Brain: Empathy, Perspective Taking, and Attention Shifts Differentially Predict Altruistic Giving. AB - Altruistic behavior varies considerably across people and decision contexts. The relevant computational and motivational mechanisms that underlie its heterogeneity, however, are poorly understood. Using a charitable giving task together with multivariate decoding techniques, we identified three distinct psychological mechanisms underlying altruistic decision-making (empathy, perspective taking, and attentional reorienting) and linked them to dissociable neural computations. Neural responses in the anterior insula (AI) (but not temporoparietal junction [TPJ]) encoded trial-wise empathy for beneficiaries, whereas the TPJ (but not AI) predicted the degree of perspective taking. Importantly, the relative influence of both socio-cognitive processes differed across individuals: participants whose donation behavior was heavily influenced by affective empathy exhibited higher predictive accuracies for generosity in AI, whereas those who strongly relied on cognitive perspective taking showed improved predictions of generous donations in TPJ. Furthermore, subject-specific contributions of both processes for donations were reflected in participants' empathy and perspective taking responses in a separate fMRI task (EmpaToM), suggesting that process-specific inputs into altruistic choices may reflect participants' general propensity to either empathize or mentalize. Finally, using independent attention task data, we identified shared neural codes for attentional reorienting and generous donations in the posterior superior temporal sulcus, suggesting that domain-general attention shifts also contribute to generous behavior (but not in TPJ or AI). Overall, our findings demonstrate highly specific roles of AI for affective empathy and TPJ for cognitive perspective taking as precursors of prosocial behavior and suggest that these discrete routes of social cognition differentially drive intraindividual and interindividual differences in altruistic behavior. SIGNIFICANCE STATEMENT: Human societies depend on the altruistic behavior of their members, but teasing apart its underlying motivations and neural mechanisms poses a serious challenge. Using multivariate decoding techniques, we delineated three distinct processes for altruistic decision-making (affective empathy, cognitive perspective taking, and domain-general attention shifts), linked them to dissociable neural computations, and identified their relative influence across individuals. Distinguishing process-specific computations both behaviorally and neurally is crucial for developing complete theoretical and neuroscientific accounts of altruistic behavior and more effective means of increasing it. Moreover, information on the relative influence of subprocesses across individuals and its link to people's more general propensity to engage empathy or perspective taking can inform training programs to increase prosociality, considering their "fit" with different individuals. PMID- 27122032 TI - Susceptibility of Primary Sensory Cortex to Spreading Depolarizations. AB - Spreading depolarizations (SDs) are recognized as actors in neurological disorders as diverse as migraine and traumatic brain injury (TBI). Migraine aura involves sensory percepts, suggesting that sensory cortices might be intrinsically susceptible to SDs. We used optical imaging, MRI, and field potential and potassium electrode recordings in mice and electrocorticographic recordings in humans to determine the susceptibility of different brain regions to SDs. Optical imaging experiments in mice under isoflurane anesthesia showed that both cortical spreading depression and terminal anoxic depolarization arose preferentially in the whisker barrel region of parietal sensory cortex. MRI recordings under isoflurane, ketamine/xylazine, ketamine/isoflurane, and urethane anesthesia demonstrated that the depolarizations did not propagate from a subcortical source. Potassium concentrations showed larger increases in sensory cortex, suggesting a mechanism of susceptibility. Sensory stimulation biased the timing but not the location of depolarization onset. In humans with TBI, there was a trend toward increased incidence of SDs in parietal/temporal sensory cortex compared with other regions. In conclusion, SDs are inducible preferentially in primary sensory cortex in mice and most likely in humans. This tropism can explain the predominant sensory phenomenology of migraine aura. It also demonstrates that sensory cortices are vulnerable in brain injury. SIGNIFICANCE STATEMENT: Spreading depolarizations (SDs) are involved in neurologic disorders as diverse as migraine and traumatic brain injury. In migraine, the nature of aura symptoms suggests that sensory cortex may be preferentially susceptible. In brain injury, SDs occur at a vulnerable time, during which the issue of sensory stimulation is much debated. We show, in mouse and human, that sensory cortex is more susceptible to SDs. We find that sensory stimulation biases the timing but not the location of the depolarizations. Finally, we show a relative impairment of potassium clearance in sensory cortex, providing a potential mechanism for the susceptibility. Our data help to explain the sensory nature of the migraine aura and reveal that sensory cortices are vulnerable in brain injury. PMID- 27122033 TI - Motor Nerve Arborization Requires Proteolytic Domain of Damage-Induced Neuronal Endopeptidase (DINE) during Development. AB - Damage-induced neuronal endopeptidase (DINE)/endothelin-converting enzyme-like 1 (ECEL1) is a membrane-bound metalloprotease, which we originally identified as a nerve regeneration-associated molecule. Abundant expression of DINE is observed in regenerating neurons, as well as in developing spinal motor neurons. In line with this, DINE-deficient (DINE KO) embryos fail to arborize phrenic motor nerves in the diaphragm and to form proper neuromuscular junctions (NMJ), which lead to death shortly after birth. However, it is unclear whether protease activity of DINE is involved in motor nerve terminal arborization and how DINE participates in the process. To address these issues, we performed an in vivo rescue experiment in which three types of motor-neuron specific DINE transgenic mice were crossed with DINE KO mice. The DINE KO mice, which overexpressed wild-type DINE in motor neurons, succeeded in rescuing the aberrant nerve terminal arborization and lethality after birth, while those overexpressing two types of protease domain-mutated DINE failed. Further histochemical analysis showed abnormal behavior of immature Schwann cells along the DINE-deficient axons. Coculture experiments of motor neurons and Schwann cells ensured that the protease domain of neuronal DINE was required for proper alignment of immature Schwann cells along the axon. These findings suggest that protease activity of DINE is crucial for intramuscular innervation of motor nerves and subsequent NMJ formation, as well as proper control of interactions between axons and immature Schwann cells. SIGNIFICANCE STATEMENT: Damage-induced neuronal endopeptidase (DINE) is a membrane-bound metalloprotease; expression is abundant in developing spinal motor neurons, as well as in nerve-injured neurons. DINE-deficient (KO) embryos fail to arborize phrenic motor nerves in the diaphragm and to form a neuromuscular junction, leading to death immediately after birth. To address whether proteolytic activity of DINE is involved in this process, we performed in vivo rescue experiments with DINE KO mice. Transgenic rescue of DINE KO mice was accomplished by overexpression of wild-type DINE, but not by protease domain mutated DINE. Immature Schwann cells were abnormally aligned along the DINE protease-deficient axons. Thus, the protease activity of DINE is crucial for motor axon arborization, as well as the interaction between axons and immature Schwann cells. PMID- 27122034 TI - Mutations in Cockayne Syndrome-Associated Genes (Csa and Csb) Predispose to Cisplatin-Induced Hearing Loss in Mice. AB - Cisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly understood, as are the specific DNA repair pathways that protect these cells. Nucleotide excision repair (NER) is a conserved and versatile DNA repair pathway for many DNA-distorting lesions, including cisplatin-DNA adducts. Progressive sensorineural hearing loss is observed in a subset of NER-associated DNA repair disorders including Cockayne syndrome and some forms of xeroderma pigmentosum. We investigated whether either of the two overlapping branches that encompass NER, transcription-coupled repair or global genome repair, which are implicated in Cockayne syndrome and xeroderma pigmentosum group C, respectively, modulates cisplatin-induced hearing loss and cell death in the organ of Corti, the auditory sensory epithelium of mammals. We report that cochlear hair cells and supporting cells in transcription-coupled repair-deficient Cockayne syndrome group A (Csa(-/-)) and group B (Csb(-/-)) mice are hypersensitive to cisplatin, in contrast to global genome repair-deficient Xpc(-/-) mice, both in vitro and in vivo We show that sensory hair cells in Csa( /-) and Csb(-/-) mice fail to remove cisplatin-DNA adducts efficiently in vitro; and unlike Xpc(-/-) mice, Csa(-/-) and Csb(-/-) mice lose hearing and manifest outer hair cell degeneration after systemic cisplatin treatment. Our results demonstrate that Csa and Csb deficiencies predispose to cisplatin-induced hearing loss and hair/supporting cell damage in the mammalian organ of Corti, and emphasize the importance of transcription-coupled DNA repair in the protection against cisplatin ototoxicity. SIGNIFICANCE STATEMENT: The utility of cisplatin in chemotherapy remains limited due to serious side effects, including sensorineural hearing loss. We show that mouse models of Cockayne syndrome, a progeroid disorder resulting from a defect in the transcription-coupled DNA repair (TCR) branch of nucleotide excision repair, are hypersensitive to cisplatin-induced hearing loss and sensory hair cell death in the organ of Corti, the mammalian auditory sensory epithelium. Our work indicates that Csa and Csb, two genes involved in TCR, are preferentially required to protect against cisplatin ototoxicity, relative to global genome repair-specific elements of nucleotide excision repair, and suggests that TCR is a major force maintaining DNA integrity in the cochlea. The Cockayne syndrome mice thus represent a model for testing the contribution of DNA repair mechanisms to cisplatin ototoxicity. PMID- 27122035 TI - Stimulus-Elicited Connectivity Influences Resting-State Connectivity Years Later in Human Development: A Prospective Study. AB - Although the functional architecture of the brain is indexed by resting-state connectivity networks, little is currently known about the mechanisms through which these networks assemble into stable mature patterns. The current study posits and tests the long-term phasic molding hypothesis that resting-state networks are gradually shaped by recurring stimulus-elicited connectivity across development by examining how both stimulus-elicited and resting-state functional connections of the human brain emerge over development at the systems level. Using a sequential design following 4- to 18-year-olds over a 2 year period, we examined the predictive associations between stimulus-elicited and resting-state connectivity in amygdala-cortical circuitry as an exemplar case (given this network's protracted development across these ages). Age-related changes in amygdala functional connectivity converged on the same regions of medial prefrontal cortex (mPFC) and inferior frontal gyrus when elicited by emotional stimuli and when measured at rest. Consistent with the long-term phasic molding hypothesis, prospective analyses for both connections showed that the magnitude of an individual's stimulus-elicited connectivity unidirectionally predicted resting-state functional connectivity 2 years later. For the amygdala-mPFC connection, only stimulus-elicited connectivity during childhood and the transition to adolescence shaped future resting-state connectivity, consistent with a sensitive period ending with adolescence for the amygdala-mPFC circuit. Together, these findings suggest that resting-state functional architecture may arise from phasic patterns of functional connectivity elicited by environmental stimuli over the course of development on the order of years. SIGNIFICANCE STATEMENT: A fundamental issue in understanding the ontogeny of brain function is how resting-state (intrinsic) functional networks emerge and relate to stimulus elicited functional connectivity. Here, we posit and test the long-term phasic molding hypothesis that resting-state network development is influenced by recurring stimulus-elicited connectivity through prospective examination of the developing human amygdala-cortical functional connections. Our results provide critical insight into how early environmental events sculpt functional network architecture across development and highlight childhood as a potential developmental period of heightened malleability for the amygdala-medial prefrontal cortex circuit. These findings have implications for how both positive and adverse experiences influence the developing brain and motivate future investigations of whether this molding mechanism reflects a general phenomenon of brain development. PMID- 27122036 TI - FGF-1 Triggers Pannexin-1 Hemichannel Opening in Spinal Astrocytes of Rodents and Promotes Inflammatory Responses in Acute Spinal Cord Slices. AB - We show here that the growth factor FGF-1 is proinflammatory in the spinal cord and explore the inflammatory mechanisms. FGF-1 applied to rat spinal astrocytes in culture initiates calcium signaling and induces secretion of ATP that within minutes increases membrane permeability to ethidium (Etd(+)) and Ca(2+) by activating P2X7 receptors (P2X7Rs) that open pannexin hemichannels (Px1 HCs) that release further ATP; by 7 h treatment, connexin 43 hemichannels (Cx43 HCs) are also opened. In acute mouse spinal cord slices ex vivo, we found that FGF-1 treatment for 1 h increases the percentage of GFAP-positive astrocytes that show enhanced Px1 HC-mediated Etd(+) uptake. This response to FGF-1 was not observed in astrocytes in slices of cerebral cortex. FGF-1-induced dye uptake by astrocytes is prevented by BAPTA-AM or a phospholipase C (PLC) inhibitor. Furthermore, in spinal cord slices, P2X7R antagonists (BBG and A740003) and Px1 HC blockers ((10)Panx1 and carbenoxolone) prevent the increase in Etd(+) uptake by astrocytes, whereas Gap19, a selective Cx43 HC blocker, has no effect on dye uptake at this time. Microglia are not required for the increase in Etd(+) uptake by astrocytes induced by FGF-1, although they are activated by FGF-1 treatment. The morphological signs of microglia activation are inhibited by P2X7R antagonists and (10)Panx1 and are associated with elevated levels of proinflammatory cytokines in cord slices treated with FGF-1. The FGF-1 initiated cascade may play an important role in spinal cord inflammation in vivo SIGNIFICANCE STATEMENT: We find that FGF-1 elevates [Ca(2+)]i in spinal astrocytes, which causes vesicular release of ATP and activation of P2X7Rs to trigger opening of Px1 HCs, which release further ATP. This regenerative response occurs in astrocyte cultures and in acute spinal cord slices. In the latter, FGF 1 application promotes the activation of microglia and increases the production of proinflammatory cytokines through mechanisms depending on P2X7 receptors and Px1 HCs. This proinflammatory microenvironment may favor recruitment of leukocytes into the spinal cord and impacts negatively on neuronal structure and function in vivo Any step in these processes provides a potential therapeutic target for treatment of secondary damage in various spinal cord pathologies. PMID- 27122038 TI - Neurotrophin-3 Regulates Synapse Development by Modulating TrkC-PTPsigma Synaptic Adhesion and Intracellular Signaling Pathways. AB - Neurotrophin-3 (NT-3) is a secreted neurotrophic factor that binds neurotrophin receptor tyrosine kinase C (TrkC), which in turn binds to presynaptic protein tyrosine phosphatase sigma (PTPsigma) to govern excitatory synapse development. However, whether and how NT-3 cooperates with the TrkC-PTPsigma synaptic adhesion pathway and TrkC-mediated intracellular signaling pathways in rat cultured neurons has remained unclear. Here, we report that NT-3 enhances TrkC binding affinity for PTPsigma. Strikingly, NT-3 treatment bidirectionally regulates the synaptogenic activity of TrkC: at concentrations of 10-25 ng/ml, NT-3 further enhanced the increase in synapse density induced by TrkC overexpression, whereas at higher concentrations, NT-3 abrogated TrkC-induced increases in synapse density. Semiquantitative immunoblotting and optogenetics-based imaging showed that 25 ng/ml NT-3 or light stimulation at a power that produced a comparable level of NT-3 (6.25 MUW) activated only extracellular signal-regulated kinase (ERK) and Akt, whereas 100 ng/ml NT-3 (light intensity, 25 MUW) further triggered the activation of phospholipase C-gamma1 and CREB independently of PTPsigma. Notably, disruption of TrkC intracellular signaling pathways, extracellular ligand binding, or kinase activity by point mutations compromised TrkC-induced increases in synapse density. Furthermore, only sparse, but not global, TrkC knock-down in cultured rat neurons significantly decreased synapse density, suggesting that intercellular differences in TrkC expression level are critical for its synapse-promoting action. Together, our data demonstrate that NT-3 is a key factor in excitatory synapse development that may direct higher-order assembly of the TrkC/PTPsigma complex and activate distinct intracellular signaling cascades in a concentration-dependent manner to promote competition based synapse development processes. SIGNIFICANCE STATEMENT: In this study, we present several lines of experimental evidences to support the conclusion that neurotrophin-3 (NT-3) modulates the synaptic adhesion pathway involving neurotrophin receptor tyrosine kinase C (TrkC) and presynaptic protein tyrosine phosphatase sigma (PTPsigma) in a bidirectional manner at excitatory synapses. NT 3 acts in concentration-independent manner to facilitate TrkC-mediated presynaptic differentiation, whereas it acts in a concentration-dependent manner to exert differential effects on TrkC-mediated organization of postsynaptic development. We further investigated TrkC extracellular ligand binding, intracellular signaling pathways, and kinase activity in NT-3-induced synapse development. Last, we found that interneuronal differences in TrkC levels regulate the synapse number. Overall, these results suggest that NT-3 functions as a positive modulator of synaptogenesis involving TrkC and PTPsigma. PMID- 27122037 TI - Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area. AB - Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposure in vivo leads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA). We tested the hypothesis that Epac mediates cocaine-induced changes in AMPAR subunit composition in the VTA. We report that a single cocaine injection in vivo in wild type mice leads to inward rectification of EPSCs and renders EPSCs sensitive to a GluA2-lacking AMPAR blocker in VTA dopamine neurons. The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1 deficient mice. In addition, activation of Epac with the selective Epac agonist 8 CPT-2Me-cAMP (8-CPT) recapitulated the cocaine-induced increase in GluA2-lacking AMPARs, and the effects of 8-CPT were mediated by Epac2. We also show that conditioned place preference to cocaine was impaired in Epac2-deficient mice and in mice in which Epac2 was knocked down in the VTA but was not significantly altered in Epac1-deficient mice. Together, these results suggest that Epac2 is critically involved in the cocaine-induced change in AMPAR subunit composition and drug-cue associative learning. SIGNIFICANCE STATEMENT: Addictive drugs, such as cocaine, induce long-lasting adaptions in the reward circuits of the brain. A single intraperitoneal injection of cocaine leads to changes in the composition and property of the AMPAR that carries excitatory inputs to dopamine neurons. Here, we provide evidence that exchange protein directly activated by cAMP (Epac), a cAMP sensor protein, is required for the cocaine-induced changes of the AMPAR. We found that the effects of cocaine were mimicked by activation of Epac but were blocked by genetic deletion of Epac. Furthermore, cocaine-cue associative learning was impaired in mice lacking Epac. These findings uncovered a critical role of Epac in regulating the cellular and behavioral actions of cocaine. PMID- 27122039 TI - The Neural Feedback Response to Error As a Teaching Signal for the Motor Learning System. AB - When we experience an error during a movement, we update our motor commands to partially correct for this error on the next trial. How does experience of error produce the improvement in the subsequent motor commands? During the course of an erroneous reaching movement, proprioceptive and visual sensory pathways not only sense the error, but also engage feedback mechanisms, resulting in corrective motor responses that continue until the hand arrives at its goal. One possibility is that this feedback response is co-opted by the learning system and used as a template to improve performance on the next attempt. Here we used electromyography (EMG) to compare neural correlates of learning and feedback to test the hypothesis that the feedback response to error acts as a template for learning. We designed a task in which mixtures of error-clamp and force-field perturbation trials were used to deconstruct EMG time courses into error-feedback and learning components. We observed that the error-feedback response was composed of excitation of some muscles, and inhibition of others, producing a complex activation/deactivation pattern during the reach. Despite this complexity, across muscles the learning response was consistently a scaled version of the error-feedback response, but shifted 125 ms earlier in time. Across people, individuals who produced a greater feedback response to error, also learned more from error. This suggests that the feedback response to error serves as a teaching signal for the brain. Individuals who learn faster have a better teacher in their feedback control system. SIGNIFICANCE STATEMENT: Our sensory organs transduce errors in behavior. To improve performance, we must generate better motor commands. How does the nervous system transform an error in sensory coordinates into better motor commands in muscle coordinates? Here we show that when an error occurs during a movement, the reflexes transform the sensory representation of error into motor commands. To learn from error, the nervous system scales this feedback response and then shifts it earlier in time, adding it to the previously generated motor commands. This addition serves as an update to the motor commands, constituting the learning signal. Therefore, by providing a coordinate transformation, the feedback system generates a template for learning from error. PMID- 27122040 TI - GluD2 Endows Parallel Fiber-Purkinje Cell Synapses with a High Regenerative Capacity. AB - Although injured axons usually do not regenerate in the adult CNS, parallel fibers (PFs) regenerate synaptic connections onto cerebellar Purkinje cells (PCs). In this study, we investigated the role of GluD2 in this regenerative process after PF transection using GluD2-knock-out (KO) mice. All dendritic spines on distal dendrites were innervated by PFs in sham-operated wild-type controls, whereas one-third were devoid of innervation in GluD2-KO mice. In both genotypes, a steep drop in the number of PF synapses occurred with a reciprocal surge in the number of free spines on postlesion day 1, when the PF territory aberrantly expanded toward the proximal dendrites. In wild-type mice, the territory and number of PF synapses were nearly fully restored to normal on postlesion day 7, although PF density remained low. Moreover, presynaptic and postsynaptic elements were markedly enlarged, and the PF terminal-to-PC spine contact ratio increased from 1:1 to 1:2 at most synapses. On postlesion day 30, the size and contact ratio of PF synapses returned to sham-operated control values and PF density recovered through the sprouting and elongation of PF collaterals. However, GluD2-KO mice showed neither a hypertrophic response nor territorial restoration 7 d postlesion, nor the recovery of PF axons or synapses on postlesion day 30. This suggests that PF wiring regenerates initially by inducing hypertrophic responses in surviving synaptic elements (hypertrophic phase), followed by collateral formation by PF axons and retraction of PF synapses (remodeling phase). Without GluD2, no transition to these regenerative phases occurs. SIGNIFICANCE STATEMENT: The glutamate receptor GluD2 expressed at parallel fiber (PF)-Purkinje cell (PC) synapses regulates the formation and maintenance of the synapses. To investigate the role of GluD2 in their extraordinarily high regenerative capacity, the process after surgical transection of PFs was compared between wild-type and GluD2-knock-out mice. We discovered that, in wild-type mice, PF synapses regenerate initially by inducing hypertrophic responses in surviving synaptic elements, and then by sprouting and elongation of PF collaterals. Subsequently, hypertrophied PF synapses remodel into compact synapses. In GluD2-knock-out mice, PF wiring remains in the degenerative phase, showing neither a hypertrophic response nor recovery of PF axons or synapses. Our finding thus highlights that synaptic connection in the adult brain can regenerate with aid of GluD2. PMID- 27122042 TI - Responses to Pop-Out Stimuli in the Barn Owl's Optic Tectum Can Emerge through Stimulus-Specific Adaptation. AB - Here, we studied neural correlates of orientation-contrast-based saliency in the optic tectum (OT) of barn owls. Neural responses in the intermediate/deep layers of the OT were recorded from lightly anesthetized owls confronted with arrays of bars in which one bar (the target) was orthogonal to the remaining bars (the distractors). Responses to target bars were compared with responses to distractor bars in the receptive field (RF). Initially, no orientation-contrast sensitivity was observed. However, if the position of the target bar in the array was randomly shuffled across trials so that it occasionally appeared in the RF, then such sensitivity emerged. The effect started to become significant after three or four positional changes of the target bar and strengthened with additional trials. Our data further suggest that this effect arises due to specific adaptation to the stimulus in the RF combined with suppression from the surround. By jittering the position of the bar inside the RF across trials, we demonstrate that the adaptation has two components, one position specific and one orientation specific. The findings give rise to the hypothesis that barn owls, by active scanning of the scene, can induce adaptation of the tectal circuitry to the common orientation and thus achieve a "pop-out" of rare orientations. Such a model is consistent with several behavioral observations in owls and may be relevant to other visual features and species. SIGNIFICANCE STATEMENT: Natural scenes are often characterized by a dominant orientation, such as the scenery of a pine forest or the sand dunes in a windy desert. Therefore, orientation that contrasts the regularity of the scene is perceived salient for many animals as a means to break camouflage. By actively moving the scene between each trial, we show here that neurons in the retinotopic map of the barn owl's optic tectum specifically adapt to the common orientation, giving rise to preferential representation of odd orientations. Based on this, we suggest a new mechanism for orientation-based camouflage breaking that links active scanning of scenes with neural adaptation. This mechanism may be relevant to pop-out in other species and visual features. PMID- 27122041 TI - Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model. AB - Schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110delta, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110delta reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110delta as a target for antipsychotic drug development. SIGNIFICANCE STATEMENT: Schizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory-inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia. PMID- 27122043 TI - Maternal Loss of Ube3a Impairs Experience-Driven Dendritic Spine Maintenance in the Developing Visual Cortex. AB - Dendritic spines are a morphological feature of the majority of excitatory synapses in the mammalian neocortex and are motile structures with shapes and lifetimes that change throughout development. Proper cortical development and function, including cortical contributions to learning and memory formation, require appropriate experience-dependent dendritic spine remodeling. Dendritic spine abnormalities have been reported for many neurodevelopmental disorders, including Angelman syndrome (AS), which is caused by the loss of the maternally inherited UBE3A allele (encoding ubiquitin protein ligase E3A). Prior studies revealed that UBE3A protein loss leads to reductions in dendritic spine density and diminished excitatory synaptic transmission. However, the decrease in spine density could come from either a reduction in spine formation or an increase in spine elimination. Here, we used acute and longitudinal in vivo two-photon microscopy to investigate developmental and experience-dependent changes in the numbers, dynamics, and morphology of layer 5 pyramidal neuron apical dendritic spines in the primary visual cortex of control and AS model mice (Ube3a(m-/p+) mice). We found that neurons in AS model mice undergo a greater elimination of dendritic spines than wild-type mice during the end of the first postnatal month. However, when raised in darkness, spine density and dynamics were indistinguishable between control and AS model mice, which indicates that decreased spine density in AS model mice reflects impaired experience-driven spine maintenance. Our data thus demonstrate an experience-dependent anatomical substrate by which the loss of UBE3A reduces dendritic spine density and disrupts cortical circuitry. SIGNIFICANCE STATEMENT: Reduced dendritic spine densities are common in the neurodevelopmental disorder Angelman syndrome (AS). Because prior reports were based on postmortem tissue, it was unknown whether this anatomical deficit arises from decreased spine formation and/or increased spine elimination. Here, we used in vivo two-photon imaging to track spines over multiple days in a mouse model of AS. We found that spine formation is normal, but experience dependent spine maintenance is reduced in the visual cortex of AS model mice. Our data pinpoint the anatomical process underlying the loss of dendritic spines, which can account for the decreased excitatory synaptic connectivity associated with AS. Therefore, normalizing spine maintenance is a potential therapeutic strategy. PMID- 27122044 TI - Knockdown of Dyslexia-Gene Dcdc2 Interferes with Speech Sound Discrimination in Continuous Streams. AB - Dyslexia is the most common developmental language disorder and is marked by deficits in reading and phonological awareness. One theory of dyslexia suggests that the phonological awareness deficit is due to abnormal auditory processing of speech sounds. Variants in DCDC2 and several other neural migration genes are associated with dyslexia and may contribute to auditory processing deficits. In the current study, we tested the hypothesis that RNAi suppression of Dcdc2 in rats causes abnormal cortical responses to sound and impaired speech sound discrimination. In the current study, rats were subjected in utero to RNA interference targeting of the gene Dcdc2 or a scrambled sequence. Primary auditory cortex (A1) responses were acquired from 11 rats (5 with Dcdc2 RNAi; DC ) before any behavioral training. A separate group of 8 rats (3 DC-) were trained on a variety of speech sound discrimination tasks, and auditory cortex responses were acquired following training. Dcdc2 RNAi nearly eliminated the ability of rats to identify specific speech sounds from a continuous train of speech sounds but did not impair performance during discrimination of isolated speech sounds. The neural responses to speech sounds in A1 were not degraded as a function of presentation rate before training. These results suggest that A1 is not directly involved in the impaired speech discrimination caused by Dcdc2 RNAi. This result contrasts earlier results using Kiaa0319 RNAi and suggests that different dyslexia genes may cause different deficits in the speech processing circuitry, which may explain differential responses to therapy. SIGNIFICANCE STATEMENT: Although dyslexia is diagnosed through reading difficulty, there is a great deal of variation in the phenotypes of these individuals. The underlying neural and genetic mechanisms causing these differences are still widely debated. In the current study, we demonstrate that suppression of a candidate-dyslexia gene causes deficits on tasks of rapid stimulus processing. These animals also exhibited abnormal neural plasticity after training, which may be a mechanism for why some children with dyslexia do not respond to intervention. These results are in stark contrast to our previous work with a different candidate gene, which caused a different set of deficits. Our results shed some light on possible neural and genetic mechanisms causing heterogeneity in the dyslexic population. PMID- 27122047 TI - Neuroprotective effects of resveratrol against traumatic brain injury in rats: Involvement of synaptic proteins and neuronal autophagy. AB - Traumatic brain injury (TBI) involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death, leading to long-term cognitive deficits, and effective therapeutic strategies targeting neuronal death remain elusive. The present study aimed to determine whether the administration of resveratrol (100 mg/kg) was able to significantly enhance functional recovery in a rat model of TBI and whether resveratrol treatment was able to upregulate synaptic protein expression and suppress post-TBI neuronal autophagy. The results demonstrated that daily treatment with resveratrol attenuated TBI-induced brain edema and improved spatial cognitive function and neurological impairment in rats. The expression of synaptic proteins was downregulated following TBI and this phenomenon was partly reversed by treatment with resveratrol. In addition, resveratrol was observed to significantly reduce the levels of the autophagic marker proteins, microtubule-associated protein light chain 3-II and Beclin1, in the hippocampus compared with the TBI group. Therefore, these results suggest that resveratrol may represent a novel therapeutic strategy for TBI, and that this protection may be associated with the upregulation of synaptophysin, postsynaptic density protein 95 and the suppression of neuronal autophagy. PMID- 27122046 TI - The healthy human microbiome. AB - Humans are virtually identical in their genetic makeup, yet the small differences in our DNA give rise to tremendous phenotypic diversity across the human population. By contrast, the metagenome of the human microbiome-the total DNA content of microbes inhabiting our bodies-is quite a bit more variable, with only a third of its constituent genes found in a majority of healthy individuals. Understanding this variability in the "healthy microbiome" has thus been a major challenge in microbiome research, dating back at least to the 1960s, continuing through the Human Microbiome Project and beyond. Cataloguing the necessary and sufficient sets of microbiome features that support health, and the normal ranges of these features in healthy populations, is an essential first step to identifying and correcting microbial configurations that are implicated in disease. Toward this goal, several population-scale studies have documented the ranges and diversity of both taxonomic compositions and functional potentials normally observed in the microbiomes of healthy populations, along with possible driving factors such as geography, diet, and lifestyle. Here, we review several definitions of a 'healthy microbiome' that have emerged, the current understanding of the ranges of healthy microbial diversity, and gaps such as the characterization of molecular function and the development of ecological therapies to be addressed in the future. PMID- 27122049 TI - Retraction Note: Undertreatment of breast cancer in the elderly. PMID- 27122048 TI - Maternal corticosterone exposure in the mouse programs sex-specific renal adaptations in the renin-angiotensin-aldosterone system in 6-month offspring. AB - Short-term maternal corticosterone (Cort) administration at mid-gestation in the mouse reduces nephron number in both sexes while programming renal and cardiovascular dysfunction in 12-month male but not female offspring. The renal renin-angiotensin-aldosterone system (RAAS), functions in a sexually dimorphic manner to regulate both renal and cardiovascular physiology. This study aimed to identify if there are sex-specific differences in basal levels of the intrarenal RAAS and to determine the impact of maternal Cort exposure on the RAAS in male and female offspring at 6 months of age. While intrarenal renin concentrations were higher in untreated females compared to untreated males, renal angiotensin II concentrations were higher in males than females. Furthermore, basal plasma aldosterone concentrations were greater in females than males. Cort exposed male but not female offspring had reduced water intake and urine excretion. Cort exposure increased renal renin concentrations and elevated mRNA expression of Ren1, Ace2, and Mas1 in male but not female offspring. In addition, male Cort exposed offspring had increased expression of the aldosterone receptor, Nr3c2 and renal sodium transporters. In contrast, Cort exposure increased Agtr1a mRNA levels in female offspring only. This study demonstrates that maternal Cort exposure alters key regulators of renal function in a sex-specific manner at 6 months of life. These finding likely contribute to the disease outcomes in male but not female offspring in later life and highlights the importance of renal factors other than nephron number in the programming of renal and cardiovascular disease. PMID- 27122050 TI - A novel, integrated PET-guided MRS technique resulting in more accurate initial diagnosis of high-grade glioma. AB - Glioblastoma multiforme (GBM) is the most common and lethal malignant glioma in adults. Currently, the modality of choice for diagnosing brain tumor is high resolution magnetic resonance imaging (MRI) with contrast, which provides anatomic detail and localization. Studies have demonstrated, however, that MRI may have limited utility in delineating the full tumor extent precisely. Studies suggest that MR spectroscopy (MRS) can also be used to distinguish high-grade from low-grade gliomas. However, due to operator dependent variables and the heterogeneous nature of gliomas, the potential for error in diagnostic accuracy with MRS is a concern. Positron emission tomography (PET) imaging with (11)C methionine (MET) and (18)F-fluorodeoxyglucose (FDG) has been shown to add additional information with respect to tumor grade, extent, and prognosis based on the premise of biochemical changes preceding anatomic changes. Combined PET/MRS is a technique that integrates information from PET in guiding the location for the most accurate metabolic characterization of a lesion via MRS. We describe a case of glioblastoma multiforme in which MRS was initially non diagnostic for malignancy, but when MRS was repeated with PET guidance, demonstrated elevated choline/N-acetylaspartate (Cho/NAA) ratio in the right parietal mass consistent with a high-grade malignancy. Stereotactic biopsy, followed by PET image-guided resection, confirmed the diagnosis of grade IV GBM. To our knowledge, this is the first reported case of an integrated PET/MRS technique for the voxel placement of MRS. Our findings suggest that integrated PET/MRS may potentially improve diagnostic accuracy in high-grade gliomas. PMID- 27122051 TI - The association between multimorbidity and hospitalization is modified by individual demographics and physician continuity of care: a retrospective cohort study. AB - BACKGROUND: Multimorbidity poses a significant clinical challenge and has been linked to greater health services use, including hospitalization; however, we have little knowledge about the influence of contextual factors on outcomes in this population. OBJECTIVES: To describe the extent to which the association between multimorbidity and hospitalization is modified by age, gender, primary care practice model, or continuity of care (COC) among adults with at least one chronic condition. METHODS: A retrospective cohort study with linked population based administrative data. SETTING: Ontario, Canada. COHORT: All individuals 18 and older with at least one of 16 priority chronic conditions as of April 1, 2009 (baseline). MAIN OUTCOME MEASURES: Any hospitalization, 3 or more hospitalizations, non-medical discharge delay, and 30-day readmission within the 1 year following baseline. RESULTS: Of 5,958,514 individuals, 484,872 (8.1 %) experienced 646,347 hospitalizations. There was a monotonic increase in the likelihood of hospitalization and related outcomes with increasing multimorbidity which was modified by age, gender, and COC but not primary care practice model. The effect of increasing multimorbidity was greater in younger adults than older adults and in those with lower COC than with higher COC. The effect of increasing multimorbidity on hospitalization was greater in men than women but reversed for the other outcomes. CONCLUSIONS: The effect of multimorbidity on hospitalization is influenced by age and gender, important considerations in the development of person-centred care models. Greater continuity of physician care lessened the effect of multimorbidity on hospitalization, further demonstrating the need for care continuity across providers for people with chronic conditions. PMID- 27122052 TI - Identification of the cysteine residue responsible for oxidative inactivation of mouse galectin-2. AB - Galectins are a group of animal lectins characterized by their specificity for beta-galactosides. Mouse galectin-2 (mGal-2) is predominantly expressed in the gastrointestinal tract and has been identified as one of the main gastric mucosal proteins that are uniquely sensitive to S-nitrosylation. We have previously reported that oxidation of mGal-2 by hydrogen peroxide (H2O2) resulted in the loss of sugar-binding ability, whereas pre-treatment of mGal-2 with S nitrosocysteine prevented H2O2-induced inactivation. In this study, we used point mutated recombinant mGal-2 proteins to study which of the two highly conserved Cys residues in mGal-2 must be S-nitrosylated for protection against oxidative inactivation. Mutation of Cys57 to a Met residue (C57M) did not result in lectin inactivation following H2O2 treatment, whereas Cys75 mutation to Ser (C75S) led to significantly reduced lectin activity, as is the case for wild-type mGal-2. However, pre-treatment of the C75S mutant with S-nitrosocysteine protected the protein from H2O2-induced inactivation. Therefore, Cys57 is suggested to be responsible for oxidative inactivation of the mGal-2 protein, and protection of the sulfhydryl group of the Cys57 in mGal-2 by S-nitrosylation is likely important for maintaining mGal-2 protein function in an oxidative environment such as the gastrointestinal tract. PMID- 27122053 TI - Apoptotic Effects of Rotundic Acid on Human Esophagus and Lung Cancer Cells. AB - Rotundic acid (RA) is a pentacyclic triterpenic acid. Apoptotic effects of RA at 4, 8, or 16 uM in OE33 and A549 cell lines, an esophageal squamous cancer cell line and a non-small-cell lung cancer cell line, were examined. RA at 4 to 16 uM inhibited the survival of both cell lines. RA at 8 and 16 uM decreased Bcl-2 expression and at 4 to 16 uM upregulated Bax and cleaved caspase-3 expression. RA treatments decreased the ratio of Bcl-2/Bax in those cells. RA at 4 to 16 uM lowered Na+-K+-ATPase activity and reduced mitochondrial membrane potential in OE33 and A549 cells. RA at 8 and 16 uM enhanced DNA fragmentation and caspase-3 and caspase-9 expression in OE33 cells. In A549 cells, RA increased caspase-3 expression in a concentration-dependent manner; but only at 8 and 16 uM, it upregulated caspase-9 expression. RA treatments at 4 to 16 uM decreased protein kinase c activity, suppressed the expression of cytochrome c and apoptosis inducing factor, and lowered the production of reactive oxygen species, vascular endothelial growth factor, transforming growth factor-beta1, and tumor necrosis factor-alpha in both cell lines. RA at 8 and 16 uM downregulated hypoxia inducible factor-1alpha expression. These findings suggest that RA could penetrate into OE33 and A549 cells and execute cytotoxic activities. PMID- 27122055 TI - DWI-MRI and Fabry disease: what can we learn? PMID- 27122054 TI - Real-time two- and three-dimensional imaging of monocyte motility and navigation on planar surfaces and in collagen matrices: roles of Rho. AB - We recently found that macrophages from RhoA/RhoB double knockout mice had increased motility of the cell body, but severely impaired retraction of the tail and membrane extensions, whereas RhoA- or RhoB-deficient cells exhibited mild phenotypes. Here we extended this work and investigated the roles of Rho signaling in primary human blood monocytes migrating in chemotactic gradients and in various settings. Monocyte velocity, but not chemotactic navigation, was modestly dependent on Rho-ROCK-myosin II signaling on a 2D substrate or in a loose collagen type I matrix. Viewed by time-lapse epi-fluorescence microscopy, monocytes appeared to flutter rather than crawl, such that the 3D surface topology of individual cells was difficult to predict. Spinning disk confocal microscopy and 3D reconstruction revealed that cells move on planar surfaces and in a loose collagen matrix using prominent, curved planar protrusions, which are rapidly remodeled and reoriented, as well as resorbed. In a dense collagen type I matrix, there is insufficient space for this mode and cells adopt a highly Rho dependent, lobular mode of motility. Thus, in addition to its role in tail retraction on 2D surfaces, Rho is critical for movement in confined spaces, but is largely redundant for motility and chemotaxis in loose matrices. PMID- 27122056 TI - Sitagliptin inhibits endothelin-1 expression in the aortic endothelium of rats with streptozotocin-induced diabetes by suppressing the nuclear factor kappaB/IkappaBalpha system through the activation of AMP-activated protein kinase. AB - Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors, including sitagliptin, exert favourable effects on the vascular endothelium. DPP 4 inhibitors suppress the degradation of glucagon-like peptide-1 (GLP-1), which has been reported to enhance nitric oxide (NO) production. However, the effects of DPP-4 inhibitors on endothelin-1 (ET-1) expression in the aorta, as well as the underlying mechanisms responsible for these effects, have yet to be investigated in animal models of diabetes mellitus (DM). In the present study, the rats were randomly divided into the following four groups: i) control; ii) DM; iii) DM + low-dose sitagliptin (10 mg/kg); and iv) DM + high-dose sitagliptin (30 mg/kg). Apart from the control group, all the rats received a high-fat diet for 8 weeks prior to the induction of diabetes with an intraperitoneal injection of streptozotocin. The treatments were then administered for 12 weeks. The serum levels of ET-1, NO, GLP-1 and insulin were measured as well as endothelial function. The expression of ET-1, AMP-activated protein kinase (AMPK) and nuclear factor (NF)-kappaB/IkappaBalpha were determined. After 12 weeks of treatment, the diabetic rats receiving sitagliptin showed significantly elevated serum levels of GLP-1 and NO, and reduced levels of ET-1. Moreover, sitagliptin significantly attenuated endothelial dysfunction as well as the remodeling of the aortic wall. Notably, sitagliptin inhibited ET-1 expression at the transcriptional and translational level in the aorta, which may have been mediated by the suppression of the NF-kappaB/IkappaBalpha system induced by AMPK activation. The majority of the above-mentioned effects were dose dependent. Taken together, the findings of the present study indicate that sitagliptin inhibits ET-1 expression in the aortic endothelium by suppressing the NF-kappaB/IkappaBalpha system through the activation of the AMPK pathway in diabetic rats. These findings further demonstrate some of the vasoprotective properties of DPP-4 inhibitors in vivo. PMID- 27122057 TI - Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses. AB - Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis((r)) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89 97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential. PMID- 27122058 TI - Oncostatin M overexpression induces skin inflammation but is not required in the mouse model of imiquimod-induced psoriasis-like inflammation. AB - Oncostatin M (OSM) has been reported to be overexpressed in psoriasis skin lesions and to exert proinflammatory effects in vitro on human keratinocytes. Here, we report the proinflammatory role of OSM in vivo in a mouse model of skin inflammation induced by intradermal injection of murine OSM-encoding adenovirus (AdOSM) and compare with that induced by IL-6 injection. Here, we show that OSM potently regulates the expression of genes involved in skin inflammation and epidermal differentiation in murine primary keratinocytes. In vivo, intradermal injection of AdOSM in mouse ears provoked robust skin inflammation with epidermal thickening and keratinocyte proliferation, while minimal effect was observed after AdIL-6 injection. OSM overexpression in the skin increased the expression of the S100A8/9 antimicrobial peptides, CXCL3, CCL2, CCL5, CCL20, and Th1/Th2 cytokines, in correlation with neutrophil and macrophage infiltration. In contrast, OSM downregulated the expression of epidermal differentiation genes, such as cytokeratin-10 or filaggrin. Collectively, these results support the proinflammatory role of OSM when it is overexpressed in the skin. However, OSM expression was not required in the murine model of psoriasis induced by topical application of imiquimod, as demonstrated by the inflammatory phenotype of OSM deficient mice or wild-type mice treated with anti-OSM antibodies. PMID- 27122059 TI - Sibling eating behaviours and parental feeding practices with siblings: similar or different? AB - OBJECTIVE: Little is known about whether siblings have similar or different eating behaviours or whether parents tailor their feeding practices to different siblings. The main objectives of the present study were to examine similarities and differences in child eating behaviours and parental feeding practices with siblings and to determine whether child eating behaviours and parental feeding practices differ depending on sibling concordant (i.e. both siblings overweight or healthy weight) or discordant (i.e. one sibling overweight and one sibling healthy weight) weight status. DESIGN: Cross-sectional, mixed-methods study. SETTING: In-home visits were conducted by research staff. Surveys were conducted with parents and anthropometry was collected on parents and siblings. SUBJECTS: Children (n 88) aged 6-12 years (mean age 9 (sd 2) years), their parents (mean age 34 (sd 7) years) and near-age siblings (mean age 9 (sd 4) years) from diverse racial/ethnic and low-income households participated. RESULTS: Results indicated that siblings with higher BMI engaged in higher levels of emotional eating compared with siblings with lower BMI. Additionally, results indicated that when families had sibling dyads discordant on weight status, the sibling who was overweight had higher food enjoyment and lower levels of food satiety. Additionally, within siblings with discordant weight status, parents were more likely to use restrictive feeding practices with the overweight sibling and pressure-to-eat and encouragement-to-eat feeding practices with the healthy weight sibling. CONCLUSIONS: Family-based childhood obesity interventions may need to assess for sibling weight status when researching the home environment and intervene with parents to avoid using restriction or pressure-to-eat feeding practices when siblings are discordant on weight status. PMID- 27122060 TI - Subclinical cardiovascular changes in pediatric solid organ transplant recipients. PMID- 27122061 TI - Rhizoma Dioscoreae extract protects against alveolar bone loss by regulating the cell cycle: A predictive study based on the protein-protein interaction network. AB - Rhizoma Dioscoreae extract (RDE) exhibits a protective effect on alveolar bone loss in ovariectomized (OVX) rats. The aim of this study was to predict the pathways or targets that are regulated by RDE, by re-assessing our previously reported data and conducting a protein-protein interaction (PPI) network analysis. In total, 383 differentially expressed genes (>=3-fold) between alveolar bone samples from the RDE and OVX group rats were identified, and a PPI network was constructed based on these genes. Furthermore, four molecular clusters (A-D) in the PPI network with the smallest P-values were detected by molecular complex detection (MCODE) algorithm. Using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA) tools, two molecular clusters (A and B) were enriched for biological process in Gene Ontology (GO). Only cluster A was associated with biological pathways in the IPA database. GO and pathway analysis results showed that cluster A, associated with cell cycle regulation, was the most important molecular cluster in the PPI network. In addition, cyclin-dependent kinase 1 (CDK1) may be a key molecule achieving the cell-cycle-regulatory function of cluster A. From the PPI network analysis, it was predicted that delayed cell cycle progression in excessive alveolar bone remodeling via downregulation of CDK1 may be another mechanism underling the anti-osteopenic effect of RDE on alveolar bone. PMID- 27122062 TI - Chemical bonding motifs from a tiling of the many-electron wavefunction. AB - A method is presented to partition the 3N-dimensional space of a many-electron wavefunction into hyper-regions related by permutation symmetry. These hyper regions represent unit cells, or "tiles" of the wavefunction from which the wavefunction may be regenerated in its entirety upon application of the set of permutations of like-spin electrons. The method, wherein a Voronoi diagram is constructed from the (even permutations of the) average position of a swarm of Monte Carlo walkers sampling |Psi|(2), determines a self-consistent partitioning of the wavefunction. When one of the identical 3N-dimensional Voronoi sites is projected onto the coordinates of each electron, chemical motifs naturally appear, such as core electrons, lone-pairs, single-bonds and banana-bonds. The structures determined for N2, O2, F2, and other molecules correspond to the double-quartet theory of Linnett. When the procedure is applied to C2, we arrive at an interpretation of its bonding in terms of a near triple bond with singlet coupled outer electrons. PMID- 27122063 TI - Toxicant exposure from smoking a little cigar: further support for product regulation. AB - BACKGROUND: Although numerous studies have documented the prevalence and increasing use of little cigars and other cigar products, the present study is the first direct, head-to-head laboratory comparison of little cigar and cigarette smoking. The study addressed a fundamental objective to compare exposure and use characteristics of little cigar and cigarette smoking. METHODS: Smoking patterns, toxicant exposure and subjective measures were collected and analysed in 21 adults after smoking a little cigar (Winchester) and a cigarette (own brand). Participants were dual users of little cigars and cigarettes. RESULTS: Similar to cigarettes, little cigars delivered substantial nicotine and relatively more carbon monoxide. Puff volume, puff duration and time to smoke were significantly greater after cigarettes, but the temporal pattern of smoking more intensively at the beginning was similar in little cigars and cigarettes. Both little cigars and cigarettes reduced urge to smoke. Participants consistently mentioned that the lower cost of little cigars was a reason for initiation and continuation of their use. CONCLUSIONS: The results support the notion that regulation of little cigars is appropriate in light of public health considerations. PMID- 27122065 TI - Botulinum toxin for foot dystonia in patients with Parkinson's disease having deep brain stimulation: A case series and a pilot study. AB - BACKGROUND: Six patients with Parkinson's disease with deep brain stimulation who were experiencing disabling foot dystonia were referred to the spasticity clinic for a trial of botulinum toxin. The foot and ankle muscles were injected with onabotulinum toxin (Botox) to determine the effects on foot dystonia, pain and lower limb functional outcomes. DESIGN: Case series. SUBJECTS/PATIENTS: Six patients with Parkinson's disease with deep brain stimulation experiencing disabling foot dystonia. METHODS: Dystonic foot and ankle muscles were identified and injected with 250-400 units botulinum toxin and re-coded pre- and 3 weeks post-injection with the Burke Fahn Marsden Dystonia score, visual analogue score of pain, Unified Parkinson's Disease Rating Scale (UPDRS) - lower limb score, Timed up and Go test (TUG), 6-Minute Walk Test (6MWT), gait velocity, cadence in an instrumented walkway, and Goal Attainment Scale (GAS). RESULTS: Three weeks after botulinum toxin injection, significant improvements were noted in dystonia, pain, UPDRS, 6MWT, gait velocity, and cadence. Five out of 6 patients improved on the TUG test. Patients also reported improvements in their GAS goals. CONCLUSION: Botox injection significantly improved foot dystonia, pain and lower limb functional outcomes in patients with Parkinson's disease with deep brain stimulation. PMID- 27122064 TI - Contribution of smoking to socioeconomic inequalities in mortality: a study of 14 European countries, 1990-2004. AB - BACKGROUND: Smoking contributes to socioeconomic inequalities in mortality, but the extent to which this contribution has changed over time and driven widening or narrowing inequalities in total mortality remains unknown. We studied socioeconomic inequalities in smoking-attributable mortality and their contribution to inequalities in total mortality in 1990-1994 and 2000-2004 in 14 European countries. METHODS: We collected, harmonised and standardised population wide data on all-cause and lung-cancer mortality by age, gender, educational and occupational level in 14 European populations in 1990-1994 and 2000-2004. Smoking attributable mortality was indirectly estimated using the Preston-Glei-Wilmoth method. RESULTS: In 2000-2004, smoking-attributable mortality was higher in lower socioeconomic groups in all countries among men, and in all countries except Spain, Italy and Slovenia, among women, and the contribution of smoking to socioeconomic inequalities in mortality varied between 19% and 55% among men, and between -1% and 56% among women. Since 1990-1994, absolute inequalities in smoking-attributable mortality and the contribution of smoking to inequalities in total mortality have decreased in most countries among men, but increased among women. CONCLUSIONS: In many European countries, smoking has become less important as a determinant of socioeconomic inequalities in mortality among men, but not among women. Inequalities in smoking remain one of the most important entry points for reducing inequalities in mortality. PMID- 27122066 TI - Australian contemporary management of synchronous metastatic colorectal cancer. AB - INTRODUCTION: This article outlines the current Australian multidisciplinary treatment of synchronous metastatic colorectal adenocarcinoma and assesses the factors that influence patient outcome. METHODS: This is a retrospective analysis of the prospective 'Treatment of Recurrent and Advanced Colorectal Cancer' registry, describing the patient treatment pathway and documenting the extent of disease, resection of the colorectal primary and metastases, chemotherapy and biological therapy use. Cox regression models for progression-free and overall survival were constructed with a comprehensive set of clinical variables. Analysis was intentionn-ton-treat, quantifying the effect of treatment intent decided at the multidisciplinary team meeting (MDT). RESULTS: One thousand one hundred and nine patients presented with synchronous metastatic disease between July 2009 and November 2015. Median follow-up was 15.8 months; 4.4% (group 1) had already curative resections of primary and metastases prior to MDT, 22.2% (group 2) were considered curative but were referred to MDT for opinion and/or medical oncology treatment prior to resection and 70.2% were considered palliative at MDT (group 3). Overall, 83% received chemotherapy, 55% had their primary resected and 23% had their metastases resected; 13% of resections were synchronous, 20% were staged with primary resected first and 62% had only the colorectal primary managed surgically. Performance status, metastasis resection (R0 versus R1 versus R2 versus no resection), resection of the colorectal primary and treatment intent determined at MDT were the most significant factors for progression-free and overall survival. CONCLUSIONS: This is the largest Australian series of synchronous metastatic colorectal adenocarcinoma and offers insight into the nature and utility of contemporary practice. PMID- 27122067 TI - DNA Repair in Despair-Vitamin D Is Not Fair. AB - The role of vitamin D as a treatment option for neoplastic diseases, once considered to have a bright future, remains controversial. The preclinical studies discussed herein show compelling evidence that Vitamin D Derivatives (VDDs) can convert some cancer and leukemia cells to a benign phenotype, by differentiation/maturation, cell cycle arrest, or induction of apoptosis. Furthermore, there is considerable, though still evolving, knowledge of the molecular mechanisms underlying these changes. However, the attempts to clearly document that the treatment outcomes of human neoplastic diseases can be positively influenced by VDDs have been, so far, disappointing. The clinical trials to date of VDDs, alone or combined with other agents, have not shown consistent results. It is our contention, shared by others, that there were limitations in the design or execution of these trials which have not yet been fully addressed. Based on the connection between upregulation of JNK by VDDs and DNA repair, we propose a new avenue of attack on cancer cells by increasing the toxicity of the current, only partially effective, cancer chemotherapeutic drugs by combining them with VDDs. This can impair DNA repair and thus kill the malignant cells, warranting a comprehensive study of this novel concept. J. Cell. Biochem. 117: 1733-1744, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27122068 TI - [Living with incurable cancer]. AB - Anti-cancer treatments for various subtypes of cancer have significantly improved. As a result, the number of cancer patients who cannot be completely cured but may live for a considerable period of time is growing. A 72-year-old woman was diagnosed with metastatic EGFR-mutated non-small-cell lung cancer. She received anti-tumour treatment with gefitinib for almost two years and experienced only limited side effects. She was anxious about not knowing her prognosis but after visiting a psychologist she feels as if she can continue life. A 46-year-old woman started to experience symptoms of depression two years after treatment for metastatic breast cancer. A visit to a psycho-oncologist proved to be very helpful. She does not want to know her prognosis and is particularly happy that everything is going well at present. These two cases illustrate that patients living longer with incurable cancer may experience specific dilemmas. We make several recommendations for the care of this group of patients. PMID- 27122069 TI - [Neonatal herpes simplex infection]. AB - Neonatal encephalitis caused by herpes simplex virus (HSV) is a familiar disease with a high mortality and morbidity rate. Isolated skin-eye-mouth infection is less familiar among professionals. In this article we present two neonates with an isolated skin lesion caused by an HSV infection. Of the neonates infected with HSV, 40-45% show isolated skin-eye-mouth disease. With correct treatment, the risk of spread to the central nervous system will decrease from 50-60% to 5-10%. Typical HSV skin lesions may present at a late stage of the disease or may be masked by a secondary bacterial infection. When a neonate presents with atypical skin lesions starting 7-12 days after the birth, immediate testing for HSV and immediate treatment are required, to decrease the risk of further progression of the disease. PMID- 27122070 TI - [Overactive muscles: it can be more serious than common myalgia or cramp]. AB - Positive muscle phenomena are due to muscle overactivity. Examples are cramp, myalgia, and stiffness. These manifestations have mostly acquired causes, e.g. side-effects of medication, metabolic disorders, vitamin deficiency, excessive caffeine intake or neurogenic disorders. We report on three patients with various positive muscle phenomena, to illustrate the clinical signs that indicate an underlying myopathy. Patient A, a 56-year-old man, was diagnosed with muscle cramp in the context of excessive coffee use and previous lumbosacral radiculopathy. Patient B, a 71-year-old man, was shown to have RYR1-related myopathy. Patient C, a 42-year-old man, suffered from Brody myopathy. We propose for clinicians to look out for a number of 'red flags' that can point to an underlying myopathy, and call for referral to neurology if indicated. Red flags include second wind phenomenon, familial occurrence of similar complaints, marked muscle stiffness, myotonia, muscle weakness, muscle hypertrophy, and myoglobinuria. Establishing a correct diagnosis is important for proper treatment. Certain myopathies call for cardiac or respiratory screening. PMID- 27122071 TI - [The Dutch College of General Practitioners practice guideline on 'Sexual problems']. AB - The Dutch College of General Practitioners practice guideline on 'Sexual problems' describes the diagnostics and management of common sexual problems. An adequate sexual anamnesis is essential in order to obtain a good picture of the patient's symptoms and of any underlying causes. Additional physical or other medical examination is of limited value. The provision of information and advice are central to the treatment of sexual problems. Attention should be paid to the different aspects of sexual functioning: physical, psychological, relational and sociocultural, and to gender differences. In many cases, management is determined by the causal factor, for instance comorbidity, sexual trauma or relational problems. In other cases, a more specific problem is diagnosed, and management is based on this. PMID- 27122072 TI - [Spontaneous dissection of the upper mesenteric artery: a rare cause of acute abdominal pain]. AB - BACKGROUND: Acute abdominal pain is a common complaint and one with which many general practitioners and first-line specialists are faced. The differential diagnosis is extensive and appropriate selection of additional diagnostics is therefore very important. CASE DESCRIPTION: We present a 48-year-old male with acute abdominal pain and with no medical history suggesting the cause of this pain. Physical examination revealed no abnormalities other than considerable pain on pressure in the epigastric region. On the basis of CT angiography, we ultimately diagnosed dissection of the upper mesenteric artery and the patient was treated conservatively. CONCLUSION: A spontaneous dissection of the upper mesenteric artery is a rare cause of acute abdominal pain. The diagnosis is made using CT angiography. Conservative management may be selected in patients with no aneurysm or stenosis in the upper mesenteric artery and without mesenteric ischaemia. PMID- 27122073 TI - [Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients]. AB - OBJECTIVE: To assess influence of stage at breast cancer diagnosis, tumour biology, and therapy on survival in contemporary times of better (neo-)adjuvant systemic therapy. DESIGN: Prospective nationwide population based study. METHOD: Female primary breast cancer patients diagnosed between 1999 and 2012 (173,797). Participants were subdivided into two time cohorts on the basis of breast cancer diagnosis; 1999 through 2005 (n = 80,228) and 2006 through 2012 (n = 93,569). Main outcome measures were relative survival, compared between both cohorts, and the influence of traditional prognostic factors on overall mortality, analyzed with Cox regression for both cohorts separately. RESULTS: Compared to 1999-2005 patients from 2006-2012 had smaller ( <= T1 65 vs. 60%; p < 0.001), more often lymph node negative (N0 68 vs. 65%; p < 0.001) tumours, but they received more chemotherapy, hormonal therapy, and targeted therapy (neo-adjuvant/adjuvant systemic therapy 60 vs. 53%; p < 0.001). Median follow-up was 9.8 years for 1999 2005 and 3.9 years for 2006-2012. Relative 5-years survival rate was 96% in 2006 2012, improved in all tumour and nodal stages compared to 1999-2005, and 100% in tumours <= 1 cm. With multivariable analyses, adjusted for age and tumour type, overall mortality decreased by surgery (especially breast conserving), radiotherapy and systemic therapies. Mortality increased with progressing tumour size in both cohorts (2006-2012 T1c vs. T1a HR 1.54, 95% CI 1.33 to 1.78), but without significant difference in invasive breast cancers until 1 cm (2006-2012 T1b vs. T1a HR 1.04, 95% CI 0.88 to 1.22), and independently with progressing number of positive lymph nodes (2006-2012 N1 vs. N0 HR 1.25, 95% CI 1.17 to 1.32). CONCLUSION: Tumour stage at breast cancer diagnosis influences overall survival significantly also in the current era of effective systemic therapy. Early tumour stage at breast cancer diagnosis remains vital. PMID- 27122074 TI - [How representative is the healthcare assessment website Zorgkaart Nederland? The evaluation of medical specialists by patients in the Netherlands]. AB - OBJECTIVE: To describe the number of ratings and the corresponding scores given to medical specialists on the Dutch healthcare assessment website 'Zorgkaart Nederland.nl', and evaluation of this website as tool for evaluation of quality. DESIGN: Explorative descriptive study. METHOD: In July 2015, data were gathered from the public section of the healthcare assessment website 'ZorgkaartNederland.nl'. The number of specialists, the mean ratings per department (group mark), the number of evaluations, the number of medical specialists without a rating and the number of specialists with at least 9 ratings were registered per speciality, per hospital. Outcomes measures were the median number of ratings per speciality and the group score. Data were analysed using descriptive and non-parametric statistics. RESULTS: Each month, 763,000 unique visitors access ZorgkaartNederland.nl; on average, 0.08% of these registers a vote. There were 15,337 medical specialists, spread across 97 hospitals and 2,060 specialities on ZorgkaartNederland.nl, with a total of 45,548 evaluations. Of these, 6,682 (43.4%) specialists were not rated, and 1.165 (7.6%) had >= 9 ratings. Additionally, 327 (15.9%) departments were unrated. Surgical departments were evaluated more often, and their grades were significantly higher, than those of non-surgical departments. CONCLUSION: The website ZorgkaartNederland.nl shows ratings for 56.6% of all medical specialists. When the lower limit of at least 9 evaluations per specialist introduced by ZorgkaartNederland.nl was applied, only the grades for 7.6% of all specialists are valid. On average, 0.08% of unique visitors cast a vote. Surgical specialities have a higher number of evaluations and a higher score than non surgical ones. ZorgkaartNederland.nl in its current form does not constitute a valid tool for evaluation of the quality of medical specialist care in the Netherlands. This article provides recommendations for improvement. PMID- 27122075 TI - [Sexual history-taking in medical practice: the elephant in the room?]. AB - Recently, the Dutch College of General Practitioners released a Practice Guideline on Sexual Problems which provides clear directives for the diagnosis and management of various sexual disorders in men and women. Patients who are managed in general practice and in outpatient clinics might experience distress related to sexual problems due to their age, medical condition or treatment, or distress related to problems in establishing and maintaining intimate relationships. We present two clinical cases. The first case is a woman aged 44 years with breast cancer treated by mastectomy and adjuvant tamoxifen. The second case is a man aged 54 years with heart failure due to myocardial infarction and resultant loss of physical strength. Both cases illustrate that taking a short sexual history could result in the right treatment and patient satisfaction, without having to go into detail about very intimate and private matters. PMID- 27122076 TI - [The entrance to the guild chamber of the Amsterdam Guild of Surgeons]. AB - In the 17th and 18th centuries the entrance to the guild chamber of the Amsterdam Guild of Surgeons was located in the right corner-tower of the Waag on the Nieuwmarkt in Amsterdam. The surgeons entered their guild chamber through this door for guild meetings or to take surgical exams. The entrance also gave access to the anatomy theatre, the 'Theatrum Anatomicum', where anatomical dissections - anatomy lessons - took place. There was a bust of Hippocrates in the facade above the door, and the inscription 'Theatrum Anatomicum'. The series of 'anatomy lessons' reminds us of the famous paintings that were commissioned by the Surgeons' Guild. At the beginning of the 17th century, a skeleton was painted on the door in the gateway, and this marked the entrance to the Surgeons' Guild for almost 200 years. We examined, from a historical perspective, how the gateway to the guild chamber of the Amsterdam Guild of Surgeons was transformed over time. PMID- 27122077 TI - [After surgery or thanks to surgery?]. AB - In this issue of the Dutch Journal of Medicine (NTvG), Saadatmand and colleagues report the results of a large retrospective study on breast cancer patients in the Netherlands. One of their conclusions is that breast-conserving therapy results in better survival compared to breast amputation. Here we argue that retrospective studies are not designed to draw any conclusions with regard to outcome. Confounding by indication is the main reason why differences in outcome may not be causally connected in the context of retrospective data. In the case of different options for breast cancer surgery, many randomised trials have firmly concluded that survival is not influenced by type of surgery. Despite the association found in this retrospective analysis, this study does not alter that conclusion. PMID- 27122078 TI - [Medical history in the information age; new impetus for the section 'Historical perspective' in the Dutch Journal of Medicine]. AB - Over the past half century, medicine has evolved into 'informational medicine'. Physicians today no longer necessarily have to possess specialist knowledge, but have to know how to access this knowledge. This means that it is important that they do not just 'grab' for loose bits of information, but systematically and judiciously search for relevant knowledge. Medical-historical insights could be helpful, alongside critical-appraisal skills. Medical knowledge has a certain structure that has developed historically under the influence of assumptions (some implicit), presuppositions and social forces and interests. By exposing this underlying structure, medical history provides an overview of and insight into relationships within medical knowledge and practice. Now in particular, in the current age of information and disinformation, there is a great need for such 'overviews'. This offers opportunities for the revitalization of the 'Historical perspective' section in the Dutch Journal of Medicine (NTvG), especially if this section evolves into a shared platform for physicians and historians. PMID- 27122079 TI - Wolbachia from Drosophila incompta: just a hitchhiker shared by Drosophila in the New and Old World? AB - Wolbachia are intracellular endosymbionts that infect arthropods and filarial nematodes, occasionally causing a wide variety of modifications in host biology, such as male-killing and cytoplasmic incompatibility (CI), amongst others. This study assembled draft genomes for Wolbachia infecting Drosophila incompta, a species that uses flowers as exclusive breeding and feeding sites, in two distinct Brazilian populations. The absence of four genes involved in CI from this genome, together with literature reports of low frequencies of infected flies in wild populations that contain high mitogenome polymorphism, suggests that this bacterium does not induce CI in D. incompta. Phylogenomic analysis placed Wolbachia infecting D. incompta as closely related to the wMel strain which received such name since it was originally detected in Drosophila melanogaster. In addition, phylogenetic analysis using the Wolbachia surface protein gene and five genes used for multilocus sequence typing of Wolbachia found infecting Drosophila and other arthropod species of Old and New World displayed a complex evolutionary scenario involving recent horizontal transfer bursts in all major clades of Wolbachia pipens belonging to the supergroup A in both geographical regions. PMID- 27122080 TI - Effects of acute aerobic exercise on a task-switching protocol and brain-derived neurotrophic factor concentrations in young adults with different levels of cardiorespiratory fitness. AB - What is the central question of this study? Neurocognitive functions can be enhanced by acute aerobic exercise, which could be associated with changes in serum brain-derived neurotrophic factor (BDNF) concentrations. We aimed to explore acute exercise-induced changes in BDNF concentrations, neuropsychological and neurophysiological performances when individuals with different levels of cardiorespiratory fitness performed a cognitive task. What is the main finding and its importance? Only young adults with higher cardiorespiratory fitness could attain switching cost and neurophysiological benefits via acute aerobic exercise. The mechanisms might be fitness dependent. Although acute aerobic exercise could enhance serum BDNF concentrations, changes in peripheral BDNF concentrations could not be the potential factor involved in the beneficial effects on neurocognitive performance. This study investigated the effects of acute aerobic exercise on neuropsychological and neurophysiological performances in young adults with different cardiorespiratory fitness levels when performing a task switching protocol and explored the potential associations between acute aerobic exercise-induced changes in serum brain-derived neurotrophic factor (BDNF) concentrations and various neurocognitive outcomes. Sixty young adults were categorized into one control group (i.e. non-exercise-intervention; n = 20) and two exercise-intervention (EI) groups [i.e. higher (EIH , n = 20) and lower (EIL , n = 20) cardiorespiratory fitness] according to their maximal oxygen consumption. At baseline and after either an acute bout of 30 min of moderate intensity aerobic exercise or a control period, the neuropsychological and neurophysiological performances and serum BDNF concentrations were measured when the participants performed a task-switching protocol involving executive control and greater demands on working memory. The results revealed that although acute aerobic exercise decreased reaction times across three (i.e. pure, switching and non-switching) conditions in both EI groups, only the EIH group showed a smaller switching cost and larger P3 amplitudes after acute exercise, supporting the view that the mechanisms of neural functioning that underlie the effects of such exercise may be fitness dependent. In addition, serum BDNF concentrations were elevated after acute exercise for both EI groups, but there were no significant correlations between the changes in BDNF concentrations and changes in neuropsychological and neurophysiological performances for either group, suggesting that serum BDNF could not be the potential factor involved in the beneficial effects on neuropsychological and neurophysiological performances seen in young adults after acute aerobic exercise. PMID- 27122083 TI - Abstracts: 2013 American College of Clinical Pharmacology Annual Meeting. PMID- 27122081 TI - A high-throughput neutralizing assay for antibodies and sera against hepatitis E virus. AB - Hepatitis E virus (HEV) is the aetiological agent of enterically transmitted hepatitis. The traditional methods for evaluating neutralizing antibody titres against HEV are real-time PCR and the immunofluorescence foci assay (IFA), which are poorly repeatable and operationally complicated, factors that limit their applicability to high-throughput assays. In this study, we developed a novel high throughput neutralizing assay based on biotin-conjugated p239 (HEV recombinant capsid proteins, a.a. 368-606) and staining with allophycocyanin-conjugated streptavidin (streptavidin APC) to amplify the fluorescence signal. A linear regression analysis indicated that there was a high degree of correlation between IFA and the novel assay. Using this method, we quantitatively evaluated the neutralization of sera from HEV-infected and vaccinated macaques. The anti-HEV IgG level had good concordance with the neutralizing titres of macaque sera. However, the neutralization titres of the sera were also influenced by anti-HEV IgM responses. Further analysis also indicated that, although vaccination with HEV vaccine stimulated higher anti-HEV IgG and neutralization titres than infection with HEV in macaques, the proportions of neutralizing antibodies in the infected macaques' sera were higher than in the vaccinated macaques with the same anti-HEV IgG levels. Thus, the infection more efficiently stimulated neutralizing antibody responses. PMID- 27122082 TI - Harnessing NMR relaxation interference effects to characterise supramolecular assemblies. AB - Solution-state NMR spectroscopy remains the primary method for characterising synthetic supramolecular assemblies. Yet, in their NMR spectra, relaxation interference effects can significantly alter peak intensities hindering interpretation. Here, we present a simple experiment for synthetic chemists to analyse this effect, allowing interpretation of these distorted spectra and validation of spectral assignments. We apply this experiment to synthetic porphyrin oligomers with molecular weights approaching those of protein domains (10 kDa). Our experiment provides a simple means to gain additional structural and dynamical information that will become increasingly useful as chemists create larger molecular architectures. PMID- 27122084 TI - From the Editor-in-Chief. PMID- 27122085 TI - Past, Present and Future: The Outlook from Mid-Career Nurse Informaticians. AB - Nursing informatics (NI), as a specialty of nursing, can trace its origins back as far as the 1960s. While difficult to find empirical evidence to pinpoint exactly when NI moved from the fringes of nursing to more mainstream recognition, the late 1990s to early 2000s was a period of significant growth in the desire to leverage information technology as a means of collecting more robust and reliable healthcare information. This, in turn, has led to a significant increase in the number of nurses working as NI specialists. Those who have remained in NI roles since this time are now reaching the "mid-career" point. This paper will examine the current NI landscape and the experience of a number of early and mid-career nurses who chose to focus on NI by exploring how and why they chose this career path, the opportunities and challenges they have faced to date and their predictions for the future of NI. PMID- 27122086 TI - The Big Data Revolution: Opportunities for Chief Nurse Executives. AB - Informatics competency adoption is a recognized issue across nursing roles in digital health practice settings. Further, it has been suggested that the health system's inability to reap the promised benefits of electronic health/patient records is, in part, a manifestation of inadequate development of informatics competency by chief nurse executives (CNEs) and other clinicians (Amendola 2008; Simpson 2013). This paper will focus on CNE informatics competency and nursing knowledge development as it pertains to the Big Data revolution. With the paper's aim of showing how CNEs armed with informatics competency can harness the full potential of Big Data offering new opportunities for nursing knowledge development in their clinical transformation roles as eHealth project sponsors. It is proposed that informatics-savvy CNEs are the new transformational leaders of the digital age who will have the advantage to successfully advocate for nurses in leading 21st-century health systems. Also, transformational CNEs armed with informatics competency will position nurses and the nursing profession to achieve its future vision, where nurses are perceived by patients and professionals alike as knowledge workers, providing the leadership essential for safe, quality care and demonstrating nursing's unique contributions to fiscal health through clinically relevant, evidence-based practices (McBride 2005b). PMID- 27122087 TI - The Case for Standardized Data in Nursing. AB - With the increased focus on quality and safety within the healthcare system, the collection, reporting and use of standardized data are essential to understanding the impact of clinicians practice on patient care. This article examines how the Canadian Health Outcomes for Better Information and Care (C-HOBIC) dataset can support clinical decision-making and facilitate improved sharing of information as patients transition between sectors of the healthcare system. If the benefits of electronic health records are to be fully realized, it is vital that information is collected in a standardized format to support point-of-care clinicians in decision-making, as well as for health system use. PMID- 27122088 TI - An International Perspective on Nursing Informatics: In Conversation with Nick Hardiker. PMID- 27122089 TI - EHR Learning - It's about Nursing, Leadership and Long-Term Commitments. AB - Despite a global commitment to the adoption of technologies, such as electronic health records (EHRs), to support the delivery of health services, there is little empirical guidance to support effective planning for the integration of these tools into practice settings (Suter et al. 2009). In particular, although EHR learning is known to positively influence integration (Byrne 2012), individual perspectives are often overlooked because of investigative designs that devalue such viewpoints by exploring the utility of technologies rather than the lived experiences of individual users of the technology. Therefore, this qualitative study offered nurse participants opportunities to make sense of EHR learning through talking about their experiences. This narrative inquiry was a collaborative interpretive method of discovery: stories and thematic analysis were the two separate yet complementary frames used to support data analysis. Finally, several practice implications and recommendations about EHR learning are presented with an emphasis placed upon patient safety as a way to impart accountability on behalf of learners, educators and those charged with governing responsibilities during times of EHR integration. PMID- 27122090 TI - Social Media and Nurs Leadersh (Tor Ont): Unifying Professional Voice and Presence. PMID- 27122091 TI - Informatics Activities at the Canadian Nurses Association. AB - The Canadian Nurses Association (CNA) has been participating in nursing informatics activities since hosting the 1992 national consensus conference that resulted in Health Information: Nursing Components (HI:NC). This article will provide a synopsis of the CNA Strategic Plan 2015-2019 and CNA nursing informatics activities. PMID- 27122092 TI - Informatics and Nursing in a Post-Nursing Informatics World: Future Directions for Nurses in an Automated, Artificially Intelligent, Social-Networked Healthcare Environment. AB - The increased adoption and use of technology within healthcare and society has influenced the nursing informatics specialty in a multitude of fashions. Namely, the nursing informatics specialty currently faces a range of important decisions related to its knowledge base, established values and future directions - all of which are in need of development and future-proofing. In light of the increased use of automation, artificial intelligence and big data in healthcare, the specialty must also reconceptualize the roles of both nurses and informaticians to ensure that the nursing profession is ready to operate within future digitalized healthcare ecosystems. To explore these goals, the author of this manuscript outlines an examination of technological advancements currently taking place within healthcare, and also proposes implications for the nursing role and the nursing informatics specialty. Finally, recommendations and insights towards how the roles of nurses and informaticians might evolve or be shaped in the growing post-nursing informatics era are presented. PMID- 27122093 TI - Role of RANKL in the regulation of NFATc1 and c-Src mRNA expression in osteoclast like cells. AB - This study was designed to determine the effects of receptor activator of nuclear factor kappaB ligand (RANKL) on the mRNA expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) and c-Src in rat osteoclast-like cells. The marrow cells were exposed to macrophage colony stimulating factor (M-CSF; 25 ng/ml) and different concentrations of RANKL (0, 50, 75 and 100 ng/ml) for 9 days. The mRNA expression of NFATc1 and c-Src was determined by polymerase chain reaction. Compared with the M-CSF (25 ng/ml)+RANKL (0 ng/ml) group, the levels of NFATc1 and c-Src mRNA expression were significantly increased in the M-CSF (25 ng/ml)+RANKL (75 and 100 ng/ml) groups (P<0.01, P<0.01, P<0.01 and P<0.01, respectively). Compared with the M-CSF (25 ng/ml)+RANKL (50 ng/ml) group, the levels of NFATc1 and c-Src mRNA expression was significantly increased in the M-CSF (25 ng/ml)+RANKL (75 and 100 ng/ml) groups (P<0.05, P<0.01, P<0.01 and P<0.01, respectively). Compared with M-CSF (25 ng/ml)+RANKL (75 ng/ml) group, the levels of NFATc1 and c-Src mRNA expression was significantly increased in the M-CSF (25 ng/ml)+RANKL (100 ng/ml) group, (P<0.01 and P<0.01, respectively). These data suggest that RANKL could regulate the expression of NFATc1 and c-Src mRNA in the marrow culture system. PMID- 27122095 TI - Pheromone-trapping the nun moth, Lymantria monacha (Lepidoptera: Lymantriidae) in Inner Mongolia, China. AB - The nun moth, Lymantria monacha L., is one of the most important defoliators of Eurasian coniferous forests. Outbreaks during 2011-2015 in the natural/planted larch, and larch-birch mixed forests of the Greater Khingan Range in Inner Mongolia, China, caused tremendous timber losses from severe defoliation and tree mortality. A series of trapping experiments were conducted in these outbreak areas to evaluate the efficacy of a synthetic species-specific pheromone lure based on the female pheromone blend of European nun moth populations. Our results clearly show that the nun moth in Inner Mongolia is highly and specifically attracted to this synthetic pheromone, with few gypsy moths (Lymantria dispar) captured. Flight activity monitoring of L. monacha male moths using pheromone baited Unitraps at 2 locations during the summer of 2015 indicated that the flight period started in mid-July, peaking in early August at both locations. Based on male moth captures, there was a strong diurnal rhythm of flight activity throughout the entire scotophase, peaking between 22:00 and 24:00. Unitraps and wing traps had significantly and surprisingly higher catches than the gypsy moth traps. Unitraps fastened to tree trunks 2 m above ground caught significantly more male moths than those at the ground level or at 5 m height. Male L. monacha moths can be attracted to pheromone-baited traps in open areas 150-200 m distant from the infested forest edge. Our data should allow improvement on the performance of pheromone-baited traps for monitoring or mass-trapping to combat outbreaks of this pest in northeastern China. PMID- 27122094 TI - The enhancing effect of a laser photochemotherapy with cisplatin or zolendronic acid in primary human osteoblasts and osteosarcoma cells in vitro. AB - BACKGROUND: Photodynamic therapies (PDT) have become increasingly popular in the adjuvant treatment of different tumour entities. Chemotherapeutic agents, such as cisplatin may be used in combination with low-level laser therapy (LLLT) as laser photochemotherapy. The aim of this study was to investigate the effect of LLLT on cell bioviability of normal and malignant bone cells under chemotherapeutic conditions with either cisplatin or zolendronic acid in vitro. METHODS: Primary human osteoblasts (HOB) and an osteosarcoma cell line (Saos-2) were treated with different concentrations of zolendronic acid or cisplatin and irradiated twice with a diode laser (wavelength 670 nm, 120 s, energy outputs of 100mW/cm2 , continuous wave mode). Cell viability was tested by XTT-assay and via histomorphological analysis. RESULTS: LLLT alone increased bioviability for both cell lines. LLLT lowered HOB viability at the three highest concentrations of cisplatin and zolendronic acid. For Saos-2, LLLT reduced cell viability at every concentration of cisplatin. In cases of incubation with zolendronic acid, similar to osteoblasts, LLLT lowered cell viability at the highest concentration only. CONCLUSIONS: Based on the conditions of this study, laser photochemotherapy may be able to raise the cytotoxicity of cisplatin and zolendronic acid in benign and malignant bone cells. This could be of interest in the development of new therapeutic treatment modalities against neoplastic bone diseases like osteosarcoma. PMID- 27122096 TI - Internal maxillary artery to intracranial artery bypass: a case series of 31 patients with chronic internal carotid/middle cerebral arterial-sclerotic steno occlusive disease. AB - OBJECTIVE: To evaluate the effectiveness of internal maxillary artery (IMA) - radial artery graft (RAG) - middle cerebral artery (MCA) bypass surgery for chronic arterial-sclerotic severe stenosis or occlusion of the internal carotid artery (ICA) or MCA. METHODS: A retrospective study was conducted in 31 patients with ischemic cerebrovascular disease who underwent bypass surgery of the IMA with a RAG of the MCA. Twenty-seven patients had complete occlusion of the ICA or MCA, and four patients had severe stenosis of the M1 segment of the MCA. RESULTS: Patent IMA-RAG-MCA in 30 (96.8%) patients was confirmed by angiography after surgery. One case developed a new motor aphasia due to unsuccessful bypass. Eleven transient ischemic attacks (TIA) and five ischemic strokes resolved following surgery. The other 14 cases showed some improvement without ischemic events at one month following surgery. Prior to surgery, mean +/- SD National Institute of Health Stroke Scale (NIHSS) score was 5.4 +/- 1.1 in the ischemic stroke group. In the first month post-procedure, the NIHSS score decreased significantly to 3.8 +/- 1.2, (p < 0.01). Perfusion weighted imaging (PWI) or computed tomography perfusion (CTP) indicated improved hemodynamics in 30 patients. In addition, seven patients demonstrated improved glucose metabolism on 18-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET) postoperatively. No new neurological deficit occurred in the 30 patients during a 2.19 +/- 1.59 years of follow-up. CONCLUSIONS: By supplying an adequate flow to a larger flow territory of chronically stenotic/occlusive major cerebral arteries, IMA bypass surgery is efficient for restoring hemodynamics in selected patients and improving their neurological deficits. PMID- 27122097 TI - Solution-based intramolecular singlet fission in cross-conjugated pentacene dimers. AB - We show unambiguous and compelling evidence by means of pump-probe experiments, which are complemented by calculations using ab initio multireference perturbation theory, for intramolecular singlet fission (SF) within two synthetically tailored pentacene dimers with cross-conjugation, namely XC1 and XC2. The two pentacene dimers differ in terms of electronic interactions as evidenced by perturbation of the ground state absorption spectra stemming from stronger through-bond contributions in XC1 as confirmed by theory. Multiwavelength analysis, on one hand, and global analysis, on the other hand, confirm that the rapid singlet excited state decay and triplet excited state growth relate to SF. SF rate constants and quantum yields increase with solvent polarity. For example, XC2 reveals triplet quantum yields and rate constants as high as 162 +/- 10% and (0.7 +/- 0.1) * 10(12) s(-1), respectively, in room temperature solutions. PMID- 27122099 TI - Connexin 43 Acts as a Proapoptotic Modulator in Cisplatin-Induced Auditory Cell Death. AB - AIMS: Gap junction coupling is known to play a role in intercellular communication by the Good Samaritan effect or bystander effect. Nonjunctional connexins (Cxs) may also play certain gap junction-independent roles in cell death or survival. The purpose of the present study was to investigate the role of junctional and nonjunctional Cxs in ototoxic drug-induced auditory cell death by focusing on Cx43 in the cochlea. RESULTS: Nonjunctional Cx43 conditions were prepared by low confluence culture (5 * 103/cm2) or a trafficking inhibitor, brefeldin A (BFA), in auditory cells, and short lengthened Cx43s with amino terminal (NT; amino acids 1-256) or carboxy-terminal (CT; amino acids 257-382) were transfected into Cx-deficient HeLa cells to avoid gap junction formation. Knockdown of nonchannel Cx43 (small interfering RNA [siRNA]) inhibited Cis diamminedichloroplatinum (cisplatin)-induced cell death regardless of gap junction formation; however, a gap junction blocker, 18 alpha-glycyrrhetinic acid (18alpha-GA), showed inhibitory effect only under the junctional condition. BFA did not show any additive influence on the inhibitory effect of siRNA Cx43. Shortened Cx43-transfected HeLa cells also resulted in a significant increase in cell death under cisplatin. In the animal studies with cisplatin-treated rats, hearing thresholds of auditory brainstem response were significantly preserved by a gap junction blocker, carbenoxolone, showing much more preserved stereocilia of hair cells in scanning electron microscopic findings. Innovation and Conclusion: Cx43 plays a proapoptotic role in cisplatin-induced auditory cell death in both junctional and nonjunctional conditions. Targeting the Cx-mediated signaling control may be helpful in designing new therapeutic strategies for drug-induced ototoxicity. Antioxid. Redox Signal. 25, 623-636. PMID- 27122100 TI - Absorption, distribution, metabolism and elimination of 14C-ETX0914, a novel inhibitor of bacterial type-II topoisomerases in rodents. AB - 1. ETX0914 is a novel bacterial topoisomerase inhibitor that has a novel mode-of inhibition and is in clinical development for the treatment of infections caused by Neisseria gonorrhoeae. 2. The in vitro biotransformation studies of ETX0914 using mouse, rat, dog and human hepatocytes showed moderate intrinsic clearance in mouse and rat and low intrinsic clearance in dog and human. 3. Following intravenous administration of [14C]-ETX0914 in rats, the mean recovery of administered dose in urine, bile and feces was approximately 15%, 55% and 24%, respectively. Unchanged ETX0914 recovered in urine and bile was less than 5% of the dose, indicating that ETX0914 underwent extensive metabolism in rats. Metabolites M1, M2, M4, M6 and M12 detected in both rat and mouse urine samples were not detected in mouse urine when predosed with 1-aminobenzotriazole, indicating that these metabolites were cytochrome P450 mediated products. The major fecal metabolites observed in rats were not formed when ETX0914 was incubated with fresh feces from germ free rats under sterile condition or in incubations with rat intestinal microsome and cytosol, suggesting that most likely ETX0914 was directly excreted into gut lumen where metabolites were formed as intestinal microflora-mediated products. The major sites of metabolism by CYP enzymes were in the morpholine and oxazolidinone rings while it was benzisoxazole reduction with the gut microflora. PMID- 27122101 TI - Ultrafast Imaging using Spectral Resonance Modulation. AB - CCD cameras are ubiquitous in research labs, industry, and hospitals for a huge variety of applications, but there are many dynamic processes in nature that unfold too quickly to be captured. Although tradeoffs can be made between exposure time, sensitivity, and area of interest, ultimately the speed limit of a CCD camera is constrained by the electronic readout rate of the sensors. One potential way to improve the imaging speed is with compressive sensing (CS), a technique that allows for a reduction in the number of measurements needed to record an image. However, most CS imaging methods require spatial light modulators (SLMs), which are subject to mechanical speed limitations. Here, we demonstrate an etalon array based SLM without any moving elements that is unconstrained by either mechanical or electronic speed limitations. This novel spectral resonance modulator (SRM) shows great potential in an ultrafast compressive single pixel camera. PMID- 27122098 TI - Myoscape controls cardiac calcium cycling and contractility via regulation of L type calcium channel surface expression. AB - Calcium signalling plays a critical role in the pathogenesis of heart failure. Here we describe a cardiac protein named Myoscape/FAM40B/STRIP2, which directly interacts with the L-type calcium channel. Knockdown of Myoscape in cardiomyocytes decreases calcium transients associated with smaller Ca(2+) amplitudes and a lower diastolic Ca(2+) content. Likewise, L-type calcium channel currents are significantly diminished on Myoscape ablation, and downregulation of Myoscape significantly reduces contractility of cardiomyocytes. Conversely, overexpression of Myoscape increases global Ca(2+) transients and enhances L-type Ca(2+) channel currents, and is sufficient to restore decreased currents in failing cardiomyocytes. In vivo, both Myoscape-depleted morphant zebrafish and Myoscape knockout (KO) mice display impairment of cardiac function progressing to advanced heart failure. Mechanistically, Myoscape-deficient mice show reduced L type Ca(2+)currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. Finally, Myoscape expression is reduced in hearts from patients suffering of terminal heart failure, implying a role in human disease. PMID- 27122102 TI - Faculty of Radiation Oncology Position Paper on the use of Image-Guided Radiation Therapy. AB - The development of technology such as intensity-modulated radiotherapy (IMRT), volumetric arc therapy (VMAT) and stereotactic ablative body radiotherapy (SABR) has resulted in highly conformal radiotherapy treatments. While such technology has allowed for improved dose delivery, it has also meant that improved accuracy in the treatment room is required. Image-guided radiotherapy (IGRT), the use of imaging prior to or during treatment delivery, has been shown to improve the accuracy of treatment delivery and in some circumstances, clinical outcomes. Allied with the adoption of highly conformal treatments, there is a need for stringent quality assurance processes in a multidisciplinary environment. In 2015, the Royal Australian and New Zealand College of Radiologist (RANZCR) updated its position paper on IGRT. The draft document was distributed through the membership of the Faculty of Radiation Oncology (FRO) for review and the final version was endorsed by the board of FRO. This article describes issues that radiotherapy departments throughout Australia and New Zealand should consider. It outlines the role of IGRT and reviews current clinical evidence supporting the benefit of IGRT in genitourinary, head and neck, and lung cancers. It also highlights important international publications which provide guidance on implementation and quality assurances for IGRT. A set of key recommendations are provided to guide safe and effective IGRT implementation and practice in the Australian and New Zealander context. PMID- 27122103 TI - Re-expansion pulmonary oedema: a novel emergency therapeutic option. AB - Re-expansion pulmonary oedema (REPO) is a rare complication of pleural fluid thoracocentesis and has been associated with a high mortality rate. There is limited evidence to inform on its most effective management. We present two cases of large volume thoracocentesis resulting in acute respiratory decompensation that was treated by reintroducing the drained pleural fluid back into the pleural cavity. We also present a review of the literature specifically assessing the reported incidence rate of REPO after pleural fluid drainage. In both of our cases, symptoms and signs of respiratory instability were promptly reversed on reintroduction of the drained pleural fluid into the patient's pleural space-a therapy we have termed 'rapid pleural space re-expansion'. This was not associated with any short-term adverse outcomes. The occurrence of REPO is a rare event with most cohort studies reporting an incidence of between 0% and 1%. PMID- 27122104 TI - Cannabinoid hyperemesis syndrome and the onset of a manic episode. AB - Cannabinoid hyperemesis syndrome is a rare, recently described, clinically diagnosed condition that is characterised by a chronic history of cannabis use, cyclic nausea and vomiting, symptomatic relief with hot water bathing, and resolution with cessation of use. We present a case of this syndrome concurrent in a patient with bipolar mania. We suggest that a 3-week period of vomiting in the context of this syndrome contributed to the precipitation of a manic episode by lowering mood stabiliser serum levels, and that this syndrome will have significant consequences for the patient's mental health. PMID- 27122105 TI - Unusual case of intracranial dural AV fistula presenting with acute myelopathy. AB - We present a case of intracranial arteriovenous fistula with perimedullary venous drainage presenting with acute myelopathy, which is an unusual presentation of this uncommon condition. Subsequent catheter angiogram defined the arterial feeders from the meningohypophyseal trunk and petrosal branch of the middle meningeal artery. The patient was successfully embolised, resulting in complete obliteration of the fistula, and significant resolution of brainstem and cervical cord changes along with clinical improvement. PMID- 27122106 TI - A benign ancient schwannoma of the tibia nerve. PMID- 27122107 TI - Home parenteral nutrition-associated thromboembolic and bleeding events: results of a cohort study of 236 individuals. AB - Essentials Sparse or outdated studies focus on thrombotic and bleeding risk in home parenteral nutrition (HPN). 236 HPN patients followed at a single center for a total of 684 patient-years were evaluated. Rates of venous thrombosis and major bleeding, and prevalence of vena cava syndrome are provided. Anticoagulants might reduce thrombosis risk, but population-specific safety concerns remain. SUMMARY: Background Home parenteral nutrition (HPN) is necessary for patients with intestinal failure. Recurrent catheter-related thrombosis (CRT) is common, leading to infectious complications, pulmonary embolism, vascular access loss and intestinal transplantation. The efficacy and safety of anticoagulants are unknown in this setting and based on sparse and low-quality observational data. Objectives Our aim was to estimate the incidence of thromboembolic, bleeding and anticoagulant-related complications in HPN patients, and evaluate risk factors for first venous thrombosis (VT). Methods This retrospective cohort study included all adult patients followed for long-term HPN at our center between 1986 and 2014. Primary outcomes were symptomatic objectively diagnosed VT, encompassing CRT and venous thromboembolism, and major bleeding. Secondary outcomes were vena cava syndrome and heparin-induced thrombocytopenia or hypersensitivity. Results A total of 236 patients were included (median HPN duration, 17 months) and 136 received anticoagulants at HPN onset (57.6%). Overall, the annual incidence of first VT was 11.4% (95% confidence interval [95% CI], 8.6-14.7%); VT was associated with a personal history of thrombosis (adjusted hazard ratio, 2.22; 95% CI, 1.06-4.64), whereas anticoagulation seemed to account only for a mild protection (adjusted hazard ratio, 0.72; 95% CI, 0.36 1.44). The annual incidence of major bleeding was 4.3% for patients on anticoagulants vs. 1.8% for those off anticoagulants. Vena cava syndrome developed in 20.7% of patients with VT. One patient had isolated heparin-induced thrombocytopenia (0.6%) and four had heparin hypersensitivity (2.5%). Conclusions Patients on HPN have a significant risk of venous thrombosis, major bleeding and vena cava syndrome. Anticoagulants might reduce thrombosis risk, but population specific safety concerns remain. PMID- 27122109 TI - A CE-LIF method based on long wavelength fluorescence labeling for the analysis of thiols in human urine. AB - A rapid and robust CE method using a long wavelength fluorescent reagent 1,7 dimethyl-3,5-distyryl-8-phenyl-(2-maleimide)difluoroboradiaza-s-indacene as the labeling reagent has been developed for the simultaneous determination of thiols, including glutathione, cysteine, homocysteine, N-acetylcysteine, cysteinylglycine, and penicillamine. The derivatization reaction was carried out in 14 mmol/L pH 8.5 borate buffer at 30 degrees C for 6 min and the labeled thiols derivatives were separated with the running buffer containing 30 mmol/L pH 7.4 phosphate, 30% v/v acetonitrile and 8 mmol/L SDS within 12 min. Detection limits ranged from 0.4 to 2.4 nmol/L. To demonstrate the capability of this method, it was applied to the analysis of thiols in human urine with recoveries of 92.4-105.6%. The derivatization reaction was much faster at milder conditions, and the analysis was rapider. Moreover, with excitation wavelength at long wavelength region, background interference from samples was reduced effectively. The present method seems to be a potential choice for quantifying thiols in human urine. PMID- 27122108 TI - The structural basis of chicken, swine and bovine CD8alphaalpha dimers provides insight into the co-evolution with MHC I in endotherm species. AB - It is unclear how the pivotal molecules of the adaptive immune system (AIS) maintain their inherent characteristics and relationships with their co-receptors over the course of co-evolution. CD8alpha, a fundamental but simple AIS component with only one immunoglobulin variable (IgV) domain, is a good example with which to explore this question because it can fold correctly to form homodimers (CD8alphaalpha) and interact with peptide-MHC I (p/MHC I) with low sequence identities between different species. Hereby, we resolved the crystal structures of chicken, swine and bovine CD8alphaalpha. They are typical homodimers consisting of two symmetric IgV domains with distinct species specificities. The CD8alphaalpha structures indicated that a few highly conserved residues are important in CD8 dimerization and in interacting with p/MHC I. The dimerization of CD8alphaalpha mainly depends on the pivotal residues on the dimer interface; in particular, four aromatic residues provide many intermolecular forces and contact areas. Three residues on the surface of CD8alpha connecting cavities that formed most of the hydrogen bonds with p/MHC I were also completely conserved. Our data propose that a few key conserved residues are able to ensure the CD8alpha own structural characteristics despite the great sequence variation that occurs during evolution in endotherms. PMID- 27122116 TI - Dosing of Enteric-Coated Mycophenolate Sodium Under Routine Conditions: An Observational, Multicenter Study in Kidney Transplantation. AB - BACKGROUND Dosing of enteric-coated mycophenolate sodium (EC-MPS) should be adjusted to reflect concomitant immunosuppression, but it is largely undocumented whether such modifications are carried out during routine clinical practice. MATERIAL AND METHODS MyLIFE was an observational study of adult kidney-only or kidney-pancreas transplant patients starting -EC-MPS at 33 French transplant centers. Data were collected at first EC-MPS dose and 6 months later. The primary objective was to describe initial EC-MPS dosing according to concomitant immunosuppression. RESULTS There were 461 patients analyzed (174 started EC-MPS by month 1 post-transplant ['de novo'] and 287 started EC-MPS >1 month post transplant ['maintenance']), receiving cyclosporine (CsA) (n=76), tacrolimus (n=363), or a mammalian target of rapamycin (mTOR) inhibitor (n=22). Mean (SD) starting dose was 1130 (511) mg/day, 1006 (441) mg/day, and 769 (300) mg/day in the CsA, tacrolimus, and mTOR inhibitor groups, respectively (p=0.003). In the de novo subpopulation, the starting dose was 1440 mg/day in 66.7% (14/21) of CsA treated patients and 71.9% (110/153) of tacrolimus-treated patients, with an intensified dose of 2160 mg/day in 28.6% (6/21) and 8.5% (13/153), respectively. There was a non-significant trend to a higher rate of biopsy-proven acute rejection in patients receiving CsA versus tacrolimus or an mTOR inhibitor (p=0.082). Adverse events with a suspected relation to EC-MPS occurred in 21.0%, 23.1%, and 9.1% of the CsA, tacrolimus, and mTOR inhibitor subpopulations, respectively. CONCLUSIONS EC-MPS is usually initiated at the dose recommended for de novo CsA-treated kidney transplant patients, then titrated downwards as required. An early intensified regimen is not used frequently. The EC-MPS dose is modified in <20% of de novo patients to account for concomitant tacrolimus therapy instead of CsA administration. PMID- 27122117 TI - Finding a new role for NEMO: A key player in preventing hepatocyte apoptosis and liver tumorigenesis by inhibiting RIPK1. PMID- 27122119 TI - Prediction of substrate specificity in NS3/4A serine protease by biased sequence search threading. AB - Proteases recognize specific substrate sequences and catalyze the hydrolysis of targeted peptide bonds to activate or degrade them. It is particularly important to identify the recognition and binding mechanisms of protease-substrate complex structures in studies of drug development. Cleavage specificity in protease systems is generally determined by the amino acid profile, structural features, and distinct molecular interactions. In this work, substrate variability and substrate specificity of the NS3/4A serine protease encoded by the hepatitis C virus (HCV) was investigated by the biased sequence search threading (BSST) methodology. The available crystal structures of peptide-bound protease were used as templates as well as new complex structures that were generated via docking calculations. Threading various binding and nonbinding sequences as starting sequences over multiple templates, the potential sequence space was efficiently explored by a low-resolution knowledge-based scoring potential. The low-energy substrate sequences generated by the biased search are correlated with the natural substrates with conserved amino acid preferences, although some positions exhibit variability. Specifically, the amino acids which play essential roles in cleavage are mostly preferred. Potential substrate sequences were predicted by statistical probability approaches that consider the pairwise and triplewise interdependencies among residue positions in the low-energy sequences. The predicted substrate sequences also reproduce most of the natural substrate sequences, implying the complex interdependence between the different substrate residues. Consequently, the BSST seems to provide a powerful methodology for predicting the substrate specificity for the NS3/4A protease, which is a target in drug discovery studies for HCV. PMID- 27122120 TI - Insertion of (t)BuNC into thorium-phosphorus and thorium-arsenic bonds: phosphaazaallene and arsaazaallene moieties in f element chemistry. AB - The reactivity of thorium-phosphido and thorium-arsenido bonds was probed using tert-butyl isocyanide, (t)BuNC. Reaction of (C5Me5)2Th[E(H)R]2, E = P, As; R = 2,4,6-(i)Pr3C6H2, 2,4,6-Me3C6H2 with (t)BuNC affords the first phosphaazaallene and arsaazaallene moieties with an f-element. PMID- 27122121 TI - Treatment of rheumatoid arthritis (RA) in India-how and by whom: results from a speciality clinic-use of low-dose methotrexate (MTX) was inexplicably suboptimal. AB - This study was conducted in order to study (a) seropositive RA patients for their prior caregivers, diagnosis makers, drugs and doses taken and (b) the disease status at the first visit and the last visit, from the standpoint of whether they received optimum or suboptimum DMARD treatment. Prospectively entered data were extracted from a rheumatology-specific electronic health record for demography, diagnostic delay, prior caregivers, diagnosis makers, intake of DMARDs and glucocorticoids and disease activity state at first presentation and at the last visit using structured query language. Among 316 patients, prior caregivers were orthopaedicians (73.4 %), alternative systems of medicine practitioners (62 %), internists (38 %), rheumatologists (35.8 %), general practitioners (17 %) and others (12 %). The diagnosis of RA was made by rheumatologists (55.6 %), orthopaedicians (21 %), internists (12.6 %), physiotherapists (3.5 %), homeopaths (2.8 %), general practitioner (2.1 %), neurologists (1.4 %) and Ayurvedic physicians (0.7 %). The mean and the median diagnostic delay among 142 patients where information was available were 18 and 8.5 months, respectively (SD +23.2). Thirty-two percent of the patients had early disease, 48 % established disease and 20 % late disease at presentation. Sixty-six percent of the patients had taken DMARDs-methotrexate (56 %), hydroxychloroquine (46.2 %), leflunomide (18.7 %) and sulfasalazine (20.6 %)-and often in combinations. Different preparations, doses and schedules of glucocorticoids were taken orally or parentally by 51 %. Only one (0.3 %) patient had taken biological DMARDs prior to visiting this clinic. High or moderate disease activity was present in 84 % at the first clinic visit that fell to 14 % at the last clinic visit. The majority of patients with RA were treated by orthopaedicians and practitioners of alternative systems of medicine with only a third by rheumatologists. In 80 % of patients, the diagnosis was made 18 months at the onset, yet in 84 %, the disease control was poor. Non use or suboptimal use of methotrexate appeared to be the main reason. PMID- 27122122 TI - Attenuation assessment of medical protective eyewear: the AVEN experience. AB - The goal of this paper is to test the attenuation capability of seven models of protective eyewear used in routine clinical practice. Scattered radiation from a standard patient was simulated by using a water tank located over the treatment couch of a GE Innova 3100 x-ray angiography system. Seven protective eyewear models were tested using an anthropomorphic phantom mimicking the first operator. At each test, 4 thermoluminiscent dosimeters were placed on the phantom (respectively in front of the protective eyewear, under the eyewear, on the left earpiece and at chest level) in order to have an eyewear-independent reference. A test session without glasses was also acquired. Each model was tested with standard posterior-anterior (PA) projections and the two most common protective eyewear were tested using LAO90 degrees and LAO45 degrees CRA30 degrees projections. A worst-case scenario was created to be sure of having an upper limit for the assessment of eyewear attenuation in routine clinical practice. In PA projections, the absolute attenuation value ranged between 71% and 81%, while relative attenuation between dose measured at eye lens and that measured at eyewear earpiece ranged from 67% to 85%. The slightly wider range was probably due to scatter radiation variability; anyway, differences are still included in the variable uncertainty of experimental measurements. It is worth noting that #3 eyewear model (the one without lateral protection) allows an attenuation similar to that of #5 eyewear model (with 0.5 mm lead lateral protection) in LAO90 degrees and LAO45 degrees CRA30 degrees projections. Despite the experimental limitations, a description of the radiation properties of protective eyewear concerning radiation attenuation can be useful to rely on protection devices which can be used in routine clinical practice. PMID- 27122123 TI - Variation of skeletal degenerative joint disease features in an identified Italian modern skeletal collection. AB - OBJECTIVES: The objective of this study was to investigate the relationship of degenerative joint disease (DJD) features (marginal lipping, porosity, surface osteophytes, eburnation, and loss of joint morphology) with sex, age, and occupation. MATERIALS AND METHODS: We devised a recording method for scoring the single features in the shoulder, elbow, wrist, hip, knee, and ankle of an Italian skeletal sample of 332 individuals (males = 161, females = 171) of known sex, age, and occupation from the Frassetto collection (Sassari, Sardinia, 19th-20th century). RESULTS: Our data revealed that: (1) the frequency of all features increases with age; (2) porosity is the first feature to appear, being in general the most frequent feature in young adults; (3) sex differences are especially found in the upper limbs of mature and elderly adults; (4) marginal lipping and surface osteophytes show a lesser age correlation and, in general, higher frequencies in the left lower limb; (5) no differences were found among different occupations. DISCUSSION: We explain these results in light of different metabolic and adaptive processes in relation to age and sex. Static (weight-bearing) rather than dynamic mechanical stress could play a pivotal role in the distribution of the features observed in the lower limbs. The considerable increase in marginal lipping and surface osteophytes in elderly adults may be an adaptation for sustaining mechanical loading, balancing the loss of bone tissue which is characteristic of ageing processes (osteopenia, osteoporosis). Am J Phys Anthropol, 2016. (c) 2016 Wiley Periodicals, Inc. Am J Phys Anthropol 160:683 693, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27122124 TI - Microbial Community Composition Associated with Maotai Liquor Fermentation. AB - The solid-state fermentation state of Chinese Maotai liquor involves the interaction of several complex microbial communities leading to the generation of the most complex liquor fermentation system in the world and contributes to the unique flavor and aroma of the liquor. In this study, total DNA was extracted from 3 fermented grain samples (FG1, FG2, and FG3) and 12 environmental samples, including Daqu (DA1, DA2, DA3, and DA4), cellar mud (CS1, CS2, and CS3), soil (SL1 and SL2), air (A1 and A2), and sorghum (SH), and the 16S and 18S rRNA genes were amplified. The distribution of typical microorganisms in the samples was analyzed using nested PCR-denaturing gradient gel electrophoresis, while quantitative PCR amplification of 16S rRNA and internal transcribed spacer genes was performed to estimate the microbial abundance present in each sample. The results indicated that Daqu was the primary source of bacteria, followed by the air, soil, and sorghum samples, while the majority of the fungi responsible for Maotai liquor fermentation were from Daqu and sorghum. Highest bacterial concentrations were found in fermented grains, followed by Daqu and sorghum, while the highest fungal concentrations were found in Daqu, followed by sorghum and an air sample from outside the liquor production area. The findings of this study may provide information regarding the mechanisms responsible for flavor development in Maotai liquor, and may be used to further optimize the traditional art of making liquor. PMID- 27122118 TI - Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling: A CASP-CAPRI experiment. AB - We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014. The targets included mostly homodimers, a few homotetramers, and two heterodimers, and comprised protein chains that could readily be modeled using templates from the Protein Data Bank. On average 24 CAPRI groups and 7 CASP groups submitted docking predictions for each target, and 12 CAPRI groups per target participated in the CAPRI scoring experiment. In total more than 9500 models were assessed against the 3D structures of the corresponding target complexes. Results show that the prediction of homodimer assemblies by homology modeling techniques and docking calculations is quite successful for targets featuring large enough subunit interfaces to represent stable associations. Targets with ambiguous or inaccurate oligomeric state assignments, often featuring crystal contact-sized interfaces, represented a confounding factor. For those, a much poorer prediction performance was achieved, while nonetheless often providing helpful clues on the correct oligomeric state of the protein. The prediction performance was very poor for genuine tetrameric targets, where the inaccuracy of the homology-built subunit models and the smaller pair-wise interfaces severely limited the ability to derive the correct assembly mode. Our analysis also shows that docking procedures tend to perform better than standard homology modeling techniques and that highly accurate models of the protein components are not always required to identify their association modes with acceptable accuracy. Proteins 2016; 84(Suppl 1):323 348. (c) 2016 Wiley Periodicals, Inc. PMID- 27122125 TI - The effects of interventions on quality of life, morbidity and consultation frequency in frequent attenders in primary care: A systematic review. AB - BACKGROUND: Patients visiting their GPs exceptionally often (frequent attenders, FAs) have high rates of somatic disease, emotional distress, psychiatric illnesses and social problems and require a disproportionate amount of their GPs' time. OBJECTIVES: To summarize which types of FA have been studied and what the effects of interventions were on quality of life (QoL), symptom severity of underlying illness(es) and consultation frequency. To discover when patients are considered FAs. METHODS: Systematic review of RCTs using a comprehensive search (MEDLINE, PsycINFO, CINAHL and EMBASE, from 1980 to August 2015) and no language restrictions. Two investigators extracted data. Results were summarized qualitatively. RESULTS: We included 17 RCTs. Heterogeneity at the level of populations, interventions and outcomes precluded statistical pooling. In-depth analysis by GPs assessing a patient's reasons for frequent attendance decreased consultation frequency by four to six per year. A small effect on symptom severity was noted in depressed FAs, although this finding was not replicated in a recent trial. Multi-component therapy and medication in FAs with medically unexplained symptoms (MUS) improved QoL (SF36 odds ratio: 1.92; 95%CI: 1.08-3.40) and morbidity (CES-D 3.17; 95%CI: 1.27-5.08). CONCLUSION: RCTs on intervention effects in frequent attenders to primary care used different patient populations, interventions, comparators and outcome measures. Consistent evidence on the effects of particular interventions in specific patient domains is lacking. A tailored approach based on in-depth analysis among GPs of potential reasons for frequent attendance may decrease consultation frequency. Research involving the screening and treating for FAs with MUS may be useful in future trials. PMID- 27122126 TI - Risk factors, clinical variants and therapeutic outcome of retronychia: a retrospective study of 18 patients. AB - Retronychia is a form of post-traumatic ingrowing nail disease that involves proximal nail plate embedding into the proximal nail fold, with multiple generations of nail plate beneath the proximal nail. This disease is probably underdiagnosed because of incomplete clinical forms. The aim of this study was to report clinical and aetiological variants of retronychia and to evaluate their therapeutic outcome. A retrospective review was performed on 18 patients who were seen in our institution between 2007 and 2013. The diagnostic criteria for retronychia were paronychia and interruption of nail growth. A female predominance (83.3%) was reported. Various precipitating factors were found, including traumatisms in 10 patients (55%), pregnancy and postpartum period in two patients (11%), and compartment syndrome in one patient (5%). The mean duration of paronychia was eight months (15 days to four years). The fingers most affected were the great toes. Retronychia occurred bilaterally in five cases (27%) and unilaterally in one case (61%). The commonest signs were, in decreasing order, xanthonychia (yellow discolouration of nail plate), longitudinal nail over curvature, swelling of proximal nail fold, elevation of the proximal nail plate, granulation tissue, subungual hyperkeratosis, superficial leuconychia, distal onycholysis, subungueal haemorrhage, and Beau's lines. Most of the cases improved after proximal nail plate avulsion. Recurrence occurred in three cases (16.6%). In our opinion, ischaemic damage is the main cause of retronychia. Evaluation of clinical variants is mandatory to propose appropriate treatment. The limitations of this study include the retrospective design. PMID- 27122128 TI - Pooling across cells to normalize single-cell RNA sequencing data with many zero counts. AB - Normalization of single-cell RNA sequencing data is necessary to eliminate cell specific biases prior to downstream analyses. However, this is not straightforward for noisy single-cell data where many counts are zero. We present a novel approach where expression values are summed across pools of cells, and the summed values are used for normalization. Pool-based size factors are then deconvolved to yield cell-based factors. Our deconvolution approach outperforms existing methods for accurate normalization of cell-specific biases in simulated data. Similar behavior is observed in real data, where deconvolution improves the relevance of results of downstream analyses. PMID- 27122127 TI - Polyphenols from Korean prostrate spurge Euphorbia supina induce apoptosis through the Fas-associated extrinsic pathway and activation of ERK in human leukemic U937 cells. AB - The Korean prostrate spurge Euphorbia supina (Euphorbiaceae family) has been used as a folk medicine in Korea against a variety of ailments such as bronchitis, hemorrhage, jaundice and multiple gastrointestinal diseases. Polyphenols from Korean E. supina (PES) which include quercetin and kaempferol derivatives have anticancer properties. Hence, we investigated the anticancer effects of PES on U937 human leukemic cells. Firstly, PES significantly inhibited the proliferation of U937 cells in a dose-dependent manner. PES induced accumulation of the sub-G1 DNA content (apoptotic cell population), apoptotic bodies and chromatin condensation and DNA fragmentation in the U937 cells. PES also induced activation of caspase-3, -8 and -9, subsequent cleavage of PARP, and significantly suppressed XIAP, cIAP-1 and cIAP-2 in a dose-dependent manner. Furthermore, PES activated Bid, and induced the loss of mitochondrial membrane potential (MMP, DeltaPsim) along with upregulation of pro-apoptotic proteins (Bax and Bad), and downregulation of anti-apoptotic proteins (Bcl-2 and Bcl-xL) and cytochrome c release. The Fas receptor was upregulated by PES in a dose-dependent manner, suggesting that the extrinsic pathway was also involved in the PES-induced apoptosis. Moreover, the PES-induced apoptosis was at least in part associated with extracellular signal-regulated kinase (ERK) activation in the U937 human leukemic cells. This study provides evidence that PES may be useful in the treatment of leukemia. PMID- 27122129 TI - Frequency and prognostic significance of t(v;11q23)/KMT2A rearrangements in adult patients with acute lymphoblastic leukemia treated with risk-adapted protocols. AB - The karyotype is an important predictor of outcome in acute lymphoblastic leukemia (ALL). Rearrangements of the 11q23 region involving the KMT2A gene confer an unfavorable prognosis. Forty-six adult ALL patients from the PETHEMA Group treated with risk-adapted protocols, with t(v;11q23) were selected for this study. Complete response (CR) was attained in 38 patients; 25 remained in CR after consolidation. Twelve (48%) received allogeneic hematopoietic stem cell transplantation (HSCT) and 13 delayed intensification and maintenance. The 5-year CR duration probability was 37% (95% CI, 19%-55%). A trend for a longer CR duration was observed in patients undergoing HSCT vs. those receiving chemotherapy. The 5-year overall survival (OS) probability was 20% (95% CI, 5% 35%). The OS was better, albeit not significant, in patients with a MRD level <0.1% after induction (39% [95% CI, 14%-64%] vs. 13% [95% CI, 0%-36%]). Specific treatment approaches are required to improve the outcome of patients with KMT2A rearrangements. PMID- 27122130 TI - Complete genome sequence of a sapovirus from a child in Zhejiang, China. AB - Although Sapovirus (Caliciviridae) has been accepted as one of the causes of acute gastroenteritis worldwide, little is known about the genetic characteristics of the whole genome of sapoviruses in China, especially those that infect humans. Here we report the complete genome sequence of a sapovirus strain, Human/Zhejiang1/2015/China, obtained from a child with acute gastroenteritis in Hangzhou, Zhejiang Province, China. Samples were collected and delivered to the CDC laboratories and were detected by RT-PCR. Sanger sequencing was used to obtain the full genome and molecular characterization of the genome was determined. A phylogenetic analysis of the genome was also performed. The results indicated that Human/Zhejiang1/2015/China belongs to Genogroup I. No recombination events were detected. This is the first complete sequence from a child to be reported in China. The sequence information is important for surveillance of this emerging gastrointestinal infection. PMID- 27122131 TI - Gestational age, mode of birth and breastmilk feeding all influence acute early childhood gastroenteritis: a record-linkage cohort study. AB - BACKGROUND: Acute gastroenteritis (AGE) is a leading cause of infectious morbidity in childhood. Clinical studies have implicated caesarean section, early birth and formula feeding in modifying normal gut microbiota development and immune system homeostasis in early life. Rates of early birth and cesarean delivery are also increasing worldwide. This study aimed to investigate the independent and combined associations of the mode and timing of birth and breastmilk feeding with AGE hospitalisations in early childhood. METHODS: Population-based record-linkage study of 893,360 singleton livebirths of at least 33 weeks gestation without major congenital conditions born in hospital, New South Wales, Australia, 2001-2011. Using age at first AGE hospital admission, Cox regression was used to estimate the associations for gestational age, vaginal birth or caesarean delivery by labour onset and formula-only feeding while adjusting for confounders. RESULTS: There were 41,274 (4.6 %) children admitted to hospital at least once for AGE and the median age at first admission was 1.4 years. Risk of AGE admission increased with decreasing gestational age (37-38 weeks: 15 % increased risk, 33-36 weeks: 25 %), caesarean section (20 %), planned birth (17 %) and formula-only feeding (18 %). The rate of AGE admission was highest for children who were born preterm by modes of birth other than vaginal birth following the spontaneous onset of labour and who received formula-only at discharge from birth care (62-78 %). CONCLUSIONS: Vaginal birth following spontaneous onset of labour at 39+ weeks gestation with any breastfeeding minimised the risk of gastroenteritis hospitalisation in early childhood. Given increasing trends in early planned birth and caesarean section worldwide, these results provide important information about the impact obstetric interventions may have on the development of the infant gut microbiota and immunity. PMID- 27122132 TI - Comparison of ipsilateral breast tumor recurrence after breast-conserving surgery between ductal carcinoma in situ and invasive breast cancer. AB - BACKGROUND: We aimed to evaluate the differences in the rates and predictive factors for ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) between ductal carcinoma in situ (DCIS) and invasive breast cancer. And, we evaluated the impact of IBTR on overall survival and distant metastasis. METHODS: We retrospectively reviewed 322 consecutive patients with DCIS or invasive breast cancer who underwent BCS between 2004 and 2010. We evaluated the rates of IBTR of DCIS and invasive breast cancer. Univariate and multivariate analyses were performed to determine the predictive factors for IBTR, and survival rates were analyzed with Kaplan-Meier estimates. RESULTS: With a median follow-up period of 57 months, 5 (10%) out of 50 DCIS patients and 14 (5.1%) out of 272 invasive cancer patients had developed IBTR. Factors associated with IBTR on univariate and multivariate analyses were positive resection margin status in DCIS and omission of radiotherapy in invasive cancer, respectively. The hormone receptor negativity was strong independent predictive factors for IBTR in both DCIS and invasive breast cancer. Although the differences of survival curve did not reach statistical significance, the 5-year overall survival and distant metastasis-free survival of invasive cancer patients who suffered IBTR were inferior to those without (84 vs. 98% and 63.3 vs. 96.5%, respectively). Advanced initial stage, lymph node metastasis and experience of IBTR were associated with poor overall survival and distant metastasis on univariate and multivariate analyses. CONCLUSIONS: The hormone receptor negativity was revealed as independent predictive factor for IBTR after BCS in both DCIS and invasive cancer. Experience of IBTR was independent prognostic factor for poor overall outcome in patients with invasive breast cancer. Aggressive local control and adjuvant therapy should be made in hormone receptor-negative patients who receive treatment with BCS. PMID- 27122134 TI - Demographics and etiologic factors of nasal pyogenic granuloma. AB - BACKGROUND: Nasal pyogenic granuloma (lobular capillary hemangioma) is a rare benign tumor of unclear etiology. This study describes the clinical characteristics and possible etiologic factors in a series of patients with pyogenic granuloma. METHODS: All adult patients with a histologic diagnosis of pyogenic granuloma of the nasal cavity were identified between January 2005 and May 2015. A total of 128 charts were reviewed retrospectively for age, gender, clinical presentation, location of lesion, and medical history. RESULTS: Thirty eight patients were identified including 13 (34%) men and 25 (66%) women with a mean age of 45 years (range, 18-80 years). The majority (92%) presented with epistaxis and 76% had the lesion located on the septum. All patients had the lesion surgically excised with final pathology confirming pyogenic granuloma. Out of 38 patients, 15 (40%) had a concurrent history of altered hormonal activity (due to hormone therapy, pregnancy, or tumor), and 7 (18%) had prior injury to the nasal cavity. CONCLUSION: This study is 1 of the largest case series of nasal pyogenic granuloma to be reported. In this series, this disease process was seen in approximately twice as many women as compared to men. Our data further supports prior studies, suggesting that altered hormonal activity and nasal injury may increase the risk of developing nasal pyogenic granuloma. PMID- 27122133 TI - Pre-operative stroke and neurological disability do not independently affect short- and long-term mortality in infective endocarditis patients. AB - BACKGROUND: Infective endocarditis (IE) is still associated with high morbidity and mortality. The impact of pre-operative stroke on mortality and long-term survival is controversial. In addition, data on the severity of neurological disability due to pre-operative stroke are scarce. We analysed the impact of pre operative stroke and the severity of its related neurological disability on short and long-term outcome. METHODS: We retrospectively reviewed our data from patients operated for left-sided IE between 01/2007 and 04/2013. We performed univariate (Chi-Square and independent samples t test) and multivariate analyses. RESULTS: Among 308 consecutive patients who underwent cardiac surgery for left sided IE, pre-operative stroke was present in 87 (28.2 %) patients. Patients with pre-operative stroke had a higher pre-operative risk profile than patient without it: higher Charlson comorbidity index (8.1 +/- 2.6 vs. 6.6 +/- 3.3) and higher incidence of Staphylococcus aureus infection (43 vs. 17 %) and septic shock (37 vs. 19 %). In-hospital mortality was equal but 5-year survival was significantly worse with pre-operative stroke (33.1 % vs. 45 %, p = 0.006). 5-year survival was worst in patients with severe neurological disability compared to mild disability (19.0 vs. 0.58 %, p = 0.002). However, neither pre-operative stroke nor the degree of neurological disability appeared as an independent risk factor for short or long-term mortality by multivariate analysis. CONCLUSIONS: Pre-operative stroke and the severity of neurological disability do not independently affect short- and long-term mortality in patients with infective endocarditis. It appears that patients with pre-operative stroke present with a generally higher risk profile. This information may substantially affect decision-making. PMID- 27122135 TI - Digital PCR methods improve detection sensitivity and measurement precision of low abundance mtDNA deletions. AB - Mitochondrial DNA (mtDNA) mutations are a common cause of primary mitochondrial disorders, and have also been implicated in a broad collection of conditions, including aging, neurodegeneration, and cancer. Prevalent among these pathogenic variants are mtDNA deletions, which show a strong bias for the loss of sequence in the major arc between, but not including, the heavy and light strand origins of replication. Because individual mtDNA deletions can accumulate focally, occur with multiple mixed breakpoints, and in the presence of normal mtDNA sequences, methods that detect broad-spectrum mutations with enhanced sensitivity and limited costs have both research and clinical applications. In this study, we evaluated semi-quantitative and digital PCR-based methods of mtDNA deletion detection using double-stranded reference templates or biological samples. Our aim was to describe key experimental assay parameters that will enable the analysis of low levels or small differences in mtDNA deletion load during disease progression, with limited false-positive detection. We determined that the digital PCR method significantly improved mtDNA deletion detection sensitivity through absolute quantitation, improved precision and reduced assay standard error. PMID- 27122138 TI - Editorial: systematic reviews and meta-analyses of gene association studies. PMID- 27122136 TI - Ex vivo imaging of active caspase 3 by a FRET-based molecular probe demonstrates the cellular dynamics and localization of the protease in cerebellar granule cells and its regulation by the apoptosis-inhibiting protein survivin. AB - BACKGROUND: Apoptosis takes place in naturally occurring neuronal death, but also in aging, neurodegenerative disorders, and traumatic brain injuries. Caspase 3 (Casp3) is the most important effector protease in apoptosis: being inactive inside the cell, it undergoes enzymatic cleavage and - hence - activation once the apoptotic cascade is triggered. Immunological techniques with antibodies against cleaved Casp3 (cCasp3) or assays with colorimetric/fluorogenic substrates are commonly in use, but they do not allow to directly follow the dynamics of activation in alive neurons that may be committed to die. RESULTS: By combined biolistic transfection, confocal microscopy, and fluorescence resonance energy transfer (FRET), we have implemented a methodology to dynamically monitor Casp3 activation in organotypic cerebellar slices from postnatal mice. After transfection with pSCAT3 FRET probes, we measured the ratio of the emissions of the donor/acceptor pair (ECFPem/Venusem) in fixed or alive cultures. In so doing, we i. discriminated the cellular compartment(s) of enzyme activation (nucleus, perikaryon, neurites); ii. demonstrated that Casp3 was constitutively active in the granule cells; iii. followed the fluctuations of ECFPem/Venusem, and its response to 25 mM KCl depolarization, or to increased intracellular Ca(++) after NMDA (1 mM), kainic acid (1 mM), or A23187 (100-200 MUM). The specificity of the active pSCAT3-DEVD probe was confirmed with RNA interference and after inhibition of Casp3 with Ac-DEVD-CMK (100 MUM), as both sets of experiments brought ECFPem/Venusem to the values recorded with the control probe pSCAT3-DEVG. After double-transfection with pSCAT3-DEVD + pHcRed1-C1-survivin, we also showed a 44 56% reduction of basal Casp3 activity in cells overexpressing survivin, a protein member of the family of apoptosis inhibitors, with augmented survival (2.82 folds). Survivin-rescued cells were sensitive to 5 mM H2O2 oxidative stress but died without intervention of Casp3. CONCLUSIONS: This ex vivo FRET-based methodology provides quantitative information on the functional and histological dynamics of Casp3 activation in individual neurons at a cell level resolution. Not only it can be combined with experimental manipulation of the apoptotic machinery inside the cell, but offers several advantages over existing protocols for monitoring apoptosis in live mammalian neurons, and has potential to be transferred in vivo. Due to the pivotal role of Casp3 in apoptosis, our approach is relevant for a better comprehension of molecular neurodegeneration in the normal and pathological brain. PMID- 27122137 TI - Rapid evolution of tolerance to toxic Microcystis in two cladoceran grazers. AB - Evolutionary adaptation could assist organisms to cope with environmental changes, yet few experimental systems allow us to directly track evolutionary trajectory. Using experimental evolution, evolutionary tolerance to Microcystis aeruginosa was investigated in two cladocerans (Daphnia pulex and Simocephalus vetulus) to test the hypothesis that cladoceran grazers rapidly adapt to toxic cyanobacteria. After exposure for either three or six months, both grazers evolved a higher tolerance. The intrinsic rate of population increases in S. vetulus feeding on cyanobacteria was negatively correlated with that on green algae, which suggests that evolutionary adaptation in tolerance would carry a cost in the absence of cyanobacteria. However, the cyanobacterial selection resulted in a general increase in D. pulex when fed both cyanobacteria and green algae. Following a three-month relaxation of selection, S. vetulus in the selection line exhibited reverse evolution back to their original state when their diets were switched back to pure green algae. The present experimental evolution, both forwards and reverse, not only demonstrates the evolutionary responses of cladoceran grazers to toxic cyanobacterial cells in the laboratory, but also indicates that the grazer-cyanobacteria interaction would be an effective system to empirically study rapid evolution to environmental changes. PMID- 27122139 TI - Health Promotion Efforts as Predictors of Physical Activity in Schools: An Application of the Diffusion of Innovations Model. AB - BACKGROUND: Implementing a comprehensive school physical activity program (CSPAP) effectively addresses public health issues by providing opportunities for physical activity (PA). Grounded in the Diffusion of Innovations model, the purpose of this study was to identify how health promotion efforts facilitate opportunities for PA. METHODS: Physical and health education teachers (N = 256) nationwide were surveyed using a CSPAP Index to identify teacher's efforts for providing opportunities for PA within a school setting. RESULTS: A hierarchical regression analysis revealed total number of PA opportunities was significantly predicted by teachers' health promotion efforts, p < .001. Sex and years of experience were not significant covariates, p = .35, in the final step of the model. Accounting for teaching environments, the model was significant, p < .001. The strongest predictors were the promotional efforts of PA for family and community, p < .001, PA for staff members, p < .01, PA during the school day, p < .05, and PA before school, p < .05. CONCLUSIONS: To increase PA opportunities for children in schools, emphasis should be placed on health promotion. This study confirms the importance of teachers involving family, community, and staff members as co-health promoters when trying to increase PA engagement surrounding schools. PMID- 27122140 TI - Fluid Intake and Cognitive Performance: Should Schoolchildren Drink During Lessons? AB - BACKGROUND: Evidence suggests that an insufficient fluid intake impairs cognitive performance. Drinking policies at schools-especially drinking during lessons-is a point of controversy. To provide a scientific base for this debate, more empirical evidence is needed on which aspects of fluid intake are crucial for cognitive performance. This study makes a contribution by investigating associations between quantitative and temporal aspects of fluid intake and cognitive performance in everyday school life. METHODS: The study comprised 125 children (age: mean = 10.98 years, SD = 0.38). Amount of fluid intake and time span between fluid intake and completion of cognitive tests were determined on basis of self-reports. Cognitive performance was assessed by standardized tests. RESULTS: Quantitative and temporal aspects were associated with cognitive performance: The more fluid the children consumed and the shorter the time span between their last fluid intake and test completion, the better they performed. CONCLUSIONS: The amount of fluid intake should be adequate and moreover the time span between intake and cognitive efforts should be as short as possible. Schoolchildren are thus recommended to drink at regular intervals and also during lessons. PMID- 27122142 TI - Reliability and Validity of the Physical Education Activities Scale. AB - BACKGROUND: Measuring adolescent perceptions of physical education (PE) activities is necessary in understanding determinants of school PE activity participation. This study assessed reliability and validity of the Physical Education Activities Scale (PEAS), a 41-item visual analog scale measuring high school adolescent perceptions of school PE activity participation. METHODS: Adolescents (N = 529) from the Pacific Northwest aged 15-19 in grades 9-12 participated in the study. Construct validity was assessed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Measurement invariance across sex groups was tested by multiple-group CFA. Internal consistency reliability was analyzed using Cronbach's alpha. Inter-subscale correlations (Pearson's r) were calculated for latent factors and observed subscale scores. RESULTS: Exploratory factor analysis suggested a 3-factor solution explaining 43.4% of the total variance. Confirmatory factor analysis showed the 3-factor model fit the data adequately (comparative fit index [CFI] = 0.90, Tucker-Lewis index [TLI] = 0.89, root mean squared error of approximation [RMSEA] = 0.063). Factorial invariance was supported. Cronbach's alpha of the total PEAS was alpha = 0.92, and for subscales alpha ranged from 0.65 to 0.92. Independent t-tests showed significantly higher mean scores for boys than girls on the total scale and all subscales. CONCLUSION: Findings provide psychometric support for using the PEAS for examining adolescent's psychosocial and environmental perceptions to participating in PE activities. PMID- 27122141 TI - The Impact of the CHILE Intervention on the Food Served in Head Start Centers in Rural New Mexico. AB - BACKGROUND: The Child Health Initiative for Lifelong Eating and Exercise is a multicomponent obesity-prevention intervention, which was evaluated among Head Start (HS) centers in American Indian and predominantly Hispanic communities in rural New Mexico. This study examines the intervention's foodservice outcomes: fruits, vegetables, whole grains, discretionary fats, added sugars, and fat from milk served in meals and snacks. METHODS: Sixteen HS centers were randomized to intervention/comparison groups, following stratification by ethnicity and preintervention median body mass index of enrolled children. The foodservice component included quarterly trainings for foodservice staff about food purchasing and preparation. Foods served were evaluated before and after the 2 year intervention, in the fall 2008 and spring 2010. RESULTS: The intervention significantly decreased fat provided through milk and had no significant effect on fruit, vegetables and whole-grain servings, discretionary fats, and added sugar served in HS meals and snacks. When effect modification by site ethnicity was examined, the effect on fat provided through milk was only found in American Indian sites. CONCLUSIONS: Foodservice interventions can reduce the amount of fat provided through milk served in HS. More research is needed regarding the implementation of foodservice interventions to improve the composition of foods served in early education settings. PMID- 27122143 TI - School Health Promotion Policies and Adolescent Risk Behaviors in Israel: A Multilevel Analysis. AB - BACKGROUND: Health promotion policies targeting risk-taking behaviors are being implemented across schools in Israel. This study identified the most effective components of these policies influencing cigarette smoking and alcohol consumption among adolescents. METHODS: Logistic hierarchical linear model (HLM) analysis of data for 5279 students in 95 Jewish public schools from the Health Behavior in School-Aged Children (HBSC) 2010-2011 survey in Israel enabled simultaneous estimation of the relationship between student- and school-level variables (health promotion policy) to alcohol consumption and smoking behavior. Principals of participating schools also were interviewed to ascertain their degree of adoption and implementation of a health promotion policy. RESULTS: Most of the variance in adolescent risk behaviors is explained by student-level variables: negative perceptions of school, lack of parental support for school issues, and more time spent with friends. Among the school-level policy measures, parental participation in health promotion intervention programs was repeatedly associated with lower rates of risk behaviors, over and above student characteristics. CONCLUSIONS: School health promotion policies should focus on parents' involvement in intervention programs and should seek to improve students' perceptions of school and their sense of well-being to promote resilience. Further research is needed to identify additional factors that may increase the effectiveness of school health promotion policies. PMID- 27122144 TI - Association Between Markers of Classroom Environmental Conditions and Teachers' Respiratory Health. AB - BACKGROUND: Studies have assessed health in schoolchildren. Less is known about the environmental and occupational health of teachers. METHODS: A cross-sectional survey of teachers was conducted in 24 randomly selected public elementary schools. Questionnaire included sociodemographic information, healthcare, school conditions, and health outcomes. Chi-square and logistic regression were used to analyze bivariate relationships. Multivariable logistic regression model was created for each health outcome, adjusted for sex and smoking to calculate estimates of association (OR) for variables that were significant in bivariate analysis. RESULTS: Response rate was 71.2 % (N = 797). Classroom conditions significantly associated with respiratory symptoms included having no windows or windows that do not open were associated with asthma or colds (OR 2.0); carpeting was associated with having asthma, itchy eyes, and eye irritation (OR 1.9); mold or water damage was associated with respiratory infections, eye irritation (OR 2.1), nasal congestion (OR 2.4), and sore throat (OR 2.7); visible dust was associated with frequent colds (OR 2.2), nasal congestion (OR 1.7), and sore throat (1.9). CONCLUSIONS: Asthma, respiratory infections, colds, eye irritation, nasal congestion, and sore throat were associated with the classroom environment. Results indicate that the school environment could affect teachers' respiratory health. Further assessments are necessary to establish causation. PMID- 27122145 TI - Systematic Review of School-Based Interventions to Modify Dietary Behavior: Does Intervention Intensity Impact Effectiveness? AB - BACKGROUND: Owing to the associations between diet and health, it is important that effective health promotion strategies establish healthful eating behaviors from an early age. We reviewed the intensity of school-based interventions aimed to modify dietary behavior in preadolescent and adolescents and related intervention characteristics to effectiveness. METHODS: Our systematic literature search of 8 databases sought to identify interventions measuring dietary intake in school settings to students aged 9 to 18. We evaluated these studies for effectiveness, intensity, intervention category, and follow-up measures. RESULTS: Of the 105 interventions 81 were found to be effective immediately postintervention, irrespective of intensity. Studies that were 6 weeks to 5 months in duration, targeted students' environment or group (alone or in combination), and reached students only in schools were more effective. Only one fifth of interventions conducted a follow-up measure, and a majority showed a loss of effectiveness from postintervention to follow-up. CONCLUSIONS: We identified characteristics of effective interventions. These findings may inform the development of future interventions targeting dietary behavior in preadolescents and adolescents in the school-based setting. PMID- 27122146 TI - Active Travel to School: Findings From the Survey of US Health Behavior in School Aged Children, 2009-2010. AB - BACKGROUND: Whereas children's active travel to school (ATS) has confirmed benefits, only a few large national surveys of ATS exist. METHODS: Using data from the Health Behavior in School-aged Children (HBSC) 2009-2010 US survey, we conducted a logistic regression model to estimate the odds ratios of ATS and a linear regression model to estimate the adjusted mean differences of the percentage of ATS within a school. RESULTS: Overall, 21.4% of children engaged in at least one way of active travel to or from school. ATS was less common for trips to school than from school. Greater distance to school was a major barrier preventing children from ATS. Children living in large cities were more likely to engage in ATS, and schools located in a large city had higher proportions of ATS rate. Children having lower family satisfaction, or engaging in a greater number of physically active days during the past week were all more likely to engage in ATS. CONCLUSIONS: Although ATS is low among US children, significant variation exists. HBSC is a promising data source for an ATS study. As the first study to explore the variation of ATS at school level, this research contributes uniquely to current knowledge. PMID- 27122147 TI - Food Insecurity and Rural Adolescent Personal Health, Home, and Academic Environments. AB - BACKGROUND: Food-insecure (FIS) adolescents struggle in school and with health and mental health more often than food-secure (FS) adolescents. Rural communities experience important disparities in health, but little is known about rural FIS adolescents. This study aims to describe select characteristics of rural adolescents by food-security status. METHODS: Baseline analysis using data from a randomized trial to increase school breakfast participation (SBP) in rural Minnesota high schools. Students completed a survey regarding food security, characteristics, and home and school environments. Schools provided academic data and staff measured height and weight. Food security was dichotomized as FS vs FIS. Bivariate analysis, multivariate linear/logistic regression, and testing for interaction of food security and sex were performed. RESULTS: Food-insecure adolescents reported poorer health, less exercise, had lower grades, and higher SBP (p < .01). Food-insecure adolescents reported marginally fewer barriers (p = .06) and more benefits of breakfast (p = .05). All associations except reported benefits remained significant after adjustment. Interactions were identified with girls' grade point average and with boys' caloric and added sugar intake. CONCLUSIONS: Negative associations among food insecurity and positive youth development are identified in our sample. Policy and environmental strategies should address the complexities of these associations, including exploration of the role of school meals. PMID- 27122148 TI - Addressing inaccuracies in BLOSUM computation improves homology search performance. AB - BACKGROUND: BLOSUM matrices belong to the most commonly used substitution matrix series for protein homology search and sequence alignments since their publication in 1992. In 2008, Styczynski et al. discovered miscalculations in the clustering step of the matrix computation. Still, the RBLOSUM64 matrix based on the corrected BLOSUM code was reported to perform worse at a statistically significant level than the BLOSUM62. Here, we present a further correction of the (R)BLOSUM code and provide a thorough performance analysis of BLOSUM-, RBLOSUM- and the newly derived CorBLOSUM-type matrices. Thereby, we assess homology search performance of these matrix-types derived from three different BLOCKS databases on all versions of the ASTRAL20, ASTRAL40 and ASTRAL70 subsets resulting in 51 different benchmarks in total. Our analysis is focused on two of the most popular BLOSUM matrices - BLOSUM50 and BLOSUM62. RESULTS: Our study shows that fixing small errors in the BLOSUM code results in substantially different substitution matrices with a beneficial influence on homology search performance when compared to the original matrices. The CorBLOSUM matrices introduced here performed at least as good as their BLOSUM counterparts in ~75 % of all test cases. On up-to date ASTRAL databases BLOSUM matrices were even outperformed by CorBLOSUM matrices in more than 86 % of the times. In contrast to the study by Styczynski et al., the tested RBLOSUM matrices also outperformed the corresponding BLOSUM matrices in most of the cases. Comparing the CorBLOSUM with the RBLOSUM matrices revealed no general performance advantages for either on older ASTRAL releases. On up-to-date ASTRAL databases however CorBLOSUM matrices performed better than their RBLOSUM counterparts in ~74 % of the test cases. CONCLUSIONS: Our results imply that CorBLOSUM type matrices outperform the BLOSUM matrices on a statistically significant level in most of the cases, especially on up-to-date databases such as ASTRAL >=2.01. Additionally, CorBLOSUM matrices are closer to those originally intended by Henikoff and Henikoff on a conceptual level. Hence, we encourage the usage of CorBLOSUM over (R)BLOSUM matrices for the task of homology search. PMID- 27122149 TI - How to fix out of hours care. PMID- 27122150 TI - Retinyl Palmitate Supplementation Modulates T-bet and Interferon Gamma Gene Expression in Multiple Sclerosis Patients. AB - Vitamin A derivatives such as retinoic acid may improve the impaired balance of CD4+ T cells in autoimmune and inflammatory diseases. This study is a double blind randomized trial to evaluate the effect of vitamin A (as form of retinyl palmitate) supplementation on multiple sclerosis (MS) patients. Thirty-nine patients were enrolled and randomly assigned to two groups. Both groups were followed for 6 months. The experimental group received 25,000 IU of retinyl palmitate daily, while the control group received a placebo. Before and after the study, the expression of interferon gamma (IFN-gamma) and T-bet genes was evaluated in peripheral blood mononuclear cells of patients by RT-PCR. The results showed that after 6 months of supplementation, expression of IFN-gamma and T-bet was significantly decreased. These data suggest that retinyl palmitate supplementation can modulate the impaired balance of Th1 and Th2 cells and vitamin A products that may be involved in the therapeutic mechanism of vitamin A in MS patients. This study provides information regarding the decreased gene expression of IFN-gamma and T-bet in MS by retinyl palmitate supplementation. PMID- 27122152 TI - A roadmap to translating the microbiome. PMID- 27122151 TI - Promoter-Specific Hypomethylation Correlates with IL-1beta Overexpression in Tuberous Sclerosis Complex (TSC). AB - In tuberous sclerosis complex (TSC), overexpression of numerous genes associated with inflammation has been observed. Among different proinflammatory cytokines, interleukin-1beta (IL-1beta) has been shown to be significantly involved in epileptogenesis and maintenance of seizures. Recent evidence indicates that IL 1beta gene expression can be regulated by DNA methylation of its promoter. In the present study, we hypothesized that hypomethylation in the promoter region of the IL-1beta gene may underlie its overexpression observed in TSC brain tissue. Bisulfite sequencing was used to study the methylation status of the promoter region of the IL-1beta gene in TSC and control samples. We identified hypomethylation in the promoter region of the IL-1beta gene in TSC samples. IL 1beta is overexpressed in tubers, and gene expression is correlated with promoter hypomethylation at CpG and non-CpG sites. Our results provide the first evidence of epigenetic modulation of the IL-1beta signaling in TSC. Thus, strategies that target epigenetic alterations could offer new therapeutic avenues to control the persistent activation of interleukin-1beta-mediated inflammatory signaling in TSC brain. PMID- 27122153 TI - Retraction Note: Stress urinary incontinence: long-term results of laparoscopic Burch colposuspension. PMID- 27122154 TI - MicroRNA-199a-5p inhibits tumor proliferation in melanoma by mediating HIF 1alpha. AB - The expression of hypoxia-inducible factor 1alpha (HIF-1alpha) is often abundant in human cancer and it is associated with poor prognosis. The present study aimed to investigate its regulation by microRNA (miRNA). The expression of miRNA-199a 5p (miR-199a-5p) in melanoma was detected by quantitative polymerase chain reaction on samples from 25 melanoma patients. The target of miR-199a-5p was predicted and demonstrated by a dual-luciferase reporter system. The effects of miR-199a-5p on melanoma cells were assayed in B16 and HME1 melanoma cell lines. Furthermore, the potential of miR-199a-5p as a therapeutic target was illustrated in xenograft nude mice models. Low expression of miR-199a-5p in tumor melanoma tissue samples from patients was associated with high histological grade and advanced tumor stage. The 3'-untranslated region of HIF-1alpha was identified as a target of miR-199a-5p by Targetscan software. The dual-luciferase reporter assay demonstrated that miR-199a-5p transfection of mimics decreased the luciferase activity significantly (P<0.05). In the B16 and HME1 cell lines, overexpression of miR-199a-5p suppressed cell proliferation and arrested the cell cycle in the G1 phase. In vivo overexpression of miR-199a-5p significantly suppressed xenograft growth and downregulated the expression of HIF-1alpha (P<0.05). The results from the present study suggest that miR-199a-5p suppressed melanoma proliferation via HIF-1alpha, suggesting it may be a potential therapeutic target for melanoma treatment. PMID- 27122156 TI - 5-fluorouracil toxicity in the treatment of colon cancer associated with the genetic polymorphism 2846 A>G (rs67376798). AB - Colorectal cancer is the second most common cancer in Europe. Most antineoplastic regimens in first-line treatment involve 5-fluorouracil or oral prodrug capecitabine, combined with other antineoplastic agents such as oxaliplatin or irinotecan. It is well known that 5-fluorouracil and capecitabine are agents that can be toxic in cases of decreased dihydropyrimidine dehydrogenase activity because this enzyme is the main limiting factor in the metabolism of both agents. In this paper, we describe the case of a patient who developed severe toxicity to 5-fluouracil and who had a mutation in the gene encoding the enzyme dihydropyrimidine dehydrogenase. PMID- 27122155 TI - Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs). AB - BACKGROUND: Rap proteins from Bacilli directly target response regulators of bacterial two-component systems and modulate their activity. Their effects are controlled by binding of signaling peptides to an allosteric site. Hence Raps exemplify a class of monomeric signaling receptors, which we call switchable allosteric modulator proteins (SAMPs). These proteins have potential applications in diverse biomedical and biotechnical settings, but a quantitative understanding of the impact of molecular and cellular factors on signal transduction is lacking. Here we introduce mathematical models that elucidate how signals are propagated though the network upon receptor stimulation and control the level of active response regulator. RESULTS: Based on a systematic parameter analysis of the models, we show that key features of the dose-response behavior at steady state are controlled either by the molecular properties of the modulator or the signaling context. In particular, we find that the biochemical activity (i.e. non enzymatic vs. enzymatic) and allosteric properties of the modulator control the response amplitude. The Hill coefficient and the EC50 are controlled in addition by the relative ligand affinities. By tuning receptor properties, either graded or more switch-like (memory-less) response functions can be fashioned. Furthermore, we show that other contextual factors (e.g. relative concentrations of network components and kinase activity) have a substantial impact on the response, and we predict that there exists a modulator concentration which is optimal for response amplitude. CONCLUSION: We discuss data on Rap-Phr systems in B. subtilis to show how our models can contribute to an integrated view of SAMP signaling by combining biochemical, structural and physiological insights. Our results also suggest that SAMPs could be evolved or engineered to implement diverse response behaviors. However-without additional regulatory controls-they can generate rather variable cellular outputs. PMID- 27122157 TI - Chronology of UPR activation in skeletal muscle adaptations to chronic contractile activity. AB - The mitochondrial and endoplasmic reticulum unfolded protein responses (UPR(mt) and UPR(ER)) are important for cellular homeostasis during stimulus-induced increases in protein synthesis. Exercise triggers the synthesis of mitochondrial proteins, regulated in part by peroxisome proliferator activator receptor-gamma coactivator 1alpha (PGC-1alpha). To investigate the role of the UPR in exercise induced adaptations, we subjected rats to 3 h of chronic contractile activity (CCA) for 1, 2, 3, 5, or 7 days followed by 3 h of recovery. Mitochondrial biogenesis signaling, through PGC-1alpha mRNA, increased 14-fold after 1 day of CCA. This resulted in 10-32% increases in cytochrome c oxidase activity, indicative of mitochondrial content, between days 3 and 7, as well as increases in the autophagic degradation of p62 and microtubule-associated proteins 1A/1B light chain 3A (LC3)-II protein. Before these adaptations, the UPR(ER) transcripts activating transcription factor-4, spliced X-box-binding protein 1, and binding immunoglobulin protein were elevated (1.3- to 3.8-fold) at days 1-3, while CCAAT/enhancer-binding protein homologous protein (CHOP) and chaperones binding immunoglobulin protein and heat shock protein (HSP) 70 were elevated at mRNA and protein levels (1.5- to 3.9-fold) at days 1-7 of CCA. The mitochondrial chaperones 10-kDa chaperonin, HSP60, and 75-kDa mitochondrial HSP, the protease ATP-dependent Clp protease proteolytic subunit, and the regulatory protein sirtuin-3 of the UPR(mt) were concurrently induced 10-80% between days 1 and 7 To test the role of the UPR in CCA-induced remodeling, we treated animals with the endoplasmic reticulum stress suppressor tauroursodeoxycholic acid and subjected them to 2 or 7 days of CCA. Tauroursodeoxycholic acid attenuated CHOP and HSP70 protein induction; however, this failed to impact mitochondrial remodeling. Our data indicate that signaling to the UPR is rapidly activated following acute contractile activity, that this is attenuated with repeated bouts, and that the UPR is involved in chronic adaptations to CCA; however, this appears to be independent of CHOP signaling. PMID- 27122158 TI - Caveolin-1 regulates corneal wound healing by modulating Kir4.1 activity. AB - The expression of caveolin-1 (Cav1) in corneal epithelium is associated with regeneration potency. We used Cav1(-/-) mice to study the role of Cav1 in modulating corneal wound healing. Western blot and whole cell patch clamp were employed to study the effect of Cav1 deletion on Kir4.1 current density in corneas. We found that Ba(2+)-sensitive K(+) currents in primary cultured murine corneal epithelial cells (pMCE) from Cav1(-/-) were dramatically reduced (602 pA) compared with those from wild type (WT; 1,300 pA). As a consequence, membrane potential was elevated in pMCE from Cav1(-/-) compared with that from WT (-43 +/- 7.5 vs. -58 +/- 4.0 mV, respectively). Western blot showed that either inhibition of Cav1 expression or Ba(2+) incubation stimulated phosphorylation of the EGFR. The transwell migration assay showed that Cav1 genetic inactivation accelerated cell migration. The regrowth efficiency of human corneal epithelial cells (HCE) transfected with siRNA-Cav1 or negative control was evaluated by scrape injury assay. With the presence of mitomycin C (10 MUg/ml) to avoid the influence of cell proliferation, Cav1 inhibition with siRNA significantly increased migration compared with control siRNA in HCE. This promoting effect by siRNA-Cav1 could not be further enhanced by cotransfection with siRNA-Kcnj10. By using corneal debridement, we found that wound healing was significantly accelerated in Cav1(-/ ) compared with WT mice (70 +/- 10 vs. 36 +/- 3%, P < 0.01). Our findings imply that the mechanism by which Cav-1 knockout promotes corneal regrowth is, at least partially, due to the inhibition of Kir4.1 which stimulates EGFR signaling. PMID- 27122159 TI - Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. AB - Vitamin C (ascorbic acid, AA) is indispensable for normal metabolism of all mammalian cells including pancreatic acinar cells (PACs). PACs obtain AA from their surroundings via transport across the cell membrane. Chronic alcohol exposure negatively affects body AA homeostasis; it also inhibits uptake of other micronutrients into PACs, but its effect on AA uptake is not clear. We examined this issue using both in vitro (266-6 cells) and in vivo (mice) models of chronic alcohol exposure. First, we determined the relative expression of the AA transporters 1 and 2 [i.e., sodium-dependent vitamin C transporter-1 (SVCT-1) and SVCT-2] in mouse and human PACs and found SVCT-2 to be the predominant transporter. Chronic exposure of 266-6 cells to alcohol significantly inhibited AA uptake and caused a marked reduction in SVCT-2 expression at the protein, mRNA, and heterogeneous nuclear RNA (hnRNA) levels. Similarly, chronic alcohol feeding of mice significantly inhibited AA uptake and caused a marked reduction in level of expression of the SVCT-2 protein, mRNA, and hnRNA. These findings suggest possible involvement of transcriptional mechanism(s) in mediating chronic alcohol effect on AA uptake by PACs. We also observed significant epigenetic changes (histone modifications) in the Slc23a2 gene (reduction in H3K4me3 level and an increase in H3K27me3 level) in the alcohol-exposed 266-6 cells. These findings show that chronic alcohol exposure inhibits PAC AA uptake and that the effect is mediated, in part, at the level of transcription of the Slc23a2 gene and may involve epigenetic mechanism(s). PMID- 27122160 TI - The Ste20 kinases SPAK and OSR1 travel between cells through exosomes. AB - Proteomics studies have identified Ste20-related proline/alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) in exosomes isolated from body fluids such as blood, saliva, and urine. Because proteomics studies likely overestimate the number of exosome proteins, we sought to confirm and extend this observation using traditional biochemical and cell biology methods. We utilized HEK293 cells in culture to verify the packaging of these Ste20 kinases in exosomes. Using a series of centrifugation and filtration steps of conditioned culture medium isolated from HEK293 cells, we isolated nanovesicles in the range of 40-100 nm. We show that these small vesicles express the tetraspanin protein CD63 and lack endoplasmic reticulum and Golgi markers, consistent with these being exosomes. We show by Western blot and immunogold analyses that these exosomes express SPAK, OSR1, and Na-K-Cl cotransporter 1 (NKCC1). We show that exosomes are not only secreted by cells, but also accumulated by adjacent cells. Indeed, exposing cultured cells to exosomes produced by other cells expressing a fluorescently labeled kinase resulted in the kinase finding its way into the cytoplasm of these cells, consistent with the idea of exosomes serving as cell-to cell communication vessels. Similarly, coculturing cells expressing different fluorescently tagged proteins resulted in the exchange of proteins between cells. In addition, we show that both SPAK and OSR1 kinases entering cells through exosomes are preferentially expressed at the plasma membrane and that the kinases in exosomes are functional and maintain NKCC1 in a phosphorylated state. PMID- 27122162 TI - Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPbeta regulated atrogin1 expression in cancer cachexia. AB - Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPbeta), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPbeta responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPbeta, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPbeta binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia. PMID- 27122161 TI - The mitochondrial Ca2+ uniporter: regulation by auxiliary subunits and signal transduction pathways. AB - Mitochondrial Ca(2+) homeostasis, the Ca(2+) influx-efflux balance, is responsible for the control of numerous cellular functions, including energy metabolism, generation of reactive oxygen species, spatiotemporal dynamics of Ca(2+) signaling, and cell growth and death. Recent discovery of the molecular identity of the mitochondrial Ca(2+) uniporter (MCU) provides new possibilities for application of genetic approaches to study the mitochondrial Ca(2+) influx mechanism in various cell types and tissues. In addition, the subsequent discovery of various auxiliary subunits associated with MCU suggests that mitochondrial Ca(2+) uptake is not solely regulated by a single protein (MCU), but likely by a macromolecular protein complex, referred to as the MCU-protein complex (mtCUC). Moreover, recent reports have shown the potential role of MCU posttranslational modifications in the regulation of mitochondrial Ca(2+) uptake through mtCUC. These observations indicate that mtCUCs form a local signaling complex at the inner mitochondrial membrane that could significantly regulate mitochondrial Ca(2+) handling, as well as numerous mitochondrial and cellular functions. In this review we discuss the current literature on mitochondrial Ca(2+) uptake mechanisms, with a particular focus on the structure and function of mtCUC, as well as its regulation by signal transduction pathways, highlighting current controversies and discrepancies. PMID- 27122164 TI - Corrigendum. PMID- 27122163 TI - The Relationship Between Intracholecystic Papillary-Tubular Neoplasms and Invasive Carcinoma of the Gallbladder. AB - INTRODUCTION: The term intracholecystic papillary-tubular neoplasm (ICPN) is suggested by some authors for a group of exophytic lesions of the gallbladder. In our study, demographic, pathological, and immunohistochemical features of 45 ICPN cases and their relationship with invasive carcinoma were analyzed. MATERIAL AND METHODS: A total of 45 ICPN cases were retrieved out of 7334 cholecystectomies performed between1996 and 2014. Cases were evaluated with regard to demographic, pathological, and immunohistochemical features. Correlation between the clinical and histopathological data and occurrence of invasion was sought. RESULTS: The incidence of ICPN was 0.61% in our series. Invasive carcinoma was observed in 56% of cases. Factors associated with invasion were diffuse high-grade dysplasia (P = .002), papillary growth pattern (P = .001), greatest diameter of the lesion, and high Ki67 proliferation index (P < .0001). DISCUSSION: Some authors have reported that small intracholecystic exophytic lesions without high-grade dysplasia are considered to be inconsequential. However, there are not enough data concerning the features of large lesions with high-grade dysplasia and their prognoses. Our data suggest that cases with diffuse high-grade dysplasia and tubulopapillary/papillary growth pattern, large tumor size, and high Ki67 proliferation index should be studied for the presence of invasion. PMID- 27122165 TI - Delamination of neural crest cells requires transient and reversible Wnt inhibition mediated by Dact1/2. AB - Delamination of neural crest (NC) cells is a bona fide physiological model of epithelial-to-mesenchymal transition (EMT), a process that is influenced by Wnt/beta-catenin signalling. Using two in vivo models, we show that Wnt/beta catenin signalling is transiently inhibited at the time of NC delamination. In attempting to define the mechanism underlying this inhibition, we found that the scaffold proteins Dact1 and Dact2, which are expressed in pre-migratory NC cells, are required for NC delamination in Xenopus and chick embryos, whereas they do not affect the motile properties of migratory NC cells. Dact1/2 inhibit Wnt/beta catenin signalling upstream of the transcriptional activity of T cell factor (TCF), which is required for EMT to proceed. Dact1/2 regulate the subcellular distribution of beta-catenin, preventing beta-catenin from acting as a transcriptional co-activator to TCF, yet without affecting its stability. Together, these data identify a novel yet important regulatory element that inhibits beta-catenin signalling, which then affects NC delamination. PMID- 27122166 TI - Mitochondrial biogenesis is required for axonal growth. AB - During early development, neurons undergo complex morphological rearrangements to assemble into neuronal circuits and propagate signals. Rapid growth requires a large quantity of building materials, efficient intracellular transport and also a considerable amount of energy. To produce this energy, the neuron should first generate new mitochondria because the pre-existing mitochondria are unlikely to provide a sufficient acceleration in ATP production. Here, we demonstrate that mitochondrial biogenesis and ATP production are required for axonal growth and neuronal development in cultured rat cortical neurons. We also demonstrate that growth signals activating the CaMKKbeta, LKB1-STRAD or TAK1 pathways also co activate the AMPK-PGC-1alpha-NRF1 axis leading to the generation of new mitochondria to ensure energy for upcoming growth. In conclusion, our results suggest that neurons are capable of signalling for upcoming energy requirements. Earlier activation of mitochondrial biogenesis through these pathways will accelerate the generation of new mitochondria, thereby ensuring energy-producing capability for when other factors for axonal growth are synthesized. PMID- 27122167 TI - Diversity in cell motility reveals the dynamic nature of the formation of zebrafish taste sensory organs. AB - Taste buds are sensory organs in jawed vertebrates, composed of distinct cell types that detect and transduce specific taste qualities. Taste bud cells differentiate from oropharyngeal epithelial progenitors, which are localized mainly in proximity to the forming organs. Despite recent progress in elucidating the molecular interactions required for taste bud cell development and function, the cell behavior underlying the organ assembly is poorly defined. Here, we used time-lapse imaging to observe the formation of taste buds in live zebrafish larvae. We found that tg(fgf8a.dr17)-expressing cells form taste buds and get rearranged within the forming organs. In addition, differentiating cells move from the epithelium to the forming organs and can be displaced between developing organs. During organ formation, tg(fgf8a.dr17) and type II taste bud cells are displaced in random, directed or confined mode relative to the taste bud they join or by which they are maintained. Finally, ascl1a activity in the 5-HT/type III cell is required to direct and maintain tg(fgf8a.dr17)-expressing cells into the taste bud. We propose that diversity in displacement modes of differentiating cells acts as a key mechanism for the highly dynamic process of taste bud assembly. PMID- 27122168 TI - Ihha induces hybrid cartilage-bone cells during zebrafish jawbone regeneration. AB - The healing of bone often involves a cartilage intermediate, yet how such cartilage is induced and utilized during repair is not fully understood. By studying a model of large-scale bone regeneration in the lower jaw of adult zebrafish, we show that chondrocytes are crucial for generating thick bone during repair. During jawbone regeneration, we find that chondrocytes co-express genes associated with osteoblast differentiation and produce extensive mineralization, which is in marked contrast to the behavior of chondrocytes during facial skeletal development. We also identify the likely source of repair chondrocytes as a population of Runx2(+)/Sp7(-) cells that emanate from the periosteum, a tissue that normally contributes only osteoblasts during homeostasis. Analysis of Indian hedgehog homolog a (ihha) mutants shows that the ability of periosteal cells to generate cartilage in response to injury depends on a repair-specific role of Ihha in the induction as opposed to the proliferation of chondrocytes. The large-scale regeneration of the zebrafish jawbone thus employs a cartilage differentiation program distinct from that seen during development, with the bone forming potential of repair chondrocytes potentially due to their derivation from osteogenic cells in the periosteum. PMID- 27122169 TI - Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway. AB - Primary cilia have been linked to signaling pathways involved in cell proliferation, cell motility and cell polarity. Defects in ciliary function result in developmental abnormalities and multiple ciliopathies. Patients affected by severe ciliopathies, such as Meckel syndrome, present several ocular surface disease conditions of unclear pathogenesis. Here, we show that primary cilia are predominantly present on basal cells of the mouse corneal epithelium (CE) throughout development and in the adult. Conditional ablation of cilia in the CE leads to an increase in proliferation and vertical migration of basal corneal epithelial cells (CECs). A consequent increase in cell density of suprabasal layers results in a thicker than normal CE. Surprisingly, in cilia deficient CE, cilia-mediated signaling pathways, including Hh and Wnt pathways, were not affected but the intensity of Notch signaling was severely diminished. Although Notch1 and Notch2 receptors were expressed normally, nuclear Notch1 intracellular domain (N1ICD) expression was severely reduced. Postnatal development analysis revealed that in cilia-deficient CECs downregulation of the Notch pathway precedes cell proliferation defects. Thus, we have uncovered a function of the primary cilium in maintaining homeostasis of the CE by balancing proliferation and vertical migration of basal CECs through modulation of Notch signaling. PMID- 27122170 TI - Role of the ABC transporter Mdr49 in Hedgehog signaling and germ cell migration. AB - Coalescence of the embryonic gonad in Drosophila melanogaster requires directed migration of primordial germ cells (PGCs) towards somatic gonadal precursor cells (SGPs). It was recently proposed that the ATP-binding cassette (ABC) transporter Mdr49 functions in the embryonic mesoderm to facilitate the transmission of the PGC attractant from the SGPs; however, the precise molecular identity of the Mdr49-dependent guidance signal remained elusive. Employing the loss- and gain-of function strategies, we show that Mdr49 is a component of the Hedgehog (hh) pathway and it potentiates the signaling activity. This function is direct because in Mdr49 mutant embryos the Hh ligand is inappropriately sequestered in the hh-expressing cells. Our data also suggest that the role of Mdr49 is to provide cholesterol for the correct processing of the Hh precursor protein. Supporting this conclusion, PGC migration defects in Mdr49 embryos are substantially ameliorated by a cholesterol-rich diet. PMID- 27122172 TI - Syk kinases are required for spinal commissural axon repulsion at the midline via the ephrin/Eph pathway. AB - In the hematopoietic system, Syk family tyrosine kinases are essential components of immunoreceptor ITAM-based signaling. While there is increasing data indicating the involvement of immunoreceptors in neural functions, the contribution of Syk kinases remains obscure. Previously, we identified phosphorylated forms of Syk kinases in specialized populations of migrating neurons or projecting axons. Moreover, we identified ephrin/Eph as guidance molecules utilizing the ITAM bearing CD3zeta (Cd247) and associated Syk kinases for the growth cone collapse response induced in vitro Here, we show that in the developing spinal cord, Syk is phosphorylated in navigating commissural axons. By analyzing axon trajectories in open-book preparations of Syk(-/-); Zap70(-/-) mouse embryos, we show that Syk kinases are dispensable for attraction towards the midline but confer growth cone responsiveness to repulsive signals that expel commissural axons from the midline. Known to serve a repulsive function at the midline, ephrin B3/EphB2 are obvious candidates for driving the Syk-dependent repulsive response. Indeed, Syk kinases were found to be required for ephrin B3-induced growth cone collapse in cultured commissural neurons. In fragments of commissural neuron-enriched tissues, Syk is in a constitutively phosphorylated state and ephrin B3 decreased its level of phosphorylation. Direct pharmacological inhibition of Syk kinase activity was sufficient to induce growth cone collapse. In conclusion, Syk kinases act as a molecular switch of growth cone adhesive and repulsive responses. PMID- 27122171 TI - Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish. AB - The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face. PMID- 27122173 TI - Release from Xenopus oocyte prophase I meiotic arrest is independent of a decrease in cAMP levels or PKA activity. AB - Vertebrate oocytes arrest at prophase of meiosis I as a result of high levels of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activity. In Xenopus, progesterone is believed to release meiotic arrest by inhibiting adenylate cyclase, lowering cAMP levels and repressing PKA. However, the exact timing and extent of the cAMP decrease is unclear, with conflicting reports in the literature. Using various in vivo reporters for cAMP and PKA at the single cell level in real time, we fail to detect any significant changes in cAMP or PKA in response to progesterone. More interestingly, there was no correlation between the levels of PKA inhibition and the release of meiotic arrest. Furthermore, we devised conditions whereby meiotic arrest could be released in the presence of sustained high levels of cAMP. Consistently, lowering endogenous cAMP levels by >65% for prolonged time periods failed to induce spontaneous maturation. These results argue that the release of oocyte meiotic arrest in Xenopus is independent of a reduction in either cAMP levels or PKA activity, but rather proceeds through a parallel cAMP/PKA-independent pathway. PMID- 27122174 TI - The EGFR signaling pathway controls gut progenitor differentiation during planarian regeneration and homeostasis. AB - The planarian Schmidtea mediterranea maintains and regenerates all its adult tissues through the proliferation and differentiation of a single population of pluripotent adult stem cells (ASCs) called neoblasts. Despite recent advances, the mechanisms regulating ASC differentiation into mature cell types are poorly understood. Here, we show that silencing of the planarian EGF receptor egfr-1 by RNA interference (RNAi) impairs gut progenitor differentiation into mature cells, compromising gut regeneration and maintenance. We identify a new putative EGF ligand, nrg-1, the silencing of which phenocopies the defects observed in egfr 1(RNAi) animals. These findings indicate that egfr-1 and nrg-1 promote gut progenitor differentiation, and are thus essential for normal cell turnover and regeneration in the planarian gut. Our study demonstrates that the EGFR signaling pathway is an important regulator of ASC differentiation in planarians. PMID- 27122175 TI - Fat3 and Ena/VASP proteins influence the emergence of asymmetric cell morphology in the developing retina. AB - Neurons exhibit asymmetric morphologies throughout development - from migration to the elaboration of axons and dendrites - that are correctly oriented for the flow of information. For instance, retinal amacrine cells migrate towards the inner plexiform layer (IPL) and then retract their trailing processes, thereby acquiring a unipolar morphology with a single dendritic arbor restricted to the IPL. Here, we provide evidence that the Fat-like cadherin Fat3 acts during multiple stages of amacrine cell development in mice to orient overall changes in cell shape towards the IPL. Using a time-lapse imaging assay, we found that developing amacrine cells are less directed towards the IPL in the absence of Fat3, during both migration and retraction. Consistent with its predicted role as a cell-surface receptor, Fat3 functions cell-autonomously and is able to influence the cytoskeleton directly through its intracellular domain, which can bind and localize Ena/VASP family actin regulators. Indeed, a change in Ena/VASP protein distribution is sufficient to recapitulate the Fat3 mutant amacrine cell phenotype. Thus, Fat-like proteins might control the polarized development of tissues by sculpting the cytoskeleton of individual cells. PMID- 27122176 TI - Re-epithelialization of cutaneous wounds in adult zebrafish combines mechanisms of wound closure in embryonic and adult mammals. AB - Re-epithelialization of cutaneous wounds in adult mammals takes days to complete and relies on numerous signalling cues and multiple overlapping cellular processes that take place both within the epidermis and in other participating tissues. Re-epithelialization of partial- or full-thickness skin wounds of adult zebrafish, however, is extremely rapid and largely independent of the other processes of wound healing. Live imaging after treatment with transgene-encoded or chemical inhibitors reveals that re-epithelializing keratinocytes repopulate wounds by TGF-beta- and integrin-dependent lamellipodial crawling at the leading edges of the epidermal tongue. In addition, re-epithelialization requires long range epithelial rearrangements, involving radial intercalations, flattening and directed elongation of cells - processes that are dependent on Rho kinase, JNK and, to some extent, planar cell polarity within the epidermis. These rearrangements lead to a massive recruitment of keratinocytes from the adjacent epidermis and make re-epithelialization independent of keratinocyte proliferation and the mitogenic effect of FGF signalling, which are only required after wound closure, allowing the epidermis outside the wound to re-establish its normal thickness. Together, these results demonstrate that the adult zebrafish is a valuable in vivo model for studying and visualizing the processes involved in cutaneous wound closure, facilitating the dissection of direct from indirect and motogenic from mitogenic effects of genes and molecules affecting wound re epithelialization. PMID- 27122177 TI - Ti-Ag-Pd alloy with good mechanical properties and high potential for biological applications. AB - Ti-based alloys containing Ag were produced by tilt-casting method and their properties were studied. Even in its as-cast state, Ti94Ag3Pd3 showed relatively high tensile properties, good electrochemical behavior, and good biocompatibility. The relatively good mechanical properties of the as-cast alpha Ti-type Ti94Ag3Pd3 alloy (tensile strength up to 850 MPa and elongation of ~10%) can be explained by its severely deformed, fine crystalline structure. The high biocompatibility of Ti94Ag3Pd3 can be explained by the Ag-Pd interaction, which inhibits the release of Ag ions from the surface. Ag, in combination with Pd has no toxic effects and demonstrates useful antimicrobial properties. The Ti94Ag3Pd3 alloy shows a good potential to be applied as a biomedical implant alloy. PMID- 27122178 TI - Introduction of rubella-containing-vaccine to Madagascar: implications for roll out and local elimination. AB - Few countries in Africa currently include rubella-containing vaccination (RCV) in their immunization schedule. The Global Alliance for Vaccines Initiative (GAVI) recently opened a funding window that has motivated more widespread roll-out of RCV. As countries plan RCV introductions, an understanding of the existing burden, spatial patterns of vaccine coverage, and the impact of patterns of local extinction and reintroduction for rubella will be critical to developing effective programmes. As one of the first countries proposing RCV introduction in part with GAVI funding, Madagascar provides a powerful and timely case study. We analyse serological data from measles surveillance systems to characterize the epidemiology of rubella in Madagascar. Combining these results with data on measles vaccination delivery, we develop an age-structured model to simulate rubella vaccination scenarios and evaluate the dynamics of rubella and the burden of congenital rubella syndrome (CRS) across Madagascar. We additionally evaluate the drivers of spatial heterogeneity in age of infection to identify focal locations where vaccine surveillance should be strengthened and where challenges to successful vaccination introduction are expected. Our analyses indicate that characteristics of rubella in Madagascar are in line with global observations, with an average age of infection near 7 years, and an impact of frequent local extinction with reintroductions causing localized epidemics. Modelling results indicate that introduction of RCV into the routine programme alone may initially decrease rubella incidence but then result in cumulative increases in the burden of CRS in some regions (and transient increases in this burden in many regions). Deployment of RCV with regular supplementary campaigns will mitigate these outcomes. Results suggest that introduction of RCV offers a potential for elimination of rubella in Madagascar, but also emphasize both that targeted vaccination is likely to be a lynchpin of this success, and the public health vigilance that this introduction will require. PMID- 27122179 TI - Microscopic and infrared spectroscopic comparison of the underwater adhesives produced by germlings of the brown seaweed species Durvillaea antarctica and Hormosira banksii. AB - Adhesives from marine organisms are often the source of inspiration for the development of glues able to create durable bonds in wet environments. In this work, we investigated the adhesive secretions produced by germlings of two large seaweed species from the South Pacific, Durvillaea antarctica, also named 'the strongest kelp in the word', and its close relative Hormosira banksii The comparative analysis was based on optical and scanning electron microscopy imaging as well as Fourier transform infrared (FTIR) spectroscopy and principal component analysis (PCA). For both species, the egg surface presents peripheral vesicles which are released soon after fertilization to discharge a primary adhesive. This is characterized by peaks representative of carbohydrate molecules. A secondary protein-based adhesive is then secreted in the early developmental stages of the germlings. Energy dispersive X-ray, FTIR and PCA indicate that D. antarctica secretions also contain sulfated moieties, and become cross-linked with time, both conferring strong adhesive and cohesive properties. On the other hand, H. banksii secretions are complemented by the putative adhesive phlorotannins, and are characterized by a simple mechanism in which all constituents are released with the same rate and with no apparent cross-linking. It is also noted that the release of adhesive materials appears to be faster and more copious in D. antarctica than in H. banksii Overall, this study highlights that both quantity and quality of the adhesives matter in explaining the superior attachment ability of D. antarctica. PMID- 27122180 TI - Can a linguistic serial founder effect originating in Africa explain the worldwide phonemic cline? AB - It has been proposed that a serial founder effect could have caused the present observed pattern of global phonemic diversity. Here we present a model that simulates the human range expansion out of Africa and the subsequent spatial linguistic dynamics until today. It does not assume copying errors, Darwinian competition, reduced contrastive possibilities or any other specific linguistic mechanism. We show that the decrease of linguistic diversity with distance (from the presumed origin of the expansion) arises under three assumptions, previously introduced by other authors: (i) an accumulation rate for phonemes; (ii) small phonemic inventories for the languages spoken before the out-of-Africa dispersal; (iii) an increase in the phonemic accumulation rate with the number of speakers per unit area. Numerical simulations show that the predictions of the model agree with the observed decrease of linguistic diversity with increasing distance from the most likely origin of the out-of-Africa dispersal. Thus, the proposal that a serial founder effect could have caused the present observed pattern of global phonemic diversity is viable, if three strong assumptions are satisfied. PMID- 27122181 TI - Correction to 'Punctuated equilibrium in the large-scale evolution of programming languages'. PMID- 27122182 TI - Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy. AB - Increasing evidence has demonstrated that the activation of heme oxygenase (HO)-1 reduces autophagy stimulated by oxidative stress injury, in which the supraphysiological production of reactive oxygen species (ROS) is detected. However, the potential mechanism underlying this effect remains unclear. The present study aimed to investigate the function of HO-1 activation in the regulation of autophagy in glomerular mesangial cells subjected to H2O2-induced oxidative stress injury. The results demonstrated that the HO-1 agonist, hemin, reduces the LC3 protein level, which was enhanced by H2O2 treatment. Furthermore, hemin-activated HO-1 may function as a regulator of oxidative stress-induced autophagy in a dose-dependent manner. Pharmacological activation of c-Jun N terminal kinase (JNK) inhibited the effect of hemin, indicating that the JNK signaling pathway is associated with the mechanism of HO-1 in impeding excessive autophagy. In addition to successfully alleviating H2O2-induced oxidative stress and cellular apoptosis, hemin-activated HO-1 may provide cytoprotection against rapamycin, a specific autophagy agonist. The present result suggested the inhibitory action of HO-1 in the avoidance of a potentially enhanced linkage between autophagy and apoptosis, particularly in the setting of excessive ROS. Therefore, enhancing the intracellular activity of HO-1 may assist the crosstalk between oxidative stress, autophagy and apoptosis, and represent a novel therapeutic strategy for renal ischemic disease. PMID- 27122184 TI - Are blood ammonia concentrations dependent on gamma-glutamyl-transferase levels in plasma? PMID- 27122183 TI - Normal saline as a natural intravascular contrast agent for dynamic perfusion weighted MRI of the brain: Proof of concept at 1.5T. AB - PURPOSE: Gadolinium-based contrast agents have associated risks. Normal saline (NS) is a nontoxic sodium chloride water solution that can significantly increase the magnetic resonance imaging (MRI) relaxation times of blood via transient hemodilution (THD). The purpose of this pilot study was to test in vivo in the head the potential of normal saline as a safer, exogenous perfusion contrast agent. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant prospective study was approved by the local Institutional Review Board (IRB): 12 patients were scanned with T1 -weighted inversion recovery turbo spin echo pulse sequence at 1.5T. The dynamic inversion recovery pulse sequence was run before, during, and after the NS injection for up to 5 minutes: 100 ml of NS was power-injected via antecubital veins at 3-4 ml/s. Images were processed to map maximum enhancement area-under-the-curve, time-to peak, and mean-transit-time. These maps were used to identify the areas showing significant NS injection-related signal and to generate enhancement time curves. Hardware and pulse sequence stability were studied via phantom experimentation. Main features of the time curves were tested against theoretical modeling of THD signal effects using inversion recovery pulse sequences. Pearson correlation coefficient (R) mapping was used to differentiate genuine THD effects from motion confounders and noise. RESULTS: The scans of 8 out of 12 patients showed NS injection-related effects that correlate in magnitude with tissue type (gray matter ~15% and white matter ~3%). Motion artifacts prevented ascertaining NS signal effects in the remaining four patients. Positive and negative time curves were observed in vivo and this dual THD signal polarity was also observed in the theoretical simulations. R-histograms that were approximately constant in the range 0.1 < |R| < 0.8 and leading to correlation fractions of Fcorr (|R| > 0.5) = 0.45 and 0.59 were found to represent scans with genuine THD signal effects. CONCLUSION: A measurable perfusion effect in brain tissue was demonstrated in vivo using NS as an injectable intravascular contrast agent. J. Magn. Reson. Imaging 2016;44:1580-1591. PMID- 27122185 TI - Fully automated PCR detection of KRAS mutations on pancreatic endoscopic ultrasound fine-needle aspirates. AB - AIMS: In cystic and solid pancreatic lesions, KRAS mutational status refines the diagnosis of uncertain endoscopic ultrasound (EUS) aspirates. This test should have a fast turnaround time and ideally be performed at the centre where the patient is diagnosed. The Idylla KRAS Mutation Test enables standardisation even in units without molecular expertise. METHODS: The Idylla test was designed for use with formalin-fixed paraffin-embedded (FFPE) sections. However, we directly pipetted 3 uL (corresponding to 1/10th of a DNA preparation from the aspirate sample) in the cartridge, which was automatically run as if an FFPE sample had been inserted. The performance was compared with Sanger sequencing, Allele Specific Locked Nucleic Acid PCR (ASLNAqPCR), and 454 Next Generation Sequencing (454-NGS) in light of clinicopathological end points. RESULTS: Idylla yielded valid results in 49/52 (94.2%) cases, in 2 h. A total of 18/49 cases showed mutation either in KRAS exon 2 (14/18) or in exon 3 (4/18). Idylla KRAS test had 100% specificity and a sensitivity (55.1%) higher than Sanger sequencing (41.3%) and identical to ASLNAqPCR (55.1%). When the low-abundant mutant allele (<5%) cases were excluded from the analysis, the Idylla KRAS Mutation Test clinical sensitivity increased to 61.9% approaching that of 454-NGS (66.6%). CONCLUSIONS: This is the first study that applied the novel Idylla KRAS test to the clinical setting of pancreatic cancer. In particular, this system can be easily implemented in the routine assessment of pancreatic EUS-fine-needle aspiration derived DNA samples to quickly provide information on KRAS mutational status to supplement cytological evaluation. PMID- 27122186 TI - Rapid identification and antimicrobial susceptibility testing of positive blood cultures using MALDI-TOF MS and a modification of the standardised disc diffusion test: a pilot study. AB - AIMS: In an era when clinical microbiology laboratories are under increasing financial pressure, there is a need for inexpensive, yet effective, rapid microbiology tests. The aim of this study was to evaluate a novel modification of standard methodology for the identification and antimicrobial susceptibility testing (AST) of pathogens in positive blood cultures, reducing the turnaround time of laboratory results by 24 h. METHODS: 277 positive blood cultures had a Gram stain performed and were subcultured and incubated at 37 degrees C in a CO2 atmosphere for 4-6 h. Identification of the visible growth was performed using matrix-assisted laser desorption time of flight mass spectrometry (MALDI-TOF MS). Taking a modified approach to the Clinical and Laboratory Standards Institute standardised AST methodology, an inoculum density of 0.5 McFarland was prepared from the early growth for disc diffusion testing. The standard AST method was also performed on the 18-24 h culture. RESULTS: 96% (n=73/76) of gram-negative organisms were correctly identified by MALDI-TOF MS. Comparative analysis of the rapid and standard AST results showed an overall interpretive category error rate of 7.7% (6.7% minor errors, 0.6% major errors and 0.4% very major errors). 100% of Staphylococcus aureus (n=41) and enterococcus isolates (n=9) were correctly identified after 4-6 h incubation. The overall AST categorical agreement was also 100% for these isolates. CONCLUSIONS: An incubation of 4-6 h directly from positive blood cultures allowed for both a rapid species identification and an antimicrobial susceptibility result approximately 24 h earlier than is possible using standard methodology. PMID- 27122187 TI - PAX5 interacts with RIP2 to promote NF-kappaB activation and drug-resistance in B lymphoproliferative disorders. AB - Paired box protein 5 (PAX5) plays a lineage determination role in B-cell development. However, high expression of PAX5 has been also found in various malignant diseases, including B-lymphoproliferative disorders (B-LPDs), but its functions and mechanisms in these diseases are still unclear. Here, we show that PAX5 induces drug resistance through association and activation of receptor interacting serine/threonine-protein kinase 2 (RIP2; also known as RIPK2), and subsequent activation of NF-kappaB signaling and anti-apoptosis gene expression in B-lymphoproliferative cells. Furthermore, PAX5 is able to interact with RIP1 and RIP3, modulating both RIP1-mediated TNFR and RIP2-mediated NOD1 and NOD2 pathways. Our findings describe a new function of PAX5 in regulating RIP1 and RIP2 activation, which is at least involved in chemotherapeutic drug resistance in B-LPDs. PMID- 27122188 TI - The first intracellular loop of GLUT4 contains a retention motif. AB - Glucose transporter GLUT4 (also known as SLC2A4) plays a major role in glucose homeostasis and is efficiently retained intracellularly in adipocytes and myocytes. To simplify the analysis of its retention, here, various intracellular GLUT4 domains were fused individually to reporter molecules. Of the four short cytoplasmic loops of GLUT4, only the first nine-residue-long loop conferred intracellular retention of truncated forms of the transferrin receptor and CD4 in adipocytes. In contrast, the same loop of GLUT1 was without effect. The reporter molecules to which the first loop of GLUT4 was fused localized, unlike GLUT4, to the trans-Golgi network (TGN), possibly explaining why these molecules did not respond to insulin. The retention induced by the GLUT4 loop was specific to adipocytes as it did not induce retention in preadipocytes. Of the SQWLGRKRA sequence that constitutes this loop, mutation of either the tryptophan or lysine residue abrogated reporter retention. Mutation of these residues individually into alanine residues in the full-length GLUT4 molecule resulted in a decreased retention for GLUT4-W105A. We conclude that the first intracellular loop of GLUT4 contains the retention motif WLGRK, in which W105 plays a prominent role. PMID- 27122189 TI - An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response. AB - Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). In mammalian cells, UPR signals generated by several ER-membrane-resident proteins, including the bifunctional protein kinase endoribonuclease IRE1alpha, control cell survival and the decision to execute apoptosis. Processing of XBP1 mRNA by the RNase domain of IRE1alpha promotes survival of ER stress, whereas activation of the mitogen-activated protein kinase JNK family by IRE1alpha late in the ER stress response promotes apoptosis. Here, we show that activation of JNK in the ER stress response precedes activation of XBP1. This activation of JNK is dependent on IRE1alpha and TRAF2 and coincides with JNK-dependent induction of expression of several antiapoptotic genes, including cIap1 (also known as Birc2), cIap2 (also known as Birc3), Xiap and Birc6 ER-stressed Jnk1(-/-) Jnk2(-/-) (Mapk8(-/-) Mapk9(-/-)) mouse embryonic fibroblasts (MEFs) display more pronounced mitochondrial permeability transition and increased caspase 3/7 activity compared to wild-type MEFs. Caspase 3/7 activity is also elevated in ER-stressed cIap1(-/-) cIap2(-/-) and Xiap(-/-) MEFs. These observations suggest that JNK-dependent transcriptional induction of several inhibitors of apoptosis contributes to inhibiting apoptosis early in the ER stress response. PMID- 27122190 TI - Artemisinin inhibits monocyte adhesion to HUVECs through the NF-kappaB and MAPK pathways in vitro. AB - The adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) plays a crucial role in the initiation of atherosclerosis. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important molecules involved in the adhesion of monocytes to HUVECs. Previous studies have suggested that artemisinin, apart from an anti-malarial agent, also has other effects. In the present study, we found that artemisinin significantly decreased the adhesion of monocytes to tumor necrosis factor-alpha (TNF-alpha) stimulated HUVECs in a dose-dependent manner and suppressed the mRNA and protein level of ICAM-1 and VCAM-1 in the TNF-alpha-stimulated HUVECs. In addition, the nuclear factor-kappaB (NF-kappaB) inhibitor, Bay 11-7082, and mitogen-activated protein kinase (MAPK) inhibitors (SB203580 and U0126) respectively reduced the adhesion of monocytes to TNF-alpha-stimulated HUVECs, and suppressed ICAM-1 and VCAM-1 expression in TNF-alpha stimulated HUVECs. Moreover, artemisinin impeded the activation of the NF-kappaB and MAPK signaling pathways. Furthermore, Bay 11 7082 significantly decreased the phosphorylation of levels extracellular signal regulated protein kinase (ERK)1/2, p38 and c-Jun N-terminal kinase (JNK). Taken together, the findings of our study indicated that artemisinin blocked monocyte adhesion to TNF-alpha-stimulated to HUVECs by downregulating ICAM-1 and VCAM-1 expression in the TNF-alpha-stimulated HUVECs. Artemisinin may thus have potential for use in the protection against the early development of atherosclerotic lesions. PMID- 27122192 TI - A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process. AB - New techniques are urgently needed to replace conventional long and costly pre clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco 2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre clinical testing process subject to animal testing upon adaptation in new drug discovery. PMID- 27122194 TI - Valuable verities on vitamin D. PMID- 27122193 TI - Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance. AB - Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform. PMID- 27122195 TI - Vitamin D: The unexplored immunomodulator. PMID- 27122196 TI - The sequelae of barium aspiration. PMID- 27122197 TI - Individualized Dosing of Oral Oxybutynin for the Treatment of Primary Focal Hyperhidrosis in Children and Teenagers. AB - BACKGROUND/OBJECTIVES: Oral anticholinergic drugs, such as oxybutynin, are often used in the treatment of hyperhidrosis, but few studies have focused on dosing strategies for children. The objective was to assess the effectiveness and safety of individualized dosing regimens of oral oxybutynin for treating primary focal hyperhidrosis (PFH) in children and teenagers. METHODS: A prospective study was performed including patients who initiated treatment for hyperhidrosis between November 2011 and November 2014. Response to treatment and adverse effects were evaluated using the Hyperhidrosis Disease Severity Scale at baseline and at 3 and 12 months. RESULTS: Of 16 patients included in the study, 15 (93.8%) had responded to treatment at the 3-month follow-up (62.5% with excellent response). At the 12-month follow-up, the 11 patients who continued the treatment were still responding (63.6% with excellent response). Adverse effects were reported for 68.8% of the patients at 3 months and 54.5% at 12 months, with a predominance of oropharyngeal xerosis. No serious adverse effects were observed. CONCLUSION: Dose individualization of oral oxybutynin according to clinical response and tolerance observed in each patient is a useful management strategy in children and teenagers. PMID- 27122198 TI - Investigational therapies for renal disease-induced anemia. AB - INTRODUCTION: The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs. AREAS COVERED: By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis. Finally, the challenges encountered with these drug candidates are discussed. EXPERT OPINION: Current peptidic ESAs are effective and well-tolerated, but are costly, require parenteral application and iron supplementation. ESA resistance may develop calling for increased doses. Therefore, orally available hypoxia inducible factor (HIF) stabilizing compounds are attractive alternatives, which may be approved in the near future. Prominent compounds are molidustat, daprodustat and roxadustat. HIF stabilizers suppress hepcidin production and improve iron balance as the present ESAs, but also raise safety concerns in association with their pleiotropic actions. Other investigational erythropoietic biologics are growth-differentiation factor-11 (GDF11) ligand traps (sotatercept, luspatercept), which are also well advanced in development. Possibly, they will provide an add-on for established therapies. However, immunogenicity of these compounds still needs to be carefully investigated. PMID- 27122199 TI - Evaluating 3D printing to solve the sample-to-device interface for LRS and POC diagnostics: example of an interlock meter-mix device for metering and lysing clinical urine samples. AB - This paper evaluates the potential of 3D printing, a semi-automated additive prototyping technology, as a means to design and prototype a sample-to-device interface, amenable to diagnostics in limited-resource settings, where speed, accuracy and user-friendly design are critical components. As a test case, we built and validated an interlock meter-mix device for accurately metering and lysing human urine samples for use in downstream nucleic acid amplification. Two plungers and a multivalve generated and controlled fluid flow through the device and demonstrate the utility of 3D printing to create leak-free seals. Device operation consists of three simple steps that must be performed sequentially, eliminating manual pipetting and vortexing to provide rapid (5 to 10 s) and accurate metering and mixing. Bretherton's prediction was applied, using the bond number to guide a design that prevents potentially biohazardous samples from leaking from the device. We employed multi-material 3D printing technology, which allows composites with rigid and elastomeric properties to be printed as a single part. To validate the meter-mix device with a clinically relevant sample, we used urine spiked with inactivated Chlamydia trachomatis and Neisseria gonorrhoeae. A downstream nucleic acid amplification by quantitative PCR (qPCR) confirmed there was no statistically significant difference between samples metered and mixed using the standard protocol and those prepared with the meter-mix device, showing the 3D-printed device could accurately meter, mix and dispense a human urine sample without loss of nucleic acids. Although there are some limitations to 3D printing capabilities (e.g. dimension limitations related to support material used in the printing process), the advantages of customizability, modularity and rapid prototyping illustrate the utility of 3D printing for developing sample-to device interfaces for diagnostics. PMID- 27122200 TI - Investigation of the Sequential Actions of Doxorubicin and p53 on Tumor Cell Growth Via Branched Polyethylenimine-beta-cyclodextrin Conjugates. AB - The combination of gene therapy and chemotherapy has showed increased therapeutic efficacy in the treatment of cancers, but it is not well investigated about the actual coordination pattern between therapeutic gene and chemical drug. In this work, p53/BPEI-beta-CD/AD-dox complex was fabricated and employed to investigate the interaction manner between p53 and doxorubicin (Dox). Briefly, branched polyethylenimine (BPEI) was conjugated with beta-cyclodextrin hydrate (beta-CD) to form BPEI-beta-CD backbone, and p53 plasmid was condensed by positively charged BPEI via electrostatic interaction, while Dox was first conjugated with adamantine (AD) and then assembled with BPEI-beta-CD backbone via the host-guest interaction. It was found that the BPEI-beta-CD backbone possessed high endocytosis efficiency but low cytotoxicity. Moreover, p53/BPEI-beta-CD/AD-dox complex released Dox and enabled the expression of p53 gene in a sequential manner, and the released Dox and expressed p53 gene showed successive inhibition of the growth of HeLa cells in vitro. With the ability to co-deliver chemical drug and therapeutic gene and exert their inhibitory actions on tumor cell growth in a sequential manner, this DNA/BPEI-beta-CD/AD-drug complex via electrostatic interaction and host-guest assembly not only achieved long-term efficacy in inhibiting tumor cell growth but also can be employed as a platform to investigate the coordination pattern between chemical drugs and therapeutic genes for other purposes. PMID- 27122201 TI - Consensus properties and their large-scale applications for the gene duplication problem. AB - Solving the gene duplication problem is a classical approach for species tree inference from gene trees that are confounded by gene duplications. This problem takes a collection of gene trees and seeks a species tree that implies the minimum number of gene duplications. Wilkinson et al. posed the conjecture that the gene duplication problem satisfies the desirable Pareto property for clusters. That is, for every instance of the problem, all clusters that are commonly present in the input gene trees of this instance, called strict consensus, will also be found in every solution to this instance. We prove that this conjecture does not generally hold. Despite this negative result we show that the gene duplication problem satisfies a weaker version of the Pareto property where the strict consensus is found in at least one solution (rather than all solutions). This weaker property contributes to our design of an efficient scalable algorithm for the gene duplication problem. We demonstrate the performance of our algorithm in analyzing large-scale empirical datasets. Finally, we utilize the algorithm to evaluate the accuracy of standard heuristics for the gene duplication problem using simulated datasets. PMID- 27122202 TI - Multi-layer composite mechanical modeling for the inhomogeneous biofilm mechanical behavior. AB - Experiments showed that bacterial biofilms are heterogeneous, for example, the density, the diffusion coefficient, and mechanical properties of the biofilm are different along the biofilm thickness. In this paper, we establish a multi-layer composite model to describe the biofilm mechanical inhomogeneity based on unified multiple-component cellular automaton (UMCCA) model. By using our model, we develop finite element simulation procedure for biofilm tension experiment. The failure limit and biofilm extension displacement obtained from our model agree well with experimental measurements. This method provides an alternative theory to study the mechanical inhomogeneity in biological materials. PMID- 27122203 TI - Vegetative Bacillus amyloliquefaciens cells do not confer protection against necrotic enteritis in broilers despite high antibacterial activity of its supernatant against Clostridium perfringens in vitro. AB - In this study, the effect of Bacillus amyloliquefaciens on Clostridium perfringens was tested in vitro and in vivo. Using an agar well diffusion assay, the inhibitory activity of B. amyloliquefaciens supernatant was analysed against a large collection of netB-positive and netB-negative C. perfringens strains. Although strong growth inhibiting activity was detected against all C. perfringens isolates, it was significantly higher against virulent netB-positive C. perfringens strains compared with avirulent netB-negative isolates. Subsequently, the efficacy of in-feed administration of lyophilised vegetative cells of B. amyloliquefaciens to prevent necrotic enteritis was tested in vivo using an established experimental infection model in broilers. Ross 308 broilers received either B. amyloliquefaciens supplemented or unsupplemented feed throughout the experiment. No significant differences could be detected between the untreated positive control group and the B. amyloliquefaciens treated group in body weight, the number of chickens that developed necrotic lesions and in pathological lesion scores. These results demonstrate that despite its substantial inhibitory activity in vitro, lyophilised vegetative B. amyloliquefaciens cells had no beneficial effect against necrotic enteritis in the in vivo model used here. PMID- 27122204 TI - Natural radioactivity in reservoir sediment near an industrial park of northwest China. AB - The activity concentration of natural radionuclides in the sediment of a reservoir near an industrial park of northwest China was determined using gamma ray spectrometry. The activity concentrations of (226)Ra, (232)Th and (40)K in the investigated samples range from 30.2 to 37.5, 56.5 to 79.8 and 785.6 to 940.3 Bq kg(-1) with an average of 33.2, 71.8 and 866.2 Bq kg(-1), respectively, which are higher than the corresponding activity concentrations in the control sample. Radium equivalent activity, external hazard index, internal hazard index, indoor air absorbed dose rate and annual effective dose rate were calculated to assess the radiation hazards associated with the use of this sediment in the construction of dwellings. It was concluded that the radiation levels in the reservoir sediment do not give rise to radiological health concerns and the sediment can be safely used in the construction of buildings. PMID- 27122205 TI - Nutritional composition of school meals serving children from 7 to 36 months of age in municipal day-care centres in the metropolitan area of Curitiba, Parana, Brazil. AB - The Brazilian National School Feeding Program (PNAE) seeks to meet student's nutritional needs during the period they remain in school. This study aimed to determine the nutritional composition of meals provided in municipal day-care centres serving children of 7-11 months (group A) and 12-36 months (group B) of age and to compare observed values with the PNAE's and dietary reference intakes' (DRI) recommendations. This cross-sectional study was conducted in 4 day-care centres in the metropolitan area of Curitiba, Parana, Brazil, between June and November 2013. Food samples of six daily meals were collected during 20 non consecutive days, totalling 120 samples. For each meal, average served and consumed portions were submitted for laboratory analysis of moisture, ash, proteins, lipids, carbohydrates, dietary fibre, Na, Ca and Fe and compared with the PNAE's and DRI's values. No statistically significant difference was found between age groups (P=0.793) regarding portion sizes and nutritional composition. The same menu was offered to both groups in 95 % of the meals (n 114), although the groups' nutritional needs were different. For group A, served meals met PNAE's recommendations for energy, carbohydrates, proteins, Na and Ca content, and consumed portions provided 70 % of the nutritional needs for carbohydrates, proteins and Ca. For group B, served portions complied with the PNAE's values for proteins, Na and Ca. Proteins and Na reached 70 % of the nutritional needs when consumed food was evaluated. School feeding in day-care centres partially meet PNAE's guidelines and children's nutritional requirements, contradicting the primary objective established by the national programme. PMID- 27122206 TI - Paintball-related traumatic liver injury. AB - Paintball is a popular recreational sport played at both amateur and professional level. Ocular injuries are well recognised, although there is a growing body of literature documenting superficial vascular as well as deep solid organ injuries. An 18-year-old man presented with signs and symptoms consistent with acute appendicitis. Intraoperatively, a grade III liver injury was identified and packed before a relook at 48 h. No further active bleeding was identified; however, follow-up ultrasound at 3 weeks demonstrated non-resolution of a large subcapsular haematoma. The patient was readmitted for a short period of observation and discharged with repeat ultrasound scheduled for 3 months. This represents the first report of paintball-related blunt traumatic injury to the liver. Solid organ injuries of this nature have only been reported three times previously-all in the urological setting. This case also highlights issues surrounding the use of routine follow-up imaging in blunt liver trauma and provides a concise discussion of the relevant literature. PMID- 27122207 TI - [Application of aromatase inhibitors in male Hypogonadism]. PMID- 27122208 TI - [Clinicopathological characteristics and prognostic analysis of primary intestinal diffuse large B-cell lymphoma]. AB - OBJECTIVE: To analyze the clinicopathological characteristics, treatment protocls and prognostic factors in patients with primary intestinal diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 54 patients with DLBCL who were treated in Cancer Hospital of Chinese Academy of Medical Sciences in the period from August 2003 to November 2012 were retrospectively analyzed, and the relevant prognostic factors of DLBCL were analyzed. RESULTS: Of the 54 patients, there were 43 males and 11 females (male?female ratio was 3.91?1), with a median age of onset of 49 (7-76) years. Most patients (64.8%) were in Lugano stage I-II. Of all the patients, 50 were followed up for a median of 49 (1-118) months. The 1-, 3- and 5-year overall survival (OS) rates were 82.0%, 69.9% and 60.7%, respectively; the 1-, 3- and 5-year progression-free survival (PFS) rates were 68.0%, 58.0% and 53.4%, respectively. Univariate analysis showed that the factors affecting prognosis of DLBCL patients included Lugano stage, B symptom, International Prognostic Index (IPI) score, lactate dehydrogenase level, beta2-microglobulin level, tumor size, and treatment protocols (all P<0.05). The 5-year OS rate was 67.1% in the patients treated with surgery plus chemoradiotherapy, and 40.0% in those treated with surgery or chemotherapy alone (P<0.05). In the patients treated with chemotherapy combined with rituximab, the 5-year OS rate was higher than in those treated with chemotherapy alone (71.2% vs 47.6%, P<0.05). Multivariate analysis indicated that tumor size (RR=7.686, P=0.022) and lactate dehydrogenase level (RR=10.131, P=0.017) were independent prognostic risk factors affecting OS. CONCLUSIONS: Primary intestinal DLBCL is a highly heterogeneous malignancy. Surgery combined with chemoradiotherapy and rituximab may help improve the overall prognosis of DLBCL patients. PMID- 27122209 TI - [Relationship between CD4+ CD28null T cell and atherosclerosis progression in patients with type 2 diabetes]. AB - OBJECTIVE: To explore the effect of CD4+ CD28null T cell on occurrence and progression of atherosclerosis in patients with type 2 diabetes. METHODS: A total of 188 patients who were diagnosed as type 2 diabetes in the department of endocrinology were selected in this study.The carotid atherosclerosis was detected using color Doppler ultrasound.The patients with intima-media thickness>1.1 mm or plaques were classified as the carotid atherosclerosis group (95 cases), the others were classified as the control group (93 cases). According to the intima-media thickening and plaques, carotid atherosclerosis group was divided into three subgroups: the thickening group (30 cases), the plaque group (28 cases) and the thickening+plaque group (37 cases). Percentage of CD4+ CD28null T cell in peripheral blood was detected using a flow cytometry, and thus compared and analyzed between the carotid atherosclerosis group and the control group.The relationships between percentage of CD4+ CD28null T cell and age, C reactive protein (CRP), blood sugar, blood lipids, the body mass index (BMI), waist circumference, hip circumference, diastolic blood pressure, systolic blood pressure and other data were also analyzed. RESULTS: Percentage of CD4+ CD28null T cell of the carotid atherosclerosis group was significantly higher than that of the control group (4.07%+/-3.21% vs 2.99%+/-2.34%, P<0.01). Percentage of CD4+ CD28null T cell of the thickening+ plaque group was higher than that of the plaque group and thickening group (both P<0.05), and percentage of CD4+ CD28null T cell of the plaque group was higher than the thickening group (P<0.05). Logistic regression analysis indicated that CRP, FPG and percentage of CD4+ CD28null T cell were the independent risk factors of atherosclerosis in patients with type 2 diabetes.Furthermore, multiple linear regression analysis showed that percentage of CD4+ CD28null T cell was linear correlated to CRP (P<0.01). CONCLUSION: The type 2 diabetes patients with atherosclerosis had a higher percentage of CD4+ CD28null T cell, which was increased with the atherosclerosis progression.CD4+ CD28null T cell may affect arterial intimal thickening and plaque formation via mediating inflammatory response in the patients with type 2 diabetes. PMID- 27122210 TI - [Association of serum free triiodothyronine with long-term outcome in heart failure patients receiving cardiac resynchronization therapy]. AB - OBJECTIVE: To explore the prognostic role of free triiodothyronine (FT3) on all cause mortality and heart failure (HF) hospitalization in patients receiving cardiac resynchronization therapy (CRT). METHODS: In this single-center retrospective cohort study, a total of 202 chronic heart failure (CHF) patients who had CRT implantation from January 2010 to December 2014 were enrolled. Clinical outcomes were defined as all-cause mortality (including heart transplantation) and new heart failure (HF) hospitalization. Patients were divided into three groups according to FT3 tertiles: FT3<=4.08 pmol/L group (n=67), FT3 4.09-4.71 pmol/L group (n=68) and FT3>4.71 pmol/L group (n=67). Kaplan-Meier analyses were performed for each outcome. Cox proportional-hazards regression analyses were used to evaluate the independent prognosis of FT3 in CRT treated patients. RESULTS: Patients in FT3<=4.08 pmol/L group tended to be older, with more women patients, and had lower estimated glomerular filtration rate (eGFR), hemoglobin and serum sodium concentration. They were also less frequently subjected to smoking, alcohol consumption and were less likely prescribed with renin-angiotensin-aldosterone system inhibitors. Also, this group had highest proportion of NYHA class IV patients. Kaplan-Meier analyses demonstrated that FT3 4.09-4.71 pmol/L group was associated with a significantly better survival (P=0.022) and less new hospitalizations for HF event (P=0.020). Cox regression analyses indicated that FT3 4.09-4.71 pmol/L was an independent protective factor for both all-cause mortality (HR=0.220, 95%CI: 0.069-0.700, P=0.011) and HF hospitalization (HR=0.490, 95%CI: 0.241-0.996, P=0.049). Left ventricular end diastolic diameter (LVEDd) enlargement was an independent risk factor of all cause mortality(HR=1.043, 95%CI: 1.004-1.083, P=0.031). CONCLUSION: Patients in FT3 4.09-4.71 pmol/L group had the lowest risk of all-cause mortality and HF hospitalization after CRT implantation. PMID- 27122211 TI - [The preliminary study on the function of methylenetetrahydrofolate dehydrogenase 2 in hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the expression of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in hepatocellular carcinoma (HCC) tissues and its correlation with clinical parameters. METHOD: Fluorogenic quantitative-polymerase chain reaction (FQ-PCR) was used to measure the MTHFD2 mRNA expression. The MTHFD2 protein expression was detected by immunohistochemical staining in cancerous tissues and adjacent noncancerous counterparts. The relationship of MTHFD2 expression, clinicopathological parameters and the prognosis of hepatocellular carcinoma was subsequently analysed. RESULTS: The MTHFD2 mRNA expression in cancerous tissues was higher than that in adjacent noncancerous counterparts (31/47) (P<0.05). The positive rate of MTHFD2 protein in cancerous tissues was significantly higher than that in adjacent noncancerous counterparts (69.5% vs. 33.9%) (P<0.05). MTHFD2 overexpression was found to correlate with clinical pathological parameters such as tumor metastasis, recurrence and poor prognosis (P<0.05). The patients with overexpressed MTHFD2 had shorter tumor-free survival time. CONCLUSIONS: Overexpression of MTHFD2 in HCC may be a risk factor of tumor metastasis and recurrence. MTHFD2 could be a new biomarker for prognosis of HCC. PMID- 27122212 TI - [Evaluation of the 1 mg overnight dexamethasone suppression test in the diagnosis of the subclinical Cushing's syndrome in patients with Adrenal Incidentaloma]. AB - OBJECTIVE: To evaluate efficacy of the 1 mg overnight dexamethasone suppression test (1 mg overnight DST) in the diagnosis of subclinical Cushing's syndrome, and to explore the best diagnostic cut-off value. METHODS: The clinical data of patients with adrenal incidentaloma in Chinese PLA General Hospital from 1995 to 2013 were gathered. The data of subclinical Cushing's syndrome (SCS) and non functional adrenal adenoma (NFA) was retrospectively analyzed. The ROC curve was used to evaluate the efficacy of the 1 mg overnight DST and to explore the best cut-off value with high sensitivity and specificity. RESULTS: There were 447 patients with NFA (224 male and 223 female), and the mean age was 53+/-11 years old.49 patients were with SCS (19 male and 30 female), and the mean age was 47+/ 12 years old. The area under the ROC of serum cortisol level after 1 mg overnight DST was 0.967 (95%CI: 0.942-0.993). The best cut-off value of serum cortisol after 1 mg overnight DST was 63.65 nmol/L, with a sensitivity of 100.0% and a specificity of 88.8%. The best cut-off value of the suppression ratio of serum cortisol was 85.64%, with a sensitivity of 83.3% and a specificity of 84.6%. CONCLUSIONS: The best criterion for 1 mg overnight DST in the diagnosis of SCS was serum cortisol level , and the recommend cut-off point was 63.65 nmol/L, with both a higher sensitivity and specificity. The suppression ratio of serum cortisol after 1 mg overnight DST was also considered as a suitable criterion in the diagnosis of SCS. PMID- 27122213 TI - [Analysis of clinical therapeutic effect using percutaneous mechanical thrombectomy in the treatment of acute deep venous thrombosis]. AB - OBJECTIVE: To evaluate the use of percutaneous mechanical thrombectomy in the treatment of acute deep venous thrombosis. METHODS: Eight cases of acute deep venous thrombosis were reviewed who had received percutaneous mechanical thrombectomy from January to July, 2015 in Beijing Tsinghua Changgung Hospital. All cases were diagnosed as iliofemoral venous thrombosis, 2 cases with vena cava thrombosis. All cases received anticoagulation treatment for 3 to 6 months and pressure treatment after the procedure. Every patient was scheduled to follow up at 1, 3, 6 months, respectively. RESULTS: Technical success were achieved in all cases with restoring of good flow in previous lesions. Grade III (complete) lysis was achieved in 2 cases and grade II(50%-99% ) lysis in 6 cases, swelling legs were mostly fade away. Of all study follow up , only one case with mild post thrombotic syndrome after six months. CONCLUSION: Percutaneous mechanical thrombectomy is safe and effective in the treatment of acute deep venous thrombosis. PMID- 27122214 TI - [Efficacy of Botulinum-A toxin injection into bladder to treat neurogenic incontinence in patients with spinal cord injury: comparison of two doses]. AB - OBJECTIVE: To evaluate the efficacy of Botulinum-A toxin injection into bladder to treat neurogenic incontinence in patients with spinal cord injury and compare effectiveness of two different doses (200 U and 300 U). METHODS: Between January 2009 and October 2014, A total of 60 adult patients with spinal cord injury above the sacral (mean age, 32 years; male 56, female 4) were selected in Beijing Bo'ai Hospital of China Rehabilitation Research Center. All the patients kept voiding diary and underwent urodynamic examination before operation. All the patients were allocated with a random number table into 200 U Botulinum-A toxin injection group or 300 U group (both n=30). In the 200 U group, 200 U of Botulinum-A toxin were dissolved in 10 ml of normal saline, which was injected into 20 different sites (0.5 ml for each site) of bladder wall, including 10 outside the bladder trigone and the remaining 10 inside trigone. In the 300 U group, 300 U of Botulinum-A toxin were dissolved in 15 ml of normal saline, which was injected into 30 different sites (0.5 ml for each site) in bladder outside of the bladder trigone using a flexible cystoscopic needle. The evaluation of the effects and follow-up included voiding diary, urodynamic testing and observation of adverse and toxic effects. RESULTS: At baseline, mean urinary incontinence frequencies were (15.2+/-3.2) episodes/day and (16.2+/-2.9) episodes/day in 200 U and 300 U group, which reduced to (2.9+/-1.2) episodes/day and (2.5+/-1.4) episodes/day, respectively in week 4 (P<0.05). However, continence rate was not significantly different between the two dose groups [63% (19/30) vs 70% (21/30), P>0.05]. The effect of botulinum-A toxin started to be observed from the 1(st) posttreatment week on average. Obvious improvements in maximum cystometric capacity, end filling maximum detrusor pressure, and bladder compliance were observed at week 4 as shown by urodynamics (all P<0.05), but with no significant difference between the 200 U and 300 U groups. In the follow-up period of (6.3+/-1.2) months, no toxic or adverse effects were observed after injection in the two groups. CONCLUSIONS: The regimen of Botulinum-A toxin 200 U injection involving trigone of the bladder can achieve a short-term effect comparable with that of the standard 300 U injection excluding trigone. It may be an effective and safe treatment for neurogenic incontinence in spinal cord injury patients. PMID- 27122215 TI - [Microsurgical anatomy and DSA research about venous anastomosis of superficial cerebral veins]. AB - OBJECTIVE: To investigate the distribution and clinical significance about venous anastomosis of superficial cerebral vein in normal adult. METHODS: The digital subtraction angiography (DSA) images of the venous phase from 50 normal adults were retrospectively analyzed, and the morphology of venous anastomosis of superficial cerebral veins was observed and measured. While venous anastomosis of superficial cerebral veins of 15 (30 sides) cadaveric heads was observed through blood vessel perfusion. RESULTS: Trolard vein and Labbe vein were the main venous anastomosis of superficial cerebral veins. A total of 55 Trolard veins were found out of 50 sides DSA venous phase images, including left 27, right 28; 34 Trolard veins, left 18, right 16, were found from the 30 sides of the brain hemispheres. 51 Labbe veins, left 25, right 26, were found from the 50 sides DSA venous phase images, and 31 Labbe veins, left 15, right 16, were found from the 30 sides of the brain hemispheres. CONCLUSIONS: Venous anastomosis of superficial cerebral veins is variable. The DSA venous phase image is consistent with the microscopic anatomy, and the preoperative DSA examination is beneficial for the protection of venous anastomosis of superficial cerebral veins. PMID- 27122216 TI - [Establish and analyze the predictive model of early stage brain metastases in patients with breast cancer]. AB - OBJECTIVE: To investigate the risk factors of cerebral metastasis of breast cancer and to provide guidance for the early diagnosis and treatment of brain metastases. METHODS: Clinical data of postoperative patients with breast cancer were collected in our hospital from 2005 to 2009. All the patients were divided into two groups, with or without brain metastasis. The risk factors of brain metastases of patients with breast cancer were analyzed by the logistic regression. RESULTS: Eight hundred and twenty four early postoperative patients with breast cancer were enrolled. The median follow-up time was 68 months and 199 cases had brain metastasis. The univariate logistic regression results showed that higher grade of tumor, <35 years, premenopausal, clinical stage III, HER-2 positive and ER negative, no adjuvant chemotherapy, no adjuvant normal therapy were the risk factors of brain metastasis. The multivariate logistic regression result showed that higher grade of tumor, <35 years, premenopausal, clinical stage III, HER-2 positive, ER negative were the risk factors. The mathematical model was used to predict the probability of occurrence of brain metastasis. ROC curve were draw by the value of predict probability as test variable and the brain metastasis status as state variables. The AUC value of this predictive model was 0.743+/-0.018. The specificity and sensitivity are relative high. CONCLUSION: Age<35 years, premenopausal, clinical stage III, HER-2 positive and ER negative were independent risk factors for brain metastases. This model has the predictive value for the occurrence of brain metastases from breast cancer. PMID- 27122217 TI - [Effect of ERK1/2 pathway in the expression of MHC-IIof intestinal dendritic cells in viscerally hypersensitive rats]. AB - OBJECTIVE: To study the phenotypic alteration of intestinal dendritic cells (DC) in a rat model of irritable bowel syndrome (IBS) and the change of mitogen activated protein kinase (MAPK) signaling pathway, in order to explore the potential mechanism of ERK1/2 pathway mediation in abnormal DC immune response. METHODS: IBS rat model was established by combining neonatal maternal separation and colorectal distension in 10 SD rats, and 10 healthy rats served as controls. Visceral sensitivity was evaluated with abdominal withdrawal reflex (AWR). Mesenteric lymph node DC (MLNDC) was isolated and purified by magnetic label based technique after modeling. Expression of surface major histocompatibility complex (MHC)-IIin control rats was determined by flow cytometric analyses. Western-blot was used to determine the expression of MHC-II, p-p38, p38, phosphorylated extracellular regulated protein kinase (p-ERK1/2), ERK1/2, phosphorylated c-Jun N-terminal kinase (p-JNK), and JNK in MLNDC. RESULTS: Visceral sensitivity was significantly higher in the IBS group than in the control group. The purity of the OX62 positivity MLNDC following magnetic sorting was about 85.57%+/-7.67%. MLNDC in the control group expressed high level of MHC II. The expression of MHC-II and p-ERK1/2 in MLNDC in the IBS group were higher than those in the control group (1.05+/-0.13 vs 0.67+/-0.18, t=-2.973, P=0.041; 3.21+/-0.48 vs 2.34+/-0.85, t=-3.130, P=0.035); while there was no significant difference in the expressions of p-JNK and p-p38 compared with the control groups (0.95+/-0.17 vs 0.76+/-0.36, t=0.808, P=0.464; 1.07+/-1.13 vs 1.19+/-0.91, t=0.137, P=0.897). CONCLUSION: The intestinal DC in IBS rats show a upregulated expression of MHC-II, which may be related to the activation of intracellular ERK1/2 pathway. PMID- 27122218 TI - [Study of FN1 and ZNF438 gene expression negatively regulated by androgen receptor in androgen-independent LNCaP cells]. AB - OBJECTIVE: To verify whether FN1 and ZNF438 are the androgen receptor(AR) target genes in LNCaP-AI cells and investigate the effects of AR exerts on FN1 and ZNF438 gene expression. METHODS: ChIP-PCR and agarose gel electrophoresis were performed to verify the fact that AR acted on FN1 and ZNF438 gene. Subsequently, LNCaP-AI cells were treated with dihydrotestosterone(DHT)and lentivirus transfection to down-regulate AR expression. The expression of FN1 and ZNF438 gene in mRNA and protein levels were analyzed by RT-qPCR and Western blot. RESULTS: FN1 and ZNF438 gene enrichment of AR-ChIP group were 7.274+/-0.290 and 6.843+/-0.078, significantly higher than the IgG-ChIP group of 1.004+/-0.113 and 1.000+/-0.014 (t(FN1)=34.91, t(ZNF438)=128.377, P<0.05). Differences were statistical significance. After DHT stimulation, the expression of FN1 and ZNF438 gene in mRNA and protein levels were 0.434+/-0.050 and 0.069+/-0.042, significantly lower than the control group of 1.000+/-0.016 and 1.025+/-0.277 (t(FN1)=18.532, t(ZNF438)=5.905, P<0.05). Differences were statistical significance. Moreover, after AR down-regulation, the expression of FN1 and ZNF438 gene in mRNA and protein levels were 17.579+/-4.415 and 1.895+/-0.424, significantly higher than the control group of 1.028+/-0.445 and 1.041+/-0.190 (t(FN1)=6.461, t(ZNF438)=3.184, P<0.05). Differences were statistical significance. CONCLUSIONS: FN1 and ZNF438 gene are AR negatively regulated target genes in LNCaP-AI cells. The study might provide a new sight to further explore the mechanism of LNCaP-AI cells grow in androgen-depleted conditions. PMID- 27122219 TI - [Therapeutic effects and mechanisms of androgen and simvastatin on osteoporosis in castrated rats]. AB - OBJECTIVE: To study the therapeutic effects and mechanisms of androgen and simvastatin on osteoporosis in castrated rats. METHODS: Fifty 12-month-old male SD rats were divided into five groups randomly: castrated group (A), sham operated group (B), androgen group (C), simvastatin group (D), androgen+ simvastatin group (E). Each group has 10 rats. In this study, osteoporosis model was established by castration.All the groups were given testis and epididymis resection except sham operated group. The drugs were administrated on 9 weeks after operation. C, D and E group were treated by the different drugs lavage for 12 weeks. A and B group were given normal saline at the same time. Lumbar spine bone mineral densities (BMD) of rats were measured on pre-operation, before administration, 6 weeks and 12 weeks after administration.All rats were sacrificed on 12 weeks after administration. Serum osteocalcin (BGP), interleukin 6 (IL-6) and Ca2+ were measured. Bone histology was observed. RESULTS: After the treatment by simvastatin or androgen for 12 weeks, BMD of the group C and group D was significantly higher than that of group A (P<0.01). After the treatment by simvastatin and androgen for 6 weeks, BMD of the group E was significantly higher than that of group A, C and D (P<0.05). The level of serum BGP in group A was significantly lower than that in group B (P<0.05) and the level of serum BGP in group E was significantly higher than that in group B (P<0.05). The serum IL-6 in each treated group were significantly lower than that in group A (P<0.05). CONCLUSION: The combination of simvastatin and androgen could inhibit bone absorption and promote bone formation, which could improve the osteoporosis. PMID- 27122220 TI - [Effects of 1, 25-(OH)2D3 on airway remodeling and airway epithelial cell apoptosis in a murine model of asthma]. AB - OBJECTIVE: To investigate the effects of calcitriol on airway remodeling and airway epithelial cell apoptosis in a murine model of bronchial asthma. METHODS: Twenty-four SPF female Balb/c mice were randomly allocated into three groups according to a random digits table with 8 mice in each group: the control group, the chronic asthma group and the calcitriol intervention group.(1) The chronic asthma group: the mice were sensitized by intraperitoneal injection of Ovalbumin (OVA, 20 MUg) and aluminium hydroxide (50 MUl) on days 1 and 14.From day 21, the mice were challenged by inhalation of 1% OVA solution (10 ml, 30 min/time, three times a week for consecutively 8 weeks). (2) The calcitriol intervention group: the mice were sensitized and challenged as above, and were given calcitriol 100 ng through intraperitoneal injection 30 min before every inhalation.(3) The control group: the mice were sensitized and challenged by saline instead of OVA.The mice were sacrificed 24 hours after the last challenge, and the left lung were removed, fixed with paraformaldehyde, embedded with paraffin and sectioned.HE staining, Alcian blue and Periodic acid Schiff (AB-PAS) staining, Masson staining, and alpha-smooth muscle actin (alpha-SMA) immunohistochemistry staining were conducted.Bronchial basement membrane perimeter (Pbm), total bronchial wall area and positive areas of AB-PAS staining, Masson staining, and alpha-SMA staining were determined with image analysis software.The results were standardized with the basement membrane perimeter.Paraffin sections of mice lung tissue were detected with terminal transferase deoxyuridine triphosphate (dUTP) nick end labeling enzyme mediated method (TUNEL) for apoptosis of airway epithelial cells and with immunohistochemistry staining for expression of B cell lymphoma/lewkmia-2 (Bcl-2) in the airway epithelium. RESULTS: The mice in the chronic asthma group and calcitriol intervention group showed characteristic airway inflammation and airway remodeling of asthma.The ratios between the total bronchial wall area and positive areas of AB-PAS staining, Masson staining and alpha-SMA staining and the basement membrane perimeter in the calcitriol intervention group were (14.12+/-2.13), (3.72+/-0.57), (4.31+/-0.65) and (3.27+/ 0.46) MUm2/MUm, respectively, all of them were significantly lower than (19.24+/ 1.70), (5.23+/-0.90), (7.63+/-1.55) and (5.40+/-0.69) MUm2/MUm in the chronic asthma group and higher than (7.79+/-1.01), (0.05+/-0.03), (1.37+/-0.25) and (1.40+/-0.24) MUm2/MUm in the control group (all P<0.01). The airway epithelial cell apoptosis index in the calcitriol intervention group was significantly lower than that in the chronic asthma group and higher than the control group [(14.89+/ 1.75)% vs (29.73+/-5.74)% and (0.45+/-0.38)%, both P<0.01]. The relative expression of Bcl-2 in the calcitriol intervention group was significantly higher than that in the chronic asthma group and lower than the control group (0.114+/ 0.009 vs 0.091+/-0.023 and 0.160+/-0.021, both P<0.05). CONCLUSIONS: Calcitriol attenuates airway remodeling and reduces the apoptosis of airway epithelial cells in a murine model of chronic asthma.The mechanism of calcitriol in reducing apoptosis of airway epithelial cells is by regulation of expression of the important molecule Bcl-2 protein in mitochondrial apoptotic pathway. PMID- 27122221 TI - HAT inhibitor, garcinol, exacerbates lipopolysaccharide-induced inflammation in vitro and in vivo. AB - Acetylation modification catalyzed by histone acetyl transferases (HATs) is important for transcriptional regulation. The present study investigated the effects of the HAT inhibitor garcinol on the expression of inflammation associated genes in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages and LPS-challenged mice. The levels of pro-inflammatory cytokines were determined by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The degree of multi-organ injury was evaluated by histopathological examination of the lung, determination of the alanine aminotransferase and blood urea nitrogen in plasma samples and by monitoring the survival rate of the experimental animals. The results of the current study demonstrated that garcinol promoted LPS-induced expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in RAW264.7 cells. These effects were associated with reduced acetylation of nuclear factor-kappaB p65. Additionally, treatment with garcinol enhanced LPS-induced expression of TNF alpha and IL-6, exacerbated LPS-induced lung injury, increased LPS-induced elevation of plasma alanine aminotransferase and blood urea nitrogen, and reduced the survival rate of LPS-challenged mice. These data indicated that the HAT inhibitor, garcinol, enhances LPS-induced inflammation in vitro and in vivo, suggesting that acetylation modification has an important regulatory function during inflammation. PMID- 27122222 TI - Electrochemical and in situ X-ray spectroscopic studies of MnO2/reduced graphene oxide nanocomposites as a supercapacitor. AB - Electrochemical and in situ X-ray absorption spectroscopy (XAS) measurements of various MnO2-coated carbon materials (MnO2/acid-functionalized carbon nanotubes (C-CNT), MnO2/reduced graphene oxide (RGO), and MnO2/RGO-Au electrodes) were conducted to evaluate the supercapacitive performances and electronic structures. MnO2 was deposited on the surface of C-CNT, RGO, and RGO-Au via a spontaneous redox reaction to facilitate the growth of the bulk form of MnO2/C-CNT and the surface forms of MnO2/RGO-based materials. Various forms of MnO2 on the carbon materials exhibited different charge/discharge behaviors. The specific capacitances of the MnO2/RGO and MnO2/RGO-Au electrodes at a current density of 1 A g(-1) were about 433 and 469 F g(-1), respectively; these values are about 1.5 times that of the MnO2/C-CNT (259 F g(-1)) electrode. Specific capacitances of 220 and 281 F g(-1) with retention rates of about 50-60% were obtained from MnO2/RGO and MnO2/RGO-Au, respectively, even at a high current density of 80 A g( 1). Experimental results revealed that the long-term electrochemical stability of the MnO2/RGO-based electrodes (with ~90% retention) exceeded that of the MnO2/C CNT electrode (with ~60% retention) after 1000 cycles at a high scan rate of 80 A g(-1). This finding indicates that MnO2/RGO-based electrodes feature excellent cycling stability and rate capacity retention performance. To elucidate the atomic/electronic structures of the MnO2/C-CNT, MnO2/RGO, and MnO2/RGO-Au electrodes during the charge/discharge process, in situ XAS of the Mn K-edge was performed. The MnO2/RGO-based electrodes exhibited the least variations in the pre-peak intensity of the Mn K-edge during the charge/discharge process because a nano-network of MnO2 is homogeneously decorated on the outer surfaces of RGO based electrodes to facilitate the growth of surface forms of MnO2/RGO and MnO2/RGO-Au. Analytical results further revealed suppression of changes in tunnel size and promotion of insertion/extraction behavior. This work, particularly the combination of cyclic voltammetry with in situ XAS measurements, will be of general value in the fields of nanomaterials and nanotechnology, and in their use in energy storage. PMID- 27122223 TI - Intrinsic disorder accelerates dissociation rather than association. AB - The intrinsically disordered protein (IDP) has distinct properties both physically and biologically: it often becomes folded when binding to the target and is frequently involved in signal transduction. The physical property seems to be compatible with the biological property where fast association and dissociation between IDP and the target are required. While fast association has been well studied, fueled by the fly-casting mechanism, the dissociation kinetics has received less attention. We here study how the intrinsic disorder affects the dissociation kinetics, as well as the association kinetics, paying attention to the interaction strength at the binding site (i.e., the quality of the "fly lure"). Coarse-grained molecular dynamics simulation of the pKID-KIX system, a well-studied IDP system, shows that the association rate becomes larger as the disorder-inducing flexibility that was imparted to the model is increased, but the acceleration is marginal and turns into deceleration as the quality of the fly lure is worsened. In contrast, the dissociation rate is greatly enhanced as the disorder is increased, indicating that intrinsic disorder serves for rapid signal switching more effectively through dissociation than association. Proteins 2016; 84:1124-1133. (c) 2016 Wiley Periodicals, Inc. PMID- 27122224 TI - Antibacterial effect of N-acetylcysteine on common canine otitis externa isolates. AB - BACKGROUND: N-Acetylcysteine (NAC) has the potential to be a useful therapeutic agent for the treatment of otitis externa due to its antimicrobial and mucolytic properties, as well as its ability to disrupt bacterial biofilm. HYPOTHESIS/OBJECTIVES: To determine the antibacterial activity of NAC against common bacterial isolates associated with canine otitis externa. ANIMALS: Twenty two isolates from canine clinical cases of otitis externa were identified and tested, including five Staphylococcus pseudintermedius, six Pseudomonas aeruginosa, five Corynebacterium spp. and six beta-haemolytic Streptococcus spp. isolates. METHODS: Each isolate was grown on blood agar for 24 h and transferred to Mueller Hinton Broth (MHB) to achieve a final concentration of 5 * 10(5) CFU/mL. NAC was diluted in MHB to a starting concentration of 160 mg/mL and serial two-fold microdilution assays were performed in triplicate with negative controls for all isolates tested. Concentrations of NAC tested ranged from 0.125 to 80 mg/mL. A 50 MUL volume of bacterial suspension was used to inoculate each well. RESULTS: The minimum inhibitory concentration (MIC) of NAC for all isolates tested ranged from 5 to 20 mg/mL. CONCLUSIONS AND CLINICAL RELEVANCE: N Acetylcysteine inhibits clinically relevant and drug resistant bacteria in vitro, and has potential for use as a novel agent for treatment of otitis externa. PMID- 27122225 TI - Lovastatin causes FaDu hypopharyngeal carcinoma cell death via AMPK-p63-survivin signaling cascade. AB - Statins are used widely to lower serum cholesterol and the incidence of cardiovascular diseases. Growing evidence shows that statins also exhibit beneficial effects against cancers. In this study, we investigated the molecular mechanisms involved in lovastatin-induced cell death in Fadu hypopharyngeal carcinoma cells. Lovastatin caused cell cycle arrest and apoptosis in FaDu cells. Lovastatin increased p21(cip/Waf1) level while the survivin level was decreased in the presence of lovastatin. Survivin siRNA reduced cell viability and induced cell apoptosis in FaDu cells. Lovastatin induced phosphorylation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK) and transcription factor p63. Lovastatin also caused p63 acetylation and increased p63 binding to survivin promoter region in FaDu cells. AMPK-p38MAPK signaling blockade abrogated lovastatin-induced p63 phosphorylation. Lovastatin's enhancing effect on p63 acetylation was reduced in HDAC3- or HDAC4- transfected cells. Moreover, transfection of cells with AMPK dominant negative mutant (AMPK-DN), HDAC3, HDAC4 or p63 siRNA significantly reduced lovastatin's effects on p21(cip/Waf1) and survivin. Furthermore, lovastatin inhibited subcutaneous FaDu xenografts growth in vivo. Taken together, lovastatin may activate AMPK-p38MAPK p63-survivin cascade to cause FaDu cell death. This study establishes, at least in part, the signaling cascade by which lovastatin induces hypopharyngeal carcinoma cell death. PMID- 27122226 TI - Non-commutativity measure of quantum discord. AB - Quantum discord is a manifestation of quantum correlations due to non commutativity rather than entanglement. Two measures of quantum discord by the amount of non-commutativity via the trace norm and the Hilbert-Schmidt norm respectively are proposed in this paper. These two measures can be calculated easily for any state with arbitrary dimension. It is shown by several examples that these measures can reflect the amount of the original quantum discord. PMID- 27122227 TI - A Microfluidic Paper-Based Origami Nanobiosensor for Label-Free, Ultrasensitive Immunoassays. AB - Microfluidic paper-based analytical devices (MUPADs) represent a promising platform technology for point-of-care diagnosis. Highly sensitive, rapid, and easy-to-perform immunoassays implemented on MUPADs are desirable to fulfill the promise of the MUPAD technology. This article reports the first microfluidic paper-based origami nanobiosensor (origami MUPAD), which integrates zinc oxide nanowires (ZnO NWs) and electrochemical impedance spectroscopy (EIS) biosensing mechanism, for label-free, ultrasensitive immunoassays. The EIS mechanism features simple and label-free assay operations which take less than 25 min to be finished, while the ZnO NWs allow covalent bonding for immobilizing probe proteins and improve the biosensing performance with such features as high surface-area-to-volume ratios and high sensitivity to surface binding. The calibration of the device reveals an ultralow limit of detection (LOD) of 60 fg mL(-1) (>100 times lower than those of existing MUPADs) for rabbit immunoglobulin G in phosphate-buffered saline. The detection of human immunodeficiency virus p24 antigen in human serum with a low LOD of 300 fg mL(-1) (>33 times lower than that of a commercial p24 antigen test kit) is also demonstrated. This novel MUPAD design offers ultrahigh sensitivity, short assay time, and ease of operation, and thus possesses significant potential for low-cost, rapid molecular diagnosis of early-stage diseases. PMID- 27122228 TI - Highly loaded Ni-based catalysts for low temperature ethanol steam reforming. AB - This paper describes the design of high-loading Ni/Al2O3 catalysts (78 wt% Ni) for low temperature ethanol steam reforming. The catalysts were synthesized via both co-precipitation (COP) and impregnation (IMP) methods. All the catalysts were measured by N2 adsorption-desorption, XRD, H2-TPR, and H2 pulse chemisorption. The characterization results demonstrated that the preparation method and the loading significantly affected the nickel particle size, active nickel surface area and catalytic performance. Over COP catalysts, large nickel particles were presented in nickel aluminum mixed oxides. In comparison, IMP catalysts gained more "free" NiO particles with weak interaction with the aluminum oxide. Consequently, COP catalysts yielded smaller nickel particles and larger active nickel surface areas than those of IMP catalysts. High loading is beneficial for obtaining sufficient active nickel sites when nickel particles are dispersed via COP, whereas excessive nickel content is not desired for catalysts prepared by IMP. Specifically, the 78 wt% nickel loaded catalyst synthesized by COP possessed small nickel particles (~6.0 nm) and an abundant active nickel area (35.1 m(2) gcat(-1)). Consequently, COP-78 achieved superior stability with 92% ethanol conversion and ~35% H2 selectivity at 673 K for 30 h despite the presence of a considerable amount of coke. PMID- 27122229 TI - Weight status, fatness and body image perception of North African immigrant women in Italy. AB - OBJECTIVE: To investigate the nutritional status of North African (NA) immigrant women in Italy, analysing their body size, adiposity and body image perception in comparison to Italian natives and NA residents. DESIGN: The study utilized a cross-sectional design. Anthropometric traits were directly measured and a few indices were computed as proxy measures of nutritional status and adiposity. Body image perception was assessed using silhouette drawings. ANCOVA, adjusted for age, was used to compare anthropometric traits among different groups of women and the chi 2 test to analyse differences in the prevalence of nutritional status. SETTING: Italy and North Africa (Tunisia, Morocco). SUBJECTS: A sample of 433 women aged 18-60 years old: NA immigrants (n 105); Italians (n 100); Tunisians (n 104); Moroccans (n 124). RESULTS: Overweight/obesity prevalence was very high in immigrants (79.8 %). Immigrants had the highest BMI value, the greatest hip circumference and mid upper-arm circumference. Their triceps skinfold thickness was significantly higher than that of Italians, but lower than that of NA residents. CONCLUSIONS: NA immigrant women in Italy showed a higher incidence of overweight compared with Italians and NA residents. All groups showed a preference for a thinner body in comparison to their actual bodies and the immigrants are the most dissatisfied. Immigrants remain a high-risk group for obesity. Assessment of their body composition and health risk profile should be improved by using specific anthropometric measures that are easy to collect even in the case of large migration flows. PMID- 27122230 TI - A quantitative threshold for high/low extent of urinary excretion of compounds in humans. AB - In this study, a quantitative threshold was determined for the high/low extent of urinary excretion (UE) of compounds in humans, using a straightforward but robust statistical method known as receiver operating characteristic curve (ROC) analysis, and also 18 potential physicochemical determinants of UE were evaluated. Data on the percent of drug excreted unchanged into the urine, %Ae , were used to determine the threshold for high/low UE. Compounds can be divided into high/low UE groups using the threshold value of Ae = 16.8%, namely those with Ae > 16.8% are classified as high UE and those with Ae <= 16.8% as low UE. The %Ae negatively correlated with cLogP (r = -0.56); however, cLogP could not quantitatively predict the value of %Ae (R(2) adj. = 0.32). Several determinants of the extent of UE, including cLogP, ACD labs cLogP and ACD labs cLogD(pH=7.4) , were successfully evaluated as a priori indicators of the extent of UE using two cut-off values for each parameter. Moreover, 87% of the 90 compounds in the external validation set were correctly classified using this approach. Analysis of the physicochemical spaces of compounds in these two groups showed significant overlap, which hinders the a priori determination of the extent of UE of compounds using a single threshold/cut-off value of simple physicochemical parameters. In conclusion, 16.8% is a quantitative threshold value to distinguish between high and low UE and new molecular entities with cLogP and ACD labs cLogP values of <=0.7 and >=1.0 and ACD labs cLogD(pH=7.4) values of <=0.0 and >=0.5 could be identified as exhibiting high and low UE, respectively. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27122231 TI - Accurate and Rigorous Prediction of the Changes in Protein Free Energies in a Large-Scale Mutation Scan. AB - The prediction of mutation-induced free-energy changes in protein thermostability or protein-protein binding is of particular interest in the fields of protein design, biotechnology, and bioengineering. Herein, we achieve remarkable accuracy in a scan of 762 mutations estimating changes in protein thermostability based on the first principles of statistical mechanics. The remaining error in the free energy estimates appears to be due to three sources in approximately equal parts, namely sampling, force-field inaccuracies, and experimental uncertainty. We propose a consensus force-field approach, which, together with an increased sampling time, leads to a free-energy prediction accuracy that matches those reached in experiments. This versatile approach enables accurate free-energy estimates for diverse proteins, including the prediction of changes in the melting temperature of the membrane protein neurotensin receptor 1. PMID- 27122232 TI - Information Needs in the Precision Medicine Era: How Genetics Home Reference Can Help. AB - Precision medicine focuses on understanding individual variability in disease prevention, care, and treatment. The Precision Medicine Initiative, launched by President Obama in early 2015, aims to bring this approach to all areas of health care. However, few consumer-friendly resources exist for the public to learn about precision medicine and the conditions that could be affected by this approach to care. Genetics Home Reference, a website from the US National Library of Medicine, seeks to support precision medicine education by providing the public with summaries of genetic conditions and their associated genes, as well as information about issues related to precision medicine such as disease risk and pharmacogenomics. With the advance of precision medicine, consumer-focused resources like Genetics Home Reference can be foundational in providing context for public understanding of the increasing amount of data that will become available. PMID- 27122233 TI - Failure mechanisms in CoCrMo modular femoral stems for revision total hip arthroplasty. AB - In this retrieval study, we reported the failure mechanisms of the CoCrMo-based hip implants. Systematic analyses on the clinically failed modular femoral stems from RevitanTM revision prostheses revealed a multistep fracture process. Multiple microcracks were first developed under the combined action of pitting corrosion and dynamic tensile stress on the lateral side of the CoCrMo connection taper. These microcracks then served as the initiation sites of further corrosion fatigue cracking leading to the final catastrophic failure. This crack initiation process has not been previously reported on retrieved CoCrMo components and our findings provide valuable information on the clinical performance of such implants, as well as the material selection and structural designs of future modular stems. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1525-1535, 2017. PMID- 27122234 TI - Preclinical Evaluation of an Anti-Nectin-4 ImmunoPET Reagent in Tumor-Bearing Mice and Biodistribution Studies in Cynomolgus Monkeys. AB - PURPOSE: Nectin-4 is selectively overexpressed in a variety of cancers and is currently under clinical investigation as a therapeutic target. A monoclonal antibody against nectin-4 (AGS-22M6) was evaluated as an Immuno-positron emission tomography (ImmunoPET) reagent. Its ability to assay nectin-4 expression as well as detect nectin-4 positive tumors in the liver and bone was evaluated using mouse models. PROCEDURES: The biodistribution of [(89)Zr]AGS-22M6 was evaluated in mice bearing tumors with varying levels of nectin-4 expression. An isogenic breast cancer tumor line was used to model metastatic liver and bone disease in mice. The biodistribution of [(18)F]AGS-22M6 in cynomolgus monkeys was evaluated. RESULTS: A positive correlation was demonstrated between tumor nectin-4 expression and [(89)Zr]AGS-22M6 uptake. Tumors in the liver and bone were detected and differentiated based on nectin-4 expression. [(18)F]AGS-22M6 showed limited uptake in cynomolgus monkey tissues. CONCLUSIONS: [(89)Zr]AGS-22M6 is a promising ImmunoPET reagent that can assay nectin-4 expression in both primary and metastatic lesions. PMID- 27122235 TI - Low free triiodothyronine levels are related to symptomatic intracranial hemorrhage and poor functional outcomes after intravenous thrombolysis in acute ischemic stroke patients. AB - BACKGROUND AND OBJECTIVE: Low free triiodothyronine (fT3) levels have been associated with increased mortality and poor functional outcomes in patients with stroke. However, the research of relationship between fT3 levels and acute ischemic stroke (AIS) patients with intravenous thrombolysis (IVT) is scarce. We aimed to investigate the association of fT3 levels with symptomatic intracranial hemorrhage (sICH) and functional outcomes at discharge in AIS patients with IVT. METHODS: Patients with AIS admitted to West China hospital, Sichuan University, who had underwent IVT treatment, were consecutively and retrospectively included. Demographic and clinical information were collected and analyzed according to the levels of fT3. We used logistic regression analysis to estimate the multivariable adjusted association of fT3 levels and post-IVT sICH, and functional outcomes at discharge. RESULTS: Among the 46 patients (26 males; mean age, 63.6 years) in the final analysis, 17 patients (37.0%) had fT3 levels lower than the reference range. After adjustment for age, gender, and statistically important variables (NIHSS on admission, urea levels and creatinine levels), low fT3 levels were significantly associated with post-IVT sICH (p = 0.01, OR = 0.27, 95% CI 0.10 0.77) and poor functional outcomes at discharge (p = 0.04 OR = 2.58, 95% CI 1.05 6.35). CONCLUSION: We found that lower free T3 levels are independently related to post-IVT sICH and poor functional outcomes at discharge in AIS patients with IVT, which should be verified and extended in large cohorts in the future. PMID- 27122236 TI - Interrupting CD28 costimulation before antigen rechallenge affects CD8(+) T-cell expansion and effector functions during secondary response in mice. AB - The role of CD28-mediated costimulation in secondary CD8(+) T-cell responses remains controversial. Here, we have used two tools - blocking mouse anti-mouse CD28-specific antibodies and inducible CD28-deleting mice - to obtain definitive answers in mice infected with ovalbumin-secreting Listeria monocytogenes. We report that both blockade and global deletion of CD28 reveal its requirement for full clonal expansion and effector functions such as degranulation and IFN-gamma production during the secondary immune response. In contrast, cell-intrinsic deletion of CD28 in transferred TCR-transgenic CD8(+) T cells before primary infection leads to impaired clonal expansion but an increase in cells able to express effector functions in both primary and secondary responses. We suggest that the proliferation-impaired CD8(+) T cells respond to CD28-dependent help from their environment by enhanced functional differentiation. Finally, we report that cell-intrinsic deletion of CD28 after the peak of the primary response does not affect the establishment, maintenance, or recall of long-term memory. Thus, if given sufficient time, the progeny of primed CD8(+) T cells adapt to the absence of this costimulator. PMID- 27122237 TI - A Simple Method for Optimization of Reference Gene Identification and Normalization in DNA Microarray Analysis. AB - BACKGROUND: Comparative DNA microarray analyses typically yield very large gene expression data sets that reflect complex patterns of change. Despite the wealth of information that is obtained, the identification of stable reference genes is required for normalization of disease- or drug-induced changes across tested groups. This is a prerequisite in quantitative real-time reverse transcription PCR (qRT-PCR) and relative RT-PCR but rare in gene microarray analysis. The goal of the present study was to outline a simple method for identification of reliable reference genes derived from DNA microarray data sets by comparative statistical analysis of software-generated and manually calculated candidate genes. MATERIAL AND METHODS: DNA microarray data sets derived from whole-blood samples obtained from 14 Zucker diabetic fatty (ZDF) rats (7 lean and 7 diabetic obese) were used for the method development. This involved the use of software generated filtering parameters to accomplish the desired signal-to-noise ratios, 75th percentile signal manual normalizations, and the selection of reference genes as endogenous controls for target gene expression normalization. RESULTS: The combination of software-generated and manual normalization methods yielded a group of 5 stably expressed, suitable endogenous control genes which can be used in further target gene expression determinations in whole blood of ZDF rats. CONCLUSIONS: This method can be used to correct for potentially false results and aid in the selection of suitable endogenous control genes. It is especially useful when aimed to aid the software in cases of borderline results, where the expression and/or the fold change values are just beyond the pre-established set of acceptable parameters. PMID- 27122238 TI - Copper Exposure Perturbs Brain Inflammatory Responses and Impairs Clearance of Amyloid-Beta. AB - Copper promotes a toxic buildup of amyloid-beta (Abeta) and neurofibrillary tangle pathology in the brain, and its exposure may increase the risk for Alzheimer's disease (AD). However, underlying molecular mechanisms by which copper triggers such pathological changes remain largely unknown. We hypothesized that the copper exposure perturbs brain inflammatory responses, leading to impairment of Abeta clearance from the brain parenchyma. Here, we investigated whether copper attenuated Abeta clearance by microglial phagocytosis or by low density lipoprotein-related receptor protein-1 (LRP1) dependent transcytosis in both in vitro and in vivo When murine monocyte BV2 cells were exposed to copper, their phagocytic activation induced by fibrillar Abeta or LPS was significantly reduced, while the secretion of pro-inflammatory cytokines, such as IL-1beta, TNF alpha, and IL-6, were increased. Interestingly, not only copper itself but also IL-1beta, IL-6, or TNF-alpha were capable of markedly reducing the expression of LRP1 in human microvascular endothelial cells (MVECs) in a concentration dependent manner. While copper-mediated downregulation of LRP1 was proteasome dependent, the cytokine-induced loss of LRP1 was proteasome- or lysosome independent. In the mouse model, copper exposure also significantly elevated neuroinflammation and downregulated LRP1 in the brain, consistent with our in vitro results. Taken together, our findings support the pathological impact of copper on inflammatory responses and Abeta clearance in the brain, which could serve as key mechanisms to explain, in part, the copper exposure as an environmental risk factor for AD. PMID- 27122239 TI - Metallothionein MT2A A-5G Polymorphism as a Risk Factor for Chronic Kidney Disease and Diabetes: Cross-Sectional and Cohort Studies. AB - Metallothioneins (MTs) are proteins that protect cells from toxic agents such as heavy metal ions or reactive oxygen species. MT2A A-5G is a single nucleotide polymorphism in the promoter region of the MT2A gene, and the minor G allele results in lower transcription efficiency. We aimed to elucidate associations between MT2A A-5G and risks of 2 diseases potentially related to lowered MT expression, chronic kidney disease (CKD), and diabetes mellitus (DM), in a community-dwelling population. Study subjects were Nagoya city residents participating in the Japan Multi-Institutional Collaborative Cohort Study (J MICC) Daiko Study, comprised 749 men and 2,025 women, aged 39-75 years. CKD (>stage 3) and DM were defined by standard guidelines. Associations were evaluated using logistic regression models with adjustments for age, sex and potential confounders in a cross-sectional study, and verified in a 5-year longitudinal study. Odds ratios (OR [95% confidence interval]) were calculated relative to the AA genotype. Serum MT (I + II), Cd and zinc levels were also determined by genotype. The OR of the GG genotype for CKD risk was 3.98 (1.50, 10.58) in the cross-sectional study and 5.17 (1.39, 19.28) in the longitudinal study. The OR of the GA genotype for DM was 1.86 (1.26, 2.75) in the cross sectional study and 2.03 (1.19, 3.46) in the longitudinal study. MT2A A-5G may be associated with CKD and DM risks. This polymorphism is a promising target for evaluations of CKD and DM risks with possible involvement of low-dose chronic exposure to environmental pollutants. PMID- 27122240 TI - Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR 21, -200c, and -423. AB - Drug-induced acute kidney injury (AKI) is often encountered in hospitalized patients. Although serum creatinine (SCr) is still routinely used for assessing AKI, it is known to be insensitive and nonspecific. Therefore, our objective was to evaluate kidney injury molecule 1 (KIM-1) in conjunction with microRNA (miR) 21, -200c, and -423 as urinary biomarkers for drug-induced AKI in humans. In a cross-sectional cohort of patients (n = 135) with acetaminophen (APAP) overdose, all 4 biomarkers were significantly (P < .004) higher not only in APAP-overdosed (OD) patients with AKI (based on SCr increase) but also in APAP-OD patients without clinical diagnosis of AKI compared with healthy volunteers. In a longitudinal cohort of patients with malignant mesothelioma receiving intraoperative cisplatin (Cp) therapy (n = 108) the 4 biomarkers increased significantly (P < .0014) over time after Cp administration, but could not be used to distinguish patients with or without AKI. Evidence for human proximal tubular epithelial cells (HPTECs) being the source of miRNAs in urine was obtained first, by in situ hybridization based confirmation of increase in miR-21 expression in the kidney sections of AKI patients and second, by increased levels of miR-21, -200c, and -423 in the medium of cultured HPTECs treated with Cp and 4 aminophenol (APAP degradation product). Target prediction analysis revealed 1102 mRNA targets of miR-21, -200c, and -423 that are associated with pathways perturbed in diverse pathological kidney conditions. In summary, we report noninvasive detection of AKI in humans by combining the sensitivity of KIM-1 along with mechanistic potentials of miR-21, -200c, and -423. PMID- 27122241 TI - Multiple Endocrine Disrupting Effects in Rats Perinatally Exposed to Butylparaben. AB - Parabens comprise a group of preservatives commonly added to cosmetics, lotions, and other consumer products. Butylparaben has estrogenic and antiandrogenic properties and is known to reduce sperm counts in rats following perinatal exposure. Whether butylparaben exposure can affect other endocrine sensitive endpoints, however, remains largely unknown. In this study, time-mated Wistar rats (n = 18) were orally exposed to 0, 10, 100, or 500 mg/kg bw/d of butylparaben from gestation day 7 to pup day 22. Several endocrine-sensitive endpoints were adversely affected. In the 2 highest dose groups, the anogenital distance of newborn male and female offspring was significantly reduced, and in prepubertal females, ovary weights were reduced and mammary gland outgrowth was increased. In male offspring, sperm count was significantly reduced at all doses from 10 mg/kg bw/d. Testicular CYP19a1 (aromatase) expression was reduced in prepubertal, but not adult animals exposed to butylparaben. In adult testes, Nr5a1 expression was reduced at all doses, indicating persistent disruption of steroidogenesis. Prostate histology was altered at prepuberty and adult prostate weights were reduced in the high dose group. Thus, butylparaben exerted endocrine disrupting effects on both male and female offspring. The observed adverse developmental effect on sperm count at the lowest dose is highly relevant to risk assessment, as this is the lowest observed adverse effect level in a study on perinatal exposure to butylparaben. PMID- 27122243 TI - Experience of early implantation of retropupillary iris-claw intraocular lens in childhood. PMID- 27122244 TI - Bit1-a potential positive regulator of epithelial-mesenchymal transition in lens epithelial cells. AB - PURPOSE: Posterior capsule opacification (PCO) is a common postoperative complication of cataract surgery. Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is an important initial step of PCO pathogenesis. We have previously shown that Bit1 expresses in rat LECs. In this study, we aim to investigate the role of Bit1 in the EMT of human LECs. METHODS: The expression of Bit1 was firstly detected in human PCO-attached LECs and human lens cell line SRA01/04 by real-time PCR and immunofluorescence staining. The proliferation and migration of Bit1 knockdown SRA01/04 cells were evaluated by cell counting, wound healing assay, and transwell migration assay. The EMT of LECs was triggered by TGF-beta2, and then the effect of Bit1 on EMT with a key biomarker of alpha smooth muscle actin (alpha-SMA) was analyzed by siRNA knockdown assay, and the reversal of EMT was validated by real-time PCR and western blot. RESULTS: Bit1 was obviously augmented in LECs derived from PCO tissues and Bit1 expressed with high levels in the cytoplasm of cultured SRA01/04 cells. Cell proliferation, invasion, and migration, as well as alpha-SMA expression, were significantly decreased in Bit1 knockdown SRA01/04 cells. While TGF-beta2 elevated Bit1 and alpha-SMA expression levels in a dose-dependent manner, with peak levels at 10 ng/ml of TGF-beta2 treatment, suppression of Bit1 in SRA01/04 cells reversed the EMT process. TGF-beta2 induced elevation of alpha-SMA expression level, as well as migration, and invasion abilities were all suppressed by Bit1 deficiency. CONCLUSIONS: These findings reveal that Bit1 promotes TGF-beta2 induced alpha-SMA expression and acts as an positive regulator of EMT. Suppressing Bit1 inhibits the proliferation, migration, and EMT of LECs. Bit1 may be a potential novel therapeutic target for the prevention and treatment of PCO. PMID- 27122245 TI - Lamellar macular hole in high myopic eyes with posterior staphyloma: morphological and functional characteristics. AB - PURPOSE: To study morphological and functional characteristics of myopic lamellar macular hole (LMH) with posterior staphyloma. METHODS: Retrospective observational longitudinal study. Forty myopic eyes affected by LMH and posterior staphyloma have been examined. Pathological myopia was defined as axial length equal or superior to 26.5 mm. LMH was defined on the basis of the following characteristics: irregular foveal contour, inner retinal defect with or without intraretinal splitting and absence of full thickness retinal defect. Demographic and functional parameters were: age, sex, status of lens and best corrected visual acuity (BCVA). Tomographic parameters were: type of LMH, macular retinoschisis (MRS), posterior vitreous detachment (PVD), type of epiretinal membrane (ERM), integrity of ellipsoid zone (EZ) and external limiting membrane (ELM), residual foveal thickness (RFT) and maximal diameter of intraretinal splitting (MDIRS). RESULTS: The statistical analysis showed a significant prevalence of posterior vitreous adherence in the atypical ERM subgroup (P = 0.001). EZ (P = 0.006) and ELM (P = 0.007) damages were significantly associated with the atypical ERM subgroup. RFT was statistically lower in the atypical ERM subgroup compared to the conventional ERM subgroup (P = 0.015). During the follow up, the statistical analysis showed a significant reduction of RFT in the atypical ERM subgroup (P = 0.041). CONCLUSIONS: Myopic lamellar macular hole (LMH) associated with atypical ERM is a more severe clinical entity than myopic LMH associated with conventional ERM. PMID- 27122246 TI - Propensities of peptides containing the Asn-Gly segment to form beta-turn and beta-hairpin structures. AB - The propensities of peptides that contain the Asn-Gly segment to form beta-turn and beta-hairpin structures were explored using the density functional methods and the implicit solvation model in CH2 Cl2 and water. The populations of preferred beta-turn structures varied depending on the sequence and solvent polarity. In solution, beta-hairpin structures with betaI' turn motifs were most preferred for the heptapeptides containing the Asn-Gly segment regardless of the sequence of the strands. These preferences in solution are consistent with the corresponding X-ray structures. The sequence, H-bond strengths, solvent polarity, and conformational flexibility appeared to interact to determine the preferred beta-hairpin structure of each heptapeptide, although the beta-turn segments played a role in promoting the formation of beta-hairpin structures and the beta hairpin propensity varied. In the heptapeptides containing the Asn-Gly segment, the beta-hairpin formation was enthalpically favored and entropically disfavored at 25 degrees C in water. The calculated results for beta-turns and beta-hairpins containing the Asn-Gly segment imply that these structural preferences may be useful for the design of bioactive macrocyclic peptides containing beta-hairpin mimics and the design of binding epitopes for protein-protein and protein-nucleic acid recognitions. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 653-664, 2016. PMID- 27122247 TI - Direct CVD Graphene Growth on Semiconductors and Dielectrics for Transfer-Free Device Fabrication. AB - Graphene is the most broadly discussed and studied two-dimensional material because of its preeminent physical, mechanical, optical, and thermal properties. Until now, metal-catalyzed chemical vapor deposition (CVD) has been widely employed for the scalable production of high-quality graphene. However, in order to incorporate the graphene into electronic devices, a transfer process from metal substrates to targeted substrates is inevitable. This process usually results in contamination, wrinkling, and breakage of graphene samples - undesirable in graphene-based technology and not compatible with industrial production. Therefore, direct graphene growth on desired semiconductor and dielectric substrates is considered as an effective alternative. Over the past years, there have been intensive investigations to realize direct graphene growth using CVD methods without the catalytic role of metals. Owing to the low catalytic activity of non-metal substrates for carbon precursor decomposition and graphene growth, several strategies have been designed to facilitate and engineer graphene fabrication on semiconductors and insulators. Here, those developed strategies for direct CVD graphene growth on semiconductors and dielectrics for transfer-free fabrication of electronic devices are reviewed. By employing these methods, various graphene-related structures can be directly prepared on desired substrates and exhibit excellent performance, providing versatile routes for varied graphene-based materials fabrication. PMID- 27122248 TI - Development of an accelerated leaching method for incineration bottom ash correlated to toxicity characteristic leaching protocol. AB - Heavy metals and some metalloids are the most significant inorganic contaminants specified in toxicity characteristic leaching procedure (TCLP) in determining the safety of landfills or further utilization. As a consequence, a great deal of efforts had been made on the development of miniaturized analytical devices, such as Microchip Electrophoresis (ME) and MUTAS for on-site testing of heavy metals and metalloids to prevent spreading of those pollutants or decrease the reutilization period of waste materials such as incineration bottom ash. However, the bottleneck lied in the long and tedious conventional TCLP that requires 18 h of leaching. Without accelerating the TCLP process, the on-site testing of the waste material leachates was impossible. In this study, therefore, a new accelerated leaching method (ALM) combining ultrasonic assisted leaching with tumbling was developed to reduce the total leaching time from 18 h to 30 min. After leaching, the concentrations of heavy metals and metalloids were determined with ICP-MS or ICP-optical emission spectroscopy. No statistical significance between ALM and TCLP was observed for most heavy metals (i.e., cobalt, manganese, mercury, molybdenum, nickel, silver, strontium, and tin) and metalloids (i.e., arsenic and selenium). For the heavy metals with statistical significance, correlation factors derived between ALM and TCLP were 0.56, 0.20, 0.037, and 0.019 for barium, cadmium, chromium, and lead, respectively. Combined with appropriate analytical techniques (e.g., ME), the ALM can be applied to rapidly prepare the incineration bottom ash samples as well as other environmental samples for on-site determination of heavy metals and metalloids. PMID- 27122249 TI - Early development of the root-knot nematode Meloidogyne incognita. AB - BACKGROUND: Detailed descriptions of the early development of parasitic nematodes are seldom available. The embryonic development of the plant-parasitic nematode Meloidogyne incognita was studied, focusing on the early events. RESULTS: A fixed pattern of repeated cell cleavages was observed, resulting in the appearance of the six founder cells 3 days after the first cell division. Gastrulation, characterized by the translocation of cells from the ventral side to the center of the embryo, was seen 1 day later. Approximately 10 days after the first cell division a rapidly elongating two-fold stage was reached. The fully developed second stage juvenile hatched approximately 21 days after the first cell division. CONCLUSIONS: When compared to the development of the free-living nematode Caenorhabditis elegans, the development of M. incognita occurs approximately 35 times more slowly. Furthermore, M. incognita differs from C. elegans in the order of cell divisions, and the early cleavage patterns of the germ line cells. However, cytoplasmic ruffling and nuclear migration prior to the first cell division as well as the localization of microtubules are similar between C. elegans and M. incognita. PMID- 27122250 TI - Interaction of Caveolin-3 and HCN is involved in the pathogenesis of diabetic cystopathy. AB - A growing body of research suggests that impaired bladder Cajal-like interstitial cells (ICCs) are a important component in the pathogenesis of diabetes-induced bladder dysfunction, although the molecular mechanisms have not been illustrated completely. The purpose of this study was to examine whether the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in ICCs-DM were responsible for the detrusor weak contractility of Diabetic cystopathy (DCP) and to study the possible mechanism of regulating the expression and function of HCN channels. HCN channels expression were decreased at the mRNA and protein levels. Forskolin (FSK), which can elevate intracellular cAMP levels, increased the density of the hyperpolarization-activated current and intracellular calcium concentration in both normal control (NC) rats and DCP rats, but the sensitivity of FSK on HCN channels was clearly down-regulated in DCP rats. The loss of caveolae and caveolin was in accordance with the decrease in HCN channels. Caveolin-3 co-localizes with and affects the expression and function of HCN. Taken together, these results indicate that the loss of caveolae and HCN channels in ICCs-DM is important in the pathogenesis of DCP. Increasing the number of caveolae to enhance the function of HCN channels may represent a viable target for the pharmacological treatment of DCP. PMID- 27122251 TI - The genetic diversity of SMLS (Sitobion miscanthi L type symbiont) and its effect on the fitness, mitochondrial DNA diversity and Buchnera aphidicola dynamic of wheat aphid, Sitobion miscanthi (Hemiptera: Aphididae). AB - SMLS (Sitobion miscanthi L type symbiont) is a recently discovered aphid secondary symbiont. Using evidence extracted from 16S rRNA sequences, previous studies indicate that SMLS is the most widely distributed and most recently transferred secondary symbiont in Chinese Sitobion miscanthi populations. Here, we further investigated genetic diversity among SMLS geographic strains with multiloci data. Furthermore, the influence of SMLS on S. miscanthi was uncovered with ecological and evolutionary evidence. The results indicated that there was limited influence of infection with SMLS on variation and evolutionary patterns of S. miscanthi mitochondrial DNA. By hemolymph injection, the SMLS-infected and SMLS-uninfected S. miscanthi clones with the identical genetic background were built in this study. Although similar Buchnera aphidicola dynamics were observed between SMLS-infected and SMLS-uninfected S. miscanthi population, B. aphidicola density of SMLS-infected S. miscanthi population was always significantly higher than SMLS-uninfected ones. The results of fitness measurements indicated that under laboratory rearing conditions, transfection of SMLS could confer modest advantages to some fitness components of S. miscanthi, that is, total number of offspring, longevity, age of first reproduction and weight of adult. However, as SMLS is not strictly associated with S. miscanthi, further investigations are needed to uncover the mechanisms responsible for this inconceivable association. PMID- 27122252 TI - Antioxidant and Antitumor Activities of the Extracts from Chinese Yam (Dioscorea opposite Thunb.) Flesh and Peel and the Effective Compounds. AB - The aims of this study are to investigate the antioxidant and antitumor activities of the water and ethanol extracts isolated from Chinese yam (Dioscorea opposite Thunb.) flesh (CYF) and peel (CYP) and the effective compounds. It was found that all peel portions have a better effect on reactive oxygen (ROS) scavenging assay than meat portions, especially for the water extract of Chinese yam peel (CYP-W). Its IC50 values for hydroxyl radical (OH*) scavenging assay (744.25 +/- 3.46 MUg/mL) and for 1,1-diphenyl-2-picrylhydrazyl scavenging assay (374.85 +/- 6.78 MUg/mL) were both lower than that of yam flesh (CYF-W). Furthermore, the antitumor property of yam peel was more effective than that of yam flesh (CYF-W) on mouse models, with tumor inhibition rates were 47.92% and 27.41% for Ehrlich Ascites Tumor (EAC) model and 40.44% and 24.22% for H22 hepatocarcinoma tumor (H22) model. Meanwhile, extracts of peel showed higher allantoin, total flavonoids, and total phenolics contents than extracts of flesh. In conclusion, this study demonstrated that CYP-W exerted better antitumor activity than flesh extracts and the scavenging ROS effects were also significantly higher in the CYP-W in vitro. Moreover, the data indicated that allantoin may play an important role on antioxidative and antitumor capacity in yam peel. PMID- 27122253 TI - Interleukin-4 enzyme-linked immunospot assay may be useful for diagnosing sensitization to house dust mite. AB - BACKGROUND: The skin prick test (SPT) is considered a standard test for identification of allergens, but it has some limitations in clinical practice. The multiple allergen simultaneous test (MAST), which measures allergen-specific immunoglobulin E in patients' serum, is a widely used alternative test, but is limited by its relatively low sensitivity and specificity. As a novel diagnostic test to identify allergens, we investigated the sensitivity and specificity of an interleukin-4 (IL-4) enzyme-linked immunospot (ELISpot) assay for Dermatophagoides farinae (Der f) and Dermatophagoides pteronyssinus (Der p). METHODS: Based on the symptoms and SPT results, 43 house dust mite (HDM) allergic rhinitis (AR) patients and 41 control subjects were included. Peripheral blood was drawn from each subject for IL-4 ELISpot assay and MAST. The receiver operating characteristic (ROC) curve analysis was conducted to determine the cutoff values. Sensitivity, specificity, and positive and neg predictive values were compared between the 2 tests. RESULTS: The sensitivity, specificity, and areas under the ROC curve (AUCs) of the IL-4 ELISpot assay were 88.4%, 97.6%, and 0.939 for Der f, and 95.3%, 97.5%, and 0.971 for Der p, respectively. However, the sensitivity, specificity, and AUC of MAST were 76.7%, 73.2%, and 0.777 for Der f, and 69.8%, 75.6%, and 0.788 for Der p, respectively. CONCLUSION: The IL-4 ELISpot assay showed higher sensitivity, specificity, and AUC than MAST, which indicates its clinical feasibility for diagnosing allergy for HDM. A further study is needed to determine the accuracy of the IL-4 ELISpot assay for other common allergens. PMID- 27122254 TI - Gains following perceptual learning are closely linked to the initial visual acuity. AB - The goal of the present study was to evaluate the dependence of perceptual learning gains on initial visual acuity (VA), in a large sample of subjects with a wide range of VAs. A large sample of normally sighted and presbyopic subjects (N = 119; aged 40 to 63) with a wide range of uncorrected near visual acuities (VA, -0.12 to 0.8 LogMAR), underwent perceptual learning. Training consisted of detecting briefly presented Gabor stimuli under spatial and temporal masking conditions. Consistent with previous findings, perceptual learning induced a significant improvement in near VA and reading speed under conditions of limited exposure duration. Our results show that the improvements in VA and reading speed observed following perceptual learning are closely linked to the initial VA, with only a minor fraction of the observed improvement that may be attributed to the additional sessions performed by those with the worse VA. PMID- 27122255 TI - Regulation of expression of microRNAs by DNA methylation in lung cancer. AB - Differential expression of miRNAs has been linked with lung carcinogenesis. Recent studies have indicated that DNA hypermethylation can lead to silencing of tumor suppressor miRNA-encoding genes. Restoration of tumor suppressor miRNAs using inhibitors of DNA methyltransferases has been shown to suppress cell proliferation, angiogenesis, invasion and metastasis implying that modulation of methylation of specific miRNAs can be used as novel therapeutic targets in lung cancer. In this review, we highlight tremendous progress which has been made in the identification of methylation-mediated silencing of miRNAs and their contribution in lung carcinogenesis along with the clinical utility of methylated miRNAs. PMID- 27122256 TI - Longer duration of the Pringle maneuver is associated with hepatocellular carcinoma recurrence following curative resection. AB - OBJECTIVES: To evaluate the effect of Pringle maneuver time on tumor recurrence following liver resection in patients with hepatocellular carcinoma (HCC). METHODS: In this single-center study, we retrospectively evaluated the effect of Pringle maneuver time on HCC recurrence over a 10-year period from 1999 to 2008 using a Cox regression analysis. RESULTS: This study enrolled a total of 2,368 patients. A Pringle maneuver time of 15 min was associated with HCC recurrence (log likelihood ratio test, P = 0.001). A Pringle maneuver time less than 15 min was not a significant risk factor for HCC recurrence (hazard ratio, HR = 0.97, P = 0.708). However, a Pringle maneuver time greater than 15 min was an independent predictor of HCC recurrence (HR = 1.41, P < 0.001). The patients who underwent the Pringle maneuver for over 15 min had lower overall survival (OS) and recurrence-free survival (RFS) than did those who either did not undergo the maneuver or underwent the maneuver for less than 15 min (both P < 0.001). CONCLUSIONS: These results suggest that a longer duration of the Pringle maneuver increases the risk of tumor recurrence in patients with HCC. However, a shorter duration of the Pringle maneuver decreases this risk. J. Surg. Oncol. 2016;114:112-118. (c) 2016 Wiley Periodicals, Inc. PMID- 27122257 TI - MHPE programs in Pakistan: concerns for quality. PMID- 27122258 TI - In vitro effects of nicotine on the non-small-cell lung cancer line A549. AB - OBJECTIVE: To investigate in vitro effects of nicotine on the non-small-cell lung cancer line A549. METHODS: The case-control study was conducted at the First Affiliated Hospital of Nanchang University from 1st January to 30th June, 2014 and comprised A549 cells which were treated with a series of concentrations of nicotine (0.01 uM, 0.1 uM, 1 uM and 10 uM) for 24 hours. Control cells were incubated under the same conditions without the addition of nicotine. Cell growth was detected by monotetrazolium salt [3-(4, 5-dimethyl-2-thiazolyl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. Cell apoptosis was detected by Haematoxylin and Eosin staining, immunofluorescence analysis of Filamentous actin and electron microscope observation. RESULTS: Nicotine had no significant effect on A549 cell growth at the dose of 0.01uM (p>0.05), but had significant growth inhibitory effects at the doses of 0.1uM, 1uM and 10uM (p< 0.05 each). A significant decrease in cell numbers was observed on staining (p< 0.05). Significant changes in the size and shape of cells and concomitant changes in cytoskeletons and organelles were observed by immunofluorescence and electron microscope observation (p< 0.05). CONCLUSIONS: The growth inhibitory effects of nicotine on A549 cells were found to be dose-dependent. PMID- 27122259 TI - Perceptions of medical students regarding dimensions of environmental wellness. AB - OBJECTIVE: To explore the status of awareness on environmental wellness in medical students of Karachi. METHODS: The cross-sectional questionnaire-based survey was carried out at Bahria University Medical & Dental College, Karachi, from January 2009 to July 2013, and comprised randomly selected medical students. The response options were; never, sometimes, mostly and always (numbered 0-4) and these were analyzed in terms of frequency, proportion and percentages by Predictive analysis software version18. RESULTS: Out of 800 questionnaires distributed, 736(92%) were received fully completed. There were 210(28.5%) male and 526(71.5%) female respondents, with a male-to-female ratio of 1:2.5. Female medical students were more serious in taking care of their environment tasks (p< 0.0001). They knew their responsibility to preserve environment and consciously tried to conserve energy more than the male students (p=0.034). The proportions of admitting disposal of garbage in dustbins was found more in females than males (p< 0.0005). Though 486(66%) participants were interested in knowing about environmental problems, females tended to be more in liking greenery in their place of residence (p< 0.0005) and lived in harmony with nature and universe (p< 0.001). CONCLUSIONS: Medical students were aware of the concept of environmental wellness, but female medical students had a better perception and were a step ahead in its realization. PMID- 27122260 TI - Increase in serum alkaline phosphatase due to fatty meal in undergraduate students of Khyber Medical University, Khyber Pakhtunkhwa. AB - OBJECTIVE: To evaluate the effect of fatty meal on intestinal alkaline phosphatase. METHODS: The cross-sectional study was conducted at Khyber Medical University, Peshawar, Pakistan from March to April 2014 and comprised young healthy individuals 18-25 years of age. Whole blood samples were collected from the subjects in ethylenediaminetetraacetic acid anti-coagulated and plane serum tubes. For blood group analysis, blood group anti sera were used, while for serum alkaline phosphatase, a chemistry analyser was used. Alkaline phosphatase levels in the blood before and after breakfast were compared. RESULTS: Of the 177 subjects, there were 139(78.5%) men and 38(21.4%) women. Mean fasting alkaline phosphatise level was 144.22+/-75.57, while mean random value was 174.15+/-96.70 (p=0.001). CONCLUSIONS: Serum alkaline phosphatise must be analysed in fasting state early in the morning. PMID- 27122261 TI - Interim18 F-FLUORO-2-deoxy-d-glucose positron emission tomography scan/computed tomography scan in diffuse large B cell lymphoma-as a prognostic tool. AB - OBJECTIVE: To assess the role of interim [18F]-Fluoro-2-deoxy-d-glucose positron emission tomography scan/computed tomography scan in the management of diffuse large B-cell lymphoma in terms of progression-free survival and overall survival prediction. METHODS: The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital, Lahore, and comprised data of newly diagnosed patients of diffuse large B-cell lymphoma treated between January 2010 and June 2013.Baseline characteristics of patients were documented and compared. Response on interim positron emission tomography/computed tomography and end of treatment scan was taken a look at, and .progression-free survival and overall survival for positive/negative scans were calculated. Data was also reviewed for sensitivity, specificity, positive predictive value and negative predictive value for relapse. SPSS 19 was used for statistical analysis. RESULTS: Data of 119 patients was reviewed, and 87(73%) of them were males. Overall median age was 33 years (range 18-50). Interim scan was positive for 63(53%) patients and negative for 53(47%), and showed positive predictive value, negative predictive value, sensitivity and specificity for relapse of 35%, 89%, 79% and 55% respectively. Two-years progression-free survival and overall survival for scan-positive patients was 66% and 72% compared to 88% (p=0.002) and 92% (p=0.005) for scan-negative patients. Corresponding values at 2 years for patients having positive end-of-treatment scan were 35% and 44% against 94% (p< 0.001) and 96%(p< 0.001) for patients with negative scan. CONCLUSIONS: Interim positron emission tomography/computed tomography had high sensitivity and negative predictive value for relapse in diffuse large B-cell lymphoma. Both interim and end-of-treatment scans were predictors of progression-free survival and overall survival. PMID- 27122262 TI - Vaginal douching practice: Frequency, associated factors and relationship with vulvovaginal symptoms. AB - OBJECTIVE: To determine the frequency, associated factors and relationship with vulvovaginal symptoms and vaginal douching among Turkish women. METHODS: The cross-sectional, analytical study was conducted at Merkez Efendi Hospital, Manisa, Turkey, from January to June 2014 using a questionnaire. Statistical analysis was carried out using SPSS 17. RESULTS: Of the total 343 women in the study, 91(26.5%) had reported vaginal douching in the preceding year. Statistically significant relationship was determined between the vaginal douching behaviour and couples who had low educationand low income levels, having unplanned pregnancy and had someone in their neighbourhood who douched (p< 0.05 each). The most common reason for using vaginal douching was reported to be cleanliness by 85(93.4%) women, prevention of genital infections 75(82.4%), cleaning after/before sexual intercourse 72(79%), during menstruation 49(54%), prevention of vaginal discharge 69(76%), decreasing of unpleasant odours 65(71.4%) and religious beliefs 46(50.5%). Self-reported history of vaginal infection was significantly more common for women who douched compared those who did not (p< 0.05). CONCLUSIONS: Healthcare providers should determine the reason and risky groups of women and educate the women to stop the vaginal douching behaviour and harmful effects of vaginal douching. PMID- 27122263 TI - Middle and long term radiologic and functional results of childhood supracondylar humeral fractures operated in first 24 hours with limited medial approach. AB - OBJECTIVE: To investigate the middle- and long-term radiological and functional results of children with type III supracondylar humerus fractures treated with a limited medial approach and internal fixation. METHODS: The retrospective study was conducted at Department of Orthopaedics in Goztepe Training and Research Hospital, Istanbul, Turkey, and comprised data of children who underwent surgery between April 1991 and June 2009. Patients in group I underwent surgery within the first 8 hours after admission, and those in group II did so 8-24 hours after admission. Patients were evaluated according to the Flynn scoring system. RESULTS: Of the 79 patients, 52(65.8%) were male and 27(34.2%) were female. Fractures involved the left side in 49(62%) patients. Group I had 39(49.4%) patients and group II 40(50.6%). The overall mean age was 6.2+/-2.95 years (range: 2-13 years), and the mean follow-up was 53.2+/-14.9 months (range: 26-193 months). Functional scores were satisfactory (excellent, good and fair results) in all cases in both groups (100%), and the cosmetic results were satisfactory in 37(95%) in group I, and 39(97.5%) in group II (p>0.05). CONCLUSIONS: Limited medial approach to the treatment of supracondylar humerus fractures yielded successful functional and cosmetic results. PMID- 27122264 TI - Effects of male literacy on family size: A cross sectional study conducted in Chakwal city. AB - OBJECTIVE: To determine the effects of male education on family size, the desired family size, knowledge and use of contraception and opinion about female education. METHODS: The cross-sectional study was carried out in Chakwal city, Punjab, Pakistan, from June to October 2009. A pre-tested questionnaire was used for data collection. The respondents were males and data on their demographics, age at marriage, actual and desired family size, knowledge about methods of contraception, and opinion about female education was collected. SPSS 15 was used for statistical analysis. RESULTS: Out of the 178 respondents, 52(29.2%) were illiterate and 126(70.8%) were educated. Among the educated, 97(77%) were in favour of small families compared to only 10(19.2%) of the uneducated males (p< 0.001). Besides, 118 (93.6%) educated males were aware of any method of contraception. The most important source of awareness was television 45(37.8%) followed by lady health visitors 40(33.9%). Among the respondents, 38(21.3%) were not using any contraceptive method because they considered it unIslamic, 16(9.1%) had fear of side effects, 57(32.0%) were desirous of large families, while 67(37.6%) had other reasons, like trying to conceive. Among the uneducated males, 17(32.7%) didn't discuss any family planning issue with their wives compared to 14(11.3%) of educated males (p< 0.001). CONCLUSIONS: Educational status of the males had an effect on the desired family size, contraceptive use and views in favour of female education. PMID- 27122265 TI - Medical electives: Students perspective. AB - OBJECTIVE: To identify possible learning targets of undergraduates who opted for local and foreign medical electives and to quantify their level of achievement. METHODS: The cross-sectional study was conducted at Foundation University Medical College, Islamabad, in February 2014, and apprised undergraduates of either gender from second to final year MBBS who had already done medical electives in local or foreign hospitals for 2-4 weeks. Data collection tool was an anonymous questionnaire with four possible intended learning areas; career choice, learning from advanced system, career enhancement and peer pressure. Possible learning objectives were accredited with 'yes' or 'no' option and their level of achievement were quantified on Likert scale of 1 to 5. RESULTS: Among the 45 undergraduates, 12(26.6%) were males and 33(73.3%)were females. A total of 26(57%) believed that electives helped them in making career choice, while 6(14%) disagreed and 7(16%) were not sure. Besides, 20(66%) students were expecting to learn from advanced system, 12(26.66%) felt that their expectations were met, and 11(24%) felt them better than expected. Career enhancement was the main objective of 16(38%) students with an achievement level of 4 and 5 in 11(24%) of students. Only 7(16%) considered peer pressure as one of the motivating factors for electives. CONCLUSIONS: Main professional targets of undergraduates who had done medical electives were found to be learning from advanced system and career selection and an overall significant number felt that their target achievement was up to or beyond their expectations. PMID- 27122266 TI - Association of ovarian reserve with age, BMI and serum FSH level in subfertile women. AB - OBJECTIVE: To examine the association of age, body mass index, serum follicle stimulating hormone levels and antral follicular count with fertility outcomes in terms of conception and delivery. METHODS: The prospective cohort study was conducted at Baqai Institute of Reproductive and Developmental Sciences, Karachi, from January to December 2012.and comprised women undergoing the first cycle of in-vitro fertilisation who were categorised into groups A and B depending upon age. Group A consisted of women below 35 years of age, while Group B had women over 35 years of age. Age body mass index (BMI), basal level of serum follicle stimulating hormone and antral follicular count were determined in all subjects. Intracytoplasmic sperm injection was dispensed, and all subjects were followed up prospectively and their cycle outcomes were recorded. SPSS 20 was used for statistical analysis. RESULTS: Of the 148 women in the study, 98(66%) were in Group A and 50(44%) in Group B. In Group A, 15(38.5%) women with body mass index < 25 and 24(61.5%) with >25with normal follicle stimulating hormone levels showed positive outcome. Moreover, 20(51.3%) women with normal ovarian reserve and 19(48.7%) with higher reserves showed positive pregnancy test and outcome. Group B showed < 7 follicular count on ultrasonic examination, < 5 eggs were retrieved in 36(72%) women and all of them (100%) had negative outcome. CONCLUSIONS: Sub fertile women at age 35 years and above and body mass index over 33 had reduced fertility potential compared to younger women, and ultimately had lower success rate of fertility treatment, including in-vitro fertilisation. PMID- 27122267 TI - Nutritional status of low birth weight infants in Makkah region: Evaluation of anthropometric and biochemical parameters. AB - OBJECTIVE: To assess the nutritional status of low birth weight infants from Makkah area immediately after birth. METHODS: The prospective study was conducted between October and December 2012 at Al-Noor Speciality Hospital, Makkah, Saudi Arabia, and comprised low birth weight infants who were divided into three equal groups according to their birth weight: group A (low birthweight1501-2500gm), group B (very low birthweight1001-1500gm), and group C (extremely low birth weight < 1000gm). Mothers who had delivered low birth weight infants were enrolled. Weight, length, head circumference, complete blood count, and blood tests were performed for all the infants under investigation. RESULTS: There were 300 infants in the study; 100(33.3%) in each of the 3 groups. Group C showed the lowest gestational age, length, and head circumferences (p< 0.05 each). No significant discrepancies were found in complete blood count results among the three groups (p>0.05). Normal serum phosphorus, potassium and magnesium levels and mild hypocalcaemia were observed in all infants. However, hypernatraemia was significantly evident (p< 0.05) for group C. All infants had hyperglycaemia and hyperbilirubinaemia. Albumin content decreased significantly (p< 0.05) as birth weight decreased. Groups B and C infants showed higher serum urea than group A infants (p< 0.05). CONCLUSIONS: Low newborn birth weight was related to the deteriorated nutritional status in terms of low anthropometric and abnormal biochemical measures. It was not possible to correlate the birth weight of the neonates to the parameters of the complete blood tests. PMID- 27122268 TI - Structured performance monitoring of TB-care at facility, district and province levels - Pakistan experience. AB - OBJECTIVE: To develop and evaluate a more structured process for effective tuberculosis control monitoring. METHODS: The quasi-experimental exploratory study was conducted from April 2007 to January 2008 in the Punjab province of Pakistan. Eight intervention districts were compared with eight control districts. Intervention consisted of managers using performance monitoring guidelines and tools for monitoring meetings at the facility and district levels. Proportion of tuberculosis suspects among outpatients, registered confirmed cases and patients' default rate were monitored. Semi-structured interviews were done to assess the experience of the participants. RESULTS: The proportion of TB suspects among outpatient attendees was significantly higher in the intervention districts (95% confidence interval 1.6-1.8%). The pre-registration default also showed difference (p=0.07). The case finding during 9 months of the intervention showed 96.3% increase compared to the 9 months of the preceding year. CONCLUSIONS: The new process was effective in improving tuberculosis case finding. The process may be used to improve tuberculosis monitoring systems and other such healthcare services. PMID- 27122269 TI - Frequency of depression in type 2 diabetes mellitus and an analysis of predictive factors. AB - OBJECTIVE: To determine frequency of depression in patients with diabetes mellitus type 2 and to identify predictive factors. METHODS: The observational study was carried out at 1 Mountain Medical Battalion, Bagh, Azad Kashmir, Pakistan, from June 2013 to May 2014, and comprised type 2 diabetic patients who were not using anti-depressants and did not have history of other psychiatric illnesses. Demographic data, duration of diabetes, presence of hypertension and type of treatment were recorded and body mass index was calculated. Patient Health Questionnaire-9, translated into Urdu, was administered during face-to face interviews. Scores >5 indicated depression, which was classified into different grades of severity using standard cut-off values. RESULTS: Of the 133 patients, 51(38.35%) were depressed. Depression was mild in 34(26%), moderate in 12(9.6%), moderately severe in 4(2.9%) and severe in 1(0.7%) patient. On univariate binary logistic regression, female gender (odds ratio=3.07; 95% confidence interval = 1.43, 6.59), lesser education (odds ratio = 0.90; 95% confidence interval 0.84, 0.97) shorter duration of diabetes (odds ratio=0.87; 95% confidence interval = 0.80, 0.96) and higher body mass index (odds ratio=1.41; 95% confidence interval = 1.05, 1.25) were significantly associated with depression. Only shorter duration of diabetes (odds ratio=0.90; 95% confidence interval = 0.82, 0.99) remained significant after adjustment for confounders. Age, level of education, glycaemic control and type of treatment did not predict depression. CONCLUSIONS: A significant proportion of type 2 diabetics were depressed. Shorter duration of diabetes reliably predicted depression in these patients. PMID- 27122270 TI - Experience of ventriculo-peritoneal shunt insertion in late presenting congenital hydrocephalus. AB - OBJECTIVE: To evaluate the outcomes of insertion of ventriculo-peritoneal shunts in paediatric neglected hydrocephalus. METHODS: The quasi-experimental study was conducted at the Combined Military Hospital, Rawalpindi, from January 2012 to June 2014, and comprised infants of both genders who presented late with congenital hydrocephalus, having fronto-occipital circumference more than 98 percentile of matched age group. Pre-operative assessment was based upon detailed history, clinical examination, laboratory investigations and computed tomography scan of head. After insertion of ventriculo-peritoneal shunt, patients were followed up for outcomes. Data was analysed using SPSS 17. RESULTS: Of the 30 infants, 12(40%) were girls and 18(60%) were boys. Overall mean age was 7.73+/ 1.41 months (range: 5-10 months). Mean fronto-occipital circumference was 54.30+/ 3.08. Cerebrospinal fluid infection was documented in 12(40%). Abdominal wound complications were observed in 7(23.3%) infants. Ventriculo-peritoneal shunt was removed in 18(60%) and eventually replaced in 18(60%). In-hospital mortality on account of complications was encountered in 13(43.3%). Correlation of fronto occipital circumference to mortality was significant (p=0.001). CONCLUSIONS: To shunt or not to shunt remains a dilemma for poor-risk infants, but timely reporting of infants with hydrocephalus, proper case selection may improve the outcome of surgical intervention. PMID- 27122271 TI - Effect of high-dose fluoride on antioxidant enzyme activities of amniotic Fluid in rats. AB - OBJECTIVE: To investigate the effect of high-dose fluoride on antioxidant enzyme activities of amniotic fluid and fluoride of serum in rats. METHODS: The experimental study was conducted from January 8, 2008, to December 14, 2010, at the Suleyman Demirel University Experimental Animals Laboratory and the Medical Biochemistry Department Research Laboratory, Isparta, Turkey. Impregnated Wistar albino rats were divided into two equal groups. Group I had controls, while Group II rats were exposed to high-dose fluoride. Group I was given drinking water mixed with 0.1 mg/kg/b.w./day of natrium fluoride, while group II was given drinking water mixed with 10 mg/kg/b.w./day of natrium fluoride for 18 days. At the end of 18 days, amniotic fluid and blood samples were collected from control and experimental groups of pregnancy. Superoxide dismutase, glutathione peroxidase, catalase activities and thiobarbituric acid reactive substances as antioxidant enzymes in amniotic fluid and levels of fluoride in serum samples were investigated. RESULTS: There were 14 rats, with 7(50%) in each group. Foetal weight in group II significantly decreased compared to the control group (p< 0.05). Antioxidant enzyme activities in amniotic fluid were significantly higher in group II than group I (p< 0.05) although thiobarbituric acid reactive substances in amniotic fluid and serum fluoride levels were significantly lower in group II than group I (p< 0.05). CONCLUSIONS: Fluoride that created oxidative stress inhibited lipid peroxidation and apparently increased the antioxidant defence system. PMID- 27122272 TI - A thirteen year audit of manuscripts related to medical education published in leading medical journals of Pakistan. AB - OBJECTIVE: To audit the number and type of published articles related to medical education in leading Pakistani biomedical journals. METHODS: The audit covered the period from January 2001 to December 2013. Journals either indexed in Medline or having an impact factor were selected. The audit was done in two phases. First, articles related to medical education were screened by reading the titles. Then abstracts were studied and articles were placed into several pre-defined categories based on article type and research topic. Data was analysed using SPSS 20. RESULTS: A total of 118 relevant articles were published. Of them, 60(51%) articles were published in the Journal of Pakistan Medical Association, 42(35.6%) in the Journal of College of Physicians and Surgeons Pakistan, 4(3.4%) in Pakistan Journal of Medical Sciences, and 12(10.2%) in the Journal of Ayub Medical College. Articles related to curriculum development were 33(28.0 %), teaching 28(23.7%), assessment 29(24.6%), faculty training 5(4.2%), continuous medical education 4(3.4%), ethics 3(2.5%), and others 16(13.6%). CONCLUSIONS: There is a need to increase the quality of health profession education research, documentation and audit of the global contribution of Pakistani medical educationists. PMID- 27122273 TI - Knowledge, attitude, and practice (KAP) of food hygiene among schools students' in Majmaah city, Saudi Arabia. AB - OBJECTIVE: To determine the level of knowledge, attitude, and practice of food hygiene among primary, intermediate and high school students and explore association, if any, with socio-demographic differences. METHODS: The observational cross-sectional study was conducted at boy's schools in Majmaah, Kingdom of Saudi Arabia, from February to May 2014. Data was collected using stratified random sampling technique from students aged 8-25 year. Two schools from each level (primary, intermediate and high school) were randomly selected and data was collected from the selected schools using simple random sampling method. A self-administered modified Sharif and Al-Malki questionnaire for knowledge, attitude and practice of food hygiene was used with Arabic translation. RESULTS: The mean age of 377 male students in the study was 14.53+/ 2.647 years. Knowledge levels was less in primary school students compared to high school students (p=0.026). Attitude level was high in primary school students compared to intermediate school students (p< 0.001). No significant difference was observed between groups with regard to practice levels (p=0.152). CONCLUSIONS: The students exhibited good practice levels, despite fair knowledge and attitude levels. PMID- 27122274 TI - Selenium, copper, zinc, iron levels and mortality in patients with sepsis and systemic inflammatory response syndrome in Western Black Sea Region, Turkey. AB - OBJECTIVE: To evaluate the changing levels of selenium, copper, zinc and iron in patients with sepsis and systemic inflammatory response syndrome and their influence on mortality. METHODS: The prospective study was conducted at a tertiary care university hospital in Zonguldak city in the western Black Sea region of Turkey from January 2012 to December 2013, and comprised patients with sepsis and systemic inflammatory response syndrome. Blood samples were taken on 1st, 3rd, 5th and 7th days to measure serum selenium, copper, zinc and iron levels. Patients' demographic data, presence of additional diseases and mortality were recorded. RESULTS: Of the 57 patients, 28(49.1%) were female and 29(50.9%) were male, with an overall mean age of 60.3+/-19.4 years, mean height of 166.1+/ 11.4cm, mean weight of 76.5+/-17.5kg. Copper and zinc levels were in the normal range, while selenium and iron levels were lower than the limit values at all measuring periods. There was no significant difference between first and other days in accordance with element levels (p>0.05). Baseline copper levels in patients with malignancy were lower than patients without malignancy (p< 0.05). In hypertensive patients, baseline copper levels were higher and 7th day levels were lower than non-hypertensive (p< 0.05). Baseline selenium levels of those who died were lower than the other patients (p< 0.05). Selenium and iron levels were decreased in patients with sepsis-systemic inflammatory response syndrome and copper levels were lower in patients with malignancy, hypertension and chronic obstructive pulmonary disease (p< 0.05). There was no change in zinc levels of the patients. CONCLUSIONS: Reduced basal selenium levels of patients with sepsis and systemic inflammatory response syndrome were associated with mortality. PMID- 27122275 TI - Reliability and validity of the faculty evaluation instrument used at King Saud bin Abdulaziz University for Health Sciences: Results from the Haematology Course. AB - OBJECTIVE: To assess reliability and validity of evaluation tool using Haematology course as an example. METHODS: The cross-sectional study was conducted at King Saud Bin Abdul Aziz University of Health Sciences, Riyadh, Saudi Arabia, in 2012, while data analysis was completed in 2013. The 27-item block evaluation instrument was developed by a multidisciplinary faculty after a comprehensive literature review. Validity of the questionnaire was confirmed using principal component analysis with varimax rotation and Kaiser normalisation. Identified factors were combined to get the internal consistency reliability of each factor. Student's t-test was used to compare mean ratings between male and female students for the faculty and block evaluation. RESULTS: Of the 116 subjects in the study, 80(69%) were males and 36(31%) were females. Reliability of the questionnaire was Cronbach's alpha 0.91. Factor analysis yielded a logically coherent 7 factor solution that explained 75% of the variation in the data. The factors were group dynamics in problem-based learning (alpha0.92), block administration (alpha 0.89), quality of objective structured clinical examination (alpha 0.86), block coordination (alpha 0.81), structure of problem-based learning (alpha 0.84), quality of written exam (alpha 0.91), and difficulty of exams (alpha0.41). Female students' opinion on depth of analysis and critical thinking was significantly higher than that of the males (p=0.03). CONCLUSIONS: The faculty evaluation tool used was found to be reliable, but its validity, as assessed through factor analysis, has to be interpreted with caution as the responders were less than the minimum required for factor analysis. PMID- 27122276 TI - Warfarin continuation vs interruption during procedures of cardiac rhythm devices: A Meta-analysis of randomized controlled trials. AB - To compare the safetyand efficacy of warfarin treatment continuation and heparin bridging therapy during cardiac rhythm device (CRD) implantation in patients chronically treated with anticoagulants.We performed a search and analysis of peer-reviewed studies Four randomized controlled trials (RCTs)were included in our analysis with 941 patients. The bleeding risk in patients continuing warfarin perioperatively was lower than those interrupting warfarin and using a heparin bridge (RD -0.08, 95% CI -0.17 to 0.02, p< 0.05). There was no significant difference in ischaemic risk between two methods (RD 0, 95% CI -0.01 to 0.02, p=1.00). Hence, in patients undergoing long-term warfarin therapy, continuation of warfarin treatment is a safe and efficacious perioperative strategy for during CRD implantations, while interruption of warfarin with a heparin bridge may increase the bleeding risk in these patients. PMID- 27122277 TI - Use of statistical tests and statistical software choice in 2014: tale from three Medline indexed Pakistani journals. AB - Statistical tests help infer meaningful conclusions from studies conducted and data collected. This descriptive study analyzed the type of statistical tests used and the statistical software utilized for analysis reported in the original articles published in 2014 by the three Medline-indexed journals of Pakistan. Cumulatively, 466 original articles were published in 2014. The most frequently reported statistical tests for original articles by all three journals were bivariate parametric and non-parametric tests i.e. involving comparisons between two groups e.g. Chi-square test, t-test, and various types of correlations. Cumulatively, 201 (43.1%) articles used these tests. SPSS was the primary choice for statistical analysis, as it was exclusively used in 374 (80.3%) original articles. There has been a substantial increase in the number of articles published, and in the sophistication of statistical tests used in the articles published in the Pakistani Medline indexed journals in 2014, compared to 2007. PMID- 27122278 TI - Repeated small bowel resection in a patient with Buerger's disease and intestinal involvement. AB - Buerger's disease, also called thromboangiitis obliterans, is a recurrent and an uncommon vaso-occlusive inflammatory disease, which typically affects small and medium-sized arteries, veins and nerves of the upper and lower extremities. Mesenteric and multisystem involvement of two or more organs is extremely rare. Here we report the case of a 39-year-old male heavy smoker who had undergone four repetitive laparotomies and multiple small bowel resections for ischaemic involvement of Buerger's disease. He had below-the-knee amputation of the right leg and finger of the left hand because of that disease before bowel involvement. Histopathological findings revealed that the arteries and veins of the resected small intestine were occluded with organised thrombi. Inflammatory cell infiltration was recognised mainly in the intima of distal branches of mesenteric artery. These findings were compatible with previous findings in histopathological examinations of amputated extremities. PMID- 27122279 TI - Nutcracker syndrome complicating with renal abscess. AB - The nutcracker syndrome refers to compression of left renal vein between the superior mesenteric artery and aorta. Renal abscess consists of purulent and necrotic material localised to the renal parenchyma. These two entities are extremely rare and their coincidence has not previously been described in literature. Here, we report a case of a 10-year-old girl who developed left renal abscess probably due to nutcracker syndrome. PMID- 27122280 TI - Oesophagus obstruction due to ingestion of multiple foreign bodies. AB - The ingestion of a foreign body (FB) is a potentially serious condition. In children, the most common years for FB ingestion are from the age of 6 months to 6 years. FB ingestion also occurs in those with psychiatric disorders or mental retardation and among adult prisoners and alcoholics. Most ingested FBs spontaneously pass out of the body via the gastrointestinal system. An endoscopic or surgical approach is only needed if the object fails to progress through the gastrointestinal tract. All objects impacted in the oesophagus require urgent treatment. This study reports a case of multiple FB ingestion and provides a literature review. PMID- 27122281 TI - Large-cell lung cancer originating from tracheal bronchus - A rare case. AB - Tracheal bronchus is a rarely seen congenital anomaly generally originating from the right lateral wall of the trachea and approximately 2 cm above the carina. It was firstly defined by Sandifort in 1785 and its frequency of incidence in normal population changes between 0.1% and 2%. There are two types called ''Supernumerary'' and ''Displaced''. It is a rarely seen kind of tracheal anomaly although fairly well defined. The cases accompanied by lung cancer are seen more rarely. Nine cases of this association were reported in literature and tracheal bronchus-lung cancer association whose pathological result is undifferentiated large-cell carcinoma has not been stated so far. We present a 75 years old male patient as possibly the first case having tracheal bronchus and large-cell carcinoma association in literature. PMID- 27122282 TI - Persistent very high output lymphatic drainage after radical nephrectomy successfully treated with surgical management. AB - Persistent lymphatic drainage is uncommon after most of the surgical operations. It is related with mechanical, nutritional and immunological problems as well as electrolyte imbalance and protein deficiency. It is most commonly seen in retroperitoneal surgeries including abdominal aortic surgery and retroperitoneal lymph node dissection. Conservative management is the first treatment choice and resolves the problem in most cases. However persistent high output drainage may not be resolved with conservative approach and surgical or invasive treatment may become necessary. Additionally, surgical management of persistent lymphatic drainage has not been sufficiently discussed in the literature. In this study, we present a case of persistent very high output lymphatic drainage after right radical nephrectomy which failed with conservative approach and was successfully treated with surgical management. PMID- 27122283 TI - The cardiovascular phenotype: impact on choice of glucose- lowering therapy. AB - One of the major endpoints to be considered while choosing glucose-lowering therapy is their impact on cardiovascular outcomes. As a corollary, the cardiovascular health assessment of a person with diabetes informs the choice of glucose-lowering treatment. The clinical aspects included in this bidirectional relationship are described in this review as the cardiovascular phenotype. Vital signs, cardiac autonomic function, myocardial health and coronary status influence, and are influenced by, choice of glucose-lowering therapy. Such therapy also has an impact on cerebrovascular and peripheral arterial health. These aspects should be considered while planning treatment for type 2 diabetes mellitus. PMID- 27122284 TI - Professional hazards of diabetes care professionals. AB - While the current emphasis on patient-centered, or person-centered care, is welcome, it should not neglect the health and rights of persons who serve the patient. The diabetes care professional is an equally important part of diabetes praxis. Her/His health determines the quality of diabetes care offered to the person with diabetes. Here we highlight two specific professional hazards faced by diabetes care professionals, i.e., needle stick injuries and compassion fatigue. These complications can easily be prevented or managed easily, provided attention is paid to them. PMID- 27122285 TI - TAVR - The future of aortic stenosis management. PMID- 27122286 TI - Comment on Muhammad Zeeshan Sarwar et al (J Pak Med Assoc 2015; 65: 1075-1078). PMID- 27122287 TI - Comment on Khaula Atif et al (J Pak Med Assoc 2016; 66: 63-67) Do doctors have hidden distress; a study conducted at tertiary care hospital at Lahore. PMID- 27122288 TI - Response to comment on Khaula Atif et al (J Pak Med Assoc 2016; 66: 63-67) Do doctors have hidden distress; a study conducted at tertiary care hospital at Lahore. PMID- 27122289 TI - Comment on Shama Chaudhry et al (J Pak Med Assoc 2016; 66: 107-110) Rare primary fallopian tube carcinoma; a gynaecologist's dilemma. PMID- 27122290 TI - Response to comment on Shama Chaudhry et al (J Pak Med Assoc 2016; 66: 107-110) Rare primary fallopian tube carcinoma; a gynaecologist's dilemma. PMID- 27122291 TI - Anomalous right coronary artery arising from left coronary cusp with coexisting valvular heart disease. AB - We report an unusual case, a 50 year old female with an abnormal right coronary artery originating from the left coronary cusp. The patient, who had a history of hypertension presented with chest pain and shortness of breath to the emergency department. She was diagnosed with ischaemic heart disease (IHD) and had hypertension as one of the coronary risk factor. Echocardiography revealed poor progression of R waves. She was scheduled for echocardiography thereafter which revealed severe aortic stenosis with aortic root dilatation. The patient was discharged due to absence of any complications or other anomalies. This case is unique because of the simultaneously presenting valvular pathology, along with the anomalous origin of the right coronary artery which was detected, as an incidental finding, during coronary angiography. PMID- 27122292 TI - Propensity scoring - A novel research methodology. PMID- 27122293 TI - RETRACTION OF ARTICLE ON GROUNDS OF REDUNDANT/DUPLICATE PUBLICATION. PMID- 27122294 TI - GP admits to falsifying clinical trial of insomnia drug. PMID- 27122295 TI - Associative Activation and Its Relation to Exploration and Exploitation in the Brain. AB - Associative activation is commonly assumed to rely on associative strength, such that if A is strongly associated with B, B is activated whenever A is activated. We challenged this assumption by examining whether the activation of associations is state dependent. In three experiments, subjects performed a free-association task while the level of a simultaneous load was manipulated in various ways. In all three experiments subjects in the low-load conditions provided significantly more diverse and original associations compared with subjects in the high-load conditions, who exhibited high consensus. In an additional experiment, we found increased semantic priming of immediate associations under high load and of remote associations under low load. Taken together, these findings imply that activation of associations is an exploratory process by default, but is narrowed to exploiting the more immediate associations under conditions of high load. We propose a potential mechanism for processing associations in exploration and in exploitation modes, and suggest clinical implications. PMID- 27122296 TI - A study of high-dose lenalidomide induction and low-dose lenalidomide maintenance therapy for patients with hypomethylating agent refractory myelodysplastic syndrome. AB - Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by bone marrow failure which frequently progress to acute myeloid leukemia. Patients who fail to respond to, or progress on first-line DNA hypomethylating agents (HMA) have a poor prognosis. Conventionally dosed lenalidomide has activity in 5q-MDS. In other subtypes, it may reduce RBC transfusion requirements but does not result in cytogenetic responses. We previously reported that high dose lenalidomide induction (50 mg/day) results in complete remissions in a high fraction of patients. We, therefore, conducted a Phase 2 trial of the same regimen in MDS refractory to HMA. Marrow complete remissions were seen in 33% of patients and hematological improvement in 8% of patients. Significant infections complicated more than 50% of cases. Future trials to explore alternative dosing schedules of high-dose lenalidomide to increase efficacy while decreasing toxicity are warranted. PMID- 27122297 TI - Comparison of the properties of collagen-chitosan scaffolds after gamma-ray irradiation and carbodiimide cross-linking. AB - The property of collagen-chitosan porous scaffold varies according to cross linking density and scaffold composition. This study was designed to compare the properties of collagen-chitosan porous scaffolds cross-linked with gamma irradiation and carbodiimide (CAR) for the first time. Eleven sets of collagen chitosan scaffolds containing different concentrations of chitosan at a 5% increasing gradient were fabricated. Fourier transform infrared spectroscopy was performed to confirm the success of cross-linking in the scaffolds. The scaffold morphology was evaluated under scanning electron microscope (SEM). SEM revealed that chitosan was an indispensable material for the fabrication of gamma-ray irradiation scaffold. The microstructure of gamma-ray irradiation scaffold was less stable than those of alternative scaffolds. Based upon swelling ratio, porosity factor, and collagenase degradation, gamma-ray irradiation scaffold was less stable than CAR and 25% proportion of chitosan scaffolds. Mechanical property determines the orientation in gamma-irradiation and CAR scaffold. In vitro degradation test indicated that gamma-irradiation and CAR cross-linking can elevate the scaffold biocompatibility. Compared with gamma-ray irradiation, CAR cross-linked scaffold containing 25% chitosan can more significantly enhance the bio-stability and biocompatibility of collagen-chitosan scaffolds. CAR cross linked scaffold may be the best choice for future tissue engineering. PMID- 27122298 TI - Shensong Yangxin capsules prevent ischemic arrhythmias by prolonging action potentials and alleviating Ca2+ overload. AB - Shensong Yangxin capsules (SSYX) are an effective traditional Chinese medicine that has been used to treat coronary heart disease clinically. The present study aimed to establish whether SSYX prevent ischemic arrhythmias in rats, and to explore the underlying mechanisms. Male rats were pretreated with distilled water, SSYX and amiodarone for one week. Acute myocardial ischemia (AMI) was performed to induce ischemic arrhythmias. The incidence and severity of ischemic arrhythmias were evaluated. The action potential, transient outward K+ current (Ito) and inward rectifier K+ current (IK1) of rat cardiomyocytes were measured using the patch-clamp technique. The intracellular Ca2+ concentration of the cardiomyocytes was measured using a laser scanning confocal microscope. The results revealed that SSYX lowered the incidence of arrhythmia markedly during AMI. Furthermore, SSYX delayed the appearance, and reduced the severity, of ischemic arrhythmias compared with the control. In addition, SSYX markedly decreased the ratio of the myocardial infarction region to the whole heart. In an in vitro study, SSYX prolonged the action potential duration of rat cardiomyocytes, and inhibited Ito and IK1 markedly. Additionally, SSYX inhibited Ca2+ elevation induced by KCl in cardiomyocytes. These results suggested that SSYX prevents ischemic arrhythmia, and the underlying mechanism responsible for this process may include prolonging the action potential and alleviating Ca2+ overload. PMID- 27122299 TI - Low protein diets produce divergent effects on energy balance. AB - Diets deficient in protein often increase food consumption, body weight and fat mass; however, the underlying mechanisms remain poorly understood. We compared the effects of diets varying in protein concentrations on energy balance in obesity-prone rats. We demonstrate that protein-free (0% protein calories) diets decreased energy intake and increased energy expenditure, very low protein (5% protein) diets increased energy intake and expenditure, whereas moderately low protein (10% protein) diets increased energy intake without altering expenditure, relative to control diet (15% protein). These diet-induced alterations in energy expenditure are in part mediated through enhanced serotonergic and beta adrenergic signaling coupled with upregulation of key thermogenic markers in brown fat and skeletal muscle. The protein-free and very low protein diets decreased plasma concentrations of multiple essential amino acids, anorexigenic and metabolic hormones, but these diets increased the tissue expression and plasma concentrations of fibroblast growth factor-21. Protein-free and very low protein diets induced fatty liver, reduced energy digestibility, and decreased lean mass and body weight that persisted beyond the restriction period. In contrast, moderately low protein diets promoted gain in body weight and adiposity following the period of protein restriction. Together, our findings demonstrate that low protein diets produce divergent effects on energy balance. PMID- 27122301 TI - Champions of an Older Adult Exercise Program: Believers, Promoters, and Recruiters. AB - Champions, who support, market, and promote programs, are a vital part of successful program adoption, implementation, and maintenance. Enhance(r)Fitness (EF) is an evidence-based, community-delivered group exercise program for older adults. Using semistructured phone interviews with 20 participants, 17 instructors, and 15 staff, we explored the roles of champions in adopting, implementing, and maintaining EF at YMCA-affiliated sites. Interviews revealed EF champions play critical roles in program dissemination. Champions are outgoing, passionate, and enthusiastic about EF. They believe in the program and its benefits (believers), are "walking advertisements" (promoters), and have magnetic personalities, persuading newcomers to join (recruiters). EF champions were not purposefully selected but naturally arose during the course of program delivery. Community sites adopting evidence-based programs can foster and support champions by engaging with them, and capitalizing on their energy as an emerging resource throughout the adoption, implementation, and maintenance of programs. PMID- 27122300 TI - Is it getting hot in here? Adjustment of hydraulic parameters in six boreal and temperate tree species after 5 years of warming. AB - Global temperatures (T) are rising, and for many plant species, their physiological response to this change has not been well characterized. In particular, how hydraulic parameters may change has only been examined experimentally for a few species. To address this, we measured characteristics of the hydraulic architecture of six species growing in ambient T and ambient +3.4 degrees C T plots in two experimentally warmed forest sites in Minnesota. These sites are at the temperate-boreal ecotone, and we measured three species from each forest type. We hypothesized that relative to boreal species, temperate species near their northern range border would increase xylem conduit diameters when grown under elevated T. We also predicted a continuum of responses among wood types, with conduit diameter increases correlating with increases in the complexity of wood structure. Finally, we predicted that increases in conduit diameter and specific hydraulic conductivity would positively affect photosynthetic rates and growth. Our results generally supported our hypotheses, and conduit diameter increased under elevated T across all species, although this pattern was driven predominantly by three species. Two of these species were temperate angiosperms, but one was a boreal conifer, contrary to predictions. We observed positive relationships between the change in specific hydraulic conductivity and both photosynthetic rate (P = 0.080) and growth (P = 0.012). Our results indicate that species differ in their ability to adjust hydraulically to increases in T. Specifically, species with more complex xylem anatomy, particularly those individuals growing near the cooler edge of their range, appeared to be better able to increase conduit diameters and specific hydraulic conductivity, which permitted increases in photosynthesis and growth. Our data support results that indicate individual's ability to physiologically adjust is related to their location within their species range, and highlight that some wood types may adjust more easily than others. PMID- 27122302 TI - New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats. AB - For antibody drug conjugates (ADCs), the fate of the cytotoxic payload in vivo needs to be well understood to mitigate toxicity risks and properly design the first in-patient studies. Therefore, a distribution, metabolism, and excretion (DME) study with a radiolabeled rat cross-reactive ADC ([(3)H]DM1-LNL897) targeting the P-cadherin receptor was conducted in female tumor-bearing nude rats. Although multiple components [total radioactivity, conjugated ADC, total ADC, emtansine (DM1) payload, and catabolites] needed to be monitored with different technologies (liquid scintillation counting, liquid chromatography/mass spectrometry, enzyme-linked immunosorbent assay, and size exclusion chromatography), the pharmacokinetic data were nearly superimposable with the various techniques. [(3)H]DM1-LNL897 was cleared with half-lives of 51-62 hours and LNL897-related radioactivity showed a minor extent of tissue distribution. The highest tissue concentrations of [(3)H]DM1-LNL897-related radioactivity were measured in tumor. Complimentary liquid extraction surface analysis coupled to micro-liquid chromatography-tandem mass spectrometry data proved that the lysine (LYS)-4(maleimidylmethyl) cyclohexane-1-carboxylate-DM1 (LYS-MCC-DM1) catabolite was the only detectable component distributed evenly in the tumor and liver tissue. The mass balance was complete with up to 13.8% +/- 0.482% of the administered radioactivity remaining in carcass 168 hours postdose. LNL897 derived radioactivity was mainly excreted via feces (84.5% +/- 3.12%) and through urine only to a minor extent (4.15% +/- 0.462%). In serum, the major part of radioactivity could be attributed to ADC, while small molecule disposition products were the predominant species in excreta. We show that there is a difference in metabolite profiles depending on which derivatization methods for DM1 were applied. Besides previously published results on LYS-MCC-DM1 and MCC DM1, maysine and a cysteine conjugate of DM1 could be identified in serum and excreta. PMID- 27122303 TI - Interplay of dysphoria and anxiety sensitivity in relation to emotion regulatory cognitions of smoking among treatment-seeking smokers. AB - BACKGROUND AND OBJECTIVES: There is evidence that anxiety sensitivity (AS) plays a role in the maintenance of smoking, yet there is little understanding of how AS interplays with other affective symptomatology variables that are also related to smoking, such as dysphoria. Therefore, the current cross-sectional study evaluated the interactive effects of AS and dysphoria on emotion regulatory cognitions, including smoking negative affect reduction expectancies, perceived barriers for cessation, and smoking-specific experiential avoidance. METHOD: A total of 448 adult treatment-seeking daily smokers, who responded to study advertisements, were recruited to participate in a smoking cessation treatment trial (47.8% female; Mage = 37.2, SD = 13.5). The current study utilized self report baseline data from trial participants. RESULTS: After accounting for covariates, simple slope analyses revealed that AS was positively related to negative affect reduction expectancies (beta = .03, p = .01), perceived barriers to cessation (beta = .22, p = .002), and smoking avoidance and inflexibility (beta = .07, p = .04), among smokers with lower (vs. higher) levels of dysphoria. CONCLUSIONS: The current findings suggest that higher levels of dysphoria may mitigate the relation between AS and emotion regulatory cognitions of smoking. SCIENTIFIC SIGNIFICANCE: The current findings highlight the unique and additive clinical relevance of AS and dysphoria regarding emotion regulatory smoking cognitions that may impede quit success. (Am J Addict 2016;25:267-274). PMID- 27122304 TI - Association between interleukin-21 gene polymorphisms (rs12508721) and HBV related hepatocellular carcinoma. AB - Interleukin-21 (IL-21), as a multifunctional cytokine, plays an important role in many diseases, such as cancer, inflammatory and autoimmune diseases. We aimed to investigate the relationship between polymorphisms of IL-21 gene and susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in a Chinese population. Studied subjects were divided into three groups: 100 patients with HBV-related HCC, 115 patients with chronic HBV infection and 127 healthy controls. Genomic DNA was isolated from peripheral blood, and the polymerase chain reaction-ligase detection reaction (PCR-LDR) method was used to genotype the SNPs (rs2221903, rs907715 and rs12508721) within IL-21 gene. Our results showed that IL-21 polymorphisms were associated with the risk of HCC and chronic HBV infection when compared with healthy controls. The rs2221903A/G AG genotype was associated with a higher risk of chronic HBV infection when compared with healthy controls [AG versus AA + GG, P = 0.036, OR = 1.898, 95%CI = 1.038 3.471]. The rs12508721C/T TT genotype was related with a lower risk of chronic HBV infection and HBV-related HCC than in healthy controls [TT versus CT + CC, P = 0.026, OR = 0.451, 95%CI = 0.221-0.920; P = 0.049, OR = 0.482, 95%CI = 0.231 1.005]. No significant difference in the genotype and allele distrubutions of rs907715G/A SNP was observed in the HBV-related HCC group, chronic HBV-infected group and the healthy control group when compared to each other. Our findings suggest that the rs12508721T/C and rs2221903A/G polymorphisms of IL-21 gene are associated with the susceptibility of HBV-related HCC and chronic HBV infection. The genetic variant may in fact cause protection against the HBV-related HCC. However, the function in these SNPs of IL-21 gene needs to clarify the mechanisms involved in the pathogenesis of HBV-related HCC further. PMID- 27122305 TI - Clinical and radiographic evaluation of implants placed by means of inferior alveolar nerve lateralization: a 5-year follow-up study. AB - OBJECTIVE: To evaluate clinical and radiological responses of implants placed in combination with inferior alveolar nerve lateralization, analyzing survival and success rates over 5 years functional loading. MATERIALS AND METHODS: This prospective, longitudinal, single-center study recruited 40 patients with mandibular atrophy in the posterior sectors, who underwent lateralization of the inferior alveolar nerve. Three months after surgery and implant placement, the implants were loaded by means of screw-retained implant-supported partial prostheses or fixed complete prostheses. Clinical and radiographic examinations were performed immediately after implant placement and at 12, 24, 36, 48 and 60 month follow-up visits. RESULTS: The 40 patients received a total of 129 implants (Phibo TSATM , Phibo Dental Solutions, Sentmenat, Barcelona, Spain). Two implants were lost in the first month after surgery, generating an implant cumulative survival rate (CSR) of 98.44%. The success rate after 5 years of loading was 98.44%. No intra-operative or postoperative soft tissue or prosthetic complications occurred during the 5-year follow-up. CONCLUSIONS: Inferior alveolar nerve lateralization performed to allow placement of (Phibo TSATM ) implants in patients with mandibular atrophy obtained predictable clinical and radiological results over five years of functional loading. PMID- 27122306 TI - MicroRNA-130b promotes cell proliferation and invasion by inhibiting peroxisome proliferator-activated receptor-gamma in human glioma cells. AB - MicroRNA-130b (miR-130b) is a novel tumor-related miRNA that has been found to be involved in several biological processes. However, there is limited evidence regarding the role of miR-130b in the tumorigenesis of human gliomas. In the present study, reverse transcription-quantitative polymerase chain reaction (RT qPCR) assays were used to quantify miR-130b expression levels in human glioma tissues and glioma cell lines (U251, U87, SNB19 and LN229). The expression level of miR-130b was found to be markedly higher in human glioma tissues than in non neoplastic brain specimens. Specifically, higher expression levels of miR-130b were observed in the glioma cell lines, compared with those in normal human astrocytes (NHA). We also confirmed that miR-130b interacted with the 3' untranslated region of peroxisome proliferator-activated receptor-gamma (PPAR gamma), which negatively affected the protein levels of E-cadherin. Furthermore, its effects on cell proliferation and invasion were examined using CCK8, colony formation, cell cycle and Transwell assays. We found that the upregulation of miR 130b induced cell proliferation, decreased the percentage of cells in the G0/G1 phase and enhanced the invasiveness of U251 glioma cells whereas the downregulation of miR-130b exerted opposing effects. Moreover, it was demonstrated that the downregulation of miR-130b in U251 glioma cells restored the expression of PPAR-gamma and E-cadherin, and inhibited the expression of beta catenin. Notably, PPAR-gamma knockdown abolished the inhibitory effect of miR 130b inhibitor on the proliferation and invasivness of U251 cells. Taken together, these findings suggest that miR-130b promotes the proliferation and invasion of U251 glioma cells by inhibiting PPAR-gamma. PMID- 27122307 TI - Trapping mammalian protein complexes in viral particles. AB - Cell lysis is an inevitable step in classical mass spectrometry-based strategies to analyse protein complexes. Complementary lysis conditions, in situ cross linking strategies and proximal labelling techniques are currently used to reduce lysis effects on the protein complex. We have developed Virotrap, a viral particle sorting approach that obviates the need for cell homogenization and preserves the protein complexes during purification. By fusing a bait protein to the HIV-1 GAG protein, we show that interaction partners become trapped within virus-like particles (VLPs) that bud from mammalian cells. Using an efficient VLP enrichment protocol, Virotrap allows the detection of known binary interactions and MS-based identification of novel protein partners as well. In addition, we show the identification of stimulus-dependent interactions and demonstrate trapping of protein partners for small molecules. Virotrap constitutes an elegant complementary approach to the arsenal of methods to study protein complexes. PMID- 27122308 TI - Invisible Support: Effects on the Provider's Positive and Negative Affect. AB - BACKGROUND: Social support that goes unnoticed by receivers (i.e. invisible support) seems to be most beneficial for the receivers' well-being. The providers' well-being, however, has been neglected so far. This study examines how invisible support is related to the providers' well-being and whether this association is dependent on the providers' relationship satisfaction. METHODS: Overall, 97 non-smoking partners of smokers who were about to quit smoking were examined. Invisible support was assessed dyadically: partners' reports on smoking specific provided social support together with smokers' reports on received support were assessed at baseline. Partners' relationship satisfaction was also assessed at baseline. Partners' positive and negative affect were measured at baseline and six-week follow-up. RESULTS: No main effects of invisible instrumental or emotional support occurred. However, partners' relationship satisfaction moderated the association between invisible instrumental support and change in partners' negative and positive affect: For partners with lower relationship satisfaction more invisible instrumental support was related to increased negative affect and decreased positive affect, whereas for partners with higher relationship satisfaction the inverse effects occurred. CONCLUSIONS: The study's results emphasise that invisible instrumental support might have emotional costs for the providers. Relationship satisfaction seems to serve as a protective factor. PMID- 27122309 TI - Unravelling and controlling hidden imprint fields in ferroelectric capacitors. AB - Ferroelectric materials have a spontaneous polarization that can point along energetically equivalent, opposite directions. However, when ferroelectric layers are sandwiched between different metallic electrodes, asymmetric electrostatic boundary conditions may induce the appearance of an electric field (imprint field, Eimp) that breaks the degeneracy of the polarization directions, favouring one of them. This has dramatic consequences on functionality of ferroelectric based devices such as ferroelectric memories or photodetectors. Therefore, to cancel out the Eimp, ferroelectric components are commonly built using symmetric contact configuration. Indeed, in this symmetric contact configuration, when measurements are done under time-varying electric fields of relatively low frequency, an archetypical symmetric single-step switching process is observed, indicating Eimp ~ 0. However, we report here on the discovery that when measurements are performed at high frequency, a well-defined double-step switching is observed, indicating the presence of Eimp. We argue that this frequency dependence originates from short-living head-to-head or tail-to-tail ferroelectric capacitors in the device. We demonstrate that we can modulate Eimp and the life-time of head-to-head or tail-to-tail polarization configurations by adjusting the polarization screening charges by suitable illumination. These findings are of relevance to understand the effects of internal electric fields on pivotal ferroelectric properties, such as memory retention and photoresponse. PMID- 27122310 TI - Depot- and sex-specific effects of maternal obesity in offspring's adipose tissue. AB - According to the Developmental Origin of Health and Disease (DOHaD) concept, alterations of nutrient supply in the fetus or neonate result in long-term programming of individual body weight (BW) setpoint. In particular, maternal obesity, excessive nutrition, and accelerated growth in neonates have been shown to sensitize offspring to obesity. The white adipose tissue may represent a prime target of metabolic programming induced by maternal obesity. In order to unravel the underlying mechanisms, we have developed a rat model of maternal obesity using a high-fat (HF) diet (containing 60% lipids) before and during gestation and lactation. At birth, newborns from obese dams (called HF) were normotrophs. However, HF neonates exhibited a rapid weight gain during lactation, a key period of adipose tissue development in rodents. In males, increased BW at weaning (+30%) persists until 3months of age. Nine-month-old HF male offspring was normoglycemic but showed mild glucose intolerance, hyperinsulinemia, and hypercorticosteronemia. Despite no difference in BW and energy intake, HF adult male offspring was predisposed to fat accumulation showing increased visceral (gonadal and perirenal) depots weights and hyperleptinemia. However, only perirenal adipose tissue depot exhibited marked adipocyte hypertrophy and hyperplasia with elevated lipogenic (i.e. sterol-regulated element binding protein 1 (Srebp1), fatty acid synthase (Fas), and leptin) and diminished adipogenic (i.e. peroxisome proliferator-activated receptor gamma (Ppargamma), 11beta-hydroxysteroid dehydrogenase type 1 (11beta-Hds1)) mRNA levels. By contrast, very few metabolic variations were observed in HF female offspring. Thus, maternal obesity and accelerated growth during lactation program offspring for higher adiposity via transcriptional alterations of visceral adipose tissue in a depot- and sex-specific manner. PMID- 27122311 TI - Redox proteomic analysis of serum from aortic anerurysm patients: insights on oxidation of specific protein target. AB - OBJECTIVES: oxidative stress is undoubtedly one of the main players in abdominal aortic aneurysm (AAA) pathophysiology. Recent studies in AAA patients reported an increase in the indices of oxidative damage at the tissue level and in biological fluids coupled with the loss of counter-regulatory mechanisms of protection from oxidative stress. We recently reported, in a proteomic analysis of AAA patient sera, changes in the expression of several proteins exerting important modulatory activities on cellular proliferation, differentiation and response to damage. This study aimed to explore the involvement of protein oxidation, at peripheral levels, in AAA. METHODS: a redox proteomic approach was used to investigate total and specific protein carbonylation and protein-bound 4-hydroxy-2-nonenal (HNE) in the serum of AAA patients compared with age-matched controls. RESULTS: our results show increased oxidative damage to protein as indexed by the total carbonyl levels and total protein-bound HNE. By redox proteomics we identified specific carbonylation of three serum proteins: serum retinol-binding protein, vitamin D-binding protein and fibrinogen alpha-chain HNE. We also identified increased protein-bound HNE levels for hemopexin, IgK chain C region and IgK chain V-III region SIE. In addition we found a high correlation between specific protein carbonylation and protein-bound HNE and the aortic diameter. Moreover the analysis of serum proteins with antioxidant activity demonstrates the oxidation of albumin together with the overexpression of transferrin, haptoglobin and HSPs 90, 70, 60 and 32. CONCLUSIONS: this study support the involvement of oxidative stress in the pathogenesis of AAA and might provide a further degree of knowledge in the cause-effect role of oxidative stress shedding new light on the molecular candidates involved in the disease. PMID- 27122312 TI - Emerging treatment for ALK-positive lung cancer. AB - INTRODUCTION: Lung cancer is associated with poor prognosis and limited benefit from chemotherapy. The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the discovery of targetable genetic alterations, including the ALK fusion oncogene. AREAS COVERED: Three drugs have been approved for clinical use in ALK-positive patients - crizotinib, ceritinib and alectinib. Unfortunately, treatment resistance inevitably develops. Several mechanisms of acquired resistance are reported. In this review, we will discuss emerging treatment options in ALK-positive advanced NSCLC and strategies to overcome resistance mechanisms, including newer generation of ALK inhibitors, Hsp90 inhibitors and immunotherapy. EXPERT OPINION: Tremendous advances have been made in the treatment of ALK-positive lung cancers, but management hurdles still exist, including universal development of resistance to ALK inhibitors and limited CNS activity. Given that specific treatment strategies target distinct patterns of resistance, re-biopsy at the time of progression appears necessary to optimize management. However, there remain many issues in routine clinical application including the burden placed on the patients by serial biopsies and the risks of repeat invasive procedures. Future studies are needed to validate the usage of non- or minimally invasive tests and to determine the optimal orders of utilizing different ALK inhibitors. PMID- 27122313 TI - Interaction of HIF1alpha and beta-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice. AB - Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1alpha (HIF1alpha) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice. MMP13 is up-regulated by the Wnt/beta-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1alpha in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1alpha (?Hif1alpha(chon)) with joint instability. Specific loss of HIF1alpha exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1alpha lowered transcription factor 4 (TCF4)-beta-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1alpha interacting with beta-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, DeltaHif1alpha(chon) mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4-beta-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1alpha-beta-catenin interaction is a negative regulator of Wnt signaling and MMP13 transcription, thus reducing catabolism in OA. Our study contributes to the understanding of the role of HIF1alpha in OA and highlights the HIF1alpha-beta catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage. PMID- 27122314 TI - Astrocytes regulate cortical state switching in vivo. AB - The role of astrocytes in neuronal function has received increasing recognition, but disagreement remains about their function at the circuit level. Here we use in vivo two-photon calcium imaging of neocortical astrocytes while monitoring the activity state of the local neuronal circuit electrophysiologically and optically. We find that astrocytic calcium activity precedes spontaneous circuit shifts to the slow-oscillation-dominated state, a neocortical rhythm characterized by synchronized neuronal firing and important for sleep and memory. Further, we show that optogenetic activation of astrocytes switches the local neuronal circuit to this slow-oscillation state. Finally, using two-photon imaging of extracellular glutamate, we find that astrocytic transients in glutamate co-occur with shifts to the synchronized state and that optogenetically activated astrocytes can generate these glutamate transients. We conclude that astrocytes can indeed trigger the low-frequency state of a cortical circuit by altering extracellular glutamate, and therefore play a causal role in the control of cortical synchronizations. PMID- 27122315 TI - Eyespot-dependent determination of the phototactic sign in Chlamydomonas reinhardtii. AB - The biflagellate green alga Chlamydomonas reinhardtii exhibits both positive and negative phototaxis to inhabit areas with proper light conditions. It has been shown that treatment of cells with reactive oxygen species (ROS) reagents biases the phototactic sign to positive, whereas that with ROS scavengers biases it to negative. Taking advantage of this property, we isolated a mutant, lts1-211, which displays a reduction-oxidation (redox) dependent phototactic sign opposite to that of the wild type. This mutant has a single amino acid substitution in phytoene synthase, an enzyme that functions in the carotenoid-biosynthesis pathway. The eyespot contains large amounts of carotenoids and is crucial for phototaxis. Most lts1-211 cells have no detectable eyespot and reduced carotenoid levels. Interestingly, the reversed phototactic-sign phenotype of lts1-211 is shared by other eyespot-less mutants. In addition, we directly showed that the cell body acts as a convex lens. The lens effect of the cell body condenses the light coming from the rear onto the photoreceptor in the absence of carotenoid layers, which can account for the reversed-phototactic-sign phenotype of the mutants. These results suggest that light-shielding property of the eyespot is essential for determination of phototactic sign. PMID- 27122317 TI - Sequential construction of a model for modular gene expression control, applied to spatial patterning of the Drosophila gene hunchback. AB - Gene network simulations are increasingly used to quantify mutual gene regulation in biological tissues. These are generally based on linear interactions between single-entity regulatory and target genes. Biological genes, by contrast, commonly have multiple, partially independent, cis-regulatory modules (CRMs) for regulator binding, and can produce variant transcription and translation products. We present a modeling framework to address some of the gene regulatory dynamics implied by this biological complexity. Spatial patterning of the hunchback (hb) gene in Drosophila development involves control by three CRMs producing two distinct mRNA transcripts. We use this example to develop a differential equations model for transcription which takes into account the cis regulatory architecture of the gene. Potential regulatory interactions are screened by a genetic algorithms (GAs) approach and compared to biological expression data. PMID- 27122318 TI - Assessment of translational importance of mammalian mRNA sequence features based on Ribo-Seq and mRNA-Seq data. AB - Ribosome profiling technology (Ribo-Seq) allowed to highlight more details of mRNA translation in cell and get additional information on importance of mRNA sequence features for this process. Application of translation inhibitors like harringtonine and cycloheximide along with mRNA-Seq technique helped to assess such important characteristic as translation efficiency. We assessed the translational importance of features of mRNA sequences with the help of statistical analysis of Ribo-Seq and mRNA-Seq data. Translationally important features known from literature as well as proposed by the authors were used in analysis. Such comparisons as protein coding versus non-coding RNAs and high- versus low-translated mRNAs were performed. We revealed a set of features that allowed to discriminate the compared categories of RNA. Significant relationships between mRNA features and efficiency of translation were also established. PMID- 27122319 TI - Conserved features of complexes of TATA-box binding proteins with DNA. AB - A comparative analysis of all available structures of complexes of TATA-box binding proteins (TBPs) with DNA is performed. Conserved features of DNA-protein interaction are described, including nine amino acid residues that form conserved hydrogen bonds, 13 residues participating in formation of two conserved hydrophobic clusters at DNA-protein interface, and four conserved water-mediated contacts. Partial symmetry of conserved contacts reflects quasi-symmetry of TBP structure. PMID- 27122320 TI - Parallel workflow manager for non-parallel bioinformatic applications to solve large-scale biological problems on a supercomputer. AB - Rapid expansion of online resources providing access to genomic, structural, and functional information associated with biological macromolecules opens an opportunity to gain a deeper understanding of the mechanisms of biological processes due to systematic analysis of large datasets. This, however, requires novel strategies to optimally utilize computer processing power. Some methods in bioinformatics and molecular modeling require extensive computational resources. Other algorithms have fast implementations which take at most several hours to analyze a common input on a modern desktop station, however, due to multiple invocations for a large number of subtasks the full task requires a significant computing power. Therefore, an efficient computational solution to large-scale biological problems requires both a wise parallel implementation of resource hungry methods as well as a smart workflow to manage multiple invocations of relatively fast algorithms. In this work, a new computer software mpiWrapper has been developed to accommodate non-parallel implementations of scientific algorithms within the parallel supercomputing environment. The Message Passing Interface has been implemented to exchange information between nodes. Two specialized threads - one for task management and communication, and another for subtask execution - are invoked on each processing unit to avoid deadlock while using blocking calls to MPI. The mpiWrapper can be used to launch all conventional Linux applications without the need to modify their original source codes and supports resubmission of subtasks on node failure. We show that this approach can be used to process huge amounts of biological data efficiently by running non-parallel programs in parallel mode on a supercomputer. The C++ source code and documentation are available from http://biokinet.belozersky.msu.ru/mpiWrapper . PMID- 27122321 TI - Meta-analysis of transcriptome data identified TGTCNN motif variants associated with the response to plant hormone auxin in Arabidopsis thaliana L. AB - Auxin is the major regulator of plant growth and development. It regulates gene expression via a family of transcription factors (ARFs) that bind to auxin responsive elements (AuxREs) in the gene promoters. The canonical AuxREs found in regulatory regions of many auxin responsive genes contain the TGTCTC core motif, whereas ARF binding site is a degenerate TGTCNN with TGTCGG strongly preferred. Thereby two questions arise: which TGTCNN variants are functional AuxRE cores and whether different TGTCNN variants have distinct functional roles? In this study, we performed meta-analysis of microarray data to reveal TGTCNN variants essential for auxin response and to characterize their functional features. Our results indicate that four TGTCNN motifs (TGTCTC, TGTCCC, TGTCGG, and TGTCTG) are associated with auxin up-regulation and two (TGTCGG, TGTCAT) with auxin down regulation, but to a lesser extent. The genes having some of these motifs in their regulatory regions showed time-specific auxin response. Functional annotation of auxin up- and down-regulated genes also revealed GO terms specific for the auxin-regulated genes with certain TGTCNN variants in their promoters. Our results provide an idea that various TGTCNN motifs may play distinct roles in the auxin regulation of gene expression. PMID- 27122322 TI - Now you see me, now you don't: The case of a vanishing outflow gradient in a patient with hypertrophic cardiomyopathy. AB - Cardiogenic shock is well described in hypertrophic cardiomyopathy (HCM) as acute hemodynamic collapse can develop in the setting of acute worsening of left ventricular outflow tract (LVOT) obstruction. We present the case of a 60-year old man with drug refractory LVOT obstruction due to hypertrophic cardiomyopathy. On the evening prior to planned alcohol septal ablation, the patient presented in cardiogenic shock. Interestingly, his previously recorded LVOT gradients of 50 mm Hg at rest and 118 mm Hg at peak exercise were absent. With recovery of left ventricular function, significant left ventricular outflow obstruction returned. The patient then underwent successful septal reduction therapy. (c) 2016 Wiley Periodicals, Inc. PMID- 27122323 TI - Transparent and flexible high-performance supercapacitors based on single-walled carbon nanotube films. AB - Transparent and flexible energy storage devices have garnered great interest due to their suitability for display, sensor and photovoltaic applications. In this paper, we report the application of aerosol synthesized and dry deposited single walled carbon nanotube (SWCNT) thin films as electrodes for an electrochemical double-layer capacitor (EDLC). SWCNT films exhibit extremely large specific capacitance (178 F g(-1) or 552 MUF cm(-2)), high optical transparency (92%) and stability for 10 000 charge/discharge cycles. A transparent and flexible EDLC prototype is constructed with a polyethylene casing and a gel electrolyte. PMID- 27122324 TI - Evaluation of Galleria mellonella larvae as an in vivo model for assessing the relative toxicity of food preservative agents. AB - Larvae of Galleria mellonella are widely used for evaluating the virulence of microbial pathogens and for measuring the efficacy of anti-microbial agents and produce results comparable to those that can be obtained using mammals. In this work, the suitability of using G. mellonella larvae to measure the relative toxicity of a variety of food preservatives was evaluated. The response of larvae to eight commonly used food preservatives (potassium nitrate, potassium nitrite, potassium sorbate, sodium benzoate, sodium nitrate, sodium chloride, sodium nitrite and sodium acetate) administered by feeding or by intra-haemocoel injection was measured. A significant correlation between the LD50 (R (2) = 0.8766, p = 0.0006) and LD80 (R (2) = 0.7629, p = 0.0046) values obtained due to oral or intra-haemocoel administration of compounds was established. The response of HEp-2 cells to the food preservatives was determined, and a significant correlation (R (2) = 0.7217, p = 0.0076) between the LD50 values of the compounds administered by feeding in larvae with the IC50 values of the compounds in HEp-2 cells was established. A strong correlation between the LD50 values of the eight food preservatives in G. mellonella larvae and rats (R (2) = 0.6506, p = 0.0156) was demonstrated. The results presented here indicate that G. mellonella larvae may be used as a model to evaluate the relative toxicity of food preservatives, and the results show a strong positive correlation to those obtained using established cell culture and mammalian models. PMID- 27122325 TI - [Reference value for micronucleus frequency of peripheral blood lymphocytes in general Chinese population: a method of Monte Carlo simulation]. AB - OBJECTIVE: To estimate the reference value for micronucleus frequency of peripheral blood lymphocytes in general Chinese population, and to guide the genotoxicity evaluation and risk analysis for populations exposed to environmental or occupational chemicals. METHODS: A fulltext search was performed in CNKI with the key words of "micronucleus" and "human", and PubMed was searched with "cytokinesis-block micronucleus","CBMN","humans", and "adults", to obtain the articles published at home and abroad from 2001 to 2014 in which cytokinesis block micronucleus (CBMN)assay was applied for micronucleus detection and populations not exposed to genotoxins were established as a control. Monte Carlo simulation was performed based on the micronucleus frequency, standard deviation, and sample size provided in these articles to calculate the micronucleus frequency for general population and to analyze the influence of sex, smoking, and drinking on micronucleus frequency. RESULTS: A total of 23 articles were included in the final analysis. The minimum mean micronucleus frequency was 0.390/00, and the maximum mean micronucleus frequency was 25.30/00. There were 1623 subjects in the control group in total (range 22~178, mean 70.6). Monte Carlo simulation was performed 100 times, and the mode of micronucleus frequency was 0 or 10/00; the values of P0, P25, P50 , P75, and P95 were 00/00, 10/00, 20/00~30/00, 50/00~60/00, and 140/00~190/00, respectively; the mean value was 4.360/00(range 4.220/00~4.570/00). With the application of one-sided 95% range(x+/-1.64 s), the upper limit of the range of reference value was calculated to be 13.460/00~14.750/00. CONCLUSION: The micronucleus frequency of peripheral blood lymphocytes in general Chinese population is 4.360/00, the interquartile range is 10/00~50/00 or 10/00~60/00, and the upper limit of reference value is 14.170/00. The factors of living area, sex, smoking, and drinking may influence micronucleus frequency. PMID- 27122326 TI - [Health status of thyroid and related influencing factors in seamen in Zhoushan, China]. AB - OBJECTIVE: To investigate the health status of the thyroid and related influencing factors in the seamen in Zhoushan, China. METHODS: A total of 136 coastal seamen (coastal group), 104 deep-sea seamen (deep-sea group), and 272 base staff (base group) who underwent physical examinations in 2014 were selected. Questionnaire survey and ultrasound were performed, and levels of thyroid hormone and urinary iodine were measured. RESULTS: Compared with the coastal group and the base group, the deep-sea group had a significantly higher rate of abnormal ultrasound findings (49.04% vs 30.88%/28.67%, P<0.05), as well as a significantly higher rate of abnormal serum free thyroxine (FT4) (25.00% vs 9.56%/6.25%, P<0.05). The logistic regression analysis showed that in the coastal group, the risk factors for thyroid abnormality on ultrasound were obesity shown by body mass index (BMI) (OR=2.55, 95% CI=1.13~4.13) and annual working time>6 months (OR=4.25, 95% CI=2.02~8.26) (both P<0.05); in the deep-sea group, the risk factors for thyroid abnormality on ultrasound were obesity shown by BMI (OR=3.45, 95% CI=1.28~7.02) and annual working time>6 months (OR=5.33, 95% CI=3.18~9.23) (both P<0.05). CONCLUSION: The thyroid abnormality in deep-sea seamen is caused by various reasons and is correlated with annual working time, working environment and area, and iodine nutritional status. PMID- 27122327 TI - [Changes in mRNA expression of p53 and related downstream genes in peripheral blood lymphocytes in workers occupationally exposed to arsenic]. AB - OBJECTIVE: To investigate the changes in mRNA expression of p53 and related downstream genes in peripheral blood lymphocytes in workers occupationally exposed to arsenic as well as its influencing factors, and to analyze the mechanism of genetic toxicity of arsenic. METHODS: With cluster random sampling, 79 workers from an arsenic smelting plant were selected as exposure group, and another 24 people without occupational exposure to arsenic were selected as control group. The relative mRNA expression of p53 and related downstream genes in the peripheral blood lymphocytes of the two groups was determined by quantitative realtime PCR. The levels of inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) in urine were determined by hydride generation-atomic absorption spectrometry. RESULTS: The exposure group had significantly higher levels of iAs, MMA, and DMA than the control group (P<0.01); the exposure group had significantly higher relative mRNA expression (2(-DeltaDeltaCt)) of p53 and four related downstream genes in peripheral blood lymphocytes than the control group (P<0.05); the relative mRNA expression of p53 and related downstream genes was positively correlated with each other (P<0.01), with a correlation coefficient greater than 0.4; the levels of arsenic compounds in urine were positively correlated with the relative mRNA expression of p53 and some of its downstream genes (P<0.05). CONCLUSION: The changes in mRNA expression of p53 and related downstream genes are closely related to the metabolic transformation of inorganic arsenic in workers occupationally exposed to arsenic, and it also plays an important role in genetic toxicity and carcinogenic effect in people exposed to arsenic. PMID- 27122328 TI - [Distribution of rubidium, cesium, beryllium, strontium, and barium in blood and urine in general Chinese population]. AB - OBJECTIVE: To investigate the distribution of rubidium (Rb), cesium (Cs), beryllium (Be), strontium (Sr), and barium (Ba) in blood and urine in general Chinese population. METHODS: A total of 18 120 subjects aged 6~60 years were enrolled from 24 regions in 8 provinces in Eastern, Central, and Western China from 2009 to 2010 based on the method of cluster random sampling. Questionnaire survey was conducted to collect the data on living environment and health status. Blood and urine samples were collected from these subjects, and the levels of Rb, Cs, Be, Sr, and Ba in these samples were determined by inductively coupled plasma mass spectrometry. The distribution of these elements in blood and urine in male or female subjects living in different regions was analyzed statistically. RESULTS: In the general Chinese population, the concentration of Be in the whole blood was below the detection limit (0.06 MUg/L); the geometric mean (GM) of Ba in the whole blood was below the detection limit (0.45 MUg/L), with the 95th percentile (P95)of 1.37 MUg/L; the GMs (95% CI)of Rb, Cs, and Sr in the whole blood were 2 374(2 357~2 392) MUg/L, 2.01 (1.98~2.05) MUg/L, and 23.5 (23.3~23.7) MUg/L, respectively; in males and females, the GMs (95%CI)of blood Rb, Cs, and Sr were 2 506 (2 478~2 533) MUg/L and 2 248 (2 227~2 270) MUg/L, 1.88 (1.83~1.94) MUg/L and 2.16 (2.11~2.20) MUg/L, and 23.4 (23.1~23.7) MUg/L and 23.6 (23.3~23.9) MUg/L, respectively(P<0.01, P>0.05, and P>0.05). In the general Chinese population, the GM of urine Be was below the detection limit (0.06 MUg/L), while the GMs (95%CI)of urine Rb, Cs, Sr, and Ba were 854 (836~873) MUg/L, 3.65 (3.56~3.74) MUg/L, 39.5 (38.4~40.6) MUg/L, and 1.10 (1.07~1.12) MUg/L, respectively; in males and females, the GMs (95%CI)of urine Rb, Cs, Sr, and Ba were 876 (849~904) MUg/L and 832 (807~858) MUg/L, 3.83 (3.70~3.96) MUg/L and 3.47 (3.35~3.60) MUg/L, 42.5 (40.9~44.2) MUg/L and 36.6 (35.1~38.0) MUg/L, and 1.15 (1.12~1.19) MUg/L and 1.04 (1.01~1.07) MUg/L, respectively (all P< 0.01). Correlation analyses showed that there were weak correlations between blood Rb and urine Rb (r=0.197)and between blood Sr and urine Sr (r=0.180), but a good correlation between blood Cs and urine Cs (r=0.487). CONCLUSION: The levels of Rb, Cs, Be, Sr, and Ba in the general Chinese population are similar to those reported in other countries, and there is a significant difference in the concentration of each element among the populations living in different regions, as well as significant differences in blood Rb, urine Rb, urine Cs, urine Sr, and urine Ba between males and females. PMID- 27122329 TI - [A multilevel model analysis of correlation between population characteristics and work ability of employees]. AB - OBJECTIVE: To analyze the correlation between population characteristics and work ability of employees with a multilevel model, to investigate the important influencing factors for work ability, and to provide a basis for improvement in work ability. METHODS: Work ability index (WAI)was applied to measure the work ability of 1686 subjects from different companies (n=6). MLwi N2.0 software was applied for two-level variance component model fitting. RESULTS: The WAI of employees showed differences between various companies (chi2=3.378 6, P=0.0660); working years was negatively correlated with WAI (chi2=38.229 2, P=0.0001), and the WAI of the employees with 20 or more working years was 1.63 lower than that of the employees with less than 20 working years; the work ability of manual workers was lower than that of mental-manual workers (chi2=8.2726, P=0.0040), and the work ability showed no significant difference between mental workers and mental-manual workers (chi2=2.086 0, P=0.148 7). CONCLUSION: From the perspective of probability, the multilevel model analysis reveals the differences in work ability of employees between different companies, and suggests that company, work type, and working years are the important influencing factors for work ability of employees. These factors should be improved and adjusted to protect or enhance the work ability of employees. PMID- 27122330 TI - [Study on the epidemilolgical characteristics of death among working population from 2010 to 2014 in Jinan, China]. PMID- 27122331 TI - [Noise hazard and hearing loss in workers in automotive component manufacturing industry in Guangzhou, China]. AB - OBJECTIVE: To investigate noise hazard and its influence on hearing loss in workers in the automotive component manufacturing industry. METHODS: Noise level in the workplace of automotive component manufacturing enterprises was measured and hearing examination was performed for workers to analyze the features and exposure levels of noise in each process, as well as the influence on hearing loss in workers. RESULTS: In the manufacturing processes for different products in this industry, the manufacturing processes of automobile hub and suspension and steering systems had the highest degrees of noise hazard, with over-standard rates of 79.8% and 57.1%, respectively. In the different technical processes for automotive component manufacturing, punching and casting had the highest degrees of noise hazard, with over-standard rates of 65.0% and 50%, respectively. The workers engaged in the automotive air conditioning system had the highest rate of abnormal hearing ability (up to 3.1%). CONCLUSION: In the automotive component manufacturing industry, noise hazard exceeds the standard seriously. Although the rate of abnormal hearing is lower than the average value of the automobile manufacturing industry in China, this rate tends to increase gradually. Enough emphasis should be placed on the noise hazard in this industry. PMID- 27122332 TI - [Application of risk grading and classification for occupational hazards in risk management for a shipbuilding project]. AB - OBJECTIVE: To investigate the application of risk grading and classification for occupational hazards in risk management for a shipbuilding project. METHODS: The risk management for this shipbuilding project was performed by a comprehensive application of MES evaluation, quality assessment of occupational health management, and risk grading and classification for occupational hazards, through the methods of occupational health survey, occupational health testing, and occupational health examinations. RESULTS: The results of MES evaluation showed that the risk of occupational hazards in this project was grade 3, which was considered as significant risk; Q value calculated by quality assessment of occupational health management was 0.52, which was considered to be unqualified; the comprehensive evaluation with these two methods showed that the integrated risk rating for this shipbuilding project was class D, and follow- up and rectification were needed with a focus on the improvement in health management. CONCLUSION: The application of MES evaluation and quality assessment of occupational health management in risk management for occupational hazards can achieve objective and reasonable conclusions and has good applicability. PMID- 27122333 TI - [An investigation of brucellosis in occupational population in Yuxi, China]. AB - OBJECTIVE: To investigate the epidemic status of brucellosis in the occupational population in Yuxi, China, and to develop effective prevention and control strategies. METHODS: Serological test was performed for 2320 employees involved in breeding, slaughtering, meat and dairy product processing, veterinary medicine, and sales in counties and districts where brucellosis was detected from 2008 to 2014 in Yuxi; pathogenic detection was performed for those in the occupational population who were suspected of brucellosis. RESULTS: The results of serological test showed that the infection rate of brucellosis reached 3.32% , and 15 cases of brucellosis had clinical symptoms. The employees involved in breeding had the highest infection rate (4.89%) (chi2=25.75, P<0.05). From 2008 to 2014, the infection rate of brucellosis was 0.37%~4.93% and tended to increase; 67.85% of the occupational population did not take personal protective measures and had a significantly higher infection rate than those who took personal protective measures (4.45% vs 0.94%; chi2=19.42, P<0.05). Among the 161 patients suspected of brucellosis, 42 cases were diagnosed as current brucellosis confirmed by laboratory pathogenic detection. CONCLUSION: The infection rate of brucellosis and the number of newly diagnosed cases tend to increase in the occupational population in Yuxi, and the employees involved in breeding are the major infected population. PMID- 27122334 TI - [Selection of decontaminants for experimental phenol burn wounds]. AB - OBJECTIVE: To investigate the effect of the decontaminants frequently used for phenol burn wounds. METHODS: The central part of the dorsal skin of adult male Sprague-Dawley rats were burned with 90% (W/V)phenol solution for 2 min, and water, 75% ethanol, polyethylene glycol 400 (PEG400), and Diphoterine were applied for decontamination for 15 min. The changes in wounds were observed, and the depth of skin burns at 24 hours after treatment and changes in six indicators of organ injuries, i.e., serum levels of total bilirubin (TBil), creatinine (Crea), alanine aminotransferase (ALT), alanine aminotransferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH), at 6 hours after treatment were compared. RESULTS: After phenol burns, the Diphoterine group had a significantly better effect and significantly lower degrees of skin and organ injuries compared with the water group (P<0.05). The effect of decontamination and degrees of skin and organ injuries were similar between the 75% ethanol group and the PEG400 group, and both groups had a better effect of decontamination compared with the water group; the 75% ethanol group had significantly lower serum levels of CK and LDH than the water group (P<0.05). Among these four groups, the water group had the worst effect, the deepest wounds, and the most severe organ injuries. CONCLUSION: After phenol burns, early decontamination with water has a poor effect, while Diphoterine can reduce the depth of phenol burns and the degrees of injuries of vital organs, and has a good effect of decontamination. PMID- 27122335 TI - [An accident of acute hydrogen sulfide poisoning when cleaning up a salted vegetables pool]. PMID- 27122336 TI - [The treatment experience on four cases acute aniline poisoning]. PMID- 27122337 TI - [Discussion on the treatment of increased intracranial pressure caused by the occupational acute 1,2-dichloroethane poisoning]. PMID- 27122338 TI - [One case of phenol burn]. PMID- 27122339 TI - [Determination of stannum in urine by graphite furnace atomic absorption spectrometry]. AB - OBJECTIVE: To establish the method of graphite furnace atomic absorption spectrometry for the measurement of stannum in urine with calcium nitrate as the matrix modifier. METHODS: Graphite tube was pretreated with calcium nitrate as the matrix modifier, the urine sample was diluted with 1% nitric acid and then direct injection was performed for these samples, and graphite furnace atomic absorption spectrometry was applied for measurement. RESULTS: The concentration of stannum in urine showed a good linear relationship within the range of 8.0~40.0 MUg/L, with a correlation coefficient of 0.9981. The minimum detectable concentration was 0.72 MUg/L, the degree of precision was 1.54%~6.69%, and the recovery rate was 99.23%~107.63%. CONCLUSION: This method can determine the content of stannum in urine accurately and rapidly, with a high sensitivity and a low cost. PMID- 27122340 TI - [Development and clinical application of paraquat test tube]. PMID- 27122341 TI - [Determination of ethylene glycol in workplace air by capillary column gas chromatography]. AB - OBJECTIVE: To establish the method of capillary column gas chromatography for determination of ethylene glycol in workplace air. METHODS: Ethylene glycol in workplace air was collected with silicone tube, desorbed with methanol, separated with FFAP (nitroterephthalic acid-modified polyethylene glycol)capillary column, and measured with flame ionization detector. RESULTS: The detection limit of ethylene glycol was 0.41 mg/L, the lower limit of quantification was 1.4 mg/L, the range of measurement was 1.4~163.9 mg/L, and the minimum detectable concentration was 0.3 mg/m3 (1.5 L of air was collected as the sample). This method had a good repeatability, the relative standard deviation was 1.4%~5.2%, the average desorption efficiency was 94.4%~101.7%, and the sampling efficiency was 99.2%~100%. The penetrating capacity of 200 mg silicone was higher than 6.9 mg, and the samples could be preserved for 14 days at room temperature. CONCLUSION: The method has a low detection limit, high accuracy, and good precision, which is feasible for determination of ethylene glycol in workplace air. PMID- 27122342 TI - [Determination of selenium in whole blood by microwave digestionatomic fluorescence spectrometry]. AB - OBJECTIVE: To establish a rapid, simple, and accurate method for measuring selenium in whole blood by atomic fluorescence spectrometry. METHODS: The whole blood samples were treated by microwave digestion and the acids were dispelled. After that the samples were pretreated with 50% hydrochloric acid as a reducing agent. Then the content of selenium in the pretreated samples was measured by hydride generation atomic fluorescence spectrometry. RESULTS: The calibration curve for selenium is linear in the range of 0~60 MUg/L (r=0.9999). The detection limit, relative standard deviation, and recovery rate were 0.133 MUg/L, 1.22%~2.08%, and 96.5%~101.8%, respectively. CONCLUSION: This method is simple, with less consumption of chemical reagents, less pollution, and enough accuracy and sensitivity for determination of selenium in whole blood samples. PMID- 27122343 TI - [Evaluation of measurement uncertainty of welding fume in welding workplace of a shipyard]. AB - OBJECTIVE: To evaluate the measurement uncertainty of welding fume in the air of the welding workplace of a shipyard, and to provide quality assurance for measurement. METHODS: According to GBZ/T 192.1-2007 "Determination of dust in the air of workplace-Part 1: Total dust concentration" and JJF 1059-1999 "Evaluation and expression of measurement uncertainty", the uncertainty for determination of welding fume was evaluated and the measurement results were completely described. RESULTS: The concentration of welding fume was 3.3 mg/m(3), and the expanded uncertainty was 0.24 mg/m(3). The repeatability for determination of dust concentration introduced an uncertainty of 1.9%, the measurement using electronic balance introduced a standard uncertainty of 0.3%, and the measurement of sample quality introduced a standard uncertainty of 3.2%. CONCLUSION: During the determination of welding fume, the standard uncertainty introduced by the measurement of sample quality is the dominant uncertainty. In the process of sampling and measurement, quality control should be focused on the collection efficiency of dust, air humidity, sample volume, and measuring instruments. PMID- 27122344 TI - [Determination of N acetyl-S-(2-carbamoylethyl)-cysteine in urine by high performance liquid chromatography]. AB - OBJECTIVE: To establish the method of high-performance liquid chromatography HPLC for the determination of N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) in urine. METHODS: After acid hydrolysis, AAMA in urine was converted into S-2-carboxyethyl cysteine (CEC). CEC reacted with the derivative reagent ophthalaldehyde and formed the derivative with strong fluorescence absorption. The HPLC-fluorescence detector was applied, with an excitation wavelength of 340 nm and an emission wavelength of 450 nm. RESULTS: Urinary AAMA demonstrated an excellent linearity in the range of 5.3~123.5 MUmol/L, with a correlation coefficient of 0.9994. The minimum detectable concentration was 0.1 MUmol/L (the volume of urine sample was 1.0 ml), the recovery of standard addition was 97.4%~104.2%, and the between-run precision was 2.3%~4.3%. The sample could be stored in the refrigerator for at least 7 days at a temperature of 4C. CONCLUSION: The method is simple, with a low cost, a high sensitivity, and good precision and accuracy, and the instrument and equipment commonly seen in laboratories are applied. Therefore, this method is worthy of wide application. PMID- 27122345 TI - [Introduction to NIOSH health hazard evalution program]. PMID- 27122346 TI - [Comparision of diagnostic criteria of occupational noiseinduced hearing loss in China and abroad]. PMID- 27122347 TI - [Status of study on self-management and behavior of patients with pneumoconiosis]. PMID- 27122348 TI - Elevated RNA expression of long non-coding HOTAIR promotes cell proliferation and predicts a poor prognosis in patients with diffuse large B cell lymphoma. AB - Diffuse large B cell lymphoma (DLBCL) is one of the most common types of malignancy worldwide. The lack of clear symptoms and early detection make it difficult to diagnose at an early stage, leading to poor prognosis of the patients. Long non-coding RNAs (lncRNAs) have come into focus for their important regulatory roles in fundamental biological processes, particularly in cancer initiation, development and progression. The aim of the present study was to investigate the expression of lncRNA Hox transcript antisense intergenic RNA (HOTAIR) in a cohort of patients with DLBCL to assess its clinical value and biological function in DLBCL. The reverse transcription-polymerase chain reaction was used to detect HOTAIR expression levels and cells were transfected with small interfering RNA to compare cell proliferation, cell cycle progression and apoptosis. Western blotting was also conducted to detect possible signaling pathways. It was first found that the expression levels of HOTAIR were upregulated in DLBCL tumor tissues and cell lines, compared with normal tissues and cells. In addition, HOTAIR was significantly correlated with tumor size, clinical stage, B symptoms and International Prognostic Index scores; and higher expression levels of HOTAIR were correlated with improved prognosis. Univariate and multivariate analyses verified that HOTAIR was a key independent predictive factor for DLBCL prognosis. Furthermore, it was revealed that the knockdown of the expression of HOTAIR led to growth inhibition, cell cycle arrest and apoptosis in vitro, possibly through the phosphoinositide 3-kinase/AKT/nuclear factor-kappaB pathway. These results suggested that HOTAIR may be regarded as a novel indicator of poor prognosis, and may serve as a potential target for gene therapy in the treatment of DLBCL. PMID- 27122349 TI - Determination of Kamlet-Taft parameters for selected solvate ionic liquids. AB - The normalised polarity E and Kamlet-Taft parameters of recently described solvate ionic liquids, composed of lithium bis(trifluoromethyl)sulfonimide (LiTFSI) in tri- () or tetraglyme () have been determined and compared to the parent glyme ( and ). We show that these solvate ionic liquids have a high polarity (, (E) = 1.03; , (E) = 1.03) and display very high electron pair accepting characteristics (, alpha = 1.32; , alpha = 1.35). Molecular dynamics simulations suggest that the chelated lithium cation is responsible for this observation. The relatively small hydrogen bond acceptor (beta) values for these systems (, beta = 0.41; , beta = 0.37) are thought to be due primarily to the TFSI anion, which is supplemented slightly by the glyme oxygen atom. In addition, these solvate ionic liquids are found to have a high polarisability (, pi* = 0.94; , pi* = 0.90). PMID- 27122350 TI - The Restorer-of-fertility-like 2 pentatricopeptide repeat protein and RNase P are required for the processing of mitochondrial orf291 RNA in Arabidopsis. AB - Eukaryotes harbor mitochondria obtained via ancient symbiosis events. The successful evolution of energy production in mitochondria has been dependent on the control of mitochondrial gene expression by the nucleus. In flowering plants, the nuclear-encoded pentatricopeptide repeat (PPR) superfamily proteins are widely involved in mitochondrial RNA metabolism. Here, we show that an Arabidopsis nuclear-encoded RNA-binding protein, Restorer-of-fertility-like PPR protein 2 (RFL2), is required for RNA degradation of the mitochondrial orf291 transcript via endonucleolytic cleavage of the transcript in the middle of its reading frame. Both in vivo and in vitro, this RNA cleavage requires the activity of mitochondrial proteinaceous RNase P, which is possibly recruited to the site by RFL2. The site of RNase P cleavage likely forms a tRNA-like structure in the orf291 transcript. This study presents an example of functional collaboration between a PPR protein and an endonuclease in RNA cleavage. Furthermore, we show that the RFL2-binding region within the orf291 gene is hypervariable in the family Brassicaceae, possibly correlated with the rapid evolution of the RNA recognition interfaces of the RFL proteins. PMID- 27122351 TI - Bright Field Microscopy to Detect Decoy Cells Due to BK Virus Infection in the Fresh and Unstained Urine Sediment in Kidney Allograft Recipients. AB - BACKGROUND: BK virus (BKV) may reactivate in kidney allograft recipients ultimately leading to BKV nephropathy and graft loss. Decoy cells (DCs) are one of the early marks of BKV reactivation, and these can be detected in the urine sediment. METHODS: A cohort of 102 kidney transplant patients was followed during months 3 and 6 after the transplant procedure. Urine samples were obtained to detect the presence of DC in the fresh and unstained urine sediment under bright field microscopy (BFM), in concomitance to the determination of the amount of BK viruria by qPCR. RESULTS: Decoy cells were found in 14.7% of patients (15/102). There was a strong agreement (P < 0.001) between qualitative DC detection by two experienced analysts and by qPCR. The positive predictive value, negative predictive value, specificity, and accuracy of BFM were 80%, 75%, 97%, and 75%, respectively. Test sensitivity was 16%. The comparative method was the qPCR. CONCLUSIONS: Despite its limited sensitivity, BFM of unstained urine sediment is an easily available, fast and cheap method to identify DCs in the population of kidney allograft recipients. The diagnostic performance of BFM on the hands of less experienced analysts deserves further investigation. PMID- 27122352 TI - 'Black Henna Tattoo': art or allergen? PMID- 27122353 TI - Whispering galleries and the control of artificial atoms. AB - Quantum computation using artificial-atoms, such as novel superconducting circuits, can be sensitively controlled by external electromagnetic fields. These fields and the self-fields attributable to the coupled artificial-atoms influence the amount of quantum correlation in the system. However, control elements that can operate without complete destruction of the entanglement of the quantum-bits are difficult to engineer. Here we investigate the possibility of using closely spaced-linear arrays of metallic-elliptical discs as whispering gallery waveguides to control artificial-atoms. The discs confine and guide radiation through the array with small notches etched into their sides that act as scatterers. We focus on pi-ring artificial-atoms, which can generate their own spontaneous fluxes. We find that the micro-discs of the waveguides can be excited by terahertz frequency fields to exhibit whispering-modes and that a quantum phase-gate composed of pi-rings can be operated under their influence. Furthermore, we gauge the level of entanglement through the concurrence measure and show that under certain magnetic conditions a series of entanglement sudden deaths and revivals occur between the two qubits. This is important for understanding the stability and life-time of qubit operations using, for example, a phase gate in a hybrid of quantum technologies composed of control elements and artificial-atoms. PMID- 27122356 TI - Dietary acculturation among the South-Asian Surinamese population in the Netherlands: the HELIUS study. AB - OBJECTIVE: To test Kocturk's model of dietary change among South-Asian Surinamese in the Netherlands. The model categorizes foods into staple, complementary and accessory foods and postulates that dietary change after migration begins with accessory foods while foods associated with ethnic identity (staple foods) change at a slower rate. DESIGN: Cross-sectional data from the HELIUS study. Dietary intake was assessed with an FFQ. Acculturation was based on social contacts and sense of belonging and was translated into four strategies of acculturation: assimilation, integration, separation and marginalization. Other indicators of acculturation included residence duration, age at migration and migration generation status. SETTING: Amsterdam, the Netherlands. SUBJECTS: Participants of Dutch (n 1456) and South-Asian Surinamese origin (n 968). RESULTS: Across all acculturation strategies, South-Asian Surinamese participants reported significantly higher intakes of rice (staple food) and chicken (complementary food) and significantly lower intakes of red meat and vegetables (complementary foods) and cookies and sweets (accessory food) than Dutch participants. Men, second-generation and assimilated South-Asian Surinamese were inclined towards Dutch foods such as potato, pasta and red meat. Accessory foods like fruits showed variation across acculturation strategies. CONCLUSIONS: Consistent with the Kocturk model, the intake of staple foods was stable among South-Asian Surinamese irrespective of acculturation strategy while the intake of accessory foods like fruit varied. Contrary to expectations, South-Asian Surinamese showed consistently high intakes of complementary foods like chicken and fish irrespective of acculturation strategy. Public health practitioners should take into consideration the complex and dynamic nature of dietary acculturation. PMID- 27122355 TI - The Genetics of Fetal Alcohol Spectrum Disorders. AB - The term "fetal alcohol spectrum disorders" (FASD) defines the full range of ethanol (EtOH)-induced birth defects. Numerous variables influence the phenotypic outcomes of embryonic EtOH exposure. Among these variables, genetics appears to play an important role, yet our understanding of the genetic predisposition to FASD is still in its infancy. We review the current literature that relates to the genetics of FASD susceptibility and gene-EtOH interactions. Where possible, we comment on potential mechanisms of reported gene-EtOH interactions. Early indications of genetic sensitivity to FASD came from human and animal studies using twins or inbred strains, respectively. These analyses prompted searches for susceptibility loci involved in EtOH metabolism and analyses of candidate loci, based on phenotypes observed in FASD. More recently, genetic screens in animal models have provided an additional insight into the genetics of FASD. Understanding FASD requires that we understand the many factors influencing phenotypic outcome following embryonic EtOH exposure. We are gaining ground on understanding some of the genetics behind FASD, yet much work remains to be carried out. Coordinated analyses using human patients and animal models are likely to be highly fruitful in uncovering the genetics behind FASD. PMID- 27122357 TI - A Tandem Catalyst with Multiple Metal Oxide Interfaces Produced by Atomic Layer Deposition. AB - Ideal heterogeneous tandem catalysts necessitate the rational design and integration of collaborative active sites. Herein, we report on the synthesis of a new tandem catalyst with multiple metal-oxide interfaces based on a tube-in tube nanostructure using template-assisted atomic layer deposition, in which Ni nanoparticles are supported on the outer surface of the inner Al2 O3 nanotube (Ni/Al2 O3 interface) and Pt nanoparticles are attached to the inner surface of the outer TiO2 nanotube (Pt/TiO2 interface). The tandem catalyst shows remarkably high catalytic efficiency in nitrobenzene hydrogenation over Pt/TiO2 interface with hydrogen formed in situ by the decomposition of hydrazine hydrate over Ni/Al2 O3 interface. This can be ascribed to the synergy effect of the two interfaces and the confined nanospace favoring the instant transfer of intermediates. The tube-in-tube tandem catalyst with multiple metal-oxide interfaces represents a new concept for the design of highly efficient and multifunctional nanocatalysts. PMID- 27122358 TI - Label-free detection of DNA single-base mismatches using a simple reflectance based optical technique. AB - Rapid and quantitative detection of the binding of nucleic acids to surface immobilized probes remains a challenge in many biomedical applications. We investigated the hybridization of a set of fully complementary and defected 12 base long DNA oligomers by using the Reflective Phantom Interface (RPI), a recently developed multiplexed label-free detection technique. Based on the simple measurement of reflected light intensity, this technology enables to quantify the hybridization directly as it occurs on the surface with a sensitivity of 10 pg mm(-2). We found a strong effect of single-base mismatches and of their location on hybridization kinetics and equilibrium binding. In line with previous studies, we found that DNA-DNA binding is weaker on a surface than in the bulk. Our data indicate that this effect is a consequence of weak nonspecific binding of the probes to the surface. PMID- 27122359 TI - An Internet-Based Physical Activity Intervention to Improve Quality of Life of Inactive Older Adults: A Randomized Controlled Trial. AB - BACKGROUND: Increasing physical activity is a viable strategy for improving both the health and quality of life of older adults. OBJECTIVE: The aim of this study was to assess if an Internet-based intervention aimed to increase physical activity was effective in improving quality of life of inactive older adults. In addition, we analyzed the effect of the intervention on quality of life among those participants who successfully reached their individually targeted increase in daily physical activity as indicated by the intervention program, as well as the dose-response effect of increasing physical activity on quality of life. METHODS: The intervention was tested in a randomized controlled trial and was comprised of an Internet program-DirectLife (Philips)-aimed at increasing physical activity using monitoring and feedback by accelerometry and feedback by digital coaching (n=119). The control group received no intervention (n=116). Participants were inactive 60-70-year-olds and were recruited from the general population. Quality of life and physical activity were measured at baseline and after 3 months using the Research ANd Development 36-item health survey (RAND-36) and wrist-worn triaxial accelerometer, respectively. RESULTS: After 3 months, a significant improvement in quality of life was seen in the intervention group compared to the control group for RAND-36 subscales on emotional and mental health (2.52 vs -0.72, respectively; P=.03) and health change (8.99 vs 2.03, respectively; P=.01). A total of 50 of the 119 participants (42.0%) in the intervention group successfully reached their physical activity target and showed a significant improvement in quality of life compared to the control group for subscales on emotional and mental health (4.31 vs -0.72, respectively; P=.009) and health change (11.06 vs 2.03, respectively; P=.004). The dose-response analysis showed that there was a significant association between increase in minutes spent in moderate-to-vigorous physical activity (MVPA) and increase in quality of life. CONCLUSIONS: Our study shows that an Internet-based physical activity program was effective in improving quality of life in 60-70-year-olds after 3 months, particularly in participants that reached their individually targeted increase in daily physical activity. TRIAL REGISTRATION: Nederlands Trial Register: NTR 3045; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3045 (Archived by WebCite at http://www.webcitation.org/6fobg2sjJ). PMID- 27122360 TI - Protein malnutrition during pregnancy alters maternal behavior and anxiety-like behavior in offspring. AB - OBJECTIVE: The aim of this study was to evaluate the effects of protein malnutrition during pregnancy on maternal behavior, on the early behavior in pups by ultrasonic vocalizations (USVs) emission, and on the behavior of offspring in adulthood in an elevated T-maze. METHODS: Pregnant female rats were fed a normal protein-powdered diet (22% casein; control) or a low-protein (hypoproteic) diet (6% casein; protein restriction) during the first 2 weeks of pregnancy. On the fifth postpartum day (PND5), the number of USV was rated. On PND7, maternal behavior was assessed. Male offspring in adulthood were evaluated for behavioral performance in an elevated T-maze. RESULTS: Our results demonstrated that a hypoproteic diet during early pregnancy increased the maternal behavior, increased the number of USV by pups, and reduced the inhibitory avoidance responses in an elevated T-maze during adulthood. In addition, there was a reduction in weight gain of rats during pregnancy and of offspring during lactation. CONCLUSION: In conclusion, the data found in our study suggest that the increase in USV emitted by pups due to hypoproteic diet during pregnancy accentuated maternal behavior. In addition, an increase in maternal care promoted the reduction in anxiety-like behavior in adult male offspring. PMID- 27122361 TI - Topiramate for Treatment in Patients With Migraine and Epilepsy. AB - BACKGROUND: Antiepileptic drugs (AED) are often considered first line for monotherapy in treatment of patients with migraines, and also those with comorbid migraine and epilepsy. Topiramate, a newer generation AED, has broad mechanism of action and evidence of benefit in patients with either episodic or chronic migraine along with epilepsy, both generalized and focal. METHODS: Our goal is to review the relevant mechanisms of action along with any supportive evidence published to date on the use of topiramate (TPM) in patients with both migraine headache and epilepsy. CONCLUSIONS: There has been very little published to date on the use of TPM in patients diagnosed with both disorders. Despite this, TPM has been adopted as first line therapy in this patient population. Future studies investigating the effectiveness of this treatment strategy are warranted in order to determine the most effective use of this medication in patients diagnosed with migraine headaches and epilepsy. PMID- 27122362 TI - Oral pressure therapy (winx) for obstructive sleep apnea: a meta-analysis updating the systematic review. PMID- 27122363 TI - A three-step estimation procedure using local polynomial smoothing for inconsistently sampled longitudinal data. AB - Parametric mixed-effects models are useful in longitudinal data analysis when the sampling frequencies of a response variable and the associated covariates are the same. We propose a three-step estimation procedure using local polynomial smoothing and demonstrate with data where the variables to be assessed are repeatedly sampled with different frequencies within the same time frame. We first insert pseudo data for the less frequently sampled variable based on the observed measurements to create a new dataset. Then standard simple linear regressions are fitted at each time point to obtain raw estimates of the association between dependent and independent variables. Last, local polynomial smoothing is applied to smooth the raw estimates. Rather than use a kernel function to assign weights, only analytical weights that reflect the importance of each raw estimate are used. The standard errors of the raw estimates and the distance between the pseudo data and the observed data are considered as the measure of the importance of the raw estimates. We applied the proposed method to a weight loss clinical trial, and it efficiently estimated the correlation between the inconsistently sampled longitudinal data. Our approach was also evaluated via simulations. The results showed that the proposed method works better when the residual variances of the standard linear regressions are small and the within-subjects correlations are high. Also, using analytic weights instead of kernel function during local polynomial smoothing is important when raw estimates have extreme values, or the association between the dependent and independent variable is nonlinear. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27122364 TI - Intraoperative image-guided navigation system: development and applicability in 65 patients undergoing liver surgery. AB - BACKGROUND: Image-guided systems have recently been introduced for their application in liver surgery. We aimed to identify and propose suitable indications for image-guided navigation systems in the domain of open oncologic liver surgery and, more specifically, in the setting of liver resection with and without microwave ablation. METHOD: Retrospective analysis was conducted in patients undergoing liver resection with and without microwave ablation using an intraoperative image-guided stereotactic system during three stages of technological development (accuracy: 8.4 +/- 4.4 mm in phase I and 8.4 +/- 6.5 mm in phase II versus 4.5 +/- 3.6 mm in phase III). It was evaluated, in which indications image-guided surgery was used according to the different stages of technical development. RESULTS: Between 2009 and 2013, 65 patients underwent image-guided surgical treatment, resection alone (n = 38), ablation alone (n = 11), or a combination thereof (n = 16). With increasing accuracy of the system, image guidance was progressively used for atypical resections and combined microwave ablation and resection instead of formal liver resection (p < 0.0001). CONCLUSION: Clinical application of image guidance is feasible, while its efficacy is subject to accuracy. The concept of image guidance has been shown to be increasingly efficient for selected indications in liver surgery. While accuracy of available technology is increasing pertaining to technological advancements, more and more previously untreatable scenarios such as multiple small, bilobar lesions and so-called vanishing lesions come within reach. PMID- 27122365 TI - Growth, biomass allocation and photosynthetic responses are related to intensity of root severance and soil moisture conditions in the plantation tree Cunninghamia lanceolata. AB - We employed the warm temperate conifer Cunninghamia lanceolata (Lamb.) Hook. as a model of plantation forest species to investigate ecophysiological responses to root treatments (control (0%), and ~25, 50 or 75% of the initial root mass) under well-watered and water-limited conditions. Our results indicated that total root dry mass accumulation was negatively associated with the severity of root pruning, but there was evidence of multiple compensatory responses. The plants exhibited higher instantaneous and long-term (assessed by carbon isotope composition, delta(13)C) water-use efficiency in pruning treatments, especially under low water availability. Root pruning also increased the fine root/total root mass ratio, specific root length and fine root vitality in both water availability treatments. As a result of the compensatory responses, under well watered conditions, height, stem dry mass accumulation, leaf/fine root biomass ratio (L/FR), transpiration rate, photosynthetic capacity and photosynthetic nitrogen-use efficiency (EN) were the highest under 25% pruning. Yet, all these traits except L/FR and foliage nitrogen content were severely reduced under 75% pruning. Drought negatively affected growth and leaf gas exchange rates, and there was a greater negative effect on growth, water potential, gas exchange and EN when >25% of total root biomass was removed. The stem/aboveground mass ratio was the highest under 25% pruning in both watering conditions. These results indicate that the responses to root severance are related to the excision intensity and soil moisture content. A moderate root pruning proved to be an effective means to improve stem dry mass accumulation. PMID- 27122366 TI - Insulin increases sympathetic nerve activity in part by suppression of tonic inhibitory neuropeptide Y inputs into the paraventricular nucleus in female rats. AB - Following binding to receptors in the arcuate nucleus (ArcN), insulin increases sympathetic nerve activity (SNA) and baroreflex control of SNA via a pathway that includes the paraventricular nucleus of the hypothalamus (PVN). Previous studies in males indicate that the sympathoexcitatory response is mediated by alpha melanocyte stimulating hormone (alpha-MSH), which binds to PVN melanocortin type 3/4 receptors (MC3/4R). The present study was conducted in alpha-chloralose anesthetized female rats to test the hypothesis that suppression of inhibitory neuropeptide Y (NPY) inputs to the PVN is also involved. In support of this, blockade of PVN NPY Y1 receptors with BIBO 3304 (NPY1x), ArcN insulin nanoinjections, and PVN NPY1x followed by ArcN insulin each increased lumbar SNA (LSNA) and its baroreflex regulation similarly. Moreover, prior PVN injections of NPY blocked the sympathoexcitatory effects of ArcN insulin. Finally, PVN nanoinjections of the MC3/4R inhibitor SHU9119 prevented both the acute (15 min) and longer, more slowly developing (60 min), increases in LSNA in response to ArcN insulin. In conclusion, in females, ArcN insulin increases LSNA, in part, by suppressing tonic PVN NPY inhibition, which unmasks excitatory alpha-MSH drive of LSNA. Moreover, the steadily increasing rise in LSNA induced by ArcN insulin is also dependent on PVN MC3/4R. PMID- 27122367 TI - Ascending aorta of hooded seals with particular emphasis on its vasa vasorum. AB - The pressure-volume relationship in the ascending aorta ("windkessel") of the hooded seal was determined and the morphology of its vasa vasorum described in some detail. We found that the ascending aorta has a high compliance and can easily accommodate the entire stroke volume when the peripheral vascular resistance becomes much increased and maintain perfusion pressure during the much extended diastole and thereby reduce cardiac stroke work during diving. We also found that the 3- to 5-mm thick wall of the ascending aorta had a very elaborate vasa vasorum interna with a hitherto undescribed vascular structure that penetrates the entire vascular wall. If similar structures with similar importance for the nutrition of the wall of the vessel are found in humans, important implications for the understanding of pathological conditions, such as aneurisms, may be indicated. PMID- 27122368 TI - Divergent effects of ERalpha and ERbeta on fluid intake by female rats are not dependent on concomitant changes in AT1R expression or body weight. AB - Estradiol (E2) decreases both water and saline intakes by female rats. The ERalpha and ERbeta subtypes are expressed in areas of the brain that control fluid intake; however, the role that these receptors play in E2's antidipsogenic and antinatriorexigenic effects have not been examined. Accordingly, we tested the hypothesis that activation of ERalpha and ERbeta decreases water and saline intakes by female rats. We found a divergence in E2's inhibitory effect on intake: activation of ERalpha decreased water intake, whereas activation of ERbeta decreased saline intake. E2 decreases expression of the angiotensin II type 1 receptor (AT1R), a receptor with known relevance to water and salt intakes, in multiple areas of the brain where ERalpha and ERbeta are differentially expressed. Therefore, we tested for agonist-induced changes in AT1R mRNA expression by RT-PCR and protein expression by analyzing receptor binding to test the hypothesis that the divergent effects of these ER subtypes are mediated by region-specific changes in AT1R expression. Although we found no changes in AT1R mRNA or binding in areas of the brain known to control fluid intake associated with agonist treatment, the experimental results replicate and extend previous findings that body weight changes mediate alterations in AT1R expression in distinct brain regions. Together, the results reveal selective effects of ER subtypes on ingestive behaviors, advancing our understanding of E2's inhibitory role in the controls of fluid intake by female rats. PMID- 27122369 TI - Fatty acid-induced astrocyte ketone production and the control of food intake. AB - Obesity and Type 2 diabetes are major worldwide public health issues today. A relationship between total fat intake and obesity has been found. In addition, the mechanisms of long-term and excessive high-fat diet (HFD) intake in the development of obesity still need to be elucidated. The ventromedial hypothalamus (VMH) is a major site involved in the regulation of glucose and energy homeostasis where "metabolic sensing neurons" integrate metabolic signals from the periphery. Among these signals, fatty acids (FA) modulate the activity of VMH neurons using the FA translocator/CD36, which plays a critical role in the regulation of energy and glucose homeostasis. During low-fat diet (LFD) intake, FA are oxidized by VMH astrocytes to fuel their ongoing metabolic needs. However, HFD intake causes VMH astrocytes to use FA to generate ketone bodies. We postulate that these astrocyte-derived ketone bodies are exported to neurons where they produce excess ATP and reactive oxygen species, which override CD36 mediated FA sensing and act as a signal to decrease short-term food intake. On a HFD, VMH astrocyte-produced ketones reduce elevated caloric intake to LFD levels after 3 days in rats genetically predisposed to resist (DR) diet-induced obesity (DIO), but not leptin-resistant DIO rats. This suggests that, while VMH ketone production on a HFD can contribute to protection from obesity, the inherent leptin resistance overrides this inhibitory action of ketone bodies on food intake. Thus, astrocytes and neurons form a tight metabolic unit that is able to monitor circulating nutrients to alter food intake and energy homeostasis. PMID- 27122370 TI - Sulfate transporters involved in sulfate secretion in the kidney are localized in the renal proximal tubule II of the elephant fish (Callorhinchus milii). AB - Most vertebrates, including cartilaginous fishes, maintain their plasma SO4 (2-) concentration ([SO4 (2-)]) within a narrow range of 0.2-1 mM. As seawater has a [SO4 (2-)] about 40 times higher than that of the plasma, SO4 (2-) excretion is the major role of kidneys in marine teleost fishes. It has been suggested that cartilaginous fishes also excrete excess SO4 (2-) via the kidney. However, little is known about the underlying mechanisms for SO4 (2-) transport in cartilaginous fish, largely due to the extraordinarily elaborate four-loop configuration of the nephron, which consists of at least 10 morphologically distinguishable segments. In the present study, we determined cDNA sequences from the kidney of holocephalan elephant fish (Callorhinchus milii) that encoded solute carrier family 26 member 1 (Slc26a1) and member 6 (Slc26a6), which are SO4 (2-) transporters that are expressed in mammalian and teleost kidneys. Elephant fish Slc26a1 (cmSlc26a1) and cmSlc26a6 mRNAs were coexpressed in the proximal II (PII) segment of the nephron, which comprises the second loop in the sinus zone. Functional analyses using Xenopus oocytes and the results of immunohistochemistry revealed that cmSlc26a1 is a basolaterally located electroneutral SO4 (2-) transporter, while cmSlc26a6 is an apically located, electrogenic Cl(-)/SO4 (2-) exchanger. In addition, we found that both cmSlc26a1 and cmSlc26a6 were abundantly expressed in the kidney of embryos; SO4 (2-) was concentrated in a bladder-like structure of elephant fish embryos. Our results demonstrated that the PII segment of the nephron contributes to the secretion of excess SO4 (2-) by the kidney of elephant fish. Possible mechanisms for SO4 (2-) secretion in the PII segment are discussed. PMID- 27122371 TI - Role of aortic arch vascular mechanics in cardiovagal baroreflex sensitivity. AB - Cardiovagal baroreflex sensitivity (cvBRS) measures the efficiency of the cardiovagal baroreflex to modulate heart rate in response to increases or decreases in systolic blood pressure (SBP). Given that baroreceptors are located in the walls of the carotid sinuses (CS) and aortic arch (AA), the arterial mechanics of these sites are important contributors to cvBRS. However, the relative contribution of CS and AA mechanics to cvBRS remains unclear. This study employed sex differences as a model to test the hypothesis that differences in cvBRS between groups would be explained by the vascular mechanics of the AA but not the CS. Thirty-six young, healthy, normotensive individuals (18 females; 24 +/- 2 yr) were recruited. cvBRS was measured using transfer function analysis of the low-frequency region (0.04-0.15 Hz). Ultrasonography was performed at the CS and AA to obtain arterial diameters for the measurement of distensibility. Local pulse pressure (PP) was taken at the CS using a hand-held tonometer, whereas AA PP was estimated using a transfer function of brachial PP. Both cvBRS (25 +/- 11 vs. 19 +/- 7 ms/mmHg, P = 0.04) and AA distensibility (16.5 +/- 6.0 vs. 10.5 +/- 3.8 mmHg(-1) * 10(-3), P = 0.02) were greater in females than males. Sex differences in cvBRS were eliminated after controlling for AA distensibility (P = 0.19). There were no sex differences in CS distensibility (5.32 +/- 2.3 vs. 4.63 +/- 1.3 mmHg(-1) * 10(-3), P = 0.32). The present data demonstrate that AA mechanics are an important contributor to differences in cvBRS. PMID- 27122372 TI - Electrically Polarized Biomaterials. AB - Electrically polarized biomaterials and their interactions with the surrounding biological environment is important for understanding the host response, growth and inhibition of biological species as well as the long-term fate and performance of the implants. Polarized materials possess electrical charges at the surface due to polar or electret properties. As these surfaces are at the frontier of biological reactions understanding biological interactions at the interface with polarized biomaterials requires a convergence of understanding multiple disciplines. This article discusses progress that has taken place in the fields of surface and interface science, materials science and biomedical device engineering to obtain a better perspective of such interactions. PMID- 27122373 TI - Molecular crowding impacts the structure of apolipoprotein A-I with potential implications on in vivo metabolism and function. AB - The effect molecular crowding, defined as the volume exclusion exerted by one soluble inert molecule upon another soluble molecule, has on the structure and self-interaction of lipid-free apoA-I were explored. The influence of molecular crowding on lipid-free apoA-I oligomerization and internal dynamics has been analyzed using electron paramagnetic resonance (EPR) spectroscopy measurements of nitroxide spin label at selected positions throughout the protein sequence and at varying concentrations of the crowding agent Ficoll-70. The targeted positions include sites previously shown to be sensitive for detecting intermolecular interaction via spin-spin coupling. Circular dichroism was used to study secondary structural changes in lipid-free apoA-I imposed by increasing concentrations of the crowding agent. Crosslinking and SDS-PAGE gel analysis was employed to further characterize the role molecular crowding plays in inducing apoA-I oligomerization. It was concluded that the dynamic apoA-I structure and oligomeric state was altered in the presence of the crowding agent. It was also found that the C-terminal was slightly more sensitive to molecular crowding. Finally, the data described the region around residue 217 in the C-terminal domain of apoA-I as the most sensitive reporter of the crowding-induced self association of apoA-I. The implications of this behavior to in vivo functionality are discussed. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 683-692, 2016. PMID- 27122374 TI - Nicotine without smoke-putting electronic cigarettes in context. PMID- 27122375 TI - The Role of Angiogenesis in the Persistence of Chemoresistance in Epithelial Ovarian Cancer. AB - OBJECTIVE: Chemoresistance remains a major challenge in the treatment of ovarian cancer. As part of a survival mechanism, tumor cells have been shown to release proangiogenic factors, such as vascular endothelial growth factor (VEGF), through a mechanism that involves the upregulation of hypoxia-induced factor (HIF) 1alpha. The objective of this study was to compare the expression of VEGF and its receptors (R1 and R2) as well as HIF-1alpha in chemoresistant epithelial ovarian cancer (EOC) cells to their chemosensitive counterparts and determine their impact on angiogenesis. METHODS: Two human EOC cell lines, MDAH-2774 and SKOV-3, and their cisplatin- or taxotere-resistant counterparts were used. Total RNA and protein were subjected to real-time reverse transcriptase-polymerase chain reaction, immunoprecipitation/Western blot and enzyme-linked immunosorbent assay to evaluate the expression of VEGF, VEGF receptors (R1 and R2), and HIF-1alpha. Angiogenesis was assessed with an in vitro angiogenesis assay. Data were analyzed using independent Student t tests and chi-square. RESULTS: Both taxotere- and cisplatin-resistant MDAH-2774 and SKOV-3 EOC cell lines manifested a significant decrease in VEGF, VEGF receptors, HIF-1alpha messenger RNA, and protein levels as compared to their chemosensitive counterparts. There was a significant decrease in the number and thickness of polygon blood vessel formation in chemoresistant EOC cells compared to chemosensitive counterparts. CONCLUSION: Cisplatin- and taxotere-resistant EOC cells are characterized by lower VEGF, VEGF receptors, and HIF-1alpha, and decreased angiogenesis. These findings may indicate a decrease in drug delivery at the tumor site, hence allowing the persistence of chemoresistant EOC cells. PMID- 27122376 TI - Comparison of ESwab and Wound Fiber Swab Specimen Collection Devices for Use with Xpert SA Nasal Complete Assay. AB - Paired nasal swab specimens were collected from patients who were undergoing routine methicillin-resistant Staphylococcus aureus (MRSA) screening prior to elective cardiac or orthopedic procedures. Each patient was swabbed using a traditional wound fiber liquid Stuart swab and an ESwab device, a flocked swab with a modified liquid Amies microbiology transport medium. The two specimens were tested using the Cepheid Xpert SA Nasal Complete assay. Results demonstrated a 95.5% agreement between the ESwab and the FDA-cleared wound fiber swab collection device. PMID- 27122377 TI - Comparison of Culture-Based Methods for Identification of Colonization with Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus in the Context of Cocolonization. AB - Two screening methods to detect staphylococcal colonization in humans were compared. Direct plating to CHROMagar (BD Diagnostics) was compared to a broth preenrichment followed by plating to Baird-Parker agar. The broth-enrichment method was comparable to CHROMagar for methicillin-resistant Staphylococcus aureas (MRSA) detection, but the enrichment method was optimum for recovery of coagulase-positive Staphylococcus spp. PMID- 27122378 TI - Clinical Evaluation of the Luminex NxTAG Respiratory Pathogen Panel. AB - An evaluation of the Luminex NxTAG Respiratory Pathogen Panel was performed on 404 clinical respiratory specimens. Clinical sensitivities and specificities of the assay compared to those of the reference methods were 80.0% to 100.0% and 98.9% to 100.0%, respectively. Correct genotyping information was provided for 95.5% of influenza virus A specimens. The closed-tube format of the assay simplified the workflow and minimized carryover contamination. PMID- 27122379 TI - Multisite Evaluation of Cepheid Xpert Carba-R Assay for Detection of Carbapenemase-Producing Organisms in Rectal Swabs. AB - Rapid identification of patients who are colonized with carbapenemase-producing organisms (CPO) is included in multiple national guidelines for containment of these organisms. In a multisite study, we evaluated the performance of the Cepheid Xpert Carba-R assay, a qualitative diagnostic test that was designed for the rapid detection and differentiation of the blaKPC, blaNDM, blaVIM, blaOXA-48, and blaIMP-1 genes from rectal swab specimens. A double rectal swab set was collected from 383 patients admitted at four institutions (2 in the United States, 1 in the United Kingdom, 1 in Spain). One swab was used for reference culture (MacConkey broth containing 1 mg/liter of meropenem and subcultured to a MacConkey agar plate with a 10-MUg meropenem disk) and for sequencing of DNA obtained from carbapenem-nonsusceptible isolates for carbapenemase identification. The other swab was used for the Xpert Carba-R assay. In addition to the clinical rectal swabs, 250 contrived specimens (108 well-characterized CPO and 142 negative controls spiked onto negative rectal swabs) were tested. Overall, 149/633 (23.5%) samples were positive by the Xpert Carba-R assay. In 6 samples, multiple targets were detected (4 VIM/OXA-48, 1 IMP-1/NDM, and 1 NDM/KPC). The Xpert Carba-R assay detected 155 targets (26 IMP-1, 30 VIM, 27 NDM, 33 KPC, 39 OXA-48) within a time range of 32 to 48 min. The sensitivity, specificity, and positive and negative predictive values of the Xpert Carba-R assay compared to those of the reference culture and sequencing results were 96.6% (95% confidence interval [CI], 92.2% to 98.9%), 98.6% (95% CI, 97.1% to 99.4%), 95.3%, and 99.0%, respectively. The Cepheid Xpert Carba-R assay is an accurate and rapid test to identify rectal colonization with CPO, which can guide infection control programs to limit the spread of these organisms. PMID- 27122380 TI - Clinical Evaluation of the New High-Throughput Luminex NxTAG Respiratory Pathogen Panel Assay for Multiplex Respiratory Pathogen Detection. AB - A broad range of viral and bacterial pathogens can cause acute respiratory tract infection. For rapid detection of a broad respiratory pathogen spectrum, multiplex real-time PCR is ideal. This study evaluated the performance of the new Luminex NxTAG Respiratory Pathogen Panel (NxTAG-RPP) in comparison with the BioFire FilmArray Respiratory Panel (FA-RP) or singleplex real-time PCR as reference. A total of 284 clinical respiratory specimens and 3 influenza A/H7N9 viral culture samples were tested. All clinical specimens were processed and analyzed in parallel using NxTAG-RPP and the reference standard method. The H7N9 viral culture samples were tested using NxTAG-RPP only. Overall, the NxTAG-RPP demonstrated >=93% sensitivity and specificity for all respiratory targets except human coronavirus OC43 (HCoV-OC43) and HCoV-HKU1. The H7N9 virus was detected by the influenza A virus matrix gene target, while other influenza A virus subtyping gene targets in the panel remained negative. Complete concordance between NxTAG RPP and FA-RP was observed in 98.8% (318/322) of positive results (kappa = 0.92). Substantial agreement was found for most respiratory targets, but significant differences were observed in human metapneumovirus (P = 0.001) and parainfluenza virus type 3 (P = 0.031). NxTAG-RPP has a higher sample throughput than FA-RP (96 samples versus 1 sample per run) while the turnaround times for NxTAG-RPP and FA RP were 5 h (up to 96 samples) and 1 h (for one sample), respectively. Overall, NxTAG-RPP demonstrated good diagnostic performance for most respiratory pathogens. The high sample throughput with reasonable turnaround time of this new assay makes it a suitable multiplex platform for routine screening of respiratory specimens in hospital-based laboratories. PMID- 27122381 TI - Use of Shotgun Metagenome Sequencing To Detect Fecal Colonization with Multidrug Resistant Bacteria in Children. AB - Prevention of multidrug-resistant (MDR) bacterial infections relies on accurate detection of these organisms. We investigated shotgun metagenome sequencing for the detection of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE), and MDR Enterobacteriaceae Fecal metagenomes were analyzed from high-risk inpatients and compared to those of low-risk outpatients and controls with minimal risk for a MDR bacterial infection. Principal-component analysis clustered patient samples into distinct cohorts, confirming that the microbiome composition was significantly different between cohorts (P = 0.006). Microbial diversity and relative anaerobe abundance were preserved in outpatients compared to those in controls. Relative anaerobe abundance was significantly reduced in inpatients compared to that in outpatients (P = 0.006). Although the potential for MDR bacteria was increased in inpatients and outpatients compared to that in controls (P < 0.001), there was no difference between inpatients and outpatients. However, 9 (53%) inpatients had colonization with a MDR bacterium that was not identified by culture. Unlike culture, shotgun sequencing quantitatively characterizes the burdens of multiple MDR bacteria relative to all of the microbiota within the intestinal community. We propose consideration of key microbiome features, such as diversity and relative anaerobe abundance, in addition to the detection of MDR bacteria by shotgun metagenome sequencing as a novel method that might better identify patients who are at increased risk of a MDR infection. PMID- 27122382 TI - DISCOVERING PALLADINO'S MEDIUMSHIP. OTERO ACEVEDO, LOMBROSO AND THE QUEST FOR AUTHORITY. AB - In 1888, the spiritist Ercole Chiaia challenged Cesare Lombroso to go to Naples and study a brilliant though still unknown medium: Eusapia Palladino. At that time Lombroso turned down the challenge. However, in 1891 he became fascinated by the medium's phenomena. Despite the abundant literature on Palladino, there is still an episode that needs to be explored: in 1888, the Spanish doctor Manuel Otero Acevedo accepted the challenge rejected by Lombroso, spent three months in Naples studying the medium and invited the Italian psychiatrist to join his investigations. This unexplored episode serves to examine the role of scientific authority, testimony, and material evidence in the legitimization of mediumistic phenomena. The use Otero Acevedo made of the evidence he obtained in Naples reveals his desire to proclaim himself an authority on psychical research before other experts, such as Lombroso, Richet, and Aksakof. PMID- 27122383 TI - Costs incurred by family caregivers of patients with palliative care needs. PMID- 27122384 TI - The association between smoking status and hospital length of stay: evidence from a hospital-based cohort. AB - OBJECTIVES: Smoking is recognized as one of the main preventable causes of mortality and morbidity that imposes a high financial burden on healthcare systems and society. This study aimed to examine the association between smoking status and hospital length of stay (LOS) among patients with lung cancer (LC), chronic obstructive pulmonary disease (COPD) and ischemic heart diseases (IHD) in Iran in 2014. METHODS: A total of 1271 patients (415 LC patients, 427 COPD patients and 429 IHD patients) were included in the study. Data on age, sex, insurance status and LOS was extracted from the patients' medical records and smoking status was obtained from the patients using telephone survey. The LOS among current smokers, former smokers, and nonsmokers was compared using a zero truncated poisson regression. Analysis was done using STATA v.12. RESULTS: The mean LOS for current smokers, former smokers and nonsmokers was 9.4+/-8.4, 7.3 +/ 5.3 and 6.02+/-5.05 days, respectively. The unadjusted and adjusted probabilities of LOS for current smokers and former smokers were 56% and 21% and 48% and 15% higher, respectively, than when compared with the nonsmoker category. CONCLUSION: The study demonstrated longer LOS for the current and former smokers, contributing to the drain on large hospital resources in Iran. The results of the study provide useful information for health-policy makers that contribute to the planning and designing of smoking cessation interventions in this area. PMID- 27122386 TI - Why we love glycobiology. PMID- 27122387 TI - Translational glycobiology: Patient-oriented glycoscience research. PMID- 27122388 TI - Development of a real-time quantitative RT-PCR to detect REV contamination in live vaccine. AB - Based on the published Avian reticuloendotheliosis virus (REV) whole genome sequence, primers and TaqMan probes were designed and synthesized, and the TaqMan probe fluorescence real-time quantitative RT-PCR (qRT-PCR) method for detecting the REV pol gene was established by optimizing the reaction conditions. Sensitivity analysis showed that the qRT-PCR method had a sensitivity that was 1,000-fold higher than conventional PCR. Additionally, no amplification signals were obtained when we attempted to detect DNA or cDNA of ALV-A/B/J, MDV, CIAV, IBDV, ARV, NDV, AIV, or other viruses, suggesting a high specificity for our method. Various titers of REV were artificially "spiked" into the FPV and MDV vaccines to simulate REV contamination in attenuated vaccines to validate this qRT-PCR method. Our findings indicated that this qRT-PCR method could detect REV contamination at a dose of 1 TCID50/1,000 feathers, which was 10,000-fold more sensitive than the regular RT-PCR detection (10(4) TCID50/1000 feathers). PMID- 27122389 TI - Early Parental Adaptation, Prenatal Distress, and High-Risk Pregnancy. AB - OBJECTIVES: To examine the examined the effects of high risk pregnancy and prenatal distress on parental postnatal adaptation. METHODS: A sample of 111 expecting parents, consisting of 32 high risk pregnancy (HRP) mothers and 21 spouses and 36 matched low risk pregnancy (LRP) mothers and 22 spouses completed reports of depression symptoms (BDI) and pregnancy related concerns prenatally. At three months postpartum, parent-infant direct observations and reports of parenting alliance (PAI), stress (PSI-SF), satisfaction and efficacy (PSOC) were gathered. Data was analyzed with GLM multivariate analyses and the actor-partner interdependence model. RESULTS: Parents' prenatal BDI predicted postnatal parental stress. BDI and concerns predicted postnatal satisfaction, but only for mothers. Mother's concerns predicted low maternal and high paternal parenting alliance. Partner effect was found so that high concerns predicted high reports of parenting alliance by spouse. Mean-group differences were found between HRP and LRP during parent-infant observations, so that HRP parents displayed lower sensitivity and reciprocity. CONCLUSIONS: Prenatal distress, and to some degree high risk pregnancy, are risk factors that may interfere with the early formation of parent-infant relationship. Clinical implications of these findings are presented. PMID- 27122390 TI - Age and cellular composition influence overall survival in a collective of non immunocompromised patients with EBV-positive diffuse large B-cell lymphoma from a German lymphoma center. AB - We investigated 41 diffuse large B-cell lymphomas (DLBCL) diagnosed at one center harboring >=50% of latently Epstein-Barr virus (EBV)-infected neoplastic cells occurring in 34 patients aged >=50 years and in 7 patients younger than 50 years in the absence of any known immunodeficiency for the expression patterns of EBV latent and immediate-early proteins, for the differentiation stage of the neoplastic cells, the presence of cytogenetic alterations and a possible co infection with the human herpes virus (HHV)-8. Here, we show that EBV-positive DLBCLs rarely arise from naive and more frequently from post-germinal center B cells that often contain crippling immunoglobulin gene mutations. Most of the lymphomas did not exhibit breaks in the BCL2, BCL6, and MYC genes and none of the cases investigated contained HHV-8 sequences. Patients aged <50 years performed better than older ones while in patients aged >=50 years only the cellular composition had an impact on overall survival. PMID- 27122391 TI - The relation between polysomnography and subjective sleep and its dependence on age - poor sleep may become good sleep. AB - Women complain more about sleep than men, but polysomnography (PSG) seems to suggest worse sleep in men. This raises the question of how women (or men) perceive objective (PSG) sleep. The present study sought to investigate the relation between morning subjective sleep quality and PSG variables in older and younger women. A representative sample of 251 women was analysed in age groups above and below 51.5 years (median). PSG was recorded at home during one night. Perceived poor sleep was related to short total sleep time (TST), long wake within total sleep time (WTSP), low sleep efficiency and a high number of awakenings. The older women showed lower TST and sleep efficiency and higher WTSP for a rating of good sleep than did the younger women. For these PSG variables the values for good sleep in the older group were similar to the values for poor sleep in the young group. It was concluded that women perceive different levels of sleep duration, sleep efficiency and wake after sleep onset relatively well, but that older women adjust their objective criteria for good sleep downwards. It was also concluded that age is an important factor in the relation between subjective and objective sleep. PMID- 27122392 TI - Identification of a novel HLA-A allele, HLA-A*02:590, in a Korean individual. AB - A*02:590 differs from A*02:01:01:01 by a nucleotide substitution at codon 152 (GTG -> GCG) with amino change. PMID- 27122394 TI - Forensic Archaeological Recovery of a Large-Scale Mass Disaster Scene: Lessons Learned from Two Complex Recovery Operations at the World Trade Center Site. AB - In 2006, unexpected discoveries of buried World Trade Center (WTC) debris and human remains were made at the World Trade Center mass disaster site. New York City's Office of Chief Medical Examiner (OCME) was given the task of systematically searching the site for any remaining victims' remains. The subsequent OCME assessment and archaeological excavation conducted from 2006 until 2013, resulted in the recovery of over 1,900 victims' remains. In addition, this operation demonstrated the essential skills archaeologists can provide in a mass disaster recovery operation. The OCME excavation data illustrates some of the challenges encountered during the original recovery effort of 2001/2002. It suggests that when understood within the larger site recovery context, certain fundamental components of the original recovery effort, such as operational priorities and activities in effect during the original recovery, directly or indirectly resulted in unsearched deposits that contained human remains. PMID- 27122395 TI - SNP Miniplexes for Individual Identification of Random-Bred Domestic Cats. AB - Phenotypic and genotypic characteristics of the cat can be obtained from single nucleotide polymorphisms (SNPs) analyses of fur. This study developed miniplexes using SNPs with high discriminating power for random-bred domestic cats, focusing on individual and phenotypic identification. Seventy-eight SNPs were investigated using a multiplex PCR followed by a fluorescently labeled single base extension (SBE) technique (SNaPshot((r)) ). The SNP miniplexes were evaluated for reliability, reproducibility, sensitivity, species specificity, detection limitations, and assignment accuracy. Six SNPplexes were developed containing 39 intergenic SNPs and 26 phenotypic SNPs, including a sex identification marker, ZFXY. The combined random match probability (cRMP) was 6.58 * 10(-19) across all Western cat populations and the likelihood ratio was 1.52 * 10(18) . These SNPplexes can distinguish individual cats and their phenotypic traits, which could provide insight into crime reconstructions. A SNP database of 237 cats from 13 worldwide populations is now available for forensic applications. PMID- 27122396 TI - Next-Generation Sequencing of the Bacterial 16S rRNA Gene for Forensic Soil Comparison: A Feasibility Study. AB - Soil has the potential to be valuable forensic evidence linking a person or item to a crime scene; however, there is no established soil individualization technique. In this study, the utility of soil bacterial profiling via next generation sequencing of the 16S rRNA gene was examined for associating soils with their place of origin. Soil samples were collected from ten diverse and nine similar habitats over time, and within three habitats at various horizontal and vertical distances. Bacterial profiles were analyzed using four methods: abundance charts and nonmetric multidimensional scaling provided simplification and visualization of the massive datasets, potentially aiding in expert testimony, while analysis of similarities and k-nearest neighbor offered objective statistical comparisons. The vast majority of soil bacterial profiles (95.4%) were classified to their location of origin, highlighting the potential of bacterial profiling via next-generation sequencing for the forensic analysis of soil samples. PMID- 27122398 TI - Blind Detection of Region Duplication Forgery Using Fractal Coding and Feature Matching. AB - Digital image forgery detection is important because of its wide use in applications such as medical diagnosis, legal investigations, and entertainment. Copy-move forgery is one of the famous techniques, which is used in region duplication. Many of the existing copy-move detection algorithms cannot effectively blind detect duplicated regions that are made by powerful image manipulation software like Photoshop. In this study, a new method is proposed for blind detecting manipulations in digital images based on modified fractal coding and feature vector matching. The proposed method not only detects typical copy move forgery, but also finds multiple copied forgery regions for images that are subjected to rotation, scaling, reflection, and a mixture of these postprocessing operations. The proposed method is robust against tampered images undergoing attacks such as Gaussian blurring, contrast scaling, and brightness adjustment. The experimental results demonstrated the validity and efficiency of the method. PMID- 27122397 TI - Screening Test for Shed Skin Cells by Measuring the Ratio of Human DNA to Staphylococcus epidermidis DNA. AB - A novel screening method for shed skin cells by detecting Staphylococcus epidermidis (S. epidermidis), which is a resident bacterium on skin, was developed. Staphylococcus epidermidis was detected using real-time PCR. Staphylococcus epidermidis was detected in all 20 human skin surface samples. Although not present in blood and urine samples, S. epidermidis was detected in 6 of 20 saliva samples, and 5 of 18 semen samples. The ratio of human DNA to S. epidermidisDNA was significantly smaller in human skin surface samples than in saliva and semen samples in which S. epidermidis was detected. Therefore, although skin cells could not be identified by detecting only S. epidermidis, they could be distinguished by measuring the S. epidermidis to human DNA ratio. This method could be applied to casework touch samples, which suggests that it is useful for screening whether skin cells and human DNA are present on potential evidentiary touch samples. PMID- 27122399 TI - Reliable Gait Recognition Using 3D Reconstructions and Random Forests - An Anthropometric Approach. AB - Photogrammetric measurements of bodily dimensions and analysis of gait patterns in CCTV are important tools in forensic investigations but accurate extraction of the measurements are challenging. This study tested whether manual annotation of the joint centers on 3D reconstructions could provide reliable recognition. Sixteen participants performed normal walking where 3D reconstructions were obtained continually. Segment lengths and kinematics from the extremities were manually extracted by eight expert observers. The results showed that all the participants were recognized, assuming the same expert annotated the data. Recognition based on data annotated by different experts was less reliable achieving 72.6% correct recognitions as some parameters were heavily affected by interobserver variability. This study verified that 3D reconstructions are feasible for forensic gait analysis as an improved alternative to conventional CCTV. However, further studies are needed to account for the use of different clothing, field conditions, etc. PMID- 27122400 TI - The Effects of Soil Texture on the Ability of Human Remains Detection Dogs to Detect Buried Human Remains. AB - Despite technological advances, human remains detection (HRD) dogs still remain one of the best tools for locating clandestine graves. However, soil texture may affect the escape of decomposition gases and therefore the effectiveness of HDR dogs. Six nationally credentialed HRD dogs (three HRD only and three cross trained) were evaluated on novel buried human remains in contrasting soils, a clayey and a sandy soil. Search time and accuracy were compared for the clayey soil and sandy soil to assess odor location difficulty. Sandy soil (p < 0.001) yielded significantly faster trained response times, but no significant differences were found in performance accuracy between soil textures or training method. Results indicate soil texture may be significant factor in odor detection difficulty. Prior knowledge of soil texture and moisture may be useful for search management and planning. Appropriate adjustments to search segment sizes, sweep widths and search time allotment depending on soil texture may optimize successful detection. PMID- 27122401 TI - A Retrospective Demographic and Clinicopathologic Review of Deaths Resulting from Minefield Explosions During Migrants' Attempts to Enter Greece from Turkey Between 1997 and 2008. AB - Until 2008, the easternmost land borders of the European Union (Greek-Turkish land zone) were planted with minefields spanning 11 km. Therefore, numerous fatalities occurred in peacetime as migrants attempted to avoid Greek border checks. Numerous fatal incidents (51) were detected inside the Greek minefields between 1997 and 2008. Determination of age, sex, time of death, and nationality were evaluated in every case. The injuries' anatomical dispersion, their severity, and the mechanism of death were examined in relation to the victims' position at the moment of the explosion. Data research indicated that all victims were male, aged 18-30 in their majority, crossing border minefields mainly during the night. Their distance and position in relation to the point of detonation was a key factor in the trauma localization and severity. This review highlights the devastating consequences of the residual mines during peacetime, a situation that continues to be a persistent international problem. PMID- 27122402 TI - Suicidal Drug Overdoses in New Mexico: A 5-year Retrospective Review. AB - To better understand the changing toxicology trends in suicidal drug overdoses in the setting of an increased national trend of multidrug overdoses, a retrospective review of electronic records from New Mexico's Office of the Medical Investigator database was performed between 2008 and 2012 to assess the drug type and current risk factors in suicide deaths. Information on demographics, circumstances, suicide risk factors, toxicology findings, and death certificates was collected and analyzed. Three hundred and forty-two suicide cases of suicide overdoses were identified. Decedents were predominantly female (61.8%). Scene investigation revealed risk factors including suicide ideation (47.4%), previous suicide attempts (38%), and suicide note (38%). Psychiatric illness was present in 72% of cases, with depression being the most common illness. Chronic pain was seen in 27.2% of cases. Most deaths were attributed to multiple drugs (76%). Utilizing the toxicology information will assist in creating public awareness and provide a framework to support targeted efforts to attempt to prevent future suicides. PMID- 27122403 TI - Brain Fluid Content Related to Body Position and Postmortem Interval - An Animal Model. AB - Adult male Sprague Dawley rats were euthanized and placed in a horizontal or vertical (head-down) position at room temperature, after which brain fluid content was measured by a moisture analysis technique at variable time points. No significant difference in brain fluid content was observed between horizontal and vertical postmortem positions. A significant increase in brain fluid content was demonstrated 3, 6, and 24 h after death, with maximal fluid content observed at 24 h. Specifically, the brain fluid content of control animals was 77.79 +/- 0.36%, increasing to 80.05 +/- 0.22% at 24 h (p < 0.0001). This study has demonstrated no significant differences in brain fluid content related to postmortem position, suggesting that a head-down position is not associated with increased brain fluid content or swelling. However, significant temporal increases in brain fluid content after death, most likely related to cerebral liquefaction, occur. PMID- 27122404 TI - Histological Changes in the Thyroid Gland in Cases of Infant and Early Childhood Asphyxia-A Preliminary Study. AB - A retrospective blinded study of thyroid gland histology was undertaken in 50 infants and young children aged from 1 to 24 months. Deaths were due to (i) suffocation (N = 7), hanging (4), wedging (3), and chest and/or neck compression (4), and (ii) SIDS (20), noncervical trauma (7), organic disease, (4) and drug toxicity (1). In the asphyxia group (N = 18), thyroid gland congestion ranged from 0 to 3+ with 39% of cases (7/18) having moderate/marked congestion. In three cases, focal aggregates of red blood cells (blood islands) were observed within the intrafollicular colloid. These deaths involved chest compression, chest and/or neck compression, and crush asphyxia in a vehicle accident, and all had facial petechiae. Only 22% of the 32 control cases (7/32) had moderate/marked congestion with no blood islands being identified (p < 0.05). Blood islands within the thyroid gland may be caused by congestion associated with crushing or compression and may provide supportive evidence for this diagnosis. PMID- 27122405 TI - Incidence of Low Body Mass Index in the Elderly in Forensic Cases-A Possible Marker for Frailty Syndrome? AB - Diagnosing frailty syndrome at autopsy may be difficult if no adequate clinical history is provided. As low body mass index (BMI) may be associated with frailty in the elderly, the following study was undertaken to determine the percentage of medicolegal cases with BMIs < 18.5 in decedents aged over 75 years. Review was undertaken over three time periods: January to December 1986, January to December 2006, and January to December 2012. In 1986, 16% (15 of 93) of individuals aged >=75 years had BMIs < 18.5, in 2006, 15% (50 of 336), and in 2012, 13% (35 of 274). In no case was frailty syndrome mentioned. This study demonstrates that frailty syndrome appears to be an underappreciated diagnosis in forensic practice despite a significant percentage of elderly decedents (13-16% over a 27-year period) having low BMIs. Prospective assessment of this group is required to determine the incidence and contribution to mortality of frailty syndrome in a forensic context. PMID- 27122406 TI - Pig Organ Energy Loss Comparison Experiments Using BBs. AB - Torso models for ballistics research require that the mechanical properties of simulant materials must match the heterogeneous nature of tissues/organs within the human thorax/abdomen. A series of energy loss experiments were conducted on fresh porcine organs/tissues at room temperature and 37 degrees C, using steel 4.5 mm BBs fired from a Daisy((r)) brand air rifle. They were compared to FBI and NATO specification ordnance gelatin and a candidate surrogate material called Simulant "A". Two CED M2 chronographs measured BB velocity. The resulting energy loss was established using KE = 1/2 mv2 before and after target perforation. The combined results at room temperature and 37 degrees C were as follows: FBI specification gelatin was similar (p > 0.05) to heart and lung, spleen was similar to NATO specification gelatin, Simulant "A" was similar to hindquarter muscle, and hindquarter muscle, kidney, and spleen were similar to each other regarding energy retardation. These results can be used as a basis for the development of simulant materials to create an anatomically correct heterogeneous model. PMID- 27122407 TI - Molecular Autopsy of Desmosomal Protein Plakophilin-2 in Sudden Unexplained Nocturnal Death Syndrome. AB - Plakophilin-2 (PKP2) variants could produce a phenotype of Brugada syndrome (BrS), which seems to be most likely the same allelic disorder as some sudden unexplained nocturnal death syndrome (SUNDS). All coding regions of PKP2 gene in 119 SUNDS victims were genetically screened using PCR and direct Sanger sequencing methods. Three novel mutations (p.Ala159Thr, p.Val200Val, and p.Gly265Glu), one novel rare polymorphism (p.Thr723Thr), and eight reported polymorphisms were identified. A compound mutation (p.Ala159Thr and p.Gly265Glu) and a rare polymorphism (p.Thr723Thr) were found in one SUNDS case with absence of the cardiomyopathic features. The detected compound mutation identified in this first investigation of PKP2 genetic phenotype in SUNDS is regarded as the plausible genetic cause of this SUNDS case. The rare incidence of PKP2 mutation in SUNDS (1%) supports the previous viewpoint that SUNDS is most likely an allelic disorder as BrS. PMID- 27122408 TI - Associations between Exposure to Alienating Behaviors, Anxiety, and Depression in an Italian Sample of Adults. AB - The aim of this study was to examine associations between exposure to alienating behaviors (ABs) and anxiety and depression as mediated through psychological maltreatment and parental bonding in a sample of Italian adults in the community. Five hundred and nine adults were given a measure of exposure to ABs, the Baker Strategy Questionnaire; the Psychological Maltreatment Measure; the Parental Bonding Instrument; the State-Trait Anxiety Inventory-Y; and the Beck Depression Inventory-II. Exposure to ABs was associated with psychological maltreatment, which was associated with parental bonding, which was associated with each of the three mental health outcomes: depression, state anxiety, and trait anxiety. The authors conclude that exposure to ABs in childhood represents a risk factor for subsequent poor mental health. PMID- 27122409 TI - Among a German Sample of Forensic Patients, Previous Animal Abuse Mediates Between Psychopathy and Sadistic Actions. AB - In an attempt to explain the relationship between psychopathy and severe violent behavior, this study associates previous animal abuse, psychopathy, and sadistic acting in forensic patients. Two topics are addressed: (i) whether previous animal abuse can be identified by a patient's Psychopathy Checklist profile and (ii) whether animal abuse statistically mediates between psychopathy and sadistic acting. In a German forensic hospital, 60 patients were investigated. Animal abuse was assessed using face-to-face interviews and the Psychopathy Checklist: Screening Version (PCL:SV), and sadistic acting was identified by file records.Discriminant analysis separated previous animal abuse (10/60) by high adolescent antisocial behavior, superficiality, lack of remorse, lack of empathy, and grandiosity. The mediation from psychopathy to sadistic acting (6/60) through animal abuse was found to be complete.The results, although sample size is limited and base rate of animal abuse and sadistic acting are low, fit with a model suggestive of animal abuse as a causal step toward sadistic crimes. Animal abuse correlates with callous, unemotional traits, and a development of sadistic crimes. PMID- 27122410 TI - Characterization of Printing Inks Using DART-Q-TOF-MS and Attenuated Total Reflectance (ATR) FTIR. AB - The rise in improved and widely accessible printing technology has resulted in an interest to develop rapid and minimally destructive chemical analytical techniques that can characterize printing inks for forensic document analysis. Chemical characterization of printing inks allows for both discrimination of inks originating from different sources and the association of inks originating from the same source. Direct analysis in real-time mass spectrometry (DART-MS) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used in tandem to analyze four different classes of printing inks: inkjets, toners, offset, and intaglio. A total of 319 samples or ~ 80 samples from each class were analyzed directly on a paper substrate using the two methods. DART-MS was found to characterize the semi-volatile polymeric vehicle components, while ATR-FTIR provided chemical information associated with the bulk components of these inks. Complimentary data results in improved discrimination when both techniques are used in succession resulting in >96% discrimination for all toners, 95% for all inkjets, >92% for all offset, and >54% for all intaglio inks. PMID- 27122411 TI - A Novel Forensic Tool for the Characterization and Comparison of Printing Ink Evidence: Development and Evaluation of a Searchable Database Using Data Fusion of Spectrochemical Methods. AB - A searchable printing ink database was designed and validated as a tool to improve the chemical information gathered from the analysis of ink evidence. The database contains 319 samples from printing sources that represent some of the global diversity in toner, inkjet, offset, and intaglio inks. Five analytical methods were used to generate data to populate the searchable database including FTIR, SEM-EDS, LA-ICP-MS, DART-MS, and Py-GC-MS. The search algorithm based on partial least-squares discriminant analysis generates a similarity "score" used for the association between similar samples. The performance of a particular analytical method to associate similar inks was found to be dependent on the ink type with LA-ICP-MS performing best, followed by SEM-EDS and DART-MS methods, while FTIR and Py-GC-MS were less useful in association but were still useful for classification purposes. Data fusion of data collected from two complementary methods (i.e., LA-ICP-MS and DART-MS) improves the classification and association of similar inks. PMID- 27122412 TI - Evaluation of the Forensic Utility of Scanning Electron Microscopy-Energy Dispersive Spectroscopy and Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry for Printing Ink Examinations. AB - Improvements in printing technology have exacerbated the problem of document counterfeiting, prompting the need for analytical techniques that better characterize inks for forensic analysis and comparisons. In this study, 319 printing inks (toner, inkjet, offset, and Intaglio) were analyzed directly on the paper substrate using scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP MS). As anticipated, the high sensitivity of LA-ICP-MS pairwise comparisons resulted in excellent discrimination (average of ~ 99.6%) between different ink samples from each of the four ink types and almost 100% correct associations between ink samples known to originate from the same source. SEM-EDS analysis also resulted in very good discrimination for different toner and intaglio inks (>97%) and 100% correct association for samples from the same source. SEM-EDS provided complementary information to LA-ICP-MS for certain ink types but showed limited utility for the discrimination of inkjet and offset inks. PMID- 27122413 TI - Manners of Death in Drug-Related Fatalities in Florida. AB - To understand the mortality patterns among drug users and potential risk factors, we evaluated drug-related deaths reported to the Florida Medical Examiners Commission from 2001 to 2013, by substances, demographics, and manner of death. The annual drug-related fatalities increased by 57% from 2001 to 2013 (total n = 100,882); 51.8% were accidental, 7.9% homicide, 18.6% natural, and 19.6% suicide. The different manners of death exhibited distinct demographic profiles and drug composition. The gender gap was more prominent in homicide. Age >=55 years was more closely associated with natural death and suicide. Age <35 years and central nervous system (CNS) stimulants including amphetamines and cocaine showed higher relative risks for accidental death and homicide, whereas CNS depressants including benzodiazepines, carisoprodol, opioids, and zolpidem were more strongly associated with accidental death and/or suicide. The findings aid in identifying populations more vulnerable to drug-related deaths, developing targeted interventions and thereby improving efficiency of preventive efforts. PMID- 27122414 TI - Reliability of the Walker Cranial Nonmetric Method and Implications for Sex Estimation. AB - The cranial trait scoring method presented in Buikstra and Ubelaker (Standards for data collection from human skeletal remains. Fayetteville, AR: Arkansas Archeological Survey Research Series No. 44, 1994) and Walker (Am J Phys Anthropol, 136, 2008 and 39) is the most common nonmetric cranial sex estimation method utilized by physical and forensic anthropologists. As such, the reliability and accuracy of the method is vital to ensure its validity in forensic applications. In this study, inter- and intra-observer error rates for the Walker scoring method were calculated using a sample of U.S. White and Black individuals (n = 135). Cohen's weighted kappas, intraclass correlation coefficients, and percentage agreements indicate good agreement between trials and observers for all traits except the mental eminence. Slight disagreement in scoring, however, was found to impact sex classifications, leading to lower accuracy rates than those published by Walker. Furthermore, experience does appear to impact trait scoring and sex classification. The use of revised population-specific equations that avoid the mental eminence is highly recommended to minimize the potential for misclassifications. PMID- 27122415 TI - D5S818 Typing Discrepancy Between PowerPlex((r)) Fusion and Other STR Kits Including GlobalFiler((r)) Caused by a One-base Deletion in 31 Nucleotides Upstream of the Repeat Region. AB - Short tandem repeat (STR) typing is widely used in forensic investigation. When the same DNA sample is analyzed with different STR typing kits, a typing discrepancy is occasionally observed. In this study, we examined the cause of a typing discrepancy in a sample at D5S818 locus. This sample was designated as 10, 12 using Identifiler((r)) , Identifiler((r)) Plus, GlobalFiler((r)) , PowerPlex((r)) 16HS, and PowerPlex((r)) 18D, but as 9.3, 12 using PowerPlex((r)) Fusion. Sequencing results indicated that the shorter allele in the sample had a deletion (U31Tdel) at 31 nucleotides upstream of the repeat region (AGAT)10 . This deletion was located in the binding site of the published D5S818 forward primer in PowerPlex((r)) 16 and was only 9 and 11 nucleotides downstream of our estimated 5' end position of D5S818 forward primer in GlobalFiler((r)) and PowerPlex((r)) 18D, respectively. We also examined the effect of primer length on the heterozygous peak balance in this sample. PMID- 27122416 TI - Analytical Characterization of Erythritol Tetranitrate, an Improvised Explosive. AB - Erythritol tetranitrate (ETN), an ester of nitric acid and erythritol, is a solid crystalline explosive with high explosive performance. Although it has never been used in any industrial or military application, it has become one of the most prepared and misused improvise explosives. In this study, several analytical techniques were explored to facilitate analysis in forensic laboratories. FTIR and Raman spectrometry measurements expand existing data and bring more detailed assignment of bands through the parallel study of erythritol [(15) N4 ] tetranitrate. In the case of powder diffraction, recently published data were verified, and (1) H, (13) C, and (15) N NMR spectra are discussed in detail. The technique of electrospray ionization tandem mass spectrometry was successfully used for the analysis of ETN. Described methods allow fast, versatile, and reliable detection or analysis of samples containing erythritol tetranitrate in forensic laboratories. PMID- 27122417 TI - The Influence of Wood Grain on the Bullet's Ricochet Behavior. AB - When a bullet ricochets from wood, various parameters will influence its behavior. In this study, the influence of the wood grain on the ricochet angle (beta) and deflection angle (gamma) is assessed. Series of five .32 Auto bullets were fired at different angles of incidence (alpha) on boards of six wood types. The results confirm the previously shown effect that the mean beta-angles usually exceed alpha and increase when alpha increases. Overall, the maximum mean gamma occurs when the angle of wood grain (zeta), in relation to the plane of impact, lies between 30 degrees and 75 degrees but differs per combination of wood and alpha. The results show the inclination of gamma toward the left or right, depending on the bullets left or right rotation while also showing that the direction of zeta can enhance or counteract this effect considerably, especially when alpha is close to the critical ricochet angle. PMID- 27122418 TI - Homemade Heavy Caliber Rifles-Two Unusual Firearms. AB - Historically, in crimes involving heavy caliber rifles, only conventional factory made versions have been used. However, in recent years the number of homemade long-barreled rifles is increasing. The characteristics of two such firearms that have been submitted to the Turkish Criminal Laboratory are discussed here. When the main parts of the guns were examined in detail, it was noted that nearly all of the parts had been made carelessly, with several structural defects visible. It was determined that the homemade heavy caliber rifles were unfit for efficient use and it was possible that they could have seriously harmed the shooter had they been fired. The development of these kinds of gun and the possibility of their use spreading throughout the country in terrorist attacks could cause a serious threat to national security. PMID- 27122419 TI - Investigation of Ballistic Evidence through an Automatic Image Analysis and Identification System. AB - Automated firearms identification (AFI) systems contribute to shedding light on criminal events by comparison between different pieces of evidence on cartridge cases and bullets and by matching similar ones that were fired from the same firearm. Ballistic evidence can be rapidly analyzed and classified by means of an automatic image analysis and identification system. In addition, it can be used to narrow the range of possible matching evidence. In this study conducted on the cartridges ejected from the examined pistol, three imaging areas, namely the firing pin impression, capsule traces, and the intersection of these traces, were compared automatically using the image analysis and identification system through the correlation ranking method to determine the numeric values that indicate the significance of the similarities. These numerical features that signify the similarities and differences between pistol makes and models can be used in groupings to make a distinction between makes and models of pistols. PMID- 27122420 TI - A Comparison of Various Fixatives for Casting Footwear Impressions in Sand at Crime Scenes. AB - Footwear examination can provide an important link between the crime scene and the suspect. Casts have been taken from snow, soil, and sand substrates to assist with the examination and to accurately depict the impression. However, there has been some discrepancy on what kind of fixative, if any, should be used with impressions present in sand. This study tested four different fixatives on three sandy substrates. Eight gross characteristics were added to a boot sole, and thirty sand impressions were created in each substrate. Except for one control set that remained untreated, the impressions were treated with a fixative agent before casting. The ninety shoe casts were examined by a qualified footwear examiner and scored based on his ability to see the eight characteristics. The results indicated that pump-action hairspray was the most successful on play and construction sand, while beach sand impressions without any fixative scored highest. PMID- 27122421 TI - Refreshing the Aged Latent Fingerprints with Ionizing Radiation Prior to the Cyanoacrylate Fuming Procedure: A Preliminary Study. AB - One of the crucial factors determining the cyanoacrylate deposit quality over latent fingerprints appeared to be the extent of the humidity. This work focuses on the enhancement/refreshment of age-degraded latent fingerprints by irradiating the samples with UV, X-ray, or thermal neutrons prior to the cyanoacrylate (CA) fuming. Age degradation of latent fingerprints deposited on glass surfaces was examined through the decrease in the number of characteristic minutiae counts over time. A term "critical day" was introduced for the time at which the average number of identifiable minutiae definitions drops to one-half. Fingerprints older than their "critical day" were exposed to either UV, X-ray, or thermal neutrons. Identical reference samples were kept unexposed. All samples, both reference and irradiated, were developed during a single CA fuming procedure. Comparative latent fingerprint analysis showed that exposure to ionizing radiation enhances the CA fuming, yielding a 20-30% increase in average minutiae count. PMID- 27122422 TI - Comparison of Dimensional Accuracies Using Two Elastomeric Impression Materials in Casting Three-dimensional Tool Marks. AB - The purpose of this study was to evaluate two types of impression materials which were frequently used for casting three-dimensional tool marks in China, namely (i) dental impression material and (ii) special elastomeric impression material for tool mark casting. The two different elastomeric impression materials were compared under equal conditions. The parameters measured were dimensional accuracies, the number of air bubbles, the ease of use, and the sharpness and quality of the individual characteristics present on casts. The results showed that dental impression material had the advantage of special elastomeric impression material in casting tool marks in crime scenes; hence, it combined ease of use, dimensional accuracy, sharpness and high quality. PMID- 27122423 TI - Determination of the sequence of intersecting lines using Focused Ion Beam/Scanning Electron Microscope. AB - The aim of this study was to verify that the combination of focused ion beam (FIB) and scanning electron microscope/energy-dispersive X-ray (SEM/EDX) could be applied to determine the sequence of line crossings. The samples were transferred into FIB/SEM for FIB milling and an imaging operation. EDX was able to explore the chemical components and the corresponding elemental distribution in the intersection. The technique was successful in determining the sequence of heterogeneous line intersections produced using gel pens and red sealing ink with highest success rate (100% correctness). These observations show that the FIB/SEM was the appropriate instrument for an overall examination of document. PMID- 27122424 TI - An Examination of the Sequence of Intersecting Lines using Microspectrophotometry. AB - The potential of microspectrophotometry as a technique to determine the sequence of intersecting lines was examined. The technique was used to determine the sequence of heterogeneous line intersections produced using inkpad, stamp-pad ink and ballpoint pens, gel pens, fountain pens, laser and ink-jet printers. The study was carried out with an assumption that the peak characteristics of spectra from the point of intersection should correspond to the peak characteristics of pure ink which was executed later. According to spectral reflectance curves, microspectrophotometry was possible to determine whether the ink was above or below the inkpad/stamp-pad ink seals. In blind testing, microspectrophotometry technique results were directly compared to those obtained by five experienced forensic document examiners using optical microscopy regularly employed in casework. As the results obtained from the study were positive, microspectrophotometry technique was found to be very successful in determining the sequence of heterogeneous line intersections under some conditions. PMID- 27122425 TI - TOF-SIMS Analysis of Red Color Inks of Writing and Printing Tools on Questioned Documents. AB - Time-of-flight secondary ion mass spectrometry (TOF-SIMS) is a well-established surface technique that provides both elemental and molecular information from several monolayers of a sample surface while also allowing depth profiling or image mapping to be performed. Static TOF-SIMS with improved performances has expanded the application of TOF-SIMS to the study of a variety of organic, polymeric, biological, archaeological, and forensic materials. In forensic investigation, the use of a minimal sample for the analysis is preferable. Although the TOF-SIMS technique is destructive, the probing beams have microsized diameters so that only small portion of the questioned sample is necessary for the analysis, leaving the rest available for other analyses. In this study, TOF SIMS and attenuated total reflectance Fourier transform infrared (ATR-FTIR) were applied to the analysis of several different pen inks, red sealing inks, and printed patterns on paper. The overlapping areas of ballpoint pen writing, red seal stamping, and laser printing in a document were investigated to identify the sequence of recording. The sequence relations for various cases were determined from the TOF-SIMS mapping image and the depth profile. TOF-SIMS images were also used to investigate numbers or characters altered with two different red pens. TOF-SIMS was successfully used to determine the sequence of intersecting lines and the forged numbers on the paper. PMID- 27122426 TI - Storm-Related Postmortem Damage to Skeletal Remains. AB - In April 2011, human skeletons were exposed to heavy storms at the outdoor Anthropology Research Facility (ARF) in Knoxville, Tennessee. Of the approximate 125 skeletons at the ARF in April 2011, 30 donations exhibited postmortem damage that could be attributed to the storms. At least 20 of the affected donations exhibit postmortem damage clearly associated with hailstones due to the oval shape and similar small size of the defects observed. The irregular shape and larger size of other defects may be a product of other falling objects (e.g., tree branches) associated with the storms. Storm-related damage was observed throughout the skeleton, with the most commonly damaged skeletal elements being the scapula and ilium, but more robust elements (i.e., femora and tibiae) also displayed characteristic features of hailstone damage. Thus, hailstone damage should be considered when forensic practitioners observe unusual postmortem damage in skeletal remains recovered from the outdoor context. PMID- 27122427 TI - Analysis of Mitochondrial DNA from a Burned, Ninhydrin-Treated Paper Towel. AB - Contact-based evidence is likely to have limited quantities of DNA and may yield mixed profiles due to preexisting or contaminating DNA. In a recent arson investigation, a paper towel was collected and used as circumstantial evidence. The paper towel was partially burned and was likely set on fire with flammable liquid. As part of the investigation, the paper towel was treated with ninhydrin to visualize fingerprint evidence. Initial DNA analysis of two swabs was negative for short tandem repeat (STR) markers and revealed a mixture of mitochondrial DNA (mtDNA). Analysis of 13 additional cuttings yielded four more mixed profiles, but also two samples with a common single-source profile. The single-source mtDNA profile matched that of the primary suspect in the case. Thus, even if initial mtDNA analysis yields a mixed profile, a sampling strategy involving multiple locations can improve the chance of obtaining valuable single-source mtDNA profiles from compromised evidence in criminal casework. PMID- 27122428 TI - Meeting a Forensic Podiatry Admissibility Challenge: A Daubert Case Study. AB - This article is an introduction to the United States Supreme Court's standard of admissibility of forensic evidence and testimony at trial, known as the Daubert standard, with emphasis on how this standard applies to the field of forensic podiatry. The author, a forensic podiatrist, provided law enforcement with evidence tying a bloody sock-clad footprint found at the scene of a homicide to the suspect. In 2014, the author testified at a pretrial hearing, known as "a Daubert hearing," to address the admissibility of this evidence in court. This was the first instance of forensic podiatry being the primary subject of a Daubert hearing. The hearing resulted in the court ordering this evidence admissible. The expert's testimony contributed to the suspect's conviction. This article serves as a reference for forensic podiatrists and experts in similar fields that involve impression evidence, providing evidentiary standards and their impact on expert evidence and testimony. PMID- 27122429 TI - Mechanisms of Lethal Cerebrovascular Accidents in Turner Syndrome. AB - A case of intracerebral hemorrhage in Turner syndrome is reported with an analysis of possible causes of cerebrovascular accidents in this condition. A 42 year-old woman with known Turner syndrome died soon after hospital admission having been found unconscious at her home address. At autopsy, she showed typical features of Turner syndrome with short stature, webbing of the neck, underdeveloped breasts, and an increased carrying angle of the arm. Death was due to a large left-sided intracerebral hemorrhage extending from the left basal ganglia into the white matter of the frontal lobe and lateral ventricle. Cases of unexpected death in Turner syndrome may arise from occult cerebrovascular accidents which may be hemorrhagic or nonhemorrhagic. Associated features include hypertension, vascular malformations, accelerated atherogenesis, cystic medial necrosis, and moyamoya syndrome. The possibility of Turner syndrome should be considered in cases where there has been a lethal cerebrovascular event in a younger woman. PMID- 27122430 TI - Self-inflicted Firearm Discharge from Heating Using a Gas Burner. AB - A male in his 70s was found lying dead in the living room of his house. A gunshot entrance wound was observed in the left orbit, with a lead slug and wadding left in the skull, which exhibited fatal cranio-cerebral trauma. A cartridge had been discharged from a handmade launcher, or zip gun, that had been fixed to a spare gun barrel on a pipe chair, by heating the launcher from the side using a gas burner. The deceased had owned guns for hunting in the past and had returned the license, but he had retained a spare barrel and live cartridges at home. In this unique case of suicide, a zip gun was discharged by heating with a gas burner. PMID- 27122431 TI - Sudden Death Due to Undiagnosed Rheumatic Heart Disease in a Child. AB - We report the case of a 5-year-old boy who died from complications of rheumatic heart disease with atypical presentation. He was hospitalized for recent inflammatory and neurological symptoms. He was diagnosed with viral encephalitis. He died the day after he was discharged. The macroscopic autopsy findings were unremarkable. Histology revealed typical rheumatic heart disease. Neuropathology showed cerebral infarction due to an embolic event linked with the rheumatic valvulitis. The cause of death was determined as heart failure due to rheumatic heart disease secondary to an undiagnosed acute rheumatic fever. It is related to an autoimmune response to infection with group A streptococcus. It mainly affects children in developing countries. In our case, viral encephalitis was consistent with the medical history and the proper diagnosis was made on histological analysis. Forensic pathologists should consider this diagnosis facing a sudden unexpected death in childhood, even in industrialized countries. PMID- 27122432 TI - Skull and Encephalic Injuries Caused by Beach Umbrellas: Case Reports and Review of Literature. AB - This study reports two unusual cases of skull-encephalic injuries in bathers that were caused by violent impacts with beach umbrellas. The first case concerned a 36-year-old man who, while lying on a sun bed, was struck on his left temple by a beach umbrella, which had been blown away by a gust of wind. The second case concerned a six-year-old child who was struck on the right temporal region while he was playing on the sand. Both subjects died. A review of the literature was carried out. Various skull and brain injuries caused by several objects were found, but no injuries caused by beach umbrellas were detected. There were only cases of injuries caused by normal umbrellas. These cases showed that several objects can be responsible for traumas causing skull and brain injuries, therefore forensic investigation must be supplemented by circumstantial data. PMID- 27122433 TI - A Novel Forensic Investigation Applied to Bone Remains Exhumed near to Quirra Interforce Firing Range. AB - The need to implement novel techniques, able to support a causal link between exposure and pathology, has been emerged over the recent years. The application of scanning electron microscope coupled with probe X-ray microanalysis (by means of an energy-dispersive spectroscopy) has been developed by our research group for the bone remains investigation. It was aimed to testify the exposure to microsized and nanosized pollutions, due to military activities in the Quirra interforce firing range, of a Sardinian shepherd, died of acute leukemia. Metallic debris with a combustive morphology and with an oncogenic potential has been surely detected inside his bone marrow canal. This novel technique has proved to be able to bring to light a source of past exposure preserved over time within the bone marrow canal. It can be useful for postmortem analyses, delivering a new avant-garde approach to modern forensic science. PMID- 27122434 TI - Somnophilia and Sexual Abuse Using Vaginal Administration of Triazolam. AB - Somnophilia is a rare paraphilia, a form of sexual fetishism which is characterized by the desire to have sex with an unconscious human object who is unable to respond. To the author's knowledge, this is the first case study concerning somnophilic sexual abuse associated with vaginal administration of triazolam. The perpetrator video-recorded his sexual acts with two unconscious female victims with whom he also had normal sexual intercourse and who were unaware of his paraphilic activities. His Internet conversations with other persons whom he thought to be interested in somnophilic sex and his plans to kidnap a child were recorded by the police. It was evident that sex with an unconscious object played a specific fetishistic role for this man. He obviously used a combination of drugs mixed with alcoholic drinks to make his victims fall sleep and videotaped vaginal administration of triazolam used to deepen the victim's unconscious state. PMID- 27122435 TI - Homicidal Poisoning in China Using Several Anesthetic Drugs. AB - The authors describe a case of a well-designed homicidal poisoning in China. A male was treated with starvation, intravenous fluids and antibiotics while in the hospital for acute diarrhea. He suddenly suffered from shortness of breath and subsequently died. A forensic autopsy was carried out, and several specimens were collected for toxicological screening. Propofol was tentatively identified in the blood by GC-MS. Based on the presence of propofol in the blood, a suspect confessed that two other drugs, namely midazolam and vecuronium, were involved in this murder. Analytical drug quantification was then performed by GC-MS and LC MS/MS. Blood analysis revealed the following: propofol at 0.5 MUg/mL, midazolam at 0.098 MUg/mL, and vecuronium at 0.10 MUg/mL. These results suggest that the cause of death was respiratory depression due to the acute combined effect of several anesthetic drugs administered by the victim's companion. PMID- 27122436 TI - Forensic Analysis of Human Autopsy Tissue for the Presence of Polydimethylsiloxane (Silicone) and Volatile Cyclic Siloxanes using Macro FT-IR, FT-IR Spectroscopic Imaging and Headspace GC-MS. AB - This study describes effective and straightforward primary and secondary methods for the detection of silicone in human autopsy tissue. The primary method is polydimethylsiloxane (PDMS) specific and employs either macro-attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectroscopy for samples with a high PDMS concentration (relative to that of the matrix) or micro-FT-IR spectroscopic imaging in a reflection/absorption modality for samples with a low PDMS concentration. Although the secondary method is not PDMS specific, it employs headspace gas chromatography with mass spectrometric detection (HS/GC-MS) for the detection of low molecular weight volatile cyclic siloxanes (VCS), which are characteristic marker compounds for PDMS. Overall, the combined results from the primary and secondary analyses provide reliable evidence for the presence of silicone. PMID- 27122437 TI - Fatal Intoxication with Toluene Due to Inhalation of Glue. AB - Two cases of fatal intoxications with toluene due to glue sniffing are described. In case 1, the autopsy did not indicate cause of death, while in case 2, the cause of death was determined to possibly be due to mechanical asphyxia by drowning. As the decedents had a history of glue sniffing, toxicological analyses were performed. Using gas chromatography with flame ionization detector and gas chromatography/mass spectrometry (GC/MS) with headspace method, toluene was detected in biological samples. Toluene ranged from 3.81 to 20.97 MUg/g, with the highest concentrations observed in liver and brain (13.82-20.97 MUg/g) in both cases. Based upon this data, the cause of death in both cases was determined to be toluene poisoning. Toxicological investigations are extremely important and should be considered mandatory in all deaths thought to be due to volatile substance abuse, as well as all deaths that are thought to be due to poisoning in young people. PMID- 27122438 TI - Retraction: Suicide trends in Upper Egypt. PMID- 27122439 TI - Optimization of microwave-assisted extraction and pressurized liquid extraction of phenolic compounds from Moringa oleifera leaves by multiresponse surface methodology. AB - This work aims at studying the optimization of microwave-assisted extraction (MAE) and pressurized liquid extraction (PLE) by multi-response surface methodology (RSM) to test their efficiency towards the extraction of phenolic compounds from Moringa oleifera (M. oleifera) leaves. The extraction yield, total phenolic content (TPC), total flavonoid content (TF), DPPH scavenging method and trolox equivalent antioxidant capacity (TEAC) assay were considered as response variables while effects of extraction time, percentage of ethanol, and temperature were studied. Extraction time of 20 min, 42% ethanol and 158 degrees C were the MAE optimum conditions for achieving extraction yield of 26 +/- 2%, EC50 15 +/- 2 MUg/mL, 16 +/- 1 Eq Trolox/100 g dry leaf, 5.2 +/- 0.5 mg Eq quercetin/g dry leaf, and 86 +/- 4 mg GAE/g dry leaf. Regarding PLE, the optimum conditions that allowed extraction yield of 56 +/- 2%, EC50 21 +/- 3 MUg/mL, 12 +/- 2 mmol Eq Trolox/100 g dry leaf, 6.5 +/- 0.2 mg Eq quercetin/g dry leaf, and 59 +/- 6 mg GAE/g dry leaf were 128 degrees C, 35% of ethanol, and 20 min. PLE enabled the extraction of phenolic compounds with a higher number of hydroxyl type substituents such as kaempferol diglycoside and its acetyl derivatives and those that are sensitive to high temperatures (glucosinolates or amino acids) while MAE allowed better recoveries of kaempferol, quercetin, and their glucosides derivatives. PMID- 27122440 TI - A contact lens causing blood-stained tears. PMID- 27122441 TI - "Evaluating normative epistemic frameworks in medicine: EBM and casuistic medicine". AB - Since its inception in the early 1990s, evidence-based medicine (EBM) has become the dominant epistemic framework for Western medical practice. However, in light of powerful criticisms against EBM, alternatives such as casuistic medicine have been gaining support in both the medical and philosophical community. In the absence of empirical evidence in support of the claim that EBM improves patient outcomes, and in light of considerations that it is unlikely that such evidence will be forthcoming, another standard is needed to assess EBM against its alternatives. In this paper, I propose a set of criteria for this purpose based on Helen Longino's criteria for assessing the objectivity of a knowledge productive community. I then apply these criteria to assess EBM against a casuistic framework for medical knowledge. I argue that EBM's strict adherence to a hierarchical organization of knowledge can reasonably be expected to block it from fulfilling a high level of objectivity. A casuistic framework, on the other hand, because it emphasizes critical evaluation in conjunction with the flexibility of a case-based approach, could be expected to better facilitate a more optimal epistemic community. PMID- 27122442 TI - High Blood Pressure and Self-Reported Systemic Hypertension in Elderly Enrolled in the Family Health Strategy Program. AB - OBJECTIVE: This study aimed to determine the prevalence of high blood pressure (HBP), self-reported hypertension, and associated factors among in elderly enrolled in the Family Health Strategy (FHS) Program. METHOD: This is a cross sectional study with in elderly enrolled in the FHS Program of Campina Grande/Paraiba/Brazil. This study determined the prevalence of HBP and self reported hypertension and their associations with demographic, socioeconomic variables, lifestyle, and number of self-reported morbidities. Three blood pressure measurements were performed, and the average value was used for analysis. To control possible confounding factors, data were modeled by the method of linear models generalized with Poisson log modeling to determine prevalence ratios and confidence intervals. The SPSS 22.0 statistical application was used, and 5% significance level was adopted. RESULTS: High prevalence of HBP (80.9%) was observed, which was associated with the number of self-reported morbidities, both in the univariate and multivariate analyses. High prevalence of self-reported hypertension (66.4%) was also observed. In the final model, positive association between hypertension and demographic and socioeconomic variables and lifestyle was verified. DISCUSSION: Monitor hypertension should be a priority action given its association with genetic, social and behavioral conditions presented by individuals. PMID- 27122443 TI - Obesity and Sexuality Among Older Couples: Evidence From the National Social Life, Health, and Aging Project. AB - OBJECTIVE: We investigate whether obesity is associated with sexual activity, sexual frequency, and the range of sexual behaviors in heterosexual older couples. We assess to what extent associations between obesity and sexuality are explained by physical, psychological, and sexual health, and by relationship quality. METHOD: We use data from 1,698 older adults in 849 partnered dyads in the 2010-2011 wave of the National Social Life, Health, and Aging Project and conduct couple-level analysis featuring women's and men's characteristics. RESULTS: Women's obesity-particularly at severe levels-is negatively associated with coupled sexual activity, but the association is not mediated by hypothesized mediators. Men's obesity did not have any association with sexual activity. There was no significant difference between overweight and normal weight adults across all three sexuality measures. DISCUSSION: The growing number of older adults with high levels of body mass index, particularly women, may face certain difficulties in maintaining active sexual lives. PMID- 27122444 TI - The Influences of Daily Stressors on Morning Cortisol Levels in Midlife and Older Retirees: The Moderating Roles of Age and Gender. AB - OBJECTIVES: This study extends the field of retirement and health by examining the impacts of daily stressors on morning cortisol levels in 253 retirees between 55 and 75 years of age ( M = 66.80, SD = 4.96) and the moderating roles of age and gender. METHOD: Participants derived from the second wave of the Daily Diary Study portion of the National Survey of Midlife Development in the United States (MIDUS-II). Across eight consecutive evenings, participants completed telephone interviews about their daily experiences and provided saliva samples across 4 days. RESULTS: Findings from the multilevel models showed that in the context of navigating the day-to-day responsibilities, older retirees were at a greater risk for subsequent hypothalamic pituitary adrenal (HPA) dysregulation than younger retirees. DISCUSSION: Together, better identification of the associations between daily stressors and physiological functioning will help contribute to the knowledge on ways to promote greater quality of life in retirement. PMID- 27122445 TI - Discrete Choice Experiment Response Rates: A Meta-analysis. AB - This paper uses meta-regression analysis to test how aspects of discrete choice experiment (DCE) study design influence survey response rates. DCEs are a survey based method used to elicit preferences for health and health care and are prone to survey errors of coverage, sampling, non-response and measurement. However, research on DCE response rates is lacking. Our analysis is motivated by a social exchange theory of survey response. We find that DCE response rates are related to the survey's cognitive burden and the relevance to the surveyed population. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27122446 TI - 2D quasi-ordered nitrogen-enriched porous carbon nanohybrids for high energy density supercapacitors. AB - Two-dimensional (2D) quasi-ordered nitrogen-enriched porous carbon (QNPC) nanohybrids, with the characteristics of an ultrathin graphite nanosheet framework and thick quasi-ordered nitrogen-doped carbon cladding with a porous texture, have been synthesized via an in situ polymerization assembly method. In the synthesis, the expandable graphite (EG) is enlarged by an intermittent microwave method, and then aniline monomers are intercalated into the interlayers of the expanded EG with the assistance of a vacuum. Subsequently, the intercalated aniline monomers could assemble on the interlayer surface of the expanded EG, accompanied by the in situ polymerization from aniline monomers to polyaniline. Meanwhile, the expanded EG could be exfoliated to graphite nanosheets. By subsequent pyrolysis and activation processes, the QNPC nanohybrids could be prepared. As supercapacitor electrodes, a typical QNPC12-700 sample derived from the precursor containing an EG content of 12%, with a high level of nitrogen doping of 5.22 at%, offers a high specific capacitance of 305.7 F g(-1) (1 A g(-1)), excellent rate-capability and long-term stability. Notably, an extremely high energy density of 95.7 Wh kg(-1) at a power density of 449.7 W kg(-1) in an ionic liquid electrolyte can be achieved. The unique structural features and moderate heteroatom doping of the QNPC nanohybrids combines electrochemical double layer and faradaic capacitance contributions, which make these nanohybrids ideal candidates as electrode materials for high-performance energy storage devices. PMID- 27122447 TI - Three-dimensional CT for preoperative detection of the left gastric artery and left gastric vein in laparoscopy-assisted distal gastrectomy. AB - INTRODUCTION: We evaluated 3-D CT imaging for preoperative classification of the left gastric artery and vein in patients with early gastric cancer and estimated its clinical benefit. METHODS: Between April 2009 and March 2014, 279 patients underwent preoperative 3-D CT using a 64-row multi-detector CT scanner, followed by laparoscopy-assisted distal gastrectomy. The 3-D CT images of the arterial and portal phases were reconstructed and fused. The operative outcomes were compared between patients who had not undergone 3-D CT (2007-2008) and who had undergone 3 D CT (2009-2011). RESULTS: According to Adachi's classification, the numbers of type I, II, III, IV, V, and VI arterial patterns were 253, 15, 1, 3, 3, and 1, respectively. Three cases could not be classified. According to the Douglass classification, the left gastric vein flowed into the portal vein, splenic vein, junction of the portal vein and splenic vein, and left branch of the portal vein in 119, 111, 36, and 5 patients, respectively. The left gastric vein could not be visualized in six patients, and two patients could not be classified. In addition, the relation was absent for an Adachi type I vein and one of the "other" types of veins. The total operative time was significantly shorter with 3 D CT than without it (P = 0.01), and the degree of lymph-node dissection was significantly higher (P = 0.01). Inflammatory parameters and operative morbidity tended to decrease with 3-D CT. CONCLUSION: Three-dimensional CT is a useful modality to visualize the vessel anatomy around the stomach, and it improves clinical effectiveness and reduces the invasiveness of surgery. PMID- 27122448 TI - Comment on article: King-Devick test reference values and associations with balance measures in high school American football players. PMID- 27122449 TI - Author's response to "Response to recently published article regarding King Devick Test". PMID- 27122450 TI - Free breathing three-dimensional late gadolinium enhancement cardiovascular magnetic resonance using outer volume suppressed projection navigators. AB - PURPOSE: To develop a three-dimensional, free-breathing, late gadolinium enhancement (3D FB-LGE) cardiovascular magnetic resonance (CMR) technique, and to compare it with clinically used two-dimensional breath-hold LGE (2D BH-LGE). METHODS: The proposed 3D FB-LGE method consisted of inversion preparation, inversion delay, fat saturation, outer volume suppression, one-dimensional projection navigators, and a segmented stack of spirals acquisition. The 3D FB LGE and 2D BH-LGE scans were performed on 29 cardiac patients. Qualitative analysis and quantitative analysis (in patients with scar) were performed. RESULTS: No significant differences were noted between the 3D FB-LGE and 2D BH LGE data sets in terms of overall image quality score (2D: 4.69 +/- 0.60 versus 3D: 4.55 +/- 0.51, P = 0.46) and image artifact score (2D: 1.10 +/- 0.31 versus 3D: 1.17 +/- 0.38; P = 0.63). The average difference in fractional scar volume between the 3D and 2D methods was 1.9% (n = 5). Acquisition time was significantly shorter for the 3D FB-LGE over 2D BH-LGE by a factor of 2.83 +/- 0.77 (P < 0.0001). CONCLUSIONS: The 3D FB-LGE is a viable option for patients, particularly in acute settings or in patients who are unable to comply with breath-hold instructions. Magn Reson Med 77:1533-1543, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27122451 TI - Plasma and synovial fluid inflammatory cytokine profiles in primary knee osteoarthritis. AB - OBJECTIVE: The objective of this study is to compare inflammatory cytokine levels in primary knee osteoarthritis (OA) patients and healthy controls. METHODS: A total of 32 knee OA patients and 14 healthy controls were enrolled. A multiplex immunoassay was utilized for 10 cytokines in plasma and synovial fluid. RESULTS: Plasma IL-2, IL-4, and IL-6 concentrations were significantly greater in knee OA patients than controls. Moreover, both plasma IL-4 and IL-6 were positively correlated with the radiographic severity of knee OA. CONCLUSIONS: Plasma IL-4 and IL-6 may serve as biomarkers reflecting the severity of OA. PMID- 27122452 TI - Behavior Change Techniques Present in Wearable Activity Trackers: A Critical Analysis. AB - BACKGROUND: Wearable activity trackers are promising as interventions that offer guidance and support for increasing physical activity and health-focused tracking. Most adults do not meet their recommended daily activity guidelines, and wearable fitness trackers are increasingly cited as having great potential to improve the physical activity levels of adults. OBJECTIVE: The objective of this study was to use the Coventry, Aberdeen, and London-Refined (CALO-RE) taxonomy to examine if the design of wearable activity trackers incorporates behavior change techniques (BCTs). A secondary objective was to critically analyze whether the BCTs present relate to known drivers of behavior change, such as self-efficacy, with the intention of extending applicability to older adults in addition to the overall population. METHODS: Wearing each device for a period of 1 week, two independent raters used CALO-RE taxonomy to code the BCTs of the seven wearable activity trackers available in Canada as of March 2014. These included Fitbit Flex, Misfit Shine, Withings Pulse, Jawbone UP24, Spark Activity Tracker by SparkPeople, Nike+ FuelBand SE, and Polar Loop. We calculated interrater reliability using Cohen's kappa. RESULTS: The average number of BCTs identified was 16.3/40. Withings Pulse had the highest number of BCTs and Misfit Shine had the lowest. Most techniques centered around self-monitoring and self-regulation, all of which have been associated with improved physical activity in older adults. Techniques related to planning and providing instructions were scarce. CONCLUSIONS: Overall, wearable activity trackers contain several BCTs that have been shown to increase physical activity in older adults. Although more research and development must be done to fully understand the potential of wearables as health interventions, the current wearable trackers offer significant potential with regard to BCTs relevant to uptake by all populations, including older adults. PMID- 27122453 TI - [Multidisciplinary discrimination and comprehensive management of pulmonary hypertension]. PMID- 27122454 TI - [Expert Forum Interventional treatment in chronic thromboembolic pulmonary hypertension]. PMID- 27122455 TI - [Expression of PAI-2 mRNA in peripheral blood leucocytes and regulation by sGC activator in pulmonary hypertension]. AB - OBJECTIVE: To investigate the mRNA expression level of plasminogen activator inhibitor-2 (PAI-2) in peripheral blood leucocytes and regulation by soluble guanylate cyclase (sGC) activator in pulmonary hypertension. METHODS: The human pulmonary arterial smooth muscle cells were treated with sGC activator Cinaciguat. The mRNA and protein expression levels of PAI-2 were detected with Real-time PCR and Western blot. The fresh blood samples of 8 patients with pulmonary arterial hypertension (PAH) (collected at the China-Japan Friendship Hospital from November 2014 to March 2015), 16 patients with chronic thromboembolic pulmonary hypertension (CTEPH) (collected at the China-Japan Friendship Hospital from November 2014 to March 2015), 24 age- and gender- matched healthy controls (collected at Beijing Hospital in March 2015) were treated with Cinaciguat for 8 hours. Then RNA of peripheral leukocytes was extracted and performed with reverse transcription and Real-time PCR to detect the mRNA level of PAI-2, which was compared between healthy controls and patients with pulmonary hypertension, before and after the treatment of Cinaciguat. At last, the correlation of PAI-2 mRNA level and the clinic severity of pulmonary hypertension were identified. RESULTS: The mRNA and protein expression levels of PAI-2 were promoted by Cinaciguat in human pulmonary arterial smooth muscle cells. The baseline mRNA level of PAI-2 in peripheral leukocytes was significantly lower in PAH patients compared to the healthy controls (0.201+/ 0.152, 0.660+/-0.440, P=0.021). There was no significant difference in the mRNA expression level of PAI-2 between the CTEPH patients and controls (0.428+/-0.364, 0.769+/-0.682, P=0.152). After Cinaciguat treatment, the mRNA expression levels of PAI-2 were up-regulated in PAH patients and CTEPH patients (1.352+/-1.127, 1.203+/-1.008), there was no significant difference in the mRNA expression level of PAI-2 among the PAH patients, CTEPH patients and controls (P=0.130, P=0.534). The baseline mRNA level of PAI-2 was negative correlated with echocardiography estimated systolic pulmonary arterial pressure (sPAP) (r=-0.744, P=0.034). CONCLUSIONS: The mRNA expression level of PAI-2 is significantly down-regulated in peripheral blood leucocytes and up-regulated by sGC activator in pulmonary hypertension. PAI-2 could be used as potential biomarker of pulmonary vascular remodeling in PAH. PMID- 27122456 TI - [Clinical features of Takayasu arteritis patients with pulmonary hypertension due to pulmonary artery involvement]. AB - OBJECTIVE: To summarize the clinical features of Takayasu arteritis (TA) patients with pulmonary hypertension due to pulmonary artery involvement. METHODS: Ninety four TA patients with pulmonary artery involvement treated in Fuwai Hospital from Jun 1988 to Jun 2014 were retrospectively summarized. Patients were divided into two groups according to whether aorta and its main branches affected (APTA, n=48) or not (PTA, n=46). Clinical features and angiographic data were further analyzed. RESULTS: Of all the patients, male to female rate was 1?3.3, age ranged from 8 to 60 years with median age of 33.5 years when symptom onset. Main symptoms included dyspnea on exertion. Heart murmur and mid-systolic murmur in pulmonic area were commonly found by physical examination. All patients had pulmonary hypertension by echocardiographic examination. Angiographic data showed that multi-lobular and multi-segmental pulmonary branches were predominantly affected, followed by sub-segmental and peripheral branches. Both sides of pulmonary artery involvement were more common than one side involvement, while the right pulmonary arteries were more often affected than the left. Most of the clinical symptoms and signs between APTA group and PTA group were comparable. However, erythrocyte sedimentation rate and N-terminal pro-natriuretic peptide were significant higher in APTA group than that in PTA group when admission [14.0(5.0, 28.0) vs 8.5(3.0, 19.3) mm/1 h and (1 936+/-1 769) vs (1 627+/-1 153) ng/L, both P<0.05]. CONCLUSIONS: Dyspnea on exertion may be the main manifestation of TA with pulmonary artery involvement. All patients present with pulmonary hypertension and moderate to severe heart failure when symptom onset. PMID- 27122457 TI - [Association between OR2T3 gene and pulmonary arterial hypertension]. AB - OBJECTIVE: To explore the pathogenic genes of pulmonary arterial hypertension (PAH) and validate the association between OR2T3 gene and PAH. METHODS: Whole exome sequencing was performed in four patients and one healthy person as control in two pulmonary arterial hypertension pedigree; patient-specific variations were screened by bioinformatics methods and comparison between groups. To further analyze the association between these variations and PAH, Sanger sequencing was used to analyze the genotype of patient-specific variations of 30 patients with idiopathic PAH, 90 healthy people and 30 patients with chronic thromboembolic pulmonary hypertension. RESULTS: The preliminary findings of whole exome sequencing were 57 variations may be associated with PAH; Among them, there were 6 AG heterozygotes due to OR2T3rs148748995 in the 30 idiopathic PAH patients, while no G allele carrier was found in other healthy people of two pulmonary arterial hypertension pedigree (AI-1, AII-3, BII-1) and 90 normal control, and the difference was statistically significant (P<0.05). The variation also didn't exist in 30 chronic thromboembolic pulmonary hypertension patients. CONCLUSION: OR2T3 gene may be the pathogenic gene of PAH and OR2T3rs148748995 could have a role in the development of PAH. PMID- 27122458 TI - [Mutation screening of 433 families with Duchenne/Becker muscular dystrophy]. AB - OBJECTIVE: Mutation analysis of unrelated families with Duchenne/Becker muscular dystrophy (DMD/BMD) was performed to investigate the characteristic of DMD gene mutation, especially the distribution pattern of point mutation of DMD gene in Chinese population. METHODS: A total of 433 unrelated DMD/BMD families were collected at the Center of Prenatal Diagnosis of the First Affiliated Hospital of Zhengzhou University from March 2010 to December 2014. The deletions or duplications in 79 exons of DMD gene were screened using multiplex ligation dependent probe amplification (MLPA). Any single-exon deletion detected by MLPA was further validated by PCR amplification. In the 117 unrelated Chinese families in which large-scale deletions and duplications had been excluded by MLPA, the point mutation in 79 exons of DMD gene were tested in the propositus using next generation sequencing (NGS), and further verified the point mutation using Sanger sequencing. RESULTS: In the 433 unrelated DMD/BMD families, 316 families with DMD deletions/duplications were identified by MLPA. Out of 57 single-exon deletions detected by MLPA, 3 were found as point mutations by PCR and Sanger sequencing, including 2 nonsense mutation (c.1729G>T [p.Glu577X], c. 3346A>T [p.Lys1116X]) and 1 frame-shift mutation (c.8605_8606delGT [p.Val2869ThrfsX25]). Direct sequencing with Ion PGM and Sanger sequencing in 117 families with negative results in MLPA detected 92 different point mutations in 96 families, including 46 novel mutations, 42 previously reported ones, and 4 possible polymorphisms (rs189143447, rs202008454, rs200213555, rs187617705). The 46 novel mutations consisted of 16 nonsense mutations (c.100A>T [p.Lys34X], c. 1201C>T [p.Gln401X], c. 1707C>A [p.Cys569X], c. 1831G>T [p.Glu611X], c. 1912C>T [p.Gln638X], c. 2213C>G [p.Ser738X], c. 3673_3673delA [p.Ile1225X], c. 3774C>A [p.Cys1258X], c. 4858G>T [p.Glu1620X], c. 5764A>T [p.Lys1922X], c. 6035T>G [p.Leu2012X], c. 6408G>A [p.Trp2136X], c. 7717C>T [p.Gln2573X], c. 7864G>T [p.Glu2622X], c. 8184_8185insT [p.Lys2729X], c. 8215C>T [p.Gln2739X]), 5 missense mutations (c.139G>A [p.Gly47Arg], c. 238G>C [p.Ala80Pro], c. 335G>T [p.Trp112Leu], c. 804A>C [p.Leu268Phe], c. 1149G>T [p.Glu383Asp]), 6 splice-site mutations (c.2293 3C>A, c. 2380+ 1G>T, c. 3277-1G>C, c.4519-7A>G, c. 5740-15G>T, c. 7661-1G>C), 16 small deletions (c.688_688delA [p.Met230CysfsX14], c.1760_1791del32 [p.Thr587IlefsX37], c. 2271_2271delA [p.Asp774ThrfsX22], c. 2281_2285delGAAAA [p.Glu761SerfsX10], c. 2527_2527delG [p.Glu843SerfsX3], c. 3405_3405delC [p.Asn1135LysfsX18], c. 4450_4450delC [p.His1484ThrfsX14], c. 4770_4770delA [p.Thr1590ThrfsX5], c. 4937_4937delA [p.Glu1646GlyfsX11], c. 5253_5256delATTA [p.Lys1751LysfsX2], c. 5654_5654delA [p.Gln1885ArgfsX6], c. 7441_7441delG [p.Glu2481AsnfsX13], c. 7860_7860delC [p.Ile2620IlefsX18], c. 8668-8668delG /c.8668+ 1-8668+ 1delG, c. 9009_9009delC [p.Thr3003ThrfsX18], c. 9021_9021delT [p.Ile3007IlefsX14]), and 3 small insertions (c.305_306insG [p.Gly102GlyfsX4], c. 3116_3117insA [p.His1039GlufsX11], c. 9197_9198insATCTC [p.Ser3066SerfsX25]). And 87.4% (83/95) of the pathologic point mutations disrupted the translational reading frame (46 nonsense mutations, 24 frame-shift mutations, and 13 splice site mutations). CONCLUSIONS: Inexpensive and efficient genetic/prenatal diagnosis of DMD/BMD may be plausible by MLPA analysis, NGS, and Sanger sequencing. Most of the mutations identified in this study led to a predictable premature stop codon or splicing defects, resulting in defective function of dystrophin. PMID- 27122459 TI - [Impact of improvement of diabetes on survival after radical pancreatic resection in patients with pancreatic cancer and diabetes]. AB - OBJECTIVE: To explorer the effect of improvement of diabetes on survival after radical pancreatic resection in patients with pancreatic cancer and diabetes. METHODS: Seventy-three patients who underwent radical resection for pancreatic cancer at Ruijin Hospital (Shanghai, China) between July 2007 and December 2011 and had preoperative diabetes were retrospectively analyzed. Clinical characteristics and overall postoperative survival were compared between patients with controlled/uncontrolled diabetes. Among patients with uncontrolled diabetes, comparison was made in clinical characteristics and overall postoperative survival between patients with long-term (>=2 years) diabetes and those with new onset (<2 years) diabetes. RESULTS: Controlled diabetes after radical pancreatic resection was observed in 38.4% (28/73) in the patients with pancreatic cancer and diabetes. The median follow-up time was 44.5 months (95CI: 31.7-57.2 months). Patients in whom diabetes was controlled had well-differentiated tumors and longer overall survival compared to patients with uncontrolled diabetes [median overall survival (95%CI) 41.0 (34.2-47.7) months vs 17.0 (14.8-19.2) months, P<0.001]. Among the 45 patients with uncontrolled diabetes, there was no differences in clinic characteristic and overall survival between new-onset (n=21) and long-term diabetes (n=24) [median overall survival (95%CI): 17.8 (15.7 20.1) months vs 15.8 (10.5-21.1) months, P=0.198]. CONCLUSION: Good postoperative control of diabetes after radical pancreatic resection in patients with pancreatic cancer and diabetes may predict favorable survival. PMID- 27122460 TI - [Analysis of clinical predictive factors of pathologic complete response after neoadjuvant chemoradiotherapy in rectal cancer]. AB - OBJECTIVE: To evaluate the clinical predictive factors associated with pathologic complete response (pCR) after neoadjuvant chemoradiotherapy in rectal cancer. METHODS: A retrospective analysis was performed on clinical data of 87 patients with rectal cancer, who underwent neoadjuvant chemoradiotherapy followed by radical surgery from April 2007 to May 2015. All patients received pelvic intensity-modulated radiotherapy (50 Gy/25 fractions) with concurrent fluorouracil- based chemotherapy and then underwent radical surgery 4-8 weeks later. The clinical factors associated with pCR or non-pCR were analyzed by Logistic regression. RESULTS: Eighty-three patients had completed treatment, of which 15 patients (18.1%) achieved pCR after neoadjuvant chemoradiotherapy. Univariate analysis showed non-diabetes(P=0.033), pre-chemoradiotherapy plasma glucose(<=6.1 mmol/L)(P=0.033), pre-chemoradiotherapy CEA(<=5 MUg/L)(P=0.026), pre- chemoradiotherapy plasma lymphocytes count(<=1.5*10(9)/L)(P=0.042), pre- chemoradiotherapy plasma platelet(<=240*10(12))(P=0.043), tumor pathological type(adenocarcinoma)(P=0.036)were significantly correlated with pCR after neoadjuvant chemoradiotherapy in rectal cancer. Logistic regression revealed that non-diabetes, pre-chemoradiotherapy plasma glucose, pre-chemoradiotherapy CEA(<=5 MUg/L), pre-chemoradiotherapy plasma lymphocytes count(<=1.5*10(9)/L), tumor pathological type(adenocarcinoma) were independent predictive factors of pCR after neoadjuvant chemoradiotherapy in rectal cancer. CONCLUSION: Patients with non-diabetes, normal plasma glucose, normal CEA, lower plasma lymphocytes count and adenocarcinoma were associated with pCR after neoadjuvant chemoradiotherapy for rectal cancer. PMID- 27122461 TI - [Selective bladder preservation in muscle-invasive bladder cancer by transurethral resection combined with intravesical instillation therapy: analysis of clinical effect in the elderly]. AB - OBJECTIVE: To explore the therapeutic effect and quality of life in elderly patients of muscle-invasive bladder cancer by transurethral resection combined with intravesical instillation therapy. METHODS: From January 2005 to January 2015, 136 cases were diagnosed with T2 bladder cancer by transurethralplasmakinetic therapy or transurethral laser therapy. The data of 136 cases were analyzed retrospectively. RESULTS: In transurethralplasmakinetic therapy group, the overall survival rate was 73.3%, the cancer-specific survival rate was 85.6%, the average survival time were 65 months. In transurethral laser therapy group, the overall survival rate was 73.9%, the cancer-specific survivalrate was 87.2%, the average survival time were 70 months. Two methods also can improve the patient's quality of life. CONCLUSION: For the aged with invasive bladder cancer (T2), we could try the transurethral resection combined with intravesical instillation therapy. PMID- 27122462 TI - [Effects of intubating laryngeal mask airway in prevention of extubation responses in patients with hypertensive cerebral hemorrhage during general anesthesia recovery period]. AB - OBJECTIVE: To evaluate the effects of intubating laryngeal mask airway (ILMA) in prediction of extubation responses in patients with hypertensive cerebral hemorrhage during general anesthesia recovery period. METHODS: A total of 120 patients with hypertensive cerebral hemorrhage aged 47-71 years, with Glasgow Coma Scale (GCS)11-15 scores and American Society of Anesthesiologists (ASA) physical status I or II, undergoing craniotomy surgery from December 2012 to December 2014 in the Affiliated First Municipal Hospital of Fujian Medical University were randomly divided into 2 groups (n=60): tracheal intubation (Group T) and intubating laryngeal mask airway (Group I), by using a random number table. Variations of invasive arterial blood pressure and responses of endotracheal extubation were compared between two groups before and after extubation. RESULTS: There were no significant differences in ages, sex ratio, preoperative GCS, operation time and the time from the end of operation to Train of Four stimulation (TOF) becoming to 4 between the two groups. The mean arterial pressure (MAP) at the time point of extubation (T3), 1 min (T4), 3 min (T5), 5 min (T6) after extubation were (136+/-20), (130+/-16), (128+/-12), (125+/-10) mmHg in Group T, and heart rate(HR) at these four time points were (105+/-11), (96+/-8), (92+/-7), (86+/-6) bpm, respectively. While in group I, MAP were (108+/ 10), (106+/-8), (105+/-9), (106+/-7) mmHg, and HR were (75+/-8), (76+/-7), (68+/ 5), (67+/-6) bpm, respectively. MAP and HR of the two groups at these four time points had significant differences (T3: t=10.91, 17.20; T4: t=13.72, 14.69; T5: t=12.54, 13.35; T6: t=13.39, 11.27; all P<0.01). During recovery, the incidences of extubation responses of group T and group I were 92% and 2%, respectively, and the difference had statistically significant (chi(2)=94.05, P<0.01). The incidences of coughing of group T and group I were 97% and 0, respectively, and the difference had statistically significant (chi(2)=148.69, P<0.01). CONCLUSION: Compared with tracheal intubation, ILMA can decrease the incidence of extubation responses and coughing in patients with hypertensive cerebral hemorrhage during general anesthesia recovery period, and avoid cere-brovascular accidents. PMID- 27122463 TI - [Application of spontaneous acrosome reaction of sperm in prediction of outcome of in-vitro fertilization and embryo transfer]. AB - OBJECTIVE: To investigate the clinical application of spontaneous acrosome reaction (AR) rate of sperm in predicting the outcome of in-vitro fertilization and embryo transfer (IVF-ET). METHODS: The spontaneous AR rate of the sperm of patients who underwent IVF-ET treatment in our center during the period from November to December 2014 were studied. The cut-off value from 6% to 12% were set and analyzed its association between the IVF-ET outcomes (including fertility rates, normal fertilization rates and high-quality embryo rates). For those who underwent fresh embryo transplantation, the rates of chemical pregnancy and clinical pregnancy were calculated, and compared the spontaneous AR rates and quantity of acrosomal enzyme according to the pregnancy outcome. RESULTS: There were 202 patients in this study and the mean spontaneous AR rate was 5.99%+/ 5.18%. For patients with the spontaneous AR rate >=9% versus <9%, the fertility rate, normal fertilization rate and high-quality embryo rate were 81.33% vs 83.85%, 60.53% vs 60.99%, and 51.10% vs 59.67%, respectively, with statistically significant difference in the high-quality embryo rate (P=0.02). For patients who underwent fresh embryo transplantation, when comparison was made between those with spontaneous AR rate >=8% and those <8%, the rate of chemical pregnancy and clinical pregnancy were 48.57% (17/35) vs 69.64% (78/112) and 37.14% (13/35) vs 63.39% (71/112), respectively, both with statistically significant difference (P=0.02 and P<0.01). The patients with clinical pregnancy had lower spontaneous AR rate than those without clinical pregnancy (5.41%+/-3.87% vs 7.40%+/-6.79%, P=0.04), while the quantity of acrosomal enzyme showed no significant difference [(131.79+/-68.50) vs (153.62+/-59.59) MUU/10(6,) P=0.06]. Logistic regression analysis demonstrated association between spontaneous AR rates and clinical pregnancy (OR=0.93, 95%CI: 0.87-0.99, P=0.03). CONCLUSIONS: The spontaneous AR rate of sperm may have clinical significance in predicting the outcome of IVF-ET, as it is reversely correlated with IVF high-quality embryo rate and pregnancy rate. The quantity of acrosomal enzyme may not have significant predictive value for the outcome of IVF. PMID- 27122464 TI - [Comparative proteomics study on lung tissue in early stage of burn-blast combined injury in rats]. AB - OBJECTIVE: To explore changes in the proteomics of lung tissue in early stage of burn-blast combined injury in rats. METHODS: According to a random digital table, a total number of 18 Sprague Dawley (SD) rats were divided into burn-blast combined injury group (n=9) and blast injury group (n=9). Lung protein samples were collected at 6 h post injury. 2-DE was performed to separate proteins. After silver staining, the protein of differential expression were analyzed by PQ Quest and then identified by matrix-assisted laser desorption/ionization time of fight mass spectrometry (MALDI-TOF-MS). The features of the changes of proteomics of rat lung after burn-blast combined injury were studied by biological spectrometry, protein bank and reference article analysis technique. At same time, pathologic changes of the lung were monitored after injury. RESULTS: After removing death drain during the experiment, each group contained 8 rats and the results were analyzed statistically. Well focused and distinct 2-DE maps with good reproducibility were obtained, means of 736+/-47 and 782+/-30 protein spots were detected from the blast injury group and burn-blast combined injury group and the matching rates were 91%. From the two groups, 14 differential protein spots expressions were analyzed by MALDI-TOF-MS, of which 10 proteins were up regulated and 4 proteins were down-regulated in burn-blast combined injury group. 12 different expression proteins were identified in the lung through 2-DE, mass spectrometry and protein date base, including heat shock 27 protein 1, heat shock 70 protein 1, carbonic anhydrase 2, cytochrome c oxidase, ATP synthase subunit alpha, Ca(2+) -transporting ATPase et al, which took part in stress reaction, metabolism, immune response and cytoskeleton. CONCLUSIONS: Burn-blast combined injury could induce dramatically changes of proteomics in lung tissue at early stage. The mechanism probably involves several proteins associated with oxidative stress, energy metabolism, immune response and cytoskeleton. PMID- 27122465 TI - [miR-34b-3p regulates the angiogenesis of senescent endothelial cell]. AB - OBJECTIVE: To investigate the effect of miR-34b-3p on the proliferation, migration and tube formation of senescent endothelial cell. METHODS: Primary human umbilical vein endothelial cells (HUVECs) were cultured in vitro, and population doubling levels (PDLs) were calculated by passage. The young endothelial cell was defined as PDL8. The senescent endothelial cell was defined as PDL44. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was applied to detect the expression of miR-34b-3p in PDL8 and PDL44 HUVECs. miR-34b-3p mimic and inhibitor were transfected into PDL8 and PDL44 HUVECs. Then, cell counting kit-8 (CCK-8), transwell and tube formation assays were used to determine the proliferation, migration and tube formation of HUVECs, respectively. RESULTS: miR-34b-3p was significantly up-regulated approximately 4.3 times in PDL44 HUVECs than that in PDL44 HUVECs (t=-4.528, P<0.05). The proliferation, migration, total tube length and branch points of miR-34b-3p in PDL8 HUVECs group were significantly higher approximately 1.2 (0.67/0.57), 1.2 (106/86), 1.4 (10 605/7 735) and 1.3 (41/31) times than that in PDL44 HUVECs group, respectively (t=3.237, 3.564, 5.165, 3.487, P<0.05 or P<0.01). Overexpression of miR-34b-3p had significantly inhibited proliferation, migration, total tube length and branch points approximately 2.2 (0.67/0.30), 2.3 (106/46), 1.6 (10 605/6 652) and 1.9 (41/22) times in PDL8 HUVECs, respectively (F=145.898, 53.026, 41.997, 36.341, all P<0.01). Repression of miR-34b-3p had significantly increased proliferation, migration, total tube length and branch points approximately 1.4 (0.77/0.57), 2.3 (198/86), 1.7 (13 073/7 735) and 2.3 (71/31) times in PDL44 HUVECs, respectively (F=14.815, 42.970, 167.063, 258.340, all P<0.01). CONCLUSION: The high expression of miR-34b-3p in senescent HUVECs could impair the proliferation, migration and tube formation of senescent endothelial cell. PMID- 27122466 TI - Enantioselective Oxetane Ring Opening with Chloride: Unusual Use of Wet Molecular Sieves for the Controlled Release of HCl. AB - An unprecedented enantioselective oxetane opening with chloride provides access to a range of highly functionalized three-carbon building blocks. The excellent enantiocontrol is enabled not only by a new catalyst, but also by the unusual use of wet molecular sieves for the controlled release of HCl. PMID- 27122467 TI - Results of AANP 2016 Election. PMID- 27122468 TI - Cataloguing versus synthesizing knowledge as a scholarly activity. PMID- 27122469 TI - Inequalities in use of total hip arthroplasty for hip fracture: population based study. AB - OBJECTIVES: To determine whether the use of total hip arthroplasty (THA) among individuals with a displaced intracapsular fracture of the femoral neck is based on national guidelines or if there are systematic inequalities. DESIGN: Observational cohort study using the National Hip Fracture Database (NHFD). SETTING: All hospitals that treat adults with hip fractures in England, Wales, and Northern Ireland. PARTICIPANTS: Patients within the national database (all aged >=60) who received operative treatment for a non-pathological displaced intracapsular hip fracture from 1 July 2011 to 31 April 2015. MAIN OUTCOME MEASURES: Provision of THA to patients considered eligible under criteria published by the National Institute for Health and Care Excellence (NICE). RESULTS: 114 119 patients with hip fracture were included, 11 683 (10.2%) of whom underwent THA. Of those who satisfied the NICE criteria, 32% (6780) : received a THA. Of patients who underwent THA, 42% (4903) did not satisfy the NICE criteria. A recursive partitioning algorithm found that the NICE eligibility criteria did not optimally explain which patients underwent THA. A model with superior explanatory power drew distinctions that are not supported by NICE, which were an age cut off at 76 and a different ambulation cut off. Among patients who satisfied the NICE eligibility, the use of THA was less likely with higher age (odds ratio 0.88, 95% confidence interval 0.87 to 0.88), worsening abbreviated mental test scores (0.49 (0.41 to 0.58) for normal cognition v borderline cognitive impairment)), worsening American Society of Anesthesiologists score (0.74, 0.66 to 0.84), male sex (0.85, 0.77 to 0.93), worsening ambulatory status (0.32, 0.28 to 0.35 for walking with a stick v independent ambulation), and fifths of worsening socioeconomic area deprivation (0.76 (0.66 to 0.88) for least v most deprived fifth). Patients receiving treatment during the working week were more likely to receive THA than at the weekend (0.90, 0.83 to 0.98). CONCLUSIONS: There are wide disparities in the use of THA among individuals with hip fractures, and compliance with NICE guidance is poor. Patients with higher levels of socioeconomic deprivation and those who require surgery at the weekend were less likely to receive THA. Inconsistent compliance with NICE recommendations means that the optimal treatment for older adults with hip fractures can depend on where and when they present to hospital. PMID- 27122470 TI - Rauvolfia serpentina N-methyltransferases involved in ajmaline and Nbeta methylajmaline biosynthesis belong to a gene family derived from gamma-tocopherol C-methyltransferase. AB - Ajmaline biosynthesis in Rauvolfia serpentina has been one of the most studied monoterpenoid indole alkaloid (MIA) pathways within the plant family Apocynaceae. Detailed molecular and biochemical information on most of the steps involved in the pathway has been generated over the last 30 years. Here we report the identification, molecular cloning and functional expression in Escherichia coli of two R. serpentinacDNAs that are part of a recently discovered gamma-tocopherol like N-methyltransferase (gamma-TLMT) family and are involved in indole and side chain N-methylation of ajmaline. Recombinant proteins showed remarkable substrate specificity for molecules with an ajmalan-type backbone and strict regiospecific N-methylation. Furthermore, N-methyltransferase gene transcripts and enzyme activity were enriched in R. serpentina roots which correlated with accumulation of ajmaline alkaloid. This study elucidates the final step in the ajmaline biosynthetic pathway and describes the enzyme responsible for the formation of Nbeta -methylajmaline, an unusual charged MIA found in R. serpentina. PMID- 27122471 TI - Commentary on "An Investigation of the Relationship Between Alcohol Use and Major Depressive Disorder Across Hispanic National Groups" by Jetelina and Colleagues. PMID- 27122472 TI - Unbroken Perovskite: Interplay of Morphology, Electro-optical Properties, and Ionic Movement. AB - Hybrid organic-inorganic perovskite materials have risen up as leading components for light-harvesting applications. However, to date many questions are still open concerning the operation of perovskite solar cells (PSCs). A systematic analysis of the interplay among structural features, optoelectronic performance, and ionic movement behavior for FA0.83 MA0.17 Pb(I0.83 Br0.17 )3 PSCs is presented, which yield high power conversion efficiencies up to 20.8%. PMID- 27122473 TI - Study design and rationale of the heterotopic implantation of the Edwards-Sapien XT transcatheter valve in the inferior VEna cava for the treatment of severe tricuspid regurgitation (HOVER) trial. AB - BACKGROUND: Tricuspid regurgitation (TR) is an under treated disease. Although surgery for TR remains an effective therapy, many patients are considered to be at a high risk or otherwise inoperable. Caval valve implant (CAVI) offers an alternative to surgery in these patients. Trials assessing the safety and efficacy of caval valve implant are lacking. METHODS: The Heterotopic Implantation Of the Edwards-Sapien XT Transcatheter Valve in the Inferior VEna cava for the treatment of severe Tricuspid Regurgitation (HOVER) trial is an FDA approved, physician initiated, prospective, non-blinded (open label), non randomized safety and feasibility study to determine the safety and efficacy of the heterotopic implantation of the Edwards-Sapien XT valve in the inferior vena cava for the treatment of severe TR in patients who are at high risk or inoperable. Patients with severe TR in the absence of severe pulmonary hypertension will be recruited. They will be evaluated by a multi-disciplinary team who will agree by consensus that the patients' symptoms are from TR. They will undergo imaging to assess the size of the inferior vena cava (IVC) to determine feasibility of the procedure. If patients meet the inclusion criteria and are free from exclusion criteria, after informed consent they will be eligible for enrollment in the study. A total of 30 patients will be enrolled. The primary objective of the study will be to demonstrate procedural success at 30-days and patient success at 1-year. CONCLUSION: Caval valve implant may present an alternative for patients who are at high risk or inoperable for tricuspid valve surgery (TVS) for TR. (c) 2016 Wiley Periodicals, Inc. PMID- 27122475 TI - Prices For Common Medical Services Vary Substantially Among The Commercially Insured. AB - Using a national multipayer commercial claims database containing allowed amounts, we examined variations in the prices for 242 common medical services in forty-one states and the District of Columbia. Ratios of average state prices to national prices ranged from a low of 0.79 in Florida to a high of 2.64 in Alaska. Two- to threefold variations in prices were identified within some states and Metropolitan Statistical Areas. PMID- 27122476 TI - Transcutaneous and Percutaneous Neurostimulation for Headache Disorders. AB - Noninvasive and minimally invasive extracranial stimulation has now been widely investigated for the treatment of primary headache disorders, particularly migraine. In this review, we describe methodological challenges in studying occipital and supraorbital stimulation devices. We explore the efficacy and safety of implantable occipital nerve stimulation for primary headache disorders, including the 3 randomized, sham-controlled clinical trials for chronic migraine treatment. We also review noninvasive supraorbital transcutaneous stimulation as a preventive therapy for episodic migraine. PMID- 27122477 TI - Bioaccessibility of polyphenols from selected cereal grains and legumes as influenced by food acidulants. AB - BACKGROUND: Polyphenols in food are valued for their health-beneficial influences. Food acidulants lime juice and amchur used in Indian cookery were evaluated for their influence on polyphenol bioaccessibility from food grains. RESULTS: Lime juice increased bioaccessible flavonoids by 25% in roasted finger millet, while there was no change in total bioaccessible polyphenols in pressure cooked, open-pan-boiled and roasted finger millet in the presence of food acidulants. Addition of amchur to pressure-cooked and microwave-heated pearl millet increased bioaccessible flavonoids by 30 and 53% respectively, while lime juice increased them by 46% in pressure-cooked pearl millet. Increased bioaccessibility of specific phenolic acids from finger millet and pearl millet was observed upon addition of these food acidulants. The presence of either lime juice or amchur increased bioaccessible flavonoids from both legumes studied. Addition of lime juice and amchur, however, exerted a negative effect on the bioaccessibility of several phenolic compounds from food grains in native state and under certain processing conditions. CONCLUSION: Thus food acidulants lime juice and amchur had a significant influence on the bioaccessibility of health beneficial phenolic compounds from food grains. Use of food acidulants in food preparations could be a strategy to enhance the bioavailability of polyphenols, especially flavonoids from grains. (c) 2016 Society of Chemical Industry. PMID- 27122478 TI - Accidental Trauma Mimicking Homicidal Violence. AB - Homicide investigations represent an important function of death investigators. Although recognizing nonobvious homicides is crucial, an equally important role involves the identification of cases that initially present as possible homicides, but are ultimately discovered to not represent homicides. Failure to recognize such cases results in wasted time, squandered resources, false allegations, and potential life-altering consequences. The authors review a series of cases wherein initial investigation suggested a possibility that the deaths represented homicides. By carefully considering additional information, including scene findings, history, and postmortem examination, each was determined to represent an accidental traumatic death. In addition to highlighting the importance of recognizing accidental traumatic deaths that initially present as homicides, the cases serve to highlight the fact that forensic pathology cannot be practiced without knowledge of appropriate ancillary information. Although guarding against cognitive bias is important in all forensic disciplines, including forensic pathology, access to vital case-related ancillary information is an essential component of practicing medicine as a forensic pathologist. PMID- 27122479 TI - Distribution of Eschar in Pediatric Scrub Typhus. AB - BACKGROUND: Identifying an eschar in scrub typhus is useful for initiation of prompt and appropriate antibiotic therapy. METHODS: The distribution of eschars in all children <15 years of age admitted with confirmed scrub typhus over a 5 year period is described. RESULTS: Of 431 children admitted with scrub typhus, eschars were present in 176 (40.8%) children with the following distribution: head, face and neck, 33 (19.1%); axillae, 37 (21%); chest and abdomen, 21 (11.9%); genitalia, inguinal region and buttocks, 58 (33%); back, 8 (4.5%); upper extremities, 13 (7.4%); and lower extremities, 5 (2.8%). The commonest sites of eschars were scrotum (27 of 106; 25.5%) and axillae (15 of 106; 14.2%) in males and axillae (22 of 70; 31.4%) and groin (16 of 70; 22.9%) in females. Eschars were seen within skin folds in 100 of 176 (56.8%) children. CONCLUSION: Children should be carefully examined for the presence of eschar especially in the skin folds of the genitalia, axillae and groin to make an early diagnosis of scrub typhus. PMID- 27122480 TI - Factors Associated with Stunting among Pre-school Children in Southern Highlands of Tanzania. AB - BACKGROUND: Stunting is a major public health problem in Africa and is associated with poor child survival and development. We investigate factors associated to child stunting in three Tanzanian regions. METHODS: A cross-sectional two-stage cluster sampling survey was conducted among children aged 6-59 months. The sample included 1360 children aged 6-23 months and 1904 children aged 24-59 months. Descriptive statistics and binary and multivariate logistic regression analyses were used. RESULTS: Our main results are: in the younger group, stunting was associated with male sex (adjusted odds ratio [AOR]: 2.17; confidence interval [CI]: 1.52-3.09), maternal absence (AOR: 1.93; CI: 1.21-3.07) and household diet diversity (AOR: 0.61; CI: 0.41-0.92). Among older children, stunting was associated with male sex (AOR: 1.28; CI: 1.00-1.64), age of 4 and 5 (AOR: 0.71; CI: 0.54-0.95; AOR: 0.60; CI: 0.44-0.83), access to improved water source (AOR: 0.70; CI: 0.52-0.93) and to a functioning water station (AOR: 0.63; CI: 0.40 0.98) and mother breastfeeding (AOR: 1.97; CI: 1.18-3.29). CONCLUSIONS: Interventions that increase household wealth and improve water and sanitation conditions should be implemented to reduce stunting. Family planning activities and programmes supporting mothers during pregnancy and lactation can positively affect both newborns and older siblings. PMID- 27122481 TI - Real-Time Measurement of the Tool-Tissue Interaction in Minimally Invasive Abdominal Surgery: The First Step to Developing the Next Generation of Smart Laparoscopic Instruments. AB - Introduction Analysis of force application in laparoscopic surgery is critical to understanding the nature of the tool-tissue interaction. The aim of this study is to provide real-time data about manipulations to abdominal organs. Methods An instrumented short fenestrated grasper was used in an in vivo porcine model, measuring force at the grasper handle. Grasping force and duration over 5 small bowel manipulation tasks were analyzed. Forces required to retract gallbladder, bladder, small bowel, large bowel, and rectum were measured over 30 seconds. Four parameters were calculated-T(hold), the grasp time; T(close), time taken for the jaws to close; F(max), maximum force reached; and F(rms), root mean square force (representing the average force across the grasp time). Results Mean F(max) to manipulate the small bowel was 20.5 N (+/-7.2) and F(rms) was 13.7 N (+/-5.4). Mean T(close) was 0.52 seconds (+/-0.26) and T(hold) was 3.87 seconds (+/-1.5). In individual organs, mean F(max) was 49 N (+/-15) to manipulate the rectum and 59 N (+/-13.4) for the colon. The mean F(max) for bladder and gallbladder retraction was 28.8 N (+/-7.4) and 50.7 N (+/-3.8), respectively. All organs exhibited force relaxation, the F(rms) reduced to below 25 N for all organs except the small bowel, with a mean F(rms) of less than 10 N. Conclusion This study has commenced the process of quantifying tool-tissue interaction. The static measurements discussed here should evolve to include dynamic measurements such as shear, torque, and retraction forces, and be correlated with evidence of histological damage to tissue. PMID- 27122482 TI - Louis de Wecker (1832-1906) and His Innovations in Ocular Surgery. AB - Louis de Wecker (1832-1906) was a famous French ophthalmologist and was considered one of the greatest ophthalmologists of his time with worldwide reputation. He introduced many innovative surgical techniques such as his method for iridotomy, "anterior sclerotomy," and the so-called "de Wecker's capsular advancement" for the treatment of strabismus. He also invented surgical instruments such as "de Wecker's pince-ciseaux" and "de Wecker's double advancement hook." PMID- 27122483 TI - Effectiveness of a Multimodal Intervention Program for Restraint Prevention in an Acute Spanish Psychiatric Ward. AB - BACKGROUND: International recommendations have called to implement strategies to reduce the use of coercion in psychiatric settings. However, in Spain there is a lack of research about intervention programs to reduce mechanical restraint in acute psychiatric units. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a multimodal intervention program based on the principles of six core strategies to reduce the frequency of use of mechanical restraint in an acute psychiatric ward. DESIGN: The design was a retrospective analysis of the frequency and duration of episodes of mechanical restraint prior to the intervention program (2012) and during the intervention program (2013) in one acute psychiatric ward. The intervention was governed by four strategies: (1) leadership and organizational changes, (2) registration and monitoring of risk patients, (3) staff training, and (4) involving patients in the treatment program. RESULTS: There was a significant difference between the mean number of monthly episodes of mechanical restraint per 1,000 patient days, pre-intervention (18.54 +/- 8.78) compared with postintervention (8.53 +/- 7.00; p = .005). We found the probability that mechanical restraint would occur in a hospital admission decreased after performing the intervention (odds ratio = .587; confidence interval = 0.411-0.838; p = .003) after adjusting for confounding variables. The total percentage of restrained patients fell from 15.07% to 9.74%. CONCLUSIONS: The main implication of the study is to support the effectiveness of specific intervention programs based on different measures to reduce mechanical restraint and without contemplating all the strategies that are considered effective. PMID- 27122484 TI - Bayesian Validation of the Indirect Immunofluorescence Assay and Its Superiority to the Enzyme-Linked Immunosorbent Assay and the Complement Fixation Test for Detecting Antibodies against Coxiella burnetii in Goat Serum. AB - Although many studies have reported the indirect immunofluorescence assay (IFA) to be more sensitive in detection of antibodies to Coxiella burnetii than the complement fixation test (CFT), the diagnostic sensitivity (DSe) and diagnostic specificity (DSp) of the assay have not been previously established for use in ruminants. This study aimed to validate the IFA by describing the optimization, selection of cutoff titers, repeatability, and reliability as well as the DSe and DSp of the assay. Bayesian latent class analysis was used to estimate diagnostic specifications in comparison with the CFT and the enzyme-linked immunosorbent assay (ELISA). The optimal cutoff dilution for screening for IgG and IgM antibodies in goat serum using the IFA was estimated to be 1:160. The IFA had good repeatability (>96.9% for IgG, >78.0% for IgM), and there was almost perfect agreement (Cohen's kappa > 0.80 for IgG) between the readings reported by two technicians for samples tested for IgG antibodies. The IFA had a higher DSe (94.8%; 95% confidence interval [CI], 80.3, 99.6) for the detection of IgG antibodies against C. burnetii than the ELISA (70.1%; 95% CI, 52.7, 91.0) and the CFT (29.8%; 95% CI, 17.0, 44.8). All three tests were highly specific for goat IgG antibodies. The IFA also had a higher DSe (88.8%; 95% CI, 58.2, 99.5) for detection of IgM antibodies than the ELISA (71.7%; 95% CI, 46.3, 92.8). These results underscore the better suitability of the IFA than of the CFT and ELISA for detection of IgG and IgM antibodies in goat serum and possibly in serum from other ruminants. PMID- 27122485 TI - Parenteral Vaccination Can Be an Effective Means of Inducing Protective Mucosal Responses. AB - The current paradigm in vaccine development is that nonreplicating vaccines delivered parenterally fail to induce immune responses in mucosal tissues. However, both clinical and experimental data have challenged this concept, and numerous studies have shown that induction of mucosal immune responses after parenteral vaccination is not a rare occurrence and might, in fact, significantly contribute to the protection against mucosal infections afforded by parenteral vaccines. While the mechanisms underlying this phenomenon are not well understood, the realization that parenteral vaccination can be an effective means of inducing protective mucosal responses is paradigm-shifting and has potential to transform the way vaccines are designed and delivered. PMID- 27122486 TI - 10 Best resources on... intersectionality with an emphasis on low- and middle income countries. AB - Intersectionality has emerged as an important framework for understanding and responding to health inequities by making visible the fluid and interconnected structures of power that create them. It promotes an understanding of the dynamic nature of the privileges and disadvantages that permeate health systems and affect health. It considers the interaction of different social stratifiers (e.g. 'race'/ethnicity, indigeneity, gender, class, sexuality, geography, age, disability/ability, migration status, religion) and the power structures that underpin them at multiple levels. In doing so, it is a departure from previous health inequalities research that looked at these forms of social stratification in isolation from one another or in an additive manner. Despite its potential use and long history in other disciplines, intersectionality is uncommonly used in health systems research in low- and middle-income countries (LMICs). To orient readers to intersectionality theory and research, we first define intersectionality and describe its role in public health, and then we review resources on intersectionality. We found that applications in public health mostly increased after 2009, with only 14 out of 86 articles focused on LMICs. To arrive at 10 best resources, we selected articles based on the proportion of the article that was devoted to intersectionality, the strength of the intersectionality analysis, and its relevance to LMICs. The first four resources explain intersectionality as a methodology. The subsequent six articles apply intersectionality to research in LMIC with quantitative and qualitative analysis. We provide examples from India, Swaziland, Uganda and Mexico. Topics for the studies range from HIV, violence and sexual abuse to immunization and the use of health entitlements. Through these 10 resources, we hope to spark interest and open a needed conversation on the importance and use of intersectional analysis in LMICs as part of understanding people-centred health systems. PMID- 27122487 TI - Distinguishing ventricular septal bulge versus hypertrophic cardiomyopathy in the elderly. AB - The burgeoning evidence of patients diagnosed with sigmoidal hypertrophic cardiomyopathy (HCM) later in life has revived the quest for distinctive features that may help discriminate it from more benign forms of isolated septal hypertrophy often labelled ventricular septal bulge (VSB). HCM is diagnosed less frequently than VSB at older ages, with a reversed female predominance. Most patients diagnosed with HCM at older ages suffer from hypertension, similar to those with VSB. A positive family history of HCM and/or sudden cardiac death and the presence of exertional symptoms usually support HCM, though they are less likely in older patients with HCM, and poorly investigated in individuals with VSB. A more severe hypertrophy and the presence of left ventricular outflow obstruction are considered diagnostic of HCM, though stress echocardiography has not been consistently used in VSB. Mitral annulus calcification is very prevalent in both conditions, whereas a restrictive filling pattern is found in a minority of older patients with HCM. Genetic testing has low applicability in this differential diagnosis at the current time, given that a causative mutation is found in less than 10% of elderly patients with suspected HCM. Emerging imaging modalities that allow non-invasive detection of myocardial fibrosis and disarray may help, but have not been fully investigated. Nonetheless, there remains a considerable morphological overlap between the two conditions. Comprehensive studies, particularly imaging based, are warranted to offer a more evidence-based approach to elderly patients with focal septal thickening. PMID- 27122488 TI - Depletion of human serum albumin in embryo culture media for in vitro fertilization using monolithic columns with immobilized antibodies. AB - Affinity depletion of abundant proteins such as HSA is an important stage in routine sample preparation prior to MS/MS analysis of biological samples with high range of concentrations. Due to the charge competition effects in electrospray ion source that results in discrimination of the low-abundance species, as well as limited dynamic range of MS/MS, restricted typically by three orders of magnitude, the identification of low-abundance proteins becomes a challenge unless the sample is depleted from high-concentration compounds. This dictates a need for developing efficient separation technologies allowing fast and automated protein depletion. In this study, we performed evaluation of a novel immunoaffinity-based Convective Interaction Media analytical columns (CIMac) depletion column with specificity to HSA (CIMac-alphaHSA). Because of the convective flow-through channels, the polymethacrylate CIMac monoliths afford flow rate independent binding capacity and resolution that results in relatively short analysis time compared with traditional chromatographic supports. Seppro IgY14 depletion kit was used as a benchmark to control the results of depletion. Bottom-up proteomic approach followed by label-free quantitation using normalized spectral indexes were employed for protein quantification in G1/G2 and cleavage/blastocyst in vitro fertilization culture media widely utilized in clinics for embryo growth in vitro. The results revealed approximately equal HSA level of 100 +/- 25% in albumin-enriched fractions relative to the nondepleted samples for both CIMac-alphaHSA column and Seppro kit. In the albumin-free fractions concentrated 5.5-fold by volume, serum albumin was identified at the levels of 5-30% and 20-30% for the CIMac-alphaHSA and Seppro IgY14 spin columns, respectively. PMID- 27122489 TI - Does physiological acclimation to climate warming stabilize the ratio of canopy respiration to photosynthesis? AB - Given the contrasting short-term temperature dependences of gross primary production (GPP) and autotrophic respiration, the fraction of GPP respired by trees is predicted to increase with warming, providing a positive feedback to climate change. However, physiological acclimation may dampen or eliminate this response. We measured the fluxes of aboveground respiration (Ra ), GPP and their ratio (Ra /GPP) in large, field-grown Eucalyptus tereticornis trees exposed to ambient or warmed air temperatures (+3 degrees C). We report continuous measurements of whole-canopy CO2 exchange, direct temperature response curves of leaf and canopy respiration, leaf and branch wood respiration, and diurnal photosynthetic measurements. Warming reduced photosynthesis, whereas physiological acclimation prevented a coincident increase in Ra . Ambient and warmed trees had a common nonlinear relationship between the fraction of GPP that was respired above ground (Ra /GPP) and the mean daily temperature. Thus, warming significantly increased Ra /GPP by moving plants to higher positions on the shared Ra /GPP vs daily temperature relationship, but this effect was modest and only notable during hot conditions. Despite the physiological acclimation of autotrophic respiration to warming, increases in temperature and the frequency of heat waves may modestly increase tree Ra /GPP, contributing to a positive feedback between climate warming and atmospheric CO2 accumulation. PMID- 27122490 TI - Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: a randomized clinical trial. AB - STUDY QUESTION: Does a single intrauterine infusion of human chorionic gonadotropin (hCG) at the time corresponding to a Day 3 embryo transfer in oocyte donors induce favorable molecular changes in the endometrium for embryo implantation? SUMMARY ANSWER: Intrauterine hCG was associated with endometrial synchronization between endometrial glands and stroma following ovarian stimulation and the induction of early decidual markers associated with stromal cell survival. WHAT IS KNOWN ALREADY: The clinical potential for increasing IVF success rates using an intrauterine hCG infusion prior to embryo transfer remains unclear based on previously reported positive and non-significant findings. However, infusion of CG in the non-human primate increases the expression of pro survival early decidual markers important for endometrial receptivity, including alpha-smooth muscle actin (alpha-SMA) and NOTCH1. STUDY DESIGN, SIZE, DURATION: Oocyte donors (n=15) were randomly assigned to receive an intrauterine infusion of 500 IU hCG (n=7) or embryo culture media vehicle (n=8) 3 days following oocyte retrieval during their donor stimulation cycle. Endometrial biopsies were performed 2 days later, followed by either RNA isolation or tissue fixation in formalin and paraffin embedding. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reverse transcription of total RNA from endometrial biopsies generated cDNA, which was used for analysis in the endometrial receptivity array (ERA; n = 5/group) or quantitative RT-PCR to determine relative expression of ESR1, PGR, C3 and NOTCH1. Tissue sections were stained with hematoxylin and eosin followed by blinded staging analysis for dating of endometrial glands and stroma. Immunostaining for ESR1, PGR, alpha-SMA, C3 and NOTCH1 was performed to determine their tissue localization. MAIN RESULTS AND THE ROLE OF CHANCE: Intrauterine hCG infusion was associated with endometrial synchrony and reprograming of stromal development following ovarian stimulation. ESR1 and PGR were significantly elevated in the endometrium of hCG-treated patients, consistent with earlier staging. The ERA did not predict an overall positive impact of intrauterine hCG on endometrial receptivity. However, ACTA2, encoding alpha-SMA was significantly increased in response to intrauterine hCG. Similar to the hCG-treated non-human primate, sub-epithelial and peri-vascular alpha-SMA expression was induced in women following hCG infusion. Other known targets of hCG in the baboon were also found to be increased, including C3 and NOTCH1, which have known roles in endometrial receptivity. LIMITATIONS, REASONS FOR CAUTION: This study differs from our previous work in the hCG-treated non-human primate along with clinical studies in infertile patients. Specifically, we performed a single intrauterine infusion in oocyte donors instead of either continuous hCG via an osmotic mini pump in the baboon or infusion followed by blastocyst-derived hCG in infertile women undergoing embryo transfer. Therefore, the full impact of intrauterine hCG in promoting endometrial receptivity may not have been evident. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest a potential clinical benefit for intrauterine hCG prior to embryo transfer on Day 3 in counteracting endometrial dyssynchrony from ovarian stimulation and promoting expression of markers important for stromal survival. Finally, there were no obvious negative effects of intrauterine hCG treatment. STUDY FUNDING/COMPETING INTERESTS: Funding for this work was provided by NICHD R01 HD042280 (A.T.F.) and NICHD F30 HD082951 (M.R.S.). C.S. and P.D.-G are co-inventors of the patented ERA, which is owned by IGENOMIX SL and was used in this study, and C.S. is a shareholder in IGENOMIX SL. M.R.-A. is employed by IGENOMIX SL. No other authors have any conflicts of interest to report. TRIAL REGISTRATION NUMBER: This study was registered with ClinicalTrials.gov (NCT01786252). TRIAL REGISTRATION DATE: 5 February 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 10 May 2013. PMID- 27122491 TI - Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering. AB - Hypertension is recognized as an important risk factor for cardiovascular morbidity and mortality. Lowering of blood pressure has been shown to minimize the risk of cardiovascular events, with the majority of antihypertensives demonstrating a similar ability to reduce coronary events and stroke for a given reduction in blood pressure. Agents that modify the activity of the renin angiotensin system (RAS) have been proposed to exhibit additional effects that might go beyond simple blood pressure lowering. The RAS is a crucial system that regulates extracellular fluid volume and blood pressure. Proposed potential benefits of RAS blockade that go beyond blood pressure lowering include a reduction in platelet aggregation and thrombosis, blunting of cardiac and vascular remodeling, favorable metabolic effects and reno- and cerebro protection. However, factors such as treatment adherence, duration of action of antihypertensive agents and differences in effects on central versus brachial blood pressure may also result in apparent differences in efficacy of different antihypertensives. The aim of this review article is to examine the available data from clinical studies of antihypertensive drugs for evidence of effects that might legitimately be claimed to go beyond simple blood pressure lowering. PMID- 27122492 TI - Aldosterone is associated with left ventricular hypertrophy in hemodialysis patients. AB - OBJECTIVES: Patients with chronic kidney disease present a higher degree of left ventricular hypertrophy than expected for hypertension levels. In chronic kidney disease the plot between the quotient extracellular water/total body water and aldosterone is shifted up and to the right. There are few studies that verified the role of aldosterone in cardiac remodeling in this set of patients. The aim of this study was to evaluate the relationship between serum aldosterone and left ventricular mass index in patients with chronic kidney disease on hemodialysis. METHODS: The patients were submitted to clinical and laboratory evaluation, bioelectrical impedance, echocardiography and ambulatory blood pressure monitoring. The 27 patients included were divided into two groups according to aldosterone level and compared with each other. RESULTS: The group of patients with higher aldosterone levels had higher left ventricular mass index. These groups were heterogeneous with regard to ambulatory systolic blood pressure, body mass index, and aldosterone levels and homogeneous with regard to the quotient extracellular water/total body water, renin-angiotensin-aldosterone system blockers, beta blocker use and other clinical characteristics. The association between aldosterone levels and left ventricular mass index was adjusted to confounding variables by a multiple linear regression analysis in which aldosterone was independently associated with left ventricular mass index. CONCLUSION: The data presented are consistent with a pathogenic role of aldosterone in left ventricular hypertrophy in patients with chronic kidney dialysis in dialysis patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01128101. PMID- 27122493 TI - Methyl Anthranilate as a Repellent for Western Corn Rootworm Larvae (Coleoptera: Chrysomelidae). AB - Methyl anthranilate was identified as the active compound in extracts of maize (Zea mays L.) roots that were shown to be repellent to neonate western corn rootworm (Diabrotica virgifera virgifera LeConte) larvae. A bioassay-driven approach was used to isolate the active material from diethyl ether extracts of roots from germinating maize seeds. Separation of the extract on a Florisil column yielded an active fraction of 90:10 hexane:diethyl ether. Analysis with gas chromatography-mass spectrometry identified two compounds in the active fraction: indole (2,3-benzopyrrole) and methyl anthranilate (methyl 2 aminobenzoate). When tested in behavioral bioassays, methyl anthranilate elicited a significant (P < 0.05) repellent response at doses of 1, 10, and 100 ug. In subsequent single-choice bioassays, 1, 10, and 100 ug of methyl anthranilate prevented larvae from approaching 10 mmol/mol concentrations of carbon dioxide, which is normally highly attractive to the larvae. Indole, the other compound identified from the active fraction, did not elicit a behavioral response by the larvae. Methyl anthranilate has potential for development as a management tool for western corn rootworm larvae and may be best suited for use in a push-pull control strategy. PMID- 27122494 TI - Laboratory and Field Evaluation of Zyrox Fly Granular Bait Against Asian and German Cockroaches (Dictyoptera: Blattellidae). AB - The Asian cockroach (Blattella asahinai Mizukubo) was introduced to Florida in 1986 and has since spread throughout the Southeastern United States. Blattella asahinai is a peridomestic pest and high population densities in residential areas can become a nuisance, especially when adults fly into homes. Few studies to date have been conducted on Asian cockroach control, and we evaluated the efficacy of Zyrox Fly Granular Bait and Maxforce Complete Granular Insect Bait against this species in the laboratory compared with the closely related German cockroach (Blattella germanica (L.)). In no-choice and two-choice assays with both species, Zyrox bait and Maxforce bait achieved nearly 100% mortality within two and five days, respectively. We also tested Zyrox bait against B. asahinai in an invasive field population in North Carolina at the label rate (2 g/m(2)) and at approximately three times the label rate (6.9 g/m(2)), and found that broadcast applications at both rates reduced populations by an average of 64 and 92%, respectively, for 35 d after the initial application. Zyrox Fly Bait appears to be effective against the Asian and German cockroaches, and could be another tool in an integrated pest management program, if its label could be extended or the active ingredient (cyantraniliprole) formulated into a cockroach bait. PMID- 27122495 TI - Genetically Engineered Ricin Suppresses Bactrocera dorsalis (Diptera: Tephritidae) based on Demographic Analysis of Group-Reared Life Table. AB - The oriental fruit fly, Bactrocera dorsalis (Hendel), reduces the quantity and quality of many host fruits through the process of oviposition and larval feeding, and this insect has been considered a major insect pest in several Asian countries for decades. Using an earlier-developed, female-specific system that combines the toxicity of the ricin A chain (RTA) and the alternative RNA splicing property of doublesex (Bddsx), we show that transgenic male flies harboring the RTA-Bddsx transgene unevenly repress the pest population through inheritable effects. In age-stage, two-sex life-table analyses, high larval mortality and a delay in pupation were observed after introducing the transgene. The high male to female ratio in DsRed+ flies demonstrates the lethal effect of ricin on females. The fitness of both the DsRed+- and DsRed--transformed females was reduced as shown in the decrease of the net reproductive rate (R0), intrinsic rate (r), and finite rate (lambda) values compared with the wild-type populations. The integrity of the RTA-Bddsx transgene remained in more than 80% of DsRed+ males after ten generations, supporting the stable inheritance of the transgene. All of the data from this study support the proposed RTA-Bddsx SIT approach, which provides a species-specific and environmentally friendly method of suppressing, rather than eradiating, B. dorsalis. PMID- 27122496 TI - Assessment of Bacterial Communities in Thirteen Species of Laboratory-Cultured Domestic Mites (Acari: Acaridida). AB - House dust mites (HDMs) and stored-product mites (SPMs) of various species inhabit human homes and stored agricultural products. These mites are carriers and hosts of microorganisms that enable their survival. The bacteriome from 13 species of SPMs and HDMs was analyzed and compared by 454 pyrosequencing of partial 16S rRNA gene amplicons. Altogether 128,052 sequences were obtained and assigned to 71 operational taxonomic units (OTUs) at the 97% identity level. The number of sequences in the OTUs between species of mites ranged from 6 to 31 in the individual mite species. We did not find any significant effect of diet or evolutionary origin of mites or their interaction on the composition of the mite bacteriome. In mite species with low bacterial diversity, the bacterial communities were dominated by potential symbiotic or parasitic bacteria, i.e., Cardinium in Dermatophagoides farinae (Hughes, 1961) and Aeroglyphus robustus (Banks 1906) and the enteric bacteria Erwinia in Blomia tropicalis Van Bronswijk, de Cock & Oshima, 1974 and Xenorhabdus in Tyroborus lini (Oudemans, 1924). Among the bacterial species identified, Staphylococcus, Bacillus, Kocuria, Brevibacterium, Corynebacterium, and Brachybacterium likely serve as food sources for the mites. The domestic acaridid mites carried high numbers of various bacteria that are potential threats to human health. These results contribute to the general understanding of the ecology of mite adaptation to human-made habitats. PMID- 27122497 TI - Bt Toxin Cry1Ie Causes No Negative Effects on Survival, Pollen Consumption, or Olfactory Learning in Worker Honey Bees (Hymenoptera: Apidae). AB - The honey bee (Apis mellifera L.) is a key nontarget insect in environmental risk assessments of insect-resistant genetically modified crops. In controlled laboratory conditions, we evaluated the potential effects of Cry1Ie toxin on survival, pollen consumption, and olfactory learning of young adult honey bees. We exposed worker bees to syrup containing 20, 200, or 20,000 ng/ml Cry1Ie toxin, and also exposed some bees to 48 ng/ml imidacloprid as a positive control for exposure to a sublethal concentration of a toxic product. Results suggested that Cry1Ie toxin carries no risk to survival, pollen consumption, or learning capabilities of young adult honey bees. However, during oral exposure to the imidacloprid treatments, honey bee learning behavior was affected and bees consumed significantly less pollen than the control and Cry1Ie groups. PMID- 27122498 TI - Field-Based Assessment of Resistance to Bt Corn by Western Corn Rootworm (Coleoptera: Chrysomelidae). AB - Western corn rootworm, Diabrotica virgifera virgifera LeConte, is a serious pest of corn and is managed with corn that produces insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt). Beginning in 2009, resistance to Cry3Bb1 corn, and severe injury to Cry3Bb1 corn in the field, was observed in Iowa. However, few data exist on how Cry3Bb1-resistant western corn rootworm interact with various management practices in the field. Using a field experiment, we measured adult emergence and feeding injury to corn roots for both Cry3Bb1-resistant and Cry3Bb1-susceptible populations of western corn rootworm when tested against various Bt corn hybrids and a soil-applied insecticide. Between 2012 and 2013, we evaluated five fields that were associated with greater than one node of feeding injury to Cry3Bb1 corn by western corn rootworm (i.e., problem-field populations), and a laboratory strain that had never been exposed to Bt corn (i.e., control population). Adult emergence for western corn rootworm and root injury to corn were significantly higher in problem-field populations than control populations for both Cry3Bb1 corn and mCry3A corn. By contrast, corn with Cry34/35Ab1, either alone or pyramided with Cry3Bb1, significantly reduced adult emergence and root injury in both problem fields and control fields. In problem fields, application of the soil-applied insecticide to Cry3Bb1 corn significantly reduced root injury, but not adult emergence. Our results are discussed in terms of developing strategies for managing western corn rootworm with resistance to Cry3Bb1 and mCry3A, and delaying the additional evolution of Bt resistance by this pest. PMID- 27122499 TI - Interlaboratory ring trial to evaluate CFT proficiency of European laboratories for diagnosis of glanders in equids. AB - To evaluate the routine complement fixation test (CFT) used to detect Burkholderia mallei antibodies in equine sera, an interlaboratory proficiency test was held with 24 European laboratories, including 22 National Reference Laboratories for glanders. The panels sent to participants were composed of sera with or without B mallei antibodies. This study confirmed the reliability of CFT and highlighted its intralaboratory reproducibility. However, the sensitivity of glanders serodiagnosis and laboratory proficiency may be improved by standardising critical reagents, including antigens, and by developing a standard B mallei serum. PMID- 27122500 TI - Bovine besnoitiosis (Besnoitia besnoiti) in an Irish dairy herd. AB - Bovine besnoitiosis, caused by the apicomplexan protozoan parasite Besnoitia besnoiti, was diagnosed in an Irish dairy herd. This is the first diagnosis of besnoitiosis in Ireland or the UK and the most northerly European outbreak yet described. The diagnosis occurred following a farm investigation in June 2015 into an unusual dermatological problem that had been ongoing since 2010. On an annual basis, 1-2 per cent of cows in the herd exhibited clinical signs, including skin thickening, alopecia, weight loss and poor performance. Others displayed pyrexia, limb oedema, respiratory distress and reduced milk yield. Histopathological examination of skin revealed granulomatous and eosinophilic dermatitis, with characteristic intradermal protozoal cysts, consistent with cutaneous besnoitiosis. Follow-up serological testing and clinical examination of cattle (n=228) on the farm found that 68 per cent (144/212) were seropositive for B. besnoiti In addition, 51 per cent (117/228) had characteristic scleral conjunctival cysts and 68 per cent (134/198) had vulval cysts. Postmortem examination of a severely affected animal revealed typical gross and histopathological lesions of B. besnoiti infection. These results confirmed endemic infection with B. besnoiti The identification of this exotic disease highlights the importance of veterinary surveillance at both local and national level, particularly in relation to emerging diseases. PMID- 27122501 TI - Editorial: Yes, we still need scientific congresses. PMID- 27122502 TI - Commentary: Clinical and financial benefits of intra-articular tranexamic acid in total knee arthroplasty. PMID- 27122503 TI - Clinical and financial benefits of intra-articular tranexamic acid in total knee arthroplasty. AB - PURPOSE: To determine whether intra-articular tranexamic acid (TXA) use after total knee arthroplasty (TKA) results in decreased postoperative blood transfusion and length of hospital stay. METHODS: Medical records of 1981 patients (mean age, 69.2 years) who underwent primary TKA with (n=1006) or without (n=975) TXA use by any of 4 knee arthroplasty surgeons were reviewed. TXA (3000 mg/30ml) was administered via an epidural catheter into the knee joint after wound closure. Postoperative blood transfusion was given to patients with haemoglobin (Hb) level <80 g/dl on days 1 and 2 or with symptoms of acute anaemia. RESULTS: Intra-articular TXA use after TKA resulted in a lower blood transfusion rate (4.5% [45/1006] vs. 14.8% [144/975], p<0.0001), fewer units of blood transfused (86 vs. 313 units, p<0.0001), fewer units of blood transfused per 100 patients (8.5 vs. 32.1, p<0.0001), and shorter length of hospital stay (4.7+/-2.3 vs. 5.3+/-2.7 days, p<0.0001). Total cost savings with respect to the reduction in blood transfusion was AU$143.68 per patient. When the change in length of hospital stay and TXA costs were included, the overall saving was AU$631.36 per patient. CONCLUSION: Intra-articular TXA use can reduce costs as a result of decreased blood transfusion rate and length of hospital stay in patients undergoing TKA. PMID- 27122504 TI - Quality of cementation in conventional versus minimally invasive total knee arthroplasty. AB - PURPOSE: To review the immediate postoperative radiographs of 108 patients following conventional or minimally invasive total knee arthroplasty (TKA) to assess the quality of cementation in terms of cement voids and retained cement. METHODS: Records of 20 male and 88 female consecutive patients aged 50 to 83 (mean, 67.5) years who underwent conventional TKA (n=56) or computer-assisted minimally invasive TKA (n=52) for osteoarthritis by a single senior surgeon were reviewed. Immediate postoperative radiographs were assessed by a single blinded assessor for the quality of cementation in terms of cement void and retained cement in different zones of the femoral, tibial, and patellar components along the prosthesis-bone interface using the Knee Society total knee arthroplasty roentgenographic evaluation and scoring system. RESULTS: The 2 groups were comparable in terms of baseline demographics as well as cement void and retained cement on the femoral, tibial, and patellar components, except that in the minimally invasive group, cement void beneath the anterior flange of the femoral component was wider (0.32 vs. 0 mm, p=0.001), and retained cement in the posterior or lateral aspects of the tibial component was more common (50.0% vs. 28.6%, p=0.018). CONCLUSION: Minimally invasive TKA resulted in a wider cement void beneath the anterior flange of the femoral component and a higher rate of retained cement around the tibial component. PMID- 27122505 TI - Posterior condylar cartilage thickness and posterior condylar offset of the femur: a magnetic resonance imaging study. AB - PURPOSE: To measure the femoral posterior condylar cartilage (PCC) thickness and the posterior condylar offset (PCO) and determine the correlation between the 2 parameters in 530 normal subjects using magnetic resonance imaging (MRI). METHODS: Records of 287 male and 243 female patients (mean age, 40.7 years) who underwent MRI for traumatic soft tissue knee injuries not involving the femoral PCC and did not have symptomatic knee arthritis were reviewed. RESULTS: The PCC thickness was comparable in the lateral and medial sides (2.04 vs. 1.99 mm, p=0.13). Males had thicker PCC in the medial (2.05 vs. 1.92 mm, p=0.0006) and lateral (2.16 vs. 1.86, p<0.0001) sides than females. Age did not correlate with PCC thickness. The bony PCO was larger in the medial than lateral side (25.8 vs. 22.6 mm, p<0.0001). Males had a larger PCO than females in the medial side only (26.1 vs. 25.5 mm, p = 0.0195). The bony PCO did not correlate with PCC thickness. CONCLUSION: Femoral PCC thickness was comparable in the medial and lateral sides. Males had thicker PCC in the medial and lateral sides than females. PMID- 27122506 TI - Weekly injection of teriparatide for bone ingrowth after cementless total knee arthroplasty. AB - PURPOSE: To compare bone mineral density (BMD) in patients with or without weekly injection of teriparatide to promote bone ingrowth after cementless total knee arthroplasty (TKA). METHODS: Records of 8 men and 32 women (mean age, 75.6 years) who underwent cementless TKA for medial knee osteoarthritis with (n=20) or without (n=20) once-weekly subcutaneous/hypodermic injection of teriparatide for 48 weeks were reviewed. BMD and bone volume/total volume (BV/TV) of the bone prosthesis interface of the proximal tibia in 6 regions of interest (ROI) were assessed at 3, 6, 9, and 12 months using multi-detector computed tomography. RESULTS: Patients with or without weekly injection of teriparatide after cementless TKA were comparable in terms of baseline characteristics and pre- and post-operative knee range of motion and Knee Society knee and function scores. In ROI 1 (medial), ROI 3 (anteromedial), and ROI 4 (posteromedial), the BV/TV increased throughout the postoperative period in patients with weekly injection of teriparatide and declined after 6 months in patients without weekly injection of teriparatide. These 3 ROIs of the 2 groups differed significantly only in BMD at 6, 9, and 12 months. In ROI 2 (lateral), ROI 5 (anterolateral), and ROI 6 (posterolateral), both BV/TV and BMD showed a decreasing trend, and these 3 ROIs of the 2 groups did not differ significantly. CONCLUSION: Weekly injection of teriparatide after cementless TKA promoted bone ingrowth mostly in the medial aspect of the bone-prosthesis interface. PMID- 27122507 TI - A Kirschner wire as a transverse-axis guide to improve acetabular cup positioning. AB - PURPOSE: To compare cup-positioning accuracy in total hip arthroplasty (THA) with or without use of a Kirschner wire as a transverse-axis guide for pelvic alignment. METHODS: Records of 18 men and 73 women (mean age, 60 years) who underwent primary THA with (n=49) or without (n=42) use of a Kirschner wire as a transverse-axis guide for pelvic alignment were reviewed. A 2.4-mm Kirschner wire as a transversea-xis guide was inserted to the anterior superior iliac spine and was parallel to a line linking the left and right anterior superior iliac spine. The safe zone for cup positioning was defined as 30o to 50 degrees abduction and 10o to 30o anteversion. Of the 5 operative surgeons, 2 were classified as experienced (total surgical volume >300) and 3 as inexperienced (total surgical volume of <50). The proportion of patients with the cup in the safe zone was compared in patients with or without use of the transverse-axis guide and in experienced and inexperienced surgeons. RESULTS: For inexperienced surgeons, the use of the transverse-axis guide significantly improved the proportion of patients with the cup in the safe zone from 90% to 100% for abduction, from 50% to 82.4% for anteversion, and from 40% to 82.4% for both. Patients with the cup inside or outside the safe zone were comparable in terms of body height, weight, BMI, subcutaneous fat thickness, incision length, and acetabular cup size. CONCLUSION: The use of the transverse-axis guide improved the accuracy of cup positioning by inexperienced surgeons. PMID- 27122508 TI - Midterm outcome of total hip arthroplasty for rapidly destructive coxarthrosis. AB - PURPOSE: To compare the midterm outcome in 12 women who underwent total hip arthroplasty (THA) for rapidly destructive coxarthrosis (RDC) and in 12 controls who underwent THA for osteoarthritis. METHODS: Records of 12 women aged 50 to 80 (mean, 72.3) years who underwent THA for RDC after a mean of 9 (range, 4-11) months since symptom onset were reviewed. They were compared with 12 age-and sex matched controls who underwent THA for primary or secondary osteoarthritis. Acetabular bone deficiency of the 12 RDC patients was classified as type I (n=7), type II (n=4), or type III (n=1). Type I was treated with cementless THA, and types II and III were treated with THA with a cemented acetabular component. The femoral component was cementless. Pre- and post-operative Harris Hip Score was assessed. Radiographs of the hip were evaluated for implant migration, osteolysis, and periprosthetic radiolucency in the acetabulum and proximal femur. RESULTS: The 12 women who underwent THA for RDC and the 12 controls who underwent THA for osteoarthritis were comparable in terms of pre-, intra-, and post operative parameters. After a mean follow-up of 9.3 years, the mean Harris Hip Score improved from 38.3 to 81.1 in RDC patients and from 43.6 to 84.2 in controls (p=0.13). One RDC patient had dislocation but did not require revision surgery. One RDC patient developed a radiolucent line <2 mm in zones 1 and 7 of the femoral component, but no migration occurred. No patient had progression of bony destruction, loosening, osteolysis, migration, or radiolucency of the acetabular component. CONCLUSION: Despite the rapid destruction of the acetabulum and femoral head in RDC patients, cemented or cementless THA achieved a good midterm outcome comparable to that for patients with primary or secondary osteoarthritis. PMID- 27122509 TI - Standard preoperative analgesia with or without fascia iliaca compartment block for femoral neck fractures. AB - PURPOSE: To compare the visual analogue score (VAS) for pain in patients with femoral neck fracture who received standard preoperative analgesia with or without fascia iliaca compartment block (FICB). METHODS: In patients with femoral neck fracture, 69 patients who received standard preoperative analgesia (regular paracetamol 1g 4 times a day, codeine 60 mg 4 times a day, and opioid 10 mg 2 hourly as required) were compared with 50 patients who received standard preoperative analgesia plus FICB. VAS for pain at rest and on movement (hip flexion) was assessed before FICB and 15 minutes, 2 and 8 hours after FICB. The amount of additional opioid required and the incidence of opioid overdose (necessitating administration of naloxone) were determined. RESULTS: VAS for pain was significantly lower after standard analgesia plus FICB than standard analgesia alone (p=0.001). The analgesic effect (pre-score minus post-score) of standard analgesia plus FICB did not differ between genders (p=0.57) or fracture patterns (p=0.79). 19 (38%) patients with standard analgesia plus FICB required no additional opioid analgesia. Compared with standard analgesia alone, addition of FICB reduced the mean dose of opioid from 6.2 to 2.0 (p=0.001) and the number of opioid overdose from 7.2% to 0% (p=0.001). No patient had any complication following FICB. CONCLUSION: In patients with femoral neck fracture, FICB reduced the need for additional opioid analgesia and avoided the risk of opioid overdose and respiratory depression. PMID- 27122510 TI - Trends in the incidence of atypical femoral fractures and bisphosphonate therapy. AB - PURPOSE: To report the trends in the incidence of typical and atypical femoral fractures (AFF) in patients aged >50 years from 2009 to 2014 and in the prescription of bisphosphonates for osteoporosis from 2001 to 2013 in Australia. METHODS: 175 patients aged >50 years presenting to our hospital with an AO type 32 femoral shaft fracture between October 2009 and October 2014 were identified using a trauma database. Of them, 21 male and 110 female patients with a mean age of 75 years were reviewed. Radiographs were reviewed by 2 investigators blinded to the use of bisphosphonates. The femoral shaft fractures were classified as typical or atypical using the American Society of Bone and Mineral Research definition, and their annual incidence was compared. The trend and number of prescriptions for various bisphosphonates in Australia was determined using the Pharmaceutical Benefits Scheme statistics from 2001 to 2013. RESULTS: Of the 131 femoral shaft fractures, 65 were typical and 66 were atypical subtrochanteric (n=19) or diaphyseal (n=47) fractures that were complete (n=60) or incomplete (n=6). Four patients had sequential bilateral AFF. The 66 AFFs accounted for 5% of hip and shaft fractures. Women accounted for 80% of all femoral shaft fractures and 95% of AFF. The proportion of AFF was higher in women than men (63/110 vs. 3/21, relative risk=3.95, 95% CI=1.37- 11.39, p=0.0006). The mean length of hospital stay was 9.7 days shorter in the AFF patients (14.1 vs. 23.8 days, 95% CI=2.6-16.8 days, p=0.008). Patients with AFF were 8 years younger than those with proximal femoral fracture (73 vs. 81 years, p<0.0001). There was no trend in the annual incidence or proportion of AFF from 2009 to 2014 (p=0.70). The bisphosphonate usage was highest in 2007 with 260 000 yearly patient treatments and had declined by 30% by the end of 2013. CONCLUSION: AFF accounted for half of all femoral shaft fractures in patients aged >50 years. Women accounted for 80% of all femoral shaft fractures and 95% of AFF. The incidence of AFF was no longer increasing possibly related to decreased prescription of bisphosphonates in preceding years. PMID- 27122511 TI - Morbidity and in-hospital mortality after hip fracture surgery on weekends versus weekdays. AB - PURPOSE: To compare morbidity and in-hospital mortality in patients who underwent surgery for femoral neck fracture on weekends versus on weekdays. METHODS: Records of 90 men and 225 women (mean age, 80.5 years) who underwent surgery for femoral neck fractures on weekends or public holidays (n=110) or on weekdays (n=205) were retrospectively reviewed. The morbidity and in-hospital mortality of the 2 groups were compared. RESULTS: The 2 groups were comparable in terms of age, sex, and time to surgery, but more hemiarthroplasties were performed on weekdays (35.0% vs. 25.0%, p=0.036). Compared with surgery on weekdays, surgery on weekends was associated with increased in-hospital mortality (3.4% vs. 9.1%, p=0.04). None of the potential confounders (age, type of surgery, presenting hospital, and time to surgery) had a significant effect on in-hospital mortality. CONCLUSION: In patients with femoral neck fractures, surgery on weekends was associated with increased in-hospital mortality but not with increased morbidity after adjusting for confounders, compared with surgery on weekdays. PMID- 27122512 TI - A clinical and ultrasonographic study of risk factors for elbow injury in young baseball players. AB - PURPOSE: To determine the risk factors for elbow injury and its association with glenohumeral internal rotation deficit among young baseball players. METHODS: 229 baseball players aged 9 to 14 (mean, 11) years completed a self-administered questionnaire with items related to years of playing baseball, hours of training per weekday, days of training per week, and past and present experience of elbow pain. Two orthopaedic surgeons measured the range of motion of both shoulders and elbows. Another 2 orthopaedic surgeons performed ultrasonography to detect any elbow abnormality such as fragmentation of the medial epicondylar apophysis and osteochondritis dissecans of the capitellum. Using univariate and multivariable analyses, participants with or without elbow abnormality were compared to determine the risk factors for elbow abnormality. RESULTS: Elbow abnormality was detected in 100 of the participants and comprised osteochondritis dissecans of the capitellum (n=18) and fragmentation of the medial epicondylar apophysis (n=82). Elbow abnormality was associated with being a pitcher, past and present experience of elbow pain, loss of elbow extension, and the side-to-side internal rotation difference. The 100 participants with elbow abnormality were stratified into symptomatic (n=57) or asymptomatic (n=43) of elbow pain. Those with elbow abnormality and elbow pain was associated with being a pitcher. CONCLUSION: Being a pitcher was a risk factor for both elbow abnormality and elbow pain. Nonetheless, 43% of baseball players with elbow abnormality were asymptomatic. The use of ultrasonography was effective in detecting elbow abnormality and enabling early treatment. PMID- 27122513 TI - Bone-peg grafting for osteochondritis dissecans of the humeral capitellum. AB - PURPOSE: To review the outcome of bone-peg grafting for osteochondritis dissecans (OCD) grade II lesions of the humeral capitellum. METHODS: Records of 10 male adolescent baseball players aged 10 to 15 (mean, 12.3) years who underwent bone peg grafting for OCD grade II lesions of the humeral capitellum of the dominant arm were reviewed. The mean time from symptom onset to presentation was 11 (range, 1-36) months. The mean duration of conservative treatment was 5 (range, 1 25) months. The mean time from symptom onset to surgery was 17 (range, 3-39) months; it was >6 months in 6 patients. The mean size of the lesions was 13x14 mm. Patients were assessed for elbow pain, range of elbow and forearm motion, Timmerman- Andrews elbow score, return to sports activity level, and radiographic evidence of healing, osteoarthritic changes, and radial head hypertrophy. RESULTS: The mean follow-up period was 25 (range, 10-52) months. Postoperatively, elbow pain was absent in 6, mild in 2, and moderate in 2 patients. The mean range of elbow motion changed from 136o to 139 degrees (p=0.80). The mean Timmerman Andrews elbow score improved from 163 to 189 (p=0.014); it was excellent in 7, good in 2, and fair in one patient. The mean extent of lesion healing was 71% (range, 33-100%). Five patients achieved complete healing after a mean of 5.2 (range, 5-6) months and returned to sports at a competitive level. The other 5 achieved partial healing of 33 to 56% (mean, 41%) that occurred laterally but not medially. Two of them returned to sports at a competitive level: one changed the throwing side and another had radial head hypertrophy. The remaining 3 underwent arthroscopic debridement of the unhealed lesion at 5, 10, and 15 months. One patient developed secondary osteoarthritis and further underwent costal osteochondral autografting 10 months later. None of the 5 patients with partial healing versus 4 of the 5 patients with complete healing underwent surgery within 6 months of symptom onset. All 3 patients with a dot at the interface versus 2 of the 6 patients with a line at the interface between the fragment and the lesion on MRI had complete healing. CONCLUSION: Bone-peg grafting is a viable option for OCD grade II lesions of the humeral capitellum when performed within 6 months of symptom onset and when the interface between the fragment and the lesion appears as a dot (rather than a line) on MRI. PMID- 27122514 TI - Screw fixation versus arthroplasty versus plate fixation for 3-part radial head fractures. AB - PURPOSE: To compare the outcome following headless compression screw fixation versus radial head arthroplasty versus plate fixation for 3-part Mason types III or IV radial head fracture. METHODS: Records of 25 men and 16 women aged 21 to 80 (mean, 43.3) years who underwent fixation using 2 to 3 2-mm cannulated headless compression screws (n=16), radial head arthroplasty (n=13), or fixation with a 2 mm Synthes plate (n=12) for 3-part Mason types III or IV radial head and neck fracture were reviewed. Treatment option was decided by the surgeon based on the presence of associated injury, neurovascular deficit, and the Mason classification. Bone union, callus formation, and complications (such as heterotopic ossification, malunion, and nonunion) were assessed by an independent registrar or consultant using radiographs. The Mayo Elbow Performance Score and range of motion were assessed by an independent physiotherapist. RESULTS: The median age of the 3 groups were comparable. Associated injuries were most common in patients with arthroplasty, followed by screw fixation and plate fixation (61.5% vs. 50% vs. 33%, p=0.54). The median time to bone union was shorter after screw fixation than plate fixation (55 vs. 86 days, p=0.05). No patient with screw fixation had nonunion, but 4 patients with plate fixation had nonunion. The 3 groups were comparable in terms of the mean Mayo Elbow Performance Score (p=0.56) and the mean range of motion (p=0.45). The complication rate was highest after plate fixation, followed by screw fixation and arthroplasty (50% vs. 18.8% vs. 15.4%, p=0.048). Excluding 20 patients with associated injuries (8 in screw fixation, 8 in arthroplasty, and 4 in plate fixation), the 3 groups were comparable in terms of the median time to bone union (p=0.109), mean Mayo Elbow Performance Score (p=0.260), mean range of motion (p=0.162), and complication rate (p=0.096). CONCLUSION: Headless compression screw fixation is a viable option for 3-part radial head fracture. It achieves earlier bone union with fewer complications. PMID- 27122515 TI - Platelet-rich plasma versus steroid injection for subacromial impingement syndrome. AB - PURPOSE: To compare the 6-week and 6-month outcome in 60 patients who received a single-dose injection of platelet-rich plasma (PRP) or steroid for subacromial impingement syndrome (SIS). METHODS: 22 men and 38 women (mean age, 49.7 years) opted to receive a single-dose injection of PRP (n=30) or steroid (n=30) for SIS that had not responded to conservative treatment for >3 months. The PRP or a mixture of 1 ml 40 mg methylprednisolone and 8 ml prilocaine was administered via a dorsolateral approach through the interval just beneath the dorsal acromial edge. Both groups were instructed to perform standard rotator cuff stretching and strengthening exercises for 6 weeks. The use of non-steroid anti-inflammatory drugs was prohibited. Patients were evaluated before and 6 weeks and 6 months after treatment using the Constant score, visual analogue scale (VAS) for pain, and range of motion (ROM) of the shoulder. RESULTS: No local or systemic complication occurred. Improvement in the Constant score and VAS for pain at week 6 and month 6 was significantly better following steroid than PRP injection. The difference in the Constant score was greater than the mean clinically important difference of 10.4. Nonetheless, the 2 groups were comparable for improvement in ROM of the shoulder. CONCLUSION: Steroid injection was more effective than PRP injection for treatment of SIS in terms of the Constant score and VAS for pain at 6 weeks and 6 months. PMID- 27122516 TI - Single versus double blade technique for skin incision and deep dissection in surgery for closed fracture: a prospective randomised control study. AB - PURPOSE: To compare blade cultures in surgery for closed fracture using a single or double blade technique to determine whether the current practice of double blade technique is justified. METHODS: 155 men and 29 women aged 20 to 60 (mean, 35) years who underwent surgery for closed fracture with healthy skin at the incision site were included. Patients were block randomised to the single (n=92) or double (n=92) blade technique. Blades were sent for bacteriological analysis. Outcome measures were early surgical site infection (SSI) within 30 days and cultures from the blades. RESULTS: The 2 groups were comparable in baseline characteristics. In the single blade group, 6 surgical blades and 2 control blades showed positive cultures; 4 patients developed SSI, but only one had a positive culture from the surgical blade (with different organism isolated from the wound culture). In the double blade group, 6 skin blades, 7 deep blades, and 0 control blade showed positive culture; only 2 patients had the same bacteria grown from both skin and deep blade. Five patients developed SSI, but only one patient had a positive culture from the deep blade (with different organism isolated from the wound culture). The difference in incidence of culture-positive blade or SSI between the 2 groups was not significant. The relative risk of SSI in the single blade group was 0.8. Positive blade culture was not associated with SSI in the single or double blade group. CONCLUSION: The practice of changing blade following skin incision has no effect on reducing early SSI in surgery for closed fracture in healthy patients with healthy skin. PMID- 27122517 TI - Risk factors for early implant-related surgical site infection. AB - PURPOSE: To identify the risk factors and microbes associated with early implant related surgical site infection (SSI). METHODS: Records of 193 implant-related SSIs secondary to primary orthopaedic surgery were reviewed. Early and late SSI was defined as infection diagnosed within and after 3 months of surgery, respectively. RESULTS: Of the 193 implant-related SSIs, 29 were superficial incisional, 127 were deep incisional, and 37 were organ/space-related. 144 (90%) out of 160 SSIs used cefazolin in their prophylactic antibiotic regimen. In univariate analysis, early SSI was associated with diabetes mellitus, American Society of Anesthesiologists (ASA) score of >2, emergency procedures, and lack of antibiotic prophylaxis. In multivariable analysis, early SSI was associated with an ASA score of >2 (p=0.016). CONCLUSION: It is important to cross-check ASA score with co-morbidities to reduce early SSIs. Peri-operative optimisation and antibiotic prophylaxis should be administered prior to surgery. Appropriate modification of antibiotic prophylaxis should be considered. PMID- 27122518 TI - Use of erythrocyte sedimentation rate and C-reactive protein to predict osteomyelitis recurrence. AB - PURPOSE: To determine the association between both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and osteomyelitis recurrence. METHODS: Records of 81 males and 27 females aged 10 to 87 (median, 54) years who underwent antibiotic/ surgical treatment for primary (n=68) or recurrent (n=40) osteomyelitis that was related (n=26) or unrelated (n=82) to a prosthesis were reviewed. Of the 40 cases of osteomyelitis recurrence followed up for a median of 23.4 (range, 0.6-74.0) months, 7 and 33 were related and unrelated to a prosthesis, respectively. The cutoff points of lowest ESR and CRP for osteomyelitis recurrence were calculated. Risk factors for osteomyelitis recurrence were determined. RESULTS: Osteomyelitis recurrence was associated with diabetes mellitus, ischaemic heart disease, non-healing wound, infection in the lower limb, and infection with methicillin-resistant Staphylococcus aureus. The cutoff points of CRP >=5 mg/l and ESR >=20 mm/h were used for osteomyelitis recurrence. Risk factors for osteomyelitis recurrence were ESR >=20 mm/h, infection with methicillin-resistant S aureus, and infection in the lower limb. CONCLUSION: ESR was more sensitive, specific, and independently associated with osteomyelitis recurrence and should be used to guide the duration of antibiotic treatment. PMID- 27122519 TI - Wrist fusion through centralisation of the ulna for recurrent giant cell tumour of the distal radius. AB - PURPOSE: To review the outcome of wide resection and wrist fusion through centralisation of the ulna for recurrent giant cell tumour (GCT) of the distal radius in 10 patients. METHODS: Records of 7 women and 3 men aged 25 to 40 years who underwent wide resection and wrist fusion through centralisation of the ulna for grade I (n=6) and grade II (n=4) recurrent GCT of the distal radius were reviewed. Functional outcome was evaluated using the modified Musculoskeletal Tumor Society scoring system. Grip strength and range of motion of the metacarpophalangeal joint were also assessed. RESULTS: The mean follow-up period was 45 (range, 30-60) months. All tumours were benign and there was no evidence of metastasis. The mean grip strength was 45% (range, 30-70%) of the contralateral side. All patients achieved normal range of motion of the metacarpophalangeal and interphalangeal joints, but 4 patients had an extensor lag of the thumb. The mean time to wrist fusion was 6 (range, 4-8) months: 3 to 4 months for the 6 patients with bone grafting and 5 to 6 months for the 4 patients without bone grafting who developed painful subluxation necessitating total wrist arthrodesis using a plate and morcellised bone grafts. CONCLUSION: Wrist fusion through centralisation of the ulna for recurrent GCT of the distal radius is a viable option, despite a loss of wrist motion. PMID- 27122520 TI - Segmental excision versus intralesional curettage with adjuvant therapy for giant cell tumour of bone. AB - PURPOSE: To review the functional outcome and local recurrence rate of 29 patients who underwent segmental excision or intralesional curettage with adjuvant therapy for giant cell tumour (GCT) of bone. METHODS: Records of 17 men and 12 women (mean age, 30.17 years) who underwent segmental excision (n=18) or intralesional curettage followed by adjuvant therapy (n=11) for GCT of the femur (n=13), tibia (n=8), radius (n=6), or ulna (n=2) were reviewed. Nine of the patients had recurrent GCT of bone and had undergone segmental excision (n=6) or intralesional curettage (n=3) elsewhere. Functional outcome was evaluated using the Musculoskeletal Tumour Society (MSTS) scoring system. RESULTS: The mean follow-up period was 6.4 (range, 3-13.5) years. 14 patients were followed up for 3 to 5 years, 12 for 5 to 10 years, and 3 for >10 years. Of 20 patients with primary GCT of bone, 12 underwent segmental excision and had no recurrence, and 8 underwent intralesional curettage, 2 of whom developed local recurrence. Of the remaining 9 patients with recurrent GCT of bone, there was one re-recurrence in each surgical option. Local recurrence was not associated with Campanacci grading or type of surgery. One of 18 patients with segmental excision and 3 of 11 patients with intralesional curettage had local recurrence (5.6% vs. 27.3%, p=0.139). The MSTS score was excellent in 7, good in 6, moderate in 2, fair in 2, and poor in one patient after segmental excision, whereas the score was excellent in 9 and good in 2 patients after intralesional curettage (p=0.206). The proportion of yielding an excellent outcome was higher after intralesional curettage (38.9% vs. 81.8%, p=0.0289). Nonetheless, the mean MSTS score of the 2 groups was comparable (74.17% vs. 86.36%, p=0.054). CONCLUSION: Local recurrence of GCT was not associated with the surgical option. Nonetheless, intralesional curettage resulted in better functional outcome. PMID- 27122521 TI - Relationship among cervical, thoracic, and lumbopelvic sagittal alignment in healthy adults. AB - PURPOSE: To evaluate the association between cervical sagittal alignment and thoracic/lumbopelvic sagittal alignment in healthy Japanese adults. METHODS: 30 male and 22 female healthy adults aged 22 to 50 years were recruited. Spinal parameters were measured on radiographs, including the cervical sagittal vertical axis, sagittal vertical axis, C7 tilt angle, Ishihara index for cervical lordosis, thoracic kyphosis, lumbar lordosis, sacral slope, pelvic tilt, and pelvic incidence. RESULTS: The C7 tilt angle positively correlated with the Ishihara index (r=0.52, p<0.0001) and thoracic kyphosis (r=0.53, p<0.0001). The Ishihara index positively correlated with thoracic kyphosis (r=0.34, p=0.01) and C7 tilt angle (r=0.52, p<0.0001). Pelvic incidence positively correlated with sacral slope (r=0.45, p=0.001), lumbar lordosis (r=0.26, p=0.07), and pelvic tilt (r=0.29, p=0.03). Compared with men, women had a smaller Ishihara index (0.07 vs. 0.001, p=0.03), thoracic kyphosis (30.5o vs 24.1o, p=0.02), and C7 tilt angle (23.1o vs. 16.8o, p=0.02). Women had less cervical lordosis and thoracic kyphosis, that is, a straighter cervico-thoracic sagittal alignment. CONCLUSION: In healthy Japanese adults, cervical sagittal alignment is associated with thoracic sagittal alignment but not with lumbopelvic alignment. PMID- 27122522 TI - Cage subsidence after anterior cervical discectomy and fusion using a cage alone or combined with anterior plate fixation. AB - PURPOSE: To compare the extent of cage subsidence after anterior cervical discectomy and fusion (ACDF) using a cage alone or combined with anterior plate fixation, and to assess the effect of end plate removal on cage subsidence. METHODS: Records of 23 men and 13 women aged 32 to 82 (mean, 54) years who underwent ACDF for 61 levels using the Solis cage alone (n=46) or combined with anterior plate fixation (n=15) were reviewed. The extent of cage subsidence was determined by comparing immediately postoperative (within one week) with final follow-up radiographs. Cage subsidence was defined as the sum subsidence of the superior and inferior part of the cage into the vertebral body. Mild and major cage subsidence was defined as <=2 mm and >2 mm, respectively. RESULTS: Patients who underwent ACDF using a cage alone or combined with anterior plate fixation were comparable in terms of age, gender, follow-up duration, and number of levels decompressed. Cage subsidence occurred in 33 (54%) of the 61 levels decompressed. In the cage alone group, the extent of cage subsidence was greater (1.68 vs. 0.57 mm, p=0.039) and the rate of major cage subsidence was higher (28% vs. 7%, p=0.08). The inferior part of the cage was more vulnerable to subsidence compared with the superior part (median subsidence: 3.0 vs. 1.4 mm, p<0.0001). Cage subsidence occurred more often when the end plate was removed rather than preserved (58% vs. 18%, p<0.002). CONCLUSION: The extent of cage subsidence was greater after ACDF with cage alone. Cage subsidence occurred more often when the end plate was removed. Additional anterior plate fixation is recommended when the end plate is removed. PMID- 27122523 TI - Transfibular ankle arthrodesis using burring, curettage, multiple drilling, and fixation with two retrograde screws through a single lateral incision. AB - PURPOSE: To review the outcome of 23 ankle arthrodeses using burring, curettage, multiple drilling, and fixation with 2 retrograde screws through a single lateral incision. METHODS: Records of 22 consecutive patients aged 39 to 79 (mean, 62.4) years who underwent 23 ankle arthrodeses for end-stage ankle arthritis were reviewed. Through a single lateral incision, articular cartilage was removed using burring and curettage, and multiple holes were drilled using a Kirschner wire, followed by fixation with 2 retrograde screws. The resected distal fibula was fixed to the distal part of the talus and tibia. The position of the ankle and subtalar joint arthrosis was assessed by 2 orthopaedic specialists. Pre- and post-operative American Orthopaedic Foot and Ankle Society (AOFAS) scores were evaluated. RESULTS: The mean operating time was 122 minutes. The mean follow-up period was 41 months. The mean postoperative ankle alignment was suboptimal: 2.7o varus, 6.7o plantar flexion, and 2.9o internal rotation. The mean AOFAS score improved from 30 to 71 (p<0.01). The postoperative varus ankle alignment was not associated with the AOFAS score (r= -0.13, p=0.569). Of the 23 cases, one was nonunion and 22 achieved bone union after a mean of 5.4 (range, 2-16) months; 3 of them were delayed union. Despite bone union, 7 patients complained of persistent pain; 4 of them had progressive arthrosis of the adjacent subtalar joints (n=2) or subtalar and talonavicular joints (n=2). CONCLUSION: Ankle arthrodesis using burring, curettage, multiple drilling, and fixation with 2 retrograde screws achieved a high union rate and acceptable functional score without serious complications. PMID- 27122524 TI - Expression of inflammation/pain-related genes in the dorsal root ganglion following disc puncture in rats. AB - PURPOSE: To determine the expression of inflammation- and pain-related genes at days 1 and 3 in the dorsal root ganglion (DRG) of rats with or without disc puncture, using real-time quantitative polymerase chain reaction (RT-qPCR) with the TaqMan low-density array (TLDA). METHODS: 53 female Sprague-Dawley rats were used. The left facet joint between L4 and L5 was removed, and the DRG and intervertebral disc between the vertebrae were exposed. The L4-5 intervertebral disc was punctured using a 0.4-mm diameter injection needle (disc puncture group) or left unpunctured (sham group). After one or 3 days, the 53 DRGs were harvested, frozen, and assessed for expression of inflammation-related genes. Total RNA was isolated from the DRGs. Expression of 119 genes related to inflammation and pain in the DRG after disc puncture were analysed using RT-qPCR with the TLDA. RESULTS: Of the 95 inflammation-related genes, 78 genes were reliably detected. Two genes were significantly up-regulated: cysteinyl leukotriene receptor 1 (CYSLTR1) at day 3 and interleukin 2 receptor gamma (IL2RG) at day 1, and one gene was significantly down-regulated: phospholipase C beta 3 (PLCB3) at day 1. Of the 24 pain-related genes, 18 genes were reliably detected. Two genes were significantly up-regulated: nitric oxide synthase 1 (NOS1) at days 1 and 3 and 5-HT2A receptor (HTR2A) at day 1. CONCLUSION: Disc puncture may elicit changes in the expression of a variety of genes. Gene expression profiling is a useful tool for detecting new potential pharmaceutical targets for spinal pain syndromes. PMID- 27122525 TI - Novel stress radiography technique for avulsion fracture of the lateral malleolus in children: a report of three cases. AB - This study reports a novel stress radiography technique to evaluate an avulsion fracture at the lateral malleolus in children. Radiographs in the stress anteroposterior view or the Haraguchi calcaneofibular ligament or anterior tarofibular ligament (ATFL) projection could not detect any fracture; only manual inversion stress radiography in the Haraguchi ATFL projection could identify the avulsion fracture. PMID- 27122526 TI - Total knee arthroplasty with extra- or intra-articular correction technique for arthritic knees with extra-articular deformity of the femur or tibia: a report of three cases. AB - This study reports 3 patients who underwent total knee arthroplasty combined with extra- or intra-articular correction technique for arthritic knees with extra articular deformity of the femur or tibia. PMID- 27122527 TI - Symptomatic epidural haematoma after cervical laminoplasty: a report of three cases. AB - Symptomatic epidural haematoma after cervical laminoplasty is rare. We report 3 patients who required emergency evacuation of an epidural haematoma. Timely diagnosis and removal of the haematoma is important to prevent neurological deficits. The causative factors in these patients were preoperative coagulopathy, hypertension, and the malfunction of a closed-suction drain. PMID- 27122528 TI - Osteochondromatosis and osteochondroma involving bilateral patella and patellar tendon: a case report. AB - We present a 22-year-old man with osteochondromatosis and osteochondroma involving bilateral patella and patellar tendon with restriction of joint movement and severe arthritis. PMID- 27122529 TI - Osteosarcoma of the talus misdiagnosed as ankle arthritis: a case report. AB - We present a 65-year-old man with osteosarcoma of the talus that was misdiagnosed as osteoarthritis. The patient eventually underwent below-knee amputation and adjuvant chemotherapy. PMID- 27122530 TI - Letter to the Editor: Intra-articular tranexamic acid wash during bilateral total knee arthroplasty. PMID- 27122531 TI - Letter to the Editor: Intra-articular tranexamic acid wash during bilateral total knee arthroplasty. PMID- 27122532 TI - Letter to the Editor: Epidural versus intra-articular infusion analgesia following total knee replacement. PMID- 27122533 TI - Letter to the Editor: Curettage without bone grafting for a simple bone cyst in the capitate. PMID- 27122534 TI - Letter to the Editor: Correlation between survival and tumour characteristics in patients with chondrosarcoma. PMID- 27122535 TI - Letter to the Editor: Minimally invasive plate osteosynthesis for proximal humeral fractures. PMID- 27122536 TI - Letter to the Editor: Total knee arthroplasty in women with asymptomatic urinary tract infection. PMID- 27122537 TI - Activation of soluble guanylyl cyclase by BAY 58-2667 improves bladder function in cyclophosphamide-induced cystitis in mice. AB - Activators of soluble guanylyl cyclase (sGC) interact directly with its prosthetic heme group, enhancing the enzyme responsiveness in pathological conditions. This study aimed to evaluate the effects of the sGC activator BAY 58 2667 on voiding dysfunction, protein expressions of alpha1 and beta1 sGC subunits and cGMP levels in the bladder tissues after cyclophosphamide (CYP) exposure. Female C57BL/6 mice (20-25 g) were injected with CYP (300 mg/kg ip) to induce cystitis. Mice were pretreated or not with BAY 58-2667 (1 mg/kg, gavage), given 1 h before CYP injection. The micturition patterns and in vitro bladder contractions were evaluated at 24 h. In freely moving mice, the CYP injection produced reduced the micturition volume and increased the number of urine spots. Cystometric recordings in CYP-injected mice revealed significant increases in basal pressure, voiding frequency, and nonvoiding contractions (NVCs), along with decreases in bladder capacity, intercontraction interval, and compliance. BAY 58 2667 significantly prevented the micturition alterations observed in both freely moving mice and cystometry and normalized the reduced in vitro carbachol-induced contractions in the CYP group. Reduced protein expressions of alpha1 and beta1 sGC subunits and of cGMP levels were observed in the CYP group, all of which were prevented by BAY 58-2667. CYP exposure significantly increased reactive-oxygen species (ROS) generation in both detrusor and urothelium, and this was normalized by BAY 58-2667. The increased myeloperoxidase and cyclooxygenase-2 activities in the bladders of the CYP group remained unchanged by BAY 58-2667. Activators of sGC may constitute a novel and promising therapeutic approach for management of interstitial cystitis. PMID- 27122538 TI - Glomerular pathology and the progression of chronic kidney disease. AB - Structural studies of the glomerulus, largely undertaken in animal models, have informed our understanding of the progression of chronic kidney disease (CKD) for decades. A fundamental tenet of that understanding is that a loss of podocytes underlies progression in many or most cases of progressive CKD. Recent attempts have been made to reconcile earlier findings from glomerular physiology (the primacy of glomerular capillary hypertension in causation of secondary glomerular sclerosis) with structural findings and have suggested a more detailed model of the mechanisms underlying podocyte detachment as viable cells. A new appreciation of the main locus of mechanical challenges to the podocyte (in the filtration slit) may both explain the renoprotective action of some current therapies and help to suggest novel therapeutic strategies. PMID- 27122539 TI - The expression, regulation, and function of Kir4.1 (Kcnj10) in the mammalian kidney. AB - Kir4.1 is an inwardly rectifying potassium (K(+)) channel and is expressed in the brain, inner ear, and kidney. In the kidney, Kir4.1 is expressed in the basolateral membrane of the late thick ascending limb (TAL), the distal convoluted tubule (DCT), and the connecting tubule (CNT)/cortical collecting duct (CCD). It plays a role in K(+) recycling across the basolateral membrane in corresponding nephron segments and in generating negative membrane potential. The renal phenotypes of the loss-function mutations of Kir4.1 include mild salt wasting, hypomagnesemia, hypokalemia, and metabolic alkalosis, suggesting that the disruption of Kir4.1 mainly impairs the transport in the DCT. Patch-clamp experiments and immunostaining demonstrate that Kir4.1 plays a predominant role in determining the basolateral K(+) conductance in the DCT. However, the function of Kir4.1 in the TAL and CNT/CCD is not essential, because K(+) channels other than Kir4.1 are also expressed. The downregulation of Kir4.1 in the DCT reduced basolateral chloride (Cl(-)) conductance, suppressed the expression of ste20 proline-alanine-rich kinase (SPAK), and decreased Na-Cl cotransporter (NCC) expression and activity. This suggests that Kir4.1 regulates NCC expression by the modulation of the Cl(-)-sensitive with-no-lysine kinase-SPAK pathway. PMID- 27122540 TI - Wnt6 regulates epithelial cell differentiation and is dysregulated in renal fibrosis. AB - Diabetic nephropathy is the most common microvascular complication of diabetes mellitus, manifesting as mesangial expansion, glomerular basement membrane thickening, glomerular sclerosis, and progressive tubulointerstitial fibrosis leading to end-stage renal disease. Here we describe the functional characterization of Wnt6, whose expression is progressively lost in diabetic nephropathy and animal models of acute tubular injury and renal fibrosis. We have shown prominent Wnt6 and frizzled 7 (FzD7) expression in the mesonephros of the developing mouse kidney, suggesting a role for Wnt6 in epithelialization. Importantly, TCF/Lef reporter activity is also prominent in the mesonephros. Analysis of Wnt family members in human renal biopsies identified differential expression of Wnt6, correlating with severity of the disease. In animal models of tubular injury and fibrosis, loss of Wnt6 was evident. Wnt6 signals through the canonical pathway in renal epithelial cells as evidenced by increased phosphorylation of GSK3beta (Ser9), nuclear accumulation of beta-catenin and increased TCF/Lef transcriptional activity. FzD7 was identified as a putative receptor of Wnt6. In vitro Wnt6 expression leads to de novo tubulogenesis in renal epithelial cells grown in three-dimensional culture. Importantly, Wnt6 rescued epithelial cell dedifferentiation in response to transforming growth factor-beta (TGF-beta); Wnt6 reversed TGF-beta-mediated increases in vimentin and loss of epithelial phenotype. Wnt6 inhibited TGF-beta-mediated p65-NF-kappaB nuclear translocation, highlighting cross talk between the two pathways. The critical role of NF-kappaB in the regulation of vimentin expression was confirmed in both p65(-/-) and IKKalpha/beta(-/-) embryonic fibroblasts. We propose that Wnt6 is involved in epithelialization and loss of Wnt6 expression contributes to the pathogenesis of renal fibrosis. PMID- 27122541 TI - What we need to know about the effect of lithium on the kidney. AB - Lithium has been a valuable treatment for bipolar affective disorders for decades. Clinical use of lithium, however, has been problematic due to its narrow therapeutic index and concerns for its toxicity in various organ systems. Renal side effects associated with lithium include polyuria, nephrogenic diabetes insipidus, proteinuria, distal renal tubular acidosis, and reduction in glomerular filtration rate. Histologically, chronic lithium nephrotoxicity is characterized by interstitial nephritis with microcyst formation and occasional focal segmental glomerulosclerosis. Nevertheless, this type of toxicity is uncommon, with the strongest risk factors being high serum levels of lithium and longer time on lithium therapy. In contrast, in experimental models of acute kidney injury and glomerular disease, lithium has antiproteinuric, kidney protective, and reparative effects. This paradox may be partially explained by lower lithium doses and short duration of therapy. While long-term exposure to higher psychiatric doses of lithium may be nephrotoxic, short-term low dose of lithium may be beneficial and ameliorate kidney and podocyte injury. Mechanistically, lithium targets glycogen synthase kinase-3beta, a ubiquitously expressed serine/threonine protein kinase implicated in the processes of tissue injury, repair, and regeneration in multiple organ systems, including the kidney. Future studies are warranted to discover the exact "kidney-protective dose" of lithium and test the effects of low-dose lithium on acute and chronic kidney disease in humans. PMID- 27122542 TI - Par3A is dispensable for the function of the glomerular filtration barrier of the kidney. AB - Polarity signaling through the atypical PKC (aPKC)-Par polarity complex is essential for the development and maintenance of the podocyte architecture and the function of the glomerular filtration barrier of the kidney. To study the contribution of Par3A in this complex, we generated a novel Pard3 podocyte specific knockout mouse model by targeting exon 6 of the Pard3 gene. Genetic deletion of Pard3a did not impair renal function, neither at birth nor later in life. Even challenging the animals did not result in glomerular disease. Despite its well-established role in aPKC-mediated signaling, Par3A appears to be dispensable for the function of the glomerular filtration barrier. Moreover, its homolog Pard3b, and not Pard3a, is the dominant Par3 gene expressed in podocytes and found at the basis of the slit diaphragm, where it partially colocalizes with podocin. In conclusion, Par3A function is either dispensable for slit diaphragm integrity, or compensatory mechanisms and a high redundancy of the different polarity proteins, including Par3B, Lgl, or PALS1, maintain the function of the glomerular filtration barrier, even in the absence of Par3A. PMID- 27122544 TI - 50 Years of renal physiology from one man and the perfused tubule: Maurice B. Burg. AB - Technical advancements in research techniques in science are made in slow increments. Even so, large advances from insight and hard work of an individual with a single technique can have astonishing ramifications. Here, we examine the impact of Dr. Maurice B. Burg and the isolated perfused renal tubule technique and celebrate the 50th anniversary of the publication by Dr. Burg and his colleagues of their landmark paper in the American Journal of Physiology in 1966. In this study, we have taken a scientific visualization approach to study the scientific contributions of Dr. Burg and the isolated perfused tubule preparation as determining research impact by the number of research students, postdoctoral fellows, visiting scientists, and national and international collaborators. Additionally, we have examined the research collaborations (first and second generation scientists), established the migrational visualization of the first generation scientists who worked directly with Dr. Burg, quantified the metrics indices, identified and quantified the network of coauthorship of the first generation scientists with their second generation links, and determined the citations analyses of outputs of Dr. Burg and/or his first generation collaborators as coauthors. We also review the major advances in kidney physiology that have been made with the isolated perfused tubule technique. Finally, we are all waiting for the discoveries that the isolated perfused preparation technique will bring during the next 50 years. PMID- 27122543 TI - Collecting duct (pro)renin receptor targets ENaC to mediate angiotensin II induced hypertension. AB - The (pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (ANG II). The present study was conducted to investigate the role of CD PRR during ANG II-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk ANG II infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). ANG II infusion in floxed mice increased urinary renin activity and selectively induced renal medullary alpha-epithelial sodium channel (alpha-ENaC) mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using a volt ohmmeter was transiently stimulated by acute ANG II treatment, which was abolished by a PRR antagonist, PRO20. In a chronic setting, ANG II treatment induced alpha-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated ANG II-induced hypertension. Overall, the present study suggests that CD PRR contributes to ANG II-induced hypertension at least partially via activation of renal medullary ENaC. PMID- 27122545 TI - MAD2B-mediated SnoN downregulation is implicated in fibroblast activation and tubulointerstitial fibrosis. AB - MAD2B, an anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase zeta, is indispensible for mitotic checkpoint control and DNA repair. Previously, we established that MAD2B is expressed in glomerular and tubulointerstitial compartments and participates in high glucose-induced podocyte injury. However, its role in other renal diseases remains elusive. In the present study, we aim to illustrate the potential role of MAD2B in the pathogenesis of renal fibrosis. By immunofluorescence and Western blotting, we found MAD2B expression is obviously increased in tubulointerstitial fibrosis (TIF) patients and unilateral ureteral obstruction (UUO) mice. It is widely accepted that resident fibroblasts are the major source of collagen-producing myofibroblasts during TIF. Therefore, we evaluated the level of MAD2B in fibroblasts (NRK-49F) exposed to transforming growth factor (TGF)-beta1 by immunoblotting and revealed that MAD2B is upregulated in a time-dependent manner. Intriguingly, SnoN, a transcriptional repressor of the TGF-beta1/Smad signaling pathway, is decreased in TGF-beta1-treated fibroblasts as well as the kidney cortex from TIF patients and UUO mice. Either in vitro or in vivo, local genetic depletion of MAD2B by lentiviral transfection could preserve SnoN abundance and suppress Smad3 phosphorylation, which finally dampens fibroblast activation, ECM accumulation, and alleviates the severity of TIF. However, the ubiquitin ligase APC/C is not involved in the MAD2B-mediated SnoN decline, although this process is ubiquitination dependent. In conclusion, our observation proposes that besides cell cycle management, MAD2B has a profibrotic role during fibroblast activation and TIF by suppressing SnoN expression. Targeting the MAD2B-SnoN pathway is a promising intervention for TIF. PMID- 27122546 TI - Evaluating the Factors Associated With the Completion of a Community-Based Group Exercise Program Among Older Women. AB - Despite the well-known benefits of exercise, only 50% of U.S. women met recommended physical activity levels in 2014. To combat this issue, the Healthy Aging Regional Collaborative of South Florida has been offering the EnhanceFitness (EF) program in community-based settings since 2008. In the current study, we examined the factors associated with the program completion among older women (>= 60 years). During the first 4 years, 3,829 older women attended EF sessions. Of these, 924 (24.2%) attended the recommended 32 sessions within first 4 months. Results revealed that women who lived in Miami-Dade County, were >= 80 years, and did not report depression and/or risk factors for chronic conditions were more likely to complete EF. Black women were less likely to complete the program. Recognition of these factors might help identify at-risk individuals. More efforts are needed to improve completion rates. Theory-based interventions would allow comprehensive understanding of all factors and, therefore, should be explored in the future. PMID- 27122547 TI - A biorobotic model of the suction-feeding system in largemouth bass: the roles of motor program speed and hyoid kinematics. AB - The vast majority of ray-finned fishes capture prey through suction feeding. The basis of this behavior is the generation of subambient pressure through rapid expansion of a highly kinetic skull. Over the last four decades, results from in vivo experiments have elucidated the general relationships between morphological parameters and subambient pressure generation. Until now, however, researchers have been unable to tease apart the discrete contributions of, and complex relationships among, the musculoskeletal elements that support buccal expansion. Fortunately, over the last decade, biorobotic models have gained a foothold in comparative research and show great promise in addressing long-standing questions in vertebrate biomechanics. In this paper, we present BassBot, a biorobotic model of the head of the largemouth bass (Micropterus salmoides). BassBot incorporates a 3D acrylic plastic armature of the neurocranium, maxillary apparatus, lower jaw, hyoid, suspensorium and opercular apparatus. Programming of linear motors permits precise reproduction of live kinematic behaviors including hyoid depression and rotation, premaxillary protrusion, and lateral expansion of the suspensoria. BassBot reproduced faithful kinematic and pressure dynamics relative to live bass. We show that motor program speed has a direct relationship to subambient pressure generation. Like vertebrate muscle, the linear motors that powered kinematics were able to produce larger magnitudes of force at slower velocities and, thus, were able to accelerate linkages more quickly and generate larger magnitudes of subambient pressure. In addition, we demonstrate that disrupting the kinematic behavior of the hyoid interferes with the anterior-to posterior expansion gradient. This resulted in a significant reduction in subambient pressure generation and pressure impulse of 51% and 64%, respectively. These results reveal the promise biorobotic models have for isolating individual parameters and assessing their role in suction feeding. PMID- 27122548 TI - A role for acoustic distortion in novel rapid frequency modulation behaviour in free-flying male mosquitoes. AB - We describe a new stereotypical acoustic behaviour by male mosquitoes in response to the fundamental frequency of female flight tones during mating sequences. This male-specific free-flight behaviour consists of phonotactic flight beginning with a steep increase in wing-beat frequency (WBF) followed by rapid frequency modulation (RFM) of WBF in the lead up to copula formation. Male RFM behaviour involves remarkably fast changes in WBF and can be elicited without acoustic feedback or physical presence of the female. RFM features are highly consistent, even in response to artificial tones that do not carry the multi-harmonic components of natural female flight tones. Comparison between audiograms of the robust RFM behaviour and the electrical responses of the auditory Johnston's organ (JO) reveals that the male JO is tuned not to the female WBF per se but, remarkably, to the difference between the male and female WBFs. This difference is generated in the JO responses as a result of intermodulation distortion products (DPs) caused by non-linear interaction between male-female flight tones in the vibrations of the antenna. We propose that male mosquitoes rely on their own flight tones in making use of DPs to acoustically detect, locate and orientate towards flying females. We argue that the previously documented flight tone harmonic convergence of flying male and female mosquitoes could be a consequence of WBF adjustments so that DPs generated through flight-tone interaction fall within the optimal frequency ranges for JO detection. PMID- 27122549 TI - Biomarkers associated with checkpoint inhibitors. AB - Checkpoint inhibitors (CPI), namely anti-CTLA4 and anti-PD1/PD-L1 antibodies, demonstrated efficacy across multiple types of cancer. However, only subgroups of patients respond to these therapies. Additionally, CPI can induce severe immune related adverse events (irAE). Biomarkers that predict efficacy and toxicity may help define the patients who may benefit the most from these costly and potentially toxic therapies. In this study, we review the main biomarkers that have been associated with the efficacy (pharmacodynamics and clinical benefit) and the toxicity (irAE) of CPIs in patients. PMID- 27122550 TI - Evidence for r- and K-selection in a wild bird population: a reciprocal link between ecology and evolution. AB - Understanding the variation in selection pressure on key life-history traits is crucial in our rapidly changing world. Density is rarely considered as a selective agent. To study its importance, we partition phenotypic selection in fluctuating environments into components representing the population growth rate at low densities and the strength of density dependence, using a new stochastic modelling framework. We analysed the number of eggs laid per season in a small song-bird, the great tit, and found balancing selection favouring large clutch sizes at small population densities and smaller clutches in years with large populations. A significant interaction between clutch size and population size in the regression for the Malthusian fitness reveals that those females producing large clutch sizes at small population sizes also are those that show the strongest reduction in fitness when population size is increased. This provides empirical support for ongoing r- and K-selection in this population, favouring phenotypes with large growth rates r at small population sizes and phenotypes with high competitive skills when populations are close to the carrying capacity K This selection causes long-term fluctuations around a stable mean clutch size caused by variation in population size, implying that r- and K-selection is an important mechanism influencing phenotypic evolution in fluctuating environments. This provides a general link between ecological dynamics and evolutionary processes, operating through a joint influence of density dependence and environmental stochasticity on fluctuations in population size. PMID- 27122551 TI - Biotic and abiotic variables influencing plant litter breakdown in streams: a global study. AB - Plant litter breakdown is a key ecological process in terrestrial and freshwater ecosystems. Streams and rivers, in particular, contribute substantially to global carbon fluxes. However, there is little information available on the relative roles of different drivers of plant litter breakdown in fresh waters, particularly at large scales. We present a global-scale study of litter breakdown in streams to compare the roles of biotic, climatic and other environmental factors on breakdown rates. We conducted an experiment in 24 streams encompassing latitudes from 47.8 degrees N to 42.8 degrees S, using litter mixtures of local species differing in quality and phylogenetic diversity (PD), and alder (Alnus glutinosa) to control for variation in litter traits. Our models revealed that breakdown of alder was driven by climate, with some influence of pH, whereas variation in breakdown of litter mixtures was explained mainly by litter quality and PD. Effects of litter quality and PD and stream pH were more positive at higher temperatures, indicating that different mechanisms may operate at different latitudes. These results reflect global variability caused by multiple factors, but unexplained variance points to the need for expanded global-scale comparisons. PMID- 27122552 TI - Coevolution of venom function and venom resistance in a rattlesnake predator and its squirrel prey. AB - Measuring local adaptation can provide insights into how coevolution occurs between predators and prey. Specifically, theory predicts that local adaptation in functionally matched traits of predators and prey will not be detected when coevolution is governed by escalating arms races, whereas it will be present when coevolution occurs through an alternate mechanism of phenotype matching. Here, we analyse local adaptation in venom activity and prey resistance across 12 populations of Northern Pacific rattlesnakes and California ground squirrels, an interaction that has often been described as an arms race. Assays of venom function and squirrel resistance show substantial geographical variation (influenced by site elevation) in both venom metalloproteinase activity and resistance factor effectiveness. We demonstrate local adaptation in the effectiveness of rattlesnake venom to overcoming present squirrel resistance, suggesting that phenotype matching plays a role in the coevolution of these molecular traits. Further, the predator was the locally adapted antagonist in this interaction, arguing that rattlesnakes are evolutionarily ahead of their squirrel prey. Phenotype matching needs to be considered as an important mechanism influencing coevolution between venomous animals and resistant prey. PMID- 27122554 TI - New insights on equid locomotor evolution from the lumbar region of fossil horses. AB - The specialization of equid limbs for cursoriality is a classic case of adaptive evolution, but the role of the axial skeleton in this famous transition is not well understood. Extant horses are extremely fast and efficient runners, which use a stiff-backed gallop with reduced bending of the lumbar region relative to other mammals. This study tests the hypothesis that stiff-backed running in horses evolved in response to evolutionary increases in body size by examining lumbar joint shape from a broad sample of fossil equids in a phylogenetic context. Lumbar joint shape scaling suggests that stability of the lumbar region does correlate with size through equid evolution. However, scaling effects were dampened in the posterior lumbar region, near the sacrum, which suggests strong selection for sagittal mobility in association with locomotor-respiratory coupling near the lumbosacral joint. I hypothesize that small-bodied fossil horses may have used a speed-dependent running gait, switching between stiff backed and flex-backed galloping as speed increased. PMID- 27122553 TI - Sexual selection on male vocal fundamental frequency in humans and other anthropoids. AB - In many primates, including humans, the vocalizations of males and females differ dramatically, with male vocalizations and vocal anatomy often seeming to exaggerate apparent body size. These traits may be favoured by sexual selection because low-frequency male vocalizations intimidate rivals and/or attract females, but this hypothesis has not been systematically tested across primates, nor is it clear why competitors and potential mates should attend to vocalization frequencies. Here we show across anthropoids that sexual dimorphism in fundamental frequency (F0) increased during evolutionary transitions towards polygyny, and decreased during transitions towards monogamy. Surprisingly, humans exhibit greater F0 sexual dimorphism than any other ape. We also show that low-F0 vocalizations predict perceptions of men's dominance and attractiveness, and predict hormone profiles (low cortisol and high testosterone) related to immune function. These results suggest that low male F0 signals condition to competitors and mates, and evolved in male anthropoids in response to the intensity of mating competition. PMID- 27122555 TI - Molecular assessment of the effect of light and heterotrophy in the scleractinian coral Stylophora pistillata. AB - Corals acquire nutrients via the transfer of photosynthates by their endosymbionts (autotrophy), or via zooplankton predation by the animal (heterotrophy). During stress events, corals lose their endosymbionts, and undergo starvation, unless they increase their heterotrophic capacities. Molecular mechanisms by which heterotrophy sustains metabolism in stressed corals remain elusive. Here for the first time, to the best of our knowledge, we identified specific genes expressed in heterotrophically fed and unfed colonies of the scleractinian coral Stylophora pistillata, maintained under normal and light-stress conditions. Physiological parameters and gene expression profiling demonstrated that fed corals better resisted stress than unfed ones by exhibiting less oxidative damage and protein degradation. Processes affected in light stressed unfed corals (HLU), were related to energy and metabolite supply, carbohydrate biosynthesis, ion and nutrient transport, oxidative stress, Ca(2+) homeostasis, metabolism and calcification (carbonic anhydrases, calcium transporting ATPase, bone morphogenetic proteins). Two genes (cp2u1 and cp1a2), which belong to the cytochrome P450 superfamily, were also upregulated 249 and 10 times, respectively, in HLU corals. In contrast, few of these processes were affected in light-stressed fed corals (HLF) because feeding supplied antioxidants and energetic molecules, which help repair oxidative damage. Altogether, these results show that heterotrophy helps prevent the cascade of metabolic problems downstream of oxidative stress. PMID- 27122556 TI - Consecutive cohort effects driven by density-dependence and climate influence early-life survival in a long-lived bird. AB - Conditions during early life, including maternal cohort effects, can influence the future fitness of individuals. This may be particularly true for long distance migrating birds, because, apart from conditions experienced by cohorts during rearing, conditions during early life in regions far from breeding grounds may also influence their population dynamics. Very little is known about the fitness consequences of those conditions experienced by juveniles after independence, especially in wild populations and for long-lived birds. We used multi-event capture-recapture-recovery models and a unique 26-year dataset for the Audouin's gull (Larus audouinii) to assess for the first time whether survival was influenced by early conditions, both during the rearing period (i.e. a maternal cohort effect potentially affected by density dependence) and the first winter (i.e. a cohort effect driven by climate when birds disperse to wintering grounds). Our results show that juvenile survival was highly sensitive to early-life conditions and that survival decreased with stronger density dependence and harsh climate. The two consecutive cohort effects were of similar magnitude and they may represent a selection filter. Thus, early-life conditions had a strong impact on survival, and neglecting this complexity may hinder our understanding on how populations of long-lived animals fluctuate and respond to perturbations. PMID- 27122557 TI - Intoxicated copepods: ingesting toxic phytoplankton leads to risky behaviour. AB - Understanding interactions between harmful algal bloom (HAB) species and their grazers is essential for determining mechanisms of bloom proliferation and termination. We exposed the common calanoid copepod, Temora longicornis to the HAB species Alexandrium fundyense and examined effects on copepod survival, ingestion, egg production and swimming behaviour. A. fundyense was readily ingested by T. longicornis and significantly altered copepod swimming behaviour without affecting copepod survival or fitness. A. fundyense caused T. longicornis to increase their swimming speed, and the straightness of their path long after the copepods had been removed from the A. fundyense treatment. Models suggest that these changes could lead to a 25-56% increase in encounter frequency between copepods and their predators. This work highlights the need to determine how ingesting HAB species alters grazer behaviour as this can have significant impacts on the fate of HAB toxins in marine systems. PMID- 27122558 TI - Maintenance of biodiversity on islands. AB - MacArthur and Wilson's theory of island biogeography predicts that island species richness should increase with island area. This prediction generally holds among large islands, but among small islands species richness often varies independently of island area, producing the so-called 'small-island effect' and an overall biphasic species-area relationship (SAR). Here, we develop a unified theory that explains the biphasic island SAR. Our theory's key postulate is that as island area increases, the total number of immigrants increases faster than niche diversity. A parsimonious mechanistic model approximating these processes reproduces a biphasic SAR and provides excellent fits to 100 archipelago datasets. In the light of our theory, the biphasic island SAR can be interpreted as arising from a transition from a niche-structured regime on small islands to a colonization-extinction balance regime on large islands. The first regime is characteristic of classic deterministic niche theories; the second regime is characteristic of stochastic theories including the theory of island biogeography and neutral theory. The data furthermore confirm our theory's key prediction that the transition between the two SAR regimes should occur at smaller areas, where immigration is stronger (i.e. for taxa that are better dispersers and for archipelagos that are less isolated). PMID- 27122559 TI - The colonization history of British water vole (Arvicola amphibius (Linnaeus, 1758)): origins and development of the Celtic fringe. AB - The terminal Pleistocene and Early Holocene, a period from 15 000 to 18 000 Before Present (BP), was critical in establishing the current Holarctic fauna, with temperate-climate species largely replacing cold-adapted ones at mid latitudes. However, the timing and nature of this process remain unclear for many taxa, a point that impacts on current and future management strategies. Here, we use an ancient DNA dataset to test more directly postglacial histories of the water vole (Arvicola amphibius, formerly A terrestris), a species that is both a conservation priority and a pest in different parts of its range. We specifically examine colonization of Britain, where a complex genetic structure can be observed today. Although we focus on population history at the limits of the species' range, the inclusion of additional European samples allows insights into European postglacial colonization events and provides a molecular perspective on water vole taxonomy. PMID- 27122560 TI - Crossing fitness valleys: empirical estimation of a fitness landscape associated with polymorphic mimicry. AB - Characterizing fitness landscapes associated with polymorphic adaptive traits enables investigation of mechanisms allowing transitions between fitness peaks. Here, we explore how natural selection can promote genetic mechanisms preventing heterozygous phenotypes from falling into non-adaptive valleys. Polymorphic mimicry is an ideal system to investigate such fitness landscapes, because the direction of selection acting on complex mimetic colour patterns can be predicted by the local mimetic community composition. Using more than 5000 artificial butterflies displaying colour patterns exhibited by the polymorphic Mullerian mimic Heliconius numata, we directly tested the role of wild predators in shaping fitness landscapes. We compared predation rates on mimetic phenotypes (homozygotes at the supergene controlling colour pattern), intermediate phenotypes (heterozygotes), exotic morphs (absent from the local community) and palatable cryptic phenotypes. Exotic morphs were significantly more attacked than local morphs, highlighting predators' discriminatory capacities. Overall, intermediates were attacked twice as much as local homozygotes, suggesting the existence of deep fitness valleys promoting strict dominance and reduced recombination between supergene alleles. By including information on predators' colour perception, we also showed that protection on intermediates strongly depends on their phenotypic similarity to homozygous phenotypes and that ridges exist between similar phenotypes, which may facilitate divergence in colour patterns. PMID- 27122561 TI - Temporal and spatial expression patterns of biomineralization proteins during early development in the stony coral Pocillopora damicornis. AB - Reef-building corals begin as non-calcifying larvae that, upon settling, rapidly begin to accrete skeleton and a protein-rich skeletal organic matrix that attach them to the reef. Here, we characterized the temporal and spatial expression pattern of a suite of biomineralization genes during three stages of larval development in the reef-building coral Pocillopora damicornis: stage I, newly released; stage II, oral-aborally compressed and stage III, settled and calcifying spat. Transcriptome analysis revealed 3882 differentially expressed genes that clustered into four distinctly different patterns of expression change across the three developmental stages. Immunolocalization analysis further reveals the spatial arrangement of coral acid-rich proteins (CARPs) in the overall architecture of the emerging skeleton. These results provide the first analysis of the timing of the biomineralization 'toolkit' in the early life history of a stony coral. PMID- 27122562 TI - Metapopulation dominance and genomic-island acquisition of Bradyrhizobium with superior catabolic capabilities. AB - Root nodule-forming rhizobia exhibit a bipartite lifestyle, replicating in soil and also within plant cells where they fix nitrogen for legume hosts. Host control models posit that legume hosts act as a predominant selective force on rhizobia, but few studies have examined rhizobial fitness in natural populations. Here, we genotyped and phenotyped Bradyrhizobium isolates across more than 800 km of the native Acmispon strigosus host range. We sequenced chromosomal genes expressed under free-living conditions and accessory symbiosis loci expressed in planta and encoded on an integrated 'symbiosis island' (SI). We uncovered a massive clonal expansion restricted to the Bradyrhizobium chromosome, with a single chromosomal haplotype dominating populations, ranging more than 700 km, and acquiring 42 divergent SI haplotypes, none of which were spatially widespread. For focal genotypes, we quantified utilization of 190 sole-carbon sources relevant to soil fitness. Chromosomal haplotypes that were both widespread and dominant exhibited superior growth on diverse carbon sources, whereas these patterns were not mirrored among SI haplotypes. Abundance, spatial range and catabolic superiority of chromosomal, but not symbiosis genotypes suggests that fitness in the soil environment, rather than symbiosis with hosts, might be the key driver of Bradyrhizobium dominance. PMID- 27122563 TI - Habituation in non-neural organisms: evidence from slime moulds. AB - Learning, defined as a change in behaviour evoked by experience, has hitherto been investigated almost exclusively in multicellular neural organisms. Evidence for learning in non-neural multicellular organisms is scant, and only a few unequivocal reports of learning have been described in single-celled organisms. Here we demonstrate habituation, an unmistakable form of learning, in the non neural organism Physarum polycephalum In our experiment, using chemotaxis as the behavioural output and quinine or caffeine as the stimulus, we showed that P. polycephalum learnt to ignore quinine or caffeine when the stimuli were repeated, but responded again when the stimulus was withheld for a certain time. Our results meet the principle criteria that have been used to demonstrate habituation: responsiveness decline and spontaneous recovery. To distinguish habituation from sensory adaptation or motor fatigue, we also show stimulus specificity. Our results point to the diversity of organisms lacking neurons, which likely display a hitherto unrecognized capacity for learning, and suggest that slime moulds may be an ideal model system in which to investigate fundamental mechanisms underlying learning processes. Besides, documenting learning in non-neural organisms such as slime moulds is centrally important to a comprehensive, phylogenetic understanding of when and where in the tree of life the earliest manifestations of learning evolved. PMID- 27122564 TI - The evolution of the competition-dispersal trade-off affects alpha- and beta diversity in a heterogeneous metacommunity. AB - Difference in dispersal ability is a key driver of species coexistence in metacommunities. However, the available frameworks for interpreting species diversity patterns in natura often overlook trade-offs and evolutionary constraints associated with dispersal. Here, we build a metacommunity model accounting for dispersal evolution and a competition-dispersal trade-off. Depending on the distribution of carrying capacities among communities, species dispersal values are distributed either around a single strategy (evolutionarily stable strategy, ESS), or around distinct strategies (evolutionary branching, EB). We show that limited dispersal generates spatial aggregation of dispersal traits in ESS and EB scenarios, and that the competition-dispersal trade-off strengthens the pattern in the EB scenario. Importantly, individuals in larger (respectively (resp.) smaller) communities tend to harbour lower (resp. higher) dispersal, especially under the EB scenario. We explore how dispersal evolution affects species diversity patterns by comparing those from our model to the predictions of a neutral metacommunity model. The most marked difference is detected under EB, with distinctive values of both alpha- and beta-diversity (e.g. the dissimilarity in species composition between small and large communities was significantly larger than neutral predictions). We conclude that, from an empirical perspective, jointly assessing community carrying capacity with species dispersal strategies should improve our understanding of diversity patterns in metacommunities. PMID- 27122566 TI - Correction to 'Competition both drives and impedes diversification in a model adaptive radiation'. PMID- 27122565 TI - Biodiversity response to natural gradients of multiple stressors on continental margins. AB - Sharp increases in atmospheric CO2 are resulting in ocean warming, acidification and deoxygenation that threaten marine organisms on continental margins and their ecological functions and resulting ecosystem services. The relative influence of these stressors on biodiversity remains unclear, as well as the threshold levels for change and when secondary stressors become important. One strategy to interpret adaptation potential and predict future faunal change is to examine ecological shifts along natural gradients in the modern ocean. Here, we assess the explanatory power of temperature, oxygen and the carbonate system for macrofaunal diversity and evenness along continental upwelling margins using variance partitioning techniques. Oxygen levels have the strongest explanatory capacity for variation in species diversity. Sharp drops in diversity are seen as O2 levels decline through the 0.5-0.15 ml l(-1) (approx. 22-6 uM; approx. 21-5 matm) range, and as temperature increases through the 7-10 degrees C range. pCO2 is the best explanatory variable in the Arabian Sea, but explains little of the variance in diversity in the eastern Pacific Ocean. By contrast, very little variation in evenness is explained by these three global change variables. The identification of sharp thresholds in ecological response are used here to predict areas of the seafloor where diversity is most at risk to future marine global change, noting that the existence of clear regional differences cautions against applying global thresholds. PMID- 27122567 TI - Biogeographic and bathymetric determinants of brachiopod extinction and survival during the Late Ordovician mass extinction. AB - The Late Ordovician mass extinction (LOME) coincided with dramatic climate changes, but there are numerous ways in which these changes could have driven marine extinctions. We use a palaeobiogeographic database of rhynchonelliform brachiopods to examine the selectivity of Late Ordovician-Early Silurian genus extinctions and evaluate which extinction drivers are best supported by the data. The first (latest Katian) pulse of the LOME preferentially affected genera restricted to deeper waters or to relatively narrow (less than 35 degrees ) palaeolatitudinal ranges. This pattern is only observed in the latest Katian, suggesting that it reflects drivers unique to this interval. Extinction of exclusively deeper-water genera implies that changes in water mass properties such as dissolved oxygen content played an important role. Extinction of genera with narrow latitudinal ranges suggests that interactions between shifting climate zones and palaeobiogeography may also have been important. We test the latter hypothesis by estimating whether each genus would have been able to track habitats within its thermal tolerance range during the greenhouse-icehouse climate transition. Models including these estimates are favoured over alternative models. We argue that the LOME, long regarded as non-selective, is highly selective along biogeographic and bathymetric axes that are not closely correlated with taxonomic identity. PMID- 27122568 TI - Metabolomics of reef benthic interactions reveals a bioactive lipid involved in coral defence. AB - Holobionts are assemblages of microbial symbionts and their macrobial host. As extant representatives of some of the oldest macro-organisms, corals and algae are important for understanding how holobionts develop and interact with one another. Using untargeted metabolomics, we show that non-self interactions altered the coral metabolome more than self-interactions (i.e. different or same genus, respectively). Platelet activating factor (PAF) and Lyso-PAF, central inflammatory modulators in mammals, were major lipid components of the coral holobionts. When corals were damaged during competitive interactions with algae, PAF increased along with expression of the gene encoding Lyso-PAF acetyltransferase; the protein responsible for converting Lyso-PAF to PAF. This shows that self and non-self recognition among some of the oldest extant holobionts involve bioactive lipids identical to those in highly derived taxa like humans. This further strengthens the hypothesis that major players of the immune response evolved during the pre-Cambrian. PMID- 27122569 TI - The DNA of coral reef biodiversity: predicting and protecting genetic diversity of reef assemblages. AB - Conservation of ecological communities requires deepening our understanding of genetic diversity patterns and drivers at community-wide scales. Here, we use seascape genetic analysis of a diversity metric, allelic richness (AR), for 47 reef species sampled across 13 Hawaiian Islands to empirically demonstrate that large reefs high in coral cover harbour the greatest genetic diversity on average. We found that a species's life history (e.g. depth range and herbivory) mediates response of genetic diversity to seascape drivers in logical ways. Furthermore, a metric of combined multi-species AR showed strong coupling to species richness and habitat area, quality and stability that few species showed individually. We hypothesize that macro-ecological forces and species interactions, by mediating species turnover and occupancy (and thus a site's mean effective population size), influence the aggregate genetic diversity of a site, potentially allowing it to behave as an apparent emergent trait that is shaped by the dominant seascape drivers. The results highlight inherent feedbacks between ecology and genetics, raise concern that genetic resilience of entire reef communities is compromised by factors that reduce coral cover or available habitat, including thermal stress, and provide a foundation for new strategies for monitoring and preserving biodiversity of entire reef ecosystems. PMID- 27122570 TI - A bundle improves eye care in PICU. AB - BACKGROUND: Intensive care patients are susceptible to developing painful corneal epithelial deficits. Provision of eye care to prevent deficits was limited in our paediatric intensive care unit (PICU) population. INTERVENTIONS: A new eye care bundle was introduced, comprising a guideline for eye care, the addition of eye lubricants to the electronic prescribing order set for new admissions to PICU and staff education on the importance of eye care. Weekly examinations over a 2-month period following implementation of the bundle evaluated eye care provision and presence of corneal epithelial deficits on ophthalmic examination. RESULTS: Provision of formal eye care improved from 19% to 96%. The incidence of deficits was lower than previously, simple eye ointment reduced the risk of deficits, even in incompletely closed eyes. CONCLUSIONS: Use of an eye care bundle, together with a multidisciplinary team approach to eye care, improves the provision of eye care in PICU. PMID- 27122571 TI - Life without complex I: proteome analyses of an Arabidopsis mutant lacking the mitochondrial NADH dehydrogenase complex. AB - The mitochondrial NADH dehydrogenase complex (complex I) is of particular importance for the respiratory chain in mitochondria. It is the major electron entry site for the mitochondrial electron transport chain (mETC) and therefore of great significance for mitochondrial ATP generation. We recently described an Arabidopsis thaliana double-mutant lacking the genes encoding the carbonic anhydrases CA1 and CA2, which both form part of a plant-specific 'carbonic anhydrase domain' of mitochondrial complex I. The mutant lacks complex I completely. Here we report extended analyses for systematically characterizing the proteome of the ca1ca2 mutant. Using various proteomic tools, we show that lack of complex I causes reorganization of the cellular respiration system. Reduced electron entry into the respiratory chain at the first segment of the mETC leads to induction of complexes II and IV as well as alternative oxidase. Increased electron entry at later segments of the mETC requires an increase in oxidation of organic substrates. This is reflected by higher abundance of proteins involved in glycolysis, the tricarboxylic acid cycle and branched-chain amino acid catabolism. Proteins involved in the light reaction of photosynthesis, the Calvin cycle, tetrapyrrole biosynthesis, and photorespiration are clearly reduced, contributing to the significant delay in growth and development of the double-mutant. Finally, enzymes involved in defense against reactive oxygen species and stress symptoms are much induced. These together with previously reported insights into the function of plant complex I, which were obtained by analysing other complex I mutants, are integrated in order to comprehensively describe 'life without complex I'. PMID- 27122572 TI - Silicon-induced reversibility of cadmium toxicity in rice. AB - Silicon (Si) modulates tolerance to abiotic stresses, but little is known about the reversibility of stress effects by supplementing previously stressed plants with Si. This is surprising since recovery experiments might allow mechanisms of Si-mediated amelioration to be addressed. Rice was exposed to 10 uM CdCl2 for 4 d in hydroponics, followed by 0.6mM Si(OH)4 supplementation for 4 d. Si reversed the effects of Cd, as reflected in plant growth, photosynthesis, elemental composition, and some biochemical parameters. Cd-dependent deregulation of nutrient homeostasis was partially reversed by Si supply. Photosynthetic recovery within 48h following Si supply, coupled with strong stimulation of the ascorbate glutathione system, indicates efficient activation of defense. The response was further verified by transcript analyses with emphasis on genes encoding members of the stress-associated protein (SAP) family. The transcriptional response to Cd was mostly reversed following Si supply. Reprogramming of the Cd response was obvious for Phytochelatin synthase 1, SAP1 , SAP14, and the transcription factor genes AP2/Erf020, Hsf31, and NAC6 whose transcript levels were strongly activated in roots of Cd-stressed rice, but down-regulated in the presence of Si. These findings, together with changes in biochemical parameters, highlight the significance of Si in growth recovery of Cd-stressed rice and indicate a decisive role for readjusting cell redox homeostasis. PMID- 27122573 TI - Improved analysis of C4 and C3 photosynthesis via refined in vitro assays of their carbon fixation biochemistry. AB - Plants operating C3 and C4 photosynthetic pathways exhibit differences in leaf anatomy and photosynthetic carbon fixation biochemistry. Fully understanding this underpinning biochemical variation is requisite to identifying solutions for improving photosynthetic efficiency and growth. Here we refine assay methods for accurately measuring the carboxylase and decarboxylase activities in C3 and C4 plant soluble protein. We show that differences in plant extract preparation and assay conditions are required to measure NADP-malic enzyme and phosphoenolpyruvate carboxylase (pH 8, Mg(2+), 22 degrees C) and phosphoenolpyruvate carboxykinase (pH 7, >2mM Mn(2+), no Mg(2+)) maximal activities accurately. We validate how the omission of MgCl2 during leaf protein extraction, lengthy (>1min) centrifugation times, and the use of non-pure ribulose-1,5-bisphosphate (RuBP) significantly underestimate Rubisco activation status. We show how Rubisco activation status varies with leaf ontogeny and is generally lower in mature C4 monocot leaves (45-60% activation) relative to C3 monocots (55-90% activation). Consistent with their >3-fold lower Rubisco contents, full Rubisco activation in soluble protein from C4 leaves (<5min) was faster than in C3 plant samples (<10min), with addition of Rubisco activase not required for full activation. We conclude that Rubisco inactivation in illuminated leaves primarily stems from RuBP binding to non-carbamylated enzyme, a state readily reversible by dilution during cellular protein extraction. PMID- 27122574 TI - Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies. AB - Although antibodies to the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein have been studied extensively for their ability to block viral infectivity, little data are currently available on nonneutralizing functions of these antibodies, such as their ability to eliminate virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 Env-specific antibodies of diverse specificities, including potent broadly neutralizing and nonneutralizing antibodies, were therefore tested for ADCC against cells infected with a lab-adapted HIV-1 isolate (HIV-1NL4-3), a primary HIV-1 isolate (HIV-1JR FL), and a simian-human immunodeficiency virus (SHIV) adapted for pathogenic infection of rhesus macaques (SHIVAD8-EO). In accordance with the sensitivity of these viruses to neutralization, HIV-1NL4-3-infected cells were considerably more sensitive to ADCC, both in terms of the number of antibodies and magnitude of responses, than cells infected with HIV-1JR-FL or SHIVAD8-EO ADCC activity generally correlated with antibody binding to Env on the surfaces of virus infected cells and with viral neutralization; however, neutralization was not always predictive of ADCC, as instances of ADCC in the absence of detectable neutralization, and vice versa, were observed. These results reveal incomplete overlap in the specificities of antibodies that mediate these antiviral activities and provide insights into the relationship between ADCC and neutralization important for the development of antibody-based vaccines and therapies for combating HIV-1 infection. IMPORTANCE: This study provides fundamental insights into the relationship between antibody-dependent cell mediated cytotoxicity (ADCC) and virus neutralization that may help to guide the development of antibody-based vaccines and immunotherapies for the prevention and treatment of HIV-1 infection. PMID- 27122575 TI - Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry. AB - Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion-TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSVDeltaG), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. IMPORTANCE: With more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor. PMID- 27122577 TI - NSs Virulence Factor of Rift Valley Fever Virus Engages the F-Box Proteins FBXW11 and beta-TRCP1 To Degrade the Antiviral Protein Kinase PKR. AB - Rift Valley fever virus (RVFV, family Bunyaviridae, genus Phlebovirus) is a relevant pathogen of both humans and livestock in Africa. The nonstructural protein NSs is a major virulence factor known to suppress the type I interferon (IFN) response by inhibiting host cell transcription and by proteasomal degradation of a major antiviral IFN effector, the translation-inhibiting protein kinase PKR. Here, we identified components of the modular SCF (Skp1, Cul1, F-box protein)-type E3 ubiquitin ligases as mediators of PKR destruction by NSs. Small interfering RNAs (siRNAs) against the conserved SCF subunit Skp1 protected PKR from NSs-mediated degradation. Consequently, RVFV replication was severely reduced in Skp1-depleted cells when PKR was present. SCF complexes have a variable F-box protein subunit that determines substrate specificity for ubiquitination. We performed an siRNA screen for all (about 70) human F-box proteins and found FBXW11 to be involved in PKR degradation. The partial stabilization of PKR by FBXW11 depletion upregulated PKR autophosphorylation and phosphorylation of the PKR substrate eIF2alpha and caused a shutoff of host cell protein synthesis in RVFV-infected cells. To maximally protect PKR from the action of NSs, knockdown of structurally and functionally related FBXW1 (also known as beta-TRCP1), in addition to FBXW11 deletion, was necessary. Consequently, NSs was found to interact with both FBXW11 and beta-TRCP1. Thus, NSs eliminates the antiviral kinase PKR by recruitment of SCF-type E3 ubiquitin ligases containing FBXW11 and beta-TRCP1 as substrate recognition subunits. This antagonism of PKR by NSs is essential for efficient RVFV replication in mammalian cells. IMPORTANCE: Rift Valley fever virus is a pathogen of humans and animals that has the potential to spread from Africa and the Arabian Peninsula to other regions. A major virulence mechanism is the proteasomal degradation of the antiviral kinase PKR by the viral protein NSs. Here, we demonstrate that NSs requires E3 ubiquitin ligase complexes of the SCF (Skp1, Cul1, F-box protein) type to destroy PKR. SCF-type complexes can engage variant ubiquitination substrate recognition subunits, and we found the F-box proteins FBXW11 and beta TRCP1 to be relevant for the action of NSs against PKR. Thus, we identified the host cell factors that are critically needed by Rift Valley fever virus to uphold its replication against the potent antiviral kinase PKR. PMID- 27122576 TI - Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation. AB - HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4(+) T cells and with less efficient virion production ex vivo We also found that a potent HIV-specific CD8(+) T cell response was present only in those HICs whose CD4(+) T cells produced virus ex vivo Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV specific CD8(+) T cell response to counteract efficient viral reactivation events. IMPORTANCE: There is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4(+) T cells in vitro were the most difficult were those with diminished CD8(+) T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission. PMID- 27122578 TI - Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis. AB - The emergence of a distinct subpopulation of human or simian immunodeficiency virus (HIV/SIV) sequences within the brain (compartmentalization) during infection is hypothesized to be linked to AIDS-related central nervous system (CNS) neuropathology. However, the exact evolutionary mechanism responsible for HIV/SIV brain compartmentalization has not been thoroughly investigated. Using extensive viral sampling from several different peripheral tissues and cell types and from three distinct regions within the brain from two well-characterized rhesus macaque models of the neurological complications of HIV infection (neuroAIDS), we have been able to perform in-depth evolutionary analyses that have been unattainable in HIV-infected subjects. The results indicate that, despite multiple introductions of virus into the brain over the course of infection, brain sequence compartmentalization in macaques with SIV-associated CNS neuropathology likely results from late viral entry of virus that has acquired through evolution in the periphery sufficient adaptation for the distinct microenvironment of the CNS. IMPORTANCE: HIV-associated neurocognitive disorders remain prevalent among HIV type 1-infected individuals, whereas our understanding of the critical components of disease pathogenesis, such as virus evolution and adaptation, remains limited. Building upon earlier findings of specific viral subpopulations in the brain, we present novel yet fundamental results concerning the evolutionary patterns driving this phenomenon in two well characterized animal models of neuroAIDS and provide insight into the timing of entry of virus into the brain and selective pressure associated with viral adaptation to this particular microenvironment. Such knowledge is invaluable for therapeutic strategies designed to slow or even prevent neurocognitive impairment associated with AIDS. PMID- 27122579 TI - Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation. AB - Human cytomegalovirus (HCMV) may cause disseminated/end-organ disease in congenitally infected newborns and immunosuppressed transplant recipients. Two glycoprotein complexes, gH/gL/gO and gH/gL/pUL128/pUL130/pUL131 (gH/gL/pUL128L; referred to as the pentamer), are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively, in the presence of the viral fusion protein gB. In addition, gH/gL/gO was recently reported to also be required for infection of endothelial/epithelial cells. Virus entry into human fibroblasts involves fusion of the virus envelope with the plasma membrane, whereas entry into endothelial/epithelial cells involves macropinocytosis or endocytosis and low-pH-dependent fusion with endosomes. A large set of neutralizing monoclonal antibodies (MAbs), directed to gH, gB, and multiple components of the pentamer, was developed. In addition, novel anti-gO human monoclonal antibodies were recently isolated. It is known that epithelial cell infection with a wild HCMV strain at a high multiplicity of infection produces a large number of syncytia. Incubation of heavily HCMV VR1814-infected ARPE-19 epithelial cells with neutralizing MAbs to one, two, or three components of the pUL128L portion of the pentamer blocked syncytium formation at an antibody concentration of 10 MUg/ml, whereas only a partial inhibitory effect was displayed for MAbs to gO, gH, or gB at the same concentration. A blocking effect was also exhibited by convalescent phase sera from primary HCMV infections. These findings indicate that the pentamer is required for syncytium formation in epithelial cells. IMPORTANCE: Human cytomegalovirus (HCMV) mostly infects epithelial and endothelial cells in vivo Recently, the pentamer protein complex (gH/gL/pUL128L) was identified as being required for infection of these cells, in association with the other protein complex, gH/gL/gO. In primary infections, HCMV migrates to endothelial cells and then to leukocytes, which disseminate the infection throughout the body. The virus then spreads to organs and tissues, mostly infecting either single cells or multinucleated epithelial giant cells (syncytia), depending on the viral load. Potent neutralizing human MAbs directed to distinct binding sites of the pUL128L portion of the pentamer were shown in the past to block virus dissemination. In the present study, MAbs to pUL128L were shown to block syncytium formation with a higher potency than that of MAbs to gO, gH, or gB, thus suggesting their role in limiting virus dissemination. This finding provides additional information useful for the development of anti-HCMV therapeutic antibodies and subunit vaccines. PMID- 27122580 TI - Migration of Nucleocapsids in Vesicular Stomatitis Virus-Infected Cells Is Dependent on both Microtubules and Actin Filaments. AB - The distribution of vesicular stomatitis virus (VSV) nucleocapsids in the cytoplasm of infected cells was analyzed by scanning confocal fluorescence microscopy using a newly developed quantitative approach called the border-to border distribution method. Nucleocapsids were located near the cell nucleus at early times postinfection (2 h) but were redistributed during infection toward the edges of the cell. This redistribution was inhibited by treatment with nocodazole, colcemid, or cytochalasin D, indicating it is dependent on both microtubules and actin filaments. The role of actin filaments in nucleocapsid mobility was also confirmed by live-cell imaging of fluorescent nucleocapsids of a virus containing P protein fused to enhanced green fluorescent protein. However, in contrast to the overall redistribution in the cytoplasm, the incorporation of nucleocapsids into virions as determined in pulse-chase experiments was dependent on the activity of actin filaments with little if any effect on inhibition of microtubule function. These results indicate that the mechanisms by which nucleocapsids are transported to the farthest reaches of the cell differ from those required for incorporation into virions. This is likely due to the ability of nucleocapsids to follow shorter paths to the plasma membrane mediated by actin filaments. IMPORTANCE: Nucleocapsids of nonsegmented negative-strand viruses like VSV are assembled in the cytoplasm during genome RNA replication and must migrate to the plasma membrane for assembly into virions. Nucleocapsids are too large to diffuse in the cytoplasm in the time required for virus assembly and must be transported by cytoskeletal elements. Previous results suggested that microtubules were responsible for migration of VSV nucleocapsids to the plasma membrane for virus assembly. Data presented here show that both microtubules and actin filaments are responsible for mobility of nucleocapsids in the cytoplasm, but that actin filaments play a larger role than microtubules in incorporation of nucleocapsids into virions. PMID- 27122581 TI - Highly Pathogenic Avian Influenza H5N6 Viruses Exhibit Enhanced Affinity for Human Type Sialic Acid Receptor and In-Contact Transmission in Model Ferrets. AB - Since May 2014, highly pathogenic avian influenza H5N6 virus has been reported to cause six severe human infections three of which were fatal. The biological properties of this subtype, in particular its relative pathogenicity and transmissibility in mammals, are not known. We characterized the virus receptor binding affinity, pathogenicity, and transmissibility in mice and ferrets of four H5N6 isolates derived from waterfowl in China from 2013-2014. All four H5N6 viruses have acquired a binding affinity for human-like SAalpha2,6Gal-linked receptor to be able to attach to human tracheal epithelial and alveolar cells. The emergent H5N6 viruses, which share high sequence similarity with the human isolate A/Guangzhou/39715/2014 (H5N6), were fully infective and highly transmissible by direct contact in ferrets but showed less-severe pathogenicity than the parental H5N1 virus. The present results highlight the threat of emergent H5N6 viruses to poultry and human health and the need to closely track their continual adaptation in humans. IMPORTANCE: Extended epizootics and panzootics of H5N1 viruses have led to the emergence of the novel 2.3.4.4 clade of H5 virus subtypes, including H5N2, H5N6, and H5N8 reassortants. Avian H5N6 viruses from this clade have caused three fatalities out of six severe human infections in China since the first case in 2014. However, the biological properties of this subtype, especially the pathogenicity and transmission in mammals, are not known. Here, we found that natural avian H5N6 viruses have acquired a high affinity for human-type virus receptor. Compared to the parental clade 2.3.4 H5N1 virus, emergent H5N6 isolates showed less severe pathogenicity in mice and ferrets but acquired efficient in-contact transmission in ferrets. These findings suggest that the threat of avian H5N6 viruses to humans should not be ignored. PMID- 27122582 TI - Human Norovirus Interactions with Histo-Blood Group Antigens and Human Milk Oligosaccharides. AB - Human noroviruses interact with both human histo-blood group antigens (HBGAs) and human milk oligosaccharides (HMOs). The former are believed to be important for a virus infection, while the latter might act as natural decoys in the host during an infection. However, certain noroviruses are known to bind poorly to HBGAs and yet still cause infections; some interact with numerous HBGA types but are nonprevalent; and yet others bind HBGAs and seem to be increasing in prevalence. HBGAs and HMOs can be found as soluble antigens in humans, can be structurally alike, and can interact with equivalent residues at identical binding pockets on the capsid. In this Gem, we discuss HBGA and HMO binding studies for human noroviruses, concentrating on the clinically important genogroup II noroviruses. In short, the roles of HBGA and HMO interactions in norovirus infections are still unclear. PMID- 27122583 TI - Analysis of Conformational Stability of Abnormal Prion Protein Aggregates across the Spectrum of Creutzfeldt-Jakob Disease Prions. AB - The wide phenotypic variability of prion diseases is thought to depend on the interaction of a host genotype with prion strains that have self-perpetuating biological properties enciphered in distinct conformations of the misfolded prion protein PrP(Sc) This concept is largely based on indirect approaches studying the effect of proteases or denaturing agents on the physicochemical properties of PrP(Sc) aggregates. Furthermore, most data come from studies on rodent-adapted prion strains, making current understanding of the molecular basis of strains and phenotypic variability in naturally occurring diseases, especially in humans, more limited. To fill this gap, we studied the effects of guanidine hydrochloride (GdnHCl) and heating on PrP(Sc) aggregates extracted from 60 sporadic Creutzfeldt Jakob disease (CJD) and 6 variant CJD brains. While denaturation curves obtained after exposure of PrP(Sc) to increasing GdnHCl concentrations showed similar profiles among the 7 CJD types analyzed, PrP(Sc) exposure to increasing temperature revealed significantly different and type-specific responses. In particular, MM1 and VV2, the most prevalent and fast-replicating CJD types, showed stable and highly resistant PrP(Sc) aggregates, whereas VV1, a rare and slowly propagating type, revealed unstable aggregates that easily dissolved at low temperature. Taken together, our results indicate that the molecular interactions mediating the aggregation state of PrP(Sc), possibly enciphering strain diversity, are differently targeted by GdnHCl, temperature, and proteases. Furthermore, the detected positive correlation between the thermostability of PrP(Sc) aggregates and disease transmission efficiency makes inconsistent the proposed hypothesis that a decrease in conformational stability of prions results in an increase in their replication efficiency. IMPORTANCE: Prion strains are defined as infectious isolates propagating distinctive phenotypic traits after transmission to syngeneic hosts. Although the molecular basis of prion strains is not fully understood, it is largely accepted that variations in prion protein conformation drive the molecular changes leading to the different phenotypes. In this study, we exposed abnormal prion protein aggregates encompassing the spectrum of human prion strains to both guanidine hydrochloride and thermal unfolding. Remarkably, while exposure to increasing temperature revealed significant strain-specific differences in the denaturation profile of the protein, treatment with guanidine hydrochloride did not. The findings suggest that thermal and chemical denaturation perturb the structure of prion protein aggregates differently. Moreover, since the most thermostable prion protein types were those associated with the most prevalent phenotypes and most rapidly and efficiently transmitting strains, the results suggest a direct correlation between strain replication efficiency and the thermostability of prion protein aggregates. PMID- 27122584 TI - Biphasic CD8+ T-Cell Defense in Simian Immunodeficiency Virus Control by Acute Phase Passive Neutralizing Antibody Immunization. AB - Identifying human immunodeficiency virus type 1 (HIV-1) control mechanisms by neutralizing antibodies (NAbs) is critical for anti-HIV-1 strategies. Recent in vivo studies on animals infected with simian immunodeficiency virus (SIV) and related viruses have shown the efficacy of postinfection NAb passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. Here, we describe SIV control in macaques showing biphasic CD8(+) cytotoxic T lymphocyte (CTL) responses following acute-phase NAb passive immunization. Analysis of four SIVmac239-infected rhesus macaque pairs matched with major histocompatibility complex class I haplotypes found that counterparts receiving day 7 anti-SIV polyclonal NAb infusion all suppressed viremia for up to 2 years without accumulating viral CTL escape mutations. In the first phase of primary viremia control attainment, CD8(+) cells had high capacities to suppress SIVs carrying CTL escape mutations. Conversely, in the second, sustained phase of SIV control, CTL responses converged on a pattern of immunodominant CTL preservation. During this sustained phase of viral control, SIV epitope-specific CTLs showed retention of phosphorylated extracellular signal-related kinase (ERK)(hi)/phosphorylated AMP-activated protein kinase (AMPK)(lo) subpopulations, implying their correlation with SIV control. The results suggest that virus-specific CTLs functionally boosted by acute-phase NAbs may drive robust AIDS virus control. IMPORTANCE: In early HIV infection, NAb responses are lacking and CTL responses are insufficient, which leads to viral persistence. Hence, it is important to identify immune responses that can successfully control such HIV replication. Here, we show that monkeys receiving NAb passive immunization in early SIV infection strictly control viral replication for years. Passive infusion of NAbs with CTL cross-priming capacity resulted in induction of functionally boosted early CTL responses showing enhanced suppression of CTL escape mutant virus replication. Accordingly, the NAb infused animals did not show accumulation of viral CTL escape mutations during sustained SIV control, and immunodominant CTL responses were preserved. This early functional augmentation of CTLs by NAbs provides key insights into the design of lasting and viral escape mutation-free protective immunity against HIV 1 infection. PMID- 27122585 TI - Colony-Stimulating Factor 1 Receptor Antagonists Sensitize Human Immunodeficiency Virus Type 1-Infected Macrophages to TRAIL-Mediated Killing. AB - Strategies aimed at eliminating persistent viral reservoirs from HIV-1-infected individuals have focused on CD4(+) T-cell reservoirs. However, very little attention has been given to approaches that could promote elimination of tissue macrophage reservoirs. HIV-1 infection of macrophages induces phosphorylation of colony-stimulating factor 1 receptor (CSF-1R), which confers resistance to apoptotic pathways driven by tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), thereby promoting viral persistence. In this study, we assessed whether CSF-1R antagonists (PLX647, PLX3397, and PLX5622) restored apoptotic sensitivity of HIV-1-infected macrophages in vitro PLX647, PLX3397, and PLX5622 at clinically relevant concentrations blocked the activation of CSF-1R and reduced the viability of infected macrophages, as well as the extent of viral replication. Our data show that strategies targeting monocyte colony-stimulating factor (MCSF) signaling could be used to promote elimination of HIV-1-infected myeloid cells and to contribute to the elimination of persistent viral reservoirs. IMPORTANCE: As the HIV/AIDS research field explores approaches to eliminate HIV-1 in individuals on suppressive antiviral therapy, those approaches will need to eliminate both CD4(+) T-cell and myeloid cell reservoirs. Most of the attention has focused on CD4(+) T-cell reservoirs, and scant attention has been paid to myeloid cell reservoirs. The distinct nature of the infection in myeloid cells versus CD4(+) T cells will likely dictate different approaches in order to achieve their elimination. For CD4(+) T cells, most strategies focus on promoting virus reactivation to promote immune-mediated clearance and/or elimination by viral cytopathicity. Macrophages resist viral cytopathic effects and CD8(+) T-cell killing. Therefore, we have explored clearance strategies that render macrophages sensitive to viral cytopathicity. This research helps inform the design of strategies to promote clearance of the macrophage reservoir in infected individuals on suppressive antiviral therapy. PMID- 27122586 TI - Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection. AB - Influenza A and B virus infections both cause a host innate immunity response. Here, we report that the robust production of type I and III interferons (IFNs), IFN-stimulated genes, and proinflammatory factors can be induced by influenza B virus rather than influenza A virus infection in alveolar epithelial (A549) cells during early infection. This response is mainly dependent on the retinoic acid inducible gene I (RIG-I)-mediated signaling pathway. Infection by influenza B virus promotes intense Lys63-linked ubiquitination of RIG-I, resulting in cytokine eruption. It is known that the influenza A virus NS1 protein (NS1-A) interacts with RIG-I and TRIM25 to suppress the activation of RIG-I-mediated signaling. However, the present results indicate that the influenza B virus NS1 protein (NS1-B) is unable to interact with RIG-I but engages in the formation of a RIG-I/TRIM25/NS1-B ternary complex. Furthermore, we demonstrate that the N terminal RNA-binding domain (RBD) of NS1-B is responsible for interaction with TRIM25 and that this interaction blocks the inhibitory effect of the NS1-B C terminal effector domain (TED) on RIG-I ubiquitination. Our findings reveal a novel mechanism for the host cytokine response to influenza B virus infection through regulatory interplay between host and viral proteins. IMPORTANCE: Influenza B virus generally causes local mild epidemics but is occasionally lethal to individuals. Existing studies describe the broad characteristics of influenza B virus epidemiology and pathology. However, to develop better prevention and treatments for the disease, determining the concrete molecular mechanisms of pathogenesis becomes pivotal to understand how the host reacts to the challenge of influenza B virus. Thus, we aimed to characterize the host innate immune response to influenza B virus infection. Here, we show that vigorous Lys63-linked ubiquitination of RIG-I and cytokine eruption dependent on RIG-I-mediated signal transduction are induced by virus infection. Additionally, TRIM25 positively regulates RIG-I-mediated signaling by ablating the inhibitory function of NS1-B on RIG-I ubiquitination. PMID- 27122587 TI - Rearrangement of Influenza Virus Spliced Segments for the Development of Live Attenuated Vaccines. AB - Influenza viral infections represent a serious public health problem, with influenza virus causing a contagious respiratory disease which is most effectively prevented through vaccination. Segments 7 (M) and 8 (NS) of the influenza virus genome encode mRNA transcripts that are alternatively spliced to express two different viral proteins. This study describes the generation, using reverse genetics, of three different recombinant influenza A/Puerto Rico/8/1934 (PR8) H1N1 viruses containing M or NS viral segments individually or modified M or NS viral segments combined in which the overlapping open reading frames of matrix 1 (M1)/M2 for the modified M segment and the open reading frames of nonstructural protein 1 (NS1)/nuclear export protein (NEP) for the modified NS segment were split by using the porcine teschovirus 1 (PTV-1) 2A autoproteolytic cleavage site. Viruses with an M split segment were impaired in replication at nonpermissive high temperatures, whereas high viral titers could be obtained at permissive low temperatures (33 degrees C). Furthermore, viruses containing the M split segment were highly attenuated in vivo, while they retained their immunogenicity and provided protection against a lethal challenge with wild-type PR8. These results indicate that influenza viruses can be effectively attenuated by the rearrangement of spliced segments and that such attenuated viruses represent an excellent option as safe, immunogenic, and protective live attenuated vaccines. Moreover, this is the first time in which an influenza virus containing a restructured M segment has been described. Reorganization of the M segment to encode M1 and M2 from two separate, nonoverlapping, independent open reading frames represents a useful tool to independently study mutations in the M1 and M2 viral proteins without affecting the other viral M product. IMPORTANCE: Vaccination represents our best therapeutic option against influenza viral infections. However, the efficacy of current influenza vaccines is suboptimal, and novel approaches are necessary for the prevention of disease caused by this important human respiratory pathogen. In this work, we describe a novel approach to generate safer and more efficient live-attenuated influenza virus vaccines (LAIVs) based on recombinant viruses whose genomes encode nonoverlapping and independent M1/M2 (split M segment [Ms]) or both M1/M2 and NS1/NEP (Ms and split NS segment [NSs]) open reading frames. Viruses containing a modified M segment were highly attenuated in mice but were able to confer, upon a single intranasal immunization, complete protection against a lethal homologous challenge with wild type virus. Notably, the protection efficacy conferred by our viruses with split M segments was better than that conferred by the current temperature-sensitive LAIV. Altogether, these results open a new avenue for the development of safer and more protective LAIVs on the basis of the reorganization of spliced viral RNA segments in the genome. PMID- 27122588 TI - Furin Cleavage of L2 during Papillomavirus Infection: Minimal Dependence on Cyclophilins. AB - Despite an abundance of evidence supporting an important role for the cleavage of minor capsid protein L2 by cellular furin, direct cleavage of capsid-associated L2 during human papillomavirus 16 (HPV16) infection remains poorly characterized. The conserved cleavage site, close to the L2 N terminus, confounds observation and quantification of the small cleavage product by SDS-PAGE. To overcome this difficulty, we increased the size shift by fusing a compact protein domain, the Propionibacterium shermanii transcarboxylase domain (PSTCD), to the N terminus of L2. The infectious PSTCD-L2 virus displayed an appreciable L2 size shift during infection of HaCaT keratinocytes. Cleavage under standard cell culture conditions rarely exceeded 35% of total L2. Cleavage levels were enhanced by the addition of exogenous furin, and the absolute levels of infection correlated to the level of L2 cleavage. Cleavage occurred on both the HaCaT cell surface and extracellular matrix (ECM). Contrary to current models, experiments on the involvement of cyclophilins revealed little, if any, role for these cellular enzymes in the modulation of furin cleavage. HPV16 L2 contains two consensus cleavage sites, Arg5 (2RHKR5) and Arg12 (9RTKR12). Mutant PSTCD-L2 viruses demonstrated that although furin can cleave either site, cleavage must occur at Arg12, as cleavage at Arg5 alone is insufficient for successful infection. Mutation of the conserved cysteine residues revealed that the Cys22-Cys28 disulfide bridge is not required for cleavage. The PSTCD-L2 virus or similar N-terminal fusions will be valuable tools to study additional cellular and viral determinants of furin cleavage. IMPORTANCE: Furin cleavage of minor capsid protein L2 during papillomavirus infection has been difficult to directly visualize and quantify, confounding efforts to study this important step of HPV infection. Fusion of a small protein domain to the N terminus greatly facilitates direct visualization of the cleavage product, revealing important characteristics of this critical process. Contrary to the current model, we found that cleavage is largely independent of cyclophilins, suggesting that cyclophilins act either in parallel to or downstream of furin to trigger exposure of a conserved N-terminal L2 epitope (RG 1) during infection. Based on this finding, we strongly caution against using L2 RG-1 epitope exposure as a convenient but indirect proxy of furin cleavage. PMID- 27122589 TI - Calcium-Dependent Rubella Virus Fusion Occurs in Early Endosomes. AB - The E1 membrane protein of rubella virus (RuV) is a class II membrane fusion protein structurally related to the fusion proteins of the alphaviruses, flaviviruses, and phleboviruses. Virus entry is mediated by a low pH-dependent fusion reaction through E1's insertion into the cell membrane and refolding to a stable homotrimer. Unlike the other described class II proteins, RuV E1 contains 2 fusion loops, which complex a metal ion between them by interactions with residues N88 and D136. Insertion of the E1 protein into the target membrane, fusion, and infection require calcium and are blocked by alanine substitution of N88 or D136. Here we addressed the requirements of E1 for calcium binding and the intracellular location of the calcium requirement during virus entry. Our results demonstrated that N88 and D136 are optimally configured to support RuV fusion and are strongly selected for during the virus life cycle. While E1 has some similarities with cellular proteins that bind calcium and anionic lipids, RuV binding to the membrane was independent of anionic lipids. Virus fusion occurred within early endosomes, and chelation of intracellular calcium showed that calcium within the early endosome was required for virus fusion and infection. Calcium triggered the reversible insertion of E1 into the target membrane at neutral pH, but E1 homotrimer formation and fusion required a low pH. Thus, RuV E1, unlike other known class II fusion proteins, has distinct triggers for membrane insertion and fusion protein refolding mediated, respectively, by endosomal calcium and low pH. IMPORTANCE: Rubella virus causes a mild disease of childhood, but infection of pregnant women frequently results in miscarriage or severe birth defects. In spite of an effective vaccine, RuV disease remains a serious problem in many developing countries. RuV infection of host cells involves endocytic uptake and low pH-triggered membrane fusion and is unusual in its requirement for calcium binding by the membrane fusion protein. Here we addressed the mechanism of the calcium requirement and the required location of calcium during virus entry. Both calcium and low pH were essential during the virus fusion reaction, which was shown to occur in the early endosome compartment. PMID- 27122591 TI - Intranasal Vaccination With Salmonella-Derived Serodominant Secreted Effector Protein B Associated With Gas-Filled Microbubbles Partially Protects Against Gut Infection in Mice. AB - Salmonella infection is an increasingly important public health problem owing to the emergence of multidrug resistance and the lack of broadly efficient vaccines. Novel strategies of vaccination are required to induce protective immune responses at mucosal surfaces and in the circulation, to limit bacteria entry and dissemination. To this aim, intranasal anti-Salmonella vaccination with an innovative formulation composed of gas-filled microbubbles and the pathogen derived protective protein serodominant secreted effector protein B (SseB-MB) was evaluated in a mouse infection model. Intranasal application of SseB-MB induced gut and systemic immunoglobulin A, T-helper type 17 cell (Th17), and Th1 responses, all of which are associated with natural immunity against Salmonella In vaccinated mice, a significant reduction in bacterial load was observed in intestinal tissues and the spleen after an otherwise lethal oral infection. Therefore, MB serve as an efficient carrier for nasal delivery of a Salmonella antigen that results in protection upon activation of the common mucosal immune system. PMID- 27122590 TI - Systematic Surveillance Detects Multiple Silent Introductions and Household Transmission of Methicillin-Resistant Staphylococcus aureus USA300 in the East of England. AB - BACKGROUND: The spread of USA300 methicillin-resistant Staphylococcus aureus (MRSA) across the United States resulted in an epidemic of infections. In Europe, only sporadic cases or small clusters of USA300 infections are described, and its prevalence in England is unknown. We conducted prospective surveillance for USA300 in the east of England. METHODS: We undertook a 12-month prospective observational cohort study of all individuals with MRSA isolated from community and hospital samples submitted to a microbiology laboratory. At least 1 MRSA isolate from each individual underwent whole-genome sequencing. USA300 was identified on the basis of sequence analysis, and phylogenetic comparisons were made between these and USA300 genomes from the United States. RESULTS: Between April 2012 and April 2013, we sequenced 2283 MRSA isolates (detected during carriage screening and in clinical samples) from 1465 individuals. USA300 was isolated from 24 cases (1.6%). Ten cases (42%) had skin and soft tissue infection, and 2 cases had invasive disease. Phylogenetic analyses identified multiple introductions and household transmission of USA300. CONCLUSIONS: Use of a diagnostic laboratory as a sentinel for surveillance has identified repeated introductions of USA300 in eastern England in 2012-2013, with evidence for limited transmission. Our results show how systematic surveillance could provide an early warning of strain emergence and dissemination. PMID- 27122592 TI - Host Polymorphisms in TLR9 and IL10 Are Associated With the Outcomes of Experimental Haemophilus ducreyi Infection in Human Volunteers. AB - BACKGROUND: In humans inoculated with Haemophilus ducreyi, there are host effects on the possible clinical outcomes-pustule formation versus spontaneous resolution of infection. However, the immunogenetic factors that influence these outcomes are unknown. Here we examined the role of 14 single-nucleotide polymorphisms (SNPs) in 7 selected pathogen-recognition pathways and cytokine genes on the gradated outcomes of experimental infection. METHODS: DNAs from 105 volunteers infected with H. ducreyi at 3 sites were genotyped for SNPs, using real-time polymerase chain reaction. The participants were classified into 2 cohorts, by race, and into 4 groups, based on whether they formed 0, 1, 2, or 3 pustules. chi(2) tests for trend and logistic regression analyses were performed on the data. RESULTS: In European Americans, the most significant findings were a protective association of the TLR9 +2848 GG genotype and a risk-enhancing association of the TLR9 TA haplotype with pustule formation; logistic regression showed a trend toward protection for the TLR9 +2848 GG genotype. In African Americans, logistic regression showed a protective effect for the IL10 -2849 AA genotype and a risk-enhancing effect for the IL10 AAC haplotype. CONCLUSIONS: Variations in TLR9 and IL10 are associated with the outcome of H. ducreyi infection. PMID- 27122594 TI - Renal Function and Tenofovir Disoproxil Fumarate for Preexposure Prophylaxis: How Safe Is Safe Enough? PMID- 27122595 TI - Reply to: Dr Macaluso's Letter. PMID- 27122593 TI - Maintenance of HIV-Specific Memory B-Cell Responses in Elite Controllers Despite Low Viral Burdens. AB - Human immunodeficiency virus (HIV)-specific B-cell responses in infected individuals are maintained by active HIV replication. Suppression of viremia by antiretroviral therapy (ART) leads to quantitative and qualitative changes that remain unclear. Accordingly, B-cell responses were investigated in elite controllers (ECs), who maintain undetectable HIV levels without ART, and in individuals whose viremia was suppressed by ART. Despite a higher HIV burden in the ART group, compared with the EC group, frequencies of HIV-specific B cells were higher in the EC group, compared with those in the ART group. However, the initiation of ART in several ECs was associated with reduced frequencies of HIV specific B cells, suggesting that responses are at least in part sustained by HIV replication. Furthermore, B-cell responses to tetanus toxin but not influenza hemagglutinin in the ART group were lower than those in the EC group. Thus, the superior HIV-specific humoral response in ECs versus ART-treated individuals is likely due to a more intact humoral immune response in ECs and/or distinct responses to residual HIV replication. PMID- 27122596 TI - Identification of Protease Specificity by Combining Proteome-Derived Peptide Libraries and Quantitative Proteomics. AB - We present protease specificity profiling based on quantitative proteomics in combination with proteome-derived peptide libraries. Peptide libraries are generated by endoproteolytic digestion of proteomes without chemical modification of primary amines before exposure to a protease under investigation. After incubation with a test protease, treated and control libraries are differentially isotope-labeled using cost-effective reductive dimethylation. Upon analysis by liquid chromatography-tandem mass spectrometry, cleavage products of the test protease appear as semi-specific peptides that are enriched for the corresponding isotope label. We validate our workflow with two proteases with well characterized specificity profiles: trypsin and caspase-3. We provide the first specificity profile of a protease encoded by a human endogenous retrovirus and for chlamydial protease-like activity factor (CPAF). For CPAF, we also highlight the structural basis of negative subsite cooperativity between subsites S1 and S2'. For A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4, -5, and -15, we show a canonical preference profile, including glutamate in P1 and glycine in P3'. In total, we report nearly 4000 cleavage sites for seven proteases. Our protocol is fast, avoids enrichment or synthesis steps, and enables probing for lysine selectivity as well as subsite cooperativity. Due to its simplicity, we anticipate usability by most proteomic laboratories. PMID- 27122599 TI - HR-pQCT: a non-invasive 'biopsy' to assess bone structure and strength. PMID- 27122600 TI - The left atrial appendage: from embryology to prevention of thromboembolism. AB - The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches. PMID- 27122601 TI - Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. AB - AIMS: To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. METHODS AND RESULTS: Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, while fasting sampling may be considered when non fasting triglycerides >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides >=2 mmol/L (175 mg/dL), total cholesterol >=5 mmol/L (190 mg/dL), LDL cholesterol >=3 mmol/L (115 mg/dL), calculated remnant cholesterol >=0.9 mmol/L (35 mg/dL), calculated non HDL cholesterol >=3.9 mmol/L (150 mg/dL), HDL cholesterol <=1 mmol/L (40 mg/dL), apolipoprotein A1 <=1.25 g/L (125 mg/dL), apolipoprotein B >=1.0 g/L (100 mg/dL), and lipoprotein(a) >=50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides >=1.7 mmol/L (150 mg/dL). Life threatening concentrations require separate referral when triglycerides >10 mmol/L (880 mg/dL) for the risk of pancreatitis, LDL cholesterol >13 mmol/L (500 mg/dL) for homozygous familial hypercholesterolaemia, LDL cholesterol >5 mmol/L (190 mg/dL) for heterozygous familial hypercholesterolaemia, and lipoprotein(a) >150 mg/dL (99th percentile) for very high cardiovascular risk. CONCLUSION: We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cut-points. Non-fasting and fasting measurements should be complementary but not mutually exclusive. PMID- 27122602 TI - Dynamic myosin activation promotes collective morphology and migration by locally balancing oppositional forces from surrounding tissue. AB - Migrating cells need to overcome physical constraints from the local microenvironment to navigate their way through tissues. Cells that move collectively have the additional challenge of negotiating complex environments in vivo while maintaining cohesion of the group as a whole. The mechanisms by which collectives maintain a migratory morphology while resisting physical constraints from the surrounding tissue are poorly understood. Drosophila border cells represent a genetic model of collective migration within a cell-dense tissue. Border cells move as a cohesive group of 6-10 cells, traversing a network of large germ line-derived nurse cells within the ovary. Here we show that the border cell cluster is compact and round throughout their entire migration, a shape that is maintained despite the mechanical pressure imposed by the surrounding nurse cells. Nonmuscle myosin II (Myo-II) activity at the cluster periphery becomes elevated in response to increased constriction by nurse cells. Furthermore, the distinctive border cell collective morphology requires highly dynamic and localized enrichment of Myo-II. Thus, activated Myo-II promotes cortical tension at the outer edge of the migrating border cell cluster to resist compressive forces from nurse cells. We propose that dynamic actomyosin tension at the periphery of collectives facilitates their movement through restrictive tissues. PMID- 27122603 TI - alpha-Actinin links extracellular matrix rigidity-sensing contractile units with periodic cell-edge retractions. AB - During spreading and migration, the leading edges of cells undergo periodic protrusion-retraction cycles. The functional purpose of these cycles is unclear. Here, using submicrometer polydimethylsiloxane pillars as substrates for cell spreading, we show that periodic edge retractions coincide with peak forces produced by local contractile units (CUs) that assemble and disassemble along the cell edge to test matrix rigidity. We find that, whereas actin rearward flow produces a relatively constant force inward, the peak of local contractile forces by CUs scales with rigidity. The cytoskeletal protein alpha-actinin is shared between these two force-producing systems. It initially localizes to the CUs and subsequently moves inward with the actin flow. Knockdown of alpha-actinin causes aberrant rigidity sensing, loss of CUs, loss of protrusion-retraction cycles, and, surprisingly, enables the cells to proliferate on soft matrices. We present a model based on these results in which local CUs drive rigidity sensing and adhesion formation. PMID- 27122604 TI - Quiescent Saccharomyces cerevisiae forms telomere hyperclusters at the nuclear membrane vicinity through a multifaceted mechanism involving Esc1, the Sir complex, and chromatin condensation. AB - Like other eukaryotes, Saccharomyces cerevisiae spatially organizes its chromosomes within the nucleus. In G1 phase, the yeast's 32 telomeres are clustered into 6-10 foci that dynamically interact with the nuclear membrane. Here we show that, when cells leave the division cycle and enter quiescence, telomeres gather into two to three hyperclusters at the nuclear membrane vicinity. This localization depends on Esc1 but not on the Ku proteins. Telomere hypercluster formation requires the Sir complex but is independent of the nuclear microtubule bundle that specifically assembles in quiescent cells. Importantly, mutants deleted for the linker histone H1 Hho1 or defective in condensin activity or affected for histone H4 Lys-16 deacetylation are impaired, at least in part, for telomere hypercluster formation in quiescence, suggesting that this process involves chromosome condensation. Finally, we establish that telomere hypercluster formation is not necessary for quiescence establishment, maintenance, and exit, raising the question of the physiological raison d'etre of this nuclear reorganization. PMID- 27122598 TI - Physiology, Biochemistry, and Applications of F420- and Fo-Dependent Redox Reactions. AB - 5-Deazaflavin cofactors enhance the metabolic flexibility of microorganisms by catalyzing a wide range of challenging enzymatic redox reactions. While structurally similar to riboflavin, 5-deazaflavins have distinctive and biologically useful electrochemical and photochemical properties as a result of the substitution of N-5 of the isoalloxazine ring for a carbon. 8-Hydroxy-5 deazaflavin (Fo) appears to be used for a single function: as a light-harvesting chromophore for DNA photolyases across the three domains of life. In contrast, its oligoglutamyl derivative F420 is a taxonomically restricted but functionally versatile cofactor that facilitates many low-potential two-electron redox reactions. It serves as an essential catabolic cofactor in methanogenic, sulfate reducing, and likely methanotrophic archaea. It also transforms a wide range of exogenous substrates and endogenous metabolites in aerobic actinobacteria, for example mycobacteria and streptomycetes. In this review, we discuss the physiological roles of F420 in microorganisms and the biochemistry of the various oxidoreductases that mediate these roles. Particular focus is placed on the central roles of F420 in methanogenic archaea in processes such as substrate oxidation, C1 pathways, respiration, and oxygen detoxification. We also describe how two F420-dependent oxidoreductase superfamilies mediate many environmentally and medically important reactions in bacteria, including biosynthesis of tetracycline and pyrrolobenzodiazepine antibiotics by streptomycetes, activation of the prodrugs pretomanid and delamanid by Mycobacterium tuberculosis, and degradation of environmental contaminants such as picrate, aflatoxin, and malachite green. The biosynthesis pathways of Fo and F420 are also detailed. We conclude by considering opportunities to exploit deazaflavin-dependent processes in tuberculosis treatment, methane mitigation, bioremediation, and industrial biocatalysis. PMID- 27122605 TI - HIPK family kinases bind and regulate the function of the CCR4-NOT complex. AB - The serine/threonine kinase HIPK2 functions as a regulator of developmental processes and as a signal integrator of a wide variety of stress signals, such as DNA damage, hypoxia, and reactive oxygen intermediates. Because the kinase is generated in a constitutively active form, its expression levels are restricted by a variety of different mechanisms. Here we identify the CCR4-NOT complex as a new regulator of HIPK2 abundance. Down-regulation or knockout of the CCR4-NOT complex member CNOT2 leads to reduced HIPK2 protein levels without affecting the expression level of HIPK1 or HIPK3. A fraction of all HIPK family members associates with the CCR4-NOT components CNOT2 and CNOT3. HIPKs also phosphorylate the CCR4-NOT complex, a feature that is shared with their yeast progenitor kinase, YAK1. Functional assays reveal that HIPK2 and HIPK1 restrict CNOT2 dependent mRNA decay. HIPKs are well known regulators of transcription, but the mutual regulation between CCR4-NOT and HIPKs extends the regulatory potential of these kinases by enabling posttranscriptional gene regulation. PMID- 27122606 TI - Distinct stages in the recognition, sorting, and packaging of proTGFalpha into COPII-coated transport vesicles. AB - In addition to its role in forming vesicles from the endoplasmic reticulum (ER), the coat protein complex II (COPII) is also responsible for selecting specific cargo proteins to be packaged into COPII transport vesicles. Comparison of COPII vesicle formation in mammalian systems and in yeast suggested that the former uses more elaborate mechanisms for cargo recognition, presumably to cope with a significantly expanded repertoire of cargo that transits the secretory pathway. Using proTGFalpha, the transmembrane precursor of transforming growth factor alpha (TGFalpha), as a model cargo protein, we demonstrate in cell-free assays that at least one auxiliary cytosolic factor is specifically required for the efficient packaging of proTGFalpha into COPII vesicles. Using a knockout HeLa cell line generated by CRISPR/Cas9, we provide functional evidence showing that a transmembrane protein, Cornichon-1 (CNIH), acts as a cargo receptor of proTGFalpha. We show that both CNIH and the auxiliary cytosolic factor(s) are required for efficient recruitment of proTGFalpha to the COPII coat in vitro. Moreover, we provide evidence that the recruitment of cargo protein by the COPII coat precedes and may be distinct from subsequent cargo packaging into COPII vesicles. PMID- 27122607 TI - Long-term outcomes after resection of Stage IV cavoatrial tumour extension using deep hypothermic circulatory arrest. AB - OBJECTIVES: Renal neoplasms frequently expand into renal veins and inferior vena cava from the early stages of the disease. In this study, we set out to define the long-term outcomes of patients with Stage IV tumorous cavoatrial extension, undergoing radical nephrectomy with excision of cavoatrial extension in deep hypothermic circulatory arrest (DHCA). METHODS: Thirty-five patients with Stage IV cavoatrial extension of renal cell carcinoma underwent radical nephrectomy combined with en bloc excision of cavoatrial tumour-thrombus extension, performed in DHCA. The preoperative staging of the tumour and assessment of the intravascular position of the tumour were performed using standard imaging techniques, including computed tomography angiography, magnetic resonance imaging and echocardiography. Patient data were collected in the patient data bank and analysed retrospectively. RESULTS: In this study cohort, we demonstrate acceptable long-term results (the mean overall survival of 4.9 +/- 1.0 years and the 5-year survival rate of 40%) and outline several clear predictors for postoperative long-term survival of the patients. Preoperative evidence of remote tumour metastases and tumourous lymph node involvement conversely predicts inferior postoperative survival. However, a high local postoperative tumour recurrence rate does not limit patient survival in this group. CONCLUSIONS: The data provide evidence for perioperative safety and acceptable long-term results of radical nephrectomy with excision of cavoatrial extension in DHCA in patients with Stage IV cavoatrial extension of renal neoplasm. Thus, this radical surgical procedure can provide effective long-term palliation in the absence of evident metastatic disease. PMID- 27122608 TI - Risk scores and how to evaluate them. PMID- 27122610 TI - An incentive-based approach for improving data reproducibility. PMID- 27122609 TI - Reduction of ischaemia-reperfusion injury in a rat lung transplantation model by low-concentration GV1001. AB - OBJECTIVES: Lung ischaemia-reperfusion (IR) injury is one of the major complications following lung transplantation. The novel peptide GV1001, which is derived from human telomerase reverse transcriptase, has been reported to possess both antitumour and anti-inflammatory effects. In this study, we focused on the anti-inflammatory effects of GV1001 to investigate the IR injury prevention effect of GV1001 in a rat lung transplantation model. METHODS: An orthotopic left lung transplantation rat model was established using the modified cuff technique. We applied 50 ml of normal saline (control), Perfadex (low-potassium standard dextran containing perfusion solution), Perfadex with 5 mg GV1001 (5-mg GV, low concentration) and Perfadex with 50 mg GV1001 (50-mg GV, high concentration) as both flushing and preservation solutions. The left lung was stored in the same solution as the flushing solution at 4 degrees C for 3 h. After transplantation, the recipient rats were monitored for 3 h. Arterial blood gas analysis (ABGA), bronchoalveolar lavage (BAL) analysis, wet/dry ratio, histological analysis, apoptotic cell analysis and cytokine [tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6)] analysis were performed to determine the reduction or prevention effect of GV1001 regarding lung IR injury. RESULTS: Compared with the control group, the neutrophil count in BAL, reperfusion oedema and cytokine (TNF alpha, IL-6) levels of the transplanted lung were significantly decreased in the 5-mg GV group. Compared with the Perfadex group (16.85 +/- 2.43), the neutrophil count in BAL was also significantly decreased in the 5-mg GV group (5.39 +/- 0.81) (P< 0.001). In addition, the cytokine (TNF-alpha, IL-6) levels of the transplanted lung were also significantly decreased in the 5-mg GV group (41.99 +/- 12.79, 1069.74 +/- 98.48 pg/ml) compared with the Perfadex group (90.73 +/- 23.87, 2051.92 +/- 243.57 pg/ml) (P < 0.05 and P < 0.001, respectively). However, the 50-mg GV group showed less effect than the 5-mg GV group. CONCLUSIONS: Adding a low concentration of GV1001 to the lung preservation solution (Perfadex) provided potential protective effects against IR injury after lung transplantation in rats. Therefore, GV1001 should be considered as a promising anti-inflammatory agent for IR injury. PMID- 27122611 TI - On the path to a science of patient input. AB - It is early days in the creation of a science of patient input. Participants are establishing rigorous methods to better integrate patient perspectives, needs, and priorities throughout biomedical and bioengineering R&D and care delivery to patients. To assess progress and unmet needs, FasterCures tracked more than 70 collaborative initiatives clustered in six categories that are defining and shaping this developing field. No longer is patient engagement a fanciful notion as it was at the start of our journey in 2003, and the rush of activity is welcome and vital. PMID- 27122612 TI - IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections. AB - Boosting innate immunity represents an important therapeutic alternative to antibiotics. However, the molecular selectivity of this approach is a major concern because innate immune responses often cause collateral tissue damage. We identify the transcription factor interferon regulatory factor 7 (IRF-7), a heterodimer partner of IRF-3, as a target for non-antibiotics-based therapy of bacterial infections. We found that the efficient and self-limiting innate immune response to bacterial infection relies on a tight balance between IRF-3 and IRF 7. Deletion of Irf3 resulted in overexpression of Irf7 and led to an IRF-7-driven hyperinflammatory phenotype, which was entirely prevented if Irf7 was deleted. We then identified a network of strongly up-regulated, IRF-7-dependent genes in Irf3(-/-) mice with kidney pathology, which was absent in Irf7(-/-) mice. IRF-3 and IRF-7 from infected kidney cell nuclear extracts were shown to bind OAS1, CCL5, and IFNB1 promoter oligonucleotides. These data are consistent in children with low IRF7 expression in the blood: attenuating IRF7 promoter polymorphisms (rs3758650-T and rs10902179-G) negatively associated with recurrent pyelonephritis. Finally, we identified IRF-7 as a target for immunomodulatory therapy. Administering liposomal Irf7 siRNA to Irf3(-/-) mice suppressed mucosal IRF-7 expression, and the mice were protected against infection and renal tissue damage. These findings offer a response to the classical but unresolved question of "good versus bad inflammation" and identify IRF7 as a therapeutic target for protection against bacterial infection. PMID- 27122613 TI - ZP2 peptide beads select human sperm in vitro, decoy mouse sperm in vivo, and provide reversible contraception. AB - Gamete recognition in the female reproductive tract occurs at the surface of the zona pellucida surrounding ovulated eggs. The acellular zona matrix is composed of three (mouse) or four (human) proteins (ZP1 to ZP4), and the amino terminus of ZP2 is the primary sperm-binding ligand. Mouse and human sperm bind, respectively, to recombinant moZP2(35-149) and huZP2(39-154) peptides attached to agarose beads. Mouse ZP2 peptide beads markedly inhibited fertilization of ovulated mouse eggs inseminated in vitro and incubated overnight. Similarly, human ZP2 peptide beads prevented sperm binding and penetration of transgenic ZP2(Rescue) zonae pellucidae, in which human ZP2 replaced mouse ZP2. When mouse ZP2 peptide beads were transcervically deposited into the uterus, there was no change in mating behavior and copulatory plugs were present, but bound sperm did not progress into the oviduct and female mice were infertile. On average, contraception lasted >10 estrus cycles but was reversible with no detectable pathology in the reproductive tract. Despite the long-term contraceptive effect, initial sperm binding to the peptide beads was reversible in vitro. We exploited this observation to select human sperm that were better able to penetrate the zonae of human ZP2(Rescue) eggs, and the approach holds promise for identifying superior sperm for human assisted reproductive technologies (ART). We conclude that the amino-terminal ZP2 peptide supports sperm binding, which is initially reversible but, with time, becomes irreversible. Short-term, reversible binding may be useful in selecting sperm for ART, and long-term binding decoys sperm and results in effective contraception in mice. PMID- 27122614 TI - MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. AB - Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome. PMID- 27122616 TI - Early or late surgery for endocarditis with neurological complications. AB - BACKGROUND: The European Society of Cardiology 2015 guidelines advise urgent surgery for endocarditis complicated by cerebral embolism or transient ischemic events (1B evidence). Nevertheless, the timing of surgery remains contentious. This study aimed to review our experience of early versus delayed surgery in a selected cohort. METHODS: Our surgical database was examined for patients with a discharge diagnosis of endocarditis from 2005 to 2011. Selection was limited to patients who fulfilled the Duke criteria and underwent brain imaging for a clinically diagnosed preoperative neurological event. Patients were categorized as early surgery (<=7 days of clinical or cerebral imaging diagnosis of stroke) or delayed surgery (>7 days after diagnosis). RESULTS: Thirty-nine patients were identified: 20 in the early group (mean age 52 +/- 15 years, diagnosis-to-surgery time 4 +/- 2 days) and 19 in the delayed group (mean age 45 +/- 15 years, diagnosis-to-surgery time 17 +/- 11 days). There were no statistical differences in preoperative risks, operative data (cardiopulmonary bypass and crossclamp times) or postoperative neurological and mortality outcomes between the 2 groups. The size of the cerebral lesion was not a significant predictor of postoperative hemorrhagic or neurological outcome. Multivariate analysis did not show any independent predictor of mortality during follow-up (mean 51 +/- 27 months). There was no difference in long-term survival, freedom from reoperation, or recurrent endocarditis between the 2 groups. CONCLUSIONS: This study showed no statistical excess of mortality or neurological outcomes after early surgical intervention, regardless of the preoperative cerebral lesion size. PMID- 27122617 TI - Evaluating Hospice and Palliative Medicine Education in Pediatric Training Programs. AB - BACKGROUND: Hospice and Palliative Medicine (HPM) competencies are of growing importance in training general pediatricians and pediatric sub-specialists. The Accreditation Council for Graduate Medical Education (ACGME) emphasized pediatric trainees should understand the "impact of chronic disease, terminal conditions and death on patients and their families." Currently, very little is known regarding pediatric trainee education in HPM. METHODS: We surveyed all 486 ACGME accredited pediatric training program directors (PDs) - 200 in general pediatrics (GP), 57 in cardiology (CARD), 64 in critical care medicine (CCM), 69 in hematology-oncology (ONC) and 96 in neonatology (NICU). We collected training program's demographics, PD's attitudes and educational practices regarding HPM. RESULTS: The complete response rate was 30% (148/486). Overall, 45% offer formal HPM curriculum and 39% offer a rotation in HPM for trainees. HPM teaching modalities commonly reported included conferences, consultations and bedside teaching. Eighty-one percent of all respondents felt that HPM curriculum would improve trainees' ability to care for patients. While most groups felt that a HPM rotation would enhance trainees' education [GP (96%), CARD (77%), CCM (82%) and ONC (95%)], NICU PDs were more divided (55%; p < 0.05 for all comparisons vs. NICU). CONCLUSION: While most programs report perceived benefit from HPM training, there remains a paucity of opportunities for pediatric trainees. Passive teaching methods are frequently utilized in HPM curricula with minimal diversity in methods utilized to teach HPM. Opportunities to further emphasize HPM in general pediatric and pediatric sub-specialty training remains. PMID- 27122615 TI - Initiation of immune tolerance-controlled HIV gp41 neutralizing B cell lineages. AB - Development of an HIV vaccine is a global priority. A major roadblock to a vaccine is an inability to induce protective broadly neutralizing antibodies (bnAbs). HIV gp41 bnAbs have characteristics that predispose them to be controlled by tolerance. We used gp41 2F5 bnAb germline knock-in mice and macaques vaccinated with immunogens reactive with germline precursors to activate neutralizing antibodies. In germline knock-in mice, bnAb precursors were deleted, with remaining anergic B cells capable of being activated by germline-binding immunogens to make gp41-reactive immunoglobulin M (IgM). Immunized macaques made B cell clonal lineages targeted to the 2F5 bnAb epitope, but 2F5-like antibodies were either deleted or did not attain sufficient affinity for gp41-lipid complexes to achieve the neutralization potency of 2F5. Structural analysis of members of a vaccine-induced antibody lineage revealed that heavy chain complementarity-determining region 3 (HCDR3) hydrophobicity was important for neutralization. Thus, gp41 bnAbs are controlled by immune tolerance, requiring vaccination strategies to transiently circumvent tolerance controls. PMID- 27122618 TI - Addressing Our Deficiencies in End-of-Life Care: Perspectives From a Resident Physician. PMID- 27122619 TI - Time Delay to Rheumatology Consultation: Rheumatoid Arthritis Diagnostic Concordance Between Primary Care Physician and Rheumatologist. PMID- 27122620 TI - Chest Radiographs Immediately After Cardiac Surgery. PMID- 27122621 TI - Burnout's Prevalence Estimations: A House of Cards? PMID- 27122622 TI - Mastering Medical Devices for Safe Use. PMID- 27122623 TI - Diabetes and Obesity Trends in Tonga Over 40 Years. AB - Disparate population surveys of type 2 diabetes mellitus (T2DM) have been conducted in Tonga for 4 decades. This study standardizes these surveys to enable assessment of T2DM and obesity trends in Tongans aged 25 to 64 years over 1973 2012, and projects T2DM prevalence to 2020 based on demographic and population weight changes. Eight surveys were standardized to the nearest census to produce nationally representative estimates. Linear period trends and prevalence projections to 2020 were produced using random-effects meta-regression. Over 1973 2012, T2DM prevalence increased from 5.2% to 19.0% (1.9%/5 years) and obesity prevalence from 56.0% to 70.2% (2.7%/5 years). T2DM prevalence period projection to 2020 is 22.3%. Based on modeling using body mass index, T2DM prevalence in 2020 could have been 12.7% and 16.8% in 2020 had mean population weight been 1 to 4 kg lower than 2012 levels. PMID- 27122624 TI - Role of Individual, Family, and Peers in Sexual Initiation Among Late Adolescents Attending Institutions of Higher Learning in Malaysia. AB - This cross-sectional study aimed to determine the prevalence and the factors associated with sexual initiation among the late adolescents in 6 institutions of higher learning in Malaysia. A total of 1572 students completed self-administered questionnaires between April and September 2013. Hierarchical multivariate logistic regression analyses stratified by gender were employed to identify the correlates of sexual initiation. The analyses were further adjusted by sampling weights. The overall prevalence of sexual initiation was 9.8% (95% confidence interval [CI] = 8.3-11.6), 18.1% (95% CI = 15.1-21.5) among males, and 4.1% (95% CI = 2.9-5.9) among females. The risk factors identified in this study supported the influence of the individual, family, and peer factors in the social ecological model on adolescents' behaviors. The findings suggest the need for risk-reduction strategies aimed at the individual, family, and peer levels as well as the importance of gender-specific focus in assuring better outcomes. PMID- 27122625 TI - Family Planning Practice Among Rural Reproductive-Age Married Women in Myanmar. AB - A cross-sectional study was undertaken to investigate family planning (FP) practices and associated factors among reproductive-age married women. Data were collected by interviewing the 300 married women living in a rural area of Myanmar. The questionnaire had reliability coefficients ranging from .8 to .9. Results indicated that 73.3% of women performed FP, and contraceptive injection was the most common method. Significant associations were found with age 21 to 35 years (adjusted odds ratio [adj OR] = 3.748, 95% CI = 2.179-6.445), adequacy of income (adj OR = 2.520, 95% CI = 1.477-4.290), good attitude toward FP (adj OR = 0.386, 95% CI = 0.228-0.656), good support from health care providers (adj OR = 0.129, 95% CI = 0.054-0.313), good support from family (adj OR = 0.304, 95% CI = 0.163-0.565), good support from friends (adj OR = 0.344, 95% CI = 0.193-0.613), and FP practice. It is recommended that designing FP programs with peers and family involvement could increase the practice of FP among rural Myanmar women. PMID- 27122626 TI - Analysis of Validity and Reliability of the Health Literacy Index for Female Marriage Immigrants (HLI-FMI). AB - The purpose of this study was to obtain an independent evaluation of the factor structure of the 12-item Health Literacy Index for Female Marriage Immigrants (HLI-FMI), the first measure for assessing health literacy for FMIs in Korea. Participants were 250 Asian women who migrated from China, Vietnam, and the Philippines to marry. The HLI-FMI was originally developed and administered in Korean, and other questionnaires were translated into participants' native languages. The HLI-FMI consisted of 2 factors: (1) Access-Understand Health Literacy (7 items) and (2) Appraise-Apply Health Literacy (5 items); Cronbach's alpha = .73. Confirmatory factor analysis indicated adequate fit for the 2-factor model. HLI-FMI scores were positively associated with time since immigration and Korean proficiency. Based on classical test theory and item response theory, strong support was provided for item discrimination and item difficulty. Findings suggested that the HLI-FMI is an easily administered, reliable, and valid scale. PMID- 27122627 TI - The Lipid Hypothesis in Calcific Aortic Valve Disease: The Role of the Multi Ethnic Study of Atherosclerosis. PMID- 27122629 TI - Correction. PMID- 27122628 TI - Vascular Regeneration by Stem/Progenitor Cells. PMID- 27122630 TI - Notice of Retraction. PMID- 27122631 TI - Long noncoding RNAs in gastric cancer carcinogenesis and metastasis. AB - Recent studies of the human transcriptome, most prominently by the ENCyclopedia Of DNA Elements project, have revealed an unexpected number of noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs) are typically referred to a heterogeneous group of polyadenylated long ncRNAs, with a length of > 200 nt. LncRNAs constitute an integral part of tumor biology, with many lncRNAs discovered to be aberrantly expressed in various cancer types. They are involved in many aspects of cancer pathogenesis from its initiation to progression, metastasis and treatment response. Gastric cancer (GC) is the third leading cause of cancer death worldwide. Despite the current improvements of life expectancy and survival rate, most of the patients are diagnosed when their cancer has been progressed to advanced stages. Therefore, unraveling the molecular mechanisms of GC to find early-stage biomarkers is urgent. As the list of lncRNAs with deregulated expression in GC is steadily expanding, these molecules offer a source for developing GC-specific biomarkers. In this review, we will present and discuss those lncRNAs whose expression has been shown to be deregulated in GC. PMID- 27122632 TI - C. elegans flavin-containing monooxygenase-4 is essential for osmoregulation in hypotonic stress. PMID- 27122633 TI - Is the Epididymis a Series of Organs Placed Side By Side? AB - The mammalian epididymis is more than a highly convoluted tube divided into four regions: initial segment, caput, corpus and cauda. It is a highly segmented structure with each segment expressing its own and overlapping genes, proteins, and signal transduction pathways. Therefore, the epididymis may be viewed as a series of organs placed side by side. In this review we discuss the contributions of septa that divide the epididymis into segments and present hypotheses as to the mechanism by which septa form. The mechanisms of Wolffian duct segmentation are likened to the mechanisms of segmentation of the renal nephron and somites. The renal nephron may provide valuable clues as to how the Wolffian duct is patterned during development, whereas somitogenesis may provide clues as to the timing of the development of each segment. Emphasis is also placed upon how segments are differentially regulated, in support of the idea that the epididymis can be considered a series of multiple organs placed side by side. One region in particular, the initial segment, which consists of 2 or 4 segments in mice and rats, respectively, is unique with respect to its regulation and vascularity compared to other segments; loss of development of these segments leads to male infertility. Different ways of thinking about how the epididymis functions may provide new directions and ideas as to how sperm maturation takes place. PMID- 27122634 TI - Growing Mouse Oocytes Transiently Activate Folate Transport via Folate Receptors As They Approach Full Size. AB - The folate cycle is central to cellular one-carbon metabolism, where folates are carriers of one-carbon units that are critical for synthesis of purines, thymidylate, and S-adenosylmethionine, the universal methyl donor that forms the cellular methyl pool. Although folates are well-known to be important for early embryo and fetal development, their role in oogenesis has not been clearly established. Here, folate transport proteins were detected in developing neonatal ovaries and growing oocytes by immunohistochemistry, Western blot, and immunofluorescence. The folate receptors FOLR1 and FOLR2 as well as reduced folate carrier 1 (RFC1, SLC19A1 protein) each appeared to be present in follicular cells including granulosa cells. In growing oocytes, however, only FOLR2 immunoreactivity appeared abundant. Localization of apparent FOLR2 immunofluorescence near the plasma membrane increased with oocyte growth and peaked in oocytes as they neared full size. We assessed folate transport using the model folate leucovorin (folinic acid). Unexpectedly, there was a transient burst of folate transport activity for a brief period during oocyte growth as they neared full size, while folate transport was otherwise undetectable for the rest of oogenesis and in fully grown germinal vesicle stage oocytes. This folate transport was inhibited by dynasore, an inhibitor of endocytosis, but insensitive to the anion transport inhibitor stilbene 4-acetamido-40-isothiocyanato-stilbene 2,20-disulfonic acid, consistent with folate receptor-mediated transport but not with RFC1-mediated transport. Thus, near the end of their growth, growing oocytes may take up folates that could support the final stage of oogenesis or be stored to provide the endogenous folates needed in early embryogenesis. PMID- 27122635 TI - Cellular Dynamics of Mouse Trophoblast Stem Cells: Identification of a Persistent Stem Cell Type. AB - Mouse trophoblast stem cells (TSCs) proliferate indefinitely in vitro, despite their highly heterogeneous nature. In this study, we sought to characterize TSC colony types by using methods based on cell biology and biochemistry for a better understanding of how TSCs are maintained over multiple passages. Colonies of TSCs could be classified into four major types: type 1 is compact and dome-shaped, type 4 is flattened but with a large multilayered cell cluster, and types 2 and 3 are their intermediates. A time-lapse analysis indicated that type 1 colonies predominantly appeared after passaging, and a single type 1 colony gave rise to all other types. These colony transitions were irreversible, but at least some type 1 colonies persisted throughout culture. The typical cells comprising type 1 colonies were small and highly motile, and they aggregated together to form primary colonies. A hierarchical clustering based on global gene expression profiles suggested that a TSC line containing more type 1 colony cells was similar to in vivo extraembryonic tissues. Among the known TSC genes examined, Elf5 showed a differential expression pattern according to colony type, indicating that this gene might be a reliable marker of undifferentiated TSCs. When aggregated with fertilized embryos, cells from types 1 and 2, but not from type 4, distributed to the polar trophectoderm in blastocysts. These findings indicate that cells typically found in type 1 colonies can persist indefinitely as stem cells and are responsible for the maintenance of TSC lines. They may provide key information for future improvements in the quality of TSC lines. PMID- 27122636 TI - MicroRNA-183-96-182 Cluster Regulates Bovine Granulosa Cell Proliferation and Cell Cycle Transition by Coordinately Targeting FOXO1. AB - Large-scale expression profiling of micro-RNAs (miRNAs) in bovine granulosa cells from dominant and subordinate follicles on Day 19 of the estrous cycle revealed enriched micro-RNA-183-96-182 cluster miRNAs in preovulatory dominant follicles that coordinately regulate the forkhead box protein O1 (FOXO1) gene. However, little is known about the role of this cluster in bovine granulosa cell function. We used an in vitro granulosa cell culture model to investigate this role. Granulosa cells aspirated from small growing follicles (3-5 mm in diameter) were cultured in Dulbecco modified Eagle medium/F-12 medium supplemented with fetal bovine serum and transfected with locked nucleic acid-based miRNA mimics, inhibitors, and corresponding negative controls. Overexpression of the miRNA cluster resulted in suppression of FOXO1 mRNA and protein, whereas inhibition of the cluster increased expression of FOXO1 mRNA. Overexpression also increased the relative rate of cell proliferation, whereas inhibition slowed it down. Similarly, the proportion of cells under G0/G1 arrest declined, whereas the ratio of cells in S phase increased in response to miR-183-96-182 overexpression. Selective knockdown of FOXO1 mRNA using anti-FOXO1 small interfering RNA increased the rate of granulosa cell proliferation, decreased the proportion of cells under G0/G1 arrest, and increased the proportion of cells in the S phase of cell cycle. Our data suggest that miR-183-96-182 cluster miRNAs promote proliferation and G1/S transition of bovine granulosa cells by coordinately targeting FOXO1, suggesting a critical role in granulosa cell function. MicroRNA 183-96-182 cluster regulates bovine granulosa cell function by targeting FOXO1 gene. PMID- 27122637 TI - A problem with problem solving: motivational traits, but not cognition, predict success on novel operant foraging tasks. AB - Rates of innovative foraging behaviours and success on problem-solving tasks are often used to assay differences in cognition, both within and across species. Yet the cognitive features of some problem-solving tasks can be unclear. As such, explanations that attribute cognitive mechanisms to individual variation in problem-solving performance have revealed conflicting results. We investigated individual consistency in problem-solving performances in captive-reared pheasant chicks, Phasianus colchicus, and addressed whether success depends on cognitive processes, such as trial-and-error associative learning, or whether performances may be driven solely via noncognitive motivational mechanisms, revealed through subjects' willingness to approach, engage with and persist in their interactions with an apparatus, or via physiological traits such as body condition. While subjects' participation and success were consistent within the same problems and across similar tasks, their performances were inconsistent across different types of task. Moreover, subjects' latencies to approach each test apparatus and their attempts to access the reward were not repeatable across trials. Successful individuals did not improve their performances with experience, nor were they consistent in their techniques in repeated presentations of a task. However, individuals that were highly motivated to enter the experimental chamber were more likely to participate. Successful individuals were also faster to approach each test apparatus and more persistent in their attempts to solve the tasks than unsuccessful individuals. Our findings therefore suggest that individual differences in problem-solving success can arise from inherent motivational differences alone and hence be achieved without inferring more complex cognitive processes. PMID- 27122640 TI - Corruption and inequality of wealth amongst the very rich. AB - Corruption may lead to tax evasion and unbalanced favors and this may lead to extraordinary wealth amongst a few. We study for 13 countries 6 years of Forbes rankings data and we examine whether corruption leads to more inequality amongst the wealthiest. When we correct in our panel model for current and one-year lagged competitiveness and GDP growth rates, we find no such effect. In fact, we find that more competitiveness decreases inequality amongst the wealthiest. PMID- 27122641 TI - Joint analysis of longitudinal and survival data measured on nested timescales by using shared parameter models: an application to fecundity data. AB - We consider the joint modelling, analysis and prediction of a longitudinal binary process and a discrete time-to-event outcome. We consider data from a prospective pregnancy study, which provides day level information regarding the behaviour of couples attempting to conceive. Reproductive epidemiologists are particularly interested in developing a model for individualized predictions of time to pregnancy (TTP). A couple's intercourse behaviour should be an integral part of such a model and is one of the main focuses of the paper. In our motivating data, the intercourse observations are a long series of binary data with a periodic probability of success and the amount of available intercourse data is a function of both the menstrual cycle length and TTP. Moreover, these variables are dependent and observed on different, and nested, timescales (TTP is measured in menstrual cycles whereas intercourse is measured on days within a menstrual cycle) further complicating its analysis. Here, we propose a semiparametric shared parameter model for the joint modelling of the binary longitudinal data (intercourse behaviour) and the discrete survival outcome (TTP). Further, we develop couple-based dynamic predictions for the intercourse profiles, which in turn are used to assess the risk for subfertility (i.e. TTP longer than six menstrual cycles). PMID- 27122642 TI - Measure for Measure: How Proficiency-Based Accountability Systems Affect Inequality in Academic Achievement. AB - How do proficiency-based accountability systems affect inequality in academic achievement? This paper reconciles mixed findings in the literature by demonstrating that three factors jointly determine accountability's impact. First, by analyzing student-level data from a large urban school district, we find that when educators face accountability pressure, they focus attention on students closest to proficiency. We refer to this practice as educational triage, and show that the difficulty of the proficiency standard affects whether lower or higher performing students gain most on high-stakes tests used to evaluate schools. Less difficult proficiency standards decrease inequality in high-stakes achievement, while more difficult ones increase it. Second, we show that educators emphasize test-specific skills with students near proficiency, a practice that we refer to as instructional triage. As a result, the effects of accountability pressure differ across high and low-stakes tests; we find no effects on inequality in low-stakes reading and math tests of similar skills. Finally, we provide suggestive evidence that instructional triage is most pronounced in the lowest performing schools. We conclude by discussing how these findings shape our understanding of accountability's impacts on educational inequality. PMID- 27122643 TI - Patterns of internationalization and criteria for research assessment in the social sciences and humanities. AB - This article investigates the developments during the last decades in the use of languages, publication types and publication channels in the social sciences and humanities (SSH). The purpose is to develop an understanding of the processes of internationalization and to apply this understanding in a critical examination of two often used general criteria in research evaluations in the SSH. One of them is that the coverage of a publication in Scopus or Web of Science is seen in itself as an expression of research quality and of internationalization. The other is that a specific international language, English, and a specific type of publication, journal articles, are perceived as supreme in a general hierarchy of languages and publication types. Simple distinctions based on these criteria are contrary to the heterogeneous publication patterns needed in the SSH to organize their research adequately, present their results properly, reach their audiences efficiently, and thereby fulfil their missions. Research quality, internationalization, and societal relevance can be promoted in research assessment in the SSH without categorical hierarchies of publications. I will demonstrate this by using data from scholarly publishing in the SSH that go beyond the coverage in the commercial data sources in order to give a more comprehensive representation of scholarly publishing in the SSH. PMID- 27122644 TI - Scientific workflows for bibliometrics. AB - Scientific workflows organize the assembly of specialized software into an overall data flow and are particularly well suited for multi-step analyses using different types of software tools. They are also favorable in terms of reusability, as previously designed workflows could be made publicly available through the myExperiment community and then used in other workflows. We here illustrate how scientific workflows and the Taverna workbench in particular can be used in bibliometrics. We discuss the specific capabilities of Taverna that makes this software a powerful tool in this field, such as automated data import via Web services, data extraction from XML by XPaths, and statistical analysis and visualization with R. The support of the latter is particularly relevant, as it allows integration of a number of recently developed R packages specifically for bibliometrics. Examples are used to illustrate the possibilities of Taverna in the fields of bibliometrics and scientometrics. PMID- 27122645 TI - Science system path-dependencies and their influences: nanotechnology research in Russia. AB - In this paper, we study the influence of path dependencies on the development of an emerging technology in a transitional economy. Our focus is the development of nanotechnology in Russia in the period between 1990 and 2012. By examining outputs, publication paths and collaboration patterns, we identify a series of factors that help to explain Russia's limited success in leveraging its ambitious national nanotechnology initiative. The analysis highlights four path-dependent tendencies of Russian nanotechnology research: publication pathways and the gatekeeping role of the Russian Academy of Sciences; increasing geographical and institutional centralisation of nanotechnology research; limited institutional diffusion; and patterns associated with the internationalisation of Russian research. We discuss policy implications related to path dependence, nanotechnology research in Russia and to the broader reform of the Russian science system. PMID- 27122646 TI - Obstacles to prior art searching by the trilateral patent offices: empirical evidence from International Search Reports. AB - Despite many empirical studies having been carried out on examiner patent citations, few have scrutinized the obstacles to prior art searching when adding patent citations during patent prosecution at patent offices. This analysis takes advantage of the longitudinal gap between an International Search Report (ISR) as required by the Patent Cooperation Treaty (PCT) and subsequent national examination procedures. We investigate whether several kinds of distance actually affect the probability that prior art is detected at the time of an ISR; this occurs much earlier than in national phase examinations. Based on triadic PCT applications between 2002 and 2005 for the trilateral patent offices (the European Patent Office, the US Patent and Trademark Office, and the Japan Patent Office) and their family-level citations made by the trilateral offices, we find evidence that geographical distance negatively affects the probability of capture of prior patents in an ISR. In addition, the technological complexity of an application negatively affects the probability of capture, whereas the volume of forward citations of prior art affects it positively. These results demonstrate the presence of obstacles to searching at patent offices, and suggest ways to design work sharing by patent offices, such that the duplication of search costs arises only when patent office search horizons overlap. PMID- 27122647 TI - Research data explored: an extended analysis of citations and altmetrics. AB - In this study, we explore the citedness of research data, its distribution over time and its relation to the availability of a digital object identifier (DOI) in the Thomson Reuters database Data Citation Index (DCI). We investigate if cited research data "impacts" the (social) web, reflected by altmetrics scores, and if there is any relationship between the number of citations and the sum of altmetrics scores from various social media platforms. Three tools are used to collect altmetrics scores, namely PlumX, ImpactStory, and Altmetric.com, and the corresponding results are compared. We found that out of the three altmetrics tools, PlumX has the best coverage. Our experiments revealed that research data remain mostly uncited (about 85 %), although there has been an increase in citing data sets published since 2008. The percentage of the number of cited research data with a DOI in DCI has decreased in the last years. Only nine repositories are responsible for research data with DOIs and two or more citations. The number of cited research data with altmetrics "foot-prints" is even lower (4-9 %) but shows a higher coverage of research data from the last decade. In our study, we also found no correlation between the number of citations and the total number of altmetrics scores. Yet, certain data types (i.e. survey, aggregate data, and sequence data) are more often cited and also receive higher altmetrics scores. Additionally, we performed citation and altmetric analyses of all research data published between 2011 and 2013 in four different disciplines covered by the DCI. In general, these results correspond very well with the ones obtained for research data cited at least twice and also show low numbers in citations and in altmetrics. Finally, we observed that there are disciplinary differences in the availability and extent of altmetrics scores. PMID- 27122648 TI - Estimating search engine index size variability: a 9-year longitudinal study. AB - One of the determining factors of the quality of Web search engines is the size of their index. In addition to its influence on search result quality, the size of the indexed Web can also tell us something about which parts of the WWW are directly accessible to the everyday user. We propose a novel method of estimating the size of a Web search engine's index by extrapolating from document frequencies of words observed in a large static corpus of Web pages. In addition, we provide a unique longitudinal perspective on the size of Google and Bing's indices over a nine-year period, from March 2006 until January 2015. We find that index size estimates of these two search engines tend to vary dramatically over time, with Google generally possessing a larger index than Bing. This result raises doubts about the reliability of previous one-off estimates of the size of the indexed Web. We find that much, if not all of this variability can be explained by changes in the indexing and ranking infrastructure of Google and Bing. This casts further doubt on whether Web search engines can be used reliably for cross-sectional webometric studies. PMID- 27122649 TI - On the bibliometric coordinates of four different research fields in Geography. AB - This study is a bibliometric analysis of the highly complex research discipline Geography. In order to identify the most popular and most cited publication channels, to reveal publication strategies, and to analyse the discipline's coverage within publications, the three main data sources for citation analyses, namely Web of Science, Scopus and Google Scholar, have been utilized. This study is based on publication data collected for four individual evaluation exercises performed at the University of Vienna and related to four different subfields: Geoecology, Social and Economic Geography, Demography and Population Geography, and Economic Geography. The results show very heterogeneous and individual publication strategies, even in the same research fields. Monographs, journal articles and book chapters are the most cited document types. Differences between research fields more related to the natural sciences than to the social sciences are clearly visible, but less considerable when taking into account the higher number of co-authors. General publication strategies seem to be established for both natural science and social sciences, however, with significant differences. While in natural science mainly publications in international peer-reviewed scientific journals matter, the focus in social sciences is rather on book chapters, reports and monographs. Although an "iceberg citation model" is suggested, citation analyses for monographs, book chapters and reports should be conducted separately and should include complementary data sources, such as Google Scholar, in order to enhance the coverage and to improve the quality of the visibility and impact analyses. This is particularly important for social sciences related research within Geography. PMID- 27122650 TI - Moral Preferences. AB - In this brief response to Etzioni's paper we argue that satisfying one's preferences and seeking to live up to one's moral standards are not incompatible ways of living one's life, and that choosing to act morally need not involve self sacrifice. PMID- 27122651 TI - Making Moral Judgments from a World-Historic Standpoint: The Case of Woodrow Wilson. AB - This comment reflects on the recent row over Woodrow Wilson's legacy, which has focussed on his undeniable racism. This was in pursuit of a 'Progressive' agenda which paved the way for the United States to become the geopolitical force that it continues to be today. Without necessarily approving of Wilson's particular judgements, I argue that he operated with a 'world-historic' sense of morality characteristic of Realpolitik, a perspective which might be worth considering by those who believe that modern preoccupations with 'race', 'class' and 'gender' will remain part of the sociological firmament indefinitely.?. PMID- 27122652 TI - Toward a Theory of Coexistence in Shared Social-Ecological Systems: The Case of Cook Inlet Salmon Fisheries. AB - Coexistence theory (CT) in community ecology provides a functional perspective on how multiple competing species coexist. Here, I explore CT's usefulness for understanding conflict and coexistence among human groups with diverse livelihood interests in shared resources such as fisheries. I add three concepts from social science research on coexistence: adaptability, pluralism, and equity and apply this expanded theoretical framework to the case of salmon fisheries in Alaska's Cook Inlet, synthesizing catch records with anthropological research. The analysis addresses issues of inequity, such as who bears the costs of conservation measures, a lack of pluralism, in that people have come to devalue their neighbors, and a decline in resilience for some sectors, all of which undermine the likelihood of these groups continuing coexistence. I discuss policy options for addressing escalating conflict in the region, such as improving equity in management and the resilience of some fishing groups to temporary closures. Finally, I discuss points of engagement for CT with other areas of sustainability science such as resilience thinking. PMID- 27122653 TI - REDD+ on the rocks? Conflict Over Forest and Politics of Justice in Vietnam. AB - In Vietnam, villagers involved in a REDD+ (reduced emissions from deforestation and forest degradation) pilot protect areas with rocks which have barely a tree on them. The apparent paradox indicates how actual practices differ from general ideas about REDD+ due to ongoing conflict over forest, and how contestations over the meaning of justice are a core element in negotiations over REDD+. We explore these politics of justice by examining how the actors involved in the REDD+ pilot negotiate the particular subjects, dimensions, and authority of justice considered relevant, and show how politics of justice are implicit to practical decisions in project implementation. Contestations over the meaning of justice are an important element in the practices and processes constituting REDD+ at global, national and local levels, challenging uniform definitions of forest justice and how forests ought to be managed. PMID- 27122654 TI - Lost in Translation: State Policies and Micro-politics of Water Governance in Namibia. AB - Water governance in rural Namibia has profoundly changed since the early 1990s. After independence and in accordance with global environmental policies, it became a central theme of Namibia's environmental legislation to transfer the responsibility for managing natural resources to local user associations. In this article, I explore the emergence of new social forms at the intersection of existing cultural models and new rationalities for governance. Doing so combines an analysis of state legislation with the micro-politics of water governance in 60 pastoral communities. The ethnographic analysis reveals that different actors, including state bureaucrats as well as rich and poorer herd owners, have different understandings of how to share water. While the poorer often agree with the state policy that water is an economic good and should be paid for accordingly, only in about half of the communities do corresponding institutional regimes emerge. Using critical institutionalism as a theoretical guide, I offer a contribution to understanding how more than 20 years after Rio local institutions of resource governance emerge at the intersection of different, and often heterogeneous and intertwined, social fields. PMID- 27122655 TI - Diagnostic Laparoscopy with Ultrasound Still Has a Role in the Staging of Pancreatic Cancer: A Systematic Review of the Literature. AB - Background. The reported incidence of noncurative laparotomies for pancreatic cancer using standard imaging (SI) techniques for staging remains high. The objectives of this study are to determine the diagnostic accuracy of diagnostic laparoscopy with ultrasound (DLUS) in assessing resectability of pancreatic tumors. Study Design. We systematically searched the literature for prospective studies investigating the accuracy of DLUS in determining resectability of pancreatic tumors. Results. 104 studies were initially identified and 19 prospective studies (1,573 patients) were included. DLUS correctly predicted resectability in 79% compared to 55% for SI. DLUS prevented noncurative laparotomies in 33%. Of those, the most frequent DLUS findings precluding resection were liver metastases, vascular involvement, and peritoneal metastases. DLUS had a morbidity rate of 0.8% with no mortalities. DLUS remained superior to SI when analyzing studies published only in the last five years (100% versus 81%), enrolling patients after the year 2000 (74% versus 58%), or comparing DLUS to modern multidimensional CT (100% versus 78%). Conclusion. DLUS seems to still have a role in the preoperative staging of pancreatic cancer. With its ability to detect liver metastases, vascular involvement, and peritoneal metastases, the use of DLUS leads to less noncurative laparotomies. PMID- 27122657 TI - Endothelial Dysfunction and Inflammation: Immunity in Rheumatoid Arthritis. AB - Inflammation, as a feature of rheumatoid arthritis (RA), leads to the activation of endothelial cells (ECs). Activated ECs induce atherosclerosis through an increased expression of leukocyte adhesion molecules. Endothelial dysfunction (ED) is recognized as a failure of endothelial repair mechanisms. It is also an early preclinical marker of atherosclerosis and is commonly found in RA patients. RA is now established as an independent cardiovascular risk factor, while mechanistic determinants of ED in RA are still poorly understood. An expanding body of study has shown that EC at a site of RA is both active participant and regulator of inflammatory process. Over the last decade, a role for endothelial dysfunction in RA associated with cardiovascular disease (CVD) has been hypothesized. At the same time, several maintenance drugs targeting this phenomenon have been tested, which has promising results. Assessment of endothelial function may be a useful tool to identify and monitor RA patients. PMID- 27122658 TI - Intersection of toxicogenomics and high throughput screening in the Tox21 program: an NIEHS perspective. AB - Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the toxicological effects of chemicals. Tox21 is a collaboration among US government agencies initiated in 2008 that aims to shift chemical hazard assessment from traditional animal toxicology to target-specific, mechanism based, biological observations using in vitro assays and lower organism models. HTS uses biocomputational methods for probing thousands of chemicals in in vitro assays for gene-pathway response patterns predictive of adverse human health outcomes. In 1999, NIEHS began exploring the application of toxicogenomics to toxicology and recent advances in NextGen sequencing should greatly enhance the biological content obtained from HTS platforms. We foresee an intersection of new technologies in toxicogenomics and HTS as an innovative development in Tox21. Tox21 goals, priorities, progress, and challenges will be reviewed. PMID- 27122659 TI - Crohn's disease presenting as acute gastrointestinal hemorrhage. AB - Severe gastrointestinal (GI) hemorrhage is a rare complication of Crohn's disease (CD). Although several surgical and non-surgical approaches have been described over the last 2 decades this complication still poses significant diagnostic and therapeutic challenges. Given the relative infrequency of severe bleeding in CD, available medical literature on this topic is mostly in the form of retrospective case series and reports. In this article we review the risk factors, diagnostic modalities and treatment options for the management of CD presenting as GI hemorrhage. PMID- 27122656 TI - Dendritic Cells in Systemic Lupus Erythematosus: From Pathogenic Players to Therapeutic Tools. AB - System lupus erythematosus (SLE) is a multifactorial systemic autoimmune disease with a wide variety of presenting features. SLE is believed to result from dysregulated immune responses, loss of tolerance of CD4 T cells and B cells to ubiquitous self-antigens, and the subsequent production of anti-nuclear and other autoreactive antibodies. Recent research has associated lupus development with changes in the dendritic cell (DC) compartment, including altered DC subset frequency and localization, overactivation of mDCs and pDCs, and functional defects in DCs. Here we discuss the current knowledge on the role of DC dysfunction in SLE pathogenesis, with the focus on DCs as targets for interventional therapies. PMID- 27122661 TI - Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease. AB - AIM: To establish a mouse model of alcohol-driven hepatocellular carcinoma (HCC) that develops in livers with alcoholic liver disease (ALD). METHODS: Adult C57BL/6 male mice received multiple doses of chemical carcinogen diethyl nitrosamine (DEN) followed by 7 wk of 4% Lieber-DeCarli diet. Serum alanine aminotransferase (ALT), alpha fetoprotein (AFP) and liver Cyp2e1 were assessed. Expression of F4/80, CD68 for macrophages and Ly6G, MPO, E-selectin for neutrophils was measured. Macrophage polarization was determined by IL-1beta/iNOS (M1) and Arg-1/IL-10/CD163/CD206 (M2) expression. Liver steatosis and fibrosis were measured by oil-red-O and Sirius red staining respectively. HCC development was monitored by magnetic resonance imaging, confirmed by histology. Cellular proliferation was assessed by proliferating cell nuclear antigen (PCNA). RESULTS: Alcohol-DEN mice showed higher ALTs than pair fed-DEN mice throughout the alcohol feeding without weight gain. Alcohol feeding resulted in increased ALT, liver steatosis and inflammation compared to pair-fed controls. Alcohol-DEN mice had reduced steatosis and increased fibrosis indicating advanced liver disease. Molecular characterization showed highest levels of both neutrophil and macrophage markers in alcohol-DEN livers. Importantly, M2 macrophages were predominantly higher in alcohol-DEN livers. Magnetic resonance imaging revealed increased numbers of intrahepatic cysts and liver histology confirmed the presence of early HCC in alcohol-DEN mice compared to all other groups. This correlated with increased serum alpha-fetoprotein, a marker of HCC, in alcohol DEN mice. PCNA immunostaining revealed significantly increased hepatocyte proliferation in livers from alcohol-DEN compared to pair fed-DEN or alcohol-fed mice. CONCLUSION: We describe a new 12-wk HCC model in adult mice that develops in livers with alcoholic hepatitis and defines ALD as co-factor in HCC. PMID- 27122660 TI - Nonalcoholic fatty liver disease as a multi-systemic disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD includes a wide spectrum of liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis and advanced hepatic fibrosis. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic diseases. Therefore, NAFLD is usually associated with cardiovascular disease, chronic kidney disease, type 2 diabetes, obesity, and dyslipidemia. NAFLD is highly prevalent in the general population and is associated with increased cardiovascular morbidity and mortality. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. This review focuses on pathogenesis of NAFLD and its relation with other systemic diseases. PMID- 27122662 TI - Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines. AB - AIM: To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7B mutations in cell culture. METHODS: The most common Wilson disease (WD) mutations p.H1069Q, p.R778L and p.C271*, found in the ATP7B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7B was used to stably express WD mutants. mRNA and protein expression of mutant ATP7B, survival of cells, apoptosis, and protein trafficking were determined. RESULTS: Low temperature increased ATP7B protein expression in several mutants. Intracellular ATP7B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069Q and to a lesser extent p.C271* improved by D-penicillamine (DPA) treatment, while mutant p.R778L showed a pronounced response to zinc (Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability. CONCLUSION: The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines. PMID- 27122663 TI - Combined mesenchymal stem cell transplantation and interleukin-1 receptor antagonism after partial hepatectomy. AB - AIM: To study the therapeutic effects of mesenchymal stem cells (MSCs) and an interleukin-1 receptor antagonist (IL-1Ra) in acute liver failure. METHODS: Chinese experimental miniature swine (15 +/- 3 kg, 5-8 mo) were obtained from the Laboratory Animal Centre of the Affiliated Drum Tower Hospital of Nanjing University Medical School. Acute liver failure was induced via 85% hepatectomy, and animals were treated by MSC transplantation combined with IL-1Ra injection. Blood samples were collected for hepatic function analysis, and the living conditions and survival time were recorded. Liver injury was histologically analyzed. Hepatic cell regeneration and apoptosis were studied by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. The levels of protein kinase B and nuclear factor-kappaB expression were analyzed by Western blotting. RESULTS: MSCs were infected with a lentivirus for expression of green fluorescent protein (GFP) for subsequent identification; 97.3% of the MSCs were positive for GFP as assessed by flow cytometry. Additional flow cytometric analysis of cell surface marker expression demonstrated that > 90% of GFP-expressing MSCs were also positive for CD29, CD44, and CD90, indicating that most of these cells expressed typical markers of MSCs, and the population of MSCs was almost pure. Transplantation of MSCs in combination with 2 mg/kg IL-1Ra therapy significantly improved survival time compared to the acute liver failure model group (35.3 +/- 6.7 d vs 17.3 +/- 5.5 d, P < 0.05). Combined therapy also promoted improvement in serum inflammatory cytokines and biochemical conditions. The observed hepatic histopathologic score was significantly lower in the group with combined therapy than in the model group (3.50 +/- 0.87 vs 8.17 +/- 1.26, P < 0.01). In addition, liver cell apoptosis in the combined therapy group was significantly inhibited (18.1 +/- 2.1% vs 70.8 +/- 3.7%, P < 0.01), and hepatic cell regeneration increased. A significant increase in protein kinase B expression and decrease in nuclear factor-kappaB expression were observed (P < 0.01), which supports their important roles in liver regeneration. CONCLUSION: MSCs and IL-1Ra had a synergistic effect in liver regeneration via regulation of inflammation and apoptotic signaling. PMID- 27122664 TI - Recombinant adenovirus containing hyper-interleukin-6 and hepatocyte growth factor ameliorates acute-on-chronic liver failure in rats. AB - AIM: To investigate the protective efficacy of recombinant adenovirus containing hyper-interleukin-6 (Hyper-IL-6, HIL-6) and hepatocyte growth factor (HGF) (Ad HGF-HIL-6) compared to that of recombinant adenovirus containing either HIL-6 or HGF (Ad-HIL-6 or Ad-HGF) in rats with acute-on-chronic liver failure (ACLF). METHODS: The recombinant adenoviruses containing HIL-6 and/or HGF were constructed. We established an ACLF model, and rats were randomly assigned to control, model, Ad-GFP, Ad-HIL-6, Ad-HGF or Ad-HGF-HIL-6 group. We collected serum and liver tissue samples to test pathological changes, biochemical indexes and molecular biological indexes. RESULTS: Attenuated alanine aminotransferase, prothrombin time, high-mobility group box 1 (HMGB1), endotoxin, tumour necrosis factor (TNF)-alpha and interferon-gamma were observed in the Ad-HGF-, Ad-HIL-6- and Ad-HGF-HIL-6-treated rats with ACLF. Likewise, reduced hepatic damage and apoptotic activity, as well as reduced HMGB1 and Bax proteins, but raised expression of Ki67 and Bcl-2 proteins and Bcl-2/Bax ratio were also observed in the Ad-HGF-, Ad-HIL-6- and Ad-HGF-HIL-6-treated rats with ACLF. More significant changes were observed in the Ad-HGF-HIL-6 treatment group without obvious side effects. Furthermore, caspase-3 at the protein level decreased in the Ad-HIL-6 and Ad-HGF-HIL-6 treatment groups, more predominantly in the latter group. CONCLUSION: This study identifies that the protective efficacy of Ad-HGF-HIL-6 is more potent than that of Ad-HGF or Ad-HIL-6 in ACLF rats, with no significant side effects. PMID- 27122665 TI - Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. AB - AIM: To elucidate the mechanism of thymoquinone (TQ)-induced apoptosis in human gastric cancer cells in vitro and in vivo. METHODS: HGC27, BGC823, and SGC7901 cells were cultured in vitro and treated with TQ (0, 10, 25, 50, 75, 100, 125 MUmol/L) for 12 h, 24 h, and 36 h, and then the proliferation inhibitory rates were detected by methylthiazole tetrazolium assay. Apoptosis was observed after Hoechst staining. The protein expressions of signal transducer and activator of transcription (STAT)3, p-STAT3, STAT5, p-STAT5, phospho-janus-activated kinase 2 (JAK2), JAK2, p-Src, Src, glyceraldehyde-3-phosphate dehydrogenase, lamin-A, survivin, Cyclin D, Bcl-2, Bax, peroxisome proliferator activated receptor, and caspase-3,7,9 were detected by western blot. Cell cycle and apoptosis were determined with flow cytometry. TQ induced dose-dependent apoptotic cell death in HGC27 cells was measured by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) analysis and Hoechst 33258. RESULTS: TQ inhibited the phosphorylation of STAT3 but not STAT5. TQ-induced downregulation of STAT3 activation was associated with a reduction in JAK2 and c-Src activity. TQ also downregulated the expression of STAT3-regulated genes, such as Bcl-2, cyclin D, survivin, and vascular endothelial growth factor, and activated caspase-3,7,9. Consistent with the in vitro results, TQ was significantly effective as an antitumor agent in a xenograft tumor mouse model. CONCLUSION: This study provides strong evidence that downregulation of the STAT3 signaling pathway mediates TQ-induced apoptosis in gastric cancer. PMID- 27122666 TI - Total pancreatectomy with islet cell transplantation vs intrathecal narcotic pump infusion for pain control in chronic pancreatitis. AB - AIM: To evaluate pain control in chronic pancreatitis patients who underwent total pancreatectomy with islet cell transplantation or intrathecal narcotic pump infusion. METHODS: We recognized 13 patients who underwent intrathecal narcotic pump (ITNP) infusion and 57 patients who underwent total pancreatectomy with autologous islet cell transplantation (TP + ICT) for chronic pancreatitis (CP) pain control between 1998 and 2008 at Indiana University Hospital. All patients had already failed multiple other modalities for pain control and the decision to proceed with either intervention was made at the discretion of the patients and their treating physicians. All patients were evaluated retrospectively using a questionnaire inquiring about their pain control (using a 0-10 pain scale), daily narcotic dose usage, and hospital admission days for pain control before each intervention and during their last follow-up. RESULTS: All 13 ITNP patients and 30 available TP + ICT patients were evaluated. The mean age was approximately 40 years in both groups. The median duration of pain before intervention was 6 years and 7 years in the ITNP and TP + ICT groups, respectively. The median pain score dropped from 8 to 2.5 (on a scale of 0-10) in both groups on their last follow up. The median daily dose of narcotics also decreased from 393 mg equivalent of morphine sulfate to 8 mg in the ITNP group and from 300 mg to 40 mg in the TP + ICT group. No patient had diabetes mellitus (DM) before either procedure whereas 85% of those who underwent pancreatectomy were insulin dependent on their last evaluation despite ICT. CONCLUSION: ITNP and TP + ICT are comparable for pain control in patients with CP however with high incidence of DM among those who underwent TP + ICT. Prospective comparative studies and longer follow up are needed to better define treatment outcomes. PMID- 27122667 TI - Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model. AB - AIM: To develop a mathematical model for the early detection of hepatocellular carcinoma (HCC) with a panel of serum proteins in combination with alpha fetoprotein (AFP). METHODS: Serum levels of interleukin (IL)-8, soluble intercellular adhesion molecule-1 (sICAM-1), soluble tumor necrosis factor receptor II (sTNF-RII), proteasome, and beta-catenin were measured in 479 subjects categorized into four groups: (1) HCC concurrent with hepatitis C virus (HCV) infection (n = 192); (2) HCV related liver cirrhosis (LC) (n = 96); (3) Chronic hepatitis C (CHC) (n = 96); and (4) Healthy controls (n = 95). The R package and different modules for binary and multi-class classifiers based on generalized linear models were used to model the data. Predictive power was used to evaluate the performance of the model. Receiver operating characteristic curve analysis over pairs of groups was used to identify the best cutoffs differentiating the different groups. RESULTS: We revealed mathematical models, based on a binary classifier, made up of a unique panel of serum proteins that improved the individual performance of AFP in discriminating HCC patients from patients with chronic liver disease either with or without cirrhosis. We discriminated the HCC group from the cirrhotic liver group using a mathematical model (-11.3 + 7.38 * Prot + 0.00108 * sICAM + 0.2574 * beta-catenin + 0.01597 * AFP) with a cutoff of 0.6552, which achieved 98.8% specificity and 89.1% sensitivity. For the discrimination of the HCC group from the CHC group, we used a mathematical model [-10.40 + 1.416 * proteasome + 0.002024 * IL + 0.004096 * sICAM-1 + (4.251 * 10(-4)) * sTNF + 0.02567 * beta-catenin + 0.02442 * AFP] with a cutoff 0.744 and achieved 96.8% specificity and 89.7% sensitivity. Additionally, we derived an algorithm, based on a binary classifier, for resolving the multi-class classification problem by using three successive mathematical model predictions of liver disease status. CONCLUSION: Our proposed mathematical model may be a useful method for the early detection of different statuses of liver disease co-occurring with HCV infection. PMID- 27122668 TI - Effects of interactions between environmental factors and KIF1B genetic variants on the risk of hepatocellular carcinoma in a Chinese cohort. AB - AIM: To examine the effect of the potential interaction between KIF1B variants (rs17401966 and rs3748578) and environmental factors on the risk of hepatocellular carcinoma (HCC) in a high-risk region in China. METHODS: Three hundred and six patients with HCC and 306 hospital-based control participants residing in the Shunde region of Guangdong Province, China were enrolled. Clinical characteristics were collected by reviewing the complete medical histories from the patient archives, and epidemiological data were collected using a questionnaire and clinical examination. Two single nucleotide polymorphisms (SNPs) of KIF1B (rs17401966 and rs3748578) were chosen for the current study. All subjects were genotyped using a TaqMan real-time polymerase chain reaction. Multiplicative and additive logistic regression models were used to evaluate various gene-environment interactions. RESULTS: Smoking, frequent consumption of raw freshwater fish, hepatitis B virus (HBV) infection, and a family history of HCC were important risk factors for HCC in this population. Chronic infection with HBV was the most important environmental risk factor for HCC [odds ratio (OR) = 12.02; 95% confidence interval (95%CI): 6.02-24.00]. No significant association was found between the KIF1B variants alone and the risk of HCC. Nevertheless, a significant additive effect modification was observed between rs17401966 and alcohol consumption (P for additive interaction = 0.0382). Compared with non-drinkers carrying either the AG or GG genotype of rs17401966, individuals classified as alcohol consumers with the AA genotype of rs17401966 had a significantly increased risk of HCC (OR = 2.36; 95%CI: 1.49-3.74). CONCLUSION: The gene-environment interaction between the KIF1B rs17401966 variant and alcohol consumption may contribute to the development of HCC in Chinese individuals. PMID- 27122669 TI - Urinary nuclear magnetic resonance spectroscopy of a Bangladeshi cohort with hepatitis-B hepatocellular carcinoma: A biomarker corroboration study. AB - AIM: To establish if a distinct urinary metabolic profile could be identified in Bangladeshi hepatitis-B hepatocellular carcinoma (HCC) patients compared to cirrhosis patients and controls. METHODS: Urine samples from 42 Bangladeshi patients with HCC (39 patients with hepatitis-B HCC), 47 with cirrhosis on a background of hepatitis B, 46 with chronic hepatitis B, and seven ethnically matched healthy controls were analyzed using nuclear magnetic resonance (NMR) spectroscopy. A full dietary and medication history was recorded for each subject. The urinary NMR data were analyzed using principal component analysis (PCA) and orthogonal partial least squared discriminant analysis (OPLS-DA) techniques. Differences in relative signal levels of the most discriminatory metabolites identified by PCA and OPLS-DA were compared between subject groups using an independent samples Kruskal-Wallis one-way analysis of variance (ANOVA) test with all pairwise multiple comparisons. Within the patient subgroups, the Mann-Whitney U test was used to compare metabolite levels depending on hepatitis B e-antigen (HBeAg) status and treatment with anti-viral therapy. A Benjamini Hochberg adjustment was applied to acquire the level of significance for multiple testing, with a declared level of statistical significance of P < 0.05. RESULTS: There were significant differences in age (P < 0.001), weight (P < 0.001), and body mass index (P < 0.001) across the four clinical subgroups. Serum alanine aminotransferase (ALT) was significantly higher in the HCC group compared to controls (P < 0.001); serum alpha-fetoprotein was generally markedly elevated in HCC compared to controls; and serum creatinine levels were significantly reduced in the HCC group compared to the cirrhosis group (P = 0.004). A three-factor PCA scores plot showed clustering of the urinary NMR spectra from the four subgroups. Metabolites that contributed to the discrimination between the subgroups included acetate, creatine, creatinine, dimethyamine (DMA), formate, glycine, hippurate, and trimethylamine-N-oxide (TMAO). A comparison of relative metabolite levels confirmed that carnitine was significantly increased in HCC; and creatinine, hippurate, and TMAO were significantly reduced in HCC compared to the other subgroups. HBeAg negative patients showed a significant increase in creatinine (P = 0.001) compared to HBeAg positive patients in the chronic hepatitis B subgroup, whilst HBeAg negative patients showed a significant decrease in DMA (P = 0.004) in the cirrhosis subgroup compared to HBeAg positive patients. There were no differences in metabolite levels in HCC patients who did or did not receive antiviral treatment. CONCLUSION: Urinary NMR changes in Bangladeshi HCC were identified, corroborating previous findings from Egypt and West Africa. These findings could form the basis for the development of a cost-effective HCC dipstick screening test. PMID- 27122670 TI - Influence of antibiotic-regimens on intensive-care unit-mortality and liver cirrhosis as risk factor. AB - AIM: To assess the rate of infection, appropriateness of antimicrobial-therapy and mortality on intensive care unit (ICU). Special focus was drawn on patients with liver cirrhosis. METHODS: The study was approved by the local ethical committee. All patients admitted to the Internal Medicine-ICU between April 1, 2007 and December 31, 2009 were included. Data were extracted retrospectively from all patients using patient charts and electronic documentations on infection, microbiological laboratory reports, diagnosis and therapy. Due to the large hepatology department and liver transplantation center, special interest was on the subgroup of patients with liver cirrhosis. The primary statistical endpoint was the evaluation of the influence of appropriate versus inappropriate antimicrobial-therapy on in-hospital-mortality. RESULTS: Charts of 1979 patients were available. The overall infection-rate was 53%. Multiresistant-bacteria were present in 23% of patients with infection and were associated with increased mortality (P < 0.000001). Patients with infection had significantly increased in hospital-mortality (34% vs 17%, P < 0.000001). Only 9% of patients with infection received inappropriate initial antimicrobial-therapy, no influence on mortality was observed. Independent risk-factors for in-hospital-mortality were the presence of septic-shock, prior chemotherapy for malignoma and infection with Pseudomonas spp. Infection and mortality-rate among 175 patients with liver cirrhosis was significantly higher than in patients without liver-cirrhosis. Infection increased mortality 2.24-fold in patients with cirrhosis. Patients with liver cirrhosis were at an increased risk to receive inappropriate initial antimicrobial therapy. CONCLUSION: The results of the present study report the successful implementation of early-goal-directed therapy. Liver cirrhosis patients are at increased risk of infection, mortality and to receive inappropriate therapy. Increasing burden are multiresistant-bacteria. PMID- 27122671 TI - Lymphocyte-to-monocyte ratio predicts survival after radiofrequency ablation for colorectal liver metastases. AB - AIM: To test the correlation between lymphocyte-to-monocyte ratio (LMR) and survival after radiofrequency ablation (RFA) for colorectal liver metastasis (CLMs). METHODS: From July 2003 to Feb 2012, 127 consecutive patients with 193 histologically-proven unresectable CLMs were treated with percutaneous RFA at the University of Foggia. All patients had undergone primary colorectal tumor resection before RFA and received systemic chemotherapy. LMR was calculated by dividing lymphocyte count by monocyte count assessed at baseline. Treatment related toxicity was defined as any adverse events occurred within 4 wk after the procedure. Overall survival (OS) and time to recurrence (TTR) were estimated from the date of RFA by Kaplan-Meier with plots and median (95%CI). The inferential analysis for time to event data was conducted using the Cox univariate and multivariate regression model to estimate hazard ratios (HR) and 95%CI. Statistically significant variables from the univariate Cox analysis were considered for the multivariate models. RESULTS: Median age was 66 years (range 38-88) and patients were prevalently male (69.2%). Median LMR was 4.38% (0.79-88) whereas median number of nodules was 2 (1-3) with a median maximum diameter of 27 mm (10-45). Median OS was 38 mo (34-53) and survival rate (SR) was 89.4%, 40.4% and 33.3% at 1, 4 and 5 years respectively in the whole cohort. Running log-rank test analysis found 3.96% as the most significant prognostic cut-off point for LMR and stratifying the study population by this LMR value median OS resulted 55 mo (37-69) in patients with LMR > 3.96% and 34 (26-39) mo in patients with LMR <= 3.96% (HR = 0.53, 0.34-0.85, P = 0.007). Nodule size and LMR were the only significant predictors for OS in multivariate analysis. Median TTR was 29 mo (22 35) with a recurrence-free survival (RFS) rate of 72.6%, 32.1% and 21.8% at 1, 4 and 5 years, respectively in the whole study group. Nodule size and LMR were confirmed as significant prognostic factors for TTR in multivariate Cox regression. TTR, when stratified by LMR, was 35 mo (28-57) in the group > 3.96% and 25 mo (18-30) in the group <= 3.96% (P = 0.02). CONCLUSION: Our study provides support for the use of LMR as a novel predictor of outcome for CLM patients. PMID- 27122672 TI - Predictors of poor outcome in gastrointestinal bleeding in emergency department. AB - AIM: To determine the prognostic risk factors of gastrointestinal bleeding in emergency department cases. METHODS: The trial was a retrospective single-center study involving 600 patients over 18-years-old and carried out with approval by the Institutional Ethics Committee. Patient data included demographic characteristics, symptoms at admission, past medical history, vital signs, laboratory results, endoscopy and colonoscopy results, length of hospital stay, need of intensive care unit (ICU) admission, and mortality. Mortality rate was the principal endpoint of the study, while duration of hospital stay, required interventional treatment, and admission to the ICU were secondary endpoints. RESULTS: The mean age of patients was 61.92-years-old. Among the 600 total patients, 363 (60.5%) underwent upper gastrointestinal endoscopy and the most frequent diagnoses were duodenal ulcer (19.2%) and gastric ulcer (12.8%). One hundred-and-fifteen (19.2%) patients required endoscopic treatment, 20 (3.3%) required surgical treatment, and 5 (0.8%) required angiographic embolization. The mean length of hospital stay was 5.21 +/- 5.85 d. The mortality rate was 6.3%. The ICU admission rate was 5.3%. Patients with syncope, higher blood glucose levels, and coronary artery disease had significantly higher ICU admission rates (P = 0.029, P = 0.043, and P = 0.002, respectively). Patients with low thrombocyte levels, high creatinine, high international normalized ratio, and high serum transaminase levels had significantly longer hospital stay (P = 0.02, P = 0.001, P = 0.019, and P = 0.005, respectively). Patients who died had significantly higher serum blood urea nitrogen and creatinine levels (P = 0.016 and P = 0.038), and significantly lower mean blood pressure and oxygen saturation (P = 0.004 and P = 0.049). Malignancy and low Glasgow coma scale (GCS) were independent predictive factors of mortality. CONCLUSION: Prognostic factors for gastrointestinal bleeding in emergency room cases are malignancy, hypotension on admission, low GCS, and impaired kidney function. PMID- 27122673 TI - Eukaryotic elongation factor-1alpha 2 knockdown inhibits hepatocarcinogenesis by suppressing PI3K/Akt/NF-kappaB signaling. AB - AIM: To assess the impact of eukaryotic elongation factor 1 alpha 2 (eEF1A2) on hepatocellular carcinoma (HCC) cell proliferation, apoptosis, migration and invasion, and determine the underlying mechanisms. METHODS: eEF1A2 levels were detected in 62 HCC tissue samples and paired pericarcinomatous specimens, and the human HCC cell lines SK-HEP-1, HepG2 and BEF-7402, by real-time PCR and immunohistochemistry. Experimental groups included eEF1A2 silencing in BEL-7402 cells with lentivirus eEF1A2-shRNA (KD group) and eEF1A2 overexpression in SK-HEP 1 cells with eEF1A2 plasmid (OE group). Non-transfected cells (control group) and lentivirus-based empty vector transfected cells (NC group) were considered control groups. Cell proliferation (MTT and colony formation assays), apoptosis (Annexin V-APC assay), cell cycle (DNA ploidy assay), and migration and invasion (Transwell assays) were assessed. Protein levels of PI3K/Akt/NF-kappaB signaling effectors were evaluated by Western blot. RESULTS: eEF1A2 mRNA and protein levels were significantly higher in HCC cancer tissue samples than in paired pericarcinomatous and normal specimens. SK-HEP-1 cells showed lower eEF1A2 mRNA levels; HepG2 and BEL-7402 cells showed higher eEF1A2 mRNA levels, with BEL-7402 cells displaying the highest amount. Efficient eEF1A2 silencing resulted in reduced cell proliferation, migration and invasion, increased apoptosis, and induced cell cycle arrest. The PI3K/Akt/NF-kappaB signaling pathway was notably inhibited. Inversely, eEF1A2 overexpression resulted in promoted cell proliferation, migration and invasion. CONCLUSION: eEF1A2, highly expressed in HCC, is a potential oncogene. Its silencing significantly decreases HCC tumorigenesis, likely by inhibiting PI3K/Akt/NF-kappaB signaling. PMID- 27122674 TI - Transient elastography compared to liver biopsy and morphometry for predicting fibrosis in pediatric chronic liver disease: Does etiology matter? AB - AIM: To evaluate transient elastography (TE) as a noninvasive tool in staging liver fibrosis compared with liver biopsy and morphometry in children with different chronic liver diseases. METHODS: A total of 90 children [50 with chronic hepatitis C virus (HCV), 20 with autoimmune hepatitis (AIH) and 20 with Wilson disease] were included in the study and underwent liver stiffness measurement (LSM) using TE. Liver biopsies were evaluated for fibrosis, qualitatively, by Ishak score and quantitatively by fibrosis area fraction (FAF) using digital image analysis (morphometry). LSM was correlated with fibrosis and other studied variables using spearman correlation. A stepwise multiple regression analysis was also performed to examine independent factors associated with LSM. Different cut-off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. Cut-off values with optimal clinical performance (optimal sensitivity and specificity simultaneously) were selected. RESULTS: The majority of HCV group had minimal activity (80%) and no/mild fibrosis (72%). On the other hand, the majority of AIH group had mild to moderate activity (70%) and moderate to severe fibrosis (95%) and all Wilson disease group had mild to moderate activity (100%) and moderate to severe fibrosis (100%). LSM correlated significantly with both FAF and Ishak scores and the correlation appeared better with the latter (r = 0.839 vs 0.879, P < 0.0001 for both). LSM discriminated individual stages of fibrosis with high performance. Sensitivity ranged from 81.4% to 100% and specificity ranged from 75.0% to 97.2%. When we compared LSM values for the same stage of fibrosis, they varied according to the different etiologies. Higher values were in AIH (16.15 +/ 7.23 kPa) compared to Wilson disease (8.30 +/- 0.84 kPa) and HCV groups (7.43 +/ 1.73 kPa). Multiple regression analysis revealed that Ishak fibrosis stage was the only independent variable associated with higher LSM (P < 0.0001). CONCLUSION: TE appears reliable in distinguishing different stages of liver fibrosis in children. However, its values vary according to the disease type. For that, a disease-specific estimation of cut-off values for fibrosis staging is worthy. PMID- 27122675 TI - Predictive effects of bilirubin on response of colorectal cancer to irinotecan based chemotherapy. AB - AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP glucuronosyltransferase (UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy. METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer (mCRC) patients treated with irinotecan-based chemotherapy (NCT01282658). Baseline serum bilirubin levels, including total bilirubin (TBil) and unconjugated bilirubin (UBil), were measured, and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve (ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or <= 13.0 groups; the UBil values were categorized into > 4.1 or <= 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as CoBil, patients were classified into three groups. The classifier's performance of UGT1A1*28 and CoBil for predicting treatment response was evaluated by ROC analysis. Associations between response and CoBil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models. RESULTS: Among the 120 mCRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil (P = 0.018) and a higher UBil (P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on CoBil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil <= 13.0 and UBil > 4.1; and Group 3 was patients with TBil <= 13.0 and UBil <= 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple (OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple (OR = 16.001; 95%CI: 2.802 -91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28 (TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous (TA)6 genotype in the simple (OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple (OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier's performance of CoBil and UGT1A1*28 were comparable. CONCLUSION: CoBil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of mCRC patients to irinotecan-based chemotherapy. After validation, CoBil, an easily determinable index in the clinic, might be helpful in facilitating stratification of mCRC patients for individualized treatment options. PMID- 27122676 TI - Pancreaticoduodenal artery aneurysm associated with coeliac artery occlusion from an aortic intramural hematoma. AB - Pancreaticoduodenal artery aneurysms are a rare type of visceral artery aneurysm, whose rupture is associated with high mortality. These aneurysms are of particular interest because local haemodynamic change caused by coeliac artery obstruction plays an important role in their development. However, the pathophysiological mechanism of coeliac artery obstruction is not completely understood. Pressure from the median arcuate ligament is most frequently reported cause. Although it is well-known that stenosis or occlusion of the visceral vessels may be caused by aortic syndrome, reports of pancreaticoduodenal artery aneurysm associated with coeliac artery occlusion due to aortic syndrome are extremely rare. Our case indicates a new aetiology for a pancreaticoduodenal artery aneurysm and demonstrates the rapid deterioration of the patient affected. PMID- 27122677 TI - Urgent endoscopic ultrasound-guided choledochoduodenostomy for acute obstructive suppurative cholangitis-induced sepsis. AB - Acute obstructive suppurative cholangitis (AOSC) due to biliary lithiasis is a life-threatening condition that requires urgent biliary decompression. Although endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is the current gold standard for biliary decompression, it can sometimes be difficult because of failed biliary cannulation. In this retrospective case series, we describe three cases of successful biliary drainage with recovery from septic shock after urgent endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) was performed for AOSC due to biliary lithiasis. In all three cases, technical success in inserting the stents was achieved and the patients completely recovered from AOSC with sepsis in a few days after EUS-CDS. There were no procedure-related complications. When initial ERCP fails, EUS-CDS can be an effective life-saving endoscopic biliary decompression procedure that shortens the procedure time and prevents post-ERCP pancreatitis, particularly in patients with AOSC-induced sepsis. PMID- 27122678 TI - Occult gastric cancer with distant metastasis proven by random gastric biopsy. AB - Krukenberg tumor, a rare metastatic ovarian tumor arising from gastrointestinal adenocarcinoma mainly, tends to occur in premenopausal females. Finding the origin of a Krukenberg tumor is crucial for determining prognosis. In Eastern countries, the most common origin of Krukenberg tumor is stomach cancer, which is generally diagnosed via endoscopic biopsy to investigate an abnormal mucosal lesion. Here, we describe a case of huge adnexal mass in a 33-year-old woman who presented with abdominal distension. Two independent endoscopic examinations performed by experts in two tertiary university hospitals revealed no abnormal mucosal lesion. The patient was diagnosed with a Krukenberg tumor according to findings from random endoscopic biopsies taken from normal-looking gastric mucosa in our hospital. It is very rare to be diagnosed via a random biopsy in cases where three well-trained endoscopists had not found any mucosal lesion previously. Thus, in this case, random biopsy was helpful in finding the origin of a Krukenberg tumor. PMID- 27122679 TI - Coronary Vasospastic Angina: Current Understanding and the Role of Inflammation. AB - Coronary vasospastic angina (CVsA) plays an important role in myocardial ischemia including stable angina, acute coronary syndromes, and sudden cardiac death. Inflammation status from either endothelium or adventitia can cause endothelial dysfunction. Thereafter, the endothelial dysfunction further induces vascular smooth muscle hypercontraction through the enhanced rho-kinase with the resultant clinical event. With better understanding of the interactions between inflammation, endothelium, and smooth muscle cells, we and other investigators have provided new insights into the basic pathophysiology of CVsA. Apart from calcium channel blockers, nitrates, and the rho-kinase inhibitor fasudil, anti inflammatory treatment is helpful in some patients with refractory CVsA. Additional studies are needed to clarify the mechanisms of recurrent CVsA. KEY WORDS: Anticoagulants; Deep vein thrombosis; Diagnosis; Treatment. PMID- 27122680 TI - Effect of 8-Week Combination Therapy with an Extended-Release alpha1-Blocker (Bunazosin or Doxazosin) in Inadequate Responders to an Angiotensin II Antagonist (Valsartan) in Patients with Stage 1 or 2 Essential Hypertension. AB - BACKGROUND: Given the favorable impact of alpha1-blockers on lipid and glucose metabolism, this study was designed to compare the efficacy of two extended release alpha1-blockers (bunazosin and doxazosin) as an add-on treatment in subjects with stage 1 or 2 essential hypertension which was inadequately controlled by valsartan 80 mg/day. METHODS: After a 5-week treatment of valsartan monotherapy, subjects with inadequately controlled hypertension were randomized to receive either extended-release bunazosin (n = 47) or doxazosin (n = 46) after breakfast for 8 weeks. Office sitting blood pressure (BP), 24-hour ambulatory BP, and metabolic profiles were measured at baseline, start of study drug, and study end. RESULTS: In the intention-to-treat population (n = 93), the average daily doses of bunazosin and doxazosinwere 2.8 mg and 3.6 mg, respectively. The two add on treatments achieved significant and similar BP reductions from monotherapy (bunazosin, 13.2/9.3 mmHg; doxazosin, 9.2/8.5 mmHg, all p < 0.001). However, in patients with stage 2 hypertension, patients randomized to the bunazosin group, compared to those in the doxazosin group, achieved a significantly greater reduction in sitting systolic BP (14.4 +/- 8.1 vs. 6.6 +/- 13.8 mmHg, p = 0.015). In addition, patients who received bunazosin had significant changes in night-day systolic and diastolic BP ratios compared with those who received doxazosin ( 0.02 vs. 0.02, p = 0.04 and 0 vs. 0.04, p = 0.04). No significant changes in metabolic profiles were observed in both add-on groups. Both drugs were well tolerated, but adverse events related to the study drugs were marginally more frequent in the doxazosin group than in the bunazosin group (20% vs. 6%, p = 0.058). CONCLUSIONS: Both extended-release bunazosin and doxazosinwerewell tolerated and similarly effective as add-on therapy in hypertensive patients uncontrolled by valsartan monotherapy. However, add-on treatment with bunazosin seemed to be associated with favorable night-day BP ratio and greater sitting systolic BP reductions in stage 2 hypertensive patients. KEY WORDS: Combination therapy; Hypertension; alpha1-blocker. PMID- 27122681 TI - Effects of Anti-Hypertensive Monotherapy with Either Calcium Channel Blocker or Angiotensin Receptor Blocker on Arterial Stiffness, Central Hemodynamics, and Ventriculo-Arterial Coupling in Uncomplicated Hypertension Patients. AB - OBJECTIVES: This study is designed to investigate the effects of anti hypertensive monotherapy [either calcium channel blocker (CCB) or angiotensin receptor blocker (ARB)] on pulsatile hemodynamic parameters in patients with uncomplicated hypertension. METHODS: This is a longitudinal observational study. For simplicity, we included patients with uncomplicated hypertension who receivedmono anti-hypertensive therapy with ARB or CCB. Hemodynamic parameters including central arterial pressure (CAP), aortic characteristic impedance (Zc), augmentation index (AI), brachial-ankle pulse wave velocity (baPWV), heart-ankle pulse wave velocity (haPWV), cardiac ultrasonographic parameters and ventriculo arterial (VA) coupling were measured before, 1 month and 3 months after treatment. RESULTS: A total of 74 subjects were included in our study for analysis from 2007-2008. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic arterial pressure (CSAP) were significantly reduced 1 and 3 months after initiation of therapy. Among the pulsatile hemodynamic parameters, only the baPWV was significantly reduced (from1537.78 +/- 200.63 cm/s to 1460.06 +/- 186.09 cm/s to 1456.53 +/- 196.03 cm/s, p for trend = 0.016). The haPWV only decreased with borderline significance (from 1015.38 +/- 124.26 cm/s to 978.88 +/- 126.55 cm/s to 967.99 +/- 103.37 cm/s, p for trend = 0.041). The other pulsatile hemodynamic parameters remained unchanged before and after therapy. Subgroup analysis (age above or below52 years) showed that the baPWVwas significantly reduced only in the younger group. CONCLUSIONS: Among the pulsatile hemodynamic parameters, only the baPWV was effectively reduced by either CCB or ARB. The improvement of PWV was more evident in younger subjects. KEY WORDS: Arterial stiffness; Central arterial pressure; Hypertension; Pulse wave velocity; Ventriculo-arterial coupling. PMID- 27122682 TI - Renin-Angiotensin System Genes Polymorphisms and Long-Term Prognosis in Taiwanese Patients with Hypertension and Coronary Artery Disease. AB - OBJECTIVES: The objective of this study was to evaluate the renin-angiotensin system genetic effects and pharmacogenetic interactions for angiotensin converting enzyme (ACE) inhibitors in hypertensive coronary artery disease (CAD) patients. METHODS: Subjects with hypertension and angiographic CAD were recruited from 1995 to 2003. Baseline characteristics and genetic polymorphisms [ACE gene insertion/deletion (I/D) polymorphism, six polymorphisms of the angiotensinogen (AGT) gene, and A1166C polymorphisms of the angiotensin II type I receptor gene (AGT1R)] were collected. Patients were assigned to 2 groups (ACE inhibitor or No ACE inhibitor) and followed-for up to 12 years. Kaplan-Meier curves and Cox regression models were used to demonstrate the survival and major cardiovascular events (MACE) event-free survival trends. Pharmacogenetic effects were determined by several Cox regression models. RESULTS: Of the 518 patients in our study, 290 were treated with ACE inhibitors and 228 were not. Prescription of ACE inhibitors was associated with a lower rate of MACE at 4000 days. In addition, ACE I/D gene D was associated with a higher rate of MACE in a multivariate regression analysis [hazard ration (HR): 1.64, 95% confidence interval (CI): 1.27-1.98, p < 0.001]. This effect could be attenuated by the pharmacogenetic interaction of ACE inhibitors and the ACE gene (ACE in hibitors*ACE D gene, HR: 0.68, 95% CI: 0.52 0.84, p = 0.014). CONCLUSIONS: The use of ACE inhibitors was associated with a significant decrease in MACE in hypertensive patients diagnosed with CAD. Genetic variants were also associated with event-free survival, but their effects were modified by the use of ACE inhibitors. KEY WORDS: Angiotensin-converting enzyme inhibitors; Coronary artery disease; Hypertension; Pharmacogenetic. PMID- 27122683 TI - Baseline Serum Aldosterone-to-Renin Ratio is Associated with the Add-on Effect of Thiazide Diuretics in Non-Diabetic Essential Hypertensives. AB - BACKGROUND: The baseline status of renin-angiotensin-aldosterone system (RAAS) might modify the blood pressure (BP) lowering effects of thiazide diuretics. This study aimed to determine if baseline RAAS indicated by serum aldosterone-to-renin ratio (ARR) could be associated with the add-on effects of thiazide on BP lowering in patients with other concomitant antihypertensive medication. METHODS: Non-diabetic hypertensive patients, either untreated or unsatisfactorily treated, were enrolled if their office systolic BP was >= 140 or diastolic BP >= 90 mmHg. After 2 weeks of diet control and lifestyle modification, patients with persistently elevated BP were prospectively given hydrochlorothiazide 50 mg daily for 2 weeks. Serum aldosterone-to-renin ratio (ARR) was determined before thiazide treatment. Patients with a significant (>= 10%) reduction of office mean artery pressure (MAP) by thiazide treatment were defined as responders. RESULTS: Among the 66 patients studied, 27 were defined as responders after a 2-week hydrochlorothiazide treatment. Baseline serum renin level was reduced and ARR increased (p = 0.009) in the responders as compared with the non-responders. A similar pattern was also apparent in patients with or without concomitant medications. Furthermore, baseline renin level was inversely and ARR positively correlated to the MAP reduction both in the whole patient group and in patients with concomitant medications. By stepwise multiple linear regression analysis, ARR was the only independent predictor for the response to thiazide treatment (beta = 0.051, p = 0.007). CONCLUSIONS: Baseline ARR could be associated with the add-on effects of hydrochlorothiazide on BP reduction in patients with other concomitant antihypertensive treatment. KEY WORDS: Add-on; Aldosterone-to-renin ratio; Blood pressure; Hydrochlorothiazide; Hypertension; Renin; Thiazide. PMID- 27122684 TI - Secular Trends in Prescription Patterns of Single-Pill Combinations of an Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Plus a Thiazide Diuretic for Hypertensive Patients in Taiwan. AB - BACKGROUND: Poor adherence to recommended drug regimens is one of the fundamental issues behind suboptimal control rates of hypertension worldwide. Single-pill combinations (SPCs) improve patient adherence, decrease cost, and are increasingly prescribed in the Western societies. We conducted this study to elucidate the prescription patterns and the secular trends of SPCs in Taiwan. METHODS: We retrospectively reviewed the reimbursement database of Taiwan's National Health Insurance from 2002 to 2007. Among the one million-person random samples, information from those coded with ICD-9 401-405 and antihypertensive prescriptions was obtained. RESULTS: From 2002 to 2007, there had been amore than 7.5-fold increase in annual prescription frequency of SPCs of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) plus a thiazide diuretic (from 1.1% to 8.5%, p < 0.001) among 302,628 hypertensive patients. Likewise, among patients treated with at least ACEIs or ARBs and diuretics, the relative proportion of SPC use, in contrast to free combinations, increased markedly (from 10.8% to 54.2%, p = 0.005). Incorporating patient antihypertensive treatment prior to SPCs prescription,we categorized the SPC prescription patterns into 3 groups: naive, switch, and add-on. The increase in patients taking SPCs came mostly from the naive SPC prescription group (from 2.3% in 2002 to 28.8% in 2007 among all patients treated with ACEIs or ARBs and thiazide diuretics, p = 0.003). Compared to both naive and add-on SPC users, patients in the switch group had a greater pill burden and more comorbidities, whichmight drive physicians to switch from free combinations to SPCs. CONCLUSIONS: Single-pill combinations are well-accepted and increasingly prescribed in Taiwan, particularly in drug-naive hypertensive patients. This finding might indicate an aggressive attitude towards early hypertension control among physicians in Taiwan. KEY WORDS: Angiotensin-converting enzyme inhibitor; Angiotensin receptor blocker; Diuretic; Hypertension; Single-pill combinations. PMID- 27122685 TI - The Impact of Metabolic Syndrome, Homocysteine, and B Vitamins on Carotid Artery Intima-Media Thickness in Hypertensive Patients. AB - OBJECTIVES: To examine the correlation between metabolic syndrome (MS), plasma total homocysteine (tHcy) level, and serum B vitamin levels on carotid intima media thickness (CIMT) in hypertensive patients. METHODS: A total of 73 medically treated hypertensive patients (42 men, mean age 70.7 years), fasted for 10 hours, and provided fasting blood samples for measurement of plasma tHcy, serum folic acid, and serum vitamin B12 levels. Additionally, B-mode ultrasound of the distal right common carotid arteries was performed on all participants. RESULTS: There were 50 patients with and 23 patients without MS. Patients with MS had larger CIMT than patient without (0.81 +/- 0.13 vs. 0.74 +/- 0.10 mm, p = 0.018). Patients with MS had larger waist circumference (p < 0.001), higher body mass index (p < 0.001), elevated serum triglyceride level (p < 0.001), lower serum high density lipoprotein level (p = 0.016), higher prevalence of diabetes mellitus (p = 0.012), higher prevalence of hyperlipidemia (p = 0.019), and a higher prevalence of fibrate usage (p = 0.025) than patients without MS. In univariate analysis, CIMT correlated significantly with the presence of MS (r = 0.256; p = 0.029), usage of angiotensin receptor blocker (ARB; r = -0.256; p = 0.029), and male gender (r = 0.247; p = 0.035). The relationships between CIMT and serum folic acid level (r = -0.212; p = 0.072) or statin usage (r = 0.207; p = 0.079) were borderline significant. In multivariate regression analysis, after adjusting for age and gender, only usage of ARB (beta value -0.078, 95% CI: 0.140 to -0.015, p = 0.016) and the presence of MS (beta value 0.075, 95% CI: 0.020 to 0.131, p = 0.009) were associated with CIMT. In anothermodel, after adjusting four additional parameters including age, gender, systolic blood pressure and usage of statin, usage of ARB (beta value -0.074, 95% CI: -0.137 to 0.011, p = 0.022) and presence of MS (beta value 0.069, 95% CI: 0.012 to 0.125, p = 0.017) remained significantly correlated with CIMT. CONCLUSION: MS and usage of ARB are associated with CIMT in hypertensive patients. KEY WORDS: Folic acid; Homocysteine, Intima-media thickness, Metabolic syndrome. PMID- 27122686 TI - Cardiac Remodeling, Adaptations and Associated Myocardial Mechanics in Hypertensive Heart Diseases. AB - Hypertension is the leading cause of heart failure and cardiovascular comorbidities in developed countries. Left ventricular structural/functional alterations such as concentric remodeling or hypertrophy have been extensively studied in hypertensive heart diseases. Furthermore, it is also well-recognized that diastolic function actually deteriorates in hypertensive subjects prior to overt heart failure. Novel imaging modality techniques such as myocardial deformation have allowed for early detection of regional/global myocardial contractile dysfunction. Myocardial deformation, which can be quantified by measuring the systolic strain and strain rate in three different directions (longitudinal, circumferential and radial), has facilitated new insights into the understanding of cardiac systolic mechanics in subjects with early stage myocardial damage. Previous studies had shown that longitudinal function remains the most sensitive parameter in identifying hypertension-related myocardial dysfunction, particularly for those patients who had developed LV hypertrophy. Instead, preserved or enhanced short-axis function, when presented as circumferential or radial strains, may remain relatively preserved or enhanced in order to compensate for longitudinal functional decline. In this manner, global cardiac pumping in terms of ejection fraction may remain relatively unchanged. The early recognition of subclinical systolic dysfunction and associated mechanical compensation in the context of hypertension is crucial, which potentially helps to identify a disease stage that is still responsive to therapeutic intervention. KEY WORDS: Concentric remodeling; Hypertension; Myocardial mechanics; Strain; Subclinical systolic dysfunction. PMID- 27122687 TI - LDL Cholesterol Goal Attainment in Hypercholesterolemia: CEPHEUS Indonesian Survey. AB - BACKGROUND: Several studies have shown that lipid-lowering therapy to address hypercholesterolemia is generally inadequate because the target cholesterol goal is not achieved. Our study reviews the cholesterol goal attainment among patients receiving lipid lowering therapy in Indonesian hypercholesterolemic patients. METHODS: This surveywas part of the Pan-Asian CEPHEUS (CEntralized Pan-Asian survey on tHE Under-treatment of hypercholeSterolemia) study, involving hypercholesterolemic patients >= 18 years of age, who were on lipid- lowering treatment for >= 3 months. Lipid concentrations were measured, demographic and other clinically relevant information were collected. Definitions and criteria set by the updated 2004 National Cholesterol Education Program - Adult Treatment Program III was applied. RESULTS: In this survey, 149 physicians enrolled 979 patients, of whom only 834 were included in the final analysis. The mean age was 56.5 years, 53.5% male, and 82.3% were on statin monotherapy. The LDL-C goal attainment rate amongst Indonesians (31.3%)was belowthat of the overall Asian rate (49.1%). The lowest attainment (12.1%)was found in patients with a therapeutic target < 70 mg/dL. Additionally, the goal attainment rate in patients with metabolic syndrome (28%) was significantly lower than in patients without metabolic syndrome (37.5%, p = 0.006). Goal attainment was inversely related to cardiovascular risk and baseline LDL-C (p < 0.001). It was also noted that approximately 65.1% of patients believed he/she could miss a dosage without affecting his/her blood cholesterol concentration. CONCLUSIONS: High proportions of Indonesian hypercholesterolemic patients on lipid-lowering drug are not at the recommended LDL-C levels, and remain at risk for cardiovascular disease. KEY WORDS: Cardiovascular disease; Dyslipidemia; Hypercholesterolemia; Indonesian; LDL cholesterol. PMID- 27122688 TI - Predictors for Regression of Large Secundum Atrial Septal Defects Diagnosed in Infancy. AB - PUPOSE: To determine predictive factors of spontaneous closure or size reduction in large secundum-type atrial septal defects (ASD) diagnosed in infancy prior to catheterization or surgical intervention. METHODS: From June 2003 to October 2009, 59 infants diagnosed with secundum-type ASDs measuring >= 8 mm in the first year of life were retrospectively enrolled. We reviewed medical records, as well as electrocardiography and echocardiography findings. Patients were divided into 2 groups according to the last ASD size: group A (n = 23), ASD reduction in size to < 5 mm or spontaneous closure; group B (n = 36), size of ASD remained >= 5 mm. RESULTS: The ASDs spontaneously closed in 10 (17%) patients at a median age of 26.0 +/- 5.1 months (range, 15-58 months), or decreased to < 5 mm in 13 (22%) (range, 6-27 months) patients. There was a significant difference in age at diagnosis between the 2 groups (p = 0.014). Patients in group A were younger than those in group B at the time of diagnosis. Changes in ASD size (p < 0.001) and body weight percentile (p = 0.01) were also significantly different fromthe 6 month follow-up. ASD diameter of >= 10 mm was a negative predictive factor for size reduction (p = 0.017). CONCLUSIONS: Spontaneous closure or size reduction of large ASDs was not uncommon in patients diagnosed during infancy. Patients with initial ASD sizes between 8 and 10 mm who were younger at the time of diagnosis and showed better weight gain were more likely to have favorable outcomes. KEY WORDS: Infancy; Large secundum atrial septal defect; Natural course; Spontaneous closure. PMID- 27122689 TI - Comparison of Clinical Features between Typical and Atypical Takotsubo Cardiomyopathy: A Single Center, Retrospective, Case-Controlled Study. AB - BACKGROUND: The incidence and possible differences between typical and atypical Takotsubo cardiomyopathy (TTC) in Taiwanese patients have not yet been assessed. METHODS: We reviewed the records of 2171 patients who underwent left heart catheterization for suspected acute coronary syndrome (ACS) between January 2003 and March 2011 to identify TTC. Demographic, clinical presentations, laboratory data, and electrocardiographic, echocardiographic and angiographic findings were assessed in all patients. RESULTS: We found that fourteen patients had typical TTC, and six had atypical TTC. There were no differences in the clinical presentations, ejection fraction and in-hospital course of illness between patients with typical TTC (the TT group) and patients with atypical TTC (the AT group). However, the patients in the AT group were relatively younger than those in the TT group (mean ages 60 vs. 73 years, respectively, p = 0.018), and fewer patients had hypertension in the AT group than in the TT group (33% vs. 86%, respectively, p = 0.037). In electrocardiography, ST segment elevation was noted less frequently in the AT group than in the TT group (33% vs. 86%, respectively, p = 0.037). CONCLUSIONS: Atypical TTC and typical TTC may be the same syndrome with different manifestations. They seemed to have different patient characteristics and electrocardiographic changes. KEY WORDS: Acute coronary syndrome; Takotsubo cardiomyopathy; Transient left ventricular apical ballooning. PMID- 27122691 TI - Surgical Treatment of Pseudoaneurysm of Innominate Artery Infected with Burkholderia Pseudomallei. AB - The management of melioidosis, caused by Burkholderia pseudomallei, presenting as an infected pseudoaneurysm requires radical debridement and prolonged antibiotics because the pathogen is resistant to host immunity. An extra-anatomical bypass might be a better treatment choice than in situ graft interposition or other methods.We report on a 76-year-oldman with an infected pseudoaneurysmlocated in the innominate artery and a method of extra-anatomical bypass that has not yet been reported in the literature. The patient recovered well without recurrence of infection after the surgical procedure. KEY WORDS: Burkholderia pseudomallei; Extra-anatomical bypass; Innominate artery; Melioidosis; Pseudoaneurysm. PMID- 27122690 TI - Misdiagnosed Chest Pain: Spontaneous Esophageal Rupture. AB - Chest pain is one of themost common complaints expressed by patients presenting to the emergency department, and any initial evaluation should always consider life-threatening causes. Esophageal rupture is a serious condition with a highmortality rate. If diagnosed, successful therapy depends on the size of the rupture and the time elapsed between rupture and diagnosis.We report on a 41-year old woman who presented to the emergency department complaining of left-sided chest pain for two hours. KEY WORDS: Chest pain; Coronary artery disease; Esophageal rupture; Misdiagnosis. PMID- 27122692 TI - Acute Myocardial Infarction in Association with Occult Ovarian Cancer. AB - Acute myocardial infarction is usually caused by rupture of an atheromatous plaque in the coronary arteries. For patients without risk factors of atherosclerosis, other causes should be considered. We report on a 47-year-old woman with acute myocardial infarction but no cardiovascular risk factors, which was followed by deep vein thrombosis one week after recovery from acute myocardial infarction. Although deep vein thrombosis may be medically addressed by prolonged bed rest or heart failure in patients with acute myocardial infarction, the clustering of these two diseases in patients without risk factors of atherosclerosis or venous thrombosis is unusual. In situ coronary thrombosis secondary to hypercoagulable state was presumed to be the cause for her myocardial infarction. Further investigation revealed hidden advanced ovarian cancer in the patient. This case should remind cardiologists that, for patients without clinical evidence of atherosclerosis, unusual underlying causes of acute myocardial infarction should be comprehensively investigated, such as malignancy related hypercoagulable state. KEY WORDS: Deep vein thrombosis; Hypercoagulability; Myocardial infarction; Ovarian cancer; Trousseau's syndrome. PMID- 27122693 TI - Isolated Pulmonary Arteriovenous Fistula in a Patient with Recurrent Stroke. AB - Paradoxical embolism is a risk factor for cryptogenic stroke in young adults, and can be primarily attributed to the presence of patent foramen ovale (PFO). Although contrast echocardiography may facilitate diagnosis, it would be difficult to distinguish a PFO from a pulmonary arteriovenous fistula (PAVF), which could also result in paradoxical embolism. We report a 46-year-old woman with recurrent ischemic stroke, who was scheduled for PFO closure because of a right-to-left shunt detected by contrast echocardiography. The diagnosis turned out to be a PAVF confirmed by angiography. Thereafter, coil embolization of this PAVF was performed successfully. KEY WORDS: Embolic stroke; Patent foramen ovale; Pulmonary arteriovenous fistula; Right-to-left shunt. PMID- 27122694 TI - Statement of the Chairman of the Publication Committee of Acta Cardiologica Sinica. PMID- 27122696 TI - Primary Sjogren's Syndrome and the Risk of Acute Myocardial Infarction: A Nationwide Study. AB - BACKGROUND: Patients with autoimmune diseases have a high cardiovascular risk. However, few data are available on the risk of acute myocardial infarction (AMI) in patients diagnosed with primary Sjogren's syndrome (PSS). We conducted a large nationwide cohort study to investigate the possible association between PSS and the risk of AMI. METHODS: Between the years 2000-2006, a total of 5205 patients with newly diagnosed PSS and no history of AMI were identified from the Registry of Catastrophic Illness, a sub-dataset of the National Health Insurance Research Database in Taiwan. The control group, which consisted of subjects without systemic autoimmune disease or previous AMI, was matched by the date of enrollment, age, gender, history of coronary artery disease, diabetes, hypertension, chronic kidney disease, and hyperlipidemia. The study endpoints were the occurrence of AMI. RESULTS: Of the 5205 subjects with PSS and 5205 controls included in the study, 77 (35 PSS patients and 42 controls) developed AMI during the mean 3.7-year (interquartile range, 2.1-5.1 years) follow-up period. The incidence of AMI was similar in PSS patients and controls (1.91/1000 versus 2.25/1000 person-years). Multivariate analysis adjusted for baseline covariates demonstrated an insignificant association between PSS and AMI [adjusted hazard ratio, 0.86; 95% confidence interval (CI), 0.55-1.35; p = 0.506], suggesting that PSS does not increase the risk of AMI. CONCLUSIONS: PSS is not associated with a higher risk of subsequent AMI. KEY WORDS: Acute myocardial infarction; Atherosclerosis; Primary Sjogren's syndrome. PMID- 27122695 TI - The Impacts of In-Hospital Invasive Strategy on Long-Term Outcome in Elderly Patients with Non-ST-Elevation Myocardial Infarction. AB - BACKGROUND: The benefit of utilizing an invasive strategy in elderly Chinese patients with non-ST-elevation myocardial infarction (NSTEMI) remains unclear. The aim of this study was to determine whether in-hospital revascularization is associated with long-term prognosis in elderly Chinese patients with NSTEMI, as compared with younger patients. METHODS: All patients were followed up for at least 3 years or until the occurrence of a major event. The primary endpoint was all-cause mortality, and the secondary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including death, nonfatal MI, and ischemic stroke. RESULTS: A total of 343 consecutive NSTEMI patients (148 over the age of 75 years and 195 aged < 75 years) were enrolled. Coronary angiography was performed less frequently in elderly patients (66% vs. 76%; p = 0.027). Multiple logistic regression analysis confirmed the benefit of in-hospital revascularization in the elderly and younger patients, with a statistically significant reduction in the odds of all-cause death and MACE at 1 year and 3 years, respectively. In a multivariable Cox regression analysis, in-hospital revascularization was an independent predictor of future MACE not only in elderly patients [hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.38-0.97] but also in younger patients as well (HR, 0.51; 95% CI, 0.31-0.84). CONCLUSIONS: In Chinese patients with NSTEMI, in-hospital revascularization was associated with significant benefits at 1 year and 3 years in both younger and elderly groups. These results are consistent with the published literature and suggest that advanced age alone should not be regarded as a contraindication to invasive management following presentation with NSTEMI. KEY WORDS: Elderly; Invasive strategy; Myocardial infarction. PMID- 27122698 TI - The Impacts of Serum Uric Acid on arterial hemodynamics and Cardiovascular Risks. AB - Hyperuricemia, and its clinical manifestation gout, is a metabolic disease process that has been recognized since the dawn of medical inquiry. Uric acid was hypothesized to be a mediator of cardiovascular disease for period of time. Epidemiological correlations of hyperuricemia with hypertension and cardiovascular events were evident for two centuries' studies. With recent animal studies shedding light on the causal mechanisms of hypertension, and clinical trials suggesting that urate-lowering therapy can lower blood pressure, there appears to be growing evidence of a connection between hyperuricemia and cardiovascular disease. To help bring this recent uric acid research into context, we have undertaken this narrative review of hyperuricemia, hypertension, its hemodynamics and its outcomes, and the risk for cardiovascular diseases. KEY WORDS: Cardiovascular risk; Hemodynamics; Uric acid. PMID- 27122699 TI - Diagnostic Performance of 64- versus 256-Slice Computed Tomography Coronary Angiography Compared with Conventional Coronary Angiography in Patients with Suspected Coronary Artery Disease. AB - PUPOSE: The newer 256-slice computed tomography coronary angiography (CTCA) has the capability of improving diagnostic performance in the detection of obstructive coronary artery disease (CAD) compared to 64-slice CTCA. The aim of this study was to compare the diagnostic performance of 64- versus 256-slice CTCA in two similar populations. METHODS: Our study included 120 consecutive patients who were referred for CTCA and subsequently underwent conventional coronary angiography (CCA). Sixty patients were studied by 64-slice CTCA, with the other 60 by 256-slice CTCA. We compared the technical characteristics and diagnostic performance of 64- and 256-slice CTCA for the detection of >= 50% stenosis of the coronary arteries on CCA. RESULTS: The 256-slice CTCA had a shorter scanning time (4.4 +/- 0.6 sec vs. 5.0 +/- 0.7 sec, p < 0.001) compared to 64-slice CTCA. The diagnostic accuracy rates of 256-slice CTCA based on patient analysis (97% vs. 83%, p < 0.05), vessel analysis (95% vs. 85%, p < 0.05), and segment analysis (94% vs. 88%, p < 0.05) were significantly superior to those of 64-slice CTCA. The diagnostic accuracy rates of 64- and 256-slice CTCA were affected by the presence of stent (65% vs. 75%, respectively, p > 0.05) and severe calcifications (75% vs. 82%, respectively, p > 0.05). CONCLUSIONS: In two similar populations, 256-slice CTCA displayed superior diagnostic performance than 64-slice CTCA. However, the performance of 256-slide CTCA is affected in those segments that are severely calcified and/or stented. KEY WORDS: Computed tomography coronary angiography (CTCA); Conventional coronary angiography; Diagnostic performance; 64 slice helical CTCA; 256-slice helical CTCA. PMID- 27122697 TI - Contemporary Management of Coronary Artery Disease and Acute Coronary Syndrome in Patients with Chronic Kidney Disease and End-Stage Renal Disease. AB - Chronic kidney disease (CKD) and end-stage renal disease (ESRD) have emerged as a worldwide public health problem. Due to the remarkably higher incidence and prevalence of this chronic disease in Taiwan than in other countries, CKD/ESRD has contributed to a significant health burden in Taiwan. Patients with CKD/ESRD have an increased risk of coronary artery disease (CAD) and acute coronary syndrome (ACS) compared to the normal population. Patients with ACS alone can present differently than patients with ACS and CKD/ESRD. Also, due to the lower prevalence of chest pain and ST-segment elevation, CKD/ESRD patients were more difficult to diagnose than other patients. Furthermore, whether advances in ACS management with medical therapy and an early invasive approach could improve patient outcomes with CKD/ESRD is not known. The use of antiplatelets such as aspirin and other antithrombotic agents might reduce the incidence of ACS or stroke in CKD patients. However, such use could also increase bleeding risk and even increase the likelihood of mortality, especially in dialysis patients. While recent clinical data suggest the potential benefit of aggressive management with coronary intervention for CAD and ACS in this category of patients, further clinical studies are still indicated for the proper medical strategy and revascularization therapy to improve the outcomes of CAD and ACS in CKD/ESRD patients, both in Taiwan and worldwide. KEY WORDS: Acute coronary syndrome; Chronic kidney disease; Coronary artery disease; Diagnosis; End-stage renal disease; Management. PMID- 27122700 TI - Direct Renin Inhibitor Attenuates Left Ventricular Remodeling in Post-Myocardial Infarction Heart Failure Mice. AB - BACKGROUND: The role of direct renin inhibitors in myocardial ischemia-induced heart failure is controversial. We hypothesized that direct renin inhibitors play a positive role, affecting in vivo myocardial function as well as in vitro extracellular matrix change. METHODS: Ten-week-old C57BL/6J male mice with 2 kidney 1-clip (2K1C) model were enrolled in this study. The mice were divided into 3 groups each with 18 mice; group 1 sham-operated, group 2 coronary artery ligation- induced heart failure, and group 3 coronary artery ligation-induced heart failure receiving aliskiren minipump infusion. These mice were assessed for systemic hemodynamics and left ventricular function by 2-dimensional echocardiography (iE33, Philips). Myocardial tissue was stained and crude protein was isolated from the non- ischemic viable left ventricle. Myocardial tissue contents of anti-angiotensin II type 1 (AT1) receptor, matrix metalloproteinase (MMP)-2 and MMP-9 were examined. RESULTS: There were 54 mice that received 2K1C and were followed up for three weeks. Baseline characteristics showed no difference. At follow-up, the heart failure-only group had greater left ventricular mass and worse systolic function as compared to the sham group. Whereas the heart failure-aliskiren group had lower left ventricle mass and better systolic function as compared to the heart failure-only group. AT1 receptor, MMP-2 and MMP-9 levels were increased in the heart failure-only model while direct renin inhibitor attenuated this significantly. CONCLUSIONS: Direct renin inhibitors improved myocardial function in a myocardial ischemia-induced heart failure mouse model. The improvement seen is present in myocardial mass, left ventricular systolic function and also in myocardial interstitial tissue. KEY WORDS: Direct renin inhibitor; Echocardiography; Heart failure. PMID- 27122702 TI - Effects of Dexmedetomidine on L-Type Calcium Current in Rat Ventricular Myocytes. AB - BACKGROUND: Dexmedetomidine is a highly selective alpha2-adrenoreceptor agonist with sedative, analgesic and sympatholytic properties. Its cardiac protective effect cannot be ignored, notwithstanding its associated adverse drug reactions. This study aimed to investigate the effects of dexmedetomidine on L-type calcium current (ICa-L) in adult rat ventricular myocytes, and to clarify the electrophysiological mechanism of its effect on cardiomyocytes. METHODS: Single rat ventricular myocytes were obtained by enzymatic dissociation method. Myocytes were perfused with external solutions containing various concentrations of dexmedetomidine at a flow rate of 2-3 ml/min for 5 min. Whole-cell current recordings were performed using the conventional whole-cell patch-clamp technique. Besides, the effects of 1 MUM yohimbine, an alpha-2 adrenergic antagonist, were given alone or in combination with 10 ng/ml dexmedetomidine. RESULTS: Dexmedetomidine inhibited the amplitude of ICa-L in a concentration dependent manner. The current voltage curve was shifted upwards. The steady activated curves were shifted to the right and the V1/2 activation of the ICa-L were increased by dexmedetomidine at the high concentration (10 and 200 ng/ml). Dexmedetomidine did not affect the ICa-L steady-state inactivation curve, but shifted down the recovery curve. Yohimbine did not have influence on ICa-L. However, inhibition of ICa-L by dexmedetomidine at the concentration of 10 ng/ml was partially reversed by yohimbine. CONCLUSIONS: Dexmedetomidine can attenuate ICa-L in adult rat ventricular myocytes, which may contribute to its negative effects on myocardia contractility and cardiac electrophysiology. Its inhibitory effect on ICa-L is partially associated with alpha-2 adrenergic receptors. KEY WORDS: Cardiology; Dexmedetomidine; L-type calcium current; Ventricular myocytes; Whole-cell patch clamp. PMID- 27122701 TI - Long-Term Outcomes of Native Coarctation of the Aorta after Balloon Angioplasty or Surgical Aortoplasty in Newborns and Young Infants Less Than 3 Months of Age. AB - BACKGROUND: Balloon angioplasty of native coarctation of the aorta, though effective, is frequently associated with early restenosis, repeated interventions and aneurysm formation, especially in very young patients. However, available long-term data are limited. METHODS: From Jan. 1986 to Dec. 2007, eighty-eight patients with simple aortic coarctation, isolated or associated with patent ductus arteriosus or ventricular septal defect, and survived angioplasty (n = 17) or surgery (n = 71) within 3 months of age in National Taiwan University Hospital were enrolled. RESULTS: The average length of follow-up was 10.1 +/- 5.1 years. The long-term outcomes between these two groups were comparable in hypertension, left ventricular outflow tract obstruction, and aortic aneurysm. Patients in the angioplasty group had a greater likelihood of reintervention (64.7% vs. 42.3%, p = 0.096) and repeated reintervention (29.4% vs. 7.0%, p = 0.027) as compared with surgery group. The 10-year freedom from reintervention was 35.3% and 59.2% in the angioplasty and surgery group, respectively (p = 0.046); there were no deaths reported in that 10-year span. Patients with angioplasty and those with patent ductus arteriosus were more likely to require surgical aortoplasty at reintervention. CONCLUSIONS: The long-term outcomes of aortic coarctation in newborns and young infants after balloon angioplasty were effective and beneficial. However, those outcomes were accompanied by concomitant higher risks of reintervention and surgical reintervention, particularly in those with patent ductus arteriosus. KEY WORDS: Aortic operation; Coarctation; Infant; Outcomes. PMID- 27122703 TI - Spontaneous Retro-Orbital Subperiosteal Hemorrhage with Complete Resolution Following Percutaneous Coronary Intervention for Acute Myocardial Infarction. AB - Among the several treatment strategies available for acute myocardial infarction, primary percutaneous coronary intervention concomitant with antithrombotic agents is the primary treatment used to facilitate coronary reperfusion. However, bleeding can create major complications. Here we have presented a case of acute myocardial infarction treated with reperfusion therapy, after which developed a sudden onset of proptosis, with high intraocular pressure, blurred vision, and ecchymosis of the left eye. Spontaneous retro-orbital subperiosteal hemorrhage, a rare complication, was diagnosed based on those symptoms as noted above, as well as other orbital signs and imaging evaluation. Multiple antithrombotic agents, including antiplatelets, low molecular weight heparin, and glycoprotein IIb/IIIa receptor inhibitor were thought to be the main precipitating factors of this complication. Thereafter, conservative medical treatment was applied. In the following 2 weeks, all the patient's orbital signs resolved gradually without visual impairment. In conclusion, our experience with a rare case of complications arising from reperfusion therapy used to treat myocardial infarction suggests that clinicians should remain vigilant for any hemorrhagic events during acute myocardial infarction treatment. KEY WORDS: Acute myocardial infarction; Percutaneous coronary intervention; Retro-orbital subperiosteal hemorrhage. PMID- 27122704 TI - Repair of Traumatic Tricuspid Regurgitation. AB - Severe tricuspid regurgitation (TR) after blunt chest trauma is rare and often results from damage to the subvalvular apparatus. When injured, the damaged subvalvular apparatus may break immediately or at a later stage due to mechanical fatigue. We report the case of a 30-year-old man who sustained a blunt thoraco abdominal trauma in a motorbike accident. The patient's condition immediately after the accident precluded any intervention for the moderate TR that was detected by transesophageal echocardiography. However, he later developed a severe TR which required surgical intervention 11 months after the accident. The operative findings included a ruptured anterior common chordae, a contracted and perforated anterior leaflet, and an enlarged annulus. A satisfactory valve competence was achieved with several techniques including chordae re implantation, suture commissurotomy, and ring annuloplasty. This report highlights the unpredictable course of deterioration in traumatic TR and the possibility of complex repair. KEY WORDS: Blunt cardiac injury; Tricuspid regurgitation; Tricuspid valve repair. PMID- 27122705 TI - Hypercalcemia-Induced New Onset Left Bundle Branch Block Mimicking Acute Myocardial Infarction in a Patient with Primary Hyperparathyroidism. AB - A 78-year-old women with a recent diagnosis of primary hyperparathyroidism presented with vague chest pain, and new onset left bundle block (LBBB) on the electrocardiogram (ECG) mimicking acute myocardial infarction (AMI). LBBB resolved without abnormal Q waves only after correction of hypercalcemia. The cardiac enzymes, including creatine kinase, creatine kinase-MB, and troponin-I were all within normal range. Hypercalcemia provoking ECG changes that mimic acute myocardial infarction is infrequently reported. To our knowledge, this is the first report of hypercalcemia-induced new onset LBBB mimicking AMI. Emergency physicians should include hypercalcemia-induced new onset LBBB on the ECG in the differential diagnosis of AMI. KEY WORDS: Acute myocardial infarction; Hypercalcemia; Hyperparathyroidism; left bundle branch block. PMID- 27122707 TI - Do Not Use Cycloxigenase-2 Inhibitors in STEMI. PMID- 27122706 TI - Paroxysmal Supraventricular Tachycardia with QRS Duration Alternans, Electrical Alternans, and Pulsus Alternans but without Cycle Length Alternans. AB - We reported a 60-year-old male patient who had a paroxysmal supraventricular tachycardia with QRS duration alternans (alternation between narrow QRS and wide QRS beats) and electrical alternans, but without any cycle length alternans. In the laboratory, slow-fast atrioventricular nodal reentrant tachycardia was easily induced by an atrial extrastimulus, and the arterial pressure recordings displayed a simultaneous pulsus alternans during tachycardia. The patient also underwent coronary angiography which revealed a total occlusion of the left anterior descending artery. In this report, we have proposed that the QRS duration alternans, electrical alternans and pulsus alternans during the paroxysmal supraventricular tachycardiamay have been due to the prolongation of the effective refractory period of the right bundle branch, caused by myocardial ischemia. KEY WORDS: Electrical alternans; Myocardial ischemia; Supraventricular tachycardia. PMID- 27122708 TI - Pharmacology of Aldosterone and the Effects of Mineralocorticoid Receptor Blockade on Cardiovascular Systems. AB - It is well-known that aldosterone plays an important role in reabsorption of sodium and fluid, and in potassium excretion in kidneys via epithelial mineralocorticoid receptor (MR) activation. Recent studies have shown that aldosterone causes cardiovascular remodeling not only in a blood pressure dependent manner, but also in a blood pressure-independent manner by decreasing nitric oxide bioavailability and modulating oxidative stress, leading to vascular inflammation. In addition, MR blockade does provide beneficial effects associated with cardiovascular protection, resulting in a reduction of cardiovascular morbidity and mortality. A growing body of evidence suggests that MR blockade is a promising therapeutic target to help prevent cardiovascular events. KEY WORDS: Aldosterone; Mineralocorticoid receptor; Nitrix oxide; Renin-angiotensin aldosterone system. PMID- 27122709 TI - C-Reactive Protein Gene Polymorphisms and the Risk of Atrial Fibrillation in a Chinese Population in Taiwan. AB - BACKGROUND: Elevated plasma C-reactive protein (CRP) levels can be used to predict an increased risk of future atrial fibrillation (AF). However, several single polynucleotide polymorphisms (SNPs) in the CRP gene affect CRP levels. This study aims to elucidate the correlation between CRP gene polymorphisms and the risk of AF among a Chinese population in Taiwan. METHODS: A total of 200 patients with AF and 240 age- and gender-comparable control subjects were enrolled in this study. From these patients, five SNPs in the CRP gene were selected and genotyped. RESULTS: Patients with AF had significantly higher plasma CRP levels than the controls. In the total study population, the minor alleles of rs3091244 and rs1205 were significantly associated with higher CRP level (p = 0.001 and 0.045, respectively). The frequency of rs1800947 minor allele (C) was significantly higher in patients with AF than that in control subjects (12.8% and 4.6%, respectively; p < 0.001). On multivariate analysis, the presence of the C allele of rs1800947 was significantly and independently associated with AF after adjustment for age, gender, body mass index, hypertension, diabetes, smoking, hypercholesterolemia, coronary artery disease, concomitant medication, and CRP levels (odds ratio = 3.21; 95% confidence interval = 1.54-6.68; p = 0.01). Haplotype analysis further verified that the rs3091244C and rs1800947C bi-loci haplotype was significantly overpresented in patients with AF than in the controls. CONCLUSIONS: Our results suggest that the presence of the C allele of rs1800947 may indicate susceptibility to AF in a Chinese population in Taiwan. KEY WORDS: Atrial fibrillation; C-reactive protein; Polymorphism. PMID- 27122710 TI - Nitric Oxide Synthase 1 Adaptor Protein, an Emerging New Genetic Marker for QT Prolongation and Sudden Cardiac Death. AB - Sudden cardiac death (SCD) is defined as sudden unexplained death due to cardiac causes with an acute change in cardiovascular status within 1 hour of onset of symptoms. Alternatively, in unwitnessed cases, SCD can also be defined as a person last seen functionally normal 24 hours before being found dead. Despite significant advances in understanding the pathophysiology of cardiovascular diseases and the resultant improvement in resuscitation science, SCD remains a major healthcare challenge worldwide. Although the most pronounced risk factor for SCD is the presence of coronary artery disease in the setting of a depressed left ventricular function, most deaths occur in the larger, lower-risk subgroups where genetic variations and other conditions may be the precipitating factors in triggering SCD. Recently, a common genetic variation in a neuronal nitric oxide synthase regulator, nitric oxide synthase 1 adaptor protein (NOS1AP) also known as carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (CAPON) gene, has been identified as a new genetic marker in modulating QT interval prolongation and SCD in general populations. Animal study revealed that NOS1AP is expressed in the heart and interacts with NOS1-NO pathways to modulate cardiac repolarization via suppressing the sarcolemmal L-type calcium current and enhancing the IKr current. This important genetic implication was soon replicated in other racial/ethnic populations and extended to a variety of clinical settings including diabetes mellitus, coronary artery disease, myocardial infarction, and congenital or drug-induced long QT syndrome. The purpose of this review aims to provide up-to-date information about the emerging new genetic marker, NOS1AP, in relation to QT prolongation and SCD. KEY WORDS: NOS1AP; QT interval; Sudden cardiac death. PMID- 27122711 TI - Gene Therapy for Cardiac Arrhythmias. AB - Morbidity and mortality caused by cardiac arrhythmias are a major issue in developed countries. Although conventional therapeutic options including pharmacological therapy, catheter ablation, and implantable devices have shown extensive advances to help reduce morbidity and mortality, a certain segment of these arrhythmias is still refractory to treatment. Therefore, gene therapy was explored as a potential additional or alternative therapy. Gene therapy trials have been developed for bradycardia, atrial fibrillation, and ventricular tachycardia. For the treatment of bradycardia, "biological pacemaker" attempts have been examined utilizing virus vectors to eliminate inward rectifier potassium current, or to overexpress the If current to convert quiescent myocytes into spontaneously active cells. These gene therapy attempts were soon followed by gene and cell hybrid therapies, and cell transplantation therapies utilizing pacemaker cells derived from stem cells. For the treatment of tachycardia, two major strategies were conceived: 1) to increase the effective refractory period, or 2) to recover the conduction velocity. The establishment of a selective and highly efficient gene transfer method would enable us to apply these concepts into the atrial fibrillation and ventricular tachycardia models. Both concepts resulted in an elimination or reduction of tachyarrhythmias in large animal models. Although these trials proved the concept of gene therapy as an adjuvant or alternative approach for the treatment of cardiac arrhythmias, the limitation of these studies is the long-term efficacy and safety. Consequently, an improvement in the gene delivery method is required to overcome these issues. KEY WORDS: Atrial fibrillation; Biological pacemaker; Gene therapy; Ion channel; Ventricular tachycardia. PMID- 27122713 TI - Prognostic Value of Functional Variables as Assessed by Gated Thallium-201 Myocardial Perfusion Single Photon Emission Computed Tomography for Major Adverse Cardiac Events in Patients with Coronary Artery Disease. AB - PURPOSE: Gated single photon emission computed tomography (SPECT) using thallium 201 (Tl-201) has the capacity to evaluate the earlier post-stress (PS) function compared to technetium-99m labeled tracers, and may be more sensitive in detecting transient ventricular dysfunction caused by stress-induced ischemia. The purpose of this study was to assess the prognostic value of functional variables obtained from Tl-201 gated SPECT as a predictor of major adverse cardiac events (MACE). METHODS: Four hundred and thirty-eight subjects who had known or suspected coronary artery disease and underwent clinically indicated dipyridamole-stress electrocardiography-gated Tl-201 SPECT were included in this study. Functional variables, including PS-ejection fraction (EF), PS-end systolic volume (ESV), PS-regional wall motion abnormality (RWA), reversible RWA and EF worsening, were generated to study the correlation with MACE (cardiac death, nonfatal infarction, unstable angina and coronary revascularization). RESULTS: Sixty-eight of the total 438 patients (15.5%) had MACE during the period of follow-up (a median time of 31 months), including 2 cardiac deaths, 9 non-fatal infarctions, 9 unstable angina and 48 coronary revascularizations. These events occurred significantly more frequently in patients with reversible RWA (28.8% vs. 7.1%, p < 0.0001), EF worsening (34.8% vs. 12.1%, p < 0.0001), PS-RWA (29.9% vs. 11.4%, p < 0.0001) and PS-EF < 45% (27.8% vs. 14.4%, p = 0.034). Using the Cox proportional hazards regression analysis, reversible RWA and EF worsening were two independent predictors of MACE, providing incremental prognostic value over clinical and perfusion-alone information. CONCLUSIONS: The functional assessment with Tl-201 gated SPECT was a useful prognosticator for patients who had known or suspected coronary artery disease. KEY WORDS: Coronary artery disease; Gated SPECT; Major adverse cardiac events; Tl-201. PMID- 27122714 TI - Fenofibrate Modulates HO-1 and Ameliorates Endothelial Expression of Cell Adhesion Molecules in Systolic Heart Failure. AB - BACKGROUND: Endothelial activation and dysfunction have been implicated in the pathogenesis and progression of heart failure (HF). In the present study, we investigated if endothelial expression of cell adhesion molecules (CAMs) is inhibited by fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist with anti-inflammatory and vascular protective effects, through the regulation of heme oxygenase-1 (HO-1). METHODS: We recruited a total of 20 patients with advanced systolic HF and 20 healthy volunteers who all provided blood samples. Cultured human pulmonary artery endothelial cells (HPAECs) were treated with 70% sera obtained from study individuals, with or without pretreatment with fenofibrate. The endothelial expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and HO-1 were analyzed by mRNA expression and Western blot. RESULTS: Stimulation of cultured HPAECs with serum from HF patients significantly activated nuclear factor-kappa B (NF-kappaB) and increased VCAM-1 and ICAM-1 expression but attenuated HO-1 expression. Immunohistochemistry study also confirmed that CAMs were up-regulated, whereas HO-1 was down-regulated in HF patients. HO-1 small interfering RNA significantly suppressed HO-1 expression and exaggerated the HF serum-induced CAM expression, whereas HO-1 inducer cobalt protoporphyrin IX simultaneously stimulated HO-1 expression and suppressed CAM expression. Pretreatment with fenofibrate prevented the decrease of HO-1 expression and the activation of NF-kappaB as well as the increase of CAM expression that induced by HF patient serum. CONCLUSIONS: Our study demonstrated that fenofibrate may exert beneficial effects in patients with systolic HF through regulation of HO-1 expression and amelioration of endothelial activation. KEY WORDS: Cell adhesion molecules; Endothelial cells; Heart failure; Heme oxygenase-1; Peroxisome proliferator-activated receptor-alpha. PMID- 27122712 TI - Warfarin Pharmacogenetics: New Life for an Old Drug. AB - Warfarin was first introduced in the 1950s and quickly became the most commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation, or prosthetic heart valve replacement. Warfarin is highly effective in treating these diseases; however, several factors prevent it from even wider use, especially in Asian populations. It is difficult for patients on warfarin to reach desired anticoagulation due to its narrow therapeutic index and highly variable dose response. The major adverse event is bleeding which is associated with overdose of warfarin. Clinical and genetic factors such as polymorphisms in CYP2C9 and VKORC1 associated with an individual's warfarin maintenance have been identified. More than 20 dose prediction algorithms incorporating both genetic and clinical factors have been developed, and some of them have been tested clinically. However, most of the algorithms were tested in small populations. Several major clinical trials are now underway. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges of clinical implementation of warfarin pharmacogenetics. KEY WORDS: CYP2C9; Pharmacogenetics; VKORC1; Warfarin. PMID- 27122717 TI - Contrast-Induced Encephalopathy after Percutaneous Coronary Intervention. AB - Contrast-induced encephalopathy (CIE) is a rare complication that presents with transient neurologic deficits and is caused by neurotoxicity of intravascular contrast media. The prognosis can be extremely favorable even in comatose patients. We reported a 76-year-old woman admitted for scheduled coronary angiography. The total amount of Optiray contrast media used was 150 mL. Immediately after the procedure, the patient developed consciousness disturbance, global aphasia, cortical blindness and right-sided weakness. CIE was diagnosed by computed tomography and subsequent magnetic resonance imaging. The patient recovered completely within 48 hours without any neurological deficits. KEY WORDS: Angioplasty; Contrast-induced encephalopathy; Percutaneous coronary intervention. PMID- 27122716 TI - A Large Institutional Study on Outcomes and Complications after Transcatheter Closure of a Perimembranous-Type Ventricular Septal Defect in 890 Cases. AB - PURPOSE: To investigate the incidence, cause, and prevention of complications associated with interventional therapy for perimembranous ventricular septal defects (pmVSDs). METHODS: A retrospective analysis was performed on 890 patients with pmVSDs after interventional therapy. The complications were then analyzed by electrocardiography and echocardiography during or after interventional therapy. During the follow-up period of 12-52 (mean of 26.9 +/- 21.6) months, the technical success rate was 97.9% (871/890). RESULTS: The incidence of serious complication was 1.12% (10/890), including five cases of third-degree atrioventricular block, two of severe tricuspid valve regurgitation, one of cerebral infarction in the basal ganglia area, and two of femoral artery thrombosis. No death was reported during patient follow-up. CONCLUSIONS: Transcatheter closure of pmVSDs in selected patients was found to be effective and safe. KEY WORDS: Complication; Interventional therapy; Ventricular septal defect. PMID- 27122715 TI - High Flow-Mediated Vasodilatation Predicts Pulmonary Edema in Liver Transplant Patients. AB - BACKGROUND: Early pulmonary edema is common after orthotopic liver transplantation. Associated pathogenic mechanisms might involve increased activity of cardiac-inhibitory systems due to increased vasodilator production, mainly nitric oxide (NO). NO is primarily responsible for flow-mediated vasodilatation (FMD). We investigated the incidence of pulmonary edema in liver transplant patients and its correlation with FMD. METHODS: We prospectively evaluated traditional risk factors, Doppler echocardiographic findings, derived hemodynamic data, and brachial artery nitroglycerin-induced vasodilatation (NTD) and FMD within 1 week prior to liver transplantation in 54 consecutive liver transplant patients with cirrhosis. Post-transplantation chest roentgenography was performed daily. In-hospital outcomes, transfusion volume of blood components, and hemodynamic data during surgery and at the intensive care unit were analyzed. RESULTS: Twenty-nine patients (53.7%) developed radiological pulmonary edema within 1 week of transplantation. Diffuse-type interstitial and alveolar pulmonary edema constituted 13 cases (24.1%). Patients with pulmonary edema had higher pretransplantation Child-Turcotte-Pugh scores (p = 0.01), cardiac output (p = 0.03), FMD (p < 0.01), NTD (p = 0.01), and FMD/NTD ratio (p = 0.02). Although the total volume of intravenous fluid transfused was higher in the pulmonary edema group, the net fluid retention during surgery was statistically insignificant. The lengths of intensive care unit stay and hospitalization, as well as mortality rates, were not different in these groups. CONCLUSIONS: The high incidence of pulmonary edema after living donor liver transplantation was associated with a high FMD and FMD/NTD ratio at pretransplantation. FMD is the only significant predictor associated with pulmonary edema. However, we observed no alteration in mortality rates. KEY WORDS: Cirrhotic cardiomyopathy; Flow-mediated vasodilatation; Liver transplantation; Pulmonary edema. PMID- 27122718 TI - A Lethal Complication after Coronary Angiography in a Patient with Ehlers-Danlos Syndrome. AB - A 51-year-old man with Ehlers-Danlos syndrome presented to our emergency department with the chief complaint of chest tightness. The patient was diagnosed with acute coronary syndrome, due to his crescendo pattern of typical angina without elevated troponin-I, which was managed with dual-antiplatelet agents and intravenous heparinization. However, the symptoms persisted, and coronary angiography was performed smoothly via the left radial artery with manual compression applied for wound closure. Nonetheless, a left arm hematoma with compartment syndrome due to delayed arterial leakage developed, which was treated with an emergency fasciotomy. Three days later, during general anesthesia for surgical wound closure, extensive subarachnoid hemorrhage occurred due to a remarkable fluctuation of blood pressure. The patient remained comatose in the following months. This case suggests that the undertaking of an endovascular procedure should be reserved for life-threatening scenarios to avoid any life threatening complications for patients with Ehlers-Danlos Syndrome, especially the vascular type. Moreover, prolonged manual direct compression or trans-radial band may be mandatory for post-angiographic hemostasis. KEY WORDS: Coronary angiography; Endovascular procedure; Vascular Ehlers-Danlos syndrome; Vascular rupture. PMID- 27122719 TI - Recurrent Supraventricular Tachycardia with a Different Retrograde Atrial Activation Sequence: What is the Mechanism? AB - A young man underwent 2 catheter ablation procedures because of frequent episodes of paroxysmal supraventricular tachycardia (SVT). A left accessory pathway was ablated in the first procedure. The patient underwent the second ablation procedure due to a recurrent SVT demonstrated by 12-lead electrocardiogram two weeks after the first procedure. During the second procedure, a SVT with a different retrograde atrial activation sequence was present. Programmed stimulation at the right ventricular apex showed multiple retrograde atrial activation sequences. Thereafter, careful analysis of the intracardiac electrograms helped us to successfully ablate the SVT. KEY WORDS: Ablation; Electrophysiology; Supraventricular tachycardia. PMID- 27122720 TI - Late Intervention-Related Complication - A Huge Subepicardial Hematoma. AB - A 75-year-old man had a history of triple vessel coronary artery disease. In August 2009, he had undergone successful percutaneous coronary intervention to the left circumflex coronary artery (LCX) for management of an in-stent restenosis (ISR) lesion. However, in September 2010, he began experiencing recurrent episodes of exertional chest pain. Chest radiography showed the left cardiac border bulging upwards. Transthoracic echocardiography and chest computed tomography revealed a huge oval mass of about 10.4 cm * 7.9 cm * 8.6 cm, which showed calcification and was obliterating the LCX. Subsequent coronary angiography revealed significant instent restenosis, with extravasation of a small amount of contrast material at the stent location, suggesting that the coronary artery had ruptured. We implanted a polytetrafluoroethylene-covered stent to seal the coronary perforation and to release the occlusion. The patient was symptom-free and had an uneventful outcome until the 1-year follow up. KEY WORDS: Coronary artery perforation; Covered stent; Hematoma. PMID- 27122721 TI - Cardiovascular Toxicity of Molecular Targeted Therapy in Cancer Patients: A Double-Edged Sword. AB - The annual incidence of cancer has increased over the past 20 years, yet the 5 year relative survival rate for cancer has improved with the increasing availability of advanced therapies, including molecular targeted therapy. Cardiovascular toxicity can develop with this type of targeted therapy, which can cause serious side effects including left ventricular dysfunction, hypertension, hypotension, QT prolongation, thromboembolism, and myocardial ischemia. In many ways, the quality of life primarily depends on the health status of patient cardiopulmonary function. However, risk factor assessment, routine monitoring, and prompt intervention remain the best strategy to deal with these patients with malignancies, to ensure that their cardiopulmonary function is maintained at the highest possible level. Most previous studies on cardiovascular toxicity have focused on conventional chemotherapy. Molecular targeted therapy is a novel anticancer treatment; however, due to potentially adverse cardiovascular events from this therapy, oncologists and cardiologists need to work together to maximize the benefits. In this review, we focused on target therapy-induced cardiovascular toxicities, in particular cardiac structural, electrophysiological, and vascular effects. KEY WORDS: Cardiovascular toxicity; Molecular target therapy. PMID- 27122722 TI - Gender Difference in Idiopathic Right Ventricular Outflow Tract-Ventricular Tachycardia. AB - BACKGROUND: Few studies have discussed gender differences in idiopathic right ventricular outflow tract-ventricular tachycardia (RVOT-VT). This study explored possible gender differences in electrophysiological characteristics and catheter ablation for idiopathic RVOT-VT in Taiwan. METHODS: Ninety-three patients (mean age 38.7 +/- 15.5years, 30 males) were diagnosed as having idiopathic RVOT-VT between 1998 and 2010, and were enrolled and analyzed as part of our investigation. RESULTS: The age of onset, syncope episodes, underlying hypertension, diabetes mellitus, hyperlipidemia or family history of ventricular arrhythmias did not differ between males and females. Male patients had longer QRS width (99.9 +/- 19.4 ms vs. 88.4 +/- 20.7 ms, p = 0.02). Female patients had lower right ventricular mean voltage (3.0 +/- 0.7 mV vs. 3.7 +/- 0.9 mV, p = 0.03), and more low voltage zone over the right ventricular outflow tract free wall (27.0% vs. 6.7%, p = 0.02). Eighty-one patients received catheter ablation (23 males). The acute success rate, repeated catheter ablation rate and VT recurrence rate were similar between the genders. CONCLUSIONS: Our study did reveal differences in electroanatomical characteristics by gender for patients who had idiopathic RVOT-VT, but overall outcomes after catheter ablation were similar. KEY WORDS: Gender; Right ventricular outflow tract-ventricular tachycardia. PMID- 27122723 TI - Prevalence of Atrial Fibrillation in Patients with Brugada Syndrome in Taiwan. AB - PURPOSE: The aim of this study was to assess the prevalence of atrial fibrillation (AF) in patients with Brugada syndrome (BrS) and their clinical characteristics in Taiwan. METHODS: The patient group consisted of 47 symptomatic BrS patients consecutively enrolled from 2000 to 2010. The definition of BrS patients with AF was a BrS patient with at least one episode of AF in a 12-lead electrogram or 24-hour holter (permanent, persistent or paroxysmal) during follow up, or before diagnosis of BrS. RESULTS: Six BrS patients were identified with AF, and all of them were male. Two experienced sudden cardiac death (SCD), 2 presented with seizure and 4 with syncope. The mean age at onset of BrS was 47 +/ 16 years, similar to those BrS patients without AF (45 +/- 14, p = 0.67). Compared to those BrS patients without AF, significantly higher percentages of the BrS patients with AF presented with seizure and documented ventricular tachyarrhythmia (p = 0.02 and 0.03, respectively). Five of them had spontaneous Brugada type I electrogram, similar to those BrS patients without AF (p = 0.9). The SCN5A mutation rate is similar between BrS patients with AF and those without AF (p = 0.69). The prevalence of AF in BrS patients in Taiwan was 12.7% (6/47, 95% confidence interval 0.06-0.19) which is not significantly lower than the 20% prevalence found in the Caucasian population (p = 0.16). CONCLUSIONS: BrS patients with AF had distinct clinical features from those patients without AF in Taiwan. KEY WORDS: Atrial fibrillation; Brugada syndrome; Taiwan. PMID- 27122724 TI - Next-Generation Sequencing in the Genetics of Human Atrial Fibrillation. AB - The International Human Genome Sequencing Consortium published the first draft of the human genome in the journal Nature in February 2001, providing the sequence of the entire genome's three billion base pairs. The Human Genome Project involves a concerted effort to better understand the human DNA sequence through identification of all the genes. The knowledge that can be derived from the genome could result in the development of novel diagnostic assays, targeted therapies and the improved ability to predict the onset, severity and progression of diseases. This has been made possible by many parallelized, high-throughput technologies such as next-generation sequencing. In this review, we discuss the possible application of next-generation sequencing in finding the susceptibility gene(s) or disease mechanism of an important human arrhythmia called atrial fibrillation. KEY WORDS: Arrhythmia; Atrial fibrillation; Genetics, Next generation sequencing. PMID- 27122725 TI - ACEI and ARB did not Reduce the Incidence of Dementia in Patients with Atrial Fibrillation: A Nationwide Cohort Study. AB - PUPOSE: Atrial fibrillation (AF) is associated with increased risk of thromboembolism, and is also a predisposing factor to dementia. Our investigation was a retrospective observational study to evaluate whether the usage of angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) could reduce the incidence of dementia in patients with AF. METHODS: A total of 5221 patients over 20 years of age who had a history of AF as noted in ambulatory and inpatient claims data were enrolled from the National Health Insurance Research Database of Taiwan in 1997 and 1998. Patients with ACEI or ARB were designated as group 1 (4343 patients), and patients without ACEI or ARB were designated as group 2 (878 patients). RESULTS: During a follow-up of 5.90 +/- 3.39 years, 135 patients of group 1 (3.1%) and 25 of group 2 (2.8%) developed new onset dementia. Group 1 and group 2 had similar proportions of new-onset dementia (p = 0.75). The Kaplan-Meier curve demonstrated that patients with ACEI or ARB were not associated with a lower incidence of dementia during the follow-up period (log rank p = 0.91). Cox-regression analysis also showed that usage of ACEI or ARB was not associated with a lower risk of new-onset dementia after adjustment for gender and comorbidities. (Hazard ratio = 0.942, 95% confidence interval 0.589~1.506, and p = 0.80). CONCLUSIONS: ACEI or ARB may be ineffective in reducing the incidence of dementia in patients with AF. KEY WORDS: Angiotensin converting-enzyme inhibitor; Angiotensin II receptor blocker; Atrial fibrillation; Dementia. PMID- 27122726 TI - Intracellular Ca(2+) Transient Phase II Can be Assessed by Half-Logistic Function Model in Isolated Aequorin-Injected Mouse Left Ventricular Papillary Muscle. AB - BACKGROUND: Myocardial contraction and relaxation are regulated by increases and decreases in intracellular cytoplasmic calcium (Ca(2+)) concentration ([Ca(2+)]i). In previous studies, we found that a half-logistic (h-L) function, which represents a half-curve of a symmetrical sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phase (CaTI) and the second half of the descending phase of the [Ca(2+)]i transient curve (CaTIV) better than a mono-exponential (m-E) function. In the present study, we investigated the potential application of an h-L function to the analysis of the second half of the ascending phase of the [Ca(2+)]i transient curve (CaTII). METHODS: The [Ca(2+)]i transient was measured using the Ca(2+) sensitive photoprotein aequorin, which was microinjected into 15 isolated left ventricular (LV) papillary muscles of mice. The observed CaTII data during the time duration from the point corresponding to the maximum of the first-order time derivative of Ca(2+) concentration (dCa/dtmax) to the point corresponding to the peak Ca(2+) concentration was curve-fitted by the least-squares method using the h-L and m-E function equations. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E curve-fits for CaTII were 0.9996 and 0.9984, respectively. The Z transformation of h-L r was larger than that of m-E r (p < 0.0001). H-L residual mean square (RMS) was smaller than m-E RMS (p < 0.001). CONCLUSIONS: The h-L function tracks the magnitudes and time courses of CaTII more accurately than the m-E function in isolated aequorin-injected mouse LV papillary muscle. Compared with the m-E time constant, the h-L time constant of CaTII is a more reliable index for evaluating the time duration of the change in the increase in [Ca(2+)]i during the combination of the middle part of the contraction process and the early part of the relaxation process. CaTII can be assessed by the h-L function model in cardiac muscles. The h-L approach may provide a more useful model for studying each process in myocardial Ca(2+) handling. KEY WORDS: Calcium handling; Calcium transient; Curve-fit; Half Logistic function; Time constant. PMID- 27122727 TI - Curve-Fitting the Intracellular Calcium Dynamics. AB - "No one believes modeling results except the one who performed the calculation; ...everyone believes the experimental results except the one who did the measurements." P. J. Roache - Computational Physicist. PMID- 27122728 TI - How Long Should Prophylactic Antibiotics be Prescribed for Permanent Pacemaker Implantations? One Day versus Three Days. AB - BACKGROUND: The implantation of a pacemaker is frequently a life-saving procedure. However, the process of implantation may carry an uncommon but potentially life-threatening infective complication. The prescription of prophylactic antibiotics is an effective way to reduce the risk of infection. The aim of the present study was to investigate the efficacy of 2 prophylactic antibiotic schemes and the possible risk factors associated with device-related infections. METHODS: A total of 194 consecutive patients who received permanent pacemaker (PPM) implantations were enrolled in this study. Prophylactic antibiotics were prescribed for every patient with a duration of either 1 day or 3 days. The follow-up period was 3 months, and any event of device-related infection was recorded. RESULTS: Out of the total 194 patients, there were 5 patients who experienced infective complications after PPM implantation (1 patient in the 1-day group and 4 patients in the 3-day group). The rate of infective complications showed no significant difference between the 2 kinds of antibiotic regimens (1.7% vs. 2.9%, p > 0.99). In the multivariate analysis, only the presence of pocket hematoma was an independent risk factor for infective complications (odds ratio = 3.14, p = 0.018). CONCLUSIONS: Our study showed that the efficacies for prevention of PPM-related infections were similar between the 1-day and 3-day regimens of prophylactic antibiotics. Pocket hematoma was an independent risk factor of infective complications, and a longer duration of antibiotic treatment may be considered for these patients. Otherwise, a 1-day course of antibiotic prophylaxis may be effective enough to prevent device related infections, and may further reduce the lengths of hospitalizations. KEY WORDS: Complication; Infection; Permanent pacemaker implantation; Prophylatic antibiotics. PMID- 27122729 TI - Radiofrequency Catheter Ablation of Atrial Tachyarrhythmias in Adults with Repaired Congenital Heart Disease: Constraints from Multiple and New Arrhythmic Foci. AB - BACKGROUND: Radiofrequency catheter ablation (RFCA) for atrial tachyarrhythmias in postoperative congenital heart disease (CHD) patients has a low success rate and a high recurrence rate. This study explores the reasons for these constraints. METHODS: A total of 49 consecutive postoperative CHD patients who received RFCA for atrial tachyarrhythmias between 1993 and 2010 were enrolled. RESULTS: Overall, there were 86 RFCA procedures performed, 32 with the conventional method and 54 using CARTO-guided mapping. The interval between the operation and the first ablation was 13 years. Isthmus-dependent atrial flutter (AFL) was the most common type of tachycardia (37, 76%), followed by intra-atrial re-entry tachycardia (IART; 37%), and ectopic atrial tachycardia (EAT; 31%). By applying CARTO-guided mapping, the success rate was elevated compared to that of conventional ablation (84% vs. 56%, p = 0.006), but there was no improvement in the recurrence rate (22% vs. 28%, p = 0.75). Multiple atrial tachyarrhythmias occurred in 26 (53%) patients, and 17 presented during the initial electrophysiological study. The presence of multiple arrhythmias during the initial study predicted ablation failure or multiple ablations (11/17 vs. 3/32, p < 0.001). Among the 15 patients with new tachyarrhythmias, EAT and IART predominated. However, applying antiarrhythmia agents immediately following ablation may decrease arrhythmia recurrence (1/10 vs. 14/25, p = 0.02). CONCLUSIONS: Although electroanatomical mapping improves the results of RFCA in atrial tachyarrhythmias, the recurrence rate remains high because of multiple and new atrial tachyarrhythmias. Therefore, short-term pharmacological treatment following RFCA for positive remodeling should be considered. KEY WORDS: Ablation; Antiarrhythmia agents; Atrial tachyarrhythmia; Congenital heart disease; Multiple arrhythmias. PMID- 27122730 TI - Coronary Artery Complications in Pediatric Patients with Kawasaki Disease: A 12 Year National Survey. AB - BACKGROUND: Coronary artery complications are the predominant causes of morbidity and mortality in childhood Kawasaki disease (KD). The aim of this study was to investigate the incidence of coronary artery complications and cardiac sequelae in pediatric patients with KD. METHODS: Using the Taiwan National Health Insurance (NHI) database from 1997 to 2008, records of patients with KD were reviewed retrospectively, utilizing the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 446.1 in pediatric patients aged 18 years or under. The ICD-9CM was also used to identify the outcomes for coronary artery complications (ICD-9-CM codes 410-414), including coronary artery aneurysm (CAA) (ICD-9-CM code 414.11). RESULTS: From the records of pediatric patients with KD admitted to hospitals between 1997 and 2004, 8148 patients without any history of coronary artery complications before KD were selected for study. Of those patients, 694 patients (8.5%) were followed-up until the end of 2008 to estimate the incidence of coronary artery complications. The ratio of boys to girls with coronary artery complications was 1.84, and the incidence of coronary artery complications was 11.53 per 1,000 person-years. Among the 8148 pediatric patients with KD, 12 patients (0.15%; 8 boys and 4 girls) had myocardial infarction, and 20 patients (0.25%; 12 boys and 8 girls) died during follow-up. CONCLUSIONS: This study is the first report regarding the incidence of coronary artery complications in KD children aged 18 years or younger. The incidence of coronary artery complications was higher as patients progressed in age, and increased by year. However, major complications such as death and myocardial infarction did not frequently occur. KEY WORDS: Cardiac sequelae; Coronary artery complications; Incidence; Kawasaki disease. PMID- 27122731 TI - Subaortic-Right Atrial Fistula after Endocarditis in Hypertrophic Cardiomyopathy. AB - Infective endocarditis in hypertrophic obstructive cardiomyopathy is rare. Management of this disease is challenging due to the unique features of dynamic pressure gradient over the left ventricular outflow tract and its unpredictable interaction with the management of sepsis. The added complexity of infective endocarditis further complicates an already difficult situation. A 72-year-old man with hypertrophic obstructive cardiomyopathy presented with acute stroke, fever, and Staphylococcus aureus bacteremia. Infective endocarditis of the aortic valve was confirmed. Despite treatment with antibiotics and aortic valve replacement, the patient had recurrent bacteremia and developed a periannular abscess and a subaortic-right atrial fistula, with a resulting fatal outcome. KEY WORDS: Aortic valve replacement; Endocarditis; Hypertrophic obstructive cardiomyopathy; Subaortic-right atrial fistula. PMID- 27122732 TI - Dynamic Left Ventricular Outflow Tract Obstruction with Cardiogenic Shock in Apical Ballooning Syndrome. AB - Apical ballooning syndrome, also called Takotsubo cardiomyopathy, is characterized by transient systolic dysfunction of mid to apical segments and hyperkinesis of basal segments of the left ventricle that mimic acute myocardial infarction without significant coronary artery stenosis. We reported a 51-year old man with chest distress, hypotension and abnormal electrocardiogram. Echocardiography revealed extensive akinesia of the mid to apical portions of the left ventricle, hyperkinesia of basal segments of the left ventricle, increasing left ventricle outflow tract velocity and severe mitral regurgitation. Cardiac catheterization showed a normal coronary angiography and an obvious pressure gradient between the left ventricle and aorta. After we discontinued administration of nitrates, provided mild hydration and initiated intravenous dopamine infusion, the patient's hypotension, left ventricular to aortic pressure gradient, and severe mitral regurgitation resolved the next day. Thereafter, apical ballooning syndrome with dynamic left ventricular outflow tract obstruction, severe mitral regurgitation and cardiogenic shock was diagnosed. KEY WORDS: Apical ballooning syndrome; Cardiogenic shock; Left ventricular outflow tract obstruction; Mitral regurgitation. PMID- 27122733 TI - Asymptomatic Right Ventricular Perforation by a Temporary Transvenous Pacing Lead in an Infant. AB - A 3-month-old male infant received transvenous temporary pacemaker for acquired complete atrioventricular block. However, a right ventricle perforation by the pacing lead was found incidentally when the patient was receiving permanent pacemaker implantation nineteen days after temporary pacing. There was no pacemaker dysfunction, active bleeding or hemopericardium. The temporary pacing lead was extracted and the site of perforation was sutured. This case is unique because of the patient's unusual clinical presentation, and we suggested that echocardiography should be performed cautiously to check the pacing catheter tip daily, even if asymptomatic and/or normal function of pacemaker. KEY WORDS: Complete atrioventricular block; Right ventricle perforation; Transvenous pacing lead. PMID- 27122734 TI - Obesity Paradox - The Controversial Role of Body Mass Index and Plasma Adiponectin in Coronary Artery Disease and Acute Coronary Syndrome. AB - Body mass index (BMI) is an anthropometric index used to evaluate a person's weight. In the general population, higher BMI is associated with more adverse outcomes as well as cardiovascular risk factors. The current clinical guidelines suggest weight control within desirable BMI as 18.5 to 24.9 kg/m(2). In the event of coronary artery disease or acute coronary syndrome, the impact of BMI on clinical outcomes still remains controversial. Some studies have demonstrated that overweight and obese patients had better prognosis than normal weight patients. Adiponectin, a secretory protein produced by adipocytes and inversely proportional to BMI, is a possible mediator for the so-called "obesity paradox", a term for the obese-protective phenomenon. Lower plasma adiponectin is associated with the progression of coronary artery disease. However, in the presence of acute coronary syndrome, patients with higher plasma adiponectin could be associated with adverse outcomes. Further studies including serial change of plasma adiponectin, or the use of other methods to discriminate lean and fat body mass are necessary to investigate this seemingly contradictory topic. KEY WORDS: Adiponectin; Body mass index; Obesity paradox. PMID- 27122735 TI - Five-Year Outcomes after Acute Myocardial Infarction in Patients with and without Diabetes Mellitus in Taiwan, 1996-2005. AB - BACKGROUND: Diabetes mellitus (DM) is a strong risk factor of cardiovascular disease. To date, the impact of DM on outcomes after acute myocardial infarction (AMI) in Taiwan is undetermined. The aim of this study was to compare five-year outcomes after AMI in patients with and without diabetes in Taiwan. METHODS: A nationwide cohort of 25,028 diabetic and 56,028 non-diabetic patients who were first hospitalized with AMI between 1996 and 2005 was enrolled through linkage with the Taiwan National Health Insurance research database. Patient mortality rates within 30 days after AMI, and 1, 3, and 5 years thereafter were compared. RESULTS: Length of hospital stay (8.9 +/- 8.7 vs. 8.2 +/- 8.0 days, p < 0.01) and medical cost during admission (in Taiwan dollars: $129,123 +/- $158,073 vs. $121,631 +/- $157,018, p < 0.01) were significantly higher in diabetic patients. The difference in mortality rate within 30 days was insignificant between diabetic and non-diabetic patients (18.1% vs. 17.6%, p = 0.06). Mortalities within 1 year (31.0% vs. 26.8%, p < 0.01), 3 years (42.4% vs. 34.7%, p < 0.01), and 5 years (50.6% vs. 41.1%, p < 0.01) were significantly higher in diabetic patients. In patients with AMI who underwent percutaneous coronary intervention (PCI) during index admission, the mortality rate within 30 days was insignificant (6.3% vs. 6.4%, p = 0.70) but mortalities within 1 year (15.2% vs. 11.6%, p < 0.01), 3 years (24.1% vs. 17.2%, p < 0.01), and 5 years (32.2% vs. 22.6%, p < 0.01) were significantly higher in diabetic patients. CONCLUSIONS: The average patient length of hospital stay and medical cost during admission were significantly higher in diabetic patients. Additionally, the difference in mortality rate within 30 days after AMI was insignificant between diabetic and non-diabetic patients. Also, long-term mortality after AMI was significantly higher in diabetic patients. KEY WORDS: Acute myocardial infarction; Diabetes mellitus; Length of hospital stay; Medical cost; Mortality; National health insurance. PMID- 27122736 TI - Chronic Kidney Disease, But Not Diabetes, Can Predict 30-Day Outcomes in Patients with ST-Elevation Myocardial Infarction after Primary Percutaneous Coronary Intervention: A Single-Center Experience. AB - BACKGROUND: Patients with acute coronary syndrome and impaired renal function have been shown to have high mortality. However, there is scarce literature to date addressing the impact of diabetes mellitus (DM) and renal function on clinical outcomes of ST elevation myocardial infarction (STEMI) in Taiwan. METHOD: This study enrolled 512 STEMI patients who received primary percutaneous coronary intervention. Patients were divided into 4 groups including group 1: patients without DM or CKD (nDM-nCKD); group 2: patients with DM but without CKD (DM-nCKD); group 3: patients with CKD but without DM (nDM-CKD); group 4: patients with DM and CKD (DM-CKD). Patients were also classified into four groups based on their estimated glomerular filtration rates (eGFR): stage 1 (eGFR >= 90 ml/min/1.73 m(2), n = 163), stage 2 (eGFR = 89-60 ml/min/1.73 m(2), n = 171), stage 3 (eGFR = 59-30 ml/min/1.73 m(2), n = 136), and stage 4 (eGFR < 30 ml/min/1.73 m(2), n = 42). The complication rates, length of hospital stay, and 30-day outcomes were analyzed. RESULTS: The patients in both the nDM-CKD group and DM-CKD group had higher incidences of hypotension, intra-aortic balloon counterpulsation use, and respiratory failure (p < 0.005). They had significantly longer hospital stay and 30-day mortality rates (p < 0.001). The patients with CKD stage 3 and 4 had longer hospital stay and higher 30-day mortality rates (p < 0.001). However, DM was not an independent factor on the length of hospital stay and 30-day mortality rates. CONCLUSIONS: STEMI patients with impaired renal function, but not DM, had significantly longer hospital stay and higher 30-day mortality rates. KEY WORDS: Chronic kidney disease; Diabetes mellitus; Mortality; Primary percutaneous coronary intervention; ST-segment elevation myocardial infarction. PMID- 27122737 TI - The Effect of Intensified Low Density Lipoprotein Cholesterol Reduction on Recurrent Myocardial Infarction and Cardiovascular Mortality. AB - BACKGROUND: Lipid-lowering therapy plays an important role in preventing the recurrence of cardiovascular events in patients after acute myocardial infarction (AMI). This study aimed to assess the effect of intensified low density lipoprotein cholesterol (LDL-C) reduction on recurrent myocardial infarction and cardiovascular mortality in patients after AMI. METHOD: The 562 enrolled AMI patients (84.2% male) were divided into two groups according to 3-month LDL-C decrease percentage equal to or more than 40% (n = 165) and less than 40% (n = 397). To evaluate the long-term efficacy of LDL-C reduction, the 5-year outcomes were collected, including time to the first occurrence of myocardial infarction and time to cardiovascular death. RESULTS: The baseline characteristics and complication rates were not different between the two study groups. The patients with 3-month LDL-C decrease >= 40% had higher baseline LDL-C and lower 3-month, 1 year, 2-year, 3-year, 4-year and 5-year LDL-C than the patients with 3-month LDL C decrease < 40%. In Kaplan-Meier analyses, those patients with 3-month LDL-C decrease >= 40% had a higher rate of freedom from myocardial infarction (p = 0.006) and survival rate (p = 0.02) at 5-year follow-up. The 3-month LDL-C < 40% parameter was significantly related to cardiovascular death (HR: 9.62, 95% CI 1.18-78.62, p < 0.04). CONCLUSIONS: After acute myocardial infarction, 3-month LDL-C decrease < 40% was identified to be a significant risk factor for predicting 5-year cardiovascular death. The patients with 3-month LDL-C decrease >= 40% had a higher rate of freedom from myocardial infarction and lower cardiovascular mortality, even though these patients had higher baseline LDL-C value. KEY WORDS: Acute myocardial infarction; Cardiovascular death; Low-density lipoprotein cholesterol; Mortality; Statin. PMID- 27122738 TI - Body Mass Index and Outcome of Acute Myocardial Infarction - Is There an Obesity Paradox? AB - BACKGROUND: Although there have been some studies focusing on the relationship between body mass index (BMI), coronary artery disease (CAD) and acute coronary syndrome, the clinical effects of BMI on outcomes after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) are not well known in a Taiwanese population. METHODS: From January 2005 to December 2011, 1298 AMI patients who received PCI were enrolled from a single center in Taiwan. The patients were divided into 4 groups according to their BMI: underweight (BMI < 18.5 kg/m(2)); normal weight (18.5 <= BMI < 24 kg/m(2)); overweight (24 <= BMI < 27 kg/m(2)) and obese (BMI >= 27). All patients had been followed up for at least 12 months, and 30-day and 5-year all-cause and cardiovascular-cause mortality were compared among the study groups. RESULTS: The patients in the underweight group had a lower 30-day survival rate than the other 3 groups, and the underweight and normal weight patients had a lower 5-year survival rate than the overweight and obese patients. The multivariate regression analysis showed that Killip class >= 2, non-use of statin, older age, hemoglobin < 12 g/dl and chronic kidney disease, but not BMI, are independent predictors of all-cause mortality. CONCLUSIONS: In this present study, the major factors affecting long-term survival are lack of using statin and older age, but not obese paradox. KEY WORDS: Acute myocardial infarction; Mortality; Obesity; Percutaneous coronary intervention; Survival. PMID- 27122739 TI - Increased Rosuvastatin Dose versus Concomitant Fenofibrate and Rosuvastatin Therapy to Achieve Lipid Goal in Patients with Diabetes or Atherosclerosis with Metabolic Syndrome. AB - PUPOSE: We aimed to ascertain whether increased rosuvastatin dose is non-inferior to concomitant fenofibrate and rosuvastatin therapy in patients with diabetes or atherosclerosis with metabolic syndrome. METHODS: After treatment with rosuvastatin 5 mg/day for 12 weeks, 112 patients were randomly assigned to receive either 10 mg/day rosuvastatin (group A) or 80 mg/day supra-film coated fenofibrate plus 5 mg/day rosuvastatin (group B). The therapy effects were evaluated by measuring the serum lipid profile, liver and muscle enzymes, and renal function after the treatment period. RESULTS: After the treatment, the total cholesterol, high-density-lipoprotein cholesterol (HDL-C), non HDL-C, low density-lipoprotein cholesterol (LDL-C), and triglyceride were comparable between the 2 groups. The change in the non-HDL-C were -7.39 +/- 26.58 (-6.62%) and -0.68 +/- 24.49 (-1.19%) mg/dl (p = 0.28); and the change in the triglyceride were 36.61 +/- 62.51 (-14.00%) and -44.77 +/- 77.35 (-23.17%) mg/dl (p = 0.64), respectively. While 41.37% of group A and 38.69% of group B achieved their LDL-C goal (< 100 mg/dl) (p = 0.79), 37.26% of group A and 42.31% of group B achieved their triglyceride goal (< 150 mg/dl) (p = 0.53), respectively. The changes in the serum transaminase and creatinine phosphokinase were similar between the 2 groups. CONCLUSIONS: After 5 mg/day of rosuvastatin, the lipid profile in patients with diabetes or atherosclerotic vascular diseases with metabolic syndrome could be improved by increasing rosuvastatin dose, and the resultant decrease of non-HDL and triglyceride were similar to those obtained with combination therapy. Both therapies were safe and feasible. KEY WORDS: Combination therapy; Diabetes; Fenofibrate; Metabolic syndrome; Monotherapy; Statin. PMID- 27122740 TI - Combined Framingham Risk Score and Coronary Artery Calcium Score Predict Subclinical Coronary Plaque Assessed by Coronary Computed Tomography Angiogram in Asymptomatic Taiwanese Population. AB - BACKGROUND: We sought to determine the predictive value of the combined traditional Framingham risk score (FRS) and coronary artery calcium score (CACS) for subclinical coronary plaque detected by computed tomography coronary angiogram (CTCA) in asymptomatic subjects. METHOD: We evaluated 167 asymptomatic Taiwanese subjects (mean age, 57 +/- 11.2 years), who underwent CTCA as part of a health evaluation. We examined the associations between FRS, CACS, serum biomarkers, and coronary plaque assessed by CTCA. RESULTS: Out of 167 subjects in the study, 95 had coronary artery atheroma. Of those possible predictors for coronary atherosclerosis, both FRS and CACS were independent predictors for the presence of coronary plaque [relative risk (RR): 1.29, 95% confidence interval (CI): 1.07-1.54, p = 0.006 and RR: 1.42, 95% CI: 1.16-1.75, p = 0.001, respectively]. Receiver operating characteristics curve analysis revealed that CACS and FRS were indicators of the presence of coronary plaque. The area under the curve for FRS and CACS was 0.729 and 0.889, respectively (p < 0.001). Furthermore, the area under the curve for combination of FRS and CACS was 0.936 (95% CI: 0.887-0.969, p < 0.001), and this combination provided a better diagnostic advantage than either FRS or CACS alone (p < 0.001 and p = 0.012 by C statistic, respectively). CONCLUSIONS: In asymptomatic Taiwanese subjects with low to intermediate cardiovascular risk, both FRS and CACS were independently related to subclinical atherosclerosis. A combined FRS and CACS evaluation improved the efficacy of prediction for atherosclerotic plaque burden. KEY WORDS: Atherosclerosis; Computed coronary tomography angiogram; Coronary artery calcium score; Framingham risk score; Subclinical coronary plaque. PMID- 27122741 TI - Falls and Atrial Fibrillation in Elderly Patients. AB - BACKGROUND: Atrial fibrillation is a common heart rhythm disorder in older adults, and its prevalence has increased rapidly in recent years. The health issues associated with atrial fibrillation are not limited to physiological problems, as it also contributes to an increased risk of falls, which may be related to cardiovascular co-morbidities and medication use. The aim of this study was to determine which cardiovascular co-morbidities and medication use are associated with falls in older adults with atrial fibrillation. METHODS: Four hundred and one patients 75 years of age or older (82.2 +/- 0.2 years) were enrolled in a geriatric evaluation and management unit in Taiwan. Events associated with patient falls and medication use were recorded, and comprehensive geriatric assessment was conducted during admission. RESULTS: Among the study participants, 66 (16.5%) patients had atrial fibrillation and 234 (58.4%) patients had a history of fall. We found a significantly higher prevalence of falls in patients with atrial fibrillation [odds ration (OR) 1.98, 95% confidence interval (CI) 1.08-3.63, p = 0.026] compared with those without atrial fibrillation. Using multivariate logistic regression, we found that benzodiazepine use (OR 18.22, 95% CI 2.71-122.38, p = 0.003), a history of paroxysmal atrial fibrillation (OR 12.18, 95% CI 1.37-108.70, p = 0.025) and hypertension (OR 9.49, 95% CI 1.19-75.57, p = 0.034) were independent factors for falls in atrial fibrillation patients. CONCLUSIONS: A diagnosis of atrial fibrillation in elderly patients is associated with falls. Benzodiazepine use, history of paroxysmal atrial fibrillation, and hypertension were associated with a high falling prevalence among patients with atrial fibrillation. KEY WORDS: Atrial fibrillation; Benzodiazepine; Falls; Hypertension. PMID- 27122742 TI - Image Quality of 256-Slice Computed Tomography for Coronary Angiography. AB - PURPOSE: To assess the image quality of 256-slice computed tomographic angiography (CTA) and to identify possible impact factors associated with image quality. METHODS: From November 2009 to January 2010, 506 patients underwent 256 slice CTA at our institute. A total of 451 patients were enrolled in our study, after 55 patients were excluded because of prior bypass surgery and stenting. CTA image quality was graded by two observers using a 4-point scale: excellent (score 1), good (score 2), moderate (score 3), poor and non-diagnostic (score 4). The coronary arteries were divided into 15 segments. Image quality was correlated to the subjects' age, gender, body mass index, heart rate, and calcium scores. RESULTS: We evaluated 6650 coronary segments from CTA images of our enrolled 451 patients. The mean image quality score of all coronary segments was 1.14. Most coronary segments (99.7%) were assessable, and only 21 segments (0.3%) were non diagnostic. A total of 5824 coronary segments were classified as having excellent image quality. Forty-two patients (9.3%) required control of heart rate with beta blockers before CTA could be performed. Male patients had better image quality than female patients. Heart rate and severity of calcification were impact factors associated with image quality. CONCLUSIONS: Examination with 256-slice CTA provides good image quality and can effectively evaluate most coronary segments. KEY WORDS: Coronary angiography; Heart rate; Image quality; Multi-slice computed tomography. PMID- 27122743 TI - Utilization of Pulsatile flow to Decellularize the Human Umbilical Arteries to Make Small-Caliber Blood Vessel Scaffolds. AB - PURPOSE: To explore the effect of pulsatile flow in the decellularization process of small blood vessels. METHODS: A total of 30 human umbilical cords were used in the current study. The umbilical cords were flushed with 0.25% trypsin/0.01% EDTA for 30 minutes, followed by treatment with 1% sodium dodecyl sulfate sodium dodecyl sulfate for 3 hours. The effectiveness of decellularization on the umbilical artery wall was analyzed by mechanical analysis. The scaffolds' biocompatibility was observed by co-culture with the human umbilical endothelial cells. RESULTS: The maximum stress of the arteries before and after denuding was 3.55 +/- 0.42N and 3.50 +/- 0.43N, respectively. Under the pressure of 300 mmHg, 28 pieces of umbilical cords remained intact before and after the flushing, while 2 pieces ruptured under 300 mmHg. There was no significant difference in mechanical properties between flushed and control arteries. Isolated human umbilical endothelial cells grow and spread well on the decellularized umbilical artery scaffolds. CONCLUSIONS: Decellularization by pulsatile flow in human umbilical artery is a convenient, rapid and efficient approach to increase the availability of small caliber blood vessel scaffolds. KEY WORDS: Decellularization; Human umbilical artery; Scaffolds; Small diameter blood vessel; Vascular tissue engineering. PMID- 27122744 TI - Outcome of Circumferential Pulmonary Vein Isolation for Ablation of Atrial Fibrillation: A Single Center Experience. AB - BACKGROUND: Atrial fibrillation (AF) is the most common heart rhythm disorder in adults. Currently, use of the circumferential pulmonary vein isolation (CPVI) technique is the cornerstone of ablation therapy for paroxysmal atrial fibrillation. In this report, we described our ablation strategy and outcomes when treating a limited number of AF patients. METHODS: This study enrolled patients with paroxysmal or persistent AF that were resistant to at least one anti-arrhythmia drug. We used the CARTO XP system for electro-anatomic mapping, facilitated by left atrium multi-slice computed tomography imaging. The ablation strategy was to obtain CPVI by using an irrigation catheter and the end-point was complete entry and exit block at each pulmonary veins. AF recurrence was defined through review of symptoms and AF documentation via electrocardiography (ECG) or Holter ECG. RESULTS: From 2007 to 2011, 108 patients (76% paroxysmal AF) received ablation by means of our standard procedures, and the AF recurrence rate was 22% during a mean follow up of 20.6 +/- 10.2 months. The major complication rate was less than 3% in all the patients that received AF ablation in our center. CONCLUSIONS: Our AF ablation results were comparable to those results reported in major electrophysiology centers, with acceptable complication rates. KEY WORDS: Ablation; Atrial fibrillation; Pulmonary vein isolation. PMID- 27122746 TI - Thyroid Storm and Incidental Anterior Mediastinal Teratoma: Coincidence or Correlation? AB - Teratoma is a rare cause of thyrotoxicosis. Among the different types of teratoma, struma ovarii is the main type which contains thyroid tissue. There is no evidence in the literature that would indicate mediasternal teratoma would also lead to thyrotoxicosis or thyroid storm. Herein we report a 37-year-old woman who suffered from palpitation. Her chest X-ray showed a mass lesion at the left hilum, and chest computed tomography scan yielded a suspicion of pericardial cyst. Thereafter, video-assisted thoracoscopic surgery was performed, and thymic cyst was diagnosed during the operation. However, subsequent pathological studies confirmed a diagnosis of mature cystic teratoma. A thyroid function test demonstrating hyperthyroidism was completed prior to the patient's operation, and thyroid storm was diagnosed by clinical presentation. The patient's symptoms did not improve after the operation until we added beta blocker and anti-thyroid agents. Therefore, was the presence of thyroid storm and anterior mediastinal teratoma coincident or correlative in this case? The special stain of teratoma tissues did not reveal any thyroid tissues. In conclusion, thyroid storm and anterior mediastinal teratoma in our case occurred coincidentally. However, a survey of possible hyperthyroidism in patients with anterior mediastinal tumor before operation is critical to avoid perioperative complications. KEY WORDS: Anterior mediastinal tumor; Hyperthyroidism; Teratoma. PMID- 27122745 TI - Recurrent Thrombosis in a Case of Coronary Ectasia with Large Thrombus Burden Successfully Treated by Adjunctive Warfarin Therapy. AB - Coronary ectasia (CE) is an uncommon disease. Most patients with CE have coexisting coronary artery stenosis, which can easily lead to acute myocardial infarction (AMI). The current standard treatment for AMI is well-established. However, for CE patients, the standard treatment might fail because of the large thrombus burden. We report a case of CE suffering from AMI twice during a two week period. Percutaneous coronary intervention with aspiration thrombectomy was performed but failed to restore adequate blood flow. Heparin and antiplatelet treatment including glycoprotein IIb/IIIa inhibitor was given for pharmacological management, but follow-up angiography still revealed a poor result. This patient was finally treated with dual antiplatelet therapy in combination with warfarin treatment. Follow-up coronary angiography a few months later showed restored TIMI 3 flow. This patient reminds us that in CE patients with large thrombus burden, if standard treatment fails, long-term warfarin in combination with antiplatelet might be a good alternative choice to decrease thrombus burden and enhance blood flow. KEY WORDS: Acute myocardial infarction; Anticoagulation; Aspiration thrombectomy; Coronary ectasia; Warfarin. PMID- 27122747 TI - Successful Treatment of Peripartum Cardiomyopathy with Plasmapheresis. AB - Peripartum cardiomyopathy (PPCM) is a rare, life-threatening disease of late pregnancy and early puerperium among previously healthy women. Management of this challenging disease is similar to other forms of systolic heart failure. Unfortunately, only 30% to 50% of patients recover completely. Among the remaining patients, continued poor ejection fraction indicates irreversible cardiomyopathy and portends a poor outcome. Immune complexes, autoantibodies, or toxic proteins are likely causative agents. Herein, we report first two PPCM cases that were successfully managed with plasmapheresis. KEY WORDS: Peripartum cardiomyopathy; Plasmapheresis. PMID- 27122749 TI - Predicting Trends in Dyspnea and Fatigue in Heart Failure Patients' Outcomes. AB - BACKGROUND: Dyspnea and fatigue are distressing symptoms commonly seen in heart failure (HF) patients, and are closely related to patients' disease trajectory of contributes. Identifying the effect of symptom trends on disease outcomes is important to develop effective symptom management interventions in HF patients. METHODS: One hundred and twenty-two patients were recruited. Dyspnea, fatigue, clinical characteristics, and disease outcomes were measured at the baseline assessment, three months, and 12 months. Latent class growth model and Kaplan Meier survival analysis were used on dyspnea and fatigue to examine the relationship of disease trajectories and effects on disease outcomes. RESULTS: A total of 122 patients were examined (mean age 62.8 +/- 13.0 yrs; 79% male; 39% NYHA III/IV; 48% preserved systolic function HF). Three groups based on HF patients' dyspnea-fatigue trends were identified as "constant good," "recovery," and "getting worse." The cumulative incidence of a first cardiac event in both dyspnea and fatigue groups yielded similar results. The quality of life score for the getting worse group was significantly higher than that of the constant good and recovery groups. The result of the log-rank test was significant (chi(2) = 8.11, p = 0.017). Post hoc comparison showed that the prognosis status of the constant good group was better than that of the getting worse (p = 0.046) and recovery groups (p = 0.020), while getting worse and recovery groups did not differ in prognosis status (p = 0.30). CONCLUSIONS: The results demonstrate the value of tracking symptoms over time to determine symptom trajectories as well as severe baseline (even with improvements at follow-ups) or increased fatigue over time were related to a worse event-free survival as compared with low but stable fatigue. KEY WORDS: Disease outcome; Kaplan-Meier survival analysis; Symptom trajectory. PMID- 27122748 TI - Clinical Application of Endothelial Progenitor Cell: Are We Ready? AB - The discovery of circulating endothelial progenitor cells (EPCs) opened up a new era of EPC-based therapies for cardiovascular diseases. While researchers are enthusiastic about applying EPCs to clinical therapy, progress has been substantially limited due to the lack of a thorough characterization and understanding of early and late outgrowth EPCs (also called endothelial colony forming cell, ECFCs) biology. As a means of facilitating the understanding of how late EPCs can most effectively be applied to clinical therapeutics, this article reviews the recent progress covering 5 important issues: (1) The best passages of ex vivo-cultivated EPCs for cell therapy; (2) inflammatory activation of late EPCs: a real world consideration; (3) late EPC is not an endothelial cell: an issue of cell contamination; (4) ways to improve EPC function and differentiation; and (5) how to separate and delete smooth muscle progenitor cells (SPCs). KEY WORDS: Cardiovascular disease; Cell therapy; Endothelial progenitor cell; Smooth muscle progenitor cell. PMID- 27122750 TI - An Overview of Current Cardiac Resynchronization Therapy. AB - Cardiac resynchronization therapy (CRT) is currently an established device therapy for heart failure (HF) patients. Existing knowledge of implantation techniques, advances in device-based technologies and clinical trial experience have all significantly impacted this evolving therapy in recent years. This review article will address the updated CRT guidelines, and potentially new indications for CRT such as patients with mild HF symptoms and prolonged QRS duration; it also highlights new approaches for placement of the left ventricular (LV) lead, multi-site LV pacing, and the role of automatic device optimization in CRT. KEY WORDS: Cardiac resynchronization therapy; Guideline; Heart failure; Optimization. PMID- 27122751 TI - Clinical Assessment and Implication of Left Ventricular Mechanical Dyssynchrony in Patients with Heart Failure. AB - There have been numerous studies focusing on the assessment of left ventricular mechanical dyssynchrony. These studies are diverse in their purposes, which include more effectively predicting the response to cardiac resynchronization therapy, improving the guidance of the left ventricular lead position, and better prediction of outcome in patients with heart failure. This article reviews the current assessment methods, clinical applications and limitations of left ventricular dyssynchrony indices derived from echocardiography, magnetic resonance imaging and radionuclide imaging in patients with heart failure. KEY WORDS: Cardiac resynchronization therapy; Dyssynchrony; Echocardiography; Heart failure. PMID- 27122752 TI - Cardiac Systolic Mechanics in Heart Failure with Preserved Ejection Fraction: New Insights and Controversies. AB - Heart failure with preserved ejection fraction (HFpEF) is a cardinal and complex syndrome tightly linked to several co-morbidities, and is currently emerging as a new public health problem in the elderly population. However, despite aggressive intervention, patients with HFpEF typically have a poor prognosis. Part of the reason underlying this phenomenon can be attributed to the insufficiently understood pathophysiology behind this syndrome. Traditional echocardiography derived parameters such as left ventricular (LV) ejection fraction (LVEF) may not be useful in characterizing such a clinical disorder, or in further identifying the subjects at risk, owing in part to its lack of power to disclose subclinical systolic dysfunction in such a clinical scenario. Herein, we briefly reviewed the clinical manifestations and risk factors of HFpEF, and further provided insights into the understanding of the ventricular architecture and cardiac mechanics underlying HFpEF by utilizing advanced cardiovascular imaging modalities, with a special focus on myocardial deformation. KEY WORDS: Heart failure; Speckle tracking imaging; Strain. PMID- 27122753 TI - The Effects of Fasudil at Different Doses on Acute Myocardial Infarction in Rats. AB - PURPOSE: To explore the effects of different doses of fasudil on cardiomyocytes in rats with acute myocardial infarction (AMI). METHODS: A model of rats experiencing AMI was randomly divided into control groups and fasudil treatment groups according to the different doses of fasudil. After four weeks, hemodynamic parameters were measured. Expression levels of Rho kinase mRNA by the reverse transcription polymerase chain reaction method and the expression levels of apoptosis related proteins, Bcl-2 and bax, were determined by the immunohistochemical method. RESULTS: In the model of AMI in rats, their hemodynamic deteriorated, and the expression level of the Rho kinase mRNA increased in the myocardial tissue; but the expression level of apoptosis-related protein bcl-2 decreased, and Bax increased (p < 0.01). After the administration of fasudil, hemodynamic levels improved (p < 0.05), expression levels of Rho kinase mRNA and Bax (p < 0.01) decreased, expression levels of bcl-2 increased, and with the added element of dosage increase, the effect was significant (p < 0.05). CONCLUSIONS: By administration of different doses of fasudil, the expression level of Rho kinase in myocardial tissue decreased and apoptosis reduced in rats with AMI. Fasudil plays an important role in protecting ischemic myocardium and improving cardiac function post AMI in rats, the effects of which were enhanced as the dosage was increased. KEY WORDS: Apoptosis; Myocardial infarction; Rho kinase. PMID- 27122754 TI - Short-Term Safety and Efficacy of Femoral Vascular Closure after Percutaneous Coronary Intervention with Combination of the Boomerang(TM) Device and Intravenous Protamine Sulfate. AB - BACKGROUND: The Cardiva Boomerang(TM) is a device used to perform femoral vascular closure. It facilitates passive hemostasis at the arteriotomy site, leaving no residual foreign body. METHODS: We performed a controlled, randomized study of 60 patients undergoing percutaneous coronary intervention. Patients were randomized into two groups (30 per group) to undergo vascular closure with the Boomerang(TM) or the Perclose(TM) suture-based device after the intravenous administration of protamine sulfate. We compared overall success rates, patient reported pain, length of time to achieve hemostasis and mobilization of the patient, and the frequency of complications in the two groups. RESULTS: Overall success rates using the Boomerang(TM) and Perclose(TM) devices were similarly high, at 93% and 97%, respectively. The Boomerang(TM) was significantly quicker to deploy than the PercloseTM, device deployment time, median (Q1-Q3), [2.00 (1.33-2.75) vs. 3.84 (2.75-4.38) mins, p < 0.001)]. The pain score was significantly lower in the Boomerang(TM) group (1.1 +/- 1.7 vs. 6.4 +/- 2.9, p < 0.001). The time the device remained in the artery and manual compression time were significantly longer with the Boomerang(TM) (p < 0.001), as well as the time taken to achieve hemostasis and time to ambulation. There were no major complications in either group and no significant differences between the groups in the frequency of minor complications. CONCLUSIONS: We conclude that when used in combination with intravenous protamine sulfate, the Boomerang(TM) device is as safe and effective as the Perclose(TM) device for femoral vascular closure, but quicker to deploy and less painful to patients. KEY WORDS: Boomerang; Percutaneous intervention; Vascular closure device. PMID- 27122755 TI - Outpatient Hypertension Control and Prescribing Habits for Hypertension in Taiwan. AB - BACKGROUND: Hypertension control is of the utmost importance for reducing cardiovascular risk. In Taiwan, the hypertension control rate of the general population is low (25%). We investigated the factors affecting outpatient hypertension control to determine whether the low control rate stems from clinician unawareness or inadequate public education. METHODS: Hypertensive patients were recruited between 2003 and 2004 by 13 cardiologists and 9 non cardiologists from 19 hospitals distributed across four geographical areas of Taiwan. Each clinician recruited 100 consecutive patients from outpatient clinics and reported their drug prescriptions, co-morbidities, and blood pressure (BP) levels. Data were analyzed using the chi square test and multivariate logistic regression analyses. RESULTS: Of the 2145 enrolled patients, 63% attained the BP goal of < 140/90 mmHg. BP control rates were higher in older patients, and in patients who were treated by cardiologists and at medical centers. The control rate of high risk co-morbidity patients (BP goal of < 130/80 mmHg) was 36%, which was significantly lower than the 62% control rate of low risk patients (BP goal of < 140/90 mmHg). Cardiologists achieved higher BP control rates (65% vs. 60%; p = 0.0039), and prescribed more combination regimens (p < 0.0001) and beta blockers than non-cardiologists. Overall, 63% of patients received combination therapy. Calcium channel blockers were the most commonly prescribed antihypertensive drugs, followed by beta blockers, angiotensin receptor blockers, diuretics, and angiotensin-converting enzyme inhibitors. CONCLUSIONS: Two-thirds of the entire study population received combination therapy, although BP control rate is still less than optimal in the high risk patients. Ultimately, a more aggressive strategy is strongly encouraged for patients considered to be at high risk. KEY WORDS: Combination therapy; Hypertension control rate; Prescribing habit. PMID- 27122756 TI - Effects of Coronary Arterial Injection of Tirofiban on Diabetes Mellitus Complicated with Acute Myocardial Infarction in the Elderly. AB - OBJECTIVE: This work aims to explore the short-term efficacy and safety of coronary arterial injection of tirofiban in elderly diabetic patients complicated with acute myocardial infarction (AMI) who underwent emergency percutaneous coronary intervention (PCI). METHODS: Ninety-seven elderly diabetic patients complicated with ST-elevation myocardial infarction (STEMI) who underwent emergency PCI were selected and randomized into control (group A, 49 cases) and tirofiban (group B, 48 cases) groups. Another 129 nonelderly diabetic patients (group C) complicated with STEMI who underwent emergency PCI and tirofiban treatment in the corresponding period were also involved for comparison. RESULTS: Thrombolysis in myocardial infarction 3 (TIMI3) flow was significantly higher in groups B and C than in group A after PCI (p < 0.01). TIMI myocardial perfusion grades (TMPG) 0 to 1 and 2 were distinctly lower (p < 0.01, p < 0.05) and TMPG3 was obviously higher (p < 0.01) in groups B and C than in group A. The average length of hospital stay, post-infarction angina pectoris, severe arrhythmia, and cardiac function Killip III to IV were markedly lower in groups B and C than in group A (p < 0.01, p < 0.05). Meanwhile, mucocutaneous hemorrhage was significantly higher in groups B and C than in group A (p < 0.01). CONCLUSIONS: Tirofiban effectively improved TIMI flow and TMPG perfusion in elderly diabetic patients complicated with AMI and reduced the incidence of serious complications without increasing the occurrence of severe hemorrhage. KEY WORDS: Acute myocardial infarction; Diabetes mellitus; Emergency percutaneous coronary intervention; Tirofiban. PMID- 27122757 TI - Surgical Management for Complications during Closure of Atrial Septal Defect with Amplatzer Device. AB - BACKGROUND: Transcatheter closure of secundum type atrial septal defect (ASD) has become a standard procedure in most medical centers. Although the procedure is invasive and has a shorter recovery duration and a lower complication rate compared with surgery, it is not risk-free. In this retrospective chart review case series, we report our experience of management of complications after placement of an ASD occluder. METHODS: Between January 2000 and December 2010, a total of 508 patients in our hospital underwent closure of secundum type ASD using an Amplatzer septal occluder (ASO). Six of the patients (1.2%) had device embolization or migration warranting surgical retrieval and repair. RESULTS: All the devices were removed and the defects were repaired successfully without any mortality. CONCLUSIONS: Surgical intervention for complications of ASO placement in patients who underwent closure of secundum type ASD is safe and effective. KEY WORDS: Amplatzer occluder; Atrial septal defect; Surgical management. PMID- 27122758 TI - Silent Left Ventricular Hemangioma. AB - Cardiac hemangiomas are extremely rare, and account for 5-10% of benign cardiac tumors. Most clinical presentations involve patient dyspnea on exertion and arrhythmia; asymptomatic patients are uncommon. A 45-year-old man had an asymptomatic left ventricular mass that was found incidentally during an echocardiogram. Magnetic resonance images showed an isointense protruding mass attached to the lateral wall of the left ventricle. The patient underwent a complete surgical resection with a good outcome. Histopathological examination revealed a cavernous hemangioma. The natural course of cardiac hemangiomas varies, and total resection is the favored treatment. KEY WORDS: Asymptomatic; Cardiac hemangioma; Resection. PMID- 27122759 TI - Late-Onset Cyanosis and Finger Clubbing in a 37-Year-Old Female with Ebstein's Anomaly and Atrial Septal Defect. AB - It is common to suspect Eisenmenger syndrome when patients with atrial septal defect (ASD) show cyanosis and clubbing. However, ASD accompanying Ebstein's anomaly frequently shows cyanosis without severe pulmonary hypertension, especially in the early period after birth. So the medical decision to decline surgical treatment in those patients should not be determined merely by clinical features such as cyanosis and clubbing. We report a case of a 37-year-old female with Ebstein's anomaly and secundum ASD who showed lip cyanosis and finger clubbing, but maintained normal pulmonary artery pressure and thus underwent successful surgical correction. KEY WORDS: Atrial septal defect; Cyanosis; Ebstein's anomaly; Eisenmenger syndrome. PMID- 27122760 TI - Anomaly of the Conus Artery Arising from the Right Coronary Artery. AB - Some anomalies of the conus artery are relatively common, such as those arising from the discrete ostium of the right coronary artery. We report a 63 y/o male with an unusual anatomic variation of the conus artery terminating in the pericardium. Coronary anomalies may cause coronary ischemia, infarction and sudden cardiac death; hence, it is significant to identify coronary anomalies. Here, we identify an unusual conus artery anomaly for the first time, with accompanying imaging showing its very rare anatomical features that may be of interest to the larger medical community. KEY WORDS: Anomaly; Coronary angiography; Coronary artery. PMID- 27122761 TI - Assessment of Coronary Plaque Vulnerability with Optical Coherence Tomography. AB - Several catheter-based imaging modalities have been developed over the past 2 decades for visualizing the morphological features of coronary atherosclerotic plaques that are susceptible to future development of serious cardiovascular events. Optical coherence tomography (OCT) is a new high-resolution intracoronary imaging modality based on near-infrared interferometry, and it has been shown to be able to identify various components of atheromatous plaques. In this review, we examine the histopathology of vulnerable plaques as a target for imaging technology, and discuss the evidence of OCT in identifying vulnerable atherosclerotic lesions in patients with coronary artery disease. KEY WORDS: Coronary artery disease; Optical coherence tomography; Vulnerable plaque. PMID- 27122763 TI - CHA2DS2-VASc Score and Heart Rate Predict Ischemic Stroke Outcomes in Patients withAtrial Fibrillation. AB - PURPOSE: To evaluate the factors determining the severity and outcome of ischemic stroke in patients with atrial fibrillation (AF). METHODS: Our study examined 210 patients with AF and acute ischemic stroke to investigate the relative risks of age, gender, comorbidities, CHADS2 and CHA2DS2-VASc scores, warfarin use, heart rate, and blood pressure on stroke severity, hospitalization duration, and mortality rate. RESULTS: Patients with poor outcomes [n = 109, National Institutes of Health Stroke Scale (NIHSS) scores of >= 8] had elevated CHA2DS2 VASc scores [5, interquartile range (IQR) 3-6 versus 4, IQR 2.5-5, p = 0.005] and were older with a female predominance, less prior warfarin use, and a higher heart rate (93 +/- 24 versus 84 +/- 20 beats/min, p = 0.004) in the emergency department, with a longer duration of hospitalization (24 +/- 23 versus 11 +/- 12 days, p < 0.001) and a higher mortality rate (11.0% versus 0.0%, p = 0.002) than those with better outcomes (n = 101, low NIHSS scores of <= 7). Patients who died (n = 12) were older and had a higher NIHSS, CHADS2 (3.5, IQR 2-4.75 versus 2, IQR 1-4, p = 0.040), or CHA2DS2-VASc (5.5, IQR 4-6 versus 4, IQR 3-5, p = 0.046) scores than patients who survived. The multivariate analysis showed that female gender, no prior warfarin use, and heart rate were independent predictors of stroke severity. CONCLUSIONS: Our results showed that CHADS2 and CHA2DS2-VASc scores, and heart rate were useful parameters for predicting outcomes in AF patients with stroke. KEY WORDS: Atrial fibrillation; CHA2DS2-VASc score; Heart rate; Ischemic stroke. PMID- 27122762 TI - Association of Small-Conductance Calcium-Activated Potassium Channels and Atrial Fibrillation - How Far Have We Gone? AB - Atrial fibrillation (AF) is the most common sustained and most important arrhythmia in clinical practice. The mechanisms underlying AF initiation and maintenance are known to be complex and heterogeneous. The general understanding of the detailed molecular basis of AF is still incomplete. Recently, these is increasing evidence that small conductance calcium-activated potassium (SK) channels are associated with atrial action potential repolarization and the pathogenesis of AF. Although the functional role of SK channels in the genesis of AF is not entirely clear, new insights into the basic pathophysiological mechanism of AF have been provided. Besides, genome-wide association studies also implicate that genes coding for SK channels are related to the risk of developing AF. This article reviews recent work on the association of SK channels and AF, genetic studies of SK channels, and discuss future investigation and developments regarding this field. KEY WORDS: Atrial fibrillation; Genetics; Small conductance calcium-activated potassium channels. PMID- 27122764 TI - Long-Term Prognosis in Recipients of Implantable Cardioverter-Defibrillators for Secondary Preventions in Taiwan - A Multicenter Registry Study. AB - BACKGROUND: The use of an implantable cardioverter-defibrillator (ICD) has a proven capacity to prevent sudden cardiac death (SCD), and can also improve survival duration in well-selected patients. The goal of the present study was to investigate the long-term prognosis and predictors of mortalities among ICD recipients in Taiwan. METHODS: From 1998 to 2009, 238 consecutive patients who experienced SCDs or life-threatening ventricular tachyarrhythmias without correctable causes and received ICD implantations in 3 medical centers (Taipei, Taichung and Kaohsiung Veterans General Hospital) were enrolled in this study. The clinical endpoint was defined as the occurrence of all-cause mortality during the follow-up. RESULTS: The mean age of the patients was 63.0 +/- 15.3 years, and 76.5% of them were male. Ischemic cardiomyopathy was the leading cause for the ICD implantations (39.1%). During the mean follow-up duration of 36.8 +/- 29.8 months, there were 48 patients (20.2%) who died. Patients with structural heart diseases had a higher mortality rate than those without such diseases. Additionally, old age, low left ventricular ejection fraction (LVEF) and a history of diabetes mellitus (DM) were significant predictors of mortality. The optimal cutoff values for age (70 years) and LVEF (40%) in predicting mortality were further identified using the receiver operating characteristic curves. CONCLUSIONS: Based on the ICD registry from 3 medical centers in Taiwan, the annual mortality rate was around 6.6% and was higher in those patients with structural heart diseases. We observed that old age, low LVEF and a history of DM were significant predictors of mortality. KEY WORDS: Implantable cardioverter defibrillator; Mortality; Predictor; Taiwan. PMID- 27122765 TI - Sitagliptin Modulates the Electrical and Mechanical Characteristics of Pulmonary Vein and Atrium. AB - BACKGROUND: The pulmonary veins (PVs) and atria are important foci during that period when atrial fibrillation (AF) is generated and maintained. It is well understood that hypertension and diabetes mellitus (DM) are important risk factors for AF. Dipeptidyl peptidase-IV (DPP-4) inhibitors are new agents in the fight against type 2 DM, though they have been found to have several cardiovascular effects. However, it is not clear whether DPP-4 may modulate the electrical and mechanical characteristics in hypertensive atrium or PVs. METHODS: Conventional microelectrodes were used to record the action potentials (APs) in isolated PVs, right atrium (RA), and left atrium (LA) in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with or without sitagliptin (10 mg/kg) for 4 weeks. RESULTS: WKY (n = 5), SHR (n = 7), sitagliptin-treated WKY (n = 5) and sitagliptin-treated SHR (n = 7) had similar PV or sinoatrial spontaneous beating rates. However, the sitagliptin-treated WKY had fewer sinoatrial-PV beating rate differences than WKY, SHR or sitagliptin-treated SHR. WKY and SHR had shorter 90% (APD90) of RA AP duration than sitagliptin-treated WKY or sitagliptin-treated SHR. In contrast, WKY had longer LA APD90 than sitagliptin- treated WKY, but SHR and sitagliptin-treated SHR had similar LA APD90. Sitagliptin-treated WKY or sitagliptin- treated SHR had larger (RA-LA) APD90 differences than WKY or SHR, respectively. Moreover, as compared to WKY the post rest potentiation of contraction was decreased in SHR, sitagliptin-treated WKY, and sitagliptin-treated SHR. CONCLUSIONS: Sitagliptin significantly affects the electromechanical characteristics of PVs and atria, which can be modulated by hypertension. KEY WORDS: Atrial fibrillation; Atrium; Dipeptidyl peptidase inhibitor-4; Hypertension; Pulmonary vein. PMID- 27122766 TI - Hydrogen Peroxide Modulates Electrophysiological Characteristics of Left Atrial Myocytes. AB - BACKGROUND: Oxidative stress plays an important role in the pathophysiology of atrial fibrillation (AF). The hydrogen peroxide (H2O2) mainly underlies the cellular oxidative stress and free radicals. Left atrium (LA) is the most important AF substrate. However, the effects of H2O2 on the action potential (AP) and ionic currents in LA myocytes have not been fully elucidated. METHODS: The whole-cell patch clamp was used to investigate the APs and ionic currents of L type calcium current (ICa-L), transient outward currents (Ito), ultra-rapid delayed rectifier potassium current (IKur), delayed rectifier potassium currents (IK), inward rectifier potassium current (IK1), and sodium-calcium exchanger (NCX) before and after H2O2 (100 MUM) in isolated rabbit LA myocytes. RESULTS: H2O2 (100 MUM) shortened by 50% (from 40 +/- 7 to 21 +/- 5 ms) and 90% the AP duration (from 95 +/- 12 to 74 +/- 11 ms) in LA myocytes (n = 9), but did not change the resting membrane potentials. The H2O2 (100 MUM) decreased Ito, but increased IKur and IK. H2O2 (100 MUM) also reduced the ICa-L and the reverse mode NCX. However, H2O2 (100 MUM) did not change IK1. CONCLUSIONS: H2O2 directly modulated the AP morphology and ionic currents in LA myocytes, which may contribute to the genesis of AF in oxidative stress. KEY WORDS: Action potential; Ionic current; Oxidative stress. PMID- 27122767 TI - Bipolar Disorder and Schizophrenia Present Different Risks of Atrial fibrillation: A Nationwide Population-Based Analysis. AB - BACKGROUND: Atrial fibrillation (AF) is increasingly prevalent in society, and can elevate cardiac morbidity and mortality. Psychosis and gender are known to play important roles in the genesis of AF. However, it is not clear whether gender modulates the impact of different psychoses on the occurrences of AF. METHODS: We identified patients suffering from bipolar disorder and schizophrenia, with and without AF, using the Taiwan National Health Insurance nationwide database. The identified patient population consisted of 927,915 subjects (463,050 males and 464,865 females) from 2001 to 2008, which included 2,963 (3.2 0/00) schizophrenia patients (1,650 males and 1,313 females) and 5,112 (5.5 0/00) bipolar-disorder patients (1,934 males and 3,178 females). RESULTS: The male and female bipolar-disorder patients had higher prevalences of AF than did male (16.5 0/00 vs. 2.4 0/00, p < 0.001) and female (12.9 0/00 vs. 2.3 0/00, p < 0.001) schizophrenia patients. Furthermore, male and female bipolar-disorder patients had higher AF prevalences than did males (8.5 0/00, p < 0.001) and females (7.2 0/00, p < 0.001) in the general population. Schizophrenia patients had lower AF prevalence than the general population in male, but not in female gender. Males had a higher AF prevalence than females. However, male and female bipolar disorder and schizophrenia patients had similar AF prevalences. Those patients with schizophrenia and bipolar-disorder patients with AF were older than those without AF. CONCLUSIONS: Differing risk factors for AF were identified in bipolar-disorder and schizophrenia patients. Compared to the general population, gender may have different impacts on the occurrence of AF in psychosis patients. KEY WORDS: Atrial fibrillation; Bipolar disorder; Population-based study; Schizophrenia. PMID- 27122768 TI - The Connection between Cardiac and Mental Disorder: Atrial Fibrillation in Patients with Psychiatric Disorder. PMID- 27122769 TI - Dung-Shen Downregulates the Synergistic Apoptotic Effects of Angiotensin II Plus Leu 27-IGF II on Cardiomyoblasts. AB - BACKGROUND: Insulin growth factor II (IGFII) is expressed after ischemic stress in pig hearts and after myocardial infarction in humans. However, its receptor (IGFIIR) cannot be found in normal adult hearts. Moreover, a mouse IGFII overexpression model showed a heart and kidney hypertrophy phenomenon similar to Beckwith-Wiedemann syndrome in humans. The previous studies from our lab showed that an increase in AngII in H9c2 cells causes an elevation in IGFII and IGFIIR through MEK and JNK activation, leading to a rise in intracellular Ca(2+) ions, activation of calcineurin by PLC-beta3 via Galphaq, insertion into mitochondrial membranes of BAD, and apoptosis via activation of caspases 9 and 3. Codonopsis pilosula (Dung-shen) has various uses in traditional Chinese medicine, including lowering blood pressure, and increasing red and white blood cell counts. METHODS: The purpose of our study is to investigate whether the addition of C. pilosula will attenuate the AngII plus Leu27-IGFII-induced apoptosis in H9c2 cardiomyoblast cells. RESULTS: From MTT [3-(4, 5-dimethyl-2-thiazolyl)-2, 5 diphenyl-2-tetrazolium bromide] results, it was revealed that AngII plus Leu(27) IGFII significantly reduced cell viability, which was reversed by C. pilosula. Additionally, C. pilosula also reversed apoptosis (TUNEL staining) increased by AngII plus Leu27-IGFII. Up-regulation of caspase 3 by AngII plus Leu27-IGFII was attenuated by C. pilosula treatment, as shown in western blotting assay and immunofluorescence microscopy results. CONCLUSIONS: C. pilosula is able to suppress the apoptotic pathway enhanced by AngII plus Leu27-IGFII in myocardial cells. KEY WORDS: Angiotensin II; Apoptosis; Codonopsis pilosula; Leucine27 insulin like growth factor II; Mitochondrial outer membrane permeability. PMID- 27122770 TI - Rosuvastatin Modulates the Post-Translational Acetylome in Endothelial Cells. AB - BACKGROUND: Statins are lipid-lowering drugs that can simultaneously evoke pleiotropic effects on cardioprotection, vasodilation, and diabetes prevention. Recently, statins have been reported to be able to activate the AMP-activated protein kinase, thereby up-regulating sirtuin (SIRT) that functions as non histone deacetylases. Therefore, it is essential to investigate the post translational acetylome that might explain the mechanism of statin-modulated pleiotropic effects. METHODS: Endothelial cells EAhy 926 treated with rosuvastatin were used to monitor the expression of SIRTs proteins. The protein lysates of both mock- and rosuvastatin-treated cells were further separated by two- dimensional gel electrophoresis coupled with western blotting analysis. The significantly changed acetyl- containing proteins detected by using an anti acetyl lysine antibody were collected from another preparative gel for mass spectrometric assay to identify the acetylated site in the proteins. RESULTS: Rosuvastatin treatment was shown to increase the SIRT1 expression when compared with SIRT2. Among 100 detected proteins with acetylated signal, 12 showed an increased level of acetylation, whereas 6 showed a decreased level of acetylation (deacetylation). The acetylated lysine (K) sites of 3 heat shock proteins, i.e., HSP47/K(165), HSP70/K(380), and heat shock-inducible protein/K(417), were determined. We also found that beta-filamin, elongation factor, galectin and hCG22067 have 2 acetylated lysine sites in their peptide sequences. These dynamic acetylations might alter the protein's function and are thought to be important in regulating statin-mediated pleiotropic effect. CONCLUSIONS: Our study provided a feasible methodology for detecting acetylated proteins. This acetylome information may be utilized to explain, at least partially, the mechanisms of statin-derived pleiotropic effects. KEY WORDS: Acetylation/deacetylation; Acetylome; Endothelial cell; Proteomics; Rosuvastatin; Sirtuin. PMID- 27122771 TI - Establishment of a Weight Management Scale for Patients with Congestive Heart Failure. AB - PURPOSE: The aim of this study was to develop a rating scale for the weight management of patients with congestive heart failure (CHF). METHODS: The original pool of items was created through in-depth interviews and a literature review. Scale validity was analyzed based on face validity, content validity, and structure validity. The content validity and structure validity were evaluated. The overall internal consistency reliability were assessed by using Cronbach's alpha and retest reliability test. RESULTS: A total of 190 CHF patients were enrolled but 5 refused. The original 19 items were then refined to a scale of 16 items. The final scale included four factors (weight monitoring, knowledge, confidence, and behaviours related to weight management), which accounted for 58.7% of the variance. Content validity ratio on the content validity was 0.88. The Cronbach's alpha was 0.843 and the retest reliability was 0.833. CONCLUSIONS: The Chinese CHF-related weight management scale developed has high reliability and validity. KEY WORDS: Congestive heart failure; Reliability; Scale; Validity; Weight management. PMID- 27122772 TI - A Pregnant Woman with Acute Massive Pulmonary Embolism. AB - A 30-year-old pregnant woman who suffered from massive pulmonary embolism presented in an unstable hemodynamic status. Angiojet catheter embolectomy and extracorporeal membrane oxygenation (ECMO) were performed, which caused the patient's condition to improve. Use of ECMO was continued during the weaning program, but the patient died of intracranial hemorrhage, a complication of ECMO. KEY WORDS: Angiojet; Extracorporeal membrane oxygenation (ECMO); Pregnancy; Pulmonary embolism; Thromboectomy. PMID- 27122773 TI - Cardiac Amyloidosis Presenting as Recurrent Syncope. AB - Cardiac amyloidosis is an uncommon disease that is rarely diagnosed clinically. In this study, we present a case of a 63-year-old man with recurrent syncope and elevated troponin I levels. The patient's coronary angiography showed no significant stenosis. An implantable cardioverter-defibrillator was implanted into the patient due to episodes of ventricular tachycardia. The diagnosis of cardiac amyloidosis was made by endomyocardial biopsy. The patient died of a combination of cardiogenic shock and rapid deterioration of renal function. Although cardiac amyloidosis is rarely diagnosed, it should be considered as a differential diagnosis in patients with recurrent syncope, because it is potentially treatable. KEY WORDS: Cardiac amyloidosis; Syncope; Troponin I; Ventricular tachycardia. PMID- 27122774 TI - The Influence of Acute Kidney Injury on Acute Cardiovascular Disease. AB - Acute kidney injury (AKI) is an important issue in the management of acute cardiovascular diseases. The risk, injury, failure, loss of kidney function, and end-stage renal failure (RIFLE) criteria, and acute kidney injury network (AKIN) criteria have been proposed to stage and predict the outcomes of patients with AKI. In this article, we review AKI in the context of a variety of acute cardiovascular diseases, e.g., acute myocardial infarction (AMI), myocarditis, aortic dissection, and post-cardiotomy cardiogenic shock. For earlier detection of AKI, numerous biomarkers have been proposed and Cystatin C has been shown to have predictive value for AKI in patients with AMI. KEY WORDS: Acute cardiovascular disease; Acute kidney injury. PMID- 27122776 TI - Nicotine: A Double-Edged Sword in Atherosclerotic Disease. AB - Chronic cigarette smoking is well-known to damage vascular endothelium, which initiates atherosclerosis by first manifesting as endothelial dysfunction and later progressing to cardiovascular diseases (CVD). Nicotine, a major component of tobacco smoke, is traditionally thought to be responsible for increased cardiovascular events through stimulation of the sympathetic nervous system, increased myocardial metabolic demand, impaired lipid metabolism, and activated platelet function. However, recent studies have demonstrated that nicotine, at lower doses, may be beneficial to the cardiovascular system. With binding to specific nicotinic acetylcholine receptors, nicotine can induce migration and proliferation of vascular cells, and hence enhances angiogenesis. Therefore, these seemingly inconsistent properties of nicotine may in fact give rise to novel and efficacious management strategies of CVD. KEY WORDS: Angiogenesis; Atherosclerosis; nicotinic acetylcholine receptors (nAChRs); Nicotine. PMID- 27122775 TI - Angiotensin Receptor Blockades Effect on Peripheral Muscular and Central Aortic Arterial Stiffness: A Meta-Analysis of Randomized Controlled Trials and Systematic Review. AB - BACKGROUND: Previous clinical trials have demonstrated the impact of blocking upstream renin-angiotensin-axis with angiotensin converting enzyme inhibitors (ACEIs) on arterial stiffness as evaluated by pulse-wave velocity (PWV). We ran a meta-analysis to evaluate the anti-stiffness effect of powerful downstream angiotensin receptor blockades (ARBs) on peripheral and central arterial stiffness (brachial to ankle, ba-PWV; carotid to femoral, cf-PWV, respectively), using a systematic review to assess the clinical arterial stiffness issues. METHODS: For our study, we searched the PubMed and Cochrane Library databases from inception to June 2013, targeting randomized controlled trials. ARBs along with other antihypertensive agents, ACEIs, calcium channel blockers (CCBs), beta blockers and diuretics were evaluated to ascertain their comparable effect on ba PWV and cf-PWV, respectively. A meta-analysis was conducted utilizing the fixed or random effect of the weighted mean change difference between the ARB and comparator groups, depending on the I(2) statistic heterogeneity measurement. RESULTS: In 2 trials treating patients with ARBs (n = 30), the ARBs insignificantly reduced levels of ba-PWV (pooled mean change difference -188, 95% CI -687, 311, p = 0.24 with significant heterogeneity) as compared to other hypertensive agents (ACEIs and CCBs, n = 77). Interestingly, ARBs (n = 20) had a superior capacity to reduce levels of ba-PWV than CCBs (n = 20) in single study results (mean change difference -400, 95% CI -477, -322, p < 0.05). In 7 trials which included a total of 653 patients, treatment with ARBs (n = 308) also insignificantly reduced cf-PWV (pool mean change difference -0.197, 95% CI -0.54, 0.14, p = 0.218) as compared to other anti-hypertensive agents. CONCLUSIONS: Our data suggested that ARBs had a similar effect as other anti-hypertensive agents in reducing ba-PWV and cf-PWV. Upon systematic review, the renin-angiotensin-axis system mechanism seems more significant than the direct vessel dilatation system in anti-arterial stiffness mechanism. KEY WORDS: Angiotension receptor blockage; Arterial stiffness; Meta-analysis; Systematic review. PMID- 27122777 TI - The Role of the Renin-Angiotensin System in Amyloid Metabolism of Alzheimer's Disease. AB - The etiology of Alzheimer's disease (AD) remains unclear. Epidemiologic studies suggest hypertension plays a contributing role to AD. Recently, several experimental and observational studies showed interaction between the renin angiotensin system and amyloid-beta, a key pathologic feature of AD, with diverse results. This article reviews molecular, genetic, experimental and clinical data to clarify the impact on an AD patient with angiotensin converting enzyme inhibitor and angiotensin II receptor blocker therapy, with some guidance for the direction of possible future research. KEY WORDS: Alzheimer's disease; Amyloid beta; Renin angiotensin system. PMID- 27122778 TI - Predictive Value of Elevated Uric Acid in Turkish Patients Undergoing Primary Angioplasty for ST Elevation Myocardial Infarction. AB - BACKGROUND: Uric acid (UA) is an independent risk factor for the development of coronary heart disease. Serum UA levels have been correlated with all major forms of death from cardiovascular disease, including acute, subacute, and chronic forms of coronary artery disease (CAD), heart failure, and stroke. However, its value in acute ST-segment elevation myocardial infarction (STEMI) remains unclear. The aim of this study was to evaluate the prognostic value of UA in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). METHODS: We prospectively enrolled 434 consecutive Turkish STEMI patients (mean age 55.4 +/- 12.4 years, 341 male, 93 female) undergoing primary PCI. The study population was divided into tertiles based on admission UA values. The high UA group (n = 143) was defined as a value in the third tertile (> 5.7 mg/dl), and the low UA group (n = 291) included those patients with a value in the lower two tertiles (<= 5.7 mg/dl). Clinical characteristics, in-hospital and six-month outcomes of primary PCI were analyzed. RESULTS: Compared to the low UA group, only Killip class > 1 at admission was more prevalent in the high UA group (3.4% vs. 17.5%, p < 0.001, respectively). Higher in-hospital cardiovascular mortality and six-month all-cause mortality rates were observed in the high UA group than in the lower group (12.6% vs. 1.7%, respectively, p < 0.001) and (19.6% vs. 4.1%, respectively, p < 0.001). In Cox multivariate analysis; a high admission UA value (> 5.7 mg/dl) was found to be a powerful independent predictor of six-month all cause mortality (hazard ratio: 5.57, 95% confidence interval: 1.903-16.3, p = 0.002). CONCLUSIONS: These results suggest that a high level of UA on admission was associated with increased in-hospital cardiovascular mortality, and six-month all-cause mortality in Turkish patients with STEMI undergoing primary PCI. KEY WORDS: Primary angioplasty; ST elevation myocardial infarction; Uric acid. PMID- 27122779 TI - Endovascular Declotting of Wall-Adherent Thrombi in Hemodialysis Vascular Access. AB - BACKGROUND: To investigate the efficacy, safety, and patency following treatment of wall-adherent thrombus in hemodialysis vascular access with a wall-contact device, the Arrow-Trerotola percutaneous thrombolytic device (PTD). METHODS: We retrospectively reviewed an existing database of procedures fulfilling the following criteria: thrombosed hemodialysis access, wall-adherent thrombus, and use of PTD for mechanical thrombectomy. Data on immediate success, complications, and patency were collected from medical records, dialysis records, and angiographic reports. RESULTS: Ninety-three patients with 108 episodes of vascular access thrombosis were included in the study. Fifty-three of the procedures were performed on native fistulas, and 55 were on synthetic grafts. Anatomical and clinical success was achieved in 97% and 96% of the procedures, respectively. The average procedure time was 52 +/- 23 minutes. Complications occurred in three of the procedures (2.7%), but none of these complications were device-related. The primary patency rates in the native fistula group were 57% and 42% at three and six months, respectively. The primary patency rates in the synthetic graft group were 40% at three months, and 27% at six months. The secondary patency rates at six months were 91% in the native fistula group, and 93% in the synthetic graft group. CONCLUSIONS: Our results show that a wall contact mechanical device, PTD, is effective and safe for endovascular removal of wall-adherent thrombi in hemodialysis vascular access in both native fistulas and synthetic grafts. KEY WORDS: Adherent; Angioplasty; Endovascular; Hemodialysis; Thrombectomy; Vascular access. PMID- 27122780 TI - Myocardial Tissue Doppler Imaging Detects Right Ventricular Dysfunction after Percutaneous Angioplasty of Dysfunctional Hemodialysis Access in Uremic Patients. AB - BACKGROUND: Right ventricular dysfunction has been observed in uremic patients receiving percutaneous transluminal angioplasty (PTA). This prospective study focuses on the impact of tissue Doppler imaging echocardiographic parameters on assessing right ventricle function in uremic patients post PTA of dysfunctional hemodialysis access. METHODS: Sixty uremic patients were divided into two groups by angiographic findings: an occlusive group (26 patients) and a stenotic group (34 patients). All uremic patients underwent routine echocardiography with tissue Doppler imaging both before and immediately following PTA to assess the right ventricular (RV) function and pulmonary artery systolic pressure (PASP). The right ventricular (RV) myocardial performance index (MPI) was obtained during tissue Doppler imaging over the lateral tricuspid annulus. The M index was measured and defined as the peak early diastolic mitral inflow velocity divided by the RV MPI. The RV MPI, RV isovolumic relaxation time (IVRT) and M-index were used to evaluate RV function post-PTA. RESULTS: Immediately following PTA, PASP (31.6 +/- 11.3 mmHg versus 42.6 +/- 12.0 mmHg, p = 0.001), RV MPI (0.46 +/- 0.08 versus 0.62 +/- 0.13, p < 0.001) and IVRT (75.1 +/- 12.9 versus 98.4 +/- 27.7 ms, p < 0.001) increased significantly in the occlusive group. However, PASP and RV function did not change significantly in the stenotic group. In 42.3% patients from the occlusive group, the M-index fell below 112 and RV MPI rose above 0.55 post-PTA; this occurred in only 8.8% of the stenotic group. CONCLUSIONS: This prospective study demonstrated that there was a higher incidence of RV dysfunction in uremic patients with elevated PASP with totally occluded hemodialysis access than those with stenotic access post-PTA. KEY WORDS: Myocardial performance index; Percutaneous transluminal angioplasty; Pulmonary hypertension; Tissue Doppler image; Uremic. PMID- 27122781 TI - Effect of Vitamin D3 on Monocyte Chemoattractant Protein 1 Production in Monocytes and Macrophages. AB - BACKGROUND: Chemokine is important in the initiation and progression of atherosclerosis, the clinically manifest stages of atherosclerosis and acute coronary syndrome. Vitamin D deficiency has been reportedly linked with hypertension and myocardial infarction, as well as other cardiovascular-related diseases, such as congestive heart failure, peripheral vascular disease and atherosclerosis. Monocyte chemoattractant protein 1 (MCP-1) mediates atherosclerosis and other cardiovascular diseases. However, there have been few studies conducted about the role of 1alpha,25-(OH)2D3 on MCP-1 expression in human monocytes. METHODS: We investigated the effects of vitamin A, C and 1alpha,25-(OH)2D3, three common vitamins, to better ascertain MCP-1 expression in human monocyte and also the associated intracellular mechanism. Human monocyte cell line (THP-1 cell) and THP-1 cell-induced macrophage were treated with varying doses of vitamin A, C and 1alpha,25-(OH)2D3 for 2 hours before LPS stimulation. Supernatants were harvested to measure MCP-1 levels by the enzyme linked immunosorbent assay (ELISA). The intracellular mechanism about the effects of vitamin A, C and 1alpha,25-(OH)2D3 on the expression of MCP-1 expression in human monocytes was assessed by western blot. RESULTS: We found that Lipopolysaccharides (LPS)-induced MCP-1 production was suppressed by 1alpha,25 (OH)2D3 in THP-1 cells and THP-1-induced macrophage. Only high concentration of vitamin A and C could reduce LPS-induced MCP-1 production in THP-1-induced macrophage, but not in THP-1 cells. LPS-induced p38 expression in THP-1 cells was suppressed by 1alpha,25-(OH)2D3. A selective p38 pathway inhibitor SB203580 could also suppress LPS-induced MCP-1 production. However, vitamin D receptor blocking antibody could reverse the suppressive effect of 1alpha,25-(OH)2D3 on MCP-1 expression. CONCLUSIONS: These data demonstrate that 1alpha,25-(OH)2D3 is effective in down-regulating LPS-induced MCP-1. The suppressive effect on MCP-1 may, at least in part, involve the vitamin D receptor and down-regulation of LPS induced p38 expression. KEY WORDS: Chemokine; Monocyte chemoattractant protein 1 (MCP-1); Monocyte; p38; Vitamin D. PMID- 27122782 TI - Clinical Characteristics and In-Hospital Prognosis of Infective Endocarditis in Two Eastern Counties of Taiwan. AB - BACKGROUND: Infective endocarditis (IE) is a common and potentially serious disease. Although it is an illness that affects populations around the world, narrower descriptions of this disease as it impacts specific regions are uncommon. We analyzed the clinical characteristics of IE patients from two eastern counties in Taiwan and studied the relationship between the isolated pathogens and clinical outcomes in these patients. METHODS: This is a retrospective chart review study which enrolled patients who received services between January 2007 and December 2010. Subsequent to chart review, IE was confirmed in a total of 55 patients by the modified Duke criteria. RESULTS: Of these patients, 17 (31%) had previous traumatic open skin wounds. Pre-existing cardiac abnormalities were found in 47 (85%) patients, 28 of whom had valvular abnormalities. Staphylococcus aureus was isolated from the blood as the leading pathogen in 25 (45%) patients (including 23 methicillin-sensitive and 2 methicillin-resistant). Septic emboli and shock occurred in 27 (49%) of 55 patients; surgery was performed on 11 (20%) of those patients, and 4 (36%) of them died post-operatively. The total in-hospital mortality rate was 40% (n = 22). Staphylococcus aureus infection was associated with significantly higher complication and mortality rate than non-Staphylococcus aureus infection (59% vs. 41% and 64% vs. 36%, respectively; p < 0.05). In addition, patients with complications had a very high mortality rate (81.5%). CONCLUSIONS: We found that Staphylococcus aureus was the most common pathogen of IE in Eastern Taiwan, and was associated with higher rates of morbidities and mortality. KEY WORDS: Infective endocarditis; Septic shock; Staphylococcus aureus; Systemic embolization. PMID- 27122784 TI - Endovascular Angioplasty of Celiac Axis Obstruction Prior to Pancreaticoduodenectomy in a Patient with Pancreatic Neuroendocrine Carcinoma. AB - In patients with celiac axis stenosis or occlusion, a pancreaticoduodenectomy procedure can increase the risk of hepato-pancreato-biliary and other organ ischemia or failure unless a complete revascularization of the celiac axis is performed prior to or simultaneous with such surgery. Celiac axis occlusion does not appear to be an uncommon finding in cases of pancreaticoduodenectomy. Preoperative abdominal angiography can play an important role in diagnosing this high risk comorbid disease, and adequate intervention can lead to a successful operation and good postoperative outcome. Herein, we reported a patient with periampullary malignancy and metastatic liver cancer, whose preoperative diagnosis of severe celiac axis stenosis was proved by preoperative abdominal angiography. Preoperative angioplasty was subsequently performed. After angioplasty, pancreaticoduodenectomy with resection of segments 4, 6 and 7 of liver was done and the postoperative course was uneventful. KEY WORDS: Celiac axis occlusion; Endovascular angioplasty; Pancreaticoduodenectomy. PMID- 27122783 TI - Abnormal Changes of a 12-Lead Electrocardiogram in Male Patients with Left Primary Spontaneous Pneumothorax. AB - BACKGROUND: Typical electrocardiographic (ECG) changes associated with left primary spontaneous pneumothorax (PSP) have previously been well-described. However, there were no reports in the literature about the characteristic of ECG in estimating the severity of pneumothorax. METHODS: From 2003 through 2008, 63 male patients who had left PSP were divided into two groups: 1) large PSP, Light index >= 20% (n = 43), and 2) small PSP, Light index < 20% (n = 20). The ECGs of 64 age-matched disease-free men were used as the normal control. Those medical records reviewed that provided data for this study included patient backgrounds, severity of PSP, and 12-lead ECG characteristics. RESULTS: As compared to the normal controls, left PSP patients had lower body mass index, more rapid heart beat rate and lower voltages in V3R-V6R. In analyzing QRS voltages, the amplitudes of V2S and V3S were significantly different. As with both V2S < 12 mm and V3S < 9 mm, the sensitivity, specificity and positive predictive value to predict patients who had large left PSP area were estimated at 42% (18/43), 100% (20/20) and 100% (18/18), respectively. CONCLUSIONS: Using the criteria of V2S < 12 mm, V3S < 9 mm and electrical alternans could predict pneumothorax size exceeding 20% in patients who already had left PSP. KEY WORDS: 12-lead electrocardiogram; Male; Primary spontaneous pneumothorax. PMID- 27122785 TI - Surgical Treatment of Castleman Disease Using Cardiopulmonary Bypass. AB - Castleman disease is a rare benign lymphoproliferative disorder of unknown etiology. A 29-year-old woman presented with intermittent chest pain for 2 years. Upon examination, computed tomography showed an intensely enhanced solid mass that encased her right pulmonary artery. The tumor was resected safely and completely via standard thoracotomy with cardiopulmonary bypass. KEY WORDS: Castleman disease; Middle mediastinal tumor; Surgery. PMID- 27122786 TI - Myocardial Infarction with Normal Coronary Arteries in a Patient with Heroin Use and Infective Endocarditis. AB - Myocardial infarction with normal coronary arteries typically occurs in patients under 50 years of age. There is usually no history of angina or previous myocardial infarction, and risk factors for ischemic heart disease are frequently absent. We report a 27-year-old heroin user with normal coronary arteries and inferior wall infarction secondary to infective endocarditis. The left ventricular dysfunction normalized after antibiotic and surgical treatments for infective endocarditis. He was followed at our outpatient clinic for one year without recurrence. KEY WORDS: Heroin; Infective endocarditis; Left ventricular ballooning syndrome; Myocardial infarction with normal coronary arteries. PMID- 27122787 TI - Comparison between Exclusive and Selective Drug-Eluting Stent Strategies in Treating Patients with Multivessel Coronary Artery Disease. AB - BACKGROUND: The expanded usage of drug-eluting stents (DES) in treating patients with multivessel coronary artery disease (CAD) may sometimes be limited in real world practice due to cost concerns. We compared the clinical outcomes of exclusive and selective DES use in treating patients with multivessel CAD. METHODS: From November 2004 to December 2011, 110 patients with multivessel CAD who received four or more stents were enrolled into this study, and divided into two groups according to the DES strategy employed: exclusive DES (n = 52), or selective DES (n = 58). In the selective DES group, DES was reserved for complex lesions only, such that the incidence and predictors of clinical events were assessed. RESULTS: At a mean follow-up of 41.4 +/- 26.5 months, there were no significant differences between the two strategies in terms of baseline characteristics, all-cause mortality (exclusive vs. selective: 1.9% vs. 6.9%, p = 0.21), cardiac death (1.9% vs. 1.7%, p = 0.94) and nonfatal myocardial infarction (3.8% vs. 5.2%, p = 0.74). Despite the presence of more ostial lesions in the exclusive DES group, there was a trend such that major adverse cardiac events (MACE) and target lesion revascularization (TLR) rates were higher in the selective DES group (MACE: 17.3% vs. 31%, p = 0.16; TLR: 11.5% vs. 24.1%, p = 0.08). The higher MACE rate in the selective DES group was mainly driven by a higher target vessel revascularization (TVR) rate (15.4% vs. 29.3%, p = 0.08). In the exclusive DES group, SYNTAX score was an independent predictor of MACE [Haxard ratio (HR): 1.09, 95% confidence internal (CI): 1.02-1.16, p = 0.01] and TVR (HR 1.08, 95% CI 1.01-1.15, p = 0.04). CONCLUSIONS: Compared to the exclusive DES strategy, the selective DES strategy with reservation of DES for complex lesions is associated with numerically higher, but not statistically significant, rates of MACE and all-cause mortality in this small group of patients with multivessel CAD receiving four or more stents. KEY WORDS: Bare metal stent; Drug eluting stent; Multivessel coronary artery disease. PMID- 27122788 TI - The Effect of Slow Coronary Artery Flow on Microvolt T-Wave Alternans. AB - BACKGROUND: Slow coronary artery flow (SCF) is characterized by angiographically confirmed delayed vessel opacification in the absence of any evidence of obstructive epicardial coronary artery disease. Microvolt T-wave alternans (MTWA) is defined as beat-to-beat changes in shape, amplitude, or timing of ST segments and T waves, and is utilized in predicting sudden cardiac death and life threatening malign ventricular arrhythmias in high-risk patients. In our study, we aimed to evaluate the effects of slow coronary artery flow on MTWA. METHODS: Thirty-nine consecutive patients (SCF group: 6 women and 33 men; mean age, 49 +/- 10 years) with angiographally documented SCF in at least 1 major epicardial artery and 39 patients (control group: 13 women and 26 men; mean age, 50 +/- 10 years) with normal coronary arteries were included in the study. Coronary flow rates of all patients were calculated by thrombolysis in myocardial infarction frame count (TFC). The MTWAs of all patients were analyzed using the time-domain modified moving average method by means of a treadmill exercise stress test. RESULTS: The age distribution , body mass index, and diastolic and systolic blood pressure (BP) were similar in the SCF and control group. In the SCF group, the three epicardial coronary artery corrected TFCs and mean TFCs were significantly higher than in the control group (for all, p < 0.001). MTWA positivity in the SCF group was statistically significant compared to the control group (p = 0.006). Spearman's correlation analysis, showed a positive correlation between MTWA and right coronary artery (RCA) TFC and mean TFC (r = 0.368, p = 0.001 and r = 0.271, p = 0.016, respectively). In linear regression analysis, only the right coronary artery TFC was correlated with positive MTWA (p = 0.001). CONCLUSIONS: The results of our study suggest that diagnosed SCF is associated with MTWA positivity. Furthermore, we determined that only RCA TFC was predictive of positive MTWA. KEY WORDS: Microvolt T-wave alternans; Slow coronary flow. PMID- 27122789 TI - Coronary Slow Flow is Associated with Depression and Anxiety. AB - BACKGROUND: There is an established relationship between depression/anxiety disorders and cardiovascular morbidity and mortality which has been previously documented. However, there has been no study evaluating coronary slow flow in association with depression and anxiety. METHODS AND RESULTS: A total of consecutive 90 patients were included in the study. All patients completed scoring scales for depression [Hamilton Rating Scale for Depression (HAMD)] and anxiety (STAI-1, State anxiety subscale of State-Trait Anxiety Inventory; STAI-2, Trait anxiety subscale of State-Trait Anxiety Inventory). Thereafter, they underwent selective coronary angiography and 2 groups were formed: coronary slow flow (n = 42), and normal coronary flow (n = 48). The two groups had comparable baseline characteristics. However, significant differences were found between coronary slow flow and normal coronary flow groups regarding depression (13.1 +/- 8.2 and 6.9 +/- 6.7, p < 0.001 for HAMD, respectively) and anxiety (46.2 +/- 15.0 vs. 32.6 +/- 9.9, p < 0.001 for STAI-1 and 51.0 +/- 16.7 vs. 43.0 +/- 10.7, p = 0.009 for STAI-2, respectively) scores. There were also significant positive correlations between depression/anxiety scores and TIMI frame counts of all major epicardial coronary arteries. In addition, after adjustment for smoking, hypertension, scoring scales, and the presence of depressive mood, all scoring scales and depressive mood were found to be independent risk factors for coronary slow flow in multivariable logistic regression analysis. CONCLUSIONS: Significant association was found among coronary slow flow, depression/anxiety scores and depressive mood. KEY WORDS: Anxiety; Coronary slow flow; Depression; Scale. PMID- 27122790 TI - Leptin-to-Adiponectin Ratio is Related to Low Grade Inflammation and Insulin Resistance Independent of Obesity in Non-Diabetic Taiwanese: A Cross-Sectional Cohort Study. AB - BACKGROUND: Leptin and adiponectin are secreted from adipose tissue and exert opposing effects on C-reactive protein (CRP) levels and insulin resistance. As hypertrophic adipocytes secrete more leptin and less adiponectin, the leptin-to adiponectin ratio (LAR) has been proposed as a useful measure of insulin resistance and vascular risk. We investigated whether LAR may serve as a better predictor than either leptin or adiponectin alone for low-grade inflammation and insulin resistance independent of obesity in a non-diabetic Taiwanese population. METHODS: This study included 568 non-diabetic Taiwanese individuals (297 men, 271 women). CRP, leptin and adiponectin were measured using enzyme-linked immunosorbent assay. The degree of insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: In the receiver operator characteristic analysis, the area under the curve of LAR in predicting individuals with elevated CRP and insulin resistance was significantly greater than that for either leptin (p = 0.0035 vs. elevated CRP, p < 0.0001 vs. insulin resistance) or adiponectin alone (p = 0.0131 vs. elevated CRP, p = 0.0006 vs. insulin resistance), suggesting that LAR might be a better predictor of individuals with low grade inflammation and insulin resistance. In the multivariable analysis adjusted for age, gender, smoking status, and components of metabolic syndrome, LAR was still strongly associated with levels of CRP (p < 0.001, all participants; p = 0.002, nonobese individuals; p < 0.001, obese individuals) and HOMA-IR index (p < 0.001, all participants, obese and nonobese individuals). CONCLUSIONS: The LAR is related to low grade inflammation and insulin resistance independent of obesity in non-diabetic Taiwanese, and the strength of associations between LAR with CRP and HOMA-IR are greater than the association with leptin or adiponectin alone. KEY WORDS: Adiponectin; C-reactive protein; Insulin resistance; Leptin; Obesity. PMID- 27122792 TI - Association between Plasma Fibrinogen Level and Saphenous Vein Graft Patency. AB - BACKGROUND: Fibrinogen is related to the pathogenesis of atherosclerosis. The inflammatory process in atherosclerosis may cause an increase in plasma fibrinogen level. Therefore, in this study we proposed to investigate whether plasma fibrinogen is associated with the patency of saphenous vein graft in patients at least 1 year after coronary artery bypass graft (CABG) surgery. METHODS: Patients who had undergone CABG surgery at least 1 year previously with at least one saphenous vein graft were included in the study. Patients were directed to cardiac catheterization for stable anginal symptoms or positive stress test results. Before coronary angiography, all patients underwent routine blood tests including assessment of plasma fibrinogen levels. RESULTS: Saphenous vein grafts were found to be patent in 199 patients and occluded in 132 patients. Plasma fibrinogen levels were significantly different between the two groups (2.85 +/- 0.49 g/L vs. 3.62 +/- 0.82 g/L, p < 0.001, respectively). Although the time duration after CABG operation differs significantly between the two groups (p = 0.004), multiple logistic regression analysis showed that plasma fibrinogen levels were found to be significantly associated with the patency of vein graft (odds ratio = 0.27, 95% confidence internal: 0.16-0.48, p < 0.001). CONCLUSIONS: Our results demonstrated that plasma fibrinogen levels were higher in patients with an occluded saphenous vein graft. To conclusively prove the relationship between plasma fibrinogen values and saphenous vein graft patency, additional investigation would be necessary. KEY WORDS: Atherosclerosis; Coronary artery bypass graft; Fibrinogen; Saphenous vein. PMID- 27122791 TI - Activation of Kruppel-Like Factor 2 with Ginkgo Biloba Extract Induces eNOS Expression and Increases NO Production in Cultured Human Umbilical Endothelial Cells. AB - BACKGROUND: The mechanisms responsible for the effects of Ginkgo biloba extract (GbE) are not fully understood. Kruppel-like factor 2 (KLF2), a zinc transcription factor, has vasculoprotective effects if activated. The present study attempted to explore whether GbE may activate KLF2 and its consequences. METHODS: To determine the effects of GbE on endothelial cells, human umbilical vein endothelial cells (HUVECs) were incubated with various concentrations of GbE. KLF2 expression levels were determined by quantitative reverse transcription polymerase chain reaction. Cytoskeleton staining and cell migration assays were performed to determine the effects of KLF2 activation. Moreover, endothelial NO synthase (eNOS) expression levels were detected by PCR and Western blot testing. Nitric oxide (NO) production was also measured with 4,5-diaminofluorescein. A knockdown of KLF2 was performed to identify the role of KLF2 in GbE-induced eNOS expression and NO production. RESULTS: HUVECs that were incubated with GbE increased KLF2 expression. These cells demonstrated an altered cell morphology, cytoskeleton rearrangement, and inhibited migration activity. Moreover, eNOS expression and NO production increased in a dose-dependent manner when cells were treated with GbE. Correspondingly, silencing of KLF2 in HUVECs decreased eNOS expression and NO production in GbE-treated cells. CONCLUSIONS: GbE significantly activated KLF2 expression and KLF2-related endothelial function, including cytoskeleton rearrangement, inhibition of migration, eNOS activation, and NO production. These findings suggest that GbE may induce a vasculoprotective effect in endothelial cells. KEY WORDS: Endothelial cells; eNOS; Ginkgo biloba extract; KLF2; NO. PMID- 27122793 TI - Long-Term Survival of Multicenter Automatic Defibrillator Implantation Trial (MADIT) II-Eligible Patients in Taiwan. AB - BACKGROUND: he Multicenter Automatic Defibrillator Implantation Trial (MADIT) II showed that use of a prophylactic implantable cardioverter defibrillator (ICD) improved the survival of patients with poor left ventricular ejection fraction after myocardial infarction. The major concerns about primary ICD prevention in Asian countries are the long-term survival and the incidence of sudden cardiac death. Whether long-term outcomes within the Taiwanese population are comparable to the MADIT II trial remains unclear. METHODS: We retrospectively reviewed the clinical records of 1909 inpatients who had both myocardial infarction and heart failure in the discharge diagnoses from Jan. 2001 through Dec. 2006, and 313 patients without ICD implantation who satisfied the MADIT II criteria were included for survival analysis. RESULTS: After 4.60 +/- 4.31 years of follow-up, 152 (49%) patients had died. Of these patients, 68 (45%) died of sudden cardiac death, similar to the conventional group (patients without ICD implantation) in the MADIT II study (51%). The Kaplan-Meier curve showed that survival during the first two years in this cohort was inferior to the conventional group of the MADIT II population. After two years, the survival curve was similar to the conventional group but still inferior to the defibrillator group in the MADIT II study. Multivariate Cox regression analysis showed old age and blood urea nitrogen > 25 mg/dL were independent predictors of mortality. A history of percutaneous coronary intervention was associated with lower mortality. CONCLUSIONS: The long-term outcomes of Taiwanese patients who are eligible within MADIT II criteria are similar to the conventional group in the MADIT II study. KEY WORDS: Heart failure; Implantable cardioverter defibrillator; Myocardial infarction; Sudden cardiac death. PMID- 27122794 TI - Improvement of Right Ventricular Function in Pulmonary Arterial Hypertension with Disease-Specific Therapy - A Clinical Observational Study. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a serious and progressive disorder that can result in right ventricular (RV) dysfunction and mortality. Consequently, it is important to monitor RV function during management of PAH. The aim of this study was to investigate the change in RV function by echocardiography before and after disease-specific therapy. METHODS: We recruited 31 PAH patients with functional class (FC) III or IV. All the patients received a comprehensive assessment before disease-specific therapy was administered, including observation of clinical symptoms, 6-min walk distance (6MWD), serum brain natriuretic peptide (BNP) level, and transthoracic echocardiography. The assessment was repeated 12 weeks after therapy. RESULTS: Twenty-eight patients with a mean age of 40 years completed the study, of whom 82% were women. We found that the etiologies were mainly connective tissue disease-associated and idiopathic PAH. Of the patients in our study, 36% received endothelin receptor antagonist and 64% received phosphodiesterase-5 inhibitor. There was a significant improvement in FC after disease-specific therapy (p < 0.001). The 6MWD increased from 326 to 403 m (p < 0.001), and the serum BNP level decreased from 242 to 130 pg/mL (p = 0.008) after treatment. Echocardiography showed significant reduction in the right atrial and RV areas, pulmonary artery pressure, RV free wall thickness, and inferior vena cava diameter. The myocardial performance index and left ventricular eccentricity index were significantly reduced after therapy. CONCLUSIONS: For PAH patients in our study, disease specific therapy for 12 weeks resulted in an improvement in FC, 6MWD, serum BNP levels, and RV function. KEY WORDS: Disease-specific therapy; Pulmonary arterial hypertension; Right ventricular function. PMID- 27122795 TI - Inoue-Balloon Percutaneous Transvenous Mitral Valvuloplasty through the Left Femoral Vein in Anomalous Inferior Vena Cava. AB - Inoue-balloon percutaneous transvenous mitral valvuloplasty is conventionally performed via the right femoral vein. However, atrial transseptal access can be technically challenging. Herein, we describe a 54-year-old male who had balloon mitral valvuloplasty performed via the left femoral vein because of an anomalous inferior vena cava course, including the technical issues encountered using this approach. KEY WORDS: Anomalous inferior vena cava; Left femoral vein approach; Mitral valvuloplasty. PMID- 27122796 TI - Type A Aortic Dissection Presenting with Inferior ST-Elevation Myocardial Infarction. AB - Type A aortic dissection with concurrent ST-elevation myocardial infarction (STEMI) is relatively rare. However, it can be potentially fatal and easily misdiagnosed as STEMI alone. Misdiagnosis will lead to inappropriate administration of anticoagulant and thrombolytic therapy and delayed surgical repair of the aorta. In patients with STEMI, short reperfusion time is associated with improved survival, and minimizing the door-to-balloon time is the goal of therapy worldwide. However, signs critical for differential diagnosis may be overlooked in the rush to primary percutaneous coronary intervention. When a patient is encountered who presents with chest pain and ST elevation on electrocardiogram, STEMI should not be the only diagnosis considered. By using bedside available information, detailed history taking and focused physical examination, it is possible to avoid a mistaken diagnosis. Here we report a case of Stanford type A aortic dissection with STEMI that was initially misdiagnosed as sole acute inferior wall myocardial infarction. Patient mortality may have resulted from delayed diagnosis and surgical treatment. KEY WORDS: Acute myocardial infarction; Aortic dissection. PMID- 27122797 TI - Syncope Due to Impending Cardiac Tamponade in Hashimoto's Thyroiditis. AB - Pericardial effusion develops in 25 to 35% of patients with severe hypothyroidism. These effusions can be large, but rarely if ever cause tamponade. We report here a 36-year-old woman who presented with recurrent syncopal attack, which turned out to be a case of Hashimoto's thyroiditis complicated by massive pericardial effusion with impending tamponade. KEY WORDS: Cardiac tamponade; Hashimoto's thyroiditis; Syncope. PMID- 27122798 TI - Heart Rate Acceleration and Recovery Indices are Not Related to the Development of Ventricular Premature Beats During Exercise Test. AB - BACKGROUND: Changes in heart rate (HR) during exercise and recovery from exercise are mediated by the balance between sympathetic and vagal activity. HR acceleration (HRA) and recovery (HRR) are important measures of cardiac autonomic dysfunction and directly correlated with sympathetic and parasympathetic activity. It is not known if the autonomic nervous system related to ventricular arrhythmias during exercise. The purpose was to evaluate the HRA and HRR in patients with and without premature ventricular complex (PVC) during exercise, and to examine the factors that might affect HRA and HRR. METHODS: The records of consecutive patients undergoing routine exercise test were reviewed. The characteristics and the HRA and HRR were compared between patients with and without PVC during exercise. RESULTS: A total of 232 patients (145 men) were recruited; 156 (103 men) developed PVCs during the exercise. Max HR was significantly lower in men with PVCs than in those without, which were not mirrored in women. There was no difference in HRA and HRR between the patients with and without exercise-induced PVCs in both genders. Compared to the men with PVCs, women had higher body mass index, shorter total exercise time, and higher HRA indices after the 3 and 6 minutes exercise. In patients with PVCs, the HRA and HRR indices were similar regardless of the presence of coronary artery disease and the phase of exercise test where PVC developed. CONCLUSIONS: Although exercise performance may be different between the genders, the HRA or HRR indices were not related to the development of PVC during exercise in both genders. KEY WORDS: Exercise-induced arrhythmias; Heart rate acceleration; Heart rate recovery. PMID- 27122799 TI - Coronary Diameters in Taiwanese Children Younger than 6 Years Old: Z-Score Regression Equations Derived from Body Surface Area. AB - BACKGROUND: The measurements of coronary diameters, usually obtained by 2 dimentsional echocardiography, play important roles oin the management and follow up of Kawasaki disease (KD). However, in Taiwan, domestic normgrams and a Z-score calculator for coronary artery diameters are still not available. METHODS: Echocardiography was performed on 412 healthy children younger than 6 years of age. The appropriate exponential regression model was fitted to correspond with body surface area (BSA). The computed Z-scores of all subjects were also tested for normal distribution. RESULTS: Using the model ln (measurement) = beta1 + beta2 * ln (BSA), the adjusted R(2) values were 0.611 and 0.484 for the models of the left main coronary artery (LMCA) and the right (RCA), respectively. Analysis of computed Z-score distribution showed acceptable goodness of fit for a normal distribution [p = 0.90 (LMCA); p = 0.17 (RCA)]. CONCLUSIONS: We have established reference ranges for the coronary artery diameters in Taiwanese children younger than 6 years of age. The regression equations and Z-score calculators for the LMCA and RCA provide an objective determination of coronary dilatation in a large population, which is important for the care and medical management of KD patients in Taiwan. KEY WORDS: Coronary diameter; Kawasaki disease; Taiwan; Z-score. PMID- 27122800 TI - Gender and Age Differences in Short- and Long-Term Outcomes Following Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction. AB - BACKGROUND: Studies have reported that women with ST elevation myocardial infarction (STEMI) have worse short- and long-term outcomes than men. It has not yet been confirmed whether these differences reflect differences in age between men and women. METHODS: We retrospectively enrolled 1035 consecutive STEMI patients treated with primary percutaneous coronary intervention (PCI). Baseline clinical characteristics, coronary anatomy, and outcome were compared between young (< 65 years old) and older patients (>= 65 years old) of both sexes. RESULTS: Younger women presented with a lower incidence of typical angina (83% vs. 93%, p = 0.03), single-vessel disease (21% vs. 35%, p = 0.03), and total occlusion of infarct-related artery (65% vs. 83%, p = 0.001) than younger men, with no gender difference noted in the older group. Younger women in the study had a higher incidence of reinfarction, heart failure requiring admission, or mortality (23% vs. 6%, p < 0.001) during follow-up, compared with younger men, with no gender difference in the older group. Using the Kaplan-Meier analysis, younger women had lower rates of event-free survival (p < 0.001 by log-rank test) than younger men, with no gender difference in the older group. In multivariate analysis, age could predict long-term outcome in men (Hazard ratio 4.43, 95% confidence interval: 2.89-6.78, p < 0.001) but not in women. CONCLUSIONS: In STEMI patients receiving primary PCI, sex-related long-term outcome differences were age-dependent, with younger women likely to have a worse long-term outcome when compared with younger men. KEY WORDS: Coronary heart disease; Gender; Myocardial infarction. PMID- 27122801 TI - Thrombolysis Followed by Early Percutaneous Coronary Intervention via Transradial Artery Approach in Patients with ST-Segment Elevation Infarction. AB - BACKGROUND: The purpose of this study was to investigate the safety and efficacy of thrombolysis followed by early percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 161 patients were enrolled in the study. Fifty-three of them who underwent thrombolysis in non-PCI hospital and immediately transferred to receive early PCI were assigned to the early PCI group (E-PCI); the rest of the patients were assigned to the primary PCI group (P-PCI). Coronary angiography and PCI were performed via the transradial artery approach for patients in both groups. Angiographic parameters, bleeding complications and total hospital stay were compared between the two groups. All patients were followed-up for 30 days to evaluate major adverse cardiac events (MACE). RESULTS: Before PCI procedure, the thrombus score of IRA in the E-PCI group was lower, and the percentage of TIMI flow grade (TFG) 3 was higher (both p < 0.05) compared to those in the P-PCI group. The myocardial reperfusion in the E-PCI group was better than that in the P-PCI group. There was a trend towards a lower peak value of serum creatine kinase MB in the E-PCI group, and left ventricular ejection fraction (LVEF) before discharge in E-PCI was higher than that in the P-PCI group (54.38 +/- 5.29% vs. 52.19 +/- 7.00%, respectively, p = 0.028). No significant differences were found in the incidences of bleeding complications and hospital stay between the two groups. There was no significant difference in the 30-day MACE between the two groups (p = 0.863), and no significance of cumulative MACE-free survival rates were found between the two groups as well (p = 0.522). Variables predicting MACE upon patient follow-up according to univariable Cox regression analyses showed that a history of hyperlipidemia, smokers, TFG of infarction related artery before PCI < 2, and low levels of LVEF were associated with poor clinical outcomes (all p < 0.05). CONCLUSIONS: It is safe and efficacious for STEMI patients to receive thrombolysis followed by early PCI via the transradial artery approach. KEY WORDS: Major adverse cardiac event; Percutaneous coronary intervention; Radial artery; ST-segment elevation myocardial infarction; Thrombolysis. PMID- 27122802 TI - Facilitated Percutaneous Coronary Intervention in STEMI Patients: Does It Work in Asian Patients? PMID- 27122803 TI - A Pharmacokinetic and Pharmacodynamic Study of Intravenous Levosimendan in Healthy Chinese Volunteers and Ethnic Comparisons. AB - BACKGROUND: The objective of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous levosimendan and the metabolites (OR1855 and OR1896) in healthy Chinese male subjects and to post hoc compare with Caucasian subjects. METHODS: One single 2 mg dose of levosimendan was infused intravenously over 10 minutes to each of 14 healthy male subjects. Plasma levosimendan was analyzed by high performance liquid chromatography. Pharmacodynamics was evaluated using echocardiography. RESULTS: The Cmax (peak concentration) and AUCinfinity (area under the curve from time 0 to infinity) of levosimendan of Chinese subjects were significantly higher than for Caucasian subjects as 256.1 +/- 37.8 (mean +/- SD) vs. 142.1 +/- 17.5 ng/mL and 207.5 +/- 35.2 vs. 117.0 +/- 17.0 hr.ng/mL, respectively. The clearance of Chinese subjects was significantly lower than Caucasian subjects at 9.9 +/- 1.8 vs. 17.4 +/- 2.7 L/hr, respectively. The elimination half-life of Chinese subjects was significantly longer than for Caucasian subjects (1.18 +/- 0.18 vs. 0.76 +/- 0.10 hr, respectively). Chinese subjects eliminated levosimendan significantly slower than Caucasian subjects, leading to a higher exposure of levosimendan in Chinese subjects. However, this higher exposure did not significantly change the most pharmacodynamic properties of levosimendan except for ejection fraction (EF). The EF increased 12.2 +/- 11.4% in Chinese subjects 20 min after the end of intravenous infusion, which was significantly lower than Caucasian subjects with EF increased by 22.7 +/- 7.0%. CONCLUSIONS: The intravenous levosimendan in healthy Chinese volunteers was safe, and well-tolerated with significant inotropic effect. The clearance of levosimendan of Chinese subjects was significantly lower and elimination half life longer than Caucasian subjects. KEY WORDS: Chinese; Ethnic comparison; Levosimendan; Pharmacodynamics; Pharmacokinetics; Volunteer. PMID- 27122805 TI - Effects of Losartan and Amlodipine on Left Ventricular Remodeling and Function in Young Stroke-Prone Spontaneously Hypertensive Rats. AB - BACKGROUND: The purpose of this study was to evaluate the effects of prehypertensive losartan and amlodipine administration on left ventricular (LV) remodeling and function in spontaneously hypertensive rats-stroke prone (SHRSP). METHODS: Spontaneously hypertensive rats-stroke prone were prehypertensively administered losartan, amlodipine, or vehicle. Wistar-Kyoto rats were used as a control. Blood pressure of the rats was determined by tail-cuff method, and LV structure and function were measured by echocardiography and LV cannulation. Collagen volume fraction was analyzed by picrosirius red staining. Protein expressions of brain natriuretic peptide (BNP) and angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors were determined by use of the Western blotting method. RESULTS: Although both drugs downregulated BNP protein expression, the LV remodeling and function were more improved with losartan than with amlodipine treatment. Losartan upregulated AT1R and downregulated AT2R protein expression. CONCLUSIONS: Both drugs inhibited LV remodeling and improved LV function in prehypertensively treated SHRSP. Losartan provided better continued heart protection, potentially due to its persistent inhibition of AT1R and activation of AT2R in the myocardium. KEY WORDS: Amlodipine; Blood pressure; Heart; Losartan; Prehypertension. PMID- 27122804 TI - Andrographolide, a Novel NF-kappaB Inhibitor, Inhibits Vascular Smooth Muscle Cell Proliferation and Cerebral Endothelial Cell Inflammation. AB - BACKGROUND: Aberrant vascular smooth muscle cell (VSMC) proliferation and cerebral endothelial cell (CEC) dysfunction contribute significantly in the pathogenesis of cardiovascular diseases. Therefore, inhibition of these cellular events would be by candidate agents for treating these diseases. In the present study, the mechanism of anti-proliferative and anti-inflammatory effects of andrographolides, a novel nuclear factor-kappaB inhibitor, was investigated in VSMC and CEC cells. METHODS: VSMCs and CECs were isolated from rat artery and mouse brain, respectively, and cultured before experimentation. The effect of andro on platelet-derived growth factor-BB (PDGF-BB) induced VSMC cell proliferation was evaluated by cell number, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The expression of extracellular signal regulated kinase 1/2 (ERK1/2), proliferating cell nuclear antigen (PCNA), and the effects on lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and, cyclooxygenase-2 (COX2) were detected by Western blotting. RESULTS: Andro significantly inhibited PDGF-BB (10 ng/ml) induced cell proliferation in a concentration (20-100 MUM) dependent manner, which may be due to reducing the expression of ERK1/2, and by inhibiting the expression of PCNA. Andro also remarkably diminished LPS-induced iNOS and COX2 expression. CONCLUSIONS: The results of this study suggested that the effects of andro against VSMCs proliferation and CECs dysfunction may represent a promising approach for treatment of vascular diseases. KEY WORDS: Andrographolide; CECs; COX2/iNOS; ERK/PCNA; LPS; PDGF-BB; VSMCs. PMID- 27122806 TI - Factors Associated with Lipid Goal Attainment among Patients with Deployed Drug Eluting Stent. AB - BACKGROUND: Drug-eluting stents (DES) have provided significant benefits for patients with complex coronary lesions. Intensive lipid control through statin therapy decreases the risk of late target lesion revascularization in patients with implanted DES. Therefore, we investigated lipid management in patients with implanted DES and analyzed the predictors for achieving target lipid goals. METHODS: A retrospective study was performed on consecutive patients who underwent percutaneous coronary intervention (PCI) with DES deployment from 2010 to 2012. Fasting lipid profiles were obtained for all patients both on the day of and 6 months after PCI. Logistic regression analysis was used to predict factors for achieving target lipid goals. RESULTS: A total of 419 patients (mean age: 62; 80% men) were included. Only 20.8% of patients achieved the target low-density lipoprotein cholesterol (LDL-C) level of < 70 mg/dL, and 61.6% of patients achieved the target LDL-C level of < 100 mg/dL. An equivalent dose of statins was statistically significant in attaining LDL-C levels of < 70 mg/dL [adjusted odds radio (AOR): 1.30; p < 0.001] and < 100 mg/dL (AOR: 1.27; p < 0.001). In addition, a baseline LDL-C level < 130 mg/dL is a leading predictor of achieving target LDL-C levels (AOR: 2.3, p = 0.012 for LDL-C < 70 mg/dL; AOR: 2.01, p = 0.006 for LDL-C < 100 mg/dL). CONCLUSIONS: Achievement of target LDL-C levels is difficult in patients with implanted DES and a baseline LDL-C level of >=130 mg/dL who are not treated with statins. Therefore, these patients should be treated with more aggressive statin therapy. KEY WORDS: Drug-eluting stents; Low density lipoprotein. PMID- 27122807 TI - Ligation of Macroscopically Detectable Arteriovenous Fistulas in Stewart-Bluefarb Syndrome. AB - We herein describe the case of a 21-year-old woman with Stewart-Bluefarb syndrome presenting with recurrent ulcers on the right foot and multiple congenital arteriovenous malformations. The painful recurrent ulcers and brownish macules at the dorsum of the right foot had appeared at 13 years of age, and the size of the right foot gradually became larger than the left. She underwent conservative treatment and polyvinyl alcohol embolization but the ulcer was recurrent. Two macroscopic detectable feeding arteries to arteriovenous fistulas were ligated under Doppler sonography. At her 6 month follow-up, the chronic ulcer had begun to heal and pain had been alleviated. KEY WORDS: Acroangiodermatitis; Arteriovenous malformation; Recurrent foot ulcer; Stewart-Bluefarb syndrome. PMID- 27122808 TI - Velocity-Encoded Phase-Contrast Magnetic Resonance Imaging for Diagnosing Severe Bilateral Subclavian Steal Syndrome with Complete Vertebral Reversal. AB - Subclavian steal syndrome (SSS) involves changes in hemodynamics secondary to proximal subclavian artery stenosis and/or occlusion where the subclavian artery "drains" the blood from the vertebral artery. It sometimes induces neuromuscular symptoms, especially in cases with bilateral involvement. We report the case of a 65-year-old symptomatic male with severe bilateral SSS with complete vertebral reversal. Doppler ultrasonography yielded inconclusive results because of a scar in the left lower neck region leading to poor acoustic windows. Subsequent magnetic resonance imaging with contrast-enhanced magnetic resonance angiography and velocity-encoded phase-contrast magnetic resonance imaging provided the vascular morphology and blood flow pattern which allowed subsequent interventions to be successfully performed. KEY WORDS: Angioplasty; Phase-contrast magnetic resonance imaging; Subclavian steal syndrome. PMID- 27122809 TI - Delayed Infective Endocarditis with Mycotic Aneurysm Rupture below the Mechanical Valved Conduit after the Bentall Procedure. AB - The Bentall procedure is the gold standard for treating aortic dissection complicated with valvular and ascending aorta disease. Recent results for this procedure have been excellent; nearly 100% of patients remain free of infective endocarditis in long-term follow-up. We report a case of delayed Streptococcus agalactiae infective endocarditis complicated by mycotic aneurysm in a man who had undergone the Bentall procedure with a mechanical valve conduit 15 years previously. The mycotic aneurysm was located in the remnant aortic root, below the mechanical valve conduit, and later ruptured into the right atrium. The patient was treated conservatively and survived the acute period. Later, the aortic root defect was repaired successfully by means of a hybrid technique using a Amplatzer duct occluder. KEY WORDS: Amplatzer duct occluder; Aortic dissection; Bentall technique; Infective endocarditis; Mycotic aneurysm. PMID- 27122810 TI - Left Ventricular Pseudoaneurysm Caused by Infective Endocarditis. AB - A 32-year-old male presented with infective endocarditis and left ventricular pseudoaneurysm (PA). The patient was treated with oxacillin but remained intermittently febrile for the next 3 weeks. Blood culture revealed Staphylococcus aureus. Treatment with oxacillin 2 g every 4 hours gradually reduced the fever. Echocardiography then showed an aneurysm-like structure communicating with the left ventricle. However, the patient refused further examinations and insisted on discharge. After 4 days, he was readmitted to our ward with severe dyspnea. Chest computed tomography showed the heart was behind a huge PA. The selected treatments for this rare case of multiple medical conditions were surgical resection of the PA and mitral valve replacement surgery, which achieved a gradual recovery. In this case, early diagnosis and timely surgical intervention resulted in an excellent prognosis. KEY WORDS: Infective endocarditis; Pseudoaneurysm; Staphylococcus aureus. PMID- 27122811 TI - Cardiac Rehabilitation in Patients with Heart Failure. AB - Reduced exercise capacity negatively affects the ability of patients with heart failure (HF) to perform activities required for daily life, further decreasing their independence and quality of life (QoL). Cardiac rehabilitation (CR) can effectively improve aerobic fitness and overall health status in patients with HF. Low referral rate is an important limitation that may impede successful CR, whereas the automatic referral and liaison strategies performed by some healthcare providers manifestly increase the CR referral rate. However, there is still controversy regarding the most effective exercise strategy for improving hemodynamic efficiency during daily activities in the HF population. Aerobic interval training (AIT), that includes alternating high- and low-intensity exercise sessions, may be a more effective modality for improving functional capacity than traditional moderate continuous training (MCT) in patients with HF. A novel AIT regimen designed in our previous study may substantially enhance the ability of ventilation-perfusion matching during exercise, which effects are accompanied by an improved global and disease-specific QoL in HF patients. Conversely, the traditional MCT regimen may only maintain these physiologic responses to exercise at pre-interventional status. By elucidating the relationship between physical activity and hemodynamic property, this review attempts to provide a CR strategy for developing suitable exercise prescription that ameliorates hemodynamic disturbance, further retarding the disease progression and improving health-related QoL in patients with HF. KEY WORDS: Aerobic capacity; Heart failure; Hemodynamics; Rehabilitation. PMID- 27122812 TI - What Could be Changed in the 2012 Taiwan ST-Segment Elevation Myocardial Infarction Guideline? AB - The 2012 guidelines of the Taiwan Society of Cardiology for the management of ST segment elevation myocardial infarction (STEMI) is an important reference commonly used by a variety of medical professionals in Taiwan. However, there are several points that may need to be changed or added to the 2012 edition due to the scientific development. First, timely primary percutaneous coronary intervention (PCI) has become the major reperfusion therapy in Taiwan. Immediate transfer to qualified PCI-capable hospitals by ambulance for all STEMI patients is the preferred strategy. Second, dual antiplatelet therapy with aspirin and P2Y12 inhibitor is important for STEMI patients. The newer P2Y12 inhibitors, ticagrelor or prasugrel, have a more potent platelet inhibitory effect and can be used for STEMI patients prepared for primary PCI if there is no contraindication. Third, aspiration thrombectomy and newer generation drug-eluting stents can be considered during primary PCI. For patients with multivessel disease, typically only an infarct-related artery should be treated at the time of primary PCI. All these evidence-based suggestions together provide an ideal initial treatment strategy for acute STEMI in Taiwan. KEY WORDS: Guideline; Myocardial infarction; Taiwan. PMID- 27122813 TI - Pluripotent Stem Cell Therapy in Ischemic Cardiovascular Disease. AB - Stem cell therapy has been viewed as a promising therapeutic strategy in ischemic cardiovascular disease for almost a decade. Although many progenitor/stem cells obtained from patients have been investigated, and are alleged to be suitable for autologous transplantation, their therapeutic application has been limited by their inability to yield a sufficient number of stem cells, as well as impaired regeneration capacity from ageing and cardiovascular risk factors. Pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have the capacity for functional multi-lineage differentiation and properties of self-renewal and immortality, and can generate clinically relevant amounts of stem cells. The regeneration capacity of these cells is not affected by ageing. Patient-specific pluripotent stem cells, iPSCs, can be established by epigenetically reprogramming somatic fibroblasts. iPSCs and iPSC-derived stem cells share similar phenotypes and gene expressions of ESCs and ESC-derived stem cells. Transplantation of pluripotent stem cell-derived endothelial cells, mural cells, cardiomyocytes, or cardiovascular progenitor cells contribute to neovascularization and cardiomyogenesis with better limb perfusion and recovery of myocardial contractility in the preclinical studies. Several strategies have been developed to enhance the efficacy of reprogramming and engrafting, and improve graft survival, proliferation, and electromechanical coupling by tissue engineering. However, the therapeutic application of ESCs and derivatives is limited by ethical concerns. Before wide clinical application of these cells in regeneration therapy occurs, substantial effort should be undertaken to discover the most promising cell type and derivatives, the best protocol regarding cell preparation, reprogramming and differentiation, and the most efficacious methods to avoid adverse effects. KEY WORDS: Embryonic stem cells; Induced pluripotent stem cells; Limb ischemia; Myocardial infarction. PMID- 27122814 TI - Effects of Cardiovascular Risk Factors on Endothelial Progenitor Cell. AB - Atherosclerosis is a systemic inflammatory disease of arterial wall and initiated by endothelial damage. The integrity and functional activity of endothelial monolayer play an important role in atherogenesis. The extent of endothelial injury may represent a balance between the magnitude of injury and the capacity for repair. Traditional view suggested endothelium integrity is maintained by neighboring mature endothelial cells which migrate and proliferate to restore the injured endothelial cells. However, a series of clinical and basic studies prompted by the discovery of bone marrow-derived endothelial progenitor cells (EPCs) have demonstrated that the injured endothelial monolayer may be regenerated partly by circulating EPCs. These circulating EPCs are mobilized endogenously triggered by tissue ischemia or exogenously by cytokine stimulation. Clinical studies demonstrated that levels of circulating EPCs are associated with vascular endothelial function and cardiovascular risk factors, and help to identify patients at increased cardiovascular risk. Reduced levels of circulating EPCs independently predict atherosclerotic disease progression and development of cardiovascular events. Therefore, a better understanding of the relation between EPCs and atherosclerosis would provide additional insight into the pathogenesis of cardiovascular disease and create novel therapeutic strategies. Here, we will make a brief review to clarify the effects of cardiovascular risk factors on circulating EPCs. KEY WORDS: Atherosclerosis; endothelial function; endothelial progenitor cell. PMID- 27122815 TI - Current Status and Perspectives in Stem Cell Therapy for Heart. AB - For most patients, the prognosis of heart failure remains poor despite therapeutic advancement in recent decades. The option of cardiac transplantation is high risk and limited by a shortage of donors. Traditionally, the heart had been considered a terminally differentiated organ incapable of regeneration. However, numerous preclinical and clinical studies have been performed since the first report of cell therapy in heart failure using skeletal myoblasts in 2001. These investigations looked at the promising potential and use of several kinds of stem cells, which could some day dramatically alter the understanding of the regenerative capacity of the heart. To date, although there is no existing cardiac cell therapy that has been conclusively reported to be effective, stem cell-related cardiomyocyte regeneration strategies have become significant areas of research in modern cardiovascular medicine. In this review, we outline a variety of common cell sources, surface biomarkers of stem cells, and provide information related to cardiac cell therapy clinical trials. KEY WORDS: Clinical trial; Stem cell. PMID- 27122816 TI - Mesenchymal Stem Cell Derived Exosomes: A New Hope for the Treatment of Cardiovascular Disease? AB - Cardiovascular disease is a major target for numerous experimental stem (progenitor) cell-based therapies. Mesenchymal stem cells (MSCs) from different sources confer regenerative effects in animal models of cardiovascular disease. Some of these investigations have proceeded into phase I and II clinical trials for limb ischemia, heart failure, and acute myocardial infarction. The rationale for MSC therapy is increasingly recognized on a secretion (paracrine) rather than differentiation mechanism. Recently, several groups have demonstrated that the "exosome" is a secreted agent mediating MSC therapeutic efficacy. Unlike cell therapy, exosomes have no risk of aneuploidy, and a lower rate of immune rejection following allogeneic administration. In this short review, we will focus on the potential of using this novel therapeutic modality for the treatment of cardiovascular disease, particularly acute myocardial infarction. KEY WORDS: Cardiovascular disease; Exosome; Mesenchymal. PMID- 27122818 TI - QTc Heterogeneity in Rest Magnetocardiography is Sensitive to Detect Coronary Artery Disease: In Comparison with Stress Myocardial Perfusion Imaging. AB - BACKGROUND: Stress nuclear myocardial perfusion imaging (MPI) is an established method for diagnosis and prognosis of coronary artery disease (CAD). However, radiation exposure limits its clinical application. Magnetocardiography (MCG) has been proposed as a non-contact, rapid and non-radiation technique with high reproducibility. The aim of the study was to evaluate the diagnostic efficacy of rest MCG in CAD comparing to stress MPI. METHODS: We prospectively enrolled 55 patients with suspected CAD (64 +/- 10 years) who were scheduled for coronary angiography (CA). MCG, stress (201)Tl MPI and CA were performed within 3 months. The spatial distribution maps of QTc interval (21 * 21 in resolution) were derived from a 64-channel MCG system (KRISS, Korea). T-wave propagation mapping, repolarization heterogeneity index with QTc dispersion and smoothness index of QTc (SI-QTc) were analyzed, and the diagnostic criteria for CAD were developed based on the receiver operating characteristic (ROC) curve analysis. RESULTS: Patients with significant CAD (>= 70% luminal stenosis, n = 36) had higher QTc dispersion and SI-QTc than controls (both p < 0.05). The diagnostic sensitivity and specificity were 0.8330, 0.6842 for QTc dispersion >= 79 ms; 0.7778, 0.6842 for SI-QTc >= 9.1 ms; and 0.8611, 0.6842 for combination. There was no difference of area under ROC curve by using criteria of QTc dispersion >= 79 ms, SI-QTc >= 9.1 ms or combination (0.7588, 0.7310, 0.7727, p = NS), and non-inferior to stress MPI (p = NS). CONCLUSIONS: The QTc heterogeneity parameters of rest MCG yield a good sensitivity and acceptable specificity for detection of CAD, and may provide an alternative to stress MPI without stress and radiation. KEY WORDS: Coronary artery disease (CAD); Magnetocardiography (MCG); Myocardial perfusion imaging (MPI); Repolarization. PMID- 27122819 TI - Moderate Hypothermia (33 degrees C) Decreases the Susceptibility to Pacing Induced Ventricular Fibrillation Compared with Severe Hypothermia (30 degrees C) by Attenuating Spatially Discordant Alternans in Isolated Rabbit Hearts. AB - BACKGROUND: Severe hypothermia (SH, 30 degrees C) increases the risk of pacing induced ventricular fibrillation (PIVF) by enhancing spatially discordant alternans (SDA). Whether moderate hypothermia (MH, 33 degrees C), which is clinically used for therapeutic hypothermia, also facilitates SDA remains unclear. We hypothesized that MH attenuates SDA occurrence compared with that achieved by SH, and decreases the susceptibility of PIVF. METHODS: Using an optical mapping system, action potential duration (APD)/conduction velocity restitutions and thresholds of APD alternans were determined by S1 pacing in Langendorff-perfused isolated rabbit hearts. In the MH group (n = 7), S1 pacing was performed at baseline (37 degrees C), after 5-min MH, and after 5-min rewarming (37 degrees C). In the SH group (n = 9), pacing was also performed at baseline (37 degrees C), after 5-min SH, and after 5-min rewarming (37 degrees C). The thresholds of APD alternans were defined as the longest S1 pacing cycle length at which APD alternans were detected. RESULTS: Although the thresholds of APD alternans were not different between the MH (273 +/- 46 ms) and the SH (300 +/- 35 ms) (p = 0.281) groups, SDA threshold was shorter (at a faster heart rate) during MH (228 +/- 33 ms) than that during SH (289 +/- 42 ms) (p = 0.028). At APD alternans threshold, SH hearts showed more SDA than that during MH (SH: 7 hearts, MH: 2 hearts, p = 0.049). SDA could be induced in all 9 SH hearts (100%), while only 4 MH hearts (57%) had SDA (p = 0.029). The PIVF inducibility during SH (44 +/- 53%) was higher than that during MH (0%) (p = 0.043). CONCLUSIONS: Compared with SH, the MH group showed greater attenuation of SDA and decreased the susceptibility of PIVF. Therefore, MH is safer as a procedural guideline for use in clinical therapeutic hypothermia than SH. KEY WORDS: Cardiac alternans; Conduction velocity; Hypothermia; Optical mapping. PMID- 27122820 TI - The Translational Proteome Modulated by 20(S)-Protopanaxadiol in Endothelial Cells. AB - BACKGROUND: 20(S)-protopanaxadiol (PPD), a natural compound of dammarane ginsenoside purified from the ginseng plant, exhibits strong anticancer properties. It has also been reported to have strong antioxidant activity and plays a role in cardiovascular protection. However, the downstream signaling mechanism PPD employs is still unclear and requires further elucidation. METHODS: Endothelial cells (ECs) EAhy 926 were used to investigate the growth promoting effect of PPD. The protein lysates extracted from both mock- and PPD-treated cells were separated by two-dimensional gel electrophoresis (2-DE) to monitor protein changes. After image analysis, proteins with significant change in the expression level were further identified by mass spectrometry. Western blot was applied to further confirm the protein variations in the 2-DE assay. RESULTS: In the current study, we found that treatment with PPD (10 MUg/ml) significantly increased ECs healing. The translational proteome was established according to 16 up-regulated and 8 down-regulated proteins identified in 2-DE. These proteins were reported to function as energy homeostasis and in the prevention of oxidative stress. The elevated expressions of heme oxygenase 1 (HO-1) and glutathione synthetase (GSS) were further confirmed in the western blot analysis. CONCLUSIONS: According to the information obtained from translational proteome, we delineated that PPD mediated vascular homeostasis through the up-regulation of anti-oxidative proteins. Additional functional investigations are necessary regarding the HO-1 and GSS proteins. KEY WORDS: Dammarane sapogenins; Endothelial cell; Glutathione synthetase; Heme oxygenase 1; Proteome; 20(S)-protopanaxadiol. PMID- 27122821 TI - Curcumin Suppress Cardiac Fibroblasts Activities by Regulating Proliferation, Migration, and the Extracellular Matrix. AB - BACKGROUND: Cardiac fibrosis plays a critical role in the pathophysiology of cardiovascular disease. It has been observed that curcumin has several cardiovascular effects. The purpose of this study was to evaluate whether curcumin can attenuate cardiac fibroblasts activity. METHODS AND RESULTS: We evaluated the migration, proliferation, collagen production, and transcription signaling in rat cardiac fibroblasts isolated from Sprague-Dawley rats (males, weighing 300-350 g) that were or were not incubated with curcumin (25 MUM) and the co-administration of transforming growth factor (TGF)- beta1 (10 ng/ml) or angiotensin (Ang) II (100 nM) by a cell migration analysis, proliferation assay, and Western blot analysis. Compared to those without curcumin, curcumin-treated cardiac fibroblasts exhibited lower migratory, proliferative abilities and collagen production at the baseline and after the co-administration of TGF-beta1 or Ang II. Curcumin-treated cardiac fibroblasts had increased matrix metalloproteinase (MMP)-2 activity in the presence of Ang II treatment. Curcumin treated cardiac fibroblasts down-regulated phosphorylated protein kinase B (Akt) and phosphorylated Smad2/3 expression irrespective of TGF-beta1 treatment. Curcumin also decreased phosphorylated extracellular signal-regulated kinase (ERK)1/2 levels in the presence of Ang II. CONCLUSIONS: Curcumin attenuated Akt, Smad2/3, and ERK1/2 phosphorylation which were mediated by TGF-beta1 and angiotensin II. This resulted in decreased cardiac fibroblast activation and supports the assertion that curcumin is an effective antifibrotic agent which can be used to treat heart failure. KEY WORDS: Angiotensin; Curcumin; Fibroblasts; Heart failure; Transforming growth factor. PMID- 27122822 TI - Curcumin: Another Potential Translational Candidate for Anti-Fibrosis on Heart Failure? PMID- 27122823 TI - [Not Available]. AB - Saphenous vein graft (SVG) failure secondary to degeneration can cause significant problems after coronary artery bypass surgery (CABG). Repeat revascularization by percutaneous coronary intervention can be performed after SVG failure but is often associated with less favourable clinical outcome. Treatment for chronic total occlusion (CTO) of native vessels after SVG failure among patients with prior CABG is frequently performed. However, revascularization of CTO vessels in patients with prior CABG may be more complex and require more frequent use of the retrograde approach. Good septal or epicardial collateral channels are usually needed for the retrograde CTO approach. However, suitable native collateral channels may be absent and alternative retrograde routes should be considered. In this case report, we described a patient who had prior CABG and developed recurrent angina after SVG failure. His native CTO lesion was successfully revascularized by using a totally occluded vein graft as a retrograde conduit. KEY WORDS: Chronic total occlusions; Coronary artery bypass grafts; Percutaneous coronary intervention; Saphenous vein graft. PMID- 27122824 TI - Transcatheter Repair of Iatrogenic Aortic Perforation Complicating Transseptal Puncture for a Catheter Ablation of Atrial Arrhythmia. AB - Aortic root perforation is a potentially life-threatening complication that may occur during transseptal puncture and requires immediate repair. We present a 71 year-old man who was admitted for catheter ablation of persistent atypical atrial flutter. Fluoroscopic-guided transseptal puncture was performed to gain access to the left atrium. An unrecognized puncture of the aortic root by Brockenbrough needle and inadvertent advancement of Mullins sheath resulted in aortic root perforation. We decided to seal the hole transcatheterly with an occluder device. Severe aortic regurgitation (AR) was noted by transesophageal echocardiography after deployment of a 6 mm Amplatzer septal occluder (ASO). Thereafter, we switched to a 6/4-mm Amplatzer duct occluder (ADO) and only minimal AR was noted after deployment. This is because the diameter of the left atrial disc of ASO is larger than the diameter of the retention skirt of ADO to interfere with the movement of aortic valve leaflet. During 6 months of echocardiographic follow-up, the ADO remained in place and no residual shunt was observed. KEY WORDS: Aortic perforation; Transcatheter repair; Transseptal puncture. PMID- 27122817 TI - 2014 Guidelines of Taiwan Society of Cardiology (TSOC) for the Management of Pulmonary Arterial Hypertension. AB - Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic condition, defined as a mean pulmonary arterial pressure exceeding 25 mmHg at rest. According to the recent classifications, it is grouped into pulmonary arterial hypertension (PAH), heart-related, lung-related, thromboembolic, and miscellaneous PH. In the past two decades, tremendous advances have occurred in the field of PH. These include (1) development of clinical diagnostic algorithm and a monitoring strategy dedicated to PAH, (2) defining strong rationales for screening at-risk populations, (3) advent of pulmonary specific drugs which makes PAH manageable, (4) recognition of needs of having proper strategy of combining existing pulmonary specific drugs, and/or potential novel drugs, (5) pursuit of clinical trials with optimal surrogate endpoints and study durations, (6) recognition of critical roles of PH/right ventricular function, as well as interdependence of ventricles in different conditions, especially those with various phenotypes of heart failure, and (7) for rare diseases, putting equal importance on carefully designed observation studies, various registries, etc., besides double blind randomized studies. In addition, ongoing basic and clinical research has led to further understanding of relevant physiology, pathophysiology, epidemiology and genetics of PH/PAH. This guidelines from the working group of Pulmonary Hypertension of the Taiwan Society of Cardiology is to provide updated guidelines based on the most recent international guidelines as well as Taiwan's domestic research on PH. The guidelines are mainly for the management of PAH (Group 1) ; however the majority of content can be helpful for managing other types of PH. KEY WORDS: Pulmonary arterial hypertension; Taiwan guidelines. PMID- 27122825 TI - Acute Stanford Type A Aortic Dissection Mimicking Acute Myocardial Infarction: A Hidden Catastrophe Which Should Prompt Greater Vigilance. AB - Stanford type A aortic dissection involving the coronary artery ostium and leading to a concomitant acute myocardial infarction (AMI) is an infrequent but life-threatening condition, necessitating a prompt diagnosis and appropriate treatment. Unfortunately, the diagnosis of this entity can be extremely challenging and misdiagnosis is sometimes unavoidable because it usually mimics a common AMI. Herein, we describe the case of a 56-year-old man who presented with severe retrosternal chest pain and dynamic ECG change which was initially misdiagnosed solely as an AMI. However, the patient was finally diagnosed to have a type A aortic dissection complicated by coronary artery involvement. Following emergent surgery treatment, the patient made a good recovery. KEY WORDS: Acute myocardial infarction; Aortic dissection; Coronary angiography. PMID- 27122826 TI - Precordial ST-Segment Elevation Caused by Proximal Occlusion of a Non-Dominant Right Coronary Artery. AB - For patients with ST-segment elevation myocardial infarction, primary percutaneous coronary intervention to the culprit lesion via electrocardiographic guidance is essential. We herein report the rare case of a 49-year-old man who presented with ST-segment elevation in the precordial leads, while coronary angiography results indicated total occlusion of the proximal non-dominant right coronary artery. We evaluated its possible pathophysiologic mechanisms and thoroughly discussed isolated right ventricular infarction and its electrocardiography findings. KEY WORDS: Coronary angiography; Myocardial infarction; Total occlusions. PMID- 27122827 TI - Soluble ST2: A Novel Prognostic Biomarker of Heart Failure. PMID- 27122828 TI - Clinical Applications of Extracorporeal Membranous Oxygenation: A Mini-Review. AB - The clinical usage of extracorporeal membranous oxygenation began more than 40 years ago. Although the indications for its use have expanded over the years, it has been challenging to conduct randomized controlled trials to prove that extracorporeal membranous oxygenation is more effective than traditional approaches. Through a review of retrospective reports and data from registries, we attempted to evaluate the appropriateness of its application for acute respiratory distress syndrome, cardiopulmonary resuscitation, postcardiotomy cardiogenic shock, and sepsis. Our investigation revealed that using extracorporeal membranous oxygenation when readily available is appropriate for all patients with cardiopulmonary resuscitation or postcardiotomy cardiogenic shock, and for selected patients with acute respiratory distress syndrome or sepsis. KEY WORDS: Acute respiratory distress syndrome; Cardiopulmonary resuscitation; Extracorporeal membranous oxygenation; Postcardiotomy cardiogenic shock; Sepsis. PMID- 27122829 TI - Primary Infected Aortic Aneurysm: Clinical Presentation, Pathogen, and Outcome. AB - PURPOSE: Infected aneurysm of the aorta and adjacent arteries is rarely occurring and can be fatal without surgical intervention. Within the medical community, the most efficacious treatment strategy to address infected aortic aneurysm remains controversial. In this study, we have reviewed our treatment experience with 109 patients. METHODS: We included in our study all consecutive patients treated for primary infected aortic aneurysm at our facility between 1995 and 2011. Aneurysm related mortality was defined as the presence of in-hospital and late mortality related to infection or postoperative complications. RESULTS: The median patient age was 72 years (range, 35-88), and 87 (80%) were male. Pathogen was isolated in 101 patients, and the most common microorganism identified was non-typhoid Salmonella in 61 (60%), followed by Staphylococcus aureus in 16 (16%) and Streptococci species in 7 (7%). Eighty-five (78%) patients underwent surgical treatment. Surgery included open repair with in-situ graft replacement in 77 (71%) and endovascular repair in 8 (7%). The aneurysm-related mortality rate was 67% in medically treated and 21% in surgically treated patients, with a median follow-up duration of 31.5 months (range 1-189). Additionally, risk factors for aneurysm-related mortality included old age, chronic lung disease, psoas muscle abscess, short duration of preoperative antibiotics, no operation, and probably endovascular repair. CONCLUSIONS: Non-typhoid Salmonella was the most common pathogen found in our study group patients with infected aortic aneurysm. It appears that prolonged preoperative antibiotic treatment followed by open in-situ graft replacement remains the preferred and most effective treatment strategy. KEY WORDS: Infected aortic aneurysm; Outcome; Pathogen; Surgery. PMID- 27122830 TI - Role of Left Main Coronary Artery Stenosis on Intraoperative Conversion and Mortality in Off-Pump Coronary Artery Bypass. AB - BACKGROUND: Intraoperative conversion is a major threat in off-pump coronary artery bypass (OPCAB). The conversion rate depends on patient selection and surgeon experience. Previous studies have demonstrated the feasibility of OPCAB for patients with left main coronary artery stenosis (LMCAS) >= 50%. However, no studies have focused on the role of LMCAS >= 90%. We sought to assess the impact of LMCAS >= 90% on the conversion rate and mortality in OPCAB. METHODS: We conducted a retrospective review of 1055 consecutive unselected patients undergoing OPCAB between 2000 and 2012. The patients in our study were divided into 3 groups by the severity of LMCAS. RESULTS: LMCAS was < 50% in 704, 50-90% in 266, and >= 90% in 85 patients. LMCAS was not associated with major postoperative complications and hospital mortality, although preoperative cardiogenic shock was present in 6.3%. Overall, the conversion rate was 10.1%:11.4% in LMCAS < 50%, 5.6% in LMCAS 50-90%, and 14.1% in LMCAS >= 90%. Operation status, cardiogenic shock, left ventricular ejection fraction < 30% and operation before 2007 were noted as independent predictors of conversion. The overall hospital mortality rate was 5.1%: 4.8% in LMCAS < 50%, 4.5% in LMCAS 50 90%, and 9.4% in LMCAS >= 90%. Operation status, cardiogenic shock, left ventricular ejection fraction < 30% and intraoperative conversion were observed to be independent predictors of mortality. However, LMCAS did not predict either conversion or hospital mortality. CONCLUSIONS: LMCAS >= 90% was not an independent predictor of intraoperative conversion or hospital mortality in OPCAB. KEY WORDS: Conversion; Left main coronary artery stenosis; Off-pump coronary artery bypass. PMID- 27122831 TI - Some Ethical Legal Issues in Heart Disease Surgery. AB - Ethical concerns, cultural norms, and legal issues must be carefully considered when treating a patient with heart disease. Although physicians or surgeons must play a role in course of treatment decision making, they should be guided by evidence-based data and the preferences of patients and/or the patient's parents. However, there is no obligation to provide this type of informed consultation and approval unless these ethical issues become law - which typically occurs through litigation. In this review, we examined common ethical principles that are integral to the regular decisions made by clinicians every day. Some special ethical issues and associated litigation, if any, which might occur perioperatively will also be reviewed. Finally, the final judgments of civil and criminal courts of Taiwan, particularly lawsuits involving physicians associated with coronary artery disease care or aortic aneurysm, will also be introduced. KEY WORDS: Criminal lawsuit; Medical ethic; Medical litigation; Medical negligence. PMID- 27122832 TI - Application of 270 mgI/mL Iodinated Contrast Media in Dual-Source Computed Tomography Coronary Artery Imaging. AB - BACKGROUND: This study aimed to explore the application of 270 mg I/mL iodinated contrast agent with a tube voltage of 100 kV scanning in coronary computed tomography angiography (CCTA). METHODS: This CCTA study was a prospective observational study. The two radiologists were blinded to both patient information and image date arrangement. One-hundred twenty patients (body mass index < 25.0 kg/m(2)) were randomly divided into three groups based on contrast agent concentrations of 370, 320, and 270 mg I/mL, scanning at an injection rate of 5 ml/s. Then, the coronary artery branches of the three groups were compared, and the display rate, mean computed tomography (CT) value, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), image noise, and radiation dose were analyzed. RESULTS: The artery display rates of the four main branches of coronaries in the three groups were all 100%, and the difference in the display rates of the remaining small branches in the three groups exhibited no statistical significance (p > 0.05). A comparison of the mean CT value of the coronary artery of three groups in the ascending aorta, descending aorta, left main, left ventricular wall, right coronary artery, left anterior descending, and left circumflex showed a statistically significant difference (p < 0.05). A comparison of the SNR, CNR, image noise, and radiation dose showed no statistically significant difference (p > 0.05). CONCLUSIONS: Using a tube voltage of 100 kV combined with 270 mg I/mL iodinated contrast media in CCTA examination can achieve the "double low dose" effect while ensuring image quality. KEY WORDS: Contrast agent; Contrast to noise ratio; Coronary angiography; Signal noise ratio. PMID- 27122833 TI - The Relationship between Pre-Infarction Angina and Serum Sphingosine-1-Phosphate Levels. AB - BACKGROUND: Pre-infarction angina reduces myocardial infarct size by preventing the myocardium from being subjected to ischemia reperfusion (I/R) injury. Ischemic preconditioning is the proposed mechanism for this effect. Sphingosine 1 phosphate (S1P) activates ischemic preconditioning pathways and may play a role in the presence of cardioprotective effects of pre-infarction angina. Therefore, we evaluated the relationship between pre-infarction angina and serum S1P levels. METHODS: Between May 2011 and January 2012, 79 patients with acute myocardial infarction were included in the study. In addition to taking routine medical histories, all of the patients were questioned as to whether or not they had pre infarction angina. We determined patients serum levels of S1P at admission and discharge, and peak creatine kinase MB and troponin levels were also measured in the pre-infarction angina positive and negative groups. RESULTS: Of the 79 patients included in the study, 36 had pre-infarction angina and 43 had not. Baseline characteristics were similar between the groups. The median level of serum S1P in patients with pre-infarction angina was significantly higher than in those without pre-infarction angina both at admission and discharge [0.54 (0.14 1.35) vs. 0.26 (0.12-0.62) p = 0.014/0.51 (0.20-1.81) vs. 0.30 (0.13-0.68) p = 0.010]. Serum high sensitive troponin levels were significantly lower in patients with pre-infarction angina [0.97 (0.39-3.07) vs. 2.56 (0.9-6.51) p = 0.034]. Serum S1P levels both at admission and discharge tended to be higher in patients with more angina episodes, but the differences between these subgroups were not statistically significant. CONCLUSIONS: Patients who experienced pre-infarction angina had higher serum S1P levels than patients without pre-infarction angina. This study supported our hypothesis that the cardioprotective effects of pre infarction angina may in part be mediated by S1P. KEY WORDS: Ischemic preconditioning; Pre-infarction angina; Sphingosine 1 phosphate. PMID- 27122834 TI - Drug-Eluting Stents versus Bare-Metal Stents in Taiwanese Patients with Acute Coronary Syndrome: An Outcome Report of a Multicenter Registry. AB - BACKGROUND: The study aims to compare cardiovascular outcomes of using bare-metal stents (BMS) and drug-eluting stents (DES) in patients with acute coronary syndrome (ACS) through analysis of the database from the Taiwan ACS registry. Large domestic studies comparing outcomes of interventional strategies using DES and BMS in a Taiwanese population with ACS are limited. METHODS AND RESULTS: Collected data regarding characteristics and cardiovascular outcomes from the registry database were compared between the BMS and DES groups. A Cox regression model was used in an unadjusted or adjusted manner for analysis. Baseline characteristics apparently varied between DES group (n = 650) and BMS group (n = 1672) such as ACS types, Killip's classifications, or coronary blood flows. Compared with the BMS group, the DES group was associated with significantly lower cumulative incidence of all-cause mortality (3.4% vs. 5.8%, p = 0.008), target vessel revascularization (TVR) (5.2% vs. 7.4%, p = 0.035), or major adverse cardiac events (MACE) (10.2% vs. 15.6%, p < 0.001) at 1 year in a real world setting. Cox regression analysis showed the BMS group referenced as the DES group had significantly higher risk-adjusted total mortality [hazard ratio (HR) = 1.85, p = 0.026], target vessel revascularization (TVR) (HR = 1.59, p = 0.035), and MACE (HR = 1.68, p = 0.001). CONCLUSIONS: The data show use of DES over BMS provided advantages to patients with ACS in terms of lower 1-year mortality, TVR, and MACE. The study suggests implantation of DES compared with BMS in Taiwanese patients with ACS is safe and beneficial in the real-world setting. KEY WORDS: Acute coronary syndrome; Bare-metal stent; Cardiovascular outcome; Drug-eluting stent; Percutaneous coronary intervention. PMID- 27122835 TI - The AMBITIOUS Study Design and Rationale: Ambulatory Blood Pressure in Taiwanese Occupational Healthcare Staff. AB - BACKGROUND: Sudden death is a rare but real threat to hospital-based physicians and surgeons. The association between sudden death and blood pressure (BP) fluctuations in healthcare providers has not been documented. We hypothesized that work-shift loading may lead to variable BP surges in hospital-based healthcare staff, which might contribute to their development of cardiovascular disease. METHODS: Our intention is to ask 150 healthcare staff (doctors, medical technicians, and nurses) working in the coronary catheterization lab, intensive care unit, and the medical wards, respectively, to volunteer for the study. Their changes in BP would automatically be recorded every 60 minutes on an ambulatory BP monitoring machine for 24 hours during a normal workday. All events and activities would be recorded in a diary, which would allow us to coordinate BP changes with the work being done during the shift. All cardiovascular outcomes would be followed-up for a five-year duration. CONCLUSIONS: We herein report the rationale and design of this first multicenter trial in Taiwan to explore the BP behavior associated with long work shifts in healthy hospital-based healthcare providers. KEY WORDS: Ambulatory blood pressure; Health-care staff; Occupation; Work shift. PMID- 27122836 TI - Rapid Resolution of Severe Myocardial Dysfunction in a Patient with Rheumatoid Arthritis by Intravenous Immunoglobulin and Steroid Treatment. AB - A 64-year-old man with rheumatoid arthritis (RA) presented to our emergency department with severe chest tightness and dyspnea. His electrocardiography (ECG) showed multiple premature atrial complexes (PACs) with wide QRS, and transthoracic echocardiography revealed severe hypokinesis of the left ventricle. The patient later developed sudden cardiovascular collapse with presumed fulminant myocarditis and cardiogenic shock. Further investigation showed that coronary angiogram, viral studies and autoimmune vasculitis markers were all negative. After high-dose intravenous immunoglobulin (IVIG) and systemic steroid were administered, a dramatic improvement of clinical conditions was observed, with an increase of the left ventricular ejection fraction (LVEF) from 10% to 42% within one week, and a resolution of the wide QRS on the ECG. The rapid recovery from left ventricular dysfunction by treatment with IVIG and systemic steroid suggests immunotherapy might be effective in RA patients with acute fulminant myocarditis. KEY WORDS: Fulminant myocarditis; Intravenous immunoglobulin; Rheumatoid arthritis; Systemic steroid. PMID- 27122837 TI - A Case of Takotsubo Cardiomyopathy Precipitated by Thyroid Storm and Diabetic Ketoacidosis with Poor Prognosis. AB - Takotsubo cardiomyopathy (TCMP) is known as stress cardiomyopathy, and long-term prognosis is generally excellent if recovering from an acute stage. Both thyroid storm and diabetic ketoacidosis (DKA) are reported to be rare causes of TCMP. However, there are no studies discussing TCMP as induced by a combination of thyroid storm and DKA, and the prognosis is unknown. Herein we report an 81-year old female with type-2 diabetes mellitus initially presenting with palpitation, chest tightness, and gastrointestinal symptoms. She was further diagnosed as TCMP after echocardiogram and coronary angiography, and DKA was confirmed later. However, the patient's general condition didn't improve under proper treatment. Thereafter, thyroid storm was discovered fortuitously. Despite appropriate treatment, the patient finally expired due to acute respiratory distress syndrome progression. This rare case reminds us that despite TCMP being a transient cardiomyopathy with good prognosis, physicians should survey the possible underlying disease cautiously to avoid catastrophic clinical outcome. KEY WORDS: Acute respiratory distress syndrome; Diabetic ketoacidosis; Stress cardiomyopathy; Takotsubo cardiomyopathy; Thyroid storm. PMID- 27122838 TI - Two Consecutive Episodes of Acute Myocardial Infarction Occurring in Different Coronary Arteries of a Single Patient with Sepsis. AB - Although recurrent ST-segment elevation myocardial infarction (STEMI) in the same coronary artery due to acute stent thrombosis has been reported in the literature, there have been no reported cases discussing consecutive STEMI recurring in different coronary arteries in the same patient in one day. Herein, we report an elderly male patient initially suffering from STEMI over the inferior wall who subsequently had another episode of STEMI over the anterior wall within several hours. Despite primary percutaneous coronary intervention being performed over both the right coronary artery and the left anterior descending artery, the patient eventually expired notwithstanding intensive care. This case should caution physicians that consecutive STEMI in different coronary arteries is an extremely rare but still possible medical phenomenon, and could lead to catastrophic clinical outcome. KEY WORDS: Myocardial infarction; Primary percutaneous coronary intervention; Recurrent ST-elevation. PMID- 27122839 TI - Dynamic Compression of the Left Coronary Artery by a Left Ventricular Pseudoaneurysm after Myocarditis. AB - A 69-year-old man with a recent diagnosis of suspected leptospirosis infection related myocarditis presented with antecedent arthralgia, myalgia, fever, intermittent anterior chest pain, yellowish sclera, yellowish skin and shortness of breath. His symptoms improved after antibiotic treatment with penicillin for 14 days. However, recurrent chest pain and progressive dyspnea upon exertion developed 2 months later. A newly developed left ventricular outflow tract pseudoaneurysm was identified by cardiac sonography and multi-detector computed tomography of the heart. A subsequent coronary arteriogram demonstrated an left ventricular (LV) pseudoaneurysm causing compression to both the left circumflex coronary artery and the left anterior descending coronary artery with significant stenosis. To the best of our knowledge, this is the first reported case of a LV pseudoaneurysm developing after a clinical course of suspected leptospirosis related myocardit is causing dynamic compression of the left coronary artery. KEY WORDS: Dynamic compression of coronary artery; Left ventricular pseudoaneurysm; Leptospirosis; Myocarditis. PMID- 27122840 TI - Decreased Cardiac Expression of Heat Shock Protein 27 is Associated with Atrial Fibrillation in Patients with Rheumatic Heart Disease. AB - BACKGROUND: The objective of this study was to compare the expression of heat shock proteins (HSPs) between rheumatic heart disease (RHD) patients with atrial fibrillation (AF) and RHD patients without AF, and its efficacy in predicting the occurrence of AF in RHD patients. METHODS: Ninety-five patients were enrolled in our study, including 60 RHD patients with AF, and 35 RHD patients without AF. The baseline characteristics of the patients such as gender, age, AF duration, left atrial diameter and left ventricular ejection fraction were collected, and erythrocyte sedimentation rate and high-sensitivity C-reaction protein were measured from all patients. Tissue samples were obtained from the right atrial appendage during open-heart surgery and then detected using immunohistochemical methods and Western blot with HSP27, HSP60, HSP70 and HSP90 antibodies. RESULTS: Compared with RHD patients without AF, the density of HSP27 positive protein in RHD patients with AF was significantly lower. The density of HSP60, HSP70 or HSP90 antibodies did not indicate significant difference between the two groups. Use of the Western blot experiment showed consistent results with immunohistochemical staining. In RHD patients with AF, the expression level of HSP27 protein was negatively associated with AF duration and left atrial diameter. Left atrial enlargement and low expression of HSP27 were the independent predictors of AF. CONCLUSIONS: The decreased expression level of HSP27 is associated with AF in RHD patients. KEY WORDS: Atrial fibrillation; Heat shock protein; Rheumatic heart disease. PMID- 27122841 TI - Long-Term Follow-Up of Catheter Ablation of Ventricular Arrhythmias: Experiences from a Tertiary Referral Center in Taiwan. AB - BACKGROUND: Radiofrequency catheter ablation (RFCA) is an alternative therapeutic management for drug-refractory ventricular arrhythmias (VA). However, long-term follow-up of clinical outcome after RFCA for VAs in Taiwan remains unknown. METHODS: From 1999 to 2013, patients undergoing RFCA for VAs from a single referral center were consecutively enrolled. The annual distribution of cases, clinical characteristics, etiology, disease entity and electrophysiological studies were investigated. The clinical outcomes and recurrences between distinct entities were compared. RESULTS: A total of 502 patients receiving RFCA of VAs were eligible, including 388 patients for idiopathic VAs and 114 for substrate VAs. The annual distribution displayed a tendency towards a gradual increase in ablation cases within 2009-2013 compared with the prior decade (p < 0.001). Acute success was achieved in 453 patients (90.2%), partial success in 3 (0.6%), and failed ablation in 46 (9.2%). During a mean follow-up of 39.77 +/- 48.75 months, 126 (25.1%) patients developed recurrences. Kaplan-Meier analysis demonstrated better prognosis after RFCA in patients with idiopathic fascicular VT and RVOT VAs (p < 0.001) and attenuation of the occurrences of sustained VT/VF, ICD therapies, and mortality in patients with BrS and ARVD/C (p = 0.036), as well as overall ICD interventions in substrate VAs (p < 0.001). CONCLUSIONS: RFCA could be an effective and alternative strategy in the elimination of idiopathic VAs and prevention of malignant events in substrate VAs at an experienced referral center in Taiwan. Distinct location of arrhythmogenic trigger and disease entities may result in non-uniform recurrences and prognosis. KEY WORDS: Idiopathic; Radiofrequency catheter ablation; Recurrence; Substrate; Ventricular arrhythmias. PMID- 27122842 TI - MiR-196a2 rs11614913 T>C Polymorphism is Associated with an Increased Risk of Tetralogy of Fallot in a Chinese Population. AB - BACKGROUND: MicroRNAs (miRNAs) are a family of endogenous, small, noncoding single-stranded RNAs that act as post-transcriptional gene regulatory elements. MiRNA polymorphisms may be associated with susceptibility to congenital heart disease (CHD). The aim of this study was to evaluate the impact of miRNA single nucleotide polymorphisms (SNPs) on CHD susceptibility. METHODS: We genotyped two functional SNPs, miR-196a2 rs11614913 and miR-146a rs2910164, in a case-control cohort of 173 Chinese patients with tetralogy of Fallot (TOF) and 207 non-CHD controls. RESULTS: When the miR-196a2 rs11614913 TT homozygote genotype was used as the reference group, the TC genotype was not associated with an increased risk of TOF. The CC genotype was associated with a borderline significantly increased risk for TOF. In the recessive model, when the miR-196a2 rs11614913 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a significantly increased risk of TOF (OR = 1.96, 95% CI = 1.18 3.25, p = 0.01). The miR-146a rs2910164 C>G polymorphism was not associated with developing TOF. CONCLUSIONS: Our findings suggested that the miR-196a2 rs11614913 T>C polymorphism may play a role in the development of TOF. Future larger studies that include populations of other ethnicities are required to confirm these findings. KEY WORDS: Congenital heart disease; MiRNA; Molecular epidemiology; Polymorphisms; Tetralogy of Fallot. PMID- 27122843 TI - Mobilization of Endothelial Progenitor Cells Following Creation of Arteriovenous Access in Patients with End-Stage Renal Disease. AB - BACKGROUND: A patent arteriovenous (AV) fistula induces activation of regional vascular endothelium and vascular shear force. Shear stress is an important physiological force in mobilizing endothelial progenitor cells (EPCs). This study aimed to explore the perioperative changes of circulating EPC levels for patients who require hemodialysis and underwent radiocephalic fistula operation. METHODS: This prospective cohort study included patients who received a radiocephalic fistula surgery when they were between 25 and 65 years of age. The subjects were followed for 90 days postoperatively for any stenotic events or immaturity of the fistula. Blood samples were obtained on the day before surgery and at postoperation day (POD) 3 and 30. CD133+/KDR+ cells, defined as EPCs, were analyzed using flow cytometry. Blood flow of the fistula was followed on POD 3 and 30. RESULTS: A total of 30 patients were enrolled in the study from July 2009 to December 2011. One patient dropped out of the study and seven patients developed a stenotic (or immature) AV fistula (7/29, 24.1%). There were positive linear relationships between EPC numbers and shear rate postoperatively, which were more significant on POD 30. In addition, postoperative mobilization of EPCs was significantly higher in patients who developed a stenotic fistula than those without. CONCLUSIONS: The mobilization of circulating EPCs correlated with a compromised arteriovenous fistula. The biological significance of increased EPC numbers need to be determined in future studies. KEY WORDS: Arteriovenous fistula; Endothelial progenitor cells. PMID- 27122844 TI - Parthenolide-Induced Cytotoxicity in H9c2 Cardiomyoblasts Involves Oxidative Stress. AB - BACKGROUND: Cardiac cellular injury as a consequence of ischemia and reperfusion involves nuclear factor-kappaB (NF-kappa B), amongst other factors, and NF-kappa B inhibitors could substantially reduce myocardial infarct size. Parthenolide, a sesquiterpene lactone compound which could inhibit NF-kappa B, has been shown to ameliorate myocardial reperfusion injury but may also produce toxic effects in cardiomyocytes at high concentrations. The aim of this study was to examine the cytotoxic effects of this drug on H9c2 cardiomyoblasts, which are precursor cells of cardiomyocytes. METHODS: Cell viability and apoptosis were examined by MTT and TUNEL assay, respectively, and protein expression was analyzed by western blot. Reactive oxygen species (ROS) production was measured using DCFH-DA as dye. Cytosolic Ca(2+) concentration and mitochondrial membrane potential were measured microfluorimetrically using, respectively, fura 2 and rhodamine 123 as dyes. RESULTS: Parthenolide caused apoptosis at 30 MU M, as judged by TUNEL assay and Bax and cytochrome c translocation. It also caused collapse of mitochondrial membrane potential and endoplasmic reticulum stress. Parthenolide triggered ROS formation, and vitamin C (antioxidant) partially alleviated parthenolide-induced cell death. CONCLUSIONS: The results suggested that parthenolide at high concentrations caused cytotoxicity in cardiomyoblasts in part by inducing oxidative stress, and demonstrated the imperative for cautious and appropriate use of this agent in cardioprotection. KEY WORDS: Cardiomyoblast; Endoplasmic reticulum stress; Oxidative stress; Parthenolide; Reperfusion injury. PMID- 27122845 TI - Association of Serum Uric Acid with Cardiovascular Disease in Taiwanese Patients with Primary Hypertension. AB - BACKGROUND: Hyperuricemia is closely linked to hypertension and may be a marker of susceptibility or an intermediate step in the development of metabolic syndrome. However, recently, there have been conflicting conclusions regarding the independent role of uric acid as a risk factor of cardiovascular disease (CVD). The specific role of serum uric acid (SUA) in relation to CVD remains controversial, and there are limited reports utilizing Asian data available on this issue. Therefore, this study investigated the association between SUA and cardiovascular disease in Taiwanese patients with essential hypertension. METHODS: There were 3472 participants from 55-80 years of age (1763 males, 1709 females) from 38 sites across Taiwan in this hospital-based cross-sectional study, covering the period November 2005 to December 2006. The CVD included diagnosed angina pectoris, myocardial infarction, congestive heart failure, and stroke. RESULTS: Hyperuricemia is positively associated with CVD in both sexes when a unified cut-off SUA level of 7 mg/dl was used. However, the odds ratios (ORs) for all CVD were greater in magnitude in hypertensive women than in men when there was co-morbidity of diabetes. The ORs of all CVD in the diabetes subgroup were statistically significantly (p = 0.01 for women, p = 0.07 for men). By multivariate analysis, hyperuricemia did not confer an increased risk of CVD. CONCLUSIONS: Hyperuricemia may be associated with increased risk of CVD, but is not an independent risk factor of CVD in essential hypertensive Taiwanese patients. KEY WORDS: Cardiovascular disease; Hypertension; Hyperuricemia; Uric acid. PMID- 27122846 TI - Clinical Research on Brain Natriuretic Peptide Guiding the Application of beta1 Receptor Blocker in Patients with Moderate to Severe Heart Failure. AB - BACKGROUND: This study aimed to explore the feasibility of guiding the application of metoprolol succinate in patients with moderate to severe heart failure (HF) through monitoring plasma brain natriuretic peptide (BNP) levels. METHODS: A total of 195 patients with moderate to severe HF (NYHA Functional Class III to IV) were selected and randomized into two groups: an observation group and a BNP group. The groups were established to observe the clinical conditions and establish plasma BNP levels to guide the application of metoprolol succinate. The average start-up of metoprolol succinate and average dose of metoprolol succinate after one month, as well as the recurrence rate and mortality of HF during hospital stay were compared between the two groups. RESULTS: Start-up of metoprolol succinate was shorter in the BNP group than in the observation group [(5.89 +/- 1.76) d vs. (7.03 +/- 2.08) d, p < 0.01], but no significant differences in recurrence rate (26.60% vs. 23.91%, p > 0.05) and mortality (6.38% vs. 5.43%, p > 0.05) of HF were observed between the two groups. The average dose of metoprolol succinate after one month was higher in the BNP group compared with that of the observation group [(47.65 +/- 13.09) mg/d vs. (35.08 +/- 11.08) mg/d, p < 0.01]. CONCLUSIONS: Although monitoring plasma BNP might have limited the clinical impact on the change of left ventricular ejection fraction, recurrence of HF or mortality within 1 month, it could safely facilitate early use and up-titration of the metoprolol succinate in patients with moderate to severe HF. KEY WORDS: BNP; Heart failure; beta receptor blocker. PMID- 27122847 TI - Arterial Stiffness Index and Coronary Artery Plaques in Patients with Subclinical Coronary Atherosclerosis. AB - BACKGROUND: Arterial stiffness is a physiologic quantitative value used to measure arterial compliance. It is predictive of coronary atherosclerosis in patients with intermediate to high cardiovascular risk. However, a correlation between arterial stiffness and subclinical coronary atherosclerosis has yet to be established. Therefore, the purpose of this study was to evaluate arterial stiffness using an arterial stiffness index (ASI) and investigate its association with coronary artery plaque in patients with subclinical coronary atherosclerosis. METHODS: Our study enrolled 156 consecutive subjects who underwent health screening using a 64-slice cardiac computed tomography angiography (CCTA). Their arterial stiffness index was assessed noninvasively by CardioVision((r)) MS-2000. The atheroma on the coronary vessel walls was analyzed. RESULTS: Of the 156 patients, 53 displayed at least one > 50% stenotic lesion over the coronary arteries in CCTA images. The patients with at least one > 50% coronary stenotic plaque were older and had higher systolic blood pressure and ASI values than patients without > 50% coronary stenotic plaque. After dividing the study population into 2 groups by those patients over and under 50 years of age, the ASI positively correlated with the presentation of at least one > 50% coronary stenotic plaque in patients aged >= 50 years (odds ratio = 1.02, 95% confidence interval: 1.00-1.04, p = 0.03). CONCLUSIONS: The ASI could play a role in risk stratification systems for coronary artery disease in patients with subclinical coronary atherosclerosis, and is a useful clinical marker for the correlation of early coronary plaque. KEY WORDS: Arterial stiffness; Arterial stiffness index; Atherosclerosis; Coronary artery plaque. PMID- 27122849 TI - Transradial Percutaneous Coronary Intervention in a Patient with a Rare Coronary Anomaly: Twin Circumflex Arteries. AB - Coronary artery anomalies are rare in population and most of them are found incidentally during coronary angiography. Percutaneous treatment of critical lesions on anomalous arteries may lead to difficulties due to their abnormal origin or course. Herein, we report a 65-year-old male patient presented with recent onset chest pain. Electrocardiogram and transthoracic echocardiography were in normal range. Treadmill exercise test revealed ST segment depression in lead V4-V6. Angiography revealed an unusual coronary anomaly: twin circumflex arteries originating from left main coronary artery and same orifice of right coronary artery, respectively. There was a significant stenosis on the right sided circumflex artery, which was treated percutaneously via transradial access. KEY WORDS: Coronary artery anomalies; Percutaneous coronary intervention; Transradial access; Twin circumflex arteries. PMID- 27122848 TI - A Novel Medical Treatment for Lipid Control in Patients with Unstable Angina Pectoris and Statin-Induced Liver Dysfunction. AB - BACKGROUND: This study aims to evaluate the safety and efficacy of Xuezhikang in the treatment of unstable angina pectoris (UAP) in patients with elevated liver enzymes caused by statins. METHODS: Ninety UAP patients with elevated liver enzymes (higher than 3-fold the upper limits of normal caused by statins) were randomly divided into 3 groups: withdrawal of simvastatin (group A), continued taking of simvastatin (group B) and switching to Xuezhikang capsules (group C). RESULTS: Blood lipids and high-sensitivity C-reactive protein (hs-CRP) were measured before and after treatment, and liver enzymes were measured every two weeks. As the liver enzymes of the patients in group A returned to normal, they could again undertake administration of simvastatin. If the liver enzyme levels remained abnormal at four weeks, polyene phosphatidylcholine would be added. The endpoint events of each group were followed-up. After treatment for 4 weeks, the liver enzymes decreased in all of the three groups and there was a significant difference (p < 0.05). However, at 8 weeks the liver enzymes showed no significant difference among the three groups (p > 0.05). The blood lipids and hs CRP were both reduced in group B and C. The decreased triglyceride and hs-CRP levels and increased high-density lipoprotein cholesterol level in group C were more remarkable than those in group B (p < 0.05). The incidence rate of endpoint events in group A was the highest (p < 0.05) among the three groups. CONCLUSIONS: Xuezhikang is safe and effective in the treatment for UAP patients with elevated liver enzymes caused by statins. KEY WORDS: Liver enzymes; Simvastatin; Unstable angina pectoris; Xuezhikang capsules. PMID- 27122850 TI - Urgent Balloon Aortic Valvuloplasty for Worsening Heart Failure in a Patient with Acute Myocardial Infarction and Critical Aortic Stenosis. AB - A 91-year-old man was admitted to our hospital with dyspnea and chest pain. His electrocardiogram showed ST-segment elevation in the V1-4 leads, and an emergency coronary angiogram revealed subtotal occlusion in the left descending coronary artery. A successful primary percutaneous coronary intervention was subsequently performed using aspiration thrombectomy and bare metal stent implantation. However, his hemodynamic condition deteriorated with severe pulmonary congestion. Administration of inotropes with diuretics and mechanical ventilation were not effective, and an echocardiogram showed coexisting severe aortic stenosis. As a bailout procedure, we performed balloon aortic valvuloplasty (BAV) with a 12- and 14-mm balloon on the next day. After BAV, the patient's condition improved, and he was weaned from the ventilator. It is commonly understood that onset of acute myocardial infarction may trigger worsening of heart failure in patients with compensated aortic stenosis. However, emergency balloon aortic valvuloplasty, when timely administered, is considered a simple and effective procedure for such patients, and can lead to substantial clinical improvement. KEY WORDS: Acute coronary syndrome; Balloon aortic valvuloplasty; Congestive heart failure; Valvular heart disease. PMID- 27122851 TI - Transcatheter Aortic Valve Implantation in a Woman with Porcelain Aorta, Previous Sternotomy for Coronary Artery Bypass Grafting, and Critical Aortic Stenosis. AB - A 74-year-old woman who was diagnosed with right breast cancer at age 39 had been treated with mastectomy, and repeated cycles of chemotherapy and radiotherapy. She also had a history of coronary artery disease, wherein two coronary artery bypass grafts were performed 3 years ago. At that time, porcelain aorta was detected during surgery. In the year prior to admission, the patient presented with severe symptomatic critical aortic stenosis. Due to the prohibitively high surgical risk and need for aortic valve replacement, she underwent successful transcatheter aortic valve implantation with transfemoral implantation of a 29 mm Medtronic CoreValve prosthesis. The patient experienced a good result with reduction of the transaortic gradient and mild residual aortic regurgitation. KEY WORDS: Aortic stenosis; Coronary artery bypass grafting; Porcelain aorta; Radiation; Transcatheter aortic valve implantation. PMID- 27122852 TI - Apical Hypertrophic Cardiomyopathy: The Ace-of-Spades as the Disease Card. AB - Apical cardiac hypertrophy (Yamaguchi syndrome) is a relatively rare form of hypertrophic cardiomyopathy. A 67-year-old woman presented with exertional angina and moderate dyspnea. Her electrocardiogram showed sinus rhythm, flattened T waves in the limb leads and a strain pattern in the V2-V6 leads. Echocardiographic examination showed that apical wall thickness of the left ventricle (LV) was 19 mm. Coronary angiography was normal, but left ventriculography revealed a spade-like shaped LV cavity, typical for apical cardiac hypertrophy. The diagnostic criteria for apical cardiac hypertrophy are: 1) asymmetric LV hypertrophy - predominantly at the apex of the ventricle; 2) LV wall thickness of 15 mm or more during diastole; and 3) apical to posterior wall thickness ratio of 1.5 or more determined by 2-dimensional echocardiography or cardiac magnetic resonance imaging. Although relatively rare, Yamaguchi syndrome must enter into the differential diagnosis of patients presenting with exertional angina pectoris. KEY WORDS: Angina pectoris; Hypertrophic cardiomyopathy. PMID- 27122853 TI - Hyperuricemia as an Outcome Predictor in Patients with ST-Segment Elevation Myocardial Infarction: Too Good to be True? PMID- 27122854 TI - Plasma High-Sensitivity C-Reactive Protein Level is Associated with Impaired Estimated Glomerular Filtration Rate in Hypertensives. AB - BACKGROUND: Both inflammation and chronic kidney disease (CKD) are related to cardiovascular disease. Whether inflammatory biomarkers are associated with impaired glomerular filtration rate (GFR) is unclear in hypertensives. METHODS: We recruited hypertension patients from the cardiovascular clinic of a tertiary medical center in Taiwan. GFR was calculated using the 7-item Modification of Diet in Renal Disease (MDRD) study equation and impaired GFR (IGFR) was defined as GFR less than 60 ml/min/1.73 m(2). High-sensitivity C-reactive protein (hsCRP) kits were used for the measurement of the CRP levels. RESULTS: In our study, 572 consecutive hypertensive patients were enrolled. The range of patient age was 26 91 years (mean 60.5 +/- 11.7), and hsCRP and GFR ranged from 0.01 to 9.99 mg/L and 16.6 to 239.6 ml/min//1.73 m(2), respectively. HsCRP levels were correlated with GFR (p = 0.01) and the presence of IGFR (p = 0.009). Multivariate regression analysis showed hsCRP (p = 0.03), age (p < 0.001) and urinary albumin-to creatinine ratio (UACR) (p = 0.002) are independent factors associated with GFR. Furthermore, hsCRP levels [odds ratio (OR) = 1.16, 95% CI = 1.03-1.31, p = 0.02], age (OR = 1.09, 95% CI = 1.07-1.12, p < 0.001), and UACR (OR = 1.02, 95% CI = 1.01-1.04, p < 0.001) independently predicted the presence of IGFR using binary logistic regression analysis. CONCLUSIONS: Information obtained from our study showed that hsCRP is associated with IGFR in hypertensives. KEY WORDS: Chronic kidney disease; C-reactive protein; Glomerular filtration rate; Hypertension; Inflammation. PMID- 27122855 TI - Significant Correlation between Brachial Pulse Pressure Index and Renal Resistive Index. AB - BACKGROUND: The renal resistive index (RI) is calculated as (peak systolic velocity - minimum diastolic velocity)/peak systolic velocity, and has been significantly associated with renal function. Pulse pressure index (PPI) is derived from a formula similar to renal RI, i.e. (systolic blood pressure - diastolic blood pressure)/systolic blood pressure. The purpose of this study was to investigate whether brachial PPI had a significant correlation with renal RI and could be used in identifying patients with impaired renal function. METHODS: We consecutively enrolled 255 patients referred for echocardiographic examination. The renal RI was measured from Doppler ultrasonography and blood pressure was measured from an ABI-form device. RESULTS: Patients with brachial PPI >= 0.428 (mean value of brachial PPI) had a lower estimated glomerular filtration rate (eGFR) than those with brachial PPI < 0.428 (p < 0.001). After the multivariate analysis was completed, brachial PPI had a significant correlation with renal RI (unstandardized coefficient beta = 0.53, p < 0.001). The areas under the curve for brachial PPI and renal RI in prediction of eGFR < 45 mL/min/1.73 m(2) were 0.682 and 0.893 (both p < 0.001), respectively. CONCLUSIONS: Brachial PPI was significantly correlated with renal RI. Patients with higher brachial PPI had a more reduced renal function. Hence, brachial PPI may be able to quickly reflect the intrarenal vascular hemodynamics, and may serve as an important tool for screening and follow-up for patients with abnormal renovascular resistance. KEY WORDS: Chronic kidney disease; Pulse pressure index; Resistive index. PMID- 27122856 TI - Proteinuria and Reduced Estimated Glomerular Filtration Rate Independently Predict Risk for Acute Myocardial Infarction: Findings from a Population-Based Study in Keelung, Taiwan. AB - BACKGROUND: The aim of this study was to evaluate the independent roles of proteinuria and reduced estimated glomerular filtration rate (GFR) in the development of acute myocardial infarction in a northern Taiwanese population. METHODS: We conducted a community-based prospective cohort study in Keelung, the northernmost county of Taiwan. A total of 63,129 subjects (63% women) >= 20 years of age who had no history of coronary heart disease were recruited and followed up. Univariate and multivariate proportional hazards regression analysis was performed to assess the association between proteinuria and estimated GFR and the risk of acute myocardial infarction. RESULTS: There were 305 new cases of acute myocardial infarction (114 women and 191 men) documented during a four-year follow-up period. After adjustment of potential confounding covariates, heavier proteinuria (dipstick urinalysis reading 3+) and estimated GFR of less than 60 ml/min/1.73 m(2) independently predicted increased risk of developing acute myocardial infarction. The adjusted hazard ratio (aHR) of heavier proteinuria for occurrence of acute myocardial infarction was 1.85 [95% confidence intervals (CI), 1.17-2.91, p < 0.01] (vs. the reference group: negative dipstick proteinuria). The aHR of estimated GFR of 30-59 ml/min/1.73 m(2) for occurrence of acute myocardial infarction was 2.4 (95% CI, 1.31-4.38, p < 0.01) (vs. the reference group: estimated GFR >= 90 ml/ min/1.73 m(2)), and that of estimated GFR of 15-29 ml/min/1.73 m(2) was 5.26 (95% CI, 2.26-12.26, p < 0.01). CONCLUSIONS: We demonstrated that both heavier proteinuria and lower estimated GFR are significant independent predictors of developing future acute myocardial infarction in a northern Taiwanese population. KEY WORDS: Acute myocardial infarction; Estimated glomerular filtration rate; Proteinuria. PMID- 27122857 TI - Association of Plasma Thrombospondin-1 Level with Cardiovascular Disease and Mortality in Hemodialysis Patients. AB - BACKGROUND: Thrombospondin-1 (TSP-1) is known to be involved in the regulation of angiogenesis, inflammation, and vascular function. Clinical studies have demonstrated its correlation with peripheral artery disease, coronary artery disease, and pulmonary hypertension. In this study, we explored its potential roles in the background of end-stage renal disease (ESRD). METHODS: A total of 140 ESRD outpatients (ages 61.0 +/- 12.4 years) were prospectively followed for 34 +/- 7 months. Their TSP-1 levels were analyzed from pre-hemodialysis blood sample. Cardiovascular survey included ankle- brachial index (ABI), echocardiography and Tl-201 dipyridamole single-photon emission computed tomography (SPECT). RESULTS: Plasma TSP-1 levels were higher in those patients with preexisting clinical evidence of cardiovascular disease (CVD) than those without (p = 0.002). TSP-1 concentrations were also correlated with ABI, left ventricular ejection fraction, and scar burden in SPECT. Stepwise logistic regression analysis revealed that TSP-1 level was independently associated with the presence of CVD, with an odds ratio of 1.38 [95% confidence interval (CI), 1.09-1.75, p = 0.008]. In survival analyses, 31 patients (22%) died during the follow-up, 16 (52%) arising from cardiovascular causes. Cox hazards analysis revealed that the patients with TSP-1 levels in the highest tertile had a 5.32- and 6.75-fold higher risk for all-cause and cardiovascular mortality than those in the lowest tertile. This predictive value for all-cause mortality still persisted after multivariate adjustment (hazard ratio, 8.71; 95% CI, 1.36-55.68; p = 0.02). CONCLUSIONS: This study hallmarks the association of elevated TSP-1 level with CVD and adverse outcome among hemodialysis patients. KEY WORDS: Thrombospondin-1; End-stage renal disease; Cardiovascular disease; Mortality. PMID- 27122858 TI - The Effects of Niacin on Inflammation in Patients with Non-ST Elevated Acute Coronary Syndrome. AB - BACKGROUND: In this study, we aimed to evaluate the effects of niacin on high sensitivity C reactive protein (hs-CRP) and cholesterol levels in non-ST elevated acute coronary syndrome (NSTE-ACS) patients. METHODS: In this prospective, open label study, 48 NSTE-ACS were randomized to niacin or control group. Patients continued their optimal medical therapy in the control group. In the niacin group patients were assigned to receive extended-release niacin 500 mg/day. Patients were contacted 1 month later to assess compliance and side effects. Blood samples for hs-CRP were obtained upon admittance to the coronary care unit, in the third day and in the first month of the treatment. Fasting blood samples for cholesterol levels were obtained before and 30 days after the treatment. The primary end point of the study was to evaluate changes in hs-CRP, cholesterol levels, short-term cardiovascular events, and the safety of niacin in NSTE-ACS. RESULTS: Baseline demographic, clinical and laboratory characteristics were similar between the two groups. Logarithmic transformation of baseline and 3(rd) day hs-CRP levels were similar between the groups; but 1 month later, logarithmic transformation of hs-CRP level was significantly lower in the niacin group (0.43 +/- 0.39 to 0.83 +/- 0.91, p = 0.04). HDL-C level was significantly increased in the niacin group during follow-up. Drug related side effects were seen in 7 patients in the niacin group but no patients discontinued niacin. CONCLUSIONS: Our findings demonstrate that lower dose extended release niacin can be used safely and decreases hs-CRP and lipid parameters successfully in NSTE-ACS patients. KEY WORDS: Acute coronary syndrome; hs-CRP; Inflammation; Niacin. PMID- 27122859 TI - Shorter Door-to-Balloon Time in ST-Elevation Myocardial Infarction Saves Insurance Payments: A Single Hospital Experience in Taiwan. AB - BACKGROUND: The relationship between quality of care and cost of medical services is a popular topic. In this study, we examined whether a reduced door-to-balloon (D2B) time led to cost savings, benefitted insurance payers, and improved patient outcomes. METHODS: We retrospectively enrolled consecutive patients who presented with ST-segment elevation myocardial infarction (STEMI) and received primary percutaneous coronary intervention (PCI) between Feb. 1, 2007, and Jul. 31, 2009, at a tertiary hospital in Taiwan. The patient data were collected by chart review. We utilized claims data from the hospital financial system as the proxy for insurance payer costs. We only included the claims data, regardless of whether patients were inpatients or outpatients, associated with the first three cardiovascular related ICD-9 codes. Multivariable logistic regression was used to examine the relationships between the D2B time, in-hospital mortality and one year cardiovascular readmission. We utilized a multivariable linear regression to test the relationships between the D2B time, hospitalization cost and one-year cardiovascular-related cost. RESULTS: The D2B time did not influence the in hospital mortality rate, but a D2B time greater than 90 min increased the probability of one-year cardiovascular readmission (p = 0.018). The D2B time did not increase the index hospitalization cost, but patients with a D2B time above 90 min had 14.6% higher one-year cardiovascular- related costs. CONCLUSIONS: Our study shows that the D2B time in patients with STEMI could impact the one-year cardiovascular readmission and one-year cardiovascular-related health cost. These results suggest that the pursuit of high-quality care not only leads to better outcomes, but also reduces costs. KEY WORDS: Acute myocardial infarction; Cost; Door-to-balloon time; Insurance payer; Quality. PMID- 27122860 TI - Impact of Aortic Stiffness Evaluated by Aortic Pulsatility on Fractional Flow Reserve. AB - BACKGROUND: Fractional flow reserve (FFR) is a highly reproducible, accurate and lesion-specific index to indicate inducible ischemia for a particular coronary artery lesion. Invasively measured aortic pulsatility (AP) is an indicator of aortic stiffness. In this study we aimed to evaluate the possible impact of AP in terms of aortic stiffness on FFR measurement. METHODS: In this study, we reviewed the FFR evaluation of 90 patients who had intermediate lesions (40-70% stenosis measured with quantitative coronary analysis) at the left anterior descending artery (LAD). AP was calculated as the ratio of aortic pulse pressure (systolic diastolic pressure) to mean pressure. RESULTS: Aortic systolic pressure, aortic diastolic pressure, aortic pulse pressure and also aortic pulsatility did not differ significantly between patients with FFR <= 0.80 and FFR > 0.80 (p = 0.44, p = 0.28, p = 0.93 and p = 0.41, respectively). In subgroups arranged according to the degree of luminal narrowing (40-50%, 51-60%, and 61-70%), we did not observe significant correlation between AP and FFR value in subgroups with 40-50% and 51-60% lesions (r = 0.03, p = 0.95 and r = 0.07, p = 0.69, respectively). However, a statistically significant negative correlation between FFR value and AP in the subgroup of patients with 61-70% lesions was detected (r = -0.54, p = 0.04). CONCLUSIONS: These findings suggested that aortic stiffness might have a possible impact on FFR measurement in coronary lesions of 61-70% stenosis evaluated quantitatively. KEY WORDS: Aortic pulsatility; Fractional flow reserve; Stiffness. PMID- 27122861 TI - Effects of Tissue-Type Plasminogen Site-Specific Transgene in Gelatin-Coated Dacron on the Fibrinolysis Activity of Rabbit Left Atrium. AB - BACKGROUND: To investigate the effects of tissue-type plasminogen activator (tPA) gene transfer with left-atrium local positioning on the fibrinolytic activity of rabbit left atrial blood. METHODS: A total of 48 rabbits were randomly divided into 3 groups (n = 16): gene therapy, vector control, and blank control groups. Each group was divided into 2 subgroups (8 rabbits in each subgroup) according to the sacrifice time on the postoperative 3(rd) and 14(th) days. The tPA mRNA transcriptional level and exogenous tPA protein expression within regional myocardial tissues of the left atrium were detected on the postoperative 3(rd) and 14(th) days. After excluding the animals that died, 6 samples of each subgroup were randomly selected for the statistics (n = 6). RESULTS: The tPA activities in rabbit left atrial blood and peripheral blood were also detected. The tPAmRNA and tPA protein expressions within regional myocardial tissues were detected on the postoperative 3(rd) and 14(th) days. The tPA activity in left atrial blood in the gene therapy group was higher than the tPA activity of other groups (p < 0.02). No significant differences were observed in the tPA activity of peripheral blood among the 3 groups before surgery. A gelatin-coated Dacron piece, which carried the tPA gene, was implanted in the left atrial appendage. CONCLUSIONS: The gelatin-coated Dacron piece could express and secrete tPA proteins in the region, thus enhancing the fibrinolytic activity of left atrial blood. KEY WORDS: Fibrinolytic activity; Gelatin coating; Gene; Left atrium; Tissue-type plasminogen activator. PMID- 27122862 TI - Locally Deliver the Tissue-Type Plasminogen Activator (tPA) Plasmid for Preventing Thrombosis. PMID- 27122863 TI - Percutaneous Transluminal Angioplasty and Stenting for Hepatic Vessel Stenosis after Orthotopic Liver Transplantation. AB - BACKGROUND: This study aimed to evaluate the efficacy of vascular intervention in percutaneous transluminal angioplasty (PTA) for the treatment of hepatic artery and hepatic vein stenosis after liver transplantation (LT), including thrombotic total occluded lesions. METHODS: Percutaneous transluminal angioplasty after orthotopic liver transplantation was performed to re-open hepatic vessel lesions. We daily used routine Doppler ultrasound during admission for early detection of graft hepatic vessel lesions, including hepatic artery and vein lesions. In outpatients, Doppler ultrasound was performed every month. Urokinase was delivered with a dose of 150,000-300,000 IU by catheter before PTA for thrombotic total occlusion of the graft for hepatic artery patients. Laboratory data were collected to evaluate the effects of the PTA procedure. RESULTS: The study involved a total of seven patients, six of whom were successfully treated by a first PTA procedure. Thrombolysis use of urokinase in totally occluded donor hepatic arteries post-LT following stenting was successful in three patients. One complication occurred, an arterial dissection and perforation, finalizing the success rate at ~86% and the complication rate at ~14%. Therefore, our study has a primary patency rate of 100% at 1 and 3 months. Also, the graft survival rate was 100 % and 86 % in the first and third months, respectively. CONCLUSIONS: PTA with stenting is an effective treatment for hepatic vessel stenosis, including hepatic arteries and hepatic veins, after a liver transplantation without an increase in the complication rate. In addition, thrombolysis using urokinase intra-artery infusion in graft thrombotic total occluded patients is a good treatment strategy as well. KEY WORDS: Angioplasty; Complication; Liver transplantation. PMID- 27122864 TI - Effect of Tempol on Cerebral Resuscitation Caused by Asphyxia-Induced Cardiac Arrest. AB - BACKGROUND: This study was conducted to investigate the effect and mechanism of the nitrogen oxide 4-hydroxy- 2,2,6,6-tetramethylpiperidine (Tempol) on cerebral resuscitation caused by asphyxia-induced cardiac arrest. METHODS: Airway occlusion-induced asphyxia at the end of expiration was used to establish the rat cerebral ischaemia-hypoxia injury model. A total of 90 adult male Sprague-Dawley rats were randomly divided into the three groups. The Tempol and conventional cardiopulmonary resuscitation (CPR) groups were further divided into four subgroups according to different time points. RESULTS: After cerebral ischaemia, independent heart rate following asphyxia appeared earlier, and the success rate of primary recovery and the neurological function score of rats were higher in the Tempol group than in the conventional CPR group. The serum neuron-specific enolase (NSE) levels in the Tempol and conventional CPR groups were significantly higher within 6 to 48 h than that in the blank control group. The serum NSE level was significantly lower in the Tempol group than the conventional CPR group. CONCLUSIONS: After global cerebral ischaemia-hypoxia, the antioxidant Tempol improved cerebral resuscitation by reducing oxidative stress injuries and post CPR cerebral damage. The NSE level can be used as an early detection index in the diagnosis of global cerebral ischaemia-hypoxia injuries. KEY WORDS: Cerebral ischemia; Neuron-specific enolase; Rats; Tempol. PMID- 27122865 TI - Management of a Primary Cardiac Neoplasm with Tumor Blush by a Stent Graft. AB - Primary cardiac tumors are rare. When they do occur, their symptoms and signs depend on the location and size of the tumor. Imaging multimodalities play an important role in evaluating cardiac tumors. "Tumor blush" is a specific character of certain cardiac tumors on coronary angiography. The current treatment of these tumors is associated with observed clinical symptoms, and the main treatment option is surgical resection. Coronary stent grafts have been used for treatment of coronary artery perforation, coronary pseudoaneurysm, and coronary artery fistula. In this article, we presented a 53-year-old woman who had a cardiac tumor with tumor blush complicated by pericardial effusion which was medically managed by use of a stent graft. KEY WORDS: Cardiac neoplasm; Stent graft; Tumor blush. PMID- 27122866 TI - Consecutive Sessions of Rescue Balloon Aortic Valvuloplasty for Critical Aortic Valve Stenosis Followed by Successful Bridging to Trans-Catheter Aortic Valve Implantation. AB - Percutaneous balloon aortic valvuloplasty (BAV) was a rare procedure in catheterization laboratories because of its limited prognostic impact. The recent advent of transcatheter aortic valve implantation (TAVI) has led to a resurgence of BAV, opening the way to a new indication as a bridge to TAVI. Herein, we reported an 83-year-old man with critical aortic valve stenosis and pulmonary edema, who strongly declined surgical aortic valve replacement. He also lacked financial support or insurance reimbursement for TAVI. He received BAV for relief of syncope, pulmonary edema and impending respiratory failure 4 times within 4 years and was successfully bridged to TAVI after receiving charity aid funding from the hospital. KEY WORDS: Aortic valve stenosis; Balloon aortic valvuloplasty (BAV); Transcatheter aortic valve implantation (TAVI). PMID- 27122867 TI - Chronic Papillary Muscle Rupture: 14-Year Survival without Surgical Treatment. AB - Papillary muscle rupture is a life-threatening complication of myocardial infarction which is usually refractory to medical treatment. We present a very rare case of a 65-year-old woman who had a myocardial infarction and posteromedial papillary muscle rupture which was only treated with medical therapy, including her corresponding 14-year follow-up. However, surgical intervention is still strongly recommended because the prognosis of acute papillary muscle rupture associated with myocardial infarction remains poor. KEY WORDS: Complication; Myocardial infarction; Papillary muscle rupture; Survival. PMID- 27122868 TI - Nightmare: Simultaneous Subacute Stent Thrombosis of Different New-Generation Drug-Eluting Stents in Multiple Coronary Arteries. AB - Simultaneous stent thrombosis (ST) of first-generation drug-eluting stents (DES) has been rarely reported and could lead to high morbidity and mortality. However, to date there was no literature discussing simultaneous ST of different new generation DESs in multiple coronary arteries. Herein, we report a 60-year-old male suffering from acute myocardial infarction complicated with cardiogenic shock. He had percutaneous coronary intervention (PCI) performed approximately 7 days prior to admission at a local teaching hospital, with different DES devices implanted over the left anterior descending and the left circumflex artery. Emergency coronary angiography revealed simultaneous subacute ST over both vessels. After PCI, there was a gradual improvement in both cardiogenic shock and acute pulmonary edema. High dose clopidogrel (150 mg) was used initially, which was later shifted to ticagrelor. Genetic testing of CYP2C19*2 G681A polymorphism revealed heterozygous genotype and platelet function testing showed substantial inhibition after a medication change. This rare case should remind physicians that new-generation DES thrombosis in multiple vessels is still a possible complication of PCI, and checking genetic and/or platelet function testing might be indicated in these high risk patients. The use of a new antiplatelet drug was also strongly suggested to avoid possible clopidogrel resistance. KEY WORDS: Clopidogrel resistance; Drug-eluting stents; Genetic testing; Platelet function; Stent thrombosis. PMID- 27122869 TI - Atrial Functions and Aortic Elasticity in Children with Aortic Coarctation. AB - BACKGROUND: Coarctation of the aorta (CoA) is a chronic vascular disease characterized by a persistence of myocardial and vascular alterations. We aimed to evaluate children who have had successful coarctation surgery or balloon dilatation to evaluate the elasticity of the aorta, left atrial ejection force (AEF) and myocardial performance collectively at midterm follow-up. METHODS: Nineteen patients (7.15 +/- 0.9 years of age) and 21 age-sex matched healthy children were included in this study. Left AEF index is defined as the product of mass and acceleration of blood expelled from the left atrium. Aortic stiffness and distensibility were estimated using ascending and descending aorta diameters. RESULTS: The left atrial force index [(g?cm/s(2))/m(2)] in the patient group was found to be significantly higher (12.69 +/- 7.29, 5.74 +/- 2.59, respectively, p = 0.001). Distensibility of the ascending aorta (cm(2)/dynes 10(-6)) was significantly lower in the patient group than in the control group (42.13 +/- 24.02, 78.79 +/- 20.49, respectively, p < 0.001). The stiffness index of the ascending aorta was significantly higher in the patient group (p < 0.001). We also documented that atrial force index is associated with peak E velocity, right arm systolic blood pressure and left ventricular mass index. CONCLUSIONS: Our investigation showed that AEF is higher in children who have had successful coarctation surgery or balloon dilatation, and AEF is associated with systolic blood pressure, peak E velocity and left ventricular mass index. Distensibility of the ascending aorta was lower, and stiffness index was higher in children with corrected CoA than in healthy subjects. KEY WORDS: Atrial ejection force; Balloon dilatation; CoA; Coarctation surgery; Distensibility; Stiffness index. PMID- 27122870 TI - Six-Minute Walking Test: Normal Reference Values for Taiwanese Children and Adolescents. AB - BACKGROUND: The 6-minute walking test (6MWT) is a simple method used to evaluate exercise capacity in adults and children with cardiac diseases. Normal reference values in pediatric populations have been reported, but significant variations in the walking distance (6MWD) were noted among different studies. We aimed to provide and validate normal reference values of the 6MWD for healthy Taiwanese pediatric population between 7 and 17 years of age. METHODS: Healthy children and adolescents were recruited from 13 randomly selected schools in Kaohsiung City. From that recruitment effort, 762 participants (50.1% male) were included, and the 6MWT was conducted using standardized protocols. The main outcome measure utilized was the 6MWD, which was used to construct centile charts and Z score equations. Data from additional 64 healthy volunteers recruited from the National Taiwan University Children's Hospital were used to validate these standards. RESULTS: There was an overall linear trend of increase in the 6MWD between 7 and 17 years of age (p < 0.001). Males covered significantly more distance than females after the age of 14 years, when the 6MWD essentially plateaued in female adolescents. Upon multivariate analysis, height was the most significant positive predictor of the 6MWD, while body mass index negatively correlated with the 6MWD. The height-based normal reference values of the 6MWD, derived from the 6MWT conducted in the school settings, were validated by a second cohort who received 6MWT inside the hospital. CONCLUSIONS: Normal reference values of the 6MWD in healthy Taiwanese children and adolescents may serve as useful references for future clinical and research studies. KEY WORDS: Adolescents; Children; Six minute walking test; Taiwan. PMID- 27122871 TI - Application of the Transtheoretical Model to Exercise Behavior and Physical Activity in Patients after Open Heart Surgery. AB - PURPOSE: To assess exercise behavior and physical activity levels after open heart surgery. METHODS: This prospective cohort study included 130 patients (70.8% male, aged 61.0 +/- 12.2 years, 53.8% coronary bypass grafting) who underwent open heart surgery. The exercise behavior and physical activity of these patients were assessed at the 3- and 6-month follow-up appointments. Additional interviews were also conducted to further assess exercise behavior. Physical activity duration and metabolic equivalents were calculated from self reported questionnaire responses. Moreover, possible related demographic factors, clinical features, participation in cardiac rehabilitation programs, and physical activity levels were additionally evaluated. RESULTS: Six months after hospital discharge, most patients were in the action (39.2%) and maintenance (37.7%) stages. Other subjects were in the precontemplation (11.5%), contemplation (5.4%), and preparation (6.2%) stages. The average physical activity level was 332.6 +/- 377.1 min/week and 1198.1 +/- 1396.9 KJ/week. Subjects in the action and maintenance stages exercised an average of 399.4 +/- 397.6 min/week, significantly longer than those in other stages (116.2 +/- 176.2 min/week, p = 0.02). Subjects that participated in outpatient cardiac rehabilitation programs after discharge may have the better exercise habit. Gender had no significant effect on exercise behavior 6 months after hospital discharge. CONCLUSIONS: Most subjects following open heart surgery may maintain regular exercise behavior at 6 months after hospital discharge. Physical activity levels sufficient for cardiac health were achieved by subjects in the active and maintenance stages. Outpatient cardiac rehabilitation programs are valuable for encouraging exercise behavior after heart surgery. KEY WORDS: Exercise behavior; Open heart surgery; Physical activity; Transtheoretical model. PMID- 27122872 TI - Differentiation of Enhanced Green Fluorescent Protein-Labeled Mouse Amniotic Fluid-Derived Stem Cells into Cardiomyocyte-Like Beating Cells. AB - BACKGROUND: Amniotic fluid-derived stem cells (AFSCs) possess optimal differentiation potential and are a promising resource for cell therapy and tissue engineering. Mouse is a good model to be studied for pre-clinical research. METHODS: In this study, we successfully established enhanced green fluorescent protein mouse-derived amniotic fluid stem cells (EGFP-mAFSCs) and investigated whether EGFP-mAFSCs possess the ability to differentiate into cardiomyocytes by in vitro culture. We evaluated stem-cell differentiation using immunofluorescence. RESULTS: This study showed that EGFP-mAFSCs can give rise to spontaneously beating cardiomyocyte-like cells expressing the specific markers c kit, myosin heavy chain, and cardiac troponin I. CONCLUSIONS: We demonstrated that mAFSCs have the in vitro propensity to acquire a cardiomyogenic phenotype and to a certain extent cardiomyocytes; however the process efficiency which gives rise to cardiomyocyte-like cells remains quite low (2 out of 10 were found). KEY WORDS: Amniotic fluid; Cardiomyocytes; In vitro differentiation; Stem cells. PMID- 27122873 TI - Effects of Door-to-Balloon Times on Outcomes in Taiwanese Patients Receiving Primary Percutaneous Coronary Intervention: A Report of Taiwan Acute Coronary Syndrome Full Spectrum Registry. AB - PURPOSE: The impact of door-to-balloon (DTB) time on patient outcomes is unclear in a Taiwanese population receiving primary percutaneous coronary intervention (PCI). The study aimed to investigate the relationship between stratified DTB times and outcomes through analysis of the database from the Taiwan acute coronary syndrome full spectrum registry. METHODS: Relevant data were collected from case report forms of patients receiving primary PCI who were categorized as group 1, 2, 3, and 4 according to the DTB time < 45, 45-90, 91-135, and > 135 minutes, respectively. The differences were analyzed by using ANOVA and Kaplan Meier analyses. RESULTS: There were significant variations in DTB times at baseline, which included patients salvaged at centers, patients with prior cardiovascular disease, and those patients with different coronary artery flows (p < 0.01) separated into 4 groups (n = 189, 443, 299, and 401, respectively). The in-hospital adverse event rates were identical among the 4 groups except for a higher rate of acute renal failure and a longer hospital stay observed in group 4 (p < 0.01). The results showed no decrease in the incidences of repeated revascularization, major adverse cardiac event, or cardiovascular composite at 1 year in group 1. CONCLUSIONS: This study suggested that the DTB time is not a good determinant for outcomes in Taiwanese patients receiving primary PCI. KEY WORDS: Acute myocardial infarction; Cardiovascular outcome; Door-to-balloon time; Myocardial ischemia; Percutaneous coronary intervention. PMID- 27122874 TI - Left Ventricular Dyssynchrony Predicts Left Main Coronary Artery Disease in Patients with Non-ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: The purpose of our study was to examine whether left ventricular dyssynchrony predicts left main coronary artery stenosis in patients with non-ST segment elevation myocardial infarction. METHODS: A total of 100 consecutive patients with non-ST-segment elevation myocardial infarction underwent echocardiography and coronary artery angiography. The 3-dimensional echocardiography-derived left ventricular dyssynchrony parameter was determined by using the standard deviation of the time to the minimal systolic volume for the 16 segments. A stenosis >= 50% of the diameter of the left main coronary artery or a stenosis >= 70% in 1 or more of the major epicardial vessels or their main branches was considered significant. RESULTS: The logistic regression analysis revealed that this parameter (odds ratio 1.2; 95% confidence interval, 1.01-1.42; p = 0.04) was the independent predictor of left main coronary artery stenosis. The receiver operating characteristic curve analysis revealed 8.86 as the optimal cutoff value to predict left main coronary artery stenosis (sensitivity, 71.4%; specificity, 89.2%). CONCLUSIONS: The assessment of left ventricular dyssynchrony by 3-dimensional echocardiography is useful for a noninvasive diagnosis of the left main coronary artery stenosis in patients with non-ST-segment elevation myocardial infarction. KEY WORDS: Dyssynchrony; Left main coronary artery stenosis; Non-ST-segment elevation myocardial infarction. PMID- 27122875 TI - Anatomic Consideration of Stitch Depth in Tricuspid Valve Annuloplasty. AB - BACKGROUND: The durability of De Vega's tricuspid valve annuloplasty might be related to tension of the annulus and could be reinforced by increasing stich depth. However, depth of stitches to date has not been addressed in the literature. Thus, it is important to better understand the anatomical distance between the tricuspid valve annulus and the right coronary artery. METHODS: From 1998 to 2009, we measured the distances between TV annulus and RCA (TRD) on 46 explanted human hearts during heart transplantation. Five points were measured from the anterior/septal leaflet commissure to the posterior/septal leaflet commissure clockwise. Statistical significance was tested in the analyses. RESULTS: We found the TRD were independent from sex, age, body weight, and etiology. With a minimum of 10 mm at the posterior/septal leaflet commissure, the distances increased counterclockwise to the maximum of 20 mm at the anterior/septal leaflet commissure. CONCLUSIONS: Stitch depth within 10 millimeter will not injure the right coronary artery in making De Vega's tricuspid annuloplasty. KEY WORDS: De Vega's tricuspid valve annuloplasty. PMID- 27122876 TI - A Novel Technique for Percutaneous Coronary Intervention for Anomalous Right Coronary Artery Arising from the Left Sinus of Valsalva. AB - BACKGROUND: Percutaneous coronary intervention (PCI) for anomalous right coronary artery (RCA) arising from the left sinus of Valsalva (LSOV) is a technical challenge due to inadequate guiding catheter support to overcome the acute rightward course of the anomalous RCA. In this study we describe a novel technique for PCI for an anomalous RCA arising from the LSOV. METHODS: Six patient cases with anomalous RCA arising from the LSOV who underwent PCI from January 2001 to January 2014. The Judkins left (JL) guiding catheter tip orientation is modified by manually bending at the distal tip 90 degrees vertically to fit the acute rightward course. RESULTS: Of the six patients (mean age: 63 +/- 16.7 years), the indication for PCI was acute inferior myocardial infarction (MI) in two, recent inferior MI in two, and angina in two of the cases. Three procedures were performed via a transfemoral approach and the other three via a transradial approach. The median duration of the intervention and total procedure time were 44 and 69.5 minutes, respectively. All patients received successful revascularization without complications. CONCLUSIONS: This novel technique is simple, safe and effective with a 100% procedure success rate for PCI for anomalous RCA arising from the LSOV. KEY WORDS: Anomalous right coronary artery; Left sinus of Valsalva; Percutaneous coronary intervention. PMID- 27122877 TI - Fainting After Chest Pain. AB - Variant angina presenting acute chest pain and ST elevation on electrocardiogram accounts for an underdiagnosed scenario in acute coronary syndrome and contributes to syncope as a consequence of ventricular arrhythmia. Here, we report a case of a 48-year-old man with a recent onset of chest pain and palpitations followed by syncope. Holter monitoring documented 2 episodes of evolving ST elevation associated with non-sustained ventricular tachycardia. Emergent cardiac catheterization indicated insignificant coronary narrowing. A non-invasive brachial artery ultrasound, which demonstrated endothelial dysfunction that was salvaged by exogenic nitrate, was used instead of intracoronary provocation. There was no clinical or electrocardiographic recurrence of variant angina after vasodilator treatment. In conclusion, variant angina represents an important but overlooked etiology for syncope. Holter monitoring facilitates the diagnostic and prognostic assessment in patients with syncope precipitated by chest pain. KEY WORDS: Flow-mediated vasodilation; Holter monitoring; Variant angina; Ventricular arrhythmia. PMID- 27122878 TI - Complete AV Block and Torsades de Pointes in a Case of Primary Cardiac T-Cell Lymphoma. AB - Primary cardiac lymphoma is very rare, and the most common electrocardiographic finding in this condition is complete atrioventricular block. After electrolytic, metabolic, ischemic, infectious, and traumatic etiologies have been excluded, primary cardiac lymphoma should be consided as a possible cause of reversible atrioventricular block. Most patients with primary cardiac lymphoma are immunocompromised and have disease with a B-cell etiology. This is the first case report of a primary cardiac T-cell lymphoma with complete atrioventricular block and torsades de pointes in an immunocompetent patient who was successfully treated using chemotherapy. KEY WORDS: Atrioventricular block; T-cell lymphoma; Torsades de pointes. PMID- 27122879 TI - Prolonged Use of Levitronix Left Ventricular Assist Device as a Bridge to Heart Transplantation. AB - A 61-year-old male presented to our emergency room with chest tightness, dyspnea, and cold sweat. He underwent a 12-lead EKG which showed ST-elevation from leads V1-V4 and T wave inversion in leads II, III, and aVF. His troponin-I level was elevated to 70.3 ng/ml. He went into cardiogenic shock when he was in the catheter room. After advanced cardiac life support was administered for 30 min, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) cannulation was set up using 21-french arterial and 21-french venous cannula through the right femoral artery and right femoral vein by the puncture method for hemodynamic support. Subsequently, a coronary artery bypass graft (CABG) for acute myocardial infarction was performed. However, the patient was unable to be weaned from the VA-ECMO. Four days later, a CentriMag (Levitronix LLC, Waltham, MA, USA) left ventricular assist device (LVAD) was applied to avoid ECMO-related complications such as severe hemolysis, ischemic, deteriorated liver and renal function. The patient subsequently underwent a successful orthotopic heart transplant after 87 days on the CentriMag LVAD. The patient was extubated on the next postoperative day and was discharged 2 weeks later. KEY WORDS: Acute myocardial infarction; Extracorporeal membrane oxygenation; Heart transplantation; Ventricular assist device. PMID- 27122880 TI - "DK Crush" Technique for a Tightly Stenosed Conjoined SVG Lesion in a Patient with Acute Coronary Syndrome and Cardiogenic Shock. AB - Coronary artery bifurcation disease of saphenous venous graft (SVG) is extremely rare. SVG disease remains a challenging lesion to treat because of increased morbidity and mortality with repeated coronary artery bypass graft surgery (CABG), high rates of periprocedural complications, and in-stent restenosis or occlusion requiring repeat revascularization with percutaneous coronary intervention. Herein, we present the first reported case of using the "DK crush" technique to treat an inverted Y-shaped SVG bifurcation disease in a patient with a prior CABG and new-onset acute coronary syndrome. Arising from our treatment, favorable immediate and mid-term angiographic and clinical outcomes were obtained. KEY WORDS: Coronary artery bypass surgery (CABG); "DK crush" technique; Saphenous venous graft (SVG). PMID- 27122881 TI - Tumor Invasion of Myocardium Presented with Acute Coronary Syndrome. AB - Cardiac metastases of malignant tumors are rare but associated with various presentations, including arrhythmia, heart failure and myocardial infarction. However, it may also cause typical electrocardiographic (ECG) changes, mimicking ST-segment elevated myocardial infarction (STEMI) when patients have chest pain. We reported a 59 year-old woman with cardiac metastases of buccal squamous cell carcinoma, which presented with myocardial infarction ECG pattern due to both atrial and ventricular involvements. Rather than alternatives to emergent coronary angiogram may be considered, thrombolytic therapy for acute myocardial infarction could be inappropriate in that it creates a risk for patients with malignancies in certain situations mimicking STEMI. KEY WORDS: Arrhythmia; Cardiac tumor; ST-segment elevated myocardial infarction. PMID- 27122883 TI - Editorial Comment. PMID- 27122882 TI - Percutaneous Coronary Intervention for Left Main Coronary Artery Disease - A Single Hospital Experience without On-Site Cardiac Surgery. AB - BACKGROUND: To investigate the safety and outcome of percutaneous coronary intervention for left main coronary artery disease in hospital without on-site cardiac surgery. METHODS: Between January 2007 and December 2010, all patients diagnosed with left main coronary artery disease and refused coronary artery bypass graft surgery in our hospital or a tertiary center, were enrolled. Data including clinical course, angiographic characteristics, and 1- and 3-years outcomes were recorded and analyzed. RESULTS: Seventy patients (mean age 73.4 +/- 10.2 years, 47 male, 23 females) were treated with a mean SYNTAX score of 34.8 +/ 12.6 and EuroSCORE of 6.7 +/- 3.3. Thirty-two (45.7%) patients had stable angina, 35 (50.0%) had unstable angina/non ST-elevation myocardial infarction, and 3 (4.3%) had ST-elevation Myocardial infarction. Forty-three (61.4%) patients received a single-stent, 26 (37.1%) received two-stents, and 1 (1.4%) received balloon angioplasty. No procedure-related mortalities were noted and no emergency coronary artery bypass graft surgery was required. In the 3-year follow-up period, 2 (2.9%) patients had non-fetal myocardial infarction, 11 (15.7%) had left main target lesion revascularization. The major adverse cardiac and cerebrovascular events rates were 24.3% at 1 year and 37.1% at 3-years. The all cause mortality rate was 41.4% (29 patients), including 18 (25.7%) cases of septic shock, 7 (10.0%) of sudden cardiac death, 2 (2.8%) of hypovolemic shock due to upper gastrointestinal bleeding, 1 (1.4%) of terminal stage malignancy, and 1 (1.4%) of suffocation at 3 years. CONCLUSIONS: Percutaneous coronary intervention for patients with left main coronary artery disease was found to be a safe and effective strategy in our hospital without on-site cardiac surgery. KEY WORDS: Incomplete revascularization; Left main coronary artery (LM); No cardiac surgery; Percutaneous coronary intervention (PCI). PMID- 27122884 TI - Impact of Prolonged Door-to-Balloon Times on the Diastolic Function in Acute ST Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention. AB - BACKGROUND: Emerging evidence indicates that diastolic left ventricular (LV) function is a powerful outcome predictor after acute ST-elevation myocardial infarction (STEMI). We hypothesized that shorter door-to-balloon (D2B) times with early restoration of coronary perfusion may preserve diastolic LV function in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). METHODS: This study enrolled 340 consecutive STEMI patients who underwent PPCI with D2B times of < 90 min in 232 patients and D2B times >= 90 min in 108 patients, who all received subsequent echocardiographic examination within 48 hours of hospitalization. RESULTS: Although the LV ejection fraction was similar (50.92% vs. 51.66%, p = 0.573), the proportion of E/E' ratio > 15 was greater in patients with D2B times >= 90 min compared to those with D2B times < 90 min (44.4% vs. 30.6%, p = 0.013). Logistic regression analysis revealed that D2B time >= 90 min [odds ratio (OR): 1.82, 95% confidence interval (Cl): 1.04-3.17, p = 0.035] was an independent predictor for LV diastolic dysfunction. The effect was more prominent in patients >= 65 years of age (OR: 2.77, 95% CI: 1.09-7.00, p = 0.032), in whom the fraction of LV diastolic dysfunction increased proportionally with prolonged D2B times. CONCLUSIONS: Prolonged D2B time of greater than 90 min predicted LV diastolic dysfunction, particularly in aged subjects. D2B times shortening is important to preserve diastolic heart function after PPCI. KEY WORDS: Acute myocardial infarction; Diastolic dysfunction; Door-to-balloon time; Primary percutaneous coronary intervention. PMID- 27122885 TI - The Effect of High Dose Cilostazol and Rosuvastatin on Periprocedural Myocardial Injury in Patients with Elective Percutaneous Coronary Intervention. AB - BACKGROUND: The aim of our study was to assess the effect of pretreatment with cilostazol and rosuvastatin combination before elective percutaneous coronary intervention (PCI) on peri-procedural myocardial injury (PPMIJ). METHODS: We randomly assigned 172 patients with stable angina pectoris scheduled for elective PCI to pre- treatment with Cilostazol 200mg and Rosuvastatin 40 mg (group 1), or to pretreatment with Rosuvastatin 40 mg group (group 2). The primary end-point was the occurrence of PPMIJ defined as any cardiac troponin I (Tn I) level elevated above the upper normal limit (UNL). The occurrence of peri-procedural myocardial infarction (PPMIN) was defined as a post-procedural increase in cTnI level >= 5 times above the UNL. RESULTS: There was no significant difference in baseline characteristics between group 1 (n = 86) and group 2 (n = 86). The rate of PPMIJ (21% vs. 24%, p = 0.58) and PPMIN (2.3% vs. 7%, p = 0.27) were similar between the two study groups. Subgroup analysis performed on those patients without statin therapy before PCI (53 patients in group 1 and 50 patients in group 2) showed that the incidence of PPMIJ was significantly lower in the group 1 patients without chronic statin treatment [17% (9/53) versus 34% (17/50); p = 0.04], but the rate of PPMIN was similar between the two groups for those patients without chronic statin treatment [1.9% (1/53) versus 10% (5/50); p = 0.07]. CONCLUSIONS: We found that adjunct cilostazol and rosuvastatin pre treatment did not significantly reduce PPMIJ after elective PCI in patients with stable angina pectoris. However, adjunct cilostazol pre-treatment could reduce PPMIJ in patients without chronic statin therapy before elective PCI. KEY WORDS: Cilostazol; Myocardial injury; Percutaneous coronary intervention; Statin. PMID- 27122886 TI - Effect of Danhong Injection Combined with Naoxintong Tablets on Prognosis and Inflammatory Factor Expression in Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND: Danhong is a Chinese medical component that has been broadly used to treat various cerebrovascular diseases. This work aimed to investigate the effect of Danhong injection combined with Naoxintong tablets on the short-term prognosis and expression of inflammatory factor-soluble CD40 ligand (sCD40L) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). METHODS: A total of 100 ACS patients with PCI were randomly divided equally into treatment and control groups. The control group was treated with conventional secondary prevention of coronary heart disease. Based on secondary prevention, Danhong injection combined with Naoxintong tablets was administered in the treatment group. The incidences of major adverse cardiovascular events and cardiac functions, including ejection fraction (EF) and six-minute walk test distance, during hospital discharge and at the third postoperative month were observed. The serum sCD40 levels at different times were also noted. RESULTS: There were 2 patients in the treatment group and 7 in the control group that were lost during follow-up, so the collected data were from only 48 patients in the treatment and 43 in the control group. During hospital discharge and at the third postoperative month, no significant difference in death, myocardial infarction, stroke, angina pectoris and readmission were observed between the two groups (p > 0.05). Upon hospital discharge, EF, six-minute walk test distance and serum sCD40L level in the two groups were not significantly different (p > 0.05). At the third postoperative month, EF and six-minute walk test distance in treatment group were significantly higher than those in the control group (p < 0.05), and the serum sCD40L level in the treatment group was significantly lower than that in the control group (p < 0.01). In addition, serum sCD40L levels in the two groups at the third postoperative month were significantly lower than those during hospital discharge (p < 0.01). CONCLUSIONS: Danhong injection combined with Naoxintong tablets decreased serum sCD40L level and improved cardiac functions in ACS patients undergoing PCI at 3 months following discharge, but not at discharge. KEY WORDS: Acute coronary syndrome; Danhong injection; Naoxintong tablets; sCD40. PMID- 27122887 TI - The Relationship between Expressive/Suppressive Hostility Behavior and Cardiac Autonomic Activations in Patients with Coronary Artery Disease. AB - BACKGROUND: Hostility is an important psychosocial risk factor in coronary artery disease (CAD). Expressive and suppressive hostility behaviors are related to cardiovascular response in healthy adults. However, the relationships of these behavioral dimensions to cardiac autonomic activations in CAD remain unclear. METHOD: This study involved 76 patients with CAD to whom a hostility inventory was administered, who were instructed to recall a neutral event and an anger related event. Heart rate and blood pressure were obtained for each patient as the indices of cardiovascular response; heart rate variability was transformed from electrocardiograph and as the indices of cardiac autonomic activation. RESULTS: The results showed that CAD patients with expressive hostility behavior experienced higher cardiovascular autonomic activations during the neutral and anger recall tasks, and lower parasympathetic activations during the recovery after an anger episode. On the other hand, CAD patients with suppressive hostility behavior experienced both sympathetic and parasympathetic activations during the baseline and recovery stages, as well as simultaneously activated higher parasympathetic response. CONCLUSIONS: The results of this study suggested that it is appropriate to extend the cardiac autonomic activation model for expressive and suppressive hostility behaviors in patients with CAD. KEY WORDS: Cardiac autonomic; Coronary artery disease; Expressive hostility; Suppressive hostility behaviors. PMID- 27122888 TI - The Electrical Characteristics and Clinical Significance of the Effect of Adenosine on Dissociated Activity after Circumferential Venous Isolation in Patients with Atrial Fibrillation. AB - BACKGROUND: Dissociated activity can occur after circumferential thoracic vein isolation for treating atrial fibrillation (AF). However, its clinical significance and response to adenosine remain unclear. METHODS: Fifty-three patients (10 women, 11 with non-paroxysmal AF, with mean age 54.4 +/- 11.2 years) with slow dissociated activity after thoracic vein isolation for AF ablation were analyzed. Adenosine (12 mg) was injected intravenously into 30 patients, and the responses of the dissociated activities were recorded. RESULTS: The clinical characteristics and the rate of recurrence did not differ between patients with and without dissociated activity. Dissociated activity was most frequently observed at the right superior pulmonary vein (PV) (61%), left superior PV (26%), right inferior PV (5%), left inferior PV (4%), and non-PV sites (4%). The locations of dissociated activities were associated with the AF trigger sites (p = 0.004). Adenosine injection decreased the cycle length of dissociated activity in 13 patients (group 1) and increased it in 17 patients (group 2). Dissociated activity disappeared in 7 patients (41%) (group 2) after adenosine injection. During the mean 33 +/- 17 months of follow-up, group 2 patients had a lower AF recurrence rate (24%) than group 1 patients (62%) (p = 0.035). CONCLUSIONS: The locations of dissociated activity were closely associated with the AF trigger sites. The responses to adenosine may predict AF recurrence in patients with dissociated activity. KEY WORDS: Ablation; Atrial fibrillation; Dissociated activity. PMID- 27122889 TI - Right Atrium Volume Index in Patients with Secondary Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Right atrium volume index has recently been described as a quantitative and highly reproducible echocardiographic parameter associated with right ventricle systolic dysfunction in patients with chronic systolic heart failure. The aim of the current study was to assess right atrium remodeling and to establish correlations with echocardiographic parameters of right ventricle systolic and diastolic dysfunction in patients with pulmonary hypertension due to chronic obstructive pulmonary disease (COPD). METHODS: The study was conducted on 40 patients with secondary pulmonary hypertension due to COPD and 40 healthy volunteers (mean age 59 +/- 6 years) who submitted to detailed echocardiographic examinations. Plasma levels of the soluble interleukin-1 receptor family member, N-terminal pro-B type natriuretic peptide and galectin-3 were measured in both groups. RESULTS: The right atrium volume index was significantly higher in the test group (45.7 +/- 15.3 vs. 25.4 +/- 4.0 mL/m(2)) and showed strong correlations to tricuspid annular plane systolic excursion (r = -0.733, p < 0.0001), right ventricle fractional area change (r = -0.662, p < 0.0001), right ventricle ejection fraction (r = -0.741, p < 0.0001), and systolic pulmonary artery pressures (r = 0.721, p < 0.0001). Multivariate analysis facilitated the construction of a linear regression model which showed that right ventricle systolic dysfunction parameters (R(2)-adjusted = 0.62, p < 0.001), elevated systolic pulmonary artery pressure (R(2)-adjusted = 0.52, p < 0.001) and heart failure biomarkers (log-transformed sST2, galectin-3 and N-terminal pro-B type natriuretic peptide) (R(2)-adjusted = 0.41, p < 0.001) were independently associated with right atrium volume index. CONCLUSIONS: Right ventricle systolic dysfunction and elevated systolic pulmonary artery pressure are independently associated with right atrium volume index in patients with pulmonary hypertension due to COPD. KEY WORDS: Echocardiography; Right atrium volume index; Right ventricular diastolic function; Right ventricular systolic function. PMID- 27122890 TI - Differential Effects of Continuous and Interval Exercise Training on the Atherogenic Index of Plasma in the Non-Obese Young Male. AB - BACKGROUND: The process of atherogenicity is known to be influenced by exercise. However, appropriate exercise stimulus necessary to generate the response and adaptation in sedentary non-obese individuals has not yet been investigated. The purpose of the present study was to compare the effects of an 8-week continuous training and corresponding interval training on the atherogenic index of plasma in sedentary Nigerian males. METHODS: Overall, there were 54 male university students that participated in our study, which used a pretest- posttest control group design. Participants (18 males per group) were assigned into continuous, interval and control groups respectively. During the first two weeks, training was done 3 times weekly for 30 minutes each day, and was increased by 5 minutes every 2 weeks. Continuous training was done at 70-84% of heart rate reserve. Interval training was done at 70-84%/30-39% heart rate reserve in 1:2 minutes work/rest intervals, respectively. The control group did not participate in the training. Data collected were analysed using descriptive, paired t-test, analysis of covariance and Bonferroni post-hoc analysis. RESULTS: Young sedentary non obese males were at high risk (atherogenic index of plasma > 0.24) of cardiovascular diseases/conditions. However, continuous training led to significant reductions (p = 0.002) in the atherogenic index of plasma. In contrast, non-significant increase (p = 0.084) followed interval training. After controlling for baseline values, only continuous training still had significant effects on atherogenic index of plasma when compared with other groups. CONCLUSIONS: Continuous training of vigorous intensity is better than a corresponding interval training protocol as a natural anti-atherogenic method of reducing risk of cardiovascular event in sedentary non-obese males. KEY WORDS: Atherogenicity; Cholesterol; Exercise; Training; Vigorous. PMID- 27122892 TI - Right Ventricular Pacing-Induced Heart Failure after Mitral Valve Replacement. AB - It is an unfortunate fact that pacing-induced heart failure after cardiac surgery is frequently ignored by medical professionals. A 60-year-old woman with chronic atrial fibrillation with a single-lead right ventricular permanent pacemaker for a prolonged ventricular pause underwent mitral valve replacement 6 months later for severe stenosis (NYHA functional class III). The patient's pacing rate was increased from the preoperative level of 60 beats per minute (bpm) to 70 bpm in order to facilitate weaning from the cardiopulmonary bypass. However, her postoperative low cardiac output continued to progress, despite the presence of inotropes. The patient's cold limbs and oliguria persisted until she underwent echocardiographic imaging, which showed dyssynchronous ventricular contraction 29 days post-surgery but which improved after the pacing rate was reduced below her spontaneous rate. Ultimately, clinicians should exercise caution when increasing right ventricular pacing for postoperative stunned myocardium. Due to the problems that can arise from an increased pacing rate, postoperative pacing strategy in patients complicated with low cardiac output after mitral valve replacement merits further discussion. KEY WORDS: Dyssynchrony; Mitral valve replacement; Right ventricular pacing; Stunned myocardium. PMID- 27122893 TI - A Rare and Life-Threatening Complication of Infective Endocarditis: Pseudoaneurysm of the Mitral - Aortic Intervalvular Fibrosa. AB - A 59 year-old previously healthy male was admitted to the hospital with fever reportedly several days in duration. His physical examination was unremarkable at first. Pneumonia was initially diagnosed, but acute pulmonary edema with a new grade III to and fro murmur developed 1 week later. Transesophageal echocardiography (TEE) disclosed a pseudoaneurysm of the mitral-aortic intervalvular fibrosa (P-MAIVF). Subsequent consultation with a cardiovascular surgeon resulted in a repaired aorta with otherwise uneventful results. P-MAIVF is a very rare complication of prosthetic aortic valve (AV) infective endocarditis, and even in native AV. Therefore a careful and through physical examination of patients and early TEE examination are essential in this rare complication of infective endocarditis. KEY WORDS: Echocardiography; Infective endocarditis; Mitral-aortic intervalvular fibrosa; Pseudoaneurysm. PMID- 27122891 TI - Application of Real-Time Three-Dimensional Echocardiography to Evaluate the Pre- and Postoperative Right Ventricular Systolic Function of Patients with Tetralogy of Fallot. AB - Tetralogy of Fallot (ToF) can be challenging for clinicians to both diagnose and treat, given the multiple heart defects that are by definition associated with the illness. This study investigates the value of real-time three- dimensional echocardiography (RT-3DE) in evaluating the pre-and postoperative right ventricular systolic function of patients with tetralogy of Fallot. A total of 41 ToF patients were divided into two groups: the child group (CG) and the adult group (AG) according to age. The right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV), and the right ventricular ejection fraction (RVEF) of ToF patients were measured before surgery, 7 days, and 3 months after the surgery. The correlation between the preoperative Nakata index and RVEF was then analyzed. Compared with the RVEDV and RVESV prior to surgery, those of the postoperative 7-day and 3-month were not statistically significant (p > 0.05). However, RVEF decreased, and the difference was statistically significant (p < 0.05). The differences in RVEDV, RVESV, and RVEF between postoperative 3-month and 7-day were not significant (p > 0.05). Compared with the pre-and postoperative RVEDV and RVESV of CG, those of AG increased. However, RVEF decreased, and the differences were statistically significant (p < 0.05). Our study indicated that the correlation between preoperative Nakata index and RVEF was good. Ultimately, we did confirm that RT-3DE can quantitatively evaluate the right ventricular volume and systolic function of ToF patients, thereby providing clinical significance in determining postoperative efficacy and prognosis evaluation. KEY WORDS: Echocardiography; Right; Tetralogy of Fallot; Three-dimensional; Ventricular function. PMID- 27122894 TI - Catecholaminergic Polymorphic Ventricular Tachycardia: A Rare Cause of Cardiac Arrest Following Blunt Chest Trauma. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an electrophysiological disorder of a physically normal heart that occurs in children when the body is subjected to intense emotional or physical stress that causes adrenergic discharge. This troubling disease can be sporadic (spontaneous) or familial (genetic/inherited). Unfortunately, its associated ventricular tachycardia may cause sudden death, so early diagnosis of CPVT is very important. Treatment modalities include medical treatment, implantation of a cardioverter defibrillator, or surgical sympatectomy; but the implantable cardioverter defibrillator (ICD) should be the first choice in patients with a history of cardiac arrest. We herein present the case of a patient diagnosed with CPVT after a successful cardiopulmonary resuscitation triggered by blunt chest trauma. We implanted an implantable cardioverter defibrillator and started oral B-blocker treatment. During the course of follow-up, flecainide was added to his treatment depending on the patient's status regarding recurrent ICD shock. The patient has now continued follow-up without recurrent ICD shock since flecainide treatment was initiated. In conclusion, in patients with syncope and sudden cardiac arrest secondary to physical stress or blunt chest trauma, CPVT should be considered and an implantable cardioverter defibrillator must be implanted. Additionally, flecainide theraphy should be considered to decrease recurrent ICD shock. KEY WORDS: Blunt chest trauma; Cardiac arrest; CPVT. PMID- 27122895 TI - Rescue of Coronary Injury with Right Internal Mammary Artery Bypass during Repair of a Complex Congenital Heart. AB - A 10-year-old boy with polysplenia syndrome was diagnosed with complex congenital heart disease, including common atrium, bilateral superior vena cava, complete atrioventricular canal defect, severe pulmonary stenosis, interrupted inferior vena cava, and patent ductus arteriosus. Previously, he underwent a bilateral bidirectional Glenn shunt operation with ligation of the patent ductus arteriosus in April, 2009, when he was six years old. During the operation, his left anterior descending coronary artery (LAD) was injured accidently due to abnormally high coronary artery takeoff. Consequently, a coronary artery bypass graft [right internal mammary artery (RIMA) to LAD proximal, end-to-end] was performed. On July 24, 2013, he received the last stage of a total cavopulmonary connection with an extracardiac conduit (22 mm PTFE graft) at ten years of age. The RIMA was not injured during redo-sternotomy and he was discharged uneventfully 11 days after the operation. KEY WORDS: Congenital heart disease; Coronary artery bypass surgery; Coronary injury. PMID- 27122896 TI - Early Administration of Intracoronary Nitroprusside Compared with Thrombus Aspiration in Myocardial Perfusion for Acute Myocardial Infarction: A 3-Year Clinical Follow-Up Study. AB - BACKGROUND: Intracoronary nitroprusside and thrombus aspiration have been demonstrated to improve myocardial perfusion during percutaneous coronary interventions (PCI) for ST-segment elevation acute myocardial infarction (STEMI) However, no long-term clinical studies have been performed comparing these approaches. METHODS: A single medical center retrospective study was conducted to evaluate the effects of intracoronary nitroprusside administration before slow/no reflow phenomena versus thrombus aspiration during primary PCI. Forty-three consecutive patients with STEMI were enrolled in the intracoronary nitroprusside treatment group. One hundred twenty-four consecutive STEMI patients who received thrombus aspiration were enrolled; ninety-seven consecutive STEMI patients who did not receive either thrombus aspiration or intracoronary nitroprusside treatment were enrolled and served as control subjects. Patients with cardiogenic shock, who had received platelet glycoprotein IIb/IIIa inhibitor, or intra-aortic balloon pump insertion were excluded. Thrombolysis in Myocardial Infarction (TIMI) flow grade, corrected TIMI frame count and TIMI myocardial perfusion grade (TMPG) were assessed prior to and following PCI by two independent cardiologists blinded to the procedures. The rate of major adverse cardiac events (MACE) at 30 days, 1 year, and 3 years after study enrollment as a composite of recurrent myocardial infarction, target-vessel revascularization, and cardiac death were recorded. RESULTS: The control group had a significantly lower pre-PCI TIMI flow (<= 1; 49.5% vs. 69.8% vs. 77.4%; p = < 0.001) compared with the nitroprusside and thrombus aspiration groups. The thrombus aspiration group had a significantly higher pre-PCI thrombus score (> 4; 98.4% vs. 88.4% vs. 74.3%; p = < 0.001) and post-PCI TMPG (3; 39.5% vs. 16.3% vs. 20.6%; p = 0.001) compared with the nitroprusside and control groups. No significant differences were noted in the post-PCI thrombus score, 30-day, 1-year and 3-year MACE rate, and Kaplan-Meier curve among 3 groups of patients. CONCLUSIONS: Although thrombus aspiration provided improved TMPG compared with early administration of intracoronary nitroprusside and neither of both during primary PCI, it did not have a significant impact on 30-day, 1-year and 3-year MACE rate. KEY WORDS: Acute myocardial infarction; Intracoronary nitroprusside; Thrombus aspiration. PMID- 27122897 TI - Comparison of Bare-Metal Stent and Drug-Eluting Stent for the Treatment of Patients Undergoing Percutaneous Coronary Intervention for Unprotected Left Main Coronary Artery Disease - Long-Term Result from a Single Center Experience. AB - BACKGROUND: Percutaneous coronary intervention (PCI) has become an alternative treatment for left main (LM) coronary artery disease. The aim of our study was to compare long-term clinical outcomes of patients undergoing unprotected LM PCI with bare-metal stent (BMS) or drug-eluting stent (DES) in a high-risk population. METHODS AND RESULTS: We enrolled 223 consecutive patients with unprotected LM coronary artery disease undergoing PCI (mean age: 71.1 +/- 11.2 years, 187 male), including 94 patients receiving BMS and 129 patients receiving DES. The patients receiving DES had a significantly higher SYNTAX score (p = 0.05). During the mean follow-up period of 2.5 years, there were 31 cardiovascular deaths (BMS: 21 cases, DES: 10 cases, p = 0.04 by log-rank test), 56 major adverse cardiovascular events (MACE, including cardiovascular death, non fatal myocardial infarction (MI) and clinical-driven target lesion revascularization; BMS: 33 cases, DES: 23 cases, p = 0.03 by log-rank test) and 6 cases with definite/probable stent thrombosis (BMS: 5 cases, DES: 1 cases, p = 0.09). In multivariate Cox analysis, the use of DES was identified as an independent protective factor against cardiovascular death [hazard ratio (HR) = 0.34, 95% confidence interval (Cl) = 0.15-0.79, p = 0.01] and MACE (HR = 0.50, 95% CI = 0.28-0.88, p = 0.02). The clinical outcome analyses in propensity-score matched the cohort (87 matched pair of patients receiving BMS and DES) and yielded similar results. CONCLUSIONS: In the general practice among a high-risk population undergoing unprotected LM PCI, the use of DES appeared to be beneficial in reducing the risk of long-term cardiovascular death and MACE. KEY WORDS: Bare-mental stent; Drug-eluting stent; Left main coronary artery disease; Percutaneous coronary intervention. PMID- 27122898 TI - Clinical Profile and Long-Term Prognostic Factors of a Young Chinese Han Population (<= 40 Years) Having ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: The proportion of the mainland Chinese population with premature ST segment elevation myocardial infarction is significantly elevated. Young patients with ST-segment elevation myocardial infarction have a different risk factor profile and clinical outcome compared with elder patients, and may also differ as compared to young patients in Western populations. METHODS: We analyzed a total of 9462 consecutive ST-segment elevation myocardial infarction patients, and recruited 341 consecutive cases who had survived their first ST-segment elevation myocardial infarction at the age less than 40 years, and followed-up these patients for 5 years. RESULTS: The most prevalent risk factor in young Chinese ST segment elevation myocardial infarction patients was smoking (307/341, 90.03%) and male gender (328/341, 96.19%), although young patients had fewer traditional risk factors of acute myocardial infarction than the control group [(1.63 +/- 1.03) vs. (2.38 +/- 1.15), p < 0.01]. The number of affected vessels in cases was significantly less than in the elder control group (p < 0.01). During the follow up, blood lipids and blood pressure of most patients reached the target level, while 42.10% of patients reported continuation of smoking. Multivariable data analysis showed that persistence of smoking (OR: 3.784, 95% CI: 1.636-8.751, p < 0.01) was the most significant prognostic factor of cardiac events after adjusting for various confounding factors. CONCLUSIONS: We demonstrated that cigarette smoking is the most prevalent factor among the avoidable cardiovascular risk factors for young ST-segment elevation myocardial infarctions in China. Accordingly, continued smoking is the most powerful predictor for the recurrence of cardiac events in young Chinese patients with ST-segment elevation myocardial infarction. KEY WORDS: Premature myocardial infarction; Prognosis; Risk factor. PMID- 27122899 TI - Influence of Cigarette Smoking on Burden and Characteristics of Coronary Artery Plaques in Chinese Men. AB - BACKGROUND: It is generally well-known that smoking has a substantial impact on general health, and cardiovascular health in particular. The purpose of this study was to analyze the effects of different smoking status on the burden and characteristics of coronary artery plaques in Chinese men. METHODS: Our study enrolled 1920 individuals with suspected coronary artery disease undergoing 256 detector-row computed tomography scan after clinical assessment. These study participants were stratified into three groups: never smoker, current smoker, and former smoker, according to their smoking status. Thereafter, the associations of different smoking status with the coronary artery plaques were assessed using both univariable and multivariable logistic regression. RESULTS: The prevalences of any plaque, significant stenosis and coronary artery calcium score (CACS) >= 10 were highest in the current smokers (all p < 0.05). The proportion of calcified plaques was the lowest and the prevalence of non-calcified plaques was the highest in current smokers (p = 0.004). The higher pack-years group had significantly elevated percentages of any plaque, significant stenosis, >= 2/LM vessel disease and CACS >= 10 than the lower pack-years group (all p < 0.001). The percent of calcified plaques was lower and the percent of non-calcified plaques was higher in the higher (> 20) pack-years group than in the lower pack years group (<= 20) (p = 0.024). Current smoking with higher pack-years was the independent risk factor for any plaque, significant stenosis, CACS >= 10, non calcified and mixed plaques (all p < 0.05) after multivariate adjustments. CONCLUSIONS: The current smokers had the most serious burden of coronary artery plaques and the highest percentage of non-calcified plaques. Current smoking with higher pack-years was a significant risk factor for coronary artery plaque burden and non-calcified and mixed plaques. KEY WORDS: Chinese men; Cigarette smoking; Coronary artery calcium score; Coronary artery plaques; Non-calcified plaques. PMID- 27122900 TI - Establishment of Rabbit Abdominal Aortic Atherosclerosis Model by Pancreatic Elastase Infiltration Associated with High Fat Diet. AB - BACKGROUND: The aim of this study was to evaluate the feasibility of a high fat diet (HFD) associated with pancreatic elastase (PE) infiltration, in establishing the rabbit aortic atherosclerosis model. METHODS: The HFD+PE method and the HFD+saccule injury (SI) method were simultaneously used to prepare the rabbit atherosclerosis model; the control group was established with the normal diet. Biochemical indicators, radiological imaging, pathomorphology and immunohistochemistry were used to evaluate the HFD+PE modeling results. RESULTS: There were significant changes in the blood lipid contents, as well as the pathomorphological and immunohistochemical results between the two experimental groups and the control group (p < 0.05). However, there was no difference between the two experimental groups. The rabbit aortic atherosclerosis model prepared by the HFD+PE method had no significant difference in the local vascular pathomorphological and immunohistochemical results with the traditional HFD+SI method. CONCLUSIONS: The use of HFD with PE infiltration is feasible in establishing the rabbit aortic atherosclerosis model. KEY WORDS: Animal model; Atherosclerosis; Rabbit. PMID- 27122901 TI - Stimulatory Influences of Far Infrared Therapy on the Transcriptome and Genetic Networks of Endothelial Progenitor Cells Receiving High Glucose Treatment. AB - BACKGROUND: Endothelial progenitor cells (EPCs) play a fundamental role in vascular repair and angiogenesis- related diseases. It is well-known that the process of angiogenesis is faulty in patients with diabetes. Long-term exposure of peripheral blood EPCs to high glucose (HG-EPCs) has been shown to impair cell proliferation and other functional competencies. Far infrared (FIR) therapy can promote ischemia-induced angiogenesis in diabetic mice and restore high glucose suppressed endothelial progenitor cell functions both in vitro and in vivo. However, the detail mechanisms and global transcriptome alternations are still unclear. METHODS: In this study, we investigated the influences of FIR upon HG EPC gene expressions. EPCs were obtained from the peripheral blood and treated with high glucose. These cells were then subjected to FIR irradiation and functional assays. RESULTS: Those genes responsible for fibroblast growth factors, Mitogen-activated protein kinases (MAPK), Janus kinase/signal transducer and activator of transcription and prostaglandin signaling pathways were significantly induced in HG-EPCs after FIR treatment. On the other hand, mouse double minute 2 homolog, genes involved in glycogen metabolic process, and genes involved in cardiac fibrosis were down-regulated. We also observed complex genetic networks functioning in FIR-treated HG-EPCs, in which several genes, such as GATA binding protein 3, hairy and enhancer of split-1, Sprouty Homolog 2, MAPK and Sirtuin 1, acted as hubs to maintain the stability and connectivity of the whole genetic network. CONCLUSIONS: Deciphering FIR-affected genes will not only provide us with new knowledge regarding angiogenesis, but also help to develop new biomarkers for evaluating the effects of FIR therapy. Our findings may also be adapted to develop new methods to increase EPC activities for treating diabetes-related ischemia and metabolic syndrome-associated cardiovascular disorders. KEY WORDS: Endothelial progenitor cell; Far infrared; Microarray; Systems biology. PMID- 27122902 TI - Comparative Analysis of Mechanical Properties of PWV, NO and Ascending Aorta between WHY Rats and SHR Rats. AB - BACKGROUND: The aim of this study was to compare and analyze the tensile mechanical properties of the ascending aorta (AA) in Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs), for the purpose of providing a biomechanical basis for hypertension prevention. METHODS: Pulse wave velocities (PWV) and serum nitric oxide (NO) concentrations were determined in 6-month-old WKY rats and SHRs (n = 21, n = 21, respectively). Then, 20 AAs from each group were obtained for longitudinal tensile testing. RESULTS: The maximum stress, maximum strain, and strain at a tensile stress of 16 Kpa were greater in WKY rats than in SHRs (p < 0.05). The aortic elastic modulus and PWV value were greater in SHRs than in WKY rats (p < 0.05 for both), while NO concentrations were lower in the SHR group than in the WKY group (p < 0.05). CONCLUSIONS: The AA tensile mechanical properties differed between the WKY rats and SHRs, and the tensile mechanical properties of the SHR model had changed. KEY WORDS: Ascending aorta; Hypertension; Mechanical properties; Pulse wave velocity; SHR rats; WKY rats. PMID- 27122903 TI - Assessment of the Risk Factors and Outcomes for Postoperative Atrial Fibrillation Patients Undergoing Isolated Coronary Artery Bypass Grafting. AB - BACKGROUND: Atrial fibrillation is the most common complication of cardiac surgery and is associated with significant morbidity and mortality. Recognizing patients at high risk for developing postoperative atrial fibrillation (POAF) may help identify those who could benefit from strategies to prevent POAF. This study was conducted to delineate outcomes and to assess risk factors for POAF among Taiwanese patients undergoing coronary artery bypass grafting (CABG). METHODS: From January 2009 until February 2012, this prospective study included 266 consecutive patients admitted to our hospital with coronary artery disease. All patients underwent isolated CABG. Patients with preoperative permanent atrial fibrillation and concomitant surgery were excluded. Multiple risk factors associated with the incidence of POAF were collected and evaluated. RESULTS: POAF occurred in 126 of 226 patients (47.37%). Univariate analysis revealed that significant risk factors for the condition were age, gender, diabetes, dyslipidemia, smoking, impaired renal function, impaired cardiac function, and increased serum electrolytes. Multivariate analysis showed dyslipidemia [hazard ratio (HR): 0.418; 95% confidence interval (Cl): 0.190-0.915, p = 0.029], impaired renal function as indicated by an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) (HR: 3.174; 95% CI: 1.432-7.037, p = 0.004), and serum sodium (HR: 1.112; 95% Cl: 1.047-1.182, p = 0.001) prior to cardiopulmonary bypass as significant. Moreover, POAF was associated with lower 30-day, 1- and 3-year cumulative survival rates and higher early postoperative complications. CONCLUSIONS: Patients with isolated CABG who were administered beta-blockers, angiotensin converting enzyme inhibitor/angiotensin receptor blockers treatment, and lipid therapy before CABG were associated with reduced POAF, while those with impaired renal function and higher serum sodium before CABG predisposed POAF in a Taiwanese population. KEY WORDS: Atrial fibrillation (AF); Coronary artery bypass grafting (CABG); Coronary artery disease (CAD); Postoperative atrial fibrillation (POAF). PMID- 27122904 TI - Heart Rate Turbulence Analysis in Subclinical Hypothroidism Heart Rate Turbulence in Hypothyroidism. AB - BACKGROUND: Heart rate turbulence (HRT) is a baroreflex-mediated biphasic reaction of heart rate in response to premature ventricular beats. Abnormal HRT identifies patients with autonomic dysfunction or impaired baroreflex sensitivity. The aim of the present study was to demonstrate the effect of subclinical hypothyroidism (SCH) on cardiac autonomic function using HRT parameters. METHODS: The study sample consisted of 25 patients (10 men, 15 women with a mean age of 39.7 +/- 15.5 years) who were diagnosed with SCH and 35 euthyroid patients (13 males, 22 females with a mean age 38.4 +/- 11.7 years). All patients underwent 24 h ambulatory electrocardiography monitorization. The study calculated two HRT parameters, turbulence slope (TS) and turbulence onset (TO), and these HRT parameters were compared between the groups to examine the relationship between HRT and thyroid-stimulating hormone (TSH) levels. RESULTS: The characteristics of SCH patients and control cases were similar with regard to age, sex except for TSH levels. Serum TSH levels were significantly higher in SCH patients than in the controls (7.3 +/- 1.8 MUIU/ml vs. 2.4 +/- 1.0 MUIU/ml, p < 0.001). TO was significantly higher in SCH patients compared with controls (-1.51 +/- 0.5 vs. -2.2 +/- 1.0, p = 0.002). SCH patients had lower TS values than controls (7.6 +/- 2.4 vs. 10.8 +/- 3.4, p < 0.001). TO was positively correlated with serum TSH levels (r = 0.276, p = 0.033). There was also a negative correlation between TS and serum TSH levels (r = -0.437, p < 0.001). CONCLUSIONS: The results of our study indicated that cardiac autonomic function is impaired in patients with SCH. KEY WORDS: Heart rate; Holter electrocardiography; Hypothyroidism. PMID- 27122905 TI - Diffuse ST-Segment Depression with ST-Segment Elevation in Lead aVR in 12-Lead Electrocardiography May Indicate Ischemic Change of Severe Aortic Stenosis. AB - Diffuse ST-segment depression with ST-segment elevation in the lead augmented vector right (aVR) in 12-lead electrocardiography may indicate the possibility of coronary artery disease involving the left main coronary artery or proximal left anterior descending artery, pulmonary embolism or takotsubo cardiomyopathy. We report a 69-year-old female with severe aortic stenosis, who had similar electrocardiographic findings which indicated ischemic change and led to cardiogenic shock and ventricular tachycardia. Intubation and insertion of an intra- aortic balloon pump (IABP) were performed and the result of coronary angiography showed only less than 40% stenosis. Her blood pressure gradually stabilized, and diffuse ST-segment depression or ST-segment elevation in lead aVR was not noted in the 12-lead electrocardiography. However, we removed the IABP and after 6 hours, sudden profound shock refractory to combined vasopressors occurred. Electrocardiography again showed ST- segment elevation in aVR with and diffuse ST-segment depression. After several episodes of ventricular tachycardia, cardiopulmonary resuscitation was not successful and the patient expired in our hospital. KEY WORDS: Diffuse ST depression; Severe aortic stenosis; ST elevation in aVR. PMID- 27122906 TI - Correction of Stent Distortion and Overhanging Stent Struts during Left Main Bifurcation Stenting by Selective Distal Stent Cell Re-Wiring: A Novel Guidewire Approach. AB - Stent malapposition and overhanging stent struts in front of the side branch (SB) ostium are not uncommon following bifurcation stenting that might lead to stent thrombosis. We herein present 2 cases, in which optical frequency domain imaging and intravascular ultrasound effectively revealed stent malapposition and overhanging struts inside the ostium of the SB following left main coronary artery stenting. Therefore, we introduced a novel technique for rectification of these incidental findings by selective SB re-wiring through the most distal stent cell with the adjunctive help of a double lumen microcatheter. KEY WORDS: Distal stent strut; Left main bifurcation; Overhanging struts; Side branch re-crossing; Stent optimization. PMID- 27122907 TI - An Unusual Case of Loffler Endomyocarditis after Takotsubo Cardiomyopathy Induced by Deep Neck Infection. AB - In this case, we herein have described a 72-year-old female patient with deep neck infection induced Takotsubo cardiomyopathy and idiopathic hypereosinophilic syndrome with Loffler endocarditis characterized by right atrial thrombus and right ventricular fibrothrombotic obliteration within two months. KEY WORDS: Cardiac thrombi; Hypereosinophilic syndrome; Takotsubo cardiomyopathy. PMID- 27122908 TI - Contrast Pooling and Layering in a Patient with Left Main Coronary Artery Occlusion and Cardiogenic Shock. AB - A 57-year-old male with type 2 diabetes mellitus presented to the emergency department with sudden onset of chest pain. Shock status and considerably low right arm blood pressure were detected. The patient underwent contrast-enhanced computed tomography (CT) which revealed dependent contrast pooling and layering of contrast material within the inferior vena cava. Post-processing CT angiography depicted total occlusion of the left main coronary artery. Sudden cardiac arrest developed after CT examination, and following emergency coronary angiography we confirmed the diagnosis of left main coronary artery occlusion and cardiogenic shock. Clinical physicians should recognize these CT findings of imminent cardiovascular decompensation and provide prompt medical management to prevent further patient deterioration. KEY WORDS: Cardiogenic shock; Dependent pooling; Layering; Left main coronary artery disease. PMID- 27122909 TI - Right Ventricle Mass Induced Coronary Artery Steal Phenomenon: A Rare Clinical Manifestation on One Leiomyosarcoma Patient. AB - We report a 43-year-old female with the underlying disease of retroperitoneal leiomyosarcoma and initial presentation of ST elevation myocardial infarction. Coronary angiography showed an absence of coronary artery stenosis and a huge, ill-defined cardiac mass which was fed by both the left anterior descending artery and the right coronary artery. Coronary blood flow was obviously shunted by the neovascularized cardiac tumor. Right ventricle metastatic leiomyosarcoma was diagnosed according to her clinical course, images of echocardiography and computed tomography. In conclusion, we speculated that ST-segment elevation in electrocardiogram and typical anginal symptoms can provide significant evidence for myocardial ischemia caused by coronary steal phenomenon due to a right ventricular metastatic leiomyosarcoma. KEY WORDS: Coronary steal phenomenon; Leiomyosarcoma; Myocardial infarction. PMID- 27122910 TI - High Sensitivity C Reactive Protein (hs-CRP) in Adolescent and Young Adult Patients with History of Kawasaki Disease. AB - BACKGROUND: For children with a history of Kawasaki disease (KD), low grade inflammation was generally reported to be associated with persistent coronary artery lesions (CAL). However, this association has not been clearly demonstrated to hold true in KD adolescents and young adults (10-25 years of age). METHODS: We enrolled 104 subjects into our study, who were separated into the following 3 groups and controls: 1): 22 KD patients with angiography-confirmed CAL which persisted for an average of 12.5 years after onset of KD; 2) 38 KD patients with regressed aneurysms; 3) 44 KD patients without any coronary complications from the disease onset; and 4) 31 age-matched (18.7 +/- 1.88 years old) healthy controls. Plasma levels of high-sensitivity C reactive protein (hs-CRP) were measured for all participants. RESULTS: Plasma levels of hs-CRP were significantly higher in KD patients than in the controls, regardless of their coronary severity. However, there was no significant difference in hs-CRP levels among KD patients with different severities of CAL. Of the candidate risk factors of elevated hs-CRP such as body mass index, gender, coronary severity, and levels of high-density lipoprotein-cholesterol, linear regression analysis showed the only independent predictor of hs-CRP levels was BMI (beta = 0.306, p = 0.01), rather than patient grouping (p = 0.091). CONCLUSIONS: Our study found that levels of hs-CRP are significantly higher in adolescent and young adult patients with a history of KD, compared with age-matched controls. Low grade inflammation may play a minor role when KD patients enter into adulthood. body mass index (BMI), rather than coronary severity, was independently associated with the elevation of hs-CRP levels, one of biomarkers for further cardiovascular event. Therefore, ongoing control and management of BMI may be one of beneficial strategies that can be employed to help avoid elevation of hs-CRP levels in KD patients. KEY WORDS: Adolescents; High sensitivity-C reactive protein; Kawasaki disease; Young adult. PMID- 27122911 TI - Assessing Late Cardiopulmonary Function in Patients with Repaired Tetralogy of Fallot Using Exercise Cardiopulmonary Function Test and Cardiac Magnetic Resonance. AB - BACKGROUND: Patients with repaired tetralogy of Fallot (TOF) usually experience progressive right ventricle (RV) dysfunction due to pulmonary regurgitation (PR). This could further worsen the cardiopulmonary function. This study aimed to compare the changes in patient exercise cardiopulmonary test and cardiac magnetic resonance imaging, and consider the implication of these changes. METHODS: Our study examined repaired TOF patients who underwent cardiopulmonary exercise test (CPET) to obtain maximal (peak oxygen consumption, peak VO2) and submaximal parameters (oxygen uptake efficiency plateau, oxygen uptake efficiency plateau (OUEP), and ratio of minute ventilation to carbon dioxide production, VE/VCO2 slope). Additionally, the hemodynamic status was assessed by using cardiac magnetic resonance. Criteria for exclusion included TOF patients with pulmonary atresia, atrioventricular septal defect, or absence of pulmonary valve syndrome. RESULTS: We enrolled 158 patients whose mean age at repair was 7.8 +/- 9.1 years (range 0.1-49.2 years) and the mean patient age at CPET was 29.5 +/- 12.2 years (range 7.0-57.0 years). Severe PR (PR fraction >= 40%) in 53 patients, moderate in 55, and mild (PR fraction < 20%) in 50 patients were noted. The mean RV end diastolic volume index (RVEDVi) was 113 +/- 35 ml/m(2), with 7 patients observed to have a RVEDVi > 163 ml/m(2). The mean left ventricular ejection fraction (LVEF) was 63 +/- 8%, left ventricular end-diastolic volume index (LVEDVi) was 65 +/- 12 ml/m(2), and LVESVi was 25 +/- 14 ml/m(2). CPET revealed significantly decreased peak VO2 (68.5 +/- 14.4% of predicted), and fair OUEP (90.3 +/- 14.1% of predicted) and VE/VCO2 slope (27.1 +/- 5.3). PR fraction and age at repair were negatively correlated with maximal and submaximal exercise indicators (peak VO2 and OUEP). Left ventricular (LV) function and size were positively correlated with peak VO2 and OUEP. CONCLUSIONS: The results of CPET showed that patients with repaired TOF had a low maximal exercise capacity (peak VO2), but a fair submaximal exercise capacity (OUEP and VE/VCO2 slope), suggesting limited exercise capability in high intensity circumstances. PR, LV function and age at total repair were the most important determinants of CPET performance. KEY WORDS: Cardiac magnetic resonance; Cardiopulmonary exercise function; Pulmonary regurgitation; Surgical age; Tetralogy of Fallot. PMID- 27122912 TI - Early Elevated B-Type Natriuretic Peptide Levels are Associated with Cardiac Dysfunction and Poor Clinical Outcome in Pediatric Septic Patients. AB - BACKGROUND: To determine the B-type natriuretic peptide (BNP) level in pediatric septic patients, and to investigate its association with cardiovascular dysfunction and clinical outcome. METHODS: Pediatric patients with sepsis or septic shock were prospectively enrolled in our pediatric intensive care unit (PICU). On day 1 of admission, plasma BNP levels were measured at the time-point of echocardiography. Myocardial dysfunction was defined as left ventricular fractional shortening (FS) < 30%. Inotropic support was quantified by inotropic scores and disease severity was assessed by Pediatric Risk of Mortality (PRISM) III scores. Therafter, associations between BNP levels and clinical parameters were analyzed. RESULTS: There were 94 patients (mean: 5.6 yr, range: 2 mo-17 yr) that were consecutively enrolled in this study. The median BNP level was 127 pg/ml (range: 5 to 4950 pg/ml). BNP levels were correlated with PRISM III (rho = 0.36, p = 0.001) and C-reactive protein level (r = 0.39, p = 0.001). The median BNP levels were not only higher in patients with septic shock (n = 34) than those with sepsis (n = 58) (213 vs. 54 pg/ml, p = 0.0004), but also higher in patients with myocardial dysfunction (n = 18) than those with preserved myocardial function (n = 66) (765 vs. 65 pg/ml, p < 0.001). We also found that BNP levels correlated negatively with FS (r = -0.56, p < 0.001) and positively with inotropic scores (r = 0.34, p = 0.04). Most importantly, the median BNP levels were higher in non-survivors (n = 13) than survivors (n = 81) (367 vs. 106 pg/ml, p = 0.003). CONCLUSIONS: BNP levels are elevated in pediatric septic patients early in the disease course, and increased levels are associated with cardiovascular dysfunction and worse clinical outcome. KEY WORDS: B-type natriuretic peptide; Cardiac function; Pediatric; Sepsis; Septic shock. PMID- 27122914 TI - Preconception Counseling for Women with Congenital Heart Disease. AB - With advances that have been made over the recent decades in transcatheter and surgical interventions, most patients with congenital heart disease (CHD) can survive into adulthood. Overall, probably half of these surviving patients are female. When these female CHD patients reach childbearing age, however, pregnancy management will be a major issue. In order to meet the demands of fetal growth, the maternal cardiovascular system starts a series of adaptations beginning in early pregnancy. These adaptations include: decreased systemic and pulmonary vascular resistances, decreased blood pressure, expansion of the blood volume, increased heart rate and increased cardiac output. For women with CHD, this hemodynamic alteration may increase the risks of adverse cardiovascular events as well as the fetal and neonatal complications. Therefore, proper risk stratification and effective counseling for women with CHD who are planning their pregnancies is an important undertaking. KEY WORDS: Congenital heart disease; Pregnancy. PMID- 27122913 TI - Interventional Transcatheter Closure Ameliorates the Leukocyte Rho Kinase Activities among Patients with Patent Ductus Arteriosus. AB - BACKGROUND: Patent ductus arteriosus (PDA) causes increased pulmonary blood flow, which can lead to pulmonary arterial hypertension (PAH). Rho-associated coiled coil containing protein kinase (ROCK) may play an important pathophysiological role in PAH. We hypothesized that the increased pulmonary artery (PA) flow from PDA could activate ROCK. METHODS: Patients who received a PDA transcatheter closure in our hospital were consecutively enrolled in this study. Basic demographics and clinical hemodynamic data of the study participants were recorded. Then, ROCK activity was measured before and after the PDA occlusion procedure. ROCK activity was defined as the phosphorylation ratio of myosin binding subunit by Western blot measurement. We also sub-divided patients into the coil group and occluder group based on the occlusion device used in each patient's procedure. RESULTS: From January 2009 to December 2011, 25 patients with a median age of 2.3 years, ranging from 10 months to 72 years were enrolled. The mean PDA size was 0.31 +/- 0.14 cm, the mean Qp/Qs shunt was 1.54 +/- 0.41, and the mean systolic pulmonary artery pressure was 26.9 +/- 10.3 mmHg. There were 10 patients (one boy and nine girls) in the coil group and 15 patients (four boys and eleven girls) in the occluder group. Following the closure of the PDA, ROCK activity significantly decreased (1.78 +/- 2.25 vs. 0.77 +/- 0.69, p < 0.01). There was a strong correlation between the leukocyte ROCK activity with the systolic PA pressure (y = 5.4608x + 22.54, R2 = 0.5539, p < 0.05), but not the Qp/Qs value. Both subgroups showed significant changes of ROCK activity after the procedure. Interestingly, when comparing the coil group with the occluder group, the decrease in ROCK activity was more apparent in the occluder group. CONCLUSIONS: The findings of this study indicated that ROCK activity is higher in patients with PDA and correlates with PA pressure. The decrease in ROCK activity following the device closure suggests that ROCK may be an important biomarker for PDA patency. KEY WORDS: Patent ductus arteriosus (PDA); Pulmonary arterial pressure; Rho kinase; Transcatheter closure. PMID- 27122915 TI - Insight into Pulmonary Arterial Hypertension Associated with Congenital Heart Disease (PAH-CHD): Classification and Pharmacological Management from a Pediatric Cardiological Point of View. AB - Compared with adult patients with pulmonary hypertension (PH), pulmonary vascular disease is characterized by complex heterogeneity in pediatric patients. The Nice PH classification does not completely characterize or individualize any subgroup of pediatric PH. This is in contrast to the Panama classification, in which prenatal and fetal origins of many pulmonary vascular diseases in neonates and children, perinatal pulmonary vascular maladaptation, prenatal and postnatal pulmonary vascular mal-development, and pulmonary vascular hypoplasia are included. Currently, the updated treatment algorithm for adults with pulmonary arterial hypertension (PAH), including PAH associated with congenital heart disease (PAH-CHD) and idiopathic PAH, etc. has been reported. It has been suggested to treat FC III patients with Eisenmenger syndrome (ES) with bosentan. However, there is no evidence-based treatment algorithm for children with PAH CHD. Moreover, it is necessary to develop a more comprehensive algorithm in which multiple specific pediatric risk factors are determined, and the critical goal of treatment should be to permit normal activities without the need to self-limit in children with PAH-CHD. Together, the beneficial data on specific-target pharmacologic interventions are still quite preliminary, and large trials are warranted. Specifically, the extrapolation of the other forms of the disease, such as ES, should be undertaken carefully. KEY WORDS: Congenital heart disease; Eisenmenger syndrome; Pulmonary arterial hypertension; Target therapy. PMID- 27122916 TI - The Challenges in Managing Pulmonary Arterial Hypertension Associated with Congenital Heart Disease. AB - Congenital heart disease; Eisenmenger syndrome; Pulmonary arterial hypertension. PMID- 27122917 TI - Abnormalities of Selected Trace Elements in Patients with Coronary Artery Disease. AB - BACKGROUND: Coronary artery diseases are multifactorial, and over the last several decades particular consideration and research have been devoted to investigating the imbalance of patient elemental levels. Our current study aimed to investigate the comparative distribution of Ca, Mg, Fe, Zn, Cu, Co, Mn, Cr, Cd and Pb in the blood of coronary artery disease patients and healthy subjects. METHODS: Blood samples collected from both groups were digested into a HNO3-HCLO4 (10:1 v/v) mixture in a microwave oven, followed by quantification of the elements by atomic absorption spectrometry. RESULTS: The average levels of Pb and Cr were markedly higher (p < 0.001) while those of Ca, Fe, Cu and Mn were moderately higher (p < 0.05) in blood of the patients compared to the controls. However, correlation study showed divergent relationships between various elements in the blood of both groups. Multivariate cluster analysis revealed two major clusters of the elements for patients: Ca-Mg-Mn-Co-Cd and Pb-Cu-Fe-Zn-Cr; whereas three common groups were observed for controls: Ca-Mg-Zn-Cu, Cr-Mn-Fe and Co-Cd-Pb. Variations in the elemental levels were also observed to be associated with gender, habitat, food and smoking habits of the subjects. CONCLUSIONS: Overall, the distribution, correlation and apportionment of elemental data indicated an imbalance of the toxic/essential elements in blood of the patients compared to the controls. KEY WORDS: AAS; Blood; Cluster analysis; Coronary artery disease; Essential/toxic element. PMID- 27122918 TI - Lack of Association between High-Density Lipoprotein Cholesterol and Angiographic Coronary Lesion Severity in Chinese Patients with Low Background Low-Density Lipoprotein Cholesterol. AB - BACKGROUND: The atheroprotective role of high-density lipoprotein (HDL-C) particles as measured by HDL-C level in coronary arterial disease (CAD) remains unsettled. The aim of our study was to ascertain whether HDL-C was associated with the development and severity of coronary artery disease in Chinese patients who underwent coronary angiogram with low background Low-density lipoprotein (LDL C) levels, which has not been previously investigated. METHODS: Between March 1995 and May 2000, 566 consecutive patients (408 males, 66.7 +/- 11.3 years of age) with background LDL-C less than 100 mg/dl who underwent coronary artery angiography at our cath lab for suspected CAD were retrospectively recruited into the study. The severity of coronary lesions was measured by conventional coronary angiography and modified Gensini scores. RESULTS: In those subjects with significant coronary lesions, there were more males and conventional CAD risk factors of diabetes mellitus, smoking, and chronic renal disease. They were also older compared to those in the control group. However, total cholesterol, LDL-C, HDL-C, triglyceride levels and use of statins were similar in both groups. In those subjects with significant coronary lesions, there was no difference in conventional coronary lesion severity or modified Gensini score between the quartered HDL-C subgroups. Furthermore, there was no significant correlation between serum HDL-C level and modified Gensini scores. In linear regression analysis, HDL-C was not an independent predictor for modified Gensini scores. Furthermore, HDL-C was also not an independent risk factor for the presence of significant coronary lesions in low LDL-C patients in logistic regression analysis. CONCLUSIONS: In Chinese patients with low background LDL-C, serum HDL-C was not associated with development of CAD or lesion severity in patients with suspected CAD. Therefore, HDL-C did not appear to be atheroprotective in these patients. KEY WORDS: Coronary artery disease; Gensini score; High-density lipoprotein cholesterol. PMID- 27122919 TI - Variation in Cardiac Vein System is Associated with Coronary Artery Calcium - A Venous-Atherosclerosis Paradox? AB - BACKGROUND: The factors that determine the different patterns of venous anatomy are not well understood. This study was designed to evaluate the relationship between variation in the cardiac vein system and the extent of coronary artery calcium score (CACS). METHODS: We reviewed the results of 64-slice CTs of 226 subjects (age 57.2 +/- 11.2; 133M) enrolled in our study. The subjects were divided into 3 groups based on coronary artery calcium: 92 patients. with CACS = 0 AU (Agatston Unit, AU); 56 with CACS = 1-100 AU; and 78 patients with CACS > than 100 AU. The cardiac venous system was reconstructed during the optimal phase of the cardiac cycle in each subject. RESULTS: Subjects with a higher CACS had a better quality of vein images (p < 0.01). The number of visible veins differed between the groups. Eight subjects (8.7%) in the group with CACS = 0 AU, 7 (12.5%) in the group with CACS = 1-100 AU, and 23 (29.5%) in the group with CACS > 100 AU had five or more visible veins (p < 0.001), whereas the proportion of subjects with less than three visible veins was 56 (60.8%), 31 (55.4%) and 30 (38.4%), respectively (p < 0.05). The number of visible veins correlated with CACS (r = 0.28; p < 0.05). In a multivariate regression analysis, which included age, gender, CACS, LV ejection fraction, myocardial volume and heart rate, the CACS was found to be an independent determinant of the number of visible veins (p < 0.05). CONCLUSIONS: The results of our study suggested that there is a link between a variation in the cardiac venous system and the extent of atherosclerosis. KEY WORDS: Coronary artery calcium score (CACS); Computed tomography; Coronary veins. PMID- 27122920 TI - Electrophysiological Effects of Dexmedetomidine on Sinoatrial Nodes of Rabbits. AB - BACKGROUND: The purpose of this study was to investigate the electrophysiological effects of dexmedetomidine on pacemaker cells in sinoatrial nodes of rabbits. METHODS: Healthy rabbits were anesthetized intravenously with sodium pentobarbital, and the hearts were quickly dissected and mounted in a tissue bath. Machine-pulled glass capillary microelectrodes which were connected to a high input impedance amplifier and impaled in dominant pacemaker cells. Thereafter, an intracellular microelectrode technique was used to record action potential. RESULTS: The amplitude of action potential, velocity of diastolic (phase 4) depolarization, and rate of pacemaker firing in normal pacemaker cells in sinoatrial node were decreased by use of dexmedetomidine (0.5 ng/ml, 5 ng/ml, 50 ng/ml) in a concentration-dependent manner. Pretreatment with yohimbine (1 MUM), did not alter the effects of dexmedetomidine (5 ng/ml) on sinoatrial node pacemaker cells. Pretreatment with CsCl (2 mmol/L), dexmedetomidine (5 ng/ml) decreased the amplitude of action potential, but had no significant effect on other parameters of action potential. CONCLUSIONS: Dexmedetomidine exerts inhibitory electrophysiological effects on pacemaker cells in sinoatrial nodes of rabbits in a concentration-dependent manner, which may not be mediated by alpha 2 adrenoreceptor. KEY WORDS: Action potential; Cardiology; Dexmedetomidine; Pacemaker activity; Sinoatrial node. PMID- 27122921 TI - Feasibility and Safety of Coronary Procedures via an Arteriovenous Graft Approach in Patients on Maintenance Hemodialysis. AB - BACKGROUND: Traditionally, a radial or brachial arterial approach is unadvisable in hemodialysis patients. Consequently, coronary angiography or angioplasty is usually performed via a femoral artery approach in these patients, who carry a higher risk of vascular access complications. In hemodialysis patients, arteriovenous grafts (AVG) are created for repeated punctures; however, the feasibility and safety of a trans-AVG approach for coronary angiography or angioplasty remains unclear. METHODS: In our institution, cardiac catheterizations were attempted via AV grafts in hemodialysis patients with a U shaped forearm AVG. We retrospectively identified coronary angiography or angioplasty procedures in hemodialysis patients from a computer-based database in our hospital. The procedure details and outcomes were obtained from review of the clinical, angiographic and hemodialysis records. RESULTS: From 2008 to 2013, 167 procedures in hemodialysis patients were identified from 2866 diagnostic or interventional coronary procedures in our institution. Out of these, 24 procedures in 17 patients were performed via a trans-AVG approach. In all AVG procedures, a 6F 16-cm or 7F 10-cm sheath was placed from the AVG into the brachial artery. All diagnostic procedures were successfully performed. In 14 procedures, the patients also underwent angioplasty and all of the angioplasty procedures were successful. There was no arterial spasm, arterial dissection, puncture site hematoma, or acute thrombosis of the AVG during or after the procedures. CONCLUSIONS: A trans-AVG approach appears to be a feasible and safe route for coronary angiography or angioplasty in hemodialysis patients with a U shaped forearm AVG. However, further studies with a larger patient number are necessary. KEY WORDS: Arteriovenous graft; Hemodialysis; Percutaneous coronary intervention. PMID- 27122922 TI - Congenital Anomaly of Single Dominant Right Coronary Artery with Hypoplastic Left Coronary Artery. AB - With the popularization of new imaging technology, more people are deciding to undergo non-invasive studies such as multidetector computerized tomography (MDCT) before receiving coronary angiography. For this reason, coronary anomalies of coronary artery are being encountered more frequently. We here report a 68-year old male presenting with typical angina. The MDCT images suggested chronic total occlusion of the left anterior descending (LAD) artery with collateral circulation from the right coronary artery (RCA). The patient's coronary angiography showed a congenital coronary anomaly with a single dominant RCA supplying the entire coronary circulation of the heart with both LAD and left circumflex artery hypoplasia. KEY WORDS: Angiography; Anomaly; Computerized tomography; Coronary artery. PMID- 27122923 TI - Primary Intimal Sarcoma of Thoracic Aorta Presenting as Hypertensive Crisis. AB - We report a 45-year-old woman who presented to our facility in a hypertensive crisis. Computed tomography (CT) revealed a thoracic aortic tumor, and tissues obtained via endovascular biopsy revealed undifferentiated sarcoma. A final diagnosis of intimal sarcoma was made by intra-operative pathological examination. Despite undergoing surgical resection followed by adjuvant chemotherapy, the patient died from progressive multiple metastasis and severe sepsis. Although aortic sarcoma is rarely diagnosed, it should be considered a possible etiology of hypertensive crisis. KEY WORDS: Aortic tumor; Endovascular biopsy; Hypertension crisis; Intimal sarcoma. PMID- 27122924 TI - Brain Stem Hemorrhage in a 2-Year-10-Month-Old Child with Renovascular Hypertension Related to Fibromuscular Dysplasia. AB - Renovascular hypertension due to fibromuscular dysplasia is an uncommon but important cause of pediatric hypertension. It is usually ignored and diagnosed after a long delay because blood pressure is infrequently measured in children. We report a case of previously undiagnosed renovascular hypertension complicated with right renal infarction in a 2-year-10-month-old child, who initially presented as a case of conscious disturbance. The patient's brain CT displayed brain stem hemorrhage, and a brain MRI showed acute hemorrhage and multiple old intracerebral hemorrhage. Therefore, intimal fibromuscular dysplasia of the right renal artery was diagnosed by computed tomography and confirmed after renal angiography. Her blood pressure was gradually normalized after medical therapy, including use of Losartan. She is presently asymptomatic on OPD follow-up. The importance of BP measurement can not be overemphasized in pediatric patients less than three years of age with underlying diseases. KEY WORDS: Conscious disturbance; Fibromuscular dysplasia; Renovascular hypertension. PMID- 27122925 TI - Accordion Stent Deformation upon Retrieval of a Side-Branch Protective Guidewire. AB - In this case we herein report a dangerous complication from primary percutaneous coronary intervention, where an unnoticed loop of the guidewire was inadvertently made around the stent during provisional stenting. Since the guidewire and the stent were entangled, efforts to retrieve the guidewire only exacerbated the problem by compressing the stent like an accordion. We review those factors that may have influenced stent compression in our case, as well as possible ways to avoid it from occurring in the future. KEY WORDS: Catheterization; Coronary stenosis; Embolism; Myocardial infarction; Percutaneous coronary intervention; Stents. PMID- 27122926 TI - Isolated Congenital Unilateral Agenesis of the Left Pulmonary Artery with Left Lung Hypoplasia in an Asymptomatic Adult Patient. AB - The congenital unilateral agenesis of pulmonary artery is a congenital cardiovascular anomaly rarely seen in adulthood. A 21-year-old asymptomatic male was admitted to our hospital to obtain a routine health report to accompany a job application. Posteroanterior chest radiograph revealed a mediastinal shift to the left, with increased radiopacity in the left lung and increased radiolucency in the right lung. Thoracoabdominal computed tomography revealed hypoplasia of the left pulmonary artery. Transthoracic echocardiography excluded any accompanying cardiac abnormalities. Pulmonary angiography was undertaken and confirmed diffuse hypoplasia of the left pulmonary artery while right pulmonary artery was significantly enlarged. The patient's pulmonary artery pressure was within the normal limits, after which he decided to be carefully followed-up. KEY WORDS: Cardiovascular anomaly; Hypoplasia; Pulmonary artery. PMID- 27122928 TI - Statin Dose and the Risk of Intracerebral Hemorrhage: A Population-Based Longitudinal Study in Taiwan. AB - BACKGROUND: In the last 15 years, there has been considerable interest in statin use as a means to reduce the likelihood of vascular events. Several clinical trials have shown that high-dose statin (HDS) treatment could reduce vascular events. In high-risk populations, lipid treatment guidelines have generally suggested prescribing statin up to the highest recommended dosage. However, there remains concern about the risk of intracerebral hemorrhage (ICH) with HDS treatment. METHODS: This was a national population-based cohort study from the National Health Insurance Research Database of Taiwan extending from July 2001 to December 2008. Patients with cerebrovascular or cardiovascular disease were enrolled. The HDS group was defined as those patients receiving more than 420 mg per year of atorvastatin or an equivalent potency statin. Moderate dose statin group (MDS) was defined as those patients receiving atorvastatin in amounts between 196-420 mg per year or an equivalent potency statin. Low dose statin (LDS) group was defined as those receiving less than 196 mg per year of atorvastatin or an equivalent statin. The primary endpoint is ICH. The secondary endpoints are myocardial infarction (MI), ischemic stroke (IS) and new-onset DM (NDM). RESULTS: A total of 5459 patients were enrolled in our study, with study participant ages ranging from 62.91 +/- 11.85 years and a mean follow-up time of 2039 +/- 6 days. After adjusting for age, gender, diabetes and hypertension, Cox regression analysis found ICH risk was lower in HDS and MDS groups compared with LDS (HR 0.49, 95% CI 0.26-0.91, p = 0.0246 and HR 0.45, 95% CI 0.24-0.86, p = 0.0157). The risk of IS is lower in patients with HDS treatment (HR 0.68, 95% CI 0.55-0.83, p < 0.01). However, the risk of MI and NDM incidence are not statistically significant between the different dose groups. CONCLUSIONS: In the real-world data provided by Taiwan's National Health Insurance research database, it was shown that patients who received a higher dose of statin had a reduced and not elevated risk of intracerebral hemorrhage. KEY WORDS: High-dose statin; Hyperlipidemia; Intracerebral hemorrhage; Ischemic stroke; New-onset DM. PMID- 27122929 TI - The Relation between the Timing of Percutaneous Coronary Intervention and Outcomes in Patients with Acute Coronary Syndrome with Routine Invasive Strategy Data from Taiwan Acute Coronary Syndrome Full Spectrum Data Registry. AB - BACKGROUND: Several large trials have indicated that a routine invasive strategy was favored for high-risk patients with non-ST-elevation acute coronary syndromes. However, the optimal timing for this intervention is unclear. METHODS: We included patients with unstable angina or non-ST elevation myocardial infarction (NSTEMI) undergoing percutaneous coronary intervention (PCI) from the Taiwan acute coronary syndrome registry. Thrombolysis in Myocardial Infarction (TIMI) score was used to stratify our patients into three groups: low (TIMI 0-2), intermediate (TIMI 3-4) and high risk (TIMI 5-7).We analyzed outcomes according to the timing of PCI. RESULTS: Overall, 984 patients were included in this study. For primary outcomes including cardiac death and recurrent myocardial infarction, early PCI within 24 hours did not show benefits over late PCI (24-72 or > 72 hours) (p > 0.05) in the low and intermediate risk groups. However, in the high risk group, patients who underwent PCI after 72 hours had significantly worse primary outcomes than those who underwent PCI within 24-72 hours. For secondary outcomes including non-cardiac death, unplanned revascularization, and major bleeding, the events rate was significantly higher for early or delayed PCI in low-risk patients when compared with patients who underwent PCI within 24-72 hours. CONCLUSIONS: In our study, for high-risk NSTE-ACS patients, PCI within 24 72 hours from symptom onset is demonstrably the optimum time for PCI. Delayed PCI over 72 hours is associated with the worst outcomes and should be avoided. For patients with low risks, routine early PCI < 24 hours after PCI is not beneficial. KEY WORDS: Acute coronary syndrome; Early invasive strategy. PMID- 27122930 TI - The Current Status of Performing Left Ventriculography in Taiwan. AB - BACKGROUND: Left ventriculography (LVG) is a gold standard examination of left ventricular function, although it also involves a small but significant risk of complications. However, it was recently reported to be overused in the USA in comparison to an alternative imaging modality. In this study, our aim was to analyze the real-world use of LVG in Taiwan. METHODS: This cohort study analyzed the data in the Taiwan National Health Insurance Bureau database for patients undergoing coronary angiography from 1996-2008. The most recent imaging modalities were used to evaluate left ventricular function including echocardiography and single-photon emission computed tomography (SPECT) within 30 day. The primary outcome was the concomitant use of LVG during coronary angiography. RESULTS: Of 8653 patients who underwent coronary angiography, LVG was performed on 4634 (53.6%) of those study participants. The frequency of LVG use was lower in the groups indicating left ventricular function evaluation, including acute myocardial infarction, heart failure and shock (49.5 vs. 57.1%, p < 0.001). In the population that had undergone a recent left ventricular assessment, the use of LVG was lower (52.2% vs. 54.7%, p = 0.03). Multivariate analysis found that 30-day imaging tests are not a predictor for use of LVG. CONCLUSIONS: In Taiwan, about one half of those patients whose data we reviewed actually received coronary angiography and LVG at the same time. Ultimately, we found that there was no overuse of LVG in those patients with recent alternative imaging modality performed. KEY WORDS: Angiography; Coronary; Ventriculography. PMID- 27122931 TI - Heart Failure Functional Class Associated with Depression Severity But Not Anxiety Severity. AB - BACKGROUND: Depression and anxiety are common in heart failure (HF) patients and associated with adverse clinical outcomes. However, there are little or no published data that focuses on the relationship between these commonly observed situations and HF classes. The aim of this study was to evaluate the relationship between these psychiatric co-morbidities and HF symptom classes. As a second objective of our study, the associations between patient characteristics and depression severity were also assessed. METHODS: Our study enrolled a total of 420 HF study participants. The severity of depressive and anxiety symptoms was evaluated by Beck's depression and anxiety. The measured total scores were used to grade depression severity and anxiety as minimal/mild and moderate/severe. RESULTS: According to NYHA Functional Classification, 228 patients (51%) had class I symptoms, 101 (23%) had class II symptoms, 31 (7%) had class III symptoms, and class IV symptoms were noted in the remaining 60 patients (19%). The mean Beck's depression and anxiety scores were 12.4 +/- 11.1 and 13.4 +/- 9.0, respectively. While no association between HF symptom classes and anxiety severity was observed, a significant positive relation between HF symptom class and depression score was found. CONCLUSIONS: The results of our study suggested that HF symptom class was positively associated with severity of depression. On the other hand, there was no association between HF symptom class and anxiety score in a wide population of heart failure patients. KEY WORDS: Anxiety; Depression; Heart failure. PMID- 27122932 TI - Psychiatric Comorbidity and Psychosocial Factors Matter in Heart Failure. AB - Comment on "Heart failure functional class associated with depression severity but not anxiety severity" by Celik E. et al. Acta Cardiologica Sinica 2016;32:55 61. PMID- 27122927 TI - Management of Venous Thromboembolisms: Part I. The Consensus for Deep Vein Thrombosis. AB - Deep vein thrombosis (DVT) is a potentially catastrophic condition because thrombosis, left untreated, can result in detrimental pulmonary embolism. Yet in the absence of thrombosis, anticoagulation increases the risk of bleeding. In the existing literature, knowledge about the epidemiology of DVT is primarily based on investigations among Caucasian populations. There has been little information available about the epidemiology of DVT in Taiwan, and it is generally believed that DVT is less common in Asian patients than in Caucasian patients. However, DVT is a multifactorial disease that represents the interaction between genetic and environmental factors, and the majority of patients with incident DVT have either inherited thrombophilia or acquired risk factors. Furthermore, DVT is often overlooked. Although symptomatic DVT commonly presents with lower extremity pain, swelling and tenderness, diagnosing DVT is a clinical challenge for physicians. Such a diagnosis of DVT requires a timely systematic assessment, including the use of the Wells score and a D-dimer test to exclude low-risk patients, and imaging modalities to confirm DVT. Compression ultrasound with high sensitivity and specificity is the front-line imaging modality in the diagnostic process for patients with suspected DVT in addition to conventional invasive contrast venography. Most patients require anticoagulation therapy, which typically consists of parenteral heparin bridged to a vitamin K antagonist, with variable duration. The development of non-vitamin K oral anticoagulants has revolutionized the landscape of venous thromboembolism treatment, with 4 agents available,including rivaroxaban, dabigatran, apixaban, and edoxaban. Presently, all 4 drugs have finished their large phase III clinical trial programs and come to the clinical uses in North America and Europe. It is encouraging to note that the published data to date regarding Asian patients indicates that such new therapies are safe and efficacious. Ultimately, our efforts to improve outcomes in patients with DVT rely on the awareness in the scientific and medical community regarding the importance of DVT. KEY WORDS: Combination therapy; Hypertension; alpha1-blocker. PMID- 27122933 TI - Half-Logistic Function Model for First Half of Descending Phase of Cardiomyocyte Cytoplasmic Ca(2+) Concentration ([Ca(2+)]i)-Time Curve (CaTCIII) in Isolated Aequorin-Injected Mouse Left Ventricular Papillary Muscle. AB - BACKGROUND: Myocardial contraction and relaxation are regulated by increases and decreases in cytoplasmic calcium concentration ([Ca(2+)]i). In previous studies, we found that a half-logistic (h-L) function, which represents a half-curve of a symmetrical sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phase and the second half of the descending phase of the [Ca(2+)]i transient curve better than a mono-exponential (m-E) function. In the present study, we investigated the potential application of an h-L function to analyse the first half of the descending phase of CaTC (CaTCIII). METHODS: The [Ca(2+)]i was measured using the Ca(2+)-sensitive aequorin, which was microinjected into 15 isolated mouse left ventricular (LV) papillary muscles. The observed CaTCIII data in the interval from the point corresponding to the peak [Ca(2+)]i to the point corresponding to dCa/dtmin was curve-fitted using the h-L and m-E function equations by the least-squares method. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E function best curve-fits for 11 CaTCIIIs were 0.9986 and 0.9982, respectively. The Z transformation of h-L r (3.64 +/- 0.45) was larger than that of m-E r (3.50 +/- 0.33) (p < 0.05). CONCLUSIONS: The h-L function can evaluate most CaTCIIIs more accurately than the m-E function in isolated aequorin-injected mouse LV papillary muscle. The three calculated h-L parameters i.e., amplitude constant, time constant, and non-zero asymptote, are more reliable indices than m-E for evaluating the magnitude and time course of the change in the decrease in [Ca(2+)]i. KEY WORDS: Ca(2+) transient; Half-logistic amplitude constant; Half logistic non-zero asymptote; Half-logistic time constant; Myocardial Ca(2+) handling. PMID- 27122934 TI - Serum Paraoxonase Levels are Correlated with Impaired Aortic Functions in Patients with Chronic Kidney Disease. AB - BACKGROUND: The correlation between aortic functions and paraoxonase levels has been previously demonstrated by several earlier studies. In this study, we aimed to investigate the correlation between serum paraoxonase levels and aortic functions among patients with chronic kidney disease. METHODS: Our study enrolled 46 chronic kidney disease patients and 45 healthy controls. From these patients, serum cholesterol, creatinine, hemoglobin, and paraoxonase-1 levels were analyzed. RESULTS: Paraoxonase-1 levels were significantly lower in patients with chronic kidney disease compared to the controls (p < 0.001). Additionally, the extent of aortic stiffness index (%) was significantly higher in chronic kidney disease patients, but aortic strain and aortic distensibility were significantly higher in healthy controls (p < 0.001, p < 0.001, and p < 0.001, respectively). We further found that paraoxonase-1 levels were correlated with aortic stiffness index, aortic strain, and aortic distensibility (p < 0.001, p < 0.001, and p < 0.001, respectively). CONCLUSIONS: Our study demonstrated that serum paraoxonase 1 levels were significantly correlated with impaired aortic functions. The results of this study highlight the impact of serum paraoxonase-1 activity on atherosclerosis and cardiovascular adverse events. KEY WORDS: Aortic functions; Atherosclerosis; Chronic kidney disease; Echocardiography; Paraoxonase. PMID- 27122935 TI - Total Flavonoids of Astragalus Plays a Cardioprotective Role in Viral Myocarditis. AB - BACKGROUND: Viral myocarditis is initiated by viral infection of myocardial tissue leading to dilated cardiomyopathy and congestive heart failure. Recent studies have linked viral myocarditis with dysfunctions in endoplasmic reticulum (ER) mediated Ca(2+) homeostasis and the unfolded protein response (UPR). Currently there are no effective treatments for this viral infection. METHODS: We employed the use of a well-characterized pathogen coxsackievirus B3 (CVB3) to induce mouse viral myocarditis. After intraperitoneal administration of total flavonoids of Astragalus (TFA), we examined the protective effect of TFA on CVB3 induced heart function impairment and decreased calumenin mRNA levels. Furthermore, calumenin protein level was studied in vivo and in vitro with CVB3 infection in the presence or absence of TFA. The interaction between calumenin and the sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) was also tested in HL-1 cells. RESULTS: Whereas customarily we would expect that CVB3 infection would decrease mRNA and protein levels of the Ca(2+) binding ER chaperone calumenin, here TFA treatment prevented this decline in both CVB3 infected mice and in an in vitro system of infected HL-1 cardiomyocytes. CVB3 infection in HL-1 cells prevented the association of calumenin with the calcium mobilizing protein SERCA2, and TFA treatment rescued this interaction. CONCLUSIONS: This study identified that CVB3 infection promotes cardiomyocyte dysfunction by effecting expression levels and activity of the cardio protective ER chaperone calumenin. For the first time, TFA was shown to prevent loss of mRNA and protein levels of calumenin and also rescued the association of this protein with SERCA2. KEY WORDS: Calumenin; Sarco/endoplasmic reticulum Ca(2+)-ATPase; Total flavonoids of Astragalus; Viral myocarditis. PMID- 27122936 TI - Acute Beta Blockade at Peak Stress: Will It Alter the Sensitivity of Dobutamine Stress Echocardiography in Patients with Normal Resting Wall Motion? AB - BACKGROUND: We compared the accuracy of recovery phase images following administration of intravenous propranolol with peak stress images, for detection of coronary artery disease in patients with no resting wall motion abnormalities undergoing dobutamine stress echocardiography. METHODS: We enrolled 100 consecutive patients with no resting wall motion abnormalities who underwent dobutamine stress echocardiography. Propranolol was injected after termination of dobutamine infusion. Positive peak stress images were defined as the induction of wall motion abnormalities at any stage before propranolol injection. Positive recovery phase images were defined as maintenance or worsening of wall motion abnormalities induced at peak stress, or the appearance of new wall motion abnormalities during recovery phase. Significant coronary stenosis was defined as >= 50% obstruction of >= 1 sizable artery by coronary angiography. RESULTS: Seventy-two patients (72%) had significant coronary artery disease. Analysis of peak stress images revealed sensitivity, specificity, positive and negative predictive values of 80.6%, 85.7%, 93.5%, and 63.2%; the overall accuracy was 82%. Analysis of the recovery phase images revealed sensitivity, specificity, positive and negative predictive values of 91.7%, 75%, 90.4%, and 77.8%; here, the overall accuracy was 87%. CONCLUSIONS: In patients with no resting wall motion abnormalities, acute beta blockade during dobutamine stress echocardiography improved the sensitivity of recovery phase images for detection of significant coronary artery disease versus peak stress images, but with reduced specificity. KEY WORDS: Accuracy; Beta blocker; Coronary artery disease; Dobutamine stress echocardiography; Recovery phase images. PMID- 27122937 TI - Early Percutaneous Heparin-Free Veno-Venous Extra Corporeal Life Support (ECLS) is a Safe and Effective Means of Salvaging Hypoxemic Patients with Complicated Chest Trauma. AB - BACKGROUND: The objective of this study was to assess the feasibility and safety of heparin-free veno-venous extracorporeal life support (VV ECLS) as a means of salvaging polytrauma patients with life-threatening hypoxemia. METHODS: This is a retrospective observational study on 7 consecutive trauma patients who underwent VV ECLS for severe chest trauma unresponsive to conventional measures. RESULTS: The median time to ECLS was within 10 hrs (IQR 2-53) of mechanical ventilation. Surgical interventions were performed before and during ECLS based on management priorities consistent with advanced trauma life support guidelines. No heparin was used for at least 4 days in this group with activated coagulation time (ACT) approximating 170 seconds by the 3(rd) and 4(th) day. There were no thromboembolic complications. Four patients were successfully discharged and three of these survivors had concomitant traumatic brain injury (TBI) without neurologic sequel. CONCLUSIONS: Early VV ECLS can be used for salvage of patients with traumatic lung injury. Acute trauma care can be continued as needed under heparin-free ECLS without the fear of thromboembolic complications. KEY WORDS: Adult respiratory distress syndrome; Extracorporeal life support; Multiple trauma; Thoracic injury; Traumatic brain injury. PMID- 27122938 TI - Areca Nut Chewing Complicated with Non-Obstructive and Obstructive ST Elevation Myocardial Infarction. AB - Areca nut chewing is one of the most prevalent substance abuse habits in the world, and it is associated with the risk of a variety of medical challenges including hypertension, arrhythmia, and coronary artery disease (CAD). However, ST elevation myocardial infarction (STEMI) is an extremely rare complication of areca nut chewing. Herein we report two cases where patients suffered from STEMI after areca nut chewing. The first case involved a patient with non-obstructive CAD and non-sustained ventricular tachycardia during hospitalization. The second case revealed left circumflex artery total occlusion, and primary percutaneous coronary intervention was performed. Initially, the levels of arecoline and arecaidine plasma were checked in these two cases after admission. Although both cases revealed increased levels, the second case showed substantially higher values than the first case. In general, these two cases remind physicians that areca nut chewing may cause myocardial injury with different severity, although STEMI with true coronary obstruction remains an extremely rare but possible complication after areca nut chewing. KEY WORDS: Areca nut chewing; Coronary obstruction; ST elevation myocardial infarction. PMID- 27122939 TI - Huge Left Atrial Pseudoaneurysm in a 5-Month-Old Baby Presented with Supraventricular Tachycardia. AB - Cardiac pseudoaneurysm is an extremely rare condition in children. It can be congenital or acquired and has been primarily described in the left side of the heart. The congenital form of pseudoaneurysm is thought to be related to muscular dysplasia of the muscular layer of the heart. The acquired form is related to myocardial infarction, infective endocarditis or chest trauma. In this report we described a 5-month-old baby with left atrial pseudoaneurysm who was referred to our hospital due to tachycardia and hemodynamic instability. After diagnosis of left atrial pseudoaneurysm, aneurysmectomy was performed and the left atrial wall was successfully repaired by surgery three days after admission. In conclusion, due to life threatening complications such as dissection, arrhythmias, compression of aneurysm and tromboembolic complications, pseudoaneurysm should be treated by surgery. KEY WORDS: Chest trauma; Left atrial pseudoaneurysm; Supraventricular arrhythmias. PMID- 27122940 TI - Carcinoid Heart Disease in a Primary Ovarian Carcinoid. AB - Ovarian carcinoids are very rare, and only their insular form is associated with carcinoid syndrome. We herein describe a case report of an elderly woman who presented with typical carcinoid syndrome, which is routinely characterized by right-sided heart failure, diarrhoea, flushes, and other common manifestations. Further examination and biochemical testing of the patient confirmed suspected carcinoid tumor. However, the tumor was surprisingly localized in the left ovary. The presence of the patient's severe combined tricuspid valve disease would create impossible surgical management conditions, so we decided to first perform cardio-surgery with tricuspid valve replacement. After tumor removal, levels of hydroxyindolacetic acid did not normalize and although the patient was asymptomatic, a small lesion was detected by tectrotyd scan paravertebrally. Treatment with lanreotide led to complete remission with negative biochemical and imaging signs of tumor. Thus, to summarize, carcinoid tumor even in an atypical localization (ovary) should be considered in elderly female patients with severe combined tricuspid valve disease due to carcinoid syndrome. KEY WORDS: Carcinoid syndrome; Ovarian carcinoid; Tricuspid valve. PMID- 27122941 TI - Pulmonary Arteriovenous Fistula with Pulmonary Hypertension - To Close or Not to Close? AB - A 37-year-old female presented to our facility suffering from exertional dyspnea for 2-3 months. Her chest x-ray showed a nodular shadow in the right lower lung, and chest CT revealed a pulmonary arteriovenous fistula (PAVF). Subsequent echocardiographic examination detected no intra-cardiac shunt but did indicate pulmonary hypertension as evidenced by a tricuspid regurgitation flow velocity of 4.17 M/sec. Contrast echocardiography with antecubital vein injection of agitated normal saline demonstrated visualization of the left heart chambers compatible with PAVF. At cardiac catheterization, pulmonary arterial pressure was 59/26 mmHg, mean 34 mmHg. Because there was no intra-cardiac communication detected, primary pulmonary hypertension was tentatively diagnosed. Pulmonary angiography demonstrated a PAVF arising from the lower right pulmonary artery, forming a secular structure on its course in draining into the left atrium through a long pulmonary vein. In this particular anomaly, a concurrence of PAVF with pulmonary hypertension, we judged that the PAVF might serve as a safety valve for pulmonary hypertension and should not be closed. We therefore left the PAVF untreated and thereafter provided medical management for this patient. The concomitant presence of PAVF and pulmonary hypertension is a rare clinical condition. The ultimate treatment strategy for this uncommon condition should be carefully considered. KEY WORDS: Computed tomography; Contrast echocardiography; Pulmonary angiography; Pulmonary arteriovenous fistula; Pulmonary hypertension. PMID- 27122942 TI - Renal Function Should be Considered in Determining Superiority of Drug-Eluting Stents over Bare-Metal Stents in Patients with Acute Coronary Syndrome. PMID- 27122943 TI - Author Reply to Letter to the Editor: Drug-Eluting Stents versus Bare-Metal Stents in Taiwanese Patients with Acute Coronary Syndrome: An Outcome Report of a Multicenter Registry. PMID- 27122944 TI - Introduction to Cardiovascular Magnetic Resonance: Technical Principles and Clinical Applications. AB - Cardiovascular magnetic resonance (CMR) is a set of magnetic resonance imaging (MRI) techniques designed to assess cardiovascular morphology, ventricular function, myocardial perfusion, tissue characterization, flow quantification and coronary artery disease. Since MRI is a non-invasive tool and free of radiation, it is suitable for longitudinal monitoring of treatment effect and follow-up of disease progress. Compared to MRI of other body parts, CMR faces specific challenges from cardiac and respiratory motion. Therefore, CMR requires synchronous cardiac and respiratory gating or breath-holding techniques to overcome motion artifacts. This article will review the basic principles of MRI and introduce the CMR techniques that can be optimized for enhanced clinical assessment. KEY WORDS: Cardiovascular MR * Coronary arteries * Flow quantification * Myocardial fibrosis * Myocardial perfusion * Myocardial scarring * Regional wall motion * Ventricular function. PMID- 27122945 TI - The Incremental Diagnostic Performance of Coronary Computed Tomography Angiography Added to Myocardial Perfusion Imaging in Patients with Intermediate to-High Cardiovascular Risk. AB - PURPOSE: Several studies have suggested that a combined approach of stress myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) can provide diagnostic results with excellent accuracy. We aimed to explore whether the addition of CCTA to stress MPI provides incremental diagnostic value in intermediate-to-high cardiovascular risk patients. METHODS: A total of 106 consecutive patients (93 male, 65 +/- 10.4 years) underwent coronary artery calcium scoring (CACS), CCTA and (201)Thallium stress MPI before coronary angiography was reviewed. Thirty-seven patients (34.9%) had a history of proven coronary artery disease (CAD) or revascularization procedures, and four had documented non-significant CAD (3.8%). The remaining patients consisted of 17 (16.0%) classified as intermediate, and 48 (45.3%) as the high-risk groups. RESULTS: Obstructive CAD was diagnosed by invasive coronary angiography in 88 patients with 161 vessels. The sensitivity and specificity in a patient-based analysis for obstructive CAD were 99% and 17% for CCTA, 80% and 50% for MPI and 91% and 67% for the combined method, respectively. The per-vessel diagnostic sensitivity and specificity were 95% and 54% for CCTA, 59% and 75% for MPI and 84% and 76% for the combined method. There were significant differences (p < 0.05) when comparing the combined method with MPI or CCTA by areas under the curve in a patient- or vessel-based analysis. However, CACS of 400 or more could not further stratify the patients with obstructive CAD. CONCLUSIONS: CCTA, not CACS, provided additional diagnostic values to stress MPI in patients with intermediate-to-high cardiovascular risk. KEY WORDS: Coronary artery disease (CAD) * Coronary computed tomography angiography (CCTA) * Myocardial perfusion imaging (MPI) * Single-photon emission computed tomography (SPECT). PMID- 27122947 TI - The Emerging Roles of Coronary Computed Tomographic Angiography: Acute Chest Pain Evaluation and Screening for Asymptomatic Individuals. AB - Coronary computed tomographic angiography (CCTA) has been widely available since 2004. After that, the diagnostic accuracy of CCTA has been extensively validated with invasive coronary angiography for detection of coronary arterial stenosis. In this paper, we reviewed the updated evidence of the role of CCTA in both scenarios including acute chest pain and screening in asymptomatic adults. Several large-scale studies have been conducted to evaluate the diagnostic value of CCTA in the context of acute chest pain patients. CCTA could play a role in delivering more efficient care. For risk stratification of asymptomatic patients using CCTA, latest studies have revealed incremental benefits. Future studies evaluating the totality of plaque characteristics may be useful for determining the role of noncalcified plaque for risk stratification in asymptomatic individuals. KEY WORDS: Acute chest pain * Computed tomography * Coronary artery disease * Health screening * Stable angina. PMID- 27122946 TI - New Trends in Radionuclide Myocardial Perfusion Imaging. AB - Radionuclide myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) has been widely used clinically as one of the major functional imaging modalities for patients with coronary artery disease (CAD) for decades. Ample evidence has supported the use of MPI as a useful and important tool in the diagnosis, risk stratification and treatment planning for CAD. Although popular in the United States, MPI has become the most frequently used imaging modality among all nuclear medicine tests in Taiwan. However, it should be acknowledged that MPI SPECT does have its limitations. These include false positive results due to certain artifacts, false-negative due to balanced ischemia, complexity and adverse reaction arising from current pharmacological stressors, time consuming nature of the imaging procedure, no blood flow quantitation and relatively high radiation exposure. The purpose of this article was to review the recent trends in nuclear cardiology, including the utilization of positron emission tomography (PET) for MPI, new stressor, new SPECT camera with higher resolution and higher sensitivity, dynamic SPECT protocol for blood flow quantitation, new software of phase analysis for evaluation of LV dyssynchrony, and measures utilized for reducing radiation exposure of MPI. KEY WORDS: Coronary artery disease * Myocardial flow reserve * Myocardial perfusion imaging * Phase analysis * PET * SPECT. PMID- 27122948 TI - Intrinsic Cardiac Autonomic Ganglionated Plexi within Epicardial Fats Modulate the Atrial Substrate Remodeling: Experiences with Atrial Fibrillation Patients Receiving Catheter Ablation. AB - BACKGROUND: A recent study reported the close relationship between high dominant frequent (DF) sites [atrial fibrillation (AF) nest] and the intrinsic cardiac autonomic nervous system. The aim of this study was to investigate the correlation between the regional distribution of epicardial fat and the properties of the biatrial substrates in AF patients. METHODS: We studied 32 patients with paroxysmal (n = 23) and persistent (n = 9) AF. The epicardial fat volume around the left atrium (LA) was evaluated using 64-slice multidetector computed tomography and the topographic distribution of the fat volume was assessed. The biatrial DFs, voltages, and total activation times (TATs) were obtained during sinus rhythm. RESULTS: Out of the 8 divided LA regions, a significant linear correlation existed between the LA fat and mean DF values in the right upper anterior LA, left upper anterior LA, right lower anterior LA, right upper posterior LA, left upper posterior LA, and left lower posterior LA. There was no significant correlation between the regional LA fat distribution and regional LA peak-to-peak bipolar voltage and TAT. During a mean follow-up of 17 +/- 8 months, 22 of the 32 (69%) patients were free of AF. In the multivariate analysis, only the mean LA DF was found to be a significant predictor of recurrence. CONCLUSIONS: There was a close association between the regional distribution of the LA epicardial fat and the atrial substrate manifesting high frequency during sinus rhythm (AF nest). Those nests were related to ablation outcome. Hence, epicardial fat may play a significant role in atrial substrate remodeling and thereby in the pathogenesis and maintenance of AF. KEY WORDS: Atrial fibrillation * Dominant frequency * Epicardial fat * Nest * Recurrence. PMID- 27122949 TI - Renal Dysfunction on Admission Predicts No-Reflow Phenomenon in Patients Undergoing Manual Thrombus Aspiration during Primary Percutaneous Coronary Intervention. AB - BACKGROUND: No-reflow is a frequent complication during percutaneous coronary intervention (PCI) for acute ST segment elevation myocardial infarction (STEMI). Available data is limited regarding its impact on short-term outcomes in patients undergoing manual thrombus aspiration. Renal impairment is also associated with higher complication rates in STEMI. Herein, we aimed to evaluate the impact of baseline renal dysfunction on the no- reflow phenomenon and the association of no reflow phenomenon with early clinical outcomes. METHODS: A total of 94 consecutive STEMI patients who underwent primary stent-based PCI and thrombus aspiration were enrolled. No-reflow was established by the use of angiographic and electrocardiographic reperfusion criteria, respectively. Additionally angiographic and clinical follow-up data were also recorded. RESULTS: In our study, the no-reflow phenomenon was observed in 10 patients (11%) angiographically and in 23 patients (24%) electrocardiographically. Whereas, the the estimated glomerular filtration rate (eGFR) [odds ratio (OR) 10.4], hypertension (OR 6.2), previous MI (OR 6.5), previous PCI history, (OR 4.2), predilatation (OR 7.2), final balloon pressure (OR 0.9) were found to be the significant predictors of angiographic no-reflow, only reperfusion time was the predictor of electrocardiographic no-reflow (OR 1.12) at univariate analysis. After adjustment, lower eGFR (OR 14.8) was found to be the independent predictor for angiographic no-reflow. In-hospital mortality was more common in patients with either no-reflow condition separately. CONCLUSIONS: Longer ischemic time and lower initial eGFR values were associated with no-reflow phenomenon. Irrespective of poor reperfusion criteria, no-reflow phenomenon is associated with in-hospital outcome. Future efforts should be made to reduce the incidence of no-reflow especially in patients with lower initial eGFR values. KEY WORDS: Acute myocardial infarction * Glomerular filtration rate * No-reflow phenomenon * Primary percutaneous coronary intervention. PMID- 27122950 TI - Impact of Admission Glucose on Non-Diabetic Patients with ST-Segment Elevation Myocardial Infarction Treated with Percutaneous Coronary Intervention: A Meta Analysis. AB - BACKGROUND: Impaired admission glucose (AG) is thought to significantly increase the risk of both early and late death with ST-segment elevation myocardial infarction (STEMI), especially for non-diabetic patients. However, several earlier studies contradict these relationships. Through our meta-analysis, we aimed to evaluate such a relation between impaired AG, the risk of death and STEMI. METHODS: We accessed PubMed, EMBASE, Web of Science, and the Cochrane Library and systematically searched their databases to identify all related prospective cohort studies. The relative risks (RRs) with their 95% confidence interval (CI) were pooled quantitatively. RESULTS: The pooled, unadjusted relative risks of early outcome events indicated that patients who had glucose concentrations >= the range of 6.1-11.1 mmol/L, had a 4.38-fold (95% CI, 3.23 5.94) higher early mortality. For late outcome events, the pooled unadjusted RR indicated patients who had glucose concentrations >= the range 7.8-11.1 mmol/L, and had a 2.69-fold (95% CI, 2.16-3.34) higher late mortality based on full participants, whereas patients had a 1.65-fold (95% CI, 1.33-2.04) higher late mortality based on based on in-hospital or 30-day survivors. CONCLUSIONS: In conclusion, the present meta-analysis demonstrated that impaired admission glucose may be an effective prognostic marker for significantly increased risk of early death. Regarding the long-term outcomes based on full population or early survival, high admission glucose also has a distinct but poorer prognostic impact on long-term mortality than early mortality. KEY WORDS: Admission glucose * Meta analysis * Myocardial infarction * Non-diabetic. PMID- 27122951 TI - Prognostic Factors for Neurologic Outcome in Patients with Carotid Artery Stenting. AB - BACKGROUND: Carotid artery stenting (CAS) is a valid treatment for patients with carotid artery stenosis. The long-term outcome and prognostic factors in Asian population after CAS are not clear. This study aimed to identify the prognostic factors among Asian patients who have undergone CAS. METHODS: We retrospectively analyzed 246 patients with CAS. Annual carotid duplex ultrasound was used to identify restenosis. Peri-procedural complications, restenosis, neurologic outcomes, and mortality were recorded. Cox regression analyses were used to identify prognostic factors. RESULTS: The mean follow-up time was 49.2 months. Procedural success was achieved in 237 patients (98.3%), and protection devices were used in 208 patients (84.5%). Within 30 days of CAS, 13 (4.3% per procedure) peri-procedural complications occurred. During the follow-up period, 24 (9.7%) patients developed restenosis, and 37 (15.0%) developed ischemic strokes. In a multiple logistic regression analysis, head and neck radiotherapy [hazard ratio (HR) = 9.9, 95% confidence interval (CI), 3.38-29.1, p < .001], stent diameter (HR = 0.72, 95% CI, 0.58-0.89, p = .003), and predilatation (HR = 3.08 95% CI, 1.21-7.81, p = .018) were independent predictors for restenosis. In Cox regression analysis, hypercholesterolemia (HR = 0.25, 95% CI, 0.07-0.94, p = .04), head and neck radiotherapy (HR = 6.2, 95% CI, 1.8-21.3, p = .004), and restenosis (HR = 3.6, 95% CI, 1.1-11.18, p = .04) were predictors for recurrent ipsilateral ischemic stroke. CONCLUSIONS: CAS provides reliable long-term results in Asian patients with carotid stenosis. Restenosis is associated with an increased rate of recurrent stroke and should be monitored carefully following CAS. KEY WORDS: Carotid artery disease * Prognosis * Cerebrovascular disease. PMID- 27122952 TI - Non-Carriers of Reduced-Function CYP2C19 Alleles are Most Susceptible to Impairment of the Anti-Platelet Effect of Clopidogrel by Proton-Pump Inhibitors: A Pilot Study. AB - BACKGROUND: The phenomenon of CYP2C19 polymorphism affects the metabolism of both clopidogrel and proton-pump inhibitors (PPI). However, concomitant use of both drugs may reduce the desired therapeutic effects. In this study, we evaluated whether individuals with different numbers of reduced-function CYP2C19 alleles were equally affected and whether PPIs with different dependencies on CYP2C19 metabolism were equally involved. METHODS: Thirty healthy volunteers were recruited to a six-week regimen of clopidogrel. Three PPIs with different metabolic dependencies on CYP2C19 were included and separately administered in this order. Each PPI was given for a week, followed by a one-week washout period before the intervention of the next PPI. The anti-platelet effect was examined by Thromboelastography Platelet Mapping(TM) (TEG(r)) and vasodilator-stimulated phosphoprotein (VASP) assays. RESULTS: Both TEG(r) and VASP tests showed the same general qualitative trend, but TEG(r) detected a statistically significant fluctuation of platelet aggregation in response to different drug interventions. The TEG(r) results also demonstrated that non-carriers experienced the most significant impairment of anti-platelet effect of clopidogrel after concomitant use of PPIs. This impairment was closely related to the metabolic dependence on CYP2C19 of PPI. CONCLUSIONS: Our study indicated that non-carriers of reduced function CYP2C19 alleles are most susceptible to impairment of the anti-platelet effect of clopidogrel after concomitant PPI use. Individual subjects are not equally affected, and PPIs are not equally involved. However, large-scale randomized clinical trials are needed to evaluate the clinical outcome. KEY WORDS: Clopidogrel * CYP2C19 polymorphism * Platelet aggregation * Proton pump inhibitors * TEG * VASP. PMID- 27122953 TI - The Prognostic Role of QTc Interval in Acute Myocarditis. AB - BACKGROUND: Acute myocarditis is an inflammatory disease of the myocardium. Although a fulminant course of the disease is difficult to predict, it may lead to acute heart failure and death. Previous studies have demonstrated that reduced left ventricular systolic function and prolonged QRS duration can predict the fulminant course of acute myocarditis. This study aimed to identify whether prolonged QTc interval could also be predictive of fulminant disease in this population. METHODS: We retrospectively included 40 patients diagnosed with acute myocarditis who were admitted to our hospital between 2002 and 2013. They were divided into the fulminant group (n = 9) and the non-fulminant group (n = 31). Clinical symptoms, laboratory findings, electrocardiographic, and echocardiographic parameters were analyzed. Multivariate logistic regression analysis was used to identify the independent factors predictive of fulminant disease. RESULTS: Patients with fulminant myocarditis had a higher mortality rate than those with non-fulminant disease (55.6% vs. 0%, p < 0.001). Multivariate analysis revealed that wider QRS durations (133.22 +/- 45.85 ms vs. 92.81 +/- 15.56 ms, p = 0.030) and longer QTc intervals (482.78 +/- 69.76 ms vs. 412.00 +/- 33.31 ms, p = 0.016) were significant predictors associated with a fulminant course of myocarditis. CONCLUSIONS: Prolonged QRS duration and QTc interval, upon patient admission, may be associated with an increased risk of fulminant disease and increased in-hospital mortality. Therefore, early recognition of fulminant myocarditis and early mechanical support could provide improved patient outcomes. KEY WORDS: Fulminant myocarditis * Predictors * QRS complex * QTc interval. PMID- 27122954 TI - The Association between Serum Ferritin Level, Tissue Doppler Echocardiography, Cardiac T2* MRI, and Heart Rate Recovery in Patients with Beta Thalassemia Major. AB - BACKGROUND: It is generally well-understood that iron-mediated cardiomyopathy is the major complication that can arise from beta thalassemia major (TM). Therefore, early diagnosis, risk stratification, and the effective treatment of beta TM patients are clinically important to optimize long-term positive outcomes. METHODS: This study included 57 beta TM patients with a mean age of 25 +/- 7 years. We determined the serum ferritin level, echocardiography, heart rate recovery (HRR), and cardiac magnetic resonance (CMR) T2* in all patients. CMR T2* findings were categorized as normal myocardium (T2* > 20 ms), and myocardial involvement (T2* <= 20 ms). HRR values at 1-5 min (HRR1-5) were recorded; Subsequently. HRR was calculated by subtracting the heart rate at each time point from the heart rate at peak exercise. RESULTS: There was a significant negative correlation between the serum ferritin level and the cardiac T2* MRI findings (r = -0.34, p = 0.009). A similar result was found in the negative correlation between serum ferritin and all heart rate recovery values. There was a significant positive correlation between HRR1, HRR2, and HRR3 values, and CMR T2* (T2* heart rate recovery (HRR)1: r = 0.51, p < 0.001; T2* HRR2: r = 0.48, p < 0.001; T2* HRR3: r = 0.47, p < 0.001, respectively). CONCLUSIONS: The serum ferritin level and echocardiography can be used to predict the presence of myocardial iron load in beta TM patients. Therefore, HRR can be used to screen beta TM patients, and the clinical use of HRR can be a predictive marker for autonomic dysfunction in beta TM patients. KEY WORDS: Beta thalassemia major * Cardiac magnetic resonance T2* * Heart rate recovery * Iron overload * Serum ferritin level * Tissue Doppler imaging. PMID- 27122955 TI - Heart Attack Causes Head-Ache - Cardiac Cephalalgia. AB - Chest pain is the typical symptom of myocardial infarction (MI), and there are many atypical manifestations such as stomachache or dyspnea. Headache is a rare presentation of MI, which has specifically been termed "cardiac cephalalgia" or "cardiac cephalgia". In this article, we have reported a case of sudden onset headache and neck pain, of whom MI was confirmed by electrocardiography, cardiac markers, and coronary angiogram. The patient's headache subsided dramatically after coronary angioplasty, and it had not recurred in the following one year. Additionally, diagnostic clues and possible mechanisms of cardiac cephalalgia are discussed as well. KEY WORDS: Headache * Cardiac cephalgia * Cardiac cephalalgia * Myocardial infarction. PMID- 27122956 TI - Regorafenib-Related Myocardial Injury during Atrial Fibrillation. AB - Multikinase inhibitors with an anti-vascular endothelial growth factor effect have been reported to increase the risk of myocardial infarction or ischemia. We have presented the case of a 72-year-old male who had a metastatic gastrointestinal stromal tumor for which he received targeted therapy and who was admitted to our hospital for recurrent episodes of myocardial injury during atrial fibrillation. Coronary angiography showed insignificant coronary artery stenosis. We also reviewed the incidence of cardiovascular events in patients receiving regorafenib, and the current understanding of the mechanism of targeted therapy-induced myocardial ischemia/infarction. KEY WORDS: Multikinase inhibitor * Myocardial infarction * Myocardial ischemia * Vascular endothelial growth factor. PMID- 27122957 TI - A Rare Cause of Pulmonary Embolism and Seizure in a Young Man: Antiphospholipid Syndrome. AB - Pulmonary embolism (PE) is a complication of underlying vascular thrombosis. The causes of PE are multi-factorial, and patients with PE present with various symptoms. We herein have presented the case of a 21-year-old man who initially developed palpitation, dyspnea, and seizure. Computed tomography of the chest ultimately indicated PE, and antiphospholipid syndrome (APS) was diagnosed with clinical thrombosis events and series presence of antiphospholipid antibodies. APS commonly causes vascular thrombosis within the vascular tree; however, nonthrombotic manifestations, such as seizure, may also occur. Clinicians should be aware of such non-thrombotic manifestations of APS to avoid misdiagnosis and inappropriate management. KEY WORDS: Antiphospholipid syndrome * Pulmonary embolism * Seizure. PMID- 27122958 TI - An Extremely Rare Anatomical Variation: Abnormal Drainage of the Anterior Interventricular Coronary Vein. AB - Variation of anterior interventricular vein draining into the left atrium is an extremely rare occurrence. Multidetector computed tomography (MDCT) coronary angiography has recently become the gold standard for depicting anatomical variations and anomalies of coronary arteries and veins. We herein have reported the case of a 36-year-old male whose anterior interventricular vein draining into the left atrium was demonstrated by MDCT coronary angiography. KEY WORDS: Angiography * Computed tomography * Coronary vein * Variation. PMID- 27122959 TI - Academic Growth Trajectories and Family Relationships among African American Youth. AB - This study explored trajectories of African American youths' academic functioning and assessed whether changes in parent-adolescent relationships were associated with changes in youths' academic functioning. The data were drawn from a three year longitudinal study of gender socialization and development in two-parent African American families and included 197 families. Findings revealed gender differences in achievement trajectories and indicated that boys not only had lower levels of academic achievement compared to girls, but also experienced steeper declines in school self-esteem during adolescence. Changes in parent adolescent relationship quality were linked to changes in academic functioning: Increases in conflict were related to decreases in GPA, school bonding, and school self-esteem and increases in warmth were related to increases in school bonding and school self-esteem. PMID- 27122960 TI - Engaging Urban Parents of Early Adolescents in Parenting Interventions: Home Visits vs. Group Sessions. AB - Interventions targeting parents of young children have shown effectiveness, but research is lacking about best practices for engaging parents of early adolescents. Low levels of enrollment and attendance in parenting interventions present major problems for researchers and clinicians. Effective and efficient ways to engage and collaborate with parents to strengthen parenting practices and to promote healthy development of early adolescents are needed. This exploratory mixed methods study examined the feasibility of three methods of engaging parents in positive parenting activities. Participants were parents of youth ages 11-13 enrolled in three urban, public middle schools in neighborhoods characterized by high rates of community violence. Families (N = 144) were randomized into one of three interventions: six home sessions, two home sessions followed by four group sessions, or six group sessions. The majority of parents were single, non Hispanic, African American mothers. Urban parents of middle school students were more likely to participate in home visits than in group sessions; offering a combination did not increase participation in the group sessions. As only 34% of those who consented participated in the intervention, qualitative data were examined to explain the reasons for non-participation. PMID- 27122961 TI - Probing the Protein-Nanoparticle Interface: The Role of Aromatic Substitution Pattern on Affinity. AB - A new class of cationic gold nanoparticles has been synthesized bearing benzyl moieties featuring -NO2 and -OMe groups to investigate the regioisomeric control of aromatic nanoparticle-protein recognition. In general, nanoparticles bearing electron withdrawing group demonstrated higher binding affinities towards green fluorescent protein (GFP) compared to electron-donating groups. Significantly, a ~7.5 and ~4.3 fold increase in binding with GFP was observed for -NO2 groups in meta- and para-position respectively, while ortho-substitution showed similar binding compared to the unsubstituted ring. These findings demonstrated that nanoparticle-protein interaction can be controlled by the tuning the spatial orientation and the relative electronic properties of the aromatic substituents. This improved biomolecular recognition provides opportunities for enhanced biosensing and functional protein delivery to the cells. PMID- 27122962 TI - Optimizing two-photon multiple fluorophore imaging of the human trabecular meshwork. AB - PURPOSE: Advances in two-photon (2P) deep tissue imaging provide powerful options for simultaneously viewing multiple fluorophores within tissues. We determined imaging parameters for optimally visualizing three fluorophores in the human trabecular meshwork (TM) to simultaneously detect broad-spectrum autofluorescence and multiple fluorophores through a limited number of emission filters. METHODS: 2P imaging of viable human postmortem TM was conducted to detect Hoechst 33342 labeled nuclei, Alexa-568-conjugated phalloidin labeling of filamentous actin, and autofluorescence of the structural extracellular matrix (ECM). Emission detection through green (500-550 nm), near-red (565-605 nm), and far-red (590-680 nm) filters following 2P excitation at 750, 800, 850, and 900 nm was analyzed. Region-of-interest (ROI) image analysis provided fluorescence intensity values for each fluorophore. RESULTS: Red-channel Alexa 568 fluorescence was of highest intensity with 2P 750 nm and 800 nm excitation. Alexa 568 was imperceptible with 900 nm excitation. With excitation at 750 nm and 800 nm, Hoechst 33,342 intensity swamped autofluorescence in the green channel, and marked bleed-through into red channels was seen. 850 nm excitation yielded balanced Hoechst 33342 and autofluorescence intensities, minimized their bleed-through into the far-red channel, and produced reasonable Alexa 568 intensities in the far-red channel. CONCLUSIONS: 2P excitation at 850 nm and long-wavelength emission detection in the far-red channel allowed simultaneous visualization of the specific mix of endogenous and exogenous fluorophores with reasonably balanced intensities while minimizing bleed-through when imaging the human TM. PMID- 27122964 TI - Myelin-specific Th17 cells induce severe relapsing optic neuritis with irreversible loss of retinal ganglion cells in C57BL/6 mice. AB - PURPOSE: Optic neuritis affects most patients with multiple sclerosis (MS), and current treatments are unreliable. The purpose of this study was to characterize the contribution of Th1 and Th17 cells to the development of optic neuritis. METHODS: Mice were passively transferred myelin-specific Th1 or Th17 cells to induce experimental autoimmune encephalomyelitis (EAE), a model of neuroautoimmunity. Visual acuity was assessed daily with optokinetic tracking, and 1, 2, and 3 weeks post-induction, optic nerves and retinas were harvested for immunohistochemical analyses. RESULTS: Passive transfer experimental autoimmune encephalomyelitis elicits acute episodes of asymmetric visual deficits and is exacerbated in Th17-EAE relative to Th1-EAE. The Th17-EAE optic nerves contained more inflammatory infiltrates and an increased neutrophil to macrophage ratio. Significant geographic degeneration of the retinal ganglion cells accompanied Th17-EAE but not Th1. CONCLUSIONS: Th17-induced transfer EAE recapitulates pathologies observed in MS-associated optic neuritis, namely, monocular episodes of vision loss, optic nerve inflammation, and geographic retinal ganglion cell (RGC) degeneration. PMID- 27122963 TI - Molecular studies of phenotype variation in canine RPGR-XLPRA1. AB - PURPOSE: Canine X-linked progressive retinal atrophy 1 (XLPRA1) caused by a mutation in retinitis pigmentosa (RP) GTPase regulator (RPGR) exon ORF15 showed significant variability in disease onset in a colony of dogs that all inherited the same mutant X chromosome. Defective protein trafficking has been detected in XLPRA1 before any discernible degeneration of the photoreceptors. We hypothesized that the severity of the photoreceptor degeneration in affected dogs may be associated with defects in genes involved in ciliary trafficking. To this end, we examined six genes as potential disease modifiers. We also examined the expression levels of 24 genes involved in ciliary trafficking (seven), visual pathway (five), neuronal maintenance genes (six), and cellular stress response (six) to evaluate their possible involvement in early stages of the disease. METHODS: Samples from a pedigree derived from a single XLPRA1-affected male dog outcrossed to unrelated healthy mix-bred or purebred females were used for immunohistochemistry (IHC), western blot, mutational and haplotype analysis, and gene expression (GE). Cell-specific markers were used to examine retinal remodeling in the disease. Single nucleotide polymorphisms (SNPs) spanning the entire RPGR interacting and protein trafficking genes (RAB8A, RPGRIP1L, CEP290, CC2D2A, DFNB31, and RAB11B) were genotyped in the pedigree. Quantitative real time PCR (qRT-PCR) was used to examine the expression of a total of 24 genes, including the six genes listed. RESULTS: Examination of cryosections from XLPRA1 affected animals of similar age (3-4 years) with different disease severity phenotype revealed mislocalization of opsins and upregulation of the Muller cell gliosis marker GFAP. Four to ten haplotypes per gene were identified in RAB8A, RPGRIP1L, CEP290, CC2D2A, DFNB31, and RAB11B for further assessment as potential genetic modifiers of XLPRA1. No correlation was found between the haplotypes and disease severity. During mutational analysis, several new variants, including a single intronic mutation in RAB8A and three mutations in exon 3 of DFNB31 were described (c.970G>A (V324I), c.978T>C (G326=), and c.985G>A (A329T)). Expression analysis of stress response genes in 16-week-old predisease XLPRA1 retinas revealed upregulation of GFAP but not HSPA5, DDIT3, HSPA4, HSP90B1, or HIF1A. Western blot analysis confirmed GFAP upregulation. In the same predisease group, no significant differences were found in the expression of 18 selected genes (RHO, OPN1LW, OPN1MW, RLBP1, RPGRORF15, RAB8A, RPGRIP1L, CEP290, CC2D2A, DFNB31, RAB11B, CRX, RCVRN, PVALB, CALB1, FGFR1, NTRK2, and NTRK3) involved in neuronal function. CONCLUSIONS: Lack of association between haplotypes of RAB8A, RPGRIP1L, CEP290, CC2D2A, DFNB31, and RAB11B and the disease phenotype suggests that these genes are not genetic modifiers of XLPRA1. Upregulation of GFAP, an established indicator of the Muller cell gliosis, manifests as an important early feature of the disease. PMID- 27122965 TI - A novel start codon mutation of the MERTK gene in a patient with retinitis pigmentosa. AB - PURPOSE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations characterized by progressive loss of photoreceptor cells and RPE functions. More than 70 causative genes are known to be responsible for RP. This study aimed to identify the causative gene in a patient from a consanguineous family with childhood-onset severe retinal dystrophy. METHODS: To identify the defective gene, whole exome sequencing was performed. Candidate causative variants were selected and validated using Sanger sequencing. Segregation analysis of the causative gene was performed in additional family members. To verify that the mutation has an effect on protein synthesis, an expression vector containing the first ten amino acids of the mutant protein fused with the DsRed2 fluorescent protein was constructed and transfected into HEK293T cells. Expression of the fusion protein in the transfected cells was measured using fluorescence microscopy. RESULTS: By filtering against public variant databases, a novel homozygous missense mutation (c.3G>A) localized in the start codon of the MERTK gene was detected as a potentially pathogenic mutation for autosomal recessive RP. The c.3G>A mutation cosegregated with the disease phenotype in the family. No expression of the first ten amino acids of the MerTK mutant fused with the DsRed2 fluorescent protein was detected in HEK293T cells, indicating that the mutation affects the translation initiation site of the gene that may lead to loss of function of the MerTK signaling pathway. CONCLUSIONS: We report a novel missense mutation (c.3G>A, p.0?) in the MERTK gene that causes severe vision impairment in a patient. Taken together with previous reports, our results expand the spectrum of MERTK mutations and extend our understanding of the role of the MerTK protein in the pathogenesis of retinitis pigmentosa. PMID- 27122966 TI - Aqueous humor cytokine profiling in patients with wet AMD. AB - PURPOSE: To investigate the chemokine expression profiles in the aqueous humor of wet age-related macular degeneration (wet AMD) patients and to correlate their levels with clinical findings. METHODS: Undiluted aqueous humor samples (100-200 MUl) were obtained from 16 wet AMD eyes and 12 control eyes. Forty chemokines were measured using a multiplex method. A 6*6 mm area of the macular region centered on the fovea was examined using spectral domain optical coherence tomography (SD-OCT). RESULTS: The detection rates were 50% or more for 15 chemokines. Compared with the control group, the aqueous humor in wet AMD patients showed a significantly higher expression of CXCL10 (p=0.004), CCL14 (p=0.002), CXCL16 (p=0.013), CXCL7 (p=0.033), and CCL22 (p=0.037), while growth related oncogene (GRO) was significantly decreased in the wet AMD patients (p=0.001). When compared with treatment-naive patients, the recurrent group had significant upregulation of CXCL10 (p=0.012) and CCL22 (p=0.002). CXCL16 was positively correlated with lesion size, and CCL22 was higher in patients whose OCT images showed intraretinal fluid (IRF) or hyperreflective foci (HF). CONCLUSIONS: Elevated levels of inflammation-related chemokines, including CXCL10, CCL14, CXCL16, CXCL7, and CCL22, in the aqueous humor of AMD patients may suggest a pathogenic role for inflammation. CXCL10 and CCL22 were more elevated in eyes with recurrent wet AMD than in treatment-naive eyes. CXCL16 was positively correlated with lesion size. The increase in CCL22 was correlated with the presence of IRF or HF. These data may be of interest in the search for biomarkers associated with wet AMD and may potentially indicate different treatment strategies. PMID- 27122969 TI - Guideposts for quests in the realm of oncology careers. PMID- 27122967 TI - The regulatory role of hepatoma-derived growth factor as an angiogenic factor in the eye. AB - PURPOSE: Hepatoma-derived growth factor (HDGF) is a mitogen that promotes endothelial proliferation and neuronal survival. Using a unique technology of ligandomics, we recently identified HDGF as a retinal endothelial binding protein. The purpose of this study is to examine the role of HDGF in regulating ocular vasculature and the expression of HDGF in the retina. METHODS: HDGF expression in the retinal was analyzed with western blot and immunohistochemistry. Angiogenic activity was investigated in human retinal microvascular endothelial cells (HRMVECs) with in vitro endothelial proliferation, migration, and permeability assays. In vivo angiogenic activity was quantified with a corneal pocket assay. The Evans blue assay and western blot using anti-mouse albumin were performed to detect the capacity of HDGF to induce retinal vascular leakage. RESULTS: Immunohistochemistry revealed that HDGF is expressed in the retina with a distinct pattern. HDGF was detected in retinal ganglion cells and the inner nuclear layer but not in the inner plexiform layer, suggesting that HDGF is expressed in the nucleus, but not in the cytoplasm, of retinal neurons. In contrast to family member HDGF-related protein 3 (HRP-3) that has no expression in photoreceptors, HDGF is also present in the outer nuclear layer and the inner and outer segments of photoreceptors. This suggests that HDGF is expressed in the nucleus as well as the cytoplasm of photoreceptors. In vitro functional assays showed that HDGF induced the proliferation, migration, and permeability of HRMVECs. Corneal pocket assay indicated that HDGF directly stimulated angiogenesis in vivo. Intravitreal injection of HDGF significantly induced retinal vascular leakage. CONCLUSIONS: These results suggest that HDGF is an angiogenic factor that regulates retinal vasculature in physiologic and pathological conditions. Identification of HDGF by ligandomics and its independent characterization in this study also support the validity of this new technology for systematic identification of cellular ligands, including angiogenic factors. PMID- 27122968 TI - Comparative analysis of three purification protocols for retinal ganglion cells from rat. AB - PURPOSE: To make comparative analyses of the common three purification protocols for retinal ganglion cells (RGCs), providing a solid practical basis for selecting the method for purifying RGCs for use in subsequent experiments. METHODS: Rat RGCs were isolated and purified using three methods, including two step immunopanning (TIP) separation, two-step immunopanning-magnetic (TIPM) separation, and flow cytometric (FC) separation. Immunocytochemical staining, quantitative real-time PCR, flow cytometry, electrophysiology, and Cell Counting Kit-8 (CCK-8) analyses were performed to compare the purity, yield, and viability of the RGCs. RESULTS: The RGC yields from the TIP, TIPM, and FC methods were 24.60+/-15.98 * 10(4), 5.28+/-4.42 * 10(4), and 5.4+/-2.7 * 10(3) per retina, respectively. We easily controlled the relative purity of the RGCs with the FC method and even reached 100% of the maximum expected purity. However, the RGC purity was only 80.97+/-5.45% and 95.41+/-3.23% using the TIP and TIPM methods, respectively. The contaminant cells were mainly large, star-shaped, glial fibrillary acidic protein (GFAP)-positive astrocytes and small, round, syntaxin 1 positive amacrine cells with multiple short neurites. The RGCs purified with FC could not be cultured successively in our study; however, the TIP-RGCs survived more than 20 days with good viability, while the TIPM-RGCs survived less than 9 days. CONCLUSIONS: The three protocols for purifying the RGCs each had its own pros and cons. The RGCs isolated by the TIP method exhibited the highest viability and yield but had low purity. The purity of the RGCs isolated with the FC method could reach approximately 100% but had a low yield and cell viability. The TIPM method was reliable and produced RGCs with considerable purity, yield, and viability. This study provides a solid practical basis for selecting the method for purifying RGCs for use in subsequent experiments. PMID- 27122970 TI - Training the trainer: five practical considerations for your first five years in practice. PMID- 27122971 TI - Research output and the public health burden of cancer: is there any relationship? AB - PURPOSE: The relative distribution of research output across cancer sites is not well described. Here, we evaluate whether the volume of published research is proportional to the public health burden of individual cancers. We also explore whether research output is proportional to research funding. METHODS: Statistics from the Canadian and American cancer societies were used to identify the top ten causes of cancer death in 2013. All journal articles and clinical trials published in 2013 by Canadian or U.S. authors for those cancers were identified. Total research funding in Canada by cancer site was obtained from the Canadian Cancer Research Alliance. Descriptive statistics and Pearson correlation coefficients were used to describe the relationship between research output, cancer mortality, and research funding. RESULTS: We identified 19,361 publications and 2661 clinical trials. The proportion of publications and clinical trials was substantially lower than the proportion of deaths for lung (41% deaths, 15% publications, 16% clinical trials), colorectal (14%, 7%, 6%), pancreatic (10%, 7%, 5%), and gastroesophageal (7%, 5%, 3%) cancers. Conversely, research output was substantially greater than the proportion of deaths for breast cancer (10% deaths, 29% publications, 30% clinical trials) and prostate cancer (8%, 15%, 17%). We observed a stronger correlation between research output and funding (publications r = 0.894, p < 0.001; clinical trials r = 0.923, p < 0.001) than between research output and cancer mortality (r = 0.363, p = 0.303; r = 0.340, p = 0.337). CONCLUSIONS: Research output is not well correlated with the public health burden of individual cancers, but is correlated with the relative level of research funding. PMID- 27122972 TI - Identification of performance indicators across a network of clinical cancer programs. AB - BACKGROUND: Cancer quality indicators have previously been described for a single tumour site or a single treatment modality, or according to distinct data sources. Our objective was to identify cancer quality indicators across all treatment modalities specific to breast, prostate, colorectal, and lung cancer. METHODS: Candidate indicators for each tumour site were extracted from the relevant literature and rated in a modified Delphi approach by multidisciplinary groups of expert clinicians from 3 clinical cancer programs. All rating rounds were conducted by e-mail, except for one that was conducted as a face-to-face expert panel meeting, thus modifying the original Delphi technique. Four high level indicators were chosen for immediate data collection. A list of confounding variables was also constructed in a separate literature review. RESULTS: A total of 156 candidate indicators were identified for breast cancer, 68 for colorectal cancer, 40 for lung cancer, and 43 for prostate cancer. Iterative rounds of ratings led to a final list of 20 evidence- and consensus-based indicators each for colorectal and lung cancer, and 19 each for breast and prostate cancer. Approximately 30 clinicians participated in the selection of the breast, lung, and prostate indicators; approximately 50 clinicians participated in the selection of the colorectal indicators. CONCLUSIONS: The modified Delphi approach that incorporates an in-person meeting of expert clinicians is an effective and efficient method for performance indicator selection and offers the added benefit of optimal clinician engagement. The finalized indicator lists for each tumour site, together with salient confounding variables, can be directly adopted (or adapted) for deployment within a performance improvement program. PMID- 27122973 TI - Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission. AB - BACKGROUND: Outcomes in metastatic breast cancer (mbc) positive for her2 (human epidermal growth factor receptor 2) are generally unfavourable. Trastuzumab has revolutionized the prognosis of her2-positive mbc. Some her2-positive mbc patients go into prolonged remission, and a few patients remain in remission even after discontinuation of trastuzumab, suggesting the possibility of a cure. In our practice, 4 her2-positive mbc patients treated with chemotherapy and trastuzumab have remained in remission on maintenance therapy for 5 years or more. Of those 4 patients, 2 have continued in remission after discontinuation of trastuzumab for more than 1 year. The objective of the present paper was therefore to address the duration of trastuzumab therapy in her2-positive mbc patients in prolonged remission. METHODS: We conducted a literature review of the duration of trastuzumab in her2-positive mbc patients in remission. We also conducted an online survey of oncologists in Ontario to determine their treatment practices in her2-positive mbc patients. RESULTS: The literature search found no specific evidence about the optimal duration of trastuzumab maintenance therapy in her2-positive mbc in prolonged remission. However, retrospective studies suggest predictive markers of good prognosis in patients in complete remission taking maintenance trastuzumab. Identifying those markers could lead to more personalized treatment. Our survey of oncologists about their treatment practices in her2-positive mbc patients revealed that 82.93% of respondents (n = 34) follow the currently available guidelines. CONCLUSIONS: With the emergence of patients in prolonged remission, duration of trastuzumab in her2-positive mbc has become an important and relevant clinical question worldwide. Collaborative efforts are needed for the further study of this topic. PMID- 27122975 TI - Follow-up for cervical cancer: a Program in Evidence-Based Care systematic review and clinical practice guideline update. AB - BACKGROUND: In 2009, the Program in Evidence-based Care (pebc) of Cancer Care Ontario published a guideline on the follow-up of cervical cancer. In 2014, the pebc undertook an update of the systematic review and clinical practice guideline for women in this target population. METHODS: The literature from 2007 to August 2014 was searched using medline and embase [extended to 2000 for studies of human papillomavirus (hpv) dna testing]. Outcomes of interest were measures of survival, diagnostic accuracy, and quality of life. A working group evaluated the need for changes to the earlier guidelines and incorporated comments and feedback from internal and external reviewers. RESULTS: One systematic review and six individual studies were included. The working group concluded that the new evidence did not warrant changes to the 2009 recommendations, although hpv dna testing was added as a potentially more sensitive method of detecting recurrence in patients treated with radiotherapy. Comments from internal and external reviewers were incorporated. RECOMMENDATIONS SUMMARY: Follow-up care after primary treatment should be conducted and coordinated by a physician experienced in the surveillance of cancer patients. A reasonable follow-up strategy involves visits every 3-4 months within the first 2 years, and every 6-12 months during years 3-5. Visits should include a patient history and complete physical examination, with elicitation of relevant symptoms. Vaginal vault cytology examination should not be performed more frequently than annually. Combined positron-emission tomography and computed tomography, other imaging, and biomarker evaluation are not advocated; hpv dna testing could be useful as a method of detection of recurrence after radiotherapy. General recommendations for follow-up after 5 years are also provided. PMID- 27122974 TI - Canadian recommendations for the management of breakthrough cancer pain. AB - Breakthrough cancer pain (btcp) represents an important element in the spectrum of cancer pain management. Because most btcp episodes peak in intensity within a few minutes, speed of medication onset is crucial for proper control. In Canada, several current provincial guidelines for the management of cancer pain include a brief discussion about the treatment of btcp; however, there are no uniform national recommendations for the management of btcp. That lack, accompanied by unequal access to pain medication across the country, contributes to both regional and provincial variability in the management of btcp. Currently, immediate-release oral opioids are the treatment of choice for btcp. This approach might not always offer optimal speed for onset of action and duration to match the rapid nature of an episode of btcp. Novel transmucosal fentanyl formulations might be more appropriate for some types of btcp, but limited access to such drugs hinders their use. In addition, the recognition of btcp and its proper assessment, which are crucial steps toward appropriate treatment selection, remain challenging for many health care professionals. To facilitate appropriate management of btcp, a group of prominent Canadian specialists in palliative care, oncology, and anesthesiology convened to develop a set of recommendations and suggestions to assist Canadian health care providers in the treatment of btcp and the alleviation of the suffering and discomfort experienced by adult cancer patients. PMID- 27122976 TI - A first look at relative survival by stage for colorectal and lung cancers in Canada. AB - Monitoring and reporting on cancer survival provides a mechanism for understanding the effectiveness of Canada's cancer care system. Although 5-year relative survival for colorectal cancer and lung cancer has been previously reported, only recently has pan-Canadian relative survival by stage been analyzed using comprehensive registry data. This article presents a first look at 2-year relative survival by stage for colorectal and lung cancer across 9 provinces. As expected, 2-year age-standardized relative survival ratios (arsrs) for colorectal cancer and lung cancer were higher when the cancer was diagnosed at an earlier stage. The arsrs for stage i colorectal cancer ranged from 92.2% in Nova Scotia [95% confidence interval (ci): 88.6% to 95.1%] to 98.4% in British Columbia (95% ci: 96.2% to 99.3%); for stage iv, they ranged from 24.3% in Prince Edward Island (95% ci: 15.2% to 34.4%) to 38.8% in New Brunswick (95% ci: 33.3% to 44.2%). The arsrs for stage i lung cancer ranged from 66.5% in Prince Edward Island (95% ci: 54.5% to 76.5%) to 84.8% in Ontario (95% ci: 83.5% to 86.0%). By contrast, arsrs for stage iv lung cancer ranged from 7.6% in Manitoba (95% ci: 5.8% to 9.7%) to 13.2% in British Columbia (95% ci: 11.8% to 14.6%). The available stage data are too recent to allow for meaningful comparisons between provinces, but over time, analyzing relative survival by stage can provide further insight into the known differences in 5-year relative survival. As the data mature, they will enable an assessment of the extent to which interprovincial differences in relative survival are influenced by differences in stage distribution or treatment effectiveness (or both), permitting targeted measures to improve population health outcomes to be implemented. PMID- 27122977 TI - Formal evaluation of PYNK: Breast Cancer Program for Young Women-the patient perspective. AB - PURPOSE: The aim of the present study was to assess patient satisfaction with pynk: Breast Cancer Program for Young Women so as to determine how the program might be improved and to provide feedback to donors. METHODS: All pynk patients who had consented to have their information entered in our database and who supplied us with their e-mail address were invited to complete a 58-item online questionnaire consisting of multiple choice and open-ended questions. Domains included demographics, provision of written and spoken information, support, infertility risk, research awareness, attitudes toward discharge, and general feedback. RESULTS: Of 120 pynk patients approached, 61 (51%) participated. More than 90% were satisfied or very satisfied with the timing, usefulness, and clarity of spoken and written information given, and 69% found the service and support provided by the nurse navigator to be the most helpful component of the program. Of those who had received systemic therapy, 93% recalled a health care provider initiating a discussion of the risk of treatment-related infertility, and 67% were referred to a fertility clinic. On the negative side, 11%-27% were unaware of various services provided by pynk, and 11% were unaware of pynk's ongoing research. One third of patients were unhappy or ambivalent about the prospect of discharge from the program. CONCLUSIONS: Patient satisfaction with this novel program for young women with breast cancer is high. This study highlights the critical role that the nurse navigator plays in patient support and dissemination of information. In contrast to other reported surveys of young cancer patients, pynk patients are routinely given the opportunity to undergo fertility preservation. PMID- 27122978 TI - Costs of cervical cancer treatment: population-based estimates from Ontario. AB - OBJECTIVES: The objectives of the present study were to estimate the overall and specific medical care costs associated with cervical cancer in the first 5 years after diagnosis in Ontario. METHODS: Incident cases of invasive cervical cancer during 2007-2010 were identified from the Ontario Cancer Registry and linked to administrative databases held at the Institute for Clinical Evaluative Sciences. Mean costs in 2010 Canadian dollars were estimated using the arithmetic mean and estimators that adjust for censored data. RESULTS: Mean age of the patients in the study cohort (779 cases) was 49.3 years. The mean overall medical care cost was $39,187 [standard error (se): $1,327] in the 1st year after diagnosis. Costs in year 1 ranged from $34,648 (se: $1,275) for those who survived at least 1 year to $69,142 (se: $4,818) for those who died from cervical cancer within 1 year. At 5 years after diagnosis, the mean overall unadjusted cost was $63,131 (se: $3,131), and the cost adjusted for censoring was $68,745 (se: $2,963). Inpatient hospitalizations and cancer-related care were the two largest components of cancer treatment costs. CONCLUSIONS: We found that the estimated mean costs that did not account for censoring were consistently undervalued, highlighting the importance of estimates based on censoring-adjusted costs in cervical cancer. Our results are reliable for estimating the economic burden of cervical cancer and the cost-effectiveness of cervical cancer prevention strategies. PMID- 27122979 TI - A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival. AB - BACKGROUND: Recent studies have suggested an effect of metformin on mortality for patients with both diabetes and colorectal cancer (crc). However, the literature is contradictory, with both positive and negative effects being identified. We set out to determine the effect of metformin with respect to prognosis in crc patients. METHODS: After a retrospective chart review of crc patients treated at the Cancer Centre of Southeastern Ontario, Kaplan-Meier analyses and Cox proportional hazards regression models were used to compare overall survival (os) in patients with and without diabetes. RESULTS: We identified 1304 crc patients treated at the centre. No significant differences between the diabetic and nondiabetic groups were observed with respect to tumour pathology, extent of metastatic disease, time or toxicity of chemotherapy, and the os rate (1-year os: 85.6% vs. 86.4%, p = 0.695; 2-year os: 73.6% vs. 77.0%, p = 0.265). In subgroup analysis, diabetic patients taking metformin survived significantly longer than their counterparts taking other diabetes treatments (os for the metformin group: 91% at 1 year; 80.5% at 2 years; os for the group taking other treatments, including diet control: 80.6% at 1 year, 67.4% at 2 years). Multivariate analysis suggests that patients with diabetes taking treatments other than metformin experience worse survival (p = 0.025). CONCLUSIONS: Our results suggest that crc patients with diabetes, excluding those taking metformin, might have a worse crc prognosis. Taking metformin appears to have a positive association with prognosis. The protective nature of metformin needs further evaluation in prospective analyses. PMID- 27122980 TI - Hematogones: a sensitive prognostic factor for Chinese adult patients with acute myeloid leukemia. AB - BACKGROUND: Hematogones (hgs) are normal B-lymphocyte precursors that increase in some hematologic diseases. Many studies indicate that hgs might be a favourable prognostic factor. We thus considered it important to determine whether hgs are also a prognostic factor for Chinese adult patients with acute myeloid leukemia (aml) and whether the hg-positive and hg-negative groups show any serologic or phenotypic differences. METHODS: Chinese adult aml patients (n = 177) who were all initially hg-negative underwent standard chemotherapy and were thereafter divided into hg-positive and hg-negative groups according to hg levels in bone marrow during their first remission. RESULTS: The follow-up study confirmed that survival duration (both leukemia-free and overall) was significantly greater in the hg-positive group than in the hg-negative group and was accompanied by a lower relapse rate. A retrospective study of patient characteristics at the time of first diagnosis revealed some differences between the hg-positive and the hg negative groups, including elevations in white blood cells, lactate dehydrogenase, and beta2-microglobulin in the hg-negative group. Retrospective phenotypic analysis revealed a significantly lower proportion of abnormal chromosome karyotype and CD34 expression in hg-positive patients. Finally, we evaluated whether additional intensive chemotherapy after standard chemotherapy could further increase hgs. CONCLUSIONS: The present work verified the validity of hgs as a prognostic factor for Chinese adult patients with aml. Compared with hg-negative patients, hg-positive patients not only experienced longer survival and a lower relapse rate, but they also had some serologic and phenotypic characteristics that are all considered indicators of better outcome. Additional intensive chemotherapy could further increase the level of hgs, which might imply better clinical results. PMID- 27122982 TI - Collaborative case conferences in rectal cancer: case series in a tertiary care centre. AB - BACKGROUND: In many hospitals, resource barriers preclude the use of preoperative multidisciplinary cancer conferences (mccs) for consecutive patients with cancer. Collaborative cancer conferences (cccs) are modified mccs that might overcome such barriers. METHODS: We established a ccc at an academic tertiary care centre to review preoperative plans for patients with rectal cancer. Attendees included only surgeons who perform colorectal cancer procedures and a radiologist with expertise in cross-sectional imaging. Individual reviews began with the primary surgeon presenting the case information and initial treatment recommendations. Cross-sectional images were then reviewed, the case was discussed, and consensus on ccc-treatment recommendations was achieved. Outcomes for the present study were changes in treatment recommendations defined as "major" (that is, redirection of patient to preoperative radiation from straight-to-surgery or uncertain plan, or redirection of the patient to straight-to-surgery from preoperative radiation or plan uncertain) or as "minor" (that is, referral to a multidisciplinary cancer clinic, request additional tests, change type of neoadjuvant therapy, change type of surgery). Chart reviews provided relevant patient, tumour, and treatment information. RESULTS: Between September 2011 and September 2012, 101 rectal cancer patients were discussed at a ccc. Of the 35 management plans (34.7%) that were changed as a result, 8 had major changes, and 27 had minor changes. Available patient and tumour factors did not predict for a change in treatment recommendation. CONCLUSIONS: Preoperative cccs at a tertiary care centre changed treatment recommendations for one third of patients with rectal cancer. Given that no specific factor predicted for a treatment plan change, it is likely prudent that all rectal cancer patients undergo some form of collaborative review. PMID- 27122981 TI - Involved-field irradiation in definitive chemoradiotherapy for T4 squamous cell carcinoma of the esophagus. AB - OBJECTIVES: Definitive concurrent chemoradiotherapy (ccrt) is currently a therapeutic option for locally advanced esophageal cancer. However, clinical practice differs with respect to the target volume for irradiation. The purpose of the present study was to analyze failure patterns and survival, and to determine the feasibility of using involved-field irradiation (ifi) with concurrent chemotherapy for T4 squamous cell carcinoma (scc) of the esophagus. METHODS: Between January 2003 and January 2013, 56 patients with clinical T4M0 scc of the esophagus received ccrt using ifi. The radiation field included the primary tumour and clinically involved lymph nodes. Target volumes and sites of failure were analyzed, as were treatment-related toxicity and survival time. RESULTS: In this 56-patient cohort, 13 patients (23.2%) achieved a complete response, and 21 (37.5%) achieved a partial response, for a total response rate of 60.7%. The major toxicities experienced were leucocytopenia and esophagitis, with 14 patients (25.0%) experiencing grade 3 toxicities. At a median follow-up of 34 months, 48 patients (85.7%) had experienced failure: 39 (69.6%) in-field, 7 (12.5%) elective nodal, and 19 (33.9%) distant. Only 1 patient (1.8%) experienced isolated elective nodal failure. The 1-, 2-, and 3-year survival rates were 39.3%, 21.4%, and 12.5% respectively. CONCLUSIONS: For patients with T4M0 scc of the esophagus, definitive ccrt using ifi resulted in an acceptable rate of isolated elective nodal failure and an overall survival comparable to that achieved with elective nodal irradiation. A limited radiation therapy target volume, including only clinically involved lesions, would therefore be a feasible choice for this patient subgroup. PMID- 27122983 TI - But other than mesothelioma? An estimate of the proportion of work-related cancers in Quebec. AB - BACKGROUND: More than 30 exposures in the workplace are proven carcinogens. In the present study, we aimed to estimate the burden of occupational cancer in Quebec so as to increase awareness among stakeholders and to prioritize research activities. METHODS: Work-attributable fractions-that is, the proportions of cancers attributable to work-as published in Finland and the United Kingdom were applied to Quebec 2002-2006 cancer incidence and mortality data to estimate the number of work-related cases for 28 cancer sites. RESULTS: Overall, 6.0% of incident cancers (men: 9.1%; women: 2.7%) and 7.6% of cancer deaths (men: 11.8%; women: 2.8%) could be attributable to work, resulting annually in an average of 2160 new cancer diagnoses and 1190 cancer deaths in Quebec. Incident cancers of the lung, prostate, skin, bladder, and (female) breast were the most numerous; cancer sites resulting in more deaths were lung, (female) breast, and pleura. During the same period, compensation statistics reported annual averages of 94.3 incident cancers and 61.9 cancer deaths, mostly involving mesothelioma (64% of compensated incident cancers) and lung cancer (30% of compensated incident cancers). CONCLUSIONS: Increased recognition of workplace cancers by all stakeholders, from workers and employers to treating physicians, will foster appropriate preventive measures for safer workplaces. PMID- 27122984 TI - Immunotherapy with imiquimod and interferon alfa for metastasized Merkel cell carcinoma. AB - Merkel cell carcinoma (mcc) is a highly aggressive neuroendocrine tumour of the skin. Remission rates are high with chemotherapy in patients with metastasis, but without any improvement in overall survival. We present the case of a 90-year-old woman with facial mcc. After radiation and surgery, the mcc recurred with widespread cutaneous and regional lymph node metastases. The metastases were treated with weekly intralesional injections of 1-2*10(6) IU interferon alfa-2a, accompanied by topical imiquimod 5% cream 3 times weekly. After partial regression, subcutaneous pegylated interferon alfa-2b was added at a dose of 30 MUg weekly, which was then increased to 50 MUg weekly. At 4 months after the start of immunotherapy, all cutaneous metastases and the intralesionally treated lymph node metastases receded. Interruption or reduction of systemic interferon application resulted in locoregional relapses that were successfully treated with surgery or intralesional interferon injections. The patient remains alive 30 months after initiation of immunotherapy, suggesting that locally metastasized mcc might be able to be controlled with local and systemic immunotherapy. PMID- 27122985 TI - Synchronous metastatic skull base chordoma to the breast: case report and literature review. AB - CLINICAL SCENARIO: During routine staging work-up for a left breast mass, a 68 year-old woman complained of dysphagia and dysphonia. During further investigations, a left-sided lesion at the foramen magnum was observed on brain imaging. Both lesions were biopsied and showed a classical chordoma. MANAGEMENT: The skull-base lesion and the breast lesion were surgically resected, and adjuvant radiotherapy was given. SUMMARY: Chordoma is a rare primary central nervous system tumour that seldom metastasizes. The lung is the most common site of metastasis. Synchronous breast metastasis from a skull-base chordoma is very rare, and a safe management option includes a maximum resection followed by adjuvant radiotherapy. PMID- 27122986 TI - Second-line treatment of non-small-cell lung cancer with wild-type EGFR status. What is the best approach? PMID- 27122987 TI - Response to: Second-line treatment of non-small-cell lung cancer with wild-type EGFR status. What is the best approach? PMID- 27122988 TI - Accrual of adolescents and young adults with cancer to clinical trials. PMID- 27122989 TI - MicroRNA expression profiling of sputum for the detection of early and locally advanced non-small-cell lung cancer: a prospective case-control study. AB - BACKGROUND: Non-small-cell lung cancer (nsclc) is associated with very poor overall survival because 70% of patients present with locally advanced or metastatic disease at the time of diagnosis. Micrornas (mirnas) are a class of short, noncoding rna molecules whose presence in samples of biologic fluids such as sputum has demonstrated promise as a potential means of detecting nsclc. We investigated the stage-specific nsclc detection potential of an efficient panel of 3 mirnas (mir-21, mir-210, mir-372) using a single sputum sample. METHODS: A single spontaneously expectorated sputum sample was prospectively collected from 21 early nsclc (<=stage ii) patients, 22 advanced nsclc (>=stage iii) patients, and 10 control subjects. Mirna expression profiles were determined by quantitative real-time polymerase chain reaction and were analyzed by unsupervised hierarchical cluster analysis. RESULTS: Mean tumour size (+/-95% confidence interval) in the early and advanced nsclc patients was 3.3 cm +/- 0.9 cm and 4.8 cm +/- 0.7 cm respectively. Adenocarcinoma constituted 61.9% of the early and 45.5% of the advanced nsclc cases respectively. In comparing the early nsclc group with the control group, the mirna panel yielded a diagnostic sensitivity of 67% and a specificity of 90.0%. For the advanced nsclc group, the mirna panel detected nsclc with a sensitivity and specificity of 64% and 100% respectively. CONCLUSIONS: A sputum mir-21, mir-210, and mir-372 expression profile might provide a sensitive and highly specific means for detecting nsclc. Sputum mirna analysis demonstrates promise as a potential complementary screening tool. PMID- 27122990 TI - Expression of APPL1 is correlated with clinicopathologic characteristics and poor prognosis in patients with gastric cancer. AB - BACKGROUND: Although appl1 is overexpressed in many cancers, its status in gastric cancer (gc) is not known. In the present study, we used relevant pathologic and clinical data to investigate appl1 expression in patients with gc. METHODS: In 47 gc and 27 non-gc surgical specimens, immunohistochemistry was used to detect the expression of appl1, and reverse-transcriptase polymerase chain reaction (rt-pcr) was used to detect messenger rna (mrna). A scatterplot visualized the relationship between survival time and mrna expression in gc patients. The log-rank test and other survival statistics were used to determine the association of appl1 expression with the pathologic features of the cancer and clinical outcomes. RESULTS: In gc, appl1 was expressed in 28 of 47 specimens (59.6%), and in non-gc, it was expressed in 7 of 23 specimens (30.4%, p < 0.05). The expression of mrna in gc was 0.82 [95% confidence interval (ci): 0.78 to 0.86], and in non-gc, it was 0.73 (95% ci: 0.69 to 0.77; p < 0.05). Immunohistochemistry demonstrated that, in gc, appl1 expression was correlated with depth of infiltration (p = 0.005), lymph node metastasis (p = 0.017), and TNM stage (p = 0.022), but not with pathologic type (p = 0.41). Testing by rt-pcr demonstrated that, in gc, appl1 mrna expression was correlated with depth of infiltration (p = 0.042), lymph node metastasis (p = 0.031), and TNM stage (p = 0.04), but again, not with pathologic type (p = 0.98). The correlation coefficient between survival time and mrna expression was -0.83 (p < 0.01). Overexpression of appl1 protein (hazard ratio: 3.88; 95% ci: 1.07 to 14.09) and mrna (hazard ratio: 4.23; 95% ci: 3.09 to 15.11) was a risk factor for death in patients with gc. CONCLUSIONS: Expression of appl1 is increased in gc. Overexpression is prognostic for a lethal outcome. PMID- 27122991 TI - Which Neurons Will Be the Engram - Activated Neurons and/or More Excitable Neurons? AB - During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression. PMID- 27122992 TI - Induction of Nerve Injury-Induced Protein 1 (Ninjurin 1) in Myeloid Cells in Rat Brain after Transient Focal Cerebral Ischemia. AB - Nerve injury-induced protein-1 (Ninjurin-1, Ninj1) was initially identified as a novel adhesion molecule in rat sciatic nerve and to be up-regulated in neurons and Schwann cells of distal nerve segments after nerve transection or crush injury. Recently, Ninj1 was found to act as a modulator of cell migration, angiogenesis, and apoptosis. Accumulating evidence indicates that innate immune response plays beneficial and deleterious roles in brain ischemia, and the trans endothelial migration of blood-derived immune cells is key initiator of this response. In the present study, we examined the expression profile and cellular distribution of Ninj1 in rat brain after transient focal cerebral ischemia. Ninj1 expression was found to be significantly induced in cortical penumbras 1 day after 60 min of middle cerebral artery occlusion (MCAO) and to increase gradually for 8 days and then declined. In infarction cores of cortices, patterns of Ninj1 expression were similar to those observed in cortical penumbras, except induction was maintained for 10 days. At 1 day post-MCAO, Ninj1 inductions were detected mainly in neutrophils and endothelial cells in both infarction cores and penumbras, but reactive macrophages were the major cellular expressers of Ninj1 at 4 days post-MCAO. Expressional induction in reactive macrophages was maintained in infarction cores after 12 days post-MCAO but not in penumbras. These dynamic expressions of Ninj1 in different immune cells at different times suggest that this protein performs various, critical roles in the modulation of acute and delayed immune responses in the postischemic brain. PMID- 27122993 TI - Fluoride Induces a Volume Reduction in CA1 Hippocampal Slices Via MAP Kinase Pathway Through Volume Regulated Anion Channels. AB - Regulation of cell volume is an important aspect of cellular homeostasis during neural activity. This volume regulation is thought to be mediated by activation of specific transporters, aquaporin, and volume regulated anion channels (VRAC). In cultured astrocytes, it was reported that swelling-induced mitogen-activated protein (MAP) kinase activation is required to open VRAC, which are thought to be important in regulatory volume decrease and in the response of CNS to trauma and excitotoxicity. It has been also described that sodium fluoride (NaF), a recognized G-protein activator and protein phosphatase inhibitor, leads to a significant MAP kinase activation in endothelial cells. However, NaF's effect in volume regulation in the brain is not known yet. Here, we investigated the mechanism of NaF-induced volume change in rat and mouse hippocampal slices using intrinsic optical signal (IOS) recording, in which we measured relative changes in intracellular and extracellular volume as changes in light transmittance through brain slices. We found that NaF (1~5 mM) application induced a reduction in light transmittance (decreased volume) in CA1 hippocampus, which was completely reversed by MAP kinase inhibitor U0126 (10 uM). We also observed that NaF-induced volume reduction was blocked by anion channel blockers, suggesting that NaF-induced volume reduction could be mediated by VRAC. Overall, our results propose a novel molecular mechanism of NaF-induced volume reduction via MAP kinase signaling pathway by activation of VRAC. PMID- 27122994 TI - Reversal of an Unconditioned Behavioral Preference for Specific Food Pellets by Intervention of Whisker Sensory Inputs. AB - Adenylyl cyclase type-5 (AC5) is preferentially expressed in the dorsal striatum. Recently, we reported that AC5 knockout (KO) mice preferred food pellets carrying an olfactory cue produced by AC5 KO mice during food consumption (AC5 KO pellets) over food pellets that had been taken by wildtype (WT) mice. In the present study, we demonstrated that whisker trimming on the right side of the face but not the left in AC5 KO mice blocked the behavioral preference for AC5 KO pellets. Conversely, whisker trimming on the right but not the left in WT mice induced a behavioral preference for AC5 KO pellets. Mice lacking D2 dopamine receptor (D2 KO mice) also showed a behavioral preference for AC5 KO pellets. In D2 mice, whisker trimming on the right side of the face but not the left blocked a behavioral preference for AC5 KO food pellets. AC5 KO mice had increased level of phospho-CaMKIIalpha in the dorsal striatum, and WT mice with whiskers cut on either side also showed increased p-CaMKIIalpha level in the dorsal striatum. The siRNA-mediated inhibition of CaMKIIalpha in the dorsal striatum in either the right or the left hemisphere in AC5 KO mice and D2 KO mice blocked the behavioral preference for AC5 KO pellets. However, behavioral changes induced by this inhibition on each side showed asymmetrical time courses. These results suggest that an unconditioned behavioral preference for specific food pellets can be switched on or off based on the balance of states of neural activity in the dorsal striatum regulated by a signaling pathway centered on AC5 and D2 and the sensory inputs of whiskers from the right side of the face. PMID- 27122995 TI - Pupil Size in Relation to Cortical States during Isoflurane Anesthesia. AB - In neuronal recording studies on anesthetized animals, reliable measures for the transitional moment of consciousness are frequently required. Previous findings suggest that pupil fluctuations reflect the neuronal states during quiet wakefulness, whose correlation was unknown for the anesthetized condition. Here, we investigated the pupillary changes under isoflurane anesthesia simultaneously with the electroencephalogram (EEG) and electromyogram (EMG). The pupil was tracked by using a region-based active contour model. The dose was given to the animal in a stepwise increasing mode (simulating induction of anesthesia) or in a stepwise decreasing mode (simulating emergence of anesthesia). We found that the quickly widening pupil action (mydriasis) characterizes the transitional state in anesthesia. Mydriasis occurred only in the light dose in the emergence phase, and the events were accompanied by an increase of burst activity in the EEG followed by EMG activity in 47% of the mydriasis events. Our findings suggest that recording such pupil changes may offer a noncontact monitoring tool for indexing the transitional state of the brain, particularly when a lower threshold dose is applied. PMID- 27122996 TI - Fractionated Stereotactic Gamma Knife Radiosurgery for Medial Temporal Lobe Epilepsy: A Case Report. AB - An 18-year-old left-handed male harbored intractable medial temporal lobe epilepsy (MTLE) underwent fractionated gamma knife surgery (GKS) instead of open surgery, considering the mental retardation and diffuse cerebral dysfunction. GKS treatment parameters were: target volume, 8.8 cm(3); total marginal dose, 24 Gy in 3 fractionations at the 50% isodose line. The patient has been free from seizures since 9 months after GKS, with notable improvement in cognitive outcome. Fractionated GKS could be considered as a safe tool for seizure control and neuropsychological improvement in patients with MTLE. PMID- 27122997 TI - Frequency, Awareness, Treatment and Control of Hypertension in the over 40 Population of Erzincan. AB - To determine distribution of blood pressure (BP) and prevalence, awareness, treatment and control of hypertension in 5 primary health care centers of Erzincan. A population-based cross-sectional survey was carried out in January - May 2009. A two-stage sampling method was used to select a sample of adult population 40 and over years of age. The total number of participants was 1570. Data were collected by face-to-face interview technique in the primary health care setting. Main outcome measures; mean systolic and diastolic blood pressures, distribution of blood pressure, prevalence of hypertension (mean systolic BP>=140 mmHg or mean diastolic BP >=90 mmHg, or previously diagnosed and/or taking antihypertensive drugs) awareness, treatment and control of hypertension were assessed. The overall hypertension prevalence was 67.0% in the study sample and 77.4% of them were aware of their hypertension and received a pharmacologic treatment. Of the patients who were aware of the disease, 51.8% use drug treatment. Of the patients who had a drug treatment, 33.9 % were under control in terms of blood pressure. Our data indicate that hypertension is a highly prevalent but inadequately managed health problem in Erzincan. There is an urgent need for population-based strategies to improve prevention, early detection, and control of hypertension. PMID- 27122998 TI - Essential Others and Spontaneous Recovery in the Life and Work of Emily Carr: Implications for Understanding Remission of Illness and Resilience. AB - Artist Emily Carr 1A majority of paintings by Emily Carr are in the permanent collection of the Vancouver Art Gallery. Others may be viewed in the National Gallery of Ontario and the British Columbia Archives in Victoria, BC. They are also available as photographed reproductions on the web at vancouverartgallery.bc.ca. 1 (1871-1945) has attained iconic status in Canada and throughout the world for her prodigious output as a painter and writer of the Pacific Northwest. This article describes how the arrival of three "essential others" at pivotal moments in middle life helped lift Carr out of a serious, lifelong depression and nurtured and inspired her creative output. I propose that Carr's productivity and psychological recovery were facilitated by sequential, cumulative input from these generative human contacts. The creative partnership formed between an artist and her muse has features akin to the patient/therapist dyad, ranging from sparking new and healthier adaptations, to reshaping the internal landscape via internalization, to facilitation and promotion of unique talent. This psychobiographical study of Emily Carr is a vehicle for clinicians to further contemplate elements imbedded in our daily work that give rise to greater resilience, spontaneous recovery from illness, and personal transformation in the lives of our patients. PMID- 27122999 TI - Musical Sounds, Motor Resonance, and Detectable Agency. AB - This paper discusses the paradox that while human music making evolved and spread in an environment where it could only occur in groups, it is now often apparently an enjoyable asocial phenomenon. Here I argue that music is, by definition, sound that we believe has been in some way organized by a human agent, meaning that listening to any musical sounds can be a social experience. There are a number of distinct mechanisms by which we might associate musical sound with agency. While some of these mechanisms involve learning motor associations with that sound, it is also possible to have a more direct relationship from musical sound to agency, and the relative importance of these potentially independent mechanisms should be further explored. Overall, I conclude that the apparent paradox of solipsistic musical engagement is in fact unproblematic, because the way that we perceive and experience musical sounds is inherently social. PMID- 27123001 TI - Advanced Fuzzy Potential Field Method for Mobile Robot Obstacle Avoidance. AB - An advanced fuzzy potential field method for mobile robot obstacle avoidance is proposed. The potential field method primarily deals with the repulsive forces surrounding obstacles, while fuzzy control logic focuses on fuzzy rules that handle linguistic variables and describe the knowledge of experts. The design of a fuzzy controller--advanced fuzzy potential field method (AFPFM)--that models and enhances the conventional potential field method is proposed and discussed. This study also examines the rule-explosion problem of conventional fuzzy logic and assesses the performance of our proposed AFPFM through simulations carried out using a mobile robot. PMID- 27123000 TI - Non-targeted UHPLC-MS metabolomic data processing methods: a comparative investigation of normalisation, missing value imputation, transformation and scaling. AB - INTRODUCTION: The generic metabolomics data processing workflow is constructed with a serial set of processes including peak picking, quality assurance, normalisation, missing value imputation, transformation and scaling. The combination of these processes should present the experimental data in an appropriate structure so to identify the biological changes in a valid and robust manner. OBJECTIVES: Currently, different researchers apply different data processing methods and no assessment of the permutations applied to UHPLC-MS datasets has been published. Here we wish to define the most appropriate data processing workflow. METHODS: We assess the influence of normalisation, missing value imputation, transformation and scaling methods on univariate and multivariate analysis of UHPLC-MS datasets acquired for different mammalian samples. RESULTS: Our studies have shown that once data are filtered, missing values are not correlated with m/z, retention time or response. Following an exhaustive evaluation, we recommend PQN normalisation with no missing value imputation and no transformation or scaling for univariate analysis. For PCA we recommend applying PQN normalisation with Random Forest missing value imputation, glog transformation and no scaling method. For PLS-DA we recommend PQN normalisation, KNN as the missing value imputation method, generalised logarithm transformation and no scaling. These recommendations are based on searching for the biologically important metabolite features independent of their measured abundance. CONCLUSION: The appropriate choice of normalisation, missing value imputation, transformation and scaling methods differs depending on the data analysis method and the choice of method is essential to maximise the biological derivations from UHPLC-MS datasets. PMID- 27123002 TI - A Dynamic Health Assessment Approach for Shearer Based on Artificial Immune Algorithm. AB - In order to accurately identify the dynamic health of shearer, reducing operating trouble and production accident of shearer and improving coal production efficiency further, a dynamic health assessment approach for shearer based on artificial immune algorithm was proposed. The key technologies such as system framework, selecting the indicators for shearer dynamic health assessment, and health assessment model were provided, and the flowchart of the proposed approach was designed. A simulation example, with an accuracy of 96%, based on the collected data from industrial production scene was provided. Furthermore, the comparison demonstrated that the proposed method exhibited higher classification accuracy than the classifiers based on back propagation-neural network (BP-NN) and support vector machine (SVM) methods. Finally, the proposed approach was applied in an engineering problem of shearer dynamic health assessment. The industrial application results showed that the paper research achievements could be used combining with shearer automation control system in fully mechanized coal face. The simulation and the application results indicated that the proposed method was feasible and outperforming others. PMID- 27123003 TI - Serum Immunoglobulin A (IgA) Level Is a Potential Biomarker Indicating Cirrhosis during Chronic Hepatitis B Infection. AB - Background. Serum immunoglobulins (Igs) are frequently elevated in patients with chronic liver disease, but currently there is a lack of sufficient data on serum Igs in patients with chronic hepatitis B virus (CHB) infection. This study aimed to evaluate serum IgA, IgG, and IgM levels in patients with HBV-related cirrhosis and to analyze, if altered, immunoglobulin levels that were associated with cirrhosis progress. Methods. A cohort of 174 CHB patients including 104 with cirrhosis (32 decompensated and 72 compensated) and 70 without cirrhosis and 55 healthy controls were enrolled. Serum immunoglobulin levels and biochemical and virological parameters were determined in the enrollment blood samples. Results. Serum IgA levels were significantly increased in cirrhosis group compared with noncirrhosis group and healthy controls (all P < 0.001). Furthermore, serum IgA concentrations in decompensated cirrhosis patients were significantly higher than that of compensated patients (P = 0.002). Multivariate analysis suggested that serum IgA, platelets, and albumin were independent predictors for cirrhosis (all P < 0.001). Conclusions. Elevated IgA levels may function as an independent factor indicating cirrhosis, and there appears to be a strong association between increasing serum IgA level and disease progressing in patients with chronic HBV infection. PMID- 27123004 TI - A Comparison of Tissue versus Swab Culturing of Infected Diabetic Foot Wounds. AB - Objective. To compare the efficacy of swabbing versus tissue biopsy for microbiological diagnosis of diabetic foot infection. Methods. This was a prospective trial. Fifty-six patients with diabetic foot infection were divided into the following 3 groups according to the PEDIS grading system: grade 2 (n = 10), grade 3 (n = 29), and grade 4 (n = 17). Two specimens were collected from each wound for microbial culturing after debridement, including a superficial swab and a deep tissue punch biopsy specimen. Results. Swab culturing identified all of the microorganisms isolated from the corresponding deep tissue specimens in 9/10 of grade 2 wounds (90.0%), and this proportion decreased to 12/29 (41.4%) and 7/17 (41.2%) for grades 3 and 4 wounds, respectively (p = 0.02). Moreover, the sensitivity for identifying Gram-negative bacteria, such as E. coli and Citrobacter, by swabbing was low (33.3%). In addition, some Gram-negative bacteria, such as Serratia and Ralstonia pickettii, were isolated from deep tissues but not from swabs. Conclusions. Swab culturing may be reliable for identification of pathogens in diabetic foot wounds classified as grade 2. However, it is advisable to culture deep tissue specimens for wounds of grade >=3 because swab culturing is associated with a high risk of missing pathogens, especially Gram-negative bacteria. PMID- 27123005 TI - Spread of TEM, VIM, SHV, and CTX-M beta-Lactamases in Imipenem-Resistant Gram Negative Bacilli Isolated from Egyptian Hospitals. AB - Carbapenem-resistant Gram-negative bacilli resulting from beta-lactamases have been reported to be an important cause of nosocomial infections and are a critical therapeutic problem worldwide. This study aimed to describe the prevalence of imipenem-resistant Gram-negative bacilli isolates and detection of bla VIM, bla TEM, bla SHV, bla CTX-M-1, and bla CTX-M-9 genes in these clinical isolates in Egyptian hospitals. The isolates were collected from various clinical samples, identified by conventional methods and confirmed by API 20E. Antibiotic susceptibility testing was determined by Kirby-Bauer technique and interpreted according to CLSI. Production of bla VIM, bla TEM, bla SHV, and bla CTX-M genes was done by polymerase chain reaction (PCR). Direct sequencing from PCR products was subsequently carried out to identify and confirm these beta-lactamases genes. Out of 65 isolates, (46.1%) Escherichia coli, (26.2%) Klebsiella pneumoniae, and (10.7%) Pseudomonas aeruginosa were identified as the commonest Gram-negative bacilli. 33(50.8%) were imipenem-resistant isolates. 22 isolates (66.7%) carried bla VIM, 24(72.7%) had bla TEM, and 5(15%) showed bla SHV, while 12(36%), 6(18.2%), and 0(0.00%) harbored bla CTX-M-1, bla CTX-M-9, and bla CTX-M-8/25, respectively. There is a high occurrence of beta-lactamase genes in clinical isolates and sequence analysis of amplified genes showed differences between multiple SNPs (single nucleotide polymorphism) sites in the same gene among local isolates in relation to published sequences. PMID- 27123006 TI - Prognostic Factors on the Graft-versus-Host Disease-Free and Relapse-Free Survival after Adult Allogeneic Hematopoietic Stem Cell Transplantation. AB - The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including graft-versus-host disease (GVHD), relapse, and death. A novel composite endpoint of GVHD-free/relapse-free survival (GRFS) in which events include grades 3-4 acute GVHD, chronic GVHD requiring systemic therapy, relapse, or death is censored to completely characterize the survival without mortality or ongoing morbidity. In this regard, studies attempting to identify the prognostic factors of GRFS are quite scarce. Thus, we reviewed 377 adult patients undergoing allogeneic HSCT between 2003 and 2013. The 1- and 2-year GRFS were 40.8% and 36.5%, respectively, significantly worse than overall survival and disease-free survival (log-rank p < 0.001). European Group for Blood and Marrow Transplantation (EBMT) risk score > 2 (p < 0.001) and hematologic malignancy (p = 0.033) were poor prognostic factors for 1-year GRFS. For 2-year GRFS, EBMT risk score > 2 (p < 0.001), being male (p = 0.028), and hematologic malignancy (p = 0.010) were significant for poor outcome. The events between 1-year GRFS and 2 year GRFS predominantly increased in relapsed patients. With prognostic factors of GRFS, we could evaluate the probability of real recovery following HSCT without ongoing morbidity. PMID- 27123007 TI - Enhanced Proliferation of Porcine Bone Marrow Mesenchymal Stem Cells Induced by Extracellular Calcium is Associated with the Activation of the Calcium-Sensing Receptor and ERK Signaling Pathway. AB - Porcine bone marrow mesenchymal stem cells (pBMSCs) have the potential for application in regenerative medicine. This study aims to investigate the effects of extracellular calcium ([Ca(2+)]o) on pBMSCs proliferation and to explore the possible underlying mechanisms. The results demonstrated that 4 mM [Ca(2+)]o significantly promoted pBMSCs proliferation by reducing the G0/G1 phase cell percentage and by increasing the S phase cell proportion and the proliferation index of pBMSCs. Accordingly, [Ca(2+)]o stimulated the expression levels of proliferative genes such as cyclin A2, cyclin D1/3, cyclin E2, and PCNA and inhibited the expression of p21. In addition, [Ca(2+)]o resulted in a significant elevation of intracellular calcium and an increased ratio of p-ERK/ERK. However, inhibition of calcium-sensing receptor (CaSR) by its antagonist NPS2143 abolished the aforementioned effects of [Ca(2+)]o. Moreover, [Ca(2+)]o-induced promotion of pBMSCs proliferation, the changes of proliferative genes expression levels, and the activation of ERK1/2 signaling pathway were effectively blocked by U0126, a selective ERK kinase inhibitor. In conclusion, our findings provided evidence that the enhanced pBMSCs proliferation in response to [Ca(2+)]o was associated with the activation of CaSR and ERK1/2 signaling pathway, which may be useful for the application of pBMSCs in future clinical studies aimed at tissue regeneration and repair. PMID- 27123009 TI - In Vitro Differentiation of First Trimester Human Umbilical Cord Perivascular Cells into Contracting Cardiomyocyte-Like Cells. AB - Myocardial infarction (MI) causes an extensive loss of heart muscle cells and leads to congestive heart disease (CAD), the leading cause of mortality and morbidity worldwide. Mesenchymal stromal cell- (MSC-) based cell therapy is a promising option to replace invasive interventions. However the optimal cell type providing significant cardiac regeneration after MI is yet to be found. The aim of our study was to investigate the cardiomyogenic differentiation potential of first trimester human umbilical cord perivascular cells (FTM HUCPVCs), a novel, young source of immunoprivileged mesenchymal stromal cells. Based on the expression of cardiomyocyte markers (cTnT, MYH6, SIRPA, and CX43) FTM and term HUCPVCs achieved significantly increased cardiomyogenic differentiation compared to bone marrow MSCs, while their immunogenicity remained significantly lower as indicated by HLA-A and HLA-G expression and susceptibility to T cell mediated cytotoxicity. When applying aggregate-based differentiation, FTM HUCPVCs showed increased aggregate formation potential and generated contracting cells within 1 week of coculture, making them the first MSC type with this ability. Our results indicate that young FTM HUCPVCs have superior cardiomyogenic potential coupled with beneficial immunogenic properties when compared to MSCs of older tissue sources, suggesting that in vitro predifferentiation could be a potential strategy to increase their effectiveness in vivo. PMID- 27123010 TI - Association between Toll-Like Receptor 4 and Occurrence of Type 2 Diabetes Mellitus Susceptible to Pulmonary Tuberculosis in Northeast China. AB - The purpose of this study is to explore why type 2 diabetes mellitus (T2DM) patients are susceptible to pulmonary tuberculosis through detection of serum Toll-like receptor 4 (TLR4), an important immune-related receptor, especially in terms of content and TLR4 gene polymorphism. Patients with T2DM complicated by pulmonary tuberculosis (T2DMTB) were selected as the case group and T2DM patients without tuberculosis were selected as the control group. Forty patients in each group were randomly selected and their serum TLR4 levels were detected and compared. Determination of six sites of TLR4 gene polymorphism was carried out in 238 T2DMTB patients and 310 patients with T2DM, and results showed that the serum TLR4 content of the T2DMTB group was significantly lower than that of the T2DM group (p < 0.05). The six sites of TLR4 gene polymorphism did not show significant associations with T2DMTB risk. No statistically significant differences in genotype distributions were observed between T2DMTB patients and patients with T2DM when studied using the recessive and dominant genetic models. How two diseases with contradictory nutritional statuses can occur in the same person is difficult to explain from environmental factors perspective alone. Future research should study the causes of T2DMTB from the perspective of genetics. PMID- 27123008 TI - Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization. AB - Hematopoietic stem cell transplant (HSCT) using mobilized peripheral blood hematopoietic stem cells (HSPCs) is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers. PMID- 27123012 TI - Determinants of Early Marriage from Married Girls' Perspectives in Iranian Setting: A Qualitative Study. AB - Early marriage is a worldwide problem associated with a range of health and social consequences for teenage girls. Designing effective health interventions for managing early marriage needs to apply the community-based approaches. However, it has received less attention from policymakers and health researchers in Iran. Therefore, the current study aimed to explore determinants of early marriage from married girls' perspectives. The study was conducted from May 2013 to January 2015 in Ahvaz, Iran. A purposeful sampling method was used to select fifteen eligible participants. Data were collected through face-to-face, semistructured interviews and were analyzed using the conventional content analysis approach. Three categories emerged from the qualitative data including "family structure," "Low autonomy in decision-making," and "response to needs." According to the results, although the participants were not ready to get married and intended to postpone their marriage, multiple factors such as individual and contextual factors propelled them to early marriage. Given that early marriage is a multifactorial problem, health care providers should consider a multidimensional approach to support and empower these vulnerable girls. PMID- 27123011 TI - Netrin-1 Peptide Is a Chemorepellent in Tetrahymena thermophila. AB - Netrin-1 is a highly conserved, pleiotropic signaling molecule that can serve as a neuronal chemorepellent during vertebrate development. In vertebrates, chemorepellent signaling is mediated through the tyrosine kinase, src-1, and the tyrosine phosphatase, shp-2. Tetrahymena thermophila has been used as a model system for chemorepellent signaling because its avoidance response is easily characterized under a light microscope. Our experiments showed that netrin-1 peptide is a chemorepellent in T. thermophila at micromolar concentrations. T. thermophila adapts to netrin-1 over a time course of about 10 minutes. Netrin adapted cells still avoid GTP, PACAP-38, and nociceptin, suggesting that netrin does not use the same signaling machinery as any of these other repellents. Avoidance of netrin-1 peptide was effectively eliminated by the addition of the tyrosine kinase inhibitor, genistein, to the assay buffer; however, immunostaining using an anti-phosphotyrosine antibody showed similar fluorescence levels in control and netrin-1 exposed cells, suggesting that tyrosine phosphorylation is not required for signaling to occur. In addition, ELISA indicates that a netrin-like peptide is present in both whole cell extract and secreted protein obtained from Tetrahymena thermophila. Further study will be required in order to fully elucidate the signaling mechanism of netrin-1 peptide in this organism. PMID- 27123013 TI - Self-Reported Knowledge and Attitude of Dentists towards Prescription of Fluoride. AB - OBJECTIVES: This study aimed to assess the self-reported knowledge and attitude of dentists towards fluoride prescription. MATERIALS AND METHODS: A questionnaire survey was conducted at the national annual dental congress in 2010 in Tehran Iran. Dentists' level of knowledge about the preventive effects of systemic and topical administration of fluoride was assessed as well as their attitudes towards its application. Self-reported practice for two paper patients (a child and an adult with high risk of dental caries) was assessed. Data were analyzed using SPSS, chi-square test and logistic regression. RESULTS: A total of 347 dentists including 232 (73.4%) males and 84 (26.6%) females responded; 84.7% agreed/strongly agreed with addition of fluoride to water and 66% agreed with prescription of fluoride tablets/drops in fluoride-deficient areas. Fluoridated toothpastes were considered useful by 85.3%; this rate was 78.7% for fluoride rinse and 87.6% for fluoride varnish, foam or gel. The majority of dentists (67.4%) reported no access to clear guidelines on fluoride application; 83% considered fluoride to be effective for caries prevention in children less than 12 years and 39.2% believed it was useful for adults and adolescents; 50% of the respondents correctly managed the high-risk child and adult with respect to appropriate selection of fluoride product. Younger dentists (OR=0.94; 95% CI 0.8 0.9; P=0.043) and new graduates (OR=0.94; 95% CI 0.89-0.99; P=0.034) were more likely to correctly manage the high-risk child. CONCLUSION: Dentists had good knowledge and positive attitudes towards fluoride application. New graduates were more likely to correctly manage the young high-risk patient. PMID- 27123014 TI - Effect of In-Office Carbamide Peroxide-Based Tooth Bleaching System on Wear Resistance of Silorane-Based and Methacrylate-Based Dental Composites. AB - OBJECTIVES: Several studies have assessed the characteristics and properties of silorane-based composites and adhesive systems. Considering the extensive application of tooth-whitening agents, possible deteriorative effects of tooth bleaching agents on these restorative materials must be studied. The aim of this study was to evaluate the effect of an in-office carbamide peroxide-based tooth bleaching agent on the wear resistance of a silorane-based and a conventional microhybrid dimethyl methacrylate-based dental composite with two different application times. MATERIALS AND METHODS: Thirty cylindrical specimens were made of Z250 and P90 dental composite resins (n=15 for each composite). Samples made of each composite were divided into three groups (n=5) for immersion in an in office bleaching agent (Opalescence(r) Quick 45%) for either three or eight hours or saline solution (control). Wear tests were conducted after bleaching using a pin-on disk apparatus under the load of 40N at a constant sliding speed of 0.5 ms(-1) for a sliding distance of 300 m. The samples were weighed before and after the wear test. Repeated measures ANOVA was used to statistically analyze the obtained data (alpha=0.05). RESULTS: There was a significant decrease in the weight of samples after the wear test (P<0.001). However, no significant difference was found among groups in the mean weight of samples before and after the wear test (P>0.05). CONCLUSION: Bleaching for three or eight hours using 45% carbamide peroxide had no deteriorative effect on the wear resistance of Z250 and P90 composites. PMID- 27123015 TI - Bonding Durability of Four Adhesive Systems. AB - OBJECTIVES: This study aimed to compare the durability of four adhesive systems by assessing their microtensile bond strength (MTBS) and microleakage during six months of water storage. MATERIALS AND METHODS: A total of 128 human third molars were used. The adhesives tested were Scotch Bond Multipurpose (SBMP), Single Bond (SB), Clearfil-SE bond (CSEB), and All-Bond SE (ABSE). After sample preparation for MTBS testing, the microspecimens were subjected to microtensile tester after one day and six months of water storage. For microleakage evaluation, facial and lingual class V cavities were prepared and restored with composite. After thermocycling, microleakage was evaluated. Bond strength values were subjected to one-way ANOVA and Tamhane's test, and the microleakage data were analyzed by the Kruskal-Wallis, Dunn, Mann Whitney and Wilcoxon tests (P<0.05). RESULTS: Single Bond yielded the highest and ABSE yielded the lowest bond strength at one day and six months. Short-term bond strength of SBMP and CSEB was similar. After six months, a significant decrease in bond strength was observed in ABSE and SBMP groups. At one day, ABSE showed the highest microleakage at the occlusal margin; however, at the gingival margin, there was no significant difference among groups. Long-term microleakage of all groups at the occlusal margins was similar, whilst gingival margins of SBMP and SB showed significantly higher microleakage. CONCLUSION: The highest MTBS and favorable sealability were obtained by Clearfil SE bond. Water storage had no effect on microleakage of self-etch adhesives at the gingival margin or MTBS of CSEB and SB. PMID- 27123016 TI - Diagnostic Accuracy of Inverted and Unprocessed Digitized Periapical Radiographs for Detection of Peri-Implant Defects. AB - OBJECTIVES: This study aimed to compare the diagnostic accuracy of inverted and unprocessed digitized periapical radiographs for detection of peri-implant defects. MATERIALS AND METHODS: A total of 30 osteotomy sites were prepared in three groups of control, study group 1 with 0.425 mm defects and study group 2 with 0.725 mm defects using the SIC and Astra Tech drill systems with 4.25mm and 4.85mm diameters. Small and large defects were randomly created in the coronal 8mm of 20 implant sites; implants (3.4mm diameter, 14.5mm length) were then placed. Thirty periapical (PA) radiographs were obtained using Digora imaging system (Soredex Corporation, Helsinki, Finland), size 2 photostimulable storage phosphor (PSP) plate sensors (40.0mm*30.0mm) and Scanora software. Unprocessed images were inverted using Scanora software by applying image inversion and a total of 60 images were obtained and randomly evaluated by four oral and maxillofacial radiologists. Data were analyzed using the t-test. RESULTS: Significant differences were observed in absolute and complete sensitivity and specificity of the two imaging modalities for detection of small and large defects (P<0.05). Unprocessed digital images had a higher mean in terms of absolute sensitivity for detection of small defects, complete sensitivity for detection of large peri-implant defects and definite rule out of defects compared with inverted images. CONCLUSION: Unprocessed digital images have a higher diagnostic value for detection of small and large peri-implant defects and also for definite rule out of defects compared with inverted images. PMID- 27123017 TI - Effect of Ingested Liquids on Color Change of Composite Resins. AB - OBJECTIVES: Color change of composite restorations is well known to dentists. However, the effect of commonly consumed drinks on discoloration of composite resins has yet to be determined. This study sought to assess the color change of a nanofilled (Premise) and a flowable composite resin (Premise flowable) following simulated consumption of tea, cola, iron drops and multivitamin syrup. MATERIALS AND METHODS: Forty disk-shaped specimens (7 mm in diameter and 2 mm thick) were fabricated from each composite resin. The baseline color values were measured according to the CIE L*a*b* system using digital imaging. The specimens of each restorative material were randomly divided into five groups (eight each) according to the storage media namely tea, cola, iron drops, multivitamin syrup or distilled water (control). The specimens were immersed in staining solutions for three hours daily over a 40-day test period. Following this, the color change values (DeltaE*) were calculated. For statistical analyses, the color differences were analyzed using two-way ANOVA and Tukey's test (P< 0.05). RESULTS: There was no significant difference in DeltaE* values between the two types of composite resins (P>0.05). In both composite materials, the difference among the solutions was not significant (P>0.05). CONCLUSION: Under the tested experimental conditions, both restorative materials were susceptible to discoloration by all four staining solutions. The color change values were not related to the solution or the type of material used. PMID- 27123018 TI - In Vitro Comparison of the Effects of Diode Laser and CO2 Laser on Topical Fluoride Uptake in Primary Teeth. AB - OBJECTIVES: Fluoride therapy is important for control and prevention of dental caries. Laser irradiation can increase fluoride uptake especially when combined with topical fluoride application. The objective of this study was to compare the effects of CO2 and diode lasers on enamel fluoride uptake in primary teeth. MATERIALS AND METHODS: Forty human primary molars were randomly assigned to four groups (n=10). The roots were removed and the crowns were sectioned mesiodistally into buccal and lingual halves as the experimental and control groups. All samples were treated with 5% sodium fluoride (NaF) varnish. The experimental samples in the four groups were irradiated with 5 or 7W diode or 1 or 2W CO2 laser for 15 seconds and were compared with the controls in terms of fluoride uptake, which was determined using an ion selective electrode after acid dissolution of the specimens. Data were analyzed by SPSS version 16 using ANOVA treating the control measurements as covariates. RESULTS: The estimated amount of fluoride uptake was 59.5+/- 16.31 ppm, 66.5+/- 14.9 ppm, 78.6+/- 12.43 ppm and 90.4+/- 11.51 ppm for 5W and 7 W diode and 1W and 2 W CO2 lasers, respectively, which were significantly greater than the values in the conventional topical fluoridation group (P<0.005). There were no significant differences between 7W diode laser and 1W CO2 laser, 5W and 7W diode laser, or 1W and 2W CO2 laser in this regard. CONCLUSION: The results showed that enamel surface irradiation by CO2 and diode lasers increases the fluoride uptake. PMID- 27123019 TI - Antifungal Efficacy of Green Tea Extract against Candida Albicans Biofilm on Tooth Substrate. AB - OBJECTIVES: Biomechanical preparation and irrigation with antimicrobial solutions are necessary to disinfect the root canal space. This in vitro study aimed to examine the antifungal effect of green tea extract on Candida albicans biofilm formed on tooth substrate. MATERIALS AND METHODS: Minimum fungicidal concentration (MFC) and minimum inhibitory concentration at which 90% of the isolates were inhibited (MIC90) were studied using green tea extract and sodium hypochlorite with the broth macro-dilution method. Then, anti-candida effects of this extract were tested on tooth substrates of 45 extracted single-canal premolar teeth. After biomechanical cleaning of the root canals, the teeth were sectioned vertically and randomly divided into three groups of 30. All the samples were infected with C. albicans (PTCC 5027) and exposed to the test solutions (sodium hypochlorite, green tea, normal saline) for five, 10 and 15 minutes. Data analyses of the samples were performed using two-way ANOVA. RESULTS: The average number of microorganisms showed a significant decrease after five, 10 and 15 minutes of exposure to green tea extract and sodium hypochlorite. The average number of C. albicans in green tea extract and sodium hypochlorite groups decreased to 1/3 and 1/2 of the initial values, respectively. CONCLUSION: Antifungal activity of green tea extract was time-dependent and its inhibitory action did not decrease significantly over time. It is recommended to consider other properties of green tea such as tissue solubility, impact on dentin structure and use as an intracanal medicament or for smear layer removal in the clinical setting. PMID- 27123020 TI - In Vitro Evaluation of Apical Sealing Ability of HEROfill(r) Obturator Versus Cold Lateral Condensation in Curved Root Canals. AB - OBJECTIVES: This study aimed to assess and compare the apical sealing ability of HEROfill(r) Soft-Core system and lateral condensation technique in fine curved canals using the fluid filtration method. MATERIALS AND METHODS: Forty human mesiobuccal root canals of mandibular first molars with 25 degrees to 40 degrees curvatures were instrumented to an apical size 30/0.04. Roots were randomly assigned to two experimental groups of 15, designated as groups A and B. Two control groups, each containing five teeth, served as positive and negative controls. Group A was obturated using lateral condensation technique and group B with the HEROfill(r) Soft-Core system. The groups were tested for microleakage using an in vitro fluid filtration apparatus with 0.5 atm pressure at zero, two, four, six, eight and 10 minutes. Independent t-test was used to analyze the microleakage data. RESULTS: The mean and standard deviation (SD) values for fluid microleakage in the lateral condensation group were 0.58+/-0.49 MUL/min, 0.68+/ 0.35 MUL/min, 0.74+/-0.22 MUL/min, 0.71+/-0.29 MUL/min and 0.60+/- 0.29 MUL/min at two, four, six, eight and 10 minutes, respectively. The mean and SD values for fluid microleakage in the HEROfill(r) group were 0.53+/-0.42 MUL/min, 0.67+/-0.34 MUL/min, 0.69+/-0.26 MUL/min, 0.73+/-0.33 MUL/min and 0.63+/-0.26 MUL/min at two, four, six, eight and 10 minutes, respectively. The difference between the lateral condensation and HEROfill(r) groups was not statistically significant at two (P=0.776), four (P=0.909), six (P=0.562), eight (P=0.861) or 10 (P=0.765) minutes. CONCLUSION: The HEROfill(r) system and cold lateral condensation technique were equally effective for apical sealing of curved canals. PMID- 27123021 TI - In-Vitro Effect of Casein Phosphopeptide Amorphous Calcium Phosphate on Enamel Susceptibility to Staining by Tea during Bleaching Treatment. AB - OBJECTIVES: Bleached enamel is more susceptible to staining, and application of remineralizing agents may decrease enamel susceptibility to staining. This study sought to assess the effect of casein phosphopeptide amorphous calcium phosphate (CPP-ACP) on enamel susceptibility to staining during bleaching treatment. MATERIALS AND METHODS: Forty central and lateral incisors and first premolar teeth were evaluated in four groups of 10. Group one specimens were subjected to in-office bleaching. Group two underwent in-office bleaching followed by surface treatment with CPP-ACP. Group three specimens received home bleaching and group four underwent home bleaching followed by CPP-ACP surface treatment. After each course of daily bleaching, specimens were immersed in tea solution. Home bleaching (15% carbamide peroxide) was performed for 14 days and in-office bleaching (40% hydrogen peroxide) was carried out in two sessions with an eight day interval. The color of specimens was analyzed at baseline and post intervention using Easy Shade Shade-Selection Device. Two-way ANOVA was used to evaluate the effects of bleaching type and surface treatment on color change. Then, the means were compared by Tukey's HSD test (P=0.05). RESULTS: The interaction effect of surface treatment and type of bleaching was not significant on any color parameter (P>0.05). Surface treatment had significant effects on DeltaL (P=0.004). Type of bleaching had a significant effect on "b" parameter (P=0.00). The effect of bleaching type on DeltaE was significant (P=0.00) but the effect of surface treatment was not (P=0.34). CONCLUSION: CPP-ACP had no significant effect on preventing enamel staining by tea during bleaching treatment. PMID- 27123022 TI - Implant Rehabilitation in Advanced Generalized Aggressive Periodontitis: A Case Report and Literature Review. AB - Dental implants have provided exceptional rehabilitative options for edentulous and partially edentulous patients. However, as more implants come into play, the more the clinicians come across problems where specific considerations must be taken into account to meet expectations. The Toronto Bridge is a treatment modality proposed for restoring several teeth lost in patients with increased crown height (interarch) space. Herein, we applied the Toronto Bridge to rehabilitate a patient with generalized aggressive periodontitis; this article suggests that an implant-supported Toronto Bridge can be a reliable and acceptable treatment modality for patients suffering from tooth loss and vertical bone loss as the result of generalized aggressive periodontal disease. PMID- 27123023 TI - Quantitative Pfirrmann Disc Degeneration Grading System to Overcome the Limitation of Pfirrmann Disc Degeneration Grade. AB - OBJECTIVE: Pfirrmann disc degeneration grade is one of morphologic disc degeneration grading system and it was reliable on routine T2-weighted magnetic resonance (MR) images. The purpose of this study was to evaluate the agreement of Pfirrmann disc degeneration grade, and check the alternative technique of disc degeneration grading system. METHODS: Fifteen volunteers (4 medical doctors related to spinal disease, 2 medical doctors not related to spinal disease, 6 nurses in spinal hospital, and 3 para-medicines) were included in this study. Three different digitalized MR images were provided all volunteers, and they checked Pfirrmann disc degeneration grade of each disc levels after careful listening to explanation. Indeed, all volunteers checked the signal intensity of disc degeneration at the points of nucleus pulposus (NP), disc membrane, ligaments, fat, and air to modify the quantitative Pfirrmann disc degeneration grade. RESULTS: Total 225 grade results of Pfirrmann disc degeneration grade and 405 signal intensity results of quantitative Pfirrmann disc degeneration grade were analyzed. Average interobserver agreement was "moderate (mean+/-standard deviation, 0.575+/-0.251)" from poor to excellent. Completely agreed levels of Pfirrmann disc degeneration grade were only 4 levels (26.67%), and the disagreement levels were observed in 11 levels; two different grades in 8 levels (53.33%) and three different grades in 3 levels (20%). Quantitative Pfirrmann disc degeneration showed relatively cluster distribution with the interobserver deviations of 0.41-1.56 at the ratio of NP and disc membrane, and it showed relatively good cluster and distribution indicating that the proposed grading system has good discrimination ability. CONCLUSION: Pfirrmann disc degeneration grade showed the limitation of different interobserver results, but this limitation could be overcome by using quantitative techniques of MR signal intensity. Further evaluation is needed to access its advantage and reliabilities. PMID- 27123024 TI - The Applicability of Intraoperative Neuromonitoring in Patients with Preoperative Motor Weakness during Spine Surgery. AB - OBJECTIVE: The purpose of our study is to evaluate the success rate and feasibility of intraoperative neuromonitoring (IONM) focusing on transcranial motor evoked potential (TcMEP) monitoring for patients with preoperative motor weakness in spine surgery. METHODS: Between November 2011 and December 2013, TcMEP and somatosensory evoked potential (SSEP) monitoring were attempted in 130 consecutive patients undergoing spine surgeries for cervical or thoracic cord lesions. Patients ranged in age from 14 to 81 years (mean+/-standard deviation, 56.7+/-14.8 years), and 84 patients were male. The success rates of both SSEP and MEPs monitoring were assessed according to the preoperative Medical Research Council (MRC) and Nurick grades. RESULTS: TcMEP was recorded successfully in 0%, 28.6%, 72.3%, and 100% of patients with MRC grades 1, 2, 3, 4, and 5, respectively. SSEP was obtained from 0%, 37.5%, 21.5%, 61.4%, and 85.4% of patients with MRC grades 1, 2, 3, 4, and 5, respectively. TcMEP was recorded successfully in 84% of patients with Nurick grades 1-3 and 26% of patients with Nurick grades 4-5. SSEPs were recorded successfully in 76.3% of patients with Nurick grades 1-3 and 24% of patients with grades 4-5. CONCLUSION: IONM during spine surgery may be useless in patients with MRC grades 1-2, applicable MRC grade 3, and useful MRC grades 4-5. MRC grade 3 is a critical point of indication for application of MEPs. In unmonitorable cases with MRC grade 3, increasing stimulus intensity or facilitation techniques may be considered to improve the usefulness of TcMEP. PMID- 27123025 TI - Stand-Alone Cages for Anterior Cervical Fusion: Are There No Problems? AB - OBJECTIVE: There are complications in stand-alone cage assisted anterior cervical discectomy and fusion (ACDF), such as cage subsidence and kyphosis. Here we report our clinical result on ACDF, comparing with stand-alone cages and with cervical plate system for degenerative cervical spine diseases. METHODS: Patients with degenerative cervical disease who were diagnosed and treated in Konyang University Hospital between January 2004 and December 2014 were included in this study. Patients who had operation in single level ACDF were selected. Patients scored the degree of pain using visual analog scale before and after the surgery. Subsidence was defined as >=3-mm decrease of the segmental height, and cervical kyphosis was defined as progression of >=5 degrees at 12 months after postoperative follow-up compared to that measured at the immediate postoperative period. RESULTS: A total of 81 patients were enrolled for this study. Forty-five patients were included in a cervical plate group and the others were in stand alone cage group. There was no statistical difference in pain score between the 2 groups. Segmental subsidence was observed in 7 patients (15.6%) in plate-assisted cervical fusion group, and 13 patients (36.1%) in stand-alone cage group. Segmental kyphosis was observed in 4 patients (8.9%) in plate-assisted cervical fusion group, and 10 patients (27.8%) in stand-alone cage group. There was statistical difference between the 2 groups. CONCLUSION: There was no difference in pain between 2 groups. But stand-alone case group showed higher incidence rate than plate-assisted cervical fusion group in segmental subsidence and cervical kyphosis. When designing cervical fusion, more attention should be given selecting the surgical technique. PMID- 27123026 TI - Is Surgical Drain Useful for Lumbar Disc Surgery? AB - OBJECTIVE: Surgical drains are commonly used after the spine surgeries for minimizing hematoma formation, which can delay wound healing and may become a source of fibrosis, infection, and pain. The drain, however, may provide a direct route for infection if it is contaminated. Our objective was to survey the relationship between surgical drains and infection. METHODS: The 70 patients who had undergone single-level lumbar discectomy from April 2011 to March 2012 were retrospectively analyzed. Each patient's medical chart and magnetic resonance image were thoroughly reviewed after all the patients had been divided into the drainage and the nondrainage groups. The amounts and durations of the surgical drains in the drainage group were analyzed. Additionally, the levels of C reactive protein, rates of infection, scores of preoperative and postoperative visual analog scale (VAS), and lengths of hospital stay after operation were compared between the 2 groups. RESULTS: In this study, 70 patients were retrospectively analyzed; out of which, 42 and 28 patients were included in the drainage and the nondrainage groups, respectively. Two of the postoperative infection cases in the nondrainage group required to undergo repeated operations. The frequency of the postoperative infection cases was higher in the nondrainage group than in the drainage group; however, there was no significant statistical difference between the 2 groups (p=0.157). CONCLUSION: Surgical drains did not elevate postoperative infection. Furthermore, drain tip cultures allowed us to detect postoperative infection at an early stage, and it led to faster initiation of antibiotics treatment. PMID- 27123027 TI - The Use Fibrin Sealant after Spinal Intradural Tumor Surgery: Is It Necessary? AB - OBJECTIVE: A fibrin sealant is commonly applied after closure of an incidental or intended durotomy to reduce the complications associated with the leakage of cerebrospinal fluid. Routine usage might not be essential after closure of an intended durotomy, which has clear cut-margins. We investigated the efficacy of fibrin sealants for primary intradural spinal cord tumor surgery. METHODS: A retrospective review was performed for 231 consecutive surgically treated patients with primary intradural spinal cord tumors without extradural extension. Fibrin sealants were not used for 47 patients (group I: age, 51.57+/-16.75 years) and were applied to 184 patients (group II: age, 48.8+/-14.7 years). The surgical procedures were identical except for the use of a fibrin sealant after closure of the durotomy. The primary outcome was the occurrence of complications (wound problems, hematoma collection, infection, and neurological deterioration). The covariates were age, sex, body mass index, operation time, pre-/postoperative ambulation, number of laminectomies, and type of tumor. RESULTS: Schwannoma was the most common pathology (n=134), followed by meningioma (n=35) and ependymoma (n=31). Complications occurred in 13 patients (3 in group I and 10 in group II, p=0.73). The postoperative ambulation status (p<0.01; odds ratio, 28.8; 95% confidence interval, 6.9-120.0) and operation time (p=0.04; cutoff, 229 minutes; sensitivity, 62%; specificity, 72%) were significant factors, whereas the use of a fibrin glue was not (p=0.47). CONCLUSION: The use of a fibrin sealant might not be essential to reduce complications after surgery for primary spinal intradural tumor. PMID- 27123028 TI - Multiple Intradural Disc Herniations Masquerading as Intradural Extramedullary Tumors: A Case Report and Review of the Literature. AB - Intradural disc herniation is a very rare condition, and multiple intradural disc herniations have not been reported to date. The latter may be confused with intradural extramedullary (IDEM) spinal tumors. Here, we report a case of multiple intradural disc herniations masquerading as multiple IDEM tumors and review the relevant literature. We retrospectively reviewed the patient's medical chart, reviewed the intraoperative microscopic findings, and reviewed of PubMed articles on intradural disc herniation. The masses considered to be IDEM tumors were confirmed to be multiple intradural disc herniations. A nonenhancing mass was found to have migrated along the intra-arachnoid space. Two enhancing masses could not migrate because of adhesion and showed peripheral neovascularization. We report an extremely rare case of multiple intradural lumbar disc herniations showing diverse enhancing patterns and masquerading as multiple IDEM tumors. In case of multiple enhancing IDEM masses suspected preoperatively, surgeons should consider the possibility of intradural disc herniation. PMID- 27123029 TI - Concomitant Double Tumors of Myxopapillary Ependymoma Presented at Cauda Equina Filum Terminale in Adult Patient. AB - A 32-year-old man presented with gradually increasing bilateral buttock pain. He had intermittent claudication. Multiple, homogenously enhanced intradural extramedullary lesions at L2-L3 and L5-S1 levels were observed on magnetic resonance imaging. The tumors were debulked and were removed in piecemeal pattern until they had completely been resected. Histopathological examination of the surgical specimens confirmed that both tumors were myxopapillary ependymomas (MPE). MPE presenting as concomitant double tumor at conus-cauda-filum level are very rare. This kind of presentation could not be directly considered as dissemination, since both tumors were in the site of classical origin of MPE. Ten cases of double spinal MPEs have been reported to date. Including the present case, analysis of the 11 patients revealed some facts. There is a male predominance, which is opposite to the ependymomas that are commonly observed in females. Median age at presentation is 15 years. Most pronounced symptom is low back pain that sometimes radiates to lower extremities. Surgical approach was aimed in all tumors, which could be succeeded in all tumors except one. Adjuvant radiation therapy was applied in 5 patients. No recurrences have been reported after surgery or surgery + radiotherapy regimens. PMID- 27123030 TI - Enlargement of Neural Foramina and Dynamic Stabilization in Spondylolisthesis without Restoring the Alignment: Technical Note. AB - It is well known that the cause of radiculopathy is the compression of the nerve root within the foramina which is narrowed secondary to sliding of the corpus and reduced disc height. In some patients, unroofing the foramen does not resolve this problem. We described a new decompression technique using pedicle removal and transpedicular dynamic instrumentation to stabilization the spine. We performed this operation in 2 patients and achieved very good results. PMID- 27123031 TI - Analysis of Advantages and Disadvantages of the Location Methods of International Auricular Acupuncture Points. AB - The international standardization of auricular acupuncture points (AAPs) is an important basis for auricular therapy or auricular diagnosis and treatment. The study on the international standardization of AAPs has gone through a long process, in which the location method is one of the key research projects. There are different points of view in the field of AAPs among experts from different countries or regions. By only analyzing the nine representative location methods, this paper tried to offer a proper location method to locate AAPs. Through analysis of the pros and cons of each location method, the location method applied in the WFAS international standard of AAPs is thoroughly considered as an appropriate method. It is important to keep the right direction during developing an International Organization for Standardization (ISO) international standard of auricular acupuncture points and to improve the research quality of international standardization for AAPs. PMID- 27123032 TI - Formula Compatibility Identification of Dachengqi Decoction Based on the Effects of Absorbed Components in Cerulein-Injured Pancreatic AR42J Cells. AB - Objective. To identify the herbal formula compatibility law based on the effects of the absorbed components from DCQD on the cerulein-injured AR42J cells. Methods. AR42J cells were pretreated for 30 min with or without the different concentrations of the absorbed components from DCQD individually or in combination or DCQD and coincubated with cerulein (10 nM) for a further 24 h. Cell viability, lactate dehydrogenase (LDH) release, and the levels of apoptosis and necrosis were measured. Results. Compared to DCQD, the individual or combination components partially protected cerulein-injured AR42J cells by increasing cell viability, reducing LDH release, and promoting apoptosis. Rhein, naringin, and honokiol were the main absorbed components from DCQD in cerulein induced pancreatitis. Moreover, rhein in combination with naringin and honokiol had synergistic effects in protecting cerulein-injured AR42J cells and was better than the individual or the pairwise combination of the three components. Conclusions. The ten effective components from DCQD may elicit similar protective effects as DCQD on cerulein-induced pancreatitis. The principle of the formula compatibility of DCQD may be identified based on the effects of its absorbed components in cerulein-injured AR42J cells. PMID- 27123033 TI - Evaluating Emotional Well-Being after a Short-Term Traditional Yoga Practice Approach in Yoga Practitioners with an Existing Western-Type Yoga Practice. AB - The purpose of the present study was to examine the influence of a traditional yoga practice approach (morning daily practice, TY) compared to that of a Western yoga practice approach (once-twice weekly, evening practice, WY) on determinants of emotional well-being. To that end, in a pre/posttest between-subject design, measures of positive (PA) and negative affect (NA), mindfulness, perceived stress, and arousal states were taken in 24 healthy participants (20 women; mean age: 30.5, SD = 8.1 years) with an already existing WY practice, who either maintained WY or underwent a 2-week, five-times-per-week morning practice (TY). While WY participants maintained baseline values for all measures taken, TY participants showed significant beneficial changes for PA, NA, and mindfulness and a trend for improved ability to cope with stress at the completion of the intervention. Furthermore, TY participants displayed decreased subjective energy and energetic arousal. Altogether, findings indicate that the 2-week TY is beneficial over WY for improving perceived emotional well-being. The present findings (1) undermine and inspire a careful consideration and utilization of yoga practice approach to elicit the best benefits for emotional well-being and (2) support yoga as an evidence-based practice among healthy yoga practitioners. PMID- 27123034 TI - Asparagus cochinchinensis Extract Alleviates Metal Ion-Induced Gut Injury in Drosophila: An In Silico Analysis of Potential Active Constituents. AB - Metal ions and sulfate are components of atmospheric pollutants that have diverse ways of entering the human body. We used Drosophila as a model to investigate the effect of Asparagus cochinchinensis (A. cochinchinensis) extracts on the gut and characterized gut homeostasis following the ingestion of metal ions (copper, zinc, and aluminum). In this study, we found that the aqueous A. cochinchinensis extract increased the survival rate, decreased epithelial cell death, and attenuated metal ion-induced gut morphological changes in flies following chronic exposure to metal ions. In addition, we screened out, by network pharmacology, six natural products (NPs) that could serve as putative active components of A. cochinchinensis that prevented gut injury. Altogether, the results of our study provide evidence that A. cochinchinensis might be an effective phytomedicine for the treatment of metal ion-induced gut injury. PMID- 27123035 TI - Electroacupuncture Attenuates Cerebral Ischemia and Reperfusion Injury in Middle Cerebral Artery Occlusion of Rat via Modulation of Apoptosis, Inflammation, Oxidative Stress, and Excitotoxicity. AB - Electroacupuncture (EA) has several properties such as antioxidant, antiapoptosis, and anti-inflammatory properties. The current study was to investigate the effects of EA on the prevention and treatment of cerebral ischemia-reperfusion (I/R) injury and to elucidate possible molecular mechanisms. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. EA stimulation was applied to both Baihui and Dazhui acupoints for 30 min in each rat per day for 5 successive days before MCAO (pretreatment) or when the reperfusion was initiated (treatment). Neurologic deficit scores, infarction volumes, brain water content, and neuronal apoptosis were evaluated. The expressions of related inflammatory cytokines, apoptotic molecules, antioxidant systems, and excitotoxic receptors in the brain were also investigated. Results showed that both EA pretreatment and treatment significantly reduced infarct volumes, decreased brain water content, and alleviated neuronal injury in MCAO rats. Notably, EA exerts neuroprotection against I/R injury through improving neurological function, attenuating the inflammation cytokines, upregulating antioxidant systems, and reducing the excitotoxicity. This study provides a better understanding of the molecular mechanism underlying the traditional use of EA. PMID- 27123036 TI - Identification of "Multiple Components-Multiple Targets-Multiple Pathways" Associated with Naoxintong Capsule in the Treatment of Heart Diseases Using UPLC/Q-TOF-MS and Network Pharmacology. AB - Naoxintong capsule (NXT) is a commercial medicinal product approved by the China Food and Drug Administration which is used in the treatment of stroke and coronary heart disease. However, the research on the composition and mechanism of NXT is still lacking. Our research aimed to identify the absorbable components, potential targets, and associated pathways of NXT with network pharmacology method. We explored the chemical compositions of NXT based on UPLC/Q-TOF-MS. Then, we used the five principles of drug absorption to identify absorbable ingredients. The databases of PharmMapper, Universal Protein, and the Molecule Annotation System were used to predict the main targets and related pathways. By the five principles of drug absorption as a judgment rule, we identified 63 compositions that could be absorbed in the blood in all 81 chemical compositions. Based on the constructed networks by the significant regulated 123 targets and 77 pathways, the main components that mediated the efficacy of NXT were organic acids, saponins, and tanshinones. Radix Astragali was the critical herbal medicine in NXT, which contained more active components than other herbs and regulated more targets and pathways. Our results showed that NXT had a therapeutic effect on heart diseases through the pattern "multiple components multiple targets-multiple pathways." PMID- 27123037 TI - Bioactive Components of Chinese Propolis Water Extract on Antitumor Activity and Quality Control. AB - To understand the material basis of antitumor activity of Chinese propolis water extract (CPWE), we developed a simple and efficient method using macroporous absorptive resin coupled with preparative high performance liquid chromatography and separated and purified eleven chemical components (caffeic acid, ferulic acid, isoferulic acid, 3,4-dimethoxycinnamic acid, pinobanksin, caffeic acid benzyl ester, caffeic acid phenethyl ester, apigenin, pinocembrin, chrysin, and galangin) from CPWE; then we tested the antitumor activities of these eleven components using different human tumor cell lines (MCF-7, MDA-MB-231, HeLa, and A549). Furthermore, cell migration, procaspase 3 level, and reactive oxygen species (ROS) of effective components from CPWE were investigated. Our data showed that antitumor activities of the eleven components from CPWE were different from each other. CPWE and its effective components induced apoptosis by inhibiting tumor cell migration, activating caspase 3, and promoting ROS production. It can be deduced that the antitumor effects of propolis did not depend on a single component, and there must exist "bioactive components," which also provides a new idea for Chinese propolis quality control. PMID- 27123038 TI - Antiobesity Effects of the Combined Plant Extracts Varying the Combination Ratio of Phyllostachys pubescens Leaf Extract and Scutellaria baicalensis Root Extract. AB - The antiobesity effects of several different combinations of extracts (BS) prepared from two plants, Phyllostachys pubescens leaf (bamboo leaf: BL) and Scutellaria baicalensis root (SB), were investigated using a high fat diet (HFD) induced obese mouse model. In order to find the most effective mixture among the mixtures of the two plant extracts, experimental preparations were made by combining BL and SB by different proportions of 3 : 1 (BS31), 2 : 1 (BS21), 1 : 1 (BS11), 1 : 2 (BS12), and 1 : 3 (BS13). Body weight, weight of adipose tissues, size of adipocytes, levels of glucose, leptin and adiponectin, and lipid profile in serum, and fat accumulation in liver were investigated. We have found that BS21 is the most effective in antiobesity among the five mixtures investigated, indicated by reduction in body weight gain, total mass of adipose tissue, and the size of adipocyte. In addition, BS21 has shown to be beneficial in serum lipid profile, levels of glucose, leptin, and adiponectin in serum, and fat accumulation in liver. By chromatographic separation of BS21, the two maker compounds, isoorientin and baicalin, were identified and quantified for the standardization of BS21. PMID- 27123040 TI - An improved procedure for isolation of high-quality RNA from nematode-infected Arabidopsis roots through laser capture microdissection. AB - BACKGROUND: Cyst nematodes are biotrophs that form specialized feeding structures in the roots of host plants, which consist of a syncytial fusion of hypertrophied cells. The formation of syncytium is accompanied by profound transcriptional changes and active metabolism in infected tissues. The challenge in gene expression studies for syncytium has always been the isolation of pure syncytial material and subsequent extraction of intact RNA. Root fragments containing syncytium had been used for microarray analyses. However, the inclusion of neighbouring cells dilutes the syncytium-specific mRNA population. Micro sectioning coupled with laser capture microdissection (LCM) offers an opportunity for the isolation of feeding sites from heterogeneous cell populations. But recovery of intact RNA from syncytium dissected by LCM is complicated due to extended steps of fixation, tissue preparation, embedding and sectioning. RESULTS: In the present study, we have optimized the procedure of sample preparation for LCM to isolate high quality of RNA from cyst nematode induced syncytia in Arabidopsis roots which can be used for transcriptomic studies. We investigated the effect of various sucrose concentrations as cryoprotectant on RNA quality and morphology of syncytial sections. We also compared various types of microscopic slides for strong adherence of sections while removing embedding material. CONCLUSION: The use of optimal sucrose concentrations as cryoprotection plays a key role in RNA stability and morphology of sections. Treatment with higher sucrose concentrations minimizes the risk of RNA degradation, whereas longer incubation times help maintaining the morphology of tissue sections. Our method allows isolating high-quality RNA from nematode feeding sites that is suitable for downstream applications such as microarray experiments. PMID- 27123039 TI - Rubus crataegifolius Bunge regulates adipogenesis through Akt and inhibits high fat diet-induced obesity in rats. AB - BACKGROUND: Obesity is one of the greatest public health problems and major risk factors for serious metabolic diseases and significantly increases the risk of premature death. The aim of this study was to determine the inhibitory effects of Rubus crataegifolius Bunge (RCB) on adipocyte differentiation in 3 T3-L1 cells and its anti-obesity properties in high fat diet (HFD)-induced obese rats. METHODS: 3 T3-L1 adipocytes and HFD-induced obese rats were treated with RCB, and its effect on gene expression was analyzed using RT-PCR and Western blotting experiments. RESULTS: RCB treatment significantly inhibited adipocyte differentiation by suppressing the expression of C/EBPbeta, C/EBPalpha, and PPARgamma in the 3 T3-L1 adipocytes. Subsequently, the expression of the PPARgamma target genes aP2 and fatty acid synthase (FAS) decreased following RCB treatment during adipocyte differentiation. In uncovering the specific mechanism that mediates the effects of RCB, we demonstrated that the insulin-stimulated phosphorylation of Akt strongly decreased and that its downstream substrate phospho-GSK3beta was downregulated following RCB treatment in the 3 T3-L1 adipocytes. Moreover, LY294002, an inhibitor of Akt phosphorylation, exerted stronger inhibitory effects on RCB-mediated suppression of adipocyte differentiation, leading to the inhibition of adipocyte differentiation through the downregulation of Akt signaling. An HFD-induced obesity rat model was used to determine the inhibitory effects of RCB on obesity. Body weight gain and fat accumulation in adipose tissue were significantly reduced by the supplementation of RCB. Moreover, RCB treatment caused a significant decrease in adipocyte size, associated with a decrease in epididymal fat weight. The serum total cholesterol (TC) and triglyceride (TG) levels decreased in response to RCB treatment, whereas HDL cholesterol (HDL-C) increased, indicating that RCB attenuated lipid accumulation in adipose tissue in HFD-induced obese rats. CONCLUSION: Our results demonstrate an inhibitory effect of RCB on adipogenesis through the reduction of the adipogenic factors PPARgamma, C/EBPalpha, and phospho-Akt. RCB had a potent anti-obesity effect, reducing body weight gain in HFD-induced obese rats. PMID- 27123042 TI - Concordance of oral HPV prevalence between patients with oropharyngeal cancer and their partners. AB - BACKGROUND: Human papilloma virus (HPV) is a known causative factor in oropharyngeal squamous cell cancer (OPC). In this prospective study, we sought to define the risk of HPV transmission between OPC patients and their sexual partners by performing HPV genotyping on oral cytology brushings. METHODS: Newly diagnosed OPC patients and their sexual partners underwent oral mouth swabs and answered a risk factor questionnaire. Patient tumor samples and oral swabs from both the patient and partner were assessed for HPV status and genotyped using Easy-Chip HPV Blot PCR. RESULTS: We enrolled 227 patient-partner pairs and obtained sufficient analyzable DNA from both members in 198 pairs. Of 144 patients with available OPC tumor tissue, 128 (89 %) had HPV-positive tumors by either in situ hybridization or p16 immunohistochemical analysis (104 or 121, respectively). In total, there were 28 patients and 30 partners who were HPV positive by oral swab. The prevalence rate of oral HPV in partners was 15 %. There were 39 patient-partner pairs who had one or both members returning positive for HPV in the oral swab, and 49 % of these pairs were concordant for their HPV-genotype. Female partners had a higher oral HPV prevalence (16 %) than did male partners (11 %). Patients who were non-white were also found to have a higher oral prevalence of HPV (p = 0.032) by mouth swab. CONCLUSIONS: Partners of OPC patients may have a higher prevalence of oral HPV and should be studied prospectively to understand their OPC risk. Additional future research is needed to identify oral HPV persistence in partners to OPC patients and to determine the optimal sampling methods and technologies to screen patients at high risk for HPV related disease. PMID- 27123041 TI - Beyond Telomerase: Telomere Instability as a Novel Target for Cancer Therapy. AB - Telomeres are areas of heterochromatin composed of TTAGGG repeats located at the ends of linear chromosomes. They play a critical role in keeping genome stable and preventing premature aging diseases and the development of cancer. Characterizing mechanisms of telomere maintenance and understanding how their deregulation contributes to human diseases are therefore important for developing novel therapies. A key mechanism driving telomere maintenance and replicative immortality in cancer cells is telomere elongation by telomerase, and many emerging potential telomere-based therapies have focused on targeting telomerase components. By contrast, recent studies on telomere maintenance mechanism suggest that disrupting telomere stability by interfering with alternative mechanisms of telomere synthesis or protection may also yield new strategies for the treatment of cancer. This review will focus on emerging regulators of telomere synthesis or maintenance, such as G4 telomeric DNA, the CST complex, the t-loop, and shelterins, and discuss their potential as targets for anti-cancer chemotherapeutic intervention in the future. PMID- 27123043 TI - The relationship between parenting attitudes, negative cognition, and the depressive symptoms according to gender in Korean adolescents. AB - BACKGROUND: Parenting style is one potential contributor to the development of adolescents' cognitions, self-esteem and emotional problems. This study examined the relationship between maternal parenting attitudes and adolescents' negative cognitions, and depressive symptoms according to gender. METHODS: A total of 401 middle and high school students were recruited (i.e. 221 males and 180 females; mean age, 13.92 +/- 1.31 years). The Maternal Behavior Research Instrument assessed maternal parenting attitudes. Analyses examined the relationship between parenting attitudes and affective symptoms, with self-esteem and negative automatic thoughts as mediators of these relations. RESULTS: Maternal rejecting attitudes were positively associated with depressive symptoms via increasing negative autonomic thoughts and decreasing self-esteem among female adolescents. Among male adolescents, maternal rejecting attitudes were associated with low self-esteem, but they were not associated with depressive symptoms. CONCLUSIONS: Maternal parenting has a larger impact on the emotional adjustment of females compared to males. Interventions to increase self-esteem and correct negative cognitions may be helpful for depressed female adolescents, specifically for those whose mothers are rejecting. PMID- 27123044 TI - The major horse satellite DNA family is associated with centromere competence. AB - BACKGROUND: The centromere is the specialized locus required for correct chromosome segregation during cell division. The DNA of most eukaryotic centromeres is composed of extended arrays of tandem repeats (satellite DNA). In the horse, we previously showed that, although the centromere of chromosome 11 is completely devoid of tandem repeat arrays, all other centromeres are characterized by the presence of satellite DNA. We isolated three horse satellite DNA sequences (37cen, 2P1 and EC137) and described their chromosomal localization in four species of the genus Equus. RESULTS: In the work presented here, using the ChIP-seq methodology, we showed that, in the horse, the 37cen satellite binds CENP-A, the centromere-specific histone-H3 variant. The 37cen sequence bound by CENP-A is GC-rich with 221 bp units organized in a head-to-tail fashion. The physical interaction of CENP-A with 37cen was confirmed through slot blot experiments. Immuno-FISH on stretched chromosomes and chromatin fibres demonstrated that the extension of satellite DNA stretches is variable and is not related to the organization of CENP-A binding domains. Finally, we proved that the centromeric satellite 37cen is transcriptionally active. CONCLUSIONS: Our data offer new insights into the organization of horse centromeres. Although three different satellite DNA families are cytogenetically located at centromeres, only the 37cen family is associated to the centromeric function. Moreover, similarly to other species, CENP-A binding domains are variable in size. The transcriptional competence of the 37cen satellite that we observed adds new evidence to the hypothesis that centromeric transcripts may be required for centromere function. PMID- 27123045 TI - Chromosomes in a genome-wise order: evidence for metaphase architecture. AB - BACKGROUND: One fundamental finding of the last decade is that, besides the primary DNA sequence information there are several epigenetic "information layers" like DNA-and histone modifications, chromatin packaging and, last but not least, the position of genes in the nucleus. RESULTS: We postulate that the functional genomic architecture is not restricted to the interphase of the cell cycle but can also be observed in the metaphase stage, when chromosomes are most condensed and microscopically visible. If so, it offers the unique opportunity to directly analyze the functional aspects of genomic architecture in different cells, species and diseases. Another aspect not directly accessible by molecular techniques is the genome merged from two different haploid parental genomes represented by the homologous chromosome sets. Our results show that there is not only a well-known and defined nuclear architecture in interphase but also in metaphase leading to a bilateral organization of the two haploid sets of chromosomes. Moreover, evidence is provided for the parental origin of the haploid grouping. CONCLUSIONS: From our findings we postulate an additional epigenetic information layer within the genome including the organization of homologous chromosomes and their parental origin which may now substantially change the landscape of genetics. PMID- 27123047 TI - TLR7 agonist induced repression of hepatocellular carcinoma via the TLR7-IKK-NF kappaB-IL6 signaling pathway. AB - Toll-like receptors (TLRs) are key members of innate immunity, involved in the defense against diseases, and evidence has revealed that TLR4/5 is involved in the carcinogenesis of hepatic cancer. TLR7 belongs to the TLR family, and its roles in immune-associated hepatic diseases have been well characterized; however, the consequences of agonist targeting of TLR7 in hepatic cancer have not previously been reported. The present study aimed to investigate the effects and underlying mechanisms of Imiquimod, a TLR7 agonist, on hepatic carcinogenesis by affecting the self-renewal of hepatic cancer stem cells. To detect the effects of this TLR7 agonist on hepatic cancer cells an MTT assay, mammosphere formation assay, ALDEFLUORTM fluorescence-based stem cell sorting was used, and the potential signaling involved in the mechanism was investigated by western blot analysis. The TLR7 agonist Imiquimod demonstrated inhibitory effects on the cell proliferation and mammosphere formation of hepatic cells and stem cells, and decreased stem cell number (P<0.01). These effects may be achieved via the TLR7/IkappaB kinase/nuclear factor-kappaB/interleukin-6 signaling pathway, with decreased levels of Snail expression. The present study demonstrated the effects and mechanisms of the TLR7 agonist on hepatic cancer occurred via suppression of the self-renewal of cancer stem cells, indicating novel potential functions of the TLR7 agonist in the treatment of HCC. PMID- 27123046 TI - Lauren classification and individualized chemotherapy in gastric cancer. AB - Gastric cancer is one of the most common malignancies worldwide. During the last 50 years, the histological classification of gastric carcinoma has been largely based on Lauren's criteria, in which gastric cancer is classified into two major histological subtypes, namely intestinal type and diffuse type adenocarcinoma. This classification was introduced in 1965, and remains currently widely accepted and employed, since it constitutes a simple and robust classification approach. The two histological subtypes of gastric cancer proposed by the Lauren classification exhibit a number of distinct clinical and molecular characteristics, including histogenesis, cell differentiation, epidemiology, etiology, carcinogenesis, biological behaviors and prognosis. Gastric cancer exhibits varied sensitivity to chemotherapy drugs and significant heterogeneity; therefore, the disease may be a target for individualized therapy. The Lauren classification may provide the basis for individualized treatment for advanced gastric cancer, which is increasingly gaining attention in the scientific field. However, few studies have investigated individualized treatment that is guided by pathological classification. The aim of the current review is to analyze the two major histological subtypes of gastric cancer, as proposed by the Lauren classification, and to discuss the implications of this for personalized chemotherapy. PMID- 27123048 TI - Expression and mutation of c-Kit in intracranial germ cell tumors: A single centre retrospective study of 30 cases in China. AB - Although primary central nervous system (CNS) germ cell tumors (GCTs) are one of the most treatable types of malignant brain tumor, a subset of patients remain resistant to standard chemotherapy. Gain-of-function mutations of the c-Kit gene, and KIT protein expression, have been observed in a number of GCTs, including testicular seminoma, ovarian dysgerminoma and mediastinal seminoma in various ethnic groups. Although a small number of studies have reported the role of c-Kit in CNS GCTs, few have focused on Chinese patients exhibiting CNS GCTs. In the present study, the frequency and location of c-Kit mutations and KIT protein expression levels in CNS GCTs were investigated in 30 patients, between January 1994 and October 2014. Immunohistochemical assays suggested that KIT protein expression was present in 59.1% patients (66.7% in males and 42.9% in females); however, no statistically significant correlation was identified between KIT protein expression and patient clinicopathological features. By performing PCR amplification and direct sequencing, 4 mutational hot spots of the c-Kit gene (exons 9, 11, 13 and 17) were examined, and c-Kit gene mutation was identified in 1/17 (5.9%) CNS germinoma cases. This mutation was located in exon 11 at codon 557-558 WK (Tryptophan-Lysine). No c-Kit gene mutations were detected in non germinomatous GCTs. Imatinib, a tyrosine kinase inhibitor, may be an effective treatment against standard chemotherapy-resistant CNS germinoma patients exhibiting c-Kit mutations. PMID- 27123049 TI - Synchronous occurrence of gastrointestinal stromal tumor and acute myeloid leukemia: A case report and review of the literature. AB - Gastrointestinal stromal tumors (GISTs) originate from the mesenchymal tissue of the gastrointestinal tract. The pathogenesis of GIST is associated with the mutational activation of the receptor tyrosine kinase cluster of differentiation (CD)117 or platelet-derived growth factor receptor-alpha. Overall, ~60% of GISTs occur in the stomach. Clinically, GISTs may coexist with various types of cancer, including liver cancer, pancreatic tumors and lymphoma, either synchronously or metachronously. The present study reports the case of a patient with the synchronous occurrence of a CD117-positive GIST and acute myeloid leukemia. A 69 year-old man was hospitalized for heart palpitations and dizziness, and was diagnosed with acute myeloid leukemia (AML) by bone marrow aspiration and flow cytometry analysis. An abdominal computed tomograpy and gastroscopy revealed the presence of GIST. The patient received chemotherapy in combination with imatinib (400 mg/day), and the mass was removed 2 months later. To the best of our knowledge, the present study is the first reported case of the synchronous development of a CD117-positive GIST and AML. Additional studies are required in order to understand the association between GIST and hematological malignancies. PMID- 27123050 TI - Low-dose bevacizumab induces radiographic regression of vestibular schwannomas in neurofibromatosis type 2: A case report and literature review. AB - The current case study aimed to explore the efficacy of a low-dose bevacizumab regimen in inhibiting tumor growth and minimizing adverse effects. A 55-year-old man with neurofibromatosis type 2 (NF2) suffered bilateral vestibular schwannomas (VS) measuring 5.25 and 2.54 cm3 on the left and right, respectively. His capacity for bilateral language recognition was impaired. However, the patient refused microsurgical tumor resection and gamma knife therapy. Low-dose bevacizumab regimen (3.3-2.2 mg/kg every 2-4 weeks) was administered by intravenous injection for ~1.5 years to inhibit tumor growth and avoid further deterioration of hearing. Compared with baseline measurements prior to treatment, the bilateral VS regressed to 3.59 cm3 (68%) and 2.08 cm3 (82%) on the left and right, respectively. No hearing improvement was detected; however, the patient subjectively experienced a significant hearing improvement as his ability to communicate with people and distinguish voices was restored. No adverse effects were observed. Bevacizumab provides an alternative treatment option for those who refuse surgical intervention. Given the adverse effects commonly induced by bevacizumab, the use of a low-dose regimen would appear to be promising with regard to tumor regression and hearing preservation for patients with VS in NF2. However, the minimum dose required to sustain a response to bevacizumab in NF2 patients remains unknown. Finding the minimum effective dose sufficient to sustain hearing and/or volumetric response for individual patients is required. PMID- 27123051 TI - Derived neutrophil to lymphocyte ratio predicts prognosis for patients with HBV associated hepatocellular carcinoma following transarterial chemoembolization. AB - The derived neutrophil to lymphocyte ratio (dNLR) has been proposed as an easily determinable prognostic factor for cancer patients, but the prognostic significance of the dNLR in hepatocellular carcinoma (HCC) has not been investigated. The present study aimed to validate the prognostic power of the NLR and dNLR in HCC patients undergoing transarterial chemoembolization (TACE). The data of 279 consecutive patients who underwent TACE for unresectable HBV associated HCC between September 2009 and November 2011 at the Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center (Guangzhou, China) were retrieved from a prospective database. The cut-off values for the NLR and dNLR were determined by receiver operating characteristic (ROC) analysis. The association between the NLR and dNLR and the clinicopathological characteristics and overall survival (OS) rates and times of patients was analyzed. The area under the curve (AUC) was calculated to evaluate the discriminatory ability of the NLR and dNLR. The median follow-up period was 446 days, the 1, 2 and 3-year OS rates were 38.8, 18.5 and 11.1% respectively, and the median OS time was 264 days. The cut-off values were determined as 2.6 and 1.8 for the NLR and dNLR, respectively. The NLR and dNLR were each associated with patient age, presence of vascular invasion, tumor size, AST level and ALP level. Multivariate analysis showed that the NLR, dNLR, ALT level and AFP level were independent prognostic factors for OS. An elevated NLR or dNLR was associated with a poor prognosis (P=0.001 and P=0.002, respectively). The prognostic power of NLR [AUC=0.539; 95% confidence interval (CI), 0.423-0.656] and dNLR (AUC=0.522; 95% CI, 0.406-0.638) was similar. Elevated dNLR predicted poor prognosis for patients with HBV associated HCC undergoing TACE, with similar prognostic power to NLR. The dNLR may be used as an alternative to the NLR, as it is easily available and inexpensive. PMID- 27123052 TI - Prognostic significance of claudin-1 and cyclin B1 protein expression in patients with hypopharyngeal squamous cell carcinoma. AB - Claudin-l and cyclin B1 are abnormally expressed in certain malignancies, but their expression in hypopharyngeal squamous cell carcinoma (HSCC) has not been reported thus far. Studying the expression levels of claudin-1 and cylin B1 in HSCC tissues and their association with clinical stage, pathological grade and prognosis in patients with HSCC may provide a theoretical basis and guide future research on HSCC targeted therapy. The protein expression levels of the above two biomarkers was immunohistochemically detected in 97 HSCC cases and 90 matched adjacent tissue samples. The correlation between the expression levels of claudin 1 and cylin B1 and the patients' clinical parameters was analyzed via Pearson's chi2 test, while survival analysis was performed using a log-rank test. The results of the current study revealed that claudin-1 and cyclin B1 were highly expressed in HSCC tissues, and the expression of claudin-1 was associated with tumor differentiation degree and lymph node metastasis, while cyclin B1 expression was associated with tumor differentiation degree. Furthermore, Kaplan Meier analysis revealed that claudin-1 expression correlated with survival (P=0.003), and the expression levels of claudin-1 and cyclin B1 were observed to be positively correlated, in patients with HSCC. Cyclin B1 and claudin-1 exhibited an elevated expression in HSCC specimens, thus suggesting their use as tumor markers. Therefore, the joint detection of claudin-1 and cyclin B1 may aid to guide cancer therapy and to determine prognosis in HSCC. Furthermore, claudin 1 may be used as an HSCC-monitoring index, and may serve as a therapeutic target. PMID- 27123053 TI - Oxidored-nitro domain-containing protein 1 expression is associated with the progression of hepatocellular carcinoma. AB - Hepatocarcinogenesis is a stepwise process during which multiple genes are altered. Understanding the molecular mechanisms that induce hepatocarcinogenesis may improve the screening, prevention and treatment of patients with hepatocellular carcinoma (HCC). In recent years, the oxidored-nitro domain containing protein 1 (NOR1) gene has been identified to have an important role in the development of HCC in vitro experiments. The current study aimed to examine the expression of NOR1 mRNA and protein expression in specimens of normal liver, hepatitis, cirrhosis and HCC, together representing the process of HCC development. Furthermore, the association between NOR1 expression and clinicopathological parameters of HCC patients was analyzed. Tissue microarrays containing the specimens of human normal liver, hepatitis, cirrhosis and HCC were purchased, and in situ hybridization and immunohistochemistry were used to detect the expression of NOR1 mRNA and protein expression, respectively. It was revealed that the positive rate of NOR1 protein and mRNA expression in the specimens of hepatitis and cirrhosis were not significantly different from that in the normal liver samples. However, the specimens of HCC exhibited an increased positive rate of NOR1 protein and mRNA expression in comparison with the normal liver samples. In addition, a higher positive rate of NOR1 protein expression was observed in HCC patients with a poor pathological differentiation grade and high tumor node metastasis (TNM) stage. In conclusion, the present study provides evidence, for the first time, of the increased expression of NOR1 in human HCC tissues, and its correlation with the pathological stage and TNM status. These findings indicate that NOR1 may be involved in the progression of HCC and it could be employed as a predictive biomarker in HCC development. PMID- 27123054 TI - Identification of potential therapeutic target genes and mechanisms in head and neck squamous cell carcinoma by bioinformatics analysis. AB - The present study aimed to identify the potential target genes and underlying molecular mechanisms involved in head and neck squamous cell carcinoma (HNSCC) by bioinformatics analysis. Microarray data of a Gene Expression Omnibus series GSE6631 was downloaded from the Gene Expression Omnibus database, which was generated from paired samples of HNSCC and normal tissue from 22 patients, and was used to identify differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to investigate the functions of the identified DEGs. Furthermore, the protein protein interaction (PPI) network of these DEGs was constructed using Cytoscape software. Between HNSCC and normal samples there was a difference in 419 DEGs, including 196 upregulated and 223 downregulated genes. The upregulated DEGs were mainly enriched in GO terms of cell adhesion, extracellular matrix (ECM) organization and collagen metabolic process, while the downregulated DEGs were mainly associated with epidermis development and epidermal cell differentiation. The DEGs were enriched in pathways such as ECM-receptor interaction, focal adhesion and drug metabolism. Fibronectin 1 (FN1), epidermal growth factor receptor (EGFR), collagen type I alpha 1 (COL1A1) and matrix metallopeptidase-9 (MMP-9) were hub nodes in the PPI network. These results suggested that cell adhesion and drug metabolism may be associated with HNSCC development, and genes such as FN1, EGFR, COL4A1 and MMP-9 may be potential therapeutic target genes in HNSCC. PMID- 27123055 TI - Effects of resveratrol on the proliferation, apoptosis and telomerase ability of human A431 epidermoid carcinoma cells. AB - The aim of the present study was to investigate the effect of resveratrol on cell apoptosis, ability of telomerase and the human telomerase reverse transcriptase (hTERT) protein expression in human A431 epidermoid carcinoma cells. A431 cells were treated with different concentrations of resveratrol, and the cell appearance was then observed under a microscope. In addition, the cell proliferation was examined using an MTT assay, and the ability of telomerase was detected using telomeric repeat amplification protocol-polymerase chain reaction ELISA. Resveratrol significantly inhibited the ability of telomerase and decreased the expression of hTERT protein in a concentration-dependent manner. In conclusion, resveratrol is capable of downregulating the expression of hTERT protein and inhibits the ability of telomerase of A431, which is an important mechanism of action of resveratrol with regard to inhibition of A431 cell proliferation. PMID- 27123056 TI - Reflectance confocal microscopy and dermoscopy for in vivo, non-invasive skin imaging of superficial basal cell carcinoma. AB - Superficial basal cell carcinoma (sBCC) is the second most frequent histological type of basal cell carcinoma (BCC), usually requiring a skin biopsy to confirm the diagnosis. It usually appears on the upper trunk and shoulders as erythematous and squamous lesions. Although it has a slow growth and seldom metastasizes, early diagnosis and management are of crucial importance in preventing local invasion and subsequent disfigurement. Dermoscopy is nowadays an indispensable tool for the dermatologist when evaluating skin tumors. Reflectance confocal microscopy (RCM) is a novel imaging technique that allows the non invasive, in vivo quasi-microscopic morphological and dynamic assessment of superficial skin tumors. Moreover, it offers the advantage of performing infinite repeatable determinations to monitor disease progression and non-surgical treatment for sBCC. Herein, we present three lesions of sBCC evaluated using in vivo and non-invasive imaging techniques, emphasizing the usefulness of combining RCM with dermoscopy for increasing the diagnostic accuracy of sBCC. PMID- 27123057 TI - Efficacy of microwave ablation for the treatment of endometrial carcinoma: A report of 3 cases. AB - Microwave endometrial ablation (MEA) is effective for the emergency control of uterine hemorrhage. However, to the best of our knowledge, there has been only a single report of life-threatening hemorrhage induced by endometrial carcinoma that was treated with MEA. The present report evaluates the efficacy of MEA as an emergency therapeutic option for the control of bleeding due to advanced endometrial carcinoma and minimally-invasive, early-stage endometrial carcinoma in 3 patients. MEA was able to effectively control massive uterine bleeding due to endometrial carcinoma in 2 patients with advanced disease and was curative in a patient with minimally-invasive endometrial carcinoma. Given its safety, simplicity and effectiveness, MEA may be utilized for the emergency treatment of uterine bleeding in advanced endometrial carcinoma, and may be used as a curative treatment in early-stage endometrial carcinoma. PMID- 27123058 TI - Suppression of human epidermal growth factor receptor 2 via interference increases the chemosensitivity of ovarian carcinoma. AB - The function of human epidermal growth factor receptor 2 (HER2) in the chemosensitivity of ovarian carcinoma has not been fully investigated, therefore, the present study aimed to analyze the potential role of HER2 in ovarian carcinoma chemosensitivity in further detail. SKOV3 cells were transfected with lentiviral-mediated HER2-small hairpin RNA (shRNA) molecules to establish the stable expression of HER2-shRNA in the SKOV3 cell line (knockdown cells; KD) and negative control cell line (NC). The untransfected SKOV3 cell line served as the blank control (CON) group. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect the expression of HER2 in the three different cell types, which were subsequently examined for growth inhibition using a cell counting kit-8 assay. The CON and KD cell strains were utilized to establish xenograft models in nude mice, primarily to detect the expression of the HER2 protein, and additionally to observe tumor size changes under the treatment of cisplatin (DDP) chemotherapy. RT-qPCR and western blot analysis demonstrated a significant decrease in the levels of HER2 mRNA and protein in the KD cells. The suppression of HER2 expression resulted in an increase of chemotherapy sensitivity in the SKOV3 cells. HER2 protein expression decreased significantly following transduction with specific HER2-shRNA. Additionally, growth slowed significantly under treatment with DDP in ovarian cancer transplantation tumors. In conclusion, lentivirus-mediated HER2-shRNA effectively inhibits the expression of the HER2 gene, and increases the chemosensitivity to DDP in ovarian carcinoma. PMID- 27123059 TI - Co-expression of pregnane X receptor and ATP-binding cassette sub-family B member 1 in peripheral blood: A prospective indicator for drug resistance prediction in non-small cell lung cancer. AB - The aim of the present study was to investigate the protein expression profiling of pregnane X receptor (PXR) and ATP-binding cassette sub-family B member 1 (ABCB1; also known as MDR1 or P-gp), present in the peripheral blood mononuclear cells (PBMCs) and cancerous tissues of cases of non-small cell lung cancer (NSCLC). Furthermore, the study aimed to assess the feasibility of predicting drug resistance through the medium of PBMCs. Of the subjects included in the study, 37 were histopathologically diagnosed with NSCLC and 17 were control patients without cancer. ThinPrep liquid-based smears with cytosine were applied in the examination of the PBMCs and proved quite effective in preserving the morphology and surface antigens of the lymphocytes. Measurements of expression levels in the PBMCs and cancerous tissues were obtained by immunohistochemical means. The results showed that, with the exception of the selective PXR expression in the normal lung tissues, the two types of proteins existed extensively throughout the PBMCs, normal tissues and tumors. Among the cancer patients, prior to chemotherapy, a significant rise in ABCB1 expression could be observed in the PBMCs, together with a similar rise in ABCB1 and PXR expression in the tumor specimens. Marked upregulation of the two proteins was detected in the PBMCs following 1 cycle of first-line chemotherapy. ABCB1 expression, correlated with PXR, persisted mostly in the PBMCs and tissue samples. When bound to and activated by ligands, PXR translocates from the cytoplasm to the nucleus of the cells. PXR subsequently binds to its DNA response elements as a heterodimer with the retinoid X receptor. A PXR translocation of moderate or low differentiation was identified in 3 cases of adenocarcinoma, which were co expressing the two genes in the PBMCs prior to chemotherapy. During follow-up visits, tumor recurrence was observed within 3 months in 5 cases, which were characterized by PXR translocation. These findings indicate that the combined expression of PXR and ABCB1 in PBMCs may be used as a prospective indicator in diagnosis prior to histopathological diagnosis, and therefore may function as a novel biomarker for the prediction of drug resistance. PMID- 27123060 TI - Expression and regulatory effects of microRNA-182 in osteosarcoma cells: A pilot study. AB - The aim of the present study was to evaluate the expression level of microRNA-182 (miRNA-182) in human osteosarcoma (OS) MG-63 cells and OS tissues, and to elucidate the effect of miRNA-182 on the biological activity of tumors. In the present study, the expression of miRNA-182 in human OS MG-63 cells, OS tissues and normal osteoblast hFOB1.19 cells was determined using quantitative polymerase chain reaction. Subsequently, a miRNA-182 mimic and inhibitor were utilized to regulate the expression level of this miRNA in MG-63 cells. Cell viability and proliferation were examined using cell counting kit-8 assays, and cell apoptosis was detected by flow cytometry. Cell invasion and migration assays were performed using Transwell chambers to analyze the biological functions of miRNA-182 in vitro. The present study demonstrated that the expression level of miRNA-182 in MG-63 cells and OS tissues was significantly increased compared with the hFOB1.19 cell line (P<0.05). The present study successfully performed cell transfections of miRNA-182 inhibitor and miRNA-182 mimic into MG-63 cells and achieved the desired transfection efficiency. The present study confirmed that upregulation of miRNA-182 promotes cell apoptosis and inhibits cell viability, proliferation, invasion and migration. The present findings additionally demonstrated that miRNA 182 is a tumor suppressor gene in OS. Therefore, regulating the expression of miRNA-182 may affect the biological behavior of OS cells, which suggests a potential role for miRNA-182 in molecular therapy for malignant tumors. PMID- 27123061 TI - Pulmonary mucormycosis: A case report and review of the literature. AB - The current study reports the case of a 15-year-old male who presented to The First Affiliated Hospital of Soochow University (Suzhou, Jiangsu, China) with a 3 day history of anergy and epistaxis. The patient was diagnosed with T-cell acute lymphoblastic leukemia according to the results of a bone marrow examination and received chemotherapy. During the agranulocytosis period, the patient developed pneumonia of the right upper lung (RUL). Once complete remission was achieved, the patient underwent a lobectomy of the RUL, together with amphotericin B therapy, following the confirmation of pulmonary mucormycosis by the histopathological results. The patient experienced 12 months of uneventful follow up post-surgery. PMID- 27123063 TI - Thoracoscopic resection of bulky thymoma assisted with artificial pneumothorax: A report of 19 consecutive cases. AB - The aim of the present study was to examine the feasibility and efficacy of thoracoscopic radical resection of large retrosternal thymoma using artificial pneumothorax. A retrospective analysis was performed on 19 patients with bulky thymoma who underwent thoracoscopic resection using artificial pneumothorax by CO2 insufflation. The operations were performed with unilateral or bilateral thoracic incisions via single lumen endotracheal intubation and two-lung ventilation. This approach provided excellent exposure of the thoracic cavity and reliable control of the neuro-vascular structures in the anterior mediastinum, which was of vital importance for the extended resection of malignant thymoma. The operation time was 140.0+/-51.4 min without conversion to thoracotomy or sternotomy. The pathological diagnosis was confirmed by immunohistochemistry, including 5 cases of thymus lipomyoma, 1 case of thymus hyperplasia, 1 case of thymus cyst, 2 cases of type AB thymoma, 4 cases of type B1 thymoma, 4 cases of type B3 thymoma, and 2 cases of thymic carcinoma. Furthermore, there were no complications such as recurrent laryngeal nerve injury, phrenic nerve injury, pulmonary infection or atelectasis, with a hospital stay of 5.0+/-3.0 days. In conclusion, the thoracoscopic resection of thymoma using artificial pneumothorax is a preferable approach, that may be considered for patients with bulky retrosternal tumors. PMID- 27123062 TI - Effects of TLR4 gene silencing on the proliferation and apotosis of hepatocarcinoma HEPG2 cells. AB - Toll-like receptors (TLRs) are key factors in the innate immune system and initiate an inflammatory response to foreign pathogens, such as bacteria, fungi and viruses. TLR4-mediated signaling has been implicated in tumor cell proliferation and apoptosis in numerous cancers. The present study aimed to investigate the biological effect of TLR4 on the proliferation and apoptosis of human liver cancer cells and the mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown. Three TLR4 small interfering (si)RNA constructs, consisting of TLR4-siRNA-1, TLR4-siRNA-2 and TLR4-siRNA-3, were transiently transfected into HepG2 cells using Lipofectamine 2000. TLR4 knockdown was confirmed using reverse transcription-polymerase chain reaction and western blotting. The effect of the TLR4 siRNA on tumor cell proliferation was monitored by methyl thiazolyl tetrazolium assay and cell apoptosis was observed by flow cytometry. The expression of TLR4-associated proteins, consisting of myeloid differentiation primary response 88 (MyD88), Toll-interleukin-1R-domain containing adapter-inducing interferon-beta (TRIF), interferon regulatory factor 3 (IRF3), nuclear factor (NF)-kappaB, NF-kappaB inhibitor alpha (IkappaBalpha), phosphorylated IkappaBalpha (p-IkappaBalpha), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), was detected by western blot analysis. TLR4-siRNA-1 had the strongest knockdown effect and inhibited TLR4 messenger RNA and protein expression. TLR4 knockdown with TLR4-siRNA-1 reduced cell proliferation and promoted cell apoptosis. MyD88, TRIF, IRF3, IkappaBalpha, JNK and ERK were markedly suppressed in the cells transfected with TLR4 siRNA. However, nuclear expression of NF-kappaB and p-IkappaBalpha increased in HepG2 cells with TLR4 gene knockdown. The present study revealed that TLR4-mediated signaling plays a key role in the proliferation and apoptosis of cultured hepatocarcinoma cells. Therefore, RNA interference-directed targeting of TLR4 may raise the potential of the application of TLR4 knockdown for liver cancer therapy. PMID- 27123064 TI - Pathological complete response rate in hormone receptor-negative breast cancer treated with neoadjuvant FEC, followed by weekly paclitaxel administration: A retrospective study and review of the literature. AB - While tumor size, the presence of inflammatory carcinoma and lymph node involvement are the main prognostic factors of women with locally advanced breast cancer, the prognostic value of the estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) status has not been fully clarified. The present study examined the therapeutic efficacy of a neoadjuvant fluorouracil, epirubicin and cyclophosphamide regimen (FEC), followed by weekly paclitaxel and/or trastuzumab administration, in the treatment of hormone receptor-negative breast cancer patients. Between April 2012 and February 2014, 14 patients with hormone receptor-negative local breast cancer (triple-negative type, 9 patients; HER2 type, 5 patients) were included in the study. In all cases, the histological type of the primary cancer was invasive ductal carcinoma. Among the 14 women who received the regimen, 5 presented with stage I cancer (35.7%), 3 with stage IIA (21.4%), 3 with stage IIB (21.4%), 1 with stage IIIB (7.1%) and 2 with stage IIIC (14.3%), according to the American Joint Committee on Cancer staging system. With regard to the tumor-node-metastasis classification, 5 patients were T1N0M0 (35.7%), 3 were T2N0M0 (21.4%), 3 were T2N1M0 (21.4%), 2 were T3N3M0 (14.3%) and 1 was T4N1M0 (7.1%). The pathological response was evaluated using resected tissue following neoadjuvant chemotherapy, according to the criteria established by the Japanese Breast Cancer Society. Patients were classified into pathological responders (grades 2 and 3, 71.4% of all patients) and non-responders (grade 1, 28.6% of all patients). A pathological complete response (pCR) was achieved in 50.0% of all cases (7/14); 44.4% of triple-negative-type cases (4/9) and 60.0% of HER2-type cases (3/5). Hematological and non-hematological toxicity was reversible and manageable. No patients withdrew from treatment, and favorable compliance was achieved. The present study demonstrated that neoadjuvant FEC followed by weekly administration of paclitaxel and/or trastuzumab induces a high pathological response and a high pCR rate in patients with hormone receptor-negative breast cancer. Due to the high clinical benefit rate and acceptable safety profile, this regimen should be considered an acceptable neoadjuvant treatment option for hormone receptor negative breast cancer. PMID- 27123065 TI - Radiation recall dermatitis occurring 6 years and 4 months after breast conserving surgery: A case report. AB - Currently in Japan, breast-conserving therapy, consisting of breast-conserving surgery and post-operative radiation therapy, is performed frequently for the treatment of invasive breast cancer. It has been demonstrated that radiation therapy not only prevents recurrence in the preserved breast, but that it also contributes to improved patient survival. The present study describes the case of a 37-year-old woman with radiation recall dermatitis that occurred 6 years and 4 months after breast-conserving surgery. Erythema with a relatively distinct border was observed at the irradiated site on the left breast; eczema was diagnosed by a dermatologist. Inflammatory breast cancer was ruled out, since chest X-ray, abdominal ultrasound and bone scintigraphy were negative. Following ~1 month of topical corticosteroid application and oral second generation antihistamine treatment, the erythema was alleviated and the subjective symptoms also disappeared. Only a few cases of radiation recall dermatitis have been described in the fields of radiology and dermatology, but not yet in the surgical field. In the future, the incidence of radiation recall dermatitis is predicted to increase due to the increasing number of patients undergoing breast-conserving therapy. Whether in the surgical, radiological or dermatological field, if erythema is detected at the irradiated site during post-operative follow-up, routine care should be provided, keeping in mind the possibility of radiation recall dermatitis and inflammatory breast cancer. PMID- 27123066 TI - Apigenin suppresses colorectal cancer cell proliferation, migration and invasion via inhibition of the Wnt/beta-catenin signaling pathway. AB - Abnormal activation of the Wnt/beta-catenin signaling pathway has a significant role in human tumorigenesis. The search for potential anticancer drugs has included widespread screening of inhibitors of the Wnt signaling pathway. Recently, one of the most common flavonoids, apigenin, demonstrated potential anti-tumor effects on multiple human cancer cell lines, with low cytotoxicity and no mutagenic activity. However, the association between apigenin and the Wnt/beta catenin signaling pathway remains to be elucidated. The results of wound healing and Transwell invasion assays revealed that apigenin was able to significantly suppress colorectal cancer cell proliferation, migration and invasion in a dose dependent manner. An organoid culture assay revealed that apigenin was also able to suppress the growth of intestinal organoids. Furthermore, apigenin inhibited beta-catenin/T-cell factor/lymphoid enhancer factor signaling activation, which was induced by LiCl in a dose-dependent manner. This inhibited beta-catenin nuclear entry, and therefore the expression of Wnt downstream target genes. In conclusion, apigenin significantly suppressed colorectal cancer cell proliferation, migration, invasion and organoid growth by inhibiting the Wnt/beta catenin signaling pathway. PMID- 27123067 TI - Clinical pathology of metastatic gastric carcinoma to the breast: A report of two cases and a review of literature. AB - The breast is an unusual site for metastasis from a gastric carcinoma. The present study reports two cases of metastatic gastric carcinoma to the breast. The first patient, a 37-year-old woman, initially presented with gastric adenocarcinoma, prior to developing metastatic cancer to the breast 4 years later. The second female patient presented with a breast mass, and a modified radical mastectomy was performed; however, the subsequent pathological examination revealed the mass to be a metastatic signet ring cell carcinoma. An abdominal computed tomography scan revealed a diffuse gastric wall thickening that was consistent with gastric cancer. The findings suggest that immunohistochemistry is a useful tool to differentiate between primary breast tumors and gastrointestinal carcinomas that have metastasized to the breast. Additional studies are required in order to define the optimal treatment. PMID- 27123068 TI - Primary diffuse large B-cell lymphoma of the central nervous system: A case report and literature review. AB - The present study reports the clinical diagnosis and management of a patient with primary diffuse large B-cell lymphoma (Bcl) of the central nervous system (CNS). Making an early diagnosis of primary diffuse large Bcl is challenging due to the variable and complicated clinical manifestations of the disease. The relevant literature was reviewed, and high-dose methotrexate, whole brain radiotherapy and highly active antiretroviral therapy was recommended for the patient. The present study elucidates the role of positron emission tomography-computed tomography scans for the diagnosis and management of primary diffuse large Bcl of the CNS, and demonstrates the importance of resection surgery in the management of the disease. Specifically, the present study proposes that resection surgery may be applied in the early stages of disease for patients with a single occupied lesion and increased intracranial pressure. PMID- 27123069 TI - The progression of CD56+ myeloid sarcoma: A case report and literature review. AB - The current study presents a case of cluster of differentiation (CD)56+ myeloid sarcoma in a patient that initially presented with skin lesions, and provides evidence for the clinical and differential diagnosis of myeloid sarcoma. The patient of the present case report was a 65-year-old man who was admitted to hospital with a six-month history of bilateral purple-red papules and nodules, which were present on the upper limbs of the patient and had spread over his whole body one month prior to admission to the hospital. Pathological examination demonstrated a diffuse infusion of primitive round cells at the papillary dermis and subcutaneous tissues. The infiltrated cells were 40-60 um in diameter and morphologically identical. Immunohistochemical examination revealed that the cells expressed myeloperoxidase, CD56, CD43 and T-cell intracytoplasmic antigen. In addition, several cells expressed CD34, and 90% of the cells expressed Ki67. While the majority of cells in myeloid sarcoma do not express CD56, the present case was a myeloid sarcoma that expressed CD56, which is extremely rare. The sarcoma in the present patient progressed rapidly, and the patient died eight months following the onset of disease. Clinicians should be aware of CD56+ myeloid sarcoma, which is easily misdiagnosed and inappropriately treated. Consequently, myeloid sarcoma may have a high malignancy and poor outcome for patients. PMID- 27123070 TI - Malignant transformation of an epidermoid cyst in the temporal and prepontine region: Report of a case and differential diagnosis. AB - Malignant transformation of an epidermoid cyst is rare. The current report presents a case of a 55-year-old female patient with squamous cell carcinoma arising from a benign epidermoid cyst in the left temporal region and prepontine area. She had undergone subtotal resection of an epidermoid cyst 7 months previously. Preoperative imaging findings included a focal enhancing area adjacent to the lesion. Postoperative computed tomography demonstrated an increase in the size of the enhancing area. The patient underwent removal of the lesion and postoperative histological examination revealed a squamous cell carcinoma possibly arising from the epidermoid cyst. Accurate diagnosis of malignant transformation prior to operation is difficult; however, the possibility of an intracranial epidermoid cyst must be considered if a focally enhancing area is visible. Postoperative histological examinations may be used to determine a definite diagnosis, and accurate diagnosis is important for planning a rational therapeutic strategy. PMID- 27123071 TI - alpha-fetoprotein-producing gastric carcinoma: A case report of a rare subtype and literature review. AB - alpha-fetoprotein (AFP)-producing gastric carcinoma is a rare type of gastric cancer, and the characteristics have not yet been fully elucidated. The present study reports the case of a patient with this type of gastric cancer. A 66-year old male was referred to the Department of Gastrointestinal Surgery, Qianfoshan Hospital, Shandong University (Jinan, China) with a 20-day history of retrosternal pain. A computed tomography (CT) scan revealed a thickening of the wall of the cardia and massive lymph node swelling in the region of the lesser curvature of the stomach. A laboratory investigation revealed that the serum AFP levels of the patient were elevated to 46.49 ng/ml (normal level, <12.00 ng/ml), and the serum carcinoembryonic antigen (CEA) levels were 382.22 ng/ml (normal range, <5.00 ng/ml). An endoscopy revealed an elevated tumor and AFP-producing gastric cancer was diagnosed. As the tumor was surgically unresectable, the patient received systemic adjuvant chemotherapy [consisting of 1 cycle of oxaliplatin (150 mg; day 1)-fluorouracil(1.0 g; days 2-6)-calcium folinate (0.3 g; days 2-6), 4 cycles of paclitaxel (80 mg; day 1 and 8, repeated day 21) and capecitabine (1,000 g/m2, twice daily; days 1-14, repeated day 21), and 2 cycles of oxaliplatin (130 mg/m2; day 1, repeated day 21) and S-1 (100 mg/d; day 1- day 14; repeated day 21)]. During the chemotherapy intermission, the patient experienced partial remission; the serum AFP levels remained between 44.5 and 32.7 ng/ml, and serum CEA levels decreased to a normal level. The CT scan revealed that the enlarged lymph nodes of the patient had decreased in size. During the preoperative examinations, an abdominal CT scan revealed no metastasis to the liver. A radical gastrectomy was performed on October 20, 2014. Additionally, the tumor did not demonstrate the diffusion of AFP. The histopathological examination revealed a poorly differentiated adenocarcinoma, with local and neuroendocrine differentiation and no hepatoid features. According to these histopathological findings, the tumor was diagnosed as AFP-producing non hepatoid adenocarcinoma of the stomach. The patient was treated with systemic immunity-enhancing therapy and has been free of recurrence for 2 months. The present study describes a rare case of AFP-producing non-hepatoid adenocarcinoma of the stomach, with a review of the literature and an investigation of the clinical features. PMID- 27123072 TI - Computed tomography and magnetic resonance features of intracranial hemangioendothelioma: A study of 7 cases. AB - The current study aimed to present the neuroradiological and histopathological features of intracranial hemangioendothelioma (HE). The computed tomography (CT; n=3) and magnetic resonance imaging (MRI; n=7) features, and the clinical presentations of 7 patients with pathologically documented HEs were retrospectively analyzed. Lesions were observed in the right side of the skull (the frontal bone in 1 patient and the parietal bone in 1 patient), the tentorium (2 patients), the cerebral falx (1 patient), the right cavernous sinus (1 patient) and the right temporal lobe (1 patient). The tumor was lobulated in 5 cases and round in 2 cases. The majority of tumors appeared isointense or hypointense with multiple scattered hyperintensities on T1-weighted MRI. Moreover, the lesions appeared as inhomogeneous hyperintense regions with multiple enlarged and tortuous blood flow voids on T2-weighted MRI. The lesions also showed marked gadolinium enhancement in a honeycomb pattern. CT scan results showed a isoattenuation region (32-47 HU), with numerous small, round, high density foci. The 2 cases with skull lesions presented with local bone destruction and discontinuous bone lines of the tabula interna ossis cranii. In 1 case, MR angiography revealed abnormal vessels in the basilar region. A total of 4 cases were epithelial HE, 2 were retiform HE and 1 was kaposiform HE. Histological examination revealed endothelial cell proliferation with vascular lesions and a mucous matrix or dense fibrous mesenchyme. In conclusion, intracranial HE is rare, but should be considered in the differential diagnosis when evaluating intracranial neoplasms. A well-defined lobulated mass and imaging features that include internal heterogeneity, small scattered hemorrhages and thromboses, signal voids of vessels, and marked and delayed enhancement may confirm the diagnosis of HE. PMID- 27123073 TI - Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling. AB - Breast cancer remains a major public health problem worldwide. Chemotherapy serves an important role in the treatment of breast cancer. However, resistance to chemotherapeutic agents, in particular, multi-drug resistance (MDR), is a major cause of treatment failure in cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. Pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, has been shown to possess antitumor, anti-inflammatory, antioxidant and insecticidal properties. The aim of the present study was to investigate whether pristimerin can override chemoresistance in MCF-7/adriamycin (ADR)-resistant human breast cancer cells. The results demonstrated that pristimerin indeed displayed potent cytocidal effect on multidrug-resistant MCF-7/ADR breast cancer cells, and that these effects occurred through the suppression of Akt signaling, which in turn led to the downregulation of antiapoptotic effectors and increased apoptosis. These findings indicate that use of pristimerin may represent a potentially promising approach for the treatment of ADR-resistant breast cancer. PMID- 27123074 TI - Primary adrenal sarcomatoid carcinoma metastatic to the lung: Case report and review of the literature. AB - Adrenal sarcomatoid carcinoma is a rare adrenal carcinoma. To the best of our knowledge, only 11 cases have been reported since 1987. Adrenal sarcomatoid carcinoma presents a diagnostic challenge due to its atypical symptoms and histological patterns. At the time of diagnosis, a large percentage of patients are already at the metastatic stage and succumb within a few months. The present study reports a case of a 59-year-old man presenting with asthenia and weight loss with adrenal sarcomatoid carcinoma metastatic to the lung. A computed tomography (CT) scan and ultrasonography of the patient's abdomen suggested a large homogeneous mass in the right adrenal gland, and a CT scan of his chest suggested lung metastasis. Right adrenalectomy was performed. Histological examination revealed that the tumor was composed of sarcomatous and carcinomatous differentiation elements. Immunohistochemical examination revealed tumor cell positivity for vimentin and cytokeratin. At the 6-month follow-up the patient exhibited no disease progression and refused further proposed treatment. The patient was alive at the time of writing the current report. The present case report additionally reviews the literature, for the purpose of raising awareness of these rare lesions and assisting in achieving accurate diagnoses and effective treatment. PMID- 27123075 TI - Downregulation of SASH1 correlates with tumor progression and poor prognosis in ovarian carcinoma. AB - SAM- and SH3-domain containing 1 (SASH1) is a recently identified tumor suppressor gene that is required in the tumorigenesis of breast and other solid carcinomas. The SASH1 protein contains SH3 and SAM domains, indicating that it may serve an important role in intracellular signal transduction. The purpose of the present study was to investigate the expression of SASH1 in ovarian carcinoma and the correlation between its expression with clinical pathological features and clinical significance, and the effect of SASH1 on cell proliferation, apoptosis and migration of ovarian SKOV3 cells. The human ovarian carcinoma tissues and adjacent normal tissues were collected following surgery. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to detect the expression levels of SASH1 mRNA and protein, respectively. The expression levels of SASH1 mRNA and protein in ovarian carcinoma tissues were significantly lower than that observed in adjacent normal tissues (P<0.05). The expression levels of SASH1 in samples from patients without lymph nodes metastasis and patients with early FIGO stage was lower than those with lymph nodes metastasis and patients with advanced FIGO stage (P<0.05). Flow cytometry analysis and Transwell invasion chamber experiments were used to investigate the effect of SASH1 on the cell proliferation, apoptosis and migration of SKOV3 cells. The recombinant plasmid pcDNA3.1-SASH1 was constructed and transfected into SKOV3 cells. In addition, the SKOV3 cells in the pcDNA3.1 SASH1 group exhibited significantly reduced cell growth, proliferation, and migration ability compared to the empty vector group and normal group (P<0.01). There were a greater number of apoptotic cells in the pcDNA3.1-SASH1 group compared to the empty vector group and normal group (P<0.01). Taken together, these results indicated that SASH1 may be a tumor suppressor gene in ovarian carcinoma, and SASH1 expression inhibited growth, proliferation and migration, and enhanced apoptosis of SKOV3 cells. PMID- 27123076 TI - Esophageal cancer diagnosed by high-resolution manometry of the esophagus: A case report. AB - A 48-year-old female who presented with a history of dysphagia for 5 months and regurgitation for 1 week was referred to the Sir Run Run Shaw Hospital (Hangzhou, China) for further evaluation, since the gastroscopy and endoscopic ultrasound performed in local hospitals did not reveal the presence of cancer. High resolution manometry (HRM) of the esophagus was performed to determine the patient's condition, and revealed an abnormal high-pressure zone that was located 33 cm from the incisor and did not relax upon swallowing. Synchronous waves were observed, and the pressure of the esophageal lumen was found to increase with secondary synchronous peristaltic waves. The lower esophageal sphincter was 39 cm from the incisor and relaxed upon swallowing. The abnormal high-pressure zone could have been caused by an obstruction, and therefore an upper gastrointestinal series (barium swallow) test and gastroscopy were recommended to further pinpoint the cause. Following the two examinations, mid-esophageal cancer was considered as a possible diagnosis. A biopsy was performed and the final diagnosis was that of basaloid squamous cell carcinoma. The findings of the present study suggest that, for patients with evident symptoms of esophageal motor dysfunction without significant gastroscopy findings, HRM is recommended. PMID- 27123077 TI - Primary extragastrointestinal stromal tumor of the pleura: A case report. AB - Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the gastrointestinal tract. The stomach and small intestine are the most common sites of occurrence. GISTs are mesenchymal neoplasms originating from the interstitial cells of Cajal (ICCs), and are characterized by positivity for cluster of differentiation (CD) 117, also known as proto-oncogene c-Kit. While the majority of GISTs develop in the alimentary tract, in rare cases they may also be found in extragastrointestinal tissues. This type of GIST is known as an extragastrointestinal stromal tumor (EGIST). Despite the fact that EGISTs have been reported in the mesentery, omentum and retroperitoneum, primary intrathoracic EGISTs, arising from the pleura or lungs, are rare. The patient presented in the current study was a 40-year-old man, who presented with a cough and pyrexia, with pleural effusion on the left side. Multiple nodules throughout the parietal pleura were identified by thoracoscopy and a diagnosis of primary GIST of pleura was established, since they were positive for CD117 and discovered on GIST-1 and there was no evidence of gastrointestinal tumors. Subsequently, the patient was administered with imatinib and had no signs of disease recurrence 2 years later. PMID- 27123078 TI - Myoepithelial carcinoma of the vallecula: A case report and review of the literature. AB - Myoepithelial carcinoma (MEC) of the vallecula is relatively rare, and there is no specific surgical guideline for resecting MEC in the vallecula. To the best of our knowledge, the current study reports the first case of MEC involving the vallecula of a 48-year-old female patient. In the present study, the lesion was correctly diagnosed as MEC and successfully managed using lateral pharyngotomy and by the construction of a sternohyoid myofascial flap. The patient was free of local recurrence or metastasis 18 months after surgery. The present study briefly reviews the current knowledge concerning the diagnosis and treatment of MECs in the head and neck area and offers suggestions for managing MEC in the vallecula. To conclude, MEC of the vallecula may be successfully managed by surgical treatment without evident post-surgery complications. PMID- 27123079 TI - Successful treatment of biliary intraepithelial neoplasia in the common bile duct via local excision: A case report. AB - Biliary intraepithelial neoplasia (BilIN), a precursor lesion of bile duct adenocarcinomas, rarely occurs in the extrahepatic bile duct, and therefore uniform treatment guidelines are lacking. The present study reports a case of BilIN in the common bile duct (CBD) in a 77-year-old man, who presented with upper abdominal malaise without jaundice. Imaging modalities revealed a CBD luminal tumor and dilated intrahepatic and extrahepatic bile ducts. To the best of our knowledge, local excision of the lesion was performed for the first time for this type of tumor in the present study. Pathological examination gave a definite diagnosis of high-grade BilIN in the CBD. No evidence of recurrence was observed during a 3-year follow-up period. This case report suggests that local excision is able to successfully treat BilIN in the CBD. PMID- 27123080 TI - Side population in hepatocellular carcinoma HCCLM3 cells is enriched with stem like cancer cells. AB - Substantial evidence implicates that low-abundance cancer stem cells (CSCs) are responsible for tumor metastasis and recurrence in hepatocellular carcinoma (HCC). Side population (SP) cells possess typical CSCs-like features, and are frequently considered as a special subpopulation in which CSCs are enriched and in studies may be considered as a substitute for CSCs. The aim of the present study was to examine the abundance of SP cells in human HCC cell lines with different metastatic potentials and compare their CSC-like, tumorigenic and invasive properties with those of the main population (MP) cells. An experimental system is described for identifying SP cells and analyzing their CSC-like properties. The relative abundance of SP cells correlated directly with the metastatic potential of the HCC cell line: HCCLM3, 16.3+/-2.2%; MHCC97-H, 8.4+/ 0.7%; MHCC97-L, 4.7+/-0.5%; and Huh7, 1.0+/-0.3% (P<0.05). SP cells isolated from HCCLM3 cultures showed significantly higher proliferation rates and clonogenicity than the corresponding MP cells, in addition to higher migration and invasive abilities in vitro and greater tumorigenicity in mice. Expression levels of all CSC-associated genes tested, except EpCAM and Oct4, were significantly higher in SP cells. The findings revealed that the proportion of SP cells correlates with metastatic potential, and SP cells demonstrated the characteristics expected of CSCs, implicating them in HCC metastasis. Further studies on the identification and characterization of SP cells using clinical HCC specimens will contribute to the understanding of how SP cells are involved in these disease processes. PMID- 27123081 TI - A double suicide gene system driven by vascular endothelial growth factor promoter selectively kills human hepatocellular carcinoma cells. AB - The aim of the present study was to investigate the selective killing effect on hepatocellular carcinoma (HCC) cells of an adenovirus (Ad)-mediated cytosine deaminase (CD) in combination with thymidine kinase (TK) suicide gene system, driven by the vascular endothelial growth factor promoter (VEGFp), in vitro and in vivo. A double suicide gene system with VEGFp, named Ad-VEGFp-CDglyTK, was constructed and transfected into human HCC cells (BEL-7402 or HepG2; the latter cell type is deficient in VEGF) and human umbilical vein vascular endothelial cells (HUVEC). Green fluorescent protein expression was detected by fluoroscopy to verify transfection efficiency, and CDglyTK gene expression was detected by reverse transcription-polymerase chain reaction (PCR). The selective killing effect of Ad-VEGFp-CDglyTK was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and flow cytometry (FCM) in vitro and by xenograft studies in vivo. PCR revealed that the transgenic CDglyTK gene was expressed in BEL-7402 cells and HUVEC, but not in HepG2 cells. The cell survival rate significantly decreased in line with increasing concentrations of the prodrugs, ganciclovir (GCV) alone, 5-fluorocytosine (5-FC) alone or a combination of the two, in HUVEC and BEL-7402 cells with the transfected CDglyTK gene, but not in untransfected HUVEC or BEL-7402 cells, or in transfected or untransfected HepG2 cells. This result was additionally confirmed by FCM. GCV and 5-FC inhibited the HUVEC and BEL-7402 cells containing the transfected CDglyTK gene and also inhibited adjacent unmodified cells via the 'bystander effect'. No similar results were observed in HepG2 cells. Compared with the control group, tumors with the transfected CDglyTK gene were smaller and the microvessel density of the tumor tissue was significantly decreased. It was concluded that a combination TK/GCV and CD/5-FC suicide gene system driven by VEGFp may provide a promising treatment strategy for HCC. PMID- 27123082 TI - Retroperitoneal lymphangioma: A report of 2 cases and a review of the literature regarding the differential diagnoses of retroperitoneal cystic masses. AB - Cystic lymphangioma is a type of benign tumor originating from the lymph vessels. The tumor commonly occurs in childhood, in the head or neck regions, and retroperitoneal localization and presentations in adulthood are rare. Determining a pre-operative diagnosis is often challenging, and in the majority of cases, a diagnosis is only possible subsequent to the histological examination of the surgical specimen. A radical resection is the recommended treatment for cystic lymphangioma, and recurrence is usually due to an incomplete excision of the mass. The present study reports 2 cases of cystic lymphangioma, localized in the pancreatic gland and duodenal wall respectively, which were treated with surgical resection. The study also briefly reviews the literature regarding the differential diagnosis of retroperitoneal cystic masses. PMID- 27123083 TI - Demethylation drug 5-Aza-2'-deoxycytidine-induced upregulation of miR-200c inhibits the migration, invasion and epithelial-mesenchymal transition of clear cell renal cell carcinoma in vitro. AB - The microRNA (miR)-200 family has been found to be involved in the process of mesenchymal-epithelial transition during renal development. Deregulation of miR 200c has been suggested to be involved in clear cell renal cell carcinoma (ccRCC). However, the precise role of miR-200c in the regulation of ccRCC metastasis has not been previously reported. In the present study, it was observed that miR-200c was frequently downregulated in ccRCC tissue compared with matched adjacent normal tissue. The expression of miR-200c was additionally reduced in ccRCC cell lines when compared with levels in normal renal cells. The DNA demethylation drug 5-Aza-2'-deoxycytidine (Aza) was used to treat several ccRCC cell lines, and it was observed that the expression of miR-200c was significantly increased following Aza treatment. Furthermore, treatment with Aza markedly inhibited ccRCC cell invasion and migration, while treatment with miR 200c inhibitor significantly enhanced invasion and migration of ccRCC cells. In addition, Aza treatment significantly promoted expression of E-cadherin and inhibited the expression of N-cadherin, while the inhibition of miR-200c downregulated E-cadherin and upregulated the expression of N-cadherin, suggesting that miR-200c has a suppressive role in epithelial-mesenchymal transition (EMT) of ccRCC cells. In conclusion, it was suggested that demethylation drug Aza induced upregulation of miR-200c may inhibit migration, invasion and EMT in ccRCC cells. PMID- 27123084 TI - Ultra-early microsurgical treatment within 24 h of SAH improves prognosis of poor grade aneurysm combined with intracerebral hematoma. AB - Spontaneous subarachnoid hemorrhage (SAH) is the most common cerebrovascular disease. The conventional treatment for SAH is usually associated with high mortality. The present study aims to assess the prognosis of microsurgical treatment for patients with poor-grade aneurysm (Hunt and Hess grades IV-V) associated with intracerebral hematoma. A total of 18 consecutive patients who were diagnosed with poor-grade aneurysm accompanied with intracerebral hematoma were retrospectively recruited. All patients underwent microsurgical treatment between April 2010 and June 2013 at The 101st Hospital of Chinese People's Liberation Army (Wuxi, China). Among them, 15 cases underwent microsurgery within 24 h of SAH, and 3 cases underwent microsurgery 24 h following SAH. All 18 cases were examined by computed tomography angiography (CTA). The outcome was assessed during a follow-up time of 6-36 months. According to the Glasgow Outcome Scale, 4 patients experienced a good recovery, 6 were dissatisfied with the outcome, 4 were in vegetative state and 4 succumbed to disease. Poor outcome occurred in patients with an aneurysm diameter >10 mm, exhibited >50 ml volume of intracerebral hematoma or presented cerebral hernia prior to the surgical operation. The outcome of ultra-early surgery (within 24 h of SAH) was improved, compared with that of surgery following 24 h of SAH (P=0.005). Among 7 patients who accepted extraventricular drainage, good outcomes were achieved in 4 of them, whereas dissatisfaction and mortality occurred in 2 and 1 patients, respectively. Therefore, ultra-early microsurgery (within 24 h of SAH) combined with extraventricular drainage may improve the prognosis of patients with poor-grade aneurysm. PMID- 27123085 TI - Bortezomib and etoposide combinations exert synergistic effects on the human prostate cancer cell line PC-3. AB - Novel treatment modalities are urgently required for androgen-independent prostate cancer. In order to develop an alternative treatment for prostate cancer, the cytotoxic effects of the 26S proteasome inhibitor bortezomib, either alone or in combination with the two commonly used chemotherapeutic agents irinotecan and etoposide, on the human prostate cancer cell line PC-3 were evaluated in the present study. The PC-3 cell line was maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum and treated with various doses of bortezomib, irinotecan, etoposide or their combinations. The growth inhibitory and cytotoxic effects were determined by water-soluble tetrazolium (WST)-1 assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or iCELLigence system. The combination index values were determined by the Chou-Talalay method. The half maximal inhibitory concentration (IC50) value of bortezomib on the PC-3 cell line was determined to be 53.4 nM by WST-1 assay, whereas the IC50 values of irinotecan and etoposide were determined to be 2.1 and 26.5 uM, respectively. These results suggest that the 26S proteasome inhibitor bortezomib is more potent, compared with irinotecan and etoposide, in the androgen-insensitive and tumor protein p53-null cell line PC-3. The combined effects of bortezomib+irinotecan and bortezomib+etoposide were also tested on PC 3 cells. The effect of bortezomib+irinotecan combination was not significantly different than that produced by either monotherapy, according to the results of iCELLigence system and MTT assay. However, 40 nM bortezomib+5 uM etoposide or 40 nM bortezomib+20 uM etoposide combinations were observed to be more effective than each drug tested alone. The results of the current study suggest that bortezomib and etoposide combination may be additionally evaluated in clinical trials for the treatment of hormone-refractory prostate cancer. PMID- 27123086 TI - Association between intraosseous schwannoma occurrence and the position of the intraosseous nutrient vessel: A case report. AB - Intraosseous schwannoma is a rare benign bone tumor that originates from Schwann cells of the nerve sheath. The majority of intraosseous schwannomas arise in the mandible and sacrum, but an intraosseous schwannoma involving the ulna is described in the present case report. Radiologically, the current case presented as a well-defined lytic lesion, with a pathological fracture and no intralesional calcification, in the proximal metaphysis of the left ulna. Using magnetic resonance imaging, an intraosseous mass spreading out from the cortical defect was observed. The lesion appeared isointense to skeletal muscle on T1-weighted images, and hyperintense or heterogeneous on T2-weighted images. The differential diagnosis comprised benign bone tumors, including bone cyst, aneurysmal bone cyst, giant cell tumor and fibrous dysplasia. Based on the results of a needle biopsy, a schwannoma involving the ulnar bone was diagnosed, and tumor marginal resection followed by artificial bone grafting and fixation was performed. A total of one year subsequent to surgery, the patient exhibits no symptoms, and there is no evidence of disease recurrence. PMID- 27123087 TI - Diagnostic accuracy of pre-operative imaging findings in presumed clinical T1a renal cell carcinomas. AB - Despite the development of recent imaging modalities, certain pathological misdiagnoses remain for surgical specimens of presumed small renal cell carcinomas (RCCs). In the present study, a retrospective analysis of benign pathological lesions diagnosed as small RCC prior to surgery was performed. In total, the cases of 196 sporadic renal tumors that was surgically treated as clinical T1a RCCs were reviewed, and the accuracy of the pathological diagnoses was calculated. The pre-operative findings for benign pathological lesions was investigated, and the lesions were observed in 13 (6.63%) of the 196 tumors. Pre operative computed tomography images were obtained in all cases, and magnetic resonance images were available in 10 cases. The diagnostic accuracy of imaging modalities was significantly lower in the tumors with a diameter of <=20 mm. In all cases, the possible pathological diagnosis of RCC could not be excluded even by retrospective imaging analysis. Several benign pathological lesions were found in small renal masses presumed to be clinical T1a RCC. In conclusion, there may be limitations to the pre-operative imaging for certain types of small renal mass. PMID- 27123088 TI - Traumatic arteriovenous fistula of the left parotid region: A case report. AB - The formation of arteriovenous fistula beneath the parotid is relatively rare. To the best of our knowledge, the present study reports the first case of a 48-year old man with a pulsatile mass on the left parotid region, which had been present for >3 years following penetrating wounds. Computed tomography angiography and digital subtraction angiography revealed a fistula between the left external carotid artery and the left jugular vein. The patient was successfully managed through surgical excision without embolization. Intraoperative facial nerve monitoring was employed to prevent postoperative facial paralysis. The present study briefly reviewed the current literature, illustrating the pathophysiology, symptoms, imaging studies and treatment for arteriovenous fistula in the head and neck region. To conclude, arteriovenous fistula located near the facial nerve may be successfully managed by surgical treatment, without permanent facial paralysis. PMID- 27123089 TI - Re-sensitization of radiation resistant colorectal cancer cells to radiation through inhibition of AMPK pathway. AB - Radiotherapy (RT) is commonly used to treat multi-tumors to attenuate the risk of recurrence. Despite impressive initial clinical responses, a large proportion of patients experience resistance to RT. Therefore, identification of functionally relevant biomarkers would be beneficial for radioresistant patients. Adenosine monophosphate-activated kinase (AMPK) is recognized as a mediator of tumor suppressor gene function. In the present study, radio-sensitive and -resistant colon cancer patient samples were compared and the AMPK pathway was observed to be highly activated in radioresistant patients. In addition, the protein and mRNA levels of AMPK were upregulated in radioresistant colon cancer cells in comparison to radiosensitive colon cancer cells. The present study provides evidence that activation of AMPK by metformin contributes to radioresistance. Inhibition of AMPK by either small interfering RNA or Compound C, which is a specific inhibitor of AMPK, re-sensitized radiation resistant cells. The data presented indicates a synergistic effect on radiation resistant cancer cells by the combination of Compound C and radiation. In summary, the present study proposes that inhibition of the AMPK pathway is a potential strategy for reversing radiation resistance and may contribute to the development of therapeutic anticancer drugs. PMID- 27123090 TI - Bladder cancer in a young patient: Undiscovered risk factors. AB - Bladder cancer is one of the most common forms of malignancies involving the urinary system and multiple risk factors have been associated with its etiology. The most common of which include cigarette smoking and various occupational or chemical exposures. It is usually diagnosed in older individuals with an average age of 70. In rare cases it is observed in children as well as young adults where it usually presents as a low-grade, non-invasive disease. In the present case report a 27-year-old male patient is discussed: The patient presented with no significant risk factors and was treated for mucinous adenocarcinoma of the bladder while further investigations were performed to identify other associated factors related to this form of malignancy. Debate in the literature exists in regards to the characteristics of bladder neoplasms in younger patients compared with older patients, however there is a lack of research into the etiology or prognosis in young patients. The present case study illustrates the case of a young adult with no clear risk factors who was diagnosed with a rare case of mucinous adenocarcinoma of the bladder. PMID- 27123091 TI - Efficacy of peritoneovenous shunt for treating tolvaptan-resistant refractory ascites in a cirrhotic patient with portal vein thrombosis: A case report. AB - Peritoneovenous shunt is normally used for the treatment of refractory ascites. However, its efficacy in treating tolvaptan-resistant refractory ascites has not been reported thus far. In addition, the impact of peritoneovenous shunt on the prognosis of cirrhotic patients remains controversial. In the present report, a case of tolvaptan-resistant refractory ascites associated with liver cirrhosis and portal vein thrombosis is described. The male patient was diagnosed with hepatitis C virus-related liver cirrhosis at the age of 51 years. At the age of 56 years, the patient developed portal vein thrombosis, resulting in the development of refractory ascites. Since the ascites was resistant to treatment with a low-sodium diet and diuretics such as tolvaptan, a peritoneovenous shunt was implanted upon obtaining consent. The shunt immediately increased the urine volume, and the ascites was markedly decreased. The patient's body weight decreased from 62.7 to 57.1 kg in 2 days, and his ascites symptom inventory-7 score decreased from 23 to 0 points in 31 days. Although the patient succumbed to sepsis on day 486 following the shunt implant, his activities of daily living were preserved until 8 days prior to mortality. Thus, the present case supports the efficacy of peritoneovenous shunt for the treatment of tolvaptan-resistant refractory ascites associated with liver cirrhosis and portal vein thrombosis. Furthermore, the present case suggests that peritoneovenous shunt may prolong the survival of cirrhotic patents with refractory ascites. PMID- 27123092 TI - Perirenal hematoma in a patient treated with bevacizumab for metastatic colon cancer: A case report. AB - The present study reports the case of a patient that developed spontaneous perirenal hematoma during treatment with bevacizumab-containing chemotherapy. A 44-year-old woman with metastatic sigmoid colon cancer, who was being treated with bevacizumab (5 mg/kg, intravenous, 90 min biweekly), was admitted to hospital following 3 cycles of chemotherapy, with a sudden onset of dyspnea and oliguria. An emergency hemodialysis was performed and a large right perirenal hematoma was diagnosed using computed tomography. The patient was immediately instructed to discontinue chemotherapy, including bevacizumab. However, the right perirenal hematoma increased in size and a left perirenal hematoma developed 3 weeks later. The two perirenal hematomas stabilized 7 weeks subsequent to the termination of bevacizumab treatment. Spontaneous perirenal hematoma due to bevacizumab treatment is an extremely rare occurrence. However, physicians should be aware of this potential complication associated with bevacizumab treatment. PMID- 27123093 TI - Delayed bronchobiliary fistula following radiofrequency ablation in a patient with hepatocellular carcinoma: A case report and lesson regarding treatment. AB - Bronchobiliary fistula (BBF) is a rare complication of radiofrequency ablation (RFA) of hepatocellular carcinoma. The rupture of a biloma following RFA may result in the development of BBF, with their early detection and timely management important in the prevention of BBF. The current study presents a case of BBF, which developed at 17 months after radiofrequency ablation (RFA), due to biloma rupture in a patient with hepatocellular carcinoma. Despite the percutaneous drainage of the biloma following BBF, the persistent fever did not resolve due to biliary infection. Finally, an extensive surgical intervention was performed. The magnetic resonance imaging (MRI) scans that had been performed following RFA were reviewed, and it was found that the biloma and increased bile leakage had presented prior to biloma rupture. For that reason, it is advised that patients who present with biloma following RFA should receive regular follow up MRI scans. Biloma enlargement could be a predictor for the development of BBF; therefore, timely drainage of an enlarging biloma may be able to prevent this complication. PMID- 27123094 TI - Statistics and outlook of primary hepatic angiosarcoma based on clinical stage. AB - Hepatic angiosarcoma is a rare condition that has been associated with exposure to colloidal solutions of thorium dioxide, vinyl chloride, arsenic and radiation. Therapeutic guidelines have not been definitively established due to the small number of cases of this disease. The present study reviewed 28 cases of hepatic angiosarcoma from studies that had been published between January 2000 and December 2012, in addition to 6 cases diagnosed at Tri-Service General Hospital (Taipei, Taiwan). Clinical staging was based on American Joint Committee on Cancer staging system for soft tissue sarcoma (2014). With a mean follow-up of 27.5 months (range, 0.27-102 months), 18% (6/34) of the patients survived. The 1 , 3- and 5-year survival rates were 68.0+/-9.3, 42.1+/-10.2 and 32.7+/-9.8% for patients with stage I disease (mean follow-up, 32.7 months), whilst the 1- and 3 year survival rates were 33.3+/-15.7 and 22.2+/-13.9% for patients with stage IV disease (mean follow-up, 13.0 months). Determining an appropriate therapeutic strategy for this patient group is necessary. New studies encompassing larger patient populations are required in order to analyze and define standard prognostic parameters and to standardize a treatment approach for this extremely rare neoplasm. PMID- 27123095 TI - Radiotherapy of brain metastases from breast cancer: Treatment results and prognostic factors. AB - Brain metastases (BM) from breast cancer are associated with high morbidity and a poor prognosis. The aim of this study was to analyse the role of radiotherapy in treatment of BM from breast cancer in the context of modern local therapy modalities, current systemic treatment options and prognostic factors. A retrospective analysis of 86 consecutive female patients treated with radiotherapy for BM from breast cancer between 2000 and 2010 was conducted. Patient and treatment characteristics were registered and survival data calculated. All patients received whole-brain radiotherapy (WBRT) with a median dose of 36 Gy, and 19 patients were treated with an additional boost; this included fractionated schemes (median dose, 18 Gy) and radiosurgery (5 and 17 Gy). The median overall survival time from the start of WBRT was 4.1 months in the present cohort. Patients receiving a boost survived 19.7 months in comparison to 3.1 months for patients treated with WBRT alone (P<0.001). Other factors that improved overall survival, based on a univariate analysis, were dose of WBRT and number of BM. There was no statistical evidence for the influence of the human epidermal growth factor receptor 2 status on survival in the current study. The administration of boost treatment following WBRT was also identified as a significant factor influencing survival on multivariate analysis (P=0.030). In conclusion, radiotherapy affects the survival time of patients with BM from breast cancer. In particular, the implementation of boost treatment following WBRT in selected patients seems to extend survival time. PMID- 27123097 TI - BIRC3 alterations in chronic and B-cell acute lymphocytic leukemia patients. AB - Deletions within chromosome 11q22-23, are considered among the most common chromosomal aberrations in chronic lymphocytic leukemia (CLL), and are associated with a poor outcome. In addition to the ataxia telangiectasia mutated (ATM) gene, the baculoviral IAP repeat-containing 3 (BIRC3) gene is also located in the region. BIRC3 encodes a negative regulator of the non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) protein. Disruption of BIRC3 is known to be restricted to CLL fludarabine-refractory patients. The aim of the present study was to determine the frequency of copy number changes of BIRC3 and to assess its association with two known predictors of negative CLL outcome, ATM and tumor protein 53 (TP53) gene deletions. To evaluate the specificity of BIRC3 alterations to CLL, BIRC3 copy numbers were assessed in 117 CLL patients in addition to 45 B-cell acute lymphocytic leukemia (B-ALL) patients. A commercially available multiplex ligation dependent probe amplification kit, which includes four probes for the detection of TP53 and four probes for ATM gene region, was applied. Interphase-directed fluorescence in situ hybridization was used to apply commercially available probes for BIRC3, ATM and TP53. High resolution array-comparative genomic hybridization was conducted in selected cases. Genetic abnormalities of BIRC3 were detected in 23/117 (~20%) of CLL and 2/45 (~4%) of B-ALL cases. Overall, 20 patients with CLL and 1 with B-ALL possessed a BIRC3 deletion, whilst 3 patients with CLL and 1 with B-ALL harbored a BIRC3 duplication. All patients with an ATM deletion also carried a BIRC3 deletion. Only 2 CLL cases possessed deletions in BIRC3, ATM and TP53 simultaneously. Evidently, the deletion or duplication of BIRC3 may be observed rarely in B-ALL patients. BIRC3 duplication may occur in CLL patients, for which the prognosis requires additional studies in the future. The likelihood that TP53 deletions occur simultaneously with BIRC3 and/or ATM aberrations is low. However, as ATM deletions may, but not always, associate with BIRC3 deletions, each region should be considered in the future diagnostics of CLL in order to aid treatment decisions, notably whether to treat with or without fludarabine. PMID- 27123098 TI - Late recurrent cutaneous breast angiosarcoma in an elderly woman: A case report. AB - Breast angiosarcomas are malignant tumours of the vascular endothelium that arise frequently following radiation therapy. Their clinical and radiological aspects are highly heterogeneous. The current study reports an unusual case, never previously reported, of a late recurrent breast angiosarcoma occurring in an 83 year old female patient 11 years after a breast-conserving surgery followed by radiation therapy for an invasive ductal carcinoma, and 5 years after her initial angiosarcoma excision. The first physician to examine the patient noted a palpable mass near the scar and, following ultrasonography, described the breast lesion as suggestive of an abscess, despite the previous history of neoplasia. Typically, recurrences of breast angiosarcoma occur within the first postsurgical year. The present patient remains alive at 25 months after her last surgical treatment, and no evidence of any local or distant disease is observable. PMID- 27123096 TI - Alcohol consumption and corresponding factors: A novel perspective on the risk factors of esophageal cancer. AB - Esophageal cancer is the eighth most common type of cancer in the world, and the sixth most common cause of mortality from cancer. Alcohol consumption is the major risk factor for esophageal cancer, due to the worldwide prevalence and high carcinogenicity of the ethanol metabolite. In epidemiological studies, the efficiency of alcohol intake to enhance the risk of esophageal cancer is altered by daily ethanol consumption, type of alcoholic beverages ingested, time since quitting drinking, age of drinking initiation, differences in population and subtypes of esophageal cancer. Corresponding factors, including gene polymorphisms, tobacco smoking, oral microorganisms and folate deficiency, reveal a synergistic effect in concurrent alcohol users that may lead to an increased risk of developing esophageal cancer. Consequently, esophageal cancer prevention involves multiple aspects, including quitting drinking and smoking, maintaining an adequate oral health and ingesting adequate quantities of folate, particularly in genetically high-risk populations. PMID- 27123099 TI - Overexpression of SPARC correlates with poor prognosis in patients with cervical carcinoma and regulates cancer cell epithelial-mesenchymal transition. AB - Secreted protein acidic and rich in cysteine (SPARC) is associated with the progression of numerous types of cancer. However, the role of SPARC in the progression of cervical cancer has not yet been adequately elucidated. In the current study, reverse transcription-quantitative polymerase chain reaction (RT qPCR) and immunohistochemistry were employed to evaluate the mRNA and protein expression of SPARC in normal cervical tissue, cervical intraepithelial neoplasia (CIN) and cervical cancer. In addition, three epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin) were detected by immunohistochemistry in the same specimens, and an enzyme-linked immunosorbent assay was conducted to detect the serum levels of SPARC in patients with cervical neoplasia. In highly invasive subclones of human cervical carcinoma cells, HeLa-1 and SiHa-1, lentiviral transfections were performed and RT-qPCR and western blot were used to investigate the effects of downregulated EGF-containing fibulin-like extracellular matrix protein 1 on the expression of E-cadherin, N-cadherin and vimentin. The results revealed that, in cervical carcinoma tissue, SPARC expression was significantly upregulated in a manner that positively correlated with N-cadherin and vimentin expression, and negatively correlated with E cadherin expression. SPARC overexpression and high serum levels were significantly associated with the progression of cervical cancer and adverse prognosis of cervical cancer patients. Downregulation of SPARC can markedly reduce the expression of N-cadherin and vimentin and increase the expression of E cadherin. Thus, overexpression of SPARC is significantly associated with poor prognostic clinicopathological characteristics in cervical carcinoma, and may be important in EMT. The results of the current study suggest that SPARC may be a potential therapeutic option for individuals diagnosed with cervical carcinoma. PMID- 27123100 TI - Surgical treatment of a retroperitoneal benign tumor surrounding important blood vessels by fractionated resection: A case report and review of the literature. AB - Retroperitoneal tumors are lesions with diverse pathological subtypes that originate from the retroperitoneal space; ~40% of these tumors are benign. Due to such lesions often surrounding and associating with vital abdominal blood vessels, a complete surgical resection is difficult. The current study presents a novel surgical approach, known as fractionation, through which a benign retroperitoneal tumor surrounding important abdominal blood vessels was completely resected. A 21-year-old man was admitted to The First Affiliated Hospital of Chongqing Medical University (Chongqing, China), presenting with a ~7.5*7.2-cm tumor that was located in the retroperitoneal pancreatic head region and the first hepatic hilum. The tumor completely surrounded the celiac axis and the splenic, common hepatic and superior mesenteric arteries, and was closely associated with the abdominal aorta and the portal, splenic, superior mesenteric and left renal veins. A pre-operative computed tomography scan and intraoperative frozen biopsy indicated that the lesion was a benign tumor. A fractionation approach was subsequently adopted, with fractionation of the lesion being performed according to the location of the tumor itself and the direction of the surrounding abdominal blood vessels. In this manner, a complete tumor resection was conducted. Post-operative pathological examination confirmed the diagnosis of a retroperitoneal ganglioneuroma. The patient was followed up for a year and a half, with no evidence of tumor recurrence. In the present case, a fractionation approach for the complete resection of the retroperitoneal benign tumor achieved a positive outcome and demonstrated the feasibility of the technique. PMID- 27123101 TI - Preclinical pharmacodynamic evaluation of antibiotic nitroxoline for anticancer drug repurposing. AB - The established urinary antibiotic nitroxoline has recently regained considerable attention, due to its potent activities in inhibiting angiogenesis, inducing apoptosis and blocking cancer cell invasion. These features make nitroxoline an excellent candidate for anticancer drug repurposing. To rapidly advance nitroxoline repurposing into clinical trials, the present study performed systemic preclinical pharmacodynamic evaluation of its anticancer activity, including a methyl thiazolyl tetrazolium assay in vitro and an orthotopic urological tumor assay in vivo. The current study determined that nitroxoline exhibits dose-dependent anti-cancer activity in vitro and in urological tumor orthotopic mouse models. In addition, it was demonstrated that the routine nitroxoline administration regimen used for urinary tract infections was effective and sufficient for urological cancer treatment, and 2 to 4-fold higher doses resulted in obvious enhancement of anticancer efficacy without corresponding increases in toxicity. Furthermore, nitroxoline sulfate, one of the most common metabolites of nitroxoline in the urine, effectively inhibited cancer cell proliferation. This finding increases the feasibility of nitroxoline repurposing for urological cancer treatment. Due to the excellent anticancer activity demonstrated in the present study, and its well-known safety profile and pharmacokinetic properties, nitroxoline has been approved to enter into a phase II clinical trial in China for non-muscle invasive bladder cancer treatment (registration no. CTR20131716). PMID- 27123102 TI - Long-term follow-up and clinical course of a rare case of von Hippel-Lindau disease: A case report and review of the literature. AB - von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited neoplastic syndrome that increases susceptibility to a variety of benign and malignant neoplasms. It has been well documented that, despite complete excision of initial neoplasms, VHL patients may develop further lesions, in some cases many years after the initial diagnosis. Therefore, the varied and complex clinical manifestations and radiological findings of VHL are of interest. The current study is the first to describe a case of VHL disease with lateral ventricular hemangioblastomas and subsequent pancreatic neuroendocrine tumor, bilateral renal cysts and renal cell carcinoma. The complete clinical course, radiological findings, including ultrasound, computed tomography and magnetic resonance imaging (MRI), and associated pathological findings are presented. Radiology is critical in the accurate diagnosis, treatment and follow-up of VHL. Continuous close and long-term follow-up with radiological examination, particularly MRI, must be conducted in patients with VHL disease. To the best of our knowledge, the current case is a rare phenomenon that has not yet been described in the English literature. PMID- 27123103 TI - N-glycosylation of R-spondin1 at Asn137 negatively regulates its secretion and Wnt/beta-catenin signaling-enhancing activity. AB - N-glycosylation is a post-translational protein modification with a wide variety of functions. It has been predicted that R-spondin1 (RSPO1) is N-glycosylated, although this remains unknown. The present study identified that RSPO1 was N glycosylated at Asn137, and that N-glycosylation of RSPO1 negatively influenced its secretion and enhancing effect on Wnt/beta-catenin signaling. In vitro treatment with peptide-N-glycosidase F increased the electrophoretic mobility of RSPO1. Furthermore, treatment of wild-type (wt) RSPO1-overexpressing HT1080 cells with tunicamycin (TM), which inhibits N-glycosylation, resulted in a significant reduction in the molecular weight of RSPO1. However, TM treatment had no effect in the RSPO1 mutant whereby the Asn137 residue was replaced by Gln (N137Q). These results demonstrated for the first time that RSPO1 is N-glycosylated at Asn137. RSPO1 is a secreted protein that has Wnt/beta-catenin signaling-enhancing activity and is expected to have therapeutic applications. The role of N glycosylation in RSPO1 was evaluated by conducting comparative experiments with wt and N137Q RSPO1, which revealed that the N137Q mutant increased the secretion and Wnt/beta-catenin signaling-enhancing effect of RSPO1, compared with wt RSPO1. These results suggest that N-glycosylation of RSPO1 has a negative influence on its secretion and Wnt/beta-catenin signaling-enhancing effect. PMID- 27123104 TI - Docetaxel combined with intraperitoneal hyperthermic perfusion chemotherapy and hyperthermia in the treatment of advanced ovarian cancer. AB - Ovarian cancer is a clinical type of gynecological malignant tumor with poor prognosis and a high mortality rate. At present, the primary treatment method used is surgery, with chemotherapy as an ajdunctive therapy. Thus, new short-term treatments should be identified. The aim of the present study was to investigate the short-term curative effects and safety of docetaxel combined with intraperitoneal cisplatin chemotherapy and hyperthermia treatment of advanced ovarian cancer. A total of 112 cases of advanced (stage III-IV) ovarian cancer patients confirmed by clinical diagnosis between October 2014 and December 2015 were included in the study. The patients were randomly divided into the study and control groups (n=56 cases). The control group was treated with docetaxel and intraperitoneal cisplatin hyperthermic perfusion chemotherapy, while the study group was treated with docetaxel venous chemotherapy and intraperitoneal cisplatin cyclical hyperthermic perfusion chemotherapy with BR-TRG-1 body cavity hyperthermic perfusion treatment system. Clinical treatment results for short term curative effects and adverse reactions were compared and analyzed 8 weeks after treatment. The total effective rate of the study and control groups were 87.5 and 62.5%, respectively, and the difference was statistically significant (P<0.05). The controlled rate of ascites, remission rate of tumor and descent rate of CA125 of patients in the study group were better than patients in the control group (P<0.05). The rate of adverse reactions of patients in the study group was 39.3%, and the grade of toxicity was from I to II, while the rate of adverse reactions of patients in the control group was 55.4%, and the grade of toxicity was from II to III. The difference between the two groups was statistically significant (P<0.05). In conclusion, applying the combination of docetaxel, intraperitoneal cisplatin hyperthermic perfusion chemotherapy and hyperthermia to treat advanced ovarian cancer can improve the curative effects with little toxicity; thus, it is worthy of promotion and application. PMID- 27123105 TI - Primary follicular thyroid carcinoma metastasis to the kidney and widespread dissemination: A case report. AB - Distant metastases are more common in follicular thyroid carcinoma (FC) than in papillary thyroid carcinoma. However, FC metastasis to the kidney with eggshell calcification, as observed in the present case, is rare. The current report presents a case of a 67-year-old woman exhibiting a solitary tumor in the mid pole of the left kidney. Radical nephrectomy was performed, as the tumor was diagnosed as a primary renal carcinoma using contrast-enhanced computed tomography. Once the tumor was confirmed to be FC, total thyroidectomy was performed. Following administration of an oral therapeutic dose of 100 mCi 131I, functional imaging demonstrated the presence of multifocal metastases in the chest and abdomen. Euthyrox(r) was prescribed orally to aid normal thyroid function. Follow-up 6 months later using radionuclide imaging demonstrated the disappearance of the multifocal metastases in the chest and abdomen. The distant metastasis of FC may represent the initial symptom of the primary lesion, which was neglected. Ultrasound is an effective method to examine nodules located on the thyroid. PMID- 27123106 TI - Intra-abdominal desmoplastic small round cell tumors: CT and FDG-PET/CT findings with histopathological association. AB - Desmoplastic small round cell tumors (DSRCTs) are rare and aggressive malignant tumors. The aim of the present study was to analyze computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT imaging features of intra-abdominal desmoplastic DSRCT, and investigate the association of these features with histopathological results. The present study was a retrospective investigation of 4 patients with DSRCT. All patients underwent CT and dynamic CT, and 1 additionally underwent FDG-PET/CT scanning. Following a tumor resection, routine hematoxylin and eosin staining, and immunostaining, were performed and evaluated. Multiple large abdominopelvic masses were identified in all 4 patients; however, no indications of their site of origin were demonstrated. CT revealed soft-tissue masses with patchy foci of hypodense lesions. Contrast enhanced CT revealed slightly or moderately heterogeneous enhancement of the lesions. Other observations from these patients included calcification (n=2), peritoneal seeding (n=3), hepatic metastasis (n=3), retroperitoneal lymphadenopathy (n=3) and ascites (n=2). FDG-PET/CT revealed multiple nodular increased FDG uptake in the abdominopelvic masses, and in the liver and peritoneum in 1 case. Intra-abdominal DSRCT demonstrated significant diagnostic characteristics on plain and contrast-enhanced CT. Multiple, bulky soft-tissue masses inside the peritoneal cavity, particularly in male adolescents and young adults, should be considered as potential cases of DSRCT. FDG-PET/CT techniques may be utilized to aid the staging of tumors. PMID- 27123107 TI - Coexisting and possible primary extra-gastrointestinal stromal tumors of the pancreas and liver: A single case report. AB - Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms of the gastrointestinal tract (GI) that are defined, in part, by the expression of CD117, a c-Kit proto-oncogene protein. GISTs emerge outside of the GI at a very low frequency, typically in a single organ or location. GISTs that occasionally emerge outside of the GI are classified as extra-gastrointestinal stromal tumors (EGIST). The present study reports an extremely rare case of EGIST detected in the pancreas and the liver. The pancreatic and liver tumors were 4.5*2.5 cm and 2.0*1.5 cm in size, respectively. Both tumors consisted of CD117-positive spindle cells with a similar mitotic rate of 1-2 per 50 high power fields. The pancreatic and the hepatic EGISTs were at a low risk of malignancy, and both tumors were proposed to be primary stromal tumors. To the best of our knowledge, this is the first report of likely primary EGIST identified in the pancreas and liver of the same patient. PMID- 27123108 TI - The proliferative effects of asbestos-exposed peripheral blood mononuclear cells on mesothelial cells. AB - Malignant mesothelioma (MM) is thought to arise from the direct effect of asbestos on mesothelial cells. However, MM takes a long time to develop following exposure to asbestos, which suggests that the effects of asbestos are complex. The present study examined the effects of asbestos exposure on the cell growth of MeT-5A human mesothelial cells via cytokines produced by immune cells. Peripheral blood mononuclear cells (PBMCs) were stimulated with antibodies against cluster of differentiation (CD)3 and CD28 upon exposure to the asbestos chrysotile A (CA) or crocidolite (CR); the growth of MeT-5A cells in media supplemented with PBMC culture supernatants was subsequently examined. MeT-5A cells exhibited an increase in proliferation when grown in supernatant from the 7-day PBMC culture exposed to CA or CR. Analysis of cytokine production demonstrated increased levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1alpha, IL-1beta, IL-3, IL 5, IL-13 and IL-17A in supernatants. Individual administration of these cytokines, excluding G-CSF and GM-CSF, led to an increase in cell growth of MeT 5A, whereas this effect was not observed following the combined administration of these cytokines. The results indicate that cytokines secreted by immune cells upon exposure to asbestos cause an increase in the growth activity of mesothelial cells, suggesting that alterations in the production of cytokines by immune cells may contribute to tumorigenesis in individuals exposed to asbestos. PMID- 27123109 TI - Downregulation of O-linked N-acetylglucosamine transferase by RNA interference decreases MMP9 expression in human esophageal cancer cells. AB - O-linked N-acetylglucosamine transferase (OGT) catalyzes O-linked glycosylation (O-GlcNAcylation). O-GlcNAcylation is a post-translational carbohydrate modification of diverse nuclear and cytosolic proteins by the addition of O linked beta-N-acetylglucosamine. It was recently demonstrated that OGT and the level of O-GlcNAcylation are upregulated in esophageal cancer; however, the physiological consequences of this upregulation remain unknown. The current study reports that OGT knockdown by short hairpin RNA (shRNA) did not affect cell viability; however, cell migration in esophageal cancer Eca-109 cells was significantly reduced. OGT-specific shRNA vectors efficiently decreased the protein and mRNA levels of OGT and the RL2 level (a marker of O-GlcNAcylation levels) in Eca-109 esophageal cancer cells. In addition, colony formation and cell proliferation assays demonstrated that OGT-specific shRNA decreased the proliferation of Eca-109 cells; however, there was no significant statistical difference between OGT-specific shRNA and control shRNA. Notably, transwell assays demonstrated that the migratory ability of Eca-109 cells was significantly suppressed following knockdown of the OGT gene. Correspondingly, western blot analyses demonstrated that OGT knockdown significantly downregulated the expression of matrix metalloproteinase 9 (MMP9) in Eca-109 cells. These results suggest that OGT may promote the migration, invasion and metastasis of esophageal cancer cells by enhancing the stability or expression of MMP9. PMID- 27123110 TI - Primary carcinoma of the ureteral stump following radical nephrectomy for renal cell carcinoma: A case report and literature review. AB - The occurrence of primary carcinoma of the ureteral stump following radical nephrectomy for renal cell carcinoma is extremely rare; 7 patients with the disease have been reported previously. All these patients were males with transitional cell carcinoma. The current study reports the case of a 61-year-old woman, who presented with gross hematuria following a radical nephrectomy for local clear cell renal carcinoma. A computed tomography scan revealed the presence of a mass on the ureteral stump. The patient underwent a left ureteral stump and bladder cuff excision. The histological diagnosis was high-grade transitional cell carcinoma of the ureteral stump, with focal interstitial cancer cell infiltrates. There was no evidence of recurrence during a follow-up period of 35 months. In addition, the present study reviewed the literature for previous patients with ureteral stump carcinoma following a radical nephrectomy for renal cell carcinoma; 7 previous patients with the disease were identified. The present study suggests that, if patients who have previously undergone a radical nephrectomy for renal cell carcinoma present with hematuria, the possibility of ureteral stump carcinoma should be considered, particularly in East Asian countries. The existence or a history of bladder carcinoma should be considered as a high-risk factor for developing ureteral stump carcinoma. A ureteral stump and bladder cuff excision should be performed once ureteral stump carcinoma is diagnosed. PMID- 27123111 TI - Identification of key genes for laryngeal squamous cell carcinoma using weighted co-expression network analysis. AB - Laryngeal squamous cell carcinoma (LSCC) is the most common malignant tumor in the head and neck, and can seriously affect the daily life of patients. To study the mechanisms of LSCC, the microarray of GSE51958 was analyzed in the present study. GSE51958 was downloaded from Gene Expression Omnibus, and included a collection of LSCC tissue samples and matched adjacent non-cancerous tissue samples from 10 patients. Differentially-expressed genes (DEGs) were identified using limma package. Next, a weighted co-expression network was constructed for the DEGs by WGCNA package in R. Modules of the weighted co-expression network were obtained through constructing a hierarchical clustering tree using the hybrid dynamic shear tree method. Using the clusterProfiler package, the potential functions of DEGs in the modules correlated with LSCC were predicted by pathway enrichment analysis. In total, 959 DEGs were screened from the LSCC samples compared with the adjacent non-cancerous samples, including 553 upregulated and 406 downregulated genes. The appointed black, brown, gray, pink and yellow modules were screened for the DEGs in the weighted co-expression network. For the DEGs in the brown and yellow modules, the enriched pathways were cytokine-cytokine receptor interaction and metabolic pathways, respectively. The DEGs in the pink module were involved in the majority of pathways. With high connectivity degrees in the pink module, TPX2, microtubule-associated (TPX2; degree, 25), minichromosome maintenance complex component 2 (MCM2; degree, 25), ubiquitin-like with PHD and ring finger domains 1 (UHRF1; degree, 22), cyclin dependent kinase 2 (CDK2; degree, 20) and protein regulator of cytokinesis 1 (PRC1; degree, 20) may be involved in LSCC. Overall, In conclusion, from the integrated bioinformatics analysis of genes that may be associated with LSCC, 959 DEGs were obtained from LSCC samples compared with adjacent non-cancerous samples, and TPX2, MCM2, UHRF1, CDK2 and PRC1 were found to hold a possible association with the disease. PMID- 27123112 TI - The impact of FcgammaRIIa and FcgammaRIIIa gene polymorphisms on responses to RCHOP chemotherapy in diffuse large B-cell lymphoma patients. AB - Rituximab is a monoclonal antibody routinely used in the treatment of B-cell non Hodgkin lymphomas. It mediates antibody-dependent cellular cytotoxicity of B lymphocytes by bridging them with Fcgamma receptors (FcgammaR) on effector cells. Several polymorphisms in the FcgammaR genes have been identified to influence rituximab binding to FcgammaR, thus altering its antitumor effect in indolent lymphomas. In the present study, the impact of FcgammaRIIa and FcgammaRIIIa polymorphisms on the survival and response to immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone was evaluated in diffuse large B-cell lymphoma (DLBCL) patients. A total of 29 Slovenian DLBCL patients were studied. Genotyping was conducted for FcgammaRIIa 27, FcgammaRIIa-131, FcgammaRIIIa-48 and FcgammaRIIIa-158 polymorphisms. The median follow-up time was 29.7 months (range, 9.7-45.4 months). No significant impact of the genotypes was observed on the treatment response, progression-free or overall survival of DLBCL patients. There was a non-significant trend of an improved response to chemotherapy without additional irradiation in patients homozygous for Val at FCgammaIIIa-158 compared to Phe carriers. The findings of the present study indicate that FcgammaR polymorphisms have no influence on the survival of DLBCL patients. PMID- 27123113 TI - Solitary cardiac metastasis of uterine cervical cancer with antemortem diagnosis: A case report and literature review. AB - Cardiac metastasis of uterine cervical cancer with antemortem diagnosis is extremely rare. Therefore, its landscape epidemiology has not been well elucidated to date. In the present study, a case of solitary cardiac metastasis of uterine cervical cancer diagnosed antemortem is reported, and a review of the currently available literature (which includes 18 cases of cardiac metastasis of uterine cervical cancer) is conducted. In January 2013, a 78-year-old woman with squamous cell carcinoma (SCC) of the uterine cervix (International Federation of Gynecology and Obstetrics stage IIIb) underwent definitive radiotherapy at Gunma University Hospital (Gunma, Japan). Follow-up examination at 5 months after completion of the treatment indicated no evidence of recurrence or metastasis. In April 2014, the patient reported epigastric discomfort and general malaise. Electrocardiogram suggested myocardial dysfunction. Transthoracic echocardiography revealed the presence of a mass occupying the right ventricle and pericardial effusion. Cine magnetic resonance imaging demonstrated a filling defect in the right ventricle, and transcatheter biopsy confirmed SCC. The patient was diagnosed with a solitary cardiac metastasis of uterine cervical cancer. Despite aggressive medical therapy, the patient succumbed to disease 31 days after admission to hospital. A review of the current literature revealed that 84% of cases of cardiac metastasis develop within 2 years of completion of the initial treatment, and that electrocardiogram and echocardiography reveal findings of myocardial dysfunction and the presence of a mass in the right ventricle, respectively. A treatment strategy for cardiac metastasis of uterine cervical cancer has not been standardized thus far, and the prognosis is very poor, as the majority of patients succumbed to disease within 1 year. In summary, the current case and the literature review conducted in the present study suggest that: i) Cardiac metastasis should be included in the differential diagnosis in cases with nonspecific complaints such as epigastric discomfort and general malaise when patients have a history of uterine cervical cancer, particularly within the previous 2 years; and ii) electrocardiogram and echocardiography are convenient and effective modalities for the diagnosis of cardiac metastasis of uterine cervical cancer. PMID- 27123114 TI - Differential diagnostic value of computed tomography perfusion combined with vascular endothelial growth factor expression in head and neck lesions. AB - There are numerous types of head and neck lesions (HNLs), and conventional computed tomography (CT) has low specificity and sensitivity in the definitive and differential diagnosis of HNLs. The aim of the present study was to evaluate the value of perfusion CT (CTP) combined with vascular endothelial growth factor (VEGF) expression in the differentiation between malignant and benign HNLs. In total, 41 HNLs, which were pathologically confirmed, underwent CTP and VEGF expression analysis. All lesions were divided into three groups: Group A, benign hypovascular lesions; Group B, benign hypervascular lesions; and Group C, malignant lesions. Time density curve (TDC) and CTP parameters [maximum intensity projection (MIP), blood volume (BV), blood flow (BF), mean transit time and capillary permeability] were analyzed. The association between perfusion measurements and VEGF was assessed using Pearson's correlation. TDCs were classified into three types, and type I was more frequently identified in benign tumors (Groups A and B) compared with malignant tumors (Group C) (P=0.003). Malignant tumors primarily had a TDC of type II and III. MIP, BF and BV were all significantly higher in Groups B and C compared to Group A (P<0.01). VEGF expression of malignant tumors was significantly higher than benign tumors (P=0.007). No correlation was identified between VEGF and any CTP parameter. The present findings suggest that CTP combined with VEGF may differentiate between malignant and benign HNLs, and between benign hypovascular and hypervascular lesions. PMID- 27123115 TI - Laparoscopic resection of benign schwannoma in the hepatoduodenal ligament: A case report and review of the literature. AB - Schwannomas are mesenchymal neoplasms with a low malignant potential, which arise from Schwann cells. The tumors can occur in most parts of the body; however, the head, neck and flexor surfaces of the extremities are the most common locations. Schwannomas occurring in the hepatoduodenal ligament are extremely rare. To the best of our knowledge, only two cases of schwannoma in the hepatoduodenal ligament have been reported in the literature, and treatment of such cases by laparoscopic surgery has not yet been reported. The present study reports a case of schwannoma in the hepatoduodenal ligament in a 50-year-old male patient. Physical and laboratory examinations showed no abnormal results. Ultrasound and computed tomography failed to definitively diagnose the mass and identify its location. During laparoscopic surgery, a mass was identified in the hepatoduodenal ligament and was completely removed. The gross specimen was a 4.5*2.5*2.5-cm localized mass, yellowish-white in color. Microscopic examination revealed that the tumor was mainly composed of spindle-shaped cells and no atypical cells were identified. Immunohistochemical staining showed a strong positive S-100 protein reaction, whereas cluster of differentiation 34 and epithelial membrane antigen were negative. The final diagnosis of the lesion was benign schwannoma of the hepatoduodenal ligament. The patient was followed-up for 7 months and, at the time of writing, was healthy and without any complications. The aim of the present study was to describe a rare case of hepatoduodenal ligament schwannoma in a 50-year-old male patient, and present a review of the literature. To the best of our knowledge, this is the first case of hepatoduodenal ligament schwannoma treated by laparoscopic surgery. PMID- 27123117 TI - Comparison of recovery effect for sufentanil and remifentanil anesthesia with TCI in laparoscopic radical resection during colorectal cancer. AB - The aim of the present study was to compare the recovery of sufentanil and remifentanil anesthesia by target-controlled infusion (TCI) in elderly patients with laparoscopic-assisted radical resection of colorectal cancer. The effect of anesthesia on patient stress response and cellular immune function was also observed. Elderly patients (n=192) who underwent laparoscopic radical resection of colorectal cancer between July 2014 and October 2015 were randomly divided into the sufentanil and remifentanil groups (n=96 per group). The two groups used sufentanil- and remifentanil-based anesthesia by TCI. The wake-up time, extubation time, orientation recovery time, vital signs, stress response, distribution of T-cell subsets and incidence of adverse reactions were recorded and compared. The wake-up and extubation times of the remifentanil group were significantly shorter than those of the sufentanil group. The difference of orientation recovery time was not statistically significant. The differences in heart rate, mean arterial pressure, and arterial oxygen saturation following anesthesia and during surgery and those prior to anesthesia of the sufentanil group were not statistically significant. However, those of the remifentanil group significantly improved following anesthesia. The concentrations of glucose, cortisol (COR), and interleukin-6 and C-reactive protein were stable in the sufentanil group, whereas the indices in the remifentanil group had a tendency of increasing during the anesthesia and surgery, and had a longer postoperative recovery time. The decreasing degree of T-cell subsets in the sufentanil group was significantly lower than that in the remifentanil group, and had a short recovery of cellular immunity following surgery. The adverse reactions rate during anesthesia of the remifentanil group was significantly higher than that of the sufentanil group. In conclusion, sufentanil- and remifentanil-based anesthesia with TCI has certain advantages, including improved recovery effect, less stress response, less inhibition of cellular immunity and fewer adverse reactions. It has the potential to become the first choice of anesthetic in the clinic for elderly patients who undergo laparoscopic radical resection for colorectal cancer. PMID- 27123118 TI - Expression of endothelin-1 in laryngocarcinoma tissues and its clinical significance. AB - In recent years, the incidence of laryngeal carcinoma has been on the increase. The aim of the present study was to examine the expression level of endothelin-1 (ET-1) in laryngeal carcinoma tissues and to establish its clinical significance. A total of 82 cases of laryngeal carcinoma tissues were examined, of which 27 cases were stage I, 34 were stage II, and 21 were stage III. The normal mucosal tissues beyond the surgical incision margin in the 82 laryngeal carcinoma patients were used as the normal control. An additional 80 tissue specimens collected from laryngeal carcinoma outpatients were used as benign lesions. ET-1 expression levels in different tissues were determined using streptavidin peroxidase (SP) immunohistochemistry. The results showed that the ET-1 expression level was highest in laryngeal carcinoma tissues and was significantly higher than that in the other two groups (P<0.05). The ET-1 expression level was higher in stage III compared to that in stage I and II (P<0.05) and higher than that of the normal control (P<0.05). The ET-1 expression level was higher in stage II compared to that in stage I (P<0.05). In conclusion, ET-1 was strongly expressed in laryngeal carcinoma tissues and may play an important role in the pathogenesis and development of laryngeal carcinoma tissues. ET-1 expression in laryngeal carcinoma tissues was associated with the clinical staging of laryngeal carcinoma. PMID- 27123119 TI - Clinicopathological evaluation of pre-operative chemoradiotherapy with S-1 as a treatment for locally advanced oral squamous cell carcinoma. AB - The administration of pre-operative chemotherapy with S-1 and concurrent radiotherapy at a total dose of 30 Gy was clinicopathologically evaluated as a treatment for locally advanced oral squamous cell carcinoma (OSCC) in the present study. The participants comprised 81 patients with OSCC, consisting of 29 patients with stage II disease, 12 patients with stage III disease and 40 patients with stage IV disease. All patients received a total radiation dose of 30 Gy in daily fractions of 2 Gy, 5 times a week, for 3 weeks, and the patients were concurrently administered S-1 at a dose of 80-120 mg, twice daily, over 4 consecutive weeks. Radical surgery was performed in all cases at 2-6 weeks subsequent to the end of pre-operative chemoradiotherapy. The most common adverse event was oropharyngeal mucositis, but this was transient in all patients. No severe hematological or non-hematological toxicities were observed. The clinical and histopathological response rates were 70.4 and 75.3%, respectively. Post operatively, local failure developed in 6 patients (7.4%) and neck failure developed in 2 patients (2.5%). Distant metastases were found in 7 patients (8.6%). The overall survival rate, disease-specific survival rate and locoregional control rate at 5 years were 87.7, 89.9 and 90.6%, respectively. Locoregional recurrence occurred more frequently in patients that demonstrated a poor histopathological response compared with patients that demonstrated a good response (P<0.01). These results indicate that pre-operative S-1 chemotherapy with radiotherapy at a total dose of 30 Gy is feasible and effective for patients with locally advanced OSCC, and that little or no histopathological response may be a risk factor for locoregional recurrence in this treatment. PMID- 27123116 TI - Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors. AB - Regression in melanoma is a frequent biological event of uncertain prognostic value as the lesion exhibits heterogeneous phenotypical features, both at the morphological and immunohistochemical level. In the present study, we examined the expression of tissue inhibitors of metalloproteinases (TIMP1, TIMP2 and TIMP3) in melanoma with regression. We specifically examined the expression levels of these TIMPs in regressed components (RC) and non-regressed components (NRC) of the tumor and compared their expression levels with those in non regressed melanomas. We found that TIMP1 was overexpressed in the NRC of melanomas with partial regression (PR) compared with the NRC in melanomas with segmental regression (SR) (P=0.011). TIMP2 was overexpressed in the NRC of melanomas with PR compared with the NRC in melanomas with SR (PR/SR, P=0.009); or compared with the NRC in melanomas with simultaneous SR-PR (P=0.002); or compared with melanomas without regression (absence of regression) (P=0.037). Moreover, TIMP3 was overexpressed in the NRC of all melanomas with SR as compared to the RC component (P=0.007). Our findings on the differential expression of TIMP1, TIMP2 and TIMP3 in melanomas with regression support the hypothesis that the morphological differences identified in the melanoma regression spectrum may have a correlation with prognosis. This may explain the controversial findings within the literature concerning the biological and prognostic role of regression in melanoma. PMID- 27123120 TI - Simvastatin blocks TGF-beta1-induced epithelial-mesenchymal transition in human prostate cancer cells. AB - In recent years, the use of statins has been reported to be associated with a reduced risk of prostate cancer (PCa), particularly metastatic PCa. The mechanisms underlying these epidemiological observations are poorly understood. Epithelial-mesenchymal transition (EMT) is a critical initial step and a hallmark for cancer metastasis. In the present study, the relationship between simvastatin and EMT in PCa and the mechanism involved was investigated. It was demonstrated that simvastatin inhibited the EMT as assessed by reduced expression of N cadherin and vimentin, and increased E-cadherin in TGF-beta1 treated DU145 PCa cells. Furthermore, simvastatin inhibited TGF-beta1-induced migration and invasion of DU145 cells. The TGF-beta1/Smad pathway and non-Smad pathway were investigated in simvastatin-treated DU145 cells. Simvastatin had no effect on TGF beta1-induced phosphorylation of Smad2 and Smad3. In the non-Smad pathway, simvastatin reduced TGF-beta1-induced p38 MAPK phosphorylation, but had no effect on TGF-beta1-induced Erk1/2 phosphorylation. Simvastatin attenuated TGF-beta1 induced EMT, cell migration and invasion in DU145 cells. These effects may have been mediated by the inhibition of p38 MAPK phosphorylation, not through the canonical Smad pathway. Therefore simvastatin may be a promising therapeutic agent for treating PCa. PMID- 27123121 TI - Cyst fluid hemoglobin species in endometriosis and its malignant transformation: The role of metallobiology. AB - The aim of the present study was to assess the relative concentrations of hemoglobin (Hb) species in endometriosis as a possible indicator of malignancy. Electronic absorption spectroscopy was employed to quantify the Hb species present in the cyst fluid collected from 8 patients with endometriosis-associated ovarian cancer (EAOC), and compared with those present in the cyst fluid of 35 patients with benign endometriotic cysts. The 620/580 nm ratio in the electronic absorption spectrum, which was used as a surrogate indicator of the methemoglobin (metHb)/(oxyhemoglobin+metHb) ratio, was measured in each cyst fluid by ultraviolet/visible grating spectrophotometric microplate reader. The optimal cutoff value was defined according to the analysis of receiver operating characteristic (ROC) curve. The sensitivity and specificity of detection were calculated on the basis of the cutoff value to differentiate EAOC from endometriosis. The 620/580 nm ratio of cyst fluid in EAOC patients was much lower than that measured in women with benign cysts (0.389+/-0.266 vs. 0.666+/-0.188, P=0.021). ROC curve analysis performed using 0.35 as the optimal cutoff value indicated that the 620/580 nm ratio had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value of 62.5, 100.0, 100.0 and 92.1%, respectively, in the diagnosis of EAOC. In conclusion, metHb is one of the most abundant Hb species in benign cysts, and the absorption 620/580 nm ratio of cyst fluid exhibits high specificity and PPV as a surveillance test for the early detection of malignant transformation of endometriosis. Thus, metallobiology highlights diverse features involved in Hb homeostasis and the pathogenesis of malignant transformation of endometriosis. PMID- 27123122 TI - Comparison of plan optimization for single and dual volumetric-modulated arc therapy versus intensity-modulated radiation therapy during post-mastectomy regional irradiation. AB - The aim of the present study was to investigate volumetric-modulated arc therapy (VMAT) with single arc (1ARC) and dual arc (2ARC), and intensity-modulated radiation therapy (IMRT), and to evaluate the quality and delivery efficiency of post-mastectomy regional irradiation. A total of 24 female patients who required post-mastectomy regional irradiation were enrolled into the current study, and 1ARC, 2ARC and IMRT plans were designed for each individual patient. The quality of these plans was evaluated by calculating the homogeneity index (HI), conformity index (CI) and specific volume dose to the ipsilateral lung, double lungs, contralateral breast, heart and spinal cord. For the delivery efficiency of these plans, the total treatment time (TTT) and the number of monitor units (MUs) were evaluated. The 1ARC and 2ARC VMAT plans exhibited significantly better HIs and CIs than IMRT. For dose-volume histogram analysis, 1ARC and 2ARC VMAT spared a more specific volume dose to the ipsilateral lung, double lungs, contralateral breast, heart and spinal cord than IMRT (P<0.05). A lower MU per 2.0-Gy fraction was required for 1ARC (539 MU) and 2ARC (608 MU) than for IMRT (1,051 MU). Thus, TTT was correspondingly reduced in 1ARC and 2ARC compared to IMRT (P<0.05). There was no significant dose-volume difference in all the organs at risk (OARs) between the 1ARC and 2ARC plans (P>0.05), and 2ARC VMAT displayed a better HI and CI than 1ARC VMAT (P<0.05). By contrast, 1ARC VMAT was superior to 2ARC VAMT with regard to MU and TTT (P<0.05). The 1ARC and 2ARC VMAT plans demonstrated significantly better dose distribution in a shorter treatment time than IMRT for post-mastectomy regional irradiation, and spared the majority of OARs without compromising target coverage. The results of the present study suggest that 2ARC VMAT may be an alternative to 1ARC in order to obtain a more optimal HI and CI. PMID- 27123123 TI - Recurrent intracranial neurenteric cyst with malignant transformation: A case report and literature review. AB - Neurenteric cysts (NCs) are uncommon congenital cystic lesions. Malignantly transformed NCs are extremely rare. The present study reports the case of a recurrent foramen magnum NC with a malignant transformation and reviews 8 previously reported cases. A 58-year-old woman with a 5-month history of occasional headaches, dizziness and vomiting presented to the Beijing Tiantan Hospital (Beijing, China) with palsy of the left cranial IX and X nerves, decreased sensation in the limbs on the right side and an ataxic gait. Magnetic resonance imaging (MRI) scans revealed a cystic mass in the left side of the foramen magnum, positioned anteriolaterally to the medulla oblongata. Surgery using a left suboccipital retrosigmoid approach was performed. The lesion was partially resected and was histopathologically diagnosed as an NC with focal hyperplasia of the epithelial cells. Additional MRI scans that were performed 25 months later revealed a solid lesion posterior to the medullar oblongata. Therefore, surgery using a suboccipital midline approach was performed. The solid lesion was sub-totally removed and was histopathologically diagnosed as a well differentiated papillary adenocarcinoma. At 1 month post-surgery, the patient's condition worsened, eventually resulting in mortality due to respiratory failure. Based on the findings of the present case and previous literature, strict criteria for malignant-transformed NCs were created. The location distribution of malignant-transformed NCs does not coincide with the location distribution of all NCs, and malignantly transformed NCs usually occur in adult patients and present as atypical radiological features. Surgery is the optimal treatment for malignantly transformed NCs, and the effectiveness of adjuvant therapy requires additional studies. PMID- 27123124 TI - Predominance of M2-polarized macrophages in bladder cancer affects angiogenesis, tumor grade and invasiveness. AB - Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype. Thus, the aim of the present study was to clarify the correlation of vascularity and TAMs, in particular the M2 phenotype in the stroma and tumor areas, with the clinical and pathological outcomes of patients with bladder cancer. The TAM counts and microvessel counts (MVCs) were determined immunohistochemically in 21 patients with bladder cancer. The number of infiltrating TAMs was measured using immunohistochemistry with anti-cluster of differentiation (CD)68 and anti-CD163 antibodies, to identify a macrophage lineage marker and an M2-polarized-specific cell surface receptor, respectively. CD68+ and CD163+ macrophages were evaluated in the stroma and tumor areas, and areas with a high density of infiltrating cell spots were counted. MVCs were determined using immunohistochemistry with anti-CD34 antibodies. The results revealed that the higher ratio of CD163+/CD68+ macrophages in the stroma, tumor and total tumor tissues were correlated with a higher stage and grade (P<0.05). In addition, the low ratio of CD68+/CD34+ microvessels was correlated with a higher stage (P<0.05). There was also a positive correlation between TAMs and MVC (r2=0.25; P<0.05). These results suggest that the TAM polarized M2 phenotype affects microvessels, pathological outcome, tumor grade and invasiveness. PMID- 27123125 TI - Brunner's gland cyst in combination with gastrointestinal stromal tumor: A case report. AB - Brunner's gland cysts are rare benign lesions that are mainly observed in the first and the second regions of the duodenum. Patients with Brunner's gland cyst demonstrate no specific symptoms. The present study reports the case of a patient with Brunner's gland cyst located in the duodenum in combination with a gastrointestinal stromal tumor (GIST) in the same region. To the best of our knowledge, the present study reports the first case of Brunner's gland cyst with GIST. A 58-year-old female patient was referred to Tianchang Hospital of Traditional Chinese Medicine (Tianchang, China) with a one-month history of upper abdominal discomfort, diarrhea and recurrent vomiting following the intake of food. Upper gastrointestinal endoscopy and a computed tomography scan revealed the presence of a round, cystic-like lesion with internal low density located within the duodenum. Pathological examination revealed that the cyst measured 0.3 cm in diameter and was consistent with a diagnosis of Brunner's gland cyst. Histopathology revealed that the cyst possessed characteristics of GIST. The patient underwent surgical exploration and tumor resection, and was discharged 2 weeks post-surgery. During the 12 month post-operative follow-up period, the outcome of the patient was good. This case study of Brunner's gland cyst combined with GIST enriches the present literature and promotes better understanding of the two diseases. Further investigation is required to explain the mechanism and association between the two rare diseases. PMID- 27123126 TI - Dermatomyositis as a symptom of primary lung cancer: A case report and review of the literature. AB - Dermatomyositis (DM) is a rare autoimmune disease associated with manifestations of proximal muscle weakness and typical cutaneous skin rash. Patients with DM have a higher incidence rate of cancer, compared with the general population, since DM usually presents as a paraneoplastic syndrome. The present study reports a case of a 69-year-old male patient presenting with typical cutaneous rash and aggravating proximal muscle weakness for 3 months. When first admitted to the Department of Dermatology of Shandong Provincial Hospital Affiliated to Shandong University (Jinan, China), the patient was diagnosed with DM. Subsequently, chest computed tomography scan revealed a neoplasm located in the right upper lobe. Video-assisted thoracoscopic surgery right upper lobectomy and lymph node dissection were then performed. The patient experienced a fast recovery from the surgery. The removal of the neoplasm clearly improved the symptoms of DM. Considering that DM is usually associated with the existence of a tumor, cases of DM require a thorough diagnostic investigation in order to exclude an underlying malignancy. PMID- 27123127 TI - Skull sclerosing epithelioid fibrosarcoma: A case report and review of the literature. AB - Sclerosing epithelioid fibrosarcoma (SEF) is an unusual variant of fibrosarcoma that was previously considered to be a low-grade tumor with an indolent course. The tumor occurs most commonly in the soft tissue of the limb, trunk, head and neck, and occasionally in the bone and visceral organs. The skull is a rare primary site for SEF, with only 3 cases reported to date. The current study reports a case of SEF occurring in the occipital bone of a 24-year-old man, who lacked neurological symptoms. Imaging revealed a large mass emanating from the occipital bone and involving the superior sagittal sinus, torcular herophili and adjacent brain tissue. Histological and immunohistochemical characteristics confirmed the diagnosis of SEF. The patient experienced local recurrence and distant metastasis at 10 and 15 months, respectively, subsequent to the resection of the primary mass. The current case and review of the literature suggest that skull SEF may behave clinically as an aggressive malignant sarcoma. Radiological findings indicated the biological and histopathological characteristics of the tumor. Thus, its clinical behavior and certain imaging features may suggest this diagnosis. PMID- 27123128 TI - Extended field intensity-modulated radiotherapy plus concurrent nedaplatin treatment in cervical cancer. AB - The present study assessed the efficacy and toxicity of definitive extended-field intensity-modulated radiotherapy (EF-IMRT) plus concurrent chemotherapy in cervical cancer. A total of 48 patients with cervical cancer received the planning target volume between 39.6 and 50.4 Gy in 1.8-2.0 Gy daily fractions, while the enlarged pelvic and/or para-aortic nodes were treated with a total dose of 55-60 Gy in 2.0-2.4 Gy daily fractions using simultaneous integrated boost IMRT. All patients underwent high dose-rate brachytherapy. Concurrent to EF-IMRT, nedaplatin was administered weekly at a median dose of 30 mg/m2 (range, 25-40 mg/m2) for 5 weeks with a total of 150 mg/m2. Of the 48 patients, 46 patients exhibited initial complete responses and 2 patients had partial responses, with a response rate of 100%. After 4-24 months of treatment, 12 patients (27.08%) had local and/or distant failure and 39 patients (81.25%) were alive at the last follow-up. The 12-month overall survival (OS) and disease-free survival (DFS) were 87.5 and 75.8%, respectively, while the 24-month OS and DFS were 69.7 and 49.7%, respectively. Grade >=3 acute neutropenia and thrombcytopenia occurred in 20 (41.7%) and 4 (8.3%) patients, respectively, while 2 patients (4.2%) developed grade >=3 diarrhea and 2 (4.2%) had grade >=3 late toxicities. However, no patients exhibited grade >=3 vomiting. Thus, concurrent nedaplatin chemotherapy with definitive EF-IMRT was effective and relatively safe for treating patients with cervical cancer. Furthermore, EF-IMRT was able to deliver <=60 Gy to enlarged para-aortic and/or pelvic nodes using simultaneous integrated boost without increased acute and late gastrointestinal toxicity. PMID- 27123129 TI - Fever and arthralgia as the initial symptoms of primary bone marrow diffuse large B-cell lymphoma: A case report. AB - Primary bone marrow diffuse large B-cell lymphoma (DLBCL) is rare, and only a few cases have been reported. Fever and arthralgia as the initial symptom are extremely rare; however, awareness must be made of this presentation. The current study describes the clinical and pathological findings of a 41-year-old man affected by fever and arthralgia. Blood tests revealed leukopenia and anemia. Multiple bone marrow biopsies were conducted and confirmed the diagnosis of primary bone marrow DLBCL. Primary bone marrow DLBCL is a rare and frequently misdiagnosed subset of non-Hodgkin's lymphoma. The current case demonstrates that utility of bone marrow biopsy for diagnosis should not be ignored, and that repeated bone marrow punctures in multiple locations may be necessary. PMID- 27123131 TI - IgG4-related inflammatory pseudotumor of the kidney mimicking renal cell carcinoma: A case report. AB - IgG4-related disease is a recently recognized clinical entity. It is characterized by diffuse organ swelling or mass formation, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells with fibrosis and typically an increased serum IgG4 concentration, which may affect various organs. An 80-year-old woman with an otherwise unremarkable previous medical history was revealed to have a renal mass that was indicative of renal malignant carcinoma, for which a radical nephrectomy was performed. The mass was diagnosed as an IgG4 related inflammatory pseudotumor, which was histopathologically confirmed. The patient is currently well without evidence of IgG4-related disease at 3 months post-surgery, and did not require any additional therapy. PMID- 27123130 TI - Clinical treatment of gastrinoma: A case report and review of the literature. AB - Gastrinoma is a gastrin-secreting tumor that is associated with Zollinger-Ellison syndrome. The majority of cases occur in the pancreas, followed by the duodenum. Early diagnosis is difficult due to the relative rarity of the tumor and the lack of specific symptoms. In the current study, a 68-year-old female patient presented at the Second Affiliated Hospital, Zhejiang University (Hangzhou, China) due to intermittent abdominal pain and watery diarrhea. The patient was treated by surgical resection and was pathologically diagnosed with a well differentiated pancreatic neuroendocrine tumor (gastrinoma; grade 1). No evidence of recurrence was observed during 1 year of follow-up. Furthermore, a review of the Chinese literature was performed, which analyzed an additional 17 published cases of gastrinoma. The tumor size ranged between 0.5*0.5 cm and 7.5*6.3*5.1 cm. The pancreas was the most common site of occurrence, accounting for 72% (13/18) of cases, followed by the duodenum (28%; 5/18). The most common initial symptom was abdominal pain (89%; 16/18), followed by diarrhea (56%; 10/18). In 18 cases, including the present case and 17 previous cases, the level of gastrin ranged between 137 and 1,550 pg/ml (normal range, 5-100 pg/ml). Of the 17 previous cases, 11 patients underwent surgery and 6 patients received conservative therapy due to metastasis or patient choice. Overall, gastrinoma remains a rare disease. Complete removal of the lesion is the standard curative treatment and conservative treatment is only recommended for patients unsuitable for surgery or for those with widespread metastasis. PMID- 27123132 TI - Derived neutrophil/lymphocyte ratio predicts gemcitabine therapy outcome in unresectable pancreatic cancer. AB - As gemcitabine is a key anti-tumor agent for unresectable pancreatic ductal adenocarcinoma (PDAC), it is important to predict the outcomes of gemcitabine chemotherapy. The present study aimed to confirm whether the derived neutrophil to-lymphocyte ratio (dNLR) is able to predict chemotherapy outcomes. To elucidate the role of dNLR in patients that underwent chemotherapy, the current study evaluated clinicopathological variables in 31 patients with unresectable PDAC treated with gemcitabine. The correlation between clinicopathological variables, and progression-free survival (PFS) and overall survival (OS) time were investigated. Univariate analysis revealed that there were no significant differences in PFS and OS as a function of age (<65 vs. >=65 years), gender, tumor location (pancreas head vs. body/tail), tumor diameter (<23 vs. >=23 mm) or serum carbohydrate antigen 19-9 concentration level (<3,800 vs. >=3,800 U/ml). However, disease stage (locally advanced vs. metastatic) and the dNLR (<2.5 vs. >=2.5) significantly affected PFS and OS. Multivariate analysis subsequently revealed that a dNLR of >=2.5 was an independent prognostic factor for poor PFS (P=0.003) and OS (P=0.026). In conclusion, data from the present study suggests that the pre-treatment dNLR is an independent prognostic factor to predict PFS and OS in patients with unresectable PDAC treated with gemcitabine. This indicates that dNLR has a potential role in stratifying patients that may benefit from gemcitabine therapy. PMID- 27123133 TI - Progestin-releasing intrauterine device insertion plus palliative radiotherapy in frail, elderly uterine cancer patients unfit for radical treatment. AB - The present study investigated the combination of levonorgestrel-releasing intrauterine device (LNG-IUD) insertion and palliative radiotherapy (RT) as a potential approach for treating frail, elderly endometrial cancer (EC) patients considered unfit for curative oncological treatments. The inclusion criteria were an age of >=65 years, pathological confirmation of a uterine neoplasm, a Charlson comorbidity index (CCI) value of >=4 and the presence of vaginal bleeding. Patients underwent intrauterine insertion of an LNG-IUD, and thereafter, received a total dose of 30 Gy at 3 Gy per fraction, over 10 days. The clinical target volume (CTV) was defined as the uterus and disease-involved tissues in the pelvis plus a 1-cm margin. The planning target volume was obtained by adding a 1-cm isotropic margin to the CTV. A total of 9 patients with EC (median age, 85 years; Eastern Cooperative Oncology Group performance status >=2, >=88.8%; obesity, 55.5%; median CCI, 5) received an LNG-IUD plus RT. An early complete resolution of bleeding was documented in 8 patients (88.8%), while the remaining patient experienced a marked improvement. The median duration of bleeding control was 18 months, while the 2-year actuarial rate of bleeding-free survival was 53.3% (median follow-up time, 20 months; range, 9-60 months). No LNG-IUD- or severe RT related complications were documented. Overall, a high rate of bleeding remission, durable bleeding-free survival in face of the easy intrauterine insertion of an LNG-IUD and a negligible toxicity profile of the complete treatment were documented in this study, indicating a requirement for further investigation in a larger series. PMID- 27123134 TI - Knockdown of LMP1-induced miR-155 sensitizes nasopharyngeal carcinoma cells to radiotherapy in vitro. AB - The present study aimed to confirm the promotion of microRNA (miR)-155 expression by latent membrane protein 1 (LMP1), and to recognize the oncogenic role of LMP1 and LMP1-promoted miR-155 in nasopharyngeal carcinoma (NPC), particularly the influence of miR-155 knockdown on the radiosensitivity of CNE-2 cells. Following the regulation of the levels of LMP1 or miR-155 and/or subsequent to radiation treatment, the proliferation ability of CNE-2 cells was examined using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation and Cell Counting Kit-8 assays. The results demonstrated that miR-155 was upregulated by overexpression of LMP1 in CNE-2 cells, and LMP1 overexpression and miR-155 mimic transfection increased CNE-2 cell proliferation, whereas miR-155 knockdown attenuated the promotion of CNE-2 cell growth induced by LMP1 overexpression. Furthermore, knockdown of miR-155 enhanced the radiosensitivity of CNE-2 cells. In conclusion, the present study confirmed the oncogenic role of miR-155 in NPC, and demonstrated that knockdown of miR-155 inhibited the growth of NPC cells and sensitized NPC cells to radiotherapy. PMID- 27123135 TI - Imaging features of soft tissue epithelioid angiosarcoma in the lower extremity: A case report. AB - Epithelioid angiosarcomas are extremely rare malignant tumors formed from endothelial cells. The majority of studies reporting these tumors have been concerned with the clinical and pathological aspects, with limited reporting of radiological diagnosis. The aim of the present study was to provide a reference to improve understanding of diagnosis, treatment choice and prognosis assessment of epithelioid angiosarcoma. The current study reports the case of a 44-year-old woman with epithelioid angiosarcoma located in the deep soft tissue of the lower extremities. Physical examination of the right thigh revealed a palpable hard mass and movement was clearly restricted and painful. X-ray, computed tomography (CT) scans and magnetic resonance imaging (MRI) were used to evaluate the imaging features of the tumor. Using X-ray and CT scanning, an inhomogenous tumor with osteolytic osseous destruction was observed. MRI revealed that the bordering skeletal muscles were infiltrated. The patient was treated with palliative surgery and chemotherapy, but succumbed to disease 1 year later. PMID- 27123136 TI - Giant cell tumor of the tendon sheath originating from the ankle capsule: A case report and literature review. AB - Giant cell tumor of the tendon sheath (GCTTS), also termed tendosynovial giant cell tumor, is a benign, slow-growing tumor that originates from the tendon sheath or bursa. GCTTS of the foot and ankle is much less frequently reported compared with GCTTS of the hand and knee. However, GCTTS should be considered as a differential diagnosis of soft tissue tumors of the foot and ankle. The optimal treatment strategy for GCTTS in the foot and ankle is controversial due to a scarcity of cases. The present study reports the case of a patient that presented with localized intra-articular GCTTS originating from the capsule of the ankle, which is a rare anatomical location for this tumor. Considering the proximity of the tumor to the adjacent non-tumorous structures, a less radical but complete resection of the tumor was performed, followed by a hydrogen peroxide lavage. There was no evidence of recurrence during a follow-up period of 12 months, and adjuvant radiotherapy was not administered to the patient. A pre-operative diagnosis for GCTTS in the foot and ankle is mainly based on the findings of clinical examination and magnetic resonance imaging, which also facilitates the determination of a surgical strategy. For a localized tumor, an integral resection, as opposed to a radical resection, with a hydrogen peroxide lavage may result in a favorable prognosis. However, the optimal treatment for diffuse GCTTS remains to be identified. PMID- 27123137 TI - Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells. AB - Smad4 is a common Smad and is a key downstream regulator of the transforming growth factor-beta signaling pathway, in which Smad4 often acts as a potent tumor suppressor and functions in a highly context-dependent manner, particularly in pancreatic cancer. However, little is known regarding whether Smad4 regulates other signaling pathways involved in pancreatic cancer. The present study demonstrated that Smad4 downregulates c-Jun N-terminal kinase (JNK) activity using a Smad4 loss-of-function or gain-of-function analysis. Additionally, stable overexpression of Smad4 clearly affected the migration of human pancreatic epithelioid carcinoma PANC-1 cells, but did not affect cell growth. In addition, the present study revealed that upregulation of mitogen-activated protein kinase phosphatase-1 is required for the reduction of JNK activity by Smad4, leading to a decrease in vascular endothelial growth factor expression and inhibiting cell migration. Overall, the present findings indicate that Smad4 may suppress JNK activation and inhibit the tumor characteristics of pancreatic cancer cells. PMID- 27123138 TI - Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience. AB - Rituximab (RTX) improves the outcome in patients with systemic diffuse large B cell lymphoma (DLBCL), but its benefit in primary central nervous system lymphoma (PCNSL) is unclear. In the present study, a single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL. PMID- 27123139 TI - Evaluation of effects of thymidylate synthase and excision repair cross complementing 1 polymorphisms on chemotherapy outcome in patients with gastrointestinal tumors using peripheral venous blood. AB - The aim of the present study was to evaluate the effects of thymidylate synthase (TYMS) and excision repair cross-complementing 1 (ERCC1) polymorphisms on chemotherapeutic efficacy in patients with gastrointestinal tumors using peripheral venous blood. Preoperative peripheral venous blood and tumor tissue samples of 43 patients with gastric cancer and the peripheral venous blood samples of 76 patients with cancer who underwent chemotherapy were studied. The 3R/3R and 2R/2R or 2R/3R genotypes of TYMS were identified in 72.09 and 27.91%, respectively (P<0.01), of untreated patients, and the C/C and T/T or C/T genotypes of ERCC1 were present in 81.39 and 18.61%, respectively (P<0.01), of patients. The 3R/3R and 2R/2R or 2R/3R genotypes of TYMS were identified in 65.79 and 34.21%, respectively, of chemotherapy-treated patients. The overall response rates (ORRs) for the two aforementioned genotypes were 18.00 and 57.69%, respectively (P<0.01), and those for the C/C and T/T or C/T genotypes of ERCC1 were 63.16 and 36.84%, respectively. The ORRs were 47.91 and 3.57%, respectively (P<0.01). In conclusion, peripheral blood samples may be used to replace tumor tissue for detecting TYMS and ERCC1 polymorphisms, and may be used to evaluate the efficacy of 5-fluorouracil and platinum drugs. PMID- 27123140 TI - Serum B-type natriuretic peptide levels as a marker for anthracycline-induced cardiotoxicity. AB - Observational and experimental studies have produced inconsistent evidence about the association of serum levels of B-type natriuretic peptide (BNP) with anthracycline-induced cardiotoxicity (AIC). Therefore, the current meta-analysis examined the association between serum BNP levels and AIC by using data from high quality studies published in peer-reviewed journals. Relevant studies were identified through literature searches of China National Knowledge Infrastructure (CNKI), Web of Science, PubMed, Google Scolar and China BioMedicine (CBM). STATA software was used in this meta-analysis for statistical analysis. In addition, the crude standardized mean difference (SMD) with 95% confidence interval (CI) for the highest vs. the lowest category of serum BNP levels was calculated. A total of 8 independent case-control studies, containing 126 AIC patients and 569 healthy controls, were included for the current meta-analysis. The results indicated a significant difference in serum BNP levels between the cardiotoxic group and normal group, with respect to post-treatment and pretreatment with anthracyclines. Specifically, the serum levels of BNP increased remarkably after treatment with anthracyclines in the cardiotoxic group, compared with the normal group. No publication bias was detected in this meta-analysis. The findings of the present study provide strong evidence that serum BNP levels may be associated with AIC. PMID- 27123141 TI - Infrahyoid flap in oropharyngeal reconstruction following carcinoma resection: A study of 6 patients and literature review. AB - The present study aimed to describe the techniques used and the results obtained with the infrahyoid flap for the reconstruction of medium-sized oropharyngeal defects following resection for advanced squamous cell cancer. During a period of 1 year, six patients with oropharyngeal defects were reconstructed using the infrahyoid flap. The tumor characteristics, location and size of the defect, resective and reconstructive techniques employed and the complications and outcomes of the speech and swallowing functions, as identified in the follow-up visits every 3 months, were evaluated. All flaps were performed simultaneously in association with tumoral excision and ipsilateral supraomohyoid neck dissection. The mean size of the skin paddle was 7.0*3.5 cm. The donor site was primarily sutured. The postoperative course was uneventful and all flaps were viable. One case of marginal skin paddle loss occurred without affecting the survival of the flap. Five patients received postoperative radiotherapy and one patient received concurrent postoperative chemotherapy. During the follow-up period (mean, 63 months), all patients showed excellent oral swallowing. Speech was excellent in five patients and in one patient speech was classified as good. The aesthetic results of the cervical donor site were good. Based on the present case report and the literature review, the infrahyoid flap is a simple and safe procedure for the reconstruction of the oropharynx, with a high success rate, minimal donor site morbidity and good aesthetic and functional results. The infrahyoid flap is a valid surgical option that may be considered in selected oncological patients undergoing reconstruction of medium-size oropharyngeal defects. PMID- 27123142 TI - Prognostic factors of intraperitoneal chemotherapy for peritoneal carcinomatosis of gastric cancer: A retrospective study from a single center. AB - Peritoneal carcinomatosis (PC) of gastric origin is currently recognized as a terminal disease with a poor prognosis. Advancements in novel therapeutic approaches, including intraperitoneal chemotherapy (IPC), have recently been made and it is believed that this may have contributed to the improved survival observed in patients with PC. The present study aimed to investigate overall survival (OS) and the associated prognostic factors in patients with PC of gastric origin who underwent IPC. A total of 57 patients were studied, with a median age of 51 years. The median follow-up time was 12.4 months. PC was diagnosed in all patients with gastric cancer. The median survival time of all patients was 10.1 months, whilst the OS rate at 1, 2 and 3 years was observed to be 46, 19 and 12%, respectively. Symptomatic ascites and a signet ring cell (SRC) histopathological type were demonstrated to signify a poor prognosis. Complete resection of all gross disease (CCR-0) and an increased number of cycles of systemic chemotherapy were independent factors that were observed to correlate with increased OS. The most common morbidities of grade 3/4 adverse effects were bone marrow suppression, nausea or vomiting, and diarrhea. In conclusion, IPC is an important treatment option for patients with PC that has originated from gastric cancer. Symptomatic ascites and SRC adenocarcinoma serve as negative clinicopathological prognostic factors, whilst CCR-0 and increased systemic chemotherapy cycles (>=4 cycles) may prove to be an important therapeutic option for PC patients. PMID- 27123143 TI - The association between four SNPs of X-ray repair cross complementing protein 1 and the sensitivity to radiotherapy in patients with esophageal squamous cell carcinoma. AB - Early stage diagnosis and therapeutic outcomes of esophageal squamous cell carcinoma remain poor. In order to evaluate the association between 4 single nucleotide polymorphisms (SNPs) of X-ray repair cross complementing protein 1 (XRCC1) and the sensitivity to radiotherapy in patients with esophageal squamous cell carcinoma (ESCC), the present study identified 4 SNPs of XRCC1 and evaluated the distribution of these genotypes among patients with ESCC. Venous blood samples from 175 patients with ESCC were collected and DNA was extracted. The 4 SNPs of the XRCC1 gene fragment were amplified using three primer pairs, which were sequenced. The mismatches were analyzed and identified using Basic Local Alignment Search Tool software. The sensitivity to radiotherapy was graded as effective and non-effective, according to the treatment results of the patients. The present study successfully amplified and sequenced 4 SNPs of XRCC1 in 112 out of the 175 patients with ESCC. The effective response rate of radiotherapy was 84.8% among the 112 patients. The effective response rate of patients with no mutation in the SNPs was 74.3%, and the rate increased to 89.6% in patients that had >=1 mutation out of the 4 SNPs (chi2=4.389; P=0.036). For G28152A and G28152A mutations the effective response rate of patients was 91.2% (chi2=4.014; P=0.045) and 91.5% (chi2=4.451; P=0.035), respectively, which was significantly different compared to patients with no mutation (P=0.045 and P=0.035, respectively). The present results suggest that the 4 SNPs of XRCC1 are associated with the effective response rate of radiotherapy in patients with ESCC. The mutation of SNP G28152A was particularly important and may be a potential genomic predictor for radiotherapy sensitivity in patients with ESCC. PMID- 27123144 TI - TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance. AB - Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule associated protein. TPX2 is considered to be an important gene in tumorigenesis; however, the particular function of TPX2 in the development of human renal cell carcinoma (RCC) is unknown. In the present study, the expression, function and prognostic significance of TPX2 in human RCC was analyzed. A total of 286 tissue samples from patients with RCC who had undergone nephrectomies were utilized. Subsequently, the expression of TPX2 protein was investigated using immunohistochemistry and western blotting, and TPX2 mRNA expression was examined using reverse transcription-quantitative polymerase chain reaction. To establish the effect of TPX2 on the proliferation and invasion of the RCC cells, TPX2 expression was increased by stable transfection with a TPX2 vector and TPX2 expression was decreased using small interfering RNA. Proliferation of the RCC cells was analyzed using a WST-1 assay and an animal xenograft model with BALB/c nude mice, whilst invasion of the RCC cells was examined using a Matrigel-coated invasion chamber. It was demonstrated that TPX2 expression was significantly higher in the RCC tissues compared with normal kidney tissues (P<0.05). Furthermore, TPX2 expression was associated with tumor size, histological grade and tumor stage (P<0.05), and was observed to markedly increase the proliferation and invasion of the RCC cells. It may be concluded that the expression of TPX2 is significantly upregulated in RCC tissue, subsequently increasing the proliferative and invasive ability of RCC cells. Therefore, the protein may serve as a therapeutic target and independent prognostic factor in the treatment of human RCC. PMID- 27123145 TI - Association between dynamic contrast enhanced MRI imaging features and WHO histopathological grade in patients with invasive ductal breast cancer. AB - The present study aimed to investigate the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and World Health Organization (WHO) histopathological grade in patients with invasive ductal breast cancer. A retrospective analysis on the results of DCE-MRI of 92 patients, who were diagnosed with invasive ductal breast cancer following surgery or biopsy, and these results were correlated with WHO histopathological grade. The statistical analysis demonstrated that the tumor size, shape and characteristics of early enhancement were associated with the WHO histopathological grade: The larger the lesion's long diameter, the higher the WHO histopathological grade; the WHO histopathological grades of round and oval masses were relatively lower, while those of lobulated and irregular masses were higher; and tumors with heterogeneous and ring-like enhancement exhibited higher WHO histopathological grades, while those of homogeneous enhancement were lower. The lesion's margin shape was not associated with the WHO histopathological grade. The present study demonstrates that features of DCE-MRI and WHO histopathological grade in patients with invasive ductal breast cancer are correlated, and these MRI features could be used to evaluate the biological behavior and prognosis of lesions. PMID- 27123146 TI - Synergistic antitumor activity of gemcitabine combined with triptolide in pancreatic cancer cells. AB - Pancreatic cancer is a fatal human malignancy associated with an exceptionally poor prognosis. Novel therapeutic strategies are urgently required to treat this disease. In addition to immunosuppressive activity, triptolide possesses strong antitumor activity and synergistically enhances the antitumor activities of conventional chemotherapeutic drugs in preclinical models of pancreatic cancer. The present study investigated the antitumor effects of triptolide in pancreatic cancer cells, either in combination with gemcitabine, or alone. The pancreatic cancer BxPC-3 and PANC-1 cell lines were treated with triptolide, which resulted in time- and dose-dependent growth arrest. When incorporated into a sequential schedule, triptolide synergistically increased gemcitabine-induced cell growth inhibition and apoptosis, in addition to the cooperative regulation of B-cell lymphoma 2 family proteins and loss of mitochondrial membrane potential. Furthermore, triptolide enhanced gemcitabine-induced S phase arrest and DNA double-strand breaks, possibly through checkpoint kinase 1 suppression. The results of the present study suggest that triptolide has therapeutic potential for the treatment of pancreatic cancer, particularly when administered in combination with gemcitabine. PMID- 27123147 TI - Network and pathway analysis of microRNAs, transcription factors, target genes and host genes in human glioma. AB - To date, there has been rapid development with regard to gene and microRNA (miR/miRNA) research in gliomas. However, the regulatory mechanisms of the associated genes and miRNAs remain unclear. In the present study, the genes, miRNAs and transcription factors (TFs) were considered as elements in the regulatory network, and focus was placed on the associations between TFs and miRNAs, miRNAs and target genes, and miRNAs and host genes. In order to show the regulatory correlation clearly, all the elements were investigated and three regulatory networks, namely the differentially-expressed, related and global networks, were constructed. Certain important pathways were highlighted, with analysis of the similarities and differences among the networks. Next, the upstream and downstream elements of differentially-expressed genes, miRNAs and predicted TFs were listed. The most notable aspect of the present study was the three levels of network, particularly the differentially-expressed network, since the differentially-expressed associations that these networks provide appear at the initial stages of cancers such as glioma. If the states of the differentially expressed associations can be adjusted to the normal state via alterations in regulatory associations, which were also recorded in the study networks and tables, it is likely that cancer can be regulated or even avoided. In the present study, the differentially-expressed network illuminated the pathogenesis of glioma; for example, a TF can regulate one or more miRNAs, and a target gene can be targeted by one or more miRNAs. Therefore, the host genes and target genes, the host genes and TFs, and the target genes and TFs indirectly affect each other through miRNAs. The association also exists between TFs and TFs, target genes and target genes, and host genes and host genes. The present study also demonstrated self-adaption associations and circle-regulations. The related network further described the regulatory mechanism associated with glioma. These results can be utilized to adjust the states. The present study expounded the regulatory mechanisms of glioma and supplied theoretical data for further studies, in which greater attention should be focused on the highlighted genes and miRNAs. PMID- 27123148 TI - Arthroscopic excision of giant cell tumor of the tendon sheath in the knee mimicking patellar tendinopathy: A case report. AB - Giant cell tumor of the tendon sheath (GCTTS) predominantly occurs in the tendon sheaths of the hand, but rarely in those of the knee. The current study reports the case of a 36-year-old male patient presenting with anterior knee pain. The patient was ultimately diagnosed with GCTTS in the knee mimicking patellar tendinopathy. To the best of our knowledge, this is the first case of its kind. Magnetic resonance imaging revealed a well-defined oval intra-articular lesion located at the proximal segment of the infrapatellar fat pad. The lesion was completely excised under arthroscopy and pathological examination confirmed the diagnosis of GCTTS. There was no evidence of recurrence at the 2-year follow-up examination. The findings of the present study suggest that, despite its rarity, GCTTS should be considered in the differential diagnosis of patellar tendinopathy. PMID- 27123149 TI - EGFR-tyrosine kinase inhibitor treatment in a patient with advanced non-small cell lung cancer and concurrent exon 19 and 21 EGFR mutations: A case report and review of the literature. AB - Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered to be effective treatments for advanced non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations, including exon 19 deletion and exon 21 L858R mutations. However, with the development of EGFR mutation detection assays, patients with complex EGFR mutations are emerging, and their response to EGFR-TKIs remains unclear. The present study reports a case of a 62-year-old, non smoking female patient with advanced NSCLC, presenting with concurrent EGFR 19+21 sensitizing mutations, who had a poor response to the first-line EGFR-TKI erlotinib and succumbed 5 months subsequent to diagnosis. Furthermore, the present study performed a literature review, and 18 patients with complex EGFR 19+21 mutations that had received EGFR-TKIs were identified. The majority of these patients responded well to EGFR-TKIs. To the best of our knowledge, the present case is the first to report a patient with lung adenocarcinoma with complex EGFR 19+21 sensitizing mutations that had a poor clinical response to a first-line EGFR-TKI. Despite the 70% response rate of sensitizing EGFR-mutant NSCLCs to EGFR-TKIs, there is still a proportion of patients that experience de novo resistance, and heterogeneity is likely to be important in this resistance mechanism. Therefore, comprehensive genomic detection assays and multi-targeted therapies for patients with NSCLC with complex EGFR mutations require additional investigation. PMID- 27123150 TI - 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane potentiates in vitro and in vivo antitumor effects of irinotecan on human colorectal cancer cells. AB - 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane (DPD), a diamantane derivative, was previously noted as an anticancer compound through anticancer drug screening with NCI-60 human tumor cells. Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is clinically active in the treatment of colorectal cancer, with no cross-resistance. The current study conducted a pharmacokinetic evaluation of DPD, an essential component of drug discovery. Subsequent pathway analysis of microarray gene expression data indicated that the anticancer mechanisms of DPD were associated with cell cycle progression and apoptosis. The combined effect of DPD and CPT-11 with regard to the mechanisms of apoptosis-related pathways in COLO 205 cells, and the antitumor effects in colon cancer xenograft mice, were investigated. The plasma concentration and pharmacokinetic parameters of DPD in male albino rats were analyzed following a single dose of DPD by injection. The protein expression of active caspase-3, procaspase-3 and poly ADP-ribose polymerase (PARP) in COLO 205 cells treated with DPD and CPT-11, alone or combined, was evaluated by western blotting. A trypan blue dye exclusion assay revealed that, whilst DPD alone demonstrated good antitumor effects, this effect was potentiated when combined with CPT-11. Combined treatment with DPD and CPT-11 upregulated the expression of cleaved PARP, procaspase-3, caspase-3 and active caspase-3 in COLO 205 cells. In the colon cancer xenograft model, compared with the control (vehicle-treated) mice, the sizes of the tumors were significantly lower in mice treated with DPD and CPT 11, alone or in combination. Thus, DPD may be a potential therapeutic agent for the treatment of colorectal cancer via upregulating apoptosis-related pathways. PMID- 27123151 TI - Temporary Stabilization with External Fixator in 'Tripolar' Configuration in Two Steps Treatment of Tibial Pilon Fractures. AB - BACKGROUND: The tibial pilon fractures represent a complex therapeutic problem for the orthopedic surgeon, given the frequent complications and outcomes disabling. The recent medical literature indicates that the best strategy to reduce amount of complications in tibial pilon fractures is two-stages procedure. We describe our experience in the primary stabilization of these fractures. METHODS: We treated 36 cases with temporary external fixation in a simple configuration, called "tripolar": this is an essential structure (only three screws and three rods), that is possible to perform even without the availability of X-rays and with simple anesthesia or sedation. RESULTS: We found a sufficient mechanical stability for the nursing post-operative, in absence of intraoperative and postoperative problems. The time between trauma and temporary stabilization ranged between 3 and 144 hours; surgical average time was 8.4 minutes. Definitive treatment was carried out with a delay of a minimum of 4 and a maximum of 15 days from the temporary stabilization, always without problems, both in case of ORIF (open reduction, internal fixation) or circular external fixation. CONCLUSION: Temporary stabilization with external fixator in 'tripolar' configuration seems to be the most effective strategy in two steps treatment of tibial pilon fractures. These preliminary encouraging results must be confirmed by further studies with more cases. PMID- 27123152 TI - Mental Health Nursing, Mechanical Restraint Measures and Patients' Legal Rights. AB - Coercive mechanical restraint (MR) in psychiatry constitutes the perhaps most extensive exception from the common health law requirement for involving patients in health care decisions and achieving their informed consent prior to treatment. Coercive measures and particularly MR seriously collide with patient autonomy principles, pose a particular challenge to psychiatric patients' legal rights, and put intensified demands on health professional performance. Legal rights principles require rationale for coercive measure use be thoroughly considered and rigorously documented. This article presents an in-principle Danish Psychiatric Complaint Board decision concerning MR use initiated by untrained staff. The case illustrates that, judicially, weight must be put on the patient perspective on course of happenings and especially when health professional documentation is scant, patients' rights call for taking notice of patient evaluations. Consequently, if it comes out that psychiatric staff failed to pay appropriate consideration for the patient's mental state, perspective, and expressions, patient response deviations are to be judicially interpreted in this light potentially rendering MR use illegitimated. While specification of law criteria might possibly improve law use and promote patients' rights, education of psychiatry professionals must address the need for, as far as possible, paying due regard to meeting patient perspectives and participation principles as well as formal law and documentation requirements. PMID- 27123153 TI - Use of Self-Matching to Control for Stable Patient Characteristics While Addressing Time-Varying Confounding on Treatment Effect: A Case Study of Older Intensive Care Patients. AB - Exposure-crossover design offers a non-experimental option to control for stable baseline confounding through self-matching while examining causal effect of an exposure on an acute outcome. This study extends this approach to longitudinal data with repeated measures of exposure and outcome using data from a cohort of 340 older medical patients in an intensive care unit (ICU). The analytic sample included 92 patients who received >=1 dose of haloperidol, an antipsychotic medication often used for patients with delirium. Exposure-crossover design was implemented by sampling the 3-day time segments prior (Induction) and posterior (Subsequent) to each treatment episode of receiving haloperidol. In the full cohort, there was a trend of increasing delirium severity scores (Mean+/-SD: 4.4+/-1.7) over the course of the ICU stay. After exposure-crossover sampling, the delirium severity score decreased from the Induction (4.9) to the Subsequent (4.1) intervals, with the treatment episode falling in-between (4.5). Based on a GEE Poisson model accounting for self-matching and within-subject correlation, the unadjusted mean delirium severity scores was -0.55 (95% CI: -1.10, -0.01) points lower for the Subsequent than the Induction intervals. The association diminished by 32% (-0.38, 95%CI: -0.99, 0.24) after adjusting only for ICU confounding, while being slightly increased by 7% (-0.60, 95%CI: -1.15, -0.04) when adjusting only for baseline characteristics. These results suggest that longitudinal exposure-crossover design is feasible and capable of partially removing stable baseline confounding through self-matching. Loss of power due to eliminating treatment-irrelevant person-time and uncertainty around allocating person-time to comparison intervals remain methodological challenges. PMID- 27123154 TI - Oxidative Stress after Surgery on the Immature Heart. AB - Paediatric heart surgery is associated with increased inflammation and the production of reactive oxygen species. Use of the extracorporeal cardiopulmonary bypass during correction of congenital heart defects generates reactive oxygen species by various mechanisms: haemolysis, neutrophil activation, ischaemia reperfusion injury, reoxygenation injury, or depletion of the endogenous antioxidants. The immature myocardium is more vulnerable to reactive oxygen species because of developmental differences compared to the adult heart but also because of associated congenital heart diseases that can deplete its antioxidant reserve. Oxidative stress can be manipulated by various interventions: exogenous antioxidants, use of steroids, cardioplegia, blood prime strategies, or miniaturisation of the cardiopulmonary bypass circuit. However, it is unclear if modulation of the redox pathways can alter clinical outcomes. Further studies powered to look at clinical outcomes are needed to define the role of oxidative stress in paediatric patients. PMID- 27123155 TI - Zinc Chelation Mediates the Lysosomal Disruption without Intracellular ROS Generation. AB - We report the molecular mechanism for zinc depletion caused by TPEN (N,N,N',N' Tetrakis(2-pyridylmethyl)ethylenediamine) in neuroblastoma cells. The activation of p38 MAP kinase and subsequently caspase 3 is not due to or followed by redox imbalance or ROS generation, though these are commonly observed in literature. We found that TPEN is not responsible for ROS generation and the mechanism involves essentially lysosomal disruption caused by intracellular zinc depletion. We also observed a modest activation of Bax and no changes in the Bcl-2 proteins. As a result, we suggest that TPEN causes intracellular zinc depletion which can influence the breakdown of lysosomes and cell death without ROS generation. PMID- 27123156 TI - Redox Signaling and Neural Control of Cardiovascular Function. PMID- 27123157 TI - Complete genome sequences of Geobacillus sp. WCH70, a thermophilic strain isolated from wood compost. AB - Geobacillus sp. WCH70 was one of several thermophilic organisms isolated from hot composts in the Middleton, WI area. Comparison of 16 S rRNA sequences showed the strain may be a new species, and is most closely related to G. galactosidasius and G. toebii. The genome was sequenced, assembled, and annotated by the DOE Joint Genome Institute and deposited at the NCBI in December 2009 (CP001638). The genome of Geobacillus species WCH70 consists of one circular chromosome of 3,893,306 bp with an average G + C content of 43 %, and two circular plasmids of 33,899 and 10,287 bp with an average G + C content of 40 %. Among sequenced organisms, Geobacillus sp. WCH70 shares highest Average Nucleotide Identity (86 %) with G. thermoglucosidasius strains, as well as similar genome organization. Geobacillus sp. WCH70 appears to be a highly adaptable organism, with an exceptionally high 125 annotated transposons in the genome. The organism also possesses four predicted restriction-modification systems not found in other Geobacillus species. PMID- 27123158 TI - Cancer Activation and Polymorphisms of Human Cytochrome P450 1B1. AB - Human cytochrome P450 enzymes (P450s, CYPs) are major oxidative catalysts that metabolize various xenobiotic and endogenous compounds. Many carcinogens induce cancer only after metabolic activation and P450 enzymes play an important role in this phenomenon. P450 1B1 mediates bioactivation of many procarcinogenic chemicals and carcinogenic estrogen. It catalyzes the oxidation reaction of polycyclic aromatic carbons, heterocyclic and aromatic amines, and the 4 hydroxylation reaction of 17beta-estradiol. Enhanced expression of P450 1B1 promotes cancer cell proliferation and metastasis. There are at least 25 polymorphic variants of P450 1B1 and some of these have been reported to be associated with eye diseases. In addition, P450 1B1 polymorphisms can greatly affect the metabolic activation of many procarcinogenic compounds. It is necessary to understand the relationship between metabolic activation of such substances and P450 1B1 polymorphisms in order to develop rational strategies for the prevention of its toxic effect on human health. PMID- 27123159 TI - Bio-Inspired Green Nanoparticles: Synthesis, Mechanism, and Antibacterial Application. AB - In the recent years, noble nanoparticles have attracted and emerged in the field of biology, medicine and electronics due to their incredible applications. There were several methods have been used for synthesis of nanoparticles such as toxic chemicals and high energy physical procedures. To overcome these, biological method has been used for the synthesis of various metal nanoparticles. Among the nanoparticles, silver nanoparticles (AgNPs) have received much attention in various fields, such as antimicrobial activity, therapeutics, bio-molecular detection, silver nanocoated medical devices and optical receptor. Moreover, the biological approach, in particular the usage of natural organisms has offered a reliable, simple, nontoxic and environmental friendly method. Hence, the current article is focused on the biological synthesis of silver nanoparticles and their application in the biomedical field. PMID- 27123160 TI - Hair Growth-Promoting Effects of Lavender Oil in C57BL/6 Mice. AB - The purpose of this study was to determine the hair growth effects of lavender oil (LO) in female C57BL/6 mice. The experimental animals were divided into a normal group (N: saline), a vehicle control group (VC: jojoba oil), a positive control group (PC: 3% minoxidil), experimental group 1 (E1: 3% LO), and experimental group 2 (E2: 5% LO). Test compound solutions were topically applied to the backs of the mice (100 MUL per application), once per day, 5 times a week, for 4 weeks. The changes in hair follicle number, dermal thickness, and hair follicle depth were observed in skin tissues stained with hematoxylin and eosin, and the number of mast cells was measured in the dermal and hypodermal layers stained with toluidine blue. PC, E1, and E2 groups showed a significantly increased number of hair follicles, deepened hair follicle depth, and thickened dermal layer, along with a significantly decreased number of mast cells compared to the N group. These results indicated that LO has a marked hair growth promoting effect, as observed morphologically and histologically. There was no significant difference in the weight of the thymus among the groups. However, both absolute and relative weights of the spleen were significantly higher in the PC group than in the N, VC, E1, or E2 group at week 4. Thus, LO could be practically applied as a hair growth-promoting agent. PMID- 27123161 TI - External Application of Apo-9'-fucoxanthinone, Isolated from Sargassum muticum, Suppresses Inflammatory Responses in a Mouse Model of Atopic Dermatitis. AB - Allergic skin inflammation such as atopic dermatitis is characterized by skin barrier dysfunction, edema, and infiltration with various inflammatory cells. The anti-inflammatory effects of Apo-9'-fucoxanthinone, isolated from Sargassum muticum, have been described in many diseases, but the mechanism by which it modulates the immune system is poorly understood. In this study, the ability of Apo-9'-fucoxanthinone to suppress allergic reactions was investigated using a mouse model of atopic dermatitis. The Apo-9'-fucoxanthinone-treated group showed significantly decreased immunoglobulin E in serum. Also, Apo-9'-fucoxanthinone treatment resulted in a smaller lymph node size with reduced the thickness and length compared to the induction group. In addition, Apo-9'-fucoxanthinone inhibited the expression of interleukin-4, interferon-gamma and tumor necrosis factor-alpha by phorbol 12-myristate 13-acetate and ionomycin-stimulated lymphocytes. These results suggest that Apo-9'-fucoxanthinone may be a useful therapeutic strategy for treating chronic inflammatory diseases. PMID- 27123162 TI - Modulation of Apoptosis and Differentiation by the Treatment of Sulfasalazine in Rabbit Articular Chondrocytes. AB - This study was conducted to examine the cellular regulatory mechanisms of sulfasalazine (SSZ) in rabbit articular chondrocytes treated with sodium nitroprusside (SNP). Cell phenotype was determined, and the MTT assay, Western blot analysis and immunofluorescence staining of type II collagen was performed in control, SNP-treated and SNP plus SSZ (50~200 MUg/mL) rabbit articular chondrocytes. Cellular proliferation was decreased significantly in the SNP treated group compared with that in the control (p < 0.01). SSZ treatment clearly increased the SNP-reduced proliferation levels in a concentration-dependent manner (p < 0.01). SNP treatment induced significant dedifferentiation and inflammation compared with control chondrocytes (p < 0.01). Type II collagen expression levels increased in a concentration-dependent manner in response to SSZ treatment but were unaltered in SNP-treated chondrocytes (p < 0.05 and < 0.01, respectively). Cylooxygenase-2 (COX-2) expression increased in a concentration-dependent manner in response to SSZ treatment but was unaltered in SNP-treated chondrocytes (p < 0.05). Immunofluorescence staining showed that SSZ treatment increased type II collagen expression compared with that in SNP-treated chondrocytes. Furthermore, phosphorylated extracellular regulated kinase (pERK) expression levels were decreased significantly in the SNP-treated group compared with those in control chondrocytes (p < 0.01). Expression levels of pERK increased in a concentration-dependent manner by SSZ but were unaltered in SNP treated chondrocytes. pp38 kinase expression levels increased in a concentration dependent manner by SSZ but were unaltered in control chondrocytes (p < 0.01). In summary, SSZ significantly inhibited nitric oxide-induced cell death and dedifferentiation, and regulated extracellular regulated kinases 1 and 2 and p38 kinase in rabbit articular chondrocytes. PMID- 27123165 TI - Melanogenesis-Promoting Effects of Rhynchosia nulubilis and Rhynchosia volubilis Ethanol Extracts in Melan-a Cells. AB - We evaluated the antioxidant activity and melanogenic effects of black soybean ethanol extracts, including Rhynchosia nulubilis bean ethanol extract (RNBEE), R. nulubilis leaf ethanol extract (RNLEE), R. volubilis bean ethanol extract (RVBEE), and R. volubilis leaf ethanol extract (RVLEE). The total polyphenol contents of RNBEE, RNLEE, RVBEE, and RVLEE were 16.0, 57.7, 365.9, and 260.1 mg/g, respectively. The total flavonoid contents of RNBEE, RNLEE, RVBEE, and RVLEE were 40.4, 91.7, 84.7, and 216.5 mg/g, respectively. The electron-donating abilities of RNBEE, RNLEE, RVBEE, and RVLEE at 1,000 MUg/mL were 32.4%, 12.7%, 83.5%, and 84.5%, respectively. RNBEE, RNLEE, RVBEE, and RVLEE at 50 MUg/mL significantly increased (p < 0.01) melanin contents by 30.4%, 32.1%, 35.5%, and 37.4%, respectively, compared to that of the control. RNBEE, RNLEE, RVBEE, and RVLEE at 50 MUg/mL significantly increased (p < 0.01) intracellular tyrosinase activity by 18.4%, 21.8%, 21.5%, and 21.1%, respectively, compared to that of the control. These results demonstrated that black soybean ethanol extracts promote melanogenesis in melan-a cells. Among the black soybean ethanol extracts, R. volubilis was found to be more effective than R. nulubilis, and leaf extract was found to be more effective than bean extract. The potential mechanism underlying the hyperpigmentation effects of black soybeans is the promotion of tyrosinase activity. PMID- 27123163 TI - Neurobehavioural Changes and Brain Oxidative Stress Induced by Acute Exposure to GSM900 Mobile Phone Radiations in Zebrafish (Danio rerio). AB - The impact of mobile phone (MP) radiation on the brain is of specific interest to the scientific community and warrants investigations, as MP is held close to the head. Studies on humans and rodents revealed hazards MP radiation associated such as brain tumors, impairment in cognition, hearing etc. Melatonin (MT) is an important modulator of CNS functioning and is a neural antioxidant hormone. Zebrafish has emerged as a popular model organism for CNS studies. Herein, we evaluated the impact of GSM900MP (GSM900MP) radiation exposure daily for 1 hr for 14 days with the SAR of 1.34W/Kg on neurobehavioral and oxidative stress parameters in zebrafish. Our study revealed that, GSM900MP radiation exposure, significantly decreased time spent near social stimulus zone and increased total distance travelled, in social interaction test. In the novel tank dive test, the GSM900MP radiation exposure elicited anxiety as revealed by significantly increased time spent in bottom half; freezing bouts and duration and decreased distance travelled, average velocity, and number of entries to upper half of the tank. Exposed zebrafish spent less time in the novel arm of the Y-Maze, corroborating significant impairment in learning as compared to the control group. Exposure decreased superoxide dismutase (SOD), catalase (CAT) activities whereas, increased levels of reduced glutathione (GSH) and lipid peroxidation (LPO) was encountered showing compromised antioxidant defense. Treatment with MT significantly reversed the above neurobehavioral and oxidative derangements induced by GSM900MP radiation exposure. This study traced GSM900MP radiation exposure induced neurobehavioral aberrations and alterations in brain oxidative status. Furthermore, MT proved to be a promising therapeutic candidate in ameliorating such outcomes in zebrafish. PMID- 27123164 TI - Effect of Thiol-reducing Agents and Antioxidants on Sulfasalazine-induced Hepatic Injury in Normotermic Recirculating Isolated Perfused Rat Liver. AB - Sulfasalzine is a widely administered drug against inflammatory-based disorders in human. However several cases of liver injury are associated with its administration. There is no stabilized safe protective agent against sulfasalazine-induced liver injury. Current investigation was designed to evaluate if N-acetylcysteine (NAC) and dithioteritol (DTT) as thiol reducing agents and/or vitamins C and E as antioxidants have any protective effects against sulfasalazine-induced hepatic injury in an ex vivo model of isolated rat liver. Rat liver was canulated and perfused via portal vein in a closed recirculating system. Different concentrations of sulfasalazine and/or thiol reductants and antioxidants were administered and markers of organ injury were monitored at different time intervals. It was found that 5 mM of sulfasalazine caused marked liver injury as judged by rise in liver perfusate level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) (p < 0.05). A significant amount of lipid peroxidation and hepatic glutathione depletion were detected in drug-treated livers, accompanied with significant histopathological changes of the organ. Administration of NAC (500 MUM), DTT (400 MUM), Vitamin C (200 MUM), or vitamin E (200 MUM) significantly alleviated sulfasalazine-induced hepatic injury in isolated perfused rat liver. The data obtained from current investigation indicate potential therapeutic properties of thiol reductants and antioxidants against sulfasalazine-induced liver injury. PMID- 27123166 TI - A Probiotic Preparation Alleviates Atopic Dermatitis-Like Skin Lesions in Murine Models. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex etiology that encompasses immunologic responses. AD is frequently associated with elevated immunoglobulin (Ig) E levels, and common environmental factors contribute to its pathogenesis. Several recent studies have documented the role of specific lactic acid bacteria in the treatment and prevention of AD in humans and mice. In this study, the efficacy of Duolac ATP, a probiotic preparation, was determined in a mouse model with AD-like skin lesions. Alterations in the cytokine levels and histological staining suggested the alleviation of AD. The in vivo test showed that T helper (Th)2 cytokines, IgE, interleukin (IL)-4, and IL 5, were significantly downregulated, whereas Th1 cytokines, IL-12p40 and interferon (IFN)-gamma, were upregulated in all groups of mice treated with Duolac ATP compared to that observed in the group of mice treated with 1-chloro 2,4-dinitrobenzene (DNCB) alone. Moreover, the scratch score decreased in all mice treated with Duolac ATP. Staining of the dorsal area of the mice in each group with hematoxylin and eosin and toluidine blue further confirmed the alleviation of AD in mice orally treated with Duolac ATP. These results suggest that Duolac ATP inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the Th2 cell response and increasing the Th1 cell response. Thus, Duolac ATP is beneficial and effective for the treatment of AD-like skin lesions. PMID- 27123167 TI - Oral Toxicity Study and Skin Sensitization Test of a Cricket. AB - Crickets have been attracting considerable interest in the field of nutrition and toxicology due to the global exhaustion of food resulting from a growing population. The cricket is normally eaten in several countries after roasting, similar to the grasshopper; however, safety evaluation data on cricket powder is limited. Here, we performed general toxicity studies of cricket powder including a single, 2-week repeated dose range evaluation test, a 13-week repeated oral dose toxicity test in Sprague-Dawley rats, a single oral dose toxicity test in Beagle dogs, and a skin sensitization test in guinea pigs following the Organization for Economic Cooperation and Development test guidelines 406 and 408 in addition to Good Laboratory Practice. To investigate the NOAEL and target organs of cricket powder, Sprague-Dawley rats were allocated to 4 groups: vehicle control, 1,250 mg/kg, 2,500 mg/kg, 5,000 mg/kg dose test groups and cricket powder was administered over 13 weeks after single dose and dose range finding studies in rats based on the results of the single oral administration toxicity study in rats and Beagle dogs. The results of the study showed that the NOAEL of cricket powder was over 5,000 mg/kg for both sexes of rats without adverse effects in a 13-week repeated oral toxicity study and there was no skin hypersensitivity reaction. Therefore, our results reveal that crickets can be widely used as a new substitute food or nutrient resource. PMID- 27123168 TI - Erratum to "Evaluation of Genotoxicity and 28-day Oral Dose Toxicity on Freeze dried Powder of Tenebrio molitor Larvae (Yellow Mealworm)" [ Toxicol. Res. 30 (2014) 121-130 ]. AB - [This corrects the article on p. 121 in vol. 30, PMID: 25071922.]. PMID- 27123169 TI - From population to public institutions: what needs to be changed to benefit from the full value of vaccination. AB - The poor perception of the benefits of vaccines, and their subsequent underuse, can result in substantial economic, societal, and political burden. Adequate support and communication from health authorities and governments is essential to promote the benefits of vaccination and reduce the risk of infectious diseases outbreaks. Cost-containment policies in the vaccine procurement processes could also be a threat to the long-term sustainability of the vaccine industry and manufacturing sites in Europe. Biologicals, such as vaccines, are highly technical and complex products to manufacture and only a few industries are engaged in this activity. Developing incentives to encourage vaccine manufacturers and identifying means of taking into consideration the specificities of vaccines in economic evaluations could allow the full value of vaccination to be appreciated. In conclusion, governments, international agencies, and other stakeholders have an important role to play to help society regain confidence in vaccination and ensure that the benefits of vaccination programmes are fully recognised and valued. PMID- 27123171 TI - Vaccination: short- to long-term benefits from investment. AB - In the context of current economic difficulties across Europe, accurate budgeting and resource allocation have become increasingly important. Vaccination programmes can respond to the needs of governments to budget with confidence. It may be more reliable and accurate to forecast budget and resource allocation for a vaccination programme than for unpredictable seasonal disease peaks of infections such as rotavirus gastroenteritis, influenza, and pneumonia. In addition, prevention through vaccination involves low levels of investment relative to the substantial benefits that may be obtained. In France, total lifelong vaccination costs, per fully compliant individual, ranged from ?865 to ?3,313, covering 12 to 16 diseases, which is comparable to, or lower than, costs of other preventive measures. In addition, effectively implemented vaccination programmes have the potential to generate substantial savings both in the short and in the long term. For example, vaccination programmes for rotavirus, meningitis C, human papillomavirus, influenza, and pneumonia have all been shown to significantly reduce the disease burden, and thus the associated costs, in the first years following vaccination implementation. These programmes demonstrate the potential for health authorities to obtain early, and often substantial, return on investment. PMID- 27123170 TI - A review of the value of innovation in inhalers for COPD and asthma. AB - BACKGROUND: Appropriate use of inhaled therapies for asthma and chronic obstructive pulmonary disease (COPD) is critical to ensuring good patient outcomes, efficient use of healthcare resources and limiting the effects of high morbidity. The appropriate choice of inhaler and active therapy, incorporating patient preferences, can help improve treatment adherence and long-term outcomes. Despite this, many current inhalers are non-intuitive to use, and require extensive training. METHODS: In this review, an expert panel considers the evidence for the use of inhaler devices in management of COPD and asthma. The panel also evaluates the value of innovation in inhaler technologies, which optimise the use of existing molecules from a clinical, economic and societal perspective. CONCLUSIONS: The panel conclusion is that there remains a substantial unmet need in inhaler technology and that innovation in inhaler devices can provide real-world health benefits to patients. Furthermore, we recommend that these innovations should be supported by healthcare systems through appropriate pricing and reimbursement mechanisms. PMID- 27123172 TI - National Immunization Therapeutic Advisory Group: it is time for experience sharing and best practice learning. PMID- 27123173 TI - Current process and future path for health economic assessment of pharmaceuticals in France. AB - The Social Security Funding Law for 2012 introduced the Economic and Public Health Assessment Committee (Commission Evaluation Economique et de Sante Publique, or CEESP) in the Social Security Code as a specialised committee affiliated with the Haute Autorite de Sante in charge of providing recommendations and health economic opinions. This article provides an in-depth description of the CEESP's structure and working methods, and analyses the impact of health economic assessment on market access of drugs in France. It also points out the areas of uncertainty and the conflicting rules following the introduction of the health economic assessment in France. The authors also provide their personal opinion on the likely future of health economic assessment of drugs in France, including the possible merge of the CEESP and the Transparency Committee, the implementation of a French threshold, and the extension of health economic assessment to a larger number of products. PMID- 27123174 TI - Role of vaccination in economic growth. AB - The health of a population is important from a public health and economic perspective as healthy individuals contribute to economic growth. Vaccination has the potential to contribute substantially to improving population health and thereby economic growth. Childhood vaccination programmes in Europe can offer protection against 15 important infectious diseases, thus preventing child fatalities and any serious temporary and permanent sequelae that can occur. Healthy children are more able to participate in education, thus preparing them to become healthy and productive adults. Vaccination programmes can also prevent infectious diseases in adolescents, thus allowing them to continue their development towards a healthy adulthood. Protecting adults against infectious diseases ensures that they can fully contribute to productivity and economic development by avoiding sick leave and lower productivity. Vaccination in older adults will contribute to the promotion of healthy ageing, enabling them to assist their familiy with, for instance, childcare, and also help them avoid functional decline and the related impacts on health and welfare expenditure. Effective vaccination programmes for all ages in Europe will thus contribute to the European Union's 2020 health and economic strategies. Indeed, beyond their impact on healthcare resources and productivity, reductions in mortality and morbidity also contribute to increased consumption and gross domestic product. Therefore, assessment of the value of vaccines and vaccination needs to consider not just the direct impact on health and healthcare but also the wider impact on economic growth, which requires a macroeconomic analysis of vaccination programmes. PMID- 27123175 TI - Reimbursement of licensed cell and gene therapies across the major European healthcare markets. AB - OBJECTIVE: The aim of this research is to identify the pricing, reimbursement, and market access (P&R&MA) considerations most relevant to advanced therapy medicinal products (ATMPs) in the Big5EU, and to inform their manufacturers about the key drivers for securing adoption at a commercially viable reimbursed price. METHODOLOGY: The research was structured following three main steps: 1) Identifying the market access pathways relevant to ATMPs through secondary research; 2) Validating the secondary research findings and addressing any data gaps in primary research, by qualitative interviews with national, regional, and local-level payers and their clinical and economic advisors; 3) Collating of primary and secondary findings to compare results across countries. RESULTS: The incremental clinical benefit forms the basis for all P&R&MA processes. Budget impact is a key consideration, regardless of geography. Cost-effectiveness analyses are increasingly applied; however, only the United Kingdom has a defined threshold that links the cost per quality-adjusted life year (QALY) specifically and methodologically to the reimbursed price. Funding mechanisms to enable adoption of new and more expensive therapies exist in all countries, albeit to varying extents. Willingness to pay is typically higher in smaller patient populations, especially in populations with high disease burden. Outcomes modelling and risk-sharing agreements (RSAs) provide strategies to address the data gap and uncertainties often associated with trials in niche populations. CONCLUSIONS: The high cost of ATMPs, coupled with the uncertainty at launch around their long-term claims, present challenges for their adoption at a commercially viable reimbursed price. Targeting populations of high disease burden and unmet needs may be advantageous, as the potential for improvement in clinical benefit is greater, as well as the potential for capitalising on healthcare cost offsets. Also, targeting small populations can also help reduce both payers' budget impact concerns and the risk of reimbursement restrictions being imposed. PMID- 27123176 TI - Market access pathways for cell therapies in France. AB - INTRODUCTION AND OBJECTIVE: Cell therapies can be classified into three main categories of products: advanced therapy medicinal products (ATMPs), ATMPs prepared on a non-routine basis (hospital exemptions), and minimally manipulated cells. Despite the benefits that cell therapies can bring to patients, they are subject to complex pathways to reach the market in France. The objective of this study was to identify and describe routes to market access for cell therapies in France and how these vary by regulatory status. METHODOLOGY: The research was structured following five main steps: (1) identification of the French regulatory framework for cell therapies; (2) identification of the health products categorised as cell therapies in France; (3) mapping of the market access pathways per category of cell therapy; (4) validation of findings by interviewing experts; and (5) development of a roadmap summarising market access pathways for cell therapies in France. The secondary research methodology included a comprehensive literature review conducted on websites of French public health institutions, complemented by a research for peer-reviewed articles, abstracts, and grey literature. RESULTS: Different market access pathways are possible depending on the cell therapy category. For ATMPs, market access pathways depend on the licensing status of the therapy. Licensed ATMPs followed the same market access pathways as 'conventional' pharmaceuticals, whereas not-yet-licensed ATMPs can be funded via a specific financial allowance under the framework of a Temporary Authorisation for Use procedure or various research programmes. For new ATMPs that are associated with a separate medical device (not considered as 'combined ATMPs') or associated with a new medical procedure, additional pathways will apply for the medical device and/or medical procedure to be reimbursed in the ambulatory settings or at hospital. The most likely funding option for ATMPs prepared on a non-routine basis is outside the diagnosis-related group (DRG) system through Missions of General Interest and Support to Contracting (MIGAC). For minimally manipulated cells, four different funding processes are applicable, depending on the type of activity: (1) inclusion in a DRG; (2) inclusion in the list of products and services qualifying for reimbursement (LPPR) (as a medical device); (3) an annual lump sum provided by regional health agencies; and (4) a financial allowance under Missions of General Interest (MIG). CONCLUSION: Cell therapy is a diverse and promising category of medical interventions. Its heterogeneity and complexity mean that several funding options and market access pathways apply. The main challenges facing cell therapies relate to (1) the identification of the most appropriate path to reimbursement, and (2) price setting, whereas high manufacturing costs of these therapies will dictate a high price that could only be achieved by a product that leads to important additional patient benefits compared to available treatment options. More specific funding options could emerge as the number of cell therapies increases and the authorities face the need to structure and stabilise funding. It will be vital for manufacturers to have a clear understanding of the various temporary funding opportunities early in a product's lifecycle for the adoption of a stepwise approach to secure permanent funding. Furthermore, due to the very limited Health Technology Assessment (HTA) bodies experience for cell therapies, manufacturers should enter into dialogues with HTA agencies at an early stage to optimise market access conditions. PMID- 27123177 TI - A chart review of management of ischemic stroke patients in Germany. AB - BACKGROUND: Ischemic stroke (IS) poses physical, emotional, and economic burdens on both patients and the healthcare system in Germany. However, the management of IS is not well described, especially after hospital discharge. In this study, we aim to describe the management of IS at onset, admission, and during follow-up. METHODS: German general practitioners (GPs) (n=40) extracted data on patient characteristics, hospitalizations, discharge, and ambulatory care from both GPs patient databases and hospital letters. Descriptive analyses were conducted. RESULTS: The sample included 185 patients with a mean age of 70 years [standard deviation (SD)=11.7]. Most patients (63%) contacted the Emergency Medical Services, while 36% contacted their GPs. The majority of patients were hospitalized within 1 h from onset, and the length of stay was on average 14 days. Half of the patients (50%) were admitted to the stroke unit, and 16% of patients received thrombolysis treatment with 2 h (SD=2.6) of time to treatment. Of the admitted patients, 32% were discharged to their homes, while the remaining patients were discharged to nursing homes (16.2%) and rehabilitation centers (47.6%). During the 12 months follow-up, 22% of patients were re-hospitalized and patients visited their GP (11.7 times), psychologist or psychiatrist (9.5 times), and neurologist (2.2 times). Death rate after stroke event was 13%. CONCLUSION: The rate of patients who received thrombolysis is lower than the optimal rate in Germany. More research is needed to determine the factors that could predict the utilization of thrombolysis treatment. PMID- 27123178 TI - The societal role of lifelong vaccination. AB - The full economic and societal value of vaccination is complex to assess. Although direct protection is the immediate goal of vaccination programmes, it is rare that 100% uptake is attained. An important facet of vaccines value comes from the indirect (or herd) protection they provide. The evolving dynamics of our society, including the increase in the proportion of older individuals enhances the value of indirect protection in reducing disease transmission within the family setting and the society as a whole. For example, grandparents are increasingly involved in childcare, putting them at risk of disease transmission if they or the children are not vaccinated. Preventing disease in children can also reduce absenteeism for parents who otherwise would take days off work to care for their sick children, leading to a substantial societal burden. Preventing disease in working adults reduces absenteeism and presenteeism, enhancing productivity and contributing in turn to economic growth. Quality of life is essential at all ages. It is fundamental in children for their life chances, educational achievements, and healthy wellbeing. Additionally, preventing common diseases in adults and the elderly also contributes to their quality of life and helps to assure healthy ageing for growing ageing populations. These wider economic and societal values, although difficult to measure, should be taken into consideration in assessments of the economic value and cost-effectiveness of vaccination programmes. PMID- 27123179 TI - Ischemic stroke management in West Scotland: a chart review. AB - BACKGROUND: Little information is available about the long-term management of ischemic stroke (IS) in West Scotland. In this study we aim to describe the management of IS at onset, admission, and during follow-up among patients who survived an IS event. METHODS: General practitioners (GPs) (n=20) were randomly selected to recruit IS patients and extract data about patient characteristics, hospitalizations, discharge, and ambulatory care from GP databases, hospital letters, and direct contact with patients and their relatives. Descriptive analyses were conducted. RESULTS: One hundred and one patients were included, with a mean age of 65.6+/-13.4. About half of the patients contacted their GPs at the time of onset (45.4%). Cardiovascular history was prevalent in 29.7% of cases, and 14% of all cases were recurrences. Of the patients, 89 (88%) were hospitalized with mean length of stay (LOS) 11.8 days. Treatment was administered on average within 12.9 hours of admission and 23.6% of the admitted patients received thrombolytic treatment. During the 1-year follow-up period, 33.6% of patients were rehospitalized and the mean LOS was 15.1+/-29.5 days. Further, patients on average sought nursing care (10.9%), physical therapy (45.5%), occupational therapy (27.7%), speech therapy (12.9%), and professional caregivers (12%). CONCLUSION: The health-care resource utilization of IS patients is a major driver of economic burden. PMID- 27123180 TI - A review of accessibility of administrative healthcare databases in the Asia Pacific region. AB - OBJECTIVE: We describe and compare the availability and accessibility of administrative healthcare databases (AHDB) in several Asia-Pacific countries: Australia, Japan, South Korea, Taiwan, Singapore, China, Thailand, and Malaysia. METHODS: The study included hospital records, reimbursement databases, prescription databases, and data linkages. Databases were first identified through PubMed, Google Scholar, and the ISPOR database register. Database custodians were contacted. Six criteria were used to assess the databases and provided the basis for a tool to categorise databases into seven levels ranging from least accessible (Level 1) to most accessible (Level 7). We also categorised overall data accessibility for each country as high, medium, or low based on accessibility of databases as well as the number of academic articles published using the databases. RESULTS: Fifty-four administrative databases were identified. Only a limited number of databases allowed access to raw data and were at Level 7 [Medical Data Vision EBM Provider, Japan Medical Data Centre (JMDC) Claims database and Nihon-Chouzai Pharmacy Claims database in Japan, and Medicare, Pharmaceutical Benefits Scheme (PBS), Centre for Health Record Linkage (CHeReL), HealthLinQ, Victorian Data Linkages (VDL), SA-NT DataLink in Australia]. At Levels 3-6 were several databases from Japan [Hamamatsu Medical University Database, Medi-Trend, Nihon University School of Medicine Clinical Data Warehouse (NUSM)], Australia [Western Australia Data Linkage (WADL)], Taiwan [National Health Insurance Research Database (NHIRD)], South Korea [Health Insurance Review and Assessment Service (HIRA)], and Malaysia [United Nations University (UNU)-Casemix]. Countries were categorised as having a high level of data accessibility (Australia, Taiwan, and Japan), medium level of accessibility (South Korea), or a low level of accessibility (Thailand, China, Malaysia, and Singapore). In some countries, data may be available but accessibility was restricted based on requirements by data custodians. CONCLUSIONS: Compared with previous research, this study describes the landscape of databases in the selected countries with more granularity using an assessment tool developed for this purpose. A high number of databases were identified but most had restricted access, preventing their potential use to support research. We hope that this study helps to improve the understanding of the AHDB landscape, increase data sharing and database research in Asia-Pacific countries. PMID- 27123181 TI - Overview of external reference pricing systems in Europe. AB - BACKGROUND AND OBJECTIVES: External reference pricing (ERP) is a price regulation tool widely used by policy makers in the European Union (EU) Member States (MS) to contain drug cost, although in theory, it may contribute to modulate prices up and down. The objective of this article was to summarise and discuss the main findings of part of a large project conducted for the European Commission ('External reference pricing of medicinal products: simulation-based considerations for cross-country coordination'; see www.ec.europa.eu/health/healthcare/docs/erp_reimbursement_medicinal_products_en.p f) that aimed to provide an overview of ERP systems, both on processes and potential issues in 31 European countries (28 EU MS, Iceland, Norway, and Switzerland). METHODS: A systematic structured literature review was conducted to identify and characterise the use of ERP in the selected countries, to describe its impact on the prices of pharmaceuticals, and to discuss the possible cross country coordination issues in EU MS. This research was complemented with a consultation of competent authorities' and international organisations' representatives to address the main issues or uncertainties identified through the literature review. RESULTS: All selected countries applied ERP, except the United Kingdom and Sweden. Twenty-three countries used ERP as the main systematic criterion for pricing. In the majority of European countries, ERP was based on legislated pricing rules with different levels of accuracy. ERP was applied either for all marketed drugs or for specific categories of medicines; it was mainly used for publicly reimbursed medicines. The number of reference countries included in the basket varied from 1 to 31. There was a great variation in the calculation methods used to compute the price; 15 countries used the average price, 7 countries used the lowest price, and 7 countries used other calculation methods. Reported limitations of ERP application included the lack of reliable sources of price information, price heterogeneity, exchange rate volatility, and hidden discounts. Spill-over effect and downward price convergence have often been mentioned as ERP's consequences leading to pricing strategies from pharmaceutical companies. CONCLUSION: While ERP is widely used in Europe, processes and availability of price information vary from one country to another, thus limiting ERP implementation. Furthermore, ERP spill-over effect is a major concern of pharmaceutical firms leading to implementation of the so-called 'launch sequence strategies'. PMID- 27123182 TI - The intangible benefits of vaccination - what is the true economic value of vaccination? AB - Previous economic evaluations of new vaccines largely focussed on a narrow set of benefit categories, including primarily health gains and disease-related medical cost-savings, which probably resulted in underestimates of the true value of these vaccines. Other economic benefits of vaccines could be considered to assess the full economic value of vaccination, such as, for example, impact of the human papillomavirus vaccine on women's fertility through the decrease in precancerous lesions and, therefore, in the number of diagnostic and treatment interventions, which can be associated with an increased risk of subsequent pregnancy complications. Vaccines' impact on resource allocation at hospital level or on antimicrobial resistance, such as pneumococcal conjugate vaccines that have substantially reduced infections due to antimicrobial non-susceptible strains, thereby rendering the residual disease easier to treat, are other examples of intangible benefits of vaccination. These benefits are generally not considered in economic evaluations because they may not be immediately visible and are difficult to quantify. However, they should be taken into consideration in health technology assessments to enable those responsible for healthcare policies to make well-informed decisions on vaccination. PMID- 27123183 TI - Efficacy, tolerability, and safety of aripiprazole once-monthly versus other long acting injectable antipsychotic therapies in the maintenance treatment of schizophrenia: a mixed treatment comparison of double-blind randomized clinical trials. AB - BACKGROUND: Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia. OBJECTIVE: This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety. DATA SOURCES: A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013. STUDY SELECTION: Studies were required to have >=24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo. DATA EXTRACTION: Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms. DATA SYNTHESIS: Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant difference between any study outcome, including the risk of relapse, the risk of discontinuations, and safety outcomes. CONCLUSIONS: Aripiprazole once-monthly is similarly efficacious to other LAIs with relatively low rates of discontinuation due to AEs and due to reasons other than AEs than other LAIs. PMID- 27123184 TI - Can we well assess the relative efficacy and tolerability of a new drug versus others at the time of marketing authorization using mixed treatment comparisons? A detailed illustration with escitalopram. AB - OBJECTIVE: To assess the variation of relative efficacy and tolerability of an antidepressant versus others based on both pre-marketing (registration studies) and post-marketing studies versus pre-marketing studies only in patients with major depressive disorder. METHODS: The relative efficacy and tolerability of antidepressants was assessed by mixed treatment comparisons (MTCs) using data acquired over two time periods: before registration of the reference drug escitalopram (1989-2002) and up to 5 years later (1989-2007). Ranking probability outputs were presented for efficacy, using change from baseline to 8 weeks on Montgomery-Asberg Depression Rating Scale total score, and tolerability, using withdrawals due to adverse events. RESULTS: The relative efficacy and tolerability of some selected antidepressants, including escitalopram, varied considerably over the two time periods. The improved relative efficacy and tolerability of escitalopram over time, compared with citalopram, was demonstrated by greater separation of ranking probability curves for efficacy and tolerability. In 2002, escitalopram ranked low with 13.9% and 5.1% probability of being in the top four antidepressants' relative efficacy and tolerability, respectively. In 2007, ranking probabilities for relative efficacy and tolerability of escitalopram increased to 52.5% and 82.1%, respectively. CONCLUSIONS: Time of marketing authorization may not be the most appropriate time to evaluate the relative efficacy and tolerability of a new antidepressant based on MTC approach due to the asymmetry of information between new and older compounds. However, the first evaluation of relative effect of a new drug for health technology assessment recommendations is commonly done at this time. Re evaluation of a drug several years after its launch is likely to provide a more accurate indication of its relative efficacy and tolerability. PMID- 27123185 TI - Cost savings of anti-TNF therapy using a test-based strategy versus an empirical dose escalation in Crohn's disease patients who lose response to infliximab. AB - BACKGROUND: The use of pharmacokinetics is associated with cost savings in anti tumor necrosis factor (anti-TNF) therapy, but the long-term cost savings in a large cohort of Crohn's disease (CD) patients are unknown. AIM: The goal of this study was to compare the cost of anti-TNF therapy in two cohorts of CD patients losing response to infliximab, one using a test-based strategy and one an empirical dose escalation. METHODS: We used a selected mathematical model to describe the trajectories of CD patients based on a discrete event system. This design allowed us to track over a given period a double cohort of patients who moved randomly and asynchronously from one state to another, while keeping all the information on their entire trajectory. Both cohorts were modeled using state diagram parameters where transition probabilities from one state to another are derived from literature data. Costs were estimated based on the French health care system. RESULTS: Cost savings among the 10,000 CD patients using a test based strategy were ?131,300,293 at 5 years. At 5 years the mean cost saving was ?13,130 per patient. The direct cost of the test had no impact on the results until the cost per test reached ?2,000. CONCLUSIONS: A test-based strategy leads to major cost savings related to anti-TNF therapy in CD. PMID- 27123187 TI - The economic value of vaccination: why prevention is wealth. PMID- 27123188 TI - Role of vaccination in the sustainability of healthcare systems. AB - The use of vaccines to prevent diseases in children, adults, and the elderly results in fewer medical visits, diagnostic tests, treatments, and hospitalisations, which leads to substantial savings in healthcare costs each year in Europe and elsewhere. Vaccines also contribute to reducing resource utilisation by preventing nosocomial infections, such as rotavirus gastroenteritis, which can increase hospital stays by 4-12 days. Vaccination also has an important role in the prevention of cancers with, for example, human papillomavirus or hepatitis B vaccines. Since the financial impact of cancer is high for patients, healthcare systems, and society as a whole, any cases prevented will reduce this impact. Newer vaccines, such as the herpes zoster vaccine, can provide an answer to unmet medical needs by preventing and reducing the severity of shingles and associated post-herpetic neuralgia, which are difficult conditions to treat. Thus, in the context of increasing pressure on healthcare budgets, vaccination can contribute to the sustainability of healthcare systems through reduced and more efficient use of healthcare resources. PMID- 27123186 TI - The Economic Value of Vaccination: Why Prevention is Wealth. PMID- 27123189 TI - Vaccination: the cornerstone of an efficient healthcare system. AB - Vaccination has made an important contribution to the decreased incidence of numerous infectious diseases and associated mortality. In 2013, it was estimated that 103 million cases of childhood diseases in the United States had been prevented by the use of vaccines since 1924. These health effects translate into positive economic results, as vaccination can provide significant savings by avoiding the direct and indirect costs associated with treating the disease and possible long-term disability. A recent US study estimated that every dollar spent on childhood vaccination could save US$3 from a payer perspective and US$10 from a societal perspective. The first vaccines set a high standard from a public health 'return on investment' perspective, because they are highly cost-saving. Today, however, where only a few healthcare interventions are considered to be cost-saving, the challenge that decision-makers typically face is to identify such healthcare interventions that are deemed cost-effective, that is, provide extra benefit at a reasonable extra cost. Some of the newer vaccines provide a solution to some of today's important health issues, such as cervical cancers with human papillomavirus vaccines, or debilitating diseases with herpes zoster vaccines. These recent, more expensive vaccines have been shown to be cost effective in several economic analyses. Overall, vaccination can still be regarded as one of the most cost-effective healthcare interventions. PMID- 27123190 TI - A comparison of HAS & NICE guidelines for the economic evaluation of health technologies in the context of their respective national health care systems and cultural environments. AB - BACKGROUND: Health technology assessment (HTA) has been reinforced in France, notably with the introduction of economic evaluation in the pricing process for the most innovative and expensive treatments. Similarly to the National Institute for Clinical Excellence (NICE) in England, the National Authority for Health (HAS), which is responsible for economic evaluation of new health technologies in France, has published recommendations on the methods of economic evaluation. Since economic assessment represents a major element of HTA in England, exploring the differences between these methodological guidelines might help to comprehend both the shape and the role economic assessment is intended to have in the French health care system. METHODS: Methodological guidelines for economic evaluation in France and England have been compared topic-by-topic in order to bring out key differences in the recommended methods for economic evaluation. RESULTS: The analysis of both guidelines has revealed multiple similarities between France and England, although a number of differences were also noted regarding the elected methodology of analysis, the comparison of studies' outcomes with cost effectiveness thresholds, the study population to consider, the quality of life valuation methods, the perspective on costs, the types of resources considered and their valuation, the discount rates to apply in order to reflect the present value of interventions, etc. To account for these differences, modifications will be required in order to adapt economic models from one country to the other. CONCLUSIONS: Changes in HTA assessment methods occur in response to different challenges determined by the different philosophical and cultural considerations surrounding health and welfare as well as the political considerations regarding the role of public policies and the importance of their evaluation. PMID- 27123191 TI - Drug pricing reform in China: analysis of piloted approaches and potential impact of the reform. AB - OBJECTIVES: In 2009, the Chinese government launched a national healthcare reform programme aiming to control healthcare expenditure and increase the quality of care. As part of this programme, a new drug pricing reform was initiated on 1 June 2015. The objective of this study was to describe the changing landscape of drug pricing policy in China and analyse the potential impact of the reform. METHODS: The authors conducted thorough research on the drug pricing reform using three Chinese databases (CNKI, Wanfang, and Weipu), Chinese health authority websites, relevant press releases, and pharmaceutical blogs and discussion forums. This research was complemented with qualitative research based on targeted interviews with key Chinese opinion leaders representing the authorities' and prescribers' perspectives. RESULTS: With the current reform, the government has attempted to replace its direct control over the prices of reimbursable drugs with indirect, incentive-driven influence. Although the exact implementation of the reform remains unclear at the moment, the changes introduced so far and the pilot project designs indicate that China is considering adaptation of some form of internal and external reference pricing policies, commonly used in the Organisation for Economic Co-operation and Development countries. Several challenges related to the potential new mechanism were identified: 1) the risk of hospital underfunding, if hospital funding reform is not prioritised; 2) the risk of promoting the use of cheap, low-quality drugs, if a reliable quality control system is not in place and discrepancy between the available drugs is present; 3) the risk of increasing disparity in access to care between poor and rich regions, in case of country-wide price convergence; and 4) the risk of industry underinvestment, resulting in reduced competition, issues with quality and sustainability of supply, and potentially negative social impact. CONCLUSIONS: Foreign pricing policies cannot be transferred to China without prioritising historical, cultural, and economic contextualisation. Otherwise, the new policy may be counterproductive and affect the whole healthcare chain, as well as the health outcomes of Chinese patients. PMID- 27123192 TI - The value of innovation under value-based pricing. AB - OBJECTIVE: The role of cost-effectiveness analysis (CEA) in incentivizing innovation is controversial. Critics of CEA argue that its use for pricing purposes disregards the 'value of innovation' reflected in new drug development, whereas supporters of CEA highlight that the value of innovation is already accounted for. Our objective in this article is to outline the limitations of the conventional CEA approach, while proposing an alternative method of evaluation that captures the value of innovation more accurately. METHOD: The adoption of a new drug benefits present and future patients (with cost implications) for as long as the drug is part of clinical practice. Incidence patients and off-patent prices are identified as two key missing features preventing the conventional CEA approach from capturing 1) benefit to future patients and 2) future savings from off-patent prices. The proposed CEA approach incorporates these two features to derive the total lifetime value of an innovative drug (i.e., the value of innovation). RESULTS: The conventional CEA approach tends to underestimate the value of innovative drugs by disregarding the benefit to future patients and savings from off-patent prices. As a result, innovative drugs are underpriced, only allowing manufacturers to capture approximately 15% of the total value of innovation during the patent protection period. In addition to including the incidence population and off-patent price, the alternative approach proposes pricing new drugs by first negotiating the share of value of innovation to be appropriated by the manufacturer (>15%?) and payer (<85%?), in order to then identify the drug price that satisfies this condition. CONCLUSION: We argue for a modification to the conventional CEA approach that integrates the total lifetime value of innovative drugs into CEA, by taking into account off-patent pricing and future patients. The proposed approach derives a price that allows manufacturers to capture an agreed share of this value, thereby incentivizing innovation, while supporting health-care systems to pursue dynamic allocative efficiency. However, the long-term sustainability of health-care systems must be assessed before this proposal is adopted by policy makers. PMID- 27123193 TI - Advanced therapy medicinal products: current and future perspectives. AB - BACKGROUND: Advanced therapy medicinal products (ATMPs) are innovative therapies that encompass gene therapy, somatic cell therapy, and tissue-engineered products. These therapies are expected to bring important health benefits, but also to substantially impact the pharmaceuticals budget. OBJECTIVE: The aim of this study was to characterise the ATMPs in development and discuss future implications in terms of market access. METHODS: Clinical trials were searched in the following databases: EudraCT (EU Drug Regulating Authorities Clinical Trials), ClinicalTrials.gov, and ICTRP (International Clinical Trials Registry Platform of the World Health Organization). Trials were classified by category of ATMP as defined by European regulation EC No. 1394/2007, as well as by development phase and disease area. RESULTS: The database search identified 939 clinical trials investigating ATMPs (85% ongoing, 15% completed). The majority of trials were in the early stages (Phase I, I/II: 64.3%, Phase II, II/III: 27.9%, Phase 3: 6.9%). Per category of ATMP, we identified 53.6% of trials for somatic cell therapies, 22.8% for tissue-engineered products, 22.4% for gene therapies, and 1.2% for combined products (incorporating a medical device). Disease areas included cancer (24.8%), cardiovascular diseases (19.4%), musculoskeletal (10.5%), immune system and inflammation (11.5%), neurology (9.1%), and others. Of the trials, 47.2% enrolled fewer than 25 patients. Due to the complexity and specificity of ATMPs, new clinical trial methodologies are being considered (e.g., small sample size, non-randomised trials, single-arm trials, surrogate endpoints, integrated protocols, and adaptive designs). Evidence generation post launch will become unavoidable to address payers' expectations. CONCLUSION: ATMPs represent a fast-growing field of interest. Although most of the products are in an early development phase, the combined trial phase and the potential to cure severe chronic conditions suggest that ATMPs may reach the market earlier than standard therapies. Targeted therapies have opened the way for new trial methodologies, from which ATMPs could benefit to get early access. ATMPs may be the next source of major impact on payers' drug budgets. PMID- 27123195 TI - Evaluation of Risk Factors Associated with Endometriosis in Infertile Women. AB - BACKGROUND: Endometriosis affects women's physical and mental wellbeing. Symptoms include dyspareunia, dysmenorrhea, pelvic pain, and infertility. The purpose of this study is to assess the correlation between some relevant factors and symptoms and risk of an endometriosis diagnosis in infertile women. MATERIALS AND METHODS: A retrospective study of 1282 surgical patients in an infertility Institute, Iran between 2011 and 2013 were evaluated by laparoscopy. Of these, there were 341 infertile women with endometriosis (cases) and 332 infertile women with a normal pelvis (comparison group). Chi-square and t tests were used to compare these two groups. Logistic regression was done to build a prediction model for an endometriosis diagnosis. RESULTS: Gravidity [odds ratio (OR): 0.8, confidence interval (CI): 0.6-0.9, P=0.01], parity (OR: 0.7, CI: 0.6-0.9, P=0.01), family history of endometriosis (OR: 4.9, CI: 2.1-11.3, P<0.001), history of galactorrhea (OR: 2.3, CI: 1.5-3.5, P=0.01), history of pelvic surgery (OR: 1.9, CI: 1.3-2.7, P<0.001), and shorter menstrual cycle length (OR: 0.9, CI: 0.9-0.9, P=0.04) were associated with endometriosis. Duration of natural menstruation and age of menarche were not correlated with subsequent risk of endometriosis (P>0.05). Fatigue, diarrhea, constipation, dysmenorrhea, dyspareunia, pelvic pain and premenstrual spotting were more significant among late-stage endometriosis patients than in those with early-stage endometriosis and more prevalent among patients with endometriosis than that of the comparison group. In the logistic regression model, gravidity, family history of endometriosis, history of galactorrhea, history of pelvic surgery, dysmenorrhoea, pelvic pain, dysparaunia, premenstrual spotting, fatigue, and diarrhea were significantly associated with endometriosis. However, the number of pregnancies was negatively related to endometriosis. CONCLUSION: Endometriosis is a considerable public health issue because it affects many women and is associated with the significant morbidity. In this study, we built a prediction model which can be used to predict the risk of endometriosis in infertile women. PMID- 27123194 TI - Immune Aspects of Female Infertility. AB - Immune infertility, in terms of reproductive failure, has become a serious health issue involving approximately 1 out of 5 couples at reproductive age. Semen that is defined as a complex fluid containing sperm, cellular vesicles and other cells and components, could sensitize the female genital tract. The immune rejection of male semen in the female reproductive tract is explained as the failure of natural tolerance leading to local and/or systemic immune response. Present active immune mechanism may induce high levels of anti-seminal/sperm antibodies. It has already been proven that iso-immunization is associated with infertility. Comprehensive studies with regards to the identification of antibody-targets and the determination of specific antibody class contribute to the development of effective immuno-therapy and, on the other hand, potential immuno-contraception, and then of course to complex patient diagnosis. This review summarizes the aspects of female immune infertility. PMID- 27123196 TI - Metabolic and Endocrine Characteristics of Indian Women with Polycystic Ovary Syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrinological disorders among women of reproductive age and the leading cause of female infertility. This study intends to evaluate the lipid profile, hormonal levels [free T3 (fT3), free T4 (fT4), thyroid stimulating hormone (TSH), insulin, luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin] in PCOS women from Nellore and its surrounding districts of Andhra Pradesh, India. MATERIALS AND METHODS: This cross-sectional study included 80 newly diagnosed PCOS women and an equal number of age and body mass index (BMI) matched healthy controls. We used the photometry methods to determine serum glucose levels and the lipid profile. An immunoturbidometry method was employed to measure high sensitive C-reactive protein (hsCRP). All hormonal parameters were measured using chemiluminescence immunoassays. Insulin resistance was evaluated using the homeostatic model assessment-insulin resistance (HOMA-IR) method. Statistical analysis was done using SPSS software version 20.0. RESULTS: The PCOS patients presented statistically higher levels of total cholesterol (TC), triglycerides (TG) and low density lipoprotein cholesterol (LDL-c, P<0.0001) when compared to those of controls. PCOS patients had elevated fasting glucose, hsCRP, fasting insulin, TSH, LH and prolactin levels (P<0.001). An increased LH/FSH ratio (>1.5) was seen in women with PCOS compared with control women. In addition, we observed a direct correlation between fasting insulin with fasting glucose and HOMA-IR. LH was inversely proportional to BMI. CONCLUSION: The present study showed a higher prevalence of insulin resistance, dyslipidemia, and hypothyroidism in PCOS women. Furthermore this study showed increased LH concentrations, a higher LH/FSH ratio, and higher prolactin levels in PCOS women. PMID- 27123197 TI - Correlation of Serum Lipoprotein Ratios with Insulin Resistance in Infertile Women with Polycystic Ovarian Syndrome: A Case Control Study. AB - BACKGROUND: Dyslipidemia and insulin resistance (IR), occurring in most infertile women with polycystic ovarian syndrome (PCOS), increase the risk of cardiovascular disease (CVD) and type 2 diabetes. This study aimed to assess the relationships between lipoprotein ratios and IR in PCOS women. MATERIALS AND METHODS: Thirty six infertile women with PCOS selected based on Androgen Excess Society (AES) criteria and 29 healthy women matched for age were recruited to this case-control study. After physical measurements, fasting serum glucose (Glu), insulin and lipid profile levels [triglycerides (TGs), total cholesterol (TC), low-density lipoproteincholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)] were measured, while lipoprotein ratios (TC/HDL-C, LDL-C/HDL C, TG/HDL-C) were calculated. IR was also calculated using homeostasis model assessment (HOMA)-IR. The optimal cutoffs of lipoprotein ratios in relation to HOMA-IR were calculated based on the Receiver Operating Characteristics (ROC) curve analysis using the area under curve (AUC). RESULTS: Waist circumference (WC), insulin levels, HOMA-IR, TG levels, and all lipoprotein ratios were significantly higher, while HDL-C was lower in PCOS group as compared to healthy controls. All lipoprotein ratios, TG levels, and WC are significantly correlated with insulin levels and HOMA-IR. Among lipoprotein ratios, the highest AUC of the ROC belonged to TG/HDL-C ratio with sensitivity of 63.6% and specificity of 84.4% (TG/HDL-C>3.19) as a marker of IR in infertile PCOS women. CONCLUSION: Lipoprotein ratios, particularly TG/HDL-C, are directly correlated with insulin levels and can be used as a marker of IR (HOMA-IR) in infertile PCOS patients. PMID- 27123198 TI - Relationships between Serum Luteinizing Hormone Level, Endometrial Thickness and Body Mass Index in Polycystic Ovary Syndrome Patients with and without Endometrial Hyperplasia. AB - BACKGROUND: The endometrial hyperplasia measured by ultrasound in polycystic ovary syndrome (PCOS) women is strongly related to pathologic endometrial thickness, but there is no consensus on the relation between serum luteinizing hormone (LH) and either of these factors: pathologic endometrial hyperplasia and body mass index (BMI). MATERIALS AND METHODS: In this observational cross sectional study, three hundred fifty infertile PCOS women were involved in this research. An endometrial biopsy was taken by using a pipelle instrument, regardless of menstrual cycle's day and all samples were reported by the same pathologist. Basal serum LH level was compared between two subgroups (hyperplasia and non-hyperplasia). The intended population was divided into three groups according to BMI and basal serum LH, later on the comparison was made in three groups. Chi-square test was applied to compare nominal variables between groups. Mann-Whitney U, and one way ANOVA tests were used to compare means on the basis of the result of normality test. RESULTS: The frequency of endometrial hyperplasia was 2.6%. Endometrial thickness in the patients with endometrial hyperplasia was significantly higher than that of a normal endometrium (10.78 +/- 3.70 vs. 7.90 +/- 2.86 respectively, P=0.020). There was no relation between endometrial hyperplasia and serum LH (P=0.600). The ANOVA test showed serum LH levels were not the same among three BMI groups (P=0.007). Post hoc test was also performed. It showed that the LH level in normal BMI group was significantly higher than those of other groups (P=0.005 and P=0.004), but there was no statistical difference between overweight and obese groups (P=0.8). We found no relationship between BMI and endometrial thickness in PCOS patients (P=0.6). CONCLUSION: Sonographic endometrial stripe thickness is predictive for endometrial hyperplasia in PCOS women. We could not find out any relationship between serum LH level and BMI with endometrial thickness in PCOS patients. However, our study confirmed a diverse relationship between serum LH level and BMI in PCOS patients. PMID- 27123199 TI - Effect of Laparoscopic Ovarian Drilling on Outcomes of In Vitro Fertilization in Clomiphene-Resistant Women with Polycystic Ovary Syndrome. AB - BACKGROUND: Recently the laparoscopic ovarian drilling (LOD) has been used as a surgical treatment for ovulation in women with polycystic ovarian syndrome (PCOS), although its mechanism and outcomes are still unclear. This study was undertaken to evaluate the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes in clomiphene-resistant women with PCOS who were treated with LOD. MATERIALS AND METHODS: In this retrospective study, we reviewed the medical records of 300 women between 20 to 35 years old with clomiphene resistant PCOS who had an ovulatory infertility and who were nominated for IVF/ICSI. Based on their treatment history, they were located into the following two groups: group I (n=150) including PCOS women who had history of LOD at least 6 months to 3 years before IVF/ICSI, and group II (n=150) including PCOS patients without history of drilling. Both groups were treated with antagonist protocol in the assisted reproductive technology (ART) process. The duration of treatment cycles, number of oocytes and embryos obtained, chemical and clinical pregnancy rate, the number of embryos transferred, and presence of ovarian hyper stimulation syndrome (OHSS) were measured. To compare means and frequencies, Student's t test, Mann-whitney and chi-square tests were used. RESULTS: Our results showed that ovarian cauterization before IVF/ICSI in patients with PCOS reduced the risk of OHSS (P=0.025). Despite the same pregnancy rate in both groups (P=0.604), more obtained oocytes and embryos were seen on women without ovarian drilling than women with LOD (P?0.001 and P=0.033, respectively). CONCLUSION: There is no difference between the pregnancy rate in both groups. Due to significant reduction in OHSS in women undergoing LOD, this surgical treatment may be considered as a useful technique in the management of patients who have previously developed OHSS. However, there are ongoing concerns about long-term effects of LOD on ovarian function. PMID- 27123200 TI - A Comparison of Success Rates of Embryo Transfer on Weekdays and Weekends. AB - BACKGROUND: The aim of this study is to examine the effect of the embryo transfer (ET) day on clinical pregnancy success rates in in vitro fertilization-ET (IVF ET) cycles. MATERIALS AND METHODS: In this retrospective study, we divided patients with infertility who underwent IVF-ET with fresh embryos into two groups depending on whether the ET was performed on weekdays or weekends. The main outcome measure was to compare the clinical pregnancy rates of patients with similar demographic and clinical characteristics who underwent ET on weekdays or weekends. RESULTS: A total of 188 patients underwent IVF-ET on weekdays (n=156) or weekends (n=32). Both groups had similar demographic and cycle characteristics. The overall pregnancy rate was 42.8%. Among the study groups, the weekday group had a 40.2% ET success rate and the weekend group had a 54.8% success rate (P=0.517). Although no statistically significant difference existed between the two groups, we observed an absolute 14.6% increase in pregnancy rate for ETs performed during weekends compared to those performed on weekdays, with a 35% statistical power. CONCLUSION: ETs performed during weekends were more successful than ETs performed during weekdays with an absolute 14.6% increase in clinical pregnancy rate. This finding should be confirmed by conducting further studies with larger groups of patients. PMID- 27123201 TI - Effects of Crocin Supplementation during In Vitro Maturation of Mouse Oocytes on Glutathione Synthesis and Cytoplasmic Maturation. AB - BACKGROUND: Crocin is an active ingredient of saffron (Crocus sativus L.) and its antioxidant properties have been previously investigated. This carotenoid scavenges free radicals and stimulates glutathione (GSH) synthesis; consequently, it may protect cells against oxidative stress. The aim of this research is to protect oocytes from oxidative stress by the addition of a natural source antioxidant. MATERIALS AND METHODS: In the present in vitro experimental study, we collected cumulus oocyte complexes (COCs) from mouse ovaries of euthanized, 6 8 week-old female Naval Medical Research Institute (NMRI) mice. Oocytes were subjected to in vitro maturation (IVM) in the presence of either crocin (5 or 10 MUg/ml), 5 mM buthionine-[S-R]- sulfoximine (BSO), or the combination of crocin plus BSO. Oocytes that matured in vitro in a medium without crocin or BSO supplements were considered as controls. Following 16-18 hours of IVM, matured oocytes (n=631) were fertilized by capacitated sperm from NMRI male mice, and cultured in vitro for up to 96 hours to assess preimplantation embryonic development. The levels of GSH in metaphase II (MII) oocytes after IVM (n=240) were also assessed by the 5, 5-dithio-bis (2-nitrobenzoic acid) (DTNB)-GSH reductase recycling assay. RESULTS: Supplementation of IVM media with 10 ug/ml crocin significantly (P<0.05) increased nuclear maturation, preimplantation development and GSH concentrations compared with the control group. Maturation of oocytes in IVM medium supplemented with BSO alone or the combination of 5 ug/ml crocin and BSO drastically decreased GSH concentrations and subsequently resulted in low rates of maturation, fertilization and blastocyst development. However, the combination of 10 ug/ml crocin with 5 mM BSO increased the level of nuclear maturation which was comparable to the control group. CONCLUSION: Supplementation of IVM media with crocin can improve nuclear maturation rates and subsequent developmental potential of mouse oocytes. This may occur by its beneficial effect in increasing GSH concentrations in MII oocytes. PMID- 27123202 TI - Fetal RHD Genotyping Using Real-Time Polymerase Chain Reaction Analysis of Cell Free Fetal DNA in Pregnancy of RhD Negative Women in South of Iran. AB - BACKGROUND: Maternal-fetal RhD antigen incompatibility causes approximately 50% of clinically significant alloimmunization cases. The routine use of prophylactic anti-D immunoglobulin has dramatically reduced hemolytic disease of the fetus and newborn. Recently, fetal RHD genotyping in RhD negative pregnant women has been suggested for appropriate use of anti-D immunoglobulin antenatal prophylaxis and decrease unnecessary prenatal interventions. MATERIALS AND METHODS: In this prospective cohort study, in order to develop a reliable and non-invasive method for fetal RHD genotyping, cell free fetal DNA (cffD- NA) was extracted from maternal plasma. Real-time quantitative polymerase chain reaction (qPCR) for detection of RHD exons 7, 5, 10 and intron 4 was performed and the results were compared to the serological results of cord blood cells as the gold standard method. SRY gene and hypermethylated Ras-association domain family member 1 (RASSF1A) gene were used to confirm the presence of fetal DNA in male and female fetuses, respectively. RESULTS: Out of 48 fetuses between 8 and 32 weeks (wks) of gestational age (GA), we correctly diagnosed 45 cases (93.75%) of RHD positive fetuses and 2 cases (4.16%) of the RHD negative one. Exon 7 was amplified in one sample, while three other RHD gene sequences were not detected; the sample was classified as inconclusive, and the RhD serology result after birth showed that the fetus was RhD-negative. CONCLUSION: Our results showed high accuracy of the qPCR method using cffDNA for fetal RHD genotyping and implicate on the efficiency of this technique to predict the competence of anti-D immunoglobulin administration. PMID- 27123203 TI - Crocin Improves Damage Induced by Nicotine on A Number of Reproductive Parameters in Male Mice. AB - BACKGROUND: Crocin, a carotenoid isolated from Crocus sativus L. (saffron), is a pharmacologically active component of saffron. Nicotine consumption can decrease fertility in males through induction of oxidative stress and DNA damage. The aim of this study is to determine the effects of crocin on reproductive parameter damages in male mice exposed to nicotine. MATERIALS AND METHODS: In this experimental study, we divided 48 mice into 8 groups (n=6 per group): control (normal saline), nicotine (2.5 mg/kg), crocin (12.5, 25 and 50 mg/kg) and crocin (12.5, 25 and 50 mg/kg)+nicotine (2.5 mg/kg). Mice received once daily intraperitoneal injections of crocin, nicotine and crocin+nicotine for 4 weeks. Sperm parameters (count, motility, and viability), testis weight, seminiferous tube diameters, testosterone, and serum nitric oxide levels were analyzed and compared. RESULTS: Nicotine administration significantly decreased testosterone level; sperm count, viability, and motility; testis weight and seminiferous tubule diameters compared to the control group (P<0.05). However, increasing the dose of crocin in the crocin and crocin+nicotine groups significantly boosted sperm motility and viability; seminiferous tubule diameters; testis weight; and testosterone levels in all groups compared to the nicotine group (P<0.05). CONCLUSION: Crocin improves nicotine-induced adverse effects on reproductive parameters in male mice. PMID- 27123204 TI - Ethyl Pyruvate Ameliorates The Damage Induced by Cyclophosphamide on Adult Mice Testes. AB - BACKGROUND: Cyclophosphamide (CP) is a chemotherapy drug which causes deleterious effects on testicular tissue and increases free radicals in the body. The aim of this study is to investigate the protective effects of ethyl pyruvate (EP) on testicular improvement in CP treated animals. MATERIALS AND METHODS: In this experimental study, 15 male mice (6-8 weeks) were divided into 3 groups. The control group received normal saline (0.1 ml/day), intraperitoneal (IP), CP group received CP (15 mg/kg/week, IP), and the CP+EP group received EP (40 mg/kg/day, IP) plus CP. After 35 days, we assessed serum total antioxidant capacity (TAC) along with histomorphometric and histochemical analyses of the testicles. RESULTS: The mean thickness of the germinal epithelium, diameter of seminiferous tubules, and the number of Leydig cells in the CP+EP group were higher than those of the CP group (P<0.05). The number of the mast cells in the CP+EP group significantly reduced compared with the CP group (P<0.05). Alkaline phosphatase (ALP), periodic acid-schiff (PAS) positive reactions and lipid granules in cytoplasm of the Leydig cells in the CP group increased compared with the other groups (P<0.05). TAC in the CP group significantly reduced compared with the other groups (P<0.05). CONCLUSION: This study showed the ability of EP to reduce the destructive side effects of CP in the adult mice reproductive system. PMID- 27123205 TI - The Effects of Testosterone on Oxidative Stress Markers in Mice with Spinal Cord Injuries. AB - BACKGROUND: Spinal cord injury (SCI) causes infertility in male patients through erectile dysfunction, ejaculatory dysfunction, semen and hormone abnormalities. Oxidative stress (OS) is involved in poor semen quality and subsequent infertility in males with SCI. The aim of this study is to examine the effects of SCI on the level of testosterone hormone. MATERIALS AND METHODS: In this experimental study, we evaluated the effects of exogenous testosterone on the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as the levels of malondialdehyde (MDA) and protein carbonylation (PCO), as markers of OS, in 10 groups of SCI mice. Total antioxidant capacity (TAC) was determined using the 2,29-azinobis-(3 ethylbenzothiazoline- 6-sulfonic acid) (ABTS) radical cation assay. RESULTS: Exogenous testosterone administration in mice with SCI significantly reduced SOD and GPx enzyme activities and MDA level. There was no significant decrease in PCO content. In addition, TAC remarkably increased in the sham and SCI groups not treated with testosterone but remained unchanged in all other experimental groups. Exogenous testosterone also reduced serum testosterone levels in all groups except the positive control group. CONCLUSION: Our cumulative data indicated that SCI could cause sterility by disturbing the plasmatic testosterone balance. The normal level of endogenous testosterone was not completely restored by exogenous testosterone administration. PMID- 27123206 TI - Investigation of Personality Traits between Infertile Women Submitted to Assisted Reproductive Technology or Surrogacy. AB - BACKGROUND: Personality traits affect human relationships, social interactions, treatment procedures, and essentially all human activities. The purpose of this study is to investigate the personality traitsincluding sensation seeking, flexibility, and happiness among a variety of infertile women who were apt to choose assisted reproductive technology (ART) or surrogacy. MATERIALS AND METHODS: This is a cross-sectional study that was performed on 251 infertile women who visited Isfahan and Tehran Reproductive Medicine Center. These fertility clinics are located in Isfahan and Tehran, Iran. In this study, 201 infertile women who underwent treatment using ART and 50 infertile women who tended to have surrogacy were chosen by convenience sampling. Zuckerman's Sensation Seeking Scale Form V (SSS-V), Psychological Flexibility Questionnaire (adapted from NEO Personality Inventory-Revised) and Oxford Happiness Questionnaire (OHQ) were used as research instruments. All participants had to complete the research instruments in order to be included in this study. Data were analyzed by descriptive-analytical statistics and statistical tests including multivariate analysis of variance (MANOVA) and Z Fisher. Statistically significant effects were accepted for P<0.05. RESULTS: In the sensation-seeking variable, there was a meaningful difference between under-study groups. However, the flexibility and happiness variables did not have a significant difference between under-study groups (P<0.001). Interaction between education, employment, and financial status was effective in happiness of infertile women underwent ART (P<0.05), while age, education and financial status were also effective in happiness of infertile women sought surrogacy (P<0.05). A positive meaningful relationship was seen between sensation seeking and flexibility variables in both groups (P<0.05). And a negative meaningful relationship was seen between sensation seeking and happiness in infertile women who sought surrogacy (P<0.05). The difference in rate of relationship between sensation seeking and flexibility was meaningful in infertile women who sought either ART or surrogacy (P<0.05). CONCLUSION: Sensations seeking as a personality trait is lower in infertile women who underwent treatment using ART compared women who tended to have surrogacy. This study shows that demographic variables are effective in happiness of infertile women. Also, there is a significant relation among sensation seeking, flexibility and happiness in infertile women. PMID- 27123207 TI - Effect of Group Positive Psychotherapy on Improvement of Life Satisfaction and The Quality of Life in Infertile Woman. AB - BACKGROUND: Positive psychotherapy is one of the new approaches in psychology which is innovated for treating psychological disorders and enhancing positive emotions. The aim of this study is to investigate the effectiveness of the group positive psychotherapy on elevation of life satisfaction and quality of life in infertile women. MATERIALS AND METHODS: In a randomized trial study, Beck Depression Inventory II (BDI-II) and clinical interview were used in a pre-test post-test control group design. After analyzing the result of the questionnaire, 36 infertile women who showed signs of mild to moderate depression were randomly placed into two following groups: control (n=18) and intervention (n=18). Before the treatment, the members of both groups answered BDI-II, Satisfaction With Life Scale (SWLS) and 12 item Short Form Health Survey (SF-12). The intervention group received six sessions of group positive psychotherapy, but the treatment of the control group began six weeks after the intervention group. RESULTS: The results showed that the life satisfaction scores of the intervention group were significantly elevated from 22.66 in pre-test to 26.13 in post-test (P<0.001), while this improvement was not significant in the control group (P=0.405). The difference between life satisfaction scores of the intervention and the control groups was also significant (F=8.92, P=0.006). However, no significant change in the quality of life level of the intervention and control groups was observed (P=0.136). CONCLUSION: Thus it can be deduced from the findings that this treatment method could be introduced as solution to increase the life satisfaction in infertile women, but not as a treatment for elevating their quality of life (Registration Number: IRCT2013042810063N3). PMID- 27123208 TI - Development and Validation of Attitude toward Gestational Surrogacy Scale in Iranian Infertile Couples. AB - BACKGROUND: Surrogacy is one of the most challenging infertility treatments engaging ethical, psychological and social issues. Attitudes survey plays an important role to disclosure variant aspects of surrogacy, to help meeting legislative gaps and ambiguities, and to convert controversial dimensions surrounding surrogacy to a normative concept that eliminates stigma. The aim of this study is to develop a comprehensive scale for gestational surrogacy attitudes. MATERIALS AND METHODS: Development process of gestational surrogacy attitudes scale (GSAS) performed based on a descriptive cross-sectional study and included a rich data pool gathered from literature reviews, a qualitative pilot study on 15 infertile couples (n=30), use of expert advisory panel (EAP) consisting of 20 members, as well as use of content validity through qualitative and quantitative study by the means of content validity ratio (CVR) and content validity index (CVI). Also internal consistence using Cronbach's alpha and test retest reliability using intracalss correlation coefficient (ICC) were evaluated. Application of GSAS was tested in a cross-sectional study that was conducted on 200 infertile couples (n=400) at Royan Institute, Tehran, Iran, during 2014. RESULTS: Final version of GSAS had 30 items within five subscales including "acceptance of surrogacy", "Surrogacy and public attitudes", "Child born through surrogacy", "Surrogate mother", and "Intentional attitude and surrogacy future attempt". Content validity was represented with values of CVR=0.73 and CVI =0.98. Cronbach's alpha value was 0.91 for the overall scale, while ICC value due to test-retest responses was 0.89. CONCLUSION: Acceptable level of competency and capability of GSAS is significantly indicated; therefore, it seems to be an appropriate tool for the evaluation of gestational surrogacy attitudes in Iranian infertile couples. PMID- 27123209 TI - A Preliminary Study: N-acetyl-L-cysteine Improves Semen Quality following Varicocelectomy. AB - BACKGROUND: Surgery is considered the primary treatment for male infertility from clinical varicocele. One of the main events associated with varicocele is excessive production of reactive oxygen species (ROS). N-acetyl-L-cysteine (NAC), an antioxidant that scavenges free radicals, is considered a supplement to alleviate glutathione (GSH) depletion during oxidative stress. Despite beneficial effects of NAC in other pathological events, there is no report on the effect of NAC in individuals with varicocele. Therefore, the aim of this study is to evaluate the outcome of NAC on semen quality, protamine content, DNA damage, oxidative stress and fertility following varicocelectomy. MATERIALS AND METHODS: This prospective clinical trial included 35 infertile men with varicocele randomly divided into control (n=20) and NAC (n=15) groups. We assessed semen parameters, protamine content [chromomycin A3 (CMA3)], DNA integrity [terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL)] and oxidative stress [2', 7'-dichlorodihydrofluorescein-diacetate (DCFH-DA)] before and three months after varicocelectomy. RESULTS: Percentage of abnormal semen parameters, protamine deficiency, DNA fragmentation and oxidative stress were significantly decreased in both groups compared to before surgery. We calculated the percentage of improvement in these parameters compared to before surgery for each group, then compared the results between the groups. Only percentage of protamine deficiency and DNA fragmentation significantly differed between the NAC and control groups. CONCLUSION: The results of this study, for the first time, revealed that NAC improved chromatin integrity and pregnancy rate when administered as adjunct therapy post-varico- celectomy (Registeration Number: IRCT201508177223N5). PMID- 27123210 TI - Correlation of Adiponectin mRNA Abundance and Its Receptors with Quantitative Parameters of Sperm Motility in Rams. AB - BACKGROUND: Adiponectin and its receptors (AdipoR1 and AdipoR2), known as adiponectin system, have some proven roles in the fat and glucose metabolisms. Several studies have shown that adiponectin can be considered as a candidate in linking metabolism to testicular function. In this regard, we evaluated the correlation between sperm mRNA abundance of adiponectin and its receptors, with sperm motility indices in the present study. MATERIALS AND METHODS: In this completely randomized design study, semen samples from 6 adult rams were fractionated on a two layer discontinuous percoll gradient into high and low motile sperm cells, then quantitative parameters of sperm motility were determined by computer-assisted sperm analyzer (CASA). The mRNA abundance levels of Adiponectin, AdipoR1 and AdipoR2 were measured quantitatively using real-time reverse transcriptase polymerase chain reaction (qRT-PCR) in the high and low motile groups. RESULTS: Firstly, we showed that adiponectin and its receptors (AdipoR1 and AdipoR2) were transcriptionally expressed in the ram sperm cells. Using Pfaff based method qRT- PCR, these levels of transcription were significantly higher in the high motile rather than low motile samples. This increase was 3.5, 3.6 and 2.5 fold change rate for Adiponectin, AdipoR1 and AdipoR2, respectively. Some of sperm motility indices [curvilinear velocity (VCL), straight-line velocity (VSL), average path velocity (VAP), linearity (LIN), wobble (WOB) and straightness (STR)] were also significantly correlated with Adiponectin and AdipoR1 relative expression. The correlation of AdipoR2 was also significant with the mentioned parameters, although this correlation was not comparable with adiponectin and AdipoR1. CONCLUSION: This study revealed the novel association of adiponectin system with sperm motility. The results of our study suggested that adiponectin is one of the possible factors which can be evaluated and studied in male infertility disorders. PMID- 27123211 TI - Herlyn Werner Wunderlich Syndrome with Hematocolpos: An Unusual Case Report of Full Diagnostic Approach and Treatment. AB - Herlyn-Werner-Wunderlich (HWW) syndrome is an uncommon combined mullerian duct anomalies (MDAs) and mesonephric duct malformation of female urogenital tract characterized by uterus didelphys and obstructed hemi-vagina and ipsilateral renal agenesis (OHVIRA) syndrome. We present a rare and unusual case of this syndrome in a 19 year-old female who suffered from hypomenorrhoea and abdominal pain. She had an obstructed hemi-vagina on right side which led to marked distention of ipsilateral cervix, while proximal hemi-vagina compressed the contralateral side causing its partial obstruction resulting in hypomenorrhoea. Understanding the imaging findings of this rare condition is important for early diagnosis in order to prevent complications which may lead to infertility. PMID- 27123212 TI - Sources, Outcomes, and Resolution of Conflicts in Marriage among Iranian women: A qualitative study. AB - INTRODUCTION: Family's conflict is the important determinant of the quality and quantity of relationships among family members. No study of which we are aware has assessed conflicts, especially among normal or apparently satisfied couples in the Iranian context. This study explored that how women deal with different points, ideas and behaviors in marital life. METHODS: For the study, we recruited 30 to 45-year-old housewives who visited health centers in Tehran, Iran. The participants (n = 45) were selected using purposefully convenient sampling. In depth interviews and focus group discussions were used. The data were analyzed qualitatively using MAXQDA 10. RESULTS: Themes, including conflicting situations, causes of conflict, consequences of conflict, and conflict resolution styles were extracted. CONCLUSION: Although Iranian women were dissatisfied with their lives, they tried to protect their marriages. PMID- 27123213 TI - Postgraduate medical students' acceptance and understanding of scientific information databases and electronic resources. AB - INTRODUCTION: The significance and validity of web-based scientific databases are increasing dramatically in the scientific community. Moreover, a great number of students use these resources without having sufficient and accurate knowledge and understanding. In order for students to use these databases and electronic resources optimally, identifying the factors that affect the understanding and acceptance of these resources seems necessary. The aim of this study was to determine postgraduate medical students' acceptance and understanding of these resources. METHODS: This cross-sectional study was conducted on 311 postgraduate medical students from Kerman University of Medical Science (KMU) in 2013. Data were collected using a researcher-made questionnaire, and the data were analyzed using SPSS. In order to design the model (i.e., the interaction between study variables and to determine the relationships between them in an integrated pattern), LISREL version 8.7 and a structural equation model were used. Descriptive statistics and t-tests also were used in data analysis. RESULTS: The results showed that the average components of the perception of usefulness, perception of ease of use, attitude towards use, decision to use, using to perform duties, and using to increase knowledge were 4.31, 4.14, 4.24, 16.27, 20.85, and 16.13 respectively. Accordingly, the average of all these indicators was significantly higher than the assumed amount (p < 0.01). Moreover, the results obtained from factor analysis and the structural equation model indicated that the model of the present study fit the data perfectly. CONCLUSIONS: Based on the findings of this study, the more these databases are considered useful and easy to use, the more they are used. Therefore, designers of databases and electronic resources can design systems that are both useful and easy to learn by considering the components of the research model. PMID- 27123214 TI - Evaluation of the Quality of Health Service Providers: The Iranian People Perspective 2014. AB - INTRODUCTION: Quality is the center of attention in all service providing organizations that are effective in promoting satisfaction of patients who are referred to medical centers. The aim of this study was to investigate the quality of health service providers in a case study of Qazvin, Iran, in 2014. METHODS: This descriptive study was conducted on 1,002 people who were residents of Qazvin Province (Iran) in 2014. The people were selected randomly from the population of the study area. The main variables studied were education, perceptions, expectations, and gaps in service quality. The data collection tool was the standard Servequal questionnaire. To determine the reliability of the research tool, we used Cronbach's Alpha coefficient and the test-retest method. Statistical analyses were conducted using SPSS and the ANOVA test. RESULTS: The mean age of people included in the study was 32 +/- 9.9 years, and the average waiting time to receive services was 73 +/- 47 minutes. Hospitals and doctors' offices had the highest quality gap of -1.420 +/- 0.82 and -1.01 +/- 0.75, respectively. The service quality gaps in medical centers, health providers of rural area, and health providers of urban area were -0.883 +/- 0.67, -0.882 +/- 0.83, and -0.804 +/- 0.62, respectively. There was a significant relationship between peoples' perceptions and expectations concerning the quality of health services and their educational levels. CONCLUSION: The higher gaps in quality in hospitals and in doctors' offices require more attention. Managers and policy makers should consider developing and implementing plans to reduce these gaps in quality and to promote better health services in these two sectors. PMID- 27123215 TI - Prevalence and Risk Factors associated with Extended Spectrum Beta Lactamase Producing Escherichia coli and Klebsiella pneumoniae Isolates in Hospitalized Patients in Kashan (Iran). AB - INTRODUCTION: Production of extended spectrum beta lactamase (ESBL) is an important mechanism of antimicrobial resistance in Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) isolates. This study was performed to determine the prevalence and risk factors associated with ESBL producing strains of E. coli and K. pneumoniae. METHODS: In this cross-sectional study, 250 strains (134 E. coli and 116 K. pneumoniae) were obtained, and ESBL producing isolates were detected by the combination disk test in Shahid Beheshti Hospital in Kashan, Iran, from February 2012 to June 2013. Antimicrobial resistance was screened by the disk diffusion method and was confirmed by E-test. Furthermore, risk factors of ESBL producing E. coli and K. pneumoniae microorganisms were determined. Data were analyzed by SPSS version 16, using descriptive statistics, chi-squared, independent-samples t-test, and logistic regression analysis. RESULTS: One hundred and two (40.8%) of all strains were ESBL producers, of which 54 (52.9%) were E. coli and 48 (47.1%) were K. pneumoniae (p = 0.86). Furthermore, 40.3% of E. coli and 41.4% of K. pneumoniae isolates were ESBL producers (p = 0.86). The most antimicrobial resistance was to ampicillin, and no imipenem resistance was detected. Risk factors for ESBL producing E. coli included admission duration exceeding 7 days (p = 0.011) and antibiotic use in the last month (p < 0.001), and the associated risk factor for ESBL producing K. pneumoniae was antibiotic use during the recent month (p = 0.002). CONCLUSION: This study identified a relatively high prevalence of ESBL production among E. coli and K. pneumoniae strains. Furthermore, anti-bimicrobial use and admission duration were risk factors for ESBL producing isolates. Therefore, more comprehensive investigations are needed for the development of new strategies to control the dissemination of these microbes. PMID- 27123216 TI - The Effect of Exposure to High Noise Levels on the Performance and Rate of Error in Manual Activities. AB - INTRODUCTION: Sound is among the significant environmental factors for people's health, and it has an important role in both physical and psychological injuries, and it also affects individuals' performance and productivity. The aim of this study was to determine the effect of exposure to high noise levels on the performance and rate of error in manual activities. METHODS: This was an interventional study conducted on 50 students at Shiraz University of Medical Sciences (25 males and 25 females) in which each person was considered as its own control to assess the effect of noise on her or his performance at the sound levels of 70, 90, and 110 dB by using two factors of physical features and the creation of different conditions of sound source as well as applying the Two-Arm coordination Test. The data were analyzed using SPSS version 16. Repeated measurements were used to compare the length of performance as well as the errors measured in the test. RESULTS: Based on the results, we found a direct and significant association between the levels of sound and the length of performance. Moreover, the participant's performance was significantly different for different sound levels (at 110 dB as opposed to 70 and 90 dB, p < 0.05 and p < 0.001, respectively). CONCLUSION: This study found that a sound level of 110 dB had an important effect on the individuals' performances, i.e., the performances were decreased. PMID- 27123217 TI - Frequency of sacroiliitis among patients with low back pain. AB - INTRODUCTION: Sacroiliitis is one of the important symptoms in patients attending infectious diseases and rheumatology clinics. Some patients with sacroiliitis are asymptomatic, and some have unspecific symptoms. The aim of this study was to determine the frequency of sacroiliitis causes among patients attending Shahid Sadoughi's infectious disease and rheumatology clinics. METHODS: In this study, we evaluated patients attending Shahid Sadoughi rheumatology and infectious diseases clinic in 2014. Patients who had positive findings in favor of sacroiliitis were evaluated by history, physical exam, laboratory tests, and imaging. The patients were divided into infectious, inflammatory non-infectious, and degenerative causes. The data were analyzed by IBM SPSS version 20 using the independent samples t-test, ANOVA, the chi-squared test, and the Fisher's exact test. RESULTS: We studied 136 patients. Among them 64 (47.1%) were male, and 72 (52.9%) were female. The mean age of the participants was 34.28 +/- 10.36 years. Among the patients, 12 (8.8%) had infectious causes, 120 (88.2%) had inflammatory non-infectious causes, and four (2.9%) had degenerative causes. CONCLUSION: Based on our results, inflammatory non-infectious causes are at the top of the list of sacroiliitis causes, but we should always consider infectious causes, including brucellosis. PMID- 27123218 TI - Measurement of Quality of Educational Hospital Services by the SERVQUAL Model: The Iranian Patients' Perspective. AB - INTRODUCTION: The main mission of hospitals in any health system is to deliver high quality healthcare for patients and meet their needs and expectations. The aim of the current study was to assess the quality of the service of educational hospitals affiliated with Kermanshah University of Medical Sciences in 2015, from the perspective of patients. METHODS: In this cross-sectional study, the perspectives of 400 patients were assessed about the quality of the services provided by educational hospitals in Kermanshah (western Iran) in 2015. The quality was assessed by the SERVQUAL questionnaire with five dimensions, i.e., tangibility, reliability, responsiveness, assurance, and empathy. In addition, the Wilcoxon test and the Kruskal-Wallis test were used to explore any association between the dependent variable and explanatory variables. The data were analyzed using Stata V.12 software. RESULTS: There were negative gaps in all five dimensions. The highest and lowest gaps in the mean score were found in the assurance (-0.88) and responsiveness (-0.56) dimensions. The patients ranked responsiveness as the most important dimension of the quality of healthcare. CONCLUSION: There were gaps between the patients' perceptions and their expectation about the five dimensions that were studied based on the SERVQUAL model. Also, it is recommended that improving the quality of healthcare is possible by various policies, such as good responsiveness, access to health workers, and delivering healthcare in less time. PMID- 27123219 TI - Comparison of lifestyles of young women with and without primary dysmenorrhea. AB - INTRODUCTION: Dysmenorrhea is one of the most common gynecologic disorders that affects women's quality of life and social activities. Lifestyle, eating behaviors, and general health are essential to the management of menstrual symptoms. This study was conducted to examine the relationship between lifestyle and primary dysmenorrhea in students at Sari University of Medical Sciences in 2015 in order to facilitate the performance of lifestyle-improving interventions among young women. METHODS: This study was conducted on 250 students with and without primary dysmenorrhea at Sari University of Medical Sciences in 2015. Data were collected using personal-social and lifestyle questionnaires (addressing nutrition, physical activity, stress, social relationships, improper health behaviors, and self-care). The data were analyzed by SPSS software, version 18, using the independent-samples t-test, the chi-squared test, and logistic regression analysis. RESULTS: Given the scores obtained on the lifestyle questionnaire, significant differences were observed between the groups with and without dysmenorrhea in terms of eating behavior (p=0.008), physical activity (p=0.011), stress (p=0.041), and social relationships (p=0.000). No differences were observed in terms of self-care (p=0.115) and smoking, drinking, and drug use (p=0.355). According to the logistic regression analysis, age (OR=1.208, p=0.014), physical activity (OR=1.008, p=0.040) and social relationship (OR=0.952, p=0.002) were different in the two groups, but there was no statistical differences in their eating behavior, self-care, and stress. CONCLUSION: To prevent and reduce the incidence of primary dysmenorrhea, knowledge and awareness should be raised in young women through proper lifestyle education and health promotion measures. PMID- 27123221 TI - Active listening: The key of successful communication in hospital managers. AB - INTRODUCTION: One of the important causes of medical errors and unintentional harm to patients is ineffective communication. The important part of this skill, in case it has been forgotten, is listening. The objective of this study was to determine whether managers in hospitals listen actively. METHODS: This study was conducted between May and June 2014 among three levels of managers at teaching hospitals in Kerman, Iran. Active Listening skill among hospital managers was measured by self-made Active Listening Skill Scale (ALSS), which consists of the key elements of active listening and has five subscales, i.e., Avoiding Interruption, Maintaining Interest, Postponing Evaluation, Organizing Information, and Showing Interest. The data were analyzed by IBM-SPSS software, version 20, and the Pearson product-moment correlation coefficient, the chi squared test, and multiple linear regressions. RESULTS: The mean score of active listening in hospital managers was 2.32 out of 3.The highest score (2.27) was obtained by the first-level managers, and the top managers got the lowest score (2.16). Hospital mangers were best in showing interest and worst in avoiding interruptions. The area of employment was a significant predictor of avoiding interruption and the managers' gender was a strong predictor of skill in maintaining interest (p < 0.05). The type of management and education can predict postponing evaluation, and the length of employment can predict showing interest (p < 0.05). CONCLUSION: There is a necessity for the development of strategies to create more awareness among the hospital managers concerning their active listening skills. PMID- 27123220 TI - Efficacy of Platelet-Rich Plasma versus Hyaluronic Acid for treatment of Knee Osteoarthritis: A systematic review and meta-analysis. AB - INTRODUCTION: Knee osteoarthritis is a very common chronic degenerative disease that could impose significant costs to the health system. Although osteoarthritis can affect all joints, knee osteoarthritis is the most common type among adolescents. Non-surgical treatments include corticosteroids injection, hyaluronic acid, and platelet-rich plasma. The aim of this study was to investigate the efficiency of platelet-rich plasma versus hyaluronic acid for the treatment of knee osteoarthritis. METHODS: Pubmed, Cochran library, Scopus and Ovid databases were investigated to identify related studies from 2000 through August 2015. To study the efficiency, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) outcome using the Standard Mean Difference (SMD) index was calculated using a random model and a confidence interval of 95%. In addition, sensitivity and cumulative analysis were conducted. The data were analyzed using RevMan 5.3.5 and Stata 12 software. RESULTS: Seven studies with 722 subjects (364 participants in PRP and 358 participants in the HA group) were analyzed. The WOMAC PRP compared to HA, SMD = -0.75 (95% CI: -1.33 to -0.18, I2 = 92.6%) in treatment of knee osteoarthritis was statistically significant and PRP was more effective. CONCLUSION: The results of this meta-analysis two years after PRP injection showed the efficacy of PRP versus HA. However, further studies are required to determine the longer-term effects. PMID- 27123222 TI - Association between Organizational Commitment and Personality Traits of Faculty Members of Ahvaz Jundishapur University of Medical Sciences. AB - INTRODUCTION: Individual characteristics are important factors influencing organizational commitment. Also, committed human resources can lead organizations to performance improvement as well as personal and organizational achievements. This research aimed to determine the association between organizational commitment and personality traits among faculty members of Ahvaz Jundishapur University of Medical Sciences. METHODS: the research population of this cross sectional study was the faculty members of Ahvaz Jundishapur University of Medical Sciences (Ahvaz, Iran). The sample size was determined to be 83. Data collection instruments were the Allen and Meyer questionnaire for organizational commitment and Neo for characteristics' features. The data were analyzed through Pearson's product-moment correlation and the independent samples t-test, ANOVA, and simple linear regression analysis (SLR) by SPSS. RESULTS: Continuance commitment showed a significant positive association with neuroticism, extroversion, agreeableness, and conscientiousness. Normative commitment showed a significant positive association with conscientiousness and a negative association with extroversion (p = 0.001). Openness had a positive association with affective commitment. Openness and agreeableness, among the five characteristics' features, had the most effect on organizational commitment, as indicated by simple linear regression analysis. CONCLUSION: Faculty members' characteristics showed a significant association with their organizational commitment. Determining appropriate characteristic criteria for faculty members may lead to employing committed personnel to accomplish the University's objectives and tasks. PMID- 27123223 TI - Relationship between Work Ability Index and Cognitive Failure among Nurses. AB - INTRODUCTION: Frequent nursing errors are considered as factors that affect the quality of healthcare of patients. Capable nurses who are compatible with work conditions are more focused on their tasks, and this reduces their errors and cognitive failures. Therefore, this study was conducted with the aim of investigating the relationship between work ability index (WAI) and cognitive failures (CFs) as well as some factors that affect them in nurses working in the ICU, CCU, and emergency wards. METHODS: This descriptive-analytical and cross sectional study was conducted with 750 nurses at educational hospitals affiliated with the Tehran University of Medical Sciences in 2015. A questionnaire of work ability index and cognitive failures was used to collect data. The data were analyzed using SPSS 20 and the Pearson and Spearman correlation coefficients, chi squared, ANOVA, and the Kruskal-Wallis tests. RESULTS: Using the Pearson correlation test, the results of this study showed that there is a significant, inverse relationship between WAI, personal prognosis of work ability, and mental resources with CFs along with all its subscales in nurses (p < 0.05). In addition, there was an inverse and significant relationship between the total score of CFs and the estimated work impairment due to diseases (p < 0.05). There was a significant positive correlation of CFs with age and experience, while WAI was inversely related to age, work experience, and body mass index (BMI) (p < 0.05). WAI and CFs were related significantly to working units (p < 0.05). CONCLUSION: Considering the results obtained in this study, WAI and the cognitive status of nurses were lower than the specified limit. It is suggested that the work ability of nurses be improved and that their CFs be reduced through various measures, including pre-employment examinations, proper management of work-shift conditions, and using engineering and administrative strategies to ensure the safety of hospitalized patients. PMID- 27123224 TI - Risk Assessment of Using Entonox for the Relief of Labor Pain: A Healthcare Failure Modes and Effects Analysis Approach. AB - INTRODUCTION: In order to prevent medical errors, it is important to know why they occur and to identify their causes. Healthcare failure modes and effects analysis (HFMEA) is a type of qualitative descriptive that is used to evaluate the risk. The aim of this study was to assess the risks of using Entonox for labor pain by HFMEA. METHODS: A mixed-methods design (qualitative action research and quantitative cross-sectional research) was used. The modes and effects of failures in the process of using Entonox were detected and analyzed during 2013 2014 at Hefdahe Shahrivar Hospital, Mashhad, Iran. Overall, 52 failure modes were identified, with 25 being recognized as high-risk modes. RESULTS: The results revealed that 48.5% of these errors fall into the care process type, 22.05% belong to the communicative type, 19.1% fall into the administrative type, and 10.2% are of the knowledge and skills type. Strategies were presented in the forms of acceptance (3.2%), control (90.3%), and elimination (6.4%). CONCLUSION: The following actions are suggested for improving the process of using Entonox: Close supervision by the midwife, precise recording of all the stages of the process in the woman's medical record, the necessity of the presence of the anesthesiologist at the woman's bedside during labor, confirming the indications for use of Entonox, and close monitoring to ensure the safety of the gas cylinder guards. PMID- 27123225 TI - Principle-based concept analysis: Caring in nursing education. AB - INTRODUCTION: The aim of this principle-based concept analysis was to analyze caring in nursing education and to explain the current state of the science based on epistemologic, pragmatic, linguistic, and logical philosophical principles. METHODS: A principle-based concept analysis method was used to analyze the nursing literature. The dataset included 46 English language studies, published from 2005 to 2014, and they were retrieved through PROQUEST, MEDLINE, CINAHL, ERIC, SCOPUS, and SID scientific databases. The key dimensions of the data were collected using a validated data-extraction sheet. The four principles of assessing pragmatic utility were used to analyze the data. The data were managed by using MAXQDA 10 software. RESULTS: The scientific literature that deals with caring in nursing education relies on implied meaning. Caring in nursing education refers to student-teacher interactions that are formed on the basis of human values and focused on the unique needs of the students (epistemological principle). The result of student-teacher interactions is the development of both the students and the teachers. Numerous applications of the concept of caring in nursing education are available in the literature (pragmatic principle). There is consistency in the meaning of the concept, as a central value of the faculty student interaction (linguistic principle). Compared with other related concepts, such as "caring pedagogy," "value-based education," and "teaching excellence," caring in nursing education does not have exact and clear conceptual boundaries (logic principle). CONCLUSION: Caring in nursing education was identified as an approach to teaching and learning, and it is formed based on teacher-student interactions and sustainable human values. A greater understanding of the conceptual basis of caring in nursing education will improve the caring behaviors of teachers, create teaching-learning environments, and help experts in curriculum development. PMID- 27123226 TI - Effect of non-ionizing electromagnetic field on the alteration of ovarian follicles in rats. AB - INTRODUCTION: In recent years, there has been an increase in the attention paid to safety effects, environmental and society's health, extremely low frequency electromagnetic fields (ELF-EMF), and radio frequency electromagnetic fields (RF EMF). The aim of this research was to determine the effect of EMF on the alteration of ovarian follicles. METHODS: In this experimental study at Tabriz Medical University in 2015, we did EMF exposures and assessed the alteration of rats' ovarian follicles. Thirty three-month old rats were selected randomly from laboratory animals, and, after their ages and weights were determined, they were divided randomly into three groups. The control group consisted of 10 rats without any treatment, and they were kept in normal conditions. The second group of rats was influenced by a magnetic field of 50 Hz for eight weeks (three weeks intrauterine and five weeks ectopic). The third group of rats was influenced by a magnetic field of 50 Hz for 13 weeks (three weeks intrauterine and ten weeks ectopic). Samples were fixed in 10% buffered formaldehyde and cleared with Xylol and embedded in paraffin. After sectioning and staining, samples were studied by optic microscopy. Finally, SPSS version 17, were used for data analysis. RESULTS: EMF radiation increased the harmful effects on the formation of ovarian follicles and oocytes implantation. Studies on the effects of electromagnetic fields on ovarian follicles have shown that the nuclei of the oocytes become smaller and change shape. There were significant, harmful changes in the groups affected by electromagnetic waves. Atresia of ovarian follicles was significantly significant in both study groups compared to the control group (p < 0.05). CONCLUSION: Exposure to electromagnetic fields during embryonic development can cause morphological changes in oocytes and affect the differentiation of oocytes and folliculogenesis, resulting in decreased ovarian reserve leading to infertility or reduced fertility. PMID- 27123227 TI - The effectiveness of group positive psychotherapy on depression and happiness in breast cancer patients: A randomized controlled trial. AB - BACKGROUND: Breast cancer is one of the most prevalent cancers in women in the world. It causes fear, despair, and takes a tremendous toll on psychological status. OBJECTIVE: To determine the effectiveness of group positive psychotherapy on the depression and happiness of breast cancer patients. METHODS: This randomized controlled trial was conducted with 42 breast cancer patients in The Oncology Center at Kermanshah, Iran in 2015. The Data were gathered before intervention and ten weeks afterwards. The data were collected using Beck's Depression Inventory (BDI-II) and Oxford's happiness Inventory (OHI). The data were analyzed by SPSS-16, Kolmogorov-Smirnov (K-S), chi-squared, and multivariate analysis of covariance (MANCOVA). RESULTS: The results showed a significant reduction in the depression of the group on positive psychotherapy compared with the control group. Also the positive psychotherapy group experienced a significant increase in the patients' happiness, while there was no significant increase in the control group. CONCLUSION: The results of this research showed the effectiveness of positive psychotherapy on the reduction of mental pressure and the improvement of the mental status of breast cancer patients. This economical therapy can be used to increase patients' psychological health. CLINICAL TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials (IRST) with the identification number IRCT2013101410063N4. FUNDING: The authors received financial support for the research from Kermanshah University of Medical Sciences. PMID- 27123228 TI - Detection of Epstein-Barr virus in synovial fluid of rheumatoid arthritis patients. AB - INTRODUCTION: Rheumatoid arthritis (RA) is one of the most common chronic inflammatory disorders. Genes and environmental factors contribute to RA. Epstein Barr Virus (EBV) has been considered as one the RA pathogeneses. The aim of this study was to detect of the EBV genome in patients with RA. METHODS: In this cross sectional study, 50 samples of synovial fluid were obtained from patients with RA from 2010-2012. Using a standard of the EBV genome and EBNA-1-specific primers, the method of PCR was set up. Then, all of the samples of synovial fluids separately were subjected to DNA extraction and Polymerase Chain Reaction (PCR) amplification. Data were analyzed using SPSS version 18.0. The statistical analysis was performed by the t-test. RESULTS: The demographic and laboratory characteristic assay revealed that the mean age of patients was 49, and the patients were 60% males and 40% females. In addition, in all cases, the mean rheumatoid factor (RF) levels of the patients were below the normal level. The results of this study showed that the PCR was able to detect EBV DNA in > 60% of the cases. CONCLUSION: The results of this study indicated that EBV was frequently detected in the synovial fluid of RA patients. Thus, EBV may be a strong candidate that can act at several levels of the pathophysiology of RA. However, these findings also indicated that EBV may play a role in the pathogenesis of RA. However, the possible relationship between RA and EBV must be determined by further research. PMID- 27123229 TI - Desmopressin versus Oxybutynin for Nocturnal Enuresis in Children in Bandar Abbas: A Randomized Clinical Trial. AB - BACKGROUND: Nocturnal enuresis is among the most common disorders in children. Several pharmacological and non-pharmacological treatments are available for nocturnal enuresis. Studies for reaching the best pharmacological treatment for this disorder are continuing. OBJECTIVE: To compare the effectiveness and safety of Desmopressin and oxybutynin for treatment of nocturnal enuresis in children from Bandar Abbas in 2014. METHODS: This randomized controlled trial was conducted in 2014 and participants included 66 children with nocturnal enuresis who were more than 5 years old. Patients were randomly assigned into two groups. The first group received 120 microgram Desmopressin daily for 2 months, then 60 microgram daily for 2 months, then 60 microgram every 2 days. The second group received 5 mg oxybutynin twice a day for 6 months. The patients were followed after 1, 3, and 6 months to track treatment response. The study outcomes were frequency of nocturnal enuresis, urinary incontinency, urgency, and frequency. Data were analyzed using SPSS software. RESULTS: There were no significant differences between the two groups with respects to sex, age, place of residence, and parents' education (p<0.05). Nocturnal enuresis, incontinency, urgency, and frequency of nocturnal enuresis was significantly lower with Desmopressin treatment in comparison to the oxybutynin treated group after 1 and 3 months (p<0.05). In addition, constipation and xerostomia were more frequent among the oxybutynin group after 1, 3, and 6 months (p<0.01). Blurred vision was also more frequent among oxybutynin group after 3 months (p<0.01). After 6 months the frequency of nocturnal enuresis and its frequency was higher in oxybutynin group in comparison to the Desmopressin group (p<0.05). CONCLUSION: Desmopressin is more effective and has lower rate of side effects in comparison to oxybutynin for treatment of nocturnal enuresis. We recommend using Desmopressin for treatment of nocturnal enuresis in children. More studies are needed to achieve the best pharmacological treatment option for treatment of nocturnal enuresis. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov with a ClinicalTrials.gov Identifier: NCT02538302. FUNDING: The funder of this research is Hormozgan University of Medical Sciences. PMID- 27123230 TI - Fatigue and Depression in Iranian Amyotrophic Lateral Sclerosis Patients in Tehran in 2012. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a progressive and rapid course. Fatigue and depression are common among ALS patients. The aim of this study was to determine the relationship between depression and fatigue in Iranian ALS patients. METHODS: In this 2012 cross-sectional study, 40 ALS patients, including 22 females and 18 males, were selected through consecutive relapsing-remitting, and 40 age- and gender-matched health controls (HCs) were recruited from Loghman Hakim Hospital in Tehran, Iran. The Persian version of the Fatigue Severity Scale (FSS-Per) questionnaire and depression substance of Hospital Anxiety and Depression Scale (HADS) were used to assess fatigue and depression. Data were analyzed using the Kolmogorov-Sminov Test, Levene's test, Independent Samples t-test, and Pearson product-moment correlation coefficient. RESULTS: We identified a significant and positive relationship between fatigue and depression in patients with ALS (p=0.000). Furthermore, the scores of fatigue and depression in ALS patients were higher than in non-ALS patients. CONCLUSION: The results indicated that there was a relationship between fatigue and depression in ALS patients and that early intervention services can improve these symptoms. Further studies are suggested to investigate the direction of such relationship. PMID- 27123231 TI - Knowledge of healthy lifestyle in Iran: a systematic review. AB - INTRODUCTION: Lifestyle is a set of goals, plans, values, attitudes, behaviors, and beliefs manifested in the personal and family life of the individual and in her or his social interactions. It is an interdisciplinary concept that involves a health-oriented view of the physical, psychological, social, and spiritual domains of life. Despite their great importance, there is not much knowledge in Iran about healthy lifestyles. The present study is an attempt to address the knowledge of healthy lifestyle in Iran through a review of the literature on the subject. METHODS: The present systematic review searched Elsevier, SID, Pub Med, Magiran, IranMedex, and Google Scholar databases for relevant articles published between 2000 and 2014. We used various keywords for the searches, including knowledge, lifestyle, health, and Iran. As a result, 62 articles were included in the study. RESULTS: There has been a dramatic increase in the publication of articles on lifestyle in Iran over the past 10 years. The results obtained showed that 64% of the articles addressed physical health, 14% addressed psychological health, 10% addressed social health, and 12% addressed spiritual health. Most lifestyle studies conducted in Iran have focused on physical health, and a few have examined the psychological, social, and spiritual aspects of lifestyle. None of the studies has examined the knowledge map of healthy lifestyles in Iran. CONCLUSION: Given the changes in the causes of mortality from infectious and chronic diseases that impose greater medication and treatment costs on the society, and since diseases caused by unhealthy lifestyles have become the leading cause of death, it is essential for health researchers to focus on the root cause of these diseases, i.e., lifestyle and human behaviors. PMID- 27123232 TI - Erratum to: 'Clinical presentation, auscultation recordings, ultrasonographic findings and treatment response of 12 adult cattle with chronic suppurative pneumonia: case study'. AB - [This corrects the article DOI: 10.1186/2046-0481-66-5.]. PMID- 26949515 TI - The unfolded protein response and its potential role in Huntington's disease elucidated by a systems biology approach. AB - Huntington 's disease (HD) is a progressive, neurodegenerative disease with a fatal outcome. Although the disease-causing gene (huntingtin) has been known for over 20 years, the exact mechanisms leading to neuronal cell death are still controversial. One potential mechanism contributing to the massive loss of neurons observed in the brain of HD patients could be the unfolded protein response (UPR) activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of un- or misfolded proteins, the UPR upregulates transcription of chaperones, temporarily attenuates new translation, and activates protein degradation via the proteasome. However, persistent ER stress and an activated UPR can also cause apoptotic cell death. Although different studies have indicated a role for the UPR in HD, the evidence remains inconclusive. Here, we present extensive bioinformatic analyses that revealed UPR activation in different experimental HD models based on transcriptomic data. Accordingly, we have identified 53 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1, SLC12A5, ATG5, AKT1, CASP7 and SYVN1 that provide a potential link between UPR and HD. To further elucidate the potential role of UPR as a disease-relevant process, we examined its connection to apoptosis based on molecular interaction data, and identified a set of 40 genes including ADD1, HSP90B1, IKBKB, IKBKG, RPS3A and LMNB1, which seem to be at the crossroads between these two important cellular processes. Remarkably, we also found strong correlation of UPR gene expression with the length of the polyglutamine tract of Huntingtin, which is a critical determinant of age of disease onset in human HD patients pointing to the UPR as a promising target for therapeutic intervention. The study is complemented by a newly developed web portal called UPR-HD (http://uprhd.sysbiolab.eu) that enables visualization and interactive analysis of UPR-associated gene expression across various HD models. PMID- 26998233 TI - Profiling and tandem mass spectrometry analysis of aminoacylated phospholipids in Bacillus subtilis . AB - Cationic modulation of the dominantly negative electrostatic structure of phospholipids plays an important role in bacterial response to changes in the environment. In addition to zwitterionic phosphatidylethanolamine, Gram-positive bacteria are also abundant in positively charged lysyl-phosphatidylglycerol. Increased amounts of both types of lipids render Gram-positive bacterial cells more resistant to cationic antibiotic peptides such as defensins. Lysyl and alanyl-phosphatidylglycerol as well as alanyl-cardiolipin have also been studied by mass spectroscopy. Phospholipids modified by other amino acids have been discovered by chemical analysis of the lipid lysate but have yet to be studied by mass spectroscopy. We exploited the high sensitivity of modern mass spectroscopy in searching for substructures in complex mixtures to establish a sensitive and thorough screen for aminoacylated phospholipids. The search for deprotonated aminoacyl anions in lipid extracted from Bacillus subtilis strain 168 yielded strong evidence as well as relative abundance of aminoacyl-phosphatidylglycerols, which serves as a crude measure of the specificity of aminoacyl phosphatidylglycerol synthase MprF. No aminoacyl-cardiolipin was found. More importantly, the second most abundant species in this category is D-alanyl phosphatidylglycerol, suggesting a possible role in the D-alanylation pathway of wall- and lipo-teichoic acids. PMID- 26998236 TI - Sequence and intramolecular distance scoring analyses of microbial rhodopsins. AB - Recent accumulation of sequence and structural data, in conjunction with systematical classification into a set of families, has significantly advanced our understanding of diverse and specific protein functions. Analysis and interpretation of protein family data requires comprehensive sequence and structural alignments. Here, we present a simple scheme for analyzing a set of experimental structures of a given protein or family of proteins, using microbial rhodopsins as an example. For a data set comprised of around a dozen highly similar structures to each other (overall pairwise root-mean-squared deviation < 2.3 A), intramolecular distance scoring analysis yielded valuable information with respect to structural properties, such as differences in the relative variability of transmembrane helices. Furthermore, a comparison with recent results for G protein-coupled receptors demonstrates how the results of the present analysis can be interpreted and effectively utilized for structural characterization of diverse protein families in general. PMID- 27081477 TI - Post-chikungunya chronic inflammatory rheumatism: results from a retrospective follow-up study of 283 adult and child cases in La Virginia, Risaralda, Colombia. AB - OBJECTIVE: There are limited studies in Latin America regarding the chronic consequences of the Chikungunya virus (CHIK), such as post-CHIK chronic inflammatory rheumatism (pCHIK-CIR). We assessed the largest cohort so far of pCHIK-CIR in Latin America, at the municipality of La Virginia, Risaralda, a new endemic area of CHIK in Colombia. METHODS: We conducted a cohort retrospective study in Colombia of 283 patients diagnosed with CHIK that persisted with pCHIK CIR after a minimum of 6 weeks and up to a maximum of 26.1 weeks. pCHIK cases were identified according to validated criteria via telephone. RESULTS: Of the total CHIK-infected subjects, 152 (53.7%) reported persistent rheumatological symptoms (pCHIK-CIR). All of these patients reported joint pains (chronic polyarthralgia, pCHIK-CPA), 49.5% morning stiffness, 40.6% joint edema, and 16.6% joint redness. Of all patients, 19.4% required and attended for care prior to the current study assessment (1.4% consulting rheumatologists). Significant differences in the frequency were observed according to age groups and gender. Patients aged >40 years old required more medical attention (39.5%) than those <=40 years-old (12.1%) (RR=4.748, 95%CI 2.550-8.840). CONCLUSIONS: According to our results, at least half of the patients with CHIK developed chronic rheumatologic sequelae, and from those with pCHIK-CPA, nearly half presented clinical symptoms consistent with inflammatory forms of the disease. These results support previous estimates obtained from pooled data of studies in La Reunion (France) and India and are consistent with the results published previously from other Colombian cohorts in Venadillo (Tolima) and Since (Sucre). PMID- 27123237 TI - Intra-operative adherence to lung-protective ventilation: a prospective observational study. AB - BACKGROUND: Lung-protective ventilation in patients with acute respiratory distress syndrome improves mortality. Adopting this strategy in the perioperative period has been shown to reduce lung inflammation and postoperative pulmonary and non-pulmonary sepsis complications in patients undergoing major abdominal surgery. We conducted a prospective observational study into the intra-operative ventilation practice across the West Midlands to assess the use of lung protective ventilation. METHODS: Data was collected from all adult ventilated patients undergoing surgery across 14 hospital trusts in the West Midlands over a 2-day period in November 2013. Data collected included surgical specialty, patient's biometric data, duration of procedure, grade of anesthetist, and ventilatory parameters. Lung-protective ventilation was defined as the delivery of a tidal volume between 6 and 8 ml/kg/predicted body weight, a peak pressure of less than 30 cmH2O, and the use of positive end expiratory pressure of 6-8 cmH2O. Categorical data are presented descriptively, while non-parametric data are displayed as medians with statistical tests from Mann-Whitney U tests or Kruskal Wallis tests for independent samples while paired samples are represented by Wilcoxon signed rank tests. RESULTS: Four hundred six patients with a median age of 56 years (16-91) were included. The majority of operations (78 %) were elective procedures with the principal anesthetist being a consultant. The commonest surgical specialties were general (29 %), trauma and orthopedic (19 %), and ENT (17 %). Volume-controlled ventilation was the preferred ventilation strategy in 70 % of cases. No patients were ventilated using lung-protective ventilation. Overall peak airway pressure (pPeak) was low (median 20 cmH2O (inter quartile range [IQR] 10-43 cmH2O)) with median delivered tidal volumes of 8.4 ml/kg/predicted body weight (PBW) (IQR 3.5-14.5 ml/kg/PBW). The median positive end expiratory pressure (PEEP) was only 4 cmH2O (0-5 cmH2O) with PEEP not used in 152 cases. CONCLUSIONS: Perioperative lung protection ventilation can improve patient outcomes from major surgery. This large prospective study demonstrates that within the West Midlands lung-protective ventilation during the perioperative period is uncommon, especially in relation to the use of PEEP, and that perhaps further trials are required to promote wider adoption of practice. PMID- 27123238 TI - Atrial fibrillation and flutter following coronary artery bypass graft surgery: A retrospective study and review. AB - INTRODUCTION AND OBJECTIVES: Atrial fibrillation is a common arrhythmia following coronary artery bypass graft surgery. Its incidence can range from 10 to 60% of patients undergoing coronary artery bypass graft. This rhythm can result in shorter or longer intervals between beats. METHODS: Medical records of 143 patients from the Queen's Medical Center, Kuakini Medical Center, Saint Francis Medical Center, and Straub Hospital and Clinic, all of which are located in Honolulu, Hawaii were reviewed. An additional 39 records of patients who did not develop these complications were also reviewed as a control group. Patients were selected according to the ICD codes for atrial fibrillation/flutter and coronary artery bypass graft. Both anomalies can lead to increased health care costs, morbidity, and mortality. In this study, possible predisposing factors to these complications were investigated. The time of onset, weight gain, elapsed time, fluid status (in/out), hematocrit, and drug regimens were compared between the two groups. RESULTS: The differences in weight gain, fluid status, and hematocrit between the groups were not significant. There were a total of 17 different drugs prescribed to the group as a whole but not every patient received the same regimen. CONCLUSIONS: Atrial fibrillation and flutter were found to be more common in males, particularly between the ages of 60 and 69 years. There were no other significant findings. PMID- 27123239 TI - Dietary supplementation of Rosmarinus officinalis L. leaves in sheep affects the abundance of rumen methanogens and other microbial populations. AB - BACKGROUND: Rumen microbiome has a great influence on ruminant health and productivity. Different plant extracts have been tested for their ability to modulate the rumen microbiome to improve feed digestion and fermentation. Among the evaluated plant extracts, essential oils, tannins, and saponins appeared to have positive effects on rumen protein metabolism, volatile fatty acids production, and methane and ammonia production. METHODS: The objective of this study was to evaluate the effect of rosemary (Rosmarinus officinalis L.) leaves and essential oils on rumen microbial populations. Four ruminally cannulated sheep were used in a 4*4 Latin square design fed (21 d/period): 1) a control diet composed of alfalfa hay and concentrate pellet (CTR), 2) CTR supplemented with 7 g/d/sheep of rosemary essential oil adsorbed on an inert support (EO), 3) CTR with 10 g/d/sheep of dried and ground rosemary leaves (RL), and 4) CTR with 10 g/d of dried and ground rosemary leaves pelleted into concentrate (RL pellet). Abundance of total bacteria, archaea, protozoa, and some select bacterial species or groups was quantified using qPCR, while the community of bacteria and archaea was profiled using denaturing gradient gel electrophoresis. RESULTS: No difference in abundance was noted for total bacteria, protozoa, or Ruminococcus flavefaciens between the control and the treatments, but the rosemary leaves, either in loose form or in pellet, decreased the abundance of archaea and the genus Prevotella (P < 0.001). The rosemary leaves in loose form also decreased (P < 0.001) the abundance of Ruminococcus albus and Clostridium aminophilum, while the EO increased (P < 0.001) the abundance of Fibrobacter succinogenes. The community of bacteria and archaea was not affected by any of the supplements. CONCLUSIONS: Being able to affect the abundance of several groups of rumen microbes that are known to be involved in degradation of protein and fiber and production of methane and ammonia, rosemary leaves may be used to modulate rumen microbiome and its function. PMID- 27123240 TI - Nicotinic acetylcholine receptors and cancer. AB - Nicotine, the primary addictive constituent of cigarettes, is believed to contribute to cancer promotion and progression through the activation of nicotinic acetylcholine receptors (nAChRs), which are membrane ligand-gated cation channels. nAChRs activation can be triggered by the neurotransmitter Ach, or certain other biological compounds, such as nicotine. In recent years, genome wide association studies have indicated that allelic variation in the alpha5 alpha3-beta4 nAChR cluster on chromosome 15q24-15q25.1 is associated with lung cancer risk. The role of nAChRs in other types of cancer has also been reported. The present review highlights the role of nAChRs in types of human cancer. PMID- 27123241 TI - Role of oxidative stress in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of disability in individuals aged >65 years worldwide. AD is characterized by the abnormal deposition of amyloid beta (Abeta) peptide, and intracellular accumulation of neurofibrillary tangles of hyperphosphorylated tau protein and dementia. The neurotoxic oligomer Abeta peptide, which is the neuropathological diagnostic criterion of the disease, together with tau protein, are mediators of the neurodegeneration that is among the main causative factors. However, these phenomena are mainly initiated and enhanced by oxidative stress, a process referring to an imbalance between antioxidants and oxidants in favour of oxidants. This imbalance can occur as a result of increased free radicals or a decrease in antioxidant defense, free radicals being a species that contains one or more unpaired electrons in its outer shell. The major source of potent free radicals is the reduction of molecular oxygen in water, that initially yields the superoxide radical, which produces hydrogen peroxide by the addition of an electron. The reduction of hydrogen peroxide produces highly reactive hydroxyl radicals, termed reactive oxygen species (ROS) that can react with lipids, proteins, nucleic acids, and other molecules and may also alter their structures and functions. Thus, tissues and organs, particularly the brain, a vulnerable organ, are affected by ROS due to its composition. The brain is largely composed of easily oxidizable lipids while featuring a high oxygen consumption rate. The current review examined the role of oxidative stress in AD. PMID- 27123242 TI - MicroRNAs: Novel regulatory molecules in acute lung injury/acute respiratory distress syndrome. AB - Acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS) are common and complex inflammatory lung diseases. MicroRNAs (miRNAs), a type of non-coding RNA molecule that regulate gene expression at the post transcriptional level, have emerged as a novel class of gene regulators, which have critical roles in a wide range of human disorders and diseases, including ALI. Certain types of miRNAs are abnormally expressed in response to lung injury. miRNAs can regulate inflammation pathways by targeting specific molecules and modulate immune response in the process of lung injury and repair. The regulation of miRNA can relieve injury response and promote the recovery of ALI/ARDS. Therefore, miRNAs may serve as novel therapeutic targets in ALI/ARDS. PMID- 27123243 TI - Cell-penetrating peptides: Possible transduction mechanisms and therapeutic applications. AB - Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse peptides with 5-30 amino acids. CPPs are divided into cationic, amphipathic and hydrophobic CPPs. They are able to carry small molecules, plasmid DNA, small interfering RNA, proteins, viruses, imaging agents and other various nanoparticles across the cellular membrane, resulting in internalization of the intact cargos. However, the mechanisms of CPP internalization remain to be elucidated. Recently, CPPs have received considerable attention due to their high transduction efficiency and low cytotoxicity. These peptides have a significant potential for diagnostic and therapeutic applications, such as delivery of fluorescent or radioactive compounds for imaging, delivery of peptides and proteins for therapeutic application, and delivery of molecules into induced pluripotent stem cells for directing differentiation. The present study reviews the classifications and transduction mechanisms of CPPs, as well as their potential applications. PMID- 27123244 TI - Role of exercise in the treatment of alcohol use disorders. AB - Excessive alcohol use can cause harmful effects on the human body, which are associated with serious health problems, and it can also lead to the development of alcohol use disorders (AUDs). There is certain evidence that physical exercise positively affects excessive alcohol use and the associated problems by leading to reduced alcohol intake. A literature search was conducted using the databases PubMed, Medline and Web of Science. The search terms used as keywords were: Addiction, abuse, alcohol use disorders, exercise training, beta-endorphin, opioids, brain, ethanol and alcohol. The current study presents the studies that reported on the use of exercise in the treatment of AUDs between 1970 and 2015. The potential psychological and physiological mechanisms that contribute to the action of exercise were also reviewed, highlighting the role of beta-endorphin and the hypothalamic-pituitary-adrenal axis in AUDs and the possible association among physical activity, the endogenous opioid system and the desire for alcohol. Only 11 studies were identified that refer to the effect of exercise on alcohol consumption and/or the associated outcomes. Six of those studies concluded that exercise may have a positive impact towards alcohol consumption, abstinence rates or the urge to drink. One of those studies also indicated that a bout of exercise affects the endogenous opioids, which may be associated with the urge to drink. Another 3 studies indicated that responses to acute exercise in individuals with AUDs are different compared to those in healthy ones. Generally, despite limited research data and often contradictory results, there is certain early promising evidence for the role of exercise as an adjunctive tool in the treatment of AUDs. Physiological and biochemical parameters that would confirm that exercise is safe for individuals with AUDs should be examined in future studies. PMID- 27123245 TI - piR-651 and its function in 95-D lung cancer cells. AB - PIWI-associated RNAs (piRNAs or piRs), a new-found class of small non-coding RNAs, which are mainly expressed in germline cells and partly in somatic lines, have a vital role in carcinogenesis by maintaining genomic integrity and regulation of epigenetics. The previous studies have confirmed that the expression of piR-651 is upregulated in several cancer tissue and cell lines, including lung cancer. However, the mechanism of carcinogenesis and piR-651 remains to be elucidated. Therefore, the present study assessed the 95-D high metastasis human lung cancer cell line to detect the effect of piR-651 on carcinogenesis. Firstly, piR-651 promoted the high metastasis characteristic of the 95-D cell lines by Transwell and wound-healing assays. The influence of piR 651 on tumor cell proliferation and apoptosis was detected by the MTT assay and flow cytometry. In conclusion, piR-651 may be an oncogene in lung cancer formation and development. Therefore, piR-651 regulated carcinogenesis by influencing cell proliferation, apoptosis, migration and invasion, and may be a potential tumor marker and therapeutic target. PMID- 27123246 TI - A randomized controlled trial to compare the effects of liquid versus powdered recombinant human growth hormone in treating patients with severe burns. AB - Recombinant human growth hormone (rhGH) promotes protein utilization and synthesis, and is widely used as a therapy to treat severe burns. The present randomized controlled trial evaluated the effects of different forms of rhGH on patients with severe burns. A total of 29 adult severe burns patients were enrolled between February 2009 and November 2011, and randomly assigned to either treatment group (T, liquid rhGH) or control group (C, powder rhGH). From days 5 to 7 following the infliction of burns, both patient groups received rhGH at 0.067 mg/kg/d, once for 10 days. Median serum pre-albumin levels increased in both groups following treatment, the elevation from baseline was significantly higher in the T group on day 10 compared to the C group (88 mg/l vs. 65 mg/l, P=0.046). C-reactive protein, fasting plasma glucose and body weight decreased in both groups. Body weight was significantly lower in the T compared to the C group at baseline, Day 5 and Day 10 (P=0.046, P=0.018 and P=0.006, respectively), however the decrease from baseline levels were not significantly different. Wound healing time was similar between groups (P=0.270). In conclusion the early use of liquid rather than powder rhGH may be more beneficial for treating adult patients with severe burns. PMID- 27123247 TI - Association between the HLA-DQB1 polymorphisms and the susceptibility of chronic hepatitis B: A comprehensive meta-analysis. AB - : Single-nucleotide polymorphisms in the human leukocyte antigen (HLA)-DQB1 gene are associated with chronic inflammatory and immunological diseases. Host genetic factors have a key role in the development of chronic hepatitis B (CHB). The aim of the present study was to investigate the association between the HLA-DQB1 polymorphisms and the susceptibility to CHB. PubMed, Embase, CNKI and Wanfang databases were searched for the studies that reported the association of the HLA DQB1 polymorphisms with CHB between January 1, 1966 and July 30, 2015. HLA-DQB1 polymorphism-specific odds ratio (OR) and 95% confidence intervals (95% CI) were pooled and calculated in the fixed effects model using the Mantel-Haenszel method. Q-test and I2 test were performed to examine the heterogeneity. Begg's funnel test and Egger's test were conducted to assess publication bias. All the statistical tests were two-tailed. Subsequent to searching the databases and screening according to the inclusion criteria, 7 case-control studies were available in the present meta-analysis, including 815 CHB patients and 731 control subjects for the HLA-DQB1 polymorphisms. In conclusion, the statistically significant pooled OR of the HLA-DQB1 polymorphisms were obtained for the HLA DQB1 loci (*0201, case vs. CONTROL: I2=36.5%; P-value of heterogeneity=0.15; OR, 1.29; 95% CI, 1.02-1.64; P=0.0301; *0301, case vs. CONTROL: I2=0%; P-value of heterogeneity=0.899; OR, 1.37; 95% CI, 1.12-1.69; P=0.002; *0502, case vs. CONTROL: I2=24.9%; P-value of heterogeneity=0.239; OR, 1.50; 95% CI, 1.02-2.20; P=0.04), which were associated with an increased risk of CHB. Similar significant results were observed and acquired in the following HLA-DQB1 loci (*0303, case vs. CONTROL: I2=0%; P-value of heterogeneity=0.986; OR, 0.77; 95% CI, 0.62-0.95; P=0.017; *0604, case vs. CONTROL: I2=0%; P-value of heterogeneity=0.594; OR, 0.38; 95% CI, 0.20-0.74; P=0.003), which were associated with a decreased risk of CHB. No significant association was observed for the other HLA-DQB1 family loci. The present meta-analysis demonstrated that the HLA-DQB1 loci (*0201, *0301 and *0502) polymorphisms were significantly associated with an increased risk of CHB. However, HLA-DQB1 loci polymorphisms (*0303 and *0604) were associated with a decreased risk of CHB. These results support the hypothesis that polymorphisms of the HLA-DQB1 allele families may affect the susceptibility or resistance to CHB. PMID- 27123248 TI - Correlation between lung neoplasm and serum level of osteopontin: A meta analysis. AB - The aim of this meta-analysis was to evaluate the clinical significance of serum osteopontin (OPN) levels in lung neoplasm in patients to establish a novel diagnostic score model. Articles were identified by searching the PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure, and Wang Fang databases. Studies identified were pooled, and the standardized mean difference (SMD) and its corresponding 95% confidence interval (CI) were calculated. Subgroup analyses and publication bias detection were also conducted. Version 12.0 STATA software was used for statistical analysis. A final analysis of 1,327 subjects together (740 patients with lung neoplasms and 587 controls) was performed from 10 clinical case-control studies. The meta-analysis results showed a positive association between serum OPN levels and lung neoplasm (SMD=5.59, 95% CI: 1.85-3.32, P<0.001). The subgroup analysis by ethnicity detected that high levels of serum OPN may be the main risk factor for lung neoplasms in Asians (SMD=1.76, 95% CI: 1.24-2.29, P<0.001), but not in Caucasians (P=0.072). In conclusion, the present meta-analysis indicated that serum OPN levels were generally elevated in lung neoplasm patients, and thus, serum levels of OPN may be useful in diagnosing lung neoplasm in certain population groups. PMID- 27123249 TI - Differential proteomic analysis of respiratory failure in peripheral blood mononuclear cells using iTRAQ technology. AB - Respiratory failure (RF) is a state in which the respiratory system fails by its gas exchange functions. Failure of the lung, which is caused by all types of lung diseases, leads to hypoxaemia with type I respiratory failure. Failure of the pump leads to hypercapnia or type II respiratory failure. Using isobaric tags for relative and absolute quantification (iTRAQ) technology to identify and quantify the total proteins in peripheral blood mononuclear cells (PBMCs) of RF patients and identify the differentially expressed proteome. The present study analyzed the total proteins in the PBMCs of RF patients and healthy controls using the eight-plex iTRAQ added with strong cation-exchange chromatography and liquid chromatography coupled with tandem mass spectrometry. The differentially expressed proteins were identified by MASCOT. A total of 4,795 differentially expressed proteins were identified, and 403 proteins were upregulated and 421 were downregulated. Among them, 4 proteins were significantly differentially expressed, which were upregulated KIAA1520 protein and gamma fibrinogen type B (AA at 202) and downregulated chain A, crystal structure of recombinant human platelet factor 4 and myosin regulatory light polypeptide 9. iTRAQ technology is suitable for identifying and quantifying the proteome in the PBMCs of RF patients. The differentially expressed proteins of RF patients have been identified in the present study, and further research of the molecular mechanism of the differentially expressed proteins is required to clarify the pathogenesis and identify novel biomarkers of RF. PMID- 27123250 TI - Effect of Akti-2 on sperm motility, capacitation and acrosome reaction in a mouse model. AB - The aim of the present study was to investigate the effect of the Akt inhibitor, Akti-2, on the sperm motility and acrosome reaction in mice. Mature sperms from the adult mice, aged 8 weeks, were co-incubated with Akti-2 for ~30 min at 37 degrees C in 5% CO2, and the sperm viability was assessed by eosin-nigrosin staining. The sperm total and progressive motility were analyzed by computer aided sperm analysis. In addition, the acrosome reaction of sperms was detected by the acid phosphatase assay, Coomassie Brilliant Blue staining and fluorescein isothiocyanate conjugated pisum sativum lectin staining, respectively. Compared with the control (dimethyl sulfoxide), Akti-2 had no effect on sperm viability, but it suppressed the total and progressive motility significantly. Furthermore, the capacitation-associated protein tyrosine phosphorylation and the acrosome reaction induced by calcium ionophore A23187 could be suppressed by Akti-2. These experiments confirmed that Akti-2 significantly impaired the sperm functions, including motility, capacitation and acrosome reaction, and provide the proof for its potential in male reproductive toxicity. PMID- 27123251 TI - Effect of the Fructus Ligustri Lucidi extract and its monomers quercetin and oleanolic acid on the adhesion and migration of melanocytes and intracellular actin. AB - The present study aimed to investigate the effects of the Fructus Ligustri Lucidi (FLL) extract and its monomers quercetin and oleanolic acid on the adhesion and migration of human epidermal melanocytes (MCs) and intracellular actin. The human epidermal MCs were cultured and identified. The cells were treated with different concentrations of FLL extract, quercetin and oleanolic acid. The adhesion and migration abilities of the cells were determined by the fibronectin-coated culture experiment and Transwell assay, respectively. The structure and distribution of intracellular actin were observed by confocal laser microscopy, with semi-quantitative analysis. Results showed that compared with the control group, 0.0375-0.3 mg/ml of the FLL extract and 40 uM quercetin significantly improved the adhesion rate of MCs (P<0.05). The numbers of MCs permeating the microporous membrane in the 0.15 mg/ml FLL extract and 12 uM oleanolic acid groups were 43.7 and 30.3, respectively, significantly higher compared to the control group (P<0.01). In the control group, the intracellular actin was less, and the stress fiber structure was not clear. In the 0.15 mg/ml FLL extract, 12 uM oleanolic acid and 40 uM quercetin groups, there were numerous bunched stress fibers, indicating the aggregation of filamentous fibrous actin. The mean optical densities of actin expression in the 0.15 mg/ml FLL extract, 12 uM oleanolic acid and 40 uM quercetin groups were significantly higher compared to the control group (P<0.05). The FLL extract has a significant stimulatory effect on the adhesion and migration of human epidermal MCs. The mechanism may be associated with the promotion of intracellular actin cytoskeleton aggregation. PMID- 27123252 TI - Interaction between muscle and bone, and improving the effects of electrical muscle stimulation on amyotrophy and bone loss in a denervation rat model via sciatic neurectomy. AB - The side-to-side difference in bone mineral content and soft tissue composition of extremities and their associations have been observed in patients with stroke and the results are inconsistent. The aim of the present study was to investigate the interaction between bone mineral content (BMC), lean mass (LM) and fat mass (FM) in the paretic extremities in patients following stroke and to determine the effectiveness of electrical muscle stimulation (EMS) following sciatic neurectomy (SN) in rats. BMC, LM and FM were measured by dual-energy X-ray absorptiometry in 61 hemiplegic patients following stroke. In the rat model study, groups of 10 Sprague-Dawley rats were divided into EMS and non-EMS subgroups. Myostatin expression and tetracycline interlabel width were measured. There were significant decreases in BMC, LM and FM in paretic limbs compared to non-paretic limbs. Compared to non-EMS, downregulated myostatin mRNA, and upregulated mechano growth factor (MGF) and insulin-like growth factor 1 (IGF-1) mRNA expression levels were observed in the EMS subgroup (P<0.05). In conclusion, muscle may have an important role in maintaining BMC. EMS-induced muscle contraction effectively downregulated myostatin mRNA, upregulated MGF and IGF-1 mRNA expression in muscle fiber, and mitigated amyotrophy and cortical bone loss from SN. PMID- 27123253 TI - Adjunctive therapy of Mycobacterium vaccae vaccine in the treatment of multidrug resistant tuberculosis: A systematic review and meta-analysis. AB - A number of studies have suggested that the Mycobacterium vaccae (MV) vaccine as an adjunctive therapy has a positive effect in the treatment of multidrug resistant tuberculosis (MDR-TB). However, the result is inconclusive. The aim of the present study was to systematically evaluate the effect and safety of MV as an adjunctive therapy in the treatment of MDR-TB. A computerized search of PubMed, Embase, Cochrane Central Register of Controlled Trials, CBM, CNKI and VIP until October 2014 was conducted to collect the relevant studies. The main outcome measures were the sputum smear positive-turned-negative rate, the absorption rate of TB foci and the closure situation of the TB cavity. Two investigators identified the eligible studies and extracted data independently. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and pooled using the fixed effects model. A total of 25 studies involving 2,281 patients with MDR-TB were included. The pooled OR was 3.84 (95% CI, 3.84-4.73) for the sputum smear positive-turned-negative, 4.08 (95% CI, 3.08-5.45) for the absorption rate of TB foci, and 3.42 (95% CI, 2.68-4.37) for the closure situation of TB cavity. Therefore, MV has a significant effect as an adjunctive therapy in the treatment of MDR-TB. However, larger scale multicenter randomized controlled trials are required to confirm this evidence for limited latent bias at present. PMID- 27123254 TI - Helicobacter pylori hopQ alleles (type I and II) in gastric cancer. AB - The Helicobacter pylori (H. pylori) outer membrane protein (HopQ) of is one of the proteins involved in bacterial adherence to gastric mucosa and has been suggested to have a role in the virulence of H. pylori. The aim of the present study was to determine the association between H. pylori virulence types I and II hopQ genotypes and patients with different gastrointestinal diseases. A polymerase chain reaction-based assay was used to determine the presence of type I and type II hopQ genes in 88 H. pylori strains isolated from H. pylori-infected patients. Of the total 88 H. pylori isolates, type I and type II hopQ alleles were detected in 52 (59.1%) and 36 (40.9%), respectively. A significant association was found between type I hopQ gene and gastric cancer [odds ratio, 2.3; 95% confidence interval (CI), 1.3-4.1] and gastric ulcers (odds ratio, 2.5; 95% CI, 1.4-4.3). A significant association was also identified between the type II hopQ gene and gastric cancer (odds ratio, 2.4; 95% CI, 1.1-3.0). The association between hopQ type I and hopQ type II genotypes and clinical status suggest that these genes may be helpful in the universal prediction of specific disease risks. PMID- 27123255 TI - Changes in the Dickkopf-1 and tartrate-resistant acid phosphatase 5b serum levels in preschool children with nephrotic syndrome. AB - The aim of the present study was to investigate the changes in the serum Dickkopf 1 (DKK-1) and tartrate-resistant acid phosphatase 5b (TRACP-5b) levels in preschoolers with nephrotic syndrome (NS). A total of 50 preschoolers (3-5 years old) with NS and 20 healthy preschoolers (control group) were enrolled in the prospective single-center study. The patients with NS received glucocorticoid treatment and the control group received no treatment. The levels of serum calcium, phosphorus, TRACP-5b, DKK-1 and 25-hydroxyvitamin D3 were measured at baseline and at 3 and 6 months in all the subjects. The levels of DKK-1 and TRACP 5b were significantly higher in the NS group prior to treatment when compared to the control group (P<0.05), but did not differ significantly between the two groups following treatment (P>0.05). Therefore, DKK-1 and TRACP-5b can be used as biomarkers of bone formation and bone resorption, respectively, in the early evaluation of bone metabolism. PMID- 27123256 TI - Serum IGF-1 and IGFBP-3 levels as clinical markers for patients with lung cancer. AB - Insulin-like growth factor-1 (IGF-1) and its essential binding protein-3 (IGFBP 3) exhibit significant roles in cellular proliferation, differentiation and apoptosis in numerous malignancies, including lung cancer. The aim of the present study was to determine the clinical roles of the serum IGF-1 and IGFBP-3 levels in lung cancer patients. A total of 80 patients with lung cancer were enrolled in the study. Serum IGF-1 and IGFBP-3 concentrations were determined by ELISA methods. The median age of patients was 58.5 years old, with a range of 36-80 years. The majority of the patients had non-small cell lung cancer (NSCLC) (85%) and metastatic disease (56%). No significant differences were observed in serum IGF-1 levels between lung cancer patients and healthy subjects (P=0.403). However, baseline serum IGFBP-3 levels of the lung cancer patients were significantly lower compared to the control group (P<0.001). The male patients had elevated serum IGF-1 concentrations compared to females (P=0.025). Furthermore, patients with NSCLC histology and metastatic stage in NSCLC had elevated serum IGF-1 (P=0.022 and P=0.039, respectively) and IGFBP-3 (P=0.005 and P=0.043, respectively) levels compared with those with SCLC histology and non metastatic stage in NSCLC. However, none of the other clinical variables, including age of patient, tumor histology and chemotherapy responsiveness, were observed as correlated with serum assays of IGF-1 and IGFBP-3 (P>0.05). There was a significant association found between IGF-1 and IGFBP-3 serum levels in lung cancer patients (P<0.001). Neither serum IGF-1 nor IGFBP-3 concentrations were associated with outcome (P=0.552 and P=0.471, respectively). In conclusion, serum concentrations of IGFBP-3 may have a diagnostic predictor in patients with lung cancer compared to serum IGF-1 concentrations. However, predictive and prognostic values of the two serum assays were not observed. PMID- 27123257 TI - An association between dietary habits and traffic accidents in patients with chronic liver disease: A data-mining analysis. AB - The incidence of traffic accidents in patients with chronic liver disease (CLD) is high in the USA. However, the characteristics of patients, including dietary habits, differ between Japan and the USA. The present study investigated the incidence of traffic accidents in CLD patients and the clinical profiles associated with traffic accidents in Japan using a data-mining analysis. A cross sectional study was performed and 256 subjects [148 CLD patients (CLD group) and 106 patients with other digestive diseases (disease control group)] were enrolled; 2 patients were excluded. The incidence of traffic accidents was compared between the two groups. Independent factors for traffic accidents were analyzed using logistic regression and decision-tree analyses. The incidence of traffic accidents did not differ between the CLD and disease control groups (8.8 vs. 11.3%). The results of the logistic regression analysis showed that yoghurt consumption was the only independent risk factor for traffic accidents (odds ratio, 0.37; 95% confidence interval, 0.16-0.85; P=0.0197). Similarly, the results of the decision-tree analysis showed that yoghurt consumption was the initial divergence variable. In patients who consumed yoghurt habitually, the incidence of traffic accidents was 6.6%, while that in patients who did not consume yoghurt was 16.0%. CLD was not identified as an independent factor in the logistic regression and decision-tree analyses. In conclusion, the difference in the incidence of traffic accidents in Japan between the CLD and disease control groups was insignificant. Furthermore, yoghurt consumption was an independent negative risk factor for traffic accidents in patients with digestive diseases, including CLD. PMID- 27123258 TI - Effects of Dendropanax morbifera Leveille extracts on cadmium and mercury secretion as well as oxidative capacity: A randomized, double-blind, placebo controlled trial. AB - In this randomized, double-blind, placebo controlled clinical trial, the effects of Dendropanax morbifera (D. morbifera) Leveille on heavy metal (cadmium and mercury) excretion as well as on lipid peroxidation and Cu, Zn-superoxide dismutase (SOD1) activity were investigated. For this study, tablets containing placebo or 300 mg of the leaf extract from D. morbifera Leveille were used. A total of 60 eligible healthy subjects were enrolled in this randomized, double blind, placebo-controlled study. The differences in cadmium, mercury, and malondialdehyde (MDA) levels and SOD1 activity were measured in the serum 60 days after treatment with placebo or D. morbifera Leveille extracts. No significant differences between baseline characteristics and biochemical values were identified in subjects in the placebo and D. morbifera Leveille groups. Serum levels of cadmium, mercury and MDA decreased following consumption of D. morbifera Leveille extracts; however, no significant differences were identified. In addition, female, but not male, subjects who consumed D. morbifera Leveille extracts showed a significant increase in SOD1 activity. This result suggests that chronic consumption of D. morbifera Leveille extract can help to facilitate excretion of cadmium and mercury from serum and increase the antioxidant capacity in humans. PMID- 27123259 TI - Involvement of the NF-kappaB signaling pathway in the renoprotective effects of isorhamnetin in a type 2 diabetic rat model. AB - The aim of the present study was to investigate the renoprotective effects of isorhamnetin (ISO) in type 2 diabetic rats and its effects on the nuclear factor kappaB (NF-kappaB) signaling pathway, which is associated with diabetic nephropathy. The type 2 diabetic rat model was established by a high-fat diet plus streptozocin injection and the rats were subsequently treated with two dosages of ISO, respectively. The levels of blood glucose were determined. Urinary osteopontin, kidney injury molecule-1 (KIM-1) and albumin were measured to evaluate the renal function of the rats. Renal NF-kappaB signaling activity was assessed by measuring the levels of NF-kappaB p65, phospho-NF-kappaB p65, inhibitor of NF-kappaB (IkappaBalpha) and phospho-IkappaBalpha, and the NF-kappaB p65 DNA-binding activity. Downstream inflammatory mediators [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta1 (TGF-beta1)] of the NF-kappaB signaling pathway were investigated to evaluate the renal inflammatory response. Renal levels of malondialdehyde and total superoxide dismutase were detected to access the oxidative stress. Furthermore, glomerular mesangial cells (GMCs) were treated with lipopolysaccharide and ISO. In the cellular experiment, the NF-kappaB signaling activity, levels of TNF-alpha, IL 1beta, IL-6, ICAM-1 and TGF-beta1, and oxidative stress were also investigated. The results showed that ISO decreased the levels of urinary osteopontin, KIM-1 and albumin. ISO also inhibited the NF-kappaB signaling activity, decreased the production of inflammatory mediators and attenuated oxidative stress in diabetic rats and GMCs. The present investigations revealed that ISO had ameliorative effects on diabetes-induced renal damage and the activity may be associated with the negative regulation of NF-kappaB signaling pathway. PMID- 27123260 TI - Effect of omega-3 polyunsaturated fatty acids on the growth of IEC-6 cells injured by heavy metals. AB - Environmental pollution is a current area of focus worldwide, particularly heavy metal pollution. Feasible prevention or therapeutic strategies are required. Exploration of the correlation between omega-3 polyunsaturated fatty acids (omega 3 PUFAs) and intestinal epithelial cells injured by heavy metals may be of significance for intestinal health. In the present study, the effects of omega-3 PUFAs on the rat intestinal crypt cell line (IEC-6) injured by heavy metals and its mechanisms were determined according to the evaluation of cell viability and expression levels of reactive oxygen species (ROS), epidermal growth factor (EGF) and interleukin-6 (IL-6). The results demonstrated that omega-3 PUFAs can improve the viability of IEC-6 cells injured by heavy metals and the expression level of ROS was correlated with oxidative damage; the increased expression level of inflammatory factors is associated with cell apoptosis. In the present study, omega-3 PUFAs significantly decreased the expression levels of ROS, EGF and IL-6. This indicates that the protective action of omega-3 PUFAs was associated with a decrease of oxidative damage and pro-inflammatory cytokine expression against the damage of heavy metals. PMID- 27123261 TI - Soluble cluster of differentiation 36 concentrations are not associated with cardiovascular risk factors in middle-aged subjects. AB - Cluster of differentiation 36 (CD36) is involved in the development of atherosclerosis by enhancing macrophage endocytosis of oxidized low-density lipoproteins and foam cell formation. Soluble CD36 (sCD36) was found to be elevated in type 2 diabetic patients and possibly acted as a marker of insulin resistance and atherosclerosis. In young subjects, sCD36 was associated with cardiovascular risk factors including obesity and hypertriglyceridemia. The present study was conducted to further investigate the association between plasma sCD36 and cardiovascular risk factors among middle-aged patients with metabolic syndrome (MetS) and healthy controls. sCD36 concentrations were determined by enzyme-linked immunosorbent assays (ELISA) for 41 patients with MetS and 36 healthy controls. Data for other variables were obtained from patient medical records. sCD36 concentrations were relatively low compared to the majority of other studies and were not significantly different between the MetS group and controls (P=0.17). sCD36 was also not correlated with age, body mass index, glucose, lipid profile, serum electrolytes and blood counts. sCD36 was not significantly different between subjects with obesity, hyperglycemia, dyslipidemia, hypertension or cardiovascular disease, and those without these abnormalities (P>0.05). The inconsistency between results reported in the present study and other studies may be unique to the study population or be a result of the lack of a reliable standardized method for determining absolute sCD36 concentrations. However, further investigations are required to assess CD36 tissue expression in the study population and to assess the accuracy of various commercially available sCD36 ELISA kits. Thus, the availability of a standardized simple sCD36 ELISA that could be performed in any basic laboratory would be more favorable to the specialized flow cytometry methods that detect CD36+ microparticles if it was to be used as a biomarker. PMID- 27123262 TI - Cardiotoxicity associated with targeted cancer therapies. AB - Compared with traditional chemotherapy, targeted cancer therapy is a novel strategy in which key molecules in signaling pathways involved in carcinogenesis and tumor spread are inhibited. Targeted cancer therapy has fewer adverse effects on normal cells and is considered to be the future of chemotherapy. However, targeted cancer therapy-induced cardiovascular toxicities are occasionally critical issues in patients who receive novel anticancer agents, such as trastuzumab, bevacizumab, sunitinib and imatinib. The aim of this review was to discuss these most commonly used drugs and associated incidence of cardiotoxicities, including left ventricular dysfunction, heart failure, hypertension and thromboembolic events, as well as summarize their respective molecular mechanisms of cardiovascular adverse effects. PMID- 27123264 TI - Repeated changes of the molecular subtype in gastric metastasis from breast cancer: A case report. AB - Gastric metastasis from breast cancer is clinically diagnosed rarely. The present study described an interesting and valuable case of gastric metastasis from breast cancer, which showed repeated changes of the molecular subtype with an impact on the choice of treatment. A 42-year-old woman underwent mastectomy with axillary lymph node dissection for an invasive lobular carcinoma of the left breast. The patient received gastroscopy due to an epigastric pain during the adjuvant chemotherapy. The endoscopic examination revealed an erosive lesion at the posterior wall of the gastric body. The gastric lesion was immunohistochemically diagnosed as a metastatic disease from the breast cancer. The patient initially received hormone therapy, according to the subtype of the primary and the metastatic diseases. The gastric lesion initially disappeared; however, a relapsed lesion transformed into luminal human epidermal growth factor receptor 2 type from luminal type. Subsequently, the metastatic lesions underwent repeated subtype changing, which created difficultly when deciding the treatment strategy. The molecular profile of breast cancer can change during the treatment, resulting in the treatment resistance observed in certain cases. Therefore, the optimal treatment must be selected, according to the changed subtype. PMID- 27123266 TI - B3-lesions of the breast and cancer risk - an analysis of mammography screening patients. AB - The use of mammography screening, followed by needle core biopsy (NCB), is associated with an increasing amount of invasive procedures. A considerable amount of specimens must be classified as lesions with uncertain malignant potential (B3-lesion). In these cases, an open biopsy is indicated for further diagnosis. We evaluated patients with B3-lesions to determine the risk of malignancy corresponding to the histopathological NCB results and the type of radiological lesion identified. A total of 95 patients participating in the German mammography screening program with a B3-lesion following NCB (104 B3 lesions in total) were included in our analysis. We analyzed the correlation between the initial histopathological findings from the NCB specimen and cancer risk. We further analyzed the correlations of malignant results with the type of mammographic lesion. In 23 cases (22%), histopathological examination following excision revealed a malignant lesion, including invasive and in situ carcinoma. The positive predictive value of the subgroups of B3-lesions ranged between 0.11 and 0.31; the B3-lesion associated with the highest cancer risk was the atypical ductal hyperplasia; however, no significant difference was observed between the B3-lesion subgroups (P=0.309) regarding the risk of malignancy. Comparing the different types of mammographic findings, such as radiological mass or microcalcifications, there was no significant difference in the risk for malignancy (P=0.379). The different types of B3-lesions did not exhibit differences in the risk for malignancy, and the morphological type of mammographic lesion does not appear to be correlated with cancer risk; therefore, our results underline the need for open biopsy in patients with B3-lesions following NCB. PMID- 27123265 TI - Magnetic resonance imaging findings and prognosis of gastric-type mucinous adenocarcinoma (minimal deviation adenocarcinoma or adenoma malignum) of the uterine corpus: Two case reports. AB - Our group previously documented the first, very rare case of primary gastric-type mucinous adenocarcinoma of the uterine corpus. Although this type of endometrial cancer appears to be similar to the gastric-type adenocarcinoma of the uterine cervix, its main symptoms, appearance on magnetic resonance imaging (MRI) and prognosis have not been fully elucidated due to its rarity. We herein describe an additional case of gastric-type mucinous adenocarcinoma of the endometrium and review the relevant literature. The two cases at our institution (Kyoto University Hospital, Kyoto, Japan) involved postmenopausal women with a primary complaint of abnormal genital bleeding. Microscopic examination of the hysterectomy specimens indicated a highly differentiated mucinous adenocarcinoma with a desmoplastic stromal reaction. Immunohistochemistry for HIK1083 and/or MUC6 was positive in both cases, suggesting a gastric phenotype. Both patients were diagnosed at an advanced stage, they relapsed or recurred immediately after adjuvant chemotherapy, and eventually succumbed to the disease. The main symptom of gastric-type mucinous adenocarcinoma of the uterine cervix is watery discharge, whereas abnormal genital bleeding in addition to watery discharge is mainly observed in the mucinous type of endometrial adenocarcinoma. Cystic cavities in the tumor are present on MRI in cases of endometrial origin, and prognosis is very poor due to resistance to chemotherapy. Thus, gastric-type mucinous adenocarcinoma of the uterine endometrium exhibits a clinical behavior that is similar to tumors originating from the uterine cervix, but is associated with distinguishing clinical symptoms. The incidence of gastric-type endometrial adenocarcinoma may be higher than expected. PMID- 27123267 TI - Primary combined small and squamous cell carcinoma of the hypopharynx: A case report. AB - We herein report a very rare case of combined small-cell carcinoma (SmCC) of the hypopharynx, with a squamous cell carcinoma (SqCC) element. A 74-year-old man presented with a 3-month history of throat pain and hoarseness. On hypopharyngoscopy, a tumor was identified in the right anterior wall of the piriform sinus and, following examination of a biopsy sample, the lesion was diagnosed as SqCC. Total laryngectomy with bilateral neck dissection was performed and the malignancy was diagnosed as combined SmCC. One month after surgery, concomitant chemoradiotherapy with cisplatin and etoposide was administered. Immunohistochemically, the SmCC element was positive for CD56 and Ki-67 (50.2%), whereas the SqCC element was positive for cytokeratin 34betaE12 and Ki-67 (47.5%). Furthermore, the SmCC element was positive for KIT and platelet-derived growth factor alpha (PDGFRalpha), while the SqCC element was positive for epidermal growth factor receptor (EGFR) and PDGFRalpha. By genetic analysis, a silent mutation in the PDGFRalpha gene was recognized. The expression of KIT, PDGFRalpha and EGFR in this case provided evidence that combined SmCC may be a candidate for molecular-targeted therapy, although further investigations are required. PMID- 27123263 TI - Immunoglobulin gene translocations in chronic lymphocytic leukemia: A report of 35 patients and review of the literature. AB - Chronic lymphocytic leukemia (CLL) represents the most common hematological malignancy in Western countries, with a highly heterogeneous clinical course and prognosis. Translocations involving the immunoglobulin (IG) genes are regularly identified. From 2000 to 2014, we identified an IG gene translocation in 18 of the 396 patients investigated at diagnosis (4.6%) and in 17 of the 275 analyzed during follow-up (6.2%). A total of 4 patients in whom the IG translocation was identified at follow-up did not carry the translocation at diagnosis. The IG heavy locus (IGH) was involved in 27 translocations (77.1%), the IG kappa locus (IGK) in 1 (2.9%) and the IG lambda locus (IGL) in 7 (20.0%). The chromosome band partners of the IG translocations were 18q21 in 16 cases (45.7%), 11q13 and 19q13 in 4 cases each (11.4% each), 8q24 in 3 cases (8.6%), 7q21 in 2 cases (5.7%), whereas 6 other bands were involved once (2.9% each). At present, 35 partner chromosomal bands have been described, but the partner gene has solely been identified in 10 translocations. CLL associated with IG gene translocations is characterized by atypical cell morphology, including plasmacytoid characteristics, and the propensity of being enriched in prolymphocytes. The IG heavy chain variable region (IGHV) mutational status varies between translocations, those with unmutated IGHV presumably involving cells at an earlier stage of B-cell lineage. All the partner genes thus far identified are involved in the control of cell proliferation and/or apoptosis. The translocated partner gene becomes transcriptionally deregulated as a consequence of its transposition into the IG locus. With the exception of t(14;18)(q32;q21) and its variants, prognosis appears to be poor for the other translocations. Therefore, searching for translocations involving not only IGH, but also IGL and IGK, by banding and molecular cytogenetics is required. Furthermore, it is important to identify the partner gene to ensure the patients receive the optimal treatment. PMID- 27123268 TI - Response to chemotherapy with carboplatin plus albumin-bound paclitaxel in a patient with lymphoepithelioma-like thymic carcinoma: A case report. AB - Thymic carcinoma is a rare neoplasm with a poor outcome due to its aggressive characteristics. For patients who are not operable, radiation therapy and/or palliative chemotherapy are indicated. However, no optimal chemotherapy regimen has been established. The present study reports the case of a 22-year-old man with advanced lymphoepithelioma-like thymic carcinoma refractory to conventional chemotherapy with carboplatin plus solvent-based paclitaxel (sb-PAC) treatment. The patient was subsequently treated with carboplatin plus nanoparticle albumin bound paclitaxel (nab-PAC). The treatment resulted in a partial response following three cycles of chemotherapy. Since only grade 3 neutropenia, but no other severe adverse effects, was observed, no dose reduction was required. To the best of our knowledge, the current study is the first to present the response to chemotherapy with carboplatin plus nab-PAC in a patient with lymphoepithelioma like thymic carcinoma. Considering that no standard treatment has been established in thymic carcinoma, nab-PAC may merit further investigation in this rare, but aggressive disease. PMID- 27123269 TI - HER2-positive double primary tumor of gastric and breast cancer occur synchronously in a patient: A case report. AB - The simultaneous occurrence of primary gastric cancer and breast cancer is rare, and the positive expression of human epidermal growth factor receptor (HER)2 in double primary carcinoma of gastric and breast cancer remains to be reported. The present study presented a 46-year-old woman complaining of irregular acid reflux and stomach discomfort. The stomach cancer was diagnosed by esophagogastroduodenoscopy examination of the pathological biopsies in 2010. The patient underwent a radical gastrectomy for gastric cancer, and postoperative pathological examination revealed moderately-poorly differentiated adenocarcinoma with HER2 positive expression. The tumor invaded into the entire thickness of the gastric wall and lymph nodes. The patient received five treatments of postoperative chemotherapy. In August 2011, the patient felt a lump in the right breast. Simple excision of the right breast mass was performed on September 2011, and postoperative pathological examination revealed the invasive ductal carcinoma of the right breast with HER2 amplification by fluorescent in situ hybridization assay. The patient was treated with postoperative chemotherapy and radiotherapy, and also Trastuzumab target therapy. The patient succumbed to aggressive disease progression in March 2012. PMID- 27123270 TI - Malignant myoepithelioma of the breast: A case report and review of the literature. AB - Malignant myoepithelioma of the breast is an extremely rare tumor composed entirely or almost entirely of malignant spindle cells with myoepithelial differentiation. Only a limited number of case reports have been descibed to date; therefore the biological behavior and treatment outcomes of this rare tumor have not been clearly determined. Herein, we present a case of a 74-year-old woman who was admitted with inflammatory-like cancer of the breast, presenting with invasion of the chest wall and axillary lymph node metastasis at the time of diagnosis. The histological examination revealed a tumor composed of epithelioid and spindle cells with moderate to marked nuclear atypia, with foci of hemorrhage and necrosis. The tumor cells were immunoreactive for vimentin, p63, p53, CD10, cytokeratin (CK)8/18, CKAE1-3 and S-100. Finally, a diagnosis of myoepithelial carcinoma of the breast was established. Neoadjuvant chemotherapy was first administered and proved to be ineffective. Due to locoregional progression that was associated with the development of an abscess and subsequent excessive bleeding, a palliative mastectomy was performed. Postoperatively, one more cycle of systemic chemotherapy was administered. However, the patient experienced an early relapse to the chest wall and succumbed to septic shock due to persistent local infection. The aggressiveness and chemoresistance of the tumor in this case was consistent with the existing bibliography. PMID- 27123271 TI - Cutaneous involvement as a rare first sign of systemic mantle cell lymphoma: A case report and review of the literature. AB - Mantle cell lymphoma (MCL) is a unique type of B-cell non-Hodgkin's lymphoma, which very rarely exhibits skin involvement. We herein describe the case of a 55 year-old woman, who initially presented with a nodular mass of the right infraorbital region. On histological analysis of the subcutaneous tissue, a diffuse neoplastic cell infiltration was identified, composed of medium-sized lymphoid cells with irregular nuclei, which was diagnosed as MCL. The tumor cells were positive for CD5, CD20, CD79a, cyclin D1 and sex-determining region Y-box 11, but negative for CD10 and CD23. Our patient received six cycles of R-CHOP chemotherapy and intrathecal methotrexate as central nervous system prophylaxis. However, the patient relapsed 1 year later and was treated with two cycles of R DHAP and one cycle of intrathecal methotrexate. After achieving partial remission, the patient was consolidated with peripheral blood stem cell transplantation using the BEAM conditioning regime. While prior case studies suggest that skin invasion by MCL is associated with a poor prognosis, our patient remains alive almost 4 years after the initial presentation. Skin involvement as a first sign of systemic MCL is very rare and must be considered. PMID- 27123272 TI - An 80-gene set to predict response to preoperative chemoradiotherapy for rectal cancer by principle component analysis. AB - Preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer not only improves the postoperative local control rate, but also induces downstaging. However, it has not been established how to individually select patients who receive effective preoperative CRT. The aim of this study was to identify a predictor of response to preoperative CRT for locally advanced rectal cancer. This study is additional to our multicenter phase II study evaluating the safety and efficacy of preoperative CRT using oral fluorouracil (UMIN ID: 03396). From April, 2009 to August, 2011, 26 biopsy specimens obtained prior to CRT were analyzed by cyclopedic microarray analysis. Response to CRT was evaluated according to a histological grading system using surgically resected specimens. To decide on the number of genes for dividing into responder and non-responder groups, we statistically analyzed the data using a dimension reduction method, a principle component analysis. Of the 26 cases, 11 were responders and 15 non responders. No significant difference was found in clinical background data between the two groups. We determined that the optimal number of genes for the prediction of response was 80 of 40,000 and the functions of these genes were analyzed. When comparing non-responders with responders, genes expressed at a high level functioned in alternative splicing, whereas those expressed at a low level functioned in the septin complex. Thus, an 80-gene expression set that predicts response to preoperative CRT for locally advanced rectal cancer was identified using a novel statistical method. PMID- 27123273 TI - A retrospective study on intensity-modulated radiation therapy combined with chemotherapy after D2 radical surgery for gastric carcinoma. AB - In order to investigate the clinical value of different chemotherapies, the efficacy of intensity-modulated radiation therapy with concurrent chemotherapy following D2 radical surgery for gastric carcinoma was evaluated in this study. A total of 102 patients who underwent D2 radical surgery for gastric carcinoma followed by concurrent chemoradiotherapy (CRT) between January, 2008 and March, 2012, were selected. The 5/7 field intensity-modulated radiation therapy was used, with a planning target volume dose of 45 Gy in 25 fractions over 5 weeks. Among these patients, 45 were administered 400 mg/m2/day fluorouracil and 20 mg/m2/day tetrahydrofurfuryl alcohol through intravenous infusion 4 days before and 3 days after the radiotherapy (F-CRT group), while 57 patients received 825 mg/m2 capecitabine orally twice a day (C-CRT group). The 3-year overall and the disease-free survival rates were 75.5 and 70.5%, respectively. The overall 3-year survival rates of the F-CRT and C-CRT groups were 72.2 and 78.5% (P>0.05), respectively, and the 3-year disease-free survival rates were 67.7 and 72.8% (P>0.05), respectively. No significant differences were observed between the two groups. However, during the concurrent CRT, significant differences were found in the incidence of grade 1-2 haematological toxicity between the F-CRT and C-CRT groups (73.3 vs. 50.9%, respectively; chi2 =5.320, P=0.021). Significant differences were also found in the incidence of grade 1-2 gastrointestinal reactions between the two groups (77.8 vs. 57.9%, respectively; chi2=4.474, P=0.034). Therefore, intensity-modulated radiation therapy combined with concurrent chemotherapy following D2 radical surgery for gastric cancer was found to be safe and effective. In addition, radiotherapy was better tolerated and more likely to be completed using C-CRT rather than F-CRT. PMID- 27123274 TI - Distinct epithelial growth factor receptor mutation profile in non-small-cell lung cancer patients from the Xuanwei area of China. AB - The Xuanwei county in China has a high incidence of lung cancer and related mortality. Previous studies have suggested that these cases may be associated with a distinctive pattern of mutations in the epithelial growth factor receptor (EGFR) gene. In this retrospective study, we investigated the mutation profile of EGFR in non-small-cell lung cancer (NSCLC) tissues from patients in Xuanwei, and the associated clinicopathological characteristics. Specimens from 258 consecutive patients with lung cancer (90 from Xuanwei and 168 from other areas of Yunnan province) were subjected to amplification refractory mutation system polymerase chain reaction (ARMS-PCR) to detect EGFR mutations. In 67 specimens from Xuanwei, the results were confirmed by direct DNA sequencing for EGFR mutations. Immunohistochemistry (IHC) for the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein was performed on all specimens from Xuanwei. We observed that Xuanwei patients presented with distinctive clinicopathological characteristics, including female gender predominance, younger age, higher rate of lymph node metastasis, higher rate of adenocarcinoma histological classification and lower disease stage, and a low rate of the 'classical' mutations on EGFR exons 19 and 21 compared with non Xuanwei patients (7.8 and 21.6% vs. 49.3 and 39.7%, respectively; P<0.05 for combined data). However, a significantly higher percentage of Xuanwei patients harbored co-mutation of EGFR exons 18 and 20 compared with non-Xuanwei patients (45.1 vs. 4.1%, respectively; P<0.0001). Specimens from 2 Xuanwei patients (2.2%) were positive for the EML4-ALK fusion protein; by IHC, neither harbored EGFR mutations. There was no obvious association between EGFR mutations and disease stage or lymph node involvement. Thus, NSCLC patients in Xuanwei presented with a unique EGFR profile of high rates of co-mutation of exons 18 and 20, and low rates of exon 19 or 21 mutations when compared with patients from other areas in the same province, whereas only few of the tumors from Xuanwei patients expressed the EML4-ALK oncogene. PMID- 27123275 TI - Outcome of patients with glioblastoma in Saudi Arabia: Single center experience. AB - Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is associated with one of the worst 5 year survival rates among all human cancer types. To date, no published data are available for the outcome of this disease in Saudi Arabia. The present study performed a single-center, retrospective cohort study to evaluate the outcome of patients with GBM in Saudi Arabia. The Comprehensive Cancer Center at King Fahad Medical city (Riyadh, Saudi Arabia) was used in the present study. All adult patients (>=18 years) diagnosed with histologically proven GBM between January 2008 and December 2013 were included in the present study. A total of 90 patients were treated during the specified period. Of this, 73 (81%) patients underwent resection and 17 (19%) had biopsy only. The majority of patients (n=88; 98%) received radiotherapy (XRT): 67 (76%) with standard and 21 (24%) with hypo-fractionated dosage. Of the total patients, 65 (72%) received combined modality therapy [standard XRT concurrently with Temozolmide (TMZ)]. The 6 month progression-free survival rate was 43% for all patients and 55% for the combined modality subgroup. The median overall survival (OS) for all patients was 13.7 months. However, the median OS for patients treated with combined modality was 19.7 months. In this single-center retrospective study, the outcomes of patients with GBM were similar to those in previously reported studies. An improved outcome was associated with an improved performance status, absence of residual disease and use of adjuvant TMZ. PMID- 27123276 TI - Back to the start: Evaluation of prognostic markers in gastrointestinal stromal tumors. AB - The aim of this study was to provide a standardized risk stratification model for gastrointestinal stromal tumors (GISTs) based on tumor localization, tumor size, involved lymph nodes and metastases, as well as mitotic activity and other morphological and molecular markers, in order to improve the risk evaluation scheme for recurrence, metastatic spread and survival for patients with GIST. A total of 201 cases of patients with GIST were investigated according to standardized morphological markers, including nuclear pleomorphism, tumor cell necrosis, mucosal infiltration, ulceration, skeinoid fibers and growth pattern. In addition, all cases were immunohistochemically analyzed using a tissue microarray platform for various markers of differentiation (CD34, CD44, CD117, desmin, discovered on GIST 1, platelet-derived growth factor receptor alpha, S 100 and smooth muscle actin) and proliferation (B-cell lymphoma 2, P16, P53, phosphohistone H3 and Ki-67). These findings were correlated by uni- and multivariable analyses with clinicopathological characteristics, including recurrence, metastasis and survival. The general clinicopathological parameters of this GIST specimen cohort were comparable to previous studies. While several parameters exhibited clear associations to each other and to the defined clinical endpoints, the multivariate analysis reduced the number of relevant prognostic variables to localization, margin status, growth pattern and hematoxylin and eosin-based mitosis/Ki-67-based proliferation of GISTs. With the exception of CD34, none of the applied markers of differentiation and proliferation were found to be independent prognostic markers in GIST and the classical risk factors of GIST remain important prognostic factors. Additionally, growth pattern may predict the risk of recurrence and metastasis in GIST patients. Additional independent molecular prognostic markers remain to be identified and validated. PMID- 27123277 TI - Elevated levels of plasma lactate dehydrogenase is an unfavorable prognostic factor in patients with epidermal growth factor receptor mutation-positive non small cell lung cancer, receiving treatment with gefitinib or erlotinib. AB - Treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKIs) has been shown to prolong survival in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). The present study performed a retrospective analysis to investigate the association between the plasma lactate dehydrogenase (LDH) levels and survival in patients with EGFR mutation-positive NSCLC receiving treatment with EGFR-TKIs. The medical charts of patients with EGFR mutation positive NSCLC who were receiving treatment with EGFR-TKIs at Toyama University Hospital between 2007 and 2014 were assessed. The data from 65 patients were included in the analysis. Patients with higher plasma LDH levels exhibited shorter progression-free survival (6.2 vs. 13.2 months; P<0.01) and overall survival (10.5 vs. 36.1 months; P<0.01) periods compared with patients with lower plasma LDH levels. A Cox proportional hazards model identified that the plasma LDH level was associated with the progression-free survival (P=0.05) and overall survival (P<0.01). An association was demonstrated between the pretreatment plasma LDH level and the survival in patients with EGFR mutation-positive NSCLC receiving treatment with EGFR-TKIs. Close observation is required in EGFR mutation-positive NSCLC patients exhibiting high plasma LDH levels following the initiation of treatment with EGFR-TKIs. PMID- 27123278 TI - Polymorphous low-grade adenocarcinoma of the epiglottis: A case report. AB - Polymorphous low-grade adenocarcinoma is an uncommon malignant tumor derived from the terminal duct cells of the salivary glands. The present study described a rare case of polymorphous low-grade adenocarcinoma, T2N0M0 stage 2, in a 65-year old man, who presented with a sore throat and painful dysphagia. Computed tomography revealed an infiltrative heterogenous enhancing mass involving the left aryepiglottic fold. He underwent a tumor removal with frozen section for evaluating the surgical margin. Subsequent supraglottic laryngectomy was performed. Polymorphous low-grade adenocarcinoma was diagnosed histologically, characterized by cytologic uniformly, morphologic diversity and an infiltrative growth pattern. Epiglottic cartilaginous invasion by the tumor is demonstrated. Clinical, radiological, endoscopic and pathological features with briefly reviewed relevant literatures are discussed. This is the first reported description in the literature, to the best of our knowledge, of an epiglottic polymorphous low-grade adenocarcinoma receiving successful supraglottic laryngectomy with 7 year disease free survival. PMID- 27123279 TI - Combination chemotherapy with docetaxel and carboplatin for elderly patients with endometrial cancer. AB - Approximately half of all endometrial cancer cases are diagnosed in patients aged >65 years. The objective of this study was to compare the tolerability and effectiveness of combination chemotherapy with docetaxel and carboplatin between endometrial cancer patients older and younger than 65 years of age. Chemotherapy naive patients with endometrial cancer were enrolled in this retrospective study between April, 2008 and March, 2015. The patients received docetaxel (60 mg/m2) and carboplatin (area under the curve of 6 mg/ml/min) on day 1 of a 3-week cycle. The tolerability and effectiveness of this regimen were analyzed. A total of 41 patients with endometrial cancer were enrolled in this study, of whom 26 (63%) were aged <65 years and 15 (37%) were aged >=65 years. There were no significant differences with regard to Eastern Cooperative Oncology Group performance status score and disease stage between the two groups. Patients aged >65 years were significantly more likely to have serous or clear-cell histology and high-grade tumors compared with the younger group (P=0.014 and 0.012, respectively). Although the number of chemotherapy cycles, cycle delays and treatment interruptions were comparable between older and younger patients, there was a trend toward more dose reductions in the older group (P=0.12). The incidence of hematological toxicities did not differ significantly between the two groups. The incidence of grade 3/4 diarrhea was significantly higher in the older group (P=0.014) and hypersensitivity was significantly more frequent in the younger group (P=0.035). Patients aged >=65 years had equivalent response rates, progression-free survival and overall survival compared with those aged <65 years. These results suggest that combination chemotherapy with docetaxel and carboplatin was tolerable and effective for the treatment of elderly chemotherapy naive patients with endometrial cancer. PMID- 27123281 TI - Aplastic anemia associated with severe hemorrhagic cystitis following radiotherapy for prostate cancer. AB - Hemorrhagic cystitis is a rare complication following radiotherapy for intrapelvic cancer types, including cervical cancer, bladder cancer and prostate cancer. The severity of hemorrhagic cystitis is different in each case, although symptoms improve spontaneously in certain cases, and often significant morbidity requiring numerous interventions occurs. Since no treatment strategy exists with high evidences for such severe hemorrhagic cystitis, urologists have difficulty in solving the bleeding and pain, which the patients suffer. Aplastic anemia is a rare blood disorder, with an incidence reported as 2/1 million individuals annually. Patients have a risk of diffuse bleeding for presentation with anemia, thrombocytopenia and neutropenia. The present report presented a case of severe hemorrhagic cystitis remitted successfully by the treatment for underlying aplastic anemia. PMID- 27123280 TI - Feasibility and early outcome of high-dose-rate Ir-192 brachytherapy as monotherapy in two fractions within 1 day for high-/very high-risk prostate cancer. AB - The aim of the present study was to evaluate the feasibility and preliminary outcomes of high-dose-rate (HDR)-brachytherapy as a monotherapy in two fractions within 1 day for localized prostate cancer, including high-/very high-risk cases. Among the 68 patients treated with HDR monotherapy between July 2011 and December 2014, 65 had a minimal follow-up of 12 months without adjuvant androgen deprivation therapy and were enrolled in the present study [42/65 (64.6%) exhibited high-/very high-risk diseases]. HDR monotherapy was performed in two fractions with a minimal interval of 6 h and the prescribed dose was 13.5 Gy (*2). Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events (version 4; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 , and biochemical failure was assessed by the Phoenix definition. The median follow-up time was 30.1 months. The majority of patients had Grade 0-1 acute AEs. Four patients (6.2%) exhibited urinary retention, requiring a Foley catheter. Grade 3 acute AEs occurred at a frequency of 3.1% and hematuria at 1.5%. The majority of patients also exhibited Grade 0-1 chronic AEs. Grade 3 chronic AEs occurred at a frequency of 1.5% and urethral stricture at 1.5%, for which endoscopic treatment was indicated. Acute and chronic gastrointestinal AEs were uncommon, and no Grade 3 or above AEs developed. Biochemical failure occurred in 4 patients who all exhibited high-/very high-risk diseases. Kaplan-Meier estimated that 3 year biochemical failure-free survival was 91.6% overall and 88.0% in high-/very high-risk cases. The present two-fraction 1 day HDR monotherapy is feasible with minimal AEs and achieved acceptable biochemical control of localized prostate cancer, including high-/very high-risk cases, although long-term follow-up is required. PMID- 27123282 TI - Fibroepithelioma of Pinkus: Solitary tumor or sign of a complex gastrointestinal syndrome. AB - Fibroepithelioma of Pinkus (FEP), which is considered to be an uncommon variant of basal cell carcinoma, has been described in association with other systemic diseases. However, no specific studies are currently available on this subject. The aim of our study was to evaluate the clinical and morphological characteristics of FEP and investigate whether this rare tumor is a single entity or seen in the context of a more complex syndrome. We retrospectively analyzed 49 cases of FEP diagnosed and excised in a single academic institution from 1995 to 2011. The tumors were mainly located on the trunk (77.55%), followed by the lower extremities (12.20%) and the head and neck (10.20%). In 9 of the 49 cases (18%), FEP was associated with gastrointestinal tumors. The abovementioned cases are presented in an attempt to make clinicians more aware of a possible association between FEP and gastrointestinal cancer. Although a possible underlying common genetic background between FEP and gastrointestinal tumors was not provided, our study suggests that patients with FEP should be screened for the occurrence of gastrointestinal tumors. PMID- 27123283 TI - Prognostic performance of inflammation-based prognostic indices in locally advanced non-small-lung cancer treated with endostar and concurrent chemoradiotherapy. AB - A proportion of patients with locally advanced non-small-cell lung cancer (NSCLC) may benefit from anti-angiogenic therapy combined with concurrent chemoradiotherapy; however, effective prognostic biomarkers are required for prognosis. In this study, we aimed to establish whether inflammation-based factors offer a prognostic benefit in terms of response rate (RR) and overall survival (OS) in stage III NSCLC patients treated by endostar with concurrent chemoradiotherapy (CCRT). We retrospectively investigated an unselected cohort of stage III NSCLC patients, who were treated by combined endostar and CCRT. The log rank test was used to analyze the association between each clinical variable and OS. Cox regression models were fitted to identify risk factors associated with OS. A total of 82 patients with stage III NSCLC were treated with a combination of endostar and CCRT and 78 patients were included in the data analysis. A total of 13 patients achieved a complete response, 49 achieved a partial response, 6 had stable disease, 8 had progressive disease and 2 patients could not be evaluated. The median progression-free survival of the entire group was 10.50 months (95% CI: 6.298-14.702), while the median OS was 22.83 months (95% CI: 19.156-26.504). On chi2test analysis, the neutrophil-to-lymphocyte ratio (NLR) exerted a significant effect on RR (P=0.048). The univariate analysis identified the factors associated with OS, including NLR (P=0.004) and monocyte count (P=0.001), whereas the multivariate analysis confirmed NLR [P=0.043, hazard ratio (HR)=0.502] and monocyte count (P=0.011, HR=0.387) as independent prognostic factors for OS. Our results indicated that, in patients with stage III NSCLC treated by a combination of endostar and CCRT, pre-treatment elevated NLR and monocyte number are negatively associated with OS. PMID- 27123284 TI - Synchronous double primary cancer of the lung and nasal vestibule: A case report and literature review. AB - Squamous cell carcinoma (SCC) of the nasal vestibule is a rare tumor entity, and its occurrence combined with lung cancer is even rarer. Thus, several patients are often initially misdiagnosed or remain undiagnosed. This is the case report of a 55-year-old male patient who presented to our hospital with a neoplasm in the left lung. The patient was treated with left upper pulmonary lobectomy and the subsequent histopathological examination of the surgical specimen revealed a poorly differentiated SCC. On postoperative week 4, the patient presented with purulent and bloody discharge from the left nostril and was misdiagnosed with an upper jaw cyst. After another 3 weeks, the patient was re-admitted to the hospital with a mass of left nostril and nasal congestion. Tru-Cut biopsies from the nasal area and histopathological examination revealed a moderately differentiated SCC. According to the clinical presentation and the histopathological findings, the patient was diagnosed with double primary cancer of the lung and the nasal vestibule. The mass of the left nostril was significantly reduced in size with radiotherapy. To the best of our knowledge, there is no similar case previously reported in the literature. Due to the rarity of scc of the nasal vestibule concomittant with lung cancer, we herein present this case report with a review of the relevant literature and investigation of the clinical characteristics. PMID- 27123285 TI - Primary sarcomatoid carcinoma of the jejunum with massive intra-abdominal hemorrhage: A case report and review of the literature. AB - Primary sarcomatoid carcinoma of the jejunum is an extremely rare condition, with only 16 cases reported in the literature to date. We herein report an additional case of a giant sarcomatoid carcinoma of the jejunum in a 62-year-old male patient, presenting as massive intra-abdominal hemorrhage. During emergency laparotomy, ~5 litres of bloody ascites was found in the peritoneal cavity and the tumor was located in the proximal jejunum. The tumor involved the entire wall of the jejunum and had directly invaded the neighboring parietal peritoneum, omentum, transverse colon and mesentery, with metastatic lymph nodes. The patient underwent palliative resection of the tumor; however, the course was rapidly progressive and he succumbed to progression of abdominal and liver metastases 4 weeks after surgery. The tumor was found to be positive for epithelial and mesenchymal markers on immunohistochemical analysis. This case emphasizes the aggressive clinical course and metastatic nature of this malignant tumor, with a supplementary review of the previously published literature. PMID- 27123286 TI - Diagnosis of lateral pelvic lymph node metastasis of T1 lower rectal cancer using diffusion-weighted magnetic resonance imaging: A case report with lateral pelvic lymph node dissection of lower rectal cancer. AB - The present study presented a 35-year-old female patient in whom fecal occult blood was detected in a medical check-up. Colonoscopy revealed a superficial elevated-type tumor with central depression in the lower rectum. The tumor was diagnosed as T1 deep invasive cancer. No swollen lymph nodes or distant metastasis were found on computed tomography or [18F]-fluorodeoxyglucose-positron emission tomography with computed tomography. However, a swollen right lateral pelvic lymph node (LPLN; short axis 4 mm) was revealed on magnetic resonance imaging (MRI). This lymph node exhibited high intensity on diffusion-weighted imaging (DWI), suggesting metastasis. Low anterior resection, regional lymph node dissection and right LPLN dissection (LPLD) were performed. Histological analysis revealed metastasis in the right LPLN, as suggested by the high DWI intensity. The indication for LPLD in the current Japanese guidelines is based on the tumor location and depth of invasion (>=T3), however, not on the status of LPLN metastasis in pre-operative evaluation. The present case was cT1, which is not included in this indication. DWI is sensitive for the diagnosis of lymph node metastasis of colorectal cancer, although inflammation-induced swelling of lymph nodes in advanced rectal cancer may cause a false-positive result, which is uncommon in T1 cases. Therefore, an LPLN with a high intensity DWI signal in T1 cases is likely to be metastasis-positive. Pre-operative DWI-MRI may be useful for identifying LPLN metastasis when planning the treatment strategy in these cases. The present study suggested reinvestigation of the indication for LPLD with inclusion of LPLN status on pre-operative imaging. PMID- 27123287 TI - Papillary adenocarcinoma of the renal pelvis with renal calculus: A rare case report. AB - Papillary adenocarcinoma of the renal pelvis is a rare clinicopathology of a kidney tumor with renal calculus. In the present case report, percutaneous renal biopsy, nephroscope lithotripsy and radical nephroureterectomy within a papillary adenocarcinoma of the renal pelvis accompanied with renal calculus was performed on a 65-year-old patient, also including a report on the patient's data and a literature review. The histopathological features confirmed the diagnosis of papillary adenocarcinoma of the renal pelvis. Tumors of the renal pelvis are uncommon features of urothelial carcinoma, and papillary adenocarcinoma of the renal pelvis is a very unusual entity. The present case report describes papillary adenocarcinoma of the renal pelvis with renal calculus, which has rarely been previously reported. PMID- 27123288 TI - Paralytic ileus due to a novel anticancer drug, nab-paclitaxel: A case report. AB - Nab-paclitaxel is a recently emerged chemotherapy drug, which is widely used for the treatment of multiple types of cancer. The prospects of this novel drug are very bright as a result of its higher efficacy and lower toxicity compared with paclitaxel. Hence, the side effect, even if rare, require attention in clinical practice. The present study described an unusual case of nab-paclitaxel associated paralytic ileus. To the best of our knowledge, this is the first report to demonstrate that nab-paclitaxel may lead to acute intestinal obstruction. Since nab-paclitaxel will be used more frequently, this unusual side effect might be encountered by a clinical oncologist and must be treated correctly. This is the first reported case, to the best of our knowledge, of paralytic ileus caused by nab-paclitaxel, which will be widely used as a novel anticancer drug. PMID- 27123289 TI - A rare case of tumor-mimicking primary angiitis of the central nervous system. AB - Primary angiitis of the central nervous system (PACNS) is a rare, but severe vascular disease. The present study reports the case of a 42-year-old male who developed PACNS. Magnetic resonance imaging (MRI) scans initially led to a misleading diagnosis of malignant glioma, and surgery was performed. The mass was resected, and a pathological examination confirmed a cerebral vasculitis. Single therapy with high doses of steroid did not improve the patient's condition, while a subsequent lesion appeared on the opposite side one year later. Combined therapy with methylprednisone and cyclophosphamide resulted in a great improvement for the patient. No relapse occurred during one year's follow-up. Although a tumor-mimicking PACNS has no established imaging features, a diagnosis of tumor-mimicking PACNS should be suspected when the MRI reveals inappropriate presentations of a tumor. Greater awareness of this potential manifestation of PACNS may facilitate more prompt diagnosis and treatment. PMID- 27123290 TI - False-positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography in a patient with metallic implants following chondrosarcoma resection. AB - Positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose (18F-FDG) has been used for the staging and evaluation of recurrence in cancer patients. We herein report a false-positive result of 18F-FDG PET/computed tomography (CT) scan in a patient following chondrosarcoma resection and metallic implanting. A 35-year-old male patient with chondrosarcoma of the left iliac bone underwent radical resection, metal brace implanting and radiotherapy. A high uptake of 18F-FDG was observed in the metallic implants and adjacent tissue during PET/CT scanning in the 5th year of follow-up. Tissue biopsy and follow-up examination identified no tumor recurrence or infection at these sites, suggesting that the results of 18F-FDG PET/CT must be interpreted with caution in cancer patients with metallic implants. PMID- 27123292 TI - Clinical outcomes of anti-androgen withdrawal and subsequent alternative anti androgen therapy for advanced prostate cancer following failure of initial maximum androgen blockade. AB - The present study aimed to investigate the significance of anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy in patients with advanced prostate cancer (PC) who relapsed after initial maximum androgen blockade (MAB). The present study evaluated the clinical outcomes of 272 consecutive advanced PC patients undergoing anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy with flutamide following the failure of initial MAB using bicalutamide. With the exception of 41 patients (15.1%) who did not undergo anti-androgen withdrawal due to the characteristics of PC suggesting aggressive diseases, prostate-specific antigen (PSA) declined from the baseline value in 83 patients (35.9%), including 18 (7.8%) with PSA decline >50%, but not in the remaining 148 (64.1%). No significant difference in the overall survival (OS) or cancer-specific survival (CSS) among the three groups was observed based on the response to anti-androgen withdrawal. Following the introduction of alternative anti-androgen therapy with flutamide, PSA decline was observed in 185 patients (68.0%), including 103 (37.9%) who achieved a PSA reduction of >50%; however, the PSA level continued to elevate in the remaining 87 (32.0%). Furthermore, of the numerous factors examined, only the duration of the initial MAB therapy was shown to be significantly correlated with the PSA decline following alternative anti-androgen therapy. Multivariate analysis of several factors identified revealed that only PSA decline following alternative anti-androgen therapy was an independent predictor of CSS and OS. If initial MAB is effective, the introduction of alternative anti-androgen therapy may be considered; however, anti-androgen withdrawal should be omitted, irrespective of the characteristics of advanced PC. PMID- 27123291 TI - Bevacizumab treatment for newly diagnosed glioblastoma: Systematic review and meta-analysis of clinical trials. AB - High-grade glioma is a richly neovascularized brain solid tumor with a poor prognosis. Bevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial cell proliferation and angiogenesis, which has shown clinical efficacy in recurrent glioblastoma. MEDLINE/PubMed, EMBASE and Web of Science databases were searched for relevant studies that compared bevacizumab plus combined radiotherapy/temozolomide (RT/TMZ) with RT/TMZ alone in newly diagnosed glioblastoma (GBM). Of all the studies identified, three comparative trials were included in the systematic review. All three enrolling trials, including a total of 1,738 patients, investigated bevacizumab or placebo plus combined RT/TMZ treatment in glioblastoma. The result showed no increased overall survival (OS) (pooled hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.84 1.29; P=0.71) but increased progression-free survival (HR, 0.74; 95% CI, 0.62 0.88; P=0.0009). However, the two randomized double-blind placebo-control trials exemplified a high rate of adverse events of the bevacizumab compared with the placebo group while discrepant points were noted in term of quality-of-life outcome. Additionally, bevacizumab plus RT/TMZ did not increase the 6-month survival rate [odd ratios (ORs), 0.65; 95% CI, 0.37-1.13; P=0.13). Overall, addition of bevacizumab to radiotherapy-temozolomide treatment may be an effective therapy strategy for improving progression-free survival. OS and the 6 month survival rate was not prolonged and there was questionable efficacy of bevacizumab on the quality-of-life of glioblastoma patients, thus further clinical trials should be performed. PMID- 27123293 TI - Extrapancreatic solid pseudopapillary tumors: A clinicopathological analysis of two cases. AB - Solid pseudopapillary tumors (SPTs) are unusual neoplasms that mostly occur in the pancreas, and predominantly affect young women. As a low-grade malignant neoplasm of the exocrine pancreas, they occasionally metastasize, usually to the liver or peritoneum. It has been reported that <1% of SPTs are primary extrapancreatic SPTs. In the present study, we present two rare, but conspicuous extrapancreatic SPTs. Both occurred in young women, and showed good prognoses following surgery. One was a recurrent SPT of the pancreas that metastasized to the ovary, and the other was a distinct primary neoplasm that arose in the retroperitoneal area. The pathological features of the two tumors, including solid and pseudopapillary growth patterns with pale or eosinophilic cytoplasm, were characteristic of SPTs of the pancreas. However, in the case of the metastatic ovarian tumor, focal necrosis and an increased nuclear-to-cytoplasmic ratio were observed. The presence of positive nuclear-cytoplasmic beta-catenin, the loss of membranous E-cadherin expression, and a perinuclear punctate CD99 staining pattern on immunohistochemistical analysis, were essential features for diagnosis. The aim of the present study was to compare the morphological and immunohistochemical features of these tumors with those typical of pancreatic SPTs, and to raise awareness that SPTs are able to metastasize to unusual sites, and may also arise as primary tumors outside the pancreas, which may lead to diagnostic dilemmas. PMID- 27123294 TI - A case of juvenile polyposis of the stomach with multiple early gastric cancers. AB - The present study described the case of a 24-year-old man who was diagnosed with multiple gastric hyperplastic polyps in 2004. Repeated Helicobacter pylori tests were negative, and colonoscopy revealed no specific findings. The patient started taking a proton-pump inhibitor and iron supplements as a result of anemia caused from the occasional bleeding from the polyps. The number and size of the polyps had increased over time. Endoscopic mucosal resection was occasionally performed when bleeding occurred from large polyps. Finally, histological examination revealed that the surface of the polyp had been replaced with well-differentiated adenocarcinoma in 2014. Laparoscopy-assisted total gastrectomy with Roux-en-Y esophagojejunostomy was performed in 2014. The final diagnosis was juvenile polyposis of the stomach with multiple early gastric cancers. Juvenile polyposis of the stomach is a rare disease, and its malignant potential has been reported previously. The present case highlighted the importance of not delaying surgical intervention in cases of juvenile polyposis of the stomach, since it is associated with a high occurrence of gastric cancer. PMID- 27123295 TI - Malignant pleural and pericardial effusions and meningeal infiltrates without other metastases in breast cancer: A case report. AB - Breast cancer metastasizing to the pleura, pericardium and leptomeninges, but not to other sites, is rare. Although malignant pericardial and pleural effusions are common complications during the course of malignancies, they are rarely the initial manifestations of malignant disease, particularly pericardial effusion with cardiac tamponade. This report describes a case of breast carcinoma in a 44 year-old woman who initially presented with malignant pleural effusion and pericardial tamponade and suffered from meningeal metastases after 4.5 months. Unfortunately, the patient succumbed to pericardial tamponade 7 months later. There was no metastasis identified in other organs during the course of the disease. To the best of our knowledge, no similar case has been reported in the literature to date. PMID- 27123296 TI - Left adrenal gland metastasis of breast invasive ductal carcinoma: A case report. AB - The majority of the metastatic lesions of the adrenal gland normally originate from lung cancer, colon malignant tumor, renal cell carcinoma and melanoma. However, adrenal gland metastasis that metastasize from breast invasive ductal carcinoma are extremely rare. The present study reported a rare case of left adrenal gland metastasis in a 35-year-old female who was diagnosed as breast carcinoma 5 years ago with a mass located on the left adrenal gland, which was detected during a routine examination. The patient was asymptomatic and adrenal gland computed tomography revealed a mass in the left adrenal gland. Definitive preoperative diagnosis failed to be established. Left adrenal gland laparoscopic adrenalectomy was performed and the diagnosis of adrenal gland metastasis of breast invasive ductal carcinoma was confirmed by pathological and immunohistochemical examination. The patient remained in good condition by the time of writing. PMID- 27123297 TI - Surgical treatment of the primary tumour improves the overall survival in patients with metastatic breast cancer: A systematic review and meta-analysis. AB - Traditionally, stage IV metastatic breast cancer has been treated with systemic therapy and/or radiotherapy in order to decrease cancer-associated symptoms, maintain quality of life and control disease burden. Previous research suggests that surgical treatment of the primary tumour may prolong survival, as well achieve local control of disease. Using the PubMed and Ovid SP databases, a literature review and meta-analysis was performed in order to assess whether surgical resection of the primary tumour in metastatic breast cancer prolongs survival. In this meta-analysis, a pooled hazard ratio of 0.63 (95% confidence interval, 0.58-0.7; P<0.0001) was revealed, equating to a 37% reduction in risk of mortality in patients that underwent surgical resection of the primary tumour. Therefore, it was concluded that surgery of the primary tumour in stage IV breast cancer appears to offer a survival benefit in metastatic patients. PMID- 27123298 TI - Radiation-induced optic neuropathy following external beam radiation therapy for nasopharyngeal carcinoma: A retrospective case-control study. AB - Radiation-induced optic neuropathy (RION) is a severe ocular complication in patients with nasopharyngeal carcinoma (NPC) following external beam radiation therapy. However, the systemic risk factors for this condition remain unclear. Therefore, patients with NPC who received radiotherapy between 2004 and 2007 at the Sun Yat-Sen University Cancer Center were retrospectively reviewed in this case-control study. The study included 40 RION patients and 40 patients in the control group, who were strictly matched to the RION patients by tumor histopathology, location, Union for International Cancer Control-Tumor Node Metastasis classification and radiotherapy protocol. Univariate and multivariate statistical regression analyses were performed to identify factors predictive of RION. The univariate analysis demonstrated that age (>60 years), gender (female) and chemotherapy significantly affected the risk of RION, whereas diabetes, hypertension and hepatitis B virus infection did not exert a significant effect. The results of the multivariate analysis suggested that only gender and chemotherapy were significantly associated with an increased incidence of RION. Therefore, the results of the present study suggested that female gender and chemotherapy constitute risk factors for the development of RION following radiotherapy for NPC. The ocular symptoms of high-risk patients should be carefully investigated and reported by ophthalmologists. PMID- 27123299 TI - Effect of acid suppressants on the efficacy of tyrosine kinase inhibitors in patients with epidermal growth factor receptor-mutated non-small-cell lung cancer. AB - This retrospective study was conducted to evaluate whether oral acid suppressant (AS) therapy is associated with decreased efficacy of gefitinib and erlotinib, particularly in patients with mutated epidermal growth factor receptor (EGFR). A total of 46 consecutive patients with pathologically confirmed non-small-cell lung cancer (NSCLC), who were treated with tyrosine kinase inhibitors (TKIs) in two tertiary hospitals between September, 2005 and May, 2013, were retrospectively analyzed. Of the 46 patients, 11 received AS treatment. As regards age, gender, smoking history, performance status, histology of lung cancer, clinical stage, body surface area (BSA) and type of EGFR mutation, there were no statistically significant differences between patients with and those without AS treatment. There was no statistically significant difference in progression-free survival (PFS) or overall survival (OS) between the two groups of patients (P=0.296 and 0.613, respectively). As regards the relative dose of TKI/BSA and survival in patients with and those without AS treatment, there were no statistically significant differences in PFS and OS between the two groups of patients. Our study indicates that AS treatment may not compromise TKI efficacy (gefitinib or erlotinib) in NSCLC patients with mutated EGFR. Prospective studies and large-scale confirmation studies investigating the effect of AS co administration with TKIs in patients with mutated EGFR may be meaningful in clinical practice. PMID- 27123300 TI - Association of the CCDC26 rs4295627 polymorphism with the risk of glioma: Evidence from 7,290 cases and 11,630 controls. AB - Published data on the association between the coiled-coil domain-containing 26 (CCDC26) rs4295627 polymorphism and the risk of glioma have been inconclusive. To further investigate this association, a meta-analysis was performed. By a comprehensive literature search using PubMed and EMBASE databases, a total of 16 case-control studies were identified for inclusion in the meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess this association. Our results confirmed that the risk with allele G was higher compared with that with allele T for glioma. The results indicated that the allele G of rs4295627 polymorphism in the CCDC26 gene was associated with increased risk of glioma in the homozygote model (GG vs. TT, OR=1.936, 95 %CI: 1.500-2.658, P<0.001), the heterozygote model (GT vs. TT, OR=1.323, 95% CI: 1.241 1.412, P=0.206), the dominant model (GG+GT vs. TT, OR=1.375, 95% CI: 1.256-1.505, P=0.026), the recessive model (GG vs. GT+TT, OR=1.769, 95% CI: 1.302-2.403, P<0.001) and the allele model (G vs. T, OR=1.310, 95% CI: 1.185-1.448, P<0.001). Current evidence suggests that the rs4295627 polymorphism in the CCDC26 gene may contribute to glioma susceptibility. However, further case-control studies are required to confirm our results. PMID- 27123301 TI - Prevalence and treatment of small intestinal bacterial overgrowth in postoperative patients with colorectal cancer. AB - To investigate the prevalence of small intestinal bacterial overgrowth (SIBO) in patients with colorectal cancer (CRC) after surgical treatment and observe whether gastrointestinal symptoms may improve with rifaximin, 43 postoperative CRC patients (CRC group) and 30 healthy individuals (normal group) were subjected to the glucose hydrogen breath test (GHBT). All the patients were asked to evaluate the gastrointestinal symptoms using the visual analogue scale (VAS). SIBO-positive patients were administered rifaximin for 10 days on the basis of the original treatment. After the treatment, the patients were asked to undergo GHBT and re-evaluate the gastrointestinal symptoms score (GISS). The results demonstrated that 18 of the 43 postoperative patients with CRC were SIBO-positive (41.86%), which was significantly higher compared with the incidence in normal controls (6.67%) (P<0.05). GISS was higher in SIBO-positive patients (P<0.05). Following rifaximin treatment, 6 of the 18 (33.33%) SIBO-positive patients had improved, as evaluated by GHBT and VAS. Additionally, the GISS in the SIBO-turned negative group had improved significantly compared with that in the non-turned negative group (P<0.05). The symptoms of all 18 SIBO-positive patients following rifaximin treatment improved notably, particularly diarrhea (P<0.05). In conclusion, postoperative CRC patients are more likely to develop SIBO compared with healthy individuals, and SIBO may aggravate digestive symptoms. The administration of rifaximin improved the overall gastrointestinal symptoms, particularly diarrhea, in SIBO-positive patients. PMID- 27123302 TI - Computed tomography and magnetic resonance imaging findings of malignant fibrous histiocytoma of the head and neck. AB - The aim of this study was to analyze the imaging findings of 15 cases of malignant fibrous histiocytoma (MFH) of the head and neck, in order to better understand the tumor characteristics based on computed tomography (CT) and magnetic resonance imaging (MRI). CT (n=11) and MRI (n=4) images from 15 patients with histologically diagnosed MFH of the head and neck were retrospectively analyzed. The imaging characteristics were analyzed and compared among different histological subtypes. The lesions were primarily located in the maxillary sinus in 5 patients, the ethmoid sinus in 1 patient, the infratemporal fossa in 2 patients, the neck in 4 patients, the left mandible in 1 patient, the gingiva in 1 patient and the epiglottis in 1 patient. A total of 4 cases were associated with radiotherapy. All the lesions were ill-defined, ranging in size from 2.1 to 5.1 cm in the largest diameter. Bone fractures were evident in 9 cases. The attenuation, signal and enhancement patterns varied, although inflammatory MFH exhibited prolonged enhancement in dual-phase enhanced CT scans. MFH of the head and neck is rare but may be associated with radiotherapy. Although the imaging manifestations of MFH are various and non-specific, inflammatory MFH exhibits prolonged enhancement on dual-phase enhanced CT scans. PMID- 27123303 TI - Effect of oncological treatment on serum adipocytokine levels in patients with stage II-III breast cancer. AB - Adipose tissue-derived hormones (adipocytokines), such as adiponectin, leptin, resistin and visfatin, and the pancreatic hormone insulin, have been suggested to play a role in carcinogenesis. we therefore hypothesized that the oncological treatment of breast cancer may alter the serum levels of these adipocytokines and insulin. In this study, we aimed to compare the serum levels of adipocytokines and insulin between the pre- and post-treatment period in patients with breast cancer. In this prospective study, 20 consecutive patients with stage II and III breast cancer underwent breast-conserving surgery or total mastectomy and/or axillary dissection. The patients received adjuvant chemotherapy and radiotherapy, if necessary. Blood samples were obtained during the preoperative period and postoperatively after completion of the adjuvant therapy. There was no statistically significant difference between the pre- and post-treatment levels of visfatin, adiponectin and leptin. However, the serum insulin and resistin levels and insulin resistance were found to be statistically significantly increased following treatment (P<0.05). Post-treatment resistin levels were positively correlated with insulin resistance (r=0.45, P<0.05). Therefore, oncological treatment of stage II and III breast cancer did not affect visfatin, adiponectin and leptin levels, but statistically significantly increased resistin levels and insulin resistance. In addition, the post-treatment resistin levels were positively correlated with insulin resistance, suggesting that resistin may be involved in the development of insulin resistance in breast cancer patients following treatment. PMID- 27123304 TI - Targeted temperature management in traumatic brain injury. AB - Traumatic brain injury (TBI) is recognized as the significant cause of mortality and morbidity in the world. To reduce unfavorable outcome in TBI patients, many researches have made much efforts for the innovation of TBI treatment. With the results from several basic and clinical studies, targeted temperature management (TTM) including therapeutic hypothermia (TH) have been recognized as the candidate of neuroprotective treatment. However, their evidences are not yet proven in larger randomized controlled trials (RCTs). The main aim of this review is thus to clarify specific pathophysiology which TTM will be effective in TBI. Historically, there were several clinical trials which compare TH and normothermia. Recently, two RCTs were able to demonstrate the significant beneficial effects of TTM in one specific pathology, patients with mass evacuated lesions. These suggested that TTM might be effective especially for the ischemic reperfusional pathophysiology of TBI, like as acute subdural hematoma which needs to be evacuated. Also, the latest preliminary report of European multicenter trial suggested the promising efficacy of reduction of intracranial pressure in TBI. Conclusively, TTM is still in the center of neuroprotective treatments in TBI. This therapy is expected to mitigate ischemic and reperfusional pathophysiology and to reduce intracranial pressure in TBI. Further results from ongoing clinical RCTs are waited. PMID- 27123305 TI - Traumatic brain injury: pathophysiology for neurocritical care. AB - Severe cases of traumatic brain injury (TBI) require neurocritical care, the goal being to stabilize hemodynamics and systemic oxygenation to prevent secondary brain injury. It is reported that approximately 45 % of dysoxygenation episodes during critical care have both extracranial and intracranial causes, such as intracranial hypertension and brain edema. For this reason, neurocritical care is incomplete if it only focuses on prevention of increased intracranial pressure (ICP) or decreased cerebral perfusion pressure (CPP). Arterial hypotension is a major risk factor for secondary brain injury, but hypertension with a loss of autoregulation response or excess hyperventilation to reduce ICP can also result in a critical condition in the brain and is associated with a poor outcome after TBI. Moreover, brain injury itself stimulates systemic inflammation, leading to increased permeability of the blood-brain barrier, exacerbated by secondary brain injury and resulting in increased ICP. Indeed, systemic inflammatory response syndrome after TBI reflects the extent of tissue damage at onset and predicts further tissue disruption, producing a worsening clinical condition and ultimately a poor outcome. Elevation of blood catecholamine levels after severe brain damage has been reported to contribute to the regulation of the cytokine network, but this phenomenon is a systemic protective response against systemic insults. Catecholamines are directly involved in the regulation of cytokines, and elevated levels appear to influence the immune system during stress. Medical complications are the leading cause of late morbidity and mortality in many types of brain damage. Neurocritical care after severe TBI has therefore been refined to focus not only on secondary brain injury but also on systemic organ damage after excitation of sympathetic nerves following a stress reaction. PMID- 27123306 TI - Targeted temperature management for adult out-of-hospital cardiac arrest: current concepts and clinical applications. AB - Targeted temperature management (TTM) (primarily therapeutic hypothermia (TH)) after out-of-hospital cardiac arrest (OHCA) has been considered effective, especially for adult-witnessed OHCA with a shockable initial rhythm, based on pathophysiology and on several clinical studies (especially two randomized controlled trials (RCTs) published in 2002). However, a recently published large RCT comparing TTM at 33 degrees C (TH) and TTM at 36 degrees C (normothermia) showed no advantage of 33 degrees C over 36 degrees C. Thus, this RCT has complicated the decision to perform TH after cardiac arrest. The results of this RCT are sometimes interpreted fever control alone is sufficient to improve outcomes after cardiac arrest because fever control was not strictly performed in the control groups of the previous two RCTs that showed an advantage for TH. Although this may be possible, another interpretation that the optimal target temperature for TH is much lower than 33 degrees C may be also possible. Additionally, there are many points other than target temperature that are unknown, such as the optimal timing to initiate TTM, the period between OHCA and initiating TTM, the period between OHCA and achieving the target temperature, the duration of maintaining the target temperature, the TTM technique, the rewarming method, and the management protocol after rewarming. RCTs are currently underway to shed light on several of these underexplored issues. In the present review, we examine how best to perform TTM after cardiac arrest based on the available evidence. PMID- 27123308 TI - Pituitary apoplexy causing spontaneous remission of acromegaly following long acting octreotide therapy: a rare drug side effect or just a coincidence. AB - Pituitary apoplexy is characterized by abrupt onset of haemorrhage or non haemorrhagic infarction of a pituitary adenoma. The clinical features include acute onset severe headache, visual field defects, meningeal irritation, ophthalmoplegia and hypopituitarism. The pituitary apoplexy may be clinically silent in ~25% of patients. We report a case of acromegaly due to pituitary macroadenoma. The patient was started on long-acting octreotide therapy. On 3 month follow-up, the patient showed clinical and biochemical remission and the magnetic resonance imaging (MRI) of the brain showed subclinical haemorrhage and resolution of tumour. The octreotide therapy was stopped. On 6-month follow-up, the patient was still in remission and the MRI of brain revealed non-enhancing mixed intensities haemorrhagic and cystic areas of the pituitary gland. In our patient, whether spontaneous remission of acromegaly due to subclinical pituitary haemorrhage was coincidental or due to long-acting octreotide therapy is still a dilemma. We report this case because of rarity and clinical importance of this unusual occurrence. PMID- 27123309 TI - Thoracic aortic aneurysm: a late complication of coarctation repair. PMID- 27123307 TI - Brain injury following cardiac arrest: pathophysiology for neurocritical care. AB - Cardiac arrest induces the cessation of cerebral blood flow, which can result in brain damage. The primary intervention to salvage the brain under such a pathological condition is to restore the cerebral blood flow to the ischemic region. Ischemia is defined as a reduction in blood flow to a level that is sufficient to alter normal cellular function. Brain tissue is highly sensitive to ischemia, such that even brief ischemic periods in neurons can initiate a complex sequence of events that may ultimately culminate in cell death. However, paradoxically, restoration of blood flow can cause additional damage and exacerbate the neurocognitive deficits in patients who suffered a brain ischemic event, which is a phenomenon referred to as "reperfusion injury." Transient brain ischemia following cardiac arrest results from the complex interplay of multiple pathways including excitotoxicity, acidotoxicity, ionic imbalance, peri-infarct depolarization, oxidative and nitrative stress, inflammation, and apoptosis. The pathophysiology of post-cardiac arrest brain injury involves a complex cascade of molecular events, most of which remain unknown. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. Mitochondrial dysfunction based on the mitochondrial permeability transition after reperfusion, particularly involving the calcineurin/immunophilin signal transduction pathway, appears to play a pivotal role in the induction of neuronal cell death. The aim of this article is to discuss the underlying pathophysiology of brain damage, which is a devastating pathological condition, and highlight the central signal transduction pathway involved in brain damage, which reveals potential targets for therapeutic intervention. PMID- 27123310 TI - Polyarteritis nodosa. Diagnostic challenges in a patient with cutaneous vasculitis, psoriasis, psoriatic arthritis and pancytopenia: fatal progression after treatment with G-CSF. AB - A 60-year-old man presented with cutaneous vasculitis, leucopenia and psoriasis. He was treated initially with ciclosporin A. On withdrawal of ciclosporin, due to inadequate improvement of cutaneous vasculitis, he developed psoriatic arthritis. Worsening neutropenia and pancytopenia, believed to be immune mediated, developed. He was treated with prednisolone, methotrexate and adalimumab but developed pneumocystis pneumonia. Leucocyte levels improved markedly with granulocyte colony-stimulating factor (G-CSF). However, whilst being treated with G-CSF his condition deteriorated. He developed gastrointestinal and neurological symptoms and progressive weight loss. Diagnosis was delayed, but eventually polyarteritis nodosa was diagnosed and he was treated with cyclophosphamide. The patient improved initially but died from small bowel perforation due to vasculitis. Evidence showing a temporal association of his deterioration with use of G-CSF is shown. The use of G-CSF in patients with autoimmune conditions including vasculitis should be undertaken with great caution. PMID- 27123311 TI - Sequential occurrence of anti-glomerular basement membrane disease 9 years after anti-neutrophil cytoplasmic antibody-associated vasculitis. AB - We report a case of 63-year-old Chinese man, having a history of anti myeloperoxidase (MPO) antibody anti-neutrophil cytoplasmic antibody (ANCA) associated pulmonary-renal syndrome 9 years ago, presented with second episode of rapidly progressive glomerulonephritis (RPGN) and alveolar haemorrhage compatible with anti-glomerular basement membrane (GBM) disease. In first presentation, his anti-GBM antibody was negative. This time, anti-MPO antibody was negative, but anti-GBM antibody was positive. The long interval of sequential development of anti-GBM disease after ANCA-associated vasculitis in this patient may provide clues to the potential immunological links between these two distinct conditions. Clinicians should be aware of such double-positive association. PMID- 27123312 TI - Behcet's pulmonary artery aneurysms treated with infliximab and monitored with the 6-min walk test. AB - Pulmonary involvement in Behcet's disease (BD) is uncommon; however, it is potentially fatal due to the risk of massive haemoptysis. We describe the case of a 36-year-old male presenting with a 2-month history of worsening dyspnoea, weight loss, haemoptysis, oral ulceration, erythema nodosum and superficial thrombophlebitis. He was diagnosed with pulmonary vasculitis secondary to BD; however, his symptoms were refractory to initial treatment with cyclophosphamide, azathioprine and prednisolone. We therefore trialled infliximab alongside methotrexate, which led to a remarkable improvement in his condition, enabling eventual discontinuation of prednisolone. Whilst not being one of the treatments currently recommended for managing pulmonary involvement in BD, infliximab has previously been successfully used in cases refractory to conventional therapy. We used the 6-min walk test (distance covered and lowest oxygen saturations) to monitor his progress, which correlated with his symptoms. This may represent a useful adjunct in monitoring the activity of pulmonary vasculitis. PMID- 27123313 TI - Efficacy and safety of fondaparinux versus enoxaparin in patients undergoing percutaneous coronary intervention treated with the glycoprotein IIb/IIIa inhibitor tirofiban. AB - BACKGROUND: In worldwide, the mortality rate of acute myocardial infarction (AMI) raises year by year. Although the applications of percutaneous coronary intervention (PCI) and anticoagulants effectively reduce the mortality of patients with acute coronary syndrome (ACS), but also increase the incidence of bleeding. Therefore, drugs with stable anticoagulant effects are urgently required. METHODS: We enrolled 894 patients with acute coronary syndrome who underwent percutaneous coronary intervention in Shenyang Northern Hospital from February 2010 to May 2012; 430 patients were included in the fondaparinux group (2.5 mg/d), and 464 were included in the enoxaparin group (1 mg/kg twice daily). Fondaparinux and enoxaparin were applied for 3-7 days. All patients were treated with tirofiban (10 MUg/kg for 3 min initially and 0.15 MUg/(kg . min) for 1 to 3 days thereafter). The primary efficacy endpoint was the incidence of a major adverse cerebrovascular or cardiovascular event. The primary safety endpoint was bleeding within 30 days and 1 year after percutaneous coronary intervention. RESULTS: One-year data were available for 422 patients in the fondaparinux group and for 453 in the enoxaparin group. The incidence of a major adverse cerebrovascular or cardiovascular event (10.9 % vs 12.6 %, P = 0.433) and cardiac mortality (0.5 % vs 1.5 %, P = 0.116) were generally lower in the fondaparinux group than in the enoxaparin group, although the differences were not significant. Compared with the enoxaparin group, the fondaparinux group had a significantly decreased rate of bleeding at 30 days (0.9 % vs 2.8 %) and 1 year (2.4 % vs 5.4 %). In addition, the rate of major bleeding events was lower in the fondaparinux group, but this difference was not significant (0.2 % vs 0.9 %, 0.2 % vs 1.1 %). CONCLUSIONS: In tirofiban-treated patients with acute coronary syndrome undergoing percutaneous coronary intervention, fondaparinux presented similar efficacy for ischemia events as enoxaparin. However, fondaparinux significantly decreased the incidence of bleeding, thus providing safer anticoagulation therapy. PMID- 27123314 TI - Effects of internal iliac artery embolization on systemic inflammatory response syndrome in dogs with simulated-pelvic-fracture combined with massive bleeding. AB - BACKGROUND: Pelvic fracture combined with massive bleeding (PFCMB) is a complex issue in clinical practice. Currently, the use of angiography and embolization for the treatment of PFCMB obtains good results. The aim of this study is to observe the effects of early internal iliac artery embolization on the SIRS in dogs with simulated-pelvic-fracture combined with massive bleeding. METHODS: Twenty adult dogs were randomly divided into an embolization group (EG) and a control group (CG). For the two groups, heart rate, respiratory rate and body temperature and other physiological variables were measured, and IL-6, TNF-alpha and arterial blood gas levels were monitored. These variables were assayed every 30 min until death in the CG, while dogs in the EG underwent arterial angiography after 60 min of modeling. The internal iliac artery was embolized on the injured side. RESULTS: The average time to SIRS in the CG was 3.56 h, occurring at a rate of 90 % (9/10) within 24 h, with a mortality rate of 50 % (5/10); the average time to SIRS for the EG was 5.33 h, occurring at a rate of 30 % (3/10) within 24 h, with a mortality rate of 10 % (1/10). When SIRS occurred in the EG, the mean plasma IL-6 level was 52.66 +/- 7.38 pg/ml and the TNF-alpha level was 11.45 +/- 2.72 ng/ml, showing a significant difference with those of the CG (P < 0.05). In the two groups, the respiratory rate and leukocyte levels were higher at each monitored time after modeling than those before modeling; the mean arterial pressure, levels of hemoglobin and oxygen partial pressure were significantly lower at each time point after modeling than those before modeling except for the mean arterial pressure at 0 h in EG; the platelet levels at 4 and 8 h were higher than those before modeling; and the differences were statistically significant (P < 0.05). In the EG, the mean arterial pressure, heart rate, respiratory rate and hemoglobin levels at 2 , 4 and 8 h were lower than those at 0 h; the levels of leukocytes, platelets and carbon dioxide partial pressure at 4 and 8 h after modeling were higher than those at 0 h, and the differences were statistically significant (P < 0.05, P < 0.01); in the CG after modeling, the mean arterial pressure, levels of hemoglobin and carbon dioxide partial pressure at 2, 4 and 8 h were lower than those at 0 h; the levels of heart rate and leukocytes were higher than those before modeling; the respiratory rate and platelet levels at 4 and 8 h were higher than those at 0 h; and the differences were statistically significant (P < 0.05). The levels of the mean arterial pressure and hemoglobin at 4 and 8 h and the pH values at 8 h after modeling in the EG were significantly higher than those in the CG, while the heart rate and respiratory rate at 4 and 8 h were significantly lower than those in the CG. The pH values at 8 h after modeling were significantly lower than those of the other monitored times in the CG (P < 0.05, P < 0.01). The two groups had elevated levels of alkaline phosphatase after injury induction. CONCLUSION: Through the use of an on-spot interventional treatment cabin, early internal iliac artery embolization can control bleeding associated with pelvic fractures, delay the occurrence of SIRS, and improve the success rate of the treatment of pelvic fracture combined with bleeding. PMID- 27123315 TI - Clinical outcomes and antiretroviral therapy in 'elite' controllers: a review of the literature. AB - Elite controllers naturally suppress HIV viraemia below the level of detection using standard methods, but demonstrate persistent inflammation and low-level viraemia that is detectable via ultrasensitive assays. These factors may contribute to an increased risk of non-AIDS-related morbidity and mortality among elite controllers. Data suggest that cardiovascular disease may be of particular concern in elite controllers, as evidenced by an increased burden of subclinical cardiovascular disease upon radiographic screening and an elevated rate of hospitalisations for cardiovascular disease as compared to non-controllers who are treated with antiretroviral therapy (ART). Widespread use of ART among non controllers has led to significant declines in morbidity and mortality, but guidelines are generally silent on the role of ART in the care of elite controllers. Multiple small studies have demonstrated that laboratory markers of inflammation, immune activation and HIV burden improve after initiation of ART in elite controllers. Clinicians must consider these potential benefits of ART when deciding whether to initiate treatment in asymptomatic elite controllers. PMID- 27123317 TI - Multiparametric MRI of the prostate: the hope for the urology community. PMID- 27123316 TI - Multiparametric MRI and targeted prostate biopsy: Improvements in cancer detection, localization, and risk assessment. AB - INTRODUCTION: Multiparametric-MRI (mp-MRI) is an evolving noninvasive imaging modality that increases the accurate localization of prostate cancer at the time of MRI targeted biopsy, thereby enhancing clinical risk assessment, and improving the ability to appropriately counsel patients regarding therapy. MATERIAL AND METHODS: We used MEDLINE/PubMed to conduct a comprehensive search of the English medical literature. Articles were reviewed, data was extracted, analyzed, and summarized. In this review, we discuss the mp-MRI prostate exam, its role in targeted prostate biopsy, along with clinical applications and outcomes of MRI targeted biopsies. RESULTS: Mp-MRI, consisting of T2-weighted imaging, diffusion weighted imaging, dynamic contrast-enhanced imaging, and possibly MR spectroscopy, has demonstrated improved specificity in prostate cancer detection as compared to conventional T2-weighted images alone. An MRI suspicion score has been developed and is depicted using an institutional Likert or, more recently, a standardized reporting scale (PI-RADS). Techniques of MRI-targeted biopsy include in-gantry MRI guided biopsy, TRUS-guided visual estimation biopsy, and software co-registered MRI-US guided biopsy (MRI-US fusion). Among men with no previous biopsy, MRI-US fusion biopsy demonstrates up to a 20% increase in detection of clinically significant cancers compared to systematic biopsy while avoiding a significant portion of low risk disease. These data suggest a potential role in reducing over-detection and, ultimately, over-treatment. Among men with previous negative biopsy, 72-87% of cancers detected by MRI targeted biopsy are clinically significant. Among men with known low risk cancer, repeat biopsy by MR-targeting improves risk stratification in selecting men appropriate for active surveillance secondarily reducing the need for repetitive biopsy during surveillance. CONCLUSIONS: Use of mp-MRI for targeting prostate biopsies has the potential to reduce the sampling error associated with conventional biopsy by providing better disease localization and sampling. MRI-ultrasound fusion-targeted prostate biopsy may improve the identification of clinically significant prostate cancer while limiting detection of indolent disease, ultimately facilitating more accurate risk stratification. Literature supports the clinical applications of MRI targeted biopsy in men who have never been biopsied before, those with a prior negative biopsy, and those with low risk disease considering active surveillance. PMID- 27123318 TI - The limitations of multiparametric magnetic resonance imaging also must be borne in mind. PMID- 27123319 TI - AUTHOR'S REPLY. PMID- 27123320 TI - Laparoscopic radical cystectomy with prostate capsule sparing. Initial experience. AB - INTRODUCTION: In 2008, our department introduced a modified technique of laparoscopic radical cystectomy in which the prostatic capsule is spared in selected patients with bladder cancer. The different series published are mostly using the standard open procedure. The aim of this study is to describe this technique using the laparoscopic approach and present our preliminary results. MATERIAL AND METHODS: This study includes 20 patients selected by clinical analysis and imaging criteria operated using laparoscopic radical cystectomy with prostate capsule sparing at our department in the period between 2008 and 2012. RESULTS: Patient mean age was 58 years. Mean operative time was 390 minutes. Median follow-up was 36 months. No patient had bladder cancer recurrence. Only one patient died of disease progression, as the pathological findings was a pT3 pN1 Mx. Mean PSA before surgery: 1.3 ng/ml (03-2), mean PSA after surgery 1.0 ng/ml (0.08-1.7). No patients had prostate cancer recurrence. Satisfactory daytime and night-time continence was achieved. 90% of patients have sexual function preserved. CONCLUSIONS: Prostate-sparing radical cystectomy remains one of the most controversial topics in urology today. The laparoscopic approach could be an alternative to conventional radical cystoprostatectomy in well selected patients, done in experienced institutions in order to find better functional results, with a low disease progression and recurrence rate. PMID- 27123321 TI - Prostate capsule sparing radical cystectomy - a safe procedure for few. PMID- 27123322 TI - AUTHOR'S REPLY. PMID- 27123323 TI - Controversies in the management of clinical stage I testicular seminoma. AB - INTRODUCTION: Following orchiectomy patients with clinical stage I (CSI) testicular seminoma may be managed by active surveillance (AS) or adjuvant treatment (radiotherapy or chemotherapy). In view of the published data on long term toxicity, mainly second malignant neoplasms (SMNs), adjuvant radiotherapy (ART) is currently no longer recommended as adjuvant therapy for these patients. The purpose of our recent study was to compare the impact of two selected treatment approaches - AS versus adjuvant chemotherapy (ACT) on survival in patients with CSI testicular seminoma. MATERIAL AND METHODS: The cross-sectional study analyzed a total of 106 patients collected at a single centre between 4/2008-8/2015, with CSI testicular seminoma, stratified into two groups according to risk-adapted therapeutic approaches. RESULTS: In group A (low-risk), consisting of 84 patients, who underwent AS, relapse occurred in 10 (11.9%) patients after a mean follow-up of 13.8 months. In group B (high-risk), consisting of 22 patients, who were treated with ACT, relapse occurred in two (9.1%) patients after a mean follow-up of 13.8 months. Overall survival of patients in both groups was 100% with a mean follow-up of 25.3 months. The statistically significant difference in progression-free survival (PFS) between these two groups was not found. CONCLUSIONS: ACT seems to be adequate treatment for patients with high-risk of relapse, as well as AS for those with low-risk of relapse. Despite its excellent prognosis, optimal management of CSI testicular seminoma remains controversial, with variations in expert opinion and international guidelines. PMID- 27123324 TI - Best treatment option for clinical stage I seminoma patients. PMID- 27123325 TI - The detection and upgrade rates of prostate adenocarcinoma following transperineal template-guided prostate biopsy - a tertiary referral centre experience. AB - INTRODUCTION: We aim to present transperineal template-guided prostate biopsy (template biopsy) outcomes at a tertiary referral centre. Furthermore, to identify the detection rate of prostate cancer in those with a previous negative transrectal ultrasound guided prostate biopsy and the upgrade rate of those on active surveillance for Gleason 3 + 3 = 6 prostate adenocarcinoma. MATERIAL AND METHODS: We conducted a prospective study of 200 consecutive men who underwent template biopsy over a 22-month period in a tertiary referral centre, using a standard 24 region template prostate biopsy technique. Indications and histology results, as well as complications, were recorded. RESULTS: Median age was 67 years and median PSA was 10 ng/mL. Overall detection rate was 47%. 39.5% of cases with previous negative transrectal biopsies were found to have prostate adenocarcinoma. 47.5% of cases on active surveillance for Gleason 3 + 3 = 6 prostate adenocarcinoma were upgraded. The most frequent complication was acute urinary retention at a rate of 12.5%, however, the use of a single prophylactic dose of tamsulosin was found to be beneficial, with 13 cases needed to treat to prevent one episode. CONCLUSIONS: Template biopsies are safe and efficacious with an overall detection rate of 47% in the present series. Due to the high detection rate, one must consider template biopsy following one negative transrectal biopsy where there is persistent clinical suspicion. Furthermore, those considering active surveillance for Gleason 3 + 3 = 6 disease should be offered template biopsy to confirm the grade of their disease. PMID- 27123326 TI - Oncological results at 2 years after robotic radical prostatectomy - the Romanian experience. AB - INTRODUCTION: To assess the oncological outcomes of robotic radical prostatectomy in a country where there are no on-going national screening programs for prostate cancer. MATERIAL AND METHODS: Between November 2009 and November 2014, 220 robotic radical prostatectomies were performed at our Robotic Surgery Center. We already have the complete data for the 2-year follow-up of the first 105 patients, who were therefore included in the study group. Pre-operative (age, prostate-specific antigen, body-mass index, prostate volume, clinical staging, biopsy characteristics), post-operative (surgical technique, surgical margin status, lymph node status, pathological stage, Gleason score) and follow-up parameters (biochemical recurrence) were assessed. RESULTS: The global rate of positive surgical margins was 34.3%, with rates of 17.2% in stage pT2 and 55.3% in stage pT3. The most frequent localization for positive surgical margins was at the base and apex of the prostate. The positive surgical margins rate was correlated with the pre-operative prostate-specific antigen, clinical and pathological Gleason score, lymph node status and the number of positive biopsy cores. The rate of biochemical recurrence at the 2-year follow-up was 11.8%. The most important predictors for the biochemical recurrence were the positive surgical margins, pathological staging and Gleason score on the prostatectomy specimen. CONCLUSIONS: Robotic surgery is validated by the oncological results at medium follow-up (2 years) for localized and locally advanced prostate cancer, even in countries where there is no on-going national screening program. PMID- 27123327 TI - Quality of life in a population of Polish patients with prostate cancer. AB - INTRODUCTION: Recent advances in treatment have led to the prolongation of life among patients with prostate cancer (PCa), which implies greater interest in the issue of the quality of life (QoL) in patients who undergo treatment. The quality of life of patients with cancer questionnaire (QLQ-C30) and the quality of life questionnaire specific to PCa (QLQ-PR25) are tools used worldwide to conduct research on this subject. In our study we assessed the quality of life in a population of Polish patients suffering from prostate cancer. Differences in the quality of life depending on the stage of the disease were highlighted. MATERIAL AND METHODS: We conducted a prospective, multicenter, observational study using the QLQ-C30 and QLQ-PR25 questionnaires in a group of 1047 patients. RESULTS: The highest QoL scores (according to the QLQ-C30 questionnaire) were observed in patients with localized prostate cancer, while the lowest were recorded in the metastatic group. Sexual activity and sexual functioning assessed on the basis of QLQ-PR25 was best in the group of patients suffering from localized prostate cancer, and the worst in patients with locally advanced PCa. CONCLUSIONS: The assessment of QoL showed a significant correlation with the stage of the disease. Sexual activity and sexual functioning were the best in patients with localized cancer; worst among patients with locally advanced tumor. PMID- 27123328 TI - Clinicopathological prognostic factors for upper tract urothelial carcinoma. AB - INTRODUCTION: The aim of the present study was to evaluate the influence of clinicopathological factors including age, gender, tumor grade, tumor stage, lymphovascular invasion (LVI), tumor necrosis and previous history of non-muscle invasive bladder cancer on outcomes of patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). MATERIAL AND METHODS: A total of 60 patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma at our institute between 2005 to 2012 were included in our study. Univariate and multivariate analysis was performed using the Kaplan-Meier method, log rank statistics, the chi-square test and Cox regression models. RESULTS: The mean length of follow-up time was 33.3 months. There were 27 (45%) patients alive with the disease, whereas 33 (55%) were dead. In 19 cases (31.7%) the tumor grade was low, while in 41 cases (68.3%) it was high. Lymphovascular invasion was observed in 28 (46.7%) cases. Tumor necrosis was registered in 14 patients (23.3%). From the patients with LVI, 3 (9.6%) were alive, whereas from the patients negative for LVI, 75% were alive. Significant relationship was found between gender and grading and between positive LVI and low grading. CONCLUSIONS: Day case Variables such as gender, grading, tumor stage, LVI and tumor necrosis were all demonstrated to be significant independent prognostic factors for the overall survival. On the multivariate analysis only LVI remained statistically significant, which may explain the different clinical course in patients and could be considered as a part of pathological reporting and treatment planning for the future. PMID- 27123329 TI - Microvascular density and immunohistochemical expression of VEGF, VEGFR-1 and VEGFR-2 in benign prostatic hyperplasia, high-grade prostate intraepithelial neoplasia and prostate cancer. AB - INTRODUCTION: The aim of our study was to determine and compare angiogenesis in benign prostatic hyperplasia (BPH), high-grade prostate intraepithelial neoplasia (HGPIN) and prostate cancer (Pca). Moreover, we evaluated its role as a prognostic factor for Pca. MATERIAL AND METHODS: We examined 39, 12 and 51 samples of BPH, HGPIN and Pca, respectively. Immunohistochemical methods were applied in order to evaluate the expression of VEGF and its receptors (VEGFR-1, VEGFR-2), while microvascular density (MVD) was determined using CD105. In Pca samples, we recorded stage, differentiation, perineural invasion, adjuvant radiotherapy and their correlation with angiogenesis. RESULTS: 225 The expression of VEGF, VEGFR-1 and VEGFR-2 was significantly higher in Pca than compared to BPH (p <0.001, p <0.001 and p <0.001, respectively) and HGPIN (p <0.001, p <0.001 and p = 0.04, respectively), while there was no difference between BPH and HGPIN. MVD was higher in Pca compared to BPH (p <0.001) and HGPIN (p <0.01), while there was no difference between BPH and HGPIN. VEGF expression and MVD were significantly greater in Pca samples with poor differentiation (p = 0.044 and p = 0.038, respectively) and perineural invasion (p <0.001 and p = 0.019, respectively), while overexpression of VEGF was associated with advanced pathological stage (p = 0.047). CONCLUSIONS: Angiogenesis is more prominent in Pca than in BPH and HGPIN, while there is no difference between BPH and HGPIN. Pharmaceutical inhibition of angiogenesis could be a valuable therapeutic option for Pca in the near future. PMID- 27123330 TI - A snapshot of the adult spina bifida patient - high incidence of urologic procedures. AB - INTRODUCTION: To describe the urologic outcomes of contemporary adult spina bifida patients managed in a multidisciplinary clinic. MATERIAL AND METHODS: A retrospective chart review of patients seen in our adult spina bifida clinic from January 2004 to November 2011 was performed to identify urologic management, urologic surgeries, and co-morbidities. RESULTS: 225 patients were identified (57.8% female, 42.2% male). Current median age was 30 years (IQR 27, 36) with a median age at first visit of 25 years (IQR 22, 30). The majority (70.7%) utilized clean intermittent catheterization, and 111 patients (49.3%) were prescribed anticholinergic medications. 65.8% had urodynamics performed at least once, and 56% obtained appropriate upper tract imaging at least every other year while under our care. 101 patients (44.9%) underwent at least one urologic surgical procedure during their lifetime, with a total of 191 procedures being performed, of which stone procedures (n = 51, 26.7%) were the most common. Other common procedures included continence procedures (n = 35, 18.3%) and augmentation cystoplasty (n = 29, 15.2%). Only 3.6% had a documented diagnosis of chronic kidney disease and 0.9% with end-stage renal disease. CONCLUSIONS: Most adult spina bifida patient continue on anticholinergic medications and clean intermittent catheterization. A large percentage of patients required urologic procedures in adulthood. Patients should be encouraged to utilize conservative and effective bladder management strategies to reduce their risk of renal compromise. PMID- 27123331 TI - Continuous positive airway pressure therapy is associated with improvement in overactive bladder symptoms in women with obstructive sleep apnea syndrome. AB - INTRODUCTION: To evaluate the impact of continuous positive airway pressure (CPAP) therapy on overactive bladder (OAB) symptoms in women with obstructive sleep apnea syndrome (OSAS). MATERIAL AND METHODS: One-hundred and fifty women underwent an overnight polysomnography study between May 2014 and September 2014. Their voiding symptoms were evaluated using the OAB symptom score (OABSS) and International Consultation on Incontinence Questionnaire Short-Form at OSAS diagnosis and approximately 3-months after CPAP therapy. OSAS severity was assessed according to the apnea-hypopnea-index. RESULTS: We evaluated 140 women and 111 of them (79.3%) reported symptoms consistent with OAB. There were no statistically significant differences between OSAS severity with a prevalence of OAB (p = 0.92). The prevalence of urinary incontinence (UI) was 35.7% (n = 50) and 39.6% (n = 44) in all patients and patients with OAB, respectively. There were no statistically significant differences between UI with OAB (p = 0.58). Baseline OABSS is comparable between OSAS severity (p = 0.143). After 3-months CPAP therapy, OABSS and ICIQ-SF sum scores were significantly decreased in patients with severe and moderate OSAS (p <0.01), however, change of OABSS sum score was insignificant in patients with mild OSAS (p = 0.44). CONCLUSIONS: CPAP therapy improves the OAB, OABSS and ICIQ-SF scores in women with severe and moderate OSAS. OSAS-induced OAB may be alleviated following CPAP therapy. PMID- 27123332 TI - Outcomes of ureteroscopy for patients with stones in a solitary kidney: evidence from a systematic review. AB - INTRODUCTION: Management of urolithiasis in a solitary functioning kidney can be clinically challenging. The aim of this article was to review the outcomes of URS for patients with stone disease in a solitary kidney and critically appraise the existing evidence and outcome reporting standards. MATERIAL AND METHODS: We conducted a systematic review in line with PRISMA checklist and Cochrane guidelines between January 1980 and February 2015. Our inclusion criteria were all English language articles reporting on a minimum of 10 patients with a solitary kidney undergoing ureteroscopy for stone disease. RESULTS: A total of 116 patients (mean age 50 years) underwent URS for stones in solitary kidney. For a mean stone size of 16.8 mm (range: 5-60 mm) and 1.23 procedures/patient, the mean stone free rate was 87%. No significant change in renal function was recorded in any of the studies although a transient elevation in creatinine was reported in 10 (8.6%) patients. A total of 33 (28%) complications were recorded a majority (n = 21) of which were Clavien grade I. The Clavien grade II/III complications as reported by authors were urosepsis, steinstrasse and renal colic. None of the procedures required conversion to open surgery with no cases of renal haematoma or ureteric perforation. CONCLUSIONS: This contemporary review highlights URS as a viable treatment option for stone disease in patients with a solitary kidney. It is associated with superior clearance rates to SWL and fewer high-risk complications compared to PCNL. PMID- 27123334 TI - Solitary kidney - a clinical challenge for endourologist. PMID- 27123333 TI - Safety and feasibility of day case ureteroscopy and laser lithotripsy (URSL) in patients with a solitary kidney. AB - INTRODUCTION: The management of nephrolithiasis in patients with a solitary kidney poses a treatment challenge. The study aimed to evaluate the outcomes of ureteroscopy and laser stone fragmentation (URSL) for renal stones in these patients treated in our university teaching hospital. MATERIAL AND METHODS: Between July 2012 and December 2014, seventeen cases of URSL for stones in a solitary kidney were reviewed. Patient demographics, stone dimensions, perioperative and post-operative outcomes were recorded in a prospectively maintained database. Serum creatinine levels pre-procedure and at follow-up were also compared. RESULTS: Seventeen cases of URSL were conducted with a mean age of 52.9 +/-19.9 years. 8 of the 17 (47%) patients had stones in multiple locations and 13 (76%) were in the lower pole. The mean +/- SD stone size and BMI were 13.0 +/-8.9 mm and 31.6 +/-5.8 kg/m(2), respectively. The stone free rate (SFR) was 82.5%. Fourteen (82.5%) patients were discharged the same day and 16 cases (94%) were discharged within 24 hours. For patients with deranged pre-operative serum creatinine, the mean serum creatinine level improved from 131.2 +/-68.3 umol/L pre-URSL to 106.5 +/-36.7 umol/L at follow-up. There was one Clavien grade II complication with a patient requiring additional antibiotics for post-operative urinary tract infection. There were no other major or minor complications. CONCLUSIONS: Day case ureteroscopy for stone disease in a solitary kidney is safe and feasible with a low complication rate and an overall improvement in renal function. PMID- 27123335 TI - Tips and tricks of ureteroscopy: consensus statement. Part II. Advanced ureteroscopy. AB - Our "tips and tricks" focuses on all aspects of upper tract endourology and we hope these will be of use to all trainees and consultants who perform ureteroscopy. We report an "expert consensus view" from experienced endourological surgeons, on all aspects of advanced ureteroscopic techniques, with a particular focus on avoiding and getting out of trouble while performing ureteroscopy. In this paper we provide a summary of placing ureteric access sheath, flexible ureteroscopy, intra renal stone fragmentation and retrieval, maintaining visual clarity and biopsy of ureteric and pelvicalyceal tumours. PMID- 27123336 TI - Microarray long oligo probe designing for Escherichia coli: an in-silico DNA marker extraction. AB - INTRODUCTION: Urinary tract infections are predominant diseases which may be caused by different pathogenic microorganisms, particularly Escherichia coli (E.coli). DNA microarray technology is an accurate, rapid, sensitive, and specific diagnostic tool which may lead to definite diagnosis and treatment of several infectious diseases. DNA microarray is a multi-process method in which probe designing plays an important. Therefore, the authors of the present study have tried to design a range of effective and proper long oligo microarray probes for detection and identification of different strains of pathogenic E.coli and in particular, uropathogenic E.coli (UPEC). MATERIAL AND METHODS: E.coli O26 H11 11368 uid41021 was selected as the standard strain for probe designing. This strain encompasses the largest nucleotide sequence and the most number of genes among other pathogenic strains of E.coli. For performing this in silico survey, NCBI database, GReview Server, PanSeq Server, Oligoanalyzer tool, and AlleleID 7.7 were used to design accurate, appropriate, effective, and flexible long oligo microarray probes. Moreover, the genome of E.coli and its closely related microorganisms were compared. RESULTS: In this study, 15 long oligo microarray probes were designed for detecting and identifying different strains of E.coli such as UPEC. These probes possessed the best physico-chemical characteristics. The functional and structural properties of the designed probes were recognized by practical tools and softwares. CONCLUSIONS: The use of reliable advanced technologies and methodologies for probe designing guarentees the high quality of microarray probes and makes DNA microarray technology more flexible and an effective diagnostic technique. PMID- 27123337 TI - Urogenital tract disorders in children suspected of being sexually abused. AB - INTRODUCTION: Child sexual abuse (CSA) is generally defined as child exploitation that leads to achievement of sexual satisfaction. According to data from European countries, sexual abuse of children affects 10-40% of girls and 5-20% of boys. MATERIAL AND METHODS: The Medline, and Web of Science databases were searched with no date limitation on May 2015 using the terms 'child abuse' in conjunction with 'urinary tract', 'urologist', 'urological dysfunction', 'urologic symptoms', 'LUTS' or 'urinary infection'. RESULTS: Awareness of the CSA problem among paediatricians and urologists is very important, because they are often the only physicians who are able to recognize the problem. CSA diagnosis is possible only through the proper collection of a medical history and a thorough physical examination. Urologists have to remember that children exposed to sexual abuse rarely exhibit abnormal genital findings. In fact, absence of genital findings is the rule rather than the exception. In most cases, the final diagnosis of sexual abuse is based on the child's history and behavior, along with the onset and exacerbation of urologic symptoms. CONCLUSIONS: In this article, we present a review of studies and literature concerning urinary symptoms in sexually abused children to clarify the problem for a broad group of urologists. We present common symptoms and premises that can point to the right diagnosis and basic guidelines of proceeding after suspicion of abuse. PMID- 27123338 TI - Comprehensive flexible ureteroscopy (FURS) simulator for training in endourology: The K-box model. PMID- 27123339 TI - Laparoscopic partial nephrectomy for non-functional lower pole kidney stone. PMID- 27123340 TI - Letter to the Editor. PMID- 27123341 TI - Retinal Detachment in Down Syndrome: Characteristics and Surgical Outcomes. AB - Purpose. To determine the functional and anatomic outcomes of rhegmatogenous retinal detachment (RRD) surgery in patients with Down syndrome. Methods. A retrospective chart review was performed of patients with Down syndrome who had undergone surgery for RRD at King Khalid Eye Specialist Hospital between 1995 and 2014. Results. A total of 245 patients with Down syndrome were evaluated during the study period. Eighteen eyes of 15 patients (6.1%) with RRD were identified. Three out of 15 patients (20%) presented with bilateral retinal detachment. All eyes presented with macula off retinal detachment. The retina was successfully reattached in 16/18 (88.8%) eyes after a mean follow-up of 48 months. The final postoperative visual acuity ranged from light perception to 20/125 (median: hand motion) (11/18 eyes). Conclusions. The anatomic success rate of retinal reattachment surgery in patients with Down syndrome is comparable to the general population. Patients with Down syndrome should undergo regular ophthalmic examinations for early diagnosis. Despite late diagnosis and the presence of proliferative vitreoretinopathy (PVR) in some patients, favorable anatomical outcomes can be achieved. PMID- 27123342 TI - Experiences of Iranian Nurses on the Facilitators of Pain Management in Children: A Qualitative Study. AB - Background. Despite decades of research and the availability of effective analgesic approaches, many children continue to experience moderate-to-severe pain after hospitalization. Greater research efforts are needed to identify the factors that facilitate effective pain management. The aim of this study was to explore the perceptions of Iranian nurses on facilitators of pain management in children. Materials and Methods. This qualitative study collected the data profoundly through unstructured interviews with 19 nurses in Amirkola Children's Hospital in Babol and Children's Medical Center in Tehran, during 2013-2014. Purposeful sampling and analysis of the data were conducted using conventional qualitative content analysis. Results. Four themes were extracted through data analysis: mother and child participation in diagnosis and pain relief, the timely presence of medical staff and parents, proper communication, and training and supportive role of nurses. Conclusion. Mother and child participation in the report and diagnosis of pain and nonpharmacological interventions for pain by the mother, the timely presence of medical team at the patient's bedside, and proper interaction along with the training and supportive role of a nurse enhanced the optimal pain management in hospitalized children. PMID- 27123343 TI - Geometric Simulation Approach for Grading and Assessing the Thermostability of CALBs. AB - Candida antarctica lipase B (CALB) is a known stable and highly active enzyme used widely in biodiesel synthesis. In this work, the stability of native (4K6G) and mutant (4K5Q) CALB was studied through various structural parameters using conformational sampling approach. The contours of polar surface area and surface area of mutant CALB were 11357.67 A(2) and 30007.4 A(2), respectively, showing an enhanced stability compared to native CALB with a statistically significant P value of < 0.0001. Moreover, simulated thermal denaturation of CALB, a process involving dilution of hydrogen bond, significantly shielded against different intervals of energy application in mutant CALB revealing its augmentation of structural rigidity against native CALB. Finally, computational docking analysis showed an increase in the binding affinity of CALB and its substrate (triglyceride) in mutant CALB with Atomic Contact Energy (ACE) of -91.23 kcal/mol compared to native CALB (ACE of -70.3 kcal/mol). The computational observations proposed that the use of mutant CALB (4K5Q) could serve as a best template for production of biodiesel in the future. Additionally, it can also be used as a template to identify efficient thermostable lipases through further mutations. PMID- 27123344 TI - Multidrug Resistant CTX-M-Producing Escherichia coli: A Growing Threat among HIV Patients in India. AB - Extended Spectrum beta-Lactamases (ESBLs) confer resistance to third-generation cephalosporins and CTX-M types have emerged as the most prominent ESBLs worldwide. This study was designed to determine the prevalence of CTX-M positive ESBL-producing urinary E. coli isolates from HIV patients and to establish the association of multidrug resistance, phylogeny, and virulence profile with CTX-M production. A total of 57 ESBL producers identified among 76 E. coli strains isolated from HIV patients from South India were screened for bla CTX-M, AmpC production, multidrug resistance, and nine virulence associated genes (VAGs), fimH, pap, afa/dra, sfa/foc, iutA, fyuA, iroN, usp, and kpsMII. The majority (70.2%) of the ESBL producers harbored bla CTX-M and were AmpC coproducers. Among the CTX-M producers, 47.5% were found to be UPEC, 10% harbored as many as 7 VAGs, and 45% possessed kpsMII. Multidrug resistance (CIP(R)SXT(R)GEN(R)) was significantly more common among the CTX-M producers compared to the nonproducers (70% versus 41.2%). However, 71.4% of the multidrug resistant CTX-M producers exhibited susceptibility to nitrofurantoin thereby making it an effective alternative to cephalosporins/fluoroquinolones. The emergence of CTX-M-producing highly virulent, multidrug resistant uropathogenic E. coli is of significant public health concern in countries like India with a high burden of HIV/AIDS. PMID- 27123345 TI - Phenotypic Detection of Metallo-Beta-Lactamases in Carbapenem Resistant Acinetobacter baumannii Isolated from Pediatric Patients in Pakistan. AB - Multidrug resistant A. baumannii has emerged as an important and problematic human pathogen as it is the causative agent of several types of infections especially in neonates and immunocompromised patients because they have least capacity to fight against infections. Carbapenems are used as last resort antibiotics for treating these infections but currently resistance against carbapenems due to MBL production is on the rise. The objective of this study was to determine the frequency of antibiotic resistance in A. baumannii and also to compare the efficacy of combined disk test and double disk synergy test for detection of metallo-beta-lactamases. A total of 112 A. baumannii were identified from various clinical samples and antibiotic susceptibility profile was determined by Kirby-Bauer Disk Diffusion method. Out of 112, 66 (58.9%) isolates were resistant to both imipenem and meropenem (OXOID). These resistant isolates were tested for carbapenemase production, and 55 (83.3%) were carbapenemase producers by Modified Hodge Test. These isolates were further tested for MBL production by combined disk test and double disk synergy test. Out of 66, 49 isolates were positive by both methods, CDT and DDST, and only one isolate was detected as negative (with kappa value = 0.038). All MBL producing strains showed remarkable resistance to cephalosporins, fluoroquinolones, aminoglycosides, and piperacillin/tazobactam (OXOID). The antibiotic resistance was very high in A. baumannii which were isolated from children in Pakistan specially attending a nephrology unit. PMID- 27123346 TI - Eosinophilic Myocarditis due to Toxocariasis: Not a Rare Cause. AB - Myocarditis is a clinically important disease because of the high mortality. From the perspective of treatment strategy, eosinophilic myocarditis should be distinguished from other types of myocarditis. Toxocariasis, caused by Toxocara canis or Toxocara cati, is known as a cause of eosinophilic myocarditis but is considered rare. As it is an unpopular disease, eosinophilic myocarditis due to toxocariasis may be underdiagnosed. We experienced two cases of eosinophilic myocarditis due to toxocariasis from different geographical areas in quick succession between 2013 and 2014. Case 1 is 32-year-old man. Case 2 is 66-year old woman. In both cases, diagnosis was done by endomyocardial biopsy and IgG ELISA against Toxocara excretory-secretory antigen. Only a corticosteroid was used in Case 1, whereas a corticosteroid and albendazole were used in Case 2 as induction therapy. Both patients recovered. Albendazole was also used in Case 1 to prevent recurrence after induction therapy. Eosinophilic myocarditis by toxocariasis may in actuality not be a rare disease, and corticosteroid is an effective drug as induction therapy even before use of albendazole. PMID- 27123347 TI - The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert(r)) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema. AB - Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1 esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID- 27123348 TI - The Role of PCR in Diagnosis of a Rare Appendicular Tuberculosis and Mini Literature Review. AB - Tuberculosis is a prevalent public health problem especially in the poor developing countries and results in significant mortality. Albeit tuberculosis almost always affects any organ or system of the body, abdominal tuberculosis is less frequent; moreover, tuberculous appendicitis is very rare with an incidence estimated at about 0.1-0.6% of all gastrointestinal tuberculosis. The purpose of this report was to present an unusual case of primary tuberculous appendicitis and the approach used for accurate diagnosis as well as a current update on the disease. We are reporting a 30-year-old male who presented with acute abdominal pain, fever, and vomiting and was admitted with the clinical diagnosis of acute appendicitis. Patient was investigated thoroughly and histopathologic examination was strongly suggestive of tuberculous appendicitis; however, Ziehl-Neelsen (ZN) was negative in tissue section. To confirm the diagnosis, molecular biology [polymerase chain reaction (PCR)] study was performed from the formalin fixed paraffin embedded (FFPE) appendicular tissue and revealed presence of Mycobacterium tuberculosis. As there are numerous differential diagnoses in granulomatous lesions of appendix and due to the fact that appendicular tuberculosis is a rare phenomenon; verification etiologic agent is crucial for appropriate management of the disease. PMID- 27123349 TI - Novel GLA Deletion in a Cypriot Female Presenting with Cornea Verticillata. AB - Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of the hydrolytic enzyme alpha-galactosidase A (alpha-Gal-A). It is characterized by progressive lysosomal accumulation of globotriaosylceramide (Gb3) and multisystem pathology, affecting the skin, nervous and cerebrovascular systems, kidneys, and heart. Heterozygous females typically exhibit milder symptoms and a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. We report on a 17-year-old female in whom cornea verticillata was found during a routine ophthalmological examination but with no other clinical symptoms. Leucocyte alpha-galactosidase activity was within the overlap range between Fabry heterozygotes and normal controls. Sanger sequencing of the GLA gene failed to reveal any pathogenic variants. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis revealed a deletion of exon 7. Using a long-range PCR walking approach, we managed to identify the deletion breakpoints. The deletion spans 1182 bp, with its 5' end located within exon 6 of the GLA gene and its 3' end located 612 bp downstream of exon 7. This finding represents a novel deletion identified in the first reported Cypriot female carrier of Fabry disease. PMID- 27123350 TI - Pregnancy and Accelerated Phase of Myeloid Chronic Leukemia Treated with Imatinib: A Case Report from a Developing Country. AB - Background. Chronic myeloid leukemia is a hematological malignancy caused by expression of BCR-ABL tyrosine kinase oncogene, product of the t(9;22) Philadelphia translocation. Accelerated phase of this disease marks the onset of advanced rapidly progressive disease unresponsive to many therapies. Pregnancy limits broad number of therapies on patients because of their potential teratogenic effects. We report the case of a pregnant 34-year-old patient on accelerated phase successively managed by imatinib. She achieved a safe pregnancy and delivered at 39 weeks a healthy baby without congenital abnormalities. Our case is unusual because of the accelerated phase of the disease. Case Presentation. A 34-year-old African female with history of chronic phase of myeloid leukemia on imatinib, lost to follow-up for 4 months, presented to the hematological department for abdominal discomfort. Accelerated phase of chronic myeloid leukemia was diagnosed. Complete hematological response was achieved on high doses of imatinib. At the completion of 39 weeks, she delivered a healthy child without congenital anomalies. Conclusion. Despite its teratogenic and embryotoxic effects, front line imatinib is the only effective, well-tolerated treatment for patient on accelerated phase that can be offered to patients in sub Saharan countries. PMID- 27123351 TI - S3 Dorsal Root Ganglion/Nerve Root Stimulation for Refractory Postsurgical Perineal Pain: Technical Aspects of Anchorless Sacral Transforaminal Lead Placement. AB - Chronic perineal pain limits patients in physical and sexual activities, leading to social and psychological distress. In most cases, this pain develops after surgery in the urogenital area or as a consequence of trauma. Neuromodulation is one of the options in chronic postsurgical perineal pain treatment. We present a case of refractory perineal pain after right sided surgical resection of a Bartholin's cyst which was treated with third sacral nerve root/dorsal root ganglion stimulation using the transforaminal approach. We describe a new anchorless lead placement technique using a unique curved lead delivery sheath. We postulate that this new posterior foraminal technique of lead placement is simple, safe, and reversible and may lower the occurrence of lead related complications. PMID- 27123352 TI - A Successful Mother and Neonate Outcome for a Woman with Essential Thrombocytosis and FV Leiden Heterozygosity. AB - Essential thrombocytosis (ET) and FV Leiden heterozygosity represent an acquired and hereditable hypercoagulable state, respectively. An uncommon case of coexistence of ET and FV Leiden heterozygosity in a 36-year-old pregnant woman and her successful pregnancy outcome is described. She was considered to be at high risk of thrombosis during her pregnancy and she was treated with both prophylactic dose of LMWH and aspirin daily throughout her pregnancy and for a 6 week period postpartum. The efficacy of the anticoagulation treatment was monitored in various time points not only by measuring anti-Xa levels and D Dimers but also with new coagulation methods such as rotation thromboelastometry and multiplate. Global assessment of coagulation using additional newer laboratory tests might prove useful in monitoring coagulation pregnancies at high risk for thrombosis. PMID- 27123353 TI - A Thickened Coracohumeral Ligament and Superomedial Capsule Limit Internal Rotation of the Shoulder Joint: Report of Three Cases. AB - Adhesive capsulitis of the shoulder (also known as frozen shoulder) is a painful and disabling disorder with an estimated prevalence ranging from 2% to 5% in the general population. Although the precise pathogenesis of frozen shoulder is unclear, thickened capsule and coracohumeral ligament (CHL) have been documented to be one of the most specific manifestations. The thickened CHL has been understood to limit external rotation of the shoulder, and restriction of internal rotation of the shoulder has been believed to be related to posterior capsular tightness. In this paper, three cases of refractory frozen shoulder treated through arthroscopic release of a contracted capsule including CHL were reported. Two cases in which there is recalcitrant severe restriction of internal rotation after manipulation under anesthesia (MUA) were finally treated with arthroscopic surgery. Although MUA could release the posterior capsule, internal rotation did not improve in our cases. After release of the thickened CHL, range of motion of internal rotation was significantly improved. This report demonstrates the role of the thickened CHL in limiting the internal rotation of the shoulder. We highlight the importance of release of thickened CHL in addition to the pancapsular release, in case of severe limitation of internal rotation of shoulder. PMID- 27123354 TI - Management of Testicular Silicone Gel-Filled Prosthesis Rupture: Case Report of a Rare Event and a Review of the Literature. AB - Introduction. We report a case of spontaneous rupture of a single testicular prosthesis in a patient who had undergone bilateral orchiectomy and silicone gel filled prosthesis insertion. The consequences of this rare event are discussed. There is no management algorithm. Case Presentation. A 55-year-old man presented to our outpatient department with altered consistency in his right testicular prosthesis and a painful right hemiscrotum with no systemic symptoms thirty-three years after the implantation of the prosthesis. We removed this implant without replacement, in accordance with the patient's wishes. Conclusion. The long time between the implantation and the spontaneous rupture is remarkable and was never before described. The removal of the prosthesis was straightforward and it would have been possible to implant a new prosthesis after taking into account the condition of the skin. PMID- 27123355 TI - Urothelial Carcinoma Recurrence in an Ileal Neobladder Nine Years after Primary Surgery with Muir-Torre Syndrome. AB - We report a patient who presented with a urothelial carcinoma recurrence developed nine years after radical cystoprostatectomy, related to Muir-Torre syndrome. PMID- 27123356 TI - The Prevalence of Syphilis Infection and Its Associated Factors in the General Population of Rwanda: A National Household-Based Survey. AB - Background. The prevalence of syphilis among HIV-infected people is a public health concern, but there is limited literature to describe the true burden of syphilis in resource-limited settings. We conducted this survey in 2013 to estimate the prevalence of syphilis. Methods. A cross-sectional survey. Participants were tested for syphilis and HIV. Factors associated with syphilis infection were identified. Results. The prevalence of syphilis was 0.9% (95% CI: 0.7-1.1). This prevalence was higher in the 25-49-year-old age (1.1% [95% CI: 0.8 1.3]) than in the 15-24-year-old age (0.6% (95% CI: 0.4-0.9)). Women with lower education had a higher prevalence of syphilis (1.2% (95% CI: 0.9-1.5)) compared to others (0.4% (95% CI: 0.2-0.8)). This prevalence among HIV-infected people was six times higher: 4.8% (95% CI: 2.9-7.9) compared to HIV-negative people (0.8% (95% CI: 0.6-1.0)). The prevalence of syphilis among HIV-infected females was 5.9% (95% CI: 3.4-10.0). HIV-infected or concurrent sexual partners was associated with increased syphilis prevalence with aOR = 4.2 (95% CI: 2.5-7.2) and aOR = 4.2 (95% CI: 2.8-6.5), respectively. Conclusions. The prevalence of syphilis was significantly higher among HIV-infected patients. HIV infection and concurrent sexual partners are associated with an increased prevalence of syphilis. Preventing HIV might help in preventing syphilis. PMID- 27123357 TI - Bone Mineral Density in Postmenopausal Women Heterozygous for the C282Y HFE Mutation. AB - Mutations in the HFE gene may be associated with increased tissue iron stores reflected in an elevated serum ferritin. With homozygous mutation C282Y, the increase in serum ferritin may be associated with tissue damage in the liver, pancreas, and pituitary and with a reduced bone mineral density. With heterozygous mutation C282Y, the degree of iron retention is less but information relating to how a heterozygous C282Y mutation might impact bone mineral density is uncertain. The present study was undertaken to study the relationships between bone mineral density measured by dual energy X-ray absorptiometry and the serum ferritin and serum iron in postmenopausal women heterozygous for the C282Y mutation. The spinal bone mineral density, L2-4, was significantly less than age matched community controls (P = 0.016). There was no significant change in the femoral neck bone mineral density compared to age matched community controls. The correlation between the spinal bone mineral density, L2-4, the femoral neck bone mineral density, and the serum ferritin was not significant. The serum iron correlated significantly inversely with the femoral neck bone mineral density (P = 0.048). The heterozygous C282Y mutation may be associated with impairment of bone cell function in postmenopausal women when only small increases in the serum iron or serum ferritin have occurred. PMID- 27123358 TI - Hypothyroidism in Pancreatic Cancer: Role of Exogenous Thyroid Hormone in Tumor Invasion-Preliminary Observations. AB - According to the epidemiological studies, about 4.4% of American general elderly population has a pronounced hypothyroidism and relies on thyroid hormone supplements daily. The prevalence of hypothyroidism in our patients with pancreatic cancer was much higher, 14.1%. A retrospective analysis was performed on patients who underwent pancreaticoduodenectomy (Whipple procedure) or distal pancreatectomy and splenectomy (DPS) at Thomas Jefferson University Hospital, Philadelphia, from 2005 to 2012. The diagnosis of hypothyroidism was correlated with clinicopathologic parameters including tumor stage, grade, and survival. To further understand how thyroid hormone affects pancreatic cancer behavior, functional studies including wound-induced cell migration, proliferation, and invasion were performed on pancreatic cancer cell lines, MiaPaCa-2 and AsPC-1. We found that hypothyroid patients taking exogenous thyroid hormone were more than three times likely to have perineural invasion, and about twice as likely to have higher T stage, nodal spread, and overall poorer prognostic stage (P < 0.05). Pancreatic cancer cell line studies demonstrated that exogenous thyroid hormone treatment increased cell proliferation, migration, and invasion (P < 0.05). We conclude that exogenous thyroid hormone may contribute to the progression of pancreatic cancer. PMID- 27123359 TI - The Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology. AB - Context. Population studies of the distribution of T4/TSH set points suggest a more complex inverse relationship between T4 and TSH than that suggested by physiological studies. The reasons for the similarities and differences between the curves describing these relationships are unresolved. Methods. We subjected the curve, derived from empiric data, describing the TSH suppression response to T4, and the more mathematically derived curve describing the T4 response to TSH, to the different possible models of population variation. The implied consequences of these in terms of generating a population distribution of T4/TSH equilibrium points (a "population curve") were generated and compared to the empiric population curve. The physiological responses to primary hypothyroidism and hyperthyroidism were incorporated into the analysis. Conclusions. Though the population curve shows a similarly inverse relationship, it is describing a different relationship than the curve describing the suppression of TSH by T4. The population curve is consistent with the physiological studies of the TSH response to T4 and implies a greater interindividual variation in the positive thyroid T4 response to TSH than in the central inhibitory TSH response to T4. The population curve in the dysthyroid states is consistent with known physiological responses to these states. PMID- 27123360 TI - A Simple Spectrophotometric Method for the Determination of Thiobarbituric Acid Reactive Substances in Fried Fast Foods. AB - A simple and highly sensitive spectrophotometric method was developed for the determination of thiobarbituric acid reactive substances (TBARS) as a marker for lipid peroxidation in fried fast foods. The method uses the reaction of malondialdehyde (MDA) and TBA in the glacial acetic acid medium. The method was precise, sensitive, and highly reproducible for quantitative determination of TBARS. The precision of extractions and analytical procedure was very high as compared to the reported methods. The method was used to determine the TBARS contents in the fried fast foods such as Shami kebab, samosa, fried bread, and potato chips. Shami kebab, samosa, and potato chips have higher amount of TBARS in glacial acetic acid-water extraction system than their corresponding pure glacial acetic acid and vice versa in fried bread samples. The method can successfully be used for the determination of TBARS in other food matrices, especially in quality control of food industries. PMID- 27123361 TI - The Clinical Effectiveness of Intralesional Injection of 2% Zinc Sulfate Solution in the Treatment of Common Warts. AB - Objective. To investigate the clinical efficacy and safety of intralesional injection of 2% zinc sulfate solution in the treatment of common warts. Patients and Methods. One hundred and twenty patients (78 females and 42 males) aged 5-55 years with 225 common warts participated in this prospective monocentric randomized study. All lesions were treated with intralesional injection of 2% zinc sulfate. Results. From 225 warts injected, 135 warts (60%) cured from the first session, 51 warts (22.67%) cured from the second session, and 12 warts (5.33%) cured from the third session. There is no significant relation between improvement and patient's ages, duration, or number of warts (P > 0.05). All patients complained from pain during injection, and all treated lesions showed redness, tenderness, and swelling in the first 3 days after injection. Late complications were postinflammatory hyperpigmentation in 90 patients (75%), scaring in 9 patients (7.5%), and ulceration in 3 patients (2.5%). Recurrence occurred in 3 lesions (1.33%). Conclusion. The clinical data indicate that intralesional injection of 2% zinc sulfate is an effective maneuver in the treatment of common warts; however, its associated complications limit its use. PMID- 27123362 TI - Onychomycosis: Potential of Nail Lacquers in Transungual Delivery of Antifungals. AB - Onychomycosis constitutes the most common fungal infection of the nail (skin beneath the nail bed) that affects the finger as well as toe nails. It is an infection that is initiated by yeasts, dermatophytes, and nondermatophyte molds. Nail lacquers are topical solutions intended only for use on fingernails as well as toenails and have been found to be useful in the treatment of onychomycosis. Thus, in the present review an attempt has been made to focus on the treatment aspects of onychomycosis and the ungual delivery of antifungals via nail lacquer. Several patents issued on nail lacquer till date have also been discussed. Penetration efficiency was assessed by several researchers across the human nail plate to investigate the potentiality of nail lacquer based formulations. Various clinical trials have also been conducted in order to evaluate the safety and efficacy of nail lacquers in delivering antifungal agents. Thus, it can be concluded that nail lacquer based preparations are efficacious and stable formulations. These possess tremendous potential for clinical topical application to the nail bed in the treatment of onychomycosis. PMID- 27123363 TI - Implications of Intrathecal Chemotherapy for Anaesthesiologists: A Brief Review. AB - Intrathecal chemotherapy is routinely prescribed in medical oncology practice, either for prophylaxis or for treatment of leptomeningeal disease due to a primary haematological disease or a metastatic disease due to any other malignancy. As these groups of patients are coagulopathic either because of the disease per se or due to systemic chemotherapy, lumbar puncture in them is considered challenging and is expected to be performed by an anaesthesiologist because of their expertise in this procedure. However, the challenge is not only in performing the lumbar puncture safely but also in dealing with other issues like explaining and handling complications that can happen either due to the drug injected intrathecally or due to a neurodeficit occurring either due to the underlying coagulopathy or due to the progression of leptomeningeal disease. PMID- 27123364 TI - Development and Validation of Stability-Indicating Method for Estimation of Chlorthalidone in Bulk and Tablets with the Use of Experimental Design in Forced Degradation Experiments. AB - Chlorthalidone was subjected to various forced degradation conditions. Substantial degradation of chlorthalidone was obtained in acid, alkali, and oxidative conditions. Further full factorial experimental design was applied for acid and alkali forced degradation conditions, in which strength of acid/alkali, temperature, and time of heating were considered as independent variables (factors) and % degradation was considered as dependent variable (response). Factors responsible for acid and alkali degradation were statistically evaluated using Yates analysis and Pareto chart. Furthermore, using surface response curve, optimized 10% degradation was obtained. All chromatographic separation was carried out on Phenomenex HyperClone C 18 column (250 * 4.6 mm, 5 MU), using mobile phase comprising methanol : acetonitrile : phosphate buffer (20 mM) (pH 3.0 adjusted with o-phosphoric acid): 30 : 10 : 60% v/v. The flow rate was kept constant at 1 mL/min and eluent was detected at 241 nm. In calibration curve experiments, linearity was found to be in the range of 2-12 MUg/mL. Validation experiments proved good accuracy and precision of the method. Also there was no interference of excipients and degradation products at the retention time of chlorthalidone, indicating specificity of the method. PMID- 27123365 TI - International Air Travel to Ohio, USA, and the Impact on Malaria, Influenza, and Hepatitis A. AB - The State of Ohio led the United States in measles in 2014, ostensibly related to international air travel (IAT), and ranked lower than 43 other states in infectious disease outbreak preparedness. We conducted a retrospective cohort study using surveillance data of the total Ohio population of 11 million from 2010 through 2014 with a nested case control of air travelers to determine the risk of malaria, seasonal influenza hospitalizations (IH), and hepatitis A (HA) disease related to international travel and to estimate the association with domestic enplanement. IAT appeared protective for HA and IH with a risk of 0.031 (.02-.04) but for malaria was 2.7 (2.07-3.62). Enplanement increased the risk for nonendemic M 3.5 (2.5-4.9) and for HA and IH 1.39 (1.34-1.44). IAT's ratio of relative risk (RRR) of malaria to HA and IH was 87.1 (55.8-136) greater than 219 times versus domestic enplanement which was protective for malaria at 0.397 (0.282-0.559). Malaria is correlated with IAT with cases increasing by 6.9 for every 10,000 passports issued. PMID- 27123366 TI - Nematode orphan genes are adopted by conserved regulatory networks and find a home in ecology. AB - Nematode dauer formation represents an essential survival and dispersal strategy and is one of a few ecologically relevant traits that can be studied in laboratory approaches. Under harsh environmental conditions, the nematode model organisms Caenorhabditis elegans and Pristionchus pacificus arrest their development and induce the formation of stress-resistant dauer larvae in response to dauer pheromones, representing a key example of phenotypic plasticity. Previous studies have indicated that in P. pacificus, many wild isolates show cross-preference of dauer pheromones and compete for access to a limited food source. When investigating the genetic mechanisms underlying this intraspecific competition, we recently discovered that the orphan gene dauerless (dau-1) controls dauer formation by copy number variation. Our results show that dau-1 acts in parallel to or downstream of steroid hormone signaling but upstream of the nuclear hormone receptor daf-12, suggesting that DAU-1 represents a novel inhibitor of DAF-12. Phylogenetic analysis reveals that the observed copy number variation is part of a complex series of gene duplication events that occurred over short evolutionary time scales. Here, we comment on the incorporation of novel or fast-evolving genes into conserved genetic networks as a common principle for the evolution of phenotypic plasticity and intraspecific competition. We discuss the possibility that orphan genes might often function in the regulation and execution of ecologically relevant traits. Given that only few ecological processes can be studied in model organisms, the function of such genes might often go unnoticed, explaining the large number of uncharacterized genes in model system genomes. PMID- 27123367 TI - Context-dependent regulation of Dicer activity and small RNA production: Implications to oocyte-to-embryo transition. AB - Cellular and molecular mechanisms that suppress small RNAs in oocytes while maintaining them in zygotes remain unknown. Signal-mediated regulation of small RNA biogenesis pathway is emerging as a theme for regulating small RNA production. We recently reported that ERK-mediated phosphorylation of Dicer, a central player in small RNA biogenesis, induced Dicer to move from the cytoplasm to the nucleus. Dicer phosphorylation inhibited its function, e.g., the production of 26G endo-siRNAs in the female germline. Moreover, our findings showed that the inhibition of Dicer function was necessary for normal progression of meiosis I and oogenesis, and that Dicer function had to be restored before fertilization for normal progression of embryogenesis. Thus, extracellular signal dependent inhibition and then reactivation of Dicer is essential for oocyte-to embryo transition. Strikingly, signal-induced Dicer translocation from the cytoplasm to nucleus is evolutionarily conserved from worm, flies, mice to humans thereby suggesting the ERK-mediated control of Dicer activity may be a generalized mechanism for regulating small RNA biogenesis. PMID- 27123368 TI - How targets select activation or repression in response to Wnt. AB - In metazoans, the Wnt signaling pathway plays a key role in the regulation of binary decisions during development. During this process different sets of target genes are activated in cells where the Wnt pathway is active (classic target genes) versus cells where the pathway is inactive (opposite target genes). While the mechanism of transcriptional activation is well understood for classic target genes, how opposite target genes are activated in the absence of Wnt remains poorly characterized. Here we discuss how the key transcriptional mediator of the Wnt pathway, the TCF family member POP-1, regulates opposite target genes during C. elegans development. We examine recent findings suggesting that the direction of the transcriptional output (activation or repression) can be determined by the way TCF is recruited and physically interacts with its target gene. PMID- 27123369 TI - Levels and location are crucial in determining the effect of ROS on lifespan. AB - Reactive oxygen species (ROS) cause molecular damage that accumulates with age and have been proposed to be one of the primary causes of aging. However, recent work indicates that ROS have beneficial roles in an organism and that the relationship between ROS and aging is complex. We have shown that increasing ROS levels or oxidative damage does not necessarily lead to decreased lifespan. We have also shown that in some cases increasing ROS can promote longevity. Further investigation of the factors that determine the effect of ROS on lifespan demonstrate that both the levels and location of ROS are important in predicting the impact of ROS on longevity. Increasing superoxide levels in the cytoplasm results in decreased lifespan, while increasing superoxide levels in the mitochondria leads to increased lifespan. Within the mitochondria, mild elevation of superoxide levels promote longevity, while high levels of superoxide are toxic. Thus, a new paradigm is emerging in which ROS are neither good nor bad but levels and location makes it so. PMID- 27123370 TI - A chemical screen to identify inducers of the mitochondrial unfolded protein response in C. elegans. AB - We previously showed that inhibition of the mevalonate pathway in C. elegans causes inhibition of protein prenylation, developmental arrest and lethality. We also showed that constitutive activation of the mitochondrial unfolded protein response, UPR(mt), is an effective way for C. elegans to become resistant to the negative effects of mevalonate pathway inhibition. This was an important finding since statins, a drug class prescribed to lower cholesterol levels in patients, act by inhibiting the mevalonate pathway, and it is therefore possible that some of their undesirable side effects could be alleviated by activating the UPR(mt). Here, we screened a chemical library and identified 4 compounds that specifically activated the UPR(mt). One of these compounds, methacycline hydrochloride (a tetracycline antibiotic) also protected C. elegans and mammalian cells from statin toxicity. Methacycline hydrochloride and ethidium bromide, a known UPR(mt) activator, were also tested in mice: only ethidium bromide significantly activate the UPR(mt) in skeletal muscles. PMID- 27123371 TI - The C. elegans Ortholog of USP7 controls DAF-16 stability in Insulin/IGF-1-like signaling. AB - FOXO family transcription factors are downstream effectors of Insulin/IGF-1 signaling (IIS) and are regulated by posttranslational modification and coregulators, including components of the ubiquitin-proteasome system (UPS). Cofactors promoting DAF-16/FOXO protein stability and function in IIS have not been described yet. In a recent study, we have identified the deubiquitylating enzyme MATH-33, the ortholog of mammalian USP7/HAUSP, as an essential DAF-16 coregulator. We found that MATH-33 actively stabilizes DAF-16 protein levels when IIS is downregulated. Here we discuss how DAF-16/FOXO transcription factors are regulated by the UPS, in particular by the interplay of E3-ubiquitin ligases and deubiquitylating enzymes, which is critical for balancing DAF-16/FOXO activity and degradation. Recent findings raise the intriguing possibility that regulated oscillations in DAF-16/FOXO steady state levels play an integral role in mechanisms controlling healthspan and lifespan extension. PMID- 27123372 TI - Trouble in transitioning: activation of zygotic transcription can lead to DNA breakage and genome instability. AB - Recent work from our laboratory has identified zygotic genome activation as a source of intrinsic DNA damage during germline development in C. elegans. More specifically, we have found that the primordial germ cells Z2 and Z3 experience DNA damage and damage checkpoint activation shortly after RNA polymerase II is activated by a nutrient-dependent signal in L1 stage animals. In this Commentary we review these data, put them into context with other examples of programmed DNA double-strand breaks (DSBs) during gene activation, and speculate as to how a DSB would facilitate signal-dependent activation of gene expression. PMID- 27123373 TI - Why do worms go against the flow? C. elegans behaviors explained by simple physics. AB - Nearly half a century of neurobiological research using the nematode Caenorahbitis elegans has produced a remarkably detailed understanding of how genotype controls behavioral phenotype. However, the role of simple physical forces in regulating behavior has been understudied. Here, we review our recent observations of 3 behaviors of C. elegans suspended in solution that can be fully explained by the laws of mechanics. These behaviors are bordertaxis, the attraction toward solid surfaces; positive rheotaxis, the propensity to swim against the flow; and synchrophilia, the tendency of animals when close to each other to synchronize their gaits. Although these 3 behaviors are not directly regulated by the animal's nervous system, bordertaxis and rheotaxis require the animal to have an undulating gait. We conjecture that these behaviors are advantageous to the animals, and thus evolution may have favored microorganism that swim with an undulating gait. PMID- 27123374 TI - GATA transcription factors as tissue-specific master regulators for induced responses. AB - GATA transcription factors play important roles in directing developmental genetic programs and cell differentiation, and are conserved in animals, plants and fungi. C. elegans has 11 GATA-type transcription factors that orchestrate development of the gut, epidermis and vulva. However, the expression of certain GATA proteins persists into adulthood, where their function is less understood. Accumulating evidence demonstrates contributions of 2 terminal differentiation GATA transcription factors, ELT-2 and ELT-3, to epithelial immune responses in the adult intestine and epidermis (hypodermis), respectively. Involvement in other stress responses has also been documented. We recently showed that ELT-2 acted as a tissue-specific master regulator, cooperating with 2 transcription factors activated by the p38 pathway, ATF-7 and SKN-1, to control immune responses in the adult C. elegans intestine. Here, we discuss the broader implications of these findings for understanding the involvement of GATA transcription factors in adult stress responses, and draw parallels between ELT-2 and ELT-3 to speculate that the latter may fulfill similar tissue-specific functions in the epidermis. PMID- 27123375 TI - New insights into the metabolic and nutritional determinants of severe combined immunodeficiency. AB - Human mutations in MTHFD1 have recently been identified in patients with severe combined immunodeficiency (SCID). SCID results from inborn errors of metabolism that cause impaired T- and B-cell proliferation and function. One of the most common causes of SCID is adenosine deaminase (ADA) deficiency, which ultimately inhibits DNA synthesis and cell division. MTHFD1 has been shown to translocate to the nucleus during S-phase of the cell cycle; this localization is critical for synthesis of thymidyate (dTMP or the "T" base in DNA) and subsequent progression through the cell cycle and cell proliferation. Identification of MTHFD1 mutations that are associated with SCID highlights the potential importance of adequate dTMP synthesis in the etiology of SCID. PMID- 27123377 TI - A comparison of species composition and community assemblage of secondary forests between the birch and pine-oak belts in the mid-altitude zone of the Qinling Mountains, China. AB - The mid-altitude zone of the Qinling Mountains in China was once dominated by birch and pine-oak belts but are now mainly covered by secondary growth following large-scale deforestation. Assessing the recovery and sustainability of these forests is essential for their management and restoration. We investigated and compared the tree species composition and community assemblages of secondary forests of the birch and pine-oak belts in the Huoditang forest region of the Qinling Mountains after identical natural recoveries. Both types of belts had rich species compositions and similar floristic components but clearly different community structures. Tree diversity was significantly higher for the birch than the pine-oak belt. Niche and neutral processes simultaneously influenced the species distribution and community dynamics of the belts, and these forests were able to maintain stable development during natural recoveries. The conservation and management of these forests should receive more attention to protect biodiversity and the forest resources in the Qinling Mountains. PMID- 27123376 TI - Plastome data reveal multiple geographic origins of Quercus Group Ilex. AB - Nucleotide sequences from the plastome are currently the main source for assessing taxonomic and phylogenetic relationships in flowering plants and their historical biogeography at all hierarchical levels. One major exception is the large and economically important genus Quercus (oaks). Whereas differentiation patterns of the nuclear genome are in agreement with morphology and the fossil record, diversity patterns in the plastome are at odds with established taxonomic and phylogenetic relationships. However, the extent and evolutionary implications of this incongruence has yet to be fully uncovered. The DNA sequence divergence of four Euro-Mediterranean Group Ilex oak species (Quercus ilex L., Q. coccifera L., Q. aucheri Jaub. & Spach., Q. alnifolia Poech.) was explored at three chloroplast markers (rbcL, trnK/matK, trnH-psbA). Phylogenetic relationships were reconstructed including worldwide members of additional 55 species representing all Quercus subgeneric groups. Family and order sequence data were harvested from gene banks to better frame the observed divergence in larger taxonomic contexts. We found a strong geographic sorting in the focal group and the genus in general that is entirely decoupled from species boundaries. High plastid divergence in members of Quercus Group Ilex, including haplotypes shared with related, but long isolated oak lineages, point towards multiple geographic origins of this group of oaks. The results suggest that incomplete lineage sorting and repeated phases of asymmetrical introgression among ancestral lineages of Group Ilex and two other main Groups of Eurasian oaks (Cyclobalanopsis and Cerris) caused this complex pattern. Comparison with the current phylogenetic synthesis also suggests an initial high- versus mid-latitude biogeographic split within Quercus. High plastome plasticity of Group Ilex reflects geographic area disruptions, possibly linked with high tectonic activity of past and modern distribution ranges, that did not leave imprints in the nuclear genome of modern species and infrageneric lineages. PMID- 27123378 TI - Natural melatonin fluctuation and its minimally invasive simulation in the zebra finch. AB - Melatonin is a key hormone in the regulation of circadian rhythms of vertebrates, including songbirds. Understanding diurnal melatonin fluctuations and being able to reverse or simulate natural melatonin levels are critical to investigating the influence of melatonin on various behaviors such as singing in birds. Here we give a detailed overview of natural fluctuations in plasma melatonin concentration throughout the night in the zebra finch. As shown in previous studies, we confirm that "lights off" initiates melatonin production at night in a natural situation. Notably, we find that melatonin levels return to daytime levels as early as two hours prior to the end of the dark-phase in some individuals and 30 min before "lights on" in all animals, suggesting that the presence of light in the morning is not essential for cessation of melatonin production in zebra finches. Thus, the duration of melatonin production seems not to be specified by the length of night and might therefore be less likely to directly couple circadian and annual rhythms. Additionally, we show that natural melatonin levels can be successfully simulated through a combination of light treatment (daytime levels during subjective night) and the application of melatonin containing skin-cream (nighttime levels during subjective day). Moreover, natural levels and their fluctuation in the transition from day to night can be imitated, enabling the decoupling of the effects of melatonin, for example on neuronal activity, from sleep and circadian rhythmicity. Taken together, our high-resolution profile of natural melatonin levels and manipulation techniques open up new possibilities to answer various melatonin related questions in songbirds. PMID- 27123379 TI - Thermal summation model and instar determination of all developmental stages of necrophagous beetle, Sciodrepoides watsoni (Spence) (Coleoptera: Leiodidae: Cholevinae). AB - Necrophagous beetles are underrepresented in forensic entomology studies despite their undeniable utility for the field. In the present article, information is presented regarding the developmental biology and instar determination of Sciodrepoides watsoni (Spence, 1813), a very common species occurring across the Holarctic region. Wild collected beetles were kept in climate chambers at constant temperature (12, 15, 18, 21 and 28 degrees C) and their development was regularly documented. Parameters of thermal summation models and standard errors were calculated for each developmental stage. These models may be used for an estimation of post-mortem interval in legal investigations after further validation on local populations of S. watsoni. An additional methodology is introduced for future studies of size-based characteristics, addressing instar identification bias. The methodology provided estimations (mean, standard error and standard deviation) of S. watsoni larval head capsule width for preliminary larval instar determination. The methodology may be used with other morphological features to improve instar determination accuracy. PMID- 27123380 TI - Factors that influence the beta-diversity of spider communities in northwestern Argentinean Grasslands. AB - Beta-diversity, defined as spatial replacement in species composition, is crucial to the understanding of how local communities assemble. These changes can be driven by environmental or geographic factors (such as geographic distance), or a combination of the two. Spiders have been shown to be good indicators of environmental quality. Accordingly, spiders are used in this work as model taxa to establish whether there is a decrease in community similarity that corresponds to geographic distance in the grasslands of the Campos & Malezales ecoregion (Corrientes). Furthermore, the influence of climactic factors and local vegetation heterogeneity (environmental factors) on assemblage composition was evaluated. Finally, this study evaluated whether the differential dispersal capacity of spider families is a factor that influences their community structure at a regional scale. Spiders were collected with a G-Vac from vegetation in six grassland sites in the Campos & Malezales ecoregion that were separated by a minimum of 13 km. With this data, the impact of alpha-diversity and different environmental variables on the beta-diversity of spider communities was analysed. Likewise, the importance of species replacement and nesting on beta-diversity and their contribution to the regional diversity of spider families with different dispersion capacities was evaluated. The regional and site-specific inventories obtained were complete. The similarity between spider communities declined as the geographic distance between sites increased. Environmental variables also influenced community composition; stochastic events and abiotic forces were the principal intervening factors in assembly structure. The differential dispersal capacity of spider groups also influenced community structure at a regional scale. The regional beta-diversity, as well as species replacement, was greater in high and intermediate vagility spiders; while nesting was greater in spiders with low dispersion capacity. Geographic distance, among other factors (climate, and active and passive dispersion capacity), explains assembly structure and the decrease spider community similarity between geographically distant sites. Spiders with the highest dispersal capacity showed greater species replacement. This may be due to the discontinuity (both natural and anthropic) of the grasslands in this ecoregion, which limits the dispersal capacity of these spiders, and their close dependence on microhabitats. The dispersal capacity of the least vagile spiders is limited by geographic distance and biotic factors, such as competition, which could explain the nesting observed between their communities. PMID- 27123381 TI - Growth and physiological responses of submerged plant Vallisneria natans to water column ammonia nitrogen and sediment copper. AB - Background. The decline of submerged plant populations due to high heavy metal (e.g., Cu) levels in sediments and ammonia nitrogen (ammonia-N) accumulation in the freshwater column has become a significant global problem. Previous studies have evaluated the effect of ammonia-N on submerged macrophytes, but few have focused on the influence of sediment Cu on submerged macrophytes and their combined effects. Methods. In this paper, we selected three levels of ammonia-N (0, 3, and 6 mg L(-1)) and sediment Cu (25.75 +/- 6.02 as the control, 125.75 +/- 6.02, and 225.75 +/- 6.02 mg kg(-1)), to investigate the influence of sediment Cu and ammonia-N on submerged Vallisneria natans. We measured the relative growth rate (RGR), above- and below- ground biomass, chlorophyll, non-protein thiol (NP SH), and free proline. Results and Discussion. The below-ground biomass of V. natans decreased with increasing Cu sediment levels, suggesting that excessive sediment Cu can result in significant damage to the root of V. natans. Similarly, the above-ground biomass significantly decreased with increasing ammonia-N concentrations, indicating that excessive water ammonia-N can cause significant toxicity to the leaf of V. natans. In addition, high ammonia-N levels place a greater stress on submerged plants than sediment Cu, which is indicated by the decline of RGR and chlorophyll, and the increase of (NP-SH) and free proline. Furthermore, high sediment Cu causes ammonia-N to impose greater injury on submerged plants, and higher sediment Cu levels (Cu >= 125.75 mg kg(-1)) led to the tolerant values of ammonia-N for V. natans decreasing from 6 to 3 mg L(-1). This study suggests that high sediment Cu restricts the growth of plants and intensifies ammonia-N damage to V. natans. PMID- 27123382 TI - Winter diet and food selection of the Black-necked Crane Grus nigricollis in Dashanbao, Yunnan, China. AB - The Black-necked Crane Grus nigricollis is a globally vulnerable species whose food is the factor determining its long-term survival. Understanding dietary habits, food preferences, and related factors will facilitate the development of effective conservation plans for the protection of this vulnerable species. For this purpose, we used video recordings and sampling of food availability to examine the dietary composition and temporal variation in food selection of Black necked Cranes wintering in the Dashanbao National Nature Reserve, China. The Black-necked Crane's diet consists primarily of domestic food crops such as grains (74%) and potatoes (8%), in addition to invertebrates (14%). A much smaller proportion of the diet was comprised of turnips and wild herbaceous plants and tubers. There was monthly variation in food selection, partially related to food availability. Grains were most available in November and decreased through the winter, whereas invertebrates were more available in November and February than in December and January. Grain consumption was lowest in November but higher from December through February. Invertebrate consumption was highest in November and February. The cranes preferred to eat grains throughout winter months, while they mainly selected invertebrates in November and February. We suggested invertebrate populations sharply declined in December and January due to the low temperature. In addition, grain consumption was negatively associated with invertebrate availability. In November, when invertebrates were most abundant, and despite a concomitant peak in grain abundance, we suggested cranes exhibited a preference for invertebrates over grains. We recommend that the protection administration provide appropriate supplemental foods for cranes during freezing weather. PMID- 27123383 TI - An Overview of Head and Neck Malignancy with Perineural Spread. AB - This article provides an overview of perineural spread of head and neck malignancy. It defines the problem and explores some of the unique features, which occur with this pathology. The expectation is for a better understanding of this extraordinary disease, hopefully leading to earlier diagnosis and for a more consistent reporting of results. It summarizes the topics to be covered in this special edition, which should leave the reader with a fairly complete understanding of the contemporary issues of perineural spread. PMID- 27123386 TI - The Natural History and Treatment Outcomes of Perineural Spread of Malignancy within the Head and Neck. AB - Understanding the natural history of diseases enables the clinician to better diagnose and treat their patients. Perineural spread of head and neck cancers are poorly understood and often diagnosis is delayed resulting in poorer outcomes and more debilitating treatments. This article reviews a large personal series of head and neck malignancy presenting with perineural spread along almost exclusively the trigeminal and/or facial nerves. A detailed analysis of squamous cell carcinoma of cutaneous origin is presented including an analysis of likely primaries, which most often have occurred months to years prior. The importance of early detection is reinforced by the highly significant (p < 0.0001) differences in disease specific survival, which occur, depending on how far along a cranial nerve the disease has been allowed to spread. PMID- 27123385 TI - Mechanisms of Perineural Invasion. AB - Perineural invasion (PNI) is the neoplastic invasion of nerves. PNI is widely recognized as an important adverse pathological feature of many malignancies, including pancreatic, prostate, and head and neck cancers and is associated with a poor prognosis. Despite widespread acknowledgment of the clinical significance of PNI, the mechanisms underlying its pathogenesis remain largely unknown. Recent theories of PNI pathogenesis have placed a significant emphasis on the active role of the nerve microenvironment, with PNI resulting from well-orchestrated reciprocal interactions between cancer and host. Elucidating the mechanisms involved in PNI may translate into targeted therapies for this ominous process. PMID- 27123387 TI - The Imaging of Large Nerve Perineural Spread. AB - We present a review of the imaging findings of large nerve perineural spread within the skull base. The MRI techniques and reasons for performing different sequences are discussed. A series of imaging examples illustrates the appearance of perineural tumor spread with an emphasis on the zonal staging system. PMID- 27123384 TI - Perineural Spread in Noncutaneous Head and Neck Cancer: New Insights into an Old Problem. AB - Head and neck malignancies have the propensity to invade nerves. Perineural tumor invasion is common, with some series reporting rates of 30 to 100%. Squamous cell carcinoma and adenoid cystic carcinoma are the most commonly involved tumors. The most commonly involved nerves are the trigeminal (cranial nerve [CN] V) and facial (CN VII) and their branches. Neural spread away from a tumor is encountered less often and usually causes specific symptoms such as pain, muscle weakness, and atrophy, depending on the involved nerves. While clinical symptoms and physical examination may suggest the presence of neural invasion, specific imaging modalities such as fat-suppressed T1-weighted magnetic resonance images, should be utilized to identify perineural tumor spread in its early phases. Perineural tumor spread should be considered and addressed in the treatment planning of patients with head and neck or skull base cancers as it can influence the extent of surgery, and the dosage and fields of radiation therapy. In the current review, we discuss the clinical course of perineural tumor spread and its therapeutic implications. PMID- 27123388 TI - Pathology of Perineural Spread. AB - The perineural space is a compartment located between the nerve axons, supporting cells and tissues, and the epineural fibrous sheath. Tumor cells invade this space in response to a complex interplay of trophic factors in the local microenviroment. This attraction of tumor cells to nerves is referred to as neurotropism. The perineural space provides a conduit for tumor spread beyond the primary site of tumor occurrence. Perineural tumor growth is of two types: perineural invasion, affecting small unnamed nerves; and perineural spread, affecting larger, named nerves and presenting with clinical symptoms related to the involved nerve. Both forms of perineural tumor growth represent an adverse prognostic feature and are an essential element of the histopathologic reporting of malignancies of the head and neck region. Perineural spread is associated with decreased overall survival. Endoneurial invasion frequently accompanies perineural spread. The epineurium is more resistant to invasion and represents an important barrier to tumor spread. Immunohistochemical stains such as broad spectrum keratin can aid in defining the proximal extent of perineural tumor spread. PMID- 27123390 TI - Surgical Management of Perineural Spread of Head and Neck Cancers. AB - The surgical management of perineural spread of head and neck cancers has become an integral part in the contemporary treatment of this pathology. We now understand that tumour spreads within the epineurium and in a continuous fashion. We also can rely on the accuracy of magnetic resonance neurography in detecting and defining the extent of disease. With modern skull base techniques and a greater understanding of the anatomy in this region, specific operations can be designed to help eradicate disease. We review the current approaches and techniques used that enable us to better obtain tumour free margins and hence improve survival. PMID- 27123389 TI - Perineural Spread of Head and Neck Cancer: Ophthalmic Considerations. AB - Head and neck malignancies with orbital involvement present difficult decisions to the treating physician. When the spread is perineural, the challenges are greater due to the incipient nature of the spread and the fact that the orbit can also be involved by centrifugal spread from the non-ophthalmic branches of the trigeminal nerve. The disease is often misdiagnosed and the subsequent delay in treatment results in worse outcomes. This article discusses the evaluation of the eye and the many facets of orbital involvement by perineural spread of malignancy including the treatment of complications. PMID- 27123392 TI - Reconstruction of the Base of Skull Defect-Lessons Learned over 25 Combined Years. AB - With an increased understanding of the pathological processes involved in perinerual spread, surgery has come to play a greater role in its management. As skull base techniques have been refined, the reconstructive surgeon has been presented with increasingly complex and voluminous defects requiring repair. To enable such surgery to have acceptable outcomes, attention to form and function is paramount. This article describes the methods of repair, which have evolved over the last 25 years of practice, and that we find to be both reliable and durable. Our accumulated experience is presented as a treatment algorithm, which will aid the skull base reconstructive surgeon to achieve success for the wide variety of defects encountered with these patients. PMID- 27123391 TI - Intracranial Management of Perineural Spread in the Trigeminal Nerve. AB - Since the mid-1960s surgeons have attempted to cure intracranial perineural spread (PNS) of cutaneous malignancies. Untreated patients with trigeminal PNS die from brainstem invasion and leptomeningeal disease. It was understood that resection with clear margins was potentially curative, but early surgical attempts were unsuccessful. The prevailing wisdom considered that this surgery failed to improve the results achieved with radiation therapy alone and was associated with high morbidity. However, with improved imaging, surgical equipment, and better understanding of cavernous sinus (CS) anatomy and access, contemporary surgeons can improve outcomes for this disease. The aim of this paper is to describe a technique to access the interdural compartment of the CS and treat PNS of cutaneous squamous cell carcinoma (cSCC) in the intracranial trigeminal nerve and ganglion. It is based on the experience of the Queensland Skull Base Unit, Australia in managing PNS of cutaneous squamous cell carcinoma of the head and neck (cSCCHN). PMID- 27123393 TI - Definitive Radiotherapy for Skin and Adenoid Cystic Carcinoma with Perineural Invasion. AB - Adenoid cystic carcinomas (ACC) and, to a lesser extent, cutaneous squamous cell carcinomas and basal cell carcinomas may exhibit perineural invasion (PNI). A subset of patients have tumors with extensive PNI tracking to the skull base that are incompletely resectable and are treated with definitive radiotherapy (RT). RT may be administered with intensity-modulated RT or proton RT. Patients with ACC may also be considered for neutron RT, although the number of available neutron facilities is limited. A substantial proportion of patients with incompletely resectable ACCs and cutaneous carcinomas may be cured with definitive RT. Proton RT provides a more conformal dose distribution compared with other modalities and is likely associated with a lower risk of complications. PMID- 27123394 TI - The Role of Postoperative Radiotherapy for Large Nerve Perineural Spread of Cancer of the Head and Neck. AB - Large nerve perineural spread (LNPNS) is an uncommon but serious sequelae of cutaneous and salivary gland malignancies arising in the head and neck. This distinct clinical entity is caused by malignant cell spread along the course of larger (named) cranial nerves in a bidirectional pattern of spread toward the origins of the nerve in the brainstem and/or its most distal branches residing in the dermis. Untreated, LNPNS causes multiple cranial neuropathies that significantly impact on quality of life and ultimately is fatal. Curative treatment involves en bloc surgical resection of all known involved sites of gross disease followed by risk-adapted postoperative radiotherapy (PORT) to improve local control. We review the evidence for contemporary practice and outline the processes involved in the delivery of PORT using the zonal anatomical classification. PMID- 27123395 TI - Postoperative Imaging and Surveillance in Large Nerve Perineural Spread. AB - We present a review of the imaging surveillance following treatment for large nerve perineural spread in the skull base. The expected appearance and possible complications following surgery and radiotherapy are discussed. Imaging examples of the possible sites of disease recurrence are also presented. PMID- 27123396 TI - Conservative Management of Pneumoperitoneum in Necrotising Enterocolitis- Is it Possible? AB - INTRODUCTION: Necrotizing enterocolitis (NEC) is a common in neonatal intensive care unit (NICU) patients; especially in premature and low birth weight ones. Surgery is indicated when there is pneumoperitoneum. Other therapies include conservative observation or primary peritoneal drain (PPD). This study was conceived to evaluate peritoneal tapping, rather than primary peritoneal drain (PPD) as a treatment of NEC. MATERIAL AND METHODS: This prospective observational study conducted from December 2012 to December 2014 and including all patients of NEC having pneumoperitoneum on X-ray. RESULTS: There were 12 patients of NEC. Seven patients responded to single peritoneal tapping. Three patients needed one more tapping. Laparotomy was required in remaining two patients. One patient, who underwent laparotomy, expired due to severe sepsis. The mean duration of follow up was 4.83 months (range 2 to 8). CONCLUSION: Peritoneal tapping in NEC who develops pneumoperitoneum appears to be a viable option. Further studies in this regard may substantiate this mode of therapy. PMID- 27123397 TI - Neonatal Duodenal Obstruction: A 15-Year Experience. AB - BACKGROUND: Congenital duodenal obstruction is one of the commonest causes of neonatal intestinal obstruction. We are presenting our 15-year experience by analyzing clinical spectrum and outcome in neonates with duodenal obstruction admitted at our center. MATERIAL AND METHODS: The hospital records of all neonates admitted with duodenal obstruction from June 2000 to June 2015 were reviewed. The patient records were analyzed for antenatal diagnosis, age, sex, clinical presentation, diagnosis, associated anomalies, surgical procedures performed; postoperative morbidity and mortality. We excluded from our study malrotation of gut associated with congenital diaphragmatic hernia and abdominal wall defects. RESULTS: A total of 81 patients were admitted, out of which 56 were males and 25 were females. Polyhydramnios was detected in 24 (30%) pregnancies. Average birth weight was 2.1+/-1.0Kg and average gestational age was 38 (SD+/-1) weeks with 17 (21%) preterm neonates. Presenting features were vomiting in 81(100%) which was bilious in 81% and non-bilious in 19%, epigastric fullness in 56 (69%) and dehydration in 18 (22%) and failure to thrive in 16 (19%). Most common cause of obstruction was duodenal atresia in 38 (46.9%), followed by malrotation of gut in 33 (40.7%), and annular pancreas in 4 cases. Depending upon site of location, infra-ampullary obstruction was the most common in 64 (79%), supra-ampullary in 9 (7.4%) and ampullary 8 neonates. Both duodenal atresia and malrotation of gut was present in 4 cases. X-ray abdomen was most commonly used investigation to confirm the diagnosis. All cases were managed surgically by open laparotomy. Eleven (13.5%) patients died due to sepsis and associated congenital anomalies. CONCLUSION: Congenital duodenal obstruction most commonly presents in early neonatal period with features of upper GIT obstruction like vomiting and epigastrium fullness as in our series. Early antenatal diagnosis and surgical interventions hold the key in achieving good outcome. Associated congenital anomalies, prematurity, sepsis and delayed presentation are the main risk factors for post-operative mortality and morbidity. PMID- 27123399 TI - Retroperitoneal Mature Cystic Teratoma in a Neonate: A Case Report. AB - We report a case of retroperitoneal mature cystic teratoma in a 2-day-old neonate. Diagnostic and surgical procedure including its complexity and relevant literature review has been discussed. PMID- 27123398 TI - Gallbladder Duplication Associated with Gastro-Intestinal Atresia. AB - Gallbladder duplication in association with other GIT anomalies is a rare entity. We report two neonates; one with duodenal atresia and the other newborn with pyloric atresia, ileal atresia and colonic atresia, both were associated with gallbladder duplication which has not been reported earlier. PMID- 27123400 TI - Sacral Rachipagus Parasite: A Case Report. AB - We are reporting a case of sacral rachipagus parasite which was vaginally delivered as a large irregular mass attached to the sacral region by a vascular pedicle. This case was managed successfully by surgical excision of parasite. PMID- 27123401 TI - Cloacal Exstrophy with Mature Teratoma: A Rare Association in a Neonate. AB - Cloacal exstrophy is a very rare and complex malformation. We report a neonate of cloacal exstrophy with mature teratoma presenting as a component of exstrophy. To our knowledge this has not been reported in the literature. PMID- 27123402 TI - Mass Effect of Pulmonary Sequestration: Multiloculated-Multiseptated Pneumomediastinum. AB - Pulmonary sequestration (PS) and pneumomediastinum are two rare clinical diseases. Pneumomediastinum was generally observed in infants either with diseased lungs or who were performed assisted ventilation or resuscitation following birth. It was reported in patients with existing ectopic thoracic kidney and laryngeal cysts however, no coexisting congenital lung anomalies were reported. Here, we report the pneumomediastinum occurred due the extralobar PS because of the mass effect of the lesion. PMID- 27123403 TI - Postoperative Spontaneous Gastric Perforation in a Ruptured Exomphalos: A Case Report. AB - Spontaneous gastric perforation is a rare entity in neonates. We report a case of spontaneous gastric perforation in a neonate operated for in-utero rupture of omphalocele. PMID- 27123404 TI - Primary Transanal Management of Rectal Atresia in a Neonate. AB - Rectal atresia (RA) with a normal anus is a rare anomaly. We describe a case of rectal atresia in a newborn male presenting with an abdominal distension and failure of passing meconium. The rectal atresia was primarily operated by transanal route. PMID- 27123405 TI - Immature Gastric Teratoma in a Newborn: A Case Report. AB - A case of immature gastric teratoma in a neonate is being reported here. The neonate was presented with abdominal mass and distension and managed with excision of mass; the patient is doing fine postoperatively. PMID- 27123406 TI - Neonatal Adrenal Hemorrhage presenting as Prolonged Hyperbilirubinemia. PMID- 27123407 TI - Pneumothorax in a Neonate after Foreign Body Ingestion. PMID- 27123408 TI - Pure Esophageal Atresia without a Gap: An Unusual Variant. PMID- 27123409 TI - Gastroschisis with Concomitant Jejuno-Ileal Atresia Complicated by Jejunal Perforation. PMID- 27123410 TI - Erratum: Laparoscopic Pyloromyotomy: A Modified Simple Technique. AB - [This corrects the article on p. 3 in vol. 5, PMID: 26793595.]. PMID- 27123411 TI - Ranking Predatory Journals: Solve the Problem Instead of Removing It! AB - Predatory journals are a well-known issue for scholarly publishing and they are repositories for bogus research. In recent years, the number of predatory journals has risen and it is necessary to present a solution for this challenge. In this paper, we will discuss about a possible ranking of predatory journals. Our ranking approach is based on Beall's criteria for detection of predatory journals and it can help editors to improve their journals or convert their questionable journals to non-predatory ones. Moreover, our approach could help young editors to protect their journals against predatory practice. Finally, we present a case study to clarify our approach. PMID- 27123412 TI - Cord Blood Mononuclear Cells Have a Potential to Produce NK Cells Using IL2Rg Cytokines. AB - PURPOSE: Although bone marrow represents the main site for NK cell development and also distinct thymic-dependentNK cell pathway was identified, the cytokines effect on the NK cell generation from cord blood is unclear. Studies were identified the role of cytokines in the regulation of bone marrow and thymic NK cells. Previous studies reported that IL15 are critical for bone marrow dependent and IL7 is important for thymic NK cells. It is remain unclear the cytokines influence on the expantion of NK cells in cord blood mononuclear cells. METHODS: We evaluated cultured cord blood mononuclear cells suplememnted with combinations of cytokines using FACS in distinct time points. In this study, we presented the role of IL2, IL7 and IL15 as members of the common gamma receptor -chain (Il2rg) on the expansion NK cells from cord blood cells. RESULTS: By investigating cord blood mononuclear cells in vitro , we demonstrated that IL2 and IL15 are important for expansion of NK cells. IL2 in comparision with IL15 has more influences in NK cell expansion. In contrast IL-7 is dispensable for NK cell generation in cord blood. CONCLUSION: Thus,IL-2Rg cytokines play complementary roles and are indispensable for homeostasis of NK cell development in cord blood. Probably these cytokines could help to use NK beneficials in engrafment of transplanted cells and Anti tumor activity of NK cells. PMID- 27123413 TI - Sustained release Curcumin loaded Solid Lipid Nanoparticles. AB - PURPOSE: curcumin is poorly water soluble drug with low bioavailability. Use of lipid systems in lipophilic substances increases solubility and bioavailability of poorly soluble drugs. The aim of this study was to prepare curcumin loaded Solid Lipid Nanoparticles (SLNs) with high loading efficiency, small particle size and prolonged release profile with enhanced antibacterial efficacy. METHODS: to synthesize stable SLNs, freeze- Drying was done using mannitol as cryoprotectant. Cholesterol was used as carrier because of good tolerability and biocompatibility. SLNs were prepared using high pressure homogenization method. RESULTS: optimized SLNs had 112 and 163 nm particle size before and after freeze drying, respectively. The prepared SLNs had 71% loading efficiency. 90% of loaded curcumin was released after 48 hours. Morphologic study for formulation was done by taking SEM pictures of curcumin SLNs. RESULTS show the spherical shape of curcumin SLNs. DSC studies were performed to determine prolonged release mechanism. Antimicrobial studies were done to compare the antimicrobial efficacy of curcumin SLNs with free curcumin. DSC studies showed probability of formation of hydrogen bonds between cholesterol and curcumin which resulted in prolonged release of curcumin. Lipid structure of cholesterol could cause enhanced permeability in studied bacteria to increase antibacterial characteristics of curcumin. CONCLUSION: the designed curcumin SLNs could be candidate for formulation of different dosage forms or cosmeceutical products. PMID- 27123414 TI - The Effect of Bone Marrow Mesenchymal Stem Cells on Vitamin D3 Induced Monocytic Differentiation of U937 Cells. AB - PURPOSE: Mesenchymal stem cells (MSCs) are key components of the hematopoietic stem cells (HSCs) niche. They control the process of hematopoiesis by secreting regulatory cytokines, growth factors and expression of important cell adhesion molecules for cell-tocell interactions. In this research, we have investigated the effect of bone marrow derived MSCs on monocytic differentiation of U937 cells line. METHODS: U937 cells were cultured in both direct co-culture with MSCs and MSCs conditioned medium (C.M) driven. This study used 1,25-dihydroxyvitamin D3(VitD3) as inductor of monocytic differentiation and U937 cells treated with VitD3 morphology was examined by Wright Giemsa staining. CD14 monocytic differentiation marker was measured by flow cytometry and monocytic gene expression was assessed by real time polymerase chain reaction (RT PCR). RESULTS: The results of flow cytometric analysis showed that CD14 expression of U937 increased. The higher effect of MSCs co-culture on CD14 expression in U937 cells was observed, compared to the conditioned medium. Among ten monocytic related genes which were screened that was observed increase in 5 genes in which CXCR4 and CSF2RA showed significant increase. CONCLUSION: The results obtained show that MSCs have supportive effect on the monocytic differentiation of U937 cells. However, a distinct mechanism of that remains unclear. PMID- 27123415 TI - The Effect of Particle Size on the Deposition of Solid Lipid Nanoparticles in Different Skin Layers: A Histological Study. AB - PURPOSE: In the present study the effect of particle size, as a substantial parameters in skin penetration, on the deposition depth and rate of SLNs in different layers of skin was explored. METHODS: SLNs in different particle size ranges (80, 333 and 971 nm) made of Precirol as solid lipid were prepared using hot melt homogenization technique and pigmented by Rhodamine B to be able to be tracked in the skin under inspection of fluorescent microscopy. After 0.5 h, 3 h, 6 h and 24 h of SLNs administration on rat skin, animals were sacrificed and exercised skins were sliced by a freeze microtome. SLNs were monitored in the skin structure under fluorescence microscope. RESULTS: The size of SLNs played a crucial role in the penetration to deep skin layers. The sub100 nm size range of SLNs showed the most promising skin penetration rate and depth mainly via hair follicles. CONCLUSION: The results of the present study indicated that the selection of an appropriate size of particles may be a valuable factor impacting the therapeutic outcomes of dermal drug administration. PMID- 27123416 TI - Probiotic Assessment of Lactobacillus plantarum 15HN and Enterococcus mundtii 50H Isolated from Traditional Dairies Microbiota. AB - PURPOSE: Probiotics are microorganisms, which show beneficial health effects on hosts once consumed in sufficient amounts. Among probiotic bacteria, the bioactive compounds from lactic acid bacteria (LAB) group can be utilized as preservative agents. LAB group can be isolated and characterized from traditional dairy sources. This study aimed to isolate, identify, and biologically characterize probiotic LAB strains from Iranian traditional dairy products. METHODS: A total of 19 LAB strains were identified by sequencing of their 16S rRNA genes. They were examined for adherence to human intestinal Caco-2 cells and tolerance to low pH/high bile salts and simulated in vitro digestion conditions. Moreover, they were evaluated further to assess their ability to prevent the adhesion of Escherichia coli 026 to the intestinal mucosa, inhibitory functions against pathogens, and sensitivity to conventional antibiotics. RESULTS: L. plantarum 15HN and E. mundtii 50H strains displayed >= 71% survival rates at low pH/high bile salts and >= 40% survival rates in digestive conditions. Their adherences to Caco-2 cells were 3.2*105 and 2.6*105 CFU mL-1 respectively and high values of anti-adhesion capability were observed (>=36%). They inhibited the growth of 13 and 11 indicator pathogens respectively. Moreover, they were sensitive or semi-sensitive to seven and three out of eight antibiotics respectively. CONCLUSION: L. plantarum 15HN and E. mundtii 50H, which were isolated from shiraz product, displayed above-average results for all of the criteria. Therefore, they can be introduced as novel candidate probiotics that could be used in the food industry. PMID- 27123417 TI - Expression of Functional Recombinant Human Tissue Transglutaminase (TG2) Using the Bac-to-Bac Baculovirus Expression System. AB - PURPOSE: Tissue transglutaminase (TG2) is a unique multifunctional enzyme. The enzyme possesses enzymatic activities such as transamidation/crosslinking and non enzymatic functions such as cell migration and signal transduction. TG2 has been shown to be involved in molecular mechanisms of cancers and several neurodegenerative diseases such as Alzheimer's disease. The present study aimed at cloning and expression of full length human TG2 in Bac-to-Bac baculovirus expression system and evaluation of its activity. METHODS: pFastBac HTA donor vector containing coding sequence of human TG2 was constructed. The construct was transformed to DH10Bac for generating recombinant bacmid. The verified bacmid was transfected to insect cell line (Sf9). Expression of recombinant TG2 was examined by RT-PCR, SDS-PAGE and western blot analysis. Functional analysis was evaluated by fluorometric assay and gel electrophoresis. RESULTS: Recombinant bacmid was verified by amplification of a band near to 4500 bp. Expression analysis showed that the enzyme was expressed as a protein with a molecular weight near 80 kDa. Western blot confirmed the presence of TG2 and the activity assays including flurometric assay indicated that the recombinant TG2 was functional. The electrophoresis assay conformed that the expressed TG2 was the indeed capable of crosslinking in the presence of physiological concentration calcium ions. CONCLUSION: Human TG2 was expressed efficiently in the active biological form in the Bac-to-Bac baculovirus expression system. The expressed enzyme could be used for medical diagnostic, or studies which aim at finding novel inhibitors of the enzymes . To best of our knowledge, this is probably the first report of expression of full length human tissue transglutaminase (TG2) using the Bac-to Bac expression system. PMID- 27123418 TI - Aggregated Nanotransfersomal Dry Powder Inhalation of Itraconazole for Pulmonary Drug Delivery. AB - PURPOSE: Local therapy is a valuable and strategic approach in the treatment of lung associated diseases and dry powder inhalation (DPI) formulations play the key role in this plan. Transfersome has been introduced as a novel biocompatible vesicular system with potential for administration in pulmonary drug delivery. The present study was designed to prepare Itraconazole-loaded nanotrantransfersomal DPI formulation. METHODS: Itraconazole-loaded nanotransfersomes with three different types of surfactant in varying concentrations were prepared and characterized in the point of particle size distribution and morphology by laser light scattering and scanning electron microscopy (SEM) methods. The optimized transferosomal formulations were co-spray dried with mannitol and the aerosolization efficiency and aerodynamic properties of dry powders were determined by next generation impactor using a validated HPLC technique. RESULTS: The volume mean diameter of optimized nanotransfersomal formulation with lecithin:Span(r) 60 in the ratio of 90:10 was 171 nm with narrow size distribution pattern which increased up to 518 nm after drug loading. Different types of surfactant did not influence the particle size significantly. SEM images confirmed the formation of aggregated nanoparticles in the suitable range (1-5 um) for the pulmonary drug delivery. Aerosolization evaluation of co spray dried formulations with different amounts of mannitol indicated that 2:1 ratio of mannitol:transfersome (w:w) showed the best aerosolization efficiency (fine particle fraction (FPF)=37%). Increasing of mannitol significantly decreased the FPF of the optimized formulations. CONCLUSION: The results of this study was introduced the potential application of nanotransfersomes in the formulation of DPIs for lung delivery of various drugs. PMID- 27123419 TI - Impact of Prunus Cerasus on PGR and HAS2 in Cumulus Cells and Fertility Outcome. AB - PURPOSE: Cumulus cells have a critical role in normal oocyte development and fertilization. Prunus cerasus is an anthocyanin rich berry and performs strong antioxidant activity. The present study set to determine if Prunus cerasus can affect expression of HAS2 (hyaluronan synthase 2) and progesterone receptor in Cumulus cells and its consequences outcome of the in vitro fertilization. METHODS: 60 female and 15 male adult mice were used for mating and IVF (in vitro fertilization). Prunus cerasus extraction was added to the diet of female mice for 30 days. Ovulation induction and oocytes collection were done as routine. The cumulus cells were dissected apart, and the expression of progesterone receptor and HAS2 was detected using RT-PCR (real-time polymerase chain reaction). Fertilization rate was evaluated by IVF. All data were analyzed using t-test. RESULTS: Data was showed that expression of progesterone receptor and HAS2 in cumulus cells of mice that received prunus cerasus increased. Moreover, oocyte fertilization rate also increased significantly. CONCLUSION: Prunus cerasus as an antioxidant natural can become an important medication for improving oocyte quality and opening new opportunities for infertility treatment. It is concluded that Prunus cerasus consumption could improve fertility rate by increasing progesterone receptor and HAS2 activity in cumulus cells. PMID- 27123420 TI - Investigation of DNA-damage and Chromosomal Aberrations in Blood Cells under the Influence of New Silver-based Antiviral Complex. AB - PURPOSE: The problem of infectious diseases and drug resistance is becoming increasingly important worldwide. Silver is extensively used as an anti-infective agent, but it has significant toxic side effects. In this regard, it is topical to develop new silver compounds with high biological activity and low toxicity. This work is aimed to study DNA damage and chromosomal aberrations in blood cells under the influence of new silver-based compound of general formula C6H19Ag2N4LiO6S2, with antiviral activity. METHODS: The comet assay was applied for the genotoxic affects assessment on mice blood leukocytes. DNA damage was determined bases on the percentage of DNA in a comet tail (tail DNA), under the influence of silver complex in different concentrations. Genotoxic effect of the tested substance on the somatic cells was determined by chromosomal aberration test of bone marrow cells of mice. RESULTS: In the course of the experiments, no essential changes in the level of DNA damage in the cells were found, even at highest concentrations. The administration of the substance in doses up to 2.5 g/kg in mice did not cause any increase in the frequency of chromosomal aberration in bone marrow cells. CONCLUSION: Taking into account known silver drug genotoxic properties, the use of a given complexed silver compound has possible great advantages for potential applications in the treatment of infectious diseases. PMID- 27123421 TI - Comparative Evaluation of Dexmedetomidine and Magnesium Sulphate on Propofol Consumption, Haemodynamics and Postoperative Recovery in Spine Surgery: A Prospective, Randomized, Placebo Controlled, Double-blind Study. AB - PURPOSE: Dexmedetomidine and magnesium sulfate have been used in anesthesia as adjuvant to provide hemodynamic stability and anesthetic agents sparing effect. We compared these effects of dexmedetomidine and magnesium sulfate in spine surgeries. METHODS: Ninety patients were randomly assigned to three groups. Group D received dexmedetomidine loading dose 1 ug/kg over a period of 15 minutes and maintenance 0.5 ug/kg/h throughout the surgery. Group M received magnesium sulfate loading dose 50 mg/kg over a period of 15 minutes and maintenance 15 mg/kg/h throughout the surgery. Group C received same volume of normal saline. Heart rate (HR) and blood pressure values were recorded at various intervals. The induction and maintenance doses of anesthetics and recovery parameters were also recorded. RESULTS: Heart rate in group D and group M were significantly decreased (p<0.05) during the whole intraoperative period compared to preoperative values. There was a significant difference in HR values between group C, D and M, during the whole intraoperaive period (p<0.05). Blood pressure values were statistically significantly lower in the group D and group M compared to group C after intubation and all time observations of surgery (p<0.05). Both drugs reduced the anesthetic agent's requirement during surgery. However, the recovery parameters were statistically significant increase with magnesium sulphate compared to dexmedetomidine and control groups. CONCLUSION: Dexmedetomidine is more effective than magnesium sulfate for maintaining the hemodynamic stability in spine surgeries. Both these drugs also reduce the requirements of anesthetic agents. Recovery from dexmedetomidine is as rapid as control group compared to magnesium sulfate. PMID- 27123422 TI - Preparation and Characterization of Nanosuspension of Aprepitant by H96 Process. AB - PURPOSE: Nanosuspension in drug delivery is known to improve solubility, dissolution and eventually bioavailability of the drugs. The purpose of the study was to compare particle size of nanosuspensions prepared by the first generation approach and H96 approach and to evaluate the effectiveness of H96 approach. METHODS: The nanosuspension of aprepitant was prepared by HPH and H96 approach. The prepared nanosuspensions were characterized for their particle size and zeta potential. The optimized nanosuspension was further evaluated for DSC, FT-IR, solubility and dissolution. RESULTS: The optimized nanosuspension (NCLH5) prepared using combination of tween 80 and poloxamer 188 as stabilizer, showed particle size of 35.82 nm and improved solubility and dissolution profile over pure drug. NCLH5 was chosen optimized formulation and further evaluated for other parameters after lyophilization. Lyophilization resulted in increase in particle size. The solubility and dissolution studies showed favorable increase in the performance. The FT-IR and DSC analysis showed change in the crystallinity after nanosizing. CONCLUSION: The observations indicated that lyophilization prior to high pressure homogenization resulted in efficient particle size reduction yielding smaller particles than first generation preparation technique. H96 is a good and easy alternative to achieve efficient particle size reduction of drug in lesser time and increase its solubility and dissolution. PMID- 27123423 TI - Design and Construction of Chimeric VP8-S2 Antigen for Bovine Rotavirus and Bovine Coronavirus. AB - PURPOSE: Bovine Rotavirus and Bovine Coronavirus are the most important causes of diarrhea in newborn calves and in some other species such as pigs and sheep. Rotavirus VP8 subunit is the major determinant of the viral infectivity and neutralization. Spike glycoprotein of coronavirus is responsible for induction of neutralizing antibody response. METHODS: In the present study, several prediction programs were used to predict B and T-cells epitopes, secondary and tertiary structures, antigenicity ability and enzymatic degradation sites. Finally, a chimeric antigen was designed using computational techniques. The chimeric VP8-S2 antigen was constructed. It was cloned and sub-cloned into pGH and pET32a(+) expression vector. The recombinant pET32a(+)-VP8-S2 vector was transferred into E.oli BL21CodonPlus (DE3) as expression host. The recombinant VP8-S2 protein was purified by Ni-NTA chromatography column. RESULTS: The results of colony PCR, enzyme digestion and sequencing showed that the VP8-S2 chimeric antigen has been successfully cloned and sub-cloned into pGH and pET32a(+).The results showed that E.coli was able to express VP8-S2 protein appropriately. This protein was expressed by induction of IPTG at concentration of 1mM and it was confirmed by Ni NTA column, dot-blotting analysis and SDS-PAGE electrophoresis. CONCLUSION: The results of this study showed that E.coli can be used as an appropriate host to produce the recombinant VP8-S2 protein. This recombinant protein may be suitable to investigate to produce immunoglobulin, recombinant vaccine and diagnostic kit in future studies after it passes biological activity tests in vivo in animal model and or other suitable procedure. PMID- 27123424 TI - Alteration in Inflammation-related miR-146a Expression in NF-KB Signaling Pathway in Diabetic Rat Hippocampus. AB - PURPOSE: The purpose of the present study is to evaluate the expression of miR 146a gene, its adaptor genes (TRAF6, NF-KB, and IRAK1), and possible changes in the cellular signaling pathway in diabetic hippocampus tissue. METHODS: Male Sprague-Dawley rats are randomly selected and divided into control and diabetic (n=6) groups. Diabetes induced by the single-dose injection of nicotinamide [110 mg/kg, (i.p.)], 15 min before streptozotocin (50 mg/kg; i.p.) in 12-h fasted rats. The rats are kept at the laboratory for two months. After anaesthetization, hippocampus of the rats was removed in order to measure the expression of miR 146a, NFK-B, IRAK1, and TRAF6 genes using real-time PCR and activity of NF-KB as well as amount of apoptosis rate using ELISA. RESULTS: The results indicated a reduction in expression of miR-146a and an increase in expression of IRAK1, NF KB, and TRAF6 genes in the hippocampus of diabetic rats compared to control. Also it reveals an increase in the activity of NF-KB and apoptosis rate in the hippocampus of diabetic rats. CONCLUSION: Our results report the probability that reduction of miR-146a expression in the negative feedback loop between miR-146a and NF-KB increases NF-kB expression and thus intensifies inflammation and apoptosis in hippocampus. PMID- 27123425 TI - Advantages of Sheep Infrapatellar Fat Pad Adipose Tissue Derived Stem Cells in Tissue Engineering. AB - PURPOSE: The goal of this study has been to evaluate adipose tissue derived stem cells (ADSCs) from infrapatellar fat pad and characterize their cell surface markers using anti-human antibodies, as adipose tissue derived stem cells (ADSCs) have great potential for cellular therapies to restore injured tissues. METHODS: Adipose tissue was obtained from infrapatellar fat pad of sheep. Surface markers evaluated by flow cytometry. In order to evaluate cell adhesion, the Polycaprolactone (PCL) was sterilized under Ultraviolet (UV) light and about 1*10(5) cells were seeded on PCL. Then, ASCs- PCL construct were evaluated by Scanning Electron Microscopy (Mira3 Te Scan, Czech Republic). RESULTS: We showed that adipose tissue derived stem cells (ADSCs) maintain their fibroblastic-like morphology during different subcultures and cell adhesion. They were positive for CD44 and CD90 markers and negative for CD31 and Cd45 markers by human antibodies. CONCLUSION: Our results suggest that ASCs surface markers can be characterized by anti-human antibodies in sheep. As stem cells, they can be used in tissue engineering. PMID- 27123426 TI - The Effects of Cetirizine on P-glycoprotein Expression and Function In vitro and In situ. AB - PURPOSE: P-glycoprotein (P-gp) plays a major role in oral absorption of drugs. Induction or inhibition of P-gp by drugs contributes to variability of its transport activity and often results in clinically relevant drug-drug interactions. The purpose of this study was to investigate the effect of cetirizine, a second generation H1 antihistamine, on P-gp function and expression in vitro and in situ. METHODS: The in-vitro rhodamin-123 (Rho123) efflux assay in Caco-2 cells was used to study the effect of cetirizine on P-gp function. Western blot analysis was used for surveying the effect of cetirizine on expression of P gp in Caco-2 cells. Rat in situ single-pass intestinal permeability technique was used to calculate the intestinal permeability of a known P-gp substrate (digoxin) in the presence of cetirizine. The amounts of digoxin and cetirizine in intestinal perfusion samples were analyzed using a HPLC method. RESULTS: The results showed significant increase in Rho123 uptake (P < 0.05) and also P-gp band intensity decrease in cetirizine-treated cells in vitro. Furthermore the intestinal permeability of digoxin was also increased significantly in the presence of cetirizine (P < 0.01). CONCLUSION: Therefore it is concluded that cetirizine is a P-gp inhibitor and this should be considered in co administration of cetrizine with other P-gp substrate drugs. Further investigations are required to confirm our results and to determine the mechanism underlying P-gp inhibition by cetirizine. PMID- 27123427 TI - Comparative Study of Different Combinational Mucoadhesive Formulations of Sumatriptan-Metoclopramide. AB - PURPOSE: Sumatriptan succinate (Sum) is a Serotonin 5- HT1 receptor agonist, used in the treatment of migraine. It is absorbed rapidly but incompletely when taken orally and underwent first - pass metabolism, resulting in a low bioavailability of about 15%. The aim was to design mucoadhesive buccal discs and sublingual films of Sum and metoclopramide (Met) combined to improve their bioavailability. METHODS: In the current study, the microparticles and films were prepared by emulsion solvent diffusion (ESD) and solvent casting methods, respectively. Buccal-mucoadhesive microparticles and films with different drug to polymer ratios were prepared and characterized by encapsulation efficiency, particle size, DSC (Differential Scanning Calorimetric), folding endurance, mucoadhesive property and drug release studies. RESULTS: The best drug/s to polymer ratios in films and microparticles were 1:2.7:8 (SM2) and 1:4:6 (SM4), respectively. The film of SM2 showed 11.01 mg weight, 123 um thickness and 300 folding endurance. The production yield was 107.33% for SM4 microparticles, 323.59 um for mean particle size and 94.53% for loading efficiency (for Sum) and 104.18% (for Met). The DSC showed no stable characteristic of Sum and Met in the drug loaded films/discs and revealed amorphous form and transition of hydrate to anhydrous form for Met. The films exhibited very good mucoadhesive properties and shorter retention time (15-30 s) in comparison with the discs (130 min). The results showed that the discs prepared had slower release than the films (p<0.05). CONCLUSION: Films and discs of Sum-Met combinations were successfully prepared with improved release and mucoadhesive properties. PMID- 27123428 TI - Chromatographic Fingerprint Analysis of Marrubiin in Marrubium vulgare L. via HPTLC Technique. AB - PURPOSE: In the present study we aimed to quantify marrubiin, as the major active compound, in the aerial parts of Marrubium vulgare from Iran using a HPTLC densitometry technique. METHODS: Quantitative determination of marrubiin in M. vulgare methanol extract was performed by HPTLC analysis via a fully automated TLC scanner. Later on, the in vitro antioxidant activity of the M. vulgare methanol extract was determined using 1,1-diphenyl-2-picryl-hydrazil (DPPH) free radical scavenging assay. Furthermore, total phenolics and flavonoids contents of the methanol extract were quantified, spectrophotometrically. RESULTS: The amount of marrubiin was calculated as 156 mg/g of M. vulgare extract. The antioxidant assay revealed a strong radical scavenging activity for the M. vulgare methanol extract with RC50 value of 8.24MUg/mL. Total phenolics and flavonoids contents for M. vulgare were determined as 60.4 mg gallic acid equivalent and 12.05 mg quercetin equivalent per each gram of the extract, correspondingly. CONCLUSION: The presented fingerprint of marrubiin in M. vulgare extract developed by HPTLC densitometry afforded a detailed chemical profile, which might be useful in the identification as well as quality evaluation of herbal medications based on M. vulgare. Besides, the considerable antioxidant activity of M. vulgare was associated with the presence of marrubiin along with phenolics and flavonoids exerting a synergistic effect. PMID- 27123429 TI - Stability-Indicating HPLC Method for Simultaneous Determination of Chloramphenicol, Dexamethasone Sodium Phosphate and Tetrahydrozoline Hydrochloride in Ophthalmic Solution. AB - PURPOSE: A simple stability-indicating RP-HPLC assay method was developed and validated for quantitative determination of Chloramphenicol, Dexamethasone Sodium Phosphate and Tetrahydrozoline Hydrochloride in ophthalmic solution in the presence of 2-amino-1-(4-nitrophenyl)propane-1,3-diol, a degradation product of Chloramphenicol, and Dexamethasone, a degradation product of Dexamethasone Sodium Phosphate. METHODS: Effective chromatographic separation was achieved using C18 column (250 mm, 4.6 mm i.d., 5 MUm) with isocratic mobile phase consisting of acetonitrile - phosphate buffer (pH 4.0; 0.05 M) (30:70, v/v) at a flow rate of 1 mL/minute. The column temperature was maintained at 40 degrees C and the detection wavelength was 230 nm. RESULTS: The proposed HPLC procedure was statistically validated according to the ICH guideline, and was proved to be stability-indicating by resolution of the APIs from their forced degradation products. CONCLUSION: The developed method is suitable for the routine analysis as well as stability studies. PMID- 27123430 TI - Pertinence of the recent school-based nutrition interventions targeting fruit and vegetable consumption in the United States:a systematic review. AB - BACKGROUND: Schools are the major locations for implementing children's dietary behavior related educational or interventional programs. Recently, there has been an increase in school-based nutrition interventions. The objective of this systematic review was to overview the evidence for the effectiveness of school based nutrition intervention on fruit and vegetable consumption. METHODS: PubMed was used to search for articles on school-based nutrition interventions that measured students' fruit and vegetable consumption. Our search yielded 238 articles.The article was included if published in a peer-reviewed journal, written in English language,administered in the United States, and conducted among a population-based sample of children in Kindergarten through eighth grade. A total of 14 publications met the inclusion criteria. RESULTS: Eight articles successfully showed the positive effect on increasing fruit and or vegetable consumption while the other six did not. Several factors, including (but not limited to) intervention duration, type of theory used, style of intervention leadership, and positively affecting antecedents of fruit and vegetable consumption were compared; however, no dominant factor was found to be shared among the studies with significant findings. Given that the criteria for selection were high, the lack of consistency between interventions and positive outcomes was surprising. CONCLUSION: With high levels of scrutiny and budget constraints on school nutrition, it is imperative that more research be conducted to identify the effective intervention components. PMID- 27123431 TI - Healthy Foods, Healthy Families: combining incentives and exposure interventions at urban farmers' markets to improve nutrition among recipients of US federal food assistance. AB - BACKGROUND: Healthy Foods, Healthy Families (HFHF) is a fruit and vegetable (F&V) exposure/incentive program implemented at farmers' markets in low-income neighborhoods, targeting families receiving US federal food assistance. We examined program effects on participants' diet and associations between attendance, demographics and dietary change. METHODS: Exposure activities included F&V tastings and cooking demonstrations. Incentives included 40% F&V bonus for electronic benefit transfer (EBT) card users and $20 for use purchasing F&V at every third market visit. Self-report surveys measuring nutritional behaviors/literacy were administered to participants upon enrollment (n = 425, 46.2% Hispanic, 94.8%female). Participants were sampled for follow-up at markets during mid-season (n = 186) and at season end (n = 146). Attendance was tracked over 16 weeks. RESULTS: Participants post-intervention reported significantly higher vegetable consumption(P = 0.005) and lower soda consumption (P = 0.005). Participants reporting largest F&V increases attended the market 6-8 times and received $40 in incentives. No change in food assistance spent on F&V (P = 0.94); 70% reported significant increases in family consumption of F&V,indicating subsidies increased overall F&V purchasing. Participants reported exposure activities and incentives similarly affected program attendance. CONCLUSION: Interventions combining exposure activities and modest financial incentives at farmers' markets in low-income neighborhoods show strong potential to improve diet quality of families receiving federal food assistance. PMID- 27123432 TI - Working posture and its predictors in hospital operating room nurses. AB - BACKGROUND: This study was conducted to evaluate working posture of operating room nurses and its relationship with demographic and job details of this group. METHODS: This cross-sectional study was conducted among 147 operating room nurses in Tabriz, Iran using a questionnaire and the Rapid Entire Body Assessment (REBA) checklist. The data were analyzed with SPSS.16 using t test, Pearson correlation coefficient and analysis of variance (ANOVA) tests for univariate analysis and the linear regression test for multivariate analysis. RESULTS: The mean (SD) of REBA score was 7.7 (1.9), which means a high risk level and highlights an urgent need to change the working postures of the studied nurses. There was significant relationship between working posture and age (P = 0.003), gender (P = 0.003), regular daily exercise (P = 0.048), work experience (P = 0.003), number of shifts per month (P = 0.006) and type of operating rooms (P < 0.001) in univariate analyses. Gender and type of operating room were the predictors of working posture of nurses in multivariate analysis. CONCLUSION: The findings highlight the need for ergonomic interventions and educational programs to improve working posture of this study population, which can consequently lead to promotion of health and well-being of this group. PMID- 27123433 TI - Health promoting hospitals: a study on educational hospitals of Isfahan, Iran. AB - BACKGROUND: The current situation of health promotion (HP) services in hospitals of Iran is unclear. The aim of this study was to assess the status of HP in hospitals in Isfahan, Iran. METHODS: This study is a cross-sectional survey in which 9 educational hospitals selected through census sampling. HP self assessment was used for the data collection. The assessment teams formed, and evidence examined in line with the tools. RESULTS: The results identified five categories of HP activities in the hospitals consisted: patients,staff, environmental, community, and organizational. The mean of total score of HP was 48.8(9.8). In terms of the HP standards scores, 5 hospitals (55.5%) were at the intermediate level;3 hospitals (33.3%) were at the weak level, and 1 hospital (11.1%) was at the good level.About the standards, the highest score was "information and patient interventions" standard 79.8 (13.5), and the lowest was "continuity and cooperation" standard 36.2 (10.8). CONCLUSION: It seems that some of the health promoting hospitals (HPS) duties carried out by hospitals. So, to improve the quality of health services, it seems useful to encourage policymakers and health service managers to create coherent policies and guidelines in HPS. PMID- 27123434 TI - Relationship of work-family conflict with burnout and marital satisfaction: cross domain or source attribution relations? AB - BACKGROUND: The present study was conducted to examine the relationship between two dimensions of work-family conflict (WFC) with marital satisfaction and burnout in a society in which few studies have been done about the consequences of WFC. METHODS: A cross-sectional study was conducted in 2015. Surveys were distributed to 420 employed married women with various jobs living in Bushehr province, Iran. Data were collected using a questionnaire for demographic characteristic, the Netmeyer's WFC questionnaire, Maslach Burnout Inventory: General Survey (MBI-GS), and Enrich maritalsatisfaction questionnaire. The data were analyzed using descriptive and inferential statistics. RESULTS: There was a negatively significant association between work interference with family(WIF) and overall burnout as well as emotional exhaustion (P < .01). Family interference with work (FIW) was significantly associated with depersonalization (P < .01). The overall marital satisfaction and its subscales were significantly associated with WIF (P < .01) and FIW (P < .01 for overall marital satisfaction and P < .05 for its subscales). CONCLUSION: In terms of practical implication, to avoid creating disadvantages of WIF and FIW,facilitation in two domains of improving work and family conditions can be a useful means to prevent WFC and its consequences. PMID- 27123435 TI - Family fun or cultural free-for-all? A critique of the 2015 National Football League Super Bowl commercials. AB - BACKGROUND: The purpose of this cross-sectional study was to enumerate and describe violent and risky behaviors as well as other general health behaviors exhibited in the advertisements during the National Football League (NFL) Super Bowl 2015. METHODS: Commercials during the NFL Super Bowl 2015 were assessed for violent and risky behaviors. Additional health behaviors were indicated such as the advertisement of unhealthy food, promotion of physical activity, and sexual content. RESULTS: A total of 110 commercials were documented, accounting for 64 minutes of broadcast time. Commercials promoting automobiles, television shows, food, and movies were the most prevalent, representing just over half (53.7%) of all of the advertisements featured. Depictions of unsafe driving were found in 10.9% (n = 12) of the commercials. All 12 commercials contained some sort of risky or wild driving behavior, and speeding was observed in 11 of the 12 commercials. A total of 32 (29.1%) of the commercials were coded as including violent content.Physical activity behavior was present in 3 (2.7%) of the commercials. Conversely, substance use was observed in 3 (2.7%) of the commercials, none of which included health promotion messaging. Of the 110 commercials aired during the 2015 Super Bowl, 12.7% (n = 14) included sexual content. CONCLUSION: Parents should consider the possibility that their children may observe acts of violence or conflicting safety messages during commercial breaks. PMID- 27123436 TI - Determinants of breast cancer screening uptake in Kurdish women of Iran. AB - BACKGROUND: Recently, a national breast cancer screening program has been introduced in Iran.The aim of this study was to examine the determinants of breast cancer screening uptake among Kurdish women, in order to identify those characteristics that may be potentially associated with the screening uptake. METHODS: Through a cross sectional study, in 2014, a random sample of 561 women aged 40 years and older without the history of breast cancer and identified with Kurdish background in Baneh county, Iran, were recruited and interviewed by two trained interviewers. Data were collected using a valid and reliable researcher made questionnaire. Univariate and multivariate logistic regression models with self-reported screening history as the dependent variable were used to estimate the odds ratios (ORs) with 95% of CI. RESULTS: The mean age of women was 43.64 (SD = 5.17). The participation rate in the mammography program was 16.8% (95% CI: 13.7-19.8%). The lowest level of participation was found among women aged 60 and older (OR = 0.30, 95% CI: 0.14-0.69), illiterate (OR = 0.63,95% CI: 0.40-0.99) and post-menopausal (OR = 0.56, 95% CI: 0.35-0.91) women. CONCLUSION: It was found that the level of breast screening uptake was low among Kurdish women compared to those reported in the previous studies. Designing participation enhancing interventions with a specific focus on older, illiterate and post menopausal women are recommended. PMID- 27123437 TI - Leisure time activities of Iranian patients with multiple sclerosis: a qualitative study. AB - BACKGROUND: Leisure time is one of the most important aspects of life, especially for people with chronic diseases. The concept and types of leisure have frequently been evaluated in different socio-cultural populations. The aim of this study was to identify the nature of leisure activities among a sample of Iranian patients with multiple sclerosis (MS) and classify the identified types of activities in the context of Iranian culture. METHODS: In this qualitative study, semi-structured interview was applied to gather data from 34 MS patients that were selected through purposive sampling. The interviews were continued up to the point of saturation. Content analysis was used to explore experiences of the interviewees regarding their leisure activities. RESULTS: Six categories of leisure activities were extracted for the studied patients with MS i.e.physical, social, individual, art/cultural, educational and spiritual/religious. CONCLUSION: The results represented the range and heterogeneity of leisure activities amongst the MS patients. Considering participation in spiritual/religious and social activities as leisure time undertaking might reflect cultural diversity in the perception and use of time for recreation. For mental health promotion purposes, paying special attention to the types of activities that people of different socio-cultural background choose for their refreshment could help health care providers in giving tailored advice for patients with MS and other chronic debilitating disease. PMID- 27123438 TI - Erratum: The association between the risk of premenstrual syndrome and vitamin D, calcium, and magnesium status among university students: a case control study [Health Promotion Perspectives, 2015, 5(3), 225-230]. AB - [This corrects the article DOI: 10.15171/hpp.2015.027.]. PMID- 27123439 TI - Membrane flexibility, free fatty acids, and the onset of vascular and neurological lesions in type 2 diabetes. AB - Free fatty acids released from human adipose tissue contain a limited amount of non-esterified poly-cis-unsaturated fatty acids. In cases of elevated plasma free fatty acids, this condition ultimately leads to a shift from unsaturated to saturated fatty-acyl chains in membrane phospholipids. Because this shift promotes the physical attractive van der Waals interactions between phospholipid acyl chains, it increases stiffness of both erythrocyte and endothelial membranes, which causes a reduction in both insulin-independent and insulin dependent Class 1 glucose transporters, a reduction in cell membrane functionality, and a decreased microcirculatory blood flow which results in tissue hypoxia. Against the background of these processes, we review recently published experimental phospholipid data obtained from Drosophila melanogaster and from human erythrocytes of controls and patients with type 2 diabetes, with and without retinopathy, along the way free fatty acids interfere with eye and kidney function in patients with type 2 diabetes and give rise to endoplasmic reticulum stress, reduced insulin sensitivity, and ischemia. PMID- 27123440 TI - Differential Methylation of Genomic Regions Associated with Heteroblasty Detected by M&M Algorithm in the Nonmodel Species Eucalyptus globulus Labill. AB - Epigenetic regulation plays important biological roles in plants, including timing of flowering and endosperm development. Little is known about the mechanisms controlling heterochrony (the change in the timing or rate of developmental events during ontogeny) in Eucalyptus globulus. DNA methylation has been proposed as a potential heterochrony regulatory mechanism in model species, but its role during the vegetative phase in E. globulus has not been explored. In order to investigate the molecular mechanisms governing heterochrony in E. globulus, we have developed a workflow aimed at generating high-resolution hypermethylome and hypomethylome maps that have been tested in two stages of vegetative growth phase: juvenile (6-month leaves) and adult (30-month leaves). We used the M&M algorithm, a computational approach that integrates MeDIP-seq and MRE-seq data, to identify differentially methylated regions (DMRs). Thousands of DMRs between juvenile and adult leaves of E. globulus were found. Although further investigations are required to define the loci associated with heterochrony/heteroblasty that are regulated by DNA methylation, these results suggest that locus-specific methylation could be major regulators of vegetative phase change. This information can support future conservation programs, for example, selecting the best methylomes for a determinate environment in a restoration project. PMID- 27123441 TI - Methylation Status of Alu and LINE-1 Interspersed Repetitive Sequences in Behcet's Disease Patients. AB - Behcet's Disease (BD) is a multisystem chronic inflammatory disease. The pathology is believed to involve both genetic susceptibility and environmental factors. Hypomethylation leading to activation of interspersed repetitive sequences (IRSs) such as LINE-1 and Alu contributes to the pathologies of autoimmune diseases and cancer. Herein, the epigenetic changes of IRSs in BD were evaluated using combined bisulfite restriction analysis-interspersed repetitive sequences (COBRA-IRS). DNA from neutrophils and peripheral blood mononuclear cells (PBMCs) of BD patients with ocular involvement that were in active or inactive states and healthy controls were used to analyze LINE-1 and Alu methylation levels. For Alu sequences, significant differences were observed in the frequency of (u)C(u)C alleles between PBMCs of patients and controls (p = 0.03), and between inactive patients and controls (p = 0.03). For neutrophils, the frequency of (u)C(u)C was significantly higher between patients and controls (p = 0.006) and between inactive patients and controls (p = 0.002). The partial methylation ((u)C(m)C + (m)C(u)C) frequencies of Alu between inactive patients and control samples also differed (p = 0.02). No statistically significant differences for LINE-1 were detected. Thus, changes in the methylation level of IRS elements might contribute to the pathogenesis of BD. The role of Alu transcripts in BD should be investigated further. PMID- 27123443 TI - Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies. AB - Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK) levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES) after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB) gene c.1031G>A (p.R344Q) in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy. PMID- 27123442 TI - Magnetic Resonance Imaging of Postoperative Fracture Healing Process without Metal Artifact: A Preliminary Report of a Novel Animal Model. AB - Background. Early radiological diagnosis and continual monitoring are of ultimate importance for timely treatment of delayed union, nonunion, and infection after bone fracture surgery. Although magnetic resonance imaging (MRI) could provide superior detailed images compared with X-ray and computed tomography (CT) without ionizing radiation, metal implants used for fracture fixation lead to abundant artifacts on MRI and thus prohibit accurate interpretation. The authors develop a novel intramedullary fixation model of rat femoral fracture using polyetheretherketone (PEEK) threaded rods and investigate its feasibility for in vivo MRI monitoring of the fracture healing process without artifact. Methods. Femoral fractures of 3 adult male Sprague-Dawley rats were fixed with intramedullary PEEK threaded rods. X-ray and MRI examinations were performed at day 7 postoperatively. Radiological images were analyzed for the existence of artifact interruption and postoperative changes in bone and peripheral soft tissue. Results. Postoperative plain film revealed no loss of reduction. MRI images illustrated the whole length of femur and peripheral tissue without artifact interruption, and the cortical bone, implanted PEEK rod, and soft tissue were clearly illustrated. Conclusion. This preliminary study introduced a novel rat model for in vivo MRI monitoring of the fracture healing process without metal artifact, by using intramedullary fixation of femur with PEEK threaded rod. PMID- 27123444 TI - Does Unilateral Oocyte Retrieval due to Transvaginally Inaccessible Ovaries, Contrary to Common Beliefs, Affect IVF/ICSI Treatment Outcomes That Much? AB - Objective. To investigate in vitro fertilization (IVF) treatment outcomes of unilateral oocyte retrieval in patients with transvaginally inaccessible ovaries. Study Design. Ninety-two women who underwent unilateral oocyte retrieval were retrospectively matched for age, antral follicle count, and body mass index with 184 women who underwent bilateral oocyte retrieval. Each patient in bilateral oocyte retrieval group had the same number of cumulus oophorus complexes (COCs) from single ovary and had comparable number of follicles (+/-2) on contralateral site where follicular aspiration was performed. Results. The number of COCs, metaphase-2 oocytes, 2-pronuclei, and top-quality embryos was significantly lower in unilateral oocyte retrieval group. However, proportion of patients with an embryo transfer of at least one top-quality embryo was found to be comparable between unilateral and bilateral oocyte retrieval. Subsequently, clinical pregnancy and live birth rates were found to be similar between the groups. The ROC curve analysis revealed (AUC = 0.74, 95% CI 0.63-0.86, p = 0.001) that retrieved COCs >= 5 from single ovary had sensitivity of 76.0% and specificity of 64.2% for occurrence of a clinical pregnancy. Conclusion. The patients with unilateral oocyte retrieval have reasonable chance of success with IVF. The retrieval of >=5 COCs from accessible ovary might result in better treatment outcomes among these patients. PMID- 27123445 TI - Elevated Ratio of Th17 Cell-Derived Th1 Cells (CD161(+)Th1 Cells) to CD161(+)Th17 Cells in Peripheral Blood of Early-Onset Rheumatoid Arthritis Patients. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone with elevated levels of proinflammatory cytokines. It has been reported that IL-17 and Th17 cells play important roles in the pathogenesis of RA. Recently, plasticity in helper T cells has been demonstrated; Th17 cells can convert to Th1 cells. It remains to be elucidated whether this conversion occurs in the early phase of RA. Here, we tried to identify Th17 cells, Th1 cells, and Th17 cell-derived Th1 cells (CD161(+)Th1 cells) in the peripheral blood of early-onset RA patients. We also evaluated the effect of methotrexate on the ratio of Th17 cells in early-onset RA patients. The ratio of Th17 cell-derived Th1 cells to CD161(+)Th17 cells was elevated in the peripheral blood of early-onset RA patients. In addition, MTX reduced the ratio of Th17 cells but not Th1 cells. These findings suggest that IL 17 and Th17 play important roles in the early phase of RA; thus, anti-IL-17 antibodies should be administered to patients with RA in the early phase. PMID- 27123446 TI - Association between Family Structure and Physical Activity of Chinese Adolescents. AB - Background. This study examines the association between family structure and moderate-to-vigorous physical activity (MVPA) of adolescents in China. Methods. The participants included 612 adolescents (317 boys and 295 girls) from Shanghai with ages ranging from 10 to 16 years. Accelerometers were used to measure the duration of MVPA of adolescents, and questionnaires on family structure were completed by the parents of these adolescents. Results. Findings suggested that family structure significantly increased the likelihood of adolescents engaging in physical activity (PA) and explained 6% of MPVA variance. Adolescents living in single-parent households and step families were more physically active than those living in two-parent homes and with biological parents, respectively. However, adolescents residing with grandparents were less active than those living with neither grandparent. No significant difference was found in MVPA time between adolescents living with one sibling and those without siblings. Conclusion. Family environment may be considered in the development of PA interventions and policies, and adolescents living with their grandparents may be targeted in PA promotion. PMID- 27123447 TI - Cell Cycle Arrest and Apoptosis Induction via Modulation of Mitochondrial Integrity by Bcl-2 Family Members and Caspase Dependence in Dracaena cinnabari Treated H400 Human Oral Squamous Cell Carcinoma. AB - Dracaena cinnabari Balf.f. is a red resin endemic to Socotra Island, Yemen. Although there have been several reports on its therapeutic properties, information on its cytotoxicity and anticancer effects is very limited. This study utilized a bioassay-guided fractionation approach to determine the cytotoxic and apoptosis-inducing effects of D. cinnabari on human oral squamous cell carcinoma (OSCC). The cytotoxic effects of D. cinnabari crude extract were observed in a panel of OSCC cell lines and were most pronounced in H400. Only fractions DCc and DCd were active on H400 cells; subfractions DCc15 and DCd16 exhibited the greatest cytotoxicity against H400 cells and D. cinnabari inhibited cells proliferation in a time-dependent manner. This was achieved primarily via apoptosis where externalization of phospholipid phosphatidylserine was observed using DAPI/Annexin V fluorescence double staining mechanism studied through mitochondrial membrane potential assay cytochrome c enzyme-linked immunosorbent and caspases activities revealed depolarization of mitochondrial membrane potential (MMP) and significant activation of caspases 9 and 3/7, concomitant with S phase arrest. Apoptotic proteins array suggested that MMP was regulated by Bcl-2 proteins family as results demonstrated an upregulation of Bax, Bad, and Bid as well as downregulation of Bcl-2. Hence, D. cinnabari has the potential to be developed as an anticancer agent. PMID- 27123448 TI - tDCS and Robotics on Upper Limb Stroke Rehabilitation: Effect Modification by Stroke Duration and Type of Stroke. AB - Objective. The aim of this exploratory pilot study is to test the effects of bilateral tDCS combined with upper extremity robot-assisted therapy (RAT) on stroke survivors. Methods. We enrolled 23 subjects who were allocated to 2 groups: RAT + real tDCS and RAT + sham-tDCS. Each patient underwent 10 sessions (5 sessions/week) over two weeks. Outcome measures were collected before and after treatment: (i) Fugl-Meyer Assessment-Upper Extremity (FMA-UE), (ii) Box and Block Test (BBT), and (iii) Motor Activity Log (MAL). Results. Both groups reported a significant improvement in FMA-UE score after treatment (p < 0.01). No significant between-groups differences were found in motor function. However, when the analysis was adjusted for stroke type and duration, a significant interaction effect (p < 0.05) was detected, showing that stroke duration (acute versus chronic) and type (cortical versus subcortical) modify the effect of tDCS and robotics on motor function. Patients with chronic and subcortical stroke benefited more from the treatments than patients with acute and cortical stroke, who presented very small changes. Conclusion. The additional use of bilateral tDCS to RAT seems to have a significant beneficial effect depending on the duration and type of stroke. These results should be verified by additional confirmatory studies. PMID- 27123449 TI - Knowledge, Attitudes, and Behaviors about Breast Self-Examination and Mammography among Female Primary Healthcare Workers in Diyarbakir, Turkey. AB - Aim. This study aims to determine the knowledge level of the female primary healthcare workers about breast cancer and to reveal their attitude and behaviors about breast self-examination and mammography. Methods. This cross-sectional study was conducted on female primary healthcare workers who work in family health centres. 91% (n = 369) of female primary healthcare workers agreed to participate in the study. The questionnaire consisted of three parts: sociodemographic characteristics, knowledge about breast self-examination, and actual practice of breast self-examination. Results. The mean (SD) age of the female primary healthcare workers was 33.1 +/- 6.8 (range, 20-54 years). The healthcare workers who practiced breast self-examination had significantly higher knowledge level (P = 0.001) than those who had not. The respondents had high knowledge level of breast self-examination; however, the knowledge level of breast cancer and mammography screen was low. Conclusions. While the female primary healthcare workers in this study had adequate knowledge of breast self examination, this is not reflected in their attitudes and practices. Emphasis should be laid on breast self-examination in undergraduate and postgraduate courses for primary healthcare workers, since they are mostly involved in patient education. PMID- 27123450 TI - Public versus Private Healthcare Systems following Discharge from the ICU: A Propensity Score-Matched Comparison of Outcomes. AB - Purpose. The long-term outcomes of patients after discharge from tertiary ICUs as they relate to the public versus private healthcare systems in Brazil have not yet been evaluated. Materials and Methods. A multicenter prospective cohort study was conducted to compare the all-cause mortality and the physical functional status (PFS) 24 months after discharge from the ICU between adult patients treated in the public and private healthcare systems. A propensity score- (PS-) matched comparison of all causes of mortality and PFS 24 months after discharge from the ICU was performed. Results. In total, 928 patients were discharged from the ICU including 172 (18.6%) patients in the public and 756 (81.4%) patients in the private healthcare system. The results of the PS-matched comparison of all cause mortality revealed higher mortality rates among the patients of the public healthcare system compared to those of the private healthcare system (47.3% versus 27.6%, P = 0.003). The comparison of the PS-matched Karnofsky performance and Lawton activities of daily living scores between the ICU survivors of the public and private healthcare systems revealed no significant differences. Conclusions. The patients of private healthcare system exhibited significantly greater survival rates than the patients of the public healthcare system with similar PFS following ICU discharge. PMID- 27123451 TI - An Interoperability Platform Enabling Reuse of Electronic Health Records for Signal Verification Studies. AB - Depending mostly on voluntarily sent spontaneous reports, pharmacovigilance studies are hampered by low quantity and quality of patient data. Our objective is to improve postmarket safety studies by enabling safety analysts to seamlessly access a wide range of EHR sources for collecting deidentified medical data sets of selected patient populations and tracing the reported incidents back to original EHRs. We have developed an ontological framework where EHR sources and target clinical research systems can continue using their own local data models, interfaces, and terminology systems, while structural interoperability and Semantic Interoperability are handled through rule-based reasoning on formal representations of different models and terminology systems maintained in the SALUS Semantic Resource Set. SALUS Common Information Model at the core of this set acts as the common mediator. We demonstrate the capabilities of our framework through one of the SALUS safety analysis tools, namely, the Case Series Characterization Tool, which have been deployed on top of regional EHR Data Warehouse of the Lombardy Region containing about 1 billion records from 16 million patients and validated by several pharmacovigilance researchers with real life cases. The results confirm significant improvements in signal detection and evaluation compared to traditional methods with the missing background information. PMID- 27123452 TI - The Identification of Microdeletion and Reciprocal Microduplication in 22q11.2 Using High-Resolution CMA Technology. AB - The chromosome 22q11.2 region has long been implicated in genomic diseases. Some genomic regions exhibit numerous low copy repeats with high identity in which they provide increased genomic instability and mediate deletions and duplications in many disorders. DiGeorge Syndrome is the most common deletion syndrome and reciprocal duplications could be occurring in half of the frequency of microdeletions. We described five patients with phenotypic variability that carries deletions or reciprocal duplications at 22q11.2 detected by Chromosomal Microarray Analysis. The CytoScan HD technology was used to detect changes in the genome copy number variation of patients who had clinical indication to global developmental delay and a normal karyotype. We observed in our study three microdeletions and two microduplications in 22q11.2 region with variable intervals containing known genes and unstudied transcripts as well as the LCRs that are often flanking and within this genomic rearrangement. The identification of these variants is of particular interest because it may provide insight into genes or genomic regions that are crucial for specific phenotypic manifestations and are useful to assist in the quest for understanding the mechanisms subjacent to genomic deletions and duplications. PMID- 27123453 TI - Effect of the Crystallization Process on the Marginal and Internal Gaps of Lithium Disilicate CAD/CAM Crowns. AB - The aim of this study is to quantify the effect of the crystallization process on lithium disilicate ceramic crowns fabricated using a computer-aided design/computer-aided manufacturing (CAD/CAM) system and to determine whether the effect of crystallization is clinically acceptable by comparing values of fit before and after the crystallization process. The mandibular right first molar was selected as the abutment for the experiments. Fifteen working models were prepared. Lithium disilicate crowns appropriate for each abutment were prepared using a commercial CAD/CAM system. Gaps in the marginal area and 4 internal areas of each crown were measured twice-before and after crystallization-using the silicone replica technique. The mean values of fit before and after crystallization were analyzed using a paired t-test to examine whether the conversion that occurred during crystallization affected marginal and internal gaps (alpha = 0.05). Gaps increased in the marginal area and decreased in the internal areas after crystallization. There were statistically significant differences in all of the investigated areas (P < 0.05). None of the values for marginal and internal fit of lithium disilicate CAD/CAM crowns after crystallization exceeded 120 MUm, which is the clinically acceptable threshold. PMID- 27123454 TI - In Patients with Coronary Artery Disease and Type 2 Diabetes, SIRT1 Expression in Circulating Mononuclear Cells Is Associated with Levels of Inflammatory Cytokines but Not with Coronary Lesions. AB - While SIRT1 is significantly associated with atherosclerosis and diabetic complications, its relevance to coronary lesions in patients with coronary artery disease and type 2 diabetes has not been specifically investigated. Thus, we assessed SIRT1 expression in peripheral blood mononuclear cells in these patients. We found that SIRT1 expression did not significantly correlate with syntax scores from coronary angiography (p > 0.05). Notably, plasma levels of the inflammatory cytokines tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and high-sensitivity C-reactive protein were markedly higher in diabetic patients (p < 0.05). In addition, SIRT1 expression was negatively correlated with levels of these cytokines, as well as that of interleukin-6 (p < 0.05). In summary, the data indicate that SIRT1 expression in peripheral blood mononuclear cells is significantly correlated with inflammatory cytokines levels in patients with coronary artery disease and type 2 diabetes but not with the severity of coronary lesions. PMID- 27123455 TI - The Compound of Mangiferin-Berberine Salt Has Potent Activities in Modulating Lipid and Glucose Metabolisms in HepG2 Cells. AB - The mangiferin-berberine (MB) salt was synthesized by ionic bonding of mangiferin (M) and berberine (B) at an equal molecular ratio. This study aimed to investigate the activities of MB salt in modulating lipid and glucose metabolisms in HepG2 cells. After 24 h treatment of the studying compounds, cellular AMP activated protein kinase alpha (AMPKalpha)/acetyl-CoA carboxylase (ACC) protein levels and carnitine palmitoyltransferase (CPT) 1 activities, intracellular lipid contents, mRNA expression levels of target genes, glucose consumption, and glucose production amounts were determined. Compound C (CC) was used in the blocking experiments. Our results showed that MB salt increased p-AMPKalpha (Thr172)/p-ACC (Ser79) levels and CPT1 activity and suppressed oleic acid- (OA-) induced lipid accumulation and upregulation of lipogenic genes potently in HepG2 cells. The above activities of MB salt were AMPK dependent and were superior to those of M or B when administered at an equal molar concentration. MB salt enhanced basal and insulin-stimulated glucose consumption and suppressed gluconeogenesis more potently than M or B alone. The inhibiting activity of MB salt on cellular gluconeogenesis was AMPK dependent. Our results may support MB salt as a new kind of agent for the development of novel lipid or glucose lowering drugs in the future. PMID- 27123456 TI - Comparison of Calcium and Barium Microcapsules as Scaffolds in the Development of Artificial Dermal Papillae. AB - This study aimed to develop and evaluate barium and calcium microcapsules as candidates for scaffolding in artificial dermal papilla. Dermal papilla cells (DPCs) were isolated and cultured by one-step collagenase treatment. The DPC-Ba and DPC-Ca microcapsules were prepared by using a specially designed, high voltage, electric-field droplet generator. Selected microcapsules were assessed for long-term inductive properties with xenotransplantation into Sprague-Dawley rat ears. Both barium and calcium microcapsules maintained xenogenic dermal papilla cells in an immunoisolated environment and induced the formation of hair follicle structures. Calcium microcapsules showed better biocompatibility, permeability, and cell viability in comparison with barium microcapsules. Before 18 weeks, calcium microcapsules gathered together, with no substantial immune response. After 32 weeks, some microcapsules were near inflammatory cells and wrapped with fiber. A few large hair follicles were found. Control samples showed no marked changes at the implantation site. Barium microcapsules were superior to calcium microcapsules in structural and mechanical stability. The cells encapsulated in hydrogel barium microcapsules exhibited higher short-term viability. This study established a model to culture DPCs in 3D culture conditions. Barium microcapsules may be useful in short-term transplantation study. Calcium microcapsules may provide an effective scaffold for the development of artificial dermal papilla. PMID- 27123457 TI - Design of Infusion Schemes for Neuroreceptor Imaging: Application to [(11)C]Flumazenil-PET Steady-State Study. AB - This study aims at developing a simulation system that predicts the optimal study design for attaining tracer steady-state conditions in brain and blood rapidly. Tracer kinetics was determined from bolus studies and used to construct the system. Subsequently, the system was used to design inputs for bolus infusion (BI) or programmed infusion (PI) experiments. Steady-state quantitative measurements can be made with one short scan and venous blood samples. The GABAA receptor ligand [(11)C]Flumazenil (FMZ) was chosen for this purpose, as it lacks a suitable reference region. Methods. Five bolus [(11)C]FMZ-PET scans were conducted, based on which population-based PI and BI schemes were designed and tested in five additional healthy subjects. The design of a PI was assisted by an offline feedback controller. Results. The system could reproduce the measurements in blood and brain. With PI, [(11)C]FMZ steady state was attained within 40 min, which was 8 min earlier than the optimal BI (B/I ratio = 55 min). Conclusions. The system can design both BI and PI schemes to attain steady state rapidly. For example, subjects can be [(11)C]FMZ-PET scanned after 40 min of tracer infusion for 40 min with venous sampling and a straight-forward quantification. This simulation toolbox is available for other PET-tracers. PMID- 27123458 TI - Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic Acid, 3-Hydroxyphenylacetic Acid, and 3-Hydroxyhippuric Acid Are Elevated in Children with Autism Spectrum Disorders. AB - Autism spectrum disorders (ASDs) are a group of mental illnesses highly correlated with gut microbiota. Recent studies have shown that some abnormal aromatic metabolites in autism patients are presumably derived from overgrown Clostridium species in gut, which may be used for diagnostic purposes. In this paper, a GC/MS based metabolomic approach was utilized to seek similar biomarkers by analyzing the urinary information in 62 ASDs patients compared with 62 non ASDs controls in China, aged 1.5-7. Three compounds identified as 3-(3 hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), 3-hydroxyphenylacetic acid (3HPA), and 3-hydroxyhippuric acid (3HHA) were found in higher concentrations in autistic children than in the controls (p < 0.001). After oral vancomycin treatment, urinary excretion of HPHPA (p < 0.001), 3HPA (p < 0.005), and 3HHA (p < 0.001) decreased markedly, which indicated that these compounds may also be from gut Clostridium species. The sensitivity and specificity of HPHPA, 3HPA, and 3HHA were evaluated by receiver-operating characteristic (ROC) analysis. The specificity of each compound for ASDs was very high (>96%). After two-regression analysis, the optimal area under the curve (AUC, 0.962), sensitivity (90.3%), and specificity (98.4%) were obtained by ROC curve of Prediction probability based on the three metabolites. These findings demonstrate that the measurements of the three compounds are strong predictors of ASDs and support the potential clinical utility for identifying a subgroup of ASDs subjects. PMID- 27123459 TI - KvLEA, a New Isolated Late Embryogenesis Abundant Protein Gene from Kosteletzkya virginica Responding to Multiabiotic Stresses. AB - The LEA proteins are a kind of hydrophilic proteins, playing main functions in desiccation tolerance. However, their importance as a kind of stress proteins in abiotic stress is being clarified little by little. In this study we isolated, cloned, and identified the first KvLEA gene in Kosteletzkya virginica. Bioinformatic analysis showed that the protein encoded by this gene had common properties of LEA proteins and the multiple sequences alignment and phylogenetic analysis further showed that this protein had high homology with two Arabidopsis LEA proteins. Gene expression analysis revealed that this gene had a higher expression in root and it was induced obviously by salt stress. Moreover, the transcripts of KvLEA were also induced by other abiotic stresses including drought, high temperature, chilling, and ABA treatment. Among these abiotic stresses, ABA treatment brought about the biggest changes to this gene. Collectively, our research discovered a novel LEA gene and uncovered its involvement in multiabiotic stresses in K. virginica. This research not only enriched studies on LEA gene in plant but also would accelerate more studies on K. virginica in the future. PMID- 27123460 TI - Anti-Thyroid Peroxidase Antibodies and Male Gender Are Associated with Diabetes Occurrence in Patients with Beta-Thalassemia Major. AB - BACKGROUND: Intensive transfusion schedule and iron-chelating therapy prolonged and improved quality of life in patients with beta-thalassemia (beta-T) major. However, this led to an increased risk of developing impaired glucose tolerance or diabetes. In this study we analyzed variables associated with the occurrence of impaired glucose tolerance or diabetes in patients with beta-T major. METHODS: 388 Sardinian patients were included. Age, gender, duration of chelation therapy, body mass index, and markers of pancreatic and extrapancreatic autoimmunity were analyzed. RESULTS: Multiple logistic regression analysis showed that anti-thyroid peroxidase (TPO) antibodies (Ab) (OR = 3.36; p = 0.008) and male gender (OR = 1.98; p = 0.025) were significantly associated with glucose impairment, while the other variables were not. Ferritin levels were significantly higher in TPOAb positive compared to TPOAb negative patients (4870 +/- 1665 MUg/L versus 2922 +/- 2773 MUg/L; p < 0.0001). CONCLUSIONS: In patients with beta-T major a progressive damage of insulin-producing cells due to secondary hemosiderosis appears to be the most reasonable mechanism associated with glucose metabolism disorders. The findings need to be confirmed with additional well designed studies to address the question of whether TPOAb may have a role in the management of these patients. PMID- 27123461 TI - The Burden of NAFLD and Its Characteristics in a Nationwide Population with Type 2 Diabetes. AB - OBJECTIVE: We studied the prevalence of nonalcoholic fatty liver disease (NAFLD) and its clinical correlates in a population of patients with type 2 diabetes mellitus (T2DM). METHODS: Clinical data of 94,577 T2DM patients were retrieved from 160 diabetes clinics in Italy in a standardized format and centrally analyzed anonymously. After exclusion of 5967 cases (high or uncertain alcohol intake), in 38,880 the Fatty Liver Index (FLI) was used as a proxy for the diagnosis of NAFLD. Factors associated with FLI assessed NAFLD (FLI-NAFLD) were evaluated through multivariate analysis. RESULTS: FLI-NAFLD was present in 59.6% of patients. Compared to non-NAFLD, FLI-NAFLD was associated with impairment in renal function, higher albumin excretion, HbA1c and blood pressure, lower HDL cholesterol, and poorer quality of care. ALT was within normal limits in 73.6% of FLI-NAFLD patients (45.6% if the updated reference values were used). The prevalence of FLI-NAFLD did not differ if the whole sample (94,577 cases) was examined, irrespective of alcohol intake. CONCLUSIONS: FLI-NAFLD was present in the majority of T2DM patients of our sample and metabolic derangement, not alcohol consumption, was mainly associated with the disease. FLI-NAFLD patients have a worse metabolic profile. ALT levels are not predictive of NAFLD. PMID- 27123462 TI - Calpain-Calcineurin-Nuclear Factor Signaling and the Development of Atrial Fibrillation in Patients with Valvular Heart Disease and Diabetes. AB - Calpain, calcineurin (CaN), and nuclear factor of activated T cell (NFAT) play a key role in the development of atrial fibrillation. Patients with valvular heart disease (VHD) are prone to develop atrial fibrillation (AF). Thus, our current study was aimed at investigating whether activation of calpain-CaN-NFAT pathway is associated with the incidence of AF in the patients with VHD and diabetes. The expressions of calpain 2 and alpha- and beta-isoforms of CaN catalytic subunit (CnA) as well as NFAT-c3 and NFAT-c4 were quantified by quantitative reverse transcription-polymerase chain reaction in atrial tissues from 77 hospitalized patients with VHD and diabetes. The relevant protein content was measured by Western blot and calpain 2 in human atrium was localized by immunohistochemistry. We found that the expressions of calpain 2, CnA alpha and CnA beta, and NFAT-c3 but not NFAT-c4 were significantly elevated in the samples from patients with AF compared to those with sinus rhythm (SR). Elevated protein levels of calpain 2 and CnA were observed in patients with AF, and so was the enhanced localization of calpain 2. We thereby concluded that CaN together with its upstream molecule, calpain 2, and its downstream effector, NFAT-c3, might contribute to the development of AF in patients with VHD and diabetes. PMID- 27123464 TI - Selective Subnormal IgG1 in 54 Adult Index Patients with Frequent or Severe Bacterial Respiratory Tract Infections. AB - We characterized 54 adult index patients with reports of frequent or severe bacterial respiratory tract infections at diagnosis of selective subnormal IgG1. Mean age was 50 +/- 13 (SD) y; 87.0% were women. Associated disorders included the following: autoimmune conditions 50.0%; hypothyroidism 24.1%; atopy 38.9%; and other allergy 31.5%. In 35.5%, proportions of protective S. pneumoniae serotype-specific IgG levels did not increase after polyvalent pneumococcal polysaccharide vaccination (PPPV). Blood lymphocyte subset levels were within reference limits in most patients. Regressions on IgG1 and IgG3 revealed no significant association with age, sex, autoimmune conditions, hypothyroidism, atopy, other allergy, corticosteroid therapy, or lymphocyte subsets. Regression on IgG2 revealed significant associations with PPPV response (negative) and CD19+ lymphocytes (positive). Regression on IgG4 revealed significant positive associations with episodic corticosteroid use and IgA. Regression on IgA revealed positive associations with IgG2 and IgG4. Regression on IgM revealed negative associations with CD56+/CD16+ lymphocytes. Regressions on categories of infection revealed a negative association of urinary tract infections and IgG1. HLA-A(*)03, HLA-B(*)55 and HLA-A(*)24, HLA-B(*)35 haplotype frequencies were greater in 38 patients than 751 controls. We conclude that nonprotective S. pneumoniae IgG levels and atopy contribute to increased susceptibility to respiratory tract infections in patients with selective subnormal IgG1. PMID- 27123465 TI - Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes. AB - We assessed the prevalence of TNFRSF13B mutations and the clinical correlates in an Italian cohort of 189 CVID, 67 IgAD patients, and 330 healthy controls to substantiate the role of TACI genetic testing in diagnostic workup. We found that 11% of CVID and 13% of IgAD carried at least one mutated TNFRSF13B allele. Seven per cent of CVID had monoallelic-mutations and 4% had biallelic-mutations. The frequency of C104R monoallelic-mutations was not higher than that found in healthy controls. Biallelic-mutations were exclusively found in CVID. CVID patients carrying monoallelic-mutations had an increased prevalence of lymphadenopathy, granulomata, and autoimmune cytopenias. CVID carrying biallelic mutations had a low prevalence of autoimmunity in comparison with TACI wild-type CVID. Moreover, biallelic-mutated CVID had higher frequency of switched memory B cells and higher IgM and IgA antibodies to polysaccharide antigens than TACI wild type and monoallelic-mutated CVID. TACI-mutated IgAD patients had only monoallelic-mutations and did not display clinical difference from IgAD wild-type patients. In conclusion, TNFRSF13B genetic screening of antibody deficiencies may allow the identification of mutational patterns. However, as with counseling for risk assessment, geneticists should be aware that the interpretation of genetic testing for TACI mutations is difficult and the potential impact on clinical management is still limited. PMID- 27123467 TI - Compressed Sensing: Applications in Radar and Communications. PMID- 27123466 TI - Biologic Treatments for Sports Injuries II Think Tank-Current Concepts, Future Research, and Barriers to Advancement, Part 3: Articular Cartilage. AB - Focal chondral defects of the articular surface are a common occurrence in the field of orthopaedics. These isolated cartilage injuries, if not repaired surgically with restoration of articular congruency, may have a high rate of progression to posttraumatic osteoarthritis, resulting in significant morbidity and loss of function in the young, active patient. Both isolated and global joint disease are a difficult entity to treat in the clinical setting given the high amount of stress on weightbearing joints and the limited healing potential of native articular cartilage. Recently, clinical interest has focused on the use of biologically active compounds and surgical techniques to regenerate native cartilage to the articular surface, with the goal of restoring normal joint health and overall function. This article presents a review of the current biologic therapies, as discussed at the 2015 American Orthopaedic Society for Sports Medicine (AOSSM) Biologics Think Tank, that are used in the treatment of focal cartilage deficiencies. For each of these emerging therapies, the theories for application, the present clinical evidence, and specific areas for future research are explored, with focus on the barriers currently faced by clinicians in advancing the success of these therapies in the clinical setting. PMID- 27123463 TI - Neuroprotection as a Therapeutic Target for Diabetic Retinopathy. AB - Diabetic retinopathy (DR) is a multifactorial progressive disease of the retina and a leading cause of vision loss. DR has long been regarded as a vascular disorder, although neuronal death and visual impairment appear before vascular lesions, suggesting an important role played by neurodegeneration in DR and the appropriateness of neuroprotective strategies. Upregulation of vascular endothelial growth factor (VEGF), the main target of current therapies, is likely to be one of the first responses to retinal hyperglycemic stress and VEGF may represent an important survival factor in early phases of DR. Of central importance for clinical trials is the detection of retinal neurodegeneration in the clinical setting, and spectral domain optical coherence tomography seems the most indicated technique. Many substances have been tested in animal studies for their neuroprotective properties and for possible use in humans. Perhaps, the most intriguing perspective is the use of endogenous neuroprotective substances or nutraceuticals. Together, the data point to the central role of neurodegeneration in the pathogenesis of DR and indicate neuroprotection as an effective strategy for treating this disease. However, clinical trials to determine not only the effectiveness and safety but also the compliance of a noninvasive route of drug administration are needed. PMID- 27123469 TI - Surgically Resected Gall Bladder: Is Histopathology Needed for All? AB - Background. Laparoscopic cholecystectomy is considered to be gold standard for symptomatic gall stones. As a routine every specimen is sent for histopathological examination postoperatively. Incidentally finding gall bladder cancers in those specimens is around 0.5-1.1%. The aim of this study is to identify those preoperative and intraoperative factors in patients with incidental gall bladder cancer to reduce unnecessary work load on pathologist and cost of investigation particularly in a developing world. Methods. Retrospective records were analyzed from January 2005 to February 2015 in a surgical unit. Demographic data, preoperative imaging, peroperative findings, macroscopic appearance, and histopathological findings were noted. Gall bladder wall was considered to be thickened if >=3 mm on preoperative imaging or surgeons comment (on operative findings) and histopathology report. AJCC TNM system was used to stage gall bladder cancer. Results. 973 patients underwent cholecystectomy for symptomatic gallstone disease. Gallbladder carcinoma was incidentally found in 11 cases. Macroscopic abnormalities of the gallbladder were found in all those 11 patients. In patients with a macroscopically normal gallbladder, there were no cases of gallbladder carcinoma. Conclusion. Preoperative and operative findings play a pivotal role in determining incidental chances of gall bladder malignancy. PMID- 27123468 TI - Analogs of LDL Receptor Ligand Motifs in Dengue Envelope and Capsid Proteins as Potential Codes for Cell Entry. AB - It is established that cell entry of low density lipoprotein particles (LLPs) containing Apo B100 and Apo E is mediated by receptors and GAGs. Receptor ligand motifs, XBBBXXBX, XBBXBX, and PsiBPsiXB, and mono- and bipartite NLS sequences are abundant in Apo E and Apo B100 as well as in envelope and capsid proteins of Dengue viruses 1-4 (DENV1-4). Synthetic, fluorescence-labeled peptides of sequences in DENV2 envelope protein, and DENV3 capsid that include these motifs were used to conduct a qualitative assessment of cell binding and entry capacity using HeLa cells. DENV2 envelope peptide, Dsp2EP, 0564Gly-Gly0595, was shown to bind and remain at the cell surface. In contrast, DENV3 capsid protein peptide, Dsp3CP, 0002Asn-Gln0028, readily enters HeLa cells and accumulates at discrete loci in the nucleus. FITC-labeled dengue synthetic peptides colocalize with Low Density Lipoprotein-CM-DiI and Apo E-CM-DiI to a degree that suggests that Dengue viruses may utilize cell entry pathways used by LLPs. PMID- 27123470 TI - Arf6 and the 5'phosphatase of Synaptojanin 1 regulate autophagy in cone photoreceptors. AB - Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated Synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1 deficient zebrafish mutant, nrca14 . We found that loss of SynJ1 leads to specific accumulation of late endosomes and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate due to a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrca14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5' phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrca14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type. PMID- 27123471 TI - Socioeconomic Status and Internalizing Symptoms in Chilean Children: Does Reserve Capacity Matter? AB - Informed by the reserve capacity model, we examined pathways between socioeconomic status (SES) and internalizing symptoms (IS) in 1119 Chilean 10 year-olds. Mediators included parental disciplinary style and reserve capacity resources (RCR), namely home environment, parent-child engagement, and self esteem, and conduct problems. Using structural equation modeling, the model was stratified by gender. For boys, the SES-IS relationship was mediated by the home environment and parental disciplinary style. For girls, the SES-IS relationship was mediated by the home environment, parent-child engagement, self-esteem, and conduct problems. Findings suggest different RCR may protect against IS in a sample of Chilean children. PMID- 27123472 TI - Stabilization of the thermolabile variant S113L of carnitine palmitoyltransferase II. AB - OBJECTIVE: Muscle carnitine palmitoyltransferase (CPT) II deficiency, the most common defect of lipid metabolism in muscle, is characterized by attacks of myoglobinuria without persistent muscle weakness. METHODS: His6-N-hCPT2 (wild type) and His6-N-hCPT2/S113L (variant) were produced recombinantly in prokaryotic host and characterized according to their functional and regulatory properties. RESULTS: The wild-type and the variant S113L showed the same enzymatic activity and thermostability at 30 degrees C. The mutated enzyme, however, revealed an abnormal thermal destabilization at 40 degrees C and 45 degrees C. This was consistent with an increased flexibility (B-factor) of the variant at 40 degrees C compared with that of the wild-type shown by molecular dynamics analysis. Preincubation of the enzymes with l-carnitine and acyl-l-carnitines containing more than 10 carbons in the acyl side-chain stabilized the mutated enzyme against thermal inactivation. In contrast, palmitoyl-CoA destabilized both enzymes. CONCLUSIONS: The problems in CPT II deficiency originating from the S113L mutation are not caused by the loss of catalytically active enzyme. They might be at least partially related to an impaired thermal stability of the protein. The lower thermodynamic stability of the variant might explain why fever and prolonged exertion provoke attacks of myoglobinuria in CPT II deficiency. The stabilization by acyl-l-carnitines might provide the basis for possible preventive therapy of CPT II deficiency. PMID- 27123473 TI - New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy. AB - OBJECTIVE: The aim of this study was to analyze the association between the variations of coenzyme Q2 4-hydroxybenzoate polyprenyltransferase gene (COQ2) and Japanese patients with multiple system atrophy (MSA). METHODS: We investigated the genetic variations in exons 1, 2, 6, and 7 of the COQ2 gene in 133 Japanese patients with MSA and 200 controls and analyzed the association between the variations and MSA. RESULTS: Six DNA variations (G21S, L25V, V66L, P157S, V393A, and X422K) were found in the 133 patients with MSA, and G21S and X422K were new variations that had never been reported. V66L was a common variation that was found in all 133 patients with MSA. G21S, P157S, V393A, and X422K did not show gene frequency differences between patients with MSA and controls. On the other hand, L25V was newly proven to be the only risk factor of sporadic MSA with predominant olivopontocerebellar ataxia. CONCLUSIONS: The present study suggests L25V variant of COQ2 gene as a genetic risk factor in Japanese patients with MSA with cerebellar ataxia. PMID- 27123474 TI - Long-term follow-up and sudden unexpected death in Gaucher disease type 3 in Egypt. AB - OBJECTIVE: To describe the long-term follow-up and distinct phenotype of a large cohort of patients with Gaucher disease type 3 on enzyme replacement therapy (ERT) in Egypt. METHODS: A prospective cohort study of 78 patients on ERT who were followed for up to 9 years with yearly evaluations that included EEG and cognitive testing. RESULTS: Of the patients, 73% were homozygous for the L444P GBA1 mutation; all but 7 were neurologically symptomatic. Supranuclear gaze palsy with variable but stable cognitive function was present in 91% of patients. Convergent strabismus and bulbar dysfunction were noted in 22% and 37%, respectively. Features of oppositional defiant disorder were present in 54% of patients. Twenty-three patients (30%) developed seizures while on ERT for 1-9 years. Of those, 12 patients (15%) died suddenly and unexpectedly at a mean age of 6.7 +/- 5.0 years (range 1.5-18). Sudden death was usually associated with a seizure disorder or a terminal seizure, but 7 of 12 patients had a preceding normal EEG. An additional 11% had background slowing or epileptogenic activity on EEG without clinical seizures. There were 3 familial cases of sudden unexpected death. CONCLUSIONS: Despite having the most common GBA1 genotype known to be associated with neuronopathic Gaucher disease, patients with Gaucher disease type 3 in Egypt have a phenotype and a clinical outcome on ERT that are very different from those observed in other populations. Identifying putative modifying genes of this ethnic group is likely to lead to better therapy for neuronopathic Gaucher disease generally. PMID- 27123477 TI - Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome. AB - Kleefstra syndrome (KS; OMIM #610253), formerly known as the 9q subtelomeric deletion syndrome, is an autosomal dominant cause of intellectual disability (ID) characterized by hypotonia and facial dysmorphisms.(1,2) The cause of KS is attributed to haploinsufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene (OMIM *607001) located at chromosome 9q34.3 (i.e., distal long arm of chromosome 9), either by microdeletion or point mutation. EHMT1 encodes a histone H3 methyltransferase at position Lys-9 (H3K9).(1-3). PMID- 27123475 TI - Analysis of rare copy number variation in absence epilepsies. AB - OBJECTIVE: To identify shared genes and pathways between common absence epilepsy (AE) subtypes (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and unclassified absence epilepsy [UAE]) that may indicate common mechanisms for absence seizure generation and potentially a diagnostic continuum. METHODS: We used high-density single-nucleotide polymorphism arrays to analyze genome-wide rare copy number variation (CNV) in a cohort of 144 children with AEs (95 CAE, 26 UAE, and 23 JAE). RESULTS: We identified CNVs that are known risk factors for AE in 4 patients, including 3x 15q11.2 deletion. We also expanded the phenotype at 4 regions more commonly identified in other neurodevelopmental disorders: 1p36.33 duplication, 1q21.1 deletion, 22q11.2 duplication, and Xp22.31 deletion and duplication. Fifteen patients (10.5%) were found to carry rare CNVs that disrupt genes associated with neuronal development and function (8 CAE, 2 JAE, and 5 UAE). Four categories of protein are each disrupted by several CNVs: (1) synaptic vesicle membrane or vesicle endocytosis, (2) synaptic cell adhesion, (3) synapse organization and motility via actin, and (4) gap junctions. CNVs within these categories are shared across the AE subtypes. CONCLUSIONS: Our results have reinforced the complex and heterogeneous nature of the AEs and their potential for shared genetic mechanisms and have highlighted several pathways that may be important in epileptogenesis of absence seizures. PMID- 27123476 TI - Clinical course and prognosis in patients with Gaucher disease and parkinsonism. AB - OBJECTIVE: The goal of this study was to characterize the parkinsonian phenotype in patients with Gaucher disease (GD) who developed parkinsonism in order to evaluate clinical course and prognosis. METHODS: This is a retrospective observational study conducted at the Clinical Center of the NIH, Bethesda, MD, over a period of 10 years. The study included 19 patients with GD and parkinsonism. The severity of Gaucher and parkinsonian symptoms was determined from clinical data including physical, neurologic, pathologic, and neurocognitive evaluations, family histories, imaging studies, olfactory testing, and validated questionnaires. RESULTS: We found an earlier age at onset of parkinsonism and evidence of mild cognitive dysfunction in our cohort. Although the clinical course in some patients was similar to that of idiopathic Parkinson disease with a favorable levodopa response, others exhibited features characteristic of dementia with Lewy bodies. When we examined the patients as a group, we did not observe a uniformly aggressive form of parkinsonism after the initial onset of symptoms, contrary to other published reports. CONCLUSIONS: Appreciable clinical variation was seen in this cohort with GD and parkinsonism. Although some patients had early onset and prominent cognitive changes, others had a later, slower course, indicating that GBA1 mutations may not be a reliable prognostic indicator in Parkinson disease in clinical settings. PMID- 27123479 TI - Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis. AB - OBJECTIVE: To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients. METHODS: Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer. RESULTS: Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced. CONCLUSIONS: Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial. PMID- 27123478 TI - Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood. AB - OBJECTIVE: To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy. METHODS: Exome sequencing, long-range PCR, and Sanger sequencing to identify the pathogenic mutation. Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein. RESULTS: Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion. No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele. CONCLUSIONS: MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1. PMID- 27123480 TI - "Fork and bracket" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies. AB - Charcot-Marie-Tooth neuropathy type 4 (CMT4) comprises a large group of genetically heterogeneous progressive sensory motor neuropathies characterized by autosomal recessive inheritance. Among these, CMT4B includes 3 forms related to genes of the myotubularin family, namely CMT4B1 (MTMR2), CMT4B2 (MTMR13/SBF2), and CMT4B3 (MTMR5/SBF1). PMID- 27123481 TI - Exonic deletion of SLC9A9 in autism with epilepsy. AB - Genes encoding proteins critical for intracellular vesicular transport are an emerging area of importance for neurologists. In particular, proteins that create and maintain the correct compartmental pH, such as the endosomal Na(+)/H(+) exchangers (NHEs), have been implicated in a wide range of human diseases, including cardiovascular, inflammatory bowel, renal, and neurologic disorders, which demonstrates the critical cellular function of these proteins.(1-3) Two NHEs, NHE6 and NHE9, have been linked to neurologic disorders in children.(4) Pathologic variants in SLC9A6 encoding NHE6 cause an Angelman-like disorder called Christianson syndrome. Fewer variants have been described in SLC9A9 encoding NHE9, but individuals carrying these variants have been diagnosed with neurologic disorders ranging from autism to epilepsy to attention deficit/hyperactivity disorder. The majority of described variants are missense, resulting in amino acid substitutions, making it difficult to determine their functional consequence.(4). PMID- 27123482 TI - De novo FUS P525L mutation in Juvenile amyotrophic lateral sclerosis with dysphonia and diplopia. AB - Juvenile amyotrophic lateral sclerosis (jALS) is characterized by progressive upper and lower motor neuron degeneration leading to facial muscle spasticity, spastic dysarthria, and spastic gait with an early onset (before 25 years old). Unlike adult-onset amyotrophic lateral sclerosis (ALS), patients with jALS tend to have slower progression of motor neuron disease and prolonged survival to a normal life expectancy. Mutations in FUS gene have been reported in jALS,(1) including p.P525L mutation that has been consistently associated with early onset and aggressive presentation.(2) Here, we report a patient carrying p.P525L FUS mutation and experiencing an aggressive course of ALS presenting with dysphonia and diplopia. PMID- 27123483 TI - Familial aggregation of Parkinson disease in Utah: A population-based analysis using death certificates. AB - OBJECTIVE: To describe clustering of death from Parkinson disease (PD) in relatives in a large US study. METHODS: We analyzed the Utah Population Database resource, which includes genealogy data of more than 2.7 million individuals linked to 519,061 individuals with a Utah death certificate (DC). We identified individuals whose DC included PD as a cause of death using ICD coding. In those individuals whose Utah DC listed PD as a cause of death, the relative risk (RR) of death with PD was determined among close and distant relatives using sex-, birth year-, and birthplace-specific rates. RESULTS: We identified 4,031 individuals whose DC indicated PD. Among 18,127 first-degree relatives of probands with a Utah DC, the RR of death with PD was significantly increased (RR = 1.82, 95% confidence interval [CI] 1.61-2.04). The RR of death with PD was also significantly increased among 40,546 second-degree relatives with a Utah DC (RR = 1.44, 95% CI 1.29-1.60) and among 93,398 third-degree relatives with a Utah DC (RR = 1.10, 95% CI 1.03-1.18). CONCLUSIONS: Significant evidence for excess familial clustering was observed for PD deaths. The excess familial clustering and the significantly elevated RRs for PD among close and distant relatives strongly support a genetic contribution to PD mortality. These results confirm and expand the results of previous studies of PD by quantifying the risk of PD death among more distant relatives. PMID- 27123485 TI - Copy number variants in absence epilepsy: Further complications of the picture. AB - After years of largely unsuccessful association studies attempting to detect genetic variants underlying common epilepsies, the recent identification of copy number variants (CNVs) in epilepsy has generated a lot of excitement. CNVs are defined as genomic deletions or duplications larger than 1 kb and up to several Mb in size. A proportion occur at genomic hotspots (recurrent CNVs), whereas others can occur anywhere in the genome. Although individually rare, these CNVs collectively constitute the single largest risk factor for sporadic epilepsies known to date. Depending on the exact phenotype, CNVs have been reported in up to 28% of patients with epilepsy.(1) Subsequently, exon-disrupting deletions in a range of genes previously implicated in a variety of neurodevelopmental disorders were also identified in patients with epilepsy.(2-4) Genetic generalized epilepsy (GGE), either associated or not associated with intellectual disability, is the most commonly reported phenotype in patients carrying these CNVs. The GGEs comprise a large group of phenotypically heterogeneous disorders with a known or presumed genetic cause, which may vary from rare monogenic cases to complex polygenic inheritance. PMID- 27123484 TI - Paroxysmal hypnogenic dyskinesia is associated with mutations in the PRRT2 gene. AB - OBJECTIVE: To explore the potential causative genes of paroxysmal hypnogenic dyskinesia (PHD), which was initially considered a subtype of paroxysmal dyskinesia and has been recently considered a form of nocturnal frontal lobe epilepsy (NFLE). METHODS: Eleven patients with PHD were recruited. Mutations in proline-rich region transmembrane protein-2 (PRRT2), myofibrillogenesis regulator 1 (MR-1), solute carrier family 2, member 1 (SLC2A1), calcium-activated potassium channel alpha subunit (KCNMA1), cholinergic receptor, nicotinic, alpha 4 (CHRNA4), cholinergic receptor, nicotinic, beta 2 (CHRNB2), cholinergic receptor, nicotinic, alpha 2 (CHRNA2), and potassium channel subfamily T member 1 (KCNT1) were screened by direct sequencing. RESULTS: Two PRRT2 mutations were identified in patients with typical PHD. A mutation of c.649dupC (p.Arg217ProfsX8) was identified in a patient with PHD and his father who was diagnosed with paroxysmal kinesigenic dyskinesia. An additional mutation of c.640G>C (p.Ala214Pro) was identified in a sporadic patient and his asymptomatic mother. No mutations were found in the other screened genes. CONCLUSIONS: The present study identified PRRT2 mutations in PHD, extending the phenotypic spectrum of PRRT2 and supporting the classification of PHD as a subtype of paroxysmal dyskinesia but not NFLE. Based on the results of this study, screening for the PRRT2 mutation is recommended in patients with PHD. PMID- 27123486 TI - Deleterious mutation in GPR88 is associated with chorea, speech delay, and learning disabilities. AB - OBJECTIVE: To identify the underlying molecular basis of a familial developmental disorder characterized by chorea, marked speech delay, and learning difficulties in 4 sisters from a consanguineous family. METHODS: Whole-exome analysis of DNA of the 2 older patients followed by Sanger sequencing of the mutated exon in all family members. RESULTS: A homozygous deleterious mutation, p.C291X, was identified in the GPR88 gene in both exome analyses. The mutation segregated with the disease in the family and was absent from a large cohort of controls. CONCLUSIONS: Homozygous deleterious mutation in GPR88 in humans is associated with marked speech delay, learning disabilities, and chorea, which manifest at 8 9 years of age. The finding is consistent with the reported abundant expression of GPR88 in the striatum and the hyperkinetic activity and learning impairment observed in GPR88 knockout mice. Although further functional characterization is needed, the finding underscores the importance of GPR88 in movement control and learning. PMID- 27123487 TI - Spinocerebellar ataxia type 36 in the Han Chinese. AB - OBJECTIVE: To ascertain the genetic and clinical characteristics of the GGCCTG hexanucleotide repeat expansion in the nucleolar protein 56 gene (NOP56) in patients with spinocerebellar ataxia (SCA), sporadic ataxia, or amyotrophic lateral sclerosis (ALS) in Taiwan. METHODS: We conducted clinical and molecular genetic studies of 109 probands with molecularly unassigned SCA from 512 SCA pedigrees, 323 healthy controls, 502 patients with sporadic ataxia syndromes, and 144 patients with ALS. Repeat-primed PCR assays and PCR-fragment analysis for the number of short hexanucleotide repeats (<40 units) were performed to ascertain NOP56 hexanucleotide repeat expansion. Genotyping included 8 microsatellite markers and 17 single nucleotide polymorphisms flanking NOP56 and covering a region of 1.8 Mb to assess a possible founder effect. RESULTS: Eleven individuals from 3 SCA pedigrees have the NOP56 repeat expansions. The 3 pedigrees share a common haplotype spanning 5.3 kb flanking the NOP56 repeat expansions, suggesting a founder effect of spinocerebellar ataxia type 36 (SCA36) in the Han Chinese. The average age at symptom onset was 44.8 +/- 3.8 years with truncal ataxia as the initial manifestation. Common features included slowly progressive truncal/limb ataxia, dysarthria, generalized hyperreflexia, and hearing impairment. Evidence of lower motor neuron involvement, including atrophy and fasciculation in the limb muscles and tongue, was mostly found in patients with prolonged disease duration. NOP56 repeat expansion was not detected in controls or patients with sporadic ataxic syndromes or ALS. CONCLUSIONS: SCA36 is an uncommon subtype, which accounted for 0.6% (3/512) of SCA cases in the Han Chinese population. PMID- 27123488 TI - Clinical and genetic features of cervical dystonia in a large multicenter cohort. AB - OBJECTIVE: To characterize the clinical and genetic features of cervical dystonia (CD). METHODS: Participants enrolled in the Dystonia Coalition biorepository (NCT01373424) with initial manifestation as CD were included in this study (n = 1,000). Data intake included demographics, family history, and the Global Dystonia Rating Scale. Participants were screened for sequence variants (SVs) in GNAL, THAP1, and Exon 5 of TOR1A. RESULTS: The majority of participants were Caucasian (95%) and female (75%). The mean age at onset and disease duration were 45.5 +/- 13.6 and 14.6 +/- 11.8 years, respectively. At the time of assessment, 68.5% had involvement limited to the neck, shoulder(s), and proximal arm(s), whereas 47.4% had dystonia limited to the neck. The remaining 31.5% of the individuals exhibited more extensive anatomical spread. A head tremor was noted in 62% of the patients. Head tremor and laryngeal dystonia were more common in females. Psychiatric comorbidities, mainly depression and anxiety, were reported by 32% of the participants and were more common in females. Family histories of dystonia, parkinsonian disorder, and tremor were present in 14%, 11%, and 29% of the patients, respectively. Pathogenic or likely pathogenic SVs in THAP1, TOR1A, and GNAL were identified in 8 participants (0.8%). Two individuals harbored novel missense SVs in Exon 5 of TOR1A. Synonymous and noncoding SVs in THAP1 and GNAL were identified in 4% of the cohort. CONCLUSIONS: Head tremor, laryngeal dystonia, and psychiatric comorbidities are more common in female participants with CD. Coding and noncoding variants in GNAL, THAP1, and TOR1A make small contributions to the pathogenesis of CD. PMID- 27123489 TI - Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma. AB - OBJECTIVE: To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts. METHODS: We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers. RESULTS: Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried >=1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001). CONCLUSIONS: The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD. PMID- 27123490 TI - DNA variants in CACNA1C modify Parkinson disease risk only when vitamin D level is deficient. AB - OBJECTIVE: To evaluate the association between the genetic variants in CACNA1C, which encodes the alpha1 subunit of the L-type voltage-sensitive calcium channel (LVSCC) and Parkinson disease (PD) while accounting for interactions with vitamin D concentration. METHODS: Two independent case-control data sets (478 cases and 431 controls; 482 cases and 412 controls) were used. Joint effects of single nucleotide polymorphisms (SNPs) and SNP-vitamin D interaction were analyzed by comparing models containing vitamin D deficiency, SNP genotypes, SNP-vitamin D interaction, and covariates to a restricted model with only vitamin D deficiency and covariates. Meta-analysis was used to combine the joint effects in the 2 data sets. Analysis was stratified by vitamin D deficiency to demonstrate the pattern of SNP-vitamin D interaction. RESULTS: Vitamin D deficiency was associated with PD in both data sets (odds ratio [OR] = 1.9-2.7, p <= 0.009). SNP rs34621387 demonstrated a significant joint effect (meta-analysis, p = 7.5 * 10(-5); Bonferroni corrected, p = 0.02). The G allele at rs34621387 is associated with PD in vitamin D-deficient individuals in both data sets (OR = 2.0-2.1, confidence interval = 1.3-3.5, p = 0.002) but is not associated with PD in vitamin D nondeficient individuals (p > 0.8 in both data sets). CONCLUSIONS: Previous studies suggest that vitamin D deficiency is associated with PD and sustained opening of LVSCC contributes to the selective vulnerability of dopaminergic neurons in PD. Our data demonstrate that the association between genetic variations in CACNA1C and PD depends on vitamin D deficiency, providing one potential mechanism underlying the association between vitamin D deficiency and PD. PMID- 27123492 TI - A Health Equity Problem for Low Income Children: Diet Flexibility Requires Physician Authorization. AB - USDA programs, such as the Child and Adult Care Food Program (CACFP), School Breakfast Program (SBP), and/or National School Lunch Program (NSLP), enable child care centers and schools to provide free and reduced price meals, daily, to millions of low income children. Despite intention to equalize opportunity for every child to have a healthy diet, USDA program rules may be contributing to child obesity disparities and health inequity. USDA program rules require child care centers and schools to provide meals that include a specified number of servings of particular types of foods and beverages. The rules are designed for the average, healthy weight child to maintain weight and growth. They are not designed for the underweight child to gain weight, obese child to normalize weight, or pre-diabetic child to avoid incident diabetes. The rules allow for only one meal pattern and volume, as opposed to a flexible spectrum of meal patterns and portion sizes. Parents of children who participate in the CACFP, SBP, and/or NSLP do not have control over the amount or composition of the subsidized meals. Parents of overweight, obese, or diabetic children who participate in the subsidized meal programs can request dietary change, special meals or accommodations to address their child's health status, but child care providers and schools are not required to comply with the request unless a licensed physician signs a "Medical statement to request special meals and/or accommodations". Although physicians are the only group authorized to change the foods, beverages, and portion sizes served daily to low income children, they are not doing so. Over the past three years, despite an overweight and obesity prevalence of 30% in San Francisco child care centers serving low income children, zero medical statements were filed to request special meals or accommodations to alter daily meals in order to prevent obesity, treat obesity, or prevent postprandial hyperglycemia. Low income children have systematically less dietary flexibility than higher income children, because of reliance on free or reduced-price meals, federal food program policy, and lack of awareness that only physicians have authority to alter the composition of subsidized meals in child care centers and schools. Compared with higher income children, low income children do not have equal opportunity to change their daily dietary intake to balance energy requirements. PMID- 27123491 TI - Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL. AB - BCR-ABL1+ B progenitor acute lymphoblastic leukemia (Ph+ B-ALL) is an aggressive disease that frequently responds poorly to currently available therapies. Alterations in IKZF1, which encodes the lymphoid transcription factor Ikaros, are present in over 80% of Ph+ ALL and are associated with a stem cell-like phenotype, aberrant adhesion molecule expression and signaling, leukemic cell adhesion to the bone marrow stem cell niche, and poor outcome. Here, we show that FAK1 is upregulated in Ph+ B-ALL with further overexpression in IKZF1-altered cells and that the FAK inhibitor VS-4718 potently inhibits aberrant FAK signaling and leukemic cell adhesion, potentiating responsiveness to tyrosine kinase inhibitors, inducing cure in vivo. Thus, targeting FAK with VS-4718 is an attractive approach to overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, particularly in abrogating the adhesive phenotype induced by Ikaros alterations, and warrants evaluation in clinical trials for Ph+ B-ALL, regardless of IKZF1 status. PMID- 27123493 TI - Season of birth is associated with birth weight, pubertal timing, adult body size and educational attainment: a UK Biobank study. AB - Season of birth, a marker of in utero vitamin D exposure, has been associated with a wide range of health outcomes. Using a dataset of ~450,000 participants from the UK Biobank study, we aimed to assess the impact of this seasonality on birth weight, age at menarche, adult height and body mass index (BMI). Birth weight, age at menarche and height, but not BMI, were highly significantly associated with season of birth. Individuals born in summer (June-July-August) had higher mean birth weight (P = 8 * 10-10), later pubertal development (P = 1.1 * 10-45) and taller adult height (P = 6.5 * 10-9) compared to those born in all other seasons. Concordantly, those born in winter (December-January-February) showed directionally opposite differences in these outcomes. A secondary comparison of the extreme differences between months revealed higher odds ratios [95% confidence intervals (CI)] for low birth weight in February vs. September (1.23 [1.15-1.32], P = 4.4 * 10-10), for early puberty in September vs. July (1.22 [1.16-1.28], P = 7.3 * 10-15) and for short stature in December vs. June (1.09 [1.03-1.17], P = 0.006). The above associations were also seen with total hours of sunshine during the second trimester, but not during the first three months after birth. Additional associations were observed with educational attainment; individuals born in autumn vs. summer were more likely to continue in education post age 16 years (P = 1.1 * 10-91) or attain a degree-level qualification (P = 4 * 10-7). However, unlike other outcomes, an abrupt difference was seen between those born in August vs. September, which flank the start of the school year. Our findings provide support for the 'fetal programming' hypothesis, refining and extending the impact that season of birth has on childhood growth and development. Whilst other mechanisms may contribute to these associations, these findings are consistent with a possible role of in utero vitamin D exposure. PMID- 27123494 TI - Evolution of the macromolecular structure of sporopollenin during thermal degradation. AB - Reconstructing the original biogeochemistry of organic microfossils requires quantifying the extent of the chemical transformations they experienced during burial and maturation processes. In the present study, fossilization experiments have been performed using modern sporopollenin chosen as an analogue for the resistant biocompounds possibly constituting the wall of many organic microfossils. Sporopollenin powder has been processed thermally under argon atmosphere at different temperatures (up to 1000 degrees C) for varying durations (up to 900 min). Solid residues of each experiment have been characterized using infrared, Raman and synchrotron-based XANES spectroscopies. Results indicate that significant defunctionalisation and aromatization affect the molecular structure of sporopollenin with increasing temperature. Two distinct stages of evolution with temperature are observed: in a first stage, sporopollenin experiences dehydrogenation and deoxygenation simultaneously (below 500 degrees C); in a second stage (above 500 degrees C) an increasing concentration in aromatic groups and a lateral growth of aromatic layers are observed. With increasing heating duration (up to 900 min) at a constant temperature (360 degrees C), oxygen is progressively lost and conjugated carbon carbon chains or domains grow progressively, following a log-linear kinetic behavior. Based on the comparison with natural spores fossilized within metasediments which experienced intense metamorphism, we show that the present experimental simulations may not perfectly mimic natural diagenesis and metamorphism. Yet, performing such laboratory experiments provides key insights on the processes transforming biogenic molecules into molecular fossils. PMID- 27123495 TI - Adult Stem Cells and Diabetes Therapy. AB - The World Health Organization estimates that diabetes will be the fourth most prevalent disease by 2050. Developing a new therapy for diabetes is a challenge for researchers and clinicians in field. Many medications are being used for treatment of diabetes however with no conclusive and effective results therefore alternative therapies are required. Stem cell therapy is a promising tool for diabetes therapy, and it has involved embryonic stem cells, adult stem cells, and pluripotent stem cells. In this review, we focus on adult stem cells, especial human bone marrow stem cells (BM) for diabetes therapy, its history, and current development. We discuss prospects for future diabetes therapy such as induced pluripotent stem cells which have popularity in stem cell research area. PMID- 27123496 TI - Anti-proliferation effects of Cistanches salsa on the progression of benign prostatic hyperplasia. AB - Cistanche salsa has been used in traditional medicine for the treatment of kidney deficiency, neurasthenia, sexual dysfunction diseases, and benign prostatic hyperplasia (BPH). The aim of this study was to investigate the mechanism by which C. salsa extract (CSE) elicits an anti-proliferative effect on the prostate tissue of BPH-induced rats. The effects of CSE on BPH were evaluated in terms of prostate weight, production of serum dihydrotestosterone (DHT), and the mRNA expression of 5alpha-reductase type 1 and type 2 in the prostate tissue of BPH induced rats. In addition, hematoxylin and eosin (H&E) staining was performed for histological examination of prostate gland morphology, and protein expression levels in prostate tissue were investigated by western blot analysis. CSE treatment decreased prostate weight, serum DHT concentration, and the mRNA expression of 5alpha-reductase type 1 and type 2 in prostate tissue of BPH induced rats. In addition, CSE treatment suppressed cell proliferation by regulating the expression levels of inflammatory-related proteins (inducible nitric oxide synthase and cyclooxygenase 2) and apoptosis-associated proteins (caspase-3 and Bcl-2 family proteins). CSE may be a potential therapeutic candidate for BPH owing to its ability to regulate the expression of inflammatory and apoptosis-related proteins. PMID- 27123497 TI - Reply. PMID- 27123499 TI - Model-Based Estimation of Aortic and Mitral Valves Opening and Closing Timings in Developing Human Fetuses. AB - Electromechanical coupling of the fetal heart can be evaluated noninvasively using doppler ultrasound (DUS) signal and fetal electrocardiography (fECG). In this study, an efficient model is proposed using K-means clustering and hybrid Support Vector Machine-Hidden Markov Model (SVM-HMM) modeling techniques. Opening and closing of the cardiac valves were detected from peaks in the high frequency component of the DUS signal decomposed by wavelet analysis. It was previously proposed to automatically identify the valve motion by hybrid SVM-HMM based on the amplitude and timing of the peaks. However, in the present study, six patterns were identified for the DUS components which were actually variable on a beat-to-beat basis and found to be different for the early gestation (16-32 weeks), compared to the late gestation fetuses (36-41 weeks). The amplitude of the peaks linked to the valve motion was different across the six patterns and this affected the precision of valve motion identification by the previous hybrid SVM-HMM method. Therefore in the present study, clustering of the DUS components based on K-means was proposed and the hybrid SVM-HMM was trained for each cluster separately. The valve motion events were consequently identified more efficiently by beat-to-beat attribution of the DUS component peaks. Applying this method, more than 98.6% of valve motion events were beat-to-beat identified with average precision and recall of 83.4% and 84.2% respectively. It was an improvement compared to the hybrid method without clustering with average precision and recall of 79.0% and 79.8%. Therefore, this model would be useful for reliable screening of fetal wellbeing. PMID- 27123500 TI - The author responds. PMID- 27123501 TI - Authors' reply. PMID- 27123502 TI - Authors' reply. PMID- 27123503 TI - [Not Available]. PMID- 27123530 TI - Altered cerebral activity associated with topiramate and its withdrawal in patients with epilepsy with language impairment: An fMRI study using the verb generation task. AB - OBJECTIVE: Topiramate (TPM) is well recognized for its negative effects on language in healthy volunteers and patients with epilepsy. The aim of this study was to investigate the brain activation and deactivation patterns in TPM-treated patients with epilepsy with language impairment and their dynamic alteration during TPM withdrawal using functional magnetic resonance imaging (fMRI) with the verb generation task (VGT). METHODS: Twelve patients with epilepsy experiencing subjective language disfluency after TPM add-on treatment (TPM-on) and thirty sex and age-matched healthy controls (HCs) were recruited. All subjects received a battery of neuropsychological tests and an fMRI scan with the VGT. Withdrawal of TPM was attempted in all patients. Only six patients reached complete withdrawal without seizure relapses (TPM-off), and these patients underwent a reassessment of neuropsychological and neuroimaging tests. RESULT: The neuropsychological tests demonstrated objective language impairments in TPM-on patients. Compared with the HCs, the bilateral medial prefrontal cortex and the posterior midline and lateral parts of the default mode network (DMN) (including the bilateral posterior cingulate cortex (PCC), the right medial prefrontal cortex, the right angular gyrus, the right inferior temporal gyrus, and the bilateral supramarginal gyrus) in TPM-on patients failed to deactivate during the VGT. Their task-induced activation patterns were largely similar to those of the HCs. After TPM withdrawal, partial improvement of both task-induced deactivation of the DMN (the left parahippocampal gyrus and the bilateral PCC) and task-related activation of the language network (the right middle frontal gyrus and the left superior occipital gyrus) was identified along with partial improvement of neuropsychological tests. CONCLUSION: Task-induced deactivation is a more sensitive neuroimaging biomarker for the impaired language performance in patients administered TPM than task-induced activation. Disruption and reorganization of the balance between the DMN and the cortical language networks are found along with reversible TPM-related language impairment. These results may suggest an underlying brain mechanism by which TPM affects cognitive function. PMID- 27123531 TI - Which outcomes should we measure in adult epilepsy trials? The views of people with epilepsy and informal carers. AB - OBJECTIVE: So that informed treatment decisions can be made, clinical trials need to evaluate treatments against domains that are important to people with epilepsy (PWE), their carers, and clinicians. Health professionals have identified domains of importance to them via the International League Against Epilepsy's Commission on Outcome Measurement (COME). However, patients and carers have not been systematically asked. METHODS: Via the membership of the British Epilepsy Association, we recruited and surveyed 352 PWE and 263 of their informal carers. They were presented with 10 outcome domains (including the 5 identified by COME) and asked to rate their importance using a 9-point Likert scale. They were also asked to identify any additional domains of importance. RESULTS: The patients' mean age was 49years, the median number of years since diagnosis was 20, and 65% had experienced seizures in the prior 12months. Most carers were the spouse or parent. Patients' and carers' mean ratings indicated that their outcome priorities were similar, as were those of patients who had and had not experienced recent seizures. There was consensus among patients that 6 domains were of critical importance. These included the 5 identified by COME (namely, and in order of importance, the effects of the treatment on "Seizure severity", "Seizure frequency", "Quality of life", "Cognitive function", and "Adverse events"), as well as one additional domain ("Independence/need for support"). There was consensus among carers that the 5 COME domains were also critically important. They, however, identified 3 further domains as critically important. These were the effects of the treatment on patient "Depression", "Anxiety", and "Independence/need for support". CONCLUSIONS: Our study found some overlap between the priorities of PWE, carers, and health professionals. They, however, highlight additional areas of importance to patients and carers. Our results could inform a core outcome set for epilepsy that represents the domains that should be reported as a minimum by all trials. This could promote trials which produce meaningful results and consistency in measurement and reporting. PMID- 27123532 TI - The temporal dynamics of directed reappraisal in high-trait-anxious individuals. AB - High-trait-anxious (HTA) individuals often experience high levels of negative emotions, signaling potential abnormalities in the down-regulation of negative emotions. In this study, we used event-related potentials to examine whether HTA individuals can effectively use directed reappraisal to down-regulate negative emotions. Participants completed a passive picture-viewing task in which pictures were preceded by audio descriptions of their content. For unpleasant pictures, descriptions were either neutral or negative, whereas for neutral pictures, only neutral descriptions were given. Self-report behavioral results indicated that HTA individuals reported greater unpleasantness for the pictures than did low trait-anxious (LTA) individuals but revealed no abnormality in decreasing negative emotional experience. Such abnormality, however, did emerge neurally. Analyses focused on the central-parietal late positive potential (LPP), a neural marker of emotion regulation. LTA individuals showed an LPP reduction in response to unpleasant pictures with negative descriptions compared to neutral ones at 400 3000-ms post-picture-onset, indicating effective down-regulation of negative emotions. HTA individuals, however, showed no LPP reduction at 400- to 1,000-ms post picture onset. Instead, they showed an LPP increase in response to unpleasant pictures with negative descriptions compared to neutral ones at 1,000- to 2,000-ms post picture-onset. These abnormal central-parietal LPP patterns not only verify that HTA individuals exhibit ineffective use of directed reappraisal to down-regulate neural responses to unpleasant stimuli, but also reveal an abnormal time-course of directed reappraisal in such individuals. Our findings also suggest that the ineffective use of cognitive reappraisals may contribute to the generally elevated levels of negative emotionality in HTA individuals. (PsycINFO Database Record PMID- 27123533 TI - Giving Boys a Shot: The HPV Vaccine's Portrayal in Canadian Newspapers. AB - In January 2012, the National Advisory Committee on Immunization (NACI) of Canada recommended that males aged 9-26 years receive the human papillomavirus (HPV) vaccine to protect against genital warts and HPV-associated cancers. Estimated HPV vaccine uptake rates for Canadian males are extremely low. Using a content analysis of Canadian newspaper articles, this study investigated what information about the HPV vaccine was relayed to the public, and how this content was portrayed following the 2012 male HPV vaccine recommendation. A search was conducted using Proquest Canadian Newsstand Complete for newspaper articles published between January 1, 2012, and September 1, 2014. Researchers coded 232 articles on several relevant dimensions: article information; epidemiological information; public policy information; article topic; article and title tone; and informant testimony. The majority of articles (93%) mentioned that girls are eligible for the HPV vaccine, whereas only half (49%) mentioned male eligibility. While most articles associated HPV with cervical cancer (85%), fewer indicated its relation to other HPV-associated cancers (59%) or genital warts (52%). Most articles (60%) were positive or neutral (22%) in tone toward the HPV vaccine, while few had mixed messages (11%) or were negative (6%). Less than 5% of articles reported on issues of morality, suggesting that fears that the HPV vaccine causes promiscuity have largely subsided. Notably, article tone toward male vaccination became progressively more positive over time. However, half of the articles did not mention the vaccine's approval for males, and articles tended to report HPV's relation to cervical cancer over other HPV-associated cancers. The Canadian public may thus be unaware of male eligibility and the importance of HPV vaccine for males. The collaboration of researchers, health care providers, and policymakers with journalists is critical in order to disseminate complete and accurate HPV and HPV vaccine information. PMID- 27123534 TI - Engineering Lysosome-Targeting BODIPY Nanoparticles for Photoacoustic Imaging and Photodynamic Therapy under Near-Infrared Light. AB - Developing lysosome-targeting organic nanoparticles combined with photoacoustic imaging (PAI) and photodynamic therapy (PDT) functions toward personalized medicine are highly desired yet challenging. Here, for the first time, lysosome targeting BODIPY nanoparticles were engineered by encapsulating near-infrared (NIR) absorbed BODIPY dye within amphiphilic DSPE-mPEG5000 for high-performing lysosomal PAI and acid-activatable PDT against cancer cells under NIR light. PMID- 27123538 TI - Hypervalent-Iodine(III)-Mediated Oxidative Methodology for the Synthesis of Fused Triazoles. AB - The organic chemistry of hypervalent organoiodine compounds has been an area of unprecedented development. This surge in interest in the use of hypervalent iodine compounds has mainly been owing to their highly selective oxidizing properties, environmentally benign character and commercial availability. Hypervalent iodine reagents have also been used as an alternative to toxic heavy metals, owing to their low toxicity and ease of handling. Hypervalent organoiodine(III) reagents are versatile oxidants that have been successfully employed to extend the scope of selective oxidative transformations of complex organic molecules in synthetic chemistry. This Focus Review concerns the tandem in situ generation and 1,5-electrocyclization of N-heteroaryl nitrilimines into fused triazoles. We describe the importance of recently developed hypervalent organoiodine(III)-catalyzed oxidative cyclization reactions, building towards the conclusion that hypervalent iodine chemistry is a promising frontier for oxidative cyclization, in particular of hydrazones, for the synthesis of fused triazoles. PMID- 27123539 TI - Cell division patterns and chromosomal segregation defects in oral cancer stem cells. AB - Oral squamous cell carcinoma (OSCC) is a serious public health problem caused primarily by smoking and alcohol consumption or human papillomavirus. The cancer stem cell (CSC) theory posits that CSCs show unique characteristics, including self-renewal and therapeutic resistance. Examining biomarkers and other features of CSCs is critical to better understanding their biology. To this end, the results show that cellular SOX2 immunostaining correlates with other CSC biomarkers in OSCC cell lines and marks the rare CSC population. To assess whether CSC division patterns are symmetrical, resulting in two CSC, or asymmetrical, leading to one CSC and one cancer cell, cell size and fluorescence intensity of mitotic cells stained with SOX2 were analyzed. Asymmetrical SOX2 distribution in ~25% of the mitoses analyzed was detected. Chromosomal instability, some of which is caused by chromosome segregation defects (CSDs), is a feature of cancer cells that leads to altered gene copy numbers. We compare chromosomal instability (as measured by CSDs) between CSCs (SOX2+) and non-CSCs (SOX2-) from the same OSCC cell lines. CSDs were more common in non-CSCs (SOX2-) than CSCs (SOX2+) and in symmetrical CSC (SOX2+) mitotic pairs than asymmetrical CSC (SOX2+/SOX2-) mitotic pairs. CSCs showed fewer and different types of CSDs after ionizing radiation treatment than non-CSCs. Overall, these data are the first to demonstrate both symmetrical and asymmetrical cell divisions with CSDs in OSCC CSC. Further, the results suggest that CSCs may undergo altered behavior, including therapeutic resistance as a result of chromosomal instability due to chromosome segregation defects. (c) 2016 Wiley Periodicals, Inc. PMID- 27123540 TI - Effects of Neuromuscular Training on Children and Young Adults with Down Syndrome: Systematic Review and Meta-Analysis. AB - PURPOSE: To synthesize existing research evidence and examine effects of neuromuscular training on general strength, maximal strength, and functional mobility tasks in children and young adults with Down syndrome. METHODS: PubMed and EBSCO were used as a data source. To attain the aim of this study, literature search was performed under following inclusion criteria: (1) included participants with Down syndrome, (2) implemented a neuromuscular training intervention and measured outcome variables of general strength, maximal strength, and functional mobility tasks, (3) had a group of participants whose mean ages were under 30 years old, (4) employed a prospective controlled design, and (5) used mean and standard deviations to express the outcome variables. Effect size was calculated from each study based on pre- and post-testing value differences in general strength, maximal strength, and functional mobility tasks between control and intervention groups. The effect size was further classified in to one of the following categories: small, moderate, and large effects. RESULTS: Seven studies met inclusion criteria. Analysis indicated large to moderate effects on general strength, moderate to small effects on maximal strength, and small effect on functional mobility tasks by neuromuscular training. CONCLUSIONS: Although there were limited studies, the results showed that neuromuscular training could be used as an effective intervention in children and young adults with Down syndrome. WHAT THIS PAPER ADDS: Synthesis of seven reviewed studies indicated that neuromuscular training could be beneficial to optimize general and maximal muscular strength development in children and young adults with Down syndrome. PMID- 27123542 TI - Impact of mode of delivery on skin microcirculation in term healthy newborns within the first day of life. AB - BACKGROUND: Microcirculation is an important component of hemodynamic physiology. It can be assessed simply by clinical scores or by a variety of techniques including sidestream dark field (SDF) imaging and peripheral perfusion index (PI) measurements. Mode of delivery may have affects on microcirculation during transitional period. The aim of this study was to compare skin microcirculation in newborns born via vaginal delivery (VD) or cesarian section (C/S). METHODS: Term healthy newborns not requiring NICU admission were included. Vital signs were recorded. Skin microcirculation was determined by clinical scoring including capillary refill time, skin color, warmth of extremities, by SDF imaging where capillary density and microvascular flow is determined and by PI measurements where pulsatile and nonpulsatile capillary flow is measured. Assessments were done at 30 min and 24 h of life. Results were compared between VD and C/S groups and overtime. RESULTS: There were 12 newborns in VD group and 25 newborns in C/S group. No difference was observed in microcirculation assessments between groups. However VD group had increased hyperdynamic flow overtime. CONCLUSION: In healthy term newborns microcirculation does not seem to be affected by mode of delivery, however results may differ in sick or preterm newborns. PMID- 27123541 TI - Role of serum- and glucocorticoid-inducible kinases in stroke. AB - Increased expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) can be induced by stress and growth factors in mammals, and plays an important role in cancer, diabetes, and hypertension. A recent work suggested that SGK1 activity restores damage in a stroke model. To further investigate the role of SGKs in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome in vivo and neurotoxicity in vitro. Infarct volumes were compared in adult mice with middle cerebral artery occlusion, followed by 24 h reperfusion, in the absence or presence of SGK inhibitors. Neurotoxicity assay, electrophysiological recording, and fluorescence Ca(2+) imaging were carried out using cultured cortical neurons to evaluate the underlying mechanisms. Contrary to our expectation, infarct volume by stroke decreased significantly when SGK inhibitor, gsk650394, or EMD638683, was administrated 30 min before middle cerebral artery occlusion under normal and diabetic conditions. SGK inhibitors reduced neurotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors, a leading factor responsible for cell death in stroke. SGK inhibitors also ameliorated Ca(2+) increase and peak amplitude of NMDA current in cultured neurons. In addition, SGK inhibitor gsk650394 decreased phosphorylation of Nedd4-2 and inhibited voltage-gated sodium currents. These observations suggest that SGK activity exacerbates stroke damage and that SGK inhibitors may be useful candidates for therapeutic intervention. To investigate the role of serum- and glucocorticoid-inducible kinases (SGKs) in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome. Infarct volumes induced by middle cerebral artery occlusion were decreased significantly by SGK inhibitors. The inhibitors also reduced glutamate toxicity, at least partly, by attenuation of NMDA and voltage-gated sodium currents. Thus, SGK inhibition attenuates stroke damage. PMID- 27123543 TI - Robot-assisted Fallopian tube transection and anastomosis using the new REVO-I robotic surgical system: feasibility in a chronic porcine model. AB - OBJECTIVES: To evaluate the feasibility and safety of the new REVO-I robotic platform by performing Fallopian tube transection and anastomosis in live porcine models. SUBJECTS AND METHODS: A prospective chronic animal study was carried out in four crossbred female pigs. The primary outcome was assessment of the pigs' 2 week survival. The secondary outcomes were measurements of intra-operative variables and the complications or difficulties arising when using the REVO-I. RESULTS: Fallopian tube anastomosis was successfully performed in four porcine models. The mean (range) operating time was 66 (46-104 min), docking time 22.25 (14-53) min and console time 18 (13-20) min. The REVO-I robotic system functioned appropriately, with no technical problems or difficulties noted during the procedures. Both the surgeon and the bedside assistants reported ease of use and better performance with subsequent procedures. All pigs were alive 2 weeks after surgery, with no peri-operative complications related to the use of the robot. CONCLUSIONS: This preclinical chronic porcine study showed that the REVO-I robotic surgical system is a feasible and safe robotic instrument that can be used by surgeons to perform skillful robotic procedures in porcine models. Our next objective will be to demonstrate its safety in humans. PMID- 27123545 TI - Decision-making quality of younger and older adults in familiar and unfamiliar domains. AB - Age-related differences in purchasing decisions were examined as a function of age and familiarity. On each trial, participants received purchasing options which varied in quality but ultimately cost the same amount of money. On half the trials, participants made decisions about items familiar to younger adults and on the other half of the trials, participants made decisions about products familiar to older adults. The participants' task was to choose the option that provided the best value for the money. We were particularly interested in participants' performance when inferencing was required to select the optimal option from the two choices. Younger adults outperformed older adults in unfamiliar but not familiar domains. It appeared that both younger and older adults used inferencing and elaborative processing to make the best decision in familiar domains but that only younger adults used inferencing and elaborative processing in unfamiliar domains. PMID- 27123546 TI - Phenanthro[4,5-fgh]quinoxaline-Fused Subphthalocyanines: Synthesis, Structure, and Spectroscopic Characterization. AB - A series of four phenanthro[4,5-fgh]quinoxaline-fused subphthalocyanine derivatives 0-3 containing zero, one, two, and three phenanthro[4,5 fgh]quinoxaline moieties, respectively, were isolated from the mixed cyclotrimerization reaction of 2,9-di-tert-butylphenanthro[4,5-fgh]quinoxaline 5,6-dicarbonitrile with 4,5-bis(2,6-diisopropylphenoxy)phthalonitrile and characterized by a series of spectroscopic methods including MALDI-TOF mass, (1) H NMR, electronic absorption, magnetic circular dichroism (MCD), and fluorescence spectroscopy. The molecular structures for the compounds 0 and 2 were clearly revealed on the basis of single-crystal X-ray diffraction analysis. Their electrochemical properties were also studied by cyclic voltammetry. In particular, theoretical calculations in combination with the electronic absorption and electrochemical analyses revealed the significant influence of the fused-phenanthro[4,5-fgh]quinoxaline units on the electronic structures. PMID- 27123544 TI - Evidence for the involvement of lipid rafts localized at the ER-mitochondria associated membranes in autophagosome formation. AB - Mitochondria-associated membranes (MAMs) are subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. This membrane scrambling between ER and mitochondria appears to play a critical role in the earliest steps of autophagy. Recently, lipid microdomains, i.e. lipid rafts, have been identified as further actors of the autophagic process. In the present work, a series of biochemical and molecular analyses has been carried out in human fibroblasts with the specific aim of characterizing lipid rafts in MAMs and to decipher their possible implication in the autophagosome formation. In fact, the presence of lipid microdomains in MAMs has been detected and, in these structures, a molecular interaction of the ganglioside GD3, a paradigmatic "brick" of lipid rafts, with core-initiator proteins of autophagy, such as AMBRA1 and WIPI1, was revealed. This association seems thus to take place in the early phases of autophagic process in which MAMs have been hypothesized to play a key role. The functional activity of GD3 was suggested by the experiments carried out by knocking down ST8SIA1 gene expression, i.e., the synthase that leads to the ganglioside formation. This experimental condition results in fact in the impairment of the ER-mitochondria crosstalk and the subsequent hindering of autophagosome nucleation. We thus hypothesize that MAM raft-like microdomains could be pivotal in the initial organelle scrambling activity that finally leads to the formation of autophagosome. PMID- 27123547 TI - Assembly of a Metal-Organic Framework into 3 D Hierarchical Porous Monoliths Using a Pickering High Internal Phase Emulsion Template. AB - 3D Hierarchical porous metal-organic framework (MOF) monoliths are prepared by using Pickering high internal phase emulsion (HIPE) template. Pickering HIPEs were stabilized solely by UiO-66 MOF particles with internal phase up to 90 % of the volume. The effects of internal phase type and volume, as well as MOF particle concentration on the stability of resulting Pickering HIPEs were investigated. Furthermore, by adding small amount of polyvinyl alcohol (PVA) as binder or polymerization in the continuous aqueous phase, followed by freeze drying, two types of MOF-based 3D hierarchical porous monoliths with ultralow density (as low as 12 mg cm(-3) ) were successfully prepared. This Pickering HIPE template approach provides a facile and practical way for assembling of MOFs into complex structures. PMID- 27123548 TI - Cucurbit[7]uril inclusion complexation as a supramolecular strategy for color stabilization of anthocyanin model compounds. AB - Host-guest complexation with cucurbit[7]uril of anthocyanin model compounds in which acid-base equilibria are blocked resulted in essentially complete stabilization of their color. The color protection is a thermodynamic effect and establishes a strategy to stabilize these colored compounds at pH values of interest for practical applications. PMID- 27123549 TI - Reversible Gel-Sol Transition of a Photo-Responsive DNA Gel. AB - Stimuli-responsive DNA gels that can undergo a sol-gel transition in response to photo-irradiation provide a way to engineer functional gel material with fully designed DNA base sequences. We propose an X-shaped DNA motif that turns into a gel by hybridization of self-complementary sticky ends. By embedding a photo crosslinking artificial base in the sticky-end sequence, repetitive gel-sol transitions are achieved through UV irradiation at different wavelengths. The concentration of the DNA motif necessary for gelation is as low as 40 MUm after modification of the geometrical properties of the motif. The physical properties, such as swelling degree and diffusion coefficient, were assessed experimentally. PMID- 27123550 TI - Cytotoxic activity of a synthetic deoxypodophyllotoxin derivative with an opened D-ring. AB - Podophyllotoxin and its synthetic derivatives are valuable medicinal agents that have antitumor, insecticidal, and antifungal properties. We previously synthesized a deoxypodophyllotoxin derivative with an opened D-ring (DPD) exhibiting potent insecticidal activity. This article was firstly performed to identify the cytotoxicity of DPD toward human cancer cell lines (SGC7901, HeLa, and A549) and normal cell line (HEK293T) using MTT assay. DPD showed potent cytotoxicity against human cancer lines (HeLa and A549) and less cytotoxicity against normal cell lines HEK293T. DPD could also induce the cell cycle arrest at G2/M phase in HeLa cells and significantly increase the phosphorylation (Tyr 15) of CDC2 leading to inactivation of CDC2. The effects of DPD on cellular microtubule networks were detected using immunofluorescence technique in HeLa cells. The immunofluorescence results showed DPD influenced the arrangement and organization of cellular microtubule networks in HeLa cells. Microtubules are long, hollow cylinders made up of polymerized tubulin dimers. Total microtubules were separated after DPD treatment. Western blot results showed that the free polymerized tubulin dimers were obviously increased after DPD treatment. DPD may be a good drug candidate with the therapeutic potential to human cancer by affecting microtubule polymerization. PMID- 27123551 TI - Saikosaponin A, an active glycoside from Radix bupleuri, reverses P-glycoprotein mediated multidrug resistance in MCF-7/ADR cells and HepG2/ADM cells. AB - 1. The expression and function of P-glycoprotein (P-gp) is associated with the phenotype of multidrug resistance (MDR). Saikosaponin A (SSA) is a triterpenoid saponin isolated from Radix Bupleuri. This study was mainly designed to understand effects of SSA on MDR in MCF-7/ADR and HepG2/ADM cells. 2. MDR reversal was examined as the alteration of cytotoxic drugs IC50 in resistant cells in the presence of SSA by MTT assay, and was compared with the non resistant cells. Apoptosis and uptake of P-gp substrates in the tumor cells were detected by flow cytometry. Western blot was performed to assay the expression of P-gp. 3. Our results demonstrate SSA could increase the chemosensitivity of P-gp overexpressing HepG2/ADM and MCF-7/ADR cells to doxorubicin (DOX), vincristine (VCR) and paclitaxel. SSA promoted apoptosis of MCF-7/ADR cells in the presence of DOX. Moreover, it could also increase the retention of P-gp substrates DOX and rhodamine 123 in MCF-7/ADR cells, and decrease digoxin efflux ratio in Caco-2 cell monolayer. Finally, a mechanistic study showed that SSA reduced P-gp expression without affecting hydrolytic activity of P-gp. 4. In conclusion, our findings suggest that SSA could be further developed for sensitizing resistant cancer cells and used as an adjuvant therapy together with anticancer drugs to improve their therapeutic efficacies. PMID- 27123552 TI - The Discovery of Quinoxaline-Based Metathesis Catalysts from Synthesis of Grazoprevir (MK-5172). AB - Olefin metathesis (OM) is a reliable and practical synthetic methodology for challenging carbon-carbon bond formations. While existing catalysts can effect many of these transformations, the synthesis and development of new catalysts is essential to increase the application breadth of OM and to achieve improved catalyst activity. The unexpected initial discovery of a novel olefin metathesis catalyst derived from synthetic efforts toward the HCV therapeutic agent grazoprevir (MK-5172) is described. This initial finding has evolved into a class of tunable, shelf-stable ruthenium OM catalysts that are easily prepared and exhibit unique catalytic activity. PMID- 27123553 TI - Exploiting Co-solubilization of Warfarin, Curcumin, and Rhodamine B for Modulation of Energy Transfer: A Micelle FRET On/Off Switch. AB - Two new FRET pairs, warfarin (WF)-curcumin (CUR) and curcumin-rhodamine B (RhB), are explored by using surfactant-based self-assembled soft systems as scaffolds. The study is extended to design a two-step concurrent FRET system based on these three fluorophores, which is an important mechanism to devise artificial light harvesting/antenna systems. Surfactant systems of varying nature (cationic, anionic, nonionic, and zwitterionic) are exploited to modulate the energy transfer in different FRET systems. Interestingly, micelle/water interfacial charge-responsive FRET is observed owing to selective solubilization of the fluorophores during co-solubilization. The step-one FRET (WF->CUR) is switched on in cationic and zwitterionic media but switched off in anionic/nonionic media, whereas the step-two FRET from CUR to RhB is switched on in anionic/nonionic and zwitterionic media. However, both the FRET steps (WF->CUR->RhB) are observed to be active only in zwitterionic medium. Co-solubilized, appropriately mixed fluorophores having multistep FRET possibilities can be switched on/off selectively as and when required and energy efficiency can be tuned to an optimal level by varying the nature and geometry of the micellar scaffold. Thus, the two FRET pairs selectively acknowledge all types of media for their anticipated applications in biological systems, as structural tools, and for the development of artificial light-harvesting/antenna systems and lasers. PMID- 27123555 TI - A Capped Octahedral MHC6 Compound of a Platinum Group Metal. AB - A MHC6 complex of a platinum group metal with a capped octahedral arrangement of donor atoms around the metal center has been characterized. This osmium compound OsH{kappa(2) -C,C-(PhBIm-C6 H4 )}3 , which reacts with HBF4 to afford the 14 e(-) species [Os{kappa(2) -C,C-(PhBIm-C6 H4 )}(Ph2 BIm)2 ]BF4 stabilized by two agostic interactions, has been obtained by reaction of OsH6 (PiPr3 )2 with N,N' diphenylbenzimidazolium chloride ([Ph2 BImH]Cl) in the presence of NEt3 . Its formation takes place through the C,C,C-pincer compound OsH2 {kappa(3) -C,C,C-(C6 H4 -BIm-C6 H4 )}(PiPr3 )2 , the dihydrogen derivative OsCl{kappa(2) -C,C-(PhBIm C6 H4 )}(eta(2) -H2 )(PiPr3 )2 , and the five-coordinate osmium(II) species OsCl{kappa(2) -C,C-(PhBIm-C6 H4 )}(PiPr3 )2 . PMID- 27123554 TI - Superionic Conduction in Co-Vacant P2-Nax CoO2 Created by Hydrogen Reductive Elimination. AB - The layered P2-Nax MO2 (M: transition metal) system has been widely recognized as electronic or mixed conductor. Here, we demonstrate that Co vacancies in P2-Nax CoO2 created by hydrogen reductive elimination lead to an ionic conductivity of 0.045 S cm(-1) at 25 degrees C. Using in situ synchrotron X-ray powder diffraction and Raman spectroscopy, the composition of the superionic conduction phase is evaluated to be Na0.61 (H3 O)0.18 Co0.93 O2 . Electromotive force measurements as well as molecular dynamics simulations indicate that the ion conducting species is proton rather than hydroxide ion. The fact that the Co stoichiometric compound Nax (H3 O)y CoO2 does not exhibit any significant ionic conductivity proves that Co vacancies are essential for the occurrence of superionic conductivity. PMID- 27123556 TI - Family Perspectives on Aggressive Cancer Care Near the End of Life. PMID- 27123557 TI - Preservative-free tafluprost/timolol fixed combination: a new opportunity in the treatment of glaucoma. AB - INTRODUCTION: Medical therapy of glaucoma aims to maintain the patient's visual function and quality of life. This generally commences with monotherapy, but it is often difficult to reach the predetermined target pressure with this approach. Fixed combinations (FCs) are therefore selected as the next step of the medical therapy algorithm. By employing a prostaglandin/timolol fixed combination (PTFC) the desired target 24-hour intraocular pressure can be reached in many glaucoma patients with the convenience of once-a-day administration and the associated high rate of adherence. AREAS COVERED: The current role and value of FCs in the medical therapy of glaucoma is critically appraised. Special attention is paid to the PTFCs and the emerging role of preservative-free PTFCs. This review summarizes existing information on the efficacy and tolerability of the new preservative-free tafluprost/timolol FC (Taptiqom(r)). EXPERT OPINION: The preservative-free tafluprost/timolol FC represents a promising stepwise treatment option for those patients whose intraocular pressure is insufficiently controlled with available monotherapy options. This novel FC has the potential to substantially improve glaucoma management and through evolution of the current glaucoma treatment paradigm, to become a core therapeutic option in the future. Nonetheless, future research is needed to better delineate the therapeutic role of current and future preservative-free FCs in glaucoma therapy. PMID- 27123558 TI - Zika virus detection in cerebrospinal fluid from two patients with encephalopathy, Martinique, February 2016. AB - We report two cases of encephalopathy (one with seizures, one with electroencephalogram changes) in patients with Zika virus infection. The cases occurred on Martinique in February 2016, during the Zika virus outbreak. Awareness of the various neurological complications of Zika virus infection is needed for patients living in areas affected by Zika virus infections or for travellers to these areas. PMID- 27123559 TI - (99m) Tc-labeled tetramer and pentamer of single-domain antibody for targeting epidermal growth factor receptor in xenografted tumors. AB - The single-domain antibody EG2 can be fused with right-handed coiled-coil (RHCC) and human cartilage oligomeric matrix protein (COMP), to form the multivalent antibodies EG2-RHCC and EG2-COMP. We labeled these two antibodies with (99m) Tc and assessed their targeting efficiency for epidermal growth factor receptor (EGFR). Cell binding, uptake, efflux, and blocking studies were performed with EGFR high- and/or low-expressing cells with (99m) Tc-labeled EG2-RHCC or EG2 COMP. Single photon-emission computed tomography (SPECT) imaging and biodistribution studies were further carried out. Both (99m) Tc-EG2-RHCC and (99m) Tc-EG2-COMP can specially bind to EGFR in vitro. SPECT imaging showed that A431, which expresses high levels of EGFR, was clearly visible 6 h after (99m) Tc EG2-COMP injection; however, it was not detectable after administration of (99m) Tc-EG2-RHCC. Uptake of both antibodies by the non-EGFR-secreting OCM-1 tumors was low. EG2-COMP shows promise in identifying EGFR over-expression in tumors; however, EG2-RHCC may not be suitable for targeting EGFR in vivo. PMID- 27123560 TI - Regression analysis of case K interval-censored failure time data in the presence of informative censoring. AB - Interval-censored failure time data occur in many fields such as demography, economics, medical research, and reliability and many inference procedures on them have been developed (Sun, 2006; Chen, Sun, and Peace, 2012). However, most of the existing approaches assume that the mechanism that yields interval censoring is independent of the failure time of interest and it is clear that this may not be true in practice (Zhang et al., 2007; Ma, Hu, and Sun, 2015). In this article, we consider regression analysis of case K interval-censored failure time data when the censoring mechanism may be related to the failure time of interest. For the problem, an estimated sieve maximum-likelihood approach is proposed for the data arising from the proportional hazards frailty model and for estimation, a two-step procedure is presented. In the addition, the asymptotic properties of the proposed estimators of regression parameters are established and an extensive simulation study suggests that the method works well. Finally, we apply the method to a set of real interval-censored data that motivated this study. PMID- 27123561 TI - Preparation of Magnetic Tubular Nanoreactors for Highly Efficient Catalysis. AB - We report an efficient and controllable route to prepare magnetic tubular nanoreactors composed of a mesoporous SiO2 shell with iron-noble metal nanoparticles inside. The key of this method is to design and fabricate Fe nanoparticles encapsulated in a mesoporous SiO2 shell. Making use of a galvanic replacement reaction between Fe and noble metal ions, all of the noble metal nanoparticles are loaded inside the mesoporous SiO2 shell, and thus nanoreactors are formed. Taking Pd as an example, the prepared Pd-Fe@meso-SiO2 tubular nanoreactor exhibits a high catalytic activity and excellent reusability for styrene hydrogenation under mild conditions. This study provides a facile route to fabricate magnetic nanoreactors with enhanced catalytic properties. PMID- 27123563 TI - Facile Cucurbit[8]uril-Based Supramolecular Approach To Fabricate Tunable Luminescent Materials in Aqueous Solution. AB - Light-emitting materials with tunable properties may offer fascinating applications in optoelectronic devices, fluorescent sensors, and imaging agents. Herein, a new supramolecular approach based on host-guest interactions that greatly decreases the number of required synthetic steps and produces a system with tunable and dynamical photophysical properties was developed. Because of the novel electronic distributions of the chromophore guest within the rigid hydrophobic cavity of the cucurbit[8]uril host in this system, color tuning of emissions such as cyan, yellow, green, and white light with efficiency increased fluorescence lifetime, and quantum yield was easily achieved by simple addition of the host in aqueous solution. Stimulus-responsive tuning of color has long been an important area of research into light emissions. The current study distinguishes itself by its combination of simple steps using a single synthetic receptor and a single organic fluorophore guest in a single solution. Our results may provide a promising advancement of the fabrication of smart and tunable luminescent materials. PMID- 27123564 TI - Cost and economic burden of adverse events associated with metastatic melanoma treatments in five countries. AB - OBJECTIVE: To estimate per-event cost and economic burden associated with managing the most common and/or severe metastatic melanoma (MM) treatment-related adverse events (AEs) in Australia, France, Germany, Italy, and the UK. METHODS: AEs associated with chemotherapy (dacarbazine, paclitaxel, fotemustine), immunotherapy (ipilimumab), and targeted therapy (vemurafenib) were identified by literature review. Medical resource use data associated with managing AEs were collected through two blinded Delphi panel cycles in each of the five countries. Published costs were used to estimate per-event costs and combined with AEs incidence, treatment usage, and MM prevalence to estimate the economic burden for each country. RESULTS: The costliest AEs were grade 3/4 events due to immunotherapy (Australia/France: colitis; UK: diarrhea) and chemotherapy (Germany/Italy: neutropenia/leukopenia). Treatment of AEs specific to chemotherapy (Australia/Germany/Italy/France: neutropenia/leukopenia) and targeted therapy (UK: squamous cell carcinoma) contributed heavily to country specific economic burden. LIMITATIONS: Economic burden was estimated assuming that each patient experienced an AE only once. In addition, the context of settings was heterogeneous and the number of Delphi panel experts was limited. CONCLUSIONS: Management costs for MM treatment-associated AEs can be substantial. Results could be incorporated in economic models that support reimbursement dossiers. With the availability of newer treatments, establishment of a baseline measure of the economic burden of AEs will be crucial for assessing their impact on patients and regional healthcare systems. PMID- 27123562 TI - Driver Mutations in Uveal Melanoma: Associations With Gene Expression Profile and Patient Outcomes. AB - IMPORTANCE: Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine. OBJECTIVE: To determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014. MAIN OUTCOMES AND MEASURES: Clinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded. RESULTS: The study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter. GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1-28.5) and melanoma-specific mortality (relative risk, 15.7; 95% CI, 3.6-69.1) (P < .001 for both). After excluding GEP class, the presence of BAP1 mutations was the factor most strongly associated with metastasis (relative risk, 10.6; 95% CI, 3.4-33.5) and melanoma-specific mortality (relative risk, 9.0; 95% CI, 2.8-29.2) (P < .001 for both). CONCLUSIONS AND RELEVANCE: BAP1, SF3B1, and EIF1AX mutations occur during UM tumor progression in an almost mutually exclusive manner and are associated with different levels of metastatic risk. These mutations may have value as prognostic markers in UM. PMID- 27123565 TI - Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer. AB - Antibodies to tumor necrosis factor (anti-TNF) are used to treat inflammatory diseases, which often affect women of childbearing age. The active transfer of these antibodies across the placenta by binding of the Fc-region to the neonatal Fc receptor (FcRn) may result in adverse fetal or neonatal effects. In contrast to other anti-TNFs, certolizumab pegol lacks an Fc-region. The objective of this study was to determine whether the structure of certolizumab pegol limits active placental transfer. Binding affinities of certolizumab pegol, infliximab, adalimumab and etanercept to human FcRn and FcRn-mediated transcytosis were determined using in vitro assays. Human placentas were perfused ex vivo to measure transfer of certolizumab pegol and positive control anti-D IgG from the maternal to fetal circulation. FcRn binding affinity (KD) was 132nM, 225nM and 1500nM for infliximab, adalimumab and etanercept, respectively. There was no measurable certolizumab pegol binding affinity, similar to that of the negative control. FcRn-mediated transcytosis across a cell layer (mean+/-SD; n=3) was 249.6+/-25.0 (infliximab), 159.0+/-20.2 (adalimumab) and 81.3+/-13.1ng/mL (etanercept). Certolizumab pegol transcytosis (3.2+/-3.4ng/mL) was less than the negative control antibody (5.9+/-4.6ng/mL). No measurable transfer of certolizumab pegol from the maternal to the fetal circulation was observed in 5 out of 6 placentas that demonstrated positive-control IgG transport in the ex vivo perfusion model. Together these results support the hypothesis that the unique structure of certolizumab pegol limits its transfer through the placenta to the fetus and may be responsible for previously reported differences in transfer of other anti-TNFs from mother to fetus. PMID- 27123566 TI - Prospective memory impairment in chemotherapy-exposed early breast cancer survivors: Preliminary evidence from a clinical test. AB - We report the results of a secondary analysis of a cross-sectional study (Paquet et al., 2013 ) to evaluate the cognitive operations involved in prospective memory (PM) deficits exhibited by chemotherapy-exposed breast cancer (BC) survivors. PM was assessed with the memory for intentions screening test administered to 80 patients and 80 healthy controls. Patients performed worse than controls on the PM tasks and had more "omission" errors (indices of the prospective component of the tasks) than the controls. No group differences emerged on a recognition test. Although further studies will be needed to disentangle the multiple cognitive operations involved in PM, these findings are consistent with the notion that self-initiated retrieval processes rather than encoding are implicated in PM impairment among BC survivors. PMID- 27123567 TI - Assessing endotoxemia in alcoholic hepatitis. PMID- 27123568 TI - Regulatory mechanisms related to biofuel tolerance in producing microbes. AB - Production of renewable biofuels through either native or engineered microbes has drawn significant attention in recent years, mostly due to the increasing concerns on the energy crisis and the environmental consequences of the overutilization of petroleum-based fuels. Although significant progress has been achieved thus far, further advances are still necessary in order to decrease the manufacturing cost so that the producing processes can be more competitive to petroleum fuels. Among various possible approaches, the increase in biofuel tolerance in microbes has been suggested as one aspect which is important for the success of biofuel production at industry-scale. In this article, we critically summarize recent advances in deciphering regulatory mechanisms for enhancing biofuel tolerance in various micro-organisms, focusing on functions and utilization of several well-studied regulatory mechanisms in microbes, such as two-component signal transduction systems, sigma factors, transcription factors, noncoding RNA and other regulators. PMID- 27123569 TI - Toward an Integrated Federal Health System. PMID- 27123570 TI - Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development: Results from the Danish Calmette Study - A Randomised Clinical Trial. AB - OBJECTIVES: To assess the non-specific effect of Bacillus Calmette-Guerin (BCG) vaccination at birth on psychomotor development. DESIGN: This is a pre-specified secondary outcome from a randomised, clinical trial. SETTING: Maternity units and paediatric wards at three university hospitals in Denmark. PARTICIPANTS: Children born at gestational age (GA) 32 weeks and above. All women planning to give birth at the three sites were invited during the recruitment period. Out of 4262 randomised children, 144 were premature (GA < 37 weeks). There were 2129 children (71 premature) randomised to BCG and 2133 randomised (73 premature) to the control group. INTERVENTIONS: BCG vaccination 0.05 ml was given intradermally in the upper left arm at the hospital within seven days of birth. Children in the control group did not receive any intervention. Parents were not blinded to allocation. MAIN OUTCOME MEASURES: Psychomotor development measured using Ages and Stages Questionnaire (ASQ) completed by the parents at 12 months. Additionally, parents of premature children (gestational age < 37 weeks) completed an ASQ at 6 and 22 months. Developmental assessment was available for 3453/4262 (81%). RESULTS: The mean difference in ASQ score at 12 months adjusted for age and prematurity was -0.7 points (BCG vs. control, 95% confidence interval; -3.7 to 2.4), p = 0.67, corresponding to an effect size of Cohen's d = 0.015 (-0.082 to 0.052). The mean difference in ASQ score for premature children at 22 months was -7.8 points (-20.6 to 5.0, p = 0.23), d = -0.23 (-0.62 to 0.15). CONCLUSIONS: A negative non-specific effect of BCG vaccination at birth on psychomotor development was excluded in term children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01694108. PMID- 27123571 TI - Utility of neutrophil volume conductivity scatter (VCS) parameter changes as sepsis screen in neonates. AB - OBJECTIVE: The objective of this study was to determine changes in neutrophil volume conductivity scatter (VCS) parameters and their distribution widths (DW) in neonatal sepsis and to estimate their optimal cutoff levels using receiver operating characteristic (ROC) curves. STUDY DESIGN: In a cohort of neonates evaluated for sepsis, blood counts and blood culture were performed initially, with repeat counts and C-reactive protein (CRP) done after 24 to 48 h. Neutrophil VCS parameters from both the initial and repeat blood counts were analyzed. Babies were classified as having blood culture-positive sepsis, probable sepsis (clinical course consistent with sepsis and CRP-positive, but culture-negative) and no sepsis (clinical course not compatible with sepsis, culture- and CRP negative). RESULTS: A total of 600 babies were included: 240 (40%) babies in the sepsis group and 360 (60%) babies in the control group. All the neutrophil VCS parameters and their DWs (except for low angle light scatter in the repeat counts) were significantly different between the two groups, with an area under curve in the ROC curve of >0.6 for most parameters. The five most significant VCS parameters (mean neutrophil volume (MNV), median angle light scatter (MALS), lower median angle light scatter (LMALS), MNV-DW and ALL-DW) had around 65 to 75% sensitivity and specificity. A combination of leukopenia, thrombocytopenia, MNV and LMALS had a likelihood ratio (LR)+ of 15.3 and LR- of 0.17. With a pre-test probability of 40%, post-test probability increased to 91% for a positive test and decreased to 10% for a negative test. A prospective validation study was performed recruiting an additional 60 babies, which showed similar results, assuring that the cutoffs were robust. CONCLUSION: Neutrophil VCS parameters cannot be considered as stand-alone tests to diagnose or rule out neonatal sepsis, but can be used in combination with other hematological screening tests to improve the diagnostic accuracy of the neonatal sepsis screen. PMID- 27123572 TI - Typing Pseudomonas aeruginosa Isolates with Ultrahigh Resolution MALDI-FTICR Mass Spectrometry. AB - The introduction of standardized matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF MS) platforms in the medical microbiological practice has revolutionized the way microbial species identification is performed on a daily basis. To a large extent, this is due to the ease of operation. Acquired spectra are compared to profiles obtained from cultured colonies present in a reference spectra database. It is fast and reliable, and costs are low compared to previous diagnostic approaches. However, the low resolution and dynamic range of the MALDI-TOF profiles have shown limited applicability for the discrimination of different bacterial strains, as achieved with typing based on genetic markers. This is pivotal in cases where certain strains are associated with, e.g., virulence or antibiotic resistance. Ultrahigh resolution MALDI-FTICR MS allows the measurement of small proteins at isotopic resolution and can be used to analyze complex mixtures with increased dynamic range and higher precision than MALDI-TOF MS, while still generating results in a similar time frame. Here, we propose to use ultrahigh resolution 15T MALDI Fourier transform ion cyclotron resonance (FTICR) MS to discriminate clinically relevant bacterial strains after species identification performed by MALDI-TOF MS. We used a collection of well characterized Pseudomonas aeruginosa strains, featuring distinct antibiotic resistance profiles, and isolates obtained during hospital outbreaks. Following cluster analysis based on amplification fragment length polymorphism (AFLP), these strains were grouped into three different clusters. The same clusters were obtained using protein profiles generated by MALDI-FTICR MS. Subsequent intact protein analysis by electrospray ionization (ESI)-collision-induced dissociation (CID)-FTICR MS was applied to identify protein isoforms that contribute to the separation of the different clusters, illustrating the additional advantage of this analytical platform. PMID- 27123573 TI - Expanding the boundaries of evaluative learning research: How intersecting regularities shape our likes and dislikes. AB - Over the last 30 years, researchers have identified several types of procedures through which novel preferences may be formed and existing ones altered. For instance, regularities in the presence of a single stimulus (as in the case of mere exposure) or 2 or more stimuli (as in the case of evaluative conditioning) have been shown to influence liking. We propose that intersections between regularities represent a previously unrecognized class of procedures for changing liking. Across 4 related studies, we found strong support for the hypothesis that when environmental regularities intersect with one another (i.e., share elements or have elements that share relations with other elements), the evaluative properties of the elements of those regularities can change. These changes in liking were observed across a range of stimuli and procedures and were evident when self-report measures, implicit measures, and behavioral choice measures of liking were employed. Functional and mental explanations of this phenomenon are offered followed by a discussion of how this new type of evaluative learning effect can accelerate theoretical, methodological, and empirical development in attitude research. (PsycINFO Database Record PMID- 27123574 TI - A comparison of adaptive and fixed schedules of practice. AB - Understanding and optimizing spacing during learning is a central topic for research in learning and memory and has substantial implications for real-world learning. Spacing memory retrievals across time improves memory relative to massed practice-the well-known spacing effect. Most spacing research has utilized fixed (predetermined) spacing intervals. Some findings indicate advantages of expanding over equal spacing (e.g., Landauer & Bjork, 1978); however, evidence is mixed (e.g., Karpicke & Roediger, 2007), and the field has lacked an integrated explanation. Learning may instead depend on interactions of spacing with an underlying variable of learning strength that varies for learners and items, and it may be better optimized by adaptive adjustments of spacing to learners' ongoing performance. Two studies investigated an adaptive spacing algorithm, Adaptive Response-Time-based Sequencing or ARTS (Mettler, Massey & Kellman, 2011) that uses response-time and accuracy to generate spacing. Experiment 1 compared adaptive scheduling with fixed schedules having either expanding or equal spacing. Experiment 2 compared adaptive schedules to 2 fixed "yoked" schedules that were copied from adaptive participants, equating average spacing across conditions. In both experiments, adaptive scheduling outperformed fixed conditions at immediate and delayed tests of retention. No evidence was found for differences between expanding and equal spacing. Yoked conditions showed that learning gains were due to adaptation to individual items and learners. Adaptive spacing based on ongoing assessments of learning strength yields greater learning gains than fixed schedules, a finding that helps to understand the spacing effect theoretically and has direct applications for enhancing learning in many domains. (PsycINFO Database Record PMID- 27123575 TI - Motivated recall in the service of the economic system: The case of anthropogenic climate change. AB - The contemporary political landscape is characterized by numerous divisive issues. Unlike many other issues, however, much of the disagreement about climate change centers not on how best to take action to address the problem, but on whether the problem exists at all. Psychological studies indicate that, to the extent that sustainability initiatives are seen as threatening to the socioeconomic system, individuals may downplay environmental problems in order to defend and protect the status quo. In the current research, participants were presented with scientific information about climate change and later asked to recall details of what they had learned. Individuals who were experimentally induced (Study 1) or dispositionally inclined (Studies 2 and 3) to justify the economic system misremembered the evidence to be less serious, and this was associated with increased skepticism. However, when high system justifiers were led to believe that the economy was in a recovery, they recalled climate change information to be more serious than did those assigned to a control condition. When low system justifiers were led to believe that the economy was in recession, they recalled the information to be less serious (Study 3). These findings suggest that because system justification can impact information processing, simply providing the public with scientific evidence may be insufficient to inspire action to mitigate climate change. However, linking environmental information to statements about the strength of the economic system may satiate system justification needs and break the psychological link between proenvironmental initiatives and economic risk. (PsycINFO Database Record PMID- 27123576 TI - Caught red-minded: Evidence-induced denial of mental transgressions. AB - We suggest that when confronted with evidence of their socially inappropriate thoughts and feelings, people are sometimes less likely-and not more likely-to acknowledge them because evidence can elicit psychological responses that inhibit candid self-reflection. In 3 studies, participants were induced to exhibit racial bias (Study 1) or to experience inappropriate sexual arousal (Studies 2 and 3). Some participants were then told that the researcher had collected physiological evidence of these mental transgressions. Results showed that participants who were told about the evidence were less willing to acknowledge their mental transgressions, but only if they were told before they had an opportunity to engage in self-reflection. These results suggest that under some circumstances, confronting people with public evidence of their private shortcomings can be counterproductive. (PsycINFO Database Record PMID- 27123577 TI - Complicating decisions: The work ethic heuristic and the construction of effortful decisions. AB - The notion that effort and hard work yield desired outcomes is ingrained in many cultures and affects our thinking and behavior. However, could valuing effort complicate our lives? In the present article, the authors demonstrate that individuals with a stronger tendency to link effort with positive outcomes end up complicating what should be easy decisions. People distort their preferences and the information they search and recall in a manner that intensifies the choice conflict and decisional effort they experience before finalizing their choice. Six experiments identify the effort-outcome link as the underlying mechanism for such conflict-increasing behavior. Individuals with a stronger tendency to link effort with positive outcomes (e.g., individuals who subscribe to a Protestant Work Ethic) are shown to complicate decisions by: (a) distorting evaluations of alternatives (Study 1); (b) distorting information recalled about the alternatives (Studies 2a and 2b); and (3) distorting interpretations of information about the alternatives (Study 3). Further, individuals conduct a superfluous search for information and spend more time than needed on what should have been an easy decision (Studies 4a and 4b). (PsycINFO Database Record PMID- 27123578 TI - Switch Function and Pathological Dissociation in Acute Psychiatric Inpatients. AB - Swift switching, along with atypical ability on updating and inhibition, has been found in non-clinical dissociators. However, whether swift switching is a cognitive endophenotype that intertwines with traumatisation and pathological dissociation remains unknown. Unspecified acute psychiatric patients were recruited to verify a hypothesis that pathological dissociation is associated with swift switching and traumatisation may explain this relationship. Behavioural measures of intellectual function and three executive functions including updating, switching and inhibition were administered, together with standardised scales to evaluate pathological dissociation and traumatisation. Our results showed superior control ability on switching and updating in inpatients who displayed more symptoms of pathological dissociation. When all three executive functions were entered as predictors, in addition to intellectual quotient and demographic variables to regress upon pathological dissociation, switching rather than updating remained the significant predictor. Importantly, the relationship between pathological dissociation and switching became non significant when the effect of childhood trauma were controlled. The results support a trauma-related switching hypothesis which postulates swift switching as a cognitive endophenotype of pathological dissociation; traumatisation in childhood may explain the importance of swift switching. PMID- 27123580 TI - Drawings of Blood Cells Reveal People's Perception of Their Blood Disorder: A Pilot Study. AB - CONTEXT: Sickle cell disease (SCD) and thalassemia are rare but chronic blood disorders. Recent literature showed impaired quality of life (QOL) in people with these blood disorders. Assessing one of the determinants of QOL (i.e. illness perceptions) therefore, is an important next research area. OBJECTIVE: We aimed to explore illness perceptions of people with a blood disorder with drawings in addition to the Brief Illness Perception Questionnaire (Brief IPQ). Drawings are a novel method to assess illness perceptions and the free-range answers drawings offer can add additional insight into how people perceive their illness. METHOD: We conducted a cross-sectional study including 17 participants with a blood disorder. Participants' illness perceptions were assessed by the Brief IPQ and drawings. Brief IPQ scores were compared with reference groups from the literature (i.e. people with asthma or lupus erythematosus). RESULTS: Participants with SCD or thalassemia perceived their blood disorder as being more chronic and reported more severe symptoms than people with either asthma or lupus erythematosus. In the drawings of these participants with a blood disorder, a greater number of blood cells drawn was negatively correlated with perceived personal control (P<0.05), indicating that a greater quantity in the drawing is associated with more negative or distressing beliefs. CONCLUSION: Participants with a blood disorder perceive their disease as fairly threatening compared with people with other chronic illnesses. Drawings can add additional insight into how people perceive their illness by offering free-range answers. PMID- 27123579 TI - Bovine Leukemia Virus Small Noncoding RNAs Are Functional Elements That Regulate Replication and Contribute to Oncogenesis In Vivo. AB - Retroviruses are not expected to encode miRNAs because of the potential problem of self-cleavage of their genomic RNAs. This assumption has recently been challenged by experiments showing that bovine leukemia virus (BLV) encodes miRNAs from intragenomic Pol III promoters. The BLV miRNAs are abundantly expressed in B cell tumors in the absence of significant levels of genomic and subgenomic viral RNAs. Using deep RNA sequencing and functional reporter assays, we show that miRNAs mediate the expression of genes involved in cell signaling, cancer and immunity. We further demonstrate that BLV miRNAs are essential to induce B-cell tumors in an experimental model and to promote efficient viral replication in the natural host. PMID- 27123581 TI - Evidence of Inbreeding in Hodgkin Lymphoma. AB - Genome-wide association studies (GWASs) have identified several, mainly co dominantly acting, single-nucleotide polymorphisms (SNPs) associated with Hodgkin lymphoma (HL). We searched for recessively acting disease loci by performing an analysis of runs of homozygosity (ROH) based on windows of homozygous SNP-blocks and by calculating genomic inbreeding coefficients on a SNP-wise basis. We used data from a previous GWAS with 906 cases and 1217 controls from a population with a long history of no matings between relatives. Ten recurrent ROHs were identified among 25 055 ROHs across all individuals but their association with HL was not genome-wide significant. All recurrent ROHs showed significant evidence for natural selection. As a novel finding genomic inbreeding among cases was significantly higher than among controls (P = 2.11*10-14) even after correcting for covariates. Higher inbreeding among the cases was mainly based on a group of individuals with a higher average length of ROHs per person. This result suggests a correlation of higher levels of inbreeding with higher cancer incidence and might reflect the existence of recessive alleles causing HL. Genomic inbreeding may result in a higher expression of deleterious recessive genes within a population. PMID- 27123583 TI - A Novel Concept for the Search and Retrieval of the Derwent Markush Resource Database. AB - The representation of and search for generic chemical structures (Markush) remains a continuing challenge. Several research groups have addressed this problem, and over time a limited number of practical solutions have been proposed. Today there are two large commercial providers of Markush databases: Chemical Abstracts Service (CAS) and Thomson Reuters. The Thomson Reuters "Derwent" Markush database is currently offered via the online services Questel and STN and as a data feed for in-house use. The aim of this paper is to briefly review the existing Markush systems (databases plus search engines) and to describe our new approach for the implementation of the Derwent Markush Resource on STN. Our new approach demonstrates the integration of the Derwent Markush Resource database into the existing chemistry-focused STN platform without loss of detail. This provides compatibility with other structure and Markush databases on STN and at the same time makes it possible to deploy the specific features and functions of the Derwent approach. It is shown that the different Markush languages developed by CAS and Derwent can be combined into a single general Markush description. In this concept the generic nodes are grouped together in a unique hierarchy where all chemical elements and fragments can be integrated. As a consequence, both systems are searchable using a single structure query. Moreover, the presented concept could serve as a promising starting point for a common generalized description of Markush structures. PMID- 27123582 TI - Causal Structure of Brain Physiology after Brain Injury from Subarachnoid Hemorrhage. AB - High frequency physiologic data are routinely generated for intensive care patients. While massive amounts of data make it difficult for clinicians to extract meaningful signals, these data could provide insight into the state of critically ill patients and guide interventions. We develop uniquely customized computational methods to uncover the causal structure within systemic and brain physiologic measures recorded in a neurological intensive care unit after subarachnoid hemorrhage. While the data have many missing values, poor signal-to noise ratio, and are composed from a heterogeneous patient population, our advanced imputation and causal inference techniques enable physiologic models to be learned for individuals. Our analyses confirm that complex physiologic relationships including demand and supply of oxygen underlie brain oxygen measurements and that mechanisms for brain swelling early after injury may differ from those that develop in a delayed fashion. These inference methods will enable wider use of ICU data to understand patient physiology. PMID- 27123584 TI - The association of hypertension with asymptomatic cardiovascular organ damage in rheumatoid arthritis. AB - BACKGROUND: The association of hypertension with asymptomatic cardiovascular organ damage in patients with rheumatoid arthritis (RA) has been little studied by echocardiography. METHODS: Echocardiography was done in 134 RA patients and 102 healthy controls. Left ventricular (LV) geometry was considered abnormal if LV mass index or relative wall thickness was increased. LV diastolic dysfunction was considered present if septal early diastolic tissue velocity <8 cm/s. Systemic arterial compliance (SAC) was assessed from stroke volume index/pulse pressure ratio. RESULTS: The hypertensive RA patients (n = 72) had higher inflammatory activity, older age and more diabetes than the normotensive RA patients (n = 62) (all p < 0.05). Rates of abnormal LV geometry, LV diastolic dysfunction and lower SAC were higher among the hypertensive RA patients (p < 0.05), but similar between normotensive RA patients and controls. Hypertension was associated with a 3-fold higher prevalence both for abnormal LV geometry (odds ratio 2.89 [95% confidence interval 1.09-7.63], p = 0.03) and for diastolic LV dysfunction (odds ratio 2.92 [95% confidence interval 1.14-7.46], p = 0.03) as well as lower SAC (beta = 0.31, p = 0.001) independent of age, gender, diabetes and inflammatory activity measured by erythrocyte sedimentation rate. CONCLUSION: The presence of asymptomatic cardiovascular organ damage in RA patients is closely associated with hypertension independent of inflammatory activity. PMID- 27123585 TI - Correction: Developmental Eye Movement (DEM) Test Norms for Mandarin Chinese Speaking Chinese Children. AB - [This corrects the article DOI: 10.1371/journal.pone.0148481.]. PMID- 27123586 TI - Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease. AB - A safe and effective vaccine against respiratory syncytial virus (RSV) should confer protection without causing vaccine-enhanced disease. Here, using a cotton rat model, we investigated the protective efficacy and safety of an RSV combination vaccine composed of F-encoding plasmid DNA and virus-like particles containing RSV fusion (F) and attachment (G) glycoproteins (FFG-VLP). Cotton rats with FFG-VLP vaccination controlled lung viral replication below the detection limit, and effectively induced neutralizing activity and antibody-secreting cell responses. In comparison with formalin inactivated RSV (FI-RSV) causing severe RSV disease after challenge, FFG-VLP vaccination did not cause weight loss, airway hyper-responsiveness, IL-4 cytokines, histopathology, and infiltrates of proinflammatory cells such as eosinophils. FFG-VLP was even more effective in preventing RSV-induced pulmonary inflammation than live RSV infections. This study provides evidence that FFG-VLP can be developed into a safe and effective RSV vaccine candidate. PMID- 27123587 TI - Negative Mood Increases Selective Attention to Negatively Valenced Body Parts in Female Adolescents with Anorexia Nervosa. AB - OBJECTIVE: Previous research has yielded evidence of increased attentional processing of negatively valenced body parts in women with anorexia nervosa (AN), especially for those with high depressive symptomatology. The present study extended previous research by implementing an experimental mood manipulation. METHOD: In a within-subjects design, female adolescents with AN (n = 12) and an age matched female control group (CG; n = 12) were given a negative and a positive mood induction at a one-week interval. After each mood induction, participants underwent a 3-min mirror exposure, while their eye movements were recorded. RESULTS: After the positive mood induction, both AN and CG participants displayed longer and more frequent gazes towards their self-defined most ugly relative to their self-defined most beautiful body part. However, after the negative mood induction, only females with AN were characterized by increased attention to their most ugly compared to their most beautiful body part, while CG participants' attention distribution was balanced. Furthermore, in the negative (but not in the positive) mood induction condition gaze frequency and duration towards the most ugly body part was significantly stronger in the AN group relative to the CG. DISCUSSION: The results emphasize the role of negative mood in the maintenance of pathological information processing of the self-body. This increased body-related negativity-bias during negative mood may lead to the persistence and aggravation of AN patients' body image disturbance. PMID- 27123589 TI - Counterfeit Norco Poisoning Outbreak - San Francisco Bay Area, California, March 25-April 5, 2016. AB - On March 28, 2016, two patients were evaluated at the Contra Costa Regional Medical Center emergency department (ED) in Contra Costa County, California, for nausea, vomiting, central nervous system depression, and respiratory depression, 30 minutes after ingesting what appeared to be Norco, a prescription opioid pain medication that contains acetaminophen and hydrocodone. The patients purchased the drug from a friend a few days earlier. The two cases of drug intoxication were reported to a Contra Costa County Health Department public health official who subsequently notified the California State Health Department. PMID- 27123588 TI - One-Step Multiplex RT-qPCR Assay for the Detection of Peste des petits ruminants virus, Capripoxvirus, Pasteurella multocida and Mycoplasma capricolum subspecies (ssp.) capripneumoniae. AB - Respiratory infections, although showing common clinical symptoms like pneumonia, are caused by bacterial, viral or parasitic agents. These are often reported in sheep and goats populations and cause huge economic losses to the animal owners in developing countries. Detection of these diseases is routinely done using ELISA or microbiological methods which are being reinforced or replaced by molecular based detection methods including multiplex assays, where detection of different pathogens is carried out in a single reaction. In the present study, a one-step multiplex RT-qPCR assay was developed for simultaneous detection of Capripoxvirus (CaPV), Peste de petits ruminants virus (PPRV), Pasteurella multocida (PM) and Mycoplasma capricolum ssp. capripneumonia (Mccp) in pathological samples collected from small ruminants with respiratory disease symptoms. The test performed efficiently without any cross-amplification. The multiplex PCR efficiency was 98.31%, 95.48%, 102.77% and 91.46% whereas the singleplex efficiency was 93.43%, 98.82%, 102.55% and 92.0% for CaPV, PPRV, PM and Mccp, respectively. The correlation coefficient was greater than 0.99 for all the targets in both multiplex and singleplex. Based on cycle threshold values, intra and inter assay variability, ranged between the limits of 2%-4%, except for lower concentrations of Mccp. The detection limits at 95% confidence interval (CI) were 12, 163, 13 and 23 copies/reaction for CaPV, PPRV, PM and Mccp, respectively. The multiplex assay was able to detect CaPVs from all genotypes, PPRV from the four lineages, PM and Mccp without amplifying the other subspecies of mycoplasmas. The discriminating power of the assay was proven by accurate detection of the targeted pathogen (s) by screening 58 viral and bacterial isolates representing all four targeted pathogens. Furthermore, by screening 81 pathological samples collected from small ruminants showing respiratory disease symptoms, CaPV was detected in 17 samples, PPRV in 45, and PM in six samples. In addition, three samples showed a co-infection of PPRV and PM. Overall, the one step multiplex RT-qPCR assay developed will be a valuable tool for rapid detection of individual and co-infections of the targeted pathogens with high specificity and sensitivity. PMID- 27123590 TI - Thermal Niches of Two Invasive Genotypes of the Wheat Curl Mite Aceria tosichella: Congruence between Physiological and Geographical Distribution Data. AB - The wheat curl mite (WCM), Aceria tosichella Keifer, is a major pest of cereals worldwide. It is also a complex of well-defined genetic lineages with divergent physiological traits, which has not been accounted for in applied contexts. The aims of the study were to model the thermal niches of the two most pestiferous WCM lineages, designated MT-1 and MT-8, and to assess the extent to which temperature determines the distribution of these lineages. WCM population dynamics were modeled based on thermal niche data from March to November on the area of Poland (>311,000 km2). The most suitable regions for population development were predicted and compared to empirical field abundance data. Congruence between modeled parameters and field data for mite presence were observed for both WCM lineages although congruence between modeled thermal suitability and mite field abundance was observed only for MT-8. Thermal niche data for MT-1 and MT-8 provide biological insights and aid monitoring and management of WCM and the plant viruses it vectors. The presented models accurately estimate distributions of WCM and can be incorporated into management strategies for both current and predicted climate scenarios. PMID- 27123593 TI - Correction: Kruppel-like Factor 4, a Tumor Suppressor in Hepatocellular Carcinoma Cells Reverts Epithelial Mesenchymal Transition by Suppressing Slug Expression. AB - [This corrects the article DOI: 10.1371/journal.pone.0043593.]. PMID- 27123591 TI - shRNA-Based Screen Identifies Endocytic Recycling Pathway Components That Act as Genetic Modifiers of Alpha-Synuclein Aggregation, Secretion and Toxicity. AB - Alpha-Synuclein (aSyn) misfolding and aggregation is common in several neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies, which are known as synucleinopathies. Accumulating evidence suggests that secretion and cell-to-cell trafficking of pathological forms of aSyn may explain the typical patterns of disease progression. However, the molecular mechanisms controlling aSyn aggregation and spreading of pathology are still elusive. In order to obtain unbiased information about the molecular regulators of aSyn oligomerization, we performed a microscopy-based large-scale RNAi screen in living cells. Interestingly, we identified nine Rab GTPase and kinase genes that modulated aSyn aggregation, toxicity and levels. From those, Rab8b, Rab11a, Rab13 and Slp5 were able to promote the clearance of aSyn inclusions and rescue aSyn induced toxicity. Furthermore, we found that endocytic recycling and secretion of aSyn was enhanced upon Rab11a and Rab13 expression in cells accumulating aSyn inclusions. Overall, our study resulted in the identification of new molecular players involved in the aggregation, toxicity, and secretion of aSyn, opening novel avenues for our understanding of the molecular basis of synucleinopathies. PMID- 27123592 TI - Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics. AB - Tackling protein interfaces with small molecules capable of modulating protein protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL 10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands. PMID- 27123594 TI - Effects of Straw Return in Deep Soils with Urea Addition on the Soil Organic Carbon Fractions in a Semi-Arid Temperate Cornfield. AB - Returning straw to deep soil layers by using a deep-ditching-ridge-ploughing method is an innovative management practice that improves soil quality by increasing the soil organic carbon (SOC) content. However, the optimum quantity of straw return has not been determined. To solve this practical production problem, the following treatments with different amounts of corn straw were investigated: no straw return, CK; 400 kg ha-1 straw, S400; 800 kg ha-1 straw, S800; 1200 kg ha-1 straw, S1200; and 1600 kg ha-1 straw, S1600. After straw was returned to the soil for two years, the microbial biomass C (MBC), easily oxidized organic C (EOC), dissolved organic C (DOC) and light fraction organic C (LFOC) content were measured at three soil depths (0-10, 10-20, and 20-40 cm). The results showed that the combined application of 800 kg ha-1 straw significantly increased the EOC, MBC, and LFOC contents and was a suitable agricultural practice for this region. Moreover, our results demonstrated that returning straw to deep soil layers was effective for increasing the SOC content. PMID- 27123595 TI - How Physician Assistant Programs Use the CASPA Personal Statement in Their Admissions Process. AB - PURPOSE: This research surveyed physician assistant (PA) program admissions personnel to determine how the Central Application Service for Physician Assistants (CASPA) personal statements are used, what influence the statements had on certain admissions processes, whether there was any concern about authorship of the statements, and how important certain previously identified content themes were to admissions committees and personnel. METHODS: The PA programs participating in CASPA were contacted and interviewed using a computer assisted telephone interview system. Participants were asked a series of open ended questions related to the usefulness of the personal statement and asked to score certain items using a Likert-type scale. RESULTS: The response rate for the telephone survey was 75%. Most of the programs (93%) used the personal statement in the applicant review process, and almost two-thirds (62%) indicated that the statement was useful or very useful. Three-fourths (76%) of respondents sometimes or always used the statement for the selection of candidates for interviews. Only 29% of respondents were very to extremely concerned that the statements were not written by the applicants. CONCLUSIONS: Despite the observation that the statements were relatively homogeneous in content, respondents ranked identified content themes as an important influence on decision-making. Almost all respondents used the personal statement in their admissions process, usually in the selection of interviewees. Although there was some concern that the statements were not the original work of the applicant, less than a third of respondents were very concerned about this possibility. The homogeneity of the statements was also a concern, but the importance placed on the identified theme content areas validates the applicants' inclusion of these themes in the statements. PMID- 27123596 TI - High-Fidelity Simulation Use in Preparation of Physician Assistant Students for Neonatal and Obstetric Care. AB - PURPOSE: The study attempts to determine whether a simulation experience would increase physician assistant (PA) students' comfort level in caring for obstetric patients and assessing a neonate with an Apgar score. METHODS: First-year PA students who are in the didactic phase of their education were asked to complete a questionnaire before and after a hybrid simulation scenario, in which they aided in estimating cervical dilation, delivering a neonate, and assessing the Apgar score of a neonate. The simulation included high-fidelity simulation for 2 portions of the experience and task-trainer simulation for the remaining portion of the experience. The questionnaire asked students to rate their comfort level before and after the simulation and provide information regarding their clinical experience level with obstetrics, gynecology, or pediatrics. RESULTS: Comfort levels were significantly increased according to presession and postsession scores for each of the 3 portions of the simulation experience. Prior experience level did not affect the results of this group. Results indicate that regardless of experience, there was a statistically significant increase between presession and postsession comfort levels. CONCLUSIONS: Simulation training in obstetric and neonatal assessment increases students' comfort level to perform these difficult tasks. Physician assistant programs that are not performing simulation currently, or have not used it to train in these specialty areas should consider doing so as part of their curriculum. PMID- 27123597 TI - Effects of a Comprehensive Oral Health Curriculum on Knowledge, Behavior, and Attitude of Physician Assistant Students. AB - PURPOSE: Oral health assessment by the medical provider needs to be thorough and accurate. Many schools for medical providers are providing an increasing amount of oral health education to students during the didactic year. A dedicated and comprehensive oral health curriculum was developed for a physician assistant (PA) program in Virginia for the purpose of evaluating the effectiveness of the curriculum for changing students' attitudes, behavior, and knowledge. METHODS: First- and fourth-semester PA students attended about 18 hours of lectures, laboratories, and clinical experiences dedicated to oral health. The change in student attitude, behavior, and knowledge of oral health and assessment was assessed using a validated precurricular and postcurricular survey. RESULTS: The responses to the precurricular and postcurricular surveys were compared using paired t-tests. The analysis revealed an overall significant increase (P < .001) in attitude and knowledge of oral health after the curriculum intervention. The only significant change noted in student behavior was an increase in flossing frequency. CONCLUSION: The oral health curriculum was successful in changing the attitude and knowledge of all students, regardless of their level of education in PA school. Therefore, an oral health curriculum conceivably could be added to a medical education program at any time that the course load allows for additional hours. PMID- 27123598 TI - Burnout in Rural Physician Assistants: An Initial Study. AB - PURPOSE: To assess the prevalence and causes of burnout in rural physician assistants. (PA in this article refers to personal accomplishment. To avoid confusion, we will spell out physician assistant throughout the article, instead of using PA to refer to both physician assistant and personal accomplishment.) METHODS: Physician assistants who practice in rural communities were asked to complete the Maslach Burnout Inventory. A preliminary assessment of burnout was determined using the 3 Maslach Burnout Inventory subscale scores: emotional exhaustion, depersonalization, and personal accomplishment, as well as causes of burnout assessed for a correlation to personal and professional factors. RESULTS: Burnout within the rural physician assistant population responding to this survey (response rate = 11.3%) was measured to have high to moderate emotional exhaustion and depersonalization subscores (64% each) and a low to moderate personal accomplishment subscore (46%). CONCLUSIONS: The rural physician assistant population who responded to this survey exhibited burnout correlating to feelings of professional isolation and various workplace conditions such as the adequacy of administrative support and control over workload. To begin addressing burnout within this community, we suggest adjusting rural physician assistant workload and support, enhancing professional communications, and addressing burnout prevention techniques within physician assistant training programs. PMID- 27123599 TI - Informed Practice: Students' Clinical Experiences in the Undergraduate Phase of an Accelerated Physician Assistant Program. AB - This qualitative study explored the clinical experiences of students in an accelerated physician assistant (PA) program. The participants were either certified nursing assistants (CNAs) or emergency medical technicians-basic (EMTs B). The study was designed to elicit (1) how the participants perceived their older patients and (2) how the participants' experiences might affect their own future communications, bedside manner, and clinical preparedness as PAs. This study used a focus group to explore students' clinical experiences before the graduate phase of their accelerated PA program. Five female and 2 male PA students (N = 7) participated in the study. All participants were 23 years old and worked as either a CNA or an EMT-B. Results fell into 2 basic themes: informing practice and forming relationships. Regarding the first theme, participants felt that their experience as entry-level health care providers allowed them to improve their communication skills and bedside manner and to provide greater comfort to patients. Regarding the second theme, participants gained appreciation for older people and began to recognize the knowledge deficits and learning needs of their patients. The results suggested that a student's clinical experience as a CNA or an EMT-B before entering a PA program has a positive effect on the student's personal and professional development. The participants acquired greater appreciation and respect for older patients and members of the health care team. PMID- 27123601 TI - Stability of solution-processed MAPbI3 and FAPbI3 layers. AB - We provide a semi-empirical model based on in situ degradation measurements to predict the durability of hybrid perovskite materials under simulated thermal operation conditions. In the model, the degradation path of MAPbI3 layers is proved to follow an Arrhenius-type law. The predictive role is played by the activation energy combined with its pre-exponential factor. Our comparative study under moisture conditions with respect to vacuum and nitrogen treatments has assessed the occurrence of an intrinsic dynamic exchange of protons between the organic cations and the inorganic cage with a direct impact on the lattice stability, for which the presence of water molecules is not mandatory. This mutual interaction produces defects inside the material and volatile species, such as HI, CH3NH2 or MAI, with an associated experimental activation energy of 1.54 eV measured under vacuum conditions in dark. This value is comparable to that calculated by the density functional theory for defect generation in MAPbI3. In air, the action of water molecules reduces the activation energy for proton exchanges in dark to 0.96 eV. As an alternative solution to increase the material stability, we demonstrate that the substitution of methylammonium (MA(+)) with the formamidinium (FA(+)) cations inside the inorganic cage gives greater robustness to the overall lattice and extends the material durability due to a different interaction between the organic molecules and the inorganic cage. This definitely supports the use of FAPbI3 in applications, provided its structure can be stabilized in the dark phase at room temperature. PMID- 27123600 TI - Interprofessional Education: What Measurable Learning Outcomes Are Realistic for the Physician Assistant Profession? AB - PURPOSE: To compare physician assistant (PA) students' attitudes regarding interprofessional education by students' seniority, gender, age, and previous experience with interprofessional education. METHODS: The validated 19-item Readiness for Interprofessional Learning Scale and the 12-item Interdisciplinary Education Perception Scale were administered to matriculating and graduating PA students from 2 US institutions (N = 186). Primary outcomes were score differences by subgroup and institution using independent sample t-tests. We also examined scale validity measured by Cronbach's alpha (internal consistency) and Pearson correlation coefficients (concurrent validity). RESULTS: Student demographics at both institutions were similar. Initial comparisons did not demonstrate significant institutional differences. Consequently, data were combined for subsequent analyses. Matriculating students had significantly higher mean Readiness for Interprofessional Learning Scale scores than did graduating students. No significant differences were found by gender, age, or previous interprofessional education exposure for either scale. Both scales demonstrated high internal consistency (Readiness for Interprofessional Learning Scale alpha = 0.93; Interdisciplinary Education Perception Scale alpha = 0.84). CONCLUSIONS: Physician assistant student attitudes regarding interprofessional education are very positive at matriculation and are less positive at graduation. Physician assistant student attitudes do not vary by gender, age, or previous interprofessional education exposure. Physician assistant educators should ensure that students' interprofessional education exposure makes full use of the students' initial positive attitudes and focuses on skill development for interprofessional education competencies. PMID- 27123602 TI - Proposal of a framework for scale-up life cycle inventory: A case of nanofibers for lithium iron phosphate cathode applications. AB - Environmental assessments are crucial for the management of the environmental impacts of a product in a rapidly developing world. The design phase creates opportunities for acting on the environmental issues of products using life cycle assessment (LCA). However, the LCA is hampered by a lack of information originating from distinct scales along the product or technology value chain. Many studies have been undertaken to handle similar problems, but these studies are case-specific and do not analyze the development options in the initial design phase. Thus, systematic studies are needed to determine the possible scaling. Knowledge from such screening studies would open the door for developing new methods that can tackle a given scaling problem. The present article proposes a scale-up procedure that aims to generate a new life cycle inventory (LCI) on a theoretical industrial scale, based on information from laboratory experiments. Three techniques are described to obtain the new LCI. Investigation of a laboratory-scale procedure is discussed to find similar industrial processes as a benchmark for describing a theoretical large-scale production process. Furthermore, LCA was performed on a model system of nanofiber electrospinning for Li-ion battery cathode applications. The LCA results support material developers in identifying promising development pathways. For example, the present study pointed out the significant impacts of dimethylformamide on suspension preparation and the power requirements of distinct electrospinning subprocesses. Nanofiber-containing battery cells had greater environmental impacts than did the reference cell, although they had better electrochemical performance, such as better wettability of the electrode, improving the electrode's electrosorption capacity, and longer expected lifetime. Furthermore, material and energy recovery throughout the production chain could decrease the environmental impacts by 40% to 70%, making the nanofiber a promising battery cathode. Integr Environ Assess Manag 2016;12:465-477. (c) 2016 SETAC. PMID- 27123603 TI - A Culture of Safety Starts with Us. AB - We need to follow the evidence and own up to our role. PMID- 27123604 TI - The Vital Signs Selfie Campaign. AB - A second set of 'vital signs' for nurses. PMID- 27123605 TI - Nursing Diversity. PMID- 27123606 TI - Regulation of E-Cigarettes. PMID- 27123607 TI - On Bullying. PMID- 27123608 TI - Caring for Patients in Pain. PMID- 27123609 TI - Caring for Patients in Pain. PMID- 27123610 TI - Caring for Patients in Pain. PMID- 27123611 TI - Reducing Inappropriate Antibiotic Prescriptions. AB - A social component to an intervention appears to lower rates. PMID- 27123612 TI - Increase in Colorectal Cancer Occurring Before Age 50. AB - Earlier screening is needed in certain younger patients. PMID- 27123614 TI - The AACN Recommends Increased Palliative Care Training in Undergraduate Nursing Education. AB - Advice reflects need to provide palliative care earlier during illness. PMID- 27123616 TI - Study Challenges Views on Alcohol Consumption in Native Americans. AB - But phone survey data may not have revealed the full picture. PMID- 27123621 TI - Replicating Real Life: Simulation in Nursing Education and Practice. AB - Providing learners the experiences without the risks. PMID- 27123622 TI - An Evaluation of Rituximab for Rheumatoid Arthritis. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. PMID- 27123623 TI - A New Treatment for Chronic Hepatitis C. PMID- 27123624 TI - Medwatch: Free Patient Safety Resources. PMID- 27123625 TI - The First Drug to Improve Survival in Liposarcoma. PMID- 27123629 TI - My Name is Nurse. AB - : Editor's note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but they also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives offers articles selected to fit today's topics and times.This month's article, from the May 1993 issue, is a tongue-in-cheek editorial by former editor-in-chief Mary B. Mallison. In it, she introduces us to the "PerceptoPhone"-an imaginary device that allows the wearer to access the thoughts of nurses. PerceptoPhones are used to educate hospital trustees on nurses' essential but often invisible abilities: to identify early warning signs of complications; teach and encourage; and carefully assess, soothe, and heal abilities that are "hard to quantify with usual accounting methods." More than 20 years later, we still look for better ways to teach the public about nursing. PMID- 27123630 TI - Mentoring Clinical Nurses to Write for Publication: Strategies for Success. AB - : Clinical nurses often find writing a challenge, but it's important to disseminate clinical practice initiatives that result in notable patient outcomes. Nurses have a responsibility to share what they do to improve patient care. The increased emphasis on the development and evaluation of evidence-based practice has made it necessary for nurses to share best practices that are associated with improved patient outcomes. We developed a six-month Writing for Publication workshop series designed to teach clinical nurses about the writing process and mentor them through the stages of preparing a manuscript to submit for publication. This successful program helped novice nurse authors become published professionals and had a great impact on our organization. PMID- 27123631 TI - To Make Everything Possible, Lean In. AB - The importance of mutual support in nursing. PMID- 27123632 TI - Henoch-Schonlein Purpura in the ED. AB - Diagnosing and treating a child with the most common form of pediatric vasculitis. PMID- 27123633 TI - Telemedicine Seen as a Boon to Critical Care Nursing. AB - According to this study. PMID- 27123634 TI - Exercise Effective In Preventing Low Back Pain. AB - According to this study. PMID- 27123635 TI - The Prevalence of Childhood Asthma is no Longer Increasing. AB - According to this study. PMID- 27123636 TI - Improved Well-Being After Gastric Bypass Surgery. AB - According to this study. PMID- 27123637 TI - Understanding Hospital Value-Based Purchasing. AB - This column is designed to provide a nursing perspective on new hospital quality measurements. Future articles will cover the various quality indicators hospitals face and the role of the nurse in meeting mandated benchmarks. Reader responses to this column are welcome and will help to make it more useful to nurses in meeting the challenges posed by health care reform and changing Medicare reimbursement programs. PMID- 27123638 TI - A Year in Malawi. AB - One nurse's experience working to improve the country's limited health care capacity. PMID- 27123639 TI - Five Words. AB - A psych nurse ponders the often fleeting nature of connection. PMID- 27123640 TI - Synthesis of Water-Soluble Cyclophane Hexamers Having a Triphenylene Core and Their Enhanced Guest-Binding Behavior. AB - A key compound, a precursor of water-soluble cyclophane hexamer, was prepared via Williamson ether synthesis of tetraaza[6.1.6.1]paracyclophane derivatives bearing a bromoacetamide moiety with triphenylene-2,3,6,7,10,11-hexaol as a core. A cationic cyclophane hexamer (1) was obtained by removing the protecting groups from the precursor. Fluorescence titration experiments proved that cationic cyclophane hexamer 1 showed macrocyclic multivalency effects; i.e., 1:1 host/guest binding constants (K) of 1 with anionic guests, 6-anilinonaphthalene-2 sulfonate and 6-p-toluidinonaphthalene-2-sulfonate, were increased about 63- and 62-fold, respectively, relative to those of monomeric cyclophane. Similarly, anionic cyclophane hexamer 2, which was easily prepared from 1, showed macrocyclic multivalency effects in K values with cationic guests such as hydrochlorides of doxorubicin and daunorubicin as an anticancer drug. PMID- 27123641 TI - The Accuracy of Diagnostic Methods for Diabetic Retinopathy: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The objective of this study was to evaluate the accuracy of the recommended glycemic measures for diagnosing diabetic retinopathy. METHODS: We systematically searched MEDLINE, EMBASE, the Cochrane Library, and the Web of Science databases from inception to July 2015 for observational studies comparing the diagnostic accuracy of glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hour plasma glucose (2h-PG). Random effects models for the diagnostic odds ratio (dOR) value computed by Moses' constant for a linear model and 95% CIs were used to calculate the accuracy of the test. Hierarchical summary receiver operating characteristic curves (HSROC) were used to summarize the overall test performance. RESULTS: Eleven published studies were included in the meta-analysis. The pooled dOR values for the diagnosis of retinopathy were 16.32 (95% CI 13.86-19.22) for HbA1c and 4.87 (95% CI 4.39-5.40) for FPG. The area under the HSROC was 0.837 (95% CI 0.781-0.892) for HbA1c and 0.735 (95% CI 0.657 0.813) for FPG. The 95% confidence region for the point that summarizes the overall test performance of the included studies occurs where the cut-offs ranged from 6.1% (43.2 mmol/mol) to 7.8% (61.7 mmol/mol) for HbA1c and from 7.8 to 9.3 mmol/L for FPG. In the four studies that provided information regarding 2h-PG, the pooled accuracy estimates for HbA1c were similar to those of 2h-PG; the overall performance for HbA1c was superior to that for FPG. CONCLUSIONS: The three recommended tests for the diagnosis of type 2 diabetes in nonpregnant adults showed sufficient accuracy for their use in clinical settings, although the overall accuracy for the diagnosis of retinopathy was similar for HbA1c and 2h-PG, which were both more accurate than for FPG. Due to the variability and inconveniences of the glucose level-based methods, HbA1c appears to be the most appropriate method for the diagnosis diabetic retinopathy. PMID- 27123642 TI - Metamorphopsia Associated with Branch Retinal Vein Occlusion. AB - PURPOSE: To apply M-CHARTS for quantitative measurements of metamorphopsia in eyes with acute branch retinal vein occlusion (BRVO) and to elucidate the pathomorphology that causes metamorphopsia. METHODS: This prospective study consisted of 42 consecutive patients (42 eyes) with acute BRVO. Both at baseline and one month after treatment with ranibizumab, metamorphopsia was measured with M-CHARTS, and the retinal morphological changes were examined with optical coherence tomography. RESULTS: At baseline, metamorphopsia was detected in the vertical and/or horizontal directions in 29 (69.0%) eyes; the mean vertical and horizontal scores were 0.59 +/- 0.57 and 0.52 +/- 0.67, respectively. The maximum inner retinal thickness showed no association with the M-CHARTS score, but the M CHARTS score was correlated with the total foveal thickness (r = 0.43, p = 0.004), the height of serous retinal detachment (r = 0.31, p = 0.047), and the maximum outer retinal thickness (r = 0.36, p = 0.020). One month after treatment, both the inner and outer retinal thickness substantially decreased. However, metamorphopsia persisted in 26 (89.7%) of 29 eyes. The posttreatment M-CHARTS score was not correlated with any posttreatment morphological parameters. However, the posttreatment M-CHARTS score was weakly correlated with the baseline total foveal thickness (r = 0.35. p = 0.024) and closely correlated with the baseline M-CHARTS score (r = 0.78, p < 0.001). CONCLUSIONS: Metamorphopsia associated with acute BRVO was quantified using M-CHARTS. Initial microstructural changes in the outer retina from acute BRVO may primarily account for the metamorphopsia. PMID- 27123643 TI - High-quality bio-oil from one-pot catalytic hydrocracking of kraft lignin over supported noble metal catalysts in isopropanol system. AB - Catalytic hydrocracking of kraft lignin was carried out in isopropanol system and an orthogonal array design (OAD) was employed to optimize the experimental conditions. GC-MS/FID, elemental analysis, GPC and (1)H-(13)C HSQC NMR were carried out for entire investigation of the liquid products. The results indicated that the hydrocracking process was thermally controlled and catalysts showed significant influences on the product distributions. Comparing with Pd/C, Pt/C and Ru/C, Rh/C inhibited the self-condensation of isopropanol and reduced the formation of oxygenic-chain compounds. The excellent catalytic activity for phenols conversion was obtained over Rh/C. The routes of oxygenic-chain compounds formation and phenol conversion were proposed in detail. The least oxygenic-chain compounds formation, the highest phenols conversion (93.4%), the lowest O/C ratio (0.094) and the highest HHV (37.969MJ/kg) provided the possibility of the high quality bio-oil obtained over Rh/C in isopropanol medium. PMID- 27123660 TI - [Current Aspects of Epididymo-Orchitis]. AB - BACKGROUND: Acute epididymitis is an inflammation of the epididymis. It mostly occurs unilaterally and may spread to the testis ('epididymo-orchitis') if untreated. Increasing technological advances allow for an even more detailed examination of concurrent symptoms such as ejaculate changes and the whole spectrum of pathogenic agents, which ranges from sexually transmitted pathogens such as Chlamydia and gonococci to enterobacteria and, rarely, viruses. This review summarises major aspects of the disease including the latest scientific findings. METHODS: A selective literature search including the last 40 years was performed via Medline. RESULTS: With about 400 cases a year in 100 000 men, acute epididymitis is the most common urogenital infection in men. It occurs across all age groups including children. Despite the fact that bacterial ascension is aetiologically of utmost relevance, only one out of three men reports signs of dysuria or urethritis. In young, sexually active men, sexually transmitted pathogens are regularly found in addition to the characteristic enterobacteriae, even if these men have an unremarkable sexual history. 88% of epididymal abscess formations can be successfully treated without surgery. Patients with indwelling urethral catheters are at a high risk of multiple drug resistance and should be treated empirically with both a fluoroquinolone and a third-generation cephalosporin until antimicrobial susceptibility testing has been completed. About 40 out of 100 patients develop post-inflammatory sub-fertility. Here, virulence factors like haemolysin A produced by uropathogenic E. coli have a negative impact on semen parameters compared to those patients suffering from epididymitis induced by haemolysin A negative strains. With adequate antibiotic treatment there is no evidence for testicular atrophy. Only one out of 10 men relapses. These cases should be examined thoroughly for subvesical obstruction. Some of them may benefit from prophylactic vasectomy. CONCLUSIONS: This review presents key aspects of acute epididymitis, which are increasingly adopted in updated guidelines. PMID- 27123661 TI - A novel homozygous mutation in UNC13D presenting as Epstein-Barr-virus-associated lymphoproliferative disease at 9 years of age. PMID- 27123662 TI - Detection of Undiagnosed Disease in Medicare Beneficiaries After a Clinical Home Visit. AB - Undiagnosed chronic conditions are a common and costly problem in Medicare patients. This study examined whether a clinical home visit program was associated with an increased future detection of undiagnosed diabetes, chronic obstructive pulmonary disease (COPD), and atrial fibrillation. Members of Medicare Advantage Plans (MAP), including Chronic Special Needs Plans (C-SNP), were identified who received a comprehensive geriatric home visit under United Health Group's HouseCalls program and those who did not. Members with no medical or prescription drug claim for diabetes, COPD, and atrial fibrillation in the 12 months prior to the visit were selected. New diagnoses were then identified based on claims for office visits and/or prescription drugs in the 6 months after the HouseCalls visit. Members who received a visit had a significantly higher rate of detection of previously undiagnosed diabetes and COPD, but not of atrial fibrillation. The detection rates for diabetes within 6 months of the visit were 2.8% versus 2.3% (P < 0.01) for MAP and 7.1% versus 5.6% (P < 0.01) for C-SNP members. For COPD, 2.5% versus 2.2% (P < 0.01) of members in MAP and 5.3% versus 4.3% (P < 0.01) of members in C-SNP were newly diagnosed. New diagnoses for atrial fibrillation were not significantly more common for members in MAP (1.4% versus 1.3%)) and C-SNP (1.9% versus 2.1%). These findings suggest that a home visit program, such as HouseCalls, is a promising avenue to address the hidden disease burden and unmet care needs in the Medicare population. PMID- 27123664 TI - Spontaneous Regression of Pulmonary Nodules Presenting as Epstein-Barr Virus related Atypical Infectious Mononucleosis. AB - BACKGROUND: Pulmonary nodules associated with Epstein-Barr virus (EBV)-related atypical infectious mononucleosis have rarely been described. OBSERVATIONS: A 12 year-old Japanese boy, upon admission, revealed multiple small round nodules (a total of 7 nodules in 4 to 8 mm size) in the lungs on computed tomography. The hemorrhagic pharyngeal tonsils with hot signals on 18F-fluorodeoxyglucose positron emission tomography-computed tomography were biopsied revealing the presence of EBV-encoded small nuclear RNA (EBER)-positive cells; however, no lymphoma was noted. The patient was diagnosed as having atypical EBV-infectious mononucleosis associated with primary EBV infection. Pulmonary nodules markedly reduced in numbers and sizes spontaneously over a 2-year period. CONCLUSIONS: Differential diagnosis of pulmonary nodules in childhood should include atypical EBV infection. PMID- 27123663 TI - H2 metabolism is widespread and diverse among human colonic microbes. AB - Microbial molecular hydrogen (H2) cycling is central to metabolic homeostasis and microbial composition in the human gastrointestinal tract. Molecular H2 is produced as an endproduct of carbohydrate fermentation and is reoxidised primarily by sulfate-reduction, acetogenesis, and methanogenesis. However, the enzymatic basis for these processes is incompletely understood and the hydrogenases responsible have not been investigated. In this work, we surveyed the genomic and metagenomic distribution of hydrogenase-encoding genes in the human colon to infer dominant mechanisms of H2 cycling. The data demonstrate that 70% of gastrointestinal microbial species listed in the Human Microbiome Project encode the genetic capacity to metabolise H2. A wide variety of anaerobically adapted hydrogenases were present, with [FeFe]-hydrogenases predominant. We subsequently analyzed the hydrogenase gene content of stools from 20 healthy human subjects. The hydrogenase gene content of all samples was overwhelmingly dominated by fermentative and electron-bifurcating [FeFe]-hydrogenases emerging from the Bacteroidetes and Firmicutes. This study supports that H2 metabolism in the human gut is driven by fermentative H2 production and interspecies H2 transfer. However, it suggests that electron-bifurcation rather than respiration is the dominant mechanism of H2 reoxidation in the human colon, generating reduced ferredoxin to sustain carbon-fixation (e.g. acetogenesis) and respiration (via the Rnf complex). This work provides the first comprehensive bioinformatic insight into the mechanisms of H2 metabolism in the human colon. PMID- 27123665 TI - Pediatric Pleomorphic Xanthoastrocytoma Treated With Surgical Resection Alone: Clinicopathologic Features. AB - Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that usually occurs in children and young adults. It has characteristic histologic features and is regarded as a WHO grade II lesion. Overall survival is reported to be >60%, but published series usually consist of a range of ages and treatment modalities. Gross total resection is associated with superior survival but recurrence rates after gross total resection are not well described, particularly in a pediatric population. We describe 16 cases over 20 years at our institution of pediatric PXA treated with surgical resection alone with a 5-year relapse-free survival of 40% (95% confidence interval, 20%-82%) and overall survival of 76% (95% confidence interval, 55%-100%). Gross total resection was associated with superior relapse-free survival (P<0.05). Some cases have a very long period between symptom onset or radiologic detection and resection, but neither length of symptoms nor radiologic signs of slow growth were associated with survival. PXA is a rare and unusual entity with unpredictable behavior. Complete surgical resection is optimal but does not guarantee relapse-free survival. We propose separation of PXA from other low-grade gliomas in childhood given differing biology and behavior. PMID- 27123666 TI - DIC Complicating APL Successfully Treated With Recombinant Thrombomodulin Alfa. AB - An 8-year-old boy developed anorexia, fatigue, and fever. Laboratory examination revealed a high white blood cell (WBC) count of 145*10/MUL with 97.5% abnormal promyelocytic cells that contained Auer bodies. Faggot cells were seen. He was diagnosed with acute promyelocytic leukemia. Later, a chromosome analysis showed 46,XY,t(15;17)(q22;q12). Promyelocytic Leukemia-retinoic acid receptor alpha fused gene and chimeric mRNA were confirmed by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction, respectively. He was complicated with disseminated intravascular coagulation (DIC) and his fibrin and fibrinogen degradation product at the onset was 37.6 MUg/mL. Human recombinant thrombomodulin (rTM) was started for DIC. After dexamethasone was administered at a dose of 8 mg/m to prevent all-trans retinoic acid syndrome on day 1, all-trans retinoic acid was started at a dose of 45 mg/m on day 4. Cytarabine (100 mg/m/d) and daunorubicin (45 mg/m/d) were started on day 9. The WBC count gradually increased to 270*10/MUL on day 8, and then decreased beginning on day 9. DIC improved after the initiation of chemotherapy and only minor petechia was noted. DIC did not become worse even after rTM was stopped on day 8. The risk of DIC and bleeding is high in the early stage of treatment for acute promyelocytic leukemia, especially in patients with a high WBC count. In our patient, rTM may have prevented fatal DIC and made it possible to safely administer induction chemotherapy. PMID- 27123667 TI - Efficacy of Pulsed Radiofrequency Therapy to Dorsal Root Ganglion Adding to TENS and Exercise for Persistent Pain after Total Knee Arthroplasty. AB - The majority of patients achieve substantial pain relief and improved function after total knee arthroplasty (TKA), but a proportion continues to experience life-disturbing persistent postsurgical pain (PPSP) in the months and years after surgery. This study aimed to assess the efficacy of transcutaneous electrical nerve stimulation (TENS), exercise, and pulsed radiofrequency (PRF) treatment on pain severity, neuropathic pain, knee flexion range of motion (ROM), functional status, and patient satisfaction in patients with PPSP after TKA. This is a retrospective study of prospectively collected data. Patients who were identified retrospectively from hospital charts were divided into two groups: group 1 (n = 17) received TENS and exercise treatment and group 2 (n = 22) received TENS, exercise, and PRF application to the dorsal root ganglion (DRG). The following procedure-related parameters were collected from the special registry form: visual analog scale (VAS), Douleur Neuropathique 4 (DN4) questionnaire, knee flexion ROM, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and patient satisfaction scale scores. The mean follow-up was 253.8 +/- 109 days. When the two groups were compared, a significant difference of at least 50% improvement in the VAS (activity) and a significant reduction in the DN4 scores following the last control examination were found in group 2. There was a significant reduction in total WOMAC scores in group 1 compared with group 2 for the four study periods. Higher scores for the patient satisfaction scale were found in group 1 compared with group 2 following the last control examination. Adding PRF to TENS and exercise therapy is useful in reducing the degree of pain and the neuropathic component of PPSP in patients with PPSP. PMID- 27123668 TI - Comparison of Synovial Fluid Cytokine Levels between Traumatic Knee Injury and End-Stage Osteoarthritis. AB - Degenerative osteoarthritis (OA) has been associated with elevated synovial fluid cytokines. It is unclear whether traumatic knee injuries are a trigger to the chemical process that leads to OA. The purpose of this study was to compare the synovial fluid cytokine levels between knees undergoing arthroscopy due to a documented inciting injury and knees undergoing primary arthroplasty due to end stage OA without a previous inciting injury. Synovial fluid samples were prospectively collected from knees undergoing arthroscopic surgeries due to ligamentous or meniscal knee injuries (knee injury group, n = 16) and primary arthroplasty due to OA (end-stage OA group, n = 14). In the knee injury group, patients had none or minimal OA and at least 30 days from the inciting injury. Exclusion criteria for both groups included inflammatory arthropathy (n = 1) and insufficient fluid for analysis (n = 1). In addition to synovial fluid cytokines, preoperative demographic, clinical, and functional data (Knee Injury and Osteoarthritis Outcome Score [KOOS]) were collected and compared between the groups. The end-stage OA group had higher age (p < 0.0001), body mass index (p = 0.0061), Charlson comorbidity index (<0.0001), and OA classification (p < 0.0001). Preoperative KOOS were similar between the groups. Interleukin-6 (IL-6) and IL-8 were elevated in the end-stage OA group compared with the knee injury group (p = 0.04 and 0.006, respectively). Granulocyte-macrophage colony stimulating factor, interferon gamma, IL-1beta, IL-12p70, IL-2, IL-10, and tumor necrosis factor alpha were not statistically different between the groups. A similar synovial fluid cytokine profile was found between the two groups. The elevation of IL-6 and IL-8 in the end-stage OA group indicates the potential role that these proinflammatory cytokines may have in long-term cartilage damage. PMID- 27123669 TI - A Cadaveric Analysis of the Optimal Radiographic Angle for Evaluating Trochlear Depth. AB - Disorders of the patellofemoral joint are common. Diagnosis and management often involves the use tangential imaging of the patella and trochlear grove, with the sunrise projection being the most common. However, imaging protocols vary between institutions, and limited data exist to determine which radiographic projections provide optimal visualization of the trochlear groove at its deepest point. Plain radiographs of 48 cadaveric femora were taken at various beam-femur angles and the maximum trochlear depth was measured; a tilt-board apparatus was used to elevate the femur in 5-degree increments between 40 and 75 degrees. A corollary experiment was undertaken to investigate beam-femur angles osteologically: digital representations of each bone were created with a MicroScribe digitizer, and trochlear depth was measured on all specimens at beam-femur angles from 0 to 75 degrees. The results of the radiographic and digitizer experiments showed that the maximum trochlear grove depth occurred at a beam-femur angle of 50 degrees. These results suggest that the optimal beam-femur angle for visualizing maximum trochlear depth is 50 degrees. This is significantly lower than the beam-femur angle of 90 degrees typically used in the sunrise projection. Clinicians evaluating trochlear depth on sunrise projections may be underestimating maximal depth and evaluating a nonarticulating portion of the femur. PMID- 27123670 TI - Do we care about sustainability? An analysis of time sensitivity of social preferences under environmental time-persistent effects. AB - Environmental cost-benefit analysis has traditionally assumed that the value of benefits is sensitive to their timing and that outcomes are valued higher, the sooner in time they occur following implementation of a project or policy. Though, this assumption might have important implications especially for the social desirability of interventions aiming at counteracting time-persistent environmental problems, whose impacts occur in the long- and very long-term, respectively involving the present and future generations. This study analyzes the time sensitivity of social preferences for preservation policies of adaptation to climate change stresses. Results show that stated preferences are time insensitive, due to sustainability issues: individuals show insignificant differences in benefits they can experience within their own lifetimes compared to those which occur in the longer term, and which will instead be enjoyed by future generations. Whilst these results may be specific to the experimental design employed here, they do raise interesting questions regarding choices over time-persistent environmental problems, particularly in terms of the desirability of interventions which produce longer-term benefits. PMID- 27123671 TI - Small-Protein-Stabilized Semiconductor Nanoprobe for Targeted Imaging of Cancer Cells. AB - Recently, semiconductor nanoparticles such as quantum dots (QDs) have attracted significant attention for bioimaging. Complex chemical functionalization, surface modification, and bioconjugation chemistry are generally required to tag biomolecules to QDs for imaging of different biomarkers. In this study, we report a simple method for production of QDs stabilized by the small protein, Affibody (AF-QDs) for fluorescent imaging of the human epidermal growth factor receptor type 2 (HER2) in human A549 lung cancer cells. This one-pot synthesis of AF-QDs avoids complex chemical conjugation procedures and demonstrates a promising approach for the preparation of fluorescent nanoprobes for imaging of cancer targets. PMID- 27123672 TI - Improved child problem behavior enhances the parents' relationship quality: A randomized trial. AB - Although a large body of literature indicates that interparental discord is a primary risk factor for child maladjustment, less research has examined children's behavior as a predictor of the parents' relationship quality. The goal of this randomized trial intervention study was to examine the effects of improved problem behavior in children on the parents' relationship quality 1 year later in a community sample. One hundred couples were randomly assigned to (a) a parenting training (Triple P) or (b) an untreated control group. Interparental relationship quality, parenting behavior, and child problem behavior were assessed by means of questionnaires completed by the parents before and 2 weeks after completion of the treatment and at 6-month and 1-year follow-ups. Mother report of improved child problem behavior and father-report of improved parenting skills predicted both partners' relationship quality at the 1-year follow-up for the Triple P group only. The findings suggest that programs aimed at reducing child problem behavior hold promise to also enhance the couple's relationship quality. (PsycINFO Database Record PMID- 27123673 TI - The association between self-perceived parental role and meaning in life among gay and heterosexual fathers. AB - The association between self-perceived parental role and meaning in life (indicated by personal growth and purpose in life) was explored among 82 Israeli gay fathers that were individually matched with 82 heterosexual fathers. Self perceived parental role was associated with meaning in life and this association was moderated by sexual orientation, demonstrating a significant positive association between self-perceived parental role and meaning in life among gay fathers but not among heterosexual fathers. The results are interpreted in light of the unique parental role gay fathers possibly construct in the context of intentional parenting and through possible life circumstances which appear associated with increased feelings of personal growth and purpose in life. (PsycINFO Database Record PMID- 27123674 TI - Neuromodulation as a cognitive enhancement strategy in healthy older adults: promises and pitfalls. AB - Increases in life expectancy have been followed by an upsurge of age-associated cognitive decline. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have risen as promising approaches to prevent or delay such cognitive decline. However, consensus has not yet been reached about their efficacy in improving cognitive functioning in healthy older adults. Here we review the effects of TMS and tDCS on cognitive abilities in healthy older adults. Despite considerable variability in the targeted cognitive domains, design features and outcomes, the results generally show an enhancement or uniform benefit across studies. Most studies employed tDCS, suggesting that this technique is particularly well-suited for cognitive enhancement. Further work is required to determine the viability of these techniques as tools for long-term cognitive improvement. Importantly, the combination of TMS/tDCS with other cognitive enhancement strategies may be a promising strategy to alleviate the cognitive decline associated with the healthy aging process. PMID- 27123675 TI - Altered force-generating capacity is well-perceived regardless of the pain presence. AB - An inability to perceive changes in action capabilities may result in increased risk of injury and/or reduced performance. We investigated whether the perception of ability to perform a maximal single-leg hop was updated when the actual ability to perform the task was reduced due to experimentally altered force generating capacity and associated pain. Twenty-five healthy volunteers performed a series of maximal isometric voluntary knee extensions (MVC), performance estimates and actual performances of a maximal single-leg hop. The motor tasks were completed for each leg, before (t0_pre), and immediately (t0_post), 48 hr (t+48hr) and 1 month (t+1month) after, a neuromuscular electrical stimulation (NMES) protocol was used to decrease the force generating capacity of the quadriceps muscle of 1 leg. MVC torque decreased by ~30% after the NMES protocol for the stimulated leg at t0_post and t+48hr (p < .001). This reduction was associated with a significant decrease in estimation of performance and actual performance of the maximal single-leg hop at t0_post and t+48hr for the test leg (p < .001). The reduction in performance ability was associated with low-level pain immediately after NMES, and moderate pain and an increase in the belief that everyday motor tasks would be harmful 48 hours after NMES. Participants accurately estimated their performance capabilities during each testing period. This study provides a critical step toward understanding the potential for decreased force-generating capacity and muscle pain to modify the relationship between motor performance and perceived abilities. PMID- 27123676 TI - The processing architectures of whole-object features: A logical-rules approach. AB - In this article, we examine whether dimensions comprising the entirety of an object (e.g., size and saturation) are processed independently or pooled into a single whole-object representation. These whole-object features, while notionally separable, sometimes show empirical effects consistent with integrality. A recently proposed theoretical distinction between integral and separable dimensions that emphasizes the time course of information processing, can be used to differentiate whether whole-object features are processed independently, either in serial or in parallel, or pooled into a single coactive process (see, e.g., Little, Nosofsky, Donkin, & Denton, 2013). The current research examines this theoretical distinction in the processing of 3 sets of whole-object-featured stimuli that vary on any pair of the dimensions of saturation, size, and orientation. We found that a mixture of serial and parallel architectures underlies the processing of whole-object features. These results indicate that whole-object features are processed independently. (PsycINFO Database Record PMID- 27123677 TI - Observers' cognitive states modulate how visual inputs relate to gaze control. AB - Previous research has shown that eye-movements change depending on both the visual features of our environment, and the viewer's top-down knowledge. One important question that is unclear is the degree to which the visual goals of the viewer modulate how visual features of scenes guide eye-movements. Here, we propose a systematic framework to investigate this question. In our study, participants performed 3 different visual tasks on 135 scenes: search, memorization, and aesthetic judgment, while their eye-movements were tracked. Canonical correlation analyses showed that eye-movements were reliably more related to low-level visual features at fixations during the visual search task compared to the aesthetic judgment and scene memorization tasks. Different visual features also had different relevance to eye-movements between tasks. This modulation of the relationship between visual features and eye-movements by task was also demonstrated with classification analyses, where classifiers were trained to predict the viewing task based on eye movements and visual features at fixations. Feature loadings showed that the visual features at fixations could signal task differences independent of temporal and spatial properties of eye movements. When classifying across participants, edge density and saliency at fixations were as important as eye-movements in the successful prediction of task, with entropy and hue also being significant, but with smaller effect sizes. When classifying within participants, brightness and saturation were also significant contributors. Canonical correlation and classification results, together with a test of moderation versus mediation, suggest that the cognitive state of the observer moderates the relationship between stimulus-driven visual features and eye-movements. (PsycINFO Database Record PMID- 27123678 TI - The feeling of another's knowing: How "mixed messages" in speech are reconciled. AB - Listeners often encounter conflicting verbal and vocal cues about the speaker's feeling of knowing; these "mixed messages" can reflect online shifts in one's mental state as they utter a statement, or serve different social-pragmatic goals of the speaker. Using a cross-splicing paradigm, we investigated how conflicting cues about a speaker's feeling of (un)knowing change one's perception. Listeners rated the confidence of speakers of utterances containing an initial verbal phrase congruent or incongruent with vocal cues in a subsequent statement, while their brain potentials were tracked. Different forms of conflicts modulated the perceived confidence of the speaker, the extent to which was stronger for female listeners. A confident phrase followed by an unconfident voice enlarged an anteriorly maximized negativity for female listeners and late positivity for male listeners, suggesting that mental representations of another's feeling of knowing in face of this conflict were hampered by increased demands of integration for females and increased demands on updating for males. An unconfident phrase followed by a confident voice elicited a delayed sustained positivity (from 900 ms) in female participants only, suggesting females generated inferences to moderate the conflicting message about speaker knowledge. We highlight ways that verbal and vocal cues are real-time integrated to access a speaker's feeling of (un)knowing, while arguing that females are more sensitive to the social relevance of conflicting speaker cues. (PsycINFO Database Record PMID- 27123679 TI - Metacognitive evaluation in the avoidance of demand. AB - In the current set of experiments our goal was to test the hypothesis that individuals avoid courses of action based on a kind of metacognitive evaluation of demand in a Demand Selection Task (DST). Individuals in Experiment 1 completed a DST utilizing visual stimuli known to yield a dissociation between performance and perceived demand. Patterns of demand avoidance followed that of perceived demand. Experiment 2 provided a replication of the aforementioned results, in addition to demonstrating a second dissociation between a peripheral physiological measure of demand (i.e., blink rates) and demand avoidance. Experiment 3 directly tested the assumption that individuals make use of a general metacognitive evaluation of task demand during selections. A DST was utilized in a forced-choice paradigm that required individuals to either select the most effortful, time demanding, or least accurate of 2 choices. Patterns of selections were similar across all rating dimensions, lending credit to this notion. Findings are discussed within a metacognitive framework of demand avoidance and contrasted to current theories. (PsycINFO Database Record PMID- 27123680 TI - Fast and slow readers and the effectiveness of the spatial frequency content of text: Evidence from reading times and eye movements. AB - Text contains a range of different spatial frequencies but the effectiveness of spatial frequencies for normal variations in skilled adult reading ability is unknown. Accordingly, young skilled adult readers showing fast or slow reading ability read sentences displayed as normal or filtered to contain only very low, low, medium, high, or very high spatial frequencies. Reading times and eye movement measures of fixations and saccades assessed the effectiveness of these displays for reading. Reading times showed that, for each reading ability, medium, high, and very high spatial frequencies were all more effective than lower spatial frequencies. Indeed, for each reading ability, reading times for normal text were maintained when text contained only medium, high, or very high spatial frequencies. However, reading times for normal text and for each spatial frequency were all substantially shorter for fast readers than for slow readers, and this advantage for fast readers was similar for normal, medium, high, and very high spatial frequencies but much larger for low and very low spatial frequencies. In addition, fast readers made fewer and shorter fixations, fewer and shorter regressions, and longer forward saccades, than slow readers, and these differences were generally similar in size for normal, medium, high, and very high spatial frequencies, but larger when spatial frequencies were lower. These findings suggest that fast and slow adult readers can each use a range of different spatial frequencies for reading but fast readers make more effective use of these spatial frequencies and especially those that are lower. (PsycINFO Database Record PMID- 27123681 TI - Memory-based attention capture when multiple items are maintained in visual working memory. AB - Efficient visual search requires that attention is guided strategically to relevant objects, and most theories of visual search implement this function by means of a target template maintained in visual working memory (VWM). However, there is currently debate over the architecture of VWM-based attentional guidance. We contrasted a single-item-template hypothesis with a multiple-item template hypothesis, which differ in their claims about structural limits on the interaction between VWM representations and perceptual selection. Recent evidence from van Moorselaar, Theeuwes, and Olivers (2014) indicated that memory-based capture during search, an index of VWM guidance, is not observed when memory set size is increased beyond a single item, suggesting that multiple items in VWM do not guide attention. In the present study, we maximized the overlap between multiple colors held in VWM and the colors of distractors in a search array. Reliable capture was observed when 2 colors were held in VWM and both colors were present as distractors, using both the original van Moorselaar et al. singleton shape search task and a search task that required focal attention to array elements (gap location in outline square stimuli). In the latter task, memory based capture was consistent with the simultaneous guidance of attention by multiple VWM representations. (PsycINFO Database Record PMID- 27123682 TI - Pupils dilate for vocal or familiar music. AB - Previous research reveals that vocal melodies are remembered better than instrumental renditions. Here we explored the possibility that the voice, as a highly salient stimulus, elicits greater arousal than nonvocal stimuli, resulting in greater pupil dilation for vocal than for instrumental melodies. We also explored the possibility that pupil dilation indexes memory for melodies. We tracked pupil dilation during a single exposure to 24 unfamiliar folk melodies (half sung to la la, half piano) and during a subsequent recognition test in which the previously heard melodies were intermixed with 24 novel melodies (half sung, half piano) from the same corpus. Pupil dilation was greater for vocal melodies than for piano melodies in the exposure phase and in the test phase. It was also greater for previously heard melodies than for novel melodies. Our findings provide the first evidence that pupillometry can be used to measure recognition of stimuli that unfold over several seconds. They also provide the first evidence of enhanced arousal to vocal melodies during encoding and retrieval, thereby supporting the more general notion of the voice as a privileged signal. (PsycINFO Database Record PMID- 27123683 TI - Remembering faces and scenes: The mixed-category advantage in visual working memory. AB - We examined the mixed-category memory advantage for faces and scenes to determine how domain-specific cortical resources constrain visual working memory. Consistent with previous findings, visual working memory for a display of 2 faces and 2 scenes was better than that for a display of 4 faces or 4 scenes. This pattern was unaffected by manipulations of encoding duration. However, the mixed category advantage was carried solely by faces: Memory for scenes was not better when scenes were encoded with faces rather than with other scenes. The asymmetry between faces and scenes was found when items were presented simultaneously or sequentially, centrally, or peripherally, and when scenes were drawn from a narrow category. A further experiment showed a mixed-category advantage in memory for faces and bodies, but not in memory for scenes and objects. The results suggest that unique category-specific interactions contribute significantly to the mixed-category advantage in visual working memory. (PsycINFO Database Record PMID- 27123684 TI - Newborns' sensitivity to the visual aspects of infant-directed speech: Evidence from point-line displays of talking faces. AB - The first time a newborn is held, he is attracted by the human's face. A talking face is even more captivating, as it is the first time he or she hears and sees another human talking. Older infants are relatively good at detecting the relationship between images and sounds when someone is addressing to them, but it is unclear whether this ability is dependent on experience or not. Using an intermodal matching procedure, we presented newborns with 2 silent point-line displays representing the same face uttering different sentences while they were hearing a vocal-only utterance that matched 1 of the 2 stimuli. Nearly all of the newborns looked longer at the matching point-line face than at the mismatching 1, with prior exposure to the stimuli (Experiment 1) or without (Experiment 2). These results are interpreted in terms of newborns' ability to extract common visual and auditory information of continuous speech events despite a short experience with talking faces. The implications are discussed in the light of the language processing and acquisition literature. (PsycINFO Database Record PMID- 27123685 TI - The impact of configural superiority on the processing of spatial information. AB - The impact of context on perception has been well documented for over a century. In some cases, the introduction of context to a set of target features may produce a unified percept, leading to a quicker and more accurate classification; a configural superiority effect (Pomerantz, Sager, & Stoever, 1977). Although this effect has been well characterized in terms of the stimulus features that produce the effect, the specific impact context has on the spatial strategies adopted by observers when making perceptual judgments remains unclear. Here, we sought to address this question by using the methods of response classification and ideal observer analysis. In our main experiment, we used a stimulus set known to produce the configural superiority effect and found that although observers were faster in the presence of context, they were actually less efficient at extracting stimulus information. This surprising result was attributable to the use of a spatial strategy in which observers relied on redundant, noninformative features in the presence of context. A control experiment ruled out the possibility that the mere presence of added context led to these strategic shifts. Our results support previous notions about the nature of the perceptual shifts that are induced by the configural superiority effect. However, they also show that configural processing is more nuanced than originally thought: Although observers may be faster at making judgments when context induces the percept of a configural whole, there appears to be a hidden cost in terms of the efficiency with which information is used. (PsycINFO Database Record PMID- 27123686 TI - Seriously clowning: Medical clowning interaction with children undergoing invasive examinations in hospitals. AB - This qualitative study examined the subjective experience of children undergoing an invasive examination in the hospital when accompanied by a medical clown. In depth semi-structured interviews were conducted with nine such children and nine of their accompanying parents. The children were patients in two outpatient departments (Pediatric Gastroenterology and a Center for the Sexually Abused) in a hospital in Israel. Interviews were coded thematically using an Atlas.ti software program. Analysis of the interviews indicated that the intervention of the clown positively changed the children's perceptions of the hospital, of experiencing the examination, and of their life narrative. Medical clowns thus appear to be a central, meaningful, and therapeutic source for children undergoing invasive examinations in hospital, as well as for their parents. Therefore, it may be advisable to incorporate medical clowns as an integral part of medical teams performing invasive procedures and to include the clowns in all stages of the hospital visit. PMID- 27123687 TI - Health behaviors and demographic factors of chronic health conditions among elderly veteran men. AB - As male veterans age, there are unique opportunities for health-related prevention efforts to be introduced throughout the life cycle to ameliorate the effects of chronic health conditions such as cardiovascular disease, asthma, arthritis, and diabetes. This study analyzed data from the Behavioral Risk Factor Surveillance System (2012) with a sample of 27,187 male veterans aged 65-84 years and 4,079 male veterans over 85 years of age. The study examined associations between behaviors, demographics, and five chronic health conditions with variables that included marital status, health insurance coverage, alcohol consumption, smoking history, and income levels. These associations varied between the two age groups, suggesting the need for intervention with veterans across their lifespans. Public health social workers could help veterans modify their health behaviors to prevent the occurrence or worsening of chronic health conditions over time and across the aging process. PMID- 27123688 TI - Technology Use Among Patients in a Nonurban Southern U.S. HIV Clinic in 2015. AB - BACKGROUND: Behavioral interventions can be delivered over the Internet, but nonurban subpopulations living with HIV may still have inadequate Internet access to make this feasible. METHODS: We report on a survey conducted in 2015 among 150 patients receiving care at a university-based Infectious Disease Clinic serving a nonurban and rural population in central Virginia. Our aim was to determine the rate of computer, tablet, and smartphone usage, as well as Internet access, to inform the delivery of a novel intervention using Internet and mobile technology. RESULTS: The participants' mean age was 46; 111 patients used computers, 101 used smartphones, and 41 used tablets. The results showed that 87% of patients had Internet access. Of those, 49 reported daily Internet use, while 18% reported weekly Internet use, and 33% reported less frequent Internet use. CONCLUSIONS: The survey study data suggest that Internet access among nonurban and rural patients with HIV is adequate to support trials testing Internet-delivered interventions. It is time to develop and deliver Internet interventions tailored for this often isolated subpopulation. PMID- 27123689 TI - Icatibant as acute treatment for hereditary angioedema in adults. AB - INTRODUCTION: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by recurrent, unpredictable episodes of cutaneous and/or mucosal edema. Bradykinin, released by the activation of the contact system, binds to bradykinin B2 receptors on the endothelial cell surface to enhance vascular permeaility, which leads to angioedema. AREAS COVERED: C1-INH HAE therapy is aimed at the inhibition of bradykinin release, as well as at the blockage of its effects mediated by its receptor. Three controlled trials, three open-label extensions, and two open-label studies, and a prospective, observational study have confirmed the safety and efficacy of the bradykinin B2 receptor antagonist, icatibant administered as acute treatment for HAE attacks in adult patients with C1-INH-HAE. Expert commentary: The ready-to-use, pre-filled syringes of icatibant can be self-administered easily, effectively, safely and, importantly, conviently. - This has resulted in patients being able to quickly treat an attack and realize a dramatic change for the better in their lives. PMID- 27123690 TI - Notes from the Field: Primary Amebic Meningoencephalitis Associated with Exposure to Swimming Pool Water Supplied by an Overland Pipe - Inyo County, California, 2015. AB - On June 17, 2015, a previously healthy woman aged 21 years went to an emergency department after onset of headache, nausea, and vomiting during the preceding 24 hours. Upon evaluation, she was vomiting profusely and had photophobia and nuchal rigidity. Analysis of cerebrospinal fluid was consistent with meningitis.* She was empirically treated for bacterial and viral meningoencephalitis. Her condition continued to decline, and she was transferred to a higher level of care in another facility on June 19, but died shortly thereafter. Cultures of cerebrospinal fluid and multiple blood specimens were negative, and tests for West Nile, herpes simplex, and influenza viruses were negative. No organisms were seen in the cerebrospinal fluid; however, real-time polymerase chain reaction testing by CDC was positive for Naegleria fowleri, a free-living thermophilic ameba found in warm freshwater that causes primary amebic meningoencephalitis, an almost universally fatal infection. PMID- 27123692 TI - Predictive mathematical modeling of knee static laxity after ACL reconstruction: in vivo analysis. AB - Previous studies did not take into consideration such large variety of surgery variables which describe the performed anterior cruciate ligament (ACL) reconstruction and the interaction among them in the definition of postoperative outcome. Seventeen patients who underwent navigated Single Bundle plus Lateral Plasty ACL reconstruction were enrolled in the study. Static laxity was evaluated as the value of anterior/posterior displacement at 30 degrees and at 90 degrees of flexion, internal/external rotation at 30 degrees and 90 degrees of knee flexion, varus/valgus test at 0 degrees and 30 degrees of flexion. The evaluated surgical variables were analyzed through a multivariate analysis defining the following models: AP30estimate, AP90estimate, IE30estimate, IE90estimate, VV0estimate, VV30estimate. Surgical variables has been defined as the angles between the tibial tunnel and the three planes, the lengths of the tunnel and the relationship between native footprints and tunnels. An analogous characterization was performed for the femoral side. Performance and significance of the defined models have been quantified by the correlation ratio (eta(2)) and the corresponding p-value (*p < 0.050). The analyzed models resulted to be statistically significant (p < 0.05) for prediction of postoperative static laxity values. The only exception was the AP90estimate model. The eta(2) ranged from 0.568 (IE90estimate) to 0.995 (IE30estimate). The orientation of the tibial tunnel resulted to be the most important surgical variable for the performed laxity estimation. Mathematical models for postoperative knee laxity is a useful tool to evaluate the effects of different surgical variables on the postoperative outcome. PMID- 27123691 TI - Pandemic vaccination strategies and influenza severe outcomes during the influenza A(H1N1)pdm09 pandemic and the post-pandemic influenza season: the Nordic experience. AB - During the 2009/10 influenza A(H1N1)pdm09 pandemic, the five Nordic countries adopted different approaches to pandemic vaccination. We compared pandemic vaccination strategies and severe influenza outcomes, in seasons 2009/10 and 2010/11 in these countries with similar influenza surveillance systems. We calculated the cumulative pandemic vaccination coverage in 2009/10 and cumulative incidence rates of laboratory confirmed A(H1N1)pdm09 infections, intensive care unit (ICU) admissions and deaths in 2009/10 and 2010/11. We estimated incidence risk ratios (IRR) in a Poisson regression model to compare those indicators between Denmark and the other countries. The vaccination coverage was lower in Denmark (6.1%) compared with Finland (48.2%), Iceland (44.1%), Norway (41.3%) and Sweden (60.0%). In 2009/10 Denmark had a similar cumulative incidence of A(H1N1)pdm09 ICU admissions and deaths compared with the other countries. In 2010/11 Denmark had a significantly higher cumulative incidence of A(H1N1)pdm09 ICU admissions (IRR: 2.4; 95% confidence interval (CI): 1.9-3.0) and deaths (IRR: 8.3; 95% CI: 5.1-13.5). Compared with Denmark, the other countries had higher pandemic vaccination coverage and experienced less A(H1N1)pdm09-related severe outcomes in 2010/11. Pandemic vaccination may have had an impact on severe influenza outcomes in the post-pandemic season. Surveillance of severe outcomes may be used to compare the impact of influenza between seasons and support different vaccination strategies. PMID- 27123693 TI - Insights into the Impact of the Nafion Membrane Pretreatment Process on Vanadium Flow Battery Performance. AB - Nafion membranes are now the most widely used membranes for long-life vanadium flow batteries (VFBs) because of their extremely high chemical stability. Today, the type of Nafion membrane that should be selected and how to pretreat these Nafion membranes have become critical issues, which directly affects the performance and cost of VFBs. In this work, we chose the Nafion 115 membrane to investigate the effect of the pretreatment process (as received, wet, boiled, and boiled and dried) on the performance of VFBs. The relationship between the nanostructure and transport properties of Nafion 115 membranes is elucidated by wide-angle X-ray diffraction and small-angle X-ray scattering techniques. The self-discharge process, battery efficiencies, electrolyte utilization, and long term cycling stability of VFBs with differently pretreated Nafion membranes are presented comprehensively. An online monitoring system is used to monitor the electrolyte volume that varies during the long-term charge-discharge test of VFBs. The capacity fading mechanism and electrolyte imbalance of VFBs with these Nafion 115 membranes are also discussed in detail. The optimal pretreatment processes for the benchmark membrane and practical application are synthetically selected. PMID- 27123694 TI - Prosurvival AMBRA1 turns into a proapoptotic BH3-like protein during mitochondrial apoptosis. AB - Autophagy and apoptosis are 2 stress-response mechanisms that are closely interconnected. However, the molecular interplays between these 2 pathways remain to be clarified. Here we report that the crucial proautophagic factor AMBRA1 can act as a positive mediator of mitochondrial apoptosis. Indeed, we show that, in a proapoptotic positive feedback loop, the C-terminal part of AMBRA1, generated by CASP/CASPASE cleavage upon apoptosis induction, inhibits the antiapoptotic factor BCL2 by a direct binding through its BH3-like domain. The mitochondrial AMBRA1 BCL2 complex is thus at the crossroad between autophagy and cell death and may represent a novel target in development of therapeutic approaches in clinical diseases. PMID- 27123695 TI - A double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]-basimglurant and absolute bioavailability after oral administration and concomitant intravenous microdose administration of [13C6]-labeled basimglurant in humans. AB - 1. The emerging technique of employing intravenous microdose administration of an isotope tracer concomitantly with an [14C]-labeled oral dose was used to characterize the disposition and absolute bioavailability of a novel metabotropic glutamate 5 (mGlu5) receptor antagonist under clinical development for major depressive disorder (MDD). 2. Six healthy volunteers received a single 1 mg [12C/14C]-basimglurant (2.22 MBq) oral dose and a concomitant i.v. tracer dose of 100 MUg of [13C6]-basimglurant. Concentrations of [12C]-basimglurant and the stable isotope [13C6]-basimglurant were determined in plasma by a specific LC/MS MS method. Total [14C] radioactivity was determined in whole blood, plasma, urine and feces by liquid scintillation counting. Metabolic profiling was conducted in plasma, urine, blood cell pellet and feces samples. 3. The mean absolute bioavailability after oral administration (F) of basimglurant was ~67% (range 45.7-77.7%). The major route of [14C]-radioactivity excretion, primarily in form of metabolites, was in urine (mean recovery 73.4%), with the remainder excreted in feces (mean recovery 26.5%). The median tmax for [12C]-basimglurant after the oral administration was 0.71 h (range 0.58-1.00) and the mean terminal half-life was 77.2 +/- 38.5 h. Terminal half-life for the [14C]-basimglurant was 178 h indicating presence of metabolites with a longer terminal half-life. Five metabolites were identified with M1-Glucuronide as major and the others in trace amounts. There was minimal binding of drug to RBCs. IV pharmacokinetics was characterized with a mean +/- SD CL of 11.8 +/- 7.4 mL/h and a Vss of 677 +/- 229 L. 4. The double-tracer technique used in this study allowed to simultaneously characterize the absolute bioavailability and disposition characteristics of the new oral molecular entity in a single study. PMID- 27123696 TI - Blaming the building: How venue quality influences consumer bias against stigmatized leaders. AB - Because stigmatized individuals are viewed as incongruent with commonly held implicit leadership theories, they are often deemed less fit to lead than their nonstigmatized counterparts (Eagly & Karau, 2002). This suggests consumers might use such views to discredit not only stigmatized leaders, but also the companies they represent. However, cognition based on social categories (1 potential form of stigma) may be more likely when there are readily available alternative factors to account for one's decisions via casuistry. Across 2 complementary studies (field and experiment), we find that customers react negatively to stigmatized leaders only when the physical state of the company venue provides an ostensible defense to mask their biased behavior. When facilities are of lower quality, consumers appear to use a leader's stigma to infer lower product quality, coinciding in less patronage for companies with stigmatized as opposed to nonstigmatized leaders. Thus, consumers penalize companies with stigmatized leaders only when doing so can easily be attributed to an alternative factor (e.g., a lower quality venue) not involving the leader's stigma. (PsycINFO Database Record PMID- 27123697 TI - Trust and team performance: A meta-analysis of main effects, moderators, and covariates. AB - Cumulating evidence from 112 independent studies (N = 7,763 teams), we meta analytically examine the fundamental questions of whether intrateam trust is positively related to team performance, and the conditions under which it is particularly important. We address these questions by analyzing the overall trust performance relationship, assessing the robustness of this relationship by controlling for other relevant predictors and covariates, and examining how the strength of this relationship varies as a function of several moderating factors. Our findings confirm that intrateam trust is positively related to team performance, and has an above-average impact (rho = .30). The covariate analyses show that this relationship holds after controlling for team trust in leader and past team performance, and across dimensions of trust (i.e., cognitive and affective). The moderator analyses indicate that the trust-performance relationship is contingent upon the level of task interdependence, authority differentiation, and skill differentiation in teams. Finally, we conducted preliminary analyses on several emerging issues in the literature regarding the conceptualization and measurement of trust and team performance (i.e., referent of intrateam trust, dimension of performance, performance objectivity). Together, our findings contribute to the literature by helping to (a) integrate the field of intrateam trust research, (b) resolve mixed findings regarding the trust performance relationship, (c) overcome scholarly skepticism regarding the main effect of trust on team performance, and (d) identify the conditions under which trust is most important for team performance. (PsycINFO Database Record PMID- 27123699 TI - Maternal social support, quality of birth experience, and post-partum depression in primiparous women. AB - BACKGROUND: Social relationships provide individuals with a general sense of self worth, psychological wellbeing, as well as allowing them access to resources during stressful periods and transitions in life. Pregnancy is a time of significant life change for every woman. The aim of this study was to verify the influence of social support perceived by mothers during pregnancy on the quality of their birth experience and post-partum depression. METHOD: A longitudinal study at three different times was carried out on 179 nulliparous pregnant women. Women completed a Maternal Social Support Questionnaire during the third trimester of their pregnancy. Then, on the first day after childbirth, clinical birth indices were collected. Finally, a month after childbirth, the Edinburgh Postnatal Depression Scale was administered. RESULTS: Post-partum depression was influenced negatively by maternal perceived social support and positively by negative clinical birth indices. In addition to these direct effects, analyses revealed a significant effect of maternal perceived social support on post-partum depression, mediated by the clinical indices considered. CONCLUSIONS: Social support perceived by mothers during pregnancy plays a significant role as a protection factor against post-partum depression, both directly and indirectly, reducing the negative clinical aspects of the birth experience. PMID- 27123698 TI - In Situ Reductive Synthesis of Structural Supported Gold Nanorods in Porous Silicon Particles for Multifunctional Nanovectors. AB - Porous silicon nanodisks (PSD) were fabricated by the combination of photolithography and electrochemical etching of silicon. By using PSD as a reducing agent, gold nanorods (AuNR) were in situ synthesized in the nanopores of PSD, forming PSD-supported-AuNR (PSD/AuNR) hybrid particles. The formation mechanism of AuNR in porous silicon (pSi) was revealed by exploring the role of pSi reducibility and each chemical in the reaction. With the PSD support, AuNR exhibited a stable morphology without toxic surface ligands (CTAB). The PSD/AuNR hybrid particles showed enhanced plasmonic property compared to free AuNR. Because high-density "hot spots" can be generated by controlling the distribution of AuNR supported in PSD, surface-enhanced raman scattering (SERS) using PSD/AuNR as particle substrates was demonstrated. A multifunctional vector, PSD/AuNR/DOX, composed of doxorubicin (DOX)-loaded PSD/AuNR capped with agarose (agar), was developed for highly efficient, combinatorial cancer treatment. Their therapeutic efficacy was examined using two pancreatic cancer cell lines, PANC-1 and MIA PaCa 2. PSD/AuNR/DOX (20 MUg Au and 1.25 MUg DOX/mL) effectively destroyed these cells under near-IR laser irradiation (810 nm, 15 J.cm(-2) power, 90 s). Overall, we envision that PSD/AuNR may be a promising injectable, multifunctional nanovector for biomedical application. PMID- 27123700 TI - Visual grading evaluation of commercially available metal artefact reduction techniques in hip prosthesis computed tomography. AB - OBJECTIVE: To evaluate metal artefact reduction (MAR) techniques from four CT vendors in hip prosthesis imaging. METHODS: Bilateral hip prosthesis phantom images, obtained by using MAR algorithms for single-energy CT data or dual-energy CT (DECT) data and by monoenergetic reconstructions of DECT data, were visually graded by five radiologists using 10 image quality criteria. Comparisons between the MAR images and a reference image were performed for each scanner separately. Ordinal probit regression analysis was used. RESULTS: The MAR algorithms in general improved the image quality based on the majority of the criteria (up to between 8/10 and 10/10) with a statistical improvement in overall image quality (p < 0.001). However, degradation of image quality, such as new artefacts, was seen in some cases. A few monoenergetic reconstruction series improved the image quality (p < 0.004) for one of the DECT scanners, but it was only improved for some of the criteria (up to 5/10). Monoenergetic reconstructions resulted in worse image quality for the majority of the criteria (up to 7/10) for the other DECT scanner. CONCLUSION: The MAR algorithms improved the image quality of the hip prosthesis CT images. However, since additional artefacts and degradation of image quality were seen in some cases, all algorithms should be carefully evaluated for every clinical situation. Monoenergetic reconstructions were in general concluded to be insufficient for reducing metal artefacts. ADVANCES IN KNOWLEDGE: Qualitative evaluation of the usefulness of several MAR techniques from different vendors in CT imaging of hip prosthesis. PMID- 27123719 TI - [Allopurinol is positively associated with cardiovascular health]. PMID- 27123701 TI - Perirenal fat stranding on CT: is there an association with bladder outlet obstruction? AB - OBJECTIVE: To determine the association between perirenal fat stranding (PFS) on CT and bladder outlet obstruction (BOO). METHODS: CT scans from 122 patients who had undergone urodynamic study for lower urinary tract symptoms (LUTS) were registered after exclusion of patients with renal or retroperitoneal disease. Images were independently reviewed by two radiologists and compared with those of 244 age- and sex-matched control patients without LUTS. The PFS severity was scored on a four-point scale, and the interobserver agreement was assessed with kappa statistics. The severity score and incidence was compared between the groups, and the association with baseline characteristics was analyzed. For the LUTS group, an association between PFS severity and urodynamic and laboratory data was evaluated. RESULTS: PFS was more frequent and more severe in the LUTS group than in the control group (p-value < 0.001); its presence was significantly associated with male gender and older age (p-value < 0.001). PFS was predominantly bilateral in both groups (80.1-93.2%). In the LUTS group, PFS severity scores were significantly correlated with the maximum flow rate, maximum detrusor pressure and estimated glomerular filtration rate (p-value < 0.001). Interobserver agreements were excellent for PFS presence (kappa = 0.883) and severity (kappa = 0.816). CONCLUSION: Severe PFS was observed in older, male patients with LUTS. PFS severity was associated with the degree of BOO and impaired renal function. ADVANCES IN KNOWLEDGE: Recognition of PFS on the CT scan may warrant further evaluation of BOO and appropriate management to prevent renal impairment. PMID- 27123720 TI - [Do DPP-4-inhibitors increase the risk for heart failure?]. PMID- 27123721 TI - [Benzodiazepines don't increase risk for dementia in general]. PMID- 27123722 TI - [62-year old woman with chest pain and hyperthyreoidism]. PMID- 27123723 TI - [A change of directions is imminent]. PMID- 27123724 TI - [Endoscopic strategies in minimal invasive therapy]. AB - Due to higher detection rates of early gastrointestinal neoplasia endoscopic resection of early GI cancers or precancerous lesions is increasing. Endoscopic piece-meal resection (EMR) remains the standard technique for the endoscopic resection of large sessile colorectal adenomas. Cap-assisted EMR techniques show excellent long-term results in the endoscopic therapy of neoplastic Barrett's esophagus. For the endoscopic resection of early gastrointestinal cancers of more than 2 cm endoscopic submucosal dissection (ESD) is the method of choice. The value of endoscopic full thickness resection in the therapy of GI tumors remains to be seen. PMID- 27123725 TI - [Curative endoscopic therapy: which lesions can be addressed]. AB - Since the implementation of a nationwide screening colonoscopy the incidence of colorectal adenocarcinoma is decreasing, while the amount of early endoscopically resectable tumours is increasing. Similarly malignant tumors of the upper gastrointestinal tract are diagnosed and resected endoscopically more often. In part, this also depends on improvements in technology.The current guidelines of diagnosis and treatment of squamous carcinoma and adenocarcinoma of the esophagus, gastric cancer and colorectal cancer exactly define, which lesions can be endoscopically resected curatively. This mostly depends on the risc of metastases in regional lymph nodes. The risc of a lymphatic spread can be asessed by histopathological characteristics depending on the localisation of the lesion. Substantially, these characteristics comprise the depth of invasion in the resection specimen and the status at the resection margins after the endoscopic resection as well as the tumor subtype and the histological grading of the tumor. In addition, an infiltration in lymphatic or blood vessels has to be taken into account. PMID- 27123726 TI - [Minimally invasive endoscopic therapy of GI tumors - evidence and quality assurance aspects]. PMID- 27123727 TI - [How to do: Colonoscopy]. AB - Colonscopy is the examination of choice for the diagnostic of colorectal disease. Since 2002 it is part of the prevention programm for colorectalcancer in Germany. If you are aware of a few contraindications like acute bowel inflammation or respiratory insufficiency, the diagnostic colonoscopy is a safe procedure. Besides the experience of the examiner the bowel preparation is essential for the quality of the examination. If there are no contraindications the examination should be performed under sedation. To reach the coecum the beginner often needs to exercise patience but with sufficent anatomic background and some technically maneuver it can be done in most cases. The inspection of the mucosa at the withdrawal of the endoscope needs conscientiousness and enough time for an optimal result for the patient. PMID- 27123728 TI - [Recurrent seizures of unknown aetiology]. AB - History and admission findings | A 41year old woman presented at our internistic clinic after treatment by an emergency doctor because of confusion and amnesia accompanied by a hypoglycaemic episode while driving her car. Only by giving continuous glucose intravenously a stable clinical state could be achieved. In her medical history she took Lamotrigin for 12 years since she had seizures of unknown aetiology. 16 years ago she had similar sudden attacks with confusion and hypoglycaemia. At that time thorough diagnostics at the clinic for internal medicine did not reveal any evidence for hyperinsulinaemia. While taking Lamotrigin the patient had no seizures or similar symptoms for 12 years. Treatment and course | In the present case we detected a tumor in the pancreas and a two-fold increased insulin secretion. Histopathological work-up of the removed tissue confirmed the suspected diagnosis of insulinoma. Postoperatively, Lamotrigin treatment was terminated. Since then the patient remained asymptomatic. PMID- 27123729 TI - [Hematologic chest pain]. AB - HISTORY AND ADMISSION FINDINGS: We report the case of a 59-year-old male who was admitted to hospital with acute chest pain. Coronary heart disease was known from the medical history. The patient reported recurrent ostealgia and susceptibility for infection during the last months before admission. INVESTIGATIONS: A 75% stenosis of the circumflex branch was treated with a drug eluting stent. Platelet aggregation was inhibited with acetylsalicylic acid and clopidogrel. Due to persisting ostealgia and inflammatory state, spondylodiscitis was excluded in MRI. However, platelets remained low after successful treatment of the infection. DIAGNOSIS, TREATMENT AND COURSE: Bone marrow biopsy revealed an acute lymphoblastic leukemia with positive detection of the Philadelphia chromosome. After chemotherapy and allogenic hematopoietic cell transplantation the patient remains in remission of his acute lymphoblastic leukemia. CONCLUSIONS: Especially in patients with documented history of coronary heart disease, the differential diagnosis of chest pain can be challenging. In this case, the chest pain was based on a subacute coronary ischemia as well as on proliferation of the acute lymphoblastic leukemia. The management of dual oral anticoagulation was performed with higher transfusion limits for thrombocytes and continuous application of thrombocyte aggregation inhibitors. PMID- 27123730 TI - [Pain Management in geriatric patients]. AB - Pains belong to the most frequent reasons for a doctor's visit. In elderly people, it is the result of progressive degenerative processes (e. g. , arthrosis, Osteoarthritis, degenerative spinal changes) and a higher prevalence of cancer disease to a further increase of the patients who suffer unnecessarily from pains. By the increasing polymorbidity (e.g. diabetes mellitus, vascular disease) and a declining immune competence, the prevalence of polyneuropathy and post-herpetic neuralgia rises. Insufficiently treated chronic or periodically returning pain can lead to serious interferences of the physical, cognitive and social everyday competence and therefore to a limited quality of life. These facts shows the relevance of a sufficient pain therapy in geriatric patients. Nevertheless, on account of existing comorbidity, polypharmacy as well as of impaired organ function, the pharmacological pain therapy in old patients also poses a potential hazard. Although pain prevalence is higher with geriatric than with younger patients, significantly less analgesics are prescribed in the elderly population. This results from existing uncertainties at the treating doctors as well as the complicated pain capture, in particular with cognitive affected patients. The present article should indicate options of treatment for geriatric pain patients. PMID- 27123731 TI - [Update: Tuberculosis among adults in Germany]. AB - With an incidence of 5.6 / 100000, tuberculosis remains rare in Germany. However, for the first time since over 60 years, case numbers have began to increase since 2013. Therefore, knowledge of the clinical presentation as well as diagnostic and therapeutic approaches is important, specifically when caring for migrant patients. The broad use of molecular analyses will soon facilitate the choice of therapeutic regimens. Novel drugs already enable us to successfully treat also the increasing numbers of drug-resistant tuberculosis cases. PMID- 27123732 TI - [Prevention must become more efficient]. AB - The term "prevention" is used with several different meanings. Mistakes can be avoided by using different word for different contents. In addition to clear definitions the most frequent forms of bias have to be avoided. These forms are related to the five dimensions such as targets and endpoints as well as methods of screening, diagnostic, and finally treatment. Unless the appropriate items are selected in all five dimensions the results of the prevention strategy will not provide valid information. PMID- 27123733 TI - [Without health care proxy, no power of decision]. PMID- 27123734 TI - [Perspectives on advance directives among German intensive care physicians in leading positions]. AB - INTRODUCTION: Six years after introduction of a law for advance directives (AD) in 2009, AD are still discussed controversially. For the first time in Germany, this study investigates intensive care physicians' perspectives on implementation of AD, and corresponding experience of ethical issues. METHODS: A standardized questionnaire was sent to German hospitals with > 300 beds and anesthesiologist led intensive care units. The questionnaire was based on results of a previous qualitative study and was intended to be answered by one leading intensive care physician per hospital. RESULTS: N = 222/299 (74.2 % response) physicians answered the survey. Despite a number of reported problems regarding the implementation of AD, 70.6 % (n = 154/218) rated AD generally as helpful. 86.5 % (n = 185/214) would prefer a more goal-oriented approach to an intervention oriented approach to formulate AD. Furthermore 95.9 % (n = 207/216) plead for qualified professional counseling for intensive care topics in AD. Acceptance for interventions that equal termination of treatment can be perceived. Terminal extubation in correspondence with the patient's will is done in 79.4 % (n = 173/218) of hospitals, however 54.8 % (n = 113/206) of the physicians experience terminal extubations as burdening. DISCUSSION: Supporting concepts and measures will be necessary in order to prepare valid AD and to effectively improve implementation in intensive care practice. PMID- 27123735 TI - [Advance directive consultations - A study of selected consultation services in the Munich region]. AB - BACKGROUND: So far, advance directives (AD) are often used ineffectively in Germany. Counseling for advance directives is neither legally required nor are quality standards available. Little is known about the structure and content of the counseling offered by the many different providers. The goal of this study was to assess the current practice and possible improvements of AD consultations by different professional groups in the Munich region in Germany compared to international Advance Care Planning (ACP) programs as best practice models. METHODS: An explorative online survey (using the Likert scale) of general practitioners, notaries, nurses and hospice workers in the Munich area was conducted. The data were analyzed using SPSS and Excel. RESULTS: Content and structure of counseling services differ not only between but also within counseling groups, sometimes considerably. Consultations mostly last up to 60 minutes and included 1-2 sessions. Despite the fact that most counselors (46-79 % in the respective groups) favor routinely offered consultations, most counseling sessions are initiated by the consulted individuals themselves. Among other things, counseling sessions cover the topics of hydration (often / always [o / a] 69-97 %), permanent unconsciousness (o / a 48-94 %) and terminal illnesses (o / a 77-97 %). Especially the participation of future legal representatives in the counseling sessions (o / a 18-85 %), the drafting of emergency plans (0-45 %) and the completion of advance directives within the counseling session (29-51 %) was heterogeneous. CONCLUSIONS: The current counseling practice for advance directives varies considerably and does not yet reliably meet the best practice standards of ACP programs. This study thus underscores the need for comprehensive ACP programs. PMID- 27123740 TI - Finding the Right Candidate for the Right Position: A Fast NMR-Assisted Combinatorial Method for Optimizing Nucleic Acids Binders. AB - Development of strong and selective binders from promiscuous lead compounds represents one of the most expensive and time-consuming tasks in drug discovery. We herein present a novel fragment-based combinatorial strategy for the optimization of multivalent polyamine scaffolds as DNA/RNA ligands. Our protocol provides a quick access to a large variety of regioisomer libraries that can be tested for selective recognition by combining microdialysis assays with simple isotope labeling and NMR experiments. To illustrate our approach, 20 small libraries comprising 100 novel kanamycin-B derivatives have been prepared and evaluated for selective binding to the ribosomal decoding A-Site sequence. Contrary to the common view of NMR as a low-throughput technique, we demonstrate that our NMR methodology represents a valuable alternative for the detection and quantification of complex mixtures, even integrated by highly similar or structurally related derivatives, a common situation in the context of a lead optimization process. Furthermore, this study provides valuable clues about the structural requirements for selective A-site recognition. PMID- 27123741 TI - Pattern of employment and associated factors in long-term lymphoma survivors 10 years after high-dose chemotherapy with autologous stem cell transplantation. AB - Background This study examined employment patterns and associated factors in lymphoma survivors treated with high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT) from diagnosis to a follow-up survey at a mean of 10 years after HDT-ASCT. Patients and methods All lymphoma survivors aged >=18 years at HDT-ASCT in Norway from 1987 to 2008, and alive at the end of 2011 were eligible for this cross-sectional study performed in 2012/2013. Participants completed a mailed questionnaire. Job status was dichotomized as either employed (paid work) or not-employed (disability and retirement pension, on economic support, home-makers, or students). Results The response rate was 78%, and the sample (N = 312) contained 60% men. Mean age at HDT-ASCT was 44.3 and at survey 54.0 years. At diagnosis 85% of survivors were employed, 77% before and 77% after HDT-ASCT, and 58% at follow-up. Forty seven percent of the survivors were employed at all time points. The not-employed group at survey was significantly older and included significantly more females than the employed group. No significant between-group differences were observed for lymphoma-related variables. Fatigue, mental distress and type D personality were significantly higher among those not-employed, while quality of life was significantly lower compared to the employed group. Older age at survey, being female, work ability and presence of type D personality remained significantly related to being not employed at survey in the multivariable analysis. Conclusions Our findings show that not-employed long-term survivors after HDT-ASCT for lymphoma have more comorbidity, cognitive problems and higher levels of anxiety/depression than employed survivors. These factors should be checked and eventually treated in order to improve work ability. PMID- 27123742 TI - Cost effectiveness of pomalidomide in patients with relapsed and refractory multiple myeloma in Sweden. AB - BACKGROUND: Multiple myeloma (MM) patients who have progressed following treatment with both bortezomib and lenalidomide have a poor prognosis. In this late stage, other effective alternatives are limited, and patients in Sweden are often left with best supportive care. Pomalidomide is a new anti-angiogenic and immunomodulatory drug for the treatment of MM. Our objective was to evaluate the cost effectiveness of pomalidomide as an add-on to best supportive care in patients with relapsed and refractory MM in Sweden. MATERIAL AND METHODS: We developed a health-economic discrete event simulation model of a patient's course through stable disease and progressive disease, until death. It estimates life expectancy, quality-adjusted life years (QALYs) and costs from a societal perspective. Effectiveness data and utilities were taken from the MM-003 trial comparing pomalidomide plus low-dose dexamethasone with high-dose dexamethasone (HIDEX). Cost data were taken from official Swedish price lists, government sources and literature. RESULTS: The model estimates that, if a patient is treated with HIDEX, life expectancy is 1.12 years and the total cost is SEK 179 976 (?19 100), mainly indirect costs. With pomalidomide plus low-dose dexamethasone, life expectancy is 2.33 years, with a total cost of SEK 767 064 (?81 500), mainly in drug and indirect costs. Compared to HIDEX, pomalidomide treatment gives a QALY gain of 0.7351 and an incremental cost of SEK 587 088 (?62 400) consisting of increased drug costs (59%), incremental indirect costs (33%) and other healthcare costs (8%). The incremental cost-effectiveness ratio is SEK 798 613 (?84 900) per QALY gained. CONCLUSION: In a model of late-stage MM patients with a poor prognosis in the Swedish setting, pomalidomide is associated with a relatively high incremental cost per QALY gained. This model was accepted by the national Swedish reimbursement authority TLV, and pomalidomide was granted reimbursement in Sweden. PMID- 27123744 TI - A Practical Framework for Incentive-Based Cancer Prevention. PMID- 27123743 TI - Prospective clinical trial of hepatitis B vaccination in adults with and without type-2 diabetes mellitus. AB - : Objective: Patients with diabetes mellitus are at increased risk for hepatitis B virus (HBV) infection and its complications. HBV vaccination is recommended for adults with diabetes in the United States and other countries. However, few studies have assessed safety and immunogenicity of hepatitis B vaccine in such patients. We assessed the safety and immunogenicity of recombinant hepatitis B vaccine in subjects with and without diabetes mellitus. METHODS: Prospective, multi-country controlled study in 21 centers ( www.clinicaltrials.gov NCT01627340). Four hundred and sixteen participants with Type-2 diabetes and 258 controls matched for age and body mass index (BMI) (2:1 ratio) received 3-doses of HBV vaccine (Engerix-BTM, GSK Vaccines, Belgium) according to a 0, 1, 6 months schedule. Antibodies were measured against HBV surface antigen and expressed as seroprotection rates (anti-HBs >=10mIU/mL) and geometric mean concentration (GMC). RESULTS: The median age and BMI in patients with diabetes and controls (according-to-protocol cohort) were 54 y and 32.1 kg/m2, and 53 y and 30.8 kg/m2, respectively. Seroprotection rates (GMCs) one month post-dose-3 were 75.4% (147.6 mIU/mL) and 82.0% (384.2 mIU/mL) in patients with diabetes and controls, respectively. Age-stratified seroprotection rates for patients with diabetes were 88.5% (20-39 years), 81.2% (40-49 years), 83.2% (50-59 years), and 58.2% (>=60 years). The overall safety profile of hepatitis B vaccine was similar between groups. CONCLUSIONS: Hepatitis B vaccine is immunogenic in patients with diabetes and has a similar safety profile to vaccination in healthy controls. Because increasing age was generally associated with a reduction in seroprotection rates, hepatitis B vaccine should be administered as soon as possible after the diagnosis of diabetes. PMID- 27123745 TI - Right ventricular remodeling and updated left ventricular geometry classification: is there any relationship? AB - OBJECTIVE: We sought to evaluate right ventricular (RV) structure and function in hypertensive patients with various left ventricular (LV) geometric patterns using an updated classification for LV geometry. METHODS: This cross-sectional study included 232 hypertensive subjects. All the subjects underwent complete two dimensional (2D) and three-dimensional (3D) echocardiographic examination. Using LV mass index, LV end-diastolic diameter and relative wall thickness, according to the updated classification, all subjects were divided into six different groups: normal LV geometry, concentric remodeling, eccentric LV hypertrophy (LVH), concentric, dilated, and concentric-dilated LVH. RESULTS: RV wall thickness was increased in concentric and concentric-dilated LVH compared with normal LV geometry and LV concentric remodeling. RV longitudinal function was reduced in concentric and concentric-dilated patients compared with other hypertensive groups. 3D RV volumes were significantly higher in eccentric, dilated, and concentric-dilated LVH hypertensive subjects. Conversely, 3D RV ejection fraction was lower in these groups. CONCLUSION: RV longitudinal myocardial function and 3D RV function are significantly influenced by LV geometry in hypertensive patients. RV remodeling is the most pronounced in the patients with concentric, dilated, and concentric-dilated LVH geometric patterns. PMID- 27123746 TI - Suprasellar Hemangioblastoma Unrelated to von Hippel-Lindau Disease Successfully Treated through Extended Transsphenoidal Approach: Diagnostic Value of Von Hippel Lindau Disease Gene-Derived Protein. AB - Hemangioblastoma tends to occur in the infratentorial regions and rarely in the supratentorial regions. This tumor is strongly associated with von Hippel-Lindau disease (VHLD), especially in the supratentorial regions, with only 12 cases of suprasellar hemangioblastoma unrelated to VHLD. However, all these cases were diagnosed based on clinical screening and confirmation of family history. We report a case of suprasellar hemangioblastoma that was successfully removed through an extended transsphenoidal approach and diagnosed as a sporadic case unrelated to VHLD by immunohistochemical examination.A 67-year-old woman had mild diabetes insipidus and a visual field defect. Head magnetic resonance imaging revealed a suprasellar tumor compressing the optic chiasm upward. The tumor was totally removed without complication through an extended transsphenoidal approach. Postoperative histologic examination disclosed large vacuolated stromal cells and rich capillary networks, and the diagnosis was established as hemangioblastoma. Clinical screening and confirmation of family history revealed no specific results, and additional immunohistochemical staining showed diffuse cytoplasmic expression of anti-VHLD gene-derived protein (pVHL).We emphasize that pVHL immunohistochemical evaluation would be wise to adopt, especially for patients with a high risk of VHLD related to younger age and supratentorial lesions. PMID- 27123747 TI - Effect of Annular Defects on Intradiscal Pressures in the Lumbar Spine: An in Vitro Biomechanical Study of Diskectomy and Annular Repair. AB - Background Integrity of intervertebral disks may influence, and be influenced by, the maintenance of hydrostatic pressures inside the nucleus pulposus. Disk degeneration causes decreased pressures, leading to overload and injury of the annulus fibrosus, increasing the risk of disk herniation. Diskectomies to treat disk herniation can cause further loss of hydrostatic pressures resulting in worsening degeneration. This study investigated the impact of opening the annulus on intradiscal pressure and whether implantation of an annular closure device (ACD) can restore physiologic pressures. Methods The pressure responses under unconstrained moments in concert with axial compressive loads of nine human cadaver lumbar disks were biomechanically tested at baseline, immediately following posterior annulotomy, and immediately following implantation of the ACD. Results The analysis of variance indicated a significant difference in the pressure response (p = 0.0001) among the three rounds of testing. Specifically, the post hoc Bonferroni test revealed that the pressure response after diskectomy was significantly different when compared with baseline (p < 0.001) and after ACD implantation (p = 0.001). However, baseline and ACD pressure responses were insignificantly different (p = 1.000). Conclusion Our findings suggest that restoration of annular integrity during diskectomy with implantation of the tested ACD may restore pressures closer to preoperative levels. Whether or not restoring pressures to preoperative levels has any clinical benefit or effect on the rate of degeneration is an area for further clinical research. PMID- 27123748 TI - Comparison of Irrigation versus No Irrigation during Burr Hole Evacuation of Chronic Subdural Hematoma. AB - Objective To compare the results of the use of irrigation versus no irrigation during burr hole evacuation of chronic subdural hematoma (CSDH). Methodology The study was a retrospective chart review of those patients who underwent burr hole evacuation of CSDH during a period of 5 years. Cases were divided into two groups based on the use of irrigation during surgery. A subdural drain was placed in all patients (i.e., in both the irrigation and no-irrigation groups) and removed 24 to 48 hours postoperatively. Results The total sample size was 56, of which 34 patients were in the irrigation group and 22 in the no-irrigation group. Recurrence rate was 17.6% in the irrigation group and 9.1% in the no-irrigation group (p = 0.46). Systemic complications were predominantly cardiac related in the no-irrigation group compared with respiratory complications in the irrigation group. The irrigation group had a mortality rate of 5.9% compared with 4.5% in the no-irrigation group (p = 0.66). Conclusion No statistically significant difference was found between the two groups in terms of recurrence or mortality. PMID- 27123749 TI - Conformational Energy Landscape of the Ritonavir Molecule. AB - Conformational polymorphism of ritonavir, a well-known pharmaceutical drug, is intricately linked to its efficacy in the treatment of acquired immunodeficiency syndrome (AIDS). Polymorphic transition from the crystalline form I to form II leads to the loss of bioactivity. The constituent ritonavir molecules adopt a trans configuration about the carbamate torsion angle in the form I crystal, and a cis configuration in the form II crystal. Investigating the energetics and mechanistic features of conformational transitions at the single molecule level is a key step toward decoding the complex features of the solid state polymorphism. In this work, we employ the energy landscape framework to investigate the conformational transitions of an isolated ritonavir molecule. The landscape is explored using discrete path sampling (DPS) and visualized in terms of disconnectivity graphs. We identify two distinct funnels corresponding to the two molecular forms that are identified by crystallography. The two regions can be reliably distinguished using the carbamate torsion angle, and the corresponding interconversion rates are predicted to follow Arrhenius behavior. The results provide mechanistic insight into pathways for cis <-> trans interconversion at the molecular level and may also help in elucidating the polymorphic transitions in the crystal state. PMID- 27123750 TI - Bayesian dynamic mediation analysis. AB - Most existing methods for mediation analysis assume that mediation is a stationary, time-invariant process, which overlooks the inherently dynamic nature of many human psychological processes and behavioral activities. In this article, we consider mediation as a dynamic process that continuously changes over time. We propose Bayesian multilevel time-varying coefficient models to describe and estimate such dynamic mediation effects. By taking the nonparametric penalized spline approach, the proposed method is flexible and able to accommodate any shape of the relationship between time and mediation effects. Simulation studies show that the proposed method works well and faithfully reflects the true nature of the mediation process. By modeling mediation effect nonparametrically as a continuous function of time, our method provides a valuable tool to help researchers obtain a more complete understanding of the dynamic nature of the mediation process underlying psychological and behavioral phenomena. We also briefly discuss an alternative approach of using dynamic autoregressive mediation model to estimate the dynamic mediation effect. The computer code is provided to implement the proposed Bayesian dynamic mediation analysis. (PsycINFO Database Record PMID- 27123751 TI - Iodine-Catalyzed Oxidative Functionalization of Azaarenes with Benzylic C(sp(3)) H Bonds via N-Alkylation/Amidation Cascade: Two-Step Synthesis of Isoindolo[2,1 b]isoquinolin-7(5H)-one. AB - An efficient and practical iodine-catalyzed oxidative functionalization of azaarenes with benzylic C-H bonds via an N-alkylation and amidation cascade is developed to provide isoquinolin-1(2H)-ones. This method utilizes readily available unfunctionalized azaarenes and methylarenes as starting materials and proceeds under metal-free conditions with good to excellent yields, avoiding the use of expensive noble metal catalysts and generation of halide and metal wastes. The synthetic utility of this reaction is exemplified by the concise, two-step synthesis of isoindolo[2,1-b]isoquinolin-7(5H)-one. PMID- 27123752 TI - Single-Stranded Silencing RNAs: Hit Rate and Chemical Modification. AB - Single-stranded silencing RNAs (ss-siRNAs) are chemically modified single stranded oligomers that engage the RNA interference machinery normally used by duplex RNAs to silence gene expression. ss-siRNAs have the potential to combine advantages of antisense oligonucleotides and siRNAs. Previous work has explored the chemistry of the phosphate and the oligonucleotide body. We now describe the process of attempting to develop and optimize ss-siRNAs based on five active siRNA duplexes. Three of the sequences failed to show any activity as ss-siRNAs, and in two of those cases the ss-siRNAs showed significantly increased toxicity relative to the parent duplexes. For the two sequences that did work well as ss siRNAs, we show that the chemistry of the 3'-terminal dinucleotide also has a significant effect on the potency of ss-siRNAs. Previously published work on ss siRNAs has been based on a 2'-O-methoxyethyl-RNA (MOE) dinucleotide at the 3' terminus. To our surprise, oligomers containing 2'-O-Me-RNA modifications at the 3'-terminus showed significantly improved potency and activity relative to those modified with MOE at the same sites. Oligonucleotides with two locked nucleic acid units at the 3'-terminus showed improved activity over the MOE-modified analog for one sequence. Importantly, the fact that 2'-O-Me-RNA works so well makes the ss-siRNA approach accessible to a wider range of researchers since it can be achieved with inexpensive commercially available modifications. PMID- 27123753 TI - Anticipating syntax during reading: Evidence from the boundary change paradigm. AB - Previous evidence suggests that grammatical constraints have a rapid influence during language comprehension, particularly at the level of word categories (noun, verb, preposition). These findings are in conflict with a recent study from Angele, Laishley, Rayner, and Liversedge (2014), in which sentential fit had no early influence on word skipping rates during reading. In the present study, we used a gaze-contingent boundary change paradigm to manipulate the syntactic congruity of an upcoming noun or verb outside of participants' awareness. Across 3 experiments (total N = 148), we observed higher skipping rates for syntactically valid previews (The admiral would not confess . . .), when compared with violation previews (The admiral would not surgeon . . .). Readers were less likely to skip an ungrammatical continuation, even when that word was repeated within the same sentence (The admiral would not admiral . . .), suggesting that word-class constraints can take precedence over lexical repetition effects. To our knowledge, these results provide the first evidence for an influence of syntactic context during parafoveal word recognition. On the basis of the early time-course of this effect, we argue that readers can use grammatical constraints to generate syntactic expectations for upcoming words. (PsycINFO Database Record PMID- 27123754 TI - Semantic and plausibility preview benefit effects in English: Evidence from eye movements. AB - Theories of preview benefit in reading hinge on integration across saccades and the idea that preview benefit is greater the more similar the preview and target are. Schotter (2013) reported preview benefit from a synonymous preview, but it is unclear whether this effect occurs because of similarity between the preview and target (i.e., integration), or because of contextual fit of the preview synonyms satisfy both accounts. Studies in Chinese have found evidence for preview benefit for words that are unrelated to the target, but are contextually plausible (Yang, Li, Wang, Slattery, & Rayner, 2014; Yang, Wang, Tong, & Rayner, 2012), which is incompatible with an integration account but supports a contextual fit account. Here, we used plausible and implausible unrelated previews in addition to plausible synonym, antonym, and identical previews to further investigate these accounts for readers of English. Early reading measures were shorter for all plausible preview conditions compared to the implausible preview condition. In later reading measures, a benefit for the plausible unrelated preview condition was not observed. In a second experiment, we asked questions that probed whether the reader encoded the preview or target. Readers were more likely to report the preview when they had skipped the word and not regressed to it, and when the preview was plausible. Thus, under certain circumstances, the preview word is processed to a high level of representation (i.e., semantic plausibility) regardless of its relationship to the target, but its influence on reading is relatively short-lived, being replaced by the target word, when fixated. (PsycINFO Database Record PMID- 27123755 TI - Pseudoloma neurophilia Infection Combined with Gamma Irradiation Causes Increased Mortality in Adult Zebrafish (Danio rerio) Compared to Infection or Irradiation Alone: New Implications for Studies Involving Immunosuppression. AB - Gamma irradiation is commonly used as a bone marrow suppressant in studies of the immune system and hematopoiesis, most commonly in mammals. With the rising utility and popularity of the zebrafish (Danio rerio), gamma irradiation is being used for similar studies in this species. Pseudoloma neurophilia, a microparasite and common contaminant of zebrafish facilities, generally produces subclinical disease. However, like other microsporidia, P. neurophilia is a disease of opportunity and can produce florid infections with high morbidity and mortality, secondary to stress or immune suppression. In this study, we exposed zebrafish to combinations of P. neurophilia infection and gamma irradiation to explore the interaction between this immunosuppressive experimental modality and a normally subclinical infection. Zebrafish infected with P. neurophilia and exposed to gamma irradiation exhibited higher mortality, increased parasite loads, and increased incidences of myositis and extraneural parasite infections than fish exposed either to P. neurophilia or gamma irradiation alone. This experiment highlights the devastating effects of opportunistic diseases on immunosuppressed individuals and should caution researchers utilizing immunosuppressive modalities to carefully monitor their stocks to ensure that their experimental animals are not infected. PMID- 27123756 TI - Post-ischemic salubrinal treatment results in a neuroprotective role in global cerebral ischemia. AB - This study describes the neuroprotective effect of treatment with salubrinal 1 and 24 h following 15 min of ischemia in a two-vessel occlusion model of global cerebral ischemia. The purpose of this study was to determine if salubrinal, an enhancer of the unfolded protein response, reduces the neural damage modulating the inflammatory response. The study was performed in CA1 and CA3 hippocampal areas as well as in the cerebral cortex whose different vulnerability to ischemic damage is widely described. Characterization of proteins was made by western blot, immunofluorescence, and ELISA, whereas mRNA levels were measured by Quantitative PCR. The salubrinal treatment decreased the cell demise in CA1 at 7 days as well as the levels of matrix metalloprotease 9 (MMP-9) in CA1 and cerebral cortex at 48 h and ICAM-1 and VCAM-1 cell adhesion molecules. However, increases in tumor necrosis factor alpha and nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) inflammatory markers were observed at 24 h. Glial fibrillary acidic protein levels were not modified by salubrinal treatment in CA1 and cerebral cortex. We describe a neuroprotective effect of the post-ischemic treatment with salubrinal, measured as a decrease both in CA1 cell demise and in the blood-brain barrier impairment. We hypothesize that the ability of salubrinal to counteract the CA1 cell demise is because of a reduced ability of this structure to elicit unfolded protein response which would account for its greater ischemic vulnerability. Data of both treated and non-treated animals suggest that the neurovascular unit present a structure-dependent response to ischemia and a different course time for CA1/cerebral cortex compared with CA3. Finally, our study reveals a high responsiveness of endothelial cells to salubrinal in contrast to the limited responsiveness of astrocytes. The alleviation of ER stress by enhancing UPR with salubrinal treatment reduces the ischemic damage. This effect varies across the different neurovascular unit cell types. The salubrinal neuroprotective effect on CA1 supports differences in neurovascular unit for different brain regions and involves the inflammatory response and its time course. Thus, UPR modulation could be a therapeutic target in cerebral ischemia. PMID- 27123757 TI - Recent advances in immuno-oncology and its application to urological cancers. AB - Recent advances in immuno-oncology have the potential to transform the practice of medical oncology. Antibodies directed against negative regulators of T-cell function (checkpoint inhibitors), engineered cell therapies and innate immune stimulators, such as oncolytic viruses, are effective in a wide range of cancers. Immune'based therapies have had a clinically meaningful impact on the treatment of advanced melanoma, and the lessons regarding use of single agents and combinations in melanoma may be applicable to the treatment of urological cancers. Checkpoint inhibitors, cytokine therapy and therapeutic vaccines are already showing promise in urothelial bladder cancer, renal cell carcinoma and prostate cancer. Critical areas of future immuno-oncology research include the prospective identification of patients who will respond to current immune-based cancer therapies and the identification of new therapeutic agents that promote immune priming in tumours, and increase the rate of durable clinical responses. PMID- 27123758 TI - The Effects of Spacer Length and Composition on Aptamer-Mediated Cell-Specific Targeting with Nanoscale PEGylated Liposomal Doxorubicin. AB - Aptamer-based targeted drug delivery systems have shown significant promise for clinical applications. Although much progress has been made in this area, it remains unclear how PEG coating would affect the selective binding of DNA aptamers and thus influence the overall targeting efficiency. To answer this question, we herein report a systematic investigation of the interactions between PEG and DNA aptamers on the surface of liposomes by using a series of nanoscale liposomal doxorubicin formulations with different DNA aptamer and PEG modifications. We investigated how the spatial size and composition of the spacer molecules affected the targeting ability of the liposome delivery system. We showed that a spacer of appropriate length was critical to overcome the shielding from surrounding PEG molecules in order to achieve the best targeting effect, regardless of the spacer composition. Our findings provide important guidelines for the design of aptamer-based targeted drug delivery systems. PMID- 27123759 TI - Synthesis of isotopically labelled 2-isopropylthioxanthone from 2,2' dithiosalicylic acid and deuterium cumene. AB - Two efficient synthetic routes of stable deuterium labelled 2 isopropylthioxanthone were presented with 98.1% and 98.8% isotopic abundance in acceptable yields and excellent chemical purities. Their structures and the isotope-abundance were confirmed according to proton nuclear magnetic resonance and liquid chromatography-mass spectrometry. PMID- 27123760 TI - On confidence intervals for the hazard ratio in randomized clinical trials. AB - The log-rank test is widely used to compare two survival distributions in a randomized clinical trial, while partial likelihood (Cox, 1975) is the method of choice for making inference about the hazard ratio under the Cox (1972) proportional hazards model. The Wald 95% confidence interval of the hazard ratio may include the null value of 1 when the p-value of the log-rank test is less than 0.05. Peto et al. (1977) provided an estimator for the hazard ratio based on the log-rank statistic; the corresponding 95% confidence interval excludes the null value of 1 if and only if the p-value of the log-rank test is less than 0.05. However, Peto's estimator is not consistent, and the corresponding confidence interval does not have correct coverage probability. In this article, we construct the confidence interval by inverting the score test under the (possibly stratified) Cox model, and we modify the variance estimator such that the resulting score test for the null hypothesis of no treatment difference is identical to the log-rank test in the possible presence of ties. Like Peto's method, the proposed confidence interval excludes the null value if and only if the log-rank test is significant. Unlike Peto's method, however, this interval has correct coverage probability. An added benefit of the proposed confidence interval is that it tends to be more accurate and narrower than the Wald confidence interval. We demonstrate the advantages of the proposed method through extensive simulation studies and a colon cancer study. PMID- 27123761 TI - Ferromagnetism and Conductivity in Hydrogen Irradiated Co-Doped ZnO Thin Films. AB - Impressive changes in the transport and ferromagnetic properties of Co-doped ZnO thin films have been obtained by postgrowth hydrogen irradiation at temperatures of 400 degrees C. Hydrogen incorporation increases the saturation magnetization by one order of magnitude (up to ~1.50 MUB/Co) and increases the carrier density and mobility by about a factor of two. In addition to the magnetic characterization, the transport and structural properties of hydrogenated ZnO:Co have been investigated by Hall effect, local probe conductivity measurements, micro-Raman, and X-ray absorption spectroscopy. Particular care has been given to the detection of Co oxides and metal Co nanophases, whose influence on the increase in the transport and ferromagnetic properties can be excluded on the ground of the achieved results. The enhancement in ferromagnetism is directly related to the dose of H introduced in the samples. On the contrary, despite the shallow donor character of H atoms, the increase in carrier density n is not related to the H dose. These apparently contradictory effects of H are fully accounted for by a mechanism based on a theoretical model involving Co-VO (Co-O vacancy) pairs. PMID- 27123762 TI - Culturing conditions affect biological control activity of Trichoderma atroviride against Rhizoctonia solani in ryegrass. AB - AIMS: Effects of culture conditions on productivity, germinability and bioactivity of Trichoderma atroviride LU132 conidia were assessed to identify the factors affecting conidium 'fitness' (quantity and quality) and to withstand variable environmental conditions, increase conidial productivity, and perform optimum bioactivity. METHODS AND RESULTS: The interaction effects of temperatures (20 or 30 degrees C) vs hydrocarbon types (dextrose or sucrose in constant C : N 5 : 1) were assessed for bioactivity and colonization potential in pot experiments with ryegrass in the presence of pathogen, Rhizoctonia solani. Trichoderma atroviride produced in different culture conditions increased some growth parameters of ryegrass plant and also reduced the pathogenicity effects of R. solani. For example, Trichoderma colony produced at 20 degrees C with sucrose increased all plant growth parameters and conidia produced at 20 degrees C with dextrose gave the greatest bioactivity. CONCLUSION: The bimodal population cycle in T. atroviride recurred in pot experiments in a manner similar to that previously observed in agar plates but indicating that simulated natural conditions shortened the Trichoderma life cycle. Trichoderma colonized ryegrass root system and symbiotically interacted with ryegrass and greater ryegrass colonization resulted from medium production treatment with dextrose rather than sucrose. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report on the effects of inoculum production conditions on conidium quality of Trichoderma to colonize and to maintain populations in host rhizospheres, and also the ability to promote plant growth and suppress a soil-borne disease. The results of these experiments provide new knowledge on how manipulation of culture conditions of T. atroviride LU132 can influence conidium fitness, as a basis for optimizing commercial production of the fungus as a biological control agent. PMID- 27123763 TI - LCA case study on lawn establishment and maintenance with various peat and compost contents in substrates. AB - The environmental impacts of the establishment and maintenance of lawn, including the production and use of various substrates, were analyzed by life cycle assessment (LCA). The project focused on comparing substrates with different peat and compost contents using pilot substrates and developed a calculation tool to optimize landscaping from an ecological perspective. The impact categories were climate change, aquatic eutrophication, acidification, and use of primary energy. Life cycle assessment methodology and ISO standards 14040 and 14044 were used. Two thousand tons of substrates per hectare of lawn area were assumed to be needed; this large amount explains the importance of the substrate properties for all of the impact categories. Degradation of peat was the most significant factor of the influence of climate; thus, the most effective means of reducing the impact of landscaping on climate is to replace peat with compost. Nitrous oxide and methane emissions were related to the use of compost, but most of these emissions will occur regardless of how the sludge or biowaste is treated. Ammonia emissions from composting were the most important factor for acidification. The significance of fuel consumption by machinery in lawn establishment and mowing was low. The high contents of N and P in compost-based substrates may lead to high nutrient emissions into water systems, which can have significant local impact. The tool helps optimize substrate contents to minimize the environmental effects. Integr Environ Assess Manag 2016;12:459-464. (c) 2016 SETAC. PMID- 27123764 TI - The "Parade Blue": effects of short-term emission control on aerosol chemistry. AB - The strict control on emissions implemented in Beijing, China, during the 2015 China Victory Day Parade (V-day Parade) to commemorate the 70(th) Anniversary of Victory in World War II, provided a good opportunity to investigate the relationship between emission sources and aerosol chemistry in a heavily polluted megacity. From August 11 to September 3, 2015, an Aerosol Chemical Speciation Monitor was deployed in urban Beijing, together with other collocated instruments, for the real-time measurement of submicron aerosol characteristics. The average PM1 mass concentration was 11.3 (+/-6.7) MUg m(-3) during the V-day Parade, 63.5% lower than that before the V-day Parade. Differently to the relatively smaller decrease of organics (53%), secondary inorganic aerosols (sulfate, nitrate and ammonium) showed significant reductions of 65-78% during the V-day Parade. According to the positive matrix factorization results, primary organic aerosol (POA) from traffic and cooking emissions decreased by 41.5% during the parade, whereas secondary organic aerosol (SOA) presented a much greater reduction (59%). The net effectiveness of emission control measures was investigated further under comparable weather conditions before and during the parade. By excluding the effects of meteorological parameters, the total PM1 mass was reduced by 52-57% because of the emission controls. Although the mass concentrations of aerosol species were reduced substantially, the PM1 bulk composition was similar before and during the control period as a consequence of synergetic control of various precursors. The emission restrictions also suppressed the secondary formation processes of sulfate and nitrate, indicated by the substantially reduced SOR and NOR (molar ratios of sulfate or nitrate to the sums of the sulfate and SO2 or nitrate and NO2) during the event. The study also explored the influence of emission controls on the evolution of organic aerosol using the mass ratios of SOA/POA and oxygen-to-carbon ratios. The results showed that for northwesterly airflows, emission restrictions during the V-day Parade also reduced the oxidation degree of organic aerosol. PMID- 27123770 TI - Risk of neuroblastoma and residential proximity to industrial and urban sites: A case-control study. AB - BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children but its etiology is not clearly understood. While a small fraction of cases might be attributable to genetic factors, the role of environmental pollution factors needs to be assessed. OBJECTIVES: To ascertain the effect of residential proximity to both industrial and urban areas on neuroblastoma risk, taking into account industrial groups and toxic substances released. METHODS: We conducted a population-based case-control study of neuroblastoma in Spain, including 398 incident cases gathered from the Spanish Registry of Childhood Tumors (period 1996-2011), and 2388 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the respective subject's residences to the 1271 industries and the 30 urban areas with >=75,000 inhabitants located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1km to 5km) to industrial and urban pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. RESULTS: Excess risk (OR; 95%CI) of neuroblastoma was detected for the intersection between industrial and urban areas: (2.52; 1.20-5.30) for industrial distance of 1km, and (1.99; 1.17-3.37) for industrial distance of 2km. By industrial groups, excess risks were observed near 'Production of metals' (OR=2.05; 95%CI=1.16-3.64 at 1.5km), 'Surface treatment of metals' (OR=1.89; 95%CI=1.10-3.28 at 1km), 'Mines' (OR=5.82; 95%CI=1.04-32.43 at 1.5km), 'Explosives/pyrotechnics' (OR=4.04; 95%CI=1.31-12.42 at 4km), and 'Urban waste-water treatment plants' (OR=2.14; 95%CI=1.08-4.27 at 1.5km). CONCLUSIONS: These findings support the need for more detailed exposure assessment of certain substances released by these industries. PMID- 27123771 TI - Concentrations of organochlorine pesticides in umbilical cord blood and related lifestyle and dietary intake factors among pregnant women of the Huaihe River Basin in China. AB - Organochlorine pesticides (OCPs), one of the persistent organic pollutants (POPs) with highly lipophilic properties, long half-lives, and persistence in the environment, are prevalent in the environment even though they have been banned for >30years. We aimed to investigate the current OCP exposure levels in cord blood from healthy pregnant women residing in the Huaihe River Basin, China, and examined the association between OCP levels and dietary habits and lifestyle factors. In this study, we measured the exposure levels of 17 OCPs in the umbilical cord blood from 999 healthy pregnant women; we also administered 1000 self-reported questionnaires regarding the general characteristics and dietary habits of those women. Our results showed that rho,rho'-DDE, rho,rho'-DDT, aldrin, dieldrin, and methoxychlor, which had higher measured concentrations (2.01+/-1.89, 4.31+/-5.68, 7.29+/-8.74, 5.27+/-7.65, and 0.98+/-1.42ng/mL, respectively) and detection frequencies (99.69%, 100.00%, 81.79%, 75.00%, and 74.49%, respectively), were the predominant OCPs in cord blood, and the higher levels of DDTs, aldrin, dieldrin, and methoxychlor were mainly due to recent use. In addition, most of the HCHs in cord blood were derived not only from historical use of technical HCH, but also from the additional use of lindane. In addition, we found that the education level of the pregnant women and monthly household income were positively correlated with OCP levels, particularly rho,rho'-DDE, aldrin, and dieldrin. Furthermore, the consumption of red meat (pork, beef, and lamb), fish, and bean products may be an important contributing factor to the increased concentrations of OCPs in cord blood, while the intake of poultry and pickles was negatively correlated with aldrin level. This study is the first to provide adequate data on current OCP exposure levels in cord blood from pregnant women in the Huaihe River Basin. PMID- 27123772 TI - Incidence of Cervical Human Papillomavirus and Cervical Intraepithelial Neoplasia in Women with Positive and Negative HIV Status. AB - Objectives To evaluate the incidence and factors associated with cervical intraepithelial neoplasia (CIN) and cervical infection by human papillomavirus (HPV) among HIV-positive and HIV-negative women. Methods A cohort of 103 HIV positive and 113 HIV negative women were monitored between October 2008 and February 2012, for at least one year. Procedures included cervical cytology, DNA/HPV detection by polymerase chain reaction, colposcopy with biopsy if necessary, followed by an interview for exposure characteristics data. CIN was based on the histopathological results. Results The incidence of CIN was of 8.8 and 4.6 cases/100 women-years in HIV-positive and HIV-negative women, respectively. HIV-positive women presented a hazard ratio (HR) of 2.8 for CIN and developed lesions earlier (0.86 year) than HIV-negative women (2 years) (p = 0.01). The risk of developing CIN decreased with age (HR = 0.9) and marital status (HR = 0.4). HPV patients presented a higher incidence of CIN when compared HIV-positive and HIV-negative women (p = 0.01). The incidence of HPV cervical infection was 18.1 and 11.4 cases/100 women-years in HIV-positive and HIV negative women, respectively. Those HIV-positive presented earlier HPV infection(p = 0.002). The risk of developing HPV infection decreased with age and was higher among HIV-positive women. HPV 16 was the most common type in HIV positive women, and also the type most closely associated with CIN in HIV negative women. Conclusions HIV-positive women had a greater incidence of HPV and CIN, and in a shorter time interval. More rigorous and timely clinical control is required for this group. PMID- 27123773 TI - Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study. AB - PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311. PMID- 27123775 TI - Corrigendum. PMID- 27123774 TI - Structural Changes of a Doubly Spin-Labeled Chemically Driven Molecular Shuttle Probed by PELDOR Spectroscopy. AB - Gaining detailed information on the structural rearrangements associated with stimuli-induced molecular movements is of utmost importance for understanding the operation of molecular machines. Pulsed electron-electron double resonance (PELDOR) was employed to monitor the geometrical changes arising upon chemical switching of a [2]rotaxane that behaves as an acid-base-controlled molecular shuttle. To this aim, the rotaxane was endowed with stable nitroxide radical units in both the ring and axle components. The combination of PELDOR data and molecular dynamic calculations indicates that in the investigated rotaxane, the ring displacement along the axle, caused by the addition of a base, does not alter significantly the distance between the nitroxide labels, but it is accompanied by a profound change in the geometry adopted by the macrocycle. PMID- 27123776 TI - The association between maternal smoking and hyperemesis gravidarum: a meta analysis. AB - BACKGROUND: The majority of studies have not found hyperemesis to be a protective and some others have not. To date, no meta-analysis has quantitatively assessed the association between smoking and risk of hyperemesis gravidarum. To help close that research gap, we performed meta-analysis of the association between smoking and risk of hyperemesis gravidarum. METHODS: A literature search was carried out in PubMed, Web of Science, and Scopus from the earliest possible year to January 2016. The heterogeneity across studies was explored by Q-test and I2 statistic. The possibility of publication bias was assessed using Begg's and Egger's tests. The results were reported using odds ratio (OR) estimate with its 95% confidence intervals (CI) using a random-effects model. RESULTS: The literature search yielded 607 publications until January 2016 with 1 400 000 participants. Based on the random-effects model, compared to nonsmoker people, the estimated OR of hyperemesis gravidarum was 0.40 (95% CI: 0.24, 0.56). CONCLUSIONS: We showed based on reports in epidemiological studies that smoking before and during pregnancy is not a risk factor for hyperemesis gravidarum but also can reduce the risk of it. PMID- 27123777 TI - Anti N-methyl-D-aspartate receptor encephalitis: a game-changer? AB - INTRODUCTION: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an inflammatory disorder of the brain that has garnered significant interest within the medical and lay communities. There is a need for formal guidelines to assist physicians in identifying patients who should undergo testing for NMDAR encephalitis, recognizing the high potential for this potentially treatable disease to mimic more common disorders, and consequently remain undiagnosed. AREAS COVERED: This review highlights the impact of the discovery of NMDAR encephalitis on the fields of neurology and psychiatry, and discusses the steps that are necessary to improve recognition and treatment of NMDAR encephalitis. Expert commentary: While much progress has been made in our understanding of NMDAR encephalitis, much work remains to be done to delineate the underlying disease mechanisms and their relevance to brain function. PMID- 27123778 TI - Encapsulation of Formaldehyde and Hydrogen Cyanide in an Open-Cage Fullerene. AB - Reaction of C63 NO2 (Ph)2 (Py) (1) with o-phenylenediamine and pyridine produces a mixture of C63 H4 NO2 (Ph)2 (Py)(N2 C6 H4 ) (2) and H2 O@2. Compound 2 is a new open-cage fullerene containing a 20-membered heterocyclic orifice, which has been fully characterized by NMR spectroscopy, high-resolution mass spectrometry, and X ray crystallography. The elliptical orifice of 2 spans 7.45 A along the major axis and 5.62 A along the minor axis, which is large enough to trap water and small organic molecules. Thus, heating a mixture of 2 and H2 O@2 with hydrogen cyanide and formaldehyde in chlorobenzene affords HCN@2 and H2 CO@2, respectively. The (1) H NMR spectroscopy reveals substantial upfield shifts for the endohedral species (delta=-1.30 to -11.30 ppm), owing to the strong shielding effect of the fullerene cage. PMID- 27123779 TI - A Facile Molecular Precursor-based Synthesis of Ag2 Se Nanoparticles and Its Composites with TiO2 for Enhanced Photocatalytic Activity. AB - The reactions of different silver(I) reagents AgX (X(-) =iodide, trifluoroacetate, triflate) with selenoethers R2 Se (R=Me, tBu) in a variety of solvents were investigated in relation with their use as precursors for Ag2 Se nanomaterials. Different reaction conditions led to different reactivities and afforded either molecular complexes or metal selenide nanoparticles. The reactions leading to in situ formation of the metal selenide nanoparticles were then extended in the presence of commercial TiO2 (P25) to prepare silver selenide titania nanocomposites with different Ag/Ti ratios. These nanocomposites, well characterized by elemental analysis (Ag, Se), PXRD, TEM, BET, XPS and UV/Vis studies, were investigated as photocatalysts for the degradation of formic acid (FA) solution. The xAg2 Se-TiO2 nanocomposites (x=0.01, 0.13 and 0.25 mol %) exhibited a much higher catalytic activity as compared to P25, which is an established benchmark for the photocatalysis under UV light, and retained a good photocatalytic stability after recycling for several times. PMID- 27123780 TI - Expression of Mcl-1 and Ki-67 in Papillary Thyroid Carcinomas. AB - Studying molecules that are differentially expressed in cancers as well as benign and normal tissues is crucial for identifying novel biomarkers for cancer immunotherapy. This study aimed to investigate the clinical utility of the immunochemical expression of the proliferative cell marker Ki-67 and the apoptotic blocker Mcl-1 in papillary thyroid carcinoma (PTC). METHODS: We built a tissue microarray with 282 thyroid specimens. There were 59 PTCs including 35 classic (CPTC), 3 tall cell (TCPTC) and 21 follicular variants (FVPTC); 79 benign thyroid diseases (22 follicular adenomas; 57 adenomatoid hyperplasia); 33 Hashimoto's thyroiditis (HT) specimens; and 111 normal thyroid tissues. Clinical history and ultrasound data were retrospectively obtained by chart review. RESULTS: Mcl-1 overexpression was evident in 66.7% of the PTC tissues compared to 32% of the benign thyroid diseases. Mcl-1 strong staining distinguished benign from malignant thyroid lesions (sensitivity=61.3%; specificity=72.8%; negative predictive value, NPV=68%; positive predictive value, PPV=66.7% and 67.5% accuracy). Positive nuclear Ki-67 staining was observed in 34% of PTCs vs. 19% of thyroid adenomas (P=0.031). Strong Mcl-1 and Ki-67 co-expression was identified in 57.5% of PTCs with a higher PPV (75.8%). Mcl-1 and Ki-67 expression was not associated with any clinicopathological feature of malignancy. No deaths occurred during the follow-up. CONCLUSIONS: Mcl-1 immunochemical overexpression allowed differentiating low-risk PTC from the benign thyroid lesions. We suggest that Mcl 1 expression may help differentiate follicular patterned thyroid lesions. The influence of the Mcl-1 expression on several features of tumor aggressiveness has to be studied in large series of high-risk thyroid carcinomas. PMID- 27123781 TI - Lipid Accumulation Product: a Simple and Accurate Index for Predicting Metabolic Syndrome in Patients with Adult Growth Hormone Deficiency. AB - PURPOSE: It has been demonstrated that metabolic risk factors were increased in adult growth hormone deficiency (AGHD) patients. Lipid accumulation product (LAP) is a novel biomarker of central lipid accumulation related to risk of metabolic syndrome (MS), diabetes and cardiovascular disease. The aim of this study was to investigate the ability of LAP to identify MS in AGHD Patients. MATERIALS AND METHODS: In this cross-sectional study, 75 AGHD patients and 75 controls matched with age and gender were enrolled. The general anthropometries and blood biochemical indexes were measured. Body mass index(BMI), waist-hip ratio (WHR), LAP, HOMA-IR were calculated. Receiver operating characteristic (ROC) analysis was used to find out the cut-off points of LAP to predict MS. RESULTS: Compared with control group, waist circumference (WC), WHR, Systolic blood pressure (SBP), Diastolic blood pressure (DBP), total cholesterol (TC), triglyceride (TG) and LAP were increased in AGHD group, while high density lipoprotein cholesterol (HDL-c) level was lower in AGHD group (P<0.05). The prevalence of MS was 41.3% in AGHD patients. AGHD patients with MS had significantly higher LAP levels compared to those without MS. LAP was highly correlated with components of MS. ROC analysis showed that LAP was a significant discriminator for MS in AGHD patients, and the optimal cutoff point of LAP to predict MS was 44.96 (96.8% sensitivity, 86.4% specificity). CONCLUSIONS: LAP was associated with MS and had a strong and reliable diagnostic accuracy for MS in AGHD patients. PMID- 27123782 TI - The Impact of Dietary Factors on Glycemic Control, Insulin Sensitivity and Secretion in the First Years after Diagnosis of Diabetes. AB - BACKGROUND: Dietary factors play an important role in the prevention of diabetes mellitus. We tested the hypothesis that dietary factors related to diabetes onset also associate with its progression, i. e., early time courses of insulin sensitivity and secretion in both type 1 and type 2 diabetes. METHODS: In a prospective observational study, well-controlled recent-onset diabetes patients (n=127) underwent detailed metabolic characterization within the first year after diagnosis. A follow-up was conducted 2 years after the first examination. Insulin secretion and sensitivity were assessed by intravenous glucose tolerance testing. Baseline food consumption was analyzed by a food propensity questionnaire. Multivariate linear regression analysis was used to assess associations between consumption frequencies at baseline with metabolic changes during the first 2 years. RESULTS: Within the first 2 years, metabolic control did not change in patients with type 1 and type 2 diabetes on average. In type 1 diabetes, an increased consumption frequency of refined grains by one time/day at baseline associated with higher HbA1c by 0.60% (95% CI: 0.04; 1.16), P=0.04 after 2 years compared to baseline. In type 2 diabetes, an increased consumption frequency of meat/meat products by one time/day at baseline associated with lower beta-cell adaptation index (-7.25% (95% CI: -13.16; -0.93), P=0.03) after adjustment for age, sex, BMI, and changes of BMI and glucose-lowering medication. CONCLUSION: Dietary factors associate with the initial course of diabetes. Reduced consumption of refined grains in type 1 diabetes and of meat products in type 2 diabetes may contribute to preservation of insulin secretion and sensitivity. PMID- 27123783 TI - Peptide Binding Glucose Regulated Protein 78 Improves Type 1 Diabetes by Preventing Pancreatic beta Cell Apoptosis. AB - BACKGROUND AND OBJECTIVES: Diabetes Type 1 is characterized by hyperglycemia due to reduced insulin secretion that results from the death of pancreatic beta cells. It was suggested that endoplasmic reticulum (ER) stress is associated with the autoimmune-mediated beta cell destruction. Glucose regulated protein 78 (GRP78) functions as a key regulator to maintain the ER function. Under stress conditions GRP78 is up-regulated and expressed on the cell surface serving as a signaling receptor. Our first objective was to examine the effects of peptide binding cell surface GRP78 to reduce the deleterious effects of diabetes induced by streptozotocin. The second objective was to demonstrate the ability of the peptide to protect the pancreatic beta cells from apoptosis. METHODS: The effect of ADoPep on weight loss, HbA1c levels and anti GRP78 antibody titers was evaluated in a diabetes mouse model. The effect of ADoPep on the pancreatic beta Ins1E cell apoptosis was determined by FACS analysis. RESULTS: The administration of ADoPep to diabetic mice retained the weight loss and reduced HbA1c significantly in 60% of mice. Titers of anti GRP78 antibodies increased in 70% of the treated mice. Apoptosis was significantly inhibited in stressed pancreatic beta Ins 1E cells. CONCLUSIONS: We demonstrate that administration of the peptide ADoPep to diabetic mice improved type 1 diabetes by preventing pancreatic beta cell apoptosis. PMID- 27123784 TI - Atorvastatin Plus Metformin Confer Additive Benefits on Subjects with Dyslipidemia and Overweight/Obese via Reducing ROCK2 Concentration. AB - BACKGROUND: Atorvastatin and metformin both have pleiotropic effects. Whether atorvastatin combined with metformin could provide additive benefits on subjects with dyslipidemia and overweight/obese is unknown. And the mechanism is also not fully clear yet. METHODS: A cross-sectional research was performed and 130 subjects with dyslipidemia and overweight/obese were enrolled and randomly assigned into combined group (20 mg of atorvastatin daily plus 500 mg of metformin twice daily) and control group (20 mg of atorvastatin daily). At baseline and 8 weeks later, parameters of interest were recorded and fasting venous blood was drawn for laboratory examination. RESULTS: The rates of overweight (76.9% vs. 73.8%) and obese (23.1% vs. 26.2%) in both group were comparable. Dyslipidemia in both groups were featured by increased serum levels of triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Serum level of high sensitivity C-reactive protein (Hs-CRP) was comparably elevated in both groups at baseline, and leukocyte rho-associated kinase 2 (ROCK2) and serum nitric oxide (NO) concentrations were also comparable. Generally, the baseline characteristics between these 2 groups were no significant differences. 8 weeks later, compared to baseline, body mass index (BMI), the rates of overweight and obese, daily exercise time, smoking status, lipid profiles, Hs-CRP level, leukocyte ROCK2 and serum NO concentrations in both groups were improved. Notably, compared to control group, the rate of obese, Hs CRP level, leukocyte ROCK2 and serum NO concentrations were improved more profoundly in the combined group (p<0.05). After adjusted for age, gender, BMI, TG, LDL-C, Hs-CRP and exercise time, atorvastatin plus metformin was positively associated with serum NO concentration, with odds ratio (OR) of 1.146 (95% confidence interval (CI) 1.089-1.164, combined group vs. control group, p<0.05), and inversely associated with leukocyte ROCK2 concentration, with OR of 0.853 (95% CI 0.834-0.872, combined group vs. control group, p<0.05). CONCLUSION: In subjects with dyslipidemia and overweight/obese, atorvastatin plus metformin may confer additive benefits through reducing leukocyte ROCK2 concentration. PMID- 27123785 TI - Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels. AB - Recent studies have revealed strong associations between systemic trimethylamine N-oxide (TMAO) levels, atherosclerosis and cardiovascular risk. In addition, plasma L-carnitine levels in patients with high TMAO concentrations predicted an increased risk for cardiovascular disease and incident major adverse cardiac events. The aim of the present study was to investigate the relation between TMAO and L-carnitine plasma levels and diabetes. Blood plasma samples were collected from 12 and 20 weeks old db/db mice and patients undergoing percutaneous coronary intervention. Diabetic compared to non-diabetic db/L mice presented 10-fold higher TMAO, but lower L-carnitine plasma concentrations at 12 weeks of age. After 8 weeks of observation, diabetic db/db mice had significantly increased body weight, insulin resistance and TMAO concentration in comparison to non diabetic control. In 191 patients undergoing percutaneous coronary intervention the median (interquartile range) plasma concentration of TMAO was 1.8 (1.2-2.6) umol/L. Analysis of the samples showed a bivariate association of TMAO level with age, total cholesterol and L-carnitine. The multivariate linear regression analysis revealed that, in addition to L-carnitine as the strongest predictor of log transformed TMAO (p<0.001), the parameters of age, diabetes status and body mass index (BMI) were independently associated with increased log transformed TMAO levels (p<0.01).Our data provide evidence that age, diabetes and BMI are associated with higher TMAO levels independently of L-carnitine. These data support the hypothesis of TMAO as a cardiovascular risk marker and warrant further investigation of TMAO for diabetes research applications. PMID- 27123786 TI - A role for attention during wilderness navigation: Comparing effects of BDNF, KIBRA, and CHRNA4. AB - OBJECTIVE: To better understand what influences interindividual differences in ability to navigate in the wilderness, we hypothesized that better performance would be seen in (a) BDNF (rs6265) Val/Val homozygotes increased use of a spatial strategy, (b) KIBRA rs17070145 T/T homozygotes superior episodic memory, (c) CHRNA4 (rs1044396) T allele carriers better ability to focus visuospatial attention. METHOD: Military cadets (n = 382) genotyped for BDNF, KIBRA, and CHRNA4 SNPs used a map and compass to navigate in unmarked woods. Participants completed a morning course within 3.0 km and an afternoon course within 7.0 km. RESULTS: Success or failure in finding each point was analyzed in a logistic regression model with KIBRA, BDNF, and CHRNA4 genotypes as fixed effects. For the morning course, the adjusted odds ratio for the effect of KIBRA T/T over KIBRA C/C was 2.58 (95% CI of 1.31, 5.06) demonstrating a statistical benefit of the KIBRA T/T genotype over individuals with KIBRA C/C genotype. BDNF did not have an independent association with navigational success. For the afternoon course, the adjusted odds ratio for the effect of CHRNA4 C/T over C/C was 1.67 (95% CI of 1.24, 2.25) demonstrating a statistical benefit of CHRNA4 T allele carriers over the C/C genotype. CONCLUSIONS: Ability to navigate in the wilderness benefits less from sense of direction (BDNF and Santa Barbara Sense of Direction) and more from episodic memory (KIBRA) in the first course and heightened ability to focus attention (CHRNA4) after experience in the 2nd course. (PsycINFO Database Record PMID- 27123787 TI - Notes from the Field: Health Care-Associated Hepatitis A Outbreak - Texas, 2015. AB - On August 27-28, 2015, the Texas Department of State Health Services received calls from Fort Bend County and Harris County health departments requesting postexposure prophylaxis (PEP) recommendations for contacts of two nurses (patients A and B) with confirmed hepatitis A virus (HAV) infection. Both nurses had symptom onset during August 15-19 and worked for the same pediatric home health care agency in another jurisdiction. Because of the proximity of the onset dates, a common source exposure was suspected. The state and local health departments began an investigation to identify potentially exposed patients, their families, and other agency personnel; offer PEP; and identify the source of exposure. PMID- 27123788 TI - Autonomously Propelled Motors for Value-Added Product Synthesis and Purification. AB - A proof-of-concept design for autonomous, self-propelling motors towards value added product synthesis and separation is presented. The hybrid motor design consists of two distinct functional blocks. The first, a sodium borohydride (NaBH4 ) granule, serves both as a reaction prerequisite for the reduction of vanillin and also as a localized solid-state fuel in the reaction mixture. The second capping functional block consisting of a graphene-polymer composite serves as a hydrophobic matrix to attract the reaction product vanillyl alcohol (VA), resulting in facile separation of this edible value-added product. These autonomously propelled motors were fabricated at a length scale down to 400 MUm, and once introduced in the reaction environment showed rapid bubble-propulsion followed by high-purity separation of the reaction product (VA) by the virtue of the graphene-polymer cap acting as a mesoporous sponge. The concept has excellent potential towards the synthesis/isolation of industrially important compounds, affinity-based product separation, pollutant remediation (such as heavy metal chelation/adsorption), as well as localized fuel-gradients as an alternative to external fuel dependency. PMID- 27123789 TI - Understanding Solvent Manipulation of Morphology in Bulk-Heterojunction Organic Solar Cells. AB - Film morphology greatly influences the performance of bulk-heterojunction (BHJ) structure-based solar cells. It is known that an interpenetrating bicontinuous network with nanoscale-separated donor and acceptor phases for charge transfer, an ordered molecular packing for exciton diffusion and charge transport, and a vertical compositionally graded structure for charge collection are prerequisites for achieving highly efficient BHJ organic solar cells (OSCs). Therefore, control of the morphology to obtain an ideal structure is a key problem. For this solution-processing BHJ system, the solvent participates fully in film processing. Its involvement is critical in modifying the nanostructure of BHJ films. In this review, we discuss the effects of solvent-related methods on the morphology of BHJ films, including selection of the casting solvent, solvent mixture, solvent vapor annealing, and solvent soaking. On the basis of a discussion on interaction strength and time between solvent and active materials, we believe that the solvent-morphology-performance relationship will be clearer and that solvent selection as a means to manipulate the morphology of BHJ films will be more rational. PMID- 27123790 TI - Constraint-induced movement therapy as a rehabilitation intervention for upper extremity in stroke patients: systematic review and meta-analysis. AB - Constraint-induced movement therapy (CIMT) is a neurorehabilitation technique designed to improve upper extremity motor functions after stroke. This review aimed to investigate evidence of the effect of CIMT on upper extremity in stroke patients and to identify optimal methods to apply CIMT. Four databases (MEDLINE, EMBASE, CINHAL, and PEDro) and reference lists of relevant articles and reviews were searched. Randomized clinical trials that studied the effect of CIMT on upper extremity outcomes in stroke patients compared with other rehabilitative techniques, usual care, or no intervention were included. Methodological quality was assessed using the PEDro score. The following data were extracted for each trial: patients' characteristics, sample size, eligibility criteria, protocols of CIMT and control groups, outcome measurements, and the PEDro score. A total of 38 trials were identified according to the inclusion criteria. The trials included were heterogeneous in CIMT protocols, time since stroke, and duration and frequency of treatment. The pooled meta-analysis of 36 trials found a heterogeneous significant effect of CIMT on upper extremity. There was no significant effect of CIMT at different durations of follow-up. The majority of included articles did not fulfill powered sample size and quality criteria. The effect of CIMT changed in terms of sample size and quality features of the articles included. These meta-analysis findings indicate that evidence for the superiority of CIMT in comparison with other rehabilitative interventions is weak. Information on the optimal dose of CIMT and optimal time to start CIMT is still limited. PMID- 27123791 TI - Photoactivation of an Acid-Sensitive Ion Channel Associated with Vision and Pain. AB - We describe the reversible photoactivation of the acid sensitive ligand-gated ion channel ASIC2a, a mammalian channel found throughout the central and peripheral nervous systems that is associated with vision and pain. We also show the activation of GLIC, an acid-sensitive prokaryotic homologue of the nicotinic acetylcholine receptor. Photoactivation was achieved by using visible light irradiation of a newly synthesized water-soluble merocyanine photoacid, 1, which was designed to remove adverse channel blocking effects of a related system. Activation of ASIC2a and GLIC occurs reversibly, in a benign manner, and only upon irradiation. Further studies using transient absorption spectroscopy showed that protonation of a colorimetric base occurred rapidly (ca. 100 MUs) after excitation of 1. These results demonstrate that irradiation of 1 can induce rapid, local pH changes that can be used to investigate both biological and chemical proton transfer reactions. PMID- 27123793 TI - Dietary and Household Sources of Prenatal Exposure to Polybrominated Diphenyl Ethers (PBDEs) in the INMA Birth Cohort (Spain). AB - This study looked at predictors of exposure to polybrominated diphenyl ethers (PBDEs) with a focus on dietary and household-level factors. Concentrations of BDE-47, -99, -153, and -209 and their sum (?PBDEs) were measured in cord serum. Spanish women (n = 541) completed two semiquantitative food frequency questionnaires during the first and third trimesters of pregnancy. The daily mean intake (grams) of eggs, dairy products, meat, cereals and pasta, vegetables and pulses, fruits, shellfish and cephalopods, and fish, and the weekly mean intake (servings) of lean, large oily, other oily, and other fish from both questionnaires were averaged. Information on house size, curtains and carpets at home, mattress type, housekeeping frequency, and television use was also collected later in gestation. Multivariate censored regression was used to assess the association between PBDE concentration (log2 transformed) and potential predictors. BDE-47, -99, -209 and ?PBDE concentrations increased by 13.6%(95% CI:0.0, 29.0%), 21.1%(2.3, 43.5%), 21.7%(0.4, 47.5%) and 11.5%(2.2, 21.7%), respectively, per interquartile range increment in daily intake of shellfish and cephalopods. Fish intake was associated with BDE-99 (20.8%[1.7, 43.4%]). When fish was disaggregated by types, BDE-99 and ?PBDEs increased by 13.8%(4.0, 24.7%) and 5.7%(0.8, 10.8%), respectively, per 1-serving/week increment in large oily fish intake. BDE-153 was associated with higher housekeeping frequency (35.9%[0.4, 83.9%]) and BDE-209 with foam mattress use (48.9%[5.8, 109.7%]). In conclusion, seafood consumption, higher housekeeping frequency, and foam mattress were associated with prenatal PBDE exposure. PMID- 27123794 TI - The Economics of Autoclave-Based Sterilization: Experience from Central Sterile Supply Department of a Cancer Center in Eastern India. PMID- 27123792 TI - Prognostic Implications of Tumor Diameter in Association With Gene Expression Profile for Uveal Melanoma. AB - IMPORTANCE: Uveal melanoma (UM) can be divided into prognostically significant subgroups based on a prospectively validated and widely used 15-gene expression profile (GEP) test. Class 1 UMs have a low risk and class 2 UMs have a high risk for metastasis. OBJECTIVE: To determine whether any clinicopathologic factors provide independent prognostic information that may enhance the accuracy of the GEP classification. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational study performed at 2 ocular oncology referral centers included 339 patients in a primary cohort and 241 patients in a validation cohort. Both cohorts had a diagnosis of UM arising from the ciliary body and/or choroid. All patients underwent tumor biopsy for GEP prognostic testing. Clinicopathologic variables included patient age and sex, tumor thickness, largest basal tumor diameter (LBD), ciliary body involvement, and pathologic cell type. Patients from the primary cohort were enrolled from November 1, 1998, to March 16, 2012; from the validation cohort, from November 4, 1996, to November 7, 2013. Follow-up for the primary cohort was completed on August 18, 2013; for the validation cohort, December 10, 2013. Data were analyzed from November 12, 2013, to November 25, 2015. MAIN OUTCOME AND MEASURES: Progression-free survival (PFS). The secondary outcome was overall survival. RESULTS: The primary cohort included 339 patients (175 women [51.6%]; mean [SD] age, 61.8 [13.6] years). The most significant prognostic factor was GEP classification (exp[b], 10.33; 95% CI, 4.30-24.84; P < .001). The only other variable that provided independent prognostic information was LBD (exp[b], 1.13; 95% CI, 1.02-1.26; P = .02). Among class 2 UMs, LBD showed a modest but significant association with PFS (exp[b], 1.13; 95% CI, 1.04-1.24; P = .005). The 5-year actuarial metastasis-free survival estimates (SE) were 97% (3%) for class 1 UMs with LBD of less than 12 mm, 90% (4%) for class 1 UMs with LBD of at least 12 mm, 90% (9%) for class 2 UMs with LBD of less than 12 mm, and 30% (7%) for class 2 UMs with LBDs of at least 12 mm. The independent prognostic value of LBD and the 12-mm LBD cutoff were corroborated in the independent validation 241-patient cohort. CONCLUSIONS AND RELEVANCE: Class 2 UMs had better prognosis when the LBD was less than 12 mm at the time of treatment. These findings could have important implications for patient counseling, primary tumor treatment, clinical trial enrollment, metastatic surveillance, and adjuvant therapy. PMID- 27123795 TI - The Challenge of Pain Control. PMID- 27123796 TI - The Association Between Obesity and Hostility: The Mediating Role of Plasma Lipids. AB - OBJECTIVE: Recent research indicates an association between obesity and psychopathology status, the nature of which remains unclear. We evaluated the mediating role of biochemical disturbances in this association among a treatment seeking sample of obese individuals. METHOD: The study enrolled 143 consecutive overweight and obese individuals (mean age 35+/-9 y) and 143 normal-weight controls (mean age 34+/-9 y), matched by age and sex. We measured psychopathology features using the Symptom Checklist 90-Revised (SCL-90-R), a standardized self evaluation rating scale, and biochemical parameters (plasma cholesterol, triglyceride, and fasting glucose levels) of all participants. Nonlinear regression models were used to estimate the associations among obesity, psychopathology, and biochemical factors. RESULTS: Obesity was associated positively and significantly (P<0.05) with all of the SCL-90-R subscales, with the exception of anxiety and phobic anxiety, as well as with levels of plasma glucose, cholesterol (P<0.01), and triglycerides (P<0.001). Tests for mediation showed that obesity was significantly associated, for the mediators of plasma cholesterol [parameter estimate=-0.033, P<0.05] and triglycerides (parameter estimate=-0.059, P<0.05), only with hostility (parameter estimate=-0.024, P<0.05 and parameter estimate=-0.041, P<0.05, respectively). CONCLUSIONS: Our data suggest that biological substrates that are critically related to obesity, such as dyslipidemia, may mediate, at least in part, the association between obesity and hostility. PMID- 27123797 TI - Lithium or Valproate Adjunctive Therapy to Second-generation Antipsychotics and Metabolic Variables in Patients With Schizophrenia or Schizoaffective Disorder. AB - OBJECTIVE: People with schizophrenia are at greater risk for cardiovascular disease and their overall mortality rate is elevated compared to the general population. The metabolic side effects of antipsychotic medications have been widely studied; however, the effect of adding conventional mood stabilizers, such as lithium and valproate, to antipsychotic medication has not been assessed in terms of metabolic risk. The primary purpose of this secondary analysis was to examine whether treatment with lithium or valproate in addition to a second generation antipsychotic is associated with poorer metabolic outcomes than treatment with a second-generation antipsychotic without lithium or depakote. METHODS: Baseline data from 3 studies, which included measurement of body mass index, waist circumference, fasting glucose, insulin, homeostatic model assessment of insulin resistance, insulin sensitivity index, glucose utilization, and acute insulin response to glucose, were included in the analysis. RESULTS: No differences were found between those taking lithium or valproate and those who were not in terms of fasting glucose, fasting insulin, and homeostatic model assessment of insulin resistance. Insulin sensitivity was lower among participants taking lithium or valproate. Participants taking lithium or valproate had a higher body mass index than those not taking conventional mood stabilizers, although the difference did not reach statistical significance. CONCLUSIONS: These cross-sectional findings suggest it may be beneficial to monitor insulin sensitivity and body mass index in patients taking lithium or valproate in combination with a second-generation antipsychotic. PMID- 27123798 TI - Buprenorphine Prescribing: To Expand or Not to Expand. AB - As a result of the prescription opioid epidemic in the United States, there has been an increasing need for effective treatment interventions, both pharmacological and nonpharmacological. Buprenorphine has emerged as a critical component of the treatment of opioid use disorder, yet its adoption has not been without some concerns. This article first reviews the pharmacology, clinical use, and US legislative action related to buprenorphine, followed by a discussion of the misuse and diversion of buprenorphine in the United States as well as internationally. We then explore the impact of buprenorphine abuse as well as discussing strategies for its reduction, including changes in policy, prescription and pharmacy monitoring, and continuing medical education for guiding and improving clinical practice. PMID- 27123799 TI - Use of the Temperament and Character Inventory to Predict Response to Repetitive Transcranial Magnetic Stimulation for Major Depression. AB - OBJECTIVE: The goal of this study was to investigate the utility of the Temperament and Character Inventory (TCI) in predicting antidepressant response to repetitive transcranial magnetic stimulation (rTMS). BACKGROUND: Although rTMS of the dorsolateral prefrontal cortex is an established antidepressant treatment, little is known about predictors of response. The TCI measures multiple personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, self-transcendence, and cooperativeness), some of which have predicted response to pharmacotherapy and cognitive-behavioral therapy. A previous study suggested a possible association between self directedness and response to rTMS in melancholic depression, although this was limited by the fact that melancholic depression is associated with a limited range of TCI profiles. METHODS: Nineteen patients with a major depressive episode completed the TCI before a clinical course of rTMS over the dorsolateral prefrontal cortex. Treatment response was defined as >=50% decrease in scores on the Hamilton Rating Scale for Depression (Ham-D). Baseline scores on each TCI dimension were compared between responders and nonresponders through analysis of variance. Pearson correlations were also calculated for temperament/character scores in comparison with percentage improvement in Ham-D scores. RESULTS: Eleven of the 19 patients responded to rTMS. T-scores for persistence were significantly higher in responders than in nonresponders (P=0.022). Linear regression revealed a correlation between persistence scores and percentage improvement in Ham-D scores. CONCLUSIONS: Higher persistence scores predicted antidepressant response to rTMS. This may be explained by rTMS-induced enhancement of cortical excitability, which has been found to be decreased in patients with high persistence. Personality assessment that includes measurement of TCI persistence may be a useful component of precision medicine initiatives in rTMS for depression. PMID- 27123800 TI - Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 4: Case Report Data. AB - This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients who develop abnormal movements during treatment with antipsychotics. The first column in the series presented a patient who developed abnormal movements while being treated with aripiprazole as an augmentation strategy for major depressive disorder and reviewed data concerning the historical background, incidence, prevalence, and risk factors for tardive and spontaneous dyskinesias, the clinical presentations of which closely resemble each other. The second column in the series reviewed the unique mechanism of action of aripiprazole and reviewed preclinical studies and an early-phase human translational study that suggest a low, if not absent, risk of TD with aripiprazole. The third column in this series reviewed the registration trial data for aripiprazole across all of its indications and found a raw incidence of TD ranging from 0.004 (4 out of 987) in long-term studies of the drug as an augmentation strategy for major depressive disorder to 0.0016 (19 out of 11,897) based on all short-term (ie, weeks to <6 mo) and long-term (6 mo to 1 y) studies combined. This fourth column in the series reviews the "real world" data on aripiprazole and assesses whether these data also support the conclusion that aripiprazole has a low to absent risk of causing TD. The "real world" data consist of case reports from the medical literature and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We found 37 cases in the medical literature reporting what was termed TD in association with aripiprazole treatment as well as 27 case reports suggesting improvement in preexisting TD with aripiprazole treatment. On the basis of the case reports from the medical literature, the potential or raw incidence of TD during "real-world" treatment with aripiprazole was 0.0000062 (37 out of the 6 million individuals who had been treated with aripiprazole in the United States as of 2013 according to a report from Otsuka). A query of the FAERS yielded 312 cases of TD in which aripiprazole was the primary suspect. On the basis of the FAERS data and again assuming 6 million individuals exposed to aripiprazole, this yields a raw incidence of 0.000052 (312 out of 6 million) for TD in patients treated with aripiprazole. However, these estimates have limitations because they are based on anecdotal reports and pharmacovigilance data and, thus, the events themselves were not confirmed or verified in a systematic way. Further, the figure of 6 million people exposed to aripiprazole was based on data reported to the authors by the drug's manufacturer and only applies to exposure in the United States. The final column in this 5-part series will discuss the types of prohibitively expensive and logistically difficult studies that would be needed to determine whether a definitive causal relationship between aripiprazole and TD exists. PMID- 27123801 TI - Psychotherapy and its Role in Psychiatric Practice: A Position Paper. I. Psychiatry as a Psychobiological Discipline. AB - Economic, political, and ideological landscapes have impacted the practice of psychiatry throughout its evolution as a medical discipline. Despite enormous scientific advances over the course of the past century, many psychiatrists continue to operate with a split Cartesian picture of mind versus brain and entrenched ideological positions ranging from biological "chemical imbalance" to rigidly followed manualized psychotherapy approaches, both of which frequently result in fractured clinical care. With the impact of systemic economic and political pressures in Canada and the United States, the attention to the doctor patient relationship has taken a back seat to high-volume practices, computerized assessment tools, and the focus on evidence-based treatments for behaviorally defined syndromes in the Diagnostic and Statistical Manual of Mental Disorders that often come at the expense of the patient's experience of his or her illness. We spend much time teaching the next generation of psychiatrists what to prescribe versus how to prescribe; what manualized treatments to administer versus questioning why our patients engage in dysfunctional patterns of thinking, feeling, and relating to others, and what impact these patterns may have on their interaction with us in the here-and-now of the treatment setting. In this paper, we propose an integrative psychobiological model, in which biological interventions carry personal meanings, and relational transactions in the treatment setting are a form of learning that results in lasting physiological changes in the brain. Psychiatry needs to reconnect with its roots as a science of attachment and meaning, in which attention to the objective, subjective, and relational domains of the patient-provider experience is equally foundational for any successful treatment outcome. PMID- 27123802 TI - Atomoxetine-related Takotsubo Cardiomyopathy. AB - Many psychotropic medications target norepinephrine receptors, which can have serious cardiovascular implications, especially in the context of overdoses, polypharmacy, and high-risk populations. This article presents the case of a patient with adult attention-deficit/hyperactivity disorder who developed takotsubo cardiomyopathy subsequent to pharmacokinetic and pharmacodynamic interactions between atomoxetine, a selective norepinephrine reuptake inhibitor, and fluoxetine. Clinicians should be mindful of the potential for cardiovascular adverse effects when prescribing agents that target noradrenergic receptors. PMID- 27123804 TI - Commentary on 2 Cases of Takotsubo Cardiomyopathy Involving Psychotropic Medication. AB - Takotsubo cardiomyopathy, also known as Takotsubo syndrome (TTS), is a cardiac syndrome first described in Japan in 1990 that typically follows an acute physical or psychiatric stressor, hence its association with the terms "broken heart syndrome" and stress cardiomyopathy. Although it is relatively rare, occurring in only 0.02% of the general population and roughly 2% of patients with acute coronary syndrome, neurological or psychiatric disorders are present in over 50% of affected individuals. One of the major hypotheses regarding the pathophysiology of TTS involves a catecholamine surge, from stress directly, or in some cases from psychiatric medication used to relieve distress. Given the association of TTS with acute stress and psychiatric illness, psychiatrists may be involved in the care of patients with TTS either at the initial presentation of the condition or following recovery. The case reports presented in this issue exemplify these 2 scenarios: one case involves the development of TTS during treatment with atomoxetine, and the other case involves treatment of depression in a patient after recovery from TTS, as well as a TTS recurrence during treatment with fluoxetine. PMID- 27123803 TI - The Use of Fluoxetine in a Patient With Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy is an acute coronary syndrome that is believed to be brought on by stress. Symptoms, which are similar to an acute myocardial infarction, include chest pain, shortness of breath, arrhythmias, and cardiogenic shock, and the electrocardiogram often shows ST and T wave changes. Left ventricular wall hypokinesis along with a significantly reduced ejection fraction are seen on echocardiogram. The great majority of these symptoms all occur in the absence of occlusive disease. Many cases have been reported in which the development of takotsubo cardiomyopathy was associated with serotonin norepinephrine reuptake inhibitors and tricyclic antidepressants. However, no cases of takotsubo cardiomyopathy have been reported involving selective serotonin reuptake inhibitors. This article presents the case of a 51-year-old woman receiving stable therapy with fluoxetine who developed takotsubo cardiomyopathy after an acute stress. We also discuss the clinical presentation of takotsubo cardiomyopathy, review possible causes, and discuss the treatment of depressive symptoms in patients who are at increased risk of developing this illness. PMID- 27123805 TI - Efficacy of Baduanjin Exercise and Feasibility of Mobile Text Reminders on Follow up Participation in People With Severe Mental Illness: An Exploratory Study. AB - BACKGROUND: People with severe mental illness (SMI) frequently have poor physical health, which can in part be related to a low level of physical activity. The goal of this exploratory study was to examine the efficacy of a group participating in Baduanjin (a type of traditional Chinese exercise) on the health of individuals with SMI and the feasibility/acceptability of using short message service (SMS) reminder strategies to prompt continued exercise during a follow-up period. METHOD: Participants (N=11) participated in a Baduanjin group session for 8 weeks and then maintained home-based Baduanjin with SMS reminders for another 8 weeks. Physical and psychological tests were administered to participants. RESULTS: Significant improvements were found in balance and processing speed and in some domains of the 36-Item Short Form Health Survey (SF-36) after the Baduanjin program. Participants were able to maintain engagement in 80% of the expected practice time during the follow-up period. The acceptability of strategies to support home-based exercise, including SMS reminders, was high. CONCLUSIONS: This preliminary study suggested the efficacy of Baduanjin and the feasibility of SMS reminders in maintaining follow-up participation in people with SMI. Future studies using a larger sample size and a control group are needed to confirm the findings. PMID- 27123806 TI - An Examination of Incentive Strategies to Increase Participation in Outcomes Research for an Adolescent Inpatient Unit. AB - Tracking adolescent outcomes after inpatient hospitalization is important in informing clinical care for this age group, as inpatient care is one of the most expensive treatment modalities. This study examined 4 incentive strategies used to maintain adolescent participation in follow-up research (at 6, 12, and 18 mo) after their discharge from the hospital (N=267). A generalized estimation equation approach was taken to investigate whether different incentive strategies predicted adolescent completion of the follow-up assessments at each time point. Findings demonstrate that implementation of social worker contact significantly differed from other incentive strategies in increasing adolescent completion of follow-up assessments (Z=2.51, P=0.012) over the 3 time points, even when controlling for age and sex. Although these findings ultimately need to be confirmed through a randomized controlled study of incentive strategies, they provide preliminary support for the notion that relational incentives, such as maintaining contact with a member of the clinical team at the hospital, may be particularly important in promoting adolescent participation in outcomes research. PMID- 27123807 TI - Correction: Surface binding, localization and storage of iron in the giant kelp Macrocystis pyrifera. AB - Correction for 'Surface binding, localization and storage of iron in the giant kelp Macrocystis pyrifera' by Eric P. Miller et al., Metallomics, 2016, 8, 403 411. PMID- 27123808 TI - Computed Tomography Evaluation of Esophagogastric Necrosis After Caustic Ingestion. AB - BACKGROUND: Endoscopy is the standard of care for emergency patient evaluation after caustic ingestion. However, the inaccuracy of endoscopy in determining the depth of intramural necrosis may lead to inappropriate decision-making with devastating consequences. Our aim was to evaluate the use of computed tomography (CT) for the emergency diagnostic workup of patients with caustic injuries. METHODS: In a prospective study, we used a combined endoscopy-CT decision-making algorithm. The primary outcome was pathology-confirmed digestive necrosis. The respective utility of CT and endoscopy in the decision-making process were compared. Transmural endoscopic necrosis was defined as grade 3b injuries; signs of transmural CT necrosis included absence of postcontrast gastric/ esophageal wall enhancement, esophageal-wall blurring, and periesophageal-fat blurring. RESULTS: We included 120 patients (59 men, median age 44 years). Emergency surgery was performed in 24 patients (20%) and digestive resection was completed in 16. Three patients (3%) died and 28 patients (23%) experienced complications. Pathology revealed transmural necrosis in 9/11 esophagectomy and 16/16 gastrectomy specimens. Severe oropharyngeal injuries (P = 0.015), increased levels of blood lactate (P = 0.007), alanine aminotransferase (P = 0.027), bilirubin (P = 0.005), and low platelet counts (P > 0.0001) were predictive of digestive necrosis. Decision-making relying on CT alone or on a combined CT endoscopy algorithm was similar and would have spared 19 unnecessary esophagectomies and 16 explorative laparotomies compared with an endoscopy-alone algorithm. Endoscopy did never rectify a wrong CT decision. CONCLUSIONS: Emergency decision-making after caustic injuries can rely on CT alone. PMID- 27123809 TI - Ethical Recommendations for Video Recording in the Operating Room. PMID- 27123810 TI - Thermostability of Enzymes from Molecular Dynamics Simulations. AB - Thermodynamic stability is a central requirement for protein function, and one goal of protein engineering is improvement of stability, particularly for applications in biotechnology. Herein, molecular dynamics simulations are used to predict in vitro thermostability of members of the bacterial ribonuclease HI (RNase H) family of endonucleases. The temperature dependence of the generalized order parameter, S, for four RNase H homologues, from psychrotrophic, mesophilic, and thermophilic organisms, is highly correlated with experimentally determined melting temperatures and with calculated free energies of folding at the midpoint temperature of the simulations. This study provides an approach for in silico mutational screens to improve thermostability of biologically and industrially relevant enzymes. PMID- 27123813 TI - A Dual-Responsive Bola-Type Supra-amphiphile Constructed from a Water-Soluble Calix[4]pyrrole and a Tetraphenylethene-Containing Pyridine Bis-N-oxide. AB - Complexation between a water-soluble calix[4]pyrrole and a ditopic pyridine N oxide derivative in aqueous media produces a bola-type supra-amphiphile that self assembles to produce higher order morphologies, including multilamellar vesicles and micelles depending on the pH. The present bola-type supra-amphiphile exhibits strong fluorescence due to structural changes and aggregation induced by host guest complexation. The resulting structures may be used to recognize, encapsulate, and release non-fluorescent, water-soluble small molecules. PMID- 27123811 TI - Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin. AB - Hydroxychloroquine (HCQ) inhibits autophagy and therefore can sensitize some cancer cells to chemotherapy, but the high doses required limit its clinical use. Here we show that loading HCQ into liposomes (HCQ/Lip) decorated with a pH sensitive TH-RGD targeting peptide (HCQ/Lip-TR) can concentrate HCQ in B16F10 tumor cells and lysosomes. HCQ/Lip-TR was efficiently internalized as a result of its ability to bind ITGAV-ITGB3/integrin alphavbeta3 receptors highly expressed on the tumor cell surface and to undergo charge reversal from anionic at pH 7.4 to cationic at pH 6.5. Studies in vitro at pH 6.5 showed that the intracellular HCQ concentration was 35.68-fold higher, and lysosomal HCQ concentration 32.22 fold higher, after treating cultures with HCQ/Lip-TR than after treating them with free HCQ. The corresponding enhancements observed in mice bearing B16F10 tumors were 15.16-fold within tumor cells and 14.10-fold within lysosomes. HCQ/Lip-TR was associated with milder anemia and milder myosuppressive reductions in white blood cell and platelet counts than free HCQ, as well as less accumulation in the small intestine, which may reduce risk of intestinal side effects. In addition, co-delivering HCQ/Lip-TR with either free doxorubicin (DOX) or liposomal DOX improved the ability of DOX to inhibit tumor growth. Biochemical, electron microscopy and immunofluorescence experiments confirmed that HCQ/Lip-TR blocked autophagic flux in tumor cells. Our results suggest that loading HCQ into Lip-TR liposomes may increase the effective concentration of the inhibitor in tumor cells, allowing less toxic doses to be used. PMID- 27123812 TI - Designing helical peptide inhibitors of protein-protein interactions. AB - Short helical peptides combine characteristics of small molecules and large proteins and provide an exciting area of opportunity in protein design. A growing number of studies report novel helical peptide inhibitors of protein-protein interactions. New techniques have been developed for peptide design and for chemically stabilizing peptides in a helical conformation, which frequently improves protease resistance and cell permeability. We summarize advances in peptide crosslinking chemistry and give examples of peptide design studies targeting coiled-coil transcription factors, Bcl-2 family proteins, MDM2/MDMX, and HIV gp41, among other targets. PMID- 27123814 TI - Tracheal Smooth Muscle Cells Stimulated by Stem Cell Factor-c-Kit Coordinate the Production of Transforming Growth Factor-beta1 and Fibroblast Growth Factor-2 Mediated by Chemokine (C-C Motif) Ligand 3. AB - The aim of this study was to evaluate the mechanism involved in the stem cell factor (SCF)-induced production of fibroblast growth factor-2 (FGF-2), transforming growth factor-beta1 (TGF-beta1), and chemokine (C-C motif) ligand 3 (CCL3) in tracheal smooth muscle cells (tSMCs) and the signaling pathway involved in the process. tSMC primary cultures were stimulated with SCF and evaluated at 24 h. Cells treated with specific antibodies did not show any immunolabeling for cytokeratin or fibroblast activation protein, but were positive for alpha-smooth muscle actin, indicating the purity of the primary cell line. Western blot analysis showed constitutive phosphorylation of c-Kit, as well as increased total protein and phosphorylated c-Kit levels in tSMCs after SCF stimulation. Flow cytometry analysis also showed an increase in cell-surface c-Kit expression in the presence of SCF. SCF induced TGF-beta mRNA expression in tSMCs, as well as the production of TGF-beta1, CCL3, and FGF-2. Pretreatment with anti-CCL3 antibody blocked TGF-beta1 expression and partially inhibited FGF-2 production. On the other hand, anti-c-Kit antibody blocked TGF-beta1 expression and FGF-2 production. Thus, TGF-beta1 and FGF-2 production were mediated by CCL3 production through c-Kit. Pretreatment with mitogen-activated protein kinase kinase 1, p38, and Jun N-terminal kinase inhibitors showed that the effects mediated by SCF were involved with the modulation of mitogen-activated protein kinase (MAPK) pathways. Development of inhibitors targeting CCL3 through MAPK activation could thus be an attractive strategy to inhibit tSMC activation during asthma. PMID- 27123815 TI - Microbiology: the road to strain-level identification. PMID- 27123816 TI - A practical guide to hydrogels for cell culture. AB - There is growing appreciation of the role that the extracellular environment plays in regulating cell behavior. Mechanical, structural, and compositional cues, either alone or in concert, can drastically alter cell function. Biomaterials, and particularly hydrogels, have been developed and implemented to present defined subsets of these cues for investigating countless cellular processes as a means of understanding morphogenesis, aging, and disease. Although most scientists concede that standard cell culture materials (tissue culture plastic and glass) do a poor job of recapitulating native cellular milieus, there is currently a knowledge barrier for many researchers in regard to the application of hydrogels for cell culture. Here, we introduce hydrogels to those who may be unfamiliar with procedures to culture and study cells with these systems, with a particular focus on commercially available hydrogels. PMID- 27123818 TI - Detection of bacteria with molecular methods in prosthetic joint infection: sonication fluid better than periprosthetic tissue. AB - Background and purpose - The correct diagnosis of prosthetic joint infection (PJI) can be difficult because bacteria form a biofilm on the surface of the implant. The sensitivity of culture from sonication fluid is better than that from periprosthetic tissue, but no comparison studies using molecular methods on a large scale have been performed. We assessed whether periprosthetic tissue or sonication fluid should be used for molecular analysis. Patients and methods - Implant and tissue samples were retrieved from 87 patients who underwent revision operation of total knee or total hip arthroplasty. Both sample types were analyzed using broad-range (BR-) PCR targeting the 16S rRNA gene. The results were evaluated based on the definition of periprosthetic joint infection from the Workgroup of the Musculoskeletal Infection Society. Results - PJI was diagnosed in 29 patients, whereas aseptic failure was diagnosed in 58 patients. Analysis of sonication fluid using BR-PCR detected bacteria in 27 patients, whereas analysis of periprosthetic tissue by BR-PCR detected bacteria in 22 patients. In 6 of 7 patients in whom BR-PCR analysis of periprosthetic tissue was negative, low virulence bacteria were present. The sensitivity and specificity values for periprosthetic tissue were 76% and 93%, respectively, and the sensitivity and specificity values for sonication fluid were 95% and 97%. Interpretation - Our results suggest that sonication fluid may be a more appropriate sample than periprosthetic tissue for BR-PCR analysis in patients with PJI. However, further investigation is required to improve detection of bacteria in patients with so called aseptic failure. PMID- 27123817 TI - Measuring cell-generated forces: a guide to the available tools. AB - Forces generated by cells are critical regulators of cell adhesion, signaling, and function, and they are also essential drivers in the morphogenetic events of development. Over the past 20 years, several methods have been developed to measure these forces. However, despite recent substantial interest in understanding the contribution of these forces in biology, implementation and adoption of the developed methods by the broader biological community remain challenging because of the inherently multidisciplinary expertise required to conduct and interpret the measurements. In this review, we introduce the established methods and highlight the technical challenges associated with implementing each technique in a biological laboratory. PMID- 27123824 TI - Toward Virus-Like Surface Plasmon Strain Sensors. AB - The strong configuration dependence of collective surface plasmon resonances in an array of metal nanoparticles provides an opportunity to develop a bioinspired tool for sensing mechanical deformations in soft matter at the nanoscale. We study the feasibility of a strain sensor based on an icosahedral array of nanoparticles encapsulated by a virus capsid. When the system undergoes deformation, the optical scattering cross-section spectra as well as the induced electric field profile change. By numerical simulations, we examine how these changes depend on the symmetry and extent of the deformation and on both the propagation direction and polarization of the incident radiation. Such a sensor could prove useful in studies of the mechanisms of nanoparticle or virus translocation in the confines of a host cell. PMID- 27123825 TI - Phase shifts in circadian peripheral clocks caused by exercise are dependent on the feeding schedule in PER2::LUC mice. AB - Circadian rhythms are regulated by the suprachiasmatic nucleus (SCN) clock, which is the main oscillator and peripheral clock. SCN clock can be entrained by both photic and non-photic stimuli, and an interaction exists between photic and non photic entrainment. Moreover, peripheral circadian clocks can be entrained not only by scheduled restricted feeding, but also by scheduled exercise. Thus, the entrainment of peripheral circadian clocks may be the result of an interaction between the entrainment caused by feeding and exercise. In this study, we examined the effect of wheel-running exercise on the phase of the peripheral clocks (kidney, liver and submandibular gland) in PER2::LUC mice under various feeding schedules. Phase and waveforms of the peripheral clocks were not affected by voluntary wheel-running exercise. Exercise for a period of 4 h during the early dark period (morning) delayed the peripheral clocks, while exercise for the same duration during the late dark period (evening) advanced the peripheral clocks. The feeding phase was advanced and delayed by evening and morning exercise, respectively, suggesting that the feeding pattern elicited by the scheduled exercise may entrain the peripheral clocks. Exercise did not affect the phase of the peripheral clock under the 1 meal per day schedule. When the phase of the peripheral clocks was advanced by the feeding schedule of 2 or 4 meals per day during light and/or dark periods, wheel-running exercise during the morning period significantly and equally shifted the phase of all organs back to the original positions observed in mice maintained under free-feeding conditions and with no exercise. When the schedule of 2 meals per day during the dark period failed to affect the phase of peripheral clock, morning exercise did not affect the phase. Wheel-running exercise increased the levels of serum corticosterone, and the injection of dexamethasone/corticosterone instead of exercise shifted a phase that had advanced under the feeding schedule of 2 meals per day, back to the normal position. The liver and submandibular glands exhibit higher sensitivity to dexamethasone than the kidneys. In adrenalectomized mice, treadmill-induced normalization of the advanced phase under a feeding schedule of 2 meals per day was not observed. In summary, scheduled exercise-induced phase shifts were weaker compared to scheduled feeding-induced phase shifts. The phase advance caused by the feeding schedule of 2 or 4 meals per day was suppressed by wheel-running, treadmill exercise or dexamethasone/corticosterone injection in the early dark period (morning). Corticosterone release may be involved in exercise-induced phase shift of peripheral clocks. These results suggest that there is an interaction between the phase shifts caused by feeding and exercise schedules in peripheral clocks. PMID- 27123826 TI - Biofidelic white matter heterogeneity decreases computational model predictions of white matter strains during rapid head rotations. AB - The finite element (FE) brain model is used increasingly as a design tool for developing technology to mitigate traumatic brain injury. We developed an ultra high-definition FE brain model (>4 million elements) from CT and MRI scans of a 2 month-old pre-adolescent piglet brain, and simulated rapid head rotations. Strain distributions in the thalamus, coronal radiata, corpus callosum, cerebral cortex gray matter, brainstem and cerebellum were evaluated to determine the influence of employing homogeneous brain moduli, or distinct experimentally derived gray and white matter property representations, where some white matter regions are stiffer and others less stiff than gray matter. We find that constitutive heterogeneity significantly lowers white matter deformations in all regions compared with homogeneous properties, and should be incorporated in FE model injury prediction. PMID- 27123827 TI - Varenicline in Autism: Theory and Case Report of Clinical and Biochemical Changes. AB - OBJECTIVE: To explore the potential benefits of varenicline (CHANTIX(r)), a highly specific partial agonist of neuronal alpha4beta2 nicotinic acetylcholine receptors (nAChR), for autistic symptoms, and present resulting biochemical changes in light of dopamine-related genotype. METHODS: The clinical and biochemical changes exhibited by a 19-year-old severely autistic man following the use of low-dose varenicline in an ABA experiment of nature, and his genotype, were extracted from chart review. Clinical outcome was measured by the Ohio Autism Clinical Impression Scale and 12 relevant urine and saliva metabolites were measured by Neuroscience Laboratory. RESULTS: With varenicline, this patient improved clinically and autonomic biochemical indicators in saliva and urine normalized, including dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine, norepinephrine, taurine, and histamine levels. In addition, with varenicline, the dopamine D1 receptor (DRD1) antibody titer as well as the percent of baseline calmodulin-dependent protein kinase II (CaM KII) activity dropped significantly. When varenicline stopped, he deteriorated; when it was resumed, he again improved. Doses of 0.5, 1, and 2 mg daily were tried before settling on a dose of 1.5 mg daily. He has remained on varenicline for over a year with no noticeable side effects. CONCLUSION: This report is, to the best of our knowledge, only the second to demonstrate positive effects of varenicline in autism, the first to show it in a severe case, and the first to show normalization of biochemical parameters related to genotype. As with the previous report, these encouraging results warrant further controlled research before clinical recommendations can be made. PMID- 27123828 TI - Zebrafish as a model for acetylcholinesterase-inhibiting organophosphorus agent exposure and oxime reactivation. AB - The current research progression efforts for investigating novel treatments for exposure to organophosphorus (OP) compounds that inhibit acetylcholinesterase (AChE), including pesticides and chemical warfare nerve agents (CWNAs), rely solely on in vitro cell assays and in vivo rodent models. The zebrafish (Danio rerio) is a popular, well-established vertebrate model in biomedical research that offers high-throughput capabilities and genetic manipulation not readily available with rodents. A number of research studies have investigated the effects of subacute developmental exposure to OP pesticides in zebrafish, observing detrimental effects on gross morphology, neuronal development, and behavior. Few studies, however, have utilized this model to evaluate treatments, such as oxime reactivators, anticholinergics, or anticonvulsants, following acute exposure. Preliminary work has investigated the effects of CWNA exposure. The results clearly demonstrated relative toxicity and oxime efficacy similar to that reported for the rodent model. This review surveys the current literature utilizing zebrafish as a model for OP exposure and highlights its potential use as a high-throughput system for evaluating AChE reactivator antidotal treatments to acute pesticide and CWNA exposure. PMID- 27123829 TI - Over-expression of poplar transcription factor ERF76 gene confers salt tolerance in transgenic tobacco. AB - Ethylene response factors (ERFs) belong to a large plant-specific transcription factor family, which play a significant role in plant development and stress responses. Poplar ERF76 gene, a member of ERF TF family, can be up-regulated in response to salt stress, osmotic stress, and ABA treatment. The ERF76 protein was confirmed to be targeted preferentially in the nucleus of onion cell by particle bombardment. In order to understand the functions of ERF76 gene in salt stress response, we conducted temporal and spatial expression analysis of ERF76 gene in poplar. Then the ERF76 cDNA fragment containing an ORF was cloned from di-haploid Populus simonii*P. nigra and transferred into tobacco (Nicotiana tobacum) genome by Agrobacterium-mediated leaf disc method. Under salt stress, transgenic tobacco over-expressing ERF76 gene showed a significant increase in seed germination rate, plant height, root length, and fresh weight, as well as in relative water content (RWC), superoxide dismutase (SOD) activity, peroxidase (POD) activity, and proline content, compared to control tobacco lines. In contrast, transgenic tobacco lines displayed a decrease in malondialdehyde (MDA) accumulation, relative electrical conductivity (REC) and reactive oxygen species (ROS) accumulation in response to salt stress, compared to control tobacco lines. Over all, the results indicated that ERF76 gene plays a critical role in salt tolerance in transgenic tobacco. PMID- 27123830 TI - Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures: an individual participant data review. AB - BACKGROUND: Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001 and updated in 2013. OBJECTIVES: To review the time to withdrawal, remission and first seizure of phenytoin compared to valproate when used as monotherapy in people with partial onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (19 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2015, Issue 4), MEDLINE (1946 to 19 May 2015), SCOPUS (19 February 2013), ClinicalTrials.gov (19 May 2015), and WHO International Clinical Trials Registry Platform ICTRP (19 May 2015). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Outcomes were time to: (a) withdrawal of allocated treatment (retention time); (b) achieve 12-month remission (seizure-free period); (c) achieve six-month remission (seizure-free period); and (d) first seizure (post-randomisation). We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS: IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to partial onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes: HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes: HR > 1 indicates an advantage for valproate.The main overall results (pooled HR adjusted for seizure type) were time to: (a) withdrawal of allocated treatment 1.09 (95% CI 0.76 to 1.55); (b) achieve 12-month remission 0.98 (95% CI 0.78 to 1.23); (c) achieve six-month remission 0.95 (95% CI 0.78 to 1.15); and (d) first seizure 0.93 (95% CI 0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. We did not find any statistical interaction between treatment and seizure type (partial versus generalised). AUTHORS' CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies. PMID- 27123831 TI - Vertical integration of biochemistry and clinical medicine using a near-peer learning model. AB - Vertical integration has been extensively implemented across medical school curricula but has not been widely attempted in the field of biochemistry. We describe a novel curricular innovation in which a near-peer learning model was used to implement vertical integration in our medical school biochemistry course. Senior medical students developed and facilitated a case-based small group session for first year biochemistry students. Students were surveyed before and after the session on their attitudes about biochemistry, as well as the effectiveness of the session. Prior to the session, the students believed biochemistry was more important to understanding the basic science of medicine than it was to understanding clinical medicine or becoming a good physician. The session improved students' attitudes about the importance of biochemistry in clinical medicine, and after the session they now believe that understanding biochemistry is equally important to the basic sciences as clinical medicine. Students would like more sessions and believe the senior student facilitators were knowledgeable and effective teachers. The facilitators believe they improved their teaching skills. This novel combination of near-peer learning and vertical integration in biochemistry provided great benefit to both first year and senior medical students, and can serve as a model for other institutions. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44(6):507-516, 2016. PMID- 27123832 TI - Identification of TBK1 and IKKepsilon, the non-canonical IkappaB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes. AB - Persistent activation of NF-kappaB is a prerequisite for development of adult T cell leukemia-lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV 1). HTLV-1 genome encodes a viral transforming protein named Tax, which constitutively activates the canonical IkappaB kinases (IKK), the central regulator of NF-kappaB signaling. However, the role of the non-canonical IkappaB kinases, TBK1 and IKKepsilon, in the pathogenesis of HTLV-1-associated leukemia has not been evaluated. We here show that TBK1/IKKepsilon are crucial pro survival molecules by maintaining persistent activity of Stat3. Consistent with this finding, silencing Stat3 by the specific shRNA or by the chemical inhibitor ruxolitinib results in drastic impediment of leukemia cell growth. We further find that in HTLV-1-transformed T cells expressing Tax, TBK1 co-localizes with the canonical IkappaB kinases and Tax in the lipid raft microdomains. The wild type Tax, but not the Tax mutant defective in activating the canonical IKK, promotes the lipid raft translocation of TBK1. This phenomenon correlates with Tax activation of both NF-kappaB and Stat3. Tax does not interact directly with TBK1/IKKepsilon, and it rather engages a molecular crosstalk between the canonical IKKs and TBK1/IKKepsilon. Our data, therefore, demonstrate a key role of TBK1/IKKepsilon in the survival and proliferation of HTLV-1-transformed T cells and implicate a potential therapy targeting TBK1/IKKepsilon and Stat3 in controlling HTLV-1-mediated oncogenesis. PMID- 27123833 TI - Effectivity of a strategy in elderly AML patients to reach allogeneic stem cell transplantation using intensive chemotherapy: Long-term survival is dependent on complete remission after first induction therapy. AB - Intensive chemotherapy followed by allogeneic stem cell transplantation (alloSCT) can cure AML. Most studies on alloSCT in elderly AML report results of highly selected patient cohorts. Hardly any data exist on the effectiveness of prospective strategies intended to bring as many patients as possible to transplant. Between 2006 and 2011 we implemented a treatment algorithm for all newly diagnosed AML patients aged 61-75 years, consisting of intensive chemotherapy cycles to induce complete remission, followed by alloSCT. 44 of 60 (73%) newly diagnosed elderly AML patients started with chemotherapy. By meticulously following our algorithm in almost all patients, we could induce complete remission (CR) in 66% of patients starting with chemotherapy, and transplant 32% of these patients in continuous CR. Main reasons for failure were early relapse (16%), early death (14%), primary refractory disease (9%), and patient or physician decision to stop treatment (16%). Patients in continuous CR after first induction benefit most with 36% long-term survival. Patients not in CR after first induction benefit less; although additional chemotherapy induces CR in 45% of these patients, only 23% are transplanted and no long-term survival is observed, mainly due to relapse. Long-term survival in the group of 44 patients is 9% (median 4.5 years after alloSCT). Considering that 27% of patients do not start with chemotherapy and 64% of patients starting with chemotherapy do not reach alloSCT, the reasons for failure presented here should be used as a guide to develop new treatment algorithms to improve long-term survival in elderly AML patients. PMID- 27123845 TI - Beyond Correlation in the Detection of Climate Change Impacts: Testing a Mechanistic Hypothesis for Climatic Influence on Sockeye Salmon (Oncorhynchus nerka) Productivity. AB - Detecting the biological impacts of climate change is a current focus of ecological research and has important applications in conservation and resource management. Owing to a lack of suitable control systems, measuring correlations between time series of biological attributes and hypothesized environmental covariates is a common method for detecting such impacts. These correlative approaches are particularly common in studies of exploited fish species because rich biological time-series data are often available. However, the utility of species-environment relationships for identifying or predicting biological responses to climate change has been questioned because strong correlations often deteriorate as new data are collected. Specifically stating and critically evaluating the mechanistic relationship(s) linking an environmental driver to a biological response may help to address this problem. Using nearly 60 years of data on sockeye salmon from the Kvichak River, Alaska we tested a mechanistic hypothesis linking water temperatures experienced during freshwater rearing to population productivity by modeling a series of intermediate, deterministic relationships and evaluating temporal trends in biological and environmental time series. We found that warming waters during freshwater rearing have profoundly altered patterns of growth and life history in this population complex yet there has been no significant correlation between water temperature and metrics of productivity commonly used in fisheries management. These findings demonstrate that pairing correlative approaches with careful consideration of the mechanistic links between populations and their environments can help to both avoid spurious correlations and identify biologically important, but not statistically significant relationships, and ultimately producing more robust conclusions about the biological impacts of climate change. PMID- 27123834 TI - The miR-17~92 cluster contributes to MLL leukemia through the repression of MEIS1 competitor PKNOX1. AB - Mixed lineage leukemias have a relatively poor prognosis and arise as a result of translocations between the MLL(KMT2A) gene and one of multiple partner genes. Downstream targets of MLL are aberrantly upregulated and include the developmentally important HOX genes and MEIS1, as well as multiple microRNAs (miRNAs), including the miR-17~92 cluster. Here we examined the contribution of specific miRNAs to MLL leukemias through knockdown studies utilizing custom anti microRNA oligonucleotides. Combinatorial treatment against miR-17-5p and miR-19a 3p of the miR-17~92 cluster dramatically reduces colony forming ability of MLL fusion containing cell lines relative to non-MLL acute myeloid leukemia (AML) controls. To determine the mechanism by which these miRNAs contribute to leukemia, we validated PKNOX1 as a target of both miR-17-5p and miR-19a-3p. MEIS1 and PKNOX1 are TALE domain proteins that participate in ternary complexes with HOX and PBX partners. Here we establish the competitive relationship between PKNOX1 and MEIS1 in PBX-containing complex formation and determine the antagonistic role of PKNOX1 to leukemia in a murine MLL-AF9 model. These data implicate the miR-17~92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLL leukemia, indicating that targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen. PMID- 27123846 TI - Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, ranging from simple steatosis to cirrhosis. However, simple steatosis (SS) and steatohepatitis (NASH) cannot yet be distinguished by clinical or laboratory features. The aim of this study was to assess the relationship between alpha-ketoglutarate and the degrees of NAFLD in morbidly obese patients. MATERIALS AND METHODS: We used a gas chromatography-quadruple time-of-flight-mass spectrometry analysis to quantify alpha-ketoglutarate in serum from normal-weight subjects (n = 30) and morbidly obese women (n = 97) with or without NAFLD. RESULTS: We found that serum levels of alpha-ketoglutarate were significantly higher in morbidly obese women than in normal-weight women. We showed that circulating levels of alpha-ketoglutarate were lower in lean controls and morbidly obese patients without NAFLD. We also found that alpha-ketoglutarate serum levels were higher in both SS and NASH than in normal liver of morbidly obese patients. However, there was no difference between SS and NASH. Moreover, we observed that circulating levels of alpha-ketoglutarate were associated with glucose metabolism parameters, lipid profile, hepatic enzymes and steatosis degree. In addition, diagnostic performance of alpha-ketoglutarate has been analyzed in NAFLD patients. The AUROC curves from patients with liver steatosis exhibited an acceptable clinical utility. Finally, we showed that the combination of biomarkers (AST, ALT and alpha-ketoglutarate) had the highest accuracy in diagnosing liver steatosis. CONCLUSION: These findings suggest that alpha ketoglutarate can determine the presence of non-alcoholic fatty liver in morbidly obese patients but it is not valid a biomarker for NASH. PMID- 27123849 TI - Effect of Different Firing Temperatures on Structural Changes in Porcelain. AB - PURPOSE: To study the structural changes occurring in the dental porcelain mass fired at various firing temperatures using scanning electron microscopy (SEM) and X-ray diffraction (XRD) spectroscopy. Also, additional tests, namely compressive strength, abrasion resistance analysis, and the amount of oxides released, were conducted at different firing temperatures. MATERIALS AND METHODS: Six groups (40 specimens in each group) of porcelain mass were prepared. The dimensions and weight of all the specimens were kept constant. The specimens were then heat treated at different firing temperatures (660 degrees C, 760 degrees C, 860 degrees C, 900 degrees C, 960 degrees C, 990 degrees C). Half of the specimens of each group were subjected to a compressive strength test on a universal testing machine and then finely ground using an electrochemical grinder to prepare for XRD analysis. The other half of the specimens was weighed to analyze the amount of oxides released after each firing cycle. Following this, the specimens underwent an abrasion resistance test on a Nanovea Tribometer. The unaltered surface was scanned using SEM. The data (numerical and graphical) for all the tests were recorded and analyzed using one-way ANOVA and post hoc Tukey test. RESULTS: The specimens fired at 900 degrees C exhibited superior compressive strength and abrasion resistance. The quantity of oxides released by the specimens fired at 900 degrees C was the least compared to specimens heat treated at the other firing temperatures. XRD analysis proved that the oxide released by the porcelain mass was calcium aluminum chromium oxide. Also, the fewer peaks obtained in the XRD graphs of specimens fired at 900 degrees C signified lesser porosities in the porcelain specimens. SEM analysis depicted a homogeneous mass of porcelain at 900 degrees C. CONCLUSION: All the above findings validate the objective of studying the physical and internal structural changes of dental porcelain when subjected to an increasing firing temperature gradient. The specimens fired at 900 degrees C exhibited superior strength and abrasion resistance. SEM analysis depicted a homogeneous mass of dental porcelain, implying that firing was complete at 900 degrees C. PMID- 27123847 TI - Rotenone Susceptibility Phenotype in Olfactory Derived Patient Cells as a Model of Idiopathic Parkinson's Disease. AB - Parkinson's disease is a complex age-related neurodegenerative disorder. Approximately 90% of Parkinson's disease cases are idiopathic, of unknown origin. The aetiology of Parkinson's disease is not fully understood but increasing evidence implies a failure in fundamental cellular processes including mitochondrial dysfunction and increased oxidative stress. To dissect the cellular events underlying idiopathic Parkinson's disease, we use primary cell lines established from the olfactory mucosa of Parkinson's disease patients. Previous metabolic and transcriptomic analyses identified deficiencies in stress response pathways in patient-derived cell lines. The aim of this study was to investigate whether these deficiencies manifested as increased susceptibility, as measured by cell viability, to a range of extrinsic stressors. We identified that patient derived cells are more sensitive to mitochondrial complex I inhibition and hydrogen peroxide induced oxidative stress, than controls. Exposure to low levels (50 nM) of rotenone led to increased apoptosis in patient-derived cells. We identified an endogenous deficit in mitochondrial complex I in patient-derived cells, but this did not directly correlate with rotenone-sensitivity. We further characterized the sensitivity to rotenone and identified that it was partly associated with heat shock protein 27 levels. Finally, transcriptomic analysis following rotenone exposure revealed that patient-derived cells express a diminished response to rotenone-induced stress compared with cells from healthy controls. Our cellular model of idiopathic Parkinson's disease displays a clear susceptibility phenotype to mitochondrial stress. The determination of molecular mechanisms underpinning this susceptibility may lead to the identification of biomarkers for either disease onset or progression. PMID- 27123848 TI - The Effects of Psycho-Emotional and Socio-Economic Support for Tuberculosis Patients on Treatment Adherence and Treatment Outcomes - A Systematic Review and Meta-Analysis. AB - BACKGROUND: There is uncertainty about the contribution that social support interventions (SSI) can have in mitigating the personal, social and economic costs of tuberculosis (TB) treatment on patients, and improving treatment outcomes. OBJECTIVE: To identify psycho-emotional (PE) and socio-economic (SE) interventions provided to TB patients and to assess the effects of these interventions on treatment adherence and treatment outcomes. SEARCH STRATEGY: We searched PubMed and Embase from 1 January 1990-15 March 2015 and abstracts of the Union World Conference on Lung Health from 2010-2014 for studies reporting TB treatment adherence and treatment outcomes following SSI. SELECTION CRITERIA: Studies measuring the effects of PE or SE interventions on TB treatment adherence, treatment outcomes, and/or financial burden. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed titles and abstracts for inclusion of articles. One reviewer reviewed full text articles and the reference list of selected studies. A second reviewer double checked all extracted information against the articles. MAIN RESULTS: Twenty-five studies were included in the qualitative analysis; of which eighteen were included in the meta-analysis. Effects were pooled from 11 Randomized Controlled Trials (RCTs), including 9,655 participants with active TB. Meta-analysis showed that PE support (RR 1.37; CI 1.08-1.73), SE support (RR 1.08; CI 1.03-1.13) and combined PE and SE support (RR 1.17; CI 1.12-1.22) were associated with a significant improvement of successful treatment outcomes. Also PE support, SE support and a combination of these types of support were associated with reductions in unsuccessful treatment outcomes (PE: RR 0.46; CI 0.22-0.96, SE: RR 0.78; CI 0.69-0.88 and Combined PE and SE: RR 0.42; CI 0.23-0.75). Evidence on the effect of PE and SE interventions on treatment adherence were not meta-analysed because the interventions were too heterogeneous to pool. No evidence was found to show whether SE reduced the financial burden for TB patients. DISCUSSION AND CONCLUSIONS: Our review and meta analysis concluded that PE and SE interventions are associated with beneficial effects on TB treatment outcomes. However, the quality of evidence is very low and future well-designed evaluation studies are needed. PMID- 27123850 TI - Developing a Valuation Function for the Preference-Based Multiple Sclerosis Index: Comparison of Standard Gamble and Rating Scale. AB - OBJECTIVE: The standard gamble (SG) and rating scale (RS) are two approaches that can be employed to elicit health state preferences from patients in order to inform decision making. The objectives of this study were: (i) to contribute evidence towards the similarities and differences in the SG and the RS to reflect patient preferences, and (ii) to develop a multi-attribute utility function (MAUF) (i.e., scoring algorithm) for the PBMSI. STUDY DESIGN: Two samples were recruited for the study. The first sample provided cross-sectional data to generate the preference weights which were then used to develop (D) the MAUFD. The distribution of SG and RS were compared across levels of perceived difficulty. The second sample provided additional data to validate (V) the MAUF, termed MAUFV. RESULTS: The mean RS values ranged from 0.39 to 0.65, whereas the mean SG values were much higher ranging from 0.80 to 0.91. Correlations between the two methods were very low ranging from -0.29 to 0.15. Bland-Altman plots revealed the extent of differences in values produced by the two methods. CONCLUSION: In contemplating trade-offs in the selection of a preference-based elicitation approach for a MAUF that could guide clinical decision making, results suggest the RS is preferable in terms of feasibility and validity for MS patients. The PBMSI with patient preferences shows promise as a measure of health related quality of life for MS. PMID- 27123851 TI - Toll-Like Receptor 1/2 and 5 Ligands Enhance the Expression of Cyclin D1 and D3 and Induce Proliferation in Mantle Cell Lymphoma. AB - Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a still undefined etiology. Several lines of evidence are consistent with the possible involvement of peculiar microenvironmental stimuli sustaining tumor cell growth and survival, as the activation of Toll-like receptors (TLR) 4 and 9. However, little is known about the contribution of other TLRs of pathogenic relevance in the development of MCL. This study reports evidence that MCL cell lines and primary MCL cells express different levels of TLR2 and TLR5, and that their triggering is able to further activate the Akt, MAPK, and NF-kappaB signaling cascades, known to be altered in MCL cells. This leads to the enhancement of cyclin D1 and D3 over-expression, occurring at post-translational level through a mechanism that likely involves the Akt/GSK-3alpha/beta pathway. Interestingly, in primary B cells, TLR1/2 or TLR5 ligands increase protein level of cyclin D1, which is not usually expressed in normal B cells, and cyclin D3 when associated with CD40 ligand (CD40L), IL-4, and anti-human-IgM co-stimulus. Finally, the activation of TLR1/2 and TLR5 results in an increased proliferation of MCL cell lines and, in the presence of co-stimulation with CD40L, IL-4, and anti-human-IgM also of primary MCL cells and normal B lymphocytes. These effects befall together with an enhanced IL-6 production in primary cultures. Overall, our findings suggest that ligands for TLR1/2 or TLR5 may provide critical stimuli able to sustain the growth and the malignant phenotype of MCL cells. Further studies aimed at identifying the natural source of these TLR ligands and their possible pathogenic association with MCL are warranted in order to better understand MCL development, but also to define new therapeutic targets for counteracting the tumor promoting effects of lymphoma microenvironment. PMID- 27123852 TI - Discordant Expression of Circulating microRNA from Cellular and Extracellular Sources. AB - MicroRNA (miRNA) expression has rapidly grown into one of the largest fields for disease characterization and development of clinical biomarkers. Consensus is lacking in regards to the optimal sample source or if different circulating sources are concordant. Here, using miRNA measurements from contemporaneously obtained whole blood- and plasma-derived RNA from 2391 individuals, we demonstrate that plasma and blood miRNA levels are divergent and may reflect different biological processes and disease associations. PMID- 27123853 TI - Correction: Synergistic Structure in the Speed Dependent Modulation of Muscle Activity in Human Walking. AB - [This corrects the article DOI: 10.1371/journal.pone.0152784.]. PMID- 27123855 TI - Screening, Molecular Cloning, and Biochemical Characterization of an Alcohol Dehydrogenase from Pichia pastoris Useful for the Kinetic Resolution of a Racemic beta-Hydroxy-beta-trifluoromethyl Ketone. AB - The stereoselective synthesis of chiral 1,3-diols with the aid of biocatalysts is an attractive tool in organic chemistry. Besides the reduction of diketones, an alternative approach consists of the stereoselective reduction of beta-hydroxy ketones (aldols). Thus, we screened for an alcohol dehydrogenase (ADH) that would selectively reduce a beta-hydroxy-beta-trifluoromethyl ketone. One potential starting material for this process is readily available by aldol addition of acetone to 2,2,2-trifluoroacetophenone. Over 200 strains were screened, and only a few yeast strains showed stereoselective reduction activities. The enzyme responsible for the reduction of the beta-hydroxy-beta-trifluoromethyl ketone was identified after purification and subsequent MALDI-TOF mass spectrometric analysis. As a result, a new NADP(+) -dependent ADH from Pichia pastoris (PPADH) was identified and confirmed to be capable of stereospecific and diastereoselective reduction of the beta-hydroxy-beta-trifluoromethyl ketone to its corresponding 1,3-diol. The gene encoding PPADH was cloned and heterologously expressed in Escherichia coli BL21(DE3). To determine the influence of an N- or C terminal His-tag fusion, three different recombinant plasmids were constructed. Interestingly, the variant with the N-terminal His-tag showed the highest activity; consequently, this variant was purified and characterized. Kinetic parameters and the dependency of activity on pH and temperature were determined. PPADH shows a substrate preference for the reduction of linear and branched aliphatic aldehydes. Surprisingly, the enzyme shows no comparable activity towards ketones other than the beta-hydroxy-beta-trifluoromethyl ketone. PMID- 27123854 TI - Pathological Roles of Interleukin-22 in the Development of Recurrent Hepatitis C after Liver Transplantation. AB - OBJECTIVE: The aim of this study was to longitudinally evaluate and analyze the role of interleukin-22-producing CD4 positive cells (IL-22) in the pathogenesis of Hepatitis C Virus recurrence after Orthotopic Liver Transplantation (HCV-OLT). METHODS: 15 HCV-OLT, 15 age- and gender- matched non-HCV post-OLT (OLT) and 15 hepatitis C virus infected (HCV) patients were enrolled into our study from the liver transplantation and research center at Beijing 302 Hospital. We determined the frequencies of IL-22 using flow cytometry and expression of IL-22 mRNA using PCR in peripheral blood and liver tissue. We also divided HCV-OLT patients into rapid fibrosis progression (RFP) and slow fibrosis progression (SFP), examined IL 22 cells and analyzed the correlations between IL-22 frequencies and liver injury, fibrosis and clinical parameters. Moreover, we investigated the role of IL-22 in Human Hepatic Stellate Cells (HSCs). RESULTS: The levels of serum IL-22, frequencies of IL-22 producing cells in peripheral blood mononuclear cells, and expression of IL-22 mRNA and protein in the liver in the HCV-OLT group were significantly higher than that in the HCV and OLT groups. Furthermore, eight (53.3%) patients developed RFP after two years; another three patients were diagnosed liver cirrhosis. The frequencies of IL-22 were much higher in RFP compared with SFP, while no significant difference existed between OLT and SFP. Intrahepatic IL-22 positive cells were located in fibrotic areas and significantly correlated with alpha-smooth muscle actin (alpha-SMA) and fibrosis staging scores, not with grading scores and HCRVNA. In vitro, IL-22 administration prevented HSCs apoptosis, promoted HSCs proliferation and activation, up-regulated the expression of HSC-sourced growth factors including alpha-SMA, TGF-beta and TIMP-1, and increased the production of liver fibrosis markers including laminin, hyaluronic acid and collagen type IV. CONCLUSION: Peripheral and intrahepatic IL-22 is up-regulated and plays a pathological role in exacerbating liver fibrosis by activating HSCs in HCV-OLT patients, which may predict RFP and serve as an attractive target for anti-fibrotic therapy. PMID- 27123856 TI - Joint latent class model for longitudinal data and interval-censored semi competing events: Application to dementia. AB - Joint models are used in ageing studies to investigate the association between longitudinal markers and a time-to-event, and have been extended to multiple markers and/or competing risks. The competing risk of death must be considered in the elderly because death and dementia have common risk factors. Moreover, in cohort studies, time-to-dementia is interval-censored since dementia is assessed intermittently. So subjects can develop dementia and die between two visits without being diagnosed. To study predementia cognitive decline, we propose a joint latent class model combining a (possibly multivariate) mixed model and an illness-death model handling both interval censoring (by accounting for a possible unobserved transition to dementia) and semi-competing risks. Parameters are estimated by maximum-likelihood handling interval censoring. The correlation between the marker and the times-to-events is captured by latent classes, homogeneous sub-groups with specific risks of death, dementia, and profiles of cognitive decline. We propose Markovian and semi-Markovian versions. Both approaches are compared to a joint latent-class model for competing risks through a simulation study, and applied in a prospective cohort study of cerebral and functional ageing to distinguish different profiles of cognitive decline associated with risks of dementia and death. The comparison highlights that among subjects with dementia, mortality depends more on age than on duration of dementia. This model distinguishes the so-called terminal predeath decline (among healthy subjects) from the predementia decline. PMID- 27123857 TI - Intra-Abdominal Candidiasis: The Importance of Early Source Control and Antifungal Treatment. AB - Intra-abdominal candidiasis (IAC) is poorly understood compared to candidemia. We described the clinical characteristics, microbiology, treatment and outcomes of IAC, and identified risk factors for mortality. We performed a retrospective study of adults diagnosed with IAC at our center in 2012-2013. Risk factors for mortality were evaluated using multivariable logistic regression. We identified 163 patients with IAC, compared to 161 with candidemia. Types of IAC were intra abdominal abscesses (55%), secondary peritonitis (33%), primary peritonitis (5%), infected pancreatic necrosis (5%), and cholecystitis/cholangitis (3%). Eighty three percent and 66% of secondary peritonitis and abscesses, respectively, stemmed from gastrointestinal (GI) tract sources. C. albicans (56%) and C. glabrata (24%) were the most common species. Bacterial co-infections and candidemia occurred in 67% and 6% of patients, respectively. Seventy-two percent of patients underwent an early source control intervention (within 5 days) and 72% received early antifungal treatment. 100-day mortality was 28%, and highest with primary (88%) or secondary (40%) peritonitis. Younger age, abscesses and early source control were independent predictors of survival. Younger age, abscesses and early antifungal treatment were independently associated with survival for IAC stemming from GI tract sources. Infectious diseases (ID) consultations were obtained in only 48% of patients. Consulted patients were significantly more likely to receive antifungal treatment. IAC is a common disease associated with heterogeneous manifestations, which result in poor outcomes. All patients should undergo source control interventions and receive antifungal treatment promptly. It is important for the ID community to become more engaged in treating IAC. PMID- 27123858 TI - Effects of Culture and Gender on Judgments of Intent and Responsibility. AB - Do different cultures hold different views of intentionality? In four studies, participants read scenarios in which the actor's distal intent (a focus on a broader goal) and proximal intent (a focus on the mechanics of the act) were manipulated. In Studies 1-2, when distal intent was more prominent in the actor's mind, North Americans rated the actor more responsible than did Chinese and South Asian participants. When proximal intent was more prominent, Chinese and South Asian participants, if anything, rated the actor more responsible. In Studies 3 4, when distal intent was more prominent, male Americans rated the actor more responsible than did female Americans. When proximal intent was more prominent, females rated the actor more responsible. The authors discuss these findings in relation to the literatures on moral reasoning and cultural psychology. PMID- 27123860 TI - Carbon Allocation into Different Fine-Root Classes of Young Abies alba Trees Is Affected More by Phenology than by Simulated Browsing. AB - Abies alba (European silver fir) was used to investigate possible effects of simulated browsing on C allocation belowground by 13CO2 pulse-labelling at spring, summer or autumn, and by harvesting the trees at the same time point of the labelling or at a later season for biomass and for 13C-allocation into the fine-root system. Before budburst in spring, the leader shoots and 50% of all lateral shoots of half of the investigated 5-year old Abies alba saplings were clipped to simulate browsing. At harvest, different fine-root classes were separated, and starch as an important storage compartment was analysed for concentrations. The phenology had a strong effect on the allocation of the 13C label from shoots to roots. In spring, shoots did not supply the fine-roots with high amounts of the 13C-label, because the fine-roots contained less than 1% of the applied 13C. In summer and autumn, however, shoots allocated relatively high amounts of the 13C-label to the fine roots. The incorporation of the 13C-label as structural C or as starch into the roots is strongly dependent on the root type and the root diameter. In newly formed fine roots, 3-5% of the applied 13C was incorporated, whereas 1-3% in the <=0.5 mm root class and 1-1.5% in the >0.5-1.0 mm root class were recorded. Highest 13C-enrichment in the starch was recorded in the newly formed fine roots in autumn. The clipping treatment had a significant positive effect on the amount of allocated 13C-label to the fine roots after the spring labelling, with high relative 13C-contents observed in the <=0.5 mm and the >0.5-1.0 mm fine-root classes of clipped trees. No effects of the clipping were observed after summer and autumn labelling in the 13C-allocation patterns. Overall, our data imply that the season of C assimilation and, thus, the phenology of trees is the main determinant of the C allocation from shoots to roots and is clearly more important than browsing. PMID- 27123859 TI - Interspecies rootstocks affect cadmium accumulation in postgrafting generation plants of potential cadmium-hyperaccumulator Solanum photeinocarpum. AB - Pot and field experiments were conducted to study the effects of interspecies rootstocks on cadmium (Cd) accumulation characteristics of the potential Cd hyperaccumulator Solanum photeinocarpum postgrafting generation plants. Four treatments (ungrafted and S. photeinocarpum seedlings grafted on the rootstocks of eggplant, potato, and tomato) were utilized in the present study. In the 2 pot experiments, eggplant and potato reduced biomass of S. photeinocarpum postgrafting generation plants, whereas tomato increased shoot biomass compared with the control (ungrafted seedlings). Compared with ungrafted seedlings, tomato increased and eggplant decreased Cd contents in shoots of S. photeinocarpum postgrafting generation. Only tomato increased Cd extraction by shoots of S. photeinocarpum postgrafting generation compared with ungrafted seedlings. In the field experiment, only tomato increased shoot Cd content of S. photeinocarpum postgrafting generation by 8.31% and shoot Cd extraction by 9.30% compared with ungrafted seedlings. Therefore, use of tomato as rootstock could enhance the ability of S. photeinocarpum postgrafting generation plants to remediate Cd contaminated soil. Environ Toxicol Chem 2016;35:2845-2850. (c) 2016 SETAC. PMID- 27123861 TI - Gold-Catalyzed Reaction of ortho-Alkynylarylaldehydes with Conjugated Dienes: An Efficient Access to Highly Strained Tetracyclic Bridgehead Olefins. AB - An unprecedented access to strained tetracyclic bridgehead alkenes by reaction of easily accessible ortho-alkynylarylaldehydes with conjugated dienes is described. The process involves a chemo- and stereo-selective, gold-catalyzed, tandem intermolecular [3+2] cycloaddition/Prins-type ring-closing reaction that allows generating structural complexity in a straightforward manner. This approach for the preparation of anti-Bredt compounds is synthetically superior to those previously reported: the procedure is easy to implement, operates under mild experimental conditions, is efficient, and exhibits a good substrate scope. PMID- 27123862 TI - A qualitative meta-analysis examining clients' experiences of psychotherapy: A new agenda. AB - This article argues that psychotherapy practitioners and researchers should be informed by the substantive body of qualitative evidence that has been gathered to represent clients' own experiences of therapy. The current meta-analysis examined qualitative research studies analyzing clients' experiences within adult individual psychotherapy that appeared in English-language journals. This omnibus review integrates research from across psychotherapy approaches and qualitative methods, focusing on the cross-cutting question of how clients experience therapy. It utilized an innovative method in which 67 studies were subjected to a grounded theory meta-analysis in order to develop a hierarchy of data and then 42 additional studies were added into this hierarchy using a content meta-analytic method-summing to 109 studies in total. Findings highlight the critical psychotherapy experiences for clients, based upon robust findings across these research studies. Process-focused principles for practice are generated that can enrich therapists' understanding of their clients in key clinical decision-making moments. Based upon these findings, an agenda is suggested in which research is directed toward heightening therapists' understanding of clients and recognizing them as agents of change within sessions, supporting the client as self-healer paradigm. This research aims to improve therapists' sensitivity to clients' experiences and thus can expand therapists' attunement and intentionality in shaping interventions in accordance with whichever theoretical orientation is in use. The article advocates for the full integration of the qualitative literature in psychotherapy research in which variables are conceptualized in reference to an understanding of clients' experiences in sessions. (PsycINFO Database Record PMID- 27123863 TI - Are visual threats prioritized without awareness? A critical review and meta analysis involving 3 behavioral paradigms and 2696 observers. AB - Given capacity limits, only a subset of stimuli give rise to a conscious percept. Neurocognitive models suggest that humans have evolved mechanisms that operate without awareness and prioritize threatening stimuli over neutral stimuli in subsequent perception. In this meta-analysis, we review evidence for this 'standard hypothesis' emanating from 3 widely used, but rather different experimental paradigms that have been used to manipulate awareness. We found a small pooled threat-bias effect in the masked visual probe paradigm, a medium effect in the binocular rivalry paradigm and highly inconsistent effects in the breaking continuous flash suppression paradigm. Substantial heterogeneity was explained by the stimulus type: the only threat stimuli that were robustly prioritized across all 3 paradigms were fearful faces. Meta regression revealed that anxiety may modulate threat-biases, but only under specific presentation conditions. We also found that insufficiently rigorous awareness measures, inadequate control of response biases and low level confounds may undermine claims of genuine unconscious threat processing. Considering the data together, we suggest that uncritical acceptance of the standard hypothesis is premature: current behavioral evidence for threat-sensitive visual processing that operates without awareness is weak. (PsycINFO Database Record PMID- 27123864 TI - Quantitative Proteome Analysis of Leishmania donovani under Spermidine Starvation. AB - We have earlier reported antileishmanial activity of hypericin by spermidine starvation. In the current report, we have used label free proteome quantitation approach to identify differentially modulated proteins after hypericin treatment. A total of 141 proteins were found to be differentially regulated with ANOVA P value less than 0.05 in hypericin treated Leishmania promastigotes. Differentially modulated proteins have been broadly classified under nine major categories. Increase in ribosomal protein S7 protein suggests the repression of translation. Inhibition of proteins related to ubiquitin proteasome system, RNA binding protein and translation initiation factor also suggests altered translation. We have also observed increased expression of Hsp 90, Hsp 83-1 and stress inducible protein 1. Significant decreased level of cyclophilin was observed. These stress related protein could be cellular response of the parasite towards hypericin induced cellular stress. Also, defective metabolism, biosynthesis and replication of nucleic acids, flagellar movement and signalling of the parasite were observed as indicated by altered expression of proteins involved in these pathways. The data was analyzed rigorously to get further insight into hypericin induced parasitic death. PMID- 27123865 TI - MicroRNA Seed Region Length Impact on Target Messenger RNA Expression and Survival in Colorectal Cancer. AB - microRNAs (miRNA) repress messenger RNAs post-transcriptionally through binding to the 3' UTR of the mRNA with the miRNA seed region. It has been purported that longer seed regions have a greater efficacy on mRNA repression. We tested this hypothesis by evaluating differential expression of miRNAs involved in regulating the immune response, an important mechanism in colorectal cancer (CRC), by seed length category. We subsequently evaluated differential expression of these miRNAs' targets in colonic tissue and the impact of these miRNAs on CRC survival. We determined sequence complementarity between each miRNA seed region and the 3' UTR of each experimentally verified mRNA target gene. We classified miRNAs into groups based on seed regions matching perfectly to a mRNA UTR with six bases beginning at position two, seven bases beginning at position one, seven bases beginning at position two, or eight bases beginning at position one. We analyzed these groups in terms of miRNA differential expression between carcinoma and normal colorectal mucosa, differential colonic target mRNA expression, and risk of dying from CRC. After correction for multiple comparisons, the proportion of the miRNAs that were associated with differential mRNA expression was 0% for the 6-mer, 13.64% for the 7alpha-mer group, 12.82% for the 7beta-mer group, and 8.70% for the 8-mer group. The proportion of miRNAs associated with survival was 20% for the 6-mer group, 27.27% for the 7alpha-mer group, 10.23% for the 7beta-mer group, and 21.74% for the 8-mer group. We did not see a linear relationship between seed length and miRNA expression dysregulation, mRNA expression, or survival. Our findings do not support the hypothesis the seed region length alone influences mRNA repression. PMID- 27123866 TI - Dehydrogenative [2 + 2 + 1] Heteroannulation Using a Methyl Group as a One-Carbon Unit: Access to Pyrazolo[3,4-c]quinolines. AB - A practical and straightforward access to pyrazolo[3,4-c]quinolines by molecular sieve mediated dehydrogenative [2 + 2 + 1] heteroannulation of N-(o alkenylaryl)imines with aryldiazonium salts is described using a sp(3)-hybrid carbon atom as a one-carbon unit. The reaction enables the formation of three new chemical bonds, a C-C bond and two C-N bonds, in a single reaction and features simple operation and excellent functional group tolerance. PMID- 27123867 TI - Survival of the Curviest: Noise-Driven Selection for Synergistic Epistasis. AB - A major goal of human genetics is to elucidate the genetic architecture of human disease, with the goal of fueling improvements in diagnosis and the understanding of disease pathogenesis. The degree to which epistasis, or non-additive effects of risk alleles at different loci, accounts for common disease traits is hotly debated, in part because the conditions under which epistasis evolves are not well understood. Using both theory and evolutionary simulation, we show that the occurrence of common diseases (i.e. unfit phenotypes with frequencies on the order of 1%) can, under the right circumstances, be expected to be driven primarily by synergistic epistatic interactions. Conditions that are necessary, collectively, for this outcome include a strongly non-linear phenotypic landscape, strong (but not too strong) selection against the disease phenotype, and "noise" in the genotype-phenotype map that is both environmental (extrinsic, time-correlated) and developmental (intrinsic, uncorrelated) and, in both cases, neither too little nor too great. These results suggest ways in which geneticists might identify, a priori, those disease traits for which an "epistatic explanation" should be sought, and in the process better focus ongoing searches for risk alleles. PMID- 27123868 TI - Fitness, insulin sensitivity, and frontal lobe integrity in adults with overweight and obesity. AB - OBJECTIVE: To formally test whether insulin sensitivity mediates the relationship between fitness and brain integrity. METHODS: Eighty-four middle-aged participants without diabetes received a 6-min walk test from which maximal oxygen uptake (VO2 max) was derived, a structural magnetic resonance scan, and a medical evaluation including fasting glucose and insulin levels. RESULTS: This study showed significant associations between fitness, abdominal obesity, and insulin sensitivity and anterior cingulate cortex (ACC) volume as well as between ACC thickness and quantitative insulin-sensitivity check index (QUICKI). The relationship between ACC volume and VO2 max was completely mediated through QUICKI. Further, this strong association was confirmed by a single and very significant cluster on the ACC linking gray matter volume and QUICKI in a voxel based morphometry analysis. CONCLUSIONS: As expected, increased abdominal obesity was associated with reductions in fitness, ACC volumes, and insulin sensitivity. Importantly, this study demonstrated a significant mediation of the relationship between VO2 max and ACC volume by QUICKI. This suggests that the links between impaired insulin sensitivity and brain abnormalities in adults carrying excess weight could be alleviated through increased physical activity and fitness. PMID- 27123870 TI - Importance of timely monitoring of seasonal influenza vaccine effectiveness. PMID- 27123869 TI - Associations between first-trimester uterine artery Doppler velocimetry indices and adverse perinatal outcomes in women conceiving via in vitro fertilization. AB - AIM: To explore if first-trimester uterine artery Doppler velocimetric values might predict adverse perinatal outcomes in patients conceiving via in vitro fertilization (IVF). METHODS: We evaluated pregnancies in women who conceived via IVF (Group 1, n = 62) and compared these subjects to a control group (spontaneous pregnancies; Group 2, n = 53) in terms of first-trimester uterine artery Doppler velocimetric data. We explored whether these data predicted adverse perinatal outcomes (need for cesarean delivery, preterm birth, low birth weight, lower APGAR score, and need for referral to a neonatal intensive care unit [NICU]). RESULTS: The mean age of Group 1 patients was 29.9 +/- 4.7 years and that of Group 2 was 27.2 +/- 4.2 years. Gestational age at birth, first-minute APGAR scores, NICU referral rate, birth weight, preterm birth rate, abortion rate, delivery type, the left-side uterine arterial systole-diastole ratio (LUASD), the left-side uterine arterial resistance index (LUARI), the right-side uterine arterial systole-diastole ratio (RUASD), and the right-side uterine arterial resistance index (RUARI) differed significantly between the two groups (all p values < 0.05). In the study group, positive correlations were evident between LUASD, LUARI, RUASD, and RUARI, preterm birth rates, and NICU referral rates. Also, birth weight correlated negatively with LUASD, LUARI, RUASD, and RUARI in the study group. CONCLUSIONS: First-trimester uterine artery Doppler velocimetric indices, including the resistance index and systole-diastole ratio, usefully predict adverse perinatal outcomes of IVF pregnancies. PMID- 27123871 TI - Lyso-phosphatidylcholine: A potential metabolomic biomarker for alcoholic liver disease? PMID- 27123872 TI - s-Triazine-Based Functional Discotic Liquid Crystals: Synthesis, Mesomorphism and Photoluminescence. AB - A new series of C3 -symmetric, pi-conjugated molecules was designed, synthesized and characterized. The materials were derived from electron-accepting s-triazine, appended covalently to electron-donating styrylbenzene arms, and were readily prepared in excellent yield with high purity by means of three-fold condensation of triphosphonate with n-alkoxybenzaldehydes under Horner-Wadsworth-Emmons reaction conditions. Examination of the phase transitional properties by several complementary techniques evidenced self-assembly into a hexagonal columnar phase, occurring over wide and reasonable thermal ranges. The photophysical properties were studied both in solution and in the fluid/frozen columnar states by UV/Vis absorption and photoluminescence spectroscopy. The emission spectra obtained as a function of the temperature rule out the breaking-up of larger columns and a non radiative, thermally activated process. A study carried out on thin films of the glassy columnar state, which accounts for conserved fluorescence, defect-free orientation, and freezing ionic species, with the help of atomic force microscopy (AFM) images, suggested a homogeneous granular morphology comprising fibrillar structures. Dissimilarities in the surface morphology and birefringence of thin films of the solid and frozen columnar states were clearly shown by Raman spectroscopy. An electrochemical investigation revealed a LUMO energy of -4.0 eV. Thus, the discotic motifs presented herein meet certain criteria of organic materials, which are essential for developing electronic devices. PMID- 27123873 TI - Exceptionally Active and Stable Spinel Nickel Manganese Oxide Electrocatalysts for Urea Oxidation Reaction. AB - Spinel nickel manganese oxides, widely used materials in the lithium ion battery high voltage cathode, were studied in urea oxidation catalysis. NiMn2O4, Ni1.5Mn1.5O4, and MnNi2O4 were synthesized by a simple template-free hydrothermal route followed by a thermal treatment in air at 800 degrees C. Rietveld analysis performed on nonstoichiometric nickel manganese oxide-Ni1.5Mn1.5O4 revealed the presence of three mixed phases: two spinel phases with different lattice parameters and NiO unlike the other two spinels NiMn2O4 and MnNi2O4. The electroactivity of nickel manganese oxide materials toward the oxidation of urea in alkaline solution is evaluated using cyclic voltammetric measurements. Ni1.5Mn1.5O4 exhibits excellent redox characteristics and lower charge transfer resistances in comparison with other compositions of nickel manganese oxides and nickel oxide prepared under similar conditions.The Ni1.5Mn1.5O4modified electrode oxidizes urea at 0.29 V versus Ag/AgCl with a corresponding current density of 6.9 mA cm(-2). At a low catalyst loading of 50 MUg cm(-2), the urea oxidation current density of Ni1.5Mn1.5O4 in alkaline solution is 7 times higher than that of nickel oxide and 4 times higher than that of NiMn2O4 and MnNi2O4, respectively. PMID- 27123874 TI - Acute and subacute idiopathic interstitial pneumonias. AB - Idiopathic interstitial pneumonias (IIPs) may have an acute or subacute presentation, or acute exacerbation may occur in a previously subclinical or unrecognized chronic IIP. Acute or subacute IIPs include acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonia (NSIP), acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and AE-NSIP. Interstitial lung diseases (ILDs) including connective tissue disease (CTD) associated ILD, hypersensitivity pneumonitis, acute eosinophilic pneumonia, drug-induced lung disease and diffuse alveolar haemorrhage need to be differentiated from acute and subacute IIPs. Despite the severe lack of randomized controlled trials for the treatment of acute and subacute IIPs, the mainstream treatment remains corticosteroid therapy. Other potential therapies reported in the literature include corticosteroids and immunosuppression, antibiotics, anticoagulants, neutrophil elastase inhibitor, autoantibody-targeted treatment, antifibrotics and hemoperfusion therapy. With regard to mechanical ventilation, patients in recent studies with acute and subacute IIPs have shown better survival than those in previous studies. Therefore, a careful value-laden decision about the indications for endotracheal intubation should be made for each patient. Noninvasive ventilation may be beneficial to reduce ventilator associated pneumonia. PMID- 27123876 TI - Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. PMID- 27123875 TI - The composition, localization and function of low-temperature-adapted microbial communities involved in methanogenic degradations of cellulose and chitin from Qinghai-Tibetan Plateau wetland soils. AB - AIMS: To reveal the microbial communities from Qinghai-Tibetan Plateau wetland soils that have the potential to be used in the utilization of cellulosic and chitinous biomass at low temperatures (<=25 degrees C). METHODS AND RESULTS: Soil samples collected from six wetlands on Qinghai-Tibetan Plateau were supplemented with or without cellulose and chitin flakes, and anaerobically incubated at 25 and 15 degrees C; high-throughput 16S rRNA gene sequencing was used to access the composition and localization (in the slurry and on the surface) of enriched microbial communities; a hypothetical model was constructed to demonstrate the functional roles of involved microbes mainly at genus level. Overall, microbial communities from Qinghai-Tibetan Plateau wetlands showed significant potential to convert both cellulose and chitin to methane at low temperatures; Clostridium III, Clostridium XIVa, Paludibacter, Parcubacteria, Saccharofermentans, Pelotomaculum, Methanosaeta, Methanobrevibacter, Methanoregula, Methanospirillum and Methanosarcina participated in methanogenic degradation of both cellulose and chitin through the roles of hydrolytic, saccharolytic and secondary fermenters and methanogens respectively. Acetotrophic methanogens were mainly enriched in the slurries, while hydrogenotrophic methanogens could be both in the slurries and on the surface. CONCLUSIONS: The composition and localization of microbial communities that could effectively convert cellulose and chitin to methane at low temperatures have been revealed by high-throughput 16S rRNA gene sequencing methods, and reviewing the literatures on the microbial pure culture helped to elucidate functional roles of significantly enriched microbes. SIGNIFICANCE AND IMPACT OF THE STUDY: This study will contribute to the understanding of carbon and nitrogen cycling of cellulose and chitin in cold-area wetlands and provide fundamental information to obtain microbial resources for the utilization of biomass wastes at low temperatures. PMID- 27123877 TI - Risk-Factor Profile of Living Kidney Donors: The Australia and New Zealand Dialysis and Transplant Living Kidney Donor Registry 2004-2012. AB - BACKGROUND: Recent literature suggests that living kidney donation may be associated with an excess risk of end-stage kidney disease and death. Efforts to maximize access to transplantation may result in acceptance of donors who do not fit within current guidelines, potentially placing them at risk of adverse long term outcomes. METHODS: We studied the risk profile of Australian and New Zealand living kidney donors using data from the Australia and New Zealand Dialysis and Transplant Living Kidney Donor Registry over 2004 to 2012. We compared their predonation profile against national guidelines for donor acceptance. RESULTS: The analysis included 2,932 donors (mean age 48.8 +/- 11.2 years, range 18-81), 58% female and 87% Caucasian. Forty (1%) had measured glomerular filtration rate less than 80 mL/min; 32 (1%) had proteinuria >300 mg/day; 589 (20%) were hypertensive; 495 (18%) obese; 9 (0.3%) were diabetic while a further 55 (2%) had impaired glucose tolerance; and 218 (7%) were current smokers. Overall 767 donors (26%) had at least one relative contraindication to donation and 268 (9%) had at least one absolute contraindication according to national guidelines. CONCLUSIONS: Divergence of current clinical practice from national guidelines has occurred. In the context of recent evidence demonstrating elevated long-term donor risk, rigorous follow-up and reporting of outcomes are now mandated to ensure safety and document any change in risk associated with such a divergence. PMID- 27123878 TI - Impact of Graft Selection on Donor and Recipient Outcomes After Living Donor Liver Transplantation. AB - BACKGROUND: Balancing donor and recipient risks in living donor liver transplantation remains an issue of debate. This study assessed the impact of graft selection on outcomes and complications for left lobe (LL) versus right lobe (RL) donors and recipients. METHODS: The medical records of donors and recipients, who underwent living donor liver transplantation at our institution between 2003 and 2015, were reviewed. For donors, we evaluated graft volume, residual liver volume per standard liver volume, length of hospital stay (LOS), complications, and readmissions. For recipients, we looked at graft and patient survival, graft function at postoperative days 7 and 14, graft volume, LOS, biliary complications, Model for End-Stage Liver Disease at transplant, and hepatitis C virus status. RESULTS: At 5 years posttransplant, there were no significant differences in graft survival for LL recipients (86% [95% confidence interval, 74-93]) compared with 82% (95% confidence interval, 69-89) for RL recipients (P = 0.85) or recipient survival (90% vs 84%; P = 0.44). In LL recipients, postoperative days 7 and 14 median international normalized ratio (1.5 and 1.2, respectively) and total bilirubin (4.6 and 2.7) were significantly greater compared with RL recipients (7 and 14 days international normalized ratio [1.2, P < 0.001; 1.1, P = 0.001] and total bilirubin (2.7, P = 0.001; 2.1, P = 0.05)). The LL recipients also had a significantly greater median LOS (14 vs 10, P = 0.008). Median donor LOS was significantly greater for RL donors (7 [interquartile range, 7-8] vs 7 [interquartile range, 6-7] days, P < 0.001). CONCLUSIONS: The RL and LL grafts provide comparable long-term outcomes in properly selected donor-recipient pairs and the appropriate use of LL grafts does not impact graft or patient survival at 5 years posttransplant. PMID- 27123879 TI - Magnetic particle characterization-magnetophoretic mobility and particle size. AB - Quantitative characterization of magnetic particles is useful for analysis and separation of labeled cells and magnetic particles. A particle velocimeter is used to directly measure the magnetophoretic mobility, size, and other parameters of magnetic particle suspensions. The instrument provides quantitative video analysis of particles and their motion. The trajectories of magnetic particles in an isodynamic magnetic field are recorded using a high-definition camera/microscope system for image collection. Image analysis software then converts the image data to the parameters of interest. The distribution of magnetophoretic mobility is determined by combining fast image analysis with velocimetry measurements. Particle size distributions have been characterized to provide a better understanding of sample quality. The results have been used in the development and operation of analyzer protocols for counting particle concentrations accurately and measuring magnetic susceptibility and size for simultaneous display for routine application to particle suspensions and magnetically labeled biological cells. (c) 2016 International Society for Advancement of Cytometry. PMID- 27123880 TI - Describing Differences in Survival Curves. PMID- 27123881 TI - Embedded Instruction Improves Vocabulary Learning During Automated Storybook Reading Among High-Risk Preschoolers. AB - PURPOSE: We investigated a small-group intervention designed to teach vocabulary and comprehension skills to preschoolers who were at risk for language and reading disabilities. These language skills are important and reliable predictors of later academic achievement. METHOD: Preschoolers heard prerecorded stories 3 times per week over the course of a school year. A cluster randomized design was used to evaluate the effects of hearing storybooks with and without embedded vocabulary and comprehension lessons. A total of 32 classrooms were randomly assigned to experimental and comparison conditions. Approximately 6 children per classroom demonstrating low vocabulary knowledge, totaling 195 children, were enrolled. RESULTS: Preschoolers in the comparison condition did not learn novel, challenging vocabulary words to which they were exposed in story contexts, whereas preschoolers receiving embedded lessons demonstrated significant learning gains, although vocabulary learning diminished over the course of the school year. Modest gains in comprehension skills did not differ between the two groups. CONCLUSION: The Story Friends curriculum appears to be highly feasible for delivery in early childhood educational settings and effective at teaching challenging vocabulary to high-risk preschoolers. PMID- 27123882 TI - Balancing treatment efficacy, toxicity and complication risk in elderly patients with metastatic renal cell carcinoma. AB - The number of elderly patients with renal cell carcinoma is rising. Elderly patients differ from their younger counterparts in, among others, higher incidence of comorbidity and reduced organ function. Age influences outcome of surgery, and therefore has to be taken into account in elderly patients eligible for cytoreductive nephrectomy. Over the last decade several novel effective drugs have become available for the metastatic setting targeting angiogenesis and mammalian target of rapamycin. Immune checkpoint blockade with a programmed death 1 antibody has recently been shown to increase survival and further studies with immune checkpoint inhibitors are ongoing. In this review we summarize the available data on efficacy and toxicity of existing and emerging therapies for metastatic renal cell carcinoma in the elderly. Where possible, we provide evidence-based recommendations for treatment choices in elderly. PMID- 27123883 TI - Systemic therapy for recurrent meningioma. AB - INTRODUCTION: Meningioma comprise 20-30% of all primary brain tumors. Notwithstanding surgery and radiotherapy, a subset of patients will manifest recurrent meningioma. Systemic therapy is recommended only when further surgery and radiotherapy are not possible. No prospective study with a high level of evidence is available to inform as to recommendations regarding systemic therapy. AREAS COVERED: We aim to summarize systemic therapies for recurrent meningioma. Expert commentary: Hydroxurea, temozolomide, irinotecan, the combination of cyclophosphamide/adriamycine/vincristine, interferon-alpha, somatostatin analogs, mifepristone, megestrol acetate, imatinib, erlotinib and gefitinib are considered as having limited efficacy. Potential activity of VEGF (vascular endothelial growth factor) inhibitors such as sunitinib, valatinib, and bevacizumab is suggested in small non-controlled studies and requires validation in randomized trials. The identification of new prognostic markers such as TERT promoter mutations and potential new therapeutic targets, such as KLF4, AKT1, TRAF7, and SMO mutations hopefully facilitate this endeavor. PMID- 27123884 TI - A Photo-Triggered Traceless Staudinger-Bertozzi Ligation Reaction. AB - The use of light to control the course of a chemical/biochemical reaction is an attractive idea because of its ease of administration with high precision and fine spatial resolution. Staudinger ligation is one of the commonly adopted conjugation processes that involve a spontaneous reaction between azides and arylphosphines to form iminophosphoranes, which further hydrolyze to give stable amides. We designed an anthracenylmethyl diphenylphosphinothioester (1) that showed promising Staudinger ligation reactivity upon photo-excitation. Broadband photolysis at 360-400 nm in aqueous organic solvents induced heterolytic cleavage of its anthracenylmethyl-phosphorus bond, releasing a diphenylphosphinothioester (2) as an efficient traceless Staudinger-Bertozzi ligation reagent. The quantum yield of such a photo-induced heterolytic bond-cleavage at the optimal wavelength of photolysis (376 nm) at room temperature is >=0.07. This work demonstrated the feasibility of photocaging arylphosphines to realize the photo-triggering of the Staudinger ligation reaction. PMID- 27123885 TI - Engineered Molecular Chain Ordering in Single-Walled Carbon Nanotubes/Polyaniline Composite Films for High-Performance Organic Thermoelectric Materials. AB - Single-walled carbon nanotubes (SWNTs)/polyaniline (PANI) composite films with enhanced thermoelectric properties were prepared by combining in situ polymerization and solution processing. Conductive atomic force microscopy and X ray diffraction measurements confirmed that solution processing and strong pi-pi interactions between the PANI and SWNTs induced the PANI molecules to form a highly ordered structure. The improved degree of order of the PANI molecular arrangement increased the carrier mobility and thereby enhanced the electrical transport properties of PANI. The maximum in-plane electrical conductivity and power factor of the SWNTs/PANI composite films reached 1.44*10(3) S cm(-1) and 217 MUW m(-1) K(-2) , respectively, at room temperature. Furthermore, a thermoelectric generator fabricated with the SWNTs/PANI composite films showed good electric generation ability and stability. A high power density of 10.4 MUW cm(-2) K(-1) was obtained, which is superior to most reported results obtained in organic thermoelectric modules. PMID- 27123886 TI - [Trabeculotomy Combined with Cataract Surgery in Glaucoma: Outcome in a Rural Setting]. AB - Purpose: Intensive postoperative care is essential for the outcome of trabeculectomy. However, in a rural setting, repeated visits to the operating theatre are often not requested or possible. The objective of this study was to examine the outcome of trabeculotomy combined with cataract surgery in patients with glaucoma. Patients and Methods: 142 patients with glaucoma and cataract were included in a retrospective clinical study. All patients were operated on from November 2005 to December 2008 by a single surgeon and with a minimum follow-up of 2 months. Intraocular pressure (IOP), number of antiglaucomatous medications and surgical success rate were assessed at 2 months and at the longest follow-up (at least 1 year). Results: IOP was significantly reduced from 24.1 +/- 8.3 mmHg preoperatively to 14.9 +/- 3.3 mmHg at 2 months (p < 0.0001) and to 15.1 +/- 3 mmHg at the longest follow-up (3.71 +/- 1.5 years). The number of IOP-lowering medications was lowered from 1.35 +/- 1 preoperatively to 0.73 +/- 1 at the longest follow-up. Complete surgical success (no IOP-lowering medications, longest follow-up) was achieved in 51.3 % (IOP < 22 mmHg) and 47.5 % (IOP < 19 mmHg) of patients, respectively. Conclusions: Trabeculotomy combined with cataract surgery is a safe and effective surgical option to treat combined cataract and glaucoma without the need of intensified postoperative treatment. PMID- 27123887 TI - [Switching Therapy from Ranibizumab and/or Bevacizumab to Aflibercept in Neovascular Age-Related Macular Degeneration (AMD): One-Year Results]. AB - BACKGROUND: The presented study is a retrospective evaluation of switching therapy from ranibizumab and/or bevacizumab to aflibercept in neovascular age related macular degeneration in patients who had previously given an insufficient response to therapy with ranibizumab and/or bevacizumab. PATIENTS AND METHODS: 96 eyes with neovascular age-related macular degeneration (AMD) were included, which had been pretreated with ranibizumab and/or bevacizumab (T&E), but had responded insufficiently. An injection interval of less than six weeks or permanently persisting intra- and/or subretinal fluid or persistent pigment epithelial detachments (PED) were defined as an insufficient response. The patients were followed for 12 months after switching therapy to aflibercept. The change in central retinal thickness (CRT) was defined as the primary endpoint. Other endpoints were the axial height of PEDs and the injection interval. RESULTS: The primary endpoint, the average CRT, was significantly decreased twelve months after switching therapy to aflibercept (Wilcoxon Nemenyi-McDonald-Thompson post hoc analysis - 31.36 um; SD +/- 70.64 um; p < 0.001). Another morphological endpoint, the average axial height of PEDs, also decreased significantly (- 34.10 um; SD +/- 91.90 um, p < 0.001) from 207.82 um (SD +/- 148.12 um) at baseline to 173.72 um (SD +/- 132.30 um) at month 12. Moreover, the average injection interval increased significantly (p < 0.001; Friedman test) from 1.30 months (SD +/- 0.19 months) before switching therapy to 1.67 months (SD +/- 0.19 months) at month 12 after switching therapy to aflibercept. However, the best corrected visual acuity (BCVA) as a functional endpoint did not significantly improve (+ 0.36 ETDRS letters = 0.0972 p; SD +/- 16.94 ETDRS letters). CONCLUSION: In patients with neovascular AMD, who had initially exhibited an inadequate response to ranibizumab and/or bevacizumab, switching therapy to aflibercept improves clinical outcome measures. Besides morphological improvements, such as the decrease of the CRT and the axial height of PEDs, the average injection interval was prolonged. However, visual acuity did not improve. PMID- 27123888 TI - Linking boundary crossing from work to nonwork to work-related rumination across time: A variable- and person-oriented approach. AB - [Correction Notice: An Erratum for this article was reported in Vol 22(4) of Journal of Occupational Health Psychology (see record 2017-05746-001). There were errors in two separate sections of the article. The final sentence preceding Hypothesis 4 in "The Present Study" section should read, "We did not hypothesize that the specific forms of work-related thoughts (i.e., affective rumination, problem-solving pondering, or lack of psychological detachment) would be differently associated with stability or changes in boundary crossing behavior." The fifth sentence in the second paragraph of the "Identifying Subgroups of Boundary Crossing Behavior Across Time" subsection of the "Results" section should read, "Group 5 (n = 162, 19%), characterized by stable low boundary crossing behavior across time (M = 1.37 for Time 1 and M = 1.34 for Time 2), and Group 6 (n = 154, 18%), characterized by stable high boundary crossing behavior (M = 4.54 for Time 1 and M = 4.60 for Time 2), were almost equally large in size."] This 1-year follow-up study (N = 841) investigated the relationship between boundary crossing behavior from work to nonwork and work-related rumination (i.e., affective rumination, problem-solving pondering, and lack of psychological detachment from work during off-job time). This relationship is important to examine as work-related rumination is a risk factor for poor recovery and ill-health over time. The aims were twofold: first, to examine these relationships in terms of temporal ordering, and, second, to show how individual differences regarding stability and change of boundaries from work to nonwork are reflected in work-related rumination across time. The structural equation modeling analyses lent support to the hypothesized normal causation model compared with the reversed causation and reciprocal models. However, only the cross-lagged relationship between high boundary crossing behavior at T1 and lack of psychological detachment at T2 was significant. Through latent profile analysis, 6 subgroups of boundary crossing behavior across time were identified. Over 70% of the employees belonged to the stable (low, moderate, high) and about one-third to the changing (mostly increasing) boundary crossing subgroups. Employees in the 2 stable (high and moderate) boundary crossing subgroups reported less psychological detachment and more problem-solving pondering during off-job time than did those in the low boundary crossing subgroup. Employees in the change groups reported simultaneous expected changes, especially in their problem-solving pondering. No effects on affective rumination were found. Thus frequent boundary crossing behavior from work to nonwork plays a different role regarding the various forms of work-related rumination during nonwork. (PsycINFO Database Record PMID- 27123889 TI - Feeling vital after a good night's sleep: The interplay of energetic resources and self-efficacy for daily proactivity. AB - This study aims to investigate the role of daily vitality as an energy-based mechanism through which sleep quantity and quality relate to proactive behavior. In addition, we propose that daily self-efficacy forms a contingency condition in that self-efficacy facilitates the translation of vitality into proactive behavior. We conducted a 7-day diary study based on a sample of 66 employees who completed surveys 3 times daily. We used multilevel regression analyses to test the hypotheses while controlling for the 1-day lagged measures of vitality and proactivity. The results provide evidence for a model of moderated mediation. Sleep quality but not quantity predicted an increase in daily vitality. Self efficacy moderated the relationship between vitality and daily proactivity such that this relationship was stronger when self-efficacy was reported to be high rather than low. The conditional effect mediated by vitality was significant for sleep quality but not for sleep quantity and occurred at the within-person level of analysis. These results suggest that organizations aiming to boost daily proactivity in employees can benefit from increasing employees' self-efficacy and supporting them in developing strategies to ensure sufficient vitality. One such strategy is improving sleep quality. This study extends the literature on dynamics in proactive work behavior and its well-being-related antecedents by exploring both vitality as an underlying energetic mechanism and daily self efficacy as a boundary condition. (PsycINFO Database Record PMID- 27123890 TI - Announcement: Amyotrophic Lateral Sclerosis (ALS) Awareness Month - May 2016. AB - May is Amyotrophic Lateral Sclerosis (ALS) Awareness Month. ALS, also known as Lou Gehrig's disease, is a progressive, fatal, neurodegenerative disorder of upper and lower motor neurons. The cause of ALS is not known, and no cure exists. Persons with ALS usually die within 2-5 years of diagnosis. PMID- 27123891 TI - Nucleosome Assembly Alters the Accessibility of the Antitumor Agent Duocarmycin B2 to Duplex DNA. AB - To evaluate the reactivity of antitumor agents in a nucleosome architecture, we conducted in vitro studies to assess the alkylation level of duocarmycin B2 on nucleosomes with core and linker DNA using sequencing gel electrophoresis. Our results suggested that the alkylating efficiencies of duocarmycin B2 were significantly decreased in core DNA and increased at the histone-free linker DNA sites when compared with naked DNA conditions. Our finding that nucleosome assembly alters the accessibility of duocarmycin B2 to duplex DNA could advance its design as an antitumor agent. PMID- 27123892 TI - Facile Hydrazine-Hydrothermal Syntheses and Characterizations of Two Quaternary Thioarsenates(III): Two-Dimensional SrAg4 As2 S6 ?2 H2 O and One-Dimensional BaAgAsS3. AB - Two new quaternary thioarsenates(III), SrAg4 As2 S6 ?2 H2 O (1) and BaAgAsS3 (2), have been prepared through a hydrazine-hydrothermal method at low temperature. Compound 1 possesses a two-dimensional (2D) layer network, while compound 2 features a one-dimensional (1D) column structure. The detailed structure analysis indicates that Sr(2+) and Ba(2+) cations have different directing effects on the structures of thioarsenates(III). Both experimental and theoretical studies demonstrate that compounds 1 and 2 are narrow-gap semiconductors. Our success in synthesizing these two quaternary thioarsenates(III) proves that the hydrazine hydrothermal technique is a powerful yet facile synthetic method for exploring new complex chalcogenides with diverse crystal structures and interesting physical properties. PMID- 27123894 TI - The secret is out. PMID- 27123893 TI - Early Bone Formation at a Femur Defect Using CGF and PRF Grafts in Adult Dogs: A Comparative Study. AB - PURPOSE: The purpose of this study was to compare the predictability of new bone formation using an autologous concentrated growth factor (CGF) graft alone and platelet graft alone. MATERIALS AND METHODS: Four bony defects of 8 mm were formed, and 3.7- * 10-mm implants were placed in the right femur. The platelet rich fibrin (PRF), CGF, and synthetic bone were grafted to the bone defect area. Enzyme linked immunosorbent assay quantitative analysis and microscopic analysis of the fibrinogen structure were performed. RESULTS: At 4 weeks, the comparisons of each experimental group showed a significant difference between the CGF group and the synthetic bone graft group. When comparing the CGF and allograft material groups, the allograft group showed significantly more new bone formation. In the case of vascular endothelial growth factor, CGF had 1.5 times more than PRF. CGF showed a fibrinogen structure with a constant diameter. CONCLUSION: When applied to a clinical case, CGF is predicted to show better results than PRF. PMID- 27123895 TI - Letters From Our Readers. PMID- 27123896 TI - Letters From Our Readers. PMID- 27123897 TI - Letters From Our Readers. PMID- 27123899 TI - Position-Specific Mass Shift Analysis: A Systematic Method for Investigating the EI-MS Fragmentation Mechanism of epi-Isozizaene. AB - The EI-MS fragmentation mechanism of the bacterial sesquiterpene epi-isozizaene was investigated through enzymatic conversion of all 15 synthetic ((13) C1 )FPP isotopomers with the epi-isozizaene synthase from Streptomyces albus and GC-MS and GC-QTOF analysis including MS-MS. A systematic method, which we wish to call position-specific mass shift analysis, for the identification of the full set of fragmentation reactions was developed. PMID- 27123900 TI - Discovery of novel, high potent, ABC type PTP1B inhibitors with TCPTP selectivity and cellular activity. AB - Protein tyrosine phosphatase 1B (PTP1B) as a key negative regulator of both insulin and leptin receptor pathways has been an attractive therapeutic target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. With the goal of enhancing potency and selectivity of the PTP1B inhibitors, a series of methyl salicylate derivatives as ABC type PTP1B inhibitors (P1-P7) were discovered. More importantly, compound P6 exhibited high potent inhibitory activity (IC50 = 50 nM) for PTP1B with 15-fold selectivity over T-cell PTPase (TCPTP). Further studies on cellular activities revealed that compound P6 could enhance insulin-mediated insulin receptor beta (IRbeta) phosphorylation and insulin-stimulated glucose uptake. PMID- 27123901 TI - Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma. AB - The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt pathway. Also named the "master kinase" of the AGC family, PDK1 plays a critical role in tumorigenesis, by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation. Although there have been done huge efforts in discovering specific compounds targeting PDK1, nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1 inhibitors, herein we report the design and synthesis of a new class of molecules obtained by merging the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the PDK1 hinge region and its DFG-out binding site, respectively. To this purpose, a small series of compounds were synthesised and a tandem application of docking and Molecular Dynamic (MD) was employed to get insight into their mode of binding. The OXID-pyridonyl hybrid 8, possessing the lower IC50 (IC50 = 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumour cell migration. All together the results let us to consider 8, as a lead compound of a new generation of PDK1 inhibitors and encourage us to further studies in this direction. PMID- 27123902 TI - Synthesis and evaluation of [(18)F]-fluoromethyl triphenylphosphonium cation as a novel mitochondria-specific positron emission tomography tracer. AB - We developed a radiosynthesis of the voltage sensitive tracer [(18)F] fluoromethyltriphenylphosphonium cation ([(18)F]-FTPMP), giving high yield (30 34%, decay-corrected), radiochemical purity (>99%) and specific activity (about 760 GBq/MUmol). [(18)F]-FTPMP had suitable lipophilicity (logP = 0.91 +/- 0.03) and high in vivo/vitro stability. Biodistribution studies showed that [(18)F] FTPMP had high heart uptake (>7%ID/g from 10 min to 120 min postinjection) and rapid clearance from the background. Clear cardiac images were obtained at different time periods, and the infarction areas could be detected sensitively with small-animal PET. The autoradiography and myocardial membrane potential studies confirmed the mitochondria specific of [(18)F]-FTPMP in rat myocardia. These excellent pharmacokinetic properties suggest [(18)F]-FTPMP is a promising mitochondria-specific tracer for clinical PET imaging of myocardial diseases associated with mitochondrial dysfunction. PMID- 27123903 TI - Left Temple Ulceration. PMID- 27123904 TI - Effects of antioxidants, catalase and alpha-tocopherol on cell viability and oxidative stress variables in frozen-thawed mice spermatogonial stem cells. AB - Cryopreservation of spermatogonial stem cells is considered as a useful procedure for preserving fertility in children with testis cancer. SSCs were isolated from testes mice, and then antioxidant was added to the freezing medium. The Bax expression level in antioxidant groups was significantly (P <= 0.05) lower than the control group and a significant rise of Bcl2 expression was detected in the antioxidant groups. ROS production with antioxidant was significantly lower compared with the control group. Cryopreservation with the addition of the antioxidants can help increase the number of SSCs and improve the quality and viability of these cells after cryopreservation. PMID- 27123905 TI - Drag Reduction by Bubble-Covered Surfaces Found in PDMS Microchannel through Depressurization. AB - Drag reduction was found in polydimethylsiloxane (PDMS) microchannels when the flow was pulled by depressurization at the inlet, and it was attributed to the formation of the bubbles on the PDMS surface. The formed bubbles were examined by atomic force microscopy (AFM), and the resultant effective slip length was measured by microparticle image velocimetry (MUPIV). The drag reduction was found to decrease as the bubbles grew and detached from the surface, causing a pulsatile flow in the microchannel. PMID- 27123906 TI - The AMCP Format for Formulary Submissions: Welcome to Version 4.0. AB - Managed care pharmacists are increasingly presented with complex considerations related to prescription drug formulary management. As prescription drug spending soars, and new effective, but expensive drugs rush to the market, pharmacists and other health care decision makers must evaluate a myriad of important clinical and economic considerations in determining the relative value and, subsequently, the appropriate placement of a product within a formulary. The AMCP Format for Formulary Submissions, Version 4.0, is the next iteration of the Format, which was first released in 2000. Version 4.0, developed by pharmacists from health plan, manufacturer, and academic perspectives, provides updated recommendations on acquiring and evaluating clinical and economic evidence to inform formulary and medical policy decisions. It also includes new guidance related to emerging special topic considerations such as biosimilars, specialty pharmacy products, and companion diagnostic tests. Version 4.0 has been modified to improve the usability of the Format, with clarifying guidance related to logistical considerations such as a recommended time frame for implementation of Version 4.0, as well as dossier updates and ongoing communication between manufacturers and health care decision makers. The Format should be used as a framework for ongoing evidence-based dialogue between manufacturers and payers. The evolving health care landscape will require new levels of collaboration and communication among key stakeholders to successfully navigate the challenges of this new environment. The Format provides a framework to support these critical interactions related to product value by facilitating an evidence-based, transparent approach. DISCLOSURES: This document was prepared by Jeff Lee, PharmD, FCCP, on behalf of the AMCP Format Executive Committee. Committee members reviewed and provided feedback on the final draft. No conflicts of interest, financial or otherwise, were reported. PMID- 27123907 TI - Achieving Balance with the AMCP Format for Formulary Submissions, Version 4.0: A Dossier Producer's Perspective. AB - DISCLOSURES: Both authors are employed by Xcenda and develop AMCP Format dossiers. PMID- 27123908 TI - AMCP Format for Formulary Submissions, Version 4.0. AB - DISCLOSURES: Pannier is a member of the AMCP Format Executive Committee. The authors report no financial or other conflicts of interest related to the subject of this letter. PMID- 27123909 TI - Association Between Weight Change, Clinical Outcomes, and Health Care Costs in Patients with Type 2 Diabetes. AB - BACKGROUND: Previous research suggests that weight loss is associated with decreases in health care costs among individuals with type 2 diabetes mellitus (T2DM) and that weight change can affect clinical measures, including hemoglobin A1c (A1c), low-density lipoprotein cholesterol (LDLC), and blood pressure. Previous research has also demonstrated more pronounced impact of weight change among patients with T2DM who are obese and have no evidence of cardiovascular disease (CVD). OBJECTIVES: To (a) examine the association between weight change and all-cause and diabetes-related health care costs among patients with T2DM; (b) examine the association between weight change and select clinical measures among patients with T2DM; and (c) analyze a subgroup of obese patients with no previous CVD. METHODS: This retrospective, observational cohort study used U.S. insurance claims linked to laboratory and electronic medical records. This study included patients with T2DM aged 18 years or older who added or switched to a nonmetformin antidiabetes medication after metformin monotherapy between January 1, 2007, and June 30, 2012 (date of add/switch was the index date). The primary predictor was percentage weight change (PWC) between a weight measurement at index and a follow-up measurement 6 months later; PWC ranged from negative (weight loss) to positive (weight gain). Outcomes, measured in the 12-month period beginning at the time of follow-up weight measurement, included all-cause and diabetes-related health care costs and achievement of thresholds for A1c, blood pressure, and LDL-C. Multivariable models quantified the association between PWC (linear effect) and study outcomes. RESULTS: A total of 1,520 patients (mean age 55 years; 47% female) were included, with 780 patients (mean age 53 years; 51% female) in the subgroup sample. Mean (SD) index weight and PWC were 224.6 (52.8) lbs and +0.2% (4.7%) in the primary analysis, and 241.3 (47.3) lbs and -0.2% (4.6%) in the subgroup sample. In adjusted analyses, decreasing PWC was associated with decreasing diabetes-specific pharmacy costs (P < 0.001) in the primary analysis sample and with decreasing all-cause pharmacy costs (P = 0.018), diabetes-specific total costs (P = 0.039), diabetes-specific medical costs (P = 0.002), and diabetes-specific pharmacy costs (P < 0.001) in the subgroup sample. PWC was not associated with all-cause total health care costs or all-cause medical costs in either sample. In adjusted analyses, decreasing PWC was also associated with increasing odds of attaining the A1c goals of < 6.5% (P < 0.001) and < 7.0% (P < 0.001) in the primary analysis sample and increasing odds of attaining the A1c goals of < 6.5% (P < 0.001), < 7.0% (P < 0.001), and < 8.0% (P = 0.010) in the subgroup sample. PWC was not associated with any of the other clinical measures in either of the study samples. CONCLUSIONS: This real world study suggests that among patients with T2DM, weight loss over a short-term (6-month) period is associated with positive impact on attainment of A1c goals and decreased diabetes-specific pharmacy costs over the subsequent 12 months. In the subset of patients who were obese and had no previus CVD, weight loss over the 6-month period was also associated with decreased all-cause pharmacy costs, diabetes-specific medical costs, and diabetes-specific total health care costs. Future research is warranted to examine whether these associations change over longer-term periods of follow-up. DISCLOSURES: This study was sponsored by AstraZeneca and Bristol-Myers Squibb. Truven Health Analytics received funding from Bristol-Myers Squibb and AstraZeneca to conduct this study. Mukherjee is an employee of Bristol-Myers Squibb. Bell and Sternhufvud are employees of AstraZeneca. Johnston, Stott-Miller, and McMorrow are employees of Truven Health Analytics. Nancy Smith is a consultant to Bristol-Myers Squibb and is employed by GreenKey Resources. Study concept was created by Mukherjee, Sternhufvud, Bell, and Johnston. Stott-Miller and McMorrow took the lead in data collection, along with Johnston, with data interpretation performed by Mukherjee, Sternhufvud, Smith, Stott-Miller, and Johnston. The manuscript was written by Mukherjee, Johnston, and Stott-Miller, along with Sternhufvud and Smith, and revised by Mukherjee, Smith, and Johnston, along with Sternhufvud and Stott-Miller. PMID- 27123910 TI - Predictors of Change in Adherence Status from 1 Year to the Next Among Patients with Type 2 Diabetes Mellitus on Oral Antidiabetes Drugs. AB - BACKGROUND: Diabetes is a leading cause of morbidity, mortality, and medical resource utilization in the United States and worldwide. Treatment is aimed at keeping blood glucose levels close to normal and preventing or delaying medical complications. It has been estimated that only 50% of patients with diabetes in the United States achieve glycosylated hemoglobin A1c level < 7%. Nonadherence to antidiabetic medications has been identified as a major factor related to poor glycemic control. OBJECTIVES: To (a) assess adult patients with type 2 diabetes mellitus (T2DM) whose adherence status to oral antidiabetic drugs (OADs) changed from 1 year to the next and (b) identify predictors of change in adherence status. METHODS: This retrospective study of the Humana Medicare Advantage Database included patients with T2DM and continuous enrollment between 2010 and 2012. Proportion of days covered (PDC) by OADs was calculated for each of the 3 study years (2010, 2011, 2012). Patients were classified as adherent (PDC >= 80%) or nonadherent (PDC < 80%) during each year. Patient characteristics from the baseline period (2010) were used as covariates, and adherence status changes from baseline to follow-up year (2011) were used as response variables. Data from the subsequent study periods (2011 as baseline, 2012 as follow-up) were used to validate the model (final model). RESULTS: A total of 238,402 patients met inclusion criteria. Among them, 144,216 (60.5%) were adherent, and 94,186 (39.5%) were nonadherent during the baseline period. Change in adherence status from baseline to follow-up year was observed in 31,320 (21.7%) patients that were adherent and 39,284 (41.7%) patients that were nonadherent during the baseline year. The final model for baseline adherent patients had a receiver-operating characteristic (ROC) index of 73% and a misclassification rate of 39%. The predictors of highest importance were identified as total number of prescriptions filled with 90-day supply, diabetes-related pill burden, longest gap in OADs, total number of antidiabetic classes filled, and copay for the last OAD filled. The final model had a sensitivity value of 76.4%. The final model for baseline nonadherent patients had a ROC index of 68%, a misclassification rate of 36.4%, and sensitivity value of 52.9%. The predictors of highest importance were diabetes-related pill burden, longest gap in OADs, month-wise patient oscillation from adherent to nonadherent during baseline year, total number of prescriptions filled with a 90-day supply, and total pill burden during the baseline year. CONCLUSIONS: One third of the T2DM patients changed adherence status from 1 year to the next, and factors associated with adherence status changes were identified. Predictive models such as those used in this study can serve as useful and cost-effective tools for payers, helping to identify members that should be targeted for adherence enhancement programs and, ultimately, to improve patients' long-term outcomes. DISCLOSURES: Funding for this research was provided by Eli Lilly and Company. Comprehensive Health Insights, owned by Humana, completed this study. Peng, Fu, Ascher-Svanum, Ali, and Rodriguez are employees of Eli Lilly and Company. Saundankar and Louder are employed by Comprehensive Health Insights, and Slabaugh and Young are employed by Humana. Study concept and design were contributed by Peng, Ascher-Svanum, and Young. Saundankar and Louder took the lead in data collection, while Saundankar, Peng, Fu, and Louder interpreted the data. The manuscript was written by Saundankar, Peng, Fu, and Louder and revised by Saundankar, Rodriguez, Ali, and Louder. PMID- 27123911 TI - Hypoglycemia Incidence Rates and Associated Health Care Costs in Patients with Type 2 Diabetes Mellitus Treated with Second-Line Linagliptin or Sulfonylurea After Metformin Monotherapy. AB - BACKGROUND: Hypoglycemia poses a significant clinical and economic burden to patients with type 2 diabetes mellitus (T2DM). Minimizing the risk of hypoglycemia is an important component when managing patients with T2DM. Understanding hypoglycemia rates and the associated economic consequences can help to inform health care decision makers. OBJECTIVE: To assess hypoglycemia incidence rates and associated costs in patients who initiated second-line treatment with the antidiabetic agents linagliptin or a sulfonylurea (SU) after metformin. METHODS: A large U.S. administrative claims database was used to identify patients with T2DM (during the identification period July 2011-October 2013) who initiated linagliptin or a SU after metformin use. The date of the first prescription for linagliptin or a SU during the identification period was designated as the index date. Linagliptin users were matched to SU users based on demographic and clinical characteristics identified within a 12-month period before the index date using propensity scores (1:3 ratio, caliper: +/-0.001). Rates and costs (2013 U.S. dollars) of hypoglycemia resulting in any health care resource use were quantified during a variable follow-up period (i.e., end of the study, end of the 12-month follow-up, treatment regimen change, or disenrollment, whichever came first). Hypoglycemia rates per 100 person-years were compared using univariate Poisson regression, and hazard of hypoglycemia was obtained from multivariate Cox proportional hazards regression. Mean monthly hypoglycemia related costs, all-cause costs, and T2DM-related costs were computed for patients with hypoglycemia and compared using t-tests. RESULTS: Propensity-score matching resulted in a sample of 11,536 patients (linagliptin = 2,884; SU = 8,652) with a mean age of 56 years and 59% male. The rate of hypoglycemia (per 100 person years) was lower in the linagliptin than the SU user groups (2.51 vs. 3.63; P= 0.049). Linagliptin users had a 33% lower risk of hypoglycemia compared with SU users (HR = 0.67; 95% CI = 0.47-0.97; P= 0.031). Among patients who had hypoglycemia, linagliptin users showed numerically lower mean monthly hypoglycemia-related costs compared with SU users ($300 vs. $890; P= 0.092), which was primarily driven by differences in hypoglycemia-related costs in the hospital setting. A similar theme was observed with monthly all-cause costs (linagliptin users, $1,971 vs. SU users, $3,758; P= 0.092). CONCLUSIONS: Linagliptin use was associated with a lower incidence rate of hypoglycemia compared with SU use in patients initiating second-line therapy after metformin monotherapy. Among patients who experienced hypoglycemia, linagliptin users appeared to have lower monthly hypoglycemia-related and all-cause costs than SU users. Careful consideration of newer treatment alternatives may be prudent for optimal T2DM management, especially with regard to hypoglycemia. DISCLOSURES: Funding for the research study and resultant publication was provided by Boehringer Ingelheim. Shetty is an employee of Boehringer Ingelheim. Cai was an employee of Boehringer Ingelheim at the time of the study. Raju and D'Souza are employees of Xcenda, which received research funding from Boehringer Ingelheim for the conduct of this study and for the preparation of this manuscript. All authors contributed to concept and study design. Raju took the lead in data analysis, along with D'Souza, and all authors contributed equally to data interpretation. The manuscript was written by Raju, D'Souza, Cai, and Shetty and revised primarily by Raju, along with Shetty and D'Souza. PMID- 27123912 TI - Pharmacist Interventions in the Management of Type 2 Diabetes Mellitus: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Diabetes mellitus is a major health problem that is growing rapidly worldwide. A collaborative and integrated team approach in which pharmacists can play a pivotal role should be sought when managing patients with diabetes. OBJECTIVE: To identify and summarize the main outcomes of pharmacist interventions in the management of type 2 diabetes. METHODS: PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomized controlled trials evaluating the effectiveness of any pharmacist intervention directed at patients with type 2 diabetes in comparison with usual care. Outcome measures of interest included glycosylated hemoglobin (Alc), blood glucose, blood pressure, lipid profile, body mass index (BMI), 10-year coronary heart disease (CHD) risk, medication adherence, health-related quality of life (HRQoL), and economic outcomes. The risk of bias in included studies was assessed using the Cochrane risk of bias tool. RESULTS: Thirty-six studies were included in this systematic review, involving 5,761 participants. The studies evaluated the effects of several pharmacist interventions carried out in various countries and in different health care facilities, such as community pharmacies, primary care clinics, and hospitals. The number of studies reporting each outcome of interest varied. Alc was evaluated in 26 studies, of which 24 reported a greater reduction in this outcome in the intervention group compared with the control group, with the difference in change between groups ranging from -0.18% to -2.1%. Eighteen studies assessed change in systolic blood pressure, of which 17 studies reported a greater improvement in this outcome in the intervention group, with the difference in change between groups varying between -3.3 mmHg and -23.05 mmHg. For diastolic blood pressure, a greater effect was also observed in the intervention group in 14 out of 15 studies, with the difference in change between groups varying between -0.21 mmHg and -9.1 mmHg. Thirteen studies described total cholesterol as an outcome measure, of which 10 reported a greater improvement in this outcome in the intervention group, with the difference in change between groups ranging from +18.95 mg dL(-1) to -32.48 mg dL(-1). With regard to low density lipoprotein cholesterol, a greater reduction in this parameter in the intervention group was documented in 12 out of 15 studies, with the difference in change between groups varying between +7.35 mg dL(-1) and -30 mg dL(-1). Similarly, favorable data were reported on high-density lipoprotein cholesterol in the intervention group in 9 out of 12 studies that assessed this outcome, with the difference in change between groups ranging from -5.8 mg dL(-1) to +11 mg dL( 1). Data on triglycerides were also reported in 12 studies, of which 9 reported a greater reduction in triglycerides levels in the intervention group, with the difference in change between groups varying between +12 mg dL(-1) and -62 mg dL( 1). Overall, a beneficial effect on BMI was also described in the intervention group in 12 out of 14 studies. Of note, in all 6 studies that estimated the 10 year CHD risk among study patients, a greater improvement in the intervention group versus the control group was found. In addition, pharmacist interventions also had a positive impact on medication adherence and HRQoL in most studies that ascertained these outcomes. Finally, although only 3 studies conducted a cost effectiveness analysis, pharmacist interventions proved to be cost-effective. CONCLUSIONS: The findings from this review clearly support the involvement of pharmacists as members of health care teams in the management of patients with type 2 diabetes. DISCLOSURES: This systematic review was not funded. The authors declare that they have no conflicts of interest. Concept and study design were created by Pousinho, Morgado, and Alves. Pousinho took the lead in data collection, along with Alves, and data interpretation was performed by Pousinho, Falcao, and Alves. The manuscript was primarily written by Pousinho, along with Alves, and revised by Alves, Morgado, and Falcao. PMID- 27123913 TI - Defining and Measuring Primary Medication Nonadherence: Development of a Quality Measure. AB - Poor medication adherence has been increasingly recognized as a major public health issue and a priority for health care reform. Primary medication nonadherence (PMN) is a subset of this broader subject and occurs when a new medication is prescribed for a patient, but the patient does not obtain the medication, or an appropriate alternative, within an acceptable period of time after it was prescribed. It is increasingly evident that the public health problem of PMN is widespread. However, the lack of standardized definitions and measures inhibits the ability to establish the true incidence of this problem or to track changes in PMN rates over time. Given the limitations of current measures, the Pharmacy Quality Alliance (PQA) convened an expert working group to set parameters for a new industry measure. That new measure, which links electronic prescribing and pharmacy dispensing databases and was developed and approved by the PQA, is described here. PMN literature from 1990 to June 2015 is also reviewed, and existing PMN measures are summarized. DISCLOSURES: No funding was received for this article, and the authors declare no conflicts of interest. The views expressed in this article are those of the authors alone and do not necessarily reflect those of their respective employers. Adams has received grant support from Pfizer for adherence research. Adams and Stolpe were equally involved in all aspects of study design, data collection and interpretation, and manuscript preparation. PMID- 27123914 TI - A Multichannel Medication Adherence Intervention Influences Patient and Prescriber Behavior. AB - BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) Medicare Health Plan Quality and Performance Ratings program, or Star Ratings program, includes 3 medication adherence outcome measures (Medication Adherence for Diabetes Medications, Medication Adherence for Hypertension, and Medication Adherence for Cholesterol), which contribute to approximately 31% of a Medicare Advantage prescription drug (MA-PD) plan's Part D summary rating and 12% of its overall star rating (a weighted summary of a plan's Part C and Part D ratings). MA-PD plans have been increasing their adherence intervention efforts as an approach to improving beneficiaries' medication adherence and the plan's quality performance ratings. However, few evaluations have examined the effects of these interventions on medication adherence and performance ratings. OBJECTIVE: To assess the impact of a quasi-experimental multichannel adherence intervention on beneficiaries' medication adherence and health plan quality performance measures for 2 MA-PD plans. The intervention included a daily prescriber-directed 90-day retail refill component and a weekly member-directed refill reminder component. METHODS: Members filling 1 or more medications assessed by the 3 CMS star ratings adherence measures (oral antidiabetics [DM], antihypertensives [HTN], and statins [CHOL]) were identified for a 2-component intervention starting in April 2013. The retail-based 90-day refill component sent populated 90-day prescription letters via fax to prescribers of members who had filled a 30-day prescription. One fax per member-medication instance was sent and included the option to fax approval of a new 90-day prescription. For prescribers who approved, members were notified that a 90-day refill was available at their retail pharmacies. The refill reminder component used weekly scans of pharmacy claims to identify members' refill patterns. Reminder letters were sent to members 7 days late to refill. An intent-to-treat approach was used to assess intervention effectiveness. Pharmacy claims and health plan enrollment data were used to calculate adherence among members enrolled 1 year pre- and postintervention start (April 2013) for the intervention group and a comparator group that consisted of 4 MA-PD plans not implementing an adherence intervention. Adherence was estimated by the proportion of days covered (PDC) and generalized linear models were fit to calculate difference-in-difference (DID) estimators to control for demographics, comorbidity, and changes in adherence over the study period. To estimate the impact of the intervention on health plan quality performance, 2013 and 2014 CMS star ratings for the respective 2012 and 2013 measurement years were compared by group. RESULTS: During the first year of the intervention, 1,344 prescribers representing 6,701 members were faxed 15,284 populated prescription letters. Prescriber response rate was 53.7% and approval rate (approved letters of total sent) was 47.3%. An average of 539 refill reminder letters were sent per week. DID estimators showed positive influence of the intervention on adherence to HTN and CHOL. For the intervention group, adherence increased 2.0 percentage points (P < 0.001) for HTN and 1.8 percentage points (P < 0.001) for CHOL, relative to the control group. The odds of achieving adherence (PDC >= 80%) were greater in the intervention group compared with control for HTN (ratio of odds ratio [ROR] = 1.334; 95% CI = 1.203-1.479) and for CHOL (ROR = 1.247; 95% CI = 1.132-1.374). For the 2 plans implementing the intervention, CMS-published adherence rates for DM, HTN, and CHOL increased from 2012 to 2013 by an average 5.5, 6.0, and 7.0 percentage points, respectively, compared with the control group (3.5, 2.0, and 1.8 percentage points, respectively). CONCLUSIONS: This study found increases in adherence to HTN and CHOL in 2 MA-PD plans implementing a combined prescriber and patient-directed intervention. MA-PD plans can use broad multichannel interventions to address common adherence barriers and as an approach to improving members' adherence to maintenance medications and CMS quality performance ratings. DISCLOSURES: No funding was received in return for conducting this research. Leslie is an employee of MedImpact Healthcare Systems. The authors report no conflicts of interest. Study concept was developed primarily by Leslie, along with Gilmer. Leslie took the lead in data collection, while data interpretation was performed by Leslie, Natarajan, and Gilmer. The manuscript was written primarily by Leslie, along with Gilmer and assisted by Hovell. Leslie, Gilmer, and Hovell revised the manuscript, with assistance from Natarajan. PMID- 27123915 TI - Impact of Patient Reimbursement Timing and Patient Out-of-Pocket Expenses on Medication Adherence in Patients Covered by Private Drug Insurance Plans. AB - BACKGROUND: Adherence to prescribed medications used in the treatment of chronic diseases is suboptimal, and drug insurance plans can have an impact on adherence. There is little evidence on the impact of patient reimbursement timing on medication adherence. OBJECTIVE: To compare adherence to prescribed medications in privately insured patients from Quebec, Canada, with different patient reimbursement timing and levels of patient out-of-pocket expenses. METHODS: A retrospective cohort was constructed by selecting privately insured patients aged 18-64 years from the reMed database (2008-2012) who filled at least 1 prescription for a medication belonging to 1 of the 10 most prescribed drug classes for chronic diseases. Patient reimbursement timing was classified as immediate (immediate patient reimbursement at the point of service of the portion of the medication cost covered by the insurer) or deferred (patient reimbursement at a later time). Patient outof-pocket expenses related to the medication under study at cohort entry (available only for the immediate patient reimbursement group), which included the deductible and the coinsurance, were categorized into 5 levels (null category and quartiles): $0, $0.01-$3.59, $3.60-$8.11, $8.12 $14.40, and $14.41-$89.99. Adherence was measured with the proportion of days covered (PDC) over 1 year among new users of the medication under study. Linear regression models were used to estimate the adjusted mean difference of PDC between groups. RESULTS: There was no difference in medication adherence between the immediate (n = 1,345) and deferred patient reimbursement (n = 437; difference, 0.0%; 95% CI, -3.0 to 3.0). Patients with the highest patient out-of pocket expenses were less adherent than those with the lowest patient out-of pocket expenses (difference, -19.0%; 95% CI, -24.0 to -13.0); however, patients with no patient out-of-pocket expenses were less adherent than those with low patient out-of-pocket expenses (difference, -9.0%; 95% CI, -15.0 to -2.0). CONCLUSIONS: Medication adherence appeared to be unaffected by patient reimbursement timing but was affected by the level of patient out-of-pocket expenses. The absence of a correlation between medication adherence and timing of patient reimbursement might be explained by the relatively rapid reimbursement of expenses by insurance companies in Canada. Subjects with no patient out-of-pocket expenses at the point of service might be less adherent because they place less value on their medications than do patients who must pay even a small amount. DISCLOSURES: This study was funded by Pfizer Canada, Montreal, Quebec, Canada. Blais received research grants or honorarium from AstraZeneca, Pfizer Canada, Sanofi, Novartis, Almirall, GlaxoSmithKline, and Merck for research projects and co-chairs the AstraZeneca Endowment Pharmaceutical Chair in Respiratory Health. Despres, Kettani, and Forget have no competing interests to declare. All authors contributed to the concept and design of the study. Data were collected by Blais and Forget. Data analysis was conducted by Despres. The manuscript was written by Despres and revised by all authors. PMID- 27123916 TI - Medication Nonadherence Among Medicare Beneficiaries with Comorbid Chronic Conditions: Influence of Pharmacy Dispensing Channel. AB - BACKGROUND: Taking medications as prescribed is imperative for their effectiveness. In populations such as Medicare, where two thirds of Medicare beneficiaries have at least 2 or more chronic conditions requiring treatment with medications and account for more than 90% of Medicare health care spend, examining ways to improve medication adherence in patients with comorbidities is warranted. OBJECTIVE: To examine the association of pharmacy dispensing channel (home delivery or retail pharmacy) with medication adherence for Medicare patients taking medications with comorbid conditions of diabetes, hypertension, and high blood cholesterol (3 of the top 5 most prevalent conditions), while controlling for various confounders. METHODS: A retrospective analysis was conducted using de-identified pharmacy claims data from a large national pharmacy benefits manager between October 2010 and December 2012. Continuously eligible Medicare Part D patients (Medicare Advantage Prescription Drug plan and Prescription Drug Plan only) aged 65 years or older who had an antidiabetic, antihypertensive, and antihyperlipidemic prescription claim between October and December 2010 were identified and analyzed over a 2-year period. Multivariate logistic regression was used to evaluate the association between dispensing channel (DC) and medication adherence in calendar year (CY) 2012 controlling for prior adherence behavior (adherence in CY2011), differences in demographics, low income subsidy status, days supply, disease burden, and drug-use pattern. Patients with a proportion of days covered (PDC) of at least 80% for each of the 3 conditions were considered to be adherent, and patients with PDC less than 80% for each of the 3 conditions were considered to be nonadherent. Patients were assigned to a DC depending on where they filled at least 66.7% of their prescriptions for each of the 3 conditions, and the rest were assigned to a mixed channel group. RESULTS: The final analytical sample consisted of 40,632 patients. The adjusted odds of adherence for patients using home delivery were 1.59 (95% CI = 1.40-1.80) higher compared with patients using retail channels to obtain their prescriptions. CONCLUSIONS: Medicare Part D patients taking medications for comorbid conditions who used home delivery had a greater likelihood (adjusted) of adherence than patients who filled their antidiabetic, antihypertensive, and antihyperlipidemic prescriptions using retail channels. Managed care stakeholders looking to make informed decisions in a cost-constrained environment to assess, implement, and promote solutions that improve health outcomes should consider the use of home delivery of prescriptions to improve adherence for Medicare Part D patients with comorbid conditions. DISCLOSURES: Funding for this study was provided internally by Express Scripts Holding Company. Iyengar, LeFrancois, Henderson, and Rabbitt are employees of Express Scripts. Study concept and design were created by Iyengar and LeFrancois. Iyengar was responsible for acquisition of data, statistical analysis, and interpretation of data. The manuscript was written by Iyengar and LeFrancois and revised by all the authors. PMID- 27123917 TI - Treatment Initiation Patterns, Modifications, and Medication Adherence Among Newly Diagnosed Heart Failure Patients: A Retrospective Claims Database Analysis. AB - BACKGROUND: Heart failure (HF) is a debilitating disease associated with high mortality and frequent hospitalizations. American College of Cardiology Foundation and American Heart Association (ACCF/AHA) guidelines recommend the following drug classes for HF treatment: angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor II blocker (ARB) for patients intolerant to ACEI, beta blocker (BB), and aldosterone antagonist (AA). OBJECTIVE: To examine, in a real-word setting, the treatment initiation pattern among newly diagnosed HF patients in the United States, subsequent treatment modifications, hospitalizations and the impact of hospitalizations on therapy changes, and treatment adherence and persistence. METHODS: Using medical and pharmacy claims data from the Truven Health MarketScan database, this retrospective cohort study included adult patients with >= 2 medical claims corresponding to an HF diagnosis (ICD-9-CM codes 428.x, 402.11, 402.91, 404.01, 404.11, 404.91, 404.03, 404.13, and 404.93) between April 2009 and March 2012. The date of the first claim was defined as the index date. Patients with continuous medical and pharmacy eligibility for a minimum of 12 months pre- and post-index were included in the analysis. Patients with an HF diagnosis in the 12 months before the index date were excluded. Index treatment (within 30 days post-index), subsequent treatment modification (class addition/removal) during the study period, hospitalization, and change in treatment after hospitalization (within 15 days after hospital discharge) were determined. Adherence was evaluated using the proportion of days covered (PDC) method, and persistence was defined as the proportion of patients remaining on index treatment after a defined period of time (12 months). RESULTS: A total of 235,758 patients meeting the sample selection criteria were included in the analysis and were followed for a median of 28 months after the index date. Approximately 42% of patients were not prescribed any HF-specific treatment within 30 days post-index. Among those treated, prescriptions for ACEIs were filled by 46.42% of patients, ARBs by 17.07%, BBs by 75.62%, and AAs by 9.83%. Based on HF therapy class, monotherapy was prescribed to 51% of patients, bi therapy to 40%, and triple therapy to 9%. More than 80% of patients experienced treatment modification during the median 28 months of follow-up. A total of 174,563 (74.0%) patients had at least 1 all-cause hospitalization (mean 1.11 [SD = 0.98]) per year, with a mean length of stay (LOS) of 7.19 [SD = 8.69] days. Within 12 months post-index, 85.7% of these patients experienced an all-cause hospitalization, with 29.6% having HF-related hospitalization (mean 0.18 [0.36]) and mean LOS of 5.85 [5.45] days. More than 60% of patients continued on the same therapy after all-cause or HF hospitalization. More patients on multiple therapies remained on the same treatment (73%-89%) compared with those treated with monotherapy (60%-73%) after the first HF hospitalization. Among patients untreated before hospitalization, 9.8% and 17% received treatment after all-cause and HF hospitalization, respectively. During the entire study period (median 28 months), 29% of patients did not have a prescription fill for HF-specific treatments. The median PDC was > 0.65, and considering a gap of 30 days between ends of supply from 1 medication fill to the subsequent fill, persistence ranged from 41% (AA) to 52% (BB). CONCLUSIONS: Findings of this claims database analysis among 235,758 HF patients suggest that more than one third of newly diagnosed HF patients do not receive HF-specific medication within 30 days following initial diagnosis. Despite ACCF/AHA recommendations of initiating treatment with a combination of 2 HF drug classes, only 40% of patients had a prescription fill for bi-therapy. Hospitalization did not have a major impact on HF therapy prescribing patterns. To our knowledge, this is the first study to establish the impact of hospitalization on HF-specific treatment among newly diagnosed patients. Adherence and persistence were moderate across all HF therapies of interest. This analysis reveals the need for further research to better understand the reasons for the demonstrated delay in HF treatment initiation and limited use of guideline-directed medical therapy after initial diagnosis. DISCLOSURES: This study was funded by Novartis Pharma AG, Basel, Switzerland. Deschaseaux, McSharry, Hudson, Agrawal, and Turner are permanent employees of Novartis. Concept and study design were contributed by Deschaseaux, Hudson, and Turner, along with McSharry. McSharry took the lead in data collection, along with Deschaseaux, Hudson, and Turner. Data interpretation was performed by Hudson, along with the other authors. The manuscript was written by Agrawal, along with Deschaseaux and Turner, and revised by Deschaseaux and Turner, along with the other authors. PMID- 27123918 TI - Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy. AB - BACKGROUND: Endometriosis affects over 10 million women in the United States. Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with hypoestrogenic symptoms and bone mineral density loss. The concomitant use of add-back therapies, specifically norethindrone acetate (NETA), can alleviate these adverse effects. OBJECTIVE: To compare adherence to and persistence with LA treatment and time to endometriosis-related surgery among women treated with NETA and women treated with LA plus other add-back therapies or LA only. METHODS: This retrospective analysis was conducted using Truven Health MarketScan Commercial Claims and Encounters Database. Women with a diagnosis of endometriosis (ICD-9-CM code 617.xx) who initiated LA (index date) in 2005-2011 were selected for inclusion. Additional requirements were 12 months of continuous enrollment pre- and post-index and no evidence of endometriosis-related surgeries pre-index or up to 30 days post-index; no pre-index use of estrogen or noncontraceptive hormones; and no diagnoses of uterine fibroids, malignant neoplasms, infertility, or pregnancy. Patients were characterized as using NETA; other add-back therapies (estrogens, progestins, or estrogen-progestin combinations); or no add-back therapy. Adherence to and persistence with LA were measured over the 6 months following the index date using outpatient medical and pharmacy claims. Patients were considered adherent if their proportion of days covered was greater than or equal to 0.80. Persistence was operationalized as time to discontinuation, defined as a continuous gap of > 60 days without LA on hand. Time to endometriosis-related surgery (laparotomy, laparoscopy, excision/ablation/fulguration, oophorectomy, and hysterectomy) was measured over the 12 months following the index date. Surgeries were identified from inpatient and outpatient medical claims using procedure codes. Outcomes were compared among cohorts using multivariable logistic and Cox proportional hazards regression models controlling for demographics and baseline clinical characteristics. RESULTS: The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had a higher likelihood of being adherent to LA than LA only patients (OR = 1.91, 95% CI = 1.55-2.36 and OR = 1.95, 95% CI = 1.63-2.34) and lower likelihood of LA discontinuation (HR = 0.54, 95% CI = 0.46-0.63 and HR = 0.59, 95% CI = 0.52-0.68). NETA patients had a lower surgery rate in the 12-month post index period compared with other add-back patients (HR = 0.68, 95% CI = 0.50 0.93) or LA only patients (HR = 0.69, 95% CI = 0.52-0.92). CONCLUSIONS: For women with endometriosis, treatment with LA and concomitant add-back therapies was associated with better adherence to and persistence with LA over the 6 months following initiation, compared with treatment with LA only. The increased adherence and persistence to LA may translate into decreased need for surgical intervention, although fewer endometriosis-related surgeries were only observed in the 12 months following LA initiation for patients using concomitant NETA add back therapy. These results support an increased and earlier use of NETA add-back therapy among women who initiate LA. DISCLOSURES: This study was funded by AbbVie, which also markets the endometriosis drugs Lupron and Lupaneta Pack. AbbVie participated in the study design, research, data collection, analysis and interpretation, writing, review, and approval of this publication. Soliman and Castelli-Haley are employees of AbbVie and may own AbbVie stock or stock options. Bonafede and Farr are employees of Truven Health Analytics, which received a research contract to conduct this study with and on behalf of AbbVie. Winkel is a clinical professor in the Department of Obstetrics and Gynecology at Georgetown University in Washington, DC, and has served in a consulting role on research to AbbVie for this project. An earlier version of the current research was presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 20th Annual International Meeting; Philadelphia, PA; May 2015. All authors participated in data analysis and interpretation and contributed to the development of the manuscript. PMID- 27123919 TI - Medication Adherence and Persistence in Patients with Severe Major Depressive Disorder with Psychotic Features: Antidepressant and Second-Generation Antipsychotic Therapy Versus Antidepressant Monotherapy. AB - BACKGROUND: Major depressive disorder with psychotic features, or psychotic depression, is a severe mental health disorder often associated with a worse depression-related symptom profile when compared with major depressive disorder without psychotic features. While combination pharmacotherapy with an antidepressant and an antipsychotic is recommended as first-line therapy, antidepressant monotherapy has been found to be useful and efficacious in psychotic depression. OBJECTIVE: To assess the rates of antidepressant adherence and antidepressant persistence in Texas Medicaid patients with psychotic depression who used antidepressant plus second-generation antipsychotic (AD/SGA) therapy or antidepressant (AD) monotherapy. METHODS: Using Texas Medicaid prescription and medical claims data from September 2007 to December 2012, adult patients aged 18-63 years were included if they had no confounding psychiatric disorders, no antidepressant claims during a 6-month pre-index period, and at least 1 diagnosis for severe major depressive disorder with psychotic features (ICD-9-CM codes 296.24 and 296.34). The first claim date for an antidepressant served as the index date. All patients were required to have at least 2 antidepressant claims, and those in the AD/SGA cohort were required to have 2 or more claims for an SGA. Study covariates included age, gender, race/ethnicity, residence, Charlson Comorbidity Index (CCI) score, and tobacco use/dependence. Statistical analyses included descriptive statistics, univariate analyses, logistic regression, and Cox proportional hazards regression. RESULTS: A total of 926 patients met study criteria (AD cohort = 510; AD/SGA cohort = 416). The overall sample had a mean [+/-SD] age of 40.5 [+/-13.2] years and was primarily female (66.8%) and non-Caucasian (74.8%). When compared with the AD cohort, patients in the AD/SGA cohort had a 52.3% higher likelihood of being adherent to antidepressant therapy based on proportion of days covered (PDC; OR = 1.523; 95% CI = 1.129-2.053; P = 0.006). Similarly, antidepressant adherence was 42.0% higher for the AD/SGA cohort based on medication possession ratio (MPR; OR = 1.420; 95% CI = 1.062-1.898; P = 0.018). Younger patients, African Americans, and tobacco users/dependents had significantly worse likelihoods of antidepressant medication adherence based on PDC and MPR. The risk of antidepressant nonpersistence was 23.2% lower for patients in the AD/SGA cohort (HR = 0.768; 95% CI = 0.659-0.896; P = 0.001), compared with those in the AD cohort. Antidepressant nonpersistence was significantly higher in younger patients, African Americans, Hispanics, and tobacco users/dependents. CONCLUSIONS: Better antidepressant adherence and persistence outcomes were associated with combination pharmacotherapy with an AD and an SGA antipsychotic. This study provides real-world estimates that support the current first-line treatment recommendations for psychotic depression; however, it should be noted that the majority of study patients used AD therapy only. Future research in psychotic depression is needed. DISCLOSURES: Kim-Romo received funding to conduct this study from the PhRMA Foundation Pre-Doctoral Fellowship in Health Outcomes. Rascati, Richards, Ford, Wilson, and Beretvas declare no conflict of interest in relation to this manuscript. Kim-Romo and Rascati collaborated on the study design, data analysis, study interpretation, and writing of this manuscript. Richards, Ford, Wilson, and Beretvas provided critical evaluation of the study design, analysis, and interpretation, as well as edited this manuscript. PMID- 27123920 TI - Seeing the Forest Through the Trees: Improving Adherence Alone Will Not Optimize Medication Use. AB - Medication adherence is a problem that has received widespread attention in the medical literature and health policy circles. With the increased emphasis on recognizing and rewarding quality in the U.S. health care system, medication adherence measures are increasingly being adopted to assess quality of medication use. However, when adherence is discussed in the literature or evaluated via quality measures, there is rarely any dialogue surrounding adherence in the context of patient-centered issues such as clinical status, individualized medication needs, or personal expectations and social situation. When nonadherence is identified via a comprehensive assessment of all of a patient's medication-related issues, it typically is recognized as only the third most frequent type of medication-related problem. Issues such as requiring a medication that has not been prescribed or receiving a medication prescribed at a dose too low to achieve the intended clinical goal are more frequently experienced. Furthermore, if a patient is nonadherent to a medication because of adverse effects or if the medication prescribed is not appropriate considering the patient's individual clinical situation, promoting adherence can create unintended harm. Therefore, achieving medication adherence as typically evaluated via existing quality metrics such as proportion of days covered is only valid if the medication is first deemed to be indicated, effective, and safe for the patient. Medications are the most common medical intervention for chronic illnesses. As a result, success in achieving the Triple Aim of health care is highly dependent on optimizing medication use. When quality measures for medication use narrowly focus on measuring adherence, the resulting programs of payers and providers will likely ignore the most frequent types of medication problems that prevent improved health, create unnecessary costs, and could negatively impact patients' experience with the health care system. Strong leadership and advocacy on the part of agencies in the position to influence the quality measurement landscape in the U.S. health care system will be critical to achieve widespread awareness of medication nonadherence in the context of the full scope of medication-related problems in health care. DISCLOSURES: No outside funding supported this research. Brummel provides consulting services to other health systems; has received grants from Sanofi and speaking fees from AMCP, APhA, and ASHP; and is on the faculty at the University of Minnesota and employed by Fairview Pharmacy Services. Ekstrand provides consulting services for Alliance for Integrated Medication Management and has received speaking fees from International Diabetes Center and MN Alliance of Physician Assistants. The authors report no other conflict of interest, potential or otherwise. Study concept and design were contributed primarily by Sorensen, Brummel, and Rehrauer, along with the other authors. Rehrauer, Brummel, and Ekstrand collected the data, which were interpreted by Sorensen, Brummel, Rehrauer, and Ekstrand. Pestka and Sorensen wrote and revised the manuscript, with assistance from the other authors. PMID- 27123922 TI - Sulfur Dioxide Capture by Heterogeneous Oxidation on Hydroxylated Manganese Dioxide. AB - Here we demonstrate that sulfur dioxide (SO2) is efficiently captured via heterogeneous oxidation into sulfate on the surface of hydroxylated manganese dioxide (MnO2). Lab-scale activity tests in a fluidized bed reactor showed that the removal efficiency for a simulated flue gas containing 5000 mg.Nm(-3) SO2 could reach nearly 100% with a GHSV (gas hourly space velocity) of 10000 h(-1). The mechanism was investigated using a combination of experimental characterizations and theoretical calculations. It was found that formation of surface bound sulfate proceeds via association of SO2 with terminal hydroxyls. Both H2O and O2 are essential for the generation of reactive terminal hydroxyls, and the indirect role of O2 in heterogeneous SO2 oxidation at low temperature was also revealed. We propose that the high reactivity of terminal hydroxyls is attributed to the proper surface configuration of MnO2 to adsorb water with degenerate energies for associative and dissociative states, and maintain rapid proton dynamics. Viability analyses suggest that the desulfurization method that is based on such a direct oxidation reaction at the gas/solid interface represents a promising approach for SO2 capture. PMID- 27123921 TI - The Nicotine-Evoked Locomotor Response: A Behavioral Paradigm for Toxicity Screening in Zebrafish (Danio rerio) Embryos and Eleutheroembryos Exposed to Methylmercury. AB - This study is an adaptation of the nicotine-evoked locomotor response (NLR) assay, which was originally utilized for phenotype-based neurotoxicity screening in zebrafish embryos. Zebrafish embryos do not exhibit spontaneous swimming until roughly 4 days post-fertilization (dpf), however, a robust swimming response can be induced as early as 36 hours post-fertilization (hpf) by means of acute nicotine exposure (30-240MUM). Here, the NLR was tested as a tool for early detection of locomotor phenotypes in 36, 48 and 72 hpf mutant zebrafish embryos of the non-touch-responsive maco strain; this assay successfully discriminated mutant embryos from their non-mutant siblings. Then, methylmercury (MeHg) was used as a proof-of-concept neurotoxicant to test the effectiveness of the NLR assay as a screening tool in toxicology. The locomotor effects of MeHg were evaluated in 6 dpf wild type eleutheroembryos exposed to waterborne MeHg (0, 0.01, 0.03 and 0.1MUM). Afterwards, the NLR assay was tested in 48 hpf embryos subjected to the same MeHg exposure regimes. Embryos exposed to 0.01 and 0.03MUM of MeHg exhibited significant increases in locomotion in both scenarios. These findings suggest that similar locomotor phenotypes observed in free swimming fish can be detected as early as 48 hpf, when locomotion is induced with nicotine. PMID- 27123923 TI - Profile of Women Collegiate Strength and Conditioning Coaches. AB - Laskowski, KD and Ebben, WP. Profile of women collegiate strength and conditioning coaches. J Strength Cond Res 30(12): 3481-3493, 2016-This study describes the careers of women collegiate strength and conditioning coaches, including specifics of the universities and athletic departments they work for, responsibilities and demands of their jobs, compensation and benefits, preparation and qualifications, likes and dislikes about their work, and the role that gender plays in their work. Forty-three coaches participated for a response rate of 29.1% (43 of 148). The survey was divided into 5 sections, including university profile, position profile, personal profile, job satisfaction, and comments. Results show that women occupy approximately 32% of all strength and conditioning positions. Those who are full-time coaches work approximately 55.6 hours per week, starting their workday at 6:02 AM and ending at 5:40 PM, on average. Part-time coaches worked 42.5 hours per week. Those who were in director positions earned approximately $76,000 per year, whereas full-time assistants averaged approximately $39,300 per year. Most coaches had master's degree and held the CSCS and USAW certifications. These coaches averaged 7.14 years of full time experience. Coaches identified a variety of advantages and disadvantages associated with their work and described the influence of gender in their work. These results provide normative data about employment conditions of women strength and conditioning coaches and those who are considering this career. These data also document the current state of affairs in the profession and can be used in comparison with the past benchmarks in an attempt to understand the role of women in the collegiate strength and conditioning profession. PMID- 27123924 TI - Genomic and Molecular Characterization of Miltefosine Resistance in Leishmania infantum Strains with Either Natural or Acquired Resistance through Experimental Selection of Intracellular Amastigotes. AB - During the last decade miltefosine (MIL) has been used as first-line treatment for visceral leishmaniasis in endemic areas with antimonial resistance, but a decline in clinical effectiveness is now being reported. While only two MIL resistant Leishmania infantum strains from HIV co-infected patients have been documented, phenotypic MIL-resistance for L. donovani has not yet been identified in the laboratory. Hence, a better understanding of the factors contributing to increased MIL-treatment failure is necessary. Given the paucity of defined MIL resistant L. donovani clinical isolates, this study used an experimental amastigote-selected MIL-resistant L. infantum isolate (LEM3323). In-depth exploration of the MIL-resistant phenotype was performed by coupling genomic with phenotypic data to gain insight into gene function and the mutant phenotype. A naturally MIL-resistant L. infantum clinical isolate (LEM5159) was included to compare both datasets. Phenotypically, resistance was evaluated by determining intracellular amastigote susceptibility in vitro and actual MIL-uptake. Genomic analysis provided supportive evidence that the resistance selection model on intracellular amastigotes can be a good proxy for the in vivo field situation since both resistant strains showed mutations in the same inward transporter system responsible for the acquired MIL-resistant phenotype. In line with previous literature findings in promastigotes, our data confirm a defective import machinery through inactivation of the LiMT/LiRos3 protein complex as the main mechanism for MIL-resistance also in intracellular amastigotes. Whole genome sequencing analysis of LEM3323 revealed a 2 base pair deletion in the LiMT gene that led to the formation an early stop codon and a truncation of the LiMT protein. Interestingly, LEM5159 revealed mutations in both the LiMT and LiRos3 genes, resulting in an aberrant expression of the LiMT protein. To verify that these mutations were indeed accountable for the acquired resistance, transfection experiments were performed to re-establish MIL-susceptibility. In LEM3323, susceptibility was restored upon expression of a LiMT wild-type gene, whereas the MIL-susceptibility of LEM5159 could be reversed after expression of the LiRos3 wild-type gene. The aberrant expression profile of the LiMT protein could be restored upon rescue of the LiRos3 gene both in the LEM5159 clinical isolate and a DeltaLiRos3 strain, showing that expression of LdMT is dependent on LdRos3 expression. The present findings clearly corroborate the pivotal role of the LiMT/LiRos3 complex in resistance towards MIL. PMID- 27123925 TI - Leader Peptide Establishes Dehydration Order, Promotes Efficiency, and Ensures Fidelity During Lacticin 481 Biosynthesis. AB - The mechanisms by which lanthipeptide synthetases control the order in which they catalyze multiple chemical processes are poorly understood. The lacticin 481 synthetase (LctM) cleaves eight chemical bonds and forms six new chemical bonds in a controlled and ordered process. Two general mechanisms have been suggested for the temporal and spatial control of these transformations. In the spatial positioning model, leader peptide binding promotes certain reactions by establishing the spatial orientation of the substrate peptide relative to the synthetase active sites. In the intermediate structure model, the LctM-catalyzed dehydration and cyclization reactions that occur in two distinct active sites orchestrate the overall process by imparting a specific structure into the maturing peptide that facilitates the ensuing reaction. Using isotopically labeled LctA analogues with engineered lacticin 481 biosynthetic machinery and mass spectrometry analysis, we show here that the LctA leader peptide plays critical roles in establishing the modification order and enhancing the catalytic efficiency and fidelity of the synthetase. The data are most consistent with a mechanistic model for LctM where both spatial positioning and intermediate structure contribute to efficient biosynthesis. PMID- 27123928 TI - From Shell Midden to Midden-Mound: The Geoarchaeology of Mound Key, an Anthropogenic Island in Southwest Florida, USA. AB - Mound Key was once the capital of the Calusa Kingdom, a large Pre-Hispanic polity that controlled much of southern Florida. Mound Key, like other archaeological sites along the southwest Gulf Coast, is a large expanse of shell and other anthropogenic sediments. The challenges that these sites pose are largely due to the size and areal extent of the deposits, some of which begin up to a meter below and exceed nine meters above modern sea levels. Additionally, the complex depositional sequences at these sites present difficulties in determining their chronology. Here, we examine the development of Mound Key as an anthropogenic island through systematic coring of the deposits, excavations, and intensive radiocarbon dating. The resulting data, which include the reversals of radiocarbon dates from cores and dates from mound-top features, lend insight into the temporality of site formation. We use these insights to discuss the nature and scale of human activities that worked to form this large island in the context of its dynamic, environmental setting. We present the case that deposits within Mound Key's central area accumulated through complex processes that represent a diversity of human action including midden accumulation and the redeposition of older sediments as mound fill. PMID- 27123926 TI - Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. AB - Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/alpha-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor beta 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors. PMID- 27123927 TI - Design of a Virtual Player for Joint Improvisation with Humans in the Mirror Game. AB - Joint improvisation is often observed among humans performing joint action tasks. Exploring the underlying cognitive and neural mechanisms behind the emergence of joint improvisation is an open research challenge. This paper investigates jointly improvised movements between two participants in the mirror game, a paradigmatic joint task example. First, experiments involving movement coordination of different dyads of human players are performed in order to build a human benchmark. No designation of leader and follower is given beforehand. We find that joint improvisation is characterized by the lack of a leader and high levels of movement synchronization. Then, a theoretical model is proposed to capture some features of their interaction, and a set of experiments is carried out to test and validate the model ability to reproduce the experimental observations. Furthermore, the model is used to drive a computer avatar able to successfully improvise joint motion with a human participant in real time. Finally, a convergence analysis of the proposed model is carried out to confirm its ability to reproduce joint movements between the participants. PMID- 27123929 TI - Th1-Induced CD106 Expression Mediates Leukocytes Adhesion on Synovial Fibroblasts from Juvenile Idiopathic Arthritis Patients. AB - This study tested the hypothesis that subsets of human T helper cells can orchestrate leukocyte adhesion to synovial fibroblasts (SFbs), thus regulating the retention of leukocytes in the joints of juvenile idiopathic arthritis (JIA) patients. Several cell types, such as monocytes/macrophages, granulocytes, T and B lymphocytes, SFbs and osteoclasts participate in joint tissue damage JIA. Among T cells, an enrichment of classic and non-classic Th1 subsets, has been found in JIA synovial fluid (SF), compared to peripheral blood (PB). Moreover, it has been shown that IL-12 in the SF of inflamed joints mediates the shift of Th17 lymphocytes towards the non-classic Th1 subset. Culture supernatants of Th17, classic and non-classic Th1 clones, have been tested for their ability to stimulate proliferation, and to induce expression of adhesion molecules on SFbs, obtained from healthy donors. Culture supernatants of both classic and non classic Th1, but not of Th17, clones, were able to induce CD106 (VCAM-1) up regulation on SFbs. This effect, mediated by tumor necrosis factor (TNF)-alpha, was crucial for the adhesion of circulating leukocytes on SFbs. Finally, we found that SFbs derived from SF of JIA patients expressed higher levels of CD106 than those from healthy donors, resembling the phenotype of SFbs activated in vitro with Th1-clones supernatants. On the basis of these findings, we conclude that classic and non-classic Th1 cells induce CD106 expression on SFbs through TNF alpha, an effect that could play a role in leukocytes retention in inflamed joints. PMID- 27123930 TI - Context Dependent Effect of Landscape on the Occurrence of an Apex Predator across Different Climate Regions. AB - In studies of habitat suitability at landscape scales, transferability of species landscape associations among sites are likely to be critical because it is often impractical to collect datasets across various regions. However, limiting factors, such as prey availability, are not likely to be constant across scales because of the differences in species pools. This is particularly true for top predators that are often the target for conservation concern. Here we focus on gray-faced buzzards, apex predators of farmland-dominated landscapes in East Asia. We investigated context dependency of "buzzard-landscape relationship", using nest location datasets from five sites, each differing in landscape composition. Based on the similarities of prey items and landscape compositions across the sites, we determined several alternative ways of grouping the sites, and then examined whether buzzard-landscape relationship change among groups, which was conducted separately for each way of grouping. As a result, the model of study-sites grouping based on similarities in prey items showed the smallest DeltaAICc. Because the terms of interaction between group IDs and areas of broad leaved forests and grasslands were selected, buzzard-landscape relationship showed a context dependency, i.e., these two landscape elements strengthen the relationship in southern region. The difference in prey fauna, which is associated with the difference in climate, might generate regional differences in the buzzard-landscape associations. PMID- 27123932 TI - Correction: Genetic Diversity in the Major Capsid L1 Protein of HPV-16 and HPV-18 in the Netherlands. AB - [This corrects the article DOI: 10.1371/journal.pone.0152782.]. PMID- 27123931 TI - Inter- and Intra-Observer Repeatability of Quantitative Whole-Body, Diffusion Weighted Imaging (WBDWI) in Metastatic Bone Disease. AB - Quantitative whole-body diffusion-weighted MRI (WB-DWI) is now possible using semi-automatic segmentation techniques. The method enables whole-body estimates of global Apparent Diffusion Coefficient (gADC) and total Diffusion Volume (tDV), both of which have demonstrated considerable utility for assessing treatment response in patients with bone metastases from primary prostate and breast cancers. Here we investigate the agreement (inter-observer repeatability) between two radiologists in their definition of Volumes Of Interest (VOIs) and subsequent assessment of tDV and gADC on an exploratory patient cohort of nine. Furthermore, each radiologist was asked to repeat his or her measurements on the same patient data sets one month later to identify the intra-observer repeatability of the technique. Using a Markov Chain Monte Carlo (MCMC) estimation method provided full posterior probabilities of repeatability measures along with maximum a posteriori values and 95% confidence intervals. Our estimates of the inter observer Intraclass Correlation Coefficient (ICCinter) for log-tDV and median gADC were 1.00 (0.97-1.00) and 0.99 (0.89-0.99) respectively, indicating excellent observer agreement for these metrics. Mean gADC values were found to have ICCinter = 0.97 (0.81-0.99) indicating a slight sensitivity to outliers in the derived distributions of gADC. Of the higher order gADC statistics, skewness was demonstrated to have good inter-user agreement with ICCinter = 0.99 (0.86 1.00), whereas gADC variance and kurtosis performed relatively poorly: 0.89 (0.39 0.97) and 0.96 (0.69-0.99) respectively. Estimates of intra-observer repeatability (ICCintra) demonstrated similar results: 0.99 (0.95-1.00) for log tDV, 0.98 (0.89-0.99) and 0.97 (0.83-0.99) for median and mean gADC respectively, 0.64 (0.25-0.88) for gADC variance, 0.85 (0.57-0.95) for gADC skewness and 0.85 (0.57-0.95) for gADC kurtosis. Further investigation of two anomalous patient cases revealed that a very small proportion of voxels with outlying gADC values lead to instability in higher order gADC statistics. We therefore conclude that estimates of median/mean gADC and tumour volume demonstrate excellent inter- and intra-observer repeatability whilst higher order statistics of gADC should be used with caution when ascribing significance to clinical changes. PMID- 27123933 TI - Elucidating concepts in drug design through taste with natural and artificial sweeteners. AB - Fundamental concepts in biochemistry important for drug design often lack connection to the macroscopic world and can be difficult for students to grasp, particularly those in introductory science courses at the high school and college level. Educational research has shown that multisensory teaching facilitates learning, but teaching at the high school and college level is almost exclusively limited to the visual and auditory senses. This approach neglects the lifetime of experience our students bring to the classroom in the form of taste perception and makes our teaching less supportive of those with sensory impairment. In this article, we outline a novel guided-inquiry activity that utilizes taste perception for a series of natural and artificial sweetener solutions to introduce the concepts of substrate affinity and selectivity in the context of drug design. The findings from this study demonstrate clear gains in student knowledge, as well as an increase in enthusiasm for the fields of biochemistry and drug design. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44(6):550-554, 2016. PMID- 27123935 TI - Evaluating the GW Approximation with CCSD(T) for Charged Excitations Across the Oligoacenes. AB - Charged excitations of the oligoacene family of molecules, relevant for astrophysics and technological applications, are widely studied and therefore provide an excellent system for benchmarking theoretical methods. In this work, we evaluate the performance of many-body perturbation theory within the GW approximation relative to new high-quality CCSD(T) reference data for charged excitations of the acenes. We compare GW calculations with a number of hybrid density functional theory starting points and with eigenvalue self-consistency. Special focus is given to elucidating the trend of GW-predicted excitations with molecule length increasing from benzene to hexacene. We find that GW calculations with starting points based on an optimally tuned range-separated hybrid (OTRSH) density functional and eigenvalue self-consistency can yield quantitative ionization potentials for the acenes. However, for larger acenes, the predicted electron affinities can deviate considerably from reference values. Our work paves the way for predictive and cost-effective GW calculations of charged excitations of molecules and identifies certain limitations of current GW methods used in practice for larger molecules. PMID- 27123934 TI - Multigeneration Cross-Contamination of Mail with Bacillus anthracis Spores. AB - The release of biological agents, including those which could be used in biowarfare or bioterrorism in large urban areas, has been a concern for governments for nearly three decades. Previous incidents from Sverdlosk and the postal anthrax attack of 2001 have raised questions on the mechanism of spread of Bacillus anthracis spores as an aerosol or contaminant. Prior studies have demonstrated that Bacillus atrophaeus is easily transferred through simulated mail handing, but no reports have demonstrated this ability with Bacillus anthracis spores, which have morphological differences that may affect adhesion properties between spore and formite. In this study, equipment developed to simulate interactions across three generations of envelopes subjected to tumbling and mixing was used to evaluate the potential for cross-contamination of B. anthracis spores in simulated mail handling. In these experiments, we found that the potential for cross-contamination through letter tumbling from one generation to the next varied between generations while the presence of a fluidizer had no statistical impact on the transfer of material. Likewise, the presence or absence of a fluidizer had no statistically significant impact on cross-contamination levels or reaerosolization from letter opening. PMID- 27123936 TI - Back to the Future. PMID- 27123938 TI - Correction to Kidd et al. PMID- 27123940 TI - State Laws on Emergency Holds: Updated Data Set. PMID- 27123939 TI - Is the NHS Mental Health Service Preparing Clients to Resume Employment? PMID- 27123942 TI - News & Notes. PMID- 27123941 TI - Admission Rates and Psychiatric Beds in Hong Kong, 1999-2014: A Population-Based Study. PMID- 27123947 TI - Diverse hematological phenotypes of beta-thalassemia carriers. AB - Most beta-thalassemia carriers have mild anemia, low mean corpuscular volume and mean corpuscular hemoglobin, and elevated hemoglobin alpha2 (HbA2 ). However, there is considerable variability resulting from coinheritance with alpha- and/or delta-globin gene mutations, dominant inheritance of beta-thalassemia mutations, highly unstable variant globin chains, large deletions removing part or all of the beta-globin gene cluster, loss of heterozygosity of the beta-globin gene cluster during development, or concomitant erythroid enzyme or membrane protein abnormalities. Recognition of the specific abnormality and correct diagnosis can allay anxiety and unnecessary investigation, help formulate treatment programs, and deliver appropriate genetic and family counseling. PMID- 27123948 TI - Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: A detailed phenotypic study of a family. AB - The clinical and laboratory characteristics of patients with non-syndromic, autosomal dominant thrombocytopenia secondary to germ line ANKRD26 mutations appear to be heterogeneous. Except for a targeted molecular genotyping approach, there is no distinct clinical or laboratory phenotype that has been specifically associated with this particular gene mutation. Such heterogeneity could be due to variations in mutation and genetic background in different families. To understand the phenotypic heterogeneity, we thoroughly studied one affected family using the International Society for Thrombosis and Haemostasis bleeding assessment tool and both clinically validated standard and esoteric platelet testing (electron microscopy (EM) and flow cytometry). We found that decreased platelet aggregation with arachidonic acid and epinephrine agonists was common in affected family members. EM studies demonstrated persistent borderline low mean dense granules per platelet, decreased alpha granules and an increased canalicular network pattern in all affected members. Since these characteristics are subtle or non-pathognomonic, molecular testing for ANKRD26 mutation remains the most reliable test to render a diagnosis and should be considered when evaluating a patient or family with congenital thrombocytopenia, particularly if there is a history of myeloid neoplasms. PMID- 27123949 TI - Large-scale production of Plasmodium falciparum gametocytes for malaria drug discovery. AB - The tightly controlled induction of Plasmodium falciparum gametocytes in large scale culture is a fundamental requirement for malaria drug discovery applications including, but not limited to, high-throughput screening. This protocol uses magnetic separation for isolation of hemozoin-containing parasites in order to (i) increase parasitemia, (ii) decrease hematocrit and (iii) introduce higher levels of young red blood cells in a culture simultaneously within 2-4 h. These parameters, along with red blood cell lysis products that are generated through schizont rupture, are highly relevant for enabling optimum induction of gametocytogenesis in vitro. No other previously published protocols have applied this particular approach for parasite isolation and maximization of fresh red blood cells before inducing gametocytogenesis, which is essential for obtaining highly synchronous gametocyte classical stages on a large scale. In summary, 500-1,000 million stage IV gametocytes can be obtained within 16 d from an initial 10 ml of asexual blood-stage culture. PMID- 27123950 TI - Six alternative proteases for mass spectrometry-based proteomics beyond trypsin. AB - Protein digestion using a dedicated protease represents a key element in a typical mass spectrometry (MS)-based shotgun proteomics experiment. Up to now, digestion has been predominantly performed with trypsin, mainly because of its high specificity, widespread availability and ease of use. Lately, it has become apparent that the sole use of trypsin in bottom-up proteomics may impose certain limits in our ability to grasp the full proteome, missing out particular sites of post-translational modifications, protein segments or even subsets of proteins. To overcome this problem, the proteomics community has begun to explore alternative proteases to complement trypsin. However, protocols, as well as expected results generated from these alternative proteases, have not been systematically documented. Therefore, here we provide an optimized protocol for six alternative proteases that have already shown promise in their applicability in proteomics, namely chymotrypsin, LysC, LysN, AspN, GluC and ArgC. This protocol is formulated to promote ease of use and robustness, which enable parallel digestion with each of the six tested proteases. We present data on protease availability and usage including recommendations for reagent preparation. We additionally describe the appropriate MS data analysis methods and the anticipated results in the case of the analysis of a single protein (BSA) and a more complex cellular lysate (Escherichia coli). The digestion protocol presented here is convenient and robust and can be completed in ~2 d. PMID- 27123952 TI - Spatial resolution of tip-enhanced Raman spectroscopy - DFT assessment of the chemical effect. AB - Experimental evidence of extremely high spatial resolution of tip-enhanced Raman scattering (TERS) has been recently demonstrated. Here, we present a full quantum chemical description (at the density functional level of theory) of the non resonant chemical effects on the Raman spectrum of an adenine molecule mapped by a tip, modeled as a single silver atom or a small silver cluster. We show pronounced changes in the Raman pattern and its intensities depending on the conformation of the nanoparticle-substrate system, concluding that the spatial resolution of the chemical contribution of TERS can be in the sub-nm range. PMID- 27123951 TI - Ex vivo tools for the clonal analysis of zebrafish hematopoiesis. AB - This protocol describes the ex vivo characterization of zebrafish hematopoietic progenitors. We show how to isolate zebrafish hematopoietic cells for cultivation and differentiation in colony assays in semi-solid media. We also describe procedures for the generation of recombinant zebrafish cytokines and for the isolation of carp serum, which are essential components of the medium required to grow zebrafish hematopoietic cells ex vivo. The outcome of these clonal assays can easily be evaluated using standard microscopy techniques after 3-10 d in culture. In addition, we describe how to isolate individual colonies for further imaging and gene expression profiling. In other vertebrate model organisms, ex vivo assays have been crucial for elucidating the relationships among hematopoietic stem cells (HSCs), progenitor cells and their mature progeny. The present protocol should facilitate such studies on cells derived from zebrafish. PMID- 27123953 TI - The relationship between elevated magnesium levels and coronary artery ectasia. AB - BACKGROUND: Coronary artery ectasia (CAE) without specific symptoms is the localised or diffuse swelling of the epicardial coronary arteries. Magnessium (Mg) plays an important role in cardiac excitability, vascular tonus, contractibility, reactivity and vasodilatation. In our research, we aimed to study the vasodilatory effect of Mg in the aetiopathogenesis of ectasia. METHODS: Patients identified during routine coronary angiograms in our clinic between January 2010 and 2013 were included in the study. Sixty-two patients with isolated CAE, 57 with normal coronary angiograms (NCA), 73 with severe coronary artery disease (CAD), and 95 with stenosis of at least one coronary artery and CAE (CAD + CAE) were included in the study. Serum Mg levels were measured in mg/dl after 12 hours of fasting. RESULTS: There were no statistically significant differences between the groups in terms of age, hypertension, smoking, hyperlipidaemia, diabetes mellitus, family history of coronary artery disease and medications used. Serum glucose, thyroid stimulating hormone (TSH), urea, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, sodium and potassium levels were similar in all groups. Serum Mg levels were 1.90 +/- 0.19 mg/dl in patients with isolated CAE, 1.75 +/- 0.19 mg/dl in those with CAD, 1.83 +/- 0.20 mg/dl in those with CAD + CAE, and 1.80 +/- 0.16 mg/dl in the NCA group. These results show that Mg levels were higher in ectasia patients with or without CAD. CONCLUSIONS: The histopathological characteristics of patients with CAE were similar to those with CAD. The specific mechanism of abnormal luminal dilatation seen in CAE however remains to be elucidated. Mg is a divalent cation with powerful vasodilatory effects. In our study, serum Mg levels were found to be statistically higher in ectasia patients with or without CAD. PMID- 27123954 TI - Two Therapies Are Better than One: Optimizing Recovery from ARDS. PMID- 27123955 TI - Hyperbaric oxygen therapy for late radiation tissue injury. AB - BACKGROUND: Cancer is a significant global health problem. Radiotherapy is a treatment for many cancers and about 50% of people having radiotherapy will be long-term survivors. Some will experience late radiation tissue injury (LRTI) developing months or years later. Hyperbaric oxygen therapy (HBOT) has been suggested as a treatment for LRTI based upon the ability to improve the blood supply to these tissues. It is postulated that HBOT may result in both healing of tissues and the prevention of problems following surgery. OBJECTIVES: To assess the benefits and harms of HBOT for treating or preventing LRTI. SEARCH METHODS: We updated the searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 11), MEDLINE, EMBASE, DORCTIHM and reference lists of articles in December 2015. We also searched for ongoing trials at clinicaltrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effect of HBOT versus no HBOT on LRTI prevention or healing. DATA COLLECTION AND ANALYSIS: Three review authors independently evaluated the quality of the relevant trials using the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and extracted the data from the included trials. MAIN RESULTS: Fourteen trials contributed to this review (753 participants). There was some moderate quality evidence that HBOT was more likely to achieve mucosal coverage with osteoradionecrosis (ORN) (risk ratio (RR) 1.3; 95% confidence interval (CI) 1.1 to 1.6, P value = 0.003, number needed to treat for an additional beneficial outcome (NNTB) 5; 246 participants, 3 studies). There was also moderate quality evidence of a significantly improved chance of wound breakdown without HBOT following operative treatment for ORN (RR 4.2; 95% CI 1.1 to 16.8, P value = 0.04, NNTB 4; 264 participants, 2 studies). From single studies there was a significantly increased chance of improvement or cure following HBOT for radiation proctitis (RR 1.72; 95% CI 1.0 to 2.9, P value = 0.04, NNTB 5), and following both surgical flaps (RR 8.7; 95% CI 2.7 to 27.5, P value = 0.0002, NNTB 4) and hemimandibulectomy (RR 1.4; 95% CI 1.1 to 1.8, P value = 0.001, NNTB 5). There was also a significantly improved probability of healing irradiated tooth sockets following dental extraction (RR 1.4; 95% CI 1.1 to 1.7, P value = 0.009, NNTB 4).There was no evidence of benefit in clinical outcomes with established radiation injury to neural tissue, and no randomised data reported on the use of HBOT to treat other manifestations of LRTI. These trials did not report adverse events. AUTHORS' CONCLUSIONS: These small trials suggest that for people with LRTI affecting tissues of the head, neck, anus and rectum, HBOT is associated with improved outcome. HBOT also appears to reduce the chance of ORN following tooth extraction in an irradiated field. There was no such evidence of any important clinical effect on neurological tissues. The application of HBOT to selected participants and tissues may be justified. Further research is required to establish the optimum participant selection and timing of any therapy. An economic evaluation should be undertaken. PMID- 27123956 TI - Infant Growth following Maternal Participation in a Gestational Weight Management Intervention. AB - BACKGROUND: Obesity is widespread and treatment strategies have demonstrated limited success. Changes to obstetrical practice in response to obesity may support obesity prevention by influencing offspring growth trajectories. METHODS: This retrospective cohort study examined growth among infants born to obese mothers who participated in Nutrition in Pregnancy (NIP), a prenatal nutrition intervention at one urban hospital. NIP participants had Medicaid insurance and BMIs of 30 kg/m(2) or greater. We compared NIP infant growth to a historical control cohort, matched on maternal factors: age, race/ethnicity, prepregnancy BMI, parity, and history of prepregnancy hypertension or preterm birth. RESULTS: Growth data were available for 61 NIP and 145 control infants. Most mothers were African American (94%). Mean maternal BMI was 39.9 kg/m(2) (standard deviation [SD], 5.6) for NIP participants and 38.8 kg/m(2) (SD, 6.0) for controls. Pregnancy outcomes, including preterm birth, gestational diabetes, and birth weight, did not differ between groups. NIP participants were more likely to attend a postpartum visit (69% vs. 52%; p value, 0.03). At 1 year, 17% of NIP infants and 15% of controls had weight-for-length (WFL) >=95th percentile (p value, 0.66). Other markers of accelerated infant growth, including crossing WFL percentiles and peak infant BMI, did not differ between groups. CONCLUSIONS: There was no difference in growth between infants whose mothers participated in a prenatal nutrition intervention and those whose mothers did not. Existing prenatal programs for obese women may be inadequate to prevent pediatric obesity without pediatric collaboration to promote family-centered support beyond pregnancy. PMID- 27123957 TI - Surgical treatment of breast lesions at a Day Centre: Experience of the European Institute of Oncology. AB - Breast cancer is the commonest malignancy in women worldwide. The reduced aggressiveness of breast cancer surgery has made it possible treat patients in the day surgery setting. The European Institute of Oncology, Milan, opened its new Day Center in May 2010. From May 2010 to December 2014, 17,087 patients with breast conditions were treated by the Institute's Division of Senology, 4132 (24.2%) of these in the day surgery setting, including malignant and benign conditions; 204 (4.9%) were not discharged on the day of surgery, being converted to inpatients; five (0.1%) patients returned to hospital for persistent hematoma. Our experience of performing breast cancer surgery in the day surgery setting is in line that of the literature. It is safe, but requires a well-organized unit and multidisciplinary medical team to function smoothly, with much attention paid to patient comfort and education, so as to ensure maximum patient acceptance and satisfaction. PMID- 27123958 TI - Predictors for extensive nodal involvement in breast cancer patients with axillary lymph node metastases. AB - PURPOSE: Various prediction models have been developed to predict the risk of having no additional axillary metastases in patients with a positive sentinel lymph node biopsy (SLNB), thereby disregarding patients with a positive ultrasound-guided lymph node biopsy (UGLNB). However, in the post-Z0011 trial era it is important to identify all patients with extensive nodal involvement for whom axillary treatment might still be beneficial. Therefore, the aim of this study is to identify factors predicting extensive nodal involvement (>=3 positive nodes) in the axilla, with the emphasis on the method of axillary staging: node positivity by UGLNB versus SLNB. METHODS: All patients diagnosed with invasive breast cancer between January 2006 and December 2011 at the Maxima Medical Center were included. Univariate and multivariate logistic regression analyses were performed. RESULTS: We included 302 cases, representing 301 node positive patients, of whom 177 cases had 1 or 2 positive lymph nodes and 125 cases had >=3 positive lymph nodes. Multivariate analyses showed that a positive UGLNB (OR = 5.10; 95%CI = 2.78-9.36), lymphovascular invasion (OR = 3.60; 95%CI = 1.79-7.23) and a larger tumor size (OR = 1.03 per mm increase; 95%CI = 1.00-1.06) were significantly associated with extensive nodal involvement in patients with invasive breast cancer. CONCLUSION: This study shows that a positive axilla, determined by UGLNB, is the most important factor for predicting further extensive nodal involvement. Hence, the role of axillary staging by ultrasound should be redefined since it might play an important role in selecting patients who may still benefit from axillary treatment. PMID- 27123959 TI - Reconstruction of an Extensive Midfacial Defect Using Additive Manufacturing Techniques. AB - Malignant peripheral nerve sheath tumors are extremely rare tumors arising in peripheral nerves. Only 17 cases involving the trigeminal nerve have ever been reported. These tumors have a very poor prognosis and very high rates of recurrence and metastases. Their recommended treatment involves complete tumor resection followed by radiation. This can be problematic in the head and neck region. We present a clinical case involving a 33-year-old female patient presenting with a slow-growing, exophytic mass of the anterior maxilla. Incisional biopsy and subsequent histological examination revealed a diagnosis of a malignant peripheral nerve sheath tumor. Surgical resection involved a complete maxillectomy, rhinectomy, and resection of the upper lip and aspects of the left and right cheeks. Reconstruction of the subsequent defect incorporated the placement of four zygomatic oncology implants to aid in retention of a facial prosthesis. These implants, however, were subsequently lost; and an anatomical model of the hard tissues was manufactured via 3D printing. This model was used to design and manufacture a titanium frame (customized implant) for the patient. The frame was then fixated and secured intraoperatively with 21 cortical screws. A maxillary denture and silicone facial prosthesis were also made to fit onto this frame. This is the first known case where additive manufacturing, via the use of rapid prototyping and 3D printing, was employed to manufacture a facial prosthesis. PMID- 27123960 TI - Subject-specific musculoskeletal modelling in patients before and after total hip arthroplasty. AB - The goal of this study was to define the effect on hip contact forces of including subject-specific moment generating capacity in the musculoskeletal model by scaling isometric muscle strength and by including geometrical information in control subjects, hip osteoarthritis and total hip arthroplasty patients. Scaling based on dynamometer measurements decreased the strength of all flexor and abductor muscles. This resulted in a model that lacked the capacity to generate joint moments required during functional activities. Scaling muscle forces based on functional activities and inclusion of MRI-based geometrical detail did not compromise the model strength and resulted in hip contact forces comparable to previously reported measured contact forces. PMID- 27123961 TI - Molecular-Level Understanding of the Encapsulation and Dissolution of Poorly Water-Soluble Ibuprofen by Functionalized Organic Nanotubes Using Solid-State NMR Spectroscopy. AB - A comprehensive study of the encapsulation and dissolution of the poorly water soluble drug ibuprofen (IBU) using two types of organic nanotubes (ONT-1 and ONT 2) was conducted. ONT-1 and ONT-2 had similar inner and outer diameters, but these surfaces were functionalized with different groups. IBU was encapsulated by each ONT via solvent evaporation. The amount of IBU in the ONTs was 9.1 and 29.2 wt % for ONT-1 and ONT-2, respectively. Dissolution of IBU from ONT-1 was very rapid, while from ONT-2 it was slower after the initial burst release. One dimensional (1D) (1)H, (13)C, and two-dimensional (2D) (1)H-(13)C solid-state NMR measurements using fast magic-angle spinning (MAS) at a rate of 40 kHz revealed the molecular state of the encapsulated IBU in each ONT. Extremely mobile IBU was observed inside the hollow nanosapce of both ONT-1 and ONT-2 using (13)C MAS NMR with a single pulse (SP) method. Interestingly, (13)C cross-polarization (CP) MAS NMR demonstrated that IBU also existed on the outer surface of both ONTs. The encapsulation ratios of IBU inside the hollow nanospaces versus on the outer surfaces were calculated by waveform separation to be approximately 1:1 for ONT-1 and 2:1 for ONT-2. Changes in (13)C chemical shifts showed the intermolecular interactions between the carboxyl group of IBU and the amino group on the ONT-2 inner surface. The cationic ONT-2 could form the stronger electrostatic interactions with IBU in the hollow nanosapce than anionic ONT-1. On the other hand, 2D (1)H-(13)C NMR indicated that the hydroxyl groups of the glucose unit on the outer surface of the ONTs interacted with the carboxyl group of IBU in both ONT-1 and ONT-2. The changes in peak shape and chemical shift of the ONT glucose group after IBU encapsulation were larger in ONT-2 than in ONT-1, indicating a stronger interaction between IBU and the outer surface of ONT-2. The smaller amount of IBU encapsulation and rapid IBU dissolution from ONT-1 could be due to the weak interactions both at the outer and inner surfaces. Meanwhile, the stronger interaction between IBU and the inner surface of ONT-2 could suppress IBU dissolution, although the IBU on the outer surface of ONT-2 was released soon after dispersal in water. This study demonstrates that the encapsulation amount and the dissolution rates of poorly water-soluble drugs, a class which makes up the majority of new drug candidates, can be controlled using the functional groups on the surfaces of ONTs by considering the host-guest interactions. PMID- 27123962 TI - Biocatalytic Properties and Structural Analysis of Eugenol Oxidase from Rhodococcus jostii RHA1: A Versatile Oxidative Biocatalyst. AB - Eugenol oxidase (EUGO) from Rhodococcus jostii RHA1 had previously been shown to convert only a limited set of phenolic compounds. In this study, we have explored the biocatalytic potential of this flavoprotein oxidase, resulting in a broadened substrate scope and a deeper insight into its structural properties. In addition to the oxidation of vanillyl alcohol and the hydroxylation of eugenol, EUGO can efficiently catalyze the dehydrogenation of various phenolic ketones and the selective oxidation of a racemic secondary alcohol-4-(1-hydroxyethyl)-2 methoxyphenol. EUGO was also found to perform the kinetic resolution of a racemic secondary alcohol. Crystal structures of the enzyme in complexes with isoeugenol, coniferyl alcohol, vanillin, and benzoate have been determined. The catalytic center is a remarkable solvent-inaccessible cavity on the si side of the flavin cofactor. Structural comparison with vanillyl alcohol oxidase from Penicillium simplicissimum highlights a few localized changes that correlate with the selectivity of EUGO for phenolic substrates bearing relatively small p substituents while tolerating o-methoxy substituents. PMID- 27123963 TI - Morningness-eveningness and amplitude - development and validation of an improved composite scale to measure circadian preference and stability (MESSi). AB - Measuring morningness-eveningness is an important aspect of individual differences because it is associated with many aspects of personality and health. The present study outlines recent advancements in the field of measurement and proposes an improved assessment of morningness-eveningness, such as the measurement of circadian amplitude, updating and reflecting new item developments, addressing the clock time based measures, the morning-biased items and the aspect of uni versus multidimensionality. Four studies have been carried out in Germany to present a novel development (with a total sample of N = 1181). In study I, the exploratory factor analysis (EFA) revealed three dimensions, one of morningness, one of eveningness and one of amplitude/stability. Then, items were reduced to present a clearer factor structure by removing ambiguous items. In the second study, a shortened questionnaire was applied, with 15 items (5 per construct), but Confirmatory Factor Analysis (CFA) did not provide acceptable fit indices. Refining items were made in study III, which again showed a clearer factor structure in EFA, and subsequently, in study IV, the refined set of 15 items provided a good fit of a CFA. The final questionnaire was tested for validity by applying clock times, personality questions and alertness ratings. Thus, this newly developed questionnaire contains three distinct dimensions. To reflect the new content, the scale is labelled morningness-eveningness-stability scale improved (MESSi). PMID- 27123964 TI - Mixture of time-dependent growth models with an application to blue swimmer crab length-frequency data. AB - Understanding how aquatic species grow is fundamental in fisheries because stock assessment often relies on growth dependent statistical models. Length-frequency based methods become important when more applicable data for growth model estimation are either not available or very expensive. In this article, we develop a new framework for growth estimation from length-frequency data using a generalized von Bertalanffy growth model (VBGM) framework that allows for time dependent covariates to be incorporated. A finite mixture of normal distributions is used to model the length-frequency cohorts of each month with the means constrained to follow a VBGM. The variances of the finite mixture components are constrained to be a function of mean length, reducing the number of parameters and allowing for an estimate of the variance at any length. To optimize the likelihood, we use a minorization-maximization (MM) algorithm with a Nelder-Mead sub-step. This work was motivated by the decline in catches of the blue swimmer crab (BSC) (Portunus armatus) off the east coast of Queensland, Australia. We test the method with a simulation study and then apply it to the BSC fishery data. PMID- 27123965 TI - Bis(haloBODIPYs) with Labile Helicity: Valuable Simple Organic Molecules That Enable Circularly Polarized Luminescence. AB - Simple organic molecules (SOM) based on bis(haloBODIPY) are shown to enable circularly polarized luminescence (CPL), giving rise to a new structural design for technologically valuable CPL-SOMs. The established design comprises together synthetic accessibility, labile helicity, possibility of reversing the handedness of the circularly polarized emission, and reactive functional groups, making it unique and attractive as advantageous platform for the development of smart CPL SOMs. PMID- 27123971 TI - Quality decline and oxidative damage in sperm of freshwater crab Sinopotamon henanense exposed to lead. AB - Lead (Pb) induces male infertility in vertebrates. Whether lead is related to reproductive abnormalities in aquatic invertebrates remains uncertain. In this work, effects of Pb on the sperm quality and oxidative stress of the freshwater crab Sinopotamon henanense were investigated after 3, 5 and 7d exposure to different Pb concentrations (0, 3.675, 7.35, 14.7, 29.4 and 58.8mg/L). Sperm quality indices including sperm plasma-membrane integrity and acrosomal-membrane integrity were measured by flow cytometry. DNA integrity was measured by fluorescence microscopy. The results showed that Pb levels in sperm increased significantly upon Pb exposure in most treated groups, sperm plasma-membrane integrity, acrosomal-membrane integrity, and DNA integrity were reduced at higher concentrations after 5 d and 7d. Oxidative stress of sperm induced by Pb was reflected in significant up-regulation of reactive oxygen species (ROS) levels after 3, 5 and 7d. A significant reduction of the total antioxidant capacity levels occurred after exposure to 14.7mg/L Pb and above at 7d compared to the control. The results of oxidative damage to lipids, proteins and DNA of sperm showed that malondialdehyde, protein carbonylation and DNA-protein crosslinks were increased in a concentration- and time-dependent manner. Our findings document that Pb can induce harmful effects on several reproductive endpoints in a freshwater crab. PMID- 27123972 TI - Study of temporal trends in mercury concentrations in the primary flight feathers of Strix aluco. AB - Temporal trends in Hg concentrations were determined in the primary flight feathers of 146 specimens of Strix aluco which had died in various Wildlife Recovery Centres in Galicia (NW Spain) between 1997 and 2014. The aim of the study was to determine whether standardization of a primary flight feather (or feathers) in this species is essential for identifying temporal trends in Hg concentrations. For this purpose, we had to first standardize the feather(s) analyzed to enable comparison of the levels of Hg detected in different feathers. The results show a high degree of both inter and intra-individual variability but despite that, it was possible to identify P5 as the most representative feather taking into account the amount of metal excreted in each feather and the intra individual variability: its median was 133ng, which represents 15% (from 7% to 15%) of the total Hg present in all the primary feathers. However, this "standard feather" did not reveal any temporal trend in Hg concentrations for the study period. This lack of trend was found irrespective of the feather considered and it is expected that detection of any existing trend would also not depend on the feather considered. We conclude that use of any particular feather is not essential for identifying temporal trends in Hg concentrations, because the pattern will be identified regardless of the feather selected. PMID- 27123973 TI - The response of thyroid hormones, biochemical and enzymological biomarkers to pyrene exposure in common carp (Cyprinus carpio). AB - Polycyclic Aromatic Hydrocarbons (PAHs) are discharged into aquatic environments through anthropogenic activities mainly industrial and municipal effluents. There is little information on the adverse effects of pyrene, a member of the PAH family which is classified as a priority pollutant by the USEPA, on fish biochemical and physiological endpoints, particularly thyroid hormones. The present study investigated the effects of subacute semi-static pyrene exposure on biochemical, enzymological and ionoregulatory responses as well as thyroid hormones in common carp (Cyprinus carpio). The fish (140+/-10g, 1(+) year) were exposed to 10, 50 and 100ug/l nominal concentrations of pyrene for 35 days. The results revealed that pyrene at these concentrations significantly altered plasma levels of glucose, cholesterol, triglyceride, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Moreover, plasma thyroid hormones (T3 and T4) were significantly decreased in fish exposed to pyrene. In contrast, plasma electrolytes (sodium, potassium and calcium) levels remained statistically unchanged after exposure to the various pyrene concentrations. In conclusion, the studied biomarkers may be used as monitoring tools to evaluate pyrene toxicity. Pyrene induced diverse effects on the physiological endpoints of common carp, thus this chemical should be considered in toxicity studies concerning PAHs. Furthermore, this study confirmed that there was an interaction between pyrene and the thyroid system in fish. Therefore, the thyroid system may be used to assess the impact of pyrene on fish. PMID- 27123974 TI - alpha-fetoprotein levels after interferon therapy predict regression of liver fibrosis in patients with sustained virological response. AB - BACKGROUND AND AIMS: Eradicating chronic hepatitis C virus (HCV) infection improves liver fibrosis and reduces hepatocellular carcinoma (HCC) incidence in chronic HCV patients. We evaluated the relationship between fibrosis regression, as assessed by sequential biopsies, and clinical factors of patients with sustained virological response (SVR). METHODS: We retrospectively enrolled 130 patients (74 men; 60.1 +/- 8.1 years) with chronic HCV treated with interferon and ribavirin therapy who achieved SVR. To evaluate the change in fibrosis stage over time, all patients underwent a pre-therapy initial biopsy and a second biopsy after achieving SVR. RESULTS: The mean time between biopsies was 5.5 +/- 1.2 years. Fibrosis stage regressed in 55 patients (42.3%), remained stable in 69 (53.1%), and progressed in 6 (4.6%). The mean fibrosis stage significantly decreased, from 2.01 +/- 0.99 units to 1.61 +/- 1.24 units (P < 0.001). Aspartate aminotransferase, gamma-glutamyltransferase, and alpha-fetoprotein (AFP) levels at 24 weeks after the end of treatment (EOT) were significantly lower, and the platelet count at 24 weeks after the EOT was significantly higher in patients with fibrosis regression than in those without. Logistic regression analysis confirmed that lower AFP levels (< 5.4 ng/mL) at 24 weeks after the EOT (odds ratio [OR], 4.626; 95% confidence interval [CI], 1.557-13.153; P = 0.006) and HCV genotype 2 (OR, 2.198; 95% CI, 1.010-4.786; P = 0.047) were significant independent predictive factors for regressed fibrosis after SVR. CONCLUSIONS: Lower post-treatment AFP levels and HCV genotype 2 significantly correlated with liver fibrosis regression after SVR. PMID- 27123975 TI - Developing a Clinical Prediction Rule for First Hospital-Onset Clostridium difficile Infections: A Retrospective Observational Study. AB - BACKGROUND The healthcare burden of hospital-acquired Clostridium difficile infection (CDI) demands attention and calls for a solution. Identifying patients' risk of developing a primary nosocomial CDI is a critical first step in reducing the development of new cases of CDI. OBJECTIVE To derive a clinical prediction rule that can predict a patient's risk of acquiring a primary CDI. DESIGN Retrospective cohort study. SETTING Large tertiary healthcare center. PATIENTS Total of 61,482 subjects aged at least 18 admitted over a 1-year period (2013). INTERVENTION None. METHODS Patient demographic characteristics, evidence of CDI, and other risk factors were retrospectively collected. To derive the CDI clinical prediction rule the patient population was divided into a derivation and validation cohort. A multivariable analysis was performed in the derivation cohort to identify risk factors individually associated with nosocomial CDI and was validated on the validation sample. RESULTS Among 61,482 subjects, CDI occurred in 0.46%. CDI outcome was significantly associated with age, admission in the past 60 days, mechanical ventilation, dialysis, history of congestive heart failure, and use of antibiotic medications. The sensitivity and specificity of the score, in the validation set, were 82.0% and 75.7%, respectively. The area under the receiver operating characteristic curve was 0.85. CONCLUSION This study successfully derived a clinical prediction rule that will help identify patients at high risk for primary CDI. This tool will allow physicians to systematically recognize those at risk for CDI and will allow for early interventional strategies. Infect Control Hosp Epidemiol 2016;37:896-900. PMID- 27123977 TI - Cognitive models for panic disorder with agoraphobia: A study of disaggregated within-person effects. AB - OBJECTIVE: The purpose of this study was to test 2 cognitive models of panic disorder with agoraphobia (PDA)-a catastrophic cognitions model and a low self efficacy model-by examining the within-person effects of model-derived cognitive variables on subsequent anxiety symptoms. METHOD: Participants were 46 PDA patients with agoraphobic avoidance of moderate to severe degree who were randomly allocated to 6 weeks of either cognitive therapy, based on the catastrophic cognitions model of PDA, or guided mastery (guided exposure) therapy, based on the self-efficacy model of PDA. Cognitions and anxiety were measured weekly over the course of treatment. The data were analyzed with mixed models, using person-mean centering to disaggregate within- and between-person effects. RESULTS: All of the studied variables changed in the expected way over the course of therapy. There was a within-person effect of physical fears, loss of control fears, social fears, and self-efficacy when alone on subsequent state anxiety. On the other hand, within-person changes in anxiety did not predict subsequent cognitions. Loss of control and social fears both predicted subsequent self-efficacy, whereas self-efficacy did not predict catastrophic cognitions. In a multipredictor analysis, within-person catastrophic cognitions still predicted subsequent anxiety, but self-efficacy when alone did not. CONCLUSIONS: Overall, the findings indicate that anxiety in PDA, at least in severe and long-standing cases, is driven by catastrophic cognitions. Thus, these cognitions seem to be useful therapeutic targets. (PsycINFO Database Record PMID- 27123976 TI - Prognostic Value of Quantitative Metabolic Metrics on Baseline Pre-Sunitinib FDG PET/CT in Advanced Renal Cell Carcinoma. AB - PURPOSE: The objective of this study was to prospectively evaluate various quantitative metrics on FDG PET/CT for monitoring sunitinib therapy and predicting prognosis in patients with metastatic renal cell cancer (mRCC). METHODS: Seventeen patients (mean age: 59.0 +/- 11.6) prospectively underwent a baseline FDG PET/CT and interim PET/CT after 2 cycles (12 weeks) of sunitinib therapy. We measured the highest maximum standardized uptake value (SUVmax) of all identified lesions (highest SUVmax), sum of SUVmax with maximum six lesions (sum of SUVmax), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) from baseline PET/CT and interim PET/CT, and the % decrease in highest SUVmax of lesion (%Delta highest SUVmax), the % decrease in sum of SUVmax, the % decrease in TLG (%DeltaTLG) and the % decrease in MTV (%DeltaMTV) between baseline and interim PET/CT, and the imaging results were validated by clinical follow-up at 12 months after completion of therapy for progression free survival (PFS). RESULTS: At 12 month follow-up, 6/17 (35.3%) patients achieved PFS, while 11/17 (64.7%) patients were deemed to have progression of disease or recurrence within the previous 12 months. At baseline, PET/CT demonstrated metabolically active cancer in all cases. Using baseline PET/CT alone, all of the quantitative imaging metrics were predictive of PFS. Using interim PET/CT, the %Delta highest SUVmax, %Delta sum of SUVmax, and %DeltaTLG were also predictive of PFS. Otherwise, interim PET/CT showed no significant difference between the two survival groups regardless of the quantitative metric utilized including MTV and TLG. CONCLUSIONS: Quantitative metabolic measurements on baseline PET/CT appears to be predictive of PFS at 12 months post-therapy in patients scheduled to undergo sunitinib therapy for mRCC. Change between baseline and interim PET/CT also appeared to have prognostic value but otherwise interim PET/CT after 12 weeks of sunitinib did not appear to be predictive of PFS. PMID- 27123978 TI - Design, Synthesis, and Biological Activity of Isosyringolin A. AB - Isosyringolin A, which is an isomer of the proteasome-inhibiting natural product syringolin A, was designed and synthesized to develop analogues that are step economical and synthetically accessible in a practical manner. It was revealed that isosyringolin A exhibited proteasome-inhibitory activity comparable to that of syringolin A and that its derivatization leads to great enhancement in its proteasome inhibitory activity as well as its cytotoxicity against human myeloma cells. PMID- 27123979 TI - Distinct Biochemical Pools of Golgi Phosphoprotein 3 in the Human Breast Cancer Cell Lines MCF7 and MDA-MB-231. AB - Golgi phosphoprotein 3 (GOLPH3) has been implicated in the development of carcinomas in many human tissues, and is currently considered a bona fide oncoprotein. Importantly, several tumor types show overexpression of GOLPH3, which is associated with tumor progress and poor prognosis. However, the underlying molecular mechanisms that connect GOLPH3 function with tumorigenicity are poorly understood. Experimental evidence shows that depletion of GOLPH3 abolishes transformation and proliferation of tumor cells in GOLPH3 overexpressing cell lines. Conversely, GOLPH3 overexpression drives transformation of primary cell lines and enhances mouse xenograft tumor growth in vivo. This evidence suggests that overexpression of GOLPH3 could result in distinct features of GOLPH3 in tumor cells compared to that of non-tumorigenic cells. GOLPH3 is a peripheral membrane protein mostly localized at the trans Golgi network, and its association with Golgi membranes depends on binding to phosphatidylinositol-4-phosphate. GOLPH3 is also contained in a large cytosolic pool that rapidly exchanges with Golgi-associated pools. GOLPH3 has also been observed associated with vesicles and tubules arising from the Golgi, as well as other cellular compartments, and hence it has been implicated in several membrane trafficking events. Whether these and other features are typical to all different types of cells is unknown. Moreover, it remains undetermined how GOLPH3 acts as an oncoprotein at the Golgi. Therefore, to better understand the roles of GOLPH3 in cancer cells, we sought to compare some of its biochemical and cellular properties in the human breast cancer cell lines MCF7 and MDA-MB-231 with that of the non-tumorigenic breast human cell line MCF 10A. We found unexpected differences that support the notion that in different cancer cells, overexpression of GOLPH3 functions in diverse fashions, which may influence specific tumorigenic phenotypes. PMID- 27123980 TI - USP7 and TDP-43: Pleiotropic Regulation of Cryptochrome Protein Stability Paces the Oscillation of the Mammalian Circadian Clock. AB - Mammalian Cryptochromes, CRY1 and CRY2, function as principal regulators of a transcription-translation-based negative feedback loop underlying the mammalian circadian clockwork. An F-box protein, FBXL3, promotes ubiquitination and degradation of CRYs, while FBXL21, the closest paralog of FBXL3, ubiquitinates CRYs but leads to stabilization of CRYs. Fbxl3 knockout extremely lengthened the circadian period, and deletion of Fbxl21 gene in Fbxl3-deficient mice partially rescued the period-lengthening phenotype, suggesting a key role of CRY protein stability for maintenance of the circadian periodicity. Here, we employed a proteomics strategy to explore regulators for the protein stability of CRYs. We found that ubiquitin-specific protease 7 (USP7 also known as HAUSP) associates with CRY1 and CRY2 and stabilizes CRYs through deubiquitination. Treatment with USP7-specific inhibitor or Usp7 knockdown shortened the circadian period of the cellular rhythm. We identified another CRYs-interacting protein, TAR DNA binding protein 43 (TDP-43), an RNA-binding protein. TDP-43 stabilized CRY1 and CRY2, and its knockdown also shortened the circadian period in cultured cells. The present study identified USP7 and TDP-43 as the regulators of CRY1 and CRY2, underscoring the significance of the stability control process of CRY proteins for period determination in the mammalian circadian clockwork. PMID- 27123982 TI - Lagrange Interpolation Learning Particle Swarm Optimization. AB - In recent years, comprehensive learning particle swarm optimization (CLPSO) has attracted the attention of many scholars for using in solving multimodal problems, as it is excellent in preserving the particles' diversity and thus preventing premature convergence. However, CLPSO exhibits low solution accuracy. Aiming to address this issue, we proposed a novel algorithm called LILPSO. First, this algorithm introduced a Lagrange interpolation method to perform a local search for the global best point (gbest). Second, to gain a better exemplar, one gbest, another two particle's historical best points (pbest) are chosen to perform Lagrange interpolation, then to gain a new exemplar, which replaces the CLPSO's comparison method. The numerical experiments conducted on various functions demonstrate the superiority of this algorithm, and the two methods are proven to be efficient for accelerating the convergence without leading the particle to premature convergence. PMID- 27123981 TI - The Impact of Normal Range of Serum Phosphorus on the Incidence of End-Stage Renal Disease by A Propensity Score Analysis. AB - BACKGROUND: Although hyperphosphatemia is deemed a risk factor of the progression of chronic kidney disease (CKD), it remains unclear whether the normal range of serum phosphorus likewise deteriorates CKD. A propensity score analysis was applied to examine the causal effect of the normal range of serum phosphorus on the incidence of end-stage renal disease (ESRD). METHODS: A retrospective CKD cohort of 803 participants in a single institution was analyzed. Propensity score was estimated using 22 baseline covariates by multivariate binary logistic regression for the different thresholds of time-averaged phosphorus (TA-P) in the normal range of serum phosphorus incremented by 0.1 mg/dL from 3.3 to 4.5 mg/dL. RESULTS: The incidence rate of ESRD was 33.9 per 1,000 person-years over median follow-up of 4.3 years. Total patients showed the mean baseline phosphorus of 3.37 mg/dL and were divided to quartile. The higher quartile was associated with the parameters consistent with the advancement of CKD. A stratified Cox regression showed the highest hazard ratio (HR) at TA-P 3.4 mg/dL (HR 17.60, 95% CI 3.92-78.98) adjusted for baseline covariates such as sex, age, diabetic nephropathy, estimated GFR, serum albumin, Na-Cl, phosphorus, LDL-C and proteinuria. Adjusted HRs remained high up to TA-P 4.2 mg/dL (HR 2.22, 95% CI 1.33-3.71). After propensity score matching conducted at the thresholds of TA-P 3.4, 3.6, 3.8 and 4.0 mg/dL, the higher levels of TA-P showed the higher HRs by Kaplan-Meier analysis (p < 0.05 by stratified log-rank test). The numbers needed to treat were calculated as 3.9 to 5.3 over 5 years. CONCLUSIONS: The propensity score analysis shows that even the normal range of serum phosphorus clearly accelerates CKD progression to ESRD. Our results encourage clinicians to target serum phosphorus to inhibit CKD progression in the manner of 'the lower the better.' PMID- 27123985 TI - Erratum. PMID- 27123983 TI - The MADD-3 LAMMER Kinase Interacts with a p38 MAP Kinase Pathway to Regulate the Display of the EVA-1 Guidance Receptor in Caenorhabditis elegans. AB - The proper display of transmembrane receptors on the leading edge of migrating cells and cell extensions is essential for their response to guidance cues. We previously discovered that MADD-4, which is an ADAMTSL secreted by motor neurons in Caenorhabditis elegans, interacts with an UNC-40/EVA-1 co-receptor complex on muscles to attract plasma membrane extensions called muscle arms. In nematodes, the muscle arm termini harbor the post-synaptic elements of the neuromuscular junction. Through a forward genetic screen for mutants with disrupted muscle arm extension, we discovered that a LAMMER kinase, which we call MADD-3, is required for the proper display of the EVA-1 receptor on the muscle's plasma membrane. Without MADD-3, EVA-1 levels decrease concomitantly with a reduction of the late endosomal marker RAB-7. Through a genetic suppressor screen, we found that the levels of EVA-1 and RAB-7 can be restored in madd-3 mutants by eliminating the function of a p38 MAP kinase pathway. We also found that EVA-1 and RAB-7 will accumulate in madd-3 mutants upon disrupting CUP-5, which is a mucolipin ortholog required for proper lysosome function. Together, our data suggests that the MADD 3 LAMMER kinase antagonizes the p38-mediated endosomal trafficking of EVA-1 to the lysosome. In this way, MADD-3 ensures that sufficient levels of EVA-1 are present to guide muscle arm extension towards the source of the MADD-4 guidance cue. PMID- 27123984 TI - Effectiveness of Community Dialogue in Changing Gender and Sexual Norms for HIV Prevention: Evaluation of the Tchova Tchova Program in Mozambique. AB - Structural HIV prevention interventions have gained prominence as ways to address underlying social and cultural factors that fuel the HIV epidemic. Identifying theories that explain how structural interventions are expected to change such factors can substantially increase their success. The Tchova Tchova community dialogue program, a theory-based intervention implemented in 2009-2010 in the provinces of Zambezia and Sofala, Mozambique, aimed to change gender and sexual norms for HIV prevention. Through facilitated sessions, the program sparked critical thinking and open dialogue among participants. This article measures the program's effectiveness based on a sample of 462 participants and 453 nonparticipants. The results show that the program was successful in producing changes in three of the underlying structural factors of HIV: gender attitudes, gender roles, and HIV stigma. The program was also successful in changing other factors associated with HIV infection, including HIV prevention knowledge, discussion of HIV between sex partners, and having multiple sex partners. PMID- 27123986 TI - Maintaining the anonymity of cadavers in medical education: Historic relic or educational and ethical necessity? AB - Throughout the modern history of anatomical dissection by medical and other health science students, cadavers have been anonymized. This has meant that students have been provided with limited, if any, information on the identities or medical histories of those they are dissecting. While there was little way around this when the bodies were unclaimed, this need not be the case when the bodies have been donated. However, with a few exceptions, no efforts have been made to change this model. Recent attempts to move anatomy teaching in a more humanistic direction, by emphasizing the cadaver as the students' first patient and with the growth of commemoration services following the dissecting process, raise the question of whether cadavers should continue to be anonymized. In laying a basis for discussion of this matter, we outline what appear to be the virtues of anonymity, and the form that alternatives to anonymity might take. The options identified are nonidentification, low information; nonidentification, moderate information; and identification, full information. The virtues and drawbacks of each of these possibilities are assessed by analyzing their value for students, and also for donors and their families. Policy issues raised by alternatives are also considered. This article provides a basis for continued discussion and suggestions for further research in this area. Anat Sci Educ 10: 87-97. (c) 2016 American Association of Anatomists. PMID- 27123987 TI - Agreeing the content of a patient-reported outcome measure for primary care: a Delphi consensus study. AB - BACKGROUND: As the first contact for any health-related need, primary care clinicians often address multiple patient problems, with a range of possible outcomes. There is currently no patient-reported outcome measure (PROM) which covers this range of outcomes. Therefore, many research studies into primary care services use PROMs that do not capture the full impact of these services. OBJECTIVE: The study aim was to identify outcomes sought by primary care patients which clinicians can influence, thus providing the basis for a new primary care PROM. METHODS: We used a Delphi process starting with an outcomes list inductively derived in a prior qualitative study. Thirty-five experts were recruited into patient, clinician and academic panels. Participants rated each outcome on whether it was (i) relevant to health, (ii) influenced by primary care and (iii) detectable by patients. In each round, outcomes which passed/failed preset levels of agreement were accepted/rejected. Remaining outcomes continued to the next round. RESULTS: The process resulted in a set of outcomes occupying the domains of health status, health empowerment (internal and external), and health perceptions. Twenty-six of 36 outcomes were accepted for inclusion in a PROM. Primary care having insufficient influence was the main reason for exclusion. CONCLUSIONS: To our knowledge, this is the first time PROM outcomes have been agreed through criteria which explicitly exclude outcomes less relevant to health, uninfluenced by primary care or undetected by patients. The PROM in development covers a unique set of outcomes and offers an opportunity for enhanced research into primary care. PMID- 27123989 TI - Reply. PMID- 27123988 TI - Kidney Transplantation From Donors with Hepatitis B. AB - The growing demand for organ donors to supply the increasing number of patients on kidney waiting lists has led most transplant centers to develop protocols that allow safe use of organs from donors with special clinical situations previously regarded as contraindications. Deceased donors with previous hepatitis B may be a safe resource to increase the donor pool even if there is still controversy among transplantation centers regarding the use of hepatitis B surface antigen-positive donors for renal transplantation. However, when allocated to serology-matched recipients, kidney transplantation from donors with hepatitis B may result in excellent short-term outcome. Many concerns may arise in the long-term outcome, and studies must address the evaluation of the progression of liver disease and the rate of reactivation of liver disease in the recipients. Accurate selection and matching of both donor and recipient and correct post-transplant management are needed to achieve satisfactory long-term outcomes. PMID- 27123990 TI - Heavy-Atom Labeled Transmembrane beta-Peptides: Synthesis, CD-Spectroscopy, and X ray Diffraction Studies in Model Lipid Multilayer. AB - Transmembrane beta-peptides are promising candidates for the design of well controlled membrane anchors in lipid membranes. Here, we present the synthesis of transmembrane beta-peptides with and without tryptophan anchors, as well as a novel iodine-labeled d-beta(3) -amino acid. By using one or more of the heavy atom labeled amino acids as markers, the orientation of the helical peptide was inferred based on the electron-density profile determined by X-ray reflectivity. The beta-peptides were synthesized through manual Fmoc-based solid-phase peptide synthesis (SPPS) and reconstituted in unilamellar vesicles forming a right-handed 314 -helix secondary structure, as shown by circular dichroism spectroscopy. We then integrated the beta-peptide into solid-supported membrane stacks and carried out X-ray reflectivity and grazing incidence small-angle X-ray scattering to determine the beta-peptide orientation and its effect on the membrane bilayers. These beta-peptides adopt a well-ordered transmembrane motif in the solid supported model membrane, maintaining the basic structure of the original bilayer with some distinct alterations. Notably, the helical tilt angle, which accommodates the positive hydrophobic mismatch, induces a tilt of the acyl chains. The tilted chains, in turn, lead to a membrane thinning effect. PMID- 27123991 TI - Reactivity, Selectivity, and Stability in Sulfenic Acid Detection: A Comparative Study of Nucleophilic and Electrophilic Probes. AB - The comparative reaction efficiencies of currently used nucleophilic and electrophilic probes toward cysteine sulfenic acid have been thoroughly evaluated in two different settings-(i) a small molecule dipeptide based model and (ii) a recombinant protein model. We further evaluated the stability of corresponding thioether and sulfoxide adducts under reducing conditions which are commonly encountered during proteomic protocols and in cell analysis. Powered by the development of new cyclic and linear C-nucleophiles, the unsurpassed efficiency in the capture of sulfenic acid under competitive conditions is achieved and thus holds great promise as highly potent tools for activity-based sulfenome profiling. PMID- 27123992 TI - Lessons learnt to keep Europe polio-free: a review of outbreaks in the European Union, European Economic Area, and candidate countries, 1973 to 2013. AB - Between 1973 and 2013, 12 outbreaks of paralytic poliomyelitis with a cumulative total of 660 cases were reported in the European Union, European Economic Area and candidate countries. Outbreaks lasted seven to 90 weeks (median: 24 weeks) and were identified through the diagnosis of cases of acute flaccid paralysis, for which infection with wild poliovirus was subsequently identified. In two countries, environmental surveillance was in place before the outbreaks, but did not detect any wild strain before the occurrence of clinical cases. This surveillance nonetheless provided useful information to monitor the outbreaks and their geographical spread. Outbreaks were predominantly caused by poliovirus type 1 and typically involved unvaccinated or inadequately vaccinated groups within highly immunised communities. Oral polio vaccine was primarily used to respond to the outbreaks with catch-up campaigns implemented either nationwide or in restricted geographical areas or age groups. The introduction of supplementary immunisation contained the outbreaks. In 2002, the European region of the World Health Organization was declared polio-free and it has maintained this status since. However, as long as there are non-vaccinated or under-vaccinated groups in European countries and poliomyelitis is not eradicated, countries remain continuously at risk of reintroduction and establishment of the virus. Continued efforts to reach these groups are needed in order to ensure a uniform and high vaccination coverage. PMID- 27123993 TI - Drug Pricing Trends for Orally Administered Anticancer Medications Reimbursed by Commercial Health Plans, 2000-2014. PMID- 27123994 TI - Adult Prey Neutralizes Predator Nonconsumptive Limitation of Prey Recruitment. AB - Recent studies have shown that predator chemical cues can limit prey demographic rates such as recruitment. For instance, barnacle pelagic larvae reduce settlement where predatory dogwhelk cues are detected, thereby limiting benthic recruitment. However, adult barnacles attract conspecific larvae through chemical and visual cues, aiding larvae to find suitable habitat for development. Thus, we tested the hypothesis that the presence of adult barnacles (Semibalanus balanoides) can neutralize dogwhelk (Nucella lapillus) nonconsumptive effects on barnacle recruitment. We did a field experiment in Atlantic Canada during the 2012 and 2013 barnacle recruitment seasons (May-June). We manipulated the presence of dogwhelks (without allowing them to physically contact barnacles) and adult barnacles in cages established in rocky intertidal habitats. At the end of both recruitment seasons, we measured barnacle recruit density on tiles kept inside the cages. Without adult barnacles, the nearby presence of dogwhelks limited barnacle recruitment by 51%. However, the presence of adult barnacles increased barnacle recruitment by 44% and neutralized dogwhelk nonconsumptive effects on barnacle recruitment, as recruit density was unaffected by dogwhelk presence. For species from several invertebrate phyla, benthic adult organisms attract conspecific pelagic larvae. Thus, adult prey might commonly constitute a key factor preventing negative predator nonconsumptive effects on prey recruitment. PMID- 27123996 TI - Vitamin E and the risk of childhood asthma. AB - INTRODUCTION: Asthma, a heterogeneous disease with multiple phenotypes, remains a significant health problem. Present treatments are not curative and prevention should be our ultimate goal. Vitamin E supplementation presents a potential easy and cheap preventive therapy but the results of studies are confusing and sometimes contradictory. Clarification is needed. AREAS COVERED: Animal studies and research in pregnant women suggest enhanced lifetime resistance to asthma with appropriate fetal exposure to vitamin E. Vitamin E's preventive role is complex and includes functional variations of the different isoforms. Expert commentary: We review the most recent literature on the role of vitamin E isoforms on: lung inflammation, immune development, animal and clinical studies during pregnancy, and the potential influence of vitamin E isoforms on asthma development in offspring. We point out where data are seemingly contradictory, explain why this is so, and comment on where further clarifying research is needed and its future direction. PMID- 27123995 TI - Rebamipide Attenuates Mandibular Condylar Degeneration in a Murine Model of TMJ OA by Mediating a Chondroprotective Effect and by Downregulating RANKL-Mediated Osteoclastogenesis. AB - Temporomandibular joint osteoarthritis (TMJ-OA) is characterized by progressive degradation of cartilage and changes in subchondral bone. It is also one of the most serious subgroups of temporomandibular disorders. Rebamipide is a gastroprotective agent that is currently used for the treatment of gastritis and gastric ulcers. It scavenges reactive oxygen radicals and has exhibited anti inflammatory potential. The aim of this study was to investigate the impact of rebamipide both in vivo and in vitro on the development of cartilage degeneration and osteoclast activity in an experimental murine model of TMJ-OA, and to explore its mode of action. Oral administration of rebamipide (0.6 mg/kg and 6 mg/kg) was initiated 24 h after TMJ-OA was induced, and was maintained daily for four weeks. Rebamipide treatment was found to attenuate cartilage degeneration, to reduce the number of apoptotic cells, and to decrease the expression levels of matrix metalloproteinase-13 (MMP-13) and inducible nitric oxide synthase (iNOS) in TMJ OA cartilage in a dose-dependent manner. Rebamipide also suppressed the activation of transcription factors (e.g., NF-kappaB, NFATc1) and mitogen activated protein kinases (MAPK) by receptor activator of nuclear factor kappa-B ligand (RANKL) to inhibit the differentiation of osteoclastic precursors, and disrupted the formation of actin rings in mature osteoclasts. Together, these results demonstrate the inhibitory effects of rebamipide on cartilage degradation in experimentally induced TMJ-OA. Furthermore, suppression of oxidative damage, restoration of extracellular matrix homeostasis of articular chondrocytes, and reduced subchondral bone loss as a result of blocked osteoclast activation suggest that rebamipide is a potential therapeutic strategy for TMJ-OA. PMID- 27123998 TI - Metal-Organic-Framework-Templated Polyelectrolyte Nanocapsules for the Encapsulation and Delivery of Small-Molecule-Polymer Conjugates. AB - Herein, we report a strategy for exploiting nanoscale metal-organic frameworks (nano-MOFs) as templates for the layer-by-layer (LbL) assembly of polyelectrolytes. Because small-molecule drugs or imaging agents cannot be efficiently encapsulated by polyelectrolyte nanocapsules, we investigated two promising and biocompatible polymers (comb-shaped polyethylene glycol (PEG) and hyperbranched polyglycerol-based PEG) for the conjugation of model drugs and imaging agents, which were then encapsulated inside the nano-MOF-templated nanocapsules. Furthermore, we also systemically explored the release kinetics of the encapsulated conjugates, and examined how the encapsulation and/or release processes could be controlled by varying the composition and architecture of the polymers. We envision that our nano-MOFs-templated nanocapsules, through combining with small-molecule-polymer conjugates, will represent a new type of delivery system that could open up new opportunities for biomedical applications. PMID- 27123997 TI - Clostridium Butyricum CGMCC0313.1 Modulates Lipid Profile, Insulin Resistance and Colon Homeostasis in Obese Mice. AB - Obesity is associated with a cluster of metabolic disorders and systemic low grade inflammation involving multiple organs. Recent findings have suggested that intestine is a key organ altered in response to high fat diet (HFD) feeding. Probiotics mainly lactobacillus strains have earlier been implicated in alleviating metabolic disorders. Here we aimed to examine the effects of a naturally occurring butyrate-producing probiotic clostridium butyricum CGMCC0313.1 (CB0313.1) in limiting the development of HFD-induced obesity. Mice treated with CB0313.1 exhibited reduced lipid accumulation in liver and serum, lower circulating insulin levels and improved glucose tolerance and insulin sensitivity. Furthermore, CB0313.1 administration reversed the HFD-induced colonic inflammation as evidenced by reduced tumor necrosis factor (TNF)-alpha level and increases the interleukin (IL)-10 and IL-22 levels in colon tissue. Additionally to colonic inflammation, CB0313.1 also reduced the colon permeability by upregulating the tight junction (TJ) proteins (claudin-1 and occludin) and contributed to a decreased circulating endotoxin level. In colon content, CB0313.1 administration restored the reduced production of butyrate and other short chain fatty acids (SCFAs) caused by HFD feeding. In adipose tissue, lower transcriptional levels of pro-inflammatory TNF-alpha, IL-6, IL-1beta and monocyte chemotactic protein (MCP)-1 in adipose tissue were observed in CB0313.1 treated mice. Collectively, our data demonstrated that CB0313.1, targeting colon inflammation and permeability, ameliorated HFD-induced obesity, insulin resistance as well as adipose inflammation. PMID- 27124000 TI - A Natural Language Processing Tool for Large-Scale Data Extraction from Echocardiography Reports. AB - Large volumes of data are continuously generated from clinical notes and diagnostic studies catalogued in electronic health records (EHRs). Echocardiography is one of the most commonly ordered diagnostic tests in cardiology. This study sought to explore the feasibility and reliability of using natural language processing (NLP) for large-scale and targeted extraction of multiple data elements from echocardiography reports. An NLP tool, EchoInfer, was developed to automatically extract data pertaining to cardiovascular structure and function from heterogeneously formatted echocardiographic data sources. EchoInfer was applied to echocardiography reports (2004 to 2013) available from 3 different on-going clinical research projects. EchoInfer analyzed 15,116 echocardiography reports from 1684 patients, and extracted 59 quantitative and 21 qualitative data elements per report. EchoInfer achieved a precision of 94.06%, a recall of 92.21%, and an F1-score of 93.12% across all 80 data elements in 50 reports. Physician review of 400 reports demonstrated that EchoInfer achieved a recall of 92-99.9% and a precision of >97% in four data elements, including three quantitative and one qualitative data element. Failure of EchoInfer to correctly identify or reject reported parameters was primarily related to non-standardized reporting of echocardiography data. EchoInfer provides a powerful and reliable NLP-based approach for the large-scale, targeted extraction of information from heterogeneous data sources. The use of EchoInfer may have implications for the clinical management and research analysis of patients undergoing echocardiographic evaluation. PMID- 27123999 TI - Phosphatidylinositol 3-Kinase/AKT Pathway Inhibition by Doxazosin Promotes Glioblastoma Cells Death, Upregulation of p53 and Triggers Low Neurotoxicity. AB - Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin's (an antihypertensive drug) activity against glioblastoma cells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin's effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3beta and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent. PMID- 27124001 TI - On the Use of Biomineral Oxygen Isotope Data to Identify Human Migrants in the Archaeological Record: Intra-Sample Variation, Statistical Methods and Geographical Considerations. AB - Oxygen isotope analysis of archaeological skeletal remains is an increasingly popular tool to study past human migrations. It is based on the assumption that human body chemistry preserves the delta18O of precipitation in such a way as to be a useful technique for identifying migrants and, potentially, their homelands. In this study, the first such global survey, we draw on published human tooth enamel and bone bioapatite data to explore the validity of using oxygen isotope analyses to identify migrants in the archaeological record. We use human delta18O results to show that there are large variations in human oxygen isotope values within a population sample. This may relate to physiological factors influencing the preservation of the primary isotope signal, or due to human activities (such as brewing, boiling, stewing, differential access to water sources and so on) causing variation in ingested water and food isotope values. We compare the number of outliers identified using various statistical methods. We determine that the most appropriate method for identifying migrants is dependent on the data but is likely to be the IQR or median absolute deviation from the median under most archaeological circumstances. Finally, through a spatial assessment of the dataset, we show that the degree of overlap in human isotope values from different locations across Europe is such that identifying individuals' homelands on the basis of oxygen isotope analysis alone is not possible for the regions analysed to date. Oxygen isotope analysis is a valid method for identifying first generation migrants from an archaeological site when used appropriately, however it is difficult to identify migrants using statistical methods for a sample size of less than c. 25 individuals. In the absence of local previous analyses, each sample should be treated as an individual dataset and statistical techniques can be used to identify migrants, but in most cases pinpointing a specific homeland should not be attempted. PMID- 27124002 TI - Correction: Inhibition of Nickel Nanoparticles-Induced Toxicity by Epigallocatechin-3-Gallate in JB6 Cells May Be through Down-Regulation of the MAPK Signaling Pathways. AB - [This corrects the article DOI: 10.1371/journal.pone.0150954.]. PMID- 27124003 TI - Population Pharmacokinetics of Lithium Carbonate in Young Male Healthy Chinese Volunteers. AB - Aim: To investigate the population pharmacokinetics (PK) model of lithium carbonate in young male healthy Chinese subjects. Methods: This study was conducted using a 2-period crossover design. 20 healthy male subjects received lithium carbonate tablets from 2 different Chinese pharmaceutical manufacturers. Plasma samples were obtained by blood sampling over 72 h in each period. Population PK analysis was performed using nonlinear mixed-effects model (NONMEM) software. The final models were validated using bootstrap and visual predictive check (VPC) approaches. Results: The final PK model was a two-compartment model. The population PK parameters, clearance (CL/F), apparent distribution volume of the central compartment (V2/F), inter-compartmental clearance (Q/F) and apparent distribution volume of the peripheral compartment (V3/F), were 9.39 L/h, 10.4 L, 22.1 L/h, and 216 L, respectively. Conclusion: Population PK models for lithium carbonate have been developed and considerable inter-subject variability was found in healthy young male Chinese subjects. It takes a long time to achieve the steady state in conventional therapy. This may provide guidelines for future use of lithium carbonate in China. PMID- 27124006 TI - Nanowires: Enhanced Optoelectronic Performance of a Passivated Nanowire-Based Device: Key Information from Real-Space Imaging Using 4D Electron Microscopy (Small 17/2016). AB - Selective mapping of surface charge carrier dynamics of InGaN nanowires before and after surface passivation with octadecylthiol (ODT) is reported by O. F. Mohammed and co-workers on page 2313, using scanning ultrafast electron microscopy. In a typical experiment, the 343 nm output of the laser beam is used to excite the microscope tip to generate pulsed electrons for probing, and the 515 nm output is used as a clocking excitation pulse to initiate dynamics. Time resolved images demonstrate clearly that carrier recombination is significantly slowed after ODT treatment, which supports the efficient removal of surface trap states. PMID- 27124009 TI - QuickStats: Distribution of Long-Term Care Staffing* Hours,(?) by Staff Member Type and Sector - United States, 2014. AB - In 2014, aides provided more hours of care in the major sectors of long-term care than the other staffing types shown. Aides accounted for 60% of all staffing hours in nursing homes, compared with licensed practical or vocational nurses (21%), registered nurses (13%), activities staff members (5%), and social workers (2%). Aides accounted for 75% of all staffing hours in residential care communities, in contrast to activities staff members (11%), registered nurses (7%), licensed practical or vocational nurses (6%), and social workers (1%). In adult day services centers, aides provided 41% of all staffing hours, followed by activities staff members (32%), registered nurses (12%), licensed practical or vocational nurses (9%), and social workers (6%). PMID- 27124010 TI - The Family Revisited. PMID- 27124011 TI - A genetic overview of 23Y-STR markers in UAE population. PMID- 27124013 TI - Synthesis of Two-dimensional Microporous Carbonaceous Polymer Nanosheets and Their Application as High-performance CO2 Capture Sorbent. AB - The synthesis of two-dimensional (2D) polymer nanosheets with a well-defined microporous structure remains challenging in materials science. Here, a new kind of 2D microporous carbonaceous polymer nanosheets was synthesized through polymerization of a very low concentration of 1,4-dicyanobenzene in molten zinc chloride at 400-500 degrees C. This type of nanosheets has a thickness in the range of 3-20 nm, well-defined microporosity, a high surface area (~537 m(2) g( 1) ), and a large micropore volume (~0.45 cm(3) g(-1) ). The microporous carbonaceous polymer nanosheets exhibit superior CO2 sorption capability (8.14 wt % at 298 K and 1 bar) and a relatively high CO2 selectivity toward N2 (25.6). Starting from different aromatic nitrile monomers, a variety of 2D carbonaceous polymer nanosheets can be obtained showing a certain universality of the ionothermal method reported herein. PMID- 27124012 TI - Lean Participative Process Improvement: Outcomes and Obstacles in Trauma Orthopaedics. AB - OBJECTIVES: To examine the effectiveness of a "systems" approach using Lean methodology to improve surgical care, as part of a programme of studies investigating possible synergy between improvement approaches. SETTING: A controlled before-after study using the orthopaedic trauma theatre of a UK Trust hospital as the active site and an elective orthopaedic theatre in the same Trust as control. PARTICIPANTS: All staff involved in surgical procedures in both theatres. INTERVENTIONS: A one-day "lean" training course delivered by an experienced specialist team was followed by support and assistance in developing a 6 month improvement project. Clinical staff selected the subjects for improvement and designed the improvements. OUTCOME MEASURES: We compared technical and non-technical team performance in theatre using WHO checklist compliance evaluation, "glitch count" and Oxford NOTECHS II in a sample of directly observed operations, and patient outcome (length of stay, complications and readmissions) for all patients. We collected observational data for 3 months and clinical data for 6 months before and after the intervention period. We compared changes in measures using 2-way analysis of variance. RESULTS: We studied 576 cases before and 465 after intervention, observing the operation in 38 and 41 cases respectively. We found no significant changes in team performance or patient outcome measures. The intervention theatre staff focused their efforts on improving first patient arrival time, which improved by 20 minutes after intervention. CONCLUSIONS: This version of "lean" system improvement did not improve measured safety processes or outcomes. The study highlighted an important tension between promoting staff ownership and providing direction, which needs to be managed in "lean" projects. Space and time for staff to conduct improvement activities are important for success. PMID- 27124014 TI - Successful Experience of Laparoscopic Pancreaticoduodenectomy and Digestive Tract Reconstruction With Minimized Complications Rate by 14 Case Reports. AB - Laparoscopic pancreatic surgery is one of the most sophisticated and advanced applications of laparoscopy in the current surgical practice. The adoption of laparoscopic pancreaticoduodenectomy (LPD) has been relatively slow due to the technical challenges. The aim of this study is to review and characterize our successful LPD experiences in patients with distal bile duct carcinoma, periampullary adenocarcinoma, pancreas head cancer, and duodenal cancer and evaluate the clinical outcomes of LPD for its potential in oncologic surgery applications.We retrospectively analyzed the clinical data from 14 patients who underwent LPD from August 2013 to February 2015 in our institute.We presented our LPD experience with no cases converted to open surgery in all 14 cases, which included 10 cases of laparoscopic digestive tract reconstruction and 4 cases of open digestive tract reconstructions. There were no deaths during the perioperative period and no case of gastric emptying disorder or postoperative bleeding. The other clinical indexes were comparable to or better than open surgery.Based on our experience, LPD could be potentially safe and feasible for the treatment of early pancreas head cancer, distal bile duct carcinoma, periampullary adenocarcinoma, and duodenal cancer. The master of LPD procedure requires technical expertise but it can be accomplished with a short learning curve. PMID- 27124015 TI - Low Expression of Mucin-4 Predicts Poor Prognosis in Patients With Clear-Cell Renal Cell Carcinoma. AB - Mucin-4 (MUC4), a member of membrane-bound mucins, has been reported to exert a large variety of distinctive roles in tumorigenesis of different cancers. MUC4 is aberrantly expressed in clear-cell renal cell carcinoma (ccRCC) but its prognostic value is still unveiled. This study aims to assess the clinical significance of MUC4 expression in patients with ccRCC.The expression of MUC4 was assessed by immunohistochemistry in 198 patients with ccRCC who underwent nephrectomy retrospectively in 2003 and 2004. Sixty-seven patients died before the last follow-up in the cohort. Kaplan-Meier method with log-rank test was applied to compare survival curves. Univariate and multivariate Cox regression models were applied to evaluate the prognostic value of MUC4 expression in overall survival (OS). The predictive nomogram was constructed based on the independent prognostic factors. The calibration was built to evaluate the predictive accuracy of nomogram.In patients with ccRCC, MUC4 expression, which was determined to be an independent prognostic indicator for OS (hazard ratio [HR] 3.891; P < 0.001), was negatively associated with tumor size (P = 0.036), Fuhrman grade (P = 0.044), and OS (P < 0.001). The prognostic accuracy of TNM stage, UCLA Integrated Scoring System (UISS), and Mayo clinic stage, size, grade, and necrosis score (SSIGN) prognostic models was improved when MUC4 expression was added. The independent prognostic factors, pT stage, distant metastases, Fuhrman grade, sarcomatoid, and MUC4 expression were integrated to establish a predictive nomogram with high predictive accuracy.MUC4 expression is an independent prognostic factor for OS in patients with ccRCC. PMID- 27124016 TI - Retrospective Comparison of Radiological and Clinical Outcomes of PLIF and TLIF Techniques in Patients Who Underwent Lumbar Spinal Posterior Stabilization. AB - Degenerative disc disease and spinal stenosis lead to various symptoms. Degeneration of facet joints is added to this degenerative process with aging.Seventy-four patients who were admitted to the Spinal Column Outpatient Clinic of the Neurosurgery Department with a diagnosis of degenerative narrow spinal canal and lumbar spondylolisthesis between 2011 and 2013 and who underwent surgery were included in the study.Our study was conducted with 74 patients of whom 73.0% (n = 54) were female and 27.0% (n = 20) were male. Mean age was 54.86 +/- 7.87 years (range 34-74).Although we did not detect a difference between the two surgical methods with regard to clinical improvement, transforaminal lumbar interbody fusion (TLIF) is preferred due to radiological advantages observed one year later, ease of application, and the development of fewer complications. PMID- 27124017 TI - Rehabilitation Management of the Charcot-Marie-Tooth Syndrome: A Systematic Review of the Literature. AB - The Charcot-Marie-Tooth disease (CMT) causes significant muscular deficits in the affected patients, restricts daily activities (ADL), and involves a severe disability. Although the conservative intervention is the only treatment for the disease, there is no scientific evidence so far on rehabilitation treatment. Objectives of the review are: research the best literary evidence so far on the rehabilitation treatment of CMT; critically analyze the outcome, to build an evidence-based work protocol.A systematic review of the rehabilitation of a patient with CMT, including the results from the following databases: Pubmed, Medline, Embase, Pedro, Cinahl, Ebsco discovery. Criteria for inclusion: randomized/controlled studies, analytic studies, transversal studies on a cohort of at least 10 individuals; medium/long-term report of the results.Eleven studies in total have been admitted to the final review phase; trials about physiotherapy CMT treatment (5), about orthosis treatment (6). Despite the wide range of outcomes and proposed interventions, the data points to the following: strength or endurance trainings improve functionality and ADLs of affected patients, while orthotic role is, at the moment, not completely clear.Physiotherapy treatment is a useful tool to manage CMT; more studies on a larger number of cases are needed to define orthosis utility and to establish the gold standard of the treatment. PMID- 27124019 TI - Unusual Localization of a Primary Hydatid Cyst: Scaphoid Bone: A Case Report. AB - Because hydatidosis of the bone (echinococcus infection) is a rare parasitic infection, its diagnosis and treatment poses great difficulties. Radiologic imaging findings are generally helpful to make the diagnosis. But occurrence of disease in atypical places and lack of specific radiological findings may complicate differential diagnosis. Nevertheless, familiarity with imaging findings in patients living at endemic areas provides advantages for diagnosis and treatment.We present a cyst hydatic case in scaphoid bone which has been reported in the literature only once previously. PMID- 27124018 TI - Toll-like Receptor-4 Polymorphisms and Serum Matrix Metalloproteinase-9 in Newly Diagnosed Patients With Calcified Neurocysticercosis and Seizures. AB - We evaluated seizure profile, Toll-like receptor (TLR)-4 polymorphisms, and serum matrix metalloproteinases (MMPs) in patients with calcified neurocysticercosis.One-hundred nine patients with calcified neurocysticercosis with newly diagnosed seizures and 109 control subjects were enrolled. TLR-4 Asp299Gly and Thr399Ile polymorphisms and serum MMP-9 levels were evaluated. The patients were followed for 1 year.Asp/Gly (P = 0.012) and Thr/Ile (P = 0.002), Gly (Asp/Gly plus Gly/Gly) (P = 0.008) and Ile (Thr/Ile plus Ile/Ile) (P = 0.003) genotypes were significantly associated with calcified neurocysticercosis compared with controls. Gly/Gly and Ile/Ile genotypes were not significantly associated (P = 0.529 for Gly/Gly, P = 0.798 for Ile/Ile) with either group. The levels of MMP-9 were higher in calcified neurocysticercosis (P = < 0.001). The levels of MMP-9 were higher in patients with multiple calcified neurocysticercosis compared with single calcified neurocysticercosis (P = < 0.001).Headache (P = 0.031), status epilepticus (P = 0.029), Todd paralysis (P = 0.039), lesion size >10 mm (P = 0.001), and perilesional edema (P = < 0.001) were significantly associated with seizure recurrence. Heterozygous form Asp/Gly (P = < 0.001) and heterozygous form Thr/Ile (P = < 0.001) were significantly associated with seizure recurrence. The Gly (Asp/Gly plus Gly/Gly) (P = < 0.001) and Ile (Thr/Ile plus Ile/Ile) (P = < 0.001) genotypes were also significantly associated with seizure recurrence. Higher serum MMP-9 levels were significantly associated with seizure recurrence (P = < 0.001).The TLR-4 gene abnormalities may trigger inflammation around calcified neurocysticercosis leading to an increase in perilesional edema and provocation of seizures. PMID- 27124020 TI - Association Between Race/Ethnicity and Survival of Melanoma Patients in the United States Over 3 Decades: A Secondary Analysis of SEER Data. AB - Melanoma is a treatable and preventable skin cancer. It is responsible for 75% of deaths among all skin cancers. Previous studies have found that race/ethnicity may play a role in survival among melanoma patients. However, there are no studies that cover 30 years and take race into account for the U.S. POPULATION: This study is a secondary analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Result (SEER) Program. Adults with primary cutaneous melanoma from 1982 to 2011 were included; the final sample size was 185,219. The outcome was survival; both cause-specific and all-cause mortality were examined. The main exposure was race/ethnicity. Kaplan-Meier survival analysis was used to estimate overall survival. Cox proportional hazards regression was used to estimate unadjusted and adjusted hazard ratios (HRs). A P value less than 0.05 was considered statistically significant.More than 50% of patients in all races/ethnicities were diagnosed at the in situ or localized stage. Non-Hispanic White patients were more frequently diagnosed at the in situ stage. Overall, more men were diagnosed than women. The majority of cases among all races were men. Non-Hispanic Black females represented the smallest percentage of melanoma cases among all races. The smallest number of diagnoses across all races/ethnicities was made from 1982 to 1991. Median follow-up was 81 months and no collinearity was observed in the adjusted models. When examining cause-specific mortality and controlling for site and stage at diagnosis, gender, age and decade of diagnosis, the HR for non-Hispanic Black patients was lower than that for non-Hispanic White patients (HR 0.7; 95% confidence interval (CI): 0.6-0.8). However, when examining all-cause mortality, this difference disappeared (HR 1.1; 95% CI: 1.0-1.2). Stage at diagnosis impacted HR; patients diagnosed with distant metastases had significantly worse survival.When taking cause-specific mortality into consideration and after controlling for stage and site at diagnosis, gender, and age and decade of diagnosis, non-Hispanic Black patients had a lower HR compared to non-Hispanic White patients. However, this difference disappeared when examining all-cause mortality. Further research is needed to explore this finding and to determine what factors may be associated with late-stage melanoma diagnosis. PMID- 27124021 TI - Patient Perceptions of Expression of Empathy From Chinese Medicine Clinicians in a Chinese Population: A Cross-Sectional Study. AB - This study aims to examine the level of empathy perceived by patients receiving care from herbalists, acupuncturists and massage therapists and to investigate the factors that influence levels of perceived empathy.Participants who were 18 years or above; able to provide written informed consent; and able to read and write in Chinese without assistance were included. A total of 514 participants sampled from charity and semipublic Chinese medicine (CM) clinics in Hong Kong were recruited to assess levels of empathy perceived during various length of consultations (1-20 minutes) by the Chinese Consultation and Relational Empathy Measure (Chinese CARE). Multiple linear regressions were conducted to evaluate the associations between perceived levels of empathy and the type of CM practitioner consulted and participants' demographic and health characteristics.The average Chinese CARE total score for participants consulting CM practitioners was 34.3 of a maximum of 50. After adjusting for participants' health and demographic characteristics, acupuncturists received the highest ratings (P < 0.001), whereas massage therapists (P < 0.001) scored the lowest of the 3 modalities. Participants receiving social benefits (P = 0.013), those with longer waiting times (P = 0.002), and those with shorter consultation durations (P = 0.020) scored significantly lower on the Chinese CARE.The level of empathy perceived by participants using CM was similar to results found for those in conventional care, in contrast to findings in other geographical settings, where a high level of perceived empathy was a major motivator for participants to choose complementary medicine. PMID- 27124022 TI - Descending Control of Nociceptive Processing in Knee Osteoarthritis Is Associated With Intracortical Disinhibition: An Exploratory Study. AB - Based on the hypothesis that an imbalance in excitatory and inhibitory input is a central mechanism of knee osteoarthritis chronic pain (KOACP), this exploratory study had the following aims: to compare whether the function of the descending inhibitory pain pathway is associated with the state of inhibition in the corticospinal system indexed by the motor-evoked potential (MEP) and the cortical salient period (CSP) in patients with severe osteoarthritis (OA) and healthy controls; and to determine if there is correlation between the measures of intracortical inhibition (CSP, MEP) with changes on the numerical pain scale (NPS [0-10]) in KOACP during a conditioned pain modulation (CPM)-task considering the effect of self-reported function assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and analgesic use.In a cross-sectional study, we included females (n = 21), with disability by pain or stiffness due to KOACP and healthy controls (n = 10), aged 19 to 75 years. The motor cortex excitability parameters (MEP and CSP) were assessed using the transcranial magnetic stimulation. We assessed the pain and disability by the WOMAC, and change on NPS (0-10) during CPM-task.A Multivariate analysis of covariance revealed that the adjusted mean (SD) on the MEP amplitude was 13.53% higher in the OA than in healthy subjects (1.33 [0.49] vs 1.15 [0.13]), respectively (P = 0.16). The adjusted mean (SD) on the CSP observed in OA patients was 23.43% lower than in healthy subjects (54.54 [16.10] vs 70.94 [22.87]), respectively (P = 0.01). The function of the descending pain modulatory system assessed by change on NPS (0-10) during a CPM-task was negatively correlated with the cortical excitability parameter indexed by the CSP (P = 0.001). Also, the CSP was negatively correlated with the pain and disability assessed by the WOMAC index.These findings support the hypothesis that the change in cortical plasticity in KOACP is associated with less intracortical inhibition, as measured by the CSP. These results show that the neural change in the motor cortex in KOACP is associated with pain and disability levels, and also with decreased activation of the endogenous pain-modulating system by a CPM-task. PMID- 27124023 TI - The Association Between Glycosylation of Immunoglobulin G and Hypertension: A Multiple Ethnic Cross-Sectional Study. AB - More than half of all known proteins, and almost all membrane and extra-cellular proteins have oligosaccharide structures or glycans attached to them. Defects in glycosylation pathways are directly involved in at least 30 severe human diseases.A multiple center cross-sectional study (China, Croatia, and Scotland) was carried out to investigate the possible association between hypertension and IgG glycosylation. A hydrophilic interaction chromatography of fluorescently labeled glycans was used to analyze N-glycans attached to IgG in plasma samples from a total of 4757 individuals of Chinese Han, Croatian, and Scottish ethnicity.Five glycans (IgG with digalactosylated glycans) significantly differed in participants with prehypertension or hypertension compared to those with normal blood pressure, while additional 17 glycan traits were only significantly differed in participants with hypertension compared to those of normal blood pressure. These glycans were also significant correlated with systolic blood pressure (SBP) or diastolic blood pressure (DBP).The present study demonstrated for the 1st time an association between hypertension and IgG glycome composition. These findings suggest that the individual variation in N-glycosylation of IgG contributes to pathogenesis of hypertension, presumably via its effect on pro- and/or anti-inflammatory pathways. PMID- 27124024 TI - Statins are Associated With a Reduced Risk of Brain Cancer: A Population-Based Case-Control Study. AB - The aim of this study was to investigate whether statin utilization is associated with brain cancer risk.A population-based case-control study was conducted using nationally representative claims data from the National Health Insurance Bureau in Taiwan. Cases included all patients 50 years and older who received an index diagnosis of brain cancer between 2004 and 2011. Our controls were matched by age, sex, and index date. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression.We examined 213 brain cancer cases and 852 controls. The unadjusted ORs for any statin prescription was 0.77 (95% CI = 0.50-1.18) and the adjusted OR was 0.59 (95% CI = 0.37-0.96). Compared with no use of statins, the adjusted ORs were 0.68 (95% CI = 0.38-1.24) for the group having been prescribed with statins with cumulative defined daily dose (DDD) below 144.67 DDDs and 0.50 (95% CI = 0.28-0.97) for the group with the cumulative statin use of 144.67 DDDs or more.The results of this study suggest that statins may reduce the risk of brain cancer. PMID- 27124025 TI - Evaluating Diagnostic and Prognostic Value of Plasma miRNA133a in Acute Chest Pain Patients Undergoing Coronary Angiography. AB - Circulating microRNA has recently emerged as a promising biomarker for cardiovascular disease. This study sought to evaluate the diagnostic and prognostic value of circulating miR-133a as a marker of acute myocardial infarction in acute chest pain patients undergoing coronary angiography.Plasma was collected from 312 patients with chest pain on admission in the emergency department and 67 healthy controls. MiR-133a was detected using real-time quantitative PCR and enhanced accu-TnI, creatinine kinase-MB mass, and myoglobin were measured by immunoassay. End-point events (serious adverse cardiovascular events which require hospitalization or cardiovascular death) were examined in the AMI (acute myocardical infarction) group within 1, 6, 12, and 24 months.The miR-133a level was higher in AMI patients than in non-AMI patients (P < 0.001). In the ROC analysis, the sensitivity of miR-133a in diagnosis of AMI is 0.61 and the specificity is 0.68. In the prognostic analysis, only 1 endpoint event was observed in the non-AMI group; the amount of cases with end-point events in the AMI group at 1,6,12, and 24 months were 8, 19, 28, and 35, respectively. The cutoff value of miR-133a was determined using the median value of the AMI group and separated the patients into a positive group and a negative group. The Kaplan Meier survival curve showed no significant difference in survival was detected in AMI patients between the miR-133a positive group and negative group after follow up (12-month: x2 = 1.353, P = 0.245; 24-month: x2 = 3.722, P = 0.054). After adjusting for age, gender, Killip classes, prior myocardiac infarction history, myoglobin, LVEF (left ventricular ejection fraction), diabetes, hypertension, smoking and systolic blood pressure, miR133a had a significant association with the risk of events at 12 months (HR = 2.869, P = 0.024) and 24 months (HR = 3.936, P = 0.001).In patients undergoing coronary angiography, circulating miR 133a is upregulated in AMI patients, but it does not provide enough accuracy for clinical AMI diagnosis because it also rises in unstable angina patients. Its prognostic value in AMI is uncertain mainly for the number of cases with end point event was small and may be further validated in a larger, better designed study. PMID- 27124026 TI - 25-Hydroxy Vitamin D, Vitamin D Receptor and Toll-like Receptor 2 Polymorphisms in Spinal Tuberculosis: A Case-Control Study. AB - Vitamin D deficiency and vitamin D receptor (VDR) gene abnormalities confer susceptibility to tuberculosis. Toll-like receptors (TLRs), such asTLR-2, are also important mediators of inflammatory response against Mycobacterium tuberculosis. We evaluated serum vitamin D, and VDR and TLR-2 gene polymorphisms in patients with spinal tuberculosis.This study comprised of 3 groups: spinal tuberculosis, pulmonary tuberculosis, and controls (each with 106 subjects). Enzyme-linked immunosorbent assay was used to measure vitamin D levels, and polymerase chain reaction-sequencing method was used to analyze VDR and TLR-2 gene polymorphisms. Patients were followed up for 6 months.Vitamin D deficiency was significantly more prevalent in patients with spinal tuberculosis (P < 0.001) and pulmonary tuberculosis (P = 0.011), versus controls. The heterozygous and mutant genotypes of VDR TaqI gene were significantly associated with spinal tuberculosis (P < 0.001; odds ratio [OR] 4.74 [2.45-9.18]) and pulmonary tuberculosis (P < 0.001; OR 3.52 [1.80-6.88]) when compared with controls. The heterozygous and mutant variants of VDR ApaI gene were significantly more common in patients with spinal tuberculosis in comparison with patients with pulmonary tuberculosis (P < 0.001; OR 2.90 [1.65-5.10]) and controls (P < 0.001; OR 6.56 [3.41-12.61]). We did not observe any significantly different results for TLR-2 gene polymorphisms. Vitamin D deficiency, VDR, and TLR-2 polymorphisms did not affect the 6-month disability.Vitamin D deficiency and VDR gene polymorphisms are significantly more prevalent in people with pulmonary and spinal tuberculosis. They may, in isolation or collectively, confer susceptibility to pulmonary and spinal tuberculosis. PMID- 27124027 TI - Glomerular Filtration Rate and Urine Albumin to Creatinine Ratio Associated With Hearing Impairment Among Korean Adults With Diabetes: A Nationwide Population Based Study. AB - The objective of this study was to examine the association of estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) with hearing impairment among diabetic adults in Korea. The study was based on data from Korea National Health and Nutrition Examination Survey 2011 to 2012. Participants were 1206 diabetic adults, aged over 19 years, who completed audiometric testing supervised by nationally certified clinicians. Hearing impairment was defined in three grades: no hearing impairment (pure-tone average 0-25 dB), slight hearing impairment (26-40 dB), and disabling hearing impairment (>40 dB) in the better ear at frequencies 0.5, 1, 2, 3, 4 and 6 kHz. Using logistic regression, risk of hearing impairment was assessed after having controlled for confounding factors. Higher levels of ACR and lower levels of eGFR correlated with an increase in percentage of disabling hearing impairment both unilaterally and bilaterally (P < 0.001). Controlling for possible confounding covariates, odds ratios for hearing impairment showed tendency to increase in higher ACR groups (P for trend = 0.029). Similar pattern was examined between eGFR and hearing impairment (P for trend = 0.006). Odds ratios were 1.981 (1.146, 3.424) for ACR Q4 and 2.773 (1.286, 5.983) for eGFR < 60 mL/min. Fall in eGFR and rise in ACR correlated with severity of hearing impairment. The association existed independently of age, sex, body mass index (BMI), smoking, drinking, exercise, new onset of diabetes, education, income, mental stress, noise exposure, and metabolic syndrome. PMID- 27124028 TI - Low-Dose Sevoflurane May Reduce Blood Loss and Need for Blood Products After Cardiac Surgery: A Prospective, Randomized Pilot Study. AB - Patients undergoing cardiac surgery often experience abnormal bleeding, due primarily to cardiopulmonary bypass (CPB)-induced activation of platelets. Sevoflurane may inhibit platelet activation, raising the possibility that administering it during CPB may reduce blood loss.Patients between 18 and 65 years old who were scheduled for cardiac surgery under CPB at our hospital were prospectively enrolled and randomized to receive intravenous anesthetics alone (control group, n = 77) or together with sevoflurane (0.5-1.0 vol/%) from an oxygenator (sevoflurane group, n = 76). The primary outcome was postoperative blood loss, the secondary outcome was postoperative need for blood products.Volume of blood loss was 48% lower in the sevoflurane group than the control group at 4 hours after surgery, and 33% lower at 12 hours after surgery. Significantly fewer patients in the sevoflurane group lost >700 mL blood within 24 hours (9 of 76 vs 28 of 77, P < 0.001). As a result, the sevoflurane group received significantly smaller volumes of packed red blood cells (1.25 +/- 2.36 vs 2.23 +/- 3.75 units, P = 0.011) and fresh frozen plasma (97 +/- 237 vs 236 +/- 344 mL, P = 0.004). Thus the sevoflurane group was at significantly lower risk of requiring complex blood products after surgery (adjusted odds ratio [OR] 0.34, 95% confidence interval [CI] 0.17-0.68, P = 0.002).Sevoflurane inhalation from an oxygenator during CPB may reduce blood loss and need for blood products after cardiac surgery. PMID- 27124029 TI - Aspiration Thrombectomy and Drug-Eluting Stent Implantation Decrease the Occurrence of Angina Pectoris One Year After Acute Myocardial Infarction. AB - Angina pectoris is a treatable symptom that is associated with mortality and decreased quality of life. Angina eradication is a primary care goal of care after an acute myocardial infarction (AMI). Our aim was to evaluate factors influencing angina pectoris 1 year after an AMI.From January 2005 to December 2013, 1547 patient received primary percutaneous intervention in our hospital for an acute ST-segment elevation myocardial infarction (MI). Of these patients, 1336 patients did not experience post-MI angina during a 1-year follow-up, and 211 patients did. Univariate and multivariate logistic regression analyses were performed to identify the factors influencing angina pectoris 1 year after an AMI. Propensity score matched analyses were performed for subgroups analyses.The average age of the patients was 61.08 +/- 12.77 years, with a range of 25 to 97 years, and 82.9% of the patients were male. During 1-year follow-up, 13.6% of the patients experienced post-MI angina. There was a longer chest pain-to-reperfusion time in the post-MI angina group (P = 0.01), as well as a higher fasting sugar level, glycohemoglobin (HbA1C), serum creatinine, troponin-I and creatine kinase MB (CK-MB). The post-MI angina group also had a higher prevalence of multiple vessel disease. Manual thrombectomy, and distal protective device and intracoronary glycoprotein IIb/IIIa inhibitor injection were used frequently in the no post-MI angina group. Antiplatelet agents and post-MI medication usage were similar between the 2 groups. Multivariate logistic regression analyses demonstrated that prior MI was a positive independent predictor of occurrence of post-MI angina. Manual thrombectomy use and drug-eluting stent implantation were negative independent predictors of post-MI angina. Higher troponin-I and longer chest pain-to-reperfusion time exhibited a trend toward predicting post-MI angina.Prior MIs were strong, independent predictors of post-MI angina. Manual thrombectomy and drug-eluting stent implantation could decrease the occurrence of angina pectoris 1 year after an AMI, decrease long-term healthy costs, and increase post-MI quality of life. PMID- 27124030 TI - Utility of Red Cell Distribution Width as a Prognostic Factor in Young Breast Cancer Patients. AB - The prognosis of breast cancer occurs in young women is usually poor. Red cell distribution width (RDW), 1 of many routinely examined parameters, has recently been proposed as a prognostic marker in solid tumors. The aim of our study was to assess the predictive value of RDW for survival in young women with breast cancer.We reviewed 203 consecutive young female patients (under 40) with invasive breast cancer diagnosed at the First Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2012. Preoperational RDW, clinicopathological information, and prognostic data were collected. RDW levels were divided into 2 groups: 161 patients with low RDW (<=13.75%) and 42 patients with high RDW (>13.75%). Clinicopathological differences between the 2 groups were calculated by chi-squared test and Wilcoxon rank-sum test. Kaplan-Meier survival analysis and Cox proportional hazard regression analyses were used to examine the effect of RDW on survival.We found that high RDW was significantly associated with larger tumor size (P = 0.002), positive lymph node metastases (P = 0.011), and advanced stages (P = 0.004). Patients with high RDW showed significantly lower disease-free survival (DFS; P < 0.001) and lower overall survival (OS) rate (P < 0.001) than patients with low RDW. Moreover, the Cox regression multivariate analysis revealed that high pretreatment DRW was independently correlated with poor DFS and OS, with hazard ratio 4.819 (95% confidence interval [CI] 2.291-10.138, P < 0.001) and 5.887 (95% CI 1.666-20.802, P = 0.006), respectively.In conclusion, our study demonstrated that pretreatment RDW may be associated with DFS and OS in young women with breast cancer. Further validation and feasibility studies are required before the result of our study can be considered for clinical practice. PMID- 27124031 TI - The Periosteal Autografts Transplantation for Cartilage Defects of the Hip in Older Children With Developmental Dysplasia as an Adjunctive Procedure. AB - Cartilage lesions are at a high prevalence in dysplastic hips and may relate to arthritic changes and hip joint dysfunction. To date, the effectiveness of repair of articular cartilage defects in the dysplastic hips has not yet been thoroughly evaluated. Here we retrospectively reviewed the effects of acetabuloplasty procedures with/without concomitant autologous tibial periosteal transplantation (ATPT) for articular cartilage defects of the hip in older children with developmental dysplasia of the hip (DDH).Older DDH children with focal cartilage defects of the acetabular or femoral cartilage or both in the hip joint were treated by acetabuloplasty procedures with (Group I) or without (Group II) concomitant ATPT to evaluate the improvements in range of motion (ROM), pain relief of hip, walking tolerability (WL), radiologic evaluations, and outcomes in the long-term follow-up.More satisfactory functional outcome is readily achieved among patients treated with combined acetabuloplasty and ATPT, evidenced by marked pain relief and improved ROM and WL. The latest favorable radiologic evaluation was 70.6% in Group I and 60.0% in Group II, respectively. More hips exhibited congruency between the femoral head and the shell, with less deformity of femoral head and acetabulum or narrowed joint space in Group I. Few major complications were recorded in Group I.Application of periosteal autograft for repair of cartilage defects within the hip joint might be an effective adjunctive treatment for acetabuloplasty in preventing stiffness, reducing pain, and improving ROM and outcomes in hip rehabilitation in the long-term follow-up in older children with DDH. PMID- 27124032 TI - Perinatal HIV Status and Executive Function During School-Age and Adolescence: A Comparative Study of Long-Term Cognitive Capacity Among Children From a High HIV Prevalence Setting. AB - The aim of this study was to determine whether perinatal HIV infection (PHIV), HIV-exposed uninfected (PHEU) versus HIV-unexposed (PHU) status predicted long term executive function (EF) deficit in school-aged Ugandan children.Perinatal HIV status was determined by 18 months via DNA polymerase chain reaction test and confirmed at cognitive assessment between 6 and 18 years using HIV rapid diagnostic test. Primary outcome is child EF measured using behavior-rating inventory of executive function questionnaire across 8 subscales summed to derive the global executive composite (GEC). EF was proxy-reported by caregivers and self-reported by children 11 years or older. Descriptive analyses by perinatal HIV status included derivation of mean, standard deviations (SD), number, and percent (%) of children with EF deficits warranting clinical vigilance. Raw scores were internally standardized by age and sex adjustment. EF scores warranting clinical vigilance were defined as >= mean + 1.5SD. t Tests for mean score differences by perinatal HIV status and linear-regression models were implemented in SAS version 9.4 to derive HIV status-related EF deficits (beta) and 95% confidence intervals (CIs).Proxy-reported and self-reported EF were assessed in 166 and 82 children, respectively. GEC deficit was highest for PHIV (mean = 121.9, SD = 29.9), intermediate for PHEU (mean = 107.5, SD = 26.8), and lowest for PHU (mean = 103.4, SD = 20.7; P-trend < 0.01). GEC deficit levels warranting clinical vigilance occurred in 9 (15.8%), 5 (9.3%) and 0 (0%) PHIV, PHEU, and PHU children, respectively (P-trend = 0.01). Nineteen percent (n = 32) children had deficits requiring clinical vigilance in >=2 proxy-reported EF subscales. Of these, multisubscale deficits occurred in 35.1%, 13.0%, and 9.3% of PHIV, PHEU, and PHU respectively (P-trend = 0.001). Multivariable analyses find significantly higher GEC deficits for PHIV compared with PHU and PHEU children regardless of respondent (all P values <0.01). Proxy-reported EF performance was similar for PHEU compared with PHU; however, child self-reported GEC scores were elevated by 12.8 units (95% CI: 5.4-25.5) for PHEU compared with PHU.PHIV had long-term EF deficits compared with other groups. Furthermore, PHEU >=11 years may have long-term EF deficits compared with PHU, but future studies are needed to clarify this relationship. Cognitive remediation interventions with emphasis on EF may translate to improvements in long-term functional survival in HIV affected children from sub-Saharan Africa. PMID- 27124033 TI - Intercondylar Notch Stenosis of Knee Osteoarthritis and Relationship between Stenosis and Osteoarthritis Complicated with Anterior Cruciate Ligament Injury: A Study in MRI. AB - The aim of this study was to research whether the patients with knee osteoarthritis (OA) exist intercondylar notch stenosis and the relationship between stenosis and OA complicated with anterior cruciate ligament (ACL) injury from magnetic resonance imaging (MRI).A total of 79 cases of moderate-severe OA patients and 71 cases of healthy people were collected; among these OA patients, 38 were OA complicated with ACL injury and 41 were simple OA. The intercondylar notch was divided into A, U, and W types according to the notch shape in the axial sequence of MRI. Measurement of the notch width index (NWI) in the sequences of axial (NWI-1), coronal (NWI-2), and ACL attachment point at femoral (NWI-A) was done. The differences of NWI in different groups and different sequences were compared and the NWI cut-off values in different sequences were resolved by a receiver operating characteristic (ROC) curve which could be used as indicators for intercondylar notch narrowing were calculated.The proportion of type A in moderate-severe OA group was larger than healthy group, and similar to OA complicated with ACL injury and simple OA groups (P <0.05). The NWI values of the moderate-severe OA group in three sequences were smaller than the healthy group, and similar to OA complicated with ACL injury and simple OA groups (P <0.001). The cut-off values of ROC curve were NWI-1 <0.266, NWI-2 <0.247, and NWI A <0.253 in the moderate-severe OA group, and NWI-1 <0.263, NWI-2 <0.246, and NWI A <0.253 in the OA complicated with ACL injury group. The intercondylar notch of moderate-severe OA patients exist significant stenosis. Type A is one of the variables that predispose a notch to stenosis. Intercondylar notch stenosis and type A are risk factors for moderate-severe OA patients complicated with ACL injury. PMID- 27124034 TI - Removal of Laryngeal Mask Airway in Adults Under Target-Controlled, Propofol Fentanyl Infusion Anesthesia: Awake or Deep Anesthesia? AB - After emergence from anesthesia, the incidence and severity of adverse airway effects caused by the laryngeal mask airway (LMA) can vary, depending on when the device was removed; nonetheless, reports differ regarding the exact optimal timing of LMA removal. The purpose of this study was to compare the rate of adverse events between 2 groups: those whose LMA was removed under general anesthesia ("deep" group) or under target-controlled infusion (TCI) of propofol ("awake" group).Institutional Review Board approval and written informed consent were obtained; 124 patients were then randomly allocated into either the "awake" group or the "deep" group. Anesthesia was induced and maintained using TCI of propofol, as well as intravenous fentanyl. In the "deep" group, the LMA was removed after surgery while the patients were deeply anesthetized using a target effect-site propofol concentration of 2 MUg/mL, whereas in the "awake" group, the device was removed while the patients followed verbal instructions. The incidence of the following adverse events was recorded: coughing, straining, bronchospasm, laryngospasm, clenching, breath holding, gross purposeful movement, airway obstruction, retching, vomiting, and oxygen desaturation. If any such event occurred, the LMA removal was considered a failure. Airway hyperreactivity was recorded and graded - based on the severity of cough, breath holding, and oxygen desaturation.The failure rate was higher in the "awake" group (15/61; 24.6%) than in the "deep" group (5/60; 8.3%). Airway hyperreactivity was mild (score, <3) in both groups.Removal of the LMA under deep anesthesia using a target-controlled, effect-site propofol concentration of 2 MUg/mL may be safer and more successful than removal when patients are fully awake after surgery. PMID- 27124035 TI - Combination of Klinefelter Syndrome and Acromegaly: A Rare Case Report. AB - Klinefelter syndrome (KS) is the most common chromosomal aneuploidy in male population, which demonstrates an unusual association with acromegaly. We herein present a rare case involving the confirmation of KS 2 years after surgical treatment for acromegaly.A 27-year-old man presented with an acromegalic appearance. Endocrinological examination revealed a high growth hormone (GH) concentration, low testosterone concentration, and high follicle-stimulating hormone and luteinizing hormone concentration. Brain imaging revealed a 9 * 6 * 7 mm sellar low-density nodule suggestive of a microadenoma. Trans-sphenoidal surgery was undertaken, and immunohistochemistry revealed GH positivity. Two years after surgery, the patient underwent examination for infertility. He presented with diminished pubic hair, and small and firm testes. Hormonal assay revealed hypergonadotrophic hypogonadism on the basis of decreased serum total testosterone (<0.2 ng/mL), and elevated luteinizing hormone (14.71 mIU/mL) and follicle-stimulating hormone (21.8 mIU/mL). A chromosomal karyotype examination showed 47,XXY, confirming the diagnosis of KS. Replacement therapy with oral testosterone undecanoate was begun. Brain imaging showed no delayed enhancement in the saddle region of the pituitary gland, but the concentration of plasma insulin-like growth factor maintained a high level. The patient's GH concentration was not significantly suppressed by the GH glucose suppression test. In this consideration, he was referred for postoperative somatostatin analogue treatment to control GH hypersecretion.The misdiagnosis or delayed diagnosis of KS is mainly because of substantial variations in clinical presentation and insufficient professional awareness of the syndrome itself. As the simultaneous occurrence of KS and acromegaly is rare, and the association between them remains unclear, we suggest that complete pituitary hormonal screening and conventional pituitary MRI should be essential for patients with KS to screen for pituitary tumor. PMID- 27124036 TI - Long-Term Outcomes of Nasopharyngeal Carcinoma in 148 Children and Adolescents. AB - The aim of this study was to investigate the survival and long-term morbidities of nasopharyngeal carcinoma (NPC) in children and adolescents.We retrospectively reviewed children and adolescents with NPC treated at Sun Yat-sen University Cancer Center from February 1991 to October 2010, where the prognostic factors and long-term effects of therapy were analyzed.A total of 148 patients were identified. The median age was 15 years old (range, 5-18 years) and the male to female ratio was 3.6:1. Most of the tumor histopathology was undifferentiated nonkeratinizing carcinoma (97.3%). The number of patients staged with IVa, IVb, IVc, III, and II were 45 (30.4%), 12 (8.1%), 5 (3.4%), 70 (47.3%), and 16 (10.8%), respectively. For the whole series with a median follow-up of 81 months (range, 6-282 months), the 5-year overall survival (OS) and disease-free survival (DFS) ratios were 79.3% and 69.7%, respectively. We observed significant differences in the 5-year OS (81.1% vs 25.0%, P = 0.002) and the DFS rates (72.2% vs 0.0%, P = 0.000) between patients with stage II to IVb disease and stage IVc disease. For patients with stage II, III, IVa, and IVb disease, we found a high radiation dose (dose > 66 Gy to the primary lesion) would not significantly improve the survival compared to the sub-high radiation dose group (dose = 60-66 Gy to the primary lesion), even considering the type of radiation therapy technologies. However, the incidences of sequelae (grades I-IV) in patients with high radiation dose were apparently higher than those in patients with low radiation dose.Considering the late sequelae, a dose of 60 to 66 Gy to the primary lesions seems to be enough for children and adolescents with NPC. PMID- 27124037 TI - Association of Urinary Sodium Excretion With Insulin Resistance in Korean Adolescents: Results From the Korea National Health and Nutrition Examination Survey 2009-2010. AB - High sodium intake is a well-known risk factor for elevated blood pressure and is responsible for a higher incidence of cardiovascular events. Reports have suggested an association of sodium intake with insulin resistance (IR) and type 2 diabetes mellitus in adults. However, evidence on an association between sodium intake assessed on the basis of urinary sodium excretion and IR in adolescents is scarce. The present study aimed at investigating the association between urinary sodium excretion and IR among South Korean adolescents.This population-based, cross-sectional study analyzed the data obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) 2009 to 2010. The data of a total of 1353 adolescents (779 boys and 574 girls) were included in the final analysis. Spot urine samples were collected, and urinary sodium excretion was estimated by using the urinary sodium concentration (U[Na]), U[Na] to urinary creatinine ratio (U[Na]/Cr), and U[Na] to specific gravity unit (SGU) ratio (U[Na]/SGU). IR was assessed by using the homeostasis model assessment of IR (HOMA-IR). Hierarchical multivariable logistic regression analysis was performed to assess the risk for a high HOMA-IR according to urinary sodium excretion.The mean levels of U[Na], U[Na]/Cr, and U[Na]/SGU were significantly higher in subjects in the highest HOMA IR quartile (Q4) than in subjects in the lowest, second, or third quartiles (Q1 3) of HOMA-IR. The mean values of HOMA-IR and several cardiometabolic parameters tended to progressively increase with the U[Na], U[Na]/Cr, and U[Na]/SGU quartiles. Q3 of U[Na] was at a significantly higher risk than Q1 of U[Na] of an association with Q4 of HOMA-IR, after adjustment for confounding variables. Q3 and Q4 of U[Na]/Cr and U[Na]/SGU, respectively, had significantly higher risks, than the respective Q1s, of an association with Q4 of HOMA-IR. The risk of an association with Q4 of HOMA-IR demonstrated significantly increasing trends with increasing quartiles of U[Na], U[Na]/Cr, and U[Na]/SGU irrespective of confounding factors.Urinary sodium excretion was positively associated with IR in South Korean adolescents. The monitoring and control of urinary sodium excretion may be recommended as an important intervention for the prevention of IR and related diseases in adolescents. PMID- 27124038 TI - A Systematic Review of Des-gamma-Carboxy Prothrombin for the Diagnosis of Primary Hepatocellular Carcinoma. AB - Determining the serum des-gamma-carboxy-prothrombin (DCP) level is of great importance for the diagnosis of primary hepatocellular carcinoma (PHC). Although several studies have investigated the accuracy of diagnostic DCP tests for PHC, the results have been inconsistent.The aim of this study was to systematically evaluate DCP as a diagnostic standard for PHC.Several databases, including PubMed, EMBASE, MEDLINE (Ovid), the Chinese National Knowledge Infrastructure (CNKI), the VIP Database for Chinese Technical Periodicals (VIP), WanFang Data, and the China Biological Medicine Database (CBM), were searched from the date of database inception until July 1, 2015 to collect published international and domestic studies of DCP in the diagnosis of PHC. Two investigators screened the literature according to the inclusion and exclusion criteria, extracted the data, and assessed the methodological quality of the included studies.A total of 38 studies involving 11,124 cases were included (5298 cases in the PHC group and 5826 cases in the control group). A meta-analysis was then performed using Meta Disc 1.4 and RevMan 5.2 software. The overall sensitivity, specificity, positive likelihood ratio (+LR), and negative likelihood ratio (-LR) of DCP for the detection of PHC were 0.66 (95% confidence interval [CI]: 0.65-0.68), 0.88 (95% CI: 0.87-0.90), 7.13 (95% CI: 5.73-8.87), and 0.33 (95% CI: 0.29-0.38), respectively. The area under the curve (AUC) of the summary receiver-operating characteristic curve (SROC) was 0.9002. In conclusion, DCP has moderate diagnostic utility for PHC. Owing to the heterogeneity and limitations of the included studies, the above conclusion requires further support from additional high-quality studies. PMID- 27124039 TI - Maximum Standard Uptake Value as a Clinical Biomarker for Detecting Loss of SMAD4 Expression and Early Systemic Tumor Recurrence in Resected Left-Sided Pancreatic Cancer. AB - This study investigated the oncologic impact of loss of SMAD4 expression in resected left-sided pancreatic cancer and its correlation with tumor metabolism.From 2005 to 2011, the medical records of patients who underwent radical distal pancreatectomy for resectable pancreatic cancer were retrospectively reviewed. Formalin-fixed, paraffin embedded tissue from 32 patients was investigated. Clinicopathological characteristics, immunostaining of SMAD4, and positron emission tomography-based parameters were analyzed in relation to oncologic outcomes.Thirteen patients were women and 19 were men, with a mean age of 63 +/- 9.4 years. Mean resected tumor size was 3.3 +/- 1.5 cm. Ten patients (31.3%) showed loss of SMAD4 expression. No significant clinicopathological differences were noted according to SMAD4 expression (P > 0.05); however, patients with loss of SMAD4 showed significantly poorer disease free survival (mean 57.4 months vs mean 17.6 months, P = 0.006). As a cut-off value, a SUVmax of 4.5 was found to be predictive of loss of SMAD4 with a sensitivity of 75% and a specificity of 84.6%. In logistic regression analysis, SUVmax>4.5 was found to infer a 16-fold higher risk for loss of SMAD4 in resected left-sided pancreatic cancers (Exp[beta] = 16.5, P = 0.012, 95% confidence interval: 1.832-148.606).Loss of SMAD4 is associated with poor oncologic outcomes. SUVmax can predict loss of SMAD4 in resected left-sided pancreatic cancer. SUVmax may be a clinical biomarker for detecting loss of SMAD4 expression and predicting early systemic metastasis. PMID- 27124040 TI - Impact of Instrumented Spinal Fusion on the Development of Vertebral Compression Fracture. AB - Instrumented spinal fusion has become one of the most common surgeries for patients with various spinal disorders. Only few studies have reported subsequent vertebral compression fractures (VCFs) after instrumented spinal fusion. The purpose of this study was to evaluate the risk of new VCFs in patients undergoing instrumented spinal fusion.We obtained claims data from the National Health Insurance Research Database of Taiwan and retrospectively reviewed 6949 patients with instrumented spinal fusion as the spinal fusion cohort. Control subjects were individually matched at a ratio of 10:1 with those of the spinal fusion cohort according to age, sex, and the index day. Comorbidities were classified as those existing before the index day, and these included diabetes mellitus, hypertension, osteoporosis, and cerebrovascular accident. The end of the follow up period for the analyses was marked on the day new VCFs developed, enrolment in the National Health Insurance was terminated, on the day of death, or until the end of 2012. We used the Cox proportion hazards model to analyze the hazard ratio (HR) for developing new VCFs.Patients with instrumented spinal fusion were significantly more likely to develop new VCFs (1.87% vs .25%, HR: 8.56; P < 0.001). Female, elderly, and osteoporotic patients had a high incidence of new VCFs after spinal fusion. The HR for developing new VCFs after instrumented spinal fusion was higher in patients younger than 65 years than in those 65 years or older (HR: 10.61 vs 8.09). Male patients with instrumented spinal fusion also had a higher HR of developing new VCFs than female patients (men, HR: 26.42; women, HR: 7.53).In our retrospective cohort study, patients who had undergone instrumented spinal fusion surgery exhibited an increased risk of developing new VCFs. Particularly, the HR increased in young (age <65 years) and male patients. PMID- 27124041 TI - Roux-en-Y Gastric Bypass Versus Medical Treatment for Type 2 Diabetes Mellitus in Obese Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - The aim of the study is to compare Roux-en-Y gastric bypass (RYGB) surgery versus medical treatment for type 2 diabetes mellitus (T2DM) in obese patients.Bariatric surgery can achieve remission of T2DM in obese patients. RYGB surgery has been performed as one of the most common surgical treatment options for obese patients with T2DM, but the efficacy of RYGB surgery comparing with medical treatment alone has not been conclusively determined.A systematic literature search identified randomized controlled trials (RCTs) evaluating RYGB surgery versus medical treatment for T2DM in obese patients was conducted in PubMed, Embase, Cochrane Database, and Cochrane Clinical Trials Registry. This systematic review and meta-analysis were performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The primary outcome was T2DM remission. Additional analyses comprised hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), body mass index (BMI), waist circumference, serum lipid level, blood pressure, medication use, and adverse events. Random-effects meta analyses were calculated and presented as weighted odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CI).Six RCTs concerning 410 total obese T2DM patients were included. Follow-up ranged from 12 to 60 months. RYGB surgery was associated with a higher T2DM remission rate (OR: 76.37, 95% CI: 20.70-281.73, P < 0.001) and serum level of high-density lipoprotein cholesterol (MD: 0.24 mmol/L, 95% CI 0.18-0.30 mmol/L, P < 0.001) than medical treatment alone. HbA1c (MD: -1.25%, 95% CI: -1.88% to -0.63%, P < 0.001), BMI (MD: -6.54 kg/m, 95% CI: -9.28 to -3.80 kg/m, P < 0.001), waist circumference (MD: -15.60 cm, 95% CI: -18.21 to -13.00 cm, P < 0.001), triglyceride (MD: -0.87 mmol/L, 95% CI: -1.17 to -0.57 mmol/L, P < 0.001), low-density lipoprotein cholesterol (MD: 0.32 mmol/L, 95% CI: -0.62 to -0.02 mmol/L, P = 0.04), systolic blood pressure (MD: -2.83 mm Hg, 95% CI: -4.88 to -0.78 mm Hg, P < 0.01) were lower after RYGB surgery. However, FPG (MD: -1.58 mmol/L, 95% CI: -3.58 to 0.41 mmol/L, P = 0.12), total cholesterol (MD: -0.40 mmol/L, 95% CI: -0.92 to 0.12 mmol/L, P = 0.13), and diastolic blood pressure (MD: 0.28 mm Hg, 95% CI: -1.89 to 2.45 mm Hg, P = 0.80) were not significantly different between the 2 treatment groups. The medicine use and quality of life were solely improved in the surgical group. Nutritional deficiencies and anemia were noted more frequently in the RYGB group.RYGB surgery is superior to medical treatment for short- to medium-term remission of T2DM, improvement of metabolic condition, and cardiovascular risk factors. Further RCTs should address the safety and long-term benefits of RYGB surgery on obese patients with T2DM. PMID- 27124042 TI - Evaluation of the Immune Response to Interferon Gamma Release Assay and Tuberculin Skin Test Among BCG Vaccinated Children in East of Egypt: A Cross Sectional Study. AB - Bacille Calmette-Guerin vaccine (BCG) vaccination is used routinely in most of countries, especially developing one. The efficacy of the BCG vaccination generally decreases with time. The tuberculin skin test (TST) is a most popular diagnostic test for suspicion of tuberculosis (TB) in children till now, but it has many false positives. The interferon-gamma release assay (IGRA) is more specific than TST for detection of childhood TB, as it is more specific to Mycobacterium tuberculosis.Evaluate the interferon gamma response and TST reaction in BCG vaccinated children in east of Egypt.150 children were included in the study aged 1 month to 12 years; the collected data from the children included, full history taking, clinical examination, examination for the presence or absence of BCG scar under direct light. All the children had performed TST, IGRA.TST was done for all studied group reveal 51.3% with size of reaction <5 mm, 39.3% with size of reaction = 5 to 9 mm while 9.3% with size of reaction >=10 mm. Mean size of reaction was 4.07 mm. Interferon gamma release assay was done for all studied group reveal 5 children (3.3%) with positive test. There was significant difference between the size of TST reaction and age (P < 0.01) with old children were more frequent to show positive reaction. Also, children with age range 1 month to 1 year were frequently have negative IGRA test, while children with age range 4 years to 12 years were frequently have positive test (P < 0.01). There was moderate agreement between IGRA and TST results (Kappa [kappa] = 0.475). With high agreement between IGRA and TST results in children with absent BCG scar (kappa = 1000).Therefore, Interferon gamma release assays have higher specificity and lower cross-reactions with BCG vaccination and nontuberculous Mycobacteraie than TST. PMID- 27124043 TI - Characteristics of Venous Thromboembolism in Pancreatic Adenocarcinoma in East Asian Ethnics: A Large Population-Based Observational Study. AB - Pancreatic cancer (PC) is known to be frequently associated with venous thromboembolism (VTE). Although treatment and prophylaxis strategies for VTE in PC patients were updated recently, these were mainly based on data from Western populations and were not verified in East Asian ethnic populations.We investigated the clinical characteristics of VTE in East Asian PC patients. We reviewed electronic medical records (EMR) of 1334 patients diagnosed with pancreatic adenocarcinoma from 2005 to 2010 at single tertiary hospital in Korea. All the patients with newly diagnosed VTE were classified by anatomical site and manifestation of symptoms. The primary outcomes of interest were 2-year cumulative incidence of VTE events. Cox proportional hazards models were used to analyze associations between risk factors and clinical outcomes.A total of 1115 patients were eligible for enrollment. The 2-year cumulative VTE incidence was 9.2%. Major risk factors associated with VTE event were advanced cancer stage, major surgery, and poor performance status. Risk factors associated with mortality after PC diagnosis included advanced cancer stage, poor performance score, leukocytosis, and lower albumin level. The overall VTE did not affected mortality. However in subgroup analysis, symptomatic VTE and deep vein thrombosis/pulmonary thromboembolism (DVT/PTE) showed worse prognosis than incidental or intra-abdominal VTE.The overall incidence of VTE events in Korean PC patients was lower than previous studies. Advanced cancer stage was the most important factor for VTE event and mortality. Unlike Western population group, VTE event did not affect overall prognosis after PC diagnosis. However, symptomatic VTE and DVT/PTE showed higher mortality after VTE event. PMID- 27124044 TI - Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice: A Japanese Multicenter, Prospective Longitudinal Cohort Study for Achieving a Treat-to-Target Strategy. AB - To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice.We performed a multicenter prospective study in Japan of biological disease modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs >=3 years) and performed a subgroup analysis.CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01-1.11), time integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17-2.59), RA typical erosion at baseline (95%CI 1.56-21.1), and the introduction of bDMARDs (95%CI 0.06-0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years.We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients' disease durations. PMID- 27124045 TI - Trimethoprim/Sulfamethoxazole-Induced Severe Lactic Acidosis: A Case Report and Review of the Literature. AB - Propylene glycol (PG) is used as a solvent in numerous medications, including trimethoprim/sulfamethoxazole (TMP/SMX) and lorazepam, and is metabolized in the liver to lactic acid. Cases of lactic acidosis related to PG toxicity have been described and always involved large doses of benzodiazepines and PG. We present the first case of severe lactic acidosis after a 3-day course of TMP/SMX alone, involving allegedly safe amounts of PG.A 31-year-old female with neurofibromatosis and pilocytic astrocytoma, receiving temozolomide and steroids, was admitted to the intensive care unit for pneumonia and acute respiratory failure requiring intubation. Her initial hemodynamic and acid-base statuses were normal. She was treated with intravenous TMP/SMX for possible Pneumocystis jirovecii pneumonia and was successfully extubated on day 2. On day 3, she developed tachypnea and arterial blood gas analysis revealed a severe metabolic acidosis (pH 7.2, PCO2 19 mm Hg, bicarbonates 8 mEq/L) with anion gap of 25 mEq/L and lactate of 12.1 mmol/L. TMP/SMX was discontinued and the lactate decreased to 2.9 mmol/L within 24 hours while her plasma bicarbonates normalized, without additional intervention. The patient never developed hypotension or severe hypoxia, and her renal and liver functions were normal. No other cause for lactic acidosis was identified and it resolved after TMP/SMX cessation alone, suggesting PG toxicity.Although PG-related lactic acidosis is well recognized after large doses of lorazepam, clinicians should bear in mind that TMP/SMX contains PG as well and should suspect PG toxicity in patients developing unexplained metabolic acidosis while receiving TMP/SMX. PMID- 27124046 TI - Primary Malignant Melanoma of the Esophagus With Unusual Endoscopic Findings: A Case Report and Literature Review. AB - Primary malignant melanoma of the esophagus (PMME) is a rare disease with an extremely poor prognosis. We experienced a 79-year-old man with PMME who had unusual endoscopic findings. On endoscopy, an elongated lump was detected on 1 side of the vertical axis of the esophagus. The mass extended progressively for 15 cm along the esophageal longitudinal axis and invaded half of the esophageal circumference. These endoscopic findings were not characteristic of PMME, and the condition was confirmed with biopsy and immunohistochemical staining. Here, we present this rare case and review the recent relevant literature regarding PMME. Doctors should be aware that PMME might present with unusual endoscopic findings. PMID- 27124047 TI - Use of Electrocardiography to Predict Future Development of Hypertension in the General Population. AB - Cardiac muscle responds to increased afterload by developing hypertrophy. During the early stages of hypertension, the heart can be transiently, but frequently, exposed to increased afterload. This study was designed to test the hypothesis that left ventricular hypertrophy (LVH) assessed by electrocardiography (ECG) can be used to predict future development of hypertension.Sokolow-Lyon voltage and Cornell product were calculated using ECG in 5770 normotensive participants who visited our hospital for a physical checkup (age 52.7 +/- 11.3 years). LVH was defined as a Sokolow-Lyon voltage of >3.8 mV or a Cornell product of >2440 mm * ms. After baseline examination, participants were followed up with the endpoint being the development of hypertension.During the median follow-up period of 1089 days (15,789 person-years), hypertension developed in 1029 participants (65.2/1000 person-years). A Kaplan-Meier analysis demonstrated a significantly higher incidence of hypertension in participants with LVH than in those without LVH as assessed by Sokolow-Lyon voltage or Cornell product (P < 0.0001 for both). The hazard ratios for incident hypertension in participants with LVH defined by Sokolow-Lyon voltage and Cornell product were 1.49 (95% confidence interval [CI] 1.16-1.90, P < 0.01) and 1.34 (95% CI 1.09-1.65, P < 0.01), respectively, after adjustment for possible risk factors. Furthermore, in multivariable Cox hazard analysis, where Sokolow-Lyon voltage and Cornell product were taken as continuous variables, both indices were independent predictors of future hypertension (P < 0.0001).Both Sokolow-Lyon voltage and Cornell product are novel predictors of future development of hypertension in the general population. PMID- 27124048 TI - GALNT14 Genotype Predicts Postoperative Outcome of Stage III Colorectal Cancer With Oxaliplatin as Adjuvant Chemotherapy. AB - Adjuvant oxaliplatin-based chemotherapy is widely used for stage III colorectal cancer (CRC) after curative surgery. CRC is a molecularly heterogeneous disease, and our current knowledge of therapeutic response-related genetic factors remains limited. N-acetylgalactosaminyltransferase 14 (GALNT14)-rs9679162 genotype is a prognostic predictor for chemotherapy response in advanced hepatocellular carcinoma. Here, we investigated whether this genotype was related to the therapeutic outcome of stage III CRC.A cohort of 300 stage III CRC patients receiving curative resection followed by oxaliplatin-based chemotherapy was retrospectively recruited. GALNT14 genotypes and the clinicopathological factors were correlated with posttherapeutic prognosis.Of these patients, 18% patients had GALNT14-rs9679162 "TT" and 82% had the "GT" + "GG" genotypes. The analysis showed that the "TT" genotype was associated with unfavorable overall survival (OS, P = 0.009) but not with recurrence-free survival (RFS, P = 0.700). The subgroup analysis showed that the "TT" genotype was associated with unfavorable OS in the following subgroups: age <=65 years, men, left side CRC, N2 stage, carcinoembryonic antigen >5 ng/mL, and mucinous histology (P = 0.012, 0.011, 0.009, 0.025, 0.013, and 0.007, respectively). Within the latter 2 subgroups, the "TT" genotype was the only independent predictor for OS. Finally, the "TT" genotype was associated with the T4 tumor stage (P = 0.017) and in patients with T4 tumors, the "TT" genotype was the only independent predictor for unfavorable RFS (P = 0.007).GALNT14 "TT" genotype was associated with unfavorable OS in stage III CRC patients receiving curative surgery and adjuvant oxaliplatin-based chemotherapy. PMID- 27124049 TI - Predictive Factors of Spontaneous Bacterial Peritonitis Caused by Gram-Positive Bacteria in Patients With Cirrhosis. AB - Spontaneous bacterial peritonitis (SBP) in patients with cirrhosis is typically caused by gram-negative bacteria. However, the number of SBP cases due to gram positive bacteria is steadily increasing. To date, little is known about the predictive factors involved in SBP infections.We performed a retrospective cohort study of patients (>18 years) with SBP due to gram-positive and -negative bacteria who were enrolled from January 2006 to December 2013 at Severance Hospital in Seoul, Korea where the incidences of hepatitis B virus associated chronic liver disease, cirrhosis, and hepatocellular carcinoma are high. Only the 1st SBP episode for each patient within the study period was included in our analysis.We identified 77 patients with cirrhosis and SBP. Of these, 27 patients (35%) had gram-positive bacterial infections and 50 patients (65%) had gram negative bacterial infections. Our univariate analysis revealed that an early stage of cirrhosis (P = 0.004), lower creatinine level (P = 0.011), lower Sequential Organ Failure Assessment (SOFA) score (P = 0.001), lower Model for End Stage Liver Disease score (P = 0.005), and use of systemic antibiotics within 30 days before SBP diagnosis (P = 0.03) were significantly associated with gram positive bacterial infections. Our multivariate analysis indicated that the use of systemic antibiotics within 30 days before SBP diagnosis (odds ratio, 3.94; 95% CI, 1.11-13.96; P = 0.033) and a lower SOFA score (odds ratio, 0.56; 95% CI, 0.37-0.86; P = 0.007) were independent predictive factors of SBP caused by gram positive bacterial infections in patients with cirrhosis. However, we did not observe a statistically significant difference in the 28-day mortality between the gram-positive and -negative bacterial infection groups (40.7% vs 46.0%, respectively; P = 0.407).In this study, the incidence rate of SBP caused by gram positive bacteria in patients with cirrhosis was similar to the rates reported in recently published studies. Furthermore, the use of systemic antibiotics within 30 days before SBP diagnosis and a lower SOFA score were significantly associated with SBP caused by gram-positive bacteria in patients with cirrhosis. PMID- 27124050 TI - Multiple Primary Malignancies in Patients With Hepatocellular Carcinoma: A Largest Series With 26-Year Follow-Up. AB - Multiple primary malignancies (MPMs) are defined as 2 or more malignancies without subordinate relationship detected in different organs of an individual patient. Reports addressing MPM patients with hepatocellular carcinoma (HCC) are rare. We perform a 26-year follow-up study to investigate characteristics and prognosis of MPM patients associated with HCC due to the scarcity of relative researches.We retrospectively analyzed records of 40 patients who were diagnosed with MPM including HCC at the Departments of Surgery at Peking Union Medical College Hospital during 1989 to 2010. Their clinical characteristics and postoperative survival were compared with those of 448 patients who had HCC only during the study period.Among the 40 MPM patients, 11 were diagnosed synchronously and 29 metachronously. The most common extra-hepatic malignancies were lung cancer (15%), colorectal (12.5%), and thyroid carcinoma (12.5%). MPM patients had a negative hepatitis B virus infection rate (P = 0.013) and lower median alfa-fetoprotein (AFP) level (P = 0.001). Post-operative 1-, 3-, and 5 year overall survival (OS) rates for MPM patients were 82.5%, 64.5%, and 38.6% respectively, and showed no significant difference with those of HCC-only patients (84.7%, 54.2%, and 38.3% P = 0.726). During follow-up, 24 MPM patients died, including 17 (70.8%) who died of HCC-related causes. In univariate analysis, synchronous diagnosis, higher gamma glutamyltransferase (GGT) and/or AFP levels, tumor >5 cm and vascular invasion were significantly associated with shorter OS, but only tumor size was an independent OS factor in Cox modeling analysis.HCC should be considered as a potential second primary for all cancer survivors. Most MPM patients died of HCC-related causes and showed no significant difference in OS compared with HCC-only patients. Tumor size of HCC, rather than MPMs itself, was the only independent OS predictor for the MPM patients. PMID- 27124051 TI - The Prognostic Role of Angiotensin II Type 1 Receptor Autoantibody in Non-Gravid Hypertension and Pre-eclampsia: A Meta-analysis and Our Studies. AB - Angiotensin II type 1 receptor autoantibody (AT1-AA) is found in patients with non-gravid hypertension or pre-eclampsia, but the relationship is uncertain.The aim of the present study was to assess the association between AT1-AA and high blood pressure using meta-analysis, and to evaluate the prognosis value of AT1-AA for hypertensive diseases.Literature search from PubMed, Embase, and Cochrane databases were conducted using keywords "hypertension" or "pre-eclampsia," "angiotensin II receptor type 1 autoantibody," and its aliases from April 1999 to December 2015.Studies evaluating the association between AT1-AA and non-gravid hypertension or pre-eclampsia were included in this analysis. The quality of the eligible studies was assessed based on the Newcastle-Ottawa Scale with some modifications.Two researchers then independently reviewed all included studies and extracted all relevant data. Association between AT1-AA and hypertension was tested with pooled odds ratios (ORs) and 95% confidence intervals (CIs). Finally, we evaluated whether AT1-AA predicted the prognosis of hypertension by using a summary receiver-operating characteristic (ROC) curve and sensitivity analysis.Ten studies were finally included in this meta-analysis. AT1-AA showed more significant association with pre-eclampsia than that with non-gravid hypertension (pooled OR 32.84, 95% CI 17.19-62.74; and pooled OR 4.18, 95% CI 2.20-7.98, respectively). Heterogeneity among studies was also detected probably due to different hypertensive subtypes and AT1-AA measuring methods. Area under summary ROC curve (AUC) of pre-eclampsia was 0.92 (sensitivity 0.76; specificity 0.86). Area under the ROC curve of overall hypertensive diseases or non-gravid hypertension was lower than that of pre-eclampsia (0.86 and 0.72, respectively) with lower sensitivities (0.46 and 0.26, respectively).The major limitation of this analysis was the publication bias due to lack of unpublished data and the language limitation during literature search. Prospective study with large simple size and specific measuring data collection are needed to enhance our findings in the future.Our analysis confirms that elevated AT1-AA in serum is significantly associated with hypertensive disorder, especially pre-eclampsia. AT1-AA may be a valuable indicator for poorer prognosis of patients with pre-eclampsia, and could be used in patients with hypertensive disease for risk evaluation and making individual treatment decision. PMID- 27124052 TI - Congenital Kyphoscoliosis in Monozygotic Twins: Ten-Year Follow-up Treated by Posterior Vertebral Column Resection (PVCR): A Case Report. AB - The etiology of congenital scoliosis and its development remains unclear and has not yet been fully identified, even there are theories that congenital scoliosis could be derived from the failure of formation or failure of segmentation, which are etiologically heterogeneous with genetic, epigenetic, and environmental factors contributing to their occurrence. We reported a case of long-term follow up after posterior vertebral column resection (PVCR) in both identical twins with similar congenital kyphoscoliosis at thoracolumbar levels. Twin I had been noticed by his parents to have asymmetry of his back at age 5 years, but no treatment was given. Twin II was first noticed to have a spinal problem at 11 years of age by his parents. Overtime, spine of both twins became further deviated to the left with kyphosis and was referred to our hospital. Both monozygotic twins were treated by PVCR and satisfactory results were demonstrated at 10-year follow-up.This case is the first report on the surgical treatment with PVCR, almost simultaneously, in both identical twins who had similar congenital vertebral anomalies causing kyphoscoliosis. Both identical twins with congenital kyphoscoliosis had undergone surgical correction by PVCR, anterior support with a mesh cage and posterior fusion using pedicle screws at the age of 14 years and achieved a satisfactory correction and a stable spine without curve progression with 10-year follow-up. PMID- 27124053 TI - Interferon-gamma Genetic Polymorphism and Expression in Kawasaki Disease. AB - Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. IFNG gene encoding interferon (IFN)-gamma, produced by natural killer cells and T cells, has been suggested to play an important role in the immunopathogenesis of Kawasaki disease. The aim of this study was to examin the correlation of gene polymorphisms of the IFNG gene and plasma levels of IFN-gamma in KD patients and their outcomes.A total of 950 subjects (381 KD and 569 controls) were recruited. Three tagging single-nucleotide polymorphisms (rs2069718, rs1861493, rs2069705) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL), coronary artery aneurysms (CAA) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Plasma IFN gamma levels were also measured with an enzyme-linked immunosorbent assay.Polymorphisms of the IFNG gene were significantly different between the normal controls and KD patients. The G allele of rs1861493 conferred a better response to IVIG treatment in KD patients. AA allele frequencies of rs1861493 were also associated with a significantly higher risk of CAA in KD patients. Furthermore, the plasma IFN-gamma level was lower in the AA allele than in the GG allele of rs1861493 both before and after IVIG treatment in KD patients.This study provides the first evidence supporting an association between IFNG gene polymorphisms, susceptibility of KD, IVIG responsiveness, and plasma IFN-gamma levels in KD patients. PMID- 27124054 TI - Diagnostic Performance of Fused Diffusion-Weighted Imaging Using Unenhanced or Postcontrast T1-Weighted MR Imaging in Patients With Breast Cancer. AB - To evaluate the diagnostic performance of fused diffusion-weighted imaging (DWI) using either unenhanced (UFMR) or early postcontrast T1-weighted imaging (PCFMR) to detect and characterize breast lesions in patients with breast cancer.This retrospective observational study was approved by institutional review board in our hospital and informed consents were waived. We retrospectively selected 87 consecutive patients who underwent preoperative breast magnetic resonance imaging, including DWI and definitive surgery. Both UFMR and PCFMR were reviewed by 5 radiologists for detection, lesion size, Breast Imaging Reporting and Data System final assessment, the probability of malignancy, lesion conspicuity, and apparent diffusion coefficients.A total of 129 lesions were identified by at least 2 readers on UFMR or PCFMR. Of 645 potentially detected lesions, there were 528 (82%) with UFMR and 554 (86%) with PCFMR. Malignant lesions or index cancers showed significantly higher detection rates than benign or additional lesions on both UFMR and PCFMR (P < 0.05). Area under the characteristic curves (AUCs) for predicting malignancy ranged 0.927 to 0.986 for UFMR, and 0.936 to 0.993 for PCFMR, which was not significantly different. Lesion conspicuity was significantly higher on PCFMR than UFMR (8.59 +/- 1.67 vs 9.19 +/- 1.36, respectively; P < 0.05) across 5 readers. Mean intraclass correlation coefficients for lesion size on UFMR and PCFMR were 0.89 and 0.92, respectively.Detection rates of index malignant lesions were similar for UFMR and PCFMR. Interobserver agreement for final assessments was reliable across 5 readers. Diagnostic accuracy for predicting malignancy with UFMR versus PCFMR was similar, although lesion conspicuity was significantly greater with the latter. PMID- 27124055 TI - Liver Abscess Formation Following Transarterial Chemoembolization: Clinical Features, Risk Factors, Bacteria Spectrum, and Percutaneous Catheter Drainage. AB - To investigate the clinical features, risk factors, and bacterial spectrum of liver abscess following transarterial chemoembolization (TACE) and evaluate the therapeutic effect of percutaneous catheter drainage (PCD) on the abscesses.A retrospective review of patient charts was performed in 3613 patients who suffered from liver malignancies (2832 patients with hepatocellular carcinoma and 781 with metastatic hepatic tumor) and had undergone 11,054 TACE procedures from January 2005 to October 2013. Liver abscesses were found in 21 patients. PCD was performed in all abscess patients. The clinical features, risk factors, and bacterial spectrum of liver abscess following TACE were investigated and the therapeutic effect of PCD was evaluated.The incidence of liver abscess was 0.58% per patient and 0.19% per procedure. Approximately 57.1% of the patients had a medical history of bilioenteric anastomosis or biliary stent implantation. On computed tomography scans, the abscesses appeared as low-attenuation lesions and high-density iodinate oil scattered in the abscesses. The ultrasound showed the well defined, heterogeneously hypoechoic lesions. Positive microbiological isolates were obtained in all pus cultures and in 47.6% of blood cultures. The most common bacterium was Escherichia coli (52.4%). Twenty patients (95.2%) were cured from abscesses by using PCD, and 1 died of sepsis.Patients with predisposing factors are prone to an increased risk of liver abscess following TACE. Bacterial culture and antibiotic sensitivity tests on pus and blood help on the antibiotics selection. PCD combined with aggressive antibiotics can be recommended as the first-line therapeutic regimen. PMID- 27124056 TI - A Prognostic Model Using Inflammation- and Nutrition-Based Scores in Patients With Metastatic Gastric Adenocarcinoma Treated With Chemotherapy. AB - The outcomes of patients with metastatic gastric cancer (mGC) are poor. Recent studies have identified the prognostic impact of inflammatory response and nutritional status on survival for patients with gastric cancer. This study aims to create a prognostic model using inflammatory- and nutrition-based scores to predict survival in patients with mGC treated with chemotherapy.After institutional review board approval, patients who had mGC and were treated with chemotherapy from 2007 to 2012 at Kaohsiung Chang Gung Memorial Hospital were retrospectively reviewed. Significantly predictive factors were identified by multivariate Cox regression analyses. Based on these variables, a prognostic model using inflammatory- and nutrition-based scores was constructed to predict survival. Kaplan-Meier curves were plotted to estimate overall survival. The c statistic values with 95% confidence interval (CI) were also calculated to access their predicting performances.Our study consisted of 256 patients with a median age of 60 years and a median follow-up visit of 18.5 months. Multivariate analyses showed that neutrophil to lymphocyte ratio (NLR), modified Glasgow prognostic score (mGPS), and Patient-Generated Subjective Global Assessment (PG SGA) were independently related to survival. After computing these scores, patients were classified into favorable-, intermediate-, and poor-risk groups. The median overall survival were 27.6 versus 13.2 versus 8.2 months in favorable, intermediate, and poor-risk groups, respectively. The 2-year survival rate was 52% versus 16% versus 3% in favorable-, intermediate-, and poor-risk groups, respectively. (P < 0.001). The c-statistic value of our model at 2 years is 0.8 (95% CI, 0.75-0.86).NLR, mGPS, and PG-SGA were independently related to survival. Our prognostic model using inflammatory- and nutrition-based scores could provide prognostic information to patients and physicians. PMID- 27124058 TI - Hemolymphangioma of Greater Omentum: A Rare Case Report. AB - Hemolymphangioma is a rare vascular developmental error. It comprises malformed venous and lymphatic component in various proportion. To the best of our knowledge, only a few cases have been reported in the literature so far. Here, we report a case of huge intraperitoneal cystic mass in a 3-year-old boy that was presented to hospital with intractable abdominal pain. On examination, he had fever along with associated symptoms like cough and sputum. Abdomen was distended with no tenderness or rebound tenderness. On computed tomography scan, huge cystic mass was seen and was diagnosed as intraperitoneal benign cystic lesion. Excisional surgery of the lesion was planned. On surgery, lesion was found to be originated from greater omentum and no adhesion was seen in surrounding tissue. Complete excision of the lesion was done. Histopathological specimen after surgery suggested it to be hemolymphangioma. Follow-up for 6 months showed no recurrence.Hemolymphangioma of the greater omentum is benign tumor and accurate diagnosis before surgery is still a challenge. Presentation of disease may vary from simple well-defined cystic lesion to aggressive ill-defined lesion mimicking malignancy. Therefore, further research is needed to help doctor with preoperative radiological diagnosis and avoid unnecessary radical surgery. PMID- 27124057 TI - Adjuvant Therapeutic Modalities in Primary Small Cell Carcinoma of Esophagus Patients: A Retrospective Cohort Study of Multicenter Clinical Outcomes. AB - To evaluate the treatment pattern and survival of patients receiving radical resection for primary small cell carcinoma of the esophagus (PSCCE).This retrospective study included 150 patients who received radical resection of PSCCE. Data were retrieved from 4 centers in Western China. Thirty-nine of 150 patients received postoperative chemo-radiotherapy, 62 received postoperative chemotherapy, and 49 received radical resection only. The median radiation dosage was 50 Gy. The chemotherapeutic regimen was platinum-based and lasted for 2 to 6 cycles (median, 3).Median disease-free survival (mDFS) and overall survival (mOS) were 12.0 and 18.3 months, respectively. Subgroup analysis revealed that postoperative therapy did not improve survival in limited stage I (LSI) disease, whereas postoperative chemotherapy improved survival in limited stage II (LSII) disease. Relative to chemotherapy alone, chemoradiotherapy did not improve survival in patients with completely resected LSII disease. A multivariate analysis indicated an association of no postoperative chemotherapy with shorter DFS (P = 0.050) and OS (P = 0.010). Higher lymph node stage and length of disease longer than 3 cm were poor prognostic factors for both DFS and OS.Adjuvant chemotherapy improves survival in PSCCE patients with completely resected LSII disease. Adjuvant treatment with postoperative chemotherapy alone or postoperative chemo-radiotherapy does not increase survival in completely resected LSI disease. PMID- 27124059 TI - Evaluation of Biliary Calprotectin as a Biomarker in Primary Sclerosing Cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts with limited therapeutic options except liver transplantation. Reliable biomarkers to predict the disease course are unavailable, and currently employed disease activity scores such as the Mayo risk score (MRS) have limitations. The present study aims to evaluate biliary calprotectin as a marker of disease activity and prognosis in PSC.This is a monocentric retrospective observational study. Calprotectin concentrations were measured by an enzyme linked immunosorbent assay in bile samples collected by endoscopic retrograde cholangiography from 106 PSC patients and 20 controls. Biliary calprotectin concentrations were compared between the 2 groups. In PSC patients, results were evaluated with regard to the presence of dominant bile duct stenoses, bile microbiology, MRS, survival free of liver transplantation, and necessity for bile duct interventions in the further disease course.Median (interquartile ranges) biliary calprotectin concentrations were higher in PSC patients than in controls (3646 ng/mL, 249-9748 vs 116 ng/mL, 104-655; P < 0.001). In the PSC cohort, higher biliary calprotectin concentrations were associated with the presence of microbes in bile (P = 0.02), the occurrence of dominant bile duct stenosis at any time in the disease course (P = 0.005), and the necessity for future bile duct interventions (P = 0.02). Patients with biliary calprotectin concentrations above a cut-off of 11,610 ng/mL displayed significantly shorter transplantation-free survival than those with biliary calprotectin concentrations <=11,610 ng/mL (P < 0.001). Univariate Cox regression analysis revealed high biliary calprotectin concentration (>11,610 ng/mL) as a risk factor of shorter transplantation-free survival of PSC patients (P < 0.001) beside high plasma alkaline phosphatase (ALP) concentration (>142.5 U/L) (P = 0.006), high MRS (>=2) (P < 0.001), and nonsterility of bile (P = 0.03). Multivariate analysis identified only MRS (P = 0.002) and ALP concentration (P = 0.04) as independent risk factors.Our data strongly suggest that biliary calprotectin may be a valuable additional marker for disease activity and a predictor of outcome in PSC, so that further studies for evaluation of calprotectin in this disease are warranted. PMID- 27124060 TI - Placebo-Controlled Trials in Surgery: A Systematic Review and Meta-Analysis. AB - This systematic review was performed to investigate the ethical justification, methodological quality, validity and safety of placebo controls in randomized placebo-controlled surgical trials.Central, MEDLINE, and EMBASE were systematically searched to identify randomized controlled trials comparing a surgical procedure to a placebo. "Surgical procedure" was defined as a medical procedure involving an incision with instruments. Placebo was defined as a blinded sham operation involving no change to the structural anatomy and without an expectable physiological response in the target body compartment.Ten randomized placebo-controlled controlled surgical trials were included, all of them published in high-ranking medical journals (mean impact factor: 20.1). Eight of 10 failed to show statistical superiority of the experimental intervention. Serious adverse events did not differ between the groups (rate ratio [RR] 1.38, 95% confidence interval [CI]: 0.92-2.06, P = 0.46). None of the trials had a high risk of bias in any domain. The ethical justification for the use of a placebo control remained unclear in 2 trials.Placebo-controlled surgical trials are feasible and provide high-quality data on efficacy of surgical treatments. The surgical placebo entails a considerable risk for study participants. Consequently, a placebo should be used only if justified by the clinical question and by methodological necessity. Based on the current evidence, a pragmatic proposal for the use of placebo controls in future randomized controlled surgical trials is made. PMID- 27124061 TI - Association of Metformin Use With Cancer-Specific Mortality in Hepatocellular Carcinoma After Curative Resection: A Nationwide Population-Based Study. AB - Many preclinical reports and retrospective population studies have shown an anticancer effect of metformin in patients with several types of cancer and comorbid type 2 diabetes mellitus (T2DM). In this work, the anticancer effect of metformin was assessed in hepatocellular carcinoma (HCC) patients with T2DM who underwent curative resection.A population-based retrospective cohort design was used. Data were obtained from the National Health Insurance Service and Korea Center Cancer Registry in the Republic of Korea, identifying 5494 patients with newly diagnosed HCC who underwent curative resection between 2005 and 2011. Crude and adjusted hazard ratios (HRs) were calculated using Cox proportional hazard models to estimate effects. In the sensitivity analysis, we excluded patients who started metformin or other oral hypoglycemic agents (OHAs) after HCC diagnosis to control for immortal time bias.From the patient cohort, 751 diabetic patients who were prescribed an OHA were analyzed for HCC-specific mortality and retreatment upon recurrence, comparing 533 patients treated with metformin to 218 patients treated without metformin. In the fully adjusted analyses, metformin users showed a significantly lower risk of HCC-specific mortality (HR 0.38, 95% confidence interval [CI] 0.30-0.49) and retreatment events (HR 0.41, 95% CI 0.33-0.52) compared with metformin nonusers. Risks for HCC-specific mortality were consistently lower among metformin-using groups, excluding patients who started metformin or OHAs after diagnosis.In this large population-based cohort of patients with comorbid HCC and T2DM, treated with curative hepatic resection, metformin use was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events. PMID- 27124062 TI - The Effect of Diabetes Mellitus on Lung Cancer Prognosis: A PRISMA-compliant Meta analysis of Cohort Studies. AB - Previous studies suggested that diabetes mellitus (DM) was associated with risk and mortality of cancer, but studies investigating the correlation between DM and lung cancer prognosis remain controversial. Herein, a meta-analysis was performed to derive a more precise estimate of the prognostic role of DM in lung cancer.Medline and Embase were searched for eligible articles from inception to October 25, 2015. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) was calculated to evaluate the correlation between DM and lung cancer prognosis. Subgroup meta-analysis was performed based on the histology and the treatment methods.A total of 20 cohort studies from 12 articles were included in the meta-analysis. Also, 16 studies investigated the overall survival (OS) and 4 studies investigated the progression-free survival (PFS). DM was significantly associated with the inferior OS of lung cancer with the pooled HR 1.28 (95% CI: 1.10-1.49, P = 0.001). The association was prominent in the nonsmall cell lung cancer (NSCLC) subgroup (HR 1.35, 95%CI: 1.14-1.60, P = 0.002), whereas the association was not significant in the small cell lung cancer (SCLC) subgroup (HR 1.33, 95% CI: 0.87-2.03, P = 0.18). When NSCLC patients were further stratified by treatment methods, DM had more influence on the surgically treated subgroup than the nonsurgically treated subgroup. There was no obvious evidence for publication bias by Begg's and Egger's test.The results of this meta-analysis exhibit an association of DM with inferior prognosis amongst lung cancer patients, especially the surgically treated NSCLC patients. Given the small number of studies included in this meta-analysis, the present conclusion should be consolidated with more high-quality prospective cohort studies or randomized controlled trials. PMID- 27124063 TI - Primary Uterine Peripheral T-cell Lymphoma: A Case Report of MRI and 18F-FDG PET/CT Findings. AB - Primary uterine non-Hodgkin's lymphoma is extremely rare accounting for <1% of all extranodal non-Hodgkin's lymphomas. Imaging findings of primary uterine lymphoma have rarely been reported before. We present magnetic resonance imaging (MRI) and fluorine-18-fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/CT findings in a patient with primary uterine peripheral T-cell lymphoma.A 27-year-old female presented with intermittent fever with neutropenia for 7 months. MRI showed an ill-defined mass involved both the uterine corpus and cervix, resulting in diffuse enlargement of the uterus. This mass showed inhomogeneous hypointensity on unenhanced T1-weighted images, hyperintensity on diffusion-weighted imaging, relative hypointensity compared to the surrounding myometrium on T2-weighted images and lower enhancement than the surrounding myometrium on enhanced T1-weighted images. FDG PET/CT showed intense FDG uptake in the thickened wall of the uterine corpus and cervix with SUVmax of 26.9. There were multiple hypermetabolic lymph nodes in the pelvis and retroperitoneum. Uterine curettage and CT-guided biopsy of the uterine mass revealed peripheral T cell lymphoma. Bone marrow biopsy revealed no evidence of lymphomatous involvement. The imaging and pathologic findings were consistent with primary uterine lymphoma. After 3 circles of chemotherapy, follow-up enhanced MRI showed decreased thickness of the uterine wall.Despite its rarity, primary uterine non Hodgkin's lymphoma should be taken into consideration when a uterine tumor shows large size, relative hypointesity on both T2-weighted images and enhanced T1 weighted images compared to the surrounding myometrium, and intense FDG uptake on PET/CT. MRI may be helpful for describing the relationship between the tumor and adjacent structures. FDG PET/CT may be useful for tumor detection and staging. PMID- 27124065 TI - A Lower Gastrointestinal Bleeding Due to a Post-Traumatic Splenosis: "Wait and See" Represents a Feasible Attitude: A Case Report. AB - Splenosis represents a benign condition due to an ectopic localization of splenic tissue caused by pathologic or traumatic spleen rupture. Generally, it is asymptomatic and incidentally diagnosed during imaging performed for other reasons. Occult gastrointestinal bleeding due to an extraperitoneal localization is a rare occurrence. Differential diagnosis may be very hard and includes benign and malignant neoplasms.We describe the case of a 68-year-old Caucasian man that was admitted for an increasing lower gastrointestinal bleeding associated to a vague abdominal pain.He was assessed by means of laboratory tests, as well as by endoscopic and radiological examinations, and successfully treated with an exclusive medical approach.The patient was discharged on the ninth day and currently he is doing well.This case shows that wait and see could prove a feasible attitude for the management of clinically stable patients. PMID- 27124064 TI - Associations Between Sleep Quality and Migraine Frequency: A Cross-Sectional Case Control Study. AB - Migraine has been associated with sleep disturbances. Relationship between sleep quality and migraine frequency is yet to be determined. The present study aimed to investigate sleep disturbances among low-frequency, moderate-frequency, high frequency, and chronic migraineurs, with and without auras, with well-controlled confounding variables.This cross-sectional controlled study included 357 subjects from an outpatient headache clinic in Taiwan. Standardized questionnaires were utilized to collect demographic, migraine, sleep, depression, anxiety, and restless leg syndrome characteristics in all participants. According to frequency of migraine attacks, patients were divided into 4 groups: with 1 to 4 migraine days per month, 5 to 8 migraine days in a month, 9 to 14 migraine days in a month, and >14 migraine days per month. The Pittsburgh Sleep Quality Index (PSQI) and subgroup items were used to evaluate sleep quality. The association between migraine frequency and sleep quality was investigated using multivariable linear regression and logistic regression.The PSQI total score was highest in patients with high frequent migraine (10.0 +/- 3.4) and lowest in controls (7.0 +/- 3.4) with a significant trend analysis (P for trend = 0.006). Migraine frequency had an independent effect on the items "Cannot get to sleep within 30 minutes" (P < 0.001), "Wake up in the middle of the night or early morning" (P < 0.001), "Bad dreams" (P = 0.001), "Pain" (P = 0.004), and "Quality of sleep" (P < 0.001). The result showed the effect of migraine frequency in both the aura-present (P for trend = 0.008) and the aura-absent subgroups (P for trend = 0.011).High migraine frequency correlates with poor sleep quality and a higher prevalence of poor sleepers. These associations occur in migraine with aura and without aura. PMID- 27124066 TI - Abnormal Magnetic Resonance Imaging Findings in Patients With Sudden Sensorineural Hearing Loss: Vestibular Schwannoma as the Most Common Cause of MRI Abnormality. AB - The etiology of sudden sensorineural hearing loss (SSNHL) remains unclear in most cases. This study aimed to assess abnormal magnetic resonance imaging (MRI) findings in patients with SSNHL and evaluate the value of MRI in identifying the cause of SSNHL.A retrospective analysis of the charts and MRI findings of 291 patients with SSNHL was performed.In 291 patients, MRI abnormality, which was considered a cause of SSNHL, was detected in 13 patients. Vestibular schwannoma involving the internal auditory canal (IAC) and/or cerebellopontine angle was observed in 9 patients. All 9 patients had intrameatal tumors, and 6 of the 9 patients displayed extrameatal extension of their tumors. The tumor was small (<1 cm) or medium-sized (1.1-2.9 cm) in these 6 patients. Intralabyrinthine schwannoma, labyrinthine hemorrhage, IAC metastasis, and a ruptured dermoid cyst were each observed in 1 patient.The most commonly observed MRI abnormality in patients with SSNHL was vestibular schwannoma, and all of the lesions were small or medium-sized tumors involving the IAC. PMID- 27124067 TI - Metabolomic Research on Newborn Infants With Intrauterine Growth Restriction. AB - To compare differences in metabolites between newborns with intrauterine growth restriction (IUGR) and those who are appropriate for gestational age (AGA) in order to understand the changes in metabolites of newborns with IUGR and to explore the possible metabolic mechanism of tissue and organ damages in patients with IUGR, with the ultimate goal of providing the basis for clinical intervention.A total of 60 newborns with IUGR and 60 AGA newborns who were hospitalized in the neonatal intensive care unit of our hospital between January 2011 and December 2015 and who underwent metabolic disease screening were enrolled in this study. The differences in 21 amino acids and 55 carnitines in peripheral blood, as well as changes in the ratios of free carnitine and acylcarnitine to total carnitine, were compared.Metabolites, particularly alanine, homocysteine, leucine, methionine, ornithine, serine, tyrosine, isovaleryl carnitine, and eicosenoyl carnitine, differed according to newborns' birth weight (<3rd percentile, 3rd-5th percentiles, 5th-10th percentiles, and 10th-90th percentiles), with those with lower birth weight showing the greater difference (P < 0.05). Metabolites also differed by gestational age, and the differences observed were mainly as follows: preterm and full-term newborns showed differences in metabolites, mainly in alanine, proline, cerotoyl carnitine, and tetradecanedioyl carnitine (P < 0.05); preterm and full-term AGA newborns showed differences in metabolites, mainly in alanine, glutamine, homocysteine, pipecolic acid, proline, heptanoyl carnitine, and sebacoyl carnitine (P < 0.05); and preterm and full-term newborns with IUGR showed differences in metabolites, mainly in arginine, glutamic acid, homocysteine, histidine, leucine, isoleucine, ornithine, serine, threonine, tryptophan, valine, heptanoyl carnitine, decanoyl carnitine, linoleyl carnitine, methylmalonyl carnitine, glutarylcarnitine, sebacoyl carnitine, hydroxyacetyl carnitine, and hydroxyhexadecancenyl carnitine (P < 0.05). Among newborns with IUGR, metabolites differed among males and females, mainly in aspartic acid, glutamic acid, and hexacosenoic acid (P < 0.05). Birth weight had no significant effects on free carnitine concentration or on the ratios of free carnitine and acylcarnitine to total carnitine (P < 0.05).IUGR infants exhibit significant abnormalities in amino acid and acylcarnitine metabolism, especially those with birth weight below the third percentile. With increasing birth weight, amino acids and acylcarnitines showed compensatory increases or reductions, and when birth weight reached the 10th percentile, the newborns with IUGR resembled the AGA newborns. PMID- 27124070 TI - Health Professions Education: Make Big Data Meaningful. PMID- 27124068 TI - Relationship Between Hepatic Steatosis and the Elevation of Aminotransferases in HBV-Infected Patients With HBe-Antigen Negativity and a Low Viral Load. AB - Nonalcoholic fatty liver disease has been suggested to be associated with alanine aminotransferase (ALT) elevation in hepatitis B virus (HBV)-infected patients with HBe antigen (HBeAg)-negativity and a low HBV-DNA level. However, few studies have evaluated the association according to histological findings of the liver.Among a total of 198 HBV-infected patients who received a percutaneous liver biopsy, we studied the histological and laboratory findings of HBeAg negative patients without receiving nucleoside/nucleotide analogues treatment (N = 70) in order to evaluate whether hepatic steatosis and its related metabolic disorders were associated with an elevation in ALT levels in HBeAg-negative patients.In HBeAg-negative patients with a high serum HBV-DNA level (>=2000 IU/mL), the level of HBV-DNA was the only significant factor related to ALT elevation. However, in HBeAg-negative patients with a low HBV-DNA level, the serum ferritin level, and histologically observed hepatic steatosis were significantly associated factors with ALT elevation. When we evaluated 2 metabolic variables (serum ferritin and fasting insulin) that are suggested to be relevant to the presence of progressive disease in Japanese patients, we found that the rate of metabolic disorders was significantly higher among patients with a high ALT level and a low HBV-DNA level than it was among those with other conditions. The triglyceride level and the frequency of moderate or severe hepatic steatosis were significantly higher in patients with a low HBV-DNA level than in those with a high HBV-DNA level.Histologically proven hepatic steatosis and its related metabolic disorders are suggested to be involved in the elevation of aminotransferases of HBeAg-negative patients, particularly those with low HBV DNA levels. PMID- 27124069 TI - The Usefulness of Serum CXCR3 Ligands for Evaluating the Early Treatment Response in Tuberculosis: A Longitudinal Cohort Study. AB - Cell-mediated immunity plays an important role in the pathobiology of tuberculosis (TB). The ligands for CXC chemokine receptor 3 (CXCR3) activate the T-helper type 1 lymphocyte pathway. The CXCR3 ligands are reportedly useful clinical markers for the diagnosis and follow-up of TB. The objective of this study was to assess the utility of CXCR3 ligands for evaluating early treatment responses in TB.We recruited 88 patients who underwent antituberculous chemotherapy. The serum levels of interferon (IFN)-gamma and the CXCR3 ligands CXCL9 (monokine induced by IFN-gamma [MIG]), CXCL10 (IFN-gamma-inducible 10-kDa protein [IP-10]), and CXCL11 (IFN-inducible T-cell alpha chemoattractant [I-TAC]) were measured before and 2 months after the start of treatment. Treatment responses were divided into "fast" and "slow" based on the clinical, radiological, and bacteriological improvement at 2 months. A change in level of 20% or more at 2 months was defined as "significant."In patients with treatment success, 58 patients exhibited a fast response and 20 patients exhibited a slow response. Treatment failure occurred in 5 patients, and the diagnoses were changed to non-TB diseases in 5 patients. The levels of all CXCR3 ligands significantly decreased in the fast-response group (P < 0.01) but did not decrease in the other groups. IFN-gamma levels showed no significant changes. The ability of significant decreases in marker levels to predict a fast response was evaluated. CXCL9 showed a sensitivity of 83%, and CXCL10 showed a specificity of 100%. Use of various combinations of CXCR3 ligands resulted in improvements in sensitivity (88%-93%), while specificity (92%-96%) was similar to that using single CXCR3 ligands. The decreases in CXCR3 ligand levels were less marked in the 2-month Mycobacterium tuberculosis culture-positive group than in the culture negative group. There were significant differences in treatment outcomes in terms of 2-month culture positivity (P < 0.001), the significance of CXCL9 decreases (P < 0.01), and the significance of CXCL11 decreases (P < 0.05).In conclusion, CXCR3 ligands may be useful surrogate markers for the evaluation of early treatment response and showed utility as indicators of possible treatment failure in TB. PMID- 27124071 TI - Personality and Mentoring: Stepping Off on the Right Foot. AB - This column offers some innovative recommendations on the use of personality testing as a stepping-off point for mentorship pairing. Effective pairing increases the value and effectiveness of the mentoring relationship. J Contin Educ Nurs. 2016;47(5):201-203. PMID- 27124072 TI - Sepsis Update: A New Core Measure of Quality. AB - This column provides an update on the current literature related to sepsis as a new quality core measure. Sepsis care for adult patients in the acute care setting is outlined. J Contin Educ Nurs. 2016;47(5):204-206. PMID- 27124073 TI - Appreciative Inquiry and Implementation Science in Leadership Development. AB - Appreciative inquiry was developed to initiate and animate change. As implementation science gains a foothold in practice settings to bridge theory, evidence, and practice, appreciative inquiry takes on new meaning as a leadership intervention and training tool. J Contin Educ Nurs. 2016;47(5):207-209. PMID- 27124074 TI - Building a Culture of Health: Implications for Nurse Educators. AB - The Robert Wood Johnson Foundation (RWJF) is implementing a new program to improve health in the United States. This program, Building a Culture of Health, includes a four-point action plan, recognizes the complex social factors that contribute to a healthy society, and notes that implementing this plan will require health care organizations and professionals to think differently about the work they do and where they do it. Nurse educators are a vital force in ensuring health for all. This column discusses the RWJF program and the implications for nurse educators. J Contin Educ Nurs. 2016;47(5):210-211. PMID- 27124075 TI - Population-Focused Practice Competency Needs Among Public Health Nursing Leaders in Washington State. AB - HOW TO OBTAIN CONTACT HOURS BY READING THIS ISSUE Instructions: 1.2 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded after you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. In order to obtain contact hours you must: 1. Read the article, "Population-Focused Practice Competency Needs Among Public Health Nursing Leaders in Washington State," found on pages 212-219, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website to register for contact hour credit. You will be asked to provide your name, contact information, and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until April 30, 2019. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. OBJECTIVES Describe supports and barriers to adopting population focused care in public health nursing practice. Describe the benefit of using practice models to assess staff readiness for adopting evidence-based guidelines or practice competencies. DISCLOSURE STATEMENT Neither the planners nor the authors have any conflicts of interest to disclose. Public health nurses (PHNs) need effective strategies to reduce health disparities, requiring a workforce that can practice with a population-focus across the continuum of care and with an ecological approach to health. A statewide leadership group of county-level PHN leaders in Washington assessed their training needs in population-focused knowledge and skills. Interview findings from 17 members were coded based on the Quad Council PHN Competencies. Recommendations were organized around the Push Pull Infrastructure (PPI) practice model established to help bridge the practice research gap. The PHN leaders in Washington State want to strengthen their own leadership skills and provide support to staff in transitioning to population focused care. This article describes the assessment findings of PHN leaders' training needs using the PPI practice model and explores how the PPI might serve to develop evidence-based training for PHNs and local health department staff. J Contin Educ Nurs. 2016;47(5):212-219. PMID- 27124077 TI - Improving Online Teaching by Using Established Best Classroom Teaching Practices. AB - This pilot study explored the effectiveness of an online workshop provided to faculty teaching one course in a large online RN-to-baccalaureate nursing (BSN) program. This exploration helped to fill a gap in knowledge related to implementing best classroom teaching practices into distance education for online nursing students. Focus groups with purposeful sampling (three focus groups: two faculty focus groups with a total of 11 faculty and one student focus group with a total of six students) were used to assess the effectiveness of the workshop and faculty and student perceptions of the seven best classroom teaching practices. Themes derived from the faculty focus groups included reaffirmation, commitments from students, and opportunities for instructor improvement. Themes derived from the student focus group included engagement, availability, encouragement, and diverse learning. Online teaching recommendations, created from the emerged themes of the study, could be considered to improve teaching practices of online nurse educators. J Contin Educ Nurs. 2016;47(5):222-227. PMID- 27124078 TI - New Faculty Orientation: Discussion of Cultural Competency, Sexual Victimization, and Student Behaviors. AB - In the arena of undergraduate education in health care, orientation programs assist new faculty in transitioning from their role as clinician to educator. However, orientation typically overlooks training in the areas of cultural competency, how to assist students who are victims of sexual assault, and how to handle unprofessional student behaviors. At a large midwestern university, the new faculty orientation program in an interprofessional undergraduate department was expanded to include education in these areas by incorporating case scenarios and discussion sessions. The orientation faculty team included faculty from the areas of medicine, nursing, occupational therapy, public health, and neuropsychiatry. The goal of the enhanced orientation program was to empower new faculty members with the skills and resources they needed to be advocates for students in the areas of cultural competency, sexual victimization, and professional development. J Contin Educ Nurs. 2016;47(5):228-233. PMID- 27124079 TI - Creating a Long-Term Care New Nurse Residency Model. AB - As the impact of health care reform continues to evolve, the movement of patients from acute to post-acute settings will continue to expand. Currently, the turnover and retention of RNs nationally in long-term care is at an all-time high, with a median turnover rate of 50% for RNs. Workforce instability is a prime contributor to poor patient outcomes, increased costs, and a dissatisfied nursing workforce. Therefore, the New Jersey Action Coalition determined that the Institute of Medicine's Future of Nursing: Leading Change, Advancing Health recommendation to implement nurse residency programs across settings would be a priority for New Jersey. A 12-month new nurse residency and preceptor program was developed and implemented in long-term care, with 37 new nurses and 37 preceptors. The design and implementation processes are described, as well as lessons learned along the journey. J Contin Educ Nurs. 2016;47(5):234-240. PMID- 27124080 TI - Interprofessional Silence at the End of Life: Do Swiss General Practitioners and Hospital Physicians Sufficiently Share Information About Their Patients? AB - BACKGROUND: Empirical research suggests that the quality of patient care at the end of life (EOL) is influenced by the effectiveness of the collaboration between the general practitioners (GPs) and hospital physicians (HPs). AIM: To identify possible difficulties and barriers to effective collaboration at the EOL between GPs and HPs from the perspective of Swiss GPs. DESIGN: Twenty-three qualitative semi-structured interviews with GPs were transcribed and analyzed using Mayring's content analysis. Interdisciplinary clinical-ethical analysis focused on the quality of GP and HP professional collaboration. RESULTS: GPs described the quality of collaboration with HPs as poor, in particular the lack of communication. There were two main issues to emerge. First, infrequent communication with HPs could negatively affect the care of the patient. Second, GPs were concerned with the lack of information about hospital care and involvement in medical decision making given their longstanding relationships with their patients. CONCLUSIONS: The research showed that Swiss GPs were concerned with the quality of their patients' EOL care and the current level of GP/HP collaboration. GPs appealed for greater involvement with EOL care decisions based on their relationship of care and knowledge of patient preferences. These findings require further critical evaluation to explore the potential advantages for patient care. Existing evidence suggests that there are measurable health benefits from successful GP/HP collaborations. A change in the way GPs maintain involvement with their patients during hospitalizations would be warranted if it resulted in a better use of resources, better patient experiences, and better health outcomes. PMID- 27124082 TI - Weak O-Assistance Outcompeting Strong N,N-Bidentate Directing Groups in Copper Catalyzed C-H Chalcogenation. AB - A copper-mediated C-H chalcogenation of triazoles has been achieved by weak coordination. The user-friendly protocol showed high functional-group tolerance and ample substrate scope, yielding fully substituted 1,2,3-triazoles with complete positional site-selectivity. The C-H selenylation could likewise be achieved by means of copper catalysis. Our findings highlight for the first time that weak O-coordination can outcompete the strong N,N-bidentate coordination mode in C-H functionalization technology. PMID- 27124081 TI - The Role of Visual Eccentricity on Preference for Abstract Symmetry. AB - This study tested preference for abstract patterns, comparing random patterns to a two-fold bilateral symmetry. Stimuli were presented at random locations in the periphery. Preference for bilateral symmetry has been extensively studied in central vision, but evaluation at different locations had not been systematically investigated. Patterns were presented for 200 ms within a large circular region. On each trial participant changed fixation and were instructed to select any location. Eccentricity values were calculated a posteriori as the distance between ocular coordinates at pattern onset and coordinates for the centre of the pattern. Experiment 1 consisted of two Tasks. In Task 1, participants detected pattern regularity as fast as possible. In Task 2 they evaluated their liking for the pattern on a Likert-scale. Results from Task 1 revealed that with our parameters eccentricity did not affect symmetry detection. However, in Task 2, eccentricity predicted more negative evaluation of symmetry, but not random patterns. In Experiment 2 participants were either presented with symmetry or random patterns. Regularity was task-irrelevant in this task. Participants discriminated the proportion of black/white dots within the pattern and then evaluated their liking for the pattern. Even when only one type of regularity was presented and regularity was task-irrelevant, preference evaluation for symmetry decreased with increasing eccentricity, whereas eccentricity did not affect the evaluation of random patterns. We conclude that symmetry appreciation is higher for foveal presentation in a way not fully accounted for by sensitivity. PMID- 27124083 TI - Continuous Performance Tasks: Not Just About Sustaining Attention. AB - PURPOSE: Continuous performance tasks (CPTs) are used to measure individual differences in sustained attention. Many different stimuli have been used as response targets without consideration of their impact on task performance. Here, we compared CPT performance in typically developing adults and children to assess the role of stimulus processing on error rates and reaction times. METHOD: Participants completed a CPT that was based on response to infrequent targets, while monitoring and withholding responses to regular nontargets. Performance on 3 stimulus conditions was compared: visual letters (X and O), their auditory analogs, and auditory pure tones. RESULTS: Adults showed no difference in error propensity across the 3 conditions but had slower reaction times for auditory stimuli. Children had slower overall reaction times. They responded most quickly to the visual target and most slowly to the tone target. They also made more errors in the tone condition than in either the visual or the auditory spoken CPT conditions. CONCLUSIONS: The results suggest error propensity and reaction time variations on CPTs cannot solely be interpreted as evidence of inattention. They also reflect stimulus-specific influences that must be considered when testing hypotheses about modality-specific deficits in sustained attention in populations with different developmental disorders. PMID- 27124084 TI - Kinematic predictors of star excursion balance test performance in individuals with chronic ankle instability. AB - BACKGROUND: The Star Excursion Balance Test has identified dynamic postural control deficits in individuals with chronic ankle instability. While kinematic predictors of Star Excursion Balance Test performance have been evaluated in healthy individuals, this has not been thoroughly examined in individuals with chronic ankle instability. METHODS: Fifteen individuals with chronic ankle instability completed the anterior reach direction of the Star Excursion Balance Test and weight-bearing dorsiflexion assessments. Maximum reach distances on the Star Excursion Balance Test were measured in cm and normalized to leg length. Three-dimensional trunk, hip, knee, and ankle motion of the stance limb were recorded during each anterior reach trial using a motion capture system. Sagittal, frontal, and transverse plane displacement observed from trial initiation to the point of maximum reach was calculated for each joint or segment and averaged for analysis. Pearson product-moment correlations were performed to examine the relationships between kinematic variables, maximal reach, and weight bearing dorsiflexion. A backward multiple linear regression model was developed with maximal reach as the criterion variable and kinematic variables as predictors. FINDINGS: Frontal plane displacement of the trunk, hip, and ankle and sagittal plane knee displacement were entered into the analysis. The final model (p=0.004) included all three frontal plane variables and explained 81% of the variance in maximal reach. Maximal reach distance and several kinematic variables were significantly related to weight-bearing dorsiflexion. INTERPRETATION: Individuals with chronic ankle instability who demonstrated greater lateral trunk displacement toward the stance limb, hip adduction, and ankle eversion achieved greater maximal reach. PMID- 27124085 TI - Obesity-specific neural cost of maintaining gait performance under complex conditions in community-dwelling older adults. AB - BACKGROUND: Recent evidence of obesity-related changes in the prefrontal cortex during cognitive and seated motor activities has surfaced; however, the impact of obesity on neural activity during ambulation remains unclear. The purpose of this study was to determine obesity-specific neural cost of simple and complex ambulation in older adults. METHODS: Twenty non-obese and obese individuals, 65years and older, performed three tasks varying in the types of complexity of ambulation (simple walking, walking+cognitive dual-task, and precision walking). Maximum oxygenated hemoglobin, a measure of neural activity, was measured bilaterally using a portable functional near infrared spectroscopy system, and gait speed and performance on the complex tasks were also obtained. FINDINGS: Complex ambulatory tasks were associated with ~2-3.5 times greater cerebral oxygenation levels and ~30-40% slower gait speeds when compared to the simple walking task. Additionally, obesity was associated with three times greater oxygenation levels, particularly during the precision gait task, despite obese adults demonstrating similar gait speeds and performances on the complex gait tasks as non-obese adults. INTERPRETATION: Compared to existing studies that focus solely on biomechanical outcomes, the present study is one of the first to examine obesity-related differences in neural activity during ambulation in older adults. In order to maintain gait performance, obesity was associated with higher neural costs, and this was augmented during ambulatory tasks requiring greater precision control. These preliminary findings have clinical implications in identifying individuals who are at greater risk of mobility limitations, particularly when performing complex ambulatory tasks. PMID- 27124086 TI - Effective Inhibition of Cellular ROS Production by MXCXXC-Type Peptides: Potential Therapeutic Applications in Copper-Homeostasis Disorders. AB - Cyclic and acyclic peptides with sequences derived from metallochaperone binding sites, but differing at position 2, were analyzed for their inhibitory reactivity towards cellular ROS (reactive oxygen species) formation and catalytic activity towards oxidation with H2 O2 , in comparison with three commercial drugs clinically employed in chelation therapy for Wilson's disease. Acyclic peptides were more effective inhibitors than the cyclic ones, with one leading peptide with threonine at position 2 systematically showing the highest efficiency in reducing cellular ROS levels and in inhibiting Cu oxidation. This peptide was more effective than all commercial drugs in all aspects analyzed, and showed no toxicity towards human colon HT-29 cancer cells at concentrations 10-100 times higher than the IC50 of the commercial drugs, corroborating its high medicinal potential. PMID- 27124087 TI - Short-term comparison of tibial tuberosity advancement and tibial plateau levelling osteotomy in dogs with cranial cruciate ligament disease using kinetic analysis. AB - OBJECTIVES: This study set out to compare the outcomes of tibial tuberosity advancement (TTA) and tibial plateau levelling osteotomy (TPLO) procedures in the treatment of dogs affected with unilateral cranial cruciate ligament disease (CCLD) based on subjective parameters and objective pressure platform analysis (baropodometry). METHODS: Twenty-seven adult dogs weighing over 20 kg that were presented with unilateral CCLD and were treated by the TTA (12 dogs) or TPLO (15 dogs) surgical procedure. Patient allocation to either group was based on tibial plateau angle (TPA), according to clinical guidelines (indication for TTA for dogs was a TPA up to 25 degrees , and indication for TPLO was any TPA). Pressure platform analysis was performed prior to surgery and at four different postoperative time points (14, 30, 60 and 90 days). RESULTS: Limb function significantly improved following TTA and TPLO, with no significant differences between groups. CONCLUSION: The TTA and TPLO surgical procedures were considered to be equally effective in promoting weight bearing capacity recovery in dogs affected with unilateral CCLD under the conditions of this trial. PMID- 27124088 TI - Mono- to Octachlorinated Polychlorinated Dibenzo-p-dioxin and Dibenzofuran Emissions from Sintering Plants Synergistically Controlled by the Desulfurization Process. AB - The influence of desulfurization systems in sintering plants on polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) concentrations, profiles, and emission factors was studied. Mono- to tri-CDD/Fs and tetra- to octa-CDD/F concentrations were 4.4 +/- 2.3 and 10.5 +/- 8.3 ng m(-3), respectively, at the inlets and 0.87 +/- 0.48 and 0.47 +/- 0.22 ng m(-3), respectively, after desulfurization. The toxic equivalents (TEQs) were 0.95 +/- 0.093 and 0.51 +/- 0.040 ng of I-TEQ m(-3) at the inlets and after desulfurization, respectively. The congener profiles and homologue distributions were dominated by 2-MoCDF and MoCDF, respectively. The PCDD/F removal efficiencies achieved by desulfurization increased as the chlorination level increased. The PCDD/Fs became adsorbed to gypsum. Annual mono- to tri-CDD/Fs PCDD/F and TEQ (tetra- to octa-CDD/F) emission factors for flue gas and gypsum between 2003 and 2012 were determined. The total amounts of mono- to tri-CDD/Fs emitted in flue gas and gypsum between 2003 and 2012 were 10.7 and 10.2 kg, respectively. The total TEQs emitted in flue gas and gypsum between 2003 and 2012 were estimated to be 15486 and 1878 g of I-TEQ, respectively. PCDD/Fs adsorbed to gypsum are not effectively eliminated. The PCDD/F concentrations increased as the fly ash surface area increased moving through the electrostatic precipitator stages. PMID- 27124089 TI - Formation of Reversible Clusters with Controlled Degree of Aggregation. AB - We develop a reversible colloidal system of silica nanoparticles whose state of aggregation is controlled reproducibly from a state of fully dispersed nanoparticles to that of a colloidal gel and back. The surface of silica nanoparticles is coated with various amino silanes to identify a silane capable of forming a monolayer on the surface of the particles without causing irreversible aggregation. Of the three silanes used in this study, N-[3 (trimethoxysilyl)propyl]ethylenediamine was found to be capable of producing monolayers up to full surface coverage without inducing irreversible aggregation of the nanoparticles. At near full surface coverage the electrokinetic behavior of the functionalized silica is completely determined by that of the aminosilane. At acidic pH the ionization of the amino groups provides electrosteric stabilization and the system is fully dispersed. At basic pH, the dispersion state is dominated by the hydrophobic interaction between the uncharged aminosilane chains in the aqueous environment and the system forms a colloidal gel. At intermediate pH values the dispersion state is dominated by the balance between electrostatic and hydrophobic interactions, and the system exists in clusters whose size is determined solely by the pH. The transformation between states of aggregation is reversible and a reproducible function of pH. The rate of gelation can be controlled to be as fast as minutes while deaggregation is much slower and takes several hours to complete. PMID- 27124090 TI - Phospholipases as GTPase activity accelerating proteins (GAPs) in plants. AB - GTPase activity accelerating proteins (GAPs) are key regulators of the G-protein signaling cycle. By facilitating effective hydrolysis of the GTP bound on Galpha proteins, GAPs control the timing and amplitude of the signaling cycle and ascertain the availability of the inactive heterotrimer for the next round of activation. Until very recently, the studies of GAPs in plants were focused exclusively on the regulator of G-protein signaling (RGS) protein. We now show that phospholipase Dalpha1 (PLDalpha1) is also a bona fide GAP in plants and together with the RGS protein controls the level of active Galpha protein. PMID- 27124091 TI - Quantifying Aflatoxin B1 in peanut oil using fabricating fluorescence probes based on upconversion nanoparticles. AB - Rare earth doped upconversion nanoparticles convert near-infrared excitation light into visible emission light. Compared to organic fluorophores and semiconducting nanoparticles, upconversion nanoparticles (UCNPs) offer high photochemical stability, sharp emission bandwidths, and large anti-Stokes shifts. Along with the significant light penetration depth and the absence of autofluorescence in biological samples under infrared excitation, these UCNPs have attracted more and more attention on toxin detection and biological labelling. Herein, the fluorescence probe based on UCNPs was developed for quantifying Aflatoxin B1 (AFB1) in peanut oil. Based on a specific immunity format, the detection limit for AFB1 under optimal conditions was obtained as low as 0.2ng.ml(-1), and in the effective detection range 0.2 to 100ng.ml(-1), good relationship between fluorescence intensity and AFB1 concentration was achieved under the linear ratios up to 0.90. Moreover, to check the feasibility of these probes on AFB1 measurements in peanut oil, recovery tests have been carried out. A good accuracy rating (93.8%) was obtained in this study. Results showed that the nanoparticles can be successfully applied for sensing AFB1 in peanut oil. PMID- 27124092 TI - Hypercalcemia in a Young Man. PMID- 27124094 TI - Investigation of maternal and cord blood erythropoietin and copeptin levels in low-risk term deliveries complicated by meconium-stained amniotic fluid. AB - OBJECTIVE: To compare maternal, cord blood erythropoietin (EPO), and copeptin levels in low-risk term deliveries which are complicated by meconium-stained amniotic fluid (MSAF) to those with clear amniotic fluid. Also, to evaluate the relations between these markers and cord blood pH values. METHODS: Low-risk term pregnant women with MSAF at an active phase of labor were defined as the study group (n = 39). Pregnant women with clear amniotic fluid were selected for the control group (n = 41). The two groups were matched for age, body mass index and gestational age. Maternal, cord blood EPO and copeptin levels with cord blood pH values were also measured. RESULTS: Maternal, cord blood EPO, and copeptin levels of study and control groups were 42.6 +/- 9.0 versus 40.7 +/- 9.2, 134.2 (20.5 834.6) versus 38.4 (10.3-114.2), 4.9 (0.1-31.1) versus 4.0 (3.1-28.4), and 4.7 (2.6-25.5) versus 3.6 (2.0-23.2), respectively. The differences were statistically significant for cord blood EPO, maternal and cord blood copeptin levels (p < 0.001, p = 0.004, p < 0.001, respectively). The study group had a statistically and significantly lower cord blood pH values (7.25 +/- 0.05 versus 7.34 +/- 0.04, p < 0.001). Moreover, cord blood EPO and maternal and cord blood copeptin levels were inversely correlated with cord blood pH values in the study group (p < 0.001, p = 0.005, and p = 0.009, respectively). CONCLUSION: We suggest that higher cord blood EPO and maternal and cord blood copeptin levels may be an indicator of fetal acidosis in low-risk term deliveries complicated by MSAF. PMID- 27124095 TI - Elucidation of the Key Role of [Ru(bpy)3 ](2+) in Photocatalyzed RAFT Polymerization. AB - Photocatalysis reactions using [Ru(II) (bpy)3 ](2+) were studied on the example of visible-light-sensitized reversible addition-fragmentation chain transfer (RAFT) polymerization. Although both photoinduced electron- and energy-transfer mechanisms are able to describe this interaction, no definitive experimental proof has been presented so far. This paper investigates the actual mechanism governing this reaction. A set of RAFT agents was selected, their redox potentials measured by cyclic voltammetry, and relaxed triplet energies calculated by quantum mechanics. Gibbs free-energy values were calculated for both electron- and energy-transfer mechanisms. Quenching rate constants were determined by laser flash photolysis. The results undoubtedly evidence the involvement of a photoinduced energy-transfer reaction. Controlled photopolymerization experiments are discussed in the light of the primary photochemical process and photodissociation ability of RAFT agent triplet states. PMID- 27124093 TI - Narrative review of genes, environment, and cigarettes. AB - Tobacco use remains the leading cause of preventable death in the US, emphasizing the need to understand which genes and environments are involved in the establishment of cigarette use behaviors. However, to date, no comprehensive review of the influence of genes, the environment, and their interaction on cigarette use exists. This narrative review provides a description of gene variants and environmental factors associated with cigarette use, as well as an overview of studies investigating gene-environment interaction (GxE) in cigarette use. GxE studies of cigarette use have been useful in demonstrating that the influence of genes changes as a function of both the phenotype being measured and the environment. However, it is difficult to determine how the effect of genes contributing to different phenotypes of cigarette use changes as a function of the environment. This suggests the need for more studies of GxE, to parse out the effects of genes and the environment across the development of cigarette use phenotypes, which may help to inform potential prevention and intervention efforts aimed at reducing the prevalence of cigarette use. Key Messages No comprehensive reviews of the influence of genes, the environment, and their interaction on cigarette use exist currently. The influence of genes may change as a function of the environment and the phenotype being measured. It is difficult to determine how the effect of genes contributing to different phenotypes of cigarette use changes according to environmental context, suggesting the need for more studies of gene-environment interaction related to cigarette use to parse out effects. PMID- 27124096 TI - Testosterone Replacement Therapy: The Emperor's New Clothes. AB - The mean age of the world population has steadily increased in the last decades, as a result of increased life expectancy and reduced birth rate. Global aging has led to a greater worldwide cost for healthcare: hormonal alterations contribute to the pathogenesis of several conditions and might cause a significant reduction in the perceived sense of well-being. Menopause is archetypal of hormonal alterations occurring during aging: in males, sex hormones do not decrease abruptly, yet testosterone levels decrease steadily and continuously during aging, ultimately resulting in late-onset hypogonadism. Treatment of this condition might mitigate most symptoms; however, testosterone replacement therapy (TRT) should be prescribed only in selected patients and it should not be considered as an antiaging treatment. In recent years, different authors have questioned health risks associated with testosterone treatment; while position statements from many scientific societies seem to be reassuring, the Food and Drug Administration has issued a warning in regard to the possible side effects of this therapy. We aim to review recent controversies and discoveries in regard to TRT. PMID- 27124097 TI - Reductive Cleavage of CO2 by Metal-Ligand-Cooperation Mediated by an Iridium Pincer Complex. AB - A unique mode of stoichiometric CO2 activation and reductive splitting based on metal-ligand-cooperation is described. The novel Ir hydride complexes [((t)Bu PNP*)Ir(H)2] (2) ((t)Bu-PNP*, deprotonated (t)Bu-PNP ligand) and [((t)Bu PNP)Ir(H)] (3) react with CO2 to give the dearomatized complex [((t)Bu PNP*)Ir(CO)] (4) and water. Mechanistic studies have identified an adduct in which CO2 is bound to the ligand and metal, [((t)Bu-PNP-COO)Ir(H)2] (5), and a di CO2 iridacycle [((t)Bu-PNP)Ir(H)(C2O4-kappaC,O)] (6). DFT calculations confirm the formation of 5 and 6 as reversibly formed side products, and suggest an eta(1)-CO2 intermediate leading to the thermodynamic product 4. The calculations support a metal-ligand-cooperation pathway in which an internal deprotonation of the benzylic position by the eta(1)-CO2 ligand leads to a carboxylate intermediate, which further reacts with the hydride ligand to give complex 4 and water. PMID- 27124098 TI - Dissociation Pathways of the CH2CH2ONO Radical: NO2 + Ethene, NO + Oxirane, and a Non-Intrinsic Reaction Coordinate HNO + Vinoxy Pathway. AB - We first characterize the dissociation pathways of BrCH2CH2ONO, a substituted alkyl nitrite, upon photoexcitation at 193 nm under collision-free conditions, in a crossed laser-molecular beam scattering apparatus using vacuum ultraviolet photoionization detection. Three primary photodissociation pathways occur: photoelimination of HNO, leading to the products HNO + BrCH2CHO; C-Br bond photofission, leading to Br + CH2CH2ONO; and O-NO bond photofission, leading to NO + BrCH2CH2O. The data show that alkyl nitrites can eliminate HNO via a unimolecular mechanism in addition to the commonly accepted bulk disproportionation mechanism. Some of the products from the primary photodissociation pathways are highly vibrationally excited, so we then probe the product branching from the unimolecular dissociation of these unstable intermediates. Notably, the vibrationally excited CH2CH2ONO radicals undergo two channels predicted by statistical transition-state theory, and an additional non intrinsic reaction coordinate channel, HNO elimination. CH2CH2ONO is formed with high rotational energy; by employing rotational models based on conservation of angular momentum, we predict, and verify experimentally, the kinetic energies of stable CH2CH2ONO radicals and the angular distribution of dissociation products. The major dissociation pathway of CH2CH2ONO is NO2 + ethene, and some of the NO2 is formed with sufficient internal energy to undergo further photodissociation. Nascent BrCH2CHO and CH2Br are also photodissociated upon absorption of a second 193 nm photon; we derive the kinetic energy release of these dissociations based on our data, noting similarities to the analogous photodissociation of ClCH2CHO and CH2Cl. PMID- 27124099 TI - Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) processing speed scores as measures of noncredible responding: The third generation of embedded performance validity indicators. AB - Research suggests that select processing speed measures can also serve as embedded validity indicators (EVIs). The present study examined the diagnostic utility of Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) subtests as EVIs in a mixed clinical sample of 205 patients medically referred for neuropsychological assessment (53.3% female, mean age = 45.1). Classification accuracy was calculated against 3 composite measures of performance validity as criterion variables. A PSI <=79 produced a good combination of sensitivity (.23 .56) and specificity (.92-.98). A Coding scaled score <=5 resulted in good specificity (.94-1.00), but low and variable sensitivity (.04-.28). A Symbol Search scaled score <=6 achieved a good balance between sensitivity (.38-.64) and specificity (.88-.93). A Coding-Symbol Search scaled score difference >=5 produced adequate specificity (.89-.91) but consistently low sensitivity (.08 .12). A 2-tailed cutoff on the Coding/Symbol Search raw score ratio (<=1.41 or >=3.57) produced acceptable specificity (.87-.93), but low sensitivity (.15-.24). Failing >=2 of these EVIs produced variable specificity (.81-.93) and sensitivity (.31-.59). Failing >=3 of these EVIs stabilized specificity (.89-.94) at a small cost to sensitivity (.23-.53). Results suggest that processing speed based EVIs have the potential to provide a cost-effective and expedient method for evaluating the validity of cognitive data. Given their generally low and variable sensitivity, however, they should not be used in isolation to determine the credibility of a given response set. They also produced unacceptably high rates of false positive errors in patients with moderate-to-severe head injury. Combining evidence from multiple EVIs has the potential to improve overall classification accuracy. (PsycINFO Database Record PMID- 27124100 TI - Factorial structure and long-term stability of the Autonomy Preference Index. AB - The autonomy preference index scale (API) has been designed to measure patient preference for 2 dimensions of autonomy: Their desire to take part in making medical decisions (decision making, [DM]) and their desire to be informed about their illness and the treatment (information seeking; [IS]). The DM dimension is measured by 6 general items together with 9 items related to 3 clinical vignettes (3 * 3 items). The IS dimension is measured by 8 items. While the API is widely used, a review of literature has identified several inconsistencies in the way it is scored. The first aim of this study was to determine the best scoring structure of the API on the basis of validity and reliability evidence. The second aim was to investigate the long-term stability of API scores. Two-hundred and 85 patients with a diagnosis of psychosis were assessed as they were about to be discharged from involuntary psychiatric hospitalization and they were reassessed after 6 and 12 months. Confirmatory factor analysis (CFA) revealed that a 3-factor solution was most adequate and that 2 distinct DM subscales should be preferred to 1 total DM score. While internal consistency estimates of the 3 subscales were good, the long-term stability of API scores was only modest. Multigroup-CFA revealed scalar invariance indicating API scores kept the same meaning longitudinally. In conclusion, a 3-factor structure seemed to be most adequate for the API scale. Long-term stability estimates suggested that clinicians should regularly assess patients' preferences for autonomy because API scores fluctuate over time. (PsycINFO Database Record PMID- 27124101 TI - Development of a structured undergraduate research experience: Framework and implications. AB - Participating in undergraduate research can be a pivotal experience for students in life science disciplines. Development of critical thinking skills, in addition to conveying scientific ideas in oral and written formats, is essential to ensuring that students develop a greater understanding of basic scientific knowledge and the research process. Modernizing the current life sciences research environment to accommodate the growing demand by students for experiential learning is needed. By developing and implementing a structured, theory-based approach to undergraduate research in the life sciences, specifically biochemistry, it has been successfully shown that more students can be provided with a high-quality, high-impact research experience. The structure of this approach allowed students to develop novel, independent projects in a computational molecular modeling lab. Students engaged in an experience in which career goals, problem-solving skills, time management skills, and independence in a research lab were developed. After experiencing this approach to undergraduate research, students reported feeling challenged to think critically and prepared for future career paths. The approach allowed for a progressive learning environment where more undergraduate students could participate in publishable research. Future areas for development include implementation in a bench-top lab and extension to disciplines beyond biochemistry. In this study, it has been shown that utilizing the structured approach to undergraduate research could allow for more students to experience undergraduate research and develop into more confident, independent life scientists well prepared for graduate schools and professional research environments. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44(5):463-474, 2016. PMID- 27124103 TI - Determination of energy absorption and exposure buildup factors by using G-P fitting approximation for radioprotective agents. AB - PURPOSE: Recently, there has been an increase in interest into research into radioprotective agents. Radioprotectors are compounds that protect against radiation injury when given orally (through drinking water) prior to radiation exposure. The purpose is to achieve preferred protection of normal tissues against injury inflicted by ionizing radiation used to treat tumors. The main aim of this work is to investigate energy absorption (EABF) and exposure buildup factors (EBF) of commonly used some radioprotective agents. MATERIALS AND METHODS: We have used the Geometric Progression (G-P) fitting method for calculating the equivalent atomic number (Zeq), for EABF and EBF buildup factors of the radioprotective agents in the energy range 0.015-15 MeV for penetration depths up to 40 mean free path. RESULTS: Significant variations in both EABF and EBF values were observed for several agents at the moderate energy region. At energies below 0.1 MeV, EABF and EBF values increased with decreasing equivalent atomic number Zeq of the samples. At energies >0.15 MeV, EABF and EBF values were found to decrease with decreasing Zeq of all agents. In addition, EABF and EBF were the largest for carnosin, tempol, melatonin, interferon gamma and orientine at 0.05 and 0.06 MeV, respectively, and the minimum values of buildup factors were at 0.1 MeV for cysteine, amifostine, penicillamine and glutathione. CONCLUSIONS: Cysteine and amifostine are good compounds for gamma rays absorption applications among the selected compounds. The presented results in this study are expected to be helpful in radiation dosimetry. PMID- 27124104 TI - The effect of Nordic Walking on joint status, quality of life, physical ability, exercise capacity and pain in adult persons with haemophilia. AB - Nordic Walking is an exercise form requiring significant energy consumption, but where the use of poles minimizes the risk of injury. The aim of this pilot study was to examine the effect of 3 months of Nordic Walking on males (>40 years of age) with haemophilia, regarding joint function (Haemophilia Joint Health Score), physical ability (Haemophilia Exercise Project - Test-Questionnaire), exercise capacity (6-min walking test), pain (visual analogue scale) and quality of life (the Swedish version of The Short Form Health Survey, SF-36). Pre-interventional and post-interventional scores of above-mentioned parameters were analysed, using Wilcoxon Signed Ranks Test. Eleven participants were recruited to the study. Statistically significant improvements were observed in physical ability (P value: 0.01) and body perception (P value: 0.02). The intervention did not increase number of bleedings or factor consumption. This is the first study ever evaluating Nordic Walking in persons with haemophilia. Our results suggest that Nordic Walking is safe and efficient, also in patients with haemophilic arthropathy. PMID- 27124102 TI - Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. AB - Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment. PMID- 27124105 TI - Concerns about idarucizumab for dabigatran reversal. PMID- 27124106 TI - Protective effects of combined beta-caryophyllene and silymarin against ketoprofen-induced hepatotoxicity in rats. AB - Ketoprofen (Ket), widely utilized in treatment of many inflammatory disorders, is found to induce liver toxicity especially with overdose. This study aimed to evaluate the possible protective effects of concomitant beta-caryophyllene (Cary) and silymarin (Sily) against Ket-induced hepatotoxicity in rats. Forty adult male albino rats were divided into 5 groups (each n = 8): the control group received distilled water for 6 weeks; the Ket-treated group received distilled water for 5 weeks and Ket in a dose of 8 mg.kg(-1).day(-1) p.o. for the 6th week; the Cary + Ket treated group received Cary in a dose of 200 mg.kg(-1).day(-1) orally for 6 weeks and Ket for the 6th week; the Sily + Ket treated group received Sily in the dose of 150 mg.kg(-1).day(-1) for 6 weeks and Ket for the 6th week; and the Cary + Sily + Ket treated group received Sily and Cary for 6 weeks and Ket for the 6th week. At end of the experiment, serum ALT, AST, and albumin and liver total antioxidant capacity (t.TAC) and malondialdehyde (t.MDA) were measured in all rats. Ket increased serum ALT and AST and t.MDA and decreased t.TAC. Cary and Sily improved these changes. Combined Cary and Sily restored these liver changes to nearly normal. Combined Cary and Sily is hepatoprotective, with the ability to scavenge oxidants against Ket-induced hepatotoxicity in rats. PMID- 27124108 TI - Sintering-resistant Pt@CeO2 nanoparticles for high-temperature oxidation catalysis. AB - The key challenge that has limited the industrial utilization of nano-sized metal catalysts is their poor thermal stability and the resulting performance degradation. Here, we address this issue by designing a post-encapsulated composite structure in which individual Pt nanoparticles are surrounded by gas permeable and catalytically active CeO2 shells. Positively charged surfactants on the nanoparticle surfaces are exploited to adsorb negatively charged Ce precursor complexes spontaneously, followed by confined precipitation to form cerium dioxide. This strategy enables the creation of uniformly coated shell structures with tunable thicknesses between 2.9 and 26.5 nm, thereby enabling the investigation of how thickness affects the thermal stability and chemical reactivity of the composite particles. Enhanced metal-support interactions significantly prevent Pt agglomeration, leading to exceptionally high reactivity for methane combustion. With a shell thickness of 13.8 nm, we observe a T10 lower by more than 100 degrees C with an eight-fold higher reaction rate when compared with a bare mixture of Pt and CeO2 nanoparticles. Furthermore, their cores remain isolated even after heating them to 1000 degrees C, while complete methane oxidation was maintained for more than 50 hours at 700 degrees C. These results provide improved guidelines toward the design of a sintering-resistant, high performance catalyst for use at elevated temperatures. PMID- 27124107 TI - Neonicotinoids target distinct nicotinic acetylcholine receptors and neurons, leading to differential risks to bumblebees. AB - There is growing concern over the risk to bee populations from neonicotinoid insecticides and the long-term consequences of reduced numbers of insect pollinators to essential ecosystem services and food security. Our knowledge of the risk of neonicotinoids to bees is based on studies of imidacloprid and thiamethoxam and these findings are extrapolated to clothianidin based on its higher potency at nicotinic acetylcholine receptors. This study addresses the specificity and consequences of all three neonicotinoids to determine their relative risk to bumblebees at field-relevant levels (2.5 ppb). We find compound specific effects at all levels (individual cells, bees and whole colonies in semi field conditions). Imidacloprid and clothianidin display distinct, overlapping, abilities to stimulate Kenyon cells, indicating the potential to differentially influence bumblebee behavior. Bee immobility was induced only by imidacloprid, and an increased vulnerability to clothianidin toxicity only occurred following chronic exposure to clothianidin or thiamethoxam. At the whole colony level, only thiamethoxam altered the sex ratio (more males present) and only clothianidin increased queen production. Finally, both imidacloprid and thiamethoxam caused deficits in colony strength, while no detrimental effects of clothianidin were observed. Given these findings, neonicotinoid risk needs to be considered independently for each compound and target species. PMID- 27124109 TI - Chlorpromazine versus reserpine for schizophrenia. AB - BACKGROUND: In the 1940s reserpine, refined from a plant extract that had been used for centuries, began to be used as a treatment for people with mental disorders and was one of the very first antipsychotic drugs. Its irreversible pharmacological potency and adverse effects meant that it has been withdrawn in the UK and its role has been superceded by 'newer' compounds. The effects of reserpine are of historical interest although there are some reports of it still being used in highly specialist situations in psychiatry. Chlorpromazine is also an old drug but it is still used for treatment of people with schizophrenia. OBJECTIVES: To investigate the effects of two old medications (reserpine and chlorpromazine) for people with schizophrenia. Reserpine is now rarely used while chlorpromazine remains on the essential list of drugs of the World Health Organization (WHO). SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (24 March 2016). SELECTION CRITERIA: We included randomised clinical trials focusing on chlorpromazine versus reserpine for schizophrenia that presented useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. MAIN RESULTS: The review currently includes nine studies with an average 60 participants per study. All of these studies are now over 60 years old, conducted between 1955 and 1962. When chlorpromazine was compared with reserpine for people with schizophrenia, improvement in global state was better at short term for those receiving chlorpromazine (n = 781, 6 RCTs, RR 'not improved' 0.75 95% CI 0.62 to 0.92, low quality evidence). Short-term improvement in paranoid distortion was measured using the Multidimensional Scale for Rating Psychiatric Patients (MSRPP). Data showed no clear difference between treatment groups (n = 19, 1 RCT, RR 1.33 95% CI 0.62 to 2.89, very low-quality evidence). There was no difference in functioning: occupational adjustment, medium term (n = 40, 1 RCT, RR 0.83 95% CI 0.47 to 1.47, moderate-quality evidence) and general behaviour (n = 98, 1 RCT, RR 0.79 CI 0.41 to 1.53, moderate-quality evidence). Adverse events were poorly reported. For 'toxic reaction' there was, again, no obvious difference between the two compounds (n = 210, 3 RCTs, RR 1.68 95% CI 0.43 to 6.54, moderate-quality evidence), and this also applied to leaving the study early (n = 229, 4 RCTs, RR 1.16 95% CI 0.94 to 1.42, moderate-quality evidence). AUTHORS' CONCLUSIONS: Judged by standards of today, the evidence is largely of limited quality. However, some of these 1950s studies are remarkable in their foresight and clarity. Reserpine did have some effect on global state - but chlorpromazine did seem to perform better. Important issues regarding adverse effects were not really addressed by these trials. Chlorpromazine remains on the WHO list of essential drugs. Reserpine is now almost obsolete, although, probably as a result of evidence other than that reported in the pioneering trials used in this review. PMID- 27124110 TI - Assessment and treatment of pain in thalassemia. AB - Pain is a subjective symptom whose prevalence can be grossly underestimated. The high proportion of adults with thalassemia who experience chronic pain is evident from recent surveys. However, pain has not received enough attention in the overall management of thalassemia. The association of pain with the type and treatment of thalassemia or with its comorbidities is unclear. Abnormal spine imaging is seen in patients reporting pain, although the role of osteopenia has not been established. Pain becomes more frequent with age. The lower back is the most common site and can be particularly disabling and difficult to treat. Treatable causes, such as extramedullary masses or disc herniation or fractures, must be ruled out. Some adults experience increasing pain when the hemoglobin drops at the end of transfusion cycles. Interdisciplinary management of pain is necessary, while overreliance on medications can be counterproductive. The impact of chronic pain on the quality of life must be acknowledged. Physical therapy, psychological counseling, and vocational rehabilitation are vital to management. I recommend a proactive approach for prevention of pain by maintaining optimal bone density and an active lifestyle. I further propose that a universal tool be adopted to document and characterize pain at routine clinic visits. PMID- 27124112 TI - Electrophysiology of cerebral ischemia and reperfusion: First evidence for the role of synapse in ischemic tolerance. AB - OBJECTIVE: The subthreshold brain-damaging stimulus may protect the brain from subsequent ischemia; this phenomenon has been named "ischemic tolerance" (IT). We focused on the synaptic properties of the neurons after mild and severe ischemia to determine the association between IT and synaptic efficacy. EXPERIMENTAL DESIGN: Adult male rats were randomly divided into four experimental groups including control, sham, permanent ischemia (pI/R), and mild ischemia (mI/R). Middle cerebral artery occlusion (MCAO) method was applied to induce brain ischemia. Seven days after the insult, long-term potentiation (LTP) induced by high-frequency stimulation (HFS) and paired-pulse ratio (PPR) were monitored before and after the HFS delivery. RESULTS: The field potential recording demonstrated that mild ischemia significantly increased the basal synaptic transmission. Additionally, the HFS produced a significant potentiation compared to its baseline level in the mI/R group. Moreover, mild ischemia prevented depression of PPR by HFS. This effect was accompanied by a significant increase in the normalized PPR (PPR after HFS/PPR before HFS) in this group. CONCLUSIONS: Our data indicated that a mild reduction in brain perfusion without permanent lesion can dramatically increase the basal synaptic transmission. This effect may be associated with an increase in the neurotransmitter content of the pre synaptic neurons. This hypothesis could provide a new insight into the relationship between IT and synaptic efficacy. Synapse 70:351-360, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27124113 TI - Novel Use of CF3SO2Cl for the Metal-Free Electrophilic Trifluoromethylthiolation. AB - The regioselective trifluoromethylthiolation of indole derivatives was achieved under reductive conditions with trifluoromethanesulfonyl chloride as the readily available source of electrophilic SCF3 and a phosphine as the reducing agent. It is a straightforward process free from any metal and also applicable for the trifluoromethylthiolation of other azaarenes, enamines, and enoxysilanes. PMID- 27124111 TI - Hypoxia-Induced Changes in DNA Methylation Alter RASAL1 and TGFbeta1 Expression in Human Trabecular Meshwork Cells. AB - PURPOSE: Fibrosis and a hypoxic environment are associated with the trabecular meshwork (TM) region in the blinding disease glaucoma. Hypoxia has been shown to alter DNA methylation, an epigenetic mechanism involved in regulating gene expression such as the pro-fibrotic transforming growth factor (TGF) beta1 and the anti-fibrotic Ras protein activator like 1 (RASAL1). The purpose of this study was to compare DNA methylation levels, and the expression of TGFbeta1 and RASAL1 in primary human normal (NTM) with glaucomatous (GTM) cells and in NTM cells under hypoxic conditions. METHODS: Global DNA methylation was assessed by ELISA in cultured age-matched NTM and GTM cells. qPCR was conducted for TGFbeta1, collagen 1alpha1 (COL1A1), and RASAL1 expression. Western immunoblotting was used to determine protein expression. For hypoxia experiments, NTM cells were cultured in a 1%O2, 5%CO2 and 37 degrees C environment. NTM and GTM cells were treated with TGFbeta1 (10ng/ml) and the methylation inhibitor 5-azacytidine (5-aza) (0.5MUM) respectively to determine their effects on DNA Methyltransferase 1 (DNMT1) and RASAL1 expression. RESULTS: We found increased DNA methylation, increased TGFbeta1 expression and decreased RASAL1 expression in GTM cells compared to NTM cells. Similar results were obtained in NTM cells under hypoxic conditions. TGFbeta1 treatment increased DNMT1 and COL1A1, and decreased RASAL1 expression in NTM cells. 5-aza treatment decreased DNMT1, TGFbeta1 and COL1A1 expression, and increased RASAL1 expression in GTM cells. CONCLUSIONS: TGFbeta1 and RASAL1 expression, global DNA methylation, and expression of associated methylation enzymes were altered between NTM and GTM cells. We found that hypoxia in NTM cells induced similar results to the GTM cells. Furthermore, DNA methylation, TGFbeta1 and RASAL1 appear to have an interacting relationship that may play a role in driving pro-fibrotic disease progression in the glaucomatous TM. PMID- 27124115 TI - Robustifying Bayesian nonparametric mixtures for count data. AB - Our motivating application stems from surveys of natural populations and is characterized by large spatial heterogeneity in the counts, which makes parametric approaches to modeling local animal abundance too restrictive. We adopt a Bayesian nonparametric approach based on mixture models and innovate with respect to popular Dirichlet process mixture of Poisson kernels by increasing the model flexibility at the level both of the kernel and the nonparametric mixing measure. This allows to derive accurate and robust estimates of the distribution of local animal abundance and of the corresponding clusters. The application and a simulation study for different scenarios yield also some general methodological implications. Adding flexibility solely at the level of the mixing measure does not improve inferences, since its impact is severely limited by the rigidity of the Poisson kernel with considerable consequences in terms of bias. However, once a kernel more flexible than the Poisson is chosen, inferences can be robustified by choosing a prior more general than the Dirichlet process. Therefore, to improve the performance of Bayesian nonparametric mixtures for count data one has to enrich the model simultaneously at both levels, the kernel and the mixing measure. PMID- 27124114 TI - Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides. AB - Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deficiency of the survival of motor neuron (SMN) protein, which leads to synaptic defects and spinal motor neuron death. Neuromuscular junction (NMJ) abnormalities have been found to be involved in SMA pathogenesis in the SMNDelta7 SMA mouse model. However, whether similar NMJ pathological findings present in another commonly used mouse model, the Taiwanese SMA mouse, has not been fully investigated. To examine the NMJs of the Taiwanese severe SMA mouse model (Smn-/ ; SMN2tg/0), which is characterized by severe phenotype and death before postnatal day (P) 9, we investigated 25 axial and appendicular muscles from P1 to P9. We labelled the muscles with anti-neurofilament and anti-synaptophysin antibodies for nerve terminals and alpha-bungarotoxin for acetylcholine receptors (AChRs). We found that severe NMJ denervation (<50% fully innervated endplates) selectively occurred in the flexor digitorum brevis 2 and 3 (FDB-2/3) muscles from P5, and an increased percentage of fully denervated endplates correlated with SMA progression. Furthermore, synaptophysin signals were absent at the endplate compared to control littermate mice, suggesting that vesicle transport might only be affected at the end stage. Subsequently, we treated the Taiwanese severe SMA mice with morpholino (MO) antisense oligonucleotides (80 MUg/g) via subcutaneous injection at P0. We found that MO significantly reversed the NMJ denervation in FDB-2/3 muscles and extended the survival of Taiwanese severe SMA mice. We conclude that early NMJ denervation in the FDB-2/3 muscles of Taiwanese severe SMA mice can be reversed by MO treatment. The FDB-2/3 muscles of Taiwanese severe SMA mice provide a very sensitive platform for assessing the effectiveness of drug treatments in SMA preclinical studies. PMID- 27124116 TI - Self-Administered Domiciliary tDCS Treatment for Tinnitus: A Double-Blind Sham Controlled Study. AB - Transcranial direct current stimulation (tDCS) has shown potential for providing tinnitus relief, although positive effects have usually been observed only during a short time period after treatment. In recent studies the focus has turned from one-session experiments towards multi-session treatment studies investigating long-term outcomes with double-blinded and sham-controlled study designs. Traditionally, tDCS has been administered in a clinical setting by a healthcare professional but in studies involving multiple treatment sessions, often a trade off has to be made between sample size and the amount of labor needed to run the trial. Also, as the number of required visits to the clinic increases, the dropout rate is likely to rise proportionally.The aim of the current study was to find out if tDCS treatment for tinnitus could be patient-administered in a domiciliary setting and whether the results would be comparable to those from in hospital treatment studies. Forty-three patients with chronic (> 6 months) tinnitus were involved in the study, and data on 35 out of these patients were included in final analysis. Patients received 20 minutes of left temporal area anodal (LTA) or bifrontal tDCS stimulation (2 mA) or sham stimulation (0.3 mA) for ten consecutive days. An overall reduction in the main outcome measure, Tinnitus Handicap Inventory (THI), was found (mean change -5.0 points, p < 0.05), but there was no significant difference between active and sham treatment outcomes. Patients found the tDCS treatment easy to administer and they all tolerated it well. In conclusion, self-administered domiciliary tDCS treatment for tinnitus was found safe and feasible and gave outcome results similar to recent randomized controlled long-term treatment trials. The results suggest better overall treatment response-as measured by THI-with domiciliary treatment than with in-hospital treatment, but this advantage is not related to the tDCS variant. The study protocol demonstrated in the current study is not restricted to tinnitus only. PMID- 27124117 TI - Inhibition of SK4 Potassium Channels Suppresses Cell Proliferation, Migration and the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer Cells. AB - Treatments for triple-negative breast cancer (TNBC) are limited; intermediate conductance calcium-activated potassium (SK4) channels are closely involved in tumor progression, but little is known about these channels in TNBC. We aimed to investigate whether SK4 channels affect TNBC. First, by immunohistochemistry (IHC) and western blotting (WB), increased SK4 protein expression in breast tumor tissues was detected relative to that in non-tumor breast tissues, but there was no apparent expression difference between various subtypes of breast cancer (p>0.05). Next, functional SK4 channels were detected in the TNBC cell line MDA MB-231 using WB, real-time PCR, immunofluorescence and patch-clamp recording. By employing SK4 specific siRNAs and blockers, including TRAM-34 and clotrimazole, in combination with an MTT assay, a colony-formation assay, flow cytometry and a cell motility assay, we found that the suppression of SK4 channels significantly inhibited cell proliferation and migration and promoted apoptosis in MDA-MB-231 cells (p<0.05). Further investigation revealed that treatment with epidermal growth factor (EGF)/basic fibroblast growth factor (bFGF) caused MDA-MB-231 cells to undergo the epithelial-mesenchymal transition (EMT) and to show increased SK4 mRNA expression. In addition, the down-regulation of SK4 expression inhibited the EMT markers Vimentin and Snail1. Collectively, our findings suggest that SK4 channels are expressed in TNBC and are involved in the proliferation, apoptosis, migration and EMT processes of TNBC cells. PMID- 27124119 TI - Regional atmospheric CO2 inversion reveals seasonal and geographic differences in Amazon net biome exchange. AB - Understanding tropical rainforest carbon exchange and its response to heat and drought is critical for quantifying the effects of climate change on tropical ecosystems, including global climate-carbon feedbacks. Of particular importance for the global carbon budget is net biome exchange of CO2 with the atmosphere (NBE), which represents nonfire carbon fluxes into and out of biomass and soils. Subannual and sub-Basin Amazon NBE estimates have relied heavily on process-based biosphere models, despite lack of model agreement with plot-scale observations. We present a new analysis of airborne measurements that reveals monthly, regional scale (~1-8 * 10(6) km(2) ) NBE variations. We develop a regional atmospheric CO2 inversion that provides the first analysis of geographic and temporal variability in Amazon biosphere-atmosphere carbon exchange and that is minimally influenced by biosphere model-based first guesses of seasonal and annual mean fluxes. We find little evidence for a clear seasonal cycle in Amazon NBE but do find NBE sensitivity to aberrations from long-term mean climate. In particular, we observe increased NBE (more carbon emitted to the atmosphere) associated with heat and drought in 2010, and correlations between wet season NBE and precipitation (negative correlation) and temperature (positive correlation). In the eastern Amazon, pulses of increased NBE persisted through 2011, suggesting legacy effects of 2010 heat and drought. We also identify regional differences in postdrought NBE that appear related to long-term water availability. We examine satellite proxies and find evidence for higher gross primary productivity (GPP) during a pulse of increased carbon uptake in 2011, and lower GPP during a period of increased NBE in the 2010 dry season drought, but links between GPP and NBE changes are not conclusive. These results provide novel evidence of NBE sensitivity to short-term temperature and moisture extremes in the Amazon, where monthly and sub-Basin estimates have not been previously available. PMID- 27124118 TI - Structure and Ligand-Binding Mechanism of a Cysteinyl Leukotriene-Binding Protein from a Blood-Feeding Disease Vector. AB - Blood-feeding disease vectors mitigate the negative effects of hemostasis and inflammation through the binding of small-molecule agonists of these processes by salivary proteins. In this study, a lipocalin protein family member (LTBP1) from the saliva of Rhodnius prolixus, a vector of the pathogen Trypanosoma cruzi, is shown to sequester cysteinyl leukotrienes during feeding to inhibit immediate inflammatory responses. Calorimetric binding experiments showed that LTBP1 binds leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) but not biogenic amines, adenosine diphosphate, or other eicosanoid compounds. Crystal structures of ligand-free LTBP1 and its complexes with LTC4 and LTD4 reveal a conformational change during binding that brings Tyr114 into close contact with the ligand. LTC4 is cleaved in the complex, leaving free glutathione and a C20 fatty acid. Chromatographic analysis of bound ligands showed only intact LTC4, suggesting that cleavage could be radiation-mediated. PMID- 27124120 TI - Caveolin-1 Expression Ameliorates Nephrotic Damage in a Rabbit Model of Cholesterol-Induced Hypercholesterolemia. AB - Caveolin-1 (CAV-1) participates in regulating vesicular transport, signal transduction, tumor progression, and cholesterol homeostasis. In the present study, we tested the hypothesis that CAV-1 improves dyslipidemia, inhibits cyclophilin A (CypA)- mediated ROS production, prevents mitochondrial compensatory action and attenuates oxidative stress responses in cholesterol induced hypercholesterolemia. To determine the role of CAV-1 in mediating oxidative and antioxidative as well as cholesterol homeostasis, hypercholesterolemic rabbits were intravenously administered antenapedia-CAV-1 (AP-CAV-1) peptide for 2 wk. AP-CAV-1 enhanced CAV-1 expression by ?15%, inhibited CypA expression by ?50% (P < 0.05) and significantly improved dyslipidemia, thus reducing neutral lipid peroxidation. Moreover, CAV-1 attenuated hypercholesterolemia-induced changes in mitochondrial morphology and biogenesis and preserved mitochondrial respiratory function. In addition, CAV-1 protected against hypercholesterol-induced oxidative stress responses by reducing the degree of oxidative damage and enhancing the expression of antioxidant enzymes. CAV-1 treatment significantly suppressed apoptotic cell death, as evidenced by the reduction in the number of terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells. We concluded that CAV-1 plays a critical role in inhibiting CypA-mediated ROS production, improving dyslipidemia, maintaining mitochondrial function, and suppressing oxidative stress responses that are vital for cell survival in hypercholesterol-affected renal organs. PMID- 27124121 TI - Rab GTPase signaling in neurite outgrowth and axon specification. AB - Neurons are highly polarized cells that contain specialized subcellular domains involved in information transmission in the nervous system. Specifically, the somatodendritic compartment receives neuronal inputs while the axons convey information through the synapse. The establishment of asymmetric domains requires a specific delivery of components, including organelles, proteins, and membrane. The Rab family of small GTPases plays an essential role in membrane trafficking. Signaling cascades triggered by extrinsic and intrinsic factors tightly regulate Rab functions in cells, with Rab protein activation depending on GDP/GTP binding to establish a binary mode of action. This review summarizes the contributions of several Rab family members involved in trans-Golgi, early/late endosomes, and recycling endosomes during neurite development and axonal outgrowth. The regulation of some Rabs by guanine exchanging factors and GTPase activating proteins will also be addressed. Finally, discussion will be provided on how specific effector-mediated Rab activation modifies several molecules essential to neuronal differentiation. (c) 2016 Wiley Periodicals, Inc. PMID- 27124122 TI - Application of Geant4 simulation for analysis of soil carbon inelastic neutron scattering measurements. AB - Inelastic neutron scattering (INS) was applied to determine soil carbon content. Due to non-uniform soil carbon depth distribution, the correlation between INS signals with some soil carbon content parameter is not obvious; however, a proportionality between INS signals and average carbon weight percent in ~10cm layer for any carbon depth profile is demonstrated using Monte-Carlo simulation (Geant4). Comparison of INS and dry combustion measurements confirms this conclusion. Thus, INS measurements give the value of this soil carbon parameter. PMID- 27124123 TI - Aging decreases collagen IV expression in vivo in the dermo-epidermal junction and in vitro in dermal fibroblasts: possible involvement of TGF-beta1. AB - Collagen IV is a major component of the dermo-epidermal junction (DEJ). To study expression of collagen IV upon aging in the DEJ and dermal fibroblasts isolated from the same patients. A model of senescent fibroblasts was developed in order to identify biological compounds that might restore the level of collagen IV. Skin fragments of women (30 to 70 years old) were collected. Localisation of collagen IV expression in the DEJ was studied by immunofluorescence. Fibroblast collagen IV expression was studied by real-time PCR, ELISA, and western blotting. Premature senescence was simulated by exposing fibroblasts to subcytotoxic H2O2 concentrations. Collagen IV decreased in the DEJ and fibroblasts relative to age. TGF-beta1 treatment significantly increased collagen IV gene and protein expression in fibroblasts and restored expression in the model of senescence. Addition of TGF-beta1-neutralizing antibody to fibroblast cultures decreased collagen IV expression. Taken together, the results suggest that the decrease in collagen IV in the DEJ, relative to age, could be due to a decrease in collagen IV expression by senescent dermal fibroblasts and may involve TGF-beta1 signalling. PMID- 27124124 TI - QSPR prediction of the hydroxyl radical rate constant of water contaminants. AB - In advanced oxidation processes (AOPs), the aqueous hydroxyl radical (HO) acts as a strong oxidant to react with organic contaminants. The hydroxyl radical rate constant (kHO) is important for evaluating and modelling of the AOPs. In this study, quantitative structure-property relationship (QSPR) method is applied to model the hydroxyl radical rate constant for a diverse dataset of 457 water contaminants from 27 various chemical classes. The constricted binary particle swarm optimization and multiple-linear regression (BPSO-MLR) are used to obtain the best model with eight theoretical descriptors. An optimized feed forward neural network (FFNN) is developed to investigate the complex performance of the selected molecular parameters with kHO. Although the FFNN prediction results are more accurate than those obtained using BPSO-MLR, the application of the latter is much more convenient. Various internal and external validation techniques indicate that the obtained models could predict the logarithmic hydroxyl radical rate constants of a large number of water contaminants with less than 4% absolute relative error. Finally, the above-mentioned proposed models are compared to those reported earlier and the structural factors contributing to the AOP degradation efficiency are discussed. PMID- 27124125 TI - Reductive dehalogenation of disinfection byproducts by an activated carbon-based electrode system. AB - Low molecular weight, uncharged, halogenated disinfection byproducts (DBPs) are poorly removed by the reverse osmosis and advanced oxidation process treatment units often applied for further treatment of municipal wastewater for potable reuse. Granular activated carbon (GAC) treatment effectively sorbed 22 halogenated DBPs. Conversion of the GAC to a cathode within an electrolysis cell resulted in significant degradation of the 22 halogenated DBPs by reductive electrolysis at -1 V vs. Standard Hydrogen Electrode (SHE). The lowest removal efficiency over 6 h electrolysis was for trichloromethane (chloroform; 47%) but removal efficiencies were >90% for 13 of the 22 DBPs. In all cases, DBP degradation was higher than in electrolysis-free controls, and degradation was verified by the production of halides as reduction products. Activated carbons and charcoal were more effective than graphite for electrolysis, with graphite featuring poor sorption for the DBPs. A subset of halogenated DBPs (e.g., haloacetonitriles, chloropicrin) were degraded upon sorption to the GAC, even without electrolysis. Using chloropicrin as a model, experiments indicated that this loss was attributable to the partial reduction of sorbed chloropicrin from reducing equivalents in the GAC. Reducing equivalents depleted by these reactions could be restored when the GAC was treated by reductive electrolysis. GAC treatment of an advanced treatment train effluent for potable reuse effectively reduced the concentrations of chloroform, bromodichloromethane and dichloroacetonitrile measured in the column influent to below the method detection limits. Treatment of the GAC by reductive electrolysis at -1 V vs. SHE over 12 h resulted in significant degradation of the chloroform (63%), bromodichloromethane (96%) and dichloroacetonitrile (99%) accumulated on the GAC. The results suggest that DBPs in advanced treatment train effluents could be captured and degraded continuously by reductive electrolysis using a GAC-based cathode. PMID- 27124126 TI - Multi-species measurements of nitrogen isotopic composition reveal the spatial constraints and biological drivers of ammonium attenuation across a highly contaminated groundwater system. AB - Groundwater under industrial sites is characterised by heterogeneous chemical mixtures, making it difficult to assess the fate and transport of individual contaminants. Quantifying the in-situ biological removal (attenuation) of nitrogen (N) is particularly difficult due to its reactivity and ubiquity. Here a multi-isotope approach is developed to distinguish N sources and sinks within groundwater affected by complex industrial pollution. Samples were collected from 70 wells across the two aquifers underlying a historic industrial area in Belgium. Below the industrial site the groundwater contained up to 1000 mg N l( 1) ammonium (NH4(+)) and 300 mg N l(-1) nitrate (NO3(-)), while downgradient concentrations decreased to ~1 mg l(-1) DIN ([DIN] = [NH4(+)N] + [NO3(-)N] + [NO2(-)N]). Mean delta(15)N-DIN increased from ~20/00 to +200/00 over this flow path, broadly confirming that biological N attenuation drove the measured concentration decrease. Multi-variate analysis of water chemistry identified two distinct NH4(+) sources (delta(15)NNH4(+) from -140/00 and +50/00) within the contaminated zone of both aquifers. Nitrate dual isotopes co-varied (delta(15)N: 30/00 - +600/00; delta(18)O: 00/00 - +500/00) within the range expected for coupled nitrification and denitrification of the identified sources. The fact that delta(15)NNO2(-) values were 500/00-200/00 less than delta(15)NNH4(+) values in the majority of wells confirmed that nitrification controlled N turnover across the site. However, the fact that delta(15)NNO2(-) was greater than delta(15)NNH4(+) in wells with the highest [NH4(+)] shows that an autotrophic NO2(-) reduction pathway (anaerobic NH4(+) oxidation or nitrifier denitrification) drove N attenuation closest to the contaminant plume. This direct empirical evidence that both autotrophic and heterotrophic biogeochemical processes drive N attenuation in contaminated aquifers demonstrates the power of multiple N isotopes to untangle N cycling in highly complex systems. PMID- 27124127 TI - Event-driven model predictive control of sewage pumping stations for sulfide mitigation in sewer networks. AB - Chemicals such as Mg(OH)2 and iron salts are widely dosed to sewage for mitigating sulfide-induced corrosion and odour problems in sewer networks. The chemical dosing rate is usually not automatically controlled but profiled based on experience of operators, often resulting in over- or under-dosing. Even though on-line control algorithms for chemical dosing in single pipes have been developed recently, network-wide control algorithms are currently not available. The key challenge is that a sewer network is typically wide-spread comprising many interconnected sewer pipes and pumping stations, making network-wide sulfide mitigation with a relatively limited number of dosing points challenging. In this paper, we propose and demonstrate an Event-driven Model Predictive Control (EMPC) methodology, which controls the flows of sewage streams containing the dosed chemical to ensure desirable distribution of the dosed chemical throughout the pipe sections of interests. First of all, a network-state model is proposed to predict the chemical concentration in a network. An EMPC algorithm is then designed to coordinate sewage pumping station operations to ensure desirable chemical distribution in the network. The performance of the proposed control methodology is demonstrated by applying the designed algorithm to a real sewer network simulated with the well-established SeweX model using real sewage flow and characteristics data. The EMPC strategy significantly improved the sulfide mitigation performance with the same chemical consumption, compared to the current practice. PMID- 27124152 TI - Social dominance orientation, nonnative accents, and hiring recommendations. AB - OBJECTIVE: Discrimination against nonnative speakers is widespread and largely socially acceptable. Nonnative speakers are evaluated negatively because accent is a sign that they belong to an outgroup and because understanding their speech requires unusual effort from listeners. The present research investigated intergroup bias, based on stronger support for hierarchical relations between groups (social dominance orientation [SDO]), as a predictor of hiring recommendations of nonnative speakers. METHOD: In an online experiment using an adaptation of the thin-slices methodology, 65 U.S. adults (54% women; 80% White; Mage = 35.91, range = 18-67) heard a recording of a job applicant speaking with an Asian (Mandarin Chinese) or a Latino (Spanish) accent. Participants indicated how likely they would be to recommend hiring the speaker, answered questions about the text, and indicated how difficult it was to understand the applicant. RESULTS: Independent of objective comprehension, participants high in SDO reported that it was more difficult to understand a Latino speaker than an Asian speaker. SDO predicted hiring recommendations of the speakers, but this relationship was mediated by the perception that nonnative speakers were difficult to understand. This effect was stronger for speakers from lower status groups (Latinos relative to Asians) and was not related to objective comprehension. CONCLUSIONS: These findings suggest a cycle of prejudice toward nonnative speakers: Not only do perceptions of difficulty in understanding cause prejudice toward them, but also prejudice toward low-status groups can lead to perceived difficulty in understanding members of these groups. (PsycINFO Database Record PMID- 27124153 TI - Perceived parental psychological control, familism values, and Mexican American college students' adjustment. AB - OBJECTIVES: Drawing from cultural ecological and risk and resilience perspectives, we investigated associations among Mexican American college students' perceptions of mothers' and fathers' psychological control and familism values, and college students' adjustment (i.e., depressive symptoms and self esteem). Additionally, we examined how familism values moderated the relations between perceived psychological control and college students' adjustment. METHODS: Participants were 186 Mexican American college students (78.5% women; Mage = 21.56 years), and data were collected using self-report online surveys. RESULTS: Using path analyses, we found that perceived maternal psychological control was positively associated and familism values were negatively associated with college students' depressive symptoms. Additionally, perceived paternal psychological control was negatively associated with college students' self esteem when college students reported low, but not high, familism values. CONCLUSION: Findings highlight the importance of family relationships for Mexican American college students and the significance of examining these relationships within this cultural context. (PsycINFO Database Record PMID- 27124154 TI - If It Looks Like a Duck, Swims Like a Duck, and Quacks Like a Duck--Does It Have to Be a Duck? PMID- 27124155 TI - Successful vaginal delivery following an abdominal cerclage, predicted by serial vaginal cervical ultrasound. PMID- 27124157 TI - Effects of Vocal Fold Nodules on Glottal Cycle Measurements Derived from High Speed Videoendoscopy in Children. AB - The goal of this study is to quantify the effects of vocal fold nodules on vibratory motion in children using high-speed videoendoscopy. Differences in vibratory motion were evaluated in 20 children with vocal fold nodules (5-11 years) and 20 age and gender matched typically developing children (5-11 years) during sustained phonation at typical pitch and loudness. Normalized kinematic features of vocal fold displacements from the mid-membranous vocal fold point were extracted from the steady-state high-speed video. A total of 12 kinematic features representing spatial and temporal characteristics of vibratory motion were calculated. Average values and standard deviations (cycle-to-cycle variability) of the following kinematic features were computed: normalized peak displacement, normalized average opening velocity, normalized average closing velocity, normalized peak closing velocity, speed quotient, and open quotient. Group differences between children with and without vocal fold nodules were statistically investigated. While a moderate effect size was observed for the spatial feature of speed quotient, and the temporal feature of normalized average closing velocity in children with nodules compared to vocally normal children, none of the features were statistically significant between the groups after Bonferroni correction. The kinematic analysis of the mid-membranous vocal fold displacement revealed that children with nodules primarily differ from typically developing children in closing phase kinematics of the glottal cycle, whereas the opening phase kinematics are similar. Higher speed quotients and similar opening phase velocities suggest greater relative forces are acting on vocal fold in the closing phase. These findings suggest that future large-scale studies should focus on spatial and temporal features related to the closing phase of the glottal cycle for differentiating the kinematics of children with and without vocal fold nodules. PMID- 27124156 TI - NOTCH3 Is Induced in Cancer-Associated Fibroblasts and Promotes Angiogenesis in Oral Squamous Cell Carcinoma. AB - Recent studies have shown that Notch signaling is involved in many types of cancers, including oral squamous cell carcinomas (OSCCs). However, the role of Notch signaling in the tumor microenvironment is not yet fully understood. In this study, we investigated the roles of NOTCH3 signaling in cancer associated fibroblasts (CAFs) in OSCCs. Immunohistochemical study of 93 human tongue OSCC cases indicated that about one third of OSCCs showed NOTCH3 expression in CAFs, and that this expression significantly correlated with tumor-size. In vitro study showed that OSCC cell lines, especially HO1-N-1 cells stimulated NOTCH3 expression in normal human dermal fibroblasts (NHDFs) through direct cell-to-cell contact. Immunohistochemical and morphometric analysis using human OSCC samples demonstrated that NOTCH3 expression in CAFs significantly correlated with micro vessel density in cancer stroma. In vitro angiogenesis assays involving co culture of NHDFs with HO1-N-1 and human umbilical endothelial cells (HUVECs), and NOTCH3 knockdown in NHDFs using siRNA, demonstrated that HO1-N-1 cells significantly promoted tube formation dependent on NOTCH3-expression in NHDFs. Moreover, NOTCH3 expression in CAFs was related to poor prognosis of the OSCC patients. This work provides a new insight into the role of Notch signaling in CAFs associated with tumor angiogenesis and the possibility of NOTCH3-targeted molecular therapy in OSCCs. PMID- 27124158 TI - Enhanced Heat Stability of alpha-Chymotrypsin through Single-Enzyme Confinement in Attoliter Liposomes. AB - The entrapment of alpha-chymotrypsin (alpha-CT) within 70-140 nm liposomes formed from POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) leads to an unexpected and remarkable increase in the thermal stability of the enzyme. This finding is based on the observation that heating aqueous suspensions of alpha-CT containing POPC liposomes to 80 degrees C for 30 minutes resulted in partial enzyme inactivation, whereas the same treatment of aqueous solutions of free alpha-CT inactivated the enzyme completely. The stabilizing effect of enzyme confinement in the attoliter volumes of the liposomes was found to increase with decreasing numbers of alpha-CT molecules per liposome. Single-enzyme confinement was particularly effective, as intermolecular interactions between heat-denatured alpha-CT molecules (causing irreversible inactivation) are not possible. PMID- 27124159 TI - Hypercalcemia and diffuse osteolytic lesions in a 45-year-old patient with myeloid sarcoma with megakaryocytic differentiation. AB - Acute megakaryocytic leukemia is a rare form of acute myeloid leukemia that carries a poor prognosis. As most cases of osteolytic lesions are due to plasma cell and myeloid malignancies, maintaining a broad differential directly influences clinical course. We document a 45-year-old patient with progressive constitutional symptoms, osteolytic bone lesions in the setting of hypercalcemia, who developed acutely worsening pancytopenia. The diagnosis of myeloid sarcoma with megakaryocytic differentiation was made after obtaining tissue from osteolytic bone that stained strong for CD34. Immunohistochemical testing underscores the importance of how serologic and urine testing remains limited and can delay early diagnosis in this disease. PMID- 27124160 TI - Calcitriol-mediated hypercalcemia in a patient with bilateral adrenal non Hodgkin's B-cell lymphoma case report. AB - Calcitriol-mediated hypercalcemia is a frequent manifestation of hematological malignancies. However, there are a few reports of cases presenting with increased angiotensin-converting enzyme (ACE) level, which suggests a possible mechanism similar to that of granulomatous diseases. We present a patient with hypercalcemia, normal parathyroid hormone, and parathyroid hormone-related protein levels but high calcitriol and ACE levels that, after further investigation, was diagnosed with bilateral adrenal non-Hodgkin's B-cell lymphoma. Primary adrenal lymphoma represents only 1% of all non-Hodgkin's lymphomas and is usually asymptomatic but should be considered by clinicians among the malignancies that cause calcitriol-mediated hypercalcemia. PMID- 27124161 TI - Hydralazine-induced pauci-immune glomerulonephritis: intriguing case series with misleading diagnoses. AB - Hydralazine has been used since the 1950s for the management of hypertension. Evidence for hydralazine-associated vasculitis dates to pre-ANCA (antineutrophil cytoplasmic antibodies) era. This abstract describes two cases of ANCA-positive pauci-immune glomerulonephritis (GN) in challenging scenarios where diagnosis was misconstrued. A comprehensive literature review was done to understand the pathogenesis of drug-induced pauci-immune GN. We have described key diagnostic features that are helpful in distinguishing idiopathic ANCA vasculitis from drug induced vasculitis. Additionally, we have also described different treatments meant to provide therapy options with the least side effects. PMID- 27124162 TI - Janeway lesions: a valuable clinical sign in patients with infective endocarditis. PMID- 27124163 TI - Guillain-Barre syndrome occurring synchronously with systemic lupus erythematosus as initial manifestation treated successfully with low-dose cyclophosphamide. AB - Systemic lupus erythematous (SLE) is frequently encountered in clinical practice; a widespread immunological response can involve any organ system, sometimes leading to rare and diagnostically challenging presentations. We describe a 38 year-old female who presented with symmetric numbness and tingling of the hands and feet, and cervical pain. Imaging studies were not diagnostic of any serious underlying pathology. The patient developed ascending paresis involving lower extremities and cranial muscles (dysphagia and facial weakness). Guillain-Barre syndrome (GBS) was diagnosed on the basis of electromyography and lumbar puncture showing albuminocytologic dissociation. Intravenous immunoglobulins (IVIG) were administered for 5 days. Supported by anti-dsDNA antibody, oral ulcers, proteinuria of 0.7 g in 24 h, and neurological manifestation, she was diagnosed with lupus. After completion of IVIG, she received pulse-dose corticosteroids and one dose of low-dose cyclophosphamide. Her neurological symptoms improved and she had complete neurological recovery several months after her initial presentation. Literature search provides evidence of co-occurrence of lupus and GBS occurring mostly later in the course of the disease. However, GBS as initial manifestation of SLE is exceedingly rare and less understood. The association of GBS with lupus is important to recognize for rapid initiation of appropriate therapy and for consideration of immunosuppressive therapy which may affect the outcome. PMID- 27124164 TI - ST elevation occurring during stress testing. AB - A case is presented of significant reversible ST elevation occurring during treadmill testing, and the coronary anatomy and subsequent course are described, indicating that ischemia is a potential cause of this electrocardiographic finding. PMID- 27124165 TI - Isolated supra-cardiac partial anomalous pulmonary venous connection causing right heart failure. AB - Right heart failure (RHF) has been overlooked as left heart failure has predominated. One of the many causes of RHF is partial anomalous pulmonary venous connection (PAPVC), an extremely rare entity in nature. Physicians should consider the unusual causes of RHF after ruling out the common causes. PMID- 27124166 TI - A rare cause of chest pain in a cancer patient. AB - It is well known that cancer and hypercoagulability go hand in hand. Most thromboembolism is venous in nature although arterial thrombosis can occur. Arterial thrombosis secondary to malignancy is usually seen in the lower extremities; however, it can also be seen elsewhere. This is a case of bronchogenic carcinoma with no history of typical atherosclerotic risk factors including smoking, diabetes mellitus, hypertension, or hyperlipidemia presented with chest pain and was found to have an acute ST segment elevation myocardial infection. Coronary angiography showed a large thrombus in the left anterior descending artery in the absence of any atherosclerotic lesions. Malignancy is considered to be the major contributing factor for this myocardial infarction in the absence of both atherosclerotic risk factors and atherosclerotic lesions in the coronary angiography. We will focus on the relationship between cancer and thrombosis with special emphasis on arterial thromboembolism with subsequent development of myocardial infarction. PMID- 27124167 TI - Avoiding transthoracic echocardiography and transesophageal echocardiography for patients with variable body mass indexes in infective endocarditis. AB - BACKGROUND: Echocardiography has been a popular modality used to aid in the diagnosis of infective endocarditis (IE) with the modified Duke criteria. We evaluated the necessity between the uses of either a transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) in patients with a body mass index (BMI) greater than or equal to 25 kg/m(2) and less than 25 kg/m(2). METHODS: A single-centered, retrospective study of 198 patients between 2005 and 2012 diagnosed with IE based on modified Duke criteria. Patients, required to be above age 18, had undergone an echocardiogram study and had blood cultures to be included in the study. RESULTS: Among 198 patients, two echocardiographic groups were evaluated as 158 patients obtained a TTE, 143 obtained a TEE, and 103 overlapped with TEE and TTE. Out of these patients, 167 patients were included in the study as 109 (65%) were discovered to have native valve vegetations on TEE and 58 (35%) with TTE. TTE findings were compared with TEE results for true negatives and positives to isolate valvular vegetations. Overall sensitivity of TTE was calculated to be 67% with a specificity of 93%. Patients were further divided into two groups with the first group having a BMI >=25 kg/m(2) and the subsequent group with a BMI <25 kg/m(2). Patients with a BMI >=25 kg/m(2) who underwent a TTE study had a sensitivity and specificity of 54 and 92%, respectively. On the contrary, patients with a BMI < 25 kg/m(2) had a TTE sensitivity and specificity of 78 and 95%, respectively. CONCLUSIONS: Patients with a BMI <25 kg/m(2) and a negative TTE should refrain from further diagnostic studies, with TEE strong clinical judgment is warranted. Patients with a BMI >= 25 kg/m(2) may proceed directly to TEE as the initial study, possibly avoiding an additional study with a TTE. PMID- 27124168 TI - Effect of didactic lectures on obesity documentation and counseling among internal medicine residents. AB - BACKGROUND: Screening adult patients for obesity and offering appropriate counseling and treatment for weight loss is recommended. However, many healthcare providers feel ill-equipped to address this topic. OBJECTIVE: We examined whether didactic presentations lead to increased obesity documentation and counseling among internal medicine (IM) residents. METHODS: We reviewed medical records of patients seen at the IM Resident Continuity Clinic during April 2015. Residents were provided feedback at two didactic presentations during May 2015. To examine the effect of this intervention, we repeated medical record review during June 2015. For both reviews, we abstracted patient-specific (i.e., age, body mass index [BMI], race, sex, and number of comorbid diagnoses) and resident-specific (i.e., sex and training level) data as well as evidence of obesity documentation and counseling. We used logistic regression models to examine the effect of intervention on obesity documentation and counseling, adjusting for patient- and resident-specific variables. RESULTS: Of the 278 patients with BMI>=30 kg/m(2), 139 were seen before and 139 after the intervention. Intervention had no effect on obesity documentation or counseling with or without adjustment for confounding variables (both P>0.05). In adjusted post-hoc analyses, each additional comorbidity increased the odds of obesity documentation by 8% (OR=1.08; 95% CI=1.05-1.11; P<0.001). In addition, as compared to postgraduate year (PGY) 1 residents, PGY-3 residents were 56% (OR=0.44; 95% CI=0.21-0.95; P=0.03) less likely to counsel obese patients. CONCLUSIONS: Obesity is inadequately addressed in primary care settings, and didactic presentations were unable to increase obesity documentation or weight loss counseling. Future research to identify effective interventions is needed. PMID- 27124169 TI - A case of saddle pulmonary embolus visualized on a transthoracic echocardiography in a 69-year-old female. AB - A 69-year-old female with history of immobilization presented with shortness of breath and generalized weakness and was found to have large saddle pulmonary embolus on CT scan. Further evaluation with a transthoracic echocardiography revealed a moderately enlarged and hypokinetic right ventricle with a pulmonary artery clot of about 1.5 cm seen at the bifurcation while the ultrasound of the legs was negative for deep vein thrombosis. PMID- 27124170 TI - Impact of bowel preparation type on the quality of colonoscopy: a multicenter community-based study. AB - BACKGROUND: High-quality bowel preparation is crucial for achieving the goals of colonoscopy. However, choosing a bowel preparation in clinical practice can be challenging because of the many formulations. This study aims to assess the impact the type of bowel preparation on the quality of colonoscopy in a community hospital setting. METHODS: A retrospective, observational study was conducted utilizing a colonoscopy screening/surveillance database in central Illinois during the period of January 1, 2010, to March 31, 2014. Patients without bowel preparation assessment were excluded from this study. Controlling for the confounders, generalized linear models were used to estimate the adjusted impact [odds ratio (OR)] of bowel preparation type on the quality of preparation (excellent, good, fair, and poor), and on the detection of advanced adenoma. The association between the time of withdrawal after insertion and the quality of preparation was also examined using a linear model. RESULTS: A total of 28,368 colonoscopies; half the patients were male, and the average age was 61+/-9 years. Polyethylene glycol (PEG) was used in the majority (70.2%) of bowel preparations, followed by sodium sulfate (21.4%), sodium phosphate (2.5%), magnesium sulfate (0.4%), and others. Compared with PEG, magnesium sulfate had a poorer quality of bowel preparations (OR=0.6, 95% CI 0.4-0.9; p<0.05), whereas the quality of bowel preparation was significantly improved by using sodium sulfate (OR=5.7, 95% CI 5.4-6.1; p<0.001) and sodium phosphate (OR=2.1, 95% CI 1.8-2.5; p<0.001). For those who had adequate bowel preparation, the better quality of preparation significantly increased the detection rate of advanced adenoma (5.0, 3.6, and 2.9% for excellent, good, and fair, respectively). CONCLUSION: When possible, sodium sulfate-based preparations should be recommended in the community setting for colonoscopy because of their high quality of bowel preparation. PMID- 27124171 TI - Streptococcus agalactiae mural infective endocarditis in a structurally normal heart. AB - A 38-year-old Caucasian man with uncontrolled diabetes mellitus type 2 was admitted with a 1-week duration of fevers, chills, and a non-productive cough. He had a left ischiorectal abscess 1 month prior to admission. Physical examination revealed caries on a left upper molar and a well-healed scar on the left buttock, but no heart murmur or evidence of micro-emboli. Blood cultures grew Streptococcus agalactiae. A transesophageal echocardiogram revealed a mobile mass in the right ventricle that attached to chordae tendineae without valvular disease or dysfunction. A computed tomography (CT) with contrast revealed the mass within the right ventricle, a left lung cavitary lesion, and a splenic infarction. He was initially treated with penicillin G for a week. Subsequently, ceftriaxone was continued for a total of 8 weeks. A follow-up CT showed no evidence of right ventricular mass 8 weeks after discharge. This is the first reported case of S. agalactiae mural infective endocarditis in a structurally normal heart. PMID- 27124172 TI - Poor glycemic control as a reason for referral of diabetes patients to specialists in Israel. AB - AIMS/INTRODUCTION: Family physicians face the dilemma of when to refer patients with diabetes to specialists. This study examined attitudes of family physicians to referring patients with poor glucose control to diabetes specialists. MATERIALS AND METHODS: At continuous medical education courses, family physicians were asked to respond anonymously, as to whether they generally manage the diabetes of their patients, and specifically those with poor glycemic control (HbA1c>9.0%). RESULTS: Of 470 respondents, 426 (90%) reported that they generally manage their patients' diabetes; 202 (43%) reported that they manage the diabetes of patients with HbA1c>9.0%. Board certification in family medicine and affiliation to a health maintenance organization, but not sex, age, years of professional experience, or the proportion of patients with diabetes at their clinics, were associated with referral practices. CONCLUSIONS: Family medicine residency and organizational support appear to promote treatment by family physicians of patients with poorly controlled diabetes in the primary care setting. PMID- 27124173 TI - Over-diuresis or cardiac tamponade? An unusual case of acute kidney injury and early closure. AB - An 84-year-old man with hypertension and a history of deep venous thrombosis (on warfarin) was admitted with shortness of breath presumed to be due to congestive heart failure. Echocardiogram performed the following day showed a low-normal ejection fraction with signs of elevated right-sided pressures but was otherwise normal. He improved with diuretic therapy but after a few days was found to be hypotensive with a concomitant rise in creatinine with decreased urine output. This was felt to be secondary to over-diuresis but he did not respond to small boluses of intravenous fluids as his kidney function continued to worsen and hypotension persisted. He was transferred to the intermediate care unit where a rapid, bedside ultrasound revealed a new, moderate-sized pericardial effusion with tamponade physiology. Pericardiocentesis, with removal of 750 cc of frank blood, led to dramatic improvement in blood pressure, kidney function, and urine output. Here, we demonstrate the utility of point-of-care ultrasound in a community hospital setting where urgent echocardiogram is not routinely available. We also report acute kidney injury due to pericardial tamponade reversed with therapeutic pericardiocentesis. PMID- 27124174 TI - Emergency department Modified Early Warning Score association with admission, admission disposition, mortality, and length of stay. AB - BACKGROUND: Geisinger Health System implemented the Modified Early Warning Score (MEWS) in 2011 and is fully integrated to the Electronic Medical Record (EMR). Our objective was to assess whether the emergency department (ED) MEWS (auto calculated by EMR) is associated with admission to the hospital, admission disposition, inpatient mortality, and length of stay (LOS) 4 years after its implementation. METHODS: A random sample of 3,000 patients' first encounter in the ED was extracted in the study period (between January 1, 2014 and May 31, 2015). Logistic regression was done to analyze whether mean, maximum, and median ED MEWS is associated with admission disposition, mortality, and LOS. RESULTS: Mean, maximum, and median ED MEWS is associated with admission to the hospital, admission disposition, and mortality. It correlates weakly with LOS. CONCLUSION: MEWS can be integrated to the EMR, and the score automatically generated still helps predict catastrophic events. MEWS can be used as a triage tool when deciding whether and where patients should be admitted. PMID- 27124175 TI - Surgical treatment of unruptured dissecting intracranial aneurysms of vertebral posterior inferior cerebellar artery region. AB - A lack of published surgical experience and higher symptomatic recurrence than previously recognized prompted the authors to present their experience with the surgical treatment of unruptured intracranial dissecting aneurysms (UIDAs). Hospital records, neuroimaging studies, operative reports, and follow-up records were retrospectively reviewed. All patients underwent surgical exploration of the lesion with proximal clipping of the parent artery through a far-lateral suboccipital craniotomy with or without partial condylar resection. The surgical treatment of vertebral artery-posterior inferior cerebellar artery UIDAs has acceptable risk regarding perioperative mortality and morbidity. The incidence of aneurysmal recurrence or the need for retreatment seems to be less than that associated with anticoagulation/antiplatelet therapy or endovascular treatment. PMID- 27124176 TI - Computed tomography perfusion and computed tomography angiography in vasospasm after subarachnoid hemorrhage. AB - BACKGROUND: The aim of the study was to evaluate the effectiveness and reliability of a combined computed tomography angiography (CTA) and computed tomography perfusion (CTP) approach in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. METHODS: Nineteen patients with clinical signs of arterial vasospasm and positive transcranial Doppler (TCD) were enrolled and underwent CTP. Mean time transit (MTT), cerebral blood flow (CBF) and cerebral blood volume (CBV) values of 20 standardized ROI (regions of interest) were analyzed, and CTA used to measure the gauge of 26 arterial ramifications. CTA measurements were compared with those taken upon hospitalization. Of the 19 patients, 11 were scheduled for digital subtraction angiography (DSA), performed less than 12 hours after execution of the CTA-CTP protocol. The results were compared with findings of DSA and/or clinical follow-up and CT or TCD. RESULTS: Computed tomography angiography diagnosis of vasospasm was confirmed in all cases (100% sensitivity and 100% specificity), while CTP yielded 3 false negatives (70% sensitivity and 100% specificity). All patients sent for endovascular treatment had received diagnostic confirmation of vasospasm by angiography. CTP thresholds proved reliable in both diagnosis and indicating treatment. CONCLUSIONS: Combined one-shot CT angiography and CT perfusion represents a valid alternative to DSA in the diagnosis and management of cerebral vasospasm. PMID- 27124177 TI - Community Dialogue to Shift Social Norms and Enable Family Planning: An Evaluation of the Family Planning Results Initiative in Kenya. AB - INTRODUCTION: Use of family planning (FP) is powerfully shaped by social and gender norms, including the perceived acceptability of FP and gender roles that limit women's autonomy and restrict communication and decision-making between men and women. This study evaluated an intervention that catalyzed ongoing community dialogues about gender and FP in Siaya county, Nyanza Province, Kenya. Specifically, we explored the changes in perceived acceptability of FP, gender norms and use of FP. METHODS: We used a mixed-method approach. Information on married men and women's socio-demographic characteristics, pregnancy intentions, gender-related beliefs, FP knowledge, attitudes, and use were collected during county-representative, cross-sectional household surveys at baseline (2009; n11 = 650 women; n12 = 305 men) and endline (2012; n21 = 617 women; n22 = 317 men); exposure to the intervention was measured at endline. We assessed changes in FP use at endline vs. baseline, and fitted multivariate logistic regression models for FP use to examine its association with intervention exposure and explore other predictors of use at endline. In-depth, qualitative interviews with 10 couples at endline further explored enablers and barriers to FP use. RESULTS: At baseline, 34.0% of women and 27.9% of men used a modern FP method compared to 51.2% and 52.2%, respectively, at endline (p<0.05). Exposure to FP dialogues was associated with 1.78 (95% CI: 1.20-2.63) times higher odds of using a modern FP method at endline for women, but this association was not significant for men. Women's use of modern FP was significantly associated with higher spousal communication, control over own cash earnings, and FP self-efficacy. Men who reported high approval of FP were significantly more likely to use modern FP if reporting high approval of FP and more equitable gender beliefs. FP dialogues addressed persistent myths and misconceptions, normalized FP discussions, and increased its acceptability. Public examples of couples making joint FP decisions legitimized communication and decision-making with spouses about FP especially for men; women described partner support as key enabler of FP use. CONCLUSIONS: Our evaluation demonstrates that an intervention that catalyzes open dialogue about gender and FP can shift social norms, enable more equitable couple communication and decision-making and, ultimately, increase use of FP. PMID- 27124178 TI - Exploring the relationship between stigma and help-seeking for mental illness in African-descended faith communities in the UK. AB - BACKGROUND: Stigma related to mental illness affects all ethnic groups, contributing to the production and maintenance of mental illness and restricting access to care and support. However, stigma is especially prevalent in minority communities, thus potentially increasing ethnically based disparities. Little is known of the links between stigma and help-seeking for mental illness in African descended populations in the UK. OBJECTIVE AND STUDY DESIGN: Building on the evidence that faith-based organizations (FBOs) can aid the development of effective public health strategies, this qualitative study used semi-structured interviews with faith groups to explore the complex ways in which stigma influences help-seeking for mental illness in African-descended communities. A thematic approach to data analysis was applied to the entire data set. SETTING AND PARTICIPANTS: Twenty-six men and women who had varying levels of involvement with Christian FBOs in south London were interviewed (e.g. six faith leaders, thirteen 'active members' and seven 'regular attendees'). RESULTS: Key factors influencing help-seeking behaviour were as follows: beliefs about the causes of mental illness; 'silencing' of mental illness resulting from heightened levels of ideological stigma; and stigma (re)production and maintenance at community level. Individuals with a diagnosis of mental illness were likely to experience a triple jeopardy in terms of stigma. DISCUSSION AND CONCLUSION: 'One-size-fits-all' approaches cannot effectively meet the needs of diverse populations. To ensure that services are more congruent with their needs, health and care organizations should enable service users, families and community members to become active creators of interventions to remove barriers to help-seeking for mental illness. PMID- 27124179 TI - Analyzing Exercise Behaviors during the College Years: Results from Latent Growth Curve Analysis. AB - The objective of this study is to analyze changes in the predictors of physical activity behavior among college students. The Theory of Planned Behavior served as its theoretical framework. METHODS: Among an initial sample of 417 college students, 195 participants completed a validated questionnaire measuring attitudes, subjective norms, perceived control, intentions and self-reported physical activity, at the beginning and end of each of 3 college semesters. Latent growth curve modeling analyses were conducted to examine the relationships between the trajectories of changes in PA, intentions, attitudes, subjective norms, and perceived control. RESULTS: Good fit indices supported the validity of the proposed longitudinal model (CFI > .97, RMSEA < .05). Changes in perceived control (gamma = 0.57) were significantly linked with changes in intentions (p < .05). Perceived control (gamma = 0.28) and intention growth (gamma = 0.36) predicted behavior changes (p < .05). No gender differences were observed on attitudes, subjective norms and perceived control (p > .10). However, girls tend to have higher growth parameters on intentions and physical activity (p < .05). In summary, intentions and physical activity has significantly increased over 3 college semesters (growth parameters significant at p < .05). CONCLUSIONS: This study demonstrated that attitudes and perceived control are key determinants regarding the intentions of being active. On a longer term perspective, future physical activity interventions should focus on the enhancement of students' perceived control. Such educational context should help in promoting the adoption of an active lifestyle during college. PMID- 27124180 TI - The Relationship between Habitat Loss and Fragmentation during Urbanization: An Empirical Evaluation from 16 World Cities. AB - Urbanization results in habitat loss and habitat fragmentation concurrently, both influencing biodiversity and ecological processes. To evaluate these impacts, it is important to understand the relationships between habitat loss and habitat fragmentation per se (HLHF) during urbanization. The objectives of this study were two-fold: 1) to quantify the different forms of the HLHF relationship during urbanization using multiple landscape metrics, and 2) to test the validity of the HLHF relations reported in the literature. Our analysis was based on a long-term urbanization dataset (1800-2000) of 16 large cities from around the world. Habitat area was represented as the percentage of non-built-up area in the landscape, while habitat fragmentation was measured using several landscape metrics. Our results show that the relationship between habitat loss and habitat fragmentation during urbanization is commonly monotonic-linear, exponential, or logarithmic, indicating that the degree of habitat fragmentation per se increases with habitat loss in general. We compared our results with 14 hypothesized HLHF relationships based on simulated landscapes found in the literature, and found that four of them were consistent with those of urbanization, whereas the other ten were not. Also, we identified six new HLHF relationships when fragmentation was measured by total core area, normalized total core area, patch density, edge density and landscape shape index, respectively. In addition, our study demonstrated that the "space-for-time" approach, frequently used in ecology and geography, generated specious HLHF relationships, suggesting that this approach is largely inappropriate for analyses of urban landscapes that are highly heterogeneous in space and unusually contingent in dynamics. Our results show both generalities and idiosyncrasies of the HLHF relationship, providing new insights for assessing ecological effects of urbanization. PMID- 27124181 TI - Prostaglandin E2 Exerts Multiple Regulatory Actions on Human Obese Adipose Tissue Remodeling, Inflammation, Adaptive Thermogenesis and Lipolysis. AB - Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1alpha1, Col1alpha2 and alphaSMA in differentiated 3T3 adipocytes exposed to TGF-beta. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions driving uncontrolled inflammation and fibrosis and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT. PMID- 27124183 TI - Correction: Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring. AB - [This corrects the article DOI: 10.1371/journal.pone.0151579.]. PMID- 27124182 TI - Protection against Experimental Melioidosis with a Synthetic manno-Heptopyranose Hexasaccharide Glycoconjugate. AB - Melioidosis is an emerging infectious disease caused by Burkholderia pseudomallei and is associated with high morbidity and mortality rates in endemic areas. Antibiotic treatment is protracted and not always successful; even with appropriate therapy, up to 40% of individuals presenting with melioidosis in Thailand succumb to infection. In these circumstances, an effective vaccine has the potential to have a dramatic impact on both the scale and the severity of disease. Currently, no vaccines are licensed for human use. A leading vaccine candidate is the capsular polysaccharide consisting of a homopolymer of unbranched 1->3 linked 2-O-acetyl-6-deoxy-beta-d-manno-heptopyranose. Here, we present the chemical synthesis of this challenging antigen using a novel modular disaccharide assembly approach. The resulting hexasaccharide was coupled to the nontoxic Hc domain of tetanus toxin as a carrier protein to promote recruitment of T-cell help and provide a scaffold for antigen display. Mice immunized with the glycoconjugate developed IgM and IgG responses capable of recognizing native capsule, and were protected against infection with over 120 * LD50 of B. pseudomallei strain K96243. This is the first report of the chemical synthesis of an immunologically relevant and protective hexasaccharide fragment of the capsular polysaccharide of B. pseudomallei and serves as the rational starting point for the development of an effective licensed vaccine for this emerging infectious disease. PMID- 27124200 TI - The Dilemma of Breast Cancer Treatment and Existing Collagen Vascular Disease: A Case of Scleroderma and Review of the Literature. AB - Collagen vascular diseases present a treatment dilemma for patients with breast cancer. Due to the potential for severe, acute, and late complications of radiation therapy, a history of collagen vascular disease (CVD) is a relative contraindication to breast-conserving treatment. We present a case of early stage breast cancer in a patient with severe scleroderma treated with breast-conserving surgery without radiation and a brief review of the published literature regarding the therapeutic approach to the patient with CVD and breast cancer. PMID- 27124184 TI - Association of Baseline Depressive Symptoms with Prevalent and Incident Pre Hypertension and Hypertension in Postmenopausal Hispanic Women: Results from the Women's Health Initiative. AB - BACKGROUND: Depression and depressive symptoms are risk factors for hypertension (HTN) and cardiovascular disease (CVD). Hispanic women have higher rates of depressive symptoms compared to other racial/ethnic groups yet few studies have investigated its association with incident prehypertension and hypertension among postmenopausal Hispanic women. This study aims to assess if an association exists between baseline depression and incident hypertension at 3 years follow-up among postmenopausal Hispanic women. METHODS: Prospective cohort study, Women's Health Initiative (WHI), included 4,680 Hispanic women who participated in the observational and clinical trial studies at baseline and at third-year follow-up. Baseline current depressive symptoms and past depression history were measured as well as important correlates of depression-social support, optimism, life events and caregiving. Multinomial logistic regression was used to estimate prevalent and incident prehypertension and hypertension in relation to depressive symptoms. RESULTS: Prevalence of current baseline depression ranged from 26% to 28% by hypertension category and education moderated these rates. In age-adjusted models, women with depression were more likely to be hypertensive (OR = 1.25; 95% CI 1.04-1.51), although results were attenuated when adjusting for covariates. Depression at baseline in normotensive Hispanic women was associated with incident hypertension at year 3 follow-up (OR = 1.74; 95% CI 1.10-2.74) after adjustment for insurance and behavioral factors. However, further adjustment for clinical covariates attenuated the association. Analyses of psychosocial variables correlated with depression but did not alter findings. Low rates of antidepressant medication usage were also reported. CONCLUSIONS: In the largest longitudinal study to date of older Hispanic women which included physiologic, behavioral and psychosocial moderators of depression, there was no association between baseline depressive symptoms and prevalent nor incident pre-hypertension and hypertension. We found low rates of antidepressant medication usage among Hispanic women suggesting a possible point for clinical intervention. TRIAL REGISTRATION: Clinicaltrials.gov NCT00000611. PMID- 27124201 TI - The Relevance of Emotional Intelligence in Personnel Selection for High Emotional Labor Jobs. AB - Although a large number of studies have pointed to the potential of emotional intelligence (EI) in the context of personnel selection, research in real-life selection contexts is still scarce. The aim of the present study was to examine whether EI would predict Assessment Center (AC) ratings of job-relevant competencies in a sample of applicants for the position of a flight attendant. Applicants' ability to regulate emotions predicted performance in group exercises. However, there were inconsistent effects of applicants' ability to understand emotions: Whereas the ability to understand emotions had a positive effect on performance in interview and role play, the effect on performance in group exercises was negative. We suppose that the effect depends on task type and conclude that tests of emotional abilities should be used judiciously in personnel selection procedures. PMID- 27124202 TI - Protein complexes in focus. AB - A new advance in electron microscopy can reveal highly-detailed structures of protein complexes. PMID- 27124203 TI - Growth and Photoelectrochemical Energy Conversion of Wurtzite Indium Phosphide Nanowire Arrays. AB - Photoelectrochemical (PEC) water splitting into hydrogen and oxygen is a promising strategy to absorb solar energy and directly convert it into a dense storage medium in the form of chemical bonds. The continual development and improvement of individual components of PEC systems is critical toward increasing the solar to fuel efficiency of prototype devices. Within this context, we describe a study on the growth of wurtzite indium phosphide (InP) nanowire (NW) arrays on silicon substrates and their subsequent implementation as light absorbing photocathodes in PEC cells. The high onset potential (0.6 V vs the reversible hydrogen electrode) and photocurrent (18 mA/cm(2)) of the InP photocathodes render them as promising building blocks for high performance PEC cells. As a proof of concept for overall system integration, InP photocathodes were combined with a nanoporous bismuth vanadate (BiVO4) photoanode to generate an unassisted solar water splitting efficiency of 0.5%. PMID- 27124204 TI - HACEK endocarditis: a review. AB - INTRODUCTION: The HACEK group, referring to Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae, is a rare cause of infective endocarditis (IE). It causes the majority of Gram-negative endocarditis cases and has an excellent prognosis and simple management if properly identified. However, delay in diagnosis and associated complications can render the infection fatal. AREAS COVERED: Over the past few decades, there have been tremendous advancements in understanding the manifestations and progression of HACEK endocarditis (HE). This review tackles the epidemiology of HE, the microbiological characteristics of each organism in the HACEK group, the methods used to diagnose HE, the clinical manifestations, complications, and mortality of patients with HE, as well as the recommended treatment and preventive methods. Expert Commentary: The lack of robust randomized controlled trials in diagnosis and treatment of HE makes it difficult to determine the optimal management of such infections. Nevertheless, advancements in culturing methods have shown progress in isolating and identifying these fastidious organisms. Positive blood cultures for any of the HACEK organisms in the setting of no definite focus of infection is highly suggestive of HE. In such cases, treatment with ceftriaxone or a fluoroquinolone, even without obtaining antibiotic susceptibilities, should be initiated. Moreover, the decision to proceed with surgical intervention should be individualized. As is the case for other IE, HE requires the collaboration of a multidisciplinary team consisting of the infectious disease specialist, cardiologist, cardiothoracic surgeon, and the microbiologist. PMID- 27124205 TI - Return to Work and Social Communication Ability Following Severe Traumatic Brain Injury. AB - PURPOSE: Return to competitive employment presents a major challenge to adults who survive traumatic brain injury (TBI). This study was undertaken to better understand factors that shape employment outcome by comparing the communication profiles and self-awareness of communication deficits of adults who return to and maintain employment with those who do not. METHOD: Forty-six dyads (46 adults with TBI, 46 relatives) were recruited into 2 groups based on the current employment status (employed or unemployed) of participants with TBI. Groups did not differ in regard to sex, age, education, preinjury employment, injury severity, or time postinjury. The La Trobe Communication Questionnaire (Douglas, O'Flaherty, & Snow, 2000) was used to measure communication. Group comparisons on La Trobe Communication Questionnaire scores were analyzed by using mixed 2 * 2 analysis of variance (between factor: employment status; within factor: source of perception). RESULTS: Analysis yielded a significant group main effect (p = .002) and a significant interaction (p = .004). The employed group reported less frequent difficulties (self and relatives). Consistent with the interaction, unemployed participants perceived themselves to have less frequent difficulties than their relatives perceived, whereas employed participants reported more frequent difficulties than their relatives. CONCLUSION: Communication outcome and awareness of communication deficits play an important role in reintegration to the workplace following TBI. PMID- 27124206 TI - Probable preventive effects of placenta from oxidative stress; Evaluation of total antioxidant status, total oxidant status and oxidative stress index in fetal cord blood during the delivery. AB - Depression in pregnancy may have negative effects on birth outcomes. It may also effect the intrauterine environment of the fetus. The umbilical cord is the conduit between the fetus and placenta, and functions in the transport between fetus and mother. Investigating biochemical parameters in fetal cord blood (FCB) during delivery may be helpful to understanding to what the fetus is exposed to, at least in the last trimester. In this study, we aimed to investigate total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) in the FCB of depressed mothers and healthy controls during delivery. Our study included 33 depressed mothers and 37 healthy controls. TAS, TOS, and OSI were measured according to Erel's method. We found that TAS, TOS, and OSI levels were similar in patients and healthy controls; however, the birth weights of depressed patients were significantly lower than those of healthy controls. Our results suggest that the placental barrier may prevent from oxidative stress. Future studies should include blood samples collected simultaneously from mothers during delivery. PMID- 27124207 TI - The impact of proposed changes to ICD-11 on estimates of PTSD prevalence and comorbidity. AB - The World Health Organization's posttraumatic stress disorder (PTSD) work group has published a proposal for the forthcoming edition of the International Classification of Diseases (ICD-11) that would yield a very different diagnosis relative to DSM-5. This study examined the impact of the proposed ICD-11 changes on PTSD prevalence relative to the ICD-10 and DSM-5 definitions and also evaluated the extent to which these changes would accomplish the stated aim of reducing the comorbidity associated with PTSD. Diagnostic prevalence estimates were compared using a U.S. national community sample and two U.S. Department of Veterans Affairs clinical samples. The ICD-11 definition yielded prevalence estimates 10-30% lower than DSM-5 and 25% and 50% lower than ICD-10 with no reduction in the prevalence of common comorbidities. Findings suggest that by constraining the diagnosis to a narrower set of symptoms, the proposed ICD-11 criteria set would substantially reduce the number of individuals with the disorder. These findings raise doubt about the extent to which the ICD-11 proposal would achieve the aim of reducing comorbidity associated with PTSD and highlight the public health and policy implications of such a redefinition. PMID- 27124208 TI - Objective and subjective measurement of sleep disturbance in female trauma survivors with posttraumatic stress disorder. AB - Sleep disturbance may be the most often endorsed symptom of posttraumatic stress disorder (PTSD). Much of this research is based on subjective reports from trauma survivors; however, objective measures of sleep-related impairment have yielded findings inconsistent with self-report data. More studies investigating subjective and objective assessments concordantly are needed to understand sleep impairment in PTSD. The current study examined PTSD-related sleep disturbance in a female interpersonal violence cohort with full PTSD diagnoses (N=51) assessing subjective (global and daily diary measures) and objective (actigraphy) sleep measures concurrently. PTSD severity was positively associated with global, subjective reports of sleep impairment and insomnia. Subjective measures of sleep (including global sleep impairment, insomnia, and daily sleep diary reports of total sleep time, sleep efficiency, and sleep onset latency) were moderately to strongly correlated. However, no significant correlations between subjective and objective reports of sleep impairment were found in this cohort. Analyses demonstrated an overall elevation in subjectively reported sleep impairment when compared to objective measurement assessed concurrently. Findings demonstrate a lack of agreement between subjective and objective measurements of sleep in a PTSD-positive female cohort, suggesting objective and subjective sleep impairments are distinct sleep parameters that do not necessarily directly co vary. PMID- 27124209 TI - Heart rate variability and suicidal behavior. AB - Identification of biological indicators of suicide risk is important given advantages of biomarker-based models. Decreased high frequency heart rate variability (HF HRV) may be a biomarker of suicide risk. The aim of this research was to determine whether HF HRV differs between suicide attempters and non attempters. Using the Trier Social Stress Test (TSST), we compared HF HRV between females with and without a history of suicide attempt, all with a lifetime diagnosis of a mood disorder. To investigate a potential mechanism explaining association between HF HRV and suicide, we examined the association between self reported anger and HF HRV. Results of an Area under the Curve (AUC) analysis showed attempters had a lower cumulative HF HRV during the TSST than non attempters. In addition, while there was no difference in self-reported anger at baseline, the increase in anger was greater in attempters, and negatively associated with HF HRV. Results suggest that suicide attempters have a reduced capacity to regulate their response to stress, and that reduced capacity to regulate anger may be a mechanism through which decreased HF HRV can lead to an increase in suicide risk. Our results have implications for the prevention of suicidal behavior in at-risk populations. PMID- 27124210 TI - The Net Chance of a Longer Survival as a Patient-Oriented Measure of Treatment Benefit in Randomized Clinical Trials. AB - IMPORTANCE: Time to events, or survival end points, are common end points in randomized clinical trials. They are usually analyzed under the assumption of proportional hazards, and the treatment effect is reported as a hazard ratio, which is neither an intuitive measure nor a meaningful one if the assumption of proportional hazards is not met. OBJECTIVE: To demonstrate that a different measure of treatment effect, called the net chance of a longer survival, is a meaningful measure of treatment effect in clinical trials whether or not the assumption of proportional hazards is met. DESIGN: In this simulation study, the net chance of a longer survival by at least m months, where m months is considered clinically worthwhile and relevant to the patient, was calculated as the probability that a random patient in the treatment group has a longer survival by at least m months than does a random patient in the control group minus the probability of the opposite situation. The net chance of a longer survival is equal to zero if treatment does not differ from control and ranges from -100% if all patients in the control group fare better than all patients in the treatment group up to 100% in the opposite situation. We simulated data sets for realistic trials under various scenarios of proportional and nonproportional survival hazards and plotted the Kaplan-Meier survival curves as well as the net chance of a longer survival as a function of m. Data analysis was performed from August 14 to 18, 2015. MAIN OUTCOMES AND MEASURES: The net chance of a longer survival calculated for values of m ranging from 0 to 40 months. RESULTS: When hazards are proportional, the net chance of a longer survival approaches zero as m increases. The net chance of a longer survival (Delta) was 13% (95% CI, 6.5% 19.4%; P < .001) when any survival difference was considered clinically relevant (m = 0 months). When survival differences larger than 20 months were considered relevant (m = 20), the net chance of a longer survival was very close to zero (Delta[20] = 0.5%; 95% CI, -0.1% to 1.1%; P = .09). In contrast, when treatment effects are delayed or when some patients are cured by treatment, the net chance of a longer survival benefit remains high and tends to the cure rate. For crossing hazards, the Delta was negative (Delta = -6.9%; 95% CI, -14.0% to -0.5%; P = .047). However when large survival differences were considered (m = 20), the Delta(m) was positive (Delta[20] = 8.9%; 95% CI, 6.7%-11.1%; P < .001). CONCLUSIONS AND RELEVANCE: The net chance of a longer survival is useful whether or not the assumption of proportional hazards is met in the analysis of survival end points and may be helpful as a measure of treatment benefit that has direct relevance to patients and health care professionals. PMID- 27124211 TI - Quality of Life, Mood, and Prognostic Understanding in Patients with Metastatic Breast Cancer. AB - BACKGROUND: Although breast cancer is the second leading cause of cancer-related mortality in women in the United States, few studies focus on the supportive care needs of patients living with metastatic breast cancer (MBC). OBJECTIVE: We studied quality of life (QOL), depression, anxiety, and prognostic understanding of patients with MBC. DESIGN: We conducted a cross-sectional study of 140 patients with MBC, stratified by receipt of endocrine therapy or chemotherapy. MEASUREMENTS: We evaluated anxiety and depression using the Hospital Anxiety and Depression Scale (HADS). We assessed QOL using the Functional Assessment of Cancer Therapy-Breast (FACT-B), specifically measuring the FACT-B Trial Outcome Index (TOI), which includes physical and functional well-being and breast cancer specific symptoms. Higher FACT-B TOI scores represent better QOL. We used a 12 item questionnaire to assess patients' perceptions of their prognosis and goals of therapy. RESULTS: Compared to those taking endocrine therapy (n = 40), patients receiving chemotherapy (n = 100) reported lower scores on the FACT-B TOI (66.1 versus 72.5, p < 0.01) and more depression symptoms (HADS-D >7; 22% versus 7.5%, p = 0.03). Higher scores on the FACT-B TOI were associated with lower depression (beta, -0.16; p < 0.01) and anxiety (beta, -0.11; p < 0.01), and patients who reported frequent prognostic conversations with their oncologists had less depression (beta, -1.28; p < 0.01). Thirty-nine percent (54/140) reported that their cancer was likely curable. CONCLUSION: Patients with MBC, particularly those treated with chemotherapy, may benefit from interventions to address their physical, functional, and breast cancer-related symptoms. Many do not report accurate prognostic understanding, and more frequent prognostic conversations might address this information gap. PMID- 27124212 TI - Surveillance for Certain Health Behaviors, Chronic Diseases, and Conditions, Access to Health Care, and Use of Preventive Health Services Among States and Selected Local Areas?- Behavioral Risk Factor Surveillance System, United States, 2012. AB - PROBLEM: Chronic diseases (e.g., heart diseases, cancer, chronic lower respiratory disease, stroke, diabetes, and arthritis) and unintentional injuries are the leading causes of morbidity and mortality in the United States. Behavioral risk factors (e.g., tobacco use, poor diet, physical inactivity, excessive alcohol consumption, failure to use seat belts, and insufficient sleep) are linked to the leading causes of death. Modifying these behavioral risk factors and using preventive health services (e.g., cancer screenings and influenza and pneumococcal vaccination of adults aged >=65 years) can substantially reduce morbidity and mortality in the U.S. POPULATION: Continuous monitoring of these health-risk behaviors, chronic conditions, and use of preventive services are essential to the development of health promotion strategies, intervention programs, and health policies at the state, city, and county level. REPORTING PERIOD: January-December 2012. DESCRIPTION OF THE SYSTEM: The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing, state based, random-digit-dialed landline- and cellular-telephone survey of noninstitutionalized adults aged >=18 years residing in the United States. BRFSS collects data on health-risk behaviors, chronic diseases and conditions, access to health care, and use of preventive health services related to the leading causes of death and disability. This report presents results for all 50 states, the District of Columbia, participating U.S. territories that include the Commonwealth of Puerto Rico (Puerto Rico) and Guam, 187 Metropolitan/Micropolitan Statistical Areas (MMSAs), and 210 counties (n = 475,687 survey respondents) for the year 2012. RESULTS: In 2012, the estimated prevalence of health-risk behaviors, chronic diseases or conditions, access to health care, and use of preventive health services substantially varied by state and territory, MMSA, and county. The following portion of the abstract lists a summary of results by selected BRFSS measures. Each set of proportions refers to the range of estimated prevalence for health-risk behaviors, chronic diseases or conditions, and use of preventive health care services among geographical units, as reported by survey respondents. Adults with good or better health: 64.0%-88.3% for states and territories, 62.7%-90.5% for MMSAs, and 68.1%-92.4% for counties. Adults aged 18 64 years with health care coverage: 64.2%-93.1% for states and territories, 35.4% 93.7% for MMSAs, and 35.4%-96.7% for counties. Adults who received a routine physical checkup during the preceding 12 months: 55.7%-80.1% for states and territories, 50.6%-85.0% for MMSAs, and 52.4%-85.0% for counties. An influenza vaccination received during the preceding 12 months among adults aged >=65 years: 26.3%-70.1% for states and territories, 20.8%-77.8% for MMSAs, and 24.1%-77.6% for counties. Ever received pneumococcal vaccination among adults aged >=65 years: 22.2%-76.2% for states and territories, 15.3%-83.4% for MMSAs, and 25.8% 85.2% for counties. Adults who had a dental visit in the past year: 53.7%-76.2% for states and territories, and 44.8%-81.7% for MMSAs and counties. Adults aged >=65 years who have lost all of their natural teeth from tooth decay or gum disease: 7.0%-33.7% for states and territories, 5.8%-39.6% for MMSAs, and 5.8% 37.1% for counties. Adults aged 50-75 years who received a colorectal cancer screening on the basis of the U.S. Preventive Services Task Force recommendation: 40.0%-76.4% for states and territories, 47.1%-80.7% for MMSAs, and 47.0%-81.0% for counties. Women aged 21-65 years who had a Papanicolaou test during the preceding 3 years: 68.5% to 89.6% for states and territories, 70.3% to 92.8% for MMSAs, and 65.7%-94.6% for counties. Women aged 50-74 years who had a mammogram during the preceding 2 years: 66.5%- 89.7% for states and territories, 61.1% 91.5% for MMSAs, and 61.8%-91.6% for counties. Current cigarette smoking among adults: 10.6%-28.3% for states and territories, 5.1%-30.1% for MMSAs, and 5.1% 28.3% for counties. Binge drinking among adults during the preceding month: 10.2% 25.2% for states and territories, 6.2%-28.1% for MMSAs, and 6.2%-29.5% for counties. Heavy drinking among adults during the preceding month: 3.5%-8.5% for states and territories, 2.0%-11.0% for MMSAs, and 1.9%-11.0% for counties. Adults who reported no leisure-time physical activity: 16.3%-42.4% for states and territories, 9.2%-47.3% for MMSAs, and 9.2%-39.0% for counties. Self- reported seat belt use: 62.0%-93.7% for states and territories, 54.1%-97.1% for MMSAs, and 50.1%-97.4% for counties. Adults who were obese: 20.5%-34.7% for states and territories, 14.8%-44.5% for MMSAs and counties. Adults with diagnosed diabetes: 7.0%-16.4% for states and territories, 3.4%-17.4% for MMSAs, and 3.1%-17.4% for counties. Adults who ever had any type of cancer: 3.0%-13.7% for states and territories, 3.8%-19.2% for MMSAs, and 4.5%-19.2% for counties. Adults with current asthma: 5.8%-11.1% for states and territories, 3.1%-15.0% for MMSAs, and 3.1%-15.7% for counties. Adults with some form of arthritis: 15.6%-36.4% for states and territories, 16.8%-45.8% for MMSAs, and 14.8%-35.9% for counties. Adults having had a depressive disorder: 9.0%-23.5% for states and territories, 9.2%-28.3% for MMSAs, and 8.5%-28.4% for counties. Adults aged >=45 years who have had coronary heart disease: 7.4%-19.0% for states and territories, 6.1% 23.3% for MMSAs, and 6.1%-20.6% for counties. Adults aged >=45 years who have had a stroke: 3.1%-7.3% for states and territories, 2.1%-9.3% for MMSAs, and 1.5% 9.3% for counties. Adults with limited activities because of physical, mental, or emotional problems: 15.0%-28.6% for states and territories, 12.0%-31.7% for MMSAs, and 11.3%-31.7% for counties. Adults using special equipment because of any health problem: 4.8%-11.6% for states and territories, 4.0%-14.7% for MMSAs, and 2.8%-13.6% for counties. INTERPRETATION: This report underscores the need for continuous surveillance of health-risk behaviors, chronic diseases or conditions, health care access, and use of preventive care services at state and local levels. It will help to identify high-risk populations and to evaluate public health intervention programs and policies designed to reduce morbidity and mortality from chronic disease and injury. PUBLIC HEALTH ACTION: State and local health departments and agencies can continue to use BRFSS data to identify populations at high risk for unhealthy behaviors and chronic diseases or conditions, lack of health care access, and inadequate use of preventive care services. Additionally, states can use the data to design, implement, monitor, and evaluate public health programs and policies at state and local levels. PMID- 27124213 TI - Electro-assisted heterogeneous activation of persulfate by Fe/SBA-15 for the degradation of Orange II. AB - The removal of Orange II by activation of persulfate (S2O8(2-), PS) using synthesized Fe/SBA-15 in the electrochemical (EC) enhanced process was reported in this study. The reaction rate constants, degradation mechanism, catalyst stability, and evolution of mineralization and toxicity were detailed investigated. On the basis of radical scavenger results, both the sulfate radicals (SO4(-)) and hydroxyl radicals (OH) were responsible for the degradation of Orange II. A possible pathway is suggested to describe the degradation of Orange II according to the degradation intermediates identified. The results showed that the Fe/SBA-15 catalyst maintained strong reusability and stability with a low level of iron leaching. In addition, favorable mineralization efficiency in terms of COD removal efficiency (75.4%) and TOC removal efficiency (46.3%) was obtained when the reaction time was prolonged to 24h. The toxicity experiments implied that the toxicity of the treated solution ascended at the first 30min but then dropped to almost zero eventually. This study provides a proof-of-concept that can be applied widely for the PS remediation of contaminated water. PMID- 27124214 TI - Validity and repeatability of goniometry in normal horses. AB - PURPOSE: To assess validity and inter- and intra-tester reliability of equine goniometry and to establish values for carpal, metacarpophalangeal, tarsal, and metatarsophalangeal flexion and extension in horses. SUBJECTS: Seventeen healthy equine subjects of varied breeds were used. METHODS: Three investigators blindly and independently measured in triplicate the extension and flexion of carpal, metacarpophalangeal, tarsal, and metatarsophalangeal joints of 17 horses after sedation. Radiographs of these joints in flexion and extension were acquired while under sedation. Goniometric and radiographic measurements were compared statistically and were correlated. A Bland-Altman plot was constructed. Inter- and intra-tester repeatability of goniometry were evaluated by calculating intraclass correlation coefficients (ICC). Mean flexion and extension of carpal, metacarpophalangeal, tarsal, and metatarsophalangeal joints were calculated. RESULTS: Goniometric and radiographic measurements did not differ statistically and were significantly correlated (correlation coefficients ranged from 0.59 - 0.89). The mean difference between goniometric and radiographic measurements was 0.4 degrees . Triplicate measurements collected by the three raters did not differ significantly within raters (ICC ranging from 0.950 - 0.995) and between raters (ICC ranging from 0.942 - 0.989). CONCLUSION: Goniometry is a valid and repeatable tool for evaluation of the range of motion of carpal, metacarpophalangeal, tarsal, and metatarsophalangeal joints in standing, sedated healthy horses. PMID- 27124215 TI - Assessment of sleep disorders among patients with hypertension and coexisting metabolic syndrome. AB - PURPOSE: The coexistence of hypertension, abdominal obesity, and carbohydrate and lipid metabolism disturbances favors the acceleration of other disease entities - also apart from cardiovascular system disorders. This study was planned to estimate the relationship between the presence of metabolic syndrome and sleep disorders among a group of hypertensive patients. PATIENTS/METHODS: The study was conducted on unselected group of 261 patients from the Outpatient Hypertension Clinic. The standardized questionnaire was used to collect the data on medical history, prescribed drugs and lifestyle. Sleep disorders were diagnosed based on the Athens Insomnia Scale and STOP-Bang Questionnaire. According to the study protocol, anthropometric parameters (weight, height, waist and neck circumferences), blood pressure, serum lipids and fasting glucose laboratory measurements were performed. Metabolic syndrome was defined according to IDF criteria. RESULTS: Sleep disorders were recognized in 183 participants of the study - significantly more frequently (P=0.03) among patients with diagnosed metabolic syndrome (120; 75%) in comparison with participants without this disturbance (63; 62.38%). Male gender, poor financial situation, tingling sensations before falling asleep and combination therapy of hypertension significantly increased the risk of sleep disorder occurrence in the group of patients with metabolic syndrome. Night food intake, aging, hypertension combination therapy and poor socioeconomic status were the factors increasing the risk of sleep problems among participants without metabolic syndrome. CONCLUSIONS: Sleep disorders often coexist with metabolic syndrome in hypertensive patients. A number of factors increase the probability of occurrence of sleep disorders, but most of them are modifiable. PMID- 27124217 TI - Synchronization of Coupled Oscillators on a Two-Dimensional Plane. AB - The effect of the transfer rate of signal molecules on coupled chemical oscillators arranged on a two-dimensional plane was systematically investigated in this paper. A microreactor equipped with a surface acoustic wave (SAW) mixer was applied to adjust the transfer rate of the signal molecules in the microreactor. The SAW mixer with adjustable input powers provided a simple means to generate different mixing rates in the microreactor. A robust synchronization of the oscillators was found at an input radio frequency power of 20 dBm, with which the chemical waves were initiated at a fixed site of the oscillator system. With increasing input power, the frequency of the chemical waves was increased, which agreed well with the prediction given by the time-delayed phase oscillator model. Results from the finite element simulation agreed well with the experimental results. PMID- 27124216 TI - Co-transcriptional degradation by the 5'-3' exonuclease Rat1p mediates quality control of HXK1 mRNP biogenesis in S. cerevisiae. AB - The co-transcriptional biogenesis of export-competent messenger ribonucleoprotein particles (mRNPs) in yeast is under the surveillance of quality control (QC) steps. Aberrant mRNPs resulting from inappropriate or inefficient processing and packaging reactions are detected by the QC system and retained in the nucleus with ensuing elimination of their mRNA component by a mechanism that requires the catalytic activity of Rrp6p, a 3'-5' exonuclease associated with the RNA exosome. In previous studies, we implemented a new experimental approach in which the production of aberrant mRNPs is massively increased upon perturbation of mRNP biogenesis by the RNA-dependent helicase/translocase activity of the bacterial Rho factor expressed in S. cerevisiae. The analyses of a subset of transcripts such as PMA1 led us to substantiate the essential role of Rrp6p in the nuclear mRNP QC and to reveal a functional coordination of the process by Nrd1p. Here, we extended those results by showing that, in contrast to PMA1, Rho-induced aberrant HXK1 mRNPs are targeted for destruction by an Nrd1p- and Rrp6p-independent alternative QC pathway that relies on the 5'-3' exonuclease activity of Rat1p. We show that the degradation of aberrant HXK1 mRNPs by Rat1p occurs co transcriptionally following decapping by Dcp2p and leads to premature transcription termination. We discuss the possibility that this alternative QC pathway might be linked to the well-known specific features of the HXK1 gene transcription such as its localization at the nuclear periphery and gene loop formation. PMID- 27124218 TI - Preparation of Nanoscrolls by Rolling up Graphene Oxide-Polydopamine-Au Sheets using Lyophilization Method. AB - Graphene oxide-polydopamine-Au (GO-PDA-Au) nanoscrolls were prepared by rolling up GO-PDA-Au sheets through a simple lyophilization method. The structure of GO PDA-Au nanoscrolls and GO-PDA-Au sheets were compared by powder X-ray diffraction, Raman spectra, transmission electron microscopy, and scanning electron microscopy. The results demonstrated that the heterogeneous GO-PDA-Au nanoscrolls were synthesized successfully. Polydopamine (PDA) attached at the surface of GO sheets served as binding reagents to anchor and disperse Au nanoparticles (NPs). The electrocatalytic activity of methanol with GO-PDA-Au nanoscrolls and GO-PDA-Au sheets as electrodes were conducted. Compared to GO-PDA Au sheets, GO-PDA-Au nanoscrolls showed better electrocatalytic activity and electrochemical stability owing to their scrolled structure. This article provides a simple and effective method to prepare GO nanoscrolls containing metal NPs that broadens the applications of the graphene-based materials in optical, magnetic, and catalytic fields. PMID- 27124221 TI - Healing to fight. PMID- 27124219 TI - Evaluating the Impact of Uncertainties in Clearance and Exposure When Prioritizing Chemicals Screened in High-Throughput Assays. AB - The toxicity-testing paradigm has evolved to include high-throughput (HT) methods for addressing the increasing need to screen hundreds to thousands of chemicals rapidly. Approaches that involve in vitro screening assays, in silico predictions of exposure concentrations, and pharmacokinetic (PK) characteristics provide the foundation for HT risk prioritization. Underlying uncertainties in predicted exposure concentrations or PK behaviors can significantly influence the prioritization of chemicals, though the impact of such influences is unclear. In the current study, a framework was developed to incorporate absorbed doses, PK properties, and in vitro dose-response data into a PK/pharmacodynamic (PD) model to allow for placement of chemicals into discrete priority bins. Literature reported or predicted values for clearance rates and absorbed doses were used in the PK/PD model to evaluate the impact of their uncertainties on chemical prioritization. Scenarios using predicted absorbed doses resulted in a larger number of bin misassignments than those scenarios using predicted clearance rates, when comparing to bin placement using literature-reported values. Sensitivity of parameters on the model output of toxicological activity was examined across possible ranges for those parameters to provide insight into how uncertainty in their predicted values might impact uncertainty in activity. PMID- 27124222 TI - Accreditation and implications of clinical postgraduate PA training programs. AB - No consensus definition exists for postgraduate physician assistant (PA) training. This report from the AAPA Task Force on Accreditation of Postgraduate PA Training Programs describes the types of clinical training programs and their effects on hiring and compensation of PAs. Although completing a postgraduate program appears to have no effect on compensation, PAs who complete these programs may be favored in the hiring process and frequently report greater confidence in their skills. More research is needed and program accreditation is key to monitoring the effectiveness of these programs. PMID- 27124225 TI - Letters to the Editor. PMID- 27124223 TI - The education, role, distribution, and compensation of physician assistants in orthopedic surgery. AB - Physician assistants (PAs) have worked alongside surgeons since the 1970s, yet little is known about their postgraduate education, roles, distribution, and compensation. In 2015, an estimated 8,900 PAs were employed in orthopedics (9.4% of all clinically active PAs in the United States). This study analyzed surveys undertaken by Physician Assistants in Orthopaedic Surgery (PAOS) from 2009 to 2015 and found that most PAs working in orthopedics (85%) reported regularly assisting in surgery. Demand for PAs in orthopedics is expected to grow because of population growth, increasing incidence of musculoskeletal conditions, shortages of surgeons, and changing technology. Improved data acquisition and more detailed analyses are needed to better understand the nature of this specialized workforce. PMID- 27124226 TI - When should a provider consider insulin human inhalation powder? AB - Insulin human inhalation powder, a rapid-acting inhaled insulin, was approved by the FDA in June 2014 for patients with type 1 or type 2 diabetes. For patients reluctant to start insulin therapy because of fear of injections, insulin human inhalation powder may be an alternative. This article discusses appropriate dosing, use, and monitoring. PMID- 27124227 TI - Recognizing Charcot disease in a man with diabetes. AB - Charcot disease is a neurogenic osteoarthropathy that occurs in the foot and ankle following the loss of normal muscle tone, vascularization, and protective reflexes. Diabetes is its most common cause in the Western world. Fragmentation, destruction, and dislocation of the bones can occur spontaneously or after trauma. This article describes the care of a patient with Charcot disease. PMID- 27124228 TI - A rare case of iron-deficiency anemia rapidly progressing to a life-threatening event. AB - Giant colonic diverticula are extremely rare; however, they should be considered in a patient with a history or susceptibility to diverticular disease because of the nonspecific presentation and life-threatening complications. Giant colonic diverticula often are overlooked because of their nonspecific gastrointestinal (GI) symptoms, leading to complications of obstruction, perforation, abscess formation, and sepsis. A rare and unusual presentation of a giant colonic diverticulum is the development of a bezoar. This case describes a patient whose GI bleeding led to the diagnosis of a giant colonic diverticulum with a bezoar. PMID- 27124229 TI - Peritoneal dialysis: An effective yet underused renal replacement therapy. AB - Chronic kidney disease affects more than 30 million people in the United States, creating a significant disease burden. Peritoneal dialysis, an effective yet underused method of renal replacement therapy, can provide a high quality of life, maintain a patient's residual renal function, and decrease overall healthcare costs with little negative effect on patient morbidity or mortality. Given this, knowledge of the methods, outcomes, and costs of renal replacement therapy is essential to physician assistants. PMID- 27124230 TI - The National Ambulatory Medical Care Survey: PAs and NPs in outpatient surgery. AB - BACKGROUND: This study aimed to determine the prevalence and occupational characteristics of physician assistants (PAs) and nurse practitioners (NPs) in outpatient surgical subspecialty clinics. METHODS: The 2007 and 2008 National Ambulatory Medical Care Survey (NAMCS) databases were queried for the number and characteristics of office visits seen by different provider types (PAs or NPs, physicians, or both) in various surgical subspecialties. RESULTS: More than 250 million weighted sample visits were analyzed. PAs or NPs were involved in 5.9% of visits, though the percentage of patients seen by them alone (1.1%) was significantly lower (P<0.0001). PAs and NPs were more likely to be involved in pre- or postoperative visits, and often saw the same diagnoses alone as physicians only. The most common procedures performed by PAs and NPs varied according to subspecialty. CONCLUSIONS: PAs and NPs have a minor prevalence in the ambulatory surgical workforce during the time period studied. Further integration of these providers into the outpatient setting may help optimize efficiency in ambulatory surgical care. PMID- 27124231 TI - Small bowel obstruction. PMID- 27124232 TI - Abdominal injury after a fall. PMID- 27124233 TI - A progressive pruritic rash with blisters. AB - This article describes a patient with a progressive pruritic rash and fluid filled blisters. A punch biopsy later confirmed the diagnosis of bullous pemphigoid, an inflammatory condition that most commonly occurs in older adults and is treated with corticosteroids. PMID- 27124234 TI - What is causing this man's persistent low back pain? PMID- 27124235 TI - Like home. PMID- 27124237 TI - Bioinspired Total Syntheses of Isospongian-type Diterpenoids (-)-Kravanhins A and C. AB - The first bioinspired total syntheses of (-) kravanhins A and C were accomplished from a labdane diterpenoid derivative. The key reactions involve a photooxidation and a one-pot sequential aldol cyclization and lactonization, which provide a new plausible biosynthetic pathway for the kravanhins and other symbiotic members. PMID- 27124238 TI - Hydration-Induced Phase Transitions in Surfactant and Lipid Films. AB - For several surfactant and lipid systems, it is crucial to understand how hydration influences the physical and chemical properties. When humidity changes, it affects the degree of hydration by adding or removing water molecules. In many cases, this process induces transitions between liquid crystalline phases. This phenomenon is of general interest for numerous applications simply because of the fact that humidity variations are ubiquitous. Of particular interest are hydration-induced phase transitions in amphiphilic films, which in many cases appear as the frontier toward a vapor phase with changing humidity. Considering this, it is important to characterize the film thickness needed for the formation of 3D liquid crystalline phases and the lyotropic phase behavior of this kind of film. In this work, we study this issue by employing a recently developed method based on the humidity scanning quartz crystal microbalance with dissipation monitoring (HS QCM-D), which enables continuous scanning of the film hydration. We investigate five surfactants films (DDAO, DTAC, CTAC, SDS, and n-octylbeta-d glucoside) and one lipid film (monoolein) and show that HS QCM-D enables the fast characterization of hydration-induced phase transitions with small samples. Film thicknesses range from tens to hundreds of nanometers, and clear phase transitions are observed in all cases. It is shown that phase transitions in films occur at the same water activities as for corresponding bulk samples. This allows us to conclude that surfactant and lipid films, with a thickness of as low as 50 nm, are in fact assembled as 3D-structured liquid crystalline phases. Furthermore, liquid crystalline phases of surfactant films show liquidlike behavior, which decreases the accuracy of the absorbed water mass measurement. On the other hand, the monoolein lipid forms more rigid liquid crystalline films, allowing for an accurate determination of the water sorption isotherm, which is also true for the sorption isotherms corresponding to the solid surfactant phases. PMID- 27124236 TI - Catalyst-Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones. AB - Medicinally relevant spirocyclic indolenines, carbazoles and quinolines can each be directly synthesised selectively from common indolyl ynone starting materials by catalyst variation. The high yielding, divergent reactions all proceed by an initial dearomatising spirocyclisation reaction to generate an intermediate vinyl metal species, which then rearranges selectively by careful choice of catalyst and reaction conditions. PMID- 27124239 TI - Erratum for: Combined LC/UV/MS and NMR Strategies for the Dereplication of Marine Natural Products. PMID- 27124240 TI - LC-MS-Based Quality Assessment of a Traditional Chinese Medicine YANG XIN Formulation. AB - YANG XIN is a traditional Chinese medicine formulation used for nervous fatigue and consists of a proprietary blend of concentrated extracts from 18 plant ingredients. The 18 constituent plant ingredients, YANG XIN capsules, and formulations 2014-005_1 A and 1B were extracted by consecutive 24-hour macerations with dichloromethane followed by methanol. Metabolite separation was carried out through LC-MS in 40 minutes. Data acquisitions for qualitative and quantitative analyses of the samples were collected under (+/-) ESI modes and (+) APCI mode using full spectrum scan analysis.A total of 18 analytical markers were identified by LC-MS for YANG XIN formulations based on accurate mass measurements, molecular formula, double bond equivalent, MFG score, and error (ppm) of the measurement. Aditionally, a comparison of the data with previously reported results for the compounds, followed by identity confirmation with standard compounds, was performed. Seventeen analytical markers representing 17 plant ingredients in the different YANG XIN formulations were quantified for the first time. The YANG XIN capsules and the 2014-005_1B formulation were similar to each other and different from the 2014-005_1 A formulation based on the fact that both YANG XIN capsules and the 2014-005_1B formulation contain the same analytical markers. This method provides good linearity (r(2) > 0.9945), intraday precision (R. S. D. < 3.9 %), interday precision (R. S. D. < 5.6 %), accuracy (99.2-101 %), recovery (145.7 %), limit of detection (0.0011-0.0732 ug/mL), and limit of quantitation (0.0038-0.2441 ug/mL). PMID- 27124241 TI - Pharmacological and Toxicological Studies of Essential Oil of Lavandula stoechas subsp. luisieri. AB - The present study was carried out to evaluate the chemical and pharmacological properties of the essential oil of Lavandula stoechas subsp. luisieri, which is a spontaneous shrub widespread in Alentejo (Portugal). Oxygenated monoterpenes, such as 1,8-cineole, lavandulol, and necrodane derivatives, are the main components of essential oil. It revealed important antioxidant activity with a high ability to inhibit lipid peroxidation and showed an outstanding effect against a wide spectrum of microorganisms, such as gram-positive and gram negative bacteria and pathogenic yeasts. The analgesic effect studied in rats was dose dependent, reaching a maximum of 67 % at 60 min with the dose of 200 mg/kg and the anti-inflammatory activity with this dose caused an inhibition in carrageenan-induced rat paw oedema (83 %) that is higher than dexamethasone 1 mg/Kg (69 %). Besides, animals exhibited normal behaviour after essential oil administration, revealing low toxicity. The essential oil of L. luisieri from Alentejo presents important pharmacological properties and low toxicity, and is a promised candidate to be used as a food supplement or in pharmaceutical applications. PMID- 27124242 TI - alpha-Terpineol Induces Gastric Retention of Liquids by Inhibiting Vagal Parasympathetic Pathways in Rats. AB - alpha-Terpineol is a monoterpene with smooth muscle relaxant properties. In this study, its effects on the gastric emptying rate of awake rats were evaluated with emphasis on the mode by which it induces gastrointestinal actions. Administered by gavage, alpha-terpineol (50 mg/kg) delayed gastric emptying of a liquid test meal at 10 min postprandial. Hexamethonium or guanethidine did not interfere with the retarding effect induced by alpha-terpineol, but atropine and L-NG nitroarginine methyl ester abolished it. In vagotomized rats, alpha-terpineol did not delay gastric emptying. In isolated strips of gastric fundus, concentration effect curves in response to carbamylcholine were higher in magnitude after treatment with the monoterpene. alpha-Terpineol (1 to 2000 uM) relaxed sustained contractions induced by carbamylcholine or a high K+ concentration in a concentration-dependent manner. This relaxing effect was not affected by the presence of L-NG-nitroarginine methyl ester, 1 H-[1, 2, 4]oxadiazolo[4,3 a]quinoxalin-1-one, tetraethylammonium, or atropine. Smooth muscle contractions induced by electrical field stimulation were inhibited by alpha-terpineol. In conclusion, alpha-terpineol induced gastric retention in awake rats through mechanisms that depended on intact vagal innervation to the stomach, which involved cholinergic/nitrergic signalling. Such a retarding effect induced by alpha-terpineol appears not to result from a direct action of the monoterpene on gastric smooth muscle cells. PMID- 27124243 TI - Characterization of the Volatile and Nonvolatile Fractions of Heartwood Aqueous Extract from Pterocarpus marsupium and Evaluation of Its Cytotoxicity against Cancer Cell Lines. AB - Pterocarpus marsupium is a well-known plant due to its healing properties, in particular, the use of its aqueous extract is able to reduce blood sugar levels and blood triglyceride concentrations. Although this plant has already been widely studied, a complete characterization of its aqueous extract has not been reported. The present study deals with the characterization of the aqueous extract of P. marsupium in order to obtain a full fingerprint of the volatile and nonvolatile constituents. The volatile constituents were identified by CG-MS, whereas the nonvolatile fraction was characterized by UHPLC-MS/MS using a nontarget approach. Several compounds were identified, in particular, polyphenolic species belonging to the class of proanthocyanidins. Cytotoxicity tests were carried out on four different cancer cell lines and three different non-tumoral cell lines. Preliminary results indicate a selective cytotoxicity of the aqueous extract towards the cancer cells. The potential cytotoxicity due to the presence of metals in the aqueous extract was ruled out by testing an aqueous mixture of the metals at the same concentration found in the P. marsupium extract. PMID- 27124244 TI - Pharmacokinetics of Compound D, the Major Bioactive Component of Zingiber cassumunar, in Rats. AB - Rhizomes of Zingiber cassumunar have been used for many years in traditional Thai medicine as an anti-inflammatory agent. The major bioactive component of this plant is Compound D [E-4-(3', 4'-dimethoxyphenyl)but-3-en-1-ol], which is a strong smooth muscle relaxant, and has antihistamine and anti-inflammatory actions. There is, however, incomplete information available for the pharmacokinetics of Compound D in mammals. In this study, we examined the pharmacokinetic profiles of Compound D in male Wistar rats. A standardized extract of Z. cassumunar containing 4 % w/w Compound D was administered intravenously at 25 mg/kg or by oral gavage at 25, 75, or 250 mg/kg to Wistar rats. Blood, tissues, urine, and feces were collected from 0 to 48 h after dosing and the level of Compound D was determined by liquid chromatography-tandem mass spectrometry. The concentration of Compound D ranged from 10-100 ug/L, reached a maximum approximately 0.15 h after oral dosing. Compound D exhibited an excellent tissue to plasma ratio, ranging from 1- to 1000 in several organs at 1-4 h after oral dosing. Less than 1 % of unchanged Compound D was excreted in the urine and feces. Further studies on tissue uptake and metabolite identification are required to obtain complete pharmacokinetic information and to develop appropriate dosing strategies of Compound D and the standardized extract of Z. cassumunar. PMID- 27124245 TI - Antiplasmodial and Cytotoxic Activity of Raw Plant Extracts as Reported by Knowledgeable Indigenous People of the Amazon Region (Vaupes Medio in Colombia). AB - The in vitro antiplasmodial activity of 122 raw extracts prepared in ethanol and water from 35 medicinal plants reported by the Cubeo indigenous village of the Amazon region (Vaupes Medio in Colombia) was evaluated for efficacy against 3D7 (sensitive to chloroquine) and FCR-3 (resistant to chloroquine) Plasmodium falciparum strains. Five percent of these extracts presented a significant antiplasmodial activity (< 5 ug/mL) and 83 % of them were not cytotoxic. These findings highlight the importance of investigating traditional medicinal plants implemented by these ancestral communities of the Amazon region as well as their potential to become a source of new drugs against malaria. PMID- 27124246 TI - Nanostructured Lipid Carriers (NLC) as Vehicles for Topical Administration of Sesamol: In Vitro Percutaneous Absorption Study and Evaluation of Antioxidant Activity. AB - Sesamol is a natural phenolic compound extracted from Sesamum indicum seed oil. Sesamol is endowed with several beneficial effects, but its use as a topical agent is strongly compromised by unfavorable chemical-physical properties. Therefore, to improve its characteristics, the aim of the present work was the formulation of nanostructured lipid carriers as drug delivery systems for topical administration of sesamol.Two different nanostructured lipid carrier systems have been produced based on the same solid lipid (Compritol(r) 888 ATO) but in a mixture with two different kinds of oil phase such as Miglyol(r) 812 (nanostructured lipid carrier-M) and sesame oil (nanostructured lipid carrier PLUS). Morphology and dimensional distribution of nanostructured lipid carriers have been characterized by differential scanning calorimetry and photon correlation spectroscopy, respectively. The release pattern of sesamol from nanostructured lipid carriers was evaluated in vitro determining drug percutaneous absorption through excised human skin. Furthermore, an oxygen radical absorbance capacity assay was used to determine their antioxidant activity.From the results obtained, the method used to formulate nanostructured lipid carriers led to a homogeneous dispersion of particles in a nanometric range. Sesamol has been encapsulated efficiently in both nanostructured lipid carriers, with higher encapsulation efficiency values (> 90 %) when sesame oil was used as the oil phase (nanostructured lipid carrier-PLUS). In vitro evidences show that nanostructured lipid carrier dispersions were able to control the rate of sesamol diffusion through the skin, with respect to the reference formulations.Furthermore, the oxygen radical absorbance capacity assay pointed out an interesting and prolonged antioxidant activity of sesamol, especially when vehiculated by nanostructured lipid carrier-PLUS. PMID- 27124247 TI - Application of MALDI Mass Spectrometry in Natural Products Analysis. AB - This article presents the utility of mass spectrometry with a MALDI ionization source in natural products analysis. The advantages and drawbacks of this technique for natural products analyses will be presented and discussed. In addition, the structural determination of secondary metabolites using MALDI-MS/MS will be explored, which can guide MALDI experimental methods and stimulate new research in this area. Finally, several important approaches for MALDI data processing will be discussed. PMID- 27124248 TI - May bed rest cause greater muscle loss than limb immobilization? PMID- 27124249 TI - Gene Expression Classifier Testing and the Surgical Decision-Making Process for Patients With Thyroid Nodules. PMID- 27124250 TI - Manganese-Mediated C-H Alkylation of Unbiased Arenes Using Alkylboronic Acids. AB - The alkylation of arenes is an essential synthetic step of interest not only from the academic point of view but also in the bulk chemical industry. Despite its limitations, the Friedel-Crafts reaction is still the method of choice for most of the arene alkylation processes. Thus, the development of new strategies to synthesize alkyl arenes is a highly desirable goal, and herein, we present an alternative method to those conventional reactions. Particularly, a simple protocol for the direct C-H alkylation of unbiased arenes with alkylboronic acids in the presence of Mn(OAc)3 ?2H2 O is reported. Primary or secondary unactivated alkylboronic acids served as alkylating agents for the direct functionalization of representative polyaromatic hydrocarbons (PAHs) or benzene. The results are consistent with a free-radical mechanism. PMID- 27124251 TI - Determination of reference range of gamma glutamyl transferase in the neonatal intensive care unit. AB - OBJECTIVE: We aimed to establish the reference range of gamma glutamyl transferase (GGT) in the first week of life at each gestational age (GA). METHODS: This retrospective study included infants born and admitted before 7 days of age with no apparent congenital liver disease during four consecutive years. Early GGT levels measured at 3-7 days of age were analyzed according to GA. Differences according to sex, mode of delivery, small for gestational age, and the predictability for cholestasis were analyzed. RESULTS: We analyzed early GGT values in 2091 neonates. The average reference value in neonates (156.7 +/- 98.2 IU/L) was much higher than that in adults. The GGT values were significantly higher in preterm than in term infants and in male infants than in female infants. Mode of delivery and small for gestational age were not significantly related to GGT level. Early GGT had no predictive value for cholestasis occurrence. CONCLUSIONS: Early GGT levels were much higher in neonates, especially preterm infants with GA of 31-35 weeks. PMID- 27124252 TI - Science Publishing, Social Media, and Nursing Research on Facebook and Twitter. PMID- 27124253 TI - A Grounded Theory Study of How Nurses Integrate Pregnancy and Full-Time Employment: Becoming Someone Different. AB - BACKGROUND: A holistic exploration of the experience of how nurses integrate pregnancy and employment is lacking among the global nursing literature. OBJECTIVE: The purpose of this research was to explore how primiparous U.S. nurses integrated pregnancy and full-time employment. METHODS: Using a grounded theory approach, 20 nurses from the United States, who were pregnant and delivered their first baby-while employed full time on 12-hour work shifts provided a firsthand account of how they incorporated pregnancy with professional nursing employment. RESULTS: The basic social process, "becoming someone different," emerged to explain how U.S. nurses integrated pregnancy and full-time employment in early and late stages. Four core categories were: (a) "looking different, feeling different,"(b) "expectations while expecting," (c) "connecting differently," and (d) "transitioning labor." DISCUSSION: Within early and late stages, pregnant nurses becoming someone different navigate through various social interactions with peers and patients alike, with meaning assigned to those experiences. Research with pregnant nurses from other countries, nurses working in settings other than acute care, and multiparous nurses is needed to further expand on these findings. PMID- 27124255 TI - Evaluation of the Dogs, Physical Activity, and Walking (Dogs PAW) Intervention: A Randomized Controlled Trial. AB - BACKGROUND: To facilitate physical activity (PA) adoption and maintenance, promotion of innovative population-level strategies that focus on incorporating moderate-intensity lifestyle PAs are needed. OBJECTIVE: The purpose of this randomized controlled trial was to evaluate the Dogs, Physical Activity, and Walking intervention, a 3-month, social cognitive theory (SCT), e-mail-based PA intervention. METHODS: In a longitudinal, repeated-measures design, 49 dog owners were randomly assigned to a control (n = 25) or intervention group (n = 24). The intervention group received e-mail messages (twice weekly for 4 weeks and weekly for 8 weeks) designed to influence SCT constructs of self-efficacy, self regulation, outcome expectations and expectancies, and social support. At baseline and every 3 months through 1 year, participants completed self-reported questionnaires of individual, interpersonal, and PA variables. Linear mixed models were used to assess for significant differences in weekly minutes of dog walking and theoretical constructs between groups (intervention and control) across time. To test self-efficacy as a mediator of social support for dog walking, tests for mediation were conducted using the bootstrapping technique. RESULTS: With the exception of Month 9, participants in the intervention group accumulated significantly more weekly minutes of dog walking than the control group. On average, the intervention group accumulated 58.4 more minutes (SD = 18.1) of weekly dog walking than the control group (p < .05). Self-efficacy partially mediated the effect of social support variables on dog walking. DISCUSSION: Results indicate that a simple SCT-based e-mail intervention is effective in increasing and maintaining an increase in dog walking among dog owners at 12-month follow-up. In light of these findings, it may be advantageous to design dog walking interventions that focus on increasing self-efficacy for dog walking by fostering social support. PMID- 27124254 TI - Drug Use and Multiple Sex Partners Among Homeless Ex-Offenders: Secondary Findings From an Experimental Study. AB - BACKGROUND: Transitioning into society after release from incarceration presents real challenges for male offenders; in California, up to 60% return to prison within 3 years after release. The risk for ongoing drug use and having sex with multiple partners is a significant challenge for ex-offenders preparing to enter the community. OBJECTIVES: The aims are to describe drug use and sexual behavior (sex with multiple partners) prior to incarceration and 6 and 12 months after study enrollment using data obtained as part of a randomized controlled trial. METHODS: This is a planned secondary analysis of data obtained as part of a randomized controlled trial designed to study the effects of intensive peer coaching and nurse case management, intensive peer coaching, and brief nurse counseling on hepatitis A and B vaccination adherence compared to a usual care control treatment that also included brief peer coaching and brief nurse counseling. Self-report data from subjects enrolled at one residential drug treatment facility in Los Angeles were captured at three time points: baseline and 6- and 12-month follow-up. RESULTS: Findings showed substantive and significant reductions in drug use and engaging in sex with multiple partners 6 months after enrollment into the study compared to the baseline data, but results did not differ by study condition. At 12-month follow-up, drug use and sex with multiple partners increased but remained less than at baseline levels. DISCUSSION: Sustaining reductions in drug use and engaging in sex with multiple partners remains a challenge after incarceration. PMID- 27124256 TI - Self-Care Behaviors of Nepalese Adults With Type 2 Diabetes: A Mixed Methods Analysis. AB - BACKGROUND: Most previously reported literature on diabetes self-care is either solely quantitative or qualitative research conducted in developed countries; findings may not be generalizable to developing countries with different sociodemographic and cultural factors. PURPOSE: The study aims to develop an explanatory mediation model for self-care and enhance model interpretation through qualitative input. METHODS: A quantitatively driven, sequential, mixed method design was used. Structured questionnaires were used to collect data for the quantitative component from 230 participants. Participants for the qualitative interview were selected using maximum variation sampling (n = 13), and interviewing was guided by semistructured questions. RESULTS: Diabetes management self-efficacy had the strongest influence on diabetes self-care (standardized path coefficient = .42, p < .001), followed by perceived social support (standardized path coefficient = .26, p < .001), and educational status (standardized path coefficient = -.22, p < .001). Diabetes management self efficacy significantly and partially mediated the relationship between diabetes duration and diabetes self-care (Sobel's z = 2.65, p < .001) and between expectation regarding aging and diabetes self-care (Sobel's z = 3.03, p < .001). Perceived social support significantly and partially mediated the relation between educational status and diabetes self-care (Sobel's z = -2.81, p < .001). The qualitative component elucidated nine themes interwoven in Nepalese culture, social structure, and religious belief. Responsibilities toward family and belief in God acted as boosters for self-care in the case of Nepalese adults, which differed by age, gender, and literacy status. DISCUSSION: The results from this study suggest that tailored psychosocial interventions to promote diabetes management self-efficacy may be beneficial in promoting self-care among Nepalese adults with diabetes mellitus. PMID- 27124257 TI - Oral Health Status of Older Adults in Sweden Receiving Elder Care: Findings From Nursing Assessments. AB - BACKGROUND: Frail elderly people often have poor oral hygiene, contributing to oral health problems that can detract significantly from quality of life. OBJECTIVE: The aim of this study was to describe oral health status of frail elderly individuals using the Revised Oral Assessment Guide-Jonkoping (ROAG-J), a mouth assessment instrument that can be used in daily nursing care. METHODS: Data were obtained from the Swedish Senior Alert quality registry in one Swedish municipality. ROAG-J assessments on admission to elder care and one subsequent occasion were used. ROAG-J measurements documented oral health in nine areas: voice, lips, oral mucosa, tongue, gums, teeth, saliva, swallowing, and presence of any prostheses or implants. Assessments were made by nursing staff during the course of daily nursing care. RESULTS: Individuals 65 years of age or older and receiving elder care services (N = 667) were involved; 1,904 assessments made between November 2011 and March 2014 were used for the analysis. On the basis of both assessments, less than one third of participants had oral health problems. No significant difference in any of the oral health variables was found between first and subsequent assessments. At first assessment, men and women differed in tongue health (p < .01); at the subsequent assessment, gender differences in voice (p < .05), mucous membranes (p < .003), tongue (p < .01), and saliva (p < .006) were observed. DISCUSSION: Most participants had good oral health. Assessments made by nursing staff using the ROAG-J demonstrate that this tool can be used in daily nursing care, where different, important oral conditions may be encountered. However, knowledge about oral health conditions and the ROAG-J instrument is important to ensure high validity. The ROAG-J enables nursing staff to detect problems in the mouth and to guide decisions related to oral health interventions. PMID- 27124258 TI - Neurobiological Basis of Insight in Schizophrenia: A Systematic Review. AB - BACKGROUND: Insight in schizophrenia is defined as awareness into illness, symptoms, and need for treatment and has long been associated with cognition, other psychopathological symptoms, and several adverse clinical and functional outcomes. However, the biological basis of insight is not clearly understood. OBJECTIVE: The aim of this systematic review was to critically evaluate and summarize advances in the study of the biological basis of insight in schizophrenia and to identify gaps in this knowledge. METHODS: A literature search of PubMed, CINAHL, PsycINFO, and EMBASE databases was conducted using search terms to identify articles relevant to the biology of insight in schizophrenia published in the last 6 years. Articles that focused on etiology of insight in schizophrenia and those that examined the neurobiology of insight in schizophrenia or psychoses were chosen for analysis. Articles on insight in conditions other than schizophrenia or psychoses and which did not investigate the neurobiological underpinnings of insight were excluded from the review. RESULTS: Twenty-six articles met the inclusion criteria for this review. Of the 26 articles, 3 focused on cellular abnormalities and 23 were neuroimaging studies. Preliminary data identify the prefrontal cortex, cingulate cortex, and regions of the temporal and parietal lobe (precuneus, inferior parietal lobule) and hippocampus as the neural correlates of insight. DISCUSSION: A growing body of literature attests to the neurobiological basis of insight in schizophrenia. Current evidence supports the neurobiological basis of insight in schizophrenia and identifies specific neural correlates for insight types and its dimensions. Further studies that examine the precise biological mechanisms of insight are needed to apply this knowledge to effective clinical intervention development. PMID- 27124259 TI - A Review of Worldwide Patents: Innovations in Peak Flow Meters for Asthma. AB - BACKGROUND: Contemporary healthcare nurses increasingly rely on innovative technology for assessment, treatment, and patient self-management. Funding opportunities as well are increasingly steering toward technology development and innovation. Health researchers, including nursing scientists, who are engaged in medical device innovation need to assess the state of the art of current technology. This requires an intellectual property analysis, or patent search, which is not covered by the types of literature reviews customarily used in health science research. PURPOSE: The purposes of this article are to illustrate a methodical review of worldwide patents and to show how those results can be used to identify possible products available for use. APPROACH: An application of peak flow meters for use by patients with asthma is used to illustrate the process. The Derwent Innovations Index interface with keyword searching is illustrated, as is the use of Google Patents. From the 14 patent document results, six possible technologies were identified. The patent search revealed innovations in asthma peak flow meters for use in future research and identified future directions for device development. DISCUSSION: These results support the claim that patent literature must be included in reviews that seek to identify technology state-of-the-art healthcare applications and that advances in the nursing research paradigm should include patents as background and scholarly products. PMID- 27124261 TI - Formation of Two-Dimensional Copper Selenide on Cu(111) at Very Low Selenium Coverage. AB - Using scanning tunneling microscopy (STM), we observed that adsorption of Se on Cu(111) produced islands with a (?3*?3)R30 degrees structure at Se coverages far below the structure's ideal coverage of 1/3 monolayer. On the basis of density functional theory (DFT), these islands cannot form due to attractive interactions between chemisorbed Se atoms. DFT showed that incorporating Cu atoms into the ?3 Se lattice stabilizes the structure, which provided a plausible explanation for the experimental observations. STM revealed three types of ?3 textures. We assigned two of these as two-dimensional layers of strained CuSe, analogous to dense planes of bulk klockmannite (CuSe). Klockmannite has a bulk lattice constant that is 11 % shorter than ?3 times the surface lattice constant of Cu(111). This offers a rationale for the differences observed between these textures, for which strain limits the island size or distorts the ?3 lattice. STM showed that existing step edges adsorb Se and facet toward ?12? 1?, which is consistent with DFT. PMID- 27124260 TI - Feasibility of Hair Collection for Cortisol Measurement in Population Research on Adolescent Health. AB - BACKGROUND: Black-White disparities in adolescent health are widespread and thought to be explained, in part, by exposure to chronic stress. Cortisol assayed from hair is increasingly recognized as a valid and reliable measure for chronic physiological stress, but the feasibility of collecting hair among large probability samples of diverse adolescents is unknown. PURPOSE: The aim of the study was to investigate participation in hair collection for cortisol analyses in a probability sample of racially and socioeconomically diverse adolescents, including the extent to which sociodemographic factors and adverse exposures were associated with participation. METHODS: The study included a probability sample of 516 adolescents conducted in conjunction with a prospective cohort study on adolescent health. Data were collected over 1 week via in-home interviews, ecological momentary assessment, global positioning system methods, and in-home hair collection at the end of the week. RESULTS: Of the 516 eligible youth, 471 (91.3%) participated in the hair collection. Of the 45 youth who did not provide hair samples, 18 had insufficient hair, 25 refused, and 2 did not participate for unknown reasons. Multivariable logistic regression results indicated that non Hispanic Black youth were less likely than their non-Hispanic White peers to participate due to insufficient hair or refusal (OR = 0.24, 95% CI [0 .09, 0.60]). Despite lower rates of participation, the proportion of Black youth in the participating sample was representative of the study area. No significant differences in participation were found by other sociodemographic characteristics or adverse exposures. CONCLUSIONS: Hair collection for cortisol measurement is feasible among a probability sample of racially and socioeconomically diverse adolescents. Hair cortisol analyses may accelerate research progress to understand the biological and psychosocial bases of health disparities. PMID- 27124262 TI - Tyranny of the randomised clinical trial. AB - Researchers and clinicians often disagree about what it means to provide the best possible care. This paper's purpose is to propose ways of resolving the disagreements. The first is to have both groups re-examine the three equal components of evidence-based practice, a re-examination that begins with rejection of the randomised clinical trial's tyranny. The second is for researchers to design rehabilitation research based on a biopsychosocial rather than a biomedical model. The third is for both groups to redefine translational research so that it means both translation from the laboratory to the clinic and from the clinic to the laboratory. The fourth is to advocate for a science of dissemination that is as robust as rehabilitation's present science of discovery. Most examples are drawn from the literature on acquired neurologic speech and language disorders. PMID- 27124264 TI - Remote effects of lower limb stretching: preliminary evidence for myofascial connectivity? AB - The skeletal muscles and the fibrous connective tissue form an extensive, body wide network of myofascial chains. As fascia can modify its stiffness, strain transmission along these meridians is supposable. The goal of this trial therefore was to collect pilot data for potential remote effects of lower limb stretching on cervical range of motion (ROM). Twenty-six healthy participants (30 +/- 6 years) were included in the matched-pairs intervention study. One group (n = 13) performed three 30 s bouts of static stretching for the gastrocnemius and the hamstrings, respectively. An age- and sex-matched control group (CG; n = 13) remained inactive. Pre- and post-intervention, maximal cervical ROM in flexion/extension was assessed. A repeated measures ANOVA revealed systematic differences between groups (P < .05). ROM increased following stretching (143.3 +/- 13.9 to 148.2 +/- 14 degrees ; P < .05) but remained unchanged in the CG (144.6 +/- 16.8 to 143.3 +/- 16.8 degrees ; P > .05). Our data point towards existence of a strain transfer along myofascial meridians. Further randomised controlled studies on conditions, factors and magnitude of tensile transmission are warranted. PMID- 27124263 TI - Zn or O? An Atomic Level Comparison on Antibacterial Activities of Zinc Oxides. AB - For the first time, the influence of different types of atoms (Zn and O) on the antibacterial activities of nanosized ZnO was quantitatively evaluated with the aid of a 3D-printing-manufactured evaluation system. Two different outermost atomic layers were manufactured separately by using an ALD (atomic layer deposition) method. Interestingly, we found that each outermost atomic layer exhibited certain differences against gram-positive or gram-negative bacterial species. Zinc atoms as outermost layer (ZnO-Zn) showed a more pronounced antibacterial effect towards gram-negative E. coli (Escherichia coli), whereas oxygen atoms (ZnO-O) showed a stronger antibacterial activity against gram positive S. aureus (Staphylococcus aureus). A possible antibacterial mechanism has been comprehensively discussed from different perspectives, including Zn(2+) concentrations, oxygen vacancies, photocatalytic activities and the DNA structural characteristics of different bacterial species. PMID- 27124265 TI - Potential sex differences in the pattern of sensory reinforcers enhanced by nicotine. AB - Along with its primary and secondary reinforcing effects, nicotine acutely enhances reinforcement from rewards not directly related to nicotine, particularly those consisting of "sensory" stimuli. Less certain is the magnitude of these effects across types of sensory reinforcers commonly available in the natural environment, especially under different smoking exposure conditions of clinical relevance. This study compared reinforced responding for immediate auditory (music) or visual (video) sensory rewards, or no reward (nonspecific control), due to nicotine via ad lib smoking versus no nicotine (overnight abstinence), in a within-subjects design. Dependent smokers (N = 48; 21 male, 27 female) responded on an operant computer task for small units of the designated rewards during 2 sessions, following overnight abstinence (>12 hr; CO <= 10 ppm) or no abstinence (i.e., ad lib smoking). Preferred music and video rewards were each selected by participants to ensure their equal initial reinforcing efficacy. Responding reinforced by music and by video rewards, but not by no reward, was similarly enhanced by ad lib smoking in the entire sample. Yet, in post hoc follow-ups, the smoking-induced increase in responding for music was greater in women versus men, while the increase in responding for video was greater in men versus women. Results confirm the comparability of the reinforcement enhancing effects of nicotine via smoking on both auditory and visual rewards, consistent with the notion that enhanced sensory reinforcement may contribute to persistence of smoking behavior. However, findings also suggest the specific pattern of sensory reinforcers enhanced by nicotine may differ between men and women. (PsycINFO Database Record PMID- 27124266 TI - Discriminating unalike single nucleobase mismatches using a molecularly resolved, label-free, interfacial LNA-based assay. AB - A number of reports have been made in recent times on label-free detection of nucleic acid sequences. However, most of these studies deal with ensemble measurements, therefore lacking in molecular level resolution. These assays have usually employed ssDNA sensor probes, and often suffered from problems of irreproducibility and poor sequence-selectivity. Herein, the applicability of surface-anchored single stranded locked nucleic acid (ssLNA) probes has been assessed in the detection of target DNA sequences, as an alternative to the DNA based assay. Importantly, the effectiveness of the LNA-based assay in identifying different types of single nucleobase mismatches has been tested. Since the duplex melting temperature is an indicator of duplex stability, the ensemble on-surface Tm values of the surface-confined LNA-DNA duplexes have been compared to the duplex unbinding force values obtained from atomic force spectroscopy (AFS) experiments. A common mismatch discrimination pattern elicited by both the ensemble and the molecular level AFS approach could be identified. Apart from quantitative delineation of the different types of mismatches, the label-free AFS analysis confirms different degrees of efficiency of the purine and pyrimidine bases, present on the LNA backbone, in discriminating different nucleobase mismatch types. Importantly, the LNA-based AFS analysis can distinguish between the disease-relevant gene fragments, e.g., multidrug-resistant Mycobacterium tuberculosis (MTB) mutation, and the wild type. Since LNA probes are nuclease resistant, these findings could potentially pave way to diagnostic applications of the LNA-based AFS assay. PMID- 27124267 TI - Hybrid mechanosensing system to generate the polarity needed for migration in fish keratocytes. AB - Crawling cells can generate polarity for migration in response to forces applied from the substratum. Such reaction varies according to cell type: there are both fast- and slow-crawling cells. In response to periodic stretching of the elastic substratum, the intracellular stress fibers in slow-crawling cells, such as fibroblasts, rearrange themselves perpendicular to the direction of stretching, with the result that the shape of the cells extends in that direction; whereas fast-crawling cells, such as neutrophil-like differentiated HL-60 cells and Dictyostelium cells, which have no stress fibers, migrate perpendicular to the stretching direction. Fish epidermal keratocytes are another type of fast crawling cell. However, they have stress fibers in the cell body, which gives them a typical slow-crawling cell structure. In response to periodic stretching of the elastic substratum, intact keratocytes rearrange their stress fibers perpendicular to the direction of stretching in the same way as fibroblasts and migrate parallel to the stretching direction, while blebbistatin-treated stress fiber-less keratocytes migrate perpendicular to the stretching direction, in the same way as seen in HL-60 cells and Dictyostelium cells. Our results indicate that keratocytes have a hybrid mechanosensing system that comprises elements of both fast- and slow-crawling cells, to generate the polarity needed for migration. PMID- 27124269 TI - The clinical course of alcoholic cirrhosis: development of comorbid diseases. A Danish nationwide cohort study. AB - BACKGROUND & AIMS: We aimed to determine associations between alcoholic cirrhosis and incidence of comorbidity, and to describe the clinical course of alcoholic cirrhosis in terms of comorbidity development. The comorbid diseases we studied were acute myocardial infarction, heart failure, peripheral arterial disease, chronic obstructive pulmonary disease, chronic kidney disease, epilepsy, diabetes and cancer. METHODS: This was a registry-based nationwide historical cohort study. We included 10 650 Danish citizens diagnosed with alcoholic cirrhosis at age 45-69 years in 1994-2014 and 43 150 age- and gender-matched persons. None of them had the comorbid diseases we studied at inclusion. We compared rates and cumulative risks of comorbidity development between patients and controls. RESULTS: Patients with alcoholic cirrhosis had a higher rate of comorbidity (hazard ratio for any comorbidity = 3.74, 95% CI 3.56-3.94), including all the non-cancer comorbidities (hazard ratio for any non-cancer comorbidity = 4.33, 95% CI 4.06-4.62) except acute myocardial infarction. They also had a higher rate of developing cancer (hazard ratio = 2.94, 95% CI 2.70-3.19). Still, relatively few patients actually lived to experience development of non-cancer (10-year risk: 21.4% vs. 13.2% for controls) or cancer comorbidity (10-year risk: 10.9% vs. 10.0%) because they died before they developed any comorbid disease. Hepatocellular carcinoma and oropharyngeal cancer were the only two comorbidities that were much more likely to develop in patients than in controls. CONCLUSIONS: Alcoholic cirrhosis promotes development of several comorbid diseases, but only few patients with alcoholic cirrhosis live long enough to actually develop them. PMID- 27124268 TI - Managing Multivessel Coronary Artery Disease in Patients With ST-Elevation Myocardial Infarction: A Comprehensive Review. AB - Multivessel coronary artery disease (CAD) is found in up to 60% of the patients presenting with an ST-elevation myocardial infarction (STEMI) and worsens the prognosis proportional to the extent of CAD severity. However, the 2013 American College of Cardiology/American Heart Association STEMI guidelines, based on mostly observational data, had recommended against a routine noninfarct-related artery percutaneous coronary intervention (PCI). After these guidelines were published, a handful of randomized trials became available, and they suggested that PCI of significant lesions in a noninfarct-related artery at the time of primary PCI might result in improved patient outcomes. The incidence of major adverse cardiac events was significantly reduced by 55% at 1 year and 65% at 2 years in patients undergoing angiographically guided PCI of nonculprit vessels at the time of primary PCI, in 2 different randomized trials. Fractional flow reserve-guided PCI of nonculprit vessels in this setting has also been shown to reduce cardiac events by 44% at 1 year. Meta-analyses of both nonrandomized and randomized trials have also suggested that complete revascularization at the time of STEMI significantly improves outcomes, including long-term all-cause mortality. In view of the emerging data, a focused update on primary PCI was published in 2015 and suggested that PCI of noninfarct-related arteries might be considered in selected patients. This article is a comprehensive review of the literature on the treatment of multivessel CAD in patients with STEMI, which provides the reader a critical analysis of the available information to determine the best therapeutic approach. PMID- 27124271 TI - Computational studies on the reactivity of alkyl halides over (Al2O3)n nanoclusters: an approach towards room temperature dehydrohalogenation. AB - The role of alumina nanoclusters as a catalyst on the reactivity of alkyl halides has been explored. The thermochemical data obtained from Density Functional Theory (DFT) calculations and the analyses of the transition structures reveal that, between the two competing reactions, elimination (via E2) versus dissociative addition (via SN2), elimination is the kinetically controlled one and thus at room temperature, olefin is the major product. The results are in excellent agreement with the recent experimental observation where more than 97% of ethylene is formed at room temperature with the reaction of ethyl fluoride over an alumina surface, although the dissociative addition product is being thermodynamically more stable. We have tried to rationalize the fact by using alumina clusters of different sizes as well as different alkyl halides having beta-H for elimination. It has been shown that, during the elimination (E2) pathway, the transition structure is oriented in such a way that the eliminating halogen and the beta-H are in the interacting position with the three-centered Al and two-centered O atoms, respectively, where the Lewis acid/base interaction is the main guiding factor. We have also shown a possible pathway for regenerating the catalyst. Finally, the possibility of the reactions has been tested in the presence of H2O to mimic the same on the hydrated alumina surface. PMID- 27124270 TI - Prophylactic effects of pomegranate (Punica granatum) juice on sodium fluoride induced oxidative damage in liver and erythrocytes of rats. AB - The objective of this study was to investigate the protective effects of pomegranate (Punica granatum) juice (PGJ) on oxidative damages in liver tissue and erythrocytes of rats intoxicated by sodium fluoride (NaF). Rats were randomly divided into two groups: group I received standard diet and group II received orally 1 mL of PGJ. After 5 weeks of pretreatment, each group was divided again into two subgroups and treated for another 3 weeks as follows: group I was subdivided into a control group and a group that was treated with 100 ppm of NaF (in drinking water); group II was subdivided into one group that was treated daily with both 100 ppm NaF and PGJ (1 mL orally) and one that received daily 1 mL of pomegranate juice. Exposure to NaF decreased hematological parameters, changed the total protein, albumin, bilirubin levels, and increased the activities of hepatic marker enzymes. We also noted an increase in lipid peroxidation contents, accompanied by a decrease of reduced glutathione levels. Antioxidant enzyme activities in both tissues were modified in the NaF group compared with the control group. However, the administration of PGJ juice caused an amelioration of the previous parameters. Our results indicated the potential effects of NaF to induce oxidative damage in tissues and the ability of PGJ to attenuate NaF-induced oxidative injury. PMID- 27124272 TI - A Case of Unilateral Optic Neuropathy Following Influenza Vaccination. AB - The influenza vaccination has greatly benefited public health, leading to significant reductions in flu season hospitalizations and deaths. However, with more widespread administration of this vaccine, it is expected that the absolute number of patients that present with unusual, adverse reactions will increase. Here, we report a case of a 55-year-old woman who developed a progressive optic neuropathy and severe visual loss associated with optic disc edema following influenza virus vaccination. Our patient also experienced other concurrent symptoms, including bilateral knee effusions, muscle spasms and a facial rash. The strong temporal connection between the vaccine administration and the development of sequelae suggests that the optic neuropathy was an adverse reaction. Furthermore, HLA typing of our patient revealed alleles that have been linked to autoimmune reactions, consistent with the notion that specific HLA alleles could be involved in the pathophysiology of these adverse reactions. PMID- 27124273 TI - Towards a new era in fetal medicine in the Nordic countries. AB - Fetal medicine is a subspecialty of obstetrics investigating the development, growth and disease of the human fetus. The advances in fetal imaging (ultrasonography, MRI) and molecular diagnostic techniques, together with the possibility of intervention in utero, make fetal medicine an important, rapidly developing field within women's healthcare. Therefore, a variety of specialists, such as neonatologists, pediatric cardiologists, medical geneticists, radiologists and pediatric surgeons, are necessary to adjunct in the diagnosis and treatment of the fetus as a patient. In this commentary, we provide a description of some organizational and educational aspects of fetal medicine in the Nordic countries, using examples of the management of specific conditions such as aneuploidy screening, red cell allo-immunization and fetal interventions. Clearly, there are several cultural, legal, organizational and practical differences between the Nordic countries; these are not necessarily negative, given the high standards of care in all Nordic countries. The scope of the newly founded Nordic Network of Fetal Medicine is to enhance cooperation in clinical practice, education and research between the participant countries. Hopefully, this initiative will find the necessary political and economic support from the national authorities and bring a new era in the field of fetal medicine in the Nordic region. PMID- 27124274 TI - Transcending as a driver of development. AB - This paper draws from three different bodies of research to discuss the hypothesis that age-appropriate experiences enhance brain and cognitive development throughout the life span. These age-appropriate experiences could be considered as the drivers of development at each age, including drivers to foster development beyond adult abstract thinking, as described in Piaget's formal operational stage. We explore how a nurturing caregiver is the driver in the first 2 years of life, how language learning is the driver from 3 to 10 years, and how problem solving is the driver in the teenage years. To develop beyond adult rational thinking, we suggest that the driver is transcending thought, which can result when practicing meditations in the automatic self-transcending category, such as Transcendental Meditation. PMID- 27124277 TI - Invasive blue mussels threaten regional scale genetic diversity in mainland and remote offshore locations: the need for baseline data and enhanced protection in the Southern Ocean. AB - Human-mediated biological transfers of species have substantially modified many ecosystems with profound environmental and economic consequences. However, in many cases, invasion events are very hard to identify because of the absence of an appropriate baseline of information for receiving sites/regions. In this study, use of high-resolution genetic markers (single nucleotide polymorphisms - SNPs) highlights the threat of introduced Northern Hemisphere blue mussels (Mytilus galloprovincialis) at a regional scale to Southern Hemisphere lineages of blue mussels via hybridization and introgression. Analysis of a multispecies SNP dataset reveals hotspots of invasive Northern Hemisphere blue mussels in some mainland New Zealand locations, as well as the existence of unique native lineages of blue mussels on remote oceanic islands in the Southern Ocean that are now threatened by invasive mussels. Samples collected from an oil rig that has moved between South Africa, Australia, and New Zealand were identified as invasive Northern Hemisphere mussels, revealing the relative ease with which such non-native species may be moved from region to region. In combination, our results highlight the existence of unique lineages of mussels (and by extension, presumably of other taxa) on remote offshore islands in the Southern Ocean, the need for more baseline data to help identify bioinvasion events, the ongoing threat of hybridization and introgression posed by invasive species, and the need for greater protection of some of the world's last great remote areas. PMID- 27124276 TI - Mononostril versus Binostril Endoscopic Transsphenoidal Approach for Pituitary Adenomas: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Over the past several decades, the endoscopic endonasal transsphenoidal approach (EETA) has gradually become a preferred option of pituitary adenomas surgery because of its minimal invasiveness and high efficiency. However, some EETA operations were performed through one nostril (mononostril), while other EETA operations were performed through both nostrils (binostril). Therefore, we conducted this study to compare the pros and cons of these two methods in an attempted to confirm which method is more effective. METHODS: We executed a systematic literature search of PubMed, the Cochrane Library, and the Web of Science and Medline (1992-2015). The language is limited to English and all studies should meet the inclusion criteria. Comparisons were made for postoperative outcomes, complications, and other relevant parameters between the mononostril and the binostril group. Statistical analyses of categorical variables were undertaken by the use of Stata 12.0 and SPASS 19.0. RESULTS: Thirty studies, involving 4805 patients, were included. The two groups had similar results in GTR rate (included GTR rate of macroadenomas), hormonal remission rate, improvement in visual function, postoperative CSF leak, permanent diabetes insipidus, meningitis, and sinusitis. The binostril group had less temporary diabetes insipidus (2.9% vs. 5.3%, p = 0.022), less anterior pituitary insufficiency (2.3% vs. 6.4%, p = 0.000) and few hospitalization days (3.2 days vs. 4.4 days, p<0.05) than the mononostril group. However, the mononostril group had less rate of epistaxis (0.4% vs. 1.5%, p = 0.008) than the binostril group. For invasive macroadenomas, the binostril group seem to demonstrate a tendency towards better outcomes though there was no subgroup analysis between the two groups. CONCLUSION: The binostril approach had less temporary diabetes insipidus, anterior pituitary insufficiency, and a shorter length of hospital stay, although they demonstrated a higher rate of epistaxis than the mononstril group. Additionally, the binostril group seemed to suggest a tendency towards better outcomes for invasive macroadenomas. PMID- 27124278 TI - A Matter of Contrast: Yellow Flower Colour Constrains Style Length in Crocus species. AB - Most flowers display distinct colour patterns comprising two different areas. The peripheral large-area component of floral colour patterns attracts flower visitors from some distance and the central small-area component guides flower visitors towards landing sites. Whereas the peripheral colour is largely variable among species, the central colour, produced mostly by anthers and pollen or pollen mimicking floral guides, is predominantly yellow and UV-absorbing. This holds also for yellow flowers that regularly display a UV bull's eye pattern. Here we show that yellow-flowering Crocus species are a noticeable exception, since yellow-flowering Crocus species-being entirely UV-absorbing-exhibit low colour contrast between yellow reproductive organs and yellow tepals. The elongated yellow or orange-yellow style of Crocus flowers is a stamen-mimicking structure promoting cross-pollination by facilitating flower visitors' contact with the apical stigma before the flower visitors are touching the anthers. Since Crocus species possess either yellow, violet or white tepals, the colour contrast between the stamen-mimicking style and the tepals varies among species. In this study comprising 106 Crocus species, it was tested whether the style length of Crocus flowers is dependent on the corolla colour. The results show that members of the genus Crocus with yellow tepals have evolved independently up to twelve times in the genus Crocus and that yellow-flowering Crocus species possess shorter styles as compared to violet- and white-flowering ones. The manipulation of flower visitors by anther-mimicking elongated styles in Crocus flowers is discussed. PMID- 27124279 TI - Pediatric Pulmonology year in review 2015: Part 1. AB - Our journal covers a broad range of research and scholarly topics related to children's respiratory disorders. For updated perspectives on the rapidly expanding knowledge in our field, we will summarize the past year's publications in our major topic areas, as well as selected publications in these areas from the core clinical journal literature outside our own pages. The current review covers articles on neonatal lung disease, pulmonary physiology, and respiratory infection. Pediatr Pulmonol. 2016;51:733-739. (c) 2016 Wiley Periodicals, Inc. PMID- 27124281 TI - Synthesis and Photostability of Unimolecular Submersible Nanomachines: Toward Single-Molecule Tracking in Solution. AB - The synthesis and photophysical properties of a series of photostable unimolecular submersible nanomachines (USNs) are reported as a first step toward the analysis of their trajectories in solution. The USNs have a light-driven rotatory motor for propulsion in solution and photostable cy5-COT fluorophores for their tracking. These cy5-COT fluorophores are found to provide an almost 2 fold increase in photostability compared to the previous USN versions and do not affect the rotation of the motor. PMID- 27124280 TI - Response of Spring Diatoms to CO2 Availability in the Western North Pacific as Determined by Next-Generation Sequencing. AB - Next-generation sequencing (NGS) technologies have enabled us to determine phytoplankton community compositions at high resolution. However, few studies have adopted this approach to assess the responses of natural phytoplankton communities to environmental change. Here, we report the impact of different CO2 levels on spring diatoms in the Oyashio region of the western North Pacific as estimated by NGS of the diatom-specific rbcL gene (DNA), which encodes the large subunit of RubisCO. We also examined the abundance and composition of rbcL transcripts (cDNA) in diatoms to assess their physiological responses to changing CO2 levels. A short-term (3-day) incubation experiment was carried out on-deck using surface Oyashio waters under different pCO2 levels (180, 350, 750, and 1000 MUatm) in May 2011. During the incubation, the transcript abundance of the diatom specific rbcL gene decreased with an increase in seawater pCO2 levels. These results suggest that CO2 fixation capacity of diatoms decreased rapidly under elevated CO2 levels. In the high CO2 treatments (750 and 1000 MUatm), diversity of diatom-specific rbcL gene and its transcripts decreased relative to the control treatment (350 MUatm), as well as contributions of Chaetocerataceae, Thalassiosiraceae, and Fragilariaceae to the total population, but the contributions of Bacillariaceae increased. In the low CO2 treatment, contributions of Bacillariaceae also increased together with other eukaryotes. These suggest that changes in CO2 levels can alter the community composition of spring diatoms in the Oyashio region. Overall, the NGS technology provided us a deeper understanding of the response of diatoms to changes in CO2 levels in terms of their community composition, diversity, and photosynthetic physiology. PMID- 27124283 TI - Immunohistochemical activity of Prohibitin-2 and Stomatin-Like Protein-2 in patients with ulcerative colitis. AB - BACKGROUND/AIMS: We aimed to semi-quantitatively investigate prohibitin-2 (Phb-2) and stomatin-like protein-2 (Slp-2) expressions in patients with ulcerative colitis (UC) and healthy controls using the immunohistochemical (IHC) method. We also aimed to evaluate the correlations between the activity of UC and the expressions of these two proteins. MATERIALS AND METHODS: Ninety-five patients with UC (82 males and 13 females) and 38 healthy controls (35 males and 3 females) were included. Clinical and endoscopic activities of UC were assessed. Conventional laboratory activation parameters and severity of inflammation measures were used for the evaluation of histological activity. IHC staining of biopsy samples for the two proteins were semi-quantitatively applied, similar to previously described methods for colon adenocarcinomas. RESULTS: IHC scores of Phb-2 were lower but Slp-2 scores were higher in the UC group than in the healthy controls (p<0.05 and p=0.003, respectively). Phb-2 scores were positively correlated with clinical and histological activities (r=0.364, p<0.05 and r=0.220, p<0.032, respectively). In the UC group, endoscopic activity scores, C reactive protein levels, and sedimentation rates were also positively correlated with Phb-2 scores (r=0.279, p<0.05, r=0.216, p<0.05, and r=0.216, p<0.05, respectively). IHC scores of Slp-2 were not significantly correlated with the activity parameters of UC. However, there was a significant positive correlation between the expressions of Phb-2 and Slp-2 proteins (p<0.001). CONCLUSION: Phb-2 may serve as a valuable new biomarker for predicting the severity of all UC activity parameters. The therapeutic effectiveness of both Phb-2 and Slp-2 should be taken into consideration. PMID- 27124282 TI - Possible Increase in Serum FABP4 Level Despite Adiposity Reduction by Canagliflozin, an SGLT2 Inhibitor. AB - BACKGROUND: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) is secreted from adipocytes in association with catecholamine-induced lipolysis, and elevated serum FABP4 level is associated with obesity, insulin resistance and atherosclerosis. Secreted FABP4 as a novel adipokine leads to insulin resistance via increased hepatic glucose production (HGP). Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease blood glucose level via increased urinary glucose excretion, though HGP is enhanced. Here we investigated whether canagliflozin, an SGLT2 inhibitor, modulates serum FABP4 level. METHODS: Canagliflozin (100 mg/day) was administered to type 2 diabetic patients (n = 39) for 12 weeks. Serum FABP4 level was measured before and after treatment. RESULTS: At baseline, serum FABP4 level was correlated with adiposity, renal dysfunction and noradrenaline level. Treatment with canagliflozin significantly decreased adiposity and levels of fasting glucose and HbA1c but increased average serum FABP4 level by 10.3% (18.0 +/- 1.0 vs. 19.8 +/- 1.2 ng/ml, P = 0.008), though elevation of FABP4 level after treatment was observed in 26 (66.7%) out of 39 patients. Change in FABP4 level was positively correlated with change in levels of fasting glucose (r = 0.329, P = 0.044), HbA1c (r = 0.329, P = 0.044) and noradrenaline (r = 0.329, P = 0.041) but was not significantly correlated with change in adiposity or other variables. CONCLUSIONS: Canagliflozin paradoxically increases serum FABP4 level in some diabetic patients despite amelioration of glucose metabolism and adiposity reduction, possibly via induction of catecholamine-induced lipolysis in adipocytes. Increased FABP4 level by canagliflozin may undermine the improvement of glucose metabolism and might be a possible mechanism of increased HGP by inhibition of SGLT2. TRIAL REGISTRATION: UMIN-CTR Clinical Trial UMIN000018151. PMID- 27124284 TI - Cirrhosis with ascites: Is the presence of hemorrhagic ascites an indicator of poor prognosis? AB - BACKGROUND/AIMS: Hemorrhagic ascites in patients with cirrhosis is described as a RBC (Red Blood cell) > 50,000/mm3 and leads to increased morbidity and mortality. Positive red blood cells at a level of less than 50,000/mm3 (10,000-50,000) may be encountered in the ascites but it is not known whether this is clinically significant or not. This study aimed to examine the outcome of hemorrhagic ascites in patients with advanced cirrhosis. MATERIALS AND METHODS: Data from 329 cirrhotic patients with ascites who received paracentesis at least once due to ascites was retrospectively analyzed from the period of 2007-2013 from the Turkiye Yuksek Ihtisas Hospital, Department of Gastroenterology. Patients were divided according to the number of RBC, with greater than 10,000/mm3 being described as hemorrhagic ascites, and less than 10,000/mm3 described as the normal or control group. Patient data included: number of accepted intensive unit service stays, acute kidney injury (AKI), hepatic encephalopathy (HES), model for end-liver disease (MELD) score, Child Pugh score (CPS), degree of esophageal varices, spleen size and mortality rates. RESULTS: Patients were defined as having hemorrhagic ascites with a RBC count greater than 10,000/mm3 in 118 (35.9%) patients and as a non-hemorrhagic ascites group with less than 10,000/mm3 in 211 (64.1%) patients. The hemorrhagic ascites group had advanced liver disease symptoms compared to the control group. Meld score in the hemorrhagic group was statistically higher than in the control group (21.5+/-8.3 vs. 17.3+/-6.6; p value: 0.001). The median value of bilirubin was 5.9 (0.45-33) in the hemorrhagic ascites group and 4.01 (0.39-33) in the non-hemorrhagic group (p value: 0.001). Using multivariate logistic regression analysis, hemorrhagic ascites was also an independent predictor of mortality (HR 2.7 1.4-6.3), with other mortality indicators being HCC (HR 3.1 1.5-6.4) and HRS (HR 2.6 1.2-5.5). CONCLUSION: Patients with hemorrhagic ascites had higher HRS, SBP and admissions to the intensive care unit. We believe that the presence of hemorrhagic ascites can be used as a marker for advanced liver disease and for predicting mortality. PMID- 27124285 TI - The Dynamics of the Human Leukocyte Antigen Head Domain Modulates Its Recognition by the T-Cell Receptor. AB - Generating the immune response requires the discrimination of peptides presented by the human leukocyte antigen complex (HLA) through the T-cell receptor (TCR). However, how a single amino acid substitution in the antigen bonded to HLA affects the response of T cells remains uncertain. Hence, we used molecular dynamics computations to analyze the molecular interactions between peptides, HLA and TCR. We compared immunologically reactive complexes with non-reactive and weakly reactive complexes. MD trajectories were produced to simulate the behavior of isolated components of the various p-HLA-TCR complexes. Analysis of the fluctuations showed that p-HLA binding barely restrains TCR motions, and mainly affects the CDR3 loops. Conversely, inactive p-HLA complexes displayed significant drop in their dynamics when compared with its free versus ternary forms (p-HLA-TCR). In agreement, the free non-reactive p-HLA complexes showed a lower amount of salt bridges than the responsive ones. This resulted in differences between the electrostatic potentials of reactive and inactive p-HLA species and larger vibrational entropies in non-elicitor complexes. Analysis of the ternary p-HLA-TCR complexes also revealed a larger number of salt bridges in the responsive complexes. To summarize, our computations indicate that the affinity of each p-HLA complex towards TCR is intimately linked to both, the dynamics of its free species and its ability to form specific intermolecular salt bridges in the ternary complexes. Of outstanding interest is the emerging concept of antigen reactivity involving its interplay with the HLA head sidechain dynamics by rearranging its salt-bridges. PMID- 27124286 TI - The influence of diisocyanate antigen preparation methodology on monoclonal and serum antibody recognition. AB - Exposure to diisocyanates (dNCOs), such as methylene diphenyl diisocyanate (MDI) can cause occupational asthma (OA). Currently, lab tests for dNCO specific IgE are specific, but not sensitive, which limits their utility in diagnosing dNCO asthma. This may be due to variable preparation and poor characterization of the standard antigens utilized in these assays. The aim of this study was to produce and characterize a panel of antigens prepared using three different commonly employed methods and one novel method. The conjugates were examined for recognition by anti-MDI monoclonal antibodies (mAbs) in varying enzyme linked immunosorbant assay (ELISA) formats, extent of crosslinking, total amount of MDI, the sites of MDI conjugation, relative shape/charge, and reactivity with human serum with antibodies from sensitized, exposed workers. Results indicate that while there are minimal differences in the total amount of MDI conjugated, the extent of crosslinking, and the conjugation sites, there are significant differences in the recognition of differently prepared conjugates by mAbs. Native and denaturing polyacrylamide gel electrophoresis demonstrate differences in the mobility of different conjugates, indicative of structural changes that are likely important for antigenicity. While mAbs exhibited differential binding to different conjugates, polyclonal serum antibodies from MDI exposed workers exhibited equivalent binding to different conjugates by ELISA. While differences in the recognition of the different conjugates exist by mAb detection, differences in antigenicity could not be detected using human serum from MDI sensitized individuals. Thus, although dNCO conjugate preparation can, depending on the immunoassay platform, influence binding of specific antibody clones, serologic detection of the dNCO-exposure-induced polyclonal antibody response may be less sensitive to these differences. PMID- 27124287 TI - Patient-Centered Communication for Discussing Oncotype DX Testing. AB - Oncotype DX testing (ODX), a tumor gene expression test, may improve breast cancer care, however, communicating results remains challenging. We identified patient-centered communication strategies/gaps for discussing ODX results. We applied a patient-centered communication framework to analyze qualitative interviews with oncologists about how they communicate about ODX with patients, using template analysis in Atlas.ti. Overall, providers discussed four patient centered communication domains: exchanging information, assessing uncertainty, making decisions and cross-cutting themes. Providers did not report discussing emotional aspects of managing uncertainty, assessing decision-making preferences, and evaluating decisions. A patient-centered approach may be a model for communicating about tumor gene expression tests. PMID- 27124288 TI - Modification in hydrophobic packing of HAMP domain induces a destabilization of the auto-phosphorylation site in the histidine kinase CpxA. AB - The histidine kinases belong to the family of two-component systems, which serves in bacteria to couple environmental stimuli to adaptive responses. Most of the histidine kinases are homodimers, in which the HAMP and DHp domains assemble into an elongated helical region flanked by two CA domains. Recently, X-ray crystallographic structures of the cytoplasmic region of the Escherichia coli histidine kinase CpxA were determined and a phosphotransferase-defective mutant, M228V, located in HAMP, was identified. In the present study, we recorded 1 MUs molecular dynamics trajectories to compare the behavior of the WT and M228V protein dimers. The M228V modification locally induces the appearance of larger voids within HAMP as well as a perturbation of the number of voids within DHp, thus destabilizing the HAMP and DHp hydrophobic packing. In addition, a disruption of the stacking interaction between F403 located in the lid of the CA domain involved in the auto-phosphorylation and R296 located in the interacting DHp region, is more often observed in the presence of the M228V modification. Experimental modifications R296A and R296D of CpxA have been observed to reduce also the CpxA activity. These observations agree with the destabilization of the R296/F403 stacking, and could be the sign of the transmission of a conformational event taking place in HAMP to the auto-phosphorylation site of histidine kinase. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 670-682, 2016. PMID- 27124292 TI - Dancing with the SNARC: Measuring spatial-numerical associations on a digital dance mat. AB - According to the concept of embodied numerosity, bodily experiences influence the way in which we process numerical magnitude. The development of this influence could be anchored in the spatial ordering of numbers along a mental number line representation, which is measured by effects of spatial-numerical associations. The aim of this study was to investigate whether horizontally oriented full-body movement and visual presentation of a number line both contribute to spatial numerical associations in children. We presented fourth-graders with 2 magnitude comparison tasks that differed in the relevance of magnitude information. In both tasks, we varied the amount of bodily movement in different response conditions (responding verbally, with a foot tap, or by jumping) and the visual presentation (items were presented with or without a number line). From the data, we calculated 2 spatial-numerical effects and expected to find the strongest effects if a full-body response was combined with a number line presentation. The 2 effects were differentially influenced by response modalities, but not presentation. The SNARC (= Spatial Numerical Association of Response Codes) effect was present in all conditions and was not influenced by our manipulations. In contrast, a new relative numerical congruity effect was influenced by the variations in responses in accordance with our hypotheses. The relative numerical congruity effect results suggest that responses involving bodily movement increase activation of spatial-numerical associations compared to verbal responses. These results are the first to demonstrate such an influence in a full body approach in elementary schoolchildren. (PsycINFO Database Record PMID- 27124293 TI - Reference intervals for biochemical analytes of captive Black-Fronted Piping-Guan (Aburria jacutinga). AB - BACKGROUND: Black-Fronted Piping-Guan (Aburria jacutinga) is considered one of the most threatened bird species on the American continent. Ex situ conservation efforts have been developed in Brazil, and monitoring the health status of these populations is essential to ensure reproductive success in captivity. Reference intervals (RI) for biochemistry analytes from a larger population of Black Fronted Piping-Guan are unavailable. OBJECTIVES: This study was aimed at establishing RI for biochemical analytes of captive Black-Fronted Piping-Guan for future improved health assessments in these animals. METHODS: Blood samples were collected from 32 adult Black-Fronted Piping-Guans for serum and plasma separation. Liver and kidney function markers, and concentration of protein and lipids were measured. Reference intervals were determined using an Excel program with Reference Value Adviser (version 2.0). RESULTS: The RI of the analytes were: AST 20.7-188.0 U/L; CK 713.7-4741.4 U/L; LDH 360.7-1173.7 U/L; gamma Glutamyl Transferase 1.1-5.4 U/L; total plasma protein 3.5-6.2 g/dL; total serum protein 1.7-4.7 g/dL; uric acid 0.9-19.2 mg/dL; urea 7.0-25.3 mg/dL; cholesterol 71.8 232.2 mg/dL; triglycerides 25.6-183.4 mg/dL. CONCLUSIONS: The RI are similar to the ones published for other avian species. Only CK and uric acid values were in discordance with the usually reported avian ranges. This could be due to different methods of capture and physical restraint. Alternatively, some differences could be species-specific. In general, physical restraint should be limited to a minimum and without stress to prevent capture myopathy and death. PMID- 27124294 TI - Clinical Pharmacist Team-Based Care in a Safety Net Medical Home: Facilitators and Barriers to Chronic Care Management. AB - Collaborative care models incorporating pharmacists have been shown to improve quality of care for patients with hypertension and/or diabetes. Little is known about how to integrate such services outside of clinical trials. The authors implemented a 22-month observational study to evaluate pharmacy collaborative care for hypertension and diabetes in a safety net medical home that incorporated population risk stratification, clinical decision support, and medication dose adjustment protocols. Patients in the pharmacy group saw their primary care provider (PCP) more often and had higher baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) and A1c levels compared to patients who only received care from their PCPs. There were no significant differences in the proportion of patients achieving treatment goals (SBP <140, DBP <90; A1c < 8) or the magnitude of change in BP or A1c among patients who underwent collaborative care versus those who did not. Age, race, and number of PCP encounters were associated with BP and A1c trends. The median time to achieve disease control was longer in the pharmacy group. Although 70% of all patients with poorly controlled hypertension achieved treatment goals within 7 months, less than 50% of patients with poorly controlled diabetes achieved A1c < 8 within 15 months, suggesting that diabetes was harder to manage overall. Contextual factors that facilitated or hindered practice redesign included organizational culture, health information technology and related workflows, and pharmacy caseload optimization. Future studies should further examine implementation strategies that work best in specific settings to optimize the benefits of team-based care with clinical pharmacists. PMID- 27124295 TI - Estimating Tropical Forest Structure Using a Terrestrial Lidar. AB - Forest structure comprises numerous quantifiable biometric components and characteristics, which include tree geometry and stand architecture. These structural components are important in the understanding of the past and future trajectories of these biomes. Tropical forests are often considered the most structurally complex and yet least understood of forested ecosystems. New technologies have provided novel avenues for quantifying biometric properties of forested ecosystems, one of which is LIght Detection And Ranging (lidar). This sensor can be deployed on satellite, aircraft, unmanned aerial vehicles, and terrestrial platforms. In this study we examined the efficacy of a terrestrial lidar scanner (TLS) system in a tropical forest to estimate forest structure. Our study was conducted in January 2012 at La Selva, Costa Rica at twenty locations in a predominantly undisturbed forest. At these locations we collected field measured biometric attributes using a variable plot design. We also collected TLS data from the center of each plot. Using this data we developed relative vegetation profiles (RVPs) and calculated a series of parameters including entropy, Fast Fourier Transform (FFT), number of layers and plant area index to develop statistical relationships with field data. We developed statistical models using a series of multiple linear regressions, all of which converged on significant relationships with the strongest relationship being for mean crown depth (r2 = 0.88, p < 0.001, RMSE = 1.04 m). Tree density was found to have the poorest significant relationship (r2 = 0.50, p < 0.01, RMSE = 153.28 n ha-1). We found a significant relationship between basal area and lidar metrics (r2 = 0.75, p < 0.001, RMSE = 3.76 number ha-1). Parameters selected in our models varied, thus indicating the potential relevance of multiple features in canopy profiles and geometry that are related to field-measured structure. Models for biomass estimation included structural canopy variables in addition to height metrics. Our work indicates that vegetation profiles from TLS data can provide useful information on forest structure. PMID- 27124296 TI - Nutritional Enteric Failure: Neglected Tropical Diseases and Childhood Stunting. PMID- 27124275 TI - Principles and Overview of Sampling Methods for Modeling Macromolecular Structure and Dynamics. AB - Investigation of macromolecular structure and dynamics is fundamental to understanding how macromolecules carry out their functions in the cell. Significant advances have been made toward this end in silico, with a growing number of computational methods proposed yearly to study and simulate various aspects of macromolecular structure and dynamics. This review aims to provide an overview of recent advances, focusing primarily on methods proposed for exploring the structure space of macromolecules in isolation and in assemblies for the purpose of characterizing equilibrium structure and dynamics. In addition to surveying recent applications that showcase current capabilities of computational methods, this review highlights state-of-the-art algorithmic techniques proposed to overcome challenges posed in silico by the disparate spatial and time scales accessed by dynamic macromolecules. This review is not meant to be exhaustive, as such an endeavor is impossible, but rather aims to balance breadth and depth of strategies for modeling macromolecular structure and dynamics for a broad audience of novices and experts. PMID- 27124297 TI - The Minimal Important Difference in Physical Activity in Patients with COPD. AB - BACKGROUND: Changes in physical activity (PA) are difficult to interpret because no framework of minimal important difference (MID) exists. We aimed to determine the minimal important difference (MID) in physical activity (PA) in patients with Chronic Obstructive Pulmonary Disease and to clinically validate this MID by evaluating its impact on time to first COPD-related hospitalization. METHODS: PA was objectively measured for one week in 74 patients before and after three months of rehabilitation (rehabilitation sample). In addition the intraclass correlation coefficient was measured in 30 patients (test-retest sample), by measuring PA for two consecutive weeks. Daily number of steps was chosen as outcome measurement. Different distribution and anchor based methods were chosen to calculate the MID. Time to first hospitalization due to an exacerbation was compared between patients exceeding the MID and those who did not. RESULTS: Calculation of the MID resulted in 599 (Standard Error of Measurement), 1029 (empirical rule effect size), 1072 (Cohen's effect size) and 1131 (0.5SD) steps.day-1. An anchor based estimation could not be obtained because of the lack of a sufficiently related anchor. The time to the first hospital admission was significantly different between patients exceeding the MID and patients who did not, using the Standard Error of Measurement as cutoff. CONCLUSIONS: The MID after pulmonary rehabilitation lies between 600 and 1100 steps.day-1. The clinical importance of this change is supported by a reduced risk for hospital admission in those patients with more than 600 steps improvement. PMID- 27124298 TI - Selection and Validation of Reference Genes for qRT-PCR in Cycas elongata. AB - Quantitative reverse transcription PCR (qRT-PCR) is a sensitive technique used in gene expression studies. To achieve a reliable quantification of transcripts, appropriate reference genes are required for comparison of transcripts in different samples. However, few reference genes are available for non-model taxa, and to date, reliable reference genes in Cycas elongata have not been well characterized. In this study, 13 reference genes (ACT7, TUB, UBQ, EIF4, EF1, CLATHRIN1, PP2A, RPB2, GAPC2, TIP41, MAPK, SAMDC and CYP) were chosen from the transcriptome database of C. elongata, and these genes were evaluated in 8 different organ samples. Three software programs, NormFinder, GeNorm and BestKeeper, were used to validate the stability of the potential reference genes. Results obtained from these three programs suggested that CeGAPC2 and CeRPB2 are the most stable reference genes, while CeACT7 is the least stable one among the 13 tested genes. Further confirmation of the identified reference genes was established by the relative expression of AGAMOUSE gene of C. elongata (CeAG). While our stable reference genes generated consistent expression patterns in eight tissues, we note that our results indicate that an inappropriate reference gene might cause erroneous results. Our systematic analysis for stable reference genes of C. elongata facilitates further gene expression studies and functional analyses of this species. PMID- 27124299 TI - Pelvic Organ Support in Animals with Partial Loss of Fibulin-5 in the Vaginal Wall. AB - Compromise of elastic fiber integrity in connective tissues of the pelvic floor is most likely acquired through aging, childbirth-associated injury, and genetic susceptibility. Mouse models of pelvic organ prolapse demonstrate systemic deficiencies in proteins that affect elastogenesis. Prolapse, however, does not occur until several months after birth and is thereby acquired with age or after parturition. To determine the impact of compromised levels of fibulin-5 (Fbln5) during adulthood on pelvic organ support after parturition and elastase-induced injury, tissue-specific conditional knockout (cKO) mice were generated in which doxycycline (dox) treatment results in deletion of Fbln5 in cells that utilize the smooth muscle alpha actin promoter-driven reverse tetracycline transactivator and tetracycline responsive element-Cre recombinase (i.e., Fbln5f/f/SMA++ rtTA/Cre+, cKO). Fbln5 was decreased significantly in the vagina of cKO mice compared with dox-treated wild type or controls (Fbln5f/f/SMA++-rtTA/Cre-/-). In controls, perineal body length (PBL) and bulge increased significantly after delivery but declined to baseline values within 6-8 weeks. Although overt prolapse did not occur in cKO animals, these transient increases in PBL postpartum were amplified and, unlike controls, parturition-induced increases in PBL (and bulge) did not recover to baseline but remained significantly increased for 12 wks. This lack of recovery from parturition was associated with increased MMP-9 and nondetectable levels of Fbln5 in the postpartum vagina. This predisposition to prolapse was accentuated by injection of elastase into the vaginal wall in which overt prolapse occurred in cKO animals, but rarely in controls. Taken together, our model system in which Fbln5 is conditionally knock downed in stromal cells of the pelvic floor results in animals that undergo normal elastogenesis during development but lose Fbln5 as adults. The results indicate that vaginal fibulin-5 during development is crucial for baseline pelvic organ support and is also important for protection and recovery from parturition- and elastase-induced prolapse. PMID- 27124301 TI - Invasive fungal infections in ALL: a new 'growth' area. PMID- 27124300 TI - Defense Responses in Rice Induced by Silicon Amendment against Infestation by the Leaf Folder Cnaphalocrocis medinalis. AB - Silicon (Si) amendment to plants can confer enhanced resistance to herbivores. In the present study, the physiological and cytological mechanisms underlying the enhanced resistance of plants with Si addition were investigated for one of the most destructive rice pests in Asian countries, the rice leaf folder, Cnaphalocrocis medinalis (Guenee). Activities of defense-related enzymes, superoxide dismutase, peroxidase, catalase, phenylalanine ammonia-lyase, and polyphenol oxidase, and concentrations of malondialdehyde and soluble protein in leaves were measured in rice plants with or without leaf folder infestation and with or without Si amendment at 0.32 g Si/kg soil. Silicon amendment significantly reduced leaf folder larval survival. Silicon addition alone did not change activities of defense-related enzymes and malondialdehyde concentration in rice leaves. With leaf folder infestation, activities of the defense-related enzymes increased and malondialdehyde concentration decreased in plants amended with Si. Soluble protein content increased with Si addition when the plants were not infested, but was reduced more in the infested plants with Si amendment than in those without Si addition. Regardless of leaf folder infestation, Si amendment significantly increased leaf Si content through increases in the number and width of silica cells. Our results show that Si addition enhances rice resistance to the leaf folder through priming the feeding stress defense system, reduction in soluble protein content and cell silicification of rice leaves. PMID- 27124302 TI - Molecular Cloning, Expression Pattern and Polymorphisms of NADPH-Cytochrome P450 Reductase in the Bird Cherry-Oat Aphid Rhopalosiphum padi (L.). AB - NADPH-cytochrome P450 reductase (CPR) plays an important role in the cytochrome P450 (CYP)-mediated metabolism of endogenous and exogenous substrates. CPR has been found to be associated with insecticide metabolism and resistance in many insects. However, information regarding CPR in the bird cherry-oat aphid, Rhopalosiphum padi, is unavailable. In the current study, a full-length cDNA (2,476 bp) of CPR (RpCPR) encoding 681 amino acids was cloned from R. padi. Nucleotide sequence and deduced amino acid sequence analysis showed that RpCPR exhibits characteristics of classical CPRs and shares high identities with those of other insects, especially with the pea aphid, Acyrthosiphon pisum. The mRNA of RpCPR was expressed at all developmental stages, with the highest expression level found in the second instar and the lowest in adult. Expression levels of RpCPR in isoprocarb-resistant and imidacloprid-resistant strains were 3.74- and 3.53-fold higher, respectively, than that of a susceptible strain. RpCPR expression could also be induced by low concentrations (LC30) of isoprocarb and imidacloprid. Moreover, we sequenced the open reading frame (ORF) of RpCPR from 167 field samples collected in 11 geographical populations. Three hundred and thirty-four SNPs were detected, of which, 65 were found in more than two individuals. One hundred and ninety-four missense mutations were present in the amino acid sequence, of which, the P484S mutant had an allele frequency of 35.1%. The present results suggest that RpCPR may play an important role in the P450 mediated insecticide resistance of R. padi to isoprocarb and imidacloprid and possibly other insecticides. Meanwhile, RpCPRmaintains high genetic diversity in natural individuals, which provides the possibility of studying potential correlations between variants and certain special physiological characters. PMID- 27124304 TI - Correction: The Impact of Heterogeneous Thresholds on Social Contagion with Multiple Initiators. AB - [This corrects the article DOI: 10.1371/journal.pone.0143020.]. PMID- 27124306 TI - Reduction-Responsive Guanine Incorporated into G-Quadruplex-Forming DNA. AB - Stimulus-responsive biomolecules are attractive targets to understand biomolecule behaviour as well as to explore their therapeutic and diagnostic applications. We demonstrate that a reduction-responsive cleavable group (chemically caged unit) introduced into the guanine ring enables modulation of the secondary structure transition of an oligonucleotide in a reduction-responsive and traceless manner leaving the unmodified oligonucleotide of interest. This simple but robust strategy could yield a variety of stimuli-responsive oligonucleotides. PMID- 27124305 TI - HCV Specific IL-21 Producing T Cells but Not IL-17A Producing T Cells Are Associated with HCV Viral Control in HIV/HCV Coinfection. AB - BACKGROUND: Decreased hepatitis C virus (HCV) clearance, faster cirrhosis progression and higher HCV RNA levels are associated with Human Immunodeficiency virus (HIV) coinfection. The CD4+ T helper cytokines interleukin (IL)-21 and IL 17A are associated with virus control and inflammation, respectively, both important in HCV and HIV disease progression. Here, we examined how antigen specific production of these cytokines during HCV mono and HIV/HCV coinfection was associated with HCV virus control. METHODS: We measured HCV-specific IL-21 and IL-17A production by transwell cytokine secretion assay in PBMCs from monoinfected and coinfected individuals. Viral control was determined by plasma HCV RNA levels. RESULTS: In acutely infected individuals, those able to establish transient/complete HCV viral control tended to have stronger HCV-specific IL-21 production than non-controllers. HCV-specific IL-21 production also correlated with HCV viral decline in acute infection. Significantly stronger HCV-specific IL 21 production was detected in HAART-treated coinfected individuals. HCV-specific IL-17A production was not associated with lower plasma HCV RNA levels in acute or chronic HCV infection and responses were stronger in HIV coinfection. HCV specific IL-21/ IL-17A responses did not correlate with microbial translocation or fibrosis. Exogenous IL-21 treatment of HCV-specific CD8+ T cells from monoinfected individuals enhanced their function although CD8+ T cells from coinfected individuals were somewhat refractory to the effects of IL-21. CONCLUSIONS: These data show that HCV-specific IL-21 and IL-17A-producing T cells are induced in HIV/HCV coinfection. In early HIV/HCV coinfection, IL-21 may contribute to viral control, and may represent a novel tool to enhance acute HCV clearance in HIV/HCV coinfected individuals. PMID- 27124307 TI - Bleeding management in patients with new oral anticoagulants. AB - New oral anticoagulants (NOACs) have been developed in recent years and are increasingly used in clinical practice. Dabigatran is a direct thrombin (factor II) inhibitor while rivaroxaban, apixaban and edoxaban are direct inhibitors of factor Xa. The European Medicines Agency (EMA) currently approves these NOACs for different clinical uses. NOACs do not require routine monitoring of coagulation although an assessment of anticoagulation activity in these patients may be required in different conditions. NOACs show a similar or lower incidence of bleeding compared with conventional therapies in phase III trials. In case of bleeding, non-specific reversal strategies are available while specific reversal agents are the subject of ongoing trials. The role of this review is to summarize the current knowledge on NOCAs focusing on bleeding management in the perioperative period. PMID- 27124308 TI - Is tinea versicolor a contraindication for epidural analgesia? PMID- 27124309 TI - The end is nigh. PMID- 27124303 TI - Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome. AB - We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3' (telomeric) to PAX6 and one within a gene desert 5' (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated. PMID- 27124310 TI - Doctors' engagements with patient experience surveys in primary and secondary care: a qualitative study. AB - BACKGROUND: Patient experience surveys are increasingly important in the measurement of, and attempts to improve, health-care quality. To date, little research has focused upon doctors' attitudes to surveys which give them personalized feedback. AIM: This paper explores doctors' perceptions of patient experience surveys in primary and secondary care settings in order to deepen understandings of how doctors view the plausibility of such surveys. DESIGN, SETTING AND PARTICIPANTS: We conducted a qualitative study with doctors in two regions of England, involving in-depth semi-structured interviews with doctors working in primary care (n = 21) and secondary care (n = 20) settings. The doctors in both settings had recently received individualized feedback from patient experience surveys. FINDINGS: Doctors in both settings express strong personal commitments to incorporating patient feedback in quality improvement efforts. However, they also concurrently express strong negative views about the credibility of survey findings and patients' motivations and competence in providing feedback. Thus, individual doctors demonstrate contradictory views regarding the plausibility of patient surveys, leading to complex, varied and on balance negative engagements with patient feedback. DISCUSSION: Doctors' contradictory views towards patient experience surveys are likely to limit the impact of such surveys in quality improvement initiatives in primary and secondary care. We highlight the need for 'sensegiving' initiatives (i.e. attempts to influence perceptions by communicating particular ideas, narratives and visions) to engage with doctors regarding the plausibility of patient experience surveys. CONCLUSION: This study highlights the importance of engaging with doctors' views about patient experience surveys when developing quality improvement initiatives. PMID- 27124311 TI - Degradation of reactive blue 19 by needle-plate non-thermal plasma in different gas atmospheres: Kinetics and responsible active species study assisted by CFD calculations. AB - This study investigated the degradation of a model organic compound, reactive blue (RB-19), in aqueous solution using a needle-plate non-thermal plasma (NTP) reactor, which was operated using three gas atmospheres (Ar, air, O2) at room temperature and atmospheric pressure. The relative discharge and degradation parameters, including the peak to peak applied voltage, power, ozone generation, pH, decolorization rates, energy density and the total organic carbon (TOC) reduction were analyzed to determine the various dye removal efficiencies. The decolorization rate for Ar, air and O2 were 59.9%, 49.6% and 89.8% respectively at the energy density of 100 kJ/L. The best TOC reduction was displayed by Ar with about 8.8% decrease, and 0% with O2 and air atmospheres. This phenomenon could be explained by the formation of OH* and O3 in the Ar and O2 atmospheres, which are responsible for increased mineralization and efficient decolorization. A one-dimension model was developed using software COMSOL to simulate the RB-19 ozone reaction and verify the experiments by comparing the simulated and experimental results. It was determined that ozone plays the most important role in the dye removal process, and the ozone contribution rate ranged from 0.67 to 0.82. PMID- 27124312 TI - Chronic Galactocele. PMID- 27124314 TI - Author Response: Diagnostic Ability of Retinal Arteriolar Diameter Measurements in Glaucoma. PMID- 27124313 TI - Diagnostic Ability of Retinal Arteriolar Diameter Measurements in Glaucoma. PMID- 27124315 TI - Assessment of UVA-Riboflavin Corneal Cross-Linking Using Small Amplitude Oscillatory Shear Measurements. AB - PURPOSE: The effect of ultraviolet (UV)-riboflavin cross-linking (CXL) has been measured primarily using the strip extensometry technique. We propose a simple and reliable methodology for the assessment of CXL treatment by using an established rheologic protocol based on small amplitude oscillatory shear (SAOS) measurements. It provides information on the average cross-link density and the elastic modulus of treated cornea samples. METHODS: Three fresh postmortem porcine corneas were used to study the feasibility of the technique, one serving as control and two receiving corneal collagen cross-linking treatment. Subsequently, five pairs of fresh postmortem porcine corneas received corneal collagen cross-linking treatment with riboflavin and UVA-irradiation (370 nm; irradiance of 3 mW/cm2) for 30 minutes (Dresden protocol); the contralateral porcine corneas were used as control samples. After the treatment, the linear viscoelastic moduli of the corneal samples were measured using SAOS measurements and the average cross-linking densities extracted. RESULTS: For all cases investigated, the dynamic moduli of the cross-linked corneas were higher compared to those of the corresponding control samples. The increase of the elastic modulus of the treated samples was between 122% and 1750%. The difference was statistically significant for all tested samples (P = 0.018, 2-tailed t-test). CONCLUSIONS: We report a simple and accurate methodology for quantifying the effects of cross-linking on porcine corneas treated with the Dresden protocol by means of SAOS measurements in the linear regime. The measured dynamic moduli, elastic and viscous modulus, represent the energy storage and energy dissipation, respectively. Hence, they provide a means to assess the changing physical properties of the cross-linked collagen networks after CXL treatment. PMID- 27124316 TI - A Genome-Wide Association Study Provides New Evidence That CACNA1C Gene is Associated With Diabetic Cataract. AB - PURPOSE: Diabetic cataract is one of the major eye complications of diabetes. It was reported that cataract occurs two to five times more frequently in patients with diabetes compared with those with no diabetes. The purpose of this study was to identify genetic contributors of diabetic cataract based on a genome-wide association approach using a well-defined Scottish diabetic cohort. METHODS: We adapted linked e-health records to define diabetic cataract. A diabetic cataract case in this study was defined as a type 2 diabetic patient who has ever been recorded in the linked e-health records to have cataracts in both eyes or who had previous cataract extraction surgeries in at least one eye. A control in this study was defined as a type 2 diabetic individual who has never been diagnosed as cataract in the linked e-health records and had no history of cataract surgeries. A standard genome-wide association approach was applied. RESULTS: Overall, we have 2341 diabetic cataract cases and 2878 controls in the genetics of diabetes audit and research in Tayside Scotland (GoDARTS) dataset. We found that the P value of rs2283290 in the CACNA1C gene was 8.81 * 10(-10), which has reached genome-wide significance. We also identified that the blood calcium level was statistically different between diabetic cataract cases and controls. CONCLUSIONS: We identified supporting evidence that CACNA1C gene is associated with diabetic cataract. The role of calcium in the cataractogenesis needs to be reevaluated in future studies. PMID- 27124317 TI - Dissociations in Coherence Sensitivity Reveal Atypical Development of Cortical Visual Processing in Congenital Achromatopsia. AB - PURPOSE: While basic visual functions have been described in subjects with congenital achromatopsia (ACHM), little is known about their mid- or high-level cortical visual processing. We compared midlevel cortical visual processing in ACHM subjects (n = 11) and controls (n = 20). METHODS: Abilities to detect global form, global motion, and biological motion embedded in noise were tested across a range of light levels, including scotopic, in which both ACHM subjects and controls must rely on rods. Contrast sensitivity functions (CSFs) were also measured. RESULTS: Achromatopsia subjects showed differential impairments across tests. In scotopic conditions, global form was most impaired, while biological motion was normal. In a subset of three ACHM subjects with normal scotopic CSFs, two of the three showed global form perception worse than controls; all showed global motion comparable to controls; and strikingly, two of the three showed biological motion perception superior to controls. CONCLUSIONS: The cone signal appears to play a crucial role in the development of perception of global form, as in ACHM this is impaired even in scotopic conditions, in which controls also have to rely on rods, and even in ACHM subjects with no scotopic spatial vision loss. In contrast, the rod signal appears sufficient for the development of normal (or even superior) extrastriate biological motion perception. These results suggest that ACHM leads to atypical development of cortical vision, highlighting the need to better understand the potential for further reorganization of cortical visual processing following new therapies aimed at restoring cone function. PMID- 27124318 TI - Estimating Mean Ocular Perfusion Pressure Using Mean Arterial Pressure and Intraocular Pressure. PMID- 27124319 TI - Author Response: Helicobacter pylori-Related Impact on Glaucoma Pathophysiology. PMID- 27124320 TI - Quantification of Vessel Density in Retinal Optical Coherence Tomography Angiography Images Using Local Fractal Dimension. PMID- 27124321 TI - Author Response: Quantification of Vessel Density in Retinal Optical Coherence Tomography Angiography Images Using Local Fractal Dimension. PMID- 27124323 TI - Tilting and Tumbling of Janus Nanoparticles at Sheared Interfaces. AB - We investigate the response of a single Janus nanoparticle adsorbed at an oil water interface to imposed shear flows using molecular dynamics simulations. We consider particles of different geometry, including spheres, cylinders, and discs, and tune their degree of amphiphilicity by controlling the affinity of their two sides to the fluid phases. We observe that depending on the shape, amphiphilicity, and the applied shear rate, two modes of rotational dynamics takes place: a smooth tilt or a tumbling motion. We demonstrate that irrespective of this dynamic behavior, a steady-state orientation is eventually achieved as a result of the balance between the shear- and capillary-induced torques, which can be tuned by controlling the surface property and flow parameters. Our findings provide insight on using flow fields to tune particle orientation at an interface and to utilize it to direct their assembly into ordered monolayers. PMID- 27124322 TI - Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K 115) Eye Drop in Retinal Angiogenesis and Hypoxia. AB - PURPOSE: In this study, we investigated the therapeutic potential of a Rho associated coiled-coil-containing protein kinase (ROCK) inhibitor ripasudil (K 115) eye drop on retinal neovascularization and hypoxia. METHODS: In vitro, human retinal microvascular endothelial cells (HRMECs) were pretreated with ripasudil and then stimulated with VEGF. ROCK activity was evaluated by phosphorylation of myosin phosphatase target protein (MYPT)-1. Endothelial migration and cell viability were assessed by cell migration and MTT assay, respectively. The concentration of ripasudil in the retina was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). In vivo, normal saline, 0.4%, or 0.8% ripasudil were administered three times a day to mice with oxygen-induced retinopathy (OIR). The areas of neovascularization and avascular retina were also quantified with retinal flat-mounts at postnatal day (P) 15, P17, or P21. The retinal hypoxic area was evaluated using hypoxia-sensitive drug pimonidazole by immunohistochemistry at P17. The vascular normalization was also evaluated by immunohistochemistry at P17. RESULTS: Ripasudil but not fasudil significantly reduced VEGF-induced MYPT-1 phosphorylation in HRMECs at 30 MUmol/L. Ripasudil significantly inhibited VEGF-induced HRMECs migration and proliferation. The concentration of ripasudil in the retina was 3.8 to 10.4 MUmol/L and 6.8 to 14.8 MUmol/L after 0.4% and 0.8% ripasudil treatment, respectively. In the 0.4% and 0.8% ripasudil treated OIR mice, the areas of neovascularization as well as avascular area in the retina was significantly reduced compared with those of saline-treated mice at P17 and P21. Pimonidazole staining revealed that treatment with 0.4% and 0.8% ripasudil significantly inhibited the increase in the hypoxic area compared with saline. 0.8% ripasudil could cause intraretinal vascular sprouting and increase retinal vascular perfusion. CONCLUSIONS: Novel ROCK inhibitor ripasudil eye drop has therapeutic potential in the treatment of retinal hypoxic neovascular diseases via antiangiogenic effects as well as vascular normalization. PMID- 27124324 TI - Nutritional habits in functional dyspepsia and its subgroups: a comparative study. AB - OBJECTIVE: Research data demonstrating nutritional habits of functional dyspepsia (FD) patients are very limited. This is the first study to evaluate nutritional habits in FD subgroups according to Rome III criteria. Our aim was to evaluate nutritional habits of FD patients and determine the food items that may provoke a dyspepsia symptom. METHODS: A total of 168 adults with FD and 135 healthy control subjects participated in the study. FD subjects were divided into epigastric pain syndrome (EP-FD), postprandial distress syndrome (PS-FD), mixed (MX-FD) subgroups according to Rome Criteria III. Subjects completed a questionnaire that included a short-form food frequency questionnaire. Furthermore, subjects were asked to list the food items that were causing a dyspepsia symptom. RESULTS: Functional dyspepsia subjects had a slightly higher BMI (26.1 +/- 4.97 kg/m(2)) than control subjects (24.6 +/- 4.08 kg/m(2)). The most common symptom triggering foods among all the FD groups were fried and fatty foods (27.1%), hot spices (26.4%), and carbonated drinks (21.8%). In FD subgroups, carbonated drinks were more likely to cause a symptom in PS-FD group (37.3%) than MX-FD (25.7%) and EP-FD (22.1%) groups. There was no difference in frequency of main meals and snacks among any of the groups. CONCLUSION: Fatty and spicy foods and carbonated drinks were the most common symptom triggering food items in FD group. In subgroups, carbonated drinks and legumes were more likely to cause a symptom in PS-FD. Removing these food items during the course of treatment might help alleviate the symptoms. PMID- 27124325 TI - Clinical Diagnosis of Mental Disorders Immediately Before and After Cancer Diagnosis: A Nationwide Matched Cohort Study in Sweden. AB - IMPORTANCE: Psychiatric comorbidities are common among patients with cancer. However, whether or not there is increased risk of mental disorders during the diagnostic workup leading to a cancer diagnosis was unknown. OBJECTIVE: To examine the relative risks of depression, anxiety, substance abuse, somatoform/conversion disorder, and stress reaction/adjustment disorder during the periods before and after cancer diagnosis compared with individuals without cancer. DESIGN, SETTING, AND PARTICIPANTS: Nationwide matched cohort study from January 1, 2001, to December 31, 2010, in a Swedish population and health registers. MAIN OUTCOMES AND MEASURES: We estimated the time-varying hazard ratios (HRs) of the first clinical diagnosis of the studied mental disorders from 2 years before cancer diagnosis, through the time of diagnosis, and until 10 years after diagnosis, adjusting for age, sex, calendar period, and educational level. To assess milder mental conditions and symptoms, we further assessed the use of related psychiatric medications for patients with cancer diagnosed during 2008-2009. RESULTS: The study included 304 118 patients with cancer and 3 041 174 cancer-free individuals who were randomly selected from the Swedish population and individually matched to the patients with cancer on year of birth and sex. The median age at diagnosis for the patients with cancer was 69 years, and 46.9% of the patients were female. The relative rate for all studied mental disorders started to increase from 10 months before cancer diagnosis (HR, 1.1; 95% CI, 1.1 1.2), peaked during the first week after diagnosis (HR, 6.7; 95% CI, 6.1-7.4), and decreased rapidly thereafter but remained elevated 10 years after diagnosis (HR, 1.1; 95% CI, 1.1-1.2). The rate elevation was clear for all main cancers except nonmelanoma skin cancer and was stronger for cancers of poorer prognosis. Compared with cancer-free individuals, increased use of psychiatric medications was noted from 1 month before cancer diagnosis and peaked around 3 months after diagnosis among patients with cancer. CONCLUSIONS AND RELEVANCE: Patients diagnosed as having cancer had increased risks of several common mental disorders from the year before diagnosis. These findings support the existing guidelines of integrating psychological management into cancer care and further call for extended vigilance for multiple mental disorders starting from the time of the cancer diagnostic workup. PMID- 27124326 TI - The Society of Thoracic Surgeons Expert Consensus Statement: A Tool Kit to Assist Thoracic Surgeons Seeking Privileging to Use New Technology and Perform Advanced Procedures in General Thoracic Surgery. PMID- 27124327 TI - The Koala, an Iconic Animal under Threat. PMID- 27124328 TI - Clinical Mycoplasma sp. Infections in Free-living Three-toed Box Turtles ( Terrapene carolina triunguis) in Missouri, USA. AB - Mycoplasma species, which can cause upper respiratory tract disease (URTD), are significant pathogens of birds, mammals, fish, and reptiles. Mycoplasmosis is of high concern for chelonian conservation, with the most well-documented cases in gopher and desert tortoises. Mycoplasma sp. infections have been reported in captive and free-living box turtles ( Terrapene spp.). We documented URTD associated with Mycoplasma sp. in two free-living, three-toed box turtles ( Terrapene carolina triunguis) in Missouri, US. Both turtles were Mycoplasma sp. positive by PCR and had URTD-like clinical signs, including nasal and ocular discharge, palpebral edema, lethargy, and weight loss, during a 6-8-wk period between June and September 2014. PMID- 27124330 TI - Prevalence of Antibodies against Neospora caninum in Pere David's Deer ( Elaphurus davidianus ) in Beijing, China. AB - Neospora caninum is an apicomplexan protozoan and causes neuromuscular disorders in canids and abortions in cattle worldwide. We screened sera samples from 49 free-ranging Pere David's deer ( Elaphurus davidianus ) in a nature reserve in Beijing, China, for antibodies against N. caninum using indirect fluorescence antibody tests and western blot tests. Antibodies were found in 27% of the deer. Western blot analysis revealed antibody reactivity against immunodominant N. caninum antigens of 16, 25, and 37 kDa in size together with other visible bands. PMID- 27124329 TI - Pseudorabies Virus and Brucella abortus from an Expanding Wild Pig ( Sus scrofa ) Population in Southern Oklahoma, USA. AB - Wild pigs ( Sus scrofa ) are causing increasing ecologic and economic damage at a global scale. Because wild pigs can carry >=65 diseases that affect livestock, their widespread expansion threatens native wildlife and livestock. We screened wild pigs from south-central Oklahoma, US for antibodies against Brucella abortus , pseudorabies virus (PRV), and porcine reproductive and respiratory syndrome virus (PRRS). These pathogens were chosen because they are part of eradication programs in the US and could have large economic impacts on domestic livestock if transmitted from wild animals. We tested 282 serum samples during spring 2010 (n=149) and 2011 (n=133) and found an overall exposure rate to PRV of 24.1% (n=68); PRV was detected at two of three study sites. Two wild pigs had detectable antibody to B. abortus , and one had detectable antibody to PRRS. On average, 27% of wild pigs within a sounder were positive for PRV antibody, with 44% of the sounders (16/36) having at least one positive individual. These data highlight that wild pigs could carry pathogens that affect domestic livestock. Because the US is free of these pathogens in commercial livestock operations, continued surveillance and vaccination of domestic livestock are needed. Commercial livestock producers at the wildlife-livestock interface may benefit from spatial prioritization of risk zones to facilitate strategic control efforts. PMID- 27124331 TI - Prevalence of Batrachochytrium dendrobatidis in Eastern Hellbender (Cryptobranchus alleganiensis) Populations in West Virginia, USA. AB - The eastern hellbender (Cryptobranchus alleganiensis alleganiensis) is a North American salamander species in decline throughout its range. Efforts to identify the causes of decline have included surveillance for the chytrid fungus Batrachochytrium dendrobatidis (Bd), which has been associated with global amphibian population losses. We evaluated the prevalence of Bd in 42 hellbenders at four sites in West Virginia, US, from June to September 2013, using standard swab protocols and real-time PCR. Overall prevalence of Bd was 52% (22/42; 37.7 66.6%; 95% confidence interval). Prevalence was highest in individuals with body weight >=695 g (chi(2)=7.2487, df=1, P=0.007), and was higher in montane sampling sites than lowland sites (t=-2.4599, df=44, P=0.02). While increased prevalence in montane sampling sites was expected, increased prevalence in larger hellbenders was unexpected and hypothesized to be associated with greater surface area for infection or prolonged periods of exposure in older, larger hellbenders. Wild hellbenders have not been reported to display clinical disease associated with Bd; however, prevalence in the population is important information for evaluating reservoir status and risk to other species, and as a baseline for investigation in the face of an outbreak of clinical disease. PMID- 27124332 TI - Histopathologic and Molecular Characterization of Sarcocystis calchasi Encephalitis in White-winged Doves ( Zenaida asiatica ) and Eurasian Collared Doves ( Streptopelia decaocto ), East-central Texas, USA, 2010-13. AB - Sarcocystis calchasi is a recently described apicomplexan parasite that causes encephalitis in avian hosts. We diagnosed one White-winged Dove ( Zenaida asiatica ) and two Eurasian Collared Doves ( Streptopelia decaocto ) in Texas, US, with a history of neurologic signs with protozoal encephalitis. On histologic examination, all three doves had moderate to severe meningoencephalitis characterized by large numbers of plasma cells, lymphocytes, and macrophages with gliosis and astrocytosis. Brain sections from two doves also contained numerous Mott cells. Protozoal schizonts with rosettes or clusters of individual merozoites consistent with Sarcocystis spp. were seen within areas of inflammation. Sarcocysts were also identified in the skeletal muscle of one dove. The PCR and sequencing of brain and skeletal muscle from two doves revealed 99% identity with S. calchasi. The presence of S. calchasi in fatal cases of encephalitis in doves in Texas suggests that the geographic and host ranges of S. calchasi are broader than previously reported. PMID- 27124333 TI - Effective Reversible Immobilization of Captive Himalayan Black Bears (Selenarctos thibetanus laniger) with Medetomidine-Tiletamine-Zolazepam and Atipamezole. AB - We used a combination of medetomidine and tiletamine-zolazepam to immobilize five Himalayan black bears (Selenarctos thibetanus laniger) in Bannerghatta Biological Park, Bangalore, India. Medetomidine and tiletamine-zolazepam were administered at 0.01 mg/kg and 0.5 mg/kg, respectively. We describe procedures and observations recorded during the immobilization. PMID- 27124335 TI - Chromatin changes predict recurrence after radical prostatectomy. AB - BACKGROUND: Pathological evaluations give the best prognostic markers for prostate cancer patients after radical prostatectomy, but the observer variance is substantial. These risk assessments should be supported and supplemented by objective methods for identifying patients at increased risk of recurrence. Markers of epigenetic aberrations have shown promising results in several cancer types and can be assessed by automatic analysis of chromatin organisation in tumour cell nuclei. METHODS: A consecutive series of 317 prostate cancer patients treated with radical prostatectomy at a national hospital between 1987 and 2005 were followed for a median of 10 years (interquartile range, 7-14). On average three tumour block samples from each patient were included to account for tumour heterogeneity. We developed a novel marker, termed Nucleotyping, based on automatic assessment of disordered chromatin organisation, and validated its ability to predict recurrence after radical prostatectomy. RESULTS: Nucleotyping predicted recurrence with a hazard ratio (HR) of 3.3 (95% confidence interval (CI), 2.1-5.1). With adjustment for clinical and pathological characteristics, the HR was 2.5 (95% CI, 1.5-4.1). An updated stratification into three risk groups significantly improved the concordance with patient outcome compared with a state-of-the-art risk-stratification tool (P<0.001). The prognostic impact was most evident for the patients who were high-risk by clinical and pathological characteristics and for patients with Gleason score 7. CONCLUSION: A novel assessment of epigenetic aberrations was capable of improving risk stratification after radical prostatectomy. PMID- 27124336 TI - Comment on: 'Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort'. PMID- 27124337 TI - Meta-analysis of breast cancer mortality benefit and overdiagnosis adjusted for adherence: improving information on the effects of attending screening mammography. AB - BACKGROUND: Women require information about the impact of regularly attending screening mammography on breast cancer mortality and overdiagnosis to make informed decisions. To provide this information we aimed to meta-analyse randomised controlled trials adjusted for adherence to the trial protocol. METHODS: Nine screening mammography trials used in the Independent UK Breast Screening Report were selected. Extending an existing approach to adjust intention-to-treat (ITT) estimates for less than 100% adherence rates, we conducted a random-effects meta-analysis. This produced a combined deattenuated prevented fraction and a combined deattenuated percentage risk of overdiagnosis. RESULTS: In women aged 39-75 years invited to screen, the prevented fraction of breast cancer mortality at 13-year follow-up was 0.22 (95% CI 0.15-0.28) and it increased to 0.30 (95% CI 0.18-0.42) with deattenuation. In women aged 40-69 years invited to screen, the ITT percentage risk of overdiagnosis during the screening period was 19.0% (95% CI 15.2-22.7%), deattenuation increased this to 29.7% (95% CI 17.8-41.5%). CONCLUSIONS: Adjustment for nonadherence increased the size of the mortality benefit and risk of overdiagnosis by up to 50%. These estimates are more appropriate when developing quantitative information to support individual decisions about attending screening mammography. PMID- 27124338 TI - Reply to the comment on 'Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort'. PMID- 27124340 TI - 5'-Substituted Amiloride Derivatives as Allosteric Modulators Binding in the Sodium Ion Pocket of the Adenosine A2A Receptor. AB - The sodium ion site is an allosteric site conserved among many G protein-coupled receptors (GPCRs). Amiloride 1 and 5-(N,N-hexamethylene)amiloride 2 (HMA) supposedly bind in this sodium ion site and can influence orthosteric ligand binding. The availability of a high-resolution X-ray crystal structure of the human adenosine A2A receptor (hA2AAR), in which the allosteric sodium ion site was elucidated, makes it an appropriate model receptor for investigating the allosteric site. In this study, we report the synthesis and evaluation of novel 5'-substituted amiloride derivatives as hA2AAR allosteric antagonists. The potency of the amiloride derivatives was assessed by their ability to displace orthosteric radioligand [(3)H]4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5 a]-[1,3,5]triazin-5-yl)amino)ethyl)phenol ([(3)H]ZM-241,385) from both the wild type and sodium ion site W246A mutant hA2AAR. 4-Ethoxyphenethyl-substituted amiloride 12l was found to be more potent than both amiloride and HMA, and the shift in potency between the wild-type and mutated receptor confirmed its likely binding to the sodium ion site. PMID- 27124339 TI - Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. AB - BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance. PMID- 27124341 TI - Man With Painful Proptosis of the Left Eye. PMID- 27124359 TI - Resolving Electronic Transitions in Synthetic Fluorescent Protein Chromophores by Magnetic Circular Dichroism. AB - The detailed electronic structures of fluorescent chromophores are important for their use in imaging of living cells. A series of green fluorescent protein chromophore derivatives is examined by magnetic circular dichroism (MCD) spectroscopy, which allows the resolution of more bands than plain absorption and fluorescence. Observed spectral patterns are rationalized with the aid of time dependent density functional theory (TDDFT) computations and the sum-over-state (SOS) formalism, which also reveals a significant dependence of MCD intensities on chromophore conformation. The combination of organic and theoretical chemistry with spectroscopic techniques also appears useful in the rational design of fluorescence labels and understanding of the chromophore's properties. For example, the absorption threshold can be heavily affected by substitution on the phenyl ring but not much on the five-member ring, and methoxy groups can be used to further tune the electronic levels. PMID- 27124358 TI - Identification of miR-34 regulatory networks in settings of disease and antimiR therapy: Implications for treating cardiac pathology and other diseases. AB - Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription factor (TF)-miRNA regulatory networks has added complexity to understanding the therapeutic potential of miRNA-based therapies. Here, we sought to determine whether antimiR-34 targets secondary miRNAs via TFs which could contribute to antimiR-34-mediated protection. Using miRNA-Seq we identified differentially regulated miRNAs in hearts from mice with cardiac pathology due to transverse aortic constriction (TAC), and focused on miRNAs which were also regulated by antimiR-34. Two clusters of stress-responsive miRNAs were classified as "pathological" and "cardioprotective," respectively. Using ChIPBase we identified 45 TF binding sites on the promoters of "pathological" and "cardioprotective" miRNAs, and 5 represented direct targets of miR-34, with the capacity to regulate other miRNAs. Knockdown studies in a cardiomyoblast cell line demonstrated that expression of 2 "pathological" miRNAs (let-7e, miR-31) was regulated by one of the identified TFs. Furthermore, by qPCR we confirmed that expression of let-7e and miR-31 was lower in hearts from antimiR-34 treated TAC mice; this may explain why targeting the entire miR-34 family is more effective than targeting miR-34a alone. Finally, we showed that Acsl4 (a common target of miR-34, let-7e and miR-31) was increased in hearts from TAC antimiR-34 treated mice. In summary, antimiR-34 regulates the expression of other miRNAs and this has implications for drug development. PMID- 27124360 TI - Pumpkin-Derived Porous Carbon for Supercapacitors with High Performance. AB - Pumpkin has been employed for the first time as a renewable, low-cost precursor for the preparation of porous carbon materials with excellent performance. Unlike most other precursors, pumpkin is rich in sugars and starch, and it has advantageous properties for large-scale production. The as-prepared materials adopted a unique morphology that consisted of numerous fused sphere-like carbon grains with a high specific surface area (2968 m(2) g(-1) ), abundant micro and mesopores, and excellent electrochemical properties. The pumpkin-derived activated carbon (PAC) material not only exhibited a high specific capacitance of 419 F g(-1) , but also showed considerable cycling stability, with 93.6 % retention after 10 000 cycles. Moreover, a symmetrical supercapacitor that was based on PAC showed a high energy density of 22.1 W h kg(-1) in aqueous electrolyte. These superior properties demonstrate that PAC holds great promise for applications in electrochemical energy-storage devices. PMID- 27124361 TI - Progressive Increase in Disinfection Byproducts and Mutagenicity from Source to Tap to Swimming Pool and Spa Water: Impact of Human Inputs. AB - Pools and spas are enjoyed throughout the world for exercise and relaxation. However, there are no previous studies on mutagenicity of disinfected spa (hot tub) waters or comprehensive identification of disinfection byproducts (DBPs) formed in spas. Using 28 water samples from seven sites, we report the first integrated mutagenicity and comprehensive analytical chemistry of spas treated with chlorine, bromine, or ozone, along with pools treated with these same disinfectants. Gas chromatography (GC) with high-resolution mass spectrometry, membrane-introduction mass spectrometry, and GC-electron capture detection were used to comprehensively identify and quantify DBPs and other contaminants. Mutagenicity was assessed by the Salmonella mutagenicity assay. More than 100 DBPs were identified, including a new class of DBPs, bromoimidazoles. Organic extracts of brominated pool/spa waters were 1.8* more mutagenic than chlorinated ones; spa waters were 1.7* more mutagenic than pools. Pool and spa samples were 2.4 and 4.1* more mutagenic, respectively, than corresponding tap waters. The concentration of the sum of 21 DBPs measured quantitatively increased from finished to tap to pool to spa; and mutagenic potency increased from finished/tap to pools to spas. Mutagenic potencies of samples from a chlorinated site correlated best with brominated haloacetic acid concentrations (Br-HAAs) (r = 0.98) and nitrogen-containing DBPs (N-DBPs) (r = 0.97) and the least with Br trihalomethanes (r = 0.29) and Br-N-DBPs (r = 0.04). The mutagenic potencies of samples from a brominated site correlated best (r = 0.82) with the concentrations of the nine HAAs, Br-HAAs, and Br-DBPs. Human use increased significantly the DBP concentrations and mutagenic potencies for most pools and spas. These data provide evidence that human precursors can increase mutagenic potencies of pools and spas and that this increase is associated with increased DBP concentrations. PMID- 27124362 TI - Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants. AB - BACKGROUND: Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by Food and Drug Administration to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 A from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of wild-type HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new NNRTI in phase III clinical trials. METHODS: Using a single round HIV-1 infection assay, we tested RPV and DOR against a broad panel of NNRTI-resistant mutants to determine their respective activities. We also used molecular modeling to determine if the susceptibility profile of each compound was related to how they bind RT. RESULTS: Several mutants displayed decreased susceptibility to DOR. However, with the exception of E138K, our data suggest that the mutations that reduce the potency of DOR and RPV are non overlapping. Thus, these 2 NNRTIs have the potential to be used together in combination therapy. We also show that the location at which DOR and RPV bind with the NNRTI binding pocket of RT correlates with the differences in their respective susceptibility to the panel of NNRTI-resistance mutations. CONCLUSIONS: This shows that (1) DOR is susceptible to a number of well-known NNRTI resistance mutations and (2) an understanding of the mutational susceptibilities and binding interactions of NNRTIs with RT could be used to develop pairs of compounds with non-overlapping mutational susceptibilities. PMID- 27124365 TI - A Four-Component Heterometallic Cu-Pt Quadrilateral via Self-Sorting. AB - Herein we combine the subcomponent self-assembly and integrative self-sorting techniques with the well-established platinum(II)-pyridine coordination-driven self-assembly to report the quantitative synthesis and spectroscopic characterization of a heterometallic CuI -PtII quadrilateral QL that is formed from a total of twelve molecular components from four unique species, including 5 (pyridin-4-ylethynyl)picolinaldehyde (1), p-toluidine (2), [Cu(CH3 CN4 ](PF6 ) (3), and cis-Pt(PEt3 )2 (OTf)2 (4), in a 4:4:2:2 ratio. Despite the many different entities potentially forming from these four precursor units, the clean formation of QL is mainly guided by the different coordination preferences of the metal ions 3 and 4, and the design criteria inherent in compounds 1 and 2. PMID- 27124364 TI - Asymmetric Organocatalytic Stepwise [2+2] Entry to Tetra-Substituted Heterodimeric and Homochiral Cyclobutanes. AB - An asymmetric synthesis of tetra-substituted cyclobutanes involving an organocatalytic, stepwise [2+2]-cycloaddition is described. The secondary-amine catalyzed method allows for the hetero-dimerization of two different cinnamic acid-derived sub-units, opening a novel one-step assembly to densely functionalized, head-to-tail coupled dimeric cyclobutanes in high enantiomeric excess. A series of selective synthetic interconversions in these sensitive cycloadducts is also described. PMID- 27124363 TI - Male Partner Participation in Antenatal Clinic Services is Associated With Improved HIV-Free Survival Among Infants in Nairobi, Kenya: A Prospective Cohort Study. AB - OBJECTIVE: This prospective study investigated the relationship between male antenatal clinic (ANC) involvement and infant HIV-free survival. METHODS: From 2009 to 2013, HIV-infected pregnant women were enrolled from 6 ANCs in Nairobi, Kenya and followed with their infants until 6 weeks postpartum. Male partners were encouraged to attend antenatally through invitation letters. Men who failed to attend had questionnaires sent for self-completion postnatally. Multivariate regression was used to identify correlates of male attendance. The role of male involvement in infant outcomes of HIV infection, mortality, and HIV-free survival was examined. RESULTS: Among 830 enrolled women, 519 (62.5%) consented to male participation and 136 (26.2%) men attended the ANC. For the 383 (73.8%) women whose partners failed to attend, 63 (16.4%) were surveyed through outreach. In multivariate analysis, male report of previous HIV testing was associated with maternal ANC attendance (adjusted odds ratio = 3.7; 95% CI: 1.5 to 8.9, P = 0.003). Thirty-five (6.6%) of 501 infants acquired HIV or died by 6 weeks of life. HIV-free survival was significantly greater among infants born to women with partner attendance (97.7%) than those without (91.3%) (P = 0.01). Infants lacking male ANC engagement had an approximately 4-fold higher risk of death or infection compared with those born to women with partner attendance (HR = 3.95, 95% CI: 1.21 to 12.89, P = 0.023). Adjusting for antiretroviral use, the risk of death or infection remained significantly greater for infants born to mothers without male participation (adjusted hazards ratio = 3.79, 95% CI: 1.15 to 12.42, P = 0.028). CONCLUSIONS: Male ANC attendance was associated with improved infant HIV-free survival. Promotion of male HIV testing and engagement in ANC/prevention of mother-to-child transmission services may improve infant outcomes. PMID- 27124366 TI - ZnO/Al:ZnO Transparent Resistive Switching Devices Grown by Atomic Layer Deposition for Memristor Applications. AB - ZnO has intrinsic semiconductor conductivity because of an unintentional doping mechanism resulting from the growth process that is mainly attributable to oxygen vacancies (VO) positioned in the bandgap. ZnO has multiple electronic states that depend on the number of vacancies and the charge state of each vacancy. In addition to the individual electron states, the vacancies have different vibrational states. We developed a high-temperature precursor vapor mask technique using Al2O3 to pattern the atomic layer deposition of ZnO and Al:ZnO layers on ZnO-based substrates. This technique was used to create a memristor device based on Al:ZnO thin films having metallic and semiconducting and insulating transport properties ZnO. We demonstrated that adding combination of Al2O3 and TiO2 barrier layers improved the resistive switching behavior. The change in the resistance between the high- and low-resistivity states of the memristor with a combination of Al2O3 and TiO2 was approximately 157%. The devices were exposed to laser light from three different laser diodes. The 450 nm laser diode noticeably affected the combined Al2O3 and TiO2 barrier, creating a high-resistivity state with a 2.9% shift under illumination. The high-resistivity state shift under laser illumination indicates defect shifts and the thermodynamic transition of ZnO defects. PMID- 27124367 TI - Asbestos: Socio-legal and Scientific Controversies and Unsound Science in the Context of the Worldwide Asbestos Tragedy - Lessons to be Learned. AB - Eight to fifteen per cent of lung cancer cases and nearly all mesothelioma cases are caused by asbestos. Problems in compensation issues ensue from strict legal requirements for eligibility and regulations of the statutory accident insurance institution pertaining to eligibility for occupational disease benefits. The latter include the unscientific requirement for set numbers of asbestos bodies or fibers to be found in lung tissue in order to "prove" disease causation if lung specimen are available. Although the validity of such evidence has been discredited by independent scientists, it is still used as evidence by an influential US pathology department. Frequently, epidemiological evidence regarding causal relationships and exposure histories is also often being ignored by insurance-affiliated medical experts.Similar misleading arguments are currently being used in newly industrialized countries where white asbestos - which is carcinogenic and fibrogenic like other asbestos types - is efficiently promoted as being less harmful. As a result, asbestos use is increasing in some of these countries. Behind the worldwide asbestos tragedy, a well-designed strategy orchestrated by certain transnational or multinational industrial interest groups can be perceived.Beyond the asbestos tragedy their covert plan is motivated by economic interests and discounts the ensuing damage to health and the impact of the diseases they create on public health systems. PMID- 27124369 TI - Gene Expression Classifier Testing and the Surgical Decision-Making Process for Patients With Thyroid Nodules-Reply. PMID- 27124368 TI - PAFAH1B1 and the lncRNA NONHSAT073641 maintain an angiogenic phenotype in human endothelial cells. AB - AIM: Platelet-activating factor acetyl hydrolase 1B1 (PAFAH1B1, also known as Lis1) is a protein essentially involved in neurogenesis and mostly studied in the nervous system. As we observed a significant expression of PAFAH1B1 in the vascular system, we hypothesized that PAFAH1B1 is important during angiogenesis of endothelial cells as well as in human vascular diseases. METHOD: The functional relevance of the protein in endothelial cell angiogenic function, its downstream targets and the influence of NONHSAT073641, a long non-coding RNA (lncRNA) with 92% similarity to PAFAH1B1, were studied by knockdown and overexpression in human umbilical vein endothelial cells (HUVEC). RESULTS: Knockdown of PAFAH1B1 led to impaired tube formation of HUVEC and decreased sprouting in the spheroid assay. Accordingly, the overexpression of PAFAH1B1 increased tube number, sprout length and sprout number. LncRNA NONHSAT073641 behaved similarly. Microarray analysis after PAFAH1B1 knockdown and its overexpression indicated that the protein maintains Matrix Gla Protein (MGP) expression. Chromatin immunoprecipitation experiments revealed that PAFAH1B1 is required for active histone marks and proper binding of RNA Polymerase II to the transcriptional start site of MGP. MGP itself was required for endothelial angiogenic capacity and knockdown of both, PAFAH1B1 and MGP, reduced migration. In vascular samples of patients with chronic thromboembolic pulmonary hypertension (CTEPH), PAFAH1B1 and MGP were upregulated. The function of PAFAH1B1 required the presence of the intact protein as overexpression of NONHSAT073641, which was highly upregulated during CTEPH, did not affect PAFAH1B1 target genes. CONCLUSION: PAFAH1B1 and NONHSAT073641 are important for endothelial angiogenic function. PMID- 27124370 TI - Practical Stannylation of Allyl Acetates Catalyzed by Nickel with Bu3 SnOMe. AB - A practical and scalable nickel-catalyzed allylic stannylation of allyl acetates with Bu3 SnOMe is described. A variety of acyclic and cyclic allyl acetates, even with base-sensitive moieties, undergoes the stannylation by using NiBr2 /4,4'-di tert-butylbipyridine (dtbpy)/Mn catalyst system to afford highly functionalized allyl stannanes with excellent regioselectivity and yields. Furthermore, the scope of protocol is also extended by the reaction of propargyl acetates, giving rise to propargyl or allenyl stannanes. Additionally, a unique diastereoselectivity using the nickel catalyst different from the palladium was demonstrated for the stannylation of cyclic allyl acetates. In the reaction, inexpensive and stable nickel complexes, abundant reductant (Mn), and atom economical stannyl source were used. PMID- 27124371 TI - Impact of maternal serum levels of Visfatin, AFP, PAPP-A, sFlt-1 and PlGF at 11 13 weeks gestation on small for gestational age births. AB - OBJECTIVE: Investigating potential value of maternal serum Visfatin, sFlt-1, PlGF, AFP, PAPP-A levels at first trimester for prediction of small for gestational age (SGA) at birth. METHODS: Measurements were performed in 20 SGA and 65 control cases. Logistic regression analysis adjusted for age and weeks of pregnancy at data collection was performed to estimate odds ratios (OR), 95% confidence intervals (95% CI) and p values separately for each potential predictor. A multiple regression model was used to assess the impact of all the promising predictors adjusted for each other. Receiver operating characteristic (ROC) analysis was used to indicate the ability to discriminate between SGA cases and controls. RESULTS: There was an association of serum PlGF levels (OR 0.53 per interquartile range [IQR] increase in PlGF; 95% CI 0.24-1.16), sFlt-1/PlGF ratio (OR 1.42 per IQR increase in sFlt-1/PlGF; 95% CI 1.03-1.96), serum Visfatin levels (OR 0.31 per IQR increase in Visfatin; 95% CI 0.10-0.95) and smoking (OR 4.24; 95% CI 1.10-16.37) with SGA at birth. CONCLUSIONS: Associations between SGA and lower PlGF, Visfatin levels as well as increased sFlt-1/PlGF ratio and smoking status were detected which may contribute to predict SGA. PMID- 27124373 TI - Behavior of Halogen Bonds of the Y-X???pi Type (X, Y=F, Cl, Br, I) in the Benzene pi System, Elucidated by Using a Quantum Theory of Atoms in Molecules Dual Functional Analysis. AB - The nature of halogen bonds of the Y-X-?-pi(C6 H6 ) type (X, Y=F, Cl, Br, and I) have been elucidated by using the quantum theory of atoms in molecules (QTAIM) dual-functional analysis (QTAIM-DFA), which we proposed recently. Asterisks (?) emphasize the presence of bond-critical points (BCPs) in the interactions in question. Total electron energy densities, Hb (rc ), are plotted versus Hb (rc ) Vb (rc )/2 [=(h(2) /8m)?(2) rhob (rc )] for the interactions in QTAIM-DFA, in which Vb (rc ) are potential energy densities at the BCPs. Data for perturbed structures around fully optimized structures were used for the plots, in addition to those of the fully optimized ones. The plots were analyzed by using the polar (R, theta) coordinate for the data of fully optimized structures with (thetap , kappap ) for those that contained the perturbed structures; thetap corresponds to the tangent line of the plot and kappap is the curvature. Whereas (R, theta) corresponds to the static nature, (thetap , kappap ) represents the dynamic nature of the interactions. All interactions in Y-X-?-pi(C6 H6 ) are classified by pure closed-shell interactions and characterized to have vdW nature, except for Y-I-?-pi(C6 H6 ) (Y=F, Cl, Br) and F-Br-?-pi(C6 H6 ), which have typical hydrogen-bond nature without covalency. I-I-?-pi(C6 H6 ) has a borderline nature between the two. Y-F-?-pi(C6 H6 ) (Y=Br, I) were optimized as bent forms, in which Y-?-pi interactions were detected. The Y-?-pi interactions in the bent forms are predicted to be substantially weaker than those in the linear F-Y-? pi(C6 H6 ) forms. PMID- 27124374 TI - Refinements of and commentary on the silver staining techniques of Fernandez Galiano. AB - The original ammoniacal silver carbonate staining technique and subsequent modification developed by Fernandez-Galiano are useful for investigating ciliate protozoan systematics and/or ciliate cortical structure and morphogenesis. The technique is complicated, however, by both uncertainties arising from the need to count drops of reagents and subjective control of the staining intensity. I have resolved these complications by defining volumes of reagents rather than using drops and by defining a range of staining times. I also comment on various steps of the techniques. My techniques are simplified and refined to produce consistent, high quality staining results. PMID- 27124375 TI - Suppression of Photocyclization: Stabilization of an Aggregation-Induced Tetraaryldistyrylbenzene Emitter. AB - The synthesis of 2,3,5,6-tetrakis(2,6-difluorophenyl)di(styryl)benzene by using a conventional synthetic sequence, including Diels-Alder and Horner reactions is reported. The target is an effective aggregation-induced emitter. It is photostable with respect to electrocyclization, due to the presence of the fluorine substituents. This compound undergoes photochemical trans/cis isomerization of its styryl double bonds. PMID- 27124372 TI - Embryologic and Fetal Development of the Human Eyelid. AB - PURPOSE: To review the recent data about eyelid morphogenesis, and outline a timeline for eyelid development from the very early stages during embryonic life till final maturation of the eyelid late in fetal life. METHODS: The authors extensively review major studies detailing human embryologic and fetal eyelid morphogenesis. These studies span almost a century and include some more recent cadaver studies. Numerous studies in the murine model have helped to better understand the molecular signals that govern eyelid embryogenesis. The authors summarize the current findings in molecular biology, and highlight the most significant studies in mice regarding the multiple and interacting signaling pathways involved in regulating normal eyelid morphogenesis. RESULTS: Eyelid morphogenesis involves a succession of subtle yet strictly regulated morphogenetic episodes of tissue folding, proliferation, contraction, and even migration, which may occur simultaneously or in succession. CONCLUSIONS: Understanding the extraordinary process of building eyelid tissue in embryonic life, and deciphering its underlying signaling machinery has far reaching clinical implications beyond understanding the developmental abnormalities involving the eyelids, and may pave the way for achieving scar-reducing therapies in adult mammalian wounds, or control the spread of malignancies. PMID- 27124376 TI - Trichomonas vaginalis Repair of Iron Centres Proteins: The Different Role of Two Paralogs. AB - Trichomonas vaginalis, the causative parasite of one of the most prevalent sexually transmitted diseases is, so far, the only protozoan encoding two putative Repair of Iron Centres (RIC) proteins. Homologs of these proteins have been shown to protect bacteria from the chemical stress imposed by mammalian immunity. In this work, the biochemical and functional characterisation of the T. vaginalis RICs revealed that the two proteins have different properties. Expression of ric1 is induced by nitrosative stress but not by hydrogen peroxide, while ric2 transcription remained unaltered under similar conditions. T. vaginalis RIC1 contains a di-iron centre, but RIC2 apparently does not. Only RIC1 resembles bacterial RICs on spectroscopic profiling and repairing ability of oxidatively-damaged iron-sulfur clusters. Unexpectedly, RIC2 was found to bind DNA plasmid and T. vaginalis genomic DNA, a function proposed to be related with its leucine zipper domain. The two proteins also differ in their cellular localization: RIC1 is expressed in the cytoplasm only, and RIC2 occurs both in the nucleus and cytoplasm. Therefore, we concluded that the two RIC paralogs have different roles in T. vaginalis, with RIC2 showing an unprecedented DNA binding ability when compared with all other until now studied RICs. PMID- 27124377 TI - Hierarchy in the eye of the beholder: (Anti-)egalitarianism shapes perceived levels of social inequality. AB - Debate surrounding the issue of inequality and hierarchy between social groups has become increasingly prominent in recent years. At the same time, individuals disagree about the extent to which inequality between advantaged and disadvantaged groups exists. Whereas prior work has examined the ways in which individuals legitimize (or delegitimize) inequality as a function of their motivations, we consider whether individuals' orientation toward group-based hierarchy motivates the extent to which they perceive inequality between social groups in the first place. Across 8 studies in both real-world (race, gender, and class) and artificial contexts, and involving members of both advantaged and disadvantaged groups, we show that the more individuals endorse hierarchy between groups, the less they perceive inequality between groups at the top and groups at the bottom. Perceiving less inequality is associated with rejecting egalitarian social policies aimed at reducing it. We show that these differences in hierarchy perception as a function of individuals' motivational orientation hold even when inequality is depicted abstractly using images, and even when individuals are financially incentivized to accurately report their true perceptions. Using a novel methodology to assess accurate memory of hierarchy, we find that differences may be driven by both antiegalitarians underestimating inequality, and egalitarians overestimating it. In sum, our results identify a novel perceptual bias rooted in individuals' chronic motivations toward hierarchy maintenance, with the potential to influence their policy attitudes. (PsycINFO Database Record PMID- 27124378 TI - Personality traits below facets: The consensual validity, longitudinal stability, heritability, and utility of personality nuances. AB - It has been argued that facets do not represent the bottom of the personality hierarchy-even more specific personality characteristics, nuances, could be useful for describing and understanding individuals and their differences. Combining 2 samples of German twins, we assessed the consensual validity (correlations across different observers), rank-order stability, and heritability of nuances. Personality nuances were operationalized as the 240 items of the Revised NEO Personality Inventory (NEO-PI-R). Their attributes were examined by analyzing item residuals, controlling for the variance of the facet the item had been assigned to and all other facets. Most nuances demonstrated significant (p < .0002) cross-method agreement and rank-order stability. A substantial proportion of them (48% in self-reports, 20% in informant ratings, and 50% in combined ratings) demonstrated a significant (p < .0002) component of additive genetic variance, whereas evidence for environmental influences shared by twins was modest. Applying a procedure to estimate stability and heritability of true scores of item residuals yielded estimates comparable with those of higher-order personality traits, with median estimates of rank-order stability and heritability being .77 and .52, respectively. Few nuances demonstrated robust associations with age and gender, but many showed incremental, conceptually meaningful, and replicable (across methods and/or samples) predictive validity for a range of interest domains and body mass index. We argue that these narrow personality characteristics constitute a valid level of the personality hierarchy. They may be especially useful for providing a deep and contextualized description of the individual, but also for the prediction of specific outcomes. (PsycINFO Database Record PMID- 27124379 TI - Writer-reader contagion of inspiration and related states: Conditional process analyses within a cross-classified writer * reader framework. AB - A longstanding tradition in the humanities holds that a writer's inspiration is infectious, but this thesis has not been tested. We hypothesized that (a) inspiration is infectious, such that inspired writers are more inspiring to the average reader; (b) contagion is mediated by the insightfulness of the text; and (c) contagion is moderated by readers' openness to experience, such that open readers are more prone to contagion. To test these hypotheses, a sample of 195 student writers, each of whom wrote 1 poem, was crossed with a sample of 220 student readers, who read all poems. Data were available for 36,020 cells of the resulting Writer * Reader matrix. Our analytic approach integrated cross classified multilevel modeling with conditional process analysis. As hypothesized, writers who were more inspired elicited higher levels of inspiration in the average reader. Inspiration contagion was mediated by the insightfulness and pleasantness of the text and was partially suppressed by originality. Inspiration contagion was moderated by reader openness. Moderated mediation analyses indicated that open readers were prone to contagion because they were tolerant of the originality and sublimity of inspired writing. Additional analyses differentiated contagion of inspiration from contagion of its covariates (awe, positive affect), documented effects of writer inspiration on reader enthrallment (awe, chills), and showed that writer effort is a poor predictor of reader states. The infectiousness of inspiration-through poetry, if not also through scripture and academic writing-suggests that a given instance of inspiration may have far-reaching cultural implications, including dissemination of innovations and ideologies. (PsycINFO Database Record PMID- 27124380 TI - Long-term clinical impact of polymer-free sirolimus-eluting stents in unselected patients. AB - OBJECTIVES: The long-term clinical impact of polymer-free sirolimus-eluting stents (PF-SES) in unselected patients undergoing percutaneous coronary intervention (PCI) still remains poorly investigated. We studied the long-term clinical impact of PF-SES in a large cohort of unselected patients receiving PCI therapy at two tertiary care centers in India. METHODS: A total of 3213 patients received PCI with drug-eluting stents during the period from December 2004 to September 2011. Among these, those receiving PF-SES implantation were retrospectively included in this registry. The primary endpoint in our study was the occurrence of major adverse cardiac events (MACE), defined as the composite of death/myocardial infarction (MI) and target lesion revascularization, whereas the main secondary endpoints were cardiac death/MI and definite/probable stent thrombosis. RESULTS: A total of 1213 patients (83.8% men, 31.8% diabetics) with 1658 lesions (52.5% B2/C, according to the American College of Cardiology/American Heart Association classification) were studied. After a median follow-up of 1160 days, MACE occurred in 10.0% of patients, whereas the rates of cardiac death/MI and definite/probable ST were found to be 5.4 and 1.9%, respectively. The incidence of MACE was more common in patients aged at least 65 years [hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.13-2.52, P=0.01] and diabetics (HR=1.71, 95% CI=1.18-2.47, P=0.004). The incidence of cardiac death/MI was more common in patients aged at least 65 years (HR=2.21, 95% CI=1.32 3.70, P=0.003). The baseline risk profile did not impact the occurrence of target lesion revascularization. CONCLUSION: In this large cohort of unselected PCI patients treated in India, PF-SES shows a sustained safety and efficacy at long term follow-up. PMID- 27124381 TI - Can modifier gene mutations improve the predictive value of the modified Iron Avidity Index in Type 1 Hereditary Haemochromatosis? PMID- 27124382 TI - Towards an optimal contact metal for CNTFETs. AB - Downscaling of the contact length Lc of a side-contacted carbon nanotube field effect transistor (CNTFET) is challenging because of the rapidly increasing contact resistance as Lc falls below 20-50 nm. If in agreement with existing experimental results, theoretical work might answer the question, which metals yield the lowest CNT-metal contact resistance and what physical mechanisms govern the geometry dependence of the contact resistance. However, at the scale of 10 nm, parameter-free models of electron transport become computationally prohibitively expensive. In our work we used a dedicated combination of the Green function formalism and density functional theory to perform an overall ab initio simulation of extended CNT-metal contacts of an arbitrary length (including infinite), a previously not achievable level of simulations. We provide a systematic and comprehensive discussion of metal-CNT contact properties as a function of the metal type and the contact length. We have found and been able to explain very uncommon relations between chemical, physical and electrical properties observed in CNT-metal contacts. The calculated electrical characteristics are in reasonable quantitative agreement and exhibit similar trends as the latest experimental data in terms of: (i) contact resistance for Lc = infinity, (ii) scaling of contact resistance Rc(Lc); (iii) metal-defined polarity of a CNTFET. Our results can guide technology development and contact material selection for downscaling the length of side-contacts below 10 nm. PMID- 27124383 TI - Regions of ilium and fibula providing clinically usable bone for mandible reconstruction: "A different approach to bone comparison". AB - A variety of donor sites are available for mandibular reconstruction. We present here a different way of comparing two commonly-used bone flaps. The lengths of the usable parts in a total of 241 coxal bones, 91 mandibles and 60 fibulas were measured. The mandible was measured from condyle-to-condyle and the harvestable bone length (HBL) and usable (UBL) bone lengths in fibula and ilium were also measured. The bone thickness (BT) in 60 iliac crests was measured in two parallel lines from the anterior superior iliac spine (ASIS) along the iliac crest. The mandible was 32.17 mm shorter in females than in males. The total ilium UBL was 171.12 mm in females and 178.80 mm in males. The mean HBL of the fibula was 22.6 mm shorter in females than in males. However, in some fibulas in both females and males, only 4.2% and 21.1% of the HBL respectively could be used if the ultimate goal was to insert dental implants. We found significant correlations between BT and gender in both fibula and ilium (P<= 0.05). The ilium offers constant BT throughout the usable bone area with a similar bone length to the fibula. In contrast, the fibula showed variable bone dimensions, so not all of it is clinically usable. This should especially be considered in females when a mandibular reconstruction is planned with the goal of occlusal rehabilitation. Clin. Anat. 29:773-778, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27124385 TI - Summary of the 9th international conference on human herpesviruses 6 and 7 (HHV 6A, HHV-6B, and HHV-7). AB - The 9th International Conference on Human herpesviruses 6 and 7 (HHV-6A, HHV-6B, and HHV-7) was held at Harvard Medical School in Boston, Massachusetts from November 9 to 11, 2015. Important new information was presented regarding: the biology of these viruses, particularly HHV-6A and HHV-6B; the biology and epidemiology of inherited chromosomally integrated HHV-6A/B; improved diagnostic tests; animal models for studying HHV-6 and HHV-7, and animal viruses with similarities to HHV-6 and HHV-7; established and possible disease associations; and new approaches to treatment. Here, we summarize work of particular interest. J. Med. Virol. 88:2038-2043, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27124384 TI - A population-based registry study evaluating surgery in newly diagnosed uterine cancer. AB - INTRODUCTION: The aim was to evaluate surgical treatment of newly diagnosed uterine cancer in a Swedish population. MATERIAL AND METHODS: Data in the GynOp registry from 2008 to 2014 were analyzed. RESULTS: In total, 3443 cases were included: 430 (12%) were robotic-assisted laparoscopic, 272 (8%) laparoscopic, and 2741 (80%) abdominal operations. There was an increasing trend in minimally invasive surgery from 2008 to 2014 (41%). Women with lymph nodes removed in the robotic-assisted laparoscopic group experienced less blood loss (mean 105 vs. 377 mL), shorter length of hospital stay (2.4 vs. 4.1 days), and fewer days to normal activities of daily living (6.5 vs. 12.7 days) (all p < 0.001) compared with the abdominal group, but operating time did not differ. Similar results were found in women with no lymph node removal and in women with body mass index >=35. Major complications during hospital stay, reoperations, and time to work were less in both minimally invasive groups. More lymph nodes were retrieved in the abdominal (mean 34.4) than in the robotic-assisted laparoscopic (mean 26.0) group, but the number of women with lymph node metastases did not differ, totaling 211/960 (21.9%; 95% CI 19.4-24.7%). Isolated para-aortic lymph node metastases were found in 3.9% (95% CI 2.4-5.6%) of women. CONCLUSIONS: Minimally invasive surgery in uterine cancer patients reduces days to normal activities of daily living, number of days to return to work, length of hospital stay, and blood loss in patients without and with lymph node dissection and in obese patients. PMID- 27124388 TI - Hemoptysis from an aorto-pulmonary collateral vessel in a four month old resolved by embolization. AB - Hemoptysis in the children is a rare but serious diagnosis and is even more uncommon in infancy. Mortality is reported and depends on associated illnesses, underlying etiology, and amount of bleeding. A 4-month-old patient presented with significant hemoptysis. Flexible bronchoscopy with differential lavage confirmed the presence and site of origin of hemoptysis. She was managed with cardiac catheterization for embolization of an aorto-pulmonary collateral vessel with immediate complete resolution and no further recurrences. This highlights the importance of cardiac catheterization to detect collateral vessels as a cause for hemoptysis at this age and its successful resolution following embolization. Pediatr Pulmonol. 2016; 51:E31-E33. (c) 2016 Wiley Periodicals, Inc. PMID- 27124389 TI - Arylative Desulfonation of Diarylmethyl Phenyl Sulfone with Arenes Catalyzed by Scandium Triflate. AB - A scandium-triflate-catalyzed arylative desulfonation of diarylmethyl phenyl sulfones with arenes and heteroarenes was established. A variety of both sulfone and arene substrates were reacted to afford symmetric and nonsymmetric triarylmethanes in good yields. Further transformations of the resulting triarylmethanes and application to the concise synthesis of a bactericidal agent analogue were also demonstrated. PMID- 27124387 TI - Multiyear dual nitrate isotope signatures suggest that N-saturated subtropical forested catchments can act as robust N sinks. AB - In forests of the humid subtropics of China, chronically elevated nitrogen (N) deposition, predominantly as ammonium (NH4+ ), causes significant nitrate (NO3- ) leaching from well-drained acid forest soils on hill slopes (HS), whereas significant retention of NO3- occurs in near-stream environments (groundwater discharge zones, GDZ). To aid our understanding of N transformations on the catchment level, we studied spatial and temporal variabilities of concentration and natural abundance (delta15 N and delta18 O) of nitrate (NO3- ) in soil pore water along a hydrological continuum in the N-saturated Tieshanping (TSP) catchment, southwest China. Our data show that effective removal of atmogenic NH4+ and production of NO3- in soils on HS were associated with a significant decrease in delta15 N-NO3- , suggesting efficient nitrification despite low soil pH. The concentration of NO3- declined sharply along the hydrological flow path in the GDZ. This decline was associated with a significant increase in both delta15 N and delta18 O of residual NO3- , providing evidence that the GDZ acts as an N sink due to denitrification. The observed apparent 15 N enrichment factor (epsilon) of NO3- of about -50/00 in the GDZ is similar to values previously reported for efficient denitrification in riparian and groundwater systems. Episode studies in the summers of 2009, 2010 and 2013 revealed that the spatial pattern of delta15 N and delta18 O-NO3- in soil water was remarkably similar from year to year. The importance of denitrification as a major N sink was also seen at the catchment scale, as largest delta15 N-NO3- values in stream water were observed at lowest discharge, confirming the importance of the relatively small GDZ for N removal under base flow conditions. This study, explicitly recognizing hydrologically connected landscape elements, reveals an overlooked but robust N sink in N-saturated, subtropical forests with important implications for regional N budgets. PMID- 27124386 TI - Regulation of Tyrosine Hydroxylase Expression and Phosphorylation in Dopamine Transporter-Deficient Mice. AB - Tyrosine hydroxylase (TH) and dopamine transporters (DATs) regulate dopamine (DA) neurotransmission at the biosynthesis and reuptake steps, respectively. Dysfunction or loss of these proteins occurs in impaired locomotor or addictive behavior, but little is known about the influence of DAT expression on TH function. Differences in TH phosphorylation, DA tissue content, l-DOPA biosynthesis, and DA turnover exist between the somatodendritic and terminal field compartments of nigrostriatal and mesoaccumbens pathways. We examined whether differential DAT expression affects these compartmental differences in DA regulation by comparing TH expression and phosphorylation at ser31 and ser40. In heterozygous DAT knockout (KO) (+/-) mice, DA tissue content and DA turnover were unchanged relative to wild-type mice, despite a 40% reduction in DAT protein expression. In DAT KO (-/-) mice, DA turnover increased in all DA compartments, but DA tissue content decreased (90-96%) only in terminal fields. TH protein expression and phosphorylation were differentially affected within DA pathway compartments by relative expression of DAT. TH protein decreased (~74%), though to a significantly lesser extent than DA, in striatum and nucleus accumbens (NAc) in DAT -/- mice, with no decrease in substantia nigra or ventral tegmental area. Striatal ser31 TH phosphorylation and recovery of DA relative to TH protein expression in DAT +/- and DAT -/- mice decreased, whereas ser40 TH phosphorylation increased ~2- to 3-fold in striatum and NAc of DAT -/- mice. These results suggest that DAT expression affects TH expression and phosphorylation largely in DA terminal field compartments, further corroborating evidence for dichotomous regulation of TH between somatodendritic and terminal field compartments of the nigrostriatal and mesoaccumbens pathways. PMID- 27124390 TI - A Drug-Centric View of Drug Development: How Drugs Spread from Disease to Disease. AB - Drugs are often seen as ancillary to the purpose of fighting diseases. Here an alternative view is proposed in which they occupy a spearheading role. In this view, drugs are technologies with an inherent therapeutic potential. Once created, they can spread from disease to disease independently of the drug creator's original intentions. Through the analysis of extensive literature and clinical trial records, it can be observed that successful drugs follow a life cycle in which they are studied at an increasing rate, and for the treatment of an increasing number of diseases, leading to clinical advancement. Such initial growth, following a power law on average, has a degree of momentum, but eventually decelerates, leading to stagnation and decay. A network model can describe the propagation of drugs from disease to disease in which diseases communicate with each other by receiving and sending drugs. Within this model, some diseases appear more prone to influence other diseases than be influenced, and vice versa. Diseases can also be organized into a drug-centric disease taxonomy based on the drugs that each adopts. This taxonomy reflects not only biological similarities across diseases, but also the level of differentiation of existing therapies. In sum, this study shows that drugs can become contagious technologies playing a driving role in the fight against disease. By better understanding such dynamics, pharmaceutical developers may be able to manage drug projects more effectively. PMID- 27124392 TI - Secondary Confinement of Water Observed in Eutectic Melting of Aqueous Salt Systems in Nanopores. AB - Freezing and melting of aqueous solutions of alkali halides confined in the cylindrical nanopores of MCM-41 and SBA-15 silica was probed by differential scanning calorimetry (DSC). We find that the confinement-induced shift of the eutectic temperature in the pores can be significantly greater than the shift of the melting temperature of pure water. Greatest shifts of the eutectic temperature are found for salts that crystallize as oligohydrates at the eutectic point. This behavior is explained by the larger fraction of pore volume occupied by salt hydrates as compared to anhydrous salts, on the assumption that precipitated salt constitutes an additional confinement for ice/water in the pores. A model based on this secondary confinement effect gives a good representation of the experimental data. Salt-specific secondary confinement may play a role in a variety of fields, from salt-impregnated advanced adsorbents and catalysts to the thermal weathering of building materials. PMID- 27124391 TI - Community Water Improvement, Household Water Insecurity, and Women's Psychological Distress: An Intervention and Control Study in Ethiopia. AB - BACKGROUND: Over 650 million people worldwide lack access to safe water supplies, and even among those who have gained access to 'improved' sources, water may be seasonally unreliable, far from homes, expensive, and provide insufficient quantity. Measurement of water access at the level of communities and households remains crude, and better measures of household water insecurity are urgently needed to inform needs assessments and monitoring and evaluation. We set out to assess the validity of a quantitative scale of household water insecurity, and to investigate (1) whether improvements to community water supply reduce water insecurity, (2) whether water interventions affect women's psychological distress, and (3) the impacts of water insecurity on psychological distress, independent of socio-economic status, food security, and harvest quality. METHODS AND FINDINGS: Measures were taken before and one to six months after a community water supply improvement in three villages in rural northern Ethiopia. Villages similar in size and access to water sources and other amenities did not receive interventions, and served as controls. Household water insecurity was assessed using a 21-item scale based on prior qualitative work in Ethiopia. Women's psychological distress was assessed using the WHO Self-Reporting Questionnaire (SRQ-20). Respondents were either female heads of household or wives of the heads of household (n = 247 at baseline, n = 223 at endline); 123 households provided data at both rounds. The intervention was associated with a decline of approximately 2 points on the water insecurity scale between baseline and endline compared to the control (beta -1.99; 95% CI's -3.15, -0.84). We did not find evidence of impact of the intervention on women's psychological distress. Water insecurity was, however, predictive of psychological distress (p <0.01), independent of household food security and the quality of the previous year's harvest. CONCLUSION: These results contribute to the construct validity of our water insecurity scale, and establish our approach to measuring water insecurity as a plausible means of evaluating water interventions. Improvements to community water supplies were effective in reducing household water insecurity, but not psychological distress, in this population. Water insecurity was an important predictor of psychological distress. This study contributes to an emerging literature on quantitative assessment of household water insecurity, and draws attention to the potential impact of improved access to water on women's mental well-being. PMID- 27124394 TI - Airborne asbestos exposures associated with the installation and removal of roofing products. AB - Asbestos-containing roofing products were widely used throughout the 20th century, and certain products are still used in limited quantities today. Roofing products are generally considered non-friable and are not expected to release appreciable amounts of airborne asbestos fibers; however, despite the variety of roofing products that have contained asbestos over time, there are no comprehensive analyses of the exposure data associated with these products in the published literature. The objective of this study was to analyze the available data and characterize asbestos exposures associated with the installation, removal, and replacement of built-up roofing (BUR), felts, flashings, shingles, coatings, cements, and mastics under a variety of work practices. Published and unpublished literature that contained the following information was included in the analysis: (1) airborne fiber concentrations determined by PCM; (2) a description of the product(s) used; and (3) a description of the task(s) performed. More than 800 personal air samples from 12 studies performed between 1982 and 2010 were identified which fit the inclusion criteria. The findings indicate that short-term and full-shift exposures from the use of asbestos containing roofing products were typically well below applicable occupational exposure limits. Additionally, the cumulative exposures associated with roofing work would be well below published chrysotile no-observed-adverse-effect-levels (NOAELs) for asbestos-related diseases. PMID- 27124393 TI - Novel Tissue Level Effects of the Staphylococcus aureus Enterotoxin Gene Cluster Are Essential for Infective Endocarditis. AB - BACKGROUND: Superantigens are indispensable virulence factors for Staphylococcus aureus in disease causation. Superantigens stimulate massive immune cell activation, leading to toxic shock syndrome (TSS) and contributing to other illnesses. However, superantigens differ in their capacities to induce body-wide effects. For many, their production, at least as tested in vitro, is not high enough to reach the circulation, or the proteins are not efficient in crossing epithelial and endothelial barriers, thus remaining within tissues or localized on mucosal surfaces where they exert only local effects. In this study, we address the role of TSS toxin-1 (TSST-1) and most importantly the enterotoxin gene cluster (egc) in infective endocarditis and sepsis, gaining insights into the body-wide versus local effects of superantigens. METHODS: We examined S. aureus TSST-1 gene (tstH) and egc deletion strains in the rabbit model of infective endocarditis and sepsis. Importantly, we also assessed the ability of commercial human intravenous immunoglobulin (IVIG) plus vancomycin to alter the course of infective endocarditis and sepsis. RESULTS: TSST-1 contributed to infective endocarditis vegetations and lethal sepsis, while superantigens of the egc, a cluster with uncharacterized functions in S. aureus infections, promoted vegetation formation in infective endocarditis. IVIG plus vancomycin prevented lethality and stroke development in infective endocarditis and sepsis. CONCLUSIONS: Our studies support the local tissue effects of egc superantigens for establishment and progression of infective endocarditis providing evidence for their role in life-threatening illnesses. In contrast, TSST-1 contributes to both infective endocarditis and lethal sepsis. IVIG may be a useful adjunct therapy for infective endocarditis and sepsis. PMID- 27124395 TI - Molecular Predictors of Long-Term Survival in Glioblastoma Multiforme Patients. AB - Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain cancer, with <10% of patients surviving for more than 3 years. Demographic and clinical factors (e.g. age) and individual molecular biomarkers have been associated with prolonged survival in GBM patients. However, comprehensive systems-level analyses of molecular profiles associated with long-term survival (LTS) in GBM patients are still lacking. We present an integrative study of molecular data and clinical variables in these long-term survivors (LTSs, patients surviving >3 years) to identify biomarkers associated with prolonged survival, and to assess the possible similarity of molecular characteristics between LGG and LTS GBM. We analyzed the relationship between multivariable molecular data and LTS in GBM patients from the Cancer Genome Atlas (TCGA), including germline and somatic point mutation, gene expression, DNA methylation, copy number variation (CNV) and microRNA (miRNA) expression using logistic regression models. The molecular relationship between GBM LTS and LGG tumors was examined through cluster analysis. We identified 13, 94, 43, 29, and 1 significant predictors of LTS using Lasso logistic regression from the somatic point mutation, gene expression, DNA methylation, CNV, and miRNA expression data sets, respectively. Individually, DNA methylation provided the best prediction performance (AUC = 0.84). Combining multiple classes of molecular data into joint regression models did not improve prediction accuracy, but did identify additional genes that were not significantly predictive in individual models. PCA and clustering analyses showed that GBM LTS typically had gene expression profiles similar to non-LTS GBM. Furthermore, cluster analysis did not identify a close affinity between LTS GBM and LGG, nor did we find a significant association between LTS and secondary GBM. The absence of unique LTS profiles and the lack of similarity between LTS GBM and LGG, indicates that there are multiple genetic and epigenetic pathways to LTS in GBM patients. PMID- 27124396 TI - Racial and ethnic disparities in human papillomavirus-associated cancer burden with first-generation and second-generation human papillomavirus vaccines. AB - BACKGROUND: In the United States, the burden of human papillomavirus (HPV) associated cancers varies by racial/ethnic group. HPV vaccination may provide opportunities for primary prevention of these cancers. Herein, the authors projected changes in HPV-associated cancer burden among racial/ethnic groups under various coverage assumptions with the available first-generation and second generation HPV vaccines to evaluate changes in racial/ethnic disparities. METHODS: Cancer-specific mathematical models simulated the burden of 6 HPV associated cancers. Model parameters, informed using national registries and epidemiological studies, reflected sex-specific, age-specific, and racial/ethnic specific heterogeneities in HPV type distribution, cancer incidence, stage of disease at detection, and mortality. Model outcomes included the cumulative lifetime risks of developing and dying of 6 HPV-associated cancers. The level of racial/ethnic disparities was evaluated under each alternative HPV vaccine scenario using several metrics of social group disparity. RESULTS: HPV vaccination is expected to reduce the risks of developing and dying of HPV associated cancers in all racial/ethnic groups as well as reduce the absolute degree of disparities. However, alternative metrics suggested that relative disparities would persist and in some scenarios worsen. For example, when assuming high uptake with the second-generation HPV vaccine, the lifetime risk of dying of an HPV-associated cancer for males decreased by approximately 60%, yet the relative disparity increased from 3.0 to 3.9. CONCLUSIONS: HPV vaccines are expected to reduce the overall burden of HPV-associated cancers for all racial/ethnic groups and to reduce the absolute disparity gap. However, even with the second-generation vaccine, relative disparities will likely still exist and may widen if the underlying causes of these disparities remain unaddressed. Cancer 2016;122:2057-66. (c) 2016 American Cancer Society. PMID- 27124400 TI - Spatial generalization of imitation in dogs (Canis familiaris). AB - Dogs, like human infants, are able to imitate human actions after a delay (deferred imitation). This study demonstrates that in deferred imitation tasks, dogs can generalize imitation across context modification to a certain extent. Specifically, they can imitate an object-related action if the object used by the demonstrator is displaced to a different location. However, if the object is interchanged with a different one, their imitative performance drops while they show a spatial bias toward the location of demonstration. We used a combination of the 2-action procedure and the "Do as I do" paradigm and displaced the target objects manipulated by the demonstrator, so that, at the time of recall, dogs could only match either the original location of demonstration or the displaced object, but not both. In conditions with a single object present and displaced after the demonstration, dogs matched the action and the object on which it was shown. In conditions with the location of 2 objects interchanged, dogs more likely matched the location. However, when humans provided ostensive cues and pointing gestures to draw the subjects' attention toward the displaced target object, dogs' predisposition to follow human communication outweighed their spatial bias and, as a consequence, their object matching and imitative performance increased. We conclude that object's physical features function as retrieval cues that facilitate recalling the action. In addition to figurative information, dogs rely strongly on spatial information in Do as I do tasks. The results are discussed concerning dogs' representational system of imitative actions. (PsycINFO Database Record PMID- 27124399 TI - Inferring Intra-Community Microbial Interaction Patterns from Metagenomic Datasets Using Associative Rule Mining Techniques. AB - The nature of inter-microbial metabolic interactions defines the stability of microbial communities residing in any ecological niche. Deciphering these interaction patterns is crucial for understanding the mode/mechanism(s) through which an individual microbial community transitions from one state to another (e.g. from a healthy to a diseased state). Statistical correlation techniques have been traditionally employed for mining microbial interaction patterns from taxonomic abundance data corresponding to a given microbial community. In spite of their efficiency, these correlation techniques can capture only 'pair-wise interactions'. Moreover, their emphasis on statistical significance can potentially result in missing out on several interactions that are relevant from a biological standpoint. This study explores the applicability of one of the earliest association rule mining algorithm i.e. the 'Apriori algorithm' for deriving 'microbial association rules' from the taxonomic profile of given microbial community. The classical Apriori approach derives association rules by analysing patterns of co-occurrence/co-exclusion between various '(subsets of) features/items' across various samples. Using real-world microbiome data, the efficiency/utility of this rule mining approach in deciphering multiple (biologically meaningful) association patterns between 'subsets/subgroups' of microbes (constituting microbiome samples) is demonstrated. As an example, association rules derived from publicly available gut microbiome datasets indicate an association between a group of microbes (Faecalibacterium, Dorea, and Blautia) that are known to have mutualistic metabolic associations among themselves. Application of the rule mining approach on gut microbiomes (sourced from the Human Microbiome Project) further indicated similar microbial association patterns in gut microbiomes irrespective of the gender of the subjects. A Linux implementation of the Association Rule Mining (ARM) software (customised for deriving 'microbial association rules' from microbiome data) is freely available for download from the following link: http://metagenomics.atc.tcs.com/arm. PMID- 27124401 TI - Unveiling the "secret" of play in dogs (Canis lupus familiaris): Asymmetry and signals. AB - Due to their playful propensity, dogs are a good model to test some hypotheses about play dynamics (length, asymmetry, features of players) and communication (play bow [PBOW]; relaxed open-mouth [ROM] display). We video-recorded 203 play sessions between dogs in an off-leash dog park in Palermo, Italy. Contrary to the expectation, play asymmetry (particularly high in this species) did not differ between stranger and familiar dogs, thus suggesting the limited role of play in forming dominance relationships. Asymmetry negatively affected the duration of the session, whereas the increasing number of players was positively linked to the duration of playful interactions. The number of PBOWs exchanged by players may exert a certain influence on the session length as well. PBOWs were performed independently from the kind of play (locomotor vs. contact) the dogs were engaging in. Conversely, ROMs were preferentially emitted during contact play when "face-to-face" interactions were more likely. Body closeness is also required in case opening the mouth has not a signal function but only preludes a bite. However, in the 82% of cases play bites did not follow a ROM, thus suggesting that dogs place ROMs in the appropriate context to optimize signal detectability. In conclusion, 2 tactics may concur in coping with the asymmetry and unpredictability of play sessions in dogs. First, whenever the asymmetry increases dogs shorten the duration of their sessions thus limiting the risk of possible escalation. Second, dogs make use of a good communicative system based on the reciprocal exchange of playful signals. (PsycINFO Database Record PMID- 27124402 TI - Three actions, two groups: Looking for the origin of primate manual lateralization. AB - Handedness is the most evident behavioral asymmetry in humans: to study nonhuman primate hand preference could be optimal to investigate the evolutionary origin of handedness in our species, even though behavioral asymmetries are widespread among vertebrates. This study investigated hand preferences in 32 Old World monkeys and 26 great apes during 3 spontaneous actions, assessing the effect of taxonomic group, sex and age on primate handedness. Data about foraging, locomotion, and manipulation were collected and 50 bouts per behavioral category per subject were recorded. A bias toward right-hand use for starting locomotion was reported in both Old World monkeys and great apes. Furthermore, in the great apes, a group-level right-hand preference for manipulation was found. Results suggest an important role of factors such as posture and task complexity in the evolution of primate manual lateralization. The effect of taxonomic group, sex, and age on the hand preference are also discussed. (PsycINFO Database Record PMID- 27124403 TI - Reliability of the Radiographic Sagittal and Frontal Tibiotalar Alignment after Ankle Arthrodesis. AB - BACKGROUND: Accurate measurement of the tibiotalar alignment is important in radiographic outcome assessment of ankle arthrodesis (AA). In studies, various radiological methods have been used to measure the tibiotalar alignment leading to facultative misinterpretation of results. However, to our knowledge, no previous study has investigated the reliability of tibiotalar alignment measurement in AA. We aimed to investigate the reliability of four different methods of measurement of the frontal and sagittal tibiotalar alignment after AA, and to further clarify the most reliable method for determining the longitudinal axis of the tibia. METHODS: Thirty-eight weight bearing anterior to posterior and lateral ankle radiographs of thirty-seven patients who had undergone AA with a two screw fixation technique were selected. Three observers measured the frontal tibiotalar angle (FTTA) and the sagittal tibiotalar angle (STTA) using four different methods. The methods differed by the definition of the longitudinal tibial axis. Method A was defined by a line drawn along the lateral tibial border in anterior to posterior radiographs and along the posterior tibial border in lateral radiographs. Method B was defined by a line connecting two points in the middle of the proximal and the distal tibial shaft. Method C was drawn "freestyle"along the longitudinal axis of the tibia, and method D was defined by a line connecting the center of the tibial articular surface and a point in the middle of the proximal tibial shaft. Intra- and interobserver correlation coefficients (ICC) and repeated measurement ANOVA were calculated to assess measurement reliability and accuracy. RESULTS: All four methods showed excellent inter- and intraobserver reliability for the FTTA and the STTA. When the longitudinal tibial axis is defined by connecting two points in the middle of the proximal and the distal tibial shaft, the highest interobserver reliability for the FTTA (ICC: 0.980; CI 95%: 0.966-0.989) and for the STTA (ICC: 0.997; CI 95%: 0.996-0.999) is provided. Intergroup analysis for FTTA measurements revealed a statistically significant difference between the method in which the lateral border of the tibia was used to determine the longitudinal axis of the tibia, and the other methods in which the longitudinal axis was defined by bisecting the tibia. CONCLUSIONS: When the longitudinal axis of the tibia is defined by connecting two points in the middle of the proximal and the distal tibial shaft for measuring the FTTA and STTA, the most favorable interobserver reliability is provided. Therefore, this method can be recommended for evaluating the frontal and the sagittal alignment on anterior to posterior and lateral radiographs after ankle arthrodesis. PMID- 27124404 TI - Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review. AB - BACKGROUND: Although male hypogonadism is associated with increased cardiovascular events (CVE), recent concerns are that testosterone supplementation may increase CVE. The purpose was to determine associations with age, initiation or mode of therapy to explain these discrepancies. DATA SYNTHESIS: Meta-analyses were supplemented through Scopus and PubMed with search terms 'testosterone', 'random' and 'trial'. CVE, defined before data extraction, were death, myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, coronary bypass, syncope, arrhythmia, hospital admission for congestive heart failure or cerebrovascular event. RESULTS: There were 45 trials with 5328 subjects evaluated, with a mean age of 63.3 (SD +/-7.9) years, followed for mean study duration of 10.6 (+/- 8.6) months. Overall, testosterone supplementation was not associated with increased CVE risk ratio (rr = 1.10 (95% CI 0.86; 1.41, P = 0.45)). However, there was an increase event rate during the first 12 months (rr = 1.79 (1.13;2.83, P = 0.012)), predominantly in those >=65 years, (rr = 2.90 (1.35;6.21, P = 0.006)). Within studies with lipid data, CVE were associated with fall in HDL, P = 0.002. Intramuscular testosterone appeared neutral for CVE (rr = 0.96 (0.462;1.98, P = 0.91)) compared with oral testosterone (rr = 2.28 (95% CI 2.28;8.59, P = 0.22)) and transdermal testosterone (rr = 2.80 (1.38;5.68, P = 0.004)). Intramuscular testosterone had the least effect of lowering HDL and non-HDL cholesterol (both P < 0.001). CONCLUSIONS: Testosterone supplementation may be associated with increased CVE in those >=65 years especially during the first year. Biological actions may differ depending upon mode of testosterone administration with intramuscular testosterone having less cardiovascular risk. PMID- 27124405 TI - Sleeping for Two: An Open-Pilot Study of Cognitive Behavioral Therapy for Insomnia in Pregnancy. AB - Insomnia and disturbed sleep are common during pregnancy. This study investigated the effectiveness of group cognitive-behavioral therapy for insomnia (CBT-I) delivered in pregnancy. Thirteen pregnant women with insomnia participated in five weekly CBT-I group sessions. All participants completed the study and provided baseline and follow-up data. Significant reductions in insomnia symptoms and increases in subjective sleep quality were observed over the course of the study. Diary and actigraphy assessments of sleep also changed, such that participants reported less time in bed (TIB), shorter sleep onset latency (SOL), increased sleep efficiency (SE), and increased subjective total sleep time (TST). Additionally, symptoms of depression, pregnancy-specific anxiety, and fatigue all decreased over the course of treatment. Effect sizes ranged from medium to large. CBT-I delivered during pregnancy was associated with significant improvements in sleep and mood. The next step in this area of inquiry is to better establish effectiveness via a randomized controlled trial. PMID- 27124406 TI - Defining Population Health Management: A Scoping Review of the Literature. AB - Population health management (PHM) has increasingly been mentioned as a concept to realize improvements in population health and quality of care while reducing cost growth (the so-called Triple Aim). The concept of PHM has been used in various settings and has been defined in different ways. This study compared the definitions of PHM used in the literature in order to improve the understanding and interpretation of the concept of PHM. A scoping literature search was performed for papers published between January 2000 and January 2015 that defined PHM. PHM definitions were summarized, focusing on: (1) overall aim, (2) PHM activities, and (3) contextual factors. Eighteen articles were retrieved. The overall aim was defined in terms of health (N = 14), costs (N = 8), and/or quality of care (N = 10). Definitions varied regarding the description of PHM activities, though all definitions contained elements in common with disease management and health promotion. Data management, Triple Aim assessment, risk stratification, evaluation, and feedback cycles were less likely to be mentioned. Contextual factors were scarcely brought forward in the definitions. Moderate variations were found across definitions in the way PHM was conceptualized. Frequently, essential elements of PHM were not specified. Differences in conceptualizations of PHM should be taken into account when comparing PHM initiatives that are working toward improvements in population health, (experienced) quality of care, and reduction of costs. PMID- 27124408 TI - The Use of Assistive Technology to Promote Care of the Self and Social Inclusion in Patients with Sequels of Leprosy. AB - BACKGROUND: This study is about the contribution of occupational therapy inside a rehabilitation group, and we focus on the autonomy of patients with disabilities due to leprosy. There are few studies on the use of assistive technology by leprosy patients; to our knowledge, none of them aim to have a subjective approach of care. Our purpose was to analyze the repercussions of assistive technology on autonomy of care of the self in patients with sequels of leprosy. METHODS: A qualitative, descriptive exploratory study with a semi-structured interview and a field observation as a research method was conducted between November 2014 and February 2015 at a University Hospital in Rio de Janeiro. FINDINGS: Eight patients from the service of Occupational Therapy were interviewed, and 44 hours of observation were performed. Interviews followed a semi-structured script and a field journal was used to take notes. Analysis was conducted by the hermeneutic approach. Costs were obtained after a global cost analysis of the fixed and variable expenses and direct and indirect costs to the manufactured products with an amount of 100 dollars. Results were grouped according to the following categories: contribution of the adapted devices for the care of the self and feelings and sensations provoked by the use of self-help devices. The reports revealed feelings, perceptions and meaningful contents about the social, familiar and individual dimensions, also the stigma coupled with leprosy. However, forms of re-signification were elaborated. CONCLUSIONS: Assistive technology empowers the subject to perform care of the self and promotes social inclusion. PMID- 27124407 TI - A High-Throughput Cell-Based Screen Identified a 2-[(E)-2-Phenylvinyl]-8 Quinolinol Core Structure That Activates p53. AB - p53 function is frequently inhibited in cancer either through mutations or by increased degradation via MDM2 and/or E6AP E3-ubiquitin ligases. Most agents that restore p53 expression act by binding MDM2 or E6AP to prevent p53 degradation. However, fewer compounds directly bind to and activate p53. Here, we identified compounds that shared a core structure that bound p53, caused nuclear localization of p53 and caused cell death. To identify these compounds, we developed a novel cell-based screen to redirect p53 degradation to the Skip Cullin-F-box (SCF) ubiquitin ligase complex in cells expressing high levels of p53. In a multiplexed assay, we coupled p53 targeted degradation with Rb1 targeted degradation in order to identify compounds that prevented p53 degradation while not inhibiting degradation through the SCF complex or other proteolytic machinery. High-throughput screening identified several leads that shared a common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that stabilized p53. Surface plasmon resonance analysis indicated that these compounds bound p53 with a KD of 200 +/- 52 nM. Furthermore, these compounds increased p53 nuclear localization and transcription of the p53 target genes PUMA, BAX, p21 and FAS in cancer cells. Although p53-null cells had a 2.5+/-0.5-fold greater viability compared to p53 wild type cells after treatment with core compounds, loss of p53 did not completely rescue cell viability suggesting that compounds may target both p53-dependent and p53-independent pathways to inhibit cell proliferation. Thus, we present a novel, cell-based high-throughput screen to identify a 2-[(E) 2-phenylvinyl]-8-quinolinol core structure that bound to p53 and increased p53 activity in cancer cells. These compounds may serve as anti-neoplastic agents in part by targeting p53 as well as other potential pathways. PMID- 27124409 TI - Porphyromonas gingivalis Differentially Modulates Cell Death Profile in Ox-LDL and TNF-alpha Pre-Treated Endothelial Cells. AB - OBJECTIVE: Clinical studies demonstrated a potential link between atherosclerosis and periodontitis. Porphyromonas gingivalis (Pg), one of the main periodontal pathogen, has been associated to atheromatous plaque worsening. However, synergism between infection and other endothelial stressors such as oxidized-LDL or TNF-alpha especially on endothelial cell (EC) death has not been investigated. This study aims to assess the role of Pg on EC death in an inflammatory context and to determine potential molecular pathways involved. METHODS: Human umbilical vein ECs (HUVECs) were infected with Pg (MOI 100) or stimulated by its lipopolysaccharide (Pg-LPS) (1MUg/ml) for 24 to 48 hours. Cell viability was measured with AlamarBlue test, type of cell death induced was assessed using Annexin V/propidium iodide staining. mRNA expression regarding caspase-1, -3, -9, Bcl-2, Bax-1 and Apaf-1 has been evaluated with RT-qPCR. Caspases enzymatic activity and concentration of APAF-1 protein were evaluated to confirm mRNA results. RESULTS: Pg infection and Pg-LPS stimulation induced EC death. A cumulative effect has been observed in Ox-LDL pre-treated ECs infected or stimulated. This effect was not observed in TNF-alpha pre-treated cells. Pg infection promotes EC necrosis, however, in infected Ox-LDL pre-treated ECs, apoptosis was promoted. This effect was not observed in TNF-alpha pre-treated cells highlighting specificity of molecular pathways activated. Regarding mRNA expression, Pg increased expression of pro-apoptotic genes including caspases-1, 3,-9, Bax-1 and decreased expression of anti-apoptotic Bcl-2. In Ox-LDL pre treated ECs, Pg increased significantly the expression of Apaf-1. These results were confirmed at the protein level. CONCLUSION: This study contributes to demonstrate that Pg and its Pg-LPS could exacerbate Ox-LDL and TNF-alpha induced endothelial injury through increase of EC death. Interestingly, molecular pathways are differentially modulated by the infection in function of the pre stimulation. PMID- 27124410 TI - Exploratory Cost-Effectiveness Analysis of Response-Guided Neoadjuvant Chemotherapy for Hormone Positive Breast Cancer Patients. AB - PURPOSE: Guiding response to neoadjuvant chemotherapy (guided-NACT) allows for an adaptative treatment approach likely to improve breast cancer survival. In this study, our primary aim is to explore the expected cost-effectiveness of guided NACT using as a case study the first randomized controlled trial that demonstrated effectiveness (GeparTrio trial). MATERIALS AND METHODS: As effectiveness was shown in hormone-receptor positive (HR+) early breast cancers (EBC), our decision model compared the health-economic outcomes of treating a cohort of such women with guided-NACT to conventional-NACT using clinical input data from the GeparTrio trial. The expected cost-effectiveness and the uncertainty around this estimate were estimated via probabilistic cost effectiveness analysis (CEA), from a Dutch societal perspective over a 5-year time-horizon. RESULTS: Our exploratory CEA predicted that guided-NACT as proposed by the GeparTrio, costs additional ?110, but results in 0.014 QALYs gained per patient. This scenario of guided-NACT was considered cost-effective at any willingness to pay per additional QALY. At the prevailing Dutch willingness to pay threshold (?80.000/QALY) cost-effectiveness was expected with 78% certainty. CONCLUSION: This exploratory CEA indicated that guided-NACT (as proposed by the GeparTrio trial) is likely cost-effective in treating HR+ EBC women. While prospective validation of the GeparTrio findings is advisable from a clinical perspective, early CEAs can be used to prioritize further research from a broader health economic perspective, by identifying which parameters contribute most to current decision uncertainty. Furthermore, their use can be extended to explore the expected cost-effectiveness of alternative guided-NACT scenarios that combine the use of promising imaging techniques together with personalized treatments. PMID- 27124411 TI - Total Mechanical Unloading Minimizes Metabolic Demand of Left Ventricle and Dramatically Reduces Infarct Size in Myocardial Infarction. AB - BACKGROUND: Left ventricular assist device (LVAD) mechanically unloads the left ventricle (LV). Theoretical analysis indicates that partial LVAD support (p LVAD), where LV remains ejecting, reduces LV preload while increases afterload resulting from the elevation of total cardiac output and mean aortic pressure, and consequently does not markedly decrease myocardial oxygen consumption (MVO2). In contrast, total LVAD support (t-LVAD), where LV no longer ejects, markedly decreases LV preload volume and afterload pressure, thereby strikingly reduces MVO2. Since an imbalance in oxygen supply and demand is the fundamental pathophysiology of myocardial infarction (MI), we hypothesized that t-LVAD minimizes MVO2 and reduces infarct size in MI. The purpose of this study was to evaluate the differential impact of the support level of LVAD on MVO2 and infarct size in a canine model of ischemia-reperfusion. METHODS: In 5 normal mongrel dogs, we examined the impact of LVAD on MVO2 at 3 support levels: Control (no LVAD support), p-LVAD and t-LVAD. In another 16 dogs, ischemia was induced by occluding major branches of the left anterior descending coronary artery (90 min) followed by reperfusion (300 min). We activated LVAD from the beginning of ischemia until 300 min of reperfusion, and compared the infarct size among 3 different levels of LVAD support. RESULTS: t-LVAD markedly reduced MVO2 (% reduction against CONTROL: -56 +/- 9%, p<0.01) whereas p-LVAD did less (-21 +/- 14%, p<0.05). t-LVAD markedly reduced infarct size compared to p-LVAD (infarct area/area at risk: CONTROL; 41.8 +/- 6.4, p-LVAD; 29.1 +/- 5.6 and t-LVAD; 5.0 +/ 3.1%, p<0.01). Changes in creatine kinase-MB paralleled those in infarct size. CONCLUSIONS: Total LVAD support that minimizes metabolic demand maximizes the benefit of LVAD in the treatment of acute myocardial infarction. PMID- 27124412 TI - Trends in the Attack Rates, Incidence, and Mortality of Stroke during 1986-2012: Data of Kaunas (Lithuania) Stroke Registry. AB - BACKGROUND: There is a lack of reliable epidemiological data on longitudinal trends in stroke attack rates, incidence, and mortality in the countries of the Baltic region. AIMS: The aim of the present study was to explore the longitudinal trends of stroke in middle-aged urban population of Lithuania during the period of 1986 through 2012. METHODS: All stroke events in the studied population were ascertained and validated according to the standardized criteria outlined by the WHO MONICA Project. The study included all patients in Kaunas (Lithuania) city aged 25 to 64 years who experienced a stroke between 1986 and 2012. Estimates of time-trends of the annual percentage change in stroke attack rates, incidence of stroke, and mortality from this condition were made by applying the Joinpoint regression analysis. RESULTS: During the study period, 9,992 stroke events were registered. The overall proportion of recurrent events was 25.7%. Overall, 18.9% of the events (20.0% in men, and 17.4% in women) were fatal within 28 days. During the period of 1986 to 2012, a flat trend in the incidence of stroke was observed among both male and female middle-aged inhabitants of Kaunas city, while attack rates were increasing due to the increase in recurrent strokes. Both mortality and 28-day case fatality of stroke declined significantly over the study period in both sexes. CONCLUSIONS: An increase both in the incidence and recurrence of stroke among middle-aged men residing in Kaunas city and in the recurrence of stroke among women denotes the inefficiency of measures applied both for primary and secondary prevention of stroke in Lithuania. The revision of current prevention strategies and the introduction of new ones are of paramount importance in order to fight the epidemic of stroke. PMID- 27124415 TI - Braving the New World. PMID- 27124413 TI - Meiotic Recombination Analyses in Pigs Carrying Different Balanced Structural Chromosomal Rearrangements. AB - Correct pairing, synapsis and recombination between homologous chromosomes are essential for normal meiosis. All these events are strongly regulated, and our knowledge of the mechanisms involved in this regulation is increasing rapidly. Chromosomal rearrangements are known to disturb these processes. In the present paper, synapsis and recombination (number and distribution of MLH1 foci) were studied in three boars (Sus scrofa domestica) carrying different chromosomal rearrangements. One (T34he) was heterozygote for the t(3;4)(p1.3;q1.5) reciprocal translocation, one (T34ho) was homozygote for that translocation, while the third (T34Inv) was heterozygote for both the translocation and a pericentric inversion inv(4)(p1.4;q2.3). All three boars were normal for synapsis and sperm production. This particular situation allowed us to rigorously study the impact of rearrangements on recombination. Overall, the rearrangements induced only minor modifications of the number of MLH1 foci (per spermatocyte or per chromosome) and of the length of synaptonemal complexes for chromosomes 3 and 4. The distribution of MLH1 foci in T34he was comparable to that of the controls. Conversely, the distributions of MLH1 foci on chromosome 4 were strongly modified in boar T34Inv (lack of crossover in the heterosynaptic region of the quadrivalent, and crossover displaced to the chromosome extremities), and also in boar T34ho (two recombination peaks on the q-arms compared with one of higher magnitude in the controls). Analyses of boars T34he and T34Inv showed that the interference was propagated through the breakpoints. A different result was obtained for boar T34ho, in which the breakpoints (transition between SSC3 and SSC4 chromatin on the bivalents) seemed to alter the transmission of the interference signal. Our results suggest that the number of crossovers and crossover interference could be regulated by partially different mechanisms. PMID- 27124414 TI - Serum Levels of TNF Receptor Ligands Are Dysregulated in Sepsis and Predict Mortality in Critically Ill Patients. AB - INTRODUCTION: TNF superfamily members, including TNF-related weak inducer of apoptosis (TWEAK) and Glucocorticoid-Induced TNFR-Related Protein Ligand (GITRL) have been described as serum based biomarkers for inflammatory and immune mediated diseases. However, up to now the role of TWEAK and GITRL has not been analyzed in critical illness and sepsis. METHODS: GITRL and TWEAK serum concentrations were measured in 121 critically ill patients (84 fulfilled with septic disease), in comparison to 50 healthy controls. Results were correlated with clinical data. RESULTS: Serum levels of TWEAK and GITRL were strongly decreased in critically ill patients compared with healthy controls. Concentrations of TWEAK (but not GITRL) were further decreased in patients with sepsis and correlated with routinely used markers of inflammation and bacterial infection such as C-reactive protein, procalcitonin and Interleukin-6. Notably, we failed to detect a correlation to other TNFR ligands such as TNF or APRIL. Finally, TWEAK levels of the upper quartile of the cohort were prognostic for mortality during ICU treatment. CONCLUSION: TWEAK and GITRL levels were lower in intensive care unit medical patients. Levels of TWEAK were further decreased in septic patients, and alterations in TWEAK concentrations were linked to an unfavorable outcome. Together with recently published results on other TNFR ligands, these data indicate specific functions of the different TNFR ligands in septic diseases. PMID- 27124416 TI - Are Forensic Experts Already Biased before Adversarial Legal Parties Hire Them? AB - This survey of 206 forensic psychologists tested the "filtering" effects of preexisting expert attitudes in adversarial proceedings. Results confirmed the hypothesis that evaluator attitudes toward capital punishment influence willingness to accept capital case referrals from particular adversarial parties. Stronger death penalty opposition was associated with higher willingness to conduct evaluations for the defense and higher likelihood of rejecting referrals from all sources. Conversely, stronger support was associated with higher willingness to be involved in capital cases generally, regardless of referral source. The findings raise the specter of skewed evaluator involvement in capital evaluations, where evaluators willing to do capital casework may have stronger capital punishment support than evaluators who opt out, and evaluators with strong opposition may work selectively for the defense. The results may provide a partial explanation for the "allegiance effect" in adversarial legal settings such that preexisting attitudes may contribute to partisan participation through a self-selection process. PMID- 27124417 TI - Urothelial cancer of the upper urinary tract: emerging biomarkers and integrative models for risk stratification. AB - INTRODUCTION: The aim of this review was to provide an overview of current biomarkers and risk stratification models in urothelial cancer of the upper urinary tract (UTUC). EVIDENCE ACQUISITION: A non-systematic Medline/PubMed literature search was performed using the terms "biomarkers", "preoperative models", "postoperative models", "risk stratification", together with "upper tract urothelial carcinoma". Original articles published between January 2003 and August 2015 were included based on their clinical relevance. Additional references were collected by cross referencing the bibliography of the selected articles. EVIDENCE SYNTHESIS: Various promising predictive and prognostic biomarkers have been identified in UTUC thanks to the increasing knowledge of the different biological pathways involved in UTUC tumorigenesis. These biomarkers may help identify tumors with aggressive biology and worse outcomes. Current tools aim at predicting muscle invasive or non-organ confined disease, renal failure after radical nephroureterectomy and survival outcomes. These models are still mainly based on imaging and clinicopathological feature and none has integrated biomarkers. Risk stratification in UTUC is still suboptimal, especially in the preoperative setting due to current limitations in staging and grading. Identification of novel biomarkers and external validation of current prognostic models may help improve risk stratification to allow evidence-based counselling for kidney-sparing approaches, perioperative chemotherapy and/or risk based surveillance. CONCLUSIONS: Despite growing understanding of the biology underlying UTUC, management of this disease remains difficult due to the lack of validated biomarkers and the limitations of current predictive and prognostic tools. Further efforts and collaborations are necessaryry to allow their integration in daily practice. PMID- 27124418 TI - Early phase mixed chimerism in bone marrow does not affect long-term outcomes of myeloablative single-unit cord blood transplantation for adult patients with hematological malignancies. AB - Coexisting hematopoiesis from donor and recipient origin, called a mixed chimerism status, can occur in patients after myeloablative allogeneic hematopoietic stem cell transplantation. However, its impact on the outcomes of cord blood transplantation (CBT) has yet to be clarified. We retrospectively analyzed 150 adult patients who received myeloablative single-unit CBT for hematological malignancies in our institute. At the median time of first bone marrow analysis of 41 days after CBT, mixed chimerism was observed in 16 of the 150 patients. Among patients with mixed chimerism, 4 patients relapsed. The remaining 12 patients were alive and in remission at a median follow-up of 50 months. Bone marrow-mixed chimerism did not have a significant impact on the incidences of disease-free survival, relapse, or transplant-related mortality after CBT. These data show that early phase mixed chimerism did not have a significant impact on long-term outcomes after myeloablative single-unit CBT for hematological malignancies. PMID- 27124419 TI - Defining 'quality' from the patient's perspective: findings from focus groups with Medicaid beneficiaries and implications for public reporting. AB - BACKGROUND: With an increased emphasis on patient-centred outcomes and research, investigators seek to understand aspects of health care that are most important to patients. Such information is essential for developing report cards that present health-care quality information for consumers, which many states are adopting as a strategy to promote consumer choice. OBJECTIVE: This study examined the processes that women in Medicaid follow for selecting health plans and explored their definitions of 'good' and 'poor' quality health care. DESIGN: We conducted focus groups with Medicaid beneficiaries in four Texas communities, using quota sampling to ensure representation of different racial/ethnic, eligibility and geographic groups. RESULTS: We conducted 22 focus groups with 102 participants between October 2012 and January 2013. In a free-list exercise, 'doctors' represented the most important aspect of health care to participants, followed by cost, attention, coverage and respect. Discussions of health-care quality revealed an even mix of structural factors (e.g. timeliness) and interpersonal factors (e.g. communication), although few differences were observed by beneficiary characteristics. Participants linked themes in their overall framing of 'quality' - revealing processes of care that affect health outcomes (e.g. discontinuity of care resulting from poor communication with providers) and which were often mediated by advocate providers who assisted patients experiencing barriers to services. DISCUSSION AND CONCLUSIONS: Findings support other studies that highlight the importance of the patient-provider relationship. Patient-centred definitions of health-care quality can complement predominant provider-centred conceptual frameworks and better inform initiatives for public reporting of quality measures in these populations. PMID- 27124420 TI - I-MOVE multicentre case-control study 2010/11 to 2014/15: Is there within-season waning of influenza type/subtype vaccine effectiveness with increasing time since vaccination? AB - Since the 2008/9 influenza season, the I-MOVE multicentre case-control study measures influenza vaccine effectiveness (VE) against medically-attended influenza-like-illness (ILI) laboratory confirmed as influenza. In 2011/12, European studies reported a decline in VE against influenza A(H3N2) within the season. Using combined I-MOVE data from 2010/11 to 2014/15 we studied the effects of time since vaccination on influenza type/subtype-specific VE. We modelled influenza type/subtype-specific VE by time since vaccination using a restricted cubic spline, controlling for potential confounders (age, sex, time of onset, chronic conditions). Over 10,000 ILI cases were included in each analysis of influenza A(H3N2), A(H1N1)pdm09 and B; with 4,759, 3,152 and 3,617 influenza positive cases respectively. VE against influenza A(H3N2) reached 50.6% (95% CI: 30.0-65.1) 38 days after vaccination, declined to 0% (95% CI: -18.1-15.2) from 111 days onwards. At day 54 VE against influenza A(H1N1)pdm09 reached 55.3% (95% CI: 37.9-67.9) and remained between this value and 50.3% (95% CI: 34.8-62.1) until season end. VE against influenza B declined from 70.7% (95% CI: 51.3-82.4) 44 days after vaccination to 21.4% (95% CI: -57.4-60.8) at season end. To assess if vaccination campaign strategies need revising more evidence on VE by time since vaccination is urgently needed. PMID- 27124421 TI - Nucleoside-Based Diarylethene Photoswitches: Synthesis and Photochromic Properties. AB - Diarylethene photoswitches based on the natural nucleoside deoxyadenosine were designed and synthesized. In aqueous solution, some of them exhibited good photochromic properties, including clear changes in color upon irradiation at 365 nm, red-shifts of the absorption wavelength, with good fatigue resistance, thermal stability, conversion efficiency, and base-pairing properties. PMID- 27124422 TI - Benign Granular Cell Tumor of Breast. PMID- 27124423 TI - "Mad Scared" versus "I Was Sad": Emotional expression and response in urban adolescent males. AB - Decades of masculinity research have concluded that society places higher demands on males to adhere to norms for low emotional expression; yet, countless studies find that emotional expression is integral to well-being. Unfortunately, this contradiction places boys and men in a tenuous position as they must navigate a bombardment of societal messages about the importance of emotional stoicism and invincibility. For urban adolescents, the situation is more complicated as they encounter environmental stressors that place greater emphasis on projecting a tough facade. Thus, our primary aim was to assess to what degree dyads of close adolescent male friends from urban, low-income neighborhoods are able to engage in emotional expression and response and to explore some of the underlying mechanisms and interpersonal processes. Qualitative findings from our sample suggest that urban boys exhibit a wide range of behaviors when participating in dyadic emotional disclosure and response, including being highly emotionally expressive and supportive in the context of close male friendship. PMID- 27124424 TI - Short-term group cognitive behavior therapy contributes to recovery from mild depression: Evidence from functional and structural MRI. AB - We used the functional and structural magnetic resonance imaging to explore the neural correlates of response to group cognitive behavioral therapy (CBT) in mild depression. College students with mild depressive symptoms participated in our 4 week group CBT training. The behavioral results showed that depression symptoms decreased after participation in group CBT. After the training, the gray matter volume (GMV) in the right middle frontal gyrus (MFG) increased and amplitude of low-frequency fluctuations (ALFF) decreased. In addition, GMV in the left postcentral gyrus decreased after the group CBT. Moreover, the increase of percentage change in the right MFG was positively correlated with the decrease of the Beck Depression Inventory (BDI) score, while less decrease in percentage change in the left postcentral gyrus was significantly correlated with greater decrease of BDI score. Finally, after the training, functional connectivity between the right MFG and the insula decreased, while the connectivity between the left postcentral gyrus and the parahippocampal gyrus increased. These findings suggested that short-term participation in group CBT had an effective impact on mild depression. It contributed to decreasing negative bias (salience detection for negative stimuli). PMID- 27124425 TI - Duration of the depressive episode is correlated with ganglion cell inner plexifrom layer and nasal retinal fiber layer thicknesses: Optical coherence tomography findings in major depression. AB - Optical coherence tomography (OCT) is a relatively new, noninvasive imaging technique that has been used increasingly to diagnose and manage a variety of retinal diseases. Since the axons in retinal nerve fiber layer (RNFL) are nonmyelinated within the retina, OCT has been used in various neurodegenerative diseases to visualize the process of neurodegeneration. Decreases in RNFL and ganglion cell inner plexiform layer (GCIPL) thicknesses were observed in patients with schizophrenia. To date, there is no clinical research investigating OCT parameters in patients with MD. We compared the RNFL thickness, GCIPL thickness in 58 MD patients and 57 healthy controls, and investigated their correlation with clinical variables of depression. Depressed patients were not different from the healthy controls with regard to OCT parameters. GCIPL and nasal RNFL were correlated with the duration of the latest depressive episode. Some measures of OCT were negatively associated with clinical variables like a family history of psychiatric diagnosis and the duration of the latest episode. Larger studies including depressed patients of different severity, including structured interviews and controlling for the effect of antidepressant treatment will provide better results. PMID- 27124426 TI - The transformation of oncology. PMID- 27124428 TI - INFECTIOUS DISEASES. Yellow fever outbreak triggers vaccine alarm. PMID- 27124430 TI - ARCHAEOLOGY. Tallying the losses in Palmyra. PMID- 27124429 TI - ECOLOGY. An unhappy peace dividend. PMID- 27124432 TI - INDUSTRIAL ESPIONAGE. 3D printers vulnerable to spying. PMID- 27124431 TI - SOCIAL SCIENCE. Ironic coda to fraudulent study of bias. PMID- 27124433 TI - Only the strong survive. PMID- 27124434 TI - Global tensions rile experimental university. PMID- 27124435 TI - Poised for liftoff. PMID- 27124436 TI - Out in the cold. PMID- 27124437 TI - SURFACE WEAR. Moving superhydrophobic surfaces toward real-world applications. PMID- 27124438 TI - RIBOSWITCHES. (Meta-)genome mining for new ribo-regulators. PMID- 27124439 TI - CANCER. How neutrophils promote metastasis. PMID- 27124440 TI - PSYCHOLOGY. How to overcome prejudice. PMID- 27124441 TI - DIVERSITY IN SCIENCE. A recipe for change: Creating a more inclusive academy. PMID- 27124442 TI - BIOMOLECULAR FOLDING. Moments of excitement. PMID- 27124443 TI - CLIMATE CHANGE. A heated mirror for future climate. PMID- 27124444 TI - Grant funding: Playing the odds. PMID- 27124445 TI - Undermined by overhead accounting. PMID- 27124446 TI - Cultural costs of tropical dams. PMID- 27124447 TI - Metastasis: An evolving story. PMID- 27124448 TI - Malignant messengers. PMID- 27124449 TI - A collective route to metastasis: Seeding by tumor cell clusters. AB - Despite decades of study, there are still many unanswered questions about metastasis, the process by which a localized cancer becomes a systemic disease. One of these questions is the nature of the tumor cells that give rise to metastases. Although conventional models suggest that metastases are seeded by single cells from the primary tumor, there is growing evidence that seeding requires the collective action of tumor cells traveling together in clusters. Here, we review this evidence, which comes from analysis of both experimental models and patient samples. We present a model of metastatic dissemination that highlights the activities of clusters of tumor cells that retain and require their epithelial properties. PMID- 27124450 TI - Metastasis as an evolutionary process. AB - Therapeutic advances in oncology have not fully translated to the treatment of metastatic disease, which remains largely incurable. Metastatic subclones can emerge both early and late in the life of the primary tumor. A better understanding of the genetic evolution of metastatic disease has the potential to reveal differences in the therapeutic vulnerabilities of primary and metastatic tumors, shed light on the temporal patterns of and routes to metastatic colonization, and provide insight into the biology of the metastatic process. Here we review recent comparative studies of primary and metastatic tumors, including data suggesting that macroevolutionary shifts (the onset of chromosomal instability) contribute to the evolution of metastatic disease. We also discuss the practical challenges associated with these studies and how they might be overcome. PMID- 27124453 TI - The half-filled Landau level: The case for Dirac composite fermions. AB - In a two-dimensional electron gas under a strong magnetic field, correlations generate emergent excitations distinct from electrons. It has been predicted that "composite fermions"--bound states of an electron with two magnetic flux quanta- can experience zero net magnetic field and form a Fermi sea. Using infinite cylinder density matrix renormalization group numerical simulations, we verify the existence of this exotic Fermi sea, but find that the phase exhibits particle hole symmetry. This is self-consistent only if composite fermions are massless Dirac particles, similar to the surface of a topological insulator. Exploiting this analogy, we observe the suppression of 2k(F) backscattering, a characteristic of Dirac particles. Thus, the phenomenology of Dirac fermions is also relevant to two-dimensional electron gases in the quantum Hall regime. PMID- 27124451 TI - Hypoxic control of metastasis. AB - Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease. PMID- 27124454 TI - Extended Bose-Hubbard models with ultracold magnetic atoms. AB - The Hubbard model underlies our understanding of strongly correlated materials. Whereas its standard form only comprises interactions between particles at the same lattice site, extending it to encompass long-range interactions is predicted to profoundly alter the quantum behavior of the system. We realize the extended Bose-Hubbard model for an ultracold gas of strongly magnetic erbium atoms in a three-dimensional optical lattice. Controlling the orientation of the atomic dipoles, we reveal the anisotropic character of the onsite interaction and hopping dynamics and their influence on the superfluid-to-Mott insulator quantum phase transition. Moreover, we observe nearest-neighbor interactions, a genuine consequence of the long-range nature of dipolar interactions. Our results lay the groundwork for future studies of exotic many-body quantum phases. PMID- 27124455 TI - Exploiting the colloidal nanocrystal library to construct electronic devices. AB - Synthetic methods produce libraries of colloidal nanocrystals with tunable physical properties by tailoring the nanocrystal size, shape, and composition. Here, we exploit colloidal nanocrystal diversity and design the materials, interfaces, and processes to construct all-nanocrystal electronic devices using solution-based processes. Metallic silver and semiconducting cadmium selenide nanocrystals are deposited to form high-conductivity and high-mobility thin-film electrodes and channel layers of field-effect transistors. Insulating aluminum oxide nanocrystals are assembled layer by layer with polyelectrolytes to form high-dielectric constant gate insulator layers for low-voltage device operation. Metallic indium nanocrystals are codispersed with silver nanocrystals to integrate an indium supply in the deposited electrodes that serves to passivate and dope the cadmium selenide nanocrystal channel layer. We fabricate all nanocrystal field-effect transistors on flexible plastics with electron mobilities of 21.7 square centimeters per volt-second. PMID- 27124452 TI - Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA seq. AB - To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies. PMID- 27124456 TI - Ribose and related sugars from ultraviolet irradiation of interstellar ice analogs. AB - Ribose is the central molecular subunit in RNA, but the prebiotic origin of ribose remains unknown. We observed the formation of substantial quantities of ribose and a diversity of structurally related sugar molecules such as arabinose, xylose, and lyxose in the room-temperature organic residues of photo-processed interstellar ice analogs initially composed of H2O, CH3OH, and NH3 Our results suggest that the generation of numerous sugar molecules, including the aldopentose ribose, may be possible from photochemical and thermal treatment of cosmic ices in the late stages of the solar nebula. Our detection of ribose provides plausible insights into the chemical processes that could lead to formation of biologically relevant molecules in suitable planetary environments. PMID- 27124457 TI - Task-free MRI predicts individual differences in brain activity during task performance. AB - When asked to perform the same task, different individuals exhibit markedly different patterns of brain activity. This variability is often attributed to volatile factors, such as task strategy or compliance. We propose that individual differences in brain responses are, to a large degree, inherent to the brain and can be predicted from task-independent measurements collected at rest. Using a large set of task conditions, spanning several behavioral domains, we train a simple model that relates task-independent measurements to task activity and evaluate the model by predicting task activation maps for unseen subjects using magnetic resonance imaging. Our model can accurately predict individual differences in brain activity and highlights a coupling between brain connectivity and function that can be captured at the level of individual subjects. PMID- 27124458 TI - Durably reducing transphobia: A field experiment on door-to-door canvassing. AB - Existing research depicts intergroup prejudices as deeply ingrained, requiring intense intervention to lastingly reduce. Here, we show that a single approximately 10-minute conversation encouraging actively taking the perspective of others can markedly reduce prejudice for at least 3 months. We illustrate this potential with a door-to-door canvassing intervention in South Florida targeting antitransgender prejudice. Despite declines in homophobia, transphobia remains pervasive. For the intervention, 56 canvassers went door to door encouraging active perspective-taking with 501 voters at voters' doorsteps. A randomized trial found that these conversations substantially reduced transphobia, with decreases greater than Americans' average decrease in homophobia from 1998 to 2012. These effects persisted for 3 months, and both transgender and nontransgender canvassers were effective. The intervention also increased support for a nondiscrimination law, even after exposing voters to counterarguments. PMID- 27124459 TI - Observational constraints on mixed-phase clouds imply higher climate sensitivity. AB - Global climate model (GCM) estimates of the equilibrium global mean surface temperature response to a doubling of atmospheric CO2, measured by the equilibrium climate sensitivity (ECS), range from 2.0 degrees to 4.6 degrees C. Clouds are among the leading causes of this uncertainty. Here we show that the ECS can be up to 1.3 degrees C higher in simulations where mixed-phase clouds consisting of ice crystals and supercooled liquid droplets are constrained by global satellite observations. The higher ECS estimates are directly linked to a weakened cloud-phase feedback arising from a decreased cloud glaciation rate in a warmer climate. We point out the need for realistic representations of the supercooled liquid fraction in mixed-phase clouds in GCMs, given the sensitivity of the ECS to the cloud-phase feedback. PMID- 27124461 TI - Direct observation of transition paths during the folding of proteins and nucleic acids. AB - Transition paths, the fleeting trajectories through the transition states that dominate the dynamics of biomolecular folding reactions, encapsulate the critical information about how structure forms. Owing to their brief duration, however, they have not previously been observed directly. We measured transition paths for both nucleic acid and protein folding, using optical tweezers to observe the microscopic diffusive motion of single molecules traversing energy barriers. The average transit times and the shapes of the transit-time distributions agreed well with theoretical expectations for motion over the one-dimensional energy landscapes reconstructed for the same molecules, validating the physical theory of folding reactions. These measurements provide a first look at the critical microscopic events that occur during folding, opening exciting new avenues for investigating folding phenomena. PMID- 27124460 TI - Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio. AB - A decline in electron transport chain (ETC) activity is associated with many human diseases. Although diminished mitochondrial adenosine triphosphate production is recognized as a source of pathology, the contribution of the associated reduction in the ratio of the amount of oxidized nicotinamide adenine dinucleotide (NAD(+)) to that of its reduced form (NADH) is less clear. We used a water-forming NADH oxidase from Lactobacillus brevis (LbNOX) as a genetic tool for inducing a compartment-specific increase of the NAD(+)/NADH ratio in human cells. We used LbNOX to demonstrate the dependence of key metabolic fluxes, gluconeogenesis, and signaling on the cytosolic or mitochondrial NAD(+)/NADH ratios. Expression of LbNOX in the cytosol or mitochondria ameliorated proliferative and metabolic defects caused by an impaired ETC. The results underscore the role of reductive stress in mitochondrial pathogenesis and demonstrate the utility of targeted LbNOX for direct, compartment-specific manipulation of redox state. PMID- 27124463 TI - Erratum for the Research Article "Architecture of the type IVa pilus machine" by Y.-W. Chang, L. A. Rettberg, A. Treuner-Lange, J. Iwasa, L. Sogaard-Andersen, G. J. Jensen. PMID- 27124462 TI - A researcher discovers teaching. PMID- 27124464 TI - Erratum for the Report "MYC regulates the antitumor immune response through CD47 and PD-L1" by S. C. Casey, L. Tong, Y. Li, R. Do, S. Walz, K. N. Fitzgerald, A. M. Gouw, V. Baylot, I. Gutgemann, M. Eilers, D. W. Felsher. PMID- 27124465 TI - Towards Integrated Multi-Trophic Aquaculture: Lessons from Caprellids (Crustacea: Amphipoda). AB - The search for alternative live feed organisms and the progression of Integrative Multi-Trophic Aquaculture (IMTA) are currently being highly prioritised in EU strategies. Caprellids could potentially be an important exploitable resource in aquaculture due to their high levels of beneficial polyunsaturated fatty acids, fast growing nature and widespread distribution. Furthermore, since they are mainly detritivorous, they could be excellent candidates for integration into IMTA systems, potentially benefitting from uneaten feed pellets and faeces released by cultured fish in fish farms and sea-cage structures. Despite this, there is a lack of experimental studies to: (i) test inexpensive diets for caprellids, such as detritus, (ii) develop sustainable caprellid culture techniques and (iii) include caprellids in IMTA systems. The main aim of this study was to determine whether detritus (D) in the form of fish faeces provided an adequate diet for caprellids in comparison to other traditional diets, such as Artemia nauplii (A) or phytoplankton (P). Adult survival rate was shown to be significantly higher for caprellids fed with D. Conversely, hatchlings had the highest survival rate with A, although the juvenile growth rate and number of moults was similar in the three diets. With regard to lipid composition, caprellids fed with A had higher concentrations of Triacylglycerols (TAG) and Phosphatidylcholine (PC) while those fed with P or D were richer in polyunsaturated fatty acids, especially 22:6(n-3) (DHA). Interestingly, caprellids fed with D were also a rich source of 18:2(n-6) (LA), considered to be an essential fatty acid in vertebrates. It was found that detritus based mainly on fish faeces and uneaten feed pellets can be considered an adequate feed for adult caprellids, providing a source of both omega-3 (DHA) and omega-6 (LA) fatty acids. Hatchlings however seem to require an additional input of TAG and PC during juvenile stages to properly grow. PMID- 27124466 TI - Relationship between Resilience, Psychological Distress and Physical Activity in Cancer Patients: A Cross-Sectional Observation Study. AB - OBJECTIVE: Psychological distress remains a major challenge in cancer care. The complexity of psychological symptoms in cancer patients requires multifaceted symptom management tailored to individual patient characteristics and active patient involvement. We assessed the relationship between resilience, psychological distress and physical activity in cancer patients to elucidate potential moderators of the identified relationships. METHOD: A cross-sectional observational study to assess the prevalence of symptoms and supportive care needs of oncology patients undergoing chemotherapy, radiotherapy or chemo radiation therapy in a tertiary oncology service. Resilience was assessed using the 10-item Connor-Davidson Resilience Scale (CD-RISC 10), social support was evaluated using the 12-item Multidimensional Scale of Perceived Social Support (MSPSS) and both psychological distress and activity level were measured using corresponding subscales of the Rotterdam Symptom Checklist (RSCL). Socio demographic and medical data were extracted from patient medical records. Correlation analyses were performed and structural equation modeling was employed to assess the associations between resilience, psychological distress and activity level as well as selected socio-demographic variables. RESULTS: Data from 343 patients were included in the analysis. Our revised model demonstrated an acceptable fit to the data (chi2(163) = 313.76, p = .000, comparative fit index (CFI) = .942, Tucker-Lewis index (TLI) = .923, root mean square error of approximation (RMSEA) = .053, 90% CI [.044.062]). Resilience was negatively associated with psychological distress (beta = -.59), and positively associated with activity level (beta = .20). The relationship between resilience and psychological distress was moderated by age (beta = -0.33) but not social support (beta = .10, p = .12). CONCLUSION: Cancer patients with higher resilience, particularly older patients, experience lower psychological distress. Patients with higher resilience are physically more active. Evaluating levels of resilience in cancer patients then tailoring targeted interventions to facilitate resilience may help improve the effectiveness of psychological symptom management interventions. PMID- 27124468 TI - Pichia kudriavzevii as a representative yeast of North Patagonian winemaking terroir. AB - Terroir concept includes specific soil, topography, climate, landscape characteristics and biodiversity features. In reference to the last aspect, recent studies investigating the microbial biogeography (lately called 'microbial terroir') have revealed that different wine-growing regions maintain different microbial communities. The aim of the present work was to identify potential autochthonous fermentative yeasts isolated from native plants in North Patagonia, Schinus johnstonii, Ephedra ochreata and Lycium chilense, that could be associated to the specific vitivinicultural terroir of this region. Different Pichia kudriavzevii isolates were recovered from these plants and physiologically and genetically compared to regional wine isolates and foreign reference strains of the same species. All isolates were subjected to molecular characterization including mtDNA-RFLP, RAPD-PCR and sequence analysis. Both wine and native P. kudriavzevii isolates from Patagonia showed similar features, different from those showed by foreign strains, suggesting that this species could be part of a specific regional terroir from North Patagonia. PMID- 27124467 TI - Proteogenomic Characterization of Monocyclic Aromatic Hydrocarbon Degradation Pathways in the Aniline-Degrading Bacterium Burkholderia sp. K24. AB - Burkholderia sp. K24, formerly known as Acinetobacter lwoffii K24, is a soil bacterium capable of utilizing aniline as its sole carbon and nitrogen source. Genomic sequence analysis revealed that this bacterium possesses putative gene clusters for biodegradation of various monocyclic aromatic hydrocarbons (MAHs), including benzene, toluene, and xylene (BTX), as well as aniline. We verified the proposed MAH biodegradation pathways by dioxygenase activity assays, RT-PCR, and LC/MS-based quantitative proteomic analyses. This proteogenomic approach revealed four independent degradation pathways, all converging into the citric acid cycle. Aniline and p-hydroxybenzoate degradation pathways converged into the beta ketoadipate pathway. Benzoate and toluene were degraded through the benzoyl-CoA degradation pathway. The xylene isomers, i.e., o-, m-, and p-xylene, were degraded via the extradiol cleavage pathways. Salicylate was degraded through the gentisate degradation pathway. Our results show that Burkholderia sp. K24 possesses versatile biodegradation pathways, which may be employed for efficient bioremediation of aniline and BTX. PMID- 27124469 TI - A SNARE and specific COPII requirements define ER-derived vesicles for the biogenesis of autophagosomes. AB - The endoplasmic reticulum (ER) is a major source for the generation of autophagosomes during macroautophagy. Our recent work in yeast shows that particular ER-derived vesicles are generated for the biogenesis of autophagosomes. These vesicles not only incorporate a SNARE protein that is largely ER-resident under nonstarving conditions, but also display COPII requirements for ER-exit that differ from conventional cargo-transporting vesicles. Our results suggest that specific intracellular traffic is launched at the ER for the transport of membranes to sites of autophagosome formation. PMID- 27124471 TI - Highly Efficient Fructooligosaccharides Production by an Erythritol-Producing Yeast Yarrowia lipolytica Displaying Fructosyltransferase. AB - Currently, fructooligosaccharides (FOS) are industrially transformed from sucrose by purified enzymes or fungi cells. However, these methods are expensive and time consuming. An economical approach to producing FOS using erythritol-producing yeast cells was described in this study. Fructosyltransferase from Aspergillus oryzae was displayed on the cell surface of Yarrowia lipolytica, resulting in an engineered strain capable of transforming sucrose to FOS. An amount of 480 g/L FOS was produced within 3 h in a solution of 800 g/L sucrose and 5 g/L cells (dry cell weight, DCW) at pH 6.0 and 60 degrees C, with a yield of 60% of total sucrose and a productivity of 160 g/(L.h). The yeast pastes from the erythritol industry can be repeatedly used as the whole-cell catalysts at least 10 times by this newly developed approach. This efficient method is attractive for the large scale production of FOS from sucrose. PMID- 27124470 TI - DNA Metabolism in Balance: Rapid Loss of a RecA-Based Hyperrec Phenotype. AB - The RecA recombinase of Escherichia coli has not evolved to optimally promote DNA pairing and strand exchange, the key processes of recombinational DNA repair. Instead, the recombinase function of RecA protein represents an evolutionary compromise between necessary levels of recombinational DNA repair and the potentially deleterious consequences of RecA functionality. A RecA variant, RecA D112R, promotes conjugational recombination at substantially enhanced levels. However, expression of the D112R RecA protein in E. coli results in a reduction in cell growth rates. This report documents the consequences of the substantial selective pressure associated with the RecA-mediated hyperrec phenotype. With continuous growth, the deleterious effects of RecA D112R, along with the observed enhancements in conjugational recombination, are lost over the course of 70 cell generations. The suppression reflects a decline in RecA D112R expression, associated primarily with a deletion in the gene promoter or chromosomal mutations that decrease plasmid copy number. The deleterious effects of RecA D112R on cell growth can also be negated by over-expression of the RecX protein from Neisseria gonorrhoeae. The effects of the RecX proteins in vivo parallel the effects of the same proteins on RecA D112R filaments in vitro. The results indicate that the toxicity of RecA D112R is due to its persistent binding to duplex genomic DNA, creating barriers for other processes in DNA metabolism. A substantial selective pressure is generated to suppress the resulting barrier to growth. PMID- 27124472 TI - Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden. AB - There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human. PMID- 27124474 TI - [Can Quality of Life Be Measured in a Health Care Setting? History, Constraints and Possibilities]. AB - Quality of life concepts and scales related to health (QLRH) are beginning to be customary in clinical practice and now play an important role in bioethical discussions, particularly concerning the management of terminal patients. This paper looks at how that concept has evolved and how it relates to the health illness binomial. We illustrate some important complexities the notion of quality of life (QL) has borne since its inception and that make applicability in the health sciences difficult and, most of all, lead to tremendous biases. In our conclusions, we argue it is necessary to improve the concept of QL by including aspects and factors related to well-being. Although not entirely quantifiable, they give coherence and meaning to the patient data health professionals normally work with. PMID- 27124475 TI - [The Identity of Medicine in the Thought of Edmund D. Pellegrino]. AB - This essay addresses Pellegrino's thought on Philosophy of Medicine; it also provides an approach to his concerns on the changing relationship between patients and physicians which took place in the late twentieth century in the United States and, finally, to his contribution to the identity of Medicine debate. From an Aristotelian-Thomist way of thinking, and from a phenomenological approach to the medical act, he identifies the ending of Medicine and also its limits concerning to "healing", in his two moments, curing and helping, which includes caring. Medicine, the essence of Medicine, tends to healing, for this relationship between patient and physician tends to a "good" which ultimately ends up being its finality. Medical ethics germinates within this relationship, the clinical encounter, as a universal experience of illness, pain and humane limitation. Therefore, healing is the essence of Medicine and truly its genuine identity. Besides healing any other act is not strictly medical. From the doctrine of Pellegrino emerges that original and classic idea of "the good of the patient" as the main and ruling principle of medical ethics. Medical act is no longer just a technique, a technical act, but also a moral enterprise, which our teacher relates to the so called "medical virtues". But this "good" may not be understood nowadays in the old Hippocratic terms and should also be related to the dignity of the patients and to his or her moral autonomy. And accordingly an updating of the concept of good is demanded by the teacher who, to this intent, stresses four main aspects which are summoned in the article. PMID- 27124473 TI - A Network Biology Approach Identifies Molecular Cross-Talk between Normal Prostate Epithelial and Prostate Carcinoma Cells. AB - The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However, so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since these interactions represent an essential part of the biology of both diseased and healthy tissues, it is of paramount importance that this challenge is addressed. Here we report the definition of a network reverse engineering strategy designed to infer directional signals linking adjacent cell types within a complex tissue. The application of this inference strategy to prostate cancer genome-wide expression profiling data validated the approach and revealed that normal epithelial cells exert an anti-tumour activity on prostate carcinoma cells. Moreover, by using a Bayesian hierarchical model integrating genetics and gene expression data and combining this with survival analysis, we show that the expression of putative cell communication genes related to focal adhesion and secretion is affected by epistatic gene copy number variation and it is predictive of patient survival. Ultimately, this study represents a generalizable approach to the challenge of deciphering cell communication networks in a wide spectrum of biological systems. PMID- 27124476 TI - [Omission and Withdrawal of Vital Care. ?Killing or Letting Die? An Approach From the Moral and Legal Criteria of Action Tipification]. AB - This work aims at two objectives. Firstly, at identifying the basic criterions that underlie the conceptual distinction between letting die, on the one hand, and killing by omitting or withdrawing vital care (VCO), on the other. Secondly, at identifying the reasonableness conditions of public interference on the decision either to reject or to withdraw vital care. Based upon a theory of action inspired in the works of John Finnis, Martin Rhonheimer and Elisabeth Anscombe, it is argued that the moral criteria of typification and individuation of VCO is analogous but not identical to the corresponding legal criteria. Assuming this distinction, I suggest a three steps reasonableness test for public interference on the decision to omit or withdraw vital care. PMID- 27124477 TI - [Theory and Practice of Informed Consent]. AB - Informed consent is the process of communication between the professional (medical staff and/or investigator) and patient culminating in the decision regarding a particular intervention. However, in our country the concept of informed consent is usually limited to the document that must be signed by the patient to undergo diagnostic or therapeutic procedures riskier. This consent is best understood as a process rather than an event, and also it usually gives consent on care processes rather than on specific events: the acceptance of a process involves a tacitly acceptance of the different components that are usually part of this process. There are many steps in the care process in which a simple permission could be enough, not needing a specific and formal consent... finally, contrary to the usual practice, the acceptance document of consent should be short, clear and understandable, flexible, and with the ability to adapt to the circumstances and the patient's wishes as far as possible and, all in an atmosphere of trust and verbal information that enables the patient, not forced to confront all the information, to delegate decisions on the professional. PMID- 27124478 TI - [Transsexualism: a Brain Disorder that Begins to Known]. AB - Transsexualism describes the condition when a person's psychological gender differs from his or her biological sex. People with gender identity disorder suffer persistently from this incongruence and they search hormonal and surgical sex reassignment to the desired anatomical sex. This review, from an ethical perspective, intends to give an overview of structural and functional neurobiological correlations of transsexualism and their course under cross-sex hormonal administration. Several studies demonstrate an increased functional connectivity between cortex regions reaffirming psychosocial distress of psychologicalbiological sex incongruity. Such distress can be ascribed to a disharmonic body image due to changes in the functional connectivity of the key components of body representation network. These brain alterations seem to imply a strategic mechanism dissociating bodily emotions from bodily images. For a number of sexually dimorphic brain structures or processes, signs of feminization or masculinization are observable in transsexual individuals, who during hormonal administration seem to partly further adjust to characteristics of the desired sex. These changes allow a reduction of psychosocial distress. However, a model leading to a "gender affirmation" does not solve the problem, since brain disorders causing it are not corrected. This is a serious medical ethics issue. Prejudices should be left aside. To know what happens in the brain of transsexuals is a medical need, both to define what is and what is not, and so to choose an adequate treatment, and to decide and guide legal actions. PMID- 27124480 TI - [Commentary on the Case: Nutrition in Oncological Patient]. PMID- 27124479 TI - [Case: Nutrition in Oncological Patient]. PMID- 27124482 TI - Characteristics of Soil and Organic Carbon Loss Induced by Water Erosion on the Loess Plateau in China. AB - Soil erosion has been a common environmental problem in the Loess Plateau in China. This study aims to better understand the losses of soil organic carbon (SOC) induced by water erosion. Laboratory-simulated rainfall experiments were conducted to investigate the characteristics of SOC loss induced by water erosion. The applied treatments included two rainfall intensities (90 and 120 mm h-1), four slope gradients (10 degrees , 15 degrees , 20 degrees , and 25 degrees ), and two typical soil types- silty clay loam and silty loam. Results showed that the sediment OC enrichment ratios (ERoc) in all the events were relative stable with values ranged from 0.85 to1.21 and 0.64 to 1.52 and mean values of 0.98 and 1.01 for silty clay loam and silty loam, respectively. Similar to the ERoc, the proportions of different sized particles in sediment showed tiny variations during erosion processes. No significant correlation was observed between ERoc values and the proportions of sediment particles. Slope, rainfall intensity and soil type almost had no impact on ERoc. These results indicate that the transportation of SOC during erosion processes was nonselective. While the mean SOC loss rates for the events of silty clay loam and silty loam were 0.30 and 0.08 g m-2 min-1, respectively. Greater differences in SOC loss rates were found in events among different soil types. Meanwhile, significant correlations between SOC loss and soil loss for all the events were observed. These results indicated that the amount of SOC loss was influenced primarily by soil loss and the SOC content of the original soil. Erosion pattern and original SOC content are two main factors by which different soils can influence SOC loss. It seems that soil type has a greater impact on SOC loss than rainfall characteristics on the Loess Plateau of China. However, more kinds of soils should be further studied due to the special formation processes in the Loess Plateau. PMID- 27124481 TI - Phenotypical characterization of regulatory T cells in humans and rodents. AB - Regulatory T cells (Tregs ) constitute a fascinating subpopulation of CD4(+) T cells due to their ability to limit the immune response against self and non-self antigens. Murine models and antibodies directed against surface and intracellular molecules have allowed elucidation of the mechanisms that govern their development and function. However, these markers used to their classification lack of specificity, as they can be expressed by activated T cells. Similarly, there are slight differences between animal models, in steady state and pathological conditions, anatomical localization and strategy of analysis by flow cytometry. Here, we revised the most common markers utilized for Treg typification by flow cytometry such as CD25, forkhead box protein 3 (FoxP3) and CD127, along with our data obtained in different body compartments of humans, mice and rats. Furthermore, we revised and determined the expression of other molecules important for the phenotypical characterization of Treg cells. We draw attention to the drawbacks of those markers used in chronic states of inflammation. However, until a specific marker for the identification of Tregs is discovered, the best combination of markers will depend upon the tissue or the degree of inflammation from which Tregs derive. PMID- 27124484 TI - Development, Use, and Interpretation of Patient-Reported Outcomes for Clinical Decision Making in Ophthalmology. PMID- 27124483 TI - Real-Time Tracking of BODIPY-C12 Long-Chain Fatty Acid in Human Term Placenta Reveals Unique Lipid Dynamics in Cytotrophoblast Cells. AB - While the human placenta must provide selected long-chain fatty acids to support the developing fetal brain, little is known about the mechanisms underlying the transport process. We tracked the movement of the fluorescently labeled long chain fatty acid analogue, BODIPY-C12, across the cell layers of living explants of human term placenta. Although all layers took up the fatty acid, rapid esterification of long-chain fatty acids and incorporation into lipid droplets was exclusive to the inner layer cytotrophoblast cells rather than the expected outer syncytiotrophoblast layer. Cytotrophoblast is a progenitor cell layer previously relegated to a repair role. As isolated cytotrophoblasts differentiated into syncytialized cells in culture, they weakened their lipid processing capacity. Syncytializing cells suppress previously active genes that regulate fatty-acid uptake (SLC27A2/FATP2, FABP4, ACSL5) and lipid metabolism (GPAT3, LPCAT3). We speculate that cytotrophoblast performs a previously unrecognized role in regulating placental fatty acid uptake and metabolism. PMID- 27124485 TI - Investigating Empathy-Like Responding to Conspecifics' Distress in Pet Dogs. AB - Empathy covers a wide range of phenomena varying according to the degree of cognitive complexity involved; ranging from emotional contagion, defined as the sharing of others' emotional states, to sympathetic concern requiring animals to have an appraisal of the others' situation and showing concern-like behaviors. While most studies have investigated how animals reacted in response to conspecifics' distress, dogs so far have mainly been targeted to examine cross species empathic responses. To investigate whether dogs would respond with empathy-like behavior also to conspecifics, we adopted a playback method using conspecifics' vocalizations (whines) recorded during a distressful event as well as control sounds. Our subjects were first exposed to a playback phase where they were subjected either to a control sound, a familiar whine (from their familiar partner) or a stranger whine stimulus (from a stranger dog), and then a reunion phase where the familiar partner entered the room. When exposed to whines, dogs showed a higher behavioral alertness and exhibited more stress-related behaviors compared to when exposed to acoustically similar control sounds. Moreover, they demonstrated more comfort-offering behaviors toward their familiar partners following whine playbacks than after control stimuli. Furthermore, when looking at the first session, this comfort offering was biased towards the familiar partner when subjects were previously exposed to the familiar compared to the stranger whines. Finally, familiar whine stimuli tended to maintain higher cortisol levels while stranger whines did not. To our knowledge, these results are the first to suggest that dogs can experience and demonstrate "empathic-like" responses to conspecifics' distress-calls. PMID- 27124487 TI - Bottom-Up Colloidal Crystal Assembly with a Twist. AB - Globally ordered colloidal crystal lattices have broad utility in a wide range of optical and catalytic devices, for example, as photonic band gap materials. However, the self-assembly of stereospecific structures is often confounded by polymorphism. Small free-energy differences often characterize ensembles of different structures, making it difficult to produce a single morphology at will. Current techniques to handle this problem adopt one of two approaches: that of the "top-down" or "bottom-up" methodology, whereby structures are engineered starting from the largest or smallest relevant length scales, respectively. However, recently, a third approach for directing high fidelity assembly of colloidal crystals has been suggested which relies on the introduction of polymer cosolutes into the crystal phase [Mahynski, N.; Panagiotopoulos, A. Z.; Meng, D.; Kumar, S. K. Nat. Commun. 2014, 5, 4472]. By tuning the polymer's morphology to interact uniquely with the void symmetry of a single desired crystal, the entropy loss associated with polymer confinement has been shown to strongly bias the formation of that phase. However, previously, this approach has only been demonstrated in the limiting case of close-packed crystals. Here, we show how this approach may be generalized and extended to complex open crystals, illustrating the utility of this "structure-directing agent" paradigm in engineering the nanoscale structure of ordered colloidal materials. The high degree of transferability of this paradigm's basic principles between relatively simple crystals and more complex ones suggests that this represents a valuable addition to presently known self-assembly techniques. PMID- 27124488 TI - The Water Suitcase of Migrants: Assessing Virtual Water Fluxes Associated to Human Migration. AB - Disentangling the relations between human migrations and water resources is relevant for food security and trade policy in water-scarce countries. It is commonly believed that human migrations are beneficial to the water endowments of origin countries for reducing the pressure on local resources. We show here that such belief is over-simplistic. We reframe the problem by considering the international food trade and the corresponding virtual water fluxes, which quantify the water used for the production of traded agricultural commodities. By means of robust analytical tools, we show that migrants strengthen the commercial links between countries, triggering trade fluxes caused by food consumption habits persisting after migration. Thus migrants significantly increase the virtual water fluxes and the use of water in the countries of origin. The flux ascribable to each migrant, i.e. the "water suitcase", is found to have increased from 321 m3/y in 1990 to 1367 m3/y in 2010. A comparison with the water footprint of individuals shows that where the water suitcase exceeds the water footprint of inhabitants, migrations turn out to be detrimental to the water endowments of origin countries, challenging the common perception that migrations tend to relieve the pressure on the local (water) resources of origin countries. PMID- 27124486 TI - Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial. AB - IMPORTANCE: Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi) refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naive patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. OBJECTIVE: To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy. INTERVENTIONS: Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600. MAIN OUTCOMES AND MEASURES: The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points. RESULTS: A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for <=6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients. CONCLUSIONS AND RELEVANCE: The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01619774. PMID- 27124489 TI - Filamentous Fungi in Respiratory Infections. What Lies Beyond Aspergillosis and Mucormycosis? PMID- 27124491 TI - Placing Local Aggregations in a Larger-Scale Context: Hierarchical Modeling of Black-Footed Albatross Dispersion. AB - At-sea surveys facilitate the study of the distribution and abundance of marine birds along standardized transects, in relation to changes in the local environmental conditions and large-scale oceanographic forcing. We analyzed the form and the intensity of black-footed albatross (Phoebastria nigripes: BFAL) spatial dispersion off central California, using five years (2004-2008) of vessel based surveys of seven replicated survey lines. We related BFAL patchiness to local, regional and basin-wide oceanographic variability using two complementary approaches: a hypothesis-based model and an exploratory analysis. The former tested the strength and sign of hypothesized BFAL responses to environmental variability, within a hierarchical atmosphere-ocean context. The latter explored BFAL cross-correlations with atmospheric / oceanographic variables. While albatross dispersion was not significantly explained by the hierarchical model, the exploratory analysis revealed that aggregations were influenced by static (latitude, depth) and dynamic (wind speed, upwelling) environmental variables. Moreover, the largest BFAL patches occurred along the survey lines with the highest densities, and in association with shallow banks. In turn, the highest BFAL densities occurred during periods of negative Pacific Decadal Oscillation index values and low atmospheric pressure. The exploratory analyses suggest that BFAL dispersion is influenced by basin-wide, regional-scale and local environmental variability. Furthermore, the hypothesis-based model highlights that BFAL do not respond to oceanographic variability in a hierarchical fashion. Instead, their distributions shift more strongly in response to large-scale ocean atmosphere forcing. Thus, interpreting local changes in BFAL abundance and dispersion requires considering diverse environmental forcing operating at multiple scales. PMID- 27124492 TI - Surface Area of Carbon Nanoparticles: A Dose Metric for a More Realistic Ecotoxicological Assessment. AB - Engineered nanoparticles such as graphenes, nanodiamonds, and carbon nanotubes correspond to different allotropes of carbon and are among the best candidates for applications in fast-growing nanotechnology. It is thus likely that they may get into the environment at each step of their life cycle: production, use, and disposal. The aquatic compartment concentrates pollutants and is expected to be especially impacted. The toxicity of a compound is conventionally evaluated using mass concentration as a quantitative measure of exposure. However, several studies have highlighted that such a metric is not the best descriptor at the nanoscale. Here we compare the inhibition of Xenopus laevis larvae growth after in vivo exposure to different carbon nanoparticles for 12 days using different dose metrics and clearly show that surface area is the most relevant descriptor of toxicity for different types of carbon allotropes. PMID- 27124490 TI - Biobanking of Fresh-Frozen Human Adenocarcinomatous and Normal Colon Tissues: Which Parameters Influence RNA Quality? AB - Medical research projects become increasingly dependent on biobanked tissue of high quality because the reliability of gene expression is affected by the quality of extracted RNA. Hence, the present study aimed to determine if clinical, surgical, histological, and molecular parameters influence RNA quality of normal and tumoral frozen colonic tissues. RNA Quality Index (RQI) was evaluated on 241 adenocarcinomas and 115 matched normal frozen colon tissues collected between October 2006 and December 2012. RQI results were compared to patients' age and sex, tumor site, kind of surgery, anastomosis failure, adenocarcinoma type and grade, tumor cell percentage, necrosis extent, HIF-1alpha and cleaved caspase-3 immunohistochemistry, and BRAF, KRAS and microsatellites status. The RQI was significantly higher in colon cancer tissue than in matched normal tissue. RQI from left-sided colonic cancers was significantly higher than RQI from right-sided cancers. The RNA quality was not affected by ischemia and storage duration. According to histological control, 7.9% of the samples were unsatisfactory because of inadequate sampling. Biobanked tumoral tissues with RQI >=5 had lower malignant cells to stromal cells ratio than samples with RQI <5 (p <0.05). Cellularity, necrosis extent and mucinous component did not influence RQI results. Cleaved caspase-3 and HIF-1alpha immunolabelling were not correlated to RQI. BRAF, KRAS and microsatellites molecular status did not influence RNA quality. Multivariate analysis revealed that the tumor location, the surgical approach (laparoscopy versus open colectomy) and the occurrence of anastomotic leakage were the only parameters influencing significantly RQI results of tumor samples. We failed to identify parameter influencing RQI of normal colon samples. These data suggest that RNA quality of colonic adenocarcinoma biospecimens is determined by clinical and surgical parameters. More attention should be paid during the biobanking procedure of right-sided colon cancer or laparoscopic colectomy specimen. Histological quality control remains essential to control sampling accuracy. PMID- 27124493 TI - The Dynamics of Initiative in Communication Networks. AB - Human social interaction is often intermittent. Two acquainted persons can have extended periods without social interaction punctuated by periods of repeated interaction. In this case, the repeated interaction can be characterized by a seed initiative by either of the persons and a number of follow-up interactions. The tendency to initiate social interaction plays an important role in the formation of social networks and is in general not symmetric between persons. In this paper, we study the dynamics of initiative by analysing and modeling a detailed call and text message network sampled from a group of 700 individuals. We show that in an average relationship between two individuals, one part is almost twice as likely to initiate communication compared to the other part. The asymmetry has social consequences and ultimately might lead to the discontinuation of a relationship. We explain the observed asymmetry by a positive feedback mechanism where individuals already taking initiative are more likely to take initiative in the future. In general, people with many initiatives receive attention from a broader spectrum of friends than people with few initiatives. Lastly, we compare the likelihood of taking initiative with the basic personality traits of the five factor model. PMID- 27124494 TI - Flexible Circuits and Soft Actuators by Printing Assembly of Graphene. AB - An effective way to improve the electrical conductivity of printed graphene patterns was demonstrated by realizing the assembly of giant graphene oxide sheets during the printing process. The synergetic effect of printing-induced orientation and evaporation-induced interfacial assembly facilitated the formation of laminar-structured patterns. The resulting patterns after chemical reduction showed excellent electrical conductivity in printed graphene electronics. Because of their high conductivity, mechanical flexibility, and advantage in pattern design, printed graphene electrodes were applied in electrical-driven soft actuators, which can realize controllable deformation with low driving voltage. Such achievements will be of great significance for the development of graphene-based flexible and printed electronics. PMID- 27124495 TI - Stealth fast photoswitching of negative photochromic naphthalene-bridged phenoxyl imidazolyl radical complexes. AB - Naphthalene-bridged phenoxyl-imidazolyl radical complex (Np-PIC) is a novel fast switchable negative photochromic compound, which shows the thermal back reaction in the millisecond time scale. Upon UV light irradiation, Np-PIC shows the hypochromic effect in the UVA region due to there being less conjugation in the transient isomer. By replacing the phenoxyl unit with a naphthoxyl unit, the molecular structure has an asymmetric carbon, leading to fast chiroptical switching. This simple molecular design will be a good candidate for the future development of negative photochromic compounds. PMID- 27124497 TI - Assembling Metal-Organic Frameworks in Ionic Liquids and Supercritical CO2. AB - Ionic liquids (ILs) and supercritical carbon dioxide (scCO2 ) are both considered to be green solvents with tunable properties. Recently, studies of the synthesis of metal-organic frameworks (MOFs) in the presence of ILs and scCO2 has become a burgeoning direction in chemistry and materials science. ILs have been shown to be ideal media for the synthesis of a variety of MOFs owing to their unique properties including the ability to dissolve a wide range of organic and inorganic compounds and flexible designability. scCO2 has adjustable solvent power and excellent mass-transfer characteristics that offer the opportunity to replace organic solvents for MOF activation, MOF aerogel synthesis, and MOF construction. More interestingly, the simultaneous utilization of IL and scCO2 can combine the advantages of the two liquids, which provides novel routes for the fabrication of MOF structures. This review describes the advances in MOF synthesis in ILs, scCO2 , and IL/scCO2 systems. PMID- 27124498 TI - Synthesis and Application of Tetrahydro-2H-fluorenes by a Pd(0)-Catalyzed Benzylic C(sp(3) )-H Functionalization. AB - A new method has been developed for the synthesis of tetrahydro-2H-fluorenes based on a Pd(0)-catalyzed benzylic C(sp(3) )-H functionalization. Importantly, the success of the cyclization step was dependent on there being substituents at the two positions ortho to the benzylic group to avoid an undesired C(sp(2) )-H functionalization. This method was subsequently used to prepare the right-hand fragment of the hexacyclic triterpenoid benzohopanes, and therefore represents a powerful tool for the construction of the related compounds. PMID- 27124496 TI - Stand Composition, Tree Proximity and Size Have Minimal Effects on Leaf Function of Coexisting Aspen and Subalpine Fir. AB - Forest structural heterogeneity due to species composition, spatial relationships and tree size are widely studied patterns in forest systems, but their impacts on tree function are not as well documented. The objective of this study was to examine how stand composition, tree proximity relationships and tree size influence the leaf functional traits of aspen, an early successional species, and subalpine fir, a climax species. We measured foliar nutrients, nonstructural carbohydrates (aspen only), defense chemistry and xylem water potential of aspen and subalpine fir trees in three size classes growing in close proximity or independently from other trees under three stand conditions: aspen dominant, aspen-conifer mixed, and conifer dominant stands. Close proximity of subalpine fir to aspen reduced aspen's storage of starch in foliar tissue by 17% suggesting that competition between these species may have small effects on carbon metabolism in aspen leaves. Simple sugar (glucose + sucrose) concentrations in aspen leaves were slightly higher in larger aspen trees than smaller trees. However, no differences were found in stem water potential, foliar concentrations of nitrogen, phosphorus, or secondary defense chemicals of aspen or subalpine fir across the gradients of stand composition, tree proximity or tree size. These results suggest that mechanisms of coexistence allow both aspen and subalpine fir to maintain leaf function across a wide range of stand structural characteristics. For aspen, resource sharing through its clonal root system and high resource storage capacity may partially contribute to its functional stability in mixed aspen-conifer stands. PMID- 27124499 TI - A Microfiltration Device for Urogenital Schistosomiasis Diagnostics. AB - Schistosomiasis is a parasitic disease affecting over 200 million people worldwide. This study reports the design and development of a microfiltration device for isolating schistosome eggs in urine for rapid diagnostics of urogenital schistosomiasis. The design of the device comprises a linear array of microfluidic traps to immobilize and separate schistosome eggs. Sequential loading of individual eggs is achieved autonomously by flow resistance, which facilitates observation and enumeration of samples with low-abundance targets. Computational fluid dynamics modeling and experimental characterization are performed to optimize the trapping performance. By optimizing the capture strategy, the trapping efficiency could be achieved at 100% with 300 MUl/min and 83% with 3000 MUl/min, and the filtration procedure could be finished within 10 min. The trapped eggs can be either recovered for downstream analysis or preserved in situ for whole-mount staining. On-chip phenotyping using confocal laser fluorescence microscopy identifies the microstructure of the trapped schistosome eggs. The device provides a novel microfluidic approach for trapping, counting and on-chip fluorescence characterization of urinal Schistosoma haematobium eggs for clinical and investigative application. PMID- 27124500 TI - TRPV4 channels in the human urogenital tract play a role in cell junction formation and epithelial barrier. AB - AIM: The molecular interactions between transient receptor potential vanilloid subtype 4 channels (TRPV4) and cell junction formation were investigated in the human and mouse urogenital tract. MATERIALS AND METHODS: A qualitative study was performed to investigate TRPV4 channels, adherence junctions (AJs) and tight junctions (TJs) in kidney, ureter and bladder tissues from humans and wild-type and transgenic TRPV4 knockout (-/-) mice with immunohistochemistry, Western blotting, immunoprecipitation and reverse trasnscription-PCR. Cell junction formation in the wild-type and TRPV4 knockout (-/-) mouse was evaluated with immunohistochemistry and transmission electron microscope (TEM) techniques. RESULTS: TRPV4 channels are predominantly located in membranes of epithelial cells of the bladder, ureter and the collecting ducts of the kidney. There is a molecular interaction between the TRPV4 channel and the AJ. TEM evaluation showed that AJ formation is disrupted in the TRPV4 -/- mouse resulting in deficient intercellular connections and integrity of the epithelium. CONCLUSIONS: TRPV4 is believed to be a mechanoreceptor in the bladder. This study demonstrates that TRPV4 is also involved in intercellular connectivity and structural integrity of the epithelium. PMID- 27124502 TI - Psychometric evaluation of the 10-item Short Opiate Withdrawal Scale-Gossop (SOWS Gossop) in patients undergoing opioid detoxification. AB - INTRODUCTION: The Short Opiate Withdrawal Scale (SOWS)-Gossop is a 10-item questionnaire developed to evaluate opioid withdrawal symptom severity. The scale was derived from the original 32-item Opiate Withdrawal Scale in order to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The objective of this study was to examine the psychometric properties and provide score interpretation guidelines for the SOWS-Gossop 10-item version. METHODS: Blinded, pooled data from two trials assessing the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid detoxification were used to evaluate the quantitative psychometric properties and score interpretation of the SOWS-Gossop. RESULTS: Five hundred fifty-five (N=555) observations were available at baseline with numbers decreasing to n=213 at day 7. Mean (standard deviation) SOWS-Gossop scores were 10.4 (6.86) at baseline, 8.7 (6.49) on day 1, 10.5 (7.21) on day 2, and 3.1 (3.95) on day 7. Confirmatory factor analysis indicated that the SOWS-Gossop items loaded on a single factor consistent with a single total score. Intra-class correlations (95% confidence interval) were 0.78 (0.70-0.85) between baseline and day 1, 0.84 (0.79-0.89) between days 4 and 5, and 0.88 (0.83-0.91) between days 6 and 7, demonstrating good test-retest reliability. Mean SOWS-Gossop scores varied significantly (p<0.0001) by Modified Clinical Global Impression severity groups supporting known-groups validity. Most correlations with conceptually similar instruments were over 0.4, providing evidence of construct validity. Results suggest that a change score of approximately 2-4 points is likely a small but meaningful improvement on the SOWS-Gossop Total Score. CONCLUSIONS: The findings of this study indicate that the SOWS-Gossop includes concepts that are relevant to patients' experiences with opioid withdrawal and has excellent psychometric properties. The SOWS-Gossop is an appropriate, precise, and sensitive measure to evaluate the symptoms of acute opioid withdrawal in research or clinical settings. PMID- 27124503 TI - Borderline personality disorder and compulsive buying: A multivariate etiological model. PMID- 27124505 TI - Examining the effectiveness of a culturally adapted social-emotional intervention for African American males in an urban setting. AB - The purpose of the present study was to assess the efficacy of a culturally adapted version of the Strong Start intervention program on the social-emotional outcomes of African American male students. Externalizing behavior problems of children, specifically African American males, are of great concern for schools. Punitive discipline polices such as expulsion and suspension have proved to be ineffective and harmful. Consequently, school-based social-emotional learning (SEL) interventions have been proposed to teach children coping skills that can help them increase positive social behaviors and emotional regulation. Sixty-one African American male students enrolled in an urban elementary school participated in this intervention. This study employed a randomized delayed treatment control design. Results indicated positive effects in the areas of self regulation and self-competence. However the intervention did not have an impact on student's empathy, responsibility, or externalizing behavior. Implications are discussed in terms of developing culturally relevant school-based interventions for African American males. (PsycINFO Database Record PMID- 27124504 TI - Localization of RNAPII and 3' end formation factor CstF subunits on C. elegans genes and operons. AB - Transcription termination is mechanistically coupled to pre-mRNA 3' end formation to prevent transcription much beyond the gene 3' end. C. elegans, however, engages in polycistronic transcription of operons in which 3' end formation between genes is not accompanied by termination. We have performed RNA polymerase II (RNAPII) and CstF ChIP-seq experiments to investigate at a genome-wide level how RNAPII can transcribe through multiple poly-A signals without causing termination. Our data shows that transcription proceeds in some ways as if operons were composed of multiple adjacent single genes. Total RNAPII shows a small peak at the promoter of the gene cluster and a much larger peak at 3' ends. These 3' peaks coincide with maximal phosphorylation of Ser2 within the C terminal domain (CTD) of RNAPII and maximal localization of the 3' end formation factor CstF. This pattern occurs at all 3' ends including those at internal sites in operons where termination does not occur. Thus the normal mechanism of 3' end formation does not always result in transcription termination. Furthermore, reduction of CstF50 by RNAi did not substantially alter the pattern of CstF64, total RNAPII, or Ser2 phosphorylation at either internal or terminal 3' ends. However, CstF50 RNAi did result in a subtle reduction of CstF64 binding upstream of the site of 3' cleavage, suggesting that the CstF50/CTD interaction may facilitate bringing the 3' end machinery to the transcription complex. PMID- 27124506 TI - Retention of Mastoidectomy Skills After Virtual Reality Simulation Training. AB - IMPORTANCE: The ultimate goal of surgical training is consolidated skills with a consistently high performance. However, surgical skills are heterogeneously retained and depend on a variety of factors, including the task, cognitive demands, and organization of practice. Virtual reality (VR) simulation is increasingly being used in surgical skills training, including temporal bone surgery, but there is a gap in knowledge on the retention of mastoidectomy skills after VR simulation training. OBJECTIVES: To determine the retention of mastoidectomy skills after VR simulation training with distributed and massed practice and to investigate participants' cognitive load during retention procedures. DESIGN, SETTING, AND PARTICIPANTS: A prospective 3-month follow-up study of a VR simulation trial was conducted from February 6 to September 19, 2014, at an academic teaching hospital among 36 medical students: 19 from a cohort trained with distributed practice and 17 from a cohort trained with massed practice. INTERVENTIONS: Participants performed 2 virtual mastoidectomies in a VR simulator a mean of 3.2 months (range, 2.4-5.0 months) after completing initial training with 12 repeated procedures. Practice blocks were spaced apart in time (distributed), or all procedures were performed in 1 day (massed). MAIN OUTCOMES AND MEASURES: Performance of the virtual mastoidectomy as assessed by 2 masked senior otologists using a modified Welling scale, as well as cognitive load as estimated by reaction time to perform a secondary task. RESULTS: Among 36 participants, mastoidectomy final-product skills were largely retained at 3 months (mean change in score, 0.1 points; P = .89) regardless of practice schedule, but the group trained with massed practice took more time to complete the task. The performance of the massed practice group increased significantly from the first to the second retention procedure (mean change, 1.8 points; P = .001), reflecting that skills were less consolidated. For both groups, increases in reaction times in the secondary task (distributed practice group: mean pretraining relative reaction time, 1.42 [95% CI, 1.37-1.47]; mean end of training relative reaction time, 1.24 [95% CI, 1.16-1.32]; and mean retention relative reaction time, 1.36 [95% CI, 1.30-1.42]; massed practice group: mean pretraining relative reaction time, 1.34 [95% CI, 1.28-1.40]; mean end of training relative reaction time, 1.31 [95% CI, 1.21-1.42]; and mean retention relative reaction time, 1.39 [95% CI, 1.31-1.46]) indicated that cognitive load during the virtual procedures had returned to the pretraining level. CONCLUSIONS AND RELEVANCE: Mastoidectomy skills acquired under time-distributed practice conditions were retained better than skills acquired under massed practice conditions. Complex psychomotor skills should be regularly reinforced to consolidate both motor and cognitive aspects. Virtual reality simulation training provides the opportunity for such repeated training and should be integrated into training curricula. PMID- 27124507 TI - [In Process Citation]. PMID- 27124509 TI - [In Process Citation]. PMID- 27124508 TI - Dose Monitoring in Radiology Departments: Status Quo and Future Perspectives. AB - The number of computed tomography examinations has continuously increased over the last decades and accounts for a major part of the collective radiation dose from medical investigations. For purposes of quality assurance in modern radiology a systematic monitoring and analysis of dose related data from radiological examinations is mandatory. Various ways of collecting dose data are available today, for example the Digital Imaging and Communication in Medicine - Structured Report (DICOM-SR), optical character recognition and DICOM-modality performed procedure steps (MPPS). The DICOM-SR is part of the DICOM-standard and provides the DICOM-Radiation Dose Structured Report, which is an easily applicable and comprehensive solution to collect radiation dose parameters. This standard simplifies the process of data collection and enables comprehensive dose monitoring. Various commercial dose monitoring software devices with varying characteristics are available today. In this article, we discuss legal obligations, various ways to monitor dose data, current dose monitoring software solutions and future perspectives in regard to the EU Council Directive 2013/59/EURATOM. KEY POINTS: * Automated, systematic dose monitoring is an important element in quality assurance of radiology departments. * DICOM-RDSR capable CT scanners facilitate the monitoring of dose data. * A variety of commercial and non-commercial dose monitoring software tools are available today. * Successful dose monitoring requires comprehensive infrastructure for monitoring, analysing and optimizing radiation exposure. Citation Format: * Boos J, Meineke A, Bethge OT et al. Dose Monitoring in Radiology Departments: Status Quo and Future Perspectives. Fortschr Rontgenstr 2016; 188: 443 - 450. PMID- 27124510 TI - [In Process Citation]. PMID- 27124512 TI - [In Process Citation]. PMID- 27124511 TI - [In Process Citation]. PMID- 27124514 TI - [In Process Citation]. PMID- 27124513 TI - [In Process Citation]. PMID- 27124515 TI - [In Process Citation]. PMID- 27124516 TI - Multicomponent Double Diels-Alder/Nazarov Tandem Cyclization of Symmetric Cross Conjugated Diynones to Generate [6-5-6] Tricyclic Products. AB - The construction of complex polycyclic terpenoid products in an efficient and step-economical manner using multicomponent and tandem processes is highly valuable. Herein, we report a tandem cyclization sequence that initiates with a multicomponent double Diels-Alder reaction of cross-conjugated diynones, followed by a Nazarov cyclization to efficiently produce [6-5-6] tricyclic products with excellent regio- and diastereoselectivity. This methodology generates five new carbon-carbon bonds, three rings, quaternary or vicinal quaternary carbons, and stereogenic centers in a one-pot reaction. PMID- 27124517 TI - Food Insecurity Associated with Self-Efficacy and Acculturation. AB - Food insecurity is a significant public health issue that affects the physical and mental health of people of all ages. Higher levels of self-efficacy may reduce levels of food insecurity. In addition, acculturation is potentially an important factor for food insecurity among immigrant populations. The purpose of this study is to examine food insecurity associated with self-efficacy and acculturation among low-income primary care patients in the United States. A self administered survey was administered in May and June 2015 to uninsured primary care patients (N = 551) utilizing a free clinic that provides free primary care services to low-income uninsured individuals and families in the United States. On average, participants reported low food security. Higher levels of self efficacy were associated with lower levels of food insecurity. Higher levels of heritage language proficiency were related to lower levels of food insecurity. US born English speakers, women, and unmarried individuals potentially have higher risks of food insecurity and may need interventions to meet their specific needs. Self-efficacy should be included in nutrition education programs to reduce the levels of food insecurity. Future studies should further examine why these groups have a high risk to better understand needs for interventions. PMID- 27124518 TI - A Three-Step Method for the Deposition of Large Cuboids of Organic-Inorganic Perovskite and Application in Solar Cells. AB - A three-step method for the deposition of CH3 NH3 PbI3 perovskite films with a high crystalline structure and large cuboid overlayer morphology is reported. The method includes PbI2 deposition, which is followed by dipping into a solution of C4 H9 NH3 I (BAI) and (BA)2 PbI4 perovskite formation. In the final step, the poorly thermodynamically stable (BA)2 PbI4 phase converts into the more stable CH3 NH3 PbI3 perovskite by dipping into a solution of CH3 NH3 I. The final product is characterized by XRD, SEM, UV/Vis, and photoluminescence analysis methods. The experimental results indicate that the prepared perovskite has cuboids with high crystallinity and large sizes (up to 1 MUm), as confirmed by XRD and SEM data. Photovoltaic investigations show that the three-step method results in higher solar cell efficiency (15 % enhancement in efficiency) with a better reproducibility than the conventional two-step deposition method. PMID- 27124519 TI - Infections and coinfections by respiratory human bocavirus during eight seasons in hospitalized children. AB - The human bocavirus (hBoV) has been identified in respiratory infections in children in a large number of studies. Despite this, the pathogenic role of the HBoV is under discussion. The main objectives of the study were: to determine the incidence of HBoV in hospitalized children; to describe the main clinical features of the positive children; and to compare the data with those from other viral infections in the same population. A prospective study was performed between 2005 and 2013 including children up to 14-year old with respiratory infection admitted to the Severo Ochoa Hospital (Spain). Nasopharyngeal aspirates were taken from 3,275 patients and were tested for HBoV and other 15 respiratory viruses by RT-nested PCR. HBoV was detected in 319 patients (9.9%); 80 cases as a single pathogen, and 239 cases (75%) as coinfections with other viruses. The HBoV was the fourth most common virus detected, behind respiratory syncytial virus (39.8%), rhinovirus (30.6%), and adenovirus (15%). The most common clinical diagnosis, in cases that HBoV was detected as a single pathogen was asthma exacerbation followed by pneumonia. A seasonal distribution was shown, with higher positivity rates in December and January. Children affected by HBoV were older than children infected by other viruses. Differences in terms of clinical diagnosis were found, bronchiolitis diagnosis was lower compared with the other viruses, and HBoV was associated with diagnosis of pneumonia, with increased use of antibiotics (41.8%), and radiographic infiltrates (47%). These findings could suggest a pathogenic role of HBoV in respiratory infections in children under 14 years of age. J. Med. Virol. 88:2052-2058, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 27124520 TI - Minor populations of paroxysmal nocturnal hemoglobinuria-type cells in patients with chronic idiopathic neutropenia. AB - Chronic idiopathic neutropenia (CIN) is an acquired disorder of granulopoiesis characterized by increased apoptosis of the bone marrow (BM) granulocytic progenitor cells under the influence of pro-inflammatory mediators and oligoclonal/monoclonal T-lymphocytes. Because patients with immune-mediated BM failure display frequently paroxysmal nocturnal hemoglobinuria (PNH)-type cells in the peripheral blood (PB), we investigated the possible existence of PNH-type cells in 91 patients with CIN using flow cytometry. The patients displayed increased proportions of PNH-type glycophorin A+ /CD59dim and glycophorin A+ /CD59- red blood cells (RBCs), FLAER- /CD24- granulocytes, and FLAER- /CD14- monocytes, compared to controls (n = 55). A positive correlation was found between the proportions of PNH-type RBCs, granulocytes, and monocytes and an inverse correlation between the number of PB neutrophils and the proportions of PNH-type cell populations. The number of patients, displaying percentages of PNH type cells above the highest percentage observed in the control group, was significantly increased among patients with skewed compared to those with normal T-cell receptor repertoire suggesting that T-cell-mediated immune processes underlie the emergence of PNH-type cells in CIN. Our findings suggest that patients with CIN display PNH-type cells in the PB at a high frequency corroborating the hypothesis that CIN belongs to the immune-mediated BM failure syndromes. PMID- 27124544 TI - Adsorption Behaviors of Mixed Monolayers of n-Alkanes at the Liquid-Solid Interface. AB - To understand the self-assembly of monolayers at the liquid-solid interface, a thermodynamic model, which describes the contributions of the molecular interactions, is essential. We present an adapted Zimm-Bragg model of the cooperativity transitions for determining the Gibbs free energy for self-assembly at the liquid-solid interface. Scanning tunneling microscopy was used to observe the monolayers formed on graphite from phenyloctane solutions of binary mixtures of n-hexacosane (C26H54) and n-tetratriacontane (C34H70). This revealed that the sharp transition in the monolayers from the full surface coverage of the long chain alkane, which is adsorbed preferentially, to the full coverage of the short chain alkane is a function of the mixture composition. The model allows for the estimation of the free-energy changes associated with the difference in the alkyl chain length and the interface between the two different alkane regions in the monolayers. It is also suitable for understanding more complex systems that exhibit intermolecular interactions. PMID- 27124542 TI - Wheel running improves REM sleep and attenuates stress-induced flattening of diurnal rhythms in F344 rats. AB - Regular physical activity produces resistance to the negative health consequences of stressor exposure. One way that exercise may confer stress resistance is by reducing the impact of stress on diurnal rhythms and sleep; disruptions of which contribute to stress-related disease including mood disorders. Given the link between diurnal rhythm disruptions and stress-related disorders and that exercise both promotes stress resistance and is a powerful non-photic biological entrainment cue, we tested if wheel running could reduce stress-induced disruptions of sleep/wake behavior and diurnal rhythms. Adult, male F344 rats with or without access to running wheels were instrumented for biotelemetric recording of diurnal rhythms of locomotor activity, heart rate, core body temperature (CBT), and sleep (i.e. REM, NREM, and WAKE) in the presence of a 12 h light/dark cycle. Following 6 weeks of sedentary or exercise conditions, rats were exposed to an acute stressor known to disrupt diurnal rhythms and produce behaviors associated with mood disorders. Prior to stressor exposure, exercise rats had higher CBT, more locomotor activity during the dark cycle, and greater %REM during the light cycle relative to sedentary rats. NREM and REM sleep were consolidated immediately following peak running to a greater extent in exercise, compared to sedentary rats. In response to stressor exposure, exercise rats expressed higher stress-induced hyperthermia than sedentary rats. Stressor exposure disrupted diurnal rhythms in sedentary rats; and wheel running reduced these effects. Improvements in sleep and reduced diurnal rhythm disruptions following stress could contribute to the health promoting and stress protective effects of exercise. PMID- 27124543 TI - Overexpression of hepatocyte nuclear factor 4alpha in human mesenchymal stem cells suppresses hepatocellular carcinoma development through Wnt/beta-catenin signaling pathway downregulation. AB - Mesenchymal stem cells (MSCs) hold promise as cellular vehicles for the delivery of therapeutic gene products because they can be isolated, expanded, and genetically modified in vitro and possess tumor-oriented homing capacity in vivo. (1) Hepatocyte nuclear factor 4alpha (HNF4alpha) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis (HCC). (2,3) We have previously demonstrated that overexpression of HNF4alpha activates various hepatic-specific genes and enhances MSC differentiation. (4) However, the extent that overexpression of HNF4alpha in MSCs influences HCC progression has yet to be examined. Here we sought to investigate what effect MSCs overexpressing HNF4alpha (MSC-HNF4alpha) have on human hepatoma cells in vitro and in vivo. Conditioned medium collected from in vitro MSC-HNF4alpha cultures significantly inhibited hepatoma cell growth and metastasis compared with controls. Additionally, nude mice administered MSC-HNF4alpha exhibited significantly smaller tumors compared with controls in vivo. Immunoblot analysis of HCC cells treated with MSC-HNF4alpha displayed downregulated beta-catenin, cyclinD1, c-Myc, MMP2 and MMP9. Taken together, our results demonstrate that MSC-HNF4alpha inhibits HCC progression by reducing hepatoma cell growth and metastasis through downregulation of the Wnt/beta-catenin signaling pathway. PMID- 27124546 TI - Intramolecular Charge-Transfer Interaction of Donor-Acceptor-Donor Arrays Based on Anthracene Bisimide. AB - We designed anthracene bisimide (ABI) derivatives having two triphenylamine (TPA) groups as donor units at the 9,10-positions to form a novel pi-conjugated donor acceptor system. These compounds and their analogues with ethynylene linkers were synthesized by Suzuki-Miyaura and Sonogashira coupling reactions, respectively. In UV-vis spectra, the linker-free derivatives showed broad absorption bands arising from intramolecular charge-transfer interactions. Introducing ethynylene linkers resulted in a considerable red shift of the absorption bands. In fluorescence spectra, the ethynylene derivatives showed intense emission bands at 600-650 nm. Their photophysical and electrochemical properties were compared with those of the corresponding mono TPA derivatives on the basis of theoretical calculations and cyclic voltammetry to evaluate the intramolecular electronic interactions between the donor and acceptor units. PMID- 27124545 TI - Diagnostic Performance of Whole-Body PET/MRI for Detecting Malignancies in Cancer Patients: A Meta-Analysis. AB - BACKGROUND: As an evolving imaging modality, PET/MRI is preliminarily applied in clinical practice. The aim of this study was to assess the diagnostic performance of PET/MRI for tumor staging in patients with various types of cancer. METHODS: Relevant articles about PET/MRI for cancer staging were systematically searched in PubMed, EMBASE, EBSCO and the Cochrane Library. Two researchers independently selected studies, extracted data and assessed the methodological quality using the QUADAS tool. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated per patient and per lesion. The summary receiver-operating characteristic (SROC) curves were also constructed, and the area under the curve (AUC) and Q* estimates were obtained. RESULTS: A total of 38 studies that involved 753 patients and 4234 lesions met the inclusion criteria. On a per patient level, the pooled sensitivity and specificity with 95% confidence intervals (CIs) were 0.93 (0.90-0.95) and 0.92 (0.89-0.95), respectively. On a per-lesion level, the corresponding estimates were 0.90 (0.88-0.92) and 0.95 (0.94-0.96), respectively. The pooled PLR, NLR and DOR estimates were 6.67 (4.83 9.19), 0.12 (0.07-0.21) and 75.08 (42.10-133.91) per patient and 10.91 (6.79 17.54), 0.13 (0.08-0.19) and 102.53 (59.74-175.97) per lesion, respectively. CONCLUSION: According to our results, PET/MRI has excellent diagnostic potential for the overall detection of malignancies in cancer patients. Large, multicenter and prospective studies with standard scanning protocols are required to evaluate the diagnostic value of PET/MRI for individual cancer types. PMID- 27124547 TI - Co-effects of matrix low elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth. AB - The development of novel biomaterials that deliver precise regulatory signals to direct stem cell fate for nerve regeneration is the focus of current intensive research efforts. In this study, a hierarchically aligned fibrillar fibrin hydrogel (AFG) that was fabricated through electrospinning and the concurrent molecular self-assembly process mimics both the soft and oriented features of nerve tissue, thus providing hybrid biophysical cues to instruct cell behavior in vitro and in vivo. The electrospun hydrogels were examined by scanning electron microscopy (SEM), polarized light microscopy, small angle X-ray scattering assay and atomic force microscopy (AFM), showing a hierarchically linear-ordered structure from the nanoscale to the macroscale with a soft elastic character (elasticity ~1 kPa). We found that this low elasticity and aligned topography of AFG exhibit co-effects on promoting the neurogenic differentiation of human umbilical cord mesenchymal stem cells (hUMSCs) in comparison to random fibrin hydrogel (RFG) and tissue culture plate (TCP) control after two week cell culture in growth medium lacking supplementation with soluble neurogenic induction factors. In addition, AFG also induces dorsal root ganglion (DRG) neurons to rapidly project numerous long neurite outgrowths longitudinally along the AFG fibers for a total neurite extension distance of 1.96 mm in three days in the absence of neurotrophic factor supplementation. Moreover, the AFG implanted in a rat T9 dorsal hemisection spinal cord injury model was found to promote endogenous neural cell fast migration and axonal invasion along AFG fibers, resulting in aligned tissue cables in vivo. Our results suggest that matrix stiffness and aligned topography may instruct stem cell neurogenic differentiation and rapid neurite outgrowth, providing great promise for biomaterial design for applications in nerve regeneration. PMID- 27124548 TI - Correction: View-Invariant Visuomotor Processing in Computational Mirror Neuron System for Humanoid. AB - [This corrects the article DOI: 10.1371/journal.pone.0152003.]. PMID- 27124549 TI - Are therapists uniformly effective across patient outcome domains? A study on therapist effectiveness in two different treatment contexts. AB - As established in several studies, therapists differ in effectiveness. A vital research task now is to understand what characterizes more or less effective therapists, and investigate whether this differential effectiveness systematically depends on client factors, such as the type of mental health problem. The purpose of the current study was to examine whether therapists are universally effective across patient outcome domains reflecting different areas of mental health functioning. Data were obtained from 2 sites: the Research Consortium of Counseling and Psychological Services in Higher Education (N = 5,828) in the United States and from primary and secondary care units (N = 616) in Sweden. Outcome domains were assessed via the Outcome Questionnaire-45 (Lambert et al., 2004) and the CORE-OM (Evans et al., 2002). Multilevel models with observations nested within patients were used to derive a reliable estimate for each patient's change (which we call a multilevel growth d) based on all reported assessment points. Next, 2 multilevel confirmatory factor analytic models were fit in which these effect sizes (multilevel ds) for the 3 subscales of the OQ-45 (Study 1) and 6 subscales of CORE-OM (Study 2) were indicators of 1 common latent factor at the therapist level. In both data sets, such a model, reflecting a global therapist effectiveness factor, yielded large factor loadings and excellent model fit. Results suggest that therapists effective (or ineffective) within one outcome domain are also effective within another outcome domain. Tentatively, therapist effectiveness can thus be conceived of as a global construct. (PsycINFO Database Record PMID- 27124550 TI - Prenatal effects of transplacental exposure to ifosfamide in rats. AB - Ifosfamide is an alkylating chemotherapeutic agent that exhibits activity against a wide range of tumors. Exposure to such agent just prior to mating (preconception period) may have adverse effects on developing embryos. I investigated the rate of apoptosis and the histological changes in both placenta and developing fetal tissues after exposure to ifosfamide of young female rats before mating. I clarified the roles of the drug and the placenta in causing fetal developmental toxicity. Rats were divided into four groups: (1) untreated controls, (2) rats administered saline, (3 and 4) rats administered 25 mg/kg and 50 mg/kg ifosfamide, respectively. After treatment of females with ifosfamide, the treated females were allowed to mate with normal untreated males. All pregnant animals were sacrificed on day 18 of gestation. Treatment with high doses of ifosfamide caused small placentas, fewer viable fetuses, greater post implantation losses and more resorbed fetuses. Reduced progesterone and increased prolactin levels also were found. Immunohistochemical staining, the TUNEL technique and histological studies showed increased apoptotic cells and many histological changes in the placenta, and in fetal brain, liver and kidney tissues. Ifosfamide treatment increased apoptosis and caused hypoplasia of placental basal and labyrinth zones, which resulted in pathological changes in developing fetal tissue. PMID- 27124551 TI - From Companion Diagnostics to Theranostics: A New Avenue for Alzheimer's Disease? AB - The recent literature signals a growing paradigm shift toward integrating therapeutics and diagnostics rather than developing and deploying them separately. In this gradual move toward more effective and personalized medications, companion diagnostics are an intermediate stage. The next step may be "theranostics", in which single chemical entities are developed to deliver therapy and diagnosis simultaneously. This strategy has been successfully exploited in oncology and is now emerging as a possibility for Alzheimer's disease, where its feasibility has caught the attention of researchers from industry and academia. Medicinal chemists do not yet completely understand the nuances of theranostic action and consequently have not yet developed universally validated strategies for developing theranostic clinical applications against Alzheimer's disease. However, given the emerging indications of the potentially enormous benefits that theranostics may bring to the fight against this devastating disease, further rigorous research is warranted. PMID- 27124552 TI - Self-Assembly of Porphyrin-Paclitaxel Conjugates Into Nanomedicines: Enhanced Cytotoxicity due to Endosomal Escape. AB - Nanomedicines assembled directly from drug molecules possess several advantages, including precise molecular structure and high content of drugs. Herein, porphyrin-paclitaxel conjugates (Py-s-s-PTX) were synthesized by using a disulfide bond as a linker. The Py-s-s-PTX could self-assemble into nanoparticles (Py-s-s-PTX NPs) with a size of about 100 nm via disulfide-induced assembly. Py-s s-PTX NPs are highly stable under biological conditions and could be destroyed in the presence of reducing agents as revealed by dynamic light scattering. The obtained Py-s-s-PTX NPs could be internalized by cancer cells via endocytosis and disassociated in the reducing cytoplasm, thus releasing PTX in cancer cells. Endosomal escape triggered upon irradiation could enhance the cytotoxicity of paclitaxel, and Py-s-s-PTX NPs possess cytotoxicity comparable to that of free PTX. We believe that this disulfide-assembled nanomedicine represents a new and important development for chemotherapy in cancer therapy. PMID- 27124553 TI - Maternal plasma concentrations of the placental specific sFLT-1 variant, sFLT-1 e15a, in fetal growth restriction and preeclampsia. AB - OBJECTIVE: sFLT-1 e15a is a recently described sFlt-1 variant that is placental and primate specific. As such, it may have potential as a biomarker. Using a newly developed ELISA, we measured maternal plasma sFLT-1 e15a levels in women with fetal growth restriction and pre-eclampsia. METHOD: We performed a nested case-control study where we measured total sFLT-1 and sFLT-1 e15a plasma protein concentrations. Samples, selected from a prospective cohort study, consisted of 87 healthy controls, 11 cases that developed term preeclampsia and 20 cases where there was fetal growth restriction. We also measured sFLT-1 and sFLT-1 e15a plasma concentrations in a separate cohort: 15 cases of preterm preeclampsia and 24 healthy controls. RESULTS: The prospective case-control cohort demonstrated significantly increased sFLT-1 e15a among cases with term fetal growth restriction (p < 0.05). We also observed that total sFLT-1 (this ELISA indiscriminately detects all variants) was significantly increased in term preeclampsia (p < 0.0001), but not fetal growth restriction. The separate cohort of early-onset preeclamptics showed significantly increased sFLT-1 e15a levels (p < 0.0001). CONCLUSION: Plasma sFLT-1 e15a is significantly increased in early onset preeclampsia and term fetal growth restriction. Further assessment of the benefit for sFLT-1 e15a testing in prediction or diagnosis of these disease states is warranted. PMID- 27124554 TI - Effect of early-term birth on respiratory symptoms and lung function in childhood and adolescence. AB - BACKGROUND: Early-term-born subjects, (37-38 weeks' gestation), form a large part of the population and have an increased risk of neonatal respiratory morbidity and childhood respiratory symptoms; there is a paucity of data on their later lung function. We sought to (1) compare lung function at 8-9 and 14-17 years in early-term-born children with full-term-born children (39-43 weeks' gestation); (2) assess the role of caesarean section delivery; and (3) compare respiratory symptoms and diagnosis of asthma. METHODS: Caucasian, singleton, term births from the Avon Longitudinal Study of Parents and Children (n = 14,062) who had lung spirometry at 8-9 (n = 5,465) and/or 14-17 (n = 3,666) years were classified as early or full term. RESULTS: At 8-9 years, standardized spirometry measures, although within the normal range, were lower in the early-term-born group, (n = 911), compared to full-term controls (n = 4,554). Delivery by caesarean section did not influence later spirometry, and the effect of early-term birth was not modified by delivery by caesarean section. At 14-17 years, the spirometry measures in the early-term group, (n = 602), were similar to the full-term group (3,064), and the rates of asthma and respiratory symptoms were also similar between the two gestation groups. CONCLUSIONS: Early-term-born children had lower lung function values at 8-9 years compared to the full-term group, but were similar by 14-17 years of age. Delivery at early term should be avoided due to early and late morbidity. Pediatr Pulmonol. 2016;51:1212-1221. (c) 2016 Wiley Periodicals, Inc. PMID- 27124555 TI - Health-related Quality of Life in Breast Cancer Patients after Adjuvant Treatments. PMID- 27124556 TI - Organocatalytic Enantioselective Aza-Friedel-Crafts Reaction of Cyclic Ketimines with Pyrroles using Imidazolinephosphoric Acid Catalysts. AB - Organocatalytic enantioselective aza-Friedel-Crafts reactions of cyclic ketimines with pyrroles or indoles were catalyzed by imidazoline/phosphoric acid catalysts. The reaction was applied to various 3H-indol-3-ones to afford products in excellent yields and enantioselectivities. The chiral catalysts can be recovered by a single separation step using column chromatography and are reusable without further purification. Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction. PMID- 27124557 TI - Boom and bust: rapid feedback responses between insect outbreak dynamics and canopy leaf area impacted by rainfall and CO2. AB - Frequency and severity of insect outbreaks in forest ecosystems are predicted to increase with climate change. How this will impact canopy leaf area in future climates is rarely tested. Here, we document function of insect outbreaks that fortuitously and rapidly occurred in an ecosystem under free-air CO2 enrichment. Over the first 2 years of CO2 fumigation of a naturally established mature Eucalyptus woodland, we continuously assessed population responses of three sap feeding insect species of the psyllid genera Cardiaspina, Glycaspis and Spondyliaspis for up to ten consecutive generations. Concurrently, we quantified changes in the canopy leaf area index (LAI). Large and rapid shifts in psyllid community composition were recorded between species with either flush (Glycaspis) or senescence-inducing (Cardiaspina, Spondyliaspis) feeding strategies. Within the second year, two psyllid species experienced significant and rapid population build-up resulting in two consecutive outbreaks: first, rainfall stimulated Eucalyptus leaf production increasing LAI, which supported population growth of flush-feeding Glycaspis without impacting LAI. Glycaspis numbers then crashed and were followed by the outbreak of senescence-feeding Cardiaspina fiscella that led to significant defoliation and reduction in LAI. For all three psyllid species, the abundance of lerps, protective coverings excreted by the sessile nymphs, decreased at e[CO2 ]. Higher lerp weight at e[CO2 ] for Glycaspis but not the other psyllid species provided evidence for compensatory feeding by the flush feeder but not the two senescence feeders. Our study demonstrates that rainfall drives leaf phenology, facilitating the rapid boom-and-bust succession of psyllid species, eventually leading to significant defoliation due to the second but not the first outbreaking psyllid species. In contrast, e[CO2 ] may impact psyllid abundance and feeding behaviour, with psyllid species-specific outcomes for defoliation severity, nutrient transfer and trophic cascades. Psyllid populations feeding on Eucalyptus experience rapid boom-and-bust cycles depending on availability of suitable foliage driven by rainfall patterns and leaf phenology. PMID- 27124559 TI - Combinatorial Synthesis of Epitaxial LiCoO2 Thin Films on SrTiO3(001) via On Substrate Sintering of Li2CO3 and CoO by Pulsed Laser Deposition. AB - High-quality single-phase epitaxial LiCoO2 thin films are synthesized on 0.5 wt % Nb-doped SrTiO3(001) substrates by nanoscale alternate deposition of Li2CO3 and CoO as Li and Co sources, respectively, using a combinatorial pulsed laser deposition (PLD) technique. The formation of LiCoO2 thin films from these two sources results from the sintering reaction between Li2CO3 and CoO, which is commonly used in a bulk ceramics process, but simultaneously takes place on the substrate during the deposition at a temperature of 550 degrees C. Electrochemical characterization reveals that the charge/discharge property of LiCoO2 thin films as a cathode is severely sensitive to the nominal Li:Co composition ratio. The best-quality film shows an excellent discharge capacity comparable with the characteristic capacity of LiCoO2. PMID- 27124558 TI - Investigating Cooperative Behavior in Ecological Settings: An EEG Hyperscanning Study. AB - The coordinated interactions between individuals are fundamental for the success of the activities in some professional categories. We reported on brain-to-brain cooperative interactions between civil pilots during a simulated flight. We demonstrated for the first time how the combination of neuroelectrical hyperscanning and intersubject connectivity could provide indicators sensitive to the humans' degree of synchronization under a highly demanding task performed in an ecological environment. Our results showed how intersubject connectivity was able to i) characterize the degree of cooperation between pilots in different phases of the flight, and ii) to highlight the role of specific brain macro areas in cooperative behavior. During the most cooperative flight phases pilots showed, in fact, dense patterns of interbrain connectivity, mainly linking frontal and parietal brain areas. On the contrary, the amount of interbrain connections went close to zero in the non-cooperative phase. The reliability of the interbrain connectivity patterns was verified by means of a baseline condition represented by formal couples, i.e. pilots paired offline for the connectivity analysis but not simultaneously recorded during the flight. Interbrain density was, in fact, significantly higher in real couples with respect to formal couples in the cooperative flight phases. All the achieved results demonstrated how the description of brain networks at the basis of cooperation could effectively benefit from a hyperscanning approach. Interbrain connectivity was, in fact, more informative in the investigation of cooperative behavior with respect to established EEG signal processing methodologies applied at a single subject level. PMID- 27124560 TI - Preparation and characterization of a new monoclonal antibody against CXCR4 using lentivirus vector. AB - CXCR4 is a member of chemokine receptors and plays a vital role in numerous diseases and cancer processes, which makes the CXCR4/CXCL12 chemotactic axis a potential therapeutic target. In this study, we used lentiviral vectors as a novel technology to produce a monoclonal antibody against CXCR4. Lentivirus vector pLV-CXCR4-Puro was successfully constructed and a hybridoma cell line 1A4 was generated. The CXCR4 monoclonal antibody (MAb) 1A4 had high titer and affinity, and the isotype was identified as IgG1a. The recombinant lentivirus vector could effectively stimulate the production of 39kDa CXCR4 antibody in vivo after immunization. Western blot analysis showed that the MAb could recognize the CXCR4 antigen expressed on transfected 293T cells as well as various human cancer cell lines. Immunofluorescence assays showed that MAb 1A4 mainly localized and strongly stained on the membrane of transfected 293T cells. Immunohistochemistry assays demonstrated that 1A4 could recognize strong expression of CXCR4 on the hepatocellular carcinoma (HCC). Thus, the method using lentiviral vectors may have application on effective and large-scale production of the CXCR4 monoclonal antibody, which will be a potential tool for the diagnosis and treatment of human cancers. PMID- 27124561 TI - Effects of Surfactant Lavage Combined With Intratracheal Budesonide Instillation on Meconium-Injured Piglet Lungs. AB - OBJECTIVES: To evaluate the combined effects of surfactant lavage and intratracheally instillation of budesonide on meconium-injured piglet lungs. DESIGN: A prospective, randomized, animal model study. SETTING: An experimental laboratory. SUBJECTS: Twenty-four anesthetized and mechanically ventilated newborn piglets. INTERVENTIONS: Human meconium slurry was intratracheally instilled into piglet lungs to induce lung injury. The injured piglets were randomly assigned to either the sham treatment group (control) or one of the three therapeutic groups: the intratracheally instilled budesonide (Bud) group, the bronchoalveolar lavage with diluted surfactant (dsBAL) group, and the combination therapy of Bud and dsBAL (dsBAL + Bud) group. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary profiles were measured hourly. Proinflammatory cytokine (interleukin-1beta, interleukin-6, and interleukin-8) levels in bronchoalveolar lavage fluid were measured. Finally, the pulmonary histology of the experimental subjects was examined at the end of experiments. Both of the lavaged groups (dsBAL and dsBAL + Bud) showed significantly better oxygenation than those that had not undergone lavage (control and Bud) (p < 0.05). The dsBAL + Bud group showed a significantly higher lung compliance and required a significantly lower peak inspiratory pressure during the experimental periods than the other three groups (p < 0.05). All treatment groups had significantly lower concentrations of interleukin-1beta concentration in the bronchoalveolar lavage fluid than the control group (p < 0.05). The dsBAL + Bud group also had a significantly lower interleukin-6 concentration in the bronchoalveolar lavage fluid (p< 0.05), as well as a significantly lower lung injury score based on pulmonary histology than the control group (p < 0.05). CONCLUSIONS: Therapeutic bronchoalveolar lavage with diluted surfactant followed by intratracheal instillation of budesonide has a synergistic and beneficial effect when treating severe meconium-injured newborn piglet lungs. PMID- 27124562 TI - The Association of Central-Line-Associated Bloodstream Infections With Central Line Utilization Rate and Maintenance Bundle Compliance Among Types of PICUs. AB - OBJECTIVE: Central-line-associated bloodstream infections comprise 25% of device associated infections. Compared with other units, PICUs demonstrate a higher central-line-associated bloodstream infections prevalence. Prior studies have not investigated the association of central-line-associated bloodstream infections prevalence, central-line utilization, or maintenance bundle compliance between specific types of PICUs. DESIGN: This study analyzed monthly aggregate data regarding central-line-associated bloodstream infections prevalence, central-line utilization, and maintenance bundle compliance between three types of PICUs: 1) PICUs that do not care for cardiac patients (PICU); 2) PICUs that provide care for cardiac and noncardiac patients (C/PICU); or 3) designated cardiac ICUs (CICU). SETTING: The included units submitted data as part of The Children's Hospital Association PICU central-line-associated bloodstream infections collaborative from January 1, 2011, to December 31, 2013. PATIENTS: Patients admitted to PICUs in collaborative institutions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The overall central-line-associated bloodstream infections prevalence was low (1.37 central-line-associated bloodstream infections events/1,000 central-line days) and decreased over the time of the study. Central-line-associated bloodstream infections prevalence was not related to the type of PICU although C/PICU tended to have a higher central-line associated bloodstream infections prevalence (p = 0.055). CICU demonstrated a significantly higher central-line utilization ratio (p < 0.001). However, when examined on a unit level, central-line utilization was not related to the central line-associated bloodstream infections prevalence. The central-line maintenance bundle compliance rate was not associated with central line-associated bloodstream infections prevalence in this unit-level investigation. Neither utilization rate nor compliance rate changed significantly over time in any of the types of units. CONCLUSIONS: Although this unit-level analysis did not demonstrate an association between central-line-associated bloodstream infections prevalence and central-line utilization and maintenance bundle compliance, optimization of both should continue, further decreasing central-line-associated bloodstream infections prevalence. In addition, investigation of patient-specific factors may aid in further central-line-associated bloodstream infections eradication. PMID- 27124563 TI - Procalcitonin in the Early Course Post Pediatric Cardiac Surgery. AB - OBJECTIVE: Procalcitonin has emerged as a promising infection marker, but previous reports from small-sized studies suggest nonspecific elevation of procalcitonin after pediatric heart surgery. As procalcitonin is increasingly used as a marker for infection in the PICU, the aim of this study was to identify factors associated with postoperative procalcitonin elevation and to investigate the role of procalcitonin as an early marker of outcome after cardiac surgery. DESIGN: Prospective observational study. SETTING: Single, tertiary referral PICU. PATIENTS: Patients aged 0-16 years following cardiac surgery with or without cardiopulmonary bypass. INTERVENTIONS: Procalcitonin was measured in all patients at admission to PICU, and on postoperative day 1 and 2. Outcome variables included major adverse event, length of stay in PICU, postoperative renal failure requiring temporary dialysis, duration of mechanical ventilation and duration of inotropic support. A major adverse event was defined as cardiac arrest, need for postoperative extracorporeal life support or death within 3 months of cardiac surgery. MEASUREMENTS AND MAIN RESULTS: In 221 included patients who underwent 232 operations, procalcitonin at admission to PICU was significantly associated with mechanical ventilation prior to surgery (p = 0.001), preoperative myocardial dysfunction (p = 0.002), duration of cardiopulmonary bypass (p < 0.001), intraoperative cross-clamp time (p = 0.015), and serum lactate at admission (p < 0.001). Patients suffering a major adverse event and patients with postoperative renal failure had significantly higher procalcitonin levels at admission to PICU (p = 0.04 and 0.01, respectively). Furthermore, procalcitonin levels at admission correlated significantly with the length of stay in the PICU (p = 0.005), time on mechanical ventilation (p = 0.03), and duration of inotropic support (p = 0.02). CONCLUSIONS: Elevated levels of procalcitonin in the early phase after pediatric cardiac surgery are a marker for increased risk for major adverse events and postoperative renal failure and increased postoperative morbidity. PMID- 27124564 TI - Hemodynamic Bedside Ultrasound Image Quality and Interpretation After Implementation of a Training Curriculum for Pediatric Critical Care Medicine Providers. AB - OBJECTIVE: Bedside ultrasound for hemodynamic evaluation in critically ill children is increasingly recognized as an important skill for pediatric critical care medicine providers. Our institution implemented a training curriculum leading to institutional credentialing for pediatric critical care providers in nonprocedural bedside ultrasound core applications. We hypothesized that hemodynamic studies performed or supervised by credentialed providers (credentialed providers group) have better image quality and greater accuracy in interpretation than studies performed by non-credentialed providers without supervision (non-credentialed providers group). DESIGN: Retrospective descriptive study. SETTING: Single-center tertiary non-cardiac 55-bed PICU in a children's hospital. PATIENTS: Patients from October 2013 to January 2015, with hemodynamic bedside ultrasound performed and interpreted by pediatric critical care providers exposed to bedside ultrasound training. INTERVENTIONS: A cardiologist blinded to performer scored hemodynamic bedside ultrasound image quality for five core cardiac views (excellent = 3, good = 2, fair = 1, unacceptable = 0; median = quality score) and interpretation within 5 hemodynamic domains (agreement = 3, minor disagreement = 2, major disagreement = 1; median = interpretation score), as well as a global assessment of interpretation. MEASUREMENTS AND MAIN RESULTS: Eighty-one studies (45 in the credentialed providers group and 36 in the non credentialed providers group) were evaluated. There was no statistically significant difference in quality score between groups (median: 1.4 [interquartile range: 0.8-1.8] vs median: 1.2 [interquartile range: 0.75-1.6]; p = 0.14]. Studies in the credentialed providers group had higher interpretation score than those in the non-credentialed providers group (median: 3 [interquartile range: 2.5-3) vs median: 2.67 [interquartile range: 2.25-3]; p = 0.04). Major disagreement between critical care provider and cardiology review occurred in 25 of 283 hemodynamic domains assessed (8.8%), with no statistically significant difference between credentialed providers and non-credentialed providers groups (6.1% vs 11.9%; p = 0.12). CONCLUSION: Hemodynamic bedside ultrasound performed or supervised by credentialed pediatric critical care providers had more accurate interpretation than studies performed by unsupervised non-credentialed providers. A rigorous pediatric critical care medicine bedside ultrasound credentialing program can train intensivists to attain adequate images and interpret those images appropriately. PMID- 27124565 TI - Family Burden After Out-of-Hospital Cardiac Arrest in Children. AB - OBJECTIVES: To describe family burden among caregivers of children who survived out-of-hospital cardiac arrest and who were at high risk for neurologic disability and examine relationships between family burden, child functioning, and other factors during the first year post arrest. DESIGN: Secondary analysis of data from the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of Hospital trial. SETTING: Thirty-six PICUs in the United States and Canada. PATIENTS: Seventy-seven children recruited to the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital trial who had normal prearrest neurologic functioning and were alive 1 year post arrest. INTERVENTIONS: Family burden was assessed using the Infant Toddler Quality of Life Questionnaire for children less than 5 years old and the Child Health Questionnaire for children 5 years old or older at baseline (reflecting prearrest status), 3 months, and 12 months post arrest. Child functioning was assessed using the Vineland Adaptive Behavior Scale II, the Pediatric Overall Performance Category, and Pediatric Cerebral Performance Category scales and caregiver perception of global functioning. MEASUREMENTS AND MAIN RESULTS: Fifty-six children (72.7%) were boys, 48 (62.3%) were whites, and 50 (64.9%) were less than 5 years old prior to out-of hospital cardiac arrest. Family burden at baseline was not significantly different from reference values. Family burden was increased at 3 and 12 months post arrest compared with reference values (p < 0.001). Worse Pediatric Overall Performance Category and Pediatric Cerebral Performance Category, lower adaptive behavior, lower global functioning, and higher family burden all measured 3 months post arrest were associated with higher family burden 12 months post arrest (p < 0.05). Sociodemographics and prearrest child functioning were not associated with family burden 12 months post arrest. CONCLUSIONS: Families of children who survive out-of-hospital cardiac arrest and have high risk for neurologic disability often experience substantial burden during the first year post arrest. The extent of child dysfunction 3 months post arrest is associated with family burden at 12 months. PMID- 27124566 TI - Comparison of Pediatric Severe Sepsis Managed in U.S. and European ICUs. AB - OBJECTIVES: Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies. DESIGN: We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality. SETTING: European and U.S. PICUs. PATIENTS: Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days. CONCLUSIONS: Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future international clinical trials in pediatric severe sepsis. PMID- 27124567 TI - Development of a Prediction Model of Early Acute Kidney Injury in Critically Ill Children Using Electronic Health Record Data. AB - OBJECTIVE: Acute kidney injury is independently associated with poor outcomes in critically ill children. However, the main biomarker of acute kidney injury, serum creatinine, is a late marker of injury and can cause a delay in diagnosis. Our goal was to develop and validate a data-driven multivariable clinical prediction model of acute kidney injury in a general PICU using electronic health record data. DESIGN: Derivation and validation of a prediction model using retrospective data. PATIENTS: All patients 1 month to 21 years old admitted between May 2003 and March 2015 without acute kidney injury at admission and alive and in the ICU for at least 24 hours. SETTING: A multidisciplinary, tertiary PICU. INTERVENTION: The primary outcome was early acute kidney injury, which was defined as new acute kidney injury developed in the ICU within 72 hours of admission. Multivariable logistic regression was performed to derive the Pediatric Early AKI Risk Score using electronic health record data from the first 12 hours of ICU stay. MEASUREMENTS AND MAIN RESULTS: A total of 9,396 patients were included in the analysis, of whom 4% had early acute kidney injury, and these had significantly higher mortality than those without early acute kidney injury (26% vs 3.3%; p < 0.001). Thirty-three candidate variables were tested. The final model had seven predictors and had good discrimination (area under the curve 0.84) and appropriate calibration. The model was validated in two validation sets and maintained good discrimination (area under the curves, 0.81 and 0.86). CONCLUSION: We developed and validated the Pediatric Early AKI Risk Score, a data-driven acute kidney injury clinical prediction model that has good discrimination and calibration in a general PICU population using only electronic health record data that is objective, available in real time during the first 12 hours of ICU care and generalizable across PICUs. This prediction model was designed to be implemented in the form of an automated clinical decision support system and could be used to guide preventive, therapeutic, and research strategies. PMID- 27124568 TI - Prevalence and characteristics of coronary artery anomalies detected by coronary computed tomography angiography in 5 634 consecutive patients in a single centre in Switzerland. AB - STUDY PRINCIPLES: Coronary computed tomography angiography (CCTA) allows three dimensional visualisation of the origin, course and ending of the coronary vessels with high spatial resolution, yielding an accurate depiction of coronary artery anomalies (CAAs). This study sought to determine the prevalence, incidence and characteristics of CAAs detected with CCTA in a single centre in Switzerland. METHODS: CAAs were retrospectively identified in 5 634 consecutive patients referred for CCTA between March 2007 and July 2015. Single coronary arteries, Bland-White-Garland syndrome, anomalous coronary arteries originating from the opposite site of the sinus of Valsalva (ACAOS) with an interarterial course and coronary artery fistulas were classified as potentially malignant CAAs. RESULTS: We identified 145 patients with CAAs, resulting in an overall prevalence of 2.6% and cumulative incidence of 2.1% in all patients referred for CCTA in the observation period. Forty-nine (33.8%) patients showed malignant CAAs including 1 (0.7%) patient with Bland-White-Garland syndrome, 7 (4.8%) with single coronary arteries, 36 (24.8%) with ACAOS and an interarterial course, and 5 (3.5%) with coronary artery fistulas. The remaining 96 (66.2%) patients were classified as having benign variants. CONCLUSIONS: The prevalence of CAA detected by CCTA is not negligible. Because of its noninvasive nature, relatively low cost and low radiation exposure, a further increase in the utilisation of CCTA may be expected, which may consequently be paralleled by an increasing absolute number of incidentally detected CAAs. Hence, awareness of the main issues and possible management strategies regarding CAAs is of importance for every treating physician. PMID- 27124569 TI - The Role of Datasets on Scientific Influence within Conflict Research. AB - We inductively tested if a coherent field of inquiry in human conflict research emerged in an analysis of published research involving "conflict" in the Web of Science (WoS) over a 66-year period (1945-2011). We created a citation network that linked the 62,504 WoS records and their cited literature. We performed a critical path analysis (CPA), a specialized social network analysis on this citation network (~1.5 million works), to highlight the main contributions in conflict research and to test if research on conflict has in fact evolved to represent a coherent field of inquiry. Out of this vast dataset, 49 academic works were highlighted by the CPA suggesting a coherent field of inquiry; which means that researchers in the field acknowledge seminal contributions and share a common knowledge base. Other conflict concepts that were also analyzed-such as interpersonal conflict or conflict among pharmaceuticals, for example, did not form their own CP. A single path formed, meaning that there was a cohesive set of ideas that built upon previous research. This is in contrast to a main path analysis of conflict from 1957-1971 where ideas didn't persist in that multiple paths existed and died or emerged reflecting lack of scientific coherence (Carley, Hummon, and Harty, 1993). The critical path consisted of a number of key features: 1) Concepts that built throughout include the notion that resource availability drives conflict, which emerged in the 1960s-1990s and continued on until 2011. More recent intrastate studies that focused on inequalities emerged from interstate studies on the democracy of peace earlier on the path. 2) Recent research on the path focused on forecasting conflict, which depends on well developed metrics and theories to model. 3) We used keyword analysis to independently show how the CP was topically linked (i.e., through democracy, modeling, resources, and geography). Publically available conflict datasets developed early on helped shape the operationalization of conflict. In fact, 94% of the works on the CP that analyzed data either relied on publically available datasets, or they generated a dataset and made it public. These datasets appear to be important in the development of conflict research, allowing for cross-case comparisons, and comparisons to previous works. PMID- 27124570 TI - Assessing the Delivery of Molecules to the Mitochondrial Matrix Using Click Chemistry. AB - Mitochondria are central to health and disease, hence there is considerable interest in developing mitochondria-targeted therapies that require the delivery of peptides or nucleic acid oligomers. However, progress has been impeded by the lack of a measure of mitochondrial import of these molecules. Here, we address this need by quantitatively detecting molecules within the mitochondrial matrix. We used a mitochondria- targeted cyclooctyne (MitoOct) that accumulates several- hundredfold in the matrix, driven by the membrane potential. There, MitoOct reacts through click chemistry with an azide on the target molecule to form a diagnostic product that can be quantified by mass spectrometry. Because the membrane potential-dependent MitoOct concentration in the matrix is essential for conjugation, we can now determine definitively whether a putative mitochondrion targeted molecule reaches the matrix. This "ClickIn" approach will facilitate development of mitochondria-targeted therapies. PMID- 27124571 TI - Dermatophytosis among Schoolchildren in Three Eco-climatic Zones of Mali. AB - BACKGROUND: Dermatophytosis, and particularly the subtype tinea capitis, is common among African children; however, the risk factors associated with this condition are poorly understood. To describe the epidemiology of dermatophytosis in distinct eco-climatic zones, three cross-sectional surveys were conducted in public primary schools located in the Sahelian, Sudanian and Sudano-Guinean eco climatic zones in Mali. PRINCIPAL FINDINGS: Among 590 children (average age 9.7 years) the overall clinical prevalence of tinea capitis was 39.3%. Tinea capitis prevalence was 59.5% in the Sudano-Guinean zone, 41.6% in the Sudanian zone and 17% in the Sahelian eco-climatic zone. Microsporum audouinii was isolated primarily from large and/or microsporic lesions. Trichophyton soudanense was primarily isolated from trichophytic lesions. Based on the multivariate analysis, tinea capitis was independently associated with male gender (OR = 2.51, 95%CI [1.74-3.61], P<10(-4)) and residing in the Sudano-Guinean eco-climatic zone (OR = 7.45, 95%CI [4.63-11.99], P<10(-4)). Two anthropophilic dermatophytes species, Trichophyton soudanense and Microsporum audouinii, were the most frequent species associated with tinea capitis among primary schoolchildren in Mali. CONCLUSIONS: Tinea capitis risk increased with increasing climate humidity in this relatively homogenous schoolchild population in Mali, which suggests a significant role of climatic factors in the epidemiology of dermatophytosis. PMID- 27124572 TI - Carotid calcification in panoramic radiographs: radiographic appearance and the degree of carotid stenosis. AB - OBJECTIVES: Approximately 7% of patients examined with panoramic radiographs (PRs) for odontological reasons, and with incidental findings of carotid artery calcification (CAC), have significant (>=50%) carotid stenosis (SCS). The aim of this study was to determine if the radiographic appearance of CACs in PRs could be categorized such that we could improve the positive-predictive value (PPV) for SCS detection. METHODS: This cross-sectional study included 278 patients with CACs identified by PRs, 127 with SCS and 151 without SCS. CACs were categorized based on the following appearances: (1) single, (2) scattered or (3) vessel outlining. Correlates were derived for each category according to positivity or not for SCS in the corresponding neck sides. For a representative adult population (in dentistry) presenting with CACs in PRs, PPVs for SCS prediction were then calculated for three subgroups based on different combinations of appearances (2) and/or (3). RESULTS: Vessel-outlining CACs corresponded to 65% of neck sides with SCS vs 47% without SCS (p < 0.001). Single CACs corresponded to 15% of neck sides with SCS vs 27% without SCS (p = 0.006). Scattered CACs corresponded to 20% of neck sides with SCS vs 26% without SCS (p = 0.127). In the representative population, the PPVs for SCS detection were comparable (7.2-7.8%) for all three subgroups and when the presence of a CAC is the sole criterion (7.4%). CONCLUSIONS: Stratifying the radiographic appearance of CACs in PRs does not improve the PPV for SCS detection. Whether different radiographic appearances are associated with future risk of stroke, or other cardiovascular events, remains unknown. PMID- 27124573 TI - Concordance of interim and final estimates of influenza vaccine effectiveness: a systematic review. AB - The World Health Organization's Global Influenza Surveillance and Response System meets twice a year to generate a recommendation for the composition of the seasonal influenza vaccine. Interim vaccine effectiveness (VE) estimates provide a preliminary indication of influenza vaccine performance during the season and may be useful for decision making. We reviewed 17 pairs of studies reporting 33 pairs of interim and final estimates using the test-negative design to evaluate whether interim estimates can reliably predict final estimates. We examined features of the study design that may be correlated with interim estimates being substantially different from their final estimates and identified differences related to change in study period and concomitant changes in sample size, proportion vaccinated and proportion of cases. An absolute difference of no more than 10% between interim and final estimates was found for 18 of 33 reported pairs of estimates, including six of 12 pairs reporting VE against any influenza, six of 10 for influenza A(H1N1)pdm09, four of seven for influenza A(H3N2) and two of four for influenza B. While we identified inconsistencies in the methods, the similarities between interim and final estimates support the utility of generating and disseminating preliminary estimates of VE while virus circulation is ongoing. PMID- 27124575 TI - The effect of a novel mechanical nasal dilator on cycling performance. PMID- 27124574 TI - Germline recombination in a novel Cre transgenic line, Prl3b1-Cre mouse. AB - Spermatogenesis is a complex and highly regulated process by which spermatogonial stem cells differentiate into spermatozoa. To better understand the molecular mechanisms of the process, the Cre/loxP system has been widely utilized for conditional gene knockout in mice. In this study, we generated a transgenic mouse line that expresses Cre recombinase under the control of the 2.5 kbp of the Prolactin family 3, subfamily b, member 1 (Prl3b1) gene promoter (Prl3b1-cre). Prl3b1 was initially reported to code for placental lactogen 2 (PL-2) protein in placenta along with increased expression toward the end of pregnancy. PL-2 was found to be expressed in germ cells in the testis, especially in spermatocytes. To analyze the specificity and efficiency of Cre recombinase activity in Prl3b1 cre mice, the mice were mated with reporter R26GRR mice, which express GFP ubiquitously before and tdsRed exclusively after Cre recombination. The systemic examination of Prl3b1-cre;R26GRR mice revealed that tdsRed-positive cells were detected only in the testis and epididymis. Fluorescence imaging of Prl3b1 cre;R26GRR testes suggested that Cre-mediated recombination took place in the germ cells with approximately 74% efficiency determined by in vitro fertilization. In conclusion, our results suggest that the Prl3b1-cre mice line provides a unique resource to understand testicular germ-cell development. genesis 54:389-397, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27124576 TI - Effect of Temperature on Acidity and Hydration Equilibrium Constants of Delphinidin-3-O- and Cyanidin-3-O-sambubioside Calculated from Uni- and Multiwavelength Spectroscopic Data. AB - Delphinidin-3-O-sambubioside and cyanidin-3-O-sambubioside are the main anthocyanins of Hibiscus sabdariffa calyces, traditionally used to make a bright red beverage by decoction in water. At natural pH, these anthocyanins are mainly in their flavylium form (red) in equilibrium with the quinonoid base (purple) and the hemiketal (colorless). For the first time, their acidity and hydration equilibrium constants were obtained from a pH-jump method followed by UV-vis spectroscopy as a function of temperature from 4 to 37 degrees C. Equilibrium constant determination was also performed by multivariate curve resolution (MCR). Acidity and hydration constants of cyanidin-3-O-sambubioside at 25 degrees C were 4.12 * 10(-5) and 7.74 * 10(-4), respectively, and were significantly higher for delphinidin-3-O-sambubioside (4.95 * 10(-5) and 1.21 * 10(-3), respectively). MCR enabled the obtaining of concentration and spectrum of each form but led to overestimated values for the equilibrium constants. However, both methods showed that formations of the quinonoid base and hemiketal were endothermic reactions. Equilibrium constants of anthocyanins in the hibiscus extract showed comparable values as for the isolated anthocyanins. PMID- 27124578 TI - Epstein-Barr viral loads and serum free light chains levels are potential follow up markers of HIV-related lymphomas. PMID- 27124577 TI - Nucleosome Presence at AML-1 Binding Sites Inversely Correlates with Ly49 Expression: Revelations from an Informatics Analysis of Nucleosomes and Immune Cell Transcription Factors. AB - Beyond its role in genomic organization and compaction, the nucleosome is believed to participate in the regulation of gene transcription. Here, we report a computational method to evaluate the nucleosome sensitivity for a transcription factor over a given stretch of the genome. Sensitive factors are predicted to be those with binding sites preferentially contained within nucleosome boundaries and lacking 10 bp periodicity. Based on these criteria, the Acute Myeloid Leukemia-1a (AML-1a) transcription factor, a regulator of immune gene expression, was identified as potentially sensitive to nucleosomal regulation within the mouse Ly49 gene family. This result was confirmed in RMA, a cell line with natural expression of Ly49, using MNase-Seq to generate a nucleosome map of chromosome 6, where the Ly49 gene family is located. Analysis of this map revealed a specific depletion of nucleosomes at AML-1a binding sites in the expressed Ly49A when compared to the other, silent Ly49 genes. Our data suggest that nucleosome-based regulation contributes to the expression of Ly49 genes, and we propose that this method of predicting nucleosome sensitivity could aid in dissecting the regulatory role of nucleosomes in general. PMID- 27124579 TI - Tumor suppression in mice lacking GABARAP, an Atg8/LC3 family member implicated in autophagy, is associated with alterations in cytokine secretion and cell death. AB - GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1beta, IL-6, IL-2 and IFN-gamma from stimulated macrophages and lymphocytes. In contrast, TGF-beta1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response. PMID- 27124580 TI - GSK-3beta-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte-neuron interactions. AB - Glycogen synthase kinase-3beta (GSK-3beta) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease specific changes in GSK-3beta expression may underlie these abnormalities. Thirty three postmortem hippocampal samples from HD patients (neuropathological grades 2 4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3beta were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3beta mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3beta-Tyr(216) being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3beta-Tyr(216) was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3beta in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3beta in HD affected hippocampal neurons and astrocytes therefore points to GSK-3beta as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD. PMID- 27124582 TI - Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation. AB - Concanavalin A (Con A)-induced hepatitis model is well-established experimental T cell-mediated liver disease. Reactive oxygen species (ROS) is associated with T cell activation and proliferation, but continued ROS exposure induces T-cell hyporesponsiveness. Because glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme and is involved in T-cell development, we investigated the role of Gpx1 during Con A-induced liver injury in Gpx1 knockout (KO) mice. Male wild-type (WT) mice and Gpx1 KO mice were intravenously injected with Con A (10 mg/kg), and then killed after 8 h after Con A injection. Serum levels of aspartate transaminase and alanine transaminase were measured to assess hepatic injury. To identify that Gpx1 affects T cell-mediated inflammation, we pretreated Gpx1 inhibitor to Human Jurkat T cells then treated Con A. Con A-induced massive liver damage in WT mice but its damage was attenuated in Gpx1 KO mice. Con A-induced Th1 cytokines such as tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin (IL)-2 were also decreased in the liver and spleen of Gpx1 KO mice compared with WT mice. In Jurkat T cells, Con A-induced mRNA levels of IL-2, IFN gamma and TNF-alpha were downregulated by pretreatment of Gpx inhibitor, mercaptosuccinic acid. We also observed that Gpx1 KO mice showed increasing oxidative stress in the liver and spleen compared with WT mice. These results suggest that Gpx1 deficiency attenuates Con A-induced liver injury by induction of T-cell hyporesponsiveness through chronic ROS exposure. PMID- 27124581 TI - The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing. AB - In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by alpha-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP Htt axis in the process of the transcriptional repression-induced necrosis. PMID- 27124585 TI - Elemental electron energy loss mapping of a precipitate in a multi-component aluminium alloy. AB - The elemental distribution of a precipitate cross section, situated in a lean Al Mg-Si-Cu-Ag-Ge alloy, has been investigated in detail by electron energy loss spectroscopy (EELS) and aberration corrected high angle annular dark field scanning transmission electron microscopy (HAADF-STEM). A correlative analysis of the EELS data is connected to the results and discussed in detail. The energy loss maps for all relevant elements were recorded simultaneously. The good spatial resolution allows elemental distribution to be evaluated, such as by correlation functions, in addition to being compared with the HAADF image. The fcc-Al lattice and the hexagonal Si-network within the precipitates were resolved by EELS. The combination of EELS and HAADF-STEM demonstrated that some atomic columns consist of mixed elements, a result that would be very uncertain based on one of the techniques alone. EELS elemental mapping combined with a correlative analysis have great potential for identification and quantification of small amounts of elements at the atomic scale. PMID- 27124583 TI - CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells. AB - Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non-tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy. PMID- 27124586 TI - Nepsilon-lysine acetylation in the lumen of the endoplasmic reticulum: A way to regulate autophagy and maintain protein homeostasis in the secretory pathway. AB - The Nepsilon-lysine acetylation of cargo proteins in the lumen of the endoplasmic reticulum (ER) requires a membrane transporter (SLC33A1) and 2 acetyltransferases (NAT8B and NAT8). The ER acetylation machinery regulates the homeostatic balance between quality control/efficiency of the secretory pathway and autophagy mediated disposal of toxic protein aggregates. We recently reported that the autophagy pathway that acts downstream of the ER acetylation machinery specifically targets protein aggregates that form within the secretory pathway. Genetic and biochemical manipulation of ER acetylation in a mouse model of Alzheimer disease is able to restore normal proteostasis and rescue the disease phenotype. Here we summarize these findings and offer an overview of the ER acetylation machinery. PMID- 27124584 TI - MicroRNA-682-mediated downregulation of PTEN in intestinal epithelial cells ameliorates intestinal ischemia-reperfusion injury. AB - Intestinal ischemia-reperfusion (I/R) injury causes inflammation and tissue damage and contributes to high morbidity and mortality, but the underlying mechanism remains elusive and effective therapies are still lacking. We report here a critical role of the microRNA 682 (miR-682) as a key regulator and therapeutic target in intestinal I/R injury. MiR-682 was markedly induced in intestinal epithelial cells (IECs) during intestinal ischemia in mice and in the human colonic epithelial cells during hypoxia, but was undetected rapidly after intestinal reperfusion in IEC of mice. MiR-682 induction during hypoxia was modulated by hypoxia-inducible factor-1alpha (HIF-1alpha). On lentivirus-mediated miR-682 overexpression in vivo during intestinal reperfusion or miR-682 mimic transfection in vitro during hypoxia, miR-682 decreased the expression of phosphatase and tensin homolog (PTEN) and subsequently activated nuclear translocation of nuclear factor kappa B (NF-kappaB) p65. Consequently, NF-kappaB activation by miR-682-mediated PTEN downregulation prevented reactive oxygen species (ROS) induction, inflammatory reaction, mitochondrial-mediated apoptosis and IEC apoptosis. The effect of miR-682-mediated PTEN/NF-kappaB pathway on IECs resulted in protection against intestinal I/R injury in mice. However, NF-kappaB chemical inhibitor reversed miR-682-mediated decreased PTEN expression, ROS induction, inflammation and IEC apoptosis. Collectively, these results identify a novel miR-682/PTEN/NF-kappaBp65 signaling pathway in IEC injury induced by I/R that could be targeted for therapy. PMID- 27124587 TI - Electron Paramagnetic Resonance Spectroscopy Investigation of Radical Production by Gold Nanoparticles in Aqueous Solutions Under X-ray Irradiation. AB - Nanomaterials can enhance the effect of X-rays, but the mechanisms of enhancement can be complicated. Electron paramagnetic resonance (EPR) was used here to shed light on enhancement mechanisms by detecting the originally proposed physical enhancement of the effect of X-rays by as-made large gold nanoparticles. Specifically spin trap reagent 5-tert-butoxycarbonyl-5-methyl-1-pyrroline-N-oxide (BMPO) was used to trap radicals produced in aqueous solutions under X-ray irradiation. Even though only BMPO hydroxyl adducts were detected at the time of EPR measurement, both hydroxyl and superoxide radicals were found to contribute to the enhancement. The measured total enhancement was 0.7-fold per weight percent (wp) of Au in water using unfiltered X-rays. The theoretically predicted physical enhancement is 0.49 fold per wp of gold in water. This information, together with scavenging experimental results and the fact that the G-values are close for both radicals, suggest that hydroxyl and superoxide radicals contributing almost equally to the total measured enhancement. Further, the enhancement was found to be linearly dependent on the amount of large gold nanoparticles in water and no additional radical was produced beyond the amount predicted by type 1 physical enhancement, indicating that hydroxyl or superoxide radicals were not produced via catalytic pathways. PMID- 27124588 TI - Giemsa is the optimal counterstain for immunohistochemical detection of BRAF V600E mutation status in pigmented melanomas. PMID- 27124589 TI - Patients' use and views of real-time feedback technology in general practice. AB - BACKGROUND: There is growing interest in real-time feedback (RTF), which involves collecting and summarizing information about patient experience at the point of care with the aim of informing service improvement. OBJECTIVE: To investigate the feasibility and acceptability of RTF in UK general practice. DESIGN: Exploratory randomized trial. SETTING/PARTICIPANTS: Ten general practices in south-west England and Cambridgeshire. All patients attending surgeries were eligible to provide RTF. INTERVENTION: Touch screens were installed in waiting areas for 12 weeks with practice staff responsible for encouraging patients to provide RTF. All practices received fortnightly feedback summaries. Four teams attended a facilitated reflection session. OUTCOMES: RTF 'response rates' among consulting patients were estimated, and the representativeness of touch screen users were assessed. The frequency of staff-patient interactions about RTF (direct observation) and patient views of RTF (exit survey) were summarized. Associated costs were collated. RESULTS: About 2.5% consulting patients provided RTF (range 0.7-8.0% across practices), representing a mean of 194 responses per practice. Patients aged above 65 were under-represented among touch screen users. Receptionists rarely encouraged RTF but, when this did occur, 60% patients participated. Patients were largely positive about RTF but identified some barriers. Costs per practice for the twelve-week period ranged from L1125 (unfacilitated team-level feedback) to L1887 (facilitated team +/- practitioner level feedback). The main cost was the provision of touch screens. CONCLUSIONS: Response rates for RTF were lower than those of other survey modes, although the numbers of patients providing feedback to each practice were comparable to those achieved in the English national GP patient survey. More patients might engage with RTF if the opportunity were consistently highlighted to them. PMID- 27124590 TI - Real-Time Cell-Electronic Sensing of Coal Fly Ash Particulate Matter for Toxicity Based Air Quality Monitoring. AB - The development of a unique bioassay for cytotoxicity analysis of coal fly ash (CFA) particulate matter (PM) and its potential application for air quality monitoring is described. Using human cell lines, A549 and SK-MES-1, as live probes on microelectrode-embedded 96-well sensors, impedance changes over time are measured as cells are treated with varying concentrations (1 MUg/mL-20 mg/mL) of CFA samples. A dose-dependent impedance change is determined for each CFA sample, from which an IC50 histogram is obtained. The assay was successfully applied to examine CFA samples collected from three coal-fired power plants (CFPs) in China. The samples were separated into three size fractions: PM2.5 (<2.5 MUm), PM10-2.5 (2.5 MUm < x < 10 MUm), and PM10 (>10 MUm). Dynamic cell response profiles and temporal IC50 histograms of all samples show that CFA cytotoxicity depends on concentration, exposure time (0-60 h), and cell-type (SK MES-1 > A549). The IC50 values differentiate the cytotoxicity of CFA samples based on size fraction (PM2.5 ~ PM10-2.5 ? PM10) and the sampling location (CFP2 > CFP1 ~ CFP3). Differential cytotoxicity measurements of particulates in human cell lines using cell-electronic sensing provide a useful tool for toxicity-based air quality monitoring and risk assessment. PMID- 27124591 TI - C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man. AB - X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. Virtually all males develop progressive myelopathy (AMN). A subset of patients, however, develops a fatal cerebral demyelinating disease (cerebral ALD). Hematopoietic stem cell transplantation is curative for cerebral ALD provided the procedure is performed in an early stage of the disease. Unfortunately, this narrow therapeutic window is often missed. Therefore, an increasing number of newborn screening programs are including ALD. To identify new biomarkers for ALD, we developed an Abcd1 knockout mouse with enhanced VLCFA synthesis either ubiquitous or restricted to oligodendrocytes. Biochemical analysis revealed VLCFA accumulation in different lipid classes and acylcarnitines. Both C26:0-lysoPC and C26:0-carnitine were highly elevated in brain, spinal cord, but also in bloodspots. We extended the analysis to patients and confirmed that C26:0-carnitine is also elevated in bloodspots from ALD patients. We anticipate that validation of C26:0-carnitine for the diagnosis of ALD in newborn bloodspots may lead to a faster inclusion of ALD in newborn screening programs in countries that already screen for other inborn errors of metabolism. PMID- 27124592 TI - Genetically modified human CD4(+) T cells can be evaluated in vivo without lethal graft-versus-host disease. AB - Adoptive cell immunotherapy for human diseases, including the use of T cells modified to express an anti-tumour T-cell receptor (TCR) or chimeric antigen receptor, is showing promise as an effective treatment modality. Further advances would be accelerated by the availability of a mouse model that would permit human T-cell engineering protocols and proposed genetic modifications to be evaluated in vivo. NOD-scid IL2rgamma(null) (NSG) mice accept the engraftment of mature human T cells; however, long-term evaluation of transferred cells has been hampered by the xenogeneic graft-versus-host disease (GVHD) that occurs soon after cell transfer. We modified human primary CD4(+) T cells by lentiviral transduction to express a human TCR that recognizes a pancreatic beta cell derived peptide in the context of HLA-DR4. The TCR-transduced cells were transferred to NSG mice engineered to express HLA-DR4 and to be deficient for murine class II MHC molecules. CD4(+) T-cell-depleted peripheral blood mononuclear cells were also transferred to facilitate engraftment. The transduced cells exhibited long-term survival (up to 3 months post-transfer) and lethal GVHD was not observed. This favourable outcome was dependent upon the pre-transfer T cell transduction and culture conditions, which influenced both the kinetics of engraftment and the development of GVHD. This approach should now permit human T cell transduction protocols and genetic modifications to be evaluated in vivo, and it should also facilitate the development of human disease models that incorporate human T cells. PMID- 27124593 TI - Natural Language Processing in Oncology: A Review. AB - IMPORTANCE: Natural language processing (NLP) has the potential to accelerate translation of cancer treatments from the laboratory to the clinic and will be a powerful tool in the era of personalized medicine. This technology can harvest important clinical variables trapped in the free-text narratives within electronic medical records. OBSERVATIONS: Natural language processing can be used as a tool for oncological evidence-based research and quality improvement. Oncologists interested in applying NLP for clinical research can play pivotal roles in building NLP systems and, in doing so, contribute to both oncological and clinical NLP research. Herein, we provide an introduction to NLP and its potential applications in oncology, a description of specific tools available, and a review on the state of the current technology with respect to cancer case identification, staging, and outcomes quantification. CONCLUSIONS AND RELEVANCE: More automated means of leveraging unstructured data from daily clinical practice is crucial as therapeutic options and access to individual-level health information increase. Research-minded oncologists may push the avenues of evidence-based research by taking advantage of the new technologies available with clinical NLP. As continued progress is made with applying NLP toward oncological research, incremental gains will lead to large impacts, building a cost-effective infrastructure for advancing cancer care. PMID- 27124594 TI - Prognostication of Uveal Melanoma: A Work in Progress. PMID- 27124595 TI - Differences in intracellular calcium dynamics cause differences in alpha-granule secretion and phosphatidylserine expression in platelets adhering on glass and TiO2. AB - In this study, the activation of purified human platelets due to their adhesion on glass and TiO2 in the absence of extracellular calcium was investigated. Differences in alpha-granule secretion between platelets adhering on the two surfaces were detected by examining the expression and secretion of the alpha granule markers P-selectin (CD62P) and beta-thromboglobulin. Similarly, differences in the expression of phosphatidylserine (PS), and in the activation of the major integrin GPIIb/IIIa, on the surfaces of the adhering platelets, were also observed. While all of these activation markers were expressed in platelets adhering on glass, the surface markers were not expressed in platelets adhering on TiO2, and beta-thromboglobulin secretion levels were substantially reduced. Differences in marker expression and secretion correlated with differences in the intracellular calcium dynamics. Calcium ionophore treatment triggered alpha granule secretion and PS expression in TiO2-adhering platelets but had no effect on the activation of GPIIb/IIIa. These results demonstrate specificity in the way surfaces of artificial materials activate platelets, link differences in the intracellular calcium dynamics observed in the platelets adhering on the two surfaces to the differences in some of the platelet responses (alpha-granule secretion and PS expression), but also highlight the involvement of synergistic, calcium-independent pathways in platelet activation. The ability to control activation in surface-adhering platelets makes this an attractive model system for studying platelet signaling pathways and for tissue engineering applications. PMID- 27124596 TI - Unidirectional Living Growth of Self-Assembled Protein Nanofibrils Revealed by Super-resolution Microscopy. AB - Protein-based nanofibrils are emerging as a promising class of materials that provide unique properties for applications such as biomedical and food engineering. Here, we use atomic force microscopy and stochastic optical reconstruction microscopy imaging to elucidate the growth dynamics, exchange kinetics, and polymerization mechanism for fibrils composed of a de novo designed recombinant triblock protein polymer. This macromolecule features a silk-inspired self-assembling central block composed of GAGAGAGH repeats, which are known to fold into a beta roll with turns at each histidine and, once folded, to stack, forming a long, ribbon-like structure. We find several properties that allow the growth of patterned protein nanofibrils: the self-assembly takes place on only one side of the growing fibrils by the essentially irreversible addition of protein polymer subunits, and these fibril ends remain reactive indefinitely in the absence of monomer ("living ends"). Exploiting these characteristics, we can grow stable diblock protein nanofibrils by the sequential addition of differently labeled proteins. We establish control over the block length ratio by simply varying monomer feed conditions. Our results demonstrate the use of engineered protein polymers in creating precisely patterned protein nanofibrils and open perspectives for the hierarchical self-assembly of functional biomaterials. PMID- 27124597 TI - Incorporating Anthropogenic Influences into Fire Probability Models: Effects of Human Activity and Climate Change on Fire Activity in California. AB - The costly interactions between humans and wildfires throughout California demonstrate the need to understand the relationships between them, especially in the face of a changing climate and expanding human communities. Although a number of statistical and process-based wildfire models exist for California, there is enormous uncertainty about the location and number of future fires, with previously published estimates of increases ranging from nine to fifty-three percent by the end of the century. Our goal is to assess the role of climate and anthropogenic influences on the state's fire regimes from 1975 to 2050. We develop an empirical model that integrates estimates of biophysical indicators relevant to plant communities and anthropogenic influences at each forecast time step. Historically, we find that anthropogenic influences account for up to fifty percent of explanatory power in the model. We also find that the total area burned is likely to increase, with burned area expected to increase by 2.2 and 5.0 percent by 2050 under climatic bookends (PCM and GFDL climate models, respectively). Our two climate models show considerable agreement, but due to potential shifts in rainfall patterns, substantial uncertainty remains for the semiarid inland deserts and coastal areas of the south. Given the strength of human-related variables in some regions, however, it is clear that comprehensive projections of future fire activity should include both anthropogenic and biophysical influences. Previous findings of substantially increased numbers of fires and burned area for California may be tied to omitted variable bias from the exclusion of human influences. The omission of anthropogenic variables in our model would overstate the importance of climatic ones by at least 24%. As such, the failure to include anthropogenic effects in many models likely overstates the response of wildfire to climatic change. PMID- 27124598 TI - Early CD4+ T Cell Responses Are Associated with Subsequent CD8+ T Cell Responses to an rAd5-Based Prophylactic Prime-Boost HIV Vaccine Strategy. AB - INTRODUCTION: Initial evaluation of a candidate vaccine against HIV includes an assessment of the vaccine's ability to generate immune responses. However, the dynamics of vaccine-induced immune responses are unclear. We hypothesized that the IFN-gamma producing cytotoxic CD8+ (CD8+ IFN-gamma+) T cell responses could be predicted by early IL-2 producing CD4+ (CD4+ IL-2+) helper T cell responses, and we evaluated this hypothesis using data from a phase I/II prophylactic HIV vaccine trial. The objective was to assess the dynamics and correlations between CD4+ IL-2+ T cell and CD8+ IFN-gamma+ T cell responses after vaccination with a recombinant adenoviral serotype 5 (rAd5) HIV vaccine. METHODS: We analyzed data from the HVTN 068 HIV vaccine trial, which evaluated the immunogenicity of two different strategies for prime and boost vaccination (rAd5-rAd5 vaccine versus DNA-rAd5) in 66 healthy volunteers. Spearman correlations between immunogenicity markers across time-points were calculated. CD8+ IFN-gamma+ T cell response in the rAd5-rAd5 arm was modeled as a function of CD4+ IL-2+ T cell response and time using mixed effects regression models. RESULTS: Moderate to high correlations (r = 0.48-0.76) were observed in the rAd5-rAd5 arm between the CD4+ IL-2+ T cell response at week 2 and later CD8+ IFN-gamma+ T cell responses (weeks 2-52). Regression models confirmed this relationship with a significant association between the two markers: for a 1.0% increase in CD4+ IL-2+ T cells at week 2 post-prime, a 0.3% increase in CD8+ IFN-gamma+ T cell responses across subsequent time points, including post-boost time points, was observed (p<0.01). CONCLUSION: These results suggest an early and leading role of CD4+ T cells in the cellular response to the rAd5-rAd5 vaccine and in particular the stimulation of cytotoxic CD8+ T cell responses. These results could inform better timing of CD4+ T cell measurements in future clinical trials. PMID- 27124599 TI - MDR-TB Outbreak among HIV-Negative Tunisian Patients followed during 11 Years. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) outbreaks that evolve, from the outset, in a context strictly negative for HIV infection deserve special consideration since they reflect the true intrinsic epidemic potential of the causative strain. To our knowledge, the long-term evolution of such exceptional outbreaks and the treatment outcomes for the involved patients has never been reported hitherto. Here we provide a thorough description, over an 11-year period, of an MDR-TB outbreak that emerged and expanded in an HIV-negative context, Northern Tunisia. METHODOLOGY/PRINCIPAL FINDINGS: From October 2001 to June 2011, the MDR-TB outbreak involved 48 HIV-negative individuals that are mainly young (mean age 31.09 yrs; 89.6% male) and noninstitutionalized. Drug susceptibility testing coupled to mutational analysis revealed that initial transmission involved an isolate that was simultaneously resistant to isoniazid, rifampicin, ethambutol, and streptomycin. The causative Haarlem3-ST50 outbreak strain expanded mainly as an 11-banded IS6110 RFLP profile (77.1%), from which a 12-banded subclone evolved. After undergoing a 2-year treatment with second-line drugs, 22 (45.8%) patients were cured and 3 (6.2%) completed treatment, thus yielding an overall treatment success rate of 52.1%. Among the patients that experienced unfavorable treatment outcomes, 10 (20.8%) failed treatment, 3 (6.2%) were lost to follow-up, 5 (10.4%) died, and 5 (10.4%) could not be evaluated. Poor adherence to treatment was found to be the main independent predictor of unfavorable outcomes (HR: 9.15; 95% CI 1.72-48.73; P = 0.014). Intriguingly, the evolved 12-banded subclone proved significantly associated with unfavorable outcomes (HR: 4.90; 95% CI 1.04-23.04, P = 0.044). High rate of fatality and relapse was further demonstrated at the long-term, since 70% of those whose treatment failed have died, and 24% among those deemed successfully treated have relapsed. CONCLUSIONS/SIGNIFICANCE: Taken together, the data obtained in this study indicate that MDR-TB clinical isolates could become fit enough to cause large and severe outbreaks in an HIV-negative context. Such MDR-TB outbreaks are characterized by low treatment success rates and could evolve towards increased severity, thus calling for early detection of cases and the necessity to raise the bar of surveillance throughout and beyond the treatment period. PMID- 27124601 TI - Highly Efficient Inverted Perovskite Solar Cells With Sulfonated Lignin Doped PEDOT as Hole Extract Layer. AB - Sulfonated-acetone-formaldehyde (SAF) was grafted with alkali lignin (AL) to prepare grafted sulfonated-acetone-formaldehyde lignin (GSL). Considering the rich phenolic hydroxyl groups in GSL, we detected a hole mobility of 2.27 * 10( 6) cm(2) V(-1) s(-1) with GSL as a hole transport material by space-charge limited current model. Compared with nonconjugated poly(styrene sulfonic acid), GSL was applied as p-type semiconductive dopant for PEDOT to prepare water dispersed PEDOT: GSL. PEDOT: GSL shows enhanced conductivity compared with that of PEDOT: PSS. Simultaneously, the enhanced open-circuit voltage, short-circuit current density, and fill factor are achieved using PEDOT: GSL as a hole extract layer (HEL) in sandwich-structure inverted perovskite solar cells. The power conversion efficiency is increased to 14.94% compared with 12.6% of PEDOT: PSS based devices. Our results show that amorphous GSL is a good candidate as dopant of PEDOT, and we provide a novel prospective for the design of HEL based on lignin, a renewable biomass and phenol derivatives. PMID- 27124602 TI - Regioselective synthesis of 3,4-disubstituted isocoumarins through the Pd catalyzed annulation of 2-iodoaromatic acids with ynamides. AB - A Pd(0)-catalyzed annulation reaction of ynamides is described for the efficient synthesis of 3,4-disubstituted isocoumarins. This novel methodology allows for the concomitant construction of O-C and C-C bonds between 2-iodoaromatic acids and ynamides, exhibiting excellent regioselectivities and a wide functional group tolerance. PMID- 27124600 TI - ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production. AB - Hepatitis C virus (HCV) particles closely mimic human very-low-density lipoproteins (VLDL) to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (alpha/beta hydrolase domain containing protein 5, also known as CGI-58) as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis. PMID- 27124603 TI - Time-Domain Simulation of Three Dimensional Quantum Wires. AB - A method is presented to calculate the eigenenergies and eigenfunctions of quantum wires. This is a true three-dimensional method based on a direct implementation of the time-dependent Schrodinger equation. It makes no approximations to the Schrodinger equation other than the finite-difference approximation of the space and time derivatives. The accuracy of our method is tested by comparing it to analytical results in a cylindrical wire. PMID- 27124604 TI - Efficient Record Linkage Algorithms Using Complete Linkage Clustering. AB - Data from different agencies share data of the same individuals. Linking these datasets to identify all the records belonging to the same individuals is a crucial and challenging problem, especially given the large volumes of data. A large number of available algorithms for record linkage are prone to either time inefficiency or low-accuracy in finding matches and non-matches among the records. In this paper we propose efficient as well as reliable sequential and parallel algorithms for the record linkage problem employing hierarchical clustering methods. We employ complete linkage hierarchical clustering algorithms to address this problem. In addition to hierarchical clustering, we also use two other techniques: elimination of duplicate records and blocking. Our algorithms use sorting as a sub-routine to identify identical copies of records. We have tested our algorithms on datasets with millions of synthetic records. Experimental results show that our algorithms achieve nearly 100% accuracy. Parallel implementations achieve almost linear speedups. Time complexities of these algorithms do not exceed those of previous best-known algorithms. Our proposed algorithms outperform previous best-known algorithms in terms of accuracy consuming reasonable run times. PMID- 27124605 TI - Vertically Oriented Growth of GaN Nanorods on Si Using Graphene as an Atomically Thin Buffer Layer. AB - The monolithic integration of wurtzite GaN on Si via metal-organic vapor phase epitaxy is strongly hampered by lattice and thermal mismatch as well as meltback etching. This study presents single-layer graphene as an atomically thin buffer layer for c-axis-oriented growth of vertically aligned GaN nanorods mediated by nanometer-sized AlGaN nucleation islands. Nanostructures of similar morphology are demonstrated on graphene-covered Si(111) as well as Si(100). High crystal and optical quality of the nanorods are evidenced through scanning transmission electron microscopy, micro-Raman, and cathodoluminescence measurements supported by finite-difference time-domain simulations. Current-voltage characteristics revealed high vertical conduction of the as-grown GaN nanorods through the Si substrates. These findings are substantial to advance the integration of GaN based devices on any substrates of choice that sustains the GaN growth temperatures, thereby permitting novel designs of GaN-based heterojunction device concepts. PMID- 27124606 TI - Curcumin Lowers Serum Lipids and Uric Acid in Subjects With Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common hepatic diseases in the general adult population. Dyslipidemia, hyperuricemia, and insulin resistance are common risk factors and accompanying features of NAFLD. Curcumin is a dietary natural product with beneficial metabolic effects relevant to the treatment of NAFLD. AIM: To assess the effects of curcumin on metabolic profile in subjects with NAFLD. METHODS: Patients diagnosed with NAFLD (grades 1-3; according to liver sonography) were randomly assigned to curcumin (1000 mg/d in 2 divided doses) (n = 50) or control (n = 52) group for a period of 8 weeks. All patients received dietary and lifestyle advises before the start of trial. Anthropometric measurements, lipid profile, glucose, insulin, glycated hemoglobin, and uric acid concentrations were measured at baseline and after 8 weeks of follow-up. RESULTS: Eighty-seven subjects (n = 44 and 43 in the curcumin and control group, respectively) completed the trial. Supplementation with curcumin was associated with a reduction in serum levels of total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), non-high-density lipoprotein cholesterol (P < 0.001), and uric acid (P < 0.001), whereas serum levels of high-density lipoprotein cholesterol and glucose control parameters remained unaltered. Curcumin was safe and well tolerated during this study. CONCLUSION: Results of the present trial suggest that curcumin supplementation reduces serum lipids and uric acid concentrations in patients with NAFLD. PMID- 27124607 TI - STAT3 Suppression Is Involved in the Protective Effect of SIRT6 Against Cardiomyocyte Hypertrophy. AB - The activation of signal transducer and activator of transcription 3 (STAT3) is critical for the development of cardiac hypertrophy and heart failure. Sirtuin 6 (SIRT6) protects cardiomyocytes from hypertrophy. This study focused on the association between SIRT6 and STAT3 in the regulation of cardiomyocyte hypertrophy. In the phenylephrine (PE)-induced hypertrophic cardiomyocyte model and in the hearts of isoprenaline-induced cardiac hypertrophic rat model, the mRNA and protein expressions of STAT3 and its phosphorylated level at tyrosine 705 (P-STAT3) were significantly increased. By contrast, the deacetylation activity of SIRT6 was weakened without altering its protein expression. In addition, the nuclear localization of STAT3 and P-STAT3 was enhanced by PE, suggesting that STAT3 was activated in cardiomyocyte hypertrophy. Adenovirus infection-induced SIRT6 overexpression repressed the activation of STAT3 by decreasing its mRNA and protein levels, by suppressing its transcriptional activity, and by hindering the expressions of its target genes. Moreover, the effect of SIRT6 overexpression on eliminating PE-induced expressions of hypertrophic biomarkers, such as atrial natriuretic factor and brain natriuretic peptide, was reversed by STAT3 overexpression. Likewise, SIRT6 knockdown-induced upregulation of atrial natriuretic factor and brain natriuretic peptide was reversed by STAT3 silencing. These observations suggest that the antihypertrophic effect of SIRT6 involves STAT3 suppression. In conclusion, SIRT6 prevents PE induced activation of STAT3 in cardiomyocyte hypertrophy; the inhibitory effect of SIRT6 on STAT3 contributes to cardiac protection. PMID- 27124608 TI - Pregnancy as a critical window for blood pressure regulation in mother and child: programming and reprogramming. AB - Pregnancy is a critical time for long-term blood pressure regulation in both mother and child. Pregnancies complicated by placental insufficiency, resulting in pre-eclampsia and intrauterine growth restriction, are associated with a threefold increased risk of the mother to develop hypertension later in life. In addition, these complications create an adverse intrauterine environment, which programmes the foetus and the second generation to develop hypertension in adult life. Female offspring born to a pregnancy complicated by placental insufficiency are at risk for pregnancy complications during their own pregnancies as well, resulting in a vicious circle with programmed risk for hypertension passing from generation to generation. Here, we review the epidemiology and mechanisms leading to the altered programming of blood pressure trajectories after pregnancies complicated by placental insufficiency. Although the underlying mechanisms leading to hypertension remain the subject of investigation, several abnormalities in angiotensin sensitivity, sodium handling, sympathetic activity, endothelial function and metabolic pathways are found in the mother after exposure to placental insufficiency. In the child, epigenetic modifications and disrupted organ development play a crucial role in programming of hypertension. We emphasize that pregnancy can be viewed as a window of opportunity to improve long-term cardiovascular health of both mother and child, and outline potential gains expected of improved preconceptional, perinatal and post-natal care to reduce the development of hypertension and the burden of cardiovascular disease later in life. Perinatal therapies aimed at reprogramming hypertension are a promising strategy to break the vicious circle of intergenerational programming of hypertension. PMID- 27124609 TI - A Rapid and Sensitive Strip-Based Quick Test for Nerve Agents Tabun, Sarin, and Soman Using BODIPY-Modified Silica Materials. AB - Test strips that in combination with a portable fluorescence reader or digital camera can rapidly and selectively detect chemical warfare agents (CWAs) such as Tabun (GA), Sarin (GB), and Soman (GD) and their simulants in the gas phase have been developed. The strips contain spots of a hybrid indicator material consisting of a fluorescent BODIPY indicator covalently anchored into the channels of mesoporous SBA silica microparticles. The fluorescence quenching response allows the sensitive detection of CWAs in the MUg m(-3) range in a few seconds. PMID- 27124610 TI - Clustering Scientific Publications Based on Citation Relations: A Systematic Comparison of Different Methods. AB - Clustering methods are applied regularly in the bibliometric literature to identify research areas or scientific fields. These methods are for instance used to group publications into clusters based on their relations in a citation network. In the network science literature, many clustering methods, often referred to as graph partitioning or community detection techniques, have been developed. Focusing on the problem of clustering the publications in a citation network, we present a systematic comparison of the performance of a large number of these clustering methods. Using a number of different citation networks, some of them relatively small and others very large, we extensively study the statistical properties of the results provided by different methods. In addition, we also carry out an expert-based assessment of the results produced by different methods. The expert-based assessment focuses on publications in the field of scientometrics. Our findings seem to indicate that there is a trade-off between different properties that may be considered desirable for a good clustering of publications. Overall, map equation methods appear to perform best in our analysis, suggesting that these methods deserve more attention from the bibliometric community. PMID- 27124616 TI - S8 -Mediated Cyclization of 2-Aminophenols/thiophenols with Arylmethyl Chloride: Approach to Benzoxazoles and Benzothiazoles. AB - A metal-free approach to benzazoles from arylmethyl chlorides and 2-mercaptan/2 hydroxyanilines using elemental sulfur as a traceless oxidizing agent has been developed. The reactions proceeded in good to excellent yields, exhibiting good functional groups tolerance and gram-scale ability. A key mechanistic investigation indicated that the key intermediate trisulfide 6, which was characterized by NMR, HRMS and crystal X-ray crystallography, was separated in the reaction prior to the formation of the product. PMID- 27124615 TI - Effects of Isoflavone-Enriched Feed on the Rumen Microbiota in Dairy Cows. AB - In this study, we compared the effects of two diets containing different isoflavone concentrations on the isoflavone transfer from feed into milk and on the rumen microbiota in lactating dairy cows. The on-farm experiment was conducted on twelve lactating Czech Fleckvieh x Holstein cows divided into two groups, each with similar mean milk yield. Twice daily, cows were individually fed a diet based on maize silage, meadow hay and supplemental mixture. Control group (CTRL) received the basal diet while the experimental group (EXP) received the basal diet supplemented with 40% soybean isoflavone extract. The average daily isoflavone intake in the EXP group (16 g/day) was twice as high as that in the CTRL group (8.4 g/day, P<0.001). Total isoflavone concentrations in milk from the CTRL and EXP groups were 96.89 and 276.07 MUg/L, respectively (P<0.001). Equol concentrations in milk increased from 77.78 MUg/L in the CTRL group to 186.30 MUg/L in the EXP group (P<0.001). The V3-4 region of bacterial 16S rRNA genes was used for metagenomic analysis of the rumen microbiome. The experimental cows exhibited fewer OTUs at a distance level of 0.03 compared to control cows (P<0.05) and reduced microbial richness compared to control cows based on the calculated Inverse Simpson and Shannon indices. Non-metric multidimensional scaling analysis showed that the major contributor to separation between the experimental and control groups were changes in the representation of bacteria belonging to the phyla Bacteroidetes, Proteobacteria, Firmicutes, and Planctomycetes. Surprisingly, a statistically significant positive correlation was found only between isoflavones and the phyla Burkholderiales (r = 0.65, P<0.05) and unclassified Betaproteobacteria (r = 0.58, P<0.05). Previous mouse and human studies of isoflavone effects on the composition of gastrointestinal microbial populations generally report similar findings. PMID- 27124617 TI - Who can I trust? Extended fear during and after the Utoya terrorist attack. AB - OBJECTIVE: The aim of the study was to investigate specific peritraumatic reactions among adolescent and young adult survivors of the 2011 terrorist attack on Utoya Island, Norway. The authors focused specifically on a phenomenon that has so far not been thoroughly investigated: fear of nondangerous stimuli ("extended fear") during and immediately after the traumatic event. METHOD: In total, 325 survivors of the shooting on Utoya Island were interviewed 4-5 months after the attack and provided a free narrative of the event. Posttraumatic stress symptoms were assessed using the UCLA PTSD Reaction Index; depression and anxiety were assessed using HSCL-8. For the purpose of the current study, the authors chose participants who were under the age of 26 at the time of the terrorist attack (M = 18.4 years), which constituted the vast majority of the total sample (93%). RESULTS: The authors found that 54% of the sample felt threatened during and immediately after the attack, not only by the perpetrator himself, but by other people as well; in most cases by people who came to help them (medical personnel, policemen, volunteers). The participants who mentioned experiencing extended fear in their trauma narratives had significantly higher scores of posttraumatic stress symptoms, anxiety, and depression 5 months after the attack than participants who did not peritraumatically experience extended fear. CONCLUSIONS: Early detection of extended fear can help in identifying individuals who will later develop symptomatology. In addition, knowledge of the phenomenon could help policemen and medical personnel understand survivors' seemingly irrational reactions. (PsycINFO Database Record PMID- 27124618 TI - Domestic Travel and Regional Migration for Parathyroid Surgery Among Patients Receiving Care at Academic Medical Centers in the United States, 2012-2014. AB - IMPORTANCE: To improve outcomes after parathyroidectomy, several organizations advocate for selective referral of patients to high-volume academic medical centers with dedicated endocrine surgery programs. The major factors that influence whether patients travel away from their local community and support system for perceived better care remain elusive. OBJECTIVE: To assess how race/ethnicity and insurance status influence domestic travel patterns and selection of high- vs low-volume hospitals in different regions of the United States for parathyroid surgery. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study was conducted of 36 750 inpatients and outpatients discharged after undergoing parathyroidectomy identified in the University HealthSystem Consortium database from January 1, 2012, to December 31, 2014 (12 quarters total). Each US region (Northeast, Mid-Atlantic, Great Lakes, Central Plains, Southeast, Gulf Coast, and West) contained 20 or more low-volume hospitals (1-49 cases annually), 5 or more mid-volume hospitals (50-99 cases annually), and multiple high-volume hospitals (>=100 cases annually). Domestic medical travelers were defined as patients who underwent parathyroidectomy at a hospital in a different US region from which they resided and traveled more than 150 miles to the hospital. MAIN OUTCOMES AND MEASURES: Distance traveled, regional destination, and relative use of high- vs low-volume hospitals. RESULTS: A total of 23 268 of the 36 750 patients (63.3%) had parathyroidectomy performed at high volume hospitals. The mean (SD) age of the study cohort was 71.5 (16.2) years (95% CI, 71.4-71.7 years). The female to male ratio was 3:1. Throughout the study period, mean (SD) distance traveled was directly proportional to hospital volume (high-volume hospitals, 208.4 [455.1] miles; medium-volume hospitals, 50.5 [168.4] miles; low-volume hospitals, 27.7 [89.5] miles; P < .001). From 2012 to 2014, the annual volume of domestic medical travelers increased by 15.0% (from 961 to 1105), while overall volume increased by 4.9% (from 11 681 to 12 252; P = .03). Nearly all (2982 of 3113 [95.8%]) domestic medical travelers had surgery at high-volume hospitals, and most of these patients (2595 of 3113 [83.4%]) migrated to hospitals in the Southeast. Domestic medical travelers were significantly more likely to be white (2888 of 3113 [92.8%]; P < .001) and have private insurance (1934 of 3113 [62.1%]; P < .001). Most patients with private insurance (12 137 of 17 822 [68.1%]) and Medicare (9433 of 15 121 [62.4%]) had surgery at high-volume hospitals, while the largest proportion of patients with Medicaid and those who were uninsured had surgery at low-volume hospitals (1059 of 2715 [39.0%]). CONCLUSIONS AND RELEVANCE: Centralization of parathyroid surgery is a reality in the United States. Significant disparities based on race and insurance coverage exist and may hamper access to the highest-volume surgeons and hospitals. Academic medical centers with dedicated endocrine surgery programs should consider strategic initiatives to reduce disparities within their respective regions. PMID- 27124611 TI - Remote Physical Activity Monitoring in Neurological Disease: A Systematic Review. AB - OBJECTIVE: To perform a systematic review of studies using remote physical activity monitoring in neurological diseases, highlighting advances and determining gaps. METHODS: Studies were systematically identified in PubMed/MEDLINE, CINAHL and SCOPUS from January 2004 to December 2014 that monitored physical activity for >=24 hours in adults with neurological diseases. Studies that measured only involuntary motor activity (tremor, seizures), energy expenditure or sleep were excluded. Feasibility, findings, and protocols were examined. RESULTS: 137 studies met inclusion criteria in multiple sclerosis (MS) (61 studies); stroke (41); Parkinson's Disease (PD) (20); dementia (11); traumatic brain injury (2) and ataxia (1). Physical activity levels measured by remote monitoring are consistently low in people with MS, stroke and dementia, and patterns of physical activity are altered in PD. In MS, decreased ambulatory activity assessed via remote monitoring is associated with greater disability and lower quality of life. In stroke, remote measures of upper limb function and ambulation are associated with functional recovery following rehabilitation and goal-directed interventions. In PD, remote monitoring may help to predict falls. In dementia, remote physical activity measures correlate with disease severity and can detect wandering. CONCLUSIONS: These studies show that remote physical activity monitoring is feasible in neurological diseases, including in people with moderate to severe neurological disability. Remote monitoring can be a psychometrically sound and responsive way to assess physical activity in neurological disease. Further research is needed to ensure these tools provide meaningful information in the context of specific neurological disorders and patterns of neurological disability. PMID- 27124619 TI - Assessment of Hemophilic Arthropathy by Ultrasound: Where Do We Stand? AB - Joint hemorrhages represent the most common type of bleeding episode in persons with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the most frequent chronic complication in these patients. In recent years, in the frame of a comprehensive care approach, a growing attention has been given to the periodic assessment of the joint status in hemophilia patients with the aim to identify early arthropathic changes and to prevent the development of a clinically overt arthropathy. Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently used to evaluate joint status and to monitor the disease progression in hemophilia. Considering the limitations of X ray and MRI, growing interest has been given to ultrasound (US) as a possible tool to assess joint status and identify early arthropathic changes in hemophilia patients. In the present review, we summarize major literature evidence on the use of joint US for the evaluation of markers of disease activity (joint effusion and synovial hypertrophy) and of degenerative damages (osteochondral changes) in patients with hemophilia. On the whole, being able to identify the presence of intra- or extra-articular fluid, US examination is the fastest and most reliable technique to identify acute conditions, such as hemarthrosis. In addition, the information on joint involvement provided by US in the patient follow-up may influence treatment decisions on a personalized basis. The use of US as part of a routine clinical examination by hemophilia experts may optimize the diagnostic workflow, avoiding additional costs and long waiting lists for patients referred to imaging departments. In the frame of a comprehensive care approach, US might represent a strategy to early detect and monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extending the clinical examination and helping identify joints to be studied with a second-level examination such as MRI. PMID- 27124620 TI - Metal binding affinity and structural properties of calmodulin-like protein 14 from Arabidopsis thaliana. AB - In addition to the well-known Ca(2+) sensor calmodulin, plants possess many calmodulin-like proteins (CMLs) that are predicted to have specific roles in the cell. Herein, we described the biochemical and biophysical characterization of recombinant Arabidopsis thaliana CML14. We applied isothermal titration calorimetry to analyze the energetics of Ca(2+) and Mg(2+) binding to CML14, and nuclear magnetic resonance spectroscopy, together with intrinsic and ANS-based fluorescence, to evaluate the structural effects of metal binding and metal induced conformational changes. Furthermore, differential scanning calorimetry and limited proteolysis were used to characterize protein thermal and local stability. Our data demonstrate that CML14 binds one Ca(2+) ion with micromolar affinity (Kd ~ 12 uM) and the presence of 10 mM Mg(2+) decreases the Ca(2+) affinity by ~5-fold. Although binding of Ca(2+) to CML14 increases protein stability, it does not result in a more hydrophobic protein surface and does not induce the large conformational rearrangement typical of Ca(2+) sensors, but causes only localized structural changes in the unique functional EF-hand. Our data, together with a molecular modelling prediction, provide interesting insights into the biochemical properties of Arabidopsis CML14 and may be useful to direct additional studies aimed at understanding its physiological role. PMID- 27124622 TI - Mixed-Halide CH3 NH3 PbI3-x Xx (X=Cl, Br, I) Perovskites: Vapor-Assisted Solution Deposition and Application as Solar Cell Absorbers. AB - There have been recent reports on the formation of single-halide perovskites, CH3 NH3 PbX3 (X=Cl, Br, I), by means of vapor-assisted solution processing. Herein, the successful formation of mixed-halide perovskites (CH3 NH3 PbI3-x Xx ) by means of a vapor-assisted solution method at ambient atmosphere is reported. The perovskite films are synthesized by exposing PbI2 film to CH3 NH3 X (X=I, Br, or Cl) vapor. The prepared perovskite films have uniform surfaces with good coverage, as confirmed by SEM images. The inclusion of chlorine and bromine into the structure leads to a lower temperature and shorter reaction time for optimum perovskite film formation. In the case of CH3 NH3 PbI3-x Clx , the optimum reaction temperature is reduced to 100 degrees C, and the resulting phases are CH3 NH3 PbI3 (with trace Cl) and CH3 NH3 PbCl3 with a ratio of about 2:1. In the case of CH3 NH3 PbI3-x Brx , single-phase CH3 NH3 PbI2 Br is formed in a considerably shorter reaction time than that of CH3 NH3 PbI3 . The mesostructured perovskite solar cells based on CH3 NH3 PbI3 films show the best optimal power conversion efficiency of 13.5 %, whereas for CH3 NH3 PbI3-x Clx and CH3 NH3 PbI3 x Brx the best recorded efficiencies are 11.6 and 10.5 %, respectively. PMID- 27124621 TI - Diabetes 2030: Insights from Yesterday, Today, and Future Trends. AB - To forecast future trends in diabetes prevalence, morbidity, and costs in the United States, the Institute for Alternative Futures has updated its diabetes forecasting model and extended its projections to 2030 for the nation, all states, and several metropolitan areas. This paper describes the methodology and data sources for these diabetes forecasts and discusses key implications. In short, diabetes will remain a major health crisis in America, in spite of medical advances and prevention efforts. The prevalence of diabetes (type 2 diabetes and type 1 diabetes) will increase by 54% to more than 54.9 million Americans between 2015 and 2030; annual deaths attributed to diabetes will climb by 38% to 385,800; and total annual medical and societal costs related to diabetes will increase 53% to more than $622 billion by 2030. Improvements in management reducing the annual incidence of morbidities and premature deaths related to diabetes over this time period will result in diabetes patients living longer, but requiring many years of comprehensive management of multiple chronic diseases, resulting in dramatically increased costs. Aggressive population health measures, including increased availability of diabetes prevention programs, could help millions of adults prevent or delay the progression to type 2 diabetes, thereby helping turn around these dire projections. PMID- 27124623 TI - Zika virus: An update on epidemiology, pathology, molecular biology, and animal model. AB - Zika virus (ZIKV) was first described in 1947, and became a health emergency problem in 2016 when its association with fetal microcephaly cases was confirmed by Centers for Disease Control and Prevention (CDC) in the United States. To date, ZIKV infection has been documented in 66 countries. ZIKV is recognized as a neurotropic virus and numerous diseases manifested in multiple neurological disorders have been described, mainly in countries that have been exposed to ZIKV after the 2007 outbreak in the Federated States of Micronesia. The most dramatic consequence of ZIKV infection documented is the abrupt increase in fetal microcephaly cases in Brazil. Here, we present an update of the published research progress in the past few months. J. Med. Virol. 88:1291-1296, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27124624 TI - Long term exposure to NO2 and diabetes incidence in the Black Women's Health Study. AB - While laboratory studies show that air pollutants can potentiate insulin resistance, the epidemiologic evidence regarding the association of air pollution with diabetes incidence is conflicting. The purpose of the present study was to assess the association of the traffic-related nitrogen dioxide (NO2) with the incidence of diabetes in a longitudinal cohort study of African American women. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals (CI) for diabetes associated with exposure to NO2 among 43,003 participants in the Black Women's Health Study (BWHS). Pollutant levels at participant residential locations were estimated with 1) a land use regression model for participants living in 56 metropolitan areas, and 2) a dispersion model for participants living in 27 of the cities. From 1995 to 2011, 4387 cases of diabetes occurred. The hazard ratios per interquartile range of NO2 (9.7 ppb), adjusted for age, metropolitan area, education, vigorous exercise, body mass index, smoking, and diet, were 0.96 (95% CI 0.88-1.06) using the land use regression model estimates and 0.94 (95% CI 0.80, 1.10) using the dispersion model estimates. The present results do not support the hypothesis that exposure to NO2 contributes to diabetes incidence in African American women. PMID- 27124625 TI - Evolution and oncological outcomes of a contemporary radical prostatectomy practice in a UK regional tertiary referral centre. AB - OBJECTIVE: To investigate the clinical and pathological trends, over a 10-year period, in robot-assisted laparoscopic prostatectomy (RALP) in a UK regional tertiary referral centre. PATIENTS AND METHODS: In all, 1 500 consecutive patients underwent RALP between October 2005 and January 2015. Prospective data were collected on clinicopathological details at presentation as well as surgical outcomes and compared over time. RESULTS: The median (range) age of patients throughout the period was 62 (35-78) years. The proportion of preoperative high grade cases (Gleason score 8-10) rose from 4.6% in 2005-2008 to 18.2% in 2013 2015 (P < 0.001). In the same periods the proportion of clinical stage T3 cases operated on rose from 2.4% to 11.4% (P < 0.001). The median prostate-specific antigen (PSA) level at diagnosis did not alter significantly. Overall, 11.6% of men in 2005-2008 were classified preoperatively as high-risk by National Institute for Health and Care Excellence criteria, compared with 33.6% in 2013 2015 (P < 0.001). The corresponding proportions for low-risk cases were 48.6% and 17.3%, respectively. Final surgical pathology showed an increase in tumour stage, Gleason grade, and nodal status over time. The proportion of pT3 cases rose from 43.2% in 2005-2008 to 55.5% in 2013-2015 (P < 0.001), Gleason score 9-10 tumours increased from 1.8% to 9.1% (P < 0.001) and positive nodal status increased from 1.6% to 12.9% (P < 0.001) between the same periods. Despite this, positive surgical margin rates showed a downward trend in all pT groups across the different eras (P = 0.72). CONCLUSION: This study suggests that the patient profile for RALP in our unit is changing, with increasing proportions of higher stage and more advanced disease being referred and operated on. However, surgical margin outcomes have remained good. PMID- 27124643 TI - Prevalence of bleeding manifestations in 128 heterozygotes for Factor X deficiency, mainly for FX Friuli, matched versus 128 unaffected family members, during a long sequential observation period (23.5 years). AB - OBJECTIVES: The main objective of the study was to evaluate the incidence of bleeding manifestations in heterozygotes for FX deficiency vs. unaffected family members. Secondary objective was to compare the prevalence of arterial or venous diseases found in the two groups. PATIENTS AND METHODS: A total of 128 heterozygote patients for FX deficiency were investigated. A total of 102 patients had FX Friuli; 26 patients had other forms of FX deficiency. At time of diagnosis, each patient was paired with an unaffected family member, matched by gender and age (+/-5). Patients and their normal counterparts were checked every 1-2 yr for a mean period of 23.5 yr. The occurrence of bleeding manifestations was recorded and scored. The occurrence of arterial diseases and venous thrombosis was also recorded as a secondary finding. RESULTS: A total of 38 heterozygote patients (29.7%) had one or more than one bleeding manifestation. The most frequent one was bleeding after tooth extraction or surgery. On the contrary, only three control subjects (2.3%) had documented hemorrhagic symptoms. There was a good correlation between bleeding and FX levels. Arterial disease (acute coronary syndromes, ischemic stroke, stable angina, peripheral arteries disease) was found in eight patients (6.3%) with FX deficiency and in seven unaffected subjects (5.5%). On the contrary, no venous thrombosis was seen in the affected group, whereas three cases (2.3%) of documented venous thrombosis were observed in the control group (two deep veins and one superficial vein). CONCLUSIONS: Heterozygotes FX deficiency may be accompanied by a mild bleeding tendency. This has important implications to assure a safe FX level in case of surgery or invasive procedures. Furthermore, mild FX deficiency seems to have no protective effect on arterial disease but does seem to protect from venous thrombosis. PMID- 27124645 TI - Physicochemical Studies on Orientation and Conformation of a New Bacteriocin BacSp222 in a Planar Phospholipid Bilayer. AB - The behavior, secondary structure, and orientation of a recently discovered bacteriocin-like peptide BacSp222 in a lipid model system supported at a gold electrode was investigated by chronocoulometry, polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS), and attenuated total reflectance infrared (ATR-IR) spectroscopy. The IR spectra show that the secondary structure of BacSp222 is predominantly alpha-helical. Analysis of the spectra in the amide I region shows that the alpha-helical fragment of the peptide is inserted into bilayer at the potential range at which the bilayer is stable and attached to the Au(111) surface, i.e., from -0.5 to 0.3 V vs Ag/AgCl. Insertion of BacSp222 to the membrane significantly changes the conformation of the acyl chains of lipid molecules, from all-trans to partially melted; however, the chains become less tilted. Based on these results, we propose that BacSp222 interacts with the DMPC bilayer through the barrel-stave pore formation. In this model, alpha-helix of BacSp222 inserts into the membrane with an angle between the alpha-helix axis and membrane normal equal to ~18 degrees . The changes in orientation of the alpha helical fragment of the peptide indicate that the orientation of BacSp222 with respect to the bilayer surface is potential-dependent. The peptide is inserted into the membrane driven by the electrostatic field generated by negative charge at the metal surface. It is not inserted at negative potentials where the membrane is detached from the metal and no longer exposed to the electrostatic field of the metal. PMID- 27124644 TI - Mesenchymal stromal cells having inactivated RB1 survive following low irradiation and accumulate damaged DNA: Hints for side effects following radiotherapy. AB - Following radiotherapy, bone sarcomas account for a significant percentage of recurring tumors. This risk is further increased in patients with hereditary retinoblastoma that undergo radiotherapy. We analyzed the effect of low and medium dose radiation on mesenchymal stromal cells (MSCs) with inactivated RB1 gene to gain insights on the molecular mechanisms that can induce second malignant neoplasm in cancer survivors. MSC cultures contain subpopulations of mesenchymal stem cells and committed progenitors that can differentiate into mesodermal derivatives: adipocytes, chondrocytes, and osteocytes. These stem cells and committed osteoblast precursors are the cell of origin in osteosarcoma, and RB1 gene mutations have a strong role in its pathogenesis. Following 40 and 2000 mGy X-ray exposure, MSCs with inactivated RB1 do not proliferate and accumulate high levels of unrepaired DNA as detected by persistence of gamma-H2AX foci. In samples with inactivated RB1 the radiation treatment did not increase apoptosis, necrosis or senescence versus untreated cells. Following radiation, CFU analysis showed a discrete number of cells with clonogenic capacity in cultures with silenced RB1. We extended our analysis to the other members of retinoblastoma gene family: RB2/P130 and P107. Also in the MSCs with silenced RB2/P130 and P107 we detected the presence of cells with unrepaired DNA following X-ray irradiation. Cells with unrepaired DNA may represent a reservoir of cells that may undergo neoplastic transformation. Our study suggests that, following radiotherapy, cancer patients with mutations of retinoblastoma genes may be under strict controls to evaluate onset of secondary neoplasms following radiotherapy. PMID- 27124642 TI - Pancreatic islet blood flow and its measurement. AB - Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium-derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future. PMID- 27124647 TI - Non-Bullous Lichen Planus Pemphigoides Possibly Induced by Venlafaxine. PMID- 27124646 TI - Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity. AB - PURPOSE: A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux. METHODS: Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice. RESULTS: Homogenous nanosuspensions of 80 +/- 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis. CONCLUSIONS: The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs. PMID- 27124648 TI - Alitretinoin-induced curling of the hair. PMID- 27124649 TI - Acne keloidalis nuchae in renal transplant patients receiving tacrolimus and sirolimus. PMID- 27124650 TI - A CdSe thin film: a versatile buffer layer for improving the performance of TiO2 nanorod array:PbS quantum dot solar cells. AB - To fully utilize the multiple exciton generation effects in quantum dots and improve the overall efficiency of the corresponding photovoltaic devices, nanostructuralizing the electron conducting layer turns out to be a feasible strategy. Herein, PbS quantum dot solar cells were fabricated on the basis of morphologically optimized TiO2 nanorod arrays. By inserting a thin layer of CdSe quantum dots into the interface of TiO2 and PbS, a dramatic enhancement in the power conversion efficiency from 4.2% to 5.2% was realized and the resulting efficiency is one of the highest values for quantum dot solar cells based on nanostructuralized buffer layers. The constructed double heterojunction with a cascade type-II energy level alignment is beneficial for promoting photogenerated charge separation and reducing charge recombination, thereby responsible for the performance improvement, as revealed by steady-state analyses as well as ultra fast photoluminescence and photovoltage decays. Thus this paper provides a good buffer layer to the community of quantum dot solar cells. PMID- 27124651 TI - Borderline ankle-brachial index is associated with poor short-term clinical outcome after coronary artery intervention. AB - OBJECTIVE: To evaluate the association between borderline ankle-brachial index (ABI) and clinical outcome in patients who underwent percutaneous coronary intervention (PCI). METHODS: From August 2009 to August 2012, ABI was measured in 1291 patients who underwent PCI. Patients with borderline ABI were compared with those who had normal ABI. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction, stroke, and repeat revascularization. RESULTS: Of the 1291 patients, 1154 (82%) had normal ABI and 89 (7%) had borderline ABI. The median overall follow-up duration was 19 (interquartile range 13-26) months. After adjustment with IPTW, the incidence of stroke (HR, 6.28; CI 95%, 1.95-20.19; P < 0.01) and MACCE (HR, 2.54; CI 95%, 1.40-4.62; P < 0.01) were higher in the borderline ABI group. In a propensity score-matched population, the incidence of stroke (HR, 4.68; CI 95%, 1.18-18.52; p = 0.03) and MACCE (HR, 2.12; CI 95%, 1.09 4.11; P = 0.03) were still significantly higher. CONCLUSION: The presence of borderline ABI was associated with worse clinical outcome and increased stroke rate compared with normal ABI during the short-term follow-up period in patients who underwent coronary intervention. PMID- 27124652 TI - Algal Diet of Small-Bodied Crustacean Zooplankton in a Cyanobacteria-Dominated Eutrophic Lake. AB - Small-bodied cladocerans and cyclopoid copepods are becoming increasingly dominant over large crustacean zooplankton in eutrophic waters where they often coexist with cyanobacterial blooms. However, relatively little is known about their algal diet preferences. We studied grazing selectivity of small crustaceans (the cyclopoid copepods Mesocyclops leuckarti, Thermocyclops oithonoides, Cyclops kolensis, and the cladocerans Daphnia cucullata, Chydorus sphaericus, Bosmina spp.) by liquid chromatographic analyses of phytoplankton marker pigments in the shallow, highly eutrophic Lake Vortsjarv (Estonia) during a seasonal cycle. Copepods (mainly C. kolensis) preferably consumed cryptophytes (identified by the marker pigment alloxanthin in gut contents) during colder periods, while they preferred small non-filamentous diatoms and green algae (identified mainly by diatoxanthin and lutein, respectively) from May to September. All studied cladoceran species showed highest selectivity towards colonial cyanobacteria (identified by canthaxanthin). For small C. sphaericus, commonly occuring in the pelagic zone of eutrophic lakes, colonial cyanobacteria can be their major food source, supporting their coexistence with cyanobacterial blooms. Pigments characteristic of filamentous cyanobacteria and diatoms (zeaxanthin and fucoxanthin, respectively), algae dominating in Vortsjarv, were also found in the grazers' diet but were generally avoided by the crustaceans commonly dominating the zooplankton assemblage. Together these results suggest that the co-occurring small-bodied cyclopoid and cladoceran species have markedly different algal diets and that the cladocera represent the main trophic link transferring cyanobacterial carbon to the food web in a highly eutrophic lake. PMID- 27124653 TI - Switch hands! Mapping proactive and reactive cognitive control across the life span. AB - We investigated the effects of age on proactive and reactive cognitive control in a large population sample of 809 individuals, ranging in age between 5 and 97 years. For that purpose, we used an anticue paradigm, which required a consistent remapping of cue location and response hand: Left-sided cues required right-hand responses and vice versa. After a random preparation interval of 100-850 ms, these anticues were followed by a target stimulus, which prompted a response with the index or middle finger of 1 of 2 hands. A neutral control condition involved uninformative cues, indicating all 4 possible response locations. The primary outcome measure was the difference between neutral and anticue reaction time (RT). Negative values indicated RT costs of the anticue, relative to the neutral condition, reflecting reactive cognitive control. Positive values indicated RT benefits, reflecting proactive cognitive control. Results were twofold. First, the switch from RT costs to benefits took place at longer preparation intervals in the youngest and oldest age groups than in the intermediate age groups. Second, irrespective of preparation interval, anticue performance followed an inverted U-shaped trajectory as a function of age, with a relatively steep improvement during childhood and adolescence, relative stability between 26 and 60 years, and a slightly accelerating decline into old age. Both patterns of results suggest an age-related transition from a primarily reactive, to a primarily proactive mode of cognitive control in early life and back again from a primarily proactive, to a primarily reactive mode of control in later life. (PsycINFO Database Record PMID- 27124654 TI - Age-related differences in moral identity across adulthood. AB - In this study, age-related differences in adults' moral identity were investigated. Moral identity was conceptualized a context-dependent self structure that becomes differentiated and (re)integrated in the course of development and that involves a broad range of value-orientations. Based on a cross-sectional sample of 252 participants aged 14 to 65 years (148 women, M = 33.5 years, SD = 16.9) and a modification of the Good Self-Assessment, it was demonstrated that mean-level of moral identity (averaged across the contexts of family, school/work, and community) significantly increased in the adult years, whereas cross-context differentiation showed a nonlinear trend peaking at the age of 25 years. Value-orientations that define individuals' moral identity shifted so that self-direction and rule-conformity became more important with age. Age related differences in moral identity were associated with, but not fully attributable to changes in personality traits. Overall, findings suggest that moral identity development is a lifelong process that starts in adolescence but expands well into middle age. (PsycINFO Database Record PMID- 27124655 TI - Correction: Tauroursodeoxycholic Acid Mitigates High Fat Diet-Induced Cardiomyocyte Contractile and Intracellular Ca2+ Anomalies. AB - [This corrects the article DOI: 10.1371/journal.pone.0063615.]. PMID- 27124656 TI - Challenges and Opportunities for the Application of Boron Clusters in Drug Design. AB - There are two branches in boron medicinal chemistry: the first focuses on single boron atom compounds, and the second utilizes boron clusters. Boron clusters and their heteroatom counterparts belong to the family of cage compounds. A subset of this extensive class of compounds includes dicarbadodecaboranes, which have the general formula C2B10H12, and their metal biscarboranyl complexes, metallacarboranes, with the formula [M(C2B10H12)2(-2)]. The unique properties of boron clusters have resulted in their utilization in applications such as in pharmacophores, as scaffolds in molecular construction, and as modulators of bioactive compounds. This Perspective presents an overview of the properties of boron clusters that are pertinent for drug discovery, recent applications in the design of various classes of drugs, and the potential use of boron clusters in the construction of new pharmaceuticals. PMID- 27124657 TI - Hypertension related knowledge and behaviour associated with awareness, treatment and control of hypertension in a rural hypertensive population: a community based, cross-sectional survey. AB - BACKGROUND AND OBJECTIVE: Hypertension-related knowledge and behaviour have been identified as influential factors associated with awareness, treatment and control of hypertension in urban regions. However, there were few studies on rural areas. This study aims to investigate whether hypertension related knowledge and behaviour were associated with hypertension awareness, treatment and control in Gaoyou, a rural area of Jiangsu province, China. METHODS: A cross sectional, population-based survey was conducted among hypertensive individuals in rural areas of Gaoyou, the south-eastern of China in 2010. We identified 1943 subjects with hypertension among 4536 subjects participated in this study and collected information about medical history, use of medication, hypertension related knowledge and behaviour by a standardized questionnaire. RESULTS: This study showed that 41.07% of subjects were aware of their disease, 30.01% of subjects were taking antihypertensive medication and 5.04% of subjects controlled their blood pressure. Multivariate logistic regression analysis showed that subjects who knew the threshold, the lifelong treatment of hypertension and measured blood pressure at least once a year had better detection, treatment or control of hypertension. CONCLUSION: Hypertension related knowledge and behaviour were associated with awareness, treatment and control rate of hypertension in the rural areas of south-eastern China. PMID- 27124659 TI - Triphenylsilane-fused Porphyrins. AB - A reaction sequence of 2-(diphenylsilyl)phenylation by Negishi coupling and intramolecular sila-Friedel-Crafts reaction has been explored for the synthesis of mono-triphenylsilane-fused porphyrins 5 M and 6 M (M= Ni, Zn) and bis triphenylsilane-fused porphyrins 7 M and 8 Ni. A triply linked triphenylsilane fused Ni(II) porphyrin, 13 Ni, was synthesized in a stepwise manner involving the above reaction sequence and a final Pd-catalyzed C-H activating arylative cyclization. The silicon atom in 13 Ni takes a distorted planarized structure with an almost perpendicular Si-phenyl group, causing an electronic effect due to effective sigma*-pi* interaction. PMID- 27124658 TI - Orthostatic Hypotension and Elevated Resting Heart Rate Predict Low-Energy Fractures in the Population: The Malmo Preventive Project. AB - BACKGROUND: Autonomic disorders of the cardiovascular system, such as orthostatic hypotension and elevated resting heart rate, predict mortality and cardiovascular events in the population. Low-energy-fractures constitute a substantial clinical problem that may represent an additional risk related to such autonomic dysfunction. AIMS: To test the association between orthostatic hypotension, resting heart rate and incidence of low-energy-fractures in the general population. METHODS AND RESULTS: Using multivariable-adjusted Cox regression models we investigated the association between orthostatic blood pressure response, resting heart rate and first incident low-energy-fracture in a population-based, middle-aged cohort of 33 000 individuals over 25 years follow up. The median follow-up time from baseline to first incident fracture among the subjects that experienced a low energy fracture was 15.0 years. A 10 mmHg orthostatic decrease in systolic blood pressure at baseline was associated with 5% increased risk of low-energy-fractures (95% confidence interval 1.01-1.10) during follow-up, whereas the resting heart rate predicted low-energy-fractures with an effect size of 8% increased risk per 10 beats-per-minute (1.05-1.12), independently of the orthostatic response. Subjects with a resting heart rate exceeding 68 beats-per-minute had 18% (1.10-1.26) increased risk of low-energy fractures during follow-up compared with subjects with a resting heart rate below 68 beats-per-minute. When combining the orthostatic response and resting heart rate, there was a 30% risk increase (1.08-1.57) of low-energy-fractures between the extremes, i.e. between subjects in the fourth compared with the first quartiles of both resting heart rate and systolic blood pressure-decrease. CONCLUSION: Orthostatic blood pressure decline and elevated resting heart rate independently predict low-energy fractures in a middle-aged population. These two measures of subclinical cardiovascular dysautonomia may herald increased risks many years in advance, even if symptoms may not be detectable. Although the effect sizes are moderate, the easily accessible clinical parameters of orthostatic blood pressure response and resting heart rate deserve consideration as new risk predictors to yield more accurate decisions on primary prevention of low-energy fractures. PMID- 27124660 TI - Antibacterial activity of Litsea cubeba (Lauraceae, May Chang) and its effects on the biological response of common carp Cyprinus carpio challenged with Aeromonas hydrophila. AB - AIMS: The aims of this study were to characterize the antibacterial activity and the chemotype of Litsea cubeba leaf essential oil (EO) harvested in North Vietnam and to investigate the biological effects induced by the leaf powder on growth, nonspecific immunity and survival of common carp (Cyprinus carpio) challenged with Aeromonas hydrophila. METHODS AND RESULTS: The EO showed the prevalence of linalool (95%, n = 5). It was bactericidal against the majority of tested strains, with minimum inhibitory concentrations ranging from 0.72 to 2.89 mg ml( 1) (Aer. hydrophila, Edwarsiella tarda, Vibrio furnissii, Vibrio parahaemolyticus, Streptococcus garvieae, Escherichia coli, Salmonella Typhimurium). The fish was fed with 0 (control), 2, 4 and 8% leaf powder supplementation diets for 21 days. Nonspecific immunity parameters (lysozyme, haemolytic and bactericidal activities of plasma) were assessed 21 days after feeding period and before the experimental infection. Weight gain, specific growth rate and feed conversion ratio were improved by supplementation of L. cubeba in a dose-related manner, and a significant difference appeared at the highest dose (8%) when compared to the control. The increase in plasma lysozyme was significant for all the treated groups. Haemolysis activity was higher for the groups fed with 4 and 8% plant powder. Antibacterial activity increased significantly for the 8% dose only. CONCLUSIONS: Litsea cubeba leaf powder increased nonspecific immunity of carps in dose-related manner. After infection with Aer. hydrophila, survivals of fish fed with 4 and 8% L. cubeba doses were significantly higher than those fed with 2% dose and the control. SIGNIFICANCE AND IMPACT OF THE STUDY: A range of 4-8% L. cubeba leaf powder supplementation diet (from specific linalool-rich chemotype) can be used in aquaculture to reduce antibiotic burden and impacts of diseases caused by Aer. hydrophila. PMID- 27124662 TI - Sonography interval and the diagnosis of twin-twin transfusion syndrome. AB - OBJECTIVE: To evaluate the relationship between sonography surveillance interval and Quintero stage at diagnosis. METHODS: This was a retrospective cohort study of monochorionic diamniotic pregnancies diagnosed with twin-twin transfusion syndrome (TTTS) and followed with serial sonography between 1997 and 2013. Women were divided into three cohorts: diagnosis at initial second-trimester sonogram, at a sonogram within 14 d of the prior exam, and at a sonogram greater than 14 d from the prior exam. Isolated amniotic fluid abnormalities were also recorded. RESULTS: TTTS was identified in 48 pregnancies, with 50% of cases diagnosed at the initial sonogram, 21% within 14 d of a prior sonogram, and 29% more than 14 d from a prior sonogram. There was no association between interval and TTTS stage at diagnosis. Of 24 cases diagnosed during a follow-up sonogram, 46% had an isolated amniotic fluid abnormality preceding diagnosis. When isolated oligohydramnios (29%) or hydramnios (17%) was present, the sonography interval was significantly shorter (p = 0.003), but no difference in TTTS stage at diagnosis was found. CONCLUSIONS: Although frequent surveillance of monochorionic diamniotic pregnancies is prudent, when close follow-up of isolated fluid abnormalities was practiced, we were unable to demonstrate an effect of surveillance interval on stage of TTTS at diagnosis. PMID- 27124661 TI - Liver-Specific Deletion of Phosphatase and Tensin Homolog Deleted on Chromosome 10 Significantly Ameliorates Chronic EtOH-Induced Increases in Hepatocellular Damage. AB - Alcoholic liver disease is a significant contributor to global liver failure. In murine models, chronic ethanol consumption dysregulates PTEN/Akt signaling. Hepatospecific deletion of phosphatase and tensin homolog deleted on chromosome 10 (PTENLKO) mice possess constitutive activation of Akt(s) and increased de novo lipogenesis resulting in increased hepatocellular steatosis. This makes PTENLKO a viable model to examine the effects of ethanol in an environment of preexisting steatosis. The aim of this study was to determine the impact of chronic ethanol consumption and the absence of PTEN (PTENLKO) compared to Alb-Cre control mice (PTENf/f) on hepatocellular damage as evidenced by changes in lipid accumulation, protein carbonylation and alanine amino transferase (ALT). In the control PTENf/f animals, ethanol significantly increased ALT, liver triglycerides and steatosis. In contrast, chronic ethanol consumption in PTENLKO mice decreased hepatocellular damage when compared to PTENLKO pair-fed controls. Consumption of ethanol elevated protein carbonylation in PTENf/f animals but had no effect in PTENLKO animals. In PTENLKO mice, overall hepatic mRNA expression of genes that contribute to GSH homeostasis as well as reduced glutathione (GSH) and oxidized glutathione (GSSG) concentrations were significantly elevated compared to respective PTENf/f counterparts. These data indicate that during conditions of constitutive Akt activation and steatosis, increased GSH homeostasis assists in mitigation of ethanol-dependent induction of oxidative stress and hepatocellular damage. Furthermore, data herein suggest a divergence in EtOH-induced hepatocellular damage and increases in steatosis due to polyunsaturated fatty acids downstream of PTEN. PMID- 27124664 TI - Reference ranges for cortisol and alpha-amylase in mother and newborn saliva samples at different perinatal and postnatal periods. AB - This paper describes a reliable analytical method based on Ultra High-Performance Liquid Chromatography coupled to tandem mass spectrometry to determine cortisol in saliva samples from healthy mothers (n=87) and newborns (n=65) at different time points: (i) 38 weeks of gestation, (ii) in the immediate postnatal period (48h) after a term delivery and, (iii) 3 months after delivery. The procedure is characterized by a simple sample treatment employing a sample volume of 25MUL. In addition to this, salivary alpha-amylase was determined using a commercial kit. We have proposed potential reference ranges in saliva for cortisol (0.7-35nmolL( 1)) and alpha-amylase (2-500UmL(-1)) in mothers, and for cortisol (0.1-56nmolL( 1)) and alpha-amylase (0.1-500UmL(-1)) in newborn infants. In addition, statistical differences between the two sensitive population groups (mothers and newborns) at the perinatal and postnatal periods were studied. A lower concentration for maternal cortisol was found at 38 weeks of gestation than at 48h (p=0.048) or 3 months after delivery (p=0.021). Similar results were found for the alpha-amylase determinations. Hence, higher concentrations than could be expected from a chronic stress marker were found at 3 months after delivery than at 38 weeks of gestation (p<0.001) or 48h after delivery (p<0.001). We conclude that this analytical method could be applied to further clinical research on perinatal and postnatal stress, such as threatened preterm labor and/or parenting stress, respectively. PMID- 27124663 TI - The wMel Strain of Wolbachia Reduces Transmission of Chikungunya Virus in Aedes aegypti. AB - BACKGROUND: New approaches to preventing chikungunya virus (CHIKV) are needed because current methods are limited to controlling mosquito populations, and they have not prevented the invasion of this virus into new locales, nor have they been sufficient to control the virus upon arrival. A promising candidate for arbovirus control and prevention relies on the introduction of the intracellular bacterium Wolbachia into Aedes aegypti mosquitoes. This primarily has been proposed as a tool to control dengue virus (DENV) transmission; however, evidence suggests Wolbachia infections confer protection for Ae. aegypti against CHIKV. Although this approach holds much promise for limiting virus transmission, at present our understanding of the ability of CHIKV to infect, disseminate, and be transmitted by wMel-infected Ae. aegypti currently being used at Wolbachia release sites is limited. METHODOLOGY/PRINCIPAL FINDINGS: Using Ae. aegypti infected with the wMel strain of Wolbachia that are being released in Medellin, Colombia, we report that these mosquitoes have reduced vector competence for CHIKV, even with extremely high viral titers in the bloodmeal. In addition, we examined the dynamics of CHIKV infection over the course of four to seven days post feeding. Wolbachia-infected mosquitoes remained non-infective over the duration of seven days, i.e., no infectious virus was detected in the saliva when exposed to bloodmeals of moderate viremia, but CHIKV-exposed, wild type mosquitoes did have viral loads in the saliva consistent with what has been reported elsewhere. Finally, the presence of wMel infection had no impact on the lifespan of mosquitoes as compared to wild type mosquitoes following CHIKV infection. CONCLUSIONS/SIGNIFICANCE: These results could have an impact on vector control strategies in areas where Ae. aegypti are transmitting both DENV and CHIKV; i.e., they argue for further exploration, both in the laboratory and the field, on the feasibility of expanding this technology beyond DENV. PMID- 27124665 TI - Breast Pain and the Perception of Associated Risk. PMID- 27124666 TI - Clinical utility of a novel ultrasonic vessel sealing device in transecting and sealing large vessels during laparoscopic hysterectomy using advanced hemostasis mode. AB - OBJECTIVE(S): The ultrasonic advanced energy study device (AH device) is the first surgical device indicated to seal vessels up to and including 7mm using ultrasonic technology alone. This study assesses clinical experience during total laparoscopic hysterectomy (TLH) using advanced hemostasis mode (AHM). STUDY DESIGN: This was a prospective, non-randomized, single arm, multicenter, observational study which did not modify or influence current surgeon technique for elective TLH for benign disease. Each surgeon assessed hemostasis, defined as the hemostatic transection of the uterine vasculature (left/right) with at least one use of the AH device in AHM without the use of additional hemostatic measures other than the AH device. Patients were followed for 4-6 weeks after surgery. Vessel sealing performance was quantitatively assessed for transection and sealing of the uterine artery (UA), the uterine pedicle (UP; defined as cases where the UA could not be 'isolated') and the ovarian pedicle (OP) (when indicated). Adverse events (AEs) related to the AH device or procedures were collected. RESULTS: Forty patients underwent the procedure. Mean age was 49 years and mean body mass index was 28kg/m(2). Mean surgical duration was 88min. None required conversion to open procedure. Using only the AH device, hemostasis was achieved and maintained in 119 (94.4%) transections (both left and right sides of the UA/UP and OP). Additional hemostasis was achieved in 5 patients using conventional bipolar (4) or monopolar (1) energy. No patient required a blood transfusion postoperatively. Only one adverse event of pain was considered to be related to the use of the ultrasonic AH device during this study. CONCLUSION: These results support that the AH device with its AHM has clinical utility in sealing named vessels in TLH. The new algorithm to deliver energy in the AHM has the potential to reduce the need for additional hemostatic devices or products as well as the potential to reduce the need for multiple instrument changes during surgery. PMID- 27124667 TI - Synthesis and DFT Study of a Diphenylsilanone-Bridged Dimolybdenum Complex. AB - Reaction of the 30-electron benzylidyne complex [Mo2 Cp2 (MU-CPh)(MU-PCy2 )(MU CO)] with excess Ph2 SiH2 under visible-UV irradiation yields the silylene bridged complex [Mo2 Cp2 (MU-CPh)(MU-PCy2 )(MU-SiPh2 )]. This compound undergoes selective oxidation with O2 to give the unsaturated complex [Mo2 Cp2 (MU-CPh)(MU PCy2 )(MU-kappa(1) :kappa(1) -OSiPh2 )], which contains an unprecedented bridging diphenylsilanone ligand, as confirmed by X-ray diffraction analysis and DFT calculations. The bonding within the central Mo2 SiO ring of this complex approaches the extreme description of a dimetallacyclosiloxane according to the relevant solid-state bond lengths and theoretical calculations. PMID- 27124668 TI - The safety of progestogen in the prevention of preterm birth: meta-analysis of neonatal mortality. AB - BACKGROUND: The safety of preventive progestogen therapy for preterm birth remains to be established. This meta-analysis aimed to evaluate the effects of preventive progestogen therapy on neonatal mortality. METHODS: Randomized controlled trials (RCTs) on the preventive use of progestogen therapy, published between October 1971 and November 2015, were identified by searching MEDLINE/PubMed, EMBASE, Scopus, ClinicalTrials.gov, Cochrane Library databases, CINAHL, POPLINE, and LILACS using "progesterone" and "preterm birth" as key terms. We conducted separate analyses according to the type of progestogen administered and plurality of the pregnancy. RESULTS: Twenty-two RCTs provided data on 11,188 neonates. Preventive progestogen treatment in women with a history of preterm birth or short cervical length was not associated with increased risk of neonatal death compared to placebo in all analyzed progestogen types and pregnancy conditions. The pooled relative risks (95% confidence interval) of neonatal mortality were 0.69 (0.31-1.54) for vaginal progestogen in singleton pregnancies, 0.6 (0.33-1.09) for intramuscular progestogen in singleton pregnancies, 0.96 (0.51-1.8) for vaginal progestogen in multiple pregnancies, and 0.96 (0.49-1.9) for intramuscular progestogen in multiple pregnancies. CONCLUSIONS: The results of this meta-analysis suggest that administration of preventive progestogen treatment to women at risk for preterm birth does not appear to negatively affect neonatal mortality in single or multiple pregnancies regardless of the route of administration. PMID- 27124669 TI - Differential immunophenotype of macrophages in acute and chronic chorioamnionitis. AB - AIM: The aim of this study was to investigate the involvement and immunophenotype of macrophages in acute chorioamnionitis (ACA) and chronic chorioamnionitis (CCA), marking amniotic fluid infection and anti-fetal rejection, respectively. METHODS: Chorioamniotic membranes from (1) gestational age-matched cases without chorioamnionitis, (2) cases with ACA, and (3) cases with CCA were studied after immunohistochemical staining using antibodies against CD14, CD68, CD163, and DC SIGN. RESULTS: Macrophages increased prominently in the chorionic trophoblastic layer of both ACA and CCA cases in contrast to non-inflammatory cases. Macrophages in the decidua and the chorioamniotic membranes of ACA cases expressed CD14. Macrophages in the chorionic trophoblastic layer of CCA cases were characterized by CD68 positivity. DC-SIGN-positive cells were increased in the chorioamniotic mesodermal layer of CCA cases. CONCLUSIONS: Macrophages participate in the inflammatory response in ACA and CCA. The differential immunophenotypes of macrophages in the decidua and chorioamniotic membranes of ACA and CCA cases suggest their disease-specific and region-specific roles at the feto-maternal interface. PMID- 27124670 TI - Maternal and perinatal outcomes in pregnancies with multiple sclerosis: a case control study. AB - OBJECTIVE: To assess whether maternal multiple sclerosis (MS) is associated with adverse pregnancy outcomes by determining the clinical course of disease during pregnancy and postpartum throughout a 10-year-period in a single tertiary center. METHODS: We conducted a case-control study that included pregnancies with a definitive diagnosis of MS (n=43), matched with 100 healthy pregnant women with similar characteristics. Maternal and perinatal data were retrieved from hospital files. Groups were compared with the Mann-Whitney and chi2 tests. Logistic regression models were constructed to determine independent effects. RESULTS: Maternal demographic and baseline laboratory data were similar across the groups. Rates of preterm delivery, fetal growth restriction, preeclampsia, gestational diabetes, stillbirth, cesarean delivery, congenital malformation, and 5-min Apgar score were comparable (P>0.05 for all). General anesthesia during cesarean delivery (96% vs. 39%, P=0.002), urinary tract infection (UTI) (12% vs. 3%, P=0.04), low 1-min Apgar score (21% vs. 9%, P=0.04), and nonbreastfeeding (33% vs. 2%, P=0.001) were more frequent in women with MS. The low 1-min Apgar score and breastfeeding rates were independent of general anesthesia and UTI in regression models. CONCLUSION: MS during pregnancy was not associated with adverse maternal and perinatal outcomes except UTI, low 1-min Apgar scores, and decreased breastfeeding rates. PMID- 27124672 TI - Sertoli cell only syndrome with ambiguous genitalia. AB - The Sertoli cell only syndrome (SCOS) is a rare genetic disorder with a variable phenotype ranging from a severe ambiguous genitalia to a normal male phenotype with infertility. SCOS is diagnosed on testicular histopathology as germ cells are absent without histological impairment of Sertoli or Leydig cells. The SRY positive XX male syndrome is usually diagnosed in adulthood during infertility investigations. Here, we report a rare case of 46,XX maleness with ambiguous genitalia due to Sertoli cell only syndrome (SCOS). PMID- 27124671 TI - Translation and psychometric properties of the Persian version of self-management of type 1 diabetes for adolescents. AB - BACKGROUND: The present study was conducted to translate and assess the validation of the measure of self-management of type 1 diabetes for adolescents that developed by Schilling et al [Schilling LS, Knafl KA, Grey M. Changing patterns of self-management in youth with type I diabetes. J Pediatr Nurs 2006;21:412-24]. METHODS: The first stage of the study involved the translation of the measure of self-management of type 1 diabetes for adolescents into Persian based on the model proposed by Wild et al. in two versions [Wild D, Grove A, Martin M, Eremenco S, McElroy S, et al. Principles of good practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) measures: report of the ISPOR task force for translation and cultural adaptation. Value Health 2005;8:94-104; Wild D, Eremenco S, Mear I, Martin M, Houchin C, et al. Multinational trials - recommendations on the translations required, approaches to using the same language in different countries, and the approaches to support pooling the data: the ISPOR patient-reported outcomes translation and linguistic validation good research practices task force report. Value Health 2009;12:430-40]. The translated versions were reviewed in consultation sessions with experts and the more appropriate items were selected and the final version was translated back into English in two versions and was then sent to the measure's designer for confirmation. The content validity of the measure was then evaluated by a group of experts and found to be acceptable. The next stage evaluated the measure's construct validity. This measure contains 52 items classified under five subscales. The confirmatory factor analysis was performed to assess the measure's construct validity and was found to be acceptable. For evaluating the reliability of the measure, its internal consistency was assessed through calculating its Cronbach's alpha and intra-class correlation. The measure's consistency was measured through calculating its test-retest reliability. RESULTS: The assessment of the measure's content validity revealed a content validity index of 0.98. For the construct validity of the measure using the confirmatory factor analysis, the following figures were obtained: NFI=0.97, RMSA=0.001, AGFI=0.81, IFI=0.833, GFI=0.83. In the assessment of the measure's reliability, the intra-class correlation showed an overall Cronbach's alpha of 0.88. The test-retest showed a consistency of 0.73 for the measure. CONCLUSIONS: The validation of the 48-item measure revealed that it can be used in the population of Iranian adolescents with type 1 diabetes (8 items changed their subscales and 4 items were removed). PMID- 27124673 TI - Phytochemicals as future drugs for Parkinson's disease: a comprehensive review. AB - Parkinson's disease (PD) is the second most common chronic neurodegenerative disease that affects motor skills and cognitive performance. The conventional therapeutic approaches for the management of PD are just able to alleviate symptoms. Exploring for achieving novel substances with therapeutic benefits in PD patients is the focus of a wide range of current investigations. The aim of the present study is to comprehensively review phytochemicals with protective or therapeutic activities in PD and focus on their neuropsychopharmacological mechanisms. Various subgroups of polyphenols (flavonoids, phenolic acids, stilbenes, and lignanes) and terpenes are the most abundant groups of phytochemicals with well-established antiparkinsonian effects. Other phytochemical categories, such as alkaloids, cinnamates, carbohydrates, amino acids, and fatty acid amides, also have some representatives with positive effects in PD. Phytochemicals perform their antiparkinsonian effect through several mechanisms of action, including suppressing apoptosis (via the reduction of Bax/Bcl-2, caspase-3, -8, and -9, and alpha-synuclein accumulation), decreasing dopaminergic neuronal loss and dopamine depletion, reducing the expression of proinflammatory cytokines (such as prostaglandin E2, interleukin-6, interleukin-1beta, and nuclear factor-kappaB), and modulating nuclear and cellular inflammatory signaling, elevation of neurotrophic factors, and improvement of antioxidant status. Plant-derived natural products can be considered as future pharmaceutical drugs or adjuvant treatment with conventional therapeutic approaches to improve their efficacy and alleviate their psychological adverse effects in the management of PD. Well-designed clinical trials are mandatory to evaluate the protective and healing benefits of phytochemicals as promising future drugs in the management of neurodegenerative diseases. PMID- 27124674 TI - Anxiolytic-like effect of the leaves of Pseudospondias microcarpa (A. Rich.) Engl. in mice. AB - BACKGROUND: Pseudospondias microcarpa is a plant used for managing various diseases including CNS disorders. Previous studies showed sedative and anticonvulsant effects, suggesting possible anxiolytic activity. This study therefore assessed the anxiolytic effects of P. microcarpa hydroethanolic leaf extract (PME) in mice. METHODS: In the present study, anxiolytic-like effect of the extract in behavioural paradigms of anxiety - the elevated plus maze (EPM), light/dark box (LDB), social interaction test and stress-induced hyperthermia (SIH) - was evaluated. RESULTS: Mice treated with PME (30-300 mg kg-1, p.o.) exhibited anxiolytic-like activity similar to diazepam in all the anxiety models used. The extract increased open arm activity (p<0.05) in the EPM as well as increasing the time spent in the lit area in relation to the time spent in the dark area of the LDB. Sociability and preference for social novelty significantly (p<0.05-0.001) increased in mice treated with PME. In the SIH paradigm in mice, both PME and the benzodiazepine receptor agonist, diazepam, significantly (p<0.05) reduced the stress-induced increase in rectal temperature. The extract did not impair motor coordination and balance in the beam walk test. CONCLUSIONS: Results of the present study indicate that PME possesses anxiolytic-like effects in mice. PMID- 27124675 TI - Nephrotoxicity of sodium valproate and protective role of L-cysteine in rats at biochemical and histological levels. AB - BACKGROUND: This study investigated whether the combination of sodium valproate (SV) with L-cysteine (LC) can decrease the SV toxicity of kidneys. SV caused alternation in oxidative/antioxidant balance. METHODS: Biochemical estimations included the determination of oxidative stress markers like thiobarbituric acid reactive substances in kidney tissue, and enzymatic antioxidant activities such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase as well as total antioxidant capacity were evaluated in renal tissues. Creatinine and uric acid levels in the serum were also determined to assess kidney function. Pathological examination of the kidney was also performed. RESULTS: Increasing the levels of lipid peroxidation and decreasing the enzymatic activity (SOD, CAT, and GPx) as well as total antioxidant capacity of rats was shown with different doses of SV. Impairment in renal function tests suggests a decreased glomerular filtration rate, as serum creatinine was elevated. Histopathological changes of kidney tissue treated with SV reveal the proximal and the distal convoluted tubules that show hydropic changes (small white vacuoles within the cytoplasm and the glomeruli show hypercellularity). CONCLUSIONS: The concurrent administration of LC with SV significantly had beneficial effects on the kidney and all the above parameters have been improved. PMID- 27124676 TI - Synthesis and in vitro anti-HIV-1 activity of a series of N-arylsulfonyl-3 propionylindoles. AB - Fifteen N-arylsulfonyl-3-propionylindoles (3a-o) were prepared and preliminarily evaluated as in vitro inhibitors of human immunodeficiency virus type-1 (HIV-1). Three compounds 3c, 3g and 3i exhibited potent anti-HIV-1 activity with effective concentration (EC(50)) values of 0.8, 4.0 and 1.2 MUg/mL, and therapeutic index (TI) values of 11.7, 16.6 and 84.1, respectively. N-(m-Nitro)phenylsulfonyl-3 propionyl-6-methylindole (3i) exhibited the most promising and best activity against HIV-1 replication. The cytotoxicity of these compounds was assessed as well. PMID- 27124677 TI - EDD1 predicts prognosis and regulates gastric cancer growth in vitro and in vivo via miR-22. AB - Gastric cancer is the most common digestive malignant tumor worldwild. EDD1 was reported to be frequently amplified in several tumors and played an important role in the tumorigenesis process. However, the biological role and potential mechanism of EDD1 in gastric cancer remains poorly understood. In this study, we are aim to investigate the effect of EDD1 on gastric cancer progression and to explore the underlying mechanism. The results showed the significant up regulation of EDD1 in -gastric cancer cell tissues and lines. The expression level of EDD1 was also positively associated with advanced clinical stages and predicted poor overall patient survival and poor disease-free patient survival. Besides, EDD1 knockdown markedly inhibited cell viability, colony formation, and suppressed tumor growth. Opposite results were obtained in gastric cancer cells with EDD1 overexpression. EDD1 knockdown was also found to induce gastric cancer cells apoptosis. Further investigation indicated that the oncogenic role of EDD1 in regulating gastric cancer cells growth and apoptosis was related to its PABC domain and directly through targeting miR-22, which was significantly down regulated in gastric cancer tissues. Totally, our study suggests that EDD1 plays an oncogenic role in gastric cancer and may be a potential therapeutic target for gastric cancer. PMID- 27124678 TI - Design of a Microfluidic Chip for Magnetic-Activated Sorting of One-Bead-One Compound Libraries. AB - Molecular targeting using ligands specific to disease markers has shown great promise for early detection and directed therapy. Bead-based combinatorial libraries have served as powerful tools for the discovery of novel targeting agents. Screening platforms employing magnetic capture have been used to achieve rapid and efficient identification of high-affinity ligands from one-bead-one compound (OBOC) libraries. Traditional manual methodologies to isolate magnetized "hit" beads are tedious and lack accuracy, and existing instruments to expedite bead sorting tend to be costly and complex. Here, we describe the design and construction of a simple and inexpensive microfluidic magnetic sorting device using standard photolithography and soft lithography approaches to facilitate high-throughput isolation of magnetized positive hit beads from combinatorial libraries. We have demonstrated that the device is able to sort magnetized beads with superior accuracy compared to conventional manual sorting approaches. This chip offers a very convenient yet inexpensive alternative for screening OBOC libraries. PMID- 27124679 TI - FDG PET/CT in Hepatoid Adenocarcinoma of the Lung. AB - A right upper lung mass was incidentally found on a chest radiograph in a routine health examination in a 56-year-old man. The mass showed mild heterogeneous enhancement on contrast chest CT images and intense FDG uptake on PET/CT images. Pathological examination demonstrated hepatoid adenocarcinoma in the lung. PMID- 27124681 TI - 18F-FDG PET/CT Imaging of Burkitt Lymphoma Presenting With Unusual Muscle Involvement. AB - Extranodal involvement is more common with Burkitt lymphoma (BL) than other subtypes of non-Hodgkin lymphoma in childhood. According to our knowledge, there are rare cases in the literature about muscle involvement of BL, and its F-FDG PET/CT findings were not well defined. We report a 6-year-old girl with a histopathologic diagnosis of BL and referred for staging with PET/CT. FDG-avid abdominal lymph nodes and diffuse involvements of right quadriceps muscle were demonstrated. PMID- 27124680 TI - Survival Analysis of Papillary Thyroid Carcinoma in Relation to Stage and Recurrence Risk: A 20-Year Experience in Pakistan. AB - OBJECTIVE: The aim of this study was to evaluate the overall and progression-free survival of papillary thyroid carcinoma (PTC), comparing the American Thyroid Association (ATA) guideline for risk of recurrence with the TNM staging system with dynamic assessment at 2 years. PATIENTS AND METHODS: This study is a retrospective analysis of 689 PTC patients over a 20-year period at a single center. Disease-free survival based on the TNM staging and ATA recurrence risk was calculated using Kaplan-Meier curves. Dynamic response assessment during the first 2 years was compared for both systems. Survival was calculated based on age, baseline resectability, and postthyroidectomy serum tumor marker levels. RESULTS: Six hundred eighty-nine (72.2%) of the total thyroid cancer patients had PTC. Four hundred sixty-nine patients were females, and 220 patients were males. The age range was 6 to 87 years. Five hundred thirty-five patients were resectable, and 56 patients were unresectable. One hundred fifty-one patients were excluded due to insufficient information on recurrence risk. By ATA categorization, 39% had low risk, no disease-related mortality; 44% had intermediate risk, 3 died; and 17% had high risk, 32 died. The 5-year disease free survival was 54%, 26%, and 5% in low-, intermediate-, and high-risk groups, respectively. The log-rank test showed a significant difference in the percent survival (P < 0.01). TNM stage wise, in terms of survival, 1.3% in stage I, 2.2% in stage II, 0% in stage III, and 37.5% in stage IV died. The 20-year disease free survival showed the following: stage I, 43%; stage II, 28%; stage III, 18%; and stage IV, 2%. There is significant difference in survival rate (P < 0.01). Both ATA risk classification and TNM staging were significant predictors of disease-free survival. On bivariate analysis, ATA classification (hazards ratio, 2.1; 95% confidence interval, 1.64-2.67; P = 0.001) was better predictive of overall survival versus TNM classification (hazards ratio, 1.3; 95% confidence interval, 1.11-1.43; P = 0.063). CONCLUSIONS: The ATA risk stratification and continuous reassessment during the first 2 years predicts disease-free survival better than the TNM staging. Age older than 45 years, unresectable disease, and elevated postthyroidectomy thyroglobulin levels dictate a poorer prognosis. PMID- 27124682 TI - Ovarian Hyperstimulation and Oocyte Harvesting Prior to Systemic Chemotherapy-A Possible Pitfall in 18F-FDG PET/CT Staging of Oncologic Patients. AB - A 33-year-old woman with Hodgkin disease Ann Arbor stage IIA underwent baseline F FDG PET/CT scanning. The scan showed gross multicystic enlargement of both ovaries and a nodule at the edge of the right ovary with intense FDG uptake (SUVmax = 14.8). Differential diagnosis would include ovarian lymphoma manifestation, endometrioma, and ovarian or pelvic neoplasia. However, chart analysis revealed previous superstimulation with gonadotropins and gonadotropin release hormone antagonist, and transvaginal oocyte retrieval the day before FDG PET/CT. This led to the diagnosis of ovarian hyperstimulation syndrome, with the FDG-avid focus representing a hemorrhagic follicle after transvaginal oocyte retrieval procedure. PMID- 27124683 TI - 18F-Fluorocholine PET/CT Finding of a Vertebral Hemangioma. AB - The uptake of F-fluorocholine (FCH), a radiopharmaceutical used to study patients with prostate cancer, follow both the phosphorylcholine and acetylcholine synthesis. FCH uptake is not specific of neoplastic cells because phospholipids are a structural constituent of the membrane of all cells. Thus, PET/CT with FCH show several areas of physiologic uptake. The skeleton concentrates only mild amounts of FCH, thus a diffuse faint uptake of the radiopharmaceutical is present at a PET/CT study. Herein we present the case of a patient in which PET/CT evidenced a sharply defined vertebral "cold" area of reduced FCH uptake corresponding to a vertebral hemangioma. PMID- 27124685 TI - Clinical Nuclear Medicine at 40. PMID- 27124684 TI - Incidental Detection of Subcutaneous Myopericytoma of Trunk on FDG PET/CT and Bone Scintigraphy for Imaging of Colon Cancer. AB - Myopericytoma is a rare type of unusual soft tissue tumor with perivascular myoid differentiation. A 53-year-old man with the diagnosis of colon cancer was referred to Tc-MDP bone scan and F-FDG PET/CT for staging. A subcutaneous mass located in right lower back with heterogeneous FDG uptake was detected on PET/CT. There was increased osteoblastic activity on MDP bone scan in the same region. Mass was resected and subsequently confirmed as myopericytoma by histopathology. PMID- 27124686 TI - High Prevalence of Antimicrobial-resistant Gram-negative Colonization in Hospitalized Cambodian Infants. AB - BACKGROUND: Antimicrobial-resistant Gram-negative infections are a significant cause of mortality in young infants. We aimed to determine characteristics of, and risk factors for, colonization and invasive infection caused by 3rd generation cephalosporin (3GC) or carbapenem-resistant organisms in outborn infants admitted to a neonatal unit (NU) in Cambodia. METHODS: During the first year of operation, patients admitted to the Angkor Hospital for Children NU, Siem Reap, Cambodia, underwent rectal swabbing on admission and twice weekly until discharge. Swabs were taken also from 7 environmental sites. Swabs were cultured to identify 3GC or carbapenem-resistant Acinetobacter sp., Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. RESULTS: The study included 333 infants with a median age at NU admission of 10 days (range, 0-43). Colonization by >=1 3GC-resistant organism was detected in 85.9% (286/333). Admission swabs were collected in 289 infants: 61.9% were colonized by a 3GC-resistant organism at the time of admission, and a further 23.2% were colonized during hospitalization, at a median of 4 days [95% confidence interval: 3-5]. Probiotic treatment (hazard ratio: 0.58; 95% confidence interval: 0.35-0.98) was associated with delayed colonization. Colonization by a carbapenem-resistant organism occurred in 25 (7.5%) infants. Six infants had NU-associated K. pneumoniae bacteremia; phenotypically identical colonizing strains were found in 3 infants. Environmental colonization occurred early. CONCLUSIONS: Colonization by antimicrobial-resistant Gram-negative organisms occurred early in hospitalized Cambodian infants and was associated with subsequent invasive infection. Trials of potential interventions such as probiotics are needed. PMID- 27124687 TI - Estimating Respiratory Syncytial Virus-associated Hospitalization in the First Year of Life Among Infants Born at 32-35 Weeks of Gestation. AB - BACKGROUND: Prophylaxis against respiratory syncytial virus-associated hospitalization (RSV-H) with anti-RSV monoclonal antibody is not considered cost effective for routine use in most jurisdictions. The aim of this study was to develop a scoring tool to estimate local risk of RSV-H in the first year of life among moderately premature infants to assist in prophylaxis decision making. METHODS: A retrospective cohort was constructed from population-based databases in Nova Scotia, Canada, to follow 32- to 35-week gestation infants from the prenatal period to <12 months of age, from 1998 to 2008. Potential risk factors were entered into the logistic regression model, where the dependent variable was RSV-H. Receiver operator characteristic analysis demonstrated cutoff scores producing the highest predictive accuracy, and the likelihood ratio test was used to select the final set of variables for the predictive tool. RESULTS: In 2811 eligible infants, the overall RSV-H rate was 3.1% (88/2811). Of 17 variables considered, 3 were used to create the scoring tool: birth during December to February, household smoke exposure and household crowding. The positive likelihood ratios of predictive tool scores for high, moderate and low of RSV-H were 3.57, 3.38 and 1.95, whereas posttest probabilities (risk of RSV-H) were 11.4%, 10.8% and 1.6%, respectively. CONCLUSIONS: While able to predict infants at low risk of RSV-H, the tool did not discriminate high from moderate risk infants. The tool could be used in anticipatory care to help educate families about reducing risk of serious RSV illness in their newborn. PMID- 27124688 TI - A Disassembly Strategy for Imaging Endogenous Pyrophosphate in Mitochondria by Using an Fe(III) -salen Complex. AB - Inorganic pyrophosphate (PPi) is produced from nucleoside triphosphates in important biosynthetic reactions and is considered a diagnostic marker for various diseases, such as cancer, crystal deposition disease, and arthritis. Traditional methods for biological PPi detection rely on off-line analytics after sample destruction. Molecular probes for imaging this biologically important analyte with temporal and spatial control in living cells are currently in demand. Herein, we report an Fe(III) -salen complex as the first small reaction based probe for endogenous mitochondrial PPi following a disassembly approach. Significantly, we successfully applied this complex for the detection of increased cellular PPi levels, and its performance was not affected by the presence of mitochondrial ATP in living cells. PMID- 27124689 TI - Quality improvement in the treatment of acute coronary syndrome patients. PMID- 27124690 TI - VISUAL VIGNETTE. PMID- 27124691 TI - FREQUENCY OF FLAME SENSOR ACTIVATION IN PUBLIC PLACES AFTER ADMINISTRATION OF RADIOACTIVE IODINE TO TREAT GRAVES DISEASE: A RECENT SURVEY. AB - OBJECTIVE: Ultraviolet (UV)-perception-type flame sensors detect gamma rays emitted from iodine 131 ((131)I). Explaining the possibility of flame sensor activation to patients when they receive (131)I to treat Graves disease or other ablative purposes is important. We investigate the current situation of flame sensor activation after radioactive iodine (RAI) therapy. METHODS: A total of 318 patients (65 males and 253 females) with Graves disease who received RAI therapy at our clinic between November 2007 and June 2014 participated in this study. Patients were given both written and oral explanations regarding the possibility of flame sensor activation. Participants were surveyed with a questionnaire. The following question was asked: "Did the fire alarm (flame sensor) go off when you used a restroom in places like shopping centers within a few days after your isotope therapy?" To those who answered "yes," we asked where the fire alarm had gone off. RESULTS: Of the 318 patients, 19 (6.0%) answered "yes," 2 of whom were male while 17 were female. Of the 299 (94.0%) patients who answered "no," 63 were male and 236 were female. As to the place of restroom sensor activation, shopping centers were reported by 9 patients; supermarkets by 5; airports by 2; and a bookstore, the Kyushu Shinkansen (bullet train), and a hospital by 1 each. CONCLUSION: Explaining to patients the possibility of flame sensor activation after RAI therapy is important to avoid some complications, especially in security-sensitive areas. ABBREVIATIONS: (131)I = iodine 131 RAI = radioactive iodine UV = ultra-violet. PMID- 27124692 TI - PREDICTORS OF NONATTENDANCE AT AN ENDOCRINOLOGY OUTPATIENT CLINIC. AB - OBJECTIVE: To identify predictors potentially contributing to patients' nonattendance or to same-day cancellation of scheduled appointments at an adult endocrinology office practice. METHODS: A retrospective, records-based, cross sectional study was conducted using data from 9,305 electronic medical records of patients presenting at a U.S. metropolitan adult endocrinology clinic in 2013. Statistical analyses included multivariate regression, calculated odds ratios, and posttest probabilities. RESULTS: Of 29,178 total patient visits analyzed, 68% were attended by patients. Of total scheduled appointments, 7% resulted in nonattendance and 5% in same-day cancellation. The most significant predictors of nonatten-dance were a previous history of nonattendance (P<.001), uncontrolled diabetes (P<.001), and new patients to the practice (P<.001). Long lead-time to appointment (P = .001), younger age (P<.001), and certain insurance carriers (P<.001) also were significant predictors. CONCLUSION: Specific predictors of nonattendance at scheduled appointments were identified using statistical analysis of electronic medical record data. Previous history of nonattendance and having uncontrolled diabetes (especially in patients newly referred to the practice) are among these significant predictors. Identifying specific predictors for nonattendance enables targeted strategies to be developed. ABBREVIATIONS: APRN = Advanced Practice Registered Nurse CI = confidence interval DM = diabetes mellitus EMR = electronic medical record HbA1c = glycated hemoglobin NS = no-show OR = odds ratio SDC = same-day cancellation. PMID- 27124693 TI - UTILITY OF A GLUCOCORTICOID SPARING STRATEGY IN THE MANAGEMENT OF PATIENTS FOLLOWING TRANSSPHENOIDAL SURGERY. AB - OBJECTIVE: Following transsphenoidal surgery (TSS), it is important to assess for and manage adrenal insufficiency (AI). The goal of this study is to assess the efficacy and safety of a glucocorticoid (GC) sparing protocol to limit GC exposure in patients undergoing TSS. METHODS: Adult patients undergoing TSS (excluding Cushing disease) with adequate adrenal function prior to surgery underwent TSS without perioperative GC coverage. Following TSS, daily morning fasting serum cortisol levels were tested. GCs were administered at stress doses for serum cortisol <5 mcg/dL, between 5 and 12 mcg/dL in the presence of clinically significant symptoms of AI, or >12 mcg/dL with severe headache, nausea or vomiting, fatigue, anorexia, or hyponatremia. The primary endpoint was the use of GCs in the immediate postoperative period. RESULTS: Of 178 subjects, GCs were administered to 80 (45%) patients for the following indications: 31.3% for serum cortisol <5 mcg/dL; 36.3% for cortisol between 5 and 12 mcg/dL accompanied by symptoms or signs of AI; 8.8% for moderate to severe postoperative hyponatremia; and 7.5% for severe headache, nausea and vomiting, fatigue, or anorexia with cortisol >12 mcg/dL. Logistic regression analysis showed that longer length of hospital stay (odds ratio [OR] 1.22, confidence interval [CI] 1.02-1.45) and the presence of new postoperative anterior pituitary hormone deficiency (OR 3.3, CI 1.26-8.67) were associated with postoperative GC use. By 12 weeks, only 14% of subjects remained on GCs. There were no adverse events related to withholding GCs. CONCLUSION: Our protocol for managing GC replacement is both safe and effective for limiting GC exposure in patients undergoing TSS. ABBREVIATIONS: AI = adrenal insufficiency CI = confidence interval FSH = follicle-stimulating hormone GC = glucocorticoid GH = growth hormone IGF-1 = insulin-like growth factor-1 IV = intravenous LH = luteinizing hormone LOS = length of hospital stay OR = odds ratio TSS = transsphenoidal surgery. PMID- 27124694 TI - RISK FACTORS FOR NONREMISSION AND PROGRESSION-FREE SURVIVAL AFTER I-131 THERAPY IN PATIENTS WITH LUNG METASTASIS FROM DIFFERENTIATED THYROID CANCER: A SINGLE INSTITUTE, RETROSPECTIVE ANALYSIS IN SOUTHERN CHINA. AB - OBJECTIVE: Prognostic factors related to progression-free survival (PFS) have not received much attention in the literature regarding iodine-131 ((131)I) therapy for patients with differentiated thyroid cancer and lung metastases. We sought to explore the factors associated with PFS and nonremission in a group of patients with differentiated thyroid cancer and pulmonary metastases at initial diagnosis and to investigate the impact of (131)I therapy on pulmonary function and peripheral blood counts in the same cohort of patients. METHODS: The medical records of 1,050 patients with differentiated thyroid cancer treated at the Zhujiang Hospital of Southern Medical University from January 2006 to January 2015 were retrospectively reviewed. Among them, 107 patients fulfilled the inclusion criteria. RESULTS: Multivariate Cox regression analysis indicated that age >=45 years and (131)I nonavidity were independent risk factors for disease progression. Multivariate logistic regression analysis revealed that pulmonary nodule size >=1 cm and (131)I nonavidity were the strongest risk factors predicting nonremission. Varying cumulative (131)I dosage had no association with posttreatment pulmonary function or peripheral blood cell counts. CONCLUSION: Similar to earlier studies, our results confirm that (131)I nonavidity was associated with an increased risk of disease progression and greater odds of nonremission. In addition, patients with differentiated thyroid cancer and lung metastases with pulmonary nodules >=1 cm had a reduced likelihood of achieving remission. Furthermore, special attention is needed when monitoring patients over 45 years at a higher risk of disease progression. ABBREVIATIONS: CI = confidence interval DTC = differentiated thyroid cancer (18)F-FDG = fluoro-18 fluorodeoxyglucose FEF = forced expiratory flow FTC = follicular thyroid cancer FVC = forced vital capacity GR = granulocytes Hb = hemoglobin HR = hazard ratio (131)I = iodine-131 LN = lymph node OR = odds ratio OS = overall survival PET/CT = positive positron emission tomography/computed tomography PFS = progression free survival PT = partial thyroidectomy PTC = papillary thyroid cancer RAI = radioactive iodine RBC = red blood cell Tg = thyroglobulin TgAb = thyroglobulin antibody TSH = thyroid-stimulating hormone TT = total thyroidectomy WBC = white blood cells WBS = whole body scan. PMID- 27124695 TI - INPATIENT HYPOGLYCEMIC EVENTS IN A COMPARATIVE EFFECTIVENESS TRIAL FOR GLYCEMIC CONTROL IN A HIGH-RISK POPULATION. AB - OBJECTIVE: Inpatient hypoglycemia (glucose <=70 mg/dL) is a limitation of intensive control with insulin. Causes of hypoglycemia were evaluated in a randomized controlled trial examining intensive glycemic control (IG, target 140 mg/dL) versus moderate glycemic control (MG, target 180 mg/dL) on post-liver transplant outcomes. METHODS: Hypoglycemic episodes were reviewed by a multidisciplinary team to calculate and identify contributing pathophysiologic and operational factors. A subsequent subgroup case control (1:1) analysis (with/without) hypoglycemia was completed to further delineate factors. A total of 164 participants were enrolled, and 155 patients were examined in depth. RESULTS: Overall, insulin-related hypoglycemia was experienced in 24 of 82 patients in IG (episodes: 20 drip, 36 subcutaneous [SQ]) and 4 of 82 in MG (episodes: 2 drip, 2 SQ). Most episodes occurred at night (41 of 60), with high insulin amounts (44 of 60), and during a protocol deviation (51 of 60). Compared to those without hypoglycemia (n = 127 vs. n = 28), hypoglycemic patients had significantly longer hospital stays (13.6 +/- 12.6 days vs. 7.4 +/- 6.1 days; P = .002), higher peak insulin drip rates (17.4 +/- 10.3 U/h vs. 13.1 +/- 9.9 U/h; P = .044), and higher peak insulin glargine doses (36.8 +/- 21.4 U vs. 26.2 +/- 24.3 U; P = .035). In the case-matched analysis (24 cases, 24 controls), those with insulin-related hypoglycemia had higher median peak insulin drip rates (17 U/h vs. 11 U/h; P = .04) and protocol deviations (92% vs. 50%; P = .004). CONCLUSION: Peak insulin requirements and protocol deviations were correlated with hypoglycemia. ABBREVIATIONS: DM = diabetes mellitus ICU = intensive care unit IG = intensive glycemic control MELD = Model for End-stage Liver Disease MG = moderate glycemic control SQ = subcutaneous. PMID- 27124696 TI - VISUAL VIGNETTE. PMID- 27124697 TI - Economic analysis of paliperidone long-acting injectable for chronic schizophrenia in Portugal. AB - OBJECTIVE: Patients with chronic schizophrenia suffer a huge burden, as do their families/caregivers. Treating schizophrenia is costly for health systems. The European Medicines Agency has approved paliperidone palmitate (PP-LAI; Xeplion), an atypical antipsychotic depot; however, its pharmacoeconomic profile in Portugal is unknown. A cost-effectiveness analysis was conducted from the viewpoint of the Portuguese National Health Service. METHODS: PP-LAI was compared with long acting injectables risperidone (RIS-LAI) and haloperidol (HAL-LAI) and oral drugs (olanzapine; oral-OLZ) adapting a 1-year decision tree to Portugal, guided by local experts. Clinical information and costs were obtained from literature sources and published lists. Outcomes included relapses (both requiring and not requiring hospitalization) and quality-adjusted life-years (QALYs). Costs were expressed in 2014 euros. Economic outcomes were incremental cost-effectiveness ratios (ICERs); including cost-utility (outcome = QALYs) and cost-effectiveness analyses (outcomes = relapse/hospitalization/emergency room (ER) visit avoided). RESULTS: The base-case cost of oral-OLZ was 4447? (20% drugs/20% medical/60% hospital); HAL-LAI cost 4474? (13% drugs/13% medical/74% hospital); PP-LAI cost 5326? (49% drugs/12% medical/39% hospital); RIS-LAI cost 6223? (44% drugs/12% medical/44% hospital). Respective QALYs/hospitalizations/ER visits were oral-OLZ: 0.761/0.615/0.242; HAL-LAI: 0.758/0.623/0.250; PP-LAI: 0.823/0.288/0.122; RIS-LAI: 0.799/0.394/0.168. HAL-LAI was dominated by oral-OLZ and RIS-LAI by PP-LAI for all outcomes. The ICER of PP-LAI over oral-OLZ was 14,247?/QALY, well below NICE/Portuguese thresholds (~24,800?/30,000?/QALY). ICERs were 1973?/relapse avoided and 2697?/hospitalization avoided. Analyses were robust against most variations in input values, as PP-LAI was cost-effective over oral-OLZ in >99% of 10,000 simulations. CONCLUSION: In Portugal, PP-LAI dominated HAL-LAI and RIS-LAI and was cost-effective over oral-OLZ with respect to QALYs gained, relapses avoided, and hospitalizations avoided. PMID- 27124698 TI - Effect of Commercial Enzymes on Berry Cell Wall Deconstruction in the Context of Intravineyard Ripeness Variation under Winemaking Conditions. AB - Significant intravineyard variation in grape berry ripening occurs within vines and between vines. However, no cell wall data are available on such variation. Here we used a checkerboard panel design to investigate ripening variation in pooled grape bunches for enzyme-assisted winemaking. The vineyard was dissected into defined panels, which were selected for winemaking with or without enzyme addition. Cell wall material was prepared and subjected to high-throughput profiling combined with multivariate data analysis. The study showed that significant ripening-related variation was present at the berry cell wall polymer level and occurred within the experimental vineyard block. Furthemore, all enzyme treatments reduced cell wall variation via depectination. Interestingly, cell wall esterification levels were unaffected by enzyme treatments. This study provides clear evidence that enzymes can positively influence the consistency of winemaking and provides a foundation for further research into the relationship between grape berry cell wall architecture and enzyme formulations. PMID- 27124699 TI - Deep Neural Networks as a Computational Model for Human Shape Sensitivity. AB - Theories of object recognition agree that shape is of primordial importance, but there is no consensus about how shape might be represented, and so far attempts to implement a model of shape perception that would work with realistic stimuli have largely failed. Recent studies suggest that state-of-the-art convolutional 'deep' neural networks (DNNs) capture important aspects of human object perception. We hypothesized that these successes might be partially related to a human-like representation of object shape. Here we demonstrate that sensitivity for shape features, characteristic to human and primate vision, emerges in DNNs when trained for generic object recognition from natural photographs. We show that these models explain human shape judgments for several benchmark behavioral and neural stimulus sets on which earlier models mostly failed. In particular, although never explicitly trained for such stimuli, DNNs develop acute sensitivity to minute variations in shape and to non-accidental properties that have long been implicated to form the basis for object recognition. Even more strikingly, when tested with a challenging stimulus set in which shape and category membership are dissociated, the most complex model architectures capture human shape sensitivity as well as some aspects of the category structure that emerges from human judgments. As a whole, these results indicate that convolutional neural networks not only learn physically correct representations of object categories but also develop perceptually accurate representational spaces of shapes. An even more complete model of human object representations might be in sight by training deep architectures for multiple tasks, which is so characteristic in human development. PMID- 27124700 TI - Clinical Genetic Testing in Gastroenterology. AB - Rapid advances in genetics have led to an increased understanding of the genetic determinants of human disease, including many gastrointestinal (GI) disorders. Coupled with a proliferation of genetic testing services, this has resulted in a clinical landscape where commercially available genetic tests for GI disorders are now widely available. In this review, we discuss the current status of clinical genetic testing for GI illnesses, review the available testing options, and briefly discuss indications for and practical aspects of such testing. Our goal is to familiarize the practicing gastroenterologist with this rapidly changing and important aspect of clinical care. PMID- 27124701 TI - Maintenance of Efficacy and Continuing Safety of Golimumab for Active Ulcerative Colitis: PURSUIT-SC Maintenance Study Extension Through 1 Year. AB - OBJECTIVES: The safety and efficacy of subcutaneous golimumab through 2 years of maintenance therapy was evaluated in patients with moderate-to-severe ulcerative colitis (UC). METHODS: Patients completing treatment through week 52 (placebo, golimumab 50, 100, every-4-weeks (q4w)) and evaluations at week 54 were eligible for this long-term extension (LTE) trial. Patients receiving placebo or golimumab 50 mg with worsening disease during the LTE could receive golimumab 100 mg. Efficacy assessments included the Mayo physician's global assessment (PGA) subscore, inflammatory bowel disease questionnaire (IBDQ), and corticosteroid use. Patients who were randomized to golimumab at PURSUIT-Maintenance baseline and continued receiving golimumab during the LTE were analyzed for efficacy (using intention-to-treat and "as observed" analyses; N=195) and safety (N=200). Patients treated with golimumab at any time from induction baseline through week 104 (N=1240) constituted the overall safety population. RESULTS: Baseline demographics and disease characteristics of patients entering the LTE receiving golimumab were similar to those of all patients randomized to golimumab maintenance at baseline. At week 104, 80.5% (157/195) of patients had a PGA=0/1 (range weeks 56-104: 80.5-91.8%) and 56.4% (110/195) had a PGA=0 (weeks 56-104: range: 53.8-58.5%). Through week 104, 86% of patients maintained inactive or mild disease activity. Among 174 corticosteroid-free patients at week 54, 88.5% remained corticosteroid-free at week 104. At week 104, 62.2% (120/193) had an IBDQ score >=170. Tuberculosis, opportunistic infection, and malignancy rates were low, and the overall safety profile was similar to that reported through week 54. Two non-melanoma skin cancers, one metastatic colon cancer, and two deaths (biventricular heart dysfunction, sepsis) occurred between weeks 54 and 104. CONCLUSION: Subcutaneous golimumab q4w through 2 years maintained clinical benefit and reduced corticosteroid use among patients who did well in the maintenance study. No new safety signals were observed. PMID- 27124702 TI - Synthesis and characterization of conductive, biodegradable, elastomeric polyurethanes for biomedical applications. AB - Biodegradable conductive polymers are currently of significant interest in tissue repair and regeneration, drug delivery, and bioelectronics. However, biodegradable materials exhibiting both conductive and elastic properties have rarely been reported to date. To that end, an electrically conductive polyurethane (CPU) was synthesized from polycaprolactone diol, hexadiisocyanate, and aniline trimer and subsequently doped with (1S)-(+)-10-camphorsulfonic acid (CSA). All CPU films showed good elasticity within a 30% strain range. The electrical conductivity of the CPU films, as enhanced with increasing amounts of CSA, ranged from 2.7 +/- 0.9 * 10(-10) to 4.4 +/- 0.6 * 10(-7) S/cm in a dry state and 4.2 +/- 0.5 * 10(-8) to 7.3 +/- 1.5 * 10(-5) S/cm in a wet state. The redox peaks of a CPU1.5 film (molar ratio CSA:aniline trimer = 1.5:1) in the cyclic voltammogram confirmed the desired good electroactivity. The doped CPU film exhibited good electrical stability (87% of initial conductivity after 150 hours charge) as measured in a cell culture medium. The degradation rates of CPU films increased with increasing CSA content in both phosphate-buffered solution (PBS) and lipase/PBS solutions. After 7 days of enzymatic degradation, the conductivity of all CSA-doped CPU films had decreased to that of the undoped CPU film. Mouse 3T3 fibroblasts proliferated and spread on all CPU films. This developed biodegradable CPU with good elasticity, electrical stability, and biocompatibility may find potential applications in tissue engineering, smart drug release, and electronics. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2305-2314, 2016. PMID- 27124704 TI - Complete Assignment of the Infrared Spectrum of the Gas-Phase Protonated Ammonia Dimer. AB - The infrared (IR) spectrum of the ammoniated ammonium dimer is more complex than those of the larger protonated ammonia clusters due to close-lying fundamental and combination bands and possible Fermi resonances (FR). To date, the only theoretical analysis involved partial dimensionality quantum nuclear dynamic simulations, assuming a symmetric structure (D3d) with the proton midway between the two nitrogen atoms. Here we report an extensive study of the less symmetric (C3v) dimer, utilizing both second order vibrational perturbation theory (VPT2) and ab initio molecular dynamics (AIMD), from which we calculated the Fourier transform (FT) of the dipole-moment autocorrelation function (DACF). The resultant IR spectrum was assigned using FTed velocity autocorrelation functions (VACFs) of several interatomic distances and angles. At 50 K, we have been able to assign all 21 AIMD fundamentals, in reasonable agreement with MP2-based VPT2, about 30 AIMD combination bands, and a difference band. The combinations involve a wag or the NN stretch as one of the components, and appear to follow symmetry selection rules. On this basis, we suggest possible assignments of the experimental spectrum. The VACF-analysis revealed two possible FR bands, one of which is the strongest peak in the computed spectrum. Raising the temperature to 180 K eliminated the "proton transfer mode" (PTM) fundamental, and reduced the number of observed combination bands and FRs. With increasing temperature, fundamentals red-shift, and the doubly degenerate wags exhibit larger anharmonic splittings in their VACF bending spectra. We have repeated the analysis for the H3ND(+)NH3 isotopologue, finding that it has a simplified spectrum, with all the strong peaks being fundamentals. Experimental study of this isotopologue may thus provide a good starting point for disentangling the N2H7(+) spectrum. PMID- 27124703 TI - A systematic literature review and network meta-analysis of treatments for patients with untreated multiple myeloma not eligible for stem cell transplantation. AB - In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting. PMID- 27124705 TI - A case of scurvy associated with nilotinib. PMID- 27124706 TI - Reduced Disparities in Birth Rates Among Teens Aged 15-19 Years - United States, 2006-2007 and 2013-2014. AB - Teen childbearing can have negative health, economic, and social consequences for mothers and their children (1) and costs the United States approximately $9.4 billion annually (2). During 1991-2014, the birth rate among teens aged 15-19 years in the United States declined 61%, from 61.8 to 24.2 births per 1,000, the lowest rate ever recorded (3). Nonetheless, in 2014, the teen birth rate remained approximately twice as high for Hispanic and non-Hispanic black (black) teens compared with non-Hispanic white (white) teens (3), and geographic and socioeconomic disparities remain (3,4), irrespective of race/ethnicity. Social determinants associated with teen childbearing (e.g., low parental educational attainment and limited opportunities for education and employment) are more common in communities with higher proportions of racial and ethnic minorities (4), contributing to the challenge of further reducing disparities in teen births. To examine trends in births for teens aged 15-19 years by race/ethnicity and geography, CDC analyzed National Vital Statistics System (NVSS) data at the national (2006-2014), state (2006-2007 and 2013-2014), and county (2013-2014) levels. To describe socioeconomic indicators previously associated with teen births, CDC analyzed data from the American Community Survey (ACS) (2010-2014). Nationally, from 2006 to 2014, the teen birth rate declined 41% overall with the largest decline occurring among Hispanics (51%), followed by blacks (44%), and whites (35%). The birth rate ratio for Hispanic teens and black teens compared with white teens declined from 2.9 to 2.2 and from 2.3 to 2.0, respectively. From 2006-2007 to 2013-2014, significant declines in teen birth rates and birth rate ratios were noted nationally and in many states. At the county level, teen birth rates for 2013-2014 ranged from 3.1 to 119.0 per 1,000 females aged 15-19 years; ACS data indicated unemployment was higher, and education attainment and family income were lower in counties with higher teen birth rates. State and county data can be used to understand disparities in teen births and implement community level interventions that address the social and structural conditions associated with high teen birth rates. PMID- 27124707 TI - Inhibition of calcium carbonate deposition on stainless steel using olive leaf extract as a green inhibitor. AB - The antiscale properties of the aqueous extract of olive (Olea europaea L.) leaves as a natural scale inhibitor for stainless steel surface in Hammam raw water were investigated using chronoamperometry (CA) and electrochemical impedance spectroscopy techniques in conjunction with a microscopic examination. The X-ray diffraction analysis reveals that the scale deposited over the pipe walls consists of pure CaCO3 calcite. The CA, in accordance with electrochemical impedance spectra and scanning electron microscopy, shows that the inhibition efficiency increases with increasing extract concentration. This efficiency is considerably reduced as the temperature is increased. PMID- 27124708 TI - Two-layer regulation of PAQR3 on ATG14-linked class III PtdIns3K activation upon glucose starvation. AB - As a central node of the macroautophagy/autophagy process, the BECN1/Beclin1 PIK3C3/VPS34 complex participates in different steps of autophagy by interacting with multiple molecules. The ATG14-associated PIK3C3 complex is involved in autophagy initiation, whereas the UVRAG-associated complex mainly modulates autophagosome maturation and endosome fusion. However, the molecular mechanism that coordinates the sequential execution of the autophagy program remains unknown. We have recently discovered that a Golgi-resident protein, PAQR3, regulates autophagy initiation as it preferentially facilitates the formation of the ATG14-linked PIK3C3 complex instead of the UVRAG-associated complex. Upon glucose starvation, AMPK directly phosphorylates T32 of PAQR3, which is crucial for the activation of the ATG14-associated class III PtdIns3K. Furthermore, Paqr3 deleted mice have a deficiency in exercise-induced autophagy as well as behavioral disorders. Thus, this work not only uncovers the regulatory mechanism of PAQR3 on autophagy initiation, but also provides a potential candidate therapeutic target for neurodegenerative diseases. PMID- 27124710 TI - Violence in Gaza: An Academic-Activist Agenda for Health Communication. PMID- 27124709 TI - Synthesis and Kinetic Characterisation of Water-Soluble Fluorogenic Acyl Donors for Transglutaminase 2. AB - Small glutamate-containing peptides bearing coumarin derivatives as fluorescent leaving groups attached to the gamma-carboxylic acid group of the Glu residue were synthesised and investigated with regard to their potential to act as substrates for transglutaminase 2 (TGase 2). Their synthesis was accomplished by an efficient solid-phase approach. The excellent water solubility of the compounds enabled their extensive kinetic characterisation in the context of TGase 2-catalysed hydrolysis and aminolysis. The influence of the coumarin skeleton's substitution pattern on the kinetic properties was studied. Derivatives containing 7-hydroxy-4-methylcoumarin (HMC) revealed properties superior to those of their 7-hydroxycoumarin counterparts; analogous amides are not accepted as substrates. Z-Glu(HMC)-Gly-OH, which exhibited the best substrate properties out of the investigated derivatives, was selected for representative kinetic characterisation of acyl acceptor substrates and irreversible inhibitors. PMID- 27124711 TI - Primary Palliative Care Education in Specialty Oncology Training: More Work Is Needed. PMID- 27124712 TI - Proptosis Secondary to Orbital Bone Remodeling From Intracranial Hypertension. PMID- 27124713 TI - Loneliness over time: The crucial role of social anxiety. AB - Loneliness is known to be associated with multiple adverse physical outcomes, including higher mortality and morbidity risk. However, the impact of loneliness on mental health is less well researched, with most studies assessing how loneliness relates to depressive symptoms alone. We hypothesized that 2 mental health symptoms that relate to the fear of others-social anxiety and paranoia would contribute to loneliness. We examined how loneliness relates to social anxiety, paranoia, and depression symptoms in a general community sample aged 18 87 years old (N = 1,010). We administered online measures over 3 time points across a 6-month period. In a cross-lagged structural equation model controlling for trait levels and prior states, our results indicated that earlier loneliness positively predicted future states of social anxiety, paranoia, and depression. However, in the same model, earlier social anxiety was the only predictor of future loneliness. These results suggest that loneliness may be a potential antecedent to emerging mental health symptoms and that identifying and treating co-occurring social anxiety symptoms may reduce the severity of loneliness. (PsycINFO Database Record PMID- 27124714 TI - Sensation seeking, peer deviance, and genetic influences on adolescent delinquency: Evidence for person-environment correlation and interaction. AB - Both sensation seeking and affiliation with deviant peer groups are risk factors for delinquency in adolescence. In this study, we use a sample of adolescent twins (n = 549), 13 to 20 years old (M age = 15.8 years), in order to test the interactive effects of peer deviance and sensation seeking on delinquency in a genetically informative design. Consistent with a socialization effect, affiliation with deviant peers was associated with higher delinquency even after controlling for selection effects using a co-twin-control comparison. At the same time, there was evidence for person-environment correlation; adolescents with genetic dispositions toward higher sensation seeking were more likely to report having deviant peer groups. Genetic influences on sensation seeking substantially overlapped with genetic influences on adolescent delinquency. Finally, the environmentally mediated effect of peer deviance on adolescent delinquency was moderated by individual differences in sensation seeking. Adolescents reporting high levels of sensation seeking were more susceptible to deviant peers, a Person * Environment interaction. These results are consistent with both selection and socialization processes in adolescent peer relationships, and they highlight the role of sensation seeking as an intermediary phenotype for genetic risk for delinquency. (PsycINFO Database Record PMID- 27124715 TI - Additive genetic contribution to symptom dimensions in major depressive disorder. AB - Major depressive disorder (MDD) is a phenotypically heterogeneous disorder with a complex genetic architecture. In this study, genomic-relatedness-matrix restricted maximum-likelihood analysis (GREML) was used to investigate the extent to which variance in depression symptoms/symptom dimensions can be explained by variation in common single nucleotide polymorphisms (SNPs) in a sample of individuals with MDD (N = 1,558) who participated in the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A principal components analysis of items from the Hamilton Rating Scale for Depression (HRSD) obtained prior to treatment revealed 4 depression symptom components: (a) appetite, (b) core depression symptoms (e.g., depressed mood, anhedonia), (c) insomnia, and (d) anxiety. These symptom dimensions were associated with SNP-based heritability (hSNP2) estimates of 30%, 14%, 30%, and 5%, respectively. Results indicated that the genetic contribution of common SNPs to depression symptom dimensions were not uniform. Appetite and insomnia symptoms in MDD had a relatively strong genetic contribution whereas the genetic contribution was relatively small for core depression and anxiety symptoms. While in need of replication, these results suggest that future gene discovery efforts may strongly benefit from parsing depression into its constituent parts. (PsycINFO Database Record PMID- 27124717 TI - Layered Double Hydroxide Nanoclusters: Aqueous, Concentrated, Stable, and Catalytically Active Colloids toward Green Chemistry. AB - Increasing attention has been dedicated to the development of nanomaterials rendering green and sustainable processes, which occur in benign aqueous reaction media. Herein, we demonstrate the synthesis of another family of green nanomaterials, layered double hydroxide (LDH) nanoclusters, which are concentrated (98.7 g/L in aqueous solvent), stably dispersed (transparent sol for >2 weeks), and catalytically active colloids of nano LDHs (isotropic shape with the size of 7.8 nm as determined by small-angle X-ray scattering). LDH nanoclusters are available as colloidal building blocks to give access to meso- and macroporous LDH materials. Proof-of-concept applications revealed that the LDH nanocluster works as a solid basic catalyst and is separable from solvents of catalytic reactions, confirming the nature of nanocatalysts. The present work closely investigates the unique physical and chemical features of this colloid, the formation mechanism, and the ability to act as basic nanocatalysts in benign aqueous reaction systems. PMID- 27124716 TI - Obesity and Mortality, Length of Stay and Hospital Cost among Patients with Sepsis: A Nationwide Inpatient Retrospective Cohort Study. AB - OBJECTIVES: The objective of this study was to examine the association between obesity and all-cause mortality, length of stay and hospital cost among patients with sepsis 20 years of age or older. MATERIALS AND METHODS: It was a retrospective cohort study. The dataset was the Nationwide Inpatient Sample 2011, the largest publicly available all-payer inpatient care database in the United States. Hospitalizations of sepsis patients 20 years of age or older were included. All 25 primary and secondary diagnosis fields were screened to identify patients with sepsis using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Obesity was the exposure of interest. It was one of the 29 standardized Elixhauser comorbidity measures and readily available in the dataset as a dichotomized variable. The outcome measures were all-cause in-hospital death, length of stay and hospital cost. RESULTS: After weighting, our sample projected to a population size of 1,763,000, providing an approximation for the number of hospital discharges of all sepsis patients 20 years of age or older in the US in 2011. The overall all-cause mortality rate was 14.8%, the median hospital length of stay was 7 days and the median hospital cost was $15,917. After adjustment, the all-cause mortality was lower (adjusted OR = 0.84; 95% CI = 0.81 to 0.88); the average hospital length of stay was longer (adjusted difference = 0.65 day; 95% CI = 0.44 to 0.86) and the hospital cost per stay was higher (adjusted difference = $2,927; 95% CI = $1,606 to $4,247) for obese sepsis patients as compared to non-obese ones. CONCLUSION: With this large and nationally representative sample of over 1,000 hospitals in the US, we found that obesity was significantly associated with a 16% decrease in the odds of dying among hospitalized sepsis patients; however it was also associated with greater duration and cost of hospitalization. PMID- 27124719 TI - Polymeric Inverse Glasses for Development of Noniridescent Structural Colors in Full Visible Range. AB - Amorphous colloidal array with short-range order displays noniridescent structural colors due to the isotropic nature of the colloidal arrangement. The low angle dependence renders the colloidal glasses, which is promising for various coloration applications. Nevertheless, the colloidal glasses are difficult to develop red structural color due to strong cavity-like resonance from individual particles in the blue region. To suppress the cavity mode and develop the colors in the full visible range, we prepare inverse glasses composed of amorphous array of air cavities with short-range order. To produce the structures in a simple and reproducible manner, monodisperse silica particles are dispersed in a photocurable resin of poly(ethylene glycol) dimethacrylate (PEGDMA) at a volume fraction of 0.3. The particles spontaneously form the amorphous array with short-range order, which is rapidly captured in polymeric films by photopolymerization of the resin. Selective removal of silica particles from the polymerized resin leaves behind amorphous array of air cavities. The inverse glasses display structural colors with negligible backscattering in blue due to short optical path and low index in each cavity. Therefore, the colors can be tuned in full visible range by simply controlling the cavity size. The photocurable suspensions of silica particles can be patterned by photolithography, which enables the production of freestanding films containing patterned inverse glasses with noniridescent structural colors. PMID- 27124718 TI - Replaced gastroduodenal artery: Added benefit of the "artery first" approach during pancreaticoduodenectomy-A case report. AB - INTRODUCTION: Variations in hepatic arterial anatomy are frequently encountered in pancreas and liver surgery. These aberrancies add technical complexity to the procedure and can result in significant patient morbidity if these vascular nuances are not recognized. PRESENTATION OF CASE: We report a case whereby a superior mesenteric artery first approach was used to locate and preserve an aberrant left hepatic artery arising from a replaced gastroduodenal artery emanating from the SMA during pancreaticoduodenectomy. The procedure was done for resection of a large duodenal adenoma. DISCUSSION: High-quality preoperative imaging and mastery in surgical expertise are requirements for identification and preservation of aberrant hepatic arterial anatomy during procedures involving vital intra-abdominal organs. CONCLUSION: Our aim is to provide awareness of rare vascular anomalies encountered during pancreaticoduodenectomy and provide a unique method for successful management. PMID- 27124721 TI - Correction: Regioselectivity in the Au-catalyzed hydration and hydroalkoxylation of alkynes. AB - Correction for 'Regioselectivity in the Au-catalyzed hydration and hydroalkoxylation of alkynes' by Justin A. Goodwin et al., Chem. Commun., 2015, 51, 8730-8741. PMID- 27124720 TI - Effects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes. AB - Exhaustive exercise can cause a transient depression of immune function. Data indicate significant effects of immune activation cascades on the biochemistry of monoamines and amino acids such as tryptophan. Tryptophan can be metabolized through different pathways, a major route being the kynurenine pathway, which is often systemically up-regulated when the immune response is activated. The present study was undertaken to examine the effect of exhaustive aerobic exercise on biomarkers of immune activation and tryptophan metabolism in trained athletes. After a standardized breakfast 2 h prior to exercise, 33 trained athletes (17 women, 16 men) performed an incremental cycle ergometer exercise test at 60 rpm until exhaustion. After a 20 min rest phase, the participants performed a 20 min maximal time-trial on a cycle ergometer (RBM Cyclus 2, Germany). During the test, cyclists were strongly encouraged to choose a maximal pedalling rate that could be maintained for the respective test duration. Serum concentrations of amino acids tryptophan, kynurenine, phenylalanine, and tyrosine were determined by HPLC and immune system biomarker neopterin by ELISA at rest and immediately post exercise. Intense exercise was associated with a strong increase in neopterin concentrations (p<0.001), indicating increased immune activation following intense exercise. Exhaustive exercise significantly reduced tryptophan concentrations by 12% (p<0.001) and increased kynurenine levels by 6% (p = 0.022). Also phenylalanine to tyrosine ratios were lower after exercise as compared with baseline (p<0.001). The kynurenine to tryptophan ratio correlated with neopterin (r = 0.560, p<0.01). Thus, increased tryptophan catabolism by indoleamine 2,3-dioxygenase appears likely. Peak oxygen uptake correlated with baseline tryptophan and kynurenine concentrations (r = 0.562 and r = 0.511, respectively, both p<0.01). Findings demonstrate that exhaustive aerobic exercise is associated with increased immune activation and alterations in monoamine metabolism in trained athletes which may play a role in the regulation of mood and cognitive processes. PMID- 27124722 TI - Nanovalved Adsorbents for CH4 Storage. AB - A novel concept of utilizing nanoporous coatings as effective nanovalves on microporous adsorbents was developed for high capacity natural gas storage at low storage pressure. The work reported here for the first time presents the concept of nanovalved adsorbents capable of sealing high pressure CH4 inside the adsorbents and storing it at low pressure. Traditional natural gas storage tanks are thick and heavy, which makes them expensive to manufacture and highly energy consuming to carry around. Our design uses unique adsorbent pellets with nanoscale pores surrounded by a coating that functions as a valve to help manage the pressure of the gas and facilitate more efficient storage and transportation. We expect this new concept will result in a lighter, more affordable product with increased storage capacity. The nanovalved adsorbent concept demonstrated here can be potentially extended for the storage of other important gas molecules targeted for diverse relevant functional applications. PMID- 27124723 TI - Decision-Making under Ambiguity Is Modulated by Visual Framing, but Not by Motor vs. Non-Motor Context. Experiments and an Information-Theoretic Ambiguity Model. AB - A number of recent studies have investigated differences in human choice behavior depending on task framing, especially comparing economic decision-making to choice behavior in equivalent sensorimotor tasks. Here we test whether decision making under ambiguity exhibits effects of task framing in motor vs. non-motor context. In a first experiment, we designed an experience-based urn task with varying degrees of ambiguity and an equivalent motor task where subjects chose between hitting partially occluded targets. In a second experiment, we controlled for the different stimulus design in the two tasks by introducing an urn task with bar stimuli matching those in the motor task. We found ambiguity attitudes to be mainly influenced by stimulus design. In particular, we found that the same subjects tended to be ambiguity-preferring when choosing between ambiguous bar stimuli, but ambiguity-avoiding when choosing between ambiguous urn sample stimuli. In contrast, subjects' choice pattern was not affected by changing from a target hitting task to a non-motor context when keeping the stimulus design unchanged. In both tasks subjects' choice behavior was continuously modulated by the degree of ambiguity. We show that this modulation of behavior can be explained by an information-theoretic model of ambiguity that generalizes Bayes optimal decision-making by combining Bayesian inference with robust decision making under model uncertainty. Our results demonstrate the benefits of information-theoretic models of decision-making under varying degrees of ambiguity for a given context, but also demonstrate the sensitivity of ambiguity attitudes across contexts that theoretical models struggle to explain. PMID- 27124725 TI - A Comparative Analysis of the Financial Incentives of Two Distinct Experience Rating Programs. AB - OBJECTIVES: The aim of this study was to compare the association between insurance premium incentives and claim outcomes in two different workers' compensation programs. METHODS: Regression models were run for claim outcomes using data from two Canadian jurisdictions with different experience-rating programs-one with prospective (British Columbia) and another with retrospective (Ontario) adjustment of premiums. Key explanatory variables were past premium adjustments. RESULTS: For both programs, past premium adjustments were significantly associated with claim outcomes, suggesting adjustments provided incentives for claims reduction. The magnitudes of effects in the prospective program were smaller than the retrospective one, though relative persistence of effects over time was larger. CONCLUSION: Having large and immediate employer responses to incentives may appear desirable, but insurers should consider the time required for employers to improve and sustain good practices, and create incentives that parallel such time lines. PMID- 27124724 TI - In Heart Failure Patients with Left Bundle Branch Block Single Lead MultiSpot Left Ventricular Pacing Does Not Improve Acute Hemodynamic Response To Conventional Biventricular Pacing. A Multicenter Prospective, Interventional, Non Randomized Study. AB - INTRODUCTION: Recent efforts to increase CRT response by multiSPOT pacing (MSP) from multiple bipols on the same left ventricular lead are still inconclusive. AIM: The Left Ventricular (LV) MultiSPOTpacing for CRT (iSPOT) study compared the acute hemodynamic response of MSP pacing by using 3 electrodes on a quadripolar lead compared with conventional biventricular pacing (BiV). METHODS: Patients with left bundle branch block (LBBB) underwent an acute hemodynamic study to determine the %change in LV+dP/dtmax from baseline atrial pacing compared to the following configurations: BiV pacing with the LV lead in a one of lateral veins, while pacing from the distal, mid, or proximal electrode and all 3 electrodes together (i.e. MSP). All measurements were repeated 4 times at 5 different atrioventricular delays. We also measured QRS-width and individual Q-LV durations. RESULTS: Protocol was completed in 24 patients, all with LBBB (QRS width 171+/-20 ms) and 58% ischemic aetiology. The percentage change in LV+dP/dtmax for MSP pacing was 31.0+/-3.3% (Mean+/-SE), which was not significantly superior to any BiV pacing configuration: 28.9+/-3.2% (LV-distal), 28.3+/-2.7% (LV-mid), and 29.5+/-3.0% (LV-prox), respectively. Correlation between LV+dP/dtmax and either QRS-width or Q-LV ratio was poor. CONCLUSIONS: In patients with LBBB MultiSPOT LV pacing demonstrated comparable improvement in contractility to best conventional BiV pacing. Optimization of atrioventricular delay is important for the best performance for both BiV and MultiSPOT pacing configurations. TRIAL REGISTRATION: ClinicalTrials.gov NTC01883141. PMID- 27124726 TI - DNMT targets MiRacle torching TORCh. PMID- 27124728 TI - beta-to-beta 2,5-Pyrrolylene-Linked Cyclic Porphyrin Oligomers. AB - beta-to-beta 2,5-Pyrrolylene linked cyclic porphyrin oligomers have been synthesized by Suzuki-Miyaura coupling of 2,5-diborylpyrrole and 3,7 dibromoporphyrin. The cyclic porphyrin oligomers exhibit roughly coplanar structures, strong excitonic coupling, small electrochemical HOMO-LUMO gaps, and ultrafast excitation energy transfer between the neighboring porphyrins via the pyrrolylene bridge. PMID- 27124729 TI - Implications of Harvest on the Boundaries of Protected Areas for Large Carnivore Viewing Opportunities. AB - The desire to see free ranging large carnivores in their natural habitat is a driver of tourism in protected areas around the globe. However, large carnivores are wide-ranging and subject to human-caused mortality outside protected area boundaries. The impact of harvest (trapping or hunting) on wildlife viewing opportunities has been the subject of intense debate and speculation, but quantitative analyses have been lacking. We examined the effect of legal harvest of wolves (Canis lupus) along the boundaries of two North American National Parks, Denali (DNPP) and Yellowstone (YNP), on wolf viewing opportunities within the parks during peak tourist season. We used data on wolf sightings, pack sizes, den site locations, and harvest adjacent to DNPP from 1997-2013 and YNP from 2008 2013 to evaluate the relationship between harvest and wolf viewing opportunities. Although sightings were largely driven by wolf population size and proximity of den sites to roads, sightings in both parks were significantly reduced by harvest. Sightings in YNP increased by 45% following years with no harvest of a wolf from a pack, and sightings in DNPP were more than twice as likely during a period with a harvest buffer zone than in years without the buffer. These findings show that harvest of wolves adjacent to protected areas can reduce sightings within those areas despite minimal impacts on the size of protected wolf populations. Consumptive use of carnivores adjacent to protected areas may therefore reduce their potential for non-consumptive use, and these tradeoffs should be considered when developing regional wildlife management policies. PMID- 27124727 TI - Transformed Recombinant Enrichment Profiling Rapidly Identifies HMW1 as an Intracellular Invasion Locus in Haemophilus influenza. AB - Many bacterial species actively take up and recombine homologous DNA into their genomes, called natural competence, a trait that offers a means to identify the genetic basis of naturally occurring phenotypic variation. Here, we describe "transformed recombinant enrichment profiling" (TREP), in which natural transformation is used to generate complex pools of recombinants, phenotypic selection is used to enrich for specific recombinants, and deep sequencing is used to survey for the genetic variation responsible. We applied TREP to investigate the genetic architecture of intracellular invasion by the human pathogen Haemophilus influenzae, a trait implicated in persistence during chronic infection. TREP identified the HMW1 adhesin as a crucial factor. Natural transformation of the hmw1 operon from a clinical isolate (86-028NP) into a laboratory isolate that lacks it (Rd KW20) resulted in ~1,000-fold increased invasion into airway epithelial cells. When a distinct recipient (Hi375, already possessing hmw1 and its paralog hmw2) was transformed by the same donor, allelic replacement of hmw2AHi375 by hmw1A86-028NP resulted in a ~100-fold increased intracellular invasion rate. The specific role of hmw1A86-028NP was confirmed by mutant and western blot analyses. Bacterial self-aggregation and adherence to airway cells were also increased in recombinants, suggesting that the high invasiveness induced by hmw1A86-028NP might be a consequence of these phenotypes. However, immunofluorescence results found that intracellular hmw1A86-028NP bacteria likely invaded as groups, instead of as individual bacterial cells, indicating an emergent invasion-specific consequence of hmw1A-mediated self aggregation. PMID- 27124731 TI - One-Step Electrodeposition of NiCo2 S4 Nanosheets on Patterned Platinum Electrodes for Non-Enzymatic Glucose Sensing. AB - The preparation of NiCo2 S4 (NCS) nanosheets on photolithographically patterned platinum electrodes by electrodeposition was explored. The as-prepared nanosheets were systematically characterized by field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy techniques. The NCS-modified Pt electrode was used as a non-enzymatic glucose sensor. The sensor response exhibited two linear regions in glucose concentration, with a limit of detection of 1.2 MUm. The sensors showed that the as-prepared NCS nanosheets have excellent electrocatalytic activity towards glucose with long stability, good reproducibility, and excellent anti interference properties, and thus, this material holds promise for the development of a practical glucose sensor. PMID- 27124732 TI - Headache symptoms consistent with migraine and tension-type headaches in children with anxiety disorders. AB - OBJECTIVE: To examine the incidence of headache symptoms consistent with migraine and tension-type headache (TTH) in children with anxiety disorders. METHOD: Parents of children with anxiety disorders (n=27) and children without anxiety disorders (n=36) completed a headache questionnaire based on the International Classification of Headache Disorders (2nd edition) criteria. RESULTS: Children with anxiety disorders had a higher incidence of headache symptoms consistent with migraine and TTH compared to children without anxiety disorders. Girls with anxiety disorders and children with separation anxiety disorder had a higher incidence of headaches compared to girls without anxiety disorders and children with other anxiety disorders respectively. Children with anxiety disorders and headaches had higher self-reported anxiety symptom severity compared to children with anxiety disorders without headaches and children without anxiety disorders. CONCLUSION: Findings highlight an overlap in anxiety and headaches in children and warrant further research on factors that contribute to the etiology and maintenance of these co-occurring problems. PMID- 27124730 TI - Influenza-Specific Antibody-Dependent Phagocytosis. AB - BACKGROUND: Immunity to human influenza A virus (IAV) infection is only partially understood. Broadly non-neutralizing antibodies may assist in reducing disease but have not been well characterized. METHODS: We measured internalization of opsonized, influenza protein-coated fluorescent beads and live IAV into a monocytic cell line to study antibody-dependent phagocytosis (ADP) against multiple influenza hemagglutinin (HA) subtypes. We analyzed influenza HA-specific ADP in healthy human donors, in preparations of intravenous immunoglobulin (IVIG), and following IAV infection of humans and macaques. RESULTS: We found that both sera from healthy adults and IVIG preparations had broad ADP to multiple seasonal HA proteins and weak cross-reactive ADP to non-circulating HA proteins. The ADP in experimentally influenza-infected macaque plasma and naturally influenza-infected human sera mediated phagocytosis of both homologous and heterologous IAVs. Further, the IAV phagocytosed in an antibody-mediated manner had reduced infectivity in vitro. CONCLUSION: We conclude that IAV infections in humans and macaques leads to the development of influenza-specific ADP that can clear IAV infection in vitro. Repeated exposure of humans to multiple IAV infections likely leads to the development of ADP that is cross reactive to strains not previously encountered. Further analyses of the protective capacity of broadly reactive influenza-specific ADP is warranted. PMID- 27124733 TI - Moderate Exercise Attenuates Lipopolysaccharide-Induced Inflammation and Associated Maternal and Fetal Morbidities in Pregnant Rats. AB - Fetal growth restriction (FGR) and coagulopathies are often associated with aberrant maternal inflammation. Moderate-intensity exercise during pregnancy has been shown to increase utero-placental blood flow and to enhance fetal nutrition as well as fetal and placental growth. Furthermore, exercise is known to reduce inflammation. To evaluate the effect of moderate-intensity exercise on inflammation associated with the development of maternal coagulopathies and FGR, Wistar rats were subjected to an exercise regime before and during pregnancy. To model inflammation-induced FGR, pregnant rats were administered daily intraperitoneal injections of E. coli lipopolysaccharide (LPS) on gestational days (GD) 13.5-16.5 and sacrificed at GD 17.5. Control rats were injected with saline. Maternal hemostasis was assessed by thromboelastography. Moderate intensity exercise prevented LPS-mediated increases in white blood cell counts measured on GD 17.5 and improved maternal hemostasis profiles. Importantly, our data reveal that exercise prevented LPS-induced FGR. Moderate-intensity exercise initiated before and maintained during pregnancy may decrease the severity of maternal and perinatal complications associated with abnormal maternal inflammation. PMID- 27124734 TI - Interactions of Indole Derivatives with beta-Cyclodextrin: A Quantitative Structure-Property Relationship Study. AB - Retention factors for 31 indole derivatives, most of them with auxin activity, were determined by high-performance liquid chromatography, using bonded beta cyclodextrin as a stationary phase. A three-parameter QSPR (quantitative structure-property relationship) model, based on physico-chemical and structural descriptors was derived, which accounted for about 98% variations in the retention factors. The model suggests that the indole nucleus occupies the relatively apolar cavity of beta-cyclodextrin while the carboxyl group of the indole -3-carboxylic acids makes hydrogen bonds with the hydroxyl groups of beta cyclodextrin. The length and flexibility of the side chain containing carboxyl group strongly affect the binding of these compounds to beta-cyclodextrin. Non acidic derivatives, unlike the indole-3-carboxylic acids, are poorly retained on the column. A reasonably well correlation was found between the retention factors of the indole-3-acetic acids and their relative binding affinities for human serum albumin, a carrier protein in the blood plasma. A less satisfactory correlation was obtained when the retention factors of the indole derivatives were compared with their affinities for auxin-binding protein 1, a plant auxin receptor. PMID- 27124736 TI - Education on, Exposure to, and Management of Vascular Anomalies During Otolaryngology Residency and Pediatric Otolaryngology Fellowship. AB - IMPORTANCE: The field of vascular anomalies presents diverse challenges in diagnosis and management. Although many lesions involve the head and neck, training in vascular anomalies is not universally included in otolaryngology residencies and pediatric otolaryngology (POTO) fellowships. OBJECTIVE: To explore the education in, exposure to, and comfort level of otolaryngology trainees with vascular anomalies. DESIGN, SETTING, AND PARTICIPANTS: A survey was distributed to 39 POTO fellows and 44 residents in postgraduate year 5 who matched into POTO fellowships from April 22 through June 16, 2014. MAIN OUTCOMES AND MEASURES: Survey responses from trainees on exposure to, education on, and comfort with vascular anomalies. RESULTS: Forty-four residents in postgraduate year 5 who applied to POTO fellowships and 39 POTO fellows were emailed the survey. Fourteen respondents were unable to be contacted owing to lack of a current email address. Thirty-six of 69 residents and fellows (18 fellows and 18 residents [52%]) responded to the survey. Twenty-seven trainees (75%) reported no participation in a vascular anomalies clinic during residency; 6 of these 27 individuals (22%) trained at institutions with a vascular anomalies clinic but did not participate in the clinic, and 28 of the 36 respondents (78%) reported that they had less than adequate or no exposure to vascular anomalies in residency. Among POTO fellows, 11 of 17 (65%) did not participate in a vascular anomalies clinic during fellowship, even though 8 of the 11 had a vascular anomalies clinic at their fellowship program. During fellowship training, 12 of 18 fellows (67%) reported that they had adequate exposure to vascular anomalies. Only 20 respondents (56%) felt comfortable distinguishing among diagnoses of vascular anomalies, and only 4 residents (22%) and 9 fellows (50%) felt comfortable treating patients with vascular anomalies. All fellows believed that training in vascular anomalies was important in fellowship, and 100% of respondents indicated that increased exposure to diagnosis and management of vascular anomalies would have been beneficial to their ability to care for patients. CONCLUSIONS AND RELEVANCE: These data indicate that most otolaryngology trainees do not receive formal training in vascular anomalies in residency and that such training is valued among graduating trainees. Conversely, most POTO fellows felt their exposure was adequate and 50% of fellows felt comfortable treating vascular anomalies. However, 65% of POTO fellows had no participation in a vascular anomalies clinic, where many patients are managed by a multidisciplinary team. This finding may indicate that POTO fellows may have a false sense of confidence in managing patients with vascular anomalies and that residency and fellowship programs may consider changes in didactic and clinical programs. PMID- 27124738 TI - [Single Patient Room Design in the Neonatal Intensive Care Unit - Parent Perceptions of Open Ward vs. Single Patient Room Units]. AB - BACKGROUND: Single patient room design is not yet implemented in German neonatal intensive care units. Surveys from other countries revealed positive and negative implications on the staff, the patients and their families. The survey examines the perceptions of parents who experienced both facilities - the traditional multipatient ward and the individual patient room - during their babies' hospital stays. METHODS: A standardized questionnaire was used to assess the perceptions of parents. The results were compared to international surveys. RESULTS: During their stay in the single patient room, parents noticed improvements in privacy and data protection and a reduction in harmful environmental stimuli affecting their babies. These results are comparable to those of international surveys. CONCLUSIONS: Single patient room design is mostly perceived as an improvement by parents. The room design can complement an implemented concept of developmental and family-centered care. PMID- 27124735 TI - Does Celiac Disease Influence Survival in Sepsis? A Nationwide Longitudinal Study. AB - BACKGROUND: Individuals with celiac disease (CD) are at increased risk of sepsis. The aim of this study was to examine whether CD influences survival in sepsis of bacterial origin. METHODS: Nationwide longitudinal registry-based study. Through data on small intestinal biopsies from Sweden's 28 pathology departments, we identified 29,096 individuals with CD (villous atrophy, Marsh stage III). Each individual with CD was matched with five population-based controls. Among these, 5,470 had a record of sepsis according to the Swedish Patient Register (1,432 celiac individuals and 4,038 controls). Finally we retrieved data on mortality in sepsis patients through the Swedish Cause of Death Registry. RESULTS: CD was associated with a 19% increase in overall mortality after sepsis (95% confidence interval (CI) = 1.09-1.29), with the highest relative risk occurring in children (adjusted hazard ratio (aHR) = 1.62; 95%CI = 0.67-3.91). However, aHR for death from sepsis was lower (aHR = 1.10) and failed to reach statistical significance (95%CI = 0.72-1.69). CD did not influence survival within 28 days after sepsis (aHR = 0.98; 95%CI = 0.80-1.19). CONCLUSIONS: Although individuals with CD seem to be at an increased risk of overall death after sepsis, that excess risk does not differ from the general excess mortality previously seen in celiac patients in Sweden. CD as such does not seem to influence short-term or sepsis-specific survival in individuals with sepsis and therefore is not an independent risk factor for poor prognosis in sepsis. PMID- 27124737 TI - [Transcervical Embryoscopy after Missed Abortion in Monoamniotic Twins with Discordant Exencephaly]. AB - INTRODUCTION: Monoamniotic twins are considered a cause of high-risk pregnancies. Thereby, discordant malformations do occur rarely. A discordant exencephaly has been described in only a few cases. Transcervical embryoscopy can be performed in cases of monoamniotic twins with missed abortion directly before the abort curettage. CASE REPORT: The case of a 35-year-old G1/P0 women in the 12(th) week of pregnancy is described. She had a monoamniotic twin pregnancy with discordant exencephaly and missed abortion diagnosed at 11+2 weeks. A transcervical embryoscopy was performed immediately before the abort-curettage and identified the discordant exencephaly and an additional umbilical cord knot of the 2 foetuses as a probable cause for the abortion. DISCUSSION: The transcervical embryoscopy lead in our case report to the diagnosis of a umbilical cord knot in a monoamniotic twin pregnancy with missed abortion. We also identified a discordant exencephaly by embryoscopy. With blunt access to the amniotic cavity, the transcervical embryoscopy applies only a minor additional risk to the abort curettage. However, it should only be performed when the patient explicitly asks for enhanced diagnostics. CONCLUSION: Transcervical embryoscopy can be performed as an additional diagnostic tool in cases of monoamniotic twins with missed abortion. However, a detailed risk-benefit analysis should be done upfront in consultation with the patient. PMID- 27124739 TI - Fetal aneuploidy screening with cell-free DNA in late gestation. AB - OBJECTIVE: The aim of this study was to evaluate clinical use of NIPT at gestational ages of 23 weeks and above. METHODS: A cohort of 5579 clinical patients with singleton gestations of 23 weeks or greater submitting a blood sample for NIPT in an 18-month period were selected for this study. Clinical outcomes were requested for samples with NIPT results indicating fetal aneuploidy and compared with NIPT findings to confirm concordance or discordance. RESULTS: A review of clinical indications revealed that a significantly (p < 0.0001) larger proportion of late-gestation samples indicated abnormal ultrasound findings with or without other indications, 6.2% and 42.1%, compared with early-gestation samples, 1.8% and 6.0%, respectively. Of 5372 reported late-gestation samples, 151 (2.8%) were reported as aneuploidy detected or suspected. In late-gestation samples, the overall observed positive predictive value (PPV) for NIPT was 64.7%, with an observed PPV of 100% in the subset of cases with multiple clinical indications including abnormal ultrasound findings. CONCLUSIONS: NIPT is a highly accurate prenatal screening option for women after 23 weeks of gestation. Women who presented for NIPT in the latter stages of pregnancy more frequently specified clinical indications of abnormal ultrasound findings than women who entered screening earlier in pregnancy. PMID- 27124740 TI - Drift effects on the multivariate floral phenotype of Calceolaria polyrhiza during a post-glacial expansion in Patagonia. AB - Quaternary environmental changes substantially impacted the landscape and promoted rapid evolutionary changes in many species; however, analyses of adaptive phenotypic variation in plants have usually neglected the underlying historical context. Here, we associate phylogeography and phenotypic evolution by analysing the divergence of Calceolaria polyrhiza multivariate floral phenotype after a Pleistocene post-glacial expansion in Patagonia. Phenotypic matrix (P) properties (size, shape, orientation and phenotypic integration) of six refugium and six recent populations from two different phylogroups were compared following different approaches. We found that P-matrix shape and orientation remained stable despite the strong phylogeographic footprint of post-glacial expansion. However, average proportional reductions in matrix size supported the expectation that drift had a significant effect on the floral phenotype in the northern phylogroup. When phylogeographic history was not included in the analyses, the results overestimated phenotypic differences, whereas under explicit phylogeographic control, drift appeared as the best explanation for matrix differences. In general, recent populations showed a larger phenotypic divergence among them, but a lower overall phenotypic variation than refugium populations. Random Skewers analyses indicated a lower potential response to selection in recently colonized populations than in refugium populations. We discuss that the combination of phylogeographic analyses with geographical distribution of functional phenotypic (genotypic) variation is critical not only to understand how historical effects influence adaptive evolution, but also to improve field comparisons in evolutionary ecology studies. PMID- 27124741 TI - Expression of the significance of silent information regulator type-1 in Angioimmunoblastic T-cell lymphoma is greater association with tumorigenesis and has strong implications for adverse prognosis. AB - Silent information regulator type-1 (SIRT1) is the best-studied member of the Sirtuin (Sir2) family of nicotinamide dinucleotide (NAD)-dependent class III histone deacetylases (HDACs). Rrecently, it is suggested that SIRT1 may be involved in the development of malignant tumors including mouse lymphoma, but has not yet been explored in Angioimmunoblastic T-cell lymphoma (AITL). Therefore, we investigated the prevalence and the prognostic impact of SIRT1 expression in AITL. Immunohistochemical expression of SIRT1, p53 were evaluated by using a 2 mm core from 45 AITL patients. Positive expression of SIRT1 was seen in 71.11% (32 of 45) of patients and p53 expression were seen in 53.33% (24 of 45). SIRT1 and p53 expression were significantly associated with shorter PFS by univariate analysis (P=0.009 and P < 0.001, respectively), multivariate analysis also shows that SIRT1 expression relate to worse prognosis. We also suggest inferior survival in AITL with the combined expression of SIRT1 and clinical characteristics of high IPI scores, high clinical stage, increased serum LDH, decreased HGB and increased gamma-Globulin. In conclusion, our results indicate that SIRT1 is strongly expressed in AITL and it act as a clinically significant prognostic indicator for AITL patients, may also serve as a therapeutic target in AITL. PMID- 27124743 TI - Correction: Subcellular Partitioning of Protein Tyrosine Phosphatase 1B to the Endoplasmic Reticulum and Mitochondria Depends Sensitively on the Composition of Its Tail Anchor. AB - [This corrects the article DOI: 10.1371/journal.pone.0139429.]. PMID- 27124742 TI - Transgenic Expression of Human Lysophosphatidic Acid Receptor LPA2 in Mouse Intestinal Epithelial Cells Induces Intestinal Dysplasia. AB - Lysophosphatidic acid (LPA) acts on LPA2 receptor to mediate multiple pathological effects that are associated with tumorigenesis. The absence of LPA2 attenuates tumor progression in rodent models of colorectal cancer, but whether overexpression of LPA2 alone can lead to malignant transformation in the intestinal tract has not been studied. In this study, we expressed human LPA2 in intestinal epithelial cells (IECs) under control of the villin promoter. Less than 4% of F1-generation mice had germline transmission of transgenic (TG) human LPA2; as such only 3 F1 mice out of 72 genotyped had TG expression. These TG mice appeared anemic with hematochezia and died shortly after birth. TG mice were smaller in size compared with the wild type mouse of the same age and sex. Morphological analysis showed that TG LPA2 colon had hyper-proliferation of IECs resulting in increased colonic crypt depth. Surprisingly, TG small intestine had villus blunting and decreased IEC proliferation and dysplasia. In both intestine and colon, TG expression of LPA2 compromised the terminal epithelial differentiation, consistent with epithelial dysplasia. Furthermore, we showed that epithelial dysplasia was observed in founder mouse intestine, correlating LPA2 overexpression with epithelial dysplasia. The current study demonstrates that overexpression of LPA2 alone can lead to intestinal dysplasia. PMID- 27124744 TI - Urethral-fixation technique improves early urinary continence recovery in patients who undergo retropubic radical prostatectomy. AB - OBJECTIVES: To describe step-by-step an original urethrovesical anastomosis technique (urethral fixation) in patients undergoing retropubic radical prostatectomy (RRP), to compare their early urinary continence recovery with those in a control group receiving a standard anastomosis technique and to identify the predictors of early urinary continence recovery. PATIENTS AND METHODS: We compared 70 patients who underwent RRP with the urethral-fixation technique with a contemporary control group of 51 patients who received RRP with a standard urethrovesical anastomosis. In the urethral-fixation group, the urethrovesical anastomosis was made using eight single sutures. Specifically, to avoid retraction and/or deviations, we fixed the urethral stump laterally to the medial portion of levator ani muscle. Also, to maintain the normal position in the context of the pelvic floor, we fixed the urethral sphincter deeper to the medial dorsal raphe using a 3-0 polydioxanone suture at the 6 o'clock position before completing the incision of the urethral wall. Urinary continence recovery was evaluated at 1, 4, 8 and 12 weeks after catheter removal. Patients self reporting no urine leak were considered continent. Uni- and multivariable analyses were used to identify predictors of urinary incontinence at the different follow-up time-points. RESULTS: The evaluated groups had comparable preoperative variables. At 1 week after catheter removal, 32 (45.7%) patients in the urethral-fixation group and 10 (19.6%) in the control group were continent (P = 0.01). At 4 weeks after catheter removal, 46 (65.7%) patients in the urethral fixation group and 16 (31.4%) in the control group were continent (P = 0.001). At 8 weeks after catheter removal, 59 (84.3%) patients in the urethral-fixation group and 21 (41.2%) in the control group were continent (P < 0.001). Finally, at 12 weeks after catheter removal, 63 (90%) patients in the urethral-fixation group and 32 (62.7%) in the control group were continent (P = 0.001). The urethral fixation technique was an independent predictor of urinary continence recovery at 1 week [odds ratio (OR) 4.305; P = 0.002); 4 weeks (OR 4.784; P < 0.001); 8 weeks (OR 7.678; P < 0.001) and 12 weeks (OR 5.152; P = 0.001) after catheter removal. CONCLUSIONS: The urethral-fixation technique significantly improves early urinary continence recovery in comparison with the standard technique. Moreover, our study confirmed that this surgical technique is an independent predictor of urinary continence recovery at 1, 4, 8 and 12 weeks after catheter removal. PMID- 27124745 TI - Coagulation parameters and major bleeding in critically ill patients with cirrhosis. AB - Disturbances of coagulation and hemostasis are common in patients with liver cirrhosis. The typical laboratory pattern mimics disseminated intravascular coagulation (DIC). The aim of this study was to assess the impact of routine coagulation parameters in critically ill cirrhosis patients with regard to new onset of major bleeding and outcome. A total of 1,493 critically ill patients were studied prospectively. Routine coagulation parameters were assessed, and the DIC score was calculated based on platelets, fibrinogen, d-dimer, and prothrombin index. New onset of major bleeding during the stay at the intensive care unit and mortality were assessed. Patients were followed for 1 year. Two hundred eleven patients of the cohort had liver cirrhosis. Platelets, fibrinogen, prothrombin index, activated partial thromboplastin time, and d-dimer as well as the DIC score differed significantly between patients with and without cirrhosis (P < 0.001 for all). Moreover, fibrinogen, platelets, and activated partial thromboplastin time (but not prothrombin index) differed significantly between cirrhosis patients with and without major bleeding (P < 0.01 for all). Bleeding on admission, platelet count <30 < 10(9) /L, fibrinogen level <60 mg/dL, and activated partial thromboplastin time values >100 seconds were the strongest independent predictors for new onset of major bleeding in multivariate regression analysis. One-year mortality in cirrhosis patients with and without major bleeding was 89% and 68%, respectively (P < 0.05 between groups). CONCLUSION: Abnormal coagulation parameters and high DIC scores (primarily due to fibrinogen and platelets) correspond to increased bleeding risk in patients with liver cirrhosis in the intensive care unit, and fibrinogen and platelet count were identified as the best routine coagulation parameters for prediction of new onset of major bleeding; however, further studies are required to evaluate the potential therapeutic implications of these findings. (Hepatology 2016;64:556 568). PMID- 27124763 TI - Second-trimester plasma mannose-binding lectin levels and risk of preterm birth. AB - OBJECTIVE: To investigate whether mannose-binding lectin (MBL) gene polymorphisms and low levels of second-trimester plasma MBL were significant risk factors for preterm birth in Taiwanese women. METHODS: We conducted a prospective longitudinal study to explore the associations of MBL2 gene single nucleotide polymorphisms and plasma MBL levels between preterm birth and term controls. Blood samples were collected at 16-23 weeks of gestation, and were divided into 51 mothers with preterm births and 255 term controls after delivery. Blood samples were further collected at delivery from 11 mothers with term delivery and 9 with preterm births. DNA was isolated, and polymorphisms in exon 1, the promoter untranslated regions of MBL2 were determined by polymerase chain reaction. The plasma concentrations of MBL were measured by enzyme-linked immunosorbent assay. RESULTS: There is a positive correlation between SNP genotypes and second-trimester plasma MBL levels. Among mothers with preterm births, a higher frequency of specific genotypes with low MBL levels was not observed. The second-trimester plasma MBL levels were not significantly different between mothers with preterm births (N = 51) and term deliveries (N = 255). However, among mothers (N = 11) with term pregnancies, the MBL plasma level significantly increased from the second trimester to delivery, whereas in mothers (N = 9) who developed preterm delivery, the MBL level did not significantly change. CONCLUSION: Genotypes associated with low levels of plasma MBL during pregnancy did not increase the risk of preterm births. A low second-trimester plasma MBL level is therefore not a predictor for the development of preterm birth. PMID- 27124764 TI - Non-Uniform-Sampling Ultrahigh Resolution TOCSY NMR: Analysis of Complex Mixtures at Microgram Levels. AB - Non-uniform sampling in combination with homonuclear broadband decoupling along an indirect dimension, and indirect covariance processing are used to record ultrahigh resolution two-dimensional TOCSY spectra in less than half an hour, for typical sample concentrations in the mm range. TOCSY correlations belonging to protons separated by as little as ~2 Hz can be distinctly discerned. The utility of the technique for low concentrations has been demonstrated. PMID- 27124762 TI - Development and characterization of aptamer-based enzyme-linked apta-sorbent assay for the detection of Singapore grouper iridovirus infection. AB - AIMS: Singapore grouper iridovirus (SGIV) is a devastating aquaculture virus responsible for heavy economic losses to grouper, Epinephelus sp. aquaculture. The aim of this study was to develop a rapid and sensitive detection method for SGIV infections in infected groupers. METHODS AND RESULTS: We previously generated DNA aptamers against SGIV-infected cells. In this study, we established and characterized a novel aptamer (Q3)-based enzyme-linked apta-sorbent assay (ELASA) for the detection of SGIV infection in Epinephelus coioides. The Q3-based ELASA could detect SGIV infection rapidly in vitro and in vivo, with high specificity and stability. Q3-based ELASA specifically recognized SGIV-infected cells, but not other-virus-infected cells or uninfected cells. Q3-based ELASA detected SGIV infection in a dose-dependent manner at Q3 concentrations as low as 125 nmol l(-1) . The results in relation to SGIV-infected cells (5 * 10(4) ), incubation time (1 min) and incubation temperature (37 degrees C) demonstrated that Q3-based ELASA could detect SGIV infection quickly and stably, superior to antibody-based enzyme-linked immunosorbent assay. Q3-based ELASA could detect the presence of SGIV infection in kidney, liver and spleen samples in vivo, at dilutions of 1/50, 1/100 and 1/50 respectively. The complete detection process took 1-2 h. CONCLUSIONS: Q3-based ELASA could be a useful tool for diagnosing SGIV infection. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first developed aptamer-based ELASA for detecting SGIV infection, and is widely applicable in grouper aquaculture industry in light of its rapidity, and high specificity and stability. PMID- 27124765 TI - Critical concepts, practice recommendations, and research perspectives of pixantrone therapy in non-Hodgkin lymphoma: a SIE, SIES, and GITMO consensus paper. AB - OBJECTIVES: In this paper, we present a review of critical concepts and research perspectives and produce recommendations on the optimal use of pixantrone in non Hodgkin lymphoma (NHL) by group discussion from an expert panel appointed by the Italian Society of Hematology and the affiliate societies, Societa Italiana di Ematologia Sperimentale and Gruppo Italiano Trapianto di Midollo Osseo. METHODS: Recommendations were produced using the Delphi process. Scientific evidence on pixantrone efficacy was analyzed using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology in the areas where at least one randomized trial was published. The following key issues were addressed for practical recommendations: pixantrone monotherapy in aggressive relapsed or refractory non-Hodgkin B-cell lymphomas and toxicity risk management in patients candidates to pixantrone. RESULTS AND CONCLUSIONS: After a balanced and value oriented discussion, the panel agreed that the benefit/risk profile was in favor of pixantrone in the treatment of adult patients with multiply relapsed or refractory aggressive NHL B-cell lymphomas. Pixantrone was deemed to be contraindicated in patients with uncontrolled cardiovascular disease. Despite a low rate of cardiotoxicity of pixantrone reported in clinical trials, the panel recommended that all patients receiving pixantrone should undergo periodical cardiac monitoring. PMID- 27124766 TI - Early hominin diversity and the emergence of the genus Homo. AB - Bipedalism is a defining trait of hominins, as all members of the clade are argued to possess at least some characters indicative of this unusual form of locomotion. Traditionally the evolution of bipedalism has been treated in a somewhat linear way. This has been challenged in the last decade or so, and in this paper I consider this view in light of the considerable new fossil hominin discoveries of the last few years. It is now apparent that there was even more locomotor diversity and experimentation across hominins than previously thought, and with the discovery of taxa such as H. floresiensis and H. naledi, that diversity continues well into the genus Homo. Based on these findings,we need to reevaluate how we define members of the genus Homo, at least when considering postcranial morphology, and accept that the evolution of hominin bipedalism was a complex and messy affair. It is within that context that the modern human form of bipedal locomotion emerged. PMID- 27124767 TI - Comprehensive Mitochondrial Metabolic Shift during the Critical Node of Seed Ageing in Rice. AB - The critical node (CN) in seed aging in rice (Oryza sativa) is the transformation from Phase I (P-I) to Phase II (P-II) of the reverse S-shaped curve (RS-SC). Although mitochondrial dysfunction plays a key role in seed ageing, the metabolic shift in the CN remains poorly understood. Here, we investigated the mitochondrial regulatory mechanisms during the CN of rice seed ageing. We showed that during the CN of seed ageing, the mitochondrial ultrastructure was impaired, causing oxygen consumption to decrease, along with cytochrome c (cyt c) oxidase and malate dehydrogenase (MDH) activity. In addition, the transcript levels for the alternative pathway of the electron transport chain (ETC) were significantly induced, whereas the transcripts of the cytochrome oxidase (COX) pathway were inhibited. These changes were concomitant with the down-regulation of mitochondrial protein levels related to carbon and nitrogen metabolism, ATP synthase (ATPase) complex, tricarboxylic acid cycle (TCA) cycle, mitochondrial oxidative enzymes, and a variety of other proteins. Therefore, while these responses inhibit the production of ATP and its intermediates, signals from mitochondria (such as the decrease of cyt c and accumulation of reactive oxygen species (ROS)) may also induce oxidative damage. These events provide considerable information about the mitochondrial metabolic shifts involved in the progression of seed ageing in the CN. PMID- 27124769 TI - Tertiary work-up of apparent treatment-resistant hypertension. AB - OBJECTIVE: Treatment-resistant hypertension (TRH) has regained attention with development of new methods for treatment. However, the prevalence of TRH varies considerably from primary to secondary and tertiary care. We aimed to assess the prevalence of true TRH in a population of patients with apparent TRH in a university hospital setting of tertiary work-up and also investigate reasons for poor BP control and evaluate how work-up can be performed in general practice and secondary care. METHODS: In this cohort study, we characterize a study population from Oslo Renal Denervation (RDN) Study. Patients (n = 83) were referred for RDN from secondary care. All patients underwent thorough medical investigation and 24 h ambulatory blood pressure measurements (24ABPM) after directly observed therapy (DOT). We then assessed reasons for lack of BP control. RESULTS: Fifty-three of 83 patients did not have true TRH. Main reasons for non-TRH were poor drug adherence (32%), secondary hypertension (30%) and white coat hypertension (15%). Forty-seven percent achieved blood pressure control after DOT with subsequent 24ABPM. There were otherwise no statistically significant differences in patient characteristics between the true TRH and the non-TRH group. CONCLUSION: Despite being a highly selected cohort referred for tertiary work-up of apparent TRH, BP control was achieved or secondary causes were identified in almost two thirds of the patients. Thorough investigation according to guidelines and DOT with subsequent 24ABPM is needed in work-up of apparent TRH. PMID- 27124768 TI - Association between Spouse/Child Separation and Migration-Related Stress among a Random Sample of Rural-to-Urban Migrants in Wuhan, China. AB - BACKGROUND: Millions of people move from rural areas to urban areas in China to pursue new opportunities while leaving their spouses and children at rural homes. Little is known about the impact of migration-related separation on mental health of these rural migrants in urban China. METHODS: Survey data from a random sample of rural-to-urban migrants (n = 1113, aged 18-45) from Wuhan were analyzed. The Domestic Migration Stress Questionnaire (DMSQ), an instrument with four subconstructs, was used to measure migration-related stress. The relationship between spouse/child separation and stress was assessed using survey estimation methods to account for the multi-level sampling design. RESULTS: 16.46% of couples were separated from their spouses (spouse-separation only), 25.81% of parents were separated from their children (child separation only). Among the participants who married and had children, 5.97% were separated from both their spouses and children (double separation). Spouse-separation only and double separation did not scored significantly higher on DMSQ than those with no separation. Compared to parents without child separation, parents with child separation scored significantly higher on DMSQ (mean score = 2.88, 95% CI: [2.81, 2.95] vs. 2.60 [2.53, 2.67], p < .05). Stratified analysis by separation type and by gender indicated that the association was stronger for child-separation only and for female participants. CONCLUSION: Child-separation is an important source of migration-related stress, and the effect is particularly strong for migrant women. Public policies and intervention programs should consider these factors to encourage and facilitate the co-migration of parents with their children to mitigate migration-related stress. PMID- 27124770 TI - Metal-Free Synthesis of 3-Arylquinolin-2-ones from Acrylic Amides via a Highly Regioselective 1,2-Aryl Migration: An Experimental and Computational Study. AB - Combined experimental and theoretical investigations into the phenyliodine bis(trifluoroacetate) (PIFA)-mediated reaction of N-arylcinnamamide to produce 3 arylquinolin-2-one derivatives have been conducted. High regioselectivity during the aryl migration process was observed in 3,3-disubstituted acrylamides. Density functional theory calculation was conducted in an attempt to understand the mechanism and the origin of the regioselectivity. On the basis of both the experimental and the theoretical results, a mechanism involving an oxidative annulation, followed by an aryl migration, has been proposed. The annulation is the regioselectivity determining step. PMID- 27124771 TI - The Role of Weak Interactions in the Mechano-induced Single-Crystal-to-Single Crystal Phase Transition of 8-Hydroxyquinoline-Based Co-crystals. AB - Mechano-induced single-crystal-to-single-crystal (SCSC) phase transitions in crystalline materials that change their properties have received more and more attention. However, there are still too few examples to study molecular-level mechanisms in the mechano-induced SCSC phase transitions, making the systematic and in-depth understanding very difficult. We report that bis-(8 hydroxyquinolinato) palladium(II)-tetracyanoquinodimethane (PdQ2 -TCNQ) and bis (8-hydroxyquinolinato) copper(II)-tetracyanoquinodimethane (CuQ2 -TCNQ) show very different mechano-response behaviors during the SCSC phase transition. Phase transition in CuQ2 -TCNQ can be triggered by pricking on the crystal surface, while in PdQ2 -TCNQ it can only be induced by applying pressure uniformly over the whole crystal face. The crystallography data and Hirshfeld surface analysis indicate that the weak intra-layer C-H???O, C-H???N hydrogen bonds and inter layer stacking interactions determine the feasibility of the SCSC phase transition by mechanical stimuli. Weaker intra-layer interactions and looser inter-layer stacking make the SCSC phase transition occur much more easily in the CuQ2 -TCNQ. PMID- 27124772 TI - Superconductivity-induced magnetization depletion in a ferromagnet through an insulator in a ferromagnet-insulator-superconductor hybrid oxide heterostructure. AB - Coupling between superconducting and ferromagnetic states in hybrid oxide heterostructures is presently a topic of intense research. Such a coupling is due to the leakage of the Cooper pairs into the ferromagnet. However, tunneling of the Cooper pairs though an insulator was never considered plausible. Using depth sensitive polarized neutron reflectivity we demonstrate the coupling between superconductor and magnetic layers in epitaxial La2/3Ca1/3MnO3 (LCMO)/SrTiO3/YBa2Cu3O7-delta (YBCO) hybrid heterostructures, with SrTiO3 as an intervening oxide insulator layer between the ferromagnet and the superconductor. Measurements above and below the superconducting transition temperature (TSC) of YBCO demonstrate a large modulation of magnetization in the ferromagnetic layer below the TSC of YBCO in these heterostructures. This work highlights a unique tunneling phenomenon between the epitaxial layers of an oxide superconductor (YBCO) and a magnetic layer (LCMO) through an insulating layer. Our work would inspire further investigations on the fundamental aspect of a long range order of the triplet spin-pairing in hybrid structures. PMID- 27124773 TI - Expression of Concern: 'Reduction of Postoperative Nausea and Vomiting and Analgesic Requirement with Dexamethasone in Women Undergoing General Anesthesia for Mastectomy' by Dr. Yoshitaka Fujii. PMID- 27124774 TI - HepatoDyn: A Dynamic Model of Hepatocyte Metabolism That Integrates 13C Isotopomer Data. AB - The liver performs many essential metabolic functions, which can be studied using computational models of hepatocytes. Here we present HepatoDyn, a highly detailed dynamic model of hepatocyte metabolism. HepatoDyn includes a large metabolic network, highly detailed kinetic laws, and is capable of dynamically simulating the redox and energy metabolism of hepatocytes. Furthermore, the model was coupled to the module for isotopic label propagation of the software package IsoDyn, allowing HepatoDyn to integrate data derived from 13C based experiments. As an example of dynamical simulations applied to hepatocytes, we studied the effects of high fructose concentrations on hepatocyte metabolism by integrating data from experiments in which rat hepatocytes were incubated with 20 mM glucose supplemented with either 3 mM or 20 mM fructose. These experiments showed that glycogen accumulation was significantly lower in hepatocytes incubated with medium supplemented with 20 mM fructose than in hepatocytes incubated with medium supplemented with 3 mM fructose. Through the integration of extracellular fluxes and 13C enrichment measurements, HepatoDyn predicted that this phenomenon can be attributed to a depletion of cytosolic ATP and phosphate induced by high fructose concentrations in the medium. PMID- 27124775 TI - Efficacy of Subconjunctival Aflibercept Versus Bevacizumab for Prevention of Corneal Neovascularization in a Rat Model. AB - PURPOSE: We aimed to evaluate the efficacy of subconjunctival aflibercept, a vascular endothelial growth factor trap compound, for the treatment of corneal neovascularization in a rat model. METHODS: Chemical burn was produced in the central cornea of 31 male Sprague-Dawley rats. Animals were randomized to receive treatment with subconjunctival injection of 0.08 mL aflibercept (25 mg/mL), 0.05 mL bevacizumab (25 mg/mL), or 0.05 mL physiologic saline. Corneal neovascularization was evaluated on postinjury days 1, 3, 7, 9, and 13 by corneal photographs. The rats were killed on day 21 and samples were collected for histological and flat-mount immunofluorescence analyses. RESULTS: In all rats, vascular sprouting began on day 3, reached maximum density on days 7-9, and spontaneously regressed thereafter. Mean burn area in the central cornea comprised ~15% of the total corneal area. The aflibercept group had a significantly smaller relative area of neovascularization than both control group (P < 0.05, 12.27 +/- 9.91, 29.66 +/- 9.96 days 7) and bevacizumab group (P < 0.05, 12.27 +/- 9.91, 21.27 +/- 8.19 days 7 and 15.5 +/- 10.25, 32.38 +/- 9.44 days 9; Mann-Whitney test). On histological study, hematoxylin and eosin staining revealed blood vessels extending to the central cornea in the control and bevacizumab groups and limited to the periphery in the aflibercept group. Immunofluorescence study with an endothelial marker revealed a smaller area of staining in the aflibercept group. CONCLUSIONS: Aflibercept effectively inhibits corneal neovascularization in a rat model of chemical burn-induced neovascularization and warrants further study for potential use in humans. PMID- 27124776 TI - Simultaneous Topography-Guided Photorefractive Keratectomy and Accelerated Corneal Collagen Cross-Linking for Keratoconus. AB - PURPOSE: To study the evolution of visual and refractive outcomes through the first year after simultaneous topography-guided photorefractive keratectomy (t PRK) and corneal collagen cross-linking (CXL) in keratoconus. METHODS: This retrospective case series included 85 eyes of 66 patients with a mean age of 26.3 +/- 5.7 years, which underwent simultaneous t-PRK with accelerated CXL. Patients were examined for uncorrected distance visual acuity and corrected distance visual acuity (CDVA), flat and steep keratometry readings, and manifest refraction spherical equivalent at 1, 3, 6, and 12 months. RESULTS: At 12 months, all study parameters demonstrated a statistically significant improvement with uncorrected distance visual acuity 0.46 +/- 0.49 logMAR (vs. 0.86 +/- 0.39 logMAR preoperatively), CDVA 0.11 +/- 0.12 logMAR (vs. 0.41 +/- 0.27 logMAR preoperatively), manifest refraction spherical equivalent -2.80 +/- 4.47 D (vs. 4.51 +/- 4.68 D preoperatively), flat keratometry 43.84 +/- 3.24 D (vs. 44.61 +/- 3.12 D preoperatively), and steep keratometry 46.05 +/- 3.94 D (vs. 48.10 +/- 3.68 D preoperatively). Although 90.6% eyes gained 1 or more lines of CDVA, no eyes lost any lines of CDVA. In all, 37.6% of the eyes demonstrated an improvement of 4 or more lines of CDVA with a maximum improvement of 11 lines of CDVA in 1 eye. CONCLUSIONS: Simultaneous t-PRK with accelerated CXL improved the spherocylindrical refraction and visual function of keratoconus eyes, and the outcomes were stable through 12 months' follow-up. Future studies with longer follow-up and larger data set are necessary to validate the results of the current study and evaluate the long-term safety and efficacy. PMID- 27124777 TI - Corneal Biomechanical Properties in Patients With Arcus Senilis. AB - PURPOSE: To compare the corneal biomechanical properties and intraocular pressure (IOP) levels in patients with and without arcus senilis (AS). METHODS: Ocular response analyzer measurements were performed on the right eyes of 37 patients with AS (group 1) and 37 control eyes (group 2). Corneal hysteresis, corneal resistance factor, Goldmann-correlated IOP, and corneal compensated IOP were recorded with Ocular response analyzer. Spherical equivalent value of the refractive errors, axial length, central corneal thickness, and IOP measured with Goldmann applanation tonometer were noted for each study eyes. Statistical analyses were performed with Student t, Kruskal-Wallis, and Pearson correlation tests. RESULTS: Mean age was 67.6 +/- 9.8 years in group 1 and 65.3 +/- 8.1 years in group 2 (P = 0.308). Mean corneal hysteresis and corneal resistance factor readings were 9.8 +/- 0.9 versus 10.6 +/- 0.8 (P < 0.001) and 10.05 +/- 1.07 versus 10.9 +/- 0.9 (P < 0.001) in groups 1 and 2, respectively. Mean corneal compensated IOP and Goldmann-correlated IOP values were found as 16.1 +/- 3.3 mm Hg versus 15.8 +/- 2.6 mm Hg (P = 0.719) and 15.1 +/- 3.3 mm Hg versus 15.0 +/- 2.6 mm Hg (P = 0.912) in groups 1 and 2, respectively. There was no statistical difference in IOP measured with Goldmann applanation tonometer, central corneal thickness, spherical equivalent value of the refractive error, axial length measurements, and mean keratometry readings between the 2 groups (P = 0.983, P = 0.289, P = 0.938, P = 0.886, P = 0.07, respectively). CONCLUSIONS: The mean corneal hysteresis and corneal resistance factor values of eyes with AS were lower when compared with the controls. This study demonstrated that AS may change the corneal biomechanical properties. PMID- 27124778 TI - Size of the Lesions of Superficial Punctate Keratitis in Dry Eye Syndrome Observed With a Slit Lamp. AB - PURPOSE: To evaluate the size distribution of epithelial lesions of superficial punctate keratitis (SPK) in dry eye after staining of the ocular surface by sodium fluorescein. METHODS: Fluorescein was instilled in 10 patients with dry eye graded using the Oxford Scheme. Pictures were taken using a standard Topcon slit lamp with cobalt blue light, without barrier filter. Two magnifications (*10 and *16) were used and calibrated using a certified standard reference grating, allowing the diameter of the observed objects to be determined with ImageJ software. The most visible and isolated SPK lesions (green dots) were selected. The size of 254 SPK lesions was measured by tracing the irradiance profile and manually measuring the full width at half maximum. RESULTS: For all patients, with the 2 magnifications combined, the median diameter was 20.9 MUm (15.2-26.6 MUm, 10-90 percentile). There was a significant difference between the size of SPK lesions measured with *10 and *16 magnifications, respectively, 24.3 MUm (18.2-29.8) versus 19.0 MUm (15.2-26.6) (P < 0.001). CONCLUSIONS: Lesions seem to be smaller than normal superficial epithelial cells (which are approximately 25 * 50 MUm) and might correspond to the staining of dying shrunken cells, according to recent investigations. These new quantitative data will help in developing automated recognition algorithms to obtain reliable objective classification of corneal staining. PMID- 27124779 TI - Conjunctival Microbial Flora in Ocular Stevens-Johnson Syndrome Sequelae Patients at a Tertiary Eye Care Center. AB - PURPOSE: To evaluate the conjunctival microbial flora in cases of ocular Stevens Johnson Syndrome (SJS) in a tertiary eye care center. METHODS: This prospective study comprised 176 eyes of 88 patients with ocular SJS compared with 124 eyes of normal subjects. The conjunctival swabs were collected and sent for microbiological analysis for bacterial isolation and antibiotic sensitivity examination. The type of bacteria isolated and its antibiotic sensitivity pattern were studied. RESULTS: Of 176 eyes, 104 (59%) had positive cultures for bacteria in cases of SJS and 16 (12.9%) had positive culture in the control group, the difference being statistically significant (P = 0.001). In the SJS group, 14 different types of bacterial isolates were identified. The most common isolate was coagulase-negative staphylococci (CNS) (30/104, 28.8%) followed by Corynebacteria species (35/104, 33.6%) and Staphylococcus aureus (19/104, 18.2%). More than 1 bacteria were isolated in 7 eyes (6.7%). Most of the isolates showed resistance to ciprofloxacin with no resistance to gatifloxacin and moxifloxacin. In the control group, only 2 bacteria were isolated, which included CNS (14/16, 87.5%) and Streptococcus pneumoniae (2/16, 12.5%). CNS showed resistance to ciprofloxacin, and S. pneumoniae was resistant to tobramycin and gentamycin. CONCLUSIONS: Ocular SJS is associated with alteration of the normal microbial flora residing in the conjunctival sac. The study of which is vital in cases of infection in these eyes with compromised ocular surface. Mixed flora are seen more often in cases of ocular SJS as compared with controls. PMID- 27124780 TI - Evaluation of Corneas from Donors With Septicemia for Use in Corneal Transplant. AB - PURPOSE: To evaluate if donor corneas obtained from deaths occurring because of septicemia can be used for corneal transplantation. STUDY DESIGN: Prospective study. METHODS: Eleven septicemic donor corneas were used in the study and 10 donor corneas from deaths because of causes other than septicemia were used as controls. Blood culture reports of all patients who had donated eyes were collected, and the pathogenic organisms causing septicemia were noted. On obtaining the eyeballs, aqueous and vitreous samples were sent for polymerase chain reaction to analyze for eubacterial and panfungal genomes. Corneal and scleral tissues (3 * 3 mm) were sent for culture in brain heart infusion media. Growth from each of the samples was checked to ascertain if the same organism was isolated in all. RESULTS: One corneal and 3 scleral culture reports in the sepsis group and 1 corneal and 1 scleral culture report in the control group showed positive growth. Normal conjunctival/eyelid commensal organisms were isolated from all culture-positive samples and did not correlate with the pathogenic organism causing the septicemia. Three aqueous and vitreous samples in the sepsis group and 4 samples of aqueous and vitreous in the control group that tested positive for eubacterial genome showed no corresponding growth in the culture report of cornea and sclera. CONCLUSIONS: Corneal tissues harvested from septicemic donors do not necessarily harbor the pathogenic organisms causing the septicemia, suggesting that such corneas may be suitable for transplantation. PMID- 27124781 TI - Predictors of Early Postoperative Pain After Photorefractive Keratectomy. AB - PURPOSE: To compare the profiles of postoperative photorefractive keratectomy (PRK) pain between both eyes under the same conditions and to verify the preoperative predictors of pain such as gender, anxiety, knowledge of the procedure, and spherical equivalent refractive error (SERE). METHODS: This prospective study included 86 eyes of 43 patients with myopia who underwent PRK in both eyes at an interval of 14 days between the procedures. Before surgery, subjects answered the State Anxiety Inventory. After surgery, usual PRK pain treatment was given. Subjects answered the Visual Analog Scale, the Brief Pain Inventory (BPI), and the McGill Pain Questionnaire at 1, 24, 48, 72, and 96 hours after surgery. Pain scores and anxiety were compared between each eye using the Wald test and paired Student t test, respectively. The Wald test was performed for gender and SERE for each eye separately. RESULTS: There were no statistically significant differences between both eyes for all time points regarding the Visual Analog Scale, BPI, and McGill Pain Questionnaire-Pain Rating Index pain scores. Subjects were less anxious on average before the second surgery compared with before the first surgery (P < 0.001); however, it was not related to pain ratings after surgery. Gender did not significantly affect any scale of pain, and the SERE between -3 diopters (D) and -5 D (P = 0.035) revealed effects on the BPI. CONCLUSIONS: The profiles of postoperative pain after PRK were similar between both eyes under the same conditions. In this study, a high SERE was the only predictor for increased pain after PRK. PMID- 27124782 TI - Corneal Densitometry and Higher Order Aberrations After Bowman Layer Transplantation: 1-Year Results. AB - PURPOSE: To evaluate corneal densitometry and higher order aberrations (HOAs) up to 1 year after Bowman layer (BL) transplantation. METHODS: This was a retrospective study carried out at a tertiary referral center. Fifteen eyes of 14 patients who underwent BL transplantation for advanced keratoconus and had at least 1 year of follow-up were examined before BL transplantation and postoperatively at 1 day, 1 week, and 1, 3, 6, and 12 months. Corrected distance visual acuity (CDVA) with spectacles and contact lenses, anterior and posterior HOAs, and corneal densitometry were analyzed. RESULTS: One year after surgery, average logarithm of the minimum angle of resolution of spectacle-CDVA changed from 1.35 (+/-0.46) preoperatively to 0.96 (+/-0.32, P < 0.001), whereas average logarithm of the minimum angle of resolution of CDVA with contact lens remained stable after surgery (P = 0.126). Anterior and posterior HOA root mean square decreased from 3.08 +/- 0.59 to 2.67 +/- 0.71 MUm and 7.32 +/- 2.20 to 6.30 +/- 2.18 MUm, respectively (P < 0.05). Spherical aberration ((Equation is included in full-text article.)) improved on both anterior and posterior corneal surfaces (P < 0.001). After 1 year, corneal backscattering values showed an increase as compared with preoperative values mostly involving the central and posterior layers of the cornea, with a peak 1 month after surgery (P < 0.005 in zones 2-6 and 6-10 mm). No correlation between HOAs or corneal backscatter and CDVA was found. CONCLUSIONS: Corneal HOAs, especially spherical aberration, decreased for both anterior and posterior corneal surfaces after BL transplantation, whereas corneal backscattering increased, mostly in the central and posterior layers, where the graft has been placed. Changes in HOAs and corneal backscattering did not correlate with CDVA. PMID- 27124783 TI - Long-Term Follow-Up of Amniotic Membrane Graft for the Treatment of Symblepharon in a Patient With Recessive Dystrophic Epidermolysis Bullosa. AB - PURPOSE: To report a case of symblepharon due to epidermolysis bullosa (EB), surgical treatment, and follow-up to 14 years. METHODS: A 17-year-old white female with recessive dystrophic EB presented with decreased vision due to extensive symblepharon OU. There was opacification and neovascularization of the cornea OU with limited motility. RESULTS: The symblepharon was surgically lysed, anterior lamellar keratectomy performed, and amniotic membrane graft transplanted to the cornea and palpebral conjunctiva, first in the OS and subsequently in the OD. Visual acuity improved from counting fingers to 20/40 in the OS and from 20/200 to 20/70 in the OD at 2 months and 6 weeks postoperatively, respectively, with minimal symblepharon, mild corneal scarring, neovascularization, and haze of OU. She recovered full ductions, but noted diplopia and had a 35 prism diopter exotropia. Symblepharon resolved after 6 months, and alignment improved to 4 prism diopter exophoria. At 14 years follow-up, visual acuity was 20/20 in the OD and 20/30 in the OS, with clear cornea, maintained on fluorometholone 0.1% one drop OU at bedtime. CONCLUSIONS: Surgical symblepharolysis, superficial lamellar keratectomy, and amniotic membrane graft transplantation were effective for our patient with recessive dystrophic EB. Her postoperative exotropia resolved over time with monitoring and convergence exercises. PMID- 27124784 TI - Comparative analysis of BRCA1 and BRCA2 variants of uncertain significance in patients with breast cancer: a multifactorial probability-based model versus ACMG standards and guidelines for interpreting sequence variants. AB - PURPOSE: To investigate variants of uncertain significance (VUS) in BRCA1 and BRCA2, we assessed the multifactorial posterior probability of VUS in BRCA1 and BRCA2 and compared these analyses with interpretations according to the recently released American College of Medical Genetics and Genomics (ACMG) standards and guidelines. METHODS: The analysis involved 715 Korean patients with breast cancer. The multifactorial probability of a VUS was analyzed using the prior probability and combined likelihoods of personal and family history, the pathologic profile of the breast cancer, and co-occurrence with pathogenic variants. Results were compared with those obtained according to the ACMG standards/guidelines. RESULTS: Sixteen VUS from 51 BRCA1 VUS carriers and 28 VUS from 62 BRCA2 VUS carriers were analyzed. There was a slight agreement between the two analyses, with a kappa value of 0.14 (95% confidence interval (CI) = 0.34 to 0.62) for the BRCA1 VUS and a kappa value of 0.17 (95% CI = -0.10 to 0.49) for the BRCA2 VUS. CONCLUSION: We propose that genetic counseling should be based on the concordant results between these two analyses. When discrepancies are found, those variants are still considered VUS and careful counseling should be provided.Genet Med 18 12, 1250-1257. PMID- 27124785 TI - Section E6.1-6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow-acquired chromosomal abnormalities. AB - DISCLAIMER: These American College of Medical Genetics and Genomics standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these standards and guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cytogenetic analyses of hematological neoplasms are performed to detect and characterize clonal chromosomal abnormalities that have important diagnostic, prognostic, and therapeutic implications. At the time of diagnosis, cytogenetic abnormalities assist in the diagnosis of such disorders and can provide important prognostic information. At the time of relapse, cytogenetic analysis can be used to confirm recurrence of the original neoplasm, detect clonal disease evolution, or uncover a new unrelated neoplastic process. This section deals specifically with the standards and guidelines applicable to chromosome studies of neoplastic blood and bone marrow-acquired chromosomal abnormalities. This updated Section E6.1-6.4 has been incorporated into and supersedes the previous Section E6 in Section E: Clinical Cytogenetics of the 2009 Edition (Revised 01/2010), American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories.Genet Med 18 6, 635 642. PMID- 27124787 TI - Highly accurate molecular genetic testing for HFE hereditary hemochromatosis: results from 10 years of blinded proficiency surveys by the College of American Pathologists. AB - PURPOSE: The College of American Pathologists offers blinded proficiency testing (PT) for laboratories performing HFE genetic tests for hereditary hemochromatosis (common C282Y and H63D variants). This study used 10 years of PT data to determine laboratory performance for HFE analytical genotyping and clinical interpretation. METHODS: Laboratories were graded for accuracy of genotype determination (six possible C282Y/H63D genotypes) and clinical interpretation regarding whether the genotype was likely to have contributed to iron overload in a hypothetical patient. RESULTS: The analytical genotyping error rate was low (0.73%) in 7,663 results (from 257 unique laboratories). Genotyping errors were significantly higher in C282Y heterozygous, H63D homozygous, and C282Y homozygous samples, in non-American laboratories, and in laboratories with lower testing volume. Analytical sensitivity and specificity were >98.5 and >99.5%. The interpretive error rate (4.3%) was higher than the genotyping error rate, with two problematic genotypes (C282Y heterozygous and H63D homozygous) accounting for 77% of total interpretive errors. There was a time-dependent improvement in the interpretation of the clinical significance of HFE genotypes. CONCLUSIONS: HFE molecular genetic testing, performed by non-US Food and Drug Administration approved laboratory-developed tests, demonstrated excellent accuracy, sensitivity, and specificity. Clinical interpretations were more heterogeneous, probably owing to the low clinical penetrance of some common HFE genotypes.Genet Med 18 12, 1206-1213. PMID- 27124786 TI - Section E6.5-6.8 of the ACMG technical standards and guidelines: chromosome studies of lymph node and solid tumor-acquired chromosomal abnormalities. AB - DISCLAIMER: These ACMG standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these standards and guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cytogenetic analysis of tumor tissue is performed to detect and characterize chromosomal aberrations to aid histopathological and clinical diagnosis and patient management. At the time of diagnosis, known recurrent clonal aberrations may facilitate histopathological diagnosis and subtyping of the tumor. This information may contribute to clinical therapeutic decisions. However, even when tumors have a known recurrent clonal aberration, each tumor is genetically unique and probably heterogeneous. It is important to discover as much about the genetics of a tumor at diagnosis as is possible with the methods available for study of the tumor material. The information gathered at initial study will inform follow-up studies, whether for residual disease detection, determination of relapse and clonal evolution, or identifying a new disease clone.This updated Section E6.5-6.8 has been incorporated into and supersedes the previous Sections E6.4 and E6.5 in Section E: Clinical Cytogenetics of the 2009 Edition (Revised 01/2010), American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories. This section deals specifically with the standards and guidelines applicable to lymph node and solid tumor chromosome analysis.Genet Med 18 6, 643 648. PMID- 27124789 TI - Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden. AB - BACKGROUND: Most autosomal recessive diseases are rare, but they collectively account for a substantial proportion of disease burden, especially in consanguineous populations. Estimation of this disease burden, however, is hampered by many factors, including lack of countrywide registries. Establishing carrier frequency can be a practical surrogate to estimate disease burden, although the requirement of a large representative cohort may be challenging. PURPOSE: We propose that the application of clinical genomics in the diagnostic setting offers a unique opportunity to estimate carrier frequency in the population as a secondary benefit. METHODS: We used a data set of ~7,100 patients who underwent genomic testing for various Mendelian disorders to estimate the carrier frequency. RESULTS: We were able to calculate the frequency of 259 confirmed founder recessive mutations. We found the corresponding disease burden to be, at minimum, ~7 per 1,000 children born to first-cousin parents, with disorders related to intellectual disability and vision impairment being the most common. CONCLUSION: Our approach can be utilized to inform the design of new policies for the prevention of genetic disorders and highlights an important secondary benefit of clinical genomics.Genet Med 18 12, 1244-1249. PMID- 27124788 TI - A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation. AB - PURPOSE: Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research. METHODS: We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability. RESULTS: We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders. CONCLUSION: The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268. PMID- 27124790 TI - AN ATYPICAL CASE OF SYMPATHETIC OPHTHALMIA AFTER LIMBAL CORNEAL LACERATION. AB - BACKGROUND/PURPOSE: To report a case of atypical sympathetic ophthalmia after limbal corneal laceration. METHODS AND RESULTS: An 11-year-old child had a successful left eye corneal laceration repair at the temporal limbus with excision of exposed nonnecrotic iris tissue, resulting in good visual acuity of 20/80 and 20/25 on postoperative Days 1 and 7, respectively. The patient was prescribed 1 mg/kg oral prednisolone in a tapering dose as prophylaxis. On postoperative Day 21, the patient presented with acute onset decreased vision in both eyes. Visual acuity was counting fingers 3 feet in both eyes. On examination, anterior segment examination was quiet without any inflammation, anterior vitreous face showed 1+ cells, and dilated funduscopy revealed bilateral symmetrical serous retinal detachments along the posterior pole. Optical coherence tomography demonstrated separation and elevation of inner neurosensory layers from the outer segment marking presence of hyperreflective material along with subretinal fluid between detached surfaces. There was stippled hyperfluorescence along the posterior pole as seen in fluorescein angiography. With a diagnosis of sympathetic ophthalmia confirmed, oral prednisolone (2 mg/kg body weight) was instituted after which, there was gradual decrease in macular elevation with corresponding improvement in visual acuity with no recurrence for the last 6 months. CONCLUSION: To our knowledge, this is the first reported instance of an atypical presentation of sympathetic ophthalmia, and antecedent corticosteroid therapy would have mitigated robust anterior segment findings usually associated with the condition. PMID- 27124791 TI - BILATERAL SUBRETINAL FLUID AND RETINAL VASCULOPATHY ASSOCIATED WITH SUBACUTE SCLEROSING PANENCEPHALITIS. AB - PURPOSE: To report a case of bilateral retinopathy associated with subacute sclerosing panencephalitis. METHODS: History and clinical examination, fluorescein angiography, and optical coherence tomography. RESULTS: We report a rare case of unilateral, followed by bilateral retinopathy, subretinal fluid, and vasculopathy in a young boy. History of missed measles vaccination, behavioral and neurologic symptoms, and electroencephalogram suggested a diagnosis of subacute sclerosing panencephalitis. Retinal imaging using optical coherence tomography was performed to document changes in the retinal microstructure through the natural course of the disease. Within 8 weeks, the changes progressed to retinal atrophy in both eyes. CONCLUSION: The progressive course of retinitis associated with subacute sclerosing panencephalitis can be monitored on optical coherence tomography. Retinitis is subacute sclerosing panencephalitis rapidly progressive from the acute stage to the stage of atrophy, involving full thickness of the retina. PMID- 27124792 TI - CONCURRENT ENDOPHTHALMITIS AND ANTERIOR SEGMENT ISCHEMIA AFTER STRABISMUS SURGERY. AB - BACKGROUND/PURPOSE: To report a case of simultaneous endophthalmitis and anterior segment ischemia (ASI) that occurred in a patient after strabismus surgery. This is the first known case of both complications occurring at the same time. METHODS: Case report. RESULTS: A 60-year-old woman presented with eye pain and loss of vision 6 days after uncomplicated strabismus surgery for thyroid eye disease. On examination, she had corneal edema, anterior segment fibrin, an atonic iris, and no view to the posterior segment. On fluorescein angiography of the anterior segment, a large portion of the iris was nonperfused. Posterior segment ultrasound showed dense vitritis and a choroidal abscess. Intraoperative cultures grew methicillin-resistant Staphylococcus aureus. CONCLUSIONS: Endophthalmitis and anterior segment ischemia are both exceedingly rare complications of strabismus surgery. It is possible that each one occurred independently, but more likely one process potentiated the other. One possible mechanism is inflammation-induced thrombosis. PMID- 27124793 TI - WALDENSTROM'S MACROGLOBULINEMIA MASQUERADING AS BIRDSHOT CHORIORETINOPATHY. AB - PURPOSE: To describe Waldenstrom's macroglobulinemia (WM) as a masquerade syndrome. METHODS: Case report. RESULTS: A 59-year-old human leukocyte antigen (HLA)-A29-negative white male presented with a 7-year history of floaters, progressive vision loss, and poor contrast sensitivity along with choroidal lesions suggestive of birdshot chorioretinopathy (BCR). Fluorescein angiography, fundus autofluorescence, and indocyanine green angiography showed multiple areas of hyperfluorescence and hypofluorescence. Electroretinography showed reduced cone and rod responses. Comprehensive workup for infectious, paraneoplastic, and other causes including sarcoidosis was negative at the time. The patient was treated with multiple immunomodulatory agents without any significant improvement. Two years after initial presentation, the patient developed normocytic anemia and high levels of inflammatory markers. Further workup yielded a diagnosis of WM. His choroidal lesions were significantly reduced after treatment with rituximab and bendamustine. CONCLUSION: We report a case of WM masquerading as BCR. Other indolent diseases should be considered in the differential diagnosis for HLA-A29-negative patients presenting with birdshot like lesions, especially if they are clinically unresponsive to multiple systemic immunosuppressive agents. PMID- 27124794 TI - A CASE OF UNILATERAL RETINAL PIGMENT EPITHELIUM DYSGENESIS. AB - PURPOSE: To report a case of unilateral retinal pigment epithelium dysgenesis. METHODS: An 8-year-old boy with a large grayish lesion and leopard-spot pattern lesion at its periphery in his left eye underwent fluorescein angiography, fundus autofluorescence imaging, optical coherence tomography, and electroretinography. RESULTS: Fluorescein angiography showed an area of geographic hyperfluorescence with a peripheral pattern of dark spots. The area of retinal pigment epithelial atrophy showed hypofluorescence on fundus autofluorescence. Optical coherence tomography of the left eye showed attenuation of the inner segment-outer segment junction and choroidal thinning. Single-flash electroretinography and scotopic electroretinography showed normal results and did not differ between both the eyes. The 30-Hz flicker test and photopic electroretinography showed a decrease in amplitude in the left eye. CONCLUSION: Unilateral retinal pigment epithelium dysgenesis is very rare, and its prognosis is still unknown. Careful follow-up of the patient seems to be essential. PMID- 27124795 TI - MULTIMODAL IMAGING AND HISTOLOGIC CORRELATION OF ISOLATED METASTASIS OF PROSTATE ADENOCARCINOMA TO THE CHOROID. AB - PURPOSE: To provide correlative clinical-multimodal imaging-histopathologic findings of isolated prostatic choroidal metastasis. METHODS: Ophthalmologic examination, fluorescein angiogram, spectral-domain optical coherence tomography, fundus autofluorescence, computerized tomography, magnetic resonance imaging, positive emission tomography, CSF analysis, serologies, tissue pathology with immunohistochemistry, and examination of relevant literature. RESULTS: A 76-year old man with a history of prostate adenocarcinoma was referred for 2 months of unilateral blurry vision. Fundus examination revealed elevated deep orange choroidal lesions in the macula with overlying retinal pigment epithelium mottling and subretinal fluid. Fluorescein angiogram demonstrated alternating areas of hypofluorescence and hyperfluorescence (staining) without leakage. Optical coherence tomography revealed dome-shaped and lumpy choroidal lesions with surrounding undulating "lumpy bumpy" and "rippled/seasick" patterns. Workup for a primary or additional metastatic lesion including computerized tomography of head/chest/abdomen/pelvis, lumbar puncture, magnetic resonance imaging brain, and whole-body positive emission tomography scan was negative. Full-thickness excisional chorioretinal biopsy was obtained through pars plana vitrectomy with diathermy and vertical scissors. Histologic examination revealed adenocarcinoma with weak positive staining for prostate specific antigen, moderate positive staining for P501S (prostein), and strong positive staining for prostatic acid phosphatase, consistent with metastasis from a prostate primary. Treatment consisted of local radiation with regression of the metastatic tumor. The patient is also on concomitant androgen deprivation treatment because there is a very high incidence of systemic recurrence due to hematogenous involvement. The patient's vision has continued to improve 6 months past treatment. CONCLUSION: The authors present a unique case to highlight the multimodal imaging and histology of a rare presentation of biopsy-proven, isolated metastasis of prostate adenocarcinoma to the choroid. Systemic workup is required, and if unrevealing of a primary or metastatic lesion, full-thickness chorioretinal biopsy and histopathology can provide a definitive diagnosis, allowing optimal treatment. Chorioretinal biopsy is a useful technique and may allow for visual preservation while also giving superior histologic quality. PMID- 27124796 TI - PERIPHERAL RETINAL VASCULOPATHY IN COCKAYNE SYNDROME. AB - PURPOSE: To present peripheral retinal vasculopathy and foveal ellipsoid zone abnormalities as novel fundus manifestations of Cockayne syndrome (CS), a rare autosomal recessive condition with well-described ophthalmic associations. METHODS: Clinical examination, wide-field fundus photography, wide-field fundus autofluorescence, wide-field fluorescein angiography, and spectral domain optical coherence tomography (SD-OCT) were used to diagnose and document the patient's clinical presentation. RESULTS: Our patient presented with postnatal growth delay, neurologic dysfunction, premature aging, dental anomalies, sensory neural hearing loss, and pigmentary retinopathy. This constellation of clinical features satisfies the clinical diagnostic criteria of CS Type 1. In addition to these well-known features, we used multimodal retinal imaging to perform an in-depth analysis of the retinal manifestations of CS and report peripheral vasculopathy and ellipsoid zone abnormality as two novel features which have not previously been described in conjunction with CS. CONCLUSION: This case report is intended to assist physicians in making the correct diagnosis of this rare condition by reviewing the clinical diagnostic criteria and providing the most comprehensive fundus imaging of CS available in the literature to date. PMID- 27124797 TI - DEXAMETHASONE IMPLANT REMOVAL FROM ANTERIOR CHAMBER: SURGICAL TECHNIQUE. AB - PURPOSE: To describe a surgical technique for complete and safe dexamethasone intravitreal implant (Ozurdex; Allergan, Inc., Irvine, CA) removal from anterior chamber. METHODS: Description of a new surgical technique for Ozurdex removal using a lens injector cartridge. RESULTS: Dexamethasone implant was removed completely from anterior chamber with no damage to corneal endothelium or posterior chamber luxation in a patient with Ozurdex anterior chamber migration. CONCLUSION: Dexamethasone implants can be removed from anterior chamber in an easy, cheap, fast, and save way. PMID- 27124798 TI - The effect of fluid shear stress on the in vitro degradation of poly(lactide-co glycolide) acid membranes. AB - Poly(lactide-co-glycolide) acid (PLGA) has been widely used as a biodegradable polymer material for coating stents or fabricating biodegradable stents. Its mechanism of degradation has been extensively investigated, especially with regard to how tensile and compressive loadings may affect the in vitro degradation of PLGA. Fluid shear stress is also one of the most important factors in the development of atherosclerosis and restenosis. But the effect of fluid shear stress on the degradation process is still unclear. The purpose of this study was to characterize the in vitro degradation of PLGA membranes that experienced different fluid shear stresses in 150 mL of deionized water at 37 degrees C for 20 days. Particular emphasis was given to changes in the viscosity of the degradation solution, as well as the mechanical and morphological properties of the samples. The viscosity of the degradation solution with the mechanical loaded specimens was more severely affected than that of the control group. Increasing the fluid shear stress could accelerate the loss of the ultimate strength of PLGA membranes while it slowed down the change of the tensile elastic modulus in the early period. With regard to morphology, the surface roughness was more obviously reduced in the loaded groups. This indicated that the fluid shear stress could affect the in vitro degradation of PLGA membranes. Therefore, this study could help improve the design of PLGA membranes for biomedical applications. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2016. PMID- 27124799 TI - Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia. AB - Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function; it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia. PMID- 27124800 TI - Disease, treatment, and outcome differences between men and women with follicular lymphoma in the United States. AB - We aimed to comprehensively study sex differences in disease and patients' characteristics, treatment and outcomes in patients with follicular lymphoma (FL) in the United States (USA) utilizing the National LymphoCare Study registry (2004 2014). Among evaluable males (n = 1277) and females (n = 1375) with FL, females less commonly received anthracyclines and were more likely to receive rituximab monotherapy. Overall response rates were comparable between sex groups. With a median follow-up of 8.1 years, male sex emerged as an adverse factor for PFS (HR, 0.84, 95% CI, 0.72-0.97). Lymphoma-related mortality (HR, 0.46; 0.23-0.93) and overall survival (HR, 0.63; 0.41-0.97) favored females aged <=60 years. There are subtle differences in outcomes between male and female FL patients diagnosed and treated in the contemporary era. These data represent the largest prospective analysis of FL patients in the USA based on sex and can aid design of clinical trials for this disease. Am. J. Hematol. 91:770-775, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27124801 TI - Advanced ECG in 2016: is there more than just a tracing? AB - The 12-lead electrocardiogram (ECG) is the most frequently used technology in clinical cardiology. It is critical for evidence-based management of patients with most cardiovascular conditions, including patients with acute myocardial infarction, suspected chronic cardiac ischaemia, cardiac arrhythmias, heart failure and implantable cardiac devices. In contrast to many other techniques in cardiology, the ECG is simple, small, mobile, universally available and cheap, and therefore particularly attractive. Standard ECG interpretation mainly relies on direct visual assessment. The progress in biomedical computing and signal processing, and the available computational power offer fascinating new options for ECG analysis relevant to all fields of cardiology. Several digital ECG markers and advanced ECG technologies have shown promise in preliminary studies. This article reviews promising novel surface ECG technologies in three different fields. (1) For the detection of myocardial ischaemia and infarction, QRS morphology feature analysis, the analysis of high frequency QRS components (HF QRS) and methods using vectorcardiography as well as ECG imaging are discussed. (2) For the identification and management of patients with cardiac arrhythmias, methods of advanced P-wave analysis are discussed and the concept of ECG imaging for noninvasive localisation of cardiac arrhythmias is presented. (3) For risk stratification of sudden cardiac death and the selection of patients for medical device therapy, several novel markers including an automated QRS-score for scar quantification, the QRS-T angle or the T-wave peak-to-end-interval are discussed. Despite the existing preliminary data, none of the advanced ECG markers and technologies has yet accomplished the transition into clinical practice. Further refinement of these technologies and broader validation in large unselected patient cohorts are the critical next step needed to facilitate translation of advanced ECG technologies into clinical cardiology. PMID- 27124802 TI - Substrate-Determined Diastereoselectivity in an Enzymatic Carboligation. AB - Thiamine diphosphate-dependent enzymes catalyze the formation of C-C bonds, thereby generating chiral secondary or tertiary alcohols. By the use of vibrational circular dichroism (VCD) spectroscopy we studied the stereoselectivity of carboligations catalyzed by YerE, a carbohydrate-modifying enzyme from Yersinia pseudotuberculosis. Conversion of the non-physiological substrate (R)-3-methylcyclohexanone led to an R,R-configured tertiary alcohol (diastereomeric ratio (dr) >99:1), whereas the corresponding reaction with the S enantiomer gave the S,S-configured product (dr>99:1). This suggests that YerE catalyzed carboligations can undergo either an R- or an S-specific pathway. We show that, in this case, the high stereoselectivity of the YerE-catalyzed reaction depends on the substrate's preference to acquire a low-energy conformation. PMID- 27124803 TI - Variation of mechanical behavior of beta-TCP/collagen two phase composite scaffold with mesenchymal stem cell in vitro. AB - The primary aim of this study is to characterize the variational behavior of the compressive mechanical property of bioceramic-based scaffolds using stem cells during the cell culture period. beta-Tricalcium phosphate (TCP)/collagen two phase composites and beta-TCP scaffolds were fabricated using the polyurethane template technique and a subsequent freeze-drying method. Rat bone-marrow mesenchymal stem cells (rMSCs) were then cultured in these scaffolds for up to 28 days. Compression tests of the scaffolds with rMSCs were periodically conducted. Biological properties, such as the cell number, alkaline phosphatase (ALP) activity, and gene expressions of osteogenesis, were evaluated. The microstructural change due to cell growth and the formation of extracellular matrices was examined using a field-emission scanning electron microscope. The compressive property was then correlated with the biological properties and microstructures to understand the mechanism of the variational behavior of the macroscopic mechanical property. The porous collagen structure in the beta-TCP scaffold effectively improved the structural stability of the composite scaffold, whereas the beta-TCP scaffold exhibited structural instability with the collapse of the porous structure when immersed in a culture medium. The beta-TCP/collagen composite scaffold exhibited higher ALP activity and more active generation of osteoblastic markers than the beta-TCP scaffold. PMID- 27124804 TI - Effects of high-dose gamma irradiation on tensile properties of human cortical bone: Comparison of different radioprotective treatment methods. AB - There are growing interests in the radioprotective methods that can reduce the damaging effects of ionizing radiation on sterilized bone allografts. The aim of this study was to investigate the effects of 50kGy (single dose, and fractionated) gamma irradiation, in presence and absence of l-Cysteine (LC) free radical scavenger, on tensile properties of human femoral cortical bone. A total of 48 standard tensile test specimens was prepared from diaphysis of femurs of three male cadavers (age: 52, 52, and 54 years). The specimens were assigned to six groups (n=8) according to different irradiation schemes, i.e.; Control (Non irradiated), LC-treated control, a single dose of 50kGy (sole irradiation), a single dose of 50kGy in presence of LC, 10 fractions of 5kGy (sole irradiation), and 10 fractions of 5kGy in presence of LC. Uniaxial tensile tests were carried out to evaluate the variations in tensile properties of the specimens. Fractographic analysis was performed to examine the microstructural features of the fracture surfaces. The results of multivariate analysis showed that fractionation of the radiation dose, as well as the LC treatment of the 50kGy irradiated specimens, significantly reduced the radiation-induced impairment of the tensile properties of the specimens (P<0.05). The fractographic observations were consistent with the mechanical test results. In summary, this study showed that the detrimental effects of gamma sterilization on tensile properties of human cortical bone can be substantially reduced by free radical scavenger treatment, dose fractionation, and the combined treatment of these two methods. PMID- 27124805 TI - Study the molecular structure of poly(epsilon-caprolactone)/graphene oxide and graphene nanocomposite nanofibers. AB - In this article, poly(epsilon-caprolactone) (PCL)/graphene oxide (GO) and reduced graphene oxide (RGO) nanocomposite nanofibrous mats were prepared using electrospinning technique. Dynamic mechanical analysis of mats electrospun from solution 16wt% PCL showed 22% and 133% increment in shrink force in the presence of 0.1wt% GO and RGO nanosheets respectively. The creep resistance was also increased 24% and 41%. The good enlargement of molecular chains of PCL at presence of nanosheets and strong chemical interaction within the molecular chains of PCL and nanosheets were caused the increment of shrink force and creep resistance of electrospun mats. However, less relaxation time and higher entanglement density of molecular chains in solution 14wt% and 18wt% PCL respectively limited the interaction within molecular chains of PCL and nanosheets in electrospinning process and thus showed less increment in creep resistance and shrink force of mats electrospun from them. Moreover, tensile stress test of mats electrospun from solution 16wt% PCL showed 53% and 189% increment in the tensile stress at presence of 0.1wt% GO and RGO respectively. PMID- 27124806 TI - Role of deposition time on the properties of ZnO:Tb(3+) thin films prepared by pulsed laser deposition. AB - Terbium (Tb(3+)) doped zinc oxide (ZnO:Tb(3+)) thin films were grown on silicon (100) substrates by the pulsed laser deposition technique at different deposition times that varied from 15 to 55min. The effects of deposition time on the structural and optical properties of the ZnO:Tb(3+) films were investigated by X ray diffraction, scanning electron microscopy and photoluminescence spectroscopy. As expected, the thickness of the ZnO:Tb(3+) film has increased with an increase in the deposition time. The photoluminescence intensity of the band to band emission has also increased with deposition time, while the deep level defect emission has decreased. The blue emission was observed from all the ZnO:Tb(3+) thin films deposited at the different deposition times excited by 325nm He-Cd laser, while a green emission was observed when excited by 228nm. PMID- 27124807 TI - Adsorption of As(III) and As(V) onto colloidal microparticles of commercial cross linked polyallylamine (Sevelamer) from single and binary ion solutions. AB - This work investigates the removal of arsenic ions in trivalent (As(III)) or pentavalent form (As(V)) from single-component and binary (equal initial ion concentrations) aqueous solutions using commercial cross-linked polyallylamine (namely as Sevelamer) as adsorbent. This is the first work in literature regarding the application of that commercial material as adsorbent for ions. Sevelamer (SVL) is a widely known pharmaceutical compound and the existence of primary and secondary amino groups (with different ratios) in its molecule increases its adsorption potential. For this purpose can be easily proposed as potential sorbent. The adsorption evaluation was based on the pH-effect (optimum pH=6, where As(III) and As(V) removal was 69 and 86%, respectively), isotherms and kinetic curves. The maximum theoretical adsorption capacity (Qm) was 86 and 133mg/g for single-component solutions of As(III) and As(V), respectively. The respective values for binary mixtures of the same concentration (100mg/L) were 84 and 116mg/g, respectively (calculated after fitting to Langmuir-Freundlich isotherm model at 20 degrees C). A novel kinetic interpretation based on the raw experimental kinetics data was also developed. Although adsorption of As(III) and As(V) occurs mainly at different sites, there is an interdependence in their adsorption kinetics. It was found that adsorption from the binary mixtures is a two-stage process. The adsorption mechanism of SVL and arsenic ions interaction was elucidated using FTIR spectroscopy before and after adsorption. SEM images and XRD patterns (the material was amorphous both before and after arsenic adsorption indicating that the mechanism did not alter its physical state) were also taken for the characterization of SVL before and after arsenic adsorption. The adsorption mechanism was mainly attributed to the electrostatic interactions between negatively As ions and positively charged amino groups of SVL. For this reason, As(V) adsorption is higher than As(III). PMID- 27124808 TI - Direct preparation of La2Zr2O7 microspheres by cathode plasma electrolysis. AB - La2Zr2O7 microspheres were directly prepared by cathode plasma electrolysis (CPE) in the electrolyte of Zr(NO3)4.5H2O and La(NO3)3.6H2O. Compared with high temperature sintering methods, the energy of plasma was completely used by CPE and made it possible to prepare the microspheres without calcining. The diameters of microspheres were mostly in the range of 0.5-5MUm and the microspheres consisted of fluorite and pyrochlore structures of La2Zr2O7. Moreover, the microspheres possessed potential photocatalytic activity and fluorescence property, owing to the high crystallinity and large surface area of the microspheres. PMID- 27124809 TI - Thin bacteria/Layered Double Hydroxide films using a layer-by-layer approach. AB - This paper reports the design of thin bacteria/Layered Double Hydroxides (LDH) films in which bacterial cells of Pseudomonas sp. strain ADP were assembled alternatively with Mg2Al-NO3 LDH nanosheets by a layer-by-layer deposition method. The UV-Vis spectroscopy was used to monitor the assembly process, showing a progressive increase in immobilized bacteria amount upon deposited cycles. The {ADP/LDH}n film was characterized by X-ray diffraction, infrared spectroscopy, scanning electron microscopy and atomic force microscopy. The metabolic activity of immobilized bacteria was determined using chronoamperometry by measuring the biochemical oxygen demand in presence of glucose using an artificial electron acceptor (Fe(CN)6(3-)) at 0.5V/Ag-AgCl. A steady current of 0.250MUAcm(-2) was reached in about 30s after the addition of 5mM glucose. PMID- 27124810 TI - The effect of inositol hexaphosphate on cadmium sorption to gibbsite. AB - HYPOTHESIS: Oxides, hydrous oxides and hydroxides of aluminium and iron are important in determining the availability of trace and heavy metals in soil systems. The presence of complexing anions is also known to affect the binding of these metals in soils. Since organophosphates, such as inositol hexaphosphate (IP6), are present in most soil systems they are expected to affect the nature of the interaction between metal ions and metal (hyr)oxides. EXPERIMENTS: Both adsorption edge and isotherm experiments were conducted on Cd(II)-gibbsite and Cd(II)-IP6-gibbsite systems. In addition, solid-state (31)P MAS NMR measurements were performed on the ternary system. All results were used to develop Extended Constant Capacitance surface complexation models of both the Cd(II)-gibbsite and IP6-Cd(II)-gibbsite sorption systems. FINDINGS: The presence of IP6 significantly increased sorption of Cd(II) to gibbsite below pH 8 especially at higher concentrations of Cd(II) and IP6. The (31)P MAS NMR spectra, together with surface complexation modeling, indicated the presence of two outer-sphere ternary complexes with the first, [(SOH2)3(3+)(LHCd)(9-)](6-), important at relatively low concentrations, while the second, [SLH3(8-)Cd(2+)](6-), dominated sorption at higher sorbate concentrations. Thus the presence of organophosphates in soil systems increases sorption and may therefore decrease the availability of trace and heavy metals to plants. PMID- 27124811 TI - Highly sensitive interference-free electrochemical determination of pyridoxine at graphene modified electrode: Importance in Parkinson and Asthma treatments. AB - To reduce the side effects in the medication of Parkinson and Asthma, pyridoxine (PY) is administered along with l-3,4-dihydroxyphenyl alanine (l-dopa) and theophylline (TP), respectively. However, excessive dosage of PY leads to nervous disorder. Thus, a sensitive and selective electrochemical method was developed for the determination of PY in the presence of major interferences including TP, l-dopa, ascorbic acid (AA) and riboflavin (RB) using electrochemically reduced graphene oxide (ERGO) film modified glassy carbon electrode (GCE) in this paper. The ERGO fabrication process involves the nucleophilic substitution of graphene oxide at basic pH on amine terminal of 1,6-hexadiamine which was pre-assembled on GCE followed by electrochemical reduction. The electrocatalytic activity of the ERGO modified electrode was examined towards the oxidation of PY. It greatly enhanced the oxidation current of PY in contrast to bare and GO modified GCEs due to facile electron transfer besides pi-pi interaction between ERGO film and PY. Since TP and l-dopa drugs antagonize the drug action of PY, ERGO modified GCE was also used for the simultaneous determination of PY and l-dopa and PY and TP. Further, the selective determination of PY in the presence of other water soluble vitamins such as ascorbic acid and riboflavin was also demonstrated. Using amperometry, detection of 100nM PY was achieved and the detection limit was found to be 5.6*10(-8)M (S/N=3). The practical application of the present method was demonstrated by determining the concentration of PY in human blood serum and commercial drugs. PMID- 27124812 TI - Investigation of the influence of vanadium, iron and nickel dopants on the morphology, and crystal structure and photocatalytic properties of titanium dioxide based nanopowders. AB - Photoactive V, Fe and Ni doped TiO2 (M-TiO2) nanopowders were synthesized by a modified two-step sol-gel process in the absence of additives. Titanium oxychloride, which is a rarely-used TiO2 precursor was used to yield M-TiO2 photocatalysts with preferential photochemical performance in the presence of natural solar irradiation. The obtained samples were calcined at different calcination temperatures ranging from 450 to 800 degrees C to evaluate the influence of the sintering on the physicochemical properties. The properties of the obtained samples were examined by XRF, XRD, Raman spectroscopy, UV-visible DRS, XPS, nitrogen gas physisorption studies, SEM-EDAX and HRTEM analyses. Structural characterization of the samples revealed the incorporation of these transition metal element into TiO2. It was also depicted that the morphology, crystal structure, optical and photochemical properties of the obtained samples were largely dependent on the calcination temperature and the type of dopant used during the preparation process. The photochemical performance of the samples was investigated in the photodegradation of methylene blue in the presence of natural sunlight. The experimental results indicated that the VT600 sample possessed the highest activity due to its superior properties. This study provides a systematic preparation and selection of the precursor, dopant and calcination temperature that are suitable for the formation of TiO2-based heterogeneous photocatalysts with appealing morphology, crystal structure, optical and photochemical properties for myriad of applications. PMID- 27124813 TI - Langmuir monolayers composed of single and double tail sulfobetaine lipids. AB - HYPOTHESIS: Owing to structural similarities between sulfobetaine lipids and phospholipids it should be possible to form stable Langmuir monolayers from long tail sulfobetaines. By modification of the density of lipid tail group (number of carbon chains) it should also be possible to modulate the two-dimensional phase behaviour of these lipids and thereby compare with that of equivalent phospholipids. Potentially this could enable the use of such lipids for the wide array of applications that currently use phospholipids. The benefit of using sulfobetaine lipids is that they can be synthesised by a one-step reaction from cheap and readily available starting materials and will degrade via different pathways than natural lipids. The molecular architecture of the lipid can be easily modified allowing the design of lipids for specific purposes. In addition the reversal of the charge within the sulfobetaine head group relative to the charge orientation in phospholipids may modify behaviour and thereby allow for novel uses of these surfactants. EXPERIMENTS: Stable Langmuir monolayers were formed composed of single and double tailed sulfobetaine lipids. Surface pressure area isotherm, Brewster Angle Microscopy and X-ray and neutron reflectometry measurements were conducted to measure the two-dimensional phase behaviour and out-of-plane structure of the monolayers as a function of molecular area. FINDINGS: Sulfobetaine lipids are able to form stable Langmuir monolayers with two dimensional phase behaviour analogous to that seen for the well-studied phospholipids. Changing the number of carbon tail groups on the lipid from one to two promotes the existence of a liquid condensed phase due to increased Van der Waals interactions between the tail groups. Thus the structure of the monolayers appears to be defined by the relative sizes of the head and tail groups in a predictable way. However, the presence of sub-phase ions has little effect on the monolayer structure, behaviour that is surprisingly different to that seen for phospholipids. PMID- 27124814 TI - Triflic Acid-Catalyzed Enynes Cyclization: A New Strategy beyond Electrophilic pi Activation. AB - The cyclization of enynes, catalyzed by a transition metal, represents a powerful tool to construct an array of cyclic compounds through electrophilic pi activation. In this paper, we disclose a new and efficient strategy for enynes cyclization catalyzed by triflic acid. The salient features of this transformation includes a broad substrate scope, metal free synthesis, open flask and mild conditions, good yields, ease of operation, low catalyst loading, and easy scale-up to gram scale. A preliminary mechanism study demonstrated that the activation model of the reaction was sigma-activation, which is different from the transition-metal-catalyzed enynes cyclization. Our strategy affords a complementary method to the traditional strategies, which use transition-metal catalysts. PMID- 27124815 TI - Opioid Prescriptions Among Women of Reproductive Age Enrolled in Medicaid - New York, 2008-2013. AB - Exposure to opioids during pregnancy can lead to adverse infant outcomes, including neonatal abstinence syndrome (1) and birth defects (2). Ascertaining opioid prescriptions for women who become pregnant or have no indication of contraceptive use is important to determine the number of women who are at potential risk for adverse fetal outcomes. The New York State (NYS) Department of Health (DOH) analyzed data for women aged 15-44 years (i.e., reproductive-aged women) enrolled in Medicaid to examine opioid drug prescriptions during 2008 2013. On the basis of Medicaid drug claims for any drug with an opioid ingredient, prescriptions were identified for the enrolled population of reproductive-aged women and for three subgroups: women whose diagnosis, procedure, and drug codes indicated contraceptive use or infertility; women who were not using contraceptives and not infertile; and women who had had a live birth during the reporting year. During 2008-2013, among all women of reproductive age, 20.0% received a prescription for a drug with an opioid component; the proportion was highest (27.3%) among women with an indication of contraceptive use or infertility, intermediate (17.3%) among women who had no indication of contraceptive use, and lowest (9.5%) among women who had had a live birth. Although New York's proportion of opioid prescriptions among female Medicaid recipients who had a live birth is lower than a recent U.S. estimate (3), these results suggest nearly one in 10 women in this group may have been exposed to opioids in the prenatal period. PMID- 27124816 TI - Crystal Structure of the HMG-CoA Synthase MvaS from the Gram-Negative Bacterium Myxococcus xanthus. AB - A critical step in bacterial isoprenoid production is the synthesis of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) catalyzed by HMG-CoA synthase (HMGCS). In myxobacteria, this enzyme is also involved in a recently discovered alternative and acetyl-CoA-dependent isovaleryl CoA biosynthesis pathway. Here we present crystal structures of MvaS, the HMGCS from Myxococcus xanthus, in complex with CoA and acetylated active site Cys115, with the second substrate acetoacetyl CoA and with the product of the condensation reaction, 3-hydroxy-3-methylglutaryl CoA. With these structures, we show that MvaS uses the common HMGCS enzymatic mechanism and provide evidence that dimerization plays a role in the formation and stability of the active site. Overall, MvaS shows features typical of the eukaryotic HMGCS and exhibits differences from homologues from Gram-positive bacteria. This study provides insights into myxobacterial alternative isovaleryl CoA biosynthesis and thereby extends the toolbox for the biotechnological production of renewable fuel and chemicals. PMID- 27124817 TI - The Role of Digital Engagement in the Self-Management of Type 2 Diabetes. AB - Mobile tablet devices and applications have the potential to help type 2 diabetes patients in the self-management of their disease. However, users must be equipped with an appropriate level of digital literacy in order to use the tools and technologies effectively. This study reports from an exploratory mobile health (mHealth) pilot program that was conducted at a large, local clinic in Canberra, Australia. The research team provided digital training and support opportunities to participants as part of the longitudinal study. The aim of the research project was to examine the diverse range of participant digital literacy and how it impacted on self-management and the adoption of mHealth. Mid-study results from online surveys conducted at 2 and 5 months after enrolling 28 participants in the pilot program revealed that digital engagement is crucial to the patients' participation in mHealth activities. Support, by way of digital training, was essential to the patients' sustainable use of the devices and applications for health care. PMID- 27124818 TI - Estimation of Nasal Tip Support Using Computer-Aided Design and 3-Dimensional Printed Models. AB - IMPORTANCE: Palpation of the nasal tip is an essential component of the preoperative rhinoplasty examination. Measuring tip support is challenging, and the forces that correspond to ideal tip support are unknown. OBJECTIVE: To identify the integrated reaction force and the minimum and ideal mechanical properties associated with nasal tip support. DESIGN, SETTING, AND PARTICIPANTS: Three-dimensional (3-D) printed anatomic silicone nasal models were created using a computed tomographic scan and computer-aided design software. From this model, 3-D printing and casting methods were used to create 5 anatomically correct nasal models of varying constitutive Young moduli (0.042, 0.086, 0.098, 0.252, and 0.302 MPa) from silicone. Thirty rhinoplasty surgeons who attended a regional rhinoplasty course evaluated the reaction force (nasal tip recoil) of each model by palpation and selected the model that satisfied their requirements for minimum and ideal tip support. Data were collected from May 3 to 4, 2014. RESULTS: Of the 30 respondents, 4 surgeons had been in practice for 1 to 5 years; 9 surgeons, 6 to 15 years; 7 surgeons, 16 to 25 years; and 10 surgeons, 26 or more years. Seventeen surgeons considered themselves in the advanced to expert skill competency levels. Logistic regression estimated the minimum threshold for the Young moduli for adequate and ideal tip support to be 0.096 and 0.154 MPa, respectively. Logistic regression estimated the thresholds for the reaction force associated with the absolute minimum and ideal requirements for good tip recoil to be 0.26 to 4.74 N and 0.37 to 7.19 N during 1- to 8-mm displacement, respectively. CONCLUSIONS AND RELEVANCE: This study presents a method to estimate clinically relevant nasal tip reaction forces, which serve as a proxy for nasal tip support. This information will become increasingly important in computational modeling of nasal tip mechanics and ultimately will enhance surgical planning for rhinoplasty. LEVEL OF EVIDENCE: NA. PMID- 27124819 TI - Age-Related Macular Degeneration and Quality of Life in Latinos: The Los Angeles Latino Eye Study. AB - IMPORTANCE: This study found evidence of a threshold effect in which the presence of bilateral soft drusen and depigmentation of retinal pigment epithelium was associated with substantially low health-related quality of life (HRQoL) in adult Latinos from the United States. OBJECTIVE: To assess the association of general and vision-specific HRQoL with age-related macular degeneration (AMD), overall and by bilaterality and severity, in adult Latinos. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, population-based study included 4876 participants from the general urban community in 6 US Census tracts in La Puente, California. The data for these analyses were collected as part of a population based study of ocular diseases in adult Latinos in the Los Angeles Latino Eye Study from February 1, 2000, through May 31, 2003. The analysis was performed from November 2010 to February 2011. Additional analyses were performed in June 2014. MAIN OUTCOMES AND MEASURES: Mean-adjusted HRQoL scores and effect sizes. RESULTS: Of the 4876 participants included in the analysis, 4402 (90.3%) had no AMD, and 474 (9.7%) had any AMD, with 453 having early (9.3%) and 21 (0.4%) having late stages of the disease. The mean (SD) age of the cohort was 54.8 (10.7) years. Of the 4876 participants, 2001 (41.0%) were male and 2875 (59.0%) were female. In this cohort of Latinos, participants with AMD had lower vision specific HRQoL scores. General HRQoL was assessed by the Medical Outcomes Study 12-Item Short-Form Health Survey and self-reported vision-related HRQoL by the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25). Composite NEI-VFQ-25 scores were 59.5 (95% CI, 50.8-68.1) for those with late-stage AMD and 79.4 (95% CI, 72.5-86.1) for those with early-stage AMD, compared with participants without AMD 80.7 (95% CI, 73.9-82.4); P < .001. Several lesions of early AMD were associated with lower NEI-VFQ-25 composite scores and 8 to 10 individual scales. Large effect sizes and lower mean scores were observed for those with late AMD lesions, overall and specifically for geographic atrophy and neovascular AMD, compared with those without AMD. With the use of concatenated bilateral severity levels for AMD, decreases in the NEI-VFQ-25 composite and individual scale scores were observed at the transition from a unilateral to bilateral severity level of 40, which corresponds to having bilateral soft drusen (>125 MUm in diameter with drusen area >=196 350 MUm2) and depigmentation of retinal pigment epithelium (slope of -19.17 for the NEI-VFQ-25 composite score). Measures of general health, as assessed by the Medical Outcomes Study 12-Item Short-Form Health Survey, were not affected in this cohort. CONCLUSIONS AND RELEVANCE: In this study of adult Latinos, early AMD lesions are associated with lower self-reported, vision-specific HRQoL but not general HRQoL. Severity and bilaterality of AMD are associated with measurably lower HRQoL scores, with the largest difference in scores occurring for individuals with both eyes affected. A concatenated approach to incorporate bilateral severity might be more useful and provide better insight into the association of AMD and HRQoL. PMID- 27124820 TI - Long-Term Tracking Mesenchymal Stem Cell Differentiation with Photostable Fluorescent Nanoparticles. AB - Mesenchymal stem cells (MSCs) have proved to be a promising and abundant cell source for tissue and organ repair in regenerative medicine. However, the cell fate, distribution and migration of these transplanted cells are still unclear due to the limited tracking methods. It is desirable to develop a biocompatible and photostable probe to label the MSCs for long-term tracking without affecting the cell proliferation and potency. Herein we apply a recently developed nanoprobe system, in which di(thiophene-2-yl)-diketopyrrolopyrrole (DPP) is covalently linked in the middle of polycaprolactone (PCL) forming the PCL-DPP-PCL polymer complex. Although the PCL-DPP-PCL nanoparticles uptaken by the MSCs did not affect the cell viability, it was interesting that they exhibited different effects on the multilineage potency of the MSCs in the subsequent differentiation in vitro. Specifically, we found that the PCL-DPP-PCL labeling was unfavorable to the MSC osteogenic differentiation, whereas the labeled MSCs exhibited the same adipogenic and chondrogenic differentiations compared to the unlabeled controls as verified by gene expressions and histological staining. Furthermore, the PCL DPP-PCL nanoparticles remained strong fluorescence intensity even after 4 weeks of differentiation. This study indicated that PCL-DPP-PCL nanoparticles could be used for long-term cell tracing in MSC differentiation into adipogenic and chondrogenic lineages. PMID- 27124821 TI - On the nature of chemical bonding in the all-metal aromatic [Sb3Au3Sb3](3-) sandwich complex. AB - In a recent communication, an all-metal aromatic sandwich [Sb3Au3Sb3](3-) was synthesized and characterized. We report herein a density-functional theory (DFT) study on the chemical bonding of this unique cluster, which makes use of a number of computational tools, including the canonical molecular orbital (CMO), adaptive natural density partitioning (AdNDP), Wiberg bond index, and orbital composition analyses. The 24-electron, triangular prismatic sandwich is intrinsically electron-deficient, being held together via six Sb-Sb, three Au-Au, and six Sb-Au links. A standard, qualitative bonding analysis suggests that all CMOs are primarily located on the three Sb3/Au3/Sb3 layers, three Au 6s based CMOs are fully occupied, and the three extra charges are equally shared by the two cyclo Sb3 ligands. This bonding picture is referred to as the zeroth order model, in which the cluster can be formally formulated as [Sb3(1.5+)Au3(3-)Sb3(1.5+)](3-) or [Sb3(0)Au3(3-)Sb3(0)]. However, the system is far more complex and covalent than the above picture. Seventeen CMOs out of 33 in total involve remarkable Sb > Au electron donation and Sb <- Au back-donation, which are characteristic of covalent bonding and effectively redistribute electrons from the Sb3 and Au3 layers to the interlayer edges. This effect collectively leads to three Sb-Au-Sb three-center two-electron (3c-2e) sigma bonds as revealed in the AdNDP analyses, despite the fact that not a single such bond can be identified from the CMOs. Orbital composition analyses for the 17 CMOs allow a quantitative understanding of how electron donation and back-donation redistribute the charges within the system from the formal Sb3(0)/Au3(3-) charge states in the zeroth order model to the effective Sb3(1.5-)/Au3(0) charge states, the latter being revealed from the natural bond orbital analysis. PMID- 27124822 TI - Early Predictors of Mortality in Geriatric Patients With Trauma. AB - OBJECTIVE: To identify variables that predict mortality in geriatric patients with trauma. DESIGN: Retrospective review. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: A total of 147 geriatric patients with trauma (age >=65) with a predicted probability of survival of 10%-75% based on the Trauma Score Injury Severity Score (TRISS). MAIN OUTCOME MEASUREMENTS: Patients were divided into 2 cohorts: survivors and nonsurvivors. The following variables available at presentation were analyzed: age, mechanism of injury, temperature, systolic blood pressure, pulse rate, shock index, respiratory rate, Glasgow Coma Scale (GCS) score, base deficit, and hematocrit (HCT). The Injury Severity Score (ISS) and TRISS were calculated for both cohorts. RESULTS: Of the 147 patients analyzed, 84 (57%) died during the index hospitalization and 63 (43%) survived. The mean age of nonsurvivors was significantly higher than that of survivors (78.6 vs. 76.1 years; P < 0.04). A greater number of nonsurvivors (72.6%) sustained injuries as a result of a low-energy mechanism compared with survivors (54%; P = 0.02). GCS, temperature, and respiratory rate were significantly lower for nonsurvivors, whereas base deficit was higher (P < 0.05). The TRISS was predictive of survival (TRISS 0.27 vs. 0.53, P < 0.001), but the distinguishing capacity of the TRISS to predict mortality was limited (area under the receiver operator curve; 0.67; 95% confidence interval 0.58-0.76; P < 0.0001). CONCLUSIONS: Older age, lower GCS, and a low-energy mechanism of injury are associated with a higher mortality rate in this at-risk geriatric trauma population. Early identification of predictors of mortality may help care providers more accurately assess injury burden in geriatric patients. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27124823 TI - A Comparison of Three C-Arm Draping Techniques to Minimize Contamination of the Surgical Field. AB - The use of intraoperative fluoroscopy has become a routine and useful adjunct within orthopaedic surgery. However, the fluoroscopy machine may become an additional source of contamination in the operating room, particularly when maneuvering from the anterior-posterior position to the lateral position. Consequently, draping techniques were developed to maintain sterility of the operative field and surgeon. Despite a variety of methods, no studies exist to compare the sterility of these techniques specifically when the fluoroscopy machine is in the lateral imaging position. We evaluated the sterility of 3 c-arm draping techniques in a simulated operative environment. The 3 techniques consisted of a traditional 3-quarter sterile sheet attached to the side of the operative table, a modified clip-drape method, and a commercially available sterile pouch. Our study demonstrated that the traditional method poses a high risk for sterile field contamination, whereas the modified clip-drape method and commercially available sterile pouch kept floor contamination furthest from the surgical field. With the current data, we urge surgeons to use modified techniques rather than the traditional draping method. PMID- 27124824 TI - Membrane Induced Osteogenesis in the Management of Posttraumatic Bone Defects. AB - OBJECTIVE: To evaluate the union rate of posttraumatic bone defects treated with the induced membrane technique. DESIGN: Single-center retrospective case series. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: Thirty-three patients who sustained 34 posttraumatic bone defects (19 tibia, 15 femur). INTERVENTION: Staged management using the induced membrane technique described by Masquelet. After extensive debridement at the fracture site, a polymethylmethacrylate (PMMA) spacer was inserted into the resulting void. After soft tissue recovery, the spacer was removed, and the void, now enveloped by an induced membrane, was filled with an autologous iliac crest bone graft. MAIN OUTCOME MEASURES: Bone union rate, time to achieve bone union, length of hospital stay, number of surgeries, infection resolution, range of motion, musculoskeletal tumor society system functional score, and limb shortening. RESULTS: The mean defect size was 6.7 cm, and infection was present in 23 (68%) of the bone defects. Bone union was evident in 91% of cases (31/34). The average time to union was 8.5 months. In 7 of 23 (30%) of infected cases, the infection recurred, and in 3 of them, the graft was resorbed, resulting in treatment failure. CONCLUSION: The induced membrane technique was effective for managing posttraumatic bone defects. A recurrence of infection was associated with treatment failure. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27124825 TI - Five-Year Outcome Analysis of Intertrochanteric Femur Fractures: A Prospective Randomized Trial Comparing a 2-Screw and a Single-Screw Cephalomedullary Nail. AB - OBJECTIVES: To compare the radiological and functional outcome after fixation of intertrochanteric fractures (IF) using either an integrated 2-screw cephalomedullary nail [InterTan (IT); Smith & Nephew] or a single-screw device [Gamma3 (G3); Stryker] with a 5-year follow-up. DESIGN: Prospective, randomized. SETTINGS: A single-center study. PATIENTS: One hundred four patients with a mean age of 81.2 +/- 9.2 years were included, 33 patients were available for the final 5-year follow-up, 63 patients died, and 8 patients were lost for follow-up. INTERVENTION: Internal fixation of intertrochaneteric femur fractures using a cephalomedullary nail with either a single screw or an integrated 2-screw system. MAIN OUTCOME MEASUREMENTS: Length of hospital stay, SF-36-questionnaire, Harris Hip-Score, radiographs. RESULTS: SF-36 index at 6 months indicated that 93% of the IT group returned to their prefracture status compared with only 80% in the G3 group. For the mental health SF-36 index, the IT patients showed a significant increased level 6 months after the index procedure (IT: P = 0.02; G3: P = 0.20). The length of hospital stay was significantly (P = 0.03) shorter in the IT group. After 5 years however, neither group had significant implant-related complications or differences in terms of functional outcome. CONCLUSIONS: Regarding functional outcome and hospital stay, the IT collective performed better in the 6-month follow-up. After 5 years, no significant differences were recorded. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 27124826 TI - Time-Dependent Effectiveness of Locally Applied Vancomycin Powder in a Contaminated Traumatic Orthopaedic Wound Model. AB - OBJECTIVES: To evaluate the effectiveness of locally applied vancomycin powder at different times postinfection in a contaminated traumatic animal model. METHODS: This study used an established segmental defect rat femur model contaminated with Staphylococcus aureus UAMS-1 followed by treatment at 6 or 24 hours postinfection. Three treatments were evaluated: debridement and irrigation alone (control group) or in combination with either vancomycin powder or vancomycin impregnated poly(methyl methacrylate) beads. Serum vancomycin levels were determined at scheduled time points over 14 days; bone, surrounding muscle, and implants were harvested for bacterial and inflammatory analyses. RESULTS: Locally applied vancomycin powder and impregnated beads significantly reduced bacteria both within the bone and implant when treatment was performed at 6 hours. Delaying treatment to 24 hours significantly reduced the therapeutic efficacy of locally applied vancomycin of both groups. Serum vancomycin levels were detectable in all animals treated with vancomycin powder at 24 hours, but absorption was negligible from beads. At 14 days, vancomycin was detectable in the surrounding musculature of all animals and in serum of 20% of animals treated with vancomycin powder. CONCLUSIONS: This study suggests that vancomycin powder is a promising adjunctive therapy for preventing infection in traumatic wounds when treatment is performed early. This time-dependent effectiveness of vancomycin powder is similar to that observed with systemic and other local delivery adjuncts, which is likely attributable to biofilm formation after contamination, conferring intrinsic recalcitrance to antimicrobials. PMID- 27124827 TI - Hemorrhagic-Induced Cardiovascular Complications During Reamer-Irrigator Aspirator-Assisted Femoral Nonunion Treatment. AB - The reamer-irrigator-aspirator (RIA) is a device that has recently been developed to retrieve bone graft from the medullary canal of the femur and the tibia. As for most new surgical procedures, complications arise as part of the learning curve and/or imperfections in the design or technique. To increase awareness of potential complications and to prevent unnecessary harm to the patient, new complications need to be reported. We present case reports of 2 patients who developed severe intraoperative cardiac events presumably caused by excessive and rapid blood loss during RIA bone graft harvesting. This complication has not been described before. Increased awareness of excessive blood loss and subsequent cardiac events during an RIA procedure is warranted. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27124828 TI - Ketorolac Administered in the Recovery Room for Acute Pain Management Does Not Affect Healing Rates of Femoral and Tibial Fractures. AB - OBJECTIVES: To determine whether ketorolac administered in the immediate perioperative period affects the rate of nonunion in femoral and tibial shaft fractures. DESIGN: Retrospective comparative study. SETTING: Single Institution, Academic Level 1 Trauma Center. PATIENTS: Three hundred and thirteen skeletally mature patients with 137 femoral shaft (OTA 32) and 191 tibial shaft (OTA 42) fractures treated with intramedullary rod fixation. INTERVENTION: Eighty patients with 33 femoral shaft and 52 tibial shaft fractures were administered ketorolac within the first 24 hours after surgery (group 1-study group). Two-hundred thirty three patients with 104 femoral shaft and 139 tibial shaft fractures were not (group 2-control group). MAIN OUTCOME MEASUREMENTS: Rate of reoperation for repair of a nonunion and time to union. RESULTS: Average time to union of the femur was 147 days for group 1 and 159 days for group 2 (P = 0.57). Average time to union of the tibia was 175 days for group 1 and 175 days for group 2 (P = 0.57). There were 3 femoral nonunions (9%) in group 1 and eleven femoral nonunions (11.6%) in group 2 (P = 1.00). There were 3 tibial nonunions (5.8%) in group 1 and 17 tibial nonunions (12.2%) in group 2 (P = 0.29). The average dose of ketorolac for patients who healed their fracture was 85 mg, whereas it was 50 mg for those who did not (P = 0.27). All patients with a nonunion in the study group were current smokers. CONCLUSIONS: Ketorolac administered in the first 24 hours after fracture repair for acute pain management does not seem to have a negative impact on time to healing or incidence of nonunion for femoral or tibial shaft fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27124829 TI - Culture-Negative Infection After Operative Fixation of Fractures. AB - OBJECTIVES: (1) Compare the outcomes of patients with orthopaedic trauma with culture-negative infection with those with pathogens identified; (2) identify the incidence of culture-negative infection and describe the common characteristics. DESIGN: Retrospective study. SETTING: Two level 1 trauma centers. PATIENTS: A total of 391 patients 16 years of age or older who underwent irrigation and debridement for surgical site infection after having undergone fracture fixation were included. INTERVENTION: Patients underwent irrigation and debridement with cultures, and antibiotic therapy was initiated. MAIN OUTCOME MEASUREMENT: Treatment failure due to unsuccessful eradication of infection and time to union. RESULTS: We found 9% incidence of culture-negative infection. Approximately one third of patients in both groups went on to have treatment failure (25% of pathogen-specific infections, 38% of culture-negative infections, P = 0.15), and there was no difference between the 2 groups with regard to time to union (22 vs. 24 weeks, P = 0.55). More than one-third of patients required subsequent reconstructive procedure and 5% of patients in each group required amputation to control their infection. There was no difference between the groups with respect to the use of antibiotics before intervention and culture. CONCLUSION: This study confirms the devastating effect that postoperative infections can have and suggests that, with clinical sign of infection, negative cultures do not portend a better prognosis. These entities should be treated in a similar manner to infections with positive cultures. Furthermore, we believe that future studies should not strictly rely on the presence of positive intraoperative cultures. Consensus as to what constitutes a clinical infection, in the absence of positive cultures, is needed. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27124830 TI - Association Between Tibial Malunion Deformity Parameters and Degenerative Hip and Knee Disease. AB - OBJECTIVES: Tibia fractures are the most common long bone fracture. Criteria for closed and open reduction are based on the amount of fracture shortening, angulation, and rotation, with high success rates achieved if acceptable alignment is maintained. However, there exists limited data available regarding the long-term consequences of specific deformation patterns. METHODS: The tibiae of 2898 cadaveric skeletons were manually inspected for evidence of fracture. Specimens with midshaft fractures were identified as candidates for study; intraarticular fractures were excluded. Fracture shortening, location, angulation, rotation (torsion), and translation were measured using previously described techniques. Degenerative joint disease of the knee and hip was graded from 0 to 3 in fracture specimens using a previously published system. Correlations between fracture characteristic and osteoarthritis were evaluated. RESULTS: Thirty-seven tibia fractures were present in 36 skeletons. In patients with tibia fractures, ipsilateral knee arthritis was greater than that of the contralateral side (P < 0.001). Knee arthritis was greater in fractures with coronal plane deformity greater than 5 degrees (P = 0.006) and with rotational deformity greater than 10 degrees (P = 0.004). There were no differences in knee arthritis based on laterality, shortening, sagittal deformity, fracture type, or translation in any plane (P > 0.05 for all). There were no differences in hip arthritis on the ipsilateral side compared with the contralateral side (P = 0.149). However, tibiae that were shortened by more than 10 mm had higher grades of ipsilateral hip arthritis (P = 0.009). CONCLUSIONS: The results of this study suggest that coronal and axial plane malalignment and shortening are of the greatest consequence following tibia fracture. These conclusions strengthen the recommendations of authors who have emphasized restoring tibial length following fracture, and providing anatomic restoration in the coronal and axial planes. PMID- 27124831 TI - Water Buffalo (Bubalus bubalis) as a spontaneous animal model of Vitiligo. AB - Vitiligo is a multifactorial acquired depigmenting disorder. Recent insights into the molecular mechanisms driving the gradual destruction of melanocytes in vitiligo will likely lead to the discovery of novel therapies, which need to be evaluated in animal models that closely recapitulate the pathogenesis of human vitiligo. In humans, vitiligo is characterized by a spontaneous loss of functional melanocytes from the epidermis, but most animal models of vitiligo are either inducible or genetically programmed. Here, we report that acquired depigmentation in water buffalo recapitulates molecular, histological, immunohistochemical, and ultrastructural changes observed in human vitiligo and hence could be used as a model to study vitiligo pathogenesis and facilitate the discovery and evaluation of therapeutic interventions for vitiligo. PMID- 27124832 TI - Sophisticated Design of Covalent Organic Frameworks with Controllable Bimetallic Docking for a Cascade Reaction. AB - Precise control of the number and position of the catalytic metal ions in heterogeneous catalysts remains a big challenge. Here we synthesized a series of two-dimensional (2D) covalent organic frameworks (COFs) containing two different types of nitrogen ligands, namely imine and bipyridine, with controllable contents. For the first time, the selective coordination of the two nitrogen ligands of the 2D COFs to two different metal complexes, chloro(1,5 cyclooctadiene)rhodium(I) (Rh(COD)Cl) and palladium(II) acetate (Pd(OAc)2 ), has been realized using a programmed synthetic procedure. The bimetallically docked COFs showed excellent catalytic activity in a one-pot addition-oxidation cascade reaction. The high surface area, controllable metal-loading content, and predesigned active sites make them ideal candidates for their use as heterogeneous catalysts in a wide range of chemical reactions. PMID- 27124834 TI - Trimethylammonium-Derived Molecular Tweezers and Their Host-Guest Complexation Behaviours in Polar Media. AB - Trimethylammonium-derived alkynylplatinum(II) terpyridine molecular tweezers have been designed and synthesized in this manuscript. They show moderate binding affinity towards the complementary organoplatinum guest in polar media, such as DMSO, methanol, and water, even though the guest itself is sparingly soluble in the latter two solvents. Responsive guest encapsulation/release from the cavity of molecular tweezers can be achieved by successive addition and removal of trifluoroacetic acid, accompanying with remarkable switching of the photophysical signals, which would benefit for the fabrication of intelligent supramolecular materials with tailored functionalities. PMID- 27124833 TI - Preliminary Results of National Amyotrophic Lateral Sclerosis (ALS) Registry Risk Factor Survey Data. AB - BACKGROUND: The National ALS Registry is made up of two components to capture amyotrophic lateral sclerosis (ALS) cases: national administrative databases (Medicare, Medicaid, Veterans Health Administration and Veterans Benefits Administration) and self-identified cases captured by the Registry's web portal. This study describes self-reported characteristics of U.S. adults with ALS using the data collected by the National ALS Registry web portal risk factor surveys only from October 19, 2010 through December 31, 2013. OBJECTIVE: To describe findings from the National ALS Registry's web portal risk factor surveys. MEASUREMENTS: The prevalence of select risk factors among adults with ALS was determined by calculating the frequencies of select risk factors-smoking and alcohol (non, current and former) histories, military service and occupational history, and family history of neurodegenerative diseases such as ALS, Alzheimer's and/or Parkinson's. RESULTS: Nearly half of survey respondents were ever smokers compared with nearly 41% of adults nationally. Most respondents were ever drinkers which is comparable to national estimates. The majority were light drinkers. Nearly one-quarter of survey respondents were veterans compared with roughly 9% of US adults nationally. Most respondents were retired or disabled. The industries in which respondents were employed for the longest time were Professional and Scientific and Technical Services. When family history of neurodegenerative diseases in first degree relatives was evaluated against our comparison group, the rates of ALS were similar, but were higher for Parkinson's disease, Alzheimer's disease and any neurodegenerative diseases. CONCLUSIONS: The National ALS Registry web portal, to our knowledge, is the largest, most geographically diverse collection of risk factor data about adults living with ALS. Various characteristics were consistent with other published studies on ALS risk factors and will allow researchers to generate hypotheses for future research. PMID- 27124835 TI - Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial. AB - IMPORTANCE: More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days results in clinical benefit and manageable toxic effects. OBJECTIVE: To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib (PD0332991). DESIGN, SETTING, AND PARTICIPANTS: In this phase 2, nonrandomized, open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center, 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015. Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles. MAIN OUTCOMES AND MEASURES: Primary end point was PFS. Secondary end points included response rate and toxic effects. RESULTS: Overall, 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median (range) age was 61.5 (35-87) years; 31 patients (52%) were male; median (range) Eastern Cooperative Oncology Group score was 0 (0-1). Progression-free survival at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%), and the median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks). There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. CONCLUSIONS AND RELEVANCE: In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01209598. PMID- 27124837 TI - Privacy in paediatrics. PMID- 27124836 TI - Validation of Chinese Version of Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (Chi-PCOSQ). AB - OBJECTIVES: To evaluate the responsiveness, longitudinal validity, and measurement invariance of the Chinese version of the Polycystic Ovary Syndrome Health-related Quality of Life Questionnaire (Chi-PCOSQ). RESEARCH DESIGN AND METHOD: This prospective study was conducted in a medical center in southern Taiwan. 102 women aged 18-45 years and diagnosed with PCOS were enrolled. Objective indicators for clinical changes of PCOS included assessing the 2-hour glucose and insulin levels before and after treatment. The responsiveness of Chi PCOSQ and WHOQOL-BREF was analyzed using paired t-tests and the standard response mean. Confirmatory factor analysis was performed to assess the measurement invariance of Chi-PCOSQ. RESULTS: With improved 2-hour glucose and insulin levels, we also found significantly increased Chi-PCOSQ total and individual domain scores (total score: t (49) = 5.20; p < 0.001, domain scores: t (49) = 2.72 to 3.87; p < 0.01), except for hair growth. Half of the domains scores (3 of 6) and the total score of Chi-PCOSQ had a medium responsiveness, but WHOQOL-BREF was not sufficiently responsive to clinical changes of PCOS. Improved PCOS specific health-related quality of life (HRQoL), as indicated by Chi-PCOSQ scores, was significantly associated with improved 2-hour glucose and insulin levels. All indices of the data-model fit of the Chi-PCOSQ structure were satisfactory, except for the slightly high standardized root mean square residual values (0.087 to 0.088). The measurement invariance of Chi-PCOSQ was supported across time. CONCLUSION: Chi-PCOSQ is sufficiently sensitive in detecting clinical changes and its measurement structure is suitable for Chinese women with PCOS. It is thus a promising tool for assessing the HRQoL of ethnic Chinese women with PCOS. PMID- 27124838 TI - Privacy for neonates: 'All the world loves a baby'. PMID- 27124839 TI - Why respecting all human beings' privacy matters. PMID- 27124840 TI - Lysosomal storage disorders: A review of the musculoskeletal features. AB - The lysosomal storage disorders are a collection of progressive, multisystem disorders that frequently present in childhood. Their timely diagnosis is paramount as they are becoming increasingly treatable. Musculoskeletal manifestations often occur early in the disease course, hence are useful as diagnostics clues. Non-inflammatory joint stiffness or pain, carpal tunnel syndrome, trigger fingers, unexplained pain crises and short stature should all prompt consideration of a lysosomal storage disorder. Recurrent ENT infections, hepatosplenomegaly, recurrent hernias and visual/hearing impairment - especially when clustered together - are important extra-skeletal features. As diagnostic and therapeutic options continue to evolve, children with lysosomal storage disorders and their families are facing more sophisticated options for screening and treatment. The aim of this article is to highlight the paediatric presentations of lysosomal storage disorders, with an emphasis on the musculoskeletal features. PMID- 27124841 TI - CeasIng Cpap At standarD criteriA (CICADA): Implementation improves neonatal outcomes. AB - BACKGROUND: A previous randomised controlled trial (RCT) in babies born < 30 weeks gestation found the so-called CICADA method (ceasing continuous positive airways pressure (CPAP) with a view to remain off rather than slow weaning) significantly reduced CPAP time. Post-RCT we introduced the CICADA method and evaluated whether the improved outcomes of the CICADA method during the RCT were replicated in clinical practice. AIM: The aim of the study is to compare cardio respiratory outcomes in PBs < 30 weeks GA over three epochs: (i) pre RCT, (ii) during RCT and (iii) post RCT implementation. METHODS: The study used prospective data to compare baseline characteristics and cardio-respiratory outcomes over the three epochs. RESULTS: There were 270/393(69%) PBs < 30 weeks GA who fulfilled the inclusion criteria over the three epochs. No significant differences were found in GA or birthweight between the three epochs (27.9 +/- 1.3, 27.7 +/- 1.4, 28.0 +/- 1.3 (weeks +/- 1 standard deviation); and 1100 +/- 252, 1086 +/- 251, 1094 +/- 320 (grams +/- 1 standard deviation)). There were significant decreases in CPAP days and corrected GA to cease CPAP post implementation (20.5 +/- 2.1, 21.1 +/- 2.1, 16.5 +/- 1.8 (days +/- SE); P = 0.006 and 33.3 +/- 0.4, 33.5 +/- 0.4, 32.6 +/- 0.4 (weeks +/- SE); P = 0.01). Compared with the pre RCT epoch, there were significant reductions in patent ductus arteriosus (36/78 (46%), 33/87 (37%), 18/103 (17%); P < 0.001) and chronic lung disease (40/78 (51%), 19/87 (21%), 30/103 (29%); P < 0.001). CONCLUSIONS: CPAP time, corrected GA to cease CPAP, patent ductus arteriosus and chronic lung disease significantly reduced following the introduction of the CICADA method. Early cessation of CPAP expedites the transition from neonatal intensive care to special care. PMID- 27124842 TI - Developmental outcomes in cerebrospinal fluid proven enteroviral meningitis in neonates > 32 weeks of gestation. AB - AIM: The aim of this study is to assess the short-term and long-term (1 year) outcomes of cerebrospinal fluid (CSF) confirmed enteroviral meningitis in neonates > 32 weeks of gestation. METHODS: A retrospective audit of neonates admitted between 1 July 2002 to 30 June 2012. RESULTS: Thirty-three neonates were diagnosed with enteroviral meningitis based on a positive CSF enteroviral PCR. Physical growth and neurodevelopmental outcomes at 1 year corrected for prematurity were available for 24 infants. All infants were alive at 1 year. The median weight, length and head circumference at 1 year were in the 72nd, 62nd and 78th centile and were comparable with the birth parameters. The mean general quotient (GQ) was 98.5 (SD 7.1) and was not significantly different from the population mean of 100.2 (P = 0.27). None of the infants had a GQ > 2SD below the population mean. Neurological recovery was complete in the 24 neonates assessed except one, who developed cerebral palsy, epilepsy and progressive hydrocephalus requiring ventriculoperitoneal shunt at 1 year. CONCLUSION: Neonatal enteroviral meningitis was associated with optimal growth and neurodevelopment in the majority of the infants at 1 year corrected for prematurity. Longer term studies are needed to better define developmental outcomes. PMID- 27124843 TI - Oximetry for preterm infants at neonatal discharge: What is current practice in New Zealand and Australia? AB - AIM: The aim of the study was to survey level 2 and 3 neonatal units in Australasia to determine the prevalence of oximetry studies at discharge for preterm infants, how these oximetry studies are performed, and which measures are included in an oximetry report. METHODS: A 10-question online survey was created using Survey Monkey regarding use of predischarge oximetry and e-mailed to 46 neonatal units (all level 2 and three units in NZ and all level 3 units in Australia). RESULTS: The response rate was 59% (27/46) with a NZ response rate of 78% (18/23). There was variation in the groups of infants receiving predischarge oximetry studies, with one fifth of responding neonatal units never performing oximetry at discharge. Of the units using predischarge oximetry screening, infants being discharged home on supplemental oxygen were the only group for which all units perform predischarge oximetry. Masimo (Masimo, Irvine, California, USA) is the most common oximeter brand and profox Associates, Inc. (PROFOX Associates, Inc., Escondido, CA 92025, USA) the most common analysis software used. Measures included in oximetry reports vary between units, with profox Associates, Inc.'s default event definition of 'a drop in saturation by four or more' being the most commonly reported desaturation definition. CONCLUSIONS: These findings indicate a need for guidelines to standardise preterm infant oximetry monitoring at neonatal discharge. Further research is required to determine the utility of predischarge oximetry and to establish which infants should be screened. PMID- 27124844 TI - Fulminant liver failure in a neonate. AB - Neonatal acute liver disease is relatively rare, with multiple different aetiologies including congenital infections, metabolic disorders, gestational alloimmune liver disease, haemophagocytic lymphohistiocytosis, and ischaemic injury. We report a case of neonatal liver failure in a preterm, growth restricted infant, who underwent extensive investigation and was clinically diagnosed with gestational alloimmune liver disease, which was confirmed on post mortem examination. We then discuss management of neonatal liver failure and gestational alloimmune liver disease, including maternal management in future pregnancies. PMID- 27124845 TI - Profuse watery diarrhoea: An unusual presenting feature of streptococcal toxic shock syndrome. PMID- 27124846 TI - Agitation on emergence from sevoflurane anaesthesia can be reduced. PMID- 27124847 TI - The mother load. PMID- 27124848 TI - In premature infants born at borderline viability, do days matter? PMID- 27124849 TI - A peripherally inserted central line in a preterm infant. PMID- 27124850 TI - Verrucous pits on the palms. PMID- 27124851 TI - A peripherally inserted central line in a preterm infant. PMID- 27124852 TI - Verrucous pits on the palms. PMID- 27124854 TI - Methylphenidate and attention-deficit hyperactivity disorder. PMID- 27124853 TI - The spice of life? PMID- 27124855 TI - Toddlers can use touch screen technology purposefully. PMID- 27124856 TI - Phototherapy using filtered sunlight. PMID- 27124857 TI - Phototherapy in transport for neonates with unconjugated hyperbilirubinaemia. PMID- 27124858 TI - Embarrassing Moments. PMID- 27124859 TI - Development and Cognitive Functions in Saudi Pre-School Children with Feeding Problems without Underlying Medical Disorders. PMID- 27124861 TI - Janus all-cis-1,2,3,4,5,6-Hexafluorocyclohexane: A Molecular Motif for Aggregation-Induced Enhanced Polarization. AB - Recently synthesized all-cis-1,2,3,4,5,6-hexafluorocyclohexane is the least stable among all possible configurational isomers of 1,2,3,4,5,6 hexafluorocyclohexane. This molecule has a remarkably large dipole moment (6.2 D) as well as high facial polarization. Solid-state, dispersion-corrected DFT (DFT D3) calculations are performed on the crystalline phase of all-cis-1,2,3,4,5,6- hexafluorocyclohexane, which reveal that dispersion interactions play a crucial role in its stabilization. A number of thermodynamically favorable orientations of dimers, trimers and tetramers are demonstrated for this molecule. Parallel stacked aggregates, from dimers to higher-order aggregates, which are absent in the crystal, are found to be thermodynamically most favorable due to the presence of strong short-range C-H???F-C intermolecular hydrogen-bonding networks. Because of their cooperative nature, binding energies, dipole moments, and polarizations per molecule increase from monomer to tetramer, whereas the HOMO-LUMO gaps follow the opposite trend. Based on the DFT-D3 calculations, it is proposed that this parallel-stacked arrangement can be further extended to prepare stable a 1D crystal such that a large dipole moment and macroscopic polarizations can arise, which might be useful in designing electronic and nonlinear optical devices. Because the molecule has conformational flexibility, the potential energy surface is investigated for ring flipping and the effects of fluorine substitution are studied by comparing the barrier with respect to cyclohexane and all-cis-1,2,3 trifluorocyclohexane. PMID- 27124860 TI - Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction? AB - OBJECTIVE: To examine the effects of mirabegron, a selective beta3 -adrenoceptor agonist that has recently been approved for the treatment of overactive bladder (OAB), on erectile function. Stimulation of beta3 -adrenoceptors localised in cavernosal smooth muscle cells may play a physiological role in mediating penile erection, and offer a beneficial pharmacological action for patients who have OAB and erectile dysfunction (ED). MATERIALS AND METHODS: Corpus cavernosal (CC) specimens were obtained from patients with ED and Peyronie's disease undergoing penile prosthesis implantation. Erectile responses were also evaluated in vivo after intracavernosal injection (ICI) of mirabegron in anaesthetised rats. Mirabegron-elicited relaxation responses (10(-8) -10(-3) m) on phenylephrine induced contraction were seen in human CC (HCC) and rat CC strips in isolated organ-bath studies. The effects of inhibitors, namely L-NAME [N(G) -nitro-L arginine methyl ester, a competitive inhibitor of nitric oxide synthase (NOS), 100 MUm], ODQ [1H-(1,2,4) oxadiazolo(4,3-alpha) quinoxalin-1-one, a soluble guanylyl cyclase (sGC) inhibitor, 30MUm], methylene blue (a NOS and sGC inhibitor, 20MUm), SR59230A (beta3 -adrenoceptor blocker, 1 MUm), and fasudil [Rho-associated protein kinase (ROCK) inhibitor, 0.1 MUm], on mirabegron-induced relaxation responses were evaluated. Responses to mirabegron were compared with responses to isoprenaline and nebivolol. Immunohistochemistry was used to localise beta3 -adrenoceptors and ROCK in CC smooth muscle cells. In vivo rat data were expressed as intracavernosal pressure (ICP)/mean arterial pressure, and total ICP. RESULTS: Mirabegron resulted in a relaxation of phenylephrine-evoked CC contractions in a concentration-dependent manner and SR59230A antagonised the mirabegron-induced relaxations in HCC and rat CC. Other inhibitors, L-NAME, ODQ, and methylene blue, did not affect the mirabegron-induced relaxation responses. Mirabegron relaxation responses at concentrations (0.1-10 MUm) were enhanced by fasudil (ROCK inhibitor) in rat but not in HCC strips. KCl-induced contractions in HCC and rat CC were partially inhibited by mirabegron. In vivo, ICI of mirabegron (doses of 0.1-1 mg/kg) had a minor effect on ICP when compared with vehicle administration. Immunohistochemistry data showed beta3 -adrenoceptors localised in the smooth muscle cells of the HCC and rat CC. CONCLUSIONS: Mirabegron markedly relaxed isolated CC strips by activating beta3 -adrenoceptors independently of the NO-cGMP pathway. There is also evidence of the existence of a close functional link between beta3 -adrenoceptors and the RhoA/ROCK pathway. These results may support further clinical studies using combinations of mirabegron with ROCK and phosphodiesterase type 5 inhibitors (PDE5i) for the treatment of ED, especially in patients who do not respond to PDE5i therapy. PMID- 27124876 TI - Casting of 3-dimensional footwear prints in snow with foam blocks. AB - Commercially available foam blocks are presented as an alternative material for the casting and preservation of 3-dimensional footwear impressions located in snow. The method generates highly detailed foam casts of questioned footwear impressions. These casts can be compared to the known outsole standards made from the suspects' footwear. Modification of the commercially available foam casting blocks is simple and fast. The foam block is removed and a piece of cardboard is secured to one side of the block with painter's masking tape. The prepared foam block is then placed back into its original box, marked appropriately, closed and stored until needed. When required the foam block is carefully removed from its storage box and gently placed, foam side down, over the questioned footwear impression. Next, the crime scene technician's hands are placed on top of the cardboard and pressure is gently applied by firmly pressing down onto the impression. The foam cast is removed, dried and placed back into its original container and sealed. The resulting 3D impressions can be directly compared to the outsole of known suspected item(s) of footwear. PMID- 27124877 TI - Janus Composite Nanotubes. AB - We propose a facile method to achieve paramagnetic Janus nanotubes with two compositions compartmentalized onto the interior and exterior surfaces, respectively. A sulfonated polydivinylbenzene (PDVB) nanotube is prepared by simple sulfonation of the exterior surface of a PDVB nanotube. Silica@FeOOH dual layers are sequentially grown onto the sulfonated PDVB nanotube surface. The composite nanotubes become paramagnetic after calcination and can be broken into shorter pieces under vigorous ultrasonication. After selective modification of the interior and exterior surfaces of the paramagnetic nanotubes, the nanotube shell becomes Janus in wettability. Desired hydrophobic species can be selectively captured inside the cavity. The paramagnetic Janus composite nanotubes can align into parallel chains under a magnetic field, which is self disassembled upon removal of the magnetic field. PMID- 27124878 TI - Bimatoprost 0.03% for the Treatment of Eyebrow Hypotrichosis. AB - BACKGROUND: Eyebrow loss may have substantial negative functional and social consequences. OBJECTIVE: Evaluate the safety and efficacy of bimatoprost 0.03% in subjects with eyebrow hypotrichosis. METHODS: This multicenter, double-masked study randomized adult females or males with eyebrow hypotrichosis to receive bimatoprost 0.03% twice (BID) or once daily (QD) or vehicle BID for 7 months. Primary endpoint was overall eyebrow fullness at Month 7. Secondary endpoints included eyebrow fullness (mm), darkness (intensity units), and subject satisfaction with treatment. Safety was also assessed. RESULTS: At Month 7, the proportion of subjects with improvement was significantly higher in bimatoprost groups versus vehicle (both, p < .001). Improvements occurred in both bimatoprost groups versus vehicle after Month 1 and continued through follow-up; eyebrow fullness and darkness improved as early as Months 2 and 1, respectively (both, p < .001). Greater satisfaction was reported with bimatoprost versus vehicle at Month 2 and all subsequent time points. Overall, 38.1%, 42.4%, and 35.5% of subjects in the bimatoprost BID, QD, and vehicle groups, respectively, experienced >=1 treatment-emergent adverse event (TEAE). Most frequent TEAEs were similar across groups. No skin or iris hyperpigmentation or conjunctival hyperemia occurred. CONCLUSION: Bimatoprost 0.03% BID and QD is safe, well tolerated, and effective for eyebrow hypotrichosis. PMID- 27124879 TI - BRACHYTHERAPY ALONE OR WITH NEOADJUVANT PHOTODYNAMIC THERAPY FOR AMELANOTIC CHOROIDAL MELANOMA: Functional Outcomes and Local Tumor Control. AB - PURPOSE: To compare visual outcomes and local tumor control between two groups of patients with amelanotic choroidal melanoma treated with brachytherapy alone, or neoadjuvant photodynamic therapy before brachytherapy. METHODS: Patients diagnosed with amelanotic choroidal melanoma were recruited for the study and divided into two groups: brachytherapy alone (Group A) and photodynamic therapy preceding brachytherapy (Group B). Patients of both groups were selected to be comparable. RESULTS: Twenty-six patients with amelanotic choroidal melanoma were enrolled in the study. Within Group B, 1 month after photodynamic therapy, ultrasonography showed reduction of tumor height in 11 patients (73.4%). The mean doses of irradiation to macula and optic nerve, at baseline were 74.37 and 52.07 Gy, whereas after photodynamic therapy there was a decrease of 17.26% (P = 0.008) and 21.22% (P = 0.025), respectively. In terms of visual acuity, a mean decrease of 14 ETDRS letters and 5 ETDRS letters was observed at 24 months follow-up, in Groups A and B, respectively (P = 0.001). CONCLUSION: Photodynamic therapy as neoadjuvant therapy before brachytherapy reduces tumor thickness in 73.4% of cases. As a result, a decrease of radiation toxic effects on visual function could be obtained, without compromising disease control. PMID- 27124880 TI - SUBRETINAL FIBROSIS AFTER ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN EYES WITH MYOPIC CHOROIDAL NEOVASCULARIZATION. AB - PURPOSE: To assess the incidence and risk factors of subretinal fibrosis and their impact on visual outcome in eyes with myopic CNV. METHODS: Medical records of 72 eyes treated with antivascular endothelial growth factor (anti-VEGF) therapy in a pro re nata regimen for myopic CNV that followed up for more than 1 year were retrospectively reviewed. The presence of subretinal fibrosis after anti-VEGF therapy was determined using both fundus photographs and optical coherence tomography. The incidence and risk factors of subretinal fibrosis were evaluated, and best-corrected visual acuity was compared between the eyes with and without subretinal fibrosis. RESULTS: The incidences of subretinal fibrosis during the 1-year and whole follow-up period were 31.9% and 36.1%, respectively. Occurrence of subretinal fibrosis was associated with frequent CNV recurrence (P = 0.005) and poor baseline best-corrected visual acuity (P = 0.044) in a Cox proportional hazard model. Anatomically, the eyes with subretinal fibrosis showed more frequent progression of chorioretinal atrophy (95.7% vs. 71.4%, P = 0.027) and less frequent photoreceptor recovery (17.4% vs. 65.3%, P < 0.001) after anti VEGF therapy. Occurrence of subretinal fibrosis was associated with poor vision at baseline (P = 0.011) and the final visit (P = 0.008) when compared with the findings in the nonoccurrence group. CONCLUSION: Development of subretinal fibrosis after anti-VEGF therapy was common in eyes with myopic CNV and was associated with CNV recurrence. Myopic eyes with subretinal fibrosis show progressive chorioretinal atrophy and poor visual outcome. PMID- 27124881 TI - PROSPECTIVE RANDOMIZED SUBJECT-MASKED STUDY OF INTRAVITREAL BEVACIZUMAB MONOTHERAPY VERSUS DEXAMETHASONE IMPLANT MONOTHERAPY IN THE TREATMENT OF PERSISTENT DIABETIC MACULAR EDEMA. AB - PURPOSE: To compare intravitreal bevacizumab monotherapy with intravitreal dexamethasone delayed delivery system monotherapy for persistent diabetic macular edema. METHODS: Single-center, randomized, subject-masked study of eyes with persistent diabetic macular edema, defined as central subfield thickness (CST) >340 MUm despite >=3 anti-vascular endothelial growth factors injections within 5 months. The intravitreal bevacizumab monotherapy (n = 23 eyes) and delayed delivery system monotherapy (n = 27 eyes) groups received treatments q1month and q3months, respectively. RESULTS: Baseline best-corrected visual acuity and CST were similar in the two groups. At Month 7, the mean final best-corrected visual acuity (mean +/- SD) was 65 +/- 16 letters (mean Snellen visual acuity 20/50) and 64 +/- 11 letters (20/50) (P = 0.619), the mean change in best-corrected visual acuity was +5.6 +/- 6.1 and +5.8 +/- 7.6 letters (P = 0.785), the mean final CST was 471 +/- 157 and 336 +/- 89 MUm (P = 0.001), and the mean change in CST was 13 +/- 105 and -122 +/- 120 MUm (P = 0.005) in the intravitreal bevacizumab monotherapy and delayed delivery system monotherapy groups, respectively. The number of injections was 7.0 +/- 0.2 and 2.7 +/- 0.5 (P < 0.001) in the 2 groups. CONCLUSION: The two groups had similar best-corrected visual acuity gains. The delayed delivery system monotherapy group achieved a significantly greater reduction of CST compared with the intravitreal bevacizumab monotherapy group, with a q3month interval of treatment, and had no recurrent edema at any visit. PMID- 27124882 TI - CHOROIDAL VASCULARITY INDEX IN CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To evaluate choroidal vascularity index (CVI) in eyes with central serous chorioretinopathy (CSC) using an image binarization tool on enhanced depth imaging using spectral domain optical coherence tomography scans. METHODS: In this retrospective cohort study, enhanced depth imaging optical coherence tomography scans of both eyes of patients with CSC were taken at baseline; they were segmented and compared with enhanced depth imaging optical coherence tomography scans of fellow eyes without CSC as well as age-matched healthy subjects. Subfoveal choroidal area (1,500 MUm) was segmented into luminal area and stromal area using image binarization. Choroidal vascularity index was defined as the proportion of luminal area to the total circumscribed subfoveal choroidal area. RESULTS: Eyes with acute CSC (32 eyes) had significantly higher CVI compared with their fellow eyes (27 eyes) (P < 0.0001), 19 eyes with resolved CSC (P < 0.0001) and with 30 eyes of age-matched healthy eyes (P < 0.0001). Fellow eyes of subjects with acute CSC also had significantly higher CVI compared with eyes with resolved CSC (P < 0.0001) and age-matched healthy eyes (P < 0.0001). CONCLUSION: Increased CVI suggests increased vascular component compared with the stromal component in acute CSC. Increased CVI was noted in fellow eye of the subjects with acute CSC in comparison with age-matched healthy subjects. The CVI could be a useful index for early diagnosis of CSC and to assess the treatment response after laser photocoagulation or photodynamic therapy. PMID- 27124883 TI - LONG-TERM RETROSPECTIVE ANALYSIS OF VISUAL ACUITY AND OPTICAL COHERENCE TOPOGRAPHIC CHANGES AFTER SINGLE VERSUS DOUBLE PEELING DURING VITRECTOMY FOR MACULAR EPIRETINAL MEMBRANES. AB - PURPOSE: To determine the long-term effect of internal limiting membrane with associated epiretinal membrane (ERM) peeling versus single peeling alone in terms of best-corrected visual acuity and anatomical outcomes on spectral-domain optical coherence tomography. METHODS: This retrospective comparative cohort study of patients who had follow-up of >1 year and underwent surgery for ERM by a single surgeon (S.C.) from January 1, 2008 to December 31, 2012 compared cases in which the internal limiting membrane was stained with brilliant blue G to facilitate double peeling (n = 42) and single peeling (n = 43) of the ERM alone for up to 3 years of follow-up. For continuous variables, an independent two tailed t-test was performed. For binary variables, the Fisher's exact test was performed. Statistical significance was defined as P < 0.05. RESULTS: Eighty-five of 142 patients fit the inclusion criteria. At the last follow-up, the single peeling group were more likely to have ERM remaining in the central fovea postoperatively (P = 0.0020, becoming significant by postoperative Year 1, P = 0.022) and less likely to develop inner retinal dimpling (P = 0.000, becoming significant by postoperative Month 3, P = 0.015). At 3 years, central foveal thickness had decreased in the single-peeling group by -136.9 um and by -84.1 MUm in the double-peeling group, which was not significantly different (P = 0.08). Mean best-corrected visual acuity improved in both the groups at all time points. There was no statistically significant difference between the 2 groups at 3 years (P = 0.44; single-peeling group, 0.32 +/- 0.42, Snellen 20/42; double-peeling group, 0.23 +/- 0.27, Snellen 20/34). CONCLUSION: Brilliant blue G-assisted internal limiting membrane peeling for ERM results in a more thorough removal of residual ERM around the paracentral fovea. However, there is no difference in long-term best-corrected visual acuity at 3 years and a greater likelihood of inner retinal dimpling. PMID- 27124885 TI - Parents' and patients' experiences with paediatric oncology care in Switzerland- satisfaction and some hurdles. AB - QUESTIONS UNDER STUDY: This paper explores parents' and patients' satisfaction with care in Swiss paediatric oncology settings and examines difficulties experienced while undergoing treatment for cancer. METHODS: Semistructured interviews were conducted with 19 parents, and with 17 children who were diagnosed with cancer and receiving treatment. During these interviews questions pertaining to communication and decision-making at time of diagnosis and throughout the illness course were asked. In this paper, we examined these interviews using thematic coding to identify themes with regard to satisfaction with care. RESULTS: Generally, participants reported being very content with the care they received. Aspects that contributed to satisfaction were the friendliness and responsive nature of healthcare staff; helpful communication; and professionals going beyond their duties to care for the family. In spite of mainly being pleased with the care they received, participants underlined several issues that made their experiences at times difficult. These included frequent change of physician or receiving care from another unit, which for them represented lack of continuity of care; language problems; and challenges with reproductive health issues of the child. Additionally, patients suggested several ways to improve hospital stays and thereby patient satisfaction. CONCLUSION: Participants reported being very satisfied with care delivered by paediatric oncology units. Nevertheless, they also identified problems that are worth addressing in order to efficiently tend to the needs of patients and families undergoing this difficult experience. Future research is needed to explore how care for children with cancer and their families can be further improved. PMID- 27124884 TI - Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia. AB - Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV-specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B-CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV-specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B-CLL. Utilizing a large prospective cohort of patients with B-CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34-3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68-1.84; P = 0.65). These findings in a second independent cohort of 236 B-CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B-CLL was found. Am. J. Hematol. 91:776-781, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27124886 TI - Weighting of Facial Grading Variables to Disfigurement in Facial Palsy. AB - IMPORTANCE: A universal, health care professional-graded scale for facial assessment would be a useful tool for reporting, comparing, and assessing facial function among patients with facial paralysis. OBJECTIVES: To correlate scores of an assessment tool, the eFACE scale, with expert-rated facial disfigurement and to determine the relative contributions of facial features to facial palsy related disfigurement. DESIGN, SETTING, AND PARTICIPANTS: The eFACE scale yields 15 individual variable scores, in addition to subscores for static, dynamic, and synkinesis elements, and a total score that is based on 100-point scales. Two hundred patients with varying degrees of unilateral facial palsy underwent independent eFACE assessment and assignment of a disfigurement score by 2 facial nerve surgeons. The mean scores were determined, and multivariate regression analysis was performed to fit eFACE subset scores (static, dynamic, and synkinesis) to disfigurement ratings. A hybrid regression model was then used to weight each of the 15 eFACE variables, using stepwise regression to control for the effect of the other variables. Scoring was performed during an 8-week period from March 16 to May 8, 2015. MAIN OUTCOME AND MEASURE: Use of the 100-point eFACE variables, together with a 100-point visual analog scale of disfigurement, with 0 representing the most extreme disfigurement possible from a facial nerve disorder and 100 representing no discernible facial disfigurement. RESULTS: In the 200 patients included in analysis (126 [63.0% female]; mean [SD] age, 46.5 [16.4] years]), predicted disfigurement scores based on eFACE subset scores demonstrated excellent agreement with surgeon-graded disfigurement severity (r2 = 0.79). Variable weighting demonstrated that the 6 key contributors to overall disfigurement were (in order of importance) nasolabial fold depth at rest (normalized coefficient [NC], 0.18; P < .001), oral commissure position at rest (NC, 0.15; P < .001), lower lip asymmetry while pronouncing the long /e/ (NC, 0.09; P < .001), palpebral fissure width at rest (NC, 0.09; P < .001), nasolabial fold orientation with smiling (NC, 0.08; P = .001), and palpebral fissure width during attempts at full eye closure (NC, 0.06; P = .03). CONCLUSIONS AND RELEVANCE: A mathematical association between eFACE-measured facial features and overall expert-graded disfigurement in facial paralysis has been established. For those using the eFACE grading scale, predictions of the specific effects of various interventions on expert-rated disfigurement are now possible and may guide therapy. LEVEL OF EVIDENCE: NA. PMID- 27124887 TI - Food and Drug Administration Approval for Use of Hiberix as a 3-Dose Primary Haemophilus influenzae Type b (Hib) Vaccination Series. AB - On January 14, 2016, GlaxoSmithKline Biologicals (Research Triangle Park, North Carolina) received approval from the Food and Drug Administration (FDA) to expand use of Hiberix (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]) for a 3-dose infant primary vaccination series at ages 2, 4, and 6 months. Hiberix was first licensed in the United States in August 2009 for use as a booster dose in children aged 15 months through 4 years under the Accelerated Approval Regulations, in response to a Haemophilus influenzae type b (Hib) vaccine shortage that lasted from December 2007 to July 2009 (1). Expanding the age indication to include infants provides another vaccine option in addition to other currently licensed monovalent or combination Hib vaccines recommended for the primary vaccination series.* Hiberix contains 10 MUg purified capsular polyribosyl ribitolphosphate (PRP) conjugated to 25 MUg tetanus toxoid (PRP-T) and is supplied as a single-dose vial of lyophilized vaccine to be reconstituted with saline diluent. For the 3-dose primary series, a single (0.5 mL) dose should be given by intramuscular injection at ages 2, 4, and 6 months; the first dose may be given as early as age 6 weeks. The recommended catch-up schedule for PRP-T vaccines (http://www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html) should be followed. As previously recommended, a single booster dose should be administered to children aged 15 months through 18 months; to facilitate timely booster vaccination, Hiberix can be administered as early as age 12 months, in accordance with Hib vaccination schedules for routine and catch-up immunization (1-3). PMID- 27124888 TI - Fundamental Differences between Group 8 Metals: Unexpected Oxidation State Preferences and Mechanisms in Ruthenium Borylene Complex Formation. AB - The reaction of the salts K[Ru(CO)3 (PMe3 )(SiR3 )] (R=Me, Et) with Br2 BDur or Cl2 BDur (Dur=2,3,5,6-Me4 C6 H) leads to both boryl and borylene complexes of divalent ruthenium, the former through simple salt elimination and the latter through subsequent CO loss and 1,2-halide shift. The balance of products can be altered by varying the reaction conditions; boryl complexes can be favored by the addition of CO, and borylene complexes by removal of CO under vacuum. All of these products are in competition with the corresponding (aryl)(halo)(trialkylsilyl)borane, a reductive elimination product. The Ru(II) borylene products and the mechanisms that form them are distinctly different from the analogous reactions with iron, which lead to low-valent borylene complexes, highlighting fundamental differences in oxidation state preferences between iron and ruthenium. PMID- 27124889 TI - Testosterone undecanoate improves sexual function in men with type 2 diabetes and severe hypogonadism: results from a 30-week randomized placebo-controlled study. AB - OBJECTIVE: To evaluate the sexual function response to 30 weeks' treatment with long-acting testosterone undecanoate (TU) or placebo in 199 men with type 2 diabetes and either severe or mild hypogonadism (HG). PATIENTS AND METHODS: Men with HG were identified from seven primary care type 2 diabetes registers. A 30 week randomized placebo-controlled study of TU was carried out in 199 of these men (placebo, n = 107, TU, n = 92). The patient-reported outcome measure was the 15-item International Index of Erectile Function score. Men completing the study (n=189) were stratified, firstly, by baseline total testosterone (TT) or free testosterone (FT) into mild HG (TT 8.1-12 nmol/L or FT 0.18-0.25 nmol/L) and severe HG groups (TT <=8 nmol/L and FT <=0.18 nmol/L), and secondly, by intervention (placebo or TU), thereby creating four groups: mild HG/placebo; mild HG/TU; severe HG/placebo and severe HG/TU. STATISTICAL ANALYSIS: Changes in sexual function score (a secondary outcome of the study) at each visit within group (from baseline) and between groups (TU vs placebo) at each assessment (6, 18 and 30 weeks) were compared using a Wilcoxon signed-rank and Wilcoxon rank-sum test, respectively. RESULTS: Significant improvement in erectile function was evident only in the severe HG group after 30 weeks of TU treatment; this finding persisted when TU was compared with placebo. Intercourse satisfaction and sexual desire scores were also improved at 6, 18 and 30 weeks in the severe HG group after TU treatment; this increase in scores was also evident when compared with placebo. TU did not appear to alter orgasmic function significantly in any of the patient groups. CONCLUSIONS: The present study suggests that benefit in sexual symptoms after TU treatment is evident principally in patients with HG with TT levels <=8 nmol/L and FT levels <=0.18 nmol/L. We also suggest that 30 weeks of treatment is necessary before evaluating improvement in erectile function. PMID- 27124892 TI - Domain wall motion driven by adiabatic spin transfer torque through excitation of nonlinear dynamics. AB - Domain wall dynamics under the joint action of a linearly polarized microwave magnetic field and spin transfer torque was analysed in terms of the domain wall collective coordinates. It was found that a microwave-assisted steady domain wall motion driven by adiabatic spin transfer torque can be adequately described by three domain wall collective coordinates. Analytical expression for the domain wall velocity showed that there are two contributions to the steady domain wall motion. One is derived from the nonlinear oscillation of domain wall width excited by the microwave field, and the other is from the heterodyne process between the width oscillation and the microwave field. The former always propels a domain wall to move in the positive direction, which is defined as the direction of the applied current. The latter contribution to the domain wall velocity can be positive or negative, depending on the polarization of the microwave field. The final domain wall velocity is determined by the competition between those two contributions, which indicates that by simply changing the polarization of the microwave field, the direction of the domain wall motion can be reversed. Our analysis demonstrated that the characteristics of domain wall motion can be tuned by selective excitation of nonlinear domain wall dynamics. PMID- 27124891 TI - HIV viral suppression in TREAT Asia HIV Observational Database enrolled adults on antiretroviral therapy at the Social Health Clinic, the National Center for HIV/AIDS, Dermatology & STDs, Phnom Penh, Cambodia. AB - BACKGROUND: The Social Health Clinic at the National Center for HIV/AIDS, Dermatology & STDs (SHC-NCHADS) in Phnom Penh is a major provider of antiretroviral therapy (ART) in Cambodia. However, patient access to viral load monitoring is uncommon. We conducted a cross-sectional evaluation of HIV viral load in SHC-NCHADS patients on ART to determine the proportion experiencing virological failure and to identify factors associated with virological failure in this population. METHODS: Patients who had been using their current first- or second-line ART regimen for >=6 months were eligible. Virological failure was defined as a viral load >1,000 copies/ml, death, lost-to-follow-up or the absence of viral load testing despite presenting for care. Factors associated with virological failure were evaluated using logistic regression. RESULTS: Overall, 463 patients (53.1% male, median age 42.1 years) were included in the investigation. At the time of current regimen initiation, median CD4+ T-cell count was 101 cells/mm3 and 89.0% of patients had experienced a WHO stage III/IV event. At the time of testing/last clinic visit, 28 (6.0%) patients met our definition of virological failure. Median viral load among those failing was 9,633 copies/ml. Shorter time on current ART regimen, low CD4+ T-cell count at the time of viral load testing/last clinic visit and a record of suboptimal adherence were the strongest predictors of virological failure. CONCLUSIONS: This work demonstrates the high rate of viral suppression being achieved by the treatment programme at SHC-NCHADS and the need for future work to phase-in routine viral load monitoring in Cambodia. PMID- 27124890 TI - In Vitro and in Vivo Evaluation of Silicate-Coated Polyetheretherketone Fabricated by Electron Beam Evaporation. AB - Intrinsic bioinertness severely hampers the application of polyetheretherketone (PEEK), although in the field of dentistry it is considered to be an ideal titanium substitute implanting material. In this study, a bioactive silicate coating was successfully introduced onto PEEK surface by using electron beam evaporation (EBE) technology to improve its bioactivity and osseointegration of PEEK. Through controlling the duration of EBE, the incorporated amounts of silicon (Si) could be exquisitely adjusted to obtain proper biofunctionality, as assessed by cell adhesion, proliferation, osteogenic gene expression, and protein detection. In vivo, the samples were then tested in a femur implantation model to assay osseointegration effects in ovariectomized (OVX) rats. Remarkable enhancement of adhesion, spreading, osteogenesis, and differentiation of bone marrow stem cells (rBMSCs-OVX) were noted on silicate-coated samples. In particular, the group that was processed for 5 min with EBE (EBE-5 min) showed the most improvements in ALP activity and osteogenic-related gene expression compared to the remaining groups. Better osseointegration of the group that was processed for 8 min with EBE (EBE-8 min) was observed in vivo, as indicated by micro-CT test, fluorescent labeling, and histological and histomorphometric analyses. Collectively, the outcomes of the above experiments demonstrate that the present work is a meaningful attempt to promote osseointegration under osteoporotic conditions with only Si element incorporated to PEEK surface by the application of EBE technique. To the best of our knowledge, this work is the first demonstration of tuning the surface properties of PEEK via the adoption of an EBE-fabricated silicate coating to address an osteoporotic problem both in vitro and in vivo. PMID- 27124893 TI - The effect of bending stiffness on scaling laws for the size of colloidal nanosheets. AB - Using coarse-grained Brownian dynamics simulations, we study the relationship between hydrodynamic radius ([Formula: see text] and the lateral size ([Formula: see text] of dispersed nanosheets. Our simulation results show that the bending modulus of the nanosheets has a significant impact on the exponent of this power law relationship between the radius of gyration (and thus [Formula: see text] and [Formula: see text] The exponent can vary from 0.17 to 1. This sheds light on the interpretation of dynamic light scattering (DLS) measurements, such that DLS data can capture both nanosheet lateral size and modulus (which is, in turn, affected by nanosheet thickness). PMID- 27124894 TI - Predicting virological decay in patients starting combination antiretroviral therapy. AB - OBJECTIVE: Model trajectories of viral load measurements from time of starting combination antiretroviral therapy (cART), and use the model to predict whether patients will achieve suppressed viral load (<=200 copies/ml) within 6-months of starting cART. DESIGN: Prospective cohort study including HIV-positive adults (UK Collaborative HIV Cohort Study). METHODS: Eligible patients were antiretroviral naive and started cART after 1997. Random effects models were used to estimate viral load trends. Patients were randomly selected to form a validation dataset with those remaining used to fit the model. We evaluated predictions of suppression using indices of diagnostic test performance. RESULTS: Of 9562 eligible patients 6435 were used to fit the model and 3127 for validation. Mean log10 viral load trajectories declined rapidly during the first 2 weeks post cART, moderately between 2 weeks and 3 months, and more slowly thereafter. Higher pretreatment viral load predicted steeper declines, whereas older age, white ethnicity, and boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitors based cART-regimen predicted a steeper decline from 3 months onwards. Specificity of predictions and the diagnostic odds ratio substantially improved when predictions were based on viral load measurements up to the 4-month visit compared with the 2 or 3-month visits. Diagnostic performance improved when suppression was defined by two consecutive suppressed viral loads compared with one. CONCLUSIONS: Viral load measurements can be used to predict if a patient will be suppressed by 6-month post-cART. Graphical presentations of this information could help clinicians decide the optimum time to switch treatment regimen during the first months of cART. PMID- 27124895 TI - Targeting elimination of mother-to-child HIV transmission efforts using geospatial analysis of mother-to-child HIV transmission in Zimbabwe. AB - BACKGROUND: We assessed Zimbabwe's progress toward elimination of mother-to-child HIV transmission (MTCT) under Option A. METHODS: We analyzed 2012 and 2014 cross sectional serosurvey data from mother-infant pairs residing in the same 157 health facility catchment areas randomly sampled from five provinces. Eligible women were at least 16 years and mothers/caregivers of infants born 9-18 months prior. We aggregated individual-level questionnaire and HIV serostatus within catchment areas or district to estimate MTCT and the number of HIV-infected infants; these data were mapped using facility global positioning system coordinates. RESULTS: A weighted population of 8800 and 10 404 mother-infant pairs was included from 2012 and 2014, respectively. In 2014, MTCT among HIV exposed infants was 6.7% (95% confidence interval: 5.2, 8.6), not significantly different from 2012 (8.8%, 95% confidence interval: 6.9, 11.1, P = 0.13). From 2012 to 2014, self-reported antiretroviral therapy or prophylaxis among HIV infected women increased from 59 to 65% (P = 0.05), as did self-reported infant antiretroviral prophylaxis (63 vs. 67%, P = 0.08). In 2014, 65 (41%), 55 (35%), and 37 (24%) catchment areas had the same, lower, and higher MTCT rate as in 2012, respectively. MTCT in 2014 varied by catchment areas (median = 0%, mean = 4.9%, interquartile range = 0-10%) as did the estimated number of HIV-infected infants (median = 0, mean = 1.1, interquartile range = 0-1.0). Also in 2014, 106 (68%) catchment areas had MTCT = 0%. Geovisualization revealed clustering of catchment areas where both MTCT and the estimated number of HIV-infected infants were relatively high. CONCLUSION: Although MTCT is declining in Zimbabwe, geospatial analysis indicates facility-level variability. Catchment areas with high MTCT rates and a high burden of HIV-infected infants should be the highest priority for service intensification. PMID- 27124896 TI - Longitudinal increase in vitamin D binding protein levels after initiation of tenofovir/lamivudine/efavirenz among individuals with HIV. AB - OBJECTIVE: To examine longitudinal change in vitamin D binding protein (DBP) levels during the first year after initiation of tenofovir disoproxil fumarate (TDF)/lamivudine/efavirenz and compare these findings with concurrent changes in markers of skeletal metabolism. DESIGN: Secondary analysis of plasma samples collected from an ongoing multicenter clinical trial. METHODS: Plasma samples collected at 0, 24, and 48 weeks after initiation of TDF + lamivudine + efavirenz from 134 adult participants enrolled in a multicenter randomized trial were analyzed. Data regarding sociodemographic and clinical characteristics were obtained as part of the parent study. Laboratory analyses included plasma DBP, intact parathyroid hormone, total 25-hydroxy vitamin D, phosphorus, the bone resorption marker collagen type 1 cross-linked C-telopeptide, and the bone formation marker total procollagen type 1 N-terminal propeptide. Repeated measures analysis of variance was used to measure changes in biomarkers over time. RESULTS: Our sample included 108 men and 26 women (mean age 33.6 +/- 9.6 years). Median levels of DBP increased significantly from baseline to 48 weeks [154 (91.8-257.4) versus 198.3 (119.6-351.9) MUg/ml, P < 0.001]. A concurrent rise in intact parathyroid hormone levels was observed over the same period [32.3 (24.4-40.9) versus 45.2 (35.1-60.4) pg/ml, P < 0.001]; however, 25-hydroxy vitamin D and phosphorus levels remained stable. Bone resorption and formation markers rapidly increased from 0 to 24 weeks, followed by a slight decline or plateau, but remained significantly elevated at 48 weeks (P < 0.001). CONCLUSION: Our study provides longitudinal data supporting a potential role for DBP in bone loss associated with TDF-based therapy. Further research to elucidate the mechanistic pathways and clinical impact of these findings is warranted. PMID- 27124898 TI - Modification of the HIV-specific CD8+ T-cell response in an HIV elite controller after chikungunya virus infection. AB - OBJECTIVE: To evaluate the impact of chikungunya virus (CHIKV) infection on the quality of the HIV-specific CD8 T-cell (CTL) response in an HIV elite controller. DESIGN: Three blood samples were obtained from an elite controller at 27 days (EC CHIKV, Sample 1, S1), 41 days (S2) and 1 year (S3) after CHIKV infection. Additionally, samples from another nine elite controllers and nine viremic chronics were obtained. METHODS: CD4 T-cell counts, viral load and immune activation were recorded. Natural killer (NK) cells and HIV-specific CTL quality were evaluated. Data were analyzed using nonparametric statistics. RESULTS: A male HIV elite controller was confirmed for CHIKV infection. At S1, he presented 211 cells/MUl CD4 T-cell count, a HIV viral load blip (145 copies/ml) and high T cell activation. NK cell percentage and activation were higher at S2. All parameters were recovered by S3. CTLs at S1 were exclusively monofunctional with a high proportion (>80%) of degranulating CTLs. By S3, CTL polyfunctionality was more similar to that of a typical elite controller. The distribution of CTL memory subsets also displayed altered profiles. CONCLUSION: The results showed that the phenotype and function of HIV-specific CTLs were modified in temporal association with an HIV viral load blip that followed CHIKV infection. This might have helped to control the transient HIV rebound. Additionally, NK cells could have been involved in this control. These results provide useful information to help understand how elite controllers maintain their status, control HIV infection and alert about the negative impact to the immune function of HIV infected individuals living in CHIKV endemic areas. PMID- 27124897 TI - HIV-1 is undetectable in preejaculatory secretions from HIV-1-infected men on suppressive HAART. AB - OBJECTIVE: Preejaculatory fluid, a viscous, lubricating secretion expressed by penile urethral glands during sexual excitement, may play a role in the sexual transmission of HIV-1. The urethra has been shown to be an important site of HIV infection in men and male macaques, and preejaculatory fluid and urethral swabs from HIV-1-infected men often contain HIV. Recent studies have shown that HAART reduces but does not eliminate seminal HIV shedding in infected men, and that the penile urethra remains a site of persistent simian immunodeficiency virus infection in HAART-treated macaques. The objective of this study was to determine whether HIV-infected men on stable HAART continue to shed HIV into preejaculatory secretions. DESIGN: Single-center prospective study. METHODS: Sixty HIV-infected men on HAART were recruited to provide preejaculatory fluid, semen, and blood for HIV RNA quantification by reverse transcription-PCR. RESULTS: Eight men had detectable HIV in blood; of these four had HIV in semen (range: 40-96 000 copies/ml), and one had HIV in preejaculate (2400 copies/sample). Fifty-two men had undetectable HIV RNA in blood; of these 10 (19.2%) had HIV RNA in semen (range: 59-800 copies/ml) whereas none (0%) had HIV RNA in preejaculate (P = 0.004). CONCLUSIONS: This study documents for the first time high levels of HIV RNA in preejaculate fluid. However, none of the men on stable HAART with undetectable blood viral load had HIV RNA in preejaculate, even though many had detectable HIV in semen. The urethral glands do not appear to be a principal source of HIV in men on suppressive HAART. PMID- 27124899 TI - Non-R5-tropic HIV-1 in subtype A1 and D infections were associated with lower pretherapy CD4+ cell count but not with PI/(N)NRTI therapy outcomes in Mbarara, Uganda. AB - BACKGROUND: Previous studies suggest that infection with non-R5-tropic subtype B HIV-1, compared with R5, is associated with a more rapid decline in CD4 cell count, but does not affect PI/(N)NRTI therapy outcome. Here, we explored clinical correlates associated with viral tropism in subtype A1 and D infections. METHODS: HIV-1 subtype A1 (n = 196) and D (n = 143) pretherapy plasma samples and up to 7.5 years of posttherapy virologic and CD4 data were collected from a cross sectional cohort in Mbarara, Uganda. Tropism and subtype were inferred using env V3 (geno2pheno) and gp41 (RIP) Sanger sequences. For each subtype, R5 infection was compared with non-R5 in terms of: pretherapy viral load and CD4 cell count (Mann-Whitney tests), and therapy outcomes, including time to virologic suppression, postsuppression virologic rebound, CD4 decline and CD4 recovery (log rank tests). RESULTS: A 94% of all patients in this study achieved virologic suppression within median 3 months posttherapy. In both subtypes, non-R5 infection was associated with lower pretherapy CD4 cell count (non-R5 vs. R5; A: median 57 vs. 147 cells/MUl P = 0.005; D: 80 vs. 128 cells/MUl P = 0.006). Multivariable linear regression confirmed that tropism, not subtype nor the interaction between subtype and tropism, was a significant predictor of pretherapy CD4 cell count (P < 0.0001). None of pretherapy viral load, time to virologic suppression, virologic rebound, CD4 decline nor CD4 recovery was significantly different (all P > 0.09). CONCLUSION: Regardless of HIV-1 subtype or tropism, the majority of patients in this Ugandan cohort responded to therapy, even though non-R5 infection was associated with lower pretherapy CD4 cell count. PMID- 27124900 TI - Sensitivity of HIV rapid tests compared with fourth-generation enzyme immunoassays or HIV RNA tests. AB - OBJECTIVE: Determine the sensitivity of HIV rapid tests compared with fourth generation enzyme immunoassays (EIA) or nucleic acid amplification tests (NAAT) in clinical settings. DESIGN: Systematic review and meta-analysis. METHODS: Medline, PubMed, Embase, Cochrane Controlled Trials Register, Cochrane reviews and Cumulative Index to Nursing and Allied Health Literature were searched until 14 July 2015 for studies of adults comparing point-of-care HIV rapid tests to fourth-generation HIV EIA antibody/p24 antigen or HIV NAAT. RESULTS: From 953 titles, 18 studies were included, involving 110 122 HIV rapid test results. Compared with EIA, the estimated sensitivity (random effects) of HIV rapid tests was 94.5% [95% confidence interval (CI): 87.4-97.7]. Compared with NAAT, the sensitivity of HIV rapid tests was 93.7% (95% CI: 88.7-96.5). The sensitivity of HIV rapid tests in high-income countries was 85.7% (95% CI: 81.9-88.9) and in low income countries was 97.7% (95% CI: 95.2-98.9) compared with either EIA or NAAT (P < 0.01 for difference between settings). Proportions of antibody negative acute infections were 13.6 (95% CI: 10.1-18.0) and 4.7% (95% CI: 2.8-7.7) in studies from high-income and low-income countries, respectively (P < 0.01). CONCLUSION: In clinical settings, HIV rapid tests were less sensitive in high income countries compared with low-income countries, missing about one in seven infections, possibly because of the larger proportion of acute infections in targeted populations. This suggests that in high-income countries, HIV rapid tests should be used in combination with fourth-generation EIA or NAAT tests, except in special circumstances. Prospective Registration of Systematic Reviews registration number CRD42015020154.Supplementary video link: http://links.lww.com/QAD/A924. PMID- 27124902 TI - ASCP and OUP: Stronger Together. PMID- 27124901 TI - B-cell development and pneumococcal immunity in vertically acquired HIV infection. AB - OBJECTIVES: Many children with HIV infection now survive into adulthood. This study explored the impact of vertically acquired HIV in the era of antiretroviral therapy on the development of humoral immunity. DESIGN: Natural and vaccine related immunity to pneumococcus and B-cell phenotype was characterized and compared in three groups of young adults: those with vertically-acquired infection, those with horizontally acquired infection and healthy controls. METHODS: Serotype-specific pneumococcal (Pnc) immunoglobulin M and G concentrations before and up to 1 year post-Pnc polysaccharide (Pneumovax) immunization were determined, and opsonophagocytic activity was analysed. B-cell subpopulations and dynamic markers of B-cell signalling, turnover and susceptibility to apoptosis were evaluated by flow cytometry. RESULTS: HIV infected patients showed impaired natural Pnc immunity and reduced humoral responses to immunization with Pneumovax; this was greatest in those viraemic at time of the study. Early-life viral control before the age of 10 years diminished these changes. Expanded populations of abnormally activated and immature B-cells were seen in both HIV-infected cohorts. Vertically infected patients were particularly vulnerable to reductions in marginal zone and switched memory populations. These aberrations were reduced in patients with early-life viral control. CONCLUSION: In children with HIV, damage to B-cell memory populations and impaired natural and vaccine immunity to pneumococcus is evident in early adult life. Sustained viral control from early childhood may help to limit this effect and optimize humoral immunity in adult life. PMID- 27124903 TI - MYC Immunohistochemistry Assessment in High-Grade Lymphomas: Hit or Miss? PMID- 27124904 TI - Pathology Consultation on the Diagnosis and Treatment of Thrombotic Microangiopathies (TMAs). AB - OBJECTIVES: Pathologists specializing in transfusion medicine, apheresis medicine, and/or coagulation are often consulted by clinicians to reach a diagnosis for patients with thrombotic microangiopathy (TMA), so that disease specific, often life-saving therapy can be initiated as promptly as possible. METHODS: This article describes how to proceed when treating a patient with TMA. The differential diagnosis is broad and potentially very challenging. Thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and typical hemolytic uremic syndrome (HUS) are three such TMAs that require timely diagnosis and treatment. RESULTS: TTP is treated with daily therapeutic plasma exchange (TPE) and commonly with adjunctive immunosuppressive therapy, while aHUS may initially be managed with TPE but is best controlled with eculizumab once a presumptive diagnosis is made. TPE has no proven role in typical HUS, which is most commonly treated with supportive measures only. CONCLUSIONS: Prompt and accurate diagnosis of TMA subtypes optimizes treatment and improves patient outcomes. PMID- 27124905 TI - Identification of Factors Affecting the Success of Next-Generation Sequencing Testing in Solid Tumors. AB - OBJECTIVES: Clinical laboratories are rapidly implementing next-generation sequencing (NGS) tests for mutation analysis, but there are few guidelines regarding sample quality for successful results. METHODS: We aimed to establish tissue quality parameters for successful NGS in solid tumors and to improve NGS performance. RESULTS: Analysis of 614 clinical cases tested in 2013 using a 50 gene hotspot mutation panel identified the major cause for unsuccessful NGS analysis was DNA less than 10 ng (91%, 67/74) associated with extremely small and low cellularity samples. High success rates were associated with resection procedures (333/342, 97%) and biopsied tumor larger than 10 mm(2) (77/77, 100%). NGS can be successfully performed on bone specimens processed with formic acid based decalcification procedures (8/11, 73%). Tumor type and paraffin block age did not affect success. We demonstrated that NGS can be carried out on samples with less than 10 ng DNA. Analysis of 408 cases tested in 2014 using an optimized workflow showed improved NGS success rates from 88% to 95% (387/408) with pronounced improvement among tiny (<10 mm(2)) samples (from 76% to 94%) as well as cytology samples (from 58% to 87%). CONCLUSIONS: Identifying preanalytical tissue factors allows us to improve NGS performance and to successfully test tumors obtained from minimally invasive procedures. PMID- 27124906 TI - CD4-Positive T-Cell Primary Central Nervous System Lymphoma in an HIV Positive Patient. AB - OBJECTIVES: Primary central nervous system lymphomas (PCNSLs) in patients with human immunodeficiency virus (HIV) are predominantly B-cell lymphomas associated with Epstein-Barr virus (EBV) and rarely CD8-positive T-cell PCNSLs. METHODS: Patient history, laboratory results, cerebrospinal fluid (CSF), imaging, and brain biopsy specimens were reviewed and tested for T-cell receptor clonality. RESULTS: A 64-year-old HIV-positive woman sought treatment for lethargy and left sided weakness. Brain imaging showed regional increased T2 signal with restricted diffusion in cerebral hemispheres. CSF flow cytometry revealed CD4-positive T lymphocytes with loss of CD3, CD5, and CD7. EBV-positive T-cell lymphoma was immunohistochemically confirmed on brain biopsy specimens. Molecular analysis detected clonal T-cell receptor gene rearrangement. The patient received intrathecal methotrexate and whole-brain radiation. She did not respond to treatment and was eventually placed in hospice care. CONCLUSIONS: To our knowledge, this is the first report of CD4-positive T-cell PCNSL in an HIV positive patient and will help to raise clinical awareness of this previously unknown entity. PMID- 27124907 TI - Repeat Clostridium difficile PCR Testing After a Negative Result. PMID- 27124908 TI - Correction. PMID- 27124909 TI - Is the Hemocytometer Obsolete for Body Fluid Cell Counting? PMID- 27124910 TI - Deja Visite: Specimen Provenance Issues in Next-Generation Sequencing. PMID- 27124911 TI - Evaluation of Sysmex XN-1000 High-Sensitive Analysis (hsA) Research Mode for Counting and Differentiating Cells in Cerebrospinal Fluid. AB - OBJECTIVES: Counting cells in cerebrospinal fluid (CSF) using automated analyzers is generally problematic due to low precision at low cell numbers. To overcome this limitation, Sysmex (Kobe, Japan) developed the high-sensitive analysis (hsA) research mode specifically for counting cells in fluids that contain low cell counts. We evaluated this mode by counting RBCs, WBCs, and differentiated WBCs in CSF samples. METHODS: We analyzed 248 CSF samples using the hsA mode and compared these results with those obtained using the manual counting method. We also evaluated the linearity, detection limits, carryover, and precision of the hsA mode. RESULTS: Using the hsA mode, the lower limit of quantification for RBCs and WBCs was 10 and 2 cells/MUL, respectively. Comparing the two methods revealed good agreement with respect to WBCs (y = 1.08x + 0.52), RBCs (y = 1.07x + 0.00), lymphocytes (y = 1.00x + 0.00), neutrophils (y = 1.05x + 0.00), and monocytes (y = 0.88x + 0.07). Regression analysis for samples containing low WBCs (<10 cells/MUL) and low RBCs (<50 cells/MUL) also had good agreement, although a slight positive bias was found for RBCs. Linearity was good (r(2) >= 0.99) for all parameters evaluated. Carryover was negligible and never exceeded 0.04%. CONCLUSIONS: The XN hsA research mode provides reliable cell counts in CSF samples, even in samples containing low numbers of WBCs and RBCs. PMID- 27124912 TI - Applying Ancestry and Sex Computation as a Quality Control Tool in Targeted Next Generation Sequencing. AB - OBJECTIVES: To apply techniques for ancestry and sex computation from next generation sequencing (NGS) data as an approach to confirm sample identity and detect sample processing errors. METHODS: We combined a principal component analysis method with k-nearest neighbors classification to compute the ancestry of patients undergoing NGS testing. By combining this calculation with X chromosome copy number data, we determined the sex and ancestry of patients for comparison with self-report. We also modeled the sensitivity of this technique in detecting sample processing errors. RESULTS: We applied this technique to 859 patient samples with reliable self-report data. Our k-nearest neighbors ancestry screen had an accuracy of 98.7% for patients reporting a single ancestry. Visual inspection of principal component plots was consistent with self-report in 99.6% of single-ancestry and mixed-ancestry patients. Our model demonstrates that approximately two-thirds of potential sample swaps could be detected in our patient population using this technique. CONCLUSIONS: Patient ancestry can be estimated from NGS data incidentally sequenced in targeted panels, enabling an inexpensive quality control method when coupled with patient self-report. PMID- 27124913 TI - Optimal Scoring of Brightfield Dual-Color In Situ Hybridization for Evaluation of HER2 Amplification in Breast Carcinoma: How Many Cells Are Enough? AB - OBJECTIVES: The purpose of this study was to determine the optimum number of cells that should be counted when scoring human epidermal growth factor receptor 2 (HER2) brightfield dual-color in situ hybridization (BDISH), including cases with HER2/chromosome 17 (Chr17) ratios in the 1.80 to 2.20 range. METHODS IN TOTAL,: 131 cases of breast carcinoma with HER2 immunohistochemistry and BDISH were included. For cases with a HER2/Chr17 ratio of less than 1.80 or more than 2.20 (n = 115), BDISH scoring was performed for 60 cells using three tumor fields, and for cases with a HER2/Chr17 ratio of 1.80 to 2.20 (n = 16), scoring was performed for 120 cells using six tumor fields. Mean HER2/Chr17 ratio and HER2 copy number were calculated for cumulative cell counts. RESULTS: The HER2 status as determined by the HER2/Chr17 ratio or HER2 copy number was unchanged following counting of additional cells in 100% of cases with ratio of less than 1.80 or more than 2.20. The HER2 status of two cases with ratios of 1.80 to 2.20 changed from positive to negative following counting of 120 cells. CONCLUSIONS: Our findings support recommendations to score 20 nuclei in conjunction with careful assessment of immunohistochemistry and scan of the BDISH slide to identify areas of heterogeneity. Scoring of additional cells/fields is likely not of benefit and might be a disadvantage since the scorer moves out of the area of strongest signal. PMID- 27124914 TI - Diagnostic Evaluation of ELISA and Chemiluminescent Assays as Alternative Screening Tests to Indirect Immunofluorescence for the Detection of Antibodies to Cellular Antigens. AB - OBJECTIVES: Detection of antinuclear antibodies (ANAs) plays an important role in the diagnosis of systemic autoimmune rheumatic disease (SARD). Our goal was to evaluate the diagnostic accuracy of three commercially available enzyme-linked immunosorbent assay (ELISA) kits and one chemiluminescent assay for ANA detection, using the clinical diagnostic as the reference standard. METHODS: We evaluated serum samples from 143 patients with an established diagnosis of SARD (group 1), 166 patients with infectious diseases and other rheumatic diseases for which the ANA test is not useful in diagnosis (group 2), and 89 outpatients with suspicion of SARD (group 3). RESULTS: The sensitivity for ANA HEp-2, calculated in group 1, was 87.4% and varied between 62.9% and 90.0% for other tests. The specificity for ANA HEp-2, calculated in group 2, was 72.3% and varied between 45.2% and 90.4% for other tests. In group 3, the negative predictive value for ANA Hep-2 was 92.5% and varied between 89.3% and 100% for other tests. CONCLUSIONS: Some ELISA kits have comparable or superior diagnostic sensitivity to ANA HEp-2 and could be used as an alternative method for ANA screening, therefore allowing the immediate report of the results with fewer false negatives than ANA HEp-2. Owing to the lower specificity, ELISA-positive samples should be submitted to ANA HEp-2 for confirmation of results. PMID- 27124915 TI - Morphologic Spectrum of Desmoid-Type Fibromatosis. AB - OBJECTIVES: Desmoid-type fibromatosis is a locally aggressive neoplasm composed of long sweeping fascicles of bland fibroblasts/myofibroblasts. Tumors with classic features are easy to identify, but the morphologic spectrum of this entity spans beyond the conventional histologic pattern. Since sampling of an unrecognized histologic variant may lead to misdiagnosis, especially on small needle biopsy specimens, we sought to fully characterize the morphologic spectrum of this entity. METHODS: We examined 165 cases of desmoid-type fibromatosis and catalogued the morphologic patterns and percentage of those patterns identified in each case. Clinicopathologic variables, including age, sex, location, and recurrence, were analyzed and correlated with pattern frequency. RESULTS: Seven morphologic patterns were identified, including conventional, hyalinized/hypocellular, staghorn vessel, myxoid, keloidal, nodular fasciitis like, and hypercellular. The mean number of patterns per case was two, but some cases harbored up to five patterns. The greatest morphologic variability was seen in the intra-abdominal lesions, with these tumors having a significantly higher percentage of the keloidal and staghorn patterns compared with extra-abdominal and abdominal wall sites. No significant correlation between patient outcome (recurrence) and presence of variant morphologic pattern was observed (P = .549). CONCLUSIONS: The morphologic spectrum of desmoid-type fibromatosis is deceptively broad, and awareness of the variety of histologic patterns is critical for accurate diagnosis. PMID- 27124916 TI - Do Histopathologic Variables Affect the Reporting of Lymphovascular Invasion in Testicular Germ Cell Tumors? AB - OBJECTIVES: Identification of lymphovascular invasion (LVI) in testicular germ cell tumors (GCTs) is a challenging yet important aspect of cancer staging that can alter therapeutic management. Our study aimed to identify pathologic features that affect the reporting of LVI. METHODS: Pathology report and slide review of orchiectomies performed at our institution between 2007 and 2013 for testicular GCTs were performed. RESULTS: Seminomas grossed by residents had a higher rate of reported LVI compared with specimens grossed by pathology assistants (46% vs 15%). Tumor displacement artifact was more frequent in seminomas vs mixed GCTs (60% vs 38%). LVI concordance was high upon review (kappa = 0.77), with displacement artifact present in all discrepancies. Tumor emboli from cases reported to have LVI had a higher frequency of tumor cohesiveness, smooth contours, and adherence to vessel walls compared with tumor emboli that were considered pseudo-LVI. Presence of fibrin and RBCs were features found at a similar frequency in emboli that were reported as LVI compared with those deemed artifactual. CONCLUSIONS: Grosser type, tumor subtype, tumor displacement artifact, and characteristics of tumor emboli are pathologic features that affect the interpretation of LVI in testicular GCTs. Pathologists should be aware of these variables to more accurately diagnose LVI. PMID- 27124917 TI - The Value of Papanicolaou Tests in the Diagnosis of Endometrial Carcinoma: A Large Study Cohort From an Academic Medical Center. AB - OBJECTIVES: To determine on a large scale whether routine cervical Papanicolaou (Pap) tests play a role in endometrial carcinoma diagnosis. METHODS: A retrospective search of an academic women's hospital pathology archive for cases of surgically resected endometrial carcinoma with Pap smears within 36 months before the histologic diagnosis was performed. Demographic features, Pap test results, and tumor features were recorded. RESULTS: We identified 554 (30.5%) of 1,817 cases of endometrial carcinoma with documented Pap test results within 36 months before histologic diagnosis. Among these 554 patients, 405 (73.0%) had Pap test results within 5 months before histologic diagnosis. In total, 154 (38%) cases demonstrated abnormal glandular cells, and 25 (6.2%) had only benign endometrial cells in women 40 years or older. The presence of glandular abnormality on the Pap test is significantly correlated with tumor size, tumor type, depth of invasion, presence of cervical involvement, and presence of lymphovascular invasion (P < .05). The rate of detecting abnormal glandular cells was higher in cases with a high International Federation of Gynecology and Obstetrics (FIGO) stage than in cases with a low FIGO stage (47.5% vs 35.5%; P < .05). CONCLUSIONS: The Pap test may play a role in the detection of endometrial carcinoma, especially for those with cervical involvement, lymphovascular invasion, and/or advanced stage. PMID- 27124918 TI - Reduction in Unnecessary Clinical Laboratory Testing Through Utilization Management at a US Government Veterans Affairs Hospital. AB - OBJECTIVES: To implement an electronic laboratory utilization management system (laboratory expert system [LES]) to provide safe and effective reductions in unnecessary clinical laboratory testing. METHODS: The LES is a set of frequency filter subroutines within the Veterans Affairs hospital and laboratory information system that was formulated by an interdisciplinary medical team. RESULTS: Since implementing the LES, total test volume has decreased by a mean of 11.18% per year compared with our pre-LES test volume. This change was not attributable to fluctuations in outpatient visits or inpatient days of care. Laboratory cost savings were estimated at $151,184 and $163,751 for 2012 and 2013, respectively. A significant portion of these cost savings was attributable to reductions in high-volume, large panel testing. No adverse effects on patient care were reported, and mean length of stay for patients remained unchanged. CONCLUSIONS: Electronic laboratory utilization systems can effectively reduce unnecessary laboratory testing without compromising patient care. PMID- 27124919 TI - A Clinicopathologic Analysis of 45 Patients With Metaplastic Breast Carcinoma. AB - OBJECTIVES: Metaplastic breast carcinomas (MBCs) are rare, aggressive cancers lacking targeted therapy. Here, we review the clinicopathologic features, treatment, and outcomes of patients with MBC treated at our institution. METHODS: We searched clinical and pathology databases for patients with histologically confirmed MBC from 1999 to 2012. We estimated survival probabilities using the Kaplan-Meier method and evaluated prognostic factors using Cox regression. RESULTS: Forty-five cases were identified, including chondroid (24%), spindled (20%), sarcomatoid (16%), squamous (11%), and mixed (29%) histologic subtypes. Median tumor size was 3 cm, with 86% grade III and 69% triple-negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Most had negative lymph nodes, and two patients had metastases at diagnosis. Six patients received neoadjuvant therapy, with one pathologic complete response. All patients underwent surgery, 60% received adjuvant radiation, and 58% had adjuvant chemotherapy. Five-year recurrence-free survival was 64%; 5-year overall survival was 69%. Tumor size, history of breast cancer, and mixed histology were associated with inferior outcomes. CONCLUSIONS: We report one of the largest single-institution series of patients with MBC. MBC is associated with a poor prognosis, despite low nodal involvement. Most patients in this series had high-grade, triple-negative tumors and were treated with optimal therapy. PMID- 27124920 TI - Can We Identify Nephrogenic Adenoma in Urine Cytology Specimens? A Study Evaluating Previously Described Cytomorphologic Features in Correlation With PAX8 Immunohistochemical Staining Results. AB - OBJECTIVES: The aim of this study is to determine if the diagnosis of nephrogenic adenoma (NA) can be made on cytologic criteria alone and if pair box gene transcription factor 8 (PAX8) is useful in the diagnosis of NA in daily cytology practice. METHODS: Cytologic features of NA previously described in a literature were used to identify NA cells in urinary specimens. Subsequently, all cytology and corresponding biopsy specimens were stained with the PAX8 immunohistochemistry stain. The stains were examined; the results were tabulated. RESULTS: A total of 44 specimens were reviewed (35 with corresponding biopsy specimens diagnosed as NA and nine negative for NA diagnosis on corresponding biopsy specimens). Of them, 14 demonstrated features previously described as NA. None of atypical cells that were morphologically suspicious for NA showed positive staining, whereas all of the corresponding biopsy sections demonstrated nuclear PAX8 positivity. Only rare lymphocytes present in cytology specimens showed nuclear staining with PAX8. CONCLUSIONS: Assuming that the results of the PAX8 stain performed are accurate at least in most cases, as suggested by the presence of internal positive controls, our study shows that the previously described cytologic features of NA cannot be used as diagnostic criteria, since they are not characteristic for this entity. PMID- 27124922 TI - Neuroendocrine Differentiation in Thymic Carcinomas: A Diagnostic Pitfall: An Immunohistochemical Analysis of 27 Cases. AB - OBJECTIVES: Neuroendocrine differentiation in carcinomas of the nonneuroendocrine type has been observed in various organ systems. Awareness of this phenomenon is important since such tumors need to be separated from true neuroendocrine neoplasms because of therapeutic and prognostic consequences. To investigate this occurrence in thymic carcinomas, 27 cases of different histologies were analyzed using neuroendocrine immunohistochemical markers. METHODS: Twenty-seven conventional thymic carcinomas from thymectomies were studied immunohistochemically with antibodies directed against synaptophysin, chromogranin A, and CD56 in addition to the standard markers for these tumors. RESULTS: Focal expression of at least one neuroendocrine marker was identified in a total of 12 (44%) cases. Chromogranin A was positive in five (19%) cases, synaptophysin in eight (30%), and CD56 in 10 (37%). All three markers were coexpressed in four (15%) cases. CONCLUSIONS: Neuroendocrine differentiation in conventional thymic carcinomas is a common occurrence. It is imperative to separate these tumors from true neuroendocrine neoplasms of the thymus-especially large cell neuroendocrine carcinoma-since both entities require different treatment modalities and likely show different biologic behavior. Contrary to prior suggestions, neuroendocrine differentiation should not be used to distinguish thymic carcinomas from thymomas, and these tumors should not be regarded as "mixed carcinomas." PMID- 27124921 TI - Analysis of HSP90 Expression Is Valuable in the Differential Diagnosis of Ocular Surface Squamous Lesions. AB - OBJECTIVES: The aim of this study was to evaluate heat shock protein 90 (HSP90) expression in squamous lesions (SLs) and to assess its diagnostic value for different lesions within the SL spectrum. METHODS: A total of 70 conjunctival SLs, including 19 papillomas, 22 cases of conjunctival intraepithelial neoplasia (ConINs) I, 11 cases of ConIN II, six cases of ConIN III, and 12 squamous carcinomas (sqCAs), were evaluated using the German immunoreactive score against HSP90. RESULTS: Cytoplasmic HSP90 expression differed between low- and high-grade lesions (P < .001). Among high-grade lesions, the nuclear HSP90 score was higher in the ConIN III-sqCA group than in the ConIN II group (P = .0162). A percentage of total thickness staining of less than 73% differentiated between ConIN III and sqCA. CONCLUSIONS: The expression of HSP90 is particularly useful to differentiate low-grade from high-grade lesions of the conjunctiva. HSP90 may play an important role in the malignant transformation of SLs and could be a new target for therapy. PMID- 27124923 TI - Granuloma Faciale and Erythema Elevatum Diutinum in Relation to Immunoglobulin G4 Related Disease: An Appraisal of 32 Cases. AB - OBJECTIVES: To elucidate whether granuloma faciale (GF) and erythema elevatum diutinum (EED), two inflammatory skin dermatoses, meet the consensus histopathologic diagnostic criteria for immunoglobulin G4-related disease (IgG4 RD). METHODS: With institutional review board approval, we assessed the clinical, microscopic, and immunophenotypic features of skin specimens of patients with GF and EED. We compared these findings with previously published consensus diagnostic criteria for IgG4-RD. RESULTS: Thirty-two patients (GF, n = 25; EED, n = 7) met study inclusion criteria. Histopathologic findings of small-vessel vasculitis, dermal fibrosis, and plasma cell infiltrates were uniformly present, and eosinophilic inflammation was frequent. No specimen met diagnostic criteria for IgG4-RD. CONCLUSIONS: Our results indicate that despite some histopathologic similarities between GF/EED and IgG4-RD, the cases did not meet the consensus immunohistochemical diagnostic criteria for IgG4-RD. PMID- 27124924 TI - Evaluation of Fluorescently Labeled Aerolysin as a New Kind of Reagent for Flow Cytometry Tests: Optimization of Use of FLAER, Hints, and Limits. AB - OBJECTIVES: Diagnostic tests for paroxysmal nocturnal hemoglobinuria (PNH) are currently based on flow cytometry techniques. Typically, these tests use antibodies against glycosylphosphatidylinositol (GPI)-anchored proteins, but a new approach has been described recently, using a novel reagent named FLAER (fluorescently labeled aerolysin). In this work, we evaluate the performance and highlight the peculiarities of using this new reagent. RESULTS: We investigated the general conditions of staining and explored optimal labeling settings. We found that the kinetics of the FLAER labeling is slightly different from that of antibodies. Our results led us to select a 30-minute incubation period at room temperature using 50 nmol/L as a final concentration of FLAER. As the nonspecific binding was dependent on the balance between FLAER and its ligand, the number of target cells was also found critical. In addition, sample preparation affected FLAER staining, and the lyse-before-stain preparation was preferred. Interestingly, FLAER affinity seems restricted to certain types of GPI anchors, making it unsuitable for exploration of RBCs. Finally, we aimed to evaluate FLAER as a possible single diagnostic tool; we studied cellular background in non-PNH samples and found a limit of detection close to 0.01% in optimal conditions. CONCLUSIONS: The performance of the FLAER labeling on leukocytes proves that this reagent is a valuable tool for PNH diagnosis and particularly appropriate for high-sensitivity tests in laboratories aiming to detect minor PNH clones. PMID- 27124925 TI - Myeloproliferative Neoplasms With Calreticulin Mutations Exhibit Distinctive Morphologic Features. AB - OBJECTIVES: Calreticulin (CALR) mutations are present in 50% to 85% of JAK2/MPL wild-type (wt) myeloproliferative neoplasms (MPNs). The histopathologic features of CALR-mutated MPNs are unknown. METHODS: We identified 71 patients with essential thrombocythemia (ET), primary myelofibrosis (PMF), and post-essential thrombocythemia myelofibrosis (post-ET MF) with available CALR status. CALR was assessed using capillary electrophoresis followed by Sanger sequencing confirmation. CALR status was correlated with histopathologic features. RESULTS: The megakaryocytes of CALR-mutated PMF more often were hyperchromatic (20/21) compared with CALR-wt cases (10/14) (P = .05). CALR-mutated ET showed more megakaryocytic clustering (7/7) compared with CALR-wt cases (5/9) (P = 03). Megakaryocytes of CALR-mutated post-ET MF (8/8) had a predominance of convoluted nuclei compared with CALR-wt cases (2/4) (P = .03). CALR mutations were more frequent in post-ET MF compared with ET (P = .04). CONCLUSIONS: CALR-mutated MPNs have a higher frequency of megakaryocytic aberrancies compared with CALR-wt cases. Patients with CALR-mutated ET appear to be more likely to develop myelofibrosis compared with patients with wt CALRUpon completion of this activity you will be able to: describe morphologic features that are associated with CALR mutated myeloproliferative neoplasms.examine cases of essential thrombocythemia and primary myelofibrosis and predict which cases are more likely to be CALR mutated based on histopathologic features.initiate CALR mutation testing for cases likely to have mutations. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Exam is located at www.ascp.org/ajcpcme. PMID- 27124927 TI - Is It Time for a New Gold Standard? FISH vs Cytogenetics in AML Diagnosis. PMID- 27124928 TI - About the Journal. PMID- 27124932 TI - Prevalence of High-Risk Human Papillomavirus Infection in China: Analysis of 671,163 Human Papillomavirus Test Results From China's Largest College of American Pathologists-Certified Laboratory. AB - OBJECTIVES: This study on human papillomavirus (HPV) testing in China's largest independent laboratory accredited by the international Laboratory Accreditation Program of the College of American Pathologists extends previous reports on cervical screening test results from this Chinese facility. METHODS: A retrospective laboratory database search from 2007 to 2014 documented high-risk HPV test results using either Hybrid Capture 2 (HC2; Qiagen, Hilden, Germany) or multiplex polymerase chain reaction fluorescence testing (MPFT) methods. RESULTS: During the study period, HPV testing steadily increased, with 643,702 HC2 and 27,641 MPFT HPV tests performed. The mean ages of the tested women were 35.0 years using HC2 and 38.3 years using MPFT. The HC2 HPV-positive rate was 21.7%, significantly higher than 15.7% with MPFT (P < .0001), with bimodal peak incidence in adolescents and women aged 60 to 69 years. CONCLUSIONS: Use of HPV testing in cervical screening is increasing in China. HC2 HPV-positive rates around 20% in all age groups from more than 500,000 tested Chinese women are consistent with previous reports from China and significantly higher than published HC2 HPV-positive rates in populations with more widespread cervical screening. MPFT HPV-positive rates were slightly lower in every age group. The high HPV-positive rate likely reflects limited routine cervical screening and high cervical cancer incidence in China. PMID- 27124933 TI - Teaching High School Students About Pathology: Development of a Secondary School Focused Enrichment Course in Pathology and Physiology. AB - OBJECTIVES: Although pathology is a central discipline in medicine, many do not understand the role of pathologists and laboratory professionals. While there are efforts to educate the public, few focus on precollege students. METHODS: To define a curriculum exposing high school students to major concepts in health and disease, while introducing them to professions that employ this knowledge. A semester-long class was designed to meet for 2-hour sessions semiweekly. Each session included a lecture given by a pathologist followed by group activities including hands-on gross or virtual laboratory experiences and clinical simulations. Content included epidemiology, biostatistics, and the critical evaluation of health-related articles in the popular press. Students were evaluated by examination, group assignments, and a capstone research project presentation. RESULTS: Over 4 years (2011-2014), 114 of 122 students completed the course with a "B" or better. By course conclusion, students could articulate the link between tissue changes and clinical phenotypes. Surveys showed that 90% of students found the course appropriately challenging, 98% found the class appropriate for their learning style, and the teaching methods and course content received 99% approval. CONCLUSIONS: We present a pathology course geared toward high school students that taught the foundations of human disease that allowed students to fully understand and engage in the material. Students felt that the knowledge earned was valuable and helped them to understand human health as well as inform their future career choices. This course could serve as a model for public outreach programs and for secondary and postsecondary educators. PMID- 27124934 TI - Targeted Next-Generation Sequencing in Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia Aids Diagnosis in Challenging Cases and Identifies Frequent Spliceosome Mutations in Transformed Acute Myeloid Leukemia. AB - OBJECTIVES: Optimal integration of next-generation sequencing (NGS) into clinical practice in hematologic malignancies remains unclear. We evaluate the utility of NGS in myeloid malignancies. METHODS: A 42-gene panel was used to sequence 109 cases of myelodysplastic syndrome (MDS, n = 38), chronic myelomonocytic leukemia (CMML, n = 14), myeloproliferative neoplasm (MPN, n = 24), and MDS and/or MPN transformed to acute myeloid leukemia (AML, n = 33). RESULTS: At least one pathogenic mutation was identified in 74% of cases of MDS, 100% of CMMLs, and 96% of MPNs. In contrast, only 47% of cases of MDS (18/38) and 7% (1/14) of CMMLs exhibited abnormal cytogenetics. In diagnostically difficult cases of MDS or CMML with normal cytogenetics, NGS identified a pathogenic mutation and was critical in establishing the correct diagnosis. Spliceosomal genes and epigenetic modifiers were frequently mutated. Spliceosome mutations were also frequently detected in AML arising from MDS, CMML, or MPN (39%) compared with the reported rate in de novo AML (7%-14%). CONCLUSIONS: In difficult cases of MDS or MPN, NGS facilitates diagnosis by detection of gene mutations to confirm clonality, and AMLs evolving from MDS or MPN carry frequent mutations in spliceosomal genes. PMID- 27124935 TI - Primary Mediastinal Large B-Cell Lymphoma With Translocations Involving BCL6 and MYC (Double-Hit Lymphoma). AB - OBJECTIVES: Primary mediastinal large B-cell lymphomas (PMLBCLs) are aggressive lymphomas with characteristic clinical, morphologic, and immunophenotypic features. "Double-hit" (DH) lymphomas are B-cell neoplasms characterized by a translocation involving MYC and either BCL2 or BCL6 In the indexed literature, there are no reported cases of PMLBCL associated with DH or triple-hit events. METHODS: Herein, we present a case of a 15-year-old girl with PMLBCL who had typical clinical, morphologic, and immunophenotypic features. RESULTS: Fluorescent in situ hybridization studies showed rearrangements involving MYC and BCL6 We also excluded the possibility of a reciprocal t(3;8) (3q27;8q24) BCL6/MYC translocation. CONCLUSIONS: This case expands the current spectrum of lymphomas subtypes in which DH can be found and supports the rationale for cytogenetic testing for DH abnormalities in all cases of aggressive large B-cell lymphomas regardless of subtype. PMID- 27124936 TI - Impact of Continuous Improvement of Laboratory Test Result Comments on Requests for Consultation: A Case Series. AB - OBJECTIVES: Test interpretation is an important part of the brain-to-brain loop. Poor test comments can lead to calls for explanations and impair test interpretation and possibly patient care. There has been little study on quality improvement of test result comments. The objective of this study was to investigate the impact of improvements in test comments on requests for consultation by clinicians. METHODS: We monitored the volume of requests for consultation regarding test results before and after a test comment was modified. RESULTS: Modifications of test comments eliminated calls for three different tests. Reductions were statistically significant for all tests (P < .007). CONCLUSIONS: Quality improvement activities targeted at test comments can improve service, reduce costs, and improve patient care. PMID- 27124937 TI - IFITM1 Is Superior to CD10 as a Marker of Endometrial Stroma in the Evaluation of Myometrial Invasion by Endometrioid Adenocarcinoma. AB - BACKGROUND: Distinguishing myometrial invasion from adenomyosis involvement is important for staging of endometrial endometrioid adenocarcinoma. We aimed to compare CD10, which has limited value in this scenario, with interferon-induced transmembrane protein 1 (IFITM1), a recently described sensitive and specific marker of endometrial stroma. METHODS: We reviewed 25 hysterectomies containing endometrial endometrioid adenocarcinoma and adenomyosis. Tumor areas were classified as unequivocally myoinvasive or unequivocally noninvasive. Foci equivocal for invasion were also recorded. Immunohistochemistry for IFITM1 and CD10 was performed and scored in terms of intensity and distribution and classified as negative or positive. RESULTS: Unlike CD10, IFITM1 staining showed significant differences in mean intensity (P < .0001) and distribution (P < .0001) between invasive vs noninvasive areas. Sixteen (84.2%) invasive and 34 (97.1%) noninvasive areas were positive for CD10 (P = .22). In contrast, none of the invasive vs 25 (71.4%) noninvasive areas were positive for IFITM1 (P < .0001). IFITM1 had 71.4% sensitivity and 100% specificity in detecting stroma surrounding endometrioid adenocarcinoma, hence excluding myoinvasion. Eleven (45.8%) of 24 foci designated as equivocal stained with IFITM1. CONCLUSIONS: Compared with CD10, IFITM1 has superior performance distinguishing endometrial stroma of adenomyosis from mesenchyma surrounding invasive endometrial adenocarcinoma. IFITM1 expression is highly predictive of the absence of invasion and may be valuable in cases in which determining myoinvasion has staging implications. PMID- 27124938 TI - Patients With a History of Chemotherapy and Isolated del(20q) With Minimal Myelodysplasia Have an Indolent Course. AB - OBJECTIVES: Isolated deletion (20q) is relatively common in myeloid neoplasms and has been rarely reported in cases of therapy-related myelodysplastic syndrome (MDS). Our aim was to characterize cases of isolated del(20q) in bone marrow biopsy specimens from patients with a history of chemotherapy with morphologic findings insufficient for a diagnosis of MDS. METHODS: In this retrospective study from one institution, we identified 22 patients with isolated del(20q) and no or minimal dysplasia and evaluated clinical and pathologic characteristics. RESULTS: Eleven of the patients had a history of chemotherapy for mostly lymphoproliferative disorders. There were no statistically significant differences in peripheral blood or bone marrow features between patients with a history of chemotherapy and those without. Three patients with a history of chemotherapy had died at last follow-up; cause of death was recurrent nonmyeloid neoplasm. None of the patients with a history of chemotherapy subsequently developed a high-grade myeloid neoplasm, whereas one of the patients who had not received prior chemotherapy developed refractory anemia with excess blasts 2. CONCLUSIONS: The presence of del(20q) as an isolated bone marrow cytogenetic abnormality in the absence of morphologic findings sufficient for a diagnosis of acute myeloid leukemia, myeloproliferative neoplasm, or MDS portends an indolent clinical course, regardless of previous exposure to chemotherapy. PMID- 27124939 TI - Prospective and Retrospective Diagnosis of Barth Syndrome Aided by Next Generation Sequencing. AB - OBJECTIVES: To establish a genetic and clinical diagnosis in a newborn with fetal onset dilated cardiomyopathy using next-generation sequencing technologies. METHODS: We have conducted the clinical evaluation of the proband and the molecular characterization of his disease by means of whole-exome sequencing. In addition, the clinical evaluation and subsequent genetic screening of five relatives has been performed. This comprises two males with features of left ventricular noncompaction cardiomyopathy, two females suspected of being carriers, and one pregnant female at risk of being a carrier and thereby transmitting the disease to her child. RESULTS: We have discovered a novel variant in the TAZ gene by means of whole-exome sequencing. This, together with the performance of further clinical analyses, led to an early diagnosis of Barth syndrome in the proband. The genetic screening of the subject's familial group revealed full cosegregation of the variant with another two affected males and identified several female carriers. CONCLUSIONS: The investigation for Barth syndrome must be considered in male babies and young boys with dilated cardiomyopathy and left ventricular noncompaction. Next-generation sequencing technologies provide an accurate and rapid diagnostic tool in prospectively and retrospectively identifying individuals with this Mendelian syndrome. PMID- 27124940 TI - Audit of Use and Overuse of Serum Protein Immunofixation Electrophoresis and Serum Free Light Chain Assay in Tertiary Health Care: A Case for Algorithmic Testing to Optimize Laboratory Utilization. AB - OBJECTIVES: Overuse of laboratory tests is a persistent issue. We examined the use and overuse of serum immunofixation electrophoresis and serum free light chain assays to develop an algorithm for optimizing utilization. METHODS: A retrospective review of all tests, for investigation of monoclonal gammopathies, for all patients who had any of these tests done from April 24, 2014, through July 25, 2014, was carried out. The test orders were categorized as warranted or not warranted according to criteria presented in the article. RESULTS: A total of 237 patients were tested, and their historical records included 1,503 episodes of testing for one or more of serum protein electrophoresis, serum immunofixation electrophoresis, and serum free light chain assays. Only 46% of the serum immunofixation and 42% serum free light chain assays were warranted. Proper utilization, at our institution alone, would have obviated $64,182.95/year in health care costs, reduced laboratory cost of reagent alone by $26,436.04/year, and put $21,904.92/year of part B reimbursement at risk. CONCLUSIONS: Fewer than half of the serum immunofixation and serum free light chain assays added value. The proposed algorithm for testing should improve utilization. Risk to part B billing may be a disincentive to reducing test utilization. PMID- 27124941 TI - Mixed Adenoneuroendocrine Carcinoma, Amphicrine Type, of the Small Bowel. AB - OBJECTIVES: Amphicrine-type mixed adenoneuroendocrine carcinomas are exceedingly rare lesions of the gastrointestinal tract, comprising tumor cells simultaneously demonstrating both neuroendocrine and exocrine features. To date, only 14 cases of amphicrine carcinoma have been reported; here we report the first definitive case of amphicrine carcinoma in the small bowel. METHODS: A 72-year-old woman who sought treatment for nonspecific abdominal complaints was found to have a duodenojejunal junction tumor and underwent radical surgical resection. RESULTS: Morphologically, the tumor consisted of areas of moderately differentiated adenocarcinoma intermingled with areas characteristic of neuroendocrine tumor. The entire tumor showed strong, diffuse immunoreactivity for synaptophysin. Coexpression of exocrine and neuroendocrine features by neoplastic cells indicates bivalent differentiation, and therefore the tumor was classified as an amphicrine carcinoma of the small bowel. CONCLUSIONS: Demonstration of amphicrine carcinoma in the small bowel carries implications with regard to the common origin of exocrine and neuroendocrine cells in the gastrointestinal tract. PMID- 27124942 TI - Negative Heparin-Induced Thrombocytopenia Test Result After Massive Transfusion: Believe It or Not? AB - OBJECTIVES: Diagnosis of heparin-induced thrombocytopenia (HIT) is complicated by a high false-positive rate for the screening enzyme immunoassay (EIA) and limited availability of confirmatory platelet activation assays such as serotonin release assay (SRA). We evaluate the impact of a massive transfusion on EIA and SRA testing and emphasize that the timing of the confirmatory sample is important. METHODS: We present a case in which separate samples for HIT testing were collected before and after a major bleed requiring massive transfusion. We also discuss a recent study in which HIT serum samples were diluted in vitro and in vivo. RESULTS: The EIA was strongly positive, but SRA was negative, leading to suspicion of a false-positive EIA result. However, SRA performed on the initial EIA specimen was strongly positive. A second EIA, drawn after a massive transfusion, was negative. CONCLUSIONS: Replacement of several blood volumes diluted the HIT antibodies below the limit of detection. Confirmatory testing for HIT antibodies should be done on the specimen that initially tested positive. PMID- 27124943 TI - Effect of Lower Anogenital Squamous Terminology Recommendations on the Use of p16 Immunohistochemistry and the Proportion of High-Grade Diagnoses in Cervical Biopsy Specimens. AB - OBJECTIVES: The Lower Anogenital Squamous Terminology (LAST) group has recommended that cervical intraepithelial neoplasia (CIN) terminology be replaced by squamous intraepithelial lesion (SIL) terminology, with p16 immunohistochemistry used to separate lesions formerly diagnosed as CIN grade 2 into high-grade SILs (HSILs) and low-grade SILs. This study investigated the impact of these changes on the frequency of p16 testing and the diagnosis of high grade lesions. METHODS: Pathology reports for all cervical biopsy specimens in the 1 year before and after the introduction of LAST recommendations (July 2011 to June 2013) were examined. RESULTS: Before and after the implementation of LAST, 365 (15.4%) of 2,376 cases were diagnosed as high grade (CIN 2/3) vs 486 (17.6%) of 2,761 cases diagnosed as HSILs (P = .0343), and p16 was performed 79 (3.3%) times vs 383 (13.9%) times (P < .0001). CONCLUSIONS: Immunohistochemistry for p16 increased dramatically as a result of LAST recommendations, and high grade diagnoses increased. PMID- 27124944 TI - Pure Erythroid Leukemia and Erythroblastic Sarcoma Evolving From Chronic Myeloid Neoplasms. AB - OBJECTIVES: Pure erythroid leukemia (PEL) is an extremely rare entity that may, even more rarely, evolve from a preexisting chronic myeloid neoplasm (CMN); there is minimal literature regarding this latter phenomenon. METHODS: We describe 14 patients with PEL that represented progression from a preexisting myelodysplastic syndrome (MDS, n = 8) or myeloproliferative neoplasm (MPN, n = 6), three of which manifested as erythroblastic sarcoma (EBS), a rare entity. These patients had a highly complex karyotype with prominent clonal evolution and a very aggressive clinical course. RESULTS: Patients with PEL from MDS showed a more rapid progression time to PEL and had lower platelet counts compared with PEL from MPN. No other significant differences were found between the two groups. CONCLUSIONS: These data represent the largest cohort of patients with PEL and an antecedent CMN, as well as the largest series of EBS reported to date, and underscore the unique morphologic, cytogenetic, immunophenotypic, and clinical features of this uncommon entity. PMID- 27124945 TI - Prognostic Impact of Tumor Microenvironment in Diffuse Large B-Cell Lymphoma Uniformly Treated With R-CHOP Chemotherapy. AB - OBJECTIVES: We evaluated the prognostic impact of cell-of-origin classification as well as intratumoral regulatory T cells (Tregs), macrophages, and microvessel density (MVD) on 115 patients (74 in the training set and 41 in the validation set) diagnosed with de novo diffuse large B-cell lymphoma (DLBCL) and uniformly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. METHODS: The prognostic impact of Tregs, macrophages, and MVD was evaluated using FOXP3, CD68, and CD34 immunohistochemical stains, respectively. In addition, we designed a scoring system where 1 point was awarded per each adverse prognostic factor, including non-germinal center B-cell-like subtype, FOXP3 17% or more, CD68 less than 2%, and MVD less than 800 vessels/mm(2) RESULTS: Although only MVD was statistically significant on multivariate analysis, the scoring system significantly segregated patients into low- and high-risk groups. Patients having two or more adverse prognostic factors (high-risk group) demonstrated significantly worse event-free and progression-free survivals in the training set and event-free survival in the validation set. CONCLUSIONS: The concomitant evaluation of cell of origin along with tumor microenvironment components identifies patients with DLBCL treated with R-CHOP chemotherapy portraying a worse prognosis. PMID- 27124946 TI - Integration of Immature Granulocytes Quantification With the Version 2.0 UniCel DxH 800 in the HematoFlow Strategy. AB - OBJECTIVES: Our aim was to define whether the early granulocyte cell marker (EGC%_DxH) parameter might replace immature granulocytes counts obtained by HematoFlow (IG%_HF) and/or manual differential count (IG%_manual). METHODS: We conducted a study over a 10-day period in February 2014 whereby 402 samples were analyzed for the IG flag. We correlated the EGC%_DxH vs IG%_HF and IG%_manual, identified any discrepant results and finally looked at the impact on our workflow by incorporation of the EGC% into our WBC differential algorithm. RESULTS: On an initial training set, a receiver operating characteristic (ROC) curve analysis showed a threshold of 0.9% for EGC%_DxH (sensitivity of 91.7%, specificity of 93.5% and an area under the curve of 0.965). Further analysis of the dataset (259 samples) found a correlation of the EGC%_DxH to all our IG% counting methods (r = 0.963). Incorporation of the EGC%_DxH into the WBC HematoFlow differential resulted in a 36% reduction of samples requiring HematoFlow and/or slide review. CONCLUSIONS: The EGC% generated by the DxH 800 can be easily incorporated into existing HematoFlow and slide review algorithms. PMID- 27124947 TI - Pathology Consultation on Influenza Diagnostics. AB - OBJECTIVES: To describe the strengths and limitations of the available influenza diagnostics, with a focus on rapid antigen detection assays and nucleic acid detection assays. METHODS: A case-based presentation is used to illustrate the potential limitations of rapid antigen detection assays for influenza. RESULTS: Influenza is a seasonal illness; estimates attribute influenza to approximately 200,000 hospitalizations and 41,000 deaths in the United States annually. Antigen detection assays for influenza are rapid and convenient, and thus are widely used in a variety of health care settings, even though the sensitivity of these assays may be suboptimal. The United States Food and Drug Administration has recently created new guidelines intended to improve the oversight and performance characteristics of influenza antigen detection assays. Molecular assays, although more costly and complex, are more sensitive and may be designed to simultaneously detect multiple respiratory pathogens within a single assay. CONCLUSIONS: Diagnostic assays for influenza can vary greatly with regards to analytical performance characteristics, complexity, turnaround time and cost. This can have important patient care and infection prevention implications. PMID- 27124948 TI - Follow-up of Women With Negative Pap Test Results and Abnormal Clinical Signs or Symptoms. AB - OBJECTIVES: Abnormal signs or symptoms recorded on Papanicolaou (Pap) test requisitions may reflect disease not detected with Pap testing. Since 2009, these cases have been reviewed in our laboratory by a second cytotechnologist and a cytopathologist. The objective of this study was to document follow-up findings on these patients. METHODS: A search for Pap test results of "Negative for intraepithelial lesion or malignancy, abnormal clinical signs or symptoms" was performed for cases from January 1, 2009, to October 10, 2013. Clinical information and follow-up findings were documented. RESULTS: 1,104 cases were identified. Signs and symptoms were abnormal bleeding 897 (81%), polyps 83 (8%), pelvic mass 54 (5%), visible cervical lesions 48 (4%), vaginal lesions 17 (2%) and endometrial masses 6 (0.5%). Six hundred sixty-seven (60%) had follow-up results, including 517 with histopathologic diagnoses. Two-hundred thirty-three (45%) had nonspecific benign diagnoses, 216 (42%) had benign tumor-like conditions, 28 (4%) had insufficient specimens, 16 (3%) had precancerous diagnoses and 23 (4%) had malignancies. Endometrial malignancy was identified in 14 (61%), ovarian in 6 (26%), and miscellaneous in 3 (13%). No cervical cancers were identified. CONCLUSIONS: We report follow-up findings from patients with abnormal clinical signs or symptoms, negative Pap test results, and follow-up recommendations highlighting reported abnormal signs or symptoms. Abnormal clinical signs and symptoms should routinely be considered in assessment and management of patients with negative cervical screening test results. PMID- 27124949 TI - Mean Abnormal Result Rate: Proof of Concept of a New Metric for Benchmarking Selectivity in Laboratory Test Ordering. AB - OBJECTIVES: There is a need to develop and validate new metrics to access the appropriateness of laboratory test requests. METHODS: The mean abnormal result rate (MARR) is a proposed measure of ordering selectivity, the premise being that higher mean abnormal rates represent more selective test ordering. As a validation of this metric, we compared the abnormal rate of lab tests with the number of tests ordered on the same requisition. We hypothesized that requisitions with larger numbers of requested tests represent less selective test ordering and therefore would have a lower overall abnormal rate. RESULTS: We examined 3,864,083 tests ordered on 451,895 requisitions and found that the MARR decreased from about 25% if one test was ordered to about 7% if nine or more tests were ordered, consistent with less selectivity when more tests were ordered. We then examined the MARR for community-based testing for 1,340 family physicians and found both a wide variation in MARR as well as an inverse relationship between the total tests ordered per year per physician and the physician-specific MARR. CONCLUSIONS: The proposed metric represents a new utilization metric for benchmarking relative selectivity of test orders among physicians. PMID- 27124950 TI - Thyroid Frozen Sections in Patients With Preoperative FNAs: Review of Surgeons' Preoperative Rationale, Intraoperative Decisions, and Final Outcome. AB - OBJECTIVES: We wished to discover (1) in what circumstances surgeons wished to request frozen sections (FSs) on thyroid nodules having a prior fine needle aspiration (FNA) and the preoperative plan in these cases; (2) what the surgeons did with the information provided by FS and (3) in what types of cases was value added with the FS. METHODS: A retrospective chart review was performed of 121 consecutive patients receiving an intraoperative FS diagnosis on a thyroid nodule, all of which had been evaluated with a preoperative FNA. RESULTS: The medical record documented rationale for the request in 83% of cases. The most common reason for a FS request of a nodule was whether a planned hemithyroidectomy should proceed to a total thyroidectomy (TT). This scenario led to a TT in 9% of patients with a FNA diagnosed as benign thyroid nodule, 16% diagnosed as follicular neoplasm/suspicious for follicular neoplasm and 69% diagnosed as suspicious for malignancy. CONCLUSIONS: The stated rationale for FSs in patients with preoperative FNA was not supported by patient outcome in most cases. There may be some utility for FSs in lesions with a suspicious for malignancy preoperative FNA diagnosis. PMID- 27124951 TI - Pathology Consultation on Viscoelastic Studies of Coagulopathic Obstetrical Patients. AB - OBJECTIVES: In obstetrics, the decision to transfuse blood components has historically been driven by traditional laboratory testing in combination with direct observation of bleeding. The adjunctive use of viscoelastic testing, including thromboelastometry and thromboelastography, has gained increasing acceptance in the clinical domain. METHODS: We performed a review of the published medical literature by searching the PUBMED database for keywords "viscoelastic" and "obstetric," as well as "viscoelastic" and "postpartum hemorrhage." Additionally, case reports and expert opinion publications that referenced viscoelastic studies in obstetrical patients were evaluated. RESULTS: There is very little high-quality evidence currently published in the medical literature to support the notion that viscoelastic testing obviates the need for traditional coagulation testing or improves mortality resulting from major obstetrical hemorrhage. CONCLUSIONS: Additional research is needed to further focus the optimum role of viscoelastic tests in major obstetrical hemorrhage. PMID- 27124952 TI - Radical Nephrectomy for Renal Cell Carcinoma: Its Contemporary Role Related to Histologic Type, Tumor Size, and Nodal Status: A Retrospective Study. AB - OBJECTIVES: Staging for renal cell carcinoma (RCC) depends on tumor size and the status of the regional lymph nodes. Although lymph node involvement by tumor yields the most accurate staging and prognostic information in patients with carcinomas of various genitourinary organs, the role of lymph node sampling (LNS) in patients with RCC to definitively establish nodal metastases remains unsettled. METHODS: In this retrospective study of 399 patients with RCC treated by total nephrectomy, 115 cases were subjected to lymph node dissection. RESULTS: The corresponding primary tumors averaged larger than 8 cm. Twenty-nine showed positive lymph nodes (25%). The present review confirms that primary tumor size is a key indicator of nodal involvement. Clear cell and papillary tumors larger than 4 cm involve lymph nodes more commonly than other types of RCC. Sarcomatoid differentiation occurred in all major cell types and existed in numbers too few to predict the likelihood of nodal metastases. CONCLUSIONS: LNS in RCC for staging purposes may be warranted based on tumor size (>4 cm) as determined by imaging as well as histologic cell type, the latter suggesting a selective role for preoperative fine needle aspiration or core biopsy. PMID- 27124955 TI - Meeting Increasing Demands for Rural General Surgeons. AB - Dynamic assessment of the effective surgical workforce recommends 27,300 general surgeons in 2030; 2,525 more than are presently being trained. Rural shortages are already critical and there has been insufficient preparation for this need. A literature review of the factors influencing the choice of rural practice was performed. A systematic search was conducted of PubMed and the Web of Science to identify applicable studies in rural practice, surgical training, and rural general surgery. These articles were reviewed to identify the pertinent reports. The articles chosen for review are directed to four main objectives: 1) description of the challenges of rural practice, 2) factors associated with the choice of rural practice, 3) interventions to increase interest and preparation for rural practice, and 4) present successful rural surgical practice models. There is limited research on the factors influencing surgeons in the selection of rural surgery. The family practice literature suggests that physicians are primed for rural living through early experience, with reinforcement during medical school and residency, and retained through community involvement, and personal and professional satisfaction. However, more research into the factors drawing surgeons specifically to rural surgery, and keeping them in the community, is needed. PMID- 27124956 TI - Commentary on Meeting Increasing Demands for Rural General Surgeons. PMID- 27124954 TI - Antibiotic perturbation of the murine gut microbiome enhances the adiposity, insulin resistance, and liver disease associated with high-fat diet. AB - BACKGROUND: Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are serious health concerns, especially in Western populations. Antibiotic exposure and high-fat diet (HFD) are important and modifiable factors that may contribute to these diseases. METHODS: To investigate the relationship of antibiotic exposure with microbiome perturbations in a murine model of growth promotion, C57BL/6 mice received lifelong sub-therapeutic antibiotic treatment (STAT), or not (control), and were fed HFD starting at 13 weeks. To characterize microbiota changes caused by STAT, the V4 region of the 16S rRNA gene was examined from collected fecal samples and analyzed. RESULTS: In this model, which included HFD, STAT mice developed increased weight and fat mass compared to controls. Although results in males and females were not identical, insulin resistance and NAFLD were more severe in the STAT mice. Fecal microbiota from STAT mice were distinct from controls. Compared with controls, STAT exposure led to early conserved diet-independent microbiota changes indicative of an immature microbial community. Key taxa were identified as STAT-specific and several were found to be predictive of disease. Inferred network models showed topological shifts concurrent with growth promotion and suggest the presence of keystone species. CONCLUSIONS: These studies form the basis for new models of type 2 diabetes and NAFLD that involve microbiome perturbation. PMID- 27124957 TI - Commentary on Meeting Increasing Demands for Rural General Surgeons. PMID- 27124958 TI - Changing the Picture Frame. PMID- 27124959 TI - Representative Aspects of Some Synthetic Gametes. AB - With the development of new procedures in the production of synthetic human gametes it has become important to re-examine the manner in which reproductive cells, taking part in the generation of children, can be understood. Though this can be attempted from many different perspectives, the present study will examine the possibility of considering gametes as representing the persons from whom they originated. From this perspective, it is possible to suggest that, in procreation, the entirety of each human sperm cell may represent and reveal the man from whom it was produced and the entirety of each human egg cell may represent and reveal the woman from whom it was produced. The possible ethical consequences of using synthetic gametes for those who hold this perspective together with their understanding of relational identity will also be examined. PMID- 27124960 TI - Transhumanism: A New Kind of Promethean Hubris. AB - Asking whether transhumanist hopes of overcoming ageing and cognitive and other shortcomings are realistic, this paper pitches a Christian anthropology against a transhumanist anthropology. It is shown that on critical examination many of the technologies proposed by transhumanists in order to better or extend human life raise questions about dualism and materialism, about our nature as relational beings, and indeed even about what it means to be alive. PMID- 27124961 TI - Lessons in Biopolitics and Agency: Agamben on Addiction. AB - The concepts of 'biopolitics' and 'naked life' have become increasingly relevant in the debate on substance dependency due to the growing prominence of neuroscience in defining the nature of addiction and its threat to agency. However, these concepts are not necessarily well understood, and therefore may lead to oversight rather than insight. In this article we review the literature on Italian philosopher Giorgio Agamben, whose founding works on both concepts shed a different light on addiction. We argue that the current debate is missing a key insight from Agamben's work: the idea of agency past the subject, of agency past identity. We will illustrate how this can be an important form of agency against the stigmatization of users, making use of empirical data from our ongoing work on addiction and agency. PMID- 27124962 TI - A Systematic Review on Confidentiality, Disclosure, and Stigma in the United States: Lessons for HIV Care in Pregnancy From Reproductive Genetics. AB - The fields of HIV care in pregnancy and reproductive genetics have always been 'exceptional' in that patients are highly concerned about the potential for stigma and the corresponding need for privacy and confidentiality. However, the two fields have diverged in how they have addressed these concerns. The systematic review analyzed 61 manuscripts for similarities and differences between the fields of HIV care in pregnancy and reproductive genetics in the United States, with respect to privacy, confidentiality, disclosure, and stigma. The systematic review revealed that the field of HIV care in pregnancy has insufficiently addressed patient concerns about privacy, confidentiality, and stigma compared to the field of reproductive genetics. Failure to adequately protect confidentiality of HIV-positive patients, and failure to reduce stigma associated with HIV testing and treatment are deficiencies in the delivery of care to HIV-positive pregnant woman and barriers to reducing vertical transmission of HIV. Improvements in care and policy should mirror the field of reproductive genetics. PMID- 27124963 TI - The Evolution of Autonomy. AB - There can be little doubt, at least in the Western world, that autonomy is theruling principle in contemporary bioethics. In spite of its 'triumph' however,the dominance of the utilitarian concept of autonomy is being increasinglyquestioned. In this paper, I explore the nature of autonomy, how it came todisplace the Hippocratic tradition in medicine and how different conceptsof autonomy have evolved. I argue that the reduction of autonomy to'the exercise of personal choice' in medicine has led to a 'tyranny of autonomy' which can be inimical to ethical medical practice rather than conducive to it.I take the case of Kerrie Wooltorton as an illustration of how misplacedadherence to respect for patient autonomy can lead to tragic consequences.An analysis of autonomy based on the work of Rachel Haliburton isdescribed and applied to the role of autonomy in a recent bioethicaldebate--that arising from Savulescu's proposal that conscientious objection by health-care professionals should not be permitted in the NHS. Inconclusion, I suggest Kukla's concept of conscientious autonomy as onepromising pathway to circumvent both the limitations and adverse effectsof the dominance of current (mis)understandings of autonomy in biomedical ethics. PMID- 27124965 TI - [In remembrance of Professor Ivan Duris]. PMID- 27124964 TI - The Idea of Patents vs. the Idea of University. AB - It is generally accepted that patents are a driving force for innovation through research and development. But the university's involvement in patenting is problematic as well. In particular, it is in tension with the idea of a university itself. If patents entail a restriction on the accessibility of the scientific knowledge that has been patented, and if the main purpose of universities is to produce and disseminate knowledge to the public, then, there is a tension: when universities patent their research innovations, they are making the scientific knowledge they produce less accessible to the public. The paper argues that university patenting contradicts the very idea of a university as an institution whose mission is fundamentally to disseminate the knowledge it produces to the public. The practice of university patenting involves an un academic attitude thus: by inciting an attitude towards knowledge that is not consistent with the proper attitudes and goals of a university, university patenting hurts university's integrity. PMID- 27124966 TI - [Epidemiologic data of hyperuricaemia prevalence in the conditions of primary care in Slovakia]. AB - Hyperuricaemia represents nowaday the new risk factor for cardiovascular diseases. Prevalence data and its treatment in our patient's population are still missing. Literature data shows, that its prevalence differs in various populations significantly from 4% up to 40% with race and geographical means. In the hospital population its prevalence is about 7% and represents the important predictor of hospital mortality, e.i with heart failure. From the Framingham data relative risk was estimated of 25% for cardiovascular diseases, coronary heart disease and all-course mortality. From the epidemiologic survey Mirror Slovakia hyperuricaemia was evaluated from the sample of 20 000 patients from the primare care physicians in order to see the picture on this newer risk factor. PMID- 27124967 TI - [Management of treatment in patients with neuroendocrine neoplasmas of digestive tract]. AB - Neuroendocrine neoplasmas are a form of cancer arising from cells of diffuse neuroendocrine system. They produce peptides or amines that act as hormones or neurotransmitters. Incidence of NENs is relatively low. Diagnostic work-up and treatment requires a multidisciplinary team approach. The aim of this study was an analysis of data from patients with well-differentiated neuroendocrine neoplasmas of gastrointestinal tract. The study included patients followed up from 1998 to 2013 with histologically confirmed well-differentiated digestive neuroendocrine neoplasm with low or intermediate malignant potential. 97 patients were included; 34 men (35.1%) and 63 women (64.9%). In patients being diagnosed after 2005 interferon treatment is significantly less used than endoscopic and peptide receptor radionuclide therapy. We have identified more appropriate discriminant values of 5-HIAA and chromogranin A (6.8 mg/24 hours; 70 ng/ml) for predicting the presence of metastases at the time of diagnosis. We have identified following risk factors for overall mortality: liver metastases, presence of diarrhea, flush, small bowel primary tumor, high values of CgA and 5 HIAA at the time of diagnosis (5-HIAA > 520.52 mg/24 hours, CgA > 174.5 ng/ml). Surgical treatment was found to be a positive prognostic factor. PMID- 27124968 TI - [Specifics of using ambulatory blood pressure monitoring in the elderly]. AB - Arterial hypertension is a chronic disease which represents a major risk factor for damage of cardiovascular system. Insufficient control of elevated blood pressure is associated with the development of target organ damage, increased cardiovascular morbidity and mortality with a adverse prognostic value. Using ambulatory blood pressure monitoring (ABPM) we can improve the overall management of elderly patients at which the prevalence of arterial hypertension is particularly high. PMID- 27124969 TI - [Arterial hypertension--multicirculus vitiosus vasorum]. AB - AIM: The aim of this review is to address documents and a number of studies on hypertension published in the last years in order to assess their contribution to our expanding knowledge of arterial hypertension. DISCUSSION: Arterial hypertension is not defined by symptoms and signs but by numbers of blood pressure values. Arterial hypertension is vascular disease (vascular risk factor) of many vascular diseases (atherosclerosis; arteriolosclerosis/arteriolonecrosis/arteriolocalcinosis; arterial thrombosis; arterial embolism; arterial thromboembolism; arterial dissection; complicated arterial aneurysm) and other. CONCLUSION: Arterial hypertension is cause and consequence of functional (endothelial dysfunction) and of structural organovascular injury (multiorganomultivascular disease). Blood vessels are culprits, implements and victims of arterial hypertension and of organovascular arterial diseases. PMID- 27124970 TI - [Hormonal changes in inflammatory bowel disease]. AB - Inflammatory bowel disease is often accompanied by extraintestinal manifestations due to a common autoimmune etiopathogenesis, chronic systemic inflammation, frequent nutrition deficits, and the treatment. Endocrine system changes belong to manifestations too. Interaction is mutual, Crohn's disease and ulcerative colitis cause functional and morphological changes of endocrine tissues. On the other hand the endocrine disorders negatively influence the course of bowel disease. In the article we analyze correlation of IBD with gonadal hormone production and fertility, with adrenal function, with the function and morphology of the thyroid, with growth hormone production and growth disorders in children, and with bone mineral density reduction. This topic is not studied enough and needs more analysis and clarification. PMID- 27124971 TI - [Diagnostics of polycystic ovary syndrome]. AB - Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy among women of reproductive age and the most frequent cause of menstruation cycle disorders. It is marked by a hyperandrogenic state (clinical and/or biochemical) and ovulatory dysfunction (anovulation and/or ultrasonographic finding of polycystic ovaries), which are also criteria for its diagnosis according to Androgen Excess and PCOS Society. The syndrome has multiple phenotypic expressions, among them besides the above characteristics also a metabolic syndrome, primarily obesity and insulin resistance. Diagnosing of PCOS may be rather exacting in clinical practice and it remains to be a diagnosis per exclusionem, following elimination of other causes of hyperandrogenic state and chronic oligo-anovulation. It requires a close cooperation between a gynecologist and endocrinologist and with regard to frequent metabolic complications also with an internist, diabetologist and possibly cardiologist. PMID- 27124972 TI - [Non usual cases of hypoglycaemia--hypoglycaemia factitia]. AB - Hypoglycaemia factitia means also in recent time serious diagnostic and therapeutic problem in medical clinical practice, whereby often repeating episodes of serious hypoglycaemia in patients with diabetes mellitus, but also in patients without diabetes mellitus could be very difficult do resolve. First unsuccessful diagnosis implicit from wrong chose of examination algorithm, can lead to unidentified surgical interventions as are laparotomy and pancreatectomy, respectively. Hypoglycaemia factitia is considered to be one of many manifestations of so called Munchhausen's syndrome for that is typical acting of diabetic patient with goal to intentionally making hypoglycaemia or within suicidal attempt of patient on the basis psychological disease with intention to attract attention of surrounding community to himself due to application of insulin or sulfonylurea drugs. Diagnostic and therapeutic process could be in the case of hypoglycaemia factitia extremely difficult as from time side, than from health and also from economical side and that why necessary to approach with maximum responsibility. PMID- 27124973 TI - [Is iron important in heart failure?]. AB - Iron deficiency is a frequent comorbidity in a patient with chronic heart failure, and it associates with a worse prognosis of that patient. Mainly worse quality of life and more rehospitalizations are in these iron deficient patients. Iron metabolism is rather complex and there is some new information concerning this complexity in heart failure. We distinquish an absolute and a functional iron deficiency in heart failure. It is this deficit which is important and not as much is anemia important here. Prevalence of anaemia in heart failure is about 30-50%, higher it is in patients suffering more frequently heart failure decompensations. Treatment of iron deficiency is important and it improves prognosis of these patients. Most experiences there are with i.v. iron treatment (FERRIC HF, FAIR HF and CONFIRM HF studies), less so with per oral treatment. There are no clinical trials which analysed mortality influences. PMID- 27124974 TI - [Novel diagnostic and therapeutic procedures in diabetic nephropathy]. AB - Epidemiological studies show increasing prevalence of diabetic nephropathy. Diabetic patients with chronic kidney disease are the biggest group from among patients on renal replacement therapy. Renal Pathology Society developed pathological classification of diabetic nephropathy. The cardinal biochemical diagnostic parameters are albuminuria and estimated glomerular filtration rate. European Renal Best Practice work group developed Clinical Practice Guideline on management of patients with diabetes and chronic kidney disease stage 3b or higher. PMID- 27124976 TI - [Not Available]. PMID- 27124975 TI - [Are we to pay attention to factor XII deficiency?]. AB - Severe coagulation factor XII (FXII) deficiency is a very rare, mysterious and not well known inherited condition. Unlike other coagulation factor deficiencies, it is totally asymptomatic. Surprisingly, it does not lead to abnormal bleeding, even with major surgical procedures. The explanation for the lack of bleeding manifestations is unknown. It is suggested, but unproven, that patients are not sufficiently protected from thrombosis. FXII deficiency is usually discovered by accident through a routine coagulation testing done prior to surgery. Since FXII plays an important role in clot formation during in vitro measurements, its deficiency causes a marked prolongation of the activated partial thromboplastin time in the laboratory examination. The main concern related to FXII deficiency is the unnecessary testing, delay in health care and worry of surgical interventions that may be prompted by the abnormal laboratory result. PMID- 27124977 TI - The Responsibility of Organized Medicine in South Carolina and Thoughts from Your SCMA President. PMID- 27124979 TI - The Roe Award: Past, Present, Future. PMID- 27124978 TI - Tribute to Dr. Tim Pearce 2014-2015 SCMA President. PMID- 27124980 TI - A Community Radiologist's Perspective on Screening Mammography: Focus on Improvement. PMID- 27124981 TI - Investigation of Epidemiological Factors as Barriers to Indicated Radiation Therapy in Post-Mastectomy Breast Cancer Patients in South Carolina. PMID- 27124982 TI - Thinking Outside of the Lines: Diagnosing Babesiosis in the Lowcountry. PMID- 27124983 TI - Evaluating the Effectiveness of Simulation Training in the MUSC Family Medicine Residency Program. PMID- 27124984 TI - Suvorexant for Adults with Insomnia. PMID- 27124985 TI - A Case of Primary Cardiac Lymphoma. PMID- 27124986 TI - Stimulant Use by Medical Students. PMID- 27124988 TI - Fundamentals of the Medical Practice Act. PMID- 27124987 TI - Response from Authors. PMID- 27124989 TI - Spinning Wheels.... PMID- 27124990 TI - The Doctor as the Patient. PMID- 27124991 TI - Changing The Game in Childhood Obesity Prevention. PMID- 27124992 TI - Prescription for Parks: A Creative Approach to Combat Childhood Obesity in South Carolina and To Get South Carolina Children Moving. PMID- 27124993 TI - The Docs-Adopt School Wellness Initiative: An Innovative Program to Involve Doctors in School-Based Obesity Prevention Efforts. PMID- 27124994 TI - Team-Based Approach to Obesity Management. PMID- 27124995 TI - Development and Use of the SCMA Childhood Obesity Taskforce Toolkit. PMID- 27124996 TI - The New Impact-Healthy Lifestyle Program at Children's Hospital of Greenville. PMID- 27124997 TI - South Carolina Chapter of the American Academy of Pediatrics. PMID- 27124999 TI - Eat Smart, Move More South Carolina. PMID- 27124998 TI - The Department of Health and Environmental Control. PMID- 27125000 TI - Representing PROTeens (Program for the Reduction of Obesity in Teens) and Bariatric Solutions. PMID- 27125001 TI - COMMIT to Be FIT. PMID- 27125002 TI - Celebrating the Voice of Health Care. Honoring Dr. Bruce A. Snyder SCMA President 2013-2014. PMID- 27125003 TI - It's What Physicians Do Year After Year. PMID- 27125004 TI - Evaluation of Cost Reduction Measures at a State University Medical Center. AB - Components of a Perioperative Surgical Home (PSH), implemented at a large State University Medical Center (SUMC), have driven significant reductions in Surgical Site Infections (SSIs) and Day of Surgery (DOS) cancellations. Refined methodology for efficient and accurate assessment of these reductions was developed based on available electronic data systems and proven strategies adapted from literature. At our institution, the practice of evidence-based protocol-driven medicine has contributed to the prevention of an estimated 1073 SSIs over a 6 year period, representing avoided costs in excess of $24M. Management of logistics surrounding patients' surgeries starting in the preoperative clinic has yielded exceedingly low DOS cancellation rates (3.47% of scheduled procedures). This level of efficiency is critical given that a 1% increase in DOS cancellation rates can represent as much as a $5.6M loss of revenue to a large SUMC. PMID- 27125005 TI - The Diagnostic Significance of a Mucocele of the Appendix. AB - Appendiceal mucoceles are rare lesions with a variable clinical presentation often identified incidentally on imaging or at laparotomy/laparoscopy for an unrelated diagnosis. Mucocele of the appendix may be a benign or malignant process, making early recognition based on symptoms and key radiographic characteristics of the utmost importance for optimal patient management. Here we present the case of a patient presenting with non-specific abdominal complaints suffering from appendiceal mucocele perforation due to low-grade mucinous adenocarcinoma. PMID- 27125006 TI - Tele-Intensivist Augmented Critical Care: Report of Three-Year Experience with a Remote Tele-ICU System. PMID- 27125007 TI - Yellow Fever and the Emergence of Public Health Policy in Charleston, South Carolina. PMID- 27125009 TI - President's Annual Report. PMID- 27125010 TI - Effect of formulation variables on the physical properties and stability of Dead Sea mud masks. AB - The physical stability of Dead Sea mud mask formulations under different conditions and their rheological properties were evaluated as a function of the type and level of thickeners, level of the humectant, incorporation of ethanol, and mode of mud treatment. Formulations were evaluated in terms of visual appearance, pH, moisture content, spreadability, extrudability, separation, rate of drying at 32 degrees C, and rheological properties. Prepared mud formulations and over-the-shelf products showed viscoplastic shear thinning behavior; satisfactory rheological behavior was observed with formulations containing a total concentration of thickeners less than 10% (w/w). Casson and Herschel Bulkley models were found the most suitable to describe the rheological data of the prepared formulations. Thickener incorporation decreased phase separation and improved formulation stability. Bentonite incorporation in the mud prevented color changes during stability studies while glycerin improved spreadability. Addition of 5% (w/w) ethanol improved mud extrudability, slightly increased percent separation, accelerated drying at 32 degrees C, and decreased viscosity and yield stress values. Different mud treatment techniques did not cause a clear behavioral change in the final mud preparation. B10G and K5B5G were labeled as "best formulas" based on having satisfactory physical and aesthetic criteria investigated in this study, while other formulations failed in one or more of the tests we have performed. PMID- 27125008 TI - Now I Lay Me Down to Sleep. PMID- 27125011 TI - Feasibility study of a cosmetic cream added with aqueous extract and oil from date (Phoenix dactylifera L.) fruit seed using experimental design. AB - This article reports on the feasibility study of a cosmetic cream added with aqueous extract and oil from date (Phoenix dactylifera L.) fruit seed using experimental design. First, the mixture design was applied to optimize the cosmetic formula. The responses (dependent variables) were the spreadability (YSp) and viscosity (YVis), the factors (independent variables) being the weight proportions of the fatty phase (X1), the aqueous date seed extract (X2), and the beeswax (X3). Second, the cosmetic stability study was conducted by applying a full factorial design. Here, three responses were considered [spreadability (Sp), viscosity (Vis), and peroxide index (PI)], the independent variables being the concentration of the date seed oil (DSO) (x1), storage temperature (x2), and storage time (x3). Results showed that in the case of mixture design, the second order polynomial equations correctly described experimental data. Globally, results show that there is a relatively wide composition range to ensure a suitable cosmetic cream from the point of view of Sp and Vis. Regarding the cosmetic stability, the storage time was found to be the most influential factor on both Vis and PI, which are considered here as indicators of physical and chemical stability of the emulsion, respectively. Finally, the elaborated and commercial cosmetics were compared in terms of pH, Sp, and centrifugation test (Ct). PMID- 27125013 TI - Quantifying hair shape and hair damage induced during reshaping of hair. AB - The manipulation of hair shape, either to straighten or curl hair, is carried out on a grand scale in the hair care consumer market. Often, such changes are brought about through chemical or physical treatment, resulting in changes to hair chemistry. In this article, we review existing and present new data on methods to assess the efficacy of such treatments, mostly concentrating on imaging technologies used in conjunction with image analysis. In addition, we introduce spectroscopic imaging techniques and fluorescence spectrophotometry as tools to assess the biochemical state of the hair fiber as a result of hair shape modification regimens. Finally, we demonstrate how the structural integrity of the fiber is monitored with dynamic scanning calorimetry and traditional mechanical testing of the tensile properties of hair. PMID- 27125012 TI - Volatile profile and sensory property of Gardenia jasminoides aroma extracts. AB - The volatile profiles of aroma extracts prepared from the flower of Gardenia jasminoides by different methods were investigated using gas chromatography-mass spectrometry. The enfleurage extraction using spermaceti wax and palm oil afforded the best aroma extract with a preference that was significantly (p < 0.05) better than those from solvent extractions, as sensorially evaluated in 43 volunteers. The odor quality of the absolute de enfleurage was similar to the floral scent of fresh gardenia, as confirmed in 152 volunteers. Although female volunteers were insignificantly (p > 0.05) better sensed than male volunteers, age was significant (p < 0.05). The nuance gardenia floral scent was contributed by farnesene, Z-3-hexenyl tiglate, Z-3-hexenyl benzoate, and indole. The relaxing and refreshing sensations of the gardenia odor suggest its applications in body care, cleansing products, and perfume. This study addresses the increasing interest in floral fragrances. The aroma profile and sensory property of this sweet and elegant scent flower will strengthen and expand the applications of gardenia from traditional medicine to those of perfumery and the field of phytochemistry. PMID- 27125014 TI - Competing for domain names in the cosmetic industry: registrants versus trademark owners. PMID- 27125015 TI - Diagnostic Emergency Ultrasound: Assessment Techniques In The Pediatric Patient. AB - Emergency ultrasound is performed at the point of care to answer focused clinical questions in a rapid manner. Over the last 20 years, the use of this technique has grown rapidly, and it has become a core requirement in many emergency medicine residencies and in some pediatric emergency medicine fellowships. The use of emergency ultrasound in the pediatric setting is increasing due to the lack of ionizing radiation with these studies, as compared to computed tomography. Utilizing diagnostic ultrasound in the emergency department can allow clinicians to arrive at a diagnosis at the bedside rather than sending the patient out of the department for another study. This issue focuses on common indications for diagnostic ultrasound, as found in the pediatric literature or extrapolated from adult literature where pediatric evidence is scarce. Limitations, current trends, controversies, and future directions of diagnostic ultrasound in the emergency department are also discussed. PMID- 27125016 TI - [Pioneer Transcription Factors in Normal Development and in Carcinogenesis]. AB - Pioneer transcription factors constitute a heterogeneous group of regulatory proteins of animals, which, unlike other transcription factors, are able to recognize and bind target DNA sequences within closed chromatin. This binding can change the local chromatin structure and facilitate binding of other proteins, thus establishing competence for gene expression. The ability to bind silent genes in the closed environment makes the pioneer factors very useful in the processes leading to cardinal alteration of cell phenotype, such as differentiation in embryonic development or cell reprogramming. These proteins can remain bound to target sequences during mitotic division, and due to this probably take part in the maintenance of cellular memory. Apparently, pioneer transcription factors are active participants in carcinogenesis and maintenance of tumor cell phenotype, although their role in these processes needs additional research. It is reasonable to suppose that a further study will help to shed more light on the genetic processes in embryonic development, increase the efficiency of cell reprogramming and also develop new approaches to diagnostics and therapy of cancer diseases. PMID- 27125017 TI - [The Qualitative Analysis of the Amide Derivative of HLDF-6 Peptide and Its Metabolites with the Use of Tritium- and Deuterium-Labeled Derivatives]. AB - The goal of the study was to elaborate the pharmacokinetics methods of the amide derivative of peptide HLDF-6 (TGENHR-NH2) and its range of nootropic and neuroprotective activity is wide. The hexapeptide 41TGENHR46 is a fragment of the HDLF differentiation factor. It forms the basis for the development of preventive and therapeutic preparations for treating cerebrovascular and neurodegenerative conditions. Pharmacokinetic and molecular mechanisms of the action of the HLDF-6 peptide were studied using tritium- and deuterium-labeled derivatives of this peptide, produced with the use of the high-temperature solid-state catalytic isotope exchange reaction (HSCIE). This reaction was employed to produce the tritium-labeled peptide [3H]TGENHR-NH2 with a molar radioactivity of 230 Ci/mmol and the deuterium-labeled peptide [2H]TGENHR-NH2 with an average deuterium incorporation equal to 10.5 atoms. It was shown by the NMR spectroscopy that the isotope label distribution over the labeled peptide's molecule was uniform, which allowed qualitative analysis ofboth the peptide itself and its fragments in the organism's tissues to be conducted. The newly developed pharmacokinetics method makes it possible to avoid almost completely losses of the peptides under study due to biodegradation during the analysis of tissues. These labeled peptides were used in mice, rats and rabbits to study the pharmacokinetics of the peptide and to calculate the values of its principal pharmacokinetic parameters. Characteristics of its pharmacokinetic profile in the blood were obtained, the hypothesis of pharmacokinetics linearity tested, its metabolism analyzed and its bioavailability value, 34%, calculated. It has been shown that the studied TGENHR NH2 peptide shows high resistance to hydrolysis in the blood plasma, with dipeptidyl aminopeptidases making the largest contribution to its hydrolysis. PMID- 27125018 TI - [Anti-Inflammatory Activity of the Polypeptide of the Sea Anemone, Heteractis crispa]. AB - The anti-inflammatory effect of the recombinant polypeptide HCGS 1.20, a Kunitz type serine protease inhibitor of the sea anemone Heteractis crispa, was investigated. It was shown that the polypeptide inhibits the increase of the concentration of calcium ions in mouse bone marrow derived macrophages elicited by histamine, and reduces the content of NO in lipopolysaccharide stimulated macrophages. A presumable mechanism of anti-inflammatory action of the polypeptide was being discussed. PMID- 27125019 TI - [Interaction of Arenicin-1 with C1q Protein]. AB - The interaction between arenicin-1, that is an antimicrobial peptide from polychaeta Arenicola marina, and human complement system protein C1q was studied using enzyme-linked receptor sorbent assay and ELISA. We revealed that arenicin-1 and C1q form complex that is stable in high ionic strength condition 0.5 M NaCl. The ability of C1q to interact with arenicin-1 is comparable with the binding activity of C1q towards another antimicrobial peptide, porcine cathelicidin protegrin-1, which has a similar spatial arrangement with arenicin-1. Namely, both arenicin-1 and protegrin-1 form cystine-stabilized antiparallel beta-hairpin structure. PMID- 27125020 TI - [Ph-Sensor Properties of a Fluorescent Protein from Dendronephthya sp]. AB - Genetically encoded biosensors based on fluorescent proteins are now widely applicable for monitoring pH changes in live cells. Here, we have shown that a fluorescent protein from Dendronephthya sp. (DendFP) exhibits a pronounced pH sensitivity. Unlike most of known genetically encoded pH-sensors, fluorescence of the protein is not quenched upon medium acidification, but is shifting from the red to green spectral range. Therefore, quantitative measurements of intracellular pH are feasible by ratiometric comparison of emission intensities in the red and green spectral ranges, which makes DendFP advantageous compared with other genetically encoded pH-sensors. PMID- 27125021 TI - [Functionalized Metal Chelates Based on Diethylenetriaminetetraacetic Acids for Chemical Modification of Proteins and Small Biomolecules]. AB - Bifunctional reagents based on diethylenetriaminetetraacetic acid containing a bound metal ion and a reactive functional group for the interaction with proteins and low-molecular-weight substances have been synthesized. An Amino-derivative of a complexonate was obtained by acylation of monosubstituted diamine with diethylenetriaminepentaacetic acid dianhydride followed by deprotection ofthe amino group, purification by anion exchange chromatography and chelation of Eu3+. This metal chelate derivative was used for labeling 17alpha-hydroxyprogesterone 3 (O-carboxymethyl)oxime and horseradish peroxidase. The enzyme modified with the Eu3+ complexonate at the carbohydrate component and with a cortisol derivative at the polypeptide chain was used in a dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) as well as in an enzyme immunoassay of the steroid hormone. DELFIA showed that labeled 17alpha-hydroxyprogesterone retained the affinity for corresponding antibodies. A Eu(3+)-complexonate carboxy-derivative N-succinimide ester was obtained by acylation of the aminochelate with p-phthalic acid di-N succinimide ester. It was used for modification of amino groups of lysine residues in polypeptide chains of human serum albumin and some immunoglobulins G. Purification of Eu3+ complexonate-protein conjugates by gel-chromatography on a Superose- 12 column allowed to separate the modified proteins from unreacted low molecular weight Eu(3+)-derivatives and to determine a degree of lanthanide inclusion into a protein. The amount of Eu3+ covalently attached to a protein was determined by measuring the fluorescence of a conjugate in the dissociative enhancement solution. The obtained values correlated well with the results of ICP MS determination of Eu3+ concentration in a conjugate solution. It was shown that conjugates of monoclonal antibodies obtained by the proposed method possessed the required characteristics of fluorescence intensity, signal-to-noise ratio, sensitivity and specificity in DELFIA medical diagnostic systems. PMID- 27125022 TI - [Protein Identification of Blood Nucleoprotein Complexes]. AB - Circulating nucleoprotein complexes were isolated-from blood plasma by affinity chromatography using immobilized polyclonal anti-histone antibodies. It was found, that the main part of DNA from histone-contained nucleoprotein complexes have size 170-180 b.p., in blood of breast cancer patients DNA with size 170-180 b.p. and DNA more then 6 k.b.p. are presented in equal quantity. Proteins from circulating nucleoprotein complexes were identified using MALDI-TOF mass spectrometry. It was shown that nucleoprotein complexes from blood of breast cancer patients contain tumor-specific proteins, such as LDOC1L, ADP/ATP translocase 3 and Lamellipodin. These data indicate, that a part of circulating extracellular DNA have tumor origin. PMID- 27125023 TI - [Interaction of DNA Aptamers with the ATP-Dependent Lon Protease from Escherichia coli]. AB - ATP-dependent Lon protease of E. coli (Ec-Lon) is a key enzyme of the quality control system of the cell proteome. Ec-Lon subunit comprises N-terminal non catalytic region, ATPase module and proteolytic domain (serine-lysine endopeptidase). A distinctive feature of the Ec-Lon is its ability to interact with DNA, however either DNA binding site(s) or the role ofthe complex Ec-Lon . DNA have not yet been characterized. A promising tool for the study of molecular mechanisms of interaction between nucleic acids and protein ligands are known to be aptamers (small nucleic acids with high specificity to organic compounds of different nature). Ec-Lon-protease was found to form complexes with the previously obtained thrombin aptamers whose molecules comprise the duplex domains and G-quadruplex region. The aptamer affinities to the enzyme have been characterized. The synthesis of novel aptamers specific to Ec-Lon protease is planed for studying the mechanism of the enzyme-DNA complexation. PMID- 27125024 TI - [Preparation of Transmembrane Fragments Growth Hormone Receptor GHR in a Cell Free Expression System for Structural Studies]. AB - Growth hormone somatotropin and its membrane receptor GHR, belonging to a superfamily of the type I receptors possessing tyrosine kinase activity, are involved in the intercellular signal transduction cascade and regulate a number of important physiological and pathological processes in humans. Binding with somatotropin triggers a transition of GHR between two alternative dimer states, resulting in an allosteric activation of JAK2 tyrosine kinase in the cell cytoplasm. Transmembrane domain of GHR directly involved in this complex conformational transition. It has presumably two dimerization interfaces corresponding to the "unliganded" and the active state of GHR. In order to study the molecular basis of biochemical signal transduction mechanism across the cell membrane, we have developed an efficient cell-free production system of a TM fragment of GHR, which contains its TM domain flanked by functionally important juxtamembrane regions (GHRtm residues 254-298). The developed system allows to obtain -1 mg per 1 ml of reaction mixture of 13C- and 15N-isotope-labeled protein for structural and dynamic studies of the GHR TM domain dimerization in the membrane-mimicking medium by high-resolution heteronuclear NMR spectroscopy. PMID- 27125025 TI - [Fragment of Receptor for Advanced Glycation End Products Improves Memory State in a Model of Alzheimer's Disease]. AB - A number of synthetic peptides corresponding to potentially important regions in the sequence of the four membrane proteins known as beta-amyloid cell receptors have been investigated on their ability to improve memory state in experimental model of Alzheimer's disease. Nine fragments repeating all the exposed nonstructural regions of the RAGE protein according to X-ray data, have been synthesized. The activity of these peptides and synthesized earlier immunoprotective fragments of other three proteins (acetylcholine receptor alpha7 type, prion protein and neurotrophin receptor p75) has been investigated under intranasal administration, without immune response to the peptide. Only one fragment RAGE (60-76) was shown to have a therapeutic activity improving the memory state of bulbectomized mice and leads to decreasing in the level of brain beta-amyloid. PMID- 27125027 TI - [Modulation of Ca(2+)-Dependent Proteiolysis under the Action of Weak Low Frequency Magnetic Fields]. AB - The study aimed to determine the molecular targets of magnetic fields in living objects. Time-dependent effects of weak low-frequency magnetic field tuned to the parametric resonance for calcium ions were studied on model organisms (fish, whelk). The dynamics of Ca(2+)-dependent proteinase activity under the exposure to magnetic fields with given parameters was determined and minimal time of exposure in order to achieve inactivation of these proteinases was find out as well. As hyperactivation of Ca(2+)-dependent proteinases is a basis of degenerative pathology development the therapeutic potential of weak low frequency magnetic fields enabling to modulate Ca(2+)-dependent proteinase activity is supported. PMID- 27125026 TI - [Intracellular Protein Degradation in Growth of Atlantic Salmon, Salmo salar L]. AB - A brief review on the common characteristics and specific features of proteolytic machinery in fish skeletal muscles (based on Atlantic salmon, Salmo salar L., Salmonidae) has been given. Among a variety of proteases in the muscle tissue, those determining protein degradation level in developing and intensively growing muscles in salmon young and by this way regulating protein retention intensity and growth at all namely lysosomal cathepsins B and D and calcium-dependent proteases (calpains) were comprehensively studied. Revealed age-related differences in intracellular protease activity in salmon skeletal muscles indicate the role of proteolysis regulation in growth in general and a specific role of the individual proteolytic enzymes in particular. The data on negative correlation of cathepsin D and calpain activity levels in muscles and the rate of weight increase in juvenile salmon were obtained. A revealed positive correlation of cathepsin B activity and morphometric parameters in fish young presumably indicates its primary contribution to non-myofibrillar protein turnover. PMID- 27125028 TI - [Inhibitory Properties of Nitrogen-Containing Adamantane Derivatives with Monoterpenoid Fragments Against Tyrosyl-DNA Phosphodiesterase I]. AB - It was found that compounds combining diazaadamantane and monoterpenoid fragments are potent inhibitors of new structural type of human recombinant DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1). It was demonstrated that the inhibition efficiency depended on the length and flexibility of the aliphatic chain of the substituent. PMID- 27125029 TI - [Synthesis and Neurotropic Activity of 2,4-pyrano[4',3':4,5]pyrido[2,3 b]thieno[3,2-d] Pyrimidines]. AB - 2,4-Disubstituted derivatives of pyrano[4',3':4,5]pyrido[2,3-b]thieno[3,2-d] pyrimidines were synthesized and their pharmacological studies was carried out at animals by the tests of antagonism with subcutaneous administration of corazol and behavior of "open field" model. The method of "rotating rod" was used to evaluate of neurotoxicity. The neurotropic properties were found in the new synthesized compounds. The new synthesized compounds as well as diazepam prevented the occurrence of clonic twitchings and clonic corazol seizures in animals. However, the studied compounds in contrast of tranquilizer diazepam having the anxiolytic and activating effects in the test of "open field", induced a oppressive behavior sedative effects. PMID- 27125030 TI - [The Cytoskelrtal Protein Zvxin Interacts with the Hedgehog Receptor Patched]. AB - Earlier, we demonstrated Zyxin influence upon Hedgehog (Hh)-signaling pathway during early patterning of the central neural system (CNS) anlage of the Xenopus laevis embryo. Now we show that Zyxin can physically interact with the transmembrane receptor of Hh, Patched2 (Ptc2). Binding of Hh by this receptor activates signaling pathway, which regulates many events, including numerous types of cell differentiation during the embryonic development. In particular, patterning of the CNS anlage. The ability of Zyxin to interact with Ptc2 have been confirmed by immunoprecipitation experiments, in which we tested mutual binding affinity of Zyxin and Ptc2, as well as mutual affinity of their deletion mutants. As a result, we have established that in Xenopus levis, Zyxin binding to Ptc2 is due to the interaction of Zyxin 2nd LIM-domain (530-590 aa) with the under-membrane region of the cytoplasmic C-terminus of Ptc2 (1159-1412 aa). We have also demonstrated that similar interaction is valid for the homologous regions of the human Zyxin and human Hh receptor, Ptc1. The data obtained allow to hypothesize existence of evolutionary conserved mechanism that modulates Hh signaling and based on the interaction of Zyxin with Ptc. PMID- 27125032 TI - [Not Available]. PMID- 27125033 TI - [Not Available]. PMID- 27125031 TI - [The Point Mutation in NOGGIN2 Protein That Enhances Its Ability to Bind Activin]. AB - Earlier we have revealed the ability of Noggin family proteins to bind a member of the TUF-beta superfamily, ActivinB, and to repress the Activin-dependent Smad2 signaling cascade. In the present work we have characterized a mutant of the Xenopus laevis Noggin2, bearing the substitution W203R. We have shown that this point mutation enhances the affinity of Noggin2 to ActivinB, while weakens its affinity to BMP. Consistently, we have shown that W203 R mutant inhibits Smad2 signaling cascade more efficiently than the wild-type Noggin2. Interestingly, the mutation of human Noggin in the homologous position is associated with hereditary anomalies. The revealed effects of W203R substitution in Noggin2 demonstrate promising potential of such mutagenesis for generation of Noggin variants with enhanced affinity to different members of the TGF-beta superfamily. PMID- 27125034 TI - [Not Available]. AB - Ebola virus belongs to the Filoviridae family and includes several species, including the Ebola Zaire virus, responsible for an initial outbreak of hemorrhagic fever in 1976 and the current epidemic of West Africa. Fruit bats of tropicalforests are the likely reservoir of this enveloped RNA virus which, following the incidental infection of a human being, is efficiently transmitted from man to man. Ebola virus exhibits a wide cell and tissue tropism and causes a deleterious acute infection leading to severe sepsis burdened with a heavy mortality. During the acute phase, the virus is very abundant in biological fluids where it can temporarily retain its infectivity for several days after death. Virological diagnosis is done mainly by RT-PCR on a blood sample and needs to be practiced in high security conditions. The pathophysiology of the infection allows to consider curative treatments and vaccination which are urgently needed. PMID- 27125035 TI - [Not Available]. PMID- 27125036 TI - [Not Available]. PMID- 27125037 TI - [Not Available]. AB - Accomplishment of therapeutic clinical trials in the midst of an uncontrolled and devasta- ting epidemic in resource-poor communities is complex and challenging. Key issues rely to close collaboration between research and clinical teams involved in care in the field. Indeed, it is of prime importance to consider cultural dimensions when aiming to build trust within communities and flexibility to adapt trial procedures to field constraints. The JIKI trial, a sequential single-arm proof-of-concept trial, has been implemented in Guinea in 2014-2015 with the aim to evaluate the efficacy of the antiviralfavipiravir in decreasing mortality and tolerance in patients with acute Ebola virus disease. Research was integrated into care to inform clinical management of patients. This pioneer trial illustrates challenging inputs for producing scientific and ethical gains for the benefit of vulnerable populations in the context of an international emerging or re-emerging infectious disease event. PMID- 27125038 TI - [Not Available]. PMID- 27125039 TI - [Not Available]. PMID- 27125040 TI - [Not Available]. PMID- 27125041 TI - [Not Available]. AB - Despite a decrease in stroke mortality, the global burden of stroke is increasing worldwide, hence the importance of improving prevention, acute treatment and rehabilitation. Nume- rous randomized clinical trials have been performed in the acute treatment of the three main varieties of stroke, namely acute cerebral ischemia, intracerebral hemorrhage and suba- rachnoid hemorrhage. They have all shown that " time is brain ". Stroke, however, is only the tip of the iceberg: MRI studies have shown the frequency of silent ischemic and hemorrhagic lesions contributing to cognitive impairment and eventually to dementia. This again underlines the needfor effective prevention strategies to reduce the incidence of stroke. PMID- 27125042 TI - [Not Available]. AB - Treatment of ischemic stroke consists of (i) general patient management (maintaining vital signs, ensuring normal biological parameters except for blood pressure, preventing complications), (ii) admission to an acute stroke unit, (iii) rt-PA for in patients admitted with 4.5 hours of stroke onset who have no contraindications, sometimes followed by mechanical thrombectomy in case of proximal artery occlusion, (iv) aspirin (160 to 300 mg) for patients who are not eligible for rt-PA, and (v) decompressive surgery for patients at risk of a malignant infarct. All these treatments should be administered rapidly. A centralized emergency call system (phone number 15 in France) is the most effective way to achieve this objective. PMID- 27125043 TI - [Not Available]. AB - Intracerebral hemorrhage (ICH) is one of the most severe forms of stroke, yet several factors continue to undermine effective patient management: (1) Contrary to ischemic stroke, no dedicated ICH classification has so far been established for routine clinical use. (2) The diagnostic workup for patients presenting with acute ICH has not been standardized (3) Specific ICH treatment options remain limited. (4) Major uncertainties exist regarding preventive interventions for unruptured, hemorrhage-prone lesions such as cerebral AVMs, aneurysms, and cavernous malformations. This paper summarizes recent progress in establishing an etiology-based ICH classification, a pragmatic stepwise algorithm for the diagnostic workup of ICH, and novel treatment strategies such as rapid blood pressure-lowering therapy for acute ICH. PMID- 27125044 TI - Editorial. PMID- 27125045 TI - Building a Physician Culture for Healthcare Transformation: A Hospital's Leadership Challenge. AB - Engaging and integrating physicians has become the veritable "brass ring" for many hospital systems: many attempts and few actual wins. This is especially true in California's managed care environment and for public entities such as Palomar Health in Escondido, California. Our commitment to engage and integrate physicians continues to be a vital element of a larger cultural shift toward delivery of care that puts the patients' needs first. A key determinant of success has been the ability to align a diverse medical staff culture with administrative priorities. This alignment involves a carefully executed strategy and a structure to build a collective identity among diverse players. Palomar Health is in the third year of the journey. Some of the critical milestones have been the implementation of a physician leadership development process, creation of a physician onboarding process to codify the desired physician culture, delineation of roles and expectations for physician leadership, and formalization of dyad and triad partnerships between physicians and their clinical and administrative partners. PMID- 27125046 TI - Physician Leadership: A Central Strategy to Transforming Healthcare. AB - As the role of the physician leader becomes increasingly important in the transformation of healthcare, how hospitals, health systems, and other healthcare organizations define that role is undergoing radical change. Traditional physician leadership roles no longer are effective, and the independent medical staff approach is changing to a collaborative, team-oriented model. The dyad relationship between physician leaders and operational leaders is shifting from a rigid, siloed set of responsibilities to a model characterized by a distributed, situational framework of accountabilities, and the scope of influence of the physician leader and operational leader fluctuates depending on the situation and individuals involved. In addition, the focus of the physician leader is moving to one founded in servant leadership, with an increased emphasis on creating supportive models to enhance physicians' success and place them in the roles of leader and integrator of health. PMID- 27125047 TI - Physician Leadership in a Changing Healthcare Environment. PMID- 27125048 TI - Physicians Lead the Way in Transforming Healthcare. PMID- 27125049 TI - The Five Questions of Physician Leadership. PMID- 27125050 TI - Starting Year 20! PMID- 27125051 TI - Extemporaneous Compounding of Oral Acitretin Suspension for Pediatric Patient with Generalized Pustular Psoriasis. AB - Generalized pustular psoriasis is rare in children, but it can occur and affect an extensive body surface area of a child. Treatment regimens can include medications that are not available in pediatric dosage form. Acitretin is considered one of the treatment options for acute generalized pustular psoriasis in children, but, in Singapore, it is only available as Neotigason capsules. Extemporaneous compounding of the powder content in the capsules was developed for formulating the oral acitretin suspension with a standardized formulation table and compounding process at National Skin Centre. An appropriate beyond-use date of the extemporaneous preparation was assigned after reviewing the photostability data of acitretin, compatibility of the active ingredient and excipients, and United States Pharmacopeia <795> guidelines. It is deemed appropriate to assign a beyond-use date of 14 days when the extemporaneous preparation is stored in amber glass bottles at 2 degrees C to 8 degrees C. PMID- 27125052 TI - Microbial Identification in Pharmaceutical Compounding. AB - Compounding pharmacies and contract testing laboratories can readily utilize critical information that microbial identification methods provide. Rapidly identifying the genus and species of environmental isolates and sample contaminates provides pharmacies and laboratories the opportunity to determine the possible source and implement corrective actions to improve compounding and testing processes. The microbial identification data collected from a compounding environment is critical. It is important to have accurate and specific microbial information to guide environmental collection practices, validation studies, and troubleshooting initiatives. The different technologies available provide varying levels of identification. They range from phenotypic assays to more accurate molecular-based techniques, including macromolecular methods and whole genome sequencing. Selecting the appropriate identification methodology requires evaluating multiple factors including the level of information required (genus only, genus and species, etc.) and the pharmacy's tolerance for unidentified or incorrectly identified isolates. PMID- 27125053 TI - Basic Principles of Lyophilization, Part 2. AB - The achievement of a high-quality lyophilized (freeze-dried) dosage form involves the combination of optimal formulation design and optimal freeze-dry cycle design. Part 1 of this 2-part article discussed the basic principles and procedures of lyophilization up to a discussion on the different stages of lyophilization. The stages of lyophilization are discussed within this article. PMID- 27125054 TI - Performance Improvement in 503A Compounding Pharmacies: A PLAN FOR ASSESSMENT, IMPLEMENTATION, AND SUSTAINED SUCCESS. AB - Performance improvement is the continual effort to objectively assess current performance and then restructure the practices that support it to more closely achieve desired performance. A plan for performance improvement, unlike other approaches to correcting problems in job fulfillment, is a systematic method used to first find the root causes of areas of concern and then apply corrections to remedy those deficits. Implementing a performance improvement plan that can be easily adapted to ensure compliance with evolving and increasingly complex state and federal regulations is crucial to a successful compounding practice. In this article, we discuss the need for performance improvement in 503A compounding pharmacies, list the steps necessary to develop such a plan, and present three case reports of performance improvement plans in differing compounding settings. PMID- 27125055 TI - Antimicrobial Activity of Copaiba (Copaifera officinalis) and Pracaxi (Pentaclethra macroloba) Oils against Staphylococcus Aureus: Importance in Compounding for Wound Care. AB - The Amazon rainforest is the largest reserve of natural products in the world. Its rich biodiversity of medicinal plants has been utilized by local populations for hundreds of years for the prevention and treatment of various diseases and ailments. Oil extracts from plant species such as Copaifera officinalis and Pentaclethra macroloba are used in compounded formulations for their antiinflammatory, antimicrobial, emollient, moisturizing, and wound-healing activities. The objective of this study was to investigate the in vitro bacteriostatic effect of two Amazonian oils, Copaiba and Pracaxi, against Staphylococcus aureus, a clinically important microorganism responsible for wound infection, to support the use of these oils as novel natural products for compounded wound-treatment modalities. The antibacterial activity of Copaiba and Pracaxi oils against a standard strain of Staphylococcus aureus was assessed using broth microdilution to determine the Minimum Inhibitory Concentration and Minimum Bactericidal Concentration of the oil extracts. Copaiba oil demonstrated antibacterial activity against Staphylococcus aureus, with a Minimum Inhibitory Concentration of 0.3125 mg/mL and a Minimum Bactericidal Concentration of 0.3125 mg/mL. Conversely, Pracaxi oil failed to inhibit Staphylococcus aureus growth. While additional studies are required to further evaluate the antimicrobial activity of Pracaxi oil, even low concentrations of Copaiba oil effectively inhibited Staphylococcus aureus growth, supporting its potential use as a promising adjuvant in compounded topical formulations for wound and scar healing. PMID- 27125056 TI - Validation of Ultraviolet-visible and High-performance Liquid Chromatographic Methods for the Determination of Sodium p-Aminosalicylate and m-Aminophenol in a New Pharmaceutical Formulation. AB - Sodium p-aminosalycilate is an orphan drug used in patients affected with Multidrug-resistant Tuberculosis. Two methods, high-performance liquid chromatographic and ultraviolet spectrophotometric for the quantitative determination of sodium p-aminosalycilate and its degradation product m aminophenol in a new pharmaceutical formulation, powder for extemporaneous reconstitution, were developed in the present work. The parameters linearity, precision, accuracy, specificity, robustness, limit of detection, and limit of quantification were also studied. Chromatography was carried out by reverse-phase technique on an RP-18 column with a mobile phase composed of 50 mM monobasic/dibasic phosphate buffer and methanol (42.5:42.5:15 v/v/v) with 1.9 g of hidroxytetrabutylammonium ionic pare adjusted to pH 7.0 with orthophosphoric acid. The ultraviolet spectrophotometric method was performed at 254 nm and 280 nm for quantification of sodium p-aminosalycilate and m-aminophenol, respectively. The proposed methods are highly sensitive, precise, and accurate and can be used for the reliable quantification of sodium p-aminosalycilate in the new alternative formulation. High-performance liquid chromatographic approach demonstrated to be a stability-indicating method, therefore suitable for the investigation of the chemical stability of sodium p-aminosalycilate. PMID- 27125057 TI - A Novel Vehicle for Enhanced Drug Delivery Across the Human Nail for the Treatment of Onychomycosis. AB - The aim of this study was to use in vitro nail models to investigate the potential of a novel base formulation (Recura) containing either fluconazole or miconazole for the treatment of onychomycosis in comparison to two commercial comparators (Jublia and a Penlac generic). Initially, a modified Franz cell was used, where sections of human nail served as the barrier through which drug penetrated into an agar-filled chamber infected with dermatophytes. A second study was performed using a novel infected nail model where dermatophytes grew into human nail and adenosine triphosphate levels were used as biological marker for antimicrobial activity. The novel enhancing system Recura increased the permeation of both existing drugs through human nail sections mounted in a modified Franz cell. Furthermore, the infected nail model also confirmed that the system also enhanced the permeation through infected nail resulting in a decrease in adenosine triphosphate levels superior (P <= 0.05) to Penlac generic and equivalent (P > 0.05) to the commercial comparator Jublia. This study demonstrated that with the use of a novel permeation-enhancing formulation base, Recura enhances delivery of miconazole and fluconazole when applied ungually such that the efficacy was equivalent or superior to commercial comparators. Such a topically applied system has the possibility of overcoming the systemic side effects of antifungals when taken orally. PMID- 27125058 TI - Evaluation of the Stability of Mercaptopurine Suspension Compounded in a Commercial Vehicle and the Determination of an Appropriate Beyond-use Date. AB - Mercaptopurine is commonly used to treat acute lymphoblastic leukemia and has historically been commercially available only in tablet form. Since tablets may be difficult for children and elderly patients to swallow, many pharmacists have compounded mercaptopurine suspensions. The U.S. Food and Drug Administration recently approved a commercial suspension, but it is not widely available at this time. Therefore, pharmacists may still need to compound mercaptopurine suspension for use in areas where it is not available or if the commercial suspension is in short supply. Stability studies must be conducted in order to assign appropriate beyond-use dates for compounded preparations. The objective of this study was to evaluate the stability of extemporaneously compounded suspensions using commercially available mercaptopurine tablets, as well as active pharmaceutical ingredient in a vehicle of Ora-Sweet and Ora-Plus (1:1) stored in plastic and glass containers at room temperature. Each mercaptopurine preparation was analyzed using a validated stability-indicating high-performance liquid chromatography method at the following time points: 0, 7, 14, 21, 30, 60, and 90 days. Suspensions were also observed for changes in appearance or odor, and pH was tested at each time point. The suspension compounded from Roxane generic tablets was extremely viscous and was therefore eliminated from the study. All other suspensions showed no observed physical changes and maintained greater than 93% of initial concentration of mercaptopurine for the entire study period. PMID- 27125059 TI - The Home Field Disadvantage. PMID- 27125060 TI - Degeneration versus Regeneration. PMID- 27125061 TI - Deprivation of bFGF Promotes Spontaneous Differentiation of Human Embryonic Stem Cells into Retinal Pigment Epithelial Cells. AB - BACKGROUND: The retinal pigment epithelium (RPE), an important tissue monolayer of retina, sustains visual function and retinal homeostasis. In disease conditions such as Retinitis Pigmentosa (RP) and Age related Macular degeneration (AMD), the integrity and functional capacity of RPE monolayer is compromised. Human embryonic stem cells derived RPE (hESC-RPE) is ideal for cell based therapy because of their ability to morphologically and functionally mimic native fetal and adult RPE. However protocols for optimum culture of hESC-RPE are not well established. AIM: To describe a simplified protocol for differentiating human embryonic stem cells (hESC) into retinal pigment epithelial cells. METHODS: hESC (WA09-DL-11) cell lines were grown with standard stem cell culture protocol. After cell colonies were established, basic fibroblast growth factor (bFGF) was deprived (day 0). hESC colonies expressing pigmentation were characterized for expression of RPE65 and Zonular occludens--1 (ZO-1) with immunocytochemistry on days 0, 36, 42, 56 and 70 and western blot analysis on days 0, 40, 48, 53 and 63. In addition, morphological assessment was conducted on transformed cells longitudinally. RESULTS: Pigmented cells were noted 36 days after deprivation of bFGF from growth media. Immunofluorescence demonstrated progressive up regulation of RPE specific proteins (ZO-1 & RPE 65). Immunofluorescence of ZO-1 (in pixels) was (3.08 +/- 0.31) on day 42, (5.33 +/- 0.89, p = 0.0001) on day 56 and (4.87 +/ 0.57, p = 0.0011) on day 70. Similarly expression of RPE 65 was (2.44 +/- 0.31) on day 42, which continued to increase (4.23 +/- 0.60, p = 0.0011) on day 56 and (5.59 +/- 0.36, p < 0.0001) on day 70. Protein expression patterns using western blot confirmed the trends seen in immunofluorescence. Western blot analysis of ZO 1 expression (in optical density unit) was 272.57 +/- 31.75 on day 40, 4212.20 +/ 911.31 (p = 0.0004) on day 48, 5182.43 +/- 1230.38 (p = 0.030) on day 53 and 5848.76 +/- 241.04 (p < 0.0001) on day 63. Protein expression of RPE 65 was 1607.64 +/- 247.76 on day 40, 2448.07 +/- 152.66 on day 48 and (2341.15 +/- 52.84) on day 63. hESC-RPE cells displayed a series of specific morphological changes (cytoplasmic, nuclear pigmentary and cell shape) over the course of time frame. By day 70, cells with hexagonal pattern, dark dense nucleus and uniform cytoplasm were noted in densely pigmented RPE colonies. CONCLUSION: bFGF deprivation leads to successful differentiation of hESC into RPE cells. Longitudinal transformative changes were confirmed with measurement of ZO-1 and RPE 65, specific markers of RPE. PMID- 27125062 TI - Overview of Risk Factors for Age-Related Macular Degeneration (AMD). AB - Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make life style choices that may reduce the risk of disease. This review discusses the role of genetics, sunlight, diet, cardiovascular factors, smoking, and alcohol as possible risk factors for AMD. Genetics plays a more significant role in AMD than previously thought, especially in younger patients, histocompatibility locus antigen (HLA) and complement system genes being the most significant. Whether the risk of AMD is increased by exposure to sunlight, cardiovascular risk factors, and diet is more controversial. Smoking is the risk factor most consistently associated with AMD. Current smokers are exposed to a two to three times higher risk of AMD than non-smokers and the risk increases with intensity of smoking. Moderate alcohol consumption is unlikely to increase the risk of AMD. Optometrists as front-line informers and educators of ocular health play a significant role in increasing public awareness of the risks of AMD. Cessation of smoking, the use of eye protection in high light conditions, dietary changes, and regular use of dietary supplements should all be considered to reduce the lifetime risk of AMD. PMID- 27125063 TI - HTRA1 Overexpression Induces the Exudative Form of Age-related Macular Degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in the elderly. The dry form is more common and accounts for about 85 90% of AMD patients in US, while Japanese AMD patients predominantly progress to wet-form or polypoidal choroidal vasculopathy (PCV). Recent studies have shown HTRA1, a serine protease gene, as major risk factor for wet form AMD (De Wan et al., Science 2006). Furthermore, we reported that the Japanese typical wet form AMD patients showed significant association with ARMS2/HTRA1 (Goto, Akahori et al., JOBDI 2009). The purpose of this study is to elucidate the function of ARMS2/HTRA1 gene promoter in wet-form AMD patients. The promoter sequence experiment showed that a great number of AMD patients had specific indel mutation in 3.8 kb upstream of HTRA1 gene. 2-3-fold increase of promoter activity was observed in indel HTRA1 promoter compared to control sequence (Iejima et al., JBC 2015). Furthermore, we created transgenic mice ubiquitously overexpressing mouse HtrA1 using the chicken act in promoter, continuous induction of HtrA1 in vivo was shown to lead to CNV, similar to wet AMD patients (Nakayama, Iejima et al., IOVS 2014). These results suggest that human HTRA1 expression is enhanced by AMD specific indel mutation in the promoter region of HTRA1 gene, and this enhanced HTRA1 may be concerned with induce retinal neovasucularization. PMID- 27125064 TI - The New Era of Omega-3 Fatty Acids Supplementation: Therapeutic Effects on Dry Age-Related Macular Degeneration. AB - One of the major causes of reduced vision over the age of 50 is age-related macular degeneration (AMD). Although such a common pathology, there are no current guidelines for the first-line treatment of dry AMD. The aim of this study is to evaluate the therapeutic effects of high omega-3 fatty acids as anti inflammatory agents in two sub-groups of dry AMD patients with 1) mild to moderate visual impairment and 2) with severe visual impairment (blindness). The key feature of this investigation is the frequent monitoring of the levels of specific fatty acids in patient's blood in order to adjust the treatment dose within the ideal therapeutic window. Following the positive outcome from our initial observational studies in patients with dry AMD, who demonstrated significant improvement in visual acuity (gain of >= 1 line of vision in 4.5 months) when taking a total of 5 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), additional studies were encouraged. The latest data which is presented in this chapter suggests that the eyes which had the greatest gain in vision (>= 15 letters gain at 6 months) were from patients with mild to moderate visual impairment, who were taking between 5-7.5 g/day EPA and DHA and had a ratio of arachidonic acid (AA)/EPA < 2. In addition, a sub-group of dry AMD patients with severe visual impairment (< 6/60), showed significant increase in their visual acuity only 3 months following treatment with omega-3 fatty acids. The preliminary results indicate a promising therapeutic regime for dry AMD and perhaps for other types of retinopathies as well. Although initial results are encouraging, further investigations are necessary to establish a better understanding of the mode of action of these supplements and to observe their long-term effects. PMID- 27125065 TI - HUMAN PAPILLOMAVIRUS AND SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK. PMID- 27125066 TI - ADHD (ATTENTION DEFFICIT HYPERACTIVITY DISORDER)--A TROUBLING ENTITY, SOMETIMES PERPETUATING DURING ADULT LIFE. AB - Attention deficit hyperactivity disorder (ADHD) is considered a neurologic development disorder resulting in impairment of attention and inhibitory control, manifested as attention deficit, hyperactivity, impulsiveness; symptoms should develop between age six and twelve and have to persist for more than six months. Approximately 30-50% of the diagnosed cases are manifesting the disorder during adulthood and 2.5-5% of the adults are suffering of ADHD. Genetics are important factors in ADHD, being involved in 75% of the cases, as well in the persistence of ADHD during adult life. Three subtypes of ADHD are described--one in which is predominating the attention deficit, one with predominant hyperactivity and impulsiveness and a third combined subtype. Diagnosis criteria in ADHD are established by the American Psychiatric Association (DSM criteria) and by World Health Organization. Differential diagnosis is mainly considering bipolar disorder and borderline personality disorder. Management of ADHD is including behavioral therapies and medication, alone or combined. Stimulant medications such as amphetamine represent the therapy of choice, being effective in 80% of the cases. New data are underlying the need for following up of the cases during adulthood, since the risk for development of psychiatric conditions such as depression, anxiety, as well as the suicidal behavior is higher than in the general population. PMID- 27125067 TI - ETHICAL AND GENETIC ASPECTS REGARDING PRESYMPTOMATIC TESTING FOR NEURODEGENERATIVE DISEASES. AB - Neurodegenerative diseases, such as Alzheimer's dementia, Huntington's chorea, Parkinson's disease or spinocerebellar ataxia, manifests into adulthood with an insidious onset, slowly of progressive symptoms. All of these diseases are characterized by presimptomatic stages that preceded with many years of clinical debut. In Parkinson's disease, more than half of the dopaminergic neurons of the black substance are lost before the advent of motor characteristic manifestations. In Huntington's chorea, the progressive neurodegenerative disease could be diagnose prenatal and presymptomatic by analyse of the number of CAG repeats in exon 1 of the huntingtin gene. A similar mechanism represented by expansion of trinucleotide repeats during hereditary transmission from parents to children was identified in fragile X syndrome, spinocerebellar ataxia, spinal muscular and bulbar atrophy, or myotonic dystrophy. Presymptomatic diagnosis in all these progressive diseases raise many ethical issues, due to the psychological impact that can cause the prediction of a disease for which there is currently no curative treatment. Therefore, a positive result can produce serious psychological trauma and major changes in the lifestyle of the individual, instead, a negative result can bring joy and tranquillity. But the problem arises if presymptomatic testing in these neurodegenerative diseases brings greater benefits compared to the possible psychological damage, which can add the risk of stigmatization or discrimination. PMID- 27125068 TI - NONSELECTIVE BETA-BLOCKERS IN PATIENTS WITH CIRRHOSIS: "THE THERAPEUTIC WINDOW". AB - For over 30 years, nonselective beta-blockers (NSBB) have been successfully used for preventing variceal bleeding in patients with cirrhosis and portal hypertension. Nevertheless, recent studies suggest that NSBB may be effective only within a particular "therapeutic window" in patients with advanced liver disease. Outside of this window, in early stages of cirrhosis and in very advanced cirrhosis, NSBB may be ineffective and even potentially harmful. In this paper we review the beneficial effects and potential harms of beta-blocker therapy in cirrhosis and underline the most recent recommendations for their use in very advanced cases of liver disease. PMID- 27125069 TI - NADPH OXIDASE: STRUCTURE AND ACTIVATION MECHANISMS (REVIEW). NOTE I. AB - NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase), with its generically termed NOX isoforms, is the major source of ROS (reactive oxigen species) in biological systems. ROS are small oxygen-derived molecules with an important role in various biological processes (physiological or pathological). If under physiological conditions some processes are beneficial and necessary for life, under pathophysiological conditions they are noxious, harmful. NADPH oxidases are present in phagocytes and in a wide variety of nonphagocytic cells. The enzyme generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling them to molecular oxygen to produce superoxide anion, a reactive free-radical. Structurally, NADPH oxidase is a multicomponent enzyme which includes two integral membrane proteins, glycoprotein gp9 1 Phox and adaptor protein p22(phox), which together form the heterodimeric flavocytochrome b558 that constitutes the core of the enzyme. During the resting state, the multidomain regulatory subunits p40P(phox), p47(phox), p67(Phox) are located in the cytosol organized as a complex. The activation of phagocytic NADPH oxidase occurs through a complex series of protein interactions. PMID- 27125070 TI - ANEMIA IN INFLAMMATORY BOWEL DISEASE MORE THAN AN EXTRAINTESTINAL COMPLICATION. AB - The most common hematologic complication of inflammatory bowel disease (IBD)- ulcerative colitis and Crohn's Disease is anemia. Anemia in patients with IBD may be a result of iron, vitamin B12 or folate deficiency; anemia of chronic disease and hemolytic anemia are other causes in these patients. Factors contributing to the development of anemia include chronic gastrointestinal blood loss, vitamin B12 malabsorption secondary to terminal ileitis, folate deficiency as a result of sulfasalazine therapy. Approximately 30% of patients with IBD have hemoglobin levels below 12 g/dl. The risk of developing anemia relates to disease activity, given that blood loss and inflammatory anemia are triggered by intestinal inflammation. In the management strategy of IBD patients with anemia it is important to distinguish between the different types of anemia in order to decide an appropriate manner of treatment. PMID- 27125071 TI - ATOPIC DERMATITIS--CLINICAL EPIDEMIOLOGY AND IMMUNOLOGICAL CORRELATIONS. AB - AIM: Medical records from 2010-2014 were retrospectively reviewed and analyzed in view of determining the correlations between the clinical severity of atopic dermatitis (AD) and total IgE level, eosinophilia, place of residence, family history of atopy, type of birth, and natural or artificial feeding. MATERIAL AND METHODS: Following medical record review, 296 cases diagnosed with AD were included in the study. Statistical analysis was performed using SPSS v20 for determining the frequency and testing the hypotheses, for p < 0.05, by t tests and One-Way ANOVA. RESULTS: Of the 296 cases, 53% were male children and 47% female children aged 1 month to 16 years. According to total serum IgE level, 49.3% of patients had elevated IgE levels, 20.6% normal levels and in 30.03% of cases it was not determined. According to the SCORAD, children had mild AD in 20% of cases, moderate in 70%, and severe in 10%. The independent samples t tests showed a statistically significant difference between the means demonstrating correlations between IgE level and place of residence (p < 0.01), family history of atopy (p < 0.01), baby feeding (p < 0.01), and by one-way ANOVA for SCORAD (p < 0.05). CONCLUSIONS: Atopy in AD can be influenced by complex factors, both internal and environmental, but this remains a controversial topic. External factors acting on a background genetically predisposed to atopy trigger the manifestation of AD. PMID- 27125072 TI - ASSESSMENT OF ADVERSE DRUG REACTIONS AS CARDIOVASCULAR RISK FACTORS. AB - A wide range of pharmaceutical substances can induce side-effects expressed as cardiovascular changes or events, adding to other risk factors or worsening preexisting cardiovascular diseases. AIM: Continuous study focused on iatrogenic conditions representing cardiovascular risk factors. METHODS: We developed a descriptive study of patients admitted to the Iasi Vth Internal Medicine and Geriatrics-Gerontology Clinic between 1998-2013, focusing on iatrogenic conditions representing cardiovascular risk factors. RESULTS: We have diagnosed 81 cases of drug-induced hypertension, and 43 patients with hypertensive crises; 72 cases of iatrogenic hyperglycemia; 36 cases of drug-induced hyperuricemia; 50 cases of drug-induced dyslipidemias; and 17 cases of iatrogenic obesity. These iatrogenic diseases were more common in women and the elderly. Twenty-eight patients have developed simultaneous adverse drug reactions induced by the same drug and manifest as different cardiovascular risk factors. CONCLUSIONS: Cardiovascular risk factors can be induced to a significant extent by chronic drug administration. Some medications (e.g., NSAIDs, corticoids, beta-blockers, diuretics, contraceptives) can act on the same patient by multiple pathogenic links. The adverse drug reactions can be cardiovascular risk factors that persist in time, or can be removed (by discontinuing the administration of the implicated drug). The highest importance of their acknowledgment relies on the possibility of their prevention through carefully balancing the benefits and the risk of each new medication. PMID- 27125073 TI - PLATELET INDICES AND LIVER FIBROSIS EVALUATION IN CHRONIC HEPATITIS C. AB - Recently, several studies have reported that the mean platelet volume and platelet distribution width may give information about liver fibrosis severity in chronic hepatitis C. The aim of the present study was to evaluate whether platelet indices correlate with hepatic fibrosis measured by transient elastography in patients with chronic hepatitis C. MATERIALS AND METHODS: Patients with chronic hepatitis C were prospectively enrolled. Samples for complete blood count and routine biochemical parameters were collected and analyzed in the same day with liver fibrosis assessment by transient elastography. Mean platelet volume, platelet large cell ratio and platelet distribution width were compared with stages of liver fibrosis. Statistical analysis was carried out using SPSS 17.0 software. A P-value of less than 0.05 was considered statistically significant. RESULTS: There were 139 patients with chronic hepatitis C (70.5% males, mean age 54.8 +/- 16.7 years). Compared with mild/moderate liver fibrosis patients, those with advanced liver fibrosis had an increased mean platelet volume (10.4 +/- 0.7 vs. 10.9 +/- 0.9, p < 0.002), platelet large cell ratio (28.5 +/- 5.3 vs. 32.5 +/- 7.2, P < 0.0001), and platelet distribution width (12.8 +/- 1.5 vs. 14.1 +/- 2.7, P = 0.003). CONCLUSIONS: Increased platelet indices were associated with advanced liver fibrosis stages evaluated by transient elastography in patients with chronic hepatitis C. PMID- 27125074 TI - THE MALFUNCTIONS OF A NATIONAL TRANSPLANTATION SYSTEM: MULTI-LAYERED EXPLANATIONS FROM WITHIN. AB - Romanja has one of the lowest posthumous organ donation and transplantation rates in Europe. AIM: To explore the perspectives on the national transplantation system deficits shared by the physicians responsible for the identification and referral of potential posthumous organ donors. MATERIAL AND METHODS: The study consists of semi-structured interviews with the key informants (ICU physicians, neurologists and neurosurgeons) in county hospitals in Moldavia. RESULTS: The explanations for the current Romanian organ transplantation rate, as emerged from the participants' answers, are multi-layered. Overall, the national transplantation system is accused of being plagued with serious problems: it is underfunded, understaffed, its resources have been distributed unevenly among medical centers, the communication between its elements is disrupted, leaving the majority of the transplant professionals practically detached from its upper layer and affecting their motivation to perform their transplantation-related tasks. Furthermore, some of the participants point to the strong reluctance of the population to donate their deceased relatives' organs. CONCLUSIONS: The results suggest a set of possible multi-level interventicrnq that could alleviate these problems. PMID- 27125075 TI - CERVICAL SPINE LESIONS IN RHEUMATOID ARTHRITIS PATIENTS. AB - AIM OF THE STUDY: to gather clinical and laboratory data on rheumatoid arthritis patients with cervical spine damage (incidence and prevalence, correlation between duration of disease and the time of lesion onset, to assess signs and symptoms and the role of laboratory investigations). The spine is an axial organ with an important role in support and resistance. It is a pillar with a very complex morphological and functional structure. The vertebral column is crossed by many kinematic chains. The main problem of the cervical spine caused by rheumatoid arthritis is cervical instability which describes all cervical lesions that can lead to neurovascular damage or major disturbance of pain generating statics at movement. The evolving disease shows chronic inflammation of the synovium, which is a self-maintained process and an immunologically induced phenomenon. The chronic inflammation of the synovium forms granulation tissue that invades peripheral joints towards the center and causes ligament cartilage and bone damage. MATERIAL AND METHODS: The present paper investigated cervical spine lesions in 107 rheumatoid arthritis patients who were admitted to the 1st Rheumatology Clinic of Iasi Rehabilitation Hospital between January 2013 and December 2014. Our study focused on assessing signs and symptoms seen in spine affected by rheumatic disease. RESULTS AND DISCUSSIONS: the disease causes destructive lesions due to granulomatous infiltration of rachidian structures and medullary sheaths. These lesions lead to damaged discs and instability that produces subluxations and dislocations. The suboccipital region is most affected; in other regions of the spine, high lesions of C4-C5 prevail, where osteolysis damage of spinal apophyses are found. In atlas and axis joints, rheumatoid arthritis causes the inflammation of bursa, synovium and joint capsule and leads to synovial pannus formation. This causes the destruction of cartilage and subchondral bone. Atlantoaxial dislocation is caused by erosive synovitis of atlanto-epistrophic joint, atlanto-odontoid joint and serous bursitis separating the odontoid process from the transverse ligament. CONCLUSIONS: The dominant symptom of cervical spine damage was pain associated with stiffness and limited joint mobility, muscle stiffness, poor posture. PMID- 27125076 TI - CORRELATIONS BETWEEN ARTERIAL HYPERTENSION INDUCED BY ANGIOTENSIN II AND SYSTEMIC INFLAMMATION IN RAT. AB - Angiotensin II has articularly shown to play a key role in the regulation of inflammatory processes in hypertension. AIM: The present study aims to correlate the angiotensin II-induced hypertension 4th systemic inflammation. MATERIAL AND METHODS: We conducted an experimental study on Wistar male rats who received Ang II via subcutaneous miniosmotic pumps for 2 weeks. Rats were exposed to a 12h light /12h dark cycle. Sham rats were used as control. Systolic load pressure measurements and a flow cytometric analysis of lymphocyte surface markers were performed. After 14 days, the animals were euthanized under anesthesia with ylazine/ketaniine. RESULTS: Systolic BP progressively and significantly increased in rats 4th Ang II chronic infusion. We observed a statistical significant difference (p = 0.00001), in terms of T lymphocytes percentage between control rats plasma and Ang H treated rats lasma, in 14 days. CONCLUSIONS: Angiotensin II is an important mediator of hypertension and directly promotes inflammation by noticeably increasing the quantity of T cells in kidney tissue. PMID- 27125077 TI - SHORT TERM EVALUATION OF PERIMETRIC PROGRESSION IN PATIENTS WITH OPEN ANGLE GLAUCOMA AND DIABETES. AB - AIM OF STUDY: Progression rate in patients with glaucoma and diabetes. MATERIAL AND METHOD: cohort prospective study in Ophthalmology Clinic "Sf. Spiridon" University Hospital Iasi. We recruited patients with positive history for diabetes and of open angle glaucoma (OAG). The control group included subjects with OAG (74 eyes from 74 patients) and the study group (44 eyes, from 44 patients) included subjects with OAG and diabetes. At enrollment all patients had a complete ophthalmologic evaluation along with full metabolic status assessment. There were included only incipient and moderate forms of glaucoma, with mild or no diabetic retinopathy changes. Perimetric progression was assessed at 24 months with automated methods. RESULTS: globally, from 118 investigated eyes, 56.40% cases had primary open angle glaucoma, 41.03% normal tension glaucoma and 2.36% pseudoexfoliative glaucoma. Glaucoma severity classification showed early defects (mean deviation < -6 db) in the study group of 77.27% vs. 83.78% in control group, whereas moderate defects (mean deviation > -6 db) were found in 22.63% in study group vs. 16.21.0% in control group. Mean age of the patients was higher in absolute value in the open angle glaucoma group (64.31 +/- 1.66 years), vs. diabetes + open angle glaucoma (62.69 +/- 1.8 years), with comparable visual acuities (0.91 +/- 0.15 vs. 0.89 +/- 0.16), CID ratios and other clinical pa- rameters (p > 0.05). Mean baseline lOP in the study group was 18.18 +/- 3.55 mrnHg vs. 17.08 +/- 2.4 nimHg in controls (p > 0.05). Analysis of visual field parameters at baseline showed a significant difference (p = 0.48) between groups in MD levels -3.63 +/- 3.35 db (control group) vs. -4.40 +/- 5.78 db (study group), but no difference (p > 0.05) in PSD levels: 3.71 +/- 3.06 db (control group) vs. 4.05 +/- 3.04 dB (study group). Perimetric progression was estimated at 24 months by Glaucoma Progression Analysis software (GPA-Humphrey Visual Field Analyzer II) using 6 reliable visual field (VF) exams. Progression rate was similar between groups--0.19 +/- 0.78 dB/year (OAG) vs. -0.18 +/- 0.05 dB/year (OAG+DM), p > 0.05 and no other risk factor could have been linked to an increased progression rate, except visual field parameters at final and baseline evaluation, in both groups. CONCLUSIONS: On short term, functional deterioration in open angle glaucoma patients having early or moderate stages, occurs similarly in the presence or absence of diabetes. PMID- 27125078 TI - THE ACUTE SCROTUM IN CHILDREN. AB - The acute scrotum syndrome is a medical-surgical emergency and the recognition of this condition by both healthcare professionals and the general population may result into the patients' coming in earlier for medical examination and into the preservation of the gonad in case of torsion. The purpose of this retrospective analytical research is to point out specific epidemiological aspects in pediatric patients suffering from acute scrotum, and to review the existing diagnosis and treatment options. The study included 208 patients, of whom 16 with vanishing testis and 192 with acute scrotum (torsion of testis 25.5%, torsion of the hydatid of Morgagni 68.2%, epididymoorchitis 5.2%). The torsion of the hydatid of Morgagni occurs in boys with a mean age of 10 years and it involves both testes equally, whereas the torsion of testis usually occurs around the age of 13 and is twice more common in the left gonad. Another significant difference between the two conditions is the inflammatory syndrome, which occurs in 45.4% of the children with torsion of testis versus only 18.2% in the torsion of hydatid. Only one out of six testes torted during the neonatal period could be saved (16.6%); the gonad preservation rate was as high as 68.2% in the group of patients with testis torsion occurring outside the neonatal period. These alarming data are accounted for by the non-recognition of the severity of the condition and by the delayed surgical therapy, which occurs on the average 20 hours after the testis torsion has set in. If the asepsis and antisepsis standards are observed, patients with torsion of the hydatid of Morgagni or torsion of testis require neither fluid sampling from the tunica vaginalis for culture, nor antibiotic therapy. PMID- 27125079 TI - PROLONGED FEVER WITHOUT OBVIOUS ETIOLOGY FINALLY DIAGNOSED AS HIGH-GRADE SOFT TISSUE SARCOMA. AB - Sarcomas represent a challenge t clinicians as they are rare and diagnosis is often delayed. Soft tissue sarcomas are relatively uncommon cancers, the incidence is estimated about 1% from all malignant tumors. Due to aggressive biological behavior of pleomorphic undifferentiated sarcoma diagnosis must hi made as quickly as possible. MRI is the standard imaging modality for investigating possibl3 malignant masses. Excisional biopsy appears to be necessary for differentiating soft tissus sarcoma from expanding hematoma. FDG PET scans may be helpful in specific circum. stances (as was the situation in our case, because the lesion is composed from two components: an area without precise edges and a necrotic-cystic area). PMID- 27125080 TI - COMPLEX MANAGEMENT OF FRAILTY FRACTURES--CASE REPORT. AB - Frailty fractures encompass pelvic ring fractures in the elderly--a condition more frequently encountered in women, usually with pre-existing osteoporosis. The incidence of these fractures is increasing, following the increase in average life expectancy. Most of the times, they are the result of a minor injury, of which the patient has little or no recollection; the clinical signs and symptoms, radiological changes and the degree of fracture stability vary greatly. As such, there is a wide range of therapeutic options and one of the most important decisions for the physician is choosing between surgery and conservative treatment. We present the case of an elderly female patient with multiple pelvic ring fractures, and a medical history of cardiovascular disease and osteoporosis; the orthopedic examination recommended conservative treatment which was carried out in the Geriatric Clinic of the "Dr. C.I. Parhon" Hospital. Following the complete physical examination and through geriatric evaluation, a complex therapeutic plan was devised, which included: recovery through physiotherapy, adequate nutrition, psychological support, treatment of the cardiovascular comorbidities and prevention of the consequences of extended bed rest. The treatment lasted for 60 days and the outcome was favorable: decreased bone frailty, mainly through preserving muscle tone and osteoarticular function, correction of malnutrition, improvement of depression and partial recovery of patient's mobility; the results of our therapy made it possible for the patient to return home, where she leaves alone. She will need help with daily household chores, but she intends to continue the recovery therapy as means of increasing her quality of life and independence. PMID- 27125082 TI - ATYPICAL FEMORAL FRACTURES AFTER LONG-TERM BISPHOSPHONATES THERAPY: CASE REPORT. AB - We present a 77-year-old woman with no histor of trauma, or associated with low energy trauma, admitted to our clinic after three weeks of a left femoral fracture threated in Orthopedic Clinic. The patient was in treatment with bisphosphonates over 10 years for osteoporosis. DISCUSSION AND CONCLUSIONS: The causal re lationship between prolonged bisphosphonate use and the occurrence of atypical femora fractures (AFF) has not yet been established. For the patient at high risk of fracture, it may be beneficial to continue bisphosphonate treatment beyond five years. The absolute risk of atypical femoral fractures is low (about 100 cases per 100,000 person-years among long term users). For most people with osteoporosis, the proven fragility-fracture risk-reduction. benefits of bisphosphonates outweigh the risks of AFF. PMID- 27125081 TI - SEVERE AMIODARONE-INDUCED BRADICARDIA CONCEALES SICK SINUS SYNDROME: CASE REPORT. AB - Sinus node dysfunction is one of the most common arrhythmias in elderly patients; it is usually associated with intermittent and variable symptoms, thus making it difficult to diagnose. We present the case of an elderly female patient with a personal history of atrial fibrillation treated for the last three years with amiodarone; she was admitted to the Geriatric Clinic for non-specific symptoms with onset two months previously for which she had already sought care in different medical services. Clinical examination showed severe bradycardia; ECG and Holter ECG on admission confirmed severe bradycardia, with a heart rate between 29 and 50 beats/min (bpm). Given her long-term treatment with amiodarone we looked for and found hyperthyroidism; the endocrine examination led to the diagnosis of mixed type Amiodarone-induced thyrotoxicosis and initiation of corticosteroid and antithyroid treatment. The evolution of cardiac arrhythmia was monitored with the help of several Holter ECGs performed after amiodarone washout and return to the euthyroid state, which revealed a tachycardia-bradycardia syndrome initially masked by the side effects of the unsupervised therapy with amiodarone, and properly treated by the implantation of a pacemaker. PMID- 27125083 TI - THE PATIENT-DOCTOR-PSYCHOLOGIST TRIANGLE IN A CASE Of SEVERE IMUNOSUPRESSION IN THE HIV INFECTION. AB - In the last two years the Romanian adult population infected with the human immunodeficiency virus (HIV) has increased due to sexual transmission, both heterosexual and homosexual. The case presented is that of a 33 year-old man, admitted to the Infectious Diseases Hospital in Iasi with acute respiratory failure and a confirmation of Kaposi's sarcoma. Tests later proved positive for HIV, the patient being included in the stage AIDS C3 (acute immunodeficiency syndrome). The respiratory failure was suspected to be caused by Pneumocystis carinii and cotrimoxazol therapy, oxygen therapy and anti-retroviral therapy were established. He was also referred to the oncology hospital for treatment of Kaposi's sarcoma. The patient's adherence to therapy was influenced by a strong doctor-patient relationship, as well as by psychological counseling and support. Creating a functional doctor-patient-psychologist team is key throughout the HIV positive patient's existence, for supporting long term adherence to therapy and acceptance of the diagnosis. This case highlights the need for a strong psychosocial compartment in every medical center that deals with HIV-infected individuals. PMID- 27125084 TI - CONCENTRATIONS OF VITREAL CYTOKINES IN RHEGMATOGENOUS RETINAL DETACHMENT. AB - Proliferative vitreoretinopathy (PVR) is one of the most frequent causes of failure of rhegmatogenous retinal detachment (RRD) surgery. AIM: To measure the vitreous levels of granulocyte colony stimulating factor (G-CSF) and monocyte chemoattractant protein 1 (MCP-1) in eyes with RRD and in a control group. MATERIAL AND METHODS: A prospective study of 40 patients operated for RRD (study group) and 20 patients with epiretinal membrane or macular holes (selected as control group since they needed vitrectomy but had attached retinas). Vitreous samples were collected during vitrectomy and were assessed for the presence of cytokines using a fluorescent bead-based multiplex assay. RESULTS: The concentration of G-CSF (8.59 pg/ml) and MCP-1 (1615.2 pg/ml) were significantly increased in the study group, when compared to the control group (0 and 469.13 pg/ml, respectively). MCP-1 was also significantly increased in the subgroup of patients with PVR compared to the patients with uncomplicated RRD. CONCLUSIONS: The levels of these biomarkers support the idea that proliferative vitreoretinopathy has an inflammatory component. PMID- 27125085 TI - TREATMENT OF PUBIC DISJUNCTION IN YOUNG-BURGUESS TYPE II AND III PELVIC RING FRACTURES. AB - AIM: To present the personal experience in assessing the treatment of pubic disjunction in Young-Burguess type II and III pelvic ring fractures. MATERIAL AND METHODS: Included in the study were 30 patients with type II and III pelvic ring fractures, aged 32 to 76 years. Of these, 18 patients were treated with external fixation, and 12 patients were treated surgically: type II fractures were treated with open reduction and internal fixation (ORIF) of pubic disjunction and type III fractures underwent additionally posterior fixation. RESULTS: Mean follow-up was 1.6 years. After external fixation we found the persistence of diastasis (1.5 to 4 cm), which was asymptomatic in all cases. Complications included implant failure in 3 patients, and postoperative infection in 2 patients. Among the 5 patients with type II lesions the clinical and radiological scores were excellent in 3, good in 1, and poor in 1. Among the patients with type III lesions the clinical outcomes were excellent in 5 and good in 2. CONCLUSIONS: External fixation has proved a good treatment option for patients who cannot tolerate a more extensive surgery. There is no conclusive clinical evidence favoring the use of two perpendicular plates vs. 1 plate for pubic symphysis fixation. In osteonorotic patients the use of 2 plates is recommended. PMID- 27125086 TI - EFFECT OF TRANEXAMIC ACID USE ON POSTOPERATIVE BLOOD LOSS IN TOTAL KNEE ARTHROPLASTY. AB - AIM: To monitor the effect of tranexamic acid use (Exacyl) on postoperative bleeding (aspiration), autologous blood transfusion (autotransfusion), allogeneic blood transfusion and postoperative anemia (difference between preoperative and immediate postoperative hemoglobin levels) in total knee arthroplasty. MATERIALS AND METHODS: This retrospective observational study was conducted on a sample of 457 patients who underwent endoprosthetic knee arthroplasty in the interval January 1, 2008-July 3O, 2014 at the Traumatology-Orthopedics Clinic of the Iasi Rehabilitation Hospital. The mean age of the study group was 66 years (range 32 84 years), 74.4% were female, 39.8% presented varus and 6.1% valgus malalignment. The study group was subdivided into two groups: Group 1 served as controls and underwent surgery without the administration of tranexamic acid and Group 2 received tranexamic acid. RESULTS: In group 1 the average amount of blood lost was significantly higher than in group 2, 1168.94 ml vs. 452.9 ml (p < 0.001). The use of a cell saver was required in 70% of group 1 patients with an average amount of auto transfused blood of 480.70 ml, significantly more frequent and in greater amounts than in group 2 (below 10%) with an average of 15.05 ml (p < 0.001). In this study tranexamic acid had not a statistically significant favorable effect on blood transfusion requirements and anemia syndrome. CONCLUSION: Tranexamic acid has a favorable effect on postoperative blood loss and its associated complications, with a favorable impact on both early clinical and functional recovery. PMID- 27125087 TI - OUTCOME OF INTERNAL HEMIPELVECTOMY IN A PATIENT WITH MULTIPLE MYELOMA--CASE REPORT. AB - A patient treated for thyroid cancer was diagnosed with multiple myeloma in the context of trauma. After the pelvic tumor devascularization she underwent internal hemipelvectomy Type I + IIA Enneking Classification using polymerizing bioneutral gel embolization, "Glubran 2". The purpose of this case report is to demonstrate the importance of careful selection of treatment methods, together with adequate physical therapy in order to obtain favorable long-term results. PMID- 27125088 TI - GIANT INTRALIGAMENTARY UTERINE LEIOMYOMA AND ITS COMPLICATIONS. AB - Uterine leiomyomas are benign tumors arising from uterine smooth muscle. Although their pathogenesis remains unclear, they are the most common tumor of the female reproductive tract, occurring in as many as half of women older than 35 years. Uterine leiomyomas represent the most common benign tumors of the female reproductive tract. Giant uterine leiomyomas are very rare and represents a great diagnosis and therapeutic challenge. Uterine leiomyoma is one of the most frequent types of tumours and it is diagnosed in 20-40% of the women of reproductive age. Until the age of 50, approximately 70% of the white women and less than 80% of the black women will have had at least one leiomyoma. The frequency of the emergence of uterine leiomyoma in black women is significantly higher than in white women. PMID- 27125089 TI - DILEMMAS IN THE ATTITUDE TOWARDS SUICIDE. AB - Although apparently easy to define, the suicidal act or attempt raises complex and difficult problems due to the multitude of conditions and situations that can lead to it. In all cases the suicide's definition has always centred on the intention of one person to deliberately cause his or her death in an active manner. Defining suicide has been consecutively the temptation of philosophers, sociologists, theologians, psychologists and psychiatrists. From an epistemological point of view the suicide is an open concept without precise borders, yet not incoherent. Scientists have constantly tried to establish evaluation criteria of suicidal acts but these are variable. One can even assume that there is an infinity of combinations of characteristics that would legit- imize the label of suicide, although none of them can be particularized in any way. Not even death itself represents a necessary condition for the evaluation of an act as suicide. PMID- 27125090 TI - REDUCE CHILD MORTALITY AS A MILLENNIUM DEVELOPMENI GOAL IN ROMANIA. AB - AIM: To assess the efforts made in Romania towards achieving the Goal 4 from MDGs -Reduce Child Mortality. MATERIALS AND METHODS: A descriptive study about the deaths among Romanian children under five, between 2002 and 2015, from the perspective of the MDGs. To help track progress toward this commitment, following specific targets and indicators were developed: Target 1-Halve the mortality rate in children aged 1-4 years between 2002-2015; Target 2--Reduce infant mortality by 40% between 2002 and 2015; Target 3--Eliminate measles by 2007. The comparison allows establish the status (achieved or not) for each target. RESULTS: From 2002, the under-five mortality rate recorded a continuous descendent trend till now (20.8 to 10.3 under five deaths per 1000 inhabitants in 2013). The infant mortality rates declined from 17.3 to 8.5 deaths per 1,000 live births (2002 2013). Eliminating measles by 2007--was achieved one year later, because of the measles epidemic in 2005 and 2006. High vaccination rates have been maintained, with the proportion of children 1 year old vaccinated against measles reaching and being maintained at between 94-98%. CONCLUSIONS: Substantial progress has been made in Romania, in achieving the Millennium Development Goal no. 4. All the three targets were achieved. However, infant mortality still remains above the average of European Union (4 infant deaths per 1,000 live-births). PMID- 27125091 TI - HEALTH CARE ECONOMICS IN ROMANIA--DYNAMICS AND EVOLUTION. AB - Health economics refers to the analysis of medical institutions considering their economic and social efficacy, but also the regularity and the relationships that govern the phenomena and the processes from the field of health with the final purpose of achieving better results with the minimum of resources; it represents the study of health price in its complexity. The economics of the population's health needs and in particular the health needs in case of the poor groups of the population, consider health to be the main component of global human vulnerability. Health economics tries to change the simple interpretation of health price and disease cost into a wider consideration of a system administration similar to educational and social economics and the study of health in the context of the multiple specializations of the macro economy of the national group, as it is an instrument in the country's great economics symphony. PMID- 27125092 TI - INTRAUTERINE GROWTH RESTRICTION--PREDICTIVE SERUM MARKERS. AB - AIM: To determine during the first trimester of pregnancy some serum and ultrasound markers that could improve perinatal morbidity and mortality in women with intrauterine growth restriction (IUGR). MATERIAL AND METHODS: Prospective study of pregnant women gestational age 11 weeks and 0 days--13 weeks and 6 days, consisting in the determination of pregnancy associated plasma protein (PAPP-A), mean platelet volume (MPV), and ultrasound appearance of placenta. DISCUSSION AND CONCLUSIONS: This study suggests that screening by detailed history and PAPP-A and MPV determination during the first trimester of pregnancy in women at risk for IUGR makes possible the prophylactic treatment and monitoring of pregnancy according to a given protocol and thus neonatal morbidity and mortality to be reduced. PMID- 27125093 TI - AXIAL MODIFICATIONS OF PERMANENT LOWER MOLARS AFTER PREMATURE LOSSES OF TEMPORARY MOLARS. AB - AIM: The aim of our study was to determine the impact of premature loss of temporary lower molars upon the longitudinal axis of the first and second permanent molars. MATERIAL AND METHODS: The study groups included 61 patients, 6 9 year olds with premature loss of primary molars and a control group of 24 patients with intact temporary teeth. We evaluated the angle between longitudinal axis of first and second lower permanent molars and occlusal plane. RESULTS: It was observed that premature loss of lower second deciduous molar modifies more the vertical axis of first and second permanent molars than the premature loss of first lower primary molar. Reducing space occurs mainly through mesial inclination of molars that separates the edentulous breach. Temporary loss of both lower first molars on the same quadrant causes an accelerated eruption of both premolars increasing the prevalence of eruption sequence: "4-5-3-7". CONCLUSIONS: The preservation of the occlusal morpho-functional complex using space maintainers mainly when the premature loss of the second primary molars occurs is the best interceptive treatment option. PMID- 27125094 TI - COMBINED EFFECT OF THERMAL LOAD AND MECHANICAL LOAD IN TRANSTIBIAL PROSTHESIS. AN EMPIRICAL STUDY. AB - Probably the most important factor in evaluating a patient's prosthesis is quality of life. Transtibial amputations, are among the most frequently performed major limb amputations. Many individuals with transtibial amputations successfully achieve rehabilitation at or near their preamputation levels. Discomfort in prosthetic sockets continues to be a critical challenge faced by both prosthetists and amputees. MATERIAL AND METHODS: This paper proposes a fusion Graphic User Interface that combines two types of information (pressure and temperature). Data from pressure sensors and thermistors (an electrical resistor whose resistance is greatly reduced by heating, used for measurement and control) placed on the stump in transtibial prosthetics are collected in real time using a National Instruments Data Acquisition device. RESULTS: All the data stored in files are available for offline processing. The user has the possibility to analyse the signal by zooming or positioning the marker and window on different parts of signal. A complex analysis that involves the pressure and temperature for a location (where both sensors are placed) is available in time domain. CONCLUSIONS: Blunt-prosthesis interface is characterized by few parameters among the most important are pressure and friction. The action of these parameters during static and dynamic stage is very important because their actions can produce lesions of skin at the level of interface. Despite the advancements in surgical techniques and prostheses, much still needs to be done. We made certain that the sensors were in the same location by pressing on specific cells on the residual limb during various stages of the experimentation. The highest pressures recorded were during the stance phase of walking. The curve that shows the temperature evolution or pressure in one point could differ in different points from patient to patient. PMID- 27125095 TI - EVOLUTION OF SYNCHRONOUS BILATERAL BREAST CARCINOMA IN A YOUNG PATIENT. AB - Bilateral breast cancer incidence is appreciated to be between 0.3 to 12% and is determined either by a hereditary load associated with chromosomal instability under the effect of environmental factors, or by the evolution in a particular hormonal context which gives biological aggressiveness. We present the case of a patient, aged 38 years, clinically, imagistic and bioptic diagnosed with left axillary lymph node metastases of breast carcinoma NST invasive G3, IHC-RE = 60%, RP = 30%, HER2neu = 2 +, Ki67 = 20%, in August 2013. Patient followed neoadjuvant chemotherapy treatment during September-October 2013. In December 2013 she was clinically and imaging diagnosed with bilateral breast cancer, for which surgical intervention was done which consisted of bilateral radical Madden mastectomy with bilateral axillary lymphadenectomy. BAP-invasive carcinoma NST: left breast pT2mN3a G2, right breast--pT3mN3a G2, IHC-RE = 90%, RP =70% HER2neu = 2 +, Ki67 = 50%. During the period of January-March 2014, the patient followed adjuvant chemotherapy and Herceptin. Bilateral breast ultrasound assessment in April 2014 revealed: left axilla--liquid blade 29 / 6mm; right axilla--oval ganglion 9/5 mm. Abdominal and pelvic ultrasound: empty uterine cavity, bosselated contour; at left ovary level multiple cystic formations. During the period of May-June 2014, adjuvant radiation therapy and ovarian irradiationwas administered to the patient. Subsequently hormone therapy was initiated. Following CHT / ovarian irradiation patient continues to experience intermittent uterine bleeding, which is why a total hysterectomy with bilateral ovariectomy was done, and BAP: cervical, endometrialand left ovary with tumor multifocal infiltration with histopathological aspect of invasive breast carcinoma NST. Periodic imaging evaluations do not reveal local or distant recurrence. The particularity of this case is synchronous bilateral breast cancer diagnosis in a young patient complicated in its evolution by ovarian metastases. This form of metastasis is rare in young women and occurs in advanced stages of the disease. PMID- 27125096 TI - THERMOPLASTIC MATERIALS APPLICATIONS IN RADIATION THERAPY. AB - This is an example of the use of thermoplastic materials in a high-tech medicine field, oncology radiation therapy, in order to produce the rigid masks for positioning and immobilization of the patient during simulation of the treatment procedure, the imaging verification of position and administration of the indicated radiation dose. Implementation of modern techniques of radiation therapy is possible only if provided with performant equipment (CT simulators, linear accelerators of high energy particles provided with multilamellar collimators and imaging verification systems) and accessories that increase the precision of the treatment (special supports for head-neck, thorax, pelvis, head neck and thorax immobilization masks, compensating materials like bolus type material). The paper illustrates the main steps in modern radiation therapy service and argues the role of thermoplastics in reducing daily patient positioning errors during treatment. As part of quality assurance of irradiation procedure, using a rigid mask is mandatory when applying 3D conformal radiation therapy techniques, radiation therapy with intensity modulated radiation or rotational techninques. PMID- 27125098 TI - [Atrial Fibrillation in Cardiosurgical Patients]. PMID- 27125097 TI - A RENAISSANCE PROMOTER OF MODERN SURGERY. AB - The present paper aims, exploring the history of Renaissance medicine, to evoke the figure and work of the priest, surgeon and anatomist, Guido Guidi (Vidus Vidius) (1509-1569). The XVIth century is considered a period marked by artistic and scientific effervescence in the western part of Europe and Guido Guidi was a first order personality, grandson of Domenico Ghirlandaio and friend of Benvenuto Cellini. He was appointed by the King Francis I the first professor of anatomy and surgery at the newly founded College de France. On demand of the King, he wrote Chirurgia j Graeco in Latinum conversa Vido Vidio Florentino interprete, cum nonnullis eiusdem Vidii comentariis (1544), a beautifully illustrated original surgery book that became for the following two centuries the main source in teaching surgery. Our study realized a detailed assessment of the book and especially of its illustrations belonging to Francesco Salviati. Exploring the life of Guido Guidi, we were also able to point out other significant contributions in the field of anatomy and clinical medicine as De anatome the first book where are presented disarticulated, the bones of the skull base and also the discovery of the chickenpox. Some surgical personalities attributed to him both the elaboration of the term appendix vermiformis and the first description of an aneurysm, he treated with the help of Fallopio. Although forgotten today, Guido Guidi was a leading figure of the Renais sance medicine both in France and Italy. PMID- 27125099 TI - [Single Nucleotide Polymorphisms in T-Cadherin Gene (CDH13) Have Cumulative Effect on Body Mass in Patients With Ischemic Heart Disease]. AB - BACKGROUND: Low adiponectin concentration observed in obese patients is associated with a high risk of metabolic disorders and cardiovascular diseases and could be related to single nucleotide polymorphisms (SNPs) in T-cadherin gene (CDH13). T-cadherin is a receptor for adiponectin and low-density lipoprotein. Aim of this study was to investigate association of CDH13 SNPs with the development of obesity in patients with ischemic heart disease (IHD). RESULTS: We established a statistically significant correlation between the number of minor alleles of rs11646213, rs4783244 and rs12444338 in CDH13 gene with body mass index: patients with smaller number of minor alleles tended to have normal body weight (odds ratio 3.03, 95% confidence interval 1.03-8.87). CONCLUSION: The obtained results are indicative of the cumulative effect of SNPs in CDH13 (rs11646213, rs4783244, rs12444338) on BMI in patients with IHD. PMID- 27125100 TI - [Cardio-Ankle Vascular Index and Subclinical Peripheral Atherosclerosis in Patients With Stable Coronary Artery Disease]. AB - AIM: To study relationship between cardio-ankle vascular index (CAVI) and subclinical manifestations of noncoronary atherosclerosis in patients with stable ischemic heart disease (IHD). MATERIAL AND METHOD: We included into this study 511 patients with IHD examined within framework of a register of patients before aorto-coronary bypass surgery. CAVI was determined using VaSera-1000 device. RESULTS: We distinguished 2 groups of patients: (1) with abnormal (>= 9.0, n = 128) and (2) normal (< 9.0, n = 383) CAVI. Group 1 compared with group 2 had high mean age (p = 0.02), comprised more women (p = 0.0016), hypertensive patients (p = 0.0061), patients with three vessel coronary disease, and patients with stenoses in carotid arteries. Multiple logistic regression analysis revealed independent association between elevated arterial stiffness and age. Elevated arterial stiffness was found in 25% of group 1 patients. Abnormal CAVI was associated with increased intima-media thickness and stenoses of carotid arteries but not with presence of stenoses in arteries of lower extremities. PMID- 27125101 TI - [The Impact of Renal Dysfunction on Outcomes of In-Hospital and Remote Periods in Patients With ST-Elevation Myocardial Infarction Combined With Type 2 Diabetes Mellitus]. AB - PURPOSE. To elucidate association of renal dysfunction (RD) with unfavorable outcomes of in-hospital and long-term (1 year) treatment stages of patients with ST-elevation (STE) myocardial infarction (M) and concomitant diabetes mellitus (DM). MATERIAL AND METHODS: We enrolled in this register study 954 patients (65% men, 35% women, mean age 63.4 [62.6-64.2] years) with STE acute coronary syndrome. Mean age of men was 60.3 (59.4-61.1), of women--69.2 [68.1-70.4] years. DM was verified in 175 patients (18.3%) basing on history data and values of fasting and postprandial glycaemia. Glomerular filtration rate (GFR) was calculated by MDRD formula using serum creatinine level determined at admission. RESULTS: Four groups of patients were distinguished depending on the presence of DM and RD: with DM and RD (n = 82), with DM without RD (n = 93), without DM with RD (n = 269) and without DM and RD (n = 510). Presence of RD in acute period of MI was associated with 3.3-fold increase of risk of in-hospital and annual mortality, while the presence of DM was associated with 1.6-fold increase of in hospital mortality without significant impact on annual mortality. CONCLUSION: RD had a significant impact on realization of poor outcomes in STEMI patients with concomitant DM. Prognostic significance of combination of DM and RD was proved to be higher than that of isolated DM. PMID- 27125102 TI - [Atrial Fibrillation in Patients With Chronic Obstructive Pulmonary Disease Is Associated With Polymorphism of Interleukin 6 Gene]. AB - It can be suggested that development of atrial fibrillation (AF) in patients with chronic obstructive pulmonary disease (COPD) is directly related to the system of inflammation. Genetic polymorphism of factors of this system can be one of components of mechanism of AF in COPD. Aim: to elucidate polymorphic markers of genes of factors of the system of inflammation associated with AF in patients with COPD. Material and methods. We examined 208 patients with COPD (52 with and 156 without AF). Examination included spirometry, echocardiography, and study of frequencies of polymorphic markers G(-238)A, G(-308)A of tumor necrosis factor (TNF) gene, C(-819)T of interleukin (IL) 10 gene, G(-174)C of IL-6 gene, rs2228145(AC) of IL-6R gene, and rs2069762(A/C) of IL-2 gene. RESULTS. Factors associated with AF were left atrial volume (odds ratio [OR] 1.021, 95% confidence interval [ClI] 1.004-1.043, p = 0,027), right atrial volume (OR 1.02, 95% CI 1.001-1.040, p=0.021), and carriage of C allele of polymorphic marker G(-174)C of IL-6 gene (OR 6.02, 95% Cl 1.87-19.38, p = 0.003). CONCLUSION: C allele of polymorphic marker G(-174)C of IL-6 gene can be considered to be independently associated with development of AF in patients with COPD. PMID- 27125103 TI - [Left Atrial Remodeling and Thromboembolic Risk in Patients With Recurrent Atrial Fibrillation]. AB - PURPOSE: To assess the relationship between left ventricular and left atrial (LA) structural and functional characteristics and thromboembolic (TE) risk in patients (pts) with recurrent atrial fibrillation (AF). MATERIAL AND METHODS: Sixty pts (mean age 65 [61; 72] years, 42% men) with nonvalvular paroxysmal and persistent AF during sinus rhythm were divided into three groups based on CHA2DS2 VASc score: 1, 2, and >= 3. All pts underwent conventional and speckle tracking echocardiography. Apical four- and two-chamber views images of 6 myocardial segments in the filling phase were obtained to assess global peak left atrial longitudinal strain (PALS) in the reservoir (r) and contractile (c) phase. RESULTS. Patients with paroxysmal AF had significantly higher PALSr compared with patients with persistent AF (15.1 vs 11.2%, p = 0.0002) and PALSc (-15.0 vs 12.0%; p = 0.0002]. In logistic regression analyses, only higher PALSr was significantly associated with lower CHA2DS2-VASc score (OR 0.61; 95% Cl 0.38 0.97; p = 0.03). In order to distinguish patients with moderate and high TE risk we performed ROC curve analysis. Effective PALSr cut-off point was 16.7% with sensitivity of 62.5%, specificity of 39.0% and an area under the curve of 0.85 (95% Cl 0.72-0.98; p = 0.002). CONCLUSIONS: In patients with AF PALSr was independently associated with CHA2DS2-VASc score. Use of a PALSr threshold allows to detect patients with moderate and high TE risk and can be considered in the process of decision making on initiation of anticoagulation treatment in patients with AF and CHA2DS2-VASc score of 1. PMID- 27125104 TI - [The Possibilities of Pharmacological Correction of Endothelial Dysfunction in Patients With Arterial Hypertension]. AB - OBJECTIVE: To assess the possibility of a fixed combination of perindopril arginine and amlodipine in the correction of endothelial dysfunction (ED) in patients with arterial hypertension (AH). MATERIAL AND METHODS: The study included 49 patients with hypertension and ED receiving any antihypertensive therapy and have not reached the target level of blood pressure--blood pressure (66% women, 34% men). The mean age was 46.2 +/- 5.4 years. Patients switching to visit prescribed combination of perindopril arginine and amlodipine in different dosages depending on the level of blood pressure. The study lasted 12 weeks, on the first and last visit was assessed endothelial function. RESULTS: All patients completed the study. Mean systolic and diastolic blood pressure decreased during the 12 weeks to 162.6 +/-11.4 to 131.1 +/- 10.0 mmHg and 95.4 +/- 10.2 to 78.7 +/ 7.7 mm Hg respectively (p < 0.05). At the time of the telephone contact was a target mean arterial pressure (p > 0.05). The structure of the DE before the study was as follows: DE major arteries or resistance--28.6%; DE both types- 71.4%. After 12 weeks in patients receiving the drug in only 57.1% of the subjects had both types of ED (p < 0.05), DE or large resistive arteries was recorded in 21.4% of patients, while 21.5% were no signs of ED. The number of patients with hypertension who have reached the target blood pressure in patients receiving perindopril arginine and amlodipine increased from visit to visit, and reached 71.4% at 12 weeks. Over the 12 weeks of treatment adverse events occurred only in 2.1-4.2% of cases. CONCLUSION: Combination therapy with ACE inhibitor perindopril arginine and a calcium channel blocker amlodipine in people of working age with hypertension and ED for 12 weeks leads to a reduction of endothelial dysfunction of large and small vessels (from 71.4 to 57.1%), a significant reduction in systolic and diastolic blood pressure and achieve target blood pressure in 71.4% of cases. PMID- 27125105 TI - [Comparative Clinical Biochemical Assesment of the State of Mycardium After Coronary Artery Bypass Surgery Performed Using Various Techniques]. AB - We compared parameters of the state of myocardium after coronary artery bypass surgery (CABS) performed according to the following techniques--with complete cardiopulmonary bypass (CABS-CBP), beating heart bypass grafting with parallel normothermic perfusion (CABS- BH-NP), and beating heart bypass grafting (CABS BH). Patients (n = 100, 86% men, 14% women, age 56-69 years) were divided into 3 groups with comparable sex, age, state of the myocardium, and EUROSCORE surgical risk. In group 1 patients (n = 35) we used CABS-CHB, in group 2 (n = 32)--CABS-BH NP, in group 3 (n = 33)--CABS-BH. The following parameters were obtained on day 1 after surgery: left ventricular ejection fraction (EF, echocardiography), blood plasma levels of creatine phosphokinase (CPK), CPK-MB, and cardiac troponin I (TnI). There was no significant difference in parameters studied between groups 1 and 2 with a tendency to their more pronounced positive dynamics in group 2. In group 3 compared with groups 1 and 2 we observed significant lowering of levels of CPK (by 21.2-30.9%, p < 0.05), CPK-MB (by 9.1-13.1%, p <0.05), Tnl (by 0.6 0.7%, p < 0.05), and elevation of EF (by 9.8-11.6%, p < 0.05). Rate of development of myocardial infarction in group 3 (6.8%) was lower than in groups 1 and 2 (14.2 and 9.8%, respectively). In all groups we observed close correlation between biochemical parameters and left ventricular EF (r = 0.74-0.82, p < 0.01). PMID- 27125106 TI - [Immediate Results of Mitral Valve Surgery in Asymptomatic Patients With Severe Mitral Regurgitation Due to Degenerative Mitral VaIve Disease]. AB - Degenerative mitral valve disease nowadays is the most common cause of mitral insufficiency in developed countries and is associated with high morbidity and mortality. In the last decades repairing the mitral valve has become the operation of choice for treatment of the mitral valve prolapse, enabling to improve the geometry and function of the left ventricle and long-term survival. Nevertheless, the problem of choice of method of management of severe mitral regurgitation in asymptomatic patients with degenerative mitral valve disease remains unsolved. In this article we present immediate results of a prospective comparative study of mitral valve surgery in asymptomatic and symptomatic patients in dependence on NYHA class of heart failure. PMID- 27125107 TI - [Proignostic Factors of Cardiovascular Complications After Ischemic Stroke]. AB - We included into prospective cohort observational study 148 patients with ischemic stroke aged 60 [52; 68] years. Duration of a prospective follow-up was 35 [28; 40] months. Cardiovascular events (CVE) registered during follow-up were recurrent stroke, transient ischemic attack, myocardial infarction, unstable angina, congestive heart failure, including acute decompensation of chronic heart failure requiring hospitalization, cardiovascular death. During follow-up 37 patients (25%) had 50 CVE. On multivariate regression analysis, independent predictors of CVE after ischemic stroke were: age over 67 years, presence of chronic ischemic heart disease, high grade ventricular arrhythmias, standard deviation of cardiointervals (SDNN) less than 71 ms, absence of thiazide diuretics in the basic antihypertensive therapy. PMID- 27125108 TI - [The State of Coagulation Hemostasis and Fibrinolysis in Children With Essential Arterial Hypertension]. AB - Children with essential hypertension and increased risk of thrombotic complications are characterized by history of familial thrombosis, increased levels of fibrinogen and soluble fibrin-monomer complexes, activity and content of von Willebrand factor, activity of plasminogen. PMID- 27125109 TI - [Predictive Value of Renal Dysfunction for Early and Long-Term Outcomes of Coronary Artery Bypass Grafting]. AB - AIM: to assess value of renal dysfunction for immediate and long-term prognosis after coronary artery bypass grafting (CABG). MATERIAL AND METHODS: We examined 657 patients (419 men and 238 women) aged 54-68 (60.6 +/- 5.3) years before and after coronary artery bypass grafting (CABG). Patients with baseline glomerular filtration rate (GFR) > 90 and with GFR 89-45 ml/1.73 (n = 246) comprised groups 1 and 2, respectively. Acute kidney injury (AKI) was diagnosed using the AKI Network criteria. RESULTS: In early postoperative period AKI (perioperative AKI) was diagnosed in 97 (23.6%) and 102 (41.55) patients of group 1 and 2, respectively (chi2 = 22.4; p < 0.001). Rate of early cardio-vascular complications and hospital mortality were significantly higher in patients with compared with those without perioperative AKI. During 12 months of follow-up 6.8% of patients in group 1 developed chronic kidney disease (CKD). In group 2 we noted progression of CKD in 14.7 and 5.4% (p > 0.05) and its regression in 45.1 and 61.4% (p = 0.004) of patients with and without perioperative AKI, respectively. Programmed hemodialysis was carried out in 12 patients of group 2, including 10 with perioperative AKI (p = 0.003). CONCLUSION: Presence of CKD and development of perioperative AKI was associated with unfavorable cardiorenal prognosis after CABG. PMID- 27125110 TI - [Results of the European Congress of Cardiology 2015]. PMID- 27125111 TI - [The Efficacy and Safely of Rosuvastatin in Patients With Coronary Heart Disease]. PMID- 27125112 TI - [Inflammatory Markers and Their RoIe in Assessing Prognosis of patients With Stable Coronary Artery Disease After Coronary Stenting]. AB - In recent years, expanded data have demonstrated the association between increased inflammatory markers and risk of adverse cardiovascular events in patients undergoing percutaneous coronary intervention (PCI) with stent implantation. Particularly, several studies have demonstrated association between increased C-reactive protein (CRP) level and various risk factors of cardiovascular diseases and their complications. The role of CRP in predicting restenosis after implantation of bare metal stents has been proven, but its role in predicting drug-eluting stents restenosis is still unproved. Significant association between increased white blood cells count and risk of development and severity of coronary artery disease and as well as poor prognosis after PCI has also been demonstrated. But erythrocyte sedimentation rate has been studied insufficiently in this regard. According to some studies, including those conducted in our institute, one can suggest an association between eosinophilic inflammatory response, progression of coronary atherosclerosis, and drug-eluting stents restenosis. Identification of factors affecting prognosis of patients with coronary heart disease after PCI will allow determining further strategy of patient management. PMID- 27125113 TI - [The Results of Long-Term Observation of Patients Who Participated in the ADVANCE Trial]. AB - We present in this article data on the prevalence and risk of complications in patients with diabetes and hypertension. From the standpoint of current guidelines on the management of arterial hypertension we consider problems of target blood pressure levels and choice of antihypertensive drugs in patients with diabetes, including those with diabetic nephropathy. We also present results of long-term observation of participants of the ADVANCE trial that have shown that reduction of mortality achieved because of antihypertensive therapy in the randomized study persisted throughout follow-up. Discussion of possible mechanisms of this phenomenon and the advantages of fixed perindopril/indapamide combination is presented as well. PMID- 27125114 TI - [Aspects of the Efficacy and Safety of Rosuvastatin in Patients at Polymorbid States]. PMID- 27125116 TI - Rightsizing Your Board. AB - What's the ideal size for a hospital board of trustees? Here are several factors to consider before deciding if your own board needs to be right-sized. PMID- 27125115 TI - [The Strategy of Indapamide Retard Use in the Prevention of the Early Vascular Aging Syndrome]. PMID- 27125117 TI - IN SEARCH OF VALUE. AB - Defining value in health care isn't easy, and measurements are incomplete or even contradictory. But that isn't stopping some health care systems from going full steam ahead. PMID- 27125118 TI - Our Opioid Nightmare. AB - Abuse of opioids, including prescription painkillers and heroin, is epidemic, crossing boundaries of class, age and region. Here's how hospitals are working to stop it. PMID- 27125119 TI - Dissecting New Medicare Physician Pay. AB - A summary of key aspects of the new Medicare physician payment system and the implications for hospitals. PMID- 27125121 TI - Redesigning Care Delivery. AB - This Hospitals in Pursuit of Excellence column considers innovative care and payment models to help hospitals and health systems achieve the Triple Aim. PMID- 27125120 TI - Creating a Safer Facility. AB - Trustees and hospital executives are paying more attention to design innovations that can prevent bad things from happening to patients. PMID- 27125122 TI - Another Use for Lean. AB - The Lean principles and tools that hospitals use to transform care delivery, transparency and cost can also help to manage population health. PMID- 27125123 TI - Better Community Health. AB - Hospitals need to find and work with multiple partners to improve community health. Here's the case for doing so. PMID- 27125124 TI - [The Trend of Multidimentional Images]. PMID- 27125125 TI - [Development of a Text-Data Based Learning Tool That Integrates Image Processing and Displaying]. AB - We developed a text-data based learning tool that integrates image processing and displaying by Excel. Knowledge required for programing this tool is limited to using absolute, relative, and composite cell references and learning approximately 20 mathematical functions available in Excel. The new tool is capable of resolution translation, geometric transformation, spatial-filter processing, Radon transform, Fourier transform, convolutions, correlations, deconvolutions, wavelet transform, mutual information, and simulation of proton density-, T1-, and T2-weighted MR images. The processed images of 128 x 128 pixels or 256 x 256 pixels are observed directly within Excel worksheets without using any particular image display software. The results of image processing using this tool were compared with those using C language and the new tool was judged to have sufficient accuracy to be practically useful. The images displayed on Excel worksheets were compared with images using binary-data display software. This comparison indicated that the image quality of the Excel worksheets was nearly equal to the latter in visual impressions. Since image processing is performed by using text-data, the process is visible and facilitates making contrasts by using mathematical equations within the program. We concluded that the newly developed tool is adequate as a computer-assisted learning tool for use in medical image processing. PMID- 27125126 TI - [3D Visualization for Computer-Aided Diagnosis in Thoracic CT]. AB - Medical imaging is one of the major tools that have enriched medical science, disease detection and treatment. Computed tomography (CT) is the most widely used imaging modality in clinical practice for cancer detection, oncologic diagnosis, and treatment guidance. Recent advances in CT imaging technologies allow the high throughput extraction of informative imaging features to quantify the differences that oncologic tissues exhibit. The development of computer-aided detection/diagnosis (CADe/CADx) systems based on imaging biomakers associated with disease probabilities may become increasingly an attractive field to support clinicians in detecting early-stage diseases and determining risk-adaptive treatments. Three-dimensional visualization for CADe/CADx systems may have a large impact as various imaging modalities are routinely used in clinical practice to improve medical decision-support. In this article, we present some examples of 3D visualization for CADe/CADx systems of thoracic CT images. PMID- 27125127 TI - [Two-dimensional Projection and Image Reconstruction]. AB - Medical images are being recently reconstructed using several data sets. In x-ray and computed tomography (CT), 3-dimensional (3D) images are reconstructed using 2 dimensional (2D) projection data. Research regarding the image reconstruction method has been actively conducted. Further, 3D images include patient information and are used as diagnostic tools. Therefore, it is necessary to acquire a projection technique. There are several algorithms of the projection method. In this paper, we reviewed three methods. The first method is based on mathematical formulae, the second integrates pixel values at regular intervals along the x-ray track, and the third integrates pixel values multiplied by distance. We confirmed the usefulness of the projection method for reconstructing images. PMID- 27125128 TI - [Three Dimensional Display in Nuclear Medicine]. AB - Imaging techniques to obtain a tomographic image in nuclear medicine such as PET and SPECT are widely used. It is necessary to interpreting all of the tomographic images obtained in order to accurately evaluate the individual lesion, whereas three dimensional display is often useful in order to overview and evaluate the feature of the entire lesion or disease such as the position, size and abnormal pattern. In Japan, the use of three dimensional image analysis workstation with an application of the co-registration and image fusion between the functional images such as PET or SPECT and anatomical images such as CT or MRI has been generalized. In addition, multimodality imaging system such as a PET/CT and SPECT/CT has been widespread. Therefore, it is expected to improve the diagnostic accuracy using three dimensionally image fusion to functional images with poor anatomical information. In this commentary, as an example of a three dimensional display that are commonly used in nuclear medicine examination in Japan, brain regions, cardiac region and bone and tumor region will be introduced separately. PMID- 27125129 TI - [Medical Image Displaying Techniques for Clinical]. AB - It has been than 15 years since medical image analysis is used clinical scene. We provide 3D image for doctors to recognize easily by reconstructed CT or MRI images. It is introduced a recently technique for 3D medical image, for example, volume rendering, CPR, colon analysis, CT-SPECT fusion image. PMID- 27125130 TI - [The Three-dimensional Representation in the Nuclear Medicine]. AB - The three-dimensional representation is used by cerebral blood flow SPECT and myocardial SPECT. It is used with the statistical image analysis software (3D SSP, eZIS) in cerebral blood flow SPECT, and regional cerebral blood flow decrease can be detected. It is used with the heart function analysis software (QGS, QPS, QBS) in myocardial SPECT, and is effective for the cardiac wall motion evaluation. SPECT/CT and PET/CT are used in clinical. The three-dimensional fusion image that overlaps CT- volume rendering image with SPECT (PET) image can be constructed with an easy and high quality by SPECT/CT (PET/CT). It is effective for identification of accumulation part of radiopharmaceutical. PMID- 27125131 TI - [Three-dimensional Representation of a Medical CT Image]. AB - Recently, MSCT acquisition of volume data becomes easier. For computer processing technology has advanced, was the performance of the workstation also be improved. Therefore, three-dimensional representation of the whole body is also made possible. Three-dimensional display, is usually doing the diagnosis in only axial image, it is useful to understand the structure that traveling to the cranio caudal direction. When surgical care is necessary, an examination for CT is conducted for the purpose of a metastasis search. Use the data obtained this time, it becomes possible to provide surgical support image. I make what kind of image to use a clinical on the site three-dimensional image, and it is necessary to understand it what you want to know. PMID- 27125132 TI - [Utility of Medical Imaging Displaying Method in 3D Magnetic Resonance Imaging]. AB - The recent improvements in magnetic resonance (MR) hardware, especially 3T devices, scanning protocols, and three dimensional (3D) volumetric reconstruction software have facilitated great expansion of the role of 3D imaging. With the volumetric data, various post processing image reconstructions could readily be done on the 3D workstation. The reconstructions allow better demonstration of anatomic details, which help improve lesion localization and surgical planning. Particularly, in patients who are planned for surgery such as tumors assessment or pre-transplant evaluation, the 3D reconstructions provide not only better tumors extent, tumors volume evaluation and an excellent anatomical guide map, but also tumors relations with the blood vessels. In this review, we explain the various 3D reconstruction techniques used in MRI and demonstrate the value of 3D imaging in preoperative evaluation, diagnosis of coronary diseases, vascular diseases and each abdominal disease. PMID- 27125133 TI - [Series: Fundamental Electromagnetics for Beginners (4)]. PMID- 27125134 TI - [Series: Medical Applications of the PHITS Code (2): Acceleration by Parallel Computing]. AB - Time-consuming Monte Carlo dose calculation becomes feasible owing to the development of computer technology. However, the recent development is due to emergence of the multi-core high performance computers. Therefore, parallel computing becomes a key to achieve good performance of software programs. A Monte Carlo simulation code PHITS contains two parallel computing functions, the distributed-memory parallelization using protocols of message passing interface (MPI) and the shared-memory parallelization using open multi-processing (OpenMP) directives. Users can choose the two functions according to their needs. This paper gives the explanation of the two functions with their advantages and disadvantages. Some test applications are also provided to show their performance using a typical multi-core high performance workstation. PMID- 27125135 TI - Differentiation Potential of Mesenchymal Stem Cells from Equine Bone Marrow Cultured on Hyaluronic Acid-Chitosan Polyelectrolyte Multilayer Biofilm. AB - Nanotechnology techniques have a prominent role in the current technical and scientific scene. The layer-by-layer (LbL) deposition allows obtaining nanostructures with sophisticated multilayer, using a simple, but versatile technique. This procedure, which is used to coat and functionalize surfaces with nanometer- thick films, has applications in bioengineering, medicine, chemistry, materials and chemical engineering among other areas. Chitosan is a biomaterial, coming from the chitin, a very abundant polymer in nature, which has been recently tested as scaffolds. In this experiment we test the hypothesis that the hyaluronic acid-chitosan polyelectrolyte multilayer biofilm would be a good substrate to the adherence of equine mesenchymal stem cells derived from bone marrow. The results showed that these biofilms accelerate the process of cell adhesion on smooth surfaces, allowing a constant cell growth and creating a great option to cover surgical materials. PMID- 27125136 TI - Fat Layer from Medullary Canal Reamer Aspirate for Potential Use as a Supplemental Osteoinductive Bone Graft Material. AB - Mesenchymal stem cells (MSCs) are of therapeutic interest to clinicians and researchers, as they have been shown to augment the osteogenic properties of bone grafts. MSCs are known to be prevalent in bone marrow, but are still limited in numbers. Hence, additional sources of MSCs are beneficial to increasing grafting potential. Aspirate material collected using the Reamer/Irrigator/Aspirator (RIA) device (Synthes; Paoli, PA) during reaming of the femoral shaft consists of three main components: bone fragments, liquid flow-through, and a fat layer. Currently, only the bone and liquid layers have been examined for osteoinductive elements, and the bone fragments are exclusively used as autologous bone graft. In the present study, a method to promote cellular outgrowth, tapping proliferative capacity from the previously discarded fatty layer of RIA aspirate, is described. Proliferating cells were successfully isolated from the bone and fatty layers of a consenting patient and found to be viable after liquid nitrogen storage. The osteogenic differentiation potential of the cells isolated from the fat and bone layers was assessed. Cells from both layers of the aspirate expressed statistically significant levels (p < 0.05) of the bone cell marker alkaline phosphatase compared to the control cells, suggesting differentiation along the osteoblastic pathway. Results from this pilot study indicate that the traditionally discarded fatty element of RIA aspirate may be a source of MSCs with bone-forming capabilities and the described isolation technique is effective. Combining the aspirate fatty and bony elements may enhance the clinical success of the RIA autograft. PMID- 27125137 TI - Healing of Experimentally Created Non-Union of Femur in Rats Using Bone Precursor Cells from Mesenchymal Stem Cells (MSCs). AB - BACKGROUND AND OBJECTIVE: Around 20% of fractures have impaired or no healing. Many procedures have been tried with varying success. The objective of this study is to assess effect of osteoblast transplant (obtained after proliferation and differentiation of MSCs of bone marrow aspirate) in healing of experimentally created non-union of femur in rats. METHODS: Non-Union of femur were created in Sprague-Dawley rats weighing 200-250 grams. In 20 rats, Femur fracture was surgically created in 20 rats and 2 mm of the periosteum was cauterized on each side of the fracture and this created a non-union in 8 weeks. In 10 animals bone marrow was aspirated from the femoral shaft using 24-gauge butterfly needle and injected in special media. The two groups 10 each were marked and animals were kept in the similar surroundings. After radiological confirmation of non-union at 8 weeks, an injection containing 1 x 10 (6) osteoblasts cells (1 million cells) dissolved in 200 microliters of balanced salt solution was injected at the nonunion site. In the control group of 10 rats 1 ml of normal saline was injected. In 5 animals of each group the fracture was fixed using 1 mm kirschner wire and the other 5 were treated without fixation. After 8 weeks of implantation the animals were radiographed and euthanized. The hind legs were disarticulated from the hip joints, specimens were stored in 2% formalin and histological evaluation was performed. RESULTS: There were no deaths in both the groups and there was one superficial infection in the control group. Eight weeks post implantation of the BM-MSCs derived osteoblasts, all the fractures of the study group united with robust mineralization and new bone formation confirmed by radiograph and histopathology. In the control group there was no healing and the histopathology showed full of fibrous tissue with cartilage cells lining the fracture site. CONCLUSIONS: In conclusion, our results indicate that implant of BM-MSCs derived osteo-progenitor cells at the non-union efficiently induces a complete union. We believe a similar study should be carried out in a larger animal before any human trials. PMID- 27125138 TI - Anaerobic Glycolysis and HIF1alpha Expression in Haematopoietic Stem Cells Explains Its Quiescence Nature. AB - Metabolic alteration that a stem cell undergoes during proliferation and quiescence are decisive. These cells survive in extreme hypoxic environment that prevails in bone marrow. The present study is aimed to understand this nature in hematopoietic stem cells. These stem cells were mobilized from bone marrow into peripheral blood by giving G-CSF at a concentration of 5 MUg/Kg/d and the cells were isolated by apheresis technique. The morphological analysis of these cells using Giemsa stain and SEM showed presence of only single type of cells with conspicuous nuclei, the hematopoietic nature was assessed by the presence of CD34, a glycoprotein using anti-CD34 monoclonal antibodies. The ICC results revealed presence of CD34 marker further; pure population of CD34+ stem cells was described by FACS. These cells were cultured separately in DMEM having 5.5mM, 11.1mM and 25mM glucose respectively. In these cells GK, PK and L-LDH enzyme activities were estimated which showed increased activities at 5.5mM glucose concentration and further elevation of glucose concentration the activities were fallen considerably. Similarly, qPCR analysis of HIF1alpha and GAPDH genes showed very high expression of HIF1alpha at 5.5mM glucose concentration which reduced with increased glucose concentration. While GAPDH gene expression enhanced on elevation of glucose concentration. Thus, these results indicate high HIF1alpha expression in low glucose condition with improved anaerobic glycolysis seems to be one of the key factors in maintaining the quiescent state of CD34+ stem cells. PMID- 27125139 TI - Antiaging Effects of an Intensive Mind and Body Therapeutic Program through Enhancement of Telomerase Activity and Adult Stem Cell Counts. AB - OBJECTIVE: Key modalities of integrative medicine known to rejuvenate the mind and body are meditation, yoga, and controlled diet. It has been shown previously that intensive or prolonged mind and body therapies (MBT) may have beneficial effects on the well-being of healthy people and in patients. Telomerase activity and levels of peripheral blood adult pluripotent stem cells (PB-APSC) are reliable markers of long-term well-being that are known to decrease with age. The objective of this study is to understand the effect of our MBT program on telomerase activity and stem cells in blood collected from the participants. DESIGN: Here, we have investigated the effects of an intensive three weeks MBT retreat on telomerase activity and the peripheral blood stem cells in participants before and after the MBT. A total of 108 people were enrolled in the study; 38 men and 70 women (aged 18-90) randomly assigned for the study. RESULTS: Telomerase activity was greater in retreat participants at the end of the MBT retreat. About 45% of people showed more than one-fold increase of telomerase activity after our MBT program. Furthermore, about 27% of people showed more pronounced fold increase (2-fold) in telomerase activity after the MBT. In addition, a substantial percentage of people (about 90%) exhibited increased stem cell counts after the MBT. CONCLUSIONS: The data suggest increased telomerase activity and stem cells count in peripheral blood from MBT retreat participants that may lead to increased longevity and better quality of life at latter age. PMID- 27125140 TI - Reversal of Methanol-Induced Blindness in Adults by Autologous Bone Marrow Derived Stem Cells: A Case Series. AB - INTRODUCTION: Methanol ingestion leads to severe damage to visual pathways and permanent loss of vision. Current treatment is aimed at removal of methanol from system and prevention of generation of toxic metabolites along with symptomatic management of patient. Autologous bone marrow mononuclear stem cells (MNC) can be used to rejuvenate the damaged retinal cells and restoration of vision. METHODS: Five patients suffering from methanol induced complete blindness within three months of insult and no known comorbidities during the past 6 months were enrolled to receive autologous bone marrow derived mononuclear cell fraction on compassionate grounds. The visual acuity and visual evoked responses (VER) were done at the time of enrollment and during follow-up visits. OBSERVATIONS AND RESULTS: Visual acuity of these patients at the time of enrollment: no perception of light. Improvement in visual acuity was recorded by 7 days which reached maximum at 3 weeks after treatment in three patients and three months in two patients. The patients had acuity of 6/9, finger counting and reading with magnifying glasses with no subsequent improvement till 2 years of follow-up. Visual Evoked Responses demonstrated improvements following treatment. No adverse reactions were noticed during follow-up. CONCLUSION: Treatment with Autologous Bone marrow derived MNC offers a new line of management in patients with loss of vision following methanol ingestion. The efficacy and safety of this line of management needs to be evaluated in controlled clinical trials. PMID- 27125141 TI - Human Umbilical Cord Mesenchymal Stem Cells in the Treatment of Duchenne Muscular Dystrophy: Safety and Feasibility Study in India. AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) is a musculo-degenerative disease characterized by lack of dystrophin production with no definite cure available currently. Discarded umbilical cord is a potential source of mesenchymal stem cells which are non-immunogenic and can be used for transplantation in allogenic set ups. Given the regenerative and anti-inflammatory properties of mesenchymal stem cells (MSCs), here we investigated its role in the cellular therapy of DMD patients. DESIGN: This is a single-blinded study conducted in various hospitals of India situated in Mumbai, Delhi, and Lucknow. Inclusion criteria for enrolling the patients in the study were boys aged between 5 to 18 years, absence of dystrophin in the immunohistochemistry of muscle biopsy and mutation in dystrophin gene in cytogenetic analysis. The exclusion criteria were presence of dystrophin in the muscle biopsy, patients on corticosteroids etc. UC-MSCs (2 millions/kg body weight) were administered through IV and IM injection. Muscle power in muscles of proximal upper limb, distal upper limb, proximal lower limb, distal lower limb, hip flexors, hip extensors, hip abductors, and paraspinal muscles were measured in 11 DMD patients after UC-MSCs transplantation and were followed for up to 3 years (average follow up 1.5 years). 5 DMD patients did not receive any UC-MSCs transplantation and served as the control group. RESULTS: The treatment group (N = 11 at baseline) had a pretransplantation strength of 3.45 +/ 1.0357 and 4.090 +/- 0.8312 in muscles of proximal upper limb and distal upper limb respectively. After 1 year (N = 9) these strengths remained stable with an average of 3.78 (1.03) and 4.22 (0.83). In contrast, the control group (N = 5) has a pre-transplantation strength of 3.6 (0.54) and 4 (1) in the proximal and distal upper limb respectively. After 1 year, (N = 5) 3/5 subjects had a slight but not statistically significant decrease in the proximal upper limb, mean 3.0 (1.0) and 5/5 had a lunit decrease in strength, mean 3.0 (1.0). The treatment group had a pre-transplantation strength of 2.0909 +/- 0.8312 and 3.1181 +/- 0.8738 in muscles of distal and proximal lower limbs respectively. At 1 year (N = 9), 4/9 subjects had a 1 unit increase in strength in the distal lower limb (mean 3.78 (0.97)) and 8/9 subjects had a lunit increase in strength in the proximal lower limb, mean 3.11 (1.05). The control group has a mean of 3.41 (0.54) and 3.0 (1.0) at baseline in the distal and proximal lower limb respectively. By 1 year, 3/5 subjects had a 1 unit decrease (mean 2.8 (0.45)) and 5/5 had a lunit decrease, mean 2.0 (1.0) in distal and proximal lower limb strength. Stability in muscle function was also achieved in muscles of hip flexors, hip extensors, hip abductors, and paraspinal muscles at one year as compared to untreated group. CONCLUSION: UC-MSCs administration not only resulted in the stabilization of muscle power but also did not show GVHD or any deleterious effects on the patients and thus may be considered as safe option for treatment of DMD as compared to control untreated group although further larger double-blinded studies are needed. PMID- 27125142 TI - Evaluation of the impact of support for nursing research on scientific productivity in seven Italian hospitals: A multiple interrupted time series study. AB - BACKGROUND: Nursing research is not well-developed in Italy, and knowledge of the methodologies for conducting research is lacking. In several hospitals, including those in which this study was conducted, a research center has been established to support and educate nurses on how to conduct clinical research. AIMS AND OBJECTIVES: In this observational study, we sought to assess whether establishing a support center for nursing research has resulted in an increase in scientific production in terms of the numbers of protocols approved (primary outcome), articles published and nurse authors involved in the publications (secondary outcomes). DESIGN: Multiple interrupted time series. METHODS: Data from 2002 to 2012 were collected in seven hospitals. Research centers have been established at various times in only four of these hospitals. RESULTS: A statistically significant increase in the primary outcome (the number of protocols approved by the Research Ethics Committee in which the principal investigator was a nurse) was observed in two hospitals approximately 2years after establishing a research center. The number of nursing research articles published in scientific journals with an impact factor increased but was not statistically significant. Finally, the number of nurse authors increased significantly in two hospitals with support units. Definitive conclusions could not be reached for the other two experimental hospitals because notably few post-intervention data were available. In the control hospitals, the scientific production outcomes did not change. CONCLUSIONS: This study shows that establishing a support center for nursing research inside hospitals can facilitate the production of research. PMID- 27125143 TI - Graduate nurse experiences of support: A review. AB - The first year of practice as a nurse is recognized as stressful. Graduate nurses (GNs) report gaps in their education, reality shock, burnout and other negative experiences that influence their intentions to remain in nursing. OBJECTIVES: The aim of this literature review was to gain a greater understanding of the experiences of GNs. REVIEW METHODS: It included thirty-six articles that focused on GNs and their transition to nursing, as part of a graduate nurse program (GNP), from 2005 to present. RESULT: The review identified three main themes that influence the transition from student to registered nurse. These themes included, 1) feeling stressed and overwhelmed by nursing responsibilities, 2) the amount of support from senior nurses and 3) the importance of feedback on their performance as nurses. CONCLUSIONS: Further research that is focused on the support and feedback provided to new nurses is needed. PMID- 27125144 TI - Factors influencing nurse participation in continuing professional development activities: Survey results from the Netherlands. AB - BACKGROUND: Professionals are individually responsible for planning and carrying out continuing professional development (CPD) activities, ensuring their relevance to current practice and career development. The key factors that encourage nurses to undertake CPD activities are not yet clear. Several studies have investigated motives of nurses to participate in CPD programmes ("Motives"), the importance they attach to CPD ("Importance"), the conditions they consider necessary for participation ("Conditions"), and their actual participation in CPD activities ("Pursued"). The relationships among these variables, however, have neither been investigated nor reported to date. OBJECTIVES: The aim of this study is to investigate the nature of the relationships among those factors that influence nurse participation in CPD in the Netherlands. DESIGN: An exploratory cross-sectional study was carried out using quantitative data collected with the previously validated Questionnaire Professional Development of Nurses (Q-PDN). SETTINGS AND PARTICIPANTS: A convenience sample of 5500 registered nurses working at one Dutch university hospital and several general hospitals was addressed. METHODS: A descriptive study using a survey was undertaken. The questionnaire was completed and returned by 1226 nurses. Correlation analyses were conducted to determine which factors were related to nurses undertaking CPD activities. Structural equation modelling was deployed to determine the relationships among the variables. RESULTS: "Conditions" was found to be moderately related to "Motives", which itself was strongly related to "Importance", which itself was very strongly related to "CPD activities pursued". If nurses considered a CPD activity important they were highly likely to pursue it; however, the importance attached to specific CPD activities was influenced by the presence of particular motives, which depended in part on the way CPD conditions were perceived. CONCLUSIONS: The key factor influencing CPD participation of nurses is how important they deem particular CPD activities; the latter is a function of their CPD motives and of their perceptions that the right conditions for participation are in place. Implications are discussed. PMID- 27125145 TI - A review of mentorship measurement tools. AB - OBJECTIVES: To review mentorship measurement tools in various fields to inform nursing educators on selection, application, and developing of mentoring instruments. DESIGN: A literature review informed by PRISMA 2009 guidelines. DATA SOURCES: Six databases: CINHAL, Medline, PsycINFO, Academic Search Premier, ERIC, Business premier resource. REVIEW METHODS: Search terms and strategies used: mentor* N3 (behav* or skill? or role? or activit? or function* or relation*) and (scale or tool or instrument or questionnaire or inventory). The time limiter was set from January 1985 to June 2015. Extracted data were content of instruments, samples, psychometrics, theoretical framework, and utility. An integrative review method was used. RESULTS: Twenty-eight papers linked to 22 scales were located, seven from business and industry, 11 from education, 3 from health science, and 1 focused on research mentoring. Mentorship measurement was pioneered by business with a universally accepted theoretical framework, i.e. career function and psychosocial function, and the trend of scale development is developing: from focusing on the positive side of mentorship shifting to negative mentoring experiences and challenges. Nursing educators mainly used instruments from business to assess mentorship among nursing teachers. In education and nursing, measurement has taken to a more specialised focus: researchers in different contexts have developed scales to measure different specific aspects of mentorship. Most tools show psychometric evidence of content homogeneity and construct validity but lack more comprehensive and advanced tests. CONCLUSION: Mentorship is widely used and conceptualised differently in different fields and is less mature in nursing than in business. Measurement of mentorship is heading to a more specialised and comprehensive process. Business and education provided measurement tools to nursing educators to assess mentorship among staff, but a robust instrument to measure nursing students' mentorship is needed. PMID- 27125146 TI - Planning and executing a global health experience for undergraduate nursing students: A comprehensive guide to creating global citizens. AB - The preparation of future baccalaureate-prepared nurses will require undergraduate students to have both cultural awareness and global or international health competencies in order to meet the increasingly complex health care needs of a diverse community. Additionally, the nursing accrediting bodies have identified global healthcare as an area of core knowledge for clinical nurses. In order to meet the workforce needs, and provide global education of the undergraduate student body, we designed an international clinical experience within the undergraduate Community/Population Health course. The purpose of this article is to provide a guide for faculty in the planning, infrastructure needs, and implementation of a global clinical experience for undergraduate nursing students, in the context of the United States with addressing university concerns for student safety and security while abroad. PMID- 27125147 TI - Interprofessional training enhances collaboration between nursing and medical students: A pilot study. AB - BACKGROUND: Effective collaboration among healthcare providers is an essential component of high-quality patient care. Interprofessional education is foundational to ensuring that students are prepared to engage in optimal collaboration once they enter clinical practice particularly in the care of complex geriatric patients undergoing surgery. STUDY DESIGN: To enhance interprofessional education between nursing students and medical students in a clinical environment, we modeled the desired behavior and skills needed for interprofessional preoperative geriatric assessment for students, then provided an opportunity for students to practice skills in nurse/physician pairs on standardized patients. This experience culminated with students performing skills independently in a clinic setting. RESULTS: Nine nursing students and six medical students completed the pilot project. At baseline and after the final clinic visit we administered a ten question geriatric assessment test. Post-test scores (M=90.33, SD=11.09) were significantly higher than pre-test scores (M=72.33, SD=12.66, t(14)=-4.50, p<0.001. Nursing student post-test scores improved a mean of 22.0 points and medical students a mean of 11.7 points over pre-test scores. Analysis of observational notes provided evidence of interprofessional education skills in the themes of shared problem solving, conflict resolution, recognition of patient needs, shared decision making, knowledge and development of one's professional role, communication, transfer of interprofessional learning, and identification of learning needs. CONCLUSIONS: Having nursing and medical students "learn about, from and with each other" while conducting a preoperative geriatric assessment offered a unique collaborative educational experience for students that better prepares them to integrate into interdisciplinary clinic teams. PMID- 27125148 TI - Experiences in the workplace community and the influence of community experiences on ENP courses for nursing professionals. AB - BACKGROUND: A nursing community can be described as a discourse community or a Community of Practice (CoP). No matter what type, a nursing community exerts influences on its group members' worldviews, perspectives and beliefs. OBJECTIVES: The purpose of this research is to explore what nurses' experiences of membership within the nursing community are and how such experiences influence nurses' views of English for nursing purposes (ENP) courses. DESIGN: A qualitative case study was conducted in a medical centre in Taiwan in which many foreign patients seek medical treatment and in which English is highly valued. PARTICIPANTS: Nine nurses who had at least three years working experience in relation to clinical practice participated in the study. METHODS: Semi-structured interviews and shadowing observations were the two primary methods of data collection. RESULTS: Five themes emerged: (1) building of the nurse-patient relationship, (2) provision of patient-centred care, (3) negative caring experiences, (4) professional identity, and (5) perspectives on ENP courses. CONCLUSIONS: Nurses' connection with the community led for them to a focus in their working lives. This determined their perceptions of ENP courses. PMID- 27125149 TI - Development and psychometric evaluation of the arterial puncture self-efficacy scale. AB - BACKGROUND: Arterial puncture for arterial blood gases (ABG) analysis can be a risky, painful, difficult-to-perform procedure that is often insufficiently practised and generates stress and discomfort amongst patients and healthcare professionals. Self-efficacy is a key component in the acquisition of procedural skills. Therefore, professionals' self-efficacy in arterial puncture should be measured before attempting the procedure on real patients. OBJECTIVE: To develop and psychometrically assess a self-efficacy scale in arterial puncture. DESIGN: An observational cross-sectional design was used in this study. SETTING: Faculty of Education Sciences, Nursing and Physiotherapy in a higher education institution in the south of Spain. PARTICIPANTS: A convenience sample of 342 nursing students entered and completed the study. All participants met the following inclusion criteria: (1) >=18years old and (2) enrolled in a nursing degree programme during the 2014/2015 academic year. Participants were 74% female (n=254) and their age ranged from 18 to 50, with a mean age of 21.74years (SD=5.14). METHOD: The Arterial Puncture Self-Efficacy Scale (APSES) was developed and psychometrically tested. Reliability and content validity were studied. Predictive validity and concurrent validity assessed criterion validity. In addition, principal component analysis and known-group analysis evaluated construct validity. RESULTS: Principal component analysis revealed the two subscale structure of the final 22-item version of the Arterial Puncture Self Efficacy Scale (APSES). A total Cronbach's alpha coefficient of 0.97 showed its high reliability. The APSES' content validity index was excellent (S CVI/Ave=0.95). Predictive and concurrent validity analysis demonstrated the good criterion validity of the tool. Supporting the APSES' sensitivity and specificity, known-groups analysis evidenced significant differences (p<0.001) in self-efficacy levels between groups. CONCLUSION: The APSES showed good psychometric properties for measuring self-efficacy in arterial puncture for ABG analysis. PMID- 27125150 TI - An exploration of the value of the role of the mentor and mentoring in midwifery. AB - This research project aimed to examine the perceived value sign-off mentors (SOMs) in midwifery have for their role. Using a phenomenological approach, the results were drawn from in-depth interviews. The project included a literature review, methodology, results and discussion. The results indicate that mentors enjoy their role and they see themselves as essentials to the delivery of pre registration midwifery programmes and for the supervision and assessment of student midwives. Mentors are not sure if student midwives value their sign-off mentor, or whether senior management is aware of the sign-off role and its value. This project also confirms previous findings from other studies, particularly the problem of finding time to complete student assessment paper work, support students in clinical practice and whether there are enough SOMs within clinical practice. The study does not conclude that the issues raised are distinctive to midwifery, potentially all of the points raised translate to the various forms of nursing practice. PMID- 27125151 TI - Sexuality, sexual health and older people: A systematic review of research on the knowledge and attitudes of health professionals. AB - OBJECTIVES: Sexuality remains important to older people and should be recognised as an important part of their overall care. However, this appears to be poorly understood and addressed by many healthcare professionals. This systematic review reports on knowledge and attitudes of health professionals towards sexuality and sexual health of older people, including factors that impact knowledge and perceptions. REVIEW METHODS AND DATA SOURCES: The review, conducted using Joanna Briggs Institute methods, included 23 studies of varied methodology published between January 2004 and January 2015. RESULTS: Findings indicated that healthcare professionals often consider older people's sexuality as outside their scope of practice and there is lack of knowledge and confidence in this area. Cultural norms and taboos, length of time spent working with older people, familiarity with the older person, previous training and degree of exposure to people who are not heterosexual were all identified as factors that impact knowledge and attitude. CONCLUSIONS: Better role modelling and education are needed to improve knowledge and attitudes toward later life sexuality. PMID- 27125152 TI - Development and validation of the simulation-based learning evaluation scale. AB - BACKGROUND: The instruments that evaluate a student's perception of receiving simulated training are English versions and have not been tested for reliability or validity. PURPOSE: The aim of this study was to develop and validate a Chinese version Simulation-Based Learning Evaluation Scale (SBLES). METHODS: Four stages were conducted to develop and validate the SBLES. First, specific desired competencies were identified according to the National League for Nursing and Taiwan Nursing Accreditation Council core competencies. Next, the initial item pool was comprised of 50 items related to simulation that were drawn from the literature of core competencies. Content validity was established by use of an expert panel. Finally, exploratory factor analysis and confirmatory factor analysis were conducted for construct validity, and Cronbach's coefficient alpha determined the scale's internal consistency reliability. Two hundred and fifty students who had experienced simulation-based learning were invited to participate in this study. RESULTS: Two hundred and twenty-five students completed and returned questionnaires (response rate=90%). Six items were deleted from the initial item pool and one was added after an expert panel review. Exploratory factor analysis with varimax rotation revealed 37 items remaining in five factors which accounted for 67% of the variance. The construct validity of SBLES was substantiated in a confirmatory factor analysis that revealed a good fit of the hypothesized factor structure. The findings tally with the criterion of convergent and discriminant validity. The range of internal consistency for five subscales was .90 to .93. Items were rated on a 5-point scale from 1 (strongly disagree) to 5 (strongly agree). CONCLUSIONS: The results of this study indicate that the SBLES is valid and reliable. The authors recommend that the scale could be applied in the nursing school to evaluate the effectiveness of simulation-based learning curricula. PMID- 27125153 TI - Teaching research methods in nursing using Aronson's Jigsaw Technique. A cross sectional survey of student satisfaction. AB - BACKGROUND: To adapt nursing studies to the European Higher Education Area, new teaching methods have been included that assign maximum importance to student centered learning and collaborative work. The Jigsaw Technique is based on collaborative learning and everyone in the group must play their part because each student's mark depends on the other students. Home group members are given the responsibility to become experts in a specific area of knowledge. Experts meet together to reach an agreement and improve skills. Finally, experts return to their home groups to share all their findings. OBJECTIVE: The aim of this study was to evaluate nursing student satisfaction with the Jigsaw Technique used in the context of a compulsory course in research methods for nursing. METHODS: A cross-sectional study was conducted using a self-administered anonymous questionnaire administered to students who completed the Research Methods course during the 2012-13 and 2013-14 academic years. The questionnaire was developed taking into account the learning objectives, competencies and skills that should be acquired by students, as described in the course syllabus. The responses were compared by age group (younger or older than 22years). RESULTS: A total of 89.6% of nursing students under 22years believed that this methodology helped them to develop teamwork, while this figure was 79.6% in older students. Nursing students also believed it helped them to work independently, with differences according to age, 79.7% and 58% respectively (p=0.010). Students disagreed with the statement "The Jigsaw Technique involves little workload", with percentages of 88.5% in the group under 22years and 80% in older students. Most believed that this method should not be employed in upcoming courses, although there were differences by age, with 44.3% of the younger group being against and 62% of the older group (p=0.037). CONCLUSION: The method was not highly valued by students, mainly by those older than 22years, who concluded that they did not learn more with it than with other traditional techniques. The results of this study question whether this form of learning meets students' learning needs and its compatibility with individual and group realities. PMID- 27125154 TI - From scientific discovery to health outcomes: A synergistic model of doctoral nursing education. AB - Across the globe, health system leaders and stakeholder are calling for system level reforms in education, research, and practice to accelerate the uptake and application of new knowledge in practice and to improve health care delivery and health outcomes. An evolving bi-dimensional research-practice focused model of doctoral nursing education in the U.S. is creating unprecedented opportunities for collaborative translational and investigative efforts for nurse researchers and practitioners. The nursing academy must commit to a shared goal of preparing future generations of nurse scientists and practitioners with the capacity and motivation to work together to accelerate the translation of evidence into practice in order to place nursing at the forefront of health system improvement efforts and advance the profession. PMID- 27125155 TI - Mentor experiences of international healthcare students' learning in a clinical environment: A systematic review. AB - BACKGROUND: Globalisation has brought new possibilities for international growth in education and professional mobility among healthcare professionals. There has been a noticeable increase of international degree programmes in non-English speaking countries in Europe, creating clinical learning challenges for healthcare students. OBJECTIVE: The aim of this systematic review was to describe mentors' experiences of international healthcare students' learning in a clinical environment. The objective of the review was to identify what influences the success or failure of mentoring international healthcare students when learning in the clinical environment, with the ultimate aim being to promote optimal mentoring practice. DESIGN: A systematic review was conducted according to the guidelines of the Centre for Reviews and Dissemination. DATA SOURCES: Seven electronic databases were used to search for the published results of previous research: CINAHL, Medline Ovid, Scopus, the Web of Science, Academic Search Premiere, Eric, and the Cochrane Library. REVIEW METHODS: Search inclusion criteria were planned in the PICOS review format by including peer-reviewed articles published in any language between 2000 and 2014. Five peer-reviewed articles remained after the screening process. The results of the original studies were analysed using a thematic synthesis. RESULTS: The results indicate that a positive intercultural mentor enhanced reciprocal learning by improving the experience of international healthcare students and reducing stress in the clinical environment. Integrating international healthcare students into work with domestic students was seen to be important for reciprocal learning and the avoidance of discrimination. CONCLUSION: Many healthcare students were found to share similar experiences of mentoring and learning irrespective of their cultural background. However, the role of a positive intercultural mentor was found to make a significant difference for international students: such mentors advocated and mediated cultural differences and created a welcoming environment for international students by helping to minimise feelings of social isolation. PMID- 27125156 TI - Registered nurses' clinical reasoning in home healthcare clinical practice: A think-aloud study with protocol analysis. AB - BACKGROUND: The home healthcare context can be unpredictable and complex, and requires registered nurses with a high level of clinical reasoning skills and professional autonomy. Thus, additional knowledge about registered nurses' clinical reasoning performance during patient home care is required. OBJECTIVES: The aim of this study is to describe the cognitive processes and thinking strategies used by recently graduated registered nurses while caring for patients in home healthcare clinical practice. DESIGN: An exploratory qualitative think aloud design with protocol analysis was used. SETTINGS: Home healthcare visits to patients with stroke, diabetes, and chronic obstructive pulmonary disease in seven healthcare districts in southern Norway. PARTICIPANTS: A purposeful sample of eight registered nurses with one year of experience. METHODS: Each nurse was interviewed using the concurrent think-aloud technique in three different patient home healthcare clinical practice visits. A total of 24 home healthcare visits occurred. Follow-up interviews were conducted with each participant. The think aloud sessions were transcribed and analysed using three-step protocol analysis. RESULTS: Recently graduated registered nurses focused on both general nursing concepts and concepts specific to the domains required and tasks provided in home healthcare services as well as for different patient groups. Additionally, participants used several assertion types, cognitive processes, and thinking strategies. CONCLUSIONS: Our results showed that recently graduated registered nurses used both simple and complex cognitive processes involving both inductive and deductive reasoning. However, their reasoning was more reactive than proactive. The results may contribute to nursing practice in terms of developing effective nursing education programmes. PMID- 27125158 TI - The effect of emotional freedom technique on stress and anxiety in nursing students: A pilot study. AB - BACKGROUND: Stress and anxiety have been identified as significant issues experienced by student nurses during their education. Some studies have suggested that the stress experienced by nursing students is greater than that experienced by medical students, other non-nursing healthcare students, degreed nurses, and the female population in general. A recently introduced energy type therapy, emotional freedom technique (EFT), has shown some success in reducing symptoms of anxiety, stress, and fear in a variety of settings. OBJECTIVE: The purpose of this study was to determine the efficacy of EFT in decreasing anxiety and stress as a potential intervention to assist students in stress management. DESIGN: The study used a mixed method design of both qualitative and quantitative measures. Quantitatively, in a one group pretest-posttest design, participants received group instruction in the technique and were encouraged to repeat it daily. Self reported anxiety was measured at baseline, and then weekly for four weeks using the Perceived Stress Scale (PSS) and the State-Trait Anxiety Inventory (STAI). The qualitative survey was completed by participants at the end of the study in order to capture a more subjective experience. SETTING: The pilot study was conducted in a two-year college in the southeastern region of the United States. PARTICIPANTS: All enrolled nursing students in an associate degree nursing program were invited to participate. Participation was voluntary, resulting in an original convenience sample of thirty-nine nursing students (N=39). METHODS: Data collection instruments included a demographic questionnaire, pretest State-Trait Anxiety Inventory (STAI) and Perceived Stress Scale (PSS). A qualitative questionnaire was also administered at the end of the four weeks. STAI and PSS were administered weekly. Data analysis using RMANOVA was performed at the second, third and the fourth week. RESULTS: Decreases in anxiety as measured on both the STAI and PSS were statistically significant (p=.05). For PSS, STAI state and trait data, the reduction in self-reported stress was statistically significant with a mean difference baseline to week 4. Qualitative data suggested that nursing students experienced a decrease in feelings of stress and anxiety including a decrease in somatic symptoms. CONCLUSIONS: Overall, findings suggested that EFT can be an effective tool for stress management and anxiety relief in nursing students. PMID- 27125157 TI - Bringing your a-game: Educational gaming for student success. AB - BACKGROUND: The purpose of this article is to describe the theoretical basis for the integration of gaming in nursing education and discuss aspects related to the implementation of "The Race for Nursing Student Success" game. METHODS: This game was designed for 112 junior-level baccalaureate nursing students enrolled in a fundamentals nursing course. Students were divided into groups of 5-8 and rotated through ten specific learning activities that took place in various locations throughout the nursing building. RESULTS: Student and faculty feedback indicated positive responses to this instructional strategy and also promoted a learner centered teaching environment. CONCLUSION: This learning activity supports the use of educational gaming as a means to develop learner-centered environments that provide experiential experiences, enhance learning, and stimulate interest, and motivation for students to learn. PMID- 27125159 TI - Predicting factors of positive orientation and attitudes towards nursing: A quantitative cross-sectional study. AB - BACKGROUND: Previous studies have identified various reasons for students to choose a career in nursing. Students at the start of their programme hold a great variety of images and perceptions of nursing which can affect their orientation and attitudes towards their future profession. OBJECTIVES: This paper aims to examine nursing students' orientation and attitudes towards nursing at the beginning of their educational programme, and to explore predictors of positive orientation and attitudes. DESIGN: The study used a quantitative cross-sectional design. SETTINGS: A survey was conducted among first-year nursing students at four nursing universities of applied sciences in the Netherlands. PARTICIPANTS: Questionnaires were administered to all students enrolled in a bachelor of nursing programme (n=1414) at these universities. METHODS: Respondents completed a survey consisting of: 1) Nursing Orientation Tool, 2) Nursing Attitude Questionnaire, and 3) demographic data such as gender, living status, nursing experience, preliminary training, first-choice programme, and career choice. Kruskal Wallis tests, with post hoc Mann Whitney U tests, were used to compare group scores. Multiple regression was performed to investigate predictors of positive orientation and attitudes towards nursing. RESULTS: Students in this study sample (n=1244) strongly agreed with statements related to caring, nursing expertise, professional nursing knowledge and the application of this knowledge. Predictors of positive orientation and attitudes towards nursing include having nursing/caring experience, indicating nursing as the first choice for study, preliminary vocational training, and a desire to make a career in nursing. CONCLUSIONS: Data from this survey suggest a link between personal and environmental characteristics and motivations to select nursing as a career. Understanding which factors predict positive orientation and attitudes towards nursing could offer educators a tool in the recruitment and selection assessment of new students. PMID- 27125160 TI - Pedagogical principles underpinning undergraduate Nurse Education in the UK: A review. AB - BACKGROUND: This review provides a contextual report of the current use of pedagogy in undergraduate nursing programmes run by Higher Education Institutes (HEIs) in the United Kingdom (UK). Pedagogy provides the framework for educators to add shape and structure to the educational process, and to support student learning and programme development. Traditionally nurse education has used a behaviourist approach focusing on learning outcomes and competency based education, although there is also increasing support for the cognitive/student learning focused pedagogic approach. DESIGN: The keywords andragogy, pedagogy and student centred learning were used in a systematic stepwise descriptive content analysis of the programme specifications and programme handbooks of 40 current undergraduate programme documents, leading to an undergraduate award and professional registration as a nurse. RESULTS: 42% (17) of documents contained reference to the words, pedagogy and student centred learning, whilst no documents used the word andragogy. Where identified, pedagogy was used in a superficial manner, with only three documents identifying a specific pedagogical philosophy: one HEI citing a value based curriculum and two HEIs referencing social constructionism. Nine HEIs made reference to student centred learning but with no additional pedagogic information. A review of teaching, learning and assessment strategies indicated no difference between the documented strategies used by HEIs when comparing those with an espoused pedagogy and those without. CONCLUSION: Although educational literature supports the use of pedagogic principles in curriculum design, this is not explicit in undergraduate nursing programme documentation, and suggests that nurse educators do not view pedagogy as important to their programmes. Instead programmes appear to be developed based on operational and functional requirements with a focus on acquisition of knowledge and skills, and the fitness to practice of graduates entering the nursing workforce. PMID- 27125161 TI - Student nurse selection and predictability of academic success: The Multiple Mini Interview project. AB - BACKGROUND: With recent reports of public enquiries into failure to care, universities are under pressure to ensure that candidates selected for undergraduate nursing programmes demonstrate academic potential as well as characteristics and values such as compassion, empathy and integrity. The Multiple Mini Interview (MMI) was used in one university as a way of ensuring that candidates had the appropriate numeracy and literacy skills as well as a range of communication, empathy, decision-making and problem-solving skills as well as ethical insights and integrity, initiative and team-work. OBJECTIVES: To ascertain whether there is evidence of bias in MMIs (gender, age, nationality and location of secondary education) and to determine the extent to which the MMI is predictive of academic success in nursing. DESIGN: A longitudinal retrospective analysis of student demographics, MMI data and the assessment marks for years 1, 2 and 3. SETTINGS: One university in southwest London. PARTICIPANTS: One cohort of students who commenced their programme in September 2011, including students in all four fields of nursing (adult, child, mental health and learning disability). METHODS: Inferential statistics and a Bayesian Multilevel Model. RESULTS: MMI in conjunction with MMI numeracy test and MMI literacy test shows little or no bias in terms of ages, gender, nationality or location of secondary school education. Although MMI in conjunction with numeracy and literacy testing is predictive of academic success, it is only weakly predictive. CONCLUSIONS: The MMI used in conjunction with literacy and numeracy testing appears to be a successful technique for selecting candidates for nursing. However, other selection methods such as psychological profiling or testing of emotional intelligence may add to the extent to which selection methods are predictive of academic success on nursing. PMID- 27125162 TI - Distraction by smartphone use during clinical practice and opinions about smartphone restriction policies: A cross-sectional descriptive study of nursing students. AB - BACKGROUND: Smartphone use in healthcare settings may distract healthcare providers and disrupt patient care. Moreover, it may lead to adverse events, thereby threatening patient safety. OBJECTIVES: This study assessed nursing students' smartphone use as a source of distraction in clinical practice and identified their opinions about policies restricting smartphone use during patient care. DESIGN: A cross-sectional descriptive design was used with convenience sampling. PARTICIPANTS: Third-year nursing students (n=312) from two nursing schools in the Republic of Korea completed the survey in 2012. METHODS: A self-report questionnaire-based on addiction theories for problem behaviors and literature on the distraction caused by cellular phone use-was used to assess smartphone use, experiences of distraction caused by smartphone use, and opinions about restriction policies on smartphone use during clinical practice. RESULTS: Nearly half (46.2%) of the nursing students used smartphones at least sometimes during clinical practice and about a quarter of the respondents (24.7%) were at least sometimes distracted by smartphones during clinical practice. The majority of the respondents (83.7%) had witnessed nurses using smartphones at least sometimes during their work. A few respondents (15.7%) agreed or strongly agreed with the policy for restricting smartphone use in hospitals. Students who used smartphones more often tended to disagree with restriction policies for smartphone use in hospitals. CONCLUSION: Awareness about the risks of smartphone use, especially regarding patient safety, is necessary for nursing students in school and hospital settings. Educators and faculty of nursing schools need to develop policies that encourage intelligent and safe use of smartphones during clinical practice. PMID- 27125163 TI - Nursing students' knowledge and attitudes toward urinary incontinence: A cross sectional survey. AB - BACKGROUND: Nurses must have adequate knowledge to manage the complexities of urinary incontinence. Nursing students are the nurses of the future, yet little is known about urinary incontinence education in undergraduate nursing programs. OBJECTIVES: The aim of this study was (a) to assess the knowledge and attitudes of urinary incontinence held by undergraduate nursing students in China and (b) to explore the relationship between knowledge, attitudes and socio-demographic characteristics. DESIGN: A cross-sectional survey using cluster random sampling. SETTINGS: Undergraduate departments of Nursing within the Faculty of Health Sciences at six Universities, located in different areas of China. PARTICIPANTS: A random selection of 6 faculties with a total of 1313 full time undergraduate nursing students completed the survey. METHODS: Self-reported data were collected using two validated questionnaires, the Urinary Incontinence Knowledge Scale and the Urinary Incontinence Attitude Scale, to access students' knowledge and attitudes toward urinary incontinence. RESULTS: Overall urinary incontinence knowledge was poor (49.9%, 15.0/30) and attitudes about urinary incontinence were generally positive (71.7%, 43.0/60). A high level of interest in learning more about urinary incontinence was found. There was a weak correlation between urinary incontinence knowledge and attitudes (r=0.135, p<0.01). There was also a significant positive correlation between urinary incontinence knowledge and attitudes and nursing students' year of study, urinary incontinence education and training, and formal clinical practicum experience in urology (p<0.05). CONCLUSIONS: Chinese nursing students showed poor urinary incontinence knowledge but generally positive attitudes toward urinary incontinence. This study suggests there is a need to examine urinary incontinence content throughout undergraduate nursing curricula in China. PMID- 27125164 TI - Factors hindering clinical training of students in selected nursing educational institutions in Southeastern Nigeria. AB - BACKGROUND/AIM: Clinical training is an integral part of professional nursing education as it equips students with the required knowledge, skills, attitudes, and values needed for optimal practice in real-life situations. Inappropriate professional attributes have been observed among nursing graduates, while challenges to acquisition of clinical skills have been understudied in Nigeria. PURPOSE: This study investigated system factors related to the provision of infrastructure/equipment, training/supervisory activities, and students' factors that may hinder clinical training of nursing students in two selected institutions in Southeastern Nigeria. METHODS: This cross-sectional descriptive study purposively enlisted 283 students from a diploma and a degree nursing education program. Data were collected with researchers' developed questionnaire and analyzed in percentages, and means, with a mean decision criterion of <3.0 for identifying significant hindering factors. T-test was used for inferential statistics at p<0.05 level of significance. RESULTS: Major hindering factors identified include: non participation of teachers in students' clinical supervision; non-completion of relevant level classroom instructions and practical demonstrations before each clinical experience, inadequate equipment to practice in the clinical areas, with no preceptors to coach them at each shift (mean scores <3.0). Significant differences (p-value<0.05) exist in the deficiencies identified between the institutions. While the degree program students had significantly less opportunity for return demonstration under supervision and independent practice in the laboratory; the diploma program students had significantly fewer teachers in their school and patients in their clinical area, clinical nurses as role models were not following the standard procedures in practice and students were not evaluated by supervisors at the end of each clinical experience. CONCLUSION: Identified factors in these training environments could hinder learners' interest and acquisition of professional attributes. Rectifying these situations could enhance the acquisition and display of appropriate professional performance behavior in practice by nursing graduates. PMID- 27125165 TI - Increasing nursing students' understanding and accuracy with medical dose calculations: A collaborative approach. AB - BACKGROUND: Accurate calculation of medication dosages can be challenging for nursing students. Specific interventions related to types of errors made by nursing students may improve the learning of this important skill. OBJECTIVE: The objective of this study was to determine areas of challenge for students in performing medication dosage calculations in order to design interventions to improve this skill. DESIGN: Strengths and weaknesses in the teaching and learning of medication dosage calculations were assessed. These data were used to create online interventions which were then measured for the impact on student ability to perform medication dosage calculations. SETTING: The setting of the study is one university in Canada. PARTICIPANTS: The qualitative research participants were 8 nursing students from years 1-3 and 8 faculty members. Quantitative results are based on test data from the same second year clinical course during the academic years 2012 and 2013. METHODS: Students and faculty participated in one-to-one interviews; responses were recorded and coded for themes. Tests were implemented and scored, then data were assessed to classify the types and number of errors. RESULTS: Students identified conceptual understanding deficits, anxiety, low self-efficacy, and numeracy skills as primary challenges in medication dosage calculations. Faculty identified long division as a particular content challenge, and a lack of online resources for students to practice calculations. Lessons and online resources designed as an intervention to target mathematical and concepts and skills led to improved results and increases in overall pass rates for second year students for medication dosage calculation tests. CONCLUSION: This study suggests that with concerted effort and a multi modal approach to supporting nursing students, their abilities to calculate dosages can be improved. The positive results in this study also point to the promise of cross-discipline collaborations between nursing and education. PMID- 27125166 TI - Professional commitment and attributional style of medical-college nursing students in China: A cross-sectional study. AB - BACKGROUND: The persistent shortage of nurses has become a common phenomenon around the world. Nursing students' professional commitment affects their decision to choose nursing as a professional career. However, there is little knowledge about the professional commitment of nursing students, especially its relationship with attributional style. OBJECTIVES: To explore the professional commitment of nursing students and to identify the role of attributional style on nursing students' professional commitment. DESIGN: Cross-sectional study design. SETTINGS AND PARTICIPANTS: This study was conducted at three different medical colleges in Jinan, Shandong Province, China and included 1230 nursing students. A total of 1223 valid questionnaires were returned, yielding a response rate of 99%. METHODS: The Professional Commitment Scale and the Multidimensional Multiattributional Causality Scale (MMCS) were used to investigate nursing students' professional commitment and attributional style. Basic demographic information about the nursing students was collected. Stepwise regression analysis was used to analyze the data. RESULTS: The mean scores on the Professional Commitment Scale were 3.54+/-5.29 (mean+/-SD). Professional commitment of first year students was higher than that of second year students. Their residence affected their affective commitment, ideal commitment, and continuance commitment which were the sub-dimensions of professional commitment. Effort and ability attribution positively influenced professional commitment; however, context attribution negatively influenced it. CONCLUSIONS: It is imperative to take effective measures to improve nursing students' professional commitment. Our findings indicated that attributional style had a significant effect on professional commitment; thus, effort and ability attribution need to be emphasized. PMID- 27125167 TI - An exploration of the structure of mentors' behavior in nursing education using exploratory factor analysis and Mokken scale analysis. AB - BACKGROUND: To understand nursing students' expectation from their mentors and assess mentors' performance, a scale of mentors' behavior was developed based on literature review and focus group in China. OBJECTIVES: This study aims to explore the structure of mentors' behavior. DESIGN: A cross-sectional survey. SETTING: Data were collected from nursing students in three hospitals in southwest China in 2014. PARTICIPANT: A total of 669 pre-registered nursing students in their final year clinical learning participated in this study. METHODS: Exploratory factor analysis and Mokken scale analysis was employed to explore the structure and hierarchical property of mentors' behavior. RESULTS: Three dimensions (professional development, facilitating learning and psychosocial support) were identified by factor analysis and confirmed by Mokken scaling analysis. The three sub-scales showed internal consistency reliability from 87% to 91%, and moderate to strong precision in ordering students' expectation about mentors' behavior and a small Mokken scale showing hierarchy was identified. CONCLUSION: Some insight into the structure of mentoring in nursing education has been obtained and a scale which could be used in the study of mentoring and in the preparation of mentors has been developed. PMID- 27125168 TI - Factors influencing preventive behavior against Middle East Respiratory Syndrome Coronavirus among nursing students in South Korea. AB - BACKGROUND: Middle East Respiratory Syndrome Coronavirus (MERS-CoV), an emerging infectious disease introduced in South Korea in 2015, spreads quickly through hospitals, and Korea became one of the major areas affected by the disease after the Middle East region. To stop the spread of an emerging disease, it is important to practice prevention guidelines correctly. OBJECTIVES: The purpose of this study was to investigate factors influencing preventive behavior against MERS-CoV among Korean nursing students. METHODS: This is a cross-sectional study using a questionnaire survey. Data were collected from 429 nursing students from three colleges of nursing in Korea from June 25 to July 3 in 2015. RESULTS: Preventive behavior against MERS-CoV was affected mostly by attitude (beta=.243, p<.001). Such behavior was also high in relation to the variables of perceived risk (beta=.232, p<.001), older students (beta=.202, p<.001), knowledge level (beta=.153, p<.01), and female respondents (beta=.115, p<.05). CONCLUSION: Preventive behavior against emerging infectious diseases such as MERS-CoV was found to be affected most significantly by attitude and risk perception. It is crucial to provide nursing students with information or knowledge, but it is also important to help those in nursing education recognize that active preventive behavior can prevent this infectious disease and stop its spread. PMID- 27125169 TI - Global and public health core competencies for nursing education: A systematic review of essential competencies. AB - OBJECTIVES: Nurses are learning and practicing in an increasingly global world. Both nursing schools and nursing students are seeking guidance as they integrate global health into their learning and teaching. This systematic review is intended to identify the most common global and public health core competencies found in the literature and better inform schools of nursing wishing to include global health content in their curricula. DESIGN: Systematic review. DATA SOURCES: An online search of CINAHL and Medline databases, as well as, inclusion of pertinent gray literature was conducted for articles published before 2013. REVIEW METHODS: Relevant literature for global health (GH) and public and community health (PH/CH) competencies was reviewed to determine recommendations of both competencies using a combination of search terms. Studies must have addressed competencies as defined in the literature and must have been pertinent to GH or PH/CH. The databases were systematically searched and after reading the full content of the included studies, key concepts were extracted and synthesized. RESULTS AND CONCLUSION: Twenty-five studies were identified and resulted in a list of 14 global health core competencies. These competencies are applicable to a variety of health disciplines, but particularly can inform the efforts of nursing schools to integrate global health concepts into their curricula. PMID- 27125171 TI - Exploration of mindfulness in relation to compassion, empathy and reflection within nursing education. AB - BACKGROUND: This article will look at the viability of the inclusion of mindfulness into the nursing curriculum. In nursing, the environment rarely allows the time for contemplation, though reflection is encouraged specifically in regard to the care we confer on our patients and how that impacts on us professionally. Student nurses are taught to hide their feelings to a point where they cannot find it themselves under their professional armour. Mindfulness is a possible way of bridging this gap. DISCUSSION: Our nursing code is geared to safeguard the patient from any harm as well as our colleagues but little is done or said in support of our own personal psychological or emotional health. The helping professions are restricted by legislation which has had an impact of fostering caution and fearfulness. In using mindfulness it can be seen as a possibility in building a bridge between what actually happens in a nurse's professional life and the possibility of reengaging with that internal emotional space. If student nurses begin to incorporate mindfulness techniques, in reality this should make a difference. This was experienced with students doing these exercises, who reported anecdotally feeling more centred. As they have progressed in the course feedback from the students using the techniques has been positive not only for the students but also for them using the skills in a clinical setting, benefiting patients. CONCLUSION: Mindfulness has been used as a part of the modality of health care. It is clear that mindfulness is another way of dealing with the stressors of the modern heath service in which the students are being introduced. Incorporating this coping strategy into the curriculum ensures that students will have the tools to deal with the stressors of the course, which in turn will enhance the student experience. PMID- 27125170 TI - Family involvement in medical decision-making: Perceptions of nursing and psychology students. AB - BACKGROUND: Family members often rely on health care professionals to guide and support them through the decision-making process. Although family involvement in medical decisions should be included in the preservice curriculum for the health care professions, perceptions of students in caring professions on family involvement in medical decision-making have not yet been examined. OBJECTIVE: To examine the perceptions of nursing and psychology students on family involvement in medical decision-making for seriously ill patients. DESIGN: A descriptive cross-sectional design was used. SETTING AND PARTICIPANTS: First year undergraduate nursing and psychology students studying for their Bachelor of Arts degree were recruited. METHODS: Perceptions were assessed with a questionnaire constructed based on the Multi-Attribute Utility Theory (MAUT), which examines decision-maker preferences. The questionnaire consisted of two parts referring to the respondent once as the patient and then as the family caregiver. RESULTS: Questionnaires were completed by 116 nursing students and 156 psychology students. Most were of the opinion that family involvement in decision-making is appropriate, especially when the patient is incapable of making decisions. Nursing students were more inclined than psychology students to think that financial, emotional, and value-based considerations should be part of the family's involvement in decision-making. Both groups of students perceived the emotional consideration as most acceptable, whereas the financial consideration was considered the least acceptable. CONCLUSIONS: Nursing and psychology students perceive family involvement in medical decision-making as appropriate. In order to train students to support families in the process of decision-making, further research should examine Shared Decision-Making (SDM) programs, which involve patient and clinician collaboration in health care decisions. PMID- 27125172 TI - Effect of e-learning program on risk assessment and pressure ulcer classification - A randomized study. AB - BACKGROUND: Pressure ulcers (PUs) are a problem in health care. Staff competency is paramount to PU prevention. Education is essential to increase skills in pressure ulcer classification and risk assessment. Currently, no pressure ulcer learning programs are available in Norwegian. OBJECTIVES: Develop and test an e learning program for assessment of pressure ulcer risk and pressure ulcer classification. METHODS: DESIGN, PARTICIPANTS AND SETTING: Forty-four nurses working in acute care hospital wards or nursing homes participated and were assigned randomly into two groups: an e-learning program group (intervention) and a traditional classroom lecture group (control). Data was collected immediately before and after training, and again after three months. The study was conducted at one nursing home and two hospitals between May and December 2012. ANALYSIS: Accuracy of risk assessment (five patient cases) and pressure ulcer classification (40 photos [normal skin, pressure ulcer categories I-IV] split in two sets) were measured by comparing nurse evaluations in each of the two groups to a pre-established standard based on ratings by experts in pressure ulcer classification and risk assessment. Inter-rater reliability was measured by exact percent agreement and multi-rater Fleiss kappa. A Mann-Whitney U test was used for continuous sum score variables. RESULTS: An e-learning program did not improve Braden subscale scoring. For pressure ulcer classification, however, the intervention group scored significantly higher than the control group on several of the categories in post-test immediately after training. However, after three months there were no significant differences in classification skills between the groups. CONCLUSION: An e-learning program appears to have a greater effect on the accuracy of pressure ulcer classification than classroom teaching in the short term. For proficiency in Braden scoring, no significant effect of educational methods on learning results was detected. PMID- 27125173 TI - Online intravenous pump emulator: As effective as face-to-face simulation for training nursing students. AB - BACKGROUND: The expansion of online education for nursing students has created the challenge of finding innovative ways to teach clinical skills. An online intravenous pump emulator (IVPE) modelled on actual IV pumps used in clinical healthcare settings was developed to facilitate online education delivery. OBJECTIVES: The objectives of the study were to implement the online IVPE and evaluate student learning outcomes and perceptions of device use. DESIGN: A mixed method, quasi-experimental design was used. SETTING: The study was conducted in the School of Nursing and Midwifery at a regional university in Queensland, Australia. PARTICIPANTS: Participants were 179 first year nursing students enrolled in a medications course, ranging in age from 18 to 44years, of whom 150 were female. METHODS: Participants were assigned to one of three groups and trained in the use of IV infusion pumps. Group 1 (n=57) were trained online using the IVPE (ONL); Group 2 (n=73) were trained on-campus using an actual IV pump (ONC); Group 3 (n=49) were trained both on-campus using the actual IV pump and online using the IVPE (ONL+ONC). Competence in using the actual IV pump was assessed for all participants at the conclusion of the training period. RESULTS: No significant differences in learning outcomes, measured by assessment scores out of 80 points, were found between the ONL (M=65.5+/-9.2) and ONC (M=62.0+/ 14.8; p>.05) groups. Significantly better learning outcomes were evident for the ONL+ONC group (M=68.7+/-4.9) compared to the ONC group (p<.01). CONCLUSIONS: This study highlights that the nursing students became more competent in the skill of preparing and administrating IV infusions when face-to-face and online learning were combined. PMID- 27125174 TI - Recruitment, advising, and retention programs - Challenges and solutions to the international problem of poor nursing student retention: A narrative literature review. AB - OBJECTIVES: The aim of this literature review was to identify emerging themes in current research to identify challenges to nursing student retention internationally, as well as strategies to improve persistence. DESIGN: A narrative literature review was conducted. DATA SOURCES: Using CINAHL and HealthSource databases, journal articles were reviewed and evaluated for emerging themes related to the causes of high nursing student attrition rates and strategies to overcome this issue. REVIEW METHODS: A five-step approach was used to complete the narrative review, beginning with problem identification, followed by the literature search, data analysis, theme emergence and synthesis of the information. RESULTS: The literature review supports the idea that poor retention is related not only to student ability, but also to a lack of necessary intervention by faculty beginning with the admission process and continuing throughout the curriculum. Alterations should be made in the recruitment and student selection process. Aggressive academic advising strategies should be implemented, and retention programs should be interwoven in to the nursing curriculum. CONCLUSION: Student retention is a multifaceted issue that requires a multi-modal approach. Changes in recruitment, implementation of academic advising, and curriculum integration have the potential to help correct the problem. PMID- 27125175 TI - Efficacy of teaching methods used to develop critical thinking in nursing and midwifery undergraduate students: A systematic review of the literature. AB - BACKGROUND: The value and importance of incorporating strategies that promote critical thinking in nursing and midwifery undergraduate programmes are well documented. However, relatively little is known about the effectiveness of teaching strategies in promoting CT. Evaluating effectiveness is important to promote 'best practise' in teaching. OBJECTIVE: To evaluate the efficacy of teaching methods used to develop critical thinking skills in nursing and midwifery undergraduate students. DATA SOURCES: The following six databases; CINAHL, Ovid Medline, ERIC, Informit, PsycINFO and Scopus were searched and resulted in the retrieval of 1315 papers. REVIEW METHODS: After screening for inclusion, each paper was evaluated using the Critical Appraisal Skills Programme tool. Twenty-eight studies met the inclusion criteria and quality appraisal. RESULTS: Twelve different teaching interventions were tested in 8 countries. Results varied, with little consistency across studies using the same type of intervention or outcome tool. Sixteen tools were used to measure the efficacy of teaching in developing critical thinking. Seventeen studies identified a significant increase in critical thinking, while nine studies found no increases, and two found unexplained decreases in CT when using a similar educational intervention. CONCLUSIONS: Whilst this review aimed to identify effective teaching strategies that promote and develop critical thinking, flaws in methodology and outcome measures contributed to inconsistent findings. The continued use of generalised CT tools is unlikely to help identify appropriate teaching methods that will improve CT abilities of midwifery and nursing students and prepare them for practise. The review was limited to empirical studies published in English that used measures of critical thinking with midwifery and nursing students. Discipline specific strategies and tools that measure students' abilities to apply CT in practise are needed. PMID- 27125176 TI - Nursing students' perceptions of learning after high fidelity simulation: Effects of a Three-step Post-simulation Reflection Model. AB - BACKGROUND: High-fidelity simulation (HFS) has become a bridge between theoretical knowledge and practical skills. A safe and realistic environment is commonly used in nursing education to improve cognitive, affective and psychomotor abilities. Debriefing following a simulation experience provides opportunities for students to analyze and begin to reflect upon their decisions, actions and results. The nursing literature highlights the need to promote the concept of reflective practice and to assist students in reflection, and research indicates the need to refine and develop debriefing strategies, which is the focus of the current paper. PURPOSE: To explore the value of reflections after HFS by investigating nursing students' perceptions of their learning when a Three step Post-simulation Reflection Model is used. DESIGN: A qualitative descriptive research approach was applied. METHOD: A Three-step Post-simulation Reflection Model that combined written and verbal reflections was used after an HFS experience in a second-year course in the Bachelor Program in Nursing at Lulea University of Technology, Sweden. Reflective texts written before and after a verbal group reflection were subjected to qualitative content analysis. FINDINGS: The main theme in the first written reflections was identified as "Starting to act as a nurse", with the following categories: feeling stressed, inadequate and inexperienced; developing an awareness of the importance of never compromising patient safety; planning the work and prioritizing; and beginning to understand and implement nursing knowledge. The main theme in the second written reflections was identified to be "Maturing in the profession", with the following categories: appreciating colleagues, good communication and thoughtfulness; gaining increased self-awareness and confidence; and beginning to understand the profession. CONCLUSION: The Three-step Post-simulation Reflection Model fostered an appreciation of clear and effective communication. Having time for thoughtfulness and reflection promotes self-awareness and a better understanding of both the nursing profession and patient safety. The progress demonstrated in the depth of the themes in the written reflections indicates that repeated reflections stimulate and enhance student learning. The findings point towards the potential effectiveness of alternate methods of reflections. PMID- 27125177 TI - Minimizing cows' stress when calves were early weaned using the two-step method with nose flaps. AB - Early weaning may be used in beef cattle production to improve reproduction rates in range conditions. However, weaning causes a stress response in cows, which may be especially strong in early weaning management, as the bond between the cow and the calf is still strong. We hypothesized that weaning calves in two steps, with the aid of anti-sucking devices (nose flaps) would reduce the behavioural stress response in the cows separated from their calves 2 months after parturition. We compared the behaviour frequency and weight change in cows that were weaned abruptly, by separation of the calf on day 0 of the study, or in two steps, consisting of the use of anti-sucking nose flaps for 5 days before permanent separation; a third group was not weaned to serve as control. Thirty-six crossbred multiparous Aberdeen Angus*Hereford cows and their calves (n=12/treatment) were managed in three paddocks with similar pasture availability, with four dyads from each treatment per paddock. Cows' behaviour was observed by direct visual instantaneous sampling, at 10 min intervals from days -3 to 11. Weaning the calves in two steps clearly attenuated the behavioural stress response observed in abruptly weaned cows, which included reductions in grazing and lying, and increases in pacing, walking and vocalizing. Our results corroborate those previously shown for cows nursing older calves, and indicate that step weaning can reduce the behavioural stress response of cows at weaning, even when the calf is weaned shortly after birth, when the bond between the cow and calf is still very strong. PMID- 27125178 TI - Application of biodegradable dendrigraft poly-l-lysine to a small interfering RNA delivery system. AB - Dendrigraft poly-l-lysine (DGL), including its central core, consists entirely of lysine, hence it is completely biodegradable. We applied DGL in a small interfering RNA (siRNA) delivery system. Binary complexes with siRNA and DGL had particle sizes of 23-73 nm and zeta-potentials of 34-42 mV. The siRNA-DGL complexes showed significant silencing effects in a mouse colon carcinoma cell line expressing luciferase (Colon26/Luc cells). The siRNA-DGL complexes induced slight cytotoxicity and hematological toxicity at a high charge ratio of DGL to siRNA, probably because of their cationic charges. Therefore, we recharged the siRNA-DGL complexes with gamma-polyglutamic acid (gamma-PGA), a biodegradable anionic compound, which was reported to reduce the cytotoxicity of cationic complexes. The ternary complexes showed particle sizes of 35-47 nm at a charge ratio of greater than 14 to siRNA with negative charges. Strong silencing effects of the ternary complexes were observed in Colon26/Luc cells without cytotoxicity or hematological toxicity. The cellular uptake and degradation of the binary and ternary complexes were confirmed by fluorescence microscopy. The ternary complexes suppressed luciferase activity in the tumor after direct injection into the tumors of mice bearing Colon26/Luc cells. Thus, a potentially important siRNA delivery system was constructed using biodegradable DGL. PMID- 27125179 TI - Knockdown of zebrafish Nanog increases primordial germ cells during early embryonic development. AB - Nanog is a homeodomain transcription factor that plays a prominent role in maintaining the pluripotency and self-renewal capacity of embryonic stem cells (ESCs) in mammals. Medaka Nanog is necessary for S-phase transition and proliferation during embryonic development. However, whether Nanog regulates the proliferation of primordial germ cells (PGCs) during embryonic development has not yet been investigated. In this study, we identified the homologue of the mammalian Nanog gene in zebrafish (zNanog). The expression of both zNanog mRNA and protein was demonstrated in the spermatogonia (male germ stem cells) of the testis and the early oocytes of the ovary. During the embryonic development, zNanog mRNA is expressed in the cytoplasm of PGCs, and its protein is localized to the PGC nuclei. We also found that zNanog depletion using morpholinos resulted in the increases and aberrant localization of PGCs in the zebrafish embryos from the sphere stage to the 50% epiboly stage. These data indicated that zNanog inhibits the PGCs proliferation in early embryonic development of zebrafish. PMID- 27125180 TI - Corrigendum: Discovery of a Novel Seminal Fluid Microbiome and Influence of Estrogen Receptor Alpha Genetic Status. PMID- 27125181 TI - Pregnancy after aortic root replacement in Loeys-Dietz syndrome: High risk of aortic dissection. AB - Loeys-Dietz syndrome due to mutations in TGFBR1 and 2 is associated with early and aggressive aortic aneurysm and branch vessel disease. There are reports of uncomplicated pregnancy in this condition, but there is an increased risk of aortic dissection and uterine rupture. Women with underlying aortic root aneurysm are cautioned about the risk of pregnancy-related aortic dissection. Prophylactic aortic root replacement is recommended in women with aortopathy and aortic root dilatation to lessen the risk of pregnancy. There is limited information in the literature about the outcomes of pregnancy after root replacement in Loeys-Dietz syndrome. We present a case series of three women with Loeys-Dietz syndrome who underwent elective aortic root replacement for aneurysm disease and subsequently became pregnant and underwent Cesarean section delivery. Each of these women were treated with beta blockers throughout pregnancy. Surveillance echocardiograms and noncontrast MRA studies during pregnancy remained stable demonstrating no evidence for aortic enlargement. Despite the normal aortic imaging and careful observation, two of the three women suffered acute aortic dissection in the postpartum period. These cases highlight the high risk of pregnancy following aortic root replacement in Loeys-Dietz syndrome. Women with this disorder are recommended to be counseled accordingly. (c) 2016 Wiley Periodicals, Inc. PMID- 27125182 TI - Emerging Concepts in Glaucoma and Review of the Literature. AB - Glaucoma is the most commonly acquired optic neuropathy. It represents a public health challenge because it causes an irreversible blindness. Emerging evidence indicates that the pathogenesis of glaucoma depends on several interacting pathogenetic mechanisms, which include mechanical effects by an increased intraocular pressure, decreased neutrophine-supply, hypoxia, excitotoxicity, oxidative stress, and the involvement of autoimmune processes. In particular, alterations in serum antibody profiles have been described. However, it is still unclear whether the autoantibodies seen in glaucoma are an epiphenomenon or causative. Oxidative stress appears to be a critical factor in the neurodestructive consequences of mitochondrial dysfunction, glial activation response, and uncontrolled activity of the immune system during glaucomatous neurodegeneration. In addition, hearing loss has been identified in association with glaucoma. A higher prevalence of antiphosphatidylserine antibodies of the immunoglobulin G class was seen in normal-tension glaucoma patients with hearing loss in comparison with normal-tension glaucoma patients with normacusis. This finding suggests a similar pathological pathway as a sign for generalized disease. PMID- 27125183 TI - Challenges in assessment of the mild traumatic brain injured geriatric patient. PMID- 27125184 TI - Treatment of metastatic lesions localized in the acetabulum. AB - BACKGROUND: Metastatic lesions localized in the periacetabular area cause troublesome pain and reduced mobility of the patients. Radiotherapy effectively decreases pain, yet it does not restore the ability to load the joint. Surgical treatment involving resection of metastatic lesions and joint reconstruction using bone grafts is burdened with a high rate of complications. Modular tumor prostheses are being increasingly used. In some cases, it is possible to strengthen the acetabular roof with bone cement using vertebroplasty kits. The aim of the study was to demonstrate various methods of treatment of metastatic lesions localized in the periacetabular area together with the analysis of their results and effectiveness. METHODS: Between 2010 and 2015, 27 patients with cancer metastases to the acetabulum were treated at our department. Qualification for surgical treatment was multifaceted with numerous aspects being considered. They included patients' general condition, type of neoplasm, clinical stage, and prognosis. CT and MRI scans of the pelvis were performed in each case. Before the surgery and 3 months following the surgery, visual analogue scale (VAS) pain intensity, Karnofsky functional status, and motor ability according to the Harris scale were evaluated. Bone cement (PMMA)-augmentation was performed in 21 patients, of whom nine had cement injected precutaneously and 12 at proximal femur resection alloplasty. Hemipelvectomy Type II combined with implantation of LUMiC resection prosthesis of the acetabulum were performed in six cases. RESULTS: The quality of life improved in all the patients. After percutaneous cement injection, the mean pain intensity VAS score was 2.7, and the mean Karnofsky functional status score was 71.8. The mean postoperative Harris hip score (HHS) was 94 points. The patients who had undergone resection alloplasty on the proximal femur combined with periacetabular cement injection were walking using one crutch. In this group of patients, the mean postoperative pain intensity, functional status, and gait efficiency scores were 4.5, 65.7, and 82 points, respectively. The mean pain intensity VAS score in patients who had LUMiC prostheses implanted was 3.4. Their mean functional status score was 65 and the gait efficiency score 71 points. All the patients were able to walk on crutches. CONCLUSIONS: Strengthening of the acetabular roof with bone cement in a specific group of patients is an adequate method of treatment which decreases pain and allows for loading the affected limb while walking. Internal hemipelvectomy combined with LUMiC prosthesis implantation makes it possible for the patients to walk using crutches and significantly reduces pain. PMID- 27125185 TI - Macular oedema after uncomplicated cataract surgery. Possible relationship with the volume of intracameral cefuroxime. PMID- 27125186 TI - Favourable response to rituximab by an ocular adnexal primary lymphoma. AB - CASE REPORT: A 70-year-old woman who presented with an extranodal marginal zone B cell lymphoma in lacrimal gland and conjunctiva. Initial treatment with rituximab yielded an immediate good response. Five months later she showed lymphoid proliferation in her contralateral conjunctiva. Although no additional treatment was performed, the patient has been free of systemic symptoms and recurrences. DISCUSSION: Rituximab is a quite good therapeutic agent in low grade adnexal lymphomas. PMID- 27125187 TI - Over-diagnosis and over-treatment in Ophthalmology: A review of the literature. AB - OBJECTIVE: To determine if the pernicious effects of over-diagnosis and over treatment have been studied in the most common ocular diseases. MATERIAL AND METHODS: Bibliographic search conducted in PubMed. RESULTS: The search algorithm used retrieved 29 articles related with the topic. Most of them address the issue tangentially. Only 4 of them address the problem directly. One of them focuses on the problem of over-diagnosis and over-treatment in idiopathic intracranial hypertension. The remaining 3 focus on the problem of over-diagnosis and over treatment in glaucoma. CONCLUSION: The ophthalmology community has thought very little about the detrimental effects of over-diagnosis and over-treatment. PMID- 27125188 TI - Simultaneous determination of perfluoroalkyl iodides, perfluoroalkane sulfonamides, fluorotelomer alcohols, fluorotelomer iodides and fluorotelomer acrylates and methacrylates in water and sediments using solid-phase microextraction-gas chromatography/mass spectrometry. AB - Here, we developed and validated a headspace-solid-phase microextraction-gas chromatography/mass spectrometry (HS-SPME-GC/MS) method for the determination of 14 volatile perfluorinated alkylated substances (PFASs) in water and sediment samples according to SANTE 11945/2015 guidelines. Three fluorotelomer alcohols (FTOHs), two perfluoroalkyl iodides (PFIs), three fluorotelomer iodides (FTIs), four fluorotelomer acrylates and methacrylates (FTACs and FTMACs) and two perfluoroalkyl sulfonamides (FASAs) were analysed simultaneously to assess the occurrence of these compounds from their emission sources to the outlets in water treatment plants. Several SPME parameters were optimised for both water and sediment to maximise responses and keep analysis time to a minimum. In tap water, the limits of quantification (LOQs) were found to be between 20ng/L and 100ng/L depending on the analyte, with mean recoveries ranging from 76 to 126%. For sediments, LOQs ranged from 1 to 3ng/g dry weight depending on the target compound, with mean recoveries ranging from 74 to 125%. SPME considerably reduced sample preparation time and its use provided a sensitive, fast and simple technique. We then used this HS-SPME-GC/MS method to investigate the presence of volatile PFASs in the vicinity of an industrial facility. Only 8:2 FTOH and 10:2 FTOH were detected in a few water and sediment samples at sub-ppb concentration levels. Moreover, several non-target fluorotelomers (12:2 FTOH, 14:2 FTOH and 10:2 FTI) were identified in raw effluent samples. These long-chain fluorotelomers have high bioaccumulative potential in the aquatic environment compared with short-chain fluorotelomers such as 6:2 FTOH and 6:2 FTI. PMID- 27125189 TI - Determination of Tyrian purple by high performance liquid chromatography with diode array detection. AB - Indigotin, indirubin, 6-bromoindigotin, 6'-bromoindirubin, 6-bromoindirubin, 6,6' dibromoindigotin and 6,6'-dibromoindirubin, the colouring components of Tyrian purple, are quantified by an efficient HPLC method coupled to a diode array detector. The compounds were separated using gradient elution, on a RP-column (Alltima C18, 250mm*3.0mm i.d., 5MUm), thermostated at 35 degrees C, with a mobile phase consisting of solvents (Alpha) H2O+0.1% (v/v) trifluoroacetic acid and (Beta) acetonitrile+0.1% (v/v) trifluoroacetic acid, at a flow rate of 0.5mLmin(-1). The method was validated in terms of linearity, detection and quantification limits, precision, accuracy, ruggedness and robustness, the latter with respect to small changes in column temperature and in flow-rate, pH- and solvent composition of the mobile phase. Under optimal conditions, the developed analytical scheme offers limits of detection in the range 0.02-0.05MUgmL(-1) and satisfactory linearity up to 2.5MUgmL(-1) for all analytes. Four samples produced from the hypobranchial glands of Hexaplex (Murex) trunculus molluscs, collected in the coastlines of Tunisia and Croatia, were treated with hot DMSO and analysed by the established HPLC method, using the standards addition approach. To evaluate the matrix effect, a comparison of the slopes of the standards in solvent regression curves with those of the standard addition method's calibration curves, using the Student's t-test was carried out. The accuracy was evaluated by recovery experiments. Amounts of indigotin, indirubin, and their mono- and dibrominated derivatives ranging between 0.01 to 12.2MUgmg(-1) were found in the DMSO extracts of the four molluscan samples. PMID- 27125190 TI - Poly(lactic acid) nanofibrous scaffolds for tissue engineering. AB - Poly(lactic acid) (PLA) is a synthetic polyester that has shown extensive utility in tissue engineering. Synthesized either by ring opening polymerization or polycondensation, PLA hydrolytically degrades into lactic acid, a metabolic byproduct, making it suitable for medical applications. Specifically, PLA nanofibers have widened the possible uses of PLA scaffolds for regenerative medicine and drug delivery applications. The use of nanofibrous scaffolds imparts a host of desirable properties, including high surface area, biomimicry of native extracellular matrix architecture, and tuning of mechanical properties, all of which are important facets of designing scaffolds for a particular organ system. Additionally, nanofibrous PLA scaffolds hold great promise as drug delivery carriers, where fabrication parameters and drug-PLA compatibility greatly affect the drug release kinetics. In this review, we present the latest advances in the use of PLA nanofibrous scaffolds for musculoskeletal, nervous, cardiovascular, and cutaneous tissue engineering and offer perspectives on their future use. PMID- 27125192 TI - Poly(lactic acid) stereocomplexes: A decade of progress. AB - Upon blending enantiomeric poly(l-lactide) [i.e., poly(l-lactic acid) (PLLA)] and poly(d-lactide) (PDLA) [i.e., poly(d-lactic acid) (PDLA)] or synthesis of stereo block poly(lactide) [i.e., poly(lactic acid) (PLA)], a stereocomplex (SC) is formed. PLA SC has a higher melting temperature (or heat resistance), mechanical performance, and hydrolysis-resistance compared to those of neat PLLA and PDLA. Because of such effects, PLA SC has been extensively studied in terms of biomedical and pharmaceutical applications as well as commodity, industrial, and environmental applications. Stereocomplexation stabilizes and strengthens PLA based hydrogel or nanoparticles for biomedical applications. Stereocomplexation increases the barrier property of PLA-based materials and thereby prolongs drug release from PLA based materials. In addition, PLA SC is attracting significant attention because it can act as a nucleating agent for the widely used biobased polymer PLLA and thereby the heat resistance of PLLA-based materials can be enhanced. Interestingly, a wide variety of SCs other than PLA SC are found to have been formed in the enantiomeric substituted PLA blends and stereo block substituted PLA polymers. In the present review article, a decade of progress in investigation of PLA SCs is summarized. PMID- 27125193 TI - Onset of psoriasis upon interferon beta treatment in a multiple sclerosis patient. PMID- 27125194 TI - Analysis of constant tension-induced rupture of lipid membranes using activation energy. AB - The stretching of biomembranes and lipid membranes plays important roles in various physiological and physicochemical phenomena. Here we analyzed the rate constant kp of constant tension-induced rupture of giant unilamellar vesicles (GUVs) as a function of tension sigma using their activation energy Ua. To determine the values of kp, we applied constant tension to a GUV membrane using the micropipette aspiration method and observed the rupture of GUVs, and then analyzed these data statistically. First, we investigated the temperature dependence of kp for GUVs of charged lipid membranes composed of negatively charged dioleoylphosphatidylglycerol (DOPG) and electrically neutral dioleoylphosphatidylcholine (DOPC). By analyzing this result, the values of Ua of tension-induced rupture of DOPG/DOPC-GUVs were obtained. Ua decreased with an increase in sigma, supporting the classical theory of tension-induced pore formation. The analysis of the relationship between Ua and sigma using the theory on the electrostatic interaction effects on the tension-induced rupture of GUVs provided the equation of Ua including electrostatic interaction effects, which well fits the experimental data of the tension dependence of Ua. A constant which does not depend on tension, U0, was also found to contribute significantly to Ua. The Arrhenius equations for kp using the equation of Ua and the parameters determined by the above analysis fit well to the experimental data of the tension dependence of kp for DOPG/DOPC-GUVs as well as for DOPC-GUVs. On the basis of these results, we discussed the possible elementary processes underlying the tension-induced rupture of GUVs of lipid membranes. These results indicate that the Arrhenius equation using the experimentally determined Ua is useful in the analysis of tension-induced rupture of GUVs. PMID- 27125195 TI - ECONOMIC EVALUATION STUDIES OF SELF-MANAGEMENT INTERVENTIONS IN CHRONIC DISEASES: A SYSTEMATIC REVIEW. AB - BACKGROUND: To our knowledge, there has been no overall systematic review focusing on the methodological quality of full economic evaluation studies of self-management interventions. Our objective was to systematically review the literature of full economic evaluation studies of self-management interventions in adult chronic patients and to investigate their methodological quality and cost-effectiveness. METHODS: A data extraction form was developed to assess general and randomized controlled trial (RCT) -related characteristics, quality, of the RCTs, economic information and quality of the economic evaluation studies by means of a quality assessment (CHEC-list for trial-based studies, adjusted CHEC-list for model-based studies). RESULTS: Twenty-three reports were found. Sixteen studies (73 percent) lack information on the control intervention(s). Only one study fulfilled all three criteria for quality of RCTs and five studies (23 percent) did not meet any of these criteria. This review included one model based study; the other studies were trial-based economic evaluation studies based on a RCT. Eight studies (35 percent) used a societal perspective and 12 (60 percent) synthesized costs and effects. Seven studies were categorized into the highest category (<15 score), nine studies into the "moderate" group (9-14 score), six studies received a "low" score (<8) on the CHEC-list. Eighteen studies found the self-management intervention(s) to be cost-effective compared with other interventions Conclusions: Self-management interventions for adult chronic patients were heterogeneous and there was no clear, well-considered definition of self-management. Overall, the methodological quality of the full economic evaluation studies was moderate and, therefore, cost-effectiveness results must be interpreted with caution. Future research will benefit from further improvements in methodological quality of both economic study design and analysis, as well as a taxonomy for describing self-management interventions and their contents. PMID- 27125196 TI - Defect levels in Cu(In,Ga)Se2 studied using capacitance and photocurrent techniques. AB - This work contributes to the discussion on defect levels in Cu(In,Ga)Se2 photovoltaic material. CuInSe2- and Cu(In,Ga)Se2- based Schottky junctions, solar cells and thin films were investigated using complementary capacitance and current spectroscopic techniques. Depending on the applied technique and type of investigated structure, six different signals were observed. Out of the signals identified, three were ascribed to responses from bulk defects-two electron and one hole trap. The remainder were discussed in light of available in-literature models including carrier mobility freeze-out and non-ohmic back junction. PMID- 27125197 TI - Quantitative proteomic analysis of normal and degenerated human intervertebral disc. AB - BACKGROUND CONTEXT: Degenerative disc disease (DDD) is the most common disease of aging in humans. DDD is characterized by the gradual damage of the intervertebral discs. The disease is characterized by progressive dehydration of nucleus pulposus and disruption of annulus fibrosus of intervertebral disc. PURPOSE: Even though it is highly prevalent, there is no effective therapy to regenerate the degenerated disc, or decrease or halt the disease progression. Therefore, novel monitoring and diagnostic tests are essential to develop an alternative therapeutic strategies which can prevent further progression of disc degeneration. STUDY DESIGN: The study was designed to understand the proteome map of annulus fibrosus and nucleus pulposus tissues of intervertebral disc and its differential expression in patients with DDD. METHODS: The proteome map of the annulus fibrosus and nucleus pulposus tissues of intervertebral disc was cataloged involving one-dimensional gel electrophoresis-Fourier transform mass spectrometry/ion trap tandem mass spectrometry (FTMS/ITMSMS) analysis. The altered proteome patterns of annulus fibrosus and nucleus pulposus tissues for DDD were identified using Isobaric tag for relative and absolute quantification (iTRAQ)-based quantitative proteomics coupled with FTMS/ITMSMS and network pathway analysis. RESULTS: The study identified a total of 759 and 692 proteins from the annulus fibrosus and the nucleus pulposus tissues of the disc based on FTMS/ITMSMS analysis, which includes 118 proteins commonly identified between the two tissues. Vibrant changes were observed between the normal and the degenerating annulus fibrosus and nucleus pulposus tissues. A total of 73 and 54 proteins were identified as differentially regulated in the annulus and the nucleus tissues, respectively, between the normal and the degenerated tissues independently. Network pathway analysis mapped the differentially expressed proteins to cell adhesion, cell migration, and interleukin13 signaling pathways. CONCLUSIONS: Altogether, the current study provides a novel vision in the biomechanism of human disc degeneration and a certain number of proteins with the potential biomarker value for the preliminary diagnosis and scenario of DDD. PMID- 27125191 TI - Poly (lactic acid)-based biomaterials for orthopaedic regenerative engineering. AB - Regenerative engineering converges tissue engineering, advanced materials science, stem cell science, and developmental biology to regenerate complex tissues such as whole limbs. Regenerative engineering scaffolds provide mechanical support and nanoscale control over architecture, topography, and biochemical cues to influence cellular outcome. In this regard, poly (lactic acid) (PLA)-based biomaterials may be considered as a gold standard for many orthopaedic regenerative engineering applications because of their versatility in fabrication, biodegradability, and compatibility with biomolecules and cells. Here we discuss recent developments in PLA-based biomaterials with respect to processability and current applications in the clinical and research settings for bone, ligament, meniscus, and cartilage regeneration. PMID- 27125200 TI - Effect of gadolinium contrast-enhanced T1-weighted magnetic resonance imaging for detecting extramural venous invasion in rectal cancer. AB - PURPOSE: To evaluate the performance of gadolinium contrast-enhanced T1-weighted magnetic resonance imaging (CET1WI) in addition to high-resolution T2-weighted imaging (HRT2WI) for preoperative detection of extramural venous invasion (EMVI) in rectal cancer. METHODS: Fifty-nine patients with rectal cancer who underwent preoperative MRI were included in this study. The likelihood of EMVI was retrospectively scored by two readers on CET1WI, HRT2WI, and HRT2WI + CET1WI, using a subjective five-point scale ranging from 0 to 4. The pathological status of EMVI was used as a standard reference. Diagnostic parameters, including area under the receiver operating curve (AUC), sensitivity, and specificity, were calculated, and the diagnostic performances of HRT2WI and HRT2WI + CET1WI were compared. Interobserver variance was also evaluated. RESULTS: Eighteen (30.5%) patients showed pathological EMVI. During EMVI detection, reader A obtained an AUC of 0.768, sensitivity of 72.5%, and specificity of 73.2% from HRT2WI alone; after combination with CET1WI, these values improved to 0.864, 83.3%, and 75.6%, respectively. Differences in AUC between these techniques were not significant (p = 0.056). Reader B obtained an AUC of 0.833, sensitivity of 77.8%, and specificity of 73.2% from HRT2WI alone; after combination with CET1W1, these figures were adjusted to 0.720, 50%, and 78%; differences in AUC between techniques were significant (p = 0.027). Interobserver agreement during EMVI scoring was good for HRT2WI (kappa = 0.603) and moderate for HRT2WI + CET1WI (kappa = 0.413). CONCLUSIONS: Although interobserver agreement decreased, combination of CET1WI with HRT2WI could improve EMVI detection. PMID- 27125199 TI - The Role of Steroid Receptor Coactivators in Hormone Dependent Cancers and Their Potential as Therapeutic Targets. AB - Steroid receptor coactivator (SRC) family members (SRC-1, SRC-2, SRC-3) interact with nuclear receptors (NRs) and many transcription factors to enhance target gene transcription. Deregulation of SRCs is widely implicated in NR mediated diseases, especially hormone dependent cancers. By integrating steroid hormone signaling and growth factor pathways, SRC proteins exert multiple modes of oncogenic regulation in cancers and represent emerging targets for cancer therapeutics. Recent work has identified SRC-targeting agents that show promise in blocking tumor growth in vitro and in vivo, and have the potential to function as powerful and broadly encompassing treatments for different cancers. PMID- 27125198 TI - Mustard vesicants alter expression of the endocannabinoid system in mouse skin. AB - Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARalpha). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARalpha and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARalpha, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. PMID- 27125201 TI - Production and identification of iturin A lipopeptide from Bacillus methyltrophicus TEB1 for control of Phoma tracheiphila. AB - A lipopeptide-producing endophytic Bacillus methyltrophicus TEB1 strain exhibited potent antifungal activity against Phoma tracheiphila. Lipopeptide production started at the early growth phase plateaued after 36 h of culture where it reduced the mycelium growth by 80%. The crude lipopeptide extract harvested at the stationary phase efficiently inhibited the growth of P. tracheiphila mycelium and MIC values displaying 50 and 90% inhibition of conidia germination were around 47.5 and 100 MUg ml(-1) , respectively. Increasing lipopeptide extract till 3 mg ml(-1) induced 10% swelling and 3% crumbling of P. tracheiphila conidia whereas 5 mg ml(-1) induced 40% swelling and 20% crumbling. Mass spectrometry analysis of the lipopeptide extract indicated that surfactin production took place from 12 to 20 h, iturin A from 16 to 72 h, and fengycin from 12 to 72 h and that the main active compound against P. tracheiphila was identified as C15 iturin A lipopeptide. Iturin A appeared as a potential biological control agent able to substitute the currently used chemical pesticides in agriculture. PMID- 27125203 TI - How can we know if new drugs are effective in myeloproliferative neoplasm associated myelofibrosis? PMID- 27125204 TI - CDKN2A-independent role of BMI1 in promoting growth and survival of Ph+ acute lymphoblastic leukemia. AB - BMI1 is a key component of the PRC1 (polycomb repressive complex-1) complex required for maintenance of normal and cancer stem cells. Its aberrant expression is detected in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL), but no data exist on BMI1 requirement in ALL cells. We show here that BMI1 expression is important for proliferation and survival of Ph+ ALL cells and for leukemogenesis of Ph+ cells in vivo. Levels of BIM, interferon-alpha (IFNalpha) regulated genes and E2F7 were upregulated in BMI1-silenced cells, suggesting that repressing their expression is important for BMI1 biological effects. Consistent with this hypothesis, we found that: (i) downregulation of BIM or E2F7 abrogated apoptosis or rescued, in part, the reduced proliferation and colony formation of BMI1 silenced BV173 cells; (ii) BIM/E2F7 double silencing further enhanced colony formation and in vivo leukemogenesis of BMI1-silenced cells; (iii) overexpression of BIM and E2F7 mimicked the effect of BMI1 silencing in BV173 and SUP-B15 cells; and (iv) treatment with IFNalpha suppressed proliferation and colony formation of Ph+ ALL cells. These studies indicate that the growth-promoting effects of BMI1 in Ph+ ALL cells depend on suppression of multiple pathways and support the use of IFNalpha in the therapy of Ph+ ALL. PMID- 27125202 TI - Weighing the Evidence: A Systematic Review on Long-Term Neurocognitive Effects of Cannabis Use in Abstinent Adolescents and Adults. AB - Findings on neurocognitive effects of sustained cannabis use are heterogeneous. Previous work has rarely taken time of abstinence into account. In this review, we focus on understanding sustained effects of cannabis, which begin when clinical symptoms of the drug have worn off after at least 14 days. We conducted a search between 2004 and 2015 and found 38 studies with such a prolonged abstinence phase. Study-design quality in terms of evidence-based medicine is similar among studies. Studies found some attention or concentration deficits in cannabis users (CU). There is evidence that chronic CU might experience sustained deficits in memory function. Findings are mixed regarding impairments in inhibition, impulsivity and decision making for CU, but there is a trend towards worse performance. Three out of four studies found evidence that motor function remains impaired even after a time of abstinence, while no impairments in visual spatial functioning can be concluded. Functional imaging demonstrates clear differences in activation patterns between CU and controls especially in hippocampal, prefrontal and cerebellar areas. Structural differences are found in cortical areas, especially the orbitofrontal region and the hippocampus. Twenty studies (57 %) reported data on outcome effects, leading to an overall effect size of r mean = .378 (CI 95 % = [.342; .453]). Heavy use is found to be more consistently associated with effects in diverse domains than early age of onset. Questions of causality-in view of scarce longitudinal studies, especially those targeting co-occurring psychiatric disorders-are discussed. PMID- 27125205 TI - High prevalence and allele burden-independent prognostic importance of p53 mutations in an inner-city MDS/AML cohort. PMID- 27125206 TI - Predictors of survival in WHO-defined hypereosinophilic syndrome and idiopathic hypereosinophilia and the role of next-generation sequencing. PMID- 27125207 TI - Macrophages in Vascular Inflammation: Origins and Functions. AB - Macrophages influence various processes of cardiovascular inflammation. Whether they are of embryonic or post-natal hematopoietic origin, their balance in differential activation may direct the course of inflammation. Accelerated macrophage activation and accumulation through a pro-inflammatory signaling pathway may result in extensive tissue damage, adverse repair, and worsened clinical outcomes. Attenuation of such a mechanism and/or promotion of the anti inflammatory macrophage activation may lead to early resolution of inflammation. Elucidating multiple novel mechanisms of monocyte and macrophage activation leads to a better understanding of their roles in vascular inflammation. In turn, this begets better therapeutic target identification and biomarker discovery. Combined with increasingly sensitive and specific imaging techniques, we continue to push back early detection and monitoring to provide us with a greater window for disease modification. The potential success of cytokine-targeted therapy will be solid proof of the inflammatory hypothesis of atherothrombosis. PMID- 27125208 TI - Endoloop technique for laparoscopic cornuectomy: A safe and effective approach for the treatment of interstitial pregnancy. AB - Interstitial pregnancy (IP) occurs within the intramural portion of the tube and accounts for 2% of ectopic pregnancies. Surgery is considered the most definitive treatment for IPs, although there is no clear consensus regarding the optimal approach. In this paper we describe the advantages of cornual resection performed using the Endoloop technique and present three patients who were successfully treated using this approach. IP diagnosis was confirmed at two and three dimensional ultrasound and laparoscopy in all cases. Fertility sparing surgery with cornuectomy by Endoloop ligature technique demonstrated low mean operating time and blood loss, and allowed the quick recovery and discharge of all patients. Laparoscopy has become the gold standard surgical approach for IP. Cornual resection or excision is the most commonly performed procedure. In our case series, the Endoloop technique showed excellent treatment outcomes in terms of effectiveness, blood loss, operative time, recovery and post-procedure fertility. Because of these features, Endoloop appears to be a suitable option for the laparoscopic management of IPs, both in elective and emergency settings. PMID- 27125209 TI - Effects of hydropeaking on the spawning behaviour of Atlantic salmon Salmo salar and brown trout Salmo trutta. AB - An in situ camera set-up was used to study the spawning activity of Atlantic salmon Salmo salar and brown trout Salmo trutta throughout two consecutive seasons in a spawning area affected by hydropower-related pulse flows due to hydropeaking. The purpose was to test whether the flow variation discouraged spawning in shallow areas or motivated spawning into areas with elevated risk of incubation mortality. There were more S. salar observed on the spawning ground during days with high discharge. The presence of S. salar in the spawning grounds was not affected by the hydropeaking cycles of the preceding night. Female S. salar were observed preparing nests within the first hour after water discharge had increased to levels suitable for spawning. In contrast, the number of S. trutta was not correlated with flow and nest preparation was also observed at a discharge corresponding to the lowest discharge levels during a hydropeaking cycle. Survival was generally high in nests excavated the following winter, with only 5.4% suffering mortality due to dewatering. The results suggest that S. salar may respond rapidly to variable-flow conditions and utilize short windows with suitable flows for spawning. Smaller S. trutta may utilize low-flow conditions to spawn in areas that are not habitable by larger S. salar during low flow. PMID- 27125210 TI - Effects of dexmedetomidine on hemodynamics and respiration in intubated, spontaneously breathing patients after endoscopic submucosal dissection for cervical esophageal or pharyngeal cancer. AB - PURPOSE: We evaluated the hemodynamic and respiratory effects of dexmedetomidine in intubated, spontaneously breathing patients after endoscopic submucosal dissection (ESD) for cervical esophageal or pharyngeal cancer. METHODS: This retrospective study included 129 patients aged 66.5 +/- 8.3 years, who underwent ESD under general anesthesia, and who were kept intubated overnight to prevent airway obstruction, receiving sedation with dexmedetomidine. Constant dexmedetomidine infusion at 0.51 +/- 0.16 MUg/kg/h was started intraoperatively (n = 109) or postoperatively (n = 20), following (n = 29) or not following (n = 100) loading doses, and continued until extubation. Hemodynamic and respiratory variables, and Richmond Agitation-Sedation Scale (RASS) score, were recorded. RESULTS: Postoperatively, 129 patients remained intubated while breathing spontaneously for 16.4 +/- 3.3 h, and 124 patients could be sedated solely with dexmedetomidine, whereas 5 required rescue sedatives. During infusion, blood pressure decreased progressively until 12 h, whereas heart rate decreased only at 3 h. Hemodynamic alterations during dexmedetomidine infusion greatly depended not only on its hemodynamic effects but also on baseline hemodynamics before anesthesia. No serious adverse effect was noted. CONCLUSION: Dexmedetomidine in intubated, spontaneously breathing patients after ESD was safe and effective. Patient baseline hemodynamics could significantly affect hemodynamics during drug infusion. Without loading doses, plasma drug concentrations were expected to increase progressively. A progressive decrease in blood pressure and unchanged heart rate after an initial decrease suggested that hemodynamic effects of dexmedetomidine in our patients might differ from those reported in young volunteers, although further studies are required to elucidate these points. PMID- 27125211 TI - Inflammation modulates LC3 expression in human preterm delivery. AB - OBJECTIVE: Autophagy is an inducible intracellular process acting under stressor conditions, such as infections, inflammation and hypoxia. The aim of the present study was to analyze autophagy expression in preterm delivered human placenta. METHODS: Autophagy marker LC3 was analyzed in 25 consecutive human placentas delivered before 34 weeks of gestation, analyzed by immunohistochemistry, immunofluorescence and quantitative real-time PCR, according to the histologic classification of preterm delivery (PTD) (cases with or without placental inflammatory lesions). RESULTS: LC3 expression was observed both in cases with and without inflammatory lesions. In cases with histological inflammation, strong immunoreactivity for LC3 autophagic marker was observed in the inflammatory cell infiltration composed by neutrophils. In all PTD cases, trophoblastic cells in chorion laeve express LC3, with variable staining intensity: a significant reduction of LC3 expression was observed in chorion laeve of PTD with histological inflammation compared to PTD without inflammatory lesions. Moreover, the decrement of LC3 staining was observed to be associated to the increasing severity of the histological signs of fetal inflammatory response. CONCLUSIONS: Our data show that the expression of LC3 varies depending on different histological features, indicating an interesting and possibly clinically relevant relation between autophagy expression levels and the inflammatory status. PMID- 27125212 TI - Awareness, knowledge, and perceptions of infertility, fertility assessment, and assisted reproductive technologies in the era of oocyte freezing among female and male university students. AB - PURPOSE: The aims of our study were to analyze university student's knowledge and attitude towards parenthood, female fertility, fertility assessment, and oocyte freezing and to explore associations between these aspects and the participant's sex or degree program they were registered for. METHODS: The study was designed as an online-based cross-sectional survey. A total of 1144 participants answered 27 questions. The data were analyzed using descriptive statistics. Linear regression models were employed to explore associations between sex or university program and attitude towards parenthood, fertility assessment, and oocyte freezing. RESULTS: Female students and students of non-medical degree programs were more likely to plan to have children earlier than male students or students of medical degree programs. Female sex or medical degree program was associated with an overall better knowledge about women's fertility. The better the participant's knowledge about fertility, the more likely the students would consider assisted reproductive technology (ART) treatments as an option to become pregnant when ovarian reserve is low. The majority of students knew the principal of oocyte freezing but would not consider using it. However, in the case of a low ovarian reserve, oocyte freezing would be accepted as an option. CONCLUSIONS: Students planned to have children at an age when women's fertility is already declining. Gaps in knowledge about female fertility and the potential of ART were more pronounced in male students and students of non-medical degree programs suggesting an increase of fertility awareness is necessary in these groups to prevent them from infertility and unwanted childlessness. PMID- 27125213 TI - Characterization of gut microbiota profiles in coronary artery disease patients using data mining analysis of terminal restriction fragment length polymorphism: gut microbiota could be a diagnostic marker of coronary artery disease. AB - The association between atherosclerosis and gut microbiota has been attracting increased attention. We previously demonstrated a possible link between gut microbiota and coronary artery disease. Our aim of this study was to clarify the gut microbiota profiles in coronary artery disease patients using data mining analysis of terminal restriction fragment length polymorphism (T-RFLP). This study included 39 coronary artery disease (CAD) patients and 30 age- and sex- matched no-CAD controls (Ctrls) with coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by T-RFLP and data mining analysis using the classification and regression algorithm. Five additional CAD patients were newly recruited to confirm the reliability of this analysis. Data mining analysis could divide the composition of gut microbiota into 2 characteristic nodes. The CAD group was classified into 4 CAD pattern nodes (35/39 = 90 %), while the Ctrl group was classified into 3 Ctrl pattern nodes (28/30 = 93 %). Five additional CAD samples were applied to the same dividing model, which could validate the accuracy to predict the risk of CAD by data mining analysis. We could demonstrate that operational taxonomic unit 853 (OTU853), OTU657, and OTU990 were determined important both by the data mining method and by the usual statistical comparison. We classified the gut microbiota profiles in coronary artery disease patients using data mining analysis of T-RFLP data and demonstrated the possibility that gut microbiota is a diagnostic marker of suffering from CAD. PMID- 27125214 TI - Impact of early tumor reduction on outcome differs by histological subtype in stage III non-small-cell lung cancer treated with definitive radiotherapy. AB - BACKGROUND: We retrospectively investigated the impact on survival of early tumor reduction during definitive radiotherapy for inoperable stage III non-small cell lung cancer (NSCLC) patients, according to their histological subtypes. METHODS: Between November 2006 and December 2012, 152 consecutive patients with inoperable stage III NSCLC who underwent definitive radiotherapy were reviewed retrospectively. Forty-one patients were excluded for not satisfying the inclusion criteria. Forty-five (40.5 %) and 48 (43.2 %) patients were diagnosed with squamous cell carcinoma (SQC) and adenocarcinoma (ADC), respectively. The tumor reduction rate (TRR) was defined as follows: TRR = 1-[gross tumor volume (GTV) on computed tomography at shrinking irradiation field planning]/(GTV on computed tomography at the initial treatment planning). The Cox proportional hazard model was used to identify significant prognostic factors for overall survival (OS) and progression-free survival (PFS). RESULTS: We evaluated 111 patients, with a median follow-up time of 52.2 months in surviving patients. The median TRR was 45.9 %. In all patients, there were significant associations between TRR and PFS (P = 0.036) on multivariate analysis, although TRR had no correlation with OS (P = 0.141). With respect to histological subtype, multivariate analyses revealed that a higher TRR showed significant associations with better OS and PFS in the SQC group (P = 0.013 and 0.040, respectively). In contrast, a higher TRR was associated with poorer OS in the ADC group (P = 0.030); there was no association between TRR and PFS. CONCLUSION: We found that a higher TRR is a promising prognostic factor for better survival and disease control in SQC patients. PMID- 27125216 TI - E-cigarettes are a "gateway from smoking," RCP concludes. PMID- 27125217 TI - Long QT Syndrome Leading to Multiple Cardiac Arrests After Posaconazole Administration in an Immune-Compromised Patient with Sepsis: An Unusual Case Report. AB - BACKGROUND: We present the case of a septic patient with severe immunodeficiency, who developed QT interval prolongation followed by episodes of lethal cardiac arrhythmia. Cardiac events occurred after posaconazole administration, incriminating posaconazole use, alone or in combination with voriconazole, as the culpable agent. CASE REPORT: A 26-year-old female patient underwent orthopedic surgery to remove ectopic calcifications in her left hip joint. On the first post operative day she became septic due to a surgical wound infection. Despite being treated according to the therapeutic protocols for sepsis, no clinical improvement was noticed and further assessment revealed an underlying immunodeficiency. Considering the underlying immunodeficiency and to that point poor clinical response, an antifungal agent was added to the antibiotic regiment. Following discontinuation of multiple antifungal agents due to adverse effects, posaconazole was administered. Posaconazole oral intake was followed by episodes of bradycardia and QT interval prolongation. The patient suffered continuous incidents of cardiac arrest due to polymorphic ventricular tachycardia (torsades des pointes) that degenerated to lethal ventricular fibrillation. Posaconazole was immediately discontinued and a temporary pacemaker was installed. The patient finally recovered without any neurological deficit, and was discharged in a good clinical status. CONCLUSIONS: Close cardiac monitoring is recommended in cases where posaconazole administration is combined with coexisting risk factors, as they may lead to severe ECG abnormalities and cardiac arrhythmias such as long QT interval syndrome and torsades de pointes. Posaconazole interactions with medications metabolized via the CYP3A4 pathway should be considered an additional risk factor for lethal cardiac incidents. PMID- 27125215 TI - Extracellular Cl(-) regulates human SO4 (2-)/anion exchanger SLC26A1 by altering pH sensitivity of anion transport. AB - Genetic deficiency of the SLC26A1 anion exchanger in mice is known to be associated with hyposulfatemia and hyperoxaluria with nephrolithiasis, but many aspects of human SLC26A1 function remain to be explored. We report here the functional characterization of human SLC26A1, a 4,4'-diisothiocyanato-2,2' stilbenedisulfonic acid (DIDS)-sensitive, electroneutral sodium-independent anion exchanger transporting sulfate, oxalate, bicarbonate, thiosulfate, and (with divergent properties) chloride. Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs in its stimulation by alkaline pHo and inhibition by acidic pHo but not pHi and in its failure to transport glyoxylate. SLC26A1-mediated transport of sulfate and oxalate is highly dependent on allosteric activation by extracellular chloride or non-substrate anions. Extracellular chloride stimulates apparent V max of human SLC26A1-mediated sulfate uptake by conferring a 2-log decrease in sensitivity to inhibition by extracellular protons, without changing transporter affinity for extracellular sulfate. In contrast to SLC26A1-mediated sulfate transport, SLC26A1-associated chloride transport is activated by acid pHo, shows reduced sensitivity to DIDS, and exhibits cation dependence of its DIDS-insensitive component. Human SLC26A1 resembles SLC26 paralogs in its inhibition by phorbol ester activation of protein kinase C (PKC), which differs in its undiminished polypeptide abundance at or near the oocyte surface. Mutation of SLC26A1 residues corresponding to candidate anion binding site-associated residues in avian SLC26A5/prestin altered anion transport in patterns resembling those of prestin. However, rare SLC26A1 polymorphic variants from a patient with renal Fanconi Syndrome and from a patient with nephrolithiasis/calcinosis exhibited no loss-of-function phenotypes consistent with disease pathogenesis. PMID- 27125218 TI - Actinidia chlorotic ringspot-associated virus: a novel emaravirus infecting kiwifruit plants. AB - By integrating next-generation sequencing (NGS), bioinformatics, electron microscopy and conventional molecular biology tools, a new virus infecting kiwifruit vines has been identified and characterized. Being associated with double-membrane-bound bodies in infected tissues and having a genome composed of RNA segments, each one containing a single open reading frame in negative polarity, this virus shows the typical features of members of the genus Emaravirus. Five genomic RNA segments were identified. Additional molecular signatures in the viral RNAs and in the proteins they encode, together with data from phylogenetic analyses, support the proposal of creating a new species in the genus Emaravirus to classify the novel virus, which is tentatively named Actinidia chlorotic ringspot-associated virus (AcCRaV). Bioassays showed that AcCRaV is mechanically transmissible to Nicotiana benthamiana plants which, in turn, may develop chlorotic spots and ringspots. Field surveys disclosed the presence of AcCRaV in four different species of kiwifruit vines in five different provinces of central and western China, and support the association of the novel virus with symptoms of leaf chlorotic ringspots in Actinidia. Data on the molecular features of small RNAs of 21-24 nucleotides, derived from AcCRaV RNAs targeted by host RNA silencing mechanisms, are also reported, and possible molecular pathways involved in their biogenesis are discussed. PMID- 27125219 TI - Demonstration of Autosomal Monoallelic Expression in Thyroid Tissue Assessed by Whole-Exome and Bulk RNA Sequencing. AB - BACKGROUND: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is a disorder with a prevalence of 1/4000 live births, the cause of which remains unknown. The most common diagnostic category is thyroid ectopy, which occurs in up to 80% of CHTD cases. CHTD is predominantly not inherited and has a high discordance rate (>92%) between monozygotic (MZ) twins. The sporadic nature of CHTD might be explained by somatic events such as autosomal monoallelic expression (AME), given that genes expressed in a monoallelic way are more vulnerable to otherwise benign monoallelict genetic or epigenetic mutations. OBJECTIVE: The aim of this study was to search for complete (90%) AME in normal and dysgenetic thyroid tissues. METHODS: Aggregated analysis of whole-exome and bulk RNA sequencing was performed on two ectopic thyroids, four normal thyroids, and the human thyroid cell line Nthy-ori. RESULTS: A median of 5062 (range 2081 5270) genes per sample showed sufficient numbers of heterozygous single nucleotide polymorphisms to be informative. The median monoallelic expression represented 22 (range 16-32) of the informative genes for each thyroid sample. Examples of genes displaying AME are FCGBP, ZNF331, USP10, BCLAF1, and some HLA genes; these genes are involved in epithelial-mesenchymal transition, cell migration, cancer, and immunity. CONCLUSIONS: AME may account for the high discordance rate observed between MZ twins and for the sporadic nature of CHTD. These findings also have implications for other pathologies, including cancers and autoimmune disorders of the thyroid. PMID- 27125220 TI - Arabidopsis thaliana G2-LIKE FLAVONOID REGULATOR and BRASSINOSTEROID ENHANCED EXPRESSION1 are low-temperature regulators of flavonoid accumulation. AB - Flavonoid synthesis is predominantly regulated at the transcriptional level through the MYB-basic helix-loop-helix (bHLH)-WD40 (MBW) (MYB: transcription factor of the myeloblastosis protein family, WD40: tanscription factor with a short structural motif of 40 amino acids which terminates in an aspartic acid tryptophan dipeptide) complex, and responds to both environmental and developmental stimuli. Although the developmental regulation of flavonoid accumulation in Arabidopsis thaliana has been examined in great detail, the response of the flavonoid synthesis pathway to abiotic stress (particularly low temperature) remains unclear. A screen of a Dissociation element (Ds) transposon induced mutation collection identified two lines which exhibited an altered profile of phenylpropanoid accumulation following exposure to low-temperature stress. One of the mutated genes (BRASSINOSTEROID ENHANCED EXPRESSION1 (BEE1)) encoded a brassinosteroid enhanced expression transcription factor, while the other (G2-LIKE FLAVONOID REGULATOR (GFR)) encoded a G2-like flavonoid regulator. Phenylpropanoid-targeted analysis was performed using high-performance LC-MS, and gene expression analysis using quantitative reverse transcription-PCR. In both mutants, the accumulation of quercetins and scopolin was reduced under low temperature growing conditions, whereas that of anthocyanin was increased. BEE1 and GFR were both shown to negatively regulate anthocyanin accumulation by inhibiting anthocyanin synthesis genes via the suppression of the bHLH (TRANSPARENT TESTA8 (TT8) and GLABROUS3 (GL3)) and/or the MYB (PRODUCTION OF ANTHOCYANIN PIGMENTS2 (PAP2)) components of the MBW complex. Our results provide new insight into the regulatory control of phenylpropanoid metabolism at low temperatures, and reveal that BEE1 and GFR act as important components of the signal transduction chain. PMID- 27125221 TI - Memory-driven attentional capture reveals the waxing and waning of working memory activation due to dual-task interference. AB - Previous studies have shown that information held in working memory (WM) actively or as a residue of previous processing can lead to attentional capture by corresponding stimuli in the environment. Here, we compared attentional capture by goal-driven and residual WM activation and examined how these effects are affected by dual-task interference. In two experiments, participants performed an animacy judgment task for a word that they did or did not have to remember for a later recognition test. The word was followed in half of the trials by an arithmetic task that served to disrupt the WM activation of the previously processed word. Subsequently, WM-driven capture was assessed by having participants perform a single-target rapid serial visual presentation task in which a line drawing corresponding to the word was presented shortly before a target. The results showed that the line drawing captured attention irrespective of the presence of the arithmetic task when the word had to be remembered. In comparison, the animacy judgment alone resulted in capture only when the arithmetic task was absent, and this effect was equally strong as the capture effect caused by a to-be-remembered word. Taken together, these findings show that although residual and goal-driven WM activation may be equally potent in guiding attentional selection, these two forms of WM activation differ in that residual activation is overwritten by an attention-demanding task, whereas goal driven WM activation can lead to the reinstatement of a stimulus after performing such a task. PMID- 27125222 TI - How do pre-adolescent children interpret conditionals? AB - Studies examining children's basic understanding of conditionals have led to very different conclusions. On the one hand, conditional inference tasks suggest that young children are able to interpret familiar conditionals in a complex manner. In contrast, truth-table tasks suggest that before adolescence, children have limited (conjunctive) representations of conditionals. We hypothesized that the latter results are due to use of what are essentially arbitrary conditionals. To examine this, we gave a truth-table task using two kinds of conditional rules, Arbitrary and Imaginary categorical rules (If an animal is a bori, then it has red wings) to 9- and 12-year-olds. Results with the Arbitrary rules were consistent with those found in previous studies, with the most frequent interpretation being the Conjunctive one. However, among even the youngest children, the most frequent interpretation of the Imaginary categorical rules was the defective conditional, which is only found with much older adolescents with Arbitrary rules. These results suggest that working memory limitations are not an important developmental factor in how young children interpret conditional rules. PMID- 27125224 TI - Gene expression profiles of autophagy-related genes in multiple sclerosis. AB - Multiple sclerosis (MS) is an imflammatory disease of central nervous system caused by genetic and environmental factors that remain largely unknown. Autophagy is the process of degradation and recycling of damaged cytoplasmic organelles, macromolecular aggregates, and long-lived proteins. Malfunction of autophagy contributes to the pathogenesis of neurological diseases, and autophagy genes may modulate the T cell survival. We aimed to examine the expression levels of autophagy-related genes. The blood samples of 95 unrelated patients (aged 17 65years, 37 male, 58 female) diagnosed as MS and 95 healthy controls were used to extract the RNA samples. After conversion to single stranded cDNA using polyT priming: the targeted genes were pre-amplified, and 96*78 (samples*primers) qRT PCR reactions were performed for each primer pair on each sample on a 96.96 array of Fluidigm BioMarkTM. Compared to age- and sex-matched controls, gene expression levels of ATG16L2, ATG9A, BCL2, FAS, GAA, HGS, PIK3R1, RAB24, RGS19, ULK1, FOXO1, HTT were significantly altered (false discovery rate<0.05). Thus, altered expression levels of several autophagy related genes may affect protein levels, which in turn would influence the activity of autophagy, or most probably, those genes might be acting independent of autophagy and contributing to MS pathogenesis as risk factors. The indeterminate genetic causes leading to alterations in gene expressions require further analysis. PMID- 27125223 TI - In-home nighttime predictive low glucose suspend experience in children and adults with type 1 diabetes. AB - Overnight predictive low glucose suspend (PLGS) reduces hypoglycemia across all ages; however, there are no reports on behavior or experience differences across age groups, especially in pediatrics. As run-in for a subsequent randomized clinical trial (RCT), 127 subjects (50% male) ages 4-45 yr utilized the experimental PLGS system nightly for 5-10 nights (PLGS active phase). We analyzed the number of blood glucose (BG) checks and boluses given per age group. During the subsequent 42 night RCT phase, we analyzed sensor use, skin reactions, errors, and reasons why the experimental system was not used. In 821 nights of active PLGS, subjects ages 4-6 yr (and their parents) tested BG levels 75% of nights compared with 65% of nights (7-10 yr), 53% of nights (11-14 yr), 33% of nights (15-25 yr), and 28% of nights (26-45 yr), respectively (p < 0.001). Likewise, youngest subjects (and parents) administered insulin boluses 56% of nights during active PLGS use compared with 48%, 33%, 20%, and 25%, respectively (p < 0.001). This was unrelated to study requirements. During the RCT phase, subjects 4-6 yr experienced more frequent and severe skin reactions (p = 0.02), while adult subjects (26-45 yr) wore individual sensors a median of 26 h longer than the youngest subjects (p < 0.001). Technical problems with the sensor (errors, miscalibrations, etc.), traveling, and BG levels >270 at bedtime (study requirement) were primary contributors to non-system use. Understanding the different use patterns and challenges in pediatrics and adolescence is needed to direct patient education to optimize use of PLGS and future artificial pancreas systems. PMID- 27125225 TI - Transcriptomic analysis of Pseudostellariae Radix from different fields using RNA seq. AB - Pseudostellariae Radix is an important traditional Chinese medicine (TCM), which is consumed commonly for its positive health effects. However, a lack of transcriptomic and genomic information hinders research on Pseudostellariae Radix. Here, high-throughput RNA sequencing (RNA-seq) was employed for the de novo assembly to analyze the transcriptome in Pseudostellariae Radix, finding significantly differentially expressed genes in this TCM from different fields based on RNA-seq and bioinformatic analysis. A total of 146,408,539 paired-end reads were generated and assembled into 89,857 unigenes with an average length of 862bp. All of the assembly unigenes were annotated by running BLASTx and BLASTn similarity searches on the Non-redundant nucleotide database (NT), the Non redundant protein database (NR), Swiss-Prot, Cluster of Orthologous Groups (COG), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Interpro. On the basis of bioinformatic analysis and the expression profiles for Pseudostellariae Radix, 29 significantly differentially expressed genes were identified, which provides the basic information for exploring the molecular mechanisms that determine the quality of Pseudostellariae Radix from different fields. The expression levels of 29 genes were validated by real-time quantitative PCR (RT-qPCR). This is the first study to sample Pseudostellariae Radix, which provides an invaluable resource for understanding the genome of this herb. PMID- 27125226 TI - Economic burden of gastrointestinal cancer under the protection of the New Rural Cooperative Medical Scheme in a region of rural China with high incidence of oesophageal cancer: cross-sectional survey. AB - OBJECTIVE: To evaluate the financial burden of oesophageal cancer under the protection of the new Rural Cooperative Medical Scheme (NCMS) and to provide evidence and suggestions to policymakers in a high-incidence region in China. METHODS: We analysed inpatient claim data for oesophageal cancer, gastric cancer and colorectal cancer from 1 January to 31 December 2013. The data were extracted from the NCMS management system of Hua County, Henan Province, a typical high risk region for oesophageal cancer in China. Cancer-specific health economic indicators were calculated to evaluate the financial burden under the protection of the local NCMS. RESULTS: The total cost of oesophageal cancer was 2.7-3.6 times higher than that of gastric cancer and colorectal cancer, respectively, due to high incidence of oesophageal cancer. For each hospitalisation to treat oesophageal cancer, the average total cost and out-of-pocket expenses after reimbursement equalled an entire year's gross domestic product per capita and per capita disposable income, respectively, for the local area. The average total cost per hospitalisation for oesophageal cancer increased monotonically with hospital level for surgical hospitalisations, and it increased more rapidly for non-surgical hospitalisations (from $301 to $2589, 860%) than for gastric cancer (from $289 to $1453, 503%) and colorectal cancer (from $359 to $1610, 448%). Vulnerable groups with less access to high-level hospitals were found in different gender and age groups. CONCLUSIONS: Oesophageal cancer imposes serious financial burdens on communities and patients' households in this high-incidence region, and no preferential policy from the local NCMS has been designed to address this issue. A special supportive policy should be developed on the basis of local disease profiles and population characteristics to alleviate the financial burden of populations at high risk for certain high-cost diseases. PMID- 27125227 TI - One uterus bridging three generations: first live birth after mother-to-daughter uterus transplantation. AB - OBJECTIVE: To determine whether a uterus from the mother of a woman with absolute uterine factor infertility can be transplanted to daughter and carry a pregnancy with delivery of a healthy child. DESIGN: Part of an observational study. SETTING: University teaching hospital. PATIENT(S): Twenty eight-year-old woman with uterine agenesis, her male partner, and her 50-year-old mother. INTERVENTION(S): In vitro fertilization with embryo cryopreservation before live donor uterus transplantation (UTx). Induction immunosuppression. Embryo transfer 12 months after UTx, pregnancy controls, delivery, and hysterectomy. MAIN OUTCOME MEASURE(S): Results of IVF-ET, parameters of pregnancy/birth, and surgical data of transplantation/cesarean section/hysterectomy. RESULT(S): Two IVF cycles before UTx resulted in 10 cryopreserved embryos. Donor surgery included hysterectomy with vascular pedicles of uterine vessels and proximal vessels up to and including parts of internal iliacs. Recipient surgery was by bilateral vascular connections to external iliacs, vaginal-vaginal anastomosis, and uterine fixation. Pregnancy occurred at the first single ET, and the pregnancy proceeded uneventfully until gestational week 34, when the patient developed cholestasis with intense pruritus. Cesarean section was performed at 34+6, with delivery of a healthy boy (weight 2,335 g). Hysterectomy was performed 3.5 months after delivery. The weight of the healthy child at 12 months was 9.3 kg. Grandmother (uterus donor) and mother are in good health 3 years after UTx. CONCLUSION(S): This is the first report of a live birth after mother-to-daughter UTx, and it also represents the second birth ever after human UTx. CLINICAL TRIAL REGISTRATION: NCT01844362. PMID- 27125228 TI - Sociocultural influences on fertility in the Middle East: the role of parental consanguinity, obesity and vitamin D deficiency. PMID- 27125229 TI - Imaging and angiography in male factor infertility. AB - Ultrasound imaging and angiography play a crucial role in the diagnosis and treatment of men with subfertility. The most commonly used imaging modality is ultrasound (US), which can be used for diagnostic purposes or to aid in treatment. Scrotal US can be used to document varicoceles in subfertile men in the context of difficult examination or for confirmation before treatment. Spectral Doppler, sonoelastography, and power Doppler have aided in the evaluation and treatment of azoospermia and oligospermia. They have proven useful in the detection of spermatogenesis and sperm retrieval. In the population with congenital Wolffian duct abnormalities, renal US can evaluate renal anomalies. In subfertile men with low ejaculate volume and oligospermia or azoospermia transrectal US can be used to evaluate and assist in treatment of ejaculatory duct obstruction. Non-US-based modalities are also commonly used in evaluating and treating men with subfertility. Magnetic resonance imaging (MRI) can be used for evaluation of pituitary adenomas in hypogonadism. More invasive imaging modalities used during treatment of subfertile men include vasography for vasal obstruction, venography and angioembolization for varicocele, and US-guided needle placement for testis-sparing surgery. Male subfertility is a complex problem and the use of imaging techniques is often essential in providing accurate diagnosis and appropriate treatment. PMID- 27125230 TI - Body mass index, physical activity and fecundability in a North American preconception cohort study. AB - OBJECTIVE: To evaluate the association between adiposity, physical activity (PA), and fecundability. DESIGN: Prospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 2,062 female pregnancy planners from the United States and Canada who were enrolled during the preconception period. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Self-reported pregnancy. Fecundability ratios (FRs) and 95% confidence intervals (CIs) were estimated using proportional probabilities models that adjusted for potential confounders. RESULT(S): Relative to body mass index (BMI) 18.5-24 kg/m(2), FRs for BMI <18.5, 25-29, 30-34, 35-39, 40-44, and >=45 kg/m(2) were 1.05 (95% CI 0.76-1.46), 1.01 (95% CI 0.89-1.15), 0.98 (95% CI 0.82-1.18), 0.78 (95% CI 0.60-1.02), 0.61 (95% CI 0.42-0.88), and 0.42 (95% CI 0.23-0.76), respectively. Reduced fecundability was observed among women with the largest waist-to-hip ratios (>=0.85 vs. <0.75; FR = 0.87, 95% CI 0.74-1.01) and waist circumferences (>=36 vs. <26 inches [>=90 vs. <66 cm]; FR = 0.80, 95% CI 0.59-1.01). Tendency to gain weight in the chest/shoulders (FR = 0.63, 95% CI 0.36-1.08) and waist/stomach (FR = 0.90, 95% CI 0.79-1.02), relative to hips/thighs, was associated with lower fecundability. Moderate PA was associated with increased fecundability (>=5 vs. <1 h/wk; FR = 1.26, 95% CI 0.96-1.65), but there was no dose-response relation. Among overweight/obese women (BMI >=25 kg/m(2)), fecundability was 27% higher for vigorous PA of >=5 versus <1 h/wk (95% CI 1.02-1.57). CONCLUSION(S): Various measures of overall and central adiposity were associated with decreased fertility among pregnancy planners. Vigorous PA was associated with improved fertility among overweight and obese women only; moderate PA was associated with improved fertility among all women. PMID- 27125232 TI - [Erratum to: Macroscopic and functional anatomy of the apophyseal plate]. PMID- 27125231 TI - [Anterior knee pain after total knee arthroplasty : Causes, diagnosis and treatment]. AB - BACKGROUND: Anterior knee pain is one of the most common complications after total knee arthroplasty. An incidence of up to 30 % has been reported in peer reviewed studies. TARGET: The purpose of this study was to systematically review the literature and to identify determinants that have been analyzed with regard to anterior knee pain. CAUSES: Patient- and knee-specific characteristics, prosthetic designs and operative techniques are addressed as well as functional and neurologic determinants. Instability, increased contact pressure in the patellofemoral joint and patella maltracking due to malrotation of components, offset errors, ligament insufficiencies or patella baja are mechanical reasons for anterior knee pain. Functional causes include pathologic gait patterns, quadriceps imbalance and dynamic valgus. They have to be differentiated from infectious and inflammatory causes as well as soft tissue impingement, arthrofibrosis and neurologic diseases. TREATMENT: A differentiated treatment algorithm is recommended. Often conservative treatment options exist, however, particularly with most mechanical causes revision surgery is necessary. PMID- 27125233 TI - [Patella fractures in knee arthroplasty]. AB - Periprosthetic patella fractures occur both with and without retropatellar joint replacement. A non-operative treatment yields satisfactory results with low morbidity. It can be applied in minimally displaced fractures that have an intact retropatellar component and an intact extensor mechanism, combined with an initial immobilization. The surgical treatment is associated with relatively poor results and with high complication rates. There was only minor improvement of functional results, no matter which surgical technique was used. Surgical intervention is still required in fractures with a loosening of the patellar component, considerable dislocations of fragments, and damage to or rupture of the extensor mechanism. In particular, type II fractures require repair of the extensor mechanism and the fracture or patellectomy. Type III fractures require a revision or resection of the patella, a patelloplasty or total patellectomy. In addition, early or late reconstruction using allograft to restore the extensor mechanism can be taken in consideration. PMID- 27125234 TI - [Patellar tendon injuries after total knee arthroplasty : Classification and management]. AB - BACKGROUND: Ruptures of the patellar tendon after total knee arthroplasty represent a rare but severe complication, which in general requires surgical therapy. OBJECTIVES: To implement a classification and correspondent therapy algorithm in consideration of the current literature for the treatment of patellar tendon ruptures after TKA. MATERIAL AND METHODS: A review of the recent literature and the author's experience are summarized in a classification and correspondent therapy algorithm for the treatment of patellar tendon ruptures after TKA. RESULTS: Ruptures of the patella tendon can be classified as avulsions (Type I), acute (Type II) and chronic ruptures (Type III). Avulsions are often of iatrogenic nature and can be sufficiently treated by transosseous refixation prior to implantation of the revision TKA. Acute ruptures of the patellar tendon can originate from trauma or intraoperative injury. The rupture can be restored by primary suture in combination with a wire cerclage in the case of good tendon quality and the absence of patient comorbidities (Type IIA). In the case of poor tendon quality or existing comorbidities (Type IIB) additional augmentation of the ruptured tendon, utilizing the autologous semitendinosus/gracilis tendon, is recommended. Chronic ruptures revealing a good patellar bone stock (Type IIIA) can be treated by a combination of a semitendinosus augmentation and a turndown quadriceps tendon flap. In the case of a poor patellar bone stock (Type IIIB) transpatellar fixation of the semitendinosus tendon is virtually impossible, so that an allograft augmentation or the use of a soft tissue muscle flap (i. e. the gastrocnemius flap) has to be considered. A failed complex reconstruction with or without infection (Type IIIC) is an invidious surgical task and needs to be addressed by the utilization of a muscle flap, an allograft or a patellectomy with or without arthrodesis. PMID- 27125235 TI - [Quadriceps tendon insufficiency and rupture : Treatment options in total knee arthroplasty]. AB - Quadriceps tendon injuries and insufficiencies in total knee arthroplasty are rare, but are followed by a devastating complication that left untreated leads to a complete loss of function of the knee. This review article summarizes the functional anatomy, risk factors, and the prevalence and diagnosis of quadriceps tendon injuries, in addition to the possible management options for partial and complete ruptures. The treatment options are adapted according to the extent of the loss of function (partial, complete) and the duration of the injury (acute vs chronic). Furthermore, the choice of treatment should take into account the quality and availability of primary tissue, the patient's general health, along with their likely functional requirements. Conservative treatment is often justified in partial ruptures with good results. Complete ruptures require surgical intervention and multiple operative techniques are described. Treatment options for acute ruptures include direct primary repair with autogenous or synthetic tissue augmentation. In the case of chronic insufficiency and a lack of soft-tissue surroundings, reconstruction with the aid of a muscle flap or allograft tissue can be considered. All surgical intervention techniques used so far have been fraught with complications and rarely lead to satisfactory results. A new surgical approach to the reconstruction and augmentation of the extensor mechanism consists of the use of a synthetic mesh. The technique is described here in detail. PMID- 27125236 TI - [Causes and management of patellar instability after total knee replacement : Lateralization, subluxation and luxation]. AB - BACKGROUND: Patellofemoral complications after total knee arthroplasty are responsible for a variety of surgical revisions. OBJECTIVE: The causes of the various types of instability of the patella are listed in a differentiated way and the importance of clinical and imaging diagnostics as well as preventive strategies are elaborated. MATERIAL AND METHODS: This article is based on a selective literature search in the PubMed database and on the long-standing experience of the author. RESULTS: Besides postoperative genu valgum with malalignment of the extensor mechanisms, other risk factors for patellar maltracking are insufficiency of the medial retinaculum, weakening of the vastus medialis muscle, contracture of the quadriceps femoris or tractus iliotibialis muscle, residual valgus deformity after total knee replacement, femoral or tibial malrotation as well as malpositioning of the patella, inappropriate design of the prosthesis and asymmetrical resection of the patella. The causes with respect to incorrect component positioning, faulty preparation of the patella, leg malalignment, inappropriate design of the prosthesis and soft tissue imbalance have to be recognized in order to address the problem in a targeted way. The preferred method of choice in the case of patellofemoral instability after total knee replacement is normally surgery; however, the cause for the instability has to be identified and consequently corrected before surgery. Without a clearly identified cause surgical measures are unrewarding and almost regularly lead to an unsatisfactory outcome. CONCLUSION: Patella maltracking after total knee arthroplasty is multifactorial and requires an accurate clarification. A surgical revision is only recommended in cases of clearly defined causes of pain or a clearly defined reason for patella malpositioning. PMID- 27125238 TI - Kinetics of throwing arm joints and the trunk motion during an overarm distance throw by skilled Japanese elementary school boys. AB - The purpose of this study was to investigate joint kinetics of the throwing arms and role of trunk motion in skilled elementary school boys during an overarm distance throw. Throwing motions of 42 boys from second, fourth, and sixth grade were videotaped with three high-speed cameras operating at 300 fps. Seven skilled boys from each grade were selected on the basis of throwing distance for three dimensional kinetic analysis. Joint forces, torques, and torque powers of the throwing arm joints were calculated from reconstructed three-dimensional coordinate data smoothed at cut-off frequencies of 10.5-15 Hz and by the inverse dynamics method. Throwing distance and ball velocity significantly increased with school grade. The angular velocity of elbow extension before ball release increased with school grade, although no significant increase between the grades was observed in peak extension torque of elbow joint. The joint torque power of shoulder internal/external rotation tended to increase with school grade. When teaching the overarm throw, elementary school teachers should observe large backward twisting of trunk during the striding phase and should keep in mind that young children, such as second graders (age 8 years), will be unable to effectively utilise shoulder external/internal rotation during the throwing phase. PMID- 27125237 TI - Transformation seismology: composite soil lenses for steering surface elastic Rayleigh waves. AB - Metamaterials are artificially structured media that exibit properties beyond those usually encountered in nature. Typically they are developed for electromagnetic waves at millimetric down to nanometric scales, or for acoustics, at centimeter scales. By applying ideas from transformation optics we can steer Rayleigh-surface waves that are solutions of the vector Navier equations of elastodynamics. As a paradigm of the conformal geophysics that we are creating, we design a square arrangement of Luneburg lenses to reroute Rayleigh waves around a building with the dual aim of protection and minimizing the effect on the wavefront (cloaking). To show that this is practically realisable we deliberately choose to use material parameters readily available and this metalens consists of a composite soil structured with buried pillars made of softer material. The regular lattice of inclusions is homogenized to give an effective material with a radially varying velocity profile and hence varying the refractive index of the lens. We develop the theory and then use full 3D numerical simulations to conclusively demonstrate, at frequencies of seismological relevance 3-10 Hz, and for low-speed sedimentary soil (vs: 300-500 m/s), that the vibration of a structure is reduced by up to 6 dB at its resonance frequency. PMID- 27125239 TI - Erratum: Structural revisions of small molecules reported to cross-link G quadruplex DNA in vivo reveal a repetitive assignment error in the literature. PMID- 27125240 TI - Evaporation of droplets in a Champagne wine aerosol. AB - In a single glass of champagne about a million bubbles nucleate on the wall and rise towards the surface. When these bubbles reach the surface and rupture, they project a multitude of tiny droplets in the form of a particular aerosol holding a concentrate of wine aromas. Based on the model experiment of a single bubble bursting in idealized champagnes, the key features of the champagne aerosol are identified. In particular, we show that film drops, critical in sea spray for example, are here nonexistent. We then demonstrate that compared to a still wine, champagne fizz drastically enhances the transfer of liquid into the atmosphere. There, conditions on bubble radius and wine viscosity that optimize aerosol evaporation are provided. These results pave the way towards the fine tuning of flavor release during sparkling wine tasting, a major issue for the sparkling wine industry. PMID- 27125242 TI - HIV-Risk Index: Development and Validation of a Brief Risk Index for Hispanic Young People. AB - The prevalence of HIV risk behaviors among young people facilitates the spread of HIV, in particular regarding unsafe sex behavior, although this trend is different within this population. For this reason, identifying the riskier young population is required to prevent HIV infection. The main purpose of this study was to develop and validate a risk index to assess the different sexual HIV risk exposure among Hispanic Young people. For this purpose, 9861 Spanish young people were randomly distributed into two groups (derivation and validation group). According to the results, the factor analyses grouped the nine items of the HIV- risk index into two factors (factor 1, direct sexual risk indicators and factor 2, indirect sexual risk indicators) with an equal structure for men and women by a multi-group confirmatory factor analysis. The variance explained was 54.26 %. Moreover, the Cronbach's alpha coefficient revealed high internal reliability (alpha = .79) and the convergent validity supported its evidence based on different HIV risk indexes. Therefore, the HIV-risk index seem to be a rigorous and valid measure to estimate HIV risk exposure among young people. PMID- 27125241 TI - The Effect of Depressive Symptoms on Adherence to Daily Oral PrEP in Men who have Sex with Men and Transgender Women: A Marginal Structural Model Analysis of The iPrEx OLE Study. AB - We assessed the role of depressive symptoms on adherence to daily oral FTC/TDF for HIV PrEP in cisgender men who have sex with men (MSM) and transgender women who have sex with men (TGW) using data from the iPrEx OLE study. A marginal structural logistic regression model was used to estimate the effect of time varying CES-D scores on having protective levels of drug concentration, adjusting for confounding by sexual practices over time, prior adherence, and baseline demographic characteristics. We found a non-monotonic relationship between CES-D score and odds of protective FTC/TDF levels in MSM. We found evidence that the effect of depression on adherence varied between MSM and TGW, and that depressive symptoms did not contribute greatly to decreased adherence on a population scale. We recommend that depressive symptoms not preclude the prescription of PrEP, and that MSM and TGW be studied separately. PMID- 27125243 TI - Roles and Functions of Social Networks Among Men Who Use Drugs in ART Initiation in Vietnam. AB - Support from social network members may help to facilitate access to HIV medical care, especially in low resourced communities. As part of a randomized clinical trial of a community-level stigma and risk reduction intervention in Thai Nguyen, Vietnam for people living with HIV who inject drugs (PWID), 341 participants were administered a baseline social network inventory. Network predictors of antiretroviral therapy (ART) initiation at the 6-month follow-up were assessed. The social networks of PWID were sparse. Few participants who reported injectors in their networks also reported family members, whereas those who did not have injectors were more likely to report family members and network members providing emotional support and medical advice. In multivariate models, having at least one network member who provided medical advice predicted ART initiation at 6 months (OR 2.74, CI 1.20-6.28). These results suggest the importance of functional social support and network support mobilization for ART initiation among PWID. PMID- 27125245 TI - Microtechnology-based organ systems and whole-body models for drug screening. AB - After drug administration, the drugs are absorbed, distributed, metabolized, and excreted (ADME). Because ADME processes affect drug efficacy, various in vitro models have been developed based on the ADME processes. Although these models have been widely accepted as a tool for predicting the effects of drugs, the differences between in vivo and in vitro systems result in high attrition rates of drugs during the development process and remain a major limitation. Recent advances in microtechnology enable more accurate mimicking of the in vivo environment, where cellular behavior and physiological responses to drugs are more realistic; this has led to the development of novel in vitro systems, known as "organ-on-a-chip" systems. The development of organ-on-a-chip systems has progressed to include the reproduction of multiple organ interactions, which is an important step towards "body-on-a-chip" systems that will ultimately predict whole-body responses to drugs. In this review, we summarize the application of microtechnology for the development of in vitro systems that accurately mimic in vivo environments and reconstruct multiple organ models. PMID- 27125246 TI - Patient Education and Peritoneal Dialysis Modality Selection: A Systematic Review and Meta-analysis. AB - BACKGROUND: Educational interventions are increasingly used to promote peritoneal dialysis (PD), the most common form of home therapy for end-stage renal disease. A systematic review of the evidence in support of dialysis modality education is needed to inform the design of patient-targeted interventions to increase selection of PD. We performed a systematic review and meta-analysis to characterize the relationship between patient-targeted educational interventions and choosing and receiving PD. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Published original studies and abstracts. SELECTION CRITERIA FOR STUDIES: We searched MEDLINE, EMBASE, CINAHL and EBMR. We included controlled observational studies and randomized trials of educational interventions designed to increase PD selection. INTERVENTION: Predialysis educational interventions. OUTCOMES: The primary outcome was choosing PD, defined as intention to use PD regardless of whether PD was ever used. The secondary outcome, receiving PD, was defined as an individual receiving PD as his or her treatment. RESULTS: Of 3,540 citations, 15 studies met our inclusion criteria, including 1 randomized trial. In the single randomized trial (N=70), receipt of an educational intervention was associated with a more than 4-fold increase in the odds of choosing PD (OR, 4.60; 95% CI, 1.19-17.74). Based on results from 4 observational studies (N=7,653), patient-targeted educational interventions were associated with a 2-fold increase in the odds of choosing PD (pooled OR, 2.15; 95% CI, 1.07-4.32; I(2)=76.7%). Based on results from 9 observational studies (N=8,229), patient-targeted educational intervention was associated with a 3-fold increase in the odds of receiving PD as the initial treatment modality (OR, 3.50; 95% CI, 2.82-4.35; I(2)=24.9%). LIMITATIONS: Most studies were observational studies, which can establish an association between education and choosing PD or receiving PD, but does not establish causality. CONCLUSIONS: This systematic review demonstrates a strong association between patient-targeted education interventions and the subsequent choice and receipt of PD. PMID- 27125244 TI - Social Network Strategies to Address HIV Prevention and Treatment Continuum of Care Among At-risk and HIV-infected Substance Users: A Systematic Scoping Review. AB - Social network analysis (SNA) and social network-based interventions (SNI) are important analytical tools harnessing peer and family influences critical for HIV prevention and treatment among substance users. While SNA is an effective way to measure social network influences, SNI directly or indirectly involves network members in interventions. Even though these methods have been applied in heterogeneous ways, leading to extensive evidence-based practices, systematic reviews are however, lacking. We searched five bibliographic databases and identified 58 studies involving HIV in substance users that had utilized SNA or SNI as part of their methodology. SNA was used to measure network variables as inputs in statistical/mathematical models in 64 % of studies and only 22 % of studies used SNI. Most studies focused on HIV prevention and few addressed diagnosis (k = 4), care linkage and retention (k = 5), ART adherence (k = 2), and viral suppression (k = 1). This systematic review highlights both the advantages and disadvantages of social network approaches for HIV prevention and treatment and gaps in its use for HIV care continuum. PMID- 27125247 TI - Towards universal buckling dynamics in nanocolloidal sessile droplets: the effect of hydrophilic to superhydrophobic substrates and evaporation modes. AB - The evaporation of a nanocolloidal sessile droplet exhibits preferential particle assembly, nanoporous shell formation and buckling to form cavities with unique morphological features. Here, we have established many universal trends that explain the buckling dynamics under one umbrella irrespective of hydrophobicity, evaporation mode and particle loading. We provide a regime map explaining the droplet morphology and buckling characteristics for droplet evaporation on various substrates. Specifically, we find that the final droplet volume and the radius of curvature at the buckling onset are universal functions of particle concentration. Furthermore, we establish that post-buckling cavity growth is evaporation driven regardless of the substrate. PMID- 27125248 TI - Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index. AB - The transmembrane receptor guanylate cyclase-C (GC-C) signaling pathway has been implicated in several gastrointestinal disorders. Activation of GC-C via guanylin (Gn) and uroguanylin (Ugn) regulates intestinal fluid and electrolyte homeostasis. However, how it regulates the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Here, we investigated the activation of GC-C signaling in ulcerative colitis (UC) of different clinical severities. A total of 60 UC patients and 20 normal controls were recruited. Evaluation of the UC disease activity index (DAI) was performed using a modified Mayo scoring system. The expression of GC-C, Gn and Ugn in the colonic mucosa was measured by quantitative real-time PCR and Western blot. We found that the UC patients had significantly lower expression of GC-C, Gn and Ugn than the controls. Furthermore, there were significant differences for GC-C, Gn and Ugn expression for the UC groups of Grade 1, 2 and 3, and their expression levels were reduced with increases in their DAI. Taken together, our results demonstrate that GC-C, Gn and Ugn are downregulated in UC, and this downregulation is more significant with aggravation of the clinical condition. Therefore, the GC-C signaling pathway may be implicated in the progression of UC. PMID- 27125249 TI - Maternal control and early child dysregulation: Moderating roles of ethnicity and child delay status. AB - BACKGROUND: Maternal controlling behaviour has been found to influence child development, particularly in behavioural and emotional regulation. Given the higher rates of interfering parent control found in mothers of children with developmental delays (DD) and Latina mothers, their children could be at increased risk for behavioural and emotional dysregulation. While studies generally support this increased risk for children with DD, findings for Latino children are mixed and often attributed to cultural models of child rearing. The present study sought to determine the moderating roles of child DD and mother ethnicity in determining the relationships between two types of parent control (supportive directiveness and interference) and child dysregulation over time. METHODS: The present study, involving 178 3-year old children with DD (n = 80) or typical development (n = 98), examined observed parent control (directive versus interfering) of Latina and Anglo mothers as it relates to change in preschool child dysregulation over 2 years. RESULTS: Interfering parent control was greater for children with DD and also for Latino mothers. Supportive directive parenting generally related to relatively greater decline in child behaviour and emotion dysregulation over time, while interfering parenting generally related to less decline in child behaviour dysregulation over time. In Anglo but not Latino families, these relationships tended to vary as a function of child disability. CONCLUSIONS: Parent directives that support, rather than deter, ongoing child activity may promote positive regulatory development. These results particularly hold for children with DD and Latino families, and have implications for parenting practices and intervention. PMID- 27125251 TI - Positive predictive values of selected hospital discharge diagnoses to identify infections responsible for hospitalization in the French national hospital database. AB - PURPOSE: The identification of infections in electronic health databases is a key issue for pharmacoepidemiology research. The aim of this study was to assess the positive predictive values (PPVs) of hospitalizations for infection in the Systeme National d'Information Inter-regimes de l'Assurance Maladie, that is the electronic database recording in-and-out hospital data for the entire French population (66 million inhabitants). METHODS: The source of data was the database of hospitalizations (Programme de Medicalisation des Systemes d'Informations) of Toulouse University hospital, South of France (2880 beds). Among all hospital stays between September and December 2014, we randomly selected 100 stays with an International Classification of Diseases, 10th revision code of infection as primary diagnosis and 100 as related diagnosis. Medical charts were reviewed to assess the PPV of infection codes, as well as the PPV of correct coding of infection type among the true positive cases. RESULTS: The PPVs of codes of infection as reason for hospitalization were 0.97, 95% confidence interval (CI) [0.93-1.00] for primary diagnosis codes and 0.70, 95% CI [0.61-0.71] for related diagnosis codes. Among the true positive cases, the PPVs of correct coding of the type of infection were, respectively, 0.98, 95% CI [0.95-1.00] and 0.93, 95% CI [0.88-0.98]. CONCLUSIONS: Hospitalizations for infection codes have very good PPVs in the Programme de Medicalisation des Systemes d'Informations. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27125250 TI - PATZ1 is a target of miR-29b that is induced by Ha-Ras oncogene in rat thyroid cells. AB - The regulatory transcriptional factor PATZ1 is constantly downregulated in human thyroid cancer where it acts as a tumour suppressor by targeting p53-dependent genes involved in Epithelial-Mesenchymal Transition and cell migration. The aim of the present work was to elucidate the upstream signalling mechanisms regulating PATZ1 expression in thyroid cancer cells. The bioinformatics search for microRNAs able to potentially target PATZ1 led to the identification of several miRNAs. Among them we focused on the miR-29b since it was found upregulated in rat thyroid differentiated cells transformed by the Ha-Ras oncogene towards a high proliferating and high migratory phenotype resembling that of anaplastic carcinomas. Functional assays confirmed PATZ1 as a target of miR-29b, and, consistently, an inverse correlation between miR-29b and PATZ1 protein levels was found upon induction of Ha-Ras oncogene expression in these cells. Interestingly, restoration of PATZ1 expression in rat thyroid cells stably expressing the Ha-Ras oncogene decreased cell proliferation and migration, indicating a key role of PATZ1 in Ras-driven thyroid transformation. Together, these results suggest a novel mechanism regulating PATZ1 expression based on the upregulation of miR-29b expression induced by Ras oncogene. PMID- 27125252 TI - Prediction of HCV vertical transmission: what factors should be optimized using data mining computational analysis. AB - BACKGROUND & AIMS: Neonates born to hepatitis C virus (HCV)-positive mothers are usually not screened for HCV. Unscreened children may act as active sources for social HCV transmission, and factors contributing for vertical HCV transmitting still remained controversial and needed optimization. We aimed to investigate the factors contributing for vertical HCV transmission in Egypt; the highest HCV prevalence worldwide. METHODS: We prospectively followed the neonates born to HCV positive mother in the child-bearing period, to identify mother-to-child transmission (MTCT) factors from January 2015 to March 2016. Data mining computational analysis was used to quantify the findings. RESULTS: Among 3000 randomized pregnant women, prevalence of HCV was 46/3000 (1.53%). HCV vertical transmission was identified in eight neonates (17.39%). Only high viral load identified at 975.000 IU was the predictor risk for MTCT. CONCLUSIONS: Hepatitis C virus in pregnancy has substantial risk for vertical HCV transmission: High viral load in HCV-positive women increases the risk of HCV transmission to neonates. Screening pregnant women during early stage of pregnancy and optimizing the HCV viral load in HCV-positive women might prevent vertical HCV transmission to neonates. PMID- 27125253 TI - Topographical modulation of macrophage phenotype by shrink-film multi-scale wrinkles. AB - The host immune response to foreign materials is a major hurdle for implanted medical devices. To control this response, modulation of macrophage behavior has emerged as a promising strategy, given their prominent role in inflammation and wound healing. Towards this goal, we explore the effect of biomimetic multi-scale wrinkles on macrophage adhesion and expression of phenotype markers. We find that macrophages elongate along the direction of the uniaxial wrinkles made from shape memory polymers, and express more arginase-1 and IL-10, and less TNF-alpha, suggesting polarization towards an alternatively activated, anti-inflammatory phenotype. Materials were further implanted in the subcutaneous space of mice and tissue surrounding the material evaluated by histology and immunohistochemistry. We found that material surface topography altered the distribution of collagen deposition in the adjacent tissue, with denser collagen tissue observed near flat materials when compared to wrinkled materials. Furthermore, cells surrounding wrinkled materials exhibited higher arginase-1 expression. Together these data suggest that wrinkled material surfaces promote macrophage alternative activation, and may influence the foreign body response to implants. PMID- 27125254 TI - Identification of a small protein domain present in all plant lineages that confers high prephenate dehydratase activity. AB - l-Phenylalanine serves as a building block for the biosynthesis of proteins, but also as a precursor for a wide range of plant-derived compounds essential for plants and animals. Plants can synthesize Phe within the plastids using arogenate as a precursor; however, an alternative pathway using phenylpyruvate as an intermediate, described for most microorganisms, has recently been proposed. The functionality of this pathway requires the existence of enzymes with prephenate dehydratase (PDT) activity (EC 4.2.1.51) in plants. Using phylogenetic studies, functional complementation assays in yeast and biochemical analysis, we have identified the enzymes displaying PDT activity in Pinus pinaster. Through sequence alignment comparisons and site-directed mutagenesis we have identified a 22-amino acid region conferring PDT activity (PAC domain) and a single Ala314 residue critical to trigger this activity. Our results demonstrate that all plant clades include PAC domain-containing ADTs, suggesting that the PDT activity, and thus the ability to synthesize Phe using phenylpyruvate as an intermediate, has been preserved throughout the evolution of plants. Moreover, this pathway together with the arogenate pathway gives plants a broad and versatile capacity to synthesize Phe and its derived compounds. PAC domain-containing enzymes are also present in green and red algae, and glaucophytes, the three emerging clades following the primary endosymbiont event resulting in the acquisition of plastids in eukaryotes. The evolutionary prokaryotic origin of this domain is discussed. PMID- 27125255 TI - Safety of anti-rheumatic drugs for rheumatoid arthritis in pregnancy and lactation. AB - Women with rheumatoid arthritis (RA) are often of childbearing age and therefore questions regarding reproductive health and the use of medications, including disease-modifying anti-rheumatic drugs (DMARDs) may arise during the clinical consultation. Each patient requires individual assessment in order to effectively manage the disease while minimizing any treatment-associated risks to the fetus. Although good-quality controlled trials are lacking, there is an increasing volume of evidence surrounding the use of immunosuppressive therapies in pregnancy and lactation. This review summarizes the currently available information which can be of benefit to clinicians guiding patients and their families through the risks and benefits of continuing RA therapy during pregnancy and lactation. Further studies and ongoing surveillance of drug safety in pregnancy are required to resolve the uncertainties that remain regarding synthetic and biologic DMARDs. PMID- 27125256 TI - Smoking increases donor site complications in breast reconstruction with DIEP flap. AB - OBJECTIVE: Reconstruction with deep inferior epigastric perforator flap (DIEP) is considered to be the first choice for autologous breast reconstruction. The primary aims of this retrospective study were to find out if differences in smoking habits and BMI are useful predictors for postoperative complications in DIEP surgery. METHODS: Three hundred and one patients were included. Data regarding smoking habits, BMI, age at surgery, total and final flap weight, abdominal scars, parity, number of perforators, chemotherapy, post mastectomy radiation therapy, and preoperative mapping of perforators with either Computer Tomography Angiography or hand-held ultra sound Doppler were collected. Complications that occurred in the first 30 postoperative days were taken into account. RESULTS AND CONCLUSIONS: It was found that former smokers had a risk for donor site complication more than double that of never smokers (OR =2.12, CI =1.10-4.10, p = 0.025). Differences in BMI within the range from 18-33.7 did not have any significant impact on complication rates, neither at the donor site nor at the breast. PMID- 27125257 TI - Lisdexamfetamine: A pharmacokinetic review. AB - Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saude (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. PMID- 27125258 TI - Homo- and Heteropolynuclear Complexes Containing Bidentate Bridging 4-Phosphino-N Heterocyclic Carbene Ligands. AB - The abnormal reaction of phosphaalkenes with N-heterocyclic carbenes (NHC) offers a convenient method to introduce new functionality at the backbone of an NHC. The 4-phosphino-substituted NHC (1a) derived from 1,3-dimesitylimidazol-2-ylidene (IMes) and MesP?CPh2 is shown to be an effective bifunctional ligand for Au(I) and Pd(II). Several new complexes are reported: 2a: 1a.AuCCl, 3a: 1a.(AuCl)2, 4a: [(1a)2AuC]Cl, 5a: [(1a.AuPCl)2AuC]Cl], and 6a: 1a.(PdC) (AuPCl). The reaction of 4-phosphino-NHC 1b, derived from 1,3-di(cyclohexyl)imidazol-2-ylidene (ICy) and MesP?C(4-C6H4F)2, with (tht)AuCl (2 equiv, tht = tetrahydrothiophene) affords the fascinating tetranuclear 5b [(1b.AuPCl)2AuC][AuCl2]. The molecular structure of 5b features a close Au...Au contact (3.0988(4) A) between the bis(carbene)gold(I) cation and the dichloroaurate(I) anion. The buried volumes (%Vbur) and Tolman cone angles for representative 4-phosphino-NHCs calculated from structural data are compared to related carbenes and phosphines. The molecular structures are reported for complexes 3a, 4a, 5b, and 6a. PMID- 27125259 TI - Analysis of association of FOXO3 gene with Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy. AB - FOXO3, a member of the Forkhead family of proteins, plays a role in controlling immune response. FOXO3 gene variant rs12212067 has been associated to differential severity of infectious diseases like malaria. In this study, we assessed whether this FOXO3 gene polymorphism is related to susceptibility to infection by Trypanosoma cruzi and/or chronic Chagasic cardiomyopathy. A total of 1171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and chronic Chagasic cardiomyopathy (n = 401) were genotyped for the FOXO3 rs12212067 using TaqMan allelic discrimination. Our results showed no statistically significantly differences between allelic and genotypic frequencies of rs12212067 in seronegative individuals compared with seropositive individuals. Similarly, we observed no evidence of association when asymptomatic individuals were compared with chronic Chagasic cardiomyopathy patients. Our data suggest that the FOXO3 genetic variant rs12212067 do not play an important role in Chagas disease. PMID- 27125260 TI - Absence or low density of Propionibacterium acnes in comedonal lesions of acne patients? A surface to inside study of skin fluorescence. PMID- 27125261 TI - Association between atopic dermatitis and extracutaneous infections in US adults. PMID- 27125262 TI - Composition- and temperature-driven phase transition characteristics and associated electromechanical properties in Bi0.5Na0.5TiO3-based lead-free ceramics. AB - In this study, a lead-free ceramic system comprising (0.94 - x)Bi0.5Na0.5TiO3 0.06BaTiO3-xBi(Zn0.5Ti0.5)O3 (BNT-BT-BZT) was designed and prepared by a conventional solid-state reaction method. The effect of the addition of BZT on the phase transition characteristics and associated electromechanical properties of BNT-BT was systematically discussed and a schematic phase diagram was established. The addition of BZT had a strong impact on the phase transition as well as the strain and piezoelectric activity. The phase coexistence, which involves ferroelectric rhombohedral-relaxor pseudocubic phases, can be driven by modification with BZT and increases in temperature and can be confirmed by XRD measurements, analysis of Raman spectra and temperature-dependent changes in polarization and strain hysteresis loops. Accompanied by a shift in the ferroelectric-to-relaxor temperature TF-R to below room temperature on the addition of BZT, a compositionally induced ferroelectric-to-relaxor phase transition occurred, which gave rise to a large strain of 0.33% with a normalized strain Smax/Emax of 550 pm V(-1) at the critical BZT content x of 0.0275. The results were closely correlated with the composition and dependence on temperature of the phase transition, which significantly influenced the electromechanical properties, and the origin of the large strain observed in the present system was also addressed in detail. As a result, the design principles provided in this study open the possibility of obtaining BNT-based lead-free ceramics with enhanced electromechanical properties for actuator applications. PMID- 27125263 TI - Fenestrated Transcatheter ASD Closure in Adults with Diastolic Dysfunction and/or Pulmonary Hypertension: Case Series and Review of the Literature. AB - OBJECTIVES: This study aims to evaluate the safety and efficacy of transcatheter fenestrated ASD closure and to summarize the literature regarding the published techniques and outcomes of transcatheter partial ASD closure. BACKGROUND: Patients with left ventricular diastolic dysfunction (LVDD) or right ventricular (RV) dysfunction and/or pulmonary hypertension (PHT) may suffer untoward consequences of complete closure of an ostium secundum atrial septal defect (ASD). Therefore, for patients that fall under these categories we suggest partial occlusion of the defect, which may be better tolerated than complete defect closure. METHODS AND PATIENTS: After obtaining IRB approval, a search for patients that have undergone percutaneous ASD closure was performed in the Ahmanson/UCLA Adult Congenital Heart Disease Center database to identify which patients received a fenestrated ASD closure device. RESULTS: Eight consecutive patients ranging between 22 and 83 years of age (mean 48 years) with PHT and/or LVDD or RV dysfunction who underwent fenestrated transcatheter ASD closure at UCLA were identified. None of the subjects experienced complications related to the procedure. Postprocedure clinical evaluation showed improvement in symptoms and exercise capacity. Available follow-up transthoracic echocardiography data (mean 4 months, range 0-20 months) demonstrated patent fenestrations in four of eight patients. None of the patients had thromboembolic or infectious complications and there were no device migrations, erosions or embolizations. CONCLUSIONS: Partial ASD occlusion in patients with diastolic dysfunction or RV dysfunction and/or PHT is safe and may be better tolerated than complete ASD closure in selected patients. PMID- 27125265 TI - Publisher's Comment. PMID- 27125264 TI - Lingonberries alter the gut microbiota and prevent low-grade inflammation in high fat diet fed mice. AB - BACKGROUND: The gut microbiota plays an important role in the development of obesity and obesity-associated impairments such as low-grade inflammation. Lingonberries have been shown to prevent diet-induced obesity and low-grade inflammation. However, it is not known whether the effect of lingonberry supplementation is related to modifications of the gut microbiota. The aim of the present study was to describe whether consumption of different batches of lingonberries alters the composition of the gut microbiota, which could be relevant for the protective effect against high fat (HF)-induced metabolic alterations. METHODS: Three groups of C57BL/6J mice were fed HF diet with or without a supplement of 20% lingonberries from two different batches (Lingon1 and Lingon2) during 11 weeks. The composition and functionality of the cecal microbiota were assessed by 16S rRNA sequencing and PICRUSt. In addition, parameters related to obesity, insulin sensitivity, hepatic steatosis, inflammation and gut barrier function were examined. RESULTS: HF-induced obesity was only prevented by the Lingon1 diet, whereas both batches of lingonberries reduced plasma levels of markers of inflammation and endotoxemia (SAA and LBP) as well as modified the composition and functionality of the gut microbiota, compared to the HF control group. The relative abundance of Akkermansia and Faecalibacterium, genera associated with healthy gut mucosa and anti inflammation, was found to increase in response to lingonberry intake. CONCLUSIONS: Our results show that supplementation with lingonberries to an HF diet prevents low-grade inflammation and is associated with significant changes of the microbiota composition. Notably, the anti-inflammatory properties of lingonberries seem to be independent of effects on body weight gain. PMID- 27125266 TI - The effect of erythropoietin on biomechanical properties of the Achilles tendon during the healing process: an experimental study. AB - BACKGROUND: The aim of this study was to examine the potential biomechanical and histological benefits of systemic erythropoietin administration during the healing of Achilles tendon injury in a rat experimental model. METHODS: Eighty Sprague-Dawley female rats were included in this study. Animals were randomly assigned into two groups with 40 animals in each: erythropoietin group and control group. Then each group was further divided into four subgroups corresponding to four time points with 10 animals in each. A full-thickness cut was made on the Achilles tendon of each animal and then the tendon was sutured with modified Kessler method. Erythropoietin groups received intraperitoneal erythropoietin (500 IU/kg/day) every day at same time throughout the study period, and the control groups received saline in a similar manner. Animals were sacrificed at four time points, and tensile test was performed on each tendon sample to assess maximum load for each sample. In addition, histopathological examination and scoring was done. RESULTS: Both groups had improvement on tensile test (maximum load) over time. However, groups did not differ with regard to maximum load in any of the time points. Similarly, groups did not differ with regard to any of the histopathological scores over time. CONCLUSIONS: The findings of this study do not support the benefit of systemic erythropoietin administration in Achilles tendon healing process. Further evidence from larger experimental studies is required to justify any such potential benefit. PMID- 27125267 TI - Corticosterone Methyl Oxidase Deficiency Type 1 with Normokalemia in an Infant. AB - Isolated aldosterone synthase deficiency may result in life-threatening salt wasting and failure to thrive. The condition involves hyperkalemia accompanying hyponatremia. Two types of aldosterone synthase deficiency may be observed depending on hormone levels: corticosterone methyl oxidase type 1 (CMO 1) and CMO 2. Herein, we describe a Turkish infant patient with aldosterone synthase deficiency who presented with failure to thrive and salt wasting but with normal potassium levels. Urinary steroid characteristics were compatible with CMO I deficiency. Diagnosis of aldosterone synthase deficiency was confirmed by mutational analysis of the CYP11B2 gene which identified the patient as homozygous for two mutations: c.788T>A (p.Ile263Asn) and c.1157T>C (p.Val386Ala). Family genetic study revealed that the mother was heterozygous for c.788T>A and homozygous for c.1157T>C and the father was heterozygous for both c.788T>A and c.1157T>C. To the best of our knowledge, this is only the second Turkish case with a confirmed molecular basis of type 1 aldosterone synthase deficiency. This case is also significant in showing that spot urinary steroid analysis can assist with the diagnosis and that hyperkalemia is not necessarily part of the disease. PMID- 27125268 TI - In Vivo Trial of a Novel Atraumatic Urinary Catheter Design for Prevention of Catheter-Induced Trauma. AB - PURPOSE: Clinically significant urinary tract infection may be the most familiar complication of urinary catheterization; however, catheter-associated trauma can entail even more significant morbidity. We have designed and patented a novel atraumatic urinary catheter (AUC) and through this study, we compare its efficacy with the conventional Foley catheter (FC) in vivo. MATERIALS AND METHODS: Forty male rabbits were divided into two equal groups for FC and AUC. The animals were catheterized on day 4 for 8 hours to compare the maintenance of the tubes and sedated before standardized forcible extraction of the catheter under sedation with the balloon still inflated. They were then examined visually and by cystoscopy. RESULTS: In a number of animals in either group, the catheters failed to drain urine effectively due to anatomical issues. Those were excluded from the study. At the extraction phase, evidence of urethral trauma was found in 13 of 15 FC rabbits, but only in 4 of 14 in the AUC group (p = 0.009). Major trauma, however, was exclusively seen in the FC group, with 12 of 15 subjects sustaining deep lacerations or urethral disruption. CONCLUSION: The two catheters bear similar efficacy for maintaining urine drainage; however, traumatic injury is significantly less common following forceful extraction of the AUC than a conventional Foley. PMID- 27125269 TI - Longitudinal bioimpedance assessments to evaluate hydration in POEMS syndrome. AB - Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a rare paraneoplastic disorder associated with an underlying plasma cell dyscrasia and multiorgan failure. POEMS syndrome is potentially fatal and adversely affects quality of life. Oedema is common with many patients affected by pleural effusions, ascites and lower limb oedema. Bioelectrical impedance vector analysis (BIVA) is a non-invasive assessment tool, which enables rapid bedside assessments of nutrition and hydration. This paper describes the use of sequential BIVA assessments to evaluate the response to diuretic therapy in a woman aged 52 years with POEMS syndrome. This case illustrates the potential to use BIVA to conduct longitudinal assessments of hydration status. This provides opportunities for further research using BIVA to monitor hydration and response to interventions. This may be useful in specific situations, for example at the end of life. PMID- 27125270 TI - "A monster that lives in our lives": experiences of caregivers of people with motor neuron disease and identifying avenues for support. AB - BACKGROUND: A developing body of evidence has provided valuable insight into the experiences of caregivers of people with motor neuron disease; however, understandings of how best to support caregivers remain limited. AIM: This study sought to understand concepts related to the motor neuron disease caregiver experience which could inform the development of supportive interventions. DESIGN: A qualitative thematic analysis of a one-off semistructured interview with caregivers was undertaken. SETTING/PARTICIPANTS: Caregivers of people with motor neuron disease were recruited from a progressive neurological diseases clinic in Melbourne, Australia. RESULTS: 15 caregivers participated. Three key themes were identified: (1) The Thief: the experience of loss and grief across varied facets of life; (2) The Labyrinth: finding ways to address ever changing challenges as the disease progressed; (3) Defying fate: being resilient and hopeful as caregivers tried to make the most of the time remaining. CONCLUSIONS: Caregivers are in need of more guidance and support to cope with experiences of loss and to adapt to changeable care giving duties associated with disease progression. Therapeutic interventions which target these experiences of loss and change are worth investigation. TRIAL REGISTRATION NUMBER: ACTRN12615000120572, pre-results. PMID- 27125271 TI - Evaluation of the Impact of Pneumococcal Conjugate Vaccine on Pediatric Community Acquired Pneumonia Using an Emergency Database System. AB - Background.: A 13-valent pneumococcal conjugate vaccine (PCV13) seems to be associated with a reduction of community-acquired pneumonia (CAP) in children. Methods.: To explore the link between PCV13 implementation and children' visits in emergency departments (EDs) for pneumonia, we analyzed mandatory Electronics Emergency Department Abstracts (EEDA), in 7 EDs, located in southern France, from 2009 to 2014. Diagnosis related to visits were coded using International Classification Diseases-10 codes. All codes available for EEDA were used to define bacterial pneumonia (BP), viral pneumonia (VP), and nonspecific pneumonia (NSP). For adjustment, we also used codes related to influenza and bronchiolitis. Comparisons between periods (pre-PCV13, transitional, early post-PCV13, and late post-PCV13) were made by logistic regression. On daily aggregated data, a general linear model was constructed with daily proportion of BP as dependent variable, period as fixed factor, and daily proportion of viral respiratory infections (flu plus bronchiolitis) as covariate. Results.: Among 718 758 visits, 7284 were coded as CAP. A significant decline in CAP was noted only for children between 2 and 5 years of age. In contrast, the proportion of BP was dramatically reduced: 2.49 vs 5.17/1000 visits (odds ratio, 0.48; 95% confidence interval, 0.42-0.55), whereas the proportion of VP was similar and NSP increased. After adjustment on influenza plus bronchiolitis, the decrease of BP remained significant. Conclusions.: Electronics Emergency Department Abstracts analysis confirms an important reduction in children ED visits for BP after PCV13 implementation. The EEDA also allow a real-time surveillance of pneumonia and an adjustment on confounding factors, such as viral respiratory infections. PMID- 27125272 TI - Congenital and Neonatal Chikungunya in Colombia. AB - In Latin America and the Caribbean (LAC), chikungunya (CHIK) viral infection has emerged as a significant arboviral disease. This rapidly expanding vector-borne viral illness is associated with a substantial burden of disease in terms of acute illness and also in terms of long-term sequelae. In addition, this viral pathogen has the ability to impact different populations including pregnant women and newborns. Despite the growing threat of this arboviral infection to the region, there are insufficient reports or studies attempting to delineate the clinical and epidemiological features of congenital and neonatal cases of CHIK in LAC. In this study, we present a case of congenital CHIK and a case of neonatal CHIK infection identified in Santander, Colombia. We discuss the potential neurological impact and sequelae of CHIK infection acquired during the neonatal period. There is an urgent need for further epidemiological and clinical studies to better understand the impact of CHIK in endemic areas in LAC. PMID- 27125273 TI - Effectiveness of the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D-Conjugated Vaccine (PHiD-CV) Against Carriage and Acute Otitis Media-A Double-Blind Randomized Clinical Trial in Finland. AB - After administering the 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D-conjugated vaccine (PHiD-CV) to children aged 2 18 months, we observed a reduction in vaccine-type nasopharyngeal carriage, resulting in a reduction of overall pneumococcal nasopharyngeal carriage, which may be important for indirect vaccine effects. We noted a trend toward reduction of acute otitis media. BACKGROUND: This trial (ClinicalTrials.gov identifier NCT00839254), nested within a cluster-randomized double-blind invasive pneumococcal disease effectiveness study in Finland (ClinicalTrials.gov identifier NCT00861380), assessed the effectiveness of the 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D-conjugated vaccine (PHiD-CV or PCV10) against bacterial nasopharyngeal carriage and acute otitis media (AOM). METHODS: Infants (aged 6 weeks to 6 months) received the PHiD-CV or a control vaccine (hepatitis B) (schedule 3+1 or 2+1). Nasopharyngeal swabs were collected at 4 time points post-vaccination from all of the infants and at pre vaccination from a subset. Parent-reported physician-diagnosed AOM was assessed from first vaccination until last contact (mean follow-up, 18 months). Vaccine effectiveness (VE) was derived as (1 - relative risk)*100, accounting for cluster design in AOM analysis. Significant VE was assessed descriptively (positive lower limit of the non-adjusted 95% confidence interval [CI]). RESULTS: The vaccinated cohort included 5093 infants for carriage assessment and 4117 infants for AOM assessment. Both schedules decreased vaccine-serotype carriage, with a trend toward a lesser effect from the 2+1 schedule ( VE across timpoints 19%-56% [3+1] and 1%-38% [2+1]). Trends toward reduced pneumococcal carriage (predominantly vaccine serotypes 6B, 14, 19F, and 23F), decreased carriage of vaccine-related serotype 19A, and small increases at later time points (ages 14-15 months) in non vaccine-serotype carriage were observed. No effects on nontypeable Haemophilus influenzae, Staphylococcus aureus, or Moraxella catarrhalis carriage were observed. There were non-significant trends toward a reduction in the number of infants reporting AOM episodes (VE 3+1: 6.1% [95% CI, -2.7% to 14.1%] and 2+1: 7.4% [-2.8% to 16.6%]) and all AOM episodes (VE 3+1: 2.8% [-9.5% to 13.9%] and 2+1: 10.2% [-4.1% to 22.9%]). PHiD-CV was immunogenic and had an acceptable safety profile. CONCLUSIONS: We observed reduced vaccine-type pneumococcal carriage, a limited increase in non-vaccine-type carriage, and a trend toward AOM reduction. PMID- 27125274 TI - Gastric and pyloric sphincter muscle function and the developmental-dependent regulation of gastric content emptying in the rat. AB - Feeding intolerance is a common issue in the care of preterm neonates. The condition manifests as delayed emptying of gastric contents and represents a therapeutic challenge, since the factors accounting for its manifestations are unknown. The main goal of this study was to comparatively investigate the age related function of rat gastric and pyloric smooth muscle and their putative regulators. We hypothesized that a reduced gastric muscle contraction potential early in life contributes to the delayed gastric emptying of the newborn. Newborn and adult rat gastric (fundus) and pyloric sphincter tissues were comparatively studied in vitro. Shortening of the tissue-specific dissociated smooth muscle cell was evaluated, and expression of the key regulatory proteins Rho-associated kinase 2 and myosin light chain kinase was determined. Gastric and pyloric smooth muscle cell shortening was significantly greater in the adult than the respective newborn counterpart. Expression of myosin light chain kinase and Rho-associated kinase 2 was developmentally regulated and increased with age. Pyloric sphincter muscle expresses a higher neuronal nitric oxide synthase and phosphorylated vasodilator-stimulated phosphoprotein content in newborn than adult tissue. Compared with later in life, the newborn rat gastropyloric muscle has a Ca(2+) related reduced potential for contraction and the pyloric sphincter relaxation dependent modulators are overexpressed. To the extent that these rodent data can be extrapolated to humans, the delayed gastric emptying in the newborn reflects reduced stomach muscle contraction potential, as opposed to increased pyloric sphincter tone. PMID- 27125275 TI - Inhibition of SIRT2 suppresses hepatic fibrosis. AB - Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis. PMID- 27125276 TI - Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon. AB - Keratins (K) are intermediate filament proteins important in protection from stress. The roles of keratins in the intestine are not clear, but K8 knockout (K8(-/-)) mice develop a Th2-type colonic inflammation, epithelial hyperproliferation, and mild diarrhea caused by a keratin level-dependent decrease in short-circuit current and net sodium and chloride absorption in the distal colon. The lack of K8 leads to mistargeting or altered levels of membrane proteins in colonocytes; however, the main transporter responsible for the keratin-related ion transport defect is unknown. We here analyzed protein and mRNA levels of candidate ion transporters CFTR, PAT-1, NHE-3, and DRA in ileum, cecum, and proximal and distal colon. Although no differences were observed for CFTR, PAT-1, or NHE-3, DRA mRNA levels were decreased by three- to fourfold and DRA protein was almost entirely lost in K8(-/-) cecum and proximal and distal colon compared with K8(+/+), whereas the levels in ileum were normal. In K8(+/-) mice, DRA mRNA levels were unaltered, while decreased DRA protein levels were detected in the proximal colon. Immunofluorescence staining confirmed the loss of DRA in K8(-/-) distal colon, while K8(+/-) displayed a similar but more patchy apical DRA distribution compared with K8(+/+) DRA was similarly decreased when K8 was knocked down in Caco-2 cells, confirming that K8 levels modulate DRA levels in an inflammation-independent manner. Taken together, the loss of DRA in the K8( /-) mouse colon and cecum explains the dramatic chloride transport defect and diarrheal phenotype after K8 inactivation and identifies K8 as a novel regulator of DRA. PMID- 27125277 TI - Two-Dimensional Crystallization of P22 Virus-Like Particles. AB - Virus-like particles (VLPs) are well established platforms for constructing functional biomimetic materials. The VLP from the bacteriophage P22 can be used as a nanocontainer to sequester active enzymes, at high concentration, within its cavity through a process of directed self-assembly. Construction of ordered 2D assemblies of these catalytic VLPs can be envisioned as a functional membrane. To achieve this, it is important to establish methods to fabricate densely packed monolayers of VLPs. Highly ordered assemblies of P22 can also be utilized as a two-dimensional (2D) crystal for electron crystallography to get precise structural information on the VLP. Here we report 2D crystallization of different P22 morphologies: P22 procapsid (PC), enzyme encapsulated PC (beta-glycosidase and enhanced green fluorescent protein), empty shell (PC without scaffold proteins, ES), the expanded form of P22 (EX), and enzyme encapsulated EX (NADH oxidase). The 2D crystals of P22 VLPs were formed on a positively charged lipid monolayer at the water-air interface with a subphase containing 1% trehalose. A P22 solution, injected underneath the lipid monolayer, floated to the surface because of the density difference between the subphase and protein solution. The lipid monolayer, with adsorbed P22, was transferred to a holey carbon grid and was examined by electron microscopy. 2D crystals were obtained from a subphase containing 100 mM NaCl, 10 mM MES (pH 5.0), and 1% trehalose. The diffraction spots from the transferred film extended to the sixth order in negatively stained samples and the 10th order in cryo-electron microscopy samples. PMID- 27125281 TI - Band filling dependence of the Curie temperature in CrO2. AB - Rutile CrO2 is an important half-metallic ferromagnetic material, which is also widely used in magnetic recording. In an attempt to find the conditions, which lead to the increase of the Curie temperature (T C), we study theoretically the band-filling dependence of interatomic exchange interactions in the rutile compounds. For these purposes, we use the effective low-energy model for the magnetic t 2g bands, derived from the first-principles electronic structure calculations in the Wannier basis, which is solved by means of dynamical mean field theory. After the solution, we calculate the interatomic exchange interactions, by using the theory of infinitesimal spin rotations, and evaluate T C. We argue that, as far as the Curie temperature is concerned, the band filling realized in CrO2 is far from being the optimal one and much higher T C can be obtained by decreasing the number of t 2g electrons (n) via the hole doping. We find that the optimal n is close to 1, which should correspond to the case of VO2, provided that it is crystallized in the rutile structure. This finding was confirmed by using the experimental rutile structure for both CrO2 and VO2 and reflects the general tendency towards ferromagnetism for the narrow-band compounds at the beginning of the band filling. In particular, our results suggest that the strong ferromagnetism can be achieved in the thin films of VO2, whose crystal structure is controlled by the substrate. PMID- 27125278 TI - Histone lysine crotonylation during acute kidney injury in mice. AB - Acute kidney injury (AKI) is a potentially lethal condition for which no therapy is available beyond replacement of renal function. Post-translational histone modifications modulate gene expression and kidney injury. Histone crotonylation is a recently described post-translational modification. We hypothesized that histone crotonylation might modulate kidney injury. Histone crotonylation was studied in cultured murine proximal tubular cells and in kidneys from mice with AKI induced by folic acid or cisplatin. Histone lysine crotonylation was observed in tubular cells from healthy murine and human kidney tissue. Kidney tissue histone crotonylation increased during AKI. This was reproduced by exposure to the protein TWEAK in cultured tubular cells. Specifically, ChIP-seq revealed enrichment of histone crotonylation at the genes encoding the mitochondrial biogenesis regulator PGC-1alpha and the sirtuin-3 decrotonylase in both TWEAK stimulated tubular cells and in AKI kidney tissue. To assess the role of crotonylation in kidney injury, crotonate was used to increase histone crotonylation in cultured tubular cells or in the kidneys in vivo Crotonate increased the expression of PGC-1alpha and sirtuin-3, and decreased CCL2 expression in cultured tubular cells and healthy kidneys. Systemic crotonate administration protected from experimental AKI, preventing the decrease in renal function and in kidney PGC-1alpha and sirtuin-3 levels as well as the increase in CCL2 expression. For the first time, we have identified factors such as cell stress and crotonate availability that increase histone crotonylation in vivo Overall, increasing histone crotonylation might have a beneficial effect on AKI. This is the first observation of the in vivo potential of the therapeutic manipulation of histone crotonylation in a disease state. PMID- 27125280 TI - TLR-mediated albuminuria needs TNFalpha-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice. AB - Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs) in mice through engagement of Toll-like receptors (TLRs) is widely studied as a partial model for some forms of human nephrotic syndrome (NS). In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFalpha is crucial for TLR mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFalpha production, albuminuria and CD80-uria but does not prevent TNFalpha-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR mediated albuminuria and CD80-uria through IL-10. Thus, TNFalpha is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development. PMID- 27125282 TI - Health capability of family caregivers: how different factors interrelate and their respective contributions using a Bayesian approach. AB - BACKGROUND: The lifestyles of family caregivers pose risks to their physical, mental and social health. The capability to stay healthy may be protective in the context of poor socioeconomic conditions and risk behaviours, but the interrelations between its aspects and their respective influences remain unclear. The aim of this study was to evaluate the interrelations between the factors comprising health capability of family caregivers (HCFC) and the respective contributions of its components. METHODS: All stroke patients admitted to all hospitals in Luxembourg were identified by the 'Inspection Generale de la Securite Sociale' using the national database system for care expenditure reimbursement, and asked to designate the main person caring for them. Sixty-two caregivers (mean age 59.3 years; 40 women and 22 men) responded face to face, to a questionnaire including 20 items measuring eight aspects of health capability (physical functioning, psychological functioning, lifestyle value, self-efficacy towards the use of health services, family support, social capital, material conditions/sense of security, and satisfaction with the interactions with health services). Using a Bayesian approach, significance values were estimated by comparing the test values to the posterior distribution of the parameters. Structural equation modelling with standard deviations was applied. RESULTS: Female family caregivers had lower scores than men in physical and psychological functioning. Family caregivers with the lowest incomes had the least lifestyle value, social capital and material conditions/security. Self-efficacy towards health services increased with age. The material conditions/sense of security factor was positively correlated with almost all the others. The items that impacted health capability factors the most were - for physical functioning - fatigue, and - for family support - feeling abandoned by the family. CONCLUSIONS: During the chronic phase, relationships between risk behaviours can help guide social and health decision-makers to determine their priorities in improving the lives of family caregivers. Enhancing health capability involves implementing programs that relieve family caregivers physically, and foster family networking around the person being cared for. Special attention should also be paid to the socially disadvantaged in order to fight inequalities in health capability. PMID- 27125279 TI - High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva. AB - The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft tissue swelling (flare-ups) that trigger the ossification process. With the aim of finding a new therapeutic strategy for FOP, we developed a high-throughput screening (HTS) assay to identify inhibitors of ACVR1 gene expression among drugs already approved for the therapy of other diseases. The screening, based on an ACVR1 promoter assay, was followed by an in vitro and in vivo test to validate and characterize candidate molecules. Among compounds that modulate the ACVR1 promoter activity, we selected the one showing the highest inhibitory effect, dipyridamole, a drug that is currently used as a platelet anti-aggregant. The inhibitory effect was detectable on ACVR1 gene expression, on the whole Smad dependent BMP signaling pathway, and on chondrogenic and osteogenic differentiation processes by in vitro cellular assays. Moreover, dipyridamole reduced the process of heterotopic bone formation in vivo Our drug repositioning strategy has led to the identification of dipyridamole as a possible therapeutic tool for the treatment of FOP. Furthermore, our study has also defined a pipeline of assays that will be useful for the evaluation of other pharmacological inhibitors of heterotopic ossification. PMID- 27125284 TI - Treatment of FBSS Low Back Pain with a Novel Percutaneous DRG Wireless Stimulator: Pilot and Feasibility Study. AB - OBJECTIVES: Test a miniaturized neurostimulator transforaminally placed at the dorsal root ganglion (DRG) and evaluate the device's safety and efficacy in treating failed back surgery syndrome (FBSS) low back pain. DESIGN: Pilot, two phase study. SUBJECTS: Eleven subjects with chronic intractable neuropathic trunk and/or lower limbs pain were included. METHODS: The system consisted of an implantable, miniaturized stimulator, provided by Stimwave Technologies (Freedom 4) and an external transmitter. Only one stimulator per subject was implanted unilaterally and transforaminally at L1 to L5 levels. During Phase 1 of the study, the stimulators were not anchored. In Phase 2, the stimulators were anchored. Subjects were treated during 45 days after which the stimulator was removed. Pain reduction, implant duration, and stimulator migration were registered. RESULTS: Overall pain reduction was 59.9%, with only one device placed at one location, covering only a portion of the painful areas in the majority of the subjects. In Phase 1, the non-anchored stimulators migrated a mean of 8.80 mm and in Phase 2 a mean of 1.83 mm. Stimulator migration did not correlate with changes in pain relief. Mean time-to-implant duration was 10 minutes and no adverse events were reported during implant, follow-up period, or after explant. CONCLUSIONS: The pain reduction results indicate that the Freedom 4 spinal cord stimulation (SCS) Wireless System is a viable treatment of low back pain through stimulation of the DRG, and better overall pain reduction may be achieved by implanting multiple devices. With short percutaneous implant times and excellent safety profile, this new system may offer health cost savings. PMID- 27125283 TI - Anticancer Effects of Paris Saponins by Apoptosis and PI3K/AKT Pathway in Gefitinib-Resistant Non-Small Cell Lung Cancer. AB - BACKGROUND Paris saponins have been studied for their anticancer effects in various cancer types, but the mechanisms underlying the cytotoxic effects, especially in EGFR-TKI-resistant cells, are still unclear. We explored the potential mechanism of the antitumor effects of PSI, II, VI, VII in EGFR-TKI resistant cells and attempted to develop PSI, II, VI, VII as a systemic treatment strategy for EGFR-TKI-resistant lung cancer. MATERIAL AND METHODS Growth inhibition was detected by MTT assay. The apoptosis assay was detected using annexin-V/PI and Hoechst staining. The level of PI3K, pAKT, Bax, Bcl-2, caspase 3, and caspase-9 protein expression were detected using Western blot analysis. RESULTS The results revealed that PSI, II, VI, VII inhibited the proliferation of PC-9-ZD cells. Furthermore, PSI, II, VI, VII induced significant cell apoptosis. The levels of PI3K, pAKT, Bcl-2 protein decreased, while the Bax, caspase-3, and caspase-9 protein was increased by PSI, II, PSVI, PSVII treatment and resulted in increased sensitivity to gefitinib in PC-9-ZD cells. CONCLUSIONS The underlying mechanism of Paris saponins may be related to targeting the PI3K/AKT pathways to cause apoptosis. Our results suggest a therapeutic potential of Paris saponins in clinical settings for gefitinib-resistant NSCLC. PMID- 27125286 TI - A New Sacroiliac Joint Injection Technique and Its Short-Term Effect on Chronic Sacroiliac Region Pain. PMID- 27125289 TI - Health-related quality of life in systemic lupus erythematosus: a longitudinal study on the impact of problematic support and self-efficacy. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which can affect any organ in the body, reducing patients' health-related quality of life (HR-QOL). Psychosocial research on SLE is quite recent and is mostly based on qualitative and cross-sectional evidence. Some studies suggest that a protective role is played by perceived self-efficacy in the management of the disease, while a detrimental role is played by problematic social interactions. METHODS: In a longitudinal study, we tested the independent contribution of self efficacy and problematic social support, in predicting patients' HR-QOL after 11 months. An online questionnaire was completed by 162 participants with SLE, the second questionnaire after 11 months. RESULTS: Controlling for corticosteroids and hydroxychloroquine use, self-efficacy in the management of the disease at Time 1 showed a significant and positive effect on HR-QOL at Time 2, while problematic social support (denying/uninformed) showed a negative effect. CONCLUSIONS: HR-QOL of SLE patients is influenced by self-efficacy in the management of the disease and problematic support. Specific attention should be paid to the quality of patients' social relationships and their perceived efficacy in the management of the disease in focused interventions as in daily clinical practice. PMID- 27125290 TI - The illness experience of youth with lupus/mixed connective tissue disease: a mixed methods analysis of patient and parent perspectives. AB - OBJECTIVE: We aimed to develop a model of the illness experience for youth with systemic lupus erythematosus (SLE)/mixed connective tissue disease (MCTD). METHODS: We conducted 32 semi-structured interviews with 16 outpatient youth with SLE/MCTD, age 11 to 22 years, and their parents. We qualitatively defined key features of illness for families and distinguished profiles of youth adapting well vs poorly to SLE/MCTD. We then related these profiles to features of illness, patient-level attributes and outcomes. RESULTS: Experiences with SLE/MCTD grouped into five themes: managing disease, limitations, stigma, illness uncertainty and psychological coping. Youth adapting well experienced minimal challenges in these areas. Youth adapting poorly (4/16) experienced significant challenges in >1 thematic area, and were older with lower socioeconomic status, quality of life and psychosocial functioning, and increased disease-related morbidity. They also described suboptimal treatment adherence, healthcare utilization and transition to adult care. These findings support a dynamic model in which illness adaptation and outcomes are shaped by patient characteristics and five central illness-related challenges. CONCLUSION: Further testing of our model of illness experience may help guide comprehensive and personalized care of youth with SLE/MCTD, with targeted supports for youth at risk for negative adaptation to illness and poor outcomes. PMID- 27125291 TI - The potential protective role of hepatitis B virus infection in pristane-induced lupus in mice. AB - OBJECTIVE: The objective of this study was to investigate whether hepatitis B virus (HBV) infection plays a role in the regulation of autoimmunity for systemic lupus erythematosus (SLE). METHOD: A total of 21 female BALB/c mice and 21 female HBV transgenic BALB/c mice aged two months were randomly divided into four groups: BALB/c mice, HBV(Tg) mice, pristane-injected BALB/c mice, and pristane injected HBV(Tg) mice. BALB/c mice and HBV(Tg) mice were given an intraperitoneal injection of 0.5 ml normal saline, and the mice in the other two groups were given an intraperitoneal injection of 0.5 ml pristane. ANA and anti-dsDNA levels in serum were detected by indirect immunofluorescence. Interleukin 2 (IL-2), IL 4, IL-6, IL-17, and TNF-alpha were measured by Luminex technology. The serum BAFF level was measured using an Elisa kit. Twenty-four weeks after pristane administration, kidneys were removed, dissected, and stained with hematoxylin and eosin and periodic-acid Schiff. RESULT: At six months after injecting, the ANA titers in pristane-injected HBV(Tg) mice were significantly lower than pristane injected BALB/c mice. IL-17, TNF-alpha, and BAFF levels were significantly higher in pristane-injected BALB/c mice than BALB/c mice and pristane-injected HBV(Tg) mice. IL-2, IL-4, and IL-6 levels were much higher in pristane-injected HBV(Tg) mice than pristane-injected BALB/c mice. In pristane-injected HBV(Tg) mice and HBV(Tg) mice, fewer glomerulonephritis changes were found in the kidneys. CONCLUSIONS: Our results showed that the incidence of SLE was much lower in HBV(Tg) mice, and that HBV infection helped the SLE mice survive high levels of inflammatory cytokines and severe renal damage. All these findings demonstrated the protective role of HBV in SLE patients via the immunoregulatory networks of the cytokines. PMID- 27125292 TI - Elevated plasma interleukin-37 levels in systemic lupus erythematosus patients. AB - This study aims to evaluate the plasma interleukin (IL)-37 levels in systemic lupus erythematosus (SLE) patients, as well as its association with major clinical and laboratory features. Ninety consecutively selected SLE patients and 78 community-based healthy controls were recruited. Plasma IL-37 levels were detected by enzyme-linked immunosorbent assay (ELISA). The major clinical and laboratory data of SLE patients were also recorded. The results showed that IL-37 level was significantly higher in the plasma of patients with SLE compared with controls (p = 0.028). The correlation of plasma IL-37 levels with major clinical and laboratory data of SLE patients was also analyzed, and the results showed that anti-Sm and anti-RNP were negatively associated with plasma IL-37 levels of SLE patients, while C3 was positively associated with plasma IL-37 levels of SLE patients. No significant associations of IL-37 with other clinical and laboratory parameters were observed (all p > 0.05). In conclusion, elevated plasma IL-37 level and its associations with anti-Sm, anti-RNP and C3 in SLE patients suggest that IL-37 may be implicated in this disease. PMID- 27125293 TI - Lupus pneumonitis as the initial presentation of systemic lupus erythematosus: case series from a single institution. AB - Objective The aim of this study was to examine the clinical features, treatment and outcome of systemic lupus erythematosus (SLE) patients in our centre who presented with lupus pneumonitis as the initial manifestation. Methods We performed a retrospective review of all patients who presented with lupus pneumonitis during the initial SLE manifestation from March 2006 to March 2015. Results There were a total of five patients in our study who presented with fever and cough as the main clinical features. All patients had pulmonary infiltrates on chest radiographs. High-resolution computed tomography, which was performed in two patients, showed ground glass opacities with patchy consolidations bilaterally. All patients received high-dose steroids, 80% received intravenous cyclophosphamide and 60% received intravenous immunoglobulin. Two patients died from severe lupus pneumonitis within 2 weeks of admission despite treatment with ventilation, steroids, cyclophosphamide and intravenous immunoglobulin. Conclusions Acute lupus pneumonitis is an uncommon presentation of SLE. Mortality in this case series is 40%. PMID- 27125294 TI - Plasma copeptin may not be a sensitive marker of perinatal stress in healthy full term growth-restricted fetuses. AB - OBJECTIVE: Intrauterine-growth-restriction-(IUGR) is associated with chronic fetal stress, as well as a phase of enhanced fetal/early postnatal insulin sensitivity, followed by a later emergence of insulin resistance. We aimed to prospectively investigate concentrations of copeptin, a sensitive marker of stress and insulin resistance, in IUGR versus appropriate-for-gestational-age (AGA) fetuses. METHODS: Cord blood copeptin concentrations were determined by ELISA in well-defined, non-distressed at birth, asymmetric IUGR (n = 30) and AGA (n = 20) full-term pregnancies. Doppler studies were indicative of placental insufficiency. RESULTS: Cord blood copeptin concentrations were similar in IUGR cases and AGA controls, after controlling for delivery mode. Copeptin concentrations were markedly elevated in vaginally delivered fetuses (p = 0.001). No association was recorded between fetal copeptin concentrations and maternal age, parity, gestational age, or fetal gender. CONCLUSIONS: Cord blood copeptin concentrations are probably not affected by IUGR at term, in the absence of fetal distress, possibly due to a balance between copeptin up-regulation by chronic fetal stress, on one hand, and copeptin down-regulation in the presence of increased insulin sensitivity, on the other hand; thus, copeptin may not be a sensitive marker of chronic perinatal stress in healthy asymmetric IUGR infants. Cord blood copeptin seems to primarily reflect perinatal stress associated with delivery mode. PMID- 27125295 TI - Mechanical parameters and flight phase characteristics in aquatic plyometric jumping. AB - Plyometric jumping is a commonly prescribed method of training focused on the development of reactive strength and high-velocity concentric power. Literature suggests that aquatic plyometric training may be a low-impact, effective supplement to land-based training. The purpose of the present study was to quantify acute, biomechanical characteristics of the take-off and flight phase for plyometric movements performed in the water. Kinetic force platform data from 12 young, male adults were collected for counter-movement jumps performed on land and in water at two different immersion depths. The specificity of jumps between environmental conditions was assessed using kinetic measures, temporal characteristics, and an assessment of the statistical relationship between take off velocity and time in the air. Greater peak mechanical power was observed for jumps performed in the water, and was influenced by immersion depth. Additionally, the data suggest that, in the water, the statistical relationship between take-off velocity and time in air is quadratic. Results highlight the potential application of aquatic plyometric training as a cross-training tool for improving mechanical power and suggest that water immersion depth and fluid drag play key roles in the specificity of the take-off phase for jumping movements performed in the water. PMID- 27125296 TI - Future Directions in the Management of Twin-to-Twin Transfusion Syndrome. AB - Twin-to-twin transfusion syndrome (TTTS) is the major complication of monochorionic (MC) pregnancy. The outcomes of this condition have been significantly improved after the introduction and widespread uptake of fetoscopic laser ablation over the last decade. However, there is still a significant fetal loss rate and morbidity associated with this condition. Improvements in the management of TTTS will require improvements in many areas. They are likely to involve refinements in the prediction of the disease and clarification of the optimum frequency of surveillance and monitoring. Improvements in training for fetoscopic surgery as well as in the technique of fetoscopic laser ablation may lead to better outcomes. New technologies as well as a better understanding of the pathophysiology of TTTS may lead to adjuvant medical therapies that may also improve short- and long-term results. PMID- 27125297 TI - Naringin suppresses the development of glioblastoma by inhibiting FAK activity. AB - As the most common and lethal primary malignant brain cancer, glioblastoma is hard to timely diagnose and sensitive therapeutic monitoring. It is essential to develop new and effective drugs for glioblastoma multiform. Naringin belongs to citrus flavonoids and was found to display strong anti-inflammatory, antioxidant and antitumor activities. In this report, we found that naringin can specifically inhibit the kinase activity of FAK and suppress the FAKp-Try397and its downstream pathway in glioblastoma cells. Our study showed out that naringin can inhibit cell proliferation by inhibiting FAK/cyclin D1 pathway, promote cell apoptosis through influencing FAK/bads pathway, at the same time, it can also inhibit cell invasion and metastasis by inhibiting the FAK/mmps pathway. All these showed that naringin exerts the anti-tumor effects in U87 MG by inhibiting the kinase activity of FAK. PMID- 27125298 TI - Temporomandibular disorders symptoms in Asian adolescents and their association with sleep quality and psychological distress. AB - OBJECTIVES: The aim of this study was to investigate the prevalence of temporomandibular disorders (TMD) symptoms and their association with sleep quality and psychological distress in Chinese adolescents. METHODS: Five hundred seventy-eight adolescents were enrolled in the study and completed a self reported TMD symptom questionnaire and socio-demographics survey. Sleep quality and psychological distress were assessed. Descriptive statistics and logistic regression analysis were performed with TMD symptoms as the outcome variable. RESULTS: The prevalence of adolescents with at least one TMD symptom was 61.4%. One-third of subjects experienced disturbed sleep, depression, and stress; 65.2% experienced anxiety. Subjects with TMD symptoms had greater psychological distress and disturbed sleep than those who were symptom-free. Logistic regression analysis showed that sleep disturbance and daytime dysfunction and anxiety were significantly related to TMD symptoms. DISCUSSION: The prevalence of TMD symptoms in Asian adolescents is high. Disturbed sleep and psychological distress are correlated with TMD; thus, a further longitudinal research of the causality is warranted. PMID- 27125299 TI - Tai Chi for Chronic Pain Conditions: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - Several studies reported that Tai Chi showed potential effects for chronic pain, but its role remains controversial. This review assessed the evidence regarding the effects of Tai Chi for chronic pain conditions. 18 randomized controlled trials were included in our review. The aggregated results have indicated that Tai Chi showed positive evidence on immediate relief of chronic pain from osteoarthritis (standardized mean difference [SMD], -0.54; 95% confidence intervals [CI], -0.77 to -0.30; P < 0.05). The valid duration of Tai Chi practice for osteoarthritis may be more than 5 weeks. And there were some beneficial evidences regarding the effects of Tai Chi on immediate relief of chronic pain from low back pain (SMD, -0.81; 95% CI, -1.11 to -0.52; P < 0.05) and osteoporosis (SMD, -0.83; 95% CI, -1.37 to -0.28; P = 0.003). Therefore, clinicians may consider Tai Chi as a viable complementary and alternative medicine for chronic pain conditions. PMID- 27125301 TI - Prophylactic HPV vaccination: past, present, and future - CORRIGENDUM. PMID- 27125300 TI - The Growth Characteristics of Patients with Noonan Syndrome: Results of Three Years of Growth Hormone Treatment: A Nationwide Multicenter Study. AB - OBJECTIVE: Noonan syndrome (NS) is a multisystem disorder, and short stature is its most striking manifestation. Optimal growth hormone (GH) treatment for NS is still controversial. In this study, using a nationwide registration system, we aimed to evaluate the growth characteristics and the clinical features of NS patients in Turkey and their growth response to GH treatment. METHODS: Children and adolescents with a diagnosis of NS were included inthe study. Laboratory assessment including standard GH stimulation test results were evaluated. Height increment of patients with or without GH treatment were analyzed after three years of therapy. RESULTS: A total of 124 NS patients from different centers were entered in the web-based system. Short stature and typical face appearance were the most frequently encountered diagnostic features of our patients. Of the 84 patients who were followed long-term, 47 hadreceived recombinant human GH (rhGH). In this group of 47 patients, height standard deviation score (HSDS) increased from -3.62+/-1.14 to -2.85+/-0.96 after three years of therapy, indicating significant differences from the patients who did not receive GH treatment. PTPN11 gene was analyzed in 61 patients, and 64% of these patients were found to have a mutation. HSDS at admission was similar in patients with or without PTPN11 gene mutation. CONCLUSION: A diagnosis of NS should be kept in mind in all patients with short stature showing systemic clinical findings. GH therapy is effective for improvement of short stature especially in the first two years of treatment. Further studies are needed for optimisation of GH therapy and evaluation of final height data in NS patients. PMID- 27125302 TI - Paracrine Factors from Irradiated Peripheral Blood Mononuclear Cells Improve Skin Regeneration and Angiogenesis in a Porcine Burn Model. AB - Burn wounds pose a serious threat to patients and often require surgical treatment. Skin grafting aims to achieve wound closure but requires a well vascularized wound bed. The secretome of peripheral blood mononuclear cells (PBMCs) has been shown to improve wound healing and angiogenesis. We hypothesized that topical application of the PBMC secretome would improve the quality of regenerating skin, increase angiogenesis, and reduce scar formation after burn injury and skin grafting in a porcine model. Full-thickness burn injuries were created on the back of female pigs. Necrotic areas were excised and the wounds were covered with split-thickness mesh skin grafts. Wounds were treated repeatedly with either the secretome of cultured PBMCs (Sec(PBMC)), apoptotic PBMCs (Apo-Sec(PBMC)), or controls. The wounds treated with Apo-Sec(PBMC) had an increased epidermal thickness, higher number of rete ridges, and more advanced epidermal differentiation than controls. The samples treated with Apo-Sec(PBMC) had a two-fold increase in CD31+ cells, indicating more angiogenesis. These data suggest that the repeated application of Apo-Sec(PBMC) significantly improves epidermal thickness, angiogenesis, and skin quality in a porcine model of burn injury and skin grafting. PMID- 27125303 TI - Morphological Alterations in the Thalamus, Striatum, and Pallidum in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with cognitive, motor, and emotional symptoms. The thalamus and basal ganglia form circuits with the cortex supporting all three of these behavioral domains. Abnormalities in the structure of subcortical regions may suggest atypical development of these networks, with implications for understanding the neural basis of ASD symptoms. Findings from previous volumetric studies have been inconsistent. Here, using advanced surface-based methodology, we investigated localized differences in shape and surface area in the basal ganglia and thalamus in ASD, using T1-weighted anatomical images from the Autism Brain Imaging Data Exchange (373 male participants aged 7-35 years with ASD and 384 typically developing). We modeled effects of diagnosis, age, and their interaction on volume, shape, and surface area. In participants with ASD, we found expanded surface area in the right posterior thalamus corresponding to the pulvinar nucleus, and a more concave shape in the left mediodorsal nucleus. The shape of both caudal putamen and pallidum showed a relatively steeper increase in concavity with age in ASD. Within ASD participants, restricted, repetitive behaviors were positively associated with surface area in bilateral globus pallidus. We found no differences in overall volume, suggesting that surface based approaches have greater sensitivity to detect localized differences in subcortical structure. This work adds to a growing body of literature implicating corticobasal ganglia-thalamic circuits in the pathophysiology of ASD. These circuits subserve a range of cognitive, emotional, and motor functions, and may have a broad role in the complex symptom profile in ASD. PMID- 27125304 TI - Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor. AB - Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner. PMID- 27125305 TI - beta-Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1. AB - Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of beta-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of beta-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of beta-Catenin in these T-ALL cells and demonstrate that the MYC 3' enhancer required beta-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1. PMID- 27125306 TI - Gab2 is essential for Bcr-Abl-mediated leukemic transformation and hydronephrosis in a chronic myeloid leukemia mouse model. PMID- 27125307 TI - The NOTCH1/CD39 axis: a Treg trip-switch for GvHD. PMID- 27125308 TI - Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold-based xenograft model. AB - Although NOD-SCID IL2Rgamma-/- (NSG) xenograft mice are currently the most frequently used model to study human leukemia in vivo, the absence of a human niche severely hampers faithful recapitulation of the disease. We used NSG mice in which ceramic scaffolds seeded with human mesenchymal stromal cells were implanted to generate a human bone marrow (huBM-sc)-like niche. We observed that, in contrast to the murine bone marrow (mBM) niche, the expression of BCR-ABL or MLL-AF9 was sufficient to induce both primary acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). Stemness was preserved within the human niches as demonstrated by serial transplantation assays. Efficient engraftment of AML MLL-AF9 and blast-crisis chronic myeloid leukemia patient cells was also observed, whereby the immature blast-like phenotype was maintained in the huBM-sc niche but to a much lesser extent in mBM niches. We compared transcriptomes of leukemias derived from mBM niches versus leukemias from huBM-like scaffold-based niches, which revealed striking differences in the expression of genes associated with hypoxia, mitochondria and metabolism. Finally, we utilized the huBM-sc MLL AF9 B-ALL model to evaluate the efficacy of the I-BET151 inhibitor in vivo. In conclusion, we have established human niche models in which the myeloid and lymphoid features of BCR-ABL+ and MLL-AF9+ leukemias can be studied in detail. PMID- 27125310 TI - Editorial Comment for Mitchell et al. PMID- 27125309 TI - Influence of SiO2 shell thickness on power conversion efficiency in plasmonic polymer solar cells with Au nanorod@SiO2 core-shell structures. AB - Locating core-shell metal nanoparticles into a photoactive layer or at the interface of photoactive layer/hole extraction layer is beneficial for fully employing surface plasmon energy, thus enhancing power conversion efficiency (PCE) in plasmonic organic photovoltaic devices (OPVs). Herein, we first investigated the influence of silica shell thickness in Au nanorods (NRs)@SiO2 core-shell structures on OPV performances by inserting them into poly(3,4 ethylenedioxythiophene):poly(4-styrenesulfonate) and thieno[3,4 b]thiophene/benzodithiophene (PTB7) interface, and amazedly found that a 2-3 nm silica shell onto Au NRs induces a highest short-circuit current density of 21.2 mA cm(-2) and PCE of 9.55%. This is primarily due to an extremely strong local field and a much slower attenuation of localized surface plasmon resonance around ultrathin silica-coated Au NRs, with which the field intensity remains a high value in the active layer, thus sufficiently improves the absorption of PTB7. Our work provides a clear design concept on precise control of the shell of metal nanoparticles to realize high performances in plasmonic OPVs. PMID- 27125312 TI - Impacts of Typhoon Soudelor (2015) on the water quality of Taipei, Taiwan. AB - Typhoon Soudelor was one of the strongest storms in the world in 2015. The category 5 hurricane made landfall in Taiwan on August 8, causing extensive damage and severe impacts on the environment. This paper describes the changes of trihalomethane (THM) concentrations in tap and drinking fountain water in selected typhoon-affected areas in Taipei before and after the typhoon. Samples were taken from water transmission mains at various distances from the local water treatment plant. The results showed that organic matter increased between pre- and post-typhoon periods with a greater proportion of aromatic compounds. Although drinking fountains showed moderately less total trihalomethane (TTHM) levels than that of tap water, the intake of high turbidity water considerably diminished the efficiency of their purification systems after the typhoon. The percentage distribution of THM species increased throughout the distribution network, probably due to a longer contact time between chlorine and the organic matter in the pipelines. After 2 to 5 min of boiling, THM reduction was considerable in all cases with the greater extent in post-typhoon samples. It is evident that extreme weather conditions may have a severe impact on water quality, and thus more cautious strategies should be adopted in such cases. PMID- 27125311 TI - The association between medically unexplained physical symptoms and health care use over two years and the influence of depressive and anxiety disorders and personality traits: a longitudinal study. AB - BACKGROUND: Medically unexplained physical symptoms (MUPS) are highly prevalent and are associated with frequent health care use (HCU). MUPS frequently co-occur with psychiatric disorders. With this study we examined the longitudinal association between MUPS and HCU over 2 years and the influence of depressive and anxiety disorders and personality traits on this association. METHODS: We analysed follow-up data from 2045 to 2981 participants from the Netherlands Study of Depression and Anxiety (NESDA), a multisite cohort study. The study population included participants with a current depressive and/or anxiety disorder, participants with a lifetime risk and/or subthreshold symptoms for depressive and/or anxiety disorders and healthy controls. HCU, measured with the Trimbos and iMTA questionnaire on Costs associated with Psychiatric illness (TIC-P), was operationalized as the number of used medical services and the number of associated contacts. MUPS were measured with the Four Dimensional Symptoms Questionnaire, depressive and anxiety disorders with the Composite International Diagnostic Interview and personality traits with the NEO Five-Factory Inventory. Measurements were taken at baseline, 1 and 2 years follow-up. We used generalized estimating equations (GEE), using HCU at all three measurements as (multivariate) outcome. GEE also takes into account the dependency of observations within participants. RESULTS: MUPS were positively associated with HCU over 2 years (medical services: RR 1.020, 95 % CI 1.017-1.022; contacts: RR 1.037, 95 % CI 1.030-1.044). Neuroticism and depression had the strongest influence on the associations. After adjustment for these factors, the associations between MUPS and HCU weakened, but remained significant (services: RR 1.011, 95 % CI 1.008 1.014; contacts: RR 1.023, 95 % CI 1.015-1.032). CONCLUSIONS: Our results show that MUPS were positively associated with HCU over 2 years, even after adjusting for depressive and anxiety disorders and personality traits. PMID- 27125313 TI - High activity of the stress promoter contributes to susceptibility to stress in the tree shrew. AB - Stress is increasingly present in everyday life in our fast-paced society and involved in the pathogenesis of many psychiatric diseases. Corticotrophin releasing-hormone (CRH) plays a pivotal role in regulating the stress responses. The tree shrews are highly vulnerable to stress which makes them the promising animal models for studying stress responses. However, the mechanisms underlying their high stress-susceptibility remained unknown. Here we confirmed that cortisol was the dominate corticosteroid in tree shrew and was significantly increased after acute stress. Our study showed that the function of tree shrew CRH - hypothalamic-pituitary-adrenal (HPA) axis was nearly identical to human that contributed little to their hyper-responsiveness to stress. Using CRH transcriptional regulation analysis we discovered a peculiar active glucocorticoid receptor response element (aGRE) site within the tree shrew CRH promoter, which continued to recruit co-activators including SRC-1 (steroid receptor co-activator-1) to promote CRH transcription under basal or forskolin/dexamethasone treatment conditions. Basal CRH mRNA increased when the aGRE was knocked into the CRH promoter in human HeLa cells using CAS9/CRISPR. The aGRE functioned critically to form the "Stress promoter" that contributed to the higher CRH expression and susceptibility to stress. These findings implicated novel molecular bases of the stress-related diseases in specific populations. PMID- 27125314 TI - A new quantitative image-based method for evaluation of bony temporal hollowing in metopic synostosis. AB - OBJECTIVE: Premature craniosynostosis is a congenital disorder causing a skull deformity. For both functional and cosmetic reasons, the deformity is surgically treated with a cranioplasty before the age of 1 year. Temporal hollowing is a common and undesirable remaining deformity after cranioplasty for metopic synostosis. The most common method to determine the degree of temporal hollowing is subjective judgement of the temporal region. The aim of the present project was to develop a quantitative semi-automatic computer tool for objective measurement of bony temporal hollowing. METHODS: Using MATLAB, a tool was developed to segment computed tomography images, defining the outermost contour. The images were dorsally limited to the widest point of the head. In each case, a sex- and age-matched control was identified and the contours compared. The bony temporal hollowing of the cases was calculated. RESULTS: The intra-user coefficient of variation (CV) was 5.0% (95% CI = 4.2%-6.2%) and the inter-user CV was 3.0% (95% CI = 2.1%-8.6%). For clinical testing purposes, the tool was used in 14 patients, seven of whom had been operated on with a spring-assisted cranioplasty and seven with a cranioplasty using a bone graft. CONCLUSIONS: In summary, this study presents a new tool for objective measurement of the surgical result after cranioplasty for metopic synostosis. PMID- 27125316 TI - Evaluation of ablation of thyroid remnants with 1,850 MBq iodine-131 in 67 patients with thyroid cancer. AB - BACKGROUND: Radioiodine remnant ablation (RRA) is used to destroy residual normal thyroid tissue after total thyroidectomy in differentiated thyroid carcinoma (DTC) patients. As 1,850 MBq RRA is routinely performed at our facility, we evaluated the outcomes. METHODS: Sixty-seven DTC patients without macroscopic residual lesions after total thyroidectomy were evaluated. Thyroglobulin (Tg) was measured 2-3 months before RRA with thyrox in administration (pretreatment); just before ablation after a 3-week iodine intake restriction with thyroxin withdrawal (THW) (n = 16) or recombinant human thyroid-stimulating hormone (rhTSH) stimulation (n = 51); and 3 months after RRA after a 2-week iodine intake restriction and 3-week THW (n = 57) or rhTSH stimulation (n = 10). All patients received 131I (1,850 MBq) treatment followed by 131I scintigraphy about 8 days later (8.18+/- 0.91) and 131I scintigraphy (185 MBq) after the dosage 24 hours later 3months after RRA. Initial RRA goal was defined as negatively visible uptake in 131I thyroid bed (VUT) and a Tg level of <2 ng/mL 3 months after RRA. RESULTS: Rest 60 patients whose TSH levels were below 0.5 MUIU/mL of all 67 patients were evaluated. Negatively VUT on 3 months after RRA was shown in 56 out of 60 patients (93.3%). Initial RRA goal was achieved in 21 (42.0%) of 50 patients, excluding 3 patients whose Tg levels 3 months after RRA were not measured and 7 patients with anti-Tg antibodies. Pretreatment Tg levels (p = 0.0003) was significant predictive factor for Initial RRA goal on multivariate logistic regression analysis. CONCLUSIONS: RRA with 1,850 MBq is effective by visual diagnosis, about 40% of all intermediate or high risk DTC patients achieved initial RRA goals by both visual and Tg levels diagnosis. PMID- 27125315 TI - Expression analysis of Baf60c during heart regeneration in axolotls and neonatal mice. AB - Some organisms, such as zebrafish, urodele amphibians, and newborn mice, have a capacity for heart regeneration following injury. However, adult mammals fail to regenerate their hearts. To know why newborn mice can regenerate their hearts, we focused on epigenetic factors, which are involved in cell differentiation in many tissues. Baf60c (BRG1/BRM-associated factor 60c), a component of ATP-dependent chromatin-remodeling complexes, has an essential role for cardiomyocyte differentiation at the early heart development. To address the function of Baf60c in postnatal heart homeostasis and regeneration, we examined the detailed expression/localization patterns of Baf60c in both mice and axolotls. In the mouse heart development, Baf60c was highly expressed in the entire heart at the early stages, but gradually downregulated at the postnatal stages. During heart regeneration in neonatal mice and axolotls, Baf60c expression was strongly upregulated after resection. Interestingly, the timing of Baf60c upregulation after resection was consistent with the temporal dynamics of cardiomyocyte proliferation. Moreover, knockdown of Baf60c downregulated proliferation of neonatal mouse cardiomyocytes. These data suggested that Baf60c plays an important role in cardiomyocyte proliferation in heart development and regeneration. This is the first study indicating that Baf60c contributes to the heart regeneration in vertebrates. PMID- 27125317 TI - Purification, gene cloning, and characterization of gamma-butyrobetainyl CoA synthetase from Agrobacterium sp. 525a. AB - The report is the first of purification, overproduction, and characterization of a unique gamma-butyrobetainyl CoA synthetase from soil-isolated Agrobacterium sp. 525a. The primary structure of the enzyme shares 70-95% identity with those of ATP-dependent microbial acyl-CoA synthetases of the Rhizobiaceae family. As distinctive characteristics of the enzyme of this study, ADP was released in the catalytic reaction process, whereas many acyl CoA synthetases are annotated as an AMP-forming enzyme. The apparent Km values for gamma-butyrobetaine, CoA, and ATP were, respectively, 0.69, 0.02, and 0.24 mM. PMID- 27125318 TI - In Vivo Mesoscopic Voltage-Sensitive Dye Imaging of Brain Activation. AB - Functional mapping of brain activity is important in elucidating how neural networks operate in the living brain. The whisker sensory system of rodents is an excellent model to study peripherally evoked neural activity in the central nervous system. Each facial whisker is represented by discrete modules of neurons all along the pathway leading to the neocortex. These modules are called "barrels" in layer 4 of the primary somatosensory cortex. Their location (approximately 300-500 MUm below cortical surface) allows for convenient imaging of whisker-evoked neural activity in vivo. Fluorescence laminar optical tomography (FLOT) provides depth-resolved fluorescence molecular information with an imaging depth of a few millimeters. Angled illumination and detection configurations can improve both resolution and penetration depth. We applied angled FLOT (aFLOT) to record 3D neural activities evoked in the whisker system of mice by deflection of a single whisker in vivo. A 100 MUm capillary and a pair of microelectrodes were inserted to the mouse brain to test the capability of the imaging system. The results show that it is possible to obtain 3D functional maps of the sensory periphery in the brain. This approach can be broadly applicable to functional imaging of other brain structures. PMID- 27125319 TI - PMMA/MWCNT nanocomposite for proton radiation shielding applications. AB - Radiation shielding in space missions is critical in order to protect astronauts, spacecraft and payloads from radiation damage. Low atomic-number materials are efficient in shielding particle-radiation, but they have relatively weak material properties compared to alloys that are widely used in space applications as structural materials. However, the issues related to weight and the secondary radiation generation make alloys not suitable for space radiation shielding. Polymers, on the other hand, can be filled with different filler materials for reinforcement of material properties, while at the same time provide sufficient radiation shielding function with lower weight and less secondary radiation generation. In this study, poly(methyl-methacrylate)/multi-walled carbon nanotube (PMMA/MWCNT) nanocomposite was fabricated. The role of MWCNTs embedded in PMMA matrix, in terms of radiation shielding effectiveness, was experimentally evaluated by comparing the proton transmission properties and secondary neutron generation of the PMMA/MWCNT nanocomposite with pure PMMA and aluminum. The results showed that the addition of MWCNTs in PMMA matrix can further reduce the secondary neutron generation of the pure polymer, while no obvious change was found in the proton transmission property. On the other hand, both the pure PMMA and the nanocomposite were 18%-19% lighter in weight than aluminum for stopping the protons with the same energy and generated up to 5% fewer secondary neutrons. Furthermore, the use of MWCNTs showed enhanced thermal stability over the pure polymer, and thus the overall reinforcement effects make MWCNT an effective filler material for applications in the space industry. PMID- 27125320 TI - High rates of virological failure and drug resistance in perinatally HIV-1 infected children and adolescents receiving lifelong antiretroviral therapy in routine clinics in Togo. AB - INTRODUCTION: Antiretroviral treatment (ART) has been scaled up over the last decade but compared to adults, children living with HIV are less likely to receive ART. Moreover, children and adolescents are more vulnerable than adults to virological failure (VF) and emergence of drug resistance. In this study we determined virological outcome in perinatally HIV-1-infected children and adolescents receiving ART in Togo. METHODS: HIV viral load (VL) testing was consecutively proposed to all children and adolescents who were on ART for at least 12 months when attending HIV healthcare services for their routine follow up visit (June to September 2014). Plasma HIV-1 VL was measured using the m2000 RealTime HIV-1 assay (Abbott Molecular, Des Plaines, IL, USA). Genotypic drug resistance was done for all samples with VL>1000 copies/ml. RESULTS AND DISCUSSION: Among 283 perinatally HIV-1-infected children and adolescents included, 167 (59%) were adolescents and 116 (41%) were children. The median duration on ART was 48 months (interquartile range: 28 to 68 months). For 228 (80.6%), the current ART combination consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine and lamivudine) and one non nucleoside reverse transcriptase inhibitor (NNRTI) (nevirapine or efavirenz). Only 28 (9.9%) were on a protease inhibitor (PI)-based regimen. VL was below the detection limit (i.e. 40 copies/ml) for 102 (36%), between 40 and 1000 copies/ml for 35 (12.4%) and above 1000 copies/ml for 146 (51.6%). Genotypic drug resistance testing was successful for 125/146 (85.6%); 110/125 (88.0%) were resistant to both NRTIs and NNRTIs, 1/125 (0.8%) to NRTIs only, 4/125 (3.2%) to NNRTIs only and three harboured viruses resistant to reverse transcriptase and PIs. Overall, 86% (108/125) of children and adolescents experiencing VF and successfully genotyped, corresponding thus to at least 38% of the study population, had either no effective ART or had only a single effective drug in their current ART regimen. CONCLUSIONS: Our study provided important information on virological outcome on lifelong ART in perinatally HIV-1-infected children and adolescents who were still on ART and continued to attend antiretroviral (ARV) clinics for follow-up visits. Actual conditions for scaling up and monitoring lifelong ART in children in resource-limited countries can have dramatic long term outcomes and illustrate that paediatric ART receives inadequate attention. PMID- 27125321 TI - Spatially resolved analysis of variation in barley (Hordeum vulgare) grain micronutrient accumulation. AB - Genetic biofortification requires knowledge on natural variation and the underlying mechanisms of micronutrient accumulation. We therefore studied diversity in grain micronutrient concentrations and spatial distribution in barley (Hordeum vulgare), a genetically tractable model cereal and an important crop with widespread cultivation. We assembled a diverse collection of barley cultivars and landraces and analysed grain micronutrient profiles in genebank material and after three independent cultivations. Lines with contrasting grain zinc (Zn) accumulation were selected for in-depth analysis of micronutrient distribution within the grain by micro-proton-induced X-ray emission (MU-PIXE). Also, we addressed association with grain cadmium (Cd) accumulation. The analysis of > 120 lines revealed substantial variation, especially in grain Zn concentrations. A large fraction of this variation is due to genetic differences. Grain dissection and MU-PIXE analysis of contrasting lines showed that differences in grain Zn accumulation apply to all parts of the grain including the endosperm. Cd concentrations exceeded the Codex Alimentarius threshold in most of the representative barley lines after cultivation in a Cd-contaminated agricultural soil. Two important conclusions for biofortification are: first, high-Zn grains contain more Zn also in the consumed parts of the grain; and second, higher micronutrient concentrations are strongly associated with higher Cd accumulation. PMID- 27125322 TI - Spatial Shift in the Utilization of Mental Health Services After Hurricane Sandy Among New York City Residents Enrolled in Medicaid. AB - OBJECTIVE: Closure of several New York City (NYC) hospitals after Hurricane Sandy caused an unanticipated, extended surge in patient demand at open hospitals. This study identified hospitals with a significant increase in mental-health-related emergency department, inpatient, and outpatient visits from Medicaid patients displaced by Hurricane Sandy. METHODS: NYC Medicaid patients were classified into non-mutually-exclusive geographic categories corresponding to residence in areas served by Bellevue Hospital Center and Coney Island Hospital, the hurricane impact area, and all of NYC. For each geographic region, we compared the observed to the expected number of service visits in the 6 months after the storm. The expected number of visits was calculated from 2-year trends in mental health claims. RESULTS: Twenty-four facilities in all 5 NYC boroughs experienced patient redistribution from storm-affected areas. Eighteen facilities had a concurrent surge in total Medicaid patients, which suggested that redistribution had a greater impact on resource use at these locations. CONCLUSIONS: The redistribution of Medicaid patients after Hurricane Sandy increased mental health service utilization at facilities not near flooded areas. Our findings can aid in surge capacity planning and thereby improve the continuity of mental health care after a natural disaster. (Disaster Med Public Health Preparedness. 2016;10:420 427). PMID- 27125323 TI - New sonographic morphology score for the differentiation of malignant from benign ovarian tumors. AB - AIM: The aim of this study was to explore the efficacy of a new sonographic morphology score (SMS) to differentiate malignant from benign ovarian tumors. METHODS: Data on 84 ovarian tumors in patients hospitalized in our hospital between 2013 and 2014 were retrospectively analyzed. We established a new sonographic morphology score for ovarian tumors based on volume and structure scores. The efficacy of the new SMS was compared with that of Ueland's index (the old SMS). Receiver-operator curves (ROC) of the two SMS were constructed, and the areas under the curve were calculated and compared. The ROC of the new SMS was also compared with those for the patients' CA-125 and CA-72-4 levels. RESULTS: The area under the ROC of the new SMS for ovarian tumors was 0.836, while for the old SMS for ovarian tumors it was 0.709. By Z-test (Z = 2.452, P = 0.0384), there was a significant difference between the new SMS and the old SMS in the diagnosis of ovarian tumors. There was no significant difference in the area under the ROC between the new SMS and CA-125 and CA-72-4 in the diagnosis of ovarian tumors. With a cut-off value of 6, the sensitivity, specificity, positive prognostic value, and negative prognostic value of the new SMS were 0.797, 0.85, 0.944, and 0.567, respectively. CONCLUSION: The new SMS may be used to differentiate malignant ovarian carcinomas from benign tumors except in the case of ovarian thecoma. PMID- 27125324 TI - Does maternal hydronephrosis have an impact on urinary neutrophil gelatinase associated lipocalin (uNGAL) levels? AB - OBJECTIVE: To determine urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels and creatinine clearance values in women with different degrees of asymptomatic hydronephrosis during pregnancy. METHODS: A total of 44 pregnant women with different degrees of hydronephrosis and 46 without hydronephrosis were consecutively enrolled in this prospective study. Basic serum and urine parameters, uNGAL levels, and creatinine clearance values were evaluated. All results were compared between the two groups. Regression analysis was used to determine independent predictors, which were mostly related to hydronephrosis. RESULTS: Demographic data, basal laboratory parameters, and creatinine clearance values were similar, whereas significantly higher uNGAL levels were detected in women with hydronephrosis compared to those without hydronephrosis (45.3 versus 33.2 ng/mL, respectively) (p = 0.004). An increasing trend in uNGAL levels was detected with increasing degrees of hydronephrosis; as it was not statistically significant (p = 0.163). Linear regression analysis revealed that the parameter of "pelvic diameter" was found as a significant independent factor influencing uNGAL concentrations (beta = 0.289; 95% CI: 0.522-3.061; p = 0.006). Other independent variables were not found to influence uNGAL concentrations (p > 0.05). CONCLUSION: The results obtained from this study indicate a significant increase of urinary concentration of NGAL in the presence of asymptomatic maternal hydronephrosis. This impact is likely to be more profound in those with severe hydronephrosis although this has not been specifically investigated. This theory needs to be validated in larger populations. PMID- 27125325 TI - Effects of acute stress on aggression and the cortisol response in the African sharptooth catfish Clarias gariepinus: differences between day and night. AB - African sharptooth catfish Clarias gariepinus were housed under continuous dim light (1 lx) or 12L:12D (350-0 lx) cycles. The number of skin lesions, as indicator of aggressive acts, and plasma cortisol levels, as indicator of stress axis activity, were measured at baseline as well as following a stressor (given in the light or dark phase). Results showed that (1) baseline plasma cortisol levels were not different between photoperiods, (2) the number of baseline skin lesions was highest for C. gariepinus housed under continuous dim light, (3) stressor-induced peak levels of plasma cortisol were highest in the light phase and (4) the number of skin lesions following a stressor was highest in the dark phase. The higher number of stressor-related skin lesions in the dark (active) phase suggests increased stressor-induced aggression while in the active phase. In addition, the data suggest that housing under continuous dim light does not result in higher stress-axis activity, as measured by baseline levels of cortisol, but does result in more stressor-induced aggression, as measured by the higher number of skin lesions. The latter may be related to the fact that the continuous dim light photoperiod has twice the number of dark-phase (active) hours in which stressor-induced aggression is stronger compared to the 12L:12D photoperiod, which has a light phase in which stressor-induced aggression is lower. PMID- 27125326 TI - Fine-Needle Aspiration as a Method of Diagnosis of Subcutaneous Fat Necrosis of the Newborn. AB - A 5-day-old boy presented with cellulitis-like, fluctuant lesions since birth. Clinically, subcutaneous fat necrosis was suspected, but an infective lesion could not be excluded. By performing a fine-needle aspiration biopsy, a diagnosis was established within minutes. PMID- 27125327 TI - Root-specific expression of opine genes and opine accumulation in some cultivars of the naturally occurring genetically modified organism Nicotiana tabacum. AB - Previous studies have shown that Nicotiana tabacum contains three Agrobacterium derived T-DNA sequences inherited from its paternal ancestor Nicotiana tomentosiformis. Among these, the TB locus carries an intact mannopine synthase 2' gene (TB-mas2'). This gene is similar to the Agrobacterium rhizogenes A4-mas2' gene that encodes the synthesis of the Amadori compound deoxyfructosyl-glutamine (DFG or santhopine). In this study we show that TB-mas2' is expressed at very low levels in N. tomentosiformis and in most N. tabacum cultivars; however, some cultivars show high TB-mas2' expression levels. The TB-mas2' promoter sequences of low- and high-expressing cultivars are identical. The low/high level of expression segregates as a single Mendelian factor in a cross between a low- and a high-expression cultivar. pTB-mas2'-GUS and pA4-mas2'-GUS reporter genes were stably introduced in N. benthamiana. Both were mainly expressed in the root expansion zone and leaf vasculature. Roots of tobacco cultivars with high TB mas2' expression contain detectable levels of DFG. PMID- 27125328 TI - Post-Synthetic Decoupling of On-Surface-Synthesized Covalent Nanostructures from Ag(111). AB - The on-surface synthesis of covalent organic nanosheets driven by reactive metal surfaces leads to strongly adsorbed organic nanostructures, which conceals their intrinsic properties. Hence, reducing the electronic coupling between the organic networks and commonly used metal surfaces is an important step towards characterization of the true material. We demonstrate that post-synthetic exposure to iodine vapor leads to the intercalation of an iodine monolayer between covalent polyphenylene networks and Ag(111) surfaces. The experimentally observed changes from surface-bound to detached nanosheets are reproduced by DFT simulations. These findings suggest that the intercalation of iodine provides a material that shows geometric and electronic properties substantially closer to those of the freestanding network. PMID- 27125329 TI - NIPBL expression levels in CdLS probands as a predictor of mutation type and phenotypic severity. AB - Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous multisystem developmental disorder with a high degree of variability in its clinical presentation. Approximately 65% of probands harbor mutations in genes that encode core components (SMC1A, SMC3, and RAD21) or regulators (NIPBL, HDAC8) of the cohesin complex, of which mutations in NIPBL are the most common. Cohesin plays a canonical role in sister chromatid cohesion during cell division and non canonical roles in DNA repair, stem cell maintenance and differentiation, and regulation of gene expression. Disruption of the latter role seems to be the major contributor to the underlying molecular pathogenesis of CdLS. NIPBL is required for loading and unloading the cohesin complex onto chromosomes. The expression levels of NIPBL itself appear to be tightly regulated and highly evolutionarily conserved. Droplet digital PCR was used to quantify NIPBL mRNA expression levels with high precision from a cohort of 37 samples (NIPBL, SMC1A, SMC3, and HDAC8 mutation positive probands and negative control). Probands with severe forms of CdLS or severe mutation types were found to have lower levels of NIPBL in comparison to phenotypically milder patients and controls. Levels of NIPBL also correlated with the presence of mutations in different CdLS-causing genes. The data suggests that NIPBL levels are closely correlated with the severity of CdLS and with specific causative genes and types of mutations. ddPCR may provide a tool to assist in diagnostic approaches to CdLS, for genetic counseling and prognosis, and for monitoring potential therapeutic modalities in the future. (c) 2016 Wiley Periodicals, Inc. PMID- 27125330 TI - IgG4-related retroperitoneal fibrosis: a newly characterized disease. AB - Retroperitoneal fibrosis (RPF) is a rare disease characterized by chronic, nonspecific inflammatory and sclerotic or fibrotic tissue in the periaortic or periiliac retroperitoneum that encases adjacent structures. There will be a series of clinical manifestations once the proliferated fibrous tissues encase the abdominal aorta, iliac arteries and urinary duct. RPF is generally divided into two types: idiopathic retroperitoneal fibrosis (IRPF) without identified pathogenesis, making up about two-thirds of cases, and secondary retroperitoneal fibrosis. Recent studies on Immunoglobulin G4-related disease (IgG4-RD) reveal that abundant infiltration of IgG4 positive plasma cells is found in biopsies on the mass of RPF of some IRPF patients, which is identified as one spectrum of IgG4-RD and is named IgG4-related RPF. IgG4-related RPF is often misdiagnosed as retroperitoneal visceral malignancy and is treated with surgery. In addition, because of its good response to glucocorticoid, early detection and treatment is important. We review the definition, epidemiology, clinical features, diagnostic criteria, treatment and prognosis of IgG4-related RPF in this article to raise awareness of this newly characterized disease. PMID- 27125331 TI - Effects of intravenous terbutaline on heart rate, arterial pressure and blood gases in anesthetized horses breathing air. AB - OBJECTIVE: To investigate the effects of intravenous (IV) administration of terbutaline on PaO2, PaCO2, pH, heart rate (HR) and arterial pressures in healthy, laterally recumbent horses breathing ambient air under total intravenous anesthesia (TIVA). STUDY DESIGN: Prospective experimental study. ANIMALS: Eight healthy adult horses were enrolled. Six horses, four mares and two geldings weighing 433-624 kg, completed the study. METHODS: Horses were sedated with xylazine (1.0 mg kg-1) IV for placement of arterial and venous catheters. Anesthesia was induced with midazolam (0.1 mg kg-1) and ketamine (2.2 mg kg-1) IV and maintained with an IV infusion of guaifenesin (50 mg mL-1), ketamine (2 mg mL 1) and xylazine (0.5 mg mL-1) at 1.9 +/- 0.3 mL kg-1 hour-1. Horses were in left lateral recumbency and breathed air spontaneously. Arterial blood was collected for pH and blood gas analysis during xylazine sedation, 15 minutes after induction of anesthesia, immediately before and 5, 15 and 30 minutes after administration of terbutaline (2 MUg kg-1), and when the horse was standing after recovery from anesthesia. HR, systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressures were recorded at 5 minute intervals during anesthesia. Normal data were analyzed with anova and non-normal data were analyzed with a Friedman test with a p < 0.05 considered significant. RESULTS: The mean PaO2 decreased from baseline to <60 mmHg (8.0 kPa) during anesthesia (p < 0.0001) and did not improve after administration of terbutaline. After terbutaline administration, HR increased (p = 0.002), and SAP, MAP and DAP decreased (p < 0.001) with the greatest changes occurring immediately after terbutaline administration. CONCLUSIONS AND CLINICAL RELEVANCE: Terbutaline (2 MUg kg-1) IV did not improve PaO2 and was associated with adverse cardiovascular effects during TIVA in healthy, laterally recumbent horses breathing air. PMID- 27125332 TI - Epidemiology of globus symptoms and associated psychological factors in China. AB - OBJECTIVE: To investigate the lifetime prevalence, epidemiological characteristics and psychological factors of globus symptoms in Guangzhou (Guangzhou Province, China). METHODS: A total of 3 360 individuals were randomly selected and participated in the study. Respondents completed questionnaires about their physical and psychological characteristics, globus symptomatology and the Glasgow-Edinburgh throat scale questionnaires and quality of sleep and life. Those who had experienced a globus sensation with no history of gastroesophageal reflux disease, dysphagia, odynophagia or alerting symptoms such as weight loss and hoarseness were diagnosed as having globus. RESULTS: A total of 3 006 respondents completed the questionnaires, giving a response rate of 89.5%. The overall lifetime prevalence of globus was 21.5%, with a peak age at disease onset of 35-54 years. The prevalence of globus was higher in participants from the urban region than those from the rural areas (26.5% vs 16.4%, P = 0.001). No sex related difference was observed (P = 0.082). Anxiety (39.8% vs 22.3%, P = 0.001), depression (31.2% vs 18.0%, P = 0.001) and sleep disorders (23.7% vs 13.6%, P = 0.001) were significantly more common in respondents with globus than in those without. Scores on all dimensions of the 36-item short-form health survey, except physical function, were lower in respondents with globus than in those without (all P < 0.05). CONCLUSIONS: Globus symptoms are common and often accompanied by psychological and sleep disorders. The medical community should pay more attention to globus in clinical setting. PMID- 27125333 TI - Clinical outcomes of HIV-exposed, HIV-uninfected children in sub-Saharan Africa. AB - OBJECTIVE: HIV-exposed but HIV-uninfected (HEU) children are widely considered at increased risk of mortality and morbidity. Recent advances in prevention of mother-to-child HIV transmission (PMTCT) strategies, incorporating life-long universal maternal antiretroviral therapy (ART, "Option B+") with extended breastfeeding, may improve HEU child health substantially. We critically reviewed reports of mortality/morbidity among HEU and HIV-unexposed (HU) children in sub Saharan Africa. METHODS: We searched Medline, EMBASE, CINAHL, PsycINFO, Academic Search Premier, Global Health & Psychosocial Instruments databases, conference abstracts, and reference lists for longitudinal studies from sub-Saharan Africa reporting mortality and clinical morbidity among HIV-uninfected children aged <=10 years, by maternal HIV status. Studies were appraised by Newcastle-Ottawa Scale and ACROBAT-NRSI. Due to substantial heterogeneity of study designs, populations and results (I(2) = 75%), data were not synthesised. RESULTS: We included 37 reports (28 studies, 11 164 HEU children); methodological and reporting quality were variable. Most reports came from settings without universal access to maternal ART (n = 35). Results were conflicting, with some studies indicating increased risk of mortality, hospitalisation and/or under nutrition among HEU children, while others found no evidence of increased risk. In subanalyses, improved maternal health, ART use and breastfeeding were strongly protective for all outcomes. Only 39% (11/28) of studies adjusted for major confounders. Reports from settings using universal maternal ART with breastfeeding (n = 2) found no differences in growth or development but did not report mortality or infectious morbidity. CONCLUSIONS: The existing literature provides little insight into HEU child health under recently adopted PMTCT strategies. There is a need for robust comparative data on HEU and HIV-unexposed child health outcomes under Option B+; optimising breastfeeding practices and increasing maternal use of ART should be urgent public health priorities. PMID- 27125334 TI - Preschoolers affect others' reputations through prosocial gossip. AB - Providing evaluative information to others about absent third parties helps them to identify cooperators and avoid cheaters. Here, we show that 5-year-olds, but not 3-year-olds, reliably engage in such prosocial gossip. In an experimental setting, 5-year-old children spontaneously offered relevant reputational information to guide a peer towards a cooperative partner. Three-year-old children offered such evaluative information only rarely, although they still showed a willingness to inform in a non-evaluative manner. A follow-up study revealed that one component involved in this age difference is children's developing ability to provide justifications. The current results extend previous work on young children's tendency to manage their own reputation by showing that preschoolers also influence others' reputations via gossip. PMID- 27125335 TI - Validation of R-MIPI and prognostic value of immunoglobulin light chain restriction in mantle cell lymphoma. PMID- 27125336 TI - 3D Bioprinting Using a Templated Porous Bioink. AB - 3D tissue printing with adult stem cells is reported. A novel cell-containing multicomponent bioink is used in a two-step 3D printing process to engineer bone and cartilage architectures. PMID- 27125337 TI - The association between trajectories of endocrine therapy adherence and mortality among women with breast cancer. AB - PURPOSE: Studies examining adherence to endocrine therapy (ET) and breast cancer related outcomes have traditionally used the proportion of days covered (PDC) by medication to define adherence which may mask true treatment-outcome associations for patients with different medication use behaviors. We use group-based trajectory models to examine the association between ET adherence patterns and mortality compared to a standard PDC adherence measure. METHODS: Using Surveillance, Epidemiology and End Results-Medicare data we included 9492 women with breast cancer who initiated ET between 2007 and 2010. We excluded women who died/recurred in the 12 months after ET initiation. We used monthly group-based trajectory models to characterize longitudinal adherence patterns and adjusted Cox proportional hazard models to estimate the association between ET adherence and mortality, comparing trajectory-based adherence to traditional PDC-based measures. RESULTS: Trajectory models identified five adherence groups: (i) high (56.2%); (ii) quick decline (9.5%); (iii) moderate decline (7.9%); (iv) quick decline, then increase (16.0%); and (v) slow decline (10.5%). Mortality was significantly associated with group assignment; compared to the high adherers, there was a significantly higher risk of death among quick declines (HR = 1.41, 95%CI = 1.09-1.72) and moderate declines (HR = 1.25, 95%CI = 1.00-1.55). Using the standard PDC adherence measure women with adherence <80% over the year had a higher risk of death than those with adherence >=80% (HR = 1.21, 95%CI = 1.06 1.38). CONCLUSIONS: Defining ET adherence using trajectory models improved adherence measurement. These models could inform clinical practice by helping to identify common adherence patterns, potential areas for intervention and better isolate adherence-related outcomes in comparative effectiveness studies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27125338 TI - Hydroxytyrosol and its complex forms (secoiridoids) modulate aorta and heart proteome in healthy rats: Potential cardio-protective effects. AB - SCOPE: Hydroxytyrosol (HT) is the major phenolic compound in virgin olive oil (VOO) in both free and complex forms (secoiridoids; SEC). Proteomics of cardiovascular tissues such as aorta or heart represents a promising tool to uncover the mechanisms of action of phenolic compounds in healthy animals. METHODS AND RESULTS: Twelve female Wistar rats were separated into three groups: a standard diet and two diets supplemented in phenolic compounds (HT and SEC) adjusted to 5 mg/kg/day during 21 days. Proteomic analyses of aorta and heart tissues were performed by nano-LC and MS. Ingenuity Pathway Analysis was used to generate interaction networks. HT or SEC modulated aorta and heart proteome compared to the standard diet. The top-scored networks were related to Cardiovascular System. HT and SEC downregulated proteins related to proliferation and migration of endothelial cells and occlusion of blood vessels in aorta and proteins related to heart failure in heart tissue. SEC showed higher fold change values compared to HT, attributed to higher concentration of HT detected in heart tissue. CONCLUSION: Changes at proteomic level in cardiovascular tissues may partially account for the underlying mechanisms of VOO phenols cardiovascular protection being the SEC effects higher than free HT. PMID- 27125340 TI - Growth Mechanism of Strain-Dependent Morphological Change in PEDOT:PSS Films. AB - Understanding the mechanism of the strain-dependent conductivity change in polymers in stretched conditions is important. We observed a strain-induced growth of the conductive regions of PEDOT: PSS films, induced by a coalescence of conductive PEDOT-rich cores. This growth due to coalescence leads to a gradual decrease in the electrical resistivity up to 95%, independent of the thickness of the PEDOT: PSS films. The primary mechanism for the evolution of the PEDOT-rich cores proceeds by the cores growing larger as they consuming relatively smaller cores. This process is caused by a strain-induced local rearrangement of PEDOT segments in the vicinity of PSS shells around the cores and also changes the chemical environment in PEDOT, induced by the electron-withdrawing effects around the PEDOT chains. The strain-induced growth mechanism is beneficial to understanding the phenomenon of polymeric chain rearrangement in mechanical deformation and to modulating the electrical conductivity for practical applications. PMID- 27125341 TI - Spontaneous Aerosol Ejection: Origin of Inorganic Particles in Biomass Pyrolysis. AB - At high thermal flux and temperatures of approximately 500 degrees C, lignocellulosic biomass transforms to a reactive liquid intermediate before evaporating to condensable bio-oil for downstream upgrading to renewable fuels and chemicals. However, the existence of a fraction of nonvolatile compounds in condensed bio-oil diminishes the product quality and, in the case of inorganic materials, catalyzes undesirable aging reactions within bio-oil. In this study, ablative pyrolysis of crystalline cellulose was evaluated, with and without doped calcium, for the generation of inorganic-transporting aerosols by reactive boiling ejection from liquid intermediate cellulose. Aerosols were characterized by laser diffraction light scattering, inductively coupled plasma spectroscopy, and high-speed photography. Pyrolysis product fractionation revealed that approximately 3 % of the initial feed (both organic and inorganic) was transported to the gas phase as aerosols. Large bubble-to-aerosol size ratios and visualization of significant late-time ejections in the pyrolyzing cellulose suggest the formation of film bubbles in addition to the previously discovered jet formation mechanism. PMID- 27125342 TI - Protecting and accelerating adiabatic passage with time-delayed pulse sequences. AB - Using numerical simulations of two-photon electronic absorption with femtosecond pulses in Na2 we show that: (i) it is possible to avoid the characteristic saturation or dumped Rabi oscillations in the yield of absorption by time delaying the laser pulses; (ii) it is possible to accelerate the onset of adiabatic passage by using the vibrational coherence starting in a wave packet; and (iii) it is possible to prepare the initial wave packet in order to achieve full state-selective transitions with broadband pulses. The findings can be used, for instance, to achieve ultrafast adiabatic passage by light-induced potentials and understand its intrinsic robustness. PMID- 27125339 TI - Anti-Mullerian Hormone and Inhibin-A, but not Inhibin-B or Insulin-Like Peptide 3, may be Used as Surrogates in the Diagnosis of Polycystic Ovary Syndrome in Adolescents: Preliminary Results. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine problem in adolescents with an increasing prevalence of 30%. Pursuing new biomarkers with high specificity and sensitivity in the diagnosis of PCOS in adolescents is currently an active area of research. We aimed to investigate the diagnostic value of anti-Mullerian hormone (AMH), insulin-like peptide-3 (INSL3), inhibin-A (INH-A), and inhibin-B (INH-B) in adolescents with PCOS and also to determine the association, if any, between these hormones and clinical/laboratory findings related with hyperandrogenism. METHODS: The study group comprised 53 adolescent girls aged between 14.5 and 20 years who were admitted to our outpatient clinic with symptoms of hirsutism and/or irregular menses and diagnosed as having PCOS in accordance with the Rotterdam criteria. Twenty-six healthy peers, eumenorrheic for at least two years and body mass index-matched, constituted the controls. Fasting blood samples for hormones [luteinizing hormone (LH), follicle stimulating hormone (FSH), dehydroepiandrosterone-sulfate (DHEAS), androstenedione (D4-A), total/free testosterone (T/fT), sex hormone binding globulin (SHBG), AMH, INSL3, INH-A, INH-B] were drawn after an overnight fast. RESULTS: In the PCOS group, 83% of the subjects were oligomenorrheic/amenorrheic and 87% had hirsutism. The LH, LH/FSH ratio, total T, fT, free androgen-index (FAI), DHEAS levels were significantly higher (p=0.005, p=0.042, p=0.047, p<0.001, p=0.007, p=0.014, respectively) and SHBG was significantly lower (p=0.004) in PCOS patients as compared to the controls. Although the INSL-3 and INH-B levels showed no difference between the groups (p>0.05), AMH and INH-A levels were found to be significantly higher in the PCOS group compared to the controls (p<0.001, p<0.001, respectively). In multiple linear regression analysis, WC SDS (p=0.028), logD4-A (p=0.033), logSHBG (p=0.031), and total ovarian volume (p=0.045) had significant effects on AMH levels, and LH (p=0.003) on INH-A levels. In receiver-operating characteristic analysis, the cut-off values for AMH and INH-A were 6.1 ng/mL (sensitivity 81.1%) and 12.8 pg/mL (sensitivity 86.8%), respectively, to diagnose PCOS. When AMH and INH-A were used in combination, the sensitivity (96.2%) increased. CONCLUSION: INSL3 and INH-B were not found to have diagnostic value in adolescents with PCOS. On the other hand, it was shown that INH-A could be used as a new diagnostic biomarker in addition to AMH. PMID- 27125344 TI - Active Ageing to Gerotranscendence. PMID- 27125343 TI - Short-term MyD88 inhibition ameliorates cardiac graft rejection and promotes donor-specific hyporesponsiveness of skin grafts in mice. AB - Recognition of evolutionarily conserved ligands by Toll-like receptors (TLRs) triggers signaling cascades in innate immune cells to amplify adaptive immune responses. Nearly all TLRs require MyD88 to transduce downstream signaling. MyD88 deficiency has been shown to promote the allograft acceptance in mice. However, direct evidence for therapeutic potential of MyD88 inhibitors remains lacking. Herein, we used a MyD88 inhibitor, namely ST2825, to explore its therapeutic potential and mechanisms in fully allogeneic skin and heart transplant models. Phenotypic maturation of dendritic cells stimulated by TLR ligands was alleviated by ST2825 in parallel with reduced T-cell proliferation in vitro. A short-course treatment with ST2825 significantly prolonged cardiac graft survival (mean survival time = 18.5 +/- 0.92 days vs. 7.25 +/- 0.46 days). ST2825-treated group had significantly reduced proinflammatory cytokines in allografts compared with control group. ST2825 combined with anti-CD154 induced long-term skin allograft acceptance in about one-third of recipients (>100 days). 'Skin-tolerant' recipients showed attenuated donor-specific IFN-gamma responses, intact IL-4 responses, and compromised alloantibody responses. We conclude that MyD88 inhibitor ST2825 attenuates acute cardiac rejection and promotes donor-specific hyporesponsiveness in stringent skin transplant models. The direct evidence suggests that pharmacological inhibition of MyD88 hold promising potential for transplant rejection. PMID- 27125345 TI - Efficacy, Immunogenicity and Safety of a Human Rotavirus Vaccine RIX4414 in Singaporean Infants. AB - INTRODUCTION: This was the first study conducted to evaluate the efficacy of 2 oral doses of the human rotavirus vaccine, RIX4414 in Singaporean infants during the first 3 years of life. MATERIALS AND METHODS: Healthy infants, 11 to 17 weeks of age were enrolled in this randomised (1:1), double-blinded, placebo-controlled study to receive 2 oral doses of RIX4414 vaccine/placebo following a 0-, 1-month schedule. Vaccine efficacy against severe rotavirus (RV) gastroenteritis (Vesikari score >=11) caused by wild-type RV strains from a period starting from 2 weeks post-Dose 2 until 2 and 3 years of age was calculated with 95% confidence interval (CI). Immunogenicity and safety of the vaccine were also assessed. RESULTS: Of 6542 infants enrolled, 6466 were included in the efficacy analysis and a subset of 100 infants was included in the immunogenicity analysis. Fewer severe RV gastroenteritis episodes were reported in the RIX4414 group when compared to placebo at both 2 and 3 year follow-up periods. Vaccine efficacy against severe RV gastroenteritis at the respective time points were 93.8% (95% CI, 59.9 to 99.9) and 95.2% (95% CI, 70.5 to 99.9). One to 2 months post-Dose 2 of RIX4414, 97.5% (95% CI, 86.8 to 99.9) of infants seroconverted for anti-RV IgA antibodies. The number of serious adverse events recorded from Dose 1 until 3 years of age was similar in both groups. CONCLUSION: Two oral doses of RIX4414 vaccine was immunogenic and provided high level of protection against severe RV gastroenteritis in Singaporean children, during the first 3 years of life when the disease burden is highest. PMID- 27125346 TI - Survival Prognostication in Patients with Skeletal Metastases from Nasopharyngeal Carcinoma: An Evaluation of the Scandinavian Sarcoma Group, Katagiri and Bauer Scoring Systems. AB - INTRODUCTION: Nasopharnygeal carcinoma (NPC) is characterised by early metastases with the skeleton being the most common site of metastases. The ability to prognosticate survival is crucial in the decision whether or not to offer surgery to these patients and the choice of surgery offered. We aimed to evaluate the scoring systems namely: Bauer, Katagiri and Scandinavian Sarcoma Group (SSG) in NPC patients with skeletal metastases. MATERIALS AND METHODS: A total of 92 patients with skeletal metastases from NPC were studied. We retrospectively analysed the actual survival of these patients and compared with predicted survival according to the 3 scoring systems. The predicted survival according to each system was calculated and labelled as A scores. These were then re-scored by assigning NPC as a better prognostic tumour and labelled as B scores. The predicted survival of scores A and B were compared to actual survival. Univariate and multivariate Cox regression analyses were performed. The predictive values of each scoring were calculated. RESULTS: The median overall survival for the whole cohort was 13 months (range: 1 to 120 months). In multivariate analysis, general condition and visceral metastases showed significant effect on survival. There were statistically significant differences (P <0.001) between the subgroups of the SSG B as well as Katagiri B scoring systems where NPC was classified as a better prognostic tumour. SSG B provided the highest predictive value (0.67) as compared to the other 2 scoring systems. CONCLUSION: The SSG and Katagiri score could be used to prognosticate NPC with a statistically significant association with actual survival. PMID- 27125347 TI - Health-Related Quality of Life in Children with Biliary Atresia Living with Native Livers. AB - INTRODUCTION: This study aimed to quantify and investigate factors affecting the health-related quality of life (HRQoL) in children with biliary atresia (BA) living with their native livers. MATERIALS AND METHODS: A cross-sectional study on the HRQoL using the PedsQL4.0 generic core scales in children with BA aged between 2 to 18 years followed up at the University Malaya Medical Centre (UMMC) in Malaysia was conducted. Two groups, consisting of healthy children and children with chronic liver disease (CLD) caused by other aetiologies, were recruited as controls. RESULTS: Children with BA living with their native livers (n = 36; median (range) age: 7.4 (2 to 18) years; overall HRQoL score: 85.6) have a comparable HRQoL score with healthy children (n = 81; median age: 7.0 years; overall HQRoL score: 87.4; P = 0.504) as well as children with CLD (n = 44; median age: 4.3 years; overall score: 87.1; P = 0.563). The HRQoL of children with BA was not adversely affected by having 1 or more hospitalisations in the preceding 12 months, the presence of portal hypertension, older age at corrective surgery (>60 days), a lower level of serum albumin (<=34 g/L) or a higher blood international normalised ratio (INR) (>=1.2). Children who had liver transplantation for BA did not have a significantly better HRQoL as compared to those who had survived with their native livers (85.4 vs 85.7, P = 0.960). CONCLUSION: HRQoL in children with BA living with their native livers is comparable to healthy children. PMID- 27125348 TI - Generalised Anhidrosis Secondary to Intracranial Haemorrhage. PMID- 27125349 TI - Detection of Residual Lentigo Maligna Using the In Vivo Reflectance Confocal Microscopy. PMID- 27125350 TI - Progress in Singapore Family Medicine: Reflections over the Decades from 1931. PMID- 27125353 TI - Chemotherapy: Clocking up resistance. PMID- 27125351 TI - Sequence diversity of NanA manifests in distinct enzyme kinetics and inhibitor susceptibility. AB - Streptococcus pneumoniae is the leading pathogen causing bacterial pneumonia and meningitis. Its surface-associated virulence factor neuraminidase A (NanA) promotes the bacterial colonization by removing the terminal sialyl residues from glycoconjugates on eukaryotic cell surface. The predominant role of NanA in the pathogenesis of pneumococci renders it an attractive target for therapeutic intervention. Despite the highly conserved activity of NanA, our alignment of the 11 NanAs revealed the evolutionary diversity of this enzyme. The amino acid substitutions we identified, particularly those in the lectin domain and in the insertion domain next to the catalytic centre triggered our special interest. We synthesised the representative NanAs and the mutagenized derivatives from E. coli for enzyme kinetics study and neuraminidase inhibitor susceptibility test. Via molecular docking we got a deeper insight into the differences between the two major variants of NanA and their influence on the ligand-target interactions. In addition, our molecular dynamics simulations revealed a prominent intrinsic flexibility of the linker between the active site and the insertion domain, which influences the inhibitor binding. Our findings for the first time associated the primary sequence diversity of NanA with the biochemical properties of the enzyme and with the inhibitory efficiency of neuraminidase inhibitors. PMID- 27125354 TI - Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers. AB - Despite advances in treatment, up to 30% of breast cancer patients experience disease recurrence accompanied by more aggressive disease and poorer prognosis. Treatment of breast cancer is complicated by the presence of multiple breast cancer subtypes, including: luminal, Her2 overexpressing, and aggressive basal like breast cancers. Identifying new biomarkers specific to breast cancer subtypes could enhance the prediction of patient prognosis and contribute to improved treatment strategies. The microenvironment influences breast cancer progression through expression of growth factors, angiogenic factors and other soluble proteins. In particular, chemokine C-C ligand 2 (CCL2) regulates macrophage recruitment to primary tumors and signals to cancer cells to promote breast tumor progression. Here we employed a software-based approach to evaluate the prognostic significance of CCL2 protein expression in breast cancer subtypes in relation to its expression in the epithelium or stroma or in relation to fibroblast-specific protein 1 (Fsp1), a mesenchymal marker. Immunohistochemistry analysis of tissue microarrays revealed that CCL2 significantly correlated with Fsp1 expression in the stroma and tumor epithelium of invasive ductal carcinoma. In the overall cohort of invasive ductal carcinomas (n=427), CCL2 and Fsp1 expression in whole tissues, stroma and epithelium were inversely associated with cancer stage and tumor size. When factoring in molecular subtype, stromal CCL2 was observed to be most highly expressed in basal-like breast cancers. By Cox regression modeling, stromal CCL2, but not epithelial CCL2, expression was significantly associated with decreased recurrence-free survival. Furthermore, stromal CCL2 (HR=7.51 P=0.007) was associated with a greater hazard than cancer stage (HR=2.45, P=0.048) in multivariate analysis. These studies indicate that stromal CCL2 is associated with decreased recurrence-free survival in patients with basal-like breast cancer, with important implications on the use of stromal markers for predicting patient prognosis. PMID- 27125352 TI - From melanocytes to melanomas. AB - Melanomas on sun-exposed skin are heterogeneous tumours, which can be subtyped on the basis of their cumulative levels of exposure to ultraviolet (UV) radiation. A melanocytic neoplasm can also be staged by how far it has progressed, ranging from a benign neoplasm, such as a naevus, to a malignant neoplasm, such as a metastatic melanoma. Each subtype of melanoma can evolve through distinct evolutionary trajectories, passing through (or sometimes skipping over) various stages of transformation. This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature. PMID- 27125355 TI - A systematic comparison of three commercial estrogen receptor assays in a single clinical outcome breast cancer cohort. AB - Breast cancers are routinely assessed for estrogen receptor status using immunohistochemical assays to assist in patient prognosis and clinical management. Specific assays vary between laboratories, and several antibodies have been validated and recommended for clinical use. As numerous factors can influence assay performance, many laboratories have opted for ready-to-use assays using automated stainers to improve reproducibility and consistency. Three commonly used autostainer vendors-Dako, Leica, and Ventana-all offer such estrogen receptor assays; however, they have never been directly compared. Here, we present a systematic comparison of three platform-specific estrogen receptor ready-to-use assays using a retrospective, tamoxifen-treated, breast cancer cohort from patients who were treated in Calgary, Alberta, Canada from 1985 to 2000. We found all assays showed good intra-observer agreement. Inter-observer pathological scoring showed some variability: Ventana had the strongest agreement followed closely by Dako, whereas Leica only showed substantial agreement. We also analyzed each estrogen receptor assay with respect to 5-year disease-free survival, and found that all performed similarly in univariate and multivariate models. Determination of measures of test performance found that the Leica assay had a lower negative predictive value than Dako or Ventana, compared with the original ligand-binding assay, while other measures-sensitivity, specificity, positive predictive value, and accuracy-were comparable between the three ready to-use assays. When comparing against disease-free survival, the difference in negative predictive value between the vendor assays were not as extreme, but Dako and Ventana still performed slightly better than Leica. Despite some discordance, we found that all ready-to-use assays were comparable with or superior to the ligand-binding assay, endorsing their continued use. Our analysis also allowed for exploration of estrogen receptor-negative, progesterone receptor-positive cases, and we discovered that this phenotype was not consistent across the assays, suggesting this might be an artifact. PMID- 27125356 TI - Definition of MYC genetic heteroclonality in diffuse large B-cell lymphoma with 8q24 rearrangement and its impact on protein expression. AB - MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B cell lymphoma and may have a relevant role in modulating MYC expression. PMID- 27125357 TI - USP6 genetic rearrangements in cellular fibroma of tendon sheath. AB - Fibroma of tendon sheath is a benign (myo)fibroblastic neoplasm of the tenosynovial soft tissues, typically affecting the distal extremities. It is classically described as a paucicellular, densely collagenized tumor; however, cellular variants have been described. A subset of cellular fibromas of tendon sheath shares similar histological features with nodular fasciitis. As nodular fasciitis very frequently harbors rearrangement of ubiquitin-specific peptidase 6 (USP6), we hypothesized that cellular fibromas of tendon sheath with nodular fasciitis-like features may also contain USP6 rearrangements. Cases of fibroma of tendon sheath (n=19), including cellular (n=9) and classic (n=10) variants, were evaluated for USP6 rearrangement by fluorescence in situ hybridization studies. A subset of cases was tested for MYH9 rearrangements and MYH9-USP6 and CDH11-USP6 fusion products. Classic fibroma of tendon sheath occurred in 5 males and 5 females (median age 67 years, range 23-77 years) as soft tissue masses of the hand (n=4), finger (n=3), forearm (n=1) and foot (n=2). Cellular fibroma of tendon sheath occurred in 5 males and 4 females in a younger age group (median age 32 years, range 12-46 years) as small soft tissue masses of the finger (n=5), hand (n=3) and wrist (n=1). USP6 rearrangements were detected in 6/9 cellular fibromas of tendon sheath. Among cellular fibromas of tendon sheath with USP6 rearrangements, no MYH9 rearrangements were detected. By RT-PCR, neither the MYH9 USP6 or the CDH11-USP6 fusion products were detected in any case. Neither USP6 nor MYH9 rearrangement were detected in any classic fibroma of tendon sheath. We report for the first time the presence of USP6 rearrangements in a subset of cellular fibroma of tendon sheath. Based on the similar morphological and molecular genetic features, we suspect that a subset of cellular fibromas of tendon sheath are under-recognized examples of tenosynovial nodular fasciitis, driven by alternate USP6 fusion genes. Further investigation will delineate how these lesions should best be classified. PMID- 27125359 TI - Trigonal prismatic metal complexes: a not so rare coordination geometry? AB - The solid state structures of two metal complexes of a hexaamine macrobicyclic ligand, in which the metal ion has an exact trigonal prismatic geometry, have been determined. Theoretical calculations showed this is the most stable geometry for d(0), d(10) and high spin d(5) metal complexes of the ligand with M-N bond distances >~2.35 A. PMID- 27125360 TI - Carbon nanotube-supported Au-Pd alloy with cooperative effect of metal nanoparticles and organic ketone/quinone groups as a highly efficient catalyst for aerobic oxidation of amines. AB - Functionalised carbon nanotube (CNT)-supported Au-Pd alloy nanoparticles were highly efficient catalysts for the aerobic oxidation of amines. We achieved the highest turnover frequencies (>1000 h(-1)) for the oxidative homocoupling of benzylamine and the oxidative dehydrogenation of dibenzylamine. We discovered a cooperative effect between Au-Pd nanoparticles and ketone/quinone groups on CNTs. PMID- 27125358 TI - Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation. AB - Metastatic neuroendocrine neoplasms to the breast may show considerable morphologic overlap with primary mammary carcinomas, particularly those showing evidence of neuroendocrine differentiation, and may be misdiagnosed as such. Accurate distinction between these two entities is crucial for determination of appropriate clinical management. The histologic and immunohistochemical features of metastatic neuroendocrine neoplasms to the breast were studied and compared with the features of primary invasive mammary carcinomas with neuroendocrine differentiation, which served as controls. Of the metastatic neuroendocrine neoplasms, 15 were well-differentiated neuroendocrine tumors with carcinoid tumor type morphology and 7 were poorly differentiated/high-grade neuroendocrine carcinomas with small-cell or large-cell neuroendocrine carcinoma morphology. The majority of the metastatic neoplasms originated in the lung and gastrointestinal tract. There were histologic similarities between metastatic neuroendocrine neoplasms and invasive mammary carcinomas with neuroendocrine differentiation, both of which exhibited neuroendocrine histologic features (nested and trabecular architecture, minimal tubular differentiation, and characteristic nuclear features). Only one case of the invasive mammary carcinomas with neuroendocrine differentiation was modified Bloom-Richardson grade 1 (largely due to minimal tubular differentiation on most such tumors), and the invasive mammary carcinomas with neuroendocrine differentiation were often associated with in situ carcinoma. Immunohistochemistry was helpful in distinguishing metastatic neuroendocrine neoplasms from invasive mammary carcinomas with neuroendocrine differentiation. Whereas the majority of invasive mammary carcinomas with neuroendocrine differentiation were positive for estrogen receptor and GATA3, metastatic neuroendocrine neoplasms were typically negative for estrogen receptor and GATA3, and metastatic well-differentiated neuroendocrine tumors often showed immunoreactivity for site-specific markers. Although the histologic and immunohistochemical features of a breast tumor may raise the suspicion of a metastatic neuroendocrine neoplasm, the pathologic findings should be interpreted in the context of the clinical history and imaging findings in order to establish an accurate diagnosis. PMID- 27125361 TI - Paraneoplastic arthritis as first symptom of a liver inflammatory pseudotumor like follicular dendritic cell sarcoma. PMID- 27125362 TI - Erratum: Kallikrein-related peptidase 8 is expressed in myocardium and induces cardiac hypertrophy. PMID- 27125363 TI - Improvement of BMD after Switching from Lopinavir/R Plus Two Nucleos(T)ide Reverse Transcriptase Inhibitors to Lopinavir/R Plus Lamivudine: OLE-LIP Substudy. AB - OBJECTIVE: To compare 48-week changes in bone mineral density (BMD) and body fat distribution between patients continuing lopinavir/ritonavir and two NRTIs and those switching to lopinavir/ritonavir and lamivudine. METHODS: Substudy of a randomized, open-label, multicenter OLE study was carried out. Adult HIV-infected patients with <50 copies/mL for >=6 months were randomized (1:1) to continue lopinavir/ritonavir and two NRTIs or switching to lopinavir/ritonavir and lamivudine. Dual-energy X-ray absorptiometry (DXA) was performed at baseline and after 48 weeks to measure bone composition and body fat distribution in both the groups. RESULTS: Forty-one patients (dual-therapy, n = 23; triple-therapy, n = 18) of 239, who received at least one dose of study medication, completed the study: median age, 42 years, 71% male, 73% Caucasian. At week 48, total BMD increased by 1.04% (95% CI, 0.06 to 2.01%) among patients switching to dual therapy, whereas no significant changes occurred in patients maintaining triple therapy. Dual-therapy and older age were independently associated with total BMD increase. Among patients discontinuing tenofovir-DF, a significant increase was seen in total BMD (1.43; 95% CI, -0.04 to 2.91) and total hip (1.33%; 95% CI, 0.44 to 2.22%). A non-statistically significant decrease in femoral and spinal BMD was observed in patients who discontinued abacavir and in those continuing triple-therapy. Regarding fat distribution, no significant changes were seen in both the treatment groups. DISCUSSION: BMD increased following switching to lopinavir/ritonavir plus lamivudine in HIV-infected patients on suppressive triple-therapy with lopinavir/ritonavir and two NRTIs including tenofovir-DF. PMID- 27125364 TI - Fosamprenavir/ritonavir in patients with viral hepatitis coinfection: an observational multicohort study. AB - OBJECTIVE: Safety and tolerability evaluation of adapted dose regimens containing fosamprenavir/ritonavir (FPV/r) in HIV-infected subjects with viral hepatitis co infection. METHODS: A retrospective multicohort analysis was conducted. Subjects from three European cohorts who started FPV/r or lopinavir/ritonavir (LPV/r) as a comparator contributed data to a centralized database. Subjects were divided into five groups by treatment regimen and level of hepatic impairment (aspartate aminotransferase [AST] platelet ratio index [APRI] score < or >=2). Multivariable Cox regression analyses controlling for demographic factors, baseline CD4 count, FIB-4 score, use of antiretroviral therapy, and laboratory markers (bilirubin and platelet count) were performed to identify factors independently associated with risk of developing adverse events or safety events (eg, drug discontinuation, alanine aminotransferase (ALT) elevation, hepatic decompensation/death). RESULTS: A total of 1096 patients contributed data to the study. Fosamprenavir/ritonavir (except in subjects with APRI >=2 receiving standard dose) was associated with a higher two-year risk of drug discontinuation compared with LPV/r. Restricting the analysis to discontinuations due to adverse events (AEs), only subjects who received the reduced dose were more likely to discontinue >=1 drug in the FPV/r regimen. There were no statistical differences in ALT elevation between groups. Incidence of hepatic decompensation events was similar among groups except for subjects who received non standard doses of FPV, though the number of events was small. CONCLUSIONS: Fosamprenavir/ritonavir discontinuation rate due to AEs or ALT elevation was similar across all European-approved FPV/r doses and to that of LPV/r subjects. Although liver tolerated antiretrovirals, such as integrase inhibitor and entry inhibitor, the use of FPV/r is acceptable in HIV infected patients with viral hepatitis. PMID- 27125365 TI - Integrase Strand Transfer Inhibitors (INSTIs) Resistance Mutations in HIV-1 Infected Turkish Patients. AB - OBJECTIVES: Integrase strand transfer inhibitor (INSTI) is a new class of antiretroviral (ARV) drugs designed to block the action of the integrase viral enzyme, which is responsible for insertation of the HIV-1 genome into the host DNA. The aim of this study was to evaluate for the first time INSTI resistance mutations in Turkish patients. METHODS: This study was conducted in Turkey, between April 2013 and April 2015 using 169 HIV-1-infected patients (78 ARV naive patients and 91 ARV-experienced patients). Laboratory and clinical characteristics of ARV naive and ARV-experienced patients were as follows: gender (M/F): 71/7 and 80/11, median age: 38 and 38.4; median CD4(+) T-cell: 236 and 216 cells/mm(3), median HIV-1 RNA: 4.95+E5 and 1.08E+6 copies/ml. Population-based seqeunces of the reverse transcriptase, protease, and integrase domains of the HIV-1 pol gene were used to detect HIV-1 drug resistance mutations. RESULT: INSTI resistance mutations were not found in recently diagnosed HIV-1-infected patients. However, ARV-experienced patients had major resistance mutations associated with raltegravir and elvitegravir; the following results were generated:F121Y, Y143R, Q148R and E157Q (6/91 - 6.6%). CONCLUSIONS: The prevalence of INSTI resistant mutations in ART-experienced patients suggested that resistance testing must be incorporated as an integral part of HIV management with INSTI therapies. PMID- 27125367 TI - A cross-sectional study to evaluate the association of hyperbilirubinaemia on markers of cardiovascular disease, neurocognitive function, bone mineral density and renal markers in HIV-1 infected subjects on protease inhibitors. AB - BACKGROUND: Ongoing inflammation in controlled HIV infection contributes to non AIDS comorbidities. High bilirubin appears to exhibit an anti-inflammatory effect in vivo. We therefore examined whether increased bilirubin in persons with HIV was associated with differences in markers of inflammation and cardiovascular, bone, renal disease, and neurocognitive (NC) impairment. METHODS: This cross sectional study examined inflammatory markers in individuals with stable HIV infection treated with two nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor. Individuals recruited were those with a normal bilirubin (NBR; 0-17 MUmol/L) or high bilirubin (>2.5 * upper limit of normal). Demographic and anthropological data were recorded. Blood and urine samples were taken for analyses. Pulse wave velocity (PWV) measurement, carotid intimal thickness (CIT), and calcaneal stiffness (CSI) were measured. Males were asked to answer a questionnaire about sexual function; NC testing was performed using CogState. RESULTS: 101 patients were screened, 78 enrolled (43 NBR and 35 HBR). Atazanavir use was significantly higher in HBR. Whilst a trend for lower CIT was seen in those with HBR, no significant differences were seen in PWV, bone markers, calculated cardiovascular risk (Framingham), or erectile dysfunction score. VCAM-1 levels were significantly lower in the HBR group. HBR was associated with lower LDL and triglyceride levels. NBR was associated with a calculated FRAX significantly lower than HBR although no associations were found after adjusting for tenofovir use. No difference in renal markers was observed. Component tests of NC testing revealed differences favouring HBR but overall composite scores were similar. DISCUSSION: High bilirubin in the context of boosted PI therapy was found not to be associated with differences in with the markers examined in this study. Some trends were noted and, on the basis of these, a larger, clinical end point study is warranted. PMID- 27125366 TI - Non-classical monocytes predict progression of carotid artery bifurcation intima media thickness in HIV-infected individuals on stable antiretroviral therapy. AB - BACKGROUND: Inflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT). METHODS: Longitudinal study of HIV-infected subjects >=40 years and on stable antiretroviral therapy (ART) >=3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)) and transitional (CD14(+)CD16(-)) monocyte subsets and activated (CD38(+)HLA-DR(+)) CD8(+) T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over two years at the right common carotid artery (CIMTCCA) and right bifurcation (CIMTBIF) were outcome variables. RESULTS: We studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm(3), and with HIV RNA <= 50 copies/mL in 84%. Change in CIMTBIF correlated with log values of baseline absolute count of non-classical monocytes (r = 0.37, p = 0.020), and with MCP-1 (r = 0.42, p = 0.0024) and TNF-alpha (r = 0.30, p = 0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMTBIF, independent of Framingham Risk Score and baseline CIMTBIF. No correlation was noted between CD8 T-cell activation and CIMTBIF change. Monocyte subsets, CD8 T-cell activation, and biomarker concentrations were not correlated with changes in CIMTCCA. CONCLUSIONS: Our findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMTBIF in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors. PMID- 27125368 TI - Pooled influenza vaccine effectiveness estimates for Australia, 2012-2014. AB - Data were pooled from three Australian sentinel general practice influenza surveillance networks to estimate Australia-wide influenza vaccine coverage and effectiveness against community presentations for laboratory-confirmed influenza for the 2012, 2013 and 2014 seasons. Patients presenting with influenza-like illness at participating GP practices were swabbed and tested for influenza. The vaccination odds of patients testing positive were compared with patients testing negative to estimate influenza vaccine effectiveness (VE) by logistic regression, adjusting for age group, week of presentation and network. Pooling of data across Australia increased the sample size for estimation from a minimum of 684 to 3,683 in 2012, from 314 to 2,042 in 2013 and from 497 to 3,074 in 2014. Overall VE was 38% [95% confidence interval (CI) 24-49] in 2012, 60% (95% CI 45-70) in 2013 and 44% (95% CI 31-55) in 2014. For A(H1N1)pdm09 VE was 54% (95% CI-28 to 83) in 2012, 59% (95% CI 33-74) in 2013 and 55% (95% CI 39-67) in 2014. For A(H3N2), VE was 30% (95% CI 14-44) in 2012, 67% (95% CI 39-82) in 2013 and 26% (95% CI 1-45) in 2014. For influenza B, VE was stable across years at 56% (95% CI 37-70) in 2012, 57% (95% CI 30-73) in 2013 and 54% (95% CI 21-73) in 2014. Overall VE against influenza was low in 2012 and 2014 when A(H3N2) was the dominant strain and the vaccine was poorly matched. In contrast, overall VE was higher in 2013 when A(H1N1)pdm09 dominated and the vaccine was a better match. Pooling data can increase the sample available and enable more precise subtype- and age group specific estimates, but limitations remain. PMID- 27125373 TI - Documenting a long-term development model in the slums of Delhi. AB - BACKGROUND: Achieving development outcomes requires the inclusion of marginalised populations that have the least opportunity to participate in and benefit from development. Slum dwellers often see little of the 'urban advantage', suffering more from infectious diseases, increasing food costs, poor access to education and health care, inadequate water and sanitation, and informal employment. A recent Cochrane Review of the impact of slum upgrading strategies found a dearth of unbiased studies, making it difficult to draw firm conclusions. The Review calls for greater use of process data, and qualitative alongside quantitative methods of evaluation. India is a lower middle income nation with large gender disparities and around 65 million slum inhabitants. The Asha Community Health and Development Society, a non-governmental organisation based in Delhi, has delivered a multi-sectoral program across 71 slums since 1988. This article reports on a mixed-method study to document measureable health and social impacts, along with Asha's ethos and processes. METHODS: Several observational visits were made to 12 Asha slums where informal discussions were had with staff and residents (n = 50). Asha data records were analysed for change over time (and differences with greater Delhi) in selected indicators (maternal-child health, education, child sex ratio) using descriptive statistics. 34 semi-structured individual/small group interviews and 14 focus group discussions were held with staff, residents, volunteers, elected officials, civil servants, bankers, diplomats, school principals, slumlords and loan recipients (n = 147). RESULTS: Key indicators of health and social equity improved over time and compared favourably with those for greater Delhi. The Asha model emphasises rights, responsibilities, equity and non-violence. It employs strategies characterised by long-term involvement, systematic protocols and monitoring, development of civil society (especially women's and children's groups) to advocate for rights under the law, and links with foreign volunteers and fund-raisers. Stakeholders agreed that changes in community norms and living conditions were at least partly attributable to the Asha model. CONCLUSIONS: While lacking a control group or complete baseline data, evidence suggested substantial improvements in slum conditions and social equity. The Asha model offers some lessons for slum (and broader) development. PMID- 27125374 TI - Expert's comment concerning Grand Rounds case entitled "Management of an unusual sciatica" by A. Bourghli, A. Chaballout, I. Obeid, L. Boissiere, J.-M. Vital and G. Khoury (Eur Spine J; doi:10.1007/s00586-016-4446-z). PMID- 27125375 TI - The effect of incidental dural lesions on outcome after decompression surgery for lumbar spinal stenosis: results of a multi-center study with 800 patients. AB - PURPOSE: Incidental durotomy is one of the most common complications in lumbar spine surgery. There are conflicting reports whether a dural lesion is associated with an inferior outcome after lumbar decompression. This study analyzed the effect of incidental durotomy in this specific group of patients (Dura+) and compared the results with the remaining cohort without dural laceration (Dura-). METHODS: This prospective multi-center study included 800 patients with lumbar spinal stenosis who underwent exclusive decompression surgery. All procedures were performed as part of a multi-center investigation at three highly specialized spine clinics. Outcome measures (ODI, EQ5D, VASback pain and VASleg pain) were obtained preoperatively as well as 3 and 12 months after surgery. The effect of an incidental durotomy on the clinical outcomes was analyzed statistically between the two cohorts. RESULTS: An intraoperative dura lesion was recorded in 6.5 % (n = 52/800) of all cases. Both cohorts (Dura+ and Dura-) did not reveal any differences regarding patient demographics, risk factors, or co morbidities at baseline. The length of the hospital stay was significantly longer for the Dura+ cohort (8.0 vs. 6.4 days; p < 0.01). After 12 months, the Dura- cohort demonstrated a significantly greater improvement in VASback pain in comparison to the Dura+ cohort (Delta21.4 vs. Delta7.2 points; p < 0.05). The differences for the remaining outcome measures were not statistically significant (p > 0.05). CONCLUSIONS: The results of this study reveal that an incidental durotomy was associated with a significant increase in the patient's length of stay, and risk for re-intervention for the treatment of persisting CSF leakage. In contrast to previous reports which have investigated the effects of incidental durotomies on the clinical outcome after lumbar decompression surgery, our data further suggest a possible inferior outcome in terms of low back pain improvement in the Dura+ cohort, which became clinically apparent at the 12-month follow-up period. Future studies should investigate whether a more pronounced decompression required for adequate exposure and repair of a dural laceration may, ultimately, result in increased segmental instability and in clinically undesirable low back pain. PMID- 27125376 TI - Spinal shape modulation in a porcine model by a highly flexible and extendable non-fusion implant system. AB - PURPOSE: In vivo evaluation of scoliosis treatment using a novel approach in which two posterior implants are implanted: XSLAT (eXtendable implant correcting Scoliosis in LAT bending) and XSTOR (eXtendable implant correcting Scoliosis in TORsion). The highly flexible and extendable implants use only small, but continuous lateral forces (XSLAT) and torques (XSTOR), thereby allowing growth and preventing fusion. METHODS: Since (idiopathic) scoliosis does not occur spontaneously in animals, the device was used to induce a spinal deformity rather than correct it. Six of each implants were tested for their ability to induce scoliotic deformations in 12 growing pigs. Each implant spanned six segments and was attached to three vertebrae using sliding anchors. Radiological and histological assessments were done throughout the 8-week study. RESULTS: In all animals, the intended deformation was accomplished. Average Cobb angles were 19 degrees for XSLAT and 6 degrees for XSTOR. Average apical spinal torsion was 0 degrees for XSLAT and 9 degrees for XSTOR. All instrumented segments remained mobile and showed 20 % growth. Moderate degeneration of the facet joints was observed and some debris was found in the surrounding tissue. CONCLUSIONS: The approach accomplished the intended spinal deformation while allowing growth and preventing fusion. PMID- 27125377 TI - Engagement of CD22 on B cells with the monoclonal antibody epratuzumab stimulates the phosphorylation of upstream inhibitory signals of the B cell receptor. AB - The binding of antigen to the B cell receptor (BCR) results in a cascade of signalling events that ultimately drive B cell activation. Uncontrolled B cell activation is regulated by negative feedback loops that involve inhibitory co receptors such as CD22 and CD32B that exert their functions following phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). The CD22-targeted antibody epratuzumab has previously been shown to inhibit BCR driven signalling events, but its effects on ITIM phosphorylation of CD22 and CD32B have not been properly evaluated. The present study therefore employed both immunoprecipitation and flow cytometry approaches to elucidate the effects of epratuzumab on direct phosphorylation of key tyrosine (Tyr) residues on both these proteins, using both transformed B cell lines and primary human B cells. Epratuzumab induced the phosphorylation of Tyr(822) on CD22 and enhanced its co localisation with SHP-1. Additionally, in spite of high basal phosphorylation of other key ITIMs on CD22, in primary human B cells epratuzumab also enhanced phosphorylation of Tyr(807), a residue involved in the recruitment of Grb2. Such initiation events could explain the effects of epratuzumab on downstream signalling in B cells. Finally, we were able to demonstrate that epratuzumab stimulated the phosphorylation of Tyr(292) on the low affinity inhibitory Fc receptor CD32B which would further attenuate BCR-induced signalling. Together, these data demonstrate that engagement of CD22 with epratuzumab leads to the direct phosphorylation of key upstream inhibitory receptors of BCR signalling and may help to explain how this antibody modulates B cell function. PMID- 27125378 TI - Change of teicoplanin loading dose requirement for incremental increases of systemic inflammatory response syndrome score in the setting of sepsis. AB - Background Target trough concentrations are recommended for teicoplanin (TEIC) to minimize its adverse effects and to maximize efficacy in sepsis caused by grampositive cocci, including methicillin-resistant Staphylococcus aureus infection. However, optimal doses to attain proper trough values in patients with sepsis have not yet been well established for TEIC. Objective This study investigated whether the systemic inflammatory response syndrome (SIRS) score could predict the pharmacokinetics of TEIC in patients with sepsis. Setting This study was conducted at Fukuoka University Hospital in Japan. Methods We retrospectively reviewed the records of patients using TEIC between April 2012 and March 2015. SIRS positive was defined as infection with a SIRS score >=2. Estimates of pharmacokinetic parameters were calculated using a Bayesian method. Creatinine clearance rates were estimated by the Cockcroft-Gault formula (eCcr). Main outcome measure Change of TEIC loading dose requirement for incremental increases of SIRS score. Results In total, 133 patients were enrolled: 50 non SIRS patients and 83 patients with SIRS. The TEIC plasma trough concentration was significantly lower in SIRS than non-SIRS patients (15.7 +/- 7.1 vs. 20.1 +/- 8.6 MUg/mL; P < 0.01), although there was no significant difference in the loading dose administered. Moreover, SIRS scores were increasingly predictive of eCcr and TEIC clearance in a stepwise manner. To achieve the target trough concentration (15-30 MUg/mL), the optimal doses required in non-SIRS versus SIRS patients were 12-24 versus 18-30 mg/kg/day, respectively, during the first 48 h. Conclusions These findings suggest that the pharmacokinetics of TEIC are altered in SIRS patients, who required higher doses than non-SIRS patients to achieve the target trough concentration. We suggest that the SIRS score can become a new modality to determine the initial TEIC loading dose. PMID- 27125379 TI - [Feasibility and diagnostic value of hysterosonography performed in bleeding time in the exploration of abnormal uterine bleeding]. AB - OBJECTIVES: The aim of our study is to evaluate the feasibility, safety and diagnostic value of hysterosonography performed in an emergency setting among patients consulting for active abnormal uterine bleeding. MATERIALS AND METHODS: In this prospective study, we included 216 patients visiting our emergency department for abnormal uterine bleeding. All patients had a transvaginal ultrasound with doppler study and an hysterosonography. Secondly, the patients, in whom we diagnosed a suspected organic lesion, were addressed to an endoscopic or surgical procedure with pathological examination. Initially, we evaluated the feasibility and the safety of hysterosonography and secondly, we compared the two techniques (EEV and hysterosonography), sensitivity, specificity, LHR+and LHR-. RESULTS: The hysterosonography was performed in 98.1 % of patients and its realization has resulted in an additional period of 1.2minutes on average (extreme: 6-12) compared to ultrasound. The tolerance of the hysterosonographic examination was very good in 73.5 % of patients and good in 23.1 % of them. For the 167 patients who had been diagnosed with presumed organic lesions, pathological examination found an endometrial hyperplasia in 34.7 % of cases, polyps in 40.1 % of cases, sub-mucosal fibroids in 11.3 % of cases, endometrial cancer in 0.7 % of cases and other lesions in 13.2 % of cases. The diagnostic value of hysterosonography was superior to ultrasound in the detection of polyps (AUC: 0.894 vs 0.778, P=0.003) and fibromas (AUC: 1.000 vs 0.716, P=0.001) while the two methods showed no significant difference in the detection of hyperplasia. CONCLUSION: The purpose of our study was to focus on a particular context of use of the hysterosonography consisting on hemorrhagic period and on its realization in the emergency room. We were able to demonstrate that hysterosonography is compatible with the emergency situation as to its feasibility and its diagnostic value and that its realization would contribute to the sorting of patients to guide them immediately to a surgical or endoscopic procedure if necessary. PMID- 27125380 TI - [Safety profile of etonogestrel contraceptive implant (Nexplanon(r) and Implanon(r)) reported in France]. AB - OBJECTIVES: The aim of the study was to assess the incidence of adverse effects (AE) reported with etonogestrel contraceptive implant in France (Implanon(r) and Nexplanon(r)). MATERIALS AND METHODS: All cases of AE or unintended pregnancies reported to health authorities or to the firm were analyzed. RESULTS: During 10 years, 5433 AE and 789 unintended pregnancies were reported. Only 388 (7 %) were serious. There were 1137 reports of difficulties to remove, failure to locate or migration, 430 of insertion difficulties and 203 of deformation or expulsion of the implant. Among other AE, the most common were 1694 gynecological AE, 524 skin reactions and 437 metabolic AE. Since the marketing of Nexplanon(r) which causes less deep insertions, the incidence of migrations, removal or insertion difficulties has decreased overall (0.92 vs. 1.31/1000 patients), particularly the incidence of removal difficulties, location failures or migrations (0.12 vs 1.01/1000). The infrequent but serious AE were infectious complications at the implant site and pregnancies. When the circumstances of the pregnancy were known, the contraceptive failure was due to the apparent inefficiency of the implant (n=224), to a technique failure (n=203) or to a drug-drug interaction (n=59). CONCLUSION: This study confirms that AE of this implant are frequent but not serious, except for the pregnancies. The incidence of complications related to insertion decreased with Nexplanon(r). Among other preventable AE, unintended pregnancies due to a drug-drug interaction would require to be better known by the practitioner. PMID- 27125381 TI - [Impact of the external cephalic version on the obstetrical prognosis in a team with a high success rate of vaginal delivery in breech presentation]. AB - OBJECTIVES: To analyse the impact of external cephalic version (ECV) on caesarean section rate in a team with a high success rate of vaginal delivery in breech presentation. MATERIALS AND METHODS: Retrospective monocentric study including 298 patients with a breech presentations between 33 and 35weeks of amenorrhea followed at our university hospital and delivered after 35weeks, between 1st January 2011 and 31st December 2013. Patients were divided into 2 groups: planned ECV (n=216 patients) versus no planned ECV (n=57 patients). RESULTS: Our rate of successful vaginal breech delivery over the period of the study was 61.1%. We performed 165 ECV, with a 21.8% success rate. The average term of the attempt of ECV was 36.7weeks of amenorrhea. The caesarean section rate was not significantly different in the planned ECV group, even after adjustment on age, parity and previous caesarean delivery (adjusted OR=1.67 [0.77-3.61]). Attempt of ECV did not reduce the number of breech presentation at delivery (61.1% versus 61.4% [P=0.55]). CONCLUSION: Planned ECV in our center with a high level of breech vaginal delivery did not significantly impact our cesarean section rate. PMID- 27125382 TI - Modulation of Staphylococcus aureus spreading by water. AB - Staphylococcus aureus is known to spread rapidly and form giant colonies on the surface of soft agar and animal tissues by a process called colony spreading. So far, the mechanisms underlying spreading remain poorly understood. This study investigated the spreading phenomenon by culturing S. aureus and its mutant derivatives on Tryptic Soy Agarose (TSA) medium. We found that S. aureus extracts water from the medium and floats on water at 2.5 h after inoculation, which could be observed using phase contrast microscopy. The floating of the bacteria on water could be verified by confocal microscopy using an S. aureus strain that constitutively expresses green fluorescence protein. This study also found that as the density of bacterial colony increases, a quorum sensing response is triggered, resulting in the synthesis of the biosurfactants, phenolic-soluble modulins (PSMs), which weakens water surface tension, causing water to flood the medium surface to allow the bacteria to spread rapidly. This study reveals a mechanism that explains how an organism lacking a flagellar motor is capable of spreading rapidly on a medium surface, which is important to the understanding of how S. aureus spreads in human tissues to cause infections. PMID- 27125383 TI - Patient Preferences for Topical Psoriasis Treatments are Diverse and Difficult to Predict. AB - INTRODUCTION: Topicals are a mainstay in psoriasis vulgaris treatment and are used concomitantly even in patients receiving systemic therapy. Patient acceptance of topical treatment can impact adherence and, consequently, real-life effectiveness. This study aimed to identify patient preferences for topical treatment attributes and to evaluate patient acceptability of topical treatments. METHODS: This 5-day study evaluated three inactive presentations: fixed combination calcipotriol/betamethasone dipropionate (Cal/BD) ointment vehicle in a tube, Cal/BD gel vehicle in a bottle and Cal/BD gel vehicle in a new Applicator delivery system. Participants with psoriasis on >=2 locations were recruited, aiming for equal proportions in the categories: male/female; <40/>=40 years old; working/not working. Participants ranked a predefined 'wish list' of 13 topical treatment attributes, applied each product and evaluated them in a user survey, indicating how well the products delivered on 16 statements matching the 13 attributes. Afterward, participants indicated preference by psoriasis plaque location. RESULTS: Patient preferences differed to the extent that the proportion rating an attribute of high importance was similar to the proportion rating the same attribute of low importance. All attributes received similar mean ranking scores. Analysis by demographic characteristics revealed preferences are not associated with gender, age or employment status. Participants did not perceive much difference between the gel and ointment, but expressed preferences for different presentations to treat different plaque locations. The gel Applicator was preferred for 8/14 locations and both gel presentations were strongly preferred for hairy scalp. CONCLUSIONS: Patients with psoriasis have diverse preferences, which cannot be predicted by demographics. Individual patient choice should be considered to increase the acceptability and a range of topical formulations should be available to support treatment adherence and improve clinical outcomes. FUNDING: LEO Pharma A/S, Ballerup, Denmark. PMID- 27125384 TI - The analysis of the market success of FDA approvals by probing top 100 bestselling drugs. AB - Target-oriented drug discovery is the main research paradigm of contemporary drug discovery. In target-oriented approaches, we attempt to maximize in vitro drug potency by finding the optimal fit to the target. This can result in a higher molecular complexity, in particular, the higher molecular weight (MW) of the drugs. However, a comparison of the successful developments of pharmaceuticals with the general trends that can be observed in medicinal chemistry resulted in the conclusion that the so-called molecular obesity is an important reason for the attrition rate of drugs. When analyzing the list of top 100 drug bestsellers versus all of the FDA approvals, we discovered that on average lower-complexity (MW, ADMET score) drugs are winners of the top 100 list in terms of numbers but that, especially, up to some optimal MW value, a higher molecular complexity can pay off with higher incomes. This indicates that slim drugs are doing better but that fat drugs are bigger fishes to catch. PMID- 27125385 TI - Common SIRT1 variants modify the effect of abdominal adipose tissue on aging related lung function decline. AB - Lung function is an independent predictor of mortality and serves as an aging marker in never smokers. The protein sirtuin-1 of gene SIRT1 has profound anti inflammatory effects and regulates metabolic pathways. Its suggested longevity effects on lower organisms remain poorly studied in humans. In 1132 never smokers of the population-based SAPALDIA cohort, we investigated associations between single nucleotide polymorphisms (SNPs; rs730821, rs10997868, rs10823116) of SIRT1 and aging-related lung function decline over 11 years in terms of change in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow between 25 and 75 % of FVC (FEF25-75) using multiple linear regression models. Interactions between the SIRT1 SNPs and adiposity parameters (body mass index (BMI), its change and weight gain) were tested by including multiplicative interaction terms into the models. SIRT1 polymorphisms exhibited no main effects, but modified the association between obesity measures and FEV1/FVC and FEF25-75 decline (p = 0.009-0.046). Per risk allele, FEV1/FVC decline was accelerated up to -0.5 % (95 % CI -1.0 to 0 %) and 0.7 % (-1.3 to -0.2 %) over interquartile range increases in BMI (2.4 kg/m(2)) or weight (6.5 kg), respectively. For FEF25-75 decline, corresponding estimates were -57 mL/s (-117 to 4 mL/s) and -76 mL/s (-1429 to -9 mL/s). Interactions were not present in participants with genetically lowered C-reactive protein concentrations. Genetic variation in SIRT1 might therefore affect lung function and human longevity by modifying subclinical inflammation arising from abdominal adipose tissue. PMID- 27125386 TI - GsERF6, an ethylene-responsive factor from Glycine soja, mediates the regulation of plant bicarbonate tolerance in Arabidopsis. AB - MAIN CONCLUSION: This is an original study focus on ERF gene response to alkaline stress. GsERF6 functions as transcription factor and significantly enhanced plant tolerance to bicarbonate (HCO 3 (-) ) in transgenic Arabidopsis . Alkaline stress is one of the most harmful, but little studied environmental factors, which negatively affects plant growth, development and yield. The cause of alkaline stress is mainly due to the damaging consequence of high concentration of the bicarbonate ion, high-pH, and osmotic shock to plants. The AP2/ERF family genes encode plant-specific transcription factors involved in diverse environmental stresses. However, little is known about their physiological functions, especially in alkaline stress responses. In this study, we functionally characterized a novel ERF subfamily gene, GsERF6 from alkaline-tolerant wild soybean (Glycine soja). In wild soybean, GsERF6 was rapidly induced by NaHCO3 treatment, and its overexpression in Arabidopsis enhanced transgenic plant tolerance to NaHCO3 challenge. Interestingly, GsERF6 transgenic lines also displayed increased tolerance to KHCO3 treatment, but not to high pH stress, implicating that GsERF6 may participate specifically in bicarbonate stress responses. We also found that GsERF6 overexpression up-regulated the transcription levels of bicarbonate-stress-inducible genes such as NADP-ME, H (+) Ppase and H (+)-ATPase, as well as downstream stress-tolerant genes such as RD29A, COR47 and KINI. GsERF6 overexpression and NaHCO3 stress also altered the expression patterns of plant hormone synthesis and hormone-responsive genes. Conjointly, our results suggested that GsERF6 is a positive regulator of plant alkaline stress by increasing bicarbonate ionic resistance specifically, providing a new insight into the regulation of gene expression under alkaline conditions. PMID- 27125387 TI - Reactive oxygen species and hormone signaling cascades in endophytic bacterium induced essential oil accumulation in Atractylodes lancea. AB - MAIN CONCLUSION: Pseudomonas fluorescens induces gibberellin and ethylene signaling via hydrogen peroxide in planta . Ethylene activates abscisic acid signaling. Hormones increase sesquiterpenoid biosynthesis gene expression and enzyme activity, inducing essential oil accumulation. Atractylodes lancea is a famous Chinese medicinal plant, whose main active components are essential oils. Wild A. lancea has become endangered due to habitat destruction and over exploitation. Although cultivation can ensure production of the medicinal material, the essential oil content in cultivated A. lancea is significantly lower than that in the wild herb. The application of microbes as elicitors has become an effective strategy to increase essential oil accumulation in cultivated A. lancea. Our previous study identified an endophytic bacterium, Pseudomonas fluorescens ALEB7B, which can increase essential oil accumulation in A. lancea more efficiently than other endophytes; however, the underlying mechanisms remain unknown (Physiol Plantarum 153:30-42, 2015; Appl Environ Microb 82:1577-1585, 2016). This study demonstrates that P. fluorescens ALEB7B firstly induces hydrogen peroxide (H2O2) signaling in A. lancea, which then simultaneously activates gibberellin (GA) and ethylene (ET) signaling. Subsequently, ET activates abscisic acid (ABA) signaling. GA and ABA signaling increase expression of HMGR and DXR, which encode key enzymes involved in sesquiterpenoid biosynthesis, leading to increased levels of the corresponding enzymes and then an accumulation of essential oils. Specific reactive oxygen species and hormone signaling cascades induced by P. fluorescens ALEB7B may contribute to high efficiency essential oil accumulation in A. lancea. Illustrating the regulation mechanisms underlying P. fluorescens ALEB7B-induced essential oil accumulation not only provides the theoretical basis for the inducible synthesis of terpenoids in many medicinal plants, but also further reveals the complex and diverse interactions among different plants and their endophytes. PMID- 27125388 TI - Genetic analysis of a novel broad-spectrum powdery mildew resistance gene from the wheat-Agropyron cristatum introgression line Pubing 74. AB - MAIN CONCLUSION: A novel broad-spectrum powdery mildew resistance gene PmPB74 was identified in wheat- Agropyron cristatum introgression line Pubing 74. Development of wheat cultivars with broad-spectrum, durable resistance to powdery mildew has been restricted by lack of superior genetic resources. In this study, a wheat-A. cristatum introgression line Pubing 74, originally selected from a wide cross between the common wheat cultivar Fukuhokomugi (Fukuho) and Agropyron cristatum (L.) Gaertn (2n = 4x = 28; genome PPPP), displayed resistance to powdery mildew at both the seedling and adult stages. The putative alien chromosomal fragment in Pubing 74 was below the detection limit of genomic in situ hybridization (GISH), but evidence for other non-GISH-detectable introgressions was provided by the presence of three STS markers specific to A. cristatum. Genetic analysis indicated that Pubing 74 carried a single dominant gene for powdery mildew resistance, temporarily designated PmPB74. Molecular mapping showed that PmPB74 was located on wheat chromosome arm 5DS, and flanked by markers Xcfd81 and HRM02 at genetic distances of 2.5 and 1.7 cM, respectively. Compared with other lines with powdery mildew resistance gene(s) on wheat chromosome arm 5DS, Pubing 74 was resistant to all 28 Blumeria graminis f. sp tritici (Bgt) isolates from different wheat-producing regions of northern China. Allelism tests indicated that PmPB74 was not allelic to PmPB3558 or Pm2. Our work showed that PmPB74 is a novel gene with broad resistance to powdery mildew, and hence will be helpful in broadening the genetic basis of powdery mildew resistance in wheat. PMID- 27125389 TI - Therapies to Reduce Blood Pressure Acutely. AB - Clinicians make frequent treatment decisions regarding acute blood pressure reduction for the critically ill. Key to the decision making process is a balance between reducing arterial wall stress and maintaining perfusion to vital organs. In this article, we review the physiological considerations underlying acute blood pressure management, including the concept of cerebral autoregulation and its adaptations to chronic hypertension. We then discuss available pharmacological interventions suited for reducing blood pressure acutely. We also discuss specific blood pressure targets in common critical illnesses and consider future directions in this therapeutic area. PMID- 27125391 TI - Intellectual developmental disorder in adult psychiatry: A 24-year register study. AB - BACKGROUND: Intellectual developmental disorder (IDD) may pre-dispose for mental health disorders. It is sometimes debated whether the needs of this group are adequately met in general psychiatry. However, little is known about patients with IDD in the psychiatric clinical setting-occurrence, clinical diagnoses, or service use. AIMS: This study aimed to assess the number of adult patients diagnosed with IDD in a psychiatric clinic, their psychiatric diagnoses, and their use of psychiatric services. METHODS: Individuals with registered IDD diagnoses were identified in a university hospital adult psychiatric clinic register comprising 67 384 patients. RESULTS: IDD had been diagnosed in 0.6% of the patients. Psychotic disorders were the most common co-existing psychiatric diagnoses (25.5%). In 21.8% no psychiatric diagnosis other than IDD was registered. More than 50% had been inpatients; 21% had been compulsorily admitted. Patients with IDD had required a mean of five hospital beds per day. CONCLUSIONS: The percentage, 0.6%, of IDD diagnoses was lower than estimates of the prevalence of IDD in the general population. This may reflect a lower need for psychiatric care, barriers to access services, or diagnostic over-shadowing. One fifth of the patients in this study had no psychiatric diagnosis beside IDD, which may be due to diagnostic difficulties, or other problems (e.g. somatic or behavioural disorders) leading to psychiatric contact. Since patients with IDD use the equivalent of five inpatient beds every year, it is suggested that it may be worthwhile to consider specialized psychiatry with expertise in IDD, even though this group is small. PMID- 27125390 TI - Pathogenesis of Cardiovascular and Metabolic Diseases: Are Fructose-Containing Sugars More Involved Than Other Dietary Calories? AB - There is increasing concern that sugar consumption may be linked to the development of metabolic and cardiovascular diseases. There is indeed strong evidence that consumption of energy-dense sugary beverages and foods is associated with increased energy intake and body weight gain over time. It is further proposed that the fructose component of sugars may exert specific deleterious effects due to its propension to stimulate hepatic glucose production and de novo lipogenesis. Excess fructose and energy intake may be associated with visceral obesity, intrahepatic fat accumulation, and high fasting and postprandial blood triglyceride concentrations. Additional effects of fructose on blood uric acid and sympathetic nervous system activity have also been reported, but their link with metabolic and cardiovascular diseases remains hypothetical. There is growing evidence that fructose at physiologically consumed doses may exert important effects on kidney function. Whether this is related to the development of high blood pressure and cardiovascular diseases remains to be further assessed. PMID- 27125392 TI - Ureteral Stent-Associated Pain: A Review. AB - PURPOSE: Ureteral stent-related pain is a well-known side effect of stent placement. To date, there is a paucity of resources that address this topic. Herein, we present theories on stent pain pathophysiology, summarize available pain outcome data for different stent designs, and provide an overview of the management of stent pain, including preplacement modifiers, medical management, and other considerations. MATERIALS AND METHODS: This narrative review focused primarily on articles indexed in the PubMed((r)), Google ScholarTM, and EMBASE databases. No formal search strategy was used and no meta-analysis of data was performed. RESULTS: Stent pain pathophysiology is multifactorial and likely a result of mucosal irritation along with retrograde reflux of urine. While there is a consensus on the lack of association between stent length, diameter, and stent-related flank pain, stents should be properly sized so as to prevent dislodgement. Insufficient data exist comparing stent materials and durometry. Multiple drug-eluting stents are in development and have demonstrated promising early results. Alpha-blockers have shown efficacious results and should be considered along with or in combination with anticholinergics and nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of ureteral stent-related symptoms, with judicious consideration of their side effect profiles. Periureteral botulinum toxin A injections are a promising, novel treatment modality. CONCLUSIONS: Ureteral stent pain is common and multiple modalities have been studied and are in clinical use for its treatment. Care should be taken to avoid placement of stents if possible, with continual reassessment of indications to maintain stents in patients. Relative heterogeneity among studies and small sample sizes make creating specific evidence-based pain management recommendations challenging. Alpha-blockers, antimuscarinics, and NSAIDs are all generally well tolerated and effectively reduce symptoms, but patient-specific factors must be the paramount consideration when choosing monotherapy or combination therapy. Future studies are needed to better define ideal material characteristics and pharmacologic treatments. PMID- 27125393 TI - Is it safe to use minimally invasive surgery in the management of endometrial cancer? PMID- 27125394 TI - A challenge in the management of women with polycystic ovary syndrome. PMID- 27125395 TI - Effect of thyroid autoimmunity per se on assisted reproduction treatment outcomes: A meta-analysis. AB - OBJECTIVE: Thyroid autoimmunity (TA) is the most prevalent autoimmune disease in women of reproductive age and is often accompanied by subclinical hypothyroidism (SCH). Both TA and SCH have been associated with adverse pregnancy outcomes, but their relative influence is unclear. Therefore, we carried out a meta-analysis to evaluate the sole effect of TA on pregnancy outcomes in euthyroid women undergoing assisted reproductive technology. MATERIALS AND METHODS: Literature searches were conducted on Pubmed, EMBASE, and the Cochrane Controlled Trials Register Database from inception to May 2014. RESULTS: In euthyroid women whose SCH status is unknown, those with positive antithyroid antibodies (ATA) had a higher miscarriage rate [pooled relative risk (RR) = 1.638; 95% confidence interval (CI), 1.228-2.185] and a lower delivery rate (pooled RR = 0.856; 95% CI, 0.759-0.965) than those with negative ATA. Clinical pregnancy rates were similar between groups. However, clinical pregnancy rate, miscarriage rate, and delivery rate were all comparable between ATA-positive and ATA-negative euthyroid women without SCH. CONCLUSION: TA per se does not impair assisted reproductive treatment outcomes in women without SCH. PMID- 27125396 TI - Factors related to deterioration of renal function after singleton delivery in pregnant women with chronic kidney disease. AB - OBJECTIVE: This study is designed to evaluate which factors would relate to deterioration of renal function (DRF) after delivery in pregnant women with chronic kidney disease (CKD). MATERIALS AND METHODS: This study included 156 singleton pregnancies of 139 women with CKD at our institution from 2001 to 2010. DRF was defined as the shift of CKD stage into another more severe stage. The relevant variables were compared between women who had DRF (n = 39) and the controls (n = 117). RESULTS: The number of transplantation or dialysis cases after delivery was 5.8%. DRF occurred in 25% of the study patients. From a logistic regression model, the factors that influence DRF were the presence of glomerulonephritis [odds ratio (OR) 3.56, 95% confidence interval (CI) 1.18 10.81], significant proteinuria prior to pregnancy (>=3 g/d or 3+ more dipstick; OR 3.43, 95% CI 1.14-10.33), and treatment with antiplatelet agents (OR 0.30, 95% CI 0.09-0.94). Receiver-operating characteristic curve analysis confirmed that the estimated glomerular filtration rate (eGFR) of 75 mL/min/1.73 m(2) or more before conception is not a risk factor for DRF after delivery (negative predictive value 0.788). CONCLUSION: This was the first report to reveal a clear cutoff value regarding DRF in pregnant woman with CKD. There is an almost 78% risk of developing DRF after delivery in patients showing eGFR of 75 mL/min/1.73 m(2) or more before conception. PMID- 27125397 TI - Relationship between hypothyroidism and the incidence of gestational diabetes: A meta-analysis. AB - OBJECTIVES: Hypothyroidism disorders and gestational diabetes are among the most common endocrinopathies during pregnancy. We conducted a meta-analysis to investigate whether hypothyroidism in pregnancy is associated with gestational diabetes risk. MATERIALS AND METHODS: Published literature from PubMed and EMBASE were searched for eligible publications. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model. RESULTS: Seven articles described the relationship between hypothyroidism and risk of gestational diabetes. This meta-analysis revealed that overt hypothyroidism was associated with an increased risk of gestational diabetes (OR 1.892, 95% CI 1.679-2.132, p < 0.001). The relative risk of gestational diabetes was also increased in subclinical hypothyroidism, with the OR of 1.558 (95% CI 1.292-1.877, p < 0.001). There was no evidence of significant association between hypothyroxinemia and risk of gestational diabetes (OR 1.394, 95% CI 0.753-2.580, p = 0.291). The OR for all of the hypothyroidism was 1.749 (95% CI 1.586-1.928, p < 0.001), and an association was found. CONCLUSION: Results of this meta-analysis indicate that hypothyroidism may be a risk factor for gestational diabetes. PMID- 27125398 TI - Continuous transverse scanning of the fetal heart using a cross-sectional image database of common fetal congenital heart deformities. AB - OBJECTIVE: To provide an anatomical basis for continuous transverse scanning of the fetal heart by analyzing the typical cross-sectional characteristics of different types of congenital heart deformities (CHDs) using an anatomical image database. MATERIALS AND METHODS: The database consisted of cross-sectional images obtained from 45 cases of common fetal CHDs, which were continuously displayed by the three-dimensional software Amira 5.3.1. The following anatomical parts were observed from the database of heart samples in a bottom-to-top manner: the coronary sinus, four chambers, left ventricular outflow tract, right ventricular outflow tract, and transverse ductal and aortic arches. The anatomical characteristics of these sections were analyzed and compared with the ultrasonic transverse views obtained from the same fetuses. RESULTS: During the display of the anatomical database of 45 cases of common fetal CHDs, the aforementioned typical cross sections were successively revealed, along with the corresponding pathological features. These sections also exhibited a very good correspondence with the ultrasonic transverse views of the same cases. CONCLUSION: The database of cross-sectional anatomical images of fetal CHDs provided an anatomical basis for continuous transverse scanning of the fetal heart. PMID- 27125399 TI - Effects of interleukin 6 and tumor necrosis factor-alpha on the proliferation of porcine theca interna cells: Possible role of these cytokines in the pathogenesis of polycystic ovary syndrome. AB - OBJECTIVE: We studied the effects of interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on the proliferation of porcine theca interna (TI) cells and further elucidated the roles of IL-6 and TNF-alpha in the pathogenesis of polycystic ovary syndrome. MATERIALS AND METHODS: TI cells were treated with 10 pg/mL, 100 pg/mL, and 1000 pg/mL IL-6 or TNF-alpha. TI cell proliferation was then examined by carboxyfluorescein diacetate succinimidyl ester labeling and flow cytometry. RESULTS: Cell proliferation was not significantly different in TI cells cultured in medium alone (control) or in the presence of IL-6. At 72 hours of treatment, the mean fluorescence intensity was significantly lower in TI cells treated with 100 pg/mL and 1000 pg/mL TNF-alpha than in the control (p < 0.05). CONCLUSION: TNF-alpha, but not IL-6, was able to promote TI cell proliferation. Our results suggest that TNF-alpha might play a role in hyperandrogenism, cortex thickness, and the increased ovary volume observed in polycystic ovaries. PMID- 27125400 TI - Comparison of the laparoscopic versus conventional open method for surgical staging of endometrial carcinoma. AB - OBJECTIVE: Although laparoscopic surgery is widely utilized in the treatment of endometrial cancer, its efficacy in staging the cancer is not well established. The aim of this study was to compare staging endometrial cancer with laparoscopic and conventional open methods. MATERIALS AND METHODS: From January 2002 to June 2012, 151 patients (70 treated by laparoscopy and 81 by laparotomy) diagnosed with endometrial cancer were enrolled. This was a retrospective cohort review of endometrial cancer surgically staged using laparoscopy or laparotomy in the Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan. RESULTS: The two groups did not significantly differ in patient age, body mass index, previous obstetrical history, or amount of previous abdominal surgery. No differences between the surgical cohorts were observed in relation to cancer status, including stage, grade, myometrial invasion, lymphovascular space invasion, lymph node involvement, and recurrence rate. The laparoscopic approach had less intraoperative blood loss, longer operative time, lower uterine weight, number of removed lymph nodes, and shorter hospital stay. CONCLUSION: Our preliminary results showed that the laparoscopic method for staging endometrial cancer was technically feasible and efficient. PMID- 27125401 TI - Longitudinal parallel compression suture to control postopartum hemorrhage due to placenta previa and accrete. AB - OBJECTIVE: To assess the efficacy and safety of longitudinal parallel compression suture to control heavy postpartum hemorrhage (PPH) in patients with placenta previa/accreta. MATERIALS AND METHODS: Fifteen women received a longitudinal parallel compression suture to stop life-threatening PPH due to placenta previa with or without accreta during cesarean section. The suture apposed the anterior and posterior walls of the lower uterine segment together using an absorbable thread A 70-mm round needle with a Number-1 absorbable thread was used. The point of needle entry was 1 cm above the upper margin of the cervix and 1 cm from the right lateral border of the lower segment of the anterior wall. The suture was threaded through the uterine cavity to the serosa of the posterior wall. Then, it was directed upward and threaded from the posterior to the anterior wall at ~1-2 cm above the upper boundary of the lower uterine segment and 3-cm medial to the right margin of the uterus. Both ends of the suture were tied on the anterior aspect of uterus. The left side was sutured in the same way. RESULTS: The success rate of the procedure was 86.7% (13/15). Two of 15 cases were concurrently administered gauze packing and achieved satisfactory hemostasis. All patients resumed a normal menstrual flow, and no postoperative anatomical or physiological abnormalities related to the suture were observed. Three women achieved further pregnancies after the procedure. CONCLUSION: Longitudinal parallel compression suture is a safe, easy, effective, practical, and conservative surgical technique to stop intractable PPH from the lower uterine segment, particularly in women who have a cesarean scar and placenta previa/accreta. PMID- 27125402 TI - Is preoperative bowel preparation necessary for gynecological oncology surgery? AB - OBJECTIVE: We investigated the necessity of preoperative bowel preparation for gynecological oncology surgery. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent gynecological oncology surgery with simultaneous colon or rectal resection between April 2005 and September 2014 at the Tri-Service General Hospital, Taipei, Taiwan. Patients were divided into two groups based on whether preoperative mechanical bowel preparation (MBP) was performed. Patient characteristics, including duration of antibiotic treatment, surgical procedures, and occurrence of surgical and nonsurgical complications, were compared. RESULTS: We enrolled 124 patients who underwent gynecological oncology surgery with simultaneous colon or rectal resection, of whom 76 received MBP and 48 did not receive mechanical bowel preparation. On comparison between the two groups, no significant differences were noted in the assessed patient characteristics, including mean age (p = 0.61), Federation of Gynecology and Obstetrics stage (p = 0.9), American Society of Anesthesiologists grade (p = 0.9), body mass index (p = 0.8), and residual tumor size (p = 0.86). Furthermore, duration of antibiotic treatment (p = 0.97), surgical procedures (p = 0.99), and total hospital days (p = 0.75), were not different between groups. The risk of surgical (p = 0.78) or nonsurgical (p = 1.0) complications was not significantly higher in the non-MBP group than in the MBP group. CONCLUSION: MBP provides no significant benefit during gynecological oncology surgery. Thus, preoperative MBP is not essential before gynecological oncology surgery and can be omitted. PMID- 27125403 TI - METCAM/MUC18 promoted tumorigenesis of human breast cancer SK-BR-3 cells in a dosage-specific manner. AB - OBJECTIVE: Overexpression of METCAM/MUC18, an immunoglobulin-like cell-adhesion molecule, promotes tumorigenesis and progression of human breast cancer cells. We also observed an intriguing phenomenon that a high-expressing SK-BR-3 clone manifested a transient tumor suppression effect in vivo. The purpose of this study was to understand if this was caused by clonal variation, METCAM/MUC18 dosage effect, or the number of cells injected. MATERIALS AND METHODS: Several G418-resistant clones of SK-BR-3, expressing different levels of METCAM/MUC18, were obtained for testing effects of human METCAM/MUC18 on in vitro motility, invasiveness, and anchorage-independent colony formation (in vitro tumorigenicity) and in vivo tumorigenesis in female Balb/C athymic nude mice. Tumor sections were made for histology and immunohistochemistry analyses, and tumor lysates for Western blot analysis to determine the effects of human METCAM/MUC18 expression on levels of various downstream effectors. RESULTS: METCAM/MUC18 promoted in vitro motility, invasiveness, and in vitro tumorigenicity of SK-BR-3 cells in a dosage-specific manner. Overexpression of METCAM/MUC18 could promote in vivo tumorigenesis of SK-BR-3 cells even when one tenth of the previously used cell number (5 * 10(5)) was injected and in vivo tumorigenesis of SK-BR-3 cells was directly proportional to the dosage of the protein. The previously observed transient tumor suppression effect from the same clone was no longer observed. The downstream effector, such as phospho-AKT/AKT ratio, was elevated in the tumors. CONCLUSION: Transient suppression observed previously in the clone was caused by injection of a high cell number (2 * 10(6) 5 * 10(6)). METCAM/MUC18 positively promotes tumorigenesis of SK-BR-3 cells by increasing the survival and proliferation pathway. PMID- 27125405 TI - Effects of a traditional Chinese medicine, Longdanxiegan formula granule, on Toll like receptor pathway in female guinea pigs with recurrent genital herpes. AB - OBJECTIVE: The aim of the present study was to investigate the effects of Longdanxiegan formula granule (LDXGFG), a Chinese traditional medicine on Toll like receptor (TLR) pathway in recurrent genital herpes. MATERIALS AND METHODS: An experimental recurrent genital herpes model was constructed using herpes guinea pig model. The effect of LDXGFG on expression levels of TLR pathway genes were detected using real-time polymerase chain reaction. Furthermore, the dendritic cells and Langerhans cells were isolated and the TLR pathway genes of these cells were assayed after LDXGFG treatment. RESULTS: The result suggested two different expression patterns of TLR pathway genes in genital herpes and recurrent genital herpes, including upregulated genes and downregulated genes. TLR1, TLR4, TLR6, TLR7, TLR8, TLR9, and TLR10 showed a significant decrease while, TLR2, TLR3, and TLR5 increased in genital herpes and recurrent genital herpes guinea pigs. Meanwhile, the downregulated genes in genital herpes and recurrent genital herpes were stimulated by LDXGFG. By contrast, the upregulated genes decreased significantly after LDXGFG treatment. In both dendritic cells and Langerhans cells, the TLR pathway genes exhibited same pattern: the LDXGFG corrected the abnormal expression of TLR pathway genes. CONCLUSION: The present results suggest that LDXGFG is an alternative, inexpensive, and lasting-effect medicine for herpes simplex virus 2 infection. PMID- 27125404 TI - Prognostic role of excision repair cross complementing-1 and topoisomerase-1 expression in epithelial ovarian cancer. AB - OBJECTIVE: Epithelial ovarian cancer is the most lethal gynecologic cancer worldwide and chemoresistance is one of the major causes of treatment failure. We investigated whether ERCC1, TAU, TOPO2A, TOPO1, P53, and C-MYC expression could be used as predictors for treatment outcomes. MATERIALS AND METHODS: Immunohistochemical staining was used to examine the expression of these biomarkers in resected tumor specimens from 38 patients treated in our institute. Clinicopathological data including demographics, staging, histological type, treatment response, expression of the biomarkers, and patient outcomes were analyzed. RESULTS: The median follow-up period was 47.5 months (range, 10-135 months) and the median overall survival was 56.0 months. Patients who did not have expression of ERCC1, and those who had expression of TOPO1 had significantly better overall survival. Cox regression analysis also confirmed that these two biomarkers were significant independent factors predicting survival (ERCC1, hazard ratio 5.51, 95% confidence interval: 2.02-14.00, p = 0.001; TOPO1, hazard ratio 0.22, 95% confidence interval: 0.06-0.77, p = 0.017). CONCLUSION: We concluded that poor overall survival was significantly associated with positive ERCC1 and negative TOPO1 expression. The results might be the consequence of chemoresistance to platinum and camptothecins, both of which are commonly used regimens in the treatment of epithelial ovarian cancer. PMID- 27125406 TI - The laparoscopic approach is more preferred among nurses for benign gynecologic conditions than among nonmedical working women: A nationwide study in Taiwan. AB - OBJECTIVE: To compare the use of laparoscopy and laparotomy for hysterectomy in treating benign gynecological conditions in nurses and nonmedical working women. MATERIALS AND METHODS: A nationwide population-based study was conducted using data from inpatient expenditures of Taiwan's National Health Insurance Research Datasets between 2008 and 2011. All women undergoing total hysterectomies via laparoscopy and laparotomy between the ages of 20 years and 65 years were identified. A generalized equation estimation model was used to compare the differences in laparoscopic hysterectomy (LH) and total abdominal hysterectomy (TAH) between the two groups. RESULTS: There were 1226 nurses, and 36,624 nonmedical working women, serving as controls, in the present study. The LH rate, as compared to the TAH rate, was significantly higher among nurses than among controls (56% vs. 52%, p = 0.006). A multivariate analysis indicated that nurses were significantly more likely to undergo LH (odds ratio, 1.12; 95% confidence interval, 1.01-1.26) than TAH. Nurses were more often treated at medical centers or high-volume hospitals, and were more often treated by high-volume gynecologists. CONCLUSION: Compared to nonmedical working women, nurses are more likely to undergo LH rather than TAH. These differences may suggest the influence of medical knowledge and physician-patient interaction on the decision to undergo laparoscopy, in addition to patients' medical conditions. PMID- 27125407 TI - Dose-finding study of Leuplin depot for prevention of premature luteinizing hormone surge during controlled ovarian stimulation: a pilot study in intrauterine insemination treatment. AB - OBJECTIVE: The standard dose of depot gonadotropin releasing hormone agonist (GnRHa) may be too much to prevent premature luteinizing hormone (LH) surge in controlled ovarian stimulation (COS). The purpose of this study was to find out the minimal effective dose of Leuplin depot to prevent premature LH surge in patients undergoing intrauterine insemination (IUI). MATERIALS AND METHODS: From January 2006 to December 2007, unexplained infertile patients who were going to undergo IUI were recruited into the study. They were assigned sequentially to one of the following treatment groups. The first 50 patients received the 1/3-dose of Leuplin depot in the midluteal phase of the cycle preceding COS. If no premature LH surge occurred in the 50 patients, the study was continued with 1/4-dose of Leuplin depot in the subsequent 50 patients. Similarly, if no premature LH surge occurred with 1/4 dose, the study was continued with 1/5-dose of Leuplin depot in the following 50 patients. Ovarian stimulation was started with human menopausal gonadotropin (hMG) at 112.5 IU/d after downregulation, then IUI was performed 36 hours after human chorionic gonadotropin (hCG) injection. RESULTS: Premature LH surge was effectively prevented with 1/3-dose and 1/4-dose of Leuplin depot. Premature LH surge occurred in three of the 50 patients (6%) in the 1/5-dose group. The patients in the 1/4-dose group received a significantly lower amount of hMG and fewer days of COS, compared with the 1/3-dose group. CONCLUSION: The 1/4 dose of Leuplin depot is the minimal effective dose to prevent premature LH surge. Further trial is worthwhile to compare the reducing dose Leuplin depot and daily low-dose leuprolide in in vitro fertilization (IVF) programs. PMID- 27125408 TI - Outcomes of anti-Mullerian hormone-tailored ovarian stimulation protocols in in vitro fertilization/intracytoplasmic sperm injection cycles in women of advanced age. AB - OBJECTIVE: We aimed to compare the outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatments in women of advanced age (>40 years) using anti-Mullerian hormone (AMH)-tailored ovarian stimulation protocols versus conventional protocols based on antral follicle count (AFC). MATERIALS AND METHODS: We retrospectively reviewed 210 women who underwent IVF/ICSI cycles: 116 women underwent stimulation protocols that were tailored to their AMH levels, whereas 94 women received treatment using conventional stimulation protocols based on AFC as the ovarian reserve marker. RESULTS: The following parameters were significantly higher in the AMH-tailored group than in the conventional group: initial and total doses (IU) of recombinant follicle-stimulating hormone (rFSH) used for stimulation (514.2 +/- 137.9 vs. 452.3 +/- 135.3, p = 0.001; 4713.8 +/- 1618.8 vs. 4047.2 +/- 1366.0, p = 0.007, respectively), ovum pick-up rate (OPU; 88.8% vs. 75.5%, p = 0.016), serum estradiol (E2) level on the day of human chorionic gonadotropin (hCG) administration (1818.5 +/- 1422.4 vs. 1394.0 +/- 929.0 pg/mL, p = 0.028), number of oocytes retrieved (7.4 +/- 5.1 vs. 5.5 +/- 3.4, p = 0.007), number of embryos per case (4.2 +/- 3.2 vs. 3.3 +/- 2.5, p = 0.048), clinical pregnancy rates (22.4% vs. 8.5%, p = 0.008), implantation rates (13.1% vs. 3.9%, p = 0.001), and live birth rates per cycle (15.5% vs. 6.4%, p = 0.049). CONCLUSION: Individualized controlled ovarian stimulation (COS) protocols tailored to patients' AMH levels may improve the pregnancy rate, implantation rate, and live birth rate in women of advanced age undergoing IVF/ICSI compared with those receiving conventional stimulation protocols. PMID- 27125409 TI - Assessing the quality of life of infertile Chinese women: a cross-sectional study. AB - OBJECTIVE: To assess QoL of infertile Chinese women and determine the specific factors adversely affecting QoL for improving the care and treatment compliance of infertile women. MATERIALS AND METHODS: We conducted a cross-sectional study on a randomized, demographically matched, controlled population of infertile married Chinese women to determine their demographic, menstrual, family stress, and infertility characteristics and then applied the World Health Organization QoL Instrument (WHOQOL-100) to determine which factors would be associated with significant QoL differences between infertile women and their demographically matched fertile controls. RESULTS: Infertile women showed lower QoL scores in the facets of spirituality/religion/personal beliefs, self-esteem, financial resources, and accessibility to and quality of health and social care, as well as increased pain and discomfort, while also experiencing positive QoL adjustments in terms of mobility, daily living activities, work capacity, sexual activity, freedom, physical safety, security, and transport. CONCLUSION: Married infertile Chinese women had significantly lower overall and comprehensive QoL scores, as well as higher anxiety scores, compared with fertile controls. PMID- 27125410 TI - Vitamin C is effective for the prevention and regression of endometriotic implants in an experimentally induced rat model of endometriosis. AB - OBJECTIVE: Endometriosis is a chronic inflammatory disease pathologically defined as the presence of endometrial-like tissue outside the uterine cavity. It is one of the most important diseases affecting women of reproductive age. The process of endometriotic implant growth is mediated by many complex interactions of immunologic, hormonal, genetic, and environmental mediators. Vitamin C (ascorbic acid), besides playing a role in preventing invasion and metastasis, is an antioxidant having anti-inflammatory and -angiogenic effects. In this study, we aimed to investigate the effect of vitamin C on the prevention and regression of endometriotic implants in a rat model of endometriosis. MATERIALS AND METHODS: This was a prospective, comparative, experimental animal study. After endometriotic implants were induced simultaneously, rats were divided into three groups. Group A was given 500 mg/kg of intravenous vitamin C every 2 days, starting immediately after implantation (n = 11). All rats had a second operation 21 days after the initial one and had the lesion volumes measured. Group B was given 500 mg/kg of intravenous vitamin C every 2 days, starting 21 days after this operation (n = 11). All rats were sacrificed 21 days after the third operation. Implant volume, weight measurements, and histopathological evaluation of the lesions were carried out. Group A received vitamin C throughout the study, while Group C (n = 11) was not given any medication. The findings in the three groups were compared. RESULTS: At the second laparotomy after the induction, Group A had the smallest implant volume with a statistically significant difference compared to Group B (p = 0.012). The end-of-study volumes of endometriotic implants of group B were significantly smaller than the first volumes (p < 0.05). CONCLUSION: Intravenous vitamin C treatment might have a suppressive effect on the prevention of endometriotic implant induction and regression of endometriotic implant volumes. PMID- 27125412 TI - Systematic review: What is the best first-line approach for cesarean section ectopic pregnancy? AB - This systematic review aims to analyze the case reports, case series, or clinical studies describing the women with cesarean scar ectopic pregnancy (CSEP), and thus, to determine the efficacy and safety of different primary treatment modalities in the management of CSEP. A thorough search of electronic databases showed that 274 articles on CSEP were published between January 1978 and April 2014. Systemic methotrexate, uterine artery embolization, dilatation and curettage (D&C), hysterotomy, and hysteroscopy were the most frequently adopted first-line approaches. The success rates of systemic methotrexate, uterine artery embolization, hysteroscopy, D&C, and hysterotomy were 8.7%, 18.3%, 39.1%, 61.6%, and 92.1%, respectively. The hysterectomy rates were 3.6%, 1.1%, 0.0%, 7.3%, and 1.7% in CSEP cases that were treated by systemic methotrexate, uterine artery embolization, hysteroscopy, D&C, and hysterotomy, respectively. The ability to achieve a subsequent term pregnancy is related to successful systemic methotrexate treatment (p = 0.001) or hysterotomy (p = 0.009). Future term pregnancy was significantly more frequent in the hysterotomy group (p = 0.001). Hysteroscopy and laparoscopic hysterotomy are safe and efficient surgical procedures that can be adopted as primary treatment modalities for CSEP. Uterine artery embolization should be reserved for cases with significant bleeding and/or a high suspicion index for arteriovenous malformation. Systemic methotrexate and D&C are not recommended as first-line approaches for CSEP, as these procedures are associated with high complication and hysterectomy rates. PMID- 27125411 TI - Risk factor for first-incident hip fracture in Taiwanese postmenopausal women. AB - OBJECTIVE: The variation in hip fracture risk between countries is greater than 10-fold. The present study aimed at identifying risk factors that resulted in the first occurrence of hip fracture in Taiwanese postmenopausal women. MATERIALS AND METHODS: A case-control study with a patient group of 50 postmenopausal women, who were admitted to Keelung Chang Gung Hospital, Keelung, Taiwan due to the first incident of accidental hip fracture, was used to examine potential risk factors, including bone mass. Fifty women without hip fracture, selected from those undergoing general health evaluation at the Gynecology Outpatient Clinic at Keelung Chang Gung Hospital, were used as the control group and were matched to the case patients according to age. Evaluation consisted of a questionnaire, interview to document risk factors, physical examination (to record body height and body weight), and examination [dual-energy X-ray absorptiometry used to measure bone mineral density (BMD) of the hip and spine]. RESULTS: The average age of participants of both groups was 79.6 years. Lower level of education, younger age at menopause, increased body height, weight-bearing exercise less than three times per week, and lower BMD were associated with first-incident hip fracture. Total hip BMD was a stronger predictor than the BMD of different sites. Participants in the control group had a significantly higher prevalence of chronic diseases and a history of cataracts or glaucoma compared with those in the patient group. CONCLUSION: While total hip BMD is the strongest predictor of hip fracture, increasing awareness of osteoporosis prevention by educating people about good lifestyle habits and how to maintain BMD is prioritized for preventing the first-incident hip fracture in Taiwanese women. PMID- 27125413 TI - Prenatal diagnosis and molecular cytogenetic characterization of a de novo 4.858 Mb microdeletion in 15q14 associated with ACTC1 and MEIS2 haploinsufficiency and tetralogy of Fallot. AB - OBJECTIVE: To present prenatal diagnosis and molecular cytogenetic characterization of a de novo 15q14 microdeletion associated with tetralogy of Fallot (TOF). MATERIALS AND METHODS: This was the first pregnancy of a 31-year old primigravid woman. The pregnancy was uneventful until 23 weeks of gestation when TOF was first noted. The woman underwent amniocentesis at 23 weeks of gestation. Conventional cytogenetic analysis was performed using cultured amniocytes and parental bloods. Array comparative genomic hybridization (aCGH) was performed on uncultured amniocytes and parental bloods. Metaphase fluorescence in situ hybridization (FISH) was performed on cultured amniocytes. Quantitative fluorescent-polymerase chain reaction (QF-PCR) analysis was performed on placental tissue and parental bloods. RESULTS: Conventional cytogenetics on cultured amniocytes revealed a karyotype of 46,XY, aCGH on uncultured amniocytes revealed a de novo 4.858-Mb microdeletion in 15q14 encompassing ACTC1 and MEIS2, and metaphase FISH analysis on cultured amniocytes confirmed a 15q14 microdeletion. Postnatal phenotype included facial dysmorphism. QF-PCR assays detected a paternal origin of the 15q14 microdeletion in the fetus. CONCLUSION: Fetuses with 15q14 microdeletion may present TOF on the second trimester ultrasound. aCGH and metaphase FISH are useful for rapid prenatal diagnosis of 15q14 microdeletion associated with TOF. A prenatal diagnosis of TOF should include a differential diagnosis of 15q14 microdeletion in addition to 22q11.2 deletion syndrome and other microdeletion syndromes. PMID- 27125414 TI - Two girls with a de novo Xq rearrangement of paternal origin: t(X;9)(q24;q12) or rea(X)dup q. AB - OBJECTIVE: We report on two rare Xq rearrangements, namely a t(X;9)(q24;q12) found in a mildly-affected girl (Patient 1) and a rea(X)dup q concomitant with a rob(14;21)mat in a Down syndrome girl (Patient 2). CASE REPORT: Both rearrangements were characterized by banding techniques [Giemsa (G), constitutive heterochromatin (C), and bromodeoxyuridine (BrdU) pulse], fluorescence in situ hybridization (FISH) assays, human androgen receptor (HUMAR) assays, and microarray analyses. Patient 1 had a t(X;9)(q24;q12)dn. Patient 2 had a de novo rea(X)(qter->q23 or q24::p11.2->qter) concomitant with an unbalanced rob(14;21)mat. X-Inactivation studies in metaphases and DNA revealed a fully skewed inactivation: the normal homolog was silenced in Patient 1 and the rea(X) in Patient 2. Both rearranged X chromosomes were of paternal descent. Microarray analyses revealed no imbalances in Patient 1 whereas loss of Xp (~52 Mb) and duplication of Xq (~44 Mb) and 21q were confirmed in Patient 2. CONCLUSION: Our observations further document the cytogenetic heterogeneity and predominant paternal origin of certain de novo X-chromosome rearrangements. PMID- 27125415 TI - Acute intermittent porphyria exacerbation following in vitro fertilization treatment. AB - OBJECTIVES: Assisted reproductive technology is commonly used for women with infertility. We report a case of acute intermittent porphyria associated with in vitro fertilization treatment. CASE REPORT: A 35-year-old woman with tubal factor infertility presented to our clinic with persistent low abdominal pain and hyponatremia after transvaginal oocyte retrieval. During admission, she experienced a generalized tonic-clonic seizure attacked following by dark brown color urine. Urinary tests showed elevated porphobilinogen, 5-aminolevulinic acid, uroporphyrin, and coproporphyrin, confirming the diagnosis of acute intermittent porphyria. The patient's condition continued to improve after hemin treatment and rehabilitation. CONCLUSION: Newly onset acute intermittent porphyria during the course of controlled ovarian hyperstimulation for in vitro fertilization is a rare but possible complication. Acute intermittent porphyria should be taken into consideration for persisted unexplained abdominal pain and seriously alerted if accompanied with neurological symptoms. Special tests for acute intermittent porphyria should be taken into consideration for the differential diagnosis of lower abdominal pain after oocyte retrieval. PMID- 27125416 TI - Prenatal diagnosis and molecular cytogenetic characterization of low-level true mosaicism for trisomy 21 using uncultured amniocytes. AB - OBJECTIVE: We present a prenatal diagnosis and molecular cytogenetic characterization of low-level true mosaicism for trisomy 21 using uncultured amniocytes. CASE REPORT: A 35-year-old woman presented with a borderline-positive result of noninvasive prenatal testing for trisomy 21. She underwent amniocentesis at 18 weeks of gestation, which revealed a karyotype of 47,XY,+21(5)/46,XY(53). Repeat amniocentesis at 22 weeks of gestation revealed a karyotype of 47,XY,+21(6)/46,XY(26). Array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed mosaic levels of 10% to 15% for trisomy 21. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed a mosaic level of 21.7% (28/129 cells) for trisomy 21. Following genetic counseling and detailed ultrasound examination, the parents decided to continue the pregnancy. The pregnancy was carried to term, and a normal 3664-g male baby was delivered. The cord blood lymphocytes had a karyotype of 47,XY,+21(2)/46,XY(38). Postnatal interphase FISH analysis of urine detected no trisomy 21 in all 39/39 urinary cells. The neonate was phenotypically normal at age 7 months. CONCLUSION: Low-level true mosaicism for trisomy 21 can be associated with a favorable fetal outcome. aCGH and interphase FISH analyses on uncultured amniocytes are useful for rapid confirmation of low-level true mosaicism for trisomy 21 at repeated amniocentesis. PMID- 27125418 TI - Degenerative leiomyoma of the cervix: Atypical clinical presentation and an unusual finding. PMID- 27125417 TI - Prenatal diagnosis and molecular cytogenetic characterization of de novo partial monosomy 3p (3p26.3->pter) and partial trisomy 16q (16q23.1->qter). AB - OBJECTIVE: To present the prenatal diagnosis and molecular cytogenetic characterization of a de novo unbalanced reciprocal translocation. CASE REPORT: A 37-year-old woman, G3P1, underwent amniocentesis at 17 weeks of gestation because of her advanced maternal age. Her husband was 38 years old. Amniocentesis revealed a derivative chromosome 3 with the deletion of terminal 3p and the addendum of an unknown extra chromosomal segment on the distal 3p. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. Array comparative genomic hybridization (aCGH) analysis using cultured amniocytes revealed a 2.38-Mb deletion in 3p26.3 [arr 3p26.3 (1-2,380,760)*1] encompassing 15 genes, which included 3 OMIM genes CHL1, CNTN6, and CNTN4, and a 13.17-Mb duplication in 16q23.1-q24.3 [arr 16q23.1q24.3 (76,999,082-90,170,596)*3] encompassing 207 genes, which included 81 OMIM genes. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism. Postnatal cord blood analysis revealed a karyotype of 46,XY,der(3)t(3;16)(p26.3;q23.1)dn. Polymorphic DNA marker analysis by quantitative fluorescent polymerase chain reaction (QF-PCR) on the DNAs extracted from the placenta and parental blood showed a paternal origin of the aberrant chromosome. CONCLUSION: The aCGH and QF-PCR analyses helped in delineating the genomic imbalance and parental origin of prenatally detected de novo unbalanced reciprocal translocation. PMID- 27125419 TI - Sclerosing stromal tumor of the ovaries overexpressing vascular endothelial growth factor: two cases. PMID- 27125421 TI - Successful treatment with recombinant blood factor VIIa in severe postpartum hemorrhage-induced disseminated intravascular coagulation. PMID- 27125420 TI - Immunohistochemical study of ovarian psammocarcinoma: Report of a rare case. PMID- 27125422 TI - Prenatal diagnosis of low-level mosaicism for trisomy 2 associated with a favorable pregnancy outcome. PMID- 27125423 TI - Diagnostic value of three-dimensional power Doppler ultrasound for postmenopausal bleeding compared with endometrial thickness. PMID- 27125424 TI - Diagnostic utility of three-dimensional power Doppler ultrasound for postmenopausal bleeding compared with sonohysterography. PMID- 27125425 TI - Corrigendum to . PMID- 27125426 TI - Temporal plasticity in thermal-habitat selection of burbot Lota lota a diel migrating winter-specialist. AB - In this study, animal-borne telemetry with temperature sensors was coupled with extensive habitat temperature monitoring in a dimictic reservoir, to test the following hypotheses: behavioural thermoregulation occurs throughout the year and temperature selection varies on a diel and seasonal basis, in a winter-specialist diel-migrating fish. Burbot Lota lota demonstrated nightly behavioural thermoregulation throughout the year, with a large seasonal shift between selection for very cold temperatures (<2 degrees C) optimal for reproduction during the spawning period and selection for warmer temperatures (12-14 degrees C) optimal for hunting and feeding during non-reproductive periods. During daylight hours, while L. lota avoided habitats warmer than optimal for reproduction and feeding during the spawning and non-reproductive periods, respectively, active selection was limited to selection for 4-6 degrees C habitat during the prespawning period. Although behavioural thermoregulation explained the night-time migration, behavioural thermoregulation only partially explained daytime behaviour, indicating that diel migration is best explained by a combination of factors. Thus, thermal-habitat selection was a good predictor of night-time habitat occupancy in a diel-migrating species. Together, these results show that thermal-habitat selection by fishes may be important throughout the year and a more seasonally plastic behaviour than previously recognized. PMID- 27125427 TI - Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis. AB - Collagen XVIII has the structural properties of both collagen and proteoglycan. It has been found at the basement membrane/stromal interface where it is thought to mediate their attachment. Endostatin, a proteolytic fragment from collagen XVIII C-terminal end has been reported to possess anti-angiogenic properties. Age related vision loss in collagen XVIII mutant mice has been accompanied with a pathological accumulation of deposits under the retinal pigment epithelium (RPE). We have recently demonstrated that impaired proteasomal and autophagy clearance are associated with the pathogenesis of age-related macular degeneration. This study examined the staining levels of proteasomal and autophagy markers in the RPE of different ages of the Col18a1 (-/-) mice. Eyes from 3, 6-7, 10-13 and 18 months old mice were enucleated and embedded in paraffin according to the routine protocol. Sequential 5 MUm-thick parasagittal samples were immunostained for proteasome and autophagy markers ubiquitin (ub), SQSTM1/p62 and beclin-1. The levels of immunopositivity in the RPE cells were evaluated by confocal microscopy. Collagen XVIII knock-out mice had undergone age-related RPE degeneration accompanied by an accumulation of drusen-like deposits. Ub protein conjugate staining was prominent in both RPE cytoplasm and extracellular space whereas SQSTM1/p62 and beclin-1 stainings were clearly present in the basal part of RPE cell cytoplasm in the Col18a1 (-/-) mice. SQSTM1/p62 displayed mild extracellular space staining. Disturbed proteostasis regulated by collagen XVIII might be responsible for the RPE degeneration, increased protein aggregation, ultimately leading to choroidal neovascularization. PMID- 27125428 TI - Impact of a single universal guiding catheter on door-to-balloon time in primary transradial coronary intervention for ST segment elevation myocardial infarction. AB - The purpose of this study is to determine reduction of door-to-balloon (D2B) time using a single universal guiding catheter (Ikari-Left catheter) in transradial approach. In this procedure, we can skip a total of five steps compared with a conventional procedure (two catheter insertions, two catheter removals, and one catheter engagement). Reducing total ischemic time is important to achieving a better outcome in primary percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI). We retrospectively compared 30 consecutive STEMI patients who underwent transradial primary PCI with a single guiding catheter (IL group) with 30 consecutive patients with conventional transradial primary PCI. Patients with cardiogenic shock, heart failure, or need for intra-aortic balloon pumping support before primary PCI were excluded. Baseline characteristics were not different between the two groups. The D2B time was significantly shorter in the IL group (55 +/- 16 vs. 63 +/- 17 min, respectively; p = 0.01). Puncture-to-balloon time was also significantly shorter in the IL group (15 +/- 11 min vs. 25 +/- 11 min, respectively; p = 0.001). The total number of diagnostic and guiding catheters was significantly less in IL group (1 (IQR 1-1) vs. 3 (IQR 3-3), respectively; p < 0.0001). Primary PCI with a single universal guiding catheter reduced D2B time by skipping several procedural steps, and reduced the total number of catheters needed. This technique could reduce patient mortality as well as total medical cost. PMID- 27125429 TI - Involving children in cooking activities: A potential strategy for directing food choices toward novel foods containing vegetables. AB - Involving children in cooking has been suggested as a strategy to improve dietary habits in childhood. Interventions in schools including cooking, gardening and tasting activities have showed promising results. Several cross-sectional surveys demonstrated associations between frequency of involvement in food preparation and better diet quality. However, experimental studies confirming the beneficial effect of cooking on food choices in children are missing from the literature. The objective of the present study was to assess the effect of involving children in cooking on their willingness to taste novel foods, food intake, liking and hunger. A between-subject experiment was conducted with 137 children between 7 and 11 years old. 69 children (COOK group) participated in the preparation of three unfamiliar foods containing vegetables: apple/beetroot juice, zucchini tortilla sandwich and spinach cookies. 68 children (CONTROL group) participated, instead, in a creative workshop. Afterwards, the children were invited to choose, for an afternoon snack, between three familiar vs. unfamiliar foods: orange vs. apple/beetroot juice, potato vs. zucchini tortilla sandwich and chocolate vs. spinach cookie. The mean number of unfamiliar foods chosen per child was higher in the COOK vs. CONTROL group (P = 0.037). The overall willingness to taste the unfamiliar foods was also higher in the COOK group (P = 0.011). The liking for the whole afternoon snack (P = 0.034), for 2 of 3 unfamiliar foods and for 1 of 3 familiar foods was higher in the COOK group (P < 0.05). We did not demonstrate any difference between the two groups in overall food intake and hunger/satiety scores. This study demonstrated that involving children in cooking can increase their willingness to taste novel foods and direct food choices towards foods containing vegetables. PMID- 27125430 TI - Negative stereotypes of the Scottish diet: A qualitative analysis of deep-fried Mars bar references in bestselling newspapers in Scotland, 2011-14. AB - The Scottish diet is associated in the UK media and popular discourse with unhealthy deep-fried foods. In addition to the stereotype's negative effects on perceptions of Scottish food, culture and people, there is evidence that the stereotype of the Scottish diet has negative effects on food behaviour and public health in Scotland, having been shown to encourage consumption of deep-fried foods and discourage positive dietary change. The most notorious deep-fried food associated with Scotland is the deep-fried Mars bar (DFMB), arguably invented in Stonehaven (near Aberdeen), and first reported in the Scottish and UK press in 1995. This article reports findings from an analysis of newspaper references to the DFMB in the two highest selling newspapers in Scotland, the Scottish Sun and the Daily Record, between 2011 and 2014. A keyword search ("deep fried Mars bar") using the online media database Lexis Library generated 97 unique records, and the resulting dataset was analysed thematically and discursively. Analysis showed that both newspapers clearly associated the DFMB with Scotland. Further, both newspapers portrayed the DFMB and the broader "deep-fried" Scottish diet stereotype ambivalently (mixed positive and negative associations). However, the Daily Record actively criticised the DFMB stereotype much more often than did the Scottish Sun. These findings suggest that the Scottish population encounters different messages in the press about food and nutrition from people elsewhere in the UK, and that these messages vary depending on choice of media in Scotland. Given the known negative effects of the stereotype, differences in Scottish media discourse should be considered a potential factor in persistent health inequalities affecting Scotland. Educational efforts, and opening discussion with journalists and amongst the Scottish public, may be helpful. PMID- 27125431 TI - Acculturation and environmental factors influencing dietary behaviors and body mass index of Chinese students in the United States. AB - Focus groups (n = 7) were conducted with Chinese students (n = 43) studying in the USA to determine how acculturation and environmental factors influence dietary behavior and body mass index (BMI). This study used mixed methodology, collecting both qualitative (focus groups) and quantitative (24-h dietary recalls, food adoption scores, degree of acculturation, and height and weight measures) data. Themes emerging from focus group discussions were: a) dietary and social acculturation, b) factors influencing food intake, c) cultural importance of food, and d) changes in weight and BMI status. Environmental, behavioral, and cultural factors appear to have impacted the eating behaviors of the students. Because of the nature of the study, self-reported heights and weights were used to calculate BMI while living in China and actual heights and weights were taken for each student at the focus group to calculate current BMI after living in the USA. The majority of Chinese students (69% males; 85% females) experienced weight gain, resulting in an increased BMI based on weight/height data and as reported in focus group discussions. As a result, if students continue to gain weight, they may be at higher risk of developing chronic diseases in the future. Further, implemented dietary change may be transferred to other family members if students return to China. Results suggest that nutrition education should be provided to incoming foreign students during their orientation. PMID- 27125432 TI - Feasibility of intermittent back-filtrate infusion hemodiafiltration to reduce intradialytic hypotension in patients with cardiovascular instability: a pilot study. AB - BACKGROUND: Intradialytic hypotension (IDH) is one of the major problems in performing safe hemodialysis (HD). As blood volume depletion by fluid removal is a major cause of hypotension, careful regulation of blood volume change is fundamental. This study examined the effect of intermittent back-filtrate infusion hemodiafiltration (I-HDF), which modifies infusion and ultrafiltration pattern. METHODS: Purified on-line quality dialysate was intermittently infused by back filtration through the dialysis membrane with a programmed dialysis machine. A bolus of 200 ml of dialysate was infused at 30 min intervals. The volume infused was offset by increasing the fluid removal over the next 30 min by an equivalent amount. Seventy-seven hypotension-prone patients with over 20-mmHg reduction of systolic blood pressure during dialysis or intervention-requirement of more than once a week were included in the crossover study of 4 weeks duration for each modality. In a total of 1632 sessions, the frequency of interventions, the blood pressure, and the pulse rate were documented. RESULTS: During I-HDF, interventions for symptomatic hypotension were reduced significantly from 4.5 to 3.0 (per person-month, median) and intradialytic systolic blood pressure was 4 mmHg higher on average. The heart rate was lower during I-HDF than HD in the later session. Older patients and those with greater interdialytic weight gain responded to I-HDF. CONCLUSIONS: I-HDF could reduce interventions for IDH. It is accompanied with the increased intradialytic blood pressure and the less tachycardia, suggesting less sympathetic stimulation occurs. Thus, I-HDF could be beneficial for some hypotension-prone patients. UMIN REGISTRATION NUMBER: 000013816. PMID- 27125433 TI - Performance of the creatinine and cystatin C-based equations for estimation of GFR in Chinese patients with chronic kidney disease. AB - BACKGROUND: Currently, creatinine- or cystatin C-based glomerular filtration rate (GFR) estimation equation has been recommended to assess GFR in CKD patients. However, it is still obscure whether those equations performed consistently outstandingly in Chinese population. METHODS: The equations were validated in a population totaling 632 participants (mean age 61.6 +/- 12.3 years). The estimated GFR (eGFR) calculated separately by six equations (C-MDRD, Ccys, Cscr cys, CKD-EPIscr, CKD-EPIcys, and CKD-EPIscr-cys equations) was compared with the reference GFR (rGFR) measured by the 99mTc-DTPA renal dynamic imaging method. Participants were divided into age and rGFR specific subgroups. RESULTS: CKD EPIscr-cys equation had a larger area under receiver operating characteristic curve (ROCAUC) and relative higher sensitivity (79.8 %) and specificity (93 %) to diagnose CKD. CKD-EPIscr-cys and CKD-EPIcys equations appeared to be more accurate with higher proportion of eGFR within 30 % of rGFR (P 30) value. Those two equations performed as well in older people as in the younger population. The CKD-EPIscr-cys equation acquired the highest P 30 (80.9 %) in subgroups with rGFR >=60 mL/min/1.73 m2, while the CKD-EPIcys equation yielded the best performance in the rGFR <60 mL/min/1.73 m2 subgroup. CONCLUSION: CKD-EPIscr-cys formula had better capability to accurately evaluate GFR in the participants CKD stages 1-2 in Chinese ethnic. The application of the cystatin C-based equations may be the optimal one for patients of moderately to severely injured GFR. Considering the accuracy in the entire range of participants less ideally, the additional of the Chinese racial factor is assumed to be essential. PMID- 27125435 TI - Biodistribution of negatively charged iron oxide nanoparticles (IONPs) in mice and enhanced brain delivery using lysophosphatidic acid (LPA). AB - Effective treatment of brain disorders requires a focus on improving drug permeability across the blood-brain barrier (BBB). Herein, we examined the pharmacokinetic properties of negatively charged iron oxide nanoparticles (IONPs) and the capability of using lysophosphatidic acid (LPA) to transiently disrupt the tight junctions and allow IONPs to enter the brain. Under normal conditions, IONPs had a plasma half-life of six minutes, with the liver and spleen being the major organs of deposition. Treatment with LPA enhanced accumulation of IONPs in the brain and spleen (approximately 4-fold vs. control). LPA and IONP treated mice revealed no sign of peripheral immune cell infiltration in the brain and no significant activation of microglia or astrocytes. These studies show improved delivery efficiency of IONPs following LPA administration. Our findings suggest transient disruption of the BBB may be a safe and effective method for increasing IONP delivery to the brain. PMID- 27125436 TI - A modified method for harvesting thoracodorsal artery perforator flaps in a simple and time-saving approach. AB - BACKGROUND: With the increasing popularity of perforator flaps in several fields of reconstructive surgery, there have been many attempts to develop safer and more efficient harvesting methods. In this article, we propose a modified method for harvesting the thoracodorsal perforator (TDAP) flap during lower extremity reconstruction, and compare it with the conventional method. METHODS: Between January 2011 and December 2013, 74 TDAP flaps were used in reconstruction of lower extremity defects. The flaps included a single musculocutaneous perforator, and one artery, and one vein anastomosis were included in the study. Using the modified method for flap harvest, a reliable perforator was found and a cuff of muscle was left around the perforator without intramuscular dissection. The patient group meeting the inclusion criteria of the study comprised 20 females and 54 males ranging from 12 to 93 years of age. The conventional dissection method for harvesting the TDAP flap was used in 47 patients, the modified method in 27 patients. Flap dimensions, donor site closure, pedicle lengths, total operating times, times from skin incision to initiation of microsurgery, and complications of the two harvesting methods were compared. RESULTS: When the modified method was used, total operating time was reduced from 311 to 272 min (P < 0.05). There were no significant differences in postoperative complications related to the flap or the donor site between the two groups. CONCLUSIONS: The modified method of perforator dissection is relatively safe and straightforward. Using it significantly reduces the operating time. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:642-646, 2016. PMID- 27125434 TI - Curtain osteophytes are one of the risk factors for the poor outcome of rotational acetabular osteotomy. AB - PURPOSE: Rotational acetabular osteotomy (RAO) is one of the surgical procedures for painful dysplastic hips. Although several risk factors for poor outcome of RAO have been reported, the presence of a curtain osteophyte in the acetabulum has not been evaluated as a possible risk factor. This study aimed to analyze the risk factors affecting the outcome of RAO and to clarify whether curtain osteophytes are one of the risk factors. METHODS: We retrospectively analyzed 87 hips in 78 patients with a mean age of 36 (range, 13-54) years. The mean follow up period was 8.3 (range, 2.1-19.5) years. The radiographic severity of osteoarthritis was classified into four stages: pre-arthrosis, initial stage, advanced stage, and terminal stage. The Japanese Orthopaedic Association (JOA) hip score was used for clinical evaluation. Poor outcome was defined as a hip with a JOA score < 80 points or terminal-stage osteoarthritis at final follow-up. Several factors were evaluated by logistic regression analysis. RESULTS: At final follow-up, ten hips had a JOA score < 80 and nine hips had progressed to terminal stage osteoarthritis. Since five hips had a JOA score < 80 as well as terminal stage osteoarthritis, a total of 14 hips were determined to have poor outcome. An additional ten years of age at surgery, pre-operative minimal joint space < 2 mm, presence of a curtain osteophyte, and fair/poor congruency in abduction were identified as significant risk factors for poor outcome of RAO. CONCLUSIONS: Hips with curtain osteophyte should be evaluated carefully before RAO. PMID- 27125437 TI - Stable and durable CH3NH3PbI3 perovskite solar cells at ambient conditions. AB - Degradation of metal-organic halide perovskites when exposed to ambient conditions is a crucial issue that needs to be addressed for commercial viability of perovskite solar cells (PSCs). Here, a concept of encapsulating CH3NH3PbI3 perovskite crystals with a multi-functional graphene-polyaniline (PANI) composite coating to protect the perovskite against degradation from moisture, oxygen and UV light is presented. Hole-conducting polymers containing 2D layered sheet materials are presented here as multi-functional materials with oxygen and moisture impermeability. Specific studies involving PANI and graphene composites as coatings for perovskite crystals exhibited resistance to moisture and oxygen under continued exposure to UV and visible light. Most importantly, no perovskite degradation was observed even after 96 h of exposure of the PSCs to extremely high humidity (99% relative humidity). Our observations and results on perovskite protection with graphene/conducting polymer composites open up opportunities for glove-box-free and atmospheric processing of PSCs. PMID- 27125438 TI - Common finding of mild hyponatremia in children evaluated at the Emergency Department and its correlation with plasma C-reactive protein values. AB - BACKGROUND: In the context of infectious diseases, mild hyponatremia is supposed to be originated by a transient secretion of vasopressin mediated by non-osmotic stimuli. This study provides data supporting the view that mild hyponatremia during acute illnesses is related to a systemic inflammatory condition. METHODS: A total of 328 consecutive children (aged 3 months to 17 years) underwent blood testing at the Pediatric Emergency Department over a 2-month period and were retrospectively analyzed. RESULTS: Hyponatremia was found in 98 patients, and in most of them it was a mild condition. A significant trend towards lower levels of plasmatic sodium, along with the increase of C-reactive protein, was observed. CONCLUSIONS: A significant relationship between plasmatic sodium levels and C reactive protein was found, apart from of the underlying disease. PMID- 27125439 TI - Upper gastrointestinal bleeding in children from a hospital center of Northeast Romania. AB - BACKGROUND: The aim of this study was to investigate the common etiologies, clinical and biological patterns of upper gastrointestinal bleeding (UGIB) in children from a hospital center in Northeast Romania. METHODS: This seven-year retrospective study was performed from 2007 to 2013 in St. Mary Children's Emergency Hospital, Jassy, Romania and included all children who referred to our center with UGIB exteriorized by hematemesis or melena. Endoscopy was performed under conscious sedation/general anesthesia after the informed consent was obtained. RESULTS: One hundred and three patients aged 1-18 years were included in this study. There were 57 males and 46 females with male to female ratio 1.2:1; 43.69% presented with hematemesis, 31.07% had melena and 25.24% had both. The most common causes of UGIB were erosive gastritis (33.98%), followed by esophagitis (14.56%), duodenitis (11.65%), duodenal ulcer (10.68%), gastric ulcer (5.83%), esophageal varices (4.85%), Mallory-Weiss syndrome (1.94%); multiple etiologies counted for 16.50% cases. A certain bleeding source was found in 34.95% cases, a possible one in 39.81% of the patients; the source could not be ascertained in 25.24% of cases. Nonsteroidal anti-inflammatory drug (NSAID) consumption was documented in in 17.51% of patients. The incidence of H. pylori infection was 36.89%. CONCLUSIONS: The most common cause of of upper GI bleeding in our series was gastritis, followed by oesophagitis and duodenitis. Most of the patients presented with hematemesis; previous consumption of NSAIDs and H. pylori infection were associated with gastroduodenal ulceration and bleeding. Early endoscopy was associated with a higher detection rate of the bleeding source. PMID- 27125440 TI - Varicella-zoster virus: pathogenesis, incidence patterns and vaccination programs. AB - Varicella or chickenpox is a common and highly contagious exanthematic disease caused by the varicella-zoster virus (VZV) that during primary infection has the ability to establish latency. VZV reactivation, even decades after primary infection, causes herpes zoster. In healthy immunocompetent subjects, children in particular, varicella results in mild to moderate illness and for this reason, regardless its high morbidity, it is not considered a public health priority. Varicella still represents the most widespread vaccine preventable childhood infectious disease in industrialized countries; due to its relevant burden on healthcare resources several countries has introduced varicella vaccination into the recommended routine childhood national immunization schedule. Nowadays, live attenuated monovalent and combined MMRV vaccines are licensed worldwide. The use of several millions of doses has demonstrated the excellent safety and efficacy level of varicella vaccines as well as of combined MMRV vaccines. Universal vaccination adopted in many countries with a two-dose strategy has allowed to significantly reducing morbidity and mortality of this infectious disease. Anyway, an ample international debate is ongoing on the time range to be used between the two doses, and on the safety issues related to the use as first-dose of MMRV vaccine. Taking into account the availability of a zoster vaccine in subjects older than 50 years of age, it will be relevant to clarify if an impact on exogenous boosters and on the epidemiology of herpes zoster can occur after the adoption of extensive varicella immunization. PMID- 27125441 TI - What about obesity-related iron deficiency as a new sign of child poverty in Italy in a time of economic recession? PMID- 27125442 TI - Kawasaki disease with unusual clinical course in a young infant: case report and perspective management suggestion. PMID- 27125443 TI - Use of biological hemostatic support TachoSil(r) for reoperation in pediatric cardiac surgery. PMID- 27125444 TI - Stomagenesis versus myogenesis: Parallels in intrinsic and extrinsic regulation of transcription factor mediated specialized cell-type differentiation in plants and animals. AB - Although the last common unicellular ancestor of plants and animals diverged several billion years ago, and while having developed unique developmental programs that facilitate differentiation and proliferation specific to plant and animal systems, there still exists a high degree of conservation in the logic regulating these developmental processes within these two seemingly diverse kingdoms. Stomatal differentiation in plants involves a series of orchestrated cell division events mediated by a family of closely related bHLH transcription factors (TFs) to create a pair of mature guard cells. These TFs are in turn regulated by a number of upstream signaling components that ultimately function to achieve lineage specific differentiation and organized tissue patterning on the plant epidermis. The logic involved in the specification of the myogenic differentiation program in animals is intriguingly similar to stomatal differentiation in plants: Closely-related myogenic bHLHs, known as MRFs (Myogenic Regulatory Factors) provide lineage specificity essential for cell-fate determination. These MRFs, similar to the bHLHs in plants, are regulated by several upstream signaling cascades that succinctly regulate each differentiation step, leading to the production of mature muscle fibers. This review aims at providing a perspective on the emerging parallels in the logic employed by key bHLH transcription factors and their upstream signaling components that function to precisely regulate key cell-state transition events in the stomatal as well as myogenic cell lineages. PMID- 27125445 TI - Author Reply. PMID- 27125446 TI - Editorial Comment. PMID- 27125447 TI - Single-use technology for solvent/detergent virus inactivation of industrial plasma products. AB - BACKGROUND: Virus inactivation of plasma products is conducted using stainless steel vessels. Single-use technology can offer significant benefits over stainless such as operational flexibility, reduced capital infrastructure costs, and increased efficiency by minimizing the time and validation requirements associated with hardware cleaning. This study qualifies a single-use bag system for solvent/detergent (S/D) virus inactivation. STUDY DESIGN AND METHODS: Human plasma and immunoglobulin test materials were S/D-treated in Mobius single-use bags using 1% tri-n-butyl phosphate (TnBP) with 1% Triton X-100 or 1% Tween 80 at 31 degrees C for 4 to 6 hours to evaluate the impact on protein quality. Volatile and nonvolatile organic leachables from low-density polyethylene film (Pureflex film) used in 1-L-scale studies after exposure to S/D in phosphate-buffered saline were identified compared to controls in glass containers. Virus inactivation studies were performed with xenotropic murine leukemia virus (XMuLV) and bovine viral diarrhea virus (BVDV) to determine the kinetics of virus inactivation, measured using infectivity assays. RESULTS: S/D treatment in Mobius bags did not impact the protein content and profile of plasma and immunoglobulin, including proteolytic enzymes and thrombin generation. Cumulative leachable levels after exposure to S/D were 1.5 and 1.85 ppm when using 0.3% TnBP combined with 1% Tween 80 or 1% Triton X-100, respectively. Efficient inactivation of both XMuLV and BVDV was observed, with differences in the rate of inactivation dependent on both virus and S/D mixture. CONCLUSION: Effective S/D virus inactivation in single-use container technology is achievable. It does not alter plasma proteins and induces minimal release of leachables. PMID- 27125448 TI - Iatrogenic parasitic leiomyoma and leiomyomatosis peritonealis disseminata following uterine morcellation. AB - AIM: To assess the impact of morcellation on the spread of uterine leiomyoma. METHODS: Cases of parasitic leiomyoma involving prior laparoscopy were collected between 2012 and 2015 in a tertiary women's hospital in China. Their clinicopathological features and the associated reports were reviewed. RESULTS: All six patients with parasitic leiomyoma had laparoscopic myomectomy or hysterectomy with power morcellation 39-132 months previously. Patient 1 had widely disseminated tumors in the peritoneum and pelvis, in keeping with leiomyomatosis peritonealis disseminata (LPD). She received debulking of peritoneal tumors and lived with disease for 22 months. The implanting sites of the other parasitic tumors (patients 2-6) included the mesentery (n = 2), intestine (n = 1), pelvic parietal (n = 1), bladder (n = 1), and musculus rectus abdominis (n = 1). The diameter varied from 1 cm to 6 cm. The patients underwent abdominal subtotal hysterectomy, cervicectomy or tumor debulking and the postoperative course was unremarkable for a period of 2-32 months. Pathologically, these disseminated or parasitic leiomyomas did not show any evidence of malignancy. There were no morphological or immunohistochemical differences between the original tumor and the following seeding tumors. On literature review, 11 iatrogenic LPD have been reported after laparoscopic surgery for uterine leiomyoma. These cases may provide an alternative pathogenic mechanism for a distinct variant of LPD. CONCLUSIONS: Laparoscopic hysterectomy with tumor morcellation may increase the chance of tumor implantation and dissemination. Both clinicians and pathologists should be alert to this rare complication. PMID- 27125449 TI - Long term outcomes in 46, XX adult patients with congenital adrenal hyperplasia reared as males. AB - Patients with Congenital Adrenal Hyperplasia (CAH) owing to 21-hydroxylase deficiency and whose karyotype is 46, XX are usually assigned to the female gender. Reported herein are the long term outcomes in three patients with CAH whose karyotype is 46, XX and who were reared as males. A retrospective review of three CAH patients with a 46, XX karyotype who were reared as males was conducted. Gender assignment, clinical and biochemical data, pre and post genitoplasty genital examinations were reviewed. Gender identity was tested by an extensive questionnaire. Gender role, sexual preference, marital status and sexual satisfaction were evaluated by interview. The three patients were genotyped for the CYP21A2 gene confirming the diagnosis of CAH. Owing to genital virilization, cultural preferences for male gender and the lack of newborn screening programs the three patients reported herein were assigned to the male gender at birth before the diagnosis of CAH was established. In adulthood the patients remained significantly virilized. Thorough psychosexual assessments in adulthood revealed well established male gender identities compatible with their male gender assignments at birth. In all three patients, gender role and behavior were consistent with male gender identity including sexual intercourse with female partners. The three patients reported herein revealed that male gender assignment to CAH patients with a 46, XX karyotype may have a successful outcome providing there is strong parental support and expert endocrine care. No standard guidelines have been published for the gender assignment of CAH patients with a 46, XX karyotype and genital ambiguity. More studies concerning gender assignment in CAH patients with a 46, XX karyotype reared as males are needed. PMID- 27125450 TI - Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer. AB - Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-alpha are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management. PMID- 27125451 TI - The impact of genetic steroid disorders on human fertility. AB - Human fertility requires an exquisitely complex orchestration of steroid hormone action to affect the necessary elements of reproduction, including folliculogenesis, endometrial advancement, ovulation, and implantation. Individuals affected by genetic steroid disorders often face substantial challenges to these crucial elements of fertility, in addition to the broader health implications of their diseases. In the following article, we review the impact of genetic steroid disorders on human reproduction, as well as the treatments, where available, aimed at circumventing such hurdles. Adrenal disorders will first be described, followed by rare gonadal steroid disorders. PMID- 27125452 TI - Biotransformation of the mineralocorticoid receptor antagonists spironolactone and canrenone by human CYP11B1 and CYP11B2: Characterization of the products and their influence on mineralocorticoid receptor transactivation. AB - Spironolactone and its major metabolite canrenone are potent mineralocorticoid receptor antagonists and are, therefore, applied as drugs for the treatment of primary aldosteronism and essential hypertension. We report that both compounds can be converted by the purified adrenocortical cytochromes P450 CYP11B1 and CYP11B2, while no conversion of the selective mineralocorticoid receptor antagonist eplerenone was observed. As their natural function, CYP11B1 and CYP11B2 carry out the final steps in the biosynthesis of gluco- and mineralocorticoids. Dissociation constants for the new exogenous substrates were determined by a spectroscopic binding assay and demonstrated to be comparable to those of the natural substrates, 11-deoxycortisol and 11-deoxycorticosterone. Metabolites were produced at preparative scale with a CYP11B2-dependent Escherichia coli whole-cell system and purified by HPLC. Using NMR spectroscopy, the metabolites of spironolactone were identified as 11beta-OH-spironolactone, 18 OH-spironolactone and 19-OH-spironolactone. Canrenone was converted to 11beta-OH canrenone, 18-OH-canrenone as well as to the CYP11B2-specific product 11beta,18 diOH-canrenone. Therefore, a contribution of CYP11B1 and CYP11B2 to the biotransformation of drugs should be taken into account and the metabolites should be tested for their potential toxic and pharmacological effects. A mineralocorticoid receptor transactivation assay in antagonist mode revealed 11beta-OH-spironolactone as pharmaceutically active metabolite, whereas all other hydroxylation products negate the antagonist properties of spironolactone and canrenone. Thus, human CYP11B1 and CYP11B2 turned out to metabolize steroid-based drugs additionally to the liver-dependent biotransformation of drugs. Compared with the action of the parental drug, changed properties of the metabolites at the target site have been observed. PMID- 27125453 TI - Inflammatory cytokines induce caveolin-1/beta-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway. AB - OBJECTIVES: Apoptosis of nucleus pulposus (NP) cells is a major cause of intervertebral disc degeneration. To elucidate relationships between caveolin-1 and cytokine-induced apoptosis, we investigated the role of caveolin-1 in cytokine-induced apoptosis in rat NP cells and the related signalling pathway. MATERIALS AND METHODS: Rat NP cells were treated with interleukin (IL)-1beta or tumour necrosis factor alpha (TNF-alpha), and knockdown of caveolin-1 and beta catenin was achieved using specific siRNAs. Then, apoptotic level of rat NP cells and expression and activation of caveolin-1/beta-catenin signalling were assessed by flow cytometric analysis, qRT-PCR, western blotting and luciferase assays. The relationship between the mitogen-activated protein kinase (MAPK) pathway and caveolin-1 promoter activity was also determined by luciferase assays. RESULTS: IL-1beta and TNF-alpha induced apoptosis, upregulated caveolin-1 expression and activated Wnt/beta-catenin signalling in rat NP cells, while the induction effect of cytokines was reversed by caveolin-1 siRNA and beta-catenin siRNA. Promotion of rat NP cell apoptosis and nuclear translocation of beta-catenin induced by caveolin-1 overexpression were abolished by beta-catenin siRNA. Furthermore, pretreatment with a p38 MAPK inhibitor or dominant negative-p38, blocked cytokine dependent induction of caveolin-1/beta-catenin expression and activity. CONCLUSIONS: The results revealed the role of p38/caveolin-1/beta-catenin in inflammatory cytokine-induced apoptosis in rat NP cells. Thus, controlling p38/caveolin-1/beta-catenin activity seemed to regulate IL-1beta- and TNF-alpha induced apoptosis in the NP during intervertebral disc degeneration. PMID- 27125454 TI - Infra-red photoresponse of mesoscopic NiO-based solar cells sensitized with PbS quantum dot. AB - Sensitized NiO based photocathode is a new field of investigation with increasing scientific interest in relation with the development of tandem dye-sensitized solar cells (photovoltaic) and dye-sensitized photoelectrosynthetic cells (solar fuel). We demonstrate herein that PbS quantum dots (QDs) represent promising inorganic sensitizers for NiO-based quantum dot-sensitized solar cells (QDSSCs). The solar cell sensitized with PbS quantum dot exhibits significantly higher photoconversion efficiency than solar cells sensitized with a classical and efficient molecular sensitizer (P1 dye = 4-(Bis-{4-[5-(2,2-dicyano-vinyl) thiophene-2-yl]-phenyl}-amino)-benzoic acid). Furthermore, the system features an IPCE (Incident Photon-to-Current Efficiency) spectrum that spreads into the infra red region, reaching operating wavelengths of 950 nm. The QDSSC photoelectrochemical device works with the complexes tris(4,4'-ditert-butyl-2,2' bipyridine)cobalt(III/II) redox mediators, underscoring the formation of a long lived charge-separated state. The electrochemical impedance spectrocopy measurements are consistent with a high packing of the QDs upon the NiO surface, the high density of which limits the access of the electrolyte and results in favorable light absorption cross-sections and a significant hole lifetime. These notable results highlight the potential of NiO-based photocathodes sensitized with quantum dots for accessing and exploiting the low-energy part of the solar spectrum in photovoltaic and photocatalysis applications. PMID- 27125455 TI - Development of a solidified self-microemulsifying drug delivery system (S-SMEDDS) for atorvastatin calcium with improved dissolution and bioavailability. AB - To improve the dissolution and oral bioavailability (BA) of atorvastatin calcium (ATV), we previously introduced an optimized self-microemulsifying drug delivery system (SMEDDS) using Capmul((r)) MCM (oil), Tween((r)) 20 (surfactant), and tetraglycol (cosurfactant). In this study, various solid carriers were employed to develop a solidified SMEDDS (S-SMEDDS): mannitol (M) and lactose (L) as water soluble carriers, and Sylysia((r)) 350 (S) and Aerosil((r)) 200 (A) as water insoluble carriers. Maximum solidifying capacities (SCmax) of water-insoluble carriers were significantly greater than those of water-soluble carriers were. The resultant powders were free flowing with an angle of repose <40 degrees and Carr's index 5-20%, regardless of the solid carrier types. S-SMEDDS with mannitol (S(M)-SMEDDS) or lactose (S(L)-SMEDDS) had a smaller droplet size and greater dissolution than S-SMEDDS with Sylysia((r)) 350 (S(S)-SMEDDS) or Aerosil((r)) 200 (S(A)-SMEDDS). Following oral administration of various formulations to rats at a dose equivalent to 25mg/kg of ATV, plasma drug levels were measured by LC-MS/MS. The relative BAs (RBAs) of SMEDDS, S(M)-SMEDDS, and S(S)-SMEDDS were 345%, 216%, and 160%, respectively, compared to that of ATV suspension. Additionally, at a reduced dose of ATV equivalent to 5mg/kg, the RBAs of S(M)-SMEDDS and S(S)-SMEDDS compared to that of SMEDDS were 101% and 65%, respectively. These results suggest that S(M)-SEMDDS offers great potential for the development of solid dosage forms with improved oral absorption of drugs with poor water solubility. PMID- 27125456 TI - Detection of O-propargyl-puromycin with SUMO and ubiquitin by click chemistry at PML-nuclear bodies during abortive proteasome activities. AB - The amino-nucleoside antibiotic, puromycin, acts by covalently linking to elongating polypeptide chains on ribosomes to generate prematurely terminated immature polypeptides. The trafficking of puromycin-conjugated (puromycylated) immature polypeptides within cell has, however, remained elusive. In this study, using O-propargyl-puromycin (OP-Puro), the distribution of puromycylated polypeptides was assessed in HeLa cells by click chemistry. Under standard culture conditions, OP-Puro signals were detected in the cytoplasm and nucleus with the highest concentrations in the nucleolus. Intriguingly, when proteasome activities were aborted using MG132, OP-Puro signals began to accumulate at promyelocytic leukemia nuclear bodies (PML-NBs) in addition to the nucleolus. We also found promiscuous association of OP-Puro signals with SUMO-2/3 and ubiquitin at PML-NBs, but not at the nucleolus, during abortive proteasome activities. This study reveals a previously unknown distribution of OP-Puro that argues for a nuclear function in regulating immature protein homeostasis. PMID- 27125457 TI - In vitro CRISPR-Cas9-mediated efficient Ad5 vector modification. AB - The CRISPR-Cas9 genome editing system has been widely used in multiple cells and organisms. Here we developed a CRISPR-Cas9 based in vitro large DNA vector editing system, using the Ad5-based vector as an example. We demonstrate use of this system to generate targeted mutations, in-frame gene deletion, and gene replacement. This in vitro CRISPR editing system exhibits high efficiency and accuracy. We believe this system can be applied in a variety of experimental settings. PMID- 27125458 TI - Role of ATF5 in the invasive potential of diverse human cancer cell lines. AB - Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element-binding protein family. Our research group recently revealed that ATF5 expression increases the invasiveness of human lung carcinoma cells. However, the effects of ATF5 on the invasive potential of other cancer cells lines remain unclear. Therefore, in this study, we investigated the role of ATF5 in the invasive activity of diverse human cancer cell lines. Invasiveness was assessed using Matrigel invasion assays. ATF5 knockdown resulted in decreased invasiveness in seven of eight cancer cell lines tested. These results suggest that ATF5 promotes invasiveness in several cancer cell lines. Furthermore, the roles of ATF5 in the invasiveness were evaluated in three-dimensional (3D) culture conditions. In 3D collagen gel, HT-1080 and MDA-MB-231 cells exhibited high invasiveness, with spindle morphology and high invasion speed. In both cell lines, knockdown of ATF5 resulted in rounded morphology and decreased invasion speed. Next, we showed that ATF5 induced integrin-alpha2 and integrin-beta1 expression and that the depletion of integrin-alpha2 or integrin-beta1 resulted in round morphology and decreased invasion speed. Our results suggest that ATF5 promotes invasion by inducing the expression of integrin-alpha2 and integrin beta1 in several human cancer cell lines. PMID- 27125459 TI - Zinc fingers 1, 2, 5 and 6 of transcriptional regulator, PRDM4, are required for its nuclear localisation. AB - PRDM4 is a member of the PRDM family of transcriptional regulators which control various aspects of cellular differentiation and proliferation. PRDM proteins exert their biological functions both in the cytosol and the nucleus of cells. All PRDM proteins are characterised by the presence of two distinct structural motifs, the PR/SET domain and the zinc finger (ZF) motifs. We previously observed that deletion of all six zinc fingers found in PRDM4 leads to its accumulation in the cytosol, whereas overexpressed full length PRDM4 is found predominantly in the nucleus. Here, we investigated the requirements for single zinc fingers in the nuclear localisation of PRDM4. We demonstrate that ZF's 1, 2, 5 and 6 contribute to the accumulation of PRDM4 in the nucleus. Their effect is additive as deleting either ZF1-2 or ZF 5-6 redistributes PRDM4 protein from being almost exclusively nuclear to cytosolic and nuclear. We investigated the potential mechanism of nuclear shuttling of PRDM4 via the importin alpha/beta-mediated pathway and find that PRDM4 nuclear targeting is independent of alpha/beta mediated nuclear import. PMID- 27125460 TI - ERRF is essential for Estrogen-Estrogen Receptor alpha signaling pathway in ER positive breast cancer cells. AB - Estrogen-Estrogen Receptor alpha (ERalpha) belongs to one of the most important signaling pathways controlling breast tissue development and progression of breast cancer. ERRF was recently identified as a candidate breast cancer associated protein and showed positive association with ERalpha status in clinical samples and cell lines. To further explore the relationship between ERRF and ERalpha, we studied whether ERRF plays any roles in estrogen-ERalpha pathway. Knockdown of ERRF in ER positive breast cancer cells T-47D and BT-474 reduced the level of p-AKT, p-MAPK, and phosphorylation of ERalpha at Ser 118 and Ser 167, and the transcriptional activity of ERalpha was inhibited as well. Further mechanism study proved ERRF to be an interacting partner of ERalpha. In total, these data revealed that ERRF is essential for the activity of E2-ERalpha pathway. PMID- 27125462 TI - Pancreatic proteome profiling of type 1 diabetic mouse: Differential expression of proteins involved in exocrine function, stress response, growth, apoptosis and metabolism. AB - Type 1 diabetes (T1D) is a chronic autoimmune disease in which the pancreatic beta-cells fail to produce insulin. In addition to such change in the endocrine function, the exocrine function of the pancreas is altered as well. To understand the molecular basis of the changes in both endocrine and exocrine pancreatic functions due to T1D, the proteome profile of the pancreas of control and diabetic mouse was compared using two dimensional gel electrophoresis (2D-GE) and the differentially expressed proteins identified by electrospray ionization liquid chromatography-tandem mass spectrometry (ESI-LC-MS/MS). Among several hundred protein spots analyzed, the expression levels of 27 protein spots were found to be up-regulated while that of 16 protein spots were down-regulated due to T1D. We were able to identify 23 up-regulated and 9 down-regulated protein spots and classified them by bioinformatic analysis into different functional categories: (i) exocrine enzymes (or their precursors) involved in the metabolism of proteins, lipids, and carbohydrates; (ii) chaperone/stress response; and (iii) growth, apoptosis, amino acid metabolism or energy metabolism. Several proteins were found to be present in multiple forms, possibly resulting from proteolysis and/or post-translational modifications. Succinate dehydrogenase [ubiquinone] flavoprotein subunit, which is the major catalytic subunit of succinate dehydrogenase (SDH), was found to be one of the proteins whose expression was increased in T1D mouse pancreata. Since altered expression of a protein can modify its functional activity, we tested and observed that the activity of SDH, a key metabolic enzyme, was increased in the T1D mouse pancreata as well. The potential role of the altered expression of different proteins in T1D associated pathology in mouse is discussed. PMID- 27125461 TI - Construction and myogenic differentiation of 3D myoblast tissues fabricated by fibronectin-gelatin nanofilm coating. AB - In this study, we used a recently developed approach of coating the cells with fibronectin-gelatin nanofilms to build 3D skeletal muscle tissue models. We constructed the microtissues from C2C12 myoblasts and subsequently differentiated them to form muscle-like tissue. The thickness of the constructs could be successfully controlled by altering the number of seeded cells. We were able to build up to ~76 MUm thick 3D constructs that formed multinucleated myotubes. We also found that Rho-kinase inhibitor Y27632 improved myotube formation in thick constructs. Our approach makes it possible to rapidly form 3D muscle tissues and is promising for the in vitro construction of physiologically relevant human skeletal muscle tissue models. PMID- 27125463 TI - Transvaginal cervical length measurement at 22- to 26-week pregnancy in prediction of preterm births in twin pregnancies. AB - OBJECTIVE: To investigate the predictive role of transvaginal ultrasonographic measurement of cervical length (CL) at 22-26 weeks of gestation in determining preterm deliveries in twin pregnancies. METHODS: The study included 150 twin pregnancies. CL was measured by transvaginal ultrasonography at 22-26 weeks. Signs of preterm labor, ruptured membranes, vaginal bleeding, patients with systemic disease, and cervical incompetencies were excluded. The patients had monthly digital cervical examinations but no routine TVCL ultrasound examinations. The primary outcome was spontaneous preterm birth at before 37 weeks of gestation. RESULTS: Ninety-two percent of twin pregnancies delivered by cesarean section and 16% babies had a neonatal intensive care unit requisitioned. Ninety-two patients were delivered in smaller than 37 gestational weeks and the mean CL measurement (CLM) was <37.64 +/- 6.23 mm. According to the ROC curve analysis, CLM was found to be a discriminating parameter in patients. The area under the curve, cutoff values, sensitivity, and specificity were 0.794, 34.95, and 70-80%; respectively (p = 0.029). CONCLUSION: In women with twin pregnancy, the risk of preterm birth can be evaluated using the ultrasonographic measurement of CL at 22-26 weeks of gestation. PMID- 27125464 TI - Associations between parent-child relationship quality and obesogenic risk in adolescence: a systematic review of recent literature. AB - Adolescence is a period of significant cognitive, social and physiological change, presenting unique risk factors for weight gain. Childhood obesity research has traditionally focused on the influence of parent-level factors on children's eating and weight status. Increasingly, emphasis is turning towards the reciprocal nature of the parent-child relationship and its influence on health behaviour. A systematic literature review was conducted to investigate the relationship between parent-child relationship quality (defined as the felt emotional bond between parent and child) and obesogenic risk (weight status, eating attitudes and behaviours, level of physical activity and sedentary behaviour) in adolescence; 26 papers were included in the review. The results neither support nor challenge an association between parent-child relationship quality and weight, with study design flaws and limited measurement of the parent child relationship precluding robust conclusions. The review does however suggests that several aspects of the parent-child relationship are important in understanding eating attitudes and behaviours, including the felt emotional bond between the parent and child, the child's perception of how much the parent cares for them and the mother's sensitivity towards the child. The need for further longitudinal research into the association between parent-child relationship quality and obesity risk across this developmental period is discussed. PMID- 27125465 TI - Emerging biological agents for hepatitis C. AB - INTRODUCTION: New direct-acting antiviral agents have changed the landscape of treatment of chronic HCV infection. Despite current treatments are well tolerated with a high rate of sustained virological response (SVR), some medical needs remain. Nowadays there are a large number of approved medications for the treatment of HCV infection; nevertheless, new studies are conducted to find new agents and new combinations. AREAS COVERED: A literature research of new antiviral compounds indicated for the treatment of HCV infection was achieved by an online search of medication undergoing development on Pubmed and clinicalTrials.gov clinical trials registry. We considered phase I/II studies and some randomized Phase III trials. EXPERT OPINION: More knowledge about impact of HCV eradication on disease progression and more confidence regarding drug-drug interaction are needed. Furthermore, each treatment should be individualized targeting the patients needs with the aim not only to obtain viral suppression but also to stop progression of liver disease and HCV related conditions, and to improve patient health status. PMID- 27125466 TI - Highly Active Titanocene Catalysts for Epoxide Hydrosilylation: Synthesis, Theory, Kinetics, EPR Spectroscopy. AB - A catalytic system for titanocene-catalyzed epoxide hydrosilylation is described. It features a straightforward preparation of titanocene hydrides that leads to a reaction with low catalyst loading, high yields, and high selectivity of radical reduction. The mechanism was studied by a suite of methods, including kinetic studies, EPR spectroscopy, and computational methods. An unusual resting state leads to the observation of an inverse rate order with respect to the epoxide. PMID- 27125467 TI - Hearing loss, coloboma and left ventricular enlargement in a boy with an interstitial 10q26 deletion. AB - Distal deletion of the long arm of chromosome 10 with breakpoints mapped at 10q26 is a well-recognized contiguous genomic disorder. A wide spectrum of clinical findings is seen in affected individuals and the common clinical features include craniofacial dysmorphia, developmental delay, intellectual disability, hypotonia, cardiovascular defects, and urogenital malformations. We report herein on a male patient with a 5.5 Mb interstitial deletion of 10q26.11q2613 and compare his clinical presentation to previously reported cases. Apart from characteristic phenotypes seen in 10q26 deletion syndrome, he presents with colobomas and left ventricle enlargement. These are cardiovascular and ophthalmological findings that have not been described in prior cases. (c) 2016 Wiley Periodicals, Inc. PMID- 27125468 TI - Proteome analysis of human amniotic mesenchymal stem cells (hA-MSCs) reveals impaired antioxidant ability, cytoskeleton and metabolic functionality in maternal obesity. AB - Maternal obesity increases the risk of obesity and/or obesity-related diseases in the offspring of animal models. The aim of this study was to identify metabolic dysfunctions that could represent an enhanced risk for human obesity or obesity related diseases in newborn or in adult life, similar to what occurs in animal models. To this aim, we studied the proteome of 12 obese (Ob-) and 6 non-obese (Co-) human amniotic mesenchymal stem cells (hA-MSCs) obtained from women at delivery by cesarean section (pre-pregnancy body mass index [mean +/- SD]: 42.7 +/- 7.7 and 21.3 +/- 3.3 kg/m(2), respectively). The proteome, investigated by two-dimensional fluorescence difference gel electrophoresis/mass spectrometry, revealed 62 differently expressed proteins in Ob- vs Co-hA-MSCs (P < 0.05), nine of which were confirmed by western blotting. Bioinformatics analysis showed that these 62 proteins are involved in several statistically significant pathways (P < 0.05), including the stress response, cytoskeleton and metabolic pathways. Oxidative stress was shown to be an early triggering factor of tissue fat accumulation and obesity-related disorders in the offspring of obese animal models. Our finding of a reduced stress response in Ob-hA-MSCs suggests that a similar mechanism could occur also in humans. Long-term follow-up studies of newborns of obese mothers are required to verify this hypothesis. PMID- 27125470 TI - Openness to experience shortens duration of untreated psychosis in Serbian clinical population. AB - AIM: To determine duration of untreated psychosis (DUP) in patients with schizophrenia-spectrum disorders from Serbia and to analyse factors that potentially contribute to the treatment delay, with focus on personality traits. METHODS: Fifty seven patients (males 54.4%; age = 29.9 +/- 6.0 yrs; age at the illness onset = 24.9 +/- 5.1 yrs; IQ = 93.5 +/- 12.2) were included. The assessment consisted of Nottingham Onset Schedule (NOS), Premorbid Adjustment Scale (PAS) and NEO Personality Inventory (NEO-PI-R). We used Cox regression model to evaluate relationship between DUP and explanatory variables. RESULTS: Based on the most restrictive definition, the length of DUP in our sample was 77.8 +/- 120.6 weeks (MED = 25.0 weeks). DUP was negatively associated with openness to experience (B = -0.804, P = 0.024). CONCLUSIONS: We report the first evidence of DUP in Serbia, emphasizing that the personality domains are likely to impact the use of mental health care in persons with psychosis. PMID- 27125469 TI - Congenital malformations and other reproductive losses in goats due to poisoning by Poincianella pyramidalis (Tul.) L.P. Queiroz (=Caesalpinia pyramidalis Tul.). AB - In the semiarid region of Brazil, in areas with vegetation composed mainly of Poincianella pyramidalis, several cases of congenital malformation and reproductive losses were observed in goats and sheep from 2012 to 2014. To determine the teratogenic effect of P. pyramidalis, two groups of eight goats each were used. Goats from Group 1 received fresh P. pyramidalis, harvested daily, as the only roughage during the whole breeding and pregnancy period. Goats in Group 2 (control) received Cynodon dactylon (tifton) hay free choice. Ultrasound examination for pregnancy diagnosis was performed every 28 days. Four goats from Group 1 were pregnant on day 28 but not on day 56, suggesting embryonic death or abortion. Another goat from Group 1 died at day 70 of pregnancy, and the fetuses exhibited micrognathia. The other three goats bore six kids, three of which showed bone malformations in the limbs, spine, ribs, sternum, and head, including arthrogryposis, scoliosis and micrognathia. One kid also showed hypoplasia of the left pulmonary lobes. In the control group, all goats bore a total of 13 kids and none of them exhibited malformations. These results demonstrated that P. pyramidalis causes congenital malformations and other reproductive losses in goats. PMID- 27125471 TI - Polyamine signal through gap junctions: A key regulator of proliferation and gap junction organization in mammalian tissues? AB - We propose that interaction rules derived from polyamine exchange in connected cells may explain the spatio-temporal organization of gap junctions observed during tissue regeneration and tumorigenesis. We also hypothesize that polyamine exchange can be considered as signal that allows cells to sense the proliferation status of their neighbors. Polyamines (putrescine, spermidine, and spermine) are indeed small aliphatic polycations that serve as fuels to sustain elevated proliferation rates of the order observed in cancer cells. Based on recent reports, we consider here that polyamines can be exchanged through gap junction channels between mammalian cells. Such intercellular exchange of polyamines has critical consequences on the local control of growth. In line with this hypothesis, the complex protein network that keeps polyamine levels finely tuned in mammalian cells can translate polyamine efflux or influx into integrated signals controlling transcription, translation, and cell communications. PMID- 27125472 TI - Tacrolimus successfully used to control refractory eosinophilic granulomatosis with polyangiitis complicated by invasive aspergillosis and chronic hepatitis B. AB - While several alternatives to cyclophosphamide have been proposed for refractory eosinophilic granulomatosis with polyangiitis (EGPA), therapeutic options are limited in patients with chronic infections. We report a case of refractory EGPA complicated by invasive aspergillosis and chronic hepatitis B. Although multiple immunosuppressants, including cyclophosphamide, were not effective, tacrolimus was used successfully to control disease without exacerbating concomitant infections in the long term. Tacrolimus could be an alternative choice in the treatment of EGPA, especially when aggressive immunosuppression is unfeasible. PMID- 27125473 TI - Drug resistance mutations after the first 12 months on antiretroviral therapy and determinants of virological failure in Rwanda. AB - OBJECTIVE: To evaluate HIV drug resistance (HIVDR) and determinants of virological failure in a large cohort of patients receiving first-line tenofovir based antiretroviral therapy (ART) regimens. METHODS: A nationwide retrospective cohort from 42 health facilities was assessed for virological failure and development of HIVDR mutations. Data were collected at ART initiation and at 12 months of ART on patients with available HIV-1 viral load (VL) and ART adherence measurements. HIV resistance genotyping was performed on patients with VL >=1000 copies/ml. Multiple logistic regression was used to determine factors associated with treatment failure. RESULTS: Of 828 patients, 66% were women, and the median age was 37 years. Of the 597 patients from whom blood samples were collected, 86.9% were virologically suppressed, while 11.9% were not. Virological failure was strongly associated with age <25 years (adjusted odds ratio [aOR]: 6.4; 95% confidence interval [CI]: 3.2-12.9), low adherence (aOR: 2.87; 95% CI: 1.5-5.0) and baseline CD4 counts <200 cells/MUl (aOR 3.4; 95% CI: 1.9-6.2). Overall, 9.1% of all patients on ART had drug resistance mutations after 1 year of ART; 27% of the patients who failed treatment had no evidence of HIVDR mutations. HIVDR mutations were not observed in patients on the recommended second-line ART regimen in Rwanda. CONCLUSIONS: The last step of the UNAIDS 90-90-90 target appears within grasp, with some viral failures still due to non-adherence. Nonetheless, youth and late initiators are at higher risk of virological failure. Youth-focused programmes could help prevent further drug HIVDR development. PMID- 27125474 TI - Falsely low immunoglobulin (Ig)G4 in routine analysis: how not to miss IgG4 disease. AB - Immunoglobulin (Ig)G4 disease can have apparently 'normal' levels of IgG4 due to antigen excess conditions. IgG4 measurement therefore appears falsely low. UK National External Quality Assurance Scheme (UK NEQAS) data and other reports have suggested that this problem occurred despite pre-existing antigen excess detection steps. To determine the clinical relevance of the problem, we examined the prevalence and characteristics of prozoning in our laboratory and patient cohorts. We establish that the prevalence of raised IgG4 in routine IgG4 analysis is low (< 1%) using one of the two routine methods in use in the United Kingdom. We show that subsequent assay modification appears to have reduced the likelihood of misleading readings. However, the original version of the assay prozoned to low levels (below 0.64 g/l) in 41% of high IgG4 samples in our patients. This may explain the previous reports of low sensitivity of raised IgG4 for IgG4RD, and predictive values should be re-evaluated in this disease using modified prozone resistant protocols. All laboratories providing IgG4 measurements should verify that their assays are fit for the clinical quality requirement of detection raised IgG4 levels and must verify the upper limit of their reference ranges and freedom from prozoning. PMID- 27125475 TI - Flexible Inkjet-Printed Multielectrode Arrays for Neuromuscular Cartography. AB - Flexible Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) ( PEDOT: PSS) conductive-polymer multielectrode arrays (MEAs) are fabricated without etching or aggressive lift-off processes, only by additive solution processes. Inkjet printing technology has several advantages, such as a customized design and a rapid realization time, adaptability to different patients and to different applications. In particular, inkjet printing technology, as additive and "contactless" technology, can be easily inserted into various technological fabrication steps on different substrates at low cost. In vivo electrochemical impedance spectroscopy measurements show the time stability of such MEAs. An equivalent circuit model is established for such flexible cutaneous MEAs. It is shown that the charge transfer resistance remains the same, even two months after fabrication. Surface electromyography and electrocardiography measurements show that the PEDOT: PSS MEAs record electrophysiological activity signals that are comparable to those obtained with unitary Ag/AgCl commercial electrodes. Additionally, such MEAs offer parallel and simultaneous recordings on multiple locations at high surface density. It also proves its suitability to reconstruct an innervation zone map and opens new perspectives for a better control of amputee's myoelectric prostheses. The employment of additive technologies such as inkjet printing suggests that the integration of multifunctional sensors can improve the performances of ultraflexible brain-computer interfaces. PMID- 27125476 TI - Social determinants in the sexual health of adolescent Aboriginal Australians: a systematic review. AB - While research indicates that Aboriginal and Torres Strait Islander adolescents may be at increased risk of some sexually transmitted infections, there is limited information about factors that may place these young people at more risk of adverse sexual health than their non-Indigenous counterparts. Current research has tended to focus on surveillance-type data, but there is an increasing need to understand social determinants of sexual health risk. This systematic review assessed the evidence of social determinants impacting on Aboriginal and Torres Strait Islander adolescents' sexual health in Australia. Published, English language literature was searched across key databases from 2003 to 2015. Fourteen studies were included in the qualitative synthesis. Findings suggest that social determinants such as access to healthcare, poverty, substance use, educational disadvantage, sociocultural context, gender inequalities, status and identity, and social disadvantage impacted on Indigenous adolescents' sexual behaviours and sexual health risk. Evidence from the literature included in the review suggests that peer education may be an acceptable and appropriate approach for addressing such issues. There remains a need for programmes and services to be community developed and community-led, thus ensuring cultural appropriateness and relevance. However, there is also a significant need for such programmes to be effectively and rigorously evaluated with data that goes beyond surveillance, and seeks to unpack how sexual norms are experienced by Indigenous adolescents, particularly outside of remote Australia - and how these experiences act as either risk or protective factors to good sexual health and positive social and emotional well-being. PMID- 27125478 TI - Genome Sequence of Kocuria palustris Strain CD07_3 Isolated from the Duodenal Mucosa of a Celiac Disease Patient. AB - We report here the 2.8-Mb genome of Kocuria palustris strain CD07_3 isolated from the duodenal mucosa of a celiac disease (CD) patient. The genome of the bacterium consists of specific virulence factor genes and antibiotic resistance genes that depict its pathogenic potential. PMID- 27125477 TI - Tailoring the delivery of cancer diagnosis to adolescent and young adult patients displaying strong emotions: An observational study of two cases. AB - Delivering the bad news of a cancer diagnosis to adolescent and young adult (AYA) patients who display strong emotions is particularly challenging not the least because AYAs are at a vulnerable developmental stage. Due to the lack of research on how to personalize the delivery of bad news to AYA patients' emotions we report a case study of the communicative behavior of oncologists in two such consultations to describe the complexity of the phenomena at study. We audio recorded and transcribed consultations where oncologists delivered cancer diagnoses to nine AYAs aged 12-25 years. Two of these patients displayed particularly strong emotional behavior (anger, fear, and sadness) and were chosen as cases. An interpretative analysis in three steps was applied to investigate the oncologists' communicative behavior when delivering bad news. The focus was on how the oncologists responded to the strong but different emotional behaviors of the AYAs. We also related the oncologists' communicative behavior to elements from a widely used protocol for delivering bad news. We found that the oncologists applied five communication strategies: elicit patient perspective, provide information, respond to patient's expression of emotion (acknowledging and containing emotions), encourage commitment to treatment, and provide hope. The findings illustrate how oncologists' communicative behavior may be tailored to individual expressions of emotions in AYA cancer patients. PMID- 27125479 TI - Draft Genome Sequence of Burkholderia cenocepacia Strain CEIB S5-2, a Methyl Parathion- and p-Nitrophenol-Degrading Bacterium, Isolated from Agricultural Soils in Morelos, Mexico. AB - Burkholderia cenocepacia is an opportunistic pathogen that belongs to Burkholderia cepacia complex (BCC). Burkholderia cenocepacia strain CEIB S5-2 was isolated from agricultural soils in Morelos, Mexico, and previously has shown its abilities for bioremediation. In this study, we report the draft genome sequence of Burkholderia cenocepacia strain CEIB S5-2. PMID- 27125480 TI - Draft Genome Sequence of Mycobacterium brumae ATCC 51384. AB - Here, we report the draft genome sequence of Mycobacterium brumae type strain ATCC 51384. This is the first draft genome sequence of M. brumae, a nonpathogenic, rapidly growing, nonchromogenic mycobacterium, with immunotherapeutic capacities. PMID- 27125481 TI - Draft Genome Sequence of Microdochium bolleyi, a Dark Septate Fungal Endophyte of Beach Grass. AB - Here, we present the genome sequence of the dark septate fungal endophyte Microdochium bolleyi (Ascomycota, Sordariomycetes, Xylariales). The assembled genome size was 38.84 Mbp and consisted of 173 scaffolds and 13,177 predicted genes. PMID- 27125482 TI - Complete Genome Sequence of Serratia rubidaea Isolated in China. AB - We report here the first complete genome of Serratia rubidaea, isolated from a patient in China. PMID- 27125483 TI - Complete Genome Sequence of UV-Resistant Campylobacter jejuni RM3194, Including an 81.08-Kilobase Plasmid. AB - Campylobacter jejuni strain RM3194 was originally isolated from a human with enteritis and contains a novel 81,079-bp plasmid. RM3194 has exhibited superior survival compared to other Campylobacter jejuni strains when challenged with UV light. The chromosome of RM3194 was determined to be 1,651,183 bp, with a G+C content of 30.5%. PMID- 27125484 TI - Complete Genome Sequence of Middle East Respiratory Syndrome Coronavirus Isolated from a Dromedary Camel in Egypt. AB - We generated the near-full genome sequence of Middle East respiratory syndrome coronavirus (MERS-CoV) from a collected nasal sample of dromedary camel in Egypt. The newly characterized Egyptian strain has high similarity to the previously characterized Egyptian virus and both of viruses fell into a cluster distinct from other MERS-CoVs. PMID- 27125485 TI - Draft Genome Sequence of "Paramesorhizobium deserti" A-3-ET, a Strain Highly Resistant to Diverse beta-Lactam Antibiotics. AB - Here, we report the draft genome sequence of "Paramesorhizobium deserti" A-3 E(T), a strain isolated from the Taklimakan Desert of Xinjiang, China, which is resistant to multiple beta-lactam antibiotics and other antibiotics (kanamycin, erythromycin, streptomycin, etc.) as well. PMID- 27125486 TI - High-Quality Draft Genomes from Thermus caliditerrae YIM 77777 and T. tengchongensis YIM 77401, Isolates from Tengchong, China. AB - The draft genomes of Thermus tengchongensis YIM 77401 and T. caliditerrae YIM 77777 are 2,562,314 and 2,218,114 bp and encode 2,726 and 2,305 predicted genes, respectively. Gene content and growth experiments demonstrate broad metabolic capacity, including starch hydrolysis, thiosulfate oxidation, arsenite oxidation, incomplete denitrification, and polysulfide reduction. PMID- 27125487 TI - Full-Genome Sequences of Seven Fatal Enterovirus 71 Strains Isolated in Shenzhen, China, in 2014. AB - The whole-genome sequences of seven fatal enterovirus 71 (EV71) strains, isolated in southern China, in 2014, were determined. The complete genome sequences of these strains displayed close relationships to native EV71 strains and showed 94.2% to 99.8% identity to each other. All of these strains were assigned to subgenotype C4a based on phylogenetic analysis of the VP1 gene. PMID- 27125488 TI - Complete Genome Sequence of a Giant Sea Perch Iridovirus in Kaohsiung, Taiwan. AB - We report here the complete genome sequence of a megalocytivirus strain, GSIV-K1, isolated from a farmed giant sea perch (Lates calcarifer) in Kaohsiung, Taiwan. GSIV-K1 causes mortality in farmed marine fish, including giant sea perch and groupers. The genome sequence is nearly identical to the genome of the orange spotted grouper iridovirus. PMID- 27125489 TI - Carnosic acid alleviates chronic alcoholic liver injury by regulating the SIRT1/ChREBP and SIRT1/p66shc pathways in rats. AB - SCOPE: Carnosic acid (CA), which is extracted from rosemary, displays multiple pharmacological activities. This study aimed to investigate the effects of CA on chronic alcoholic liver injury and to elucidate the related mechanisms. METHODS AND RESULTS: An in vivo rat model was established by feeding rats a liquid diet containing ethanol, and an in vitro model was created by treating HepG2 cells with 100 mM ethanol for 48 h. In the rat model of alcohol-induced liver injury, CA significantly decreased serum aminotransferase, triglyceride and total cholesterol levels. Additionally, CA inhibited oxidative stress, inflammation, and cell death. Interestingly, CA activated SIRT1, which was associated with the downregulation of lipoprotein carbohydrate response element-binding protein (ChREBP) and growth factor adapter protein (p66shc). In HepG2 cells, ethanol induced cell injury was associated with decreased SIRT1 and increased ChREBP and p66shc protein expression. These changes were reversed by CA but enhanced by a specific SIRT1 inhibitor, EX527. Moreover, the effects of CA on SIRT1, ChREBP, and p66shc were abolished by SIRT1 siRNA or EX527, indicating that CA decreased ChREBP and p66shc expression via SIRT1 activation. CONCLUSION: CA exerted protective effects against alcoholic liver injury by activating the SIRT1/ChREBP and SIRT1/p66shc pathways, which are related to the anti-steatosis, anti-oxidant, and anti-apoptosis effects. PMID- 27125490 TI - Incentivizing Organ Donor Registrations with Organ Allocation Priority. AB - How donor organs are allocated for transplant can affect their scarcity. In 2008, Israel's Parliament passed an Organ Transplantation Law granting priority on organ donor waiting lists to individuals who had previously registered as organ donors. Beginning in November 2010, public awareness campaigns advertised the priority policy to the public. Since April 2012, priority has been added to the routine medical criteria in organ allocation decisions. We evaluate the introduction of priority for registered organ donors using Israeli data on organ donor registration from 1992 to 2013. We find that registrations increased when information about the priority law was made widely available. We find an even larger increase in registration rates in the 2 months leading up to a program deadline, after which priority would only be granted with a 3-year delay. We also find that the registration rate responds positively to public awareness campaigns, to the ease of registration (i.e. allowing for registering online and by phone) and to an election drive that included placing registration opportunities in central voting locations. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27125491 TI - Modeling of Nitrous Oxide Production from Nitritation Reactors Treating Real Anaerobic Digestion Liquor. AB - In this work, a mathematical model including both ammonium oxidizing bacteria (AOB) and heterotrophic bacteria (HB) is constructed to predict N2O production from the nitritation systems receiving the real anaerobic digestion liquor. This is for the first time that N2O production from such systems was modeled considering both AOB and HB. The model was calibrated and validated using experimental data from both lab- and pilot-scale nitritation reactors. The model predictions matched the dynamic N2O, ammonium, nitrite and chemical oxygen demand data well, supporting the capability of the model. Modeling results indicated that HB are the dominant contributor to N2O production in the above systems with the dissolved oxygen (DO) concentration of 0.5-1.0 mg O2/L, accounting for approximately 75% of N2O production. The modeling results also suggested that the contribution of HB to N2O production decreased with the increasing DO concentrations, from 75% at DO = 0.5 mg O2/L to 25% at DO = 7.0 mg O2/L, with a corresponding increase of the AOB contribution (from 25% to 75%). Similar to HB, the total N2O production rate also decreased dramatically from 0.65 to 0.25 mg N/L/h when DO concentration increased from 0.5 to 7.0 mg O2/L. PMID- 27125492 TI - Assessing Quality of Life and Medical Care in Chronic Angina: An Internet Survey. AB - BACKGROUND: Angina is a clinical syndrome whose recognition relies heavily on self-report, so its identification can be challenging. Most data come from cohorts identified by physicians and nurses at the point of care; however, current widespread access to the Internet makes identification of community cohorts feasible and offers a complementary picture of angina. OBJECTIVE: To describe a population self-identified as experiencing chronic angina by use of an Internet survey. METHODS: Using email and an Internet portal, we invited individuals with a diagnosis of angina and recent symptoms to complete an Internet survey on treatment and quality of life (QOL). In total, 1147 surveys were received. The main analysis was further limited to those reporting a definite coronary heart disease (CHD) history (N=646, 56% of overall). RESULTS: Overall, about 15% reported daily angina and 40% weekly angina. Those with more frequent angina were younger, more often depressed, and reported a shorter time since diagnosis. They also had substantially worse treatment satisfaction, physical function, and overall QOL. Fewer than 40% were on >= 2 anti-anginals, even with daily angina. The subjects without a history of definite CHD had unexpectedly low use of antianginal and evidence-based medicines, suggesting either a lack of specificity in the use of self-reported angina to identify patients with CHD or lack of access to care. CONCLUSIONS: Use of inexpensive electronic tools can identify community-based angina cohorts for clinical research. Limitation to subjects with a definite history of CHD lends diagnostic face validity to the approach; however, other symptomatic individuals are also identified. PMID- 27125494 TI - Conformational distortion of alpha-phenylethyl amine in cryogenic matrices - a matrix isolation VCD study. AB - The chiral amine alpha-phenylethyl amine (PEA) was isolated in cryogenic matrices and investigated using vibrational circular dichroism (VCD) and infrared spectroscopy. The potential energy surface (PES) of PEA features five different conformers connected by relatively low conformational transition states. Based on the IR spectra, it could be confirmed that all conformational energy barriers are passed at a deposition temperature of 20 K, and that only the global minimum conformation of PEA is populated in both argon and nitrogen matrices. However, differences in the calculated and experimental VCD spectra indicate deviations from the minimum structure by perturbation of the phenyl ring as well as of the amine orientation. The degree of the perturbation is found to also depend on the choice of the host gas, which shows the subtle influence of the environment on the conformational distortion of PEA. PMID- 27125493 TI - Bat Hunting and Bat-Human Interactions in Bangladeshi Villages: Implications for Zoonotic Disease Transmission and Bat Conservation. AB - Bats are an important reservoir for emerging zoonotic pathogens. Close human-bat interactions, including the sharing of living spaces and hunting and butchering of bats for food and medicines, may lead to spillover of zoonotic disease into human populations. We used bat exposure and environmental data gathered from 207 Bangladeshi villages to characterize bat exposures and hunting in Bangladesh. Eleven percent of households reported having a bat roost near their homes, 65% reported seeing bats flying over their households at dusk, and 31% reported seeing bats inside their compounds or courtyard areas. Twenty percent of households reported that members had at least daily exposure to bats. Bat hunting occurred in 49% of the villages surveyed and was more likely to occur in households that reported nearby bat roosts (adjusted prevalence ratio [aPR] 2.3, 95% CI 1.1-4.9) and villages located in north-west (aPR 7.5, 95% CI 2.5-23.0) and south-west (aPR 6.8, 95% CI 2.1-21.6) regions. Our results suggest high exposure to bats and widespread hunting throughout Bangladesh. This has implications for both zoonotic disease spillover and bat conservation. PMID- 27125495 TI - Monolayer Co3 O4 Inverse Opals as Multifunctional Sensors for Volatile Organic Compounds. AB - Monolayers of periodic porous Co3 O4 inverse opal (IO) thin films for gas-sensor applications were prepared by transferring cobalt-solution-dipped polystyrene (PS) monolayers onto sensor substrates and subsequent removal of the PS template by heat treatment. Monolayer Co3 O4 IO thin films having periodic pores (d~500 nm) showed a high response of 112.9 to 5 ppm C2 H5 OH at 200 degrees C with low cross-responses to other interfering gases. Moreover, the selective detection of xylene and methyl benzenes (xylene+toluene) could be achieved simply by tuning the sensor temperature to 250 and 275 degrees C, respectively, so that multiple gases can be detected with a single chemiresistor. Unprecedentedly high ethanol response and temperature-modulated control of selectivity with respect to ethanol, xylene, and methyl benzenes were attributed to the highly chemiresistive IO nanoarchitecture and to the tuned catalytic promotion of different gas-sensing reactions, respectively. These well-ordered porous nanostructures could have potential in the field of high-performance gas sensors based on p-type oxide semiconductors. PMID- 27125496 TI - Novel method for the high-throughput production of phosphorylation site-specific monoclonal antibodies. AB - Threonine phosphorylation accounts for 10% of all phosphorylation sites compared with 0.05% for tyrosine and 90% for serine. Although monoclonal antibody generation for phospho-serine and -tyrosine proteins is progressing, there has been limited success regarding the production of monoclonal antibodies against phospho-threonine proteins. We developed a novel strategy for generating phosphorylation site-specific monoclonal antibodies by cloning immunoglobulin genes from single plasma cells that were fixed, intracellularly stained with fluorescently labeled peptides and sorted without causing RNA degradation. Our high-throughput fluorescence activated cell sorting-based strategy, which targets abundant intracellular immunoglobulin as a tag for fluorescently labeled antigens, greatly increases the sensitivity and specificity of antigen-specific plasma cell isolation, enabling the high-efficiency production of monoclonal antibodies with desired antigen specificity. This approach yielded yet undescribed guinea pig monoclonal antibodies against threonine 18-phosphorylated p53 and threonine 68-phosphorylated CHK2 with high affinity and specificity. Our method has the potential to allow the generation of monoclonal antibodies against a variety of phosphorylated proteins. PMID- 27125497 TI - Prevention of falls in older people living in the community. PMID- 27125498 TI - Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma. AB - The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy. PMID- 27125499 TI - Ambient temperature and FIT performance in the Emilia-Romagna colorectal cancer screening programme. AB - OBJECTIVE: To assess the impact of ambient temperature on faecal immunochemical test (FIT) performance in the colorectal cancer screening programme of Emilia Romagna (Italy). METHODS: A population-based retrospective cohort study on data from 2005 to 2011. Positive rate, detection rate, and positive predictive value rate for cancers and adenomas, and incidence rate of interval cancers after negative tests were analysed using Poisson regression models. In addition to ambient temperature, gender, age, screening history, and Local Health Unit were also considered. RESULTS: In 1,521,819 tests analysed, the probability of a positive result decreased linearly with increasing temperature. Point estimates and 95% Confidence Intervals were estimated for six temperature classes (<5, 5 | 10, 10 |-15, 15 |-20, 20|-25 and >=25C), and referred to the 5|-10C class. The positive rate ratio was significantly related to temperature increase: 0.99 (0.97 1.02), 1, 0.98 (0.96-1.00), 0.96 (0.94-0.99), 0.93 (0.91-0.96), 0.92 (0.89-0.95). A linear trend was also evident for advanced adenoma detection rate ratio: 1.00 (0.96-1.04), 1, 0.98 (0.93-1.02), 0.96 (0.92-1.00), 0.92 (0.88-0.96), 0.94 (0.88 1.01). The effect was less linear, but still important, for cancer detection rates: 0.95 (0.85-1.06), 1, 1.00 (0.90-1.10), 0.94 (0.85-1.05), 0.81 (0.72-0.92), 0.93 (0.80-1.09). No association or linear trend was found for positive predictive values or risk of interval cancer, despite an excess of +16% in the highest temperature class for interval cancer. CONCLUSIONS: Ambient temperatures can affect screening performance. Continued monitoring is needed to verify the effect of introducing FIT tubes with a new buffer, which should guarantee a higher stability of haemoglobin. PMID- 27125500 TI - Fatigue 2 months after myocardial infarction may indicate risk for persistent fatigue. PMID- 27125501 TI - Liver: Asprosin - new hormone involved in hepatic glucose release. PMID- 27125503 TI - Antiulcer and antiproliferative properties of spent brewer's yeast peptide extracts for incorporation into foods. AB - The main objective was to study the antiulcer and antiproliferative potential of yeast peptide extract for further incorporation into functional foods. Peptide concentrates were obtained by hydrolysis of spent brewer's yeast proteins followed by a filtration process. In order to prove the possible protection of gastric mucosa, an animal model with ulcerative lesions caused by oral administration of absolute ethanol was used. The peptide fraction <3 kDa was able to reduce gastric injuries to significant levels (p < 0.001) and the effective dose (DE50) was 816 mg per kg bw. The cytoprotective effect appears to depend on a prostaglandin-mediated mechanism and also on a nonspecific mechanism. The antiproliferative activity of the extract in nine different human tumoral cell lines was tested. The results exhibited a promising antiproliferative activity against the cell line K-562 (leukemia). The results suggest that a new peptide extract can be used to develop new value-added functional food products, although further studies are required. PMID- 27125502 TI - Specific Delivery of MiRNA for High Efficient Inhibition of Prostate Cancer by RNA Nanotechnology. AB - Both siRNA and miRNA can serve as powerful gene-silencing reagents but their specific delivery to cancer cells in vivo without collateral damage to healthy cells remains challenging. We report here the application of RNA nanotechnology for specific and efficient delivery of anti-miRNA seed-targeting sequence to block the growth of prostate cancer in mouse models. Utilizing the thermodynamically ultra-stable three-way junction of the pRNA of phi29 DNA packaging motor, RNA nanoparticles were constructed by bottom-up self-assembly containing the anti-prostate-specific membrane antigen (PSMA) RNA aptamer as a targeting ligand and anti-miR17 or anti-miR21 as therapeutic modules. The 16 nm RNase-resistant and thermodynamically stable RNA nanoparticles remained intact after systemic injection in mice and strongly bound to tumors with little or no accumulation in healthy organs 8 hours postinjection, and subsequently repressed tumor growth at low doses with high efficiency. PMID- 27125504 TI - Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatran-induced anticoagulation. AB - Dabigatran is effective in decreasing the risk of ischaemic stroke in patients with atrial fibrillation. However, like all anticoagulants, it is associated with a risk of bleeding. In cases of trauma or emergency surgery, emergency reversal of dabigatran-induced anticoagulation may be required. A specific reversal agent for dabigatran, idarucizumab, has been approved by the US Food and Drug Administration. Alternative reversal agents are available, such as prothrombin complex concentrates (PCCs) and activated PCCs (aPCCs). In this review we evaluate the role of PCCs and aPCCs in the reversal of dabigatran anticoagulation and consider which tests are appropriate for monitoring coagulation in this setting. Pre-clinical studies, small clinical studies and case reports indicate that PCCs and aPCCs may be able to reverse dabigatran-induced anticoagulation in a dose-dependent manner. However, dosing based on coagulation parameters can be difficult because available assays may not provide adequate sensitivity and specificity for measuring anticoagulation induced by dabigatran or the countering effects of PCCs/aPCCs. In addition, PCCs or aPCCs can potentially provoke thromboembolic complications. Despite these limitations and the fact that PCCs and aPCCs are not yet licensed for dabigatran reversal, their use appears to be warranted in patients with life-threatening haemorrhage if idarucizumab is not available. PMID- 27125505 TI - LIX1 regulates YAP1 activity and controls the proliferation and differentiation of stomach mesenchymal progenitors. AB - BACKGROUND: Smooth muscle cell (SMC) plasticity maintains the balance between differentiated SMCs and proliferative mesenchymal progenitors, crucial for muscular tissue homeostasis. Studies on the development of mesenchymal progenitors into SMCs have proven useful in identifying molecular mechanisms involved in digestive musculature plasticity in physiological and pathological conditions. RESULTS: Here, we show that Limb Expression 1 (LIX1) molecularly defines the population of mesenchymal progenitors in the developing stomach. Using in vivo functional approaches in the chick embryo, we demonstrate that LIX1 is a key regulator of stomach SMC development. We show that LIX1 is required for stomach SMC determination to regulate the expression of the pro-proliferative gene YAP1 and mesenchymal cell proliferation. However, as stomach development proceeds, sustained LIX1 expression has a negative impact on further SMC differentiation and this is associated with a decrease in YAP1 activity. CONCLUSIONS: We demonstrate that expression of LIX1 must be tightly regulated to allow fine-tuning of the transcript levels and state of activation of the pro proliferative transcriptional coactivator YAP1 to regulate proliferation rates of stomach mesenchymal progenitors and their differentiation. Our data highlight dual roles for LIX1 and YAP1 and provide new insights into the regulation of cell density-dependent proliferation, which is essential for the development and homeostasis of organs. PMID- 27125506 TI - Osteochondritis dissecans of the elbow. AB - Capitellar osteochondritis dissecans (OCD) can be a significant problem in adolescent overhead athletes. The cause is likely multifactorial secondary to repetitive stresses, biomechanical mismatch, and a tenuous vascular supply of the capitellum. Recent literature reveals that the prevalence is likely higher than previously thought. This, in conjunction with increased levels of athletic competition in children at younger ages, has fed the recent interest in this topic. The literature continues to show that non-operative treatment is still successful for stable lesions. Unstable lesions, therefore, have been the focus of the new literature regarding operative management and outcomes. The aim of this paper is to provide a summary of current literature and an up-to-date approach to the diagnosis, evaluation, and treatment of osteochondritis dissecans of the capitellum. PMID- 27125507 TI - Traumatic insemination and female counter-adaptation in Strepsiptera (Insecta). AB - In a few insect groups, males pierce the female's integument with their penis during copulation to transfer sperm. This so-called traumatic insemination was previously confirmed for Strepsiptera but only in species with free-living females. The more derived endoparasitic groups (Stylopidia) were suggested to exhibit brood canal mating. Further, it was assumed that females mate once and that pheromone production ceases immediately thereafter. Here we examined Stylops ovinae to provide details of the mating behaviour within Stylopidia. By using MUCT imaging of Stylops in copula, we observed traumatic insemination and not, as previously suggested, brood canal mating. The penis is inserted in an invagination of the female cephalothorax and perforates its cuticle. Further we show that female Stylops are polyandrous and that males detect the mating status of the females. Compared to other strepsipterans the copulation is distinctly prolonged. This may reduce the competition between sperm of the first mating male with sperm from others. We describe a novel paragenital organ of Stylops females, the cephalothoracic invagination, which we suggest to reduce the cost of injuries. In contrast to previous interpretations we postulate that the original mode of traumatic insemination was maintained after the transition from free living to endoparasitic strepsipteran females. PMID- 27125508 TI - Blue sky and some shadows: new antibiotics and new superbugs : The ECCMID 2016 in Amsterdam. PMID- 27125509 TI - Erratum to: Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey. PMID- 27125510 TI - The detection of oesophageal varices using a novel, disposable, probe-based transnasal endoscope: a prospective diagnostic pilot study. AB - BACKGROUND & AIMS: Screening for oesophageal varices (OV) using conventional oesophagogastroduodenoscopy (C-OGD) is invasive and requires costly monitoring, recovery, and decontamination facilities. We aimed to evaluate the technical feasibility, acceptability and accuracy of a novel, portable and disposable office-based transnasal endoscope (EG ScanTM ) compared to C-OGD as the reference standard. METHODS: This was a prospective cohort study. Consecutive adult patients with cirrhosis were invited to participate. All subjects underwent the two procedures on the same day performed by two endoscopists in a blinded design. Patients completed preference and validated tolerability (10-point visual analogue scale (VAS)) questionnaires on day 0 and day 14 post procedures. RESULTS: Forty-five of 50 patients (90%) completed both interventions. Mean age was 59 years and OV prevalence was 49%. Patients reported higher preference (percentage) and better experience (mean VAS) with EG Scan compared to C-OGD on day 0 (76.5% vs. 23.5%, P < 0.001; 7.8 vs. 6.8, P = 0.058, respectively) and day 14 (77.8% vs. 22.2%, P < 0.001; 7.0 vs. 5.5, P = 0.0013 respectively). Sensitivity and specificity of the EG Scan for the diagnosis of any size OV were 0.82 (95% confidence interval (CI) 0.60-0.95), and 0.78 (95% CI 0.56-0.93) respectively. Corresponding values for the diagnosis of clinically significant (medium/large) OV were 0.92 (95% CI 0.62-1.0), 0.97 (95% CI 0.84-1.0) respectively. No serious adverse events occurred. CONCLUSIONS: EG Scan accuracy was higher for the diagnosis of medium/large OV compared to any size OV. Patients' preference and overall experience of the EG Scan was favourable compared to C-OGD 14 days after procedures. PMID- 27125511 TI - Fusiform dilatation of the internal carotid artery in childhood-onset craniopharyngioma: multicenter study on incidence and long-term outcome. AB - PURPOSE: Fusiform dilatations of the internal carotid artery (FDCA) represent a vascular complication following surgery for suprasellar tumors in children. Incidence rate and long-term prognosis of FDCA in terms of survival rates, vascular complications, and quality of survival are unknown for patients with childhood-onset craniopharyngioma. METHODS: Magnetic resonance imaging (MRI) results of 583 patients with childhood-onset craniopharyngioma, recruited from 2001 to 2015 in the German Childhood Craniopharyngioma Registry, were reviewed for FDCA. Risk factors for FDCA and long-term outcome after FDCA were analyzed. RESULTS: Fourteen of 583 patients (2.4 %) developed FDCA based on reference assessment of MRI. FDCA occurred ipsilateral to the surgical approach and was not related to degree of resection, hypothalamic involvement, or irradiation. The median time interval between first detection of FDCA and initial surgery was 0.79 years (range 0.01-5.56 years). During a median follow-up of 6.47 years (range 1.2 21.9 years) after first detection of FDCA, no bleeding or cerebrovascular events were observed in any patient. Irradiation was not related to FDCA. Survival rates and functional capacity were similar in patients with and without FDCA. Clinically the FDCA was unapparent in all cases and not treated. CONCLUSION: FDCA is a rare complication related to surgical treatment of childhood-onset craniopharyngioma without major impact on prognosis and clinical course of the disease. CLINICAL TRIAL NUMBER: KRANIOPHARYNGEOM 2000-NCT00258453; KRANIOPHARYNGEOM 2007-NCT01272622. PMID- 27125512 TI - Mesenchymal stem cells and endothelial progenitor cells accelerate intra aneurysmal tissue organization after treatment with SDF-1alpha-coated coils. AB - Recurrences of aneurysms remain the major drawback of detachable coils for the endovascular treatment of intracranial aneurysms. The aim of the present study is to develop new modified coils, coating the surface of platinum coils with silk fibroin (SF) consisting of stromal cell-derived factor-1alpha (SDF-1alpha), and evaluate its acceleration of organization of cavities and reduction of lumen size in a rat aneurysm model. The morphological characteristics of SDF-1alpha-coated coils were examined using scanning electron microscopy (SEM). Fifty experimental aneurysms were created and randomly divided into five groups: three groups were embolized with SDF-1alpha-coated coils (8 mm) and two of these groups need transplantation of mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs); one group was embolized with bare coils (8 mm) and another group severed as control. After coil implantation for 14 or 28 days, the coils were harvested and histological analysis was performed. SEM photographs showed that SF/SDF 1alpha-coated coils have uniform size and a thin film compared with bare coils. In the group treated with SDF-1alpha-coated coils, tissue organization was accelerated and the proliferation of alpha-smooth muscle actin positive cells was promoted in the aneurysmal sac. Compared with unmodified coils, on day 28, tissue organization was significantly greater in the group treated with SDF-1alpha coated coils and MSC or EPC transplantation. These results suggest that SDF 1alpha-coated coils with MSC or EPC transplantation may be beneficial in the aneurysm healing and endothelialization at the orifice of embolized aneurysm. PMID- 27125513 TI - That's a good idea, but let's keep thinking! Can we prevent our initial ideas from being forgotten as a consequence of thinking of new ideas? AB - Four experiments examined participants' ability to remember their own ideas in a modified Alternative Uses Task. Participants were asked to generate uses for objects, and on half of the trials participants were then asked to think of more uses. Memory for the initial uses they generated was then tested via a cued recall task. Results demonstrated that participants forgot their initial uses as a consequence of thinking of new uses (referred to as the thinking-induced forgetting effect), and this effect persisted even when participants chose the subset of uses they thought were the most creative and to be remembered. The only scenario in which uses were protected from forgetting was when they were required to use their uses as hints for generating more ideas. Together, these findings demonstrate that one's own ideas are susceptible to forgetting when additional ideas must be generated, indicating that thinking is a modifier of memory despite one's motivation to preserve their ideas. PMID- 27125515 TI - [Comparing self-concept between groups, bias or differences?: Comments to Castillo et al.] PMID- 27125516 TI - Genetic diversity of coronaviruses in Miniopterus fuliginosus bats. AB - Coronaviruses, such as severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, pose significant public health threats. Bats have been suggested to act as natural reservoirs for both these viruses, and periodic monitoring of coronaviruses in bats may thus provide important clues about emergent infectious viruses. The Eastern bent-wing bat Miniopterus fuliginosus is distributed extensively throughout China. We therefore analyzed the genetic diversity of coronaviruses in samples of M. fuliginosus collected from nine Chinese provinces during 2011-2013. The only coronavirus genus found was Alphacoronavirus. We established six complete and five partial genomic sequences of alphacoronaviruses, which revealed that they could be divided into two distinct lineages, with close relationships to coronaviruses in Miniopterus magnater and Miniopterus pusillus. Recombination was confirmed by detecting putative breakpoints of Lineage 1 coronaviruses in M. fuliginosus and M. pusillus (Wu et al., 2015), which supported the results of topological and phylogenetic analyses. The established alphacoronavirus genome sequences showed high similarity to other alphacoronaviruses found in other Miniopterus species, suggesting that their transmission in different Miniopterus species may provide opportunities for recombination with different alphacoronaviruses. The genetic information for these novel alphacoronaviruses will improve our understanding of the evolution and genetic diversity of coronaviruses, with potentially important implications for the transmission of human diseases. PMID- 27125517 TI - Transition metal-free generation of the acceptor/acceptor-carbene viaalpha elimination: synthesis of fluoroacetyl cyclopropanes. AB - An efficient transition metal-free approach for the generation of acceptor/acceptor-carbene followed by trapping with alkenes to provide fluoroacetyl cyclopropanes has been described. The resulting cyclopropanes could be further converted into the fluoromethyl dihydrofurans or fluorodihydropyrroles through ring-expansion processes. PMID- 27125514 TI - The management of osteoporosis in children. AB - This article reviews the manifestations and risk factors associated with osteoporosis in childhood, the definition of osteoporosis and recommendations for monitoring and prevention. As well, this article discusses when a child should be considered a candidate for osteoporosis therapy, which agents should be prescribed, duration of therapy and side effects. There has been significant progress in our understanding of risk factors and the natural history of osteoporosis in children over the past number of years. This knowledge has fostered the development of logical approaches to the diagnosis, monitoring, and optimal timing of osteoporosis intervention in this setting. Current management strategies are predicated upon monitoring at-risk children to identify and then treat earlier rather than later signs of osteoporosis in those with limited potential for spontaneous recovery. On the other hand, trials addressing the prevention of the first-ever fracture are still needed for children who have both a high likelihood of developing fractures and less potential for recovery. This review focuses on the evidence that shapes the current approach to diagnosis, monitoring, and treatment of osteoporosis in childhood, with emphasis on the key pediatric-specific biological principles that are pivotal to the overall approach and on the main questions with which clinicians struggle on a daily basis. The scope of this article is to review the manifestations of and risk factors for primary and secondary osteoporosis in children, to discuss the definition of pediatric osteoporosis, and to summarize recommendations for monitoring and prevention of bone fragility. As well, this article reviews when a child is a candidate for osteoporosis therapy, which agents and doses should be prescribed, the duration of therapy, how the response to therapy is adjudicated, and the short- and long-term side effects. With this information, the bone health clinician will be poised to diagnose osteoporosis in children and to identify when children need osteoporosis therapy and the clinical outcomes that gauge efficacy and safety of treatment. PMID- 27125518 TI - PHACE syndrome is associated with intracranial cavernous malformations. AB - INTRODUCTION: PHACE syndrome is a neurocutaneous disorder involving large facial hemangiomas in association with posterior fossa abnormalities, cerebral arterial anomalies, cardiac defects, and eye abnormalities. A recent consensus statement has delineated criteria necessary for the diagnosis of PHACE syndrome. Extracutaneous manifestations of PHACE syndrome predominately affect the cerebrovascular system. To date, there are no reports of cerebral cavernous malformations (CCMs) in children with PHACE syndrome. METHODS: We reviewed the charts of children admitted to the Children''s Hospital of Pittsburgh who met criteria for PHACE syndrome, and evaluated neuroimaging for cerebrovascular abnormalities, including the finding of CCMs. RESULTS: Six children met criteria for PHACE syndrome at our institution over a 10-year period. All children were female. All children had cerebrovascular abnormalities sufficient to meet major criteria for diagnosis. Four children (66.7 %) were found incidentally to have CCMs; all lesions measured less than 5 mm at the time of diagnosis and were asymptomatic. CONCLUSION: At present, CCMs are not listed among the diagnostic criteria for PHACE syndrome, and they have not previously been reported in association with PHACE syndrome. Hypoxic injury in utero may be the common denominator in the pathogenesis of many of the abnormalities already accepted in the criteria for PHACE syndrome and the formation of CCMs. In the setting of PHACE syndrome, we encourage clinicians to evaluate children for CCMs, which are readily apparent on the already-recommended screening MRIs. PMID- 27125519 TI - Variants in TNIP1, a regulator of the NF-kB pathway, found in two patients with neural tube defects. AB - PURPOSE: Neural tube defects (NTDs) occur in 1:1000 births. The etiology is complex, with the influence of environmental and genetic factors. Environmental factors, such as folate deficiency, diabetes, or hypoxia strongly contribute to the occurrence of NTD. Also, there is a strong genetic contribution to NTD, as highlighted by the number of genes so far identified in several different developmental pathways usually altered in NTD. Each gene identified so far accounts for a small percentage of all NTD cases, indicating a very high heterogeneity. METHODS: Exome sequencing was performed in seven sporadic patients with severe mielomeningocele. Novel coding variants shared by two or more patients were selected for further analysis. RESULTS: We identified in two unrelated patients two different variants in TNIP1, a gene not previously involved in NTD whose main role is downregulation of the NF-kB pathway. One variant, c.1089T>G (p.Phe363Leu), is de novo, whereas the c.1781C>T (p.Pro594Leu) is absent in the mother, but could not be tested in the father, as he was unavailable. The latter variant is a very rare variant in the ExAC database. CONCLUSIONS: These findings suggest that TNIP1 is a new potential predisposing gene to spina bifida (SB) and its pathway needs to be investigated in human NTD in order to confirm its role and to plan appropriate counseling to families. PMID- 27125520 TI - Developmental considerations with regard to so-called absence of the leaflets of the arterial valves. AB - BACKGROUND: Absent arterial valve leaflets are rare anomalies. On the basis of our understanding of the normal development of the arterial valves, we draw inferences that might offer clues to their morphogenesis. METHODS: We describe the findings from four human fetal autopsies with so-called "absent" arterial valvar leaflets. We then make inferences relative to these finding on the basis of our current understanding of normal development, the latter obtained by analysis of episcopic data sets from a large series of mouse embryos. RESULTS: The fetuses had died between 12 and 15 weeks of gestation. In two cases, we found absence of the leaflets of the pulmonary valve, with patency of the arterial duct, but otherwise normal hearts. In a third case, there was absence of the leaflets of both arterial valves, along with a perimembranous ventricular septal defect and a "window-type" arterial duct. This fetus had a completely muscular subaortic infundibulum. The last fetus had a pulmonary dominant common arterial trunk, with absence of the truncal valvar leaflets, but again with a muscular subtruncal infundibulum. Findings from the analysis of the mouse embryos reveal that the arterial valvar leaflets are formed from the distal outflow cushions, but that the cushions have a separate function in septating the arterial roots and the proximal outflow tracts. CONCLUSIONS: When interpreting the fetal findings in the light of development, we conclude that there had been normal fusion of the major outflow cushions, but failure in excavation of their peripheral margins in three of the cases. In the fourth case, however, the cushions had not only failed to excavate but had also failed to separate the arterial roots. PMID- 27125521 TI - How well do ACPA discriminate and predict RA in the general population: a study based on 12 590 population-representative Swedish twins. AB - OBJECTIVE: Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA), but the diagnostic accuracy of ACPA in the general population has not been thoroughly assessed. We aimed to assess the diagnostic accuracy of ACPA for RA in the general population and to further characterise the citrullinated peptide recognition pattern. METHODS: Serum samples from a large population-representative twin cohort consisting of 12 590 individuals were analysed for the presence of ACPA using anti-CCP2 ELISA. All ACPA-positive samples were further tested on ELISAs for four peptide-specific ACPA. RA cases were identified by linkage to the Swedish National Patient Register at inclusion and after a median follow-up of 37 months (IQR 31-49). RESULTS: 350 out of 12 590 individuals had a positive anti-CCP2 test, measuring ACPA. Of these, 103 had an RA diagnosis at the time of blood donation and inclusion. During a median follow up of 3 years, an additional 21 of the remaining 247 ACPA-positive individuals developed RA. Overall, a positive anti-CCP2 test had a positive predictive value of 29% for prevalent RA at inclusion (negative predictive value of 99.6%). High titres (>3* cut-off) of anti-CCP2 increased the positive predictive value to 48% (negative predictive value of 99.5%). ACPA-positive individuals without RA had lower anti-CCP2 titres and fewer peptide-specific ACPA than ACPA-positive patients with RA and higher C reactive protein levels than ACPA-negative individuals without RA. CONCLUSION: Presence of ACPA and especially high titres of anti-CCP2 have a high diagnostic accuracy for an RA diagnosis in a population setting. PMID- 27125522 TI - High disease activity according to the Ankylosing Spondylitis Disease Activity Score is associated with accelerated radiographic spinal progression in patients with early axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort. AB - OBJECTIVE: The aim of this work was to investigate the association between disease activity measured by the Ankylosing Spondylitis Disease Activity Score (ASDAS) and radiographic spinal progression in patients with early axial spondyloarthritis (axSpA). METHODS: Altogether, 178 patients with definite axSpA (100 with ankylosing spondylitis and 78 with non-radiographic axSpA) were included. Spinal radiographs (baseline and year 2) were assessed according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and for the presence of syndesmophytes. Clinical and lab data were collected at baseline and every 6 months thereafter. Time-averaged (over 2 years) values of the C-reactive protein based ASDAS were calculated. RESULTS: There was a clear positive association between disease activity according to ASDAS and radiographic spinal progression. In the logistic regression analysis, mSASSS progression by >=2 points over 2 years was significantly associated with the time-averaged ASDAS: unadjusted OR=1.64 (95% CI 1.03 to 2.62), adjusted (for presence of syndesmophytes at baseline, smoking status and intake of non-steroidal anti-inflammatory drugs) OR=1.80 (95% CI 1.04 to 3.13). Syndesmophyte formation/progression demonstrated an even stronger association with the time-averaged ASDAS: unadjusted OR=2.62 (95% CI 1.46 to 4.68), adjusted OR=2.45 (95% CI 1.26 to 4.77). CONCLUSIONS: Persisting high disease activity according to the ASDAS is associated with accelerated radiographic spinal progression in early axSpA. PMID- 27125523 TI - Genetic association of ankylosing spondylitis with TBX21 influences T-bet and pro inflammatory cytokine expression in humans and SKG mice as a model of spondyloarthritis. AB - OBJECTIVES: Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthropathy. Inflammation in AS is poorly understood. TBX21 encodes T-bet, a transcription factor, lying within a locus with genome-wide significant association with AS. T-bet is implicated in innate and adaptive immunity. However, the role of T-bet in AS pathogenesis is unclear. METHODS: We assessed the importance of T-bet in disease development and progression in peripheral blood mononuclear cells from 172 AS cases and 83 healthy controls carrying either risk or protective alleles of the peak AS-associated TBX21 single nucleotide polymorphism. Kinetics and localisation of T-bet expression in the SKG mouse model of spondyloarthropathy was examined, along with the impact of Tbx21 knockout on arthritis development in SKG mice. RESULTS: Patients with AS had higher T-bet expression than healthy individuals, driven predominantly by natural killer and CD8+ T cells, with expression levels in CD8+ T cells completely distinguishing AS cases from healthy controls. T-bet expression was increased in AS cases carrying risk compared with protective alleles of rs11657479. In curdlan treated SKG mice, T-bet expression increased early after disease initiation and persisted throughout the course of disease. There was marked reduction in gut and peripheral joint inflammation, and less IFNgamma-producing and IL-17-producing CD8+ T cells, in Tbx21-/- compared with wild-type SKG mice. CONCLUSIONS: AS associated variants in TBX21 influence T-bet expression. T-bet+ innate and adaptive immune cells have altered IL-17 and IFNgamma, and early activation marker CD69 expression than T-bet cells. This indicates that T-bet is a major component of inflammatory pathways of spondyloarthropathy in humans and mice. PMID- 27125525 TI - Hematoma Changes During Clot Resolution After Experimental Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Hematoma clearance occurs in the days after intracerebral hemorrhage (ICH) and has not been well studied. In the current study, we examined changes in the hematoma in a piglet ICH model. The effect of deferoxamine on hematoma was also examined. METHODS: The ICH model was induced by an injection of autologous blood into the right frontal lobe of piglets. First, a natural time course of hematoma changes <=7 days was determined. Second, the effect of deferoxamine on hematoma changes was examined. Hemoglobin and membrane attack complex levels in the hematoma were examined by enzyme-linked immunosorbent assay. Immunohistochemistry and Western blotting were used to examine CD47 (a regulator of erythrophagocytosis), CD163 (a hemoglobin scavenger receptor), and heme oxygenase-1 (a heme degradation enzyme) in the clot. RESULTS: After ICH, there was a reduction in red blood cell diameter within the clot with time. This was accompanied by membrane attack complex accumulation and decreased hemoglobin levels. Erythrophagocytosis occurred in the hematoma, and this was associated with reduced clot CD47 levels. Activated macrophages/microglia were CD163 and hemeoxygenase-1 positive, and these accumulated in the clot with time. Deferoxamine treatment attenuated the process of hematoma resolution by reducing member attack complex formation and inhibiting CD47 loss in the clot. CONCLUSIONS: These results indicate that membrane attack complex and erythrophagocytosis contribute to hematoma clearance after ICH, which can be altered by deferoxamine treatment. PMID- 27125524 TI - Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro. AB - Synovial sarcoma is an aggressive soft tissue sarcoma genetically defined by the fusion oncogene SS18-SSX. It is hypothesized that either SS18-SSX disrupts SWI/SNF complex inhibition of the polycomb complex 2 (PRC2) methyltransferase Enhancer of Zeste Homologue 2 (EZH2), or that SS18-SSX is able to directly recruit PRC2 to aberrantly silence target genes. This is of potential therapeutic value as several EZH2 small molecule inhibitors are entering early phase clinical trials. In this study, we first confirmed EZH2 expression in the 76% of human synovial sarcoma samples. We subsequently investigated EZH2 as a therapeutic target in synovial sarcoma in vitro. Knockdown of EZH2 by shRNA or siRNA resulted in inhibition of cell growth and migration across a series of synovial sarcoma cell lines. The EZH2 selective small-molecule inhibitor EPZ005687 similarly suppressed cell proliferation and migration. These data support the hypothesis that targeting EZH2 may be a promising therapeutic strategy in the treatment of synovial sarcoma; clinical trials are initiating enrollment currently. PMID- 27125526 TI - Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion. AB - BACKGROUND AND PURPOSE: It remains debated whether clinical scores can help identify acute ischemic stroke patients with large-artery occlusion and hence improve triage in the era of thrombectomy. We aimed to determine the accuracy of published clinical scores to predict large-artery occlusion. METHODS: We assessed the performance of 13 clinical scores to predict large-artery occlusion in consecutive patients with acute ischemic stroke undergoing clinical examination and magnetic resonance or computed tomographic angiography <=6 hours of symptom onset. When no cutoff was published, we used the cutoff maximizing the sum of sensitivity and specificity in our cohort. We also determined, for each score, the cutoff associated with a false-negative rate <=10%. RESULTS: Of 1004 patients (median National Institute of Health Stroke Scale score, 7; range, 0-40), 328 (32.7%) had an occlusion of the internal carotid artery, M1 segment of the middle cerebral artery, or basilar artery. The highest accuracy (79%; 95% confidence interval, 77-82) was observed for National Institute of Health Stroke Scale score >=11 and Rapid Arterial Occlusion Evaluation Scale score >=5. However, these cutoffs were associated with false-negative rates >25%. Cutoffs associated with an false-negative rate <=10% were 5, 1, and 0 for National Institute of Health Stroke Scale, Rapid Arterial Occlusion Evaluation Scale, and Cincinnati Prehospital Stroke Severity Scale, respectively. CONCLUSIONS: Using published cutoffs for triage would result in a loss of opportunity for >=20% of patients with large-artery occlusion who would be inappropriately sent to a center lacking neurointerventional facilities. Conversely, using cutoffs reducing the false negative rate to 10% would result in sending almost every patient to a comprehensive stroke center. Our findings, therefore, suggest that intracranial arterial imaging should be performed in all patients with acute ischemic stroke presenting within 6 hours of symptom onset. PMID- 27125527 TI - Female Sex, Time in Therapeutic Range, and Clinical Outcomes in Atrial Fibrillation Patients Taking Warfarin. AB - BACKGROUND AND PURPOSE: Female patients have higher risk for stroke than male patients in nonanticoagulated atrial fibrillation patients, but limited data are available on sex differences in stroke and bleeding outcomes among patients with anticoagulated atrial fibrillation on warfarin, especially in relation to quality of anticoagulation control, as reflected by the time in therapeutic range (TTR). METHODS: We investigated adverse outcomes in females (n=791) and males (n=1501) among 2292 patients with atrial fibrillation taking warfarin arm in the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial. RESULTS: The combined end point of cardiovascular death and stroke/systemic embolism (SSE) was similar in females versus males. There was no sex differences in either cardiovascular death or SSE. Compared with males, females had a lower risk of major bleeding (hazard ratio, 0.39; 95% confidence interval, 0.18-0.87; P=0.02). No differences were seen in mortality and stroke outcomes between females and males either in the prespecified age subgroups or in relation to TTR categories. TTR was negatively correlated with any clinically relevant bleeding in both females (r=-0.86; P=0.03) and males (r=-0.94; P=0.005). On Cox regression, TTR (but not female sex) emerged as an independent predictor for combined cardiovascular death/SSE and clinically relevant bleeding events. CONCLUSION: Anticoagulated female patients with atrial fibrillation had a similar rate of cardiovascular death and SSE, but a lower risk of major bleeding, compared with males. TTR (but not female sex) was an independent predictor for combined cardiovascular death and SSE and clinically relevant bleeding events. PMID- 27125528 TI - Reducing Readmissions After Stroke With a Structured Nurse Practitioner/Registered Nurse Transitional Stroke Program. AB - BACKGROUND AND PURPOSE: Our aim was to determine whether a standardized Transitional Stroke Clinic (TSC) led by nurse practitioners could reduce 30-day and 90-day readmissions for stroke or transient ischemic attack patients discharged home. METHODS: Phase I consisted of nurse practitioners calling only high-risk patients discharged home within 7 days and performing an office visit within 2 to 4 weeks of discharge. Phase II consisted of all patients discharged home receiving both a 2-day follow-up phone call by a registered nurse and a follow-up visit with a nurse practitioner within 7 to 14 days. Differences in process metrics and readmissions across the 2 phases and overall were assessed. Increasing complexity with multiple chronic conditions (diabetes mellitus, coronary artery disease, and congestive heart failure) was represented in a continuous variable from 0 to 3. Multivariable logistic regression models for 30 day and 90-day readmissions were performed with adjustment for National Institutes of Health Stroke Scale (NIHSS) and previous hospitalizations. RESULTS: From October 2012 through September 2015, 510 patients were enrolled. From phase I to II, a higher proportion of follow-up calls were made and days from discharge to TSC decreased. Patients readmitted within 30 days were less likely to show for TSC visits (60.85% versus 76.3%; P=0.021). Multivariable modeling showed that TSC visit was associated with a 48% reduction in 30-day readmission (odds ratio, 0.518; 95% confidence interval, 0.272-0.986), whereas multiple chronic conditions and previous stroke/transient ischemic attack increased the risk. TSC visit did not impact 90-day readmissions. CONCLUSIONS: Evaluation in a nurse practitioner led structured clinic is a model that may reduce readmissions at 30 days for stroke patients discharged home. PMID- 27125529 TI - Effects of solid-phase denitrification on the nitrate removal and bacterial community structure in recirculating aquaculture system. AB - A solid-phase denitrification (SPD) reactor packed with poly (3-hydroxybutyrate co-3-hydroxyvalerate) as a carbon source was incorporated into a recirculating aquaculture system (RAS) to remove accumulated nitrate. Bacterial community structures in different parts of the RAS, including biofilter unit, SPD reactor, and culture water, were analyzed using Illumina MiSeq sequencing technology. The data showed that nitrate levels decreased remarkably in the RAS connected with SPD reactor (RAS-DR). In contrast, nitrate levels increased continuously in the conventional RAS without SPD reactor (RAS-CK). Biofilter unit and culture water in RAS-DR developed lower species richness and higher bacterial community diversity than that in RAS-CK. The bacterial community structure of RAS was significantly affected by the SPD process and the changes included an increase in the proportion of Proteobacteria and Firmicutes and a decrease in Nitrospira abundance in RAS-DR. Firmicutes was the most abundant phylum (56.9 %) and mainly consisted of Clostridium sensu stricto (48.3 %) in SPD reactor. PMID- 27125530 TI - Assessment of intraoperative pain during Mohs micrographic surgery (MMS): An opportunity for improved patient care. AB - BACKGROUND: Intraoperative pain during Mohs micrographic surgery (MMS) has not been characterized. However, many patients report postoperative pain on the day of MMS. OBJECTIVE: We sought to determine if patients experience pain during their MMS visit. METHODS: In phase I of this study, patients were asked to report intraoperative pain level using the verbal numerical rating scale (0-10) at discharge. In phase II, pain levels were assessed before each Mohs layer and at discharge, to determine whether pain was experienced throughout the day. RESULTS: Pain was reported at some point during the MMS day for 32.8% of patients (n = 98). The mean pain number reported was 3.7 (range 1-8) out of 10. Pain was more commonly reported by patients who spent a longer time in the office, had 3 or more Mohs layers, and had a flap or graft repair. Patients most frequently reported pain with surgical sites of the periorbital area and nose. LIMITATIONS: Time between Mohs layers was not measured. There was nonstandardized use of intraoperative local anesthesia volume and oral pain medications. CONCLUSION: Some patients experience pain during MMS. However, the majority of patients report a low level of pain. Additional preventative measures could be considered in patients at higher risk. PMID- 27125531 TI - Utility of recorded guided imagery and relaxing music in reducing patient pain and anxiety, and surgeon anxiety, during cutaneous surgical procedures: A single blinded randomized controlled trial. AB - BACKGROUND: Guided imagery and music can reportedly reduce pain and anxiety during surgery, but no comparative study has been performed for cutaneous surgery to our knowledge. OBJECTIVES: We sought to determine whether short-contact recorded guided imagery or relaxing music could reduce patient pain and anxiety, and surgeon anxiety, during cutaneous surgical procedures. METHODS: Subjects were adults undergoing excisional surgery for basal and squamous cell carcinoma. Randomization was to guided imagery (n = 50), relaxing music (n = 54), or control group (n = 51). Primary outcomes were pain and anxiety measured using visual analog scale and 6-item short-form of the State-Trait Anxiety Inventory, respectively. Secondary outcomes were anxiety of surgeons measured by the 6-item short-form of the State-Trait Anxiety Inventory and physical stress of patients conveyed by vital signs, respectively. RESULTS: There were no significant differences in subjects' pain, anxiety, blood pressure, and pulse rate across groups. In the recorded guided imagery and the relaxing music group, surgeon anxiety was significantly lower than in the control group. LIMITATIONS: Patients could not be blinded. CONCLUSION: Short-contact recorded guided imagery and relaxing music appear not to reduce patient pain and anxiety during excisional procedures under local anesthetic. However, surgeon anxiety may be reduced when patients are listening to such recordings. PMID- 27125532 TI - Overconfidence in Projecting Uncertain Spatial Trajectories. AB - OBJECTIVE: The aim of this study was to understand factors that influence the prediction of uncertain spatial trajectories (e.g., the future path of a hurricane or ship) and the role of human overconfidence in such prediction. BACKGROUND: Research has indicated that human prediction of uncertain trajectories is difficult and may well be subject to overconfidence in the accuracy of forecasts as is found in event prediction, a finding that indicates that humans insufficiently appreciate the contributions of variance in nature to their predictions. METHOD: In two experiments, our paradigm required participants to observe a starting point, a position at time T, and then make a prediction of the location of the trajectory at time NT. They experienced several trajectories from the same underlying model but perturbed by random variance in heading and speed. RESULTS: In Experiment 1A, people predicted linear paths well and were better in heading predictions than in speed predictions. However, participants greatly underestimated the variance in predicted location, indicating overconfidence. In Experiment 1B, the effect was replicated with frequencies rather than probabilities used in variance estimates. In Experiment 2, people predicted nonlinear trajectories poorly, and overconfidence was again observed. Overconfidence was reduced on the more difficult predictions. In both main experiments, those better at predicting the mean were not better at predicting the variance. CONCLUSIONS: Predicting the level of uncertainty in spatial trajectories is not well done and may involve qualitatively different abilities than prediction of the mean. APPLICATION: Improving real-world performance at prediction demands developing better understanding of variability, not just the average case. Biases in prediction of uncertainty may be addressed through debiasing training and/or visualization tools that could assist in more calibrated action planning. PMID- 27125533 TI - Ergonomics and Beyond: Understanding How Chemical and Heat Exposures and Physical Exertions at Work Affect Functional Ability, Injury, and Long-Term Health. AB - OBJECTIVE: To honor Tom Waters's work on emerging occupational health issues, we review the literature on physical along with chemical exposures and their impact on functional outcomes. BACKGROUND: Many occupations present the opportunity for exposure to multiple hazardous exposures, including both physical and chemical factors. However, little is known about how these different factors affect functional ability and injury. The goal of this review is to examine the relationships between these exposures, impairment of the neuromuscular and musculoskeletal systems, functional outcomes, and health problems with a focus on acute injury. METHOD: Literature was identified using online databases, including PubMed, Ovid Medline, and Google Scholar. References from included articles were searched for additional relevant articles. RESULTS: This review documented the limited existing literature that discussed cognitive impairment and functional disorders via neurotoxicity for physical exposures (heat and repetitive loading) and chemical exposures (pesticides, volatile organic compounds [VOCs], and heavy metals). CONCLUSION: This review supports that workers are exposed to physical and chemical exposures that are associated with negative health effects, including functional impairment and injury. Innovation in exposure assessment with respect to quantifying the joint exposure to these different exposures is especially needed for developing risk assessment models and, ultimately, preventive measures. APPLICATION: Along with physical exposures, chemical exposures need to be considered, alone and in combination, in assessing functional ability and occupationally related injuries. PMID- 27125534 TI - Risk factors for long-term outcome in photoselective vaporization of the prostate. AB - OBJECTIVE: The aim of this retrospective cohort study was to investigate long term risk factors for reintervention after photoselective vaporization of the prostate (PVP). MATERIAL AND METHODS: In total, 566 consecutive patients with benign prostatic hyperplasia (BPH) underwent PVP between February 2005 and April 2011. Mean follow-up was 36.42 +/- 21.4 months. Perioperative parameters were evaluated, including surgery time, delivered energy, catheterization and duration of hospitalization, intraoperative and postoperative complications, as well as reintervention rates in manifest reobstruction. Follow-up comprised the International Prostate Symptom Score and quality of life questionnaire (IPPS QoL), maximal flow rate (Qmax) and postvoiding residual volume (PVR). RESULTS: Mean operation time was 69.8 +/- 29.3 min. Mean catheterization and hospitalization times were 1.49 +/- 1.19 days and 2.67 +/- 2.19 days, respectively. There was ongoing oral anticoagulation for 20.1% of the patients (n = 114). The overall retreatment rate was 17.6% (101 out of 566 patients) after a mean time of 9.21 months (range 0-64 months). Of these, 88 patients (15.55%) had a reobstruction and 13 (2.3%) had urethral strictures. In multivariate analysis, age, prostate volume, total applied energy, specific laser energy usage, preoperative symptomatic (IPSS/QoL) and functional obstruction grade (Qmax/PVR) were not identified as risk factors for reintervention. A poor postoperative Qmax (< 15 ml/s) measured immediately after removal of the transurethral catheter was identified as a risk factor for undergoing a reintervention (p = 0.005). CONCLUSIONS: PVP is an effective method for BPH treatment, allowing for sustained long-term improvement of the voiding function. Poor immediate postoperative urinary flow after removal of the transurethral catheter (Qmax < 15 ml/s) is a significant risk factor for reintervention. PMID- 27125536 TI - Editorial Comment. PMID- 27125537 TI - Reply by Authors. PMID- 27125535 TI - Effects of Early Post-Ischemic Reperfusion and tPA on Cerebrovascular Function and Nitrosative Stress in Female Rats. AB - Stroke is a major health issue in women. Our previous studies in male rats showed decreased myogenic tone in middle cerebral arteries (MCAs) after ischemia and reperfusion (I/R), while tone in parenchymal arterioles (PAs) was increased. This vascular response may aggravate stroke damage in males by limiting reperfusion; however, the effect in females is not known. The current study investigated the effect of I/R and tissue plasminogen activator (tPA) on myogenic tone and reactivity of MCAs and PAs in female rats. Nitrosative stress by peroxynitrite and recruitment of inflammatory neutrophils to the microvasculature were also studied. Female rats were subjected to 2-h MCA filament occlusion (n = 16) or sham surgery (n = 17) and given tPA (1 mg/kg, i.v) or vehicle followed by 30-min reperfusion. Myogenic tone and reactivity were measured in isolated and pressurized MCAs and PAs from the same animals. Cerebrovascular F-actin, 3 nitrotyrosine (3-NT, peroxynitrite marker), and intravascular neutrophils were quantified. Myogenic tone and constriction to the nitric oxide synthase inhibitor Nomega-nitro-L-arginine were decreased in MCAs but unchanged in PAs after I/R with no effect of tPA. F-actin and 3-NT expression were unaffected by I/R or tPA. Our study showed that MCAs from females, similar to what has been seen in males, are dilated after I/R and have decreased myogenic tone while tone in PAs was unchanged. Increased small vessel resistance may contribute to decreased reperfusion and worse outcome after stroke. PMID- 27125538 TI - Editorial Comment. PMID- 27125539 TI - Editorial Comment. PMID- 27125541 TI - Editorial Comment. PMID- 27125540 TI - Editorial Comment. PMID- 27125542 TI - Editorial Comment. PMID- 27125543 TI - Reply by Authors. PMID- 27125545 TI - Inherent Directionality Determines Spatial Release from Masking at the Tympanum in a Vertebrate with Internally Coupled Ears. AB - In contrast to humans and other mammals, many animals have internally coupled ears that function as inherently directional pressure-gradient receivers. Two important but unanswered questions are to what extent and how do animals with such ears exploit spatial cues in the perceptual analysis of noisy and complex acoustic scenes? This study of Cope's gray treefrog (Hyla chrysoscelis) investigated how the inherent directionality of internally coupled ears contributes to spatial release from masking. We used laser vibrometry and signal detection theory to determine the threshold signal-to-noise ratio at which the tympanum's response to vocalizations could be reliably detected in noise. Thresholds were determined as a function of signal location, noise location, and signal-noise separation. Vocalizations were broadcast from one of three azimuthal locations: frontal (0 degrees ), to the right (+90 degrees ), and to the left ( 90 degrees ). Masking noise was broadcast from each of 12 azimuthal angles around the frog (0 to 330 degrees , 30 degrees separation). Variation in the position of the noise source resulted in, on average, 4 dB of spatial release from masking relative to co-located conditions. However, detection thresholds could be up to 9 dB lower in the "best ear for listening" compared to the other ear. The pattern and magnitude of spatial release from masking were well predicted by the tympanum's inherent directionality. We discuss how the magnitude of masking release observed in the tympanum's response to spatially separated signals and noise relates to that observed in previous behavioral and neurophysiological studies of frog hearing and communication. PMID- 27125546 TI - Noninvasive Shock Wave Treatment for Capsular Contractures After Breast Augmentation: A Rabbit Study. AB - BACKGROUND: Capsular contracture is the most common complication of breast augmentation. Although numerous procedures are intended to prevent capsular contracture, their efficacy does not satisfy surgeons or patients. In the present study, we used shock waves to develop innovative protocols to treat capsular contracture in rabbits. METHODS: We used shock waves to treat capsular contracture in a rabbit model. Six clinical parameters were evaluated to determine the treatment efficacy of shock waves on the pathological histology of capsular contracture. Dual-flip-angle T1-mapping magnetic resonance imaging was used to confirm the pathological findings. RESULTS: Among the parameters, myxoid change, vascular proliferation, and lymphoplasma cell infiltration around the capsule increased more after treatment than they did in a control group. Capsular thickness, inner thinner collagen layer, and capsule wall collagen deposition decreased after shock wave treatment; only the inner thinner collagen layer and capsule wall collagen deposition changed significantly. The MRI findings for both scar thickness and water content were consistent with pathological biology findings. CONCLUSION: This was the first pilot study and trial to treat capsular contractures using shock waves. We found that shock waves can cause changes in the structure or the composition of capsular contracture. We conclude that the treatment could decrease water content, loosen structure, decrease collagen deposition, and might alleviate scar formation from capsular contracture. We believe that the treatment could be a viable remedy for capsular contractures. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27125544 TI - A high fat diet alters metabolic and bioenergetic function in the brain: A magnetic resonance spectroscopy study. AB - Diet-induced obesity and associated metabolic effects can lead to neurological dysfunction and increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Despite these risks, the effects of a high-fat diet on the central nervous system are not well understood. To better understand the mechanisms underlying the effects of high fat consumption on brain regions affected by AD and PD, we used proton magnetic resonance spectroscopy ((1)H-MRS) to measure neurochemicals in the hippocampus and striatum of rats fed a high fat diet vs. normal low fat chow. We detected lower concentrations of total creatine (tCr) and a lower glutamate-to-glutamine ratio in the hippocampus of high fat rats. Additional effects observed in the hippocampus of high fat rats included higher N-acetylaspartylglutamic acid (NAAG), and lower myo-inositol (mIns) and serine (Ser) concentrations. Post-mortem tissue analyses revealed lower phosphorylated AMP-activated protein kinase (pAMPK) in the striatum but not in the hippocampus of high fat rats. Hippocampal pAMPK levels correlated significantly with tCr, aspartate (Asp), phosphoethanolamine (PE), and taurine (Tau), indicating beneficial effects of AMPK activation on brain metabolic and energetic function, membrane turnover, and edema. A negative correlation between pAMPK and glucose (Glc) indicates a detrimental effect of brain Glc on cellular energy response. Overall, these changes indicate alterations in neurotransmission and in metabolic and bioenergetic function in the hippocampus and in the striatum of rats fed a high fat diet. PMID- 27125547 TI - A Subset of TNBCs Exhibit 9p24 Amplifications and JAK2 Dependence. AB - JAK2 focal amplifications are associated with reduced survival and resistance to chemotherapy. PMID- 27125548 TI - IDH1-Driven Reductive Carboxylation Supports Anchorage Independence. AB - Adaptation to anchorage-independent growth requires IDH1-mediated changes in citrate metabolism. PMID- 27125549 TI - Anti-CCR5 Therapy Circumvents Immune Cell Exploitation by Tumors. AB - CCL5 produced by T cells at invasive margins of colorectal cancer metastases promotes tumor growth. PMID- 27125550 TI - Chemotherapy Efficacy Is Dependent upon p53 Dynamics. AB - Drug-induced apoptosis occurs after cells reach a p53 threshold level, which increases over time. PMID- 27125551 TI - KIR3DL1/HLA-B Interactions Modulate Response to Anti-GD2 Antibodies. AB - KIR3DL1 and HLA-B allele combinations predict response to anti-GD2 mAb in neuroblastoma. PMID- 27125553 TI - Comment on: False economies in home-based parenteral antibiotic treatment: a health-economic case study of management of lower-limb cellulitis in Australia. PMID- 27125552 TI - Emergence of azole-resistant Candida parapsilosis causing bloodstream infection: results from laboratory-based sentinel surveillance in South Africa. AB - OBJECTIVES: To compare Candida species distribution and antifungal susceptibility at South African public- and private-sector hospitals. METHODS: From February 2009 through to August 2010, laboratory-based surveillance for candidaemia was undertaken at 11 public-sector hospitals and >85 private-sector hospitals across South Africa. A case was defined as a patient of any age admitted to a sentinel hospital with isolation of Candida species from blood culture. Viable isolates were identified and tested for antifungal susceptibility at a reference laboratory. Demographic and limited clinical data were abstracted from laboratory records. RESULTS: In total, 2172 cases of candidaemia were detected. Among patients with available data, almost two-thirds were critically ill (719/1138, 63%). On multivariable analysis, neonates [adjusted OR (aOR), 2.2; 95% CI, 1.5 3.1; P < 0.001] and patients diagnosed in Gauteng province (aOR, 1.9; 95% CI, 1.3 2.7; P < 0.001) or in the private sector (aOR, 1.9; 95% CI, 1.2-3.2; P = 0.008) were significantly more likely to be infected with Candida parapsilosis than any other Candida species. Of 531 C. parapsilosis isolates, only 199 (37%) were susceptible to fluconazole and voriconazole; 44% (123/282) of fluconazole resistant isolates were voriconazole cross-resistant. Factors associated with fluconazole non-susceptible C. parapsilosis infection on multivariable analysis included diagnosis in Gauteng province (aOR, 4.2; 95% CI, 2.7-6.7; P < 0.001), an ICU (aOR, 2.3; 95% CI, 1.5-3.6; P < 0.001) or the private sector (aOR, 2.2; 95% CI, 1.4-3.5; P < 0.001). CONCLUSIONS: The dominance of triazole non-susceptible C. parapsilosis limits the choice of antifungal agents for management of candidaemia among critically ill neonates, children and adults in resource limited South African hospitals. PMID- 27125554 TI - (1,3)-beta-d-Glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. AB - OBJECTIVES: To determine the effects of a strategy that uses serum (1,3)-beta-d glucan (BDG) results for antifungal treatment of ICU patients at high risk of invasive candidiasis. PATIENTS AND METHODS: Adult patients admitted to the ICU from January 2012 to June 2014 were included if they exhibited sepsis at the time of BDG testing and they met Candida score components >=3. A retrospective analysis of collected data was performed. RESULTS: In total, 198 patients were studied. Of 63 BDG-positive patients, 47 with candidaemia and 16 with probable Candida infection, all [31.8% (63/198)] received antifungal therapy. Of 135 BDG negative patients, 110 [55.5% (110/198)] did not receive antifungal therapy, whereas 25 [12.6% (25/198)] were initially treated. Overall, antifungal therapy was started in 88 cases (44.4%), mostly with echinocandins. Antifungals were discontinued in 14 of 25 patients, as negative BDG results became available, and in 16 BDG-false-positive patients for whom subsequent findings allowed candidaemia (and other forms of invasive candidiasis) to be ruled out. Candidaemia was diagnosed only in one patient who did not receive prior antifungal therapy. The median antifungal therapy duration in candidaemic patients differed significantly from that in non-candidaemic patients [14 (IQR, 6 18) days versus 4 (IQR, 3-7) days; P < 0.001]. Using this approach, antifungal therapy was avoided in ~73% of potentially treatable patients and it was shortened in another ~20%. CONCLUSIONS: This study supports the use of serum BDG results in the management of systemic antifungal drug prescription in septic patients. These findings need to be confirmed in additional studies. PMID- 27125556 TI - The atlas network: a "strategic ally" of the tobacco industry. AB - Amid growing academic and policy interest in the influence of think tanks in public policy processes, this article demonstrates the extent of tobacco industry partnerships with think tanks in the USA, and analyzes how collaborating with a network of think tanks facilitated tobacco industry influence in public health policy. Through analysis of documents from tobacco companies and think tanks, we demonstrate that the Atlas Economic Research Foundation, a network of 449 free market think tanks, acted as a strategic ally to the tobacco industry throughout the 1990s. Atlas headquarters, while receiving donations from the industry, also channeled funding from tobacco corporations to think tank actors to produce publications supportive of industry positions. Thirty-seven per cent of Atlas partner think tanks in the USA received funding from the tobacco industry; the majority of which were also listed as collaborators on public relations strategies or as allies in countering tobacco control efforts. By funding multiple think tanks, within a shared network, the industry was able to generate a conversation among independent policy experts, which reflected its position in tobacco control debates. This demonstrates a coherent strategy by the tobacco industry to work with Atlas to influence public health policies from multiple directions. There is a need for critical analysis of the influence of think tanks in tobacco control and other health policy sectors, as well as greater transparency of their funding and other links to vested interests. (c) 2016 The Authors The International Journal of Health Planning and Management Published by John Wiley & Sons Ltd. PMID- 27125555 TI - LN-1-255, a penicillanic acid sulfone able to inhibit the class D carbapenemase OXA-48. AB - OBJECTIVES: Carbapenemases are the most important mechanism responsible for carbapenem resistance in Enterobacteriaceae. Among carbapenemases, OXA-48 presents unique challenges as it is resistant to beta-lactam inhibitors. Here, we test the capacity of the compound LN-1-255, a 6-alkylidene-2'-substituted penicillanic acid sulfone, to inhibit the activity of the carbapenemase OXA-48. METHODS: The OXA-48 gene was cloned and expressed in Klebsiella pneumoniae and Escherichia coli in order to obtain MICs in the presence of inhibitors (clavulanic acid, tazobactam and sulbactam) and LN-1-255. OXA-48 was purified and steady-state kinetics was performed with LN-1-255 and tazobactam. The covalent binding mode of LN-1-255 with OXA-48 was studied by docking assays. RESULTS: Both OXA-48-producing clinical and transformant strains displayed increased susceptibility to carbapenem antibiotics in the presence of 4 mg/L LN-1-255 (2-32 fold increased susceptibility) and 16 mg/L LN-1-255 (4-64-fold increased susceptibility). Kinetic assays demonstrated that LN-1-255 is able to inhibit OXA 48 with an acylation efficiency (k2/K) of 10 +/- 1 * 10(4) M(-1) s(-1) and a slow deacylation rate (koff) of 7 +/- 1 * 10(-4) s(-1). IC50 was 3 nM for LN-1-255 and 1.5 MUM for tazobactam. Lastly, kcat/kinact was 500-fold lower for LN-1-255 than for tazobactam. CONCLUSIONS: In these studies, carbapenem antibiotics used in combination with LN-1-255 are effective against the carbapenemase OXA-48, an important emerging mechanism of antibiotic resistance. This provides an incentive for further investigations to maximize the efficacy of penicillin sulfone inhibition of class D plasmid-carried Enterobacteriaceae carbapenemases. PMID- 27125557 TI - Ultrasound window-modulated compounding Nakagami imaging: Resolution improvement and computational acceleration for liver characterization. AB - Ultrasound Nakagami imaging is an attractive method for visualizing changes in envelope statistics. Window-modulated compounding (WMC) Nakagami imaging was reported to improve image smoothness. The sliding window technique is typically used for constructing ultrasound parametric and Nakagami images. Using a large window overlap ratio may improve the WMC Nakagami image resolution but reduces computational efficiency. Therefore, the objectives of this study include: (i) exploring the effects of the window overlap ratio on the resolution and smoothness of WMC Nakagami images; (ii) proposing a fast algorithm that is based on the convolution operator (FACO) to accelerate WMC Nakagami imaging. Computer simulations and preliminary clinical tests on liver fibrosis samples (n=48) were performed to validate the FACO-based WMC Nakagami imaging. The results demonstrated that the width of the autocorrelation function and the parameter distribution of the WMC Nakagami image reduce with the increase in the window overlap ratio. One-pixel shifting (i.e., sliding the window on the image data in steps of one pixel for parametric imaging) as the maximum overlap ratio significantly improves the WMC Nakagami image quality. Concurrently, the proposed FACO method combined with a computational platform that optimizes the matrix computation can accelerate WMC Nakagami imaging, allowing the detection of liver fibrosis-induced changes in envelope statistics. FACO-accelerated WMC Nakagami imaging is a new-generation Nakagami imaging technique with an improved image quality and fast computation. PMID- 27125558 TI - Anodic aluminum oxide-epoxy composite acoustic matching layers for ultrasonic transducer application. AB - The goal of this work is to demonstrate the application of anodic aluminum oxide (AAO) template as matching layer of ultrasonic transducer. Quarter-wavelength acoustic matching layer is known as a vital component in medical ultrasonic transducers to compensate the acoustic impedance mismatch between piezoelectric element and human body. The AAO matching layer is made of anodic aluminum oxide template filled with epoxy resin, i.e. AAO-epoxy 1-3 composite. Using this composite as the first matching layer, a ~12MHz ultrasonic transducer based on soft lead zirconate titanate piezoelectric ceramic is fabricated, and pulse-echo measurements show that the transducer exhibits very good performance with broad bandwidth of 68% (-6dB) and two-way insertion loss of -22.7dB. Wire phantom ultrasonic image is also used to evaluate the transducer's performance, and the results confirm the process feasibility and merit of AAO-epoxy composite as a new matching material for ultrasonic transducer application. This matching scheme provides a solution to address the problems existing in the conventional 0-3 composite matching layer and suggests another useful application of AAO template. PMID- 27125559 TI - Gasoline identifier based on SH0 plate acoustic waves. AB - The present paper is devoted to the development of gasoline identifier based on zero order shear-horizontal (SH0) acoustic wave propagating in piezoelectric plate. It has been found that the permittivity of gasoline is increased when its octane number rises. The development of such identifier is experimentally demonstrated to be possible. PMID- 27125560 TI - Optimal working frequency of ultrasonic motors. AB - In this work, the existence of the optimal working frequency for ultrasonic motors (USMs) is theoretically and experimentally verified for the first time, at which working point the power dissipation of the motors arrives at its minimum value. The mathematical model of the mechanical quality factor is initially deduced to evaluate the loss level, because it shows an opposite tendency with losses. The derivative of the mechanical quality factor can be subsequently arrived at with the aid of the phenomenon model of the phase of the admittance. The theoretical derivation infers that the maximum value of the mechanical quality factor exists almost around the average value of the frequency of maximum conductance and the frequency of maximum resistance. Then the input power of the USM is measured under the constant velocity condition, which is supposed to counteract the loss; that is, the loss can be therefore evaluated experimentally. Measurements infer that the power dissipation of the motor reaches the minimum value around the calculated optimal working frequency. In other word, it is proven that the USM maintains an optimal working frequency from the loss reduction view point. PMID- 27125561 TI - Development of a shear-force scanning near-field cathodoluminescence microscope for characterization of nanostructures' optical properties. AB - An original scanning near-field cathodoluminescence microscope for nanostructure characterization has been developed and successfully tested. By using a bimorph piezoelectric stack both as actuator and detector, the developed setup constitutes a real improvement compared to previously reported SEM-based solutions. The technique combines a scanning probe and a scanning electron microscope in order to simultaneously offer near-field cathodoluminescence and topographic images of the sample. Share-force topography and cathodoluminescence measurements on GaN, SiC and ZnO nanostructures using the developed setup are presented showing a nanometric resolution in both topography and cathodoluminescence images with increased sensitivity compared to classical luminescence techniques. PMID- 27125562 TI - Current and future trends in antibiotic therapy of acute bacterial skin and skin structure infections. AB - In 2013 the US Food and Drug Administration (FDA) issued recommendations and guidance on developing drugs for treatment of skin infection using a new definition of acute bacterial skin and skin-structure infection (ABSSSI). The new classification includes cellulitis, erysipelas, major skin abscesses and wound infection with a considerable extension of skin involvement, clearly referring to a severe subset of skin infections. The main goal of the FDA was to better identify specific infections where the advantages of a new antibiotic could be precisely estimated through quantifiable parameters, such as improvement of the lesion size and of systemic signs of infection. Before the spread and diffusion of methicillin-resistant Staphylococcus aureus (MRSA) in skin infections, antibiotic therapy was relatively straightforward. Using an empiric approach, a beta-lactam was the preferred therapy and cultures from patients were rarely obtained. With the emergence of MRSA in the community setting, initial ABSSSI management has been changed and readdressed. Dalbavancin, oritavancin and tedizolid are new drugs, approved or in development for ABSSSI treatment, that also proved to be efficient against MRSA. Dalbavancin and oritavancin have a long half-life and can be dosed less frequently. This in turn makes it possible to treat patients with ABSSSI in an outpatient setting, avoiding hospitalization or potentially allowing earlier discharge, without compromising efficacy. In conclusion, characteristics of long-acting antibiotics could represent an opportunity for the management of ABSSSI and could profoundly modify the management of these infections by reducing or in some cases eliminating both costs and risks of hospitalization. PMID- 27125563 TI - Retooling institutional support infrastructure for clinical research. AB - Clinical research activities at academic medical centers are challenging to oversee. Without effective research administration, a continually evolving set of regulatory and institutional requirements can divert investigator and study team attention away from a focus on scientific gain, study conduct, and patient safety. However, even when the need for research administration is recognized, there can be struggles over what form it should take. Central research administration may be viewed negatively, with individual groups preferring to maintain autonomy over processes. Conversely, a proliferation of individualized approaches across an institution can create inefficiencies or invite risk. This article describes experiences establishing a unified research support office at the Duke University School of Medicine based on a framework of customer support. The Duke Office of Clinical Research was formed in 2012 with a vision that research administration at academic medical centers should help clinical investigators navigate the complex research environment and operationalize research ideas. The office provides an array of services that have received high satisfaction ratings. The authors describe the ongoing culture change necessary for success of the unified research support office. Lessons learned from implementation of the Duke Office of Clinical Research may serve as a model for other institutions undergoing a similar transition. PMID- 27125564 TI - Charged hydrophilic polymer brushes and their relevance for understanding marine biofouling. AB - The resistance of charged polymers to biofouling was investigated by subjecting cationic (PDMAEMA), anionic (PSPMA), neutral (PHEMA-co-PEG10MA), and zwitterionic (PSBMA) brushes to assays testing protein adsorption; attachment of the marine bacterium Cobetia marina; settlement and adhesion strength of zoospores of the green alga Ulva linza; settlement of barnacle (Balanus amphitrite and B. improvisus) cypris larvae; and field immersion tests. Several results go beyond the expected dependence on direct electrostatic attraction; PSPMA showed good resistance towards attachment of C. marina, low settlement and adhesion of U. linza zoospores, and significantly lower biofouling than on PHEMA-co-PEG10MA or PSBMA after a field test for one week. PDMAEMA showed potential as a contact active anti-algal coating due to its capacity to damage attached spores. However, after field testing for eight weeks, there were no significant differences in biofouling coverage among the surfaces. While charged polymers are unsuitable as antifouling coatings in the natural environment, they provide valuable insights into fouling processes, and are relevant for studies due to charging of nominally neutral surfaces. PMID- 27125565 TI - Transfusion management of factor V deficiency: three case reports and review of the literature. AB - BACKGROUND: Factor V (FV) deficiency may be inherited as an autosomal recessive disease or acquired as a result of autoantibody formation, either spontaneously or secondary to exposure to bovine thrombin or medications. Congenital FV deficiency has traditionally been treated with plasma transfusions. However, recent evidence has suggested that platelet (PLT) transfusions may be a better alternative as FV stored within PLT alpha granules has greater procoagulant potential and is released locally at sites of vascular injury. We report three cases of FV deficiency, one congenital and two acquired, and emphasize the different management approaches. CASE REPORTS: Patient 1 was a 30-year-old man with congenital FV deficiency who presented with a trauma-induced hematoma of his lower extremity. He was treated with 5 PLT units over 48 hours. Patient 2 was a 64-year-old woman who presented with an upper-extremity thrombus and was discovered to have a FV inhibitor, likely secondary to antibiotics. Patient 3 was a 75-year-old woman with hepatitis C virus (HCV) who presented with minor ecchymosis and was found to have a FV inhibitor secondary to either HCV or antibiotic exposure. Corticosteroids alone were able to eradicate the inhibitors in both patients with acquired inhibitors. CONCLUSIONS: FV deficiency can present with a diverse range of symptoms. For bleeding patients, PLT transfusions should be the initial therapy. In patients with thrombosis, the risks and benefits of anticoagulation must be carefully assessed before treatment. For patients with minor bleeds, transfusions may be withheld, and elimination of the inhibitor should be the primary objective. PMID- 27125566 TI - Regulation of ecmF gene expression and genetic hierarchy among STATa, CudA, and MybC on several prestalk A-specific gene expressions in Dictyostelium. AB - STATa, a Dictyostelium homologue of metazoan signal transducer and activator of transcription, is important for the organizer function in the tip region of the migrating Dictyostelium slug. We previously showed that ecmF gene expression depends on STATa in prestalk A (pstA) cells, where STATa is activated. Deletion and site-directed mutagenesis analysis of the ecmF/lacZ fusion gene in wild-type and STATa null strains identified an imperfect inverted repeat sequence, ACAAATANTATTTGT, as a STATa-responsive element. An upstream sequence element was required for efficient expression in the rear region of pstA zone; an element downstream of the inverted repeat was necessary for sufficient prestalk expression during culmination. Band shift analyses using purified STATa protein detected no sequence-specific binding to those ecmF elements. The only verified upregulated target gene of STATa is cudA gene; CudA directly activates expL7 gene expression in prestalk cells. However, ecmF gene expression was almost unaffected in a cudA null mutant. Several previously reported putative STATa target genes were also expressed in cudA null mutant but were downregulated in STATa null mutant. Moreover, mybC, which encodes another transcription factor, belonged to this category, and ecmF expression was downregulated in a mybC null mutant. These findings demonstrate the existence of a genetic hierarchy for pstA-specific genes, which can be classified into two distinct STATa downstream pathways, CudA dependent and independent. The ecmF expression is indirectly upregulated by STATa in a CudA-independent activation manner but dependent on MybC, whose expression is positively regulated by STATa. PMID- 27125567 TI - [Impact of the Pharmaceutical Copayment Reform on the Use of Antidiabetics, Antithrombotics and for Chronic Obstructive Airway Disease Agents, Spain]. AB - OBJECTIVE: In 2012 it changed the Spanish legislation regulating the pharmaceutical copayment by the National Health System (NHS). The objective was to know if the Spanish pharmaceutical copayment reform in 2012 has affected drugs consumptions for chronic diseases such as antidiabetics, antithrombotics and agents against obstructive conditions of the respiratory tract. METHODS: Retrospective longitudinal observational study, using general segmented linear regression models for interrupted time series. The variables analyzed were the number of defined daily doses (DDDs) and the amount corresponding to public funding and not public funding from the (NHS) since September 2010 to August 2015 (T=60). RESULTS: The estimated variation rate of DDDs is negative but decreasing for the three therapeutic subgroups at 6, 12, 24 and 38 months after the intervention: -0.1% for antidiabetics after 6 months and 0.3% after 38 months; 3.7% for antithrombotics after 6 months and -4.6% after 38 months; -2.7% for asthma and COPD drugs after 6 months and -1.3% after 38 months. A sustained and significant reduction in expenditure was estimated only in the subgroup of asthma and COPD drugs: -5.2% after 6 months, -7.0% after 12 months and after 24 months, and -6.2% after 38 months. CONCLUSIONS: The pharmaceutical copayment reform of 2012 led to an immediate and significant reduction in the number of DDDs of all three therapeutic subgroups selected in this study. This level effect is not permanent, as it is accompanied by a change in the growth trend in the post intervention months, which has partly offset the effect on the level. PMID- 27125568 TI - Si-nanocrystal-based nanofluids for nanothermometry. AB - The measurement of local temperature in nanoscale volumes is becoming a technological frontier. Photoluminescent nanoparticles and nanocolloids are the natural choice for nanoscale temperature probes. However, the influence of a surrounding liquid on the cryogenic behavior of oxidized Si-nanocrystals (Si-NCs) has never been investigated. In this work, the photoluminescence (PL) of oxidized Si-NCs/alcohol based nanocolloids is measured as a function of the temperature and the molecule length of monohydric alcohols above their melting-freezing point. The results unveil a progressive blue shift on the emission peak which is dependent on the temperature as well as the dielectric properties of the surrounding liquid. Such an effect is analyzed in terms of thermal changes of the Si-NCs bandgap, quantum confinement and the polarization effects of the embedding medium; revealing an important role of the dielectric constant of the surrounding liquid. These results are relevant because they offer a general insight to the fundamental behavior of photoluminescent nanocolloids under a cooling process and moreover, enabling PL tuning based on the dielectric properties of the surrounding liquid. Hence, the variables required to engineer PL of nanofluids are properly identified for use as temperature sensors at the nanoscale. PMID- 27125569 TI - Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin. AB - Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes. PMID- 27125570 TI - Exogenous cesarean scar pregnancies managed by suction curettage alone or in combination with other therapeutic procedures: A series of 33 cases and analysis of complication profile. AB - AIM: The aim of this study was to review our exogenous cesarean scar pregnancy (CSP) cases that were managed through transabdominal ultrasound (TAUS)-guided suction curettage either alone or with a concomitant additional therapeutic modality. The study was carried out over a 6-year period and we compared clinical outcomes, success rates and complication profiles between the two therapeutic approaches. METHODS: A total of 33 exogenous CSP patients who were managed by suction curettage were extracted from the medical records. The patients were analyzed according to the intervention applied in the two groups as: TAUS-guided suction curettage alone (Group 1); and additional therapeutic tools, such as systemic or intracavitary administration of methotrexate and intracavitary ethanol instillation, in combination with suction curettage (Group 2). Basic demographic and clinical characteristics of women experiencing hemorrhagic complications and those who did not after the treatment were also compared. RESULTS: There were no cases of uterine perforation, hysterectomy or unresponsiveness to treatment in our analyzed CSP cases. Four patients, two in each group, required blood transfusion. Our success rate in the overall patient population was 87.8% (29/33). Fourteen out of 16 patients who were treated with TAUS-guided suction curettage alone, and 15 out of 17 patients who received other interventional treatment modalities preceding suction curettage revealed successful resolution of the CSP without any complication (P = 0.948). Clinical and demographic characteristics of women who experienced any hemorrhagic complication did not significantly differ from those who did not. CONCLUSION: In appropriate CSP cases, TAUS-guided suction curettage appears to be a reliable treatment option with acceptable success rates and similar complication profile to other therapeutic options. PMID- 27125571 TI - Heads Up: a pilot trial of a psychological intervention to improve nutrition in head and neck cancer patients undergoing radiotherapy. AB - Malnutrition in head and neck cancer (HNC) patients is common and associated with poorer radiotherapy outcomes including increased mortality. This pilot trial investigates the feasibility and effectiveness of a psychological intervention to improve nutritional status, depression and mortality in HNC patients undergoing radiotherapy. Fifty-nine intervention patients received motivational interviewing and cognitive behavioural therapy compared to 70 historical controls who received treatment as usual. Participants were assessed for nutrition, depression and mortality. There were no significant differences between groups in nutritional status, depression or mortality. Subgroup analyses among patients at greater nutritional risk (cancers of the oral cavity, pharynx, larynx) revealed a potentially clinically important reduction on the PG-SGA and lower mortality (31% of controls vs. 16% intervention; P = 0.03) in favour of the intervention condition. Potential benefits in nutritional status and in mortality in this pilot trial of a psychological intervention among HNC patients at high nutritional risk suggest that a larger randomised controlled trial is warranted. PMID- 27125572 TI - Real-time estimation of the hospitalization fatality risk of influenza A(H1N1)pdm09 in Hong Kong. AB - During the early stage of an epidemic, timely and reliable estimation of the severity of infections are important for predicting the impact that the influenza viruses will have in the population. We obtained age-specific deaths and hospitalizations for patients with laboratory-confirmed H1N1pdm09 infections from June 2009 to December 2009 in Hong Kong. We retrospectively obtained the real time estimates of the hospitalization fatality risk (HFR), using crude estimation or allowing for right-censoring for final status in some patients. Models accounting for right-censoring performed better than models without adjustments. The risk of deaths in hospitalized patients with confirmed H1N1pdm09 increased with age. Reliable estimates of the HFR could be obtained before the peak of the first wave of H1N1pdm09 in young and middle-aged adults but after the peak in the elderly. In the next influenza pandemic, timely estimation of the HFR will contribute to risk assessment and disease control. PMID- 27125573 TI - The treatment of HCV in patients with haemoglobinopathy in Kurdistan Region, Iraq: a single centre experience. AB - Various variables that might influence the rapid and sustained virological response to recombinant PEG-IFN-alpha-2a were explored in Iraqi HCV-infected patients with haemoglobinopathy. Forty-three patients were evaluated for the relationship between rapid virological response (RVR), IL-28B polymorphism, viral load, liver enzyme levels, blood group, ultrasound findings, or HCV genotype and the sustained virological response (SVR) achievement. The overall RVR was 55.81% while the overall SVR was 53.49%. SVR in patients that achieved RVR was 82.61% (P = 0.0004). A significant association was found between initial alanine transaminase levels and viral load with SVR achievement (P = 0.025) and (P = 0.004), respectively. Thirty-two (74%) out of 43 of our samples were host genotyped at the IL-28B locus as CC, a significant association was found between CC group and SVR achievement (P = 0.04). Of our samples, 23/43 (53%) were typed as HCV genotype 4, 10/43 (23%) as genotype 1, 9/43 (20.9%) as genotype 3 and 1/43 (2.3%) as genotype 2. A significant association was found between genotype 3 and SVR achievement (P = 0.006). Multivariate analysis showed that only RVR achievement independently associated with SVR in the Iraqi population (P = 0.00). These results can be used to classify the patients requiring the more expensive new direct-acting antiviral drugs. PMID- 27125575 TI - Evolving epidemiology of reported cryptosporidiosis cases in the United States, 1995-2012. AB - Cryptosporidium is the leading aetiology of waterborne disease outbreaks in the United States. This report briefly describes the temporal and geographical distribution of US cryptosporidiosis cases and presents analyses of cryptosporidiosis case data reported in the United States for 1995-2012. The Cochran-Armitage test was used to assess changes in the proportions of cases by case status (confirmed vs. non-confirmed), sex, race, and ethnicity over the study period. Negative binomial regression models were used to estimate rate ratios (RR) and 95% confidence intervals (CI) for comparing rates across three time periods (1995-2004, 2005-2008, 2009-2012). The proportion of confirmed cases significantly decreased (P < 0.0001), and a crossover from male to female predominance in case-patients occurred (P < 0.0001). Overall, compared to 1995 2004, rates were higher in 2005-2008 (RR 2.92, 95% CI 2.08-4.09) and 2009-2012 (RR 2.66, 95% CI 1.90-3.73). However, rate changes from 2005-2008 to 2009-2012 varied by age group (P interaction < 0.0001): 0-14 years (RR 0.55, 95% CI 0.42 0.71), 15-44 years (RR 0.99, 95% CI 0.82-1.19), 45-64 years (RR 1.47, 95% CI 1.21 1.79) and ?65 years (RR 2.18, 95% CI 1.46-3.25). The evolving epidemiology of cryptosporidiosis necessitates further identification of risk factors in population subgroups. Adding systematic molecular typing of Cryptosporidium specimens to US national cryptosporidiosis surveillance would help further identify risk factors and markedly expand understanding of cryptosporidiosis epidemiology in the United States. PMID- 27125574 TI - Patient-level analysis of incident vancomycin-resistant enterococci colonization and antibiotic days of therapy. AB - Vancomycin-resistant enterococci (VRE) infections are a public health threat associated with increased patient mortality and healthcare costs. Antibiotic usage, particularly cephalosporins, has been associated with VRE colonization and VRE bloodstream infections (VRE BSI). We examined the relationship between antimicrobial usage and incident VRE colonization at the individual patient level. Prospective, weekly surveillance was undertaken for incident VRE colonization defined by negative admission but positive surveillance swab in a medical intensive care unit over a 17-month period. Antimicrobial exposure was quantified as days of therapy (DOT)/1000 patient-days. Multiple logistic regression was used to analyse incident VRE colonization and antibiotic DOT, controlling for demographic and clinical covariates. Ninety-six percent (1398/1454) of admissions were swabbed within 24 h of intensive care unit (ICU) arrival and of the 380 patients in the ICU long enough for weekly surveillance, 83 (22%) developed incident VRE colonization. Incident colonization was associated in bivariate analysis with male gender, more previous hospital admissions, longer previous hospital stay, and use of cefepime/ceftazidime, fluconazole, azithromycin, and metronidazole (P < 0.05). After controlling for demographic and clinical covariates, metronidazole was the only antibiotic independently associated with incident VRE colonization (odds ratio 2.0, 95% confidence interval 1.2-3.3, P < 0.009). Our findings suggest that risk of incident VRE colonization differs between individual antibiotic agents and support the possibility that antimicrobial stewardship may impact VRE colonization and infection. PMID- 27125576 TI - Cobalt-Nanocrystal-Assembled Hollow Nanoparticles for Electrocatalytic Hydrogen Generation from Neutral-pH Water. AB - Highly active and stable electrocatalysts for hydrogen generation from neutral-pH water are highly desired, but very difficult to achieve. Herein we report a facile synthetic approach to cobalt nanocrystal assembled hollow nanoparticles (Co-HNP), which serve as an electrocatalyst for hydrogen generation from neutral pH water. An electrode composed of Co-HNP on a carbon cloth (CC) produces cathodic current densities of 10 and 100 mA cm(-2) at overpotentials of -85 mV and -237 mV, respectively. The Co-HNP/CC electrode retains its high activity after 20 h hydrogen generation at a high current density of 150 mA cm(-2) , indicating the superior activity and stability of Co-HNP as electrocatalyst. PMID- 27125577 TI - The experience of patients admitted to hospital with acute low back pain: a qualitative study. AB - AIM: To understand the patient experience of being admitted to hospital with acute low back pain (LBP), with a view to developing suggestions for care and LBP management guidelines. METHOD: Interpretive phenomenological analysis (IPA) was adopted to examine semi-structured interviews from patients admitted to hospital with acute LBP. Sampling continued until thematic saturation was reached (n = 14). Data were analyzed using the Framework Method, so that data from multiple participants could be systematically summarized, compared, and analyzed. RESULTS: Four themes were identified: pain and helplessness, desire for validation, interactions with healthcare teams, and a return to pre-morbid identity and roles. Patients' initial presentation to hospital was characterized by severe pain, disability and difficulty in communicating their illness experience. Patients expected doctors to investigate for an underlying cause of the back pain. To recover, they were required to navigate a system they did not understand, interacting with healthcare workers who seemed to operate independently rather than as a team. Patients viewed medical treatment as a means of returning to pre-morbid activities of daily living, roles and relationships. Using these themes, a model of the inpatient journey was developed. CONCLUSION: We have described new patient insights which highlight how the hospital environment adds unique challenges to managing acute LBP. Several suggestions for acute LBP management guidelines are made: developing lay summaries for patients, including methods for communicating the team structure and roles to patients, and ensuring all members of treating teams are educated to ensure guidelines are consistently implemented. PMID- 27125578 TI - Classification of infantile nystagmus waveforms. AB - Classification of infantile nystagmus waveforms is an important problem because the characteristic waveforms can be used to distinguish between infantile and acquired nystagmus. A clear description of the nystagmus is also a necessary first stage in understanding its origin. Currently infantile nystagmus waveforms are classified into at least 12 different types. In this study we analyse a database of nystagmus recordings in order to investigate if this classification can be simplified. Application of principal components analysis revealed that 96.9% of the variance of the waveforms is described by a linear sum of two component waveforms. The components consist of sawtooth and pseudocycloid waveforms that account for 78.7% and 18.2% of the variance respectively for the most common single cycle waveforms. This simplified description of infantile nystagmus highlights the importance of identifying the origin of the jerk component and its synchronisation with the pseudocycloid component for the characterisation and treatment of the nystagmus. PMID- 27125579 TI - Physicians' experiences and views on the role of obstetric ultrasound in rural and urban Rwanda: a qualitative study. AB - OBJECTIVE: To explore Rwandan physicians' experiences and views on the role of obstetric ultrasound in clinical management of pregnancy, and in situations where maternal and fetal health interests conflict. METHODS: Physicians (n = 19) in public and private health facilities in urban and rural Rwanda were interviewed in 2015 as part of the CROss-Country Ultrasound Study (CROCUS). Data were analysed qualitatively. RESULTS: Ultrasound was described as an important tool in maternity care. Availability and quality of equipment varied across sites, and considerable disparities in obstetric ultrasound utilisation between rural and urban areas were described. The physicians wanted more ultrasound training and saw the potential for midwives to perform basic scans. Information about fetal sex and well-being was described as women's main expectations of ultrasound. Although women's right to autonomy in pregnancy was supported in principle by participating physicians, fetal rights were sometimes seen as needing physician 'protection'. CONCLUSIONS: There appears to be increasing use and demand for obstetric ultrasound in Rwanda, particularly in urban areas. It seems important to monitor this development closely to secure wise and fair allocation of scarce obstetric expertise and resources and to prevent overuse or misuse of ultrasound. Raising awareness about the benefits of all aspects of antenatal care, including ultrasound may be an important step to improve pregnant women's uptake of services. Increased opportunities for formal ultrasound training, including the training of midwives to perform basic scans, seem warranted. Moreover, in parallel with the transition to more medico-technical maternity care, a dialogue about maternal rights to autonomy in pregnancy and childbirth is imperative. PMID- 27125580 TI - Pulmonary Artery Perforation After Chest Tube Insertion. PMID- 27125581 TI - Self-expanding y stent for the treatment of malignant tracheobronchial stenosis. Retrospective study. AB - Palliation of malignant tracheobronchial stenosis is challenging. Published experience with self-expanding Y-shaped stents is limited and it seems necessary to evaluate whether they improve clinical results with respect to alternative prostheses. We present a retrospective case series of 20 consecutive patients with malignant tracheobronchial stenosis that underwent placement of a single unit, Y-shaped covered metallic stent. Outcomes were: safety of the procedure, palliation of dyspnea, complications, and survival. All stents were safely and easily placed using a rigid tracheoscope within 24hours of admission. Dyspnea was effectively palliated in all patients, and no early or late adverse stent-related events were observed. Thirty-day mortality was 40%. Median survival was 12.2 weeks. Placement of Y-shaped self-expanding stents is a safe and effective procedure for the palliation of malignant tracheobronchial stenosis, and is currently our stent of choice for this subgroup of patients. PMID- 27125582 TI - Asthma, Chronic Obstructive Pulmonay Disease and Other Combinations. PMID- 27125583 TI - Notes on Recurrence and Second Tumors in Lung Cancer. PMID- 27125584 TI - Gene expression changes in the tyrosine metabolic pathway regulate caste-specific cuticular pigmentation of termites. AB - In social insects, all castes have characteristic phenotypes suitable for their own tasks and to engage in social behavior. The acquisition of caste-specific phenotypes was a key event in the course of social insect evolution. However, understanding of the genetic basis and the developmental mechanisms that produce these phenotypes is still very limited. In particular, termites normally possess more than two castes with specific phenotypes (i.e. workers, soldiers, and reproductives), but proximate developmental mechanisms are far from being fully understood. In this study, we focused on the pigmentation of the cuticle as a model trait for caste-specific phenotypes, during the molts of each caste; workers, soldiers, presoldiers (intermediate stage of soldiers), and alates (primary reproductives) in Zootermopsis nevadensis. Expression patterns of cuticular tanning genes (members of the tyrosine metabolic pathway) were different among each molt, and high expression levels of several "key genes" were observed during each caste differentiation. For the differentiation of castes with well-tanned cuticles (i.e. soldiers and alates), all focal genes except DDC in the former were highly expressed. On the other hand, high expression levels of yellow and aaNAT were observed during worker and presoldier molts, respectively, but most other genes in the pathway were expressed at low levels. RNA interference (RNAi) of these key genes affected caste-specific cuticular pigmentation, leading to soldiers with yellowish-white heads and pigmented mandibular tips, presoldiers with partly pigmented head cuticles, and alates with the yellow head capsules. These results suggest that the pigmentation of caste specific cuticles is achieved by the regulation of gene expression in the tyrosine metabolic pathway. PMID- 27125585 TI - Ageing through an evolutionary, transdisciplinary, lens. PMID- 27125586 TI - Quantum hyperparallel algorithm for matrix multiplication. AB - Hyperentangled states, entangled states with more than one degree of freedom, are considered as promising resource in quantum computation. Here we present a hyperparallel quantum algorithm for matrix multiplication with time complexity O(N(2)), which is better than the best known classical algorithm. In our scheme, an N dimensional vector is mapped to the state of a single source, which is separated to N paths. With the assistance of hyperentangled states, the inner product of two vectors can be calculated with a time complexity independent of dimension N. Our algorithm shows that hyperparallel quantum computation may provide a useful tool in quantum machine learning and "big data" analysis. PMID- 27125587 TI - Role of Fusobacteria in the serrated pathway of colorectal carcinogenesis. AB - Fusobacteria are associated with colorectal cancer (CRC) and are amplified during colorectal carcinogenesis. Compared to the adenoma-carcinoma sequence of carcinogenesis, serrated neoplasm has distinct clinical features and a different molecular background. We aimed to compare the gut microbiome between tubular adenoma (TA) and sessile serrated adenoma/polyp (SSA/P). Patients with TA, SSA/P, or CRC were recruited. Three pieces of colorectal mucosal tissue were obtained from each patient by endoscopic biopsy. 16S rRNA gene pyrosequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) were performed. Among 26 enrolled patients, 8, 10, and 8 had TA, SSA/P, and CRC, respectively. The relative abundance of Fusobacteria did not differ significantly between the TA and SSA/P groups (4.3% and 1.9%, P = 0.739) but was higher in the CRC group (33.8%) than in the TA or SSA/P group, respectively (TA vs. CRC, P = 0.002, false discovery rate [FDR] = 0.023; SSA/P vs. CRC, P < 0.001, FDR = 0.001). PICRUSt revealed that most functions in the TA metagenome were similar to those in the SSA/P metagenome. The gut microbiome, including relative abundance of Fusobacteria, did not differ between TA and SSA/P, suggesting that Fusobacteria may contribute to both the serrated pathway and the adenoma carcinoma sequence. PMID- 27125588 TI - Modulator effect of a polysaccharide-rich extract from Caesalpinia ferrea stem barks in rat cutaneous wound healing: Role of TNF-alpha, IL-1beta, NO, TGF-beta. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In folk medicine stem barks of Caesalpinia ferrea (Caesalpinioideae) are used to treat enterocolitis, rheumatism and wounds and in experimental procedures, its aqueous extracts demonstrated antiulcer, anti inflammatory, analgesic, and healing effects. AIM OF THE STUDY: The healing mechanism of the polyssacharide-rich extract of C. ferrea stem barks (TPL-Cf) was investigated in a model of excisional cutaneous wound in Wistar rats. MATERIALS AND METHODS: Excisional wounds received topical treatment with TPL-Cf (0.025 0.1%) during 21 days. Hypernociception, macroscopical, histological and immunohistochemical parameters were evaluated and analyzed by ANOVA, Bonferroni and Kruskal-Wallis tests, followed by Dunn and Chi-Square tests. RESULTS: TPL-Cf (0.1%) reduced wound area and hypernociception, and increased wound contraction. TPL-Cf reduced leukocyte infiltration and vascular permeability, and stimulated fibroblasia, angiogenesis, well formed granulation tissue, collagen deposition and epithelial layer formation. TPL-Cf reduced TNF-alpha expression and the levels of PGE2 (73%-day 5), IL-1 (42%-day 2), MDA (38%-day 5), total protein (53% day 2; 73%-day 5) and MPO activity (53%-day 2), but increased the expression of i NOS (days 5 and 7), TGF-beta (day 5) and the levels of NO (3.6 fold-day 5). CONCLUSION: The polysaccharide-rich extract of C. ferra stem barks accelerates wound healing by the control of the inflammatory phase and attenuates hypernociception via modulation of inflammatory mediators (TNF-alpha, IL-1beta, NO, TGF-beta). PMID- 27125589 TI - The beneficial potential of polyphenol-enriched fraction from Erigerontis Herba on metabolic syndrome. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Erigerontis Herba is a Chinese herb that is traditionally used to treat cardiovascular disease. Recent literatures suggested that it could exert beneficial effects on various cardiovascular metabolic risk factors including hypertension and hyperlipidemia in order to exert its cardio protective effects. AIM: Erigerontis Herba contains a variety of flavonoids and polyphenols that are bioactive. The aim of the present study was to investigate the cardio-protective effects of the total polyphenols of Erigerontis Herba (EHP), particularly on the metabolic parameters which could contribute to metabolic syndrome including obesity, hepatic steatosis, hyperlipidemia and hypertension. MATERIALS AND METHODS: C57Bl/6 metabolic syndrome mice model was used to determine the effects of EHP on metabolic syndrome. High-fat diet-induced metabolic syndrome in C57Bl/6 mice is an animal model which mimics human metabolic syndrome. The model is achieved by high-fat diet feeding to C57Bl/6 mice for 8 weeks. In our study, the mice were divided into 3 groups and fed for 8 weeks with: 1) normal chow (N); 2) high-fat diet (HF); or 3) high-fat diet supplemented with 2% EHP (HF+EHP). Various parameters such as body weight, adipose tissue weight and liver weight were measured. Liver and plasma lipid levels were also determined. In addition, the effect of EHP on vasodilation in Sprague Dawley rats was also determined using ex vivo aortic ring model. RESULTS: Various types of adipose tissues weights were significantly lowered in HF+EHP vs HF mice. Hepatic lipid levels were also significantly decreased by EHP vs HF. For plasma lipid (including TC and TG), EHP exerted no significant effects on plasma lipid levels. To understand the mechanisms as to how EHP regulated lipid metabolism via liver, various hepatic gene expressions were also measured using real-time PCR. The results showed that EHP regulated the expressions of Cyp7alpha1, CD36 and PPAR-gamma. EHP showed significant vasodilative effects in both intact aortas and endothelium-removed aortas. Further mechanistic studies indicated that EHP dilated aorta endothelium-dependently through nitric oxide synthase (NOS) pathway, and endothelium-independently through BKca, Kv and Kir channels. In addition to the vasodilative effects, EHP could also inhibit aorta contraction through Ca(2+) channel. CONCLUSIONS: EHP exerted promising effects on diet-induced obesity and hepatic steatosis in C57Bl/6 mice model. It also exerted significant vasodilative effect ex vivo, suggesting the potential of EHP to be developed as a dietary supplement for metabolic syndrome. PMID- 27125591 TI - Potent in vitro anti-proliferative, apoptotic and anti-oxidative activities of semi-purified Job's tears (Coix lachryma-jobi Linn.) extracts from different preparation methods on 5 human cancer cell lines. AB - ETHONOPHARMACOLOGICAL RELEVANCES: Job's tears (Coix lacryma-jobi Linn.) is commonly used as an herbal medicine. The low incidence of cancer has been observed in the area of China where regularly consume Job's tears. The effects of preparation methods of Job's tears on anti-cancer activities were investigated. Potent in vitro anti-proliferative, apoptotic and anti-oxidative activities of semi-purified Job's tears extracts from different preparation methods on 5 human cancer cell lines comparing with standards and commercial product were observed. AIM OF STUDY: To study the anti-proliferative, apoptotic and anti-oxidative activities of semi-purified Job's tear extracts from different preparation methods on 5 human cancer cell lines. MATERIALS AND METHODS: The crude methanolic extracts of non-cooked, steamed and roasted Job's tears cultivars were prepared and further semi-purified by liquid-liquid extraction techniques. Both of crude and semi-purified extracts were tested for anti-proliferative, apoptotic induction, anti-oxidative activities and phytochemicals content. RESULTS: The highest yields of crude and-purified extracts were 4.60% and 1.46%, respectively. In crude extracts, the steamed whole Thai Black Loei Job's tears (W-TBL-S1) extract showed the highest anti-proliferative activity in mouth epidermal carcinoma cell (KB) at the IC50 of 43.61+/-0.76MUg/ml (0.005 folds of doxorubicin), whereas the roasted whole Laos White Loei Job's tears (W-LWL-R2) extract showed the highest apoptotic activity in cervical adenocarcinoma (HeLa) at 21.52+/-1.50% (0.22 and 15.05 folds of doxorubicin and commercial product, respectively). After liquid-liquid extraction, almost all of the semi-purified extracts showed increases in anti-proliferative activity. Ethyl acetate fraction of the roasted whole Laos White Loei Job's tears (W-LWL-R2) showed the highest anti-proliferative activity in HeLa cell at the IC50 of 0.97+/-0.82MUg/ml (7.82 and 45.39 folds of doxorubicin and crude extract, respectively) and apoptotic activity of 18.77+/-6.31% (0.19 folds of doxorubicin). The commercial product showed no anti-proliferative activity in all cell lines but induced apoptosis in HeLa cell at 1.43+/-0.34%. The butanol and hexane soluble fractions of the roasted whole of Laos White Loei Job's tears (W-LWL-R2) showed the highest free radical scavenging (SC50) and metal chelating activity (MC50) of 0.31+/-0.06mg/ml (0.64 folds of ascorbic acid) and 0.08+/-0.01mg/ml (6.37 folds of EDTA), respectively. All ethyl acetate fractions contain high content of carotenoid and tannin, whereas the hexane soluble fraction of the roasted hull of Laos Black Loei Job's tears (H-LBL-R1) showed the highest linoleic acid content of 8.09+/ 0.74% w/w. CONCLUSIONS: This study has demonstrated the potent anti-cancer activity of the semi-purified extracts from roasted Job's tears with high potential for further development to modern anti-cancer drug. PMID- 27125590 TI - Efficacy and short-term safety of topical Dwarf Elder (Sambucus ebulus L.) versus diclofenac for knee osteoarthritis: A randomized, double-blind, active-controlled trial. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sambucus ebulus L. (S. ebulus) has had long standing application in Traditional Persian Medicine for joint pain and for a variety of bone and joint disorders. According to traditional use of S. ebulus and its relevant pharmacologic properties, this study was designed to evaluate the efficacy and short-term safety of topical use of S. ebulus in patients with knee osteoarthritis (OA). METHODS AND MATERIALS: Seventy nine patients with knee OA were randomly enrolled in 2 parallel arms of a pilot randomized, double-blind, active-controlled clinical trial. The patients were treated by topical S. ebulus gel or 1% diclofenac gel, three times a day, as much as a fingertip unit for 4 weeks. Patients were assessed prior to enrollment and, then, 2 and 4 weeks subsequent to the intervention, in terms of scores of visual analogue scale (VAS) for self-grading of their knee joint pain, and according to 3 different domains of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. Any observed adverse effects were also scrutinized. RESULTS: The mean values of WOMAC pain score, total WOMAC score and VAS score for pain of the S. ebulus group were significantly lower compared with the diclofenac group (P=0.004, P=0.04, and P<0.001, respectively). In addition, no serious adverse effect was reported. CONCLUSION: This pilot study showed that topical treatment with S. ebulus gel can be recommended for alleviating symptoms of patients with knee OA. However, longer trials involving larger samples size, are needed for achieving a comprehensive understanding about the efficacy and safety of S. ebulus in knee OA. PMID- 27125592 TI - Anti-inflammatory and toxicological evaluation of Moussonia deppeana (Schldl. & Cham) Hanst and Verbascoside as a main active metabolite. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Moussonia deppeana, known as Tlachichinole, is a Mexican medicinal plant used for treatment of inflammatory diseases, influenza, diarrhea, gastrointestinal disorders and arthritis. AIM OF THE STUDY: In this paper the antioxidant and anti-inflammatory activities as well as the acute and sub-acute toxicological effects were evaluated for the ethanolic extract from aerial parts of M. deppeana, also its phytochemical analysis is described. MATERIALS AND METHODS: Phytochemical analysis and compound isolation were performed with thin layer chromatography. The chemical identification of the main compound was performed by (1)H NMR (COSY, NOESY, HSQC and HMBC) spectra. In vitro antioxidant capacity and total phenolic content for the ethanolic extract and its primary fractions was determined by DPPH and Folin-Ciocalteu reagent. Acute and subacute toxicity tests were evaluated on Balb/C mice. Finally acute anti inflammatory evaluation was tested for a local (TPA) and systemic (carrageenan) murine model. RESULTS: The main compound isolated from the ethanolic extract of M. deppeana was Verbascoside, which was isolated from F3 and was identified by (1)H NMR and COSY data. Furthermore oleanolic and ursolic acids were isolated from primary fractions F1 and F2. Ethanolic extract showed IC50 = 6.71mg/mL for DPPH test and 664.12ug QE/mL for the total phenolic content. The LD50 value was >2g/kg by i.g. route in male and female mice. Sub-acute administration (28 days) of the ethanolic extract (1g/kg) did not cause lethality or alter any hematological and biochemical parameters, in addition, histological analysis of the major organs exhibited no structural changes. Anti-inflammatory activity of the ethanolic extract showed an ED50 = 1.5mg/ear and 450mg/kg for TPA and carrageenan test, respectively. Primary fractions generated moderate local and systemic anti-inflammatory activity. CONCLUSION: The ethanolic extract from the aerial parts of M. deppeana did not cause any lethality or adverse effect in either of the acute and sub-acute toxicity tests. This exhibited an important local and systemic anti-inflammatory activity and also moderate antioxidant capacity. Moreover, the primary fraction F2 was more active for the TPA model while the primary fraction F3 was most active in the carrageenan model in vivo. The main compound isolated from F3 was verbascoside; on the other hand also ursolic and oleanolic acids were isolated from F1 and F2. PMID- 27125593 TI - Atheroprotective effects of Cuphea carthagenensis (Jacq.) J. F. Macbr. in New Zealand rabbits fed with cholesterol-rich diet. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Although Cuphea carthagenensis (Jacq.) J. F. Macbr. is used in Brazilian folk medicine in the treatment of atherosclerosis and circulatory disorders, no study evaluating these effects has been conducted. The aim of this study was to evaluate the possible hypolipemiant and antiatherogenic activity of the ethanol soluble fraction obtained from C. carthagenensis (ES-CC) in an experimental atherosclerosis model using New Zealand (NZ) rabbits undergoing cholesterol-rich diet (CRD). MATERIAL AND METHODS: Dyslipidemia and atherogenesis were induced by administration of standard commercial diet increased of 1% cholesterol (CRD) for 8 weeks. ES-CC was orally administered at doses of 10, 30 and 100mg/kg, once daily for four weeks, starting from the 4th week of CRD diet. Body weight measurements were weekly carried out from the beginning of experiments for 8 weeks. Serum levels of triglyceride (TG), total cholesterol (TC) and their fractions (LDL-C, VLDL-C and HDL-C) were measured at the beginning of experiments and at weeks four and eight. After euthanasia of rabbits, aorta segments (aortic arc, thoracic, abdominal and iliac segments) were macroscopically and microscopically evaluated and the intima and media layers of the arteries were measured. Additionally, the antioxidant activity of ES-CC and its influence on the functioning of hepatic antioxidant enzymes were also determined. RESULTS: CRD induced dyslipidemia and major structural changes in the aortic wall. In addition, an increase in lipid peroxidation and a reduction of hepatic glutathione and serum nitrite levels were observed. Treatment with ES-CC was able to prevent the increase in TC, LDL-C, VLDL-C levels and triglycerides and promoted an increase in HDL-C levels in NZ rabbits. These effects were accompanied by a significant reduction in oxidative stress and modulation of the catalase and superoxide dismutase function. Moreover, the intima and media layers of the arterial segments were significantly reduced by ES-CC treatment. CONCLUSIONS: This study demonstrated that ES-CC reduces serum lipids and hepatic oxidative stress when orally administered to NZ rabbits. In addition, it was able to prevent the development of CRD-induced atherosclerosis. PMID- 27125594 TI - Complementary and alternative medicine use among cancer patients in Palestine with special reference to safety-related concerns. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of CAM including herbal medicine as the most preferred CAM modality, among cancer patients who are taking prescription medications has shown to be highly prevalent worldwide as well as in several Middle Eastern countries, with a high percentage of the patients do not disclose their CAM use to treating physician. AIM OF THE STUDY: The current study aimed to evaluate the patterns of CAM use among two cohorts of cancer patients in Palestine over a three-year period, and to identify socio-demographic factors that are associated with CAM use. MATERIALS AND METHODS: Across-sectional survey of patients attending outpatient cancer clinics. The method was based on a semi structured questionnaire. In order to identify safety-related concerns associated with the products listed, a literature search was conducted using different databases (PubMed, Micromedex, AltMedDex, and the Natural Medicine Comprehensive Database). RESULTS: In 472 cancer patients including 372 of the 2011 cohort; and 100 of the 2014 cohort, the overall prevalence of CAM use was 69.5%. CAM users were more likely to be <=65 years old, village resident, being in the midst of chemotherapy, to have high interest spiritual quest, and to have no other chronic diseases. A significant number of CAM users reported using herbal preparations (98.3%, and 89.6% in the two study cohorts, respectively). In the current study, a total of 40 plant taxa belonging to 23 botanical families were reported by >=3 cancer patients in the two cohort groups. The top most commonly used plant in the 2011 cohort group was Arum palaestinum (43.5%), while Ephedra foeminea emerged as the top most commonly utilized plant (from 0.0% in 2011 to 55.2% in the 2014 cohort), mainly due to a recent publicizing and portraying of the plant in the local media as an effective cancer herbal remedy. Safety-related concerns were associated with 33 (82.5%) herbs, including herb-drug interactions with altered pharmacokinetics (8, 20% herbs), direct toxic effects (16, 40% herbs), and increased in vitro response of cancer cells to chemotherapy (30, 75% herbs). CONCLUSIONS: CAM use, especially herbal medicine in cancer is highly prevalent in Palestine. This study has demonstrated the role of the media on the emergence of new CAM herbal therapies among cancer patients in Palestine, and discussed its potential implications on patients and for oncologists who are treating them. Some of the most widely used herbal medicines by cancer patients in the present work are known to interact with conventional anticancer drugs. Hence, the disclosure of the use of herbal remedies by patients to health professionals with sufficient training in CAM use is important for the later in order to assess whether there are any possible herbal drug interactions and/or harmful drug reactions. PMID- 27125597 TI - Enhanced autophagy signaling in diabetic rats with ischemia-induced seizures. AB - Seizures are among the most common neurological sequelae of stroke, and ischemic insult in diabetes notably increases the incidence of seizures. Recent studies indicated that autophagy influences the outcome of stroke and involved in epileptogenesis. However, the association of autophagy and post-ischemic seizures in diabetes remains unclear. The present study aimed to reveal the involvement of autophagy in the seizures following cerebral ischemia in diabetes. Diabetes was induced in adult male Wistar rats by intraperitoneal injection of streptozotocin (STZ). The diabetic rats were subjected to transient forebrain ischemia. The neuronal damage was assessed using hematoxylin-eosin staining. Western blotting and immunohistochemistry were performed to investigate the alteration of autophagy marker microtubule-associated protein light chain 1B (LC3B). The results showed that all diabetic animals developed seizures after ischemia. However, no apparent cell death was observed in the hippocampus of seizure rats 12h after the insult. The expression of LC3B was significantly enhanced in naive animals after ischemia and was further increased in diabetic animals after ischemia. Immunofluorescence double-labeling study indicated that LC3B was mainly increased in neurons. Our study demonstrated, for the first time, that autophagy activity is significantly increased in diabetic animals with ischemia-induced seizures. Further studies are needed to explore the role of autophagy in seizure generation after ischemia in diabetic conditions. PMID- 27125596 TI - Mutation of rnf213a by TALEN causes abnormal angiogenesis and circulation defects in zebrafish. AB - Moyamoya disease (MMD) is characterized by a stenosis at the terminal of the internal carotid artery and an abnormal vascular network at the base of the brain. RNF213 is a susceptibility gene for MMD in East Asians. The role of RNF213 in the etiology of MMD remains unknown. Here we generated rnf213a mutant zebrafish using transcription activator-like effector nuclease (TALEN) technique and described the characteristics of a zebrafish embryonic model of MMD. rnf213a mutant zebrafish developed abnormal angiogenesis in intersegmental vessels and cranial secondary vessels. Endothelial cells exhibited the defects in morphogenesis and formation of vascular tubes despite normal cell to cell contacts under electron microscope. Circulatory disorder was induced by abnormal sprouts in the trunk and head. Reduced circulation in the abnormal vessels was revealed by microangiography. No blood flow permeated across the vessels wall despite the extremely abnormal structure. rnf213a mutant showed lower erythrocyte velocity in dorsal aorta than that in wild-type siblings. In this study, we provided a promising in vivo model for MMD, and this model would aid to understand the function of rnf213a in angiogenesis. PMID- 27125598 TI - Intra-articular Injection of platelet-rich fibrin releasates in combination with bone marrow-derived mesenchymal stem cells in the treatment of articular cartilage defects: An in vivo study in rabbits. AB - The use of mesenchymal stem cells (MSCs), which can be differentiated into chondrocytes under specific conditions, has been proposed for the treatment of cartilage defects. Blood-derived platelet-rich fibrin releasate (PRFr), which is rich in growth factors and cytokines, may improve cartilage regeneration. In this study, the therapeutic effects of PRFr in combination with bone marrow-derived MSCs for articular cartilage regeneration were evaluated in a rabbit model. Critical osteochondral defects were surgically created in the femoral condyle of the rabbits, and 3 * 106 of MSCs, 0.8 mL of PRFr, or a combination of MSCs and PRFr were injected intra-articularly and one week after first administration. The animals were sacrificed 12 weeks postoperatively, and the regenerated cartilages were assessed by gross inspection and histological examination. No treatment related adverse events were noted in any of the rabbits. The size of the defect decreased and the volume of regenerated cartilage increased in the medial femoral condyles of the MSCs + PRFr group. Relative to the MSCs or PRFr group, histological examination demonstrated that the MSCs + PRFr group had thicker hyaline-like cartilaginous tissue with normal glycosaminoglycan production. Grading scores revealed that MSCs + PRFr injection had better matrix, cell distribution, and surface indices than other groups. The results showed that intra-articular injections of MSCs + PRFr into the knee can reduce cartilage defects by regenerating hyaline-like cartilage without adverse events. This approach may provide an alternative method of autologous chondrocyte implantation to repair cartilage defects with an unlimited source of cells and releasate. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1536 1543, 2017. PMID- 27125595 TI - Pushing the threshold: How NMDAR antagonists induce homeostasis through protein synthesis to remedy depression. AB - Healthy neurons have an optimal operating range, coded globally by the frequency of action potentials or locally by calcium. The maintenance of this range is governed by homeostatic plasticity. Here, we discuss how new approaches to treat depression alter synaptic activity. These approaches induce the neuron to recruit homeostatic mechanisms to relieve depression. Homeostasis generally implies that the direction of activity necessary to restore the neuron's critical operating range is opposite in direction to its current activity pattern. Unconventional antidepressant therapies-deep brain stimulation and NMDAR antagonists-alter the neuron's "depressed" state by pushing the neuron's current activity in the same direction but to the extreme edge. These therapies rally the intrinsic drive of neurons in the opposite direction, thereby allowing the cell to return to baseline activity, form new synapses, and restore proper communication. In this review, we discuss seminal studies on protein synthesis dependent homeostatic plasticity and their contribution to our understanding of molecular mechanisms underlying the effectiveness of NMDAR antagonists as rapid antidepressants. Rapid antidepressant efficacy is likely to require a cascade of mRNA translational regulation. Emerging evidence suggests that changes in synaptic strength or intrinsic excitability converge on the same protein synthesis pathways, relieving depressive symptoms. Thus, we address the question: Are there multiple homeostatic mechanisms that induce the neuron and neuronal circuits to self correct to regulate mood in vivo? Targeting alternative ways to induce homeostatic protein synthesis may provide, faster, safer, and longer lasting antidepressants. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease. PMID- 27125599 TI - The IRIS (Insulin Resistance Intervention after Stroke) trial: A new perspective on pioglitazone. PMID- 27125600 TI - Sulfonated Polymerized Ionic Liquid Block Copolymers. AB - The successful synthesis of a new diblock copolymer, referred to as sulfonated polymerized ionic liquid (PIL) block copolymer, poly(SS-Li-b-AEBIm-TFSI), is reported, which contains both sulfonated blocks (sulfonated styrene: SS) and PIL blocks (1-[(2-acryloyloxy)ethyl]-3-butylimidazolium: AEBIm) with both mobile cations (lithium: Li(+) ) and mobile anions (bis(trifluoromethylsulfonyl)imide: TFSI(-) ). Synthesis consists of polymerization via reversible addition fragmentation chain transfer, followed by post-functionalization reactions to covalently attach the imidazolium cations and sulfonic acid anions to their respective blocks, followed by ion exchange metathesis resulting in mobile Li(+) cations and mobile TFSI(-) anions. Solid-state films containing 1 m Li-TFSI salt dissolved in ionic liquid result in an ion conductivity of >1.5 mS cm(-1) at 70 degrees C, where small-angle X-ray scattering data indicate a weakly ordered microphase-separated morphology. These results demonstrate a new ion-conducting block copolymer containing both mobile cations and mobile anions. PMID- 27125601 TI - Multiple repeat caesarean deliveries: do they increase maternal and neonatal morbidity? AB - OBJECTIVE: The aim of the present study is to evaluate the effects of the increased number of caesarean deliveries (CDs) in cases of multiple repeat caesarean deliveries (MRCDs) on maternal and neonatal morbidity. METHODS: MRCDs admitted to our hospital between January 2013 and September 2014 were analysed retrospectively. A total number of 1133 women were included in the study and were divided into 4 groups. Group 1: second CDs (n = 329); Group 2: third CDs (n = 225); Group 3: fourth CDs (n = 447); Group 4: fifth CDs (n = 132). The clinical, demographic, intraoperative and postoperative data of the patients were registered upon the review of patient files. RESULTS: The differences among the groups were found to be statistically significant in terms of mean maternal age, gravida, APGAR (Activity, Pulse, Grimace, Appearance, Respiration) scores, hospital stay and operation time. In addition, the difference was also statistically significant for severe adhesion, bladder injury and premature birth. No statistically significant difference was observed among the groups with respect to placenta previa, placenta accreta, caesarean hysterectomy, uterine scar rupture. CONCLUSIONS: According to our findings, MRCDs seem to increasing the maternal and neonatal morbidity even though they are not life-threatening. PMID- 27125602 TI - Surface-Driven Collagen Self-Assembly Affects Early Osteogenic Stem Cell Signaling. AB - This study reports how extracellular matrix (ECM) ligand self-assembly on biomaterial surfaces and the resulting nanoscale architecture can drive stem cell behavior. To isolate the biological effects of surface wettability on protein deposition, folding, and ligand activity, a polydimethylsiloxane (PDMS)-based platform was developed and characterized with the ability to tune wettability of elastomeric substrates with otherwise equivalent topology, ligand loading, and mechanical properties. Using this platform, markedly different assembly of covalently bound type I collagen monomers was observed depending on wettability, with hydrophobic substrates yielding a relatively rough layer of collagen aggregates compared to a smooth collagen layer on more hydrophilic substrates. Cellular and molecular investigations with human bone marrow stromal cells revealed higher osteogenic differentiation and upregulation of focal adhesion related components on the resulting smooth collagen layer coated substrates. The initial collagen assembly driven by the PDMS surface directly affected alpha1beta1 integrin/discoidin domain receptor 1 signaling, activation of the extracellular signal-regulated kinase/mitogen activated protein kinase pathway, and ultimately markers of osteogenic stem cell differentiation. We demonstrate for the first time that surface-driven ligand assembly on material surfaces, even on materials with otherwise identical starting topographies and mechanical properties, can dominate the biomaterial surface-driven cell response. PMID- 27125603 TI - Parenting and childhood obesity research: a quantitative content analysis of published research 2009-2015. AB - BACKGROUND: A quantitative content analysis of research on parenting and childhood obesity was conducted to describe the recent literature and to identify gaps to address in future research. METHODS: Studies were identified from multiple databases and screened according to an a priori defined protocol. Eligible studies included non-intervention studies, published in English (January 2009-December 2015) that focused on parenting and childhood obesity and included parent participants. RESULTS: Studies eligible for inclusion (N = 667) focused on diet (57%), physical activity (23%) and sedentary behaviours (12%). The vast majority of studies used quantitative methods (80%) and a cross-sectional design (86%). Few studies focused exclusively on fathers (1%) or included non residential (1%), non-biological (4%), indigenous (1%), immigrant (7%), ethnic/racial minority (15%) or low-socioeconomic status (19%) parents. DISCUSSION: While results illustrate that parenting in the context of childhood obesity is a robust, global and multidisciplinary area of inquiry, it is also evident that the vast majority of studies are conducted among Caucasian, female, biological caregivers living in westernized countries. Expansion of study foci and design is recommended to capture a wider range of caregiver types and obesity related parenting constructs, improve the validity and generalizability of findings and inform the development of culture-specific childhood obesity prevention interventions and policies. (c) 2016 World Obesity. PMID- 27125604 TI - Determination of strychnine, brucine, strychnine N-oxide, and brucine N-oxide in plasma samples after the oral administration of processed semen strychni extract by high-performance liquid chromatography with ultrasound-assisted mixed cloud point extraction. AB - A sensitive and efficient mixed cloud point extraction combined with high performance liquid chromatography was developed for the simultaneous separation and determination of four alkaloids (strychnine, strychnine N-oxide, brucine, and brucine N-oxide) in plasma after the oral administration of processed semen strychni extract. Tergitol TMN-6 and cetyl-trimethyl ammonium bromide were chosen as the mixed surfactants, and ultrasound was employed to enhance the extraction efficiency. Some important parameters affecting the mixed cloud point extraction efficiency, such as the content of Tergitol TMN-6 and cetyl-trimethyl ammonium bromide, pH, salt effect, extraction temperature, and ultrasound time were studied and optimized. Under optimum conditions, the linear range of four alkaloids was from 1.0 to 1000 ng/mL. All correlation coefficients of the calibration curves were higher than 0.9993. The intraday and interday precision were below 8.65% and the limits of detection for the four alkaloids were less than 1.0 ng/mL (S/N = 3). PMID- 27125605 TI - [Inequalities in premature mortality by indicators of material welfare in Navarre. Population monitoring study 2001-2008]. AB - BACKGROUND: To show the inequalities in premature mortality according to indicators of material welfare in Navarre. METHODS: All citizens under 75 years of age living in Navarre in 2001 were monitored for seven years to determine their vital status. House size and number of household vehicles was used as the socioeconomic status indicator. The age-adjusted total mortality rate and mortality rate from cause-specific mortality were estimated by these indicators. RESULTS: The rate ratio for all causes of death in the lower categories depending on house size is 1.14 (IC 95%: 1.05-1.24) and 1.25 (IC 95%: 1.18-1.32) in women and men respectively and 1.46 (IC 95%: 1.36-1.57) and 1.97 (IC 95%: 1.89-2.05) depending on the number of vehicles. AIDS is the leading cause of death having a greater difference in mortality rates among people with lower and higher material welfare. Other causes of death with a high difference in mortality rates are digestive diseases and diabetes mellitus in women and digestive diseases and respiratory diseases in men. CONCLUSIONS: The mortality rate in the Navarre population shows an inverse gradient to material welfare,except for some cancer sites. This gradient is higher among men than among women. PMID- 27125606 TI - [Spanish adaptation and validation of the Perception of Restraint Use Questionnaire (PRUQ) on the use of physical restraints on the elderly]. AB - BACKGROUND: To adapt and to validate in a Spanish population the Perception of Restraint Use Questionnaire (PRUQ), which assesses the importance that professionals give to the use of physical restraints when caring for older adults. METHODS: After a process of forward-back translation and linguistic adaptation, a Spanish version of the original questionnaire was obtained. A descriptive cross-sectional multicenter study was then carried out. Based on non probability sampling, 20 centers from three Spanish regions were selected; 830 professionals agreed to participate. RESULTS: 15 of the 17 items of the original questionnaire were translated literally and two required minor modifications.All were considered acceptable by an expert panel(content validity index of 0.89); a pilot study confirmed the adequate feasibility of the questionnaire. The principal components analysis identified three dimensions that explained 66.2% of variance. The confirmatory factor analysis of this tridimensional model showed an acceptable fit [CFI = 0.936; RMSEA = 0.080], being factor loadings and factor correlations statistically significant (p<0.001). The internal consistency (Cronbach's alpha) for the total score was 0.92 and the test-retest reliability (ICCa) was 0.87 (95%CI: 0.78 to 0.92) over an interval of three weeks. CONCLUSIONS: The Spanish version of the PRUQ shows good psychometric characteristics and is adapted to the cultural context of this country. It may be considered a useful tool to assess in which situations professionals consider the use of physical restraints most necessary, helping to design training activities aimed at rationalizing its application. PMID- 27125607 TI - [Percutaneous coronary intervention in Navarre. Outcomes of a low volume centre]. AB - BACKGROUND: Percutaneous coronary intervention (PCI)is currently a basic therapeutic option in patients with coronary artery disease. To carry this out specialists must be trained and accredited. It is known that the number of procedures performed each year influences results. We suggest that some low volume centres may also get good results. METHODS: Prospective analysis of clinical features and immediate results obtained in our centre following PCI performed between 2006 and 2012 and retrospective analysis of overall survival, outcome-free survival and restenosis in patients treated between 2006 and 2009.The clinical features, acute and long-term events (complications,survival and mortality) of our group were compared with other published studies. RESULTS: In our centre the likelihood of complications ina PCI was 9% with an overall mortality of 2%. PCI mortality in stable coronary disease was 0.43% and in acute coronary syndrome 6.25%. Complications at the vascular access site was 1.44% and restenosis at nine months, inpatients undergoing PCI for the first time, was 5.2%. CONCLUSIONS: Although a high interventionist volume has been shown to reduce the rate of complications and improve long-term evolution, some low volume interventional centres can obtain similar results to those of high volume interventional centres. PMID- 27125608 TI - [Characteristics and epidemiological changes for patients with urinary tract infection in the emergency department]. AB - BACKGROUND: The aim of this paper is to determine both the prevalence of urinary tract infection (UTI) in the emergency department (ED) and the most relevant epidemiological changes in the last decade, as well as the profile and management of these patients. METHODS: Descriptive cross-sectional analysis at 49 Spanish ED during 12 months. All patients with infections and UTI diagnosis were included. All patients attended to in ED during the study were recorded as well. RESULTS: The study included 2,517 patients diagnosed with UTI, with a mean age of 55 (SD 23) years, 64.6%of whom were women. These patients represent 22%of infections in the ED and 3.2% of all patients in the ED. Thirty-six per cent were over 70 years old. Fifty one point nine per cent had some underlying disease (16.5%diabetes mellitus) and 32.7% had some risk factors for multi-resistant strains of bacteria. Eight point three percent met sepsis criteria. Seventy-one point nine percent of patients were directly discharged from the ED. CONCLUSIONS: UTI are very common infections in ED, with important associated comorbidities, high mean ages and a predominance in women. With respect to a decade before UTI has increased its prevalence (3.2%vs 2.1%) and the patients have a greater age [55.5 (SD 23) vs 52 (SD 22) years], more comorbidities (51.9% vs 40.6%) and clinical severity (8.3% vs 6.5%). PMID- 27125609 TI - [Factors associated with prehospital delay in men and women with acute coronary syndrome]. AB - OBJECTIVE: To identify factors associated with prehospital delay in people who have had an acute coronary syndrome. METHODS: Using a survey we studied patients admitted due to acute coronary syndrome in the 33 Andalusian public hospitals, obtaining information about different types of variables: socio-demographic, contextual,clinical, perception, action, and transportation.Multivariate logistic regression models were applied to calculate the odds ratios for the delay. RESULTS: Of the 1,416 patients studied, more than half had a delay of more than an hour. This is associated to distance to the hospital and means of transport: when the event occurs in the same city,using the patient's own means of transport increases the delay, odds ratio = 1.51 (1.02 to 2.23); if the distance is 1 to 25 kilometers from the hospital,there is no difference between the patient's own means of transport and an ambulance, odds ratio =1.41 and odds ratio =1.43 respectively; and when the distance exceeds 25 kilometers transport by ambulance means more delay, odds ratio = 3.13 and odds ratio = 2.20 respectively. Also, typical symptoms reduce delay amongst men but increase amongst women. Also, not caring and waiting for the resolution of symptoms, seeking health care other than a hospital or emergency services, previous clinical history, being away from home, and having an income under 1,500 euros, all increase delay. Respiratory symptoms reduce delay. CONCLUSIONS: Prehospital delay times do not meet health recommendations. The physical and social environment,in addition to clinical, perceptual and attitudinal factors, are associated with this delay. PMID- 27125610 TI - [Chronic Salmonella typhimurium diarrhea in an immunocompetent patient]. AB - Chronic diarrhea caused by infection in immunocompetent patients is an infrequent condition in developed countries, although certain pathogens,generally parasites (Giardia lamblia, Isospora belli,Cryptosporidium, Cyclospora, Strongyloides, Ameba,Trichuris and Schistosoma) and some bacteria (Aeromonas,Plesiomonas, Campylobacter, Clostridium difficile, Salmonella or Mycobacterium tuberculosis)can cause persistent diarrhea.We present the case of a patient who showed Salmonella typhimurium in his stool culture and recovered following treatment with levofloxacin for 7 days. PMID- 27125611 TI - Missed Chopart dislocation. The importance of being aware of midtarsal injuries. AB - Chopart (midtarsal) joint dislocations are relatively rare but potentially serious injuries. Their low prevalence and the possible absence of evident radiological findings cannot justify misdiagnosis because an adequate and correct treatment is required to achieve a proper clinical outcome.A midtarsal joint dislocation in a 19-year-old woman is described, in which diagnosis was performed at 8 weeks of evolution. An open reduction was performed by a double approach (medial and lateral) and a Kirschner wire joint stabilization. A tone-year of follow-up, loss of reduction was not observed and the patient was pain-free, although she referred to functional limitation when running.Besides describing the treatment of this particular injury, this study is aimed at increasing the level of clinical suspicion in order to avoid misdiagnosis such as occurred in our case. PMID- 27125612 TI - [Factors modulating food intake and energy expenditure prior to liver transplantation]. AB - BACKGROUND: There is a high prevalence of nutritional disorders in patients with liver cirrhosis (LC). This study was designed to assess the relationships between liver function, IFG-I/IGFBP-3, nutritional status, leptin, ghrelin and glucagon in 21 patients waiting for liver transplantation (LT). METHODS: We studied 21 men aged 56+/-2.1 years who were on the LT list. They were classified according to Child-Pugh(CP) score from low to high liver dysfunction in CPA (n=4),CPB (n=11) and CPC (n=6). Body mass index (BMI) was calculated and body fat (%) was measured by air-displacement plethysmography. Resting energy expenditure (REE) and its variation over Harris-Benedict values (GER%) were assessed by indirect calorimetry. Fasting serum samples were taken to measure albumin, glucose, insulin, HbA1c, leptin, total ghrelin,glucagon, IGF-I and IGFBP3. RESULTS: There were no differences in fat % and leptin values in the three groups according to CP classification. The CPC group showed higher ghrelin values than CPA and CPB(p<0.05). All groups displayed high glucagon levels and GER%values superior to 100%. Positive correlations were found between glucagon and GER% (r=0.56; p<0.01) and between glucagon and ghrelin values (r=0.66; p<0.01). IGF-I and IGFBP3 were low in all groups and showed a positive correlation with plasma albumin (r=0.52; p<0.05 and r=0.45; p<0.05 respectively). CONCLUSIONS: These results show an increase in ghrelin plasma values in patients with severe liver dysfunction. Hyperglucagonemia was correlated with GER%, supporting a role of glucagon in the hypermetabolic state associated to LC,raising the possibility of becoming a therapeutic target. The measurement of IGF-I/IGFBP3 represents a good marker of liver function in patients with LC. PMID- 27125613 TI - [Unilateral vocal fold paralysis: quality of voice after speech therapy]. AB - BACKGROUND: To describe demographic factors and voice quality parameters of patients with unilateral vocal fold paralysis (UVFP) after a voice therapy protocol. METHODS: Forty-seven patients with a diagnosis of UVFP by video laryngoscopy were included. Voice therapy was applied to all patients during 15 sessions that were structured in three progressive stages. The objective was to train patients in vocal techniques, phonic-breathing coordination,blow control, vocal exercises for glottic closure and vocal setting. Glottal closure, Voice Handicap Index-10 for perception of voice impairment and GRBAS scale were used before and after the speech therapy. RESULTS: The average age was 51 years (range 20-80), 60%women. Surgery was the most frequent cause (72%), and 40% had a profession related to voice use. Median time from diagnosis to treatment was 5 months (2-12). After voice therapy, 80% had complete glottal closure, previously this had been 34% (p<0.001), the score of VHI-10 decreased from 24.24 to 16.09 points (p<0.001) and GRBAS values improved in all the qualities of voice (p<0.001).Only 8.5% of the patients required surgical intervention after treatment. CONCLUSIONS: Voice therapy is effective as first line therapy in patients with UVFP, reserving medialization with non-absorbable material or thyroplasty surgery for those with a poor outcome. However, it is necessary to reduce the time it takes the patient to reach the Voice Unit after laryngoscopic diagnosis. PMID- 27125614 TI - [Cholestasic toxic hepatitis due to clopidogrel in a patient with multiple conditions]. AB - Clopidogrel is a thienopyridine-class antiplatelet drug commonly used in ischemic heart disease,cerebrovascular disease and peripheral artery disease.Liver toxicity due to this drug is very infrequent.We found 16 cases in the literature, and in only two of them liver biopsy was carried out. We report the case of a 78 year old patient with multiple conditions affected by severe toxic cholestatic hepatitis due to clopidogrel and the results of the liver biopsy performed. Hepatitis was resolved after discontinuing the drug.Based on the characteristics of this case and other previously published cases, we review the characteristics of toxic hepatitis due to clopidogrel and its diagnosis and treatment. PMID- 27125615 TI - [Autoimmune pancreatitis: a case report]. AB - Autoimmune pancreatitis (AIP) is an infrequent pathology, although there is a growing incidence in Eastern countries, which might be due to a greater rate of detection. It can be associated with other auto immune pathologies and its association with IgG4-related systemic disease has been described.Its clinical presentation is varied and the normal treatment is medical, using corticoids.A diagnosed clinical case is described. PMID- 27125616 TI - [Value of plasma C-reactive protein and lactate dehydrogenase levels in the diagnosis of intestinal obstruction in an emergency department]. AB - BACKGROUND: Intestinal obstruction is one of the most frequent surgical emergencies. Its diagnosis is essentially based on clinical history, physical exploration and image tests. The aim of this study was to analyze the diagnostic value of acute phase reactants in patients with benign versus malign intestinal obstruction. METHOD: Historical cohort study of 53 patients who underwent surgery because of intestinal obstruction and/or non-obstructive colorectal cancer. The patients were placed in three groups: group 1 (colorectal cancer with intestinal obstruction) (n=23), group 2 (benign intestinal obstruction)(n=10) and group 3 (non-obstructive cancer of the colon)(n=20). We determined the initial plasma values of the C-reactive protein (CRP) and the lactate dehydrogenase (LDH)enzyme. RESULTS: CRP was quantitatively higher in patients with benign intestinal obstruction (group 2) (p=0.001), while LDH was quantitatively higher in group 1 (patients with obstructive cancer). The plasma levels of LDH were significantly greater in the groups with intestinal obstruction (groups 1 and 2) than in patients without obstruction (p<0.001). Plasma levels of CRP above 11 mg/l and of LDH above 317 U/L showed an acceptable diagnostic value for differentiating patients with intestinal obstruction, with areas under the ROC curve of 80% (CI 95% = 68-92%) and 86% (CI 95%= 75-96%)respectively. Their diagnostic value for differentiating benign or malign origin is lower, with areas under the ROC curve of 56% for levels of CRP > 24 ng/l (CI 95% = 30-82%) and 52% (CI 95% = 29-74%) for levels of LDH > 359 U/L. CONCLUSION: Determination of plasma concentrations of CRP can help in the diagnosis of intestinal obstruction and indicate its benign or malign origin in emergency services. PMID- 27125617 TI - [Body weight- independent variations in HDL-cholesterol following gastric bypass]. AB - BACKGROUND: Bariatric surgery has multiple beneficial effects on lipid profile in patients with morbid obesity. However, these changes can be attenuated by weight regain. This retrospective study was designed to assess the effects of gastric bypass(GBP) on different lipid fractions over a 6 year follow-up. PATIENTS AND METHODS: We studied 177 patients (135 women)with morbid obesity (BMI 44.2+0.4 kg/m2) aged 42.4+0.9 years before and 3, 6, 9, 12, 24, 36, 48, 60 and 72 months after laparoscopic proximal GBP. Anthropometry, body composition measurement (Bod Pod) and fasting blood samples were taken in all evaluations to measure total cholesterol (TC),LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides(TG), glucose and insulin. RESULTS: GPB was followed by a significant BMI reduction (nadir BMI at 18 m 28.3+0.4 kg/m2 p<0,001) and fat mass decrease(p<0,001). Maximal percentage of excess BMI lost was 84.1%and that of body fat was 87% 18 months after GBP. These numbers decreased to 65.6% and 38.3% (p<0,005 vs nadir) respectively 72 months after the operation, indicating both weight and fat mass regain. TG and LDL-C values decreased 30% with respect to preoperative levels, while HDL-C increased 97%over initial values. This HDL-C increase was progressive even over the weight regain phase. Both TC/HDL-C and TG/HDL-Cratios normalized after GBP and values were sustained over the weight regain period until the end of the study. CONCLUSIONS: These results confirm the beneficial effects of GBP on all lipid fractions, which are maintained over 6 years of follow-up. Globally, the rise in HDL-C seems to be independent of weight or fat mass changes, since it increases even over the weight regain phase, so contributing to a reduction in the prevalence of dyslipidaemia and to cardiovascular risk reduction. PMID- 27125618 TI - [Effect of antidiabetes treatment adjustment at discharge on 30-day outcomes of patients with diabetes mellitus presenting to an emergency department with hypoglycemia]. AB - BACKGROUND: To determine if antidiabetes treatment adjustment at discharge from an Emergency Department(ED) is associated with 30-day outcomes in patients with diabetes mellitus presenting to the ED with hypoglycemia. METHODS: Retrospective cohort observational study. Patients with diabetes mellitus presenting to the ED with hypoglycemia directly discharged from the ED between 2012-2014 were included. Primary outcome was a 30-day composite adverse event(mortality or revisiting). RESULTS: A total of 203 patients were included with a mean age of 69.7 (SD 18.9), mainly type 2 diabetics.Hypoglycemia was the primary diagnosis in 162(79%) of patients and antidiabetes treatment was adjusted at discharge in 98 (48%) of cases. Non-adjustment of antidiabetes treatment at ED discharge was an independent factor associated with a 30-day adverse event (OR=2.8; CI 95%=1.34 5.93; p=0.006). CONCLUSIONS: Non-adjustment of antidiabetes treatment at discharge in patients with diabetes mellitus presenting to the ED with hypoglycemia could be an independent factor of suffering a 30-day adverse event. PMID- 27125619 TI - [Quality of life in patients with inflammatory bowel diseases]. AB - BACKGROUND: To determine the health-related quality of life in patients with Crohn disease and ulcerative colitis, as well as to evaluate differences according to sex, type of disease and other sociodemographic variables. METHOD: Cross sectional study of 100 outpatients in the Digestive Service of the Navarre Hospital Complex.A questionnaire with sociodemographic and clinical variables was used, as well as a version of the Inflammatory Bowel Disease Questionnaire-32 adapted to Spanish, in order to measure quality of life. RESULTS: The average score of the questionnaire on quality of life was 166 points (D.T.=40.06) out of a maximum of 232. Statistically significant differences were found according to type of disease (p=0.005)and sex (p=0.001). CONCLUSIONS: People with Crohn disease or females perceive a worse quality of life related to health in comparison to patients with ulcerative colitis or men. PMID- 27125620 TI - [Assessment of the impact of pain on work productivity: validation of the Spanish WPAI:Pain questionnaire]. AB - BACKGROUND: Health measuring instruments are essential in daily clinical practice. However, a validation process is needed in order to certify the validity and reliability of it. The aim of our study is to validate a questionnaire to assess the consequences of pain in work productivity. METHODS: Based on the Work Productivity and Activity Impairment Questionnaire - General Health we have created a modified version called WPAI:Pain in order to be able to measure the consequences of pain in work productivity. The study was conducted following the usual guidelines of test validation, omitting face validity as WPAI:Pain is a modification of an existing questionnaire. Validity and reliability were calculated. RESULTS: A total of 577 questionnaires were obtained in 2 spanish university hospitals. The questionnaire's discriminating power was verified by Mann-Whitney test. Reliability tests were realized, Cronbach's alpha was 0.896 and Guttman split-half was 0.921. Stability was evaluated with a test retest which was significant. Construct validity was established by Pearson correlation comparing the results of the questionnaire with the pain visual analog scale, which was statistically significant for all values. CONCLUSIONS: The WPAI:Pain questionnaire is a valid instrument for measuring the consequences of pain in work productivity.It is currently the only one validated in Spanish.Major studies are needed in order to establish its universal validity. PMID- 27125621 TI - [How do primary care patients perceive information for involving themselves in self-care?]. AB - BACKGROUND: Analyze if patients receive information from their GPs to engage in self-management (medication,physical exercise or diet). METHODS: A descriptive study in which 2,401 randomly selected, primary care patients were interviewed by telephone. A short scale of 6 questions was used to analyze if they received information for self-care. Statistics included analyzing differences according to age,sex, occurrence of security incidents, whether they regularly attended the physician's surgery and length of consultation time. RESULTS: A total of 2,350 patients responded (97.9%response rate). A total of 1,253 (34.6%) of respondents obtained 5 or more points on the scale (percentile 50).Receiving information about foreseeable prognosis increased satisfaction (OR 11.2 (95% 8.3-15.3). Consultation time length (p<0.01), regularly visiting physicians(p<0.01), and not suffering an adverse event (p<0.01)were associated with higher scores on the scale. CONCLUSIONS: Patients report they receive directions for the proper management of medication at home, but claim that they receive less information to engage in healthy behaviors. PMID- 27125622 TI - Answers to Health Questions: Internet Search Results Versus Online Health Community Responses. AB - BACKGROUND: About 6 million people search for health information on the Internet each day in the United States. Both patients and caregivers search for information about prescribed courses of treatments, unanswered questions after a visit to their providers, or diet and exercise regimens. Past literature has indicated potential challenges around quality in health information available on the Internet. However, diverse information exists on the Internet-ranging from government-initiated webpages to personal blog pages. Yet we do not fully understand the strengths and weaknesses of different types of information available on the Internet. OBJECTIVE: The objective of this research was to investigate the strengths and challenges of various types of health information available online and to suggest what information sources best fit various question types. METHODS: We collected questions posted to and the responses they received from an online diabetes community and classified them according to Rothwell's classification of question types (fact, policy, or value questions). We selected 60 questions (20 each of fact, policy, and value) and the replies the questions received from the community. We then searched for responses to the same questions using a search engine and recorded the RESULTS: Community responses answered more questions than did search results overall. Search results were most effective in answering value questions and least effective in answering policy questions. Community responses answered questions across question types at an equivalent rate, but most answered policy questions and the least answered fact questions. Value questions were most answered by community responses, but some of these answers provided by the community were incorrect. Fact question search results were the most clinically valid. CONCLUSIONS: The Internet is a prevalent source of health information for people. The information quality people encounter online can have a large impact on them. We present what kinds of questions people ask online and the advantages and disadvantages of various information sources in getting answers to those questions. This study contributes to addressing people's online health information needs. PMID- 27125624 TI - Gold nanoparticles in aqueous solutions: influence of size and pH on hydrogen dissociative adsorption and Au(iii) ion reduction. AB - The shift of the localized surface plasmon resonance (LSPR) band of gold nanoparticles to shorter wavelengths upon saturation of the hydrosol with hydrogen is used as a tool to study the electrochemical processes on the particle surface. It is shown that dissociative adsorption of hydrogen takes place on the surface of a particle and results in the migration of a proton into the dispersion medium, while the electron remains on the nanoparticle, i.e., a hydrogen-like nanoelectrode is formed. It is shown that Au(iii) ions can be reduced on the gold nanoelectrodes. A thermodynamic scheme explaining the shift of the LSPR band is used to explain the peculiarities of the Au(iii) ion reduction. The reduction rate does not depend on the ion concentration and varies linearly with pH. The observed correlations are explained in terms of a simple model of electrochemical processes taking place on the nanoparticle as an electrode. It is shown that with an increase in the particle size, its capacity for dissociative adsorption of hydrogen decreases and the Au(iii) reduction slows down. PMID- 27125623 TI - Microstructured human fibroblast-derived extracellular matrix scaffold for vascular media fabrication. AB - In the clinical and pharmacological fields, there is a need for the production of tissue-engineered small-diameter blood vessels. We have demonstrated previously that the extracellular matrix (ECM) produced by fibroblasts can be used as a scaffold to support three-dimensional (3D) growth of another cell type. Thus, a resistant tissue-engineered vascular media can be produced when such scaffolds are used to culture smooth muscle cells (SMCs). The present study was designed to develop an anisotropic fibroblastic ECM sheet that could replicate the physiological architecture of blood vessels after being assembled into a small diameter vascular conduit. Anisotropic ECM scaffolds were produced using human dermal fibroblasts, grown on a microfabricated substrate with a specific topography, which led to cell alignment and unidirectional ECM assembly. Following their devitalization, the scaffolds were seeded with SMCs. These cells elongated and migrated in a single direction, following a specific angle relative to the direction of the aligned fibroblastic ECM. Their resultant ECM stained for collagen I and III and elastin, and the cells expressed SMC differentiation markers. Seven days after SMCs seeding, the sheets were rolled around a mandrel to form a tissue-engineered vascular media. The resulting anisotropic ECM and cell alignment induced an increase in the mechanical strength and vascular reactivity in the circumferential direction as compared to unaligned constructs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27125625 TI - Clinical severity of drug-induced hyponatremia: thiazides vs. psychotropics. AB - BACKGROUND: The aim of this study was to investigate the clinical characteristics of patients with hyponatremia who received thiazide diuretics, psychotropic drugs, or both. METHODS: From 2007 to 2013, 266 patients were diagnosed with hyponatremia (P-Na < 135 mol/L) associated with thiazide diuretics (T), psychotropic drugs (P), or both (C). We compared clinical characteristics among the thiazide (T) group (n = 93), the psychotropic drug (P) group (n = 83), and the combination (C) group (n = 90). RESULTS: There were no differences in clinical characteristics except for correction time among the three groups. We evaluated the clinical severity among the three groups through initial serum sodium levels (mild: > 125 mmol/L, moderate: 120 - 125 mmol/L, severe: < 120 mmol/L), patient symptoms (mild: general weakness, moderate: nausea or vomiting, severe: syncope or seizure). There were no significant differences in the incidence of severe hyponatremia on the basis of initial serum sodium levels (73.1% vs. 67.5% vs. 71.1%, p = 0.710) and symptoms (20.4% vs. 30.1% vs. 17.8%, p = 0.192) among groups. However, correction time was significantly longer in group C than in groups T or P (41.98 +/- 26.89 vs. 34.91 +/- 23.96 vs. 51.10 +/- 43.86 mg/dL, p = 0.026). CONCLUSION: Although patients in group C did not have clinical features that were any more severe than those of the other two groups in terms of initial serum sodium levels and symptoms, correction time was significantly longer for group C than for groups T or P. Therefore, it is of utmost importance to closely monitor patients who receive a thiazide and psychotropic drug simultaneously. PMID- 27125626 TI - Late-onset adverse events after a single dose of rituximab in children with complicated steroid-dependent nephrotic syndrome. AB - BACKGROUND: Rituximab (RTX) is regarded as a relatively safe and effective treatment for children with steroid-dependent nephrotic syndrome (SDNS). However, late-onset adverse events after RTX, including neutropenia, hypogammaglobulinemia, and increased risk of infections, have been rarely reported in this cohort. MATERIALS AND METHODS: This was a single-center retrospective analysis of adverse events during B-cell depletion periods after a single dose of RTX (375 mg/m2) in 60 patients with complicated SDNS (total 126 doses). After RTX, maintenance therapy with cyclosporine (CsA) or mycophenolate mofetil (MMF) was continued, and prednisolone was discontinued within 6 months. To detect potential drug toxicity, clinical and laboratory parameters were measured before and 1 week after RTX infusion and every month thereafter during B cell depletion periods (at least 6 months). A single dose of RTX was added if NS relapsed despite maintenance therapy with MMF or CsA after the re-emergence of CD19+ B cells (> 1% of total lymphocytes) in the peripheral blood. RESULTS: Severe neutropenia (neutrophil count < 500/mm3) was identified in 3 patients and hypogammaglobulinemia (IgG levels < 500 mg/dL) in 9 patients. During B-cell depletion periods (median 5 months; range 1 - 20 months), 2 patients required hospitalization because of bacterial infections. However, no lifethreatening infections were identified in our cohort. CONCLUSION: Although neutropenia and hypogammaglobulinemia should be kept in mind as late-onset adverse events of RTX therapy in patients with complicated SDNS, severe infections during B-cell depletion periods are infrequent when our treatment strategies are implemented. PMID- 27125627 TI - Evaluation of estimated glomerular filtration rate and clinical variables in systemic sclerosis patients. AB - OBJECTIVES: The most important renal complication of systemic sclerosis (SSc) is scleroderma renal crisis (SRC). Many patients demonstrate less severe renal complications, most likely associated with reduced renal blood flow and a consequent reduction in glomerular filtration rate (GFR). The mechanism of this slowly progressive form of chronic renal disease is unclear. The aim of this study was to evaluate GFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the 7-variable Modification of Diet and Renal Disease (MDRD) equations in SSc patients and to correlate estimated GFR (eGFR) with clinical variables of the disease. METHODS: 105 unselected and consecutive patients with SSc were enrolled. Serum creatinine was measured in all patients and GFR was estimated by 7-variable MDRD and CKD-EPI equations. Nailfold videocapillaroscopy was performed in all patients. RESULTS: The mean value of eGFR evaluated by both 7-variable MDRD and CKD-EPI was significantly different (p < 0.0001) in the three capillaroscopic groups and correlated negatively with the severity of capillaroscopic damage (early: 95 +/- 16 mL/min and 101 +/- 12 mL/min, active: 86 +/- 25 mL/min and 95 +/- 17 mL/min, late: 76 +/- 21 mL/min and 82 +/- 21 mL/min). The mean value of eGFR evaluated by 7-variable MDRD (97 +/- 23 mL/min vs. 74 +/- 15 mL/min, p < 0.0001) and CKD-EPI< (0.83 +/- 0.20 mL/min vs. 0.68 +/- 0.10 mL/min, p < 0.0001) was significantly higher in SSc patients without history of digital ulcers than in those with. CONCLUSION: We can conclude that in SSc patients without renal involvement, eGFR decreases with the progression of digital vascular damage. PMID- 27125628 TI - Influence of postmenopausal state, solar radiation, drugs and comorbidities on serum calcium and phosphate in 13,000 hospital admissions. AB - AIMS: Our goal was to determine the relative contributions of demographic variables, drugs, comorbidities, and weather conditions on serum calcium (Ca) and phosphate (Pi) in patients admitted to a tertiary referral center. METHODS: For 12,667 consecutive patients admitted to the Kantonsspital St. Gallen, drug history on admission, age, sex, body weight, ICD-10 diagnoses, and laboratory data were extracted from electronic medical records. Weather parameters prior to hospital admission were also integrated in a regression analysis. RESULTS: Serum Ca was normally distributed with a median (interquartile range) of 2.3 (2.2/2.4) mmol/L. In contrast Pi showed a right tailed distribution of 1.0 (0.9/1.2) mmol/L. Ca was increased in postmenopausal women. Solar radiation prior to admission was associated both with higher Ca and higher Pi. Lower blood pressure was associated with lower Ca and higher Pi. In addition Ca increased by 0.017 mmol/L per g/L increase of albumin (p < 0.0001). CONCLUSIONS: Serum Ca and Pi at hospital admission are highly dependent on patient characteristics, drugs, and comorbidities. In particular, we found higher Ca in postmenopausal women. The commonly applied albumin correction formula of Payne (0.025 mmol/L Ca per g/L albumin) may overestimate the effect of albumin; we propose using 0.017 mmol/L Ca per g/L albumin or measurement of free (ionized) Ca. PMID- 27125629 TI - Calculated insulin resistance correlates with stone-forming urinary metabolic changes and greater stone burden in high-risk stone patients. AB - AIMS: Metabolic syndrome and diabetes are associated with nephrolithiasis. Proposed mechanisms of lithogenesis include insulin resistance causing low urine pH and hyperinsulinemia leading to hypercalciuria. Herein, we sought to determine whether insulin resistance was associated with differences in stone burden and lithogenic changes on 24-hour urine samples. MATERIALS AND METHODS: All patients that underwent comprehensive metabolic workup including 24-hour urine samples and fasting insulin levels were included. Insulin resistance was defined as a homeostasis model assessment of insulin resistance value > 5 (HOMA-IR = (glucose*insulin)/405). Patients on active metabolic therapy were excluded or the 24-hour urine sample predating treatment was utilized for analysis. Stone burden was determined by totaling the maximal diameter of all stones noted on CT. RESULTS: 18 of 30 patients (60.0%) had HOMA-IR > 5. Among patients with calculated insulin resistance, stone burden was greater (17.6 mm vs. 6.3 mm, p = 0.002) and 24-hour urine samples revealed higher urine calcium (293 mg/d vs. 159 mg/d, p = 0.02) and lower urine pH and citrate (454 mg/d vs. 639 mg/d, p = 0.04 and 5.83 vs. 6.33, p = 0.04, respectively). CONCLUSIONS: Previous studies have demonstrated a correlation between metabolic syndrome, diabetes, and nephrolithiasis. This report demonstrates a quantitative increase in stone burden among patients with calculated insulin resistance. The pathway for this greater stone burden may be related to the urinary metabolic changes noted among patients with insulin resistance. In the future, targeting reduction of fasting insulin levels may represent a key element of stone disease prevention. PMID- 27125630 TI - Understanding Palladium Acetate from a User Perspective. AB - The behavior of palladium acetate is reviewed with respect to its synthesis, characterization, structure (in both solution and solid state), and activation pathways. In addition, comparisons of catalytic activities between pure palladium acetate and two common byproducts, Pd3 (OAc)5 (NO2 ) and polymeric [Pd(OAc)2 ]n , typically present in commercially available material are reviewed. Hence, this minireview serves as a concise guide for the users of palladium acetate from both academia and industry. PMID- 27125631 TI - Neurodevelopmental delay among children under the age of three years at immunization clinics in Lagos State, Nigeria - Preliminary report. AB - Late diagnosis and interventions characterize childhood neurodevelopmental disorders in Sub-Saharan Africa. This has negatively impacted on the prognosis of the children with neurodevelopmental disorders. This study examined the prevalence and pattern of neurodevelopmental delays among children under the age of 3 years attending immunization clinics in Lagos State, Nigeria and also affords opportunity of early follow-up and interventions, which had been documented to improve prognosis. The study involved two stage assessments; which consisted of first phase screening of the children for neurodevelopmental delays in immunization clinics at primary healthcare centers Lagos State, Nigeria and second phase which consists of definitive clinical evaluation and follow-up interventions for children screened positive for neurodevelopmental delays. Twenty seven (0.9%) of a total of 3,011 children under the age of 3 years were screened positive for neurodevelopmental delays and subsequently undergoing clinical evaluation and follow-up interventions. Preliminary working diagnoses among these children include cerebral palsy, autism spectrum disorder trait, nutritional deficiency, Down syndrome and Non-specific neurodevelopmental delay with co-morbid seizure disorder accounting for 33.3%, 14.8%, 18.5%, 7.4% and 25.9% respectively. This is a preliminary report that would be followed up with information on medium and long term intervention phase. PMID- 27125633 TI - Dementia: Declining dementia incidence in the UK. PMID- 27125634 TI - Parkinson disease: Insect screens for PD therapies - keep the flies in. PMID- 27125635 TI - Neural repair and rehabilitation: Man with quadriplegia uses brainwaves to control his forearm muscles. PMID- 27125632 TI - Advanced MRI and staging of multiple sclerosis lesions. AB - Over the past few decades, MRI-based visualization of demyelinated CNS lesions has become pivotal to the diagnosis and monitoring of multiple sclerosis (MS). In this Review, we outline current efforts to correlate imaging findings with the pathology of lesion development in MS, and the pitfalls that are being encountered in this research. Multimodal imaging at high and ultra-high magnetic field strengths is yielding biologically relevant insights into the pathophysiology of blood-brain barrier dynamics and both active and chronic inflammation, as well as mechanisms of lesion healing and remyelination. Here, we parallel the results in humans with advances in imaging of a primate model of MS experimental autoimmune encephalomyelitis (EAE) in the common marmoset - in which demyelinated lesions resemble their human counterparts far more closely than do EAE lesions in the rodent. This approach holds promise for the identification of innovative biological markers, and for next-generation clinical trials that will focus more on tissue protection and repair. PMID- 27125637 TI - Minimally processed foods are more satiating and less hyperglycemic than ultra processed foods: a preliminary study with 98 ready-to-eat foods. AB - Beyond nutritional composition, food structure is increasingly recognized to play a role in food health potential, notably in satiety and glycemic responses. Food structure is also highly dependent on processing conditions. The hypothesis for this study is, based on a data set of 98 ready-to-eat foods, that the degree of food processing would correlate with the satiety index (SI) and glycemic response. Glycemic response was evaluated according to two indices: the glycemic index (GI) and a newly designed index, the glycemic glucose equivalent (GGE). The GGE indicates how a quantity of a certain food affects blood glucose levels by identifying the amount of food glucose that would have an effect equivalent to that of the food. Then, foods were clustered within three processing groups based on the international NOVA classification: (1) raw and minimally processed foods; (2) processed foods; and (3) ultra-processed foods. Ultra-processed foods are industrial formulations of substances extracted or derived from food and additives, typically with five or more and usually many (cheap) ingredients. The data were correlated by nonparametric Spearman's rank correlation coefficient on quantitative data. The main results show strong correlations between GGE, SI and the degree of food processing, while GI is not correlated with the degree of processing. Thus, the more food is processed, the higher the glycemic response and the lower its satiety potential. The study suggests that complex, natural, minimally and/or processed foods should be encouraged for consumption rather than highly unstructured and ultra-processed foods when choosing weakly hyperglycemic and satiating foods. PMID- 27125636 TI - Functionalization mediates heat transport in graphene nanoflakes. AB - The high thermal conductivity of graphene and few-layer graphene undergoes severe degradations through contact with the substrate. Here we show experimentally that the thermal management of a micro heater is substantially improved by introducing alternative heat-escaping channels into a graphene-based film bonded to functionalized graphene oxide through amino-silane molecules. Using a resistance temperature probe for in situ monitoring we demonstrate that the hotspot temperature was lowered by ~28 degrees C for a chip operating at 1,300 W cm(-2). Thermal resistance probed by pulsed photothermal reflectance measurements demonstrated an improved thermal coupling due to functionalization on the graphene-graphene oxide interface. Three functionalization molecules manifest distinct interfacial thermal transport behaviour, corroborating our atomistic calculations in unveiling the role of molecular chain length and functional groups. Molecular dynamics simulations reveal that the functionalization constrains the cross-plane phonon scattering, which in turn enhances in-plane heat conduction of the bonded graphene film by recovering the long flexural phonon lifetime. PMID- 27125638 TI - Children in care often refused mental health treatment, say MPs. PMID- 27125640 TI - The Appropriateness of Contrast Metric for Reaction Times. AB - We analyzed different contrast metrics to scale the stimulus strength for suprathreshold reaction times (RTs) when it is modulated along an achromatic channel (L + M) and both chromatic channels L/M and S/(L + M) considering increments and decrements along these axes. RTs were examined as a function of the Weber luminance contrast; spatial luminance ratio (SRL) and, in terms of threshold units. The results show that when there is only luminance decreasing or increasing, RTs cluster around a single RT/luminance contrast function regardless the stimulus sign and our results indicate that both SRL, Weber luminance contrast or threshold units, equate RT values. While, if the stimulus is modulated along an isoluminant plane, the appropriate contrast is Weber (RMS) or SRL for stimuli modulated along L/M axis and for stimuli modulated along S/L + M, showing an asymmetry between S-cone decrements and increments in L/M cone pathway. Threshold units are not appropriate, showing inconsistencies: The stimulus with chromatic direction equal to 90 degrees appears as the most informative with a maximum gain. Even more so, the shared contrast gain grows as the size of the stimulus decreases. PMID- 27125639 TI - In vivo sensitivity of the embryonic and adult neural stem cell compartments to low-dose radiation. AB - The embryonic brain is radiation-sensitive, with cognitive deficits being observed after exposure to low radiation doses. Exposure of neonates to radiation can cause intracranial carcinogenesis. To gain insight into the basis underlying these outcomes, we examined the response of the embryonic, neonatal and adult brain to low-dose radiation, focusing on the neural stem cell compartments. This review summarizes our recent findings. At E13.5-14.5 the embryonic neocortex encompasses rapidly proliferating stem and progenitor cells. Exploiting mice with a hypomorphic mutation in DNA ligase IV (Lig4(Y288C) ), we found a high level of DNA double-strand breaks (DSBs) at E14.5, which we attribute to the rapid proliferation. We observed endogenous apoptosis in Lig4(Y288C) embryos and in WT embryos following exposure to low radiation doses. An examination of DSB levels and apoptosis in adult neural stem cell compartments, the subventricular zone (SVZ) and the subgranular zone (SGZ) revealed low DSB levels in Lig4(Y288C) mice, comparable with the levels in differentiated neuronal tissues. We conclude that the adult SVZ does not incur high levels of DNA breakage, but sensitively activates apoptosis; apoptosis was less sensitively activated in the SGZ, and differentiated neuronal tissues did not activate apoptosis. P5/P15 mice showed intermediate DSB levels, suggesting that DSBs generated in the embryo can be transmitted to neonates and undergo slow repair. Interestingly, this analysis revealed a stage of high endogenous apoptosis in the neonatal SVZ. Collectively, these studies reveal that the adult neural stem cell compartment, like the embryonic counterpart, can sensitively activate apoptosis. PMID- 27125641 TI - The Selective Use of Combination Therapy in Patients with Inflammatory Bowel Disease Resistant to Anti-TNF: to Whom, How and How Long? PMID- 27125642 TI - Erratum to: The real cost of sequencing: scaling computation to keep pace with data generation. PMID- 27125643 TI - Improvement of surface ECG recording in adult zebrafish reveals that the value of this model exceeds our expectation. AB - The adult zebrafish has been used to model the electrocardiogram (ECG) for human cardiovascular studies. Nonetheless huge variations are observed among studies probably because of the lack of a reliable and reproducible recording method. In our study, an adult zebrafish surface ECG recording technique was improved using a multi-electrode method and by pre-opening the pericardial sac. A convenient ECG data analysis method without wavelet transform was also established. Intraperitoneal injection of KCl in zebrafish induced an arrhythmia similar to that of humans, and the arrhythmia was partially rescued by calcium gluconate. Amputation and cryoinjury of the zebrafish heart induced ST segment depression and affected QRS duration after injury. Only cryoinjury decelerated the heart rate. Different changes were also observed in the QT interval during heart regeneration in these two injury models. We also characterized the electrocardiophysiology of breakdance zebrafish mutant with a prolonged QT interval, that has not been well described in previous studies. Our study provided a reliable and reproducible means to record zebrafish ECG and analyse data. The detailed characterization of the cardiac electrophysiology of zebrafish and its mutant revealed that the potential of the zebrafish in modeling the human cardiovascular system exceeds expectations. PMID- 27125644 TI - The amyR-deletion strain of Aspergillus niger CICC2462 is a suitable host strain to express secreted protein with a low background. AB - BACKGROUND: The filamentous fungus Aspergillus niger is widely exploited as an important expression host for industrial production. The glucoamylase high producing strain A. niger CICC2462 has been used as a host strain for the establishment of a secretion expression system. It expresses recombinant xylanase, mannase and asparaginase at a high level, but some high secretory background proteins in these recombinant strains still remain, such as alpha amylase and alpha-glucosidase; lead to a low-purity of fermentation products. The aim was to construct an A. niger host strain with a low background of protein secretion. RESULTS: The transcription factor amyR was deleted in A. niger CICC2462, and the results from enzyme activity assays and SDS-PAGE analysis showed that the glucoamylase and amylase activities of the ?amyR strains were significantly lower than those of the wild-type strain. High-throughput RNA sequencing and shotgun LC-MS/MS proteomic technology analysis demonstrated that the expression of amylolytic enzymes was decreased at both the transcriptional and translational levels in the ?amyR strain. Interestingly, the ?amyR strain growth rate better than the wild-type strain. CONCLUSIONS: Our findings clearly indicated that the ?amyR strain of A. niger CICC2462 can be used as a host strain with a low background of protein secretion. PMID- 27125645 TI - Manganese exposure disrupts SNARE protein complex-mediated vesicle fusion in primary cultured neurons. AB - Overexposure to manganese (Mn) has been known to disrupt neurotransmitter release in the brain. However, the underlying mechanisms of Mn exposure on neurotransmitter vesicle release are still unclear. The current study investigated whether the protein expression and their interaction of SNARE complex associated proteins were the media between Mn exposure and neurotransmitter vesicle fusion disorders. After the neurons were respectively exposed to Mn (0-200 MUM) for 0, 6, 12, 18, 24 h, there were different degrees of cell injury in neurons. According to the results, Mn exposures in subsequent experiments were restricted to concentrations of 100 MUM for 0, 6, 12, 18, 24 h. Mn was found to down-regulate the expression of SNAP-25 and up-regulate the expression of VAMP-2 in cultured neurons. Moreover, the interaction of Munc 18 and Syntaxin increased significantly in response to Mn treatment for 18-24h, and the interaction of VAMP-2 and Synaptophysin increased first and then decreased. FM1-43-labeled synaptic vesicles also provided evidence that the treatment with Mn resulted in neurotransmitter vesicle fusion increasing first and then decreasing, which was consistent with the 80 kDa protein levels of SNARE complexes. The findings clearly demonstrated that Mn induced the disorders of neurotransmitter vesicle release via disturbing the protein expression and their interaction of SNARE complex associated proteins. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 705-716, 2017. PMID- 27125646 TI - A cohort study of the usefulness of primary prophylaxis in patients with severe haemophilia A. AB - Primary prophylaxis is a method of haemostatic management to prevent bleeding and arthropathy in patients with severe haemophilia. The aim of this study was to evaluate the usefulness of primary prophylaxis in patients with severe haemophilia A. This study included 15 patients with haemophilia A who received primary prophylaxis at our institution for a minimum of 5 years. We evaluated the annualized bleeding ratio of joints or other sites, current joint function, and X ray images and MRI scans taken when patients were 6 years old. The range of patients' ages at the end of the study was 6.2-16.8 years, and at the start of primary prophylaxis it was 0.8-2.4 years. Factor VIII concentrates (25-40 units kg(-1) dose(-1)) were administered 3 times/week or every other day, according to the Swedish protocol. Mean joint and non-joint annualized bleeding ratios were 0.49 +/- 0.5 and 1.54 +/- 1.69, respectively. At the final evaluation, all patients displayed a normal range of motion for both elbows, knees, and ankles. The radiography and MRI findings at the age of 6 were unremarkable in all patients. Overall, primary prophylaxis for patients with severe haemophilia A was performed safely, reduced the number of bleeding events, and prevented progression to arthropathy. PMID- 27125647 TI - Identification and Localization of Gold Nanoparticles in Potassium Ion Pores: Implications for Kir Blockade. AB - INTRODUCTION: In our previous study, we found that negatively charged gold nanoparticles with spermidine have the potential of blocking inwardly rectifying potassium channels (Kir), both at the cellular and the tissue level. METHODS: For the purpose of the present study, we purified the cytoplasmic domain of the Kir 3.1 receptor from Escherichia coli. Using single particles with surface coating by transmission electron microscopy, we identified the gold nanoparticles at the cytoplasmic side of the human Kir channel. RESULTS: Energy-dispersive X-ray spectroscopy showed the presence of the gold deposits in the cytoplasmic domain of the Kir receptor. CONCLUSION: In conclusion, we could identify undecagold in the ion pore of the Kir3.1 channel in order to clarify its direct blocking effect in the Kir ion pore by undecagold. PMID- 27125649 TI - HOXB13 expression in metastatic prostate cancer. PMID- 27125648 TI - TOMATO AGAMOUS1 and ARLEQUIN/TOMATO AGAMOUS-LIKE1 MADS-box genes have redundant and divergent functions required for tomato reproductive development. AB - Within the tomato MADS-box gene family, TOMATO AGAMOUS1 (TAG1) and ARLEQUIN/TOMATO AGAMOUS LIKE1 (hereafter referred to as TAGL1) are, respectively, members of the euAG and PLE lineages of the AGAMOUS clade. They perform crucial functions specifying stamen and carpel development in the flower and controlling late fruit development. To gain insight into the roles of TAG1 and TAGL1 genes and to better understand their functional redundancy and diversification, we characterized single and double RNAi silencing lines of these genes and analyzed expression profiles of regulatory genes involved in reproductive development. Double RNAi lines did show cell abnormalities in stamens and carpels and produced extremely small fruit-like organs displaying some sepaloid features. Expression analyses indicated that TAG1 and TAGL1 act together to repress fourth whorl sepal development, most likely through the MACROCALYX gene. Results also proved that TAG1 and TAGL1 have diversified their functions in fruit development: while TAG1 controls placenta and seed formation, TAGL1 participates in cuticle development and lignin biosynthesis inhibition. It is noteworthy that both TAG1 and double RNAi plants lacked seed development due to abnormalities in pollen formation. This seedless phenotype was not associated with changes in the expression of B class stamen identity genes Tomato MADS-box 6 and Tomato PISTILLATA observed in silencing lines, suggesting that other regulatory factors should participate in pollen formation. Taken together, results here reported support the idea that both redundant and divergent functions of TAG1 and TAGL1 genes are needed to control tomato reproductive development. PMID- 27125650 TI - Electromyographic studies regarding denervation potentials in skeletal muscles at sites near and distant from the burn in rats. AB - Changes in membrane AChRs in skeletal muscles located near or distant from burn injury similar to denervated muscles may make electrodiagnostic features indistinguishable from true neuropathic changes. The aim of this study was to examine electrodiagnostic changes of muscles at sites local and distant from the burn after thermal injuries due to neuromuscular junction dysfunction. A total of 40 adult male rats were randomly allocated to four groups. Rats in group 1 received thermal burn injury over gastrocnemius muscle of one leg and sham burn on the other leg. A 20-25% and 30-35% surface body area burn and also 30-35% surface body area sham burn were produced at distant site from gastrocnemius muscle in group 2, 3 and 4, respectively. To explore any fibrillation potential, the rats underwent serial electromyographic studies of bilateral gastrocnemius muscles over 5 weeks after burn injury. There were no denervation potentials either in muscles at sites distant from 20-25% and 30-35% of total body surface area burns or in muscles beneath the burn. In the present study on rats, thermal burn injury could not make fibrillation potentials in the electrodiagnostic study of muscles located near and distant from the burn site. PMID- 27125651 TI - H-NS binding to evpB and evpC and repressing T6SS expression in fish pathogen Edwardsiella piscicida. AB - Edwardsiella piscicida is an important causative agent of hemorrhagic septicemia in fish and infects both cultured and wild fish species. Type VI secretion system (T6SS) was proved to play important roles in pathogenesis of E. piscicida. In this study, it was demonstrated that the expression of T6SS genes evpB and evpC was under control of the global regulator H-NS in E. piscicida and the transcriptional level of evpB and evpC was significantly down-regulated by H-NS. Compared to the wild type, the transcriptional levels of evpB and evpC were up regulated in hns null mutant, while down-regulated in hns overexpression strain. The results of EMSA and DNase I footprinting revealed that H-NS protein directly bound to upstream region of evpC at multiple sites. A high-affinity motif with a 9-nucleotide sequence 5'-ATATAAAAT-3' was defined for H-NS preferential recognition based on the feature of the binding sites. These results indicated that H-NS acted cooperatively to form extended nucleoprotein filaments on target DNA. Site-directed mutagenesis of H-NS further showed that R86 played an essential role in T6SS gene binding. These findings highlighted the mechanisms underlying the complex regulation network of T6SS by H-NS in E. piscicida. PMID- 27125652 TI - Spongiimicrobium salis gen. nov., sp. nov., a bacterium of the family Flavobacteriaceae isolated from a marine sponge. AB - A Gram-stain-negative, strictly aerobic, pale-yellow pigmented, rod-shaped, chemoheterotrophic bacterium, designated A6F-11(T), was isolated from a marine sponge collected in Japan. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the novel marine strain was affiliated with the family Flavobacteriaceae of the phylum Bacteroidetes and that it shared the highest (92.9 %) sequence similarity with Arenibacter palladensis LMG 21972(T). The strain could be differentiated phenotypically from related members of the family Flavobacteriaceae. The major fatty acids of strain A6F-11(T) were iso-C15:1 G, iso-C15:0, C16:1 omega6c and/or C16:1 omega7c and iso-C17:0 3-OH. The polar lipid profile consisted of phosphatidylglycerol, two unidentified aminolipids and two unidentified lipids. The DNA G+C content was 34.7 mol%, and the major respiratory quinone was menaquinone 6 (MK-6). From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel taxon in the family Flavobacteriaceae, for which the name Spongiimicrobium salis gen. nov., sp. nov. is proposed. The type strain of S. salis gen. nov., sp. nov. is A6F-11(T) (= KCTC 42753(T) = NBRC 111401(T)). PMID- 27125654 TI - Model of Prey-Predator Dynamics with Reflexive Spatial Behaviour of Species Based on Optimal Migration. AB - We consider the model of spatially distributed community consisting of two species with "predator-prey" interaction; each of the species occupies two stations. Transfer of individuals between the stations (migration) is not random, and migration stipulates the maximization of net reproduction of each species. The spatial distribution pattern is provided by discrete stations, and the dynamics runs in discrete time. For each time moment, firstly a redistribution of individuals between the stations is carried out to maximize the net reproduction, and then the reproduction takes place, with the upgraded abundances. Besides, three versions of the basic model are implemented where each species implements reflexive behaviour strategy to determine the optimal migration flow. It was found that reflexivity gives an advantage to the species realizing such strategy, for some specific sets of parameters. Nevertheless, the regular scanning of the parameters area shows that non-reflexive behaviour yields an advantage in the great majority of parameters combinations. PMID- 27125653 TI - Gastrointestinal Complications in Patients Who Undergo Radical Cystectomy with Enhanced Recovery Protocol. AB - Gastrointestinal (GI) complications are among the most common complications following radical cystectomy and urinary diversion. The most common is postoperative ileus, although its precise pathophysiology is not completely understood. Enhanced recovery after surgery (ERAS) protocols include evidence based steps to optimize postoperative recovery and shorten hospital stay, mainly through expedited GI function recovery. They include avoiding bowel preparation and postoperative nasogastric tube, early feeding, non-narcotic pain management, and the use of cholinergic and mu-receptor opioid antagonists. We reviewed the literature in regard to GI complications using enhanced recovery protocols and share our institutional experience with over 300 patients. PMID- 27125655 TI - On Determining if Tree-based Networks Contain Fixed Trees. AB - We address an open question of Francis and Steel about phylogenetic networks and trees. They give a polynomial time algorithm to decide if a phylogenetic network, N, is tree-based and pose the problem: given a fixed tree T and network N, is N based on T? We show that it is [Formula: see text]-hard to decide, by reduction from 3-Dimensional Matching (3DM) and further that the problem is fixed-parameter tractable. PMID- 27125656 TI - Dynamical Models of Task Organization in Social Insect Colonies. AB - The organizations of insect societies, such as division of labor, task allocation, collective regulation, mass action responses, have been considered as main reasons for the ecological success. In this article, we propose and study a general modeling framework that includes the following three features: (a) the average internal response threshold for each task (the internal factor); (b) social network communications that could lead to task switching (the environmental factor); and (c) dynamical changes of task demands (the external factor). Since workers in many social insect species exhibit age polyethism, we also extend our model to incorporate age polyethism in which worker task preferences change with age. We apply our general modeling framework to the cases of two task groups: the inside colony task versus the outside colony task. Our analytical study of the models provides important insights and predictions on the effects of colony size, social communication, and age-related task preferences on task allocation and division of labor in the adaptive dynamical environment. Our study implies that the smaller size colony invests its resource for the colony growth and allocates more workers in the risky tasks such as foraging while the larger colony shifts more workers to perform the safer tasks inside the colony. Social interactions among different task groups play an important role in shaping task allocation depending on the relative cost and demands of the tasks. PMID- 27125658 TI - Hybrid engineered materials with high water-collecting efficiency inspired by Namib Desert beetles. AB - Inspired by Namib Desert beetles, a hybrid superhydrophobic surface was fabricated, showing highly efficient fog harvesting with a water collection rate (WCR) of 1309.9 mg h(-1) cm(-2). And, the surface possessed an excellent robustness and self-cleaning property. PMID- 27125657 TI - A Mathematical Model of Granule Cell Generation During Mouse Cerebellum Development. AB - Determining the cellular basis of brain growth is an important problem in developmental neurobiology. In the mammalian brain, the cerebellum is particularly amenable to studies of growth because it contains only a few cell types, including the granule cells, which are the most numerous neuronal subtype. Furthermore, in the mouse cerebellum granule cells are generated from granule cell precursors (gcps) in the external granule layer (EGL), from 1 day before birth until about 2 weeks of age. The complexity of the underlying cellular processes (multiple cell behaviors, three spatial dimensions, time-dependent changes) requires a quantitative framework to be fully understood. In this paper, a differential equation-based model is presented, which can be used to estimate temporal changes in granule cell numbers in the EGL. The model includes the proliferation of gcps and their differentiation into granule cells, as well as the process by which granule cells leave the EGL. Parameters describing these biological processes were derived from fitting the model to histological data. This mathematical model should be useful for understanding altered gcp and granule cell behaviors in mouse mutants with abnormal cerebellar development and cerebellar cancers. PMID- 27125659 TI - Silver containing hydrofiber dressing promotes wound healing in paediatric patients with partial thickness burns. AB - INTRODUCTION: Burn injury is one of the most common reasons for admission in paediatric population. There is currently no international consensus on the best wound dressing material. Aquacel Ag, a new silver containing hydrofiber dressing material has been reported to produce good clinical results. Yet, only a limited number of studies exist in the paediatric population. This study aims to review our experience of burn management over the past 5 years and to evaluate the effectiveness of Aquacel Ag in the management of partial thickness burns. METHODS: A retrospective review of all patients admitted for burn injury between January 2010 and December 2014 was conducted. Patients' demographics, mechanism of injury, body surface areas involved, treatment applied, and clinical outcomes were analyzed. Patients with superficial injury, full thickness burns that required surgical debridement, burn area less than 2 % or more than 25 % of total body surface area, or incomplete clinical data were excluded from the comparative study. RESULTS: A total of 119 patients were identified. 114 (96 %) was due to domestic injury, of which 108 (91 %) was food-related. The most commonly affected areas were limbs (n = 89, 74.8 %), followed by trunk (n = 62, 74.8). 84 patients fulfilled the inclusion criteria and were recruited into the study. 31 patients received Aquacel Ag dressing and 53 patients received standard paraffin gauze dressing. The two groups showed no statistical difference in age, sex, percentage of total body surface area involved, and infection rate. Outcomes of patients treated with Aquacel Ag were compared with patients treated with standard dressing. The mean hospital stay was significantly shorter for the Aquacel Ag group (14.26 vs 23.45, p = 0.045). Aquacel Ag group required much less frequent dressing change (5.67 vs 20.59, p = 0.002). 5 patients in standard dressing group developed hypertrophic scar and required prolonged pressure garment, whereas only one hypertrophic scar was observed in the Aquacel Ag group. CONCLUSION: Aquacel Ag appears to promote early burn wound healing with less hypertrophic scar formation. PMID- 27125660 TI - Environmental enrichment as a potential intervention for heroin seeking. AB - BACKGROUND: Heroin-related cues can trigger craving and relapse in addicts or heroin seeking in rats. In the present study we investigated whether environmental enrichment (EE) implemented after heroin exposure can reduce cue induced reinstatement of heroin seeking and expression of heroin conditioned place preference. METHODS: In Experiment 1, male Long Evans rats that already acquired a heroin self-administration habit, were housed in enriched or non enriched environments, underwent extinction training and later were tested for cue-induced reinstatement of heroin seeking. In Experiment 2, rats were conditioned with heroin in one compartment of a CPP apparatus and saline in the other, exposed to 30days of enrichment or no enrichment and were later tested for heroin CPP. RESULTS: The results showed that exposure to EE significantly reduced responding during the reinstatement test (Experiment 1) and prevented the expression of heroin CPP (Experiment 2). CONCLUSION: Our findings suggest that EE can be an effective behavioral approach to diminish the effects of conditioned cues on heroin seeking. PMID- 27125662 TI - Clinical significance of serum cortisol levels following surgery for congenital heart disease. AB - OBJECTIVE: Use of hydrocortisone to treat refractory haemodynamic instability in patients recovering from surgery for congenital heart disease is common practice at many centres. We aimed to determine whether there is a relationship between total serum cortisol concentrations and haemodynamic response to this therapy. Material and methods We retrospectively reviewed patients <21 years who underwent cardiac surgery from 2011 to 2013, received hydrocortisone within 72 hours postoperatively, and had total serum cortisol measurements contemporaneous with its administration. Favourable responders were defined as patients in whom, at 24 hours after hydrocortisone initiation, either (1) systolic blood pressure was increased or unchanged and vasoactive-inotrope score was decreased or (2) systolic blood pressure increased by ?10% of baseline and vasoactive-inotrope score was unchanged. Variables were compared using t-tests or Mann-Whitney U tests as appropriate. RESULTS: In total, 24 patients were reviewed, with a median age of 1.4 months and range of 0.1-232 months. Among them, 14 (58%) patients responded favourably to hydrocortisone. At 24 hours, the median change in vasoactive-inotrope score was -18% in favourable responders and +31% in those who did not respond favourably, p=0.001. The mean pre-hydrocortisone total serum cortisol in favourable responders was 17.4+/-10.9 ug/dl compared with 46.1+/-44.7 ug/dl in those who did not respond favourably, p=0.03. CONCLUSION: Total serum cortisol obtained before initiation of hydrocortisone was significantly lower in patients who responded favourably to this therapy. Total serum cortisol may therefore be helpful in identifying children recovering from cardiac surgery who may or may not haemodynamically improve with hydrocortisone. PMID- 27125661 TI - E-cigarette advertising exposure and implicit attitudes among young adult non smokers. AB - BACKGROUND: This study tested whether exposure to e-cigarette advertising affects the subliminal-spontaneous or automatic-attitudes towards e-cigarettes as a more pleasant or safer alternative to cigarettes among non-smoking young adults. METHODS: 187 young adult (mean age=21.9; SD=4.1) current non-smokers who had never used an e-cigarette were randomly assigned to one of the 3 conditions that involved viewing magazine advertisements. Two of the 3 conditions were experimental conditions where thematically different [harm-reduction ("Health") vs. social enhancement ("Social") focused] e-cigarette ads were interspersed among ads of everyday objects. The third condition was the control condition in which participants viewed ads of everyday objects only. Participants provided data on explicit (e.g., harm perceptions) and implicit [e.g., Implicit Association Test (IAT), Affect Misattribution Procedure (AMP)] measures after viewing the ads. RESULTS: Relative to the Control condition, participants in the Social condition showed 2.8 times higher odds of being open to using an e cigarette in the future. Participants in the Health condition showed significantly higher implicit attitudes towards e-cigarettes as a safer alternative to cigarettes than participants in the Control condition. E-cigarette stimuli elicited more positive spontaneous affective reactions among participants in the Social condition than participants in the Health condition. CONCLUSIONS: E cigarette ads may implicitly promote e-cigarettes as a reduced-harm cigarette alternative. Marketing of e-cigarette use as a way to enhance social life or self image may encourage non-smoking young adults to try e-cigarettes. Findings may inform regulations on e-cigarette marketing. PMID- 27125663 TI - Needle-array to Plate DBD Plasma Using Sine AC and Nanosecond Pulse Excitations for Purpose of Improving Indoor Air Quality. AB - In this study, needle-array to plate electrode configuration was employed to generate an atmospheric air diffuse discharge using both nanosecond pulse and sine AC voltage as excitation voltage for the purpose of improving indoor air quality. Different types of voltage sources and electrode configurations are employed to optimize electrical field distribution and improve discharge stability. Discharge images, electrical characteristics, optical emission spectra, and plasma gas temperatures in both sine AC discharge and nanosecond pulse discharge were compared and the discharge stability during long operating time were discussed. Compared with the discharge excited by sine AC voltage, the nanosecond pulsed discharge is more homogenous and stable, besides, the plasma gas temperature of nanosecond pulse discharge is much lower. Using packed-bed structure, where gamma- Al2O3 pellets are filled in the electrode gap, has obvious efficacy in the production of homogenous discharge. Furthermore, both sine AC discharge and nanosecond pulse discharge were used for removing formaldehyde from flowing air. It shows that nanosecond pulse discharge has a significant advantage in energy cost. And the main physiochemical processes for the generation of active species and the degradation of formaldehyde were discussed. PMID- 27125664 TI - Post-caesarean section surgical site infections at a Tanzanian tertiary hospital: a prospective observational study. AB - Few data are available on the determinants and characteristics of post-caesarean section (CS) surgical site infections (SSIs) in resource-limited settings. We conducted a prospective observational cohort study to evaluate the rates, determinants, and microbiological characteristics of post-CS SSI at the Dodoma Regional Referral Hospital (DRRH) Gynaecology and Obstetrics Department in Tanzania. Spanning a three-month period, all pregnant women who underwent CS were enrolled and followed up for 30 days. SSI following CS occurred in 224 (48%) women. Only 10 (2.1%) women received pre-incision antibiotic prophylaxis. Urgent intervention is needed to prevent and control infections and contain the rising rate of post-CS SSI at the DRRH. PMID- 27125665 TI - Effects of chronic forced circadian desynchronization on body weight and metabolism in male mice. AB - Metabolic functions are synchronized by the circadian clock setting daily patterns of food intake, nutrient delivery, and behavioral activity. Here, we study the impact of chronic jet-lag (CJL) on metabolism, and test manipulations aimed to overcome potential alterations. We recorded weight gain in C57Bl/6 mice under chronic 6 h advances or delays of the light-dark cycle every 2 days (ChrA and ChrD, respectively). We have previously reported ChrA, but not ChrD, to induce forced desynchronization of locomotor activity rhythms in mice (Casiraghi et al. 2012). Body weight was rapidly increased under ChrA, with animals tripling the mean weight gain observed in controls by day 10, and doubling it by day 30 (6% vs. 2%, and 15% vs. 7%, respectively). Significant increases in retroperitoneal and epidydimal adipose tissue masses (172% and 61%, respectively), adipocytes size (28%), and circulating triglycerides (39%) were also detected. Daily patterns of food and water intake were abolished under ChrA In contrast, ChrD had no effect on body weight. Wheel-running, housing of animals in groups, and restriction of food availability to hours of darkness prevented abnormal increase in body weight under ChrA Our findings suggest that the observed alterations under ChrA may arise either from a direct effect of circadian disruption on metabolism, from desynchronization between feeding and metabolic rhythms, or both. Direction of shifts, timing of feeding episodes, and other reinforcing signals deeply affect the outcome of metabolic function under CJL Such features should be taken into account in further studies of shift working schedules in humans. PMID- 27125666 TI - TNF/Ang-II synergy is obligate for fibroinflammatory pathology, but not for changes in cardiorenal function. AB - Angiotensin-II (Ang-II) infusion is associated with the development of interstitial fibrosis in both heart and kidney as a result of chemokine-dependent uptake of monocytes and subsequent development of myeloid fibroblasts. This study emphasizes on the synergistic role of tumor necrosis factor (TNF) on the time course of Ang-II-induced fibrosis and inflammation in heart and kidney. In wild type (WT) hearts, Ang-II-induced fibrosis peaked within 1 week of infusion and remained stable over a 6-week period, while the myeloid fibroblasts disappeared; TNF receptor-1-knockout (TNFR1-KO) hearts did not develop a myeloid response or cardiac fibrosis during this time. WT hearts developed more accelerated cardiac hypertrophy and remodeling than TNFR1-KO In the kidney, 1-week Ang-II infusion did not evoke a fibrotic response; however, after 6 weeks, WT kidneys displayed modest but significant tubulointerstitial collagen deposition associated with the appearance of myeloid cells and profibrotic gene activation. Renal fibrosis was not seen in Ang-II-infused TNFR1-KO By contrast, while hypertension increased and cardiac function decreased more slowly in TNFR1-KO than WT, they were equivalently abnormal at 6 weeks. Similarly, serum markers for renal dysfunction were not different after 6 weeks. In conclusion, Ang-II infusion initiated fibroinflammatory responses with different time courses in heart and kidney, both requiring TNFR1 signaling, and both associated with monocyte-derived myeloid fibroblasts. TNFR1 deletion obviated the fibroinflammatory effects of Ang-II, but did not alter changes in blood pressure and cardiorenal function after 6 weeks. Thus, the synergy of TNF with Ang-II targets the fibroinflammatory component of Ang-II signaling. PMID- 27125667 TI - The effect of temperature on proliferation and differentiation of chicken skeletal muscle satellite cells isolated from different muscle types. AB - Skeletal muscle satellite cells are a muscle stem cell population that mediate posthatch muscle growth and repair. Satellite cells respond differentially to environmental stimuli based upon their fiber-type of origin. The objective of this study was to determine how temperatures below and above the in vitro control of 38 degrees C affected the proliferation and differentiation of satellite cells isolated from the chicken anaerobic pectoralis major (p. major) or mixed fiber biceps femoris (b.femoris) muscles. The satellite cells isolated from the p. major muscle were more sensitive to both cold and hot temperatures compared to the b.femoris satellite cells during both proliferation and differentiation. The expressions of myogenic regulatory transcription factors were also different between satellite cells from different fiber types. MyoD expression, which partially regulates proliferation, was generally expressed at higher levels in p. major satellite cells compared to the b.femoris satellite cells from 33 to 43 degrees C during proliferation and differentiation. Similarly, myogenin expression, which is required for differentiation, was also expressed at higher levels in p. major satellite cells in response to both cold and hot temperatures during proliferation and differentiation than b. femoris satellite cells. These data demonstrate that satellite cells from the anaerobic p. major muscle are more sensitive than satellite cells from the aerobic b. femoris muscle to both hot and cold thermal stress during myogenic proliferation and differentiation. PMID- 27125668 TI - Germline RECQL mutations in high risk Chinese breast cancer patients. AB - Recently, RECQL was reported as a new breast cancer susceptibility gene. RECQL belongs to the RECQ DNA helicase family which unwinds double strand DNA and involved in the DNA replication stress response, telomere maintenance and DNA repair. RECQL deficient mice cells are prone to spontaneous chromosomal instability and aneuploidy, suggesting a tumor-suppressive role of RECQL in cancer. In this study, RECQL gene mutation screening was performed on 1110 breast cancer patients who were negative for BRCA1, BRCA2, TP53 and PTEN gene mutations and recruited from March 2007 to June 2015 in the Hong Kong Hereditary and High Risk Breast Cancer Program. Four different RECQL pathogenic mutations were identified in six of the 1110 (0.54 %) tested breast cancer patients. The identified mutations include one frame-shift deletion (c.974_977delAAGA), two splicing site mutations (c.394+1G>A, c.867+1G>T) and one nonsense mutation (c.796C>T, p.Gln266Ter). Two of the mutations (c.867+1G>T and p.Gln266Ter) were seen in more than one patients. This study provides the basis for existing of pathogenic RECQL mutations in Southern Chinese breast cancer patients. The significance of rare variants in RECQL gene in the estimation of breast cancer risk warranted further investigation in larger cohort of patients and in other ethnic groups. PMID- 27125669 TI - Phase II clinical study of eribulin monotherapy in Japanese patients with metastatic breast cancer who had well-defined taxane resistance. AB - No clinical evidence on the efficacy and safety of eribulin monotherapy has been obtained by a prospective clinical study in patients with metastatic breast cancer (MBC) who had well-defined taxane resistance. The present Phase II, multicenter, single-arm, open-label study aimed to obtain the evidence. Japanese female patients, aged 33-74 years who had the metastasis of taxane-resistant and histopathologically confirmed breast cancer, received eribulin mesylate 1.4 mg/m(2) (equivalent to eribulin 1.23 mg/m(2) [expressed as free base]) as a 2- to 5-min intravenous infusion on days 1 and 8 of each 21-day cycle. The primary endpoint was the clinical benefit rate (CBR) [complete response (CR), partial response (PR), and long-term stable disease (LSD) >=24 weeks]. A total of 51 patients underwent chemotherapy cycles (median 4; range 1-42 cycles). The CBR was 39.2 % (CR 2.0 %; PR 23.5 %; and LSD 13.7 %), and the rate of progressive disease was 49.0 %. The median progression-free survival and the median overall survival were 3.6 months [95 % confidence interval (CI) 2.6-4.6 months] and 11.7 months (95 % CI 9.2-14.2 months), respectively. Grade 3 or greater adverse events were leukopenia (23.5 %), neutropenia (35.3 %), anemia (5.9 %), and febrile neutropenia (7.8 %). The incidences of grade 3 and 4 peripheral sensory neuropathy were 2.0 and 0 %, respectively. Eribulin showed a clinically manageable tolerability profile by dose adjustments or symptomatic treatment. Eribulin was effective and well tolerated in heavily pretreated patients with MBC who had well-defined taxane resistance, thus providing a potential therapeutic option in the clinical settings. PMID- 27125670 TI - Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation. AB - Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of the antiviral-sensing pathway, is indispensible for interferon production and antiviral defense. However, how the status of IRF3 activation is controlled remains elusive. Through a functional screen of the human kinome, we found that mammalian sterile 20-like kinase 1 (Mst1), but not Mst2, profoundly inhibited cytosolic nucleic acid sensing. Mst1 associated with IRF3 and directly phosphorylated IRF3 at Thr75 and Thr253. This Mst1-mediated phosphorylation abolished activated IRF3 homodimerization, its occupancy on chromatin, and subsequent IRF3-mediated transcriptional responses. In addition, Mst1 also impeded virus-induced activation of TANK-binding kinase 1 (TBK1), further attenuating IRF3 activation. As a result, Mst1 depletion or ablation enabled an enhanced antiviral response and defense in cells and mice. Therefore, the identification of Mst1 as a novel physiological negative regulator of IRF3 activation provides mechanistic insights into innate antiviral defense and potential antiviral prevention strategies. PMID- 27125671 TI - The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells. AB - An open and decondensed chromatin organization is a defining property of pluripotency. Several epigenetic regulators have been implicated in maintaining an open chromatin organization, but how these processes are connected to the pluripotency network is unknown. Here, we identified a new role for the transcription factor NANOG as a key regulator connecting the pluripotency network with constitutive heterochromatin organization in mouse embryonic stem cells. Deletion of Nanog leads to chromatin compaction and the remodeling of heterochromatin domains. Forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin. NANOG associates with satellite repeats within heterochromatin domains, contributing to an architecture characterized by highly dispersed chromatin fibers, low levels of H3K9me3, and high major satellite transcription, and the strong transactivation domain of NANOG is required for this organization. The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG, and loss of Sall1 recapitulates the Nanog-null phenotype, but the loss of Sall1 can be circumvented through direct recruitment of the NANOG transactivation domain to major satellites. These results establish a direct connection between the pluripotency network and chromatin organization and emphasize that maintaining an open heterochromatin architecture is a highly regulated process in embryonic stem cells. PMID- 27125673 TI - Food-derived sensory cues modulate longevity via distinct neuroendocrine insulin like peptides. AB - Environmental fluctuations influence organismal aging by affecting various regulatory systems. One such system involves sensory neurons, which affect life span in many species. However, how sensory neurons coordinate organismal aging in response to changes in environmental signals remains elusive. Here, we found that a subset of sensory neurons shortens Caenorhabditis elegans' life span by differentially regulating the expression of a specific insulin-like peptide (ILP), INS-6. Notably, treatment with food-derived cues or optogenetic activation of sensory neurons significantly increases ins-6 expression and decreases life span. INS-6 in turn relays the longevity signals to nonneuronal tissues by decreasing the activity of the transcription factor DAF-16/FOXO. Together, our study delineates a mechanism through which environmental sensory cues regulate aging rates by modulating the activities of specific sensory neurons and ILPs. PMID- 27125674 TI - CD28 and PTPN22 are associated with susceptibility to rheumatoid arthritis in Egyptians. AB - OBJECTIVE: Limited data are available on the genetics of rheumatoid arthritis (RA) in Egyptians. Therefore, we investigated whether the confirmed genetic risk factors for RA in Europeans and/or Asians contribute to RA susceptibility in Egyptians. SUBJECTS AND METHODS: A set of seven single-nucleotide polymorphisms (SNPs) in the vicinity of CD28, TNFAIP3, PTPN22, PADI4 and HLA-DRA were tested in a large multi-centric RA cohort in Egypt, consisting of 394 cases and 398 matched controls. Patients were stratified based on the positivity of either anti citrullinated protein antibodies (ACPAs) or rheumatoid factor (RF). RESULTS: Significant association was evident for three SNPs in this cohort: the CD28 (rs1980422) variant showed a strong association in the whole cohort (P=0.000119) and in seropositive subsets of the disease (PACPA+=0.004; PRF+=0.0005). Upon stratification, the PTPN22 (rs2476601) and TNFAIP3(rs5029939) variants showed association only with ACPA positive (PACPA+=0.00573) and negative (PACPA =0.00999) phenotypes, respectively. CONCLUSION: Our results suggest that CD28(rs1980422) and PTPN22(rs2476601) contribute to RA-susceptibility in Egyptians. Failure to replicate the association of PADI4(rs2240340)/(PADI4_94) in Egyptian RA patients provides further support for the notion that genetic architecture of RA is different in multiple populations of European, Asian, African, and Middle Eastern ancestries. Further investigation using large-scale studies is thus needed to maximize the power of genetic association. PMID- 27125672 TI - Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma. AB - Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2(-/-)). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2(-/-) mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell autonomous mechanism. PMID- 27125675 TI - Curcumol Suppresses Breast Cancer Cell Metastasis by Inhibiting MMP-9 Via JNK1/2 and Akt-Dependent NF-kappaB Signaling Pathways. AB - Curcumolhas been reported to possess antitumor activity. However, its effect and mechanisms against tumor metastasis are still unclear. This study is to investigate the inhibitory effect of curcumol on breast cancer cell metastasis and elucidate the underlying molecular mechanisms. Our results showed that noncytotoxicity was caused by curcumol within 10 to 40 ug/mL in MDA-MB-231 and 4T1 cells for 24 hours, whereas sustained treatment with curcumol for 14 days significantly suppressed the clonogenic activity of cells. Importantly, curcumol at noncytotoxic concentrations suppressed the migration ability of both MDA-MB 231 and 4T1 cells. Moreover, curcumol suppressed the migration and invasion of MDA-MB-231 cells in the Boyden chamber migration and invasion assay and inhibited the adhesion of MDA-MB-231 cells onto the matrigel. Further investigations revealed that curcumol decreased the enzyme activity and protein expression of matrix metalloproteinase (MMP-9) in MDA-MB-231 cells. Moreover, curcumol inhibited the activation of c-Jun N-terminal kinase (JNK) 1/2 and Akt (Ser473). Meanwhile, it also inhibited the nuclear translocation and transcriptional activity of nuclear factor kappaB (NF-kappaB). Furthermore, JNK inhibitor SP600125 and Akt (Ser473) inhibitor LY294002 enhanced the inhibition of curcumol on NF-kappaB p65 nuclear translocation. Finally, supplementation with SP600125, LY294002, or NF-kappaB inhibitor Ammonium pyrrolidinedithiocarbamate (PDTC) significantly enhanced the inhibitory effect of curcumol on MMP-9 expression and cell migration, invasion, and adhesion in MDA-MB-231 cells. Our findings provide evidence for the suppression of breast cancer cell metastasis by curcumol and suggest that the inhibition of MMP-9 via JNK1/2 and Akt (Ser473)-dependent NF kappaB signaling pathways may be the underlying mechanisms. PMID- 27125676 TI - Influence of CD26/dipeptidyl peptidase IV deficiency on immunophenotypic changes during colitis development and resolution. AB - A lot of evidence for the importance of CD26/dipeptidyl peptidase IV (CD26/DPP IV) in immunoactivation has been reported; however, its involvement in colitis remains unclear. The aim of this study was to investigate the influence of CD26/DPP IV deficiency on immunophenotypic changes associated with dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) and CD26-deficient mice. Development of clinical symptoms of colitis and animal health status parameters were assessed; the expression of the nuclear factor (NF)-kappaB p65 subunit was measured by quantitative real-time PCR, while cell characterization was determined by flow cytometry and immunohistochemical staining. DSS treatment induced loss of body weight and colon length shortening in both mouse strains. An increase of myeloperoxidase activity in CD26-deficient mice was more intensive than in WT mice, in spite of similar histopathological changes. Furthermore, a significant increase in the expression of NF-kappaB p65 subunit in the colon of CD26-deficient mice was determined. The percentage of splenic CD4(+) and CD8(+) cells in the acute phase of colitis was significantly decreased in WT mice, while in the same period, an increase in the percentage of splenic CD8(+) cells was present in CD26-deficient mice. Development of colitis was accompanied by a significant increase in the percentage of intrahepatic NKT cells in both mouse strains, but their percentage in spleen was increased only in CD26-deficient mice. CD26 deficiency was associated with a heightened response to DSS accompanied by increased expression of NF-kappaB p65 subunit and distinct changes in leukocyte trafficking. These results provide new insights into the role of CD26/DPP IV during the development of colitis. PMID- 27125678 TI - On the vortex dynamics in fractal Fourier turbulence. AB - Incompressible, homogeneous and isotropic turbulence is studied by solving the Navier-Stokes equations on a reduced set of Fourier modes, belonging to a fractal set of dimension D . By tuning the fractal dimension parameter, we study the dynamical effects of Fourier decimation on the vortex stretching mechanism and on the statistics of the velocity and the velocity gradient tensor. In particular, we show that as we move from D = 3 to D ~ 2.8 , the statistics gradually turns into a purely Gaussian one. This result suggests that even a mild fractal mode reduction strongly depletes the stretching properties of the non-linear term of the Navier-Stokes equations and suppresses anomalous fluctuations. PMID- 27125677 TI - Acidocalcisomes of eukaryotes. AB - Acidocalcisomes are organelles rich in polyphosphate and cations and acidified by proton pumps. Although they have also been described in prokaryotes they have been better characterized in unicellular and multicellular eukaryotes. Eukaryotic acidocalcisomes belong to the group of lysosome-related organelles. They have a variety of functions, from the storage of cations and phosphorus to calcium signaling, autophagy, osmoregulation, blood coagulation, and inflammation. Acidocalcisomes of several unicellular eukaryotes possess a variety of transporters, channels and pumps implying a large energetic requirement for their maintenance and suggesting other important functions waiting to be discovered. PMID- 27125679 TI - Numerical investigation of molecular nano-array in potential-energy profile for a single dsDNA. AB - A Rigorous numerical investigation on dsDNA translocation in quasi-2-dimensional nano-array filter is performed using Molecular Dynamics (MD) method. Various dsDNA molecules with different sizes are chosen in order to model Ogston sieving in a nano-array filter. The radius of gyration of dsDNA molecule is less than the characteristic length of the shallow region in nano-array. The dsDNA molecule is assumed to be in the 0.05M NaCl electrolyte. MD shows acceptable results for potential-energy profile for nano-array filter. According to the MD outcomes, the dsDNA electrophoretic mobility decreases almost linearly with dsDNA size and show the same trend as Ogston sieving for gel electrophoresis. In addition, different shapes for nano-array filter are studied for a unique dsDNA molecule. It is concluded that steeping the nano-array wall can cause the retardation of dsDNA translocation and decreases dsDNA electrophoretic mobility. PMID- 27125681 TI - Advances in surgery for movement disorders. AB - Movement disorder surgery has evolved throughout history as our knowledge of motor circuits and ways in which to manipulate them have expanded. Today, the positive impact on patient quality of life for a growing number of movement disorders such as Parkinson's disease is now well accepted and confirmed through several decades of randomized, controlled trials. Nevertheless, residual motor symptoms after movement disorder surgery such as deep brain stimulation and lack of a definitive cure for these conditions demand that advances continue to push the boundaries of the field and maximize its therapeutic potential. Similarly, advances in related fields - wireless technology, artificial intelligence, stem cell and gene therapy, neuroimaging, nanoscience, and minimally invasive surgery mean that movement disorder surgery stands at a crossroads to benefit from unique combinations of all these developments. In this minireview, we outline some of these developments as well as evidence supporting topics of recent discussion and controversy in our field. Moving forward, expectations remain high that these improvements will come to encompass an even broader range of patients who might benefit from this therapy and decrease the burden of disease associated with these conditions. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27125680 TI - Postoperative Adverse Events Inconsistently Improved by the World Health Organization Surgical Safety Checklist: A Systematic Literature Review of 25 Studies. AB - BACKGROUND: The World Health Organization Surgical Safety Checklist (SSC) has been widely implemented in an effort to decrease surgical adverse events. METHOD: This systematic literature review examined the effects of the SSC on postoperative outcomes. The review included 25 studies: two randomised controlled trials, 13 prospective and ten retrospective cohort trials. A meta-analysis was not conducted as combining observational studies of heterogeneous quality may be highly biased. RESULTS: The quality of the studies was largely suboptimal; only four studies had a concurrent control group, many studies were underpowered to examine specific postoperative outcomes and teamwork-training initiatives were often combined with the implementation of the checklist, confounding the results. The effects of the checklist were largely inconsistent. Postoperative complications were examined in 20 studies; complication rates significantly decreased in ten and increased in one. Eighteen studies examined postoperative mortality. Rates significantly decreased in four and increased in one. Postoperative mortality rates were not significantly decreased in any studies in developed nations, whereas they were significantly decreased in 75 % of studies conducted in developing nations. CONCLUSIONS: The checklist may be associated with a decrease in surgical adverse events and this effect seems to be greater in developing nations. With the observed incongruence between specific postoperative outcomes and the overall poor study designs, it is possible that many of the positive changes associated with the use of the checklist were due to temporal changes, confounding factors and publication bias. PMID- 27125682 TI - Reaction pathway and oxidation mechanisms of dibutyl phthalate by persulfate activated with zero-valent iron. AB - This study investigated reaction pathway and oxidation mechanisms of dibutyl phthalate (DBP) by persulfate (PS) activated with zero-valent iron (ZVI). The DBP degradation was studied at three pH values (acidic, neutral and basic) in the presence of different organic scavengers. Using a chemical probe method, both sulfate radical (SO4(-)) and hydroxyl radical (.OH) were found to be primary oxidants at pH3.0 and pH7.0, respectively while .OH was the major specie to oxidize DBP at pH11.0. A similar result was found in an experiment of Electron Spin Resonance spin-trapping where in addition to OH, superoxide radical (O2(-)) was detected at pH11.0. The transformation of degradation products including dimethyl phthalate (DMP), diethyl phthalate (DEP), phthalic anhydride, and acetophenone exhibited diverse variation during the reaction processes. The phthalic anhydride concentration appeared to be maximum at all pHs. Another eleven intermediate products were also found at pH3.0 by GC-MS and HPLC analysis, and their degradation mechanisms and pathways were proposed. It was suggested that dealkylation, hydroxylation, decarboxylation and hydrogen extraction were the dominant degradation mechanisms of DBP at pH3.0. PMID- 27125683 TI - The variability in iron speciation in size fractionated residual oil fly ash particulate matter (ROFA PM). AB - Ambient particulate matter (PM) containing iron can catalyze Fenton reaction leading to the production of reactive oxygen species in cells. It can also catalyze atmospheric redox reaction. These reactions are governed by the physicochemical characteristics of iron in ambient PM. As a surrogate for ambient PM, we prepared residual oil fly ash PM (ROFA PM) in a practical fire tube boiler firing residual oils with varying sulfur and ash contents. The ROFA particles were resolved into fine PM or PM2.5 (aerodynamic diameter (AD)<2.5MUm) and coarse PM or PM2.5+ (AD between 2.5MUm and 50MUm). The iron speciation in PM2.5+ was ascertained using X-ray absorption spectroscopy and leaching method while that in PM2.5 was reported earlier. The results of both studies are compared to get an insight into the variability in the iron speciation in different size fractions. The results show the predominance of ferric sulfate, with a minor spinal ferrite in both PM (i.e. ZnxNi1-xFe2O4 in PM2.5, ZnFe2O4 in PM2.5+). The iron solubility in ROFA PM depends on its speciation, mode of incorporation of iron into particle's carbonaceous matrix, the grade and composition of oils, and pH of the medium. The soluble fraction of iron in PM is critical in assessing its interaction with the biological systems and its toxic potential. PMID- 27125684 TI - Temporal variation in groundwater quality in the Permian Basin of Texas, a region of increasing unconventional oil and gas development. AB - The recent expansion of natural gas and oil extraction using unconventional oil and gas development (UD) practices such as horizontal drilling and hydraulic fracturing has raised questions about the potential for environmental impacts. Prior research has focused on evaluations of air and water quality in particular regions without explicitly considering temporal variation; thus, little is known about the potential effects of UD activity on the environment over longer periods of time. Here, we present an assessment of private well water quality in an area of increasing UD activity over a period of 13months. We analyzed samples from 42 private water wells located in three contiguous counties on the Eastern Shelf of the Permian Basin in Texas. This area has experienced a rise in UD activity in the last few years, and we analyzed samples in four separate time points to assess variation in groundwater quality over time as UD activities increased. We monitored general water quality parameters as well as several compounds used in UD activities. We found that some constituents remained stable over time, but others experienced significant variation over the period of study. Notable findings include significant changes in total organic carbon and pH along with ephemeral detections of ethanol, bromide, and dichloromethane after the initial sampling phase. These data provide insight into the potentially transient nature of compounds associated with groundwater contamination in areas experiencing UD activity. PMID- 27125686 TI - Imbalanced presence of Borrelia burgdorferi s.l. multilocus sequence types in clinical manifestations of Lyme borreliosis. AB - In this study we used typing based on the eight multilocus sequence typing scheme housekeeping genes (MLST) and 5S-23S rDNA intergenic spacer (IGS) to explore the population structure of Borrelia burgdorferi sensu lato isolates from patients with Lyme borreliosis (LB) and to test the association between the B. burgdorferi s.l. sequence types (ST) and the clinical manifestations they cause in humans. Isolates of B. burgdorferi from 183 LB cases across Europe, with distinct clinical manifestations, and 257 Ixodes ricinus lysates from The Netherlands, were analyzed for this study alone. For completeness, we incorporated in our analysis also 335 European B. burgdorferi s.l. MLST profiles retrieved from literature. Borrelia afzelii and Borrelia bavariensis were associated with human cases of LB while Borrelia garinii, Borrelia lusitaniae and Borrelia valaisiana were associated with questing I. ricinus ticks. B. afzelii was associated with acrodermatitis chronica atrophicans, while B. garinii and B. bavariensis were associated with neuroborreliosis. The samples in our study belonged to 251 different STs, of which 94 are newly described, adding to the overall picture of the genetic diversity of Borrelia genospecies. The fraction of STs that were isolated from human samples was significantly higher for the genospecies that are known to be maintained in enzootic cycles by mammals (B. afzelii, B. bavariensis, and Borrelia spielmanii) than for genospecies that are maintained by birds (B. garinii and B. valaisiana) or lizards (B. lusitaniae). We found six multilocus sequence types that were significantly associated to clinical manifestations in humans and five IGS haplotypes that were associated with the human LB cases. While IGS could perform just as well as the housekeeping genes in the MLST scheme for predicting the infectivity of B. burgdorferi s.l., the advantage of MLST is that it can also capture the differential invasiveness of the various STs. PMID- 27125685 TI - Enhanced protection from fibrosis and inflammation in the combined absence of IL 13 and IFN-gamma. AB - Persistent or dysregulated IL-13 responses are key drivers of fibrosis in multiple organ systems, and this identifies this cytokine as an important therapeutic target. Nevertheless, the mechanisms by which IL-13 blockade leads to the amelioration of fibrosis remain unclear. Because IFN-gamma exhibits potent anti-fibrotic activity, and IL-4Ralpha signalling antagonizes IFN-gamma effector function, compensatory increases in IFN-gamma activity following IL-13/IL-4Ralpha blockade might contribute to the reduction in fibrosis. To investigate the role of IFN-gamma, we developed novel IL-13(-/-) /IFN-gamma(-/-) double cytokine deficient mice and examined disease progression in models of type 2-driven fibrosis. As predicted, we showed that fibrosis in the lung and liver are both highly dependent on IL-13. We also observed increased IFN-gamma production and inflammatory activity in the tissues of IL-13-deficient mice. Surprisingly, however, an even greater reduction in fibrosis was observed in IL-13/IFN-gamma double deficient mice, most notably in the livers of mice chronically infected with Schistosoma mansoni. The increased protection was associated with marked decreases in Tgfb1, Mmp12, and Timp1 mRNA expression in the tissues; reduced inflammation; and decreased expression of important pro-inflammatory mediators such as TNF-alpha. Experiments conducted with neutralizing monoclonal antibodies to IL-13 and IFN-gamma validated the findings with the genetically deficient mice. Together, these studies demonstrate that the reduction in fibrosis observed when IL-13 signalling is suppressed is not dependent on increased IFN-gamma activity. Instead, by reducing compensatory increases in type 1-associated inflammation, therapeutic strategies that block IFN-gamma and IL-13 activity simultaneously can confer greater protection from progressive fibrosis than IL-13 blockade alone. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 27125687 TI - A new trilocus sequence-based multiplex-PCR to detect major Acinetobacter baumannii clones. AB - A collection of 163 Acinetobacter baumannii isolates detected in a large Brazilian hospital, was potentially related with the dissemination of four clonal complexes (CC): 113/79, 103/15, 109/1 and 110/25, defined by University of Oxford/Institut Pasteur multilocus sequence typing (MLST) schemes. The urge of a simple multiplex-PCR scheme to specify these clones has motivated the present study. The established trilocus sequence-based typing (3LST, for ompA, csuE and blaOXA-51-like genes) multiplex-PCR rapidly identifies international clones I (CC109/1), II (CC118/2) and III (CC187/3). Thus, the system detects only one (CC109/1) out of four main CC in Brazil. We aimed to develop an alternative multiplex-PCR scheme to detect these clones, known to be present additionally in Africa, Asia, Europe, USA and South America. MLST, performed in the present study to complement typing our whole collection of isolates, confirmed that all isolates belonged to the same four CC detected previously. When typed by 3LST based multiplex-PCR, only 12% of the 163 isolates were classified into groups. By comparative sequence analysis of ompA, csuE and blaOXA-51-like genes, a set of eight primers was designed for an alternative multiplex-PCR to distinguish the five CC 113/79, 103/15, 109/1, 110/25 and 118/2. Study isolates and one CC118/2 isolate were blind-tested with the new alternative PCR scheme; all were correctly clustered in groups of the corresponding CC. The new multiplex-PCR, with the advantage of fitting in a single reaction, detects five leading A. baumannii clones and could help preventing the spread in healthcare settings. PMID- 27125688 TI - The synergy effect of daidzein and genistein isolated from Butea superba Roxb. on the reproductive system of male mice. AB - Butea superba Roxb. (BS) has been used in Thai men as an aphrodisiac, and prevent erectile dysfunction. Nevertheless, the active ingredients, dosages, have not been cleared. Hence, this study was to investigate the effect of compounds from the BS on the reproductive parameters of male mice. The results revealed that BS was extracted to afford biochanin A and genistein, which were first reported on BS, and daidzein. The mice were treated by daidzein and genistein alone and in combination. The results showed that the sperm number and motility, cholesterol and testosterone level of all isoflavones-treated groups were significantly higher than controls (p < 0.01). Obviously, daidzein plus genistein exhibited a synergistic effect, which is also the first report, and resulted in significantly displayed higher levels of these parameters compared to others. So, the synergistic activity of these isoflavones may be useful in improving libido, erectile capacity and assist infertility of poor spermatozoa in men. PMID- 27125689 TI - Sex differences in concordance rates between auditory event-related potentials and subjective sexual arousal. AB - Much research indicates men show a greater concordance between subjective and genital sexual arousal than do women. We investigated the relationship between subjective sexual arousal and brain activation in men and women. Subjective sexual arousal and auditory N1 and P3b ERP amplitudes were measured while 38 participants viewed erotic and non-erotic films. Most notably, there was a significant correlation between N1 amplitude and sexual arousal in men; for women, there was a significant correlation between the P3b amplitude and sexual arousal. ERP amplitudes were inversely associated with reported arousal, suggesting that sexual arousal interferes with early tone processing for men, and with later tone processing for women. Lastly, for women, pornography/erotica consumption was negatively correlated with P3b amplitudes, suggesting that women who consume more pornography/erotica may also show greater attention to erotic films. PMID- 27125690 TI - Effects of alpha-tocopherol and freezing rates on the quality and heterologous in vitro fertilization capacity of stallion sperm after cryopreservation. AB - The effects of supplementation of alpha-tocopherol and different freezing rates (FRs) on the ability of stallion sperm to fertilize bovine oocytes with intact zona pellucida were investigated, in an attempt to develop a model to assess cryopreserved sperm function. Semen was obtained from four purebred Lusitano stallions (n = 4). Each ejaculate was subjected to cryopreservation with a commercial extender (Ghent, Minitub Iberia, Spain), without any supplementation (control) or supplemented with 2-mM alpha-tocopherol. The semen was exposed to two different FRs between 5 degrees C and -15 degrees C: slow (5 degrees C/min) and moderate (10 degrees C/min). After thawing, the viability (SYBR(r)-14 and propidium iodide [PI]), mitochondrial membrane potential (JC-1, 5,5',6,6' tetrachloro-1,1',3,3'tetraethylbenzimidazolyl carbocyanine iodine) and membrane lipid peroxidation (C11-BODIPY(581/591)) of each sample were determined by flow cytometry. Moreover, the heterologous IVF rate was measured to evaluate the fertilization capacity of postthaw semen in the four different treatments. For both extenders, the viability was higher for spermatozoa cooled slowly (39.40 +/- 2.17 vs. 17.59 +/- 2.25-control; 31.96 +/- 2.19 vs. 11.46 +/- 1.34-Tocopherol; P < 0.05). The alpha-tocopherol extender improved (P < 0.05) postthaw lipid peroxidation (10.28 +/- 0.70 vs. 15.40 +/- 0.95-slow FR; 10.14 +/- 0.40 vs. 13.48 +/- 0.34-moderate FR); however, it did not improve viability and mitochondrial membrane potential. Regarding the IVF rate, in the moderate FR, alpha-tocopherol supplementation reported a higher percentage of IVF (20.50 +/- 2.11; P < 0.05), comparing with the control (14.00 +/- 1.84). Regarding the slow FR, no significance differences were observed for percentage of IVF between the two extenders and the FRs. However, it seems that the alpha-tocopherol supplementation improved the IVF rate. In conclusion, this research reported that bovine oocytes intact zona pellucida can be used to evaluate the quality of postthaw stallion semen and alpha-tocopherol supplementation in the stallion freezing extender might exert a protective effect against oxidative damage during heterologous IVF. PMID- 27125692 TI - Androgenetic development of X- and Y-chromosome bearing haploid rainbow trout embryos. AB - Haploid fish embryos are important in studies regarding role of the recessive traits during early ontogeny. In fish species with the male heterogamety, androgenetic haploid embryos might be also useful tool in studies concerning role of the sex chromosomes during an embryonic development. Morphologically differentiated X and Y chromosomes have been found in a limited number of fish species including rainbow trout (Oncorhynchus mykiss Walbaum 1792). To evaluate role of the sex chromosomes during rainbow trout embryonic development, survival of the androgenetic haploids in the presence of X or Y sex chromosomes has been examined. Androgenetic haploid rainbow trout were produced by fertilization of X irradiated eggs with spermatozoa derived from the normal males (XY) and neomales, that is, sex-reversed females (XX) to produce X- and Y-bearing haploids, and all X-bearing haploids, respectively. Survival rates of the androgenetic progenies of normal males and neomales examined during embryogenesis and at hatching did not differ significantly. However, all haploids died within next few days after hatching. Cytogenetic analysis of the androgenetic embryos confirmed their haploid status. Moreover, apart from the intact paternal chromosomes, residues of the irradiated maternal chromosomes observed as chromosome fragments were identified in some of the haploids. Provided results suggested that rainbow trout X and Y chromosomes despite morphological and genetic differences are at the early stage of differentiation and still share genetic information responsible for the proper embryonic development. PMID- 27125691 TI - Effect of heat stress on the survival and development of in vitro cultured bovine preantral follicles and on in vitro maturation of cumulus-oocyte complex. AB - The deleterious effect of heat stress (HS) on competence of oocytes from antral follicles is well recognized, but there is a lack of data regarding its impact on the viability and growth of preantral follicles. In this study, we used in vitro preantral follicle cultures to investigate the effects of HS on the following parameters: survival and development of primordial follicles after in vitro culture of ovarian fragments (experiment I); growth and antrum formation of isolated advanced secondary follicles (experiment II); and maturation rates after in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) from antral follicles (>2-6 mm) grown in vivo (experiment III). Furthermore, the following end points were evaluated in all experiments: follicle/oocyte survival, reactive oxygen species (ROS), estradiol (E2) and progesterone (P4) production, as well as mRNA expression for select genes related to stress (HSP70) and apoptosis (MCL1 and BAX). In all experiments, HS consisted of exposing the structures (ovarian fragments, isolated preantral follicles and COCs) to 41 degrees C for 12 hours and then to 38.5 degrees C until the end of the culture (7 days for experiments I and II and 24 hours for experiment III). The temperature for the control group was held at 38.5 degrees C for the entire culture period. Heat stress increased (P < 0.05) the percentage of developing follicles (intermediate, primary, and secondary follicles) at 12 hours and increased levels of ROS at all evaluated time points (12, 24 hours, and D7), when compared to the control (experiment I). Heat stress did not affect (P > 0.05) any identified end points when preantral follicles were cultured in their isolated form (experiment II). However, in experiment III, HS decreased (P < 0.05) both the rates of metaphase II after 24 hours and E2 production at 12 hours of IVM. Moreover, HS increased (P < 0.0001) levels of P4 after IVM and ROS production at every evaluated time point, compared with the control (12 and 24 hours). In conclusion, HS caused: (1) early activation of primordial follicles; (2) an increase in ROS production by early preantral follicles enclosed in ovarian tissue and by COCs; (3) a short-term reduction of E2 production by COCs; and (4) an increase in P4 secretion from COCs. However, HS did not affect in vitro culture of advanced isolated secondary follicles. Experimental evidence indicates that preantral follicles are less sensitive to HS than COC. PMID- 27125693 TI - The outcome of the first stages of pregnancy on mares' bloodstream thyroid hormones. AB - The objective of this study was to compare in detail the total and free iodothyronines' pattern of mares from the first ovulation of the year over an extended period of 12 weeks. A total of 20 mares were used in the study. The mares were classified into two groups: mares mated at the ovulation (n = 10) used as observational group and mares unmated at the ovulation (n = 10) used as control group. Serum total and free triiodothyronine (T3, fT3) and thyroxine (T4, fT4) levels were measured in baseline conditions at the first ovulation of year and once a week until 12 weeks later. For the experimental group, the first week of postovulation mating was considered as the first week of gestation. One-way analysis of variance showed a significant effect of time over 12 weeks for T3 (F = 2.44; P = 0.007) in pregnant mares, with the higher levels at the seventh and 12th weeks (P < 0.05) than baseline values, and for fT3 (F = 2.36; P = 0.009), with the higher levels at the 11th week (P < 0.05) than baseline values. Two-way analysis of variance showed a significant pregnancy effect compared with nonpregnancy stage for T3 (F = 15.82; P = 0.009), with the higher levels at the seventh and 12th weeks (P < 0.05) of pregnancy than that in nonpregnant values. Thus, it appears that, under similar environment, management and nutritional regime, the first trimester of pregnancy plays a dynamic role on the thyroid patterns by their anabolic activity; therefore, significant effects of time points on the T3 and fT3 concentrations probably may contribute to the control of early embryonic growth and development, before the onset of fetal thyroid activity. Considerable additional research, outwith the aim of this study, will be required to elucidate the mechanisms by which gestational age affects the physiological thyroid function in mares and/or fetus ratio in the first pregnancy stage. PMID- 27125694 TI - Elevated serum amyloid A levels in cases of aborted equine fetuses due to fetal and placental infections. AB - Determination of fetal serum amyloid A (SAA) concentrations in aborted fetuses can provide valuable information regarding the infectious and/or inflammatory process of abortion in horses. To investigate the relationship between fetal SAA levels and the infectious/inflammatory disease process in feto-placental tissues, a SAA ELISA was used to test heart serum samples of 89 equine fetuses that were necropsied and diagnosed in the following groups: a multiorgan disease process diagnosed with an identified microorganism (14 cases, group 1); only placentitis diagnosed with an identified microorganism (nine cases, group 2); only placentitis diagnosed with no microorganism identified (six cases, group 3); and no infectious or inflammatory disease process diagnosed (60 cases, group 4). Serum amyloid A concentrations in equine fetuses were elevated from 10.5 to >=40 mg/L in 10 of 14 cases in group 1; and from less than 2.5 mg/L to greater than 40 mg/L in seven of nine cases in group 2. In group 3, SAA concentrations were found to be less than 2.5 mg/L in five of six cases. In group 4, SAA concentrations were less than 2.5 mg/L in 55 cases, whereas in five cases SAA concentrations were elevated. Statistical significant differences were found between the concentrations of SAA in fetal horse blood and the presence of infectious and/or inflammatory disease process in the feto-placental tissues when a causative microorganism was identified. These results suggest that testing SAA concentrations in fetal heart blood may aid in further understanding the causes of abortions in horses. PMID- 27125695 TI - Reproductive seasonality and sperm cryopreservation in the male tufted deer (Elaphodus cephalophus). AB - The tufted deer is a small deer, listed as near threatened on the International Union for Conservation of Nature Red List, and there is no information on the fundamental reproductive biology of this species. In this study, we report for the first time, characterization of male reproductive traits and cryopreservation of semen in this species. Males were subjected to electroejaculation during each season (autumn, winter, spring, and summer), and ejaculates were assessed for motility and quality traits. Fecal samples were collected 3 to 5 times weekly for 2 years and analyzed for androgen metabolites using enzyme immunoassay. Ejaculates with greater than 70% motility were cryopreserved using Beltsville extender (BF5F) or Triladyl. Straws were thawed and assessed subjectively as well as swim-up processed to isolate motile spermatozoa for computer-assisted sperm analysis and acrosome integrity at hourly interval. Tufted deer male reproductive and semen traits peaked in autumn. Mean fecal androgen concentrations were highest in the summer compared with baseline values during rest of the year. Sperm motility and acrosome integrity were lower immediately after thawing in both cryodiluents compared with raw ejaculates. Motility characteristics after swim-up were higher in BF5F compared with Triladyl. Four hours after thawing, both percent sperm motility and progression decreased further and were similar between BF5F and Triladyl. However, the proportion of spermatozoa with intact acrosomal membranes was higher in BF5F than Triladyl. Results indicate that tufted deer exhibit seasonal variations in reproductive traits and that BF5F better preserves sperm motility and acrosomal integrity after cryopreservation compared with Triladyl. PMID- 27125697 TI - Energy balance influences number of ovulations rather than embryo quality in the pig. AB - The present study was undertaken to examine the effect of feed restriction on ovulation rate and in vivo blastocyst development in gilts and sows. In the first experiment, gilts were feed restricted (1 vs. 2.5 times maintenance requirement) during the luteal and follicular phases before ovulation. In the second experiment, primiparous sows were feed restricted (ad lib vs. 60% thereof) during the last week of lactation before weaning. Gilts and sows were slaughtered at 5 days after ovulation to determine ovulation rate and blastocyst development. Blastocysts were also differentially stained to determine the effect of feed restriction on total, trophectoderm, and inner cell mass cell numbers. In both experiments, feed restriction delayed ovulation and reduced the number of ovulations in gilts (14.8 +/- 1.3 vs. 12.0 +/- 0.2; P < 0.05) and in sows (19.9 +/- 1.0 vs. 18.4 +/- 0.7). The number of blastocysts recovered on Day 5 was similarly reduced in gilts (12.0 +/- 1.7 vs. 9.1 +/- 1.1; P < 0.10) and in sows (15.9 +/- 1.5 vs. 14.7 +/- 1.0). However, feed restriction did not affect total, trophectoderm, or inner cell mass cell numbers in gilts or sows. In conclusion, the present study reported that energy balance influences ovulation rate and blastocyst number rather than blastocyst viability as measured by cell number. PMID- 27125696 TI - Manipulation of reproductive performance of lactating buffaloes using melatonin and controlled internal drug release device treatment during out-of-breeding season under tropical conditions. AB - Twelve lactating Murrah buffalo, divided into control and treatment group of six animals each, were used to study the effect of melatonin and controlled internal drug release (CIDR) device treatment on the resumption of ovarian activity during out-of-breeding season (summer solstice). Treated group implanted with melatonin (18-mg melatonin/50-kg body weight) for 45 days and then animals of both groups received CIDR for 9 days. All animals received intramuscular 500 IU eCG, at day before CIDR removal, and 10-MUg GnRH at day after CIDR withdrawal. All animals were subjected to estrus detection daily. Blood samples in conjunction with transrectal ultrasonography were performed once a week to determine serum concentrations of melatonin, progesterone, and antioxidant enzyme activities, as well as to monitor the ovarian activity. Melatonin treatment resulted in an increase (P < 0.01) in the overall mean superoxide dismutase activity. Melatonin and CIDR increased the diameter of CL (P < 0.01) and plasma progesterone concentration (P < 0.05). In addition, melatonin and CIDR exhibited superior ability to maintain presence of CL at Day 21 and Day 30 after artificial insemination and achieved higher percentage of conception rate than control. In conclusion, the CIDR treatment preceded by melatonin improved the reproductive performance in lactating buffaloes during out-of-breeding season under tropical conditions. PMID- 27125698 TI - Fertility of Holstein heifers after two doses of PGF2alpha in 5-day CO-Synch progesterone-based synchronization protocol. AB - The objective of the study was to determine the effect of three different PGF2alpha (PGF) treatments in the 5-day CO-Synch progesterone-based synchronization protocol on artificial insemination (AI) pregnancy rate (PR) in Holstein heifers in Turkey and the United States. We hypothesized that two doses of PGF administered concurrently or 6 hours apart would result in greater AI pregnancy compared with a single dose of PGF on Day 5 at controlled internal drug release (CIDR) removal. In Turkey, Holstein heifers (n = 450) from one farm in the province of Adana and another farm in the province of Bursa were included. In the US, Holstein heifers (n = 483) from two locations in the state of Idaho were included. Heifers within locations were randomly allocated to one of three protocol groups: 1PGF-received 25 mg IM of dinoprost at CIDR removal; 2Co-PGF received 50 mg IM of dinoprost at CIDR removal, and 2PGF-received 25 mg IM of dinoprost at CIDR removal and an additional 25 mg IM of dinoprost 6 hours later. All heifers received a CIDR (1.38 g of progesterone) and GnRH (10 MUg IM of Buserelin [Turkey] or gonadorelin hydrochloride [US]) on Day 0. The CIDRs were removed on Day 5, and each heifer was given PGF according to the assigned treatments. On Day 7, each heifer was given another dose of GnRH and concurrently inseminated at 56 hours after CIDR removal. Heifers in both experiments were examined for pregnancy status between 35 and 45 days after AI. Overall, controlling for age, the heifers in the 2PGF group had greater AI-PR (61.7% [192/311]) than heifers in 2Co-PGF (48.2% [149/309]; P < 0.001) or 1PGF (53.7% [168/313]; P < 0.05) groups. No difference was observed between 2Co-PGF and 1PGF groups (P > 0.1). In Turkey, the heifers in the 2PGF group had a greater AI-PR (60% [90/150]) than 2Co-PGF (45.3% (68/150); P < 0.01] group. No difference was observed between 2PGF and 1PGF (55.3% [83/150]) groups (P > 0.1). There was a trend for AI pregnancy between 1PGF and 2Co-PGF groups (P = 0.08). In the United States, the heifers in the 2PGF group had a greater AI-PR (63.4% [102/161]) than the heifers in 2PGF (50.9 [81/159]; P < 0.05) or 1PGF (52.1% [85/163]; P < 0.05) groups. Heifers that were 15- and 16-month old achieved greater AI-PR than 17- and 18-month-old heifers (59.2 [342/578] vs. 47.0% [168/355]; P < 0.01). In conclusion, administration of 2PGF at 6 hours apart on Day 5 at CIDR removal in a 5-day CO-Synch + CIDR protocol resulted in greater AI pregnancy. A greater number of 15- and 16-month-old heifers became pregnant compared with 17- and 18-month old heifers. PMID- 27125699 TI - Maternal testosterone and reproductive outcome in a rat model of obesity. AB - Global sex differences in obesity rates are persistent, suggesting the involvement of sex steroids. In addition, adipose tissue is a metabolic site for steroidogenesis. Here, we compared female reproductive parameters in a rat model of obesity, with the same parameters in its lean control strain, and tested for an association with integrated measures of corticosterone and testosterone. Steroids were extracted and quantified from 17 Otsuka Long Evans Tokushima Fatty (OLETF; an animal model for obesity) and 13 Long Evans Tokushima Otsuka (LETO; the lean control strain) hair samples that were collected after weaning offspring. The obese OLETF mothers had higher hair testosterone levels than the control LETO strain. Overall, testosterone, but not corticosterone, predicted litter sex ratios. Younger mothers with large litters and older mothers with small litters tended to have the highest sex ratios (i.e., male-biased litters). In the lean LETO strain, but not in the obese OLETF, maternal testosterone was positively associated with litter size and number of male pups. Corticosterone did not differ between the two strains and was not associated with testosterone or with reproductive parameters. This study suggests that long-term circulating testosterone is associated with female reproduction in multiple ways. The possible trade-off between litter size and sex ratio may be mediated by testosterone and influenced by body fat and composition, which influence the individual's well-being. Exploring the multiple roles of testosterone in females may also help explain the complex relationship between obesity and reproduction. PMID- 27125700 TI - Small-Bowel Obstruction Due to Obturator Hernia. PMID- 27125701 TI - Gastric Perineurioma. PMID- 27125702 TI - Isolated Duodenal Varices Without Cirrhosis. PMID- 27125703 TI - A Prolapsing Pile Revealing Anal Squamous Cell Carcinoma. PMID- 27125704 TI - Giardiasis and Nodular Lymphoid Hyperplasia of the Duodenum. PMID- 27125705 TI - Massive Left Pleural Effusion After Endoscopic Variceal Therapy. PMID- 27125706 TI - Granulomatous Cheilitis Associated With Crohn's Disease. PMID- 27125707 TI - Black Esophagus. PMID- 27125709 TI - Continuing Medical Education: April 2016. PMID- 27125708 TI - Management of Hemorrhagic Walled-Off Necrosis Using the Multiple Transluminal Gateway Technique. PMID- 27125710 TI - Continuing Medical Education Questions: April 2016. PMID- 27125712 TI - Continuing Medical Education Questions: April 2016. PMID- 27125711 TI - Continuing Medical Education: April 2016. PMID- 27125713 TI - Clinical Impact of Elevated Serum Triglycerides in Acute Pancreatitis: Validation from the Nationwide Epidemiological Survey in Japan. PMID- 27125714 TI - Association Between Diverticulosis and Colonic Neoplasia: A Meta-Analysis. PMID- 27125715 TI - Safety and Efficacy of Live Measles Vaccine Administered to a Crohn's Disease Patient Receiving Vedolizumab. PMID- 27125716 TI - Pitfalls of Treating Alcoholic Hepatitis: Recognizing Hemolytic Anemia in Zieve's Syndrome. PMID- 27125717 TI - Mesalamine Does Not Help Prevent Recurrent Acute Colonic Diverticulitis: Meta Analysis of Randomized, Placebo-Controlled Trials. PMID- 27125718 TI - Triamcinolone Injection and Shielding with Polyglycolic Acid Sheets and Fibrin Glue for Postoperative Stricture Prevention after Esophageal Endoscopic Resection: A Pilot Study. PMID- 27125720 TI - Corrigendum: Long-Term Outcome of Endoscopic Resection vs. Surgery for Early Gastric Cancer: A Non-Inferiority-Matched Cohort Study. PMID- 27125721 TI - Corrigendum: Status of Competency-Based Medical Education in Endoscopy Training: A Nationwide Survey of US ACGME-Accredited Gastroenterology Training Programs. PMID- 27125722 TI - Thermal stability of a free nanotube from single-layer black phosphorus. AB - Similar to a carbon nanotube fabricated from a graphene sheet, a black phosphorus nanotube (BPNT) can also be theoretically produced by curling rectangular single layer black phosphorus (SLBP). In the present study, the effect of the thermal vibration of atoms on the failure of a BPNT is investigated using molecular dynamics simulations. Two types of double-shell BPNTs obtained by curling the SLBP along its armchair/pucker and zigzag directions respectively are involved in simulation. At finite temperature, a bond on the outer shell of the tube is under tension due to both the curvature of the tube and the serious thermal vibration of the atoms. As the length of a bond with such elongation approaches its critical value, i.e. 0.279 nm, or the smallest distance between two nonbonding phosphorus atoms is over 0.389 nm caused by a great variation of the bond angle, the tube fails quickly. The critical stable states of either an armchair or a zigzag BPNT at finite temperature are calculated and compared. To achieve a stable BPNT with high robustness, the tube should have a higher radius or should work at a lower temperature. Only when the BPNT has structural stability does it have the potential application as a nanowire in a future nano electro-mechanical system. PMID- 27125723 TI - Influence of V54M mutation in giant muscle protein titin: a computational screening and molecular dynamics approach. AB - Recent genetic studies have revealed the impact of mutations in associated genes for cardiac sarcomere components leading to dilated cardiomyopathy (DCM). The cardiac sarcomere is composed of thick and thin filaments and a giant muscle protein known as titin or connectin. Titin interacts with T-cap/telethonin in the Z-line region and plays a vital role in regulating sarcomere assembly. Initially, we screened all the variants associated with giant protein titin and analyzed their impact with the aid of pathogenicity and stability prediction methods. V54M mutation found in the hydrophobic core region of the protein associated with abnormal clinical phenotype leads to DCM was selected for further analysis. To address this issue, we mapped the deleterious mutant V54M, modeled the mutant protein complex, and deciphered the impact of mutation on binding with its partner telethonin in the titin crystal structure of PDB ID: 1YA5 with the aid of docking analysis. Furthermore, two run molecular dynamics simulation was initiated to understand the mechanistic action of V54M mutation in altering the protein structure, dynamics, and stability. According to the results obtained from the repeated 50 ns trajectory files, the overall effect of V54M mutation was destabilizing and transition of bend to coil in the secondary structure was observed. Furthermore, MMPBSA elucidated that V54M found in the Z-line region of titin decreases the binding affinity of titin to Z-line proteins T-cap/telethonin thereby hindering the protein-protein interaction. PMID- 27125724 TI - Two cases of Wolffian tumor with novel magnetic resonance imaging findings reflecting characteristic pathology. AB - A Wolffian tumor is a rare tumor arising from the remnants of the mesonephric duct. Herein, we report two cases. A 61-year-old woman presented with swollen left adnexa. On T2 weighted magnetic resonance imaging (MRI), a 4.4 cm solid pelvic mass showed slightly high signal intensity, with a low-signal-intensity rim. Microscopically, cuboidal cells with bland nuclei were arranged in a dense tubular form. A 40-year-old woman complained of lower abdominal pain. On T2 weighted MRI, a 6.0 cm solid mass with a low-signal-intensity rim was found. The pathology of the resected tumor was similar to that of case 1. Both cases were diagnosed as Wolffian tumor. The rims of the tumors in both cases were composed of eosinophilic spindle-shaped cells immunoreactive to alpha-smooth muscle actin and desmin, identical to the smooth muscle cells surrounding the mesonephric duct remnants. MRI findings reflecting smooth muscle rims might contribute to an accurate preoperative diagnosis of this rare tumor. PMID- 27125725 TI - Multidisciplinary team for elucidation of any new mutation and how this approach can be useful to individualize any genetic result: the case of BRCA2 c.631G>A/c.7008-2A>T genotype Response to: Nagy PL, Mansukhani M. The role of clinical genomic testing in diagnosis and discovery of pathogenic mutations. Expert Rev Mol Diagn 2015;15(9):1101-5. PMID- 27125726 TI - Synthesis and Characterization of Dirhenadehydro[12]annulenes. AB - The 12-membered-ring metallacycles [mer-Re{=CCH=C(R)C=C-}Cl(PMe2 Ph)3 )]2 (R=CMe3 , 1-adamantyl), which are organometallic analogues of antiaromatic octadehydro[12]annulene, are prepared by heating the methyl carbyne complexes mer Re{=CCH=C(R)C=CH}(CH3 )Cl(PMe2 Ph)3 . An intermolecular sigma-bond metathesis between the Re-CH3 bond and the acetylenic C-H bond is proposed for their formation. PMID- 27125727 TI - Transitioning from acute to primary health care nursing: an integrative review of the literature. AB - AIMS AND OBJECTIVES: This paper seeks to explore the transition experiences of acute care nurses entering employment in primary health care settings. BACKGROUND: Internationally the provision of care in primary health care settings is increasing. Nurses are moving from acute care settings to meet the growing demand for a primary health care workforce. While there is significant research relating to new graduate transition experiences, little is known about the transition experience from acute care into primary health care employment. DESIGN: An integrative review, guided by Whittemore and Knafl's (2005) approach, was undertaken. Following a systematic literature search eight studies met the inclusion criteria. METHODS: Papers which met the study criteria were identified and assessed against the inclusion and exclusion criteria. Papers were then subjected to methodological quality appraisal. Thematic analysis was undertaken to identify key themes within the data. RESULTS: Eight papers met the selection criteria. All described nurses transitioning to either community or home nursing settings. Three themes were identified: (1) a conceptual understanding of transition, (2) role losses and gains and (3) barriers and enablers. CONCLUSION: There is a lack of research specifically exploring the transitioning of acute care nurses to primary health care settings. To better understand this process, and to support the growth of the primary health care workforce there is an urgent need for further well-designed research. RELEVANCE TO CLINICAL PRACTICE: There is an increasing demand for the employment of nurses in primary health care settings. To recruit experienced nurses it is logical that many nurses will transition into primary health care from employment in the acute sector. To optimise retention and enhance the transition experience of these nurses it is important to understand the transition experience. PMID- 27125729 TI - A variant allele of the Mediterranean-fever gene increases the severity of gout. AB - BACKGROUND: Gout is a clinical syndrome that occurs as an inflammatory response to increased concentration of uric acid and monosodium urate crystals. Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease with autosomal recessive inheritance. The Mediterranean fever (MEFV) gene is responsible for FMF and encodes pyrin that suppresses the inflammatory response. Most of the FMF related mutations have been identified in exon 2 (e.g., E148Q and R202Q) and exon 10 (M680I, M694V, M694I and V726A) of the MEFV gene, and each missense mutation is known to increase production of interleukin-1, a proinflammatory cytokine. Our aim was to investigate effects of MEFV variant alleles on the manifestations of gout. METHODS: Seventy-one patients diagnosed with gout (age: 61.73 +/- 11.73 years, F/M: 14/57) and 50 healthy subjects (age: 61.48 +/- 11.97, F/M: 10/40) as controls were included in this study. RESULTS: MEFV variant alleles were found in 24 (33.8%) of the gout patients and in 13 (26%) of the control subjects; the difference was not statistically significant. In the gout patients with a MEFV variant allele, the interval between the first two attacks was shorter (P = 0.014), and the platelet count was higher (P = 0.026), compared to the patients without a variant allele. In addition, the patients with a MEFV variant allele showed the higher incidence of tophus (8.5% vs. 1.4%) (P = 0.005) and the higher number of attacks per year (P = 0.001). CONCLUSION: We propose that a variant allele of the MEFV gene may be responsible for the severity of gout. PMID- 27125730 TI - Poor adherence to staging guidelines for children with malignant ovarian tumors. AB - PURPOSE: Historically, surgical staging practices for pediatric malignant ovarian tumors mirrored adult guidelines. In 2004, the Children's Oncology Group (COG) developed guidelines specific to pediatric patients with ovarian germ cell tumors. We sought to characterize the operative management of pediatric ovarian lesions and adherence to COG surgical staging guidelines. METHODS: We conducted a single institution, retrospective study of pediatric patients who underwent surgical intervention for ovarian lesions between 1995 and 2012. The primary outcome was adherence to COG staging guidelines. RESULTS: Among 502 patients, 44 (8.8%) had malignant ovarian tumors. Two patients (2/44, 4.5%) underwent correct surgical staging. Therefore, 95.5% (42/44) underwent incorrect surgical staging by omitting recommended maneuvers (surgical understaging) or performing clinically unnecessary surgical staging steps (surgical overstaging). Of the 42 patients with incorrect surgical staging, 85.7% (36/42) were surgically overstaged and 76.2% (32/42) were surgically understaged. In the entire cohort, 12 (27.3%) patients had complete staging procedures, including 10 surgically overstaged patients (10/12, 83.3%). Staging practices were not significantly different before and after the release of the 2004 COG guidelines. CONCLUSION: Incorrect surgical staging of pediatric ovarian malignancies is commonplace. These data stress the need for greater education among all surgeons caring for children with malignant ovarian tumors. PMID- 27125731 TI - Heart failure patients' future expectations and their association with disease severity, quality of life, depressive symptoms and clinical outcomes. AB - BACKGROUND: Although treatment of heart failure (HF) patients has improved, prognosis still remains poor. Current HF Guidelines recommend communication about prognosis with all patients. Little is known about HF patients' awareness of their shortened life expectancy. AIM: To explore HF patients' future expectations and to examine whether these expectations are associated with disease severity, quality of life, depressive symptoms and clinical outcomes. METHOD: Patients randomised to the intervention groups of the COACH study, who were at the end of HF hospitalisation, were asked about their future expectations. Patients were divided into three groups: patients expecting improvement/stabilisation, patients expecting deterioration and those not knowing what to expect. Depressive symptoms were measured by CES-D and quality of life with the Ladder of Life and RAND-36. RESULTS: Six hundred and seventy eight patients (age 70 +/- 12; 41% female patients; LVEF 33% +/- 15) participated in the study. Most patients (56%, N = 380) expected improvement or stabilisation, 8% (N = 55) expected deterioration and 21% (N = 144) did not know what to expect for the future. Patients who expected to deteriorate were significantly older, experienced a lower quality of life and more depressive symptoms compared with patients in the other two groups. They also had a higher mortality rate, both after 18 and 36 months, and had more HF admissions. No association with severity of the disease (NYHA-class, LVEF, BNP levels) was found. CONCLUSION: Many hospitalised HF patients are not aware of their poor prognosis. Depressive symptoms, poor quality of life, increased mortality and rehospitalisation were related to expected deterioration. Improvement of communication about prognosis with HF patients is needed in the future. PMID- 27125732 TI - Livedo racemosa and hemolytic uremic syndrome induced by gemcitabine. PMID- 27125728 TI - Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease. AB - A variety of human neurologic diseases are caused by inherited defects in DNA repair. In many cases, these syndromes almost exclusively impact the nervous system, underscoring the critical requirement for genome stability in this tissue. A striking example of this is defective enzymatic activity of polynucleotide kinase-phosphatase (PNKP), leading to microcephaly or neurodegeneration. Notably, the broad neural impact of mutations in PNKP can result in markedly different disease entities, even when the inherited mutation is the same. For example microcephaly with seizures (MCSZ) results from various hypomorphic PNKP mutations, as does ataxia with oculomotor apraxia 4 (AOA4). Thus, other contributing factors influence the neural phenotype when PNKP is disabled. Here we consider the role for PNKP in maintaining brain function and how perturbation in its activity can account for the varied pathology of neurodegeneration or microcephaly present in MCSZ and AOA4 respectively. PMID- 27125733 TI - Liver-Specific Deletion of Integrin-Linked Kinase in Mice Attenuates Hepatotoxicity and Improves Liver Regeneration After Acetaminophen Overdose. AB - Acetaminophen (APAP) overdose is the major cause of acute liver failure in the US. Prompt liver regeneration is critical for recovery after APAP hepatotoxicity, but mechanisms remain elusive. Extracellular matrix (ECM)-mediated signaling via integrin-linked kinase (ILK) regulates liver regeneration after surgical resection. However, the role of ECM signaling via ILK in APAP toxicity and compensatory regeneration is unknown, which was investigated in this study using liver-specific ILK knockout (KO) mice. ILK KO and wild-type (WT) mice were treated with 300 mg/kg APAP, and injury and regeneration were studied at 6 and 24 h after APAP treatment. ILK KO mice developed lower liver injury after APAP overdose, which was associated with decreased JNK activation (a key mediator of APAP toxicity). Further, higher glutathione levels after APAP treatment and lower APAP protein adducts levels, along with lower levels of CYP2E1, suggest decreased metabolic activation of APAP in ILK KO mice. Interestingly, despite lower injury, ILK KO mice had rapid and higher liver regeneration after APAP overdose accompanied with increased beta-catenin signaling. In conclusion, liver-specific deletion of ILK improved regeneration, attenuated toxicity after APAP overdose, and decreased metabolic activation of APAP. Our study also indicates that ILK mediated ECM signaling plays a role in the regulation of CYP2E1 and may affect toxicity of several centrilobular hepatotoxicants including APAP. PMID- 27125734 TI - Coarse-grained modeling of RNA 3D structure. AB - Functional RNA molecules depend on three-dimensional (3D) structures to carry out their tasks within the cell. Understanding how these molecules interact to carry out their biological roles requires a detailed knowledge of RNA 3D structure and dynamics as well as thermodynamics, which strongly governs the folding of RNA and RNA-RNA interactions as well as a host of other interactions within the cellular environment. Experimental determination of these properties is difficult, and various computational methods have been developed to model the folding of RNA 3D structures and their interactions with other molecules. However, computational methods also have their limitations, especially when the biological effects demand computation of the dynamics beyond a few hundred nanoseconds. For the researcher confronted with such challenges, a more amenable approach is to resort to coarse-grained modeling to reduce the number of data points and computational demand to a more tractable size, while sacrificing as little critical information as possible. This review presents an introduction to the topic of coarse-grained modeling of RNA 3D structures and dynamics, covering both high- and low resolution strategies. We discuss how physics-based approaches compare with knowledge based methods that rely on databases of information. In the course of this review, we discuss important aspects in the reasoning process behind building different models and the goals and pitfalls that can result. PMID- 27125736 TI - Klotho-Related Protein KLrP: Structure and Functions. AB - Klotho (KL) family proteins share one or two glycoside hydrolase (GH) motifs homologous to GH family 1. However, the biological significance of GH motifs in KL family proteins remains elusive. We describe here that KL-related protein (KLrP), which is composed of a single GH motif, is a cytosolic beta glucocerebrosidase (GCase, EC 3.2.1.145). We detected a neutral conduritol B epoxide (CBE)-insensitive glucosylceramide (GlcCer)-degrading activity in the cytosol fractions of human fibroblasts, rat brains, and zebrafish embryos. KL family proteins emerged as a potent candidate for the neutral GCase using a bioinformatics approach. Recombinant human KLrP, but not alpha-KL, beta-KL, or KLPH, exhibited GCase activity with a neutral pH optimum in the presence of CBE. We solved the crystal structures of KLrP and a KLrP mutant (E165Q) in complex with glucose, which indicate that KLrP forms a (beta/alpha)8TIM barrel structure with the double-displacement mechanism of the retaining beta-glycosidase. Furthermore, knockdown of endogenous KLrP in CHOP cells using small interfering RNA (siRNA) decreased the CBE-insensitive neutral GCase activity and increased the cellular levels of GlcCer, which suggests that KLrP is involved in a novel GlcCer catabolism pathway. A KLrP D106N mutant was discovered in patients with severe Gaucher disease; however, this mutation did not affect the GCase activity of KLrP. PMID- 27125735 TI - The RNA 3D Motif Atlas: Computational methods for extraction, organization and evaluation of RNA motifs. AB - RNA 3D motifs occupy places in structured RNA molecules that correspond to the hairpin, internal and multi-helix junction "loops" of their secondary structure representations. As many as 40% of the nucleotides of an RNA molecule can belong to these structural elements, which are distinct from the regular double helical regions formed by contiguous AU, GC, and GU Watson-Crick basepairs. With the large number of atomic- or near atomic-resolution 3D structures appearing in a steady stream in the PDB/NDB structure databases, the automated identification, extraction, comparison, clustering and visualization of these structural elements presents an opportunity to enhance RNA science. Three broad applications are: (1) identification of modular, autonomous structural units for RNA nanotechnology, nanobiology and synthetic biology applications; (2) bioinformatic analysis to improve RNA 3D structure prediction from sequence; and (3) creation of searchable databases for exploring the binding specificities, structural flexibility, and dynamics of these RNA elements. In this contribution, we review methods developed for computational extraction of hairpin and internal loop motifs from a non redundant set of high-quality RNA 3D structures. We provide a statistical summary of the extracted hairpin and internal loop motifs in the most recent version of the RNA 3D Motif Atlas. We also explore the reliability and accuracy of the extraction process by examining its performance in clustering recurrent motifs from homologous ribosomal RNA (rRNA) structures. We conclude with a summary of remaining challenges, especially with regard to extraction of multi-helix junction motifs. PMID- 27125737 TI - The FGF21 Receptor Signaling Complex: Klothobeta, FGFR1c, and Other Regulatory Interactions. AB - Scientific evidence is quickly growing that establishes FGF21 as a cytokine that signals both locally and systemically to induce metabolic effects. The focus of this chapter is the receptor/co-receptor signaling complex formed by endocrine FGF21. We provide an introduction to the major components of the complex including the Klotho family of co-receptors, fibroblast growth factor receptors (FGFRs), and the fibroblast growth factor ligands, placing each in the context of its own family members while emphasizing structural features that drive interaction. We subsequently focus specifically on FGF21 signaling through FGFR1c and KLB, describing what is known about each protein's structure and how this drives protein interaction and formation of the signaling complex at the plasma membrane. We subsequently explore the stoichiometry of FGFR1c and KLB at the plasma membrane before and after the addition of FGF21 ligand, comparing how unique features of the interaction could potentially affect signaling intensity. Finally, we discuss how formation of the signaling complex is potentially regulated by other regulatory interactions, including galectins, the extracellular matrix, and co-expression of FGFR5. PMID- 27125739 TI - Klotho and the Growth Hormone/Insulin-Like Growth Factor 1 Axis: Novel Insights into Complex Interactions. AB - The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is pivotal for many metabolic functions, including proper development and growth of bones, skeletal muscles, and adipose tissue. Defects in the axis' activity during childhood result in growth abnormalities, while increased secretion of GH from the pituitary results in acromegaly. In order to keep narrow physiologic concentration, GH and IGF-1 secretion and activity are tightly regulated by hypothalamic, pituitary, endocrine, paracrine, and autocrine factors. Klotho was first discovered as an aging-suppressor gene. Mice that do not express klotho die prematurely with multiple symptoms of aging, several of them are also characteristic of decreased GH/IGF-1 axis activity. Klotho is highly expressed in the brain, the kidney, and parathyroid and pituitary glands, but can also serve as a circulating hormone by its shedding, forming soluble klotho that can be detected in blood, cerebrospinal fluid, and urine. Several lines of evidence suggest an association between klotho levels and activity of the GH/IGF-1 axis: the GH-secreting cells in the anterior pituitary of klotho-deficient mice are hypotrophic; klotho levels are altered in subjects with pathologies of the GH/IGF 1 axis; and accumulating data indicate that klotho is a direct regulator of GH secretion. Thus, klotho seems to be a new player in the intricate regulation of the GH/IGF-1 axis. PMID- 27125738 TI - Klotho-Dependent Cellular Transport Regulation. AB - Klotho is a transmembrane protein that in humans is encoded by the hKL gene. This protein is known to have aging suppressor effects and is predominantly expressed in the distal convoluted tubule of the kidney, parathyroid glands, and choroid plexus of the brain. The Klotho protein exists in both full-length membrane form and a soluble secreted form, which exerts numerous distinct functions. The extracellular domain of Klotho can be enzymatically cleaved off and released into the systemic circulation where it functions as beta-glucuronidase and a hormone. Soluble Klotho is a multifunction protein present in the biological fluids including blood, urine, and cerebrospinal fluid of mammals. Klotho deficiency leads to multiple organ failure accompanied by early appearance of multiple age related disorders and early death, whereas overexpression of Klotho results in the opposite effects. Klotho, an enzyme and hormone, has been reported to participate in the regulation of cellular transport processes across the plasma membrane either indirectly through inhibiting calcitriol (1,25(OH)2D3) formation or other mechanism, or by directly affecting transporter proteins, including ion channels, cellular carriers, and Na(+)/K(+)-ATPase. Accordingly, Klotho protein serves as a powerful regulator of cellular transport across the plasma membrane. Importantly, Klotho-dependent cellular transport regulation implies stimulatory or inhibitory effects. Klotho has been shown to play a key role in the regulation of multiple calcium and potassium ion channels, and various cellular carriers including the Na(+)-coupled cotransporters such as NaPi-IIa, NaPi-IIb, EAAT3, and EAAT4, CreaT1 as well as Na(+)/K(+)-ATPase. These regulations are parts of the antiaging function of Klotho, which will be discussing throughout this chapter. Clearly, further experimental efforts are required to investigate the effect of Klotho on other transport proteins and underlying molecular mechanisms by which Klotho exerts its effect. PMID- 27125740 TI - Klotho Prevents Translocation of NFkappaB. AB - Klotho protein is a beta-glucuronidase capable of hydrolyzing steroid beta glucuronides. Two molecules are produced by the Klotho gene, a membrane bound form and a circulating form. This protein is recognized as an antiaging gene with pleiotropic functions. The activation of cellular systems is associated with the pathogenesis of several chronic and degenerative diseases associated with an inflammatory state. Inflammation is characterized by an activation of NFkappaB. Klotho suppresses nuclear factor NFkappaB activation and the subsequent transcription of proinflammatory genes. This review focuses on the current understanding of Klotho protein function and its relationship with NFkappaB regulation, emphasizing its potential involvement in the pathophysiologic process. PMID- 27125741 TI - The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders. AB - The functions of Klotho (KL) are multifaceted and include the regulation of aging and mineral metabolism. It was originally identified as the gene responsible for premature aging-like symptoms in mice and was subsequently shown to function as a coreceptor in the fibroblast growth factor (FGF) 23 signaling pathway. The discovery of KL as a partner for FGF23 led to significant advances in understanding of the molecular mechanisms underlying phosphate and vitamin D metabolism, and simultaneously clarified the pathogenic roles of the FGF23 signaling pathway in human diseases. These novel insights led to the development of new strategies to combat disorders associated with the dysregulated metabolism of phosphate and vitamin D, and clinical trials on the blockade of FGF23 signaling in X-linked hypophosphatemic rickets are ongoing. Molecular and functional insights on KL and FGF23 have been discussed in this review and were extended to how dysregulation of the FGF23/KL axis causes human disorders associated with abnormal mineral metabolism. PMID- 27125743 TI - The Role of Alpha-Klotho as a Universal Tumor Suppressor. AB - The klotho gene is implicated in many physiological activities, among them aging, glucose metabolism, and phosphate and calcium metabolism. Many cellular activities of klotho were implicated in promoting these activities. Two of them, inhibition of the insulin-like growth factor-1 pathway and of the Wnt signaling pathway, are also major pathways associated with cancer development and progression. These discoveries prompted a surge of research aiming to elucidate the role of klotho in cancer. Studies show that klotho is universally silenced in a wide array of malignancies, including breast, pancreatic, ovarian, lung, colorectal, and melanoma, and that klotho's expression can serve as an invaluable prognostic marker. Epigenetic mechanisms, ie, promoter hypermethylation and histone deacetylation, are mainly associated with klotho's silencing; however, different micro-RNAs were also demonstrated to be involved in the process. The activity of klotho on cancer cells growth was also widely investigated, and accumulating data suggest that klotho forced expression or treatment with the soluble protein can inhibit cancer development and progression. Moreover, studies now aim to reveal the specific region in klotho protein that underlies this anticancer activity in order to develop efficient and safe klotho-based medications. PMID- 27125742 TI - MicroRNA-34a and Impaired FGF19/21 Signaling in Obesity. AB - The obesity epidemic and the urgent need for effective and safe drugs to treat obesity-related diseases have greatly increased research interest in the metabolic hormones, fibroblast growth factor-19 (FGF19, FGF15 in mice), and FGF21. FGF19 and FGF21 function as endocrine hormones that play key roles in energy metabolism and counteract obesity. Importantly, in obese humans and lab animals, circulating FGF19 and FGF21 levels are elevated, and metabolic actions of these hormones are impaired but the underlying mechanisms remained unknown. Recent microRNA (miR) studies have revealed that aberrantly elevated miR-34a in obesity directly targets beta-Klotho, the obligate coreceptor for both FGF19 and FGF21, and attenuates metabolic signaling of these hormones. In this review, we will discuss recent findings in the miR and FGF19/21 fields, emphasizing the novel function of obesity-associated miR-34a in attenuation of FGF19/21 metabolic actions, and further discuss miRs, including miR-34a, as potential drug targets for obesity-related diseases. PMID- 27125744 TI - Klotho Is a Neuroprotective and Cognition-Enhancing Protein. AB - In this chapter, we will describe what has been learned about Klotho and its potential functions in the brain. Klotho is localized in the choroid plexus and, to a lesser extent, in hippocampal neurons. Cognitive decline is a common issue in human aging affecting over 50% of the population. This cognitive decline can also be seen in animal models such as the Rhesus monkey. A long-term study undertaken by our lab demonstrated that normal brain aging in rhesus monkeys and other animal models is associated with a significant downregulation of Klotho expression. This observation substantiates data from other laboratories that have reported that loss of Klotho accelerates the development of aging-like phenotypes, including cognitive deficits, whereas Klotho overexpression extends life span and enhances cognition in mice and humans. Klotho is a type 1 transmembrane pleiotropic protein predominantly expressed in kidney and brain and shed by ADAM 10 and 17 into the blood and cerebral spinal fluid, respectively. While the renal functions of Klotho are well known, its roles in the brain remain to be fully elucidated. We recently demonstrated that Klotho protects hippocampal neurons from amyloid and glutamate toxicity via the activation of an antioxidant enzymatic system suggesting Klotho is a neuroprotective protein. Furthermore, Klotho is necessary for oligodendrocyte maturation and myelin integrity. Through its diverse roles in the brain, Klotho has become a new therapeutic target for neurodegenerative diseases such as Alzheimer's disease and demyelinating diseases like multiple sclerosis. Discovery of small molecule Klotho enhancers may lead to novel treatments for these incurable disorders. PMID- 27125745 TI - Function and Change with Aging of alpha-Klotho in the Kidney. AB - The alpha-Klotho mouse is an animal model that prematurely shows phenotypes resembling human aging, such as osteoporosis, arteriosclerosis, pulmonary emphysema, and kidney damage. Interestingly, these abnormalities are triggered by a deficiency of a single protein, alpha-Klotho. The kidney is an organ that highly expresses alpha-Klotho, suggesting that alpha-Klotho is important for kidney function. Recent studies suggest that alpha-Klotho is associated with phosphate, vitamin D, and calcium homeostasis. The calcium imbalance in alpha Klotho mice may induce calpain overactivation, leading to cell death and tissue destruction. alpha-Klotho is predicted to have glycosidase activity, capable of modifying the N-glycans of channels and transporters and regulating transmembrane movement of several ions, including calcium. Interestingly, N-glycan changes are observed in the kidney of alpha-Klotho mice and normal aged mice in association with decreased alpha-Klotho levels. These results imply that glycobiology and alpha-Klotho function are interesting targets for future studies. PMID- 27125748 TI - Preface. PMID- 27125747 TI - Deficiency of Soluble alpha-Klotho as an Independent Cause of Uremic Cardiomyopathy. AB - Cardiovascular disease (CVD) is the major cause of mortality for patients with chronic kidney disease (CKD). Cardiac hypertrophy, occurring in up to 95% patients with CKD (also known as uremic cardiomyopathy), increases their risk for cardiovascular death. Many CKD-specific risk factors of uremic cardiomyopathy have been recognized, such as secondary hyperparathyroidism, indoxyl sulfate (IS)/p-cresyl, and vitamin D deficiency. However, several randomized controlled trials have recently shown that these risk factors have little impact on the mortality of CVD. Klotho is a type 1 membrane protein predominantly produced in the kidney, and CKD is known to be a Klotho-deficient state. Because of its important role in FGF23 and phosphate metabolism, Klotho is believed to affect cardiac growth and function indirectly through FGF23 and phosphate. Recent studies showed that soluble Klotho protects the heart against stress-induced cardiac hypertrophy by inhibiting TRPC6 channel-mediated abnormal Ca(2+) signaling in the heart, and the decreased level of circulating soluble Klotho in CKD is an important cause of uremic cardiomyopathy independent of FGF23 and phosphate. These new evidence suggested that Klotho is an independent contributing factor for uremic cardiomyopathy and a possible new target for treatment of this disease. PMID- 27125750 TI - Isolation of bacterial strains able to metabolize lignin and lignin-related compounds. AB - In this study, we identified five strains isolated from soil and sediments able to degrade kraft lignin, aromatic dyes and lignin derivatives. Using 16S rRNA gene sequencing, the isolates were identified as Serratia sp. JHT01, Serratia liquefacien PT01, Pseudomonas chlororaphis PT02, Stenotrophomonas maltophilia PT03 and Mesorhizobium sp. PT04. All the isolates showed significant growth on lignin with no water-extractable compounds. Synthetic aromatic dyes were used to assess the presence of oxidative enzymes. All the isolates were able to use the thiazine dye Methylene blue and the anthraquinone dye Remazol Brilliant Blue R as the sole carbon source. Guaiacol, veratryl alcohol and biphenyl were also mineralized by all the strains isolated. These results suggest they could be used for the treatment of aromatic pollutants and for the degradation of the lignocellulosic biomass. SIGNIFICANCE AND IMPACT OF THE STUDY: The valorization of waste lignin and lignocellulosic biomass by biocatalysis opens up new possibilities for the production of value-added substituted aromatics, biofuel and for the treatment of aromatic pollutants. Bacteria with ligninolytic potential could be a source of novel enzymes for controlled lignin depolymerization. In this work, five soil bacteria were isolated and studied. Every isolate showed significant growth on lignin and was able to degrade several lignin monomers and ligninolytic indicator dyes. They could thus be a source of novel ligninolytic enzymes as well as candidates for a bacterial consortium for the delignification of lignocellulosic biomass. PMID- 27125749 TI - Polysaccharide-capped silver Nanoparticles inhibit biofilm formation and eliminate multi-drug-resistant bacteria by disrupting bacterial cytoskeleton with reduced cytotoxicity towards mammalian cells. AB - Development of effective anti-microbial therapeutics has been hindered by the emergence of bacterial strains with multi-drug resistance and biofilm formation capabilities. In this article, we report an efficient green synthesis of silver nanoparticle (AgNP) by in situ reduction and capping with a semi-synthetic polysaccharide-based biopolymer (carboxymethyl tamarind polysaccharide). The CMT capped AgNPs were characterized by UV, DLS, FE-SEM, EDX and HR-TEM. These AgNPs have average particle size of ~20-40 nm, and show long time stability, indicated by their unchanged SPR and Zeta-potential values. These AgNPs inhibit growth and biofilm formation of both Gram positive (B. subtilis) and Gram negative (E. coli and Salmonella typhimurium) bacterial strains even at concentrations much lower than the minimum inhibitory concentration (MIC) breakpoints of antibiotics, but show reduced or no cytotoxicity against mammalian cells. These AgNPs alter expression and positioning of bacterial cytoskeletal proteins FtsZ and FtsA. CMT capped AgNPs can effectively block growth of several clinical isolates and MDR strains representing different genera and resistant towards multiple antibiotics belonging to different classes. We propose that the CMT-capped AgNPs can have potential bio-medical application against multi-drug-resistant microbes with minimal cytotoxicity towards mammalian cells. PMID- 27125751 TI - Patterns of Biologics Use Across Treatment Lines in Elderly (Age >65) Medicare Patients With Metastatic Colon Cancer. AB - BACKGROUND: We explored biologics receipt in metastatic colon cancer. METHODS: We used Surveillance, Epidemiology, and End Results-Medicare data of 4,545 elderly patients diagnosed with incident metastatic colon cancer from 2003 to 2009, treated with chemotherapy and/or biologics, and followed up through 2010. RESULTS: A total of 2,504 (55%) patients received a biologics-containing regimen. Treatment with biologics fluctuated between 46% and 63% of first-line regimens and 67% and 73% of second-line regimens. Bevacizumab accounted for 95% of first line and 68% of second-line biologics use. Cetuximab accounted for 33% of second line and 48% of third-line use. Panitumumab accounted for 5% of second-line and 27% of third-line use. The adjusted odds of biologics receipt decreased rapidly with age, resulting in a threefold difference between the youngest and the oldest study participants in the sample (odds ratio [OR] 0.35, p < .01). African Americans (OR 0.77, p = .03) and patients with Charlson Comorbidity Index of 1 (OR 0.83, p = .02) or >1 (OR 0.75, p < .01) were considerably less likely to receive biologics therapy. Medicare state buy-in was associated with 2% lower odds of receiving biologics (OR 0.98, p = .04). CONCLUSION: After controlling for sociodemographic and clinical differences, age, race, comorbidities, and low income had a statistically significantly negative effect on the likelihood of receiving biologics among treated patients. Use of biologics varied over time, across the treatment continuum, and by chemotherapy regimen. Bevacizumab was most frequently used in both first- and second-line treatment. Cetuximab was the second most prescribed biologic. Panitumumab use was mostly limited to third-line treatment. IMPLICATIONS FOR PRACTICE: It is well-known that patients in the "real world" receive cancer treatments that do not reflect the strict treatment protocols of clinical trials. This is particularly true for complex and elderly patients with metastatic disease, who are frequently underrepresented in clinical trials. Although this article does not provide any additional evidence about the effectiveness of one treatment regimen or treatment sequence over another, it enhances our understanding of oncology practice outside of the clinical trial setting and provides useful information for future health services and health economics research in metastatic colon cancer. PMID- 27125752 TI - Systemic Therapy for Invasive Bladder Cancer: The Value Proposition. PMID- 27125746 TI - alphaKlotho and Chronic Kidney Disease. AB - Alpha-Klotho (alphaKlotho) protein is encoded by the gene, Klotho, and functions as a coreceptor for endocrine fibroblast growth factor-23. The extracellular domain of alphaKlotho is cleaved by secretases and released into the circulation where it is called soluble alphaKlotho. Soluble alphaKlotho in the circulation starts to decline in chronic kidney disease (CKD) stage 2 and urinary alphaKlotho in even earlier CKD stage 1. Therefore soluble alphaKlotho is an early and sensitive marker of decline in kidney function. Preclinical data from numerous animal experiments support alphaKlotho deficiency as a pathogenic factor for CKD progression and extrarenal CKD complications including cardiac and vascular disease, hyperparathyroidism, and disturbed mineral metabolism. alphaKlotho deficiency induces cell senescence and renders cells susceptible to apoptosis induced by a variety of cellular insults including oxidative stress. alphaKlotho deficiency also leads to defective autophagy and angiogenesis and promotes fibrosis in the kidney and heart. Most importantly, prevention of alphaKlotho decline, upregulation of endogenous alphaKlotho production, or direct supplementation of soluble alphaKlotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiac function and morphometry, and alleviation of vascular calcification in CKD. Therefore in rodents, alphaKlotho is not only a diagnostic and prognostic marker for CKD but the enhancement of endogenous or supplement of exogenous alphaKlotho are promising therapeutic strategies to prevent, retard, and decrease the comorbidity burden of CKD. PMID- 27125753 TI - Early Recurrence After Hepatectomy for Colorectal Liver Metastases: What Optimal Definition and What Predictive Factors? AB - BACKGROUND: The purpose of this study was to determine the optimal definition and elucidate the predictive factors of early recurrence after surgery for colorectal liver metastases (CRLM). METHODS: Among 987 patients who underwent curative surgery for CRLM from 1990 to 2012, 846 with a minimum follow-up period of 24 months were eligible for this study. The minimum p value approach of survival after initial recurrence was used to determine the optimal cutoff for the definition of early recurrence. The predictive factors of early recurrence and prognostic factors of survival were analyzed. RESULTS: For 667 patients (79%) who developed recurrence, the optimal cutoff point of early recurrence was determined to be 8 months after surgery. The impact of early recurrence on survival was demonstrated mainly in patients who received preoperative chemotherapy. Among the 691 patients who received preoperative chemotherapy, recurrence was observed in 562 (81%), and survival in patients with early recurrence was significantly worse than in those with late recurrence (5-year survival 18.5% vs. 53.4%, p < .0001). Multivariate logistic analysis identified age <=57 years (p = .0022), >1 chemotherapy line (p = .03), disease progression during last-line chemotherapy (p = .024), >3 tumors (p = .0014), and carbohydrate antigen 19-9 >60 U/mL (p = .0003) as independent predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence. CONCLUSION: The optimal cutoff point of early recurrence was determined to be 8 months. The preoperative prediction of early recurrence is possible and crucial for designing effective perioperative chemotherapy regimens. IMPLICATIONS FOR PRACTICE: In this study, the optimal cutoff point of early recurrence was determined to be 8 months after surgery based on the minimum p value approach, and its prognostic impact was demonstrated mainly in patients who received preoperative chemotherapy. Five factors, including age, number of preoperative chemotherapy lines, response to last-line chemotherapy, number of tumors, and carbohydrate antigen 19-9 concentrations, were identified as predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence. For better selection of patients who could truly benefit from surgery and should also receive strong postoperative chemotherapy, the accurate preoperative prediction of early recurrence is crucial. PMID- 27125754 TI - A Validated Risk Score for Venous Thromboembolism Is Predictive of Cancer Progression and Mortality. AB - BACKGROUND: Retrospective studies have suggested an association between cancer associated venous thromboembolism (VTE) and patient survival. We evaluated a previously validated VTE Clinical Risk Score in also predicting early mortality and cancer progression. METHODS: A large, nationwide, prospective cohort study of adults with solid tumors or lymphoma initiating chemotherapy was conducted from 2002 to 2006 at 115 U.S. practice sites. Survival and cancer progression were estimated by the method of Kaplan and Meier. Multivariate analysis was based on Cox regression analysis adjusted for major prognostic factors including VTE itself. RESULTS: Of 4,405 patients, 134 (3.0%) died and 330 (7.5%) experienced disease progression during the first 4 months of therapy (median follow-up 75 days). Patients deemed high risk (n = 540, 12.3%) by the Clinical Risk Score had a 120-day mortality rate of 12.7% (adjusted hazard ratio [aHR] 3.00, 95% confidence interval [CI] 1.4-6.3), and intermediate-risk patients (n = 2,665, 60.5%) had a mortality rate of 5.9% (aHR 2.3, 95% CI 1.2-4.4) compared with only 1.4% for low-risk patients (n = 1,200, 27.2%). At 120 days of follow-up, cancer progression occurred in 27.2% of high-risk patients (aHR 2.2, 95% CI 1.4-3.5) and 16.4% of intermediate-risk patients (aHR 1.9, 95% CI 1.3-2.7) compared with only 8.5% of low-risk patients (p < .0001). CONCLUSION: The Clinical Risk Score, originally developed to predict the occurrence of VTE, is also predictive of early mortality and cancer progression during the first four cycles of outpatient chemotherapy, independent from other major prognostic factors including VTE itself. Ongoing and future studies will help determine the impact of VTE prophylaxis on survival. IMPLICATIONS FOR PRACTICE: The risk of venous thromboembolism (VTE) is increased in patients receiving cancer chemotherapy. In this article, the authors demonstrate that a popular risk score for VTE in patients with cancer is also associated with the risk of early mortality in this setting. It is important that clinicians evaluate the risk of VTE in patients receiving cancer treatment and discuss the risk and associated symptoms of VTE with patients. Individuals at increased risk should be advised that VTE is a medical emergency and should be urgently diagnosed and appropriately treated to reduce the risk of serious and life-threatening complications. PMID- 27125755 TI - Cellulose and hemicellulose decomposition by forest soil bacteria proceeds by the action of structurally variable enzymatic systems. AB - Evidence shows that bacteria contribute actively to the decomposition of cellulose and hemicellulose in forest soil; however, their role in this process is still unclear. Here we performed the screening and identification of bacteria showing potential cellulolytic activity from litter and organic soil of a temperate oak forest. The genomes of three cellulolytic isolates previously described as abundant in this ecosystem were sequenced and their proteomes were characterized during the growth on plant biomass and on microcrystalline cellulose. Pedobacter and Mucilaginibacter showed complex enzymatic systems containing highly diverse carbohydrate-active enzymes for the degradation of cellulose and hemicellulose, which were functionally redundant for endoglucanases, beta-glucosidases, endoxylanases, beta-xylosidases, mannosidases and carbohydrate-binding modules. Luteibacter did not express any glycosyl hydrolases traditionally recognized as cellulases. Instead, cellulose decomposition was likely performed by an expressed GH23 family protein containing a cellulose-binding domain. Interestingly, the presence of plant lignocellulose as well as crystalline cellulose both trigger the production of a wide set of hydrolytic proteins including cellulases, hemicellulases and other glycosyl hydrolases. Our findings highlight the extensive and unexplored structural diversity of enzymatic systems in cellulolytic soil bacteria and indicate the roles of multiple abundant bacterial taxa in the decomposition of cellulose and other plant polysaccharides. PMID- 27125756 TI - Blood pressure strategies and goals in elderly patients with hypertension. AB - The growing number of elderly subjects with hypertension in western countries represents a demanding problem to find accurate blood pressure goals with an evidence base for such patients. Previously we did not have enough evidence, but more recently new evidence has accumulated based on data from the HYVET and the SPRINT studies. For most elderly hypertensives a blood pressure goal below 150/90mmHg still seems reasonable, even if a lower goal could be defended based on the recent SPRINT study outcomes. However, the debate on the methodologies for blood pressure measurement in SPRINT is still ongoing and this is why we have to wait until a new recommendation is available. It should not be forgotten that many elderly patients are frail and will therefore not tolerate blood pressure lowering similar to other more fit elderly subjects. This is why an individualised treatment strategy has to be developed for this age group, not to deny the fit elderly the benefits of appropriate blood pressure control, but at the same time avoiding harm and adverse effects in the frail elderly patient. PMID- 27125758 TI - Relationship between cardiometabolic profile, vitamin D status and BsmI polymorphism of the VDR gene in non-institutionalized elderly subjects: Cardiometabolic profile, vitamin D status and BsmI polymorphism of the VDR gene in non-institutionalized elderly subjects. AB - This study aimed to evaluate the relationship between the cardiometabolic profile, vitamin D status and BsmI polymorphism of the VDR gene in non institutionalized elderly subjects. A cross-sectional study was conducted with a random and representative sample of 142 elderly subjects selected by cluster and recruited from a municipal assistance program. Clinical, nutritional, biochemical and inflammatory profiles, oxidative stress and genotyping for the BsmI polymorphism were evaluated. Participants had mean age of 69.9 (7.0) years, BMI of 28.3 (4.4) kg/m(2) and 80.3% were women. The prevalence of a 25-hydroxyvitamin D [25(OH)D] status <75nmol/L was 40.8%. A vitamin D level<75nmol/L was found to be associated with gender and fish consumption. The INSUF/DEF group [25(OH)D<75nmol/L] showed higher fasting blood glucose MDA values when compared to the SUF group [25(OH)D>=75nmol/L]; this relationship was maintained only for women in the analysis by sex. The BsmI polymorphism showed allelic frequencies in the SUF group of B 49% and b 51% and in the INSUF/DEF group B 38% and b 62%. The frequency of bb homozygosity was significantly associated with lower serum total cholesterol and LDL cholesterol concentrations compared to Bb, both in the general population and in the SUF group. Among individuals with bb, the INSUF/DEF group showed higher levels of triglycerides and VLDL cholesterol. Blood glucose levels and oxidative stress were increased in elderly subjects with 25(OH)D<75nmol/L. The presence of the bb genotype with adequate vitamin D status resulted in lower total and LDL cholesterol, but the benefit was lost when vitamin D insufficiency or deficiency was present. PMID- 27125757 TI - Cardiac surgery as a stressor and the response of the vulnerable older adult. AB - In an aging population, recovery and restoration of function are critical to maintaining independence. Over the past 50years, there have been dramatic improvements made in cardiac surgery processes and outcomes that allow for procedures to be performed on an increasingly older population with the goal of improving function. Although improved function is possible, major surgical procedures are associated with substantial stress, which can severely impact outcomes. Past literature has identified that frail patients, who are vulnerable to the stress of surgery, are more likely to have postoperative major adverse cardiac and cerebrovascular events (OR 4.9, 95% confidence interval 1.6, 14.6). The objective of this manuscript is to examine preoperative frailty in biological, psychological, and social domains using cardiac surgery to induce stress. We systematically searched PubMed for keywords including "cardiac surgery, frailty, and aged" in addition to the biological, psychological, and social keywords. In the biological domain, we examine the association of physiological and physical vulnerabilities, as well as, the impact of comorbidities and inflammation on negative surgical outcomes. In the psychological domain, the impact of cognitive impairment, depression, and anxiety as vulnerabilities were examined. In the social domain, social structure, coping, disparities, and addiction as vulnerabilities are described. Importantly, there is substantial overlap in the domains of vulnerability. While frailty research has largely focused on discrete physical vulnerability criteria, a broader definition of frailty demonstrates that vulnerabilities in biological, psychological, and social domains can limit recovery after the stress of cardiac surgery. Identification of vulnerability in these domains can allow better understanding of the risks of cardiac surgery and tailoring of interventions to improve outcomes. PMID- 27125760 TI - Mangiferin attenuates DSS colitis in mice: Molecular docking and in vivo approach. AB - Inflammation, oxidative stress and altered mucosal barrier permeability are potential etiopathological or triggering factors for inflammatory bowel disease (IBD). In this study, the therapeutic potential of Mangiferin was investigated in vivo in mouse model of colitis and also attempts were made to understand mechanistic insights of Mangiferin in IBD. In present study, colitis was induced by administration of 5% DSS for 11 days, followed by 3 days of DSS free period. On day 14, animals were sacrificed and colon tissues were taken for biochemical and histological analysis. Therapeutic treatment with Mangiferin after colitis induction (i.e. day 5) ameliorated symptoms of colitis (presence of blood in stools, body weight loss and diarrhea) as evidenced by reduced DAI score, attenuated the levels of catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO). It also decreased the colonic pro-inflammatory mediators tumor necrosis factor (TNF-alpha), interleukin 1beta (IL-1beta) levels, matrix metalloproteinase-9 (MMP-9) activity and histopathological score. Molecular docking of Mangiferin against TNF-alpha and MMP-9 was evaluated using GLIDE software. Mangiferin demonstrated the glide score of -8.04 kcal/mol for TNF-alpha and -9.97 kcal/mol for MMP-9, which indicated its binding potential with TNF-alpha and MMP-9. In conclusion, Mangiferin reduces colonic damage in a murine model of colitis, alleviates the oxidative and inflammatory events partly through directly influencing the activity of TNF-alpha and MMP-9 and therefore might have therapeutic usefulness in the management of inflammatory bowel disease. PMID- 27125759 TI - Gene-nutrient interaction markedly influences yeast chronological lifespan. AB - PURPOSE: Research into the genetic mechanisms of aging has expanded rapidly over the past two decades. This has in part been the result of the use of model organisms (particularly yeast, worms and flies) and high-throughput technologies, combined with a growing interest in aging research. Despite this progress, widespread consensus regarding the pathways that are fundamental to the modulation of cellular aging and lifespan for all organisms has been limited due to discrepancies between different studies. We have compared results from published genome-wide, chronological lifespan (CLS) screens of individual gene deletion strains in Saccharomyces cerevisiae in order to identify gene deletion strains with consistent influences on longevity as possible indicators of fundamental aging processes from this single-celled, eukaryotic model organism. METHODS: Three previous reports have described genetic modifiers of chronological aging in the budding yeast (S. cerevisiae) using the yeast gene deletion strain collection. We performed a comparison among the data sets using correlation and decile distribution analysis to describe concordance between screens and identify strains that consistently increased or decreased CLS. We used gene enrichment analysis in an effort to understand the biology underlying genes identified in multiple studies. We attempted to replicate the different experimental conditions employed by the screens to identify potential sources of variability in CLS worth further investigating. RESULTS: Among 3209 strains present in all three screens, nine deletions strains were in common in the longest-lived decile (2.80%) and thirteen were in common in the shortest-lived decile (4.05%) of all three screens. Similarly, pairwise overlap between screens was low. When the same comparison was extended to three deciles to include more mutants studied in common between the three screens, enrichment of cellular processes based on gene ontology analysis in the long-lived strains remained very limited. To test the hypothesis that different parental strain auxotrophic requirements or media formulations employed by the respective genome-wide screens might contribute to the lack of concordance, different CLS assay conditions were assessed in combination with strains having different ploidy and auxotrophic requirements (all relevant to differences in the way the three genome-wide CLS screens were performed). This limited but systematic analysis of CLS with respect to auxotrophy, ploidy, and media revealed several instances of gene-nutrient interaction. CONCLUSIONS: There is surprisingly little overlap between the results of three independently performed genome-wide screens of CLS in S. cerevisiae. However, differences in strain genetic background (ploidy and specific auxotrophic requirements) were present, as well as different media and experimental conditions (e.g., aeration and pooled vs. individual culturing), which, along with stochastic effects such as genetic drift or selection of secondary mutations that suppress the loss of function from gene deletion, could in theory account for some of the lack of consensus between results. Considering the lack of overlap in CLS phenotypes among the set of genes reported by all three screens, and the results of a CLS experiment that systematically tested (incorporating extensive controls) for interactions between variables existing between the screens, we propose that discrepancies can be reconciled through deeper understanding of the influence of cell intrinsic factors such as auxotrophic requirements ploidy status, extrinsic factors such as media composition and aeration, as well as interactions that may occur between them, for example as a result of different pooling vs. individually aging cultures. Such factors may have a more significant impact on CLS outcomes than previously realized. Future studies that systematically account for these contextual factors, and can thus clarify the interactions between genetic and nutrient factors that alter CLS phenotypes, should aid more complete understanding of the underlying biology so that genetic principles of CLS in yeast can be extrapolated to differential cellular aging observed in animal models. PMID- 27125762 TI - OCT-angiography for assessing risk of retinal pigment epithelium tear in patients with vascular retinal pigment epithelium detachment due to AMD. PMID- 27125761 TI - Oximes in organophosphate poisoning: 60 years of hope and despair. AB - The high number of annual fatalities following suicidal poisoning by organophosphorus (OP) pesticides and the recent homicidal use of the chemical warfare nerve agent sarin against civilian population in Syria underlines the continuous threat by these highly toxic agents. The need for an effective treatment of OP poisoning resulted in the implementation of a combination therapy with the muscarinic receptor antagonist atropine and an oxime for the reactivation of OP-inhibited acetylcholinesterase (AChE). Since the invention of the first clinically used oxime pralidoxime (2-PAM) in the 1950s ongoing research attempted to identify more effective oximes. In fact, several thousand oximes were synthesized in the past six decades. These include charged and non-charged compounds, mono- and bispyridinium oximes, asymmetric oximes, oximes with different substitutes and more recently non-oxime reactivators. Multiple in vitro and in vivo studies investigated the potential of oximes to reactivate OP inhibited AChE and to reverse OP-induced cholinergic signs. Depending on the experimental model, the investigated species and the tested OP largely variable results were obtained by different laboratories. These findings and the inconsistent effectiveness of oximes in the treatment of OP-pesticide poisoned patients led to a continuous discussion on the value of oximes. In order to provide a forward-looking evaluation of the significance of oximes in OP poisoning multiple aspects, including intrinsic toxicity, in vitro reactivation potency, efficacy and pharmacokinetics, as well as the impact of the causative OP have to be considered. The different influencing factors in order to define the benefit and limitations of oximes in OP poisoning will be discussed. PMID- 27125763 TI - Environmental stress cracking performance of polyether and PDMS-based polyurethanes in an in vitro oxidation model. AB - Environmental stress cracking (ESC) was replicated in vitro on OptimTM (OPT) insulation, a polydimethylsiloxane-based polyurethane utilized clinically in cardiac leads, using a Zhao-type oxidation model. OPT performance was compared to that of two industry standard polyether urethanes: Pellethane(r) 80A (P80A), and Pellethane(r) 55D (P55D). Clinically relevant specimen configurations and strain states were utilized: low-voltage cardiac lead segments were held in a U-shape by placing them inside of vials. To study whether aging conditions impacted ESC formation, half of the samples were subjected to a pretreatment in human plasma for 7 days at 37 degrees C; all samples were then aged in oxidative solutions containing 0.9% NaCl, 20% H2 O2 , and either 0 or 0.1M CoCl2 , with or without glass wool for 72 days at 37 degrees C. Visual and SEM inspection revealed significant surface cracking consistent with ESC on all P80A and P55D samples. Sixteen of twenty P80A and 10/20 P55D samples also exhibited breaches. Seven of 20 OPT samples exhibited shallow surface cracking consistent with ESC. ATR-FTIR confirmed surface changes consistent with oxidation for all materials. The number average molecular weight decreased an average of 31% for OPT, 86% for P80A, and 56% for P55D samples. OPT outperformed P80A and P55D in this Zhao-type in vitro ESC model. An aging solution of 0.9% NaCl, 20% H2 O2 , and 0.1M CoCl2 , with glass wool provided the best combination of ESC replication and ease of use. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1544 1558, 2017. PMID- 27125764 TI - CO2 -Breathing Induced Reversible Activation of Mechanophore within Microgels. AB - In this work, CO2 -breathing induced reversible activation of mechanophore within microgels is reported. The microgels are prepared through soap-free emulsion polymerization of CO2 -switchable monomer 2-(diethylamino)ethyl-methacrylate, using spiropyran (SP) based mechanophore MA-SP-MA as cross-linker. The microgels can be swollen by CO2 aeration. The swelling of microgels activates the SP mechanophore into merocyanine, causing distinguished color and fluorescence change. Moreover, these transitions are highly reversible, and the initial states of microgels can be easily recovered by "washing off" CO2 with N2 . The present contribution represents the first example of CO2 -breathing activation of mechanophore within microgels. PMID- 27125765 TI - Multifunctional Polymeric Nanosystems for Dual-Targeted Combinatorial Chemo/Angiogenesis Therapy of Tumors. AB - Combination of antiangiogenesis and chemotherapy holds vast promise for effective inhibition of tumor proliferation and invasion. Herein, a multifunctional self assembled nanosystem consisting of amphiphilic c(RGDyK)-functionalized low molecular-weight heparin-gambogic acid conjugate (cRHG) is developed, using c(RGDyK) peptide as alphav beta3 integrin targeting moiety to realize a double targeted delivery to both tumor cells and angiogenic vasculature. cRHG with a markedly decreased anticoagulant activity can self-assemble into nanosized particles (around 150 nm). cRHG nanoparticles effectively inhibit vascular endothelial growth factor (VEGF)-triggered tube-like formation of HUVEC and neovascularization of subcutaneous Matrigel plugs. More importantly, the targeting ability of cRHG nanoparticles is revealed by their efficient internalization by alphav beta3 integrin-positive cells (U87MG and HUVEC) in vitro and obvious accumulation of Cy7/cRHG in the tumor site with strong fluorescence signals in both cancer cells and neovasculature. Besides, cRHG maintains the in vitro cytotoxic activity of gambogic acid, while achieving the highest in vivo antitumor activity in U87MG mouse xenograft model and displaying better safety profile than free drugs solutions. Mechanistic investigations reveal the substantial inhibition of hypoxia-inducible factor-1 alpha, VEGF, and CD31 expression by cRHG nanoparticles with remarkable down-regulation of VEGFR2 phosphorylation. These results suggest that cRHG nanoparticles provide a versatile nanoplatform for efficacious combinatorial tumor therapy. PMID- 27125767 TI - Regulation of JAK/STAT signalling by SOCS in the myocardium. PMID- 27125766 TI - Pegylated interferon therapy during early pregnancy for hepatitis B infection: does it prevent vertical transmission? AB - In general, interferon (IFN) is avoided during pregnancy due to the possibility of fetal side effects. We, herein, reported two child-bearing women with chronic hepatitis B (HB) infection who used pegylated interferon alfa 2b (PEG IFNalpha 2b) in first trimester unintentionally. We compared HB contracting rates of gestations in which IFN was used and not used. The cases are unique in that they could highlight the importance of IFN use in early gestation for preventing vertical transmission particularly if combined with antiviral therapy for the rest of pregnancy. PMID- 27125768 TI - Is there a relationship between obesity and tooth loss and edentulism? A systematic review and meta-analysis. AB - This study conducted a systematic review to assess the bi-directional association between tooth loss/edentulism and obesity. Electronic searches were performed in four different databases. Observational studies that tested associations between tooth loss/edentulism and obesity as either exposures or outcomes were included. Additionally, meta-analyses, funnel plots and sensitivity analyses were conducted to synthesize the evidence. A total of 549 articles were identified in the electronic database search. Out of which, 16 studies were included within the meta-analyses: 75% considered tooth loss/edentulism as exposure and obesity as outcome, whereas 25% alternatively considered obesity as exposure and tooth loss/edentulism as outcome. Pooled estimates showed that obese individuals had 1.49 (95%CI 1.20-1.86) and 1.25 (95%CI 1.10-1.42) times higher odds of having any tooth loss and edentulism, respectively. Alternatively, when tooth loss or edentulism were considered as exposures, individuals with any tooth loss had 1.41 (95%CI 1.11-1.79) times higher odds for obesity, while edentates had even higher odds (OR 1.60; 95%CI 1.29-2.00). The results indicate a bi-directional association between tooth loss and obesity. Considering that all selected studies were of cross-sectional study design limiting inferences on temporality, longitudinal prospective studies are required to test the causal relationship between tooth loss/edentulism and obesity or vice a versa. (c) 2016 World Obesity. PMID- 27125769 TI - Proteomics goes forensic: Detection and mapping of blood signatures in fingermarks. AB - A bottom up in situ proteomic method has been developed enabling the mapping of multiple blood signatures on the intact ridges of blood fingermarks by Matrix Assisted Laser Desorption Mass Spectrometry Imaging (MALDI-MSI). This method, at a proof of concept stage, builds upon recently published work demonstrating the opportunity to profile and identify multiple blood signatures in bloodstains via a bottom up proteomic approach. The present protocol addresses the limitation of the previously developed profiling method with respect to destructivity; destructivity should be avoided for evidence such as blood fingermarks, where the ridge detail must be preserved in order to provide the associative link between the biometric information and the events of bloodshed. Using a blood mark reference model, trypsin concentration and spraying conditions have been optimised within the technical constraints of the depositor eventually employed; the application of MALDI-MSI and Ion Mobility MS have enabled the detection, confirmation and visualisation of blood signatures directly onto the ridge pattern. These results are to be considered a first insight into a method eventually informing investigations (and judicial debates) of violent crimes in which the reliable and non-destructive detection and mapping of blood in fingermarks is paramount to reconstruct the events of bloodshed. PMID- 27125770 TI - LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion. AB - The question of how spatially organized activity in the visual cortex behaves during eyes-closed, lysergic acid diethylamide (LSD)-induced "psychedelic imagery" (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes-closed, the brain may function "as if" there is visual input when there is none. In this work, resting-state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes-closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal-horizontal and vertical-vertical) and those with incongruent specificity (horizontal-vertical and vertical-horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes-closed, the early visual system behaves as if it were seeing spatially localized visual inputs. Hum Brain Mapp 37:3031-3040, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27125771 TI - Feasibility of PRIME: A Cognitive Neuroscience-Informed Mobile App Intervention to Enhance Motivated Behavior and Improve Quality of Life in Recent Onset Schizophrenia. AB - BACKGROUND: Despite improvements in treating psychosis, schizophrenia remains a chronic and debilitating disorder that affects approximately 1% of the US population and costs society more than depression, dementia, and other medical illnesses across most of the lifespan. Improving functioning early in the course of illness could have significant implications for long-term outcome of individuals with schizophrenia. Yet, current gold-standard treatments do not lead to clinically meaningful improvements in outcome, partly due to the inherent challenges of treating a population with significant cognitive and motivational impairments. The rise of technology presents an opportunity to develop novel treatments that may circumvent the motivational and cognitive challenges observed in schizophrenia. OBJECTIVE: The purpose of this study was two-fold: (1) to evaluate the feasibility and acceptability of implementing a Personalized Real Time Intervention for Motivation Enhancement (PRIME), a mobile app intervention designed to target reward-processing impairments, enhance motivation, and thereby improve quality of life in recent onset schizophrenia, and (2) evaluate the empirical benefits of using an iterative, user-centered design (UCD) process. METHODS: We conducted two design workshops with 15 key stakeholders, followed by a series of in-depth interviews in collaboration with IDEO, a design and innovation firm. The UCD approach ultimately resulted in the first iteration of PRIME, which was evaluated by 10 RO participants. Results from the Stage 1 participants were then used to guide the next iteration that is currently being evaluated in an ongoing RCT. Participants in both phases were encouraged to use the app daily with a minimum frequency of 1/week over a 12-week period. RESULTS: The UCD process resulted in the following feature set: (1) delivery of text message (short message service, SMS)-based motivational coaching from trained therapists, (2) individualized goal setting in prognostically important psychosocial domains, (3) social networking via direct peer-to-peer messaging, and (4) community "moments feed" to capture and reinforce rewarding experiences and goal achievements. Users preferred an experience that highlighted several of the principles of self-determination theory, including the desire for more control of their future (autonomy and competence) and an approach that helps them improve existing relationships (relatedness). IDEO, also recommended an approach that was casual, friendly, and nonstigmatizing, which is in line with the recovery model of psychosis. After 12-weeks of using PRIME, participants used the app, on average, every other day, were actively engaged with its various features each time they logged in and retention and satisfaction was high (20/20, 100% retention, high satisfaction ratings). The iterative design process lead to a 2- to 3-fold increase in engagement from Stage 1 to Stage 2 in almost each aspect of the platform. CONCLUSIONS: These results indicate that the neuroscience-informed mobile app, PRIME, is a feasible and acceptable intervention for young people with schizophrenia. PMID- 27125772 TI - Overuse of proton pump inhibitors for stress ulcer prophylaxis in Jordan. AB - OBJECTIVE: To determine the frequency of inappropriate proton pump inhibitor (PPI) prescriptions during hospitalization for stress ulcer prophylaxis on the general medical ward in a tertiary Jordanian hospital. MATERIALS AND METHODS: A retrospective chart review was executed on 236 patient admissions prescribed any PPI in a tertiary Jordanian hospital. For each patient, a detailed range of demographic and clinical variables was recorded. Patient's clinical variables were clustered into major vs. minor criteria for using PPIs in stress ulcer prophylaxis according to the American society of health-system pharmacists' (ASHP) therapeutic guidelines on stress ulcer prophylaxis. RESULTS: The 236 patients (51% females) had a mean age of 52 +/- 18.1 years. Approximately 56% of the patients were using PPIs before admission. All our patients started PPI use for stress ulcer prophylaxis. Of these, 86% were unnecessary and should be avoided since they do not have at least 1 major or 2 minor indications. Previous PPI use before admission or the presence of one risk factor for stress ulcer motivated initiation of therapy predominately. Recent gastrointestinal (GI) ulcer/bleeding (23%) and coagulopathy (8%) were the main major indications. High dose corticosteroid (24%) was the most frequent minor indication. CONCLUSIONS: The high frequency of inappropriate PPI prescriptions in stress ulcer prophylaxis for inpatients is a major issue in Jordan. Following the current recommended therapeutic guidelines of stress ulcer prophylaxis could minimize the overuse of PPIs in inpatient settings and thus decrease both the possible safety issues of PPIs and the economic burden on the health-care system. PMID- 27125773 TI - Acetylsalicylic acid (ASA) - How much, how often, and when? A clinical pharmacological perspective. AB - The dose of acetylsalicylic acid (ASA) commonly used in the prevention and treatment of arteriosclerotic angiopathies is equal to or less than 100 mg daily. This choice of dose is predominantly based on molecular-pharmacological findings showing an inhibition in synthesis of the prothrombotic thromboxane (TXB2) and an irreversible inhibition in blood platelet aggregation. However, an analysis of ASA dose-effect relationships for doses of 50 - 500 mg (PO and IV) shows that doses of ASA up to 100 mg daily produce only a small or moderate inhibition in collagen/epinephrine-induced platelet aggregation and have no significant effect on the important platelet factors, PF3 and PF4. Doses of ASA 300 - 500 mg, on the other hand, inhibit platelet aggregation almost completely and, in addition, produce a 50 - 70% inhibition in PF3 and PF4 lasting at least 24 hours. There is also evidence that doses of ASA above 100 mg daily markedly inhibit thromboxane synthesis for up to 24 hours and that doses of 500 mg daily produce a clinically relevant inhibition in platelet adhesion to vessel walls for up 72 hours and prevent procoagulatory shape changes for up to 12 hours. These findings suggest that a dose of >= 300 mg at intervals of 2 - 3 days would be more appropriate for primary and secondary prophylaxis of arteriosclerotic angiopathies and that the benefit-risk ratio would be greater because of the increased availability of mucoprotective prostaglandins, PGI2 (prostacyclin) and the gastroprotective, PGE2. Our viewpoint, predominantly based on findings with biomarkers, could serve as a basis for further randomized controlled studies. PMID- 27125774 TI - Safety and effectiveness of antifungal prophylaxis in preventing fungal infection after liver transplantation: a meta-analysis of randomized clinical trials. AB - BACKGROUND: Fungal infections are widely recognized as a complication of liver transplantation, and their prevention and treatment are a challenge for clinicians. METHODS: This was a randomized clinical trial (RCT)-based meta analysis investigating the safety and effectiveness of antifungal prophylaxis in preventing fungal infection after liver transplantation. Studies published before December 2013 were searched for in several databases. Patients who underwent antifungal prophylaxis were included in the treatment group. Studies that met the inclusion criteria were included in this meta-analysis. Quality assessment, data extraction, and statistical analysis were performed. RESULTS: A total of 342 articles was identified, and 7 eligible articles were included in the present study. The pooled estimate of the OR for all-cause mortality was 0.82 (95% confidence interval (CI): 0.51 - 1.30, p = 0.39). The pooled estimate of the OR of fungal infection-related mortality was 0.29 (95% CI: 0.11 - 0.75, p = 0.01), which was significantly different between the treatment and control groups. The pooled estimate of the OR of defined invasive fungal infection was 0.41 (95% CI: 0.26 - 0.63, p < 0.001). The OR of adverse events was 1.20 (95% CI: 0.68 - 2.12, p = 0.53). CONCLUSION: This meta-analysis suggests that antifungal prophylaxis could effectively reduce the risk of invasive fungal infections in patients who underwent liver transplantation. Overall mortality rate was not different with prophylaxis, according to current evidence. This needs to be further investigated. PMID- 27125775 TI - Treatment of depression in patients with cardiovascular diseases by German psychiatrists. AB - OBJECTIVE: To estimate the prevalence and the type of antidepressant medication prescribed by German psychiatrists to patients with depression and cardiovascular diseases (CVD). METHODS: This study was a retrospective database analysis in Germany using the Disease Analyzer Database (IMS Health, Germany). The study population included 2,288 CVD patients between 40 and 90 years of age from 175 psychiatric practices. The observation period was between 2004 and 2013. Follow up lasted up to 12 months and ended in April 2015. Also included were 2,288 non CVD controls matched (1 : 1) to CVD cases on the basis of age, gender, health insurance coverage, depression severity, and diagnosing physician. RESULTS: Mean age was 68.6 years. 46.2% of patients were men, and 5.9% had private health insurance coverage Mild, moderate, or severe depression was present in 18.7%, 60.7%, and 20.6% of patients, respectively. Most patients had treatment within a year, many of them immediately after depression diagnosis. Patients with moderate and severe depression were more likely to receive treatment than patients with mild depression. There was no difference between CVD and non-CVD in the proportion of patients treated. Nonetheless, CVD patients received selective serotonin reuptake inhibitors / serotonin-noradrenaline reuptake inhibitors (SSRIs/SNRIs) significantly more frequently. Conversely, patients without CVD were more often treated with TCA. CONCLUSION: There was no association between CVD and the initiation of depression treatment. Furthermore, CVD patients received SSRIs/SNRIs more frequently. PMID- 27125776 TI - Fabrication of chiral networks for a tri-substituted anthraquinone derivative using molecular self-assembly. AB - Chiral structures are recorded, with the adsorption of an achiral anthraquinone derivative and co-adsorption of achiral solvent on an achiral surface. Dimer, trimer and tetramer aggregations are observed while only the tetramer-dimer combination constructs the whole monolayer, and the formation mechanism is explained from the thermodynamic and kinetic viewpoints. PMID- 27125777 TI - Comparison of in vitro-cultivation of human mesenchymal stroma/stem cells derived from bone marrow and umbilical cord. AB - Cell-mediated therapy is currently considered as a novel approach for many human diseases. Potential uses range from topic applications with the regeneration of confined tissue areas to systemic applications. Stem cells including mesenchymal stroma/stem cells (MSCs) represent a highly attractive option. Their potential to cure or alleviate human diseases is investigated in a number of clinical trials. A wide variety of methods has been established in the past years for isolation, cultivation and characterization of human MSCs as expansion is presently deemed a prerequisite for clinical application with high numbers of cells carrying reproducible properties. MSCs have been retrieved from various tissues and used in a multitude of settings whereby numerous experimental protocols are available for expansion of MSCs in vitro. Accordingly, different isolation, culture and upscaling techniques contribute to the heterogeneity of MSC characteristics and the, sometimes, controversial results. Therefore, this review discusses and summarizes certain experimental conditions for MSC in vitro culture focusing on adult bone marrow-derived and neonatal umbilical cord-derived MSCs in order to enhance our understanding for MSC tissue sources and to stratify different procedures. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27125778 TI - Base J represses genes at the end of polycistronic gene clusters in Leishmania major by promoting RNAP II termination. AB - The genomes of kinetoplastids are organized into polycistronic gene clusters that are flanked by the modified DNA base J. Previous work has established a role of base J in promoting RNA polymerase II termination in Leishmania spp. where the loss of J leads to termination defects and transcription into adjacent gene clusters. It remains unclear whether these termination defects affect gene expression and whether read through transcription is detrimental to cell growth, thus explaining the essential nature of J. We now demonstrate that reduction of base J at specific sites within polycistronic gene clusters in L. major leads to read through transcription and increased expression of downstream genes in the cluster. Interestingly, subsequent transcription into the opposing polycistronic gene cluster does not lead to downregulation of sense mRNAs. These findings indicate a conserved role for J regulating transcription termination and expression of genes within polycistronic gene clusters in trypanosomatids. In contrast to the expectations often attributed to opposing transcription, the essential nature of J in Leishmania spp. is related to its role in gene repression rather than preventing transcriptional interference resulting from read through and dual strand transcription. PMID- 27125779 TI - Modelling variable dropout in randomised controlled trials with longitudinal outcomes: application to the MAGNETIC study. AB - BACKGROUND: Clinical trials with longitudinally measured outcomes are often plagued by missing data due to patients withdrawing or dropping out from the trial before completing the measurement schedule. The reasons for dropout are sometimes clearly known and recorded during the trial, but in many instances these reasons are unknown or unclear. Often such reasons for dropout are non ignorable. However, the standard methods for analysing longitudinal outcome data assume that missingness is non-informative and ignore the reasons for dropout, which could result in a biased comparison between the treatment groups. METHODS: In this article, as a post hoc analysis, we explore the impact of informative dropout due to competing reasons on the evaluation of treatment effect in the MAGNETIC trial, the largest randomised placebo-controlled study to date comparing the addition of nebulised magnesium sulphate to standard treatment in acute severe asthma in children. We jointly model longitudinal outcome and informative dropout process to incorporate the information regarding the reasons for dropout by treatment group. RESULTS: The effect of nebulised magnesium sulphate compared with standard treatment is evaluated more accurately using a joint longitudinal competing risk model by taking account of such complexities. The corresponding estimates indicate that the rate of dropout due to good prognosis is about twice as high in the magnesium group compared with standard treatment. CONCLUSIONS: We emphasise the importance of identifying reasons for dropout and undertaking an appropriate statistical analysis accounting for such dropout. The joint modelling approach accounting for competing reasons for dropout is proposed as a general approach for evaluating the sensitivity of conclusions to assumptions regarding missing data in clinical trials with longitudinal outcomes. TRIAL REGISTRATION: EudraCT number 2007-006227-12 . Registration date 18 Mar 2008. PMID- 27125781 TI - Global diabatic potential energy surfaces and quantum dynamical studies for the Li(2p) + H2(X(1)Sigma(+)g) -> LiH(X(1)Sigma(+)) + H reaction. AB - The global diabatic potential energy surfaces which are correlated with the ground state 1A' and the excited state 2A' of the Li(2p) + H2 reaction are presented in this study. The multi-reference configuration interaction method and large basis sets (aug-cc-pVQZ for H atom and cc-pwCVQZ for Li atom) were employed in the ab initio single-point energy calculations. The diabatic potential energies were generated by the diabatization scheme based on transition dipole moment operators. The neural network method was utilized to fit the matrix elements of the diabatic energy surfaces, and the root mean square errors were extremely small (3.69 meV for , 5.34 meV for and 5.06 meV for ). The topographical features of the diabatic potential energy surfaces were characterized and the surfaces were found to be sufficiently smooth for the dynamical calculation. The crossing seam of the conical intersections between the and surfaces were pinpointed. Based on this new analytical diabatic potential energy surfaces, time-dependent wave packet calculation were conducted to investigate the mechanism of the title reaction. At low collision energies, the product LiH molecule tends to forward scattering, while at high collision energies, the forward and backward scatterings exist simultaneously. PMID- 27125780 TI - A novel strategy for protein production using non-classical secretion pathway in Bacillus subtilis. AB - BACKGROUND: The Gram-positive bacterium Bacillus subtilis has been widely used as a cell factory for the production of proteins due to its generally regarded as safe (GRAS) nature and secretion capability. Of the known secretory pathways in B. subtilis, the majority of proteins are exported from the cytoplasm by Sec pathway, Tat pathway and ABC transporters, etc. However, the production of heterologous proteins by B. subtilis is unfortunately not that straight forward because of the bottlenecks in classical secretion pathways. The aim of this work is to explore a new method for protein production based on non-classical secretion pathway. RESULTS: One D-psicose 3-epimerase (RDPE) which converts D fructose into D-psicose from Ruminococcus sp. 5_1_39BFAA was successfully and substantially secreted into the extracellular milieu without the direction of signal peptide. Subsequently, we demonstrated that RDPE contained no native signal peptide, and the secretion of RDPE was not dependent on Sec or Tat pathway or due to cell lysis, which indicated that RDPE is a non-classically secreted protein. Then, we attempted to evaluate the possibility of using RDPE as a signal to export eighteen reporter proteins into the culture medium. Five of eleven homologous proteins, two of five heterologous proteins from other bacterium and two heterologous proteins of eukaryotic source were successfully secreted into the extracellular milieu at different secretion levels when they were fused to RDPE mediated by a flexible 21-bp linker to keep a distance between two single proteins. Furthermore, the secretion rates of two fusion proteins (RDPE-DnaK and RDPE-RFP) reached more than 50 %. In addition, most of the fusion proteins retained enzyme or biological activity of their corresponding target proteins, and all of the fusions still had the activity of RDPE. CONCLUSIONS: We found and identified a heterologous non-classically secreted protein RDPE, and showed that RDPE could direct proteins of various types into the culture medium, and thus non classical protein secretion pathway can be used as a novel secretion pathway for recombinant proteins. This novel strategy for recombinant protein production is helpful to make B. subtilis as a more ideal cell factory for protein production. PMID- 27125782 TI - Mode engineering for realistic quantum-enhanced interferometry. AB - Quantum metrology overcomes standard precision limits by exploiting collective quantum superpositions of physical systems used for sensing, with the prominent example of non-classical multiphoton states improving interferometric techniques. Practical quantum-enhanced interferometry is, however, vulnerable to imperfections such as partial distinguishability of interfering photons. Here we introduce a method where appropriate design of the modal structure of input photons can alleviate deleterious effects caused by another, experimentally inaccessible degree of freedom. This result is accompanied by a laboratory demonstration that a suitable choice of spatial modes combined with position resolved coincidence detection restores entanglement-enhanced precision in the full operating range of a realistic two-photon Mach-Zehnder interferometer, specifically around a point which otherwise does not even attain the shot-noise limit due to the presence of residual distinguishing information in the spectral degree of freedom. Our method highlights the potential of engineering multimode physical systems in metrologic applications. PMID- 27125784 TI - Royal college told to stop taking money from infant formula milk firms. PMID- 27125783 TI - Reversal of the Detrimental Effects of Post-Stroke Social Isolation by Pair Housing is Mediated by Activation of BDNF-MAPK/ERK in Aged Mice. AB - Social isolation (SI) increases stroke-related mortality and morbidity in clinical populations. The detrimental effects of SI have been successfully modeled in the laboratory using young animals. Mechanistically, the negative effects of SI in young animals are primarily mediated by an enhanced inflammatory response to injury and a reduction in neurotrophic factors. However, the response to brain injury differs considerably in the aged. Given that SI is more prevalent in aged populations, we hypothesized that isolation, even when initiated after stroke, would delay recovery in aged mice. We found that aged isolated male mice had significantly increased infarct volume, neurological deficits, and serum IL-6 levels three days after stroke compared to pair housed (PH) mice. Using RT(2) Profiler PCR Array and real-time quantitative PCR we found several important synaptic plasticity genes were differentially expressed in post-stroke SI mice. Furthermore, paired mice showed improved memory and neurobehavioral recovery four weeks after injury. Mechanistic and histological studies showed that the beneficial effects of pair housing are partially mediated by BDNF via downstream MAPK/ERK signaling and restoration of axonal basic myelin protein levels. PMID- 27125785 TI - The transcription factor p8 regulates autophagy during diapause embryo formation in Artemia parthenogenetica. AB - Autophagy is an essential homeostatic process by which cytoplasmic components, including macromolecules and organelles, are degraded by lysosome. Increasing evidence suggests that phosphorylated AMP-activated protein kinase (p-AMPK) and target of rapamycin (TOR) play key roles in the regulation of autophagy. However, the regulation of autophagy in quiescent cells remains unclear, despite the fact that autophagy is known to be critical for normal development, regeneration, and degenerative diseases. Here, crustacean Artemia parthenogenetica was used as a model system because they produced and released encysted embryos that enter a state of obligate dormancy in cell quiescence to withstand various environmental threats. We observed that autophagy was increased before diapause stage but dropped to extremely low level in diapause cysts in Artemia. Western blot analyses indicated that the regulation of autophagy was AMPK/TOR independent during diapause embryo formation. Importantly, the level of p8 (Ar-p8), a stress inducible transcription cofactor, was elevated at the stage just before diapause and was absent in encysted embryos, indicating that Ar-p8 may regulate autophagy. The results of Ar-p8 knockdown revealed that Ar-p8 regulated autophagy during diapause formation in Artemia. Moreover, we observed that activating transcription factors 4 and 6 (ATF4 and ATF6) responded to Ar-p8-regulated autophagy, indicating that autophagy targeted endoplasmic reticulum (ER) during diapause formation in Artemia. Additionally, AMPK/TOR-independent autophagy was validated in human gastric cancer MKN45 cells overexpressing Ar-p8. The findings presented here may provide insights into the role of p8 in regulating autophagy in quiescent cells. PMID- 27125787 TI - Reslizumab: First Global Approval. AB - Reslizumab (Cinqair((r))) is a humanised monoclonal interleukin-5 (IL-5) antibody developed by Teva that has been approved in the USA for patients aged >=18 years as add-on maintenance treatment for severe asthma with an eosinophilic phenotype. IL-5 stimulates the production, activation and maturation of eosinophils and is therefore thought to play a role in the development of bronchial hyper responsiveness. This article summarizes the milestones in the development of reslizumab leading to this first approval for add-on maintenance treatment of severe asthma with an eosinophilic phenotype. PMID- 27125786 TI - Response of heat shock protein genes of the oriental fruit moth under diapause and thermal stress reveals multiple patterns dependent on the nature of stress exposure. AB - Heat shock protein gene (Hsp) families are thought to be important in thermal adaptation, but their expression patterns under various thermal stresses have still been poorly characterized outside of model systems. We have therefore characterized Hsp genes and their stress responses in the oriental fruit moth (OFM), Grapholita molesta, a widespread global orchard pest, and compared patterns of expression in this species to that of other insects. Genes from four Hsp families showed variable expression levels among tissues and developmental stages. Members of the Hsp40, 70, and 90 families were highly expressed under short exposures to heat and cold. Expression of Hsp40, 70, and Hsc70 family members increased in OFM undergoing diapause, while Hsp90 was downregulated. We found that there was strong sequence conservation of members of large Hsp families (Hsp40, Hsp60, Hsp70, Hsc70) across taxa, but this was not always matched by conservation of expression patterns. When the large Hsps as well as small Hsps from OFM were compared under acute and ramping heat stress, two groups of sHsps expression patterns were apparent, depending on whether expression increased or decreased immediately after stress exposure. These results highlight potential differences in conservation of function as opposed to sequence in this gene family and also point to Hsp genes potentially useful as bioindicators of diapause and thermal stress in OFM. PMID- 27125788 TI - Asplatin enhances drug efficacy by altering the cellular response. AB - Aspirin, a widely used anti-inflammatory drug, has been shown to be effective for the prevention and remission of cancers (Science, 2012, 337(21) 1471-1473). Asplatin, a Pt(iv) prodrug of cisplatin with the ligation of aspirin (c,c,t [PtCl2(NH3)2(OH)(aspirin)]), demonstrates significantly higher cytotoxicity than cisplatin towards tumor cells and almost fully overcomes the drug resistance of cisplatin resistant cells. In this work, we have studied the molecular mechanism of asplatin by investigating the cellular response to this compound in order to understand the prominent inhibitory effect on the proliferation of cancer cells. The apoptosis analyses and the related gene expression measurements show that aspirin released from asplatin significantly modulates the cellular response to the platinum agent. Asplatin promotes the apoptosis via the BCL-2 associated mitochondrial pathway. The down-regulation of BCL-2 along with the up-regulation of BAX and BAK enhances the mitochondrial outer membrane permeability, resulting in the cytochrome c release from mitochondria into the cytosol. This event promotes the apoptosis by activation of caspase processing. Consequently, the ligation of aspirin significantly enhances the drug efficacy of the platinum complex in the low micromolar range. The alteration of the cellular response is probably responsible for the circumvention of the cisplatin resistance by asplatin. These results provide an insight into the mechanism of asplatin and provide information for designing new classic platinum drugs. PMID- 27125789 TI - Ca2 Al2 SiO7 :Ce3+ phosphors for mechanoluminescence dosimetry. AB - A series of Ce3+ ion single-doped Ca2 Al2 SiO7 phosphors was synthesized by a combustion-assisted method at an initiating temperature of 600 degrees C. The samples were annealed at 1100 degrees C for 3 h and their X-ray diffraction patterns confirmed a tetragonal structure. The phase structure, particle size, surface morphology and elemental analysis were analyzed using X-ray diffraction (XRD), transmission electron microscope (TEM), scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) spectroscopy techniques. Thermoluminescence (TL) intensity increased with increase in ultraviolet (UV) light exposure time up to 15 min. With further increase in the UV irradiation time the TL intensity decreases. The increase in TL intensity indicates that trap concentration increased with UV exposure time. A broad peak at 121 degrees C suggested the existence of a trapping level. The peak of mechanoluminescence (ML) intensity versus time curve increased linearly with increasing impact velocity of the moving piston. Mechanoluminescence intensity increased with increase in UV irradiation time up to 15 min. Under UV-irradiation excitation, the TL and ML emission spectra of Ca2 Al2 SiO7 :Ce3+ phosphor showed the characteristic emission of Ce3+ peaking at 400 nm (UV-violet) and originating from the Ce3+ transitions of 5d-4f (2 F5/2 and 2 F7/2 ). The photoluminescence (PL) emission spectra for Ca2 Al2 SiO7 :Ce3+ were similar to the ML/TL emission spectra. The mechanism of ML excitation and the suitability of the Ca2 Al2 SiO7 :Ce3+ phosphor for radiation dosimetry are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27125790 TI - Auto-oxidative hydroxysulfenylation of alkenes. AB - One-pot auto-oxidation mediated hydroxysulfenylation of electron-deficient and electron-rich olefins with phenthiols was explored. The method illustrates a selective and convenient synthesis of complex beta-hydroxysulfides using O2 as both the oxidant and the oxygen source under mild transition-metal-free conditions. The application of this new methodology to the gram-scale synthesis of anti-cancer drug bicalutamide has been accomplished in a two-step sequence with 71% overall yield. A plausible radical involved mechanism is proposed. PMID- 27125792 TI - The role of neurosurgery in the treatment of chronic pain. PMID- 27125793 TI - Futility and utility. PMID- 27125794 TI - Improving quality in prostate cancer. PMID- 27125795 TI - Lost in translation: the gap between what we know and what we do about cardiovascular disease. PMID- 27125796 TI - Tackling smoking, childhood obesity and back pain: it's not for want of trying. PMID- 27125797 TI - Forsaking cures for cancer: why are we discarding the tumour biospecimens of most patients? PMID- 27125798 TI - Surgical management of low back pain. PMID- 27125799 TI - Kitesurfing - playing with water or with fire? PMID- 27125800 TI - Ladder-related injuries in New South Wales. PMID- 27125801 TI - Increasing incidence of type 2 diabetes in Indigenous and non-Indigenous children in Western Australia, 1990-2012. PMID- 27125803 TI - Socio-demographic and structural barriers to being tested for chlamydia in general practice. PMID- 27125804 TI - Using opioids in general practice for chronic non-cancer pain: an overview of current evidence. AB - Chronic non-cancer pain (lasting more than 3 months) is highly prevalent in Australia (17% of males and 20% of females) and its optimal management is crucial to the health and wellbeing of the community. For 5% of the population, such pain interferes markedly with daily function. Part of the treatment for acute non cancer pain for many people will include opioid analgesics at least for days to weeks. However, as pain becomes chronic, evidence to support ongoing prescription of opioids is lacking. There is increasing pressure to ensure that prescribing opioid analgesics is minimised to reduce not only the risk of dependence and illicit diversion but also the potential harms associated with tolerance, side effects and complications. Frameworks for considering opioid prescribing include assessing suitability of the patient for opioids; initiating a trial of therapy; and monitoring long term use. There is limited evidence of the long term efficacy of opioids for chronic non-cancer pain, and documented clinical consequences beyond addiction include acceleration of loss of bone mineral density, hypogonadism and an association with increased risk of acute myocardial infarction. Careful clinical selection of patients can help optimise the evidence based use of opioids for chronic non-cancer pain: only treat pain that has been as well defined as possible when non-opioid therapies have not been effective; consider referral to specialist services for assessment if doses are above 100 mg oral morphine equivalent per 24 hours or the duration of therapy is longer than 4 weeks; limit prescribing to only one practitioner; seek an agreement with the patient for the initiation and potential withdrawal of opioids if the therapeutic trial is not effective. PMID- 27125805 TI - What is new in the surgical management and prevention of breast cancer? AB - Breast cancer is the most common malignancy in Australian women. As most women now survive breast cancer, improving quality-of-life outcomes is increasingly important and major changes are occurring in breast surgery to meet this challenge. Use of neoadjuvant chemotherapy results in lower mastectomy rates, broader surgical options and less surgical morbidity. Oncoplastic breast surgery (OBS) facilitates less frequent need for mastectomy, better aesthetic outcomes and improved quality of life. Immediate breast reconstruction (IBR) improves quality of life and can be considered in a large proportion of women requiring mastectomy; however, Australia's rate of IBR is low compared with similar countries. Breast cancer risk reduction can be achieved with lifestyle modifications and, in women at high risk, chemoprevention with selective oestrogen receptor modulators or aromatase inhibitors. Bilateral prophylactic mastectomy is an option for BRCA gene mutation carriers or those women otherwise established to have a high level of risk. Contralateral prophylactic mastectomy (CPM) is increasingly performed at the time of initial breast cancer management, largely driven by patient preference. However, CPM does not improve survival and has similar rates of complications as therapeutic mastectomy. It should be cautiously considered, with full discussion of risks and benefits. Breast Surgeons of Australia and New Zealand (BreastSurgANZ) coordinates training of most new breast surgeons and is fostering a broader range of multidisciplinary oncology, OBS and IBR skills in its members. The BreastSurgANZ Quality Audit monitors the quality of care provided by members. Training breast surgeons now have access to a Graduate Certificate in Surgery (Breast Surgery) to broaden their knowledge base. PMID- 27125806 TI - Acute pain management: scientific evidence, fourth edition, 2015. AB - This guideline summary describes the fourth edition of Acute pain management: scientific evidence, which was published by the Australian and New Zealand College of Anaesthetists (ANZCA) and its Faculty of Pain Medicine (FPMANZCA) in December 2015. The fourth edition summarises the best available evidence on acute pain management, following methods established over the preceding three editions. It provides additional information by scoring the quality of and reporting further details on randomised controlled trials and meta-analyses. The information is condensed into key messages that provide: concise statements on each topic, showing the highest level of evidence; and clinical practice points based on clinical experience or expert opinion. PMID- 27125807 TI - What does "futility" mean? An empirical study of doctors' perceptions. AB - OBJECTIVE: To investigate how doctors define and use the terms "futility" and "futile treatment" in end-of-life care. DESIGN, SETTING, PARTICIPANTS: A qualitative study using semi-structured interviews with 96 doctors from a range of specialties which treat adults at the end of life. Doctors were recruited from three large Brisbane teaching hospitals and were interviewed between May and July 2013. RESULTS: Doctors' conceptions of futility focused on the quality and prospect of patient benefit. Aspects of benefit included physiological effect, weighing benefits and burdens, and quantity and quality of life. Quality and length of life were linked, but many doctors discussed instances in which benefit was determined by quality of life alone. Most described assessing the prospects of achieving patient benefit as a subjective exercise. Despite a broad conceptual consensus about what futility means, doctors noted variability in how the concept was applied in clinical decision making. More than half the doctors also identified treatment that is futile but nevertheless justified, such as short term treatment that supports the family of a dying person. CONCLUSIONS: There is an overwhelming preference for a qualitative approach to assessing futility, which inevitably involves variability in clinical decision making. Patient benefit is at the heart of doctors' definitions of futility. Determining patient benefit requires discussing with patients and their families their values and goals as well as the burdens and benefits of further treatment. PMID- 27125808 TI - Quality of care achievements of the Prostate Cancer Outcomes Registry-Victoria. AB - OBJECTIVE: To analyse the performance of the quality of prostate cancer (CaP) care over a 5-year period with reference to three quality indicators (QIs) reported by the Prostate Cancer Outcomes Registry-Victoria (PCOR-Vic):QI-1: Alignment with the modified Prostate Cancer Research International Active Surveillance (PRIAS) protocol guideline;QI-2: Timeliness of CaP care for men with high risk and locally advanced disease;QI-3: Positive surgical margins (PSMs) for organ-confined pathological T2 disease. DESIGN, SETTING AND PARTICIPANTS: Between 1 January 2009 and 31 December 2013, 4708 men diagnosed with CaP who met the QI 1, QI-2 or QI-3 inclusion criteria were recruited from Victorian hospitals.Outcome measures and statistical analysis: Trend analysis was conducted to monitor performance according to QI-1, QI-2 and QI-3. We used the autoregressive integrated moving average (ARIMA) model to account for any inherent autocorrelation in the data when analysing the monthly incidence of each indicator. Differences in the annual figures for the indicators across years were also analysed by aggregating data by year and applying the ARIMA model. RESULTS AND LIMITATIONS: There was a downward trend over the 5 years in the percentage of men with low risk disease who underwent active treatment (45% to 34%; P = 0.024), an upward trend in the percentage of those with high risk and locally advanced disease who received active treatment within 12 months of diagnosis (88% to 93%; P = 0.181), and a decline in PSM rate in men with pathological T2 disease after radical prostatectomy (21% to 12%; P = 0.036). Limitations of the study include the fact that the improvement in the QIs was detected using PCOR-Vic as a single population, but there may be institutional variations in quality improvement. CONCLUSIONS: Over 2009-2013, the performance of the Victorian health system improved according to the three processes of care indicators reported by the PCOR Vic. PMID- 27125809 TI - Absolute risk of cardiovascular disease events, and blood pressure- and lipid lowering therapy in Australia. AB - OBJECTIVE: To quantify absolute cardiovascular disease (CVD) risk and treatment in Australian adults. DESIGN, PARTICIPANTS: Cross-sectional representative study of 9564 people aged 18 years or more who had participated in the 2011-12 Australian National Health Measures Survey (response rate for those aged 45-74 years: 46.5%). MAIN OUTCOME MEASURES: Prior CVD was ascertained and 5-year absolute risk of a primary CVD event calculated (using the Australian National Vascular Disease Prevention Alliance algorithm; categories: low [< 10%], moderate [10-15%], and high [> 15%] risk) on the basis of data on medical history, risk factors and medications, derived from interviews, physical measurements, and blood and urine samples. RESULTS: Absolute CVD risk increased with age and was higher among men than women. Overall, 19.9% (95% CI, 18.5-21.3%) of Australians aged 45-74 years had a high absolute risk of a future CVD event (an estimated 1 445 000 people): 8.7% (95% CI, 7.8-9.6%) had prior CVD (estimated 634 000 people) and 11.2% (95% CI, 10.2-12.2%) had high primary CVD risk (estimated 811 000 people). A further 8.6% (95% CI, 7.4-9.8%, estimated 625 000) were at moderate primary CVD risk. Among those with prior CVD, 44.2% (95% CI, 36.8-51.6%) were receiving blood pressure- and lipid-lowering medications, 35.4% (95% CI, 27.8 43.0%) were receiving only one of these, and 20.4% (95% CI, 13.9-26.9%) were receiving neither. Corresponding figures for high primary CVD risk were 24.3% (95% CI, 18.3-30.3%); 28.7% (95% CI, 22.7-34.7%); and 47.1% (95% CI, 39.9-54.3%). CONCLUSIONS: About one-fifth of the Australian population aged 45-74 years (about 1.4 million individuals) were estimated to have a high absolute risk of a future CVD event. Most (estimated 970 000) were not receiving currently recommended combination blood pressure- and lipid-lowering therapy, indicating substantial potential for health gains by increasing routine assessment and treatment according to absolute CVD risk. PMID- 27125811 TI - The shame of things to come. PMID- 27125812 TI - Evolutionary constraints over microsatellite abundance in larger mammals as a potential mechanism against carcinogenic burden. AB - Larger organisms tend to live longer, have more potentially carcinogenic cells, and undergo more cell divisions. While one might intuitively expect cancer incidence to scale with body size, this assertion does not hold over the range of different mammals. Explaining this lack of correlation, so-called 'Peto's paradox' can likely increase our understanding of how cancer defense mechanisms are shaped by natural selection. Here, we study the occurrence of microsatellite in mammal genomes and observe that animals with expanded body size restrain the number of microsatellite. To take into account of higher mutation rate in the microsatellite region compared to that of genome, limiting the abundance of somatic mutations might explain how larger organisms could overcome the burden of cancer. These observations may serve as the basis to better understand how evolution has modeled protective mechanisms against cancer development. PMID- 27125813 TI - Twin pregnancy in a Fontan-palliated patient. AB - The Fontan connection, originally described in 1971, is used to provide palliation for patients with many forms of CHDs that cannot support a biventricular circulation. An increasing number of females who have undergone these connections in childhood are now surviving into adulthood and some are becoming pregnant. We report a case of a 29-year-old woman who presented with a twin pregnancy at 33 weeks of gestation. She had significant deterioration of her cardiovascular status before the twin babies were delivered by emergency caesarean section owing to associated obstetric complications. This report also highlights the various maternal and fetal complications occurring in pregnancy of Fontan-palliated patients and suggests the need for meticulous pre-conception counselling and strict perinatal care. PMID- 27125814 TI - Western Pine Beetle Populations in Arizona and California Differ in the Composition of Their Aggregation Pheromones. AB - We compared pheromone production and response for populations of western pine beetle, Dendroctonus brevicomis LeConte, from sites in northern Arizona and northern California. Volatiles were collected from individuals of both sexes that had mined as a pair in a Pinus ponderosa log for 1 d, and they were subsequently analyzed by gas chromatography coupled to mass-spectrometry. Principal component analysis of quantities of Dendroctonus pheromone components indicated strong site associated clustering of blend composition for females but not males. Much of the clustering in females evidently was due to differences in the production of endo- and exo-brevicomin, which occurred in average ratios of 0.1:1 and 19:1 for populations in the California and Arizona sites, respectively. In the California site, exo- was better than endo-brevicomin in enhancing trap catches of both sexes to lures containing the host-tree odor alpha-pinene and the male-produced aggregation pheromone component frontalin. In an identical test in the Arizona site, endo- was a better adjuvant than exo-brevicomin for male attraction, whereas females did not show a significant preference. At neither location were the isomers antagonistic to one another in activity. Thus, one aggregation pheromone has apparently diverged between these populations, concurrent with published evidence that D. brevicomis on either side of the Great Basin are genetically distinct and are possibly different species. Furthermore, production of and response to the isomers of brevicomin by flying Dendroctonus frontalis Zimmermann in the Arizona site were similar to those of sympatric D. brevicomis. This interspecific signal overlap is likely sustainable since joint species mass attacks may assist both species in overcoming host defenses, thereby increasing host availability. PMID- 27125815 TI - The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury. AB - A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30 min intravenous infusion of AC105, magnesium sulfate (MgSO4), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO4 did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4 treatment. Finally, AC105 did not result in higher Mg2+ levels in CSF than with the use of standard MgSO4. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI. PMID- 27125816 TI - Should I Use Lidocaine With Epinephrine in Digital Nerve Blocks? PMID- 27125817 TI - Pilot Study of Kano "Attractive Quality" Techniques to Identify Change in Emergency Department Patient Experience. AB - STUDY OBJECTIVE: We describe the use of the Kano Attractive Quality analytic tool to improve an identified patient experience gap in perceived compassion by emergency department (ED) providers. METHODS: In phase 1, point-of-service surveying assessed baseline patient perception of ED provider compassion. Phase 2 deployed Kano surveys to predict the effect of 4 proposed interventions on patient perception. Finally, phase 3 compared patients receiving standard care versus the Kano-identified intervention to assess the actual effect on patient experience. RESULTS: In phase 1, 193 of 200 surveys (97%) were completed, showing a baseline median score of 4 out of 5 (interquartile range [IQR] 3 to 5), with top box percentage of 33% for patients' perception of receiving compassionate care. In phase 2, 158 of 180 surveys (88%) using Kano-formatted questions were completed, and the data predicted that increasing shared decisionmaking would cause the greatest improvement in the patient experience. Finally, in phase 3, 45 of 49 surveys (92%) were returned and demonstrated a significant improvement in perceived concern and sensitivity, 5 (IQR 5 to 5) versus 4 (IQR 3 to 5) with a difference of 1 (95% CI 0.1-1.9) and a top box rating of 79% versus 35% with a difference of 44% (95% CI 12-66) by patients who received dedicated shared decisionmaking interventions versus those receiving standard of care. CONCLUSION: Kano analysis is likely predictive of change in patient experience. Kano methods may prove as useful in changing management of the health care industry as it has been in other industries. PMID- 27125818 TI - Clinical characteristics associated with the prescribing of SSRI medication in adolescents with major unipolar depression. AB - Unipolar major depressions (MD) emerge markedly during adolescence. National Institute for Health and Care Excellence (NICE) UK recommends psychological therapies, with accompanying selective serotonin reuptake inhibitors (SSRIs) prescribed in severe cases only. Here, we seek to determine the extent and rationale of SSRI prescribing in adolescent MD before entering a randomised clinical trial. SSRI prescribing, together with their clinical characteristics was determined in 465 adolescent patients with MD prior to receiving a standardised psychological therapy as part of the Improving mood with psychoanalytic and cognitive therapies (IMPACT) clinical trial. Overall, 88 (19 %) had been prescribed antidepressants prior to psychological treatment. The clinical correlates varied by gender: respectively, depression severity in boys and self-harming behaviours in girls. Prescribing also differed between clinical research centres. Medical practitioners consider severity of depression in boys as an indicator for antidepressant prescribing. Self-injury in girls appears to be utilised as a prescribing aid which is inconsistent with past and current revised UK NICE guidelines. PMID- 27125819 TI - The role of O2 as an electron acceptor alternative to CO2 in photosynthesis of the common marine angiosperm Zostera marina L. AB - This study investigates the role of O2 as an electron acceptor alternative to CO2 in photosynthesis of the common marine angiosperm Zostera marina L. Electron transport rates (ETRs) and non-photochemical quenching (NPQ) of Z. marina were measured under saturating irradiance in synthetic seawater containing 2.2 mM DIC and no DIC with different O2 levels (air-equilibrated levels, 3 % of air equilibrium and restored air-equilibrated levels). Lowering O2 did not affect ETR when DIC was provided, while it caused a decrease in ETR and an increase in NPQ in DIC-free media, indicating that O2 acted as an alternative electron acceptor under low DIC. The ETR and NPQ as a function of irradiance were subsequently assessed in synthetic seawater containing (1) 2.2 mM DIC, air-equilibrated O2; (2) saturating CO2, no O2; and (3) no DIC, air-equilibrated O2. These treatments were combined with glycolaldehyde pre-incubation. Glycolaldehyde caused a marked decrease in ETR in DIC-free medium, indicating significant electron flow supported by photorespiration. Combining glycolaldehyde with O2 depletion completely suppressed ETR suggesting the operation of the Mehler reaction, a possibility supported by the photosynthesis-dependent superoxide production. However, no notable effect of suppressing the Mehler reaction on NPQ was observed. It is concluded that during DIC-limiting conditions, such as those frequently occurring in the habitats of Z. marina, captured light energy exceeds what is utilised for the assimilation of available carbon, and photorespiration is a major alternative electron acceptor, while the contribution of the Mehler reaction is minor. PMID- 27125820 TI - Expected and preferred retirement age in Germany. AB - BACKGROUND: Over the last 10 years the German pension system has undergone several reforms including the abandonment of early retirement policies and an increase in the statutory retirement age. Consequently, the average retirement age has increased and future retiree cohorts have adjusted the retirement expectations and preferences as to when they would like to retire. OBJECTIVE: This study was carried out to examine discrepancies between the expected and the preferred retirement age of older workers in Germany and to investigate how these discrepancies differ between groups of older workers. MATERIAL AND METHODS: Based on data from the survey "Employment after retirement", the expected and preferred retirement ages of 1500 workers aged 55 years and older were compared. Regression analyses were used to investigate the influence of educational level and professional position on deviances between the expected and preferred retirement ages. RESULTS: On average older workers would like to retire 1.75 years earlier than they actually expect to. The deviance is significantly larger for employees with a lower professional position, lower income and lower educational level. CONCLUSION: The discrepancy between expected and preferred retirement ages, in particular for older workers in vulnerable labor market positions, indicates a potential social inequality regarding the choice of retirement timing. This must be acknowledged when considering further reforms of the German pension system. PMID- 27125821 TI - Image quality and variability for routine diagnostic FDG-PET scans in a Japanese community hospital: current status and possibility of improvement. AB - PURPOSE: In Japan, commercially delivered FDG is manufactured in three batches per day at fixed constant activity and distributed in vials. Consequently, the amount of activity administered to the patient varies depending on the timing of injection. We evaluated a method for adjusting the scan time according to the body mass index (BMI) to obtain equivalent image quality for every patient. METHODS: We examined a total of 301 routine clinical oncology PET scans using commercially delivered FDG. The relation between the injected activity and the noise equivalent count per scan length (NECpatient) was evaluated as a marker of image quality; its association with BMI was also examined. RESULTS: The injected activity and NECpatient exhibited large variations (230.4 +/- 55.8 MBq and 19.9 +/- 2.9 Mcounts/m). There was a weak correlation between the injected activity and NECpatient (r ~ 0.3) for thin patients (BMI < 21 kg/m(2)), but no correlation for patients with higher BMIs. However, a significant correlation was found between BMI and NECpatient (p < 0.0001). CONCLUSION: In a community hospital using commercially delivered FDG, it is possible to reduce the variability of the NECpatient and obtain uniform image quality by changing the scan time as a function of patient BMI, even with uncontrollable injected activity. PMID- 27125822 TI - CORR Insights(r): Do Stemmed Tibial Components in Total Knee Arthroplasty Improve Outcomes in Patients With Obesity? PMID- 27125823 TI - Will My Tibial Fracture Heal? Predicting Nonunion at the Time of Definitive Fixation Based on Commonly Available Variables. AB - BACKGROUND: Accurate prediction of tibial nonunions has eluded researchers. Reliably predicting tibial nonunions at the time of fixation could change management strategies and stimulate further research. QUESTIONS/PURPOSES: We asked (1) whether data from medical records, fracture characteristics, and radiographs obtained at the time of fixation would identify features predictive of tibial fracture nonunion; and (2) whether this information could be used to create a model to assess the chance of nonunion at the time of intramedullary (IM) nail fixation of the tibia. METHODS: We retrospectively reviewed all tibial shaft fractures treated at our center from 2007 to 2014. We conducted a literature review and collected data on 35 factors theorized to contribute to delayed bone healing. Patients were followed to fracture healing or surgery for nonunion. Patients with planned prophylactic nonunion surgery were excluded because their nonunions were anticipated and our focus was on unanticipated nonunions. Our cohort consisted of 382 patients treated with IM nails for tibial shaft fractures (nonunion, 56; healed, 326). Bivariate and multivariate regression techniques and stepwise modeling approaches examined the relationship between variables available at definitive fixation. Factors were included in our model if they were identified as having a modest to large effect size (odds ratio > 2) at the p < 0.05 level. RESULTS: A multiple variable logistic regression model was developed, including seven factors (p < 0.05; odds ratio > 2.0). With these factors, we created the Nonunion Risk Determination (NURD) score. The NURD score assigns 5 points for flaps, 4 points for compartment syndrome, 3 points for chronic condition(s), 2 points for open fractures, 1 point for male gender, and 1 point per grade of American Society of Anesthesiologists Physical Status and percent cortical contact. One point each is subtracted for spiral fractures and for low-energy injuries, which were found to be predictive of union. A NURD score of 0 to 5 had a 2% chance of nonunion; 6 to 8, 22%; 9 to 11, 42%; and > 12, 61%. CONCLUSIONS: The proposed nonunion prediction model (NURDS) seems to have potential to allow clinicians to better determine which patients have a higher risk of nonunion. Future work should be directed at prospectively validating and enhancing this model. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 27125824 TI - Cortical grey matter content is associated with both age and bimanual performance, but is not observed to mediate age-related behavioural decline. AB - Declines in both cortical grey matter and bimanual coordination performance are evident in healthy ageing. However, the relationship between ageing, bimanual performance, and grey matter loss remains unclear, particularly across the whole adult lifespan. Therefore, participants (N = 93, range 20-80 years) performed a complex Bimanual Tracking Task, and structural brain images were obtained using magnetic resonance imaging. Analyses revealed that age correlated negatively with task performance. Voxel-based morphometry analysis revealed that age was associated with grey matter declines in task-relevant cortical areas and that grey matter in these areas was negatively associated with task performance. However, no evidence for a mediating effect of grey matter in age-related bimanual performance decline was observed. We propose a new hypothesis that functional compensation may account for the observed absence of mediation, which is in line with the observed pattern of increased inter-individual variance in performance with age. PMID- 27125825 TI - The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice. AB - Pyrrolizidine alkaloid (PA)-containing plants are widespread in the world and the most common poisonous plants affecting livestock, wildlife, and humans. Our previous studies demonstrated that PA-derived DNA adducts can potentially be a common biological biomarker of PA-induced liver tumor formation. In order to validate the use of these PA-derived DNA adducts as a biomarker, it is necessary to understand the basic kinetics of the PA-derived DNA adducts formed in vivo. In this study, we studied the dose-dependent response and kinetics of PA-derived DNA adduct formation and removal in male ICR mice orally administered with a single dose (40 mg/kg) or multiple doses (10 mg/kg/day) of retrorsine, a representative carcinogenic PA. In the single-dose exposure, the PA-derived DNA adducts exhibited dose-dependent linearity and persisted for up to 4 weeks. The removal of the adducts following a single-dose exposure to retrorsine was biphasic with half-lives of 9 h (t 1/2alpha) and 301 h (~12.5 days, t 1/2beta). In the 8-week multiple exposure study, a marked accumulation of PA-derived DNA adducts without attaining a steady state was observed. The removal of adducts after the multiple exposure also demonstrated a biphasic pattern but with much extended half-lives of 176 h (~7.33 days, t 1/2alpha) and 1736 h (~72.3 days, t 1/2beta). The lifetime of PA-derived DNA adducts was more than 8 weeks following the multiple dose treatment. The significant persistence of PA-derived DNA adducts in vivo supports their role in serving as a biomarker of PA exposure. PMID- 27125826 TI - The Metacaspase (Mca1p) Restricts O-glycosylation During Farnesol-induced Apoptosis in Candida albicans. AB - Protein glycolysation is an essential posttranslational modification in eukaryotic cells. In pathogenic yeasts, it is involved in a large number of biological processes, such as protein folding quality control, cell viability and host/pathogen relationships. A link between protein glycosylation and apoptosis was established by the analysis of the phenotypes of oligosaccharyltransferase mutants in budding yeast. However, little is known about the contribution of glycosylation modifications to the adaptive response to apoptosis inducers. The cysteine protease metacaspase Mca1p plays a key role in the apoptotic response in Candida albicans triggered by the quorum sensing molecule farnesol. We subjected wild-type and mca1-deletion strains to farnesol stress and then studied the early phase of apoptosis release in quantitative glycoproteomics and glycomics experiments on cell-free extracts essentially devoid of cell walls. We identified and characterized 62 new glycosylated peptides with their glycan composition: 17 N-glycosylated, 45 O-glycosylated, and 81 additional sites of N-glycosylation. They were found to be involved in the control of protein folding, cell wall integrity and cell cycle regulation. We showed a general increase in the O glycosylation of proteins in the mca1 deletion strain after farnesol challenge. We identified 44 new putative protein substrates of the metacaspase in the glycoprotein fraction enriched on concanavalin A. Most of these substrates are involved in protein folding or protein resolubilization and in mitochondrial functions. We show here that key Mca1p substrates, such as Cdc48p or Ssb1p, involved in degrading misfolded glycoproteins and in the protein quality control system, are themselves differentially glycosylated. We found putative substrates, such as Bgl2p (validated by immunoblot), Srb1p or Ugp1p, that are involved in the biogenesis of glycans. Our findings highlight a new role of the metacaspase in amplifying cell death processes by affecting several critical protein quality control systems through the alteration of the protein glycosylation machinery.Data are available via ProteomeXchange with identifier PXD003677. PMID- 27125827 TI - Uncovering a Dual Regulatory Role for Caspases During Endoplasmic Reticulum Stress-induced Cell Death. AB - Many diseases are associated with endoplasmic reticulum (ER) stress, which results from an accumulation of misfolded proteins. This triggers an adaptive response called the "unfolded protein response" (UPR), and prolonged exposure to ER stress leads to cell death. Caspases are reported to play a critical role in ER stress-induced cell death but the underlying mechanisms by which they exert their effect continue to remain elusive. To understand the role caspases play during ER stress, a systems level approach integrating analysis of the transcriptome, proteome, and proteolytic substrate profile was employed. This quantitative analysis revealed transcriptional profiles for most human genes, provided information on protein abundance for 4476 proteins, and identified 445 caspase substrates. Based on these data sets many caspase substrates were shown to be downregulated at the protein level during ER stress suggesting caspase activity inhibits their cellular function. Additionally, RNA sequencing revealed a role for caspases in regulation of ER stress-induced transcriptional pathways and gene set enrichment analysis showed expression of multiple gene targets of essential transcription factors to be upregulated during ER stress upon inhibition of caspases. Furthermore, these transcription factors were degraded in a caspase-dependent manner during ER stress. These results indicate that caspases play a dual role in regulating the cellular response to ER stress through both post-translational and transcriptional regulatory mechanisms. Moreover, this study provides unique insight into progression of the unfolded protein response into cell death, which may help identify therapeutic strategies to treat ER stress-related diseases. PMID- 27125828 TI - Safety of transesophageal echocardiography during extracorporeal life support. AB - INTRODUCTION: Use of extracorporeal life support (ECLS) has significantly increased in critically ill patients refractory to medical management. ECLS requires systemic anticoagulation to avoid thromboembolic complications and superimposed coagulopathies are common. Transesophageal echocardiography (TEE) is frequently employed to assess cannula position and cardiac function during extracorporeal therapy. The goal of this study was to assess whether TEE probe insertion and removal in systemically anticoagulated ECLS patients was safe compared to patients without ECLS and normal coagulation studies. METHODS: Eighty seven separate TEE examinations in 53 adult ECLS patients were analyzed. Detailed complication profiles were logged for each patient from initiation through discontinuation of ECLS. Routine coagulation testing was recorded within two hours prior to the TEE exams. Controls consisted of age- and gender-matched patients undergoing perioperative TEE without ECLS and normal coagulation (N=87). RESULTS: Overall TEE-associated morbidity in ECLS patients was 2.3% and consisted of minor oropharyngeal bleeding (2/87 TEE exams) exclusively. The patients presenting with oropharyngeal bleeding received heparin for anticoagulation and had two or more abnormal coagulation studies at the time of TEE. Seventy-nine percent of ECLS patients received intravenous heparin infusions, 6.8% argatroban and 3.4% epoprostenol. Ten-point-eight percent of patients were not anticoagulated at the time of TEE because of pre-existing bleeding complications and/or deranged plasmatic coagulation profiles. No major complications (e.g., esophageal perforation, gastrointestinal bleeding, accidental extubation) were recorded in either group. CONCLUSIONS: TEE remained safe in critically ill patients under ECLS, despite systemic anticoagulation, during probe insertion, manipulation and removal. TEE-related complications pertained solely to oropharyngeal bleeding amenable to conservative management. PMID- 27125829 TI - Decreased maximum clot firmness in rotational thromboelastometry (ROTEM(r)) is associated with bleeding during extracorporeal mechanical circulatory support. AB - BACKGROUND: We aimed to characterize the coagulation disturbances which may increase the risk of bleeding, thrombosis or death shortly after implantation of an extracorporeal membrane oxygenation (ECMO) or ventricular assist (VAD) device. METHODS: Antithrombotic treatment was started in 23 VAD and 24 ECMO patients according to the hospital protocol. Additionally, conventional laboratory testing, rotational thromboelastometry (ROTEM(r)) and platelet function analysis (Multiplate(r)) were performed at predetermined intervals. RESULTS: Four out of twenty-four (16.7%) of ECMO patients and 6/23 (26.1%) of VAD patients had severe bleeding after the procedure. When all the patients were analyzed together, low maximum clot firmness (MCF) in ExTEM and FibTEM analyses was associated with severe bleeding (p<0.05) and low MCF in FibTEM with 30-day mortality. Low platelet count and hematocrit levels were also associated with severe bleeding. When VAD and ECMO patients were separated into different groups, the association between ROTEM(r) parameters, bleeding and survival was found only in limited time points.Four patients with VAD had cerebral ischemia indicative of thromboembolism. However, this had no significant correlation with ROTEM(r) or Multiplate(r) parameters. CONCLUSION: Hypocoagulation shown by ROTEM(r) was associated with bleeding complications in patients with mechanical circulatory support. In contrast, hypercoagulation did not correlate with clinical thrombosis. PMID- 27125832 TI - Evaluation of Association Between Gynecologic Oncology Fellowship Length and a Career in Academic Medicine. AB - The purpose of this study is to determine the association between gynecologic oncology fellowship training factors, including fellowship length, and a career in academic medicine. A survey was sent to all 980 gynecologic oncologists identified via the SGO membership directory. The survey questions focused on demographics, fellowship training, practice- type, and research involvement. Demographics of the study population and survey responses were reported using frequencies and percentages. Chi-squared tests were used to test for associations between selected survey responses and length of fellowship. The authors received 410 (42 %) responses. Most respondents (60 %) graduated from a 3-year fellowship, while 27 and 13 % attended 2- and 4-year fellowships, respectively. Practice descriptions included academic/university (52 %), community/private practice (21 %), private practice with academic appointment (20 %), and other (7 %). A majority (64 %) reported current involvement in research as a principal investigator (PI); however, 54 % reported spending 10 % or less of their time in research-related activities. Approximately half reported that their fellowship research experience contributed to their current practice. Graduates of 3- and 4 year fellowships had similar rates of employment in academic/university settings (58 and 52 %, respectively). Graduates of 4-year fellowships were more likely to hold an advanced degree and 11 or more publications at completion of fellowship. A majority of graduates of a gynecologic oncology fellowship practice in an academic/university setting and are involved in research. Fellowship length does not correlate with a current academic medicine appointment. Graduates of 4-year fellowships are more likely to hold additional advanced degrees and more publications. PMID- 27125830 TI - Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors. AB - PURPOSE: Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology. METHODS: We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively. RESULTS: In postmenopausal women, we observed higher levels of phosphorylated IGF I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values <=0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values <=0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values <=0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values <=0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01). CONCLUSIONS: These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis. PMID- 27125831 TI - A prospective study of oral contraceptive use and colorectal adenomas. AB - PURPOSE: The influence of reproductive factors on colorectal cancer, including oral contraceptive (OC) use, has been examined, but less research is available on OC use and adenomas. METHODS: Participants of the Nurses' Health Study who had a lower bowel endoscopy between 1986 (when endoscopies were first assessed) and 2008 were included in this study. Multivariable logistic regression models for clustered data were used to estimate odds ratios and 95 % confidence intervals [OR (95 % CIs)]. RESULTS: Among 73,058 participants, 51 % (n = 37,382) reported ever using OCs. Ever OC use was associated with a slight increase in non-advanced adenomas [OR 1.11, 95 % CI (1.02, 1.21)] but not with any other endpoints. Duration of OC use was not associated with adenomas, but longer times since last OC use were associated with increased odds of adenomas [e.g., compared to never use, 15+ years since last use: OR 1.17 (1.07, 1.27)]. Shorter times since last OC use were inversely associated [e.g., <=4 years since last use: OR 0.74 (0.65, 0.84)]. CONCLUSIONS: We observed a modest borderline increase in risk of colorectal adenomas with any prior OC use. Additionally, more recent OC use may decrease risk, while exposure in the distant past may modestly increase risk of adenomas. PMID- 27125833 TI - The Role of Attitude Toward Own Aging for Fluid and Crystallized Functioning: 12 Year Evidence From the ILSE Study. AB - Objectives: Aging attitudes have been shown to affect a variety of important developmental outcomes in old age, including memory. Extending previous research, the present study examined long-term effects of attitudes toward own aging (ATOA), relying on a broader range of cognitive abilities in later life. Method: Data came from the Interdisciplinary Longitudinal Study of Adult Development and Aging (ILSE), with three measurement waves (1993/1994, 1997/1998, and 2005/2006) covering a 12-year interval. Drawing on the older of two available birth cohorts (1930-1932; n = 500), we analyzed the relationship between ATOA and change in fluid versus crystallized abilities based on overall and gender-specific latent change score models, while controlling for education and objective health. Results: As expected, ATOA predicted change in fluid functioning-but not in crystallized performance-over 12 years. Gender-specific analyses revealed a stronger association between ATOA and decline in fluid abilities for men, even after controlling for health and education. Discussion: This study adds to the understanding of long-term implications of aging attitudes for cognitive decline trajectories and shows that negative aging attitudes are a risk factor for age vulnerable cognitive abilities, particularly among men. Further research is needed to better understand the underlying mechanisms of observed relationships. PMID- 27125834 TI - Examining the Impact of Prior Criminal Justice History on 2-Year Recidivism Rates: A Comparison of Drug Court Participants and Program Referrals. AB - Drug courts seek to break the cycle of substance use and crime by providing a community-based intervention to individuals with criminal justice involvement and substance-related issues. This study examined recidivism over a 2-year follow-up period as well as factors associated with recidivism for a sample of drug court participants (i.e., graduates and terminators) and a non-equivalent comparison group (i.e., individuals referred/assessed for the program who did not enter). In the 2-year follow-up window, fewer drug court graduates had any convictions compared with program terminators and referrals; specifically, fewer drug court graduates had drug trafficking convictions compared with program terminators and referrals. Fewer graduates were arrested and incarcerated in jail and/or prison in the 2-year follow-up; furthermore, graduates had spent less time incarcerated compared with program terminators and referrals. Demographics (i.e., age, race, marital status) and prior criminal justice system involvement were associated with recidivism; however, these factors had differential impacts for the three groups (i.e., graduates, terminators, and referrals). Drug court shows promise as a community-based intervention that helps keep individuals out of the criminal justice system during a 2-year follow-up period. PMID- 27125835 TI - 26-week repeated oral dose toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in beagle dogs. AB - The needs for relatively safe botanical alternatives to relieve symptoms associated to arthritis have continued to grow in parallel with the ageing population. UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, has been used as over the counter joint care dietary supplements and a prescription medical food. Significant safety data have been documented in rodents and human for this composition. Here we evaluated the potential adverse effects of orally administered UP446 in beagle dogs following a 26-week repeated oral dose toxicity study. UP446 at doses of 250, 500 and 1000 mg/kg/day were administered orally to beagle dogs for 26 weeks. A 4-week recovery group from the high dose (1000 mg/kg) and vehicle treated groups were included. No morbidity or mortality was observed for the duration of the study. No significant differences between groups in body weights, food consumption, ophthalmological examinations, electrocardiograms, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology were documented. Emesis, loose feces and diarrhea were noted in both genders at the 1000 mg/kg treatment groups. These clinical signs were considered to be reversible as they were not evident in the recovery period. In conclusion, the no-observed-adverse-effect-level (NOAEL) of UP446 was considered to be 500 mg/kg/day both in male and female beagle dogs. PMID- 27125838 TI - Single-domain antibody based thermally stable electrochemical immunosensor. AB - Conventional monoclonal and polyclonal antibodies are sensitive to changes in environmental factors such as temperature, pH, humidity, etc. This limits the current cost-effective and portable electrochemical immunosensors in harsh environments. Using Ricin Chain-A, a naturally occurring toxin, as a model analyte we report fabrication of a thermally stable electrochemical immunosensor. Single-domain antibodies (sdAb) or nanobodies have been employed as recognition elements for direct detection of Ricin at temperatures great than 4 degrees C. Immunosensor fabricated using the conventional Ricin monoclonal and polyclonal antibodies have also been demonstrated for comparison. In the case of sdAb immunosensor, Ricin was detected in a linear range of 1log(fg/mL)-1log(MUg/mL) with a sensitivity of 0.07MUA/log(g/mL)/cm(2) using cyclic voltammetry. The fabricated miniaturized sensors have demonstrated higher shelf life and stability at temperatures up to 40 degrees C. Therefore these electrochemical sensors can be integrated as a part of a portable device for point-of-care immunosensing. PMID- 27125836 TI - Technology in Parkinson's disease: Challenges and opportunities. AB - The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27125837 TI - Interferon lambda polymorphisms associate with body iron indices and hepatic expression of interferon-responsive long non-coding RNA in chronic hepatitis C. AB - Single nucleotide polymorphisms (SNPs) within DNA region containing interferon lambda 3 (IFNL3) and IFNL4 genes are prognostic factors of treatment response in chronic hepatitis C (CHC). Iron overload, frequently diagnosed in CHC, is associated with unfavorable disease course and a risk of carcinogenesis. Its etiology and relationship with the immune response in CHC are not fully explained. Our aim was to determine whether IFNL polymorphisms in CHC patients associate with body iron indices, and whether they are linked with hepatic expression of genes involved in iron homeostasis and IFN signaling. For 192 CHC patients, four SNPs within IFNL3-IFNL4 region (rs12979860, rs368234815, rs8099917, rs12980275) were genotyped. In 185 liver biopsies, histopathological analyses were performed. Expression of five mRNAs and three long non-coding RNAs (lncRNAs) was determined with qRT-PCR in 105 liver samples. Rs12979860 TT or rs8099917 GG genotypes as well as markers of serum and hepatocyte iron overload associated with higher activity of gamma-glutamyl transpeptidase and liver steatosis. The presence of two minor alleles in any of the tested SNPs predisposed to abnormally high serum iron concentration and correlated with higher hepatic expression of lncRNA NRIR. On the other hand, homozygosity in any major allele associated with higher viral load. Patients bearing rs12979860 CC genotype had lower hepatic expression of hepcidin (HAMP; P = 0.03). HAMP mRNA level positively correlated with serum iron indices and degree of hepatocyte iron deposits. IFNL polymorphisms influence regulatory pathways of cellular response to IFN and affect body iron balance in chronic hepatitis C virus infection. PMID- 27125839 TI - An ultrasensitive fluorescence method suitable for quantitative analysis of mung bean nuclease and inhibitor screening in vitro and vivo. AB - Mung bean nuclease is a single stranded specific DNA and RNA endonuclease purified from mung bean sprouts. It yields 5'-phosphate terminated mono- and oligonucleotides. The activity level of this nuclease can act as a marker to monitor the developmental process of mung bean sprouts. In order to facilitate the activity and physiological analysis of this nuclease, we have developed a biosensing assay system based on the mung bean nuclease-induced single-stranded DNA scission and the affinity difference of graphene oxide for single-stranded DNA containing different numbers of bases. This end-point measurement method can detect mung bean nuclease in a range of 2*10(-4) to 4*10(-2) with a detection limit of 1*10(-4) unit/mL. In addition, we demonstrate the utility of the assay for screening chemical antibiotics and metal ions, resulting in the identification of several inhibitors of this enzyme in vitro. Furthermore, we firstly report that inhibiting mung bean nuclease by gentamycin sulfate and kanamycin in vivo can suppress mung bean sprouts growth. In summary, this method provides an alternative tool for the biochemical analysis for mung bean nuclease and indicates the feasibility of high-throughput screening specific inhibitors of this nuclease in vitro and in vivo. PMID- 27125840 TI - Multiplexed lateral flow biosensors: Technological advances for radically improving point-of-care diagnoses. AB - Lateral flow biosensors are a leading technology in point-of-care diagnostics due to their simplicity, rapidness and low cost. Their primacy in this arena continues through technological breakthroughs such as multiplexing: the detection of more than one biomarker in a single assay. Multiplexing capacity is critical for improving diagnostic efficiency, enhancing the diagnostic precision for specific diseases and reducing diagnostic cost. Here we review, for the first time, the various types and strategies employed for creating multiplexed lateral flow biosensors. These are classified into four main categories in terms of specific application or multiplexing level, namely linear, parameter, spatial and conceptual. We describe the practical applications and implications for each approach and compare their advantages and disadvantages. Importantly, multiplexing is still subject to limitations of the traditional lateral flow biosensor, such as sensitivity and specificity. However, by pushing the limitations of the traditional medium into the multiplex arena, several technological breakthroughs are emerging with novel solutions that further expand the utility of lateral flow biosensing for point-of-care applications. PMID- 27125841 TI - Using reciprocity for relating the simulation of transcranial current stimulation to the EEG forward problem. AB - To explore the relationship between transcranial current stimulation (tCS) and the electroencephalography (EEG) forward problem, we investigate and compare accuracy and efficiency of a reciprocal and a direct EEG forward approach for dipolar primary current sources both based on the finite element method (FEM), namely the adjoint approach (AA) and the partial integration approach in conjunction with a transfer matrix concept (PI). By analyzing numerical results, comparing to analytically derived EEG forward potentials and estimating computational complexity in spherical shell models, AA turns out to be essentially identical to PI. It is then proven that AA and PI are also algebraically identical even for general head models. This relation offers a direct link between the EEG forward problem and tCS. We then demonstrate how the quasi-analytical EEG forward solutions in sphere models can be used to validate the numerical accuracies of FEM-based tCS simulation approaches. These approaches differ with respect to the ease with which they can be employed for realistic head modeling based on MRI-derived segmentations. We show that while the accuracy of the most easy to realize approach based on regular hexahedral elements is already quite high, it can be significantly improved if a geometry-adaptation of the elements is employed in conjunction with an isoparametric FEM approach. While the latter approach does not involve any additional difficulties for the user, it reaches the high accuracies of surface-segmentation based tetrahedral FEM, which is considerably more difficult to implement and topologically less flexible in practice. Finally, in a highly realistic head volume conductor model and when compared to the regular alternative, the geometry-adapted hexahedral FEM is shown to result in significant changes in tCS current flow orientation and magnitude up to 45 degrees and a factor of 1.66, respectively. PMID- 27125842 TI - Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies. AB - Insulin-like growth factor binding protein 2 (IGFBP2) overexpression is common in high-grade glioma and is both a strong biomarker of aggressive behaviour and a well-documented prognostic factor. IGFBP2 is a member of the secreted IGFBP family that functions by interacting with circulating IGFs to modulate IGF mediated signalling. This traditional view of IGFBP2 activities has been challenged by the recognition of the diverse functions and cellular locations of members of the IGFBP family. IGFBP2 has been previously established as a driver of glioma progression to a higher grade. In this study, we sought to determine whether IGFBP2-overexpressing tumours are dependent on continued oncogene expression and whether IGFBP2 is a viable therapeutic target in glioma. We took advantage of the well-characterized RCAS/Ntv-a mouse model to create a doxycycline-inducible IGFBP2 model of glioma and demonstrated that the temporal expression of IGFBP2 has dramatic impacts on tumour progression and survival. Further, we demonstrated that IGFBP2-driven tumours are dependent on the continued expression of IGFBP2, as withdrawal of this oncogenic signal led to a significant decrease in tumour progression and prolonged survival. Inhibition of IGFBP2 also impaired tumour cell spread. To assess a therapeutically relevant inhibition strategy, we evaluated a neutralizing antibody against IGFBP2 and demonstrated that it impaired downstream IGFBP2-mediated oncogenic signalling pathways. The studies presented here indicate that IGFBP2 not only is a driver of glioma progression and a prognostic factor but is also required for tumour maintenance and thus represents a viable therapeutic target in the treatment of glioma. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27125843 TI - Plasma soluble erythropoietin receptor is decreased during sleep in Andean highlanders with Chronic Mountain Sickness. AB - Excessive erythrocytosis (EE) is the main sign of Chronic Mountain Sickness (CMS), a highly prevalent syndrome in Andean highlanders. Low pulse O2 saturation (SpO2) during sleep and serum androgens have been suggested to contribute to EE in CMS patients. However, whether these factors have a significant impact on the erythropoietin (Epo) system leading to EE is still unclear. We have recently shown that morning soluble Epo receptor (sEpoR), an endogenous Epo antagonist, is decreased in CMS patients suggesting increased Epo availability (increased Epo/sEpoR). The present study aimed to characterize the nocturnal concentration profile of sEpoR and Epo and their relationship with SpO2, Hct, and serum testosterone in healthy highlanders (HH) and CMS patients. Epo and sEpoR concentrations were evaluated every 4 h (6 PM to 6 AM) and nighttime SpO2 was continuously monitored (10 PM to 6 AM) in 39 male participants (CMS, n = 23; HH, n = 16) aged 21-65 yr from Cerro de Pasco, Peru (4,340 m). CMS patients showed higher serum Epo concentrations throughout the night and lower sEpoR from 10 PM to 6 AM. Consequently, Epo/sEpoR was significantly higher in the CMS group at every time point. Mean sleep-time SpO2 was lower in CMS patients compared with HH, while the percentage of sleep time spent with SpO2 < 80% was higher. Multiple regression analysis showed mean sleep-time SpO2 and Epo/sEpoR as significant predictors of hematocrit corrected for potential confounders (age, body mass index, and testosterone). Testosterone levels were associated neither with Hct nor with erythropoietic factors. In conclusion, our results show sustained erythropoietic stimulus driven by the Epo system in CMS patients, further enhanced by a continuous exposure to accentuated nocturnal hypoxemia. PMID- 27125844 TI - beta1-Blockade increases maximal apnea duration in elite breath-hold divers. AB - We hypothesized that the cardioselective beta1-adrenoreceptor antagonist esmolol would improve maximal apnea duration in elite breath-hold divers. In elite national-level divers (n = 9), maximal apneas were performed in a randomized and counterbalanced order while receiving either iv esmolol (150 MUg.kg-1.min-1) or volume-matched saline (placebo). During apnea, heart rate (ECG), beat-by-beat blood pressure, stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were measured (finger photoplethysmography). Myocardial oxygen consumption (MVo2) was estimated from rate pressure product. Cerebral blood flow through the internal carotid (ICA) and vertebral arteries (VA) was assessed using Duplex ultrasound. Apnea duration improved in the esmolol trial when compared with placebo (356 +/- 57 vs. 323 +/- 61 s, P < 0.01) despite similar end-apnea peripheral oxyhemoglobin saturation (71.8 +/- 10.3 vs. 74.9 +/- 9.5%, P = 0.10). The HR response to apnea was reduced by esmolol at 10-30% of apnea duration, whereas MAP was unaffected. Esmolol reduced SV (main effect, P < 0.05) and CO (main effect; P < 0.05) and increased TPR (main effect, P < 0.05) throughout apnea. Esmolol also reduced MVo2 throughout apnea (main effect, P < 0.05). Cerebral blood flow through the ICA and VA was unchanged by esmolol at baseline and the last 30 s of apnea; however, global cerebral blood flow was reduced in the esmolol trial at end-apnea (P < 0.05). Our findings demonstrate that, in elite breath-hold divers, apnea breakpoint is improved by beta1-blockade, likely owing to an improved total body oxygen sparring through increased centralization of blood volume (?TPR) and reduced MVo2NEW & NOTEWORTHY The governing bodies for international apnea competition, the Association Internationale pour le Developpment de l'Apnee and La Confederation Mondaile des Activites Subaquatiques, have banned the use of beta-blockers based on anecdotal reports that they improve apnea duration. Using a randomized placebo-controlled trial, we are the first to empirically confirm that beta-blockade improves apnea duration. This improvement in apnea duration coincided with a reduced myocardial oxygen consumption. PMID- 27125845 TI - Morphological dependency of cutaneous blood flow and sweating during compensable heat stress when heat-loss requirements are matched across participants. AB - Human heat loss is thought, in part, to be morphologically related. It was therefore hypothesized that when heat-loss requirements and body temperatures were matched, that the mass-specific surface area alone could significantly explain both cutaneous vascular and sudomotor responses during compensable exercise. These thermoeffector responses were examined in 36 men with widely varying mass-specific surface areas (range, 232.3-292.7 cm(2)/kg), but of similar age, aerobic fitness, and adiposity. Subjects completed two trials under compensable conditions (28.1 degrees C, 36.8% relative humidity), each involving rest (20 min) and steady-state cycling (45 min) at two matched metabolic heat production rates (light, ~135 W/m(2); moderate, ~200 W/m(2)). Following equivalent mean body temperature changes, forearm blood flow and vascular conductance (r = 0.63 and r = 0.65) shared significant, positive associations with the mass-specific surface area during light work (P < 0.05), explaining ~45% of the vasomotor variation. Conversely, during light and moderate work, whole body sweat rate, as well as local sweat rate and sudomotor sensitivity at three of four measured sites, revealed moderate, negative relationships with the mass specific surface area (correlation coefficient range -0.37 to -0.73, P < 0.05). Moreover, those relationships could uniquely account for between 10 and 53% of those sweating responses (P < 0.05). Therefore, both thermoeffector responses displayed a significant morphological dependency in the presence of equivalent thermoafferent drive. Indeed, up to half of the interindividual variation in these effector responses could now be explained through morphological differences and the first principles governing heat transfer. PMID- 27125846 TI - Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity. AB - Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. alpha-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 +/- 5% (SE), whereas flow to the orthotopic tumor increased by 181 +/- 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 +/- 7%) vs. prostate arterioles (55 +/- 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. PMID- 27125847 TI - Parasternal intercostal and diaphragm function during sleep. AB - Action of the uppermost medial internal intercostal muscles-the parasternals during rapid eye movement (REM) is uncertain; no direct recordings exist of shortening of these muscles during sleep. Historically, motor inhibition of skeletal muscles during REM sleep is thought to cause global loss of chest wall muscle function, REM "atonia," with preservation of only diaphragm function. However, recent evidence during wakefulness shows parasternals as distinctive obligatory inspiratory muscles. Therefore we hypothesized that attenuation of chest wall function during sleep may spare the parasternals along with the diaphragm, as essential muscles of inspiration during REM. We studied seven canines, comparing costal and crural diaphragm and parasternal intercostal muscle function during wakefulness and non-REM (NREM) and REM sleep, during normal spontaneous sleep, continuously recording ventilation and simultaneous muscle electromyogram (EMG) and length from sonomicrometry microtransducers. Ventilation during sleep declined significantly from wakefulness. From wakefulness to NREM and REM, costal and crural tidal EMG increased, while parasternal tidal EMG was preserved unchanged. Costal and crural shortening per breath during NREM and REM did not change significantly from wakefulness. Concurrently, parasternal shortening decreased equally in both NREM and REM despite preservation of the parasternal EMG. We conclude that diaphragm and parasternals are not inhibited, and both remain active together as essential inspiratory muscles, during REM sleep. The lesser contraction of parasternal intercostals compared with diaphragm may be attributed to net changes in mechanics affecting the chest wall during sleep. PMID- 27125848 TI - The emergence of Applied Physiology within the discipline of Physiology. AB - Despite the availability and utilization of the physiology textbooks authored by Albrecht von Haller during the 18th century that heralded the modern age of physiology, not all physicians or physiologists were satisfied with its presentation, contents, or application to medicine. Initial reasons were fundamental disagreements between the "mechanists," represented by Boerhaave, Robinson, and von Haller, and the "vitalists," represented by the faculty and graduates of the Montpellier School of Medicine in France, notably, Bordeu and Barthez. Subsequently, objections originated from Europe, United Kingdom, and the United States in publications that focused not only on the teaching of physiology to medical and secondary students, but on the specific applications of the content of physiology to medicine, health, hygiene, pathology, and chronic diseases. At the turn of the 20th century, texts began to appear with applied physiology in their titles and in 1926, physician Samson Wright published a textbook entitled Applied Physiology that was intended for both medical students and the medical profession. Eleven years later, physicians Best and Taylor published The Physiological Basis of Medical Practice: A University of Toronto Texbook in Applied Physiology Although both sets of authors defined the connection between applied physiology and physiology, they failed to define the areas of physiology that were included within applied physiology. This was accomplished by the American Physiological Society (APS) Publications Committee in 1948 with the publication of the Journal of Appplied Physiology, that stated the word "applied" would broadly denote human physiology whereas the terms stress and environment would broadly include work, exercise, plus industrial, climatic and social factors. NIH established a study section (SS) devoted to applied physiology in 1964 which remained active until 2001 when it became amalgamated into other SSs. Before the end of the 20th century when departments were changing their titles to reflect a stronger science orientation, many established laboratories and offered degree programs devoted to Applied Physiology. We concluded that Applied Physiology has been an important contributor to the discipline of physiology while becoming an integral component of APS. PMID- 27125849 TI - Comparing anesthesia with isoflurane and fentanyl/fluanisone/midazolam in a rat model of cardiac arrest. AB - Only one in ten patients survives cardiac arrest (CA), underscoring the need to improve CA management. Isoflurane has shown cardio- and neuroprotective effects in animal models of ischemia-reperfusion injury. Therefore, the beneficial effect of isoflurane should be tested in an experimental CA model. We hypothesize that isoflurane anesthesia improves short-term outcome following resuscitation from CA compared with a subcutaneous fentanyl/fluanisone/midazolam anesthesia. Male Sprague-Dawley rats were randomized to anesthesia with isoflurane (n = 11) or fentanyl/fluanisone/midazolam (n = 11). After 10 min of asphyxial CA, animals were resuscitated by mechanical chest compressions, ventilations, and epinephrine and observed for 30 min. Hemodynamics, including coronary perfusion pressure, systemic O2 consumption, and arterial blood gases, were recorded throughout the study. Plasma samples for endothelin-1 and cathecolamines were drawn before and after CA. Compared with fentanyl/fluanisone/midazolam anesthesia, isoflurane resulted in a shorter time to return of spontaneous circulation (ROSC), less use of epinephrine, increased coronary perfusion pressure during cardiopulmonary resusitation, higher mean arterial pressure post-ROSC, increased plasma levels of endothelin-1, and decreased levels of epinephrine. The choice of anesthesia did not affect ROSC rate or systemic O2 consumption. Isoflurane reduces time to ROSC, increases coronary perfusion pressure, and improves hemodynamic function, all of which are important parameters in CA models.NEW & NOTEWORTHY The preconditioning effect of volatile anesthetics in studies of ischemia-reperfusion injury has been demonstrated in several studies. This study shows the importance of anesthesia in experimental cardiac arrest studies as isoflurane raised coronary perfusion pressure during resuscitation, reduced time to return of spontaneous circulation, and increased arterial blood pressure in the post-cardiac arrest period. These effects on key outcome measures in cardiac arrest research are important in the interpretation of results from animal studies. PMID- 27125850 TI - Different cyclical intermittent hypoxia severities have different effects on hippocampal microvasculature. AB - Recent studies have shown an association between obstructive sleep apnea (OSA) and cognitive impairment. This study was done to investigate whether varied levels of cyclical intermittent hypoxia (CIH) differentially affect the microvasculature in the hippocampus, operating as a mechanistic link between OSA and cognitive impairment. We exposed C57BL/6 mice to sham [continuous air, arterial O2 saturation (SaO2 ) 97%], severe CIH to inspired O2 fraction (FiO2 ) = 0.10 (CIH10; SaO2 nadir of 61%), or very severe CIH to FiO2 = 0.05 (CIH5; SaO2 nadir of 37%) for 12 h/day for 2 wk. We quantified capillary length using neurostereology techniques in the dorsal hippocampus and utilized quantitative PCR methods to measure changes in sets of genes related to angiogenesis and to metabolism. Next, we employed immunohistochemistry semiquantification algorithms to quantitate GLUT1 protein on endothelial cells within hippocampal capillaries. Capillary length differed among CIH severity groups (P = 0.013) and demonstrated a linear relationship with CIH severity (P = 0.002). There was a strong association between CIH severity and changes in mRNA for VEGFA (P < 0.0001). Less strong, but nominally significant associations with CIH severity were also observed for ANGPT2 (PANOVA = 0.065, PTREND = 0.040), VEGFR2 (PANOVA = 0.032, PTREND = 0.429), and TIE-2 (PANOVA = 0.006, PTREND = 0.010). We found that the CIH5 group had increased GLUT1 protein relative to sham (P = 0.006) and CIH10 (P = 0.001). There was variation in GLUT1 protein along the microvasculature in different hippocampal subregions. An effect of CIH5 on GLUT1 mRNA was seen (PANOVA = 0.042, PTREND = 0.012). Thus CIH affects the microvasculature in the hippocampus, but consequences depend on CIH severity. PMID- 27125851 TI - Two rare antioxidative prenylated terpenoids from loop-root Asiatic mangrove Rhizophora mucronata (Family Rhizophoraceae) and their activity against pro inflammatory cyclooxygenases and lipoxidase. AB - Two new biogenic prenylated terpenoids were isolated from the methanol extract of Rhizophora mucronata. The extended C20 sesquiterpenoid with prenylated guaiane framework was characterised as (4E, 8Z)-3, 3a, 6, 7-tetrahydro-3, 9-dimethyl-5-(6 methylheptan-2-yl) cycloocta[b]furan-2-(9aH)-one (1). (35E)-1,2,3,5,6,6 icosahydro-4,4,8b,10,14,17,20,20-octamethylpicen-3-yl-34,35-dimethyloct-31-enoate (2) represents the first example of naturally occurring C40 prenylated oleanane type triterpenoid, whereas one 4,5-dimethyloct-5-enoate side chain remains attached at C-3 position of the oleanane framework formed by the E-ring closure of C30 saccharide moiety. The structures of the compounds were elucidated using NMR and mass spectrometric analysis. Compound 1 was found to have significantly greater antioxidant activities (IC50 ~ 0.75 mg/mL) compared to 2 (IC50 > 0.80 mg/mL). No significant differences in anti-cyclooxygenase-2 of these compounds were discernable (IC50 0.8 - 0.9 mg/mL), whilst compound 1 showed greater anti-5 lipoxidase activities (IC50 ~ 0.8 mg/mL) those that of 2 (IC50 0.96 mg/mL). Bioactivities of the prenylated terpenoids were inversely proportional to lipophilic and bulk descriptors. PMID- 27125852 TI - Lysosomal cathepsins and their regulation in aging and neurodegeneration. AB - Lysosomes and lysosomal hydrolases, including the cathepsins, have been shown to change their properties with aging brain a long time ago, although their function was not really understood. The first biochemical and clinical studies were followed by a major expansion in the last 20 years with the development of animal disease models and new approaches leading to a major advancement of understanding of the role of physiological and degenerative processes in the brain at the molecular level. This includes the understanding of the major role of autophagy and the cathepsins in a number of diseases, including its critical role in the neuronal ceroid lipofuscinosis. Similarly, cathepsins and some other lysosomal proteases were shown to have important roles in processing and/or degradation of several important neuronal proteins, thereby having either neuroprotective or harmful roles. In this review, we discuss lysosomal cathepsins and their regulation with the focus on cysteine cathepsins and their endogenous inhibitors, as well as their role in several neurodegenerative diseases. PMID- 27125854 TI - The role of ions in the self-healing behavior of soft particle suspensions. AB - Impurities in crystals generally cause point defects and can even suppress crystallization. This general rule, however, does not apply to colloidal crystals formed by soft microgel particles [Iyer ASJ, Lyon LA (2009) Angew Chem Int Ed 48:4562-4566], as, in this case, the larger particles are able to shrink and join the crystal formed by a majority of smaller particles. Using small-angle X-ray scattering, we find the limit in large-particle concentration for this spontaneous deswelling to persist. We rationalize our data in the context of those counterions that are bound to the microgel particles as a result of the electrostatic attraction exerted by the fixed charges residing on the particle periphery. These bound counterions do not contribute to the suspension osmotic pressure in dilute conditions, as they can be seen as internal degrees of freedom associated with each microgel particle. In contrast, at sufficiently high particle concentrations, the counterion cloud of each particle overlaps with that of its neighbors, allowing these ions to freely explore the space outside the particles. We confirm this scenario by directly measuring the osmotic pressure of the suspension. Because these counterions are then no longer bound, they create an osmotic pressure difference between the inside and outside of the microgels, which, if larger than the microgel bulk modulus, can cause deswelling, explaining why large, soft microgel particles feel the squeeze when suspended with a majority of smaller particles. We perform small-angle neutron scattering measurements to further confirm this remarkable behavior. PMID- 27125853 TI - The crucial impact of lysosomes in aging and longevity. AB - Lysosomes are the main catabolic organelles of a cell and play a pivotal role in a plethora of cellular processes, including responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation. In line with this pleiotropic importance for cellular and organismal life and death, lysosomal dysfunction is associated with many age-related pathologies like Parkinson's and Alzheimer's disease, as well as with a decline in lifespan. Conversely, targeting lysosomal functional capacity is emerging as a means to promote longevity. Here, we analyze the current knowledge on the prominent influence of lysosomes on aging-related processes, such as their executory and regulatory roles during general and selective macroautophagy, or their storage capacity for amino acids and ions. In addition, we review and discuss the roles of lysosomes as active players in the mechanisms underlying known lifespan-extending interventions like, for example, spermidine or rapamycin administration. In conclusion, this review aims at critically examining the nature and pliability of the different layers, in which lysosomes are involved as a control hub for aging and longevity. PMID- 27125855 TI - In vivo metabolic labeling of sialoglycans in the mouse brain by using a liposome assisted bioorthogonal reporter strategy. AB - Mammalian brains are highly enriched with sialoglycans, which have been implicated in brain development and disease progression. However, in vivo labeling and visualization of sialoglycans in the mouse brain remain a challenge because of the blood-brain barrier. Here we introduce a liposome-assisted bioorthogonal reporter (LABOR) strategy for shuttling 9-azido sialic acid (9AzSia), a sialic acid reporter, into the brain to metabolically label sialoglycoconjugates, including sialylated glycoproteins and glycolipids. Subsequent bioorthogonal conjugation of the incorporated 9AzSia with fluorescent probes via click chemistry enabled fluorescence imaging of brain sialoglycans in living animals and in brain sections. Newly synthesized sialoglycans were found to widely distribute on neuronal cell surfaces, in particular at synaptic sites. Furthermore, large-scale proteomic profiling identified 140 brain sialylated glycoproteins, including a wealth of synapse-associated proteins. Finally, by performing a pulse-chase experiment, we showed that dynamic sialylation is spatially regulated, and that turnover of sialoglycans in the hippocampus is significantly slower than that in other brain regions. The LABOR strategy provides a means to directly visualize and monitor the sialoglycan biosynthesis in the mouse brain and will facilitate elucidating the functional role of brain sialylation. PMID- 27125856 TI - The shapes of bird beaks are highly controlled by nondietary factors. AB - Bird beaks are textbook examples of ecological adaptation to diet, but their shapes are also controlled by genetic and developmental histories. To test the effects of these factors on the avian craniofacial skeleton, we conducted morphometric analyses on raptors, a polyphyletic group at the base of the landbird radiation. Despite common perception, we find that the beak is not an independently targeted module for selection. Instead, the beak and skull are highly integrated structures strongly regulated by size, with axes of shape change linked to the actions of recently identified regulatory genes. Together, size and integration account for almost 80% of the shape variation seen between different species to the exclusion of morphological dietary adaptation. Instead, birds of prey use size as a mechanism to modify their feeding ecology. The extent to which shape variation is confined to a few major axes may provide an advantage in that it facilitates rapid morphological evolution via changes in body size, but may also make raptors especially vulnerable when selection pressures act against these axes. The phylogenetic position of raptors suggests that this constraint is prevalent in all landbirds and that breaking the developmental correspondence between beak and braincase may be the key novelty in classic passerine adaptive radiations. PMID- 27125857 TI - Computational study of p53 regulation via the chemical master equation. AB - A stochastic model of cellular p53 regulation was established in Leenders, and Tuszynski (2013 Front. Oncol. 3 1-16) to study the interactions of p53 with MDM2 proteins, where the stochastic analysis was done using a Monte Carlo approach. We revisit that model here using an alternative scheme, which is to directly solve the chemical master equation (CME) by an adaptive Krylov-based finite state projection method that combines the stochastic simulation algorithm with other computational strategies, namely Krylov approximation techniques to the matrix exponential, divide and conquer, and aggregation. We report numerical results that demonstrate the extend of tackling the CME with this combination of tools. PMID- 27125858 TI - Grimontia celer sp. nov., from sea water. AB - Strain 96-237T, a Gram-reaction-negative, curved- to spiral-shaped motile bacterium, isolated from coastal marine water, was found to be related to species of the genus Grimontia by 16S rRNA gene sequence comparison, sharing 98.3 % similarity to Grimontia marina CECT 8713Tand 98.8 % to 'Grimontiaindica' AK16. Phenotypic analysis revealed that strain 96-237T is slightly halophilic, mesophilic and facultatively anaerobic, fermenting d-glucose, d-ribose, d mannose, d-mannitol, maltose and sucrose. It was positive for oxidase and indole production and negative for arginine dihydrolase and lysine and ornithine decarboxylases. Its major fatty acids were C16 : 1omega7c/C16 : 1omega6c (SF3), C18 : 1omega7c and C16 : 0. Its DNA G+C content was 48.4 mol%. The strain was different at the species level from all other species of the genusGrimontia, with average nucleotide identity indices of 79.6 % to Grimontia. hollisae CECT 8713T, 87.8 % to G. marina CECT 5069T and 89.1 % to 'G. indica' AK16 genomes. Thus, the strain represents a novel species for which we propose the name Grimontia celer and 96-237T (=CECT 9029T =KCTC 42960T =LMG 29238T) as the type strain. PMID- 27125859 TI - FOXN1 recombinant protein enhances T-cell regeneration after hematopoietic stem cell transplantation in mice. AB - A prolonged period of T-cell recovery is the major challenge in hematopoietic stem cell transplantation (HSCT). Thymic epithelial cells (TECs) are the major component of the thymic microenvironment for T-cell generation. However, TECs undergo degeneration over time. FOXN1 plays a critical role in TEC development and is required to maintain adult TECs for thymopoiesis. To investigate the potential application of FOXN1, we have cloned and expressed recombinant FOXN1 protein (rFOXN1) that was fused with cell-penetrating peptides. We show here that the rFOXN1 protein can translocate from the cell surface into the cytoplasm and nucleus. Administration of rFOXN1 into both congenic and allogeneic HSCT recipient mice increased the number of TECs, resulting in enhanced thymopoiesis that led to an increased number of functional T cells in the periphery. The increased number of TECs is due to the enhanced survival and proliferation of TECs. Our results suggest that rFOXN1 has the potential to be used in enhancing T cell regeneration in patients following HSCT. PMID- 27125860 TI - Long-Term Effect of Rifampicin-Based Anti-TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8-Hydroxy-Efavirenz in Ethiopian Patients. AB - We compared the pharmacokinetic (PK) exposure parameters of efavirenz (EFV) and its major inactive metabolite, 8-hydroxy-efavirenz (8-OH-EFV), in an open-label, single-sequence, and parallel design of HIV-infected and tuberculosis (TB)-HIV coinfected Ethiopian patients in the HIV-TB Pharmagene study with 20 and 33 patients, respectively. Both treatment groups underwent PK sampling following oral 600 mg EFV in week 16 of initiating EFV-based combination antiretroviral therapy. The TB-HIV-coinfected group repeated the PK sampling 8 weeks after stopping rifampin (RIF)-based anti-TB treatment. Between-treatment group analysis indicated no significant effect of RIF-based anti-TB cotreatment on PK exposure parameters of EFV, nor was there a significant effect after controlling for sex or CYP2B6 genotype. However, RIF-based therapy in TB-HIV-coinfected patients had significantly increased 8-OH-EFV PK exposure measures and metabolic ratio relative to HIV-only patients, AUC0-24 greater by 79%. The effect was more prominent in women and CYP2B6*6 carriers in within-sex and CYP2B6 genotype comparisons. Within-subject comparisons for AUC0-24 and Cmax when "on" and "off" RIF-based anti-TB cotreatment showed geometric mean ratios (90% confidence intervals) of 100.5% (98.7%-102.3%) and 100.2% (98.1%-102.4%), respectively, for EFV and 98.6% (95.5%-101.7%-) and 97.6% (92.2%-103.0%), respectively, for 8-OH EFV. We report no significant influence of RIF-based anti-TB cotherapy on the EFV PK exposure measures. The study also calls for caution related to higher exposure to 8-OH-EFV during simultaneous coadministration of EFV and RIF-based anti-TB regimens, which may be associated with neurotoxicity, particularly in female patients and CYP2B6*6 carriers. PMID- 27125861 TI - The map is not the territory: medical records and 21st century practice. AB - Documentation of care is at risk of overtaking the delivery of care in terms of time, clinician focus, and perceived importance. The medical record as currently used for documentation contributes to increased cognitive workload, strained clinician-patient relationships, and burnout. We posit that a near verbatim transcript of the clinical encounter is neither feasible nor desirable, and that attempts to produce this exact recording are harmful to patients, clinicians, and the health system. In this Viewpoint, we focus on the alternative constructions of the medical record to bring them back to their primary purpose-to aid cognition, communicate, create a succinct account of care, and support longitudinal comprehensive care-thereby to support the building of relationships and medical decision making while decreasing workload. PMID- 27125862 TI - Exploring the experiences of nurses and doctors involved in stroke care: a qualitative study. AB - AIMS AND OBJECTIVES: To describe the current stroke care delivery arrangements in Greece and to explore nursing and medical staff knowledge, skills and attitudes, towards stroke care and management. BACKGROUND: Stroke care is diverse in the Greek public healthcare system and is delivered in a medical, neurology or a recently introduced, specialised unit. These settings are available alternatively under a central rota system. DESIGN: Descriptive qualitative investigation using semi-structured interviews. METHODS: A purposeful sample of 21 hospital staff were interviewed and verbatim data was transcribed for content analysis. Staff were selected from the various settings involved in stroke care; six medical and 15 nursing staff (12 female) were interviewed. RESULTS: A number of themes emerged from the interview data and these include: (1) current facilities, (2) admission destination, (3) stroke nursing care, and (4) family involvement and continuing education needs. DISCUSSION: Innovation and development can occur, even in the face of adversity, due to the commitment, passion and insight of healthcare professionals to enhance stroke care to aspire to international standards. CONCLUSIONS: Greek stroke nurses can achieve their professional potential within the appropriate working environment. The Stroke Bay working ethos and environment enhances professional autonomy and scope of practice. RELEVANCE TO CLINICAL PRACTICE: By exploring staff's knowledge and attitudes towards stroke care, nurses and healthcare professionals in general will gain a better understanding of their multiple clinical roles as stroke care providers by reflecting on their patients' needs. PMID- 27125863 TI - Analysis of pseudoprogression after corneal cross-linking in children with progressive keratoconus. AB - PURPOSE: To analyse the long-term efficacy of corneal cross-linking (CXL) in children with keratoconus and to describe criteria for the detection of pseudoprogression. METHODS: Evaluation of retrospectively collected corneal topography (Placido system) and tomography (Scheimpflug system) results after CXL in children (age 18 or younger). Twenty-five patients (33 eyes) were included. Follow-up was assessed after 1, 2, 3 and 4 years. Progression was defined as an increase in maximal keratometry (Kmax) of at least one dioptre (D) in 1 year. RESULTS: For the entire group, mean Kmax prior to CXL was 55.3 +/- 7.3D and decreased significantly (p = 0.00001) after 1 year to 53.4 +/- 7.4D. In 23 patients, the progression could be halted. Five cases of presumed progression were identified. One case showed marked steepening in Kmax 4 years after CXL, but the topographic parameters were unchanged. The tomography was repeated and showed that Kmax was stable. Two cases with limbal vernal keratoconjunctivitis (VKC) worsened both in corneal tomography and topography. After resolution of the limbal inflammation, the Kmax values returned to the values before the inflammation. We found two cases of true progression both of which had advanced keratoconus prior to CXL with a preoperative Kmax of 64.4, respectively, 75.1D. CONCLUSION: Our results confirm that CXL is effective in stabilizing keratoconus in children. True progression after CXL could only be verified in two of 33 eyes in a follow-up period of 37.5 months (SD +/- 10 months). Two different measuring methods can help to detect diagnostic discrepancies and prevent false conclusions. Moreover, limbal vernal changes can cause transient pseudoprogression, reversible upon sufficient treatment. PMID- 27125864 TI - Hydrogenation Reactions during Pyrolysis-Gas Chromatography/Mass Spectrometry Analysis of Polymer Samples Using Hydrogen Carrier Gas. AB - Pyrolysis-gas chromatography/mass spectrometry of polymer samples is studied focusing on the effect of hydrogen (H2) carrier gas on chromatographic and spectral data. The pyrograms and the related mass spectra of high density polyethylene (HDPE), low density polyethylene, and polystyrene (PS) serve to illustrate the differences between the species formed in H2 and the helium environment. Differences in the pyrograms and the spectra are generally thought to be a result of the hydrogenation reaction of the pyrolyzates. From the peak intensity changes in the pyrograms of HDPE and PS, hydrogenation of unsaturated pyrolyzates is concluded to occur when the pyrolysis is done in H2. Moreover, additional hydrogenation of the pyrolyzates occurs in the electron ionization source of a MS detector when H2 is used as a carrier gas. Finally, the applicability of mass spectral libraries to characterize pyrograms obtained in H2 is illustrated using 24 polymers. The effect of the hydrogenation reaction on the library search results is found to be negligible for most polymer samples with polar and nonpolar monomer units. PMID- 27125865 TI - A. baumannii histone acetyl transferase Hpa2: optimization of homology modeling, analysis of protein-protein interaction and virtual screening. AB - In the current scenario, widespread multidrug resistivity in ESKAPE pathogens demands identification of novel drug targets to keep their infections at bay. For this purpose, we have identified a novel target Hpa2 of A. baumannii, a member of GNAT superfamily of HATs. But due to sequence identity of equal or less than 35%, the correct sequence alignment and construction of 3D monomeric and dimeric models of Hpa2 having optimal structural parameters is a troublesome task. To circumvent these problems, we have designed an easy and optimized protocol for Hpa2 monomer modeling, and for generation of dimeric Hpa2 model using data-driven protein-protein docking experiment. Improvement in the structural features of generated model is an onerous process and generally achieved by paying time and computational cost. Herein, it is achieved by reconciliation of FoldX commands which takes less time in execution. Evaluations performed to validate structural parameters and stability of monomeric and dimeric Hpa2 attests to its quality. Analysis of interfacial residues, energy terms and RMSD values indicated a clear correlation between experimental and theoretical interface properties of the dimers, corroborating to the regime used for Hpa2 dimer generation. Structural information from the refined models was used for virtual screening of substrate derived library and polyamines to achieve a new platform for developing A. baumannii inhibitory molecules. Molecules showing preferential binding at the dimer interface could be used as allosteric inhibitors. Binding of polyamines with model illustrated the same binding pattern as described experimentally in case of yeast Hpa2. PMID- 27125866 TI - NF-kappaB decoy polyplexes decrease P-glycoprotein-mediated multidrug resistance in colorectal cancer cells. AB - Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-kappaB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-kappaB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N dimethylaminoethylmethacrylate) diblock copolymer (pHPMA-b-pDMAEMA). Ethidium bromide intercalation and gel retardation assays demonstrated high DNA condensation capacity of pHPMA-b-pDMAEMA. Nanoparticles prepared with and without decoy ODNs did not significantly compromise cellular safety at N/P ratios ?4. Transfection efficiency of pHPMA-b-pDMAEMA polyplexes (N/P=4) in Caco-2 cells was comparable to TurboFect transfection standard, resulting in a 98% reduction in P gp protein levels. As a pharmacodynamic consequence, intracellular accumulation of the P-gp substrate Rhodamine123 significantly increased by almost twofold. In conclusion, NF-kappaB ODN polyplexes fabricated with pHPMA-b-pDMAEMA polymer effectively reduced P-gp-mediated efflux activity in Caco-2 cells, suggesting successful interference with NF-kappaB-binding sites in the promoter region of the ABCB1 gene. PMID- 27125867 TI - "Halo effect" in trauma centers: does it extend to emergent colectomy? AB - BACKGROUND: Trauma centers (TCs) have been demonstrated to improve outcomes for some nontrauma surgical conditions, such as appendicitis, but it remains unclear if this extends to all emergency general surgery procedures. Using emergent colectomy in patients with diverticulitis as index condition, this study compared outcomes between TCs and nontrauma centers (NTCs). MATERIALS AND METHODS: The Nationwide Emergency Department Sample (2006-2011) was queried for patients >=16 y with diverticulitis who underwent emergency surgical intervention. Outcomes included mortality, total charges, and length of stay (LOS). Mortality in TC and NTC was compared using logistic regression, controlling for patient, procedure, and hospital-level characteristics. Adjusted total charges and LOS were analyzed using generalized linear models with gamma and Poisson distributions, respectively. RESULTS: A total of 25,396 patients were included, 5189 (20.4%) were treated at TC and 20,207 (79.6%) at NTC. Median age and sex distribution were similar. Unadjusted proportional in-hospital mortality did not differ between TC and NTC; median charges and LOS were greater in TC. After adjusting, the odds of mortality were significantly higher in TC (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.02-1.51; P = 0.003) as were mean charges and LOS (P < 0.001). CONCLUSIONS: The improved outcomes reported for other nontrauma conditions in TC were not observed for patients undergoing an emergent colectomy for diverticulitis after accounting for patient, procedure, and hospital-level characteristics. Future research is needed to assess differences in case mix between TC versus NTC and possible case-mix effects on outcomes to elucidate potential benefit of surgical care in a TC across the breadth of emergency general surgery conditions. PMID- 27125868 TI - Central nervous system involvement by myeloid sarcoma: a report of 12 cases and review of the literature. AB - Myeloid sarcoma (MS) is an extramedullary malignancy of myeloid origin. It can occur in any organ. Common sites are skin, bone, lymph nodes, and soft tissue. Central nervous system (CNS) involvement is very uncommon. We report 12 new pathology-confirmed cases of CNS MS with literature review. Median age was 42.5 years (range: 0 - 84 years). Bone marrow involvement by hematologic neoplasia was co-incidental (n = 8) or occurred 8 - 51 months prior to CNS MS (n = 3). Abnormal radiological findings detected in all patients, included hemorrhagic (n = 5) or enhancing (n = 2) lesions, with multiple ring-enhancing dura-based masses in 1 patient. Seven tumors had abnormal cytogenetics including: t(11; 19) (q23; p13.3), +8, inv (16), t(9; 22), t(8; 21), del(5q), and +21. One had a complex karyotype and 2 were cytogenetically normal. One MS had the JAK2V617F mutation. Treatment modalities included surgery for decompression (n = 2), radiotherapy (n = 2), chemotherapy (n = 6), and stem cell transplant (n = 2). Nine patients died days to 12 months post CNS MS diagnosis (median = 4 months). Two patients were alive without evidence of disease at 16 and 50 months following MS diagnosis and one was lost to follow-up. The clinical and imaging features for CMS MS overlap with those of intracranial hemorrhage and primary CNS tumors. It is therefore important to maintain a high index of suspicion and perform a biopsy whenever clinically appropriate. A meticulous workup is necessary to avoid misdiagnosis of other hematopoietic or nonhematopoietic neoplasms. Since CNS MS is potentially curable, timely recognition is paramount. PMID- 27125869 TI - Granular cell astrocytoma: report of a case and review of the literature. AB - A 54-year-old man with no remarkable past medical history was referred to our hospital for the appearance of generalized tonic clonic seizures with loss of consciousness, preceded by phosphenes at the right eye. On magnetic resonance imaging, a contrast-enhanced tumor in the left occipital lobe with peripheral edema was noted. He underwent craniotomy, and the entire mass was removed. Microscopic examination revealed infiltrative atypical astrocytes (glial fibrillary acidic protein, GFAP, positive) with discrete borders and granular cytoplasm. Ki-67 labeling index was 40%. The tumor was diagnosed as a high-grade granular cell astrocytoma (GCA). Postoperative radiotherapy combined with temozolomide was administered. GCAs are aggressive lesions and should not to be confused with localized, benign granular cell tumors or with other non neoplastic granular cell changes in the central nervous system (CNS). GCAs are rare tumors. At this time, only 63 supratentorial/ hemispheric cases, including our case, have been reported in literature. PMID- 27125870 TI - Synthesis of 2H-Azirines by Iridium-Catalyzed Decarboxylative Ring Contraction of Isoxazol-5(4H)-ones. AB - A phosphine-free iridium-catalyzed reaction of isoxazol-5(4H)-ones (isoxazolones) has been developed, and affords 2H-azirines through decarboxylation and ring contraction. This method provides an efficient and environmentally benign protocol which could replace the conventional approaches used to synthesize 2H azirines. PMID- 27125871 TI - Detection of Leishmania DNA in wild foxes and associated ticks in Patagonia, Argentina, 2000 km south of its known distribution area. AB - BACKGROUND: Zoonotic Visceral Leishmaniasis (ZVL) is a vector-borne disease affecting humans and other mammals and caused by the protozoan parasite Leishmania (Leishmania) infantum (syn. L. chagasi), belonging to the L. donovani complex. The regions in Northern Argentina (above 32 degrees S) are its southern distribution limit in South America. RESULTS: We detected Leishmania sp. DNA (most likely belonging to the L. donovani complex) in 37.5% of 32 grey foxes (Pseudalopex griseus) captured in Argentinean Patagonia (48 degrees S and 50 degrees S). Eleven monosexual pools of Amblyomma tigrinum ticks from eight different foxes (six grey foxes and two culpeo foxes P. culpaeus) were also positive. The southernmost known distribution limit for L. infantum, and the southernmost reported capture of a phlebotominae, had previously been 2000 and 750 km north of our study area, respectively. CONCLUSIONS: This finding is significant because it markedly extends the distribution area of leishmaniasis; supports the existence of a sylvatic cycle in the absence of dogs; and has implications in transmission, indicating that either sand fly distribution is broader than currently thought or non-sand fly Leishmania maintenance is possible. Additional molecular, parasitological, epidemiological and entomological studies are still needed. PMID- 27125873 TI - The temporal evolution of diffusional kurtosis imaging in an experimental middle cerebral artery occlusion (MCAO) model. AB - PURPOSE: Diffusional kurtosis imaging (DKI), as a non-Gaussian diffusion model, has been applied in human and animal studies of ischemic stroke. This study aimed to intensively characterize the temporal evolution of DKI-derived variables in an experimental middle cerebral artery occlusion (MCAO) model, and to explore its potential application in ischemic stroke. MATERIALS AND METHODS: Eleven MCAO rats and ten control rats underwent DKI and diffusion weighted imaging (DWI) scans, at different time points of 0.5, 2, 6, 12, 24 and 72h after operation respectively. The infarct area in DKI- and DWI-derived variables was compared among different time points, and between different groups [INFARCTION, MIRROR, CONTROL-R (right side of the control group, the same side as in the infarction group), CONTROL-L (left side of the control group)] using repeated measures analysis of variance (ANOVA). The percent changes from normal to that in ischemic tissues and histology were also evaluated. RESULTS: In the infarct region, from 0.5 to 72h, MK, K?, K? demonstrated irregular high signal, whereas relative homogeneous low signals were revealed by MD, D?, D? and ADC. Compared with the MIRROR and CONTROL R group, MK, K?, K? in the infarcted area increased aggressively which peaked at 12h and gradually decreased; MD, D?, D? and ADC decreased gradually until 12h and then began to increase gradually; FA decreased rapidly from 0.5 to 72h. MD, D? and ADC were significantly different between Mirror and CONTROL-L group (P<0.05). CONCLUSION: DKI can provide more detailed information to describe ischemic lesion, and has great potential application in ischemic stroke. PMID- 27125872 TI - Prognostic performance of pre-treatment NLR and PLR in patients suffering from osteosarcoma. AB - BACKGROUND: Inflammatory response markers have been proposed to predict the clinical outcomes in various cancers. The aim of this study was to explore the influence of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) on the prognosis of osteosarcoma. METHODS: Three hundred fifty-nine patients who underwent curative surgery for osteosarcoma were enrolled from 2005 to 2010. NLR and PLR were calculated from peripheral blood cell counts taken at pre-treatment. Optimal cutoff values of NLR and PLR were determined on the basis of receiver operating characteristic curve analysis. A predictive model was established to predict the clinical outcome for overall survival, and the predictive accuracy of this model was determined by concordance index (c-index). RESULTS: Our results showed that advanced stage and metastasis at diagnosis were significantly associated with the high NLR and PLR groups. NLR was an independent prognostic indicator for overall survival (HR = 1.80, 95% CI = 1.35-2.41, P < 0.001) and progression-free survival (HR = 1.65, 95% CI = 1.26-2.15, P < 0.001), except for PLR. The nomogram could perform well in the prediction of overall survival in patients with osteosarcoma (c-index 0.829). CONCLUSIONS: Our results suggest that both NLR and PLR can reflect clinical prognosis. NLR is more predictive of overall survival and progression-free survival than PLR. PMID- 27125874 TI - An automatic tooth preparation technique: A preliminary study. AB - The aim of this study is to validate the feasibility and accuracy of a new automatic tooth preparation technique in dental healthcare. An automatic tooth preparation robotic device with three-dimensional motion planning software was developed, which controlled an ultra-short pulse laser (USPL) beam (wavelength 1,064 nm, pulse width 15 ps, output power 30 W, and repeat frequency rate 100 kHz) to complete the tooth preparation process. A total of 15 freshly extracted human intact first molars were collected and fixed into a phantom head, and the target preparation shapes of these molars were designed using customised computer aided design (CAD) software. The accuracy of tooth preparation was evaluated using the Geomagic Studio and Imageware software, and the preparing time of each tooth was recorded. Compared with the target preparation shape, the average shape error of the 15 prepared molars was 0.05-0.17 mm, the preparation depth error of the occlusal surface was approximately 0.097 mm, and the error of the convergence angle was approximately 1.0 degrees . The average preparation time was 17 minutes. These results validated the accuracy and feasibility of the automatic tooth preparation technique. PMID- 27125875 TI - Endothelial lipid phosphate phosphatase-3 deficiency that disrupts the endothelial barrier function is a modifier of cardiovascular development. AB - AIMS: Lipid phosphate phosphatase-3 (LPP3) is expressed at high levels in endothelial cells (ECs). Although LPP3 is known to hydrolyse the phosphate group from lysolipids such as spingosine-1-phosphate and its structural homologues, the function of Lpp3 in ECs is not completely understood. In this study, we investigated how tyrosine-protein kinase receptor (TEK or Tie2) promoter dependent deletion of Lpp3 alters EC activities. METHODS AND RESULTS: Lpp3(fl/fl) mice were crossed with the tg.Tie2(Cre) transgenic line. Vasculogenesis occurred normally in embryos with Tie2(Cre)-mediated deletion of Lpp3 (called Lpp3(ECKO)), but embryonic lethality occurred in two waves, the first wave between E8.5 and E10.5, while the second between E11.5 and E13.5. Lethality in Lpp3(ECKO) embryos after E11.5 was accompanied by vascular leakage and haemorrhage, which likely resulted in insufficient cardiovascular development. Analyses of haematoxylin- and eosin-stained heart sections from E11.5 Lpp3(ECKO) embryos showed insufficient heart growth associated with decreased trabeculation, reduced growth of the compact wall, and absence of cardiac cushions. Staining followed by microscopic analyses of Lpp3(ECKO) embryos revealed the presence of apoptotic ECs. Furthermore, Lpp3-deficient ECs showed decreased gene expression and protein levels of Cyclin-D1, VE-cadherin, Fibronectin, Klf2, and Klf4. To determine the underlying mechanisms of vascular leakage and barrier disruption, we performed knockdown and rescue experiments in cultured ECs. LPP3 knockdown decreased transendothelial electrical resistance and increased permeability. Re-expression of beta-catenin cDNA in LPP3-knockdown ECs partially restored the effect of the LPP3 loss, whereas re-expression of p120ctn cDNA did not. CONCLUSION: These findings demonstrate the essential roles of LPP3 in the maturation of EC barrier integrity and normal cardiovascular development. PMID- 27125876 TI - Long-term Functional, Urodynamic, and Metabolic Outcome of a Modified Orthotopic Neobladder Created With a Short Ileal Segment: Our 5-year Experience. AB - OBJECTIVE: To assess the long-term functional, urodynamic, and metabolic outcomes of our modified neobladder. MATERIALS AND METHODS: In this prospective study from January 2010 to October 2014, 42 consecutive male patients with bladder tumor underwent radical cystectomy and orthotopic urinary diversion with modified ileal neobladder using 25 cm ileal segment. During follow-up, functional outcome, urodynamic studies, metabolic parameters, and renal parameters were assessed at regular intervals. Complications were graded as early (<3 months) or late (>3 months). RESULTS: There were no perioperative deaths. At a mean follow-up of 27.2 months, good or satisfactory daytime and nighttime continence were achieved in 100% and 93.8% of patients, respectively. Mean maximal bladder capacity was 588 mL at 3 years. Mean resting pressure and voiding pressures were 20.1 cm H2O and 34.6 cm H2O at 3 years, respectively. Good bladder compliance was achieved in all patients by 1 year. Mean maximum urine flow rate (Qmax) was 18.5 mL at 3 years. Postvoid residual volume was insignificant in all the patients and none of the patients were on clean intermittent self-catheterization. None of the patients developed severe metabolic acidosis. Vitamin B12 levels were within normal range in all patients. Early complications were seen in 12 patients (28.6%), whereas late complications were observed in 5 patients (12%). CONCLUSION: Our results demonstrate that our modified technique of using a short ileal segment to create a near-spherical, compliant, low-pressure reservoir provides an acceptable, safe, and functional alternative to the standard Hautmann neobladder. PMID- 27125877 TI - The tACE/Angiotensin (1-7)/Mas Axis Protects Against Testicular Ischemia Reperfusion Injury. AB - OBJECTIVE: To investigate whether exogenous angiotensin (Ang)-(1-7) administration can protect against the damaging consequences of testicular ischemia reperfusion (tIR) injury. MATERIALS AND METHODS: Eighteen male Sprague Dawley rats were divided equally among the following 3 groups: sham, unilateral tIR injury (1 hour of ischemic treatment and 4 hours of reperfusion), and tIR + Ang-(1-7) (0.3 mg/kg). Testicular tissues obtained from the rats were evaluated for the expression of testicular angiotensin-converting enzyme (tACE), Ang-(1-7), and the Ang-(1-7)-specific receptor Mas by immunohistochemistry and enzyme-linked immunosorbent assay. Reduced spermatogenesis, induction of the caspase-8 pathway, and nitric oxide (NO) generation were assessed. The effects of tIR and Ang-(1-7) treatment on the PI3K/Akt antiapoptosis pathway were also investigated. RESULTS: Testicular morphological changes and reduced spermatogenesis associated with decreased expression of the tACE/Ang-(1-7)/Mas axis were observed during tIR. These effects were also accompanied by increased activity of caspase-3 and -8, downregulation of the survivin and BAD transcripts, and decreased NO formation. During tIR, PTEN expression was increased, leading to inactivation of the PI3K/Akt pathway. Acute treatment with Ang-(1-7) prior to reperfusion attenuated the tIR-induced damage described above. CONCLUSION: Expression of the tACE/Ang-(1 7)/Mas axis was downregulated during tIR. Administration of exogenous Ang-(1-7) prior to reperfusion rescued tACE and Mas expression and protected against germ cell apoptosis and oxidative stress. Increased NO generation and activation of the PI3K/Akt signaling pathway may have partially contributed to these effects. The tACE/Ang-(1-7)/Mas axis likely plays a role in the maintenance of normal testis physiology and spermatogenesis. PMID- 27125878 TI - Risk Factors and Microbial Distribution of Urinary Tract Infections Following Radical Cystectomy. AB - OBJECTIVE: To evaluate clinicopathologic features associated with the risk of urinary tract infection (UTI) after radical cystectomy (RC), and determine the underlying organisms responsible for these events. MATERIALS AND METHODS: We reviewed 1248 patients treated with RC for bladder cancer from 2000 to 2010 at Mayo Clinic. UTIs diagnosed within 90 days of surgery were recorded. Multivariable logistic regression analysis was performed to evaluate the association of clinicopathologic features with postoperative UTI. RESULTS: UTI was diagnosed in 129 (10.3%) patients within 90 days of RC. Median time to UTI was 22.5 days (interquartile range 14,42). On multivariable analysis, factors associated with a significantly increased UTI risk were diabetes (odds ratio [OR] 2.27; P < .001), receipt of a perioperative blood transfusion (OR 1.58; P = .03), continent urinary diversion (OR 2.17;P < .001), and development of a urine leak (OR 3.42;P < .001). Culture-specific infection data were available for 88 of the patients, with a total of 113 UTIs diagnosed among this cohort. Of these, 36.8% of UTIs were polymicrobial. Drug-resistant Staphylococcus aureus and Enterococcus were isolated in 45.0% and 12.8% of infections, respectively. Fungal elements were present in 27 (23.9%) cultures, and were the sole organism in 15 (13.3%). No significant differences in microbial distribution or timing of infections were detected between patients who underwent conduit vs continent diversion. CONCLUSION: We found that diabetes, perioperative blood transfusion, continent diversion, and urine leak were associated with UTI risk following RC. Multiple organisms, drug resistance, and fungal elements were commonly identified, supporting the use of initial broad-spectrum coverage, including consideration of antifungal therapy, upon diagnosis of UTI after RC. PMID- 27125879 TI - Evaluation of Hyperbaric Oxygen Therapy in the Treatment of Radiation-induced Hemorrhagic Cystitis. AB - OBJECTIVE: To evaluate the efficacy of hyperbaric oxygen therapy (HBO) in the treatment of postradiation hematuria (PRH) and to identify the predictive factors for a successful outcome. MATERIALS AND METHODS: We conducted a retrospective study and included all patients with PRH treated with HBO in a university hospital center between January 2003 and December 2013. We studied the patients' clinical characteristics, radiotherapy indication, treatments preceding HBO, the grade of hematuria diagnosed based on the Common Terminology Criteria for Adverse Events classification v 4.03 and the efficacy of HBO. The success of HBO was defined as the total or partial resolution of hematuria. RESULTS: We included 71 patients with a median age of 72 (39-87) years. PRHs were severe (grade >=3) in 50 (70.4%) of the cases. Radiotherapy was indicated in the treatment of prostate cancer in 61 (85.9%) patients. The median length of time between hematuria and HBO was 8 (1-154) months. Prior to HBO, 46 (64.8%) patients underwent electrocoagulation of the bladder. HBO sessions were compounded by 9 cases of barotraumatic otitis, 5 cases of transient visual disturbance, and 1 case of finger paresthesia. On average, 29 (3-50) sessions were carried out. Treatment was effective in 46 (64.8%) patients, 37 (52.1%) of whom were completely cured. A hematuria grade of less than 3 was a predictive factor in the successful treatment (P = .027). Median follow-up was 15 (1-132) months. CONCLUSION: HBO completely resolves PRH in 52.1% of cases. Prolonged patient follow-up is required to confirm the efficacy of this treatment. PMID- 27125880 TI - Simultaneous Bilateral Endoscopic Manipulation for Bilateral Renal Stones. AB - OBJECTIVE: To report the first performance of simultaneous bilateral percutaneous nephrolithotomy and flexible ureteroscopy carried out in tandem by 2 different surgeons in a patient with bilateral medium-sized renal calculi, describing step by-step details of the surgical technique. MATERIALS AND METHODS: A 46-year-old man, affected with hyperparathyroidism, was diagnosed with asymptomatic bilateral medium-sized renal stones. An abdominal noncontrast computed tomography scan revealed a left single kidney stone with a maximum diameter of 16 mm and 2 right renal stones located in the pelvis and in the lower calyx, of 21 and 19 mm in maximum diameter, respectively. A bilateral simultaneous percutaneous nephrolithotomy on the right side and flexible ureteroscopy on the left side were therefore carried out. RESULTS: The total operative time was 80 minutes. No intra or postoperative complications were experienced. On postoperative day 1, the creatinine serum level was stable (0.7 mg/dL); he was discharged home 48 hours later. Ureteral stents were removed 7 days after the procedure. At 2 weeks follow up, an abdominal noncontrast computed tomography scan showed a stone-free status and no changes in renal function were detected. CONCLUSION: A simultaneous bilateral endoscopic manipulation is feasible and safe and it can be offered in the presence of medium-sized bilateral renal stones in high-volume centers by experienced surgeons. PMID- 27125881 TI - Splenunculus Masquerading as Prostate-specific Membrane Antigen-positive Lymph Node Metastasis in a Patient With Prostate-specific Antigen Relapse After Radical Prostatectomy. AB - A 45-year-old patient presented with prostate-specific antigen relapse after radical prostatectomy. Diagnostic workup revealed a (68)Ga-labeled prostate specific membrane antigen-targeted ligand tracer uptaking nodule that was initially interpreted as lymph node metastasis but eventually identified as a splenunculus by scintigraphy with (99m)Tc pertechnetate-labeled heat-altered erythrocytes. Awareness of this constellation may spare unnecessary diagnostic procedures and inappropriate treatment. PMID- 27125882 TI - Dual energy computed tomography: a novel technique for diagnosis of gout. AB - AIM: To evaluate the sensitivity and specificity of dual energy computed tomography (DECT) for diagnosing gout compared with a composite gold standard (CGS) comprising joint aspiration and/or American College of Rheumatology clinico radiographic criteria. METHODS: Ninety patients of suspected gout underwent radiography and DECT of bilateral feet and knees. Radiographs and non-contrast CT (NCCT) were assessed for morphological characteristics, following which DECT was used to identify urate deposits. RESULTS: With CGS as a reference (n = 90), sensitivity of radiographs was 15% (95% confidence interval [CI]: 6-27%) while specificity was 100% (95% CI: 90-100%). Sensitivity of NCCT was 26% (95% CI: 15 40%) while specificity was 97% (95% CI: 85-99%). Sensitivity of DECT was 82% (95% CI: 68-90%) while specificity was 89% (95% CI: 73-96%). Fifty-five patients underwent joint aspiration. Sensitivity and specificity of radiographs and NCCT with aspiration as a reference (n = 55) were not much different from that of CGS. However, DECT showed a higher sensitivity of 100% (95% CI: 86-100%) and a lower specificity of 48% (95%CI: 28-68%) with aspiration alone. CONCLUSIONS: Dual energy computed tomography had higher sensitivity compared to conventional imaging with CGS as a reference; however, its specificity dropped with aspiration as a reference. It may be a useful adjunct for the diagnosis of gout, especially in the acute and inter-critical stage. PMID- 27125883 TI - Randomised clinical trial: mixed soluble/insoluble fibre vs. psyllium for chronic constipation. AB - BACKGROUND: Fibre supplements are useful, but whether a plum-derived mixed fibre that contains both soluble and insoluble fibre improves constipation is unknown. AIM: To investigate the efficacy and tolerability of mixed soluble/insoluble fibre vs. psyllium in a randomized double-blind controlled trial. METHODS: Constipated patients (Rome III) received mixed fibre or psyllium, 5 g b.d., for 4 weeks. Daily symptoms and stool habit were assessed using stool diary. Subjects with >=1 complete spontaneous bowel movement/week above baseline for >=2/4 weeks were considered responders. Secondary outcome measures included stool consistency, bowel satisfaction, straining, gas, bloating, taste, dissolvability and quality of life (QoL). RESULTS: Seventy-two subjects (mixed fibre = 40; psyllium = 32) were enrolled and two from psyllium group withdrew. The mean complete spontaneous bowel movement/week increased with both mixed fibre (P < 0.0001) and psyllium (P = 0.0002) without group difference. There were 30 (75%) responders with mixed fibre and 24 (75%) with psyllium (P = 0.9). Stool consistency increased (P = 0.04), straining (P = 0.006) and bloating scores decreased (P = 0.02) without group differences. Significantly more patients reported improvement in flatulence (53% vs. 25%, P = 0.01) and felt that mixed fibre dissolved better (P = 0.02) compared to psyllium. QoL improved (P = 0.0125) with both treatments without group differences. CONCLUSIONS: Mixed fibre and psyllium were equally efficacious in improving constipation and QoL. Mixed fibre was more effective in relieving flatulence, bloating and dissolved better. Mixed fibre is effective and well tolerated. PMID- 27125885 TI - State-of-the-art housekeeping proteins for quantitative western blotting: Revisiting the first draft of the human proteome. AB - Western blotting (WB) analysis is the most popular and widely used methodology for protein detection and characterization over recent decades. In accordance with the advancement of the technologies for the acquisition of WB signals, a quantitative value is used to present the abundance of target proteins in a complex sample, thereby requiring the use of specific proteins as internal references that represent total proteins. Heretofore, proteins encoded by housekeeping genes such as GAPDH, beta-tubulin and beta-actin have been commonly used as loading controls without any hesitation because their mRNA expression levels tend to be high and constant in many different cells and tissues. Experimentally, however, some of the housekeeping reference proteins are often displayed with inconsistent expression levels in both homogeneous and heterogeneous tissues, and, in terms of mRNA levels, they have a weak correlation to the abundance of proteins. To estimate accurate, reliable, and reproducible protein quantifications, it is crucial to define appropriate reference controls. For this paper, we explored the recently released large-scale, human proteomic database ProteomicsDB including 16 857 liquid chromatography tandem-mass spectrometry data from 27 human tissues, and suggest 20 ubiquitously- and constitutively-expressed, putative internal-reference controls for the quantification of differential protein expressions. Intriguingly, the most commonly used, known housekeeping genes were entirely excluded in our newly defined candidates. Although the applications of the candidates under many different biological conditions and in other organisms are yet to be empirically verified, we propose reliable, potential loading controls for a WB analysis in this paper. PMID- 27125884 TI - The growth determinants and transport properties of tunneling nanotube networks between B lymphocytes. AB - Tunneling nanotubes (TNTs) are long intercellular connecting structures providing a special transport route between two neighboring cells. To date TNTs have been reported in different cell types including immune cells such as T-, NK, dendritic cells, or macrophages. Here we report that mature, but not immature, B cells spontaneously form extensive TNT networks under conditions resembling the physiological environment. Live-cell fluorescence, structured illumination, and atomic force microscopic imaging provide new insights into the structure and dynamics of B cell TNTs. Importantly, the selective interaction of cell surface integrins with fibronectin or laminin extracellular matrix proteins proved to be essential for initiating TNT growth in B cells. These TNTs display diversity in length and thickness and contain not only F-actin, but their majority also contain microtubules, which were found, however, not essential for TNT formation. Furthermore, we demonstrate that Ca2+-dependent cortical actin dynamics exert a fundamental control over TNT growth-retraction equilibrium, suggesting that actin filaments form the TNT skeleton. Non-muscle myosin 2 motor activity was shown to provide a negative control limiting the uncontrolled outgrowth of membranous protrusions. Moreover, we also show that spontaneous growth of TNTs is either reduced or increased by B cell receptor- or LPS-mediated activation signals, respectively, thus supporting the critical role of cytoplasmic Ca2+ in regulation of TNT formation. Finally, we observed transport of various GM1/GM3+ vesicles, lysosomes, and mitochondria inside TNTs, as well as intercellular exchange of MHC II and B7-2 (CD86) molecules which may represent novel pathways of intercellular communication and immunoregulation. PMID- 27125886 TI - Survey of mental health nurses' attitudes towards risk assessment, risk assessment tools and positive risk. AB - WHAT IS KNOWN ON THE SUBJECT?: Risk assessment and safety planning are a core aspect of the role of the mental health nurse. Conflicting views exist on the value of risk assessment tools. Few studies have examined mental health nurses' attitudes towards risk, including use of tools and the role of positive risk in recovery. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: Mental health nurses view risk assessment as a core dimension of their role and not merely an exercise to fulfil organizational clinical safety and governance obligations. The majority of nurses hold positive attitudes towards therapeutic or positive risk, and consider creative risk taking as vital to people's recovery. The majority of nurses believe that risk assessment tools facilitate professional decision making, however, some are concerned that tools may negatively impact upon therapeutic relationships. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Ongoing education on the use of risk assessment tools is required to minimize views that their use is incompatible with therapeutic engagement, and to enable nurses to develop confidence to engage with positive risk and to allow service users make decisions and take responsibility. ABSTRACT: Introduction Risk assessment and safety planning are considered core components of the role of the mental health nurse; however, little is known about nurses' attitudes towards risk assessment, use of tools to assess risk or therapeutic risk taking. Aim This study aimed to explore mental health nurses' attitudes towards completing risk assessments, use of tools as an aid, and therapeutic or positive risk. Method An anonymous survey which included 13 attitudinal statements, rated on a five-point Likert scale, was completed by 381 mental health nurses working in adult services in Ireland. Findings Findings indicate strong support for the practice of risk assessment in mental health practice. The vast majority of nurses believe that risk assessment tools facilitate professional decision making; however, there is concern that the use of these tools may negatively impact upon therapeutic engagement with service users. The majority of participants have positive attitudes towards therapeutic risk, believing that service users have the right to take informed risks in the context of recovery-orientated care. Discussion The provision of education on the use of risk assessment tools within the context of engagement may help minimize views that the use of assessment tools are incompatible with therapeutic engagement. PMID- 27125887 TI - Mimicking Tissue Boundaries by Sharp Multiparameter Matrix Interfaces. AB - Engineering interfaces of distinct extracellular compartments mimicking native tissues are key for in-depth in vitro studies on developmental and disease processes in biology and medicine. Sharp interfaces of extracellular matrices are constructed based on fibrillar collagen I networks with a multiparameter control of topology, mechanics, and composition, and their distinct impact on triggering the directionality of cancer cell migration is demonstrated. PMID- 27125888 TI - Super Oxygen and Improved Water Vapor Barrier of Polypropylene Film with Polyelectrolyte Multilayer Nanocoatings. AB - Biaxially oriented polypropylene (BOPP) is widely used in packaging. Although its orientation increases mechanical strength and clarity, BOPP suffers from a high oxygen transmission rate (OTR). Multilayer thin films are deposited from water using layer-by-layer (LbL) assembly. Polyethylenimine (PEI) is combined with either poly(acrylic acid) (PAA) or vermiculite (VMT) clay to impart high oxygen barrier. A 30-bilayer PEI/VMT nanocoating (226 nm thick) improves the OTR of 17.8 MUm thick BOPP by more than 30X, rivaling most inorganic coatings. PEI/PAA multilayers achieve comparable barrier with only 12 bilayers due to greater thickness, but these films exhibit increased oxygen permeability at high humidity. The PEI/VMT coatings actually exhibit improved oxygen barrier at high humidity (and also improve moisture barrier by more than 40%). This high barrier BOPP meets the criteria for sensitive food and some electronics packaging applications. Additionally, this water-based coating technology is cost effective and provides an opportunity to produce high barrier polypropylene film on an industrial scale. PMID- 27125889 TI - Sleep disturbances during pregnancy are associated with cesarean delivery and preterm birth. AB - OBJECTIVE: The purpose of this study was to examine the associations of sleep disturbances during pregnancy with cesarean delivery and preterm birth. METHODS: In this prospective study, 688 healthy women with singleton pregnancy were selected from three hospitals in Chengdu, China 2013-2014. Self-report questionnaires, including the sleep quantity and quality as well as exercise habits in a recent month were administered at 12-16, 24-28, and 32-36 weeks' gestation. Data on type of delivery, gestational age, and the neonates' weight were recorded after delivery. After controlling the potential confounders, a serial of multi-factor logistic regression models were performed to evaluate whether sleep quality and quantity were associated with cesarean delivery and preterm birth. RESULTS: There were 382 (55.5%) women who had cesarean deliveries and 32 (4.7%) who delivered preterm. Women with poor sleep quality during the first (OR: 1.87, 95% CI [1.02-3.43]), second (5.19 [2.25-11.97]), and third trimester (1.82 [1.18-2.80]) were at high risk of cesarean delivery. Women with poor sleep quality during the second (5.35 [2.10-13.63]) and third trimester (3.01 [1.26-7.19]) as well as short sleep time (<7 h) during the third trimester (4.67 [1.24-17.50]) were at high risk of preterm birth. CONCLUSIONS: Sleep disturbances are associated with an increased risk of cesarean delivery and preterm birth throughout pregnancy. Obstetric care providers should advise women with childbearing age to practice healthy sleep hygiene measures. PMID- 27125890 TI - Prescribing patterns, adherence and LDL-cholesterol response of type 2 diabetes patients initiating statin on low-dose versus standard-dose treatment: a descriptive study. AB - AIMS: The aim of this study was to describe and compare treatment modifications and discontinuation, adherence levels and response to treatment in patients with type 2 diabetes initiating on low-dose vs. standard-dose statin treatment. METHODS: A 2-year follow-up cohort study was performed using data from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database in patients with type 2 diabetes initiating statin treatment between January 2007 and December 2012. First, we determined whether there were differences in treatment modifications and discontinuation after statin initiation between patients starting on a low-dose vs. standard-dose. Second, we looked at differences in adherence and LDL-cholesterol response after 2 years follow-up between these groups. RESULTS: Around 22% of patients initiated statin treatment on a dose lower than recommended. More than half of them remained on a low dose during a 2-year follow-up period, whereas less than 15% received a dose increase. Of the patients initiating on standard-dose, also more than half remained on the same treatment during this period, whereas 8% received a dose decrease without subsequent increase. Over 25% of patients starting on low-dose or standard-dose treatment discontinued treatment, often within the first 180 days after initiation or after a first treatment change. Patients on low-dose treatment had lower adherence levels and were less likely to have adequate LDL-cholesterol response compared with patients on standard-dose after 2 years follow-up. CONCLUSIONS: Current patterns of statin treatment in patients with type 2 diabetes are suboptimal, with discontinuation, inadequate adherence levels and lack of treatment intensification seen in those who had inadequate LDL cholesterol response after 2 years of follow-up. Patients starting on low-dose had more treatment modifications, discontinuation and adherence problems as compared with those starting on standard-dose treatment, which calls for a closer look at the rationale of starting patients on low-dose statin treatment. PMID- 27125891 TI - Erratum: Increased resting state connectivity between ipsilesional motor cortex and contralesional premotor cortex after transcranial direct current stimulation with physical therapy. PMID- 27125892 TI - Levonorgestrel release rates over 5 years with the Liletta(r) 52-mg intrauterine system. AB - OBJECTIVE: To understand the potential duration of action for Liletta(r), we conducted this study to estimate levonorgestrel (LNG) release rates over approximately 51/2years of product use. METHODS: Clinical sites in the U.S. Phase 3 study of Liletta collected the LNG intrauterine systems (IUSs) from women who discontinued the study. We randomly selected samples within 90-day intervals after discontinuation of IUS use through 900days (approximately 2.5years) and 180 day intervals for the remaining duration through 5.4years (1980days) to evaluate residual LNG content. We also performed an initial LNG content analysis using 10 randomly selected samples from a single lot. We calculated the average ex vivo release rate using the residual LNG content over the duration of the analysis. RESULTS: We analyzed 64 samples within 90-day intervals (range 6-10 samples per interval) through 900days and 36 samples within 180-day intervals (6 samples per interval) for the remaining duration. The initial content analysis averaged 52.0+/-1.8mg. We calculated an average initial release rate of 19.5mcg/day that decreased to 17.0, 14.8, 12.9, 11.3 and 9.8mcg/day after 1, 2, 3, 4 and 5years, respectively. The 5-year average release rate is 14.7mcg/day. CONCLUSION: The estimated initial LNG release rate and gradual decay of the estimated release rate are consistent with the target design and function of the product. The calculated LNG content and release rate curves support the continued evaluation of Liletta as a contraceptive for 5 or more years of use. IMPLICATIONS STATEMENT: Liletta LNG content and release rates are comparable to published data for another LNG 52-mg IUS. The release rate at 5years is more than double the published release rate at 3years with an LNG 13.5-mg IUS, suggesting continued efficacy of Liletta beyond 5years. PMID- 27125893 TI - Exploring Canadian women's knowledge of and interest in mifepristone: results from a national qualitative study with abortion patients. AB - INTRODUCTION: Although Canada decriminalized abortion in 1988, significant disparities in access to services and an uneven geographic distribution of providers persists. Health Canada registered mifepristone, the gold standard of medication abortion, in July 2015. Our study explored Canadian women's knowledge of, interest in, and perspectives on mifepristone prior to registration. METHODS: From November 2012 through July 2015 we conducted in-depth interviews with 174 Anglophone and Francophone women from Alberta, Manitoba, New Brunswick, Ontario, and Quebec about their abortion experiences and their opinions about medication abortion. We purposively recruited participants from different age cohorts and different regions within each study province to explore a range of perspectives. We analyzed these interviews for content and themes related to mifepristone using both deductive and inductive analytic techniques. RESULTS: The overwhelming majority of participants had no knowledge of mifepristone at the time of the interview. However, after providing a brief description of an evidence-based mifepristone/misoprostol regimen, more than half of the participants reported that they would have considered this method had it been available at the time of their abortion and most would have been comfortable receiving medication abortion care from a family physician or nurse practitioner. Most women supported the approval of mifepristone and felt Canadian women would benefit from having more options for early pregnancy termination. CONCLUSION: Although knowledge of mifepristone among recent abortion patients was low, considerable interest in medication abortion exists. Expanding awareness-raising efforts and supporting the approval of evidence-based regimens and provision of mifepristone appears warranted. IMPLICATIONS: The approval and introduction of mifepristone for early abortion in Canada promises to increase options and access. Creating tailored and culturally and contextually resonant messages about mifepristone is of high priority. Promoting evidence-based protocols and the inclusion of a full range of qualified professionals in service provision is also warranted. PMID- 27125894 TI - Four aspects of the scope and quality of family planning services in US publicly funded health centers: Results from a survey of health center administrators. AB - OBJECTIVES: This study aims to describe aspects of the scope and quality of family planning services provided by US publicly funded health centers before the release of relevant federal recommendations. STUDY DESIGN: Using nationally representative survey data (N=1615), we describe four aspects of service delivery: family planning services provided, contraceptive methods provided onsite, written contraceptive counseling protocols and youth-friendly services. We created a count index for each issue and used multivariable ordered logistic regression to identify health center characteristics associated with scoring higher on each. RESULTS: Half of the sample received Title X funding and about a third each were a community health center or health department clinic. The vast majority reported frequently providing contraceptive services (89%) and STD services (87%) for women in the past 3 months. Service provision to males was substantially lower except for STD screening. A total of 63% and 48% of health centers provided hormonal IUDs and implants onsite in the past 3 months, respectively. Forty percent of health centers included all five recommended contraceptive counseling practices in written protocols. Of youth-friendly services, active promotion of confidential services was among the most commonly reported (83%); offering weekend/evening hours was among the least (42%). In multivariable analyses, receiving Title X funding, having larger volumes of family planning clients and being a Planned Parenthood clinic were associated with higher scores on most indices. CONCLUSION: Many services were consistent with the recommendations for providing quality family planning services, but there was room for improvement across domains and health centers types. IMPLICATIONS STATEMENT: As assessed in this paper, the scope and quality of these family planning services was relatively high, particularly among Planned Parenthood clinics and Title X-funded centers. However, results point to important areas for improvement. Future studies should assess change as implementation of recent family planning service recommendations continues. PMID- 27125895 TI - Dual Outcomes of Rosiglitazone Treatment on Fatty Liver. AB - In previous studies, it has been reported that rosiglitazone has opposing effects on nonalcoholic fatty liver disease. The purpose of the current study is to test the hypothesis that such opposing effects are related to different levels of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in the liver. Using a gene transfer approach and mice fed a high-fat diet (HFD) as an animal model, we demonstrate that mice with low levels of PPAR-gamma expression in the liver are resistant to HFD-induced development of fatty liver when treated with rosiglitazone. Conversely, rosiglitazone treatment actually exacerbates liver steatosis in obese mice that have a higher level of PPAR-gamma. Mechanistic studies show that an elevated hepatic PPAR-gamma level is associated with an increased expression of genes responsible for lipid metabolism in the liver, particularly Cd36, Fabp4, and Mgat1. The concurrent transfer of these three genes into the mouse liver fully recapitulates the phenotypic change induced by the overexpression of PPAR-gamma. These results provide evidence in support of the importance of PPAR-gamma in the liver when rosiglitazone is considered for the treatment of fatty liver disease. Clinically, our results suggest the necessity of verifying PPAR-gamma levels in the liver when rosiglitazone is considered as a treatment option, and indicate that the direct use of rosiglitazone for treatment of nonalcoholic fatty liver may not be desirable when the patient's PPAR-gamma level in the liver is significantly elevated. PMID- 27125897 TI - The strike in numbers. PMID- 27125896 TI - Maternal fructose drives placental uric acid production leading to adverse fetal outcomes. AB - Maternal metabolic diseases increase offspring risk for low birth weight and cardiometabolic diseases in adulthood. Excess fructose consumption may confer metabolic risks for both women and their offspring. However, the direct consequences of fructose intake per se are unknown. We assessed the impact of a maternal high-fructose diet on the fetal-placental unit in mice in the absence of metabolic syndrome and determined the association between maternal serum fructose and placental uric acid levels in humans. In mice, maternal fructose consumption led to placental inefficiency, fetal growth restriction, elevated fetal serum glucose and triglyceride levels. In the placenta, fructose induced de novo uric acid synthesis by activating the activities of the enzymes AMP deaminase and xanthine oxidase. Moreover, the placentas had increased lipids and altered expression of genes that control oxidative stress. Treatment of mothers with the xanthine oxidase inhibitor allopurinol reduced placental uric acid levels, prevented placental inefficiency, and improved fetal weights and serum triglycerides. Finally, in 18 women delivering at term, maternal serum fructose levels significantly correlated with placental uric acid levels. These findings suggest that in mice, excess maternal fructose consumption impairs placental function via a xanthine oxidase/uric acid-dependent mechanism, and similar effects may occur in humans. PMID- 27125898 TI - A Model-Based Economic Evaluation of Biologic and Non-Biologic Options for the Treatment of Adults with Moderately-to-Severely Active Ulcerative Colitis after the Failure of Conventional Therapy. AB - BACKGROUND: Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. Medical management aims to induce and maintain remission and to avoid complications and the necessity for surgical intervention. Colectomy removes the source of inflammation but is associated with morbidity and mortality. Newer anti-tumour necrosis factor (TNF)-alpha therapies may improve medical outcomes, albeit at an increased cost. OBJECTIVE: Our objective was to assess the incremental cost effectiveness of infliximab, adalimumab and golimumab versus conventional therapy and surgery from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a lifetime horizon. METHODS: A Markov model was developed with health states defined according to whether the patient is alive or dead, current treatments received, history of colectomy and level of disease control. Transition probabilities were derived from network meta analyses (NMAs) of trials of anti-TNF-alpha agents in the moderate-to-severe UC population. Health utilities, colectomy rates, surgical complications and resource use estimates were derived from literature. Unit costs were drawn from standard costing sources and literature and were valued at year 2013/2014 values. RESULTS: For patients in whom surgery is an option, colectomy is expected to dominate all medical treatment options. For patients in whom colectomy is not an option, infliximab and golimumab are expected to be ruled out due to dominance, whilst the incremental cost-effectiveness ratio (ICER) for adalimumab versus conventional treatment is expected to be approximately L50,278 per quality adjusted life-year (QALY) gained. CONCLUSIONS: Based on the NMAs, the ICERs for anti-TNF-alpha therapy versus conventional treatment or surgery are expected to be at best, in excess of L50,000 per QALY gained. The cost effectiveness of withdrawing biologic therapy upon remission and re-treating relapse is unknown. PMID- 27125899 TI - Erratum: IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity. PMID- 27125900 TI - The lag-phase during diauxic growth is a trade-off between fast adaptation and high growth rate. AB - Bi-phasic or diauxic growth is often observed when microbes are grown in a chemically defined medium containing two sugars (for example glucose and lactose). Typically, the two growth stages are separated by an often lengthy phase of arrested growth, the so-called lag-phase. Diauxic growth is usually interpreted as an adaptation to maximise population growth in multi-nutrient environments. However, the lag-phase implies a substantial loss of growth during the switch-over. It therefore remains unexplained why the lag-phase is adaptive. Here we show by means of a stochastic simulation model based on the bacterial PTS system that it is not possible to shorten the lag-phase without incurring a permanent growth-penalty. Mechanistically, this is due to the inherent and well established limitations of biological sensors to operate efficiently at a given resource cost. Hence, there is a trade-off between lost growth during the diauxic switch and the long-term growth potential of the cell. Using simulated evolution we predict that the lag-phase will evolve depending on the distribution of conditions experienced during adaptation. In environments where switching is less frequently required, the lag-phase will evolve to be longer whereas, in frequently changing environments, the lag-phase will evolve to be shorter. PMID- 27125901 TI - Dual electrospinning with sacrificial fibers for engineered porosity and enhancement of tissue ingrowth. AB - Porosity, pore size and pore interconnectivity are critical factors for cellular infiltration into electrospun scaffolds. This study utilized dual electrospinning with sacrificial fiber extraction to produce scaffolds with engineered porosity and mechanical properties. Subsequently, scaffolds were covalently grafted with heparin, a known anti-coagulant with growth-factor binding properties. We hypothesized that the tissue ingrowth would correlate positively with the porosity of the scaffolds. Pellethane(r) (PU) was spun simultaneously with poly(ethylene oxide) (PEO, subsequently extracted). Low, medium and high porosity scaffolds and heparinized versions of each were characterized and implanted in vivo for evaluation of cellular infiltration and inflammation subcutaneously in male Wistar rats (7,14 and 28 days, n = 6). Average pore-size for low (76 +/- 0.2%), medium (83 +/- 0.5%) and high (90 +/- 1.0%) porosity scaffolds was 4.0 +/- 2.3 um, 9.9 +/- 4.2 um and 11.1 +/- 5.5 um (p < 0.0001). Heparinization resulted in increased fiber diameter (3.6 +/- 1.1 um vs. 1.8 +/- 0.8 um, p < 0.0001) but influenced neither pore-size (p = 0.67) nor porosity (p = 0.27). Cellular infiltration for low, medium and high porosity scaffolds reached 33 +/- 7%, 77 +/ 20% and 98 +/- 1% of scaffold width, respectively, by day 28 of implantation (p < 0001); heparinization did not affect infiltration (p = 0.89). The ultimate tensile strength (UTS) and Young's modulus (Ey ) of the constructs increased linearly with increasing PU fiber fraction (UTS: r2 = 0.97, p < 0.0001, Ey : r2 = 0.76, p < 0.0001) and heparinization resulted in decreased strength but increased stiffness compared to non-heparinized scaffolds. Increased PEO to PU fraction in the scaffold resulted in predictable losses to mechanical strength and improvements to cellular infiltration, which could make PEO to PU fraction a useful optimization parameter for small diameter vascular grafts. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1559-1572, 2017. PMID- 27125902 TI - The incretin system ABCs in obesity and diabetes - novel therapeutic strategies for weight loss and beyond. AB - Incretins are gastrointestinal-derived hormones released in response to a meal playing a key role in the regulation of postprandial secretion of insulin (incretin effect) and glucagon by the pancreas. Both incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), have several other actions by peripheral and central mechanisms. GLP-1 regulates body weight by inhibiting appetite and delaying gastric, emptying actions that are dependent on central nervous system GLP-1 receptor activation. Several other hormones and gut peptides, including leptin and ghrelin, interact with GLP-1 to modulate appetite. GLP-1 is rapidly degraded by the multifunctional enzyme dipeptidyl peptidase-4 (DPP-4). DPP-4 is involved in adipose tissue inflammation, which is associated with insulin resistance and diabetes progression, being a common pathophysiological mechanism in obesity-related complications. Furthermore, the incretin system appears to provide the basis for understanding the high weight loss efficacy of bariatric surgery, a widely used treatment for obesity, often in association with diabetes. The present review brings together new insights into obesity pathogenesis, integrating GLP-1 and DPP-4 in the complex interplay between obesity and inflammation, namely, in diabetic patients. This in turn will provide the basis for novel incretin-based therapeutic strategies for obesity and diabetes with promising benefits in addition to weight loss. (c) 2016 World Obesity. PMID- 27125903 TI - Tattoo-induced psoriasis: an umpteenth example of immunocompromised district. PMID- 27125904 TI - Neural correlates of spatial and nonspatial attention determined using intracranial electroencephalographic signals in humans. AB - Few studies have directly compared the neural correlates of spatial attention (i.e., attention to a particular location) and nonspatial attention (i.e., attention to a feature in the visual scene) using well-controlled tasks. Here, we investigated the neural correlates of spatial and nonspatial attention in humans using intracranial electroencephalography. The topography and number of electrodes showing significant event-related desynchronization (ERD) or event related synchronization (ERS) in different frequency bands were studied in 13 epileptic patients. Performance was not significantly different between the two conditions. In both conditions, ERD in the low-frequency bands and ERS in the high-frequency bands were present bilaterally in the parietal cortex (prominently on the right hemisphere) and frontal regions. In addition to these common changes, spatial attention involved right-lateralized activity that was maximal in the right superior parietal lobule (SPL), whereas nonspatial attention involved wider brain networks including the bilateral parietal, frontal, and temporal regions, but still had maximal activity in the right parietal lobe. Within the parietal lobe, spatial attention involved ERD or ERS in the right SPL, whereas nonspatial attention involved ERD or ERS in the right inferior parietal lobule. These findings reveal that common as well as different brain networks are engaged in spatial and nonspatial attention. Hum Brain Mapp 37:3041-3054, 2016. (c) 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID- 27125905 TI - Cone of skin exists in rat: A "hypertrophic scarring free" animal. AB - Cone of skin is deemed to be related to hypertrophic scarring and absent in such traditionally "hypertrophic scarring and keloid free" animals as rat. The purpose of our study is to determine whether the cone of skin exists in rat. If it was, why it was ignored, and what was the meaning of it. The depilation of left dorsum of 32 male Sprague-Dawley rats was performed using a wax/rosin mixture. Skin samples were harvested on 0 d, 3 d, 9 d, 15 d, 21 d, 27 d, 33 d, and 39 d after depilation and stained by hematoxylin and eosin methods. Light microscopic observation of the dermis-fat interface was studied at 25* magnification. It was observed that, "dome" like fat tissue bulged up into the dermis from 3 d to 27 d and hair follicle bulged down into the "dome" like fat tissue from 15 d to 27 d and a "cone" like structure was seen. Cone of skin exists in rat in certain stages of hair follicle cycle, which is a valuable addition to the scientific literature and might be a challenge to the relation between cone of skin and hypertrophic scarring. Anat Rec, 299:1140-1144, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27125906 TI - Microbiome sequencing: challenges and opportunities for molecular medicine. AB - INTRODUCTION: Since the discovery of Polymerase Chain Reaction and pioneering work on 16S ribosomal RNA genes in the 1980's, the use of molecular techniques to study microbial ecosystems and pathogenic microorganisms has been increasing exponentially. Because microbial communities inhabiting various body sites such as the skin or the intestine can influence our physiology, there has been a massive interest in studying their diversity, functions, and role in the development of acute and chronic diseases. AREA COVERED: In the present review, we gather knowledge on sequencing approaches to study microbial communities, especially human body microbiota, and give opinions on their potential and limitations, particularly with respect to clinical applications. Expert commentary: High-throughput sequencing delivered unprecedented views on complex microbial communities, but their popularization is accompanied by substantial technical hurdles that will need to be overcome for efficient implementation in routine clinical procedures. PMID- 27125907 TI - UV-induced epitaxial attachment of TiO2 nanocrystals in molecularly mediated 1D and 2D alignments. AB - Anatase TiO2 nanocrystals were crystallographically connected through UV-induced epitaxial attachments in 1D and 2D arrays with photocatalytic decomposition of the organic mediator. PMID- 27125908 TI - The application of time decay characteristics of laser-induced fluorescence in the classification of vegetation. AB - In this study, the time decay of the chlorophyll fluorescence intensity (TDCFI) of vegetation was measured based on laser-induced fluorescence (LIF) technology with a 355 nm laser serving as the excitation light source. The pseudo-color diagram of the TDCFI (PDTDCFIs) was proposed for use as a characteristic fingerprint for the analysis of various plant species based on variations in the fluorescence intensity over time. Compared with the steady-state fluorescence spectra, two-dimensional PDTDCFIs contained more spectral information, including variations in both the shape of the laser-induced fluorescence spectra and the relative intensity. The experimental results demonstrated that the PDTDCFIs of various plant species show distinct differences, and this was successfully applied in the classification of plant species. Therefore, the PDTDCFIs of plants could provide researchers with a more reliable and useful tool for the characterization of vegetation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27125909 TI - Ubiquinol-10 supplementation improves autonomic nervous function and cognitive function in chronic fatigue syndrome. AB - The aim of this study was to evaluate the benefit of oral ubiquinol-10 supplementation in CFS patients using an open-label study and a randomized, double-blinded, placebo-controlled (RCT) study. Twenty patients with CFS were randomly enrolled in an 8-week open-label oral ubiquinol-10 (150 mg ubiquinol 10/day) study. The patients and the attending physicians were not blinded to the supplementation. Forty-three patients with CFS were randomly assigned to receive either ubiquinol-10 (150 mg/day) or placebo every day for 12 weeks. The patients and the attending physicians were blinded to the supplementation, and a total of 31 patients (N = 17 in the ubiquinol group and 14 in the placebo group) completed the study. The beneficial effects of ubiquinol-10 were observed in the open-label study we conducted prior to the RCT. The RCT results suggest that supplementation with ubiquinol-10 for 12 weeks is effective for improving several CFS symptoms. (c) 2016 BioFactors, 42(4):431-440, 2016. PMID- 27125910 TI - Ultraflexible organic amplifier with biocompatible gel electrodes. AB - In vivo electronic monitoring systems are promising technology to obtain biosignals with high spatiotemporal resolution and sensitivity. Here we demonstrate the fabrication of a biocompatible highly conductive gel composite comprising multi-walled carbon nanotube-dispersed sheet with an aqueous hydrogel. This gel composite exhibits admittance of 100 mS cm(-2) and maintains high admittance even in a low-frequency range. On implantation into a living hypodermal tissue for 4 weeks, it showed a small foreign-body reaction compared with widely used metal electrodes. Capitalizing on the multi-functional gel composite, we fabricated an ultrathin and mechanically flexible organic active matrix amplifier on a 1.2-MUm-thick polyethylene-naphthalate film to amplify (amplification factor: ~200) weak biosignals. The composite was integrated to the amplifier to realize a direct lead epicardial electrocardiography that is easily spread over an uneven heart tissue. PMID- 27125911 TI - Factors Associated with HIV Status Disclosure in HIV-Infected Sub-Saharan Migrants Living in France and Successfully Treated with Antiretroviral Therapy: Results from the ANRS-VIHVO Study. AB - To estimate rates and identify correlates of HIV disclosure in migrants from sub Saharan Africa (SSA) successfully treated, a sub-analysis was conducted in HIV-1 native SSA migrants, living in France with undetectable viral load on antiretroviral, included in the VIHVO adherence study. Logistic regression models assessed factors associated with HIV disclosure. Among 246 individuals (40 % male, median age 41), 79 % of those in a steady heterosexual partnership (n = 167) had disclosed their status to their partner, 55 % of the total 246 to a relative, and 33 % to (an)other person(s). Disclosure to one's steady partner was associated with a follow-up duration since HIV diagnosis of more than 5 years, a higher literacy level, a better social context and marital status. Women were more likely to disclose their HIV status to relatives. Interventions targeting this population should be provided to improve disclosure which in turn ensures better social support, testing of the partner and lower rates of undiagnosed HIV. PMID- 27125912 TI - Influence of a 5-year serial infection control and antibiotic stewardship intervention on cardiac surgical site infections. AB - BACKGROUND: Surgical site infections (SSIs) complicate surgery, resulting in higher morbidity and mortality. Infection control bundles and antibiotic stewardship can be effective at reducing SSIs. The influence of long-term serial interventions is unclear. OBJECTIVE: The goal of this retrospective quasiexperimental study was to assess the influence of a 5-year serial infection control and antibiotic stewardship intervention on SSIs. METHODS: The multidisciplinary program actively implemented pre-, intra-, and postoperative strategies over a 5-year period from 2009-2014 for all patients undergoing coronary artery bypass graft (CABG), valve replacement, or both at a tertiary care public institution. Outcomes are compared with a 2-year preinterventions period (2007-2009) and 1-year postinterventions period (2014-2015). RESULTS: A total of 6,518 procedures were included. After interventions, the overall combined infection rate for CABG, CABG and valve, and valve procedures decreased by 66.3%, from 11.9%-4.0% (odds ratio, 0.34; 95% confidence interval, 0.23-0.49; P < .001). A significant decrease of >50% (P < .001) relative rate was observed in overall, sternum, leg, CABG, and combined CABG and valve infection rates when comparing pre- and postinterventions groups. The antibiotic stewardship intervention increased overall conformity to the internal surgical prophylaxis protocol by 46.8%, from 39.8%-86.6% (95% confidence interval, 41.0-52.4; P < .001). CONCLUSION: Long-term, serial comprehensive infection control and antibiotic stewardship interventions decrease overall SSIs in patients undergoing CABG and valve replacement procedures. PMID- 27125913 TI - Ventilator-associated complications: A study to evaluate the effectiveness of a planned teaching program for intensive care unit staff nurses-an Indian experience. AB - The role of nursing staff is important for both prevention and early diagnosis of complications associated with mechanical ventilation. The objective of our study was to assess the knowledge of nurses working in an intensive care unit for at least 6 months regarding ventilator-associated complications and its prevention. A quasiexperimental study was conducted using a questionnaire with 50 questions formulated by the panel of experts. A planned teaching program was developed based on related literature regarding ventilator-associated complications and its prevention and was presented to the staff nurses. The level of knowledge of the nursing staff was assessed before and after the workshop. Fifty nurses were included in the study. Among the staff nurses, 53.40% had average knowledge regarding ventilator-associated complications. Posttest, 77.20% of the total score was obtained for ventilator-associated complications. Regular training programs can be effective in improving the knowledge of nursing staff. PMID- 27125914 TI - Rate of colonization of health care workers by carbapenem-resistant Enterobacteriaceae in an endemic hospital: A prospective study. AB - The role of health care workers in transmission of carbapenem-resistant Enterobacteriaceae (CRE) has not been evaluated thoroughly. We sought to determine the rate of fecal carriage of CRE among health care workers in our hospital, which is endemic for CRE (prevalence of 19 out of 800 beds and incidence of 128 out of 49,325 hospital admissions). We found no carriers among the 177 health care workers that participated in the study, suggesting that transmission does not occur through personnel gastrointestinal carriage of the bacteria. PMID- 27125915 TI - Reducing the underreporting of percutaneous exposure incidents: A single-center experience. AB - Although risk reduction strategies have been implemented throughout the world, underreporting of percutaneous exposure incidents (PEIs) is common among exposed health care workers. The aim of this study was to determine the incidence rate of reported PEIs before and after implementation of an intensified reporting management policy. The introduction of an intensified reporting system led to significantly increased reporting after a PEI has occurred. However, continuous education needs to be provided to improve awareness. PMID- 27125916 TI - Alterations of collagen-producing cells in human pituitary adenomas. AB - Extracellular matrix (ECM) is essential in tissue physiology and pathologic conditions such as tumorigenesis. ECM affects tumor cell behavior, proliferation, and metastasis. Pituitary adenomas vary in their clinical characteristics, including ECM deposition. However, the mechanism of desmoplasia in pituitary adenoma is not well understood. The present study focused on the principal component of ECM, collagen, and attempted to characterize collagen-producing cells in pituitary adenomas. Specimens of human pituitary adenomas and control pituitary were obtained during surgery. In situ hybridization for collagen I and III and immunohistochemistry for alpha-smooth muscle actin (a pericyte marker) and cytokeratin (an epithelial cell marker) were performed. The results showed that pericytes were the sole collagen-producing cells in control pituitary, while four types of collagen-producing cells were present in pituitary adenomas: pericytes, myofibroblasts, fibroblasts, and newly characterized "myoepithelial like cells". Azan staining showed that fibrous matrix deposition varied among pituitary adenomas and that the area of fibrosis was associated with the number and types of collagen-producing cells. These results suggest that changes in the number and type of collagen-producing cells influence ECM arrangement, which may in turn reflect pathologic characteristics in pituitary adenomas. PMID- 27125917 TI - Hand, Foot, and Mouth Disease in China: Critical Community Size and Spatial Vaccination Strategies. AB - Hand Foot and Mouth Disease (HFMD) constitutes a considerable burden for health care systems across China. Yet this burden displays important geographic heterogeneity that directly affects the local persistence and the dynamics of the disease, and thus the ability to control it through vaccination campaigns. Here, we use detailed geographic surveillance data and epidemic models to estimate the critical community size (CCS) of HFMD associated enterovirus serotypes CV-A16 and EV-A71 and we explore what spatial vaccination strategies may best reduce the burden of HFMD. We found CCS ranging from 336,979 (+/-225,866) to 722,372 (+/ 150,562) with the lowest estimates associated with EV-A71 in the southern region of China where multiple transmission seasons have previously been identified. Our results suggest the existence of a regional immigration-recolonization dynamic driven by urban centers. If EV-A71 vaccines doses are limited, these would be optimally deployed in highly populated urban centers and in high-prevalence areas. If HFMD vaccines are included in China's National Immunization Program in order to achieve high coverage rates (>85%), routine vaccination of newborns largely outperforms strategies in which the equivalent number of doses is equally divided between routine vaccination of newborns and pulse vaccination of the community at large. PMID- 27125918 TI - High Anger Expression is Associated with Reduced Cortisol Awakening Response and Health Complaints in Healthy Young Adults. AB - The extant evidence suggests a robust positive association between expression (anger expression-out) and suppression (anger expression-in) of anger and compromised health. Nevertheless, the underlying psychobiological mechanisms which explain these relationships are not well understood. This study examined whether anger expression would predict general health, cortisol awakening response (CAR) and evening cortisol levels in a community sample of 156 healthy young adults of both genders. Participants were distributed into two groups according to their anger expression scores: high and low anger expression (HAE and LAE, respectively). Findings indicated that those with HAE had worse self reported health (p = .02) and higher CAR than the LAE group (p = .04). Moreover, high levels of anger expression-out (p < .01) and -in (p < .01, for all) predicted a worse self-reported health in both groups. On the other hand, high anger expression-out was associated with flattened CAR but only in the HAE group (p < .01). This study reinforces the need to develop effective strategies to provide mechanisms to regulate anger expression by promoting personal growth and positive skills that enhance individuals' well-being and quality of life and, in turn, their own health. PMID- 27125919 TI - Individualisation comes at a cost. PMID- 27125920 TI - Take your partners - dance fitness for the over-sixties. PMID- 27125922 TI - Unison issues warning on plans to replace bursaries with loans. PMID- 27125923 TI - Expert on dementia becomes professor emeritus. PMID- 27125924 TI - Health board and charity to provide hospice at home. PMID- 27125925 TI - Nurses use annual leave to fulfil CPD requirement. PMID- 27125927 TI - Gaps remain in end of life care services. PMID- 27125926 TI - Nurses urged to comment on draft multimorbidity guidance. PMID- 27125931 TI - The 'perfect' death. PMID- 27125934 TI - Recurrent stroke. PMID- 27125935 TI - Sleep patterns in care homes. PMID- 27125936 TI - Macular degeneration. PMID- 27125937 TI - Practice question. PMID- 27125938 TI - Comprehensive geriatric assessment of a patient with complex needs. AB - This is the third in a short series that presents case study examples of the application of comprehensive geriatric assessment (CGA) in different clinical settings. CGA is a holistic assessment model, which is designed to determine a frail older person's medical and mental health status, as well as functional, social and environmental issues. When undertaken by nurses, it can enable individualised care planning. The case study presented explores the application of CGA with an 89-year-old patient with complex health and social care needs. It demonstrates how a hospital admission was avoided and the patient's health outcomes improved, by using a nurse-led systematic approach to assessment and by careful consideration of CGA domains. PMID- 27125939 TI - Patient safety and hydration in the care of older people. AB - Ensuring patients are adequately hydrated is a fundamental part of nursing care, however, it is clear from the literature that dehydration remains a significant problem in the NHS with implications for patient safety. The development of dehydration is often multifactorial and older age is an independent risk factor for the condition. However, the media often blame nursing staff for simply not giving patients enough to drink. This article discusses the scale of the problem in acute care settings and aims to raise awareness of the importance of hydration management and accurate documentation in nursing practice. It suggests that intentional hourly rounding may provide an opportunity for nurses to ensure older patients are prompted or assisted to take a drink. PMID- 27125940 TI - Implementing digital skills training in care homes: a literature review. AB - This article is the first of a two-part series that informs and describes digital skills training using a dedicated console computer provided for staff and residents in a care home setting. This was part of a programme of culture change in a large care home with nursing in Glasgow, Scotland. The literature review shows that over the past decade there has been a gradual increase in the use of digital technology by staff and older people in community settings including care homes. Policy from the European Commission presents a persuasive argument for the advancement of technology-enabled care to counter the future impact of an increased number of people of advanced age on finite health and social care resources. The psychosocial and environmental issues that inhibit or enhance the acquisition of digital skills in care homes are considered and include the identification of exemplar schemes and the support involved. PMID- 27125941 TI - Experiences of the advanced nurse practitioner role in acute care. AB - The aim of the service evaluation presented in this article was to explore the multidisciplinary team's (MDT) experiences and perception of the advanced nurse practitioner (ANP) role on an acute health care of the older person ward. A qualitative case study was carried out comprising semi-structured interviews with members of the MDT, exploring their experiences of the ANP role. An overarching theme of 'Is it a nurse? Is it a doctor? No, it's an ANP' emerged from the data, with three subthemes: the missing link; facilitating and leading holistic care; and safe, high quality care. The ANP role is valued by the MDT working with them and provides a unique skill set that has the potential to enhance care of older patients living with frailty. While there are challenges to its introduction, it is a role worth introducing to older people's wards. PMID- 27125942 TI - Changing perceptions. PMID- 27125943 TI - The relationship between nutrition and frailty: Effects of protein intake, nutritional supplementation, vitamin D and exercise on muscle metabolism in the elderly. A systematic review. AB - BACKGROUND: Frailty is a geriatric syndrome that predicts the onset of disability, morbidity and mortality in elderly people; it is a state of pre disability and is reversible. The aim of this review is to assess how nutrition influences both the risk of developing frailty and its treatment. DATA SOURCES: We searched two databases, PubMed and Web of Science. We included epidemiologic studies and clinical trials carried out on people aged over 65 years. We included 32 studies with a total of over 50,000 participants. RESULTS: The prevalence of frailty is ranges from 15% among elderly people living in the community to 54% among those hospitalized. Furthermore, the prevalence of frailty is disproportionately high among elderly people who are malnourished. Malnutrition, which is very prevalent in geriatric populations, is one of the main risk factors for the onset of frailty. A good nutritional status and, wherever necessary, supplementation with macronutrients and micronutrients reduce the risk of developing frailty. Physical exercise has been shown to improve functional status, helps to prevent frailty and is an effective treatment to reverse it. Despite the relatively large number of studies included, this review has some limitations. Firstly, variability in the design of the studies and their different aims reduce their comparability. Secondly, several of the studies did not adequately define frailty. CONCLUSIONS: Poor nutritional status is associated with the onset of frailty. Screening and early diagnosis of malnutrition and frailty in elderly people will help to prevent the onset of disability. Effective treatment is based on correction of the macro- and micronutrient deficit and physical exercise. PMID- 27125944 TI - [Erratum to: Treatment of cardiovascular risk factors]. PMID- 27125945 TI - [Current aspects of quality assurance]. AB - The regulations for quality management in the rheumatology laboratory are demanding and on a qualitatively high level. They are the result of continuously more detailed quality requirements and their implementation. Not only the process of correctly measuring analytes but also aspects of preanalytics, postanalytics and interpretation of the results as well as validation of new test methods are becoming increasingly more important for the diagnostic process. PMID- 27125946 TI - The evolution of left atrial appendage occlusion: EWOLUTION and the WATCHMAN in practice. PMID- 27125947 TI - Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. AB - AIMS: The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts. METHODS AND RESULTS: Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine-Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24-8.98), 1.64 (1.29 2.08), and 1.77 (1.41-2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and DeltaAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and DeltaAUC = 0.02). CONCLUSIONS: Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions. PMID- 27125948 TI - Myocardial blush and microvascular reperfusion following manual thrombectomy during percutaneous coronary intervention for ST elevation myocardial infarction: insights from the TOTAL trial. AB - AIMS: Thrombectomy during primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI) has been thought to be an effective therapy to prevent distal embolization and improve microvascular perfusion. The TOTAL trial (N = 10 732), a randomized trial of routine manual thrombectomy vs. PCI alone in STEMI, showed no difference in the primary efficacy outcome. This angiographic sub-study was performed to determine if thrombectomy improved microvascular perfusion as measured by myocardial blush grade (MBG). METHODS AND RESULTS: Of the 10 732 patients randomized, 1610 randomly selected angiograms were analysable by the angiographic core laboratory. Primary outcomes included MBG and post-PCI thrombolysis in myocardial infarction (TIMI) flow grade. Secondary outcomes included distal embolization, PPCI complications, and each component of the complications. The primary end point of final myocardial blush (221 [28%] 0/1 for thrombectomy vs. 246 {30%} 0/1 for PCI alone group, P = 0.38) and TIMI flow (712 [90%] TIMI 3 for thrombectomy vs. 733 [89.5%] TIMI 3 for PCI alone arm, P = 0.73) was similar in the two groups. Thrombectomy was associated with a significantly reduced incidence of distal embolization compared with PCI alone (56 [7.1%] vs. 87 [10.7%], P = 0.01). In multivariable analysis, distal embolization was an independent predictor of mortality (HR 3.00, 95% CI 1.19 7.58) while MBG was not (HR 2.73, 95% CI 0.94-5.3). CONCLUSIONS: Routine thrombectomy during PPCI did not result in improved MBG or post-PCI TIMI flow grade but did reduce distal embolization compared with PCI alone. Distal embolization and not blush grade is independently associated with mortality. PMID- 27125949 TI - Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia. AB - AIMS: Normalization of hypercholesterolaemia, inflammation, hyperglycaemia, and obesity are main desired targets to prevent cardiovascular clinical events. Here we present a novel regulator of cholesterol metabolism, which simultaneously impacts on glucose intolerance and inflammation. METHODS AND RESULTS: Mice deficient for oxygen sensor HIF-prolyl hydroxylase 1 (PHD1) were backcrossed onto an atherogenic low-density lipoprotein receptor (LDLR) knockout background and atherosclerosis was studied upon 8 weeks of western-type diet. PHD1-/-LDLR-/- mice presented a sharp reduction in VLDL and LDL plasma cholesterol levels. In line, atherosclerotic plaque development, as measured by plaque area, necrotic core expansion and plaque stage was hampered in PHD1-/-LDLR-/- mice. Mechanistically, cholesterol-lowering in PHD1 deficient mice was a result of enhanced cholesterol excretion from blood to intestines and ultimately faeces. Additionally, flow cytometry of whole blood of these mice revealed significantly reduced counts of leucocytes and particularly of Ly6Chigh pro-inflammatory monocytes. In addition, when studying PHD1-/- in diet-induced obesity (14 weeks high-fat diet) mice were less glucose intolerant when compared with WT littermate controls. CONCLUSION: Overall, PHD1 knockout mice display a metabolic phenotype that generally is deemed protective for cardiovascular disease. Future studies should focus on the efficacy, safety, and gender-specific effects of PHD1 inhibition in humans, and unravel the molecular actors responsible for PHD1 driven, likely intestinal, and regulation of cholesterol metabolism. PMID- 27125950 TI - Rheumatic multiple valve disease and severe asymptomatic arterial occlusion. PMID- 27125951 TI - Imaging atherosclerosis with positron emission tomography. AB - Positron emission tomography (PET) provides a non-invasive method to measure biological processes that are relevant to atherosclerosis, including arterial inflammation and calcification. The vast majority of studies imaging atherosclerosis with PET have utilized the tracer 18F-fluorodeoxyglucose (FDG) to better understand how inflammation contributes to atherosclerosis development, and to test the efficacy of therapeutic interventions aimed at reducing its progression. Additional tracers such as 18F-sodium fluoride (18F-NaF) provide additional avenues for characterizing atherosclerosis development. This review examines the emerging uses of PET arterial imaging as a marker of vascular inflammation and atherosclerosis, as a prognostic tool, and as a clinical research tool. In addition, we examine emerging methods that should advance arterial imaging with PET. PMID- 27125952 TI - Giant pericardial effusion: drain it all? PMID- 27125954 TI - Introduction to special section on response shift at the item level. PMID- 27125955 TI - Individualized quality of life of severely affected multiple sclerosis patients: practicability and value in comparison with standard inventories. AB - PURPOSE: Individualized quality of life (QoL) measures differ from traditional inventories in that QoL domains/weights are not predetermined, but identified by the individual. We assessed practicability of the Schedule for the Evaluation of Individual QoL-Direct Weighting (SEIQoL-DW) interview in severely affected multiple sclerosis (MS) patients; the key QoL dimensions identified; and the correlation of the SEIQoL-DW index score with standard patient-reported outcome measures (PROMs). METHODS: Participants were people with severe MS who performed the baseline visit of the PeNSAMI trial (ISRCTN73082124). The SEIQoL-DW was administered at the patient's home by a trained examiner. Patients then received the following PROMs: the Core-Palliative care Outcome Scale (Core-POS), the Palliative care Outcome Scale-Symptoms-MS (POS-S-MS), the European Quality of Life Five Dimensions-3L (EQ-5D-3L), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Of 59 enrolled patients, 11 (19 %) did not receive the SEIQoL-DW (and the other PROMs) because of severe cognitive compromise or inability to communicate. SEIQoL-DW administration was completed and deemed valid in all 48 cases (mean age 60 years, 58 % women, median Expanded Disability Status Scale score 8.5). Mean SEIQoL-DW index score was 59.1 (SD 25.5). The most commonly nominated SEIQoL-DW areas were family (94 % of the patients), relationships, and leisure activities (both 65 %). Core-POS and POS-S-MS contained 70 % of the SEIQoL-DW-nominated areas. Nevertheless, correlations between SEIQoL-DW index, Core-POS, and POS-S-MS (and the other PROMs) were negligible. CONCLUSIONS: Individualized QoL can be assessed in severely affected MS patients, providing information that is not tracked by the standard inventories Core-POS, POS-S-MS, EQ-5D-3L, and HADS. PMID- 27125956 TI - Surface-enhanced Raman scattering via entrapment of colloidal plasmonic nanocrystals by laser generated microbubbles on random gold nano-islands. AB - Surface-enhanced Raman scattering (SERS) typically requires hot-spots generated in nano-fabricated plasmonic structures. Here we report a highly versatile approach based on the use of random gold nano-island substrates (AuNIS). Hot spots are produced through the entrapment of colloidal plasmonic nano-crystals at the interface between AuNIS and a microbubble, which is generated from the localized plasmonic absorption of a focused laser beam. The entrapment strength is strongly dependent on the shape of the microbubble, which is in turn affected by the surface wetting characteristics of the AuNIS with respect to the solvent composition. The laser power intensity required to trigger microbubble-induced SERS is as low as 200 MUW MUm(-2). Experimental results indicate that the SERS limit of detection (LOD) for molecules of 4-MBA (with -SH bonds) is 10(-12) M, R6G or RhB (without -SH bonds) is 10(-7) M. The proposed strategy has potential applications in low-cost lab-on-chip devices for the label-free detection of chemical and biological molecules. PMID- 27125957 TI - Ni(II)-Catalyzed C(sp(2))-H Alkynylation/Annulation with Terminal Alkynes under an Oxygen Atmosphere: A One-Pot Approach to 3-Methyleneisoindolin-1-one. AB - A nickel(II)-catalyzed alkynylation/annulation cascade via double C-H cleavage has been successfully achieved. This methodology adopted a removable N,O bidentate directing group with a broad range of amide substrates and terminal alkynes being well tolerated. The catalytic system allowed for atom-economical and environmentally benign one-pot construction of the corresponding 3 methyleneisoindolin-1-one derivatives using O2 as the external oxidant. PMID- 27125958 TI - Clinical challenges with calcitonin-negative medullary thyroid carcinoma. AB - PURPOSE: Medullary thyroid carcinoma (MTC) is a relatively uncommon malignant tumor of the parafollicular C cells of the thyroid, which distinguishing feature is the production of calcitonin (CT). CT is a well-recognized tool in the diagnosis and the postsurgical follow-up of patients with MTC with a high sensitivity and specificity, and represents a powerful prognostic indicator. Usually, there is a direct correlation between tumor size and basal CT levels. However, few cases of CT-negative MTCs have been reported in literature and criteria for diagnosis and follow-up are still controversial. METHODS: We performed a brief review on CT-negative MTC and reported our experience on this rare condition, focusing on the clinical characteristics at presentation, the histological and immunostaining features, and the management. RESULTS: Fifteen cases of large, palpable, CT-negative MTCs have been reported in the literature so far; moreover, we reported four cases followed at our center. CONCLUSIONS: Although CT-negative MTC is rare, normal/low serum levels of CT and CEA cannot completely exclude the possibility of the diagnosis, when suspected. It is well accepted that early diagnosis is crucial, but there is still no consensus on the optimal postoperative surveillance strategy. The ultrasound evaluation of the cervical region, together with abdominal computerized tomography scan, chest X ray, and fluorine18-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (FDG PET/CT), would be recommended in the follow-up of such cases. PMID- 27125959 TI - Efficient Regioselective Synthesis of the Crotonyl Polydatin Prodrug by Thermomyces lanuginosus Lipase: a Kinetics Study in Eco-friendly 2 Methyltetrahydrofuran. AB - Bio-based solvents have recently been discussed as sustainable green and promising alternatives to conventional organic media for enzymatic processes. In this paper, highly regioselective synthesis of the 6"-O-crotonyl-polydatin catalyzed by Thermomyces lanuginosus lipase (TLL) in biomass-derived 2 methyltetrahydrofuran (2-MeTHF) was successfully performed for the first time. The results indicated that TLL lipase displayed significantly improved catalytic performance in 2-MeTHF than in other traditional solvents. Under the optimal conditions, the initial reaction rate, 6"-regioselectivity, and maximum substrate conversion were as high as 12.38 mM h(-1), 100 %, and 100 %, respectively. Moreover, further investigations on the operational stability, kinetic parameters like V max, K m, V max/K m, and E a revealed that 2-MeTHF exhibited excellent biocompatibility and rendered the greener process of the enzymatic acylation. PMID- 27125960 TI - Comparative Analyses of the Relative Effects of Various Mutations in Major Histocompatibility Complex I-a Way to Predict Protein-Protein Interactions. AB - Protein-protein interactions (PPIs) play pivotal roles in most of the biological processes. PPI dysfunctions are therefore associated with disease situations. Mutations often lead to PPI dysfunctions, but there are certain other types of mutations which do not cause any appreciable abnormalities. This second type of mutations is called polymorphic mutations. So far, there are many studies that deal with the identification of PPI sites, but clear-cut analyses of the involvements of mutations in PPI dysfunctions are few and far between. We therefore made an attempt to link the appearances of mutations and PPI disruptions. We used major histocompatibility complex as our reference protein complex. We analyzed the mutations leading to the disease amyloidosis and also the other mutations that do not lead to disease conditions. We computed various biophysical parameters like relative solvent accessibility to discriminate between the two different types of mutations. Our analyses for the first time came up with a plausible explanation for the effects of different types of mutations in disease development. Our future plans are to build tools to detect the effects of mutations in disease developments by disrupting the PPIs. PMID- 27125961 TI - Claim of superiority of SGA in the treatment of aggressiveness in schizophrenia is not supported by data. PMID- 27125962 TI - A Simple Task Uncovers a Postdictive Illusion of Choice. AB - Do people know when, or whether, they have made a conscious choice? Here, we explore the possibility that choices can seem to occur before they are actually made. In two studies, participants were asked to quickly choose from a set of options before a randomly selected option was made salient. Even when they believed that they had made their decision prior to this event, participants were significantly more likely than chance to report choosing the salient option when this option was made salient soon after the perceived time of choice. Thus, without participants' awareness, a seemingly later event influenced choices that were experienced as occurring at an earlier time. These findings suggest that, like certain low-level perceptual experiences, the experience of choice is susceptible to "postdictive" influence and that people may systematically overestimate the role that consciousness plays in their chosen behavior. PMID- 27125963 TI - Prevalence of anxiety in Parkinson's disease: A systematic review and meta analysis. AB - OBJECTIVE: Prevalence rates of anxiety disorders in Parkinson's disease (PD) vary widely, ranging from 6% up to 55%. The aim of this systematic review was to calculate the average point prevalence of anxiety disorders and clinically relevant anxiety symptoms in PD. METHODS: Using PubMed, we carried out a systematic literature search for studies reporting Diagnostic and Statistical Manual-defined anxiety disorders or clinically relevant anxiety symptoms assessed by an anxiety rating scale. RESULTS: A total of 49 articles were included and assessed for quality, and 45 articles fulfilled the quality criteria. The average point prevalence of anxiety disorders in PD was 31%, with nonepisodic anxiety being more prevalent than episodic anxiety. Generalized anxiety disorder was the most frequent in 14%, followed by social phobia (13.8%), anxiety not otherwise specified (13.3%), and specific phobia (13.0%). Panic disorder with or without phobia was present in 6.8% of PD patients. Of the patients, 31% fulfilled the criteria for current multiple anxiety disorders. Based on anxiety rating scale cutoff scores, clinically significant anxiety symptoms were present in a weighted average of 25.7%. CONCLUSION: This systematic review confirms that anxiety, although often unrecognized, is very common and highlights the need for efficient identification of anxiety in PD. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27125964 TI - Evaluation of the genotoxicity of Euterpe oleraceae Mart. (Arecaceae) fruit oil (acai), in mammalian cells in vivo. AB - E. oleracea is a tropical plant from the Amazon region, with its fruit used for food, and traditionally, as an antioxidant, anti-inflammatory, hypocholesterolemic, for atherosclerotic disease, and has anticancer properties. The oil of the fruit has antidiarrheic, anti-inflammatory and antinociceptive activities, but without genotoxicity evaluation. Therefore, the aim of this study was to evaluate the genotoxic potential of E. oleracea fruit oil (EOO), in rat cells. Male Wistar rats were treated with EOO by gavage at doses of 30, 100 and 300 mg/kg, for 14 days, within a 24 h interval. The DNA damage in the leukocytes, liver, bone marrow and testicular cells, was assessed by the comet assay, and the clastogenic/aneugenic effects in the bone marrow cells, by the micronucleus test. Our phytochemicals characterization of the EOO showed the presence of vanillic, palmitic, gamma-linolenic, linoleic, oleic, cinnamic, caffeic, protocatechuic, ferulic, syringic acids, and flavonoids quercetin and kaempferol rutinoside as the main constituents. Both cytogenetic tests performed showed that EOO presented no significant genotoxic effects in the analyzed cells, at the three tested doses. These results indicate that, under our experimental conditions, E. oleracea fruit oil did not reveal genetic toxicity in rat cells. PMID- 27125965 TI - Low awareness of risk factors among bladder cancer survivors: New evidence and a literature overview. AB - BACKGROUND: Data on urinary bladder cancer (UBC) patients' perceptions about causes of bladder cancer is limited, while this may be important knowledge for health prevention and education. We evaluated self-reported perceptions and beliefs about the causes of bladder cancer among UBC survivors in the Netherlands. METHODS: UBC survivors identified through the Netherlands Cancer Registry from 2007 to 2012 were invited to participate. Patients who consented were asked to fill out a questionnaire, including questions on lifestyle characteristics, occupational and medical history, and family history of cancer. The final question was 'You have been diagnosed with bladder cancer. Do you have any idea what may have been the cause of your cancer?'. RESULTS: Of the 1793 UBC survivors included, 366 (20%) reported a possible cause for their bladder cancer. The most frequently reported suspected causes were smoking (10%), occupational exposure (5%), and heredity (2%). Smoking, occupational exposure and heredity were mentioned only slightly more frequently by participants with these risk factors (11%, 8%, and 5%, respectively) compared to the total population. CONCLUSIONS: Most UBC survivors did not suspect any cause that might have contributed to the development of their cancer. Even among participants with established risk factors for bladder cancer, these risk factors were not commonly perceived. This finding probably reflects the superficial knowledge of risk factors for bladder cancer in the population and highlights the importance of effective education on cancer prevention. PMID- 27125966 TI - Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer. AB - BACKGROUND: The hormonal manipulation 5-Fluoro-uracil Epirubicin Cyclophosphamide (HMFEC) trial was developed at a time of uncertainty around the dose intensity of chemotherapy given to premenopausal patients with node positive breast cancer and to the benefits of tailored endocrine therapy in such patients. PATIENTS AND METHODS: HMFEC was a multi-centre, phase III, open label, randomised controlled trial with a 2 * 2 factorial design. Eligible patients were premenopausal with node positive early breast cancer; significant cardiac disease or uncontrolled hypertension was exclusion criterion. Patients were allocated to receive either eight cycles of FE50C or FE75C (given 3 weekly) with or without hormone manipulation (HM; tamoxifen or luteinising hormone releasing hormone (LHRH) agonists according to residual hormone levels at the end of chemotherapy) irrespective of ER status. The primary end-point was disease free survival (DFS). Principal analyses were by intention to treat (ITT); however, to reflect contemporary practice, subgroup analyses according to ER status were also conducted. The mature follow-up now available from this modest sized trial enables presentation of definitive results. RESULTS: Between 1992 and 2000 a total of 785 patients were randomised into the HMFEC trial (203 FE50C-HM, 191 FE50C+HM, 198 FE75C-HM, 193 FE75C+HM). At a median follow-up of 7.4 years, 245 DFS events have been reported (92 ER-, 153 ER+/unknown). The effects on DFS were not statistically significantly different according to epirubicin dose (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.63-1.06; p = 0.13 FE75C versus FE50C); however, FE75C appeared to induce more alopecia and neutropenia. No statistically significant evidence was observed to support an improvement in DFS in patients allocated HM either overall (HR = 0.88, 95% CI 0.68-1.13; p = 0.32) or in patients with ER+/unknown disease (HR = 0.85, 95% CI 0.62-1.17; p = 0.32) although effect sizes are consistent with worthwhile clinical effects. Overall, there was no evidence of a difference in survival between any of the four treatment groups of the trial. CONCLUSION: Higher doses of epirubicin cause more adverse events in the absence of clear improvement in overall survival. Endocrine therapy with either tamoxifen or goserelin provided no significant added benefit to cytotoxic chemotherapy in this group of patients. TRIAL REGISTRATION NUMBER: ISRCTN98335268. PMID- 27125967 TI - Effects of Polyamidoamine Dendrimers on a 3-D Neurosphere System Using Human Neural Progenitor Cells. AB - The practical application of engineered nanomaterials or nanoparticles like polyamidoamine (PAMAM) dendrimers has been promoted in medical devices or industrial uses. The safety of PAMAM dendrimers needs to be assessed when used as a drug carrier to treat brain disease. However, the effects of PAMAM on the human nervous system remain unknown. In this study, human neural progenitor cells cultured as a 3D neurosphere model were used to study the effects of PAMAM dendrimers on the nervous system. Neurospheres were exposed to different G4-PAMAM dendrimers for 72 h at concentrations of 0.3, 1, 3, and 10 MUg/ml. The biodistribution was investigated using fluorescence-labeled PAMAM dendrimers, and gene expression was evaluated using microarray analysis followed by pathway and network analysis. Results showed that PAMAM dendrimer nanoparticles can penetrate into neurospheres via superficial cells on them. PAMAM-NH2 but not PAMAM-SC can inhibit neurosphere growth. A reduced number of MAP2-positive cells in flare regions were inhibited after 10 days of differentiation, indicating an inhibitory effect of PAMAM-NH2 on cell proliferation and neuronal migration. A microarray assay showed 32 dendrimer toxicity-related genes, with network analysis showing 3 independent networks of the selected gene targets. Inducible immediate early gene early growth response gene 1 (Egr1), insulin-like growth factor-binding protein 3 (IGFBP3), tissue factor pathway inhibitor (TFPI2), and adrenomedullin (ADM) were the key genes in each network, and the expression of these genes was significantly down regulated. These findings suggest that exposure of neurospheres to PAMAM-NH2 dendrimers affects cell proliferation and migration through pathways regulated by Egr1, IGFBP3, TFPI2, and ADM. PMID- 27125968 TI - Bisphenol A Impairs Mature Sperm Functions by a CatSper-Relevant Mechanism. AB - Bisphenol A (BPA), an endocrine-disrupting chemical, is widely used in the manufacture of daily necessities. Previous studies showed that BPA could impair spermatogenesis. However, its effects on mature spermatozoa are not well known. We aimed to investigate the in vivo and in vitro toxicity of BPA on mature mouse spermatozoa. Different doses of BPA (0, 10, 50, and 250 MUg.kg(-1).d(-1)) were administrated orally to C57BL/6 mice for 8 weeks. Subsequently, the sperm viability, motility, acrosome reaction (AR) ratio together with the expression/current levels of the sperm-specific Ca(2+ )channel (CatSper) and K(+ )channel (KSper) were examined. These parameters were also evaluated after applying BPA directly to normal mouse sperm to appraise the toxicity of BPA to mature sperm in vitro Significant decreases in sperm motility and AR were found in BPA administrated mice, possibly resulting from a BPA caused CatSper down regulation which was supported by both western blot and patch clamping results. Moreover, direct application of BPA to spermatozoa inhibited CatSper transiently and also caused significant reductions in sperm total motility and AR ratio. In conclusion, both in vivo administration and in vitro application of BPA impair mature sperm functions by a CatSper-relevant mechanism. PMID- 27125970 TI - Sirtuin 3 Protects against Urban Particulate Matter-Induced Autophagy in Human Bronchial Epithelial Cells. AB - Urban particulate matter (urban PM) is a heterogeneous mixture of various types of particles originating from different sources. Exposure to high concentrations of urban PM leading to adverse health effects is evaluated by using in vitro cultures of human lung epithelial cells. However, the mechanism underlying the correlation between high concentrations of urban PM exposure and adverse health effects has not been fully elucidated; urban PM-induced oxidative stress is considered as an important mechanism of urban PM-mediated cytotoxicity. Sirtuin 3 (SIRT3), a primary mitrochondrial deacetylase, controls cellular reactive oxygen species (ROS) production, and expression of antioxidant enzymes. In this study, we examined the role of SIRT3 in the regulation of urban PM-induced oxidative stress in normal primary human bronchial epithelial cells (HBEpiCs). Cell viability showed a time- and concentration-dependent decrease when exposed to urban PM, which could indicate that the amount of lactate dehydrogenase released from the cell in response to urban PM is related to cell viability in HBEpiC. The effects of urban PM on morphological and biochemical markers of autophagy in HBEpiC were analyzed by electron microscopy and Western blotting. Overexpression of SIRT3 inhibited urban PM-induced ROS generation, while concomitantly increasing the expression of antioxidant enzymes, and decreasing NF-kappaB activation and release of inflammation factors. Up-regulation of SIRT3 significantly inhibited the expression of autophagy markers and autophagic vacuole formation. Our findings provide a valuable insight into the potential role of the SIRT3 enzyme in regulating urban PM-induced autophagy by mediating urban PM-induced oxidative stress, which may contribute to urban PM-induced impairment of airway epithelial cell function. PMID- 27125969 TI - Cardiac Non-myocyte Cells Show Enhanced Pharmacological Function Suggestive of Contractile Maturity in Stem Cell Derived Cardiomyocyte Microtissues. AB - The immature phenotype of stem cell derived cardiomyocytes is a significant barrier to their use in translational medicine and pre-clinical in vitro drug toxicity and pharmacological analysis. Here we have assessed the contribution of non-myocyte cells on the contractile function of co-cultured human embryonic stem cell derived cardiomyocytes (hESC-CMs) in spheroid microtissue format. Microtissues were formed using a scaffold free 96-well cell suspension method from hESC-CM cultured alone (CM microtissues) or in combination with human primary cardiac microvascular endothelial cells and cardiac fibroblasts (CMEF microtissues). Contractility was characterized with fluorescence and video-based edge detection. CMEF microtissues displayed greater Ca(2+ )transient amplitudes, enhanced spontaneous contraction rate and remarkably enhanced contractile function in response to both positive and negative inotropic drugs, suggesting a more mature contractile phenotype than CM microtissues. In addition, for several drugs the enhanced contractile response was not apparent when endothelial cell or fibroblasts from a non-cardiac tissue were used as the ancillary cells. Further evidence of maturity for CMEF microtissues was shown with increased expression of genes that encode proteins critical in cardiac Ca(2+ )handling (S100A1), sarcomere assembly (telethonin/TCAP) and beta-adrenergic receptor signalling. Our data shows that compared with single cell-type cardiomyocyte in vitro models, CMEF microtissues are superior at predicting the inotropic effects of drugs, demonstrating the critical contribution of cardiac non-myocyte cells in mediating functional cardiotoxicity. PMID- 27125971 TI - Translating evidence-based protocol of wound drain management for total joint arthroplasty into practice: A quasi-experimental study. AB - BACKGROUND: Although various drains have long been used in total joint replacement, evidence suggests inconsistent practice exists in the use of drainage systems including intermittently applying suction or free of drainage suction, and variations in the optimal timing for wound drain removal. A comprehensive systematic review of available evidence up to 2013 was conducted in a previous study and a protocol was adapted for clinical application according to the summary of the retrieved information (Tsang, 2015). AIMS: To determine if the protocol could reduce blood loss and blood transfusion after operation and to develop a record form so as to enhance communication of drainage record amongst surgeons and nurses. METHODS: A quasi-experimental time-series design was undertaken. In the conventional group, surgeons ordered free drainage if the drain output was more than 300 ml. The time of removal of the drain was based on their professional judgement. In the protocol group the method of drainage was dependant of the drainage output as was the timing of the removal of the drain. A standardized record form was developed to guide operating room and orthopaedic ward nurses to manage the drainage system. RESULTS: The drain was removed significantly earlier in the protocol group. Blood loss rate at the first hour of post-operation was extremely low in the protocol group due to clamping effect. Blood loss in volume during the first three hours in the protocol group was significantly lower than that in the conventional group. Only in 11.1% and 4% of cases was it necessary to clamp at the three and four hour post-operative hours. No clamping was required at the two and eight hour postoperative period. There was no significant difference in blood loss during the removal of the drain and during blood transfusion, which was required for patients upon removal of the drain in the two groups. CONCLUSION: This is the first clinical study to develop an evidence-based protocol to manage wound drain effectively in Hong Kong. Total blood loss and blood transfusions were not significantly different between the conventional and protocol groups. A standard documentation document is beneficial to enhance communication between doctors and nurses as well as to monitor and observe drainage effectively. PMID- 27125972 TI - Characterization of progressive metaplasia in the gastric corpus mucosa of Mongolian gerbils infected with Helicobacter pylori. AB - Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia are considered neoplastic precursors of gastric adenocarcinoma in humans. Loss of parietal cells causes the development of SPEM in the gastric corpus and then chronic inflammation drives SPEM toward a more proliferative lineage. Mongolian gerbils infected with Helicobacter pylori develop chronic gastritis and metaplasia, mimicking aspects of human gastritis with H. pylori infection. We therefore examined metaplastic lineages in the gastric corpus mucosa of gerbils infected by H. pylori strain 7.13, which produces rapid onset of severe inflammation. Six weeks following H. pylori infection, Griffonia simplicifolia lectin II (GSII)-positive SPEM developed in the base of oxyntic glands in association with parietal cell loss and inflammation. In association with severe inflammation, SPEM glands evolved into aberrant phenotypes, including branched lesions, dilated lesions, and penetrating invasive glands. Mucin 4 (MUC4) was up regulated in SPEM and progressive SPEM. Clusterin was expressed in the tips of branched and dilated lesions and throughout regions of invasive glands. Intriguingly, clusterin-positive regions in these lesions expressed Ki67 and matrix metalloproteinase 7 (MMP-7). These same regions were also positive for expression of phospho-IkBalpha, suggestive of activated NFkB signalling. These findings suggest that clusterin-positive regions in progressive phenotypes of SPEM have invasive characteristics. Thus, H. pylori infection in gerbils induces SPEM, which then can progress to further aberrant and invasive metaplastic phenotypes. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27125974 TI - Aurora-A modulates MMP-2 expression via AKT/NF-kappaB pathway in esophageal squamous cell carcinoma cells. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. It is necessary to identify new markers for predicting tumor progression and therapeutic molecular targets. It has been reported that overexpressions of Aurora-A and matrix metalloproteinases 2 (MMP-2) may promote the malignant development of tumor. However, the relationship between Aurora-A and MMP-2 expression in tumor patients has not been investigated. In addition, the underlying mechanisms that Aurora-A regulates MMP-2 expression are still not fully elucidated. In this study, we demonstrated that Aurora-A and MMP-2 were overexpressed in ESCC tissues compared with paired normal adjacent tissues (P < 0.0001). Overexpression of Aurora-A was associated with the lymph node metastasis of ESCC (P = 0.01). Significantly, Aurora-A protein expression was positively correlated with MMP-2 protein expression in ESCC tissues (r = 0.66, P < 0.0001) as well as in ESCC cell lines. The level of Aurora-A expression was also positively correlated with the invasion capability of ESCC cells. Furthermore, Aurora-A overexpression significantly increased ESCC cell invasion by the upregulation of MMP-2 expression. In addition, Aurora-A overexpression promoted nuclear factor-kappaB (NF-kappaB) activation, and Aurora-A-mediated MMP-2 upregulation was abrogated by NF-kappaB inhibitor. Further analysis showed that activation of NF-kappaB was severely attenuated by AKT inhibitor in cells overexpressing Aurora-A. Taken together, these data indicate that Aurora-A overexpression upregulates MMP-2 expression through activating AKT/NF-kappaB signaling pathway in ESCC cells. These findings reveal that Aurora-A may be used as an important indicator for the judgment of malignant behavior of ESCC, and may be an attractive target for cancer therapy. PMID- 27125973 TI - Evaluation of artemisinins for the treatment of acute myeloid leukemia. AB - PURPOSE: Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models. METHODS: Using ten human AML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models. RESULTS: ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo. CONCLUSIONS: The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML. PMID- 27125975 TI - CMTM3 presents a secreted form released via exosomes. PMID- 27125976 TI - Calcium-mediated regulation of recombinant hybrids of full-length Physarum myosin heavy chain with Physarum/scallop myosin light chains. AB - Physarum myosin is a Ca(2+)-binding protein and its activity is inhibited by Ca(2+) In the present study, to clarify the light chains (LCs) from the different species (Physarum and scallop) and to determine the specific Ca(2+)-regulated effects, we constructed hybrid myosins with a Physarum myosin heavy chain (Ph.HC) and Physarum and/or scallop myosin LCs, and examined Ca(2+)-mediated regulation of ATPases and motor activities. In these experiments, it was found that Ca(2+) inhibited motilities and ATPase activities of Physarum hybrid myosin with scallop regulatory light chain (ScRLC) and Physarum essential light chain (PhELC) but could not inhibit those of the Physarum hybrid myosin mutant Ph.HC/ScRLC/PhELC-3A which lacks Ca(2+)-binding ability, indicating that PhELC plays a critical role in Ca(2+)-mediated regulation of Physarum myosin. Furthermore, the effects of Ca(2+) on ATPase activities of Physarum myosin constructs are in the following order: Ph.HC/PhRLC/PhELC > Ph.HC/ScRLC/PhELC > Ph.HC/PhRLC/ScELC > Ph.HC/ScRLC/ScELC, suggesting that the presence of PhRLC and PhELC leads to the greatest Ca(2+) sensitivity of Physarum myosin. Although we did not observe the motilities of Physarum hybrid myosin Ph.HC/PhRLC/ScELC and Ph.HC/ScRLC/ScELC, our results suggest that Ca(2+)-binding to the PhELC may alter the flexibility of the regulatory domain and induce a 'closed' state, which may consequently prevent full activity and force generation. PMID- 27125977 TI - Lipogenesis in myoblasts and its regulation of CTRP6 by AdipoR1/Erk/PPARgamma signaling pathway. AB - The induced lipogenesis and its regulation in C2C12 myoblasts remain largely unclear. Here, we found that the cocktail method could significantly induce lipogenesis through regulating lipid metabolic genes and Erk1/2 phosphorylation in myoblasts. Meanwhile, the expression and secretion of CTRP6 were increased during ectopic lipogenesis. Moreover, CTRP6 knockdown down-regulated the levels of lipogenic genes and phosphorylated Erk1/2 (p-Erk1/2) in the early lipogenic stage, whereas up-regulated p-Erk1/2 in the terminal differentiation. Interestingly, the effect of CTRP6 siRNA was attenuated by U0126 (a special p Erk1/2 inhibitor) in myoblasts. Furthermore, AdipoR1, not AdipoR2, was first identified as a receptor of CTRP6 during the process of mitotic clonal expansion. Collectively, we suggest that CTRP6 mediates the ectopic lipogenesis through AdipoR1/Erk/PPARgamma signaling pathway in myoblasts. Our findings will shed light on the novel biological function of CTRP6 during myoblast lipogenesis and provide a hopeful direction of improving meat quality of domestic animal by lipogenic regulation in skeletal muscle myoblasts. PMID- 27125978 TI - Increased GSK-3beta expression in DRG microglia in response to sciatic nerve crush. PMID- 27125980 TI - Cell motility and ECM proteolysis regulate tumor growth and tumor relapse by altering the fraction of cancer stem cells and their spatial scattering. AB - Tumors consist of multiple cell sub-populations including cancer stem cells (CSCs), transiently amplifying cells and terminally differentiated cells (TDCs), with the CSC fraction dictating the aggressiveness of the tumor and drug sensitivity. In epithelial cancers, tumor growth is influenced greatly by properties of the extracellular matrix (ECM), with cancer progression associated with an increase in ECM density. However, the extent to which increased ECM confinement induced by an increase in ECM density influences tumor growth and post treatment relapse dynamics remains incompletely understood. In this study, we use a cellular automata-based discrete modeling approach to study the collective influence of ECM density, cell motility and ECM proteolysis on tumor growth, tumor heterogeneity, and tumor relapse after drug treatment. We show that while increased confinement suppresses tumor growth and the spatial scattering of CSCs, this effect can be reversed when cells become more motile and proteolytically active. Our results further suggest that, in addition to the absolute number of CSCs, their spatial positioning also plays an important role in driving tumor growth. In a nutshell, our study suggests that, in confined environments, cell motility and ECM proteolysis are two key factors that regulate tumor growth and tumor relapse dynamics by altering the number and spatial distribution of CSCs. PMID- 27125979 TI - The course of lung inflation alters the central pattern of tracheobronchial cough in cat-The evidence for volume feedback during cough. AB - The effect of volume-related feedback and output airflow resistance on the cough motor pattern was studied in 17 pentobarbital anesthetized spontaneously breathing cats. Lung inflation during tracheobronchial cough was ventilator controlled and triggered by the diaphragm electromyographic (EMG) signal. Altered lung inflations during cough resulted in modified cough motor drive and temporal features of coughing. When tidal volume was delivered (via the ventilator) there was a significant increase in the inspiratory and expiratory cough drive (esophageal pressures and EMG amplitudes), inspiratory phase duration (CTI), total cough cycle duration, and the duration of all cough related EMGs (Tactive). When the cough volume was delivered (via the ventilator) during the first half of inspiratory period (at CTI/2-early over inflation), there was a significant reduction in the inspiratory and expiratory EMG amplitude, peak inspiratory esophageal pressure, CTI, and the overlap between inspiratory and expiratory EMG activity. Additionally, there was significant increase in the interval between the maximum inspiratory and expiratory EMG activity and the active portion of the expiratory phase (CTE1). Control inflations coughs and control coughs with additional expiratory resistance had increased maximum expiratory esophageal pressure and prolonged CTE1, the duration of cough abdominal activity, and Tactive. There was no significant difference in control coughing and/or control coughing when sham ventilation was employed. In conclusion, modified lung inflations during coughing and/or additional expiratory airflow resistance altered the spatio-temporal features of cough motor pattern via the volume related feedback mechanism similar to that in breathing. PMID- 27125981 TI - Umbilical cord blood transplantation is a suitable option for consolidation of acute myeloid leukemia with FLT3-ITD. PMID- 27125983 TI - Human plasmacytoid dentritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway. AB - Plasmacytoid dendritic cells (pDCs) are a major source of type I interferon (IFN) and are important for host defense by sensing microbial DNA via TLR9. pDCs also play a critical role in the pathogenesis of IFN-driven autoimmune diseases. Yet, this autoimmune reaction is caused by the recognition of self-DNA and has been linked to TLR9-independent pathways. Increasing evidence suggests that the cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) is a critical component in the detection of pathogens and contributes to autoimmune diseases. It has been shown that binding of DNA to cGAS results in the synthesis of cGAMP and the subsequent activation of the stimulator of interferon genes (STING) adaptor to induce IFNs. Our results show that the cGAS-STING pathway is expressed and activated in human pDCs by cytosolic DNA leading to a robust type I IFN response. Direct activation of STING by cyclic dinucleotides including cGAMP also activated pDCs and knockdown of STING abolished this IFN response. These results suggest that pDCs sense cytosolic DNA and cyclic dinucleotides via the cGAS-STING pathway and that targeting this pathway could be of therapeutic interest. PMID- 27125982 TI - Imatinib-induced long-term remission in a relapsed RCSD1-ABL1-positive acute lymphoblastic leukemia. PMID- 27125984 TI - Nickel on the market: a baseline survey of articles in 'prolonged contact' with skin. AB - BACKGROUND: In April 2014, the European Chemicals Agency defined the concept of 'prolonged contact with skin' as used in the EU nickel restriction. OBJECTIVES: To establish a baseline of nickel-releasing items on the Swedish market conforming with the EU nickel restriction according to the definition of 'prolonged contact' with the skin. METHODS: We performed a limited market survey in Stockholm, Sweden. Items with metallic parts that come into contact with the skin, except those explicitly mentioned in the legal text, were chosen. The dimethylglyoxime (DMG) test was used to evaluate nickel release. RESULTS: One hundred and forty-one items belonging to one of three categories - accessories, utensils for needlework, painting and writing (called utensils), and electronic devices - were tested in the study. Forty-four percent of all items were DMG test positive (releasing nickel), and 9% gave a doubtful DMG test result. CONCLUSIONS: The large proportion of nickel-releasing items in the present study shows clearly that broader parts of industry need to take action to prevent nickel allergy. The high proportion of DMG test-positive items indicates that there is still much work to be done to reduce the nickel exposure of the population. PMID- 27125985 TI - Mechanisms of lipid regulation and lipid gating in TRPC channels. AB - TRPC proteins form cation channels that integrate and relay cellular signals by mechanisms involving lipid recognition and lipid-dependent gating. The lipohilic/amphiphilic molecules that function as cellular activators or modulators of TRPC proteins span a wide range of chemical structures. In this context, cellular redox balance is likely linked to the lipid recognition/gating features of TRPC channels. Both classical ligand-protein interactions as well as indirect and promiscuous sensory mechanisms have been proposed. Some of the recognition processes are suggested to involve ancillary lipid-binding scaffolds or regulators as well as dynamic protein-protein interactions determined by bilayer architecture. A complex interplay of protein-protein and protein-lipid interactions is likely to govern the gating and/or plasma membrane recruitment of TRPC channels, thereby providing a distinguished platform for signal integration and coincident signal detection. Both the primary molecular event(s) of lipid recognition by TRPC channels as well as the transformation of these events into distinct gating movements is poorly understood at the molecular level, and it remains elusive whether lipid sensing in TRPCs is conferred to a distinct sensor domain. Recent structural information on the molecular action of lipophilic activators in distantly related members of the TRP superfamily encourages speculations on TRPC gating mechanisms involved in lipid recognition/gating. This review aims to provide an update on the current understanding of the lipid dependent control of TRPC channels with focus on the TRPC lipid sensing, signal integration hub and a short discussion of potential links to redox signaling. PMID- 27125986 TI - Paediatric International Nursing Study: using person-centred key performance indicators to benchmark children's services. AB - AIMS AND OBJECTIVES: The aim of the Paediatric International Nursing Study was to explore the utility of key performance indicators in developing person-centred practice across a range of services provided to sick children. The objective addressed in this paper was evaluating the use of these indicators to benchmark services internationally. BACKGROUND: This study builds on primary research, which produced indicators that were considered novel both in terms of their positive orientation and use in generating data that privileges the patient voice. This study extends this research through wider testing on an international platform within paediatrics. DESIGN: The overall methodological approach was a realistic evaluation used to evaluate the implementation of the key performance indicators, which combined an integrated development and evaluation methodology. METHODS: The study involved children's wards/hospitals in Australia (six sites across three states) and Europe (seven sites across four countries). Qualitative and quantitative methods were used during the implementation process, however, this paper reports the quantitative data only, which used survey, observations and documentary review. RESULTS: The findings demonstrate the quality of care being delivered to children and their families across different international sites. The benchmarking does, however, highlight some differences between paediatric and general hospitals, and between the different key performance indicators across all the sites. CONCLUSIONS: The findings support the use of the key performance indicators as a novel method to benchmark services internationally. Whilst the data collected across 20 paediatric sites suggest services are more similar than different, benchmarking illuminates variations that encourage a critical dialogue about what works and why. RELEVANCE TO CLINICAL PRACTICE: The transferability of the key performance indicators and measurement framework across different settings has significant implications for practice. The findings offer an approach to benchmarking and celebrating the successes within practice, while learning from partners across the globe in further developing person-centred cultures. PMID- 27125987 TI - Ensifer glycinis sp. nov., a rhizobial species associated with species of the genus Glycine. AB - Rhizobial strains from root nodules of Astragalus mongholicus and soybean (Glycine max) were characterized phylogenetically as members of the genus Ensifer (formerly named Sinorhizobium), based on 16S rRNA gene sequence comparisons. Results based upon concatenated sequence analysis of three housekeeping genes (recA, atpD and glnII, <= 93.8 % similarities to known species) and average nucleotide identity (ANI) values of whole genome sequence comparisons (ranging from 89.6 % to 83.4 % to Ensifer fredii and Ensifer saheli, respectively) indicated the distinct positions of these novel strains within the genus Ensifer. Phylogeny of symbiotic genes (nodC and nifH) of three novel strains clustered them with rhizobial species Ensifer fredii and Ensifer sojae, both isolated from nodules of Glycine max. Cross-nodulation tests showed that the representative strain CCBAU 23380T could form root nodules with nitrogen fixation capability on Glycine soja, Albizia julibrissin, Vigna unguiculata and Cajanus cajan, but failed to nodulate Astragalus mongholicus, its original host legume. Strain CCBAU 23380T formed inefficient nodules on G. max, and it did not contain 18 : 0, 18 : 1omega7c 11-methyl or summed feature 1 fatty acids, which differed from other related strains. Failure to utilize malonic acid as a carbon source distinguished strain CCBAU 23380T from the type strains of related species. The genome size of CCBAU 23380T was 6.0 Mbp, comprising 5624 predicted genes with DNA G+C content of 62.4 mol%. Based on the results above, a novel species, Ensifer glycinis sp. nov., is proposed, with CCBAU 23380T (=LMG 29231T =HAMBI 3645T) as the type strain. PMID- 27125988 TI - What moral status should be accorded to those human beings who have profound intellectual disabilities? A reply to Curtis and Vehmas. AB - Curtis and Vehmas present an argument in support of full moral status for those with profound intellectual disabilities based on Moore's famous defence of a common-sense view of the nature and existence of the external world. According to them, the need for such an argument arises from the disturbing inferences that can, supposedly, be drawn from the standard Lockean philosophical theory of personhood. This paper develops and supports Curtis and Vehmas's central claim concerning this equality of moral status by suggesting a basis for rejecting Locke's position, based on reflections upon Wittgenstein's remarks about games and family resemblances. It also questions the validity of the disturbing inferences. It asserts that our moral duties towards and concerning people who have and people who do not have profound intellectual disability, human and non human animals, do not derive solely from their moral status. The existence, content and strength of our moral duties towards particular people can be grounded in conditions and circumstances that pertain to us rather than to them. PMID- 27125989 TI - Doubly distributing special obligations: what professional practice can learn from parenting. AB - A traditional ethic of medicine asserts that physicians have special obligations to individual patients with whom they have a clinical relationship. Contemporary trends in US healthcare financing like bundled payments seem to threaten traditional conceptions of special obligations of individual physicians to individual patients because their population-based focus sets a tone that seems to emphasise responsibilities for groups of patients by groups of physicians in an organisation. Prior to undertaking a cogent debate about the fate and normative weight of special obligations and a traditional ethic for contemporary healthcare, we need a deeper examination of what the traditional ethic of special obligations really means. Here we offer a conception of 'doubly distributed' special obligations. Physicians and similarly minded healing professionals abiding by a traditional ethic have always spread their devotion and attention across multiple patients and have shared responsibilities with physician and non physician colleagues in much the same way devoted parents have frequently distributed their special obligations across multiple children and across multiple parents. By taking up the extended analogy of parent we argue that doubly distributing special obligations need not contradict the possibility of special obligations in restructured collective forms of healthcare delivery and financing. PMID- 27125990 TI - Response to WHO. PMID- 27125991 TI - Accidental intralenticular dexamethasone intravitreal implant with the resolution of macular oedema in central retinal vein occlusion. PMID- 27125992 TI - The Relationship Between Parental Affective Temperament Traits and Disruptive Behavior Disorders Symptoms in Children With ADHD. AB - OBJECTIVE: This study investigated the relationship between parental affective temperaments and the oppositional defiant disorder (ODD) and conduct disorder (CD) symptoms of children with ADHD. METHOD: The sample consisted of 542 treatment-naive children with ADHD and their biological parents. Children were assessed via both parent- and teacher-rated behavioral disorder scales. Parental affective temperament and ADHD symptoms were measured by self-report inventories. The relationships between psychiatric variables were evaluated using structural equation modeling. RESULTS: According to parent-rated behavioral disorder scales, paternal cyclothymic and maternal irritable temperaments were associated with ODD scores, and maternal depressive temperament was associated with CD scores. In terms of teacher-rated behavioral disorder scales, maternal anxious temperament was associated with ODD scores, and paternal cyclothymic and maternal depressive temperaments were associated with CD scores. CONCLUSION: These results suggest that certain parental affective temperaments are related to an increase in symptoms of disruptive behavioral disorders in children with ADHD. PMID- 27125993 TI - The Association of Lifestyle Factors and ADHD in Children. AB - OBJECTIVE: The objective of the study is to examine whether children aged 7 to 11 years with very well-characterized ADHD, recruited from the community, have a similar number of healthy lifestyle behaviors as compared with typically developing children from the same community. METHOD: Parents of children with (n = 184) and without (n = 104) ADHD completed a lifestyle questionnaire asking about water intake, sweetened beverage consumption, multivitamin/supplement use, reading, screen time, physical activity, and sleep. A lifestyle index was formed from these seven domains (0-7), and multivariable ordered logistic regression was used to examine the association of ADHD status and total healthy lifestyle behaviors. RESULTS: Children with ADHD were almost twice as likely to have fewer healthy behaviors, even after adjustment for age, sex, intelligence quotient (IQ), ADHD medication use, household income, and four comorbid psychiatric disorders (odds ratio [OR] [95% confidence interval] = 1.95 [1.16, 3.30], p = .01). CONCLUSION: Future research is needed to assess the effects of a combined lifestyle intervention in this group. PMID- 27125994 TI - Criteria and Concurrent Validity of DIVA 2.0: A Semi-Structured Diagnostic Interview for Adult ADHD. AB - OBJECTIVE: The aim of this study was to assess for the first time the criterion validity of the semi-structured Diagnostic Interview for ADHD in adults (DIVA 2.0), and its concurrent validity in comparison with the Conners' Adult ADHD Diagnostic Interview for DSM-IV (CAADID) and other ADHD severity scales, following the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM IV) criteria. METHOD: A transversal study was performed on 40 out-patients with ADHD to check the criteria and concurrent validity of the DIVA 2.0 compared with the CAADID. RESULTS: The DIVA 2.0 interview showed a diagnostic accuracy of 100% when compared with the diagnoses obtained with the CAADID interview. The concurrent validity demonstrated good correlations with three self-reported rating scales: the Wender Utah Rating Scale (WURS; r = .544, p < .0001), the ADHD Rating Scale (r = .720, p < .0001), and Sheehan's Dysfunction Inventory (r = .674, p < .0001). CONCLUSION: The DIVA 2.0 is a reliable tool for assessing and diagnosing Adult ADHD and is the only one that offers free online access for clinical and research purposes. PMID- 27125997 TI - Determination of Hydrocarbon Group-Type of Diesel Fuels by Gas Chromatography with Vacuum Ultraviolet Detection. AB - A GC-vacuum ultraviolet (UV) method to perform group-type separations of diesel range fuels was developed. The method relies on an ionic liquid column to separate diesel samples into saturates, mono-, di-, and polyaromatics by gas chromatography, with selective detection via vacuum UV absorption spectroscopy. Vacuum UV detection was necessary to solve a coelution between saturates and monoaromatics. The method was used to measure group-type composition of 10 oilsands-derived Synfuel light diesel samples, 3 Syncrude light gas oils, and 1 quality control sample. The gas chromatography (GC)-vacuum UV results for the Synfuel samples were similar (absolute % error of 0.8) to historical results from the supercritical fluid chromatography (SFC) analysis. For the light gas oils, discrepancies were noted between SFC results and GC-vacuum UV results; however, these samples are known to be challenging to quantify by SFC-flame ionization detector (FID) due to incomplete resolution between the saturate/monoaromatic and/or monoaromatic/diaromatic group types when applied to samples heavier than diesel (i.e., having a larger fraction of higher molecular weight species). The quality control sample also performed well when comparing both methods (absolute % error of 0.2) and the results agreed within error for saturates, mono- and polyaromatics. PMID- 27125995 TI - Predicting the geographical distributions of the macaque hosts and mosquito vectors of Plasmodium knowlesi malaria in forested and non-forested areas. AB - BACKGROUND: Plasmodium knowlesi is a zoonotic pathogen, transmitted among macaques and to humans by anopheline mosquitoes. Information on P. knowlesi malaria is lacking in most regions so the first step to understand the geographical distribution of disease risk is to define the distributions of the reservoir and vector species. METHODS: We used macaque and mosquito species presence data, background data that captured sampling bias in the presence data, a boosted regression tree model and environmental datasets, including annual data for land classes, to predict the distributions of each vector and host species. We then compared the predicted distribution of each species with cover of each land class. RESULTS: Fine-scale distribution maps were generated for three macaque host species (Macaca fascicularis, M. nemestrina and M. leonina) and two mosquito vector complexes (the Dirus Complex and the Leucosphyrus Complex). The Leucosphyrus Complex was predicted to occur in areas with disturbed, but not intact, forest cover (> 60% tree cover) whereas the Dirus Complex was predicted to occur in areas with 10-100% tree cover as well as vegetation mosaics and cropland. Of the macaque species, M. nemestrina was mainly predicted to occur in forested areas whereas M. fascicularis was predicted to occur in vegetation mosaics, cropland, wetland and urban areas in addition to forested areas. CONCLUSIONS: The predicted M. fascicularis distribution encompassed a wide range of habitats where humans are found. This is of most significance in the northern part of its range where members of the Dirus Complex are the main P. knowlesi vectors because these mosquitoes were also predicted to occur in a wider range of habitats. Our results support the hypothesis that conversion of intact forest into disturbed forest (for example plantations or timber concessions), or the creation of vegetation mosaics, will increase the probability that members of the Leucosphyrus Complex occur at these locations, as well as bringing humans into these areas. An explicit analysis of disease risk itself using infection data is required to explore this further. The species distributions generated here can now be included in future analyses of P. knowlesi infection risk. PMID- 27125996 TI - Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic chemotherapy: an innovative approach to treat peritoneal carcinomatosis. AB - BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new treatment that applies chemotherapeutic drugs into the peritoneal cavity as an aerosol under pressure. It improves local bioavailability of chemotherapeutic drugs as compared with conventional intraperitoneal chemotherapy. It has been proved to be safe and feasible if performed as an exclusive treatment in patients affected by peritoneal carcinomatosis. The first results in patients treated with PIPAC associated with systemic chemotherapy are presented. METHODS: Between June 2015 and February 2016, 57 PIPAC applications with oxaliplatin or cisplatin + doxorubicin every 6 weeks at 37 degrees C and 12 mmHg for 30 min were performed. Forty PIPAC procedures performed in 14 patients were included in this study; thirteen patients were undergoing systemic chemotherapy with a wash-out interval of at least 2 weeks before and 1 week after each PIPAC. Safety, tolerability, and postoperative complications were assessed by collection of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) 2. RESULTS: Forty PIPAC administrations were performed in 14 patients with no major perioperative complications. CTCAE grades 1 and 2 were observed after six and eight procedures, respectively, for abdominal pain and nausea. Renal and hepatic functions were not impaired; no cumulative renal toxicity was observed after repeated PIPAC procedures in association with systemic chemotherapy. CONCLUSIONS: These preliminary data show that the association of PIPAC and systemic chemotherapy does not induce significant hepatic and renal toxicity. It allows inclusion of patients with extraperitoneal disease or at a high risk of developing it. Further studies are needed to assess whether this combination therapy could become part of the standard treatment for peritoneal carcinomatosis. PMID- 27125998 TI - Pumping Electron-Positron Pairs from a Well Potential. AB - In the presence of very deep well potential, electrons will spontaneously occupy the empty embedded bound states and electron-positron pairs are created by means of a non-perturbative tunneling process. In this work, by slowly oscillating the width or depth, the population transfer channels are opened and closed periodically. We find and clearly show that by the non-synchronous ejections of particles, the saturation of pair number in a static super-critical well can be broken, and electrons and positrons can be pumped inexhaustibly from vacuum with a constant production rate. In the adiabatic limit, final pair number after a single cycle has quantized values as a function of the upper boundary of the oscillating, and the critical upper boundaries indicate the diving points of the bound states. PMID- 27125999 TI - Drosha and Dicer: Slicers cut from the same cloth. AB - DROSHA and its partner DGCR8 form a heterotrimeric complex named Microprocessor, which is essential for microRNA biogenesis. A recent study by Kwon et al. in Cell reveals the structure of a DROSHA construct in complex with the C-terminal region of DGCR8, thereby unveiling the topology and interactions between components of the Microprocessor and insights into its 'ruler'-based cleavage activity and function. PMID- 27126001 TI - Utilization of health-care services among immigrants recruited through non-profit organizations in southern Italy. AB - OBJECTIVES: The study aims were focused on acquiring information about access to health-care services and to investigate the potential barriers affecting full access to health-care services. METHODS: The study population consisted of immigrants and refugees aged 18 or more living in Italy for at least 12 months recruited through non-profit organizations. RESULTS: 961 immigrants took part in the study, with a response rate of 98.9 %. Of the participants, 85 % had access to a general practitioner (GP) at least once, and 46.6 and 22.4 % mentioned a minimum one emergency visit and hospital stay, respectively. Diagnostic procedures and/or drug prescriptions (49.7 %), chronic disease control (15.8 %), and preventive interventions (13 %) were the most reported reasons for GP access. CONCLUSIONS: This study yielded current and broader insight into the model of health-care utilization among immigrants. The findings adds to our understanding of the third-sector organizations' role in facilitating immigrants' access to services offered by the Italian National Health Service, contributing to the extensive discussion on how to best manage migrant health care in Italy. PMID- 27126000 TI - Cdh1 regulates craniofacial development via APC-dependent ubiquitination and activation of Goosecoid. AB - Craniofacial anomalies (CFAs) characterized by birth defects of skull and facial bones are the most frequent congenital disease. Genomic analysis has identified multiple genes responsible for CFAs; however, the underlying genetic mechanisms for the majority of CFAs remain largely unclear. Our previous study revealed that the Wwp2 E3 ubiquitin ligase facilitates craniofacial development in part through inducing monoubiquitination and activation of the paired-like homeobox transcription factor, Goosecoid (Gsc). Here we report that Gsc is also ubiquitinated and activated by the APC(Cdh1) E3 ubiquitin ligase, leading to transcriptional activation of various Gsc target genes crucial for craniofacial development. Consistenly, neural crest-specific Cdh1-knockout mice display similar bone malformation as Wwp2-deficient mice in the craniofacial region, characterized by a domed skull, a short snout and a twisted nasal bone. Mechanistically, like Wwp2-deficient mice, mice with Cdh1 deficiency in neural crest cells exhibit reduced Gsc/Sox6 transcriptional activities. Simultaneous deletion of Cdh1 and Wwp2 results in a more severe craniofacial defect compared with single gene deletion, suggesting a synergistic augmentation of Gsc activity by these two E3 ubiquitin ligases. Hence, our study reveals a novel role for Cdh1 in craniofacial development through promoting APC-dependent non-proteolytic ubiquitination and activation of Gsc. PMID- 27126002 TI - White matter microstructure from nonparametric axon diameter distribution mapping. AB - We report the development of a double diffusion encoding (DDE) MRI method to estimate and map the axon diameter distribution (ADD) within an imaging volume. A variety of biological processes, ranging from development to disease and trauma, may lead to changes in the ADD in the central and peripheral nervous systems. Unlike previously proposed methods, this ADD experimental design and estimation framework employs a more general, nonparametric approach, without a priori assumptions about the underlying form of the ADD, making it suitable to analyze abnormal tissue. In the current study, this framework was used on an ex vivo ferret spinal cord, while emphasizing the way in which the ADD can be weighted by either the number or the volume of the axons. The different weightings, which result in different spatial contrasts, were considered throughout this work. DDE data were analyzed to derive spatially resolved maps of average axon diameter, ADD variance, and extra-axonal volume fraction, along with a novel sub-micron restricted structures map. The morphological information contained in these maps was then used to segment white matter into distinct domains by using a proposed k means clustering algorithm with spatial contiguity and left-right symmetry constraints, resulting in identifiable white matter tracks. The method was validated by comparing histological measures to the estimated ADDs using a quantitative similarity metric, resulting in good agreement. With further acquisition acceleration and experimental parameters adjustments, this ADD estimation framework could be first used preclinically, and eventually clinically, enabling a wide range of neuroimaging applications for improved understanding of neurodegenerative pathologies and assessing microstructural changes resulting from trauma. PMID- 27126004 TI - Rare vulvar malignancies; incidence, treatment and survival in the Netherlands. AB - OBJECTIVE: To describe trends in incidence, treatment and survival of patients with basal cell carcinomas and melanomas of the vulva. Also to compare survival of vulvar and cutaneous melanoma patients. METHODS: All women with a vulvar malignancy between 1989 and 2012 were selected from the Dutch Cancer Registry (n=6436). Standardized incidence rates, estimated annual percentage change (EAPC) and 5-year relative survival rates were calculated for basal cell carcinomas (BCCs) and melanomas. Patients with vulvar melanomas were matched to women with cutaneous melanomas on period of diagnosis, age, Breslow thickness, tumour ulceration, lymph node status and distant metastases. Differences in survival were evaluated using Kaplan-Meier curves and the log rank test. RESULTS: 489 women were diagnosed with a BCC and 350 with a melanoma of the vulva. The EAPC in incidence for melanomas was 0.2% and 1.1% for BCCs. Eighty-six percent of patients with BCC underwent surgical treatment in 1989-2006 and 95% in 2005-2012. Forty-five percent with BCC and 79% with melanoma were treated in a referral centre. Five-year relative survival for BCCs was 100% and for melanomas survival increased from 37% (95%CI 28-47%) in 1989-1999 to 45% (95%CI: 37-54%) in 2000 2012. Five years after diagnosis survival of women with vulvar melanoma was 15% lower compared to matched cutaneous melanoma patients (p=0.002). CONCLUSION: No trends in age-adjusted incidence have been observed but more patients with BCC received surgical treatment over time. Having had vulvar BCC did not affect life expectancy. Well-known prognostic factors explained most of the differences in survival between cutaneous and vulvar melanoma patients, however a difference of 15% remained unexplained. PMID- 27126003 TI - A dual but asymmetric role of the dorsal anterior cingulate cortex in response inhibition and switching from a non-salient to salient action. AB - Response inhibition and salience detection are among the most studied psychological constructs of cognitive control. Despite a growing body of work, how inhibition and salience processing interact and engage regional brain activations remains unclear. Here, we examined this issue in a stop signal task (SST), where a prepotent response needs to be inhibited to allow an alternative, less dominant response. Sixteen adult individuals performed two versions of the SST each with 25% (SST25) and 75% (SST75) of stop trials. We posited that greater regional activations to the infrequent trial type in each condition (i.e., to stop as compared to go trials in SST25 and to go as compared to stop trials in SST75) support salience detection. Further, successful inhibition in stop trials requires attention to the stop signal to trigger motor inhibition, and the stop signal reaction time (SSRT) has been used to index the efficiency of motor response inhibition. Therefore, greater regional activations to stop as compared to go success trials in association with the stop signal reaction time (SSRT) serve to expedite response inhibition. In support of an interactive role, the dorsal anterior cingulate cortex (dACC) increases activation to salience detection in both SST25 and SST75, but only mediates response inhibition in SST75. Thus, infrequency response in the dACC supports motor inhibition only when stopping has become a routine. In contrast, although the evidence is less robust, the pre-supplementary motor area (pre-SMA) increases activity to the infrequent stimulus and supports inhibition in both SST25 and SST75. These findings clarify a unique role of the dACC and add to the literature that distinguishes dACC and pre-SMA functions in cognitive control. PMID- 27126005 TI - Comparison of cytology, HPV DNA testing and HPV 16/18 genotyping alone or combined targeting to the more balanced methodology for cervical cancer screening. AB - OBJECTIVES: The objective of the present study was to identify the most effective cervical cancer screening algorithm incorporating different combinations of cytology, HPV testing and genotyping. METHODS: Women 25-55years old recruited for the "HERMES" (HEllenic Real life Multicentric cErvical Screening) study were screened in terms of cytology and high-risk (hr) HPV testing with HPV 16/18 genotyping. Women positive for cytology or/and hrHPV were referred for colposcopy, biopsy and treatment. Ten screening algorithms based on different combinations of cytology, HPV testing and HPV 16/18 genotyping were investigated in terms of diagnostic accuracy. RESULTS: Three clusters of algorithms were formed according to the balance between effectiveness and harm caused by screening. The cluster showing the best balance included two algorithms based on co-testing and two based on HPV primary screening with HPV 16/18 genotyping. Among these, hrHPV testing with HPV 16/18 genotyping and reflex cytology (atypical squamous cells of undetermined significance - ASCUS threshold) presented the optimal combination of sensitivity (82.9%) and specificity relative to cytology alone (0.99) with 1.26 false positive rate relative to cytology alone. CONCLUSION: HPV testing with HPV 16/18 genotyping, referring HPV 16/18 positive women directly to colposcopy, and hrHPV (non 16/18) positive women to reflex cytology (ASCUS threshold), as a triage method to colposcopy, reflects the best equilibrium between screening effectiveness and harm. Algorithms, based on cytology as initial screening method, on co-testing or HPV primary without genotyping, and on HPV primary with genotyping but without cytology triage, are not supported according to the present analysis. PMID- 27126007 TI - Multivariate Optimization of Rizatriptan Benzoate-Loaded Solid Lipid Nanoparticles for Brain Targeting and Migraine Management. AB - The present investigation aimed at development of brain-targeted rizatriptan benzoate-loaded solid lipid nanoparticles (RB-SLNs) by design of experiment, for improvement of its anti-migraine potential. Several formulation variables affecting the fabrication of RB-SLNs were screened using the Plackett-Burman design (PBD). The PBD results demonstrated lipid (Precirol(r) ATO 5) concentration, co-surfactant (Phospholipon(r) 90 H) concentration and temperature of lipid melt to be the critical variables, having a significant effect on the achievement of minimum particle size, maximum entrapment efficiency coupled with sustained drug release. The interactions between these formulation parameters and the variability between the batches were further explored employing the Box Behnken design (BBD). The BBD results were validated by fabricating the suggested optimized solution, which yielded 220.4 +/- 2.3 nm particle size with a sufficiently high entrapment efficiency of 71.8 +/- 1.9% and 45.9 +/- 2.7% cumulative drug release in 8 h. The optimized formulation was, thereafter, characterized by FTIR spectroscopy, wide angle XRD, thermal analysis and TEM imaging technique. The in vivo studies revealed the brain uptake potential of optimized RB-SLNs to be 18.43-folds higher with respect to the pure drug in its free form, post 2 h of oral drug administration. The significant anti-migraine efficacy of RB-SLNs was corroborated through the pharmacodynamic studies on adult male Swiss albino mice. The results hence explicate that RB-SLNs have distinctly improved brain target ability and offer an apt approach for the efficient therapeutic management of migraine. PMID- 27126006 TI - Preparation and Evaluations of Mangiferin-Loaded PLGA Scaffolds for Alveolar Bone Repair Treatment Under the Diabetic Condition. AB - The aim of the present study was to prepare and evaluate a sustained-release mangiferin scaffold for improving alveolar bone defect repair in diabetes. Mangiferin-loaded poly(D,L-lactide-co-glycolide) (PLGA) scaffolds were prepared using a freeze-drying technique with ice particles as the porogen material. The produced scaffolds were examined using a scanning electron microscope (SEM). Drug content and drug release were detected using a spectrophotometer. Degradation behaviors were monitored as a measure of weight loss and examined using SEM. Then, the scaffolds were incubated with rat bone marrow stromal cells under the diabetic condition in vitro, and cell viability was assessed using an 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Afterward, the scaffolds were implanted into alveolar bone defects of diabetic rats, and bone repair was examined using hematoxylin and eosin staining. The fabricated scaffolds showed porous structures, with average pore size range from 111.35 to 169.45 MUm. A higher PLGA concentration led to decreased average pore size. A lower PLGA concentration or a higher mangiferin concentration resulted in increased drug content. The prepared scaffolds released mangiferin in a sustained manner with relatively low initial burst during 10 weeks. Their degradation ratios gradually increased as degradation proceeded. The mangiferin-loaded scaffolds attenuated cell viability decrease under the diabetic condition in vitro. Moreover, they increased histological scorings of bone regeneration and improved delayed alveolar bone defect healing in diabetic rats. These results suggest that the produced mangiferin-loaded scaffolds may provide a potential approach in the treatment of impaired alveolar bone healing in diabetes. PMID- 27126008 TI - Development of Clotrimazole Multiple W/O/W Emulsions as Vehicles for Drug Delivery: Effects of Additives on Emulsion Stability. AB - Multiple emulsions have attracted considerable attention in recent years for application as potential delivery systems for different drugs. The aim of the present work is to design a new formulation containing clotrimazole (CLT) loaded into multiple emulsions by two-step emulsification method for transdermal delivery. Different ingredients and quantities like primary and secondary co emulsifiers and the nature of oily phase were assayed in order to optimize the best system for good. Resulting formulations were characterized in terms of droplet size, conductivity, pH, entrapment efficiency, rheological behavior, and stability under various storage conditions for 180 days. pH values of multiple emulsions containing CLT ranged from 7.04 +/- 0.03 to 6.23 +/- 0.04. Droplet size increased when increasing concentration of sorbitan stearate. The addition of polysorbate 80 resulted in significant decrease of oil droplet size comparing with those prepared without this. CLT entrapment efficiency ranged between 85.64% and 97.47%. All formulations exhibited non-Newtonian pseudoplastic flow with some apparent thixotropic behavior. Cross and Herschel-Bulkley equations were the models that best fitted experimental data. In general, the addition of 1% polysorbate 80 resulted in a decrease of viscosity values. No signals of optical instability were observed, and physicochemical properties remained almost constant when samples were stored at room temperature after 180 days. On the contrary, samples stored at 40 degrees C exhibited pronounced increase in conductivity values 24 h after elaboration and some of them were unstable after 180 days of storage. JMLP01 was proposed as an innovative and stable system to incorporate CLT as active pharmaceutical ingredient. PMID- 27126009 TI - Continuous monitoring of caspase-3 activation induced by propofol in developing mouse brain. AB - The neurotoxicity of anesthetics on the developing brain has drawn the attention of anesthesiologists. Several studies have shown that apoptosis is enhanced by exposure to anesthesia during brain development. Although apoptosis is a physiological developmental step occurring before the maturation of neural networks and the integration of brain function, pathological damage also involves apoptosis. Previous studies have shown that prolonged exposure to anesthetics causes apoptosis. Exactly when the apoptotic cascade starts in the brain remains uncertain. If it starts during the early stage of anesthesia, even short-term anesthesia could harm the brain. Therefore, apoptogenesis should be continuously monitored to elucidate when the apoptotic cascade is triggered by anesthesia. Here, we describe the development of a continuous monitoring system to detect caspase-3 activation using an in vivo model. Brain slices from postnatal days 0-4 SCAT3 transgenic mice with a heterozygous genotype (n=20) were used for the monitoring of caspase-3 cleavage. SCAT3 is a fusion protein of ECFP and Venus connected by a caspase-3 cleavable peptide, DEVD. A specimen from the hippocampal CA1 sector was mounted on a confocal laser microscope and was continuously superfused with artificial cerebrospinal fluid, propofol (2,6-diisopropylphenol, 1MUM or 10MUM), and dimethyl sulfoxide. Images were obtained every hour for five hours. A pixel analysis of the ECFP/Venus ratio images was performed using a histogram showing the number of pixels with each ratio. In the histogram of the ECFP/Venus ratio, an area with a ratio>1 indicated the number of pixels from caspase-3-activated CA1 neurons. We observed a shift in the histogram toward the right over time, indicating caspase-3 activation. This right-ward shift dramatically changed at five hours in the propofol 1MUM and 10MUM groups and was obviously different from that in the control group. Thus, real-time fluorescence energy transfer (FRET) imaging was capable of identifying the onset of apoptosis triggered by propofol in neonatal brain slices. This model may be a useful tool for monitoring apoptogenesis in the developing brain. PMID- 27126011 TI - Prosecution of US psychologists who ran CIA torture program moves a step closer. PMID- 27126012 TI - My love-hate of Sci-Hub. PMID- 27126010 TI - Ethnic and Gender Differences in Help Seeking for Substance Disorders Among Black Americans. AB - This paper uses the National Survey of American Life (NSAL) to examine within group differences regarding help-seeking for substance disorders among a US sample of African American and Caribbean Black men and women. We examined ethnic and gender differences in the type of providers sought for substance disorder treatment, as well as reasons for avoiding treatment. Results indicate that overall, few ethnic differences exist; however, African Americans are more likely than Caribbean Blacks to seek help from human service professionals (including a religious or spiritual advisor) and from informal sources of treatment such as self-help groups. Black men with a substance disorder were more likely to see a psychiatrist than Black women. Findings regarding reasons for avoiding treatment suggest that there may be a need to provide better education about the utility of substance disorder treatment, even before problems reach a high level of severity. PMID- 27126014 TI - ANCIENT DNA. How Europe exported the Black Death. PMID- 27126015 TI - ARMS CONTROL. Critics complain as U.S. shops in Iran's nuclear bazaar. PMID- 27126017 TI - ASTRONOMY. Kepler enlists relativity to find planets. PMID- 27126016 TI - SCIENTIFIC COMMUNITY. Saying no to harassment. PMID- 27126018 TI - INFECTIOUS DISEASE. Scandal clouds China's global vaccine ambitions. PMID- 27126019 TI - BRAIN DRAIN. Mexico struggles to woo expat genome jocks. PMID- 27126021 TI - The frustrated science student behind Sci-Hub. PMID- 27126020 TI - Who's downloading pirated papers? Everyone. PMID- 27126022 TI - PHYSICAL BIOLOGY. A fresh eye on nonequilibrium systems. PMID- 27126023 TI - CELL SIGNALING. Liquidity in immune cell signaling. PMID- 27126024 TI - NEUROSCIENCE. Ionic control of sleep and wakefulness. PMID- 27126025 TI - BIOCHEMISTRY. A bacterial oxidase like no other? PMID- 27126026 TI - SYNTHETIC FOLDAMERS. Light flips a membrane-embedded helix. PMID- 27126027 TI - INTELLECTUAL PROPERTY AND INNOVATION. The growing problem of patent trolling. PMID- 27126028 TI - Wolbachia mosquito control: Tested. PMID- 27126029 TI - Wolbachia mosquito control: Regulated. PMID- 27126030 TI - Comment on "Extended-resolution structured illumination imaging of endocytic and cytoskeletal dynamics". AB - Li et al (Research Articles, 28 August 2015, aab3500) purport to present solutions to long-standing challenges in live-cell microscopy, reporting relatively fast acquisition times in conjunction with improved image resolution. We question the methods' reliability to visualize specimen features at sub-100 nanometer scales, because the mandatory mathematical processing of the recorded data leads to artifacts that are either difficult or impossible to disentangle from real features. We are also concerned about the chosen approach of subjectively comparing images from different super-resolution methods, as opposed to using quantitative measures. PMID- 27126031 TI - Response to Comment on "Extended-resolution structured illumination imaging of endocytic and cytoskeletal dynamics". AB - Sahl et al in their Comment raise criticisms of our work that fall into three classes: image artifacts, resolution criteria, and comparative performance on live cells. We explore each of these in turn. PMID- 27126032 TI - Online buzz: Bureaucracy or accountability? PMID- 27126033 TI - Manipulating the Microbiota. PMID- 27126034 TI - Cross-species comparisons of host genetic associations with the microbiome. AB - Recent studies in human populations and mouse models reveal notable congruences in gut microbial taxa whose abundances are partly regulated by host genotype. Host genes associating with these taxa are related to diet sensing, metabolism, and immunity. These broad patterns are further validated in similar studies of nonmammalian microbiomes. The next generation of genome-wide association studies will expand the size of the data sets and refine the microbial phenotypes to fully capture these intriguing signatures of host-microbiome coevolution. PMID- 27126035 TI - Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. AB - The intestinal microbiota, which is composed of diverse populations of commensal bacterial species, provides resistance against colonization and invasion by pathogens. Antibiotic treatment can damage the intestinal microbiota and, paradoxically, increase susceptibility to infections. Reestablishing microbiota mediated colonization resistance after antibiotic treatment could markedly reduce infections, particularly those caused by antibiotic-resistant bacteria. Ongoing studies are identifying commensal bacterial species that can be developed into next-generation probiotics to reestablish or enhance colonization resistance. These live medicines are at various stages of discovery, testing, and production and are being subjected to existing regulatory gauntlets for eventual introduction into clinical practice. The development of next-generation probiotics to reestablish colonization resistance and eliminate potential pathogens from the gut is warranted and will reduce health care-associated infections caused by highly antibiotic-resistant bacteria. PMID- 27126037 TI - Antibiotic use and its consequences for the normal microbiome. AB - Anti-infectives, including antibiotics, are essentially different from all other drugs; they not only affect the individual to whom they are given but also the entire community, through selection for resistance to their own action. Thus, their use resides at the intersection of personal and public health. Antibiotics can be likened to a four-edged sword against bacteria. The first two edges of the antibiotic sword were identified immediately after their discovery and deployment in that they not only benefit an individual in treating their infection but also benefit the community in preventing the spread of that infectious agent. The third edge was already recognized by Alexander Fleming in 1945 in his Nobel acceptance speech, which warned about the cost to the community of antibiotic resistance that would inevitably evolve and be selected for during clinical practice. We have seen this cost mount up, as resistance curtails or precludes the activities of some of our most effective drugs for clinically important infections. But the fourth edge of the antibiotic sword remained unappreciated until recently, i.e., the cost that an antibiotic exerts on an individual's own health via the collateral damage of the drug on bacteria that normally live on or in healthy humans: our microbiota. These organisms, their genes, metabolites, and interactions with one another, as well as with their host collectively, represent our microbiome. Our relationship with these symbiotic bacteria is especially important during the early years of life, when the adult microbiome has not yet formed. PMID- 27126036 TI - How colonization by microbiota in early life shapes the immune system. AB - Microbial colonization of mucosal tissues during infancy plays an instrumental role in the development and education of the host mammalian immune system. These early-life events can have long-standing consequences: facilitating tolerance to environmental exposures or contributing to the development of disease in later life, including inflammatory bowel disease, allergy, and asthma. Recent studies have begun to define a critical period during early development in which disruption of optimal host-commensal interactions can lead to persistent and in some cases irreversible defects in the development and training of specific immune subsets. Here, we discuss the role of early-life education of the immune system during this "window of opportunity," when microbial colonization has a potentially critical impact on human health and disease. PMID- 27126038 TI - Changes in the composition of brain interstitial ions control the sleep-wake cycle. AB - Wakefulness is driven by the widespread release of neuromodulators by the ascending arousal system. Yet, it is unclear how these substances orchestrate state-dependent, global changes in neuronal activity. Here, we show that neuromodulators induce increases in the extracellular K(+) concentration ([K(+)]e) in cortical slices electrically silenced by tetrodotoxin. In vivo, arousal was linked to AMPA receptor-independent elevations of [K(+)]e concomitant with decreases in [Ca(2+)]e, [Mg(2+)]e, [H(+)]e, and the extracellular volume. Opposite, natural sleep and anesthesia reduced [K(+)]e while increasing [Ca(2+)]e, [Mg(2+)]e, and [H(+)]e as well as the extracellular volume. Local cortical activity of sleeping mice could be readily converted to the stereotypical electroencephalography pattern of wakefulness by simply imposing a change in the extracellular ion composition. Thus, extracellular ions control the state-dependent patterns of neural activity. PMID- 27126039 TI - Population-level analysis of gut microbiome variation. AB - Fecal microbiome variation in the average, healthy population has remained under investigated. Here, we analyzed two independent, extensively phenotyped cohorts: the Belgian Flemish Gut Flora Project (FGFP; discovery cohort; N = 1106) and the Dutch LifeLines-DEEP study (LLDeep; replication; N = 1135). Integration with global data sets (N combined = 3948) revealed a 14-genera core microbiota, but the 664 identified genera still underexplore total gut diversity. Sixty-nine clinical and questionnaire-based covariates were found associated to microbiota compositional variation with a 92% replication rate. Stool consistency showed the largest effect size, whereas medication explained largest total variance and interacted with other covariate-microbiota associations. Early-life events such as birth mode were not reflected in adult microbiota composition. Finally, we found that proposed disease marker genera associated to host covariates, urging inclusion of the latter in study design. PMID- 27126041 TI - Kinetically controlled E-selective catalytic olefin metathesis. AB - A major shortcoming in olefin metathesis, a chemical process that is central to research in several branches of chemistry, is the lack of efficient methods that kinetically favor E isomers in the product distribution. Here we show that kinetically E-selective cross-metathesis reactions may be designed to generate thermodynamically disfavored alkenyl chlorides and fluorides in high yield and with exceptional stereoselectivity. With 1.0 to 5.0 mole % of a molybdenum-based catalyst, which may be delivered in the form of air- and moisture-stable paraffin pellets, reactions typically proceed to completion within 4 hours at ambient temperature. Many isomerically pure E-alkenyl chlorides, applicable to catalytic cross-coupling transformations and found in biologically active entities, thus become easily and directly accessible. Similarly, E-alkenyl fluorides can be synthesized from simpler compounds or more complex molecules. PMID- 27126042 TI - Pressure-dependent isotopic composition of iron alloys. AB - Our current understanding of Earth's core formation is limited by the fact that this profound event is far removed from us physically and temporally. The composition of the iron metal in the core was a result of the conditions of its formation, which has important implications for our planet's geochemical evolution and physical history. We present experimental and theoretical evidence for the effect of pressure on iron isotopic composition, which we found to vary according to the alloy tested (FeO, FeH(x), or Fe3C versus pure Fe). These results suggest that hydrogen or carbon is not the major light-element component in the core. The pressure dependence of iron isotopic composition provides an independent constraint on Earth's core composition. PMID- 27126040 TI - Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. AB - Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors. These factors collectively explain 18.7% of the variation seen in the interindividual distance of microbial composition. We could associate 110 factors to 125 species and observed that fecal chromogranin A (CgA), a protein secreted by enteroendocrine cells, was exclusively associated with 61 microbial species whose abundance collectively accounted for 53% of microbial composition. Low CgA concentrations were seen in individuals with a more diverse microbiome. These results are an important step toward a better understanding of environment-diet-microbe-host interactions. PMID- 27126043 TI - Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. AB - The cytochrome bd oxidases are terminal oxidases that are present in bacteria and archaea. They reduce molecular oxygen (dioxygen) to water, avoiding the production of reactive oxygen species. In addition to their contribution to the proton motive force, they mediate viability under oxygen-related stress conditions and confer tolerance to nitric oxide, thus contributing to the virulence of pathogenic bacteria. Here we present the atomic structure of the bd oxidase from Geobacillus thermodenitrificans, revealing a pseudosymmetrical subunit fold. The arrangement and order of the heme cofactors support the conclusions from spectroscopic measurements that the cleavage of the dioxygen bond may be mechanistically similar to that in the heme-copper-containing oxidases, even though the structures are completely different. PMID- 27126044 TI - Durable coexistence of donor and recipient strains after fecal microbiota transplantation. AB - Fecal microbiota transplantation (FMT) has shown efficacy in treating recurrent Clostridium difficile infection and is increasingly being applied to other gastrointestinal disorders, yet the fate of native and introduced microbial strains remains largely unknown. To quantify the extent of donor microbiota colonization, we monitored strain populations in fecal samples from a recent FMT study on metabolic syndrome patients using single-nucleotide variants in metagenomes. We found extensive coexistence of donor and recipient strains, persisting 3 months after treatment. Colonization success was greater for conspecific strains than for new species, the latter falling within fluctuation levels observed in healthy individuals over a similar time frame. Furthermore, same-donor recipients displayed varying degrees of microbiota transfer, indicating individual patterns of microbiome resistance and donor-recipient compatibilities. PMID- 27126045 TI - Slow waves, sharp waves, ripples, and REM in sleeping dragons. AB - Sleep has been described in animals ranging from worms to humans. Yet the electrophysiological characteristics of brain sleep, such as slow-wave (SW) and rapid eye movement (REM) activities, are thought to be restricted to mammals and birds. Recording from the brain of a lizard, the Australian dragon Pogona vitticeps, we identified SW and REM sleep patterns, thus pushing back the probable evolution of these dynamics at least to the emergence of amniotes. The SW and REM sleep patterns that we observed in lizards oscillated continuously for 6 to 10 hours with a period of ~80 seconds. The networks controlling SW-REM antagonism in amniotes may thus originate from a common, ancient oscillator circuit. Lizard SW dynamics closely resemble those observed in rodent hippocampal CA1, yet they originate from a brain area, the dorsal ventricular ridge, that has no obvious hodological similarity with the mammalian hippocampus. PMID- 27126046 TI - RNA splicing is a primary link between genetic variation and disease. AB - Noncoding variants play a central role in the genetics of complex traits, but we still lack a full understanding of the molecular pathways through which they act. We quantified the contribution of cis-acting genetic effects at all major stages of gene regulation from chromatin to proteins, in Yoruba lymphoblastoid cell lines (LCLs). About ~65% of expression quantitative trait loci (eQTLs) have primary effects on chromatin, whereas the remaining eQTLs are enriched in transcribed regions. Using a novel method, we also detected 2893 splicing QTLs, most of which have little or no effect on gene-level expression. These splicing QTLs are major contributors to complex traits, roughly on a par with variants that affect gene expression levels. Our study provides a comprehensive view of the mechanisms linking genetic variation to variation in human gene regulation. PMID- 27126047 TI - Broken detailed balance at mesoscopic scales in active biological systems. AB - Systems in thermodynamic equilibrium are not only characterized by time independent macroscopic properties, but also satisfy the principle of detailed balance in the transitions between microscopic configurations. Living systems function out of equilibrium and are characterized by directed fluxes through chemical states, which violate detailed balance at the molecular scale. Here we introduce a method to probe for broken detailed balance and demonstrate how such nonequilibrium dynamics are manifest at the mesosopic scale. The periodic beating of an isolated flagellum from Chlamydomonas reinhardtii exhibits probability flux in the phase space of shapes. With a model, we show how the breaking of detailed balance can also be quantified in stationary, nonequilibrium stochastic systems in the absence of periodic motion. We further demonstrate such broken detailed balance in the nonperiodic fluctuations of primary cilia of epithelial cells. Our analysis provides a general tool to identify nonequilibrium dynamics in cells and tissues. PMID- 27126048 TI - The hidden perks of grad school. PMID- 27126049 TI - Erratum to: 'The orientation of transcription factor binding site motifs in gene promoter regions: does it matter?'. PMID- 27126050 TI - TD-DFT investigation of D-pi-A organic dyes with thiophene moieties as pi-spacers for use as sensitizers in DSSCs. AB - The geometrical, conformational, and electronic properties of a series of D-pi-A metal-free dyes designed for use as sensitizers in DSSCs were studied using DFT and TD-DFT methods. A substituted triphenylamine moiety was used as the donor group and 2-cyanoacrylic acid as the acceptor group in these dyes. They also contained conjugated bridging pi-linker groups containing two or more thiophene rings to enhance the intramolecular charge transfer. The B3LYP, M06-HF, omegaB97XD and CAM-B3LYP functionals were utilized in combination with the 6 31G(d,p) basis set for the calculations. The dye solvation process was taken into account via the polarizable continuum model. To rationalize the relationships between dye structure and the photochemical properties of the dyes when used as sensitizers in DSSCs, the vertical excitation energies, the light-harvesting efficiencies, the free-energy changes during the process of injecting an electron into the surface of a TiO2 nanocrystalline semiconductor, and the open-circuit potentials were calculated for all of the dyes in the solvent THF using the above methods. The results of these computations are discussed and compared with the available corresponding experimental data. PMID- 27126051 TI - Characterization of key triacylglycerol biosynthesis processes in rhodococci. AB - Oleaginous microorganisms have considerable potential for biofuel and commodity chemical production. Under nitrogen-limitation, Rhodococcus jostii RHA1 grown on benzoate, an analog of lignin depolymerization products, accumulated triacylglycerols (TAGs) to 55% of its dry weight during transition to stationary phase, with the predominant fatty acids being C16:0 and C17:0. Transcriptomic analyses of RHA1 grown under conditions of N-limitation and N-excess revealed 1,826 dysregulated genes. Genes whose transcripts were more abundant under N limitation included those involved in ammonium assimilation, benzoate catabolism, fatty acid biosynthesis and the methylmalonyl-CoA pathway. Of the 16 atf genes potentially encoding diacylglycerol O-acyltransferases, atf8 transcripts were the most abundant during N-limitation (~50-fold more abundant than during N-excess). Consistent with Atf8 being a physiological determinant of TAG accumulation, a Deltaatf8 mutant accumulated 70% less TAG than wild-type RHA1 while atf8 overexpression increased TAG accumulation 20%. Genes encoding type-2 phosphatidic acid phosphatases were not significantly expressed. By contrast, three genes potentially encoding phosphatases of the haloacid dehalogenase superfamily and that cluster with, or are fused with other Kennedy pathway genes were dysregulated. Overall, these findings advance our understanding of TAG metabolism in mycolic acid-containing bacteria and provide a framework to engineer strains for increased TAG production. PMID- 27126052 TI - High specificity of a novel Zika virus ELISA in European patients after exposure to different flaviviruses. AB - The current Zika virus (ZIKV) epidemic in the Americas caused an increase in diagnostic requests in European countries. Here we demonstrate high specificity of the Euroimmun anti-ZIKV IgG and IgM ELISA tests using putative cross-reacting sera of European patients with antibodies against tick-borne encephalitis virus, dengue virus, yellow fever virus and hepatitis C virus. This test may aid in counselling European travellers returning from regions where ZIKV is endemic. PMID- 27126053 TI - Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides. AB - A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of nitrogen without the requirement for either preactivation or for metal catalysts. Mixing ammonium salts with diacetoxyiodobenzene directly converts sulfoxides into sulfoximines. This report describes the first example of using of ammonia sources with diacetoxyiodobenzene to generate an electrophilic nitrogen center. Control and mechanistic studies suggest a short-lived electrophilic intermediate, which is likely to be PhINH or PhIN(+) . PMID- 27126055 TI - Is maternal smoking during pregnancy associated with an increased risk of congenital heart defects among offspring? A systematic review and meta-analysis of observational studies. AB - OBJECTIVE: To investigate the association between maternal smoking during pregnancy and risk of congenital heart defects (CHDs) among offspring. METHODS: PubMed, EMBASE, and Web of Science were searched for eligible studies. The outcomes of interest included risk of any CHD and nine subtypes. We summarized study characteristics and used a random-effects model in meta-analysis, and a two stage dose-response model was utilized to assess the association between smoking consumption and risk. Statistical heterogeneity was assessed by a chi-squared test of the Cochrane Q statistic and I-squared value. Publication bias was assessed by funnel plots and Egger's test, and trim and fill method was utilized when publication bias existed. RESULTS: Forty-three observational epidemiologic studies were included. The pooled risk ratio (RR) of any CHD was 1.11 (95% CI: 1.04, 1.18), but it exhibited substantial statistical heterogeneity (p < 0.001, I2 = 69.0%). In sensitivity analysis, we observed significant associations for atrial septal defect (ASD) and marginally significant associations for septal defects (SPD). The two-stage dose-response analysis showed evidence to support that higher levels of tobacco smoke was associated with an increased risk of septal defects, particularly for ASD and VSD (ventricular septal defect). CONCLUSION: Our study presents evidence to support the cardiovascular teratogenic effect of maternal smoking during pregnancy, and their offspring may suffer from approximately a 10% relative increase in the risk of CHDs on average. PMID- 27126054 TI - Preoperative Sarcopenia Strongly Influences the Risk of Postoperative Pancreatic Fistula Formation After Pancreaticoduodenectomy. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is a serious complication of pancreaticoduodenectomy (PD). Sarcopenia is a newly identified marker of frailty. We performed this study to assess whether preoperative sarcopenia has an impact on clinically relevant POPF formation. METHODS: A total of 266 consecutive patients who underwent a PD between 2010 and 2014 were enrolled in this retrospective study. Skeletal muscle mass was measured using preoperative computed tomography images. The impact of preoperative sarcopenia on clinically relevant POPF formation was analyzed using univariate and multivariate analyses. RESULTS: Of the 266 patients, 132 (49.6 %) were classified as having preoperative sarcopenia. The rate of clinically relevant POPF formation was significantly higher in the sarcopenia group (22.0 vs. 10.4 %; P = 0.011). A multivariate logistic regression analysis showed that sarcopenia (odds ratio, 2.869; P = 0.007) was an independent risk factor for the development of clinically relevant POPF, along with a soft pancreas and a parenchymal thickness at the pancreatic resection site of >=8 mm. CONCLUSIONS: Preoperative sarcopenia was identified as a strong and independent risk factor for clinically relevant POPF formation after PD. Perioperative rehabilitation and nutrition therapy may contribute to the prevention of POPF formation and a safer PD. PMID- 27126056 TI - Non-linear Optical Responses of Low-Density Lipoprotein are Associated with Intima-Media Thickness of Carotid Artery in Athletes. AB - We investigated the association between the degree of oxidative modification of LDL particles by non-linear optical response of LDL (Z-scan technique) and the presence of subclinical atherosclerosis in different segments of the carotid artery. We recruited high-intensity athlete runners (n = 44) and controls (n = 51) to participate in the study. The carotid intima-media thickness (cIMT), interleukin 10 (IL-10), TNF-alpha, and the non-linear optical responses of LDL particle (Z-scan) were assessed. In athletes, the mean cIMT differed between genders, with higher values observed in female athletes compared to male athletes (P < 0.05). Higher mean values for cIMT were seen in the right carotid arteries of female athletes as compared to female controls (P < 0.05). Higher levels of TNF-alpha and IL-10 were found in athletes (P < 0.05). Yet, DeltaGammapv (transmittance curve) of Z-scan in athletes was higher than in the non-athletes, indicating less oxidation in LDL particles of athletes (P < 0.05). There was an inverse association between the DeltaGammapv and cIMT in the right internal carotid segments (beta = -0.163, P < 0.05) in all subjects, and between the VO2max and the mean cIMT (beta = -0.003, P < 0.05) in male subjects. The present study shows that the Z-scan technique enabled to detect less oxidative modifications in LDL particles from athletes. This effect was associated with cIMT in a gender-dependent mode. PMID- 27126057 TI - Systemic and spinal administration of FAAH, MAGL inhibitors and dual FAAH/MAGL inhibitors produce antipruritic effect in mice. AB - The increase of endocannabinoid tonus by inhibiting fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) represents a promising therapeutic approach in a variety of disease to overcome serious central side effects of exocannabinoids. Recent studies reported that systemic administration of FAAH and MAGL inhibitors produce antipruritic action. Dual FAAH/MAGL inhibitors have also been described to get enhanced endocannabinoid therapeutic effect. In this study, we examined and compared dose-related antipruritic effects of systemic (intraperitoneal; ip) or intrathecal (it) administration of selective FAAH inhibitor PF-3845 (5, 10, and 20 mg/kg, i.p.; 1, 5, and 10 ug, i.t.), MAGL inhibitor JZL184 (4, 20, and 40 mg/kg, i.p.; 1, 5, and 10 ug, i.t.) and dual FAAH/MAGL inhibitor JZL195 (2, 5, and 20 mg/kg, i.p.; 1, 5, and 10 ug, i.t.) on serotonin (5-HT)-induced scratching model. Serotonin (25 MUg) was injected intradermally in a volume of 50 MUl into the rostral part of skin on the back of male Balb-C mice. Both systemic or intrathecal administration of PF-3845, JZL184 or JZL195 produced similar dose-dependent antipruritic effects. Our results suggest that endocannabinoid-degrading enzymes FAAH and MAGL are involved in pruritic process at spinal level. FAAH, MAGL or dual FAAH/MAGL inhibitors have promising antipruritic effects, at least, in part through spinal site of action. PMID- 27126058 TI - Escape to the high canopy-thermal deficiency causes niche expansion in a forest floor ant. AB - The small formicoxenine ant Temnothorax saxonicus was known from about 40 localities in Central Europe nesting in anorganic substrates on floor of xerothermous forests whereas investigations of 198 tree canopies in 19 forest sites of the same region provided no indication for arboreal nesting or foraging. We present the first evidence for canopy-nesting populations of T. saxonicus on old Quercus trees in 3 sites having maximum calibrated topsoil temperatures of 17.9 +/- 0.3 degrees C which were significantly (P < 0.007) lower than 22.8 +/- 2.0 degrees C measured in 5 sites with ground-nesting populations. The thermal deficit on forest floor inhibits brood development in ground nests and caused a moving to canopy were maximum calibrated temperatures of the, now wooden, substrates are at least 26.1 degrees C for the whole canopy and 30.8 degrees C in more sun-exposed spots. T. saxonicus competed here successfully with the obligatory canopy ants T. affinis and T. corticalis. The distributional data of this rope-climbing study support former results that highest nest densities of small arboreal ants occur in temperate climate over the entire canopy mantle of single trees situated in open land or in park-like environments but occur in the top of the canopy in tree stands with high degree of canopy closure. PMID- 27126059 TI - Effect of early treatment on physical function in daily management of rheumatoid arthritis: a 5-year longitudinal study of rheumatoid arthritis patients in the National Database of Rheumatic Diseases in Japan. AB - AIM: The purpose of this study was to assess 5-year changes in physical function and factors associated with improvement among patients with rheumatoid arthritis (RA) in daily clinical practice, focusing on the effect of treatments, including biologic agents, in the early stage of disease course. METHODS: The National Database of Rheumatic Diseases by iR-net in Japan (NinJa) was searched for patients with disease duration <= 2 years and modified health assessment questionnaire (mHAQ) > 0 between 2004 and 2007, so that 510 patients were included in the final analysis. Multivariate-logistic regression analyses were used to identify predictors of 5-year mHAQ disability score improvement. RESULTS: Median mHAQ score was 0.40 at baseline and decreased to a median 0.17 after 5 years. Seventy-four percent of the patients were treated with methotrexate (MTX) and 25% with biologic agents, with early use of biologic agents (within 2 years of RA onset) increasing over time. Multivariate analyses identified higher baseline Disease Activity Score of 28 joints - C-reactive protein and early use of MTX (within 1 year of RA onset) and of biologic agents (within 2 years) as significantly associated with improved mHAQ; odds ratios of the early treatment were 1.83 (P = 0.01) for MTX and 2.23 (P = 0.04) for biologic agents, respectively. CONCLUSION: Five-year mHAQ improved in early RA patients in the NinJa database. In daily clinical management of RA, likewise in clinical trials, early administration of MTX or biologic agents is able to improve physical function outcome. PMID- 27126060 TI - Sericin in the isolating solution improves the yield of islets isolated from the pancreas. AB - Approximately half of the transplantable pancreatic islet tissue is lost during isolation, including the digestion and purification steps. Modifying the isolation method could increase the yield. This would enable the one donor-one recipient concept and improve the therapeutic effects of islet transplantation. This study aims to improve islet transplantation by increasing the yield of islets from the pancreas, both the number of islets and their size. Therefore, we used a sericin-containing isolating solution. Rat pancreatic islets were isolated by collagenase digestion and hand picking. We refer to islets isolated with or without sericin in the isolation solution as the sericin and control group, respectively. Volume yield, endocrine function, and islet morphology were compared between the groups. Histological distribution of sericin was evaluated by immunofluorescence staining to examine its mechanism of action in pancreatic islets. The pancreatic islet yield in the sericin group was significantly higher than that in the control group. The endocrine function of islets in the sericin group was comparable to that of islets isolated by conventional methods. Sericin adhered to the surface of isolated pancreatic islets and colocalized with E cadherin, a cell membrane protein, which might explain the cytoprotective effects of sericin. The islet morphology tended to be better preserved in the sericin group. Sericin could prevent cytoarchitectural damage during the isolation and purification process, resulting in increased pancreatic islet yield. This suggests that sericin could contribute to islet therapy by enhancing the stability of islets. PMID- 27126061 TI - Aging affects postural tracking of complex visual motion cues. AB - Postural tracking of visual motion cues improves perception-action coupling in aging, yet the nature of the visual cues to be tracked is critical for the efficacy of such a paradigm. We investigated how well healthy older (72.45 +/- 4.72 years) and young (22.98 +/- 2.9 years) adults can follow with their gaze and posture horizontally moving visual target cues of different degree of complexity. Participants tracked continuously for 120 s the motion of a visual target (dot) that oscillated in three different patterns: a simple periodic (simulated by a sine), a more complex (simulated by the Lorenz attractor that is deterministic displaying mathematical chaos) and an ultra-complex random (simulated by surrogating the Lorenz attractor) pattern. The degree of coupling between performance (posture and gaze) and the target motion was quantified in the spectral coherence, gain, phase and cross-approximate entropy (cross-ApEn) between signals. Sway-target coherence decreased as a function of target complexity and was lower for the older compared to the young participants when tracking the chaotic target. On the other hand, gaze-target coherence was not affected by either target complexity or age. Yet, a lower cross-ApEn value when tracking the chaotic stimulus motion revealed a more synchronous gaze-target relationship for both age groups. Results suggest limitations in online visuo motor processing of complex motion cues and a less efficient exploitation of the body sway dynamics with age. Complex visual motion cues may provide a suitable training stimulus to improve visuo-motor integration and restore sway variability in older adults. PMID- 27126062 TI - The effect of two cryopreservation methods on human sperm DNA damage. AB - Several methods are currently available for selection when conducting sperm cryopreservation, however, these methods might cause different degrees of damage on sperm DNA. The aim of the this study is to compare the effects of storage at 80 degrees C (in ultra-low temperature refrigerator) and at -196 degrees C (in liquid nitrogen) on sperm DNA damage, thus to provide a reference for choosing the right method according to different aims. We randomly collected 28 semen samples from college students of Chongqing city. The samples stored at -80 degrees C were neat semen samples and the samples stored at -196 degrees C were mixed with additional cryoprotectants. Each sample was subjected to two freezing thawing cycles, and the sperm DNA damage levels of fresh and thawed samples were measured by single cell gel electrophoresis (SCGE) and sperm chromatin structure assay (SCSA). Both SCGE and SCSA assays showed cryopreservation induced significant damage to sperm DNA. However, storage at -196 degrees C lead to more severe damage to sperm DNA than storage at -80 degrees C measured by SCSA. Sperm DNA damage increased simultaneously with the higher frequency of freezing-thawing cycles. We concluded that storage of neat semen samples at -80 degrees C had milder damage to sperm DNA than storage at -196 degrees C mixed with cryoprotectants. To avoid additional sperm DNA damage, repeated freezing and thawing should be prevented. PMID- 27126064 TI - Ecological restoration alters microbial communities in mine tailings profiles. AB - Ecological restoration of mine tailings have impact on soil physiochemical properties and microbial communities. The surface soil has been a primary concern in the past decades, however it remains poorly understood about the adaptive response of microbial communities along the profile during ecological restoration of the tailings. In this study, microbial communities along a 60-cm profile were investigated in a mine tailing pond during ecological restoration of the bare waste tailings (BW) with two vegetated soils of Imperata cylindrica (IC) and Chrysopogon zizanioides (CZ) plants. Revegetation of both IC and CZ could retard soil degradation of mine tailing by stimulation of soil pH at 0-30 cm soils and altered the bacterial communities at 0-20 cm depths of the mine tailings. Significant differences existed in the relative abundance of the phyla Alphaproteobacteria, Deltaproteobacteria, Acidobacteria, Firmicutes and Nitrospira. Slight difference of bacterial communities were found at 30-60 cm depths of mine tailings. Abundance and activity analysis of nifH genes also explained the elevated soil nitrogen contents at the surface 0-20 cm of the vegetated soils. These results suggest that microbial succession occurred primarily at surface tailings and vegetation of pioneering plants might have promoted ecological restoration of mine tailings. PMID- 27126063 TI - Multiple Imputation based Clustering Validation (MIV) for Big Longitudinal Trial Data with Missing Values in eHealth. AB - Web-delivered trials are an important component in eHealth services. These trials, mostly behavior-based, generate big heterogeneous data that are longitudinal, high dimensional with missing values. Unsupervised learning methods have been widely applied in this area, however, validating the optimal number of clusters has been challenging. Built upon our multiple imputation (MI) based fuzzy clustering, MIfuzzy, we proposed a new multiple imputation based validation (MIV) framework and corresponding MIV algorithms for clustering big longitudinal eHealth data with missing values, more generally for fuzzy-logic based clustering methods. Specifically, we detect the optimal number of clusters by auto-searching and -synthesizing a suite of MI-based validation methods and indices, including conventional (bootstrap or cross-validation based) and emerging (modularity based) validation indices for general clustering methods as well as the specific one (Xie and Beni) for fuzzy clustering. The MIV performance was demonstrated on a big longitudinal dataset from a real web-delivered trial and using simulation. The results indicate MI-based Xie and Beni index for fuzzy-clustering are more appropriate for detecting the optimal number of clusters for such complex data. The MIV concept and algorithms could be easily adapted to different types of clustering that could process big incomplete longitudinal trial data in eHealth services. PMID- 27126065 TI - Therapeutic Body Wraps in Swiss public adult acute inpatient wards. A retrospective descriptive cohort study. AB - WHAT IS KNOWN ON THE SUBJECT?: Various expert opinions reported relational benefits and tranquilizing effects of therapeutic body wraps (TBW) in adults experiencing high anxiety in the context of psychosis. Yet, this tranquilizing effect was never investigated in larger samples and in the context of modern psychopharmacology. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This is the first study to establish descriptive statistics of this mind-body therapy in French-speaking Switzerland where TBWs are routinely used in two public psychiatric hospitals. It brings knowledge on patients nowadays treated with TBW. Moreover, it opens a new area of investigation on the potential of this nursing technique, which may contribute to reduce anxiolytic medication in severely ill patients. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: This study sheds light on a clinical practice in mental health nursing and upon nurses' specific contribution to psychiatric clinic. It investigates a potential for TBWs to reduce the use of anxiolytic medications by patients who agreed to have TBW as part of their treatment. It may help to inform the mental health nursing practice. ABSTRACT: Introduction Many patients suffering from serious mental illness experience severe anxiety and those with psychosis often report the feeling of their bodies falling apart. While it is believed that these patients benefit from therapeutic body wraps (TBWs), the use of this adjunct therapy has rarely been studied in adult patients. Aims The aim of this study was to obtain descriptive statistics on the clinical, social-demographic and institutional reality of TBW therapy in Swiss public adult inpatient wards. Methods Retrospective data related to a cohort of 172 adult inpatients were retrieved from records of two public hospitals. Correlations between TBW and the prescriptions of lorazepam were explored. Results TBWs were primarily used for patients diagnosed with either schizophrenia, schizotypal, delusional and other non-mood psychotic disorders or mood disorders. Patients had, on average, four psychiatric hospitalizations, and in 30% of the cases, TBWs were offered during the first hospitalization. Moreover, TBWs were mostly practiced by nurses. Body wraps were potentially associated with a reduction in both anxiolytic and neuroleptic drugs. Discussion/Implication for practice Based on our results, TBW might contribute to the clinical management of anxiety by nurses. The efficacy of TWB regarding anxiety has yet to be investigated in a randomized controlled trial. PMID- 27126066 TI - Comments on the recent article "Adverse events associated with acupuncture: a clinicopathologic review". PMID- 27126067 TI - Immunoglubolin dynamics and cancer prevalence in Tasmanian devils (Sarcophilus harrisii). AB - Immunoglobulins such as IgG and IgM have been shown to induce anti-tumour cytotoxic activity. In the present study we therefore explore total serum IgG and IgM expression dynamics in 23 known-aged Tasmanian devils (Sarcophilus harrisii) of which 9 where affected by Devil Facial Tumour Disease (DFTD). DFTD is clonally transmissible cancer that has caused massive declines in devil numbers. Our analyses revealed that IgM and IgG expression levels as well as IgM/IgG ratios decreased with increasing devil age. Neither age, sex, IgM nor IgG expression levels affected devil DFTD status in our analyses. However, devils with increased IgM relative to IgG expression levels had significantly lower DFTD prevalence. Our results therefore suggest that IgM/IgG ratios may play an important role in determining devil susceptibility to DFTD. We consequently propose that our findings warrant further studies to elucidate the underpinning(s) of devil IgM/IgG ratios and DFTD status. PMID- 27126068 TI - Drug delivery system of basic fibroblast growth factor using gelatin hydrogel for restoration of acute vocal fold scar. AB - OBJECTIVE: There continue to be therapeutic challenges in the management of vocal fold scarring. We previously showed that basic fibroblast growth factor (bFGF) injection has therapeutic potential for vocal fold scarring. However, the working time of bFGF is relatively short, and multiple injections were required in many cases to obtain the regenerative effect. An efficacious delivery system for bFGF has yet to be established. We designed a method of sustained drug delivery system (DDS) of bFGF by using a gelatin hydrogel. Hydrogel has been developed for targeted delivery and controlled release of bFGF. Hydrogel of the particle type is also injectable and commercially available. The current study aims to investigate the effects of a single injection of bFGF-DDS on acute vocal fold scarring using a canine model. METHODS: Vocal folds from eight beagles were unilaterally scarred by stripping the lamina propria. One month later, hydrogels (0.5ml) containing 10MUg of bFGF were injected into the scarred vocal folds of four beagles (FGF-hydrogel group). Saline (0.5ml) was injected into the other four beagles (sham group). Vibratory and histological examination of excised larynges was performed 5 months after treatment. Comparative analysis between the current data and our previous data with repeated injection of bFGF solution was also completed. RESULTS: Vibratory examination demonstrated significantly improved vibration in the bFGF hydrogel-treated group. Histological examination of the bFGF hydrogel group showed restoration of hyaluronic acid in the lamina propria as compared to sham. Comparison between the DDS system and our previous bFGF solution injection indicated better effects of the DDS system on vibratory amplitude. CONCLUSION: A single injection of bFGF hydrogel has regenerative effects on acute vocal fold scarring, which is at least similar to repeated injection of bFGF solution. PMID- 27126069 TI - GH indirectly enhances the regeneration of transgenic zebrafish fins through IGF2a and IGF2b. AB - The somatotropic axis, composed essentially of the growth hormone (GH) and insulin-like growth factors (IGFs), is the main regulator of somatic growth in vertebrates. However, these protein hormones are also involved in various other major physiological processes. Although the importance of IGFs in mechanisms involving tissue regeneration has already been established, little is known regarding the direct effects of GH in these processes. In this study, we used a transgenic zebrafish (Danio rerio) model, which overexpresses GH from the beta actin constitutive promoter. The regenerative ability of the caudal fin was assessed after repeated amputations, as well as the expression of genes related to the GH/IGF axis. The results revealed that GH overexpression increased the regenerated area of the caudal fin in transgenic fish after the second amputation. Transgenic fish also presented a decrease in gene expression of the GH receptor (ghrb), in opposition to the increased expression of the IGF1 receptors (igf1ra and igf1rb). These results suggest that transgenic fish have a higher sensitivity to IGFs than to GH during fin regeneration. With respect to the different IGFs produced locally, a decrease in igf1a expression and a significant increase in both igf2a and igf2b expression was observed, suggesting that igf1a is not directly involved in fin regeneration. Overall, the results revealed that excess GH enhances fin regeneration in zebrafish through igf2a and igf2b expression, acting indirectly on this major physiological process. PMID- 27126071 TI - The effect of immunosuppressive molecules on T-cell metabolic reprogramming. AB - T lymphocytes undergo metabolic reprogramming to adapt to extracellular and intracellular cues. Specifically, T-cell metabolism results into ATP production, anabolism and catabolism pathways that not only support rapid cell growth and proliferation, but also differentiation and effector functions, recently referred as "immunometabolism". Quiescent naive T cells rely on oxidative phosphorylation whereas aerobic glycolysis (Warburg effect) occurs in activated T cells (effector CD4(+) and CD8(+)). The molecular mechanisms that sense metabolic status and influence T-cell function require metabolic checkpoints including sensors of metabolic signals and transducers (Myc, HIF-1alpha, AMPK and mTOR). These metabolic checkpoints represent a novel therapeutic strategy for immune modulation. Interestingly, many immunosuppressive drugs including mTOR inhibitors (rapamycin), calcineurin inhibitors (tacrolimus, cyclosporine A) and inhibitors of de novo purine synthesis (6-mercaptopurine, mycophenolic acid and methotrexate) provide examples into how modulating these metabolic checkpoints can regulate T-cell activation, differentiation and function. In this Review we highlight emerging concepts about metabolic reprogramming in T-cell responses and we discuss the potential therapeutic interventions to influence T-cell fate and effector function. PMID- 27126072 TI - Hepatosteatosis and estrogen increase apolipoprotein O production in the chicken. AB - Apolipoprotein O (ApoO) is a recently discovered plasma apolipoprotein that may also play a role in the mitochondrial inner membrane. Possibly due to this complexity, its physiological functions have not been elucidated yet. To gain insight from a non-mammalian experimental system, we have investigated the regulation of ApoO levels in an alternative, well-suited model for studies on lipid metabolism, the chicken. qPCR using specific primer pairs and Western blot analysis with our rabbit anti-chicken ApoO antiserum demonstrated ApoO in the liver of chickens fed a control or a fat-enriched diet, as well as in 2 chicken hepatoma cell lines, LMH cells and the estrogen-responsive LMH-2A cells, under conditions of lipid loading by incubation with BSA-complexed oleic acid. Induced triglyceride accumulation in both the liver and the hepatic cells was associated with significantly increased levels of ApoO mRNA and protein. Furthermore, upon treatment for 24 h with estrogen of the estrogen receptor-expressing LMH-2A cells, quantitative analysis of ApoO transcripts and Western blotting revealed increases of ApoO expression. Finally, upon a single administration of estrogen to roosters that leads to hyperlipidemia, higher hepatic levels of both ApoO transcript and protein were observed within 24 h. Based on these data, we propose that hepatic expression of ApoO is tightly linked not only to diet-induced hepatosteatosis, but also to increased lipoprotein-production induced by, e.g., hormones. The findings support a role of ApoO as an effector of compromised mitochondrial function that likely accompanies the onset of non-alcoholic fatty liver disease. PMID- 27126073 TI - EF-Tu from the enacyloxin producing Frateuria W-315 strain: Structure/activity relationship and antibiotic resistance. AB - In this report, we have demonstrated that the poly(U)-dependent poly(Phe) synthesis activity of elongator factor Tu (EF-Tu) from the enacyloxin producing strain Frateuria sp. W-315 is inhibited by the antibiotic similarly to that of Escherichia coli EF-Tu. The inhibitory effect of enacyloxin observed in a purified system was the same as that obtained with an S30 extract from E. coli or Frateuria sp. W-315, respectively, suggesting that antibiotic resistance of enacyloxin producing Frateuria sp. W-315 is not due neither to EF-Tu nor to other components of the translation machinery but to a still unknown mechanism. The EF Tu gene, as PCR amplified from Frateuria W-315 genomic DNA and sequenced represented an ORF of 1191 nucleotides corresponding to 396 amino acids. This protein is larger than the product of tufA from E. coli by only two amino acid residues. Alignment of the amino acid sequence of EF-Tu from E. coli with those of Frateuria and Ralstonia solanacearum indicates on average 80% identical amino acid residues and 9.7% conservative replacements between EF-Tu Frateuria and EF Tu E. coli, on one hand, and 97% identity and 1.7% conservative replacement between EF-Tu Frateuria and EF-Tu Ralstonia solanacearum, on the other hand. These strong primary structure similarities between EF-Tu from different origins are consistent with the fact that this factor is essential for the translation process in all kingdoms of life. Comparison of the effects of antibiotics on EF Tu Frateuria and EF-Tu E. coli revealed that enacyloxin, kirromycin and pulvomycin exert a stronger stimulation of the GDP dissociation rate on EF-Tu Frateuria, while the effects of the antibiotics on the GDP association rate were comparable for the two EF-Tu species. Different mutants of EF-Tu E. coli were constructed with the help of site directed mutagenesis by changing one or several residues of EF-Tu E. coli by the corresponding residues of EF-Tu Frateuria. The single A45K substitution did not modify the intrinsic GTPase activity of EF-Tu E. coli. In contrast, a 2-3 fold stimulation of the intrinsic GTPase activity was observed with the single A42E, F46Y, Q48E and the double F46Y/Q48E substitution. Finally, up to a 7 fold stimulation was observed with the quadruple substitution (mutant A42E/A45K/F46Y/Q48E. PMID- 27126070 TI - What gastric cancer proteomic studies show about gastric carcinogenesis? AB - Gastric cancer is a complex, heterogeneous, and multistep disease. Over the past decades, several studies have aimed to determine the molecular factors that lead to gastric cancer development and progression. After completing the human genome sequencing, proteomic technologies have presented rapid progress. Differently from the relative static state of genome, the cell proteome is dynamic and changes in pathologic conditions. Proteomic approaches have been used to determine proteome profiles and identify differentially expressed proteins between groups of samples, such as neoplastic and nonneoplastic samples or between samples of different cancer subtypes or stages. Therefore, proteomic technologies are a useful tool toward improving the knowledge of gastric cancer molecular pathogenesis and the understanding of tumor heterogeneity. This review aimed to summarize the proteins or protein families that are frequently identified by using high-throughput screening methods and which thus may have a key role in gastric carcinogenesis. The increased knowledge of gastric carcinogenesis will clearly help in the development of new anticancer treatments. Although the studies are still in their infancy, the reviewed proteins may be useful for gastric cancer diagnosis, prognosis, and patient management. PMID- 27126074 TI - Familial mutations in fibrinogen Aalpha (FGA) chain identified in renal amyloidosis increase in vitro amyloidogenicity of FGA fragment. AB - Amyloidoses are clinical disorders where deposition of beta-sheet rich, misfolded protein aggregates called amyloid occurs in vital organs like brain, kidney, liver or heart etc. Aggregation of several proteins such as immunoglobulin light chain, fibrinogen Aalpha chain (FGA) and lysozyme have been found to be associated with renal amyloidosis. Fibrinogen amyloidosis (AFib) is predominantly familial and is associated with the deposition of mutant FGA amyloid, primarily in kidneys. Over ten substitution and frame-shift mutations in FGA have been identified from AFib patients. Whether wild-type FGA is also involved in AFib is yet unknown. The affected tissues from AFib patients usually show ~10 kDA peptide from C-terminal 80 amino acid residues of mutant FGA. Notably, this region also encompasses all known disease-related mutations. Whether these point mutations increase the amyloidogenicity of FGA leading to disease progression, have not been studied yet. Here, we have investigated the role of two disease-related mutations in affecting amyloidogenic propensity of an FGA(496-581) fragment. We found that at physiological pH, the wild-type FGA(496-581) fragment remains monomeric, whereas its E540V mutant forms amyloid-like fibrils as observed by AFM. Also, FGA(496-581) harbouring another familial mutation, R554L, converts in vitro into globular, beta-sheet rich aggregates, showing amyloid-like properties. These findings suggest that familial mutations in FGA may have role in renal amyloidosis via enhanced amyloid formation. PMID- 27126075 TI - An Injured Psittacosaurus (Dinosauria: Ceratopsia) From the Yixian Formation (Liaoning, China): Implications for Psittacosaurus Biology. AB - We describe a Psittacosaurus specimen from the Lujiatun beds of the Yixian Formation in Liaoning, China with an abnormality on its left fibula. Although a large number of Psittacosaurus specimens are known, only a single example of a pathologic Psittacosaurus has been previously noted. The specific pathology in the current specimen is believed to be a healed fibular fracture as assessed through a combination of gross morphology, microcomputed tomography (microCT), and histology data. The fracture can be identified using microCT, but the degree of remodeling and the stage of fracture repair are best determined histologically. The fracture callus is made up of radially oriented spokes of woven bone in a cartilage matrix and the original cortical bone prior to the fracture has been largely eroded. A transverse histologic section taken at the level of the fracture shows the displacement of the proximal and distal parts of the fibula. The Psittacosaurus appears to have survived the break considering the deposition of circumferential non-pathologic bone at the periosteal surface outside of the callus. The combination of gross morphological description, microCT data, and histologic data allowed for a full diagnosis of the abnormality. While some previous authors have preferred gross morphological description above other methods for assessing paleopathologies, it is evident based on this specimen that an amalgam of techniques provides greater clarity to paleopathology diagnoses. Although this Psittacosaurus lived in an environment with many predators, it was able to survive with a fracture on its hindlimb, which undoubtedly would have impacted its locomotion. Anat Rec, 299:897-906, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27126076 TI - Changes in Free Symptom Attributions in Hypochondriasis after Cognitive Therapy and Exposure Therapy. AB - BACKGROUND: Cognitive-behavioural therapy can change dysfunctional symptom attributions in patients with hypochondriasis. Past research has used forced choice answer formats, such as questionnaires, to assess these misattributions; however, with this approach, idiosyncratic attributions cannot be assessed. Free associations are an important complement to existing approaches that assess symptom attributions. AIMS: With this study, we contribute to the current literature by using an open-response instrument to investigate changes in freely associated attributions after exposure therapy (ET) and cognitive therapy (CT) compared with a wait list (WL). METHOD: The current study is a re-examination of a formerly published randomized controlled trial (Weck, Neng, Richtberg, Jakob and Stangier, 2015) that investigated the effectiveness of CT and ET. Seventy three patients with hypochondriasis were randomly assigned to CT, ET or a WL, and completed a 12-week treatment (or waiting period). Before and after the treatment or waiting period, patients completed an Attribution task in which they had to spontaneously attribute nine common bodily sensations to possible causes in an open-response format. RESULTS: Compared with the WL, both CT and ET reduced the frequency of somatic attributions regarding severe diseases (CT: Hedges's g = 1.12; ET: Hedges's g = 1.03) and increased the frequency of normalizing attributions (CT: Hedges's g = 1.17; ET: Hedges's g = 1.24). Only CT changed the attributions regarding moderate diseases (Hedges's g = 0.69). Changes in somatic attributions regarding mild diseases and psychological attributions were not observed. CONCLUSIONS: Both CT and ET are effective for treating freely associated misattributions in patients with hypochondriasis. This study supplements research that used a forced-choice assessment. PMID- 27126077 TI - Single Female Breast Cancer Patients' Perspectives on Intimate Relationships. AB - This qualitative study examined how female breast cancer patients without partners conceptualized their relationship status. Qualitative data were collected from 20 participants who did not have partners during diagnosis and treatment. Phenomenology informed the methodology and thematic analysis. Breast cancer patients without partners discussed how they made meaning of their relationship status within the context of their cancer experience and barriers they faced dating post-diagnosis or treatment. Oncology care providers, public health professionals, and family scientists can use the study results to better understand the specific concerns and experiences of breast cancer patients without partners. Additional implications of these findings for patients, practice, and research are discussed. PMID- 27126078 TI - The effect of ethanol on hydroxyl and carbonyl groups in biopolyol produced by hydrothermal liquefaction of loblolly pine: (31)P-NMR and (19)F-NMR analysis. AB - The goal of this study was to investigate the role of ethanol and temperature on the hydroxyl and carbonyl groups in biopolyol produced from hydrothermal liquefaction of loblolly pine (Pinus spp.) carried out at 250, 300, 350 and 390 degrees C for 30min. Water and water/ethanol mixture (1/1, wt/wt) were used as liquefying solvent in the HTL experiments. HTL in water and water/ethanol is donated as W-HTL and W/E-HTL, respectively. It was found that 300 degrees C and water/ethanol solvent was the optimum liquefaction temperature and solvent, yielding up to 68.1wt.% bio-oil and 2.4wt.% solid residue. (31)P-NMR analysis showed that biopolyol produced by W-HTL was rich in phenolic OH while W/E-HTL produced more aliphatic OH rich biopolyols. Moreover, biopolyols with higher hydroxyl concentration were produced by W/E-HTL. Carbonyl groups were analyzed by (19)F-NMR, which showed that ethanol reduced the concentration of carbonyl groups. PMID- 27126079 TI - Optimizing carbon efficiency of jet fuel range alkanes from cellulose co-fed with polyethylene via catalytically combined processes. AB - Enhanced carbon yields of renewable alkanes for jet fuels were obtained through the catalytic microwave-induced co-pyrolysis and hydrogenation process. The well promoted ZSM-5 catalyst had high selectivity toward C8-C16 aromatic hydrocarbons. The raw organics with improved carbon yield (~44%) were more principally lumped in the jet fuel range at the catalytic temperature of 375 degrees C with the LDPE to cellulose (representing waste plastics to lignocellulose) mass ratio of 0.75. It was also observed that the four species of raw organics from the catalytic microwave co-pyrolysis were almost completely converted into saturated hydrocarbons; the hydrogenation process was conducted in the n-heptane medium by using home-made Raney Ni catalyst under a low-severity condition. The overall carbon yield (with regards to co-reactants of cellulose and LDPE) of hydrogenated organics that mostly match jet fuels was sustainably enhanced to above 39%. Meanwhile, ~90% selectivity toward jet fuel range alkanes was attained. PMID- 27126080 TI - Biocathodes reducing oxygen at high potential select biofilms dominated by Ectothiorhodospiraceae populations harboring a specific association of genes. AB - Biocathodes polarized at high potential are promising for enhancing Microbial Fuel Cell performances but the microbes and genes involved remain poorly documented. Here, two sets of five oxygen-reducing biocathodes were formed at two potentials (-0.4V and +0.1V vs. saturated calomel electrode) and analyzed combining electrochemical and metagenomic approaches. Slower start-up but higher current densities were observed at high potential and a distinctive peak increasing over time was recorded on cyclic voltamogramms, suggesting the growth of oxygen reducing microbes. 16S pyrotag sequencing showed the enrichment of two operational taxonomic units (OTUs) affiliated to Ectothiorodospiraceae on high potential electrodes with the best performances. Shotgun metagenome sequencing and a newly developed method for the identification of Taxon Specific Gene Annotations (TSGA) revealed Ectothiorhodospiraceae specific genes possibly involved in electron transfer and in autotrophic growth. These results give interesting insights into the genetic features underlying the selection of efficient oxygen reducing microbes on biocathodes. PMID- 27126081 TI - Selective Estrogen Receptor beta Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma. AB - Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERbeta, a second receptor for estrogen, targeting ERbeta with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERbeta agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERbeta agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM. PMID- 27126083 TI - Molecular phylogeny of Cyclophyllidea (Cestoda: Eucestoda): an in-silico analysis based on mtCOI gene. AB - Order Cyclophyllidea (of cestode platyhelminths) has a rich diversity of parasites and includes many families and species that are known to cause serious medical condition in humans and domestic and wild animals. Despite various attempts to resolve phylogenetic relationships at the inter-family level, uncertainty remains. In order to add resolution to the existing phylogeny of the order, we generated partial mtCO1 sequences for some commonly occurring cyclophyllidean cestodes and combined them with available sequences from GenBank. Phylogeny was inferred taking a total 83 representative species spanning 8 families using Bayesian analysis. The phylogenetic tree revealed Dilepididae as the most basal taxon and showed early divergence in the phylogenetic tree. Paruterinidae, Taeniidae and Anoplocephalidae showed non-monophyletic assemblage; our result suggests that the family Paruterinidae may represent a polyphyletic group. The diverse family Taeniidae appeared in two separate clades; while one of them included all the members of the genus Echinococcus and also Versteria, the representatives of the genera Taenia and Hydatigera clubbed in the other clade. A close affinity of Dipylidiidae with Taenia and Hydatigera was seen, whereas existence of a close relationship between Mesocestoididae and Echinococcus (of Taeniidae) is also demonstrated. The crown group comprised the families Anoplocephalidae, Davaineidae, Hymenolepididae and Mesocestoididae, and also all species of the genus Echinococcus and Versteria mustelae; monophyly of these families (excepting Anolplocephalidae) and the genus Echinococcus as well as its sister-taxon relation with V. mustelae is also confirmed. Furthermore, non monophyly of Anoplocephalidae is suggested to be correlated with divergence in the host selection. PMID- 27126084 TI - Exploration of electron-vibrational interaction in the 5d states of Eu2+ ions in ABaPO4 (A = Li, Na, K and Rb) phosphors. AB - This work reports the theoretical analysis of the electron-vibrational interaction (EVI) in 4f-5d optical transitions of Eu2+ ions in ABaPO4 (A = Li, Na, K and Rb) systems. The EVI parameters were estimated from the recently reported room temperature photoluminescence results, by employing the spectrum fitting method. Parameters such as the Huang-Rhys factor, effective phonon energy, Stokes shift and zero-phonon line position were estimated and are reported here. The estimated EVI parameters were validated by modeling the emission band and establishing the agreement between the experimental and modeled emission bands. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27126085 TI - Prior facility affects alopecia in adulthood for rhesus macaques. AB - Alopecia has proven to be a persistent problem for captive macaques; many cases continue to elude explanations and effective treatments. Although almost all captive populations exhibit alopecia rates higher than those seen in the wild, there also appear to be wide ranges in rates reported across primate facilities. In this study we looked at alopecia ratings for rhesus macaques (Macaca mulatta) obtained from five primary suppliers and currently housed at the Washington National Primate Research Center (WaNPRC). There were significant differences in alopecia ratings based on prior facility, despite the fact that animals had left their prior facilities at least 10 months previously and 60% had left more than 2 years previously. Possible explanations for the facility effect may include longer than anticipated time lines for alopecia amelioration, early experience effects, and genetic contributions. Our results should provide a cautionary note for those evaluating alopecia, treatments for alopecia, and the current environments of alopecic animals. It is possible that not all alopecia is caused, or can be ameliorated, by changes in the immediate environment. Am. J. Primatol. 79:e22551, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27126082 TI - The omic approach to parasitic trematode research-a review of techniques and developments within the past 5 years. AB - The evolution of technologies to explore parasite biology at a detailed level has made significant advances in recent years, particularly with the development of omic-based strategies. Whilst extensive efforts have been made in the past to develop therapeutic and prophylactic control strategies for trematode parasites, only the therapeutic anthelmintic approach can be regarded as usable in clinical practice. Currently, there is no commercialised prophylactic strategy (such as vaccination) for protection of the definitive host against any trematode parasite. Since 2010 in particular, the integration of omic technologies, including liquid chromatography-mass spectrometry (LC-MS) and next-generation sequencing (NGS), has been increasingly reported in trematode-related studies. Both LC-MS and NGS facilitate a better understanding of the biology of trematodes and provide a promising route to identifying clinically important biological characteristics of parasitic trematodes. In this review, we focus on the application, advantages, and disadvantages of omic technologies (LC-MS and NGS) in trematode research within the past 5 years and explore the use and translation of the omic-based research results into practical tools to deal with infection. PMID- 27126086 TI - Direct Mechanical Stimulation of Stem Cells: A Beating Electromechanically Active Scaffold for Cardiac Tissue Engineering. AB - The combination of stem cell therapy with a supportive scaffold is a promising approach to improving cardiac tissue engineering. Stem cell therapy can be used to repair nonfunctioning heart tissue and achieve myocardial regeneration, and scaffold materials can be utilized in order to successfully deliver and support stem cells in vivo. Current research describes passive scaffold materials; here an electroactive scaffold that provides electrical, mechanical, and topographical cues to induced human pluripotent stem cells (iPS) is presented. The poly(lactic co-glycolic acid) fiber scaffold coated with conductive polymer polypyrrole (PPy) is capable of delivering direct electrical and mechanical stimulation to the iPS. The electroactive scaffolds demonstrate no cytotoxic effects on the iPS as well as an increased expression of cardiac markers for both stimulated and unstimulated protocols. This study demonstrates the first application of PPy as a supportive electroactive material for iPS and the first development of a fiber scaffold capable of dynamic mechanical actuation. PMID- 27126087 TI - Effect of diet-induced weight loss on muscle strength in adults with overweight or obesity - a systematic review and meta-analysis of clinical trials. AB - We conducted a systematic review and meta-analysis to identify how diet-induced weight loss in adults with overweight or obesity impacts on muscle strength. Twenty-seven publications, including 33 interventions, most of which were 8-24 weeks in duration, were included. Meta-analysis of seven interventions measuring knee extensor strength by isokinetic dynamometry in 108 participants found a significant decrease following diet-induced weight loss (-9.0 [95% confidence interval: -13.8, -4.1] N/m, P < 0.001), representing a 7.5% decrease from baseline values. Meta-analysis of handgrip strength from 10 interventions in 231 participants showed a non-significant decrease (-1.7 [-3.6, 0.1] kg, P = 0.070), with significant heterogeneity (I(2) = 83.9%, P < 0.001). This heterogeneity may have been due to diet type, because there was a significant decrease in handgrip strength in seven interventions in 169 participants involving moderate energy restriction (-2.4 [-4.8, -0.0] kg, P = 0.046), representing a 4.6% decrease from baseline values, but not in three interventions in 62 participants involving very low-energy diet (-0.4 [-2.0, 1.2] kg, P = 0.610). Because of variability in methodology and muscles tested, no other data could be meta-analyzed, and qualitative assessment of the remaining interventions revealed mixed results. Despite varying methodologies, diets and small sample sizes, these findings suggest a potential adverse effect of diet-induced weight loss on muscle strength. While these findings should not act as a deterrent against weight loss, due to the known health benefits of losing excess weight, they call for strategies to combat strength loss - such as weight training and other exercises during diet-induced weight loss. (c) 2016 World Obesity. PMID- 27126089 TI - Stand-alone and biorefinery pathways to produce hydrogen through gasification and dark fermentation using Pinus Patula. AB - New efforts in the search of alternative clean and renewable energy to replace the current energy precursors have been assessed in order to reduce emissions to the environment. Lignocellulosic Biomass (LB) can be used to produce bioenergy due to its high energy potential and availability. Different ways are proposed for the transformation of these residues into high added-value products. Thermochemical and biochemical technologies are the most interest concepts focusing on the use of biomass as source for energy production at positive net balances. This study presents the techno-economic, energy and environmental assessment of five scenarios for the hydrogen production through gasification and dark fermentation based on the biorefinery and stand-alone concepts. The results demonstrated that the production of hydrogen based on the concept of a biorefinery can improve the profitability, energy efficiency and reduce the emissions of the processes compared to that based on the stand-alone way. The selection of ethanol and electricity as valuable co-products of the biorefinery in the hydrogen production process confirmed that the process scale and products diversity makes possible a flexible and suitable process to produce hydrogen and other energy carriers from Pinus Patula. PMID- 27126088 TI - Fishing for ecosystem services. AB - Ecosystems are commonly exploited and manipulated to maximize certain human benefits. Such changes can degrade systems, leading to cascading negative effects that may be initially undetected, yet ultimately result in a reduction, or complete loss, of certain valuable ecosystem services. Ecosystem-based management is intended to maintain ecosystem quality and minimize the risk of irreversible change to natural assemblages of species and to ecosystem processes while obtaining and maintaining long-term socioeconomic benefits. We discuss policy decisions in fishery management related to commonly manipulated environments with a focus on influences to ecosystem services. By focusing on broader scales, managing for ecosystem services, and taking a more proactive approach, we expect sustainable, quality fisheries that are resilient to future disturbances. To that end, we contend that: (1) management always involves tradeoffs; (2) explicit management of fisheries for ecosystem services could facilitate a transition from reactive to proactive management; and (3) adaptive co-management is a process that could enhance management for ecosystem services. We propose adaptive co management with an ecosystem service framework where actions are implemented within ecosystem boundaries, rather than political boundaries, through strong interjurisdictional relationships. PMID- 27126090 TI - Meta-analysis reveals an association between signal transducer and activator of transcription-4 polymorphism and hepatocellular carcinoma risk. AB - AIM: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer related mortality worldwide. Signal transducer and activator of transcription (STAT) proteins play a multitude of important functions in liver pathophysiology. Recent studies have indicated associations of rs7574865 single nucleotide polymorphism (SNP) in the STAT4 gene with various autoimmune diseases. The association between STAT4 polymorphism and the risk of HCC has been analyzed in several studies, but results remain inconsistent. This study used a meta-analysis approach to comprehensively investigate the correlation between STAT4 polymorphism and HCC risk based on previously published reports. METHODS: Studies were searched from the databases of PubMed, EMBase, Web of Science, and the Chinese National Knowledge Infrastructure up to 31 December 2015. The meta analysis was carried out based on the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Eight published studies, consisting of 7503 HCC patients (cases) and 13 831 individuals without HCC (controls), were included in the present study. Meta-analysis of the included studies revealed that STAT4 rs7574865 polymorphism contributed to the risk of HCC under all four genetic models, consisting of the allelic model (G vs. T: odds ratio [OR], 1.25; 95% confidence interval [CI], 1.19-1.30), the dominant effect model (GG + GT vs. TT: OR, 1.52; 95% CI, 1.26-1.84), the recessive effect model (GG vs. GT + TT: OR, 1.35; 95% CI, 1.21-1.50), and the co-dominant effect model (GG vs.. TT: OR, 1.72; 95% CI, 1.42-2.10) comparisons. No publication bias was indicated from either visualization of the funnel plot or Egger's test. CONCLUSION: A significantly increased risk of HCC associated with the rs7574865 G was found. The rs7574865 polymorphism might be used as one risk factor for HCC. PMID- 27126092 TI - Osler-Weber-Rendu syndrome: an anaesthetic challenge? AB - Osler-Weber-Rendu syndrome, or hereditary haemorrhagic telangiectasia (HHT), is an autosomal dominant vascular dysplasia characterised by mucocutaneous telangiectases and arteriovenous malformations (AVMs). Diagnosis is clinical and treatment is supportive. The authors demonstrate a safe anaesthetic approach for a patient with HHT. A 53-year-old woman with a left trochanteric fracture was scheduled for urgent orthopaedic surgery. She was diagnosed as having HHT and presented with recurrent epistaxis, telangiectases and gastrointestinal AVMs. She had undergone a nasal dermoseptoplasty 4 weeks earlier, with total nasal occlusion. Surgery was undertaken with a lumbar and sacral plexus block performed with neurostimulation. She was sedated and spontaneous ventilation was maintained. The procedure was completed without complications. Anaesthetic management of patients with HHT is a challenge. The patients should be carefully studied before surgery, to reduce perioperative morbidity and mortality. Regional anaesthesia may be a good alternative to general anaesthesia, but the use of neuroaxial techniques is still controversial. PMID- 27126091 TI - Identification of bona-fide LRRK2 kinase substrates. PMID- 27126093 TI - Meckel's diverticulum in an adult: an obscure presentation of gastrointestinal bleeding. AB - A 17-year-old boy, with a background of haemophilia A, presented to hospital with an episode of brisk and painless per rectal (PR) bleeding. Initial investigation with gastroscopy and colonoscopy revealed no source of bleeding. Examination of the small bowel including MRI, CT angiogram and capsule endoscopy revealed no abnormalities. Double balloon enteroscopy (DBE) from an antegrade position was attempted, with no abnormalities noted. The symptoms persisted and DBE was attempted again from a retrograde approach and a diverticulum was subsequently noted. Laparoscopic surgery was performed identifying a diverticulum as the source of bleeding, 110 cm from the ileocaecal valve, which is more proximal than is normally seen. Histological examination revealed a Meckel's diverticulum. The case described here, although more unusual in adults, demonstrates that complete visualisation of the small bowel remains challenging and that newer modalities of enteroscopy including DBE can help aid in the diagnosis of obscure gastrointestinal bleeding. PMID- 27126094 TI - Prostate cancer: endogenous chemical castration. AB - We report treatment of intermediate risk prostate cancer in a patient with a brief period of androgen deprivation secondary to a pituitary adenoma. This was a patient with intermediate risk prostate cancer diagnosed in the setting of an elevated prostate-specific antigen (PSA). The patient subsequently demonstrated a decline in PSA along with symptoms of hypogonadism and visual disturbance, and was consequently found to have a pituitary tumour. Trans-sphenoidal resection of the sellar mass was performed with normalisation of hormone profiles. The patient subsequently completed a course of radiation therapy for prostate cancer with PSA nadir to undetectable levels without evidence of biochemical recurrence at 7 months follow-up. PMID- 27126095 TI - Familial superior mesenteric artery syndrome. AB - Superior mesenteric artery syndrome (SMAS) has an incidence of 0.1-0.3%. It is caused by a narrow angle between the aorta and the superior mesenteric artery, resulting in the clamping of the third portion of the duodenum. It is more common in females (2:1), with no racial differences. It is also more frequent in patients under 30 years and may have a congenital or acquired aetiology. There is only one case of the familial form described in the medical literature. We present a case of a 20-year-old woman, with recurrent episodes of epigastric discomfort and vomiting since she was 10 years old. After clinical suspicion, diagnosis was achieved after digestive endoscopy, upper gastrointestinal transit and abdominal MR. The patient was kept under parenteral nutrition for 17 days before surgery. She was discharged 8 days after surgery and the postoperative course was uneventful. PMID- 27126096 TI - Primary thyroid lymphoma presenting as dermatomyositis: a first case and review of the literature. AB - A 55-year-old woman presented with a 3-week history of weakness. On examination, she had a heliotrope rash, V-neck and shawl signs. There was symmetric proximal muscle weakness, and 2/5 strength in upper and lower extremities. Laboratory values showed CK 5836, CRP 14.9, erythrocyte sedimentation rate 49, lactate dehydrogenase 633, negative antinuclear antibodies and anti-Jo1 antibodies. Muscle biopsy and immunohistochemistry findings were consistent with dermatomyositis. Treatment with high-dose steroids, cyclophosphamide and intravenous immunoglobulin (IVIG) was started, without improvement of symptoms. She was found to have cold agglutinins with a cold screen titre of 1:256,256. Work up for malignancy ensued. Positron emission tomography-computed tomography (PET-CT) showed increased uptake in the thyroid. Fine-needle thyroid biopsy with flow cytometry studies revealed atypical lymphocytes consistent with diffuse large B-cell lymphoma. The patient underwent R-CHOP therapy, with remarkable improvement of her symptoms. Dermatomyositis associated with primary thyroid lymphoma has not been previously reported. This case reinforces the importance of cancer screening in dermatomyositis patients. PMID- 27126097 TI - Resolution of the physical features of Cushing's syndrome in a patient with a cortisol secreting adrenocortical adenoma after unilateral adrenalectomy. PMID- 27126098 TI - Titer improvement and pilot-scale production of platensimycin from Streptomyces platensis SB12026. AB - Platensimycin (PTM) and platencin (PTN), isolated from several strains of Streptomyces platensis are potent antibiotics against multi-drug resistant bacteria. PTM was also shown to have antidiabetic and antisteatotic activities in mouse models. Through a novel genome-mining method, we have recently identified six PTM and PTN dual-producing strains, and generated several mutants with improved production of PTM or PTN by inactivating the pathway-specific transcriptional repressor gene ptmR1. Among them, S. platensis SB12026 gave the highest titer of 310 mg/L for PTM. In this study, we now report titer improvement by medium and fermentation optimization and pilot-scale production and isolation of PTM from SB12026. The fermentation medium optimization was achieved by manipulating the carbon and nitrogen sources, as well as the inorganic salts. The highest titer of 1560 mg/L PTM was obtained in 15-L fermentors, using a formulated medium mainly containing soluble starch, soybean flour, morpholinepropanesulfonic acid sodium salt and CaCO3. In addition, a polyamide chromatographic step was applied to facilitate the purification and 45.14 g of PTM was successfully obtained from a 60 L scale fermentation. These results would speed up the future development of PTM as human medicine. PMID- 27126099 TI - A Highly Stretchable Polymer that Can Be Thermally Healed at Mild Temperature. AB - Combining stretchability and self-healing properties in a man-made material is a challenging task. For an efficient self-healing material, weaker dynamic or reversible bonds should be presented as crosslinks so that they will first break upon damage and then reform after healing, which is not favorable when developing elastic materials. In this work, by incorporating dynamic Fe(III)-triazole coordination bonds into polydimethylsiloxane (PDMS) backbone, a highly elastic polymer is obtained that can be thermally healed at mild temperature. The as prepared polymer can be stretched to 3400% strain at low loading speed (1 mm min( 1) ). When damaged, the polymer can be thermally healed at 60 degrees C for 20 h with a healing efficiency of over 90%. The good mechanical and healable properties of this polymer can be ascribed to the unique coordination bond strength and coordination conformation of Fe(III)-triazole coordination complex. PMID- 27126101 TI - Gate-Tunable Spin Transport and Giant Electroresistance in Ferromagnetic Graphene Vertical Heterostructures. AB - Controlling tunneling properties through graphene vertical heterostructures provides advantages in achieving large conductance modulation which has been known as limitation in lateral graphene device structures. Despite of intensive research on graphene vertical heterosturctures for recent years, the potential of spintronics based on graphene vertical heterostructures remains relatively unexplored. Here, we present an analytical device model for graphene-based spintronics by using ferromagnetic graphene in vertical heterostructures. We consider a normal or ferroelectric insulator as a tunneling layer. The device concept yields a way of controlling spin transport through the vertical heterostructures, resulting in gate-tunable spin-switching phenomena. Also, we revealed that a 'giant' resistance emerges through a ferroelectric insulating layer owing to the anti-parallel configuration of ferromagnetic graphene layers by means of electric fields via gate and bias voltages. Our findings discover the prospect of manipulating the spin transport properties in vertical heterostructures without use of magnetic fields. PMID- 27126102 TI - Anxiolytic-like behavioural effects of head electroacupuncture in rats susceptible to stress. AB - AIM: To evaluate the behavioural effects of head electroacupuncture (EA) using the Holtzman rat model, a genetic strain showing susceptibility to stress-evoked helplessness. METHODS: Putative anxiolytic and antidepressant behavioural effects of head EA were investigated using the light-dark and forced swim tests, respectively. The open field test was used to investigate motor activity. A total of 28 rats were used in two experiments, each with two groups (n=7 rats each). Rats were restrained and randomised to handling only (control) or 2Hz EA on the midline head anteriorly (at Yintang) and posteriorly (at GV20) for 3 days (experiment 1) or 4 days (experiment 2). RESULTS: One day of EA did not modify behaviour in any of the tests (p>0.1); however, 2 days of 2 Hz EA treatment to the head had anxiolytic-like effects, as indicated by an improvement in ambulatory time and average velocity in the light-dark test (experiment 2). Relative to the control group, the EA group demonstrated greater ambulatory time (37.0+/-3.7 vs 25.2+/-3.6 s, p<0.05) and lower average velocity (2.73+/-0.06 vs 3.08+/-0.13 cm/s, p<0.05). However, EA treatment had no significant effects on the open field and forced swim tests in either experiment. CONCLUSIONS: Two days of EA treatment using 2 Hz pulsating electrical current at midline anterior and posterior acupuncture points on the head induces behavioural effects suggestive of anxiolysis. PMID- 27126100 TI - Transcriptional regulation of mast cell and basophil lineage commitment. AB - Basophils and mast cells have long been known to play critical roles in allergic disease and in immunity against parasitic infection. Accumulated evidence also supports that basophils and mast cells have important roles in immune regulations, host defense against bacteria and viruses, and autoimmune diseases. However, origin and molecular regulation of basophil and mast cell differentiation remain incompletely understood. In this review, we focus on recent advances in the understanding of origin and molecular regulation of mouse and human basophil and mast cell development. A more complete understanding of how basophils and mast cells develop at the molecular level will lead to development of interventions that are more effective in achieving long-term success. PMID- 27126103 TI - Simple graphs that guide combinatorial materials design. PMID- 27126104 TI - Topological features in crystal structures: a quotient graph assisted analysis of underlying nets and their embeddings. AB - Topological properties of crystal structures may be analysed at different levels, depending on the representation and the topology that has been assigned to the crystal. Considered here is the combinatorial or bond topology of the structure, which is independent of its realization in space. Periodic nets representing one dimensional complexes, or the associated graphs, characterize the skeleton of chemical bonds within the crystal. Since periodic nets can be faithfully represented by their labelled quotient graphs, it may be inferred that their topological features can be recovered by a direct analysis of the labelled quotient graph. Evidence is given for ring analysis and structure decomposition into building units and building networks. An algebraic treatment is developed for ring analysis and thoroughly applied to a description of coesite. Building units can be finite or infinite, corresponding to 1-, 2- or even 3-periodic subnets. The list of infinite units includes linear chains or sheets of corner- or edge-sharing polyhedra. Decomposing periodic nets into their building units relies on graph-theoretical methods classified as surgery techniques. The most relevant operations are edge subdivision, vertex identification, edge contraction and decoration. Instead, these operations can be performed on labelled quotient graphs, evidencing in almost a mechanical way the nature and connection mode of building units in the derived net. Various examples are discussed, ranging from finite building blocks to 3-periodic subnets. Among others, the structures of strontium oxychloride, spinel, lithiophilite and garnet are addressed. PMID- 27126105 TI - Theo Hahn (1928-2016). PMID- 27126106 TI - Aloysio Janner (1928-2016). PMID- 27126107 TI - Symmetry-adapted digital modeling I. Axial symmetric proteins. AB - Considered are axial symmetric proteins exemplified by the octameric mitochondrial creatine kinase, the Pyr RNA-binding attenuation protein, the D aminopeptidase and the cyclophilin A-cyclosporin complex, with tetragonal (422), trigonal (32), pentagonal (52) and pentagonal (52) point-group symmetry, respectively. One starts from the protein enclosing form, which is characterized by vertices at points of a lattice (the form lattice) whose dimension depends on the point group. This allows the indexing of Calpha's at extreme radial positions. The indexing is extended to additional residues on the basis of a finer lattice, the digital modeling lattice Lambda, which includes the form lattice as a sublattice. This leads to a coarse-grained description of the protein. In the crystallographic point-group case, the planar indices are obtained from a projection of atomic positions along the rotation axis, taken as the z axis. The planar indices of a Calpha are then those of the nearest projected lattice point. In the non-crystallographic case, low indices are an additional requirement. The coarse-grained bead follows from the condition imposed on the residues selected to have a z coordinate within a band of value delta above and below the height of lattice points. The choice of delta permits a variation of the coarse-grained bead model. For example, the value delta = 0.5 leads to a fine-grained indexing of the full set of residues, whereas with delta = 0.25 one gets a coarse-grained model which includes only about half of these residues. Within this procedure, the indexing of the Calpha only depends on the choice of the digital modeling lattice and not on the value of delta. The characteristics which distinguish the present approach from other coarse-grained models of proteins on lattices are summarized at the end. PMID- 27126109 TI - Symmetry-adapted digital modeling III. Coarse-grained icosahedral viruses. AB - Considered is the coarse-grained modeling of icosahedral viruses in terms of a three-dimensional lattice (the digital modeling lattice) selected among the projected points in space of a six-dimensional icosahedral lattice. Backbone atomic positions (Calpha's for the residues of the capsid and phosphorus atoms P for the genome nucleotides) are then indexed by their nearest lattice point. This leads to a fine-grained lattice point characterization of the full viral chains in the backbone approximation (denoted as digital modeling). Coarse-grained models then follow by a proper selection of the indexed backbone positions, where for each chain one can choose the desired coarseness. This approach is applied to three viruses, the Satellite tobacco mosaic virus, the bacteriophage MS2 and the Pariacoto virus, on the basis of structural data from the Brookhaven Protein Data Bank. In each case the various stages of the procedure are illustrated for a given coarse-grained model and the corresponding indexed positions are listed. Alternative coarse-grained models have been derived and compared. Comments on related results and approaches, found among the very large set of publications in this field, conclude this article. PMID- 27126108 TI - Symmetry-adapted digital modeling II. The double-helix B-DNA. AB - The positions of phosphorus in B-DNA have the remarkable property of occurring (in axial projection) at well defined points in the three-dimensional space of a projected five-dimensional decagonal lattice, subdividing according to the golden mean ratio tau:1:tau [with tau = (1+?sqrt {5})/2] the edges of an enclosing decagon. The corresponding planar integral indices n1, n2, n3, n4 (which are lattice point coordinates) are extended to include the axial index n5 as well, defined for each P position of the double helix with respect to the single decagonal lattice LambdaP(aP, cP) with aP = 2.222 A and cP = 0.676 A. A finer decagonal lattice Lambda(a, c), with a = aP/6 and c = cP, together with a selection of lattice points for each nucleotide with a given indexed P position (so as to define a discrete set in three dimensions) permits the indexing of the atomic positions of the B-DNA d(AGTCAGTCAG) derived by M. J. P. van Dongen. This is done for both DNA strands and the single lattice Lambda. Considered first is the sugar-phosphate subsystem, and then each nucleobase guanine, adenine, cytosine and thymine. One gets in this way a digital modeling of d(AGTCAGTCAG) in a one-to-one correspondence between atomic and indexed positions and a maximal deviation of about 0.6 A (for the value of the lattice parameters given above). It is shown how to get a digital modeling of the B-DNA double helix for any given code. Finally, a short discussion indicates how this procedure can be extended to derive coarse-grained B-DNA models. An example is given with a reduction factor of about 2 in the number of atomic positions. A few remarks about the wider interest of this investigation and possible future developments conclude the paper. PMID- 27126110 TI - Formulation of dynamical theory of X-ray diffraction for perfect crystals in the Laue case using the Riemann surface. AB - The dynamical theory for perfect crystals in the Laue case was reformulated using the Riemann surface, as used in complex analysis. In the two-beam approximation, each branch of the dispersion surface is specified by one sheet of the Riemann surface. The characteristic features of the dispersion surface are analytically revealed using four parameters, which are the real and imaginary parts of two quantities specifying the degree of departure from the exact Bragg condition and the reflection strength. By representing these parameters on complex planes, these characteristics can be graphically depicted on the Riemann surface. In the conventional case, the absorption is small and the real part of the reflection strength is large, so the formulation is the same as the traditional analysis. However, when the real part of the reflection strength is small or zero, the two branches of the dispersion surface cross, and the dispersion relationship becomes similar to that of the Bragg case. This is because the geometrical relationships among the parameters are similar in both cases. The present analytical method is generally applicable, irrespective of the magnitudes of the parameters. Furthermore, the present method analytically revealed many characteristic features of the dispersion surface and will be quite instructive for further numerical calculations of rocking curves. PMID- 27126111 TI - Computer simulations of X-ray six-beam diffraction in a perfect silicon crystal. I. AB - This paper reports computer simulations of the transmitted-beam intensity distribution for the case of six-beam (000, 220, 242, 044, -224, -202) diffraction of X-rays in a perfect silicon crystal of thickness 1 mm. Both the plane-wave angular dependence and the six-beam section topographs, which are usually obtained in experiments with a restricted beam (two-dimensional slit), are calculated. The angular dependence is calculated in accordance with Ewald's theory. The section topographs are calculated from the angular dependence by means of the fast Fourier transformation procedure. This approach allows one to consider, for the first time, the transformation of the topograph's structure due to the two-dimensional slit sizes and the distance between the slit and the detector. The results are in good agreement with the results of other works and with the experimental data. This method of calculation does not require a supercomputer and it was performed on a standard laptop. A detailed explanation of the main features of the diffraction patterns at different distances between the slit and the detector is presented. PMID- 27126112 TI - Monoclinic sphere packings. I. Invariant, univariant and bivariant lattice complexes. AB - All homogeneous sphere packings were derived that refer to the two invariant, the four univariant and the three bivariant lattice complexes belonging to the monoclinic crystal system. In total, sphere packings of 29 types have been found. Only for five types is the maximal inherent symmetry of their sphere packings monoclinic whereas the inherent symmetry is orthorhombic for nine types, tetragonal for five types, hexagonal for six types and cubic for four types. PMID- 27126113 TI - On the group-theoretical approach to the study of interpenetrating nets. AB - Using group-subgroup and group-supergroup relations, a general theoretical framework is developed to describe and derive interpenetrating 3-periodic nets. The generation of interpenetration patterns is readily accomplished by replicating a single net with a supergroup G of its space group H under the condition that site symmetries of vertices and edges are the same in both H and G. It is shown that interpenetrating nets cannot be mapped onto each other by mirror reflections because otherwise edge crossings would necessarily occur in the embedding. For the same reason any other rotation or roto-inversion axes from G ? H are not allowed to intersect vertices or edges of the nets. This property significantly narrows the set of supergroups to be included in the derivation of interpenetrating nets. A procedure is described based on the automorphism group of a Hopf ring net [Alexandrov et al. (2012). Acta Cryst. A68, 484-493] to determine maximal symmetries compatible with interpenetration patterns. The proposed approach is illustrated by examples of twofold interpenetrated utp, dia and pcu nets, as well as multiple copies of enantiomorphic quartz (qtz) networks. Some applications to polycatenated 2-periodic layers are also discussed. PMID- 27126114 TI - Vertex-connectivity in periodic graphs and underlying nets of crystal structures. AB - Periodic nets used to describe the combinatorial topology of crystal structures have been required to be 3-connected by some authors. A graph is n-connected when deletion of less than n vertices does not disconnect it. n-Connected graphs are a fortiari n-coordinated but the converse is not true. This article presents an analysis of vertex-connectivity in periodic graphs characterized through their labelled quotient graph (LQG) and applied to a definition of underlying nets of crystal structures. It is shown that LQGs of p-periodic graphs (p >= 2) that are 1-connected or 2-connected, but not 3-connected, are contractible in the sense that they display, respectively, singletons or pairs of vertices separating dangling or linker components with zero net voltage over every cycle. The contraction operation that substitutes vertices and edges, respectively, for dangling components and linkers yields a 3-connected graph with the same periodicity. 1-Periodic graphs can be analysed in the same way through their LQGs but the result may not be 3-connected. It is claimed that long-range topological properties of periodic graphs are respected by contraction so that contracted graphs can represent topological classes of crystal structures, be they rods, layers or three-dimensional frameworks. PMID- 27126116 TI - Multidimensional period doubling structures. AB - This paper develops the formalism necessary to generalize the period doubling sequence to arbitrary dimension by straightforward extension of the substitution and recursion rules. It is shown that the period doubling structures of arbitrary dimension are pure point diffractive. The symmetries of the structures are pointed out. PMID- 27126115 TI - The Scherrer equation and the dynamical theory of X-ray diffraction. AB - The Scherrer equation is a widely used tool to determine the crystallite size of polycrystalline samples. However, it is not clear if one can apply it to large crystallite sizes because its derivation is based on the kinematical theory of X ray diffraction. For large and perfect crystals, it is more appropriate to use the dynamical theory of X-ray diffraction. Because of the appearance of polycrystalline materials with a high degree of crystalline perfection and large sizes, it is the authors' belief that it is important to establish the crystallite size limit for which the Scherrer equation can be applied. In this work, the diffraction peak profiles are calculated using the dynamical theory of X-ray diffraction for several Bragg reflections and crystallite sizes for Si, LaB6 and CeO2. The full width at half-maximum is then extracted and the crystallite size is computed using the Scherrer equation. It is shown that for crystals with linear absorption coefficients below 2117.3 cm(-1) the Scherrer equation is valid for crystallites with sizes up to 600 nm. It is also shown that as the size increases only the peaks at higher 2theta angles give good results, and if one uses peaks with 2theta > 60 degrees the limit for use of the Scherrer equation would go up to 1 um. PMID- 27126117 TI - Hydrogen-bond-reversal symmetry and its violation in ice nanotubes. AB - Recently, a new type of generalized symmetry of ice structures was introduced which takes into account the change of direction of all hydrogen bonds. The energy nonequivalence of pairs of configurations with opposite direction of all hydrogen bonds was established in the course of computer simulation of bilayer ice and other four-coordinated structures without 'dangling' hydrogen atoms. In this article, the results of detailed investigations of the violation of the hydrogen-bond-reversal symmetry in ice nanotubes consisting of stacked n-membered rings are presented. A comprehensive classification of all possible hydrogen bonding configurations and their division into two classes (antisymmetrical and non-antisymmetrical) are given. Attention is focused on the most stable configurations that have no longitudinally arranged water molecules. This restriction made the asymmetry very difficult to find. For example, it was established that the asymmetry (non-antisymmetrical configurations) in ice nanotubes with square, pentagonal and hexagonal cross sections appears only when the number of transverse rings in the unit cell is more than six. It is shown that this is related to the well known combinatorial problem of enumerating the symmetry-distinct necklaces of black and white beads. It was found that, among the ice nanotubes that had been considered, hydrogen-bond-reversal asymmetry is most conspicuous in wide nanotubes such as heptagonal and octagonal. In this case the asymmetry is observed for unit cells of any length. In order to verify the results of the symmetry analysis and to confirm the energy nonequivalence of some (non-antisymmetrical) configurations, approximate calculations of the binding energy have been performed using the package TINKER. PMID- 27126118 TI - Estimating the difference between structure-factor amplitudes using multivariate Bayesian inference. AB - In experimental research referencing two or more measurements to one another is a powerful tool to reduce the effect of systematic errors between different sets of measurements. The interesting quantity is usually derived from two measurements on the same sample under different conditions. While an elaborate experimental design is essential for improving the estimate, the data analysis should also maximally exploit the covariance between the measurements. In X-ray crystallography the difference between structure-factor amplitudes carries important information to solve experimental phasing problems or to determine time dependent structural changes in pump-probe experiments. Here a multivariate Bayesian method was used to analyse intensity measurement pairs to determine their underlying structure-factor amplitudes and their differences. The posterior distribution of the model parameter was approximated with a Markov chain Monte Carlo algorithm. The described merging method is shown to be especially advantageous when systematic and random errors result in recording negative intensity measurements. PMID- 27126119 TI - Report of the Executive Committee for 2014. AB - The report of the Executive Committee for 2014 is presented. PMID- 27126122 TI - Phytohabitans kaempferiae sp. nov., an endophytic actinomycete isolated from the leaf of Kaempferia larsenii. AB - A novel endophytic actinomycete, designated strain KK1-3T, which formed single spores and long chains of spores (more than 10 spores) was isolated from surface sterilized Kaempferia larsenii leaf collected from Ubon Ratchathani province, Thailand. The isolate contained l-lysine, meso-diaminopimelic acid and hydroxyl diaminopimelic acid in the cell-wall peptidoglycan. The whole-cell sugars included glucose, mannose, rhamnose, ribose, galactose and xylose. The characteristic phospholipids were phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol and phosphoglycolipids. The predominant menaquinones were MK 10(H8), MK-10(H6) and MK-10(H4). The predominant cellular fatty acids were anteiso-C17 : 0 and iso-C16 : 0. The G+C content of the genomic DNA was 71 mol%. Phylogenetic analysis using 16S rRNA gene sequences revealed that strain KK1-3T should be classified as representing a member of the genus Phytohabitans. The similarity values of sequences between this strain and those of the closely related species, Phytohabitans houttuyneae K11-0057T (99.0 %), Phytohabitans suffuscus K07-0523T (98.9 %), Phytohabitans flavus K09-0627T (98.6 %) and Phytohabitans rumicisK11-0047T (98.1 %) were observed. The DNA-DNA hybridization result and some physiological and biochemical properties indicated that KK1-3T could be readily distinguished from its closest phylogenetic relatives. On the basis of these phenotypic and genotypic data, this strain represents a novel species, for which the name Phytohabitans kaempferiae sp. nov. is proposed. The type strain is strain KK1-3T (=BCC 66360T =NBRC 110005T). PMID- 27126123 TI - Active nano/microbilayer hemostatic agents for diabetic rat bleeding model. AB - Patients with diabetes mellitus have an increased cardiovascular risk due to the abnormality of hemostatic system components. Therefore, hemostasis is an important concept when considering that diabetics are under risk due to potential bleeding complications during surgical operation. The aim of our study was to examine the efficiency of a fabricated nano/microbilayer hemostatic dressing for bleeding control in diabetic patients. For this purpose, we prepared a nano/microbilayer hemostatic dressing that has a porous sublayer, including chitosan (CTS), bacterial cellulose (BC) as basement and active agents in coagulation cascade, such as vitamin K (Vit K), protamine sulfate (PS), and kaolin (Kao) as a filler and an upper layer consisting of silk fibroin (SF) or SF/phosphatidylcholine (PC) blend to achieve complete hemostasis in diabetic rats. Coagulative performances of the prepared hemostatic dressings were examined by the determination of bleeding time, blood loss, and mortality rate through diabetic rat femoral artery injury model. The percent of diabetic rat blood absorption was found to be 247 +/- 5% for gauze as opposed to 2214 +/- 56% for SF coated PS/BC/CTS. Vit K-reinforced within 138 s and SF-coated BC/CTS hemostatic dressings within 144 s showed a rapid coagulation time. In vivo coagulation studies demonstrated that hemostatic agent-reinforced BC/CTS hemostatic dressing, especially PS/BC/CTS showed a significant hemostatic plug formation. This study suggests that the high positive charge and porosity give to these hemostatic agents reinforced hemostatic dressings the ability to rapidly swell and to promote the accumulation of red blood cells and platelets through electrostatic interactions. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1573-1585, 2017. PMID- 27126124 TI - Experience with silodosin in "real life" (SiRE study). PMID- 27126125 TI - Combined treatment of solifenacin and mirabegron, an alternative in patients with overactive bladder (BESIDE study). PMID- 27126127 TI - Iron-catalyzed domino indole fluorination/allenic aza-Claisen rearrangement. AB - The synthesis of 2-allenyl-2-substituted-3,3-difluoroindolines has been accomplished, taking advantage of the reaction between N-allenyl-indoles and Selectfluor under iron catalysis. PMID- 27126126 TI - Therapeutic Ultrasound and Treadmill Training Suppress Peripheral Nerve Injury Induced Pain in Rats. AB - BACKGROUND: Although evidence suggests that therapeutic ultrasound (TU) in combination with treadmill training (TT) suppresses nerve injury-associated pain, the molecular mechanisms for this action are not clear. OBJECTIVE: The purpose of this research was to study the possible beneficial effects of TU and TT, alone and in combination, on 2 clinical indicators of neuropathic pain and correlate these findings with changes in inflammatory mediators within the spinal cord. Our experimental model used the well-known chronic constriction injury (CCI) of the rat sciatic nerve. DESIGN: This was an experimental study. METHODS: Each group contained 10 rats. Group 1 underwent only the CCI procedure. Group 2 underwent a sham operation where the sciatic nerve was exposed but not ligated. Group 3 had the sham operation followed by both TT and TU. Groups 4, 5, and 6 underwent the CCI procedure followed by TT alone, TU alone, and both the TT and TU interventions, respectively. Heat and mechanical sensitivity, interleukin-6 (IL 6), interleukin-10 (IL-10), and ionized calcium binding adaptor molecule 1 (Iba1) were evaluated. RESULTS: Compared with group 1 animals, TT or TU, or both, produced smaller decreases in mechanical withdrawal threshold and heat withdrawal latencies. The combination of TT and TU was more effective than either treatment alone. In addition, rats that received these treatments did not express the upregulation of IL-6 and Iba1 in their spinal cords on postoperative days 14 and 28, as was found in the group 1 animals. LIMITATIONS: These experimental findings may not be generalizable to humans. CONCLUSIONS: The combination of TU and TT reduces neuropathic pain more than either modality alone. This beneficial effect appears related to downregulation of proinflammatory IL-6 and Iba1, while upregulating the anti-inflammatory IL-10. PMID- 27126128 TI - Development of a Sexual Health Screening Tool for Adolescent Emergency Department Patients. AB - OBJECTIVE: The objective was to develop a content-valid audio computer-assisted self-interview (ACASI) sexual health survey (SHS) that is understandable and acceptable to adolescents and can be feasibly implemented in a pediatric emergency department (ED) for sexually transmitted infection (STI) risk assessment. METHODS: Multistep iterative qualitative study utilizing a Delphi panel of key informants for survey development and content validity, cognitive interviews with end-users to evaluate understanding, and pilot testing with end users to evaluate acceptability and feasibility. RESULTS: We developed a 20-item questionnaire through an iterative modified Delphi process with experts in adolescent and pediatric emergency medicine. All items were assessed as understandable by >90% of adolescents during the cognitive interviews. All respondents found the SHS easy to use. A total of 76.5% preferred answering questions related to sexual health through the SHS compared to face-to-face interviews. Mean (+/-SD) length of survey completion was 17.5 (+/-6.7) minutes and 88.6% of participants found survey length to be "just right." With respect to feasibility testing, there was no statistically significant difference in median ED LOS between those who piloted the SHS and those who did not (230.0 minutes vs. 219.0 minutes; p = 0.7). CONCLUSIONS: We developed a content-valid ACASI for the identification of adolescents at risk for STIs that was understandable, acceptable, and easy to use by adolescent patients and feasible for implementation in the pediatric ED. Future planned steps include the evaluation of the SHS in providing clinical decision support for targeted STI screening in the ED. PMID- 27126130 TI - Correction: Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown. AB - Correction for 'Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown' by Johans J. Fakhoury, et al., Nanoscale, 2015, 7, 20625-20634. PMID- 27126131 TI - Biomarker-driven early lung cancer therapy: the future is now? PMID- 27126129 TI - Development of a deregulating microRNA panel for the detection of early relapse in postoperative colorectal cancer patients. AB - BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide and is associated with high recurrence and mortality, despite recent advancements in therapeutic strategies. MicroRNA (miR) deregulation is associated with CRC development and recurrence; therefore, miRs may be reliable biomarkers for detecting early relapse postoperatively. METHODS: In this study ten candidates were identified using miR arrays: miR-7, miR-31, miR-93, miR-141, miR-195, miR-375, miR-429, miR-494, miR-650, and let-7b. Substantial differences were observed in their expression levels between early relapsed (recurrences within 12 months after surgery) and non-early relapsed CRC patients. The validation study, including 50 early relapsed and 54 non-early relapsed patients, confirmed miR expression alterations in cancer tissue samples. RESULTS: Using a miR real-time quantitative polymerase chain reaction (RT-qPCR), we observed that expression levels of miR-93, miR-195, and let-7b were significantly decreased, whereas those of miR-7, miR-141 and miR-494 showed increases that were more significant in the CRC tissue samples from the early relapsed patients than in those from the non-early relapsed patients. Disease-free survival and overall survival were significantly worse in the high miR-7, miR-141, and miR-494 expression subgroups and the low miR-93 and miR-195 expression subgroups (all P < 0.05). A panel of 6 miRs (miR-7, miR-93, miR-195, miR-141, miR-494, and let-7b), at a cut-off value of 2 deregulated miRs, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 76.6 % and a specificity of 71.4 %. By combining this 6-miRs panel with 6 clinicopathologic factors, at a cut-off value of 4, distinguished early relapsed CRC from non-early relapsed CRC, with a sensitivity of 89.4 % and a specificity of 88.9 %. CONCLUSIONS: This study showed that the developed miR panel has the potential to improve predicting early relapse in CRC patients. PMID- 27126132 TI - Nuss procedure for pectus excavatum in adults: long-term results in a prospective observational study. AB - OBJECTIVES: Since the end of the 1990s, the management of pectus excavatum has undergone major changes. The Nuss procedure (pectus bar) has been the method of choice for patients with pectus excavatum at Bern University Hospital for over a decade. The current study will describe our experiences, with a particular focus on long-term results in adults. METHODS: The prospective observational study began in autumn 2002. The Haller index was used to quantify pectus excavatum severity. Pulmonary function tests and cardiac examinations were performed preoperatively, and a standardized management for surgical techniques and for the pre- and postoperative treatments including long-term follow-up at 3, 12 and 36 months after surgery was developed. Quality of life and satisfaction with the cosmetic result after the Nuss procedure were evaluated. RESULTS: Better or much better quality of life after the Nuss procedure was observed: n = 108 (88.4%) at 3 months, n = 97 (89.0%) at 12 months and n = 87 (92.5%) at 36 months. Pain intensity decreased in the follow-up [pain score visual analogue scale (VAS) at 3 months: median 1 (0-7), 12 months: median 1 (0-4), 36 months: median 0.8 (0-5)]. After long-term observation, over 90% of patients described their quality of life after the operation as being better or much better. Satisfaction with the cosmetic results of the operation was also very high, with >90% of patients being satisfied. Only a very small group of patients suffered from pain in the long term follow-up. Complications were rare (14.7%) and could be treated in most cases without reoperation. CONCLUSION: Our results demonstrate that the Nuss procedure is safe and can be performed with excellent results in adults, both in the short term and in the long term. The improved quality of life and patients' satisfaction with cosmetic results remained high in the long-term follow-up, 10 years after the surgical procedure. PMID- 27126133 TI - Long-term results of mitral repair in patients with severe left ventricular dysfunction and secondary mitral regurgitation: does the technique matter? AB - OBJECTIVES: An isolated undersized annuloplasty was used to treat mitral regurgitation (MR) secondary to dilated cardiomyopathy (DCM) if the baseline coaptation depth (CD) was <1 cm. In the presence of significant tethering of the mitral leaflets (CD >=1 cm), the edge-to-edge (EE) technique was combined with annuloplasty to improve the durability of the repair. The long-term results of this approach are unknown and represent the objective of this study. METHODS: To obtain long-term outcome data, we included in the study population the first 105 consecutive patients with severe left ventricular dysfunction (ejection fraction 29 +/- 6.6%) and secondary MR submitted to mitral valve repair. Forty patients underwent isolated undersized annuloplasty and 65 patients received the EE technique combined with annuloplasty. Preoperative and postoperative data were prospectively entered into a dedicated database. Clinical and echocardiographic follow-ups were performed in our institutional outpatient clinic. RESULTS: Follow up was 90% complete. The median follow-up time was 7.2 years (interquartile range 4.3;10.4). The longest follow-up time was 16.5 years. A comparative analysis between the annuloplasty group and the EE group was performed. Baseline LV dimensions and function were slightly worse in the EE group, but only the severity of tethering was significantly more pronounced than in the annuloplasty group. Hospital mortality (3 vs 2.5%, P = 1.0) and 10-year overall survival (42 +/- 6.7 vs 55 +/- 8.5%, P = 0.2) were not significantly different in the EE and annuloplasty group, respectively. Cumulative incidence functions of cardiac death were similar as well (at 10-years, 34.3 +/- 8.1 vs 37.9 +/- 6.4%, respectively, P = 0.4). At 10 years, cumulative incidence function of recurrence of MR >=3+ was lower in the EE patients (10.3 +/- 4.1 vs 30.8+/-8.0%, P = 0.01). Isolated annuloplasty [hazard ratio (HR) 4.84, 95% confidence interval (CI) 1.46-16.1, P = 0.01] and residual MR >1+ at hospital discharge (HR 5.25, 95% CI 2.00-13.8, P < 0.001) were significantly related to the development of MR >=3. Failure of repair was associated with recurrence of New York Heart Association III or IV symptoms (P < 0.001). CONCLUSIONS: In patients with end-stage DCM and secondary MR, the association of the EE technique to the undersized annuloplasty significantly decreases the rate of recurrent MR at long-term. This higher repair durability did not translate into a better long-term prognosis in this series. PMID- 27126134 TI - Expression of a functional oxygen-labile nitrogenase component in the mitochondrial matrix of aerobically grown yeast. AB - The extreme sensitivity of nitrogenase towards oxygen stands as a major barrier to engineer biological nitrogen fixation into cereal crops by direct nif gene transfer. Here, we use yeast as a model of eukaryotic cell and show that aerobically grown cells express active nitrogenase Fe protein when the NifH polypeptide is targeted to the mitochondrial matrix together with the NifM maturase. Co-expression of NifH and NifM with Nif-specific Fe-S cluster biosynthetic proteins NifU and NifS is not required for Fe protein activity, demonstrating NifH ability to incorporate endogenous mitochondrial Fe-S clusters. In contrast, expression of active Fe protein in the cytosol requires both anoxic growth conditions and co-expression of NifH and NifM with NifU and NifS. Our results show the convenience of using mitochondria to host nitrogenase components, thus providing instrumental technology for the grand challenge of engineering N2-fixing cereals. PMID- 27126135 TI - The first meeting of the European Register of Cystic Echinococcosis (ERCE). AB - Cystic echinococcosis (CE) is a zoonotic parasitic disease endemic in southern and eastern European countries. The true prevalence of CE is difficult to estimate due to the high proportion of asymptomatic carriers who never seek medical attention and to the underreporting of diagnosed cases, factors which contribute to its neglected status. In an attempt to improve this situation, the European Register of Cystic Echinococcosis (ERCE), was launched in October 2014 in the context of the HERACLES project. ERCE is a prospective, observational, multicentre register of patients with probable or confirmed CE. The first ERCE meeting was held in November 2015 at the Italian National Institute of Health (Istituto Superiore di Sanita, ISS) in Rome, to bring together CE experts currently involved in the Register activities, to share and discuss experiences, and future developments.Although the Register is still in its infancy, data collected at the time of writing this report, had outnumbered the total of national cases reported by the European endemic countries and published by the European Centre for Disease Prevention and Control in 2015. This confirms the need for an improved reporting system of CE at the European level. The collection of standardized clinical data and samples is expected to support a more rational, stage-specific approach to clinical management, and to help public authorities harmonize reporting of CE. A better understanding of CE burden in Europe will encourage the planning and implementation of public health policies toward its control. PMID- 27126136 TI - Treatment-related fractures after combined modality therapy for soft tissue sarcomas of the proximal lower extremity: Can the risk be mitigated? AB - PURPOSE: The purpose of this study was to investigate the incidence of and risk factors associated with femur fracture after combined modality therapy for soft tissue sarcomas (STS) of the proximal lower extremity. METHODS AND MATERIALS: We reviewed the records of 596 patients with STS of the proximal lower extremity consecutively treated with surgery and radiation therapy (RT) from 1966 to 2012. One hundred ninety-seven patients (33%) received 50 Gy to the entire femur circumference (n = 197, 33%); 265 patients (45%) received perioperative chemotherapy, and during surgery, 155 patients (26%) had bone exposure, whereas 82 patients (14%) had the periosteum stripped. The Kaplan-Meier method was used to estimate actuarial outcome rates, and both Cox regression modeling and competing risk analyses using the method of Fine and Gray were performed. RESULTS: Median follow-up time was 110 months (range, 6-470 months). The actuarial 10-year local control and overall survival rates were 88% (95% confidence interval [CI], 84%-90%) and 62% (95% CI, 57%-66%). Twelve patients had pathologic fractures, which were associated with 50 Gy to the entire bone circumference (P < .001), bone exposure (P < .001), and periosteal stripping during surgery (P < .001) and use of perioperative chemotherapy (P = .04). Using a competing risk model, bone exposure (P = .001; sub-hazard ratio [SHR], 9.13; 95% CI, 2.5-33.0), periosteal stripping (P < .001; SHR, 13.03; 95% CI, 4.0-43.0), and perioperative chemotherapy (P = .03; SHR, 4.03; 95% CI, 1.1-14.4) were significantly associated with fracture. The actuarial 10-year fracture rate was 2% (95% CI, 1%-3%) when the 50-Gy isodose line encompassed the entire bone circumference without the other risk factors, whereas it increased to 37% (95% CI, 12%-45%) when all 4 treatment-related factors were present. CONCLUSIONS: Although femur fractures are rare, a component from each of the 3 therapeutic modalities contributes to the overall risk, and a multidisciplinary approach to mitigating fracture risk is needed. Although avoiding circumferential bone coverage with the 50-Gy isodose line may be a valuable dosimetric parameter, more rigorous dosimetric studies are required. PMID- 27126137 TI - Why should we invest in objective neuromuscular monitoring anyway? PMID- 27126138 TI - When perceptions defy reality: The relationships between depression and actual and perceived Facebook social support. AB - BACKGROUND: Although the relationship between depression and "offline" social support is well established, numerous questions surround the relationship between "online" social support and depression. We explored this issue by examining the social support dynamics that characterize the way individuals with varying levels of depression (Study 1) and SCID-diagnosed clinically depressed and non-depressed individuals (Study 2) interact with Facebook, the world's largest online social network. METHOD: Using a novel methodology, we examined how disclosing positive or negative information on Facebook influences the amount of social support depressed individuals (a) actually receive (based on actual social support transactions recorded on Facebook walls) and (b) think they receive (based on subjective assessments) from their Facebook network. RESULTS: Contrary to prior research indicating that depression correlates with less actual social support from "offline" networks, across both studies depression was positively correlated with social support from Facebook networks when participants disclosed negative information (p=.02 in Study 1 and p=.06 in Study 2). Yet, depression was negatively correlated with how much social support participants thought they received from their Facebook networks (p=.005 in Study 1 and p=.001 in Study 2). LIMITATIONS: The sample size was relatively small in Study 2, reflecting difficulties of recruiting individuals with Major Depressive Disorder. CONCLUSIONS: These results demonstrate that an asymmetry characterizes the relationship between depression and different types of Facebook social support and further identify perceptions of Facebook social support as a potential intervention target. (243 words; 250 max). PMID- 27126139 TI - Breastfeeding and postpartum depression: Assessing the influence of breastfeeding intention and other risk factors. AB - BACKGROUND: Risk and protective factors for postpartum depression have been extensively studied, and in recent studies an association between breastfeeding and maternal mood has been reported. The present retrospective, cross-sectional study was conducted to evaluate the association between breastfeeding-related variables and postpartum depression (based on Edinburgh Postnatal Depression Scale threshold criteria) within the context of other known risk factors. METHOD: Breastfeeding information, demographic information, and scores on the Edinburgh Postnatal Depression Scale were examined from the Canadian Maternity Experience Survey. This survey contains data collected from 6421 Canadian mothers between October 2006 and January 2007, and 2848 women between five and seven months postpartum were included in the current analyses. RESULTS: In contrast to previous research, logistic regression analyses revealed that when considered within the context of other risk factors, breastfeeding attempt and duration were not associated with postpartum depression at five to seven months postpartum. Although a relationship between the prenatal intention to combination feed and postpartum depression was observed, these variables were no longer related once other potential risk factors were controlled for. Factors that were associated with postpartum depression included lower income, higher perceived stress, lower perceived social support, no history of depression, or no recent history of abuse. LIMITATIONS: A clinical diagnostic instrument was not used and variable selection was restricted to data collected as part of this survey. CONCLUSION: These findings suggest that the association between breastfeeding and postpartum depression reported by previous researchers may in fact be due to alternative risk factors. PMID- 27126140 TI - [Somatic treatments in psychiatry: A descriptive study of laboratory tests and systematic involvement in terms of overall care]. AB - BACKGROUND: Somatic suffering concerns mental health in many ways, but numerous psychiatrists are still reluctant to take an interest in somatic care due to a supposed lack of expertise and an alteration of the psychotherapeutic link, whilst in parallel numerous fellow physicians are quite apprehensive about treating patients with mental disorders. OBJECTIVES: We have undertaken a targeted clinical audit regarding the somatic treatment of in-patients in a psychiatric unit to propose the implementation of measures of improvement. MATERIAL AND METHODS: Our study focused on the identification and treatment of abnormal liver function tests, a subject that has been overlooked in the literature, yet from clinical experience the results are often abnormal in psychiatric unit in-patients. We analysed retrospectively over a period of two years the medical records of psychiatric unit in-patients with abnormal results for at least one of the following hepatic markers: aspartate-aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP) and bilirubin. RESULTS: In total, 188 liver test results were abnormal, with an average of 1.7 per patient. The abnormal test results were in decreasing order: elevation in GGT (80 % of patients), elevation in transaminases (65.5 % for each), elevation in ALP (19.1 %) and elevation in bilirubin (7.27 %). Abnormal transaminase levels were lower than 10N, with a peak between 1N and 3N for ALT and a peak between 1N and 5N for AST. The elevation in GGT was between 1N and 34N, although 71.6 % of these values were below 5N. ALP was below 3N. The medical history was traced in 93.6 % of the records. A somatic clinical examination was only reported in 39 records (35.5 %) and was carried out by a hepato-gastroenterologist (HGE) in 30.8 % of cases, the establishment's emergency physician in 25.7 % of cases and the psychiatrists in 12.9 % of cases. Patients with abnormal liver function test results frequently underwent other biological and morphological examinations. A discharge letter was found in almost all cases. Abnormal liver function test results were indicated in less than 45 % of these discharge letters, whilst over half reported the establishment of a future treatment coordinated by the GP, in close collaboration with the gastroenterologist in at least half the cases. DISCUSSION: Our study was carried out in an open psychiatric unit in the heart of a general hospital that mainly receives patients suffering from thymus and anxiety disorders, addictive disorders, somatoform disorders, personality disorders and psycho-organic disorders. Patients suffering from schizophrenia or schizoaffective disorders comprised less than 10 % of admissions. Our retrospective study of over 750 hospital admissions over a period of two years found only 62.93 % of patients underwent liver function tests, which proved to be pathological in nearly 30 % of cases. Following a well-defined anamnesis, just over a third of patients underwent a physical examination whilst in hospital, more often a while after admission and not in the psychiatric unit. The consultation of fellow hospital physicians was limited even if the gastroenterologist was called upon in 30 % of cases. It was sometimes the treatment pathway or the fortuitous presence of co morbidities that enabled the anaesthetist or emergency physician to carry out this clinical examination. However, when this physical examination was scheduled, clinical hepatobiliary signs were discovered in 30 % of patients. CONCLUSION: An accurate, formalised reference database detailing the principles of the somatic treatment of psychiatric unit in-patients should be established. Our results indicate the necessity of a referring physician in each psychiatric department. PMID- 27126141 TI - [Interest of computer-based cognitive behavioral stress management. Feasability of the Seren@ctif program]. AB - INTRODUCTION: Cognitive-behavioural stress management programs have been studied in many countries. Many reports have shown beyond a doubt their efficacy to reduce perceived stress, anxiety symptoms and to improve quality of life of patients. Considering the very large number of people who could benefit from such programs but are unable to reach them, self-help programs have been offered. First presented as books (bibliotherapy), these programs then became enriched by computing and digital supports. Regrettably, many of the programs of stress management based on the Cognitive behavioural therapy (CBT) both in face-to-face and on digital support have been little evaluated in France. To our knowledge, the Seren@ctif program is the first French language self-help program of stress management proposed on digital support. AIM OF THE STUDY: We led a feasibility study of this program on 10 patients responding to the diagnosis of adjustment disorder with anxiety according to the DSM IV criteria. METHODS: The program includes 5 weekly sessions that the patient follows in our unit from a web site. He benefits from minimal contact with a medical member of staff before and after every session. Right from the first session an USB key is supplied to the patient containing videos, audio files, self-help book portfolio in the form of an e guide, and log books with the exercises to be realized between each sessions of the 5 session program. The patient is encouraged to practice 20 minutes of exercises 5 or 6 days per week. The program's feasibility has been assessed in accordance with a standard satisfaction scale. Anxiety symptomatology has been quantified thanks to the Spielberger State-Trait Anxiety Inventory (STAI-Y-S). RESULTS: After the scheduled 5 weeks, good results were found in terms of acceptability and attractiveness. The average score to the satisfaction survey was at least equal to 4 out of 5 for each item. The mean score on the STAI-State decreased from 53,4 (SD: 8,29) to 44,2 (SD: 7,73) following the intervention. DISCUSSION: The Seren@ctif program may be useful within the framework of a psychoeducative approach. It could also be advised for people suffering from anxiety related to stress. Soon, the program will be tested on patients with usual care suffering from adjustment disorder with anxiety in order to precisely assess its benefits. PMID- 27126142 TI - [The shame cycle in obesity]. AB - INTRODUCTION: In Western countries obesity is currently a major public health issue. Part of a complex system, it should not be studied alone. Yet it is often seen only as the result of qualitatively and/or quantitatively deviant dietary intake and is seldom questioned as a symptom in the psychoanalytic sense, i.e. as a part of a package that makes sense. OBJECTIVES OF THE STUDY: The purpose of this article is to highlight the importance of shame in the psyche of obese subjects as "subjective backup". The author questions the experience of shame in obese subjects as the cornerstone of this symptom in the psychoanalytic sense. METHODS: While reporting a clinical case, the author notes the occurrences of shame in the discourse of the patient. The subsequent analysis is presented based on the transferential and counter-transferential relationship. To carry out this study, the author drew on a device supporting catharsis. RESULTS: The author addresses successively: the complaint of obese subjects and the effect of shame, their shame as the alpha and omega of bulimic crises and lastly their body as a work of art by building a monstrosity. The author concludes with the social dimension of shame and how it is part of the symptom of body transformation in obese subjects. DISCUSSION: It appears that pathological shame reveals a difficulty to maintain a sense of existence. For this reason, it seems important to consider this effect and to establish a framework for the emergence of the latter in the consultations of patients with eating disorders. Under these conditions, the patient is able, on the pedestal of shame, to voice his shame of being and to support a subjectivity. PMID- 27126143 TI - [Validation of the French version of the "Beliefs About Voices Questionnaire Revised" (BAVQ-R)]. AB - INTRODUCTION: The BAVQ-R explores the beliefs and reactions that "voice hearers" have about their voices. Recently, the BAVQ-R was translated into French, but little is known regarding its validity and reliability. Thus, the aim of this study was to examine further the psychometric characteristics of the BAVQ-R French version. METHOD: Seventy-six adult outpatients participated in the study. In addition to the BAVQ-R, patients were administered a psychiatric symptoms severity interview, and self-esteem and quality of life questionnaires. Then, the BAVQ-R was again completed six weeks later after the seven sessions of brief group cognitive behavioral therapy: the Voices Group. RESULTS: The BAVQ-R was well accepted and was completed in less than 10minutes. All items presented floor and ceiling effects. For 15 items, item-total correlations were inferior to 0.30. Internal consistency was 0.83 for the global score, 0.83 for the malevolence, 0.81 for the benevolence, 0.64 for the omnipotence, 0.82 for the resistance and 0.77 for the engagement. The temporal stability was superior to 0.70, except for the omnipotence (0.65). Regarding, the construct validity, on the one hand malevolence, omnipotence and resistance were correlated (0.56<=r<=0.64; P<0.001) and on the other hand benevolence and engagement (r=0.62; P<0.001). Regarding convergent validity significant correlations were found between malevolence, omnipotence resistance and severity of anxio-depressive symptoms, negative self esteem (0.40<=r<=0.52; P<0.001). The BAVQ-R allows discriminating neither between psychotic and non-psychotic patients (Mann-Whitney, all P>0.05) nor between groups established on the basis of the voice sources (Kruskal-Wallis, all P>0.05). Moreover, the BAVQ-R does not seem to be sensitive to change: no difference was observed after Voices Group intervention (Mann-Whitney, all P>0.05). Sociodemographic variables are not related to BAVQ-R. DISCUSSION: The French version of the BAVQ-R has sufficiently adequate psychometric characteristics to be used in a clinical setting. However, floor and ceiling effects suggest a lack of sensitivity of the items. Psychometric characteristics of the BAVQ-R could be improved by selecting items and extending the Likert scale to score them. PMID- 27126144 TI - Breaking Narrative Ground: Innovative Methods for Rigorously Eliciting and Assessing Patient Narratives. AB - OBJECTIVE: To design a methodology for rigorously eliciting narratives about patients' experiences with clinical care that is potentially useful for public reporting and quality improvement. DATA SOURCES/STUDY SETTING: Two rounds of experimental data (N = 48 each) collected in 2013-2014, using a nationally representative Internet panel. STUDY DESIGN: Our study (1) articulates and operationalizes criteria for assessing narrative elicitation protocols; (2) establishes a "gold standard" for assessment of such protocols; and (3) creates and tests a protocol for narratives about outpatient treatment experiences. DATA COLLECTION/EXTRACTION METHODS: We randomized participants between telephone and web-based modalities and between protocols placed before and after a closed-ended survey. PRINCIPAL FINDINGS: Elicited narratives can be assessed relative to a gold standard using four criteria: (1) meaningfulness, (2) completeness, (3) whether the narrative accurately reflects the balance of positive and negative events, and (4) representativeness, which reflects the protocol's performance across respondent subgroups. We demonstrate that a five-question protocol that has been tested and refined yields three- to sixfold increases in completeness and four- to tenfold increases in meaningfulness, compared to a single open-ended question. It performs equally well for healthy and sick patients. CONCLUSIONS: Narrative elicitation protocols suitable for inclusion in extant patient experience surveys can be designed and tested against objective performance criteria, thus advancing the science of public reporting. PMID- 27126146 TI - Build On an Unforgettable Year: Living Our Dream. PMID- 27126147 TI - National Commission on Hunger Report to Congress: A Behind-the-Scenes Look from a Registered Dietitian Nutritionist Member of the Commission. PMID- 27126145 TI - Mapping the small-world properties of brain networks in deception with functional near-infrared spectroscopy. AB - Deception is not a rare occurrence among human behaviors; however, the present brain mapping techniques are insufficient to reveal the neural mechanism of deception under spontaneous or controlled conditions. Interestingly, functional near-infrared spectroscopy (fNIRS) has emerged as a highly promising neuroimaging technique that enables continuous and noninvasive monitoring of changes in blood oxygenation and blood volume in the human brain. In this study, fNIRS was used in combination with complex network theory to extract the attribute features of the functional brain networks underling deception in subjects exhibiting spontaneous or controlled behaviors. Our findings revealed that the small-world networks of the subjects engaged in spontaneous behaviors exhibited greater clustering coefficients, shorter average path lengths, greater average node degrees, and stronger randomness compared with those of subjects engaged in control behaviors. Consequently, we suggest that small-world network topology is capable of distinguishing well between spontaneous and controlled deceptions. PMID- 27126148 TI - Building a Connection between Senior Hunger and Health Outcomes. PMID- 27126149 TI - Tribal Epidemiology Centers and Native American Health. PMID- 27126150 TI - Nutrition Screening and Diagnosis with Early, Appropriate Interventions Are Critical Components of Cystic Fibrosis Management. PMID- 27126151 TI - Why, Oh Why, Are So Many Older Adults Not Drinking Enough Fluid? PMID- 27126152 TI - Diagnosing Malnutrition: Where Are We and Where Do We Need to Go? PMID- 27126153 TI - Validation of a Nutrition Screening Tool for Pediatric Patients with Cystic Fibrosis. AB - BACKGROUND: In cystic fibrosis (CF), nutrition diagnosis is of critical relevance because the early identification of nutrition-related compromise enables early, adequate intervention and, consequently, influences patient prognosis. Up to now, there has not been a validated nutrition screening tool that takes into consideration clinical variables. OBJECTIVE: To validate a specific nutritional risk screening tool for patients with CF based on clinical variables, anthropometric parameters, and dietary intake. DESIGN: Cross-sectional study. The nutrition screening tool was compared with a risk screening tool proposed by McDonald and the Cystic Fibrosis Foundation criteria. PARTICIPANTS/SETTING: Patients aged 6 to 18 years, with a diagnosis of CF confirmed by two determinations of elevated chloride level in sweat (sweat test) and/or by identification of two CF-associated genetic mutations who were receiving follow up care through the outpatient clinic of a Cystic Fibrosis Treatment Center. MAIN OUTCOME MEASURES: Earlier identification of nutritional risk in CF patients aged 6 to 18 years when a new screening tool was applied. STATISTICAL ANALYSES PERFORMED: Agreement among the tested methods was assessed by means of the kappa coefficient for categorical variables. Sensitivity, specificity, and accuracy values were calculated. The significance level was set at 5% (P<0.05). Statistical analyses were carried out in PASW Statistics for Windows version 18.0 (2009, SPSS Inc). RESULTS: Eighty-two patients (49% men, aged 6 to 18 years) were enrolled in the study. The agreement between the proposed screening tool and the tool for screening nutritional risk for CF by the McDonald method was good (kappa=0.804; P<0.001) and the sensitivity and specificity was 85% and 95%, respectively. Agreement with the Cystic Fibrosis Foundation criteria was lower (kappa=0.418; P<0.001), and the sensitivity and specificity were both 72%. CONCLUSIONS: The proposed screening tool with defined clinical variables promotes earlier identification of nutritional risk in pediatric patients with CF. PMID- 27126155 TI - Nutritional Improvement Correlates with Recovery of Activities of Daily Living among Malnourished Elderly Stroke Patients in the Convalescent Stage: A Cross Sectional Study. AB - BACKGROUND: Whether nutritional improvement correlates with functional recovery in convalescent stroke patients is unclear. OBJECTIVE: This study was conducted to examine the relationship between nutritional improvement and recovery of activities of daily living among malnourished elderly stroke patients in the convalescent stage. DESIGN: This study used a cross-sectional study design. PARTICIPANTS/SETTING: One hundred seventy-eight malnourished stroke patients aged 65 years and older from convalescent rehabilitation wards in Japan between April 2012 and December 2014 were included in the analyses. MAIN OUTCOME MEASURES: The participants were classified into three groups according to the Mini Nutritional Assessment Short-Form (MNA-SF) score at discharge (0 to 7 as no improvement, 8 to 11 as lesser improvement, and 12 to 14 as greater improvement). The primary outcome was functional independence measure (FIM) efficiency (FIM gain/length of hospital stay). The secondary outcomes were FIM gain and discharge outcome. STATISTICAL ANALYSIS: One-way analysis of variance, chi(2) test, and Kruskal Wallis test were performed for univariate analysis. Linear regression analysis was used to adjust for covariates such as age, sex, length of hospital stay, FIM (motor and cognitive) on admission, and lower-order items of MNA-SF. Binomial logistic analysis for discharge outcome (home/others) was performed to adjust for covariates such as age, sex, and FIM. RESULTS: Study participants included 85 men and 93 women with a mean age of 77 years. Based on MNA-SF, 16 were classified as no improvement, 113 as lesser improvement, and 49 as greater improvement. The median FIM efficiency and length of hospital stay were 0.27 points/day and 151.5 days, respectively. The greater improvement group had significantly higher FIM efficiency than the other groups (P<0.001). Home discharge rate was also higher in the GI group (P=0.014). Linear regression analysis for FIM efficiency indicated that mobility, neuropsychological problems, and weight loss, which were lower-order items of MNA-SF at discharge, were independent explanatory variables (R(2)=0.373; P<0.001). CONCLUSIONS: These findings suggest that nutritional improvement such as maintenance of body weight is associated with the efficient recovery of activities of daily living among malnourished elderly convalescent stroke patients. PMID- 27126154 TI - Elevated Serum Osmolality and Total Water Deficit Indicate Impaired Hydration Status in Residents of Long-Term Care Facilities Regardless of Low or High Body Mass Index. AB - BACKGROUND: Dehydration is typically associated with underweight and malnutrition in long-term care (LTC) settings. Evidence is lacking regarding the influence of the rising prevalence of overweight and obesity on risk factors, prevalence, and presentation of dehydration. OBJECTIVE: The aim of this study was to objectively assess hydration status and the adequacy of total water intake, and determine relationships between hydration status, total water intake, and body mass index (BMI) in LTC residents. DESIGN: A cross-sectional analysis of baseline data was performed. PARTICIPANTS AND SETTING: Baseline data from 247 subjects recruited from eight community-based LTC facilities participating in two randomized trials comparing nutrient and cost-efficacy of between-meal snacks vs oral nutrition supplements (ONS). MAIN OUTCOMES: Hydration status was assessed by serum osmolality concentration and total water intakes were quantified by weighed food, beverage, water, and ONS intake. STATISTICAL ANALYSES: Simple and multiple linear regression methods were applied. RESULTS: Forty-nine (38.3%) subjects were dehydrated (>300 mOsm/kg) and another 39 (30.5%) had impending dehydration (295 to 300 mOsm/kg). The variance in serum osmolality was significantly accounted for by blood urea nitrogen level, mental status score, and having diabetes (R(2)=0.46; P<0.001). Total water intake averaged 1,147.2+/-433.1 mL/day. Thus, 96% to 100% of subjects did not meet estimated requirements, with a deficit range of 700 to 1,800 mL/day. The variance in total water intake was significantly accounted for by type of liquid beverages (thin vs thick), type of ONS, total energy intake, total activities of daily living dependence, sex, and BMI (R(2)=0.56; P<0.001). CONCLUSIONS: Dehydration and inadequate total water intake is prevalent in LTC residents across all BMI categories. Type of liquid beverages, type of ONS, and type of between-meal snacks are factors that could be targeted for nutrition interventions designed to prevent or reverse dehydration. PMID- 27126156 TI - Implementation of Nutrition Support Guidelines May Affect Energy and Protein Intake in the Pediatric Intensive Care Unit. AB - BACKGROUND: Critically ill children are at risk of developing malnutrition, and undernutrition is a risk factor for morbidity and mortality. OBJECTIVE: The study evaluated changes in the energy and protein intake before and after implementation of nutrition support (NS) guidelines for a pediatric critical care unit (PICU). DESIGN: This retrospective study documented energy and protein intake for the first 8 days of PICU stay. Basal metabolic rate and protein needs were estimated by Schofield and American Society for Parenteral and Enteral Nutrition Guidelines, respectively. PARTICIPANTS/SETTING: Three hundred thirty five children from August to December 2012 (pre-implementation) and 185 from October to December 2013 (post-implementation). INTERVENTION: Implementation of NS Guidelines. MAIN OUTCOME MEASURES: Changes in actual energy and protein intake in the post- compared with the pre-Implementation period. STATISTICAL ANALYSIS PERFORMED: Unpaired t tests, Pearson's chi(2) (unadjusted analysis) were used. Logistic regressions were used to estimate odds ratios and 95% confidence intervals for protein and energy intake, adjusted for age, sex, and Pediatric Risk of Mortality score. RESULTS: After the implementation of guidelines, significant improvements were seen during days 5 through 8 in energy intake among children 2 years of age and older, and in protein intake in both age groups (P<0.05). For the 8-day period, statistically or clinically significant improvements occurred in the cumulative protein deficit/kg/day, as follows: younger than 2-year-olds, -1.5+/-0.7 g/kg/day vs -1.3+/-0.8 g/kg/day, P=0.02; 2 year-olds or older, -1.0+/-0.6 g/kg/day vs -0.7+/-0.8 g/kg/day, P=0.01; and for the energy deficit/kg/d in 2-year-olds and older, -17.2+/-13.6 kcal/kg/day vs 13.3+/-18.1 kcal/kg/day, unpaired t test, P=0.07, in the pre- vs post implementation period, respectively. CONCLUSIONS: The implementation of NS guidelines was associated with improvements in total energy in 2-year-olds and older and protein in younger than 2 and 2 years and older children by days 5 through 8, and protein deficits were significantly lower in the post- vs the pre implementation period. The implementation of NS guidelines may have had a positive effect on improving NS in critically ill children. PMID- 27126157 TI - Malnutrition Care: Preparing for the Next Level of Quality. PMID- 27126158 TI - Validation of the Academy/A.S.P.E.N. Malnutrition Clinical Characteristics. PMID- 27126159 TI - Implementing the Care Plan for Patients Diagnosed with Malnutrition-Why Do We Wait? PMID- 27126160 TI - Nutrition-Focused Physical Exam Hands-On Training Workshop. PMID- 27126161 TI - What Is Vitamin K2 and Does It Have an Impact on Bone Health? PMID- 27126162 TI - The relationship between sexual orientation and depression in a national population sample. AB - AIMS AND OBJECTIVES: The aim of this study was to examine the relationship between sexual orientation and depression in a nationally representative population to determine if sexual minorities report higher levels of depression than the remainder of the population. BACKGROUND: Depression is a highly prevalent and disabling chronic disorder worldwide. Prior research utilizing national population samples have reported that members of sexual minorities are at higher risk for depression when compared to heterosexual people. More recent studies have revealed differences in depression risk based on sexual orientation, sexual activity and sex. There have been significant shifts in societal attitudes towards sexual minorities in recent decades. Continuing research into predictors for reporting depression amongst sexual minorities is needed. METHODS: National Health and Nutrition Examination Survey cycles 2005-2012 were used to identify sexual minority status based on declared sexual orientation and presence of same sex sexual activity. Complex samples logistic and multivariate regression models were used to predict depression adjusted for sexual orientation, sexual activity, age, sex, marital status, education, income, race/ethnicity, employment and health status. RESULTS: Sexual orientation was not a significant independent predictor of depressive symptoms overall. Gay men reported lower levels of depressive symptoms than heterosexual men. In the sex stratified analyses, men who reported having sex with men were five times more likely to report depressive symptomatology compared to men who reported opposite sex partners (2005-2008 adjusted odds ratios: 5.00; 95% confidence interval: 1.44-17.38; 2009-2012 adjusted odds ratios: 5.10; 95% confidence interval: 1.33-19.54) after controlling for sexual orientation. CONCLUSIONS: Results of our analyses indicate that homosexually experienced heterosexual men appear to be at highest risk for depression. Furthermore, reported physical health status was a significant independent predictor of depression in all models, suggesting a strong link between physical and mental health. RELEVANCE TO CLINICAL PRACTICE: Health care providers should inquire about sexual orientation and sexual behaviour as part of a routine health history and be familiar with the unique health needs of sexual minorities to tailor clinical practice and foster safe, inclusive, health care environments. PMID- 27126163 TI - [Not Available]. PMID- 27126164 TI - Morphological Evaluation of Nonlabeled Cells to Detect Stimulation of Nerve Growth Factor Expression by Lyconadin B. AB - The success of drug development is greatly influenced by the efficiency of drug screening methods. Recently, phenotype-based screens have raised expectations, based on their proven record of identifying first-in-class drugs at a higher rate. Although fluorescence images are the data most commonly used in phenotype based cell-based assays, nonstained cellular images have the potential to provide new descriptive information about cellular responses. In this study, we applied morphology-based evaluation of nonlabeled microscopic images to a phenotype-based assay. As a study case, we attempted to increase the efficiency of a cell-based assay for chemical compounds that induce production of nerve growth factor (NGF), using lyconadin B as a model compound. Because the total synthesis of lyconadin B was accomplished very recently, there is no well-established cell-based assay scheme for further drug screening. The conventional cell-based assay for evaluating NGF induction requires two types of cells and a total of 5 days of cell culture. The complexity and length of this assay increase both the risk of screening errors and the cost of screening. Our findings show that analysis of cellular morphology enables evaluation of NGF induction by lyconadin B within only 9 h. PMID- 27126165 TI - Development of chitosan nanoparticles coated with hyaluronic acid for topical ocular delivery of dexamethasone. AB - The present study involved design of dexamethasone-sodium phosphate (DEX) loaded mucoadhesive chitosan nanoparticles for topical ocular delivery to improve its precorneal retention and corneal permeability. The chitosan-sodium tripolyphosphate nanoparticle (CS-NPs) was developed through ionotropic-gelation technique. The developed CS-NPs were coated with hyaluronic-acid (HA) to make discrete, free-flowing NPs and to improve their mucoadhesive characteristics. The particle-size, zeta-potential and polydispersity-index were determined by Malvern Zetasizer. The average size of the CS-NPs ranged from 305.25+/-14.29nm (without HA-coating and before freeze-drying) to 400.57+/-15.23nm (HA-coated and after freeze-drying). Due to the polyanionic nature of HA, reversing of zeta-potentials from +32.55+/-4.15 to -33.74+/-3.45 was observed. Polydispersity-indices varied from 0.178+/-0.067 (before freeze-drying of HA-coated F2) to 0.427+/-0.028 (after freeze-drying of HA-coated F2). The encapsulation and loading capacity of around 72.95% and 14.51% respectively were found in optimized CS-NPs. In simulated tear fluid 75.84% cumulative amount of released drug was detected and the in-vitro release results suggested the mechanism of drug release was Fickian-diffusion type. The clarity, pH, refractive index, surface tension and viscosity of the suspensions of DEX-CS-NPs were found promising for ocular use. Stability study on nanoparticles revealed no significant changes were observed in particle-size, encapsulation, drug release and physicochemical characteristics at 25 degrees C for 3-months storage. PMID- 27126166 TI - Effects of rutin on the redox reactions of hemoglobin. AB - Flavonoids are widely used to attenuate oxidative damage in vitro and in vivo. In this study, we investigated the influence of rutin (quercetin-3 rhamnosylglucoside) on hemoglobin (Hb)- dependent redox reactions, i.e. oxidative stability of Hb and its cytotoxic ferryl intermediate. It was found that rutin induced generation of H2O2, which in turn oxidized Hb rapidly. Meanwhile, rutin exhibited anti-oxidant effect by effectively reducing ferryl intermediate back to ferric Hb at physiological pH. In comparison with quercetin, rutin had stronger capability on reducing ferryl species while lesser pro-oxidant effect on H2O2 generation, thus it exhibited more protective effect on H2O2-induced Hb oxidation. Circular dichroism spectrum showed no significant change in the secondary structure of Hb after flavonoid addition, while molecular docking revealed different binding modes of quercetin and rutin with Hb. These results might provide new insights into the potential nutritional and physiological implications of rutin and quercetin with redox active heme proteins regarding their ani- and pro-oxidant effects. PMID- 27126167 TI - Self-assembling N-(9-Fluorenylmethoxycarbonyl)-l-Phenylalanine hydrogel as novel drug carrier. AB - Supramolecular hydrogel as a novel drug carrier was prepared from N-(9 Fluorenylmethoxycarbonyl) (Fmoc) modified l-phenylalanine. Its different properties like stability at different pH, temperature and rheology were evaluated in reference to salicylic acid (SA) as a model drug, entrapped in the supramolecular hydrogel network. The release behaviour of SA drug in supramolecular hydrogel was investigated by UV-vis spectroscopy. The influence of hydrogelator, pH values of the accepting media, temperature and concentration of SA drug on the release behaviour was investigated under static conditions. The results indicated that the release rate of SA in the supramolecular hydrogels was slightly retarded with an increase of the hydrogelator concentration. Also, the release rates of SA increased with an increase of temperature and its concentration. Furthermore, the release behaviour of SA was found to be different at various pH values in buffers. The study of the release kinetics indicated that the release behaviour of SA from the carrier was in accord with the Peppas model and the diffusion controlled mechanism involved in the Fickian model. PMID- 27126168 TI - Effect of residual sericin on the structural characteristics and properties of regenerated silk films. AB - Regenerated silk film has been increasingly attracting the research community's attention for biomedical applications due to its good biocompatibility and excellent cyto-compatibility. However, some limitations regarding its mechanical properties, such as brittleness, have restricted the use of silk films for industrial biomedical applications. In this study, regenerated silk films with different residual sericin content were prepared applying controlled degumming conditions to evaluate the effect of sericin content on the structure and properties of the films generated. When the residual sericin content increased to 0.6%, crystallinity index and breaking strength of silk films were increased. Above this value, these parameters then decreased. A 1.5 fold increase of silk film elongation properties was obtained when incorporating 16% sericin. Regardless of sericin content, all regenerated silk films showed excellent cyto compatibility, comparable to the one obtained with tissue culture plates. PMID- 27126169 TI - Superabsorbent hydrogels via graft polymerization of acrylic acid from chitosan cellulose hybrid and their potential in controlled release of soil nutrients. AB - Superabsorbent polymers fabricated via grafting polymerization of acrylic acid from chitosan (CTS) yields materials that suffer from poor mechanical strength. Hybridization of chitosan with cellulose (Cell) via chemical bonding using thiourea formaldehyde resin increases the flexibility of the produced hybrid (CTS/Cell). The hybridization process and post graft polymerization of acrylic acid was followed using Fourier transform infrared (FTIR). Also, the obtained structures were homogeneous and exhibited uniform surface as could be shown from imaging with scanning electron microscopy (SEM). Thus, the polymers derived from the grafting of polyacrylic acid from (CTS/Cell) gave rise to much more mechanically robust structures ((CTS/Cell)-g-PAA) that bear wide range of pH response due to presence of chitosan and polyacrylic acid in one homogeneous entity. Additionally, the obtained structures possessed greater water absorbency 390, 39.5g/g in distilled water and saline (0.9wt.% NaCl solution), respectively, and enhanced retention potential even at elevated temperatures as revealed by thermogravimetric analysis (TGA). This could be explained by the high grafting efficiency (GE%), 86.4%, and grafting yield (GY%), 750%. The new superabsorbent polymers proved to be very efficient devices for controlled release of fertilizers into the soil which expands their use in agriculture and horticultural applications. PMID- 27126170 TI - Effect of cellulose and lignin on disintegration, antimicrobial and antioxidant properties of PLA active films. AB - This study reports the effects on antimicrobial, antioxidant, migration and disintegrability activities of ternary nanocomposite films based on poly(lactic acid) incorporating two biobased nanofillers, (cellulose nanocrystals (CNC) and lignin nanoparticles (LNP)), in two different amounts (1 and 3% wt.). Results from antimicrobial tests revealed a capacity to inhibit the Gram negative bacterial growth of Xanthomonas axonopodis pv. vesicatoria and Xanthomonas arboricola pv. pruni along the time, offering innovative opportunities against dangerous bacterial plant pathogens. LNP proved to be highly efficient in antioxidation activity, based on the disappearance of the absorption band at 517nm of the free radical, 2,2-diphenyl-1-picrylhydrazyl (DPPH) upon reduction by an antiradical compound; moreover the combination of LNP and CNC generates a synergistic positive effect in the antioxidation response of PLA ternary films. Furthermore, all the studied formulations showed a disintegrability value up to 90% after 15days of incubation in composting conditions. Migration results showed that the films can be considered suitable for application in food packaging field. PMID- 27126171 TI - Bio-scaffolds produced from irradiated squid pen and crab chitosan with hydroxyapatite/beta-tricalcium phosphate for bone-tissue engineering. AB - In this study, bio-scaffolds have been developed using irradiated chitosan from different sources - squid pen (RS) and crab shell (RC) - with hydroxyapatite/beta tricalcium phosphate (HA/beta-TCP) at a chitosan/HA/beta-TCP ratio of 50/30/20. The bio-scaffolds were prepared at two different freezing temperature (-20 degrees C and -80 degrees C) followed by lyophilisation. To enhance the mechanical properties, the bio-scaffolds were cross-linked using sodium tripolyphosphate (TPP) followed by lyophilisation. The composition and morphology of the bio-scaffolds were characterized using XRD, SEM, TEM and MU-CT. The pore size of the porous scaffolds ranged from 90 to 220MUm and the scaffolds had 70 80% porosity. The scaffolds had a water uptake ratio of more than 10, and a controlled biodegradation in the range of 30-40%. These results suggest that the physical and biological properties of chitosan-based bio-scaffolds can be a promising biomaterial for bone-tissue regeneration. PMID- 27126172 TI - Microbial production of polyhydroxyalkanoates (PHAs) and its copolymers: A review of recent advancements. AB - Traditional mineral oil based plastics are important commodity to enhance the comfort and quality of life but the accumulation of these plastics in the environment has become a major universal problem due to their low biodegradation. Solution to the plastic waste management includes incineration, recycling and landfill disposal methods. These processes are very time consuming and expensive. Biopolymers are important alternatives to the petroleum-based plastics due to environment friendly manufacturing processes, biodegradability and biocompatibility. Therefore use of novel biopolymers, such as polylactide, polysaccharides, aliphatic polyesters and polyhydroxyalkanoates is of interest. PHAs are biodegradable polyesters of hydroxyalkanoates (HA) produced from renewable resources by using microorganisms as intracellular carbon and energy storage compounds. Even though PHAs are promising candidate for biodegradable polymers, however, the production cost limit their application on an industrial scale. This article provides an overview of various substrates, microorganisms for the economical production of PHAs and its copolymers. Recent advances in PHAs to reduce the cost and to improve the performance of PHAs have also been discussed. PMID- 27126174 TI - Half-dose photodynamic therapy for chronic central serous chorioretinopathy: Efficacy and safety outcomes in real world. AB - PURPOSE: To have an insight of the outcomes of half-dose photodynamic therapy (PDT) for patients with chronic central serous chorioretinopathy (CSC) in a real world population. MATERIAL AND METHODS: This is a retrospective consecutive case series, one-centre study, with a 12-month follow-up period. RESULTS: The study took into account 15 eyes of 13 patients. All patients were male in gender and only 1 eye belonged to a non-caucasian. The sample mean age was 51,27+/-11,66 (between 36 and 74 years); mean baseline best-corrected visual acuity (BCVA) was 0,40+/-0,25 logMAR and central macular thickness (CMT) was 411,40+/-88,44MUm. All patients had subretinal fluid (SRF) and retinal pigment epithelium (RPE) detachment involving the fovea. In a month time, BCVA and CMT had remarkable improvements with only one eye not gaining letters. At 6-month visit, 46,7% of the eyes were provided with additional treatment (intra-vitreal anti-VEGF or PDT). In the final visit no eye had worsened more than 5 letters and 53,3% had a BCVA improvement of at least 5 letters, with only 2 eyes remaining with RPE detachment and SRF. There was a steady regression in CMT throughout the follow up; 93,3% had CMT under 300MUm and CMT mean was 249,93+/-72,78MUm. There were no reported complications. CONCLUSION: These results support PDT as a valuable approach for therapeutic decisions on chronic CSC as well as the need of other add up treatments for a better final outcome. Further evaluations with longer follow-up's should be taken into consideration for safety issues. PMID- 27126173 TI - Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions. AB - The von Hippel-Lindau (VHL) tumour suppressor gene is bi-allelically inactivated in the majority of cases of clear cell renal cell carcinoma (ccRCC); however, Vhl knockout mouse models do not recapitulate human ccRCC, implying that additional mutations are required for tumour formation. Mutational inactivation of VHL sensitises renal epithelial cells to lose the primary cilium in response to other mutations or extracellular stimuli. Loss of cilia is believed to represent a second hit in VHL mutant cells that causes the development of cystic lesions that, in some cases, can progress to ccRCC. Supporting this idea, genetic ablation of the primary cilium by deletion of the kinesin family member 3A (Kif3a) gene cooperates with loss of Vhl to accelerate cyst formation in mouse kidneys. Additionally, aged Vhl/Trp53 double-mutant mice develop renal cysts and tumours at a relatively low incidence, suggesting that there is a genetic cooperation between VHL and TP53 mutation in the development of ccRCC. Here we generated renal epithelium-specific Kif3a/Trp53 and Vhl/Kif3a/Trp53 mutant mice to investigate whether primary cilium deletion would accelerate the development of cystic precursor lesions or cause their progression to ccRCC. Longitudinal microcomputed tomography (MUCT) imaging and histopathological analyses revealed an increased rate of cyst formation, increased proportion of cysts with proliferating cells, higher frequency of atypical cysts as well as the development of neoplasms in Vhl/Kif3a/Trp53 mutant kidneys compared to Kif3a/Trp53 or Vhl/Kif3a mutant kidneys. These findings demonstrate that primary cilium loss, in addition to Vhl and Trp53 losses, promotes the transition towards malignancy and provide further evidence that the primary cilium functions as a tumour suppressor organelle in the kidney. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27126175 TI - Femtosecond laser intrastromal incisions as fiducial marks for alignment of toric IOLs. PMID- 27126176 TI - Accelerating and increasing nano-scaled pore formation on electrospun poly(3 hydroxybutyrate-co-3-hydroxyvalerate) fibers. AB - Porous fibers are advantageous for filtration systems, drug delivery systems, and in the field of tissue engineering, in comparison to their non-porous counterparts. In this study, we developed a facile technique including two steps to generate poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV) porous fibers with a controllable pore size. An electrospinning technique was employed to obtain five types of PHBV/poly(ethylene oxide) (PEO)-blended fibers (PHBV:PEO = 9:1, 8:2, 7:3, 6:4, 5:5) with PEO as the porogen. PEO was leached out by simulated body fluid (SBF) and water, respectively. The pore morphology and calcium deposition of the resulting fibers were compared to those formed on film through the SEM-EDX analysis. It was revealed that pore size and number increased with increasing PEO percentage in the fiber or film. The pore size on the films (at micrometer scale) was much larger than that of nanofibers, which was in the range of 70-120 nm. The simultaneous removal of PEO and deposition of calcium phosphate through SBF buffer enhanced synergistically both the pore formation and mineral deposition. The different phase separation mechanisms explain the different pore morphologies in the film and the nanofibers. The cellular experimental results show that fibers with nanometer-scale pores and minerals can enhance the proliferation of bone marrow-derived mesenchymal stem cells. PMID- 27126177 TI - Implementing healthier foodservice guidelines in hospital and federal worksite cafeterias: barriers, facilitators and keys to success. AB - BACKGROUND: Healthy foodservice guidelines are being implemented in worksites and healthcare facilities to increase access to healthy foods by employees and public populations. However, little is known about the barriers to and facilitators of implementation. The present study aimed to examine barriers to and facilitators of implementation of healthy foodservice guidelines in federal worksite and hospital cafeterias. METHODS: Using a mixed-methods approach, including a quantitative survey followed by a qualitative, in-depth interview, we examined: (i) barriers to and facilitators of implementation; (ii) behavioural design strategies used to promote healthier foods and beverages; and (iii) how implementation of healthy foodservice guidelines influenced costs and profitability. We used a purposive sample of five hospital and four federal worksite foodservice operators who recently implemented one of two foodservice guidelines: the United States Department of Health and Human Services/General Services Administration Health and Sustainability Guidelines ('Guidelines') in federal worksites or the Partnership for a Healthier America Hospital Healthier Food Initiative ('Initiative') in hospitals. Descriptive statistics were used to analyse quantitative survey data. Qualitative data were analysed using a deductive approach. RESULTS: Implementation facilitators included leadership support, adequate vendor selections and having dietitians assist with implementation. Implementation barriers included inadequate selections from vendors, customer complaints and additional expertise required for menu labelling. Behavioural design strategies used most frequently included icons denoting healthier options, marketing using social media and placement of healthier options in prime locations. CONCLUSIONS: Lessons learned can guide subsequent steps for future healthy foodservice guideline implementation in similar settings. PMID- 27126180 TI - Effect and mechanism of a High Gradient Magnetic Separation (HGMS) and Ultraviolet (UV) composite process on the inactivation of microbes in ballast water. AB - The patented technology of a High Gradient Magnetic Separation (HGMS)-Ultraviolet (UV) composite process was used to treat ballast water. Staphylococcus aureus (S. aureus) was selected as the reference bacteria. After treatment by the HGMS-UV process, the concentration of S. aureus on the log 10 scale was lower than 2 at different flow rates, S. aureus suffered the most serious damage, and K(+) leakage of the bacteria was 1.73mg/L higher than separate 60min UV irradiation (1.17mg/L) and HGMS (0.12mg/L) processes. These results demonstrated that the HGMS-UV composite process was an effective approach to treat ballast water. Further, the HGMS process had synergistic action on the subsequent UV irradiation process and accelerated cell membrane damage. Meanwhile, the results of superoxide dismutase (SOD) activities of bacteria and DNA band analyses indicated that the inactivation mechanisms were different for HGMS and UV irradiation. PMID- 27126178 TI - Small molecules that allosterically inhibit p21-activated kinase activity by binding to the regulatory p21-binding domain. AB - p21-activated kinases (PAKs) are key regulators of actin dynamics, cell proliferation and cell survival. Deregulation of PAK activity contributes to the pathogenesis of various human diseases, including cancer and neurological disorders. Using an ELISA-based screening protocol, we identified naphtho(hydro)quinone-based small molecules that allosterically inhibit PAK activity. These molecules interfere with the interactions between the p21-binding domain (PBD) of PAK1 and Rho GTPases by binding to the PBD. Importantly, they inhibit the activity of full-length PAKs and are selective for PAK1 and PAK3 in vitro and in living cells. These compounds may potentially be useful for determining the details of the PAK signaling pathway and may also be used as lead molecules in the development of more selective and potent PAK inhibitors. PMID- 27126179 TI - Skin health and safety at work in Croatian hairdressing apprentices. AB - BACKGROUND: The risk of developing occupational skin disease (OSD) is high in hairdressers, but may differ between countries. OBJECTIVE: To evaluate safety at work measures, and the prevalence and severity of skin symptoms and their impact on quality of life (QoL), among Croatian hairdressing apprentices. METHODS: Data on self-reported skin symptoms, safety measures and QoL were collected for 101 final-year apprentices. The presence and severity of skin lesions were assessed with the Osnabrueck Hand Eczema Severity Index (OHSI). Transepidermal water loss (TEWL) was measured on the forearm and hand. RESULTS: Ninety-one percent of apprentices reported wearing gloves while dyeing hair, 45% while rinsing hair dyes, and 4% while washing hair. A history of skin symptoms was found in 35% of apprentices, and a history of dry hands in 37%. Skin changes were clinically observed in 40% of apprentices, most frequently erythema, infiltration, and desquamation. The OHSI score ranged from 0 to 6. Only washing hands >20 times per day was positively associated with TEWL. A history of skin symptoms negatively correlated with self-esteem, and social and mental functioning, and positively with anxiety and depression. CONCLUSIONS: The results indicate the need for the continuation of efforts to establish effective primary preventive programmes for OSDs at national and EU levels. PMID- 27126181 TI - Algicidal and denitrification characterization of Acinetobacter sp. J25 against Microcystis aeruginosa and microbial community in eutrophic landscape water. AB - Acinetobacter sp. J25 exhibited good denitrification and high algicidal activity against toxic Microcystis aeruginosa. Response surface methodology (RSM) experiments showed that the maximum algicidal ratio occurred under the following conditions: temperature, 30.46 degrees C; M. aeruginosa density, 960,000cellsmL( 1); and inoculum, 23.75% (v/v). Of these, inoculum produced the maximum effect. In the eutrophic landscape water experiment, 10% bacterial culture was infected with M. aeruginosa cells in the landscape water. After 24days, the removal ratios of nitrate and chlorophyll-a were high, 100% and 87.86%, respectively. The denitrification rate was approximately 0.118mgNO3(-)-N.L(-1).h(-1). Moreover, the high-throughput sequencing result showed that Acinetobacter sp. J25 was obviously beneficial for chlorophyll-a and nitrate removal performance in the eutrophic landscape water treatment. Therefore, strain J25 is promising for the simultaneous removal of chlorophyll-a and nitrate in the eutrophic landscape water treatment. PMID- 27126182 TI - Pollutant levels in discarded fish species by Spanish trawlers operating in the Great Sole Bank and the Atlantic coast of the Iberian Peninsula. AB - Organic and inorganic pollutant levels were determined for the most discarded species from trawlers operating in Great Sole and Spanish coastal fishing grounds. Results for heavy metals indicated that Cd can reach values higher than legal limits for some species and tissues, while Hg and Pb concentrations are below established values. No significant variation was noticed with fishing grounds, but both season influences in the case of Pb and interspecies variation for Hg and Cd have been detected. Valorization recommendations could be therefore established according to the levels found in the different species. PMID- 27126183 TI - Water flux management and phytoplankton communities in a Mediterranean coastal lagoon. Part II: Mixotrophy of dinoflagellates as an adaptive strategy? AB - Dinoflagellate proliferation is common in coastal waters, and trophic strategies are often advanced to explain the success of these organisms. The Biguglia lagoon is a Mediterranean brackish ecosystem where eutrophication has long been an issue, and where dominance of dinoflagellates has persisted for several years. Monthly monitoring of fluorescence-based properties of phytoplankton communities carried out in 2010 suggested that photosynthesis alone could not support the observed situation all year round. Contrasting food webs developed depending on the hydrological season, with a gradual shift from autotrophy to heterotrophy. Progressively, microphytoplankton assemblages became unequivocally dominated by a Prorocentrum minimum bloom, which exhibited very weak effective photosynthetic performance, whereas paradoxically its theoretical capacities remained fully operational. Different environmental hypotheses explaining this discrepancy were examined, but rejected. We conclude that P. minimum bloom persistence is sustained by mixotrophic strategies, with complex compromises between phototrophy and phagotrophy, as evidenced by fluorescence-based observations. PMID- 27126184 TI - The Mouse-colored Tyrannulet (Phaeomyias murina) is a species complex that includes the Cocos Flycatcher (Nesotriccus ridgwayi), an island form that underwent a population bottleneck. AB - Simultaneous examination of evolutionary history in island forms and closely related mainland relatives can provide reciprocal insight into the evolution of island and mainland faunas. The Cocos Flycatcher (Nesotriccus ridgwayi) is a small tyrant flycatcher (Tyrannidae) endemic to Cocos Island, an oceanic island in the eastern Pacific Ocean. We first established its close relationship to the mainland species Mouse-colored Tyrannulet (Phaeomyias murina) using a phylogeny from genome-wide ultraconserved elements and exons. We then used mitochondrial DNA to explore the relationships between Nesotriccus and Phaeomyias populations from across its distribution in Central and South America. We found that Nesotriccus is nested within the Phaeomyias evolutionary tree, and that Phaeomyias represents a complex of at least four evolutionarily distinct species that differ in plumage, voice, and habitat association. Nesotriccus underwent a population bottleneck subsequent to its divergence from Central American and northern South American Phaeomyias populations in the middle Pleistocene. The 46 UCE loci containing alleles that are fixed between the two species are widely distributed across the genome, which suggests that selective or neutral processes responsible for divergence have occurred genome-wide. Overall, our simultaneous examination of Phaeomyias and Nesotriccus revealed divergent levels of genetic diversity and evolutionary histories between island and mainland forms. PMID- 27126185 TI - Resolution of inter and intra-species relationships of the West Indian fruit fly Anastrepha obliqua. AB - The West Indian fruit fly, Anastrepha obliqua (Diptera: Tephritidae), is an economically important pest that inhabits areas of South and Central America, Mexico and the Caribbean with occasional infestations in the southern United States. We examine intra-specific relationships within A. obliqua as well as interspecific relationships to other Anastrepha species using a multi-locus data set comprising nine loci (seven nuclear, two mitochondrial) with 105 operational taxonomic units. The results based on a concatenated set of nuclear loci strongly support the monophyly of A. obliqua and most of the other species previously identified by morphology. A split between Peruvian A. obliqua samples and those from other locations was also identified. These results contrast with prior findings of relationships within A. obliqua based on mitochondrial data, as we found a marked discrepancy between nuclear and mitochondrial loci. These analyses suggest that introgression, particularly between A. obliqua and fraterculus species, may be one explanation for the discrepancy and the high mitochondrial diversity reported for A. obliqua could be the result of incomplete lineage sorting. PMID- 27126186 TI - Study of Gefitinib and Pemetrexed as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutation. AB - To evaluate the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Patients and methods Patients with advanced non squamous NSCLC harboring asensitive EGFR mutation were included in this study and randomly divided into gefitinib + placebo group and gefitinib + pemetrexed group. Pemetrexed or placebo was administered on day 1 at a dose of 500 mg/m(2), and gefitinib was sequentially administered on days 2 ~ 16. This treatment regimen was repeated every 3 weeks until disease progression. All investigators and participants were masked to treatment allocation. The overall response rate (ORR) and disease control rate (DCR) of gefitinib + pemetrexed group were higher than that of gefitinib + placebo group but only the difference of DCR between two groups was statistically significant (P < 0.05). The median progression-free survival (PFS) of gefitinib + placebo group and gefitinib + pemetrexed group were 14.0 months vs. 18 months respectively and the difference was statistically significant (P < 0.05). The 2-year PFS rates of gefitinib + pemetrexed group (20.00 %) was higher than that of gefitinib + placebo group (8.89 %) and the difference was statistically significant (P < 0.05). The median overall survival (OS) of gefitinib + placebo group and gefitinib + pemetrexed group were 32.0 months vs. 34 months respectively and the difference was not statistically significant (P > 0.05). The 3-year OS rates of gefitinib + pemetrexed group (44.44 %) was higher than that of gefitinib + placebo group (35.56 %) but the difference was not statistically significant (P > 0.05). Major grade 3 or 4 hematological toxicities included neutropenia, leukopenia and anemia. The main grade 3 or 4 non-hematological toxicities were infection, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, fatigue, diarrhea and pneumonitis. The difference of toxicities between two groups was not statistically significant (P > 0.05). The combination regimen of gefitinib + pemetrexed used in this study showed a higher ORR and DCR, longer median PFS and acceptable toxicity. PMID- 27126187 TI - Chemical composition and antifungal activity of Satureja hortensis L. essentiall oil against planktonic and biofilm growth of Candida albicans isolates from buccal lesions of HIV(+) individuals. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Oral candidiasis is an opportunistic infection of the oral cavity which usually occurs in the immunocompromised individuals. Candida albicans (C. albicans) is the most common species of yeast responsible for oral candidiasis. This study investigated the effects of Satureja hortensis L. essentiall oil (EO) on the planktonic, biofilm formation and mature biofilms of C. albicans isolates from buccal lesions of HIV(+) individuals. MATERIALS AND METHODS: MTT reduction assay, broth micro-dilution method and scanning electron microscopy (SEM) were employed to determine the effect of mentioned EO on the C. albicans planktonic and biofilm forms. GC-GC/MS was used to detect the major active compounds of EO. RESULTS: Thymol (45.9%), gamma-terpinen (16.71%), carvacrol (12.81%) and p-cymene (9.61%) were found as the most abundant constituents. MIC values ranged from 250 to 400 MUg/ml and MFC values ranged from 350 to 500 MUg/ml. All C. albicans isolates formed biofilm on polystyrene plats but the quantity of biofilm mass (optical density) was different for the isolates ranging from 0.850 to 0.559 nm. The mean of biofilm formation by C. albicans isolates was reduced by 87.1 +/- 3.7%, 73.6 +/- 5.1%, 69.4 +/- 5.3% and 67 +/- 4.2% at 4800, 3200, 2400 and 1600 MUg/ml, respectively. In sub-MIC concentration, SEM analysis revealed loosening of cells, deformity of three dimensional structures of biofilms and shrinkage in cell membranes of sessile cells. CONCLUSIONS: In conclusion, the substantial anti-fungal activity showed by S. hortensis L. EO suggests exploitation of this oil as potential natural anti biofilm product to deal with the problem of buccal cavity lesion associated with C. albicans. PMID- 27126189 TI - Erratum to: Liver transcriptomic networks reveal main biological processes associated with feed efficiency in beef cattle. PMID- 27126190 TI - Isorecticular Synthesis of Dissectible Molecular Bamboo Tubes of Hexarhenium(I) Benzene-1,2,3,4,5,6-hexaolate Complexes. AB - A family of bamboo-like metal-organic nanotubes consisting of in situ synthesized macromolecular blocks (MB) is reported. The MBs are composed of six fac-(CO)3 Re cores, one benzene-1,2,3,4,5,6-hexaolate plate, and six pyridine-derivative pillar ligands, which have a doubly tri-legged geometry and can be mutually assembled, piece by piece. This entire system is characterized as a simple but precise supramolecular complexation of these macromolecular blocks and further introduces an archetypal approach to systematically constructing a tunable form of dissectible molecular bamboo tubes. PMID- 27126188 TI - The Ionotropic Receptors IR21a and IR25a mediate cool sensing in Drosophila. AB - Animals rely on highly sensitive thermoreceptors to seek out optimal temperatures, but the molecular mechanisms of thermosensing are not well understood. The Dorsal Organ Cool Cells (DOCCs) of the Drosophila larva are a set of exceptionally thermosensitive neurons critical for larval cool avoidance. Here, we show that DOCC cool-sensing is mediated by Ionotropic Receptors (IRs), a family of sensory receptors widely studied in invertebrate chemical sensing. We find that two IRs, IR21a and IR25a, are required to mediate DOCC responses to cooling and are required for cool avoidance behavior. Furthermore, we find that ectopic expression of IR21a can confer cool-responsiveness in an Ir25a-dependent manner, suggesting an instructive role for IR21a in thermosensing. Together, these data show that IR family receptors can function together to mediate thermosensation of exquisite sensitivity. PMID- 27126192 TI - Pulmonary nodules in a man with a history of bone marrow transplantation. PMID- 27126193 TI - Pathological changes in herniated organs: squamous metaplasia in an inguino scrotal bladder hernia. PMID- 27126194 TI - Liposomal butamben gel formulations: toxicity assays and topical anesthesia in an animal model. AB - The aim of this study was to evaluate the in vitro cytotoxicity and the in vivo analgesic effect and local toxicity of the local anesthetic butamben (BTB) encapsulated in conventional or elastic liposomes incorporated in gel formulations. The results showed that both gel formulations of liposomal BTB reduced the cytotoxicity (p < 0.001; one-way ANOVA/Tukey's test) and increased the topical analgesic effect (p < 0.05; one-way ANOVA/Tukey's test) of butamben, compared to plain BTB gel. The gel formulations presented good rheological properties, and stability assays detected no differences in physicochemical stability up to 30 d after preparation. Moreover, histological assessment revealed no morphological changes in rat skin after application of any of the gel formulations tested. PMID- 27126191 TI - Potential pathways by which maternal second-hand smoke exposure during pregnancy causes full-term low birth weight. AB - It is well documented that maternal exposure to second-hand smoke (SHS) during pregnancy causes low birth weight (LBW), but its mechanism remains unknown. This study explored the potential pathways. We enrolled 195 pregnant women who delivered full-term LBW newborns, and 195 who delivered full-term normal birth weight newborns as the controls. After controlling for maternal age, education level, family income, pre-pregnant body mass index, newborn gender and gestational age, logistic regression analysis revealed that LBW was significantly and positively associated with maternal exposure to SHS during pregnancy, lower placental weight, TNF-alpha and IL-1beta, and that SHS exposure was significantly associated with lower placental weight, TNF-alpha and IL-1beta. Structural equation modelling identified two plausible pathways by which maternal exposure to SHS during pregnancy might cause LBW. First, SHS exposure induced the elevation of TNF-alpha, which might directly increase the risk of LBW by transmission across the placenta. Second, SHS exposure first increased maternal secretion of IL-1beta and TNF-alpha, which then triggered the secretion of VCAM 1; both TNF-alpha and VCAM-1 were significantly associated with lower placental weight, thus increasing the risk of LBW. In conclusion, maternal exposure to SHS during pregnancy may lead to LBW through the potential pathways of maternal inflammation and lower placental weight. PMID- 27126195 TI - Does Bt maize expressing Cry1Ac protein have adverse effects on the parasitoid Macrocentrus cingulum (Hymenoptera: Braconidae)? AB - The potential effects of insect-resistant, genetically engineered (GE) crops on non-target organisms, especially on predators and parasitoids, must be evaluated before their commercial cultivation. The effects of GE maize that produces Cry1Ac toxin on the parasitoid Macrocentrus cingulum were assessed by direct bioassay and indirect bioassay. In the indirect bioassay, parasitism rate, cocoon weight and the number of M. cingulum progeny produced per host were significantly reduced when M. cingulum-parasitized Cry1Ac-susceptible Ostrinia furnacalis were fed a diet containing purified Cry1Ac; however, life-table parameters of M. cingulum were not adversely affected when the same assay was performed with Cry1Ac-resistant O. furnacalis. These results indicated that the detrimental effects detected with a Cry1Ac-susceptible host were mediated by poor host quality. In a direct bioassay, no difference in life-table parameters were detected when M. cingulum adults were directly fed a 20% honey solution with or without Cry1Ac; however, survival and longevity were significantly reduced when M. cingulum adults were fed a honey solution containing potassium arsenate, which was used as a positive control. The stability and bioactivity of Cry1Ac toxin in the food sources and Cry1Ac toxin uptake by the host insect and parasitoid were confirmed by enzyme-linked immunosorbent assay and sensitive-insect bioassays. Our results demonstrate that M. cingulum is not sensitive to Cry1Ac toxin at concentrations exceeding those encountered in Bacillus thuringiensis maize fields. This study also demonstrates the power of using resistant hosts when assessing the risk of genetically modified plants on non-target organisms and will be useful for assessing other non-target impacts. PMID- 27126196 TI - Effectiveness of integrative medicine therapy on coronary artery disease prognosis: A real-world study. AB - OBJECTIVE: To evaluate the effectiveness of integrative medicine (IM) on patients with coronary artery disease (CAD) and investigate the prognostic factors of CAD in a real-world setting. METHODS: A total of 1,087 hospitalized patients with CAD from four hospitals in Beijing, China were consecutively selected between August 2011 and February 2012. The patients were assigned to two groups based on the treatment: Chinese medicine (CM) plus conventional treatment, i.e., IM therapy (IM group); or conventional treatment alone (CT group). The endpoint was major adverse cardiac events [MACE; including cardiac death, myocardial infarction (MI), and revascularization]. RESULTS: A total of 1,040 patients finished the 2 year follow-up. Of them, 49.4% (514/1,040) received IM therapy. During the 2-year follow-up, the total incidence of MACE was 11.3%. Most of the events involved revascularization (9.3%). Cardiac death/MI occurred in 3.0% of cases. For revascularization, logistic stepwise regression analysis revealed that age >= 65 years [odds ratio (OR), 2.224], MI (OR, 2.561), diabetes mellitus (OR, 1.650), multi-vessel lesions (OR, 2.554), baseline high sensitivity C-reactive protein level >= 3 mg/L (OR, 1.678), and moderate or severe anxiety/depression (OR, 1.849) were negative predictors (P<0.05); while anti-platelet agents (OR, 0.422), beta-blockers (OR, 0.626), statins (OR, 0.318), and IM therapy (OR, 0.583) were protective predictors (P<0.05). For cardiac death/MI, age >= 65 years (OR, 6.389) and heart failure (OR, 7.969) were negative predictors (P<0.05), while statin use (OR, 0.323) was a protective predictor (P<0.05) and IM therapy showed a benefifi cial tendency (OR, 0.587), although the difference was not statistically signififi cant (P=0.218). CONCLUSION: In a real-world setting, for patients with CAD, IM therapy was associated with a decreased incidence of revascularization and showed a potential benefifi t in reducing the incidence of cardiac death or MI. PMID- 27126197 TI - Self-assessment of skin tightness severity by scleroderma patients. AB - AIMS: Skin tightness progression determines the severity and mortality of systemic sclerosis (SSc). The modified Rodnan skin score (mRSS) is a skin tightness assessment tool, albeit inter-physician variability is a limitation. Our objectives were to evaluate the correlation and agreement of skin tightness assessment between patient self-assessment and physician-assessment. METHODS: A descriptive study was conducted on the masked, self-assessments of mRSS (at week 0, 4 and 12) by 23 Thai adult SSc patients seen at Srinagarind Hospital, KhonKaen University, between March 2014 and February 2015. Correlation between the physician and patient assessments was estimated using Pearson's. The intra-class correlation coefficient (ICC) and limit of agreement by Bland-Altman were determined. RESULTS: We included 23 SSc patients (female to male ratio being 1.1:1). All had the diffuse cutaneous SSc subset. The skin thickness assessment correlation was moderate at baseline (Pearson's r = 0.68) and improved to a good correlation at week 4 and 12 (r = 0.78 and 0.86, respectively). The ICC showed good agreement (0.761) at week 0 and increased to excellent at week 4 (0.846) and 12 (0.910). The patient self-assessment score was higher than the physician assessment, which slightly decreased over time: mean difference = 4.30 (95% LOA; 9.54 to 18.14) at week 0, then 3.78 (95% LOA,-10.20 to 17.77) at week 4, and 3.16 (95% LOA,-7.78 to 14.10) at week 12. CONCLUSION: The respective modified Rodnan skin score assessment by patient versus the physician was highly correlated with a high level of agreement. Validation of generalized patient self-assessment needs to be confirmed. PMID- 27126198 TI - Visfatin correlates with hot flashes in postmenopausal women with metabolic syndrome: effects of genistein. AB - During menopause, an increased prevalence of metabolic syndrome (MetS) and central obesity seems to increase hot flashes (HFs). Visfatin is an inflammatory adipokine secreted by visceral fat. We investigated visfatin levels and its relationship with hot flash number and BMI, in postmenopausal women with MetS. We also evaluated the effect of genistein, an isoflavone effective in reducing HFs, on visfatin levels and HFs after 1 year of treatment. This was a randomized, double-blind, placebo-controlled trial. Postmenopausal women with MetS were randomly assigned to receive placebo (n = 60) or 54 mg genistein (n = 60), daily for 1 year. As main outcome measures, hot flashes number and circulating visfatin levels were evaluated. Visfatin significantly correlated with BMI and HFs number in women with MetS at basal. After 6 and 12 months, our results indicate a strong correlation and a significant effect of genistein in reducing both HFs and visfatin in women with MetS. The present study suggests that visfatin plays a role in the vasomotor symptoms, at least in postmenopausal women with metabolic syndrome. Genistein may reduce HFs decreasing the circulating levels of this inflammatory adipokine. PMID- 27126199 TI - The LIM-homeodomain transcription factor Islet2a promotes angioblast migration. AB - Angioblasts of the developing vascular system require many signaling inputs to initiate their migration, proliferation and differentiation into endothelial cells. What is less studied is which intrinsic cell factors interpret these extrinsic signals. Here, we show the Lim homeodomain transcription factor islet2a (isl2a) is expressed in the lateral posterior mesoderm prior to angioblast migration. isl2a deficient angioblasts show disorganized migration to the midline to form axial vessels and fail to spread around the tailbud of the embryo. Isl2a morphants have fewer vein cells and decreased vein marker expression. We demonstrate that isl2a is required cell autonomously in angioblasts to promote their incorporation into the vein, and is permissive for vein identity. Knockout of isl2a results in decreased migration and proliferation of angioblasts during intersegmental artery growth. Since Notch signaling controls both artery-vein identity and tip-stalk cell formation, we explored the interaction of isl2a and Notch. We find that isl2a expression is negatively regulated by Notch activity, and that isl2a positively regulates flt4, a VEGF-C receptor repressed by Notch during angiogenesis. Thus Isl2a may act as an intermediate between Notch signaling and genetic programs controlling angioblast number and migration, placing it as a novel transcriptional regulator of early angiogenesis. PMID- 27126200 TI - Opening the 'black box' of performance-based financing in low- and lower middle income countries: a review of the literature. AB - Although performance-based financing (PBF) receives increasing attention in the literature, a lot remains unknown about the exact mechanisms triggered by PBF arrangements. This article aims to summarize current knowledge on how PBF works, set out what still needs to be investigated and formulate recommendations for researchers and policymakers from donor and recipient countries alike. Drawing on an extensive systematic literature review of peer-reviewed journals, we analysed 35 relevant articles. To guide us through this variety of studies, point out relevant issues and structure findings, we use a comprehensive analytical framework based on eight dimensions. The review inter alia indicates that PBF is generally welcomed by the main actors (patients, health workers and health managers), yet what PBF actually entails is less straightforward. More research is needed on the exact mechanisms through which not only incentives but also ancillary components operate. This knowledge is essential if we really want to appreciate the effectiveness, desirability and appropriate format of PBF as one of the possible answers to the challenges in the health sector of low-and lower middle-income countries. A clear definition of the research constructs is a primordial starting point for such research. PMID- 27126201 TI - Urbanization and human health in urban India: institutional analysis of water borne diseases in Ahmedabad. AB - Diseases are rapidly urbanizing. Ageing infrastructures, high levels of inequality, poor urban governance, rapidly growing economies and highly dense and mobile populations all create environments rife for water-borne diseases. This article analyzes the role of institutions as crosscutting entities among a myriad of factors that breed water-borne diseases in the city of Ahmedabad, India. It applies 'path dependency' and a 'rational choice' perspective to understand the factors facilitating the breeding of diseases. This study is based on household surveys of approximately 327 households in two case study wards and intermittent interviews with key informants over a period of 2 years. Principle component analysis is applied to reduce the data and convert a set of observations, which potentially correlate with each other, into components. Institutional analyses behind these components reveal the role of social actors in exploiting the deeply rooted inefficiencies affecting urban health. This has led to a vicious cycle; breaking this cycle requires understanding the political dynamics that underlie the exposure and prevalence of diseases to improve urban health. PMID- 27126202 TI - Morgagni hernia presenting with massive pericardial effusion and ascites: prenatal management by thoraco-amniotic shunting and fetal endoscopic tracheal occlusion (FETO) and review of the literature. AB - BACKGROUND: Morgagni hernia presents a rare type of congenital diaphragmatic hernia (CDH, about 2-5 %) (Herman, J Perinatol 21:343-344, 2001), which is characterized by an anterior mainly right-sided defect of the diaphragm. Infrequently, this is combined with a herniation of the liver into the pericardial cavity (Ake, Prenat Diagn 11:719-724, 1991; Stevens, Pediatr Radiol 26:791-793, 1996). This may cause massive pericardial effusion and subsequently lung hypoplasia (Pober et al., Congenital diaphragmatic hernia overview, University of Washington, Seattle, 2015; Ikeda, J Perinat Med 30:336-340, 2002; Hara, J Obstet Gynaecol Res 33:561-565, 2007). So far only few cases have been reported in fetal life. CASE: We report a case of Morgagni hernia with pericardiodiaphragmatic aplasia, complicated by two-compartment effusions (massive pericardial effusion and mild ascites), diagnosed in the second trimester. The case was successfully managed in utero with thoraco-amniotic shunting and late tracheal occlusion, followed by corrective surgery after birth. DISCUSSION: A review of the literature was performed, identifying 13 cases of prenatally diagnosed Morgagni hernia. The diagnosis was established by the sonographic findings of pericardial effusion und intrathoracic herniation of the liver. In only two cases a prenatal intervention was carried out. All neonates were operated postnatally with excellent final outcome. PMID- 27126203 TI - Feasibility of Cold Snare Polypectomy for Multiple Duodenal Adenomas in Patients with Familial Adenomatous Polyposis: A Pilot Study. PMID- 27126204 TI - Partner Burden: A Common Entity in Celiac Disease. AB - BACKGROUND: Caregiver burden is documented in several chronic diseases, but it has not been investigated in celiac disease (CD). AIMS: We aim to quantify the burden to partners of CD patients and identify factors that affect the perceived burden. METHODS: We surveyed patients with biopsy-proven CD and their partners. Patients completed CD-specific questions, including the validated Celiac Symptom Index (CSI) survey. Partners completed the validated Zarit Burden Interview (ZBI) and questions regarding sexual and relationship satisfaction. Univariable and multivariable analyses were used to assess the association between demographics, CD characteristics, and partner burden. RESULTS: In total, 94 patient/partner pairs were studied. Fifteen patients (16 %) reported a CSI score associated with a poor quality of life, and 34 partners (37 %) reported a ZBI score corresponding to mild-to-moderate burden. Twenty-two partners (23 %) reported moderate-to-low overall relationship satisfaction, and 12 (14 %) reported moderate-to-low sexual satisfaction. The degree of partner burden was directly correlated with patient CSI score (r = 0.27; p = 0.008), and there were moderate-to-strong inverse relationships between partners' burden and relationship quality (r = -0.70; p < 0.001) and sexual satisfaction (r = -0.42; p < 0.001). On multivariable logistic regression, predictors of mild-to-moderate partner burden were low partner relationship satisfaction (OR 17.06, 95 % CI 2.88-101.09, p = 0.002) and relationship duration >=10 years (OR 14.42, 95 % CI 1.69-123.84, p = 0.02). CONCLUSIONS: Partner burden is common in CD, with more than one-third of partners experiencing mild-to-moderate burden. Partner burden is directly correlated with patient symptom severity, and it increases with poorer sexual and relationship satisfaction. Healthcare providers should address relationship factors in their care of patients with CD. PMID- 27126205 TI - Timing of Last Preoperative Dose of Infliximab Does Not Increase Postoperative Complications in Inflammatory Bowel Disease Patients. AB - BACKGROUND: The association between preoperative use of infliximab and postoperative complications in patients with inflammatory bowel disease (IBD) is a subject of continued debate. Results from studies examining an association between the timing of last preoperative dose of infliximab and postoperative complications remain inconsistent. AIMS: To assess whether timing of last dose of infliximab prior to surgery affects the rate of postoperative complications in patients with Crohn's disease or ulcerative colitis. METHODS: Retrospective chart review of IBD patients who have undergone surgery while receiving therapy with infliximab was conducted. Forty-seven patients were included in the analysis. RESULTS: No significant association was found between timing of infliximab and the rate of postoperative complications. Age, gender, disease type, steroid use, preoperative status, surgery type, or surgeon type was not associated with increased rate of postoperative complications. CONCLUSION: Timing of last dose of infliximab does not affect the rate of postoperative complications in patients with Crohn's disease or ulcerative colitis. PMID- 27126206 TI - Drug-induced liver injury associated with high-dose ceftriaxone: a retrospective cohort study adjusted for the propensity score. AB - PURPOSE: Ceftriaxone has been recognized as a well-tolerated drug; however, in some instances, liver dysfunction occurs after using high-dose ceftriaxone. We aimed to assess the incidence of liver injury due to high-dose ceftriaxone and to determine whether there is a dose-dependent risk of liver injury with this drug. METHODS: We conducted a retrospective cohort study of hospitalized adult patients treated with ceftriaxone at a tertiary care hospital from January 2012 to October 2013. We collected demographic and clinical data by reviewing their medical records. The incidence of liver injury based on biochemical criteria, defined as a primary outcome, was compared between patients treated with high-dose ceftriaxone (4 g/day) and those treated with a normal dose of ceftriaxone (2 g/day) for >=5 consecutive days. A propensity score for the use of high-dose ceftriaxone was calculated from five factors. RESULTS: We identified 37 patients treated with high-dose ceftriaxone and 434 patients treated with a normal dose of ceftriaxone. Among these 471 patients, 15 patients (3.2 %) experienced liver injury, of whom six patients (6/37, 16.2 %) had received high-dose ceftriaxone and nine patients (9/434, 2.1 %) had received normal doses of ceftriaxone. In the multivariate analysis adjusted for the propensity score, high-dose ceftriaxone was independently associated with liver injury (odds ratio, 7.23; 95 % confidence interval, 2.01-26.0). CONCLUSIONS: The present study revealed that high-dose ceftriaxone was associated with a significantly higher incidence of liver injury compared with the normal-dose regimen. Therefore, clinicians should carefully observe for signs of liver injury after high-dose ceftriaxone use. PMID- 27126207 TI - Solar pacing of storm surges, coastal flooding and agricultural losses in the Central Mediterranean. AB - Storm surges, leading to catastrophic coastal flooding, are amongst the most feared natural hazards due to the high population densities and economic importance of littoral areas. Using the Central Mediterranean Sea as a model system, we provide strong evidence for enhanced periods of storminess leading to coastal flooding during the last 4500 years. We show that long-term correlations can be drawn between storminess and solar activity, acting on cycles of around 2200-yr and 230-yr. We also find that phases of increased storms and coastal flooding have impacted upon mid- to late Holocene agricultural activity on the Adriatic coast. Based on the general trend observed during the second half of the 20(th) century, climate models are predicting a weakening of Mediterranean storminess. By contrast, our new data suggest that a decrease in solar activity will increase and intensify the risk of frequent flooding in coastal areas. PMID- 27126208 TI - Enhanced immunity and antiviral effects of an HBV DNA vaccine delivered by a DC targeting protein. AB - DNA vaccine targeting delivery to DC represents one effective strategy to improve the immunogenicity of the vaccine. In a previous study, we developed a novel DC targeting recombinant protein that can deliver plasmid DNA to DCs by an electrostatic coupling effect and can thus improve the uptake efficiency of DCs, improving the expression of plasmid DNA in DCs. In this study, we coupled the protein with the HBV DNA vaccine pSVK-HBVA and investigated whether the immunogenicity and antiviral ability of the vaccine can be improved in HBV transgenic mice. The results show that a stronger specific immune response can be induced in mice after immunization with the coupling vaccine. The HBV DNA copy number and circulating antigen HBsAg in the serum of HBV transgenic mice were significantly decreased. Therefore, this study has demonstrated that the DC targeting protein has the ability to improve the immunogenicity and the antiviral activity of the HBV DNA vaccine pSVK-HBVA. These findings indicate that this DC targeting protein can be a potential method for the delivery of DNA vaccines directly to DCs. PMID- 27126209 TI - Multipolar interference for non-reciprocal nonlinear generation. AB - We show that nonlinear multipolar interference allows achieving not only unidirectional, but also non-reciprocal nonlinear generation from a nanoelement, with the direction of the produced light decoupled from the direction of at least one of the excitation beams. Alternatively, it may allow inhibiting the specified nonlinear response in a nanoelement or in its periodic arrangement by reversing the direction of one of the pumps. These general phenomena exploit the fact that, contrary to the linear response case, nonlinear magneto-electric interference stems from a combination of additive and multiplicative processes and includes an interference between various terms within the electric and magnetic partial waves themselves. We demonstrate the introduced concept numerically using an example of a plasmonic dimer geometry with realistic material parameters. PMID- 27126211 TI - Microjets and coated wheels: versatile tools for exploring collisions and reactions at gas-liquid interfaces. AB - This tutorial review describes experimental aspects of two techniques for investigating collisions and reactions at the surfaces of liquids in vacuum. These gas-liquid scattering experiments provide insights into the dynamics of interfacial processes while minimizing interference from vapor-phase collisions. We begin with a historical survey and then compare attributes of the microjet and coated-wheel techniques, developed by Manfred Faubel and John Fenn, respectively, for studies of high- and low-vapor pressure liquids in vacuum. Our objective is to highlight the strengths and shortcomings of each technique and summarize lessons we have learned in using them for scattering and evaporation experiments. We conclude by describing recent microjet studies of energy transfer between O2 and liquid hydrocarbons, HCl dissociation in salty water, and super-Maxwellian helium evaporation. PMID- 27126210 TI - Comparison of PTCH1, COX-2, p53, and Ki-67 protein expression in basal cell carcinomas of nodular and superficial subtypes arising on the head and trunk. AB - BACKGROUND: There is some evidence that basal cell carcinomas (BCCs) arising on different anatomic sites and developing to different histological subtypes differ in their pathophysiology. The expression of a number of proteins, including PTCH1, COX-2, p53, and Ki-67, is frequently altered in BCC development. OBJECTIVES: This study sought to determine whether protein expression differs between BCCs at different anatomic sites and of different histological subtypes. METHODS: Expression of PTCH1, COX-2, p53, and Ki-67 proteins was compared between: (i) BCCs arising on the head (n = 55) and trunk (n = 53), and (ii) nodular (n = 52) and superficial (n = 43) BCCs. The intensity of immunohistochemistry (IHC) staining (low, moderate, strong, very strong) for PTCH1 and COX-2 proteins was measured and the proportions of p53- and Ki-67 positive cells quantified. RESULTS: The proportion of cells expressing Ki-67 was higher in tumor tissue than in non-malignant epidermis, whereas the opposite was found for PTCH1. The IHC staining intensity for PTCH1 was substantially greater in truncal BCCs than in BCCs on the head (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.63-8.96). The intensity of staining for PTCH1 was greater for superficial than for nodular BCCs (OR 3.70, 95% CI 1.53-8.97), and superficial BCCs showed a higher proportion of Ki-67-positive cells (OR 5.57, 95% CI 1.66 18.67). CONCLUSIONS: These differences suggest that the pathophysiology of BCC differs between lesions on the head and trunk and between nodular and superficial subtypes, perhaps indicating differences in their etiology. PMID- 27126212 TI - Classic Spotlight: Out of the Muk, the First Chromosomal Condensin. PMID- 27126213 TI - Classic Spotlight: Staying in Shape and Discovery of the mrdAB and mreBCD Operons. PMID- 27126216 TI - Ketogenic diet - A novel treatment for early epileptic encephalopathy due to PIGA deficiency. AB - We describe the presentation and workup of two brothers with early-onset epileptic encephalopathy who became seizure-free on a ketogenic diet. Extensive testing culminated in whole exome sequencing, which led to the diagnosis of phosphatidyl inositol glycan biosynthesis class A protein (PIGA) deficiency. This familial case highlights the importance of genetic testing for early-onset epileptic encephalopathies and underscores the potential value of a ketogenic diet in the treatment of this condition. PMID- 27126217 TI - The clinical trajectory of patients with borderline personality disorder. AB - OBJECTIVE: The epidemiological data on the diagnostic course of patients with borderline personality disorder (BPD) is limited. We used a nationwide register to investigate the diagnostic stability and changes over time. METHOD: The Danish nationwide registers were used to follow all patients with a diagnosis of BPD and investigate their first-ever psychiatric diagnosis and their latest diagnosis in the time period of 1995-2012. From this, we found the diagnostic stability and described the diagnostic changes. RESULTS: A total of 10 786 patients diagnosed with BPD were identified. The prospective diagnostic stabilities were 37% for females and 25% for males, and retrospective stabilities were 20% for females and 22% for males. More than 60% of patients received other diagnoses than BPD as their first-ever diagnosis. Stress-related (17%) and depressive disorders (14%) were most frequent as first-ever diagnosis. The latest diagnosis remained BPD in nearly half of females and one third of males, followed by schizophrenia, notably for those with longer follow-up and males. CONCLUSION: This study gives a detailed display of complicated clinical trajectories. The low diagnostic stabilities demonstrate a heterogenous patient group diagnosed with many other psychiatric diagnoses over time. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27126218 TI - Behavior Rating Inventory of Executive Function Adult Version in Patients with Neurological and Neuropsychiatric Conditions: Symptom Levels and Relationship to Emotional Distress. AB - OBJECTIVES: The present study explored the level of self-and informant reported executive functioning in daily living using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) in a large sample comprising healthy adults and patient cohorts with neurological and neuropsychiatric disorders. The relationship to neuropsychological test performance and self-reported emotional distress was explored, as well as the applicability of U.S. normative data. METHODS: Scores on the self- and informant reported BRIEF-A are presented, along with scores on standardized cognitive tests, and on rating scales of self reported emotional distress in a Norwegian healthy comparison group (n=115), patients with severe traumatic brain injury (n=125), focal frontal lobe damage (n=29), focal cerebellar lesion (n=24), Parkinson's disease (n=42), attention deficit hyperactivity disorder (n=34), type II bipolar disorder (n=21), and borderline personality disorder (n=18). RESULTS: Strong associations were observed between the BRIEF-A and emotional distress in both the healthy group and in neurological groups, while no or weak relationships with IQ and performance based tests of executive function were seen. The relationship between BRIEF-A and emotional distress was weaker in the neuropsychiatric patient groups, despite high symptom load in both domains. Healthy participants tended to have BRIEF-A scores 1/2-3/4 SD below the U.S. normative mean of T score=50. CONCLUSIONS: The study demonstrates the need to interpret BRIEF-A results within a broad differential diagnostic context, where measures of psychological distress are included in addition to neuropsychological tests. Uncertainty about the appropriateness of U.S. normative data in non-U.S. countries adds to the need for interpretive caution. (JINS, 2016, 22, 682-694). PMID- 27126219 TI - Geniposide acutely stimulates insulin secretion in pancreatic beta-cells by regulating GLP-1 receptor/cAMP signaling and ion channels. AB - Geniposide, an iridoid glycoside, has antidiabetic effects. The present study aimed to evaluate whether geniposide has direct effects on insulin secretion from rat pancreatic islets. The results demonstrated that geniposide potentiated insulin secretion via activating the glucagon-like-1 receptor (GLP-1R) as well as the adenylyl cyclase (AC)/cAMP signaling pathway. Inhibition of protein kinase A (PKA) suppressed the insulinotropic effect of geniposide. Geniposide also inhibited voltage-dependent potassium (Kv) channels, and this effect could be attenuated by inhibition of GLP-1R or PKA. Current-clamp recording showed that geniposide prolonged action potential duration. These results collectively imply that inhibition of Kv channels is linked to geniposide-potentiated insulin secretion by acting downstream of the GLP-1R/cAMP/PKA signaling pathway. Moreover, activation of Ca(2+) channels by geniposide was observed, indicating that the Ca(2+) channel is also an important player in the geniposide effects. Together, these findings provide new insight into the mechanism underlying geniposide-regulated insulin secretion. PMID- 27126220 TI - Constraints to Hamari sheep farming under range conditions in Darfur and Kordofan Regions of Western Sudan. AB - The study was conducted to identify the major production constraints of Hamari sheep in Darfur and Kordofan Regions of Western Sudan. A structured questionnaire was administered to 128 farmers in Darfur and Kordofan. Feed shortages, prevalence of diseases and parasites, and predation were more severe in Darfur than Kordofan (P < 0.05). Thefts were ranked higher by farmers using the sedentary system compared to those using semi-nomadic system (P < 0.05). Water shortage was ranked higher by farmers with small flocks, large flocks, semi nomadic and sedentary husbandry system in Kordofan than their counterparts in Darfur Region (P < 0.05). Farmers practising semi-nomadic husbandry system and sedentary system in Darfur region ranked diseases, parasites and predation higher than those practising semi-nomadic and sedentary system in Kordofan region (P < 0.05). Feed shortage was ranked higher as a challenge by farmers practising semi nomadic system in Darfur Region than those practising semi-nomadic system in Kordofan Region (P < 0.05). It can be concluded that the severity of challenges facing Hamari sheep producers vary with flock size, region and production system used. PMID- 27126221 TI - Growth performance, hematology, and meat quality characteristics of Mutton Merino lambs fed canola-based diets. AB - A 56-day feeding trial was carried out to evaluate the effect of feeding canola meal (CM) on growth performance, hematology, and meat quality parameters of lambs. Twenty lambs with an average body weight of 23 +/- 2.64 kg were randomly assigned to five dietary treatments and fed in individual cages for 56 days. The soya bean meal (SBM) in the control ration was replaced with canola meal at 0 (CM0), 25 (CM25), 50 (CM50), 75 (CM75), and 100 % (CM100) inclusion levels. Average daily weight gain (ADWG) and average daily feed intake (ADFI) were significantly higher in the CM25 and CM50, respectively. Feed conversion ratio (FCR) (3.09-3.41) and slaughter weight (SLW) (33.2-34.7 kg) were, however, similar among the treatment groups. Diet had no effect on carcass length (78.7 83.7 cm) and ultimate meat pH (pHu) (5.70-5.81). Nevertheless, hot carcass weight (HCW) (16.5-18.7 kg) and cold carcass weight (CCW) (16.2-18.2 kg) were higher (P < 0.05) in the CM0 and CM50 treatment groups. The shear force measurements (1.67 2.17 kg) differed (P < 0.05) across treatments. There was no dietary effect on the lightness (L*) (33.5-35.8), redness (a*) (11.35-12.7), and yellowness (b*) (13.4-14.8) of meat. In conclusion, CM can completely replace SBM in lamb diets without any negative effects on growth performance, general health, and meat quality of Mutton Merino lambs. PMID- 27126223 TI - Mandibular Full-Arch Fixed Prostheses Supported on 4 Implants with Either Axial Or Tilted Distal Implants: A 3-Year Prospective Study. AB - PURPOSE: This prospective study evaluated the clinical and radiographic outcome of distally cantilevered 4-implant-supported fixed mandibular prostheses (4 ISFMP) with distal implants either in axial or distally tilted direction. MATERIAL AND METHODS: Forty-one mandibulary edentulous patients received acrylic veneered 4-ISFMP with casted framework. Based on distal implant placement direction patients were assigned to 2 groups: 21 patients with four (2 anterior/2 posterior) axial implants (axial-group I) and 20 patients with 2 anterior axial/2 distal tilted implants (tilted-group II). Patients were prospectively followed for 3 years by annual examinations of implants and prosthetic survival rates including assessment for biological and mechanical complications. Additionally, peri-implant marginal bone resorption [MBR], pocket depth [PD], plaque index [PI], bleeding index [BI] and gingival index [GI], and calculus index [CI] were evaluated at each annual follow-up. RESULTS: 37/41 patients (19 axial-group I, 18 tilted-group II) and 148/164 implants were followed at the 1-, 2-, and 3-year evaluation (dropout rate: 11.8%) presenting no implant and denture loss (100% survival). The overall, MBR at year 1, 2, and 3 was 1.11 +/- 0.4 mm, 1.26 +/- 0.42 mm, and 1.40 +/- 0.41 mm, respectively, representing a significant (p < .001) continuing time depending annual reduction. MBR and PD did not differ between anterior and posterior regions in both groups or for anterior and posterior regions between the groups. PI and CI were significantly (p < .001) higher for implants in anterior regions than for posterior regions in both groups. Moreover, posterior implant regions showed significantly (p < .001) higher PI and CI for axial-group I than for tilted-group II over time. Biological and mechanical complications as well as GI and BI did not differ between the groups over a 3-year follow-up period. CONCLUSION: For clinical implant and prosthesis outcome no statistical significant mean differences were noted for distally cantilevered 4-ISFMP supported by distal implants placed in tilted or axial direction. PMID- 27126222 TI - Integrated Droplet-Based Microextraction with ESI-MS for Removal of Matrix Interference in Single-Cell Analysis. AB - Integrating droplet-based microfluidics with mass spectrometry is essential to high-throughput and multiple analysis of single cells. Nevertheless, matrix effects such as the interference of culture medium and intracellular components influence the sensitivity and the accuracy of results in single-cell analysis. To resolve this problem, we developed a method that integrated droplet-based microextraction with single-cell mass spectrometry. Specific extraction solvent was used to selectively obtain intracellular components of interest and remove interference of other components. Using this method, UDP-Glc-NAc, GSH, GSSG, AMP, ADP and ATP were successfully detected in single MCF-7 cells. We also applied the method to study the change of unicellular metabolites in the biological process of dysfunctional oxidative phosphorylation. The method could not only realize matrix-free, selective and sensitive detection of metabolites in single cells, but also have the capability for reliable and high-throughput single-cell analysis. PMID- 27126224 TI - The vulnerability of family caregivers in relation to vulnerability as understood by nurses. AB - In Finland, the care of older persons is shifting from institutional care to family care. Research shows that family caregivers experience their situation much in the same way as professional nurses. The nurses' experiences have been studied in terms of vulnerability, and the same perspective could deepen our understanding of family caregivers' experiences. The aim of this study was to gain knowledge of the vulnerability of older caregivers taking care of an ageing family member. The research questions were as follows: How do family caregivers experience vulnerability? How do their experiences relate to vulnerability as understood by nurses? The study was done as a secondary analysis of focus group interviews on the experiences and daily life of older family caregivers. Four caregivers had taken part in monthly interviews during a period of 10 months. The interviews were analysed by deductive and inductive content analysis. The results showed that the caregivers saw caregiving as part of being human. They experienced a variety of feelings and moral agony and were harmed physically, mentally and socially. They showed courage, protected themselves and recognised that being a caregiver also was a source of maturing and developing. These results corresponded with the nurses' understanding of vulnerability. Shame, the experience of duty as a burden, worry and loneliness were themes that were found only among the family caregivers. The use of a matrix may have restricted the analysis, but using it in an unconstrained way allowed for new themes to be created. The results indicate a common humanness and vulnerability in professional and family caregiving. They also show that family caregivers need more support both from society and professionals. PMID- 27126225 TI - Nurse practitioner-mediated intervention for preoperative control of diabetes in elective surgery patients. AB - PURPOSE: This study evaluated the effect of nurse practitioner (NP) mediated interventions on diabetes control before elective surgery. DATA SOURCES: A program was initiated to improve preoperative diabetes control in patients with HbA1c > 8%. The intervention was initially mediated by a physician alone and subsequently changed to involve NPs. The goal of intervention was fasting blood glucose (BG) <200 mg/dL on the day of surgery (DOS). Data were collected before the program (control group), during physician-mediated intervention (phase 1), and during NP-mediated intervention (phase 2). CONCLUSIONS: There were 222 patients in the control group, 226 in phase 1, and 160 in phase 2. Mean BG (mg/dL) on DOS was 171.4 +/- 66.5 in control group, 162.6 +/- 58.1 in phase 1, and 153.4 +/- 46.6 in phase 2 (p = NS for control vs. phase 1 and <0.01 for control vs. phase 2). More patients received an intervention in phase 2 (93%) than in phase 1 (75%). Among those receiving intervention, 87% achieved target BG in phase 2 and 82% in phase 1 (p = NS). Duration of diabetes, baseline HbA1c, time available before surgery, and diabetes intervention were independent predictors of achieving target BG. IMPLICATIONS FOR PRACTICE: NP-mediated interventions increased access to care and resulted in lower BG levels and may be a good strategy for preoperative diabetes control. PMID- 27126226 TI - Coordination between growth, phenology and carbon storage in three coexisting deciduous tree species in a temperate forest. AB - In deciduous trees growing in temperate forests, bud break and growth in spring must rely on intrinsic carbon (C) reserves. Yet it is unclear whether growth and C storage occur simultaneously, and whether starch C in branches is sufficient for refoliation. To test in situ the relationships between growth, phenology and C utilization, we monitored stem growth, leaf phenology and stem and branch nonstructural carbohydrate (NSC) dynamics in three deciduous species: Carpinus betulus L., Fagus sylvatica L. and Quercus petraea (Matt.) Liebl. To quantify the role of NSC in C investment into growth, a C balance approach was applied. Across the three species, >95% of branchlet starch was consumed during bud break, confirming the importance of C reserves for refoliation in spring. The C balance calculation showed that 90% of the C investment in foliage (7.0-10.5 kg tree(-1) and 5-17 times the C needed for annual stem growth) was explained by simultaneous branchlet starch degradation. Carbon reserves were recovered sooner than expected, after leaf expansion, in parallel with stem growth. Carpinus had earlier leaf phenology (by ~25 days) but delayed cambial growth (by ~15 days) than Fagus and Quercus, the result of a competitive strategy to flush early, while having lower NSC levels. PMID- 27126227 TI - Genetic variability and heritability of chlorophyll a fluorescence parameters in Scots pine (Pinus sylvestris L.). AB - Current knowledge of the genetic mechanisms underlying the inheritance of photosynthetic activity in forest trees is generally limited, yet it is essential both for various practical forestry purposes and for better understanding of broader evolutionary mechanisms. In this study, we investigated genetic variation underlying selected chlorophyll a fluorescence (ChlF) parameters in structured populations of Scots pine (Pinus sylvestris L.) grown on two sites under non stress conditions. These parameters were derived from the OJIP part of the ChlF kinetics curve and characterize individual parts of primary photosynthetic processes associated, for example, with the exciton trapping by light-harvesting antennae, energy utilization in photosystem II (PSII) reaction centers (RCs) and its transfer further down the photosynthetic electron-transport chain. An additive relationship matrix was estimated based on pedigree reconstruction, utilizing a set of highly polymorphic single sequence repeat markers. Variance decomposition was conducted using the animal genetic evaluation mixed-linear model. The majority of ChlF parameters in the analyzed pine populations showed significant additive genetic variation. Statistically significant heritability estimates were obtained for most ChlF indices, with the exception of DI0/RC, phiD0 and phiP0 (Fv/Fm) parameters. Estimated heritabilities varied around the value of 0.15 with the maximal value of 0.23 in the ET0/RC parameter, which indicates electron-transport flux from QA to QB per PSII RC. No significant correlation was found between these indices and selected growth traits. Moreover, no genotype * environment interaction (G * E) was detected, i.e., no differences in genotypes' performance between sites. The absence of significant G * E in our study is interesting, given the relatively low heritability found for the majority of parameters analyzed. Therefore, we infer that polygenic variability of these indices is selectively neutral. PMID- 27126229 TI - Temporal and spatial patterns of internal and external stem CO2 fluxes in a sub Mediterranean oak. AB - To accurately estimate stem respiration (RS), measurements of both carbon dioxide (CO2) efflux to the atmosphere (EA) and internal CO2 flux through xylem (FT) are needed because xylem sap transports respired CO2 upward. However, reports of seasonal dynamics of FT and EA are scarce and no studies exist in Mediterranean species under drought stress conditions. Internal and external CO2 fluxes at three stem heights, together with radial stem growth, temperature, sap flow and shoot water potential, were measured in Quercus pyrenaica Willd. in four measurement campaigns during one growing season. Substantial daytime depressions in temperature-normalized EA were observed throughout the experiment, including prior to budburst, indicating that diel hysteresis between stem temperature and EA cannot be uniquely ascribed to diversion of CO2 in the transpiration stream. Low internal [CO2] (<0.5%) resulted in low contributions of FT to RS throughout the growing season, and RS was mainly explained by EA (>90%). Internal [CO2] was found to vary vertically along the stems. Seasonality in resistance to radial CO2 diffusion was related to shoot water potential. The low internal [CO2] and FT observed in our study may result from the downregulation of xylem respiration in response to a legacy of coppicing as well as high radial diffusion of CO2 through cambium, phloem and bark tissues, which was related to low water content of stems. Long-term studies analyzing temporal and spatial variation in internal and external CO2 fluxes and their interactions are needed to mechanistically understand and model respiration of woody tissues. PMID- 27126228 TI - Gene expression analysis of disabled and re-induced isoprene emission by the tropical tree Ficus septica before and after cold ambient temperature exposure. AB - Isoprene is the most abundant type of nonmethane, biogenic volatile organic compound in the atmosphere, and it is produced mainly by terrestrial plants. The tropical tree species Ficus septica Burm. F. (Rosales: Moraceae) has been shown to cease isoprene emissions when exposed to temperatures of 12 degrees C or lower and to re-induce isoprene synthesis upon subsequent exposure to temperatures of 30 degrees C or higher for 24 h. To elucidate the regulation of genes underlying the disabling and then induction of isoprene emission during acclimatization to ambient temperature, we conducted gene expression analyses of F. septica plants under changing temperature using quantitative real-time polymerase chain reaction and western blotting. Transcription levels were analyzed for 17 genes that are involved in metabolic pathways potentially associated with isoprene biosynthesis, including isoprene synthase (ispS). The protein levels of ispS were also measured. Changes in transcription and protein levels of the ispS gene, but not in the other assessed genes, showed identical temporal patterns to isoprene emission capacity under the changing temperature regime. The ispS protein levels strongly and positively correlated with isoprene emission capacity (R(2) = 0.92). These results suggest that transcriptional regulation of ispS gave rise to the temporal variation in isoprene emission capacity in response to changing temperature. PMID- 27126230 TI - Predictive models for radial sap flux variation in coniferous, diffuse-porous and ring-porous temperate trees. AB - Accurately scaling sap flux observations to tree or stand levels requires accounting for variation in sap flux between wood types and by depth into the tree. However, existing models for radial variation in axial sap flux are rarely used because they are difficult to implement, there is uncertainty about their predictive ability and calibration measurements are often unavailable. Here we compare different models with a diverse sap flux data set to test the hypotheses that radial profiles differ by wood type and tree size. We show that radial variation in sap flux is dependent on wood type but independent of tree size for a range of temperate trees. The best-fitting model predicted out-of-sample sap flux observations and independent estimates of sapwood area with small errors, suggesting robustness in the new settings. We develop a method for predicting whole-tree water use with this model and include computer code for simple implementation in other studies. PMID- 27126231 TI - A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF. AB - AIMS: Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure. METHODS: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence based medical therapy. In the follow-up phase, uptitration to guideline recommended doses was encouraged. CONCLUSION: By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure. PMID- 27126232 TI - Glucocorticoids modify effects of TGF-beta1 on multidrug resistance in the fetal blood-brain barrier. AB - Transforming growth factor-beta1 (TGF-beta1) increases P-glycoprotein (P-gp; encoded by Abcb1) activity in fetal brain endothelial cells (BECs). P-gp is important for fetal brain protection against xenobiotics including synthetic glucocorticoids (sGC). We hypothesized that antenatal sGC would modify P-gp responsiveness to TGF-beta1 in fetal BECs. Pregnant guinea pigs were treated with dexamethasone or vehicle (N = 5/group) on gestational day (GD) 48-49 and BECs derived on GD50. In BECs from control fetuses, TGF-beta1 increased Abcb1 mRNA and P-gp function, by approximately 5-fold and 55% respectively, as well as tight junction function. In contrast, TGF-beta1 had no effect on these parameters in BECs from sGC-exposed fetuses. Moreover, levels of TGF-beta1 responsive gene, Smad7, were increased 3-fold in BECs from control fetuses after TGF-beta1 but not in sGC-exposed fetuses. In conclusion, antenatal sGC alters responsiveness to TGF beta1 in fetal BECs. This study has identified novel mechanisms by which TGF beta1 and sGC modulate fetal brain protection against xenobiotics and other P-gp substrates. PMID- 27126233 TI - A Clinician's perspective on clinical exome sequencing. AB - Clinical exome sequencing has clearly improved our ability as clinicians to identify the cause of a wide variety of disorders. Prior to exome sequencing, a majority of patients with apparent syndromes never received a specific molecular genetic diagnosis despite extensive diagnostic odysseys. Even for those receiving an answer to the question of what caused their disorder, the diagnostic odyssey often spanned years to decades. Determining the particular genetic cause in an individual patient can be challenging due to inherent phenotypic and genetic heterogeneity of disease, technical limitations of testing or both. Blended phenotypes, due to multiple monogenic disorders in the same patient, are true dilemmas for traditional genetic evaluations, but are increasingly being diagnosed through clinical exome sequencing. New sequencing technologies have increased the proportion of patients receiving molecular diagnoses, while significantly shortening the time scale, providing multiple benefits for the health-care team, patient and family. PMID- 27126234 TI - Deciphering intratumor heterogeneity using cancer genome analysis. AB - Intratumor heterogeneity within individual cancer tissues underlies the numerous phenotypes of cancer. Tumor subclones ultimately affect therapeutic outcomes due to their distinct molecular features. Drug-resistant subclones are present at a low frequency in tissues at the time of biopsy, but can also arise as a result of acquired somatic mutations. A number of different approaches have been utilized to understand the nature of intratumor heterogeneity. Clonal analysis using whole exome or genome sequencing data can help monitor subclones in the context of tumor progression. Multiregional biopsies permit the molecular characterization of subclones within tumors. Deep sequencing has also provided researchers with the ability to measure the low allele fraction variant within a small number of cells. Ultimately, single-cell sequencing will enable the identification of every minor population within a tumor microenvironment. In the clinical context, the ability to identify and monitor the subclonal architecture of a tumor is valuable for the development of precise cancer therapeutic methods. PMID- 27126236 TI - Delivery of Liposomes with Different Sizes to Mice Brain after Sonication by Focused Ultrasound in the Presence of Microbubbles. AB - Imaging or therapeutic agents larger than the blood-brain barrier's (BBB) exclusion threshold of 400 Da could be delivered locally, non-invasively and reversibly by focused ultrasound (FUS) with circulating microbubbles. The size of agents is an important factor to the delivery outcome using this method. Liposomes are important drug carriers with controllable sizes in a range of nanometers. However, discrepancies among deliveries of intact liposomes with different sizes, especially those larger than 50 nm, across the BBB opened by FUS with microbubbles remain unexplored. In the present study, rhodamine-labeled long circulating pegylated liposomes with diameters of 55 nm, 120 nm and 200 nm were delivered to mice brains after BBB disruption by pulsed FUS with microbubbles. Four groups of peak rarefactional pressure and microbubble dosages were used: 0.53 MPa with 0.1 MUL/g (group 1), 0.53 MPa with 0.5 MUL/g (group 2), 0.64 MPa with 0.1 MUL/g (group 3) and 0.64 MPa with 0.5 MUL/g (group 4). The delivery outcome was observed using fluorescence imaging of brain sections. It was found that the delivery of 55-nm liposomes showed higher success rates than 120-nm or 200-nm liposomes from groups 1-3. The result indicated that it may be more difficult to deliver larger liposomes (>120 nm) passively than 55-nm liposomes after BBB opening by FUS with microbubbles. The relative fluorescence area of 55 nm liposomes to the total area of the sonicated region was statistically larger than that of the 120-nm or 200-nm liposomes. Increasing peak rarefactional pressure amplitude or microbubble dose could induce more accumulation of liposomes in the brain using FUS with microbubbles. Moreover, the distribution pattern of delivered liposomes was heterogeneous and characterized by separated fluorescence spots with cloud-like periphery surrounding a bright center, indicating confined diffusion in the extracellular matrix after extravasation from the microvasculature. These findings are expected to provide useful information for developing FUS with microbubbles as an effective trans-BBB liposomal drug delivery strategy. PMID- 27126235 TI - Biological findings from the PheWAS catalog: focus on connective tissue-related disorders (pelvic floor dysfunction, abdominal hernia, varicose veins and hemorrhoids). AB - Pelvic floor dysfunction, specifically genital prolapse (GP) and stress urinary inconsistency (SUI) presumably co-occur with other connective tissue disorders such as hernia, hemorrhoids, and varicose veins. Observations on non-random coexistence of these disorders have never been summarized in a meta-analysis. The performed meta-analysis demonstrated that varicose veins and hernia are associated with GP. Disease connections on the molecular level may be partially based on shared genetic susceptibility. A unique opportunity to estimate shared genetic susceptibility to disorders is provided by a PheWAS (phenome-wide association study) designed to utilize GWAS data concurrently to many phenotypes. We searched the PheWAS Catalog, which includes the results of the PheWAS study with P value < 0.05, for genes associated with GP, SUI, abdominal hernia, varicose veins and hemorrhoids. We found pronounced signals for the associations of the SLC2A9 gene with SUI (P = 6.0e-05) and the MYH9 gene with varicose veins of lower extremity (P = 0.0001) and hemorrhoids (P = 0.0007). The comparison of the PheWAS Catalog and the NHGRI Catalog data revealed enrichment of genes associated with bone mineral density in GP and with activated partial thromboplastin time in varicose veins of lower extremity. In cross-phenotype associations, genes responsible for peripheral nerve functions seem to predominate. This study not only established novel biologically plausible associations that may warrant further studies but also exemplified an effective use of the PheWAS Catalog data. PMID- 27126237 TI - Left Ventricular Energy Loss Assessed by Vector Flow Mapping in Patients with Prediabetes and Type 2 Diabetes Mellitus. AB - The aim of this study was to assess left ventricular (LV) energy loss (EL) using vector flow mapping in patients with prediabetes (pre-DM) and type 2 diabetes mellitus (DM). Thirty pre-DM patients, 51 DM patients, and 38 controls were studied by transthoracic echocardiography. EL-total, EL-base, EL-mid and EL-apex climaxed at different phases. Compared with controls, pre-DM and DM patients showed increased EL-total during slow ejection, isovolumic relaxation, rapid filling and slow filling (p < 0.05). Similarly, EL-base, EL-mid and EL-apex increased during certain phases. Stepwise multiple regression analysis revealed that the early transmitral valve blood flow velocity E, the late transmitral valve blood flow velocity A, the ratio of E/A, LV peak torsion, diastolic untwisting velocity, vortex circulation and area were independently associated with EL during different phases (all p < 0.05). Our study suggests that LV EL is increased during diastole and certain phases of systole in DM patients compared with controls. The changes in LV vortex and deformation mechanics were correlated with EL. PMID- 27126238 TI - Ultrasound-Guided Percutaneous Microwave Ablation for Hepatocellular Carcinoma in the Caudate Lobe. AB - Treatment for liver tumors in the caudate lobe is challenging because of their location and complex anatomy. This study was intended to evaluate the feasibility, efficacy and tolerability of ultrasound-guided percutaneous microwave (MW) ablation for treating hepatocellular carcinoma (HCC) in the caudate lobe. From December 2011 to May 2015, a total of 20 patients (mean age: 62 +/- 11 y) with HCC in the caudate lobe were enrolled in this study. Patient characteristics and tumor features were analyzed. The epigastric approach, intercostal approach and the combination were used in 4, 14 and 2 patients, respectively. Contrast-enhanced ultrasound (CEUS) guidance and temperature monitoring were applied as ancillary techniques. Ethanol injection was performed for tumors adjacent to the inferior vena cava or hepatic hilum. Contrast images were performed to evaluate treatment response after ablation. Technical success, technique efficacy, local tumor progression and complications were documented. Technique efficacy was achieved in 18 patients (18/20, 90%). Two patients received (125)I brachytherapy as palliative therapy for residual tumors that could not be ablated technically after the first ablation. Technical success was achieved in 16 patients (16/20, 80%). In 2 patients, ablation was completed after two sessions. CEUS was applied in 5 patients and temperature monitoring in 2 patients. Eight patients received an ethanol injection during ablation. Eleven patients achieved a minimum 5-mm safety margins. Local tumor progression was detected in 3 patients (16.7%, 3/18) during a median follow-up of 18.4 mo (range: 3-45 mo). Tumors in these 3 patients were all larger than 2.0 cm. No major or minor complications were observed. In conclusion, ultrasound-guided percutaneous microwave ablation combined with CEUS, temperature monitoring, and ethanol injection is a tolerable and relatively effective treatment for HCC in the caudate lobe. PMID- 27126239 TI - The Effect of Radial Extracorporeal Shock Wave Stimulation on Upper Limb Spasticity in Chronic Stroke Patients: A Single-Blind, Randomized, Placebo Controlled Study. AB - The main purpose of this study was to determine the clinical, electrophysiological and thermal effects of radial extracorporeal shock wave (rESW) stimulation on upper limb muscles affected by spasticity in patients with chronic stroke. Patients included in the study were randomly assigned into the following two groups: 30 patients stimulated with active rESW (A); and 30 patients stimulated with placebo rESW (B). All patients were analyzed using the Modified Ashworth Scale (MAS) to test the spasticity levels of the elbow (E), radio carpal (RC) and fingers (FF) joints; surface electromyography (sEMG) was performed for the resting bioelectrical activity registration of the flexor carpi radialis (FCR) and flexor carpi ulnaris (FCU) muscles; and infrared thermal imaging (IRT) was used to assess the temperature distributions of the carpal flexor muscles (CFM). All assessments were performed at baseline (t0), immediately after rESW (t1) as well as 1 and 24 h following its finalization (t2 and t3). Patients treated with active rESW showed a statistically significant reduction in the MAS score for the RC joint at t1 and for the FF joints at t1, t2 and t3 (p < 0.05). A significant decrease in sEMG activity was observed in the FCR and FCU muscles at t1, t2 and t3 (p < 0.05); significant increases in the mean and maximum values of the IRT detection was observed using inter-group comparisons in t2 and t3 (p < 0.05). No significant alterations were observed in patients after placebo rESW stimulation (p > 0.05). Applications of rESW demonstrating positive effects at reducing the level of spastic hypertonia of the upper limb muscles in patients with chronic stroke. ESW treatments should be considered as a potential anti-spastic effect to regulate vasculature. PMID- 27126240 TI - Frequency Dependence of Petechial Hemorrhage and Cardiomyocyte Injury Induced during Myocardial Contrast Echocardiography. AB - Myocardial contrast echocardiography (MCE) for perfusion imaging can induce microscale bio-effects during intermittent high-Mechanical Index scans. The dependence of MCE-induced bio-effects on the ultrasonic frequency was examined in rats at 1.6, 2.5 and 3.5 MHz. Premature complexes were counted in the electrocardiogram, petechial hemorrhages with microvascular leakage on the heart surface were observed at the time of exposure, plasma troponin elevation was measured after 4 h and cardiomyocyte injury was detected at 24 h. Increasing response to exposure above an apparent threshold was observed for all endpoints at each frequency. The effects decreased with increasing ultrasonic frequency, and the thresholds increased. Linear regressions for frequency-dependent thresholds indicated coefficients and exponents of 0.6 and 1.07 for petechial hemorrhages, respectively, and 1.02 and 0.8 for cardiomyocyte death, compared with 1.9 and 0.5 (square root) for the guideline limit of the mechanical index. The results clarify the dependence of cardiac bio-effects on frequency, and should allow development of theoretical descriptions of the phenomena and improved safety guidance for MCE. PMID- 27126242 TI - Quantitative Study on the Effect of Abnormalities on Respiration-Induced Kidney Movement. AB - Respiration-induced movement of abdominal organs hampers the targeting accuracy of non-invasive surgical techniques such as focused ultrasound surgery and radiosurgery. Unaccounted organ movement can result in either under dosage or damage to intervening healthy tissues. The respiration-induced movement is known to be significantly large in kidneys; however, the impact of abnormalities such as tumors and cysts on kidney movement is poorly understood. In this study, we quantified the movement patterns of kidneys in 48 normal and 62 affected kidneys (43 calcified cysts, 11 angiomyolipomas, 4 renal cell carcinomas and 4 polycystic kidneys) using ultrasound and simultaneously tracked the respiratory movement patterns using a stereo camera system. The kidneys were localized from 2-D ultrasound sequences using a template matching technique. The average movements of the right and left kidneys were, respectively, 24.54 +/- 6.4 and 17.06 +/- 3.66 mm in the superior-inferior and 13.62 +/- 3.71 and 9.80 +/- 3.32 mm in the transverse directions. Average movement in the superior-inferior direction of normal kidneys was greater than that of affected kidneys for both right (26.9 +/- 5.1 vs. 22.6 +/- 3.3, p < 0.001) and left (17.8 +/- 2.5 vs. 16.1 +/- 4.2, p = 0.01) kidneys. On the basis of spatial extent of abnormality, affected kidneys were categorized as category A (<10 mm in 26 patients), category B (10-20 mm in 22 patients) and category C (>20 mm in 14 patients). Compared with normal patients, the extent of movement was significantly reduced in abnormal categories B (p < 0.001) and C (p < 0.001), but the change was not significant in category A (p = 0.04). Hysteresis plots of the kidneys revealed a maximum change of 12.3 mm. The movement patterns of the kidneys also closely correlated with the respiratory movement pattern (Pearson correlation = 0.89 [right] and 0.87 [left]). We expect that the movement pattern analyses and quantification carried out in this study would aid in developing movement adaptive surgical protocols for non-invasive treatment of kidney tumors/cancers. PMID- 27126241 TI - Correlation Between Sonographic and In Vivo Measurement of A1 Pulleys in Trigger Fingers. AB - The thickness of 210 A1 pulleys of 21 male and female healthy volunteers in two different age groups (20-35 y and 50-70 y) were measured by ultrasound. In a second group, the thickness of 15 diseased A1 pulleys and 15 A1 pulleys of the corresponding other hand of 10 patients with the clinical diagnosis of trigger finger were measured by ultrasound. During open trigger finger release, a strip of A1 pulley was excised and immediately measured using an electronic caliper. The average pulley thickness of healthy volunteers was 0.43-0.47 mm, compared to 0.77-0.79 mm in patients with trigger finger. Based on the receiver operating characteristic (ROC) curve, a diagnostic cut-off value of the pulley thickness at 0.62 mm was defined in order to differ a trigger finger from a healthy finger (sensitivity and specificity of 85%). The correlation between sonographic and effective intra-operative measurements of pulley thickness was linear and very strong (Pearson coefficient 0.86-0.90). In order to distinguish between healthy and diseased A1 pulleys, 0.62 mm is a simple value to use, which can be applied regardless of age, sex, body mass index (BMI) and height in adults. PMID- 27126243 TI - Computer-Assisted Hepatocellular Carcinoma Ablation Planning Based on 3-D Ultrasound Imaging. AB - To evaluate computer-assisted hepatocellular carcinoma (HCC) ablation planning based on 3-D ultrasound, 3-D ultrasound images of 60 HCC lesions from 58 patients were obtained and transferred to a research toolkit. Compared with virtual manual ablation planning (MAP), virtual computer-assisted ablation planning (CAP) consumed less time and needle insertion numbers and exhibited a higher rate of complete tumor coverage and lower rate of critical structure injury. In MAP, junior operators used less time, but had more critical structure injury than senior operators. For large lesions, CAP performed better than MAP. For lesions near critical structures, CAP resulted in better outcomes than MAP. Compared with MAP, CAP based on 3-D ultrasound imaging was more effective and achieved a higher rate of complete tumor coverage and a lower rate of critical structure injury; it is especially useful for junior operators and with large lesions, and lesions near critical structures. PMID- 27126244 TI - Histotripsy Liquefaction of Large Hematomas. AB - Intra- and extra-muscular hematomas result from repetitive injury as well as sharp and blunt limb trauma. The clinical consequences can be serious, including debilitating pain and functional deficit. There are currently no short-term treatment options for large hematomas, only lengthy conservative treatment. The goal of this work was to evaluate the feasibility of a high intensity focused ultrasound (HIFU)-based technique, termed histotripsy, for rapid (within a clinically relevant timeframe of 15-20 min) liquefaction of large volume (up to 20 mL) extra-vascular hematomas for subsequent fine-needle aspiration. Experiments were performed using in vitro extravascular hematoma phantoms-fresh bovine blood poured into 50 mL molds and allowed to clot. The resulting phantoms were treated by boiling histotripsy (BH), cavitation histotripsy (CH) or a combination in a degassed water tank under ultrasound guidance. Two different transducers operating at 1 MHz and 1.5 MHz with f-number = 1 were used. The liquefied lysate was aspirated and analyzed by histology and sized in a Coulter Counter. The peak instantaneous power to achieve BH was lower than (at 1.5 MHz) or equal to (at 1 MHz) that which was required to initiate CH. Under the same exposure duration, BH-induced cavities were one and a half to two times larger than the CH-induced cavities, but the CH-induced cavities were more regularly shaped, facilitating easier aspiration. The lysates contained a small amount of debris larger than 70 MUm, and 99% of particulates were smaller than 10 MUm. A combination treatment of BH (for initial debulking) and CH (for liquefaction of small residual fragments) yielded 20 mL of lysate within 17.5 minutes of treatment and was found to be most optimal for liquefaction of large extravascular hematomas. PMID- 27126245 TI - Feasibility Study of Texture Analysis Using Ultrasound Shear Wave Elastography to Predict Malignancy in Thyroid Nodules. AB - Textural analysis of ultrasound shear wave elastography (SWE) was evaluated to discriminate benign and malignant thyroid nodules. Sixteen papillary thyroid cancers and 89 benign hyperplastic nodules in 105 patients underwent SWE using four static pre-compression levels. Fifteen gray level co-occurrence matrix textural features and six absolute SWE indices were computed from SWE images. Diagnostic performances of each SWE index for malignancy were calculated and compared using the area under the receiver operating characteristic curve (AUC), and optimal models were generated at each pre-compression level. The optimal model comprised two SWE textural features at the highest pre-compression level, which attained AUC, sensitivity and specificity of 0.973, 97.5% and 90.0%, respectively. By comparison, absolute SWE indices attained AUC of 0.709 as well as 18.8% sensitivity and 95.8% specificity. These preliminary results suggest SWE textural analysis can distinguish benign and malignant thyroid nodules and SWE spatial heterogeneity is greater in malignant nodules. PMID- 27126246 TI - MUL1-A new potential for a therapeutic target for Parkinson's disease a commentary on "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin" by Yun and colleagues (eLife 2014; 3: 1-26). PMID- 27126247 TI - Synthesis, Thermal Properties, and Thermoresponsive Behaviors of Cyclic Poly(2 (dimethylamino)ethyl Methacrylate)s. AB - This study aims at physicochemical properties of thermo- and pH/CO2 -responsive cyclic homopolymers. Three examples of cyclic poly(2-(dimethylamino)ethyl methacrylate)s (PDMAs) are synthesized by combining the reversible addition fragmentation chain transfer process and the Diels-Alder ring-closure reaction. After cyclization, the glass transition temperature significantly increases (DeltaTg = 51.8-59.7 degrees C) due to the different configurational entropy and end groups, and the maximum decomposition temperature to lose the pendent groups is drastically decreased from 309 to 278 degrees C. Effects of polymerization degree, polymer concentration, additive of NaCl, and pH/CO2 on lower critical solution temperature behaviors of PDMA aqueous solutions are investigated. The cloud points (Tc ) of ring PDMAs are usually higher than their linear precursors, and the DeltaTc values obtained under a fixed condition can reach up to 20.7 degrees C, revealing the crucial role of the topology effect. This study paves the way for unique properties and applications of smart cyclic polymers and their derivatives. PMID- 27126248 TI - In vivo functional connectome of human brainstem nuclei of the ascending arousal, autonomic, and motor systems by high spatial resolution 7-Tesla fMRI. AB - OBJECTIVE: Our aim was to map the in vivo human functional connectivity of several brainstem nuclei with the rest of the brain by using seed-based correlation of ultra-high magnetic field functional magnetic resonance imaging (fMRI) data. MATERIALS AND METHODS: We used the recently developed template of 11 brainstem nuclei derived from multi-contrast structural MRI at 7 Tesla as seed regions to determine their connectivity to the rest of the brain. To achieve this, we used the increased contrast-to-noise ratio of 7-Tesla fMRI compared with 3 Tesla and time-efficient simultaneous multi-slice imaging to cover the brain with high spatial resolution (1.1-mm isotropic nominal resolution) while maintaining a short repetition time (2.5 s). RESULTS: The delineated Pearson's correlation-based functional connectivity diagrams (connectomes) of 11 brainstem nuclei of the ascending arousal, motor, and autonomic systems from 12 controls are presented and discussed in the context of existing histology and animal work. CONCLUSION: Considering that the investigated brainstem nuclei play a crucial role in several vital functions, the delineated preliminary connectomes might prove useful for future in vivo research and clinical studies of human brainstem function and pathology, including disorders of consciousness, sleep disorders, autonomic disorders, Parkinson's disease, and other motor disorders. PMID- 27126249 TI - [Insulitis in type 1 diabetes]. AB - Insulitis is considered to be the key morphological lesion of type 1 diabetes mellitus (T1DM) for which the diagnostic criteria were recently defined. From the immunophenotype of the lymphocytic infiltration, its frequency and extent during the course of T1DM and the presence of autoantibodies against beta cell proteins, it has been deduced that T1DM is a chronic autoimmune disease leading to gradual destruction of the insulin-producing cells of the islets of Langerhans in the pancreas, profound insulin deficiency and chronic hyperglycemia. This review article presents the morphological findings that support this hypothesis and addresses questions that need to be answered in order to further clarify the pathogenesis and to develop specific treatment options. PMID- 27126250 TI - Quantitative blood flow velocity imaging using laser speckle flowmetry. AB - Laser speckle flowmetry suffers from a debated quantification of the inverse relation between decorrelation time (tauc) and blood flow velocity (V), i.e. 1/tauc = alphaV. Using a modified microcirculation imager (integrated sidestream dark field - laser speckle contrast imaging [SDF-LSCI]), we experimentally investigate on the influence of the optical properties of scatterers on alpha in vitro and in vivo. We found a good agreement to theoretical predictions within certain limits for scatterer size and multiple scattering. We present a practical model-based scaling factor to correct for multiple scattering in microcirculatory vessels. Our results show that SDF-LSCI offers a quantitative measure of flow velocity in addition to vessel morphology, enabling the quantification of the clinically relevant blood flow, velocity and tissue perfusion. PMID- 27126251 TI - Descriptions of Anaerotaenia torta gen. nov., sp. nov. and Anaerocolumna cellulosilytica gen. nov., sp. nov. isolated from a methanogenic reactor of cattle waste and reclassification of Clostridium aminovalericum, Clostridium jejuense and Clostridium xylanovorans as Anaerocolumna species. AB - Strictly anaerobic bacterial strains (FH052T and SN021T) belonging to clostridial cluster XIVa were isolated from a methanogenic reactor. Cells of the two strains were Gram-stain-positive, slender or curved rods producing terminal spores. The strains were slightly alkaliphilic. They fermented various carbohydrates including xylan and produced acetate, ethanol and H2. Strain SN021T decomposed cellulose. The genomic DNA G+C contents were 47.2 mol% for strain FH052T and 38.1 mol% for strain SN021T. The two strains had common cellular fatty acids such as C16 : 0, C16 : 0 dimethylacetal and C18 : 1omega7c dimethylacetal as major components. 16S rRNA gene sequence similarity between the two strains was 94.3 % and they shared closely related species such as Clostridium jejuense, Clostridium xylanovorans and Clostridium aminovalericum (92.6-95.7 % sequence similarity). Phenotypic and phylogenetic analyses suggested that these two isolates should be assigned to novel genera other than the genus Clostridium, and thus the genera Anaerotaenia gen. nov. and Anaerocolumna gen. nov. in the family Lachnospiraceae were proposed to accommodate them as Anaerotaenia torta gen. nov., sp. nov. for strain FH052T (=JCM 30820T=DSM 100431T) and Anaerocolumna cellulosilytica gen. nov., sp. nov. for strain SN021T (=JCM 30819T=DSM 100423T). For the three related Clostridium species, Anaerocolumna aminovalerica DSM 1283T (=JCM 11016T=ATCC 13725T) comb. nov., Anaerocolumna jejuensis HY-35-12T (=DSM 15929T=KCTC 5026T) comb. nov. and Anaerocolumna xylanovoransstrain HESP1T (=DSM 12503T=JCM 31057T) comb. nov. are proposed with emended descriptions of these species. PMID- 27126252 TI - A New Method for Endoscopic Sampling of Submucosal Tissue in the Gastrointestinal Tract: A Comparison of the Biopsy Forceps and a New Drill Instrument. AB - Background Sampling of submucosal lesions in the gastrointestinal tract through a flexible endoscope is a well-recognized clinical problem. One technique often used is endoscopic ultrasound-guided fine-needle aspiration, but it does not provide solid tissue biopsies with preserved architecture for histopathological evaluation. To obtain solid tissue biopsies from submucosal lesions, we have constructed a new endoscopic biopsy tool and compared it in a crossover study with the standard double cupped forceps. Methods Ten patients with endoscopically verified submucosal lesions were sampled. The endoscopist selected the position for the biopsies and used the instrument selected by randomization. After a biopsy was harvested, the endoscopist chose the next site for a biopsy and again used the instrument picked by randomization. A total of 6 biopsies, 3 with the forceps and 3 with the drill instrument, were collected in every patient. Results The drill instrument resulted in larger total size biopsies (mm2; Mann-Whitney U test, P = .048) and larger submucosal part (%) of the biopsies (Mann-Whitney U test, P = .003) than the forceps. Two patients were observed because of chest pain and suspicion of bleeding in 24 hours. No therapeutic measures were necessary to be taken. Conclusion The new drill instrument for flexible endoscopy can safely deliver submucosal tissue samples from submucosal lesions in the upper gastrointestinal tract. PMID- 27126253 TI - Alexandros Zaoussis, MD, PhD (1923-2005): An Orthopedic Surgeon and Historian and His Contribution to the Establishment of Hip Surgery. AB - The purpose of our study was to summarize all the knowledge concerning the innovative pioneer in the field of orthopedic surgery and especially hip replacement, Alexandros Zaoussis (1923-2005). He was a pioneer in hip replacement, and he contributed to several fields of orthopedic surgery with his clinical work and his international publications. He was also an eminent historian of World War II and of the Greek Resistance to the Nazi occupation in which he played a significant part. A thorough study of texts, medical books, and reports in the field of history of medicine, together with a review of the available literature in PubMed, was undertaken. He was an eminent clinical director of orthopedics who had significant contribution in teaching, practicing, and expanding the horizons of orthopedic surgery in the 20th century. A thorough review of medical texts, books, and publications in the Greek academic press was undertaken to summarize his contributions and his turbulent life to commemorate the 10th anniversary of his death. PMID- 27126254 TI - Biocompatibility versus peritoneal mesothelial cells of polypropylene prostheses for hernia repair, coated with a thin silica/silver layer. AB - Hernias are generally repaired using synthetic prostheses. Infection may already be present or develop during implantation. Based on the increasing resistance to antibiotics, and the well-known antimicrobial properties of silver (Ag), the possibility of coating hernia prostheses with a nanostructured layer containing Ag was explored. Prostheses (Clear Mesh Composite [CMC]) made up of two polypropylene layers (macroporous light mesh and thin transparent film) were tested with human mesothelial cells from omentum biopsies. Mesotheliocytes modulate abdominal wall healing producing cytokines, growth factors, and adhesion molecules. Evaluating the growth of these cells on CMC or film alone showed that cell numbers on CMC increased over time, and were higher than those on film alone. Vimentin immunostaining confirmed the cells to be mesotheliocytes. Subsequently, the biocompatibility of mesh layer, coated or not with a thin layer of Ag/SiO2 -nanoclusters, was analyzed, showing no difference in absence or presence of Ag/SiO2 . Differently, TGF-beta2 production, involved in tissue repair and fibrosis, increased in the presence of Ag/SiO2 . Moreover, Ag/SiO2 coated mesh showed antibacterial properties. In conclusion, the mesh layer coated with Ag/SiO2 afforded cell growth, and showed antibacterial activity. Coating only the mesh layer did not decrease film transparency, and did not favor the formation of adhesions on the visceral side. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1586-1593, 2017. PMID- 27126261 TI - Chlamydia trachomatis serovar G infection in a bisexual male with urethritis. AB - We report a case of Chlamydia trachomatis serovar G urogenital tract infection in a 33-year-old human immunodeficiency virus-1 (HIV-1) seropositive Indian bisexual male. This case highlights the emergence of a new serovar in India. The patient was tested positive for C. trachomatis by both cryptic plasmid and omp A gene polymerase chain reaction (PCR). On further characterization using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) and omp A gene sequencing, the strain was found to be C. trachomatis serovar G. His spouse was also found to be infected with C. trachomatis serovar G. Phylogenetic analysis was performed on the clinical isolates obtained from both partners and were found to be identical to the isolates available in GenBank. The sexual network could not be traced further. Detection of a new genotype suggests importation of a new strain into the population probably by sexual contact with a person from a geographical area where the strain is common. Identifying circulating genotypes in the community can assist in developing strategies for improved sexually transmitted disease control. PMID- 27126264 TI - [Rationale, design and methodology of physical attributes identification of the fear of falling syndrome (FISTAC study)]. AB - INTRODUCTION: The aim of this study was to identify the physical determining factors of the Fear of Falling Syndrome (FoF) in older adults with a history of falls. METHODS: An observational study was conducted on 183 subjects older than 64 years with a fall in the previous year, with data collected from the geriatrics outpatient clinic of the Complejo Hospitalario Universitario from Albacete, Spain. Sociodemographic and anthropometric data, as well as comorbidity, drugs usually taken, functional status, physical function, frailty, cognitive and affective status were collected. Muscle mass was measured using bioimpedancy meter (BIA), and densitometry (DXA), strength with digital hand-held JAMAR dynamometer and with a Leg-press machine, muscle potency with a T-Force instrument, gait variability with the Gait-Rite instrument, and postural stability with the Neurocom Balance Master posturograph were also determined. An analysis was performed to determine if the FoF is associated with physical impairments adjusted for the study covariates. RESULTS: The study included 140 subjects with FoF, and 43 without it. The mean age was 78.4 years, and 147 were women. Posturography could be measured in 182 participants, DXA in 117, BIA in 165, and muscle potency in 146. FoF was associated with female sex, frailty, depressed mood, social risk, muscle strength and power, physical function, number of drugs used, and orthostatic hypotension in the overall sample. After adjusting for sex, only frailty, depressed mood, and number of drugs remained associated. CONCLUSIONS: Rationale, design, and methods of the FISTAC study are presented. PMID- 27126265 TI - SPM-1 metallo-beta-lactamase-producing Pseudomonas aeruginosa ST277 in the UK. PMID- 27126266 TI - Impact of AP@LZ in the daily life of three persons with Alzheimer's disease: long term use and further exploration of its effectiveness. AB - AP@LZ is an electronic organiser that was designed to support the day-to-day activities of persons with Alzheimer's disease. To assess the potential of this technology, three participants (NI, JB, RD) were approached to take part in the study. They benefited from a structured cognitive intervention to learn how to operate AP@LZ; the intervention included the following learning stages: Acquisition, Application and Adaptation. Pre- and post-intervention measures were collected. NI, for whom a longitudinal study was conducted, still continued to use AP@LZ 24 months post-intervention. JB and RD also showed a gradual improvement in their performance throughout the intervention phase (sessions 1 to 19 for JB: performance increased from 50 to 100%; sessions 1 to 25 for RD: from 56 to 89%). The results of the use of AP@LZ in activities of daily living suggest that the application was beneficial for three persons with Alzheimer's disease whose profiles differed notably (age, cognitive and social profiles). Thus, results indicate that they were all able to learn how to operate AP@LZ's functions and to use them in their activities of daily living. Cognitive intervention appears to play an important role for the promotion of learning and adoption of such technology. PMID- 27126267 TI - Elevation of plasma-soluble HLA-G in childhood nephrotic syndrome is associated with IgE. AB - Background Nephrotic syndrome is related to immune system dysfunction. Soluble human leukocyte antigen-G has been suggested to have an immunomodulatory role. Additionally, human leukocyte antigen-G expression may be influenced by the 14 base pair insertion/deletion polymorphism. However, this molecule has not been investigated in nephrotic syndrome. Methods Fifty-five children with nephrotic syndrome were enrolled: 24 primary nephrotic syndrome patients and 31 recurrent nephrotic syndrome patients. A group of 120 healthy subjects were included as reference controls. Additionally, 22 patients in nephrotic syndrome remission after treatments were also included. Both nephrotic syndrome patients and healthy subjects were genotyped for the 14-base pair insertion/deletion polymorphism. Plasma soluble human leukocyte antigen-G concentrations and serum immunoglobulin concentrations were determined. Results Nephrotic syndrome patients showed significantly higher levels of both soluble human leukocyte antigen-G and immunoglobulin E compared to normal controls. Nephrotic syndrome patients presented a higher frequency of the -14-base pair allele than did normal controls. Soluble human leukocyte antigen-G concentrations in remission patients were dramatically lower compared to in nephrotic syndrome patients. Moreover, soluble human leukocyte antigen-G and immunoglobulin E were moderately correlated in nephrotic syndrome patients. Conclusions The present study demonstrated that plasma soluble human leukocyte antigen-G concentrations were significantly elevated and that a relationship between serum total immunoglobulin E in nephrotic syndrome patients and the human leukocyte antigen-G -14-base pair allele may be a risk factor for nephrotic syndrome. These findings suggest that soluble human leukocyte antigen-G may be used as a monitoring marker for nephrotic syndrome patients' condition. PMID- 27126268 TI - Thyroxine replacement: a clinical endocrinologist's viewpoint. AB - BACKGROUND: Hypothyroidism affects 2-5% of the general population. Patients with uncorrected disease suffer significant morbidity and have an increased risk of cardiovascular disease and neurocognitive impairment. Levothyroxine, the treatment of choice, is inexpensive, easy to administer and in most cases restores well-being while normalizing thyroid function. However, 30-50% of individuals on levothyroxine are either over-treated or under-treated and others remain dissatisfied with treatment despite achieving thyroid hormone concentrations within the laboratory reference interval. METHODS: This review is based on a systematic search of the literature for controlled trials, systematic reviews, guideline papers and cohort studies addressing best practice in thyroid hormone replacement. RESULTS: Recent decades have seen improvements in patient management strategies driven by a better appreciation of levothyroxine pharmacokinetics. However, aspects of therapy such as the optimal timing of medication, strategies to overcome treatment non-adherence and target thyroid stimulating hormone concentrations in pregnancy and in patients with differentiated thyroid cancer remain challenging. Furthermore, there is now a substantial body of literature on common genetic variations in the deiodinases and thyroid hormone transporters and their role in the local regulation of thyroid hormone delivery. The benefits of combination therapy with liothyronine and levothyroxine are uncertain, and while it is theoretically probable that subsets of genetically predisposed individuals will benefit from combination therapy the existing evidence is as yet limited. CONCLUSION: Despite the availability of thyroid hormone replacement for more than a century, there are still substantial challenges in practice and opportunities to improve treatment outcomes. PMID- 27126271 TI - Regioselective construction of diverse and multifunctionalized 2 hydroxybenzophenones for sun protection by indium(iii)-catalyzed benzannulation. AB - Diverse and functionalized 2-hydroxybenzophenone derivatives were synthesized efficiently in good to excellent yield via the highly regioselective indium(iii) catalyzed [2+2+2] benzannulation of 3-formylchromones with beta-enamino esters or beta-enamino ketones. This benzannulation reaction proceeds via a domino Michael/retro-Michael/6pi-electrocyclization/deformylation reaction. In addition, 2-hydroxybenzophenones were also prepared by the indium(iii)-catalyzed [4+2] benzannulation reaction between 3-substituted chromen-4-ones and beta-enamino esters or beta-enamino ketones. Furthermore, the effects of substituents and pi conjugation on the characteristics of the UV-Vis spectrum of synthesized 2 hydroxybenzophenones were examined. Compound 10s exhibited higher sun protection activity than oxybenzone which is used in most popular sunscreens. PMID- 27126269 TI - Serum microRNA-135a-5p as an auxiliary diagnostic biomarker for colorectal cancer. AB - Objective The purpose of this study was to explore serum miR-135a-5p expression in colorectal cancer and examine the potential usefulness of this molecule as a biomarker for diagnosis in colorectal cancer. Methods Serum samples were collected from 60 patients with primary colorectal cancer, 40 patients with colorectal polyps and 50 healthy controls. Serum miR-135a-5p expression levels were detected by reverse transcription quantitative real-time quantitative polymerase chain reaction. Serum carcinoembryonic antigen and carbohydrate antigen 199 concentrations were detected by MODULAR ANALYTICS E170. Results The relative expression level of serum miR-135a-5p in colorectal cancer patients, colorectal polyps patients and healthy controls was 2.451 (1.107, 4.413), 0.946 (0.401, 1.942) and 0.949 (0.194, 1.415), respectively, indicating that it was significantly higher in colorectal cancer patients than that in the other two groups ( U = 351.0, 313.0, both P < 0.001). Additionally, it was significantly correlated with different degrees of tumour differentiation ( U = 215.0, P = 0.029) and different tumour stages ( U = 202.0, P = 0.013). There was no significant correlation between the relative expression of serum miR-135a-5p and carcinoembryonic antigen ( r2 = 0.023, P = 0.293) or carbohydrate antigen 199 ( r2 = 0.067, P = 0.068) in colorectal cancer patients. Compared with colorectal polyps group, AUCROC of serum miR-135a-5p in colorectal cancer group was 0.832 with 95% CI 0.73-0.93; compared with healthy control group, AUCROC was 0.875 with 95% CI 0.80-0.95. Conclusion Serum miR-135a-5p expression in colorectal cancer patients was higher than that in patients with colorectal polyps and healthy controls, suggesting that serum miR-135a-5p may prove to be an important biomarker for auxiliary diagnosis of colorectal cancer. PMID- 27126270 TI - Highly sensitive stool DNA testing of Fusobacterium nucleatum as a marker for detection of colorectal tumours in a Japanese population. AB - Background Accumulating evidence shows an over-abundance of Fusobacterium nucleatum in colorectal tumour tissues. Although stool DNA testing of Fusobacterium nucleatum might be a potential marker for the detection of colorectal tumours, the difficulty in detecting Fusobacterium nucleatum in stool by conventional methods prevented further explorations. Therefore, we developed a droplet digital polymerase chain reaction (PCR) assay for detecting Fusobacterium nucleatum in stool and investigated its clinical utility in the management of colorectal tumours in a Japanese population. Methods Feces were collected from 60 healthy subjects (control group) and from 11 patients with colorectal non advanced adenomas (non-advanced adenoma group), 19 patients with colorectal advanced adenoma/carcinoma in situ (advanced adenoma/carcinoma in situ (CIS) group) and 158 patients with colorectal cancer of stages I to IV (colorectal cancer group). Absolute copy numbers of Fusobacterium nucleatum were measured by droplet digital PCR. Results The median copy number of Fusobacterium nucleatum was 17.5 in the control group, 311 in the non-advanced adenoma group, 122 in the advanced adenoma/CIS group, and 317 in the colorectal cancer group. In comparison with that in the control group, the Fusobacterium nucleatum level was significantly higher in the non-advanced adenoma group, the advanced adenoma/CIS group and the colorectal cancer group. Conclusions This study illustrates the potential of stool DNA testing of Fusobacterium nucleatum by droplet digital PCR to detect individuals with colorectal tumours in a Japanese population. PMID- 27126272 TI - Establishing herd immunity against Ebola through vaccination. AB - OBJECTIVES: In response to recent concern regarding Ebola outbreaks, this study aims to (1) determine the relationship between vaccination coverage and herd immunity, (2) determine the vaccination coverage necessary to establish herd immunity for previous Ebola viruses, and (3) recommend vaccination coverage thresholds for future Ebola viruses. METHODS: Herd immunity thresholds needed to block transmission of Ebola virus were determined using vaccine efficacy and number of secondary cases per infected case during an entire infectious period. RESULTS: In past Ebola outbreaks 42.2-63.0% of the population would need to be vaccinated in order to prevent transmission and outbreaks. Assuming 80% vaccine efficacy as reported by phase I clinical trials, 52.7-78.7% of the population would require vaccination coverage in order to establish herd immunity. In recent ring vaccination trials which considered the vaccine to be 100% effective after 10 days, 42.2-63.0% of the population would need to be vaccinated. CONCLUSION: For future Ebola outbreaks, the spread of the virus can be prevented by vaccinating certain percentages of the population depending on vaccine efficacy and number of secondary cases per infected case. PMID- 27126273 TI - Design, synthesis, and in vitro evaluation of a fluorescently labeled irreversible inhibitor of the catalytic subunit of cAMP-dependent protein kinase (PKACalpha). AB - The design and development of irreversible kinase inhibitors is an expanding frontier of kinase drug discovery. The current approach to develop these inhibitors utilizes ATP-competitive inhibitor scaffolds to target non-catalytic cysteines in the kinase ATP-binding site. However, this approach is limited as not all kinases have a cysteine in the ATP-binding site that can be targeted. In this work, we report a complementary approach to developing irreversible kinase inhibitors that utilizes the substrate-binding site. Using the catalytic subunit of cAMP-dependent protein kinase (PKACalpha) as a model system, we have designed and synthesized an irreversible inhibitor based on the substrate-competitive inhibitor scaffold PKI(14-22) that covalently modifies non-catalytic Cys199 in the PKACalpha substrate-binding site. The new compound inhibits PKACalpha (IC50 = 11.8 +/- 1.1 nM), is ~100-fold selective for PKACalpha in a kinase panel, and covalently labels the kinase as demonstrated by fluorescence, mass spectrometry, and kinetics experiments. This study demonstrates the feasibility of utilizing this new approach to develop irreversible inhibitors for any of the eighty-nine kinases that possess a similar non-catalytic cysteine in their substrate-binding sites. PMID- 27126274 TI - Converging flow and anisotropy cause large-scale folding in Greenland's ice sheet. AB - The increasing catalogue of high-quality ice-penetrating radar data provides a unique insight in the internal layering architecture of the Greenland ice sheet. The stratigraphy, an indicator of past deformation, highlights irregularities in ice flow and reveals large perturbations without obvious links to bedrock shape. In this work, to establish a new conceptual model for the formation process, we analysed the radar data at the onset of the Petermann Glacier, North Greenland, and created a three-dimensional model of several distinct stratigraphic layers. We demonstrate that the dominant structures are cylindrical folds sub-parallel to the ice flow. By numerical modelling, we show that these folds can be formed by lateral compression of mechanically anisotropic ice, while a general viscosity contrast between layers would not lead to folding for the same boundary conditions. We conclude that the folds primarily form by converging flow as the mechanically anisotropic ice is channelled towards the glacier. PMID- 27126276 TI - LOCAL GOVERNMENT AND COMMUNITY LEADERS' PERSPECTIVES ON CHILD HEALTH AND MORTALITY AND INEQUITY ISSUES IN RURAL EASTERN INDONESIA. AB - Since 2001 a decentralization policy has increased the responsibility placed on local government for improving child health in Indonesia. This paper explores local government and community leaders' perspectives on child health in a rural district in Indonesia, using a qualitative approach. Focus group discussions were held in May 2013. The issues probed relate to health personnel skills and motivation, service availability, the influence of traditional beliefs, and health care and gender inequity. The participants identify weak leadership, inefficient health management and inadequate child health budgets as important issues. The lack of health staff in rural areas is seen as the reason for promoting the use of traditional birth attendants. Midwifery graduates and village midwives are perceived as lacking motivation to work in rural areas. Some local traditions are seen as detrimental to child health. Husbands provide little support to their wives. These results highlight the need for a harmonization and alignment of the efforts of local government agencies and local community leaders to address child health care and gender inequity issues. PMID- 27126277 TI - Personalized intensification of insulin therapy in type 2 diabetes - does a basal bolus regimen suit all patients? AB - Many patients with type 2 diabetes mellitus (T2DM) require insulin therapy. If basal insulin fails to achieve glycemic control, insulin intensification is one possible treatment intensification strategy. We summarized clinical data from randomized clinical trials designed to compare the efficacy and safety of basal bolus and premixed insulin intensification regimens. We defined a between-group difference of >=0.3% in end-of-study glycated hemoglobin (HbA1c) as clinically meaningful. A PubMed database search supplemented by author-identified papers yielded 15 trials which met selection criteria: randomized design, patients with T2DM receiving basal-bolus (bolus injection <=3 times/day) vs. premixed (<=3 injections/day) insulin regimens, primary/major endpoint(s) HbA1c- and/or hypoglycemia-related, and trial duration >=12 weeks. Glycemic control improved with both basal-bolus and premixed insulin regimens with - in most cases - acceptable levels of weight gain and hypoglycemia. A clinically meaningful difference between regimens in glycemic control was recorded in only four comparisons, all of which favored basal-bolus therapy. The incidence of hypoglycemia was significantly different between regimens in only three comparisons, one of which favored premixed insulin and two basal-bolus therapy. Of the four trials that reported a significant difference between regimens in bodyweight change, two favored basal-bolus therapy and two favored premixed insulin. Thus, on a population level, neither basal-bolus therapy nor premixed insulin showed a consistent advantage in terms of glycemic control, hypoglycemic risk, or bodyweight gain. It is therefore recommended that clinicians should adopt an individualized approach to insulin intensification - taking into account the benefits and risks of each treatment approach and the attitude and preferences of each patient - in the knowledge that both basal-bolus and premixed regimens may be successful. PMID- 27126279 TI - Corrigendum to "Driver views on speed and enforcement" [Accid. Anal. Prev. 89 (April) (2016) 9-21]. PMID- 27126275 TI - Retinal glial responses to optic nerve crush are attenuated in Bax-deficient mice and modulated by purinergic signaling pathways. AB - BACKGROUND: Retinal ganglion cell (RGC) soma death is a consequence of optic nerve damage, including in optic neuropathies like glaucoma. The activation of the innate immune network in the retina after nerve damage has been linked to RGC pathology. Since the eye is immune privileged, innate immune functions are the responsibility of the glia, specifically the microglia, astrocytes, and Muller cells that populate the retina. Glial activation, leading to the production of inflammatory cytokines, is a hallmark feature of retinal injury resulting from optic nerve damage and purported to elicit secondary degeneration of RGC somas. METHODS: A mouse model of optic nerve crush (ONC) was used to study retinal glial activation responses. RGC apoptosis was blocked using Bax-deficient mice. Glial activation responses were monitored by quantitative PCR and immunofluorescent labeling in retinal sections of activation markers. ATP signaling pathways were interrogated using P2X receptor agonists and antagonists and Pannexin 1 (Panx1) deficient mice with RGC-specific deletion. RESULTS: ONC induced activation of both macroglia and microglia in the retina, and both these responses were dramatically muted if RGC death was blocked by deletion of the Bax gene. Macroglial, but not microglial, activation was modulated by purinergic receptor activation. Release of ATP after optic nerve damage was not mediated by PANX1 channels in RGCs. CONCLUSIONS: RGC death in response to ONC plays a principal stimulatory role in the retinal glial activation response. PMID- 27126278 TI - Distinct neuroplasticity processes are induced by different periods of acrobatic exercise training. AB - Short and long-term physical exercise induce physiological and structural changes in brain motor areas. The relationship between changes of structural and synaptic proteins in brain motor areas and acrobatic exercise is less understood. Our aim was to evaluate the expression of synapsin I (SYS), synaptophysin (SYP), microtubule-associated protein 2 (MAP2), neurofilament (NF), and a marker for recent neuronal activity (Egr-1) in the motor cortex, striatum and cerebellum of adult rats subjected to acrobatic exercise (AE, for 1-4 weeks). We used adult Wistar rats, divided into 4 groups based on duration of acrobatic training, namely 1 week (AE1, n=15), 2 weeks (AE2, n=15), 4 weeks (AE4, n=15), and sedentary (SED, n=15). In AE groups, the rats covered 5 times a circuit that was composed of obstacles, three times a week. The protein levels were analyzed by immunoblotting and immunohistochemistry. The results revealed that short-term AE (AE1 and AE2) induced MAP2 decreases and NF, SYP and Egr-1 increases in the motor cortex; an increase of MAP2, SYS and SYP in the dorsolateral striatum, whereas the dorsomedial striatum showed increased NF, SYS, SYP and Egr-1. Granular cerebellar layer showed increased NF and Egr-1, with increased NF and SYP in the molecular layer. Long-term AE (AE4) promoted an increase of MAP2, SYP and Egr-1 in motor cortex; MAP2, SYS and SYP in the dorsomedial striatum; and NF and Egr-1 in the cerebellar granular layer. In conclusion, our data suggest that different durations of AE induce distinct plastic responses among distinct cortical and subcortical circuits. PMID- 27126280 TI - Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H. AB - Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI. PMID- 27126281 TI - User acceptance of observation and response charts with a track and trigger system: a multisite staff survey. AB - AIMS AND OBJECTIVES: To examine user acceptance with a new format of charts for recording observations and as a prompt for responding to episodes of clinical deterioration in adult medical-surgical patients. BACKGROUND: Improving recognition and response to clinical deterioration remains a challenge for acute healthcare institutions globally. Five chart templates were developed in Australia, combining human factors design principles with a track and trigger system for escalation of care. Two chart templates were previously tested in simulations, but none had been evaluated in clinical practice. DESIGN: Prospective multisite survey of user acceptance of the charts in practice. METHODS: New observation and response charts were trialled in parallel with existing charts for 24 hours across 36 adult acute medical-surgical wards, covering 108 shifts, in five Australian states. Surveys were completed by 477 staff respondents, with open-ended comments and narrative from short informal feedback groups providing elaboration and context of user experiences. RESULTS: Respondents were broadly supportive of the chart format and content for monitoring patients, and as a prompt for escalating care. Some concerns were noted for chart size and style, use of ranges to graph vital signs and with specific human factors design features. Information and training issues were identified to improve usability and adherence to chart guidelines and to support improved detection and response for patients with clinical deterioration. CONCLUSIONS: This initial evaluation demonstrated that the charts were perceived as appropriate for documenting observations and as a prompt to detect clinical deterioration. Further evaluation after some minor modifications to the chart is recommended. RELEVANCE TO CLINICAL PRACTICE: Explicit training on the principles and rationale of human factors chart design, use of embedded change management strategies and addressing practical issues will improve authentic engagement, staff acceptance and adoption by all clinical users when implementing a similar observation and response chart into practice. PMID- 27126282 TI - Treating Hemodynamic Congestion Is the Key to Prevent Heart Failure Hospitalizations. PMID- 27126283 TI - Digoxin for Worsening Chronic Heart Failure: Underutilized and Underrated. PMID- 27126284 TI - The Search for a Crystal Ball to Predict Early Recovery From Peripartum Cardiomyopathy? PMID- 27126285 TI - What Is the Prevalence of Diabetes Mellitus in Patients With Principal and Secondary Takotsubo Syndrome? PMID- 27126286 TI - Reply: What Is the Prevalence of Diabetes Mellitus in Patients With Principal and Secondary Takotsubo Syndrome? PMID- 27126287 TI - Why do we love to hate ourselves? PMID- 27126288 TI - Erratum: Computerised prescribing for safer medication ordering: still a work in progress. PMID- 27126289 TI - Noradrenaline effects on social behaviour, intergroup relations, and moral decisions. AB - Recent research has begun to elucidate the neural basis of higher order social concepts, such as the mechanisms involved in intergroup relations, and moral judgments. Most theories have concentrated on higher order emotions, such as guilt, shame, or empathy, as core mechanisms. Accordingly, psychopharmacological and neurobiological studies have investigated the effects of manipulating serotonin or oxytocin activity on moral and social decisions and attitudes. However, recently it has been determined that changes in more basic emotions, such as fear and anger, might also have a significant role in social and moral cognition. This article summarizes psychopharmacological and fMRI research on the role of noradrenaline in higher order social cognition suggesting that indeed noradrenergic mediated affective changes might play key - and probably causal - role in certain social attitudes and moral judgments. Social judgments may also be directly influenced by numerous neurotransmitter manipulations but these effects could be mediated by modulation of basic emotions which appear to play an essential role in the formation of social concepts and moral behaviour. PMID- 27126291 TI - [Influence of hearing aids on monosyllabic test score and subjective everyday hearing]. AB - BACKGROUND: Pure tone and speech audiometry are essential methods for examining the indication for hearing aids, as well as for hearing aid evaluation. Additionally, the subjective benefit of hearing aids has to be evaluated with appropriate questionnaires. The aim of the present study was to investigate the correlation between speech audiometry data and the results of a simple and user friendly questionnaire, as well as to provide normative data for subjective benefit. MATERIALS AND METHODS: Data from 136 hearing aid users with bilateral sensorineural hearing loss were analyzed retrospectively. Pure tone thresholds and Freiburg monosyllabic speech perception in the binaural situation were measured at 65 dB in quiet and in noise (signal-to-noise ratio, SNR = +5 dB), with and without hearing aids. Additionally, subjective hearing in everyday life was recorded using the 12-item Oldenburg Inventory. RESULTS: Improvement of speech perception with hearing aids for the Freiburg monosyllabic test in quiet was 32.0 percentage points on average; in noise, there was an average improvement of 16.4 percentage points. There was a strong correlation between the results of pure tone and speech audiometry. With hearing aids, patients scored their everyday hearing using the Oldenburg Inventory on average 1.4 scale points better than without hearing aids. Results of the Oldenburg Inventory correlate with both pure tone and speech audiometry. CONCLUSION: Hearing aid evaluation should include both speech audiometry and systematic measurement of the subjective benefit using a suitable questionnaire. In combination, the Freiburg monosyllabic test and the Oldenburg Inventory allow for quick and comprehensive evaluation. PMID- 27126292 TI - [The vestibular craniovertebral joints]. AB - INTRODUCTION: The significance of cervical proprioception for human balance has thus far not been sufficiently elucidated. The aim of this study was to provoke selective cervico-vestibular stimulation using the trunk excursion test (TET) we ourselves constructed. This chair is designed to enable evaluation of cervico ocular reactions during isolated trunk excursion and possible effects of aging. METHODS: The previously used head excursion test (HET) was statistically compared to the TET. In both methods, 100 healthy subjects of two age groups (group(26): median age = 26 years, n = 50; group(50): median age = 50 years, n = 50) were randomized for comparison of similar neck-to-trunk-positions. RESULTS: HET enabled detection of significant nystagmus modulation in horizontal and vertical dimensions; whereas in pure cervical stimulation using the new TET, this was only evident in the horizontal dimension and only during trunk torsion. Comparison of the two methods confirmed significantly stronger nystagmus modulation through head excursion. In terms of the HET, group(50) showed significantly more vertical nystagmus activity than group(26). However, no significant difference was found between the groups in terms of their reactions to trunk excursion in the TET. In a group-specific comparison of the methods, group(26) showed a significant increase in horizontal nystagmus in head compared to trunk excursion, whereas group(50) generally displayed a significantly greater response to provocation by head excursion in HET. Analysis of the significant vertical nystagmus modulation produced with the TET method showed predominance of upbeat- (UBN) over downbeat nystagmus (DBN). Through head excursion with the HET, DBN was more frequently evoked in group(50) than in group(26). No significant age-dependent difference could be derived in UBN. CONCLUSION: The results of the pilot study indicate that head-to-trunk provocation is a suitable means of evaluating cervicotonic provocation nystagmus. Only by evaluation of adequate excursion limits and consistent analysis of patients with cervical deficiency can the effects of the method be further assessed. PMID- 27126290 TI - Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure. AB - The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 27126294 TI - Cardiovagal activity confers cardioprotection after myocardial infarction: recent advances. PMID- 27126293 TI - [S2e-guideline: "ENT-specific therapy of obstructive sleep apnea in adults" short version : Sleep Medicine Task Force of the German Society for Otorhinolaryngology, Head and Neck Surgery]. AB - The present S2e-guideline is an update of the former S2e-guideline "treatment of obstructive sleep apnea in adults". The update was performed on behalf of the German Society for Otorhinolaryngology, Head and Neck Surgery by its Sleep Medicine Task Force. The long version of the guideline is valid from 5.9.2015 to 5.9.2020 and has been available (guideline No. 017-069) since November 2015 on the official AWMF website.The subsequently presented short version of the guideline summarizes the essentials in a legible way. For further information, please refer to the long version. PMID- 27126296 TI - What we have learned about antenatal corticosteroid regimens. AB - Administration of antenatal corticosteroids has been standard of care for women between 24 and 34 weeks of gestation who are at risk for preterm delivery for more than 20 years longer in other parts of the world. Although the benefit of steroids in this population has been confirmed, there remain many questions including the frequency of dosing and whether it is possible to expand the gestational age criteria to women likely to deliver before 24 weeks or after 34 weeks. The MFMU Network has played a major role in answering some of these questions. PMID- 27126295 TI - What we have learned about treating mild gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) is associated with adverse perinatal outcomes, with risks not only associated with more severe forms of GDM, but milder forms of GDM as well. Treatment of mild GDM with dietary intervention and insulin when necessary has proven to be effective in reducing the risks of several, but not all, adverse perinatal outcomes. Less is known about the long term benefits of mild GDM treatment. This article will review the benefits of mild GDM treatment, and related risk factors, on short-term and long-term maternal and neonatal/child outcomes, with an emphasis on research conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. PMID- 27126297 TI - Preoperative risk stratification for major complications following pancreaticoduodenectomy: Identification of high-risk patients. AB - INTRODUCTION: Morbidity after pancreaticoduodenectomy (PD) remains a major concern with high rates. The aim of this study was to identify preoperative risk factors and create a new risk score to predict major complications after PD. METHODS: Medical records of patients undergoing PD between 1993 and 2014 were retrospectively reviewed according to survival and surgical and non-surgical complications. A split-sample cross validation was conducted in which the original cohort was randomly selected to a modelling and a validation group at a ratio of 2:1. Univariate and multivariate analysis were carried out on the modelling set to identify preoperative risk factors, which were entered into a binary logistic regression model with stepwise backward elimination to develop the risk score model. Receiver operating curve analysis was implemented to judge the model's prediction ability. RESULTS: PD was performed in 405 patients. A total of 29.1% (118 patients) developed major complications. On multivariate analysis, American Society of Anaesthesiologists (ASA) score and obesity as well as the presence of cardiovascular and pulmonary comorbidities were significant predictors for major complications. A risk score was derived from the regression model and successfully tested on the validation set (area under the curve = 0.84). CONCLUSION: The risk score showed a high accuracy to predict major complications after PD based on preoperative parameters only. This simple and quick approach allows for individualized risk assessment and may improve preoperative counselling and patient selection for perioperative treatment strategies. PMID- 27126298 TI - Does strabismus surgery improve quality and mood, and what factors influence this? AB - AimsTo establish the impact of adult strabismus surgery on clinical and psychosocial well-being and determine who experiences the greatest benefit from surgery and how one could intervene to improve quality of life post surgery.MethodsA longitudinal study, with measurements taken pre-surgery and at 3 and 6 months post-surgery. All participants completed the AS-20 a disease specific quality of life scale, along with measures of mood, strabismus and appearance-related beliefs and cognitions and perceived social support. Participants also underwent a full orthoptic assessment at their preoperative visit and again 3 months postoperatively. Clinical outcomes of surgery were classified as success, partial success or failure, using the largest angle of deviation, diplopia and requirement for further therapy.Results210 participants took part in the study. Strabismus surgery led to statistically significant improvements in psychosocial and functional quality of life. Those whose surgery was deemed a partial success did however experience a deterioration in quality of life. A combination of clinical variables, high expectations, and negative beliefs about the illness and appearance pre-surgery were significant predictors of change in quality of life from pre- to post-surgery.ConclusionsStrabismus surgery leads to significant improvements in quality of life up to 6 months postoperatively. There are however a group of patients who do not experience these benefits. A series of clinical and psychosocial factors have now been identified, which will enable clinicians to identify patients who may be vulnerable to poorer outcomes post-surgery and allow for the development of interventions to improve quality of life after surgery. PMID- 27126299 TI - Biocompatibility evaluation of dicalcium phosphate/calcium sulfate/poly (amino acid) composite for orthopedic tissue engineering in vitro and in vivo. AB - In vitro cytocompatibility of ternary biocomposite of dicalcium phosphate (DCP) and calcium sulfate (CS) containing 40 wt% poly (amino acid) (PAA) was evaluated using L929 fibroblasts and MG-63 osteoblast-like cells. Thereafter, the biocompatibility of biocomposite in vivo was investigated using an implantation in muscle and bone model. In vitro L929 and MG-63 cell culture experiments showed that the composite and PAA polymer were noncytotoxic and allowed cells to adhere and proliferate. The scanning electron microscope (SEM) confirmed that two kinds of cells maintained their phenotype on all of samples surfaces. Moreover, the DCP/CS/PAA composite showed higher cellular viability than that of PAA; meanwhile, the cell proliferation and ALP activity were much higher when DCP/CS had added into PAA. After implanted in muscle of rabbits for 12 weeks, the histological evaluation indicated that the composite exhibited excellent biocompatibility and no inflammatory responses were found. When implanted into bone defects of femoral condyle of rabbits, the composite was combined directly with the host bone tissue without fibrous capsule tissue, which shown good biocompatibility and osteoconductivity. Thus, this novel composite may have potential application in the clinical setting. PMID- 27126300 TI - Retinal characteristics during 1 year of insulin pump therapy in type 1 diabetes: a prospective, controlled, observational study. AB - PURPOSE: To investigate changes in retinal metabolism, function, structure and morphology in relation to initiation of insulin pump therapy (continuous subcutaneous insulin infusion, CSII). METHODS: Visual acuity, retinopathy level, dark adaptation kinetics, retinal and subfoveal choroidal thickness, macular perfusion velocities, retinal vessel diameters and blood oxygen saturations were measured at baseline and after 1, 4, 16, 32 and 52 weeks in 31 patients with type 1 diabetes who started CSII and 20 patients who continued multiple daily insulin injections (MDI). RESULTS: One year of CSII reduced haemoglobin A1c (HbA1c ) by 1.6% (17.8 mmol/mol) compared with 0.3% (3.1 mmol/mol) in the MDI group (p < 0.0001). Central retinal thickness increased by 1.5% in the CSII group (within group p = 0.0098; between-group p = 0.063) without producing macular oedema. No detectable change was found in any other primary outcome measure. The proportion of patients with retinopathy worsening did not differ between groups. At baseline, longer disease duration was associated with higher retinal artery oxygen saturation (p = 0.014) and lower macular venous perfusion velocity (p = 0.045). CONCLUSION: One year of CSII led to an HbA1c reduction relative to continued MDI and a small increase in retinal thickness but not to early retinopathy worsening or to changes in retinal vascular, structural or functional characteristics. Longer duration of type 1 diabetes appears to be associated with lower macular venous perfusion velocity and higher retinal artery oxygen saturation. The latter could potentially reflect cumulative glycaemia. PMID- 27126301 TI - 73-Year-Old Woman With Pruritus, Jaundice, and Altered Mental Status. PMID- 27126302 TI - Management of Psychotropic Drug-Induced DRESS Syndrome: A Systematic Review. AB - Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous eruption that has been linked to several common drugs and drug categories, including antiepileptics, allopurinol, sulfonamides, and various antibiotics; however, because of a number of recent case reports linking psychotropic medications to this condition, DRESS is increasingly recognized among psychiatrists. We systematically reviewed all psychotropic drugs linked to DRESS syndrome, and this article summarizes the clinical management relevant to psychiatric professionals. A comprehensive search was performed using Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus, and Litt's Drug Eruption and Reaction Database for articles published in English during the past 20 years (1996-2015) using the search terms (1) psychotropic drugs OR serotonin uptake inhibitors AND DRESS or (2) psychotropic drugs AND drug reaction (or rash) eosinophilia systemic syndrome, and all article abstracts were screened for inclusion and exclusion criteria by 3 reviewers. Two independent reviewers examined the full text of 163 articles, of which 96 (25 original articles, 12 review articles, 55 case reports, and 4 letters to the editor) were included in the systematic review. We identified 1072 cases of psychotropic drug-induced DRESS, with carbamazepine, lamotrigine, phenytoin, valproate, and phenobarbital being the most implicated drugs. Based on our review of the literature, we outline management principles that include prompt withdrawal of the causative drug, hospitalization, corticosteroid therapy, and novel treatments, including intravenous immunoglobulin, cyclophosphamide, and cyclosporine, for corticosteroid-resistant DRESS. Finally, we outline strategies for treating comorbid psychiatric illness after a DRESS reaction to the psychotropic medication. PMID- 27126304 TI - Functional neurotoxicity evaluation of noribogaine using video-EEG in cynomolgus monkeys. AB - INTRODUCTION: Continuous video-electroencephalographic (EEG) monitoring remains the gold standard for seizure liability assessments in preclinical drug safety assessments. EEG monitored by telemetry was used to assess the behavioral and EEG effects of noribogaine hydrochloride (noribogaine) in cynomolgus monkeys. Noribogaine is an iboga alkaloid being studied for the treatment of opioid dependence. METHODS: Six cynomolgus monkeys (3 per gender) were instrumented with EEG telemetry transmitters. Noribogaine was administered to each monkey at both doses (i.e., 160 and 320mg/kg, PO) with an interval between dosing of at least 6days, and the resulting behavioral and EEG effects were evaluated. IV pentylenetetrazol (PTZ), served as a positive control for induced seizures. RESULTS: The administration of noribogaine at either of the doses evaluated was not associated with EEG evidence of seizure or with EEG signals known to be premonitory signs of increased seizure risk (e.g., sharp waves, unusual synchrony, shifts to high-frequency patterns). Noribogaine was associated with a mild reduction in activity levels, increased scratching, licking and chewing, and some degree of poor coordination and related clinical signs. A single monkey exhibited brief myoclonic movements that increased in frequency at the high dose, but which did not appear to generalize, cluster or to be linked with EEG abnormalities. Noribogaine was also associated with emesis and partial anorexia. In contrast, PTZ was associated with substantial pre-ictal EEG patterns including large amplitude, repetitive sharp waves leading to generalized seizures and to typical post-ictal EEG frequency attenuation. INTERPRETATION: EEG patterns were within normal limits following administration of noribogaine at doses up to 320mg/kg with concurrent clinical signs that correlated with plasma exposures and resolved by the end of the monitoring period. PTZ was invariably associated with EEG paroxysmal activity leading to ictal EEG. In the current study, a noribogaine dose of 320mg/kg was considered to be the EEG no observed adverse effect level (NOAEL) in conscious freely moving cynomolgus monkeys. PMID- 27126305 TI - Self-Assembly of a Functional Triple Protein: Hemoglobin-Avidin-Hemoglobin via Biotin-Avidin Interactions. AB - Hypertension resulting from vasoconstriction in clinical trials of cross-linked tetrameric (alpha2beta2) human hemoglobins implicates the extravasation of the hemoglobins into endothelia where they scavenge nitric oxide (NO), which is the signal for relaxation of the surrounding smooth muscle. Thus, we sought an efficient route to create a larger species that avoids extravasation while maintaining the oxygenation function of hemoglobin. Selectively formed cysteine linked biotin conjugates of hemoglobin undergo self-assembly with avidin into a stable triple protein, hemoglobin-avidin-hemoglobin (HbAvHb), which binds and releases oxygen with moderate affinity and cooperativity. The triple protein is likely to be stabilized by interactions of each constituent hemoglobin (pI 6.9) with the oppositely charged avidin (pI 10.5) as well as the strong association of the biotin moieties on hemoglobin with avidin. PMID- 27126303 TI - Determinants of subjective well-being in people with psychosis referred for psychological therapy in South London. AB - OBJECTIVES: Improving subjective well-being (SWB) for people with mental health problems is a United Kingdom national health priority and is increasingly important in justifying funding of mental health services. Aside from the economic advantages, maximizing SWB confers obvious individual and clinical benefits for people with severe mental illness, such as psychosis. Gaining a better understanding of well-being and its determinants will enable current evidence-based interventions to be targeted and refined appropriately. This study therefore sought to identify the cross-sectional correlates of SWB in an Improving Access to Psychological Therapies for people with Severe Mental Illness psychosis demonstration site, to inform a future longitudinal investigation. METHODS: Participants with a psychosis or bipolar spectrum diagnosis referred to the demonstration site (n = 410) rated SWB as part of their initial assessment before starting psychological therapy. Potential influencing factors including age, gender, ethnicity, employment status, illness duration, perceived social support, perceived coping, and psychotic symptoms (voices and beliefs) were also assessed. RESULTS: Regression analyses showed that unemployment (beta = -.16, p < .001), lack of social support (beta = -.20, p < .001), distressing beliefs (beta = -.12, p = .004), and poorer coping (beta = -.43, p < .001) were associated with reduced SWB, together accounting for 43% of the variance in well-being, F(5, 392) = 58.42, p < .001; mean SWB = 39.09, SD = 11.61. CONCLUSIONS: This study provides preliminary insights into the determinants of SWB in a large sample of people with psychosis. Improving employability, social interactions, coping strategies, and psychotic symptoms may improve SWB. Further longitudinal investigation will determine the potential value of preferentially targeting these areas in therapy to meet national requirements to prioritize well-being outcomes. PRACTITIONER POINTS: Average well-being in people with psychosis was lower than SWB previously reported for the general population. Unemployment, lack of social support, poorer coping, and distressing beliefs were all associated with lower levels of well being in people with psychosis. Psychological interventions targeting the positive symptoms of psychosis may impact on well-being. Greater focus on promoting social contact and inclusion and facilitating a return to employment may further improve well-being outcomes following psychological intervention. The cross-sectional design of the study does not allow for firm conclusions about the causal relationship between well-being and associated factors in psychosis. The study was carried out within a particular service context, and the findings need replicating before they can be considered to be generalizable outside this setting. PMID- 27126306 TI - Insights into the dN/dS ratio heterogeneity between brain specific genes and widely expressed genes in species of different complexity. AB - In mammals, it has long been suggested that brain-specific genes (BSGs) and widely expressed genes (WEGs) have seemingly lower dN/dS ratio than any other gene sets. However, to what extent these genes differ in their dN/dS ratio has still remained controversial. Here, we have revealed lower dN/dS ratio of BSGs than WEGs in human-mouse, human-orangutan, human-chimpanzee and mouse-rat orthologous pair. The significance level of dN/dS ratio difference indicates a trend of decreasing difference as complexity of compared pairs increases. Further studies with the human-mouse pair revealed that, removal of the duplicated genes from both the dataset has nullified this difference which dictates a vital role of duplicated genes in governing the selection pressure. Conclusively, higher paralog number, expression level, and longer regulatory region length of BSGs allow fewer nucleotide substitutions within them. Our results show for the first time to our knowledge lower dN/dS ratio of BSGs than WEGs. PMID- 27126307 TI - Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals. AB - Genome-wide association studies (GWAS) point to regions with associated genetic variants but rarely to a specific gene and therefore detailed knowledge regarding the genes contributing to complex traits and diseases remains elusive. The functional role of GWAS-SNPs is also affected by linkage disequilibrium with many variants on the same haplotype and sometimes in the same regulatory element almost equally likely to mediate the effect. Using ChIP-seq data on many transcription factors, we pinpointed genetic variants in HepG2 and HeLa-S3 cell lines which show a genome-wide significant difference in binding between alleles. We identified a collection of 3713 candidate functional regulatory variants many of which are likely drivers of GWAS signals or genetic difference in expression. A recent study investigated many variants before finding the functional ones at the GALNT2 locus, which we found in our genome-wide screen in HepG2. This illustrates the efficiency of our approach. PMID- 27126308 TI - Executive Dysfunction in Female FMR1 Premutation Carriers. AB - There is now growing evidence of cognitive weakness in female premutation carriers (between 55 and 199 CGG repeats) of the fragile X mental retardation gene, including impairments associated with executive function. While an age related decline in assessments of executive function has been found for male premutation carriers, few studies have explored whether female carriers show a similar trajectory with age. A total of 20 female premutation carriers and 21 age and IQ-matched healthy controls completed a battery of tasks assessing executive function tasks, including the behavioural dyscontrol scale (BDS), symbol digit modalities test (SDMT), paced auditory serial addition test (PASAT), Haylings sentence completion test and the digit span task (forward and backward). Performance was compared between premutation carriers and healthy controls, and the association between task performance and age was also ascertained. Compared to controls, female premutation carriers had significant impairment on the BDS, SDMT, PASAT, and Haylings sentence completion task, all of which rely on quick, or timed, responses. Further analyses revealed no significant association between age and task performance for either premutation carriers or controls. This study demonstrates that a cohort of female premutation carriers have deficits on a range of tasks of executive function that require the rapid temporal resolution of responses. We propose that the understanding of the phenotype of premutation carriers will be advanced through use of such measures. PMID- 27126309 TI - Resistin, visfatin, leptin and omentin are differently related to hormonal and metabolic parameters in growth hormone-deficient children. AB - PURPOSE: The effect of growth hormone (GH) on adipose tissue and the role of adipokines in modulating metabolism are documented, but with discordant data. Our aim was to evaluate the impact of GH treatment on a series of selected adipokines known to have a metabolic role and poorly investigated in this setting. METHODS: This is a prospective study. Thirty-one prepubertal children (25 M, 6 F; aged 8.5 +/- 1.6 years) with isolated GH deficiency treated with GH for at least 12 months and 30 matched controls were evaluated. Auxological and metabolic parameters, insulin sensitivity indexes, leptin, soluble leptin receptor, adiponectin, visfatin, resistin, omentin, adipocyte fatty acid-binding protein and retinol binding protein-4 were evaluated before and after 12 months of treatment. RESULTS: At baseline, no significant difference in metabolic parameters was found between GHD children and controls, except for higher LDL cholesterol (p = 0.004) in the first group. At multivariate analysis, LDL cholesterol was independently associated with resistin (B 0.531; p = 0.002), while IGF-I was the only variable independently associated with visfatin (B 0.688; p < 0.001). After 12 months, a significant increase in fasting insulin (p = 0.008), Homa-IR (p = 0.007) and visfatin (p < 0.001) was found, with a concomitant decrease in LDL cholesterol (p = 0.015), QUICKI (p = 0.001), ISI Matsuda (p = 0.006), leptin (p = 0.015) and omentin (p = 0.003)]. At multivariate analysis, BMI was the only variable independently associated with leptin (B 0.485; p = 0.040). CONCLUSIONS: GH treatment modifies adipokine secretion and the perturbation of some adipokine levels could contribute to the clinical and metabolic changes observed during the follow-up. PMID- 27126312 TI - Editor's note. PMID- 27126310 TI - Prevalence of overweight/obesity, abdominal obesity and metabolic syndrome and atypical cardiometabolic phenotypes in the adult Romanian population: PREDATORR study. AB - PURPOSE: The objectives were to assess the prevalence of overweight/obesity, abdominal obesity and metabolic syndrome (MetS), and to evaluate the characteristics of the metabolically unhealthy lean (MUHL) and metabolically healthy overweight/obese (MHO) phenotypes in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological study with a stratified, cross-sectional, cluster random sampling design. Participants were classified into four cardiometabolic phenotypes based on the BMI, the cut-off value being 25 kg/m(2), and the presence of MetS (defined according to the Harmonization definition 2009): MUHL, MHO, metabolically healthy lean (MHL) and metabolically unhealthy overweight/obese (MUHO). RESULTS: Overall, 2681 subjects aged 20-79 years were included in the analysis. The overall age and sex-adjusted prevalence of obesity was 31.90 %, overweight was 34.7 %, abdominal obesity was 73.90 % and MetS was 38.50 %. The age- and sex-adjusted prevalence of MHO phenotype was 31.60 %, while MUHL phenotype prevalence was 3.90 %. MUHL and MHO participants had a cardiometabolic profile, kidney function and CVD risk intermediary between MHL and MUHO. MUHL had higher odds of being associated with CVD risk (OR 5.8; p < 0.001), abdominal obesity, prediabetes, diabetes, hypertriglyceridemia and hypo-HDL cholesterolemia than MHL, while MHO phenotype was associated with hypo-HDL cholesterolemia (OR 3.1; p = 0.002), prediabetes (OR 2.9; p < 0.001) and abdominal obesity. CONCLUSIONS: PREDATORR study showed a high prevalence of obesity/overweight, abdominal obesity and MetS in the adult Romanian population, and their association with kidney function and several cardiometabolic factors. PMID- 27126311 TI - Putting in vitro evidence into perspective. PMID- 27126313 TI - Terminology questioned. PMID- 27126314 TI - Rubber dam use. PMID- 27126315 TI - More on rubber dam use. PMID- 27126316 TI - Authors' response. PMID- 27126317 TI - Treat your team as professionals, and they will be. PMID- 27126318 TI - What should I do when a patient just wants antibiotics? PMID- 27126319 TI - Hanging by a thread, severe mitral regurgitation due to accessory left atrial cord. PMID- 27126320 TI - Rare cause of dyspnoea: pulmonary artery myxoma. PMID- 27126321 TI - Rapid progression of nodular calcification documented by intra-coronary imaging devices and histology. PMID- 27126322 TI - Controlled Generation of Singlet Oxygen in Living Cells with Tunable Ratios of the Photochromic Switch in Metal-Organic Frameworks. AB - Development of a photosensitizing system that can reversibly control the generation of singlet oxygen ((1) O2 ) is of great interest for photodynamic therapy (PDT). Recently several photosensitizer-photochromic-switch dyads were reported as a potential means of the (1) O2 control in PDT. However, the delivery of such a homogeneous molecular dyad as designed (e.g., optimal molar ratio) is extremely challenging in living systems. Herein we show a Zr-MOF nanoplatform, demonstrating energy transfer-based (1) O2 controlled PDT. Our strategy allows for tuning the ratios between photosensitizer and the switch molecule, enabling maximum control of (1) O2 generation. Meanwhile, the MOF provides proximal placement of the functional entities for efficient intermolecular energy transfer. As a result, the MOF nanoparticle formulation showed enhanced PDT efficacy with superior (1) O2 control compared to that of homogeneous molecular analogues. PMID- 27126323 TI - Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3beta inhibition-independent pathways. AB - Lithium promotes acute poststroke neuronal survival, which includes mechanisms that are not limited to GSK3beta inhibition. However, whether lithium induces long-term neuroprotection and enhanced brain remodeling is unclear. Therefore, mice were exposed to transient middle cerebral artery occlusion and lithium (1 mg/kg bolus followed by 2 mg/kg/day over up to 7 days) was intraperitoneally administered starting 0-9 h after reperfusion onset. Delivery of lithium no later than 6 h reduced infarct volume on day 2 and decreased brain edema, leukocyte infiltration, and microglial activation, as shown by histochemistry and flow cytometry. Lithium-induced neuroprotection persisted throughout the observation period of 56 days and was associated with enhanced neurological recovery. Poststroke angioneurogenesis and axonal plasticity were also enhanced by lithium. On the molecular level, lithium increased miR-124 expression, reduced RE1 silencing transcription factor abundance, and decreased protein deubiquitination in cultivated cortical neurons exposed to oxygen-glucose deprivation and in brains of mice exposed to cerebral ischemia. Notably, this effect was not mimicked by pharmacological GSK3beta inhibition. This study for the first time provides efficacy data for lithium in the postacute ischemic phase, reporting a novel mechanism of action, i.e. increased miR-124 expression facilitating REST degradation by which lithium promotes postischemic neuroplasticity and angiogenesis. PMID- 27126325 TI - Coherence loss of partially mode-locked fibre laser. AB - Stochastically driven nonlinear processes limit the number of amplified modes in a natural system due to competitive mode interaction, which is accompanied by loss of coherence when increasing the complexity of the system. Specifically, we find that modulation instability, which exhibits great fluctuations when it spontaneously grows from noise in conservative systems, may possess a high degree of coherence in dissipative laser system with gain. Nonlinear mode interactions can be competitive or cooperative: adjusting the intracavity polarization state controls the process of loss of coherence. Single-shot spectra reveal that, first, the fibre laser redistributes its energy from the center wavelength mode into sidebands through parametric instabilities. Subsequently, longitudinal modes are populated via cascaded four-wave-mixing. Parametric frequency conversion populates longitudinal modes with a random distribution of position, intensity and polarization, resulting in partially (rather than highly) coherent pulses. These dynamics unveil a new route towards complex pattern formation in nonlinear laser systems, and they may be also beneficial for the understanding of supercontinuum, Kerr-combs phenomena, and optical rogue waves. PMID- 27126326 TI - Screening for depression in older people on acute medical wards: the validity of the Edinburgh Depression Scale. AB - BACKGROUND: depression is common in people with poor physical health, particularly within the acute medical in-patient setting. Co-morbid depression contributes to poor outcomes, and screening for depression in acute medical in patients has been advocated. The Edinburgh Depression Scale (EDS) has been validated in a variety of general hospital patient groups, but not previously in older acute medical in-patients. METHODS: one hundred and eighteen patients aged 65 and older on acute medical wards were assessed using a standardised diagnostic interview (Present State Examination-Schedules for Clinical Assessment in Neuropsychiatry) to identify depression according to ICD-10 criteria. They subsequently completed the EDS. The performance characteristics at a range of thresholds were compared, and receiver operating characteristic curve analysis was performed. RESULTS: the optimal EDS cut-off for identifying ICD-10 depressive episode was 7/8, with a sensitivity of 88%, specificity of 77%, positive predictive value of 52% and negative predictive value of 96%. The area under the receiver operating characteristic curve was 0.91. CONCLUSION: the EDS was shown to be a useful instrument for detecting clinical depression in older people on acute medical wards in this study. Its performance was equivalent to other validated screening instruments in this population. Our findings add further weight to using the EDS as a screening instrument for depression in multiple general hospital settings. PMID- 27126324 TI - Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain. AB - Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit. PMID- 27126327 TI - Validation of the FNIH sarcopenia criteria and SOF frailty index as predictors of long-term mortality in ambulatory older men. AB - OBJECTIVE: we aimed to evaluate the Foundation for the National Institutes of Health (FNIH) criteria for weakness and low muscle mass and the Study of Osteoporotic Fractures (SOF) frailty index for prediction of long-term, all-cause mortality. DESIGN: community-based cohort study. SETTING: semi-rural community of Merelbeke (Belgium). SUBJECTS: ambulatory men aged 74 and more (n = 191). METHODS: weakness was defined on previously established criteria as low grip strength (<26 kg) or low grip strength-to-body mass index (BMI) ratio (<1.00). Low muscle mass (dual-energy x-ray absorptiometry) was categorised as low appendicular lean mass (ALM; predefined <19.75 kg) or low ALM-to-BMI ratio (predefined <0.789). Frailty status was assessed using the components of weight loss, inability to rise from a chair and poor energy (SOF index). Survival time was calculated as the number of months from assessment in 2000 until death or up to 15 years of follow-up. RESULTS: mean age of the participants was 78.4 +/- 3.5 years. Combined weakness and low muscle mass was present in 3-8% of men, depending on the criteria applied. Pre-frailty and frailty were present in 30 and 7% of men, respectively. After 15 years of follow-up, 165 men (86%) died. Both the presence of combined weakness and low ALM-to-BMI ratio (age-adjusted HR = 2.50, 95% CI = 1.30-4.79) and the presence of SOF frailty (age-adjusted HR = 2.64, 95% CI = 1.44-4.86) were associated with mortality. CONCLUSIONS: our findings confirm the predictive value for mortality of the non-distribution-based FNIH criteria and SOF index in older community-dwelling Belgian men. PMID- 27126328 TI - Social resources and cognitive ageing across 30 years: the Glostrup 1914 Cohort. AB - BACKGROUND: to examine associations between social resources and cognitive ageing over 30 years. METHODS: participants in the Glostrup 1914 Cohort, a year of birth sample, completed a standardarised battery of cognitive ability tests every 10 years from age 50 to 80, summarised as general cognitive ability. Participants also provided information concerning a range of social resources, including marital status and living arrangements from age 50, and from age 70, details regarding social support, social contact and loneliness. RESULTS: across the follow-up, participants were less likely to be married, falling from 85.0 to 40.4% between ages 50 and 80, while the proportion of those living alone increased from 13.1 to 54.2%. In separate growth curve models, being married, living with others and not feeling lonely were all associated with higher cognitive ability level, while more telephone contact had a negative association. Marital status (at ages 50 and 60) and loneliness at age 70 were the only social resources associated with cognitive change; married individuals and those not feeling lonely experienced less cognitive decline. When the social resources showing significant associations were considered together (and accounting for sex, education and social class), loneliness was associated with lower cognitive ability level and greater cognitive decline, while married individuals experienced less decline. CONCLUSIONS: in a relatively large cohort followed for up to 30 years, marital status and loneliness were associated with cognitive ability or change. Interventions designed to reduce loneliness in older adults might be supported as one avenue to reduce cognitive ageing. PMID- 27126329 TI - Association of mobility limitations with incident disability among older adults: a population-based study. AB - BACKGROUND: mobility-related limitations predict future disability; however, the extent to which individual and combined mobility tests may predict disability remains unclear. OBJECTIVES: to estimate the odds of developing disability in activities of daily living (ADL) according to limitations in walking speed, balance or both; and explore the role of chronic diseases and cognitive function. DESIGN: a prospective cohort study. SETTING: urban area of Stockholm, Sweden. SUBJECTS: one thousand nine hundred and seventy-one disability-free persons (age >=60 years, 63% women) from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), who underwent baseline examination in 2001-04 and follow-up assessments for 6 years. MEASUREMENTS: mobility limitation was defined as a one leg balance stand <5 s or walking speed <0.8 m/s. ADL disability was defined as the inability to complete one or more ADL: bathing, dressing, using the toilet, transferring and eating. RESULTS: during a total of 11,404 person-years (mean per person 5.8 years, SD 0.30) of follow-up, 119 (incidence 1.5/100 person-years) participants developed ADL disability. The demographic adjusted odds ratios (OR) (95% confidence intervals, CI) of incident ADL disability related to balance stand and walking speed limitations were 3.8 (2.3-6.3) and 8.4 (5.2-13.3), respectively. The associations remained statistically significant after controlling for number of chronic diseases and cognitive status. People with limitations in both balance and walking speed had an OR of 12.9 (95% CI 7.0-23.7) for incident disability compared with no limitation. CONCLUSION: balance and walking speed tests are simple clinical procedures that can indicate hierarchical risk of ADL dependence in older adults. PMID- 27126331 TI - Respiratory syncytial virus-associated hospitalizations over three consecutive seasons in children with congenital heart disease. AB - The purpose of this investigation was to analyze the burden of respiratory syncytial virus (RSV)-related hospitalizations in infants and children with congenital heart disease (CHD) over three consecutive RSV seasons. Retrospectively, all children with hemodynamically significant (HS-CHD) and not significant (HNS-CHD) CHD born between 2004 and 2008 at a tertiary care university hospital and identified by ICD-10 diagnoses were included. Data on RSV related hospitalizations over the first three years of life covering at least three RSV seasons (November-April) were analyzed. The overall incidence of RSV related hospitalization was 9.6 % (58/602), without a statistically significant difference between HS-CHD and HNS-CHD (7.3 % vs. 10.4 %; p = 0.258). Recommendation of palivizumab prophylaxis did not influence the RSV hospitalization rates between groups. Patients with HS-CHD and early surgery were significantly less often hospitalized due to RSV compared to those with delayed surgery (1.3 % vs. 14.3 %; p = 0.003). The median duration of hospitalization was 8.5 days (HS-CHD: 14 vs. HNS-CHD: 7 days; p = 0.003). Thirteen patients (22.4 %) were admitted to the intensive care unit (ICU), for a median of 10 days. The median age at admission was 2 months, with a significant difference between HS CHD and HNS-CHD (6 vs. 2 months; p = 0.001). The majority (97 %) of RSV-related hospitalizations occurred before 12 months of age. Patients with HS-CHD had a significantly more severe course of RSV disease and were older at the time of hospitalization. Early surgery seemed to significantly reduce the risk of RSV hospitalization during the first RSV season. PMID- 27126330 TI - Is frailty associated with life-space mobility and perceived autonomy in participation outdoors? A longitudinal study. AB - BACKGROUND: essential aspects of independence in community mobility among older people concern the control over where, when and how to participate (perceived autonomy), and actual mobility (life-space mobility; frequency, distance and need of assistance). We studied relationships between frailty and life-space mobility and perceived autonomy in participation outdoors among community-dwelling 75-90 years old people. METHODS: longitudinal analyses of the 'Life-space mobility in old age' cohort study (n = 753). Life-space mobility (Life-Space Assessment, range 0-120) and perceived autonomy in participation outdoors (Impact on Participation and Autonomy subscale 'autonomy outdoors', range 0-20) were assessed at baseline and 2 years later. Baseline frailty indicators were unintentional weight loss (self-report), weakness (5 times chair rise), exhaustion (self-report), slowness (2.44 m walk) and low physical activity (self report). RESULTS: in total, 53% had no frailty, 43% pre-frailty (1-2 frailty indicators) and 4% frailty (>=3 indicators). Generalised estimation equation models showed that life-space mobility was lower among those with frailty and pre frailty compared with those without frailty and, in addition, declined at a faster pace. Perceived autonomy in participation outdoors was more restricted among those with frailty and pre-frailty compared with those without frailty, but the rate of decline did not differ. CONCLUSION: frailty was associated with more restricted life-space mobility and poorer perceived autonomy in the decision making concerning community mobility. Over the follow-up, frailty predicted a steeper decline in life-space mobility but not in perceived autonomy. Further study is warranted to determine whether compensation strategies or changes in the valuation of activities underlie this discrepancy. PMID- 27126332 TI - Detection and epidemiology of carbapenemase producing Enterobacteriaceae in the Netherlands in 2013-2014. AB - Laboratory detection of carbapenemase-producing Enterobacteriaceae (CPE) is complicated. Screening with MIC values below clinical breakpoints followed by genotypic confirmation is recommended. We evaluated the application of recommended CPE screening and confirmation methods and provide an overview of CPE epidemiology in E. coli and K. pneumoniae in the Netherlands. Data on E. coli and K. pneumoniae isolates with elevated meropenem (>0.25 mg/L) and/or imipenem (>1 mg/L) MIC values in 2013-2014 were selected from the Infectious Disease Surveillance Information System for Antibiotic Resistance. Laboratories were requested to provide additional results of any confirmatory testing performed. Confirmation of elevated carbapenem MIC values using gradient testing was performed in 59.8 % of eligible isolates. Confirmatory testing showed elevated MIC values in 8 % of E. coli and 32 % of K. pneumoniae isolates. The overall proportion of confirmed non-susceptible E. coli and K. pneumoniae was 0.01 % and 0.16 %, respectively. Genotypic confirmation was performed in 61.0 % of isolates with confirmed elevated carbapenem MIC values. A carbapenemase gene was identified in 47 % of E. coli and 65 % of K. pneumoniae isolates. OXA-48, NDM and KPC were the most frequently found carbapenemase genes. The majority (62 %) of CPE isolates was detected through targeted screening. CPE are a rare finding in the Netherlands. Adherence to the national guideline is suboptimal and differs between laboratories, implying a risk of inadequate CPE detection. Since accurate identification of CPE is the first step in prevention of CPE spread, successful implementation of guidelines for testing and reporting of CPE is essential. PMID- 27126333 TI - Vitamin D status and parathyroid hormone levels in relation to bone mineral density in apparently healthy Syrian adults. AB - Vitamin D deficiency was highly prevalent in this study. More than half of the participants with vitamin D level less than 5 ng/mL had secondary hyperparathyroidism, which implicated a major bone health concern. After adjustment for potential predictors, parathyroid hormone (PTH) explained about 3 % of the variance in total hip bone mineral density (BMD). PURPOSE: Bone mineral density (BMD) is known to be influenced by serum 25-hydroxyvitamin D (25OHD) and intact parathyroid hormone (PTH) levels. The relationship between 25OHD and PTH with BMD has not been well documented in Syrian adults. We aimed to determine how differences in serum 25OHD and PTH levels impacted hip and lumbar spine BMD among apparently healthy Syrian adults. METHODS: 25OHD and PTH were measured in 156 participants aged 18-53 years from Damascus and its surroundings. Lumbar spine and hip BMD measurements were measured by dual-energy X-ray absorptiometry using Hologic Discovery Wi densitometer. Multivariate regression models were used to investigate the relationships between 25OHD, PTH, and BMD. RESULTS: All participants, except one male, had 25OHD <30 ng/mL (<75 nmol/L), and 89.1 % of them had 25OHD levels less than 20 ng/mL (50 nmol/L). Secondary hyperparathyroidism was significantly more prevalent in the lowest 25OHD quartile compared to that in the highest quartile (59 vs. 10.3 %, p < 0.0001). Mean bone mineral density at all sites in our participants was lower when compared to that of their Caucasian counterparts in Europe and North America. No significant correlation was found between 25OHD and BMD either at hip or at lumbar spine. In the multivariate analyses, after adjustment for potential predictors, PTH explained about 3 % of the variation in total hip BMD. CONCLUSIONS: Low BMD was relatively frequent at all measured sites. PTH, but not 25OHD, was a predictor for total hip BMD in a young population. PMID- 27126334 TI - Seven days in medicine: 20-26 April. PMID- 27126335 TI - Usefulness of radiologic examinations for diagnosing level VI lymph node metastasis in patients with laryngohypopharyngeal carcinoma. AB - The aim of this study was to estimate the usefulness of imaging modalities for diagnosing level VI lymph node metastasis in patients with laryngohypopharyngeal cancer. A retrospective review of 138 patients with squamous cell carcinoma of the larynx or hypopharynx who underwent central compartment neck dissection (CCND) was performed. Level VI metastasis occurred in 29 of 138 (21 %) patients. CT accuracy and sensitivity for level VI lymph node was 85.5 and 48.3 %, respectively. Respective values for MRI, US, and PET were 84.4 and 41.4 %, 87.7 and 44.8 %, and 81.2 and 34.5 %. CT combined with US demonstrated the best result in sensitivity (51.7 %) and negative predictive value (NPV) (88.1 %) compared to those of other imaging techniques. CT combined with US could improve sensitivity and NPV compared to CT or US alone. Considering cost-effectiveness and the highest results in all parameters compared to those of other combinations of imaging techniques, CT combined with US could be the best preoperative imaging modalities for evaluating laryngohypopharyngeal cancer. However, these imaging techniques are not absolutely reliable methods for detecting occult metastasis in the level VI due to high false-negative rates. Elective CCND should be considered in indicated patients (>N2b, T4), even if physical examinations and the radiologic findings of level VI nodes are negative. PMID- 27126336 TI - Efficacy and tolerability of an ectoine mouth and throat spray compared with those of saline lozenges in the treatment of acute pharyngitis and/or laryngitis: a prospective, controlled, observational clinical trial. AB - The aim of this observational trial was to evaluate the efficacy and tolerability of a mouth and throat spray containing ectoine in the treatment of acute pharyngitis and/or laryngitis. The outcome was compared with control treatment using saline lozenges. This study was designed as a prospective, controlled, non randomized, observational multicenter clinical trial and was conducted in Germany. The study population consisted of 95 patients. The decision for treatment with either spray or lozenges was based on the patients' preference for pharyngeal or oral application. Investigators assessed symptoms specific to acute pharyngitis/laryngitis and determined the pharyngitis symptom score. Both patients and investigators evaluated the tolerability and efficacy of the treatment applied. Treatment with the spray showed higher efficacy, 1.95 +/- 0.81 versus 1.68 +/- 0.67 (investigators) and 1.97 +/- 0.88 versus 1.57 +/- 0.69 (patients, p < 0.05). Treatment with the spray resulted in significantly greater reduction of cervical lymph node swelling (p < 0.05), ? spray = 0.44 +/- 0.62, ? lozenges = 0.21 +/- 0.62. The lozenges showed some advantage in relieving cough, ? lozenges = 0.62 +/- 0.94 versus ? spray = 0.44 +/- 0.85. Both patients and investigators rated the tolerability of both medical devices as "good" to "very good". Adverse events of mild to moderate severity were either possibly related or not related to the medical devices used. No serious adverse events occurred. Taken together, while the tolerability was consistent in both treatment groups, the ectoine-based spray showed superior efficacy in treating acute pharyngitis and/or laryngitis. PMID- 27126337 TI - Objective quantification of the vocal fold vascular pattern: comparison of narrow band imaging and white light endoscopy. AB - No clinical standard procedure has yet been defined to quantify the vascular pattern of vocal folds. Subjective classification trials have shown a lot of promise. Narrow band imaging (NBI) as an endoscopic imaging tool is useful, because it shows the vascular structure clearer than white light endoscopy (WL) alone. Endoscopic images of 74 human vocal folds (NBI and WL) were semi automatically evaluated after image processing with respect to pixels of vessels and mucosa by the software MeVisLab. The ratios of vessel/mucosa pixels were compared. Using NBI, more vocal fold vessels are visible compared with WL alone (p = 0.000). There may be a difference between the right and left vocal folds due to the handedness of the examiner (p = 0.033) without any interaction between the method (NBI/WL) and the side (right/left) (p = 0.467). MeVisLab is a suitable tool for the objective quantification of the vessel/mucosa ratio for NBI and WL endoscopic images. NBI is an appropriate endoscopic tool for examination of diseases of vocal folds with changes in the vascular pattern. There is evidence that the handedness of the examiner may have an influence on the quality of the examination between the right and left vocal folds. PMID- 27126338 TI - Erratum to: Witnessing the first sign of retinitis pigmentosa onset in the allegedly normal eye of a case of unilateral RP: a 30-year follow-up. PMID- 27126339 TI - Age-related change in fast adaptation mechanisms measured with the scotopic full field ERG. AB - PURPOSE: To quantify the response dynamics of fast adaptation mechanisms of the scotopic ERG in younger and older adults using full-field m-sequence flash stimulation. METHODS: Scotopic ERGs were measured for a series of flashes separated by 65 ms over a range of 260 ms in 16 younger (20-26, 22.2 +/- 2.1; range mean +/-1 SD) and 16 older (65-85, 71.2 +/- 7) observers without retinal pathology. A short-wavelength (lambda peak = 442 nm) LED was used for scotopic stimulation, and the flashes ranged from 0.0001 to 0.01 cd s m(-2). The complete binary kernel series was derived from the responses to the m-sequence flash stimulation, and the first- and second-order kernel responses were analyzed. The first-order kernel represented the response to a single, isolated flash, while the second-order kernels reflected the adapted flash responses that followed a single flash by one or more base intervals. B-wave amplitudes of the adapted flash responses were measured and plotted as a function of interstimulus interval to describe the recovery of the scotopic ERG. A linear function was fitted to the linear portion of the recovery curve, and the slope of the line was used to estimate the rate of fast adaptation recovery. RESULTS: The amplitudes of the isolated flash responses and rates of scotopic fast adaptation recovery were compared between the younger and older participants using a two-way ANOVA. The isolated flash responses and rates of recovery were found to be significantly lower in the older adults. However, there was no difference between the two age groups in response amplitude or recovery rate after correcting for age-related changes in the density of the ocular media. CONCLUSIONS: These results demonstrated that the rate of scotopic fast adaptation recovery of normal younger and older adults is similar when stimuli are equated for retinal illuminance. PMID- 27126340 TI - Assessment of macular function, structure and predictive value of pattern electroretinogram parameters for postoperative visual acuity in patients with idiopathic epimacular membrane. AB - PURPOSE: To evaluate macular function and structure before and after epimacular membrane surgery and to estimate the usefulness of pattern ERG test parameters in predicting the postoperative visual acuity. METHODS: We evaluated 32 eyes of 32 patients (mean age 70.8 +/- 6.7 years) before and 12 months after successful 25G pars plana vitrectomy with epimacular membrane removal and internal limiting membrane peeling. Distance best-corrected visual acuity (DBCVA-logMAR), foveal thickness (optical coherence tomography-OCT) and macular function [pattern electroretinogram-PERG (ISCEV standard): amplitudes (A) of P50- and N95-waves, implicit time (IT) of P50-wave] were assessed. To estimate the differences between the mean values of considered characteristics, the t test or Wilcoxon matched pair test was used. Correlation between preoperative data of PERG and preoperative and final DBCVA were investigated using Pearson correlation analysis. A receiver operating characteristic curve was constructed to obtain a cutoff value allowing prediction of visual prognosis. We tried to obtain the P50 and N95 amplitudes cutoff value in prediction of good visual outcome (DBCVA of 0.3 or less). RESULTS: Twelve months after surgery, mean of DBCVA significantly increased in comparison with preoperative value (0.31 +/- 0.12 vs. 0.6 +/- 0.15; p < 0.001) and 23/32 eyes (72 %) achieved visual improvement of two and more Snellen lines. In OCT test, the significant reduction in foveal thickness mean (313.34 +/- 47.01 vs. 509.03 +/- 93.88 um; p < 0.001) was obtained. In PERG test, the significant increase in the mean amplitudes of P50- (AP50) and N95 (AN95) waves as well as significant decrease in the mean implicit time (IT) of P50-wave were achieved (AP50: 3.41 +/- 1.48 vs. 2.38 +/- 1.23 uV; p < 0.001; AN95: 5.46 +/ 1.72 vs. 3.75 +/- 1.48 uV; p < 0.001; IT P50: 55.00 +/- 3.60 vs. 56.75 +/- 5.78 ms; p < 0.001). Twelve months postoperatively, DBCVA was significantly correlated with preoperative IT P50 (r = 0.39; p = 0.027), AP50 (r = -0.68; p < 0.001) and AN95 (r = -0.73; p < 0.001). CONCLUSION: Removal of idiopathic epimacular membranes with internal limiting membrane peeling not only provided increase in visual acuity and reduction in foveal thickness but also caused improvement of innermost retinal layer function in macular region. Pattern ERG test might be a valuable tool in predicting the postoperative visual acuity. PMID- 27126341 TI - 10% liquid human immunoglobulin (KIOVIG((r))) for immunomodulation in autoimmune disorders. AB - Intravenous immunoglobulins have been used to treat autoimmune disorders (ADs) for over 50 years. The etiologies of various ADs are not fully understood and although intravenous immunoglobulin treatment has proved its immunomodulatory properties, the roles of proposed mechanisms of action also remain a matter of speculation. A systemic search of the literature regarding KIOVIG((r)) (Baxalta US, Inc., MA, USA) use in clinical trials on patients with ADs and a detailed review of retrieved articles revealed eight relevant publications. These articles reported KIOVIG use in multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, idiopathic thrombocytopenic purpura, Kawasaki disease, Guillain-Barre syndrome and other autoimmune and neurologic disorders and showed that KIOVIG is an effective, safe and well-tolerated treatment in the studied populations. Nevertheless, further studies on larger patient cohorts are needed. PMID- 27126342 TI - Craniofacial CT findings of Gorham-Stout disease and generalized lymphatic anomaly. AB - INTRODUCTION: The present study aimed to assess the craniofacial CT imaging features for differentiating between Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA). METHODS: Seven patients with GSD and four patients with GLA were included in this study. All patients underwent CT examinations that encompassed the craniofacial bones. The presence, distribution, and type of craniofacial osteolysis were assessed. The clinical symptoms that were associated with craniofacial osteolysis were also reviewed. RESULTS: Craniofacial osteolysis including cranial osteolysis was seen in four of seven (57 %) patients with GSD and in three of four (75 %) patients with GLA. Facial osteolysis was seen in two (29 %) patients with GSD, but this was not observed in patients with GLA. Among patients with craniofacial osteolysis, those with GSD showed diffuse involvement, whereas those with GLA showed multifocal involvement. The craniofacial osteolysis of GSD could be classified into three patterns: medullary involvement, thinning bone, and disappearing bone. The clinical symptoms of craniofacial osteolysis were observed in all patients with GSD but were not present in patients with GLA. CONCLUSION: Craniofacial involvement was observed in both groups. The craniofacial osteolysis of GSD showed diffuse involvement with clinical symptoms, whereas that of GLA showed multifocal involvement without clinical symptoms. PMID- 27126343 TI - A Comprehensive Survey of Preclinical Microbiology Curricula Among US Medical Schools. AB - BACKGROUND: A strong foundational understanding of microbiology is crucial for the 21st century physician. Given recent major advances in medical microbiology, curricular changes will likely be needed. Before transforming curricula, we must first obtain a comprehensive understanding of contemporary medical student microbiology education. METHODS: We disseminated a 38-question survey to microbiology course directors and curriculum deans at 142 US medical schools accredited by the Liason Committee on Medical Education. Survey questions focused on course leadership, curricular structure, course content, and educator perceptions about microbiology education locally and nationally. RESULTS: One hundred and four (73%) of 142 schools completed the survey. Ninety-four (90%) schools identified a course director. Of these, 48% were led by microbiologists alone, 23% co-led by a microbiologist and a clinician, 20% by a clinician alone, and 8% by a laboratory medicine physician with or without a co-director. At 55 (53%) schools, the curricula were organized in a single block or course and at 47 (45%) it was integrated into other curricula. Areas of emerging importance, such as antimicrobial stewardship, global health, infection control, and the microbiome, were addressed at 66%, 65%, 64%, and 47% of institutions, respectively. Respondents reported the following concerns: challenges integrating microbiology into other courses, reduced total teaching hours, and difficulty balancing basic and clinical science topics. CONCLUSIONS: Preclinical microbiology course directors report significant challenges in meeting the needs of changing curriculum structure and content. Enhanced local collaboration between microbiologists and clinicians, as well as national collaboration among relevant societies to design best practices and support research, may be strategies for future success. PMID- 27126344 TI - Editorial Commentary: Recruiting the Next Generation of Infectious Diseases Physicians: How Do We Reignite the Passion? PMID- 27126345 TI - Factors Influencing Internal Medicine Resident Choice of Infectious Diseases or Other Specialties: A National Cross-sectional Study. AB - BACKGROUND: Only 49% of infectious diseases (ID) fellowship programs were filled in 2015 through the national match, but little is known about internal medicine (IM) resident perceptions of ID and factors related to IM resident career choice. METHODS: We conducted 25 interviews and disseminated a Web-based survey to graduating IM residents in the United States utilizing a 2-stage sampling strategy. Participants were categorized into 3 groups based on interest in ID: (1) applied/intended to apply to ID; (2) interested in ID but did not apply; (3) never interested in ID. We conducted all analysis using poststratification adjustment weights with survey data analysis procedures. RESULTS: Of the 590 participants, 42 (7%) selected category 1, 188 (32%) category 2, and 360 (61%) category 3. Most (65%) developed an interest in their ultimate career before residency. Of those interested in ID, >52% rated their ID medical school curriculum as very good and influential on their interest in ID. Ninety-one percent of category 2 participants felt mentorship was influential on career choice, although 43% identified an ID mentor. Category 2 chose salary as the most dissuading factor and the most likely intervention to increase ID interest. CONCLUSIONS: In this nationally representative sample of graduating IM residents, most develop an interest in their ultimate career before residency. Factors influencing this decision reside in both medical school and residency, which is consistent with career decision-making constructs. By identifying career determining factors and understanding how they fit into medical training frameworks, we can develop targeted initiatives to reinvigorate interest in ID. PMID- 27126347 TI - Sun HY, et al (Clin Infect Dis 2015; 60:36-44). PMID- 27126348 TI - Household food insecurity and child health. AB - Food insecurity, the lack of consistent access to sufficient quality and quantity of food, affects an estimated 800 million people around the world. Although household food insecurity is generally associated with poor child nutrition and health in the USA, we know less about household food insecurity and child health in developing countries. Particularly lacking is research assessing how associations between household food insecurity and children's health outcomes may differ by child age and among children beyond age 5 years in low-income settings. We use data from a population-based sample of households with children ages 3-11 years (N = 431) in Leon, Nicaragua to consider how household food insecurity is associated with three measures of child health: illness, anaemia and low height for-age. Our results provide new evidence that even mild household food insecurity is detrimental to children's health; and that child age conditions the associations between household food insecurity and child health. We find that food insecurity is especially harmful to health during early childhood, but continues to have significant associations with health into middle childhood (up to ages 7-8 years). We discuss the potential implications of these results for future child health research and policies in low-income countries. (c) 2016 John Wiley & Sons Ltd. PMID- 27126349 TI - An eruption of angiokeratomas in the setting of enoxaparin injections. PMID- 27126346 TI - Safe Reduction in CD4 Cell Count Monitoring in Stable, Virally Suppressed Patients With HIV Infection or HIV/Hepatitis C Virus Coinfection. AB - BACKGROUND: It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts >300 cell/MUL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts >=200 cells/uL during continuous HIV suppression. METHODS: The PISCIS Cohort study included data from 14 539 patients aged >=16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation. RESULTS: A total of 8695 patients were included. CD4 cell counts fell to <200 cells/uL in 7.4% patients, and the proportion was lower in patients with an initial count >350 cells/uL (1.8%) and higher in those with an initial count of 200-249 cells/uL (23.1%). CD4 cell counts fell to <200 cells/uL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/uL, 95.6% maintained counts >=200 cells/uL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts >350 cells/uL maintained counts >=200 cells/uL. CONCLUSIONS: From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts >300 cells/uL and HIV/HCV-coinfected patients with counts >350 cells/uL. PMID- 27126350 TI - Micafungin as primary antifungal prophylaxis in patients presenting with acute myeloid leukemia. AB - OBJECTIVE: To study the efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing induction chemotherapy for acute myeloid leukemia. PATIENTS AND METHODS: A prospective observational single center study of 41 patients from the hematology department between May 2012 and April 2015. Micafungin was administered once daily from the first day of induction chemotherapy to the end of the neutropenic phase. RESULTS: Neither Candida nor Aspergillus infection was documented in our 41 patients from the first day of micafungin infusion to the end of the neutropenic phase. Patients were followed for three months after discontinuation of micafungin and none of them contracted an invasive fungal infection. Only one patient presented with grade III-IV hepatic and ionic toxicities. CONCLUSION: Micafungin is associated with a good safety profile and is an interesting option for preventing invasive fungal infections in the high-risk population of patients presenting with hematological disorders. PMID- 27126351 TI - [Prevalence of Staphylococcus aureus resistant to meticillin in community acquired skin infections]. PMID- 27126352 TI - PAX6: 25th anniversary and more to learn. AB - The DNA-binding transcription factor PAX6 was cloned 25 years ago by multiple teams pursuing identification of human and mouse eye disease causing genes, cloning vertebrate homologues of pattern-forming regulatory genes identified in Drosophila, or abundant eye-specific transcripts. Since its discovery in 1991, genetic, cellular, molecular and evolutionary studies on Pax6 mushroomed in the mid 1990s leading to the transformative thinking regarding the genetic program orchestrating both early and late stages of eye morphogenesis as well as the origin and evolution of diverse visual systems. Since Pax6 is also expressed outside of the eye, namely in the central nervous system and pancreas, a number of important insights into the development and function of these organs have been amassed. In most recent years, genome-wide technologies utilizing massively parallel DNA sequencing have begun to provide unbiased insights into the regulatory hierarchies of specification, determination and differentiation of ocular cells and neurogenesis in general. This review is focused on major advancements in studies on mammalian eye development driven by studies of Pax6 genes in model organisms and future challenges to harness the technology-driven opportunities to reconstruct, step-by-step, the transition from naive ectoderm, neuroepithelium and periocular mesenchyme/neural crest cells into the three dimensional architecture of the eye. PMID- 27126354 TI - Ultrafast Band Engineering and Transient Spin Currents in Antiferromagnetic Oxides. AB - We report a dynamic structure and band engineering strategy with experimental protocols to induce indirect-to-direct band gap transitions and coherently oscillating pure spin-currents in three-dimensional antiferromagnets (AFM) using selective phononic excitations. In the Mott insulator LaTiO3, we show that a photo-induced nonequilibrium phonon mode amplitude destroys the spin and orbitally degenerate ground state, reduces the band gap by 160 meV and renormalizes the carrier masses. The time scale of this process is a few hundreds of femtoseconds. Then in the hole-doped correlated metallic titanate, we show how pure spin-currents can be achieved to yield spin-polarizations exceeding those observed in classic semiconductors. Last, we demonstrate the generality of the approach by applying it to the non-orbitally degenerate AFM CaMnO3. These results advance our understanding of electron-lattice interactions in structures out-of equilibrium and establish a rational framework for designing dynamic phases that may be exploited in ultrafast optoelectronic and optospintronic devices. PMID- 27126353 TI - Crystal growth and optical characteristics of beryllium-free polyphosphate, KLa(PO3)4, a possible deep-ultraviolet nonlinear optical crystal. AB - Deep-ultraviolet nonlinear optical crystals are of great importance as key materials in generating coherent light with wavelength below 200 nm through cascaded frequency conversion of solid-state lasers. However, the solely usable crystal in practice, KBe2BO3F2 (KBBF), is still commercially unavailable because of the high toxicity of beryllium-containing and the extreme difficulty of crystal growth. Here, we report the crystal growth and characteristics of an beryllium-free polyphosphate, KLa(PO3)4. Centimeter-sized single crystals have been easily obtained by the flux method and slow-cooling technique. The second harmonic generation efficiency of KLa(PO3)4 powder is 0.7 times that of KH2PO4; moreover, the KLa(PO3)4 crystal is phase-matchable. Remarkably, the KLa(PO3)4 crystal exhibits an absorption edge of 162 nm, which is the shortest among phase matchable phosphates so far. These attributes make KLa(PO3)4 a possible deep ultraviolet nonlinear optical crystal. An analysis of the dipole moments of the polyhedra and theoretical calculations by density functional theory were made to elucidate the structure-properties relationships of KLa(PO3)4. PMID- 27126355 TI - Characterizing ceftriaxone-induced urolithiasis and its associated acute kidney injury: an animal study and Chinese clinical systematic review. AB - OBJECTIVE: To investigate the pathophysiological process of ceftriaxone-induced urolithiasis and its associated acute kidney injury (AKI) based on an animal study and summarize the main clinical characteristics based on a Chinese clinical systematic review. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into five groups of six each according to different treatments including control; ceftriaxone; ceftriaxone with calcium; calcium; and ceftriaxone, calcium with citrate, respectively. The 24-h urine volume, serum creatinine (Scr) and blood urea nitrogen (BUN) were measured; kidney histological examination and stone analysis were performed. Systematic searches of the Chinese Knowledge Database were conducted for reports on ceftriaxone-induced urolithiasis and AKI. The eligibility of each full-text publication was accessed, and qualified data were extracted and reviewed. RESULTS: Kidney stones and a significantly low 24-h urine volume with increased high Scr and BUN levels were found in the group that received ceftriaxone combined with calcium. Citrate was able to inhibit these biochemical changes and stone formations. A total of 161 qualified patients were included in the Chinese clinical systematic review: The proportion of ceftriaxone induced urolithiasis was 21.1, 19.3, 19.3, 39.1 and 1.2 % for ages <3, 3-6, 7-17, 18-60 and >60 years. 72.7 % developed acute kidney injury eventually. CONCLUSION: Ceftriaxone-induced urolithiasis was associated with a high risk of AKI. The pathophysiological process may be related to urinary obstruction and crystalline nephropathy. Citrate was able to inhibit stone formation and prevent further kidney injury. PMID- 27126357 TI - Hydrogen bond-assisted aggregation-induced emission and application in the detection of the Zn(ii) ion. AB - The compounds of 3-aminopyridine-2-carboxylic acid with K(+) (1) and Zn(2+) (2) were found to be AIE-active. The AIE behaviours could be attributed to the restriction of intramolecular rotation (RIR) and vibration (RIV) via hydrogen bonds, resulting in rigidity enhancement of the molecules. An AIE-based fluorescence turn on chemosensor for the Zn(ii) ion has been developed in aqueous media with high selectivity and sensitivity. PMID- 27126356 TI - The effect of ambient temperature and humidity on interdialytic weight gains in end-stage renal disease patients on maintenance hemodialysis. AB - PURPOSE: Interdialytic weight gain (IDWG) is both a measure of dietary compliance and a well-established predictor of future adverse outcomes in dialysis patients. The impact of environmental conditions on IDWG in end-stage renal disease is little studied to date. METHODS: We retrospectively reviewed IDWG for 100 consenting chronic end-stage renal disease patients undergoing thrice weekly in center hemodiafiltration under three different climatic conditions in a Central European city: Weekend_1 was humid (93 %) and warm (24 degrees C); Weekend_2 was dry (38 %) and hot (33 degrees C); and Weekend_3 was dry (30 %) and warm (24 degrees C). RESULTS: The cohort's mean age was 60.9 +/- 14.7 years, all were Eastern European, and 56 % were men. Residual urine output measured 100 [25-75 % quartiles: 0, 612] mL/day, single-pool Kt/V 1.4 +/- 0.25, and albumin 40.1 +/- 3.9 g/L. Mean IDWGs measured as follows: Weekend_1 ("humid-warm"): 2973 +/- 1386 mL; Weekend_2 ("dry-hot"): 2685 +/- 1368 mL and Weekend_3 ("dry-warm"): 2926 +/- 1311 mL. Paired-samples testing for difference showed higher fluid gains on the humid-warm (239 mL; 95 % CI 21-458 mL; p = 0.032) and on the dry-warm weekends (222 mL; 95 % CI -8 to 453 mL, p = 0.059), when compared to the dry-hot weekend. Under the latter, dry-hot climatic condition, residual urine output lost its significance to impact IDWG during multiple regression analysis. CONCLUSION: While excess temperature may impact IDWG to a small degree, air humidity does not; the least weight gains occurred on the dry-hot weekend. However, the effects of both were minimal under continental summer conditions and are unlikely to explain large excesses of individual session-to-session variations. PMID- 27126358 TI - Major liver resection for recurrent hydatid cyst of the liver after suboptimal treatment. AB - Recurrent hydatid disease (HD) of the liver after a previous suboptimal invasive treatment is a clinical situation not well codified in terms of management and surgical treatment. Between June 2001 and July 2015, 1525 liver resection were performed at our unit, of whom 217 were with a laparoscopic and 20 with a robotic approach. The most common indications were hepatocellular carcinoma grown on a cirrhotic liver and colorectal metastasis. During the same period, we performed liver surgery for HD in 34 patients (21 females, 13 males). This retrospective study focused on the management and surgical treatment of three unusual cases of recurrent hydatid cyst. All patients had a course of perioperative albendazole. Thirty-four patients had a surgical treatment [open surgery in 30 (88 %) and laparoscopic in four (12 %)]. Surgical procedures were classified as radical resections in 33 patients [total cystopericystectomy (10), left lateral hepatectomy (5), left hepatectomy (2), right hepatectomy (7), segmentectomy/bisegmentectomy (9)]. One patient underwent subtotal pericystectomy as the cyst was close to a major vascular pedicle in a cirrhotic liver. Post operative complications of grade I-II occurred in 11 (32 %) patients, of grade III-IV in one (3 %). Three patients had HD recurrence after a previous suboptimal invasive treatment [PAIR (2), unroofing (1)] and all had to undergo a major liver resection for the complete removal of parasites. The HD first relapse rate for the whole surgical series was 3 %. The second relapse rate was 33 %. The overall survival rate was 100 %. Operations for recurrent HD of the liver represent a surgical challenge due to volume of the cyst, presence of adhesions related to previous invasive treatments and proximity to major vascular structures of the liver. In such instances, pericystectomy can be difficultly achieved making necessary a formal major liver resection. PMID- 27126359 TI - Anti-Sm is associated with the early poor outcome of lupus nephritis. AB - AIM: We investigated whether anti-Smith (Sm) is associated with the outcome of kidney biopsy-proven lupus nephritis. METHODS: We retrospectively analyzed clinical, laboratory and histological results in 90 patients with kidney biopsy proven lupus nephritis. We defined persistent administration of immunosuppressants for more than 3 months after the kidney biopsy as early poor outcome of lupus nephritis. We compared baseline variables and delta values of lupus nephritis-related variables between patients with and without anti-Sm. The independent predictive values for early poor outcome were analyzed using logistic regression analysis. RESULTS: The median age was 32.0 years old, and 77 patients (85.5%) were women. Anti-Sm was found in 44 of 90 patients (48.8%). When we analyzed the differences in delta values of variables reflecting the kidney function or the early poor outcome between patients with and without anti-Sm, we found significant difference in the early poor outcome between the two groups (80.0% of patients having anti-Sm vs. 56.5% of those not having anti-Sm, P = 0.022). In multivariate logistic regression analysis, along with age and Systemic Lupus Erythematosus Disease Activity Index, the presence of anti-Sm increased the potential of the early poor outcome of lupus nephritis (odds ratio 2.870, 95% confidence interval, 1.033, 7.976, P = 0.043). CONCLUSION: Our data suggest that anti-Sm identified at kidney biopsy might have a predictive value for the early poor outcome of biopsy-proven lupus nephritis during the follow-up period. PMID- 27126360 TI - Prediction models for platinum-based chemotherapy response and toxicity in advanced NSCLC patients. AB - In this study, we aimed to establish a platinum-based chemotherapy response and toxicity prediction model in advanced non-small cell lung cancer (NSCLC) patients. 416 single nucleotide polymorphisms (SNPs) in 185 genes were genotyped, and their association with drug response and toxicity were estimated using logistic regression. Nine data mining techniques were employed to establish the prediction model; the sensitivity, specificity, overall accuracy and receiver operating characteristic (ROC) curve were used to assess the models' performance. Finally, selected models were validated in an independent cohort. The models established by naive Bayesian algorithm had the best performance. The response prediction model achieved a sensitivity of 0.90 and a specificity of 0.47 with the ROC area under curve (AUC) of 0.80. The overall toxicity prediction model achieved a sensitivity of 0.86 and a specificity of 0.46 with the ROC AUC of 0.73. The hematological toxicity prediction model achieved a sensitivity of 0.89 and a specificity of 0.39 with the ROC AUC of 0.76. The gastrointestinal toxicity prediction model achieved a sensitivity of 0.93 and a specificity of 0.35 with the ROC AUC of 0.80. In conclusion, we provided platinum-based chemotherapy response and toxicity prediction models for advanced NSCLC patients. PMID- 27126361 TI - ARK5 promotes doxorubicin resistance in hepatocellular carcinoma via epithelial mesenchymal transition. AB - AMP-activated protein kinase family member 5 (ARK5) overexpression has been reported in many human cancers, and ARK5 is associated with poor prognosis in hepatocellular carcinoma (HCC). However, whether ARK5 is involved in HCC chemoresistance is unclear. The present study aimed to investigate the role of ARK5 in HCC chemoresistance and the underlying mechanism. In this study, we found that SNU387 and SNU449 HCC cell lines overexpressing ARK5 displayed low doxorubicin sensitivity compared to Huh7 and Hep3B HCC cell lines with ARK5 low expression. And knockdown of ARK5 increased the doxorubicin sensitivity in all HCC cell lines in the manner of inhibiting cell proliferation. Western blotting and immunofluorescence both showed that ARK5 knockdown upregulated E-cadherin and downregulated vimentin, which was consistent with the knockdown of TWIST, indicating ARK5 was involved in epithelial-mesenchymal transition (EMT). Moreover, suppressing ARK5 by siRNA restored E-cadherin and vimentin expression induced by doxorubicin treatment or hypoxia culture. Our results indicated ARK5 confers doxorubicin resistance in HCC via inducing EMT. PMID- 27126363 TI - Heritage, health and place: The legacies of local community-based heritage conservation on social wellbeing. AB - Geographies of health challenge researchers to attend to the positive effects of occupying, creating and using all kinds of spaces, including 'green space' and more recently 'blue space'. Attention to the spaces of community-based heritage conservation has largely gone unexplored within the health geography literature. This paper examines the personal motivations and impacts associated with people's growing interest in local heritage groups. It draws on questionnaires and interviews from a recent study with such groups and a conceptual mapping of their routes and flows. The findings reveal a rich array of positive benefits on the participants' social wellbeing with/in the community. These include personal enrichment, social learning, satisfaction from sharing the heritage products with others, and less anxiety about the present. These positive effects were tempered by needing to face and overcome challenging effects associated with running the projects thus opening up an extension to health-enabling spaces debates. PMID- 27126362 TI - Activation of AKT negatively regulates the pro-apoptotic function of death associated protein kinase 3 (DAPK3) in prostate cancer. AB - The activation of AKT governs many signaling pathways and promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer (CaP). Here, we investigated the molecular association between AKT activation and the function of death-associated protein kinase 3 (DAPK3) in CaP. An inverse correlation of pAKT and DAPK3 expression was seen in a panel of CaP cell lines. Inhibition of AKT by wortmannin/LY294002 or overexpression of DAPK3 reverts the proliferative function of AKT in CaP cells. On the other hand, ectopic expression of AKT inhibited DAPK3 function and induced proliferation of CaP cells. In addition, AKT over-expressed tumors exhibit aggressive growth when compared to control vector in xenograft models. The immunohistochemistry results revealed a down-regulation of DAPK3 expression in AKT over-expressed tumors as compared to control tumors. Finally, we examined the expression pattern of AKT and DAPK3 in human CaP specimens - the expected gradual increase and nuclear localization of pAKT was seen in higher Gleason score samples versus benign hyperplasia (BPH). On the contrary, reduced expression of DAPK3 was seen in higher Gleason stages versus BPH. This suggests that inhibition of DAPK3 may be a contributing factor to the carcinogenesis of the prostate. Understanding the mechanism by which AKT negatively regulates DAPK3 function may suggest whether DAPK3 can be a therapeutic target for CaP. PMID- 27126364 TI - Systematic review of reviews of observational studies of school-level effects on sexual health, violence and substance use. AB - For three decades there have been reports that the quality of schools affects student health. The literature is diverse and reviews have addressed different aspects of how the school environment may affect health. This paper is the first to synthesise this evidence using a review of reviews focusing on substance-use, violence and sexual-health. Twelve databases were searched. Eleven included reviews were quality-assessed and synthesised narratively. There is strong evidence that schools' success in engaging students is associated with reduced substance use. There is little evidence that tobacco-control policies and school sexual-health clinics on their own are associated with better outcomes. PMID- 27126365 TI - Immune responses to hepatitis B immunization 10-18 years after primary vaccination: a population-based cohort study. AB - We evaluated the immune response to neonatal HBV immunization in children of infected parents 10-18 years after primary vaccination. Healthy individuals immunized with an infantile course of three doses of HBV vaccine were tested for persistence of anti-HB surface antibody (HBsAb). Those with an HBsAb level of <10 IU/mL received a booster dose of the vaccine with subsequent doses to those without protective titres. HBsAb concentrations were determined 4 weeks after each dose of the booster vaccine. The data were analysed separately for three age groups: 10-11, 12-14 and 15-18 years old. A total of 541 healthy individuals were studied. The highest seroprotection rate of 48% was observed in the youngest vaccinees (10-11 years old). This declined to 26.5% in the oldest (15-18 years old) group (P = 0.008). The youngest vaccinees showed the highest rate of anamnestic immune responses (96%). However, 25% of oldest individuals failed to mount an anamnestic immune response in challenge with a booster dose of the vaccine (P = 0.005), suggesting waning immunity with increasing age. Age (OR: 0.80; P = 0.01) and prebooster HBsAb levels (OR: 0.37; P = 0.01) identified responders to first booster doses of the vaccine by logistic regression analysis. The majority of high-risk vaccinees showed anamnestic immune response 10-11 years after primary immunization. However, we found a significant proportion (25%) of older individuals with no anamnetic response, which suggests a waning of immune memory. Detailed long-term follow-up studies are necessary to determine the risk of natural infection among these individuals before a booster schedule can be recommended. PMID- 27126366 TI - The fall and rise of the Icelandic Arctic fox (Vulpes lagopus): a 50-year demographic study on a non-cyclic Arctic fox population. AB - In territorial species, observed density dependence is often manifest in lowered reproductive output at high population density where individuals have fewer resources or are forced to inhabit low-quality territories. The Arctic fox (Vulpes lagopus) in Iceland is territorial throughout the year and feeds mostly on birds, since lemmings are absent from the country. Thus, the population does not exhibit short-term population cycles that are evident in most of the species' geographical range. The population has, however, gone through a major long-term fluctuation in population size. Because of the stability in hunting effort and reliable hunting records since 1958, the total number of adult foxes killed annually can be used as an index of population size (N t ). An index of carrying capacity (K) from population growth data for five separate time blocks during 1958-2007 revealed considerable variation in K and allowed a novel definition of population density in terms of K, or N t /K. Correlation analysis suggested that the reproductive rate was largely determined by the proportion of territorial foxes in the population. Variation in litter size and cub mortality was, on the other hand, related to climatic variation. Thus, Arctic foxes in Iceland engage in typical contest competition but can adapt their territory sizes in response to both temporal and spatial variation in carrying capacity, resulting in surprisingly little variation in litter size. PMID- 27126367 TI - Personal care assistants' experiences of caring for people on home mechanical ventilation. AB - AIM: The aim of this study was to describe personal care assistants' (PCA) experiences of working with a ventilator-assisted person at home. METHODS: Data were collected from fifteen audiotaped semistructured interviews with PCAs supporting a child or adult using home mechanical ventilation (HMV). Thirteen women and two men participated; their working experience with HMV users ranged from one to 17 years (median 6 years). Data were subjected to qualitative content analysis in an inductive and interpretive manner. FINDINGS: Five categories emerged from the data: Being part of a complex work situation; Taking on a multidimensional responsibility; Caring carried out in someone's home; Creating boundaries in an environment with indistinct limits; and Being close to another's body and soul. CONCLUSIONS: The participants felt very close to the person they worked with, both physically and emotionally. They had a great responsibility and therefore a commensurate need for support, guidance and a well-functioning organisation around the HMV user. There is international consensus that advanced home care will continue to expand and personal care assistance is key in this development. We suggest that one way to move forward for PCAs working with HMV users is to create multiprofessional teams led by a key-person who coordinates the individual needs. More research is needed within this area from a broad perspective including the HMV-assisted persons, relatives, personal care assistants and management organisations. PMID- 27126368 TI - Using nanobiotechnology to increase the prevalence of epigenotyping assays in precision medicine. AB - Epigenetic silencing of genes that are important for DNA repair, cell cycle control, apoptosis, and cellular interactions with the extracellular matrix has been causally linked to several subtypes of cancer. Translating this knowledge of the implications of promoter methylation to wide and routine use in clinical pathology laboratories has been more challenging than the case of genetic analyses because epigenetic modifications do not change the underlying sequence of the affected nucleic acid, rendering polymerase chain reaction analysis alone uninformative. Two epigenotyping assays that detect promoter methylation are currently standard of care in treatment of two distinct tumor types in only a few top hospitals across the United States. Both rely on a harsh chemical step that degrades over 90% of tumor DNA samples, which are often available in limited quantities, and imparts the potential for false-negative or false-positive results if the reaction conditions are not exactly correct. Using nanotechnology and biotechnology to devise practical new analysis techniques that avoid the drawbacks of current techniques represents a powerful approach that is likely to significantly increase the clinical use of this class of biomarkers in the coming years. WIREs Nanomed Nanobiotechnol 2017, 9:e1407. doi: 10.1002/wnan.1407 For further resources related to this article, please visit the WIREs website. PMID- 27126369 TI - Isolation and characterization of circulating tumor cells using a novel workflow combining the CellSearch(r) system and the CellCelectorTM. AB - Circulating tumor cells (CTC) are rare cells which have left the primary tumor to enter the blood stream. Although only a small CTC subgroup is capable of extravasating, the presence of CTCs is associated with an increased risk of metastasis and a shorter overall survival. Understanding the heterogeneous CTC biology will optimize treatment decisions and will thereby improve patient outcome. For this, robust workflows for detection and isolation of CTCs are urgently required. Here, we present a workflow to characterize CTCs by combining the advantages of both the CellSearch(r) and the CellCelectorTM micromanipulation system. CTCs were isolated from CellSearch(r) cartridges using the CellCelectorTM system and were deposited into PCR tubes for subsequent molecular analysis (whole genome amplification (WGA) and massive parallel multigene sequencing). By a CellCelectorTM screen we reidentified 97% of CellSearch(r) SKBR-3 cells. Furthermore, we isolated 97% of CellSearch(r) -proven patient CTCs using the CellCelectorTM system. Therein, we found an almost perfect correlation of R2 = 0.98 (Spearman's rho correlation, n = 20, p < 0.00001) between the CellSearch(r) CTC count (n = 271) and the CellCelectorTM detected CTCs (n = 252). Isolated CTCs were analyzed by WGA and massive parallel multigene sequencing. In total, single nucleotide polymorphisms (SNPs) could be detected in 50 genes in seven CTCs, 12 MCF-7, and 3 T47D cells, respectively. Taken together, CTC quantification via the CellCelectorTM system ensures a comprehensive detection of CTCs preidentified by the CellSearch(r) system. Moreover, the isolation of CTCs after CellSearch(r) using the CellCelectorTM system guarantees for CTC enrichment without any contaminants enabling subsequent high throughput genomic analyses on single cell level. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:125-132, 2017. PMID- 27126370 TI - Participation of the thalamic CM-Pf complex in movement performance in patients with dystonia. AB - INTRODUCTION: The centrum medianum- parafascicular complex of the human thalamus has a critical influence on cortical activity and significantly influences somatosensory function, arousal, and attention. In addition to its cortical connections, this region of the intralaminar thalamic nuclei is also connected to motor areas of the basal ganglia and the brain stem. OBJECTIVE: The goal of this study was to identify movement-related neurons in the centrum medianum parafascicular complex and analyze the changes in their activity during voluntary movements in patients with cervical dystonia. METHODS: Single-unit activity was recorded during the micro-electrode-guided surgical ablation procedures in patients with cervical dystonia. The neural responses and synchronous electromyographic signals of the neck and finger flexor muscles were simultaneously recorded. RESULTS: We found the following 3 types of movement sensitive neurons in the centrum medianum-parafascicular complex: neurons that responded selectively to voluntary hand movement (hand-only neurons), neurons that selectively responded to neck movements (neck-only neurons), neurons responding to both hand and neck movements (combined neurons). We discovered the following 3 patterns of movement-related changes in neural activity: an increase in the firing rate, a reduction in the bursting activity, and short-term oscillations and synchronization with neighboring neurons. The most pronounced and prolonged responses were observed during movements involving neck muscles as well as during involuntary dystonic movements. CONCLUSION: The centrum medianum parafascicular complex of the thalamus is a component of the subcortical network that participates in motor behavior and may be involved in the pathophysiology of cervical dystonia. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27126371 TI - Immediate Implant Placement in Sockets with Asymptomatic Apical Periodontitis. AB - BACKGROUND: The purpose of the present study was to evaluate if the presence of granulation tissue in asymptomatic apical periodontitis compromised immediate implant placement. METHODS: Patients requiring extraction of one tooth (maxillary and mandibular incisive, canine or premolar) with asymptomatic apical periodontitis, were recruited for this prospective study. They were randomly scheduled into two groups: in first group (A) including 30 teeth, reactive soft tissue was debrided before implant placement, and in second group (B) including 30 teeth, reactive soft tissue was left in the apical lesion. Implants were positioned immediately after tooth extraction, and were loaded after 3 months in both groups. Cone beam computed tomography was performed before tooth extraction and at 1-year follow-up to evaluate the radiolucency around the root apex and the implant, bucco-lingual bone levels were also checked. RESULTS: Sixty patients were included in this study. Sixty implants were placed immediately after tooth extraction and, at 1-year follow-up, a survival rate of 100% was reported. After one year both groups showed absence of radiolucent zone at the apical region of implants. All fresh sockets presented a buccal-palatal bone reduction in both groups after one year, even if not statistically significant differences were found between baseline bone levels and within groups. CONCLUSIONS: Within the limitations of the present study, the immediate placement of implants into the extraction sockets with asymptomatic apical periodontitis, in presence of primary stability, did not lead to an increased rate of complications and rendered an equally favorable type of tissue integration. PMID- 27126372 TI - Nucleologenesis in Trypanosoma cruzi. AB - Nucleolar assembly is a cellular event that requires the synthesis and processing of ribosomal RNA, in addition to the participation of pre-nucleolar bodies (PNBs) at the end of mitosis. In mammals and plants, nucleolar biogenesis has been described in detail, but in unicellular eukaryotes it is a poorly understood process. In this study, we used light and electron microscopy cytochemical techniques to investigate the distribution of nucleolar components in the pathway of nucleolus rebuilding during closed cell division in epimastigotes of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis. Silver impregnation specific for nucleolar organizer regions and an ethylenediaminetetraacetic acid regressive procedure to preferentially stain ribonucleoprotein revealed the conservation and dispersion of nucleolar material throughout the nucleoplasm during cell division. Furthermore, at the end of mitosis, the argyrophilic proteins were concentrated in the nucleolar organizer region. Unexpectedly, accumulation of nucleolar material in the form of PNBs was not visualized. We suggest that formation of the nucleolus in epimastigotes of T. cruzi occurs by a process that does not require the concentration of nucleolar material within intermediate nuclear bodies such as mammalian and plant PNBs. PMID- 27126373 TI - Enantiomeric Lignans and Neolignans from Phyllanthus glaucus: Enantioseparation and Their Absolute Configurations. AB - Eight pairs of enantiomeric neolignans, norlignans, and sesquineolignans (1a/1b 8a/8b), together with five known neolignans (9a/9b and 10-12), have been isolated from 70% acetone extract of the whole plants of Phyllanthus glaucus Wall. (Euphorbiaceae). The racemic or partial racemic mixtures were successfully separated by chiral HPLC using different types of chiral columns with various mobile phases. Their structures were elucidated on the basis of extensive spectroscopic data. The absolute configurations of 2a/2b were determined by computational analysis of their electronic circular dichroism (ECD) spectrum, and the absolute configurations of other isolates were ascertained by comparing their experimental ECD spectra and optical rotation values with those of structure relevant compounds reported in literatures. Compounds 4a/4b featured unique sesquineolignan skeletons with a novel 7-4'-epoxy-8'-8''/7'-2'' scaffold, consisting of an aryltetrahydronaphthalene and a dihydrobenzofuran moiety. The planar structures of compounds 2, 3, 7, and 8 were documented previously; however, their absolute configurations were established for the first time in this study. The antioxidant activities of 1a/1b-8a/8b were evaluated using DPPH free radical scavenging assay, and the results demonstrated that compounds 1b and 3b showed potent DPPH radical scavenging activities with IC50 values of 5.987 +/- 1.212 and 9.641 +/- 0.865 MUg/mL, respectively. PMID- 27126374 TI - Abrogating the interplay between IGF2BP1, 2 and 3 and IGF1R by let-7i arrests hepatocellular carcinoma growth. AB - IGF2BP 1, 2 and 3 control the fate of many transcripts. Immunoprecipitation studies demonstrated the IGF2BPs to bind to IGF1R mRNA, and our laboratory has recently shown them to post-transcriptionally regulate IGF1R. This study sought to identify a microRNA regulating the IGF2BPs and consequently IGF1R. All three IGF2BPs were among the top-ranked predicted targets of let-7i. Let-7i was downregulated in HCC tissues, and transfection of HuH-7 with let-7i inhibited malignant cell behaviors and decreased IGF2BPs transcripts. Direct binding of let 7i to IGF2BP2 and IGF2BP3 3'UTRs was confirmed, and the effect of let-7i caused a decrease in the IGF2BPs' target gene, the IGF1R. IGF1R mRNA was inversely correlated with let-7i in HCC tissues and was reduced upon let-7i transfection into HuH-7. Reporter assays validated IGF1R as a target of let-7i. Therefore, let 7i may control HCC tumorigenesis by regulating IGF1R directly and indirectly by interrupting the interplay between IGF1R and the IGF2BPs. PMID- 27126375 TI - End-stage Renal Disease after Renal Surgery: Partial Nephrectomy is Protective, but to What Degree and Consequence? PMID- 27126376 TI - Re: Jeffrey C. Weinreb, Jelle O. Barentsz, Peter L. Choyke, et al. PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2. Eur Urol 2016;69:16-40: Is Contrast-enhanced Magnetic Resonance Imaging Really Necessary When Searching for Prostate Cancer? PMID- 27126378 TI - Pedicled adipofascial infraclavicular flap: Elevation technique and its use for maintaining neck contour and vessel coverage after radical and modified radical neck dissection. AB - BACKGROUND: The pedicled adipofascial infraclavicular flap (ICF) is based on the anterior perforator of the supraclavicular artery and supplies the fasciocutaneous tissue of the upper chest. This flap may be used to address neck contour defects and vessel coverage after radical and modified radical neck dissections (MRNDs). METHODS: We described the pedicled adipofascial ICF elevation technique and its use immediately after neck dissections in order to maintain soft tissue volume and vessel coverage. A video of the operation is provided. RESULTS: Our results demonstrated satisfactory neck contours with adequate volume replacement, great vessel coverage, and little donor-site morbidity. CONCLUSION: The pedicled adipofascial ICF is a technically straightforward operation with broad possible applications in head and neck surgery. It may be useful to provide vascularized soft-tissue coverage and maintain neck contour after neck dissections. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: First-1582, 2016. PMID- 27126377 TI - Prognostic significance of endogenous erythropoietin in long-term outcome of patients with acute decompensated heart failure. AB - AIMS: Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear. METHODS AND RESULTS: We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06-1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P < 0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05-2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level. CONCLUSION: A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients. PMID- 27126379 TI - Influence of zeolite shape and particle size on their capacity to adsorb uremic toxin as powders and as fillers in membranes. AB - Membranes with zeolites are promising for performing blood dialysis because zeolites can eliminate uremic toxins through molecular sieving. Although the size and the shape of zeolite particles can potentially influence the performance of the membranes with respect of creatinine uptake level, it is not clear what sizes and shapes lead to better performance. In this paper, we carry out experiments to answer this question. Spherical microparticle 840, spherical nanoparticle P-87 and rod-like nanoparticle P-371 zeolites were chosen to be used in all the experiments. Their creatinine uptake levels were first measured as powders in creatinine solutions with different concentrations, volumes and adsorption times. Then, nanofibrous membranes with zeolites were electrospun and their ability to adsorb creatinine was measured and compared against their respective powders' creatinine uptake level. The experiment shows that the zeolites have similar creatinine uptake ability as powders. However, they have significantly different creatinine uptake ability after being incorporated inside the membranes. Spherical microparticle 840 in the membrane presented the best creatinine uptake ability, at 8957 ug g-1 , which was half of its powders'. On the other hand, P-87 presented largely decreased, while P-371 presented even lower creatinine uptake ability in membranes when compared to respective powders'. The results shows that microparticle and sphere shaped particles perform better inside the membranes. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1594-1601, 2017. PMID- 27126380 TI - Microbial communities and arsenic biogeochemistry at the outflow of an alkaline sulfide-rich hot spring. AB - Alkaline sulfide-rich hot springs provide a unique environment for microbial community and arsenic (As) biogeochemistry. In this study, a representative alkaline sulfide-rich hot spring, Zimeiquan in the Tengchong geothermal area, was chosen to study arsenic geochemistry and microbial community using Illumina MiSeq sequencing. Over 0.26 million 16S rRNA sequence reads were obtained from 5-paired parallel water and sediment samples along the hot spring's outflow channel. High ratios of As(V)/AsSum (total combined arsenate and arsenite concentrations) (0.59 0.78), coupled with high sulfide (up to 5.87 mg/L), were present in the hot spring's pools, which suggested As(III) oxidation occurred. Along the outflow channel, AsSum increased from 5.45 to 13.86 MUmol/L, and the combined sulfide and sulfate concentrations increased from 292.02 to 364.28 MUmol/L. These increases were primarily attributed to thioarsenic transformation. Temperature, sulfide, As and dissolved oxygen significantly shaped the microbial communities between not only the pools and downstream samples, but also water and sediment samples. Results implied that the upstream Thermocrinis was responsible for the transformation of thioarsenic to As(III) and the downstream Thermus contributed to derived As(III) oxidation. This study improves our understanding of microbially-mediated As transformation in alkaline sulfide-rich hot springs. PMID- 27126381 TI - Usefulness of basic renal function tests in decision-making in children with loss of renal parenchyma and/or dilation of the urinary tract. AB - Basic renal function tests such as maximum urine osmolality and urinary elimination of albumin and N-acetyl-glucosaminidase often reveal abnormalities in clinical cases involving hyperpressure in the urinary tract or loss of renal parenchyma. However, in all the available algorithms dedicated to the study of children with urinary tract infection or dilation, the benefit of using these functional parameters is not mentioned. In this review, we provide information about the practical usefulness of assessing the basic renal function parameters. From these data, we propose an algorithm that combines morphological and functional parameters to make a reasoned case for voiding cystourethrography. PMID- 27126382 TI - A diagnostic method for herpes simplex keratitis by simultaneous measurement of viral DNA and virus-specific secretory IgA in tears: an evaluation. AB - PURPOSE: We performed simultaneous measurement of herpes simplex virus (HSV) DNA by real-time polymerase chain reaction (real-time PCR) and of HSV-specific secretory IgA antibody (HSV-sIgA) by enzyme-linked immunosorbent assay (ELISA) in tears obtained using Schirmer strips in order to investigate its diagnostic efficacy for herpes simplex keratitis (HSK). METHODS: A total of 59 affected eyes from 59 patients with clinically suspected HSK (HSK group) and 23 eyes from 23 healthy volunteers (control group) were enrolled in this study. The HSK group was divided into five subgroups: dendritic/geographic keratitis, disciform keratitis, necrotizing keratitis, atypical keratitis, and others. The tear samples were taken using Schirmer strips to determine the HSV DNA and HSV-sIgA levels. RESULTS: The overall sensitivity and specificity were 55.8 and 100 % for HSV DNA and 49.2 and 82.6 % for HSV-sIgA. The HSV DNA levels in the disciform keratitis subgroup (median, 3.1 * 10(2) copies/sample) were significantly lower than those in the dendritic/geographic keratitis subgroup (median, 2.3 * 10(4) copies/sample) (P < 0.05, Mann-Whitney test). The HSV-sIgA levels in the disciform keratitis subgroup (median, 50.0 NU/ml) were significantly higher than those in the control group (median, 18.0 NU/ml) (P < 0.05, Steel test). The positive and negative predictive values obtained by simultaneous measurement of HSV DNA and sIgA were 90.9 and 61.3 %, respectively. CONCLUSION: The combination of laboratory detection of HSV DNA by real-time PCR and of HSV-sIgA by ELISA using tear samples enables higher reliability in diagnosing the subgroups of HSK, although the HSV DNA value is relatively lower in disciform HSK than in dendritic/geographic HSK. PMID- 27126383 TI - The long life of an endocytic patch that misses AP-2. AB - Endocytosis is the process by which cells regulate extracellular fluid uptake and internalize molecules bound to their plasma membrane. This process requires the generation of protein-coated vesicles. In clathrin-mediated endocytosis (CME) the assembly polypeptide 2 (AP-2) adaptor facilitates rapid endocytosis of some plasma membrane receptors by mediating clathrin recruitment to the endocytic site and by connecting cargoes to the clathrin coat. While this adaptor is essential for early embryonic development in mammals, initial results suggested that it is dispensable for endocytosis in unicellular eukaryotes. The drastic effect of depleting AP-2 in metazoa and the mild effect of deleting AP-2 subunits in Saccharomyces cerevisiae have prevented a detailed analysis of the dynamics of endocytic patches in the absence of this adaptor. Using live-cell imaging of Schizosaccharomyces pombe endocytic sites we have shown that eliminating AP-2 perturbs the dynamics of endocytic patches beyond the moment of coat assembly. These perturbations affect the cell growth pattern and cell wall synthesis. Our results highlight the importance of using different model organisms to address the study of conserved aspects of CME. PMID- 27126384 TI - Phenotypic heterogeneity in a bacteriophage population only appears as stress induced mutagenesis. AB - Stress-induced mutagenesis has been studied in cancer cells, yeast, bacteria, and archaea, but not in viruses. In a recent publication, we present a bacteriophage model showing an apparent stress-induced mutagenesis. We show that the stress does not drive the mutagenesis, but only selects the fittest mutants. The mechanism underlying the observed phenomenon is a phenotypic heterogeneity that resembles persistence of the viral population. The new findings, the background for the ongoing debate on stress-induced mutagenesis, and the phenotypic heterogeneity underlying a novel phage infection strategy are discussed in this short manuscript. PMID- 27126385 TI - Summation effects in human learning: evidence from patterning discriminations in goal-tracking. AB - Participants in two human goal-tracking experiments were simultaneously trained with negative patterning (NP) and positive patterning (PP) discriminations (A+, B+, AB-, C-, D-, CD+). Both elemental and configural models of associative learning predict a PP advantage, such that NP is solved less readily than PP. However, elemental models like the unique cue approach additionally predict responding in AB- trials to be initially stronger than that in A+ and B+ trials due to summation of associative strength. Both experiments revealed a PP advantage and a strong summation effect in AB- trials in the first half of the experiments, irrespective of whether the same US was used for both discriminations (Experiment 1) or two different USs (Experiment 2). We discuss that the correct predictions of the unique cue approach are based on its assumptions of non-normalized and context-independent stimulus processing rather than elemental processing per se. PMID- 27126386 TI - Anoxybacillusgeothermalis sp. nov., a facultatively anaerobic, endospore-forming bacterium isolated from mineral deposits in a geothermal station. AB - A novel endospore-forming bacterium designated strain GSsed3T was isolated from deposits clogging aboveground filters from the geothermal power platform of Grobeta Schonebeck in northern Germany. The novel isolate was Gram-staining positive, facultatively anaerobic, catalase-positive and oxidase-positive. Optimum growth occurred at 60 degrees C, 0.5 % (w/v) NaCl and pH 7-8. Analysis of the 16S rRNA gene sequence similarity indicated that strain GSsed3T belonged to the genus Anoxybacillus, and showed 99.8 % sequence similarity to Anoxybacillus rupiensis R270T, 98.2 % similarity to Anoxybacillus tepidamans GS5 97T, 97.9 % similarity to Anoxybacillus voinovskiensis TH13T, 97.7 % similarity to Anoxybacillus caldiproteolyticus DSM 15730T and 97.6 % similarity to Anoxybacillus amylolyticus MR3CT. DNA-DNA hybridization (DDH) indicated only 16 % relatedness to Anoxybacillus rupiensis DSM 17127T. Furthermore, DDH estimation based on genomes analysis indicated only 19.9 % overall nucleotide similarity to Anoxybacillus amylolyticus DSM 15939T. The major respiratory menaquinone was MK 8. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unknown phosphoglycolipid and one unknown phospholipid. The predominant cellular fatty acids were iso-C15 : 0, iso-C17 : 0, C16 : 0, iso-C16 : 0 and anteiso-C17 : 0. The peptidoglycan type was A1gamma meso-Dpm-direct. The genomic DNA G+C content of the strain was 46.9 mol%. The phenotypic, genotypic and chemotaxonomic characterization indicated that strain GSsed3T differs from related species of the genus. Therefore, strain GSsed3T is considered to be a representative of a novel species of the genus Anoxybacillus, for which the name Anoxybacillus geothermalis sp. nov. is proposed. The type strain of Anoxybacillus geothermalis is GSsed3T (=CCOS808T =ATCC BAA2555T). PMID- 27126387 TI - Association between Type of Sedation and the Adverse Events Associated with Gastrointestinal Endoscopy: An Analysis of 5 Years' Data from a Tertiary Center in the USA. AB - BACKGROUND/AIMS: The landscape of sedation for gastrointestinal (GI) endoscopic procedures and the nature of the procedures themselves have changed over the last decade. In this study, an attempt is made to analyze the frequency and etiology of all major adverse events associated with GI endoscopy. METHODS: All adverse events extracted from the electronic database and local registry were analyzed. Although the data analysis was retrospective, the adverse events themselves were documented prospectively. These events were evaluated after subdivision into propofol-based anesthesia and intravenous conscious sedation groups. RESULTS: Cardiorespiratory events, including cardiac arrest, were the most common adverse events during esophagogastroduodenoscopy, while bleeding was more frequent in patients undergoing colonoscopy. Pancreatitis was the most frequent adverse event in patients undergoing endoscopic retrograde cholangiopancreatography. The frequencies of most adverse events were significantly higher in patients anesthetized with propofol. Automatic regression modeling showed that the type of sedation, the American Society of Anesthesiologists physical status classification, and the procedure type were some of the predictors of immediate life-threatening complications. CONCLUSIONS: Clearly, our regression modeling suggests a strong association between the type of sedation as well as various patient factors and the frequency of adverse events. The possible reasons for our results are the changing demographics, the worsening comorbidities of the patient population, and the increasing technical complexity of these procedures. Although extensive use of propofol has increased patient satisfaction and procedure acceptability, its use is also associated with more frequent adverse events. PMID- 27126388 TI - diskImageR: quantification of resistance and tolerance to antimicrobial drugs using disk diffusion assays. AB - Microbial pathogens represent an increasing threat to human health. Although many infections can be successfully treated and cleared, drug resistance is a widespread problem. The existence of subpopulations of 'tolerant' cells (where a fraction of the population is able to grow above the population resistance level) may increase the rate of treatment failure; yet, existing methods to measure subpopulation effects are cumbersome. Here we describe diskImageR, a computational pipeline that analyses photographs of disk diffusion assays to determine the degree of drug susceptibility [the radius of inhibition, (RAD)], and two aspects of subpopulation growth [the fraction of growth (FoG) within the zone of inhibition, (ZOI), and the rate of change in growth from no drug to inhibitory drug concentrations, (SLOPE)]. diskImageR was used to examine the response of the human fungal pathogen Candida albicans to the antifungal drug fluconazole across different strain backgrounds and growth conditions. Disk diffusion assays performed under Clinical and Laboratory Standards Institute (CLSI) conditions led to more susceptibility and less tolerance than assays performed using rich medium conditions. We also used diskImageR to quantify the effects of three drugs in combination with fluconazole, finding that all three combinations affected tolerance, with the effect of one drug (doxycycline) being very strain dependent. The three drugs had different effects on susceptibility, with doxycycline generally having no effect, chloroquine generally increasing susceptibility and pyrvinium pamoate generally reducing susceptibility. The ability to simultaneously quantitate different aspects of microbial drug responses will facilitate the study of mechanisms of subpopulation responses in the presence of antimicrobial drugs. PMID- 27126390 TI - Samarocene oxide: from an undesired decomposition product to a new reagent. AB - Samarocene oxide [Cp*2Sm-O-SmCp*2] is mostly considered as an undesired decomposition product of the well-established but highly air-sensitive samarocene, [Cp*2Sm(thf)2]. [Cp*2Sm-O-SmCp*2] is often formed by accidental exposure of [Cp*2Sm(thf)2] to air or wet solvents. We show here that [Cp*2Sm-O SmCp*2] acts as a mild oxide base and thus is a valuable synthetic equivalent for "O(2-)". The reaction of [Cp*2Sm-O-SmCp*2] with the inorganic and organic anhydrides COS, CS2, SO2, SO3, Re2O7, and (PhC(O))2O at room temperature resulted in each case in an O(2-) insertion. The corresponding products were isolated as their samarium complexes. PMID- 27126389 TI - Drug discovery in renin-angiotensin system intervention: past and future. AB - The renin-angiotensin system (RAS) plays a central role in the control of blood pressure in the body and the way this interacts with other systems is widely recognized. This has not always been the case and this review summarizes how our knowledge has evolved from the initial discovery of renin by Tigerstedt and Berman in 1898. This includes the identification of angiotensin in the 1950s to the proposed relationship between this system, hypertension and ultimately cardiovascular disease. While the RAS is far more complex than originally thought, much is now known about this system and the wide ranging effects of angiotensin in the body. This has enabled the development of therapies that target the various proteins in this pathway and hence are implicated in disease. The first of these treatments was the angiotensin converting enzyme inhibitors (ACE-Is), followed by the angiotensin receptor blockers (ARBs), and more recently the direct renin inhibitors (DRIs). Clinical outcome trials have shown these drugs to be effective, but as they act at contrasting points in the RAS, there are differences in their efficacy and safety profiles. RAS blockade is the foundation of modern combination therapy with a calcium channel blocker and/or a diuretic given to reduce blood pressure and limit the impact of RAS activation. Other options that complement these treatments may be available in the future and will offer more choice to clinicians. PMID- 27126391 TI - White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder. AB - OBJECTIVE: Immune alterations may play a role in bipolar disorder etiology; however, the relationship between overall immune system functioning and mood symptom severity is unknown. METHODS: The two comparative effectiveness trials, the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study (Bipolar CHOICE) and the Lithium Treatment Moderate-Dose Use Study (LiTMUS), were similar trials among patients with bipolar disorder. At study entry, white blood cell count and bipolar mood symptom severity (via Montgomery-Aasberg Depression Rating Scale and Bipolar Inventory of Symptoms Scale) were assessed. We performed analysis of variance and linear regression analyses to investigate relationships between deviations from median white blood cell and multinomial regression analysis between higher and lower white blood cell levels. All analyses were adjusted for age, gender, body mass index, smoking, diabetes, hypertension and hyperlipidemia. RESULTS: Among 482 Bipolar CHOICE participants, for each 1.0 * 109/L white blood cell deviation, the overall Bipolar Inventory of Symptoms Scale severity increased significantly among men (coefficient = 2.13; 95% confidence interval = [0.46, -3.79]; p = 0.013), but not among women (coefficient = 0.87; 95% confidence interval = [-0.87, -2.61]; p = 0.33). Interaction analyses showed a trend toward greater Bipolar Inventory of Symptoms Scale symptom severity among men (coefficient = 1.51; 95% confidence interval = [-0.81, -3.82]; p = 0.2). Among 283 LiTMUS participants, higher deviation from the median white blood cell showed a trend toward higher Montgomery-Aasberg Depression Rating Scale scores among men (coefficient = 1.33; 95% confidence interval = [-0.22, -2.89]; p = 0.09), but not among women (coefficient = 0.34; 95% confidence interval = [-0.64, -1.32]; p = 0.50). When combining LiTMUS and Bipolar CHOICE, Montgomery-Aasberg Depression Rating Scale scores increased significantly among men (coefficient = 1.09; 95% confidence interval = [0.31, -1.87]; p = 0.006) for each 1.0 * 109/L white blood cell deviation, whereas we found a weak association among women (coefficient = 0.55; 95% confidence interval = [-0.20, -1.29]; p = 0.14). Lower and higher white blood cell levels correlated with greater symptom severity and specific symptoms, varying according to gender. CONCLUSION: Deviations in an overall immune system marker, even within the normal white blood cell range, correlated with mood symptom severity in bipolar disorder, mostly among males. Studies are warranted investigating whether white blood cell count may predict response to mood stabilizing treatment. PMID- 27126392 TI - Dysphagia in Tongue Cancer Patients Before and After Surgery. AB - PURPOSE: To define factors influencing postoperative aspiration in tongue cancer patients and to analyze the characteristics of dysphagia before and after surgery. MATERIALS AND METHODS: A total of 112 tongue cancer patients participated in this work. Videofluoroscopic swallowing studies were performed in all patients before and after surgery. A Penetration-Aspiration Scale score of 3 or greater was defined as an aspiration risk. Qualitative data were collected on a frame-by-frame basis from each videofluoroscopic swallowing study and analyzed. RESULTS: Smoking (58.14%, P < .01), tongue resection greater than 50% (38.71%, P < .05), and advanced tumor stage (49.18%, P < .01) were strong risk factors for aspiration. High incidences of inadequate tongue movement, delayed oral transit time, reduced hyoid bone elevation, poor aspiration or penetration, vallecula epiglottica, and residual material in the pyriform sinuses were evident after surgery (all P < .001). The Penetration-Aspiration Scale score was significantly higher after surgery than before surgery. The incidence of silent aspiration increased to 6.25% postoperatively. CONCLUSIONS: Smoking, larger tongue resection, and advanced tumor stage were strong risk factors for postoperative aspiration and dysphagia complications in tongue cancer patients. The aspiration rate was higher after surgery. Further studies should focus on the prevention and early treatment of dysphagia, especially postoperative aspiration, in tongue cancer patients. PMID- 27126393 TI - Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain. AB - BACKGROUND: Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE 5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation. METHODS: Ischemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed. RESULTS: Although sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- (ptgs2, CD32 and CD86) and M2-like (CD206, Arg-1 and Lgals3) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2(+) microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals. CONCLUSIONS: Our findings argue that anti inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery. PMID- 27126395 TI - Echocardiography: the transition from master of the craft to admiral of the fleet. PMID- 27126394 TI - Sexual activity and concerns in people with coronary heart disease from a population-based study. AB - OBJECTIVE: Sexual activity is a central component of intimate relationships, but sexual function may be impaired by coronary heart disease (CHD). There have been few representative population-based comparisons of sexual behaviour and concerns in people with and without CHD. We therefore investigated these issues in a large nationally representative sample of older people. METHODS: We analysed cross sectional data from 2979 men and 3711 women aged 50 and older from the English Longitudinal Study of Ageing. Sexual behaviour and concerns were assessed by validated self-completion questionnaire and analyses were weighted for non response. Covariates included age, partnerships status and comorbidities. RESULTS: There were 376 men and 279 women with CHD. Men with CHD were less likely to be sexually active (68.7% vs 80.0%, adjusted OR 0.62, 95% CI 0.47 to 0.81), thought less about sex (74.7% vs 81.9%, OR 0.72, CI 0.54 to 0.95), and reported more erectile difficulties (47.4% vs 38.1%, OR 1.46, CI 1.10 to 1.93) than men without CHD. Effects were more pronounced among those diagnosed within the past 4 years. Women diagnosed <4 years ago were also less likely to be sexually active (35.4% vs 55.6%, OR 0.44, CI 0.23 to 0.84). There were few differences in concerns about sexual activity. Cardiovascular medication showed weak associations with erectile dysfunction. CONCLUSIONS: There is an association between CHD and sexual activity, particularly among men, but the impact of CHD is limited. More effective advice after diagnosis might reverse the reduction in sexual activity, leading to improved quality of life. PMID- 27126397 TI - Gender differences in coronary heart disease. PMID- 27126396 TI - Cardiovascular risk stratification in familial hypercholesterolaemia. AB - Familial hypercholesterolaemia (FH) is a common autosomal-dominant disorder in most European countries. Patients with FH are characterised by a raised level of low-density lipoprotein cholesterol and a high risk of premature coronary heart disease (CHD). Currently there is no consensus regarding the clinical utility to predict future coronary events or testing for the presence of subclinical atherosclerotic disease in asymptomatic patients with FH. Family screening of patients with FH as recommended by the UK National Institute of Health and Care Excellence guideline would result in finding many young individuals with a diagnosis of FH who are clinically asymptomatic. The traditional CHD risk scores, that is, the Framingham score, are insufficient in risk prediction in this group of young individuals. In addition, a better understanding of the genetic aetiology of the FH phenotype and CHD risk in monogenic FH and polygenic hypercholesterolaemia is needed. Non-invasive imaging methods such as carotid intima-media thickness measurement might produce more reliable information in finding high-risk patients with FH. The potential market authorisation of novel therapeutic agents such as PCSK9 monoclonal inhibitors makes it essential to have a better screening programme to prioritise the candidates for treatment with the most severe form of FH and at higher risk of coronary events. The utility of new imaging techniques and new cardiovascular biomarkers remains to be determined in prospective trials. PMID- 27126398 TI - PSYCHOTHERAPY VERSUS PHARMACOTHERAPY FOR POSTTRAUMATIC STRESS DISORDER: SYSTEMIC REVIEW AND META-ANALYSES TO DETERMINE FIRST-LINE TREATMENTS. AB - BACKGROUND: Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking. METHODS: Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials >=8 weeks in duration using structured clinical interview-based outcome measures, active-control conditions (e.g. supportive psychotherapy), and intent-to-treat analysis were selected for analyses. Independent review, data abstraction, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow-up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta-analyses for medication versus control, medication pre /posttreatment, psychotherapy versus control, and psychotherapy pre /posttreatment. RESULTS: Effect sizes for trauma-focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant. CONCLUSIONS: Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed. PMID- 27126399 TI - Effect of Inflammation on Fibrosis Staging Measured by Quantitative Elasticity Parameters in Rats With Immune Hepatitis. AB - OBJECTIVES: To investigate the effect of inflammation on fibrosis staging measured by quantitative elasticity parameters in rats with immune hepatitis. METHODS: Fifty-two rats were injected with swine serum as a model group, whereas 8 rats were injected with saline as a control group. Rats were randomly subjected to real-time tissue elastography biweekly. Tissue dispersion quantitative analysis was performed to obtain 12 quantitative elasticity parameters: relative mean value, standard deviation, blue area percentage, complexity, kurtosis, skewness, contrast, entropy, inverse difference moment, angular second moment, correlation, and liver fibrosis index. Subsequently, rats were euthanized, and liver specimens were taken for pathologic examination. The Kruskal-Wallis test was used for comparisons among groups. Spearman rank correlation analysis was used for correlation analysis. Receiver operating characteristic curves were used to optimize cutoff values and evaluate the diagnostic performance of the liver fibrosis index. RESULTS: Except for complexity, kurtosis, and correlation, the other 9 parameters had statistical differences (P < .05), and among these 9 parameters, the liver fibrosis index had the strongest correlation with fibrosis staging (r = 0.809; P < .05). Except for kurtosis and correlation, the other 10 parameters had statistical differences (P < .05), and among these 10 parameters, the liver fibrosis index had the highest correlation with inflammation grading (r= 0.766; P< .05). The fibrosis index cutoff values were 2.35 for stage S1 or higher (area under the curve [AUC], 0.940; sensitivity, 97.1%; specificity, 73.3%), 2.99 for stage S2 or higher (AUC, 0.865; sensitivity, 78.6%; specificity, 81.0%), 3.48 for stage S3 or higher (AUC, 0.924; sensitivity, 94.4%; specificity, 87.1%), and 4.05 for stage S4 (AUC, 0.933; sensitivity, 87.5%; specificity, 95.1%). CONCLUSIONS: Real-time elastography could be used to noninvasively evaluate fibrosis staging in rats with immune hepatitis. However, inflammation had an effect on the accuracy of this technique. PMID- 27126400 TI - Hysterosalpingo-Contrast Sonography With a Saline-Air Device Is Equivalent to Hysterosalpingography Only in the Presence of Tubal Patency. AB - OBJECTIVES: To compare hysterosalpingo-contrast sonography with a saline-air device to hysterosalpingography for evaluating tubal patency. METHODS: Eighty women undergoing infertility evaluations were recruited for this prospective cohort study. All patients underwent both office-based hysterosalpingo-contrast sonography with a saline-air device and hysterosalpingography as the reference standard, and the fallopian tubes were individually assessed for tubal patency in each procedure. The Cohen kappa coefficient was used to assess agreement between each procedure, and the Student t test and chi(2) test were used to compare differences in time, pain, and procedural preference. RESULTS: In total, 75 patients with 148 fallopian tubes were evaluated. Tubal patency on hysterosalpingo-contrast sonography with the saline-air device was noted in 85.8% (n = 127) of tubes compared to 92.5% (n = 137) on hysterosalpingography, with a positive predictive value of 95.2%. Tubal occlusion was noted in 21 tubes (14.2%) on hysterosalpingo-contrast sonography compared to 11 (7.4%) on hysterosalpingography, with a negative predictive value of 23.8% (24 of 28). Overall, hysterosalpingo-contrast sonography agreed with hysterosalpingography in 126 of 148 fallopian tubes (85.1%; kappa = 0.47; P < .001). The procedural time and pain scores were significantly greater for hysterosalpingo-contrast sonography compared to hysterosalpingography. CONCLUSIONS: There was a significant degree of agreement between hysterosalpingo-contrast sonography with a saline-air device and hysterosalpingography when the fallopian tube was patent but not when it was occluded. In the absence of patency, further evaluations with hysterosalpingography may be indicated to avoid false-positive results. Although the procedure time and degree of pain appear to be greater, avoidance of radiation exposure by using hysterosalpingo-contrast sonography with a saline-air device may outweigh the drawbacks. PMID- 27126401 TI - Anomalous Pulmonary Venous Return: Insights Into Prenatal Detection. AB - OBJECTIVES: To review all cases of total anomalous pulmonary venous return (TAPVR) or partial anomalous pulmonary venous return (PAPVR) identified prenatally or postnatally at a single institution and to identify factors that may lead to a correct or missed diagnosis in both high- and low-risk fetuses on screening examinations. METHODS: Fetal images from 16 cases of prenatally or postnatally diagnosed T/PAPVR were retrospectively reviewed to analyze factors that influenced interpretations and diagnoses. RESULTS: Sixteen diagnoses of T/PAPVR were made, with a final number of 10 confirmed cases, 1 of which was PAPVR. Ten fetuses with a presumptive diagnosis of T/PAPVR before delivery were at an average gestational age of 24.7 weeks, with 5 cases diagnosed postnatally. None of the diagnoses of isolated TAPVR were made during a screening examination. Twelve of the pregnancies were complicated by complex cardiac defects, including 6 with heterotaxy syndromes. Of the 5 abnormal cases identified in the postpartum period, 3 had isolated TAPVR. In the 3 patients with isolated defects, prenatal echocardiography was not performed; the anatomy scan interpretations were confounded by multiple factors. In retrospect, there was no obvious sonographic evidence of TAPVR in these patients; however, color flow Doppler imaging of the pulmonary veins was not performed on any of them. CONCLUSIONS: Although fetal echocardiography has improved the overall detection of TAPVR or PAPVR, this abnormality continues to elude prenatal diagnosis during screening in both low- and high-risk patients. We hypothesize that the use of color flow Doppler imaging in the 4-chamber view may assist in diagnosing TAPVR in screening low-risk patients, especially in those with difficult scans. PMID- 27126402 TI - Social isolation and brain development in the ant Camponotus floridanus. AB - Social interactions play a key role in the healthy development of social animals and are most pronounced in species with complex social networks. When developing offspring do not receive proper social interaction, they show developmental impairments. This effect is well documented in mammalian species but controversial in social insects. It has been hypothesized that the enlargement of the mushroom bodies, responsible for learning and memory, observed in social insects is needed for maintaining the large social networks and/or task allocation. This study examines the impact of social isolation on the development of mushroom bodies of the ant Camponotus floridanus. Ants raised in isolation were shown to exhibit impairment in the growth of the mushroom bodies as well as behavioral differences when compared to ants raised in social groups. These results indicate that social interaction is necessary for the proper development of C. floridanus mushroom bodies. PMID- 27126404 TI - Trifluoroacetic acid catalyzed highly regioselective bromocyclization of styrene type carboxylic acid. AB - A trifluoroacetic acid catalyzed highly 6-endo regioselective bromocyclization of styrene-type carboxylic acid has been developed. The resulting 3,4 dihydroisocoumarines are valuable building blocks in organic synthesis. PMID- 27126403 TI - A glutathione S-transferase gene associated with antioxidant properties isolated from Apis cerana cerana. AB - Glutathione S-transferases (GSTs) are an important family of multifunctional enzymes in aerobic organisms. They play a crucial role in the detoxification of exogenous compounds, especially insecticides, and protection against oxidative stress. Most previous studies of GSTs in insects have largely focused on their role in insecticide resistance. Here, we isolated a theta class GST gene designated AccGSTT1 from Apis cerana cerana and aimed to explore its antioxidant and antibacterial attributes. Analyses of homology and phylogenetic relationships suggested that the predicted amino acid sequence of AccGSTT1 shares a high level of identity with the other hymenopteran GSTs and that it was conserved during evolution. Quantitative real-time PCR showed that AccGSTT1 is most highly expressed in adult stages and that the expression profile of this gene is significantly altered in response to various abiotic stresses. These results were confirmed using western blot analysis. Additionally, a disc diffusion assay showed that a recombinant AccGSTT1 protein may be roughly capable of inhibiting bacterial growth and that it reduces the resistance of Escherichia coli cells to multiple adverse stresses. Taken together, these data indicate that AccGSTT1 may play an important role in antioxidant processes under adverse stress conditions. PMID- 27126405 TI - Pan-American marine coastal distribution of the acanthocephalan Profilicollis altmani based on morphometric and phylogenetic analyses of cystacanths from the mole crab Emerita brasiliensis. AB - Thorny-headed acanthocephalan worms of the genus Profilicollis are widely distributed in the oceans of the world and present complex life cycles with intermediate and definitive hosts. The genus is still poorly known, with an unstable taxonomy and, for most species, incompletely characterized geographical distributions. In this study, based on molecular and morphological evidence, we report that the species Profilicollis altmani is also distributed along the South American Atlantic coast, using the mole crab Emerita brasiliensis as an intermediate host. As such, our record shows that P. altmani has a Pan-American distribution where five species of Emerita are utilized as intermediate hosts. PMID- 27126406 TI - Perceived clinician-patient communication in the emergency department and subsequent post-traumatic stress symptoms in patients evaluated for acute coronary syndrome. AB - OBJECTIVES: Evaluation for a potentially life-threatening cardiac event in the emergency department (ED) is a stressful experience that can result in symptoms of post-traumatic stress disorder, which are associated with increased risk of morbidity and mortality in patients. No study has tested whether good clinician patient communication in the ED is associated with better psychological outcomes in these individuals and whether it can mitigate other risk factors for post traumatic stress symptoms (PSS) such as perception of life threat and vulnerability in the ED. METHODS: Data were analysed from 474 participants in the Reactions to Acute Care and Hospitalization (REACH) study, an observational cohort study of ED predictors of medical and psychological outcomes after evaluation for suspected acute coronary syndrome. Participants were recruited from November 2013 to January 2015 at a single-site academic medical centre (New York-Presbyterian-Columbia University Medical Center). Participants reported threat perceptions in the ED and provided information on their perceptions of clinician-patient communication using the Interpersonal Process of Care Survey. PSS were assessed using the Acute Stress Disorder Scale during follow-up. RESULTS: 474 subjects were enrolled in the study. Median length of follow-up was 3 days after ED presentation, range 0-30 days, 80% within 8 days. Perceptions of good clinician-patient communication in the ED were associated with lower PSS, whereas increased threat perception was associated with higher PSS. A significant interaction between clinician-patient communication and threat perception on PSS suggested that patients with higher threat perception benefited most from good clinician-patient communication. CONCLUSION: Our study found an association between good clinician-patient communication in the ED during evaluation of potentially life-threatening cardiac events and decreased subsequent post traumatic stress reactions. This association is particularly marked for patients who perceive the greatest degree of life threat and vulnerability during evaluation. PMID- 27126407 TI - Boston Keratoprosthesis Outcomes in Severe Ocular Chemical Burns in Southern China: A Retrospective Study. AB - INTRODUCTION: The objective of this study was to report clinical outcomes (functional and anatomic) of Boston keratoprosthesis (KPro) after severe chemical burns in Southern China. METHODS: Nineteen patients (19 eyes) that sustained severe chemical injuries in Southern China were enrolled in this retrospective study in our hospital between May 2009 and June 2015. KPro implantation in these patients was performed by a single experienced surgeon (Jiaqi Chen). The parameters evaluated in this study included diagnosis, comorbidity, preoperative and postoperative visual acuity (VA), complications, KPro retention, histological and immunohistochemical results of retroprosthetic membrane (RPM) and mucous membrane over the optic cylinder. RESULTS: The mean age of the patients was 42.7 +/- 11.3 years (range 29-62 years). All patients were male. Of the 19 included eyes, nine had acid burns, and 10 had alkali burns. Ten patients had previously undergone failed penetrating keratoplasty. The mean follow-up time was 41.3 +/- 5.5 months (range 36-56 months). Preoperatively, the VA of the patients ranged from hand movement to light perception. Postoperatively, 17 patients (89.4%) achieved at least 20/200 once, and 7 patients (36.8%) achieved at least 20/200 and maintained this acuity until the last follow-up. The initial KPro was retained in 14 (73.6%) eyes and successfully replaced in one eye. Postoperative complications included RPM in 10 eyes, glaucoma in 6 eyes, retinal detachment in 2 eyes, corneal melting in 5 eyes, ischemic optic neuropathy in 1 eye, and overgrowth of the mucous membrane over the optical cylinder in 2 eyes. The histological and immunohistochemical results of the RPM showed granulomatous disorders and mucous membrane over the optic cylinder of conjunctival origin. CONCLUSION: KPro surgery can restore useful vision in patients suffering from severe chemical burns. However, postoperative VA declined with the development of complications, and ocular surface disorders caused by the chemical burns were associated with a greater incidence of KPro retention failure. The retention rate was comparable in patients using ipsilateral autologous corneal tissue with allograft corneal tissue. FUNDING: Science and Technology Foundation of Guangdong Province of China, Grant Number 2014A020212714. PMID- 27126408 TI - Low-level laser therapy in 3D cell culture model using gingival fibroblasts. AB - Besides extensive data about the effects of low-level laser therapy (LLLT) on different cell types, so far, these results were obtained from monolayer cell culture models, which have limitations in terms of cell morphology and phenotype expression. Therefore, for better in vitro evaluation of the effects of LLLT, this study was performed with a 3D cell culture model, where gingival fibroblasts were seeded in collagen matrix. Cells isolated from a healthy patient were seeded in wells of 24-well plates with culture medium (DMEM) supplemented with 10 % fetal bovine serum and collagen type I solution. After 5 days, a serum-free DMEM was added to the matrices with cells that were subjected or not to three consecutive irradiations of LLLT by means of the LaserTABLE diode device (780 nm, 25 mW) at 0.5, 1.5, and 3 J/cm(2). Twenty-four hours after the last irradiation, cell viability and morphology as well as gene expression of growth factors were assessed. Histological evaluation of matrices demonstrated uniform distribution and morphology of gingival fibroblasts within the collagen matrix. LLLT at 3 J/cm(2) increased gingival fibroblast viability. Enhanced gene expression of hCOL I and hEGF was observed for 0.5 J/cm(2), while no significant changes were detected for the other irradiation densities tested. In conclusion, LLLT promoted biostimulation of gingival fibroblasts seeded in a 3D cell culture model, demonstrating that this model can be applied for phototherapy studies and that LLLT could penetrate the collagen matrix to increase cell functions related to tissue repair. PMID- 27126409 TI - Changes of oxygen status of hair cells for breast cancer presence. AB - The results of differences of wool oxygen status of healthy and cancer carrier mice with spontaneous cancer tumor are represented herein. The investigation was carried out by electronic microscopy and laser-flash photolysis. In the work, two types of breast tumors were researched. Small tumor (nearly 0.5 / 1 cm) was detected by palpation and was well encapsulated. Large tumor was operated when tumor had been disintegrated. It is shown that wool of healthy mouse has dense structure; external layer with large scales is pronounced. At the time, wool of mice with cancer tumor is thinner; external and internal layers are destroyed. Length of scales is shorter. There is difference even when tumor diameter is small. Oxygen concentration increases for cancer present, and it is related to reactive oxygen species rising within external layer. Reactive oxygen species have most distribution in general oxygen concentration in external cell layer. At the time, its increase in internal layer is insignificant. The obtained results can be used to improve optical techniques of biomedical diagnostics of cancer diseases. PMID- 27126410 TI - CO2 laser surface treatment of failed dental implants for re-implantation: an animal study. AB - The aim of the present study was to evaluate the success rate of failed implants re-implanted after surface treatment with CO2 laser. Despite the widespread use of dental implants, there are many incidents of failures. It is believed that lasers can be applied to decontaminate the implant surface without damaging the implant. Ten dental implants that had failed for various reasons other than fracture or surface abrasion were subjected to CO2 laser surface treatment and randomly placed in the maxillae of dogs. Three failed implants were also placed as the negative controls after irrigation with saline solution without laser surface treatment. The stability of the implants was evaluated by the use of the Periotest values (PTVs) on the first day after surgery and at 1, 3, and 6 months post-operatively. The mean PTVs of treated implants increased at the first month interval, indicating a decrease in implant stability due to inflammation followed by healing of the tissue. At 3 and 6 months, the mean PTVs decreased compared to the 1-month interval (P < 0.05), indicating improved implant stability. The mean PTVs increased in the negative control group compared to baseline (P < 0.05). Independent t-test showed that the mean PTVs of treated implants were significantly lower than control group at 3 and 6 months after implant placement (P < 0.05). Based on the PTVs, re-implantation of failed implants in Jack Russell Terrier dogs after CO2 laser surface debridement is associated with a high success rate in terms of implant stability. PMID- 27126411 TI - Efficacy of 694-nm fractional Q-switched ruby laser (QSRL) combined with sonophoresis on levorotatory vitamin C for treatment of melasma in Chinese patients. AB - Melasma is a common acquired and distressing pigmentary disorder presenting to dermatology clinics. It is notably difficult to cure and has a tendency to relapse. The efficacy of classical Q-switched laser in treatment of melasma remains controversial. This study aims to investigate the efficacy and safety of 694-nm fractional QSRL combined with sonophoresis on levorotatory vitamin C for the treatment of melasma patients. Twenty-six patients with melasma were enrolled. Each patient received four to six fractional QSRL treatments at pulse energies of 2.5 to 4 J/cm(2) combined with sonophoresis on levorotatory vitamin C at 2-week intervals. The severity and the area of melasma were assessed by two investigators using the melasma area and severity index (MASI). Side effects were documented. Mean MASI score decreased from 15.51 +/- 3.00 before treatment to 10.02 +/- 4.39 3 months after the final treatment (P < 0.01). Side effects were few and transient. High-density coverage fractional QSRL combined with sonophoresis on levorotatory vitamin C is safe and effective for the treatment of melasma in Chinese patients. PMID- 27126413 TI - Comments on "light-emitting diode therapy (ledt) before matches prevents increase in creatine kinase with a light dose response in volleyball players". PMID- 27126412 TI - Photodynamic inactivation of a multispecies biofilm using curcumin and LED light. AB - This study evaluated the potential of curcumin-mediated antimicrobial photodynamic inactivation (API) on multispecies biofilms of Candida albicans, Candida glabrata, and Streptococcus mutans of different ages. Acrylic samples (n = 480) were made with standardized rough surfaces and incubated with bacteria and yeast for 24 or 48 h. API was performed with curcumin (80, 100, 120 MUM) and LED light. Additional acrylic samples were treated with curcumin or LED light only. Positive control samples received neither light nor curcumin. After API, colony counts were quantified (CFU/mL), cell metabolism was determined by means of XTT assay, and the total biofilm biomass was evaluated using Crystal Violet (CV) staining assay and images were obtained by confocal laser scanning microscopy (CLSM). The data were analyzed by nonparametric two-way ANOVA and post hoc Tukey tests (alpha < 0.05). For 24-h biofilm, API resulted in statistically significant difference (rho < 0.001) of viability of C. albicans compared with control (P-L-) for all Cur concentrations. For 48-h biofilm, API resulted in statistically significant difference (rho < 0.001) compared with control only when Cur at 120 MUM was used. API promoted statistically significant difference (rho <= 0.001) in the viability of S. mutans and C. glabrata for all Cur concentrations in the two biofilm ages. In addition, API produced a statistically significant difference (rho < 0.001) of metabolic activity and of total biomass (rho < 0.001) of multispecies biofilms compared with control for all Cur concentrations. It can be concluded that both 24- and 48-h biofilms were susceptible to API mediated by Cur; however, 24-h biofilm was more sensitive than the 48-h biofilm. PMID- 27126415 TI - Historical note on the untimely passing of George Ralph Mines. PMID- 27126414 TI - George Ralph Mines (1886-1914): the dawn of cardiac nonlinear dynamics. PMID- 27126416 TI - An 'alternans' way to quantify arrhythmogenic substrates. PMID- 27126417 TI - Erratum to: AIDS Panic in the Twenty-First Century: The Tenuous Legal Status of HIV-Positive Persons in America. PMID- 27126418 TI - Mastery and observance : These right words for control and compliance. PMID- 27126419 TI - Hypogammaglobulinemia associated with nodular lymphoid hyperplasia of the intestine and pernicious anaemia. AB - BACKGROUND: Nodular lymphoid hyperplasia of the gastrointestinal tract, recurrent acute pulmonary infections and autoimmune disease are well-recognized complications of common variable immunodeficiency. AIM: We aimed to focus on clinical presentation and differential diagnosis of diffuse nodular lymphoid and hyperplasia of the gastrointestinal tract coexisting with hypogammaglobulinemia. CASE-REPORT: We report the case of nodular lymphoid hyperplasia associated with pernicious anaemia in a young man with hypogammaglobulinemia and a long history of pulmonary infections. CONCLUSION: The considerable point was a mismatch primary clinical diagnosis of familial adenomatous polyposis, due to prominent polyplike endoscopic appearance of the lesions throughout the digestive tract. PMID- 27126420 TI - A spindle cell myoepithelioma of parotid gland : a case report. AB - BACKGROUND: Myoepthelioma is a rare salivary gland tumor which is usually located in parotid gland and in minor salivary glands. CASE REPORT: We report a case of myoepithelioma arising in an accessory paritid gland in a 47-yearold woman who presented with a slowly expanding subcutaneous nodule on the left cheek, that was within the parotid gland at surgical resection . This tumor was composed of spindle cells. Immunophenotypical characterization demonstrated its myoepithelial nature. CONCLUSION: In the subcutaneous tissue, this unusual neoplasm may be confused with soft tissue tumors showing spindle cell features. PMID- 27126421 TI - Predictors of successful endoscopic colonic polypectomy. AB - BACKGROUND: Endoscopic polypectomy is the technique of choice for resection of colorectal polyps and has a major interest in the prevention of colorectal cancer. The aim of this study was to evaluate the technique, results and tolerance of colonic polypectomy. METHODS: We conducted a retrospective study including 200 consecutive patients with colorectal polyps and who underwent therapeutic endoscopic polypectomy, performed at the endoscopy unit of the Military Hospital in Tunis, between december 2008 and december 2012. RESULTS: Hundred and forty men and 60 women were included. The average age was 58.5 +/- 14.5 years. The polyp was unique in more than half of cases. The most frequent location was the sigmoid colon (30.5%). Approximately, 1/4 of the polyps was larger than 10 mm. According to the Paris endoscopic classification, 78% of polyps were sessile (Is). Seventy-two percent of polyps were adenomas. Twentyfive per cent of them contained a villous component, 40 % were advanced adenomas and 3% malignant adenomas. Regarding polypectomy, 232 polyps (64%) were treated by the cold forceps, 68 polyps (18.5 %) by the diathermic snare and 63 (17.5 %) by a mucosal resection. Thirty-one percent of polypectomy were fragmented. The evaluation of the efficacy of treatment among adenomas and potentially malignant tumors, had identified 36% of treatment failure. The common independent predictive factor of fragmented resection and treatment failure were the size >= 10 mm (p <10-3). Among a total of 363 polypectomies, 23 (6.3%) were complicated, by 11 procedural bleeding, 11 micro-perforations and 1 delayed hemorrhage. The common independent predictive factor of these complications was the size >= 10 mm (p <10-3). During following, there were 12 residual polyps (6%), 36 new polyps (18%) and 6 colorectal cancers (3%). The only independent predictive factor of an unfavorable course was the multiplicity of polyps. The colorectal polyps-free survival was 90.2% at 12 months and 88.4% at 24 months. CONCLUSION: The evaluation of colorectal polypectomy in our series had confirmed the effectiveness and the low morbidity of this practice. The polyp size was the only independent predictive factor of both treatment failure and complications. PMID- 27126422 TI - Orbital infections: review of 28 cases. AB - BACKGROUND: Orbital infections (OI) are a serious disorder that may results in visual and systemic morbidity. AIM: To study epidemiologic data and outcome of OI in a tertiary eye care center. METHODS: Retrospective study of 28 patients (28 eyes) with OI. All patients underwent detailed ophthalmic examination, otolaryngology examination, and cranio-orbital computed tomography scan. All patients received parenteral probabilistic antibiotic treatment then adapted depending on the sensitivity of antibiogram and clinical evolution, associated or not to corticosteroid treatment. The mean follow-up was 14 months. RESULTS: The mean age of our patients was 35.9 years. Fifteen patients (54%) were male. Of 28 cases, retroseptal cellulitis was the most common, noted in 67.8% of cases. subperiosteal or orbital abscess was recorded in 28.6% of the cases. Sinusitis was the most common etiology, found in 39.3% of cases. Treatment was based on empirical broad spectrum systemic antibiotics in all cases. Surgical management was performed in 39.3% of cases. Bacteriological samples were obtained for 28.5% of patients, with Staphylococcus aureus the most frequently isolated pathogen (5 cases; 62.5%). The evolution was favorable with complete resolution without sequelae in 92.8% of the cases and improvement of visual acuity in 82% of cases. Causes of poor visual outcome were corneal perforation, cataract and retinal detachment. CONCLUSIONS: In our series, OI affects children and young adults. Their prognosis is generally favorable provided rapid and appropriate management. PMID- 27126423 TI - Causes of vitamin B12 deficiency. AB - BACKGROUND: B12 Vitamin deficiency is common in adults (20% of general population of industrialized populations), especially in elderly patients (30-40%). The etiologies of Vitamin B12 deficiency have been dominated by the cobalamin syndrome nutrient and the Biermer disease, rarely by the intake or nutritional deficiency and bad absorptions. STUDY OBJECTIVE: Establish an etiology of vitamin B12 in a Tunisian population Methods: In a prospective study involving 100 patients with macrocytic anemia, a comprehensive assessment has been carried out of: B12 vitamin and folate intake, homocysteine, immunological assessment (antibodies, intrinsic anti-factor and anti-gastric parietal cells), an endoscopic exploration, and a dietary nutritional survey. RESULTS: The mean age of patients was 53.6 +/- 17,6 years (13 - 88 years), the gender ratio (female/male) is 1.22. The clinical symptomatology shows a functional anemia syndrome in 89% of cases, a digestive syndrome in 88% of cases, and neurological disorders in 67% of cases. The intake of B12 vitamin was reduced (<180 pg/ml) in 99 patients, associated with a hyperhomocysteinemia in 81.63% of cases.The intrinsic anti-factor antibodies were positives in 32 patients, and the antibody anti-gastric parietal cells in 85 patients. Gastric biopsy was performed in 54 patients, showing a chronic atrophic gastritis of fundic localization in 44 patients, antral in 5 patients and pan- gastric in 3 patients. The diagnosis of Biermer anemia was held in 75% of patients, that of FCS in 16% of patients, and a lack of intake in 8% of patients. The etiology was undetermined in 1% of cases. CONCLUSION: Vitamin B12 deficiency is common in the general population, its causes and origins are multiple, we list them in order of occurrence: Biermer disease, the FCS, and the intake deficiency in our population. PMID- 27126424 TI - Biliary atresia: experience of a nord africain center. AB - BACKGROUND: Biliary atresia (BA) is a progressive inflammatory destructive process of the bile ducts occurring in about one of every 20.000 live births. If left untreated, biliary atresia can lead to liver failure. AIM: This is the first study on biliary atresia from Africa. The Aim of our study is to describe the clinical and prognostic aspects of biliary atresia in a Tunisian medical centre, where integrated medico-surgical management of children with liver diseases is lacking and liver transplant is not available. METHODS: Patients who were diagnosed with BA and underwent portoenterostomy between January 1985 and December 2010 at a tertiary regional hospital in Tunisia were included in this analysis. RESULTS: 74 patients were diagnosed with BA. The patients included 34 boys (45.9%) and 40 girls (54.1%). All patients received Kasai operation as the primary treatment and the median patient age at Kasai operation was 60 days (range 3-180 days). The median followup time for the patients was 72 months (range 2 months-23 years 6 months). Out of the 74 patients who received Kasai operation, 49 patients are being followed regularly in the outpatient clinic. Eight patients died immediately after Kasai operation by either hepatocellular decompensation or by cholangitis. Seventeen patients were lost to follow-up. Fifteen out of 49 patients who underwent portoenterostomy for BA are alive at median six years following Kasai intervention. Ten patients out of the 49 who are being followed regularly were Jaundice free. Two patients had portal hypertension. All these patients had survived. Five patients survived with signs of liver failure in four cases. Two of them had received a liver transplant abroad. Survival with the native liver was 6.7 % at 5 years with Kasai operation alone. CONCLUSION: BA still has a very severe prognosis in Tunisia Reducing the age at Kasai operation remains the most important target to reduce the need for LT in infancy and childhood. Centralised care will help to build surgical expertise. PMID- 27126425 TI - Evolution of the prevalence of intestinal parasitosis in the region of tunis from 1996 at 2012. AB - BACKGROUND: The prevalence of intestinal parasitosis is very different according to countries. Therefore, it is always interesting to update the data in Tunisia to better direct control measures. AIM: The objectives of this survey were to estimate the prevalence of intestinal parasitosis in the region of Tunis, to study their evolution and to establish various combinations of intestinal protozoa. METHODS: This is a retrospective study carried out over a period of 17 years from 1996 at 2012 and which involved 20033 individuals. Each subject had one or more stool examination which included a direct microscopic examination and a concentration by modified Ritchie technique. RESULTS: The prevalence of intestinal parasitosis was 12.55%. Entamoeba histolytica/dispar and Giardia intestinalis accounted respectively a prevalence of 0.51% and 1.48%. Hymenolepis nana was the most predominant helminth with a prevalence rate of 0.53%, followed by Enterobius vermicularis (0.21%). Two cases of Hookworms and seven cases of Strongyloides stercoralis were diagnosed. Polyparasitism concerned 16.59% of infected individuals. Significant combinations occured mainly for amoeba in particular Entamoeba histolytica/dispar and Entamoeba coli (r=0.232). CONCLUSION: Our study confirms the decrease of the prevalence of giardiasis and amebiasis, whereas helminthiases with direct transmission remain frequent. PMID- 27126426 TI - Anthropometric profile of children and adolescents from diabetic pregnancies. AB - BACKGROUND: Exposure in utero to maternal diabetes is a risk factor for obesity and type 2 diabetes. It may contribute to the current epidemic outbreak of these diseases. AIM: to evaluate the impact of the exposure to maternal diabetes on the anthropometric profile of the offspring. METHODS: This cross-sectional study was conducted in the department "A" of the National Institute of Nutrition. It involved 120 children and adolescents who were from 5 to 19 years old and recruited between October 2008 and November 2009. They were divided into two groups : * A first group of 80 children from diabetic mothers ; * A second control group of 40 children from non-diabetic pregnancies. They have had a clinical examination. Data about diabetic pregnancies were collected from the mothers'medical records. RESULTS: body mass index and waist circumference of children from both groups were comparable. In both groups, two thirds of children had a normal weight (62.5 % in the first group versus 65% in the control group). Obesity is more common in children exposed to maternal hyperglycemia (31.3% versus 25% in the control group), but the difference is not statistically significant. The majority of obese children (88%) are those from diabetic mothers with type 2 or gestational diabetes. CONCLUSION: our results underline the need for early screening for gestational diabetes and an optimal management of diabetic pregnancy to reduce the metabolic risk in the offspring. PMID- 27126427 TI - Benzylthiouracil induced ANCA associated glomerulonephritis in patients with graves' disease. AB - BACKGROUND: Renal complications in Graves' disease are rare and may be related either to the disease itself or secondary to antithyroid drugs. AIM: We report 6 cases of renal damage in patients with Graves' disease treated with Benzylthiouracil collected over a period of 14 years. METHODS: There were 6 women with a mean age of 37.86 +/- 14.25 years. All patients developed renal vasculitis associated with ANCA. The signs were dominated by renal proteinuria and renal failure associated with hematuria in all cases. The lung involvement was the most common extrarenal manifestation occurred in 4 patients (alveolar hemorrhage in 2 cases, lymphocytic alveolitis in 1 case and pleurisy in 1 case). The benzylthiouracil was discontinued in 3 patients still under treatment. Corticosteroid therapy was used alone or in combination with cyclophosphamide in all cases. Plasmapheresis sessions were made during the alveolar hemorrhage. A complete remission was obtained in one case and incomplete remission in 2 cases. The other 3 patients required chronic hemodialysis. One patient died of sepsis. CONCLUSION: The possibility of renal impairment in antithyroid drugs treated Graves' disease requires monitoring to detect urinary abnormalities in order to early initiate therapy and improve patient's outcome. PMID- 27126428 TI - Failure of in vitro fertilization: prognosis criteriae. AB - BACKGROUND: age, obesity and increased FSH serum level in women are prognosis criteriae associated with decreased fertility and adverse Assisted Reproductive Technologies (ART) outcomes. OBJECTIVE: To assess the effect of age, FSH and BMI on pregnancy rate in ICSI. METHODS: A retrospective and comparative study of 500 women who underwent ICSI cycle during the study period from January 2004 to December 2005. Age, FSH and BMI were compared in two groups of patients: Those achieving a pregnancy: The "pregnancy+" group and those failing to have a pregnancy: The "pregnancy-"group. For each of previous parameters ROC curve and logistic regression study were performed. RESULTS: age was significantly lower in "pregnancy+" group (32,4+/-3,9 years vs 33,7+/-4,8 ans ; p=0,005). Analysis of ROC curve and logistic regression study show that for age, the most discriminative cut-off for predicting pregnancy is 38 years (Se=7,5%, Sp=75,6%) (AUC=0,572; p=0,02) (OR=2,1 ; LR+=6,7 ;IC[1 ;1,4] ; p0,009). FSH was significantly lower in "pregnancy+" group (5,5+/-1,8UI /L vs 6,2+/-3UI/L, p=0,003). Analysis of ROC curve and logistic regression study show that for FSH, the most discriminative cut-off for predicting pregnancy is 9UI/L (Se=3,7%, Sp=85.2%) (AUC=0,539 ; p=0,03) (OR=3,6; IC[1,4 ;9,3]; LR+ =10,1; p=0,003). BMI was also significantly lower in "pregnancy+" group (24,7+/- 3,6 kgm-2 vs 27,1+/ 4,5 kgm-2 ; p<10-3). The most discriminative cut-off for predicting pregnancy is 25,4 kgm- 2 (Se=31,7%, Sp=33,3%) (AUC=0,663 ; p<10-3) (OR=4; IC[2,1 ;7,7]; LR+ =19,38; p<10-3). CONCLUSION: age, FSH and BMI affect markedly the prognosis of ICSI. We found significantly lower Pregnancy rates in older women (> 38 years), in women with elevated FSH (> 9UI/L) or elevated BMI (> 25,4 kgm-2). Our results can be used when counseling and before including patients in an IVF program, to give them probability of success and weight loss required to optimize chances of pregnancy. PMID- 27126429 TI - Risk of mishaps during intrahospital transport of critically ill patients. AB - BACKGROUND: Mishaps are common during transport and may have major impacts on patients. AIMS: The main objectives of our study are: first to determine the incidence of complications during intra hospital transports (IHT) of critically ill patients, and second, to determine their risk factors. METHODS: All intra hospital transports for diagnostic and therapeutic purposes of patients consecutively admitted in an 18-bed medical surgical intensive care unit in an university hospital, have been studied prospectively during a period of six months (September 1st 2012 to February 28th 2013). RESULTS: Of 184 transports observed (164 patients), 85 (46.2%) were associated with mishaps. Eighty two mishaps were patient-related (44.5%).Oxygen desaturation (30 cases), agitation (24 cases) and hemodynamic instability (15 cases) were predominantly. One case of cardiac arrest and 3 cases of accidental extubation were occurred during IHT. Seventy three systems-based mishaps were noted (39.6%). Emergency transports, mechanical ventilation and positive end-expiratory pressure (PEEP) >= 6 cmH2O were independent risk factors for a higher rate of mishaps. In our study, complications did not statistically increase ventilator-associated pneumonia. CONCLUSION: This study confirms that IHT of critically-ill patients still involves considerable risks and mishaps incidence remains high. PMID- 27126430 TI - Evaluation of the anemic condition of type 2 diabetes cases of the city of Lubumbashi. AB - BACKGROUND: Many non- hormonal abnormalities can be observed in type 2 diabetes, including hematological disturbances and especially anemia. AIM: Determine biological characteristics of anemia in type 2 diabetes. METHODS: This is a case control study conducted from June to August 2014 in Lubumbashi (Democratic Republic of Congo) where assays of serum hemoglobin (Hb) , measuring the mean corpuscular volume (MCV ) and the calculation of the rate hematocrit ( Hct ) were done in 30 people with type 2 diabetes (group I ) and in 30 other considered healthy with a normal rate of glucose ( group II). The results obtained were compared in the two groups and the level of significance was set at p <0.05. RESULTS: Seventeen patients with diabetes (57 %) had anemia, the mean age of patients was 55 +/- 8.1 years for men and 48 +/- 4.1 years in women. Hypo hemoglobin was found in 53 % of cases in male diabetics , reduced MCV in 47 % of cases and a filtration rate decrease glomerular in 33 % of cases. In the group of female diabetic patients, 60% of cases showed a hypo hemoglobin , MCV and decreased in 33 % of cases and a filtration rate decrease glomerular in 20 % of cases. In contrast, in the control groups of both sexes, the parameters studied rates remained in the standard. CONCLUSION: Anemia is often found in diabetic patients. Its etiology appears to be dominated by the presence of diabetic nephropathy, in which the kidneys are affected by hyperglycemia and erythropoietin is affected and not known to produce red blood cells. These anemias rarely require a blood transfusion and well conducted etiological treatment allows the correction of the anemia. PMID- 27126431 TI - A study of the relationship between eating disorders, stress level and selfesteem among medicine students. AB - BACKGROUND: Stress of the higher studies leads to various disorders, especially eating ones. Such disorders, once present, may influence body image and self esteem of young students. AIM: to assess the prevalence of eating disorders among a group of Medicine students and to study its links with stress level and selfesteem. METHODS: It was a descriptive and analytic cross-sectional study, including 60 medicine students that were investigated during their revision for the final year exam. The participants had filled the perceived stress scale, the eating attitude test EAT-40 and The Rosenberg self-esteem scale. RESULTS: The eating disorders were found in 11% of the participants. Those had a low to a very low self-esteem in 40% of cases and a high perceived stress level in 36, 4% of cases. The eating disorders were significantlymore frequent among the female students (p=0, 03), the more sedentary (p=0,019), having a low to a very low self esteem (p=0,032) and a high perceived stress level (p=0,001). CONCLUSION: Our study shows that the prevalence of eating disorders is not negligible among medicine students. Their presence depends on certain personal aspects (physical activities, body image satisfaction) and contextual aspects (period of exams, stress). If existing, they would affect negatively the self-esteem, especially of the girls. These various results pave the way for a multidisciplinary approach to students particularly vulnerable to eating disorders. PMID- 27126432 TI - Transverse perineal approach in the treatment of "H" type recto vestibular fistula in children. PMID- 27126433 TI - Follicular thyroid carcinoma in patient followed for Graves' disease. An exceptional eventuality. PMID- 27126434 TI - Meningiomas of the lateral ventricle: a rare location. PMID- 27126435 TI - A colonic perforation revealing polyarteritis nodosa complicated by pulmonary aspergillosis. About a case. PMID- 27126437 TI - Severe hydatid pulmonary embolism: A case report. PMID- 27126436 TI - Verneuil's disease: a case report. PMID- 27126438 TI - Toxic heavy metals in sediments, seawater, and molluscs in the eastern and western coastal waters of Guangdong Province, South China. AB - Heavy metal concentrations and distribution were studied in sediments, seawater, and molluscs, and the possible heavy metal sources in the coastal waters of Guangdong Province, South China were discussed. The results showed that the concentrations of Cu, Pb, Zn, and Cr in sediments in eastern coastal waters were generally higher than those in the western coastal waters. However, concentrations of most metals in seawater and molluscs in western waters were higher than in the eastern waters, which was tightly related to the local economics and urbanization development, especially, the different industrial structure in two regions. The main heavy metal sources were attributed to the industrial and agricultural effluent, domestic sewage, and even waste gas. Furthermore, heavy metal contamination assessment indicated that high contamination levels of Cd, Zn, and Pb occurred in sediments in local areas, especially in the bays and harbors. The metal accumulation levels by molluscs ranked following the order of Cd > Cu > As > Zn > Pb > Cr, and the ecological risks introduced by heavy metals in different areas were in the order of Zhanjiang > Yangmao > Shantou > Shanhui. PMID- 27126439 TI - Persistence of fipronil residues in Eucalyptus seedlings and its concentration in the insecticide solution after treatment in the nursery. AB - Eucalyptus seedlings are normally protected from underground termites (Isoptera: Termitidae) by immersing them in insecticide solutions. Fipronil (phenylpyrazole) is the most frequently used product to protect seedlings in the field for up to 6 months after application. This is performed just prior to planting. However, the persistence of this product in seedlings that are treated and subjected to irrigation several days prior to planting has not yet been evaluated. This study aims to quantify the fipronil concentration in the substratum and roots of the seedlings treated and subjected to irrigation for up to 56 days prior to planting and to quantify this insecticide concentration in the solutions, without continuous stirring, for 120 min. The quantitative determination of fipronil in the seedlings and in the insecticide solution was done by high-performance liquid chromatography (HPLC) with an ultraviolet (UV) detector. It was found that irrigation up to 56 days, performed in the nurseries, did not decrease the fipronil concentration in the seedlings. The absence of stirring reduced the fipronil concentration in the insecticide solution, necessitating a homogenization system to maintain the recommended concentration of this product, to effectively treat the eucalyptus seedlings. The seedling treatment with fipronil can be conducted strictly in the nursery, reducing cost and environmental risks. PMID- 27126441 TI - A Slow-Growing Tumor on the Forehead. PMID- 27126440 TI - Factors associated with frailty in primary care: a prospective cohort study. AB - BACKGROUND: Frailty can be defined as a progressive loss of reserve and adaptive capacity associated with an overall deterioration in health that can result in disability, loss of independence, hospitalisation, extensive use of healthcare resources, admission to long-term care and death. Nevertheless, despite widespread use of the term, there is no agreement on the definition of frailty or an instrument to identify it in a straightforward way. The purpose of the current study was to explore which factors are associated with frailty-related adverse outcomes in elderly individuals and to propose a suitable tool for identifying such individuals, particularly in primary care settings. METHODS: A prospective open cohort study of community dwelling, independent individuals aged 75 or over, followed up for 2 years. The study was entirely conducted in a primary care setting. Study variables included independence status measured by Barthel's Index and the Lawton Instrumental Activities of Daily Living Scale, functional performance, assessed by Timed Up and Go (TUG) and Gait Speed (GS) tests and levels of polipharmacy, comorbidity and social support. Outcome variables were specific frailty-related adverse events, namely, loss of independence and death. RESULTS: Overall, 215 community-dwelling independent individuals initiated the study. Of these, 46 were lost to follow-up and 50 had frailty-related adverse events during the follow-up period. Individuals with adverse events during the study had poorer functional status at baseline. The multivariate model that best explained the occurrence of these events included the variables of age, presence of polipharmacy and the TUG time. The AUC (Area under the curve) of this model was 0.822. CONCLUSIONS: Given the simplicity of assessing the three derived factors and their combined discriminant power, the proposed model may be considered a suitable tool for identifying frail patients, i.e., people more likely to lose their independence or die within a relatively short time interval. PMID- 27126442 TI - Neuroenzymatic activity and physiological energetics in Manila clam, Ruditapes philippinarum, during short-term sublethal exposure to harmful alga, Heterocapsa circularisquama. AB - The harmful alga, Heterocapsa circularisquama, causes recurrent mortalities of bivalve molluscs in Japan, with demonstrated hemolysis and cytotoxicity in rabbit erythrocytes, HeLa cells, and bivalve tissues. Nonetheless, the effects of exposure to sublethal cell densities on the physiological energetics of bivalves have not been investigated, nor the potential involvement of neurotoxicity. In the present study, two sets of experiments were conducted with adult clams, Ruditapes philippinarum. In the first set, the clearance rate (CR), respiration rate (RR), absorption efficiency (AE), ingestion rate (IR), and absorption rate (AR) were examined in clams exposed to H. circularisquama to quantify the scope for growth (SFG) as an indicative of the bioenergetic status of clams (5, 50, 2.5*10(2), and 5*10(2)cellsml(-1); under 15 degrees C and 20 degrees C). In the second set, the activity of the biomarker of neurotoxic exposure, acetylcholinesterase (AChE), was monitored following 3, 6, 24, and 48h of exposure (5, 50, 5*10(2), and 10(3)cellsml(-1), at 20 degrees C) in gills of R. philippinarum, and compared to that in Mediterranean mussels, Mytilus galloprovincialis; a species also affected by H. circualrisquama and in which AChE activity was more extensively studied. At 15 degrees C, CR, IR, and AR were decreased for exposures to 50-5*10(2) cells ml(-1) resulting in a significant decrease in the absorbed energy (A), and a significant decrease in SFG at 5*10(2)cellsml(-1). At 20 degrees C, AE was null for exposures to 2.5*10(2) and 5*10(2)cellsml(-1). RR was decreased at 2.5*10(2) and 5*10(2)cellsml(-1), CR, IR, and AR were decreased at 5-5*10(2)cellsml(-1), and the AE was null for 2.5*10(2) 5*10(2)cellsml(-1) resulting in a significant decrease in the respired energy (R), but mainly in (A) especially at 2.5*10(2) and 5*10(2)cellsml(-1) decreasing the SFG over the entire range of cell density with negative values for 2.5*10(2) and 5*10(2)cellsml(-1). The activity of AChE in both clams and mussels was significantly reduced following 3-48h of exposure to 5-5*10(2)cellsml(-1). Reduction in the energy available for clams to grow and reproduce was induced mainly via decreased energy acquisition, and delayed and/or reduced functions of the digestive organs. In addition, this is the first report of decreased neuroenzymatic activity in two bivalve molluscs induced by exposure to H. circularisquama potentially via either neurotoxic compounds affecting the activity of gill cilia and/or gill muscles, and/or potentially via either neurotoxic compounds affecting the activity of gill cilia and/or gill muscles, and/or non-cholinergic affects associated with other functions; both resulting in decreased SFG. The relationship between the decreased AChE and decreased SFG should be corroborated in future research. PMID- 27126443 TI - Trait-based modelling of bioaccumulation by freshwater benthic invertebrates. AB - Understanding the role of species traits in chemical exposure is crucial for bioaccumulation and toxicity assessment of chemicals. We measured and modelled bioaccumulation of polychlorinated biphenyls (PCBs) in Chironomus riparius, Hyalella azteca, Lumbriculus variegatus and Sphaerium corneum. We used a battery test procedure with multiple enclosures in one aquarium, which maximized uniformity of exposure for the different species, such that the remaining variability was due mostly to species traits. The relative importance of uptake from either pore water or sediment ingestion was manipulated by using 28 d aged standard OECD sediment with low (1%) and medium (5%) OM content and 13 months aged sediment with medium OM (5%) content. Survival was >=76% and wet weight increased for all species. Reproduction of H. azteca and weight gain of H. azteca and S. corneum were significantly higher in the medium OM aged sediments than in other sediments, perhaps due to a more developed microbial community (i.e., increase in food resources). Biota-sediment accumulation factors (BSAF) ranged from 3 to 114, depending on species and PCB congener, with C. riparius (3-10)G mutation. PMID- 27126453 TI - A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes. AB - Based on the 7-year experience of the Italian Clinical Network for FSHD, we revised the FSHD clinical form to describe, in a harmonized manner, the phenotypic spectrum observed in FSHD. The new Comprehensive Clinical Evaluation Form (CCEF) defines various clinical categories by the combination of different features. The inter-rater reproducibility of the CCEF was assessed between two examiners using kappa statistics by evaluating 56 subjects carrying the molecular marker used for FSHD diagnosis. The CCEF classifies: (1) subjects presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B subcategories B1, B2), (3) asymptomatic/healthy subjects (category C, subcategories C1, C2), (4) subjects with myopathic phenotype presenting clinical features not consistent with FSHD canonical phenotype (D, subcategories D1, D2). The inter-rater reliability study showed an excellent concordance of the final four CCEF categories with a kappa equal to 0.90; 95 % CI (0.71; 0.97). Absolute agreement was observed for categories C and D, an excellent agreement for categories A [kappa = 0.88; 95 % CI (0.75; 1.00)], and a good agreement for categories B [kappa = 0.79; 95 % CI (0.57; 1.00)]. The CCEF supports the harmonized phenotypic classification of patients and families. The categories outlined by the CCEF may assist diagnosis, genetic counseling and natural history studies. Furthermore, the CCEF categories could support selection of patients in randomized clinical trials. This precise categorization might also promote the search of genetic factor(s) contributing to the phenotypic spectrum of disease. PMID- 27126456 TI - Associated and predictive factors of depressive symptoms in patients with Parkinson's disease. AB - Depression is one of the most common non-motor symptoms in Parkinson's disease (PD). A thorough understanding of factors associated with depressive symptomatology may facilitate early detection and guide future intervention strategies. The objective of the study was to determine associated and predictive factors of depression in patients with PD. Analyses were performed in data of the SCOPA-PROPARK cohort, a 5-year hospital-based longitudinal cohort of over 400 PD patients who have been examined annually. Linear mixed models using data of all patients were used to identify factors associated with longitudinal changes in Beck Depression Inventory (BDI) scores. A survival analysis using data of patients without depression at baseline was performed to identify risk factors for future depression (i.e. BDI >= 15). The proportion of patients with depression was approximately 20 % and remained stable during follow-up, with approximately half of cases showing a persistent course. Female gender, more severe disability, more severe motor fluctuations, autonomic and cognitive dysfunction, poorer nighttime sleep and daytime sleepiness were independently associated with higher BDI scores over time. Higher baseline BDI score, daytime sleepiness and a higher levodopa dosage were risk factors for future depression. Depression is common in PD, where it may follow a persistent or non-persistent course. Apart from motor fluctuations and levodopa dose, depressive symptoms in PD are mainly associated with factors of non-dopaminergic origin. This suggests that depression in PD is an inherent consequence of the progressive pathobiology of the disease, which may render its treatment with currently available treatment options difficult. PMID- 27126458 TI - Reply. PMID- 27126457 TI - Intraoperative MRI for deep brain stimulation lead placement in Parkinson's disease: 1 year motor and neuropsychological outcomes. AB - Traditional deep brain stimulation requires intraoperative neurophysiological confirmation of electrode placement. Recently, purely image guided methods are being evaluated as to their clinical efficacy in comparison to surgery using microelectrode recordings. We used the ClearPoint((r)) system to place electrodes in both the subthalamic nucleus and globus pallidus internus in patients with advanced Parkinson's disease. Off medication UPDRS scores were assessed before and 1 year after surgery as well as pre- and 1 year post-operative neuropsychological outcomes. Targeting precision was also assessed. Patients implanted in the subthalamic nucleus improved by 46.2 % in their UPDRS scores post-operatively (p = 0.03) whereas the globus pallidus group improved by 41 % (p = 0.06). There were no significant adverse neuropsychological outcomes in either group of patients. Mean radial error for the STN group was 1.2 +/- 0.7 mm and for the GPi group 0.8 mm +/- 0.3 mm. Image guided DBS using the ClearPoint((r))system has high targeting precision with robust clinical outcomes. Our data are in accord with recent studies using the same or similar technologies and provide a rationale for a large comparative study of image-guided versus microelectrode guided DBS. PMID- 27126459 TI - Short inter-set rest blunts resistance exercise-induced increases in myofibrillar protein synthesis and intracellular signalling in young males. AB - What is the central question of this study? Does shorter rest between sets of resistance exercise promote a superior circulating hormonal and acute muscle anabolic response compared with longer rest periods? What is the main finding and its importance? We demonstrate that short rest (1 min) between sets of moderate intensity, high-volume resistance exercise blunts the acute muscle anabolic response compared with a longer rest period (5 min), despite a superior circulating hormonal milieu. These data have important implications for the development of training regimens to maximize muscle hypertrophy. Manipulating the rest-recovery interval between sets of resistance exercise may influence training induced muscle remodelling. The aim of this study was to determine the acute muscle anabolic response to resistance exercise performed with short or long inter-set rest intervals. In a study with a parallel-group design, 16 males completed four sets of bilateral leg-press and knee-extension exercise at 75% of one-repetition maximum to momentary muscular failure, followed by ingestion of 25 g of whey protein. Resistance exercise sets were interspersed by 1 min (n = 8) or 5 min of passive rest (n = 8). Muscle biopsies were obtained at rest, 0, 4, 24 and 28 h postexercise during a primed continuous infusion of l-[ring-(13) C6 ]phenylalanine to determine myofibrillar protein synthesis and intracellular signalling. We found that the rate of myofibrillar protein synthesis increased above resting values from 0 to 4 h postexercise with 1 (76%; P = 0.047) and 5 min inter-set rest (152%; P < 0.001) and was significantly greater in the 5 min inter set rest group (P = 0.001). Myofibrillar protein synthesis rates at 24-28 h postexercise remained elevated above resting values (P < 0.05) and were indistinguishable between groups. Postexercise p70S6K(Thr389) and rpS6(Ser240/244) phosphorylation were reduced with 1 compared with 5 min inter set rest, whereas phosphorylation of eEF2(Thr56) , TSC2(Thr1462) , AMPK(Thr172) and REDD1 protein were greater for 1 compared with 5 min inter-set rest. Serum testosterone was greater at 20-40 min postexercise and plasma lactate greater immediately postexercise for 1 versus 5 min inter-set rest. Resistance exercise with short (1 min) inter-set rest duration attenuated myofibrillar protein synthesis during the early postexercise recovery period compared with longer (5 min) rest duration, potentially through compromised activation of intracellular signalling. PMID- 27126460 TI - Biodistribution and Radiation Dosimetry of [18F]Mefway in Humans. AB - PURPOSE: [18F]Mefway is a positron emission tomography (PET) radioligand for quantification of the brain serotonin 1A (5-HT1A) receptor density. The purpose of this study was to evaluate the radiation safety of [18F]Mefway in humans. PROCEDURES: Six healthy volunteers (three males and three females) were whole body PET scanned for 114 min after injection of [18F]Mefway (226 +/- 35 MBq). Estimated radiation doses were determined by the OLINDA/EXM software. RESULTS: [18F]Mefway was safe and well tolerated by all subjects. Residence time ranges from 0 (gallbladder) to 0.822 h (urinary bladder wall). While the estimated radiation doses in the reproductive and blood-forming organs were below 13.35 22.87 MUSv/MBq, radiation dose in the urinary bladder wall was 471 MUSv/MBq. The mean effective dose was 40.23 +/- 6.63 MUSv/MBq. CONCLUSION: For a typical single injection of 185 MBq (5 mCi), the dose will result in 87.1 mSv for the urinary bladder wall. To reduce radiation burden, the bladder voiding can be used before [18F]Mefway PET scan. PMID- 27126462 TI - Why Do So Many White Americans Oppose the Affordable Care Act? PMID- 27126461 TI - Identification and characterisation of the immune response properties of Lampetra japonica BLNK. AB - B cell linker protein (BLNK) is a central linker protein involved in B cell signal transduction in jawed vertebrates. In a previous study, we have reported the identification of a BLNK homolog named Lj-BLNK in lampreys. In this study, a 336 bp cDNA fragment encoding the Lj-BLNK Src homology 2 (SH2) domain was cloned into the vector pET-28a(+) and overexpressed in Escherichia coli BL21. The recombinant fragment of Lj-BLNK (rLj-BLNK) was purifiedby His-Bind affinity chromatography, and polyclonal antibodies against rLj-BLNK were raised in male New Zealand rabbits. Fluorescenceactivated cell sorting (FACS) analysisrevealed that Lj-BLNK was expressed in approximately 48% of the lymphocyte-like cells of control lampreys, and a significant increase in Lj-BLNK expression was observed in lampreys stimulated with lipopolysaccharide (LPS). Western blotting analysis showed that variable lymphocyte receptor B (VLRB) and Lj-BLNKwere distributed in the same immune-relevant tissues, and the levels of both were upregulated in supraneural myeloid bodies and lymphocyte-like cells after LPS stimulation. Immunofluorescence demonstrated that Lj-BLNK was localized in VLRB(+) lymphocyte like cells. These results indicate that the Lj-BLNK protein identified in lampreys might play an important role in the VLRB-mediated adaptive immune response. PMID- 27126463 TI - The Reply. PMID- 27126464 TI - Misconceptions on Interpretation of Risk Prediction Tools in Atrial Fibrillation. PMID- 27126465 TI - The Reply. PMID- 27126466 TI - Updated Meta-Analysis of Aspirin in Primary Prevention of Cardiovascular Disease. PMID- 27126468 TI - 64(TH) ASMS Conference on Mass Spectrometry and Allied Topics. PMID- 27126467 TI - Stethoscope: A Still-Relevant Tool and Medical Companion. PMID- 27126469 TI - Reducing Spatial Heterogeneity of MALDI Samples with Marangoni Flows During Sample Preparation. AB - This work demonstrates a method to prepare homogeneous distributions of analytes to improve data reproducibility in matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Natural-air drying processes normally result in unwanted heterogeneous spatial distributions of analytes in MALDI crystals and make quantitative analysis difficult. This study demonstrates that inducing Marangoni flows within drying droplets can significantly reduce the heterogeneity problem. The Marangoni flows are accelerated by changing substrate temperatures to create temperature gradients across droplets. Such hydrodynamic flows are analyzed semi-empirically. Using imaging mass spectrometry, changes of heterogeneity of molecules with the change of substrate temperature during drying processes are demonstrated. The observed heterogeneities of the biomolecules reduce as predicted Marangoni velocities increase. In comparison to conventional methods, drying droplets on a 5 degrees C substrate while keeping the surroundings at ambient conditions typically reduces the heterogeneity of biomolecular ions by 65%-80%. The observation suggests that decreasing substrate temperature during droplet drying processes is a simple and effective means to reduce analyte heterogeneity for quantitative applications. Graphical Abstract ?. PMID- 27126470 TI - Charge Exchange Reaction in Dopant-Assisted Atmospheric Pressure Chemical Ionization and Atmospheric Pressure Photoionization. AB - The efficiencies of charge exchange reaction in dopant-assisted atmospheric pressure chemical ionization (DA-APCI) and dopant-assisted atmospheric pressure photoionization (DA-APPI) mass spectrometry (MS) were compared by flow injection analysis. Fourteen individual compounds and a commercial mixture of 16 polycyclic aromatic hydrocarbons were chosen as model analytes to cover a wide range of polarities, gas-phase ionization energies, and proton affinities. Chlorobenzene was used as the dopant, and methanol/water (80/20) as the solvent. In both techniques, analytes formed the same ions (radical cations, protonated molecules, and/or fragments). However, in DA-APCI, the relative efficiency of charge exchange versus proton transfer was lower than in DA-APPI. This is suggested to be because in DA-APCI both dopant and solvent clusters can be ionized, and the formed reagent ions can react with the analytes via competing charge exchange and proton transfer reactions. In DA-APPI, on the other hand, the main reagents are dopant-derived radical cations, which favor ionization of analytes via charge exchange. The efficiency of charge exchange in both DA-APPI and DA-APCI was shown to depend heavily on the solvent flow rate, with best efficiency seen at lowest flow rates studied (0.05 and 0.1 mL/min). Both DA-APCI and DA-APPI showed the radical cation of chlorobenzene at 0.05-0.1 mL/min flow rate, but at increasing flow rate, the abundance of chlorobenzene M(+.) decreased and reagent ion populations deriving from different gas-phase chemistry were recorded. The formation of these reagent ions explains the decreasing ionization efficiency and the differences in charge exchange between the techniques. Graphical Abstract ?. PMID- 27126471 TI - Kinetics and Mechanism of Oxidation of Methimazole by Chlorite in Slightly Acidic Media. AB - The kinetics and mechanism of the oxidation of methimazole (1-methyl-3H imidazole), MMI, by chlorite in mildly acidic environments were studied. It is a complex reaction that gives oligo-oscillations in chlorine dioxide concentrations in excess chlorite conditions. The stoichiometry is strictly 2:1, with the sulfur center being oxidized to sulfate and the organic moiety being hydrolyzed to several indeterminate species. In excess MMI conditions over chlorite, the sulfinic acid and sulfonic acid were observed as major intermediates. The sulfenic acid, which was observed in the electrochemical oxidation of MMI, was not observed with chlorite oxidations. Initial reduction of chlorite produced HOCl, an autocatalytic species in chlorite oxidations. HOCl rapidly reacts with chlorite to produce chlorine dioxide, which, in turn, reacts rapidly with MMI to produce more chlorite. The reaction of chlorine dioxide with MMI is competitive, in rate, with the chlorite-MMI and HOCl-ClO2(-) reactions. This explains the oligo-oscillations in ClO2 concentrations. PMID- 27126473 TI - Expression and role of connexin-based gap junctions in pulmonary inflammatory diseases. AB - Connexins are transmembrane proteins that can generate intercellular communication channels known as gap junctions. They contribute to the direct movement of ions and larger cytoplasmic solutes between various cell types. In the lung, connexins participate in a variety of physiological functions, such as tissue homeostasis and host defence. In addition, emerging evidence supports a role for connexins in various pulmonary inflammatory diseases, such as asthma, pulmonary hypertension, acute lung injury, lung fibrosis or cystic fibrosis. In these diseases, the altered expression of connexins leads to disruption of normal intercellular communication pathways, thus contributing to various pathophysiological aspects, such as inflammation or tissue altered reactivity and remodeling. The present review describes connexin structure and organization in gap junctions. It focuses on connexins in the lung, including pulmonary bronchial and arterial beds, by looking at their expression, regulation and physiological functions. This work also addresses the issue of connexin expression alteration in various pulmonary inflammatory diseases and describes how targeting connexin based gap junctions with pharmacological tools, synthetic blocking peptides or genetic approaches, may open new therapeutic perspectives in the treatment of these diseases. PMID- 27126474 TI - The role of glutamine in Pseudomonas mediterranea in biotechnological processes. AB - In this work, in order to study the effect of glutamine as co-feeder on growth kinetics, biomass and PHA production in Pseudomonas mediterranea, different co metabolic strategies were employed. Unrelated (glycerol and glucose) and related (sodium octanoate) carbon sources both in presence and absence of glutamine have been tested. For each cultural condition, we (i) evaluated growth kinetics and measured the cell metabolic activity by MTT assay, (ii) monitored PHA production and (iii) estimated the expression of phaC1 and phaC2 genes through RT-PCR. Our results show that the use of glutamine as co-feeder in P. mediterranea led to an improvement of the specific growth rate and cell metabolic activity and enhanced the uptake of all the carbon sources assayed. Moreover, the use of glutamine reduced significantly the time required for PHA production and increased biopolymer yield, as consequence of an early activation of phaC1 and phaC2. PMID- 27126472 TI - MicroRNAs and drug-induced kidney injury. AB - Drug-induced kidney injury (DIKI) is a severe complication in hospitalized patients associated with higher probabilities of developing progressive chronic kidney disease or end-stage renal diseases. Furthermore, DIKI is a problem during preclinical and clinical phases of drug development leading to high rates of project terminations. Understanding the molecular perturbations caused by DIKI would pave the way for a new class of therapeutics to mitigate the damage. Yet, another approach to ameliorate DIKI is identifying sensitive and specific translational biomarkers that outperform the current diagnostic analytes like serum creatinine and facilitate early diagnosis. MicroRNAs (miRNAs), a class of non-coding RNAs, are increasingly being recognized to have a two-pronged approach toward DIKI management: 1) miRNAs have a regulatory role in gene expression and signaling pathways thereby making them novel interventional targets and 2) miRNAs enable diagnosis and prognosis of DIKI because of their stable presence in biofluids. In this review, apart from summarizing the literature on miRNAs in DIKI, we report small RNA sequencing results showing miRNA expression profiles at baseline in normal kidney samples from mice and humans. Additionally, we also compared the miRNA expression in biopsies of normal human kidneys to patients with acute tubular necrosis, and found 76 miRNAs significantly downregulated and 47 miRNAs upregulated (FDR adjusted p<0.05, +/-2-fold change). In summary, we highlight the transformative potential of miRNAs in therapeutics and translational medicine with a focus on drug-induced kidney damage. PMID- 27126475 TI - Oxygen-independent FbFP: Fluorescent sentinel and oxygen sensor component in Saccharomyces cerevisiae and Candida albicans. AB - FMN-binding fluorescent proteins (FbFPs) outperform GFP and its derivatives because of their oxygen-independence, small size and rapid maturation. FbFPs have been used successfully as reliable reporters of gene expression in the cytoplasm of pro- and eukaryotes. Here we extend previous findings on the codon-adapted CaFbFP variant, which functions in the apathogenic yeast Saccharomyces cerevisiae and the human fungal pathogen Candida albicans. In both fungal species, CaFbFP could be targeted to the nucleus and the cell wall by endogenous signals (H2B /Aga2-fusions) demonstrating its use as a fluorescent beacon in these relevant cellular locations. Transformants of both fungal species producing a CaFbFP-YFP fusion (YFOS) showed variable energy transfer from CaFbFP to YFP (FRET) that depended in its extent on external O2 concentrations. Applications as fluorescent sentinel and oxygen biosensor expand the FbFP toolbox to study oxygen-independent cellular processes under hypoxia. PMID- 27126476 TI - Preparation of ultrafine poly(methyl methacrylate-co-methacrylic acid) biodegradable nanoparticles loaded with ibuprofen. AB - Ibuprofen-loaded polymeric particles with around 9.2 nm in mean diameter, as determined by electron microscopy, dispersed in an aqueous media containing up to 12.8% solids were prepared by semicontinuous heterophase polymerization. The polymeric material is a (2/1 mol/mol) methyl methacrylate-co-methacrylic acid copolymer similar to Eudragit S100, deemed safe for human consumption and used in the manufacturing of drug-loaded pills as well as micro- and nanoparticles. The loading efficiency was 100%, attaining around 10-12% in drug content. Release studies showed that the drug is released from the nanoparticles at a slower rate than that in the case of free IB. Given their size as well as the pH values required for their dissolution, it is believed that this type of particles could be used as a basis for preparing nanosystems loaded with a variety of drugs. PMID- 27126477 TI - Two C-C Family Chemokines, Eotaxin and RANTES, Are Novel Independent Plasma Biomarkers for Abdominal Aortic Aneurysm. AB - BACKGROUND: Inflammation of the aortic wall is recognised as a key pathogenesis of abdominal aortic aneurysm (AAA). This study was undertaken to determine whether inflammatory cytokines could be used as biomarkers for the presence of AAA. METHODS AND RESULTS: Tissue profiles of 27 inflammatory cytokine were examined in AAA (n=14) and nonaneurysmal (n=14) aortic tissues. Three cytokines, regulated upon activation normally T-cell expressed and secreted (RANTES), eotaxin, and macrophage inflammatory protein 1 beta (MIP-1b), had increased expression in AAA, particularly within the adventitial layer of the aortic wall. Basic fibroblast growth factor (bFGF) had reduced expression in all layers of the AAA wall. Examination of the circulating plasma profiles of AAA (n=442) and AAA free controls (n=970) suggested a (risk factor adjusted) AAA-association with eotaxin, RANTES, and high sensitivity C-reactive protein (hsCRP). A plasma inflammatory cytokine score, calculated using these three markers, suggested a strong risk association with AAA (odds ratio, 4.8; 95% CI, 3.5-6.7; P<0.0001), independent of age, sex, history of ischemic heart disease, and smoking. CONCLUSIONS: Contrary to reports suggesting a distinct T helper 2-associated inflammatory profile in AAA, this current study suggests a more-generalized pattern of inflammation, albeit with some potentially distinct features, including elevated plasma eotaxin and decreased plasma RANTES. In combination with hsCRP, these markers may have potential utility as AAA biomarkers. PMID- 27126479 TI - NHS England should reconsider PrEP decision. PMID- 27126480 TI - Using PMTCT to raise overall health and development. PMID- 27126478 TI - Short-Term Exposure to Air Pollution and Biomarkers of Oxidative Stress: The Framingham Heart Study. AB - BACKGROUND: Short-term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community-based studies have assessed this association. METHODS AND RESULTS: Two thousand thirty-five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998-2001) and urinary creatinine indexed 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) at the seventh and eighth (2005-2008) examinations. We measured fine particulate matter (PM2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1-, 2 , 3-, 5-, and 7-day moving averages of each pollutant. Measured myeloperoxidase and 8-epi-PGF2alpha were loge transformed. We used linear regression models and linear mixed-effects models with random intercepts for myeloperoxidase and indexed 8-epi-PGF2alpha, respectively. Models were adjusted for demographic variables, individual- and area-level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2- to 7-day moving averages of PM2.5 and sulfate were consistently positively associated with 8-epi-PGF2alpha. Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. CONCLUSIONS: Our community based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress. PMID- 27126481 TI - Linkage to care: a step on the path, but not the destination. PMID- 27126482 TI - Is the UNAIDS target sufficient for HIV control in Botswana? PMID- 27126483 TI - Translating phylogeny into action for HIV surveillance. PMID- 27126484 TI - Cities central to HIV response for people who use drugs. PMID- 27126485 TI - PrEP adherence among trans women in Brazil-access needed for this key population. PMID- 27126486 TI - PrEP adherence among trans women in Brazil-access needed for this key population Authors' reply. PMID- 27126487 TI - Integrated prevention of mother-to-child HIV transmission services, antiretroviral therapy initiation, and maternal and infant retention in care in rural north-central Nigeria: a cluster-randomised controlled trial. AB - BACKGROUND: Antiretroviral therapy (ART) and retention in care are essential for the prevention of mother-to-child HIV transmission (PMTCT). We aimed to assess the effect of a family-focused, integrated PMTCT care package. METHODS: In this parallel, cluster-randomised controlled trial, we pair-matched 12 primary and secondary level health-care facilities located in rural north-central Nigeria. Clinic pairs were randomly assigned to intervention or standard of care (control) by computer-generated sequence. HIV-infected women (and their infants) presenting for antenatal care or delivery were included if they had unknown HIV status at presentation (there was no age limit for the study, but the youngest participant was 16 years old); history of antiretroviral prophylaxis or treatment, but not receiving these at presentation; or known HIV status but had never received treatment. Standard of care included health information, opt-out HIV testing, infant feeding counselling, referral for CD4 cell counts and treatment, home based services, antiretroviral prophylaxis, and early infant diagnosis. The intervention package added task shifting, point-of-care CD4 testing, integrated mother and infant service provision, and male partner and community engagement. The primary outcomes were the proportion of eligible women who initiated ART and the proportion of women and their infants retained in care at 6 weeks and 12 weeks post partum (assessed by generalised linear mixed effects model with random effects for matched clinic pairs). The trial is registered with ClinicalTrials.gov, number NCT01805752. FINDINGS: Between April 1, 2013, and March 31, 2014, we enrolled 369 eligible women (172 intervention, 197 control), similar across groups for marital status, duration of HIV diagnosis, and distance to facility. Median CD4 count was 424 cells per MUL (IQR 268-606) in the intervention group and 314 cells per MUL (245-406) in the control group (p<0.0001). Of the 369 women included in the study, 363 (98%) had WHO clinical stage 1 disease, 364 (99%) had high functional status, and 353 (96%) delivered vaginally. Mothers in the intervention group were more likely to initiate ART (166 [97%] vs 77 [39%]; adjusted relative risk 3.3, 95% CI 1.4-7.8). Mother and infant pairs in the intervention group were more likely to be retained in care at 6 weeks (125 [83%] of 150 vs 15 [9%] of 170; adjusted relative risk 9.1, 5.2 15.9) and 12 weeks (112 [75%] of 150 vs 11 [7%] of 168 pairs; 10.3, 5.4-19.7) post partum. INTERPRETATION: This integrated, family-focused PMTCT service package improved maternal ART initiation and mother and infant retention in care. An effective approach to improve the quality of PMTCT service delivery will positively affect global goals for the elimination of mother-to-child HIV transmission. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development and US National Institutes of Health. PMID- 27126488 TI - Uptake of antiretroviral therapy and male circumcision after community-based HIV testing and strategies for linkage to care versus standard clinic referral: a multisite, open-label, randomised controlled trial in South Africa and Uganda. AB - BACKGROUND: Male circumcision decreases HIV acquisition by 60%, and antiretroviral therapy (ART) almost eliminates HIV transmission from HIV-positive people who are virally suppressed; however, coverage of these interventions has lagged behind targets. We aimed to assess whether community-based HIV testing with counsellor support and point-of-care CD4 cell count testing would increase uptake of ART and male circumcision. METHODS: We did this multisite, open-label, randomised controlled trial in six research-naive communities in rural South Africa and Uganda. Eligible HIV-positive participants (aged >=16 years) were randomly assigned (1:1:1) in a factorial design to receive lay counsellor clinic linkage facilitation, lay counsellor follow-up home visits, or standard-of-care clinic referral, and then (1:1) either point-of-care CD4 cell count testing or referral for CD4 testing. HIV-negative uncircumcised men (aged 16-49 years) who could receive secure mobile phone text messages were randomly assigned (1:1:1) to receive text message reminders, lay counsellor visits, or standard clinic referral. The study biostatistician generated the randomisation schedule via a computer-generated random number program with varying block sizes (multiples of six or three) stratified by country. Primary outcomes for HIV-positive people were obtaining a CD4 cell count, linkage to an HIV clinic, ART initiation, and viral suppression at 9 months, and for HIV-negative uncircumcised men were visiting a circumcision facility and uptake of male circumcision at 3 months. We assessed social harms as a safety outcome throughout the study. We did the primary analyses by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02038582. FINDINGS: Between June 6, 2013, and March 11, 2015, 15 332 participants were tested. 2339 (15%) participants tested HIV positive, of whom 1325 (57%) were randomly assigned to receive lay counsellor clinic linkage facilitation (n=437), lay counsellor follow-up home visits (n=449), or standard clinic referral (n=439), and then point-of-care CD4 cell testing (n=206, n=220, and n=213, respectively) or referral for CD4 testing (n=231, n=229, and n=226, respectively). 12 993 (85%) participants tested HIV negative, of whom 750 (6%) uncircumcised men were randomly assigned to receive clinic referral (n=230), text message reminders (n=288), or lay counsellor follow up visits (n=232). 1218 (93%) of 1303 HIV-positive participants were linked to care, but only 488 (37%) participants initiated ART. Overall, 635 (50%) of 1272 HIV-positive individuals achieved viral suppression at 9 months: 219 (52%) of 419 participants in the clinic facilitation group, 202 (47%) of 431 participants in the lay counsellor follow-up group, and 214 (51%) of 422 participants in the clinic referral group, with no significant differences between groups (p=0.668 for clinic facilitation and p=0.273 for lay counsellor follow-up vs clinic referral). 523 (72%) of 734 HIV-negative men visited a circumcision facility, with no difference between groups. 62 (28%) of 224 men were circumcised in the male circumcision clinic referral group compared with 137 (48%) of 284 men in the text message reminder group (relative risk 1.72, 95% CI 1.36-2.17; p<0.0001) and 106 (47%) of 226 men in the lay counsellor follow-up group (1.67, 1.29-2.14; p=0.0001). No cases of study-related social harm were reported, including probing about partnership separation, unintended disclosure, gender-based violence, and stigma. INTERPRETATION: All the community-based strategies achieved high rates of linkage of HIV-positive people to HIV clinics, roughly a third of whom initiated ART, and of those more than 80% were virally suppressed at 9 months. Uptake of male circumcision was almost two-times higher in men who received text message reminders or lay counsellor visits than in those who received standard-of-care clinic referral. Clinic barriers to ART initiation should be addressed in future strategies to increase the proportion of HIV-positive people accessing treatment and achieving viral suppression. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health. PMID- 27126489 TI - Botswana's progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a population-based survey. AB - BACKGROUND: HIV programmes face challenges achieving high rates of HIV testing and treatment needed to optimise health and to reduce transmission. We used data from the Botswana Combination Prevention Project study survey to assess Botswana's progress toward achieving UNAIDS targets for 2020: 90% of all people living with HIV knowing their status, 90% of these receiving sustained antiretroviral therapy (ART), and 90% of those having virological suppression (90 90-90). METHODS: A population-based sample of individuals was recruited and interviewed in 30 rural and periurban communities from Oct 30, 2013, to Nov 24, 2015, as part of a large, ongoing community-randomised trial designed to assess the effect of a combination prevention package on HIV incidence. A random sample of about 20% of households in each community was selected. Consenting household residents aged 16-64 years who were Botswana citizens or spouses of citizens responded to a questionnaire and had blood drawn for HIV testing in the absence of documentation of positive HIV status. Viral load testing was done in all HIV infected participants, irrespective of treatment status. We used modified Poisson generalised estimating equations to obtain prevalence ratios, corresponding Huber robust SEs, and 95% Wald CIs to examine associations between individual sociodemographic factors and a binary outcome indicating achievement of the three individual and combined overall 90-90-90 targets. The study is registered at ClinicalTrials.gov, number NCT01965470. FINDINGS: 81% of enumerated eligible household members took part in the survey (10% refused and 9% were absent). Among 12 610 participants surveyed, 3596 (29%) were infected with HIV, and 2995 (83.3%, 95% CI 81.4-85.2) of these individuals already knew their HIV status. Among those who knew their HIV status, 2617 (87.4%, 95% CI 85.8-89.0) were receiving ART (95% of those eligible by national guidelines, and 73% of all infected people). Of the 2609 individuals receiving ART with a viral load measurement, 2517 (96.5%, 95% CI 96.0-97.0) had viral load of 400 copies per mL or less. Overall, 70.2% (95% CI 67.5-73.0) of HIV-infected people had virological suppression, close to the UNAIDS target of 73%. INTERPRETATION: UNAIDS 90-90-90 targets are achievable even in resource-constrained settings with high HIV burden. FUNDING: US President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention. PMID- 27126490 TI - Near real-time monitoring of HIV transmission hotspots from routine HIV genotyping: an implementation case study. AB - BACKGROUND: HIV evolves rapidly and therefore infections with similar genetic sequences are likely linked by recent transmission events. Clusters of related infections can represent subpopulations with high rates of transmission. We describe the implementation of an automated near real-time system to monitor and characterise HIV transmission hotspots in British Columbia, Canada. METHODS: In this implementation case study, we applied a monitoring system to the British Columbia drug treatment database, which holds more than 32 000 anonymised HIV genotypes for nearly 9000 residents of British Columbia living with HIV. On average, five to six new HIV genotypes are deposited in the database every day, which triggers an automated reanalysis of the entire database. We extracted clusters of five or more individuals with short phylogenetic distances between their respective HIV sequences. The system generated monthly reports of the growth and characteristics of clusters that were distributed to public health officers. FINDINGS: In June, 2014, the monitoring system detected the expansion of a cluster by 11 new cases during 3 months, including eight cases with transmitted drug resistance. This cluster generally comprised young men who have sex with men. The subsequent report precipitated an enhanced public health follow up to ensure linkage to care and treatment initiation in the affected subpopulation. Of the nine cases associated with this follow-up, all had already been linked to care and five cases had started treatment. Subsequent to the follow-up, three additional cases started treatment and most cases achieved suppressed viral loads. During the next 12 months, we detected 12 new cases in this cluster with reduction in the onward transmission of drug resistance. INTERPRETATION: Our findings show the first application of an automated phylogenetic system monitoring a clinical database to detect a recent HIV outbreak and support the ensuing public health response. By making secondary use of routinely collected HIV genotypes, this approach is cost-effective, attains near real-time monitoring of new cases, and can be implemented in all settings in which HIV genotyping is the standard of care. FUNDING: BC Centre for Excellence in HIV/AIDS, the Canadian Institutes for Health Research, the Genome Canada-CIHR Partnership in Genomics and Personalized Health, and the US National Institute on Drug Abuse. PMID- 27126492 TI - The long-term prognosis of cardiovascular disease and all-cause mortality for metabolically healthy obesity: a systematic review and meta-analysis. AB - BACKGROUND: Metabolically healthy obese phenotype (MHO) refers to obese individuals with absence of metabolic abnormalities such as dyslipidaemia, insulin resistance and hypertension. Many studies reported the long-term prognosis of MHO on diseases and mortality with inconsistent results. METHODS: We performed a meta-analysis to assess the risks of cardiovascular (CV) events and all-cause mortality for MHO individuals. Original prospective observational studies were searched in Medline, EMBASE, Web of Science and Cochrane library up to 30 September 2015. In this meta-analysis, the relative risk (RR) calculated on the basis of the incident number of disease events and deaths in participants and the corresponding multivariable-adjusted HR were both extracted to calculate pooled risk estimates. A random-effects model was used if there was heterogeneity among studies; otherwise, the fixed-effects model was used. RESULTS: 22 prospective studies, involving 584 799 participants, were archived in the analyses. With metabolically healthy normal weight as the reference, the MHO phenotype was associated with a higher risk of CV events (RR 1.50, 95% CI 1.27 to 1.77; HR 1.60, 95% CI 1.38 to 1.84). However, MHO individuals were not associated with increased risk of all-cause mortality (RR 1.18, 95% CI 0.83 to 1.66; HR 1.07, 95% CI 0.92 to 1.25). CONCLUSIONS: The meta-analysis confirms a positive association between a metabolically healthy obese phenotype and the risk of CV events. However, higher risk for all-cause mortality is not evident in metabolically healthy obese individuals. PMID- 27126493 TI - Public health lessons for refugee reception: the example of Sidi Bulgayz. PMID- 27126491 TI - Transcriptional characteristics of different sized follicles in relation to embryo transferability: potential role of hepatocyte growth factor signalling. AB - STUDY HYPOTHESIS: We hypothesized that a better discrimination between follicles containing oocytes with high developmental competence and those containing oocytes with low competence, based on a combination of a follicle's size and transcriptomic signature, will provide a reliable method to predict embryonic outcome of IVF. STUDY FINDING: This study provides new insights on the impact of follicular size on oocyte quality as measured by embryonic development and demonstrates that medium follicles yield a better percentage of transferable embryos. WHAT IS KNOWN ALREADY: Although it is generally accepted that large ovarian follicles contain better eggs, other studies report that a better follicular size subdivision and a better characterization are needed. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Individual follicles (n = 136), from a total of 33 women undergoing IVF, were aspirated and categorized on the basis of their follicular liquid volume (small, medium or large) and the embryonic outcome of the enclosed oocyte: poor or good development. Comprehensive gene expression analysis between cells from the different sized follicles was performed using microarrays and quantitative RT-PCR to find molecular markers associated with follicular maturity and oocyte developmental competence. MAIN RESULTS AND THE ROLE OF CHANCE: The analysis of embryonic outcome in relation to follicular size indicates that the medium-sized follicles category yielded more transferable embryos (35%) compared with the largest follicles (30%) (NS). Gene expression analysis revealed expression markers with significant (P < 0.05) discrimination between the poor development groups for all three follicle sizes, and good development medium-size follicles, including up-regulation of thrombomodulin, transforming growth factor, beta receptor II and chondrolecti, and those associated with hyaluronan synthesis, coagulation and hepatocyte growth factor signalling. LIMITATIONS, REASONS FOR CAUTION: These analyses were performed in a single cohort of patients coming from a single clinic and the biomarkers generated will require validation in different geographical and biological contexts to ensure their global applicability. WIDER IMPLICATIONS OF THE FINDINGS: Medium-size follicles seem to be the optimal size for a positive embryonic outcome and are associated with competence markers that may help in understanding the ideal differentiation status during late folliculogenesis. LARGE SCALE DATA: The data discussed in this publication have been deposited in The National Center for Biotechnology Information Gene Expression Omnibus database and are accessible through GEO Series accession number GSE52851. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC) to M.A.S. There are no competing interests to declare. PMID- 27126497 TI - CORRIGENDUM: Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. PMID- 27126496 TI - Live births, natural losses, and elective terminations with Down syndrome in Massachusetts. AB - PURPOSE: No studies to date have reported an estimated number of live births, elective terminations, and natural losses (miscarriages and stillbirths) for Down syndrome (DS) in Massachusetts (MA). These numbers would be helpful to estimate how many expectant parents of children with DS need support and the number of live-born children with DS who require services. METHODS: Combining robust data sets, including the Annual Reports of the MA Birth Defects Monitoring Program, we estimated the number of live births, elective terminations, and natural losses with Down syndrome from 1900 to 2010. RESULTS: The live birth prevalence for DS in MA for the most recent years for which data are available (2006-2010) was estimated at 12.4 per 10,000 live births, with a total of approximately 94 live births annually. During this period, an estimated 126 DS-related elective pregnancy terminations were performed in MA annually. As of 2008, the estimated rate at which live births with DS was reduced as a consequence of DS-related elective pregnancy terminations was 49%. CONCLUSION: The reduction of live births with DS is significantly higher in MA than in the rest of the United States as a whole. However, ethnic and racial differences in reduction rates were similar highest for Asians/Pacific Islanders, followed by non-Hispanic whites, non Hispanic blacks/Africans, and Hispanics.Genet Med 18 5, 459-466. PMID- 27126498 TI - Editorial: Valuing the knowledge of nursing: naming it and making it visible. PMID- 27126499 TI - Simulation of the inhibition of microbial sulfate reduction in a two-compartment upflow bioreactor subjected to molybdate injection. AB - Souring of oil fields during secondary oil recovery by water injection occurs mainly due to the action of sulfate-reducing bacteria (SRB) adhered to the rock surface in the vicinity of injection wells. Upflow packed-bed bioreactors have been used in petroleum microbiology because of its similarity to the oil field near the injection wells or production. However, these reactors do not realistically describe the regions near the injection wells, which are characterized by the presence of a saturated zone and a void region close to the well. In this study, the hydrodynamics of the two-compartment packing-free/packed bed pilot bioreactor that mimics an oil reservoir was studied. The packed-free compartment was modeled using a continuous stirred tank model with mass exchange between active and stagnant zones, whereas the packed-bed compartment was modeled using a piston-dispersion-exchange model. The proposed model adequately represents the hydrodynamic of the packed-free/packed-bed bioreactor while the simulations provide important information about the characteristics of the residence time distribution (RTD) curves for different sets of model parameters. Simulations were performed to represent the control of the sulfate-reducing bacteria activity in the bioreactor with the use of molybdate in different scenarios. The simulations show that increased amounts of molybdate cause an effective inhibition of the souring sulfate-reducing bacteria activity. PMID- 27126500 TI - Immobilized Kluyveromyces marxianus cells in carboxymethyl cellulose for production of ethanol from cheese whey: experimental and kinetic studies. AB - Cheese whey fermentation to ethanol using immobilized Kluyveromyces marxianus cells was investigated in batch and continuous operation. In batch fermentation, the yeast cells were immobilized in carboxymethyl cellulose (CMC) polymer and also synthesized graft copolymer of CMC with N-vinyl-2-pyrrolidone, denoted as CMC-g-PVP, and the efficiency of the two developed cell entrapped beads for lactose fermentation to ethanol was examined. The yeast cells immobilized in CMC g-PVP performed slightly better than CMC with ethanol production yields of 0.52 and 0.49 g ethanol/g lactose, respectively. The effect of supplementation of cheese whey with lactose (42, 70, 100 and 150 g/l) on fermentative performance of K. marxianus immobilized in CMC beads was considered and the results were used for kinetic studies. The first order reaction model was suitable to describe the kinetics of substrate utilization and modified Gompertz model was quite successful to predict the ethanol production. For continuous ethanol fermentation, a packed-bed immobilized cell reactor (ICR) was operated at several hydraulic retention times; HRTs of 11, 15 and 30 h. At the HRT of 30 h, the ethanol production yield using CMC beads was 0.49 g/g which implies that 91.07 % of the theoretical yield was achieved. PMID- 27126501 TI - Effect of nitrogen and/or oxygen concentration on poly(3-hydroxybutyrate) accumulation by Halomonas boliviensis. AB - The behaviour of Halomonas boliviensis during growth in fed-batch culture under different kind of nutrient restrictions was examined. The metabolic switch between growth and accumulation phase is determined by the limitation in one or more essential nutrient for bacterial growth. The aim of this study was to test the effect of applying limitations of a essential nutrient, such as nitrogen, and the influence of different O2 concentrations on poly(3-hydroxybutyrate) (PHB) production during the accumulation phase. Single limitations of nitrogen and oxygen provoke PHB accumulations of 45 and 37 % (g g(-1)), respectively, while N limitation with low O2 supply causes the highest PHB accumulation of 73 %. The characterization of the PHB production with the strain H. boliviensis would allow a better optimization of the process and enrich the knowledge about the PHB production from strains different than Cupriavidus necator. PMID- 27126502 TI - Characteristics of extracellular polymeric substances from sludge and biofilm in a simultaneous nitrification and denitrification system under high salinity stress. AB - The composition and distribution of extracellular polymeric substance (EPS) both from suspended sludge and attached biofilm were investigated in a simultaneous nitrification and denitrification (SND) system with the increase of the salinity from 1.0 to 3.0 %. Fourier-transform infrared (FTIR) spectroscopy and three dimensional excitation-emission matrix (3D-EEM) fluorescence spectroscopy were used to examine proteins (PN), polysaccharides (PS) and humic substances (HS) present in EPS. High total nitrogen removal (above 83.9 %) via SND was obtained in the salinity range of 1.0-2.5 %. Total EPS in the sludge increased from 150.2 to 200.6 mg/gVSS with the increase of salinity from 1.0 to 3.0 %, whereas the corresponding values in the biofilm achieved the maximum of 288.6 mg/g VSS at 2.0 % salinity. Dominant composition of EPS was detected as HS in both sludge and biofilm, having the percentages of 50.6-68.6 and 41.1-69.9 % in total EPS, respectively. Both PN and PS contents in soluble EPS (S-EPS), loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS) of sludge and biofilm increased with the increased salinity. The FTIR spectrum and 3D-EEM fluorescence spectroscopy of S EPS, LB-EPS and TB-EPS in the sludge and biofilm showed the changes of functional groups and conformations of the compositions in EPS with the increase of salinity. The results demonstrated that the characteristics of EPS varied from sludge to biofilm. The obtained results could provide a better understanding of the salinity effect on the EPS characteristics in a SND system. PMID- 27126503 TI - Efficient Palladium-Assisted One-Pot Deprotection of (Acetamidomethyl)Cysteine Following Native Chemical Ligation and/or Desulfurization To Expedite Chemical Protein Synthesis. AB - The acetamidomethyl (Acm) moiety is a widely used cysteine protecting group for the chemical synthesis and semisynthesis of peptide and proteins. However, its removal is not straightforward and requires harsh reaction conditions and additional purification steps before and after the removal step, which extends the synthetic process and reduces the overall yield. To overcome these shortcomings, a method for rapid and efficient Acm removal using Pd(II) complexes in aqueous medium is reported. We show, for the first time, the assembly of three peptide fragments in a one-pot fashion by native chemical ligation where the Acm moiety was used to protect the N-terminal Cys of the middle fragment. Importantly, an efficient synthesis of the ubiquitin-like protein UBL-5, which contains two native Cys residues, was accomplished through the one-pot operation of three key steps, namely ligation, desulfurization, and Acm deprotection, highlighting the great utility of the new approach in protein synthesis. PMID- 27126504 TI - Early Pharmacodynamic Effects of Exenatide Once Weekly in Type 2 Diabetes Are Independent of Weight Loss: A Pooled Analysis of Patient-level Data. AB - PURPOSE: Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP 1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level ("autotitration") after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective (~50 pg/mL) and steady-state (~300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses. METHODS: This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed. FINDINGS: Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA1c, FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not. IMPLICATIONS: Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide. PMID- 27126505 TI - Methylenetetrahydrofolate reductase C677T polymorphism, hypertension and risk of stroke: a prospective, nested case-control study. AB - BACKGROUND: Hyperhomocysteinemia is a risk factor for cardiovascular disease. To date, limited prospective studies have examined the joint effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, hyperhomocysteinemia and conventional vascular risk factors on risk of stroke and stroke death. METHODS: A total of 39 165 subjects from nine communities within Anqing, Anhui Province, China were prospectively followed from March 1995 to April 2005, with an average follow-up period of 6.2 years. None of the subjects had any history of vascular events at baseline. At follow-up, 251 incident stroke cases were identified. Using a nested, case-control study design, this analysis includes 106 cases with complete MTHFR C677T genotyping data and plasma samples. We selected 106 controls without vascular events matched for age, sex, community and years of plasma storage. Plasma total homocysteine (tHcy) level was measured by high-performance liquid chromatography. RESULTS: Hypertension was independently associated with incident stroke and stroke death after adjusting for important covariates including plasma log-transformed Hcy level. Relative to non-carriers of the MTHFR 677TT genotype with no hypertension, the adjusted odds ratio (95% confidence interval) of stroke and stroke death among hypertensive carriers of the MTHFR 677TT genotype was 10.6 (3.2 to 34.8), 5.8 (1.6 to 21.3), respectively. After excluding subjects with plasma Hcy above 20 MUmol/L, the relative odds for stroke, but not for stroke death, was more significantly pronounced (OR = 24.1, 95% CI: 2.3 to 246.1) among subjects with moderate plasma Hcy levels. However, there was no significant interactive effect between hypertensive status and the MTHFR C677T variant on the odds of the two outcomes as estimated by interaction models. CONCLUSIONS: Our major findings suggest that joint effects of the MTHFR C677T polymorphism and hypertension are consistent in predicting a significantly high risk of stroke. In addition for moderate plasma levels of Hcy, the predicted effects on the risk for the primary end point of stroke were more pronounced. These results may help to modify current approaches to vascular disease prevention in Chinese hypertensive patients. PMID- 27126506 TI - Intramolecular Electron Transfer in the Bacterial Two-Domain Multicopper Oxidase mgLAC. AB - The kinetics of the intramolecular electron transfer process in mgLAC, a bacterial two-domain multicopper oxidase (MCO), were investigated by pulse radiolysis. The reaction is initiated by CO2(-) radicals produced in anaerobic, aqueous solutions of the enzyme by microsecond pulses of radiation. A sequence of pulses of CO2(-) radicals enables examination of the reductive half-cycle of the MCO catalysis. This is done by titrations of the Type 1 (T1) Cu(II) site and monitoring of the time course and amplitude of its reoxidation by internal electron transfer (ET) to the Type 3 site. Comparison of the internal ET kinetics observed for mgLAC with those of other MCOs studied by pulse radiolysis shows that they exhibit distinct reactivities. One main cause for the different reactivities is the broad range of T1 copper redox potentials, from the moderate potential of bacterial enzymes to the high potential of fungal laccases, and this possibly also reflects evolutionary quaternary structural adaptation of the MCO family to the wide range of reducing substrates that they oxidize while maintaining efficient reduction of the common substrate, molecular oxygen. PMID- 27126507 TI - Spider behaviors include oral sexual encounters. AB - Several clades of spiders whose females evolved giant sizes are known for extreme sexual behaviors such as sexual cannibalism, opportunistic mating, mate-binding, genital mutilation, plugging, and emasculation. However, these behaviors have only been tested in a handful of size dimorphic spiders. Here, we bring another lineage into the picture by reporting on sexual behavior of Darwin's bark spider, Caerostris darwini. This sexually size dimorphic Madagascan species is known for extreme web gigantism and for producing the world's toughest biomaterial. Our field and laboratory study uncovers a rich sexual repertoire that predictably involves cannibalism, genital mutilation, male preference for teneral females, and emasculation. Surprisingly, C. darwini males engage in oral sexual encounters, rarely reported outside mammals. Irrespective of female's age or mating status males salivate onto female genitalia pre-, during, and post copulation. While its adaptive significance is elusive, oral sexual contact in spiders may signal male quality or reduce sperm competition. PMID- 27126508 TI - A first-in-class and a fished out anticancer platinum compound: cis-[PtCl2(NH3)2] and cis-[PtI2(NH3)2] compared for their reactivity towards DNA model systems. AB - Contrary to what was believed for many years, cis-PtI2(NH3)2, the diiodido analogue of cisplatin, displays high in vitro antiproliferative activity toward a set of tumour cell lines, overcoming resistance to cisplatin in a platinum resistant cancer cell line. In the context of a general reappraisal of iodinated Pt(ii) derivatives, aiming at a more systematic evaluation of their chemical and biological profiles, here we report on the reactivity of cis-PtI2(NH3)2 with selected DNA model systems, in single, double strand or G-quadruplex form, using cisplatin as a control. A combined approach has been exploited in this study, including circular dichroism (CD), UV-visible spectroscopy and electrospray mass spectrometry (ESI-MS) analyses. The data reveal that cis-PtI2(NH3)2 shows an overall reactivity towards the investigated oligonucleotides significantly higher than cisplatin. PMID- 27126509 TI - Alzheimer's disease and glaucoma: can glymphatic system dysfunction underlie their comorbidity? PMID- 27126510 TI - Twinkling artifact on color Doppler ultrasound: an advantage or a pitfall? AB - The twinkling artifact (TA) or color comet-tail artifact is characterized by a rapidly changing mixture of red and blue color Doppler signals. Even though many diseases and clinical conditions have been shown to produce this artifact, its source is not clearly understood yet. The TA may provide additional information to gray-scale ultrasound findings in several clinical situations. However, there may be pitfalls to keep in mind. We must first be aware of the TA to benefit from the advantages and avoid the pitfalls. In this review, we aim to give practicing radiologists an overview of the mechanisms and clinical applications of the TA by illustrating sample cases we have encountered. PMID- 27126511 TI - Assessment of the WHO Stunting Framework using Ethiopia as a case study. AB - Poor linear growth in children <5 years old, or stunting, is a serious public health problem particularly in Sub-Saharan Africa. In 2013, the World Health Organization (WHO) released a conceptual framework on the Context, Causes and Consequences of Childhood Stunting (the 'WHO framework') that identifies specific and general factors associated with stunting. The framework is based upon a global review of data, and we have applied it to a country-level analysis where health and nutrition policies are made and public health and nutrition data are collected. We reviewed the literature related to sub-optimal linear growth, stunting and birth outcomes in Ethiopia as a case study. We found consistent associations between poor linear growth and indicators of birth size, recent illness (e.g. diarrhoea and fever), maternal height and education. Other factors listed as causes in the framework such as inflammation, exposure to mycotoxins and inadequate feeding during and after illness have not been examined in Ethiopia, and the existing literature suggests that these are clear data gaps. Some factors associated with poor linear growth in Ethiopia are missing in the framework, such as household characteristics (e.g. exposure to indoor smoke). Examination of the factors included in the WHO framework in a country setting helps identifying data gaps helping to target further data collection and research efforts. (c) 2016 John Wiley & Sons Ltd. PMID- 27126512 TI - Bipolar radiofrequency ablation of benign thyroid nodules using a multiple overlapping shot technique in a 3-month follow-up. AB - Purpose The aim of this study was to evaluate the decrease of benign thyroid nodules after bipolar radiofrequency ablation (RFA) in a 3-month follow-up using a multiple overlapping shot technique ('MOST'). Methods A total of 18 patients with 20 symptomatic benign thyroid nodules (17 cold nodules, 3 hyperfunctioning nodules) were treated in one single session by bipolar RFA. Bipolar ablation was performed using MOST. The nodule volumes were measured prior to ablation and 3 months after the procedure using ultrasound. The population consisted of either solid (>80% solid tissue within the volume of interest), complex, or cystic nodules (<20% solid tissue within the volume of interest). Results Bipolar RFA resulted in a highly significant (p < 0.0001) decrease of nodule volume (DeltaV), median 5.3 mL (range 0.13-43.1 mL), corresponding to a relative reduction in mean of 56 +/- 17.9%. Median initial volume was 8 mL (range 0.48-62 mL); 3 months after ablation a median volume of 2.3 mL (range 0.3-32 mL) was measured. Nodule growth >=50% occurred in 70% (14 nodules). At the follow-up no complications such as infections, persisting pain, nerve injuries or immunogen stimulation occurred. Patients with cold nodules (15) remained euthyroid, with hyperfunctioning nodules either euthyroid (2) or latent hypofunctional (1). Conclusion The use of bipolar RFA is an effective, safe and suitable thermoablative technique to treat benign thyroid nodules. Combined with the multiple overlapping shot technique it allows sufficient ablation. PMID- 27126513 TI - Corrigendum: Critical dependence of magnetostructural coupling and magnetocaloric effect on particle size in Mn-Fe-Ni-Ge compounds. PMID- 27126514 TI - Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease. AB - Resident microglia and infiltrating myeloid cells play important roles in the onset, propagation, and resolution of inflammation in central nervous system (CNS) injury and disease. Identifying cell type-specific mechanisms will help to appropriately target interventions for tissue repair. Arginase-1 (Arg-1) is a well characterised modulator of tissue repair and its expression correlates with recovery after CNS injury. Here we assessed the cellular localisation of Arg-1 in two models of CNS damage. Using microglia specific antibodies, P2ry12 and Fc receptor-like S (FCRLS), we show the LysM-EGFP reporter mouse is an excellent model to distinguish infiltrating myeloid cells from resident microglia. We show that Arg-1 is expressed exclusively in infiltrating myeloid cells but not microglia in models of spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE). Our in vitro studies suggest that factors in the CNS environment prevent expression of Arg-1 in microglia in vivo. This work suggests different functional roles for these cells in CNS injury and repair and shows that such repair pathways can be switched on in infiltrating myeloid cells in pro inflammatory environments. PMID- 27126516 TI - The effect of Aloe vera gel on viability of dental pulp stem cells. AB - BACKGROUND: Dental pulp stem cells (DPSCs) can play a prominent role in tissue regeneration. Aloe vera L. (Liliaceae) contains the polysaccharide of acemannan that was shown to be a trigger factor for cell proliferation, differentiation, mineralization, and dentin formation. AIM: This study sought to determine the viability of DPSCs in Aloe vera in comparison with Hank's balanced salt solution (HBSS). MATERIALS AND METHOD: Twelve rabbits underwent anesthesia, and their incisor teeth were extracted; the pulp tissue was removed, chopped, treated with collagenase and plated in culture flasks. DPSCs from passage 3 were cultured in 24-well plates, and after 3 days, the culture media changed to 10, 25, 50, and 100% concentrations of Aloe vera at intervals of 45 and 90 min and 3 and 6 h. Distilled water was used as negative and HBSS as positive control for comparison. The cell morphology, viability, population doubling time (PDT), and growth kinetics were evaluated. RT-PCR was carried out for characterization and karyotyping for chromosomal stability. RESULTS: Aloe vera showed a significant higher viability than HBSS (74.74%). The 50% Aloe vera showed higher viability (97.73%) than other concentrations. PDT in 50% concentration was 35.1 h and for HBSS was 49.5 h. DPSCs were spindle shaped and were positive for CD73 and negative for CD34 and CD45. Karyotyping was normal. CONCLUSIONS: Aloe vera as an inexpensive and available herb can improve survival of avulsed or broken teeth in emergency cases as a transfer media. PMID- 27126518 TI - Juvenile recruitment in loggerhead sea turtles linked to decadal changes in ocean circulation. AB - Given the threats of climate change, understanding the relationship of climate with long-term population dynamics is critical for wildlife conservation. Previous studies have linked decadal climate oscillations to indices of juvenile recruitment in loggerhead sea turtles (Caretta caretta), but without a clear understanding of mechanisms. Here, we explore the underlying processes that may explain these relationships. Using the eddy-resolving Ocean General Circulation Model for the Earth Simulator, we generate hatch-year trajectories for loggerhead turtles emanating from Japan over six decades (1950-2010). We find that the proximity of the high-velocity Kuroshio Current to the primary nesting areas in southern Japan is remarkably stable and that hatchling dispersal to oceanic habitats itself does not vary on decadal timescales. However, we observe a shift in latitudes of trajectories, consistent with the Pacific Decadal Oscillation (PDO). In a negative PDO phase, the Kuroshio Extension Current (KEC) is strong and acts as a physical barrier to the northward transport of neonates. As a result, hatch-year trajectories remain mostly below 35 degrees N in the warm, unproductive region south of the Transition Zone Chlorophyll Front (TZCF). During a positive PDO phase, however, the KEC weakens facilitating the neonates to swim north of the TZCF into cooler and more productive waters. As a result, annual cohorts from negative PDO years may face a lack of resources, whereas cohorts from positive PDO years may find sufficient resources during their pivotal first year. These model outputs indicate that the ocean circulation dynamics, combined with navigational swimming behavior, may be a key factor in the observed decadal variability of sea turtle populations. PMID- 27126517 TI - The ectoparasitic mite Tropilaelaps mercedesae reduces western honey bee, Apismellifera, longevity and emergence weight, and promotes Deformed wing virus infections. AB - Historically an ectoparasite of the native Giant honey bee Apis dorsata, the mite Tropilaelaps mercedesae has switched hosts to the introduced western honey bee Apis mellifera throughout much of Asia. Few data regarding lethal and sub-lethal effects of T. mercedesae on A. mellifera exist, despite its similarity to the devastating mite Varroa destructor. Here we artificially infested worker brood of A. mellifera with T. mercedesae to investigate lethal (longevity) and sub-lethal (emergence weight, Deformed wing virus (DWV) levels and clinical symptoms of DWV) effects of the mite on its new host. The data show that T. mercedesae infestation significantly reduced host longevity and emergence weight, and promoted both DWV levels and associated clinical symptoms. Our results suggest that T. mercedesae is a potentially important parasite to the economically important A. mellifera honey bee. PMID- 27126515 TI - Magnaporthe oryzae Effector AVR-Pii Helps to Establish Compatibility by Inhibition of the Rice NADP-Malic Enzyme Resulting in Disruption of Oxidative Burst and Host Innate Immunity. AB - Plant disease resistance occurs as a hypersensitive response (HR) at the site of attempted pathogen invasion. This specific event is initiated in response to recognition of pathogen-associated molecular pattern (PAMP) and subsequent PAMP triggered immunity (PTI) and effector-triggered immunity (ETI). Both PTI and ETI mechanisms are tightly connected with reactive oxygen species (ROS) production and disease resistance that involves distinct biphasic ROS production as one of its pivotal plant immune responses. This unique oxidative burst is strongly dependent on the resistant cultivars because a monophasic ROS burst is a hallmark of the susceptible cultivars. However, the cause of the differential ROS burst remains unknown. In the study here, we revealed the plausible underlying mechanism of the differential ROS burst through functional understanding of the Magnaporthe oryzae (M. oryzae) AVR effector, AVR-Pii. We performed yeast two hybrid (Y2H) screening using AVR-Pii as bait and isolated rice NADP-malic enzyme2 (Os-NADP-ME2) as the rice target protein. To our surprise, deletion of the rice Os-NADP-ME2 gene in a resistant rice cultivar disrupted innate immunity against the rice blast fungus. Malic enzyme activity and inhibition studies demonstrated that AVR-Pii proteins specifically inhibit in vitro NADP-ME activity. Overall, we demonstrate that rice blast fungus, M. oryzae attenuates the host ROS burst via AVR-Pii-mediated inhibition of Os-NADP-ME2, which is indispensable in ROS metabolism for the innate immunity of rice. This characterization of the regulation of the host oxidative burst will help to elucidate how the products of AVR genes function associated with virulence of the pathogen. PMID- 27126520 TI - Effects of cyclone-generated disturbance on a tropical reef foraminifera assemblage. AB - The sedimentary record, and associated micropalaeontological proxies, is one tool that has been employed to quantify a region's tropical cyclone history. Doing so has largely relied on the identification of allochthonous deposits (sediments and microfossils), sourced from deeper water and entrained by tropical cyclone waves and currents, in a shallow-water or terrestrial setting. In this study, we examine microfossil assemblages before and after a known tropical cyclone event (Cyclone Hamish) with the aim to better resolve the characteristics of this known signal. Our results identify no allochthonous material associated with Cyclone Hamish. Instead, using a swathe of statistical tools typical of ecological studies but rarely employed in the geosciences, we identify new, previously unidentified, signal types. These signals include a homogenising effect, with the level of differentiation between sample sites greatly reduced immediately following Cyclone Hamish, and discernible shifts in assemblage diversity. In the subsequent years following Hamish, the surface assemblage returns to its pre cyclone form, but results imply that it is unlikely the community ever reaches steady state. PMID- 27126519 TI - Persistent part-solid nodules with solid part of 5 mm or smaller: Can the 'follow up and surgical resection after interval growth' policy have a negative effect on patient prognosis? AB - OBJECTIVE: To investigate whether "follow-up and surgical resection after interval growth" can negatively influence recurrence or mortality in patients with persistent part-solid nodules (PSNs) with solid components <=5 mm. METHODS: One hundred twenty five surgically resected persistent PSNs with solid components <=5 mm in 125 individuals were evaluated. Of the 125 PSNs, 54 and 71 PSNs were categorized into interval growth and immediate surgery groups, respectively. Cox regression analysis was performed to evaluate the association of "follow-up until interval growth" with recurrence and survival, adjusted for initial clinical and CT features. RESULTS: In the interval growth group, 30 patients showed increased nodule size, 10 increased solid parts, and the remaining 14 both patterns. Five patients showed clinical stage shifts (stage T1a, initially, to T1b after interval growth). Post-operative disease recurrence occurred in six individuals (interval growth group, n = 2/54; immediate surgery group, n = 4/71), and four individuals died (interval growth group, n = 1/54; immediate surgery group, n = 3/71). There were no significant differences between these two groups in terms of recurrence-free survival (p = 0.451) and overall survival (p = 0.185). CONCLUSION: "Follow-up and surgical resection after interval growth" did not negatively influence the prognosis of patients with persistent PSNs with solid components <=5 mm. KEY POINTS: * Incidences of post-operative recurrence or death in patients with PSN are low. * "Follow-up until interval growth" of PSNs does not negatively influence disease recurrence. * There was no survival disadvantage related with "follow-up until interval growth" in PSNs. PMID- 27126521 TI - Comparison of parental estimate of developmental age with measured IQ in children with neurodevelopmental disorders. AB - BACKGROUND: Formal IQ tests are an important part of the diagnostic and needs based assessment process for children with neurodevelopmental disorders. However, resources for such assessments are not always available. It has been suggested that parental estimates of their child's developmental age could serve as a proxy IQ when formal measures are unavailable. METHOD: Parental estimates of their child's developmental age were converted to a developmental quotient (DQ) in 197 children with Autism Spectrum Disorder (ASD) aged 4-9 years, and 108 children with ADHD and intellectual disability (ADHD + ID) aged 7-15 years. Formal IQ assessments were then conducted. Parents completed the Social Communication Questionnaire ((SCQ), a measure of autism symptomatology) and a demographic questionnaire. RESULTS: In the ASD sample, 58% of parent estimates were within 15 points (i.e. one standard deviation) of the child's measured IQ score. Lower measured IQ and lower SCQ total score predicted higher parental accuracy. In the ADHD + ID sample, 74% of parental estimates were within 15 points of measured IQ. In this group, higher child IQ predicted greater parental accuracy. Parents in the ADHD + ID group were more likely to overestimate children's ability level than parents in the ASD group. CONCLUSIONS: In this study, the majority of parents of children with ADHD and ID were able to estimate their child's intellectual ability level with some accuracy. Parents of children with ASD were less accurate, but this may be because these parents were focussing more on children's level of adaptive functioning, which is known to be typically lower than cognitive ability in ASD. PMID- 27126522 TI - Emergency management for congenital tracheal stenosis with endoluminal stenting in pediatric intensive care units. AB - OBJECTIVE: The objective of this study was to share our experience in the management of congenital tracheal stenosis (CTS) using self-expanding intraluminal stents in infants. METHODS: From January 2010 to August 2012, 31 infants with CTS treated using stents by bronchoscope in pediatric intensive care units (PICUs) were recruited for this study. RESULTS: Among the 31 patients, 17 were male and 14 were female with their ages ranging from 55 days to 22 months. CTS was associated with congenital heart disease (CHD) in 22 patients. There were no immediate stent-related airway complications. A significant and immediate improvement of respiratory obstruction following stent placement in all 31 patients led to successful weaning from the breathing machine and extubation. Granulation tissue formation as a complication was observed in three (9.7%) patients, but all were successfully managed using cryotherapy. During follow up (up to 24 months), stents in 29 infants remained functional. In seven cases, stents were retrieved under bronchoscope (the same day to 10 months), and three cases required stent replacement (each of the three cases had the stent replaced three times). Nine infants died after stenting due to other causes and two infants abandoned treatment. CONCLUSION: Airway stenting may provide an important therapeutic option in infants with CTS. PMID- 27126523 TI - A monoclonal natural human IgM protects axons in the absence of remyelination. AB - BACKGROUND: Whereas demyelination underlies early neurological symptoms in multiple sclerosis (MS), axonal damage is considered critical for permanent chronic deficits. Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic induced demyelinating disease (TMEV-IDD) with progressive axonal loss and neurologic dysfunction similar to progressive forms of MS. We previously reported that treatment of chronic TMEV-IDD mice with a neurite outgrowth-promoting natural human antibody, HIgM12, improved brainstem NAA concentrations and preserved functional motor activity. In order to translate this antibody toward clinical trial, we generated a fully human recombinant form of HIgM12, rHIgM12, determined the optimal in vivo dose for functional improvement in TMEV-IDD, and evaluated the functional preservation of descending spinal cord axons by retrograde labeling. FINDINGS: SJL/J mice at 45 to 90 days post infection (dpi) were studied. A single intraperitoneal dose of 0.25 mg/kg of rHIgM12 per mouse is sufficient to preserve motor function in TMEV-IDD. The optimal dose was 10 mg/kg. rHIgM12 treatment protected the functional transport in spinal cord axons and led to 40 % more Fluoro-Gold-labeled brainstem neurons in retrograde transport studies. This suggests that axons are not only present but also functionally competent. rHIgM12-treated mice also contained more mid-thoracic (T6) spinal cord axons than controls. CONCLUSIONS: This study confirms that a fully human recombinant neurite outgrowth-promoting monoclonal IgM is therapeutic in a model of progressive MS using multiple reparative readouts. The minimum effective dose is similar to that of a remyelination-promoting monoclonal human IgM discovered by our group that is presently in clinical trials for MS. PMID- 27126524 TI - A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma. AB - Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12 6.38; P = 2.7 * 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs). PMID- 27126525 TI - Long-Term Post-Discharge Risks in Older Survivors of Myocardial Infarction With and Without Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) associated with acute myocardial infarction (MI) confers high in-hospital mortality; however, among those patients who survive, little is known regarding their post-discharge mortality and health care use rates. OBJECTIVES: The purpose of this study was to determine 1-year survival and readmission rates after hospital discharge of older MI survivors with and without OHCA. METHODS: Using linked Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines and Medicare data, this study analyzed 54,860 patients with MI who were older than 65 years of age and who had been discharged alive from 545 U.S. hospitals between April 2011 and December 2012. Multivariable models examined the associations between MI-associated OHCA and 1-year post-discharge mortality or all-cause readmission rates. Patients discharged to hospice were excluded, given their known poor prognosis. RESULTS: Following hospital discharge, compared with older MI survivors without OHCA (n = 54,219), those with OHCA (n = 641, 1.2%) were more likely to be younger, male, and smokers, but less likely to have diabetes, heart failure, or prior revascularization. OHCA patients presented more often with ST segment elevation myocardial infarction (63.2% vs. 29.6%) and cardiogenic shock (29.0% vs. 2.2%); however, among in-hospital MI survivors, OHCA was not associated with 1-year post-discharge mortality (unadjusted 13.8% vs. 15.8%, p = 0.17, adjusted hazard ratio [HR]: 0.89; 95% confidence interval [CI]: 0.68 to 1.15). In contrast, MI survivors with OHCA actually had lower unadjusted and adjusted risk of the composite outcome of 1-year mortality or all-cause readmission than patients without OHCA (44.0% vs. 50.0%, p = 0.03, adjusted HR: 0.84; 95% CI: 0.72 to 0.97). CONCLUSIONS: Among older patients with MI who survived to hospital discharge and were not discharged to hospice, those presenting with OHCA did not have higher 1-year mortality or health care use rates compared with those MI survivors without OHCA. These findings show that the early risk of adverse events in patients with OHCA does not persist after hospital discharge, and they support efforts to improve initial survival rates of older patients with MI and OHCA. PMID- 27126526 TI - Moving Further Upstream in the Prevention of Cardiac Arrest and its Complications. PMID- 27126527 TI - Prognostic Value of Plasma Soluble Corin in Patients With Acute Myocardial Infarction. AB - BACKGROUND: Recent studies in animal models and humans have shown that corin is critically involved in the regulation of salt-water balance, blood pressure, and cardiac function. OBJECTIVES: The goal of this study was to investigate the prognostic value of plasma soluble corin in patients with acute myocardial infarction (AMI). METHODS: We enrolled 1,382 consecutive AMI patients in a prospective cohort study and explored the association of plasma corin with AMI outcomes using multivariable Cox proportional hazards analysis. RESULTS: Patients with low corin levels were more likely to be female and to have histories of hypertension and heart failure (HF). Kaplan-Meier survival curves indicated that patients with corin levels above the median had a lower incidence of major adverse cardiac events (MACE) and all-cause mortality compared with those whose corin levels were below the median. Multivariate Cox regression analysis suggested that log corin was an independent predictor of MACE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.42 to 0.96; p = 0.029), together with age, previous histories of AMI, HF, and diabetes, Killip class, percutaneous coronary intervention, coronary artery bypass graft, beta-blocker use, and log N-terminal pro-B-type natriuretic peptide. The C-statistic and integrated discrimination improvement for MACE were improved significantly by the addition of corin to the reference model. Moreover, log corin was also found to be a significant predictor of death (HR: 0.65; 95% CI: 0.41 to 0.97; p = 0.036) and HF hospitalization (HR: 0.48; 95% CI: 0.23 to 0.90; p = 0.009) after adjustment for clinical variables and established biomarkers of adverse prognosis. CONCLUSIONS: Our study demonstrates that corin is a valuable prognostic marker of MACE in patients with AMI, independent of established conventional risk factors. PMID- 27126528 TI - Corin Levels in Patients With Acute MI: Do We Need More Tools for Risk Stratification? PMID- 27126529 TI - Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis. AB - BACKGROUND: Fibrosis is a hallmark of many myocardial pathologies and contributes to distorted organ architecture and function. Recent studies have identified premature senescence as a regulatory mechanism of tissue fibrosis, but its relevance in the heart remains to be established. OBJECTIVES: This study investigated the role of premature senescence in myocardial fibrosis. METHODS: Murine models of cardiac diseases and human heart biopsies were analyzed for characteristics of premature senescence and fibrosis. Loss-of-function and gain of-function models of premature senescence were used to determine its pathophysiological role in myocardial fibrosis. RESULTS: Senescence markers p21(CIP1/WAF1), senescence-associated beta-galactosidase (SA-beta-gal), and p16(INK4a) were increased 2-, 8-, and 20-fold (n = 5 to 7; p < 0.01), respectively, in perivascular fibrotic areas after transverse aortic constriction compared with sham-treated control subjects. Similar results were observed with cardiomyocyte-specific beta1-adrenoceptor transgenic mice and human heart biopsies. Senescent cells were positive for platelet-derived growth factor receptor-alpha, vimentin, and alpha-smooth muscle actin, specifying myofibroblasts as the predominant cell population undergoing premature senescence in the heart. Inactivation of the premature senescence program by genetic ablation of p53 and p16(INK4a) (Trp53(-/-)Cdkn2a(-/-) mice) resulted in aggravated fibrosis after transverse aortic constriction, when compared with wild type control subjects (49 +/- 4.9% vs. 33 +/- 2.7%; p < 0.01), and was associated with impaired cardiac function. Conversely, cardiac-specific expression of CCN1 (CYR61), a potent inducer of premature senescence, by adeno-associated virus serotype 9 gene transfer, resulted in ~50% reduction of perivascular fibrosis after transverse aortic constriction, when compared with mock- or dominant negative CCN1-infected control subjects, and improved cardiac function. CONCLUSIONS: Our data establish premature senescence of myofibroblasts as an essential antifibrotic mechanism and potential therapeutic target in myocardial fibrosis. PMID- 27126530 TI - Fibroblast Senescence as a Therapeutic Target of Myocardial Fibrosis: Beyond Spironolactone? PMID- 27126532 TI - Are Animal Models of Pulmonary Hypertension Relevant to the Clinical Disease? PMID- 27126531 TI - Intratracheal Gene Delivery of SERCA2a Ameliorates Chronic Post-Capillary Pulmonary Hypertension: A Large Animal Model. AB - BACKGROUND: Pulmonary hypertension (PH) is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular (RV) failure, and premature death. Down-regulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in calcium ion (Ca(2+)) homeostasis and transition of pulmonary artery smooth muscle cells to a proliferative phenotype. OBJECTIVES: We assessed the feasibility of sustained pulmonary vascular SERCA2a gene expression using aerosolized delivery of adeno-associated virus type 1 (AAV1) in a large animal model of chronic PH and evaluated the efficacy of gene transfer regarding progression of pulmonary vascular and RV remodeling. METHODS: A model of chronic post-capillary PH was created in Yorkshire swine by partial pulmonary vein banding. Development of chronic PH was confirmed hemodynamically, and animals were randomized to intratracheal administration of aerosolized AAV1 carrying the human SERCA2a gene (n = 10, AAV1.SERCA2a group) or saline (n = 10). Therapeutic efficacy was evaluated 2 months after gene delivery. RESULTS: Transduction efficacy after intratracheal delivery of AAV1 was confirmed by beta-galactosidase detection in the distal pulmonary vasculature. Treatment with aerosolized AAV1.SERCA2a prevented disease progression as evaluated by mean pulmonary artery pressure, vascular resistance, and limited vascular remodeling quantified by histology. Therapeutic efficacy was supported further by the preservation of RV ejection fraction (p = 0.014) and improvement of the RV end-diastolic pressure volume relationship in PH pigs treated with aerosolized AAV1.SERCA2a. CONCLUSIONS: Airway-based delivery of AAV vectors to the pulmonary arteries was feasible, efficient, and safe in a clinically relevant chronic PH model. Vascular SERCA2a overexpression resulted in beneficial effects on pulmonary arterial remodeling, with attendant improvements in pulmonary hemodynamics and RV performance, and might offer therapeutic benefit by modifying fundamental pathophysiology in pulmonary vascular diseases. PMID- 27126534 TI - Constrictive Pericarditis Versus Restrictive Cardiomyopathy? AB - About one-half of the patients with congestive heart failure have preserved left ventricular ejection fraction (HFpEF). Although the etiology of HFpEF is most commonly related to long-standing hypertension and atherosclerosis, a significant number of suspected HFpEF patients have a restrictive cardiomyopathy or chronic pericardial disease. Recognizing these syndromes is important because early diagnosis may lead to instituting specific therapy that may prolong survival, improve quality of life, and/or recognize and treat an underlying systemic disorder. Advances in diagnostic imaging, biomarkers, and genetic testing today allow identification of the specific etiology in most cases. Novel pharmacological, immunologic, and surgical therapies are leading to improved quality of life and survival. PMID- 27126535 TI - Paying for Value: You Know it When You See it, or Do You? PMID- 27126533 TI - Inflammation as a Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction. AB - Treatment of acute myocardial infarction (AMI) has improved significantly in recent years, but many patients have adverse left ventricular (LV) remodeling, a maladaptive change associated with progressive heart failure. Although this change is usually associated with large infarcts, some patients with relatively small infarcts have adverse remodeling, whereas other patients with larger infarcts (who survive the first several days after AMI) do not. This paper reviews the relevant data supporting the hypothesis that individual differences in the intensity of the post-AMI inflammatory response, involving 1 or more inflammatory-modulating pathways, may contribute to adverse LV remodeling. It concludes by outlining how individual variations in the inflammatory response could provide important novel therapeutic targets and strategies. PMID- 27126536 TI - Educating the Next Generation of Peer Reviewers. PMID- 27126537 TI - Pre-Procedural 6-Min Walk Test as a Mortality Predictor in Patients Undergoing Transcatheter Mitral Valve Repair. PMID- 27126538 TI - Added Value of Female-Specific Factors Beyond Traditional Predictors for Future Cardiovascular Disease. PMID- 27126539 TI - Arterial Coronary Bypass Grafting: Targeting the Interventricular Septum. PMID- 27126540 TI - Association Between Migraine Headache and Cardiac Syndrome X. PMID- 27126541 TI - Caveat Emptor: Antibiotics, Endocarditis, and Statistical Artifacts. PMID- 27126542 TI - Reply: Association Between Migraine Headache and Cardiac Syndrome X. PMID- 27126543 TI - Reply: Caveat Emptor: Antibiotics, Endocarditis, and Statistical Artifacts. PMID- 27126544 TI - Molecular mechanism of prion-like tau-induced neurodegeneration. AB - INTRODUCTION: Accumulation of hyperphosphorylated tau and the disruption of microtubules are correlated with synaptic loss and pathology of Alzheimer's disease (AD). Impaired cognitive function and pathology of AD is correlated with this lesion. This review looks at the mechanism of neurodegeneration, the prion like behavior of tau in its interaction with normal MAPs in correlation with tau hyperphosphorylation. METHODS: We reviewed our work in the field as well as current literature that pertains to tau phosphorylation and the biological effects. RESULTS: Hyperphosphorylation of tau in AD, in vitro, in cells, or in animal models converts this protein into a prion-like protein that is able to propagate the altered conformation. DISCUSSION: These findings suggest that phosphorylation of tau is a critical event in neurodegeneration. The combination of phosphorylation sites can generate a gain of toxic function for tau. The mechanism of tau toxicity might involve not only the microtubule system but also interference with other cellular compartments such as the nucleus and the actin cytoskeleton. PMID- 27126545 TI - O-GlcNAcylation: A regulator of tau pathology and neurodegeneration. AB - O-GlcNAcylation is the posttranslational modification of intracellular proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc). The discovery of O-GlcNAc modification of tau and its impact on tau phosphorylation has attracted recent research interest in O-GlcNAc studies in the Alzheimer's disease (AD) field. Modification of proteins by O-GlcNAc occurs extensively in the brain. The expressions and activities of the enzymes catalyzing O-GlcNAc cycling are several fold higher in the brain than in the peripheral tissues. The O-GlcNAcylation levels of brain proteins including tau are decreased in AD brain, probably due to decreased brain glucose metabolism. The reduction of brain O-GlcNAcylation appears to mediate the molecular mechanism by which decreased brain glucose metabolism contributes to neurodegeneration. Studies on mouse models of tauopathies suggest a neuroprotective role of pharmacological elevation of brain O-GlcNAc, which could potentially be a promising approach for treating AD and other neurodegenerative diseases. PMID- 27126546 TI - Net Blood Pressure Reduction Following 9 Months of Lifestyle and High-Intensity Interval Training Intervention in Individuals With Abdominal Obesity. AB - The authors aimed to study the impact of a combined 9-month lifestyle program (Mediterranean diet nutritional counselling, and high-intensity interval training twice a week) on blood pressure (BP) in individuals with abdominal obesity, taking into account the regression-to-the-mean phenomena. A total of 115 participants (53+/-9 years; 84 women; waist circumference [WC]: 111+/-13 cm; systolic/diastolic BP [SBP/DBP]: 133+/-13/82+/-8 mm Hg; 13% diabetics; 12% smokers; and 30% taking antihypertensive therapy) were retrospectively analyzed before and after the program. After 9 months, we observed an improvement in weight (-5.2+/-5.6 kg) and WC (-6.3+/-6.0 cm), and an average SBP/DBP net decrease of -5.1+/-13.7/-2.8+/-8.7 mm Hg. These changes were not uniform: 67 participants (58%) decreased their SBP by 2 mm Hg or more. The characteristics of responders included a higher baseline BP than nonresponders (SBP/DBP: 137.2+/ 13.7/83.1+/-7.3 mm Hg vs 127.0+/-10.3/80.0+/-7.3 mm Hg, P<.05) and a higher proportion of participants with a baseline BP >=130/85 mm Hg (81% vs 52%, P=.001) or with the metabolic syndrome (75% vs 54%, P=.02). PMID- 27126547 TI - Management of Hepatic Encephalopathy: A Primer. AB - OBJECTIVE: To review the management of hepatic encephalopathy (HE), including lifestyle modifying strategies and pharmacological interventions. DATA SOURCES: A literature search of PubMed through March 2016 was conducted utilizing the keywords hepatic encephalopathy, ammonia, and cirrhosis All published articles evaluating treatments for HE were considered. STUDY SELECTION AND DATA EXTRACTION: Available English-language data from reviews, abstracts, presentations, and clinical trials of the treatment of HE in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS: HE is a prevalent complication of portal hypertension and cirrhosis that results in altered mental status and neuropsychiatric impairment. Although the pathogenesis has not been elucidated, numerous treatment options exist. This review will explore the role of dietary interventions and supplements, including use of zinc, acetyl-l-carnitine, and probiotics, in the management of HE. Additionally, the use of various ammonia-lowering agents will be evaluated. The nonabsorbable disaccharides represent first-line therapies for the management and prophylaxis of HE; rifaximin use has been demonstrated to be effective for both treatment and prophylaxis of HE symptoms, with use relegated to those patients who fail to respond to or tolerate the nonabsorbable disaccharides. In light of toxicities associated with the use of neomycin and metronidazole, recent guidelines recommend both as alternatives for the treatment of HE, with the use of vancomycin discouraged. CONCLUSION: Although numerous treatment options are available, management of HE remains a clinical challenge. Additional research is needed to explore the pathogenesis and better understand the role of pharmacotherapy in managing this condition. PMID- 27126548 TI - Successful treatment of large refractory pyoderma gangrenosum-like presentation of granulomatosis with polyangiitis by rituximab. PMID- 27126549 TI - The complex metabolism of trimethylamine in humans: endogenous and exogenous sources. AB - Trimethylamine (TMA) is a tertiary amine with a characteristic fishy odour. It is synthesised from dietary constituents, including choline, L-carnitine, betaine and lecithin by the action of microbial enzymes during both healthy and diseased conditions in humans. Trimethylaminuria (TMAU) is a disease typified by its association with the characteristic fishy odour because of decreased TMA metabolism and excessive TMA excretion. Besides TMAU, a number of other diseases are associated with abnormal levels of TMA, including renal disorders, cancer, obesity, diabetes, cardiovascular diseases and neuropsychiatric disorders. Aside from its role in pathobiology, TMA is a precursor of trimethylamine-N-oxide that has been associated with an increased risk of athero-thrombogenesis. Additionally, TMA is a major air pollutant originating from vehicular exhaust, food waste and animal husbandry industry. The adverse effects of TMA need to be monitored given its ubiquitous presence in air and easy absorption through human skin. In this review, we highlight multifaceted attributes of TMA with an emphasis on its physiological, pathological and environmental impacts. We propose a clinical surveillance of human TMA levels that can fully assess its role as a potential marker of microbial dysbiosis-based diseases. PMID- 27126550 TI - Human serum albumin-stabilized gold nanoclusters act as an electron transfer bridge supporting specific electrocatalysis of bilirubin useful for biosensing applications. AB - Human serum albumin (HSA)-stabilized Au18 nanoclusters (AuNCs) were synthesized and chemically immobilized on an Indium tin oxide (ITO) plate. The assembly process was characterized by advanced electrochemical and spectroscopic techniques. The bare ITO electrode generated three irreversible oxidation peaks, whereas the HSA-AuNC-modified electrode produced a pair of redox peaks for bilirubin at a formal potential of 0.27V (vs. Ag/AgCl). However, the native HSA protein immobilized on the ITO electrode failed to produce any redox peak for bilirubin. The results indicate that the AuNCs present in HSA act as electron transfer bridge between bilirubin and the ITO plate. Docking studies of AuNC with HSA revealed that the best docked structure of the nanocluster is located around the vicinity of the bilirubin binding site, with an orientation that allows specific oxidation. When the HSA-AuNC-modified electrode was employed for the detection of bilirubin using chronoamperometry at 0.3V (vs. Ag/AgCl), a steady state current response against bilirubin in the range of 0.2MUM to 7MUM, with a sensitivity of 0.34MUAMUM(-1) and limit of detection of 86.32nM at S/N 3, was obtained. The bioelectrode was successfully applied to measure the bilirubin content in spiked serum samples. The results indicate the feasibility of using HSA-AuNC as a biorecognition element for the detection of serum bilirubin levels using an electrochemical technique. PMID- 27126551 TI - Dendrimer-based nanocarriers: a versatile platform for drug delivery. AB - Advances in nanotechnology have had profound impacts on therapeutic delivery, leading to the development of nanomaterials engineered with large carrying capabilities and targeting functionalities. Among the nanomaterials, dendrimers have garnered particular attention from researchers owing to their well-defined structure, near-monodispersity, and ease of multifunctionalization. As hyperbranched, three-dimensional macromolecules, dendrimers can be engineered to target and deliver a wide range of therapeutic agents, including small molecules, peptides, and genes, reducing their systemic toxicities and enhancing efficacies. In this review, we provide a comprehensive overview of the commonly employed dendrimer-based nanocarrier designs, including dendrimer conjugates, Janus dendrimers, and linear-dendritic block copolymers. The discussion will progress through the basic synthetic strategies of dendrimer-based nanocarriers, followed by the potential clinical applications related to their unique structural properties. Finally, the major challenges that these nanocarriers are currently facing in their clinical translation and possible solutions to address these issues will be discussed, with the aim to provide researchers in the drug delivery field a good understanding of the potential utilities of dendrimer-based nanocarriers. WIREs Nanomed Nanobiotechnol 2017, 9:e1409. doi: 10.1002/wnan.1409 For further resources related to this article, please visit the WIREs website. PMID- 27126552 TI - Toward intensifying design of experiments in upstream bioprocess development: An industrial Escherichia coli feasibility study. AB - In this study, step variations in temperature, pH, and carbon substrate feeding rate were performed within five high cell density Escherichia coli fermentations to assess whether intraexperiment step changes, can principally be used to exploit the process operation space in a design of experiment manner. A dynamic process modeling approach was adopted to determine parameter interactions. A bioreactor model was integrated with an artificial neural network that describes biomass and product formation rates as function of varied fed-batch fermentation conditions for heterologous protein production. A model reliability measure was introduced to assess in which process region the model can be expected to predict process states accurately. It was found that the model could accurately predict process states of multiple fermentations performed at fixed conditions within the determined validity domain. The results suggest that intraexperimental variations of process conditions could be used to reduce the number of experiments by a factor, which in limit would be equivalent to the number of intraexperimental variations per experiment. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1343-1352, 2016. PMID- 27126553 TI - Effects of glucose-fructose versus glucose ingestion on stride characteristics during prolonged treadmill running. AB - Scarce research has examined the effects of carbohydrate composition on running stride characteristics. On two occasions, 14 males and 6 females completed a 120 min sub-maximal run followed by a 4-mile time trial. Participants consumed glucose (GLU) or glucose-fructose (GLU-FRU) beverages supplying 1.3 g/min carbohydrate. Substrate use, psychological affect [Feeling Scale (FS)], and stride characteristics (stride frequency, stride length, and contact time) were assessed. Effects were expressed as Cohen's d (90% confidence limits [90% CL]). CLs for stride frequency differences at 53 min (90% CL = 0.04-0.21) and 113 min (90% CL = 0.02-0.24) did not cover 0, indicating a positive effect of GLU-FRU. However, effect sizes were small (d = 0.13) and likely-to-very-likely trivial. Energy expenditure differences at sub-maximal end were very likely trivial (d = 0.08; 90% CL = 0.00-0.17), while FS ratings were possibly higher for GLU-FRU at 50 (d = 0.19; 90% CL = -0.10-0.48) and 110 min (d = 0.16; 90% CL = -0.13-0.45). During the time trial, stride length was possibly higher with GLU-FRU (d = 0.13; 90% CL = -0.08-0.33). Glucose-fructose co-ingestion has no significant effect on stride characteristics during constant-velocity running but may result in slightly higher stride length during self-paced running. PMID- 27126554 TI - Characterizing Adults Receiving Primary Medical Care in New York City: Implications for Using Electronic Health Records for Chronic Disease Surveillance. AB - INTRODUCTION: Electronic health records (EHRs) from primary care providers can be used for chronic disease surveillance; however, EHR-based prevalence estimates may be biased toward people who seek care. This study sought to describe the characteristics of an in-care population and compare them with those of a not-in care population to inform interpretation of EHR data. METHODS: We used data from the 2013-2014 New York City Health and Nutrition Examination Survey (NYC HANES), considered the gold standard for estimating disease prevalence, and the 2013 Community Health Survey, and classified participants as in care or not in care, on the basis of their report of seeing a health care provider in the previous year. We used chi(2) tests to compare the distribution of demographic characteristics, health care coverage and access, and chronic conditions between the 2 populations. RESULTS: According to the Community Health Survey, approximately 4.1 million (71.7%) adults aged 20 or older had seen a health care provider in the previous year; according to NYC HANES, approximately 4.7 million (75.1%) had. In both surveys, the in-care population was more likely to be older, female, non-Hispanic, and insured compared with the not-in-care population. The in-care population from the NYC HANES also had a higher prevalence of diabetes (16.7% vs 6.9%; P < .001), hypercholesterolemia (35.7% vs 22.3%; P < .001), and hypertension (35.5% vs 26.4%; P < .001) than the not-in-care population. CONCLUSION: Systematic differences between in-care and not-in-care populations warrant caution in using primary care data to generalize to the population at large. Future efforts to use primary care data for chronic disease surveillance need to consider the intended purpose of data collected in these systems as well as the characteristics of the population using primary care. PMID- 27126555 TI - What Rural Women Want the Public Health Community to Know About Access to Healthful Food: A Qualitative Study, 2011. AB - INTRODUCTION: Living in a rural food desert has been linked to poor dietary habits. Understanding community perspectives about available resources and feasible solutions may inform strategies to improve food access in rural food deserts. The objective of our study was to identify resources and solutions to the food access problems of women in rural, southernmost Illinois. METHODS: Fourteen focus groups with women (n = 110 participants) in 4 age groups were conducted in a 7-county region as part of a community assessment focused on women's health. We used content analysis with inductive and deductive approaches to explore food access barriers and facilitators. RESULTS: Similar to participants in previous studies, participants in our study reported insufficient local food sources, which they believe contributed to poor dietary habits, high food prices, and the need to travel for healthful food. Participants identified existing local activities and resources that help to increase access, such as home and community gardens, food pantries, and public transportation, as well as local solutions, such as improving nutrition education and public transportation options. CONCLUSION: Multilevel and collaborative strategies and policies are needed to address food access barriers in rural communities. At the individual level, education may help residents navigate geographic and economic barriers. Community solutions include collaborative strategies to increase availability of healthful foods through traditional and nontraditional food sources. Policy change is needed to promote local agriculture and distribution of privately grown food. Understanding needs and strengths in rural communities will ensure responsive and effective strategies to improve the rural food environment. PMID- 27126556 TI - Integration of Oral Health Into the Well-Child Visit at Federally Qualified Health Centers: Study of 6 Clinics, August 2014-March 2015. AB - INTRODUCTION: Early childhood caries, the most common chronic childhood disease, affects primary dentition and can impair eating, sleeping, and school performance. The disease is most prevalent among vulnerable populations with limited access to pediatric dental services. These same children generally receive well-child care at federally qualified health centers. The objective of this study was to identify facilitators and barriers to the integration of oral health into pediatric primary care at health centers to improve problem recognition, delivery of preventive measures, and referral to a dentist. METHODS: We collected and analyzed background data and data from structured observations and 39 interviews with administrators and staff at 6 clinics in 2 states, Maryland and Massachusetts. RESULTS: Participants valued oral health across professional roles but cited limited time, lack of training and expertise, low caregiver literacy, and lack of shared medical and dental electronic records as barriers to cooperation. Facilitators included an upper-level administration with the vision to see the value of integration, designated team leaders, and champions. An administration's vision, not structural determinants, patient characteristics, or geographic location, predicted the level of integration. Interviewees generated multilevel recommendations to promote delivery of oral health preventive measures and services during a well-child visit. CONCLUSION: Poor oral health contributes to health care disparities. Barriers to integrating dental care into pediatric medical practice at health centers must be overcome to improve oral health for children living in poverty, with a disability, at a rural address, or any combination of these. Implementation will require adapting delivery systems to support multidisciplinary collaboration. Strategies suggested here may point the way to enhancing children's oral health. PMID- 27126557 TI - Glucocorticoid receptor mediated the propofol self-administration by dopamine D1 receptor in nucleus accumbens. AB - Propofol, a widely used anesthetic, can cause addictive behaviors in both human and experimental animals. In the present study, we examined the involvement of glucocorticoid receptor (GR) signaling in the molecular process by which propofol may cause addiction. The propofol self-administration model was established by a fixed ratio 1 (FR1) schedule of reinforced dosing over successive 14days in rats. On day 15, the rats were treated with dexamethasone, a GR agonist (10-100MUg/kg), or RU486, a GR antagonist (10-100MUg/kg) at 1h prior to the last training. The animal behaviors were recorded automatically by the computer. The expression of dopamine D1 receptor in the nucleus accumbens (NAc) was examined by Western blot and the concentrations of plasma corticosterone were measured by enzyme-linked immunosorbent assay (ELISA). To further examine the specificity of GR in the process, mineralocorticoid receptor (MR) antagonist, spironolactone, and dexamethasone plus MR agonist, aldosterone, were also tested. Administration of dexamethasone (100MUg/kg) or RU486 (?10mg/kg) significantly attenuated the rate of propofol maintained active nose-poke responses and infusions, which were accompanied by reductions in both plasma corticosterone level and the expression of D1 receptor in the NAc. Neither spironolactone alone nor dexamethasone combined with aldosterone affected the propofol-maintaining self-administrative behavior, indicating GR, but not MR, modulates the propofol reward in rats. In addition, neither the food-maintaining sucrose responses under FR1 schedule nor the locomotor activity was affected by any doses of dexamethasone or RU486 tested. These findings provide evidence that GR signaling may play an important role in propofol reward. PMID- 27126558 TI - Inhibition of the pontine Kolliker-Fuse nucleus reduces genioglossal activity elicited by stimulation of the retrotrapezoid chemoreceptor neurons. AB - The Kolliker-Fuse (KF) region, located in the dorsolateral pons, projects to several brainstem areas involved in respiratory regulation, including the chemoreceptor neurons within the retrotrapezoid nucleus (RTN). Several lines of evidence indicate that the pontine KF region plays an important role in the control of the upper airways for the maintenance of appropriate airflow to and from the lungs. Specifically, we hypothesized that the KF region is involved in mediating the response of the hypoglossal motor activity to central respiratory chemoreflex activation and to stimulation of the chemoreceptor neurons within the RTN region. To test this hypothesis, we combined immunohistochemistry and physiological experiments. We found that in the KF, the majority of biotinylated dextran amine (BDA)-labeled axonal varicosities contained detectable levels of vesicular glutamate transporter-2 (VGLUT2), but few contained glutamic acid decarboxylase-67 (GAD67). The majority of the RTN neurons that were FluorGold (FG)-immunoreactive (i.e., projected to the KF) contained hypercapnia-induced Fos, but did not express tyrosine hydroxylase. In urethane-anesthetized sino aortic denervated and vagotomized male Wistar rats, hypercapnia (10% CO2) or N methyl-d-aspartate (NMDA) injection (0.1mM) in the RTN increased diaphragm (DiaEMG) and genioglossus muscle (GGEMG) activities and elicited abdominal (AbdEMG) activity. Bilateral injection of muscimol (GABA-A agonist; 2mM) into the KF region reduced the increase in DiaEMG and GGEMG produced by hypercapnia or NMDA into the RTN. Our data suggest that activation of chemoreceptor neurons in the RTN produces a significant increase in the genioglossus muscle activity and the excitatory pathway is dependent on the neurons located in the dorsolateral pontine KF region. PMID- 27126560 TI - We Wait Too Long to Refer Patients for Transplantation. AB - Late referral of patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) for evaluation of kidney transplantation is common. Even though renal transplantation offers a clear survival benefit to patients with advanced CKD and ESRD and should be considered the renal replacement therapy of choice, numerous barriers to early renal transplant referral have been observed. Some of these barriers can be overcome by improving the communication between the referring providers and the transplant centers. Furthermore, providing more intensive education to both patients and referring providers with regard to the eligibility of CKD and ESRD patients for a transplant will likely result in higher referral rates. This in turn will lead to improved survival outcomes in this group of patients with otherwise significantly increased morbidity and mortality. PMID- 27126559 TI - Post-treatment with prolactin protects hippocampal CA1 neurons of the ovariectomized female rat against kainic acid-induced neurodegeneration. AB - Kainic acid (KA) is a glutamate agonist widely used in studies of neurodegeneration due to its ability to induce excitotoxic damage in the rodent brain. Previously, we reported that pre-treatment with prolactin (PRL) prevents the neuron loss induced by KA administration in CA1, CA3 and CA4 of the hippocampus of the female rat. Here, we investigated if PRL has a neuroprotective effect in the dorsal hippocampus when it is administered after KA. For this, 100ng of KA or 0.9% saline was administered intracerebroventricularly (ICV) to ovariectomized female rats. One hour later, they received subcutaneous PRL (103MUg/day for 7days) or saline through an osmotic minipump. Also, to determine the hippocampal neurogenesis rate, the rats were administered bromodeoxyuridine along with the PRL treatment. Immunostaining for NeuN revealed that neuronal loss is lower in the CA1 of PRL-treated rats compared with the untreated group, but PRL did not confer any protection in the CA3 and CA4 subfields. Furthermore, PRL prevented the KA-induced cognitive deficit measured as a better performance in the novel object recognition test. The PRL treatment did not modify the neurogenesis rate. These data indicate that post-treatment with PRL confers differential neuroprotection against KA-induced neuronal loss in hippocampal subfield CA1, which correlates with a more mild cognitive deficit compared with the untreated control group. PMID- 27126561 TI - Validation of the Resilience Scale for Adolescents (READ) in Ireland: a multi group analysis. AB - Resilience is a process reflecting positive adaptation in the face of adversity. The Resilience Scale for Adolescence (READ) incorporates intrapersonal and interpersonal protective factors mapping onto the three salient domains of resilience, including individual, family and external environment. This study investigated the validity and reliability of the READ by means of factor analysis, multi-group analysis, inter-correlations and internal consistency measures. Participants were 6085 young people in Ireland aged 12-18 years. Participants completed the My World Survey - Second Level (MWS-SL), assessing risk and protective factors of mental health. Confirmatory factor analysis validated the original five-factor structure of the READ including Personal Competence, Social Competence, Structured Style, Family Cohesion, and Social Resources, chi2 (340) = 6146.02, p < 0.001, RMSEA = 0.056 (90% CI = 0.054-0.057), CFI = 0.97; GFI = 0.93. Measurement invariance indicated that the five-factor structure was similar across gender, school cycle and distress levels. Construct validity was evident, by correlating the five factors of the READ with various social, psychological and behavioural variables. The findings suggest that the READ is a valid measure to assess resilience factors among adolescents in Ireland, demonstrating its applicability in a different cultural context and with a wider age range of adolescents. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27126563 TI - Comments to "Orthostatic tremor secondary to recreational use of solvents". PMID- 27126564 TI - Reply to "Orthostatic tremor secondary to recreational use of solvents". PMID- 27126566 TI - Idiopathic chronic hydrocephalus in adults. PMID- 27126565 TI - Late-onset meningeal lymphomatosis in mantle cell lymphoma controlled with chemotherapy. PMID- 27126562 TI - Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes. AB - Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control. PMID- 27126567 TI - A comparison of alpha coefficients in independent samples: A complementary study to EUROQUEST by Marhuenda et al. PMID- 27126569 TI - Clinical and magnetic resonance imaging abnormalities of the tongue in patients with amyotrophic lateral sclerosis. PMID- 27126568 TI - Health-related quality of life in caregivers of patients with Alzheimer's disease. AB - INTRODUCTION: Informal caregivers of patients with Alzheimer's disease (AD) have a poor health-related quality of life (HRQOL). HRQOL is an increasingly common user-focused outcome measure. We have evaluated HRQOL longitudinally in caregivers of AD patients at baseline and at 12 months. METHODS: Ninety-seven patients diagnosed with AD according to the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke, and Alzheimer's Disease and Related Disorders Association) and their 97 respective primary caregivers were included in the study. We analysed the following data at the baseline visit: sociodemographic data of both patients and carers, patients' clinical variables, and data related to the healthcare provided to patients by carers. HRQOL of caregivers was measured with the SF-36 questionnaire at baseline and 12 months later. RESULTS: At 12 months, primary caregivers scored lower in the 8 subscales of the SF-36 questionnaire; differences were statistically significant in all dimensions except for 'physical function' and 'social function'. Baseline scores in our sample were lower than those of the general population. 'Vitality' is the dimension that presented the lowest scores. CONCLUSION: HRQOL in caregivers of patients with Alzheimer's disease deteriorates over time and is poorer than that of the age- and sex-matched general population. PMID- 27126570 TI - A report of reliable differences in the profile of the ACE-III. PMID- 27126571 TI - Dermoscopy in the diagnosis of extradigital glomus tumors. PMID- 27126572 TI - Anesthetic management of a pediatric patient with pulmonary arteriovenous fistula undergoing liver transplantation - a case report. AB - For patients with HPS who require anesthesia for a procedure, HPV should be maintained to prevent worsening hypoxemia. Here, the case of a 9-yr-old girl who was scheduled for a living donor liver transplantation is presented. The patient suffered from end-stage liver disease with HPS due to biliary atresia, which contributed to the development of a diffuse pulmonary AVF. Consequently, anesthetic management of this patient involved two different types of pulmonary shunt. It is important to maintain HPV, not only to prevent worsening of the hypoxia caused by HPS but also to inhibit an increase in PVR that could cause an increase of shunt flow through the pathological fistula. A TIVA technique was performed, and a nitrous oxide inhaler was prepared in case of a possible increase in PVR during the reperfusion period. There were no adverse events during the operation. Thus, anesthesiologists should be aware of the pathophysiological status of HPS and its potential to progress to a pulmonary AVF in order to meticulously determine an anesthesia plan that accounts for the hypoxia and PVR that are associated with HPS. PMID- 27126573 TI - Risk factors associated with a decreased estimated glomerular filtration rate based on cystatin C levels in school-age children with extremely low birthweight. AB - AIM: A single centre retrospective cohort study was designed to investigate the estimated glomerular filtration rate (eGFR) in school-age children born with extremely low birthweight (ELBW) and to determine risk factors predictive of decreased eGFR. METHODS: We compared eGFR based on cystatin C (CysC-eGFR) between school-age children born with ELBW (ELBW group, n = 48; median gestational age: 26.9 weeks; median birthweight: 792 g) and children born at term (control group, n = 48). The ELBW group was then further divided into a decreased CysC-eGFR subgroup (eGFR <90 mL/min per 1.73 m2 , n = 20) and a normal CysC-eGFR subgroup (n = 28), and perinatal background factors were compared. RESULTS: The ELBW group showed a significantly lower CysC-eGFR compared with the control group (P < 0.001). Comparison between the decreased and normal CysC-eGFR subgroups in the ELBW group showed that children with lower birthweight, shorter gestational age, lower 5-min Apgar score, longer length of mechanical ventilation, lower weight gain in the first 11 weeks, chronic lung disease, and postnatal corticosteroid administration had significantly decreased CysC-eGFR. Multivariate logistic regression showed that a lower 5-min Apgar score was the only independent risk factor for decreased CysC-eGFR. CONCLUSIONS: CysC-eGFR might already be decreased at school age in children born with ELBW. Renal assessment in regular follow-up examinations is recommended. PMID- 27126574 TI - Albumin as a carrier for NO delivery: preparation, physicochemical characterization, and interaction with gold nanoparticles. AB - BACKGROUND: Nitric oxide (NO) is a gaseous transmitter playing numerous physiological roles and characterized by a short half-life. Its binding to endogenous thiols increases its stability, facilitating its storage and transport. The purpose of this study was to investigate the nitrosated serum albumin (SA-SNO) and to provide a reference for its easy preparation for further use in in vitro studies. METHODS: Serum albumin (SA) was S-nitrosated by reacting with (i) NaNO2 in acidic medium; (ii) different low-molecular weight S nitrosothiols (RSNO) (S-nitrosocysteine (CysNO), S-nitrosoglutathione (GSNO), and S,S'-dinitrosobucillamine (Buc(NO)2)); and (iii) diethylamine NONOate (DEA/NO). SA-SNO was purified by size exclusion chromatography and the S-nitrosation site and the rate were studied by mass spectrometry and Griess-Saville assay, respectively. Then, SA-SNO was characterized by spectrofluorimetry, dynamic light scattering, and circular dichroism. Finally, SA-SNO reactivity with citrate stabilized gold nanoparticles (AuNP-citrate) was investigated via determination of NO release. RESULTS: S-nitrosation rates of SA were 90.1 +/- 3.3, 76.8 +/- 2.7, 80.3 +/- 3.2, 84.8 +/- 5.0, and 15.4 +/- 1.9% (n = 5), when SA was reacted with acidified NaNO2, CysNO, GSNO, Buc(NO)2, and DEA/NO, respectively. The physicochemical characterization indicated that the resulting product corresponded to a mono-S-nitrosothiol (on cysteine-34), and the conformational construction remained unchanged. Stability studies showed that the NO content was preserved over 1 week. AuNP-citrate reacted with SA-SNO with increase of its hydrodynamic diameter but preservation of SNO bond. CONCLUSIONS: SA-SNO prepared and stored under the reported conditions affords a well-defined reference suitable for in vitro studies. PMID- 27126575 TI - Eggs: good or bad? AB - Eggs have one of the lowest energy to nutrient density ratios of any food, and contain a quality of protein that is superior to beef steak and similar to dairy. From a nutritional perspective, this must qualify eggs as 'good'. The greater burden of proof has been to establish that eggs are not 'bad', by increasing awareness of the difference between dietary and blood cholesterol, and accumulating sufficient evidence to exonerate eggs from their associations with CVD and diabetes. After 60 years of research, a general consensus has now been reached that dietary cholesterol, chiefly from eggs, exerts a relatively small effect on serum LDL-cholesterol and CVD risk, in comparison with other diet and lifestyle factors. While dietary guidelines have been revised worldwide to reflect this view, associations between egg intake and the incidence of diabetes, and increased CVD risk in diabetes, prevail. These associations may be explained, in part, by residual confounding produced by other dietary components. The strength of evidence that links egg intake to increased CVD risk in diabetes is also complicated by variation in the response of serum LDL-cholesterol to eggs and dietary cholesterol in types 1 and 2 diabetes. On balance, the answer to the question as to whether eggs are 'bad', is probably 'no', but we do need to gain a better understanding of the effects of dietary cholesterol and its association with CVD risk in diabetes. PMID- 27126576 TI - Pair-eigenstates and mutual alignment of coupled molecular rotors in a magnetic field. AB - We examine the rotational states of a pair of polar (2)Sigma molecules subject to a uniform magnetic field. The electric dipole-dipole interaction between the molecules creates entangled pair-eigenstates of two types. In one type, the Zeeman interaction between the inherently paramagnetic molecules and the magnetic field destroys the entanglement of the pair-eigenstates, whereas in the other type it does not. The pair-eigenstates exhibit numerous intersections, which become avoided for pair-eigenstates comprised of individual states that meet the selection rules DeltaJi = 0, +/- 1, DeltaNi = 2n (n = 0, +/-1, +/-2,...), and DeltaMi = 0, +/- 1 imposed by the electric dipole-dipole operator. Here Ji, Ni and Mi are the total, rotational and projection angular momentum quantum numbers of molecules i = 1, 2 in the absence of the electric dipole-dipole interaction. We evaluate the mutual alignment of the pair-eigenstates and find it to be independent of the magnetic field, except for states that undergo avoided crossings, in which case the alignment of the interacting states is interchanged at the magnetic field corresponding to the crossing point. We present an analytic model which provides ready estimates of the pairwise alignment cosine that characterises the mutual alignment of the pair of coupled rotors. PMID- 27126577 TI - [Suicidal ideation of prisoners : Influence of duration of imprisonment, personality traits and disorders]. AB - BACKGROUND: Although in recent years many efforts have been made in suicide prevention, suicidal ideation in prison is still a major problem. The present study is part of a project being carried out in Saxony, Germany on the investigation and prevention of suicide in prisons. OBJECTIVE: The aim of this study was to determine whether the duration of imprisonment, personality traits and personality disorders have an influence on the suicidal ideation of prisoners. MATERIAL AND METHODS: In this study 113 volunteers among prisoners from 6 prisons in Saxony participated in a structured interview and filled out several questionnaires on sociodemographic details, personality using the personality style and disorder inventory (PSSI) and the assessment of DSM-IV personality disorders (ADP-IV) questionnaire as well as attitudes towards suicide using the questionnaire on stressful social experiences (FBS) and the Viennese instrument for suicidality on correctional institutions (VISCI). RESULTS: Significant correlations were found between personality traits and personality disorders and suicidal ideation and suicide attempts. A positive correlation was also found between personality disorders and scores in the VISCI. High scores in the PSSI were correlated with all aspects of suicidal ideation; however, length of time spent in prison and total duration of imprisonment appeared to have little impact on suicide parameters and were only correlated with the self declared current suicidal ideation. DISCUSSION: Although there were some limitations, this study could confirm data in the literature that personality disorders are associated with an increased risk of suicidal ideation in prisoners. The lack of association of suicidal thoughts as measured in this study with the total time spent in prison and duration of imprisonment is in contradiction to the results of other studies and warrants further investigation. PMID- 27126578 TI - [In Process Citation]. PMID- 27126580 TI - Change in Work-Time Control and Work-Home Interference Among Swedish Working Men and Women: Findings from the SLOSH Cohort Study. AB - PURPOSE: The aim is to study the influence of change in work-time control (WTC) on work-home interference (WHI) while adjusting for other work-related factors, demographics, changes at work and WHI at baseline among women and men. An additional aim was to explore sex differences in the relation between change in WTC and WHI. METHODS: The study included working participants of the Swedish Longitudinal Occupational Survey of Health (SLOSH) study of the third (2010) and fourth (2012) waves (n = 5440). Based on a seven-item index, four groups of WTC were formed: stable high (40 %), stable low (42 %), increasing (9 %), or decreasing (9 %) WTC over the 2 years. WHI was measured by four items and individuals were categorised in whether suffering or not suffering of WHI. Sex stratified logistic regression analyses with 95 % confidence intervals (CI) were used to estimate the odds of experiencing WHI by change in WTC. RESULTS: Controlling for demographics and work-related factors, women with stable low (OR = 1.46; 95 % CI 1.14-1.88) and women and men with decreasing WTC (women OR = 1.99; 95 % CI 1.38-2.85; men OR = 1.80; 95 % CI 1.18-2.73) had higher odds of WHI than those with a stable high WTC. Additionally, adjusting for changes at work and WHI at baseline did not alter the results substantially. Interaction analysis did not reveal any significant sex difference in the relation between WTC and WHI. CONCLUSIONS: For both women and men decreased and for women only, low control over working hours resulted in WHI also after adjusting for work-related factors and demographics. PMID- 27126579 TI - Ventromedial hypothalamic melanocortin receptor activation: regulation of activity energy expenditure and skeletal muscle thermogenesis. AB - KEY POINTS: The ventromedial hypothalamus (VMH) and the central melanocortin system both play vital roles in regulating energy balance by modulating energy intake and utilization. Recent evidence suggests that activation of the VMH alters skeletal muscle metabolism. We show that intra-VMH melanocortin receptor activation increases energy expenditure and physical activity, switches fuel utilization to fats, and lowers work efficiency such that excess calories are dissipated by skeletal muscle as heat. We also show that intra-VMH melanocortin receptor activation increases sympathetic nervous system outflow to skeletal muscle. Intra-VMH melanocortin receptor activation also induced significant changes in the expression of mediators of energy expenditure in muscle. These results support the role of melanocortin receptors in the VMH in the modulation of skeletal muscle metabolism. ABSTRACT: The ventromedial hypothalamus (VMH) and the brain melanocortin system both play vital roles in increasing energy expenditure (EE) and physical activity, decreasing appetite and modulating sympathetic nervous system (SNS) outflow. Because of recent evidence showing that VMH activation modulates skeletal muscle metabolism, we propose the existence of an axis between the VMH and skeletal muscle, modulated by brain melanocortins, modelled on the brain control of brown adipose tissue. Activation of melanocortin receptors in the VMH of rats using a non-specific agonist melanotan II (MTII), compared to vehicle, increased oxygen consumption and EE and decreased the respiratory exchange ratio. Intra-VMH MTII enhanced activity-related EE even when activity levels were held constant. MTII treatment increased gastrocnemius muscle heat dissipation during controlled activity, as well as in the home cage. Compared to vehicle-treated rats, rats with intra-VMH melanocortin receptor activation had higher skeletal muscle norepinephrine turnover, indicating an increased SNS drive to muscle. Lastly, intra-VMH MTII induced mRNA expression of muscle energetic mediators, whereas short-term changes at the protein level were primarily limited to phosphorylation events. These results support the hypothesis that melanocortin peptides act in the VMH to increase EE by lowering the economy of activity via the enhanced expression of mediators of EE in the periphery including skeletal muscle. The data are consistent with the role of melanocortins in the VMH in the modulation of skeletal muscle metabolism. PMID- 27126581 TI - Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. AB - BACKGROUND: Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimens have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006 and 2011. OBJECTIVES: To evaluate the effectiveness and safety of gonadotrophin-releasing hormone (GnRH) antagonists compared with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycles. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched from inception to May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, inception to 28 April 2015), Ovid MEDLINE (1966 to 28 April 2015), EMBASE (1980 to 28 April 2015), PsycINFO (1806 to 28 April 2015), CINAHL (to 28 April 2015) and trial registers to 28 April 2015, and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for example the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM). We contacted the authors of eligible studies for missing or unpublished data. The evidence is current to 28 April 2015. SELECTION CRITERIA: Two review authors independently screened the relevant citations for randomised controlled trials (RCTs) comparing different GnRH agonist versus GnRH antagonist protocols in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary review outcomes were live birth and ovarian hyperstimulation syndrome (OHSS). Other adverse effects (miscarriage and cycle cancellation) were secondary outcomes. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for each comparison using GRADE methods. MAIN RESULTS: We included 73 RCTs, with 12,212 participants, comparing GnRH antagonist to long course GnRH agonist protocols. The quality of the evidence was moderate: limitations were poor reporting of study methods.Live birthThere was no conclusive evidence of a difference in live birth rate between GnRH antagonist and long course GnRH agonist (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs, n = 2303, I(2)= 27%, moderate quality evidence). The evidence suggested that if the chance of live birth following GnRH agonist is assumed to be 29%, the chance following GnRH antagonist would be between 25% and 33%.OHSSGnRH antagonist was associated with lower incidence of any grade of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n = 7944, I(2) = 31%, moderate quality evidence). The evidence suggested that if the risk of OHSS following GnRH agonist is assumed to be 11%, the risk following GnRH antagonist would be between 6% and 9%.Other adverse effectsThere was no evidence of a difference in miscarriage rate per woman randomised between GnRH antagonist group and GnRH agonist group (OR 1.04, 95% CI 0.82 to 1.30; 33 RCTs, n = 7022, I(2) = 0%, moderate quality evidence).With respect to cycle cancellation, GnRH antagonist was associated with a lower incidence of cycle cancellation due to high risk of OHSS (OR 0.47, 95% CI 0.32 to 0.69; 19 RCTs, n = 4256, I(2) = 0%). However cycle cancellation due to poor ovarian response was higher in women who received GnRH antagonist than those who were treated with GnRH agonist (OR 1.32, 95% CI 1.06 to 1.65; 25 RCTs, n = 5230, I(2) = 68%; moderate quality evidence). AUTHORS' CONCLUSIONS: There is moderate quality evidence that the use of GnRH antagonist compared with long-course GnRH agonist protocols is associated with a substantial reduction in OHSS without reducing the likelihood of achieving live birth. PMID- 27126582 TI - Core curriculum illustration: brain-subdural hemorrhage in non-accidental trauma. AB - This is the 19 installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.aseronline.org/curriculum/toc.htm . PMID- 27126584 TI - Da Vinci robot emergency undocking protocol. AB - The role of robot-assisted surgery across gynaecology is evolving with increasing numbers of procedures being undertaken with varying degrees of complexity. While the risk of conversion is low at approximately 1 %, the reasons for conversion are variable. These range from technical issues with the robot, surgical complications such as haemorrhage and anaesthetics issues such as an inability to ventilate the patient adequately. While many conversions to open or laparoscopic approach are not due to life-threatening indications, it is important that the theatre staff are aware of the indication and can perform an emergency undocking as effectively, efficiently and safely as possible when the need arises. Unfortunately, there is a paucity of the literature available outlining such protocols. For this reason, we developed an emergency undocking protocol clearly outlining the role of each theatre staff member and the need for clear concise communication. PMID- 27126583 TI - Population-Scale Sequencing Data Enable Precise Estimates of Y-STR Mutation Rates. AB - Short tandem repeats (STRs) are mutation-prone loci that span nearly 1% of the human genome. Previous studies have estimated the mutation rates of highly polymorphic STRs by using capillary electrophoresis and pedigree-based designs. Although this work has provided insights into the mutational dynamics of highly mutable STRs, the mutation rates of most others remain unknown. Here, we harnessed whole-genome sequencing data to estimate the mutation rates of Y chromosome STRs (Y-STRs) with 2-6 bp repeat units that are accessible to Illumina sequencing. We genotyped 4,500 Y-STRs by using data from the 1000 Genomes Project and the Simons Genome Diversity Project. Next, we developed MUTEA, an algorithm that infers STR mutation rates from population-scale data by using a high resolution SNP-based phylogeny. After extensive intrinsic and extrinsic validations, we harnessed MUTEA to derive mutation-rate estimates for 702 polymorphic STRs by tracing each locus over 222,000 meioses, resulting in the largest collection of Y-STR mutation rates to date. Using our estimates, we identified determinants of STR mutation rates and built a model to predict rates for STRs across the genome. These predictions indicate that the load of de novo STR mutations is at least 75 mutations per generation, rivaling the load of all other known variant types. Finally, we identified Y-STRs with potential applications in forensics and genetic genealogy, assessed the ability to differentiate between the Y chromosomes of father-son pairs, and imputed Y-STR genotypes. PMID- 27126585 TI - Molecular characterization of southern bluefin tuna myoglobin (Thunnus maccoyii). AB - The primary structure of southern bluefin tuna Thunnus maccoyii Mb has been elucidated by molecular cloning techniques. The cDNA of this tuna encoding Mb contained 776 nucleotides, with an open reading frame of 444 nucleotides encoding 147 amino acids. The nucleotide sequence of the coding region was identical to those of other bluefin tunas (T. thynnus and T. orientalis), thus giving the same amino acid sequences. Based on the deduced amino acid sequence, bioinformatic analysis was performed including phylogenic tree, hydropathy plot and homology modeling. In order to investigate the autoxidation profiles, the isolation of Mb was performed from the dark muscle. The water soluble fraction was subjected to ammonium sulfate fractionation (60-90 % saturation) followed by preparative gel electrophoresis. Autoxidation profiles of Mb were delineated at pH 5.6, 6.5 and 7.4 at temperature 37 degrees C. The autoxidation rate of tuna Mb was slightly higher than that of horse Mb at all pH examined. These results revealed that tuna myoglobin was unstable than that of horse Mb mainly at acidic pH. PMID- 27126586 TI - Quantification of the antibody response to Propionibacterium acnes in a patient with prosthetic valve endocarditis: - a case report. AB - BACKGROUND: The isolation of Propionibacterium acnes in blood cultures is often considered a contaminant. On rare occasions, P. acnes can cause severe infections, including endocarditis and intravascular prosthesis-associated infections. To evaluate the discrimination between a contaminant and a clinically relevant infection we used an Ouchterlony test system to quantify the antibody response to P. acnes in a patient with a proven P. acnes endocarditis. CASE PRESENTATION: We report on a 64-year-old Caucasian man who developed P. acnes endocarditis four years following a composite valve-graft conduit replacement of the aortic root. Bacterial growth in blood cultures was detected after an incubation period of 6 days. However, the antibody titer to P. acnes was 1:8 at the time of diagnosis and declined slowly thereafter over 21/2 years. The patient's response to the antibiotic treatment was excellent, and no surgical re intervention was necessary. CONCLUSION: The working hypothesis of infective endocarditis can be substantiated by serologic testing, which, if positive, provides one additional minor criterion. Moreover, quantification of the antibody response to P. acnes, though not specific, may assist in the differentiation between contaminants and an infection. This quantification may have implications for the patient management, e.g. indication for and choice of the antibiotic therapy. PMID- 27126587 TI - Clks 1, 2 and 4 prevent chromatin breakage by regulating the Aurora B-dependent abscission checkpoint. AB - When chromatin is trapped at the intercellular bridge, cells delay completion of cytokinesis (abscission) to prevent chromosome breakage. Here we show that inhibition of Cdc-like kinases (Clks) 1, 2 or 4 accelerates midbody resolution in normally segregating cells and correlates with premature abscission, chromatin breakage and generation of DNA damage in cytokinesis with trapped chromatin. Clk1, Clk2 and Clk4 localize to the midbody in an interdependent manner, associate with Aurora B kinase and are required for Aurora B-serine 331 (S331) phosphorylation and complete Aurora B activation in late cytokinesis. Phosphorylated Aurora B-S331 localizes to the midbody centre and is required for phosphorylation and optimal localization of the abscission protein Chmp4c. In addition, expression of phosphomimetic mutants Aurora B-S331E or Chmp4c-S210D delays midbody disassembly and prevents chromatin breakage in Clk-deficient cells. We propose that Clks 1, 2 and 4 impose the abscission checkpoint by phosphorylating Aurora B-S331 at the midbody. PMID- 27126588 TI - Cryptococcus neoformans var. grubii-Induced Arthritis with Encephalitic Dissemination in a Dog and Review of Published Literature. AB - This article describes the clinical, pathological, and immunohistochemical findings associated with Cryptococcus neoformans var. grubii in a 4-year-old female Boxer dog from Uberlandia, Minas Gerais, Southeastern Brazil. Clinically, there was a swelling at the right metatarsal region and the hock joint with enlargement of regional lymph nodes. Radiographical evaluation revealed lysis of the tarsal bone; cytology demonstrated cryptococcal intralesional organisms at the swollen joint. Despite empirical antifungals therapeutic, the animal developed neurological cryptococcosis and died spontaneously. Significant pathological alterations included arthritis, lymphadenitis, and encephalitic cryptococcomas associated with numerous intralesional narrow-necked budding encapsulated yeasts. Immunohistochemistry utilising monoclonal antibodies that label C. neoformans sp. complex capsule, characterised the yeasts as C. neoformans var. grubii. Collectively, the pathological and immunohistochemical findings of this dog indicate that the intralesional organisms observed within the articular surface of the hock joint, lymph nodes, and the brain were C. neoformans var. grubii, confirming the participation of this fungal pathogen in the development of cryptococcal arthritis. In this case, the most likely pathogenesis was percutaneous inoculation with resultant abscess-like lesion, which resulted in the draining sinus, swelling of the right hind limb with progression to the articular disease. Thereafter, the fungal pathogen probably compromised the adjacent lymph nodes with subsequent haematogenous distribution to the brain, terminating with cryptococcal arthritis, lymphadenitis, and encephalitis. PMID- 27126589 TI - Genome-wide identification of suitable zebrafish Danio rerio reference genes for normalization of gene expression data by RT-qPCR. AB - In this study, to systematically identify the most stably expressed genes for internal reference in zebrafish Danio rerio investigations, 37 D. rerio transcriptomic datasets (both RNA sequencing and microarray data) were collected from gene expression omnibus (GEO) database and unpublished data, and gene expression variations were analysed under three experimental conditions: tissue types, developmental stages and chemical treatments. Forty-four putative candidate genes were identified with the c.v. <0.2 from all datasets. Following clustering into different functional groups, 21 genes, in addition to four conventional housekeeping genes (eef1a1l1, b2m, hrpt1l and actb1), were selected from different functional groups for further quantitative real-time (qrt-)PCR validation using 25 RNA samples from different adult tissues, developmental stages and chemical treatments. The qrt-PCR data were then analysed using the statistical algorithm refFinder for gene expression stability. Several new candidate genes showed better expression stability than the conventional housekeeping genes in all three categories. It was found that sep15 and metap1 were the top two stable genes for tissue types, ube2a and tmem50a the top two for different developmental stages, and rpl13a and rp1p0 the top two for chemical treatments. Thus, based on the extensive transcriptomic analyses and qrt-PCR validation, these new reference genes are recommended for normalization of D. rerio qrt-PCR data respectively for the three different experimental conditions. PMID- 27126590 TI - Gut microbiota: an Indicator to Gastrointestinal Tract Diseases. AB - PURPOSE: Gut microbiota is predicted to play a key role in manifestation of gastrointestinal tract cancers. The human gastrointestinal tract is a complex and abundant network of microbial community. Gut microbiota depicts the microbe population living in our intestine. Humans harbour more than 10(14) microbes in the gut, and the diversity and densities of the microbiota increase from stomach to colon. METHODS: The beneficial relationship between endogenous microbiota and the eukaryotic hosts helps in maintaining various metabolic activities of the body as well as temperature and pH balance. Studies using culturing methods have suggested that the oesophagus is either sterile or contains only a few transient microbes that originates from the oropharynx by swallowing or from the stomach by gastroesophageal reflux. However, metagenomics suggest that large numbers of uncultured organisms are harboured in the human gut. RESULTS: Observations suggest that research directed towards manipulation of the gut microbiota can be employed in prevention as well as treatment of these conditions. Well-designed, randomized, placebo-controlled human studies using probiotics and/or prebiotics are necessary to formulate the directions for prevention and therapy. CONCLUSIONS: Change in gut microbes in gastrointestinal (GI) tract may have major implication in gastric cancer, the fifth most occurring malignancy in the world. Affected population manifests multiple conditions and diseases, which majorly includes inflammatory bowel disease and colorectal malignancy. PMID- 27126592 TI - A neonate with dyspnoea. PMID- 27126591 TI - Benefit of Bevacizumab-Based Frontline Therapy in Patients with Metastatic Colorectal Cancer (mCRC): a Turkish Oncology Group Study. AB - BACKGROUND: Several chemotherapy regimens using bevacizumab have been developed. Our goal was to investigate regimens that have demonstrated significant clinical activity in patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: Six hundred and sixty six patients with mCRC who received first-line chemotherapy combination with bevacizumab were studied. Fluoropyrimidine (F) plus irinotecan (I)-based (FI-bev), F plus oxaliplatin (O)-based (FO-bev), and F-based (F-bev) treatment regimens were compared with respect to progression-free survival (PFS) and overall survival (OS). RESULTS: The median PFS of FI-bev (n = 414) was 10.9 months (95 % CI 10-11.8), of FO-bev (n = 211) was 9.4 months (95 % CI 8.3-10.4), and of F-bev (n = 41) was 9.5 months (95 % CI 5.9-13.1) (p = 0.089). The median OS of FI-bev was 26.3 months (95 % CI 21.7-30.9), of FO-bev was 27 months (95 % CI 24.3-29.7), and of F-bev was 23.3 months (95 % CI 12.7 33.9) (p = 0.102). In KRAS wild-type patients, the median PFS of FI-bev group was significantly longer than FO-bev group (10.5 vs. 9.1 months, p = 0.006). The FI bev group had better OS than FO-bev group with borderline significance (p = 0.058). The FI-bev group had significantly longer OS than F-bev group. Patients who underwent metastasectomy or those with Eastern Cooperative Oncology Group performance status (ECOG-PS) <=1 had longer PFS and OS independent of the type of chemotherapy regimen. CONCLUSION: FI-bev may be the preferred frontline regimen for patients with KRAS wild-type mCRC. Metastasectomy and performance score were the strongest positive predictors of OS and PFS regardless of backbone chemotherapy regimen. PMID- 27126593 TI - Cardiac Contractility Modulation in a Model of Repaired Tetralogy of Fallot: A Sheep Model. AB - The onset of right ventricular dysfunction in patients presenting with congenital heart disease is associated with a dismal long-term outcome and often represents a therapeutic dead end. Our study had several objectives: (1) to analyse the anatomical, functional, histological and cellular characteristics of an animal model of repaired tetralogy of Fallot with right ventricular dysfunction (2) to test the new electrical treatment known as cardiac contractility modulation in this animal model. Seven sheep underwent a first surgery at the age of three weeks aiming to mimic the characteristics of a repaired tetralogy of Fallot. Five controls were sham-operated. Experimental studies were performed 12 months after the initial operation. The hemodynamic, echocardiographic, and mitochondrial function studies were carried out before and after cardiac contractility modulation in closed- and open-chest conditions. In this animal model of right ventricular dysfunction, short-term cardiac contractility modulation was associated with a significant improvement in (a) right ventricular function, as evidenced by a significant increase in right ventricular dP/dt (p < 0.05) (b) left ventricular function evidenced by the increase in left ventricular dP/dt max (p < 0.05) (c) in mitochondrial function (p < 0.05). In this animal model of chronic right ventricular dysfunction, cardiac contractility modulation significantly improved acute cardiac hemodynamic and mitochondrial functions of both ventricles and may represent a promising option in patients with right heart failure. PMID- 27126594 TI - Quantitative imaging of Rac1 activity in Dictyostelium cells with a fluorescently labelled GTPase-binding domain from DPAKa kinase. AB - Small Rho GTPases are major regulators of the actin cytoskeleton dynamics in eukaryotic cells. Sophisticated tools used to investigate their activity in living cells include probes based on fluorescence resonance energy transfer (FRET), bimolecular fluorescence complementation, and photoactivation. However, such methods are of limited use in quickly migrating cells due to a short time available for image acquisition leading to a low signal-to-noise ratio. Attempts to remedy this effect by increasing the intensity of illumination are restricted by photobleaching of probes and the cell photosensitivity. Here we present design and characterization of a new fluorescent probe that selectively binds to active form of Rac1 GTPases, and demonstrate its superior properties for imaging in highly motile Dictyostelium cells. The probe is based on the GTPase-binding domain (GBD) from DPAKa kinase and was selected on the basis of yeast two-hybrid screen, GST pull-down assay and FRET measurements by fluorescence lifetime imaging microscopy. DPAKa(GBD) probe binds specifically to GTP-bound Rac1 at the cell membrane and features a low cytoplasmic background. The main advantage of DPAKa(GBD) in comparison with similar probes is its finely graded intensity distribution along the entire plasma membrane, which enables quantitative measurements of the Rac1 activity in different parts of the membrane. Finally, expression of DPAKa(GBD) induces no adverse effects on cell growth, motility and cytokinesis. PMID- 27126595 TI - Pheromone analogue efficacy in reducing cats' stress at the veterinary hospital: concerns about the design of a recent study. PMID- 27126596 TI - Modification of a commercial thromboelastography instrument to measure coagulation dynamics with three-dimensional biomaterials. AB - Three-dimensional synthetic constructs with complex geometries have immense potential for use in a multitude of blood-contacting applications. Understanding coagulation phenomena is arguably the most critical aspect for applications involving synthetic biomaterials; however, real-time evaluation of the clot formation while interfacing with these materials is difficult to achieve in a reproducible and robust manner. Here, work representing first steps toward addressing this deficit is presented, wherein modified consumables for a clinical instrument (a Thromboelastograph((r))) have been fabricated. Thromboelastography (TEG) measures viscoelastic properties throughout clot formation and therefore provides clinically relevant coagulation measurements in real time (i.e., kinetics and strength of clot formation). Through our modification, TEG consumables can readily accommodate three-dimensional materials (e.g., those for regenerative tissue applications). The authors performed proof-of-concept experiments using polymer scaffolds with a range of surface properties and demonstrated that variations in surface properties resulted in differences in blood plasma coagulation dynamics. For example, the maximum rate of thrombus generation ranged from 22.2 +/- 2.2 (dyn/cm(2))/s for fluorocarbon coated scaffolds to 8.7 +/- 1.0 (dyn/cm(2))/s for nitrogen-containing scaffolds. Through this work, the ability to make real-time coagulation activity measurements during constant coagulation factor interface with biomedically relevant materials is demonstrated. PMID- 27126597 TI - Biocompatible and target specific hydrophobically modified glycol chitosan nanoparticles. AB - Cardiovascular disease is the leading cause of death in the United States. Atherosclerosis is a major cause for cardiovascular diseases. Drugs that treat atherosclerosis usually act nonspecifically. To enhance drug delivery specificity, the authors developed a hydrophobically modified glycol chitosan (HGC) nanoparticle that can specifically target activated endothelial cells. The biocompatibility of these nanoparticles toward red blood cells and platelets was evaluated through hemolysis, platelet activation, platelet thrombogenicity, and platelet aggregation assays. The biocompatibility of these nanoparticles toward vascular endothelial cells was evaluated by their effects on endothelial cell growth, metabolic activity, and activation. The results demonstrated that HGC nanoparticles did not cause hemolysis, or affect platelet activation, thrombogenicity, and aggregation capability in vitro. The nanoparticles did not impair vascular endothelial cell growth or metabolic activities in vitro, and did not cause cell activation either. When conjugated with intercellular adhesion molecular 1 antibodies, HGC nanoparticles showed a significantly increased targeting specificity toward activated endothelial cells. These results suggested that HGC nanoparticles are likely compatible toward red blood cells, platelets, and endothelial cells, and they can be potentially used to identify activated endothelial cells at atherosclerotic lesion areas within the vasculature, and deliver therapeutic drugs. PMID- 27126598 TI - North American Thrombosis Forum, AF Action Initiative Consensus Document. AB - The North American Thrombosis Forum Atrial Fibrillation Action Initiative consensus document is a comprehensive yet practical briefing document focusing on stroke and bleeding risk assessment in patients with atrial fibrillation, as well as recommendations regarding anticoagulation options and management. Despite the breadth of clinical trial data and guideline recommendation updates, many clinicians continue to struggle to synthesize the disparate information available. This problem slows the uptake and utilization of updated risk prediction tools and adoption of new oral anticoagulants. This document serves as a practical and educational reference for the entire medical community involved in the care of patients with atrial fibrillation. PMID- 27126600 TI - Load speed regulation in compliant mechanical transmission systems using feedback and feedforward control actions. AB - The problem of controlling the load speed of a mechanical transmission system consisting of a belt-pulley and gear-pair is considered. The system is modeled as two inertia (motor and load) connected by a compliant transmission. If the transmission is assumed to be rigid, then using either the motor or load speed feedback provides the same result. However, with transmission compliance, due to belts or long shafts, the stability characteristics and performance of the closed loop system are quite different when either motor or load speed feedback is employed. We investigate motor and load speed feedback schemes by utilizing the singular perturbation method. We propose and discuss a control scheme that utilizes both motor and load speed feedback, and design an adaptive feedforward action to reject load torque disturbances. The control algorithms are implemented on an experimental platform that is typically used in roll-to-roll manufacturing and results are shown and discussed. PMID- 27126601 TI - Formal modeling and verification of fractional order linear systems. AB - This paper presents a formalization of a fractional order linear system in a higher-order logic (HOL) theorem proving system. Based on the formalization of the Grunwald-Letnikov (GL) definition, we formally specify and verify the linear and superposition properties of fractional order systems. The proof provides a rigor and solid underpinnings for verifying concrete fractional order linear control systems. Our implementation in HOL demonstrates the effectiveness of our approach in practical applications. PMID- 27126602 TI - Microemulsion electrokinetic chromatography as a suitable tool for lipophilicity determination of acidic, neutral, and basic compounds. AB - In the present work, several MEEKC systems are studied to assess their suitability for lipophilicity determination of acidic, neutral, and basic compounds. Thus, several microemulsion compositions over a wide range of pH values (from 2.0 to 12.0), containing heptane, 1-butanol and different types and amounts of surfactant (SDS or sodium cholate: from 1.3 to 3.3%) are characterized using Abraham's solvation model. The addition of acetonitrile (up to 10%) is also studied, since it increases the resolution of the technique for the most lipophilic compounds. The system coefficients obtained are very similar to those of the 1-octanol/water, used as the reference lipophilicity index, allowing simple and linear correlations between the 1-octanol/water partition values (log Po/w ) and MEEKC mass distribution ratios (log kMEEKC ). Variations in the microemulsion composition (aqueous buffer, surfactant, concentration of ACN) did not significantly affect the similarity of the MEEKC systems to log Po/w partition. PMID- 27126603 TI - Probing molecular events associated with early development of thylakoid membranes by comparative proteomics and low temperature fluorescence. AB - A comparison of protein profiles between prolamellar bodies from dark-grown etioplasts and thylakoid membranes from de-etioplasts illuminated respectively for 1, 5 and 9h revealed 155 differentially expressed CBB-stained spots. Clear results showed that the nonphototransformable Pchlide627-632 was the dominant pigment form in the PLBs of rice etioplasts during plant development in dark and transformed slowly to chlorophyllide in rice etioplasts when exposed to light. The light-induced accumulation of ACC oxidase, which catalyzes the final step of ethylene synthesis using ACC as substrate, would facilitate chlorophyll synthesis by inducing PORa/b expression via ethylene signaling. It could be also suggested that cyclic electron transport might play an important role in generation of ATP for carbon fixation and photoprotection of photosystems from excessive light in prothylakoid. Furthermore, the overproduction of ClpC1, which targets proteins to the ClpPR core complex for degradation, was observed only in Stage 1, during which period PLBs disrupted and converted into prothylakoids, suggesting that ClpC1 was of particular importance for disassembly of PLBs of etioplasts when exposed to light. This study revealed the possible biochemical and physiological processes lead to the formation of functional thylakoid membranes. BIOLOGICAL SIGNIFICANCE: In this study, we monitored the light-induced transformation of prolamellar bodies into thylakoid membranes, which is correlated to the biogenesis of photosynthetic apparatus involving a complex cascade of biochemical and structural events. Three stages of thylakoid development classified according to the thylakoid development status (Adam et al., 2011) were studied for biogenesis of photosynthetic apparatus: Stage 1, prothylakoids emerge from the disrupted PLBs; Stage 2, prothylakoids converted into primary thylakoids which were dispersed in the stroma; Stage 3, the continuous grana and stroma thylakoids are formed. The development stage-dependent changes in the proteomic profile of the thylakoids were analyzed by two-dimensional electrophoresis (2-DE). This information was complemented with the steady-state 77K chlorophyll fluorescence of thylakoids at the corresponding development stage. Together, these analyses allowed us to further understand the molecular processes connected to the formation of functional thylakoid membranes. PMID- 27126599 TI - The role of lymphangiogenesis and angiogenesis in tumor metastasis. AB - BACKGROUND: Metastasis is the main cause of mortality in cancer patients. Two major routes of cancer cell spread are currently being recognized: dissemination via blood vessels (hematogenous spread) and dissemination via the lymphatic system (lymphogenous spread). Here, our current knowledge on the role of both blood and lymphatic vessels in cancer cell metastasis is summarized. In addition, I will discuss why cancer cells select one or both of the two routes to disseminate and I will provide a short description of the passive and active models of intravasation. Finally, lymphatic vessel density (LVD), blood vessel density (BVD), interstitial fluid pressure (IFP) and tumor hypoxia, as well as regional lymph node metastasis and the recently discovered primo vascular system (PVS) will be highlighted as important factors influencing tumor cell motility and spread and, ultimately, clinical outcome. CONCLUSIONS: Lymphangiogenesis and angiogenesis are important phenomena involved in the spread of cancer cells and they are associated with a poor prognosis. It is anticipated that new discoveries and advancing knowledge on these phenomena will allow an improvement in the treatment of cancer patients. PMID- 27126605 TI - Nutritional mitigation of winter thermal stress in gilthead seabream: Associated metabolic pathways and potential indicators of nutritional state. AB - : A trial was carried out with gilthead seabream juveniles, aiming to investigate the ability of an enhanced dietary formulation (diet Winter Feed, WF, containing a higher proportion of marine-derived protein sources and supplemented in phospholipids, vitamin C, vitamin E and taurine) to assist fish in coping with winter thermal stress, compared to a low-cost commercial diet (diet CTRL). In order to identify the metabolic pathways affected by WF diet, a comparative two dimensional differential in-gel electrophoresis (2D-DIGE) analysis of fish liver proteome (pH 4-7) was undertaken at the end of winter. A total of 404 protein spots, out of 1637 detected, were differentially expressed between the two groups of fish. Mass spectrometry analysis of selected spots suggested that WF diet improved oxidative stress defense, reduced endoplasmic reticulum stress, enhanced metabolic flux through methionine cycle and phenylalanine/tyrosine catabolism, and induced higher aerobic metabolism and gluconeogenesis. Results support the notion that WF diet had a positive effect on fish nutritional state by partially counteracting the effect of thermal stress and underlined the sensitivity of proteome data for nutritional and metabolic profiling purposes. Intragroup variability and co-measured information were also used to pinpoint which proteins displayed a stronger relation with fish nutritional state. SIGNIFICANCE: Winter low water temperature is a critical factor for gilthead seabream farming in the Mediterranean region, leading to a reduction of feed intake, which often results in metabolic and immunological disorders and stagnation of growth performances. In a recent trial, we investigated the ability of an enhanced dietary formulation (diet WF) to assist gilthead seabream in coping with winter thermal stress, compared to a standard commercial diet (diet CTRL). Within this context, in the present work, we identified metabolic processes that are involved in the stress mitigating effect observed with diet WF, by undertaking a comparative analysis of fish liver proteome at the end of winter. This study brings information relative to biological processes that are involved in gilthead seabream winter thermal stress and shows that these can be mitigated through a nutritional strategy, assisting gilthead seabream to deal better with winter thermal conditions. Furthermore, the results show that proteomic information not only clearly distinguishes the two dietary groups from each other, but also captures heterogeneities that reflect intra-group differences in nutritional state. This was exploited in this work to refine the variable selection strategy so that protein spots displaying a stronger correlation with "nutritional state" could be identified as possible indicators of gilthead seabream metabolic and nutritional state. Finally, this study shows that gel-based proteomics seems to provide more reliable information than transmissive FT-IR spectroscopy, for the purposes of nutritional and metabolic profiling. PMID- 27126604 TI - Time course of lead induced proteomic changes in gill of the Antarctic limpet Nacella Concinna (Gastropoda: Patellidae). AB - : The effect of increasing levels of metals from anthropogenic sources on Antarctic invertebrates is poorly understood. Here we exposed limpets (Nacella concinna) to 0, 0.12 and 0.25 MUg L- 1 lead for 12, 24, 48 and 168 h. We subsequently quantified the changes in protein abundance from gill, using 2D gel electrophoresis and mass spectrometry. We identified several antioxidant proteins, including the metal binding Mn-superoxide dismutase and ferritin, increasing abundances early on. Chaperones involved in the redox-dependent maturation of proteins in the endoplasmic reticulum (ER) showed higher abundance with lead at 48 h. Lead also increased the abundance of Zn-binding carbonic anhydrase at 12 h, suggesting a challenge to acid-base balance. Metabolic proteins increased abundance at 168 h, suggesting a greater ATP demand during prolonged exposure. Changes in abundance of the small G-protein cdc42, a signaling protein modifying cytoskeleton, increased early and subsequently reversed during prolonged exposure, possibly leading to the modification of thick filament structure and function. We hypothesize that the replacement of metals initially affected antioxidant proteins and increased the production of reactive oxygen species. This disrupted the redox-sensitive maturation of proteins in the ER and caused increased ATP demand later on, accompanied by changes in cytoskeleton. SIGNIFICANCE: Proteomic analysis of gill tissue in Antarctic limpets exposed to different concentrations of lead (Pb) over a 168 h time period showed that proteomic changes vary with time. These changes included an increase in the demand of scavenging reactive oxygen species, acid-base balance and a challenge to protein homeostasis in the endoplasmic reticulum early on and subsequently an increase in energy metabolism, cellular signaling, and cytoskeletal modifications. Based on this time course, we hypothesize that the main mode of action of lead is a replacement of metal-cofactors of key enzymes involved in the scavenging of reactive oxygen species and the regulation of acid base balance. PMID- 27126606 TI - A study of organic acid production in contrasts between two phosphate solubilizing fungi: Penicillium oxalicum and Aspergillus niger. AB - Phosphate solubilizing fungi (PSF) have huge potentials in enhancing release of phosphorus from fertilizer. Two PSF (NJDL-03 and NJDL-12) were isolated and identified as Penicillium oxalicum and Aspergillus niger respectively in this study. The quantification and identification of organic acids were performed by HPLC. Total concentrations of organic acids secreted by NJDL-03 and NJDL-12 are ~4000 and ~10,000 mg/L with pH values of 3.6 and 2.4 respectively after five-days culture. Oxalic acid dominates acidity in the medium due to its high concentration and high acidity constant. The two fungi were also cultured for five days with the initial pH values of the medium varied from 6.5 to 1.5. The biomass reached the maximum when the initial pH values are 4.5 for NJDL-03 and 2.5 for NJDL-12. The organic acids for NJDL-12 reach the maximum at the initial pH = 5.5. However, the acids by NJDL-03 continue to decrease and proliferation of the fungus terminates at pH = 2.5. The citric acid production increases significantly for NJDL-12 at acidic environment, whereas formic and oxalic acids decrease sharply for both two fungi. This study shows that NJDL-12 has higher ability in acid production and has stronger adaptability to acidic environment than NJDL-03. PMID- 27126608 TI - Impact of a short exposure to levofloxacin on faecal densities and relative abundance of total and quinolone-resistant Enterobacteriaceae. AB - Emergence of resistant Enterobacteriaceae in the intestinal microbiota during antibiotic treatment is well documented but its early dynamic is not. Here, we compared the densities of total Enterobacteriaceae and relative abundance (RA) of quinolone-resistant Enterobacteriaceae (QRE) in the first stool passed by patients who had a short exposure to levofloxacin (levofloxacin, n=12) or not (control, n=8). Mean densities (SD) (log CFU/g stool) of total Enterobacteriaceae were lower in the levofloxacin group than in the control group-3.4 (1.6) versus 6.7 (1.7), respectively, p <0.001. Conversely, mean RA (SD) of QRE was significantly higher in the levofloxacin group than in the control group-49.7% (23.4) versus 0.1% (3.2), respectively, p <0.05). In conclusion, even a short exposure to levofloxacin has a profound impact on the densities of total Enterobacteriaceae and the QRE-RA. PMID- 27126607 TI - Diaphragm muscle sarcopenia in Fischer 344 and Brown Norway rats. AB - NEW FINDINGS: What is the central question of this study? Several rat models are commonly used to study the physiology of ageing (e.g. Fischer 344 and Brown Norway rats are recommended by the USA National Institute of Ageing). Diaphragm muscle sarcopenia (ageing-related muscle weakness and atrophy) remains incompletely described in these rat models. What is the main finding and its importance? Diaphragm muscle sarcopenia is present in both the Fischer 344 and Brown Norway rat strains, but appears more pronounced in Fischer 344 rats. The risk for respiratory diseases increases in adults >65 years of age, which may be attributable in part to ageing-related weakening and atrophy (i.e. sarcopenia) of the diaphragm muscle (DIAm). The mechanisms underlying DIAm sarcopenia remain unknown. Based on existing evidence, we hypothesized that sarcopenia is most evident in type IIx and/or IIb DIAm fibres, i.e. more fatigable motor units. Currently, the USA National Institute on Aging supports Fischer 344 (F344) and Brown Norway (BN) rat strains for ageing-related research, yet DIAm sarcopenia has not been evaluated comprehensively in either strain. Thus, the present study examined DIAm sarcopenia in older adult F344 (24 months old, 50% survival) and BN rats (32 months old, 50% survival), compared with young adult (6-month-old) F344 and BN rats. Measurements of contractility, contractile protein concentration, fibre type distribution and fibre cross-sectional area were obtained from midcostal DIAm strips. Maximal specific force was reduced by ~24 and ~13% in older F344 and BN rats, respectively. Additionally, although the cross-sectional area of type I and IIa DIAm fibres was unchanged in both F344 and BN rats, the cross-sectional area of type IIx and/or IIb DIAm fibres was reduced by ~20 and ~15% in F344 and BN rats, respectively. Thus, although there was ageing-related DIAm weakness and atrophy, selective to type IIx and/or IIb DIAm fibres, in both F344 and BN rats, the sarcopenic phenotype was more pronounced in F344 rats. PMID- 27126610 TI - Electronic Structure Theory Study of the Microsolvated F(-)(H2O) + CH3I SN2 Reaction. AB - The potential energy profile of microhydrated fluorine ion reaction with methyl iodine has been characterized by extensive electronic structure calculations. Both hydrogen-bonded F(-)(H2O)---HCH2I and ion-dipole F(-)(H2O)---CH3I complexes are formed for the reaction entrance and the PES in vicinity of these complexes is very flat, which may have important implications for the reaction dynamics. The water molecule remains on the fluorine side until the reactive system goes to the SN2 saddle point. It can easily move to the iodine side with little barrier, but in a nonsynchronous reaction path after the dynamical bottleneck to the reaction, which supports the previous prediction for microsolvated SN2 systems. The influence of solvating water molecule on the reaction mechanism is probed by comparing with the influence of the nonsolvated analogue and other microsolvated SN2 systems. Taking the CCSD(T) single-point calculations based on MP2-optimized geometries as benchmark, the DFT functionals B97-1 and B3LYP are found to better characterize the potential energy profile for the title reaction and are recommended as the preferred methods for the direct dynamics simulations to uncover the dynamic behaviors. PMID- 27126609 TI - Emergence of community-associated methicillin-resistant Staphylococcus aureus strains in the neonatal intensive care unit: an infection prevention and patient safety challenge. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infections cause significant morbidity and mortality in neonatal intensive care units (NICUs). We characterized the clinical and molecular epidemiology of MRSA strains colonizing NICU patients. Nasal MRSA isolates (n = 250, from 96 NICU patients) recovered through active surveillance from 2009 to 2014 were characterized with staphylococcal cassette chromosome mec (SCCmec) typing and detection of mupA (marker of high-level mupirocin resistance) and qacA/B (marker associated with chlorhexidine resistance). Factors associated with community-associated (CA-) or healthcare-associated (HA-) MRSA were evaluated. The overall prevalence of MRSA nasal colonization was 3.9%. Of 96 neonates in our retrospective cohort, 60 (63%) were colonized with CA-MRSA strains and 35 (36%) were colonized with HA-MRSA strains. Patients colonized with HA-MRSA were more likely to develop MRSA infections than patients colonized with CA-MRSA (13/35, 37% versus 8/60, 13%; p 0.007), although the interval from colonization to infection was shorter in CA MRSA-colonized infants (median 0 days, range -1 to 4 versus HA-MRSA-colonized infants, 7 days, -1 to 43; p 0.005). Maternal peripartum antibiotics were associated with CA-MRSA colonization (adjusted odds ratio (aOR) 8.7; 95% CI 1.7 45.0); intubation and surgical procedures were associated with HA-MRSA colonization (aOR 7.8; 95% CI 1.3-47.6 and aOR 6.0; 95% CI 1.4-24.4, respectively). Mupirocin- and chlorhexidine-resistant MRSA was isolated from four and eight patients, respectively; carriage of a mupirocin-resistant strain precluded decolonization. CA-MRSA strains are prominent in the NICU and associated with distinct risk factors. Given community reservoirs for MRSA acquisition and transmission, novel infection prevention strategies are needed. PMID- 27126612 TI - Effect of Mating Status and Age on the Male Mate Choice and Mating Competency in the Common Bed Bug, Cimex lectularius (Hemiptera: Cimicidae). AB - We investigated male mate choice and mating competency in the common bed bug, Cimex lectularius L., using video tracking for 10 min per experiment. In the male mate choice experiment, when a male was placed with two females of different mating status, males preferred to initiate copulation with the virgin female more quickly than with the mated female, and the mean total copulation duration with virgin females (38.0 +/- 3.0 s) was significantly longer than with mated females (14.6 +/- 3.0 s). When a male was placed with two females of different age, males initiated copulation more quickly with the old virgin female (29-34 d adult emergence) than with the young virgin one (<7 d adult emergence), and the mean total copulation duration with old virgin females (38.4 +/- 4.0 s) was significantly longer than with young virgin females (24.0 +/- 3.0 s). In the male mating competency experiment where a female was placed with two males of different mating status or age, the virgin males were more eager to mate than the mated males, and the old virgin males (29-34 d adult emergence) were more eager than the young virgin males (<7 d adult emergence), with eagerness measured by the percentage of first mate selected (first copulation occurred) and the total copulation duration by each group of males. Male mating competency is related to postmating duration (PMD); males mated 1 d earlier were significantly less likely to mate than virgin males. However, males mated 7 d earlier showed no significant difference in mating competency compared to virgin males. In conclusion, mate choice in C. lectularius is associated with both male and female mating status, age, and PMD. PMID- 27126611 TI - N-Heterocyclic Carbene Capture by Cytochrome P450 3A4. AB - Cytochrome P450 3A4 (CYP3A4) is the dominant P450 enzyme involved in human drug metabolism, and its inhibition may result in adverse interactions or, conversely, favorably reduce the systemic elimination rates of poorly bioavailable drugs. Herein we describe a spectroscopic investigation of the interaction of CYP3A4 with N-methylritonavir, an analog of ritonavir, widely used as a pharmacoenhancer. In contrast to ritonavir, the binding affinity of N methylritonavir for CYP3A4 is pH-dependent. At pH <7.4, the spectra are definitively type I, whereas at pH >=7.4 the spectra have split Soret bands, including a red-shifted component characteristic of a P450-carbene complex. Variable-pH UV-visible spectroscopy binding studies with molecular fragments narrows the source of this pH dependence to its N-methylthiazolium fragment. The C2 proton of this group is acidic, and variable-pH resonance Raman spectroscopy tentatively assigns it a pKa of 7.4. Hence, this fragment of N-methylritonavir is expected to be readily deprotonated under physiologic conditions to yield a thiazol-2-ylidene, which is an N-heterocyclic carbene that has high-affinity for and is presumed to be subsequently captured by the heme iron. This mechanism is supported by time-dependent density functional theory with an active site model that accurately reproduces distinguishing features of the experimental UV-visible spectra of N-methylritonavir bound to CYP3A4. Finally, density functional theory calculations support that this novel interaction is as strong as the tightest binding azaheterocycles found in P450 inhibitors and could offer new avenues for inhibitor development. PMID- 27126615 TI - Moving from awareness to action on preventing patient exposure to toxic environmental chemicals. PMID- 27126614 TI - A fuzzy-logic-based controller for methane production in anaerobic fixed-film reactors. AB - The main objective of this work was to develop a controller for biogas production in continuous anaerobic fixed-bed reactors, which used effluent total volatile fatty acids (VFA) concentration as control input in order to prevent process acidification at closed loop. To this aim, a fuzzy-logic-based control system was developed, tuned and validated in an anaerobic fixed-bed reactor at pilot scale that treated industrial winery wastewater. The proposed controller varied the flow rate of wastewater entering the system as a function of the gaseous outflow rate of methane and VFA concentration. Simulation results show that the proposed controller is capable to achieve great process stability even when operating at high VFA concentrations. Pilot results showed the potential of this control approach to maintain the process working properly under similar conditions to the ones expected at full-scale plants. PMID- 27126616 TI - August 2015 (vol. 213, no. 2, pages 188.e4, 188.e8, and 188.e10). PMID- 27126613 TI - A humanized monoclonal antibody neutralizes yellow fever virus strain 17D-204 in vitro but does not protect a mouse model from disease. AB - The yellow fever virus (YFV) vaccine 17D-204 is considered safe and effective, yet rare severe adverse events (SAEs), some resulting in death, have been documented following vaccination. Individuals exhibiting post-vaccinal SAEs are ideal candidates for antiviral monoclonal antibody (MAb) therapy; the time until appearance of clinical signs post-exposure is usually short and patients are quickly hospitalized. We previously developed a murine-human chimeric monoclonal antibody (cMAb), 2C9-cIgG, reactive with both virulent YFV and 17D-204, and demonstrated its ability to prevent and treat YF disease in both AG129 mouse and hamster models of infection. To counteract possible selection of 17D-204 variants that escape neutralization by treatment with a single MAb (2C9-cIgG), we developed a second cMAb, 864-cIgG, for use in combination with 2C9-cIgG in post vaccinal therapy. MAb 864-cIgG recognizes/neutralizes only YFV 17D-204 vaccine substrain and binds to domain III (DIII) of the viral envelope protein, which is different from the YFV type-specific binding site of 2C9-cIgG in DII. Although it neutralized 17D-204 in vitro, administration of 864-cIgG had no protective capacity in the interferon receptor-deficient AG129 mouse model of 17D-204 infection. The data presented here show that although DIII-specific 864-cIgG neutralizes virus infectivity in vitro, it does not have the ability to abrogate disease in vivo. Therefore, combination of 864-cIgG with 2C9-cIgG for treatment of YF vaccination SAEs does not appear to provide an improvement on 2C9-cIgG therapy alone. PMID- 27126617 TI - Randomised controlled trial to evaluate a physiotherapy-led functional exercise programme after total hip replacement. AB - BACKGROUND: At present, there is an insufficient evidence base to evaluate the effectiveness of physiotherapy following total hip replacement (THR). This study evaluated the effectiveness of a physiotherapy-supervised functional exercise programme between 12 and 18 weeks following THR. These time-points coincide with increased functional demand in patients. DESIGN: Adequately powered assessor blinded randomised controlled trial. SETTING: Patients were recruited at a pre operative assessment clinic and randomised following surgery. PARTICIPANTS: Sixty three subjects were randomised to either the usual care group (control, n=31) or the functional exercise+usual care group (n=32). INTERVENTIONS: Patients in the functional exercise group attended a physiotherapy-supervised functional exercise class twice weekly from 12 to 18 weeks following THR. Patients in the control group followed the usual care protocol with no exercise intervention. MAIN OUTCOME MEASUREMENT: The main outcome measurement tool was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, and the secondary outcomes included walking speed, hip abduction dynamometry, Short Form 12 physical and mental health scores, and visual analogue pain scale score. RESULTS: At 18 weeks post surgery, WOMAC function and walking speed improved significantly more in the functional exercise group [mean difference -4.0, 95% confidence interval (CI) -7.0 to 1.0 (P<0.01); mean difference 21.9m, 95% CI 0.60 to 43.3 (P<0.04)] than the control group, but there was no significant difference in hip abductor strength. CONCLUSION: This study demonstrated that patients who undertake a physiotherapy-led functional exercise programme between 12 and 18 weeks after THR may gain significant functional improvement compared with patients receiving usual care. Clinical trial registration number NCT01683201. PMID- 27126618 TI - Risk of anastomotic leak after laparoscopic versus open colectomy. AB - BACKGROUND: Anastomotic leak following colorectal surgery is associated with significant morbidity and mortality. With the widespread adoption of laparoscopy, data from initial clinical trials evaluating the efficacy of laparoscopic when compared to open surgery may not currently be generalizable. We assess the risk of anastomotic leak after laparoscopic versus open colorectal resection using a nationwide database with standardized definitions. METHODS: The 2012-2013 ACS NSQIP targeted colectomy data were queried for all elective colorectal resections. Characteristics were compared for those patients undergoing laparoscopic versus open operations. Univariable and multivariable analyses, followed by a propensity score-matched analysis, were performed to assess the impact of laparoscopy on the development of an anastomotic leak. RESULTS: Of 23,568 patients, 3.4 % developed an anastomotic leak. Laparoscopic surgery was associated with a leak rate of 2.8 % (n = 425) and open surgery, 4.5 % (n = 378, p < 0.0001). Patients who developed a leak were more likely to die within 30 days of surgery (5.7 vs. 0.6 %, p < 0.0001). Patients who underwent laparoscopic surgery compared to open were younger (61 vs. 63 years, p = 0, p = 0.045) and with fewer comorbidities. On univariable analysis laparoscopic surgery was associated with reduced odds of developing an anastomotic leak (OR 0.60, p < 0.0001), and this remained after adjusting for all significant preoperative and disease-related confounders (OR 0.69, 95 % CI 0.58-0.82). A propensity score matched analysis confirmed benefit of laparoscopic surgery over open surgery for anastomotic leak. CONCLUSION: Laparoscopic colectomy is safe and associated with reduced odds of developing an anastomotic leak following colectomy when controlling for patient-, disease- and procedure-related factors. PMID- 27126619 TI - Endoscopic balloon dilation in the management of strictures in Crohn's disease: a systematic review and meta-analysis of non-randomized trials. AB - BACKGROUND AND AIM: Crohn's disease (CD) is associated with strictures. Endoscopic balloon dilatation (EBD) may prevent or delay the need for surgical resection. The aim of this systematic review was to determine the efficacy and safety of EBD in the management of Crohn's strictures. METHODS: A comprehensive search of MEDLINE and EMBASE databases from January 1980 to May 2015 was performed. The primary outcome measurements were surgical intervention rates and major adverse events. RESULTS: A total of 24 studies involving 1163 patients were included in the analysis. The median duration from the initial diagnosis of CD to the first EBD was 10.2-17.0 years. The majority of strictures (69 %) treated were anastomotic, while the remaining strictures were naive (primary). Surgical intervention rate over a median follow-up period of 15-70 months in the reported studies was 27 %. The surgical intervention rate after dilation of anastomotic strictures was 18 % versus 29 % for primary strictures. The risk ratio for the surgical requirement of anastomotic versus primary strictures was [0.88 (95 % confidence interval [CI] 0.59-1.32); p = 0.54]. Stricture length <4 cm was associated with a significantly decreased risk of surgical intervention [risk ratio = 0.48 (95 % CI 0.26-0.90); p = 0.02]. EBD resulted in major adverse events in 4 % of the patients. CONCLUSIONS: EBD appears to be a safe alternative for surgery in the management of Crohn's strictures. Stricture length <4 cm treated with EBD is associated with a significantly decreased risk of surgical intervention. PMID- 27126620 TI - The anatomical location of the pancreas is associated with the incidence of pancreatic fistula after laparoscopic gastrectomy. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is one of the major complications after laparoscopic gastrectomy (LG). We investigated the impact of the anatomical location of the pancreas, especially in relation to the suprapancreatic lymph nodes, on the incidence of POPF after LG. METHODS: We retrospectively reviewed the preoperative computed tomography (CT) images of 246 patients who underwent LG with the suprapancreatic lymph node dissection between November 2008 and November 2015. The length between the levels of the pancreatic body surface and the root of the common hepatic artery (LPC) was measured on a CT image with an axial view. A receiver operating characteristics (ROC) curve analysis was performed to determine the cutoff LPC value. A multivariate analysis was performed to determine the predictive factors for POPF. RESULTS: POPF occurred in 11 patients (4.5 %). The median LPC was significantly longer in the patients with POPF than in those without (26 mm vs. 21 mm, p = 0.026). The ROC curve analysis revealed that the optimal cutoff LPC value for predicting POPF was 25 mm. The POPF rate was significantly higher in the long LPC group than in the short LPC group (10 vs. 1.3 %, p = 0.002). A multivariate analysis demonstrated that a long LPC (p = 0.018) and dissection of the lymph nodes along the distal splenic artery (p = 0.042) were independent predictors of POPF. The amylase level in the drainage fluid on postoperative day 1 was significantly higher in the long LPC group than in the short LPC group. CONCLUSIONS: The LPC is a simple and reliable predictor of POPF after LG. Surgeons should take the anatomical location of the pancreas into consideration when performing LG with suprapancreatic lymph node dissection. PMID- 27126621 TI - Single-stage management with combined tri-endoscopic approach for concomitant cholecystolithiasis and choledocholithiasis. AB - OBJECTIVE: The aim of this study was to investigate the value of a single stage with combined tri-endoscopic (duodenoscopy, laparoscopy and choledochoscopy) approach for patients with concomitant cholecystolithiasis and choledocholithiasis. METHODS: Fifty-three patients with combined gallbladder stones and common bile duct stones from February 2014 to April 2015 were randomized assigned to two groups: 29 patients underwent single-stage surgery with combined duodenoscope, laparoscope and choledochoscope (combined tri endoscopic group), and 29 patients underwent endoscopic sphincterotomy to remove common bile duct stones followed by laparoscopic cholecystectomy several days later (control group). The success rate of complete stone removal, procedure related complication, hospital stay and the cost of hospitalization were compared between the two groups. RESULTS: Altogether, 53 patients (29 patients in combined tri-endoscopic group and 24 patients in control group) successfully underwent the surgery and ERCP procedure. Three patients in the control group developed post ERCP pancreatitis. One case of bile leaking and one case of residual stone were noted in the combined tri-endoscopic group. There were no significant differences between the two groups with regard to both complete stone removal [96.6 % (28/29) vs. 100 % (24/24)] and procedure-related complication rate [3.4 % (1/29) vs. 12.5 % (3/24)] (p > 0.05). No open surgery was required in either group. There were significant differences between the two groups with regard to hospital stay (6.72 +/- 1.3 days vs. 10.91 +/- 1.6 days, p < 0.01) and cost of hospitalization (15,724 +/- 1613 CNY vs. 19,829 +/- 2433 CNY, p < 0.05). CONCLUSION: The single stage combined tri-endoscopic approach for concomitant cholecystolithiasis and choledocholithiasis was just as safe and successful as the control group. In addition, it resulted in a shorter hospital stay and less cost. PMID- 27126622 TI - Outcome of bariatric surgery in patients with type 1 diabetes mellitus: our experience and review of the literature. AB - BACKGROUND: The beneficial effect of bariatric surgery (BS) in type 2 diabetes mellitus patients is well established. Conversely, little is known about the efficacy of BS in type 1 diabetes mellitus (T1DM) patients, despite the increasing prevalence of obesity in this population. METHODS: A retrospective review was carried out on a prospectively collected bariatric surgery registry of all patients undergoing BS at two university hospitals between 2010 and 2015. Patients with T1DM were identified, and detailed chart reviews were obtained. RESULTS: In this time period, we operated on thirteen patients with T1DM. Eight were female (61.5 %). Median age at time of surgery was 38 +/- 8.3 (range 28-53) years. The procedures performed were laparoscopic sleeve gastrectomy (n = 10) and laparoscopic Roux-en-Y gastric bypass (n = 3). On median postoperative follow-up of 24 (range 2.5-51) months, mean body mass index significantly decreased from 39.9 +/- 4.1 to 30.1 +/- 3.9 kg/m2 (P < 0.0001) and insulin requirements were significantly reduced from 83.7 +/- 40.4 to 45.7 +/- 33.1 U/day (P < 0.01). However, there was no significant change in glycemic control assessed by HbA1C (P = 0.2). During the first months following surgery, three patients (21.4 %) experienced diabetic ketoacidosis, and four patients (28.6 %) reported more frequent episodes of hypoglycemia. CONCLUSIONS: Bariatric surgery in morbidly obese T1DM patients is an effective method for weight loss, leading to a remarkable improvement in insulin requirements. Larger prospective studies are still needed to confirm these findings, assess long-term effects of BS and better delineate its risk-to-benefit ratio in this growing population of morbidly obese patients with T1DM. PMID- 27126624 TI - Laparoscopic redo hepaticojejunostomy for children with choledochal cysts. AB - BACKGROUND: The current study is to evaluate the long-term efficacy of laparoscopic redo hepaticojejunostomy (LRH) for children with cholecochal cysts (CDCs). METHODS: Between January 2006 and January 2016, 44 CDC children who had biliary re-obstructions after primary definitive surgeries successfully underwent LRH in our hospital. The hepatic arteries were repositioned behind Roux loop. Ductoplasties and wide hepaticojejunostomies were carried out. The operative time, postoperative recovery and complications were compared with our open redo hepaticojejunostomy (ORH, n = 16) between October 2001 and December 2005. RESULTS: There was no significant difference of age at surgery between two groups. Mean operative time in the LRH group was 2.32 h, which did not differ from 2.05 h in the ORH group (p = 0.11). Average postoperative hospital stay, resumption of full diet and duration of drainage in the LRH group were 5.47, 2.11 and 3.22 days, respectively, significantly shorter than 7.37, 3.31 and 4.50 days in our ORH group (p < 0.001, respectively). Median follow-up period was 48 months (1-120 months) in the LRH group and 140 months (120-170 months) in the ORH group. No recurrent biliary obstruction, cholangitis, intrahepatic stone formation or carcinoma were detected in either group. No blood transfusion was required in the LRH group, while one patient in ORH group required 3-day hemostatic treatment and blood transfusion for postoperative bleeding. In the LRH group, one patient suffered from bile leak and spontaneously cured after 7-day drainage. Two patients in the ORH group developed wound dehiscence and required surgical repairs. Overall morbidities were 2.3 % (1/44) in LRH group and significantly <18.8 % (3/16) in ORH group (p < 0.05). Liver function parameters normalized in both groups. CONCLUSIONS: In experienced hands, LRH does not necessarily require open surgery. Long-term results of the LRH group were comparable or even superior to those of the ORH group. PMID- 27126623 TI - Stenosis rates after endoscopic submucosal dissection of large rectal tumors involving greater than three quarters of the luminal circumference. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive treatment option for large rectal tumors. There are limited data available on stenosis rates following ESD of large rectal lesions. We aimed to evaluate the stenosis rate following ESD of large rectal tumors with rectal mucosal defects greater than three quarters of the circumference. METHODS: We retrospectively identified patients who underwent rectal ESD between January 1998 and July 2014. Patients with rectal mucosal defects greater than three quarters the luminal circumference were included for analysis. Clinicopathologic characteristics, treatment outcomes and adverse events were assessed. Stenosis was defined as an inability to pass a pediatric colonoscope into the sigmoid colon. None of the patients underwent prophylactic balloon dilation. RESULTS: A total of 363 patients with 370 rectal lesions were treated by ESD. Among these, 26 patients had 26 lesions with rectal mucosal defects greater than three quarters of the luminal circumference. Median tumor size (range) was 80 (47-150) mm. Four lesions (15 %) required between 90 and <100 % circumferential dissection, while complete circumferential ESD was performed in two lesions (8 %). Dissection extended to the anal canal in six patients. The median procedure time was 220 min. En bloc resection and curative resection were achieved in 88.5 and 65.4 %, respectively. Delayed bleeding rates and perforation rates were 7.7 and 0 %, respectively. During a median follow-up period of 9.8 (0-59) months, there were no patients with complaints of constipation or fecal incontinence. One patient (4.2 %) was noted to have rectal stenosis, but was clinically asymptomatic. Endoscopic balloon dilation was not required in any patients. CONCLUSIONS: Stenosis may rarely occur after ESD of large rectal lesions with rectal mucosal defects greater than three quarters of the circumference, even without prophylactic endoscopic balloon dilation. PMID- 27126625 TI - Application of clip traction in endoscopic submucosal dissection to the treatment of early esophageal carcinoma and precancerous lesions. AB - BACKGROUND AND AIM: It is usually difficult to obtain a good view of the dissection plane during esophageal endoscopic submucosal dissection (ESD). Therefore, the aim of this study was to investigate the efficacy and safety of clip traction in ESD for the treatment of early esophageal carcinoma (EEC) or precancerous lesions. METHODS: This is a case-matched comparative study. We selected 100 EEC patients who had undergone ESD. Fifty cases underwent ESD without clip traction (non-clip group), and 50 cases underwent ESD with clip traction (clip group). The patient-related variables, dissection time, data regarding muscularis propria injury, etc. were statistically analyzed. RESULTS: ESD was successful in all cases without complication. There were no significant differences between the two groups with respect to age, gender, the longitudinal diameter of the lesions, etc. Wide visual field exposure of the submucosal tissue below the lesion was obtained by applying clip traction. The dissection time of ESD was shorter in the clip group than in the non-clip group [22.02 (6.77) min vs 26.48 (12.56); P = 0.018] when the extent of lesion was less than half of the circumference of the esophagus; otherwise, there was no difference between the two groups (P = 0.252). Moreover, the muscularis propria injuries in the clip group were obviously less than the non-clip group (10 vs 30 %, P = 0.007). CONCLUSION: Clip traction can decrease the rate of muscularis propria injury and shorten the dissection time. It is recommended as a safe and effective auxiliary procedure for the treatment of esophageal ESD. PMID- 27126626 TI - Clinical outcomes and cost-benefit analysis comparing laparoscopic and robotic colorectal surgeries. AB - BACKGROUND: The introduction of minimally invasive platforms for colorectal surgery-laparoscopy and more recently robotics-allows for smaller incisions, shortened hospital stay, less postoperative pain, and quicker return to normal activity. There exists a lack of evidence-based knowledge comparing the clinical outcomes and cost-benefit analysis of the different types of minimally invasive surgery. The aim of this study was to analyze and compare the short-term clinical outcomes and overall hospital costs between laparoscopic and robotic colorectal surgery. METHODS: After IRB approval, we conducted a retrospective chart review from 131 patients who underwent laparoscopic colorectal surgery and 96 patients who underwent robotic colorectal surgery. Data analyzed included pertinent patient demographics, operative times (OR times), conversion rates, postoperative pathology, complications, length of hospital stay, 90-day readmission rates, 30 day mortality, and overall hospital costs. RESULTS: Two hundred and twenty-seven patients were included-laparoscopic (N = 131) and robotic (N = 96) colorectal surgeries. Mean age of patients in the laparoscopic versus robotic cohort was 70.9 vs 63.6 years, (p < 0.001). Around 62 % were operated on for malignant disease. Mean OR time was 113 min for laparoscopy and 109 min for robotics, p = 0.59. Conversion rates were comparable. Mean length of hospital stay (6.6 vs 5.7 days) and postoperative complications (3.2 vs 7 %) were comparable between the laparoscopic and robotic arms. Overall hospital charges were $114,853 for laparoscopy and $107,220 for robotics, and no significant difference was noted (p = 0.448, NS). CONCLUSION: Robotic colectomies were comparable to laparoscopic colectomies in terms of overall hospital charges and short-term clinical outcomes, including length of stay and conversion rates. Robotic surgery was favored for left-sided colectomy. With shorter learning curves and wider availability, robotic approach offers a safe and economically feasible minimally invasive platform for complex colorectal resections. PMID- 27126627 TI - First protein and peptide characterization of the tarsal adhesive secretions in the desert locust, Schistocerca gregaria, and the Madagascar hissing cockroach, Gromphadorhina portentosa. AB - Peptides and proteins have been largely neglected in the analysis of insect tarsal adhesives. After extraction of the protein fraction of the tarsal secretion of the desert locust, Schistocerca gregaria, and Madagascar hissing cockroach, Gromphadorhina portentosa, we combined Fourier transform infrared spectroscopy (FTIR), sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) analyses for protein mass detection. In both these insects, SDS PAGE analysis revealed several protein bands ranging from 8-190 kDa in both the tarsal secretion and the tibia control sample. Two (S. gregaria) and one (G. portentosa) protein bands exclusively occurred in the tarsal secretion and can be considered to belong to peptides and proteins specific to this secretion. MALDI TOF analyses revealed 83 different proteins/peptides of 1-7 kDa in S. gregaria, and 48 of 1-11 kDa in G. portentosa. 59 (S. gregaria) and 27 (G. portentosa) proteins exclusively occurred in the tarsal secretion. In G. portentosa, a characteristic series of signal peaks occurred in the range of c. 10-12 kDa, each peak being approximately 160 Da apart. Such a pattern is indicative of proteins modified by glycosylation. Our approach demonstrates that extensive sampling involving considerable time and manpower to sample the adhesive fluid directly from the tarsi opens up a perspective for extracting peptides and proteins in sufficient quantities. This makes them accessible to the field of proteomics and thus to elucidate their possible function in the adhesive process. PMID- 27126629 TI - Australian and New Zealand Society for Geriatric Medicine Position Statement Abstract: Transitional care. PMID- 27126628 TI - B-cell signaling in persistent polyclonal B lymphocytosis (PPBL). AB - Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)-like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF-kappaB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF-kappaB signaling after CD40 stimulation and both B cell receptor- and Toll-like receptor 9-mediated activation remained unaffected. Reduced canonical NF-kappaB activation resulted in decreased IkappaBalpha and CD40 expression in resting cells. In PPBL patients, expression of Bcl-xL in MZ like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL-derived B cells that were observed in vitro. The B-cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ-like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF-kappaB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL. PMID- 27126630 TI - Association of Distance Traveled for Surgery with Short- and Long-Term Cancer Outcomes. AB - BACKGROUND: The influence of distance traveled for treatment on short- and long term cancer outcomes is unclear. METHODS: Patients with colon, esophageal, liver, and pancreas cancer from 2003 to 2006 were identified from the National Cancer Data Base (NCDB). Distance traveled for surgical treatment was estimated using zip code centroids. Propensity scores were generated for probability of traveling farther for treatment. Mixed effects logistic regression for 90-day mortality and Cox regression for 5-year mortality were compared between patients treated regionally and those traveling from farther away. RESULTS: The mean distance traveled for all patients for surgical resection was 30.0 +/- 227 miles, with a median distance of 7.5 (interquartile range 14.4) miles. Patients who were aged >=80 years, on Medicaid, or African American were less likely to be in the fourth quartile of distance (Q4) traveled for surgery. Patients who were in Q4 had a lower risk-adjusted 90-day mortality compared to Q1 for colon [odds ratio (OR) 0.89, 95 % confidence interval (CI) 0.82-0.96], liver (OR 0.49, 95 % CI 0.3 0.78), and pancreatic (OR 0.74, 95 % CI 0.56-0.98) cancer. Similarly, patients in Q4 for all tumor types had a lower risk-adjusted 5-year mortality compared to patients in Q1; colon (hazard ratio (HR) 0.96, 95 % CI 0.93-0.99), esophagus (HR 0.84, 95 % CI 0.75-0.94), liver (HR 0.75, 95 % CI 0.62-0.89), and pancreas (HR 0.87, 95 % CI 0.80-0.95). CONCLUSIONS: Greater travel distance for surgical resection of gastrointestinal cancers is associated with lower 90-day and 5-year mortality outcomes. This distance bias has implications for regionalization and reporting of cancer outcomes. PMID- 27126631 TI - From Conventional Radiotracer Tc-99(m) with Blue Dye to Indocyanine Green Fluorescence: A Comparison of Methods Towards Optimization of Sentinel Lymph Node Mapping in Early Stage Cervical Cancer for a Laparoscopic Approach. AB - BACKGROUND: The credibility of sentinel lymph node (SLN) mapping is becoming increasingly more established in cervical cancer. We aimed to assess the sensitivity of SLN biopsy in terms of detection rate and bilateral mapping in women with cervical cancer by comparing technetium-99 radiocolloid (Tc-99(m)) and blue dye (BD) versus fluorescence mapping with indocyanine green (ICG). METHODS: Data of patients with cervical cancer stage 1A2 to 1B1 from 5 European institutions were retrospectively reviewed. All centers used a laparoscopic approach with the same intracervical dye injection. Detection rate and bilateral mapping of ICG were compared, respectively, with results obtained by standard Tc 99(m) with BD. RESULTS: Overall, 76 (53 %) of 144 of women underwent preoperative SLN mapping with radiotracer and intraoperative BD, whereas 68 of (47 %) 144 patients underwent mapping using intraoperative ICG. The detection rate of SLN mapping was 96 % and 100 % for Tc-99(m) with BD and ICG, respectively. Bilateral mapping was achieved in 98.5 % for ICG and 76.3 % for Tc-99(m) with BD; this difference was statistically significant (p < 0.0001). CONCLUSIONS: The fluorescence SLN mapping with ICG achieved a significantly higher detection rate and bilateral mapping compared to standard radiocolloid and BD technique in women with early stage cervical cancer. Nodal staging with an intracervical injection of ICG is accurate, safe, and reproducible in patients with cervical cancer. Before replacing lymphadenectomy completely, the additional value of fluorescence SLN mapping on both perioperative morbidity and survival should be explored and confirmed by ongoing controlled trials. PMID- 27126632 TI - Role of neuroimaging in the diagnosis of hereditary cerebellar ataxias in childhood. AB - Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, characterized by cerebellar ataxia as the main clinical feature, and a large spectrum of neurological-associated symptoms and possible multi-organ affection. Image-based approaches to hereditary ataxias in childhood have already been proposed. The aim of this review is to yield the main reports of neuroimaging patterns and diagnostic algorithms and compare them with the results from our study of 23 young patients addressed for ataxia, with subsequent genetic or metabolic diagnosis. PMID- 27126633 TI - Absolute and regional cerebral perfusion assessment feasibility in head-down position with arterial spin-labeling magnetic resonance. A preliminary report on healthy subjects. AB - PURPOSE: Head-down (HD)-positioning, used in some stroke centers during early ischemic stroke management, is empirical but supported by some physiological findings. It has been shown by nonmagnetic resonance methods that this position can increase cerebral perfusion. This study aimed to investigate magnetic resonance imaging (MRI) ability to measure the response to head-down tilt (HDT) challenge in healthy volunteers. Cerebral blood flow (CBF) was assessed with arterial spin labeling (ASL) in supine and HD (-15 degrees ) positions. METHODS: Cerebral perfusion was measured in supine and HD positions in seven healthy subjects at 1.5T with a large magnet bore (70cm) MRI device. 3D pseudocontinuous arterial spin-labeling (pCASL) sequences were acquired in both positions and cerebral blood flow (CBF) maps were reconstructed. Regions of interest were subcortical gray matter structures (accumbens nuclei, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus), whole cortical gray matter and whole white matter. RESULTS: White matter and subcortical gray matter structures' CBF, averaged over the volunteers' sample, remained stable from supine to HD position. Accumbens nuclei and cortical gray matter CBF decreased by 11.5% (P=0.013) and 11.4% (P=0.018) when head position was changed from flat to -15 degrees . CONCLUSIONS: Regional CBF assessment, especially in HDT, is challenging with most perfusion techniques because of ionizing radiations, inherent limitations and logistical considerations. This preliminary report presents a noninvasive technique assessing regional and absolute cerebral blood flow changes in response to posture change. It can lead to further clinical investigations for a better understanding of cerebral perfusion. PMID- 27126634 TI - Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease. AB - White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD. PMID- 27126636 TI - CRISPR/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-linked hypophosphatemia (XLH). AB - X-linked hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy. PMID- 27126635 TI - Glucocerebrosidase modulates cognitive and motor activities in murine models of Parkinson's disease. AB - Mutations in GBA1, the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. A higher prevalence and increased severity of motor and non-motor symptoms is observed in PD patients harboring mutant GBA1 alleles, suggesting a link between the gene or gene product and disease development. Interestingly, PD patients without mutations in GBA1 also exhibit lower levels of glucocerebrosidase activity in the central nervous system (CNS), implicating this lysosomal enzyme in disease pathogenesis. Here, we investigated whether modulation of glucocerebrosidase activity in murine models of synucleinopathy (expressing wild type Gba1) affected alpha-synuclein accumulation and behavioral phenotypes. Partial inhibition of glucocerebrosidase activity in PrP-A53T-SNCA mice using the covalent inhibitor conduritol-B-epoxide induced a profound increase in soluble alpha-synuclein in the CNS and exacerbated cognitive and motor deficits. Conversely, augmenting glucocerebrosidase activity in the Thy1-SNCA mouse model of PD delayed the progression of synucleinopathy. Adeno associated virus-mediated expression of glucocerebrosidase in the Thy1-SNCA mouse striatum led to decrease in the levels of the proteinase K-resistant fraction of alpha-synuclein, amelioration of behavioral aberrations and protection from loss of striatal dopaminergic markers. These data indicate that increasing glucocerebrosidase activity can influence alpha-synuclein homeostasis, thereby reducing the progression of synucleinopathies. This study provides robust in vivo evidence that augmentation of CNS glucocerebrosidase activity is a potential therapeutic strategy for PD, regardless of the mutation status of GBA1. PMID- 27126637 TI - Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice. AB - Obesity and ectopic fat disposition are risk factors for metabolic disease. Recent data indicate that IGFBP2 expression in liver is epigenetically inhibited during hepatic steatosis. The aim of this study was to investigate if epigenetic de-regulation of hepatic Igfbp2 occurs already early in life and is associated with increased risk for diet-induced obesity (DIO) during adolescence. Male C57BL/6J mice received a high-fat diet. After 3 weeks on this diet (age of 6 weeks), DIO-susceptible (responder, Resp) and DIO-resistant (non-responder, nResp) mice were identified by early weight gain. At the age of 6 weeks, Resp mice exhibited elevated blood glucose (p < 0.05), plasma insulin (p < 0.01), HOMA IR and leptin/adiponectin ratio, whereas liver triglycerides were identical but significantly increased (p < 0.01) in Resp mice at 20 weeks of age. Igfbp2 expression was reduced in young Resp compared with nResp mice (p < 0.01), an effect that correlated with elevated DNA methylation of intronic CpG2605 (p < 0.01). The epigenetic inhibition of Igfbp2 was stable over time and preceded DIO and hepatosteatosis in adult mice. In vitro studies demonstrated that selective methylation of CpG2605 significantly reduced reporter activity by ~85%, indicating that Igfbp2 expression is modulated by methylation. In human whole blood cells, methylation of IGFBP2 at the homologous CpG site was increased in obese men with impaired glucose tolerance. In conclusion, our data show that increased methylation of hepatic Igfbp2 during infancy predicts the development of fatty liver later in life and is linked to deterioration of glucose metabolism. PMID- 27126639 TI - Safety of tumor necrosis factor inhibitor therapy in patients with a prior malignancy. AB - AIM: There is insufficient evidence to determine whether tumor necrosis factor inhibitor (TNFi) therapy is safe in patients with a recent history of cancer. The purpose of our study was to explore the influence of TNFi therapy on cancer related outcomes in patients who had undergone curative cancer treatment. METHODS: The medical records of 814 patients who received TNFi therapy at a single rheumatology clinic, between June 2005 and May 2014 were retrospectively reviewed. Among them, the data from patients having received anticancer treatment before starting TNFi therapy were collected and cancer-related outcomes were evaluated. RESULTS: Twenty patients of 814 had a history of malignancy before initiating TNFi therapy. Over the duration of TNFi exposure (median, 54.0 months; interquartile range [IQR], 23.25-72.0 months), there was no recurrence of the previous cancer. In eight patients with early-stage cancer, TNFi therapy was initiated < 5 years after conclusion of previous anticancer treatments. Notably, over the duration of the ongoing treatment follow-up period (median, 33.5 months; IQR, 13.0-75.75 months), cancer recurrence was also not identified. CONCLUSION: TNFi therapy in patients with a history of an early-stage localized cancer may not be contraindicated, even if TNFi is initiated < 5 years from completion of curative cancer treatment. PMID- 27126638 TI - Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. AB - Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is an important cause of dementia in individuals under age 65. Common variants in the TMEM106B gene were previously discovered by genome-wide association to confer genetic risk for FTLD-TDP (p = 1 * 10-11, OR = 1.6). Furthermore, TMEM106B may act as a genetic modifier affecting age at onset and age at death in the Mendelian subgoup of FTLD-TDP due to expansions of the C9orf72 gene. Evidence suggests that TMEM106B variants increase risk for developing FTLD-TDP by increasing expression of Transmembrane Protein 106B (TMEM106B), a lysosomal protein. To further understand the functional role of TMEM106B in disease pathogenesis, we investigated the cell biological effects of increased TMEM106B expression. Here, we report that increased TMEM106B expression results in the appearance of a vacuolar phenotype in multiple cell types, including neurons. Concomitant with the development of this vacuolar phenotype, cells over expressing TMEM106B exhibit impaired lysosomal acidification and degradative function, as well as increased cytotoxicity. We further identify a potential lysosomal sorting motif for TMEM106B and demonstrate that abrogation of sorting to lysosomes rescues TMEM106B-induced defects. Finally, we show that TMEM106B induced defects are dependent on the presence of C9orf72, as knockdown of C9orf72 also rescues these defects. In sum, our results suggest that TMEM106B exerts its effects on FTLD-TDP disease risk through alterations in lysosomal pathways. Furthermore, TMEM106B and C9orf72 may interact in FTLD-TDP pathophysiology. PMID- 27126640 TI - Genome-wide association study identifies loci and candidate genes for meat quality traits in Simmental beef cattle. AB - Improving meat quality is the best way to enhance profitability and strengthen competitiveness in beef industry. Identification of genetic variants that control beef quality traits can help breeders design optimal breeding programs to achieve this goal. We carried out a genome-wide association study for meat quality traits in 1141 Simmental cattle using the Illumina Bovine HD 770K SNP array to identify the candidate genes and genomic regions associated with meat quality traits for beef cattle, including fat color, meat color, marbling score, longissimus muscle area, and shear force. In our study, we identified twenty significant single nucleotide polymorphisms (SNPs) (p < 1.47 * 10(-6)) associated with these five meat quality traits. Notably, we observed several SNPs were in or near eleven genes which have been reported previously, including TMEM236, SORL1, TRDN, S100A10, AP2S1, KCTD16, LOC506594, DHX15, LAMA4, PREX1, and BRINP3. We identified a haplotype block on BTA13 containing five significant SNPs associated with fat color trait. We also found one of 19 SNPs was associated with multiple traits (shear force and longissimus muscle area) on BTA7. Our results offer valuable insights to further explore the potential mechanism of meat quality traits in Simmental beef cattle. PMID- 27126641 TI - Mouse genome-wide association study identifies polymorphisms on chromosomes 4, 11, and 15 for age-related cardiac fibrosis. AB - Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits. PMID- 27126643 TI - Which endovenous ablation method does offer a better long-term technical success in the treatment of the incompetent great saphenous vein? Review. AB - OBJECTIVE: The aim of this review article was to evaluate the long-term technical success rates of the known endovenous ablation procedures in the treatment of the incompetence of the great saphenous vein. METHODS: A literature search was conducted in the PubMed-database until the 5 January 2016. All publications with four to five years follow-up were eligible. Meta-analysis was performed by the IVhet-model. RESULTS: Eight hundred and sixty-two unique publications were found; 17 of them were appropriate for meta-analysis. Overall, 1420 limbs were included in the trial, 939 for endovenous laser ablation, 353 for radiofrequency ablation and 128 for ultrasound guided foam sclerotherapy. Overall, technical success rates were 84.8% for endovenous laser ablation, 88.7% for radiofrequency ablation and 32.8% for ultrasound guided foam sclerotherapy. There were no significant differences between endovenous laser ablation, radiofrequency ablation and ultrasound guided foam sclerotherapy regarding the great saphenous vein reopening (p = 0.66; OR: 0.22; 95% of CI: 0.08-0.62 for radiofrequency ablation vs. endovenous laser ablation; p = 0.96; OR: 0.11; 95% of CI: 0.06-0.20 for endovenous laser ablation vs. ultrasound guided foam sclerotherapy; p = 0.93; OR: 3.20; 95% of CI: 0.54-18.90 for ultrasound guided foam sclerotherapy vs. radiofrequency ablation). CONCLUSION: Both endovenous laser ablation and radiofrequency ablation are efficient in great saphenous vein occlusion on the long term. Lacking long-conducted large trials, the efficacy and reliability of ultrasound guided foam sclerotherapy to treat great saphenous vein-reflux is not affirmed. PMID- 27126642 TI - Global and local oscillatory entrainment of visual behavior across retinotopic space. AB - Ongoing brain oscillations (7-10 Hz) modulate visual perception; in particular, their precise phase can predict target perception. Here, we employ this phase dependence of perception in a psychophysical experiment to track spatial properties of entrained oscillations of visual perception across the visual field. Is this entrainment local, or a more global phenomenon? If the latter, does oscillatory phase synchronize over space, or vary with increasing distance from the oscillatory source? We presented a disc stimulus in the upper left quadrant, oscillating in luminance at different frequencies (individual alpha frequency (IAF), 5 Hz, and 15 Hz) to entrain an oscillation with specific frequency and spatial origin. Observers fixated centrally, while flash stimuli at perceptual threshold appeared at different positions and times with respect to the oscillating stimulus. IAF and 5 Hz luminance oscillations modulated detection performance at all tested positions, whereas at 15 Hz, the effect was weaker and less consistent. Furthermore, for IAF and 5 Hz entrainment, preferred phases for target detection differed significantly between spatial locations, suggesting "local" entrainment of detection performance next to the oscillatory source, whereas more distant target locations shared a "global" effect with a significantly different phase. This unexpected global component of entrainment is tentatively attributed to widespread connectivity from thalamic nuclei such as the pulvinar. PMID- 27126644 TI - Advances in Thrombosis and Hemostasis: An Introduction to the Compendium. PMID- 27126645 TI - Global Burden of Thrombosis: Epidemiologic Aspects. AB - Thromboembolic conditions were estimated to account for 1 in 4 deaths worldwide in 2010 and are the leading cause of mortality. Thromboembolic conditions are divided into arterial and venous thrombotic conditions. Ischemic heart disease and ischemic stroke comprise the major arterial thromboses and deep-vein thrombosis and pulmonary embolism comprise venous thromboembolism. Atrial fibrillation is a major risk factor for stroke and systemic arterial thromboembolism. Estimates of the global burden of disease were obtained from Global Burden of Disease Project reports, recent systematic reviews, and searching the published literature for recent studies reporting measures of incidence, burden, and disability-adjusted life-years. Estimates per 100 000 of the global incidence rate (IR) for each condition are ischemic heart disease, IR=1518.7; myocardial infarction, IR=139.3; ischemic stroke, IR=114.3; atrial fibrillation, IR=77.5 in males and 59.5 in females; and venous thromboembolism, IR=115 to 269. Mortality rates (MRs) for each condition are ischemic heart disease, MR=105.5; ischemic stroke, MR=42.3; atrial fibrillation, MR=1.7; and venous thromboembolism, MR=9.4 to 32.3. Global public awareness is substantially lower for pulmonary embolism (54%) and deep-vein thrombosis (44%) than heart attack (88%) and stroke (85%). Over time, the incidence and MRs of these conditions have improved in developed countries, but are increasing in developing countries. Public health efforts to measure disease burden and increase awareness of symptoms and risk factors need to improve, particularly in low- and middle income regions to address this leading cause of morbidity and mortality. PMID- 27126647 TI - Animal Models of Thrombosis From Zebrafish to Nonhuman Primates: Use in the Elucidation of New Pathologic Pathways and the Development of Antithrombotic Drugs. AB - Thrombosis is a leading cause of morbidity and mortality worldwide. Animal models are used to understand the pathological pathways involved in thrombosis and to test the efficacy and safety of new antithrombotic drugs. In this review, we will first describe the central role a variety of animal models of thrombosis and hemostasis has played in the development of new antiplatelet and anticoagulant drugs. These include the widely used P2Y12 antagonists and the recently developed orally available anticoagulants that directly target factor Xa or thrombin. Next, we will describe the new players, such as polyphosphate, neutrophil extracellular traps, and microparticles, which have been shown to contribute to thrombosis in mouse models, particularly venous thrombosis models. Other mouse studies have demonstrated roles for the factor XIIa and factor XIa in thrombosis. This has spurred the development of strategies to reduce their levels or activities as a new approach for preventing thrombosis. Finally, we will discuss the emergence of zebrafish as a model to study thrombosis and its potential use in the discovery of novel factors involved in thrombosis and hemostasis. Animal models of thrombosis from zebrafish to nonhuman primates are vital in identifying pathological pathways of thrombosis that can be safely targeted with a minimal effect on hemostasis. Future studies should focus on understanding the different triggers of thrombosis and the best drugs to prevent each type of thrombotic event. PMID- 27126648 TI - Platelet-Mediated Thrombosis: From Bench to Bedside. AB - The pivotal role that platelets play in thrombosis and resultant ischemic event occurrences in patients with high-risk coronary artery disease is well established. This role provides the fundamental basis for the current wide implementation of dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor. The development of user friendly point-of-care methods to assess platelet reactivity to adenosine diphosphate has increased the frequency of platelet function testing in clinical practice. Recent large observational studies have established an independent relation between the results of point-of care platelet function testing and clinical event occurrence in patients undergoing coronary artery stenting. However, prospective, randomized trials have failed to demonstrate that personalized antiplatelet therapy based on point-of care assessment of platelet function is effective in reducing ischemic event occurrences. Important limitations were associated with these trials. In addition, the concept of a therapeutic window of P2Y12 receptor reactivity with an upper threshold associated with ischemic event occurrence and a lower threshold associated with bleeding has also been proposed. In the absence of strong prospective evidence to support personalized antiplatelet therapy, clinical decision making about antiplatelet therapy rests on the large body of observational data and the fundamental importance of platelet physiology in catastrophic event occurrence in patients with high-risk coronary artery disease. PMID- 27126649 TI - Cross Talk Pathways Between Coagulation and Inflammation. AB - Anatomic pathology studies performed over 150 years ago revealed that excessive activation of coagulation occurs in the setting of inflammation. However, it has taken over a century since these seminal observations were made to delineate the molecular mechanisms by which these systems interact and the extent to which they participate in the pathogenesis of multiple diseases. There is, in fact, extensive cross talk between coagulation and inflammation, whereby activation of one system may amplify activation of the other, a situation that, if unopposed, may result in tissue damage or even multiorgan failure. Characterizing the common triggers and pathways are key for the strategic design of effective therapeutic interventions. In this review, we highlight some of the key molecular interactions, some of which are already showing promise as therapeutic targets for inflammatory and thrombotic disorders. PMID- 27126646 TI - Systems Analysis of Thrombus Formation. AB - The systems analysis of thrombosis seeks to quantitatively predict blood function in a given vascular wall and hemodynamic context. Relevant to both venous and arterial thrombosis, a Blood Systems Biology approach should provide metrics for rate and molecular mechanisms of clot growth, thrombotic risk, pharmacological response, and utility of new therapeutic targets. As a rapidly created multicellular aggregate with a polymerized fibrin matrix, blood clots result from hundreds of unique reactions within and around platelets propagating in space and time under hemodynamic conditions. Coronary artery thrombosis is dominated by atherosclerotic plaque rupture, complex pulsatile flows through stenotic regions producing high wall shear stresses, and plaque-derived tissue factor driving thrombin production. In contrast, venous thrombosis is dominated by stasis or depressed flows, endothelial inflammation, white blood cell-derived tissue factor, and ample red blood cell incorporation. By imaging vessels, patient specific assessment using computational fluid dynamics provides an estimate of local hemodynamics and fractional flow reserve. High-dimensional ex vivo phenotyping of platelet and coagulation can now power multiscale computer simulations at the subcellular to cellular to whole vessel scale of heart attacks or strokes. In addition, an integrated systems biology approach can rank safety and efficacy metrics of various pharmacological interventions or clinical trial designs. PMID- 27126651 TI - Evolving Treatments for Acute Ischemic Stroke. AB - The purpose of this article is to review advances in stroke treatment in the hyperacute period. With recent evolutions of technology in the fields of imaging, thrombectomy devices, and emergency room workflow management, as well as improvement in statistical methods and study design, there have been ground breaking changes in the treatment of acute ischemic stroke. We describe how stroke presents as a clinical syndrome and how imaging as the most important biomarker will help differentiate between stroke subtypes and treatment eligibility. The evolution of hyperacute treatment has led to the current standard of care: intravenous thrombolysis with tissue-type plasminogen activator and endovascular treatment for proximal vessel occlusion in the anterior cerebral circulation. All patients with acute ischemic stroke are in need of hyperacute secondary prevention because the risk of recurrence is highest closest to the index event. The dominant themes of modern stroke care are the use of neurovascular imaging and speed of diagnosis and treatment. PMID- 27126650 TI - Evolving Treatments for Arterial and Venous Thrombosis: Role of the Direct Oral Anticoagulants. AB - The direct oral anticoagulants (DOACs) represent a major advance in oral anticoagulant therapy and have replaced the vitamin K antagonists as the preferred treatment for many indications. By simplifying long-term anticoagulant therapy and improving its safety, the DOACs have the potential to reduce the global burden of thrombosis. Postmarketing studies suggest that the favorable results achieved with DOACs in the randomized controlled trials can be readily translated into practice, but highlight the need for appropriate patient, drug and dose selection, and careful follow-up. Leveraging on their success to date, ongoing studies are assessing the utility of DOACs for the prevention of thrombosis in patients with embolic stroke of unknown source, heart failure, coronary artery disease, peripheral artery disease, antiphospholipid syndrome, and cancer. The purpose of this article is to (1) review the pharmacology of the DOACs, (2) describe the advantages of the DOACs over vitamin K antagonists, (3) summarize the experience with the DOACs in established indications, (4) highlight current challenges and limitations, (5) highlight potential new indications; and (6) identify future directions for anticoagulant therapy. PMID- 27126652 TI - Gene Therapy for Coagulation Disorders. AB - Molecular genetic details of the human coagulation system were among the first successes of the genetic revolution in the 1980s. This information led to new molecular diagnostic strategies for inherited disorders of hemostasis and the development of recombinant clotting factors for the treatment of the common inherited bleeding disorders. A longer term goal of this knowledge has been the establishment of gene transfer to provide continuing access to missing or defective hemostatic proteins. Because of the relative infrequency of inherited coagulation factor disorders and the availability of safe and effective alternative means of management, the application of gene therapy for these conditions has been slow to realize clinical application. Nevertheless, the tools for effective and safe gene transfer are now much improved, and we have started to see examples of clinical gene therapy successes. Leading the way has been the use of adeno-associated virus-based strategies for factor IX gene transfer in hemophilia B. Several small phase 1/2 clinical studies using this approach have shown prolonged expression of therapeutically beneficial levels of factor IX. Nevertheless, before the application of gene therapy for coagulation disorders becomes widespread, several obstacles need to be overcome. Immunologic responses to the vector and transgenic protein need to be mitigated, and production strategies for clinical grade vectors require enhancements. There is little doubt that with the development of more efficient and facile strategies for genome editing and the application of other nucleic acid-based approaches to influence the coagulation system, the future of genetic therapies for hemostasis is bright. PMID- 27126653 TI - Rigenera protocol in the treatment of surgical wound dehiscence. AB - The effective management of post-operative wounds is important to prevent potential complications such as surgical-site infections and wound dehiscence. The purpose of this study was to treat wound dehiscence in elderly patients who were subjected to orthopaedic surgical interventions. The dehisced wounds were treated with autologous micro-grafts obtained using a promising CE-certified medical device called Rigeneracons. This instrument is a biological disruptor of human tissues able to specifically select progenitor cells that, as already reported in previous studies, maintain high cell viability but mainly have a high regenerative potential, allowing the repair of damaged tissues. Autologous micro grafts obtained by Rigeneracons are ready to use and can be applied alone or in combination with biological scaffolds directly on the injured area. We observed in our patients a complete remission of dehisced wounds, on average, after 30 days from micro-grafts application and a total wound re-epithelialisation after 1 year from the surgical intervention. In conclusion, although we reported only three patients, autologous micro-grafts can be considered a promising approach for the treatment of dehisced wounds, improving the wound-healing process and in general the patient's quality of life without using other dressings. PMID- 27126654 TI - Safety of Monopolar Electrocautery in Patients With Cochlear Implants. AB - OBJECTIVE: The outcomes of 2 patients with cochlear implants (CIs) who underwent adenotonsillectomy (AT) with inadvertent use of monopolar cautery are presented. The safety data regarding monopolar cautery use in CI recipients is also reviewed. STUDY DESIGN: This is a retrospective case series of 2 CI recipients that underwent AT with monopolar cautery and literature review of electrocautery safety in the setting of CI. RESULTS: Two patients with CIs underwent AT with use of monopolar cautery inadvertently by surgeons that do not routinely perform cochlear implants as part of his or her clinical practice. Patient 1 was a 9-year old female who had AT for obstructive sleep apnea (OSA) after undergoing unilateral CI for profound congenital sensorineural hearing loss (SNHL) 8 years ago. Patient 2 was a 7-year-old female who underwent AT for OSA 4 months after undergoing unilateral CI for congenital SNHL. Both patients had no immediate signs of complications with their CI use postoperatively. Both patients demonstrated unchanged postoperative neural response telemetry and behavioral audiometric testing. Patient 1 continues to have no CI-related complications 3.5 years after the procedure. Patient 2 has been followed for at least 3 months by audiometric testing and 10 months by otolaryngologist with no CI-related complications. CONCLUSION: Although animal and cadaveric studies suggest that monopolar cautery may be safely used in patients with cochlear implants, there have been no in vivo human studies that have evaluated the risk to the patient or implant. This is a report of a small, unintended experience with 2 patients, both of whom exhibit no complications or changes to CI function thus far. PMID- 27126655 TI - Ca(ii) and Ce(iii) homogeneous alginate hydrogels from the parent alginic acid precursor: a structural study. AB - Alginate hydrogels are suitable for the encapsulation of biomolecules and microorganisms for the building of bioactive materials. Several alternatives to the conventional alginate formulation are being studied for a broad range of biotechnological applications; among them the crosslinking of alginate by lanthanide cations, Ln(iii), envisages expanded biomedical applications. The performance of these functional materials is highly related to the microstructure of the alginate matrix, which in turn is affected by the conditions of synthesis. In particular, when a diffusing gradient of the crosslinking cation is involved, microstructure inhomogeneities are expected at the macroscopic level. Here we discuss the subtle differences in the microstructure, as assessed by SAXS (Small Angle X-ray Scattering), established in the direction of the gradient of diffusion of Ca(ii) or Ce(iii). PMID- 27126656 TI - Corrigendum: Abnormal proplatelet formation and emperipolesis in cultured human megakaryocytes from gray platelet syndrome patients. PMID- 27126657 TI - Difference among shock-absorbing capabilities of mouthguard materials. AB - PURPOSE: The purpose of this study was to investigate the shock absorption capability of commercial thermoforming mouthguard sheet materials. MATERIALS AND METHODS: Twelve commercial thermoforming mouthguard sheet materials were selected as test materials. The impact test was applied by a free-falling steel ball. When impact forces of approximately 660 N were applied on the commercial thermoforming mouthguard materials, the peak intensities were measured using the load cell sensor. The peak intensity and the time to peak intensity from the onset of the transmitted force were statistically analyzed using one-way anova and Tukey's honest significant difference post hoc test (P < 0.05). RESULTS: Statistical analysis for the peak intensity and the time to peak intensity from the onset of the transmitted force revealed significant differences among the thirteen groups including the control. The peak intensity of the polystyrene-polyolefin copolymer based material was lower than the peak intensity of the EVA-, polyolefin-based material. Polyolefin-based materials had a tendency of a long duration to reach peak intensity from the onset of the transmitted force. CONCLUSION: These results suggest that all of the commercially available mouthguard sheet materials had high shock-absorbing capabilities. PMID- 27126658 TI - MH17: the Malaysian experience. AB - A disaster is a natural or man-made (or technological) hazard resulting in an event of substantial extent causing significant physical damage or destruction, loss of life, or drastic change to the environment. It is a phenomenon that can cause damage to life and property and destroy the economic, social and cultural life of the people; and overwhelms the capacity of the community to cope with the event. The recent tragic aviation accidents in 2014 involving Malaysia Airlines flights MH370 and MH17 shocked the world in an unprecedented manner. This paper focuses on the Malaysian experience in the MH17 mission in Ukraine as well as the first ever international Disaster Victim Identification (DVI) operation for the Malaysian DVI team. The DVI operations in Hilversum, the Netherlands were well described in stages. The Netherlands' Landelijk Team Forensische Opsporing as the lead DVI team in Hilversum operated systematically, ensuring the success of the whole mission. This paper discusses the lessons learned by the Malaysian team on proper DVI structure, inter- and intra-agency cooperation, facilities planning and set up, logistics and health and safety aspects, as well as effective communication and collaboration with other international delegates. Several issues and challenges faced by the Malaysian team were also documented. In addition, the authors shared views, opinions and recommendations for a more comprehensive DVI operation in the future. PMID- 27126659 TI - Detection of SYT-SSX mutant transcripts in formalin-fixed paraffin-embedded sarcoma tissues using one-step reverse transcriptase real-time PCR. AB - BACKGROUND: Synovial sarcoma (SS) is a rare cancer and accounts for 5-10% of adult soft tissue sarcomas. Making an accurate diagnosis is difficult due to the overlapping histological features of SS with other types of sarcomas and the non specific immunohistochemistry profile findings. Molecular testing is thus considered necessary to confirm the diagnosis since more than 90% of SS cases carry the transcript of t(X;18)(p11.2;q11.2). The purpose of this study is to diagnose SS at molecular level by testing for t(X;18) fusion-transcript expression through One-step reverse transcriptase real-time Polymerase Chain Reaction (PCR). METHOD: Formalin-fixed paraffin-embedded tissue blocks of 23 cases of soft tissue sarcomas, which included 5 and 8 cases reported as SS as the primary diagnosis and differential diagnosis respectively, were retrieved from the Department of Pathology, Tengku Ampuan Afzan Hospital, Kuantan, Pahang. RNA was purified from the tissue block sections and then subjected to One-step reverse transcriptase real-time PCR using sequence specific hydrolysis probes for simultaneous detection of either SYT-SSX1 or SYT-SSX2 fusion transcript. RESULTS: Of the 23 cases, 4 cases were found to be positive for SYT-SSX fusion transcript in which 2 were diagnosed as SS whereas in the 2 other cases, SS was the differential diagnosis. Three cases were excluded due to failure of both amplification assays SYT-SSX and control beta-2-microglobulin. The remaining 16 cases were negative for the fusion transcript. CONCLUSION: This study has shown that the application of One-Step reverse transcriptase real time PCR for the detection SYT-SSX transcript is feasible as an aid in confirming the diagnosis of synovial sarcoma. PMID- 27126660 TI - Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience. AB - Taking cognizance of the purported variation of phyllodes tumours in Asians compared with Western populations, this study looked at phyllodes tumours of the breast diagnosed at the Department of Pathology, University of Malaya Medical Centre over an 8-year period with regards to patient profiles, tumour parameters, treatment offered and outcome. Sixty-four new cases of phyllodes tumour were diagnosed during the period, however only 30 (21 benign, 4 borderline and 5 malignant) finally qualified for entry into the study. These were followed-up for 4-102 months (average = 41.7 months). Thirteen cases (8 benign, 3 borderline, 2 malignant) were Chinese, 9 (all benign) Malay, 7 (4 benign, 1 borderline, 2 malignant) Indian and 1 (malignant) Indonesian. Prevalence of benign versus combined borderline and malignant phyllodes showed a marginally significant difference (p=0.049) between the Malays and Chinese. Patients' ages ranged from 21-70 years with a mean of 44.9 years with no significant difference in age between benign, borderline or malignant phyllodes tumours. Except for benign phyllodes tumours (mean size = 5.8 cm) being significantly smaller at presentation compared with borderline (mean size = 12.5 cm) and malignant (mean size = 15.8 cm) (p<0.05) tumours, history of previous pregnancy, breast feeding, hormonal contraception and tumour laterality did not differ between the three categories. Family history of breast cancer was noted in 2 cases of benign phyllodes. Local excision was performed in 17 benign, 2 borderline and 3 malignant tumours and mastectomy in 4 benign, 2 borderline and 2 malignant tumours. Surgical clearance was not properly recorded in 10 benign phyllodes tumours. Six benign and all 4 borderline and 5 malignant tumours had clearances of <10 mm. Two benign tumours recurred locally at 15 and 49 months after local excision, however information regarding surgical clearance was not available in both cases. One patient with a malignant tumour developed a radiologically diagnosed lung nodule 26 months after mastectomy, was given a course of radiotherapy and remained well 8-months following identification of the lung nodule. PMID- 27126661 TI - Assessment of pathological response to neoadjuvant chemotherapy in locally advanced breast cancer using the Miller-Payne system and TUNEL. AB - BACKGROUND: Responses to neoadjuvant (before surgery) chemotherapy in locally advanced breast cancer (LABC) consist of clinical and pathological responses. Evaluating chemotherapy response is essential to predict survival rate and guide future chemotherapy. Until now, the evaluation of pathological response mainly involves quantitative assessment and is often inconsistent with clinical response. We explored the evaluation of pathological responses by both quantitative and qualitative methods, i.e. by evaluating the cellularity of tumour cells and the percentage of apoptosis. MATERIALS AND METHOD: A cross sectional analytical retrospective study was conducted on tissue of LABC diagnosed between 2010 and 2014 at the Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia Cipto Mangunkusumo Hospital and Division of Surgical Oncology, Cipto Mangunkusumo Hospital. Biopsy and resection specimens were compared to evaluate reduction in cellularity, which were subsequently categorized into stages of Miller-Payne (MP) classification. The resection specimens were stained with TUNEL and the percentage of apoptosis was calculated. Reduction in cellularity between biopsy and mastectomy specimens with TUNEL staining is evaluated as a modification of the MP method. RESULTS: We found no association between clinical responses with percentage of apoptosis, MP pathological responses and modified MP. There was a correlation between the dead cell evaluated by MP and by modified MP (p=0.000). CONCLUSION: Modified MP increases the degree or grading of pathological responses, but it does not improve the correlation with clinical response. PMID- 27126662 TI - Correlation of p16INK4a immunoexpression and human papillomavirus (HPV) detected by in-situ hybridization in cervical squamous neoplasia. AB - Persistence and eventual integration of high-risk HPV (hrHPV) into the cervical cell is crucial to the progression of cervical neoplasia and it would be beneficial to morphologically identify this transformation in routine surgical pathology practice. Increased p16(INK4a) (p16) expression is a downstream event following HPV E7 binding to pRB. A study was conducted to assess the correlation between hrHPV detection using a commercial in-situ hybridization assay (Ventana INFORM HPV ISH) and p16 immunoexpression (CINtec Histology Kit) in cervical squamous intraepithelial lesions and squamous carcinoma. 27 formalin-fixed, paraffin-embedded cervical low-grade squamous intraepithelial lesions (LSIL), 21 high-grade squamous intraepithelial lesions (HSIL) and 51 squamous carcinoma (SCC) were interrogated. hrHPV was significantly more frequent in HSIL (76.2%) and SCC (88.2%) compared to LSIL(37.0%). p16 expression was similarly more frequent in HSIL (95.2%) and SCC (90.2%) compared to LSIL(3.7%). That the rates of hrHPV when compared with p16 expression were almost equivalent in HSIL and SCC while p16 was expressed in only 1 of the 10 LSIL with hrHPV, are expected considering the likelihood that transformation has occurred in HSIL and SCC but does not occur in majority of LSIL. PMID- 27126663 TI - The effects of sildenafil on smoke induced lung inflammation in rats. AB - OBJECTIVE: Sildenafil is a selective and potent inhibitor of cyclic guanosine monophosphate specific phosphodiesterase-5 and has anti-inflammatory effects. The aim of the study was to evaluate the effects of sildenafil on smoke-induced lung inflammation. MATERIAL AND METHODS: Twenty-nine Wistar-Albino rats were enrolled into 3 groups as control, smoker and sildenafil groups. Smoker and sildenafil groups were exposed to cigarette smoke for 2 hours per day for 8 weeks. Sildenafil 10 mg/kg/day was administered to the sildenafil group by nasogastric lavage after smoke exposure. The degree of lung inflammation was scored histopathologically for each group. RESULTS: The inf lammation score was 7.25+/ 0.93 in the control group, 8.18+/-1.21 in the smoker group and 7.08+/-1.66 in the sildenafil group. There was a non-significant decrease of inflammation score in sildenafil group with respect to control or smoker groups. While there was no significant difference of oedema, hyperemia, hemorrhage and mononuclear cell infiltration scores among the groups, it was found that the thickness of interalveolar septum and alveolar distortion was decreased in sildenafil group. However this decrease was not statistically significant. CONCLUSION: This study suggests that sildenafil might reduce smoke-induced inflammation in rat lungs. Future studies are needed in order to investigate the clinical effectiveness of this finding in smoking related lung diseases. PMID- 27126664 TI - Metastasis of extra-ampullary duodenal adenocarcinoma to the uterine cervix. AB - Secondary metastatic tumours of the uterine cervix are rare. There have been no reports of duodenal cancer metastasizing to the uterine cervix. Here we present a rare case of an extra-ampullary duodenal adenocarcinoma that has metastasized to the uterine cervix. The patient was a 71-year-old woman who had surgery for an extra-ampullary duodenal adenocarcinoma five years previously. Follow-up examination revealed a suspicious right ovarian mass and nodules in the cervix and posterior fornix of the vagina. Biopsies suggested squamous cell carcinoma in the cervix and adenocarcinoma in the fornix. Intraoperatively, the right ovary was enlarged and peritoneal disseminations were found in the pouch of Douglas and the sigmoid colon mesentery. Histopathology of the subsequent hysterectomy and bilateral salpingo-oophorectomy specimen revealed a cervical squamous cell carcinoma categorized as pT1b1. Adenocarcinoma infiltration into the ovaries, uterine cervix and vagina, with vascular involvement was detected. Immunohistochemistry revealed the tumour in the cervix and ovaries to be positive for CK7, MUC5AC and MUC6, and immunonegative for CK20, CDX2, Pax8, ER, MUC2 and CD10, similar to the original duodenal adenocarcinoma. This case illustrates the difficulty in making a preoperative diagnosis of metastatic adenocarcinoma in the uterine cervix with a coexisting primary cervical squamous cell carcinoma. The absence of atypia in cervical glandular cells and immunohistochemical profiling of the adenocarcinoma clusters helped to reach a final diagnosis. This is the first report of an extra-ampullary duodenal adenocarcinoma metastasis to the uterine cervix. PMID- 27126666 TI - Diffuse large B cell lymphoma with chronic granulomatous inflammation. AB - Non-necrotic epithelioid granulomas have been reported in association with neoplasms including Hodgkin and non-Hodgkin lymphoma. We report a case of diffuse large B cell lymphoma with chronic granulomatous inflammation to highlight awareness of obscure tumour cells within the granuloma, to avoid delay in diagnosis and management of lymphoma. A 39-year-old Malay lady with no past medical history, presented with a 2-month history of progressive worsening of difficulty in breathing, cough, low-grade fever, loss of weight and loss of appetite. Chest X-ray showed an anterior mediastinal mass and computed tomography (CT)-guided biopsy was reported as chronic granulomatous inflammation suggestive of tuberculosis. After 2 months of anti-TB treatment, her symptoms were not relieved. The patient underwent another CT-guided biopsy of the anterior mediastinal mass in another hospital and the histopathology revealed diffuse large B cell lymphoma. The patient was referred for treatment. On histopathological review, the first sample showed noncaseating granulomas engulfing tumour cells and large abnormal lymphoid cells which were CD20 positive and with high Ki-67 proliferative index. The patient was diagnosed with diffuse large B cell lymphoma stage IV B IPSS score 3. She underwent chemotherapy (R EPOCH) and responded well to treatment. PMID- 27126665 TI - Heterotopic ossification in appendiceal mucinous neoplasms: clinicopathological characteristics of 3 cases. AB - Heterotopic bone formation is a very rare event in the gastrointestinal tract including in the appendix. Here we report three cases of heterotopic ossification in appendiceal mucinous neoplasms, one occurring in an appendiceal mucinous cystadenoma, another in a low-grade appendiceal mucinous neoplasm, and the third occurring in an appendiceal mucinous adenocarcinoma. The clinicopathologic characteristics of these three present cases and two previously reported cases are discussed in detail. The mechanism of heterotopic ossification in appendiceal mucinous neoplasm is still unclear, but mucin extravasation and subsequent calcification may be predisposing events. PMID- 27126667 TI - Solitary fibrous tumour of the chest wall. AB - Extrapleural solitary fibrous tumours (SFTs) are rare tumours characterized by patternless spindle cells with haemangiopericytoma-like vascular spaces. Previously the tumours have been classified as haemangiopericytoma, an entity that is now considered obsolete. We report a case of extrapleural SFT arising in the soft tissue of the chest wall. The patient was a 31-year-old Malay lady presenting with a mobile swelling of the right chest wall for more than five years. During excision the tumour was noted to be well-circumscribed and yellowish in colour, giving an impression of lipoma. Microscopically, the tumour had patternless architecture, characterized by hypocellular and hypercellular areas. It was composed of uniform, spindle-shaped cells displaying oval nuclei, inconspicuous nucleoli, pale cytoplasm and indistinct cell borders. The mitotic count was 2 per 10 HPF. Branching, medium-sized thin-walled blood vessels in a haemangiopericytomatous growth pattern, some with hyalinised wall were identified. The neoplastic cells were immunoreactive to CD99 and CD34 and were non-immunoreactive to Desmin, Smooth Muscle Actin, S100 protein and EMA. We elucidate the challenges in diagnosing this tumour in this unusual location. PMID- 27126668 TI - Thyroid metastasis of bladder transitional cell carcinoma. AB - The thyroid gland is a rare site for cancer metastasis. We report a 75-year-old man who was referred with a history of hematuria and generalized bone pain for the past few months. He had a past history of partial left lobe thyroidectomy for follicular adenoma. Subsequently he was referred for a thyroid mass and a subtotal thyroidectomy showed a poorly-differentiated carcinoma. On the latest admission, the patient underwent resection of a bladder tumour with malignant histology and an immunohistochemical profile of CK7+/CK20+/34 Beta E12+/CEA-/PSA . Re-examination of thyroid sections with immunohistochemical stains revealed the malignant cells to be CK7+/CK20+/34 Beta E12+/CEA-/TTF1-. The findings were compatible with metastasis of the bladder transitional cell carcinoma to the thyroid gland.Scans revealed multiple liver and bone metastases. The patient died 2 months after the diagnosis. PMID- 27126669 TI - Scientific misconduct encountered by APAME journals: insight? PMID- 27126670 TI - Response: Scientific misconduct encountered by APAME journals: insight? PMID- 27126671 TI - Symphysiotomy for obstructed labour: a systematic review and meta-analysis. AB - BACKGROUND: Obstructed labour is a major cause of maternal mortality. Caesarean section can be associated with risks, particularly in low- and middle-income countries, where it is not always readily available. Symphysiotomy can be an alternative treatment for obstructed labour and requires fewer resources. However, there is uncertainty about the safety and effectiveness of this procedure. OBJECTIVES: To compare symphysiotomy and caesarean section for obstructed labour. SEARCH STRATEGY: MEDLINE, EMBASE, Cochrane library, CINAHL, African Index Medicus, Reproductive Health Library and Science Citation Index (from inception to November 2015) without language restriction. SELECTION CRITERIA: Studies comparing symphysiotomy and caesarean section in all settings, with maternal and perinatal mortality as key outcomes. DATA COLLECTION AND ANALYSIS: Quality of the included studies was assessed using the STROBE checklist and the Newcastle Ottawa scale. Relative risks (RR) were pooled using the random effects model. Heterogeneity was assessed using I(2) tests. MAIN RESULTS: Seven studies (n = 1266 women), all of which were set in low- and middle-income countries (as per the World Bank definition) and compared symphysiotomy and caesarean section were identified. Meta-analyses showed no significant difference in maternal (RR 0.48, 95% CI 0.13-1.76; P = 0.27) or perinatal (RR 1.12, 95% CI 0.64-1.96; P = 0.69) mortality with symphysiotomy when compared with caesarean section. There was a reduction in infection (RR 0.30, 95% CI 0.14-0.62) but an increase in fistulae (RR 4.19, 95% CI 1.07-16.39) and stress incontinence with symphysiotomy (RR 10.04, 95% CI 3.23-31.21). CONCLUSION: There was no difference in key outcomes of maternal and perinatal mortality with symphysiotomy when compared with caesarean section. TWEETABLE ABSTRACT: Symphysiotomy could be an alternative to caesarean section when resources are limited. PMID- 27126672 TI - [Clinical pharmacist influence at hospital to prevent overdosed prescription of acetaminophen]. AB - OBJECTIVES: The recommended daily dose of acetaminophen is limited to 60mg/kg/day with a maximum of 3g daily dose in adults weighing less than 50kg or in patients undergoing certain risk factors. This study aimed at assessing the fulfillment of those recommendations and the possible impact on the liver dysfunction at supra therapeutic doses of acetaminophen. METHODS: This study was performed one day in 9 services. Patients characteristics, acetaminophen dose, daily dose administered, physiopathological aspects, markers of liver damage were collected. RESULTS: Among 542 prescriptions analyzed, 343 of them contained acetaminophen. The median age of patients studied was 81 years and one third weighed less than 50kg. The main risk factor of supra-therapeutic prescriptions was the lack of dose acetaminophen based on weight with 14% patients concerned and this risk raised at 17% when the pathophysiological conditions were included. The presence of pharmacists in medicals departments was more effective than the use of informatics programs limiting the dose systematically to 3g/day, or a distant pharmaceutical validation from care services to reduce the risk of acetaminophen overdose. According to the statement of administrations, only 4 of 49 patients received doses above 60mg/kg/day with a low impact on liver function tests. CONCLUSION: The continuous presence in pharmaceutical care services was the most effective measure to ensure effective implementation of acetaminophen recommendations. PMID- 27126673 TI - [Erratum to: Prostate cancer in routine healthcare. Health-related quality of life after inpatient treatment]. PMID- 27126674 TI - [Drug-free improvement of bone health and influence on bone metabolism via football training in men with prostatecancer undergoing androgen deprivation therapy]. PMID- 27126675 TI - [Big surprise in the lesser pelvis]. AB - A 17-year-old young man presented at our clinic with asymptomatic microhematuria. Ultrasonography and computer tomography found an intraperitoneal lesion of unknown dignity located on top of the bladder. Surgical exploration and histological examination confirmed the diagnosis of a secondary pelvic spleen, a lien bipartitus. PMID- 27126676 TI - [Ruptured vascular adrenal cyst after being hit by a wave]. AB - Endothelial cysts of the adrenal gland are a rare entity of adolescents. We here present the case of a 19-year-old woman, who developed right abdominal pain after trauma. Magnetic resonance imaging showed a tumor in the right adrenal gland with suspicious signs for malignancy. Histopathological examination revealed the diagnosis of an endothelial (vascular) adrenal cyst. In most cases, cysts of the adrenal gland remain clinically inapparent. In cases of clinically manifest symptoms, surgical intervention represents the standard for therapy. PMID- 27126677 TI - [Comment on: Focal therapy for small renal masses. Observation, ablation or surgery]. PMID- 27126678 TI - A hearing self-reported survey in people over 80 years of age in China by hearing handicap inventory for the elderly-complete version vs screening version. AB - CONCLUSION: HHIE-S can be a useful tool in investigating hearing loss among people over 80 years old, with the same validity as HHIE. OBJECTIVE: To investigate the effect of hearing loss on the quality-of-life in people over 80 years of age in China, and to compare the results of the Chinese mandarin version Hearing Handicap Inventory for the Elderly (HHIE) and its screening version (HHIE S). METHODS: Eighty-four people over 80 years participated in the study. Both HHIE and HHIE-S were completed, and the hearing handicap degrees were rated according to HHIE scores and HHIE-S scores, respectively. Results obtained by HHIE and HHIE-S were compared. Multi-factor analysis of variance was used to analyze the impact of eight factors on hearing handicap in the oldest old people over 80 years of age, including age, noise exposure, ear surgery, infection, ototoxic drugs use, cardiovascular and cerebrovascular diseases, diabetes, and tumors. RESULTS: Both HHIE and HHIE-S revealed 48 subjects (57.1%) with no self perceived hearing problem, and 36 subjects (42.9%) with hearing handicap. No statistical difference was found between results of the functional hearing handicap rating by HHIE and HHIE-S (Chi-square = 1.532, p = 0.465). The HHIE and HHIE-S were in agreement with each other (kappa = 0.772, p < 0.001). All the eight factors had no significance on both HHIE and HHIE-S scores (p > 0.05), except noise exposure on S-score of HHIE-S (p = 0.032), and the R-squares of these factors were less than 5%. PMID- 27126679 TI - "Must do CPR??": strategies to cope with the new College of Physicians and Surgeons of Ontario policy on end-of-life care. AB - The College of Physicians and Surgeons of Ontario recently released a new policy, Planning for and Providing Quality End-of-Life Care. The revised policy is more accurate in its consideration of the legal framework in which physicians practice and more reflective of ethical issues that arise in end-of-life (EOL) care. It also recognizes valid instances for not offering cardiopulmonary resuscitation (CPR). Nevertheless, the policy poses a significant ethical and legal dilemma i.e., if disputes over EOL care arise, then physicians must provide CPR even when resuscitation would fall outside this medical standard of care. While the policy applies in Ontario, it is likely to influence other physician colleges across Canada as they review their standards of practice. This paper explores the rationale for the mandated CPR, clarifies the policy's impact on the medical standard of care, and discusses strategies to improve EOL care within the policy. These strategies include understanding the help-hurt line, changing the language used when discussing cardiac arrest, clarifying care plans during the perioperative period, engaging the intensive care unit team early in goals-of care discussions, mentoring hospital staff to improve skills in goals-of-care discussions, avoiding use of the "slow code", and continuing to advocate for quality EOL care and a more responsive legal adjudication process. PMID- 27126681 TI - Nano carriers for drug transport across the blood-brain barrier. AB - Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully discussed. PMID- 27126682 TI - Intracranial hypotension: diagnosis by trial of Trendelenburg positioning and imaging. PMID- 27126680 TI - Tropomodulin isoforms utilize specific binding functions to modulate dendrite development. AB - Tropomodulins (Tmods) cap F-actin pointed ends and have altered expression in the brain in neurological diseases. The function of Tmods in neurons has been poorly studied and their role in neurological diseases is entirely unknown. In this article, we show that Tmod1 and Tmod2, but not Tmod3, are positive regulators of dendritic complexity and dendritic spine morphology. Tmod1 increases dendritic branching distal from the cell body and the number of filopodia/thin spines. Tmod2 increases dendritic branching proximal to the cell body and the number of mature dendritic spines. Tmods utilize two actin-binding sites and two tropomyosin (Tpm)-binding sites to cap F-actin. Overexpression of Tmods with disrupted Tpm-binding sites indicates that Tmod1 and Tmod2 differentially utilize their Tpm- and actin-binding sites to affect morphology. Disruption of Tmod1's Tpm-binding sites abolished the overexpression phenotype. In contrast, overexpression of the mutated Tmod2 caused the same phenotype as wild type overexpression. Proximity ligation assays indicate that the mutated Tmods are shuttled similarly to wild type Tmods. Our data begins to uncover the roles of Tmods in neural development and the mechanism by which Tmods alter neural morphology. These observations in combination with altered Tmod expression found in several neurological diseases also suggest that dysregulation of Tmod expression may be involved in the pathology of these diseases. (c) 2016 Wiley Periodicals, Inc. PMID- 27126684 TI - Electrostatics and depletion determine competition between 2D nematic and 3D bundled phases of rod-like DNA nanotubes. AB - Rod-like particles form solutions of technological and biological importance. In particular, biofilaments such as actin and microtubules are known to form a variety of phases, both in vivo and in vitro, whose appearance can be controlled by depletion, confinement, and electrostatic interactions. Here, we utilize DNA nanotubes to undertake a comprehensive study of the effects of those interactions on two particular rod-like phases: a 2D nematic phase consisting of aligned rods pressed against a glass surface, and a 3D bundled network phase. We experimentally measure the stability of these two phases over a range of depletant concentrations and ionic strengths, finding that the 2D phase is slightly more stable than the 3D phase. We formulate a quantitative model of phase stability based on consideration of pairwise rod-rod and rod-surface interactions; notably, we include a careful accounting of solution electrostatics interactions using an effective-charge strategy. The model is relatively simple and contains no free parameters, yet predicts phase boundaries in good agreement with the experiment. Our results indicate that electrostatic interactions, rather than depletion, are largely responsible for the enhanced stability of the 2D phase. This work provides insight into the polymorphism of rod-like solutions, indicating why certain phases appear, and providing a means (and a predictive model) for controlling those phases. PMID- 27126683 TI - Controversies in venous thromboembolism: the unique case of isolated distal deep vein thrombosis. AB - Venous thromboembolism (VTE) represents the third leading cause of cardiovascular mortality, and it is the main cause of preventable mortality in hospitalized patients. Among VTE, there is the unique case of isolated distal deep vein thrombosis (IDDVT), which still lacks an agreement in terms of optimal therapeutic strategy. Although most IDDVTs are self-limiting and associated with a very low risk of embolic complications, still not all IDDVTs can be safely identified as stable. Lack of strong scientific evidence, fear of thromboembolic complications, and risk of bleeding upon initiation of anticoagulant treatment result in very heterogeneous therapeutic strategies among physicians. Here, we provide a comprehensive review of the literature, highlight the many controversial issues regarding IDDVTs, and call for a consensus of experts aimed to shed new light on the gray areas of IDDVT management and therapy. PMID- 27126685 TI - Emotion Knowledge and Attention Problems in Young Children: a Cross-Lagged Panel Study on the Direction of Effects. AB - Attention problems are likely to hinder children in acquiring knowledge of their own and others' emotions. Children with little knowledge of emotions tend to have difficulties with representing emotions, interpreting them, and sharing them, so that they are likely to spend more time in making sense of them and may thus appear to be inattentive. In order to disentangle the direction of effects between emotion knowledge and attention problems, 576 four- to- six-year-olds were interviewed at T1 and about 12 months later (T2) about their emotion knowledge. Their kindergarten teachers rated their attention problems, and their conduct problems at T1 and T2. A cross-lagged panel model indicates that children's emotion knowledge at T1 contributed to the explanation of their attention problems at T2, after language ability and attention problems at T1 were controlled. The other cross-path from attention problems (T1) to emotion knowledge (T2) was not significant. Adding gender, behavioral self-regulation, working memory, conduct problems, or SES as alternative explanations by third variables did not alter this direction of effects. How emotion knowledge impinges on attention problems is discussed. PMID- 27126686 TI - Determining the psychometric properties of the Enhancing Decision-making Assessment in Midwifery (EDAM) measure in a cross cultural context. AB - BACKGROUND: The ability to act on and justify clinical decisions as autonomous accountable midwifery practitioners, is encompassed within many international regulatory frameworks, yet decision-making within midwifery is poorly defined. Decision-making theories from medicine and nursing may have something to offer, but fail to take into consideration midwifery context and philosophy and the decisional autonomy of women. Using an underpinning qualitative methodology, a decision-making framework was developed, which identified Good Clinical Reasoning and Good Midwifery Practice as two conditions necessary to facilitate optimal midwifery decision-making during 2nd stage labour. This study aims to confirm the robustness of the framework and describe the development of Enhancing Decision making Assessment in Midwifery (EDAM) as a measurement tool through testing of its factor structure, validity and reliability. METHOD: A cross-sectional design for instrument development and a 2 (country; Australia/UK) x 2 (Decision-making; optimal/sub-optimal) between-subjects design for instrument evaluation using exploratory and confirmatory factor analysis, internal consistency and known groups validity. Two 'expert' maternity panels, based in Australia and the UK, comprising of 42 participants assessed 16 midwifery real care episode vignettes using the empirically derived 26 item framework. Each item was answered on a 5 point likert scale based on the level of agreement to which the participant felt each item was present in each of the vignettes. Participants were then asked to rate the overall decision-making (optimal/sub-optimal). FINDINGS: Post factor analysis the framework was reduced to a 19 item EDAM measure, and confirmed as two distinct scales of 'Clinical Reasoning' (CR) and 'Midwifery Practice' (MP). The CR scale comprised of two subscales; 'the clinical reasoning process' and 'integration and intervention'. The MP scale also comprised two subscales; women's relationship with the midwife' and 'general midwifery practice'. CONCLUSION: EDAM would generally appear to be a robust, valid and reliable psychometric instrument for measuring midwifery decision-making, which performs consistently across differing international contexts. The 'women's relationship with midwife' subscale marginally failed to meet the threshold for determining good instrument reliability, which may be due to its brevity. Further research using larger samples and in a wider international context to confirm the veracity of the instrument's measurement properties and its wider global utility, would be advantageous. PMID- 27126687 TI - Neuro-immune interactions in chemical-induced airway hyperreactivity. AB - Asthma may be induced by chemical sensitisers, via mechanisms that are still poorly understood. This type of asthma is characterised by airway hyperreactivity (AHR) and little airway inflammation. Since potent chemical sensitisers, such as toluene-2,4-diisocyanate (TDI), are also sensory irritants, it is suggested that chemical-induced asthma relies on neuro-immune mechanisms.We investigated the involvement of transient receptor potential channels (TRP) A1 and V1, major chemosensors in the airways, and mast cells, known for their ability to communicate with sensory nerves, in chemical-induced AHR.In vitro intracellular calcium imaging and patch-clamp recordings in TRPA1- and TRPV1-expressing Chinese hamster ovarian cells showed that TDI activates murine TRPA1, but not TRPV1. Using an in vivo model, in which an airway challenge with TDI induces AHR in TDI sensitised C57Bl/6 mice, we demonstrated that AHR does not develop, despite successful sensitisation, in Trpa1 and Trpv1 knockout mice, and wild-type mice pretreated with a TRPA1 blocker or a substance P receptor antagonist. TDI-induced AHR was also abolished in mast cell deficient Kit(Wsh) (/Wsh) mice, and in wild type mice pretreated with the mast cell stabiliser ketotifen, without changes in immunological parameters.These data demonstrate that TRPA1, TRPV1 and mast cells play an indispensable role in the development of TDI-elicited AHR. PMID- 27126688 TI - Physical activity and exercise capacity in patients with moderate COPD exacerbations. AB - Little is known about changes in physical activity during moderate (out-patient managed) exacerbations.6-min walking distance (6MWD) was measured during 50 exacerbations when the patients were stable, and at 3 and 7 days post exacerbation presentation. At similar time points, quadriceps maximum voluntary contraction (QMVC) was measured during 47 different exacerbations. Physical activity (SenseWear; Bodymedia Inc., Pittsburgh, PA, USA) was recorded over 2 consecutive-week periods post-presentation.6MWD fell from a median 422 m when stable to 373 m on day 3 (p=0.001). Similarly, QMVC fell from 32.6 versus 29.7 kg (p=0.026). Falls in 6MWD were associated with a rise in C-reactive protein (r= 0.364; p=0.041) and increased Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) (r= -0.44; p=0.013). Light physical activity was 2.18 h.day(-1) during the first week post-exacerbation and was less over week 2 (1.98 h.day(-1); p=0.009). Patients who had attended pulmonary rehabilitation had smaller changes in 6MWD than those who had not attended (-35.0 versus -114.9 m; p=0.013). Falls in physical activity were correlated with higher depression scores (rho= -0.51; p=0.006).These findings indicate that exercise capacity and muscle strength fall at exacerbation in chronic obstructive pulmonary disease patients who are treated at home and are free to maintain normal activity. PMID- 27126689 TI - Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. AB - We sought to present the epidemiology of idiopathic pulmonary fibrosis (IPF) in adults 18-64 years old in the USA.From adults aged 18-64 years in a large administrative claims data in 2004-2010, patients with IPF were identified using diagnosis codes. We estimated annual incidence and cumulative prevalence of IPF over time, and examined potential risk factors for the IPF diagnosis.The annual cumulative prevalence increased steadily in the first few years (from 13.4 cases per 100 000 persons in 2005 to 18.2 cases in 2010 per 100 000 persons), which is likely due to a methodological reason, while the annual incidence of IPF decreased over time (from 7.9 cases per 100 000 person-years in 2005 to 5.8 cases in 2010 per 100 000 person-years). The overall decrease was mainly driven by a decreasing trend in the younger patients (aged 18-44 years), while the incidence in older patients remained stable. Consistent trends were observed in subgroups defined by previously published more restrictive algorithms for diagnosis. Older age and male sex were associated with a higher incidence of disease (p<0.05).In US adults younger than 65 years, we observed a decreasing incidence of IPF over time which may partially explain the plateau of cumulative prevalence in the last few years of our data. PMID- 27126690 TI - Somatic DICER1 mutations in adult-onset pulmonary blastoma. PMID- 27126691 TI - Forecasting US ivacaftor outcomes and cost in cystic fibrosis patients with the G551D mutation. AB - Ivacaftor, a breakthrough treatment for cystic fibrosis (CF) patients with the G551D genetic mutation, lacks long-term clinical and cost projections. This study forecasted outcomes and cost by comparing ivacaftor plus usual care versus usual care alone.A lifetime Markov model was conducted from a US payer perspective. The model consisted of five health states: 1) forced expiratory volume in 1 s (FEV1) % pred >=70%, 2) 40%<= FEV1 % pred <70%, 3) FEV1 % pred <40%, 4) lung transplantation and 5) death. All inputs were extracted from published literature. Budget impact was also estimated. We estimated ivacaftor's improvement in outcomes compared with a non-CF referent population.Ivacaftor was associated with 18.25 (95% credible interval (CrI) 13.71-22.20) additional life years and 15.03 (95% CrI 11.13-18.73) additional quality-adjusted life-years (QALYs). Ivacaftor was associated with improvements in survival and QALYs equivalent to 68% and 56%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $3 374 584. The budget impact was $0.087 per member per month.Ivacaftor increased life years and QALYs in CF patients with the G551D mutation, and moved morbidity and mortality closer to that of their non-CF peers. Ivacaftor costs much more than usual care, but comes at a relatively limited budget impact. PMID- 27126692 TI - Pulmonary haemodynamics during recovery from maximum incremental cycling exercise. AB - Assessment of cardiac function during exercise can be technically demanding, making the recovery period a potentially attractive diagnostic window. However, the validity of this approach for exercise pulmonary haemodynamics has not been validated.The present study, therefore, evaluated directly measured pulmonary haemodynamics during 2-min recovery after maximum invasive cardiopulmonary exercise testing in patients evaluated for unexplained exertional intolerance. Based on peak exercise criteria, patients with exercise pulmonary hypertension (ePH; n=36), exercise pulmonary venous hypertension (ePVH; n=28) and age-matched controls (n=31) were analysed.By 2-min recovery, 83% (n=30) of ePH patients had a mean pulmonary artery pressure (mPAP) <30 mmHg and 96% (n=27) of ePVH patients had a pulmonary arterial wedge pressure (PAWP) <20 mmHg. Sensitivity of pulmonary hypertension-related haemodynamic measurements during recovery for ePH and ePVH diagnosis was <=25%. In ePVH, pulmonary vascular compliance (PVC) returned to its resting value by 1-min recovery, while in ePH, elevated pulmonary vascular resistance (PVR) and decreased PVC persisted throughout recovery.In conclusion, we observed that mPAP and PAWP decay quickly during recovery in ePH and ePVH, compromising the sensitivity of recovery haemodynamic measurements in diagnosing pulmonary hypertension. ePH and ePVH had different PVR and PVC recovery patterns, suggesting differences in the underlying pulmonary hypertension pathophysiology. PMID- 27126693 TI - Cigarette smoke-induced epithelial expression of WNT-5B: implications for COPD. AB - Wingless/integrase-1 (WNT) signalling is associated with lung inflammation and repair, but its role in chronic obstructive pulmonary disease (COPD) pathogenesis is unclear. We investigated whether cigarette smoke-induced dysregulation of WNT 5B contributes to airway remodelling in COPD.We analysed WNT-5B protein expression in the lung tissue of COPD patients and (non)smoking controls, and investigated the effects of cigarette smoke exposure on WNT-5B expression in COPD and control-derived primary bronchial epithelial cells (PBECs). Additionally, we studied downstream effects of WNT-5B on remodelling related genes fibronectin, matrix metalloproteinase (MMP)-2, MMP-9 and SnaiI in BEAS-2B and air-liquid interface (ALI)-cultured PBECs.We observed that airway epithelial WNT-5B expression is significantly higher in lung tissue from COPD patients than controls. Cigarette smoke extract significantly increased mRNA expression of WNT 5B in COPD, but not control-derived PBECs. Exogenously added WNT-5B augmented the expression of remodelling related genes in BEAS-2B cells, which was mediated by transforming growth factor (TGF)-beta/Smad3 signalling. In addition, WNT-5B upregulated the expression of these genes in ALI-cultured PBECs, particularly PBECs from COPD patients.Together, our results provide evidence that exaggerated WNT-5B expression upon cigarette smoke exposure in the bronchial epithelium of COPD patients leads to TGF-beta/Smad3-dependent expression of genes related to airway remodelling. PMID- 27126694 TI - Characteristics of effective self-management interventions in patients with COPD: individual patient data meta-analysis. AB - It is unknown whether heterogeneity in effects of self-management interventions in patients with chronic obstructive pulmonary disease (COPD) can be explained by differences in programme characteristics. This study aimed to identify which characteristics of COPD self-management interventions are most effective.Systematic search in electronic databases identified randomised trials on self-management interventions conducted between 1985 and 2013. Individual patient data were requested for meta-analysis by generalised mixed effects models.14 randomised trials were included (67% of eligible), representing 3282 patients (75% of eligible). Univariable analyses showed favourable effects on some outcomes for more planned contacts and longer duration of interventions, interventions with peer contact, without log keeping, without problem solving, and without support allocation. After adjusting for other programme characteristics in multivariable analyses, only the effects of duration on all cause hospitalisation remained. Each month increase in intervention duration reduced risk of all-cause hospitalisation (time to event hazard ratios 0.98, 95% CI 0.97-0.99; risk ratio (RR) after 6 months follow-up 0.96, 95% CI 0.92-0.99; RR after 12 months follow-up 0.98, 95% CI 0.96-1.00).Our results showed that longer duration of self-management interventions conferred a reduction in all-cause hospitalisations in COPD patients. Other characteristics are not consistently associated with differential effects of self-management interventions across clinically relevant outcomes. PMID- 27126695 TI - Comparative Immunophenotypic Characteristics, Proliferative Features, and Osteogenic Differentiation of Stem Cells Isolated from Human Permanent and Deciduous Teeth with Bone Marrow. AB - To find out differences and similarities in phenotypic, proliferative, and trans differentiation properties of stem cells isolated from pulp of deciduous (SHEDs) and permanent (DPSCs) teeth with human bone marrow stem cells (BMSCs), we examined the expression of mesenchymal and embryonic stem cell markers in relation to the proliferation and osteogenic differentiation potentials of these cells. In this way, after isolating SHEDs, DPSCs, and BMSCs, cell proliferation was evaluated and population doubling time was calculated accordingly. Expression patterns of mesenchymal, hematopoietic, and embryonic stem cell markers were assessed followed by examining differentiation potential toward osseous tissue through alizarin red staining and qRT-PCR. Based on the results, the proliferation rates of SHEDs and DPSCs were significantly higher than that of BMSCs (P < 0.0001). High expression of mesenchymal stem cell markers and weak expression of hematopoietic markers were observed in all the three groups. The mean expression of OCT-4 was significantly higher in SHEDs and DPSCs (P = 0.028), while the expression of SSEA-4 was lower (P = 0.006) compared to BMSCs. Osteogenic differentiation potential of SHEDs was greater than DPSCs; however, it was lower than that of BMSCs. Conclusively, the distinctive immunophenotyping, proliferation rate, and differentiation pattern of SHEDs and DPSCs discriminate these cells from BMSCs. Furthermore, dissimilarity in differentiation potential is evidence implying that SHEDs might be more primitive stem cell population compared to DPSCs. PMID- 27126696 TI - Enhanced Proteolytic Processing of Recombinant Human Coagulation Factor VIII B Domain Variants by Recombinant Furins. AB - Recombinant human factor VIII (rFVIII) is used in replacement therapy for hemophilia A. Current research efforts are focused on bioengineering rFVIII molecules to improve its secretion efficiency and stability, limiting factors for its efficient production. However, high expression yield in mammalian cells of these rFVIII variants is generally associated with limited proteolytic processing. Non-processed single-chain polypeptides constitute non-natural FVIII molecule configurations with unpredictable toxicity and/or antigenicity. Our main objective was to demonstrate the feasibility of promoting full-proteolytic processing of an rFVIII variant retaining a portion of the B-domain, converting it into the smallest natural activatable form of rFVIII, while keeping its main advantage, i.e., improved secretion efficiency. We generated and employed a CHO DG44 cell clone producing an rFVIII variant retaining a portion of the B-domain and the FVIII native cleavage site between Arg(1648) and Glu(1649). By bioengineering CHO-DG44 cells to express stably the recombinant human endoproteases PACE, PACE-SOL, PCSK5, PCSK6, or PCKS7, we were able to achieve complete intra- or extracellular proteolytic processing of this rFVIII variant. Additionally, our quantitative data indicated that removal of the B-domain segment by intracellular proteolytic processing does not interfere with this rFVIII variant secretion efficiency. This work also provides the first direct evidence of (1) intracellular cleavage at the Arg(1648) FVIII processing site promoted by wild-type PACE and PCSK7 and (2) proteolytic processing at the Arg(1648) FVIII processing site by PCSK6. PMID- 27126697 TI - Narrow time window of metabolic changes associated with transition to overt heart failure in Tgaq*44 mice. AB - BACKGROUND: The timing and consequences of alternations in substrate utilization in heart failure (HF) and their relationship with structural changes remain unclear. This study aimed to analyze metabolic changes associated with transition to overt heart failure in transgenic mouse model of HF resulting from cardiac specific overexpression of constitutively active Galphaq*. METHODS: Structural changes quantified by morphometry, relative cardiac mRNA and protein expression of PPARalpha, FAT/CD36, CPT-1, GLUT-4 and glycolytic efficiency following administration of 1-(13)C glucose were investigated in 4-14-month-old Tgalphaq*44 mice (TG), compared with age-matched FVB wild type mice (WT). RESULTS: Initial hypertrophy in TG (4-10-month of age) was featured by an accelerated glycolytic pathway that was not accompanied by structural changes in cardiomyocytes. In 10 month-old TG, cardiomyocyte elongation and hypertrophic remodeling and increased glycolytic flux was accompanied by relatively low expression of FAT/CD36, CPT-1 and PPARalpha. During the transition phase (12-month-old TG), a pronounced increase in PPARalpha with an increase in relative fatty acid (FA) flux was associated with anomalies of cardiomyocytes with accumulation of lipid droplets and glycogen as well as cell death. At the stage of overt heart failure (14-month old TG), an accelerated glycolytic pathway with a decline in FA oxidation was accompanied by further structural changes. CONCLUSION: Tgalphaq*44 mice display three distinct phases of metabolic/structural changes during hypertrophy and progression to HF, with relatively short period of increase in FA metabolism, highlighting a narrow metabolic changes associated with transition to overt heart failure in Tgaq*44 mice that have therapeutic significance. PMID- 27126698 TI - Effect of trans-chalcone on atheroma plaque formation, liver fibrosis and adiponectin gene expression in cholesterol-fed NMRI mice. AB - BACKGROUND: Trans-chalcone is the precursor molecule to flavonoids and possesses antioxidant and anti-inflammatory properties. This study aimed to evaluate the effects of trans-chalcone on atheroma plaque formation and the relevant biochemical parameters in high cholesterol diet (HCD)-fed NMRI mice. METHODS: Fifty male NMRI mice were divided into 5 groups (n=10 per group): control (received a normal diet); HCD (received an additional 2% cholesterol for 18 weeks); sham (received a HCD for 12 weeks and were then shifted to a normal diet and trans-chalcone vehicle (sunflower oil) for 6 weeks), and two experimental groups (received a HCD for 12 weeks and were then shifted to a normal diet and either 12mg/kg or 24mg/kg trans-chalcone for 6 weeks). RESULTS: After 12 weeks, HCD-induced atheroma plaques were observed by hematoxylin and eosin staining of aortic sections. At the end of experiment, the following factors had significantly increased in the HCD group: body weight, insulin resistance, and serum levels of triglycerides, total-cholesterol, glucose, insulin, leptin, liver enzymes (AST and ALT), malondialdehyde and direct bilirubin. The serum levels of high-density lipoprotein cholesterol, adiponectin, superoxide dismutase, and glutathione had considerably decreased. Histologic analysis of liver sections indicated hepatic fibrosis and steatosis. Treatment by both doses of trans chalcone, particularly the 24mg/kg dose, significantly attenuated these alterations. CONCLUSIONS: Administration of trans-chalcone improved the consequences of atheroma plaque formation and liver fibrosis via increased expression of adiponectin, generation of higher levels of antioxidant enzymes, as well as modulation of serum leptin and lipid profiles. PMID- 27126699 TI - Noxious heat threshold temperature and pronociceptive effects of allyl isothiocyanate (mustard oil) in TRPV1 or TRPA1 gene-deleted mice. AB - AIMS: To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate (AITC)-evoked nociceptive responses by comparing wild-type and gene-deficient mice. MAIN METHODS: In contrast to conventional methods of thermonociception measuring reflex latencies, we used our novel methods to determine the noxious heat threshold. KEY FINDINGS: It was revealed that the heat threshold of the tail measured by an increasing-temperature water bath is significantly higher in TRPV1(-/-), but not TRPA1(-/-), mice compared to respective wild-types. There was no difference between the noxious heat thresholds of the hind paw as measured by an increasing-temperature hot plate in TRPV1(-/-), TRPA1(-/-) and the corresponding wild-type mice. The withdrawal latency of the tail from 0 degrees C water was prolonged in TRPA1(-/-), but not TRPV1(-/-), mice compared to respective wild-types. In wild-type animals, dipping the tail or paw into 1% AITC induced an 8-14 degrees C drop of the noxious heat threshold (heat allodynia) of both the tail and paw, and 40-50% drop of the mechanonociceptive threshold (mechanical allodynia) of the paw measured by dynamic plantar esthesiometry. These AITC-evoked responses were diminished in TRPV1(-/-), but not TRPA1(-/-), mice. Tail withdrawal latency to 1% AITC was significantly prolonged in both gene-deleted strains. SIGNIFICANCE: Different heat sensors determine the noxious heat threshold in distinct areas: a pivotal role for TRPV1 on the tail is contrasted with no involvement of either TRPV1 or TRPA1 on the hind paw. Noxious heat threshold measurement appears appropriate for preclinical screening of TRP channel ligands as novel analgesics. PMID- 27126700 TI - Comparison of complications between pediatric peripherally inserted central catheter placement techniques. AB - BACKGROUND: Peripherally inserted central catheter (PICC) is among the most common procedures performed in children in the hospital setting. PICC insertion can be simplified with the use of a sheathed needle as an alternative to the modified Seldinger technique. OBJECTIVE: To retrospectively evaluate PICC placement for the technique used and the incidence of complications at a large pediatric tertiary care center. MATERIALS AND METHODS: We retrospectively reviewed all PICC placements at a single institution over a 4-year period. We reviewed patient records for demographic data, PICC placement technique, catheter size and number of lumens, and the incidence of complications (i.e. multiple attempted puncture sites, phlebitis and vessel thrombosis). We analyzed complication rates between two placement techniques using a chi-square test. RESULTS: We identified 8,816 successful PICC placements, 4,749 (53.9%) in males and 4,067 (46.1%) in females. The average age of the patients for which a line was placed was 5.6 years (range 1 day to 45 years). A direct sheathed needle puncture technique was used in 8,362 (94.9%) placements and a modified Seldinger technique was used in 454 (5.1%). Complications occurred in 312 (3.7%) of direct sheathed needle puncture placements versus 17 (3.7%) of modified Seldinger placements (P = 0.99). Multiple puncture sites were required in 175 (2.1%) attempted direct sheathed needle puncture placements compared with 8 (1.7%) attempted modified Seldinger placements (P = 0.63). Phlebitis occurred in 94 (1.1%) direct sheathed needle puncture lines versus 5 (1.1%) modified Seldinger placed lines (P = 0.96). Vessel thrombosis occurred in 43 (0.5%) direct sheathed needle puncture lines versus 4 (0.9%) modified Seldinger placed lines (P = 0.30). CONCLUSION: The direct peel-away sheathed needle vessel puncture technique and the modified Seldinger technique used to place PICC lines in children have similar complication rates. PMID- 27126701 TI - Prefrontal gray matter volume recovery in treatment-seeking cocaine-addicted individuals: a longitudinal study. AB - Deficits in prefrontal cortical (PFC) function have been consistently reported in individuals with cocaine use disorders (iCUD), and have separately been shown to improve with longer-term abstinence. However, it is less clear whether the PFC structural integrity possibly underlying these deficits is also modulated by sustained reduction in drug use in iCUD. Here, T1-weighted magnetic resonance imaging scans were acquired, and performance on a neuropsychological test battery was assessed, in 19 initially abstinent treatment-seeking iCUD, first at baseline and then after six months of significantly reduced or no drug use (follow-up). A comparison cohort of 12 healthy controls was also scanned twice with a similar inter-scan interval. The iCUD showed increased gray matter volume in the left inferior frontal gyrus and bilaterally in the ventromedial prefrontal cortex at follow-up compared to baseline; healthy controls, as expected, showed no changes over this same time period. The iCUD also showed improved decision making and cognitive flexibility, with the latter correlated significantly with the gray matter volume increases in the inferior frontal gyrus. Given its association with improved cognitive function, the longitudinal recovery in cortical gray matter volume, particularly in regions where structure and function are adversely affected by chronic drug use, reflects a quantifiable positive impact of significantly reduced drug use on cortical structural integrity. PMID- 27126702 TI - Evolutionary redesign of the Atlantic cod (Gadus morhua L.) Toll-like receptor repertoire by gene losses and expansions. AB - Genome sequencing of the teleost Atlantic cod demonstrated loss of the Major Histocompatibility Complex (MHC) class II, an extreme gene expansion of MHC class I and gene expansions and losses in the innate pattern recognition receptor (PRR) family of Toll-like receptors (TLR). In a comparative genomic setting, using an improved version of the genome, we characterize PRRs in Atlantic cod with emphasis on TLRs demonstrating the loss of TLR1/6, TLR2 and TLR5 and expansion of TLR7, TLR8, TLR9, TLR22 and TLR25. We find that Atlantic cod TLR expansions are strongly influenced by diversifying selection likely to increase the detectable ligand repertoire through neo- and subfunctionalization. Using RNAseq we find that Atlantic cod TLRs display likely tissue or developmental stage-specific expression patterns. In a broader perspective, a comprehensive vertebrate TLR phylogeny reveals that the Atlantic cod TLR repertoire is extreme with regards to losses and expansions compared to other teleosts. In addition we identify a substantial shift in TLR repertoires following the evolutionary transition from an aquatic vertebrate (fish) to a terrestrial (tetrapod) life style. Collectively, our findings provide new insight into the function and evolution of TLRs in Atlantic cod as well as the evolutionary history of vertebrate innate immunity. PMID- 27126703 TI - Occupational exposure of cashiers to Bisphenol A via thermal paper: urinary biomonitoring study. AB - PURPOSE: As an essential component of polycarbonate plastics and epoxy resins, Bisphenol A (BPA) is found in numerous industrial and consumer products. BPA may cause adverse health effects because of its endocrine activity. General population exposure to this compound mainly through diet is well documented. Thermal paper was also identified as a source of BPA through dermal intake. In this study, we investigated whether frequent contact with thermal paper is associated with an increase in urinary BPA excretion. METHODS: We evaluated the exposure to BPA in cashiers and in non-occupationally exposed workers from several workplaces. Urinary BPA was quantified in free (unconjugated) and total (unconjugated plus conjugated) forms in 24-h and spot urine samples using LC MS/MS. BPA concentration in thermal paper was also measured from each workplace. In addition, participants provided information on job, food and drink, tobacco consumption and hands wash during the sampling period through a questionnaire. RESULTS: Urine samples were collected from 90 cashiers and 44 controls. Free and total BPA were detected in all samples. The median urinary total BPA concentration was 3.54 ug/L (2.89 ug/g creatinine) for controls and 8.92 ug/L (6.76 ug/g creatinine) for cashiers. For the free BPA, the median urinary concentration was 0.20 ug/L (0.21 ug/g creatinine) for controls and 0.28 ug/L (0.22 ug/g creatinine) for cashiers. Any correlation was found between the urinary concentration levels and the number of thermal receipts handled. Hand washes frequency, age, job length of service and tobacco consumption had also no effect on the BPA excretions. CONCLUSION: A significant increase in urinary total BPA concentration was observed for cashiers handling daily thermal paper receipts. However, no significant increase was observed in urinary free BPA concentration. These findings are particularly interesting for risk assessment since all available data on occupational exposure to BPA through thermal paper were obtained from models or from simulated experiments. PMID- 27126705 TI - Five minutes with . . . Sarah Wollaston MP. PMID- 27126704 TI - Multidimensional assessment of self-reported chemical intolerance and its impact on chemosensory effects during ammonia exposure. AB - PURPOSE: Healthy individuals differ in self-reported chemical intolerance (CI). It is unclear whether this inter-individual variability impacts well-being and performance in environmental and occupational settings with chemical exposures. So far, operational definitions and questionnaires of CI have either emphasized physical symptoms or affective/behavioral disruption. In contrast, this study focused on healthy individuals who reported strong CI which generalized to awareness, physiology, affect, and behavior. We investigated whether generalized self-reported CI is associated with hyper-reactivity and reduced cognitive functioning due to chemosensory-mediated distraction during ammonia exposure. METHODS: An online sample (N = 321) answered established CI questionnaires. Based on the convergent self-reports in these questionnaires, healthy women with generalized CI and healthy female control participants were selected (total N = 26). Baseline characterization was performed using implicit association, lung and olfactory function tests, health-related self-reports, plasma inflammatory and metabolic markers. Performance in neurobehavioral tasks, perceptual ratings, nasal inflammatory, neuroendocrine, and autonomic nervous system reactivity were examined by means of a 75-min whole-body challenge to ammonia (stepwise increase: 0-10 ppm). RESULTS: Correlational analyses confirmed the multidimensionality of CI. Participants with generalized self-reported CI exhibited better olfactory function and reported stronger pungency during the challenge than controls. Cognitive performance and physiological response to the challenge were comparable between the two groups. CONCLUSIONS: Self-reports of CI are complex and not easily assessed by unidimensional questionnaires. While generalized self-reported CI is associated with altered chemosensory processing, it seems unlikely that it modulates health effects and cognitive functioning during chemical exposure. PMID- 27126706 TI - The role of choroidal thickness in diabetic retinopathy and obstructive sleep apnea syndrome. PMID- 27126709 TI - Impact of body composition changes on risk of all-cause mortality in older adults. AB - PURPOSE: This study evaluates the relationship between body mass index (BMI), fat mass index (FMI) and fat-free mass index (FFMI) changes and mortality in persons >=65 years. METHODS: Adults >=65 years with at least two body composition measurements (BCM) between 1990 and 2011 were included. We excluded persons who died within one month of the second BCM and who had two single BCM in a one-month timeframe. Mortality data was retrieved until December 2012. For each person, we calculated the regression slopes for BMI, FMI and FFMI changes. Significant positive slopes were categorized as "gain", negative slopes as "loss" and the others as "maintenance". The impact of body composition changes was evaluated by Cox regression models while adjusting for sex, age, co-morbidities and body composition at the last measurement. RESULTS: We included 791 persons with 3049 BCM. After adjustment for sex, and age and co-morbidities, a loss of FFMI, but not of FMI or BMI, increased the risk of mortality (HR 2.02, 95%CI 1.28-3.19). The prediction of mortality with FFMI loss remained significant when further adjusting for FMI loss and the last available body composition (HR 1.68, 95%CI 1.04-2.70). CONCLUSIONS: FFMI loss is related to increased mortality in older persons. PMID- 27126708 TI - Personal distress and the influence of bystanders on responding to an emergency. AB - Spontaneous helping behavior during an emergency is influenced by the personality of the onlooker and by social situational factors such as the presence of bystanders. Here, we sought to determine the influences of sympathy, an other oriented response, and personal distress, a self-oriented response, on the effect of bystanders during an emergency. In four experiments, we investigated whether trait levels of sympathy and personal distress predicted responses to an emergency in the presence of bystanders by using behavioral measures and single pulse transcranial magnetic stimulation. Sympathy and personal distress were expected to be associated with faster responses to an emergency without bystanders present, but only personal distress would predict slower responses to an emergency with bystanders present. The results of a cued reaction time task showed that people who reported higher levels of personal distress and sympathy responded faster to an emergency without bystanders (Exp. 1). In contrast to our predictions, perspective taking but not personal distress was associated with slower reaction times as the number of bystanders increased during an emergency (Exp. 2). However, the decrease in motor corticospinal excitability, a direct physiological measure of action preparation, with the increase in the number of bystanders was solely predicted by personal distress (Exp. 3). Incorporating cognitive load manipulations during the observation of an emergency suggested that personal distress is linked to an effect of bystanders on reflexive responding to an emergency (Exp. 4). Taken together, these results indicate that the presence of bystanders during an emergency reduces action preparation in people with a disposition to experience personal distress. PMID- 27126710 TI - Gastrointestinal tolerance and plasma status of carotenoids, EPA and DHA with a fiber-enriched tube feed in hospitalized patients initiated on tube nutrition: Randomized controlled trial. AB - BACKGROUND & AIMS: During the first days of tube feeding (TF) gastrointestinal (GI) complications are common and administration of sufficient nutrition is a challenge. Not all standard nutritionally complete formulas contain dietary fiber, fish oil or carotenoids, key dietary nutrients for health and wellbeing. The aim of this study was to investigate the effects of a fiber, fish oil and carotenoid enriched TF formula on diarrhea, constipation and nutrient bioavailability. METHODS: A multi-center randomized, double-blind, controlled, parallel trial compared the effects of a dietary fiber, fish oil and carotenoid enriched TF formula (test) with an isocaloric non-enriched formula (control) in 51 patients requiring initiation of TF. Incidence of diarrhea and constipation (based on stool frequency and consistency) was recorded daily. Plasma status of EPA, DHA and carotenoids was measured after 7 days. RESULTS: The incidence of diarrhea was lower in patients receiving the test formula compared with the control group (19% vs. 48%, p = 0.034). EPA and DHA status (% of total plasma phospholipids) was higher after 7 days in test compared with control group (EPA: p = 0.002, DHA: p = 0.082). Plasma carotenoid levels were higher after 7 days in the test group compared with control group (lutein: p = 0.024, alpha-carotene: p = 0.005, lycopene: p = 0.020, beta-carotene: p = 0.054). CONCLUSIONS: This study suggests that the nutrient-enriched TF formula tested might have a positive effect on GI tolerance with less diarrhea incidence and significantly improved EPA, DHA and carotenoid plasma levels during the initiation of TF in hospitalized patients who are at risk of diarrhea and low nutrient status. CLINICAL TRIAL REGISTRATION: This trial was registered at trialregister.nl; registration number 2924. PMID- 27126711 TI - Management of acute intestinal failure: A position paper from the European Society for Clinical Nutrition and Metabolism (ESPEN) Special Interest Group. AB - Intestinal failure (IF) is the consequence of a reduction of gut function below the minimum necessary for the absorption of nutrients from the gastrointestinal tract. Types I and II comprise acute intestinal failure (AIF). Although its prevalence is relatively low, type II AIF is serious and requires specialist multidisciplinary care, often for prolonged periods before its resolution. The key aspects are: sepsis control, fluid and electrolyte resuscitation, optimization of nutritional status, wound care, appropriate surgery and active rehabilitation. The ESPEN Acute Intestinal Failure Special Interest Group (AIF SIG) has devised this position paper to provide a state-of-the-art overview of the management of type II AIF and to point out areas for future research. PMID- 27126713 TI - A Systematic Review of the Uptake and Adherence Rates to Supervised Exercise Programs in Patients with Intermittent Claudication. AB - BACKGROUND: Intermittent claudication (IC) is a common and debilitating symptom of peripheral arterial disease and is associated with a significant reduction in a sufferer's quality of life. Guidelines recommend a supervised exercise program (SEP) as the primary treatment option; however, anecdotally there is a low participation rate for exercise in this group of patients. We undertook a systematic review of the uptake and adherence rates to SEPs for individuals with IC. METHODS: The MEDLINE, Embase, and PubMed databases were searched up to January 2015 for terms related to supervised exercise in peripheral arterial disease. The review had 3 aims: first, to establish the rates of uptake to SEPs, second, the rates of adherence to programs, and finally to determine the reasons reported for poor uptake and adherence. Separate inclusion and/or exclusion criteria were applied in selecting reports for each aim of the review. RESULTS: Only 23 of the 53 potentially eligible articles for uptake analysis identified on literature searches reported any details of screened patients (n = 7,517) with only 24.2% of patients subsequently recruited to SEPs. Forty-five percent of screen failures had no reason for exclusion reported. Sixty-seven articles with 4,012 patients were included for analysis of SEP adherence. Overall, 75.1% of patients reportedly completed an SEP; however, only one article defined a minimal attendance required for SEP completion. Overall, 54.1% of incomplete adherence was due to patient withdrawal and no reason for incomplete adherence was reported for 16% of cases. CONCLUSIONS: Reporting of SEP trials was poor with regard to the numbers of subjects screened and reasons for exclusions. Only approximately 1 in 3 screened IC patients was suitable for and willing to undertake SEP. Levels of adherence to SEPs and definitions of satisfactory adherence were also lacking in most the current literature. Current clinical guidelines based on this evidence base may not be applicable to most IC patients and changes to SEPs may be needed to encourage and/or retain participants. PMID- 27126712 TI - Criterion validity of the visual estimation method for determining patients' meal intake in a community hospital. AB - BACKGROUND & AIMS: The accuracy of the visual estimation method is unknown, even though it is commonly used in hospitals to measure the dietary intake of patients. We aimed to compare the difference in the validity of visual estimation according to the raters' job categories and tray divisions, and to demonstrate associations between meal characteristics and validity of visual estimation in a usual clinical setting in a community hospital. METHODS: We collected patients' dietary intake data in usual clinical settings for each tray in 3 ways: visual estimation by nursing assistants, visual estimation by dietitians, and weighing by researchers (reference method). Dietitians estimated the dietary intake using 2 divisions, namely, whole tray and food items. Then we compared the weights and visual estimation data to evaluate the validity of the visual estimation method. RESULTS: Mean nutrient consumption of target trays was significantly different when using the visual estimation of target trays than when using the weighed method (visual estimation by nursing assistants [589 +/- 168 kcal, 24.3 +/- 7.0 g/tray, p < 0.01], dietitians' whole trays [561 +/- 171 kcal, 23.0 +/- 6.9 g/tray, p < 0.05], food items [562 +/- 171 kcal/tray, p < 0.05], and dietitians' food items [23.4 +/- 7.3 g/tray, p = 0.63]). Spearman's correlations for both methods were very high for energy (rho = 0.91-0.98, p < 0.01) and protein intakes (rho = 0.88-0.96, p < 0.01), respectively. The limits of agreement in the Bland Altman plot for both dietary intake categories were -121 kcal to 147 kcal/tray and -6.4 g to 7.0 g/tray (nursing assistants, whole division), -122 kcal-106 kcal/tray and -6.7 g to 5.5 g/tray (dietitians, whole divisions), and -82 kcal to 66 kcal/tray and -4.3 g to 3.9 g/tray (dietitians, food items divisions). High intake rate of grains was significantly associated with decreased odds of a difference between two methods based on the nursing assistant's whole tray evaluation (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.76-0.94) and the dietitians' whole tray (OR: 0.80; 95% CI: 0.72-0.89) and food items evaluations (OR: 0.64; 95% CI: 0.56-0.73), respectively. In addition, minced meals were also associated with a difference between two methods, for the nursing assistants' whole tray (OR: 3.53; 95% CI: 1.66-7.51) and dietitians' food items (OR: 2.92; 95% CI: 1.37-6.22). CONCLUSIONS: Visual estimation by nursing assistants and dietitians correlated highly with the weighing method although the limits of agreement were wide. Nursing assistants and dietitians should pay attention to low consumption and modified texture meals when evaluating dietary intake using the visual estimation method. PMID- 27126714 TI - Influence of Clinically Relevant Mechanical Forces on Vascular Smooth Muscle Cells Under Chronic High Glucose: An In Vitro Dynamic Disease Model. AB - BACKGROUND: In this study, we subjected vascular smooth muscle cells (VSMC) to acute and chronic high glucose conditions under physiologically relevant levels of cyclic strain and low wall shear forces to compare phenotypic modulation and thus conceptualize a dynamic-disease test model which captures cellular response more accurately in comparison with static cultures. METHODS: P2-P6 rat aortic smooth muscle cells were seeded on type I collagen-coated silicone membranes and subjected to 0-7% cyclic strain at 1 Hz and 0.3 dynes/cm(2) shear stress from flow for 24 hr under acute (25 mM d-glucose, 84 hr) and chronic high glucose conditions (25 mM d-glucose, 3-4 weeks). Samples were analyzed for cell proliferation, percent apoptosis, cellular hypertrophy, and expression levels of smooth muscle contractile state-associated markers with 0.05 level of significance. RESULTS: Concomitant application of cyclic strain and flow shear resulted in an overall increase in proliferation of VSMCs under both acute and chronic high glucose conditions as compared with normal glucose control (P < 0.0001). Application of both cyclic strain and cyclic strain shear resulted in a significant increase in percent apoptosis with chronic high glucose treatment in comparison with both normal glucose controls (P < 0.0001) and acute high glucose (P < 0.0001). Cellular hypertrophy as estimated by measuring cell area and aspect ratio revealed a significantly altered morphology due to concomitant loading under chronic high glucose conditions with significantly higher cell area (P < 0.0001) and lower aspect ratio (P < 0.0001) indicative of a relatively rounded morphology as compared with normal glucose controls. Western blot analysis demonstrated reduced expression of SM alpha-actin (P < 0.0001), calponin (P < 0.0001), and SM22alpha (P = 0.0008) for concomitant loading under chronic high glucose treatment as compared with normal glucose controls. CONCLUSIONS: Concomitant application of cyclic strain and low wall shear stress resulted in greater phenotypic modulation of VSMCs due to chronic high glucose treatment as compared with normal glucose controls, thus implicating cellular-response differences which may impact progression of in-stent restenosis in diabetic patients with poorly controlled hyperglycemia. Similarity of VSMC response from our study to existing preclinical models of diabetes and reports of altered phenotype of VSMCs isolated from diabetic patients substantiate the relevance of our dynamic disease test model. PMID- 27126715 TI - Blunt Abdominal Aortic Injury Associated with L2 Vertebral Fracture. AB - Blunt abdominal aortic injury (BAAI) is very rare. In general, BAAI occurs in high-energy accidents. Here, we present a case of BAAI in a low-energy accident. A 70-year-old female was injured after falling 3 m. Her vital signs were stable. She had lumbar fractures (L1, L2) and BAAI associated with a fragment of the fractured L2 vertebral body. On the fifth posttrauma day, we performed an operation because computed tomography showed a bone fragment of the lumbar fractures (L1, L2) threatening the abdominal aorta. The aortic injury site was transected, and the fragment of the L2 vertebral body was removed. Even in low energy accidents, BAAI should be considered. BAAI with stable vital signs can be electively treated. PMID- 27126717 TI - Ovarian Sertoli-Leydig cell tumor with heterologous elements containing an unusual type of alpha-fetoprotein-producing cells. PMID- 27126716 TI - Systematic Literature Review on Evaluation and Management of Isolated Spontaneous Celiac Trunk Dissection. AB - BACKGROUND: The purpose of this study is to perform a systematic literature review of isolated spontaneous celiac trunk dissection (ISCTD), to evaluate initial clinical and diagnostic aspects, treatment modalities, and outcomes. METHODS: A retrospective search of MEDLINE, Cochrane, and SciELO databases was performed, using the terms celiac artery dissection, celiac trunk dissection, hepatic artery dissection, splenic artery dissection, or left gastric artery dissection to identify instances of ISCTD. Patients with associated aortic and/or other visceral artery dissection were excluded. When available, the following information was collected from each case: gender, age, associated risk factor, symptoms, diagnostic method, treatment modality, and outcome. RESULTS: A total of 60 publications were identified between 1987 and 2015, with 11 cases series and 49 case reports, achieving a total of 169 patients identified with ISCTD. Such information was collected: 99 patients were male and 17 female, with an average age of 53.1 years and the most common symptom was abdominal pain. Diagnosis was mainly made with computed tomography. The most common associated conditions were hypertension and smoking in 31% and 23% of the cases, respectively. Conservative treatment was performed in 79% of the cases. CONCLUSIONS: The profile of patients with ISCTD is male, middle aged, and almost all suffer from abdominal pain. Initial conservative treatment seems adequate for most cases, but a few patients will require interventional treatment. Clinical and radiological long-term follow up is mandatory, owing to the risk of later progression to aneurysm. PMID- 27126718 TI - Nanoporous chalcogenides for adsorption and gas separation. AB - The adsorption and gas separation properties of amorphous porous chalcogenides such as GeS2 are investigated using statistical mechanics molecular simulation. Using a realistic molecular model of such amorphous adsorbents, we show that they can be used efficiently to separate different gases relevant to environmental and energy applications (H2, CO2, CH4, N2). In addition to shedding light on the microscopic adsorption mechanisms, we show that coadsorption in this novel class of porous materials can be described using the ideal adsorbed solution theory (IAST). Such a simple thermodynamic model, which allows avoiding complex coadsorption measurements, describes the adsorption of mixture from pure component adsorption isotherms. Our results, which are found to be in good agreement with available experimental data, paves the way for the design of gas separation membranes using the large family of porous chalcogenides. PMID- 27126719 TI - Population size, growth and movements of Anguilla australis in a small lake. AB - To study growth rates, movements and estimate population size of shortfin eels Anguilla australis in a small lake (2.5 ha) near Christchurch, New Zealand, 617 A. australis were tagged with PIT tags. Tag retention was high (95%) and over the seven recapture events spread over 2 years, 55% of tagged A. australis were recaptured. Growth of recaptured A. australis averaged 13.1 mm year(-1) and declined slightly with increasing total length. Distance moved from original capture site increased with increasing time at large. Population estimates of A. australis > 400 mm (susceptible to capture by fyke net) from recaptures of individuals averaged 1451 A. australis, with a biomass of 170 kg ha(-1) . An average of 6.6% of the estimated total population matured as male silver A. australis each year. Results from radio-tracking of four A. australis gave an average nightly foraging area of 2780 m(2) , and there was no apparent preference for inshore movement (within 5-6 m of the shoreline) or offshore movement. Fyke net efficiency (total catch relative to the estimated total population available to each net) measured over four consecutive nights fishing was 88%. The lack of precision of the shoreline triangulation system used, +/-10 m, meant that the positional data were considered too coarse to be used in a proposed novel population estimation technique based on determining population size within foraging areas. PMID- 27126720 TI - Is Montelukast Benefical in Children With Atopic Dermatitis? PMID- 27126722 TI - Update on the Management of Aspirin-Exacerbated Respiratory Disease. AB - Aspirin-exacerbated respiratory disease (AERD) is an adult-onset upper and lower airway disease consisting of eosinophilic nasal polyps, asthma, and respiratory reactions to cyclooxygenase 1 (COX-1) inhibitors. Management includes guideline based treatment of asthma and sinus disease, avoidance of COX-1 inhibitors, and for some patients aspirin desensitization followed by high-dose aspirin therapy. Despite this, many patients have inadequately controlled symptoms and require multiple sinus surgeries. In this review, we discuss the current standard approaches to the management of AERD, and we introduce several therapeutics under development that may hold promise for the treatment of AERD. PMID- 27126721 TI - Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. AB - In susceptible individuals, inhalation of Aspergillus spores can affect the respiratory tract in many ways. These spores get trapped in the viscid sputum of asthmatic subjects which triggers a cascade of inflammatory reactions that can result in Aspergillus-induced asthma, allergic bronchopulmonary aspergillosis (ABPA), and allergic Aspergillus sinusitis (AAS). An immunologically mediated disease, ABPA, occurs predominantly in patients with asthma and cystic fibrosis (CF). A set of criteria, which is still evolving, is required for diagnosis. Imaging plays a compelling role in the diagnosis and monitoring of the disease. Demonstration of central bronchiectasis with normal tapering bronchi is still considered pathognomonic in patients without CF. Elevated serum IgE levels and Aspergillus-specific IgE and/or IgG are also vital for the diagnosis. Mucoid impaction occurring in the paranasal sinuses results in AAS, which also requires a set of diagnostic criteria. Demonstration of fungal elements in sinus material is the hallmark of AAS. In spite of similar histopathologic features, co existence of ABPA and AAS is still uncommon. Oral corticosteroids continue to be the mainstay of management of allergic aspergillosis. Antifungal agents play an adjunctive role in ABPA as they help reduce the fungal load. Saprophytic colonization in cavitary ABPA may lead to aspergilloma formation, which could increase the severity of the disease. The presence of ABPA, AAS, and aspergilloma in the same patient has also been documented. All patients with Aspergillus sensitized asthma must be screened for ABPA, and AAS should always be looked for. PMID- 27126723 TI - A Double-Blind, Randomized, Crossover Study to Compare the Effectiveness of Montelukast on Atopic Dermatitis in Korean Children. AB - PURPOSE: Some studies report a role of leukotrienes in the pathogenesis of atopic dermatitis and suggest a rationale for the use of leukotriene receptor antagonist (LTRA) in the treatment of atopic dermatitis. This study aimed to evaluate the treatment effectiveness of montelukast in children with atopic dermatitis. METHODS: Fifty-four children between the ages of 2 and 6 years with moderate to severe atopic dermatitis were enrolled. Group A received montelukast for 8 weeks, followed by a crossover to 8 weeks of placebo after a 2-week washout period. Group B reversed the administration according to a randomized, double-blind, placebo-controlled, crossover design. The SCORing atopic dermatitis (SCORAD) index, urinary leukotriene E4 (LTE4), and eosinophil-derived neurotoxin (EDN) were assessed at every visit. RESULTS: Forty-three patients (21 males) completed the study. Although the SCORAD index was decreased in both groups, there was no statistically significant difference between montelukast and placebo (-3.0+/-11.2 vs -5.7+/-11.3, P=0.43). The level of urinary LTE4 was decreased after taking montelukast when compared to placebo, but there was no statistically significant difference (-65.9+/-556.2 vs 87.7+/-618.3, P=0.26). The changes in urinary EDN after taking montelukast and placebo had no significant difference (37.0+/ 1,008.6 vs -195.8+/-916.7, P=0.10). When analyzing SCORAD indices, urinary LTE4, and EDN, we could not prove the effectiveness of montelukast in the atopic, non atopic or high ECP (ECP >=15 MUg/L) subgroups. CONCLUSIONS: There was no statistically significant difference in clinical improvement or biomarkers between montelukast and placebo treatment. Therefore, conventional treatments with skin care and infection control might be more important strategies in the treatment of atopic dermatitis. PMID- 27126724 TI - No Concentration Decrease of House Dust Mite Allergens With Rising Altitude in Alpine Regions. AB - PURPOSE: Several studies over the past 4 decades have indicated a significant reduction in house dust mite (HDM) and HDM allergen concentration in areas higher than 1,500 m above sea level. These have served as basis of allergen avoidance therapies for HDM allergy and asthma. However, modern construction techniques used in the insulation, heating, and glazing of buildings as well as global warming have changed the environmental parameters for HDM living conditions. The present study revisits the paradigm of decreasing HDM allergen concentrations with increasing altitude in the alpine region of Germany and Austria. METHODS: A total of 122 dust samples from different abodes (hotels, privates and mountain huts) at different altitudes (400-2,600 m) were taken, and concentrations of HDM allergens were analyzed. Humidity and temperature conditions, and numerous indoor environmental parameters such as fine dust, type of flooring, age of building, and frequency of cleaning were determined. RESULTS: HDM allergen concentrations did not significantly change with increasing altitude or relative humidity. At the level of indoor parameters, correlations could be found for different flooring types and the concentration of HDM allergens. CONCLUSIONS: In contrast to the widespread view of the relationship between altitude and HDM allergen concentrations, clinically relevant concentrations of HDM allergens could be detected in high-lying alpine regions in Austria and Germany. These results indicate that improvement in conditions of asthmatic patients sensitized against HDMs during a stay at high altitude can no longer be ascribed to decreased levels of HDM allergens, instead, other mechanisms may trigger the beneficial effect. PMID- 27126725 TI - Omalizumab Improves Quality of Life and Asthma Control in Chinese Patients With Moderate to Severe Asthma: A Randomized Phase III Study. AB - PURPOSE: Omalizumab is the preferred add-on therapy for patients with moderate-to severe persistent allergic asthma and has demonstrated efficacy and safety in various ethnicities. This study evaluated the efficacy and safety of omalizumab in Chinese patients with moderate-to-severe allergic asthma. METHODS: This randomized, double-blind, parallel-group, placebo-controlled, phase III study assessed lung function, quality of life, asthma control, and safety of omalizumab after 24-week therapy in Chinese patients (18-75 years of age). RESULTS: A total of 616 patients were randomized (1:1) to omalizumab or placebo. The primary endpoint, least squares mean treatment difference (LSM-TD) in morning peak expiratory flow (PEF) (omalizumab vs placebo), at Weeks >20-24 was 8.85 L/min (Full analysis set; P=0.062). Per-protocol analysis set showed significant improvements with LSM-TD of 11.53 L/min in mean mPEF at Weeks >20-24 (P=0.022). The FEV1 % predicted was significantly improved with omalizumab vs placebo from 8 to 24 weeks (after 24-week treatment: LSM-TD=4.12%; P=0.001). At Week 24, a higher proportion of omalizumab-treated patients achieved clinically relevant improvements in standardized AQLQ (58.2% vs 39.3%; LSM=0.51 vs 0.10; P<0.001) and ACQ (49.5% vs 35.5%; LSM=-0.51 vs -0.34; P=0.002) scores vs placebo. Total and nighttime symptom scores reduced significantly with omalizumab vs placebo (LSM TD=-0.21, P=0.048 and -0.12, P=0.011, respectively). Although the study was not powered to study differences in exacerbation rates (P=0.097), exacerbations in winter months were less frequent in the omalizumab vs placebo group (2 vs 21). Adverse event and severe adverse event rates were comparable between omalizumab and placebo. CONCLUSIONS: Omalizumab improves lung function, quality of life, and asthma control in Chinese patients with moderate-to-severe persistent allergic asthma and has a good safety profile. PMID- 27126726 TI - Detection of Allergen Specific Antibodies From Nasal Secretion of Allergic Rhinitis Patients. AB - PURPOSE: Allergic rhinitis (AR) is a common and increasing disease in which Dermatophagoides (D.) farinae is one of the most common causative allergens. The aims of this study were to confirm the presence of locally produced antibodies to D. farinae in nasal secretions between nasal provocation test (NPT)-positive and negative groups of AR patients, to evaluate their relationships with the levels of inflammatory mediators, and to determine adaptive and innate immune responses in nasal mucosa. METHODS: Sixty AR patients sensitive to house dust mites confirmed by skin prick test or serum specific IgE to D. farinae underwent NPT for D. farinae. Nasal packs were placed in both nasal cavities of the patients for 5 minutes to obtain nasal secretions after NPT. The levels of total IgE, specific IgE to D. farinae, eosinophil cationic protein (ECP), and tryptase in nasal secretions were detected by using ImmunoCAP. The levels of specific IgE, IgA, and secretory IgA antibodies to D. farinae in nasal secretions were measured by using ELISA. The levels of IL-8, VEGF, IL-25, and IL-33 were also measured by using ELISA. RESULTS: High levels of total IgE, specific IgE, specific IgA, and secretory IgA to D. farinae, as well as inflammatory mediators, such as ECP, IL 8, VEGF and tryptase, were detected in nasal secretions, although the differences were not statistically significant between the NPT-positive and NPT-negative groups. Levels of all immunoglobulins measured in this study significantly correlated with ECP, IL-8, and VEGF (P<0.05), but not with tryptase (P>0.05). IL 33 and IL-25 were also detected, and IL-25 level significantly correlated with IL 8 (r=0.625, P<0.001). CONCLUSIONS: These findings confirmed the presence of locally produced specific antibodies, including D. farinae-specific IgE and IgA, in nasal secretions collected from D. farinae-sensitive AR patients in both the NPT-positive and NPT-negative groups, and close correlations were noted between antibodies and nasal inflammatory mediators, including such as ECP, IL-8 and VEGF, indicating that locally produced antibodies may be involved in the nasal inflammation of AR. PMID- 27126728 TI - Response to Nonallergenic Irritants in Children With Allergic and Nonallergic Rhinitis. AB - PURPOSE: Nonallergenic irritants can aggravate the symptoms of rhinitis. We investigated the clinical responses of children with allergic rhinitis (AR) and nonallergic rhinitis (NAR) to nonallergenic irritants, and identified factors associated with these responses. METHODS: Children with chronic rhinitis (n=208) were classified as having AR or NAR based on the presence of aeroallergen specific IgE. Healthy controls (n=24) were recruited for comparison. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines were used to classify patients, and their irritant score (0-21 points) and current symptom score (5-35 points) were measured. Subjects with irritant scores >=3 and <3 were classified as having irritant and nonirritant rhinitis, respectively. RESULTS: The mean age of enrolled subjects was 6.8 years (range: 1.8-16.0 years). The AR and NAR groups had similar irritant scores (P=0.394) and proportions of subjects with irritant scores >=3 (P=0.105). Irritant score correlated positively with symptom score (P=0.005), and the proportion of subjects with irritant scores >=3 was greater in children with moderate-severe rhinitis than in those with mild rhinitis (P=0.046). Multiple logistic regression analysis indicated that the presence of atopic eczema increased the risk for sensitivity to a nonallergenic irritant (aOR=2.928, 95% CI 1.567-5.473, P=0.001). CONCLUSIONS: Response to a nonallergenic irritant was useful for gauging the severity of rhinitis, but not for differentiating AR from NAR. AR and NAR patients with atopic eczema may increase nasal sensitivity to nonallergenic irritants. PMID- 27126727 TI - Age-Related Changes in Immunological Factors and Their Relevance in Allergic Disease Development During Childhood. AB - PURPOSE: Allergic diseases are triggered by Th2-mediated immune reactions to allergens and orchestrated by various immunological factors, including immune cells and cytokines. Although many reports have suggested that childhood is the critical period in the onset of allergic diseases and aging leads to alter the susceptibility of an individual to allergic diseases, age-related changes in various immunological factors in healthy individuals as well as their difference between healthy and allergic children have not yet been established. METHODS: We investigated the ratio of Th1/Th2 cells and the levels of 22 allergy-related cytokines across all age groups in individuals who were classified as clinically non-atopic and healthy. We also examined their differences between healthy and allergic children to evaluate immunological changes induced by the development of allergic diseases during childhood. RESULTS: The Th1/Th2 ratio rose gradually during the growth period including childhood, reaching peak values in the twenties-thirties age group. Th1/Th2 ratios were significantly lower in allergic children than in healthy controls, whereas 14 of 22 cytokines were significantly higher in allergic children than in healthy controls. On the other hand, there were no differences in Th1/Th2 ratios and cytokines between healthy and allergic adolescents. CONCLUSIONS: In this study, age-related changes in Th1/Th2 ratios were found in normal controls across all age groups, and decreases in Th1/Th2 ratio were observed with increasing of 14 cytokines in allergic children. The results of this study may be helpful as reference values for both monitoring immunological changes according to aging in healthy individuals and distinguishing between normal and allergic subjects in terms of immune cells and soluble factors. PMID- 27126729 TI - Characteristics of Anaphylaxis in 907 Chinese Patients Referred to a Tertiary Allergy Center: A Retrospective Study of 1,952 Episodes. AB - PURPOSE: Comprehensive evaluation of anaphylaxis in China is currently lacking. In this study, we characterized the clinical profiles, anaphylactic triggers, and emergency treatment in pediatric and adult patients. METHODS: Outpatients diagnosed with "anaphylaxis" or "severe allergic reactions" in the Department of Allergy, Peking Union Medical College Hospital from January 1, 2000 to June 30, 2014 were analyzed retrospectively. RESULTS: A total of 1,952 episodes of anaphylaxis in 907 patients were analyzed (78% were adults and 22% were children). Foods are the most common cause (77%), followed by idiopathic etiologies (15%), medications (7%) and insects (0.6%). In food-induced anaphylaxis, 62% (13/21) of anaphylaxis in infants and young children (0-3 years of age) were triggered by milk, 59% (36/61) of anaphylaxis in children (4-9 years of age) were triggered by fruits/vegetables, while wheat was the cause of anaphylaxis in 20% (56/282) of teenagers (10-17 years of age) and 42% (429/1,016) in adults (18-50 years of age). Mugwort pollen sensitization was common in patients with anaphylaxis induced by spices, fruits/vegetables, legume/peanuts, and tree nuts/seeds, with the prevalence rates of 75%, 67%, 61%, and 51%, respectively. Thirty-six percent of drug-induced anaphylaxis was attributed to traditional Chinese Medicine. For patients receiving emergency care, only 25% of patients received epinephrine. CONCLUSIONS: The present study showed that anaphylaxis appeared to occur more often in adults than in infants and children, which were in contrast to those found in other countries. In particular, wheat allergens played a prominent role in triggering food-induced anaphylaxis, followed by fruits/vegetables. Traditional Chinese medicine was a cause of drug induced anaphylaxis. Furthermore, exercise was the most common factor aggravating anaphylaxis. Education regarding the more aggressive use of epinephrine in the emergency setting is clearly needed. PMID- 27126730 TI - House Dust Mite-Derived Chitin Enhances Th2 Cell Response to Inhaled Allergens, Mainly via a TNF-alpha-Dependent Pathway. AB - PURPOSE: Chitin is a potent adjuvant in the development of immune response to inhaled allergens in the airways. According to other studies, chitin is known as multi-faced adjuvants which can induce Th2 responses. Recently, we found that TNF alpha is a key mediator in the development of Th2 cell response to inhaled allergens. Here, we evaluated the immunologic mechanisms in the development of airway hypersensitivity to inhaled allergens, enhanced by house dust mite (HDM) derived chitin. METHODS: The role of TNF-alpha and TLRs was evaluated in an airway hypersensitivity mouse model induced by a sensitization with an allergen (ovalbumin, OVA) and HDM-derived chitin using mice with the null mutation of target genes. RESULTS: The present study showed that airway sensitization with HDM-derived chitin plus OVA enhanced OVA-induced airway inflammation v. OVA alone. This phenotype was associated with the increased expression of Th1, Th2, and Th17 cytokines and also with the enhanced production of OVA-specific IgE, IgG1, and IgG2a. As for T cell responses, OVA-specific Th2 cell response, enhanced by chitin, was abolished by the treatment of chitinase, whereas Th1 and Th17 cell responses enhanced by this treatment. Moreover, the null mutation of the TNF-alpha gene revealed similar effects as the chitinase treatment. In contrast, all the OVA-specific T cell responses, enhanced by chitin, were blocked by the absence of TLR2, but not of TLR1, TLR4, or TLR6. CONCLUSIONS: In conclusion, these data suggest that HDM-derived chitin may enhance airway hypersensitivity to inhaled allergens, via the TLR2-dependent pathway, and that chitin-induced TNF-alpha can be a key mediator in the development of Th2 cell response to inhaled allergens. PMID- 27126731 TI - Autologous Immunoglobulin Therapy in Patients With Severe Recalcitrant Atopic Dermatitis: Long-Term Changes of Clinical Severity and Laboratory Parameters. AB - This report evaluated long-term changes in clinical severity and laboratory parameters in 3 adult patients with severe recalcitrant atopic dermatitis (AD) who were treated with intramuscular injections of 50 mg of autologous immunoglobulin G (IgG) twice a week for 4 weeks (autologous immunoglobulin therapy, AIGT) and followed up for more than 2 years after the treatment. We observed the following 4 major findings in these 3 patients during the long-term follow-up after AIGT. (1) Two of the 3 patients showed a long-term clinical improvement for more than 36 weeks after AIGT with a maximum decrease in clinical severity score greater than 80% from baseline. (2) These 2 patients also showed long-term decreases in serum total IgE concentrations and peripheral blood eosinophil count for more than 36 weeks after AIGT with a maximum decrease in the two laboratory parameters of allergic inflammatory greater than 70% from baseline. (3) No significant side effect was observed during the 2 years of follow-up period after the AIGT in all 3 patients. (4) Serum levels of IgG anti idiotype antibodies to the F(ab')2 fragment of autologous IgG administered for the treatment were not significantly changed after AIGT in all 3 patients. These findings suggest that AIGT has long-term favorable effects on both clinical severity and laboratory parameters in selected patients with severe recalcitrant AD. Further studies are required to evaluate the clinical usefulness and therapeutic mechanism of AIGT for AD. PMID- 27126732 TI - New Allergic and Hypersensitivity Conditions Section in the International Classification of Diseases-11. AB - Allergy and hypersensitivity, originally perceived as rare and secondary disorders, are one of the fastest growing conditions worldwide, but not adequately tracked in international information systems, such as the International Classification of Diseases (ICD). Having allergic and hypersensitivity conditions classification able to capture conditions in health international information systems in a realistic manner is crucial to the identification of potential problems, and in a wider system, can identify contextually specific service deficiencies and provide the impetus for changes. Since 2013, an international collaboration of Allergy Academies has spent tremendous efforts to have a better and updated classification of allergies in the forthcoming International Classification of Diseases (ICD)-11 version, by providing scientific and technical evidences for the need for changes. The following bilateral discussions with the representatives of the ICD-11 revision, a simplification process was carried out. The new parented "Allergic and hypersensitivity conditions" section has been built under the "Disorders of the Immune System" chapter through the international collaboration of Allergy Academies and upon ICD WHO representatives support. The classification of allergic and hypersensitivity conditions has been updated through the ICD-11 revision and will allow the aggregation of reliable data to perform positive quality-improvements in health care systems worldwide. PMID- 27126733 TI - Clinical characteristics of scleroderma overlap syndromes: comparisons with pure scleroderma. AB - BACKGROUND: Scleroderma with characteristics of other connective tissue diseases is called scleroderma overlap syndrome (SOV); the clinical features of which have yet to be investigated among Thai patients. OBJECTIVE: To determine the clinical differences between pure scleroderma and SOV. METHODS: A historical cohort study was conducted among patients with pure scleroderma versus those with SOV. Subjects were over 18 years of age and followed up at Srinagarind Hospital, Khon Kaen University, Thailand, between January 2006 and December 2011. RESULTS: Four hundred and three medical records were included (276 female vs. 127 male). SOV was found in 68 cases (16.9%): (i) scleroderma-polymyositis overlap (SOV-PM), the most common type of SOV (48 cases; 70.6%); (ii) scleroderma-systemic lupus erythematosus overlap (11 cases; 16.2%); and (iii) scleroderma-rheumatoid arthritis overlap (nine cases; 13.2%). Mean age at onset of non-systemic sclerosis symptoms was 46.9 +/- 11.8 years (range, 19.8-74.3). Characteristically, sufferers of SOV as against pure scleroderma were younger, had less frequent anti-topoisomerase I (ATA) and needed moderate- to high-dose steroid and immunosuppressant therapy during follow-up. SOV-PM presented the clinical features of scleroderma at onset and during follow-up looks like pure scleroderma having vasculopathy, severity of skin tightness, and gastrointestinal, cardiopulmonary and renal involvement. Anti-Ro52 was the most common serology among sufferers of SOV (31.6%). ATA was associated with pure scleroderma patients (P = 0.047). CONCLUSIONS: SOV rather than pure scleroderma presented in younger Thai scleroderma patients and SOV-PM was the most common subtype and its clinical features were similar to those of pure scleroderma. ATA was strongly associated with the latter. PMID- 27126734 TI - Assessing health literacy and oral health: preliminary results of a multi-site investigation. AB - OBJECTIVES: To introduce a multi-site assessment of oral health literacy and to describe preliminary analyses of the relationships between health literacy and selected oral health outcomes within the context of a comprehensive conceptual model. METHODS: Data for this analysis came from the Multi-Site Oral Health Literacy Research Study (MOHLRS), a federally funded investigation of health literacy and oral health. MOHLRS consisted of a broad survey, including several health literacy assessments, and measures of attitudes, knowledge, and other factors. The survey was administered to 922 initial care-seeking adult patients presenting to university-based dental clinics in California and Maryland. For this descriptive analysis, confidence filling out forms, word recognition, and reading comprehension comprised the health literacy assessments. Dental visits, oral health functioning, and dental self-efficacy were the outcomes. RESULTS: Overall, up to 21% of participants reported having difficulties with practical health literacy tasks. After controlling for sociodemographic confounders, no health literacy assessment was associated with dental visits or dental caries self-efficacy. However, confidence filling out forms and word recognition were each associated with oral health functioning and periodontal disease self efficacy. CONCLUSIONS: Our analysis showed that dental school patients exhibit a range of health literacy abilities. It also revealed that the relationship between health literacy and oral health is not straightforward, depending on patient characteristics and the unique circumstances of the encounter. We anticipate future analyses of MOHLRS data will answer questions about the role that health literacy and various mediating factors play in explaining oral health disparities. PMID- 27126735 TI - Effect of team training on improving MRI study completion rates and no-show rates. AB - PURPOSE: Magnetic resonance imaging (MRI) is a high-cost imaging modality, and an optimized encounter ideally provides high-quality care, patient satisfaction, and capacity utilization. Our purpose was to assess the effectiveness of team training and its impact on patient show-up and completion rates for their MRI examinations. MATERIALS AND METHODS: A total of 97,712 patient visits from three tertiary academic medical centers over 1-year intervals were evaluated, totaling 49,733 visits at baseline and 47,979 after training. Each center's MRI team received team training skill training including advanced communication and team training techniques training. This training included onsite instruction including case simulation with scenarios requiring appropriate behavioral and communicative interventions. Orientation and training also utilized customized online tools and proctoring. The study completion rate and patient show-up rate during consecutive year-long intervals before and after team training were compared to assess its effectiveness. Two-sided chi-square tests for proportions using were applied at a 0.05 significance level. RESULTS: Despite differing no-show rates (5-22.2%) and study incompletion rates (0.7-3.7%) at the three academic centers, the combined patients' data showed significant (P < 0.0001) improvement in the patients' no show rates (combined decreases from 11.2% to 8.7%) and incompletion rates (combined decreases from 2.3% to 1.4%). CONCLUSION: Our preliminary results suggest training of the imaging team can improve the no-show and incompletion rates of the MRI service, positively affecting throughput and utilization. Team training can be readily implemented and may help address the needs of the current cost-conscious and consumer-sensitive healthcare environment. J. MAGN. RESON. IMAGING 2016;44:1040-1047. PMID- 27126739 TI - We use Continuous Renal Replacement Therapy for Overdoses and Intoxications. AB - Extracorporeal modalities for the removal of drugs and toxins are indicated for the treatment of overdoses and intoxications. Well-established modalities include hemodialysis (HD), high-flux HD (HfD), and charcoal hemoperfusion (HP). Recently, there have been increasing reports on the use of continuous renal replacement therapy (CRRT), such as continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemofiltration (CVVH) or CVVH combined with dialysis (CVVHDF). In the present article, we will discuss the various factors that determine the clearance of drugs and toxins and accordingly, we will propose that with few exceptions, CRRT does not have a role in the routine management of intoxications. PMID- 27126738 TI - Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants. AB - Krabbe disease is a severe, fatal neurodegenerative disorder caused by defects in the lysosomal enzyme galactocerebrosidase (GALC). The correct targeting of GALC to the lysosome is essential for the degradation of glycosphingolipids including the primary lipid component of myelin. Over 100 different mutations have been identified in GALC that cause Krabbe disease but the mechanisms by which they cause disease remain unclear. We have generated monoclonal antibodies against full-length human GALC and used these to monitor the trafficking and processing of GALC variants in cell-based assays and by immunofluorescence microscopy. Striking differences in the secretion, processing and endosomal targeting of GALC variants allows the classification of these into distinct categories. A subset of GALC variants are not secreted by cells, not proteolytically processed, and remain trapped in the ER; these are likely to cause disease due to protein misfolding and should be targeted for pharmacological chaperone therapies. Other GALC variants can be correctly secreted by cells and cause disease due to catalytic defects in the enzyme active site, inappropriate post-translational modification or a potential inability to bind essential cofactors. The classification of disease pathogenesis presented here provides a molecular framework for appropriate targeting of future Krabbe disease therapies. PMID- 27126740 TI - Divergence for residual feed intake of Holstein-Friesian cattle during growth did not affect production and reproduction during lactation. AB - Residual feed intake (RFI) is the difference between actual and predicted dry matter intake (DMI) of individual animals. Recent studies with Holstein-Friesian calves have identified an ~20% difference in RFI during growth (calf RFI) and these groups remained divergent in RFI during lactation. The objective of the experiment described here was to determine if cows selected for divergent RFI as calves differed in milk production, reproduction or in the profiles of BW and body condition score (BCS) change during lactation, when grazing pasture. The cows used in the experiment (n=126) had an RFI of -0.88 and +0.75 kg DM intake/day for growth as calves (efficient and inefficient calf RFI groups, respectively) and were intensively grazed at four stocking rates (SR) of 2.2, 2.6, 3.1 and 3.6 cows/ha on self-contained farmlets, over 3 years. Each SR treatment had equal number of cows identified as low and high calf RFI, with 24, 28, 34 and 40/11 ha farmlet. The cows divergent for calf RFI were randomly allocated to each SR. Although SR affected production, calf RFI group (low or high) did not affect milk production, reproduction, BW, BCS or changes in these parameters throughout lactation. The most efficient animals (low calf RFI) lost similar BW and BCS as the least efficient (high calf RFI) immediately post calving, and regained similar BW and BCS before their next calving. These results indicate that selection for RFI as calves to increase efficiency of feed utilisation did not negatively affect farm productivity variables (milk production, BCS, BW and reproduction) as adults when managed under an intensive pastoral grazing system. PMID- 27126741 TI - An automated tuberculosis screening strategy combining X-ray-based computer-aided detection and clinical information. AB - Lack of human resources and radiological interpretation expertise impair tuberculosis (TB) screening programmes in TB-endemic countries. Computer-aided detection (CAD) constitutes a viable alternative for chest radiograph (CXR) reading. However, no automated techniques that exploit the additional clinical information typically available during screening exist. To address this issue and optimally exploit this information, a machine learning-based combination framework is introduced. We have evaluated this framework on a database containing 392 patient records from suspected TB subjects prospectively recruited in Cape Town, South Africa. Each record comprised a CAD score, automatically computed from a CXR, and 12 clinical features. Comparisons with strategies relying on either CAD scores or clinical information alone were performed. Our results indicate that the combination framework outperforms the individual strategies in terms of the area under the receiving operating characteristic curve (0.84 versus 0.78 and 0.72), specificity at 95% sensitivity (49% versus 24% and 31%) and negative predictive value (98% versus 95% and 96%). Thus, it is believed that combining CAD and clinical information to estimate the risk of active disease is a promising tool for TB screening. PMID- 27126742 TI - Reliability of estimating active drag in swimming using the assisted towing method with fluctuating speed. AB - The reliability of active drag values was examined using a method that compared free swim speed with measurements taken by towing swimmers slightly faster than their maximum swim speed, while allowing their intra-stroke speed fluctuations. Twelve national age and open level swimmers were tested on two alternate days (Day 1 and Day 2). All participants completed four maximum swim speed, three passive drag and five active drag trials on each of the days. The reliability was determined using within-participant intra-class correlation coefficients (ICC) within each day and between the days. The ICCs for Day 1 and Day 2 were 0.82 and 0.85, respectively, while the comparison of the mean active drag values between days was 0.93. The data showed that the assisted towing method (ATM) with fluctuating speed was only moderately reliable within a single test. However, this method was more reliable when using the average value of active drag from both days (ICC = 0.93). This study identified that the ATM method with fluctuating speed had moderate reliability within-participant trials on values in a single day but high reliability for the average active drag values across different days. PMID- 27126737 TI - Neuropharmacology of N,N-dimethyltryptamine. AB - N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a number of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clinical uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered intravenously in large doses. Because of its role in nervous system signaling, DMT may be a useful experimental tool in exploring how the brain works, and may also be a useful clinical tool for treatment of anxiety and psychosis. PMID- 27126736 TI - RhoA determines lineage fate of mesenchymal stem cells by modulating CTGF-VEGF complex in extracellular matrix. AB - Mesenchymal stem cells (MSCs) participate in the repair/remodelling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFbeta-activated RhoA/ROCK signalling functions as a molecular switch regarding the fate of MSCs in arterial repair/remodelling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration. PMID- 27126743 TI - Pyoderma gangrenosum and necrotizing fasciitis-like opportunistic invasive cutaneous fungal infection. PMID- 27126744 TI - Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. AB - BACKGROUND: Acute asthma in children can be life-threatening and must be treated promptly in the emergency setting. Intravenous magnesium sulfate is recommended by various guidelines for cases of acute asthma that have not responded to first line treatment with bronchodilators and steroids. The treatment has recently been shown to reduce the need for hospital admission for adults compared with placebo, but it is unclear whether it is equally effective for children. OBJECTIVES: To assess the safety and efficacy of intravenous magnesium sulfate (IV MgSO4) in children treated for acute asthma in the emergency department (ED). SEARCH METHODS: We identified studies by searching the Cochrane Airways Review Group Specialised Register up to 23 February 2016. We also searched ClinicalTrials.gov and reference lists of other reviews, and we contacted study authors to ask for additional information. SELECTION CRITERIA: We included randomised controlled trials of children treated in the ED for exacerbations of asthma if they compared any dose of IV MgSO4 with placebo. DATA COLLECTION AND ANALYSIS: Two review authors screened the results of the search and independently extracted data from studies meeting the inclusion criteria. We resolved disagreements through discussion and contacted study authors in cases of missing data and other uncertainties relating to the studies.We analysed dichotomous data as odds ratios and continuous data as mean differences, both using fixed-effect models. We assessed each study for risk of bias and rated the quality of evidence for each outcome with GRADE and presented the results in a 'Summary of findings' table. There was insufficient evidence to conduct the planned subgroup analyses. MAIN RESULTS: Five studies (182 children) met the inclusion criteria, and four contributed data to at least one meta-analysis. The included studies were overall at low risk of bias, but our confidence in the evidence was generally low, mainly due to the small sample sizes. Treatment with IV MgSO4 reduced the odds of admission to hospital by 68% (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.14 to 0.74; children = 115; studies = 3; I(2) = 63%). This result was based on data from just three studies including 115 children. Meta-analysis for the secondary outcomes was extremely limited by paucity of data. We performed meta analysis for the outcome 'return to the emergency department within 48 hours', which showed a very imprecise effect estimate that was not statistically significant (OR 0.40, 95% CI 0.02 to 10.30; children = 85; studies = 2; I(2) = 0%). Side effects and adverse events were not consistently reported and meta analysis was not possible, however few side effects or adverse events were reported. AUTHORS' CONCLUSIONS: IV MgSO4 may reduce the need for hospital admission in children presenting to the ED with moderate to severe exacerbations of asthma, but the evidence is extremely limited by the number and size of studies. Few side effects of the treatment were reported, but the data were extremely limited. PMID- 27126746 TI - Cardiotoxic heart failure in breast cancer survivors: a concept analysis. AB - AIM: To report an analysis of the concept of cardiotoxic heart failure in breast cancer survivors. BACKGROUND: Despite numerous studies describing cardiotoxic effects of breast cancer therapies, the literature lacks consistent terminology to describe cancer treatment-induced heart failure, defined by the authors as 'cardiotoxic heart failure'. Breast cancer survivors who develop heart failure may not fit existing conceptual models. A concept analysis of cardiotoxic heart failure in breast cancer survivors is needed to integrate previous research findings and establish the scientific foundation for future intervention research. DESIGN: Concept analysis. DATA SOURCES: An integrative review (1999 2014) was conducted to examine aetiologies and risk factors for heart failure in female breast cancer survivors. Databases searched were CINAHL, Cochrane Library, EmBase, Medline and Scopus. METHODS: Walker and Avant's method for concept analysis includes: select concept; determine purpose; identify uses; define attributes; identify model case; describe borderline, related and contrary cases; identify antecedents/consequences; define empirical referents. RESULTS: In the literature, substantial variation was noted in terminology for breast cancer treatment-induced cardiotoxicity. The authors define cardiotoxic heart failure in breast cancer survivors as chronic heart failure resulting from breast cancer treatment-induced cardiotoxicity among women without pre-existing heart failure diagnosis. No studies were found that described quality of life or tested interventions to preserve quality of life for this population. CONCLUSION: Prospective studies are needed to develop interventions for symptom management to improve quality of life in breast cancer survivors with heart failure. New conceptual paradigms may be needed to improve outcomes for this vulnerable population. PMID- 27126745 TI - The All-Data-Based Evolutionary Hypothesis of Ciliated Protists with a Revised Classification of the Phylum Ciliophora (Eukaryota, Alveolata). AB - The phylum Ciliophora plays important roles in a wide range of biological studies. However, the evolutionary relationships of many groups remain unclear due to a lack of sufficient molecular data. In this study, molecular dataset was expanded with representatives from 55 orders and all major lineages. The main findings are: (1) 14 classes were recovered including one new class, Protocruziea n. cl.; (2) in addition to the two main branches, Postciliodesmatophora and Intramacronucleata, a third branch, the Mesodiniea, is identified as being basal to the other two subphyla; (3) the newly defined order Discocephalida is revealed to be a sister clade to the euplotids, strongly suggesting the separation of discocephalids from the hypotrichs; (4) the separation of mobilids from the peritrichs is not supported; (5) Loxocephalida is basal to the main scuticociliate assemblage, whereas the thigmotrichs are placed within the order Pleuronematida; (6) the monophyly of classes Phyllopharyngea, Karyorelictea, Armophorea, Prostomatea, Plagiopylea, Colpodea and Heterotrichea are confirmed; (7) ambiguous genera Askenasia, CyclotrichiumParaspathidium and Plagiocampa show close affiliation to the well known plagiopyleans; (8) validity of the subclass Rhynchostomatia is supported, and (9) the systematic positions of Halteriida and Linconophoria remain unresolved and are thus regarded as incertae sedis within Spirotrichea. PMID- 27126748 TI - Mentorship and student support. PMID- 27126747 TI - Role of OCT-1 and partner proteins in T cell differentiation. AB - The understanding of CD4 T cell differentiation gives important insights into the control of immune responses against various pathogens and in autoimmune diseases. Naive CD4 T cells become effector T cells in response to antigen stimulation in combination with various environmental cytokine stimuli. Several transcription factors and cis-regulatory regions have been identified to regulate epigenetic processes on chromatin, to allow the production of proper effector cytokines during CD4 T cell differentiation. OCT-1 (Pou2f1) is well known as a widely expressed transcription factor in most tissues and cells. Although the importance of OCT-1 has been emphasized during development and differentiation, its detailed molecular underpinning and precise role are poorly understood. Recently, a series of studies have reported that OCT-1 plays a critical role in CD4 T cells through regulating gene expression during differentiation and mediating long-range chromosomal interactions. In this review, we will describe the role of OCT-1 in CD4 T cell differentiation and discuss how this factor orchestrates the fate and function of CD4 effector T cells. PMID- 27126749 TI - An unhealthy alliance. PMID- 27126751 TI - Correction. PMID- 27126750 TI - Diagnosis, treatment and management of epidermolysis bullosa. AB - Epidermis bullosa is a genetically inherited disease in which painful blistering of the skin or mucous membranes occurs after minor trauma. It is a lifelong problem. The diagnosis should be confirmed by a specialist, preferably at a specialist unit where a treatment plan and follow-up arrangements for professionals and families can be put in place. Nurses will be involved in frequent dressings of wounds, after extra analgesia, and may need to be alert to any need for further specialist referral, especially in the case of complications such as infection, deformities, gastrointestinal strictures and possible skin cancers. Genetic counselling should also be offered to families, especially when considering the possible risks to future pregnancies. PMID- 27126752 TI - A real-world evidence study evaluating a treatment for nappy rash. AB - This retrospective open study evaluating the efficacy of Sudocrem Antiseptic Healing Cream (SAHC) in infantile nappy rash (NR) was based on real-world evidence collected using an online questionnaire that included Likert scales. Participants who had used SAHC in the past (n=2159) were recruited via social media and email. A total of 1818 respondents who had treated NR in the previous 6 months were asked to take part in the study. Over 50% of respondents saw an improvement in NR on the same day that treatment was started, and within 3 days 94.5% of respondents reported an improvement in NR. Of 1804 subjects who answered the question, 72.5% indicated that the NR had completely healed within 3 days of starting treatment and by the fifth day, 94.7% said that the NR had completely healed. A total of 71% of 1793 respondents said that an episode of NR had either no or minimal impact disrupting their normal lives, but 29% reported a noticeable impact, even though evidence suggests that mild to moderate nappy rash can be treated quickly. Based on this real-world retrospective study, the evidence suggests SAHC is rapidly effective, reduces signs and symptoms of inflammation, and heals NR. PMID- 27126753 TI - Managing pressure ulcers and moisture lesions with new hydrocolloid technology. AB - In efforts to reduce the number of avoidable pressure ulcers in a large trust, a number of initiatives have taken place to increase staff awareness about the importance of preventing and treating pressure ulcers and moisture lesions. New documentation, the use of the 'Think Pink' folders and a social media campaign have all proved successful in seeing the number of avoidable pressure ulcers reported within the trust reduce. As part of this initiative an evaluation took place of a new hydrocolloid dressing. This proved effective at reducing healing times, reducing dressing spend and facilitating regular inspection of the affected areas. PMID- 27126755 TI - Will nursing shortages threaten the integrity and functioning of the NHS? PMID- 27126754 TI - The role of nurses and dietitians in managing paediatric coeliac disease. AB - Coeliac disease (CD) is an immune-mediated genetic condition elicited by the ingestion of gluten, leading to proximal small bowel enteropathy. It affects around 1% of the population, although only a small proportion of cases are actually diagnosed. It is a multisystem disorder presenting with both gastrointestinal and extra-intestinal manifestations such as diarrhoea, abdominal pain, constipation, vomiting, iron deficiency anaemia, faltering growth, dental enamel defects, short stature, liver disease, arthropathy and recurrent aphthous ulcers. Nurses, working in different clinical settings, are best placed for early recognition and diagnosis of CD in children. Suspicion of CD should lead to immunoglobulin A (IgA)-based anti-tissue transglutaminase antibody screening tests and a diagnosis confirmed by an intestinal biopsy. Modification of European (ESPGHAN) guidelines now enables CD to be diagnosed without a small-bowel biopsy in a select group of symptomatic children. A gluten-free diet should preferably be started by paediatric dietitians. Strict adherence to a gluten-free diet is essential to maintain good health and to prevent long-term complications. A case study demonstrating some of the challenges that may be faced in children with CD in clinical practice is described. Specialist nurse-led CD clinics are gaining popularity and have been found to be equally effective in providing continuity of quality care. PMID- 27126756 TI - Patient safety perspectives from other countries: reflecting on reporting. PMID- 27126757 TI - Dementia care in hospitals: interprofessional education. PMID- 27126758 TI - Reporting from ward to board. PMID- 27126759 TI - Indications for peripheral, midline and central catheters: summary of the MAGIC recommendations. AB - Patients admitted to acute care frequently require intravenous access to effectively deliver medications and prescribed treatment. For patients with difficult intravenous access, those requiring multiple attempts, those who are obese, or have diabetes or other chronic conditions, determining the vascular access device (VAD) with the lowest risk that best meets the needs of the treatment plan can be confusing. Selection of a VAD should be based on specific indications for that device. In the clinical setting, requests for central venous access devices are frequently precipitated simply by failure to establish peripheral access. Selection of the most appropriate VAD is necessary to avoid the potentially serious complications of infection and/or thrombosis. An international panel of experts convened to establish a guide for indications and appropriate usage for VADs. This publication summarises the work and recommendations of the panel for the Michigan Appropriateness Guide for Intravenous Catheters (MAGIC). PMID- 27126760 TI - Port protectors in clinical practice: an audit. AB - This article discusses the effect on compliance and incidence of vascular access device (VAD)-related bacteraemia following the introduction of a passive disinfection device (Curos(r)) for 6 months in four areas at one hospital trust. The hospital's infection prevention and control team replaced the 'active' disinfection using a disinfection wipe with 'scrub the hub'. Disinfection wipes used for needle-free devices were removed from all four trial areas and Curos was incorporated into the aseptic non-touch technique (ANTT((r))) protocols for the trial wards. Staff training was provided before and during the study, and audits of staff compliance with Curos placement were undertaken monthly. A benchmarking audit of 'scrub the hub' techniques was conducted 1 month before audit began. The results of the audit showed VAD-related bacteraemia rates reduced by 69% from 26 cases (confirmed through review of blood culture laboratory data and source identified by consultant microbiologists) before the study, to 8 when staff compliance with Curos placement onto VADs was 80% or more. PMID- 27126761 TI - Consider the patient's voice. PMID- 27126762 TI - The importance of adequate CVC securement to prevent infection. PMID- 27126763 TI - Proactive PICC placement: evaluating the patient experience. AB - AIM: to evaluate patient experience following the proactive placement of a peripherally inserted central catheter (PICC). METHOD: all patients with a PICC in situ who had attended the chemotherapy day unit over a period of 15 weeks were invited to complete a self-administered questionnaire. Questions related to: information giving, the degree of pain on insertion and any complications experienced by the patient while the device was in situ. There was also space to allow for free-text comments after each question. RESULTS: the majority of patients felt they received enough information and that the procedure was fully explained. Pain on insertion was largely reported as being minimal, with the few patients who did report the procedure as painful also reporting there being difficulty with the insertion. Complication rates were low, the main complication reported was mechanical owing to difficulty with blood withdrawal. CONCLUSION: irrespective of how uncomfortable the patient found the procedure, the majority of patients would recommend proactive PICC insertion to other patients as 'it made the whole process much easier'. PMID- 27126764 TI - Contribution of dermal-derived mesenchymal cells during liver repair in two different experimental models. AB - Progressive liver disease is a major health issue for which no effective treatment is available, leading to cirrhosis and orthotopic liver transplantation. However, the lack of availability of donor organs and other adverse factors including rejection limit its extensive clinical application. Cell-based therapy using mesenchymal stem/stromal cells (MSCs) may represent an attractive therapeutic option. Dermal-derived mesenchymal cells (DMCs) are attractive as one of the abundant sources from which to isolate mesenchymal cells for therapeutic applications and can be easily accessed with minimal harm to the donor. In this study, we used two different animal models to investigate potential therapeutic effect of DMCs transplantation in liver injury. We found that DMCs administration alleviated liver fibrosis and restored the liver function in fibrotic mice induced by CCl4. Furthermore, in an acute irradiation induced damage model, a unique population of DMCs could engraft into the liver tissue for a long period, exhibiting the phenotype of both mesenchymal cells and macrophage cells, and improve the survival of mice exposed to 8 Gy lethally total body irradiation. These discoveries provide important evidence that DMCs therapy has a beneficial effect on liver injury, and provide new insight into liver injury therapy depending on the alternative cells. PMID- 27126766 TI - [Living donor liver transplantation for the treatment complicated hepatic cystic echinococcosis: first case report from China]. AB - OBJECTIVE: To report the first clinical experience of living donor liver transplantation(LDLT) in patient with complicated hepatic cystic echinococcosis in China. METHODS: First Affiliated Hospital of Xinjiang Medical University successfully implemented LDLT in the treatment of one patient with complicated hepatic cystic echinococcosis after four times liver surgery and secondary congestive cirrhosis on May 9, 2015. The clinical data of the patient has been retrospectively analyzed. RESULTS: LDLT procedure was successfully performed in a patient with four previous liver intervention due to his recurrence. The patient was lack of right lobe, while with significant hypertrophy in left lobe. The reoccurred lesion compressed the retrohepatic vena cava, left hepatic vein, portal vein, that led to the stricture of retrohepatic vena cava, left hepatic vein orifice. The phlebography displayed remarkable stricture in retrohepatic vena cava and rich collateral circulation by which the venous blood flow back to the right atrium via paravertebral vein. The orifice of left hepatic vein shaped as hair-like so that the stenting was impossibly. After the multi-disciplinary team discussion, the liver transplantation was proposed, while the autotransplantation was considered as first line option, and with the backup of living related donor. The laparotomy showed the hugely enlarged liver with nodular changes. The frozen section was tested twice and showed as spotty necrosis with pseudo-lobe formation. Although the enlarged left lobe about 2 000 g weight, the liver colored as grey with cotton-like texture, the plan for autotransplantation was abandoned regarding the high risk for post-operative liver failure. Therefore, LDLT was performed. The donor was her brother who donated right lobe with 685 g weight. The operation time was 1 005 min with anhepatic time 335 min. Total of 12 units red blood cell suspension was transfused. The coagulating function was back to normal in 3 days after operation. The patient was discharged at 30 days after operation, while the routine blood test and biochemical markers had back to normal levels. The patient had taken tacrolimus and methylprednisolone with normal life. The liver functions of transplanted liver were normal in 90 days after surgery. The patient was able to self-activity and regular outpatient follow-up. CONCLUSION: Hepatic CE is an infectious disease, and liver transplantation could be the last choice for complicated case, especially in combination with severe complications, like Budd Chiari syndrome. PMID- 27126765 TI - 'Crisis' and 'everyday' initiators: A qualitative study of coercion and agency in the context of methadone maintenance treatment initiation. AB - INTRODUCTION AND AIMS: Patient attrition is common among people enrolled in methadone maintenance treatment (MMT) programs and most pronounced during the first year of treatment. However, the experiences of patients initiating MMT have been overlooked in the literature. This study explores experiences of MMT initiation among MMT patients, focusing on contextual influences on MMT initiation and perceptions of MMT and their subsequent influence on treatment retention. DESIGN AND METHODS: Semi-structured qualitative interviews were conducted with 39 MMT patients in Vancouver, Canada. Individuals reporting enrolment in MMT were recruited from within two ongoing cohort studies comprised of people who use drugs. Interview transcripts were analysed using an inductive and iterative approach. RESULTS: Two groups of MMT initiators were identified: (i) 'crisis initiators' prescribed methadone following critical transition events, such as incarceration or pregnancy; and (ii) 'everyday initiators' enrolled in MMT as part of routine healthcare utilisation. While most 'crisis initiators' and some 'everyday initiators' described experiencing coercion during MMT initiation, 'crisis initiators' were further subjected to the coercive leveraging of their vulnerability to motivate 'consent' for MMT. 'Crisis initiators' developed negative views towards MMT and were more likely to discontinue treatment. Long-standing patient-provider relationships and open dialogue were associated with more positive views regarding MMT, regardless of the circumstances of initiation. DISCUSSION AND CONCLUSION: Findings underscore the need for clear and effective communication regarding treatment regimens and expectations during MMT initiation. Furthermore, training in trauma-informed care may help reduce perceptions of coercion and rates of early treatment termination. [Damon W, Small W, Anderson S, Maher L, Wood E, Kerr T, McNeil R. Crisis' and 'everyday' initiators: A qualitative study of coercion and agency in the context of methadone maintenance treatment initiation. Drug Alcohol Rev 2017;36:253-260]. PMID- 27126767 TI - Long-term functional outcome after traumatic lumbosacral dissociation. A retrospective case series of 13 patients. AB - STUDY DESIGN: Retrospective case series. INTRODUCTION: Traumatic lumbosacral dissociation (TLSD) is a rare subgroup of sacral fractures caused by high-energy trauma in healthy adults. There are no accepted treatment algorithms for these injuries. Neurologic deficits and pain are commonly associated with these injuries, however, little is known about the long-term functional outcome in patients with TLSD. The objective of this study was to assess long-term functional outcome in patients with traumatic lumbosacral dissociation (TLSD) injuries. MATERIALS AND METHODS: Thirteen patients with TLSD were retrospectively identified and followed with clinical and radiological examination mean 7.7 (3 12) years after the injury. Five were treated operatively, and eight non operatively. Sensorimotor impairments in the lower extremities were classified according to ASIA. Urinary function was assessed with uroflowmetry, and bowel- and sexual functions were assessed using a structured interview. Pain was assessed using a visual analogue scale (VAS), and patient-reported health with SF 36. CT images were scrutinized for non-union and kyphotic angulation across the fracture. RESULTS: Eleven patients had neurologic deficits corresponding to L5 and sacral roots. Urinary dysfunction was observed in nine, and bowel dysfunction in three patients. Eight patients reported problems associated with sexual activities, with pain during intercourse and erectile dysfunction being the most common problems. Twelve patients reported pain in the lumbosacral area, in combination with radiating pain in the majority. The overall patient-reported health (SF-36) was significantly lower than the normal population. All sacral fractures were united as seen on CT. Sacral kyphotic angulation was present in 11, which had increased in three patients comparing with the initial radiographs. CONCLUSION: In this long-term follow-up, functional impairments, pain, and poor patient-reported health were common findings among patients with TLSD. High rates of neurologic, urinary and sexual dysfunctions were reported. Extended follow-up several years after the injury with a special focus on urogenital dysfunctions and pain management may be beneficial to these patients. PMID- 27126768 TI - Zone 2 sacral fractures managed with partially-threaded screws result in low risk of neurologic injury. AB - BACKGROUND: Zone 2 sacral fractures account for 34% of sacral fractures with reported neurological deficit in 21-28% of patients. The purpose of this study was to examine the risk factors for neurological injury in zone 2 sacral fractures. The authors hypothesized that partially thread iliosacral screws did not increase incidence of neurologic injury. METHODS: A retrospective review of consecutive patients admitted to a level 1 trauma center with zone 2 sacral fractures requiring surgery from September 2010 to September 2014 was performed. Patients were excluded if no neurologic exam was available after surgery. Fractures were classified according to Denis and presence/absence of comminution through the neural foramen was noted. Fixation schema was recorded (sacral screws or open reduction and internal fixation with posterior tension plate). Any change in post-operative neurological exam was documented as well as exam at last clinic encounter. RESULTS: 90 patients met inclusion criteria, with zone 2 fractures and post-operative neurological exam. No patient with an intact pre-operative neurologic exam had a neurological deficit after surgery. 86 patients (95.6%) were neurologically intact at their last follow-up examination. Four patients (4.4%) had a neurological deficit at final follow-up, all of them had neurological deficit prior to surgery. 81 patients were treated with partially threaded screws of which 1 (1.2%) had neurological deficit at final follow-up. Fifty-seven fractures (63.3%) were simple fractures and 33 fractures (36.7%) were comminuted. All four patients with neurological deficit had comminuted fractures. The association between neurologic deficit in zone 2 sacral fracture and fracture comminution was found to be statistically significant (p-value=0.016). No nonunion was observed in this cohort. CONCLUSIONS: The use of partially threaded screws for zone 2 sacral fractures is associated with low risk for neurologic injury, suggesting that compression through the fracture does not cause iatrogenic nerve damage. The low rate of sacral nonunion can be attributed to compression induced by the use of partially threaded compression screws. There is a strong association between zone 2 comminution and neurologic injury. PMID- 27126769 TI - Cutaneous mucormycosis secondary to penetrative trauma. AB - INTRODUCTION: Mucormycosis is a rare but serious sequelae of penetrating trauma [1-5]. In spite of aggressive management, mortality remains high due to dissemination of infection. We completed a review of literature to determine the most optimal treatment of cutaneous mucormycosis which occurs secondary to penetrating trauma. METHODS: We completed a review regarding the management of mucormycosis in trauma patients. We selected a total of 36 reports, of which 18 were case-based, for review. RESULTS: Surgical debridement is a primary predictor of improved outcomes in the treatment of mucormycosis [3,6,7]. Anti-fungal therapy, especially lipid soluble formulation of Amphotericin B, is helpful as an adjunct or when surgical debridement has been maximally achieved. Further research is needed to fully evaluate the impact of topical dressings; negative pressure wound therapy is helpful. CONCLUSION: An aggressive and early surgical approach, even at the expense of disfigurement, is necessary to reduce mortality in the setting of cutaneous mucormycosis that results from penetrating trauma [4,8,9]. Anti-fungal therapy and negative pressure wound therapy are formidable adjuncts. PMID- 27126770 TI - Evaluation of Criteria to Detect Masked Hypertension. AB - The prevalence of masked hypertension (out-of-clinic daytime systolic/diastolic blood pressure (SBP/DBP) >=135/85 mm Hg on ambulatory blood pressure monitoring [ABPM] among adults with clinic SBP/DBP <140/90 mm Hg) is high. It is unclear who should be screened for masked hypertension. The authors derived a clinic blood pressure (CBP) index to identify populations for masked hypertension screening. Index cut points corresponding to 75% to 99% sensitivity and prehypertension were evaluated as ABPM testing criterion. In a derivation cohort (n=695), the index was clinic SBP+1.3*clinic DBP. In an external validation cohort (n=675), the sensitivity for masked hypertension using an index >=190 mm Hg and >=217 mm Hg and prehypertension status was 98.5%, 71.5%, and 82.5%, respectively. Using National Health and Nutrition Examination Survey data (n=11,778), the authors estimated that these thresholds would refer 118.6, 44.4, and 59.3 million US adults, respectively, to ABPM screening for masked hypertension. In conclusion, the CBP index provides a useful approach to identify candidates for masked hypertension screening using ABPM. PMID- 27126771 TI - Relationship between weight loss and parameters of skeletal muscle function in patients with advanced cancer and fatigue. AB - PURPOSE: This study aims to determine the influence of significant weight loss on parameters of skeletal muscle function in a population of advanced cancer patients with fatigue. METHODS: A cross-sectional and comparative study was designed between two arms of advanced cancer patients with fatigue (fatigue numeral scale (FNS) >=4). A arm (n = 27) with >=5 % weight loss in the last 6 months, and B arm (n = 22) without weight loss. Muscle strength was examined by hand grip technique and measurements of body composition by bioimpedance analysis (BIA), values of hemoglobin, albumin, lactic dehydrogenase (LDH), c-reactive protein (CRP), urine creatinine, and FNS. These variables were compared between both groups and correlated within each group. RESULTS: here were no differences concerning parameters of muscle strength between both arms. A arm had values of CRP >=10 ug/dl in 77 % compared with 38.5 % of B arm (p = 0.004). A arm showed a higher percentage of body cell mass (%BCM) than B arm (p = 0.005). The A arm also showed a lower percentage of fat mass (%FM) (p = 0.014) when compared to the B arm. FNS was higher in A arm (median 7 vs 5; p = 0.047). All the variables of muscle strength had a significant positive correlation. In A arm, BCM had a negative significant correlation with CRP (p = 0.021). CONCLUSIONS: In this study, significant weight loss and high CRP did not have influence on parameters of skeletal muscular function. We consider that further studies should be necessary, preferably with longitudinal designs to evaluate these findings. PMID- 27126772 TI - Health care experiences of long-term survivors of adolescent and young adult cancer. AB - PURPOSE: Evaluate health care access and experiences with care among long-term survivors of adolescent and young adult (AYA) cancer relative to a comparison group in the USA. METHODS: The 2008 to 2012 Medical Expenditure Panel Surveys identified 1163 survivors of cancer, diagnosed ages 15-39, current ages 20-64, who were at least 5 years after diagnosis. A comparison group without cancer was matched using age, sex, and other characteristics. Primary outcomes included having >=1 visit to doctor's office/clinic in the previous year and perceived health care quality (0 = worst to 10 = best; categorized as low (0-4), intermediate (5-7), and high (8-10)). Other experience-related outcomes (e.g., having adequate time with providers and providers show respect) were also evaluated. Bivariate analyses compared these outcomes between survivors and the comparison group. Multivariable logistic regressions identified survivor-level factors associated with health care visits and quality. RESULTS: Survivors had >=1 visit more often (82.1 vs. 75.8 %, p = 0.005) yet rated their health care quality lower (low or intermediate 30.7 vs. 23.6 %, p < 0.001) than the comparison group. Fewer survivors reported always having enough time with providers (41.7 vs. 54.6 %, p < 0.001) and that providers always show respect (57.5 vs. 67.7 %, p = 0.002). Uninsured survivors were less likely to have >=1 visit (odds ratio (OR) = 0.26, 95 % confidence interval (CI) 0.17-0.40, p < 0.001) and rated their health care quality lower (OR = 0.25, 95 % CI 0.13-0.48, p < 0.001) than privately insured. Many other factors were associated with visits and quality. CONCLUSION: Survivors of AYA cancer reported more health care visits but worse health care experiences than individuals without cancer. Targeted interventions that may improve survivors' experiences with health care should be evaluated. PMID- 27126773 TI - Bacteriophages with potential to inactivate Salmonella Typhimurium: Use of single phage suspensions and phage cocktails. AB - The aim of this study was to compare the dynamics of three previously isolated bacteriophages (or phages) individually (phSE-1, phSE-2 and phSE-5) or combined in cocktails of two or three phages (phSE-1/phSE-2, phSE-1/phSE-5, phSE-2/phSE-5 and phSE-1/phSE-2/phSE-5) to control Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) in order to evaluate their potential application during depuration. Phages were assigned to the family Siphoviridae and revealed identical restriction digest profiles, although they showed a different phage adsorption, host range, burst size, explosion time and survival in seawater. The three phages were effective against S. Typhimurium (reduction of ~2.0 log CFU/mL after 4h treatment). The use of cocktails was not significantly more effective than the use of single phages. A big fraction of the remained bacteria are phage resistant mutants (frequency of phage-resistant mutants 9.19*10(-5)-5.11*10(-4)) but phage- resistant bacterial mutants was lower for the cocktail phages than for the single phage suspensions and the phage phSE-1 presented the highest rate of resistance and phage phSE-5 the lowest one. The spectral changes of S. Typhimurium resistant and phage-sensitive cells were compared and revealed relevant differences for peaks associated to amide I (1620cm(-1)) and amide II (1515cm(-1)) from proteins and from carbohydrates and phosphates region (1080 1000cm(-1)). Despite the similar efficiency of individual phages, the development of lower resistance indicates that phage cocktails might be the most promising choice to be used during the bivalve depuration to control the transmission of salmonellosis. PMID- 27126774 TI - Antiviral activity of luteolin against Japanese encephalitis virus. AB - Japanese encephalitis virus (JEV), a member of family Flaviviridae, is a neurotropic flavivirus that causes Japanese encephalitis (JE). JEV is one of the most important causative agents of viral encephalitis in humans, and this disease leads to high fatality rates. Although effective vaccines are available, no effective antiviral therapy for JE has been developed. Hence, identifying effective antiviral agents against JEV infection is important. In this study, we found that luteolin was an antiviral bioflavonoid with potent antiviral activity against JEV replication in A549 cells with IC50=4.56MUg/mL. Luteolin also showed extracellular virucidal activity on JEV. With a time-of-drug addition assay revealing that JEV replication was inhibited by luteolin after the entry stage. Overall, our results suggested that luteolin can be used to develop an antiviral drug against JEV. PMID- 27126777 TI - Bioengineered vascular constructs as living models for in vitro cardiovascular research. AB - Cardiovascular diseases represent the most common cause of morbidity and mortality worldwide. In this review, we explore the potential of bioengineered vascular constructs as living models for in vitro cardiovascular research to advance the current knowledge of pathophysiological processes and support the development of clinical therapies. Bioengineered vascular constructs capable of recapitulating the cellular and mechanical environment of native vessels represent a valuable platform to study cellular interactions and signaling cascades, test drugs and medical devices under (patho)physiological conditions, with the additional potential benefit of reducing the number of animals required for preclinical testing. PMID- 27126776 TI - Two- and Three-Dimensional All-Carbon Nanomaterial Assemblies for Tissue Engineering and Regenerative Medicine. AB - Carbon nanomaterials such as carbon nanotubes and graphene have gained significant interest in the fields of materials science, electronics and biomedicine due to their interesting physiochemical properties. Typically these carbon nanomaterials have been dispersed in polymeric matrices at low concentrations to improve the functional properties of nanocomposites employed as two-dimensional (2D) substrates or three-dimensional (3D) porous scaffolds for tissue engineering applications. There has been a growing interest in the assembly of these nanomaterials into 2D and 3D architectures without the use of polymeric matrices, surfactants or binders. In this article, we review recent advances in the development of 2D or 3D all-carbon assemblies using carbon nanotubes or graphene as nanoscale building-block biomaterials for tissue engineering and regenerative medicine applications. PMID- 27126778 TI - Current attempts to implement siRNA-based RNAi in leukemia models. AB - Leukemias arise from genetic alterations in normal hematopoietic stem or progenitor cells, leading to abnormal blood population with transformed cells. With the advent of RNAi and its pharmacological mediator siRNA, it has become possible to downregulate specific drivers causing leukemias. In this review, we present unique aspects of RNAi-mediated therapy and delivery technologies. Recent updates on molecular targets and delivery systems are discussed emanating from in vitro cell models and preclinical animal models. We conclude with a view on the future of RNAi in leukemia therapy, emphasizing possible measures to achieve higher efficacy and improved safety. PMID- 27126779 TI - Design and use questionnaires for research in medical education. PMID- 27126780 TI - Understanding the systemic nature of cities to improve health and climate change mitigation. AB - Understanding cities comprehensively as systems is a costly challenge and is typically not feasible for policy makers. Nevertheless, focusing on some key systemic characteristics of cities can give useful insights for policy to advance health and well-being outcomes. Moreover, if we take a coevolutionary systems view of cities, some conventional assumptions about the nature of urban development (e.g. the growth in private vehicle use with income) may not stand up. We illustrate this by examining the coevolution of urban transport and land use systems, and institutional change, giving examples of policy implications. At a high level, our concern derives from the need to better understand the dynamics of urban change, and its implications for health and well-being. At a practical level, we see opportunities to use stylised findings about urban systems to underpin policy experiments. While it is now not uncommon to view cities as systems, policy makers appear to have made little use so far of a systems approach to inform choice of policies with consequences for health and well being. System insights can be applied to intelligently anticipate change - for example, as cities are subjected to increasing natural system reactions to climate change, they must find ways to mitigate and adapt to it. Secondly, systems insights around policy cobenefits are vital for better informing horizontal policy integration. Lastly, an implication of system complexity is that rather than seeking detailed, 'full' knowledge about urban issues and policies, cities would be well advised to engage in policy experimentation to address increasingly urgent health and climate change issues. PMID- 27126775 TI - 3D Bioprinting for Tissue and Organ Fabrication. AB - The field of regenerative medicine has progressed tremendously over the past few decades in its ability to fabricate functional tissue substitutes. Conventional approaches based on scaffolding and microengineering are limited in their capacity of producing tissue constructs with precise biomimetic properties. Three dimensional (3D) bioprinting technology, on the other hand, promises to bridge the divergence between artificially engineered tissue constructs and native tissues. In a sense, 3D bioprinting offers unprecedented versatility to co deliver cells and biomaterials with precise control over their compositions, spatial distributions, and architectural accuracy, therefore achieving detailed or even personalized recapitulation of the fine shape, structure, and architecture of target tissues and organs. Here we briefly describe recent progresses of 3D bioprinting technology and associated bioinks suitable for the printing process. We then focus on the applications of this technology in fabrication of biomimetic constructs of several representative tissues and organs, including blood vessel, heart, liver, and cartilage. We finally conclude with future challenges in 3D bioprinting as well as potential solutions for further development. PMID- 27126781 TI - Using GRADE to respond to health questions with different levels of urgency. AB - Increasing interest exists in applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to environmental health evidence. While ideally applied to evidence synthesized in systematic reviews and corresponding summary tables, such as evidence profiles, GRADE's correct application requires that "the evidence that was assessed and the methods that were used to identify and appraise that evidence should be clearly described." In this article, we suggest that GRADE could be applied to evidence assembled from narrative reviews, modelled (indirect) evidence, or evidence assembled as part of a rapid response, if the underlying judgments about the certainty in this evidence are based on the relevant GRADE domains and provided transparently. Health questions that require assessing the certainty in a body of evidence to provide trustworthy answers may range from hours, to days or weeks, to a few months to scenarios that allow assessing evidence without short-term time pressures. Time frames of emergent, urgent or rapid evidence assessments will often require relying on existing summaries or rapidly compiling the available evidence and making assessments. Even without available full systematic reviews, expressing the certainty in the evidence can provide useful guidance for users of the evidence and those who evaluate certainty in effects. The ratings also help clarifying disagreement between organizations tackling similar questions about the evidence. Using the structured GRADE domains, narrative or other summaries of the evidence can be presented transparently. PMID- 27126783 TI - Transcriptomic plasticity in brown adipose tissue contributes to an enhanced capacity for nonshivering thermogenesis in deer mice. AB - For small mammals living at high altitude, aerobic heat generation (thermogenesis) is essential for survival during prolonged periods of cold, but is severely impaired under conditions of hypobaric hypoxia. Recent studies in deer mice (Peromyscus maniculatus) reveal adaptive enhancement of thermogenesis in high- compared to low-altitude populations under hypoxic cold stress, an enhancement that is attributable to modifications in the aerobic metabolism of muscles used in shivering. However, because small mammals rely heavily on nonshivering mechanisms for cold acclimatization, we tested for evidence of adaptive divergence in nonshivering thermogenesis (NST) under hypoxia. To do so, we measured NST and characterized transcriptional profiles of brown adipose tissue (BAT) in high- and low-altitude deer mice that were (i) wild-caught and acclimatized to their native altitude, and (ii) born and reared under common garden conditions at low elevation. We found that NST performance under hypoxia is enhanced in wild-caught, high-altitude deer mice, a difference that is associated with increased expression of coregulated genes that influence several physiological traits. These traits include vascularization and O2 supply to BAT, brown adipocyte proliferation and the uncoupling of oxidative phosphorylation from ATP synthesis in the generation of heat. Our results suggest that acclimatization to hypoxic cold stress is facilitated by enhancement of nonshivering heat production, which is driven by regulatory plasticity in a suite of genes that influence intersecting physiological pathways. PMID- 27126782 TI - Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch. AB - MMP11 overexpression is a bad prognostic factor in various human carcinomas. Interestingly, this proteinase is not expressed in malignant cells themselves but is secreted by adjacent non-malignant mesenchymal/stromal cells, such as cancer associated fibroblasts (CAFs) and adipocytes (CAAs), which favors cancer cell survival and progression. As MMP11 negatively regulates adipogenesis in vitro, we hypothesized that it may play a role in whole body metabolism and energy homeostasis. We used an in vivo gain- (Mmp11-Tg mice) and loss- (Mmp11-/- mice) of-function approach to address the systemic function of MMP11. Strikingly, MMP11 overexpression protects against type 2 diabetes while Mmp11-/- mice exhibit hallmarks of metabolic syndrome. Moreover, Mmp11-Tg mice were protected from diet induced obesity and display mitochondrial dysfunction, due to oxidative stress, and metabolic switch from oxidative phosphorylation to aerobic glycolysis. This Warburg-like effect observed in adipose tissues might provide a rationale for the deleterious impact of CAA-secreted MMP11, favouring tumor progression. MMP11 overexpression also leads to increased circulating IGF1 levels and the activation of the IGF1/AKT/FOXO1 cascade, an important metabolic signalling pathway. Our data reveal a major role for MMP11 in controlling energy metabolism, and provide new clues for understanding the relationship between metabolism, cancer progression and patient outcome. PMID- 27126784 TI - Lack of tumor necrosis factor alpha gene polymorphism -857c/t (rs1799724) association in Pakistani rheumatoid arthritis patients. AB - BACKGROUND: Rheumatoid arthritis (RA) is a common systemic autoimmune disease, influenced greatly by the pro-inflammatory cytokine tumor necrosis factor- alpha (TNF-alpha). Single nucleotide polymorphisms (SNPs) in regulatory regions of the TNF-alpha gene play a significant role in disease development and pathogenesis. The aim of this study was to investigate the association of TNF-alpha -857C/T (rs1799724) SNP with RA activity or severity in our Pakistani study group. METHODS: The study included 134 (116 women, 18 men) patients with RA and 134 ethnically matched healthy controls (108 women, 26 men). Each patient's disease activity was measured by Disease Activity Score of 28 joints. The genotypes were determined in all included individuals following allele-specific polymerase chain reaction along with the prerequisite internal amplification controls. Statistical analysis including chi-square/Fischer exact test and one-way analysis of variance; nonparametric Kruskal-Wallis test was employed using Graphpad Prism 6 software for association study. RESULTS: The prevalence of TNF-alpha -857C/T (rs1799724) polymorphism was not differentially distributed between RA patients and controls in either allele frequency, with odds ratio (95% CI) of 0.9661 (0.6714-1.390) and P-value of 0.8527, or genotype frequency with chi2 of 0.5015 and P-value of 0.7782. Moreover, no correlation was found when genotype frequency distribution was analyzed with disease severity (P = 0.6321 and Kruskal-Wallis statistics of 1.098). CONCLUSION: The study demonstrated -857C/T (rs1799724) polymorphism may not have influenced RA susceptibility in our study group. However, investigations of genetic variability influence on disease outcome in large prospective cohorts are required, so the complicated interconnection of genetic and environmental elements can be emulated for better understanding. PMID- 27126785 TI - Application-Dedicated Selection of Filters (ADSF) using covariance maximization and orthogonal projection. AB - Visible and near-infrared (Vis-NIR) spectra are generated by the combination of numerous low resolution features. Spectral variables are thus highly correlated, which can cause problems for selecting the most appropriate ones for a given application. Some decomposition bases such as Fourier or wavelet generally help highlighting spectral features that are important, but are by nature constraint to have both positive and negative components. Thus, in addition to complicating the selected features interpretability, it impedes their use for application dedicated sensors. In this paper we have proposed a new method for feature selection: Application-Dedicated Selection of Filters (ADSF). This method relaxes the shape constraint by enabling the selection of any type of user defined custom features. By considering only relevant features, based on the underlying nature of the data, high regularization of the final model can be obtained, even in the small sample size context often encountered in spectroscopic applications. For larger scale deployment of application-dedicated sensors, these predefined feature constraints can lead to application specific optical filters, e.g., lowpass, highpass, bandpass or bandstop filters with positive only coefficients. In a similar fashion to Partial Least Squares, ADSF successively selects features using covariance maximization and deflates their influences using orthogonal projection in order to optimally tune the selection to the data with limited redundancy. ADSF is well suited for spectroscopic data as it can deal with large numbers of highly correlated variables in supervised learning, even with many correlated responses. PMID- 27126786 TI - Glycan characterization of biopharmaceuticals: Updates and perspectives. AB - Therapeutic proteins are rapidly becoming the most promising class of pharmaceuticals on the market due to their successful treatment of a vast array of serious diseases, such as cancers and immune disorders. Therapeutic proteins are produced using recombinant DNA technology. More than 60% of therapeutic proteins are posttranslationally modified following biosynthesis by the addition of N- or O-linked glycans. Glycosylation is the most common posttranslational modifications of proteins. However, it is also the most demanding and complex posttranslational modification from the analytical point of view. Moreover, research has shown that glycosylation significantly impacts stability, half-life, mechanism of action and safety of a therapeutic protein. Considering the exponential growth of biotherapeutics, this present review of the literature (2009-2015) focuses on the characterization of protein glycosylation, which has witnessed an improvement in methodology. Furthermore, it discusses current issues in the fields of production and characterization of therapeutic proteins. This review also highlights the problem of non-standard requirements for the approval of biosimilars with regard to their glycosylation and discusses recent developments and perspectives for improved glycan characterization. PMID- 27126787 TI - Fusion strategies for selecting multiple tuning parameters for multivariate calibration and other penalty based processes: A model updating application for pharmaceutical analysis. AB - New multivariate calibration methods and other processes are being developed that require selection of multiple tuning parameter (penalty) values to form the final model. With one or more tuning parameters, using only one measure of model quality to select final tuning parameter values is not sufficient. Optimization of several model quality measures is challenging. Thus, three fusion ranking methods are investigated for simultaneous assessment of multiple measures of model quality for selecting tuning parameter values. One is a supervised learning fusion rule named sum of ranking differences (SRD). The other two are non supervised learning processes based on the sum and median operations. The effect of the number of models evaluated on the three fusion rules are also evaluated using three procedures. One procedure uses all models from all possible combinations of the tuning parameters. To reduce the number of models evaluated, an iterative process (only applicable to SRD) is applied and thresholding a model quality measure before applying the fusion rules is also used. A near infrared pharmaceutical data set requiring model updating is used to evaluate the three fusion rules. In this case, calibration of the primary conditions is for the active pharmaceutical ingredient (API) of tablets produced in a laboratory. The secondary conditions for calibration updating is for tablets produced in the full batch setting. Two model updating processes requiring selection of two unique tuning parameter values are studied. One is based on Tikhonov regularization (TR) and the other is a variation of partial least squares (PLS). The three fusion methods are shown to provide equivalent and acceptable results allowing automatic selection of the tuning parameter values. Best tuning parameter values are selected when model quality measures used with the fusion rules are for the small secondary sample set used to form the updated models. In this model updating situation, evaluation of all possible models, thresholding, and iterative SRD performed equivalently for the three fusion rules with TR and PLS performed worse. While the application is model updating, the fusion processes are applicable to other situations requiring selection of multiple tuning parameter values. PMID- 27126788 TI - Quantitative generalized ratiometric fluorescence spectroscopy for turbid media based on probe encapsulated by biologically localized embedding. AB - PEBBLE (probe encapsulated by biologically localized embedding) nanosensor encapsulating an intensity-based fluorescence indicator and an inert reference fluorescence dye inside the pores of stable matrix can be used as a generalized wavelength-ratiometric probe. However, the lack of an efficient quantitative model render the choices of inert reference dyes and intensity-based fluorescence indicators used in PEBBLEs based generalized wavelength-ratiometric probes rather limited. In this contribution, an extended quantitative fluorescence model was derived specifically for generalized wavelength-ratiometric probes based on PEBBLE technique (QFMGRP) with a view to simplify the design of PEBBLEs and hence further extend their application potentials. The effectiveness of QFMGRP has been tested on the quantitative determination of free Ca(2+) in both simulated and real turbid media using a Ca(2+) sensitive PEBBLE nanosensor encapsulating Rhod-2 and eosin B inside the micropores of stable polyacrylamide matrix. Experimental results demonstrated that QFMGRP could realize precise and accurate quantification of free Ca(2+) in turbid samples, even though there is serious overlapping between the fluorescence excitation peaks of eosin B and Ca(2+) bound Rhod-2. The average relative predictive error value of QFMGRP for the test simulated turbid samples was 5.9%, about 2-4 times lower than the corresponding values of partial least squares calibration model and the empirical ratiometric model based on the ratio of fluorescence intensities at the excitation peaks of Ca(2+) bound Rhod-2 and eosin B. The recovery rates of QFMGRP for the real and spiked turbid samples varied from 93.1% to 101%, comparable to the corresponding results of atomic absorption spectrometry. PMID- 27126789 TI - Simultaneous quantitative profiling of 20 isoprostanoids from omega-3 and omega-6 polyunsaturated fatty acids by LC-MS/MS in various biological samples. AB - Isoprostanoids are a group of non-enzymatic oxygenated metabolites of polyunsaturated fatty acids. It belongs to oxylipins group, which are important lipid mediators in biological processes, such as tissue repair, blood clotting, blood vessel permeability, inflammation and immunity regulation. Recently, isoprostanoids from eicosapentaenoic, docosahexaenoic, adrenic and alpha linolenic namely F3-isoprostanes, F4-neuroprostanes, F2-dihomo-isoprostanes and F1-phytoprostanes, respectively have attracted attention because of their putative contribution to health. Since isoprostanoids are derived from different substrate of PUFAs and can have similar or opposing biological consequences, a total isoprostanoids profile is essential to understand the overall effect in the testing model. However, the concentration of most isoprostanoids range from picogram to nanogram, therefore a sensitive method to quantify 20 isoprostanoids simultaneously was formulated and measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The lipid portion from various biological samples was extracted prior to LC-MS/MS evaluation. For all the isoprostanoids LOD and LOQ, and the method was validated on plasma samples for matrix effect, yield of extraction and reproducibility were determined. The methodology was further tested for the isoprostanoids profiles in brain and liver of LDLR(-/-) mice with and without docosahexaenoic acid (DHA) supplementation. Our analysis showed similar levels of total F2-isoprostanes and F4-neuroprostanes in the liver and brain of non-supplemented LDLR(-/-) mice. The distribution of different F2 isoprostane isomers varied between tissues but not for F4-neuroprostanes which were predominated by the 4(RS)-4-F4t-neuroprostane isomer. DHA supplementation to LDLR(-/-) mice concomitantly increased total F4-neuroprostanes levels compared to F2-isoprostanes but this effect was more pronounced in the liver than brain. PMID- 27126790 TI - Fluorescent turn-off/on bioassay for hemoglobin based on dual-emission carbon nanodots-graphene oxide system with multi-detection strategies. AB - As two members of the carbon materials family, carbon nanodots (CNDs) and graphene oxide (GO) possess many excellent optical properties resulting in a wide range of applications. In this work, the fluorescence of resultant dual-emission carbon nanodots (DECNDs) could be quenched by GO. In the presence of hemoglobin (Hb), the fluorescence would recover resulting from two interactions: one was the direct stacking effect of Hb on GO; the other one was that Hb could cover the surfaces of DECNDs; both of them would prevent the fluorescence quenching of DECNDs by GO. In the light of this mechanism, a novel fluorescent turn-off/on method has been developed for the detection of Hb based on DECNDs-GO system. By virtue of the dual emissions of these CNDs, it is noteworthy that both a single emission and ratiometric of dual emissions can be used to establish linear relationships of Hb: 0.05-300 nM (lambdaem = 386 nm), 5-500 nM (lambdaem = 530 nm), and 50-500 nM (I530/I410), with the corresponding limit of detection (LOD) as low as 20 pM, 2 nM and 20 nM, respectively. This present system is highly selective toward Hb over other proteins and this reliable method has been successfully applied for the detection of Hb in whole blood samples. PMID- 27126791 TI - Simultaneous forward and reverse ABO blood group typing using a paper-based device and barcode-like interpretation. AB - A new platform of a paper-based analytical device (PAD) for simultaneous forward and reverse ABO blood group typing has been reported. This platform can overcome the discrepancy results as influenced by the individual haematocrit. The test and the control of non-haemagglutination on each channel were performed in parallel. The PAD was fabricated by printing six parallel channels with wax onto Whatman No. 4 filter paper. An LF1 blood separation membrane was used for the separation of plasma from whole blood for reverse grouping. The blood group was identified by haemagglutination of the corresponding antigen-antibody. For forward grouping, Anti-A, -B and -A,B were treated on the test line of PAD, and inactivated Anti-A, -B and -A,B were immobilized on the control line. For reverse grouping, 30% standard A-cells, B- and O- were added to the test channel after plasma separation, and O-cells were used as a control. Then, 0.9% normal saline (NSS) containing 1% Tween-20 was bi-functionally used for dilution of the blood sample and elution of the non-agglutinated RBCs within the channels. The distance of agglutinated RBCs in each test line was compared with the distance of non agglutinated RBCs in the parallel control line. The forward and reverse patterns of blood groups A, B, AB and O were a barcode-like chart in which the results can be visually analysed. The PAD has excellent reproducibility when 10 replications of the A, B, AB or O blood groups were performed. The results of both forward and reverse grouping were highly correlated with conventional methods compared with the slide method and tube method, respectively (n = 76). Thus, this ABO typing PAD holds great potential for future applications in blood typing point-of-care testing. PMID- 27126792 TI - A ratiometric fluorescent probe based on boron dipyrromethene and rhodamine Forster resonance energy transfer platform for hypochlorous acid and its application in living cells. AB - We have developed a ratiometric fluorescent probe BRT based on boron dipyrromethene (BODIPY) and rhodamine-thiohydrazide Forster resonance energy transfer (FRET) platform for sensing hypochlorous acid (HOCl) with high selectivity and sensitivity. The probe can detect HOCl in 15 s with the detection limit of 38 nM. Upon mixing with HOCl the fluorescence colour of probe BRT changed from green to orange. Moreover, probe BRT was applied to successfully monitor HOCl in living RAW 264.7 cells. PMID- 27126793 TI - High-performance liquid chromatographic enantioseparation of cyclic beta aminohydroxamic acids on zwitterionic chiral stationary phases based on Cinchona alkaloids. AB - Cyclic beta-aminohydroxamic acid enantiomer pairs were stereoselectively separated by high-performance liquid chromatography on the recently developed Cinchona alkaloid-based zwitterionic chiral stationary phases Chiralpak ZWIX(+)TM, ZWIX(-)TM, ZWIX(+A) and ZWIX(-A). The results of variation of the applied chromatographic conditions, such as the bulk solvent composition, the concentrations and ratio of the acid and base additives, the presence of water as mobile phase additive and the counter-ion concentration furnished a better understanding of the retention mechanism. A thermodynamic study in the temperature range 5-50 degrees C revealed enthalpy-controlled enantiodiscrimination in all cases. The structure-selectivity relationships clearly indicated the importance of the strereochemistry of the functional groups. From an enantiorecognition aspect, the diexo position of the functional groups always proved more favorable than the diendo position. The elution sequence was determined in all cases and was found to reversed when ZWIX(+)TM was changed to ZWIX(-)TM or ZWIX(+A) to ZWIX(-A). PMID- 27126794 TI - Subepidermal moisture (SEM) and bioimpedance: a literature review of a novel method for early detection of pressure-induced tissue damage (pressure ulcers). AB - Current detection of pressure ulcers relies on visual and tactile changes at the skin surface, but physiological changes below the skin precede surface changes and have a significant impact on tissue health. Inflammatory and apoptotic/necrotic changes in the epidermal and dermal layers of the skin, such as changes in interstitial fluid (also known as subepidermal moisture (SEM)), may precede surface changes by 3-10 days. Those same epidermal and subepidermal changes result in changes in the electrical properties (bioimpedance) of the tissue, thereby presenting an objective, non-invasive method for assessing tissue damage. Clinical studies of bioimpedance for the detection of pressure ulcers have demonstrated that changes in bioimpedance correlate with increasing severity of pressure ulcer stages. Studies have also demonstrated that at anatomical locations with pressure ulcers, bioimpedance varies with distance from the centre of the pressure ulcers. The SEM Scanner, a handheld medical device, offers an objective and reliable method for the assessment of local bioimpedance, and therefore, assessment of tissue damage before signs become visible to the unaided eye. This literature review summarises pressure ulcer pathophysiology, principles of bioimpedance and clinical research using bioimpedance technology to assess pressure ulcers. PMID- 27126795 TI - Effects of down-regulating ornithine decarboxylase upon putrescine-associated metabolism and growth in Nicotiana tabacum L. AB - Transgenic plants of Nicotiana tabacum L. homozygous for an RNAi construct designed to silence ornithine decarboxylase (ODC) had significantly lower concentrations of nicotine and nornicotine, but significantly higher concentrations of anatabine, compared with vector-only controls. Silencing of ODC also led to significantly reduced concentrations of polyamines (putrescine, spermidine and spermine), tyramine and phenolamides (caffeoylputrescine and dicaffeoylspermidine) with concomitant increases in concentrations of amino acids ornithine, arginine, aspartate, glutamate and glutamine. Root transcript levels of S-adenosyl methionine decarboxylase, S-adenosyl methionine synthase and spermidine synthase (polyamine synthesis enzymes) were reduced compared with vector controls, whilst transcript levels of arginine decarboxylase (putrescine synthesis), putrescine methyltransferase (nicotine production) and multi-drug and toxic compound extrusion (alkaloid transport) proteins were elevated. In contrast, expression of two other key proteins required for alkaloid synthesis, quinolinic acid phosphoribosyltransferase (nicotinic acid production) and a PIP family oxidoreductase (nicotinic acid condensation reactions), were diminished in roots of odc-RNAi plants relative to vector-only controls. Transcriptional and biochemical differences associated with polyamine and alkaloid metabolism were exacerbated in odc-RNAi plants in response to different forms of shoot damage. In general, apex removal had a greater effect than leaf wounding alone, with a combination of these injury treatments producing synergistic responses in some cases. Reduced expression of ODC appeared to have negative effects upon plant growth and vigour with some leaves of odc-RNAi lines being brittle and bleached compared with vector-only controls. Together, results of this study demonstrate that ornithine decarboxylase has important roles in facilitating both primary and secondary metabolism in Nicotiana. PMID- 27126796 TI - Mitogen-activated protein kinase 4-like carrying an MEY motif instead of a TXY motif is involved in ozone tolerance and regulation of stomatal closure in tobacco. AB - The mitogen-activated protein kinases (MAPKs/MPKs) are important factors in the regulation of signal transduction in response to biotic and abiotic stresses. Previously, we characterized a MAPK from tobacco, Nicotiana tabacum MPK4 (NtMPK4). Here, we found a highly homologous gene, NtMPK4-like (NtMPK4L), in tobacco as well as other species in Solanaceae and Gramineae. Deduced amino acid sequences of their translation products carried MEY motifs instead of conserved TXY motifs of the MAPK family. We isolated the full length NtMPK4L gene and examined the physiological functions of NtMPK4L. We revealed that NtMPK4L was activated by wounding, like NtMPK4. However, a constitutively active salicylic acid-induced protein kinase kinase (SIPKK(EE)), which phosphorylates NtMPK4, did not phosphorylate NtMPK4L. Moreover, a tyrosine residue in the MEY motif was not involved in NtMPK4L activation. We also found that NtMPK4L-silenced plants showed rapid transpiration caused by remarkably open stomata. In addition, NtMPK4L silenced plants completely lost the ability to close stomata upon ozone treatment and were highly sensitive to ozone, suggesting that this atypical MAPK plays a role in ozone tolerance through stomatal regulation. PMID- 27126797 TI - [Intraoperative OCT in ophthalmic microsurgery]. AB - Recent improvements in technology have enabled integration of SD-OCT into the optical path of an operating microscope. Here we present an overview of possible applications of iOCT (intraoperative optical coherence tomography) for retinal, glaucoma and corneal surgery. iOCT-based imaging can not only improve safety and quality of the surgery but also the learning curve of the surgeon. The ability to visualize barely visible or transparent structures with iOCT has achieved a significant added value intraoperatively, particularly in macular surgery, trabeculectomy and lamellar keratoplasty. Further, systematic assessment is warranted to define the usefulness of the iOCT more precisely. PMID- 27126798 TI - Assertion Practices and Beliefs Among Nurses and Physicians on an Inpatient Pediatric Medical Unit. AB - BACKGROUND: Teamwork and communication are critical elements of safe and effective patient care. Standardized communication tools have been implemented in many health care organizations, but little is known about attitudes and perceptions of assertion, the willingness to "speak up," by nurses and physicians at an academic pediatric institution. METHODS: We conducted 6 focus groups with nurses, residents, and attending physicians using a standardized semistructured focus group guide to promote discussion. Focus groups were recorded and transcribed, and results were analyzed by 2 independent reviewers to identify thematic content. RESULTS: Three themes emerged: (1) interpersonal factors, (2) organizational factors, and (3) complexity of care environment. Subthemes were the roles of hierarchy, relationships, and communication and personality style; the value of using standardized communication tools such as SBAR (Situation, Background, Assessment, Recommendation), direct face-to-face communication, and geographic and technology factors; and the need for coordinated communication and agreement across care team members about the care plans. Nurses reported reliance on peers for decision-making, on when and how to assert on behalf of patient care. Nurses and residents experienced barriers to assertion from concerns of relationships and their position within professional hierarchies. Attending physicians were supportive of being asserted to by any care team provider. CONCLUSIONS: Interpersonal relationships, power dynamics, and organizational factors impact care team providers' willingness to assert in the inpatient setting. Standardized communication tools are effective. Further development and implementation of communication models that support experience, peer reliance, and direct face-to-face communication are warranted to improve assertion communication in the inpatient setting PMID- 27126799 TI - Supramolecular exo-functionalized palladium cages: fluorescent properties and biological activity. AB - Metallosupramolecular systems are promising new tools for pharmaceutical applications. Thus, novel self-assembled Pd(ii) coordination cages were synthesized which were exo-functionalized with naphthalene or anthracene groups with the aim to image their fate in cells. The cages were also investigated for their anticancer properties in human lung and ovarian cancer cell lines in vitro. While the observed cytotoxic effects hold promise and the cages resulted to be more effective than cisplatin in both cell lines, fluorescence emission properties were scarce. Therefore, using TD-DFT calculations, fluorescence quenching observed in the naphthalene-based system could be ascribed to a lower probability of a HOMO-LUMO excitation and an emission wavelength outside the visible region. Overall, the reported Pd2L4 cages provide new insights into the chemical-physical properties of this family of supramolecular coordination complexes whose understanding is necessary to achieve their applications in various fields. PMID- 27126800 TI - In vivo assembly of DNA-fragments in the moss, Physcomitrella patens. AB - Direct assembly of multiple linear DNA fragments via homologous recombination, a phenomenon known as in vivo assembly or transformation associated recombination, is used in biotechnology to assemble DNA constructs ranging in size from a few kilobases to full synthetic microbial genomes. It has also enabled the complete replacement of eukaryotic chromosomes with heterologous DNA. The moss Physcomitrella patens, a non-vascular and spore producing land plant (Bryophyte), has a well-established capacity for homologous recombination. Here, we demonstrate the in vivo assembly of multiple DNA fragments in P. patens with three examples of effective genome editing: we (i) efficiently deleted a genomic locus for diterpenoid metabolism yielding a biosynthetic knockout, (ii) introduced a salt inducible promoter, and (iii) re-routed endogenous metabolism into the formation of amorphadiene, a precursor of high-value therapeutics. These proof-of-principle experiments pave the way for more complex and increasingly flexible approaches for large-scale metabolic engineering in plant biotechnology. PMID- 27126801 TI - Effect of laser photobiomodulation on the periodontal repair process of replanted teeth. AB - BACKGROUND/AIM: Tooth replantation is the optimal treatment in cases of avulsion. However, its success is limited due to the occurrence of external root resorption. The aim of this study was to assess the effect of laser photobiomodulation (LPBM) at lambda808 nm and lambda660 nm and of storage media on the periodontal repair process of replanted teeth in rats. MATERIAL AND METHODS: Sixty maxillary right incisors were extracted from sixty Wistar rats and randomly assigned to six groups (n = 10). Groups consisted of 10 teeth stored in paper napkins (PN), whole milk (WM), and soy milk (SM), for 45 min; and PNL, WML and SML, in which teeth were stored in the same storage media, but the root surface and the alveolus were treated with LPBM at lambda808 nm before replantation, and the buccal and palatal mucosa of the alveolus were treated with LPBM at lambda660 nm after replantation. Five rats from each group were euthanized after 15 or 30 days. The right hemimaxilla including the replanted incisor was removed and processed for histomorphometric analysis to assess root resorption areas, replacement root resorption, perimeter with ankylosis and periodontal repair, and areas of type I and III collagen deposition, using the ImageJ 1.50b software. Data were analyzed statistically by anova followed by Tukey's multiple comparison test (alpha = 5%). RESULTS: WM and SM showed smaller root resorption areas and higher collagen deposition in both experimental periods, and SM showed the largest perimeter of periodontal repair. LPBM reduced the occurrence of root resorption only in the PNL group, both at 15 and 30 days, and increased the perimeter of periodontal repair in all groups at 30 days. There was higher collagen deposition in the irradiated groups regardless of the experimental period. CONCLUSIONS: The LPBM protocol at lambda808 nm and lambda660 nm as well as whole milk and soy milk favored the periodontal repair process of replanted teeth in rats. PMID- 27126802 TI - Mental models of a water management system in a green building. AB - This intergroup case study compared users' mental models with an expert design model of a water management system in a green building. The system incorporates a constructed wetland component and a rainwater collection pond that together recycle water for re-use in the building and its surroundings. The sample consisted of five building occupants and the cleaner (6 users) and two experts who were involved with the design of the water management system. Users' mental model descriptions and the experts' design model were derived from in-depth interviews combined with self-constructed (and verified) diagrams. Findings from the study suggest that there is considerable variability in the user mental models that could impact the efficient functioning of the water management system. Recommendations for improvements are discussed. PMID- 27126803 TI - Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice. AB - AIMS/HYPOTHESIS: Pre-adipocytes and adipocytes are responsive to the acute phase protein serum amyloid A (SAA). The combined effects triggered by SAA encompass an increase in pre-adipocyte proliferation, an induction of TNF-alpha and IL-6 release and a decrease in glucose uptake in mature adipocytes, strongly supporting a role for SAA in obesity and related comorbidities. This study addressed whether SAA depletion modulates weight gain and insulin resistance induced by a high-fat diet (HFD). METHODS: Male Swiss Webster mice were fed an HFD for 10 weeks under an SAA-targeted antisense oligonucleotide (ASOSAA) treatment in order to evaluate the role of SAA in weight gain. RESULTS: With ASOSAA treatment, mice receiving an HFD did not differ in energy intake when compared with their controls, but were prevented from gaining weight and developing insulin resistance. The phenotype was characterised by a lack of adipose tissue expansion, with low accumulation of epididymal, retroperitoneal and subcutaneous fat content and decreased inflammatory markers, such as SAA3 and toll-like receptor (TLR)-4 expression, as well as macrophage infiltration into the adipose tissue. Furthermore, a metabolic status similar to chow-fed mice counterparts could be observed, with equivalent levels of leptin, adiponectin, IGF-I, SAA, fasting glucose and insulin, and remarkable improvement in glucose and insulin tolerance test profiles. Surprisingly, the expected HFD-induced metabolic endotoxaemia was also prevented by the ASOSAA treatment. CONCLUSIONS/INTERPRETATION: This study provides further evidence of the role of SAA in weight gain and insulin resistance. Moreover, we also suggest that beyond its proliferative and inflammatory effects, SAA is part of the lipopolysaccharide signalling pathway that links inflammation to obesity and insulin resistance. PMID- 27126804 TI - Positively charged residues within the MYO19 MyMOMA domain are essential for proper localization of MYO19 to the mitochondrial outer membrane. AB - Myosins are well characterized molecular motors essential for intracellular transport. MYO19 copurifies with mitochondria, and can be released from mitochondrial membranes by high pH buffer, suggesting that positively-charged residues participate in interactions between MYO19 and mitochondria. The MYO19 specific mitochondria outer membrane association (MyMOMA) domain contains approximately 150 amino acids with a pI approximately 9 and is sufficient for localization to the mitochondrial outer membrane. The minimal sequence and specific residues involved in mitochondrial binding have not been identified. To address this, we generated GFP-MyMOMA truncations, establishing the boundaries for truncations based on sequence homology. We identified an 83-amino acid minimal binding region enriched with basic residues (pI ~ 10.5). We sequentially replaced basic residues in this region with alanine, identifying residues R882 and K883 as essential for mitochondrial localization. Constructs containing the RK882-883AA mutation primarily localized with the endoplasmic reticulum (ER). To determine if ER-associated mutant MyMOMA domain and mitochondria-associated wild type MyMOMA display differences in kinetics of membrane interaction, we paired FRAP analysis with permeabilization activated reduction in fluorescence (PARF) analysis. Mitochondria-bound and ER-bound MYO19 constructs displayed slow dissociation from their target membrane when assayed by PARF; both constructs displayed exchange within their respective organelle networks. However, ER-bound mutant MYO19 displayed more rapid exchange within the ER network than did mitochondria-bound MYO19. Taken together these data indicate that the MyMOMA domain contains strong membrane-binding activity, and membrane targeting is mediated by a specific, basic region of the MYO19 tail with slow dissociation kinetics appropriate for its role(s) in mitochondrial network dynamics. (c) 2016 Wiley Periodicals, Inc. PMID- 27126807 TI - Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association. AB - Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches. PMID- 27126809 TI - The 'triradiate bump': a novel radiographic sign that may confound assessment of acetabular retroversion. AB - PURPOSE: The triradiate cartilage transiently projects medially within the pelvic brim around the time of triradiate closure, mimicking the ischial spine sign. The purpose of this study was to characterize this newly identified radiographic sign using a longitudinal radiographic study. METHODS: We identified 72 subjects from a longitudinal radiographic study of healthy adolescents, each with at least four consecutive, annual anterior-posterior radiographs of the left hip, including physeal closure. Images were reviewed to identify the presence of the triradiate bump, the year it was most prominent, and the number of years relative to triradiate closure after which it had completely remodeled. RESULTS: The transient medial projection of the triradiate cartilage (triradiate bump) was identified in 26/40 (65 %) females and 22/32 (69 %) males (p = 0.74). The medial projection of the triradiate cartilage was most prominent at 10.8 +/- 0.8 years of age in females and 12.6 +/- 0.7 years of age in males (p < 0.001). The triradiate cartilage projected medially a mean of 4.7 +/- 0.8 or 5.1 +/- 1.4 mm for females and males, respectively (p = 0.29), but remodeled completely in all cases around triradiate closure. CONCLUSIONS: The transient medial projection of the triradiate cartilage within the pelvic brim, the 'triradiate bump sign', is a common radiographic finding in healthy adolescents around the time of closure of the triradiate cartilage that may mimic the ischial spine sign. These two signs can be distinguished as the projection of the ischial spine is located more inferiorly within the pelvic brim and the triradiate bump has a horizontal limb of radiolucency extending to its medial border. PMID- 27126805 TI - DNA Damage in Major Psychiatric Diseases. AB - Human cells are exposed to exogenous insults and continuous production of different metabolites. These insults and unwanted metabolic products might interfere with the stability of genomic DNA. Recently, many studies have demonstrated that different psychiatric disorders show substantially high levels of oxidative DNA damage in the brain accompanied with morphological and functional alterations. It reveals that damaged genomic DNA may contribute to the pathophysiology of these mental illnesses. In this article, we review the roles of oxidative damage and reduced antioxidant ability in some vastly studied psychiatric disorders and emphasize the inclusion of treatment options involving DNA repair. In addition, while most currently used antidepressants are based on the manipulation of the neurotransmitter regulation in managing different mental abnormalities, they are able to prevent or reverse neurotoxin-induced DNA damage. Therefore, it may be plausible to target on genomic DNA alterations for psychiatric therapies, which is of pivotal importance for future antipsychiatric drug development. PMID- 27126808 TI - Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction. AB - RATIONALE: The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. OBJECTIVE: To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways. METHODS AND RESULTS: Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. CONCLUSIONS: Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension. PMID- 27126811 TI - Gender is inevitable: Gender-based violence is avoidable. PMID- 27126810 TI - Factors influencing the nuclear targeting ability of nuclear localization signals. AB - A nuclear localization signal (NLS) is a short amino acid sequence derived from eukaryotic nuclear proteins and viral proteins. Many NLS peptides can efficiently mediate the intranucleus transport of cargo molecules, so they have been widely used for non-viral gene transfer and shown potential ability to improve nuclear delivery of DNA. In order to maximally utilize NLS peptides to enhance gene transfer, several factors such as methods of incorporating NLS peptide, type and property of NLS peptide, number of NLS peptide, and spacer between NLS peptide and DNA should be considered. This review article summarizes how these factors influence the ability of NLS peptides in enhancing non-viral gene delivery and aids in defining the requirements for successful NLS-enhanced transfection. PMID- 27126806 TI - Neuroprotective Effect of the Novel Compound ITH33/IQM9.21 Against Oxidative Stress and Na(+) and Ca(2+) Overload in Motor Neuron-like NSC-34 Cells. AB - Alternatives for the treatment of amyotrophic lateral sclerosis (ALS) are scarce and controversial. The etiology of neuronal vulnerability in ALS is being studied in motor neuron-like NSC-34 cells to determine the underlying mechanisms leading to selective loss of motor neurons. One such mechanism is associated with mitochondrial oxidative stress, Ca(2+) overload, and low expression of Ca(2+) buffering proteins. Therefore, in order to elicit neuronal death in ALS, NSC-34 cells were exposed to the following cytotoxic agents: (1) a mixture of oligomycin 10 uM and rotenone 30 uM (O/R), or (2) phenylarsine oxide 1 uM (PAO) (to mimic excess free radical production during mitochondrial dysfunction), and (3) veratridine 100 uM (VTD) (to induce overload of Na(+) and Ca(2+) and to alter distribution of Ca(2+)-buffering proteins [parvalbumin and calbindin-D28k]). Thus, the aim of the study was to test the novel neuroprotective compound ITH33/IQM9.21 (ITH33) and to compare it with riluzole on in vitro models of neurotoxicity. Cell viability measured with MTT showed that only ITH33 protected against O/R at 3 MUM and PAO at 10 MUM, but not riluzole. ITH33 and riluzole were neuroprotective against VTD, blocked the maximum peak and the number of [Ca(2+)]c oscillations per cell, and restored the effect on parvalbumin. However, only riluzole reversed the effect on calbindin-D28k levels. Therefore, ITH33 was neuroprotective against oxidative stress and Na(+)/Ca(2+) overload, both of which are involved in ALS. PMID- 27126812 TI - The Lower Limb Functional Index - A reliable and valid functional outcome assessment in burns. AB - Lower limb injuries account for up to 40% of all burns in Western Australia and affect physical function. Lower limb specific functional assessments are available to monitor recovery, yet no scale has been assessed for use in burns. The Lower Limb Functional Index (LLFI) which is validated in musculoskeletal patients was investigated for applicability in burn. Reliability was assessed using Cronbach's alpha, principal components analysis and Rasch analysis. Validity was assessed using Spearman's correlation coefficient with quality of life assessments (BSHS-B & SF-36) and physical assessments (TUG & ankle ROM). Regression analysis was performed with burn severity measures, time of recovery and location of the burn. The LLFI-10 was applied 1368 times on 739 patients at regular time points. It was internally consistent (alpha>0.8) and unidimensional. Associations were demonstrated with the BSHS-B and SF-36 (rho=-0.56 to -0.72, p<0.001), TUG (rho=0.41, p<0.001) and ankle ROM (rho=-0.31 to -0.35, p<0.001). The LLFI-10 also showed associations (p<0.001) with time since injury (rho= 0.29), age (rho=0.12) and TBSA (rho=0.12). The LLFI-10 is a reliable and valid tool to assess function in lower limb burns. This study supports the use of the LLFI-10 as part of a battery of assessment for lower limb burn recovery. PMID- 27126813 TI - The role of silver sulphadiazine in the conservative treatment of partial thickness burn wounds: A systematic review. AB - BACKGROUND: For more than 40 years, silver sulphadiazine 1% (SSD) is considered as standard therapy for the conservative treatment of burn wounds. However, in the last 10 years, substantial disadvantages of SSD have been reported in the literature and probably as a result of this, several new dressings for burn wounds have been developed and put on the market. The objective of this systematic review is to evaluate the available evidence on SSD in the conservative treatment of burns, specifically in comparison with the newer burn dressings that are increasingly being used nowadays. MATERIALS AND METHODS: A search filter was composed to select randomized controlled trials (RCTs) from the MEDLINE database. Only RCTs studying the effect of conservative treatment on burns were selected. At least one of the two comparative groups was treated with SSD. Each included article was analysed and relevant data (baseline parameters, interventions, outcomes and methodological parameters) were registered using Microsoft Office Excel 2007. RESULTS: Many dressings showed superior healing properties compared to SSD, but no dressing was able to show a clear benefit over SSD regarding infection. The number of dressing changes, pain and patient's satisfaction are more favourable in the newer dressings, especially with solid and biological dressings. CONCLUSIONS: The results of this systematic review clearly demonstrate that a faster wound healing is obtained with the newly developed burn dressings. Additionally, these new dressings tend to be more comfortable for the patients and easier to use for care givers. The minor differences in antibacterial activity between SSD and the new products did not seem to have any influence on the rate of wound healing. Since rapid wound closure is essential to obtain an optimal functional and aesthetic outcome, it can be concluded from the results of this systemic review that the standard use of SSD in the conservative treatment of burn wounds can no longer be supported. PMID- 27126815 TI - The epidemiology of geriatric burns in Iran: A national burn registry-based study. AB - Defining the epidemiology and outcome of geriatric burn patients is critical for specialized burn centers, health-care workers, and governments. Better resource use and effective guidelines are some of the advantages of studies focusing on this aspect. The outcome of these patients serves as an objective criterion for quality control, research, and preventive programs. We used data from the burn registry program in our country. For 2 years, >28,700 burn patients were recorded, 1721 of whom were admitted. Among them, 187 patients were >=55 years old. Sixty-nine percent of patients were male and 31% female, with a male to female ratio of 2.22:1. The mean+/-standard deviation (SD) of age was 63.4+/-8.1. The cause of burns was flame (58.2%) and scalds (20.3%). Most of the burns were sustained at home. The mean duration of hospital stay was 19.5 days (range 3-59 days). The mean (SD) of the total body surface area (TBSA) was 20.3% (8.4%). The median hospital stay (length of stay (LOS)) was 11 days (SD=14). The increase in TBSA was related to a longer LOS (p<0.02). Burn wound infection developed in 44.3% of patients. The presence of inhalation injury was significantly related to mortality (p<0.001). Among the patients, 9% recovered completely, 74.9% recovered partially (requiring further treatment), 1% underwent amputation, and 12.8% died. The lack of insurance coverage did not affect the survival of our geriatric burn patients. However, being alone or single, ignition of clothing, cause of burn, comorbid illnesses, complications following the burn, TBSA, age, and sepsis were positively correlated with mortality. The mean cost of treatment for each patient was about $7450. PMID- 27126814 TI - Treatment of cervical contractures utilising a closed platysmotomy like approach: Case report and review of the literature. AB - Contractures to the cervical region as a result of burns has the capacity to cause restrictions in range of movement, function of the lower face, cervical spine distortion and poor aesthetic outcomes that remain a surgical challenge. Consequently, physical and aesthetic deformities as a result of cervical contractures are reported to cause depression having implications for patients' quality of life and psychosocial wellbeing. At the time this research was conducted, there were no case reports describing a closed platysmotomy approach in burn patients. In this article, we review the literature surrounding closed platysmotomies and present what we believe to be the first reported case in the treatment of cervical contractures utilising a closed platysmotomy approach in a burns patient. A closed platysmotomy approach for the treatment of cervical contractures is a less invasive technique. Further investigation is warranted to determine the feasibility of this reconstructive approach in the area of burn scar management. PMID- 27126816 TI - Overlapping Phenotypes in Autism Spectrum Disorder and Developmental Coordination Disorder: A Cross-Syndrome Comparison of Motor and Social Skills. AB - Motor and social difficulties are often found in children with an autism spectrum disorder (ASD) and with developmental coordination disorder (DCD), to varying degrees. This study investigated the extent of overlap of these problems in children aged 7-10 years who had a diagnosis of either ASD or DCD, compared to typically-developing controls. Children completed motor and face processing assessments. Parents completed questionnaires concerning their child's early motor and current motor and social skills. There was considerable overlap between the ASD and DCD groups on the motor and social assessments, with both groups more impaired than controls. Furthermore, motor skill predicted social functioning for both groups. Future research should consider the relationships between core symptoms and their consequences in other domains. PMID- 27126818 TI - In the Eye of the Beholder: Rapid Visual Perception of Real-Life Scenes by Young Adults with and Without ASD. AB - Typically developing (TD) adults are able to extract global information from natural images and to categorize them within a single glance. This study aimed at extending these findings to individuals with autism spectrum disorder (ASD) using a free description open-encoding paradigm. Participants were asked to freely describe what they saw when looking at briefly presented real-life photographs. Our results show subtle but consistent group-level differences. More specifically, individuals with ASD spontaneously reported the presence of people in the display less frequently than TD participants, and they grasped the gist of the scene less well. These findings argue for a less efficient rapid feedforward processing of global semantic aspects and a less spontaneous interpretation of socially salient information in ASD. PMID- 27126817 TI - Externalizing and Internalizing Symptoms Moderate Longitudinal Patterns of Facial Emotion Recognition in Autism Spectrum Disorder. AB - Facial emotion recognition (FER) is thought to be a key deficit domain in autism spectrum disorder (ASD). However, the extant literature is based solely on cross sectional studies; thus, little is known about even short-term intra-individual dynamics of FER in ASD over time. The present study sought to examine trajectories of FER in ASD youth over 18 weeks of repeated measurement, and evaluate the effects of internalizing and externalizing symptoms on these trajectories. Hierarchical Linear Modeling analyses revealed that FER errors decreased over time, even for particularly difficult stimuli. Moreover, FER improvement was enhanced by internalizing symptoms but attenuated by externalizing symptoms. Implications for models of FER development, reciprocal relations between FER and comorbidity, and intervention design and planning are discussed. PMID- 27126820 TI - Mokken analysis of the Health of the Nation Outcome Scales in acute inpatient and community samples. AB - OBJECTIVE: The structure and scoring of the Health of the Nation Outcome Scales (HoNOS) has been open to debate. Most studies have relied on factor analytic approaches to investigate HoNOS structure. Our aim is to investigate HoNOS using methods from item response theory. METHODS: Completed HoNOS forms from patients receiving mental health treatment in the community and also inpatients were subjected to Mokken analysis, which is a non-parametric form of item response theory. Confirmatory factor analysis was then used to investigate these scales. RESULTS: Two scales with the same items were found in both samples; however, the inpatient sample scored higher on both scales. The first scale contained three items (10, 11, 12) from the social scale, and the other was related to depression (2, 7, 8). Confirmatory factor analysis showed that a two scale structure had better fit statistics than other suggested structures. CONCLUSIONS: HoNOS might best be conceived as two scales measuring aspects of social adjustment and depression. PMID- 27126819 TI - Presser - the forgotten story. AB - OBJECTIVE: Regina v Presser [1958] VR 45, is the most seminal case regarding fitness to plead for accused persons in Australia and New Zealand. It is not widely understood that Presser was a 14-year-old boy with intellectual disability. We aim to describe a clearer narrative regarding Edward John Presser. METHOD: Review of attainable newspaper reports framed within an historical context of fitness and relevant case law. RESULTS: Presser's narrative is described in greater detail than previously understood by clinicians and lawyers. Ramifications for fitness assessment are discussed including doli incapax and human rights considerations. CONCLUSIONS: The Presser criteria are widely applied; however, the case involved a 14-year-old boy with intellectual disability. Greater awareness of Presser's narrative assists clinicians providing expert evidence regarding fitness to plead for adolescents and persons with intellectual disability. PMID- 27126821 TI - Transarterial chemoembolization versus transarterial radioembolization in hepatocellular carcinoma: optimization of selecting treatment modality. AB - Hepatocellular carcinoma (HCC) of intermediate stage consists of diverse tumor and patient factors in terms of tumor number, size and liver function resulting in various outcomes given by transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using radioactive isotope, beta-ray emitting Yttrium-90 with a short half-life and penetration depth, is an emerging intra-arterial brachytherapy characterized by potent anti-cancer effect given by radiation but minimal embolic effect. Although there is lack of study directly comparing the efficacy and safety between TACE and TARE in patients with unresectable HCC, several retrospective or small-scaled studies suggest that overall efficacy indicated by overall survival and time to progression is similar between two modalities and TARE has a superiority in the safety including postembolization syndrome, hospitalization days and outpatient-based therapy. In advanced HCC with portal vein (PV) invasion, TACE is not consistently recommended due to risk of hepatic decompensation or failure after procedure. On the contrary, available data suggest that TARE might be a promising treatment option in HCC with PV thrombosis if patient's liver function is preserved and the level of PV invasion is less than main trunk. Ongoing trials comparing TARE and sorafenib in advanced HCC would elucidate the role of this locoregional therapy. The need of a multidisciplinary team, complex steps of procedure and high cost of TARE are the hurdles to widespread recommendation of this therapy in intermediate or advanced HCC. The optimization of selection between TACE and TARE might be dependent on availability, experience, tumor factors and patient factors. PMID- 27126822 TI - G1 Domain of Versican Regulates Hyaluronan Organization and the Phenotype of Cultured Human Dermal Fibroblasts. AB - Variants of versican have wide-ranging effects on cell and tissue phenotype, impacting proliferation, adhesion, pericellular matrix composition, and elastogenesis. The G1 domain of versican, which contains two Link modules that bind to hyaluronan (HA), may be central to these effects. Recombinant human G1 (rhG1) with an N-terminal 8 amino acid histidine (His) tag, produced in Nicotiana benthamiana, was applied to cultures of dermal fibroblasts, and effects on proliferation and pericellular HA organization determined. rhG1 located to individual strands of cell surface HA which aggregated into structures resembling HA cables. On both individual and aggregated strands, the spacing of attached rhG1 was similar (~120 nm), suggesting interaction between rhG1 molecules. Endogenous V0/V1, present on HA between attached rhG1, did not prevent cable formation, while treatment with V0/V1 alone, which also bound to HA, did not induce cables. A single treatment with rhG1 suppressed cell proliferation for an extended period. Treating cells for 4 weeks with rhG1 resulted in condensed layers of elongated, differentiated alpha actin-positive fibroblasts, with rhG1 localized to cell surfaces, and a compact extracellular matrix including both collagen and elastin. These results demonstrate that the G1 domain of versican can regulate the organization of pericellular HA and affect phenotype. PMID- 27126824 TI - A Proteoglycan-Like Molecule Offers Insights Into Ground Substance Changes During Holothurian Intestinal Regeneration. AB - Extracellular matrix remodeling is an essential component of regenerative processes in metazoans. Among these animals, holothurians (sea cucumbers) are distinguished by their great regenerative capacities. We have previously shown that fibrous collagen as well as other fibrous components disappear from the connective tissue (CT) early during intestinal regeneration, and later return as the organ primordia form. We now report on changes of the nonfibrous component of the CT. We have used Alcian Blue staining and an antibody, Proteoglycan Like-1 (PGL-1), that recognizes a proteoglycan-like antigen to identify the presence of proteoglycans in normal and regenerating intestines. Our results show that early in regeneration, the ground substance resembles that of the mesentery, the structure from where the new intestine originates. As regeneration proceeds, Alcian Blue staining and PGL-1 labeling reorganize, so that by 4 weeks the normal intestinal CT pattern is achieved. Together with our previous findings, the data suggest that CT components that might be detrimental to regeneration disappear early on, while those that might be beneficial to regeneration, such as proteoglycans, are present throughout the regenerative process. PMID- 27126823 TI - Subepithelial Accumulation of Versican in a Cockroach Antigen-Induced Murine Model of Allergic Asthma. AB - The extracellular matrix (ECM) is an important contributor to the asthmatic phenotype. Recent studies investigating airway inflammation have demonstrated an association between hyaluronan (HA) accumulation and inflammatory cell infiltration of the airways. The ECM proteoglycan versican interacts with HA and is important in the recruitment and activation of leukocytes during inflammation. We investigated the role of versican in the pathogenesis of asthmatic airway inflammation. Using cockroach antigen (CRA)-sensitized murine models of allergic asthma, we demonstrate increased subepithelial versican in the airways of CRA treated mice that parallels subepithelial increases in HA and leukocyte infiltration. During the acute phase, CRA-treated mice displayed increased gene expression of the four major versican isoforms, as well as increased expression of HA synthases. Furthermore, in a murine model that examines both acute and chronic CRA exposure, versican staining peaked 8 days following CRA challenge and preceded subepithelial leukocyte infiltration. We also assessed versican and HA expression in differentiated primary human airway epithelial cells from asthmatic and healthy children. Increases in the expression of versican isoforms and HA synthases in these epithelial cells were similar to those of the murine model. These data indicate an important role for versican in the establishment of airway inflammation in asthma. PMID- 27126826 TI - The contribution of sleep quality and quantity to public health and work ability. PMID- 27126825 TI - Post-Irradiated Human Submandibular Glands Display High Collagen Deposition, Disorganized Cell Junctions, and an Increased Number of Adipocytes. AB - Salivary glands are vital for maintaining oral health. Head and neck radiation therapy is one of the most common causes of salivary gland hypofunction. Little is known about the structural changes that occur in salivary glands after radiation therapy. The aim of this study is to understand the structural changes that occur in post-irradiated human (submandibular gland [SMG]) as compared with untreated ones. We determined changes in epithelial polarity, presence of collagen deposition, and alteration in adipose tissue. We used formalin-fixed paraffin-embedded human SMG from two female subjects exposed to head and neck irradiation. We utilized hematoxylin and eosin staining and Masson's Trichrome staining. The immunostained tissue sections were examined using confocal microscopy. The number and size of adipocytes per tissue section were calculated using ImageJ, Prism, and SPSS software. Post-irradiated human SMG displayed high collagen deposition, disorganized cell junctions, and an increased number of adipocytes as compared with non-irradiated controls. These findings are important to improve our understanding of the individual risk and variation in radiation related salivary gland dysfunction. PMID- 27126827 TI - Management of multiple sclerosis and the integration of related specialty pharmacy programs within health systems. AB - PURPOSE: The management of multiple sclerosis (MS) and the integration of related specialty pharmacy programs within health systems are discussed. SUMMARY: MS is a progressive immune-mediated inflammatory disease of the central nervous system. Current treatment strategies include the use of disease-modifying therapies (DMTs) that have various degrees of efficacy and tolerability. These DMTs also differ with respect to frequency and route of administration, which can significantly impact patient compliance and ultimately their response to therapy. The introduction of oral and injectable DMTs requiring less-frequent injections and having better adverse-effect profiles may help patients improve adherence to therapy; however, access to these therapies is often restricted due to both their high cost and limited distribution. These DMTs include fingolimod, teriflunomide, dimethyl fumarate, and pegylated interferon beta-1a. All others, with the exception of fingolimod, have limited distribution. Pharmacists in health-system pharmacy programs can play a significant role in assisting patients with MS manage their disease efficiently and safely by educating them about their therapies, ensuring compliance with the associated risk evaluation and mitigation strategy (REMS) program, and helping them access these therapies in a timely manner. CONCLUSION: MS is a progressive neurologic disorder that requires lifelong treatment with DMTs. Good compliance, compliance with the associated REMS program, and timely access to these drugs may positively influence patient care and outcomes and provide an opportunity for the health-system pharmacists to have a active role in caring for these patients. PMID- 27126828 TI - Specialty pharmacy services for patients receiving oral medications for solid tumors. AB - PURPOSE: Currently available oral oncology therapies are reviewed, and specialty pharmacy services for patients receiving these drugs are described. SUMMARY: Market introductions of new oral oncology drugs have increased substantially over the past decade, and 25-30% of all oncology agents in development are oral medications. Oral agents for treatment of breast cancer include capecitabine, lafatinib, and palbociclib. Several oral agents are used in treating patients with lung cancer driven by mutations of genes coding for anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR); currently available agents include the ALK inhibitors certinib and crizotinib and the EGFR inhibitors afatinib, erlotinib, and gefitinib. Four oral targeted therapies are used in the treatment of melanoma associated with the B-Raf proto-oncogene, BRAF: cobimetinib, dabrafenib, trametinib, and vemurafenib. Oral agents for treatment of prostate cancer include abiraterone acetate and enzalutamide. Oral agents for treatment of renal cell carcinoma include axitinib, everolimus, pazopanib, sorafenib, and sunitinib. Specialty pharmacy services for patients receiving oral oncology agents can include (1) providing patient counseling and education on adverse effects and self-management strategies, (2) processing prior authorization requests and helping patients navigate copayment assistance programs, and (3) monitoring for medication toxicities and recommending dose adjustments as appropriate. CONCLUSION: Many oral oncology medications have been introduced over the past 10-15 years, with many others in clinical development. Due to the complexity of initiating and monitoring patients receiving these oral therapies, specialty pharmacy services are an essential component of many patients' cancer care. PMID- 27126829 TI - Implementation of a patient-focused specialty pharmacy program in an academic healthcare system. AB - PURPOSE: The development and implementation of a systemwide specialty pharmacy program in an academic healthcare system are described. SUMMARY: Although the system's pharmacy department had developed specialty pharmacy services for patients with certain conditions, it was necessary to expand and standardize those services to meet the needs of all specialty clinics because (1) many of the clinics had experienced an increased volume of prior-authorization requests due to the introduction of new specialty drugs, (2) the dispensing pharmacies were operating at maximum capacity due to the previous decentralization of specialty pharmacy operations, and (3) payers had sent notice that they would require accreditation of the specialty pharmacy program as a condition of participation in their specialty pharmacy networks. To ensure standardization of services and successful preparation for increasing numbers of specialty prescriptions, all specialty pharmacy services were centralized to the healthcare system's Pharmacy Ambulatory Clinical Care Center (PAC(3)). PAC(3) centralized the prior authorization process to selected specialty clinics. A call center was developed at PAC(3) to provide centralized specialty pharmacy services, including 24-7 patient support, a medication adherence program, home delivery service, and patient education. The program resulted in a 137% increase in specialty pharmacy revenues over a two-year period. PAC(3) processed 1860 prior-authorization cases and enrolled approximately 700 new patients in the specialty pharmacy program within nine months. CONCLUSION: A specialty pharmacy program was established along with operational and infrastructure improvements, resulting in increased revenue, systemwide services, and a fully accredited specialty pharmacy. PMID- 27126830 TI - Benefits of developing a collaborative, outcomes-based specialty pharmacy program. AB - PURPOSE: The benefits of developing a collaborative, outcomes-based specialty pharmacy program are described. SUMMARY: With the implementation of risk-based payment models and the rapid growth of specialty pharmacy spend, opportunities exist to establish collaborative and outcomes-focused specialty pharmacy contracts and related programs with regional third-party payers. University of Wisconsin (UW) Health and Unity Health Plans Insurance Corporation have established a contract that sets standards for patient management, pharmacist training and education, electronic medical record documentation, and prescription fulfillment for patients receiving specialty pharmaceuticals. Reporting on metrics of compliance, persistence, and outcomes relative to published benchmarks is required annually. While the contract defines patients by the traditional metric of specialty medication use and includes reimbursement for dispensing activities, it differentiates itself by establishing core services and longitudinal practice expectations for patient care rather than focusing on reimbursement for prescription fulfillment. While it focuses on specialty pharmacy practice, the contract provides an ancillary benefit to all patients using UW Health pharmacies by elevating ambulatory care pharmacy practice standards and improving the patient care process. CONCLUSION: The collaborative development of practice standards, service requirements, and patient management protocols offers the rapid elevation of specialty pharmacy services, which provides significant differentiation within the highly competitive specialty pharmacy and third-party payer marketplaces. PMID- 27126831 TI - Integration of outpatient infectious diseases clinic pharmacy services and specialty pharmacy services for patients with HIV infection. AB - PURPOSE: The integration of specialty pharmacy services and existing outpatient clinical pharmacy services within an infectious diseases (ID) clinic to optimize the care of patients with human immunodeficiency virus (HIV) infection is described. SUMMARY: The management of HIV-infected patients is a highly specialized area of practice, often requiring use of complex medication regimens for reduction of HIV-associated morbidity and mortality prophylaxis and treatment of opportunistic infections, and prevention of HIV transmission. To maximize the effectiveness and safety of treatment with antiretroviral agents and associated pharmacotherapies, an interdisciplinary team is often involved in patient care. At Chicago-based Northwestern Medicine (NM), the outpatient ID clinic has long worked with an interdisciplinary care team including physicians, clinical pharmacists, nurses, and social workers to care for patients with HIV infection. In April 2014, specialty pharmacy services for patients with HIV infection were added to the NM ID clinic's care model to help maintain continuity of care and enhance patient follow-up. The care model includes well-defined roles for clinical pharmacists, pharmacy residents and students on rotation, and licensed pharmacy technicians. Specialty pharmacy services, including medication education, prescription fulfillment, assistance with medication access (e.g., navigation of financial assistance programs, completion of prior-authorization requests), and treatment monitoring, allow for closed-loop medication management of the HIV-infected patient population. CONCLUSION: Integration of specialty pharmacy services with the interdisciplinary care provided in the outpatient NM ID clinic has enhanced continuity of care for patients with HIV infection in terms of prescription filling, medication counseling, and adherence monitoring. PMID- 27126832 TI - Genotype 1 hepatitis C virus and the pharmacist's role in treatment. AB - PURPOSE: The treatment of hepatitis C virus (HCV) genotype 1 has changed rapidly with recently approved direct-acting antiviral (DAA) regimens. The role of the pharmacist in the management of HCV therapy has increased. SUMMARY: Chronic HCV infection is the main cause of end-stage liver disease and the primary reason for liver transplantation, liver-related death, and hepatocellular carcinoma in the United States. The recent approval of several DAAs has led to improved tolerability, sustained virological response (SVR) rates, and shorter treatment durations compared with treatment with pegylated interferon and ribavirin. Most HCV cases can be treated with the currently available regimens, and expected SVR rates exceed 90%. Several fixed-dose and pangenotypic antiviral regimens are currently in various phases of clinical trials. Pharmacists are well equipped to assist the medical team and patients with comprehensive management of HCV treatment. Pharmacists in various settings can play an instrumental role in access to HCV medications, selection of HCV treatment, detection of drug-drug interactions, and education of patients about potential adverse effects and the importance of adherence and laboratory test monitoring during HCV treatment. However, the high cost of HCV treatment poses challenges for ubiquitous treatment. CONCLUSION: Available DAA regimens have improved HCV treatment outcomes and are selected based on efficacy, potential drug interactions, and the patient's ability to obtain medication coverage. Each of these factors provides an opportunity for pharmacist involvement in HCV management. PMID- 27126833 TI - The role of specialty pharmacy drugs in the management of inflammatory diseases. AB - PURPOSE: Specialty drugs used in patients with inflammatory disease states are reviewed, with a focus on the pharmacist's roles in facilitating medication procurement and in the clinical management of affected patients. SUMMARY: Pharmacists in the ambulatory care and community settings are strategically placed to be actively involved in specialty drug procurement and clinical management of patients with inflammatory diseases such as rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, inflammatory bowel disease, and ankylosing spondylitis. Specialty medications used in the treatment of these diseases include anti-tumor necrosis factor (TNF) disease-modifying antirheumatic drugs (DMARDs), non-TNF DMARDs, and interleukin inhibitors. Pharmacist involvement in drug procurement in this area includes navigating insurance barriers and helping patients address high out-of-pocket costs; clinical management activities can include ensuring appropriate baseline screening and vaccine administration, providing drug-specific patient education, and performing routine follow-up and assessment. Patient education is the single biggest area where pharmacists can have a direct impact on overall clinical management of patients receiving specialty drugs for the treatment of inflammatory diseases. These patients need to be educated about dosing, administration, storage and disposal, common and rare adverse effects, adverse-effect management strategies, expectations of drug effect, and considerations for unique circumstances such as illness and planned surgery. CONCLUSION: Specialty drugs represent one of the fastest-growing sectors of pharmacy spending, with inflammatory disease therapies at the forefront. As pharmacists are accessible healthcare practitioners, their responsibilities should include financial and clinical management of patients with inflammatory diseases who are receiving specialty drugs. PMID- 27126834 TI - Specialty pharmacy in the limelight. PMID- 27126835 TI - Specialty pharmacy for hematologic malignancies. AB - PURPOSE: The oral oncology medications used in the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, and non Hodgkin's lymphoma are reviewed, and the specialty pharmacy services at three large academic medical centers are described. SUMMARY: More than one dozen oral oncology medications are being used for hematologic malignancies and afford patients increased convenience and the potential to improve their quality of life. These agents include ibrutinib, idelalisib, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, thalidomide, lenalidomide, pomalidomide, panobinostat, ixazomib, and vorinostat. Despite the benefits of an autonomous-driven patient care plan, these high-risk, high-cost treatments are not without their challenges. Oral oncology medications are associated with significant barriers to adherence, including low health literacy, patient forgetfulness, complex administration instructions, troublesome adverse effects, and high copayments. Many outpatient cancer center pharmacies associated with large academic medical centers are now applying for specialty pharmacy designation. This affords the onsite dispensing pharmacy access to once-limited oral oncology medications that can be dispensed to clinic patients. In addition, the specialty pharmacy services offered within these cancer centers bridge an important gap in patient care and improve the care provided to oncology patients. CONCLUSION: As oral oncology agents continue to be approved by FDA, oncology treatment teams must establish a comprehensive plan for their management. Because of their pharmacologic expertise, access to patients' medical records, and unique position within ambulatory care oncology teams, pharmacists can play an important role in patient education, laboratory monitoring, medication adherence, and cost saving. PMID- 27126837 TI - Restraint related deaths and excited delirium syndrome in Ontario (2004-2011). AB - Restraint related death in individuals in excited delirium syndrome (ExDS) is a rare event that has been the subject of controversies for more than 3 decades. The purpose of this retrospective study was to retrieve data on all restraint related deaths (RRD) that occurred in Ontario during an 8-year period and compare them with an earlier study on RRD in ExDS covering the period 1988-1995 in Ontario. The Office of the Chief Coroner of Ontario website was consulted under verdicts and recommendations. The Canadian Legal Information Institute website was used to consult verdict explanations and coroner's summary of evidence. During the period 2004-2011, RRD occurred in 14 individuals in ExDS, a 33% reduction. Psychiatric illness as a cause of ExDS decreased from 57% to 14%. Cocaine was the cause of ExDS in 11 (79%) individuals. The number of RRD following a violent encounter in cocaine-induced ExDS (8) was identical in the 2 periods. RRD occurred in 6 individuals without ExDS following a violent encounter. Final restraint position preceding cardiorespiratory arrest was available in 36% of individuals with ExDS and 83% of individuals without ExDS. In both groups, cardiorespiratory arrests could be classified as immediate or delayed. All 4 individuals without ExDS who had immediate cardiorespiratory arrests were restrained in the prone position. Delayed cardiorespiratory arrest occurred in the non-prone position in both groups. Although many hypotheses may be put forward to explain changes in the epidemiology of RRD in ExDS in Ontario, multiple warnings and recommendations from coroners' inquests cannot be ignored. There is probably not a unique pathophysiological pathway leading to cardiorespiratory arrest in RRD. The death rate in RRD in ExDS is so low that drawing any conclusions based on statistical studies or on isolated case report could be hazardous. PMID- 27126836 TI - Deterministic assembly processes govern bacterial community structure in the Fynbos, South Africa. AB - The Mediterranean Fynbos vegetation of South Africa is well known for its high levels of diversity, endemism, and the existence of very distinct plant communities on different soil types. Studies have documented the broad taxonomic classification and diversity patterns of soil microbial diversity, but none has focused on the community assembly processes. We hypothesised that bacterial phylogenetic community structure in the Fynbos is highly governed by deterministic processes. We sampled soils in four Fynbos vegetation types and examined bacterial communities using Illumina HiSeq platform with the 16S rRNA gene marker. UniFrac analysis showed that the community clustered strongly by vegetation type, suggesting a history of evolutionary specialisation in relation to habitats or plant communities. The standardised beta mean nearest taxon distance (ses. beta NTD) index showed no association with vegetation type. However, the overall phylogenetic signal indicates that distantly related OTUs do tend to co-occur. Both NTI (nearest taxon index) and ses. beta NTD deviated significantly from null models, indicating that deterministic processes were important in the assembly of bacterial communities. Furthermore, ses. beta NTD was significantly higher than that of null expectations, indicating that co occurrence of related bacterial lineages (over-dispersion in phylogenetic beta diversity) is determined by the differences in environmental conditions among the sites, even though the co-occurrence pattern did not correlate with any measured environmental parameter, except for a weak correlation with soil texture. We suggest that in the Fynbos, there are frequent shifts of niches by bacterial lineages, which then become constrained and evolutionary conserved in their new environments. Overall, this study sheds light on the relative roles of both deterministic and neutral processes in governing bacterial communities in the Fynbos. It seems that deterministic processes play a major role in assembling the bacterial community, with neutral processes playing a more minor role. PMID- 27126838 TI - The problem of police-related cardiac arrest. AB - The term "positional asphyxia" was originally used to describe the situation in which the upper airways becomes compromised by sharp angulation of the head or neck, or where the chest wall is splinted and the diaphragm is prevented from moving because of an unusual position of the body. The term was redefined in the early 1980s to describe sudden death during physical restraint of an individual who is in a prone position. A large percent of reported victims were overweight males. Most were in early middle age and manifesting psychotic behavior at the time of death. Most were reported to have unremarkable autopsies, save for the finding, in many cases, of cocaine or methamphetamine (more recently synthetic cannabinoids and cathinones as well). As no cause of death was apparent (other than non-specific signs such as pulmonary edema), it became common practice to attribute death to force exerted on the decedent's back. When experimental studies with human volunteers disproved this notion, the term "restraint asphyxia" was substituted for positional asphyxia, but with nearly the exact same meaning. No experimental study has ever determined the actual amount of force necessary to cause asphyxia by force applied to the back (although the range of required static force is known), nor the duration for which it must be applied. This review discusses the epidemiology and the evidence for and against the theory of "restraint/positional" asphyxia. It also considers alternative theories of causation, including the findings of studies suggesting that cardiac channelopathies/cardiomyopathies may explain many cases of ARD. PMID- 27126839 TI - A checklist of beetles (Insecta, Coleoptera) on pig carcasses in the suburban area of southwestern China: A preliminary study and its forensic relevance. AB - Examining the succession pattern of carrion insects on vertebrate carcasses is widely accepted as an effective method to estimate the postmortem interval (PMI) of decayed bodies. Investigation of the community of sarcosaprophagous insects, especially flies and beetles, is the foundation of the succession pattern study. This study aimed to investigate the sarcosaprophagous beetles succession on animal carcasses in the suburban area of southwestern China and to establish a basic catalog for forensic application. The present study was conducted in 2013 in a mountain in Chongqing municipality with modified Schoenly traps. Carcasses of miniature pig were used to simulate human bodies. For most carcasses, five decomposition stages were observed. A total of 2108 adult coleopterans belonging to at least 61 species and 18 families were collected in the study, and most of the specimens occurred at the advanced decay stage. Omosita colon (Linnaeus, 1758), Necrodes nigricornis (Harold, 1875), Necrobia ruficollis (Fabricius, 1775) and Neosilusa ceylonica (Kraatz, 1857) were the dominant species. PMID- 27126840 TI - Modulation of linguistic prediction by TDCS of the right lateral cerebellum. AB - It has been postulated recently that the cerebellum contributes the same prediction and learning functions to linguistic processing as it does towards motor control. For example, repetitive TMS over posterior-lateral cerebellum caused a significant loss in predictive language processing, as assessed by the latency of saccades to target items of spoken sentences, using the Visual World task. We aimed to assess the polarity-specific effects of cerebellar TDCS, hypothesising that cathodal TDCS should impair linguistic prediction, and anodal TDCS facilitate it. Our design also tested whether TDCS modulated associative learning in this task. A between groups (sham, anodal, cathodal) design was used, with concurrent stimulation during performance of a manual variation of the Visual World paradigm, and with assessment of latency reduction over repeated presentations of the spoken sentences. Mixed model ANOVA was used to analyse change in response latency. Cathodal TDCS decreased participants' response time advantage for the predictable sentence items without change for non-predictable items, consistent with the previous TMS results. Furthermore, anodal stimulation enhanced the response time advantage for the predictable items, again without change in latencies for non-predictive items. We found a clear practice-based effect over 4 blocks. However, this difference was not significantly modulated by either anodal or cathodal stimulation. Our results therefore support the hypothesis that cerebellum contributes to predictive language processing, mirroring its predictive role in motor control, but we do not yet have evidence that the learning process was affected by cerebellar TDCS. PMID- 27126841 TI - Dynamic emotion perception and prior expectancy. AB - Social interactions require the ability to rapidly perceive emotion from various incoming dynamic, multisensory cues. Prior expectations reduce incoming emotional information and direct attention to cues that are aligned with what is expected. Studies to date have investigated the prior expectancy effect using static emotional images, despite the fact that dynamic stimuli would represent greater ecological validity. The objective of the study was to create a novel functional magnetic resonance imaging (fMRI) paradigm to examine the influence of prior expectations on naturalistic emotion perception. For this purpose, we developed a dynamic emotion perception task, which consisted of audio-visual videos that carry emotional information congruent or incongruent with prior expectations. The results show that emotional congruency was associated with activity in prefrontal regions, amygdala, and putamen, whereas emotional incongruency was associated with activity in temporoparietal junction and mid-cingulate gyrus. Supported by the behavioural results, our findings suggest that prior expectations are reinforced after repeated experience and learning, whereas unexpected emotions may rely on fast change detection processes. The results from the current study are compatible with the notion that the ability to automatically detect unexpected changes in complex dynamic environments allows for adaptive behaviours in potentially advantageous or threatening situations. PMID- 27126843 TI - Here/In This Issue and There/Abstract Thinking: Criminologists: Friends in the Wasteland. PMID- 27126844 TI - Decreasing Ambiguity in Child Protection. PMID- 27126842 TI - Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol. AB - Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Delta9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse. PMID- 27126845 TI - Developmental Effects of Prenatal Selective Serotonin Reuptake Inhibitor Exposure in Perspective: Are We Comparing Apples to Apples? PMID- 27126846 TI - The Beginning of the End? Deploying Rigorous Research in Real-World Settings to Reduce Stigma. PMID- 27126847 TI - Measuring Access to Care: An Innovative, Practical, and Partnered Approach. PMID- 27126848 TI - Psychiatry and Pediatrics: New Necessary Directions to Better Treat Adolescents. PMID- 27126850 TI - Breastfeeding and Childhood IQ: The Mediating Role of Gray Matter Volume. AB - OBJECTIVE: A substantial body of literature has established the positive effect of breastfeeding on child developmental outcomes. There is increasing consensus that breastfed children have higher IQs after accounting for key variables, including maternal education, IQ, and socioeconomic status. Cross-sectional investigations of the effects of breastfeeding on structural brain development suggest that breastfed infants have larger whole brain, cortical, and white matter volumes. To date, few studies have related these measures of brain structure to IQ in breastfed versus nonbreastfed children in a longitudinal sample. METHOD: Data were derived from the Preschool Depression Study (PDS), a prospective longitudinal study in which children and caregivers were assessed annually for 8 waves over 11 years. A subset completed neuroimaging between the ages of 9.5 and 14.11 years. A total of 148 individuals had breastfeeding data at baseline and complete data on all variables of interest, including IQ and structural neuroimaging. General linear models and process mediation models were used. RESULTS: Breastfed children had significantly higher IQ scores and larger whole brain, total gray matter, total cortical gray matter, and subcortical gray matter volumes compared with the nonbreastfed group in models that covaried for key variables. Subcortical gray matter volume significantly mediated the association between breastfeeding and children's IQ scores. CONCLUSION: The study findings suggest that the effects of breastfeeding on child IQ are mediated through subcortical gray volume. This effect and putative mechanism is of public health significance and further supports the importance of breastfeeding in mental health promotion. PMID- 27126849 TI - Gestational Exposure to Selective Serotonin Reuptake Inhibitors and Offspring Psychiatric Disorders: A National Register-Based Study. AB - OBJECTIVE: To investigate the impact of gestational exposure to selective serotonin reuptake inhibitors (SSRIs) on offspring neurodevelopment. METHOD: This is a cohort study using national register data in Finland between the years 1996 and 2010. Pregnant women and their offspring were categorized into 4 groups: SSRI exposed (n = 15,729); exposed to psychiatric disorder, no antidepressants (n = 9,651); exposed to SSRIs only before pregnancy (n = 7,980); and unexposed to antidepressants and psychiatric disorders (n = 31,394). We investigated the cumulative incidence of offspring diagnoses of depression, anxiety, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) for the 4 groups from birth to 14 years, adjusting for confounders. RESULTS: The cumulative incidence of depression among offspring exposed prenatally to SSRIs was 8.2% (95% CI = 3.1-13.3%) by age 14.9 years, compared with 1.9% (95% CI = 0.9 2.9%) in the psychiatric disorder, no medication group (adjusted hazard ratio [HR] = 1.78; 95% CI = 1.12-2.82; p = .02) and to 2.8% (95% CI = 1.4-4.3%) in the SSRI discontinued group (HR = 1.84; 95% CI = 1.14-2.97; p = .01). Rates of anxiety, ASD, and ADHD diagnoses were comparable to rates in offspring of mothers with a psychiatric disorder but no medication during pregnancy. Comparing SSRI exposed to unexposed individuals, the HRs were significantly elevated for each outcome. CONCLUSION: Prenatal SSRI exposure was associated with increased rates of depression diagnoses in early adolescence but not with ASD or ADHD. Until confirmed, these findings must be balanced against the substantial adverse consequences of untreated maternal depression. PMID- 27126852 TI - Impact of a Mental Health Curriculum on Knowledge and Stigma Among High School Students: A Randomized Controlled Trial. AB - OBJECTIVE: This study evaluated the effectiveness of a school-based mental health literacy intervention for adolescents on knowledge and stigma. METHOD: A total of 24 high schools and 534 students in the regional area of Ottawa, Ontario, Canada participated in this randomized controlled trial. Schools were randomly assigned to either the curriculum or control condition. The curriculum was integrated into the province's grade 11 and 12 "Healthy Living" courses and was delivered by teachers. Changes in mental health knowledge and stigma were measured using pre- and posttest questionnaires. Descriptive analyses were conducted to provide sample characteristics, and multilevel modeling was used to examine study outcomes. RESULTS: For the curriculum condition, there was a significant change in stigma scores over time (p = .001), with positive attitudes toward mental illness increasing from pre to post. There was also a significant change in knowledge scores over time (p < .001), with knowledge scores increasing from pre to post. No significant changes in knowledge or stigma were found for participants in the control condition. A meaningful relationship was found whereby increases in knowledge significantly predicted increases in positive attitudes toward mental health (p < .001). CONCLUSION: This is the first large randomized controlled trial to demonstrate the effectiveness in mental health literacy of an integrated, manualized mental health educational resource for high school students on knowledge and stigma. Findings also support the applicability by teachers and suggest the potential for broad-based implementation of the educational curriculum in high schools. Replication and further studies are warranted. Clinical trial registration information-Impact of a Mental Health Curriculum for High School Students on Knowledge and Stigma; http://clinicaltrials.gov/; NCT02561780. PMID- 27126851 TI - A Prospective Cohort Study of Influences on Externalizing Behaviors Across Childhood: Results From a Nurse Home Visiting Randomized Controlled Trial. AB - OBJECTIVE: This study investigated genetic and environmental influences on behavior in a cohort of 600 children followed prenatally to 18 years. METHOD: A randomized controlled trial of prenatal/infancy nurse home visits (NHV) was conducted in 600 predominantly African American mothers and their firstborn children from Memphis, TN. Mothers were assessed in pregnancy for mental health (MH), self-efficacy, and mastery. Mothers reported longitudinally on smoking and alcohol/drug use. The functional polymorphisms SLC6A4 5-HTTLPR, FKBP5 rs1360780 and DRD2/ANKK1 rs1800497 were genotyped together with 186 ancestry informative markers. Composite externalizing disorders (ED) continuous total scores from the mother-report Achenbach Child Behavior Checklist were included as dependent variables in regression analyses for time points 2, 6, 12, and 18 years. RESULTS: Behaviors at younger ages strongly predicted later behaviors (p < .0001). Children whose mothers had high self-efficacy and had received NHV were better behaved at age 2 years. Poorer maternal MH adversely influenced ED up to 12 years, but at age 18 years, maternal mastery exerted a strong, positive effect (p = .0001). Maternal smoking was associated with worse ED at 6 and 18 years. Main and interactive effects of genetic polymorphisms varied across childhood: FKBP5 rs1360780 up to age 6, 5-HTTLPR from 6 to 12, and DRD2/ANKK1 rs1800497 from 2 to 18 years. CONCLUSION: Our study suggests that maternal MH and resilience measured in pregnancy have long-lasting effects on child behavior. Maternal smoking across childhood and genetic factors also play a role. NHV had a positive effect on early behavior. Our findings have implications for prevention of pathological behaviors in adulthood. Clinical trial registration information-Age-17 Follow-Up of Home Visiting Intervention; http://clinicaltrials.gov/; NCT00708695. PMID- 27126853 TI - Access to Care for Youth in a State Mental Health System: A Simulated Patient Approach. AB - OBJECTIVE: To examine access to psychiatric care for adolescents with depression in outpatient specialty clinics within a state mental health system, using a simulated patient approach. METHOD: Trained callers posed as the mother of a 14 year-old girl with depression, following a script. A stratified random sample (n = 264) of 340 state-licensed outpatient mental health clinics that serve youth was selected. Clinics were randomly assigned to season and insurance condition. We examined whether access varied by season, clinic characteristics, and caller insurance type. Weighted logistic and linear mixed effects regression models were fitted to examine associations with appointment availability and wait times. RESULTS: Among clinics at which a treatment appointment could be scheduled, appointment availability differed by season. Clinics that had participated in state-sponsored trainings targeting access were more available. Wait times for treatment appointments varied by season and region. Wait times in New York City were shorter than in some other regions. Although callers were 4.1 times more likely to be able to schedule a psychiatry appointment in the spring, wait times for psychiatry appointments were significantly longer in the spring than in the summer (49.9 vs. 36.7 days). Wait times for therapy appointments were significantly shorter in community than in hospital clinics (19.1 days vs. 35.3 days). CONCLUSION: Access to psychiatric care for youth with depression was found to be variable in a state system. State-sponsored trainings on strategies to reduce wait times appear to improve care access. The simulated patient approach has promise for monitoring the impact of health care policy reforms on care quality measures. PMID- 27126854 TI - Developmental Trajectories of Suicidal Thoughts and Behaviors From Adolescence Through Adulthood. AB - OBJECTIVE: Little is known about the patterns among individuals in the long-term course of suicidal thoughts and behaviors (STBs). The objective of this study was to identify developmental trajectories of STBs from adolescence through young adulthood, as well as risk and protective covariates, and nonsuicidal outcomes associated with these trajectories. METHOD: A total of 180 adolescents (ages 12 18 years at recruitment) were repeatedly assessed over an average of 13.6 years (2,273 assessments) since their psychiatric hospitalization. Trajectories were based on ratings of STBs at each assessment. Covariates included psychiatric risk factors (proportion of time in episodes of psychiatric disorders, hopelessness, trait anxiety, impulsivity, and aggression in adulthood, sexual and physical abuse, parental history of suicidal behavior), protective factors (survival and coping beliefs, social support in adulthood, parenthood), and nonsuicidal outcomes (social adjustment and functional impairment in adulthood, school drop out, incarcerations). RESULTS: Using a Bayesian group-based trajectory model, 4 trajectories of STBs were identified: an increasing risk class (11%); a highest overall risk class (12%); a decreasing risk class (33%); and a low risk class (44%). The 4 classes were associated with distinct patterns of correlates in risk and protective factors and nonsuicidal outcomes. CONCLUSION: Adolescents and young adults have heterogeneous developmental trajectories of STBs. These trajectories and their covariates may inform strategies for predicting STBs and targeting interventions for individuals at risk for suicidal behavior. PMID- 27126855 TI - Point Prevalence of Co-Occurring Behavioral Health Conditions and Associated Chronic Disease Burden Among Adolescents. AB - OBJECTIVE: To examine the point prevalence of behavioral health conditions (BHCs) and co-occurring chronic medical conditions among adolescents in an integrated health system. METHOD: The sample consisted of adolescents in an integrated health care system diagnosed with at least 1 of the 5 most prevalent BHCs in 2014 (n = 30,643), and patients without a BHC matched on age, sex, and medical home facility (n = 30,643). Electronic health record data was used to identify all adolescents aged 11 to 18 years with at least 1 BHC diagnosis on their diagnosis list, which included current and pre-existing diagnoses from an outpatient (including psychiatry and chemical dependency specialty treatment), inpatient, or emergency department visit at a Kaiser Permanente Northern California (KPNC) facility between January 1, 2014, and December 31, 2014. The odds of having general medical conditions and specific chronic diseases were compared between adolescents with and without BHCs. RESULTS: Among adolescents with at least 1 BHC in 2014, the 5 most common BHCs were: depressive disorders (42%), anxiety disorders (40%), attention-deficit/hyperactivity disorders (ADHDs; 37%), substance use disorders (SUDs; 10%), and bipolar spectrum disorders (8%). Overall, patients with a BHC did not have higher odds of any medical comorbidity compared with non-BHC patients. However, compared to individuals without BHCs, adolescents with depression (odds ratio [OR] = 1.16, 95% CI = 1.08-1.26), anxiety (OR = 1.30, 95% CI = 1.20-1.41), and substance use (OR = 1.25, 95% CI = 1.05 1.49) disorders had significantly higher odds of any medical comorbidities; individuals with ADHD and bipolar disorder did not differ from patients without BHCs. CONCLUSION: BHCs were common and were associated with a disproportionately higher burden of chronic medical disease among adolescents in a large, private health care delivery system. As comorbidity can lead to elevated symptom burden, functional impairment, and treatment complexity, the study findings call for implementation of effective collaborative models of care for these patients. PMID- 27126857 TI - Guiding Lights. PMID- 27126858 TI - Erratum: Tumour angiogenesis as a chemo-mechanical surface instability. PMID- 27126856 TI - Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder. AB - OBJECTIVE: We examine weight gain and metabolic consequences of risperidone monotherapy in children with autism spectrum disorder (ASD). METHOD: This was a 24-week, multisite, randomized trial of risperidone only versus risperidone plus parent training in 124 children (mean age 6.9 +/- 2.35 years; 105 boys and 19 girls) with ASD and serious behavioral problems. We monitored height, weight, waist circumference, and adverse effects during the trial. Fasting blood samples were obtained before treatment and at week 16. RESULTS: In 97 children with a mean of 22.9 +/- 2.8 weeks of risperidone exposure, there was a 5.4 +/- 3.4 kg weight gain over 24 weeks (p < .0001); waist circumference increased from 60.7 +/ 10.4 cm to 66.8 +/- 11.3 cm (p < .0001). At baseline, 59 of 97 children (60.8%) were classified as having normal weight; by week 24, only 25 of 85 (29.4%) remained in that group. Growth curve analysis showed a significant change in body mass index (BMI) z scores from pretreatment to week 24 (p < .0001). This effect was significantly greater for children with reported increased appetite in the first 8 weeks. From before treatment to week 16, there were significant increases in glucose (p = .02), hemoglobin A1c (p = .01), insulin (p <.0001), homeostatic model assessment-insulin resistance (HOMA-IR; p < .001), alanine aminotransferase (p = .01), and leptin (p < .0001). Adiponectin declined (p = .003). At baseline, 7 children met conventional criteria for metabolic syndrome; by week 16, 12 additional children were so classified. CONCLUSION: Rapid weight gain with risperidone treatment may promote the cascade of biochemical indices associated with insulin resistance and metabolic syndrome. Appetite, weight, waist circumference, liver function tests, blood lipids, and glucose warrant monitoring. Clinical trial registration information-Drug and Behavioral Therapy for Children With Pervasive Developmental Disorders; http://clinicaltrials.gov/; NCT00080145. PMID- 27126860 TI - Acceptability of Partner Violence in 51 Societies: The Role of Sexism and Attitudes Toward Violence in Social Relationships. AB - Sexist attitudes have been claimed to play an important role in acceptability of intimate partner violence (IPV). Empirical evidence suggests that sexist individuals are also more accepting of violence in social relationships than non sexist individuals. Results from multilevel regression models of data from 72,730 respondents of 51 countries around the world showed that (a) both sexism and acceptability of general violence in social relationships were positively related to acceptability of IPV and (b) the highest levels of acceptability of IPV were found among those sexist individuals who also present positive attitudes toward the use of violence in social relationships. PMID- 27126859 TI - Oxygenation, local muscle oxygen consumption and joint specific power in cycling: the effect of cadence at a constant external work rate. AB - PURPOSE: The present study investigates the effect of cadence on joint specific power and oxygenation and local muscle oxygen consumption in the vastus lateralis and vastus medialis in addition to the relationship between joint specific power and local muscle oxygen consumption (mVO2). METHODS: Seventeen recreationally active cyclists performed 6 stages of constant load cycling using cadences of 60, 70, 80, 90, 100 and 110 rpm. Joint specific power was calculated using inverse dynamics and mVO2 and oxygenation were measured using near-infrared spectroscopy. RESULTS: Increasing cadence led to increased knee joint power and decreased hip joint power while the ankle joint was unaffected. Increasing cadence also led to an increased deoxygenation in both the vastus lateralis and vastus medialis. Vastus lateralis mVO2 increased when cadence was increased. No effect of cadence was found for vastus medialis mVO2. CONCLUSION: This study demonstrates a different effect of cadence on the mVO2 of the vastus lateralis and vastus medialis. The combined mVO2 of the vastus lateralis and medialis showed a linear increase with increasing knee joint specific power, demonstrating that the muscles combined related to power generated over the joint. PMID- 27126861 TI - Domestic Violence Shelters' Efforts to Prevent Teen Dating Violence: A National Survey. AB - This research note reports data from a national survey of 213 domestic violence shelters regarding their teen dating violence (TDV) prevention efforts. More than half of the shelters reported that they provide TDV programing to at least 1/2 of the high schools in their communities; about 1/3 of shelters provide TDV programming to parents. Approximately 85% of shelters reported that they use or adapt a TDV curriculum. Shelters use information booths and Internet-based activities most often to increase public awareness, and they work through coalitions to advocate for TDV prevention efforts. This study is a first step toward documenting shelters' TDV prevention work. PMID- 27126862 TI - Household Financial Management and Women's Experiences of Intimate Partner Violence in the Philippines: A Study Using Propensity Score Methods. AB - This study explores the causal impact of independent management of household finances upon women's experiences of intimate partner violence (IPV) in the Philippines. Propensity score matching is used to generate a casual estimate of the impact of women's roles as household financial managers on their experiences of IPV. Findings demonstrate that managing household finances independently significantly increased the severity of IPV women experienced from their partners compared with women who managed finances jointly with partners. Findings reinforce the importance of explicit attention to intrahousehold power dynamics and gender norms in the implementation of microfinance interventions intended to empower women. PMID- 27126864 TI - Prescribing sodium oxybate for narcolepsy. PMID- 27126863 TI - Genomes of parasitic nematodes (Meloidogyne hapla, Meloidogyne incognita, Ascaris suum and Brugia malayi) have a reduced complement of small RNA interference pathway genes: knockdown can reduce host infectivity of M. incognita. AB - The discovery of RNA interference (RNAi) as an endogenous mechanism of gene regulation in a range of eukaryotes has resulted in its extensive use as a tool for functional genomic studies. It is important to study the mechanisms which underlie this phenomenon in different organisms, and in particular to understand details of the effectors that modulate its effectiveness. The aim of this study was to identify and compare genomic sequences encoding genes involved in the RNAi pathway of four parasitic nematodes: the plant parasites Meloidogyne hapla and Meloidogyne incognita and the animal parasites Ascaris suum and Brugia malayi because full genomic sequences were available-in relation to those of the model nematode Caenorhabditis elegans. The data generated was then used to identify some potential targets for control of the root knot nematode, M. incognita. Of the 84 RNAi pathway genes of C. elegans used as model in this study, there was a 42-53 % reduction in the number of effectors in the parasitic nematodes indicating substantial differences in the pathway between species. A gene each from six functional groups of the RNAi pathway of M. incognita was downregulated using in vitro RNAi, and depending on the gene (drh-3, tsn-1, rrf-1, xrn-2, mut-2 and alg-1), subsequent plant infection was reduced by up to 44 % and knockdown of some genes (i.e. drh-3, mut-2) also resulted in abnormal nematode development. The information generated here will contribute to defining targets for more robust nematode control using the RNAi technology. PMID- 27126865 TI - Impacts of nutrients and pesticides from small- and large-scale agriculture on the water quality of Lake Ziway, Ethiopia. AB - The area around Lake Ziway in Ethiopia is going through a major agricultural transformation with both small-scale farmers and large horticultural companies using pesticides and fertilisers at an increased rate. To be able to understand how this influences the water quality of Lake Ziway, water quality data was gathered to study the dynamics of pesticide concentrations and physicochemical parameters for the years from 2009 to 2015. Results indicate that for some physicochemical parameters, including pH, potassium and iron, over 50 % of the values were above the maximum permissible limit of the Ethiopian standard for drinking water. The fungicide spiroxamine poses a high chronic risk when the water is used for drinking water, while the estimated intake of diazinon was approximately 50 % of the acceptable daily intake. Higher-tier risk assessment indicated that the fungicide spiroxamine poses a high acute risk to aquatic organisms, while possible acute risks were indicated for the insecticides deltamethrin and endosulfan. Longer-term monitoring needs to be established to show the water quality changes across time and space, and the current study can be used as a baseline measurement for further research in the area as well as an example for other surface water systems in Ethiopia and Africa. PMID- 27126866 TI - Thermal dechlorination of heavily PCB-contaminated soils from a sealed site of PCB-containing electrical equipment. AB - A large amount of soils are contaminated by leakage of polychlorinated biphenyls (PCBs) from sealed-up PCB-containing electrical equipment in China. Thermal dechlorination of soils contaminated with PCBs at a level of 108 mg g(-1) and PCB77 (3,3',4,4'-tetrachlorobiphenyl) as a model isomer in conjunction with calcium oxide was investigated in this study. The PCB dechlorination rate improved with increased temperature and time. The highest dechlorination rate was 85.3 %, and temperature was the main influencing factor. Pentachlorobiphenyl and tetrachlorobiphenyl in soils decreased or disappeared in response to treatment at 350 and 400 degrees C for 4 h, while monochlorinated biphenyl and biphenyl were detected after the reaction, indicating the presence of a dechlorination/hydrogenation pathway. Discrepancy in chlorine balance was observed after low-temperature thermal dechlorination. The species of dechlorination products were identified as amorphous carbon containing a crystalline graphite plane structure and a carbonyl group-containing polymerized product, demonstrating the existence of a dechlorination/polymerization pathway. The yield of amorphous carbon and high-molecular-weight intermediates increased with heating time. The results showed that the discrepancy in chlorine balance was because of the generation of polymerized products and undetected intermediates. PMID- 27126867 TI - How do PDMS-coated stir bars used as passive samplers integrate concentration peaks of pesticides in freshwater? AB - Passive samplers are theoretically capable of integrating variations of concentrations of micropollutants in freshwater and providing accurate average values. However, this property is rarely verified and quantified experimentally. In this study, we investigated, in controlled conditions, how the polydimethylsiloxane-coated stir bars (passive Twisters) can integrate fluctuating concentrations of 20 moderately hydrophilic to hydrophobic pesticides (2.18 < Log K ow < 5.51). In the first two experiments, we studied the pesticide accumulation in the passive Twisters during high concentration peaks of various durations in tap water. We then followed their elimination from the passive Twisters placed in non-contaminated water (experiment no. 1) or in water spiked at low concentrations (experiment no. 2) for 1 week. In the third experiment, we assessed the accuracy of the time-weighted average concentrations (TWAC) obtained from the passive Twisters exposed for 4 days to several concentration variation scenarios. We observed little to no elimination of hydrophobic pesticides from the passive Twisters placed in non-contaminated water and additional accumulation when placed in water spiked at low concentrations. Moreover, passive Twisters allowed determining accurate TWAC (accuracy, determined by TWAC-average measured concentrations ratios, ranged from 82 to 127 %) for the pesticides with Log K ow higher than 4.2. In contrast, fast and large elimination was observed for the pesticides with Log K ow lower than 4.2 and poorer TWAC accuracy (ranging from 32 to 123 %) was obtained. PMID- 27126870 TI - Simplified continuous simulation model for investigating effects of controlled drainage on long-term soil moisture dynamics with a shallow groundwater table. AB - Accurate modeling of soil water content is required for a reasonable prediction of crop yield and of agrochemical leaching in the field. However, complex mathematical models faced the difficult-to-calibrate parameters and the distinct knowledge between the developers and users. In this study, a deterministic model is presented and is used to investigate the effects of controlled drainage on soil moisture dynamics in a shallow groundwater area. This simplified one dimensional model is formulated to simulate soil moisture in the field on a daily basis and takes into account only the vertical hydrological processes. A linear assumption is proposed and is used to calculate the capillary rise from the groundwater. The pipe drainage volume is calculated by using a steady-state approximation method and the leakage rate is calculated as a function of soil moisture. The model is successfully calibrated by using field experiment data from four different pipe drainage treatments with several field observations. The model was validated by comparing the simulations with observed soil water content during the experimental seasons. The comparison results demonstrated the robustness and effectiveness of the model in the prediction of average soil moisture values. The input data required to run the model are widely available and can be measured easily in the field. It is observed that controlled drainage results in lower groundwater contribution to the root zone and lower depth of percolation to the groundwater, thus helping in the maintenance of a low level of soil salinity in the root zone. PMID- 27126868 TI - Leaf-based physiological, metabolic, and ultrastructural changes in cultivated cotton cultivars under cadmium stress mediated by glutathione. AB - Cadmium (Cd) pollution is present in the world over especially in the industrialized parts of the world. To reduce Cd accumulation in various crops especially food crops, alleviating agents such as reduced glutathione (GSH) can be applied, which are capable either to exclude or to sequester Cd contamination. This study investigated the leaf-based spatial distribution of physiological, metabolic, and microstructural changes in two cotton cultivars (Coker 312 and TM 1) under GSH-mediated Cd stress using single levels of Cd (50 MUM) and GSH (50 MUM) both separately and in mix along with control. Results showed that GSH revived the morphology and physiology of both cotton cultivars alone or in mix with Cd. Cd uptake was enhanced in all segments of leaf and whole leaf upon the addition of GSH. GSH alleviated Cd-induced reduction in the photosynthetic pigment compositions and chlorophyll a fluorescence parameters. Mean data of biomarkers (2,3,5-triphenyltetrazolium (TTC), total soluble protein (TSP), malondialdehyde (MDA), hydrogen peroxide (H2O2)) revealed the adverse effects of Cd stress on leaf segments of both cultivars, which were revived by GSH. The oxidative metabolism induced by Cd stress was profoundly influenced by exogenous GSH application. The microstructural alterations were mainly confined to chloroplastic regions of leaves under Cd-stressed conditions, which were greatly revived upon the GSH addition. As a whole, Cd stress greatly affected TM-1 as compared to Coker 312. These results suggest a positive role of GSH in alleviating Cd-mediated changes in different leaf sections of cotton cultivars. PMID- 27126869 TI - Cryptosporidium and cryptosporidiosis: the African perspective. AB - The present overview discusses the findings of cryptosporidiosis research conducted in Africa and highlights the currently available information on Cryptosporidium epidemiology, genetic diversity, and distribution on the African continent, particularly among vulnerable populations, including children. It also emphasizes the burden of cryptosporidiosis, which is underestimated due to the presence of many silent asymptomatic carriers.Cryptosporidiosis is recognized as one of the leading causes of childhood diarrhea in African countries. It has dramatic adverse effects on child growth and development and causes increased mortality on a continent where HIV, poverty, and lack of sanitation and infrastructure increase the risk of cryptosporidial waterborne infection. PMID- 27126871 TI - Impact of titanium dioxide nanoparticles on the bacterial communities of biological activated carbon filter intended for drinking water treatment. AB - Titanium dioxide nanoparticles (TiO2 NPs) are inevitably present in the aquatic environment owing to their increasing production and use. However, knowledge of the potential effects of TiO2 NPs on the treatment of drinking water is scarce. Herein, the effects of two types of anatase TiO2 NPs (TP1, 25 nm; TP2, 100 nm) on the bacterial community in a biological activated carbon (BAC) filter were investigated via quantitative polymerase chain reaction (Q-PCR) analysis, ATP quantification, and 454 pyrosequencing analysis. Both TP1 and TP2 significantly inhibited the bacterial ATP level (p < 0.01) and induced a decrease in the abundance of bacterial 16S rDNA gene copies at doses of 0.1 and 100 mg L(-1). Simultaneously, the diversity and evenness of the bacterial communities were considerably reduced. The relative abundances of bacteria annotated to OTUs from Nitrospira class and Betaproteobacteria class decreased upon TiO2 NP treatment, whereas those of Bacilli class and Gammaproteobacteria class increased. TiO2 NP size showed a greater effect on the bacterial composition than did the dose based on Bray-Curtis distances. These findings identified negative effects of TiO2 NPs on the bacterial community in the BAC filter. Given the fact that BAC filters are used widely in drinking water treatment plants, these results suggested a potential threat by TiO2 NP to drinking water treatment system. PMID- 27126872 TI - Natural radioactivity and radiological hazard assessment of Egyptian oil ashes. AB - Oil fly and boiler ash samples were collected from the four major Egyptian power plants in order to determine their natural radioactivity. Secular equilibrium between (238)U and (232)Th and their decay products is significantly disturbed in oil ash samples. The (226)Ra/(238)U ratios were between 440 and 1993 with an average value of 801, indicating that the concentrations of daughters (226)Ra were very high compared to the parent (238)U in the oil ash samples. While, the average ratios for (210)Pb/(226)Ra in most samples were 1.19 +/- 0.05, indicating a secular equilibrium in the (226)Ra-(210)Pb sub series. The natural radioactivity due to (238)U and (232)Th was found to be negligible. While the activity concentrations of (226)Ra ranged from 3205 to 12,320 Bq kg(-1) with an average value of 9284 Bq kg(-1), (210)Pb ranged from 5960 to 13,930 Bq kg(-1) with an average value of 11,513 Bq kg(-1). The results are compared with the reported data from other countries. The average value of radium equivalent activity was 9308 +/- 2729 Bq kg(-1), while the external and internal hazard indexes were found to be 25 +/- 7 and 50 +/- 15, respectively. All the studied radiological parameters were higher than the recommended limit by the IAEA in all ash samples. PMID- 27126873 TI - Compensatory effects of pointing and predictive cueing on age-related declines in visuospatial working memory. AB - In this study, we investigated whether the visuospatial working memory performance of young and older adults would improve if they used a multimodal as compared with a unimodal encoding strategy, and whether or not visual cues would add to this effect. In Experiment 1, participants were presented with trials consisting of an array of squares and an array of circles. They were instructed to point at one type of figure (multimodal encoding strategy) and only to observe the other (unimodal encoding strategy). After each trial, an immediate location recognition test of one of the two arrays followed. In Experiment 2, the same task was used, but a cue was provided, either before or after the encoding phase, indicating which of the two arrays would be tested. Our results showed that a multimodal, as compared with a unimodal, encoding strategy improved visuospatial working memory performance in both young and older adults (Exp. 1), and that adding visual cues to the multimodal but not to the unimodal encoding strategy improved older adults' performance up to the level of young adults (Exp. 2). In both age groups, cueing after encoding led to higher performance in the multimodal than in the unimodal condition when the second array was tested. However, cueing before encoding led to higher performance in the multimodal than in the unimodal condition when the first array of the figure sequence was tested. These results suggest that pointing together with predictive cueing can have beneficial effects on visuospatial working memory, which is especially important for older adults. PMID- 27126874 TI - Inducing mental set constrains procedural flexibility and conceptual understanding in mathematics. AB - An important goal in mathematics is to flexibly use and apply multiple, efficient procedures to solve problems and to understand why these procedures work. One factor that may limit individuals' ability to notice and flexibly apply strategies is the mental set induced by the problem context. Undergraduate (N = 41, Experiment 1) and fifth- and sixth-grade students (N = 87, Experiment 2) solved mathematical equivalence problems in one of two set-inducing conditions. Participants in the complex-first condition solved problems without a repeated addend on both sides of the equal sign (e.g., 7 + 5 + 9 = 3 + _), which required multistep strategies. Then these students solved problems with a repeated addend (e.g., 7 + 5 + 9 = 7 + _), for which a shortcut strategy could be readily used (i.e., adding 5 + 9). Participants in the shortcut-first condition solved the same problem set but began with the shortcut problems. Consistent with laboratory studies of mental set, participants in the complex-first condition were less likely to use the more efficient shortcut strategy when possible. In addition, these participants were less likely to demonstrate procedural flexibility and conceptual understanding on a subsequent assessment of mathematical equivalence knowledge. These findings suggest that certain problem-solving contexts can help or hinder both flexibility in strategy use and deeper conceptual thinking about the problems. PMID- 27126876 TI - The role of electromagnetic fields in neurological disorders. PMID- 27126877 TI - Invasive hydatidiform mole of the lung with an implantation site intermediate trophoblast: Report of a case supporting the pathways of trophoblast differentiation. PMID- 27126875 TI - Sustainability of school-located influenza vaccination programs in Florida. AB - BACKGROUND: School-located influenza vaccination (SLIV) programs are a promising strategy for increasing vaccination coverage among schoolchildren. However, questions of economic sustainability have dampened enthusiasm for this approach in the United States. We evaluated SLIV sustainability of a health department led, county-wide SLIV program in Alachua County, Florida. Based on Alachua's outcome data, we modeled the sustainability of SLIV programs statewide using two different implementation costs and at different vaccination rates, reimbursement amount, and Vaccines for Children (VFC) coverage. METHODS: Mass vaccination clinics were conducted at 69 Alachua County schools in 2013 using VFC (for Medicaid and uninsured children) and non-VFC vaccines. Claims were processed after each clinic and submitted to insurance providers for reimbursement ($5 Medicaid and $47.04 from private insurers). We collected programmatic expenditures and volunteer hours to calculate fixed and variable costs for two different implementation costs (with or without in-kind costs included). We project program sustainability for Florida using publicly available county specific student populations and health insurance enrollment data. RESULTS: Approximately 42% (n=12,853) of pre-kindergarten - 12th grade students participated in the SLIV program in Alachua. Of the 13,815 doses provided, 58% (8042) were non-VFC vaccine. Total implementation cost was $14.95/dose or $7.93/dose if "in-kind" costs were not included. The program generated a net surplus of $24,221, despite losing $4.68 on every VFC dose provided to Medicaid and uninsured children. With volunteers, 99% of Florida counties would be sustainable at a 50% vaccination rate and average reimbursement amount of $3.25 VFC and $37 non-VFC. Without volunteers, 69% of counties would be sustainable at 50% vaccination rate if all VFC recipients were on Medicaid and its reimbursement increased from $5 to $10 (amount private practices receive). CONCLUSIONS AND RELEVANCE: Key factors that contributed to the sustainability and success of an SLIV program are: targeting privately insured children and reducing administration cost through volunteers. Counties with a high proportion of VFC eligible children may not be sustainable without subsidies at $5 Medicaid reimbursement. PMID- 27126878 TI - A symbiotic view of the origin of life at hydrothermal impact crater-lakes. AB - Submarine hydrothermal vents are generally considered as the likely habitats for the origin and evolution of early life on Earth. The theory suffers from the 'concentration problem' of cosmic and terrestrial biomolecules because of the vastness of the Eoarchean global ocean. An attractive alternative site would be highly sequestered, small, hydrothermal crater-lakes that might have cradled life on early Earth. A new symbiotic model for the origin of life at hydrothermal crater-lakes is proposed here. Meteoritic impacts on the Eoarchean crust at the tail end of the Heavy Bombardment period might have played important roles in the origin of life. Impacts and collisions that created hydrothermal crater lakes on the Eoarchean crust inadvertently became the perfect crucibles for prebiotic chemistry with building blocks of life, which ultimately led to the first organisms by prebiotic synthesis. In this scenario, life arose through four hierarchical stages of increasing molecular complexity in multiple niches of crater basins. In the cosmic stage (>=4.6 Ga), the building blocks of life had their beginnings in the interstellar space during the explosion of a nearby star. Both comets and carbonaceous chondrites delivered building blocks of life and ice to early Earth, which were accumulated in hydrothermal impact crater-lakes. In the geologic stage (~4 Ga), crater basins contained an assortment of cosmic and terrestrial organic compounds, powered by hydrothermal, solar, tidal, and chemical energies, which drove the prebiotic synthesis. At the water surface, self-assembled primitive lipid membranes floated as a thick oil slick. Archean Greenstone belts in Greenland, Australia, and South Africa possibly represent the relics of these Archean craters, where the oldest fossils of thermophilic life (~3.5 Ga) have been detected. In the chemical stage, monomers such as nucleotides and amino acids were selected from random assemblies of the prebiotic soup; they were polymerized at pores of mineral surfaces with the coevolution of RNA and protein molecules to form the 'RNA/protein world'. Lipid membranes randomly encapsulated these RNA and protein molecules to initiate a molecular symbiosis in a 'RNA/protein/lipid world' that led to hierarchical emergence of several cell components: plasma membranes, ribosomes, coding RNA and proteins, DNA, and finally protocells with a primitive genetic code. In the biological stage, the emergence of the first cells capable of reproduction, heredity, variation, and Darwinian evolution is the key breakthrough in the origin of life. RNA virus and prions may represent the evolutionary relics of the RNA/protein world that survived as parasites for billions of years. Although the proposed endosymbiotic model is speculative it has intrinsic heuristic value. Future experiments on encapsulated RNA virus and prions have the potential to create a synthetic cell that may confirm a coherent narrative of this hierarchical evolutionary sequence. PMID- 27126879 TI - Spawning behaviour of Allis shad Alosa alosa: new insights based on imaging sonar data. AB - Spawning behaviour of Alosa alosa was observed by high resolution imaging sonar. Detected clouds of sexual products and micro bubbles served as a potential indicator of spawning activity. Peak spawning time was between 0130 and 0200 hours at night. Increasing detections over three consecutive nights were consistent with sounds of mating events (bulls) assessed in hearing surveys in parallel to the hydro acoustic detection. In 70% of the analysed mating events there were no additional A. alosa joining the event whilst 70% of the mating events showed one or two A. alosa leaving the cloud. In 31% of the analysed mating events, however, three or more A. alosa were leaving the clouds, indicating that matings are not restricted to a pair. Imaging sonar is suitable for monitoring spawning activity and behaviour of anadromous clupeids in their spawning habitats. PMID- 27126880 TI - Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity. AB - Serotonin (5-hydroxytryptamine [5-HT]) is a monoamine that has various functions in both neuronal and non-neuronal systems. In the central nervous system, 5-HT regulates mood and feeding behaviors as a neurotransmitter. Thus, there have been many trials aimed at increasing the activity of 5-HT in the central nervous system, and some of the developed methods are already used in the clinical setting as anti-obesity drugs. Unfortunately, some drugs were withdrawn due to the development of unwanted peripheral side effects, such as valvular heart disease and pulmonary hypertension. Recent studies revealed that peripheral 5-HT plays an important role in metabolic regulation in peripheral tissues, where it suppresses adaptive thermogenesis in brown adipose tissue. Inhibition of 5-HT synthesis reduced the weight gain and improved the metabolic dysfunction in a diet-induced obesity mouse model. Genome-wide association studies also revealed genetic associations between the serotonergic system and obesity. Several genetic polymorphisms in tryptophan hydroxylase and 5-HT receptors were shown to have strong associations with obesity. These results support the clinical significance of the peripheral serotonergic system as a therapeutic target for obesity and diabetes. PMID- 27126882 TI - Potential of OneTouch Diabetes Management Software System in Real Field for Korean Type 2 Diabetes Patients. PMID- 27126881 TI - An Update on the Effect of Incretin-Based Therapies on beta-Cell Function and Mass. AB - Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a complex and progressive pathogenesis. The two primary mechanisms of T2DM pathogenesis are pancreatic beta-cell dysfunction and insulin resistance. Pancreatic beta-cell dysfunction is recognized to be a prerequisite for the development of T2DM. Therapeutic modalities that improve beta-cell function are considered critical to T2DM management; however, blood glucose control remains a challenge for many patients due to suboptimal treatment efficacy and the progressive nature of T2DM. Incretin-based therapies are now the most frequently prescribed antidiabetic drugs in Korea. Incretin-based therapies are a favorable class of drugs due to their ability to reduce blood glucose by targeting the incretin hormone system and, most notably, their potential to improve pancreatic beta-cell function. This review outlines the current understanding of the incretin hormone system in T2DM and summarizes recent updates on the effect of incretin-based therapies on beta cell function and beta-cell mass in animals and humans. PMID- 27126883 TI - Clinical Evaluation of OneTouch Diabetes Management Software System in Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: OneTouch Diabetes Management Software (OTDMS) is an efficient way to track and monitor the blood glucose level. It is possible to download data from the OneTouch Ultra via the meter's data port, and to transform the numbers of the blood glucose level into a graph, a chart, or statistics. The objectives of this study were to evaluate whether the use of OTDMS in consultation hours would improve patients' knowledge of diabetes mellitus (DM), compliance, satisfaction with doctor and medical treatment, doctor-patient reliability, and glucose control. METHODS: All patients were randomized into either the OTDMS group using OneTouch Ultra or the control groups not using it. Both groups had conventional DM education and only the OTDMS group used data from OTDMS as explanation materials during consultation hours. At enrollment and after 6 months, we performed a questionnaire survey consisting of the diabetes knowledge test, items for compliance of treatment, patient's satisfaction, doctor-patient reliability, and glycosylated hemoglobin (HbA1c). RESULTS: We analyzed 6-month follow-up data from 92 patients (OTDMS 42 vs. control 50). Both groups showed significant improvements in HbA1c, diabetes knowledge, compliance, reliability, and satisfaction after 6 months. However, there were no significant differences between OTDMS and control groups overall. Only "weekly frequency of checking blood glucose level" of compliance and "trying to follow doctor's order" of reliability showed better results in the OTDMS group. CONCLUSION: Using the OTDMS system for explanation during consultation hours seems to be more helpful to improve patient's compliance and reliability, especially for checking blood glucose level and trying to follow the doctor's order. PMID- 27126884 TI - Hyperglycemia Is Associated with Impaired Muscle Quality in Older Men with Diabetes: The Korean Longitudinal Study on Health and Aging. AB - BACKGROUND: The study aimed to investigate the influence of hyperglycemia on muscle quality in older men with type 2 diabetes. METHODS: This was a subsidiary study of the Korean Longitudinal Study of Health and Aging. Among 326 older men consenting to tests of body composition and muscle strength, 269 men were ultimately analyzed after the exclusion because of stroke (n=30) and uncertainty about the diagnosis of diabetes (n=27). Body composition was measured using dual energy X-ray absorptiometry and computed tomography. Muscle strength for knee extension was measured using an isokinetic dynamometer. Muscle quality was assessed from the ratio of leg strength to the entire corresponding leg muscle mass. RESULTS: The muscle mass, strength, and quality in patients with type 2 diabetes did not differ significantly from controls. However, when patients with diabetes were subdivided according to their glycemic control status, patients with a glycosylated hemoglobin (HbA1c) level of >=8.5% showed significantly decreased leg muscle quality by multivariate analysis (odds ratio, 4.510; P=0.045) after adjustment for age, body mass index, smoking amount, alcohol consumption, physical activity, and duration of diabetes. Physical performance status was also impaired in subjects with an HbA1c of >=8.5%. CONCLUSION: Poor glycemic control in these older patients with diabetes was associated with significant risk of decreased muscle quality and performance status. Glycemic control with an HbA1c of <8.5% might be needed to reduce the risk of adverse skeletal and functional outcomes in this population. PMID- 27126885 TI - Importance of Lean Muscle Maintenance to Improve Insulin Resistance by Body Weight Reduction in Female Patients with Obesity. AB - BACKGROUND: It has recently been suggested that skeletal muscle has an important role in insulin resistance in obesity, in addition to exercise tolerance and the fat index. The aim of this study was to identify body composition factors that contribute to improvement of insulin resistance in female patients with obesity who reduce body weight. METHODS: We studied 92 female obese patients (age 40.9+/ 10.4 years, body mass index 33.2+/-4.6 kg/m2) who reduced body weight by >=5% after an intervention program including diet, exercise therapy, and cognitive behavioral therapy. Before and after the intervention, body composition was evaluated by dual-energy X-ray absorptiometry to examine changes in skeletal muscle mass. Homeostasis model assessment of insulin resistance (HOMA-IR) was measured as an index of insulin resistance. Cardiopulmonary exercise was also performed by all patients. RESULTS: There were significant improvements in body weight (-10.3%+/-4.5%), exercise tolerance (anaerobic threshold oxygen uptake 9.1%+/-18.4%, peak oxygen uptake 11.0%+/-14.2%), and HOMA-IR (-20.2%+/-38.3%). Regarding body composition, there were significant decreases in total body fat ( 19.3%+/-9.6%), total fat-free mass (-2.7%+/-4.3%), and % body fat (-10.1%+/ 7.5%), whereas % skeletal muscle significantly increased (8.9%+/-7.2%). In stepwise multiple linear regression analysis with change in HOMA-IR as the dependent variable, the change in % skeletal muscle was identified as an independent predictor (beta=-0.280, R2=0.068, P<0.01). CONCLUSION: Improvement of insulin resistance in female obese patients requires maintenance of skeletal muscle mass. PMID- 27126886 TI - The Effect of Glycemic Status on Kidney Stone Disease in Patients with Prediabetes. AB - BACKGROUND: While the evidence supporting a positive association between diabetes mellitus and kidney stone disease (KSD) is solid, studies examining the association between impaired fasting glucose (IFG) and KSD show inconsistent results. Currently, there are no studies examining the relationship between impaired glucose tolerance (IGT) and KSD. The objective of this study is to investigate the effects of different glycemic statuses on KSD. The results may help to motivate patients with diabetes to conform to treatment regimens. METHODS: We conducted a cross sectional study of a population that underwent health check-ups between January 2000 and August 2009 at the Health Evaluation Center of National Cheng Kung University Hospital. A total of 14,186 subjects were enrolled. The following categories of glycemic status were used according to the criteria of the 2009 American Diabetes Association: normal glucose tolerance, isolated IGT, isolated IFG, combined IFG/IGT, and diabetes. The existence of KSD was evaluated using renal ultrasonography, and the presence of any hyperechoic structures causing acoustic shadowing was considered to be indicative of KSD. RESULTS: The prevalence of KSD was 7.4% (712/9,621), 9.3% (163/1,755), 10.8% (78/719), 12.0% (66/548), and 11.3% (174/1,543) in subjects with NGT, isolated IGT, isolated IFG, combined IFG/IGT, and diabetes, respectively. Isolated IFG, combined IFG/IGT, and diabetes were associated with KSD after adjusting for other clinical variables, but isolated IGT was not. Age (41 to 64 years vs. <=40 years, >=65 years vs. <=40 years), male gender, hypertension, and hyperuricemia were also independently associated with KSD. CONCLUSION: Isolated IFG, combined IFG/IGT, and diabetes, but not isolated IGT, were associated with a higher risk of KSD. PMID- 27126887 TI - Glycosylated Hemoglobin Threshold for Predicting Diabetes and Prediabetes from the Fifth Korea National Health and Nutrition Examination Survey. AB - We aimed to estimate the threshold level of glycosylated hemoglobin (HbA1c) for the fasting plasma glucose of 100 and 126 mg/dL in the Korean adult population, using the 2011 Korea National Health and Nutrition Examination Survey. A total of 4,481 participants over 19 years of age without diabetic medications and conditions to influence the interpretation of HbA1c levels, such as anemia, renal insufficiency, liver cirrhosis, and cancers, were analyzed. A point-wise area under the receiver operating characteristic curve was used to estimate the optimal HbA1c cutoff value. A HbA1c threshold of 6.35% was optimal for predicting diabetes with a sensitivity of 86.9% and a specificity of 99.1%. Furthermore, the threshold of HbA1c was 5.65% for prediabetes, with a sensitivity of 69.3% and a specificity of 71%. Further prospective studies are needed to evaluate the HbA1c cutoff point for diagnosing prediabetes and diabetes in the Korean population. PMID- 27126888 TI - Letter: The Association of Serum Cystatin C with Glycosylated Hemoglobin in Korean Adults (Diabetes Metab J 2016;40:62-9). PMID- 27126889 TI - Response: The Association of Serum Cystatin C with Glycosylated Hemoglobin in Korean Adults (Diabetes Metab J 2016;40:62-9). PMID- 27126890 TI - An approach to holistically assess (dairy) farm eco-efficiency by combining Life Cycle Analysis with Data Envelopment Analysis models and methodologies. AB - Eco-efficiency is a useful guide to dairy farm sustainability analysis aimed at increasing output (physical or value added) and minimizing environmental impacts (EIs). Widely used partial eco-efficiency ratios (EIs per some functional unit, e.g. kg milk) can be problematic because (i) substitution possibilities between EIs are ignored, (ii) multiple ratios can complicate decision making and (iii) EIs are not usually associated with just the functional unit in the ratio's denominator. The objective of this study was to demonstrate a 'global' eco efficiency modelling framework dealing with issues (i) to (iii) by combining Life Cycle Analysis (LCA) data and the multiple-input, multiple-output production efficiency method Data Envelopment Analysis (DEA). With DEA each dairy farm's outputs and LCA-derived EIs are aggregated into a single, relative, bounded, dimensionless eco-efficiency score, thus overcoming issues (i) to (iii). A novelty of this study is that a model providing a number of additional desirable properties was employed, known as the Range Adjusted Measure (RAM) of inefficiency. These properties altogether make RAM advantageous over other DEA models and are as follows. First, RAM is able to simultaneously minimize EIs and maximize outputs. Second, it indicates which EIs and/or outputs contribute the most to a farm's eco-inefficiency. Third it can be used to rank farms in terms of eco-efficiency scores. Thus, non-parametric rank tests can be employed to test for significant differences in terms of eco-efficiency score ranks between different farm groups. An additional DEA methodology was employed to 'correct' the farms' eco-efficiency scores for inefficiencies attributed to managerial factors. By removing managerial inefficiencies it was possible to detect differences in eco-efficiency between farms solely attributed to uncontrollable factors such as region. Such analysis is lacking in previous dairy studies combining LCA with DEA. RAM and the 'corrective' methodology were demonstrated with LCA data from French specialized dairy farms grouped by region (West France, Continental France) and feeding strategy (regardless of region). Mean eco efficiency score ranks were significantly higher for farms with 30% maize in the total forage area before correcting for managerial inefficiencies. Mean eco efficiency score ranks were higher for West than Continental farms, but significantly higher only after correcting for managerial inefficiencies. These results helped identify the eco-efficiency potential of each region and feeding strategy and could therefore aid advisors and policy makers at farm or region/sector level. The proposed framework helped better measure and understand (dairy) farm eco-efficiency, both within and between different farm groups. PMID- 27126891 TI - Gyration and Permittivity of Ethylenediammonium Sulfate Crystals. AB - Ethylenediammonium sulfate (EDS) crystals were grown from aqueous solution and cleaved into thin (100-500 micron) plates. The 422 point group of EDS was confirmed by X-ray diffraction. The constitutive relations of EDS crystals were determined through generalized ellipsometry with an instrument that uses four photoelastic modulators (4PEM). The optical rotation at 500 nm, for example, was + 22.9 degrees /mm along the optic axis and - 12.1 degrees /mm perpendicular to the optic axis for the P41 21 2 crystals. Enantiomorphous twins frequently form across the (001) plane. Mirrored halves must be separated by cleavage in advance of optical measurements. Chirality 28:460-465, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27126892 TI - Synovial chondromatosis involving multiple joints in rheumatoid arthritis: A case report review of the literature. PMID- 27126893 TI - Predictors of soft-tissue complications and deep infection in allograft reconstruction of the proximal tibia. AB - BACKGROUND AND OBJECTIVES: Reconstruction of the proximal tibia after wide resection of malignant tumors in the pediatric population is very challenging. Advocates of allograft reconstruction argue as advantages bone preservation, biological reconstruction that facilitates reattachment of the extensor mechanism and other soft-tissue structures, delay of metallic prosthesis use and preservation of the distal femoral growth plate. However, complications are significant, infection being very common. METHODS: Under IRB-approved protocol, 32 patients (17 males, 15 females), 13 years old in average (2-20), who underwent 33 allograft reconstructions of the proximal tibia, were evaluated for the occurrence of soft-tissue complications and/or deep infection (infection affecting the allograft). Potential predictors of soft-tissue complications and deep infection, categorized as pre- and perioperative variables, were analyzed in relation to the risk for developing a soft-tissue complication or a deep infection. RESULTS: The prevalence of soft-tissue complications was 48% (16/33). However, we were not able to identify any significant predictors. The prevalence of deep (allograft) infection was 15% (5/33). Multivariate logistic regression determined higher BMI at the index surgical procedure and lower pre-operative WBC to be independent predictors of deep infection. For each unit of increase in BMI, the odds of deep infection increased by 40% (OR = 1.40; CI = 1.07-3.06; P < 0.05). For each one unit (1,000) of increase in the pre-operative white cell count, the odds of deep infection decreased by 70% (OR = 0.30; 95%CI = 0.01-0.89; P < 0.05). Four of the five deep infections were in patients with soft-tissue complications, mainly wound dehiscence. However, wound dehiscence or soft-tissue complications were not predictive of deep infection. CONCLUSION: Soft-tissue complications are prevalent in allograft reconstruction of the proximal tibia. Prevention is important as these may progress to deep infection. Careful attention to nutritional (BMI) and immunological status may help in patient selection for allograft reconstruction. If allograft reconstruction is opted for, efforts should focus on optimization of these factors as they proved to be independent predictors of subsequent deep infection. J. Surg. Oncol. 2016;113:811 817. (c) 2016 Wiley Periodicals, Inc. PMID- 27126895 TI - The kinematic differences between off-spin and leg-spin bowling in cricket. AB - Spin bowling is generally coached using a standard technical framework, but this practice has not been based upon a comparative biomechanical analysis of leg-spin and off-spin bowling. This study analysed the three-dimensional (3D) kinematics of 23 off-spin and 20 leg-spin bowlers using a Cortex motion analysis system to identify how aspects of the respective techniques differed. A multivariate ANOVA found that certain data tended to validate some of the stated differences in the coaching literature. Off-spin bowlers had a significantly shorter stride length (p = 0.006) and spin rate (p = 0.001), but a greater release height than leg spinners (p = 0.007). In addition, a number of other kinematic differences were identified that were not previously documented in coaching literature. These included a larger rear knee flexion (p = 0.007), faster approach speed (p < 0.001), and flexing elbow action during the arm acceleration compared with an extension action used by most of the off-spin bowlers. Off-spin and leg-spin bowlers also deviated from the standard coaching model for the shoulder alignment, front knee angle at release, and forearm mechanics. This study suggests that off-spin and leg-spin are distinct bowling techniques, supporting the development of two different coaching models in spin bowling. PMID- 27126894 TI - Herpesvirus Entry into Host Cells Mediated by Endosomal Low pH. AB - Herpesviral pathogenesis stems from infection of multiple cell types including the site of latency and cells that support lytic replication. Herpesviruses utilize distinct cellular pathways, including low pH endocytic pathways, to enter different pathophysiologically relevant target cells. This review details the impact of the mildly acidic milieu of endosomes on the entry of herpesviruses, with particular emphasis on herpes simplex virus 1 (HSV-1). Epithelial cells, the portal of primary HSV-1 infection, support entry via low pH endocytosis mechanisms. Mildly acidic pH triggers reversible conformational changes in the HSV-1 class III fusion protein glycoprotein B (gB). In vitro treatment of herpes simplex virions with a similar pH range inactivates infectivity, likely by prematurely activating the viral entry machinery in the absence of a target membrane. How a given herpesvirus mediates both low pH and pH-independent entry events is a key unresolved question. PMID- 27126897 TI - Chemical diversity and antiviral potential in the pantropical Diospyros genus. AB - A screening using a dengue replicon virus-cell-based assay was performed on 3563 ethyl acetate (EtOAc) extracts from different parts of 1500 plants. The screening led to the selection of species from the genus Diospyros (Ebenaceae), among which 25 species distributed in tropical areas showed significant inhibitory activity on dengue virus replication. A metabolic analysis was conducted from the UPLC HRMS profiles of 33 biologically active and inactive plant extracts, and their metabolic proximity is presented in the form of a dendrogram. The results of the study showed that chemical similarity is not related to plant species or organ. Overall, metabolomic profiling allowed us to define large groups of extracts, comprising both active and inactive ones. Closely related profiles from active extracts might indicate that the common major components of these extracts were responsible for the antiviral activity, while the comparison of chemically similar active and inactive extracts, will permit to find compounds of interest. Eventually, the phytochemical investigation of Diospyros glans bark EtOAc extract afforded usnic acid and 7 known ursane- and lupane-type triterpenoids, among which 5 were found significantly active against dengue virus replication. The inhibitory potency of these compounds was also evaluated on a DENV-NS5 RNA dependant RNA polymerase assay. PMID- 27126896 TI - Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. AB - Cellular amino acid uptake is critical for mTOR complex 1 (mTORC1) activation and cell proliferation. However, the regulation of amino acid uptake is not well understood. Here we describe a role for asparagine as an amino acid exchange factor: intracellular asparagine exchanges with extracellular amino acids. Through asparagine synthetase knockdown and altering of media asparagine concentrations, we show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine and histidine. Through its exchange factor role, asparagine regulates mTORC1 activity and protein synthesis. In addition, we show that asparagine regulation of serine uptake influences serine metabolism and nucleotide synthesis, suggesting that asparagine is involved in coordinating protein and nucleotide synthesis. Finally, we show that maintenance of intracellular asparagine levels is critical for cancer cell growth. Collectively, our results indicate that asparagine is an important regulator of cancer cell amino acid homeostasis, anabolic metabolism and proliferation. PMID- 27126898 TI - Optimal combination of FLAIR and T2-weighted MRI for improved lesion contrast in multiple sclerosis. AB - PURPOSE: Postacquisition combination of three-dimensional T2-weighted (T2w) and fluid-attenuated inversion recovery (FLAIR) images can improve the visualization of brain lesions in multiple sclerosis (MS). However, an optimal way to combine these images has not been described so far. The main objective of this study is to investigate an optimal combination of T2w and FLAIR to improve the conspicuity of MS lesions. MATERIALS AND METHODS: We determined the parameters for a generalized multiplicative image combination which maximize the contrast-to-noise ratio (CNR) between lesions and normal-appearing brain tissue through simulations and verified experimentally. MRI data from 11 MS patients acquired at 3 Tesla were retrospectively analyzed using the proposed approach and compared with conventional FLAIR, and to images obtained by direct multiplication of T2w and FLAIR (FLAIR2 ). Image quality was assessed by region-of-interest analysis. In addition, to evaluate the degree of cerebrospinal fluid (CSF) suppression, CSF-to gray matter (CSF/GM) ratio was calculated. Reduction in global image contrast was assessed by computing the reduction in the contrast of mid-level intensity values. RESULTS: An optimal combination was found to be the third order expression: FLAIR3 = FLAIR1.55 * T2w1.45 . Compared with FLAIR, the lesion CNR was significantly increased by 1.9* (P < 0.005) and 2.5* (P < 0.001) using FLAIR2 and FLAIR3 , respectively. CSF/GM ratio was increased by 1.7* in FLAIR2 (P < 0.001) compared with FLAIR, while it was reduced to 0.7* on FLAIR3 (P < 0.05). The mid-intensity contrast was preserved on FLAIR2 (P = 0.2), and decreased by 29% on FLAIR3 (P < 0.001). CONCLUSION: These results show that the optimized combination of FLAIR and T2w can improve MS lesion conspicuity. J. Magn. Reson. Imaging 2016;44:1293-1300. PMID- 27126899 TI - Effect of carotid endarterectomy on brain damage markers. AB - OBJECTIVES: Carotid endarterectomy (CEA) is a recommended treatment in the prevention of ischemic stroke. However, this procedure may cause neurological complications caused by cerebrovascular damage. While YKL-40 is a proinflammatory protein, neurofilament light polypeptide (NEFL) and brain lipid-binding protein (FABP7) are structural components of the brain. The aim of the study was to investigate YKL-40, NEFL, and FABP7 in the serum of patients undergoing CEA. MATERIALS AND METHODS: The study included 25 participants who underwent CEA due to internal carotid artery stenosis. Blood samples were taken from each patient at three different intervals: prior to the surgery, 12 h after the surgery, and 48 h after the surgery. Serum levels of these brain damage markers were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The study showed that the serum YKL-40 level was significantly increased 48 h after CEA when compared to the level prior to surgery and also when compared to levels 12 h after surgery. There were no statistically significant differences in serum NEFL and FABP7 levels between all three recorded measurements. CONCLUSIONS: Data from our study showed that CEA affects serum YKL-40 but not NEFL and FABP7 levels. This implicates that YKL-40 may be a valuable serum marker of brain damage after CEA. However, the observed change in serum YKL-40 level in patients after CEA does not necessarily warrant a change in recommendations concerning the use of this treatment in patients with high-grade internal carotid artery stenosis. PMID- 27126900 TI - Single-wall carbon nanotubes and graphene oxide-based saturable absorbers for low phase noise mode-locked fiber lasers. AB - Low phase noise mode-locked fiber laser finds important applications in telecommunication, ultrafast sciences, material science, and biology, etc. In this paper, two types of carbon nano-materials, i.e. single-wall carbon nanotube (SWNT) and graphene oxide (GO), are investigated as efficient saturable absorbers (SAs) to achieve low phase noise mode-locked fiber lasers. Various properties of these wall-paper SAs, such as saturable intensity, optical absorption and degree of purity, are found to be key factors determining the performance of the ultrafast pulses. Reduced-noise femtosecond fiber lasers based on such carbon based SAs are experimentally demonstrated, for which the phase noise has been reduced by more than 10 dB for SWNT SAs and 8 dB for GO SAs at 10 kHz. To the best of our knowledge, this is the first investigation on the relationship between different carbon material based SAs and the phase noise of mode-locked lasers. This work paves the way to generate high-quality low phase noise ultrashort pulses in passively mode-locked fiber lasers. PMID- 27126902 TI - Myiasis caused by Dermatobia hominis: countries with increased risk for travelers going to neotropic areas. AB - Here, we review the human botfly (Dermatobia hominis), which belongs to a group of Diptera generically known as "myiasis-causing flies," characterized by the ability of their larvae to develop in animal flesh. In addition to its medical and economic importance, there is an academic interest in this botfly because of its peculiar biology, particularly because a phoretic diptera is needed to complete the life cycle. The larvae penetrate the host's skin, causing furuncle like lesions that are pruritic, painful, and resemble subcutaneous nodules, producing irreversible perforations in the skin. Although D. hominis is distributed from Mexico to Argentina, a review performed by our working group from 1999 to 2015 determined that the countries with the highest infection rates in travelers are Belize, Bolivia, and Brazil. Interestingly, infected men show a higher variation in the distribution of the lesions than in women. Many treatment schemes have been suggested, including the application of highly dense liquids to the lesion to cause anoxia in the D. hominis larvae. We showed, for the first time, a Bayesian inference between D. hominis and other myiasis-causing flies. The flies grouped into two main clusters according to their capacity to produce facultative and obligatory myiasis, and D. hominis was phylogenetically close to Cuterebra spp. PMID- 27126903 TI - Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy. AB - The co-delivery of chemotherapeutic drugs and microRNAs (miR) represents a promising strategy for tumor therapy due to the synergistic effect achieved. In the present study, hydrophobic doxorubicin (DOX) and negatively charged miR-34a were simultaneously delivered via a reducible self-assembling disulfide cross linked stearyl-peptide-based micellar system (SHRss) using poly(l-arginine) poly(l-histidine)-stearoyl as the copolymer building unit. The nanoscale SHRss micelles exhibited a low critical micelle concentration (CMC) with positive surface charge. In addition, the present micellar system facilitated the escape of miR-34a from the endosome and release of DOX into the cell nucleus, leading to the downregulation of silent information regulator 1 (SIRT1) expression and inhibition of DU145 and PC3 androgen-independent prostate cancer cell proliferation. In addition, DOX and miR-34a, delivered by SHRss micelles, passively targeted tumor tissue. Furthermore, a synergistic anti-proliferative effect was observed compared with DOX or miR-34a treatment alone in vivo. Our results demonstrate that the SHRss micelles developed in the present study represent a promising approach for combined delivery of gene agents and hydrophobic chemotherapeutic drugs in cancer therapy. PMID- 27126901 TI - ETS transcription factors in embryonic vascular development. AB - At least thirteen ETS-domain transcription factors are expressed during embryonic hematopoietic or vascular development and potentially function in the formation and maintenance of the embryonic vasculature or blood lineages. This review summarizes our current understanding of the specific roles played by ETS factors in vasculogenesis and angiogenesis and the implications of functional redundancies between them. PMID- 27126904 TI - Stable polyanhydride synthesized from sebacic acid and ricinoleic acid. AB - Poly(anhydride) are unstable and prone to hydrolytic degradation and depolymerisation via anhydride interchange. They are stored at -20 degrees C, packed under inert atmosphere until use. We synthesized a new poly(anhydride) from ricinoleic (RA) and sebacic (SA) acid with alternating ester-anhydride structure that is stable at 25 degrees C for over 18months. The copolymer is also stable in chloroform solution and under gamma-irradiation. The polymer hydrolyses through anhydride cleavage lasting ~7days to form oligoesters, which are stable for >30days. The release of gentamycin from the synthesized alternate polymer matrix is sustained compared to the random copolymer. PMID- 27126906 TI - A scoping review of geographic information systems in maternal health. AB - BACKGROUND: Geographic information systems (GIS) are increasingly recognized tools in maternal health. OBJECTIVES: To evaluate the use of GIS in maternal health and to identify knowledge gaps and opportunities. SEARCH STRATEGY: Keywords broadly related to maternal health and GIS were used to search for academic articles and gray literature. SELECTION CRITERIA: Reviewed articles focused on maternal health, with GIS used as part of the methods. DATA COLLECTION AND ANALYSIS: Peer reviewed articles (n=40) and gray literature sources (n=30) were reviewed. MAIN RESULTS: Two main themes emerged: modeling access to maternal services and identifying risks associated with maternal outcomes. Knowledge gaps included a need to rethink spatial access to maternal care in low- and middle income settings, and a need for more explicit use of GIS to account for the geographical variation in the effect of risk factors on adverse maternal outcomes. Limited evidence existed to suggest that use of GIS had influenced maternal health policy. Instead, application of GIS to maternal health was largely influenced by policy priorities in global maternal health. CONCLUSIONS: Investigation of the role of GIS in contributing to future policy directions is warranted, particularly for elucidating determinants of global maternal health. PMID- 27126905 TI - Effects of postpartum mobile phone-based education on maternal and infant health in Ecuador. AB - OBJECTIVE: To evaluate the effects of a mobile phone-based intervention on postnatal maternal health behavior and maternal and infant health in a middle income country. METHODS: A prospective evaluation enrolled consecutive postpartum women at two public hospitals in Quito, Ecuador, between June and August 2012. Inclusion criteria were live birth, no neonatal intensive care admission, and Spanish speaking. Intervention and control groups were assigned via random number generation. The intervention included a telephone-delivered educational session and phone/text access to a nurse for 30days after delivery. Maternal and infant health indicators were recorded at delivery and 3months after delivery via chart review and written/telephone-administered survey. RESULTS: Overall, 102 women were assigned to the intervention group and 76 to the control group. At 3months, intervention participants were more likely to attend the infant's postnatal check up (P=0.022) and to breastfeed exclusively (P=0.005), and less likely to feed formula (P=0.016). They used more effective forms of contraception (more implants P=0.023; fewer condoms P=0.036) and reported fewer infant illnesses (P=0.010). There were no differences in maternal acute illness or check-up attendance. CONCLUSION: Mobile phone-based postnatal patient education is a promising strategy for improving breastfeeding, contraceptive use, and infant health in low resource settings; different strategies are needed to influence postpartum maternal health behavior. PMID- 27126907 TI - Incorporating uterine artery embolization in the treatment of cesarean scar pregnancy following diagnostic ultrasonography. AB - OBJECTIVE: To evaluate combining uterine artery embolization (UAE) with other treatments for cesarean scar pregnancy (CSP). METHODS: A retrospective study included patients attending the First affiliated Hospital of Xi'an Jiaotong University, China, between March 1, 2009 and March 31, 2014, who were diagnosed with CSP. Patients were classified by ultrasonography as having endogenous CSP (CSP type I [CSP-I]) or exogenous CSP (CSP type II [CSP-II]). Patient outcomes were compared between patients who underwent treatment that included or excluded UAE. Patient records were reviewed and patients were interviewed by telephone to report on recovery following treatment. RESULTS: In total, 52 patients met the inclusion criteria. In patients with CSP-I, the blood loss, length of hospital stay, and time before restoration of normal beta human chorionic gonadotropin levels were significantly higher in patients who were treated with methotrexate combined with dilatation and curettage compared with those treated with UAE combined with dilatation and curettage (P<0.05). In patients with CSP-II, blood loss was lower in patients treated with UAE combined with excision compared with excision alone (P<0.001). CONCLUSION: Incorporating UAE in the treatment of CSP-I and CSP-II was safe; CSP should be properly classified to select the appropriate treatment. PMID- 27126908 TI - Web-based instrument to assess skills in visual inspection of the cervix among healthcare providers. AB - OBJECTIVE: To validate a web-based instrument for assessing healthcare providers' skills in visual inspection with acetic acid or Lugol iodine (VIA/VILI) for the diagnosis and management of cervical intraepithelial neoplasia. METHODS: An observational cross-sectional study enrolled healthcare providers in a web-based assessment of VIA/VILI skills between August and November 2014. Participants participated in a four-module training course, followed by a multiple-choice test with 70 questions based on cervical photographs of HPV-positive women participating in cervical screening. Logistic regression was used to identify relationships between independent variables and success on the test. RESULTS: Overall, 255 participants completed the test and 99 (38.8%) passed. No correlation was found between age or sex and test performance. Compared with other healthcare workers, physicians (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.01-3.63; P=0.048), and participants with more colposcopy experience (OR 3.62, 95% CI 1.91-6.85; P<0.001) and postgraduate VIA/VILI training (OR 1.95, 95% CI 1.16-3.29; P=0.012) were more likely to pass the test. Participants who repeated the test (31/255 [12.2%]) were five times more likely to succeed on their second repeat (OR 5.89, 95% CI 1.46-23.73; P=0.013). CONCLUSION: Web-based training for VIA/VILI is feasible and can identify healthcare workers who are proficient in this technique. PMID- 27126909 TI - Intrapetrous Internal Carotid Artery: Evaluation of Exposure, Mobilization and Surgical Maneuvers Feasibility from a Retrosigmoid Approach in a Cadaveric Model. AB - OBJECTIVES: To provide a quantification of the exposure of the vertical and horizontal segments of the intrapetrous carotid artery (IPCA) and to evaluate the possibilities of its mobilization and of performing surgical maneuvers on it using the retrosigmoid approach. METHODS: Twelve surgical dissections were performed bilaterally on 6 fresh cadavers. Predissection computed tomography (CT) scans with bone fiducials for intraoperative navigation were acquired. A retrosigmoid craniectomy was performed. The inframeatal space was drilled, the horizontal (HoIPCA) and vertical (VeIPCA) segments of the IPCA were exposed, and their measurements were recorded. The carotid canal was enlarged, the artery was carefully detached from the bone, and a vessel loop was inserted in order to mobilize its horizontal segment. Afterwards we performed different surgical maneuvers: We inflated a 5-French Fogarty balloon to compress the IPCA and repaired a 7-mm arteriotomy with a running suture. Specimens underwent a new CT scan to evaluate the amount of bone removal and the integrity of the inner ear structures. RESULTS: The HoIPCA and VeIPCA were exposed and anatomically preserved in all specimens without injuring the surrounding neurovascular structures. The HoIPCA presented an average length of 24.89 mm (range: 19.41 31.47 mm), and the VeIPCA presented an average length of 10.07 mm (range: 8.92 11.58 mm). The possibility of IPCA mobilization and the feasibility of performing surgical maneuvers were demonstrated. Postdissection CT scan showed the preservation of inner ear structures. CONCLUSION: Exposure and mobilization of the IPCA using a retrosigmoid approach are feasible and could represent a viable option for the possibility of reaching a total resection of selected skull base tumors, even when involvement of the carotid canal is present. PMID- 27126911 TI - Pure Intrasellar Meningioma Mimicking Pituitary Macroadenoma: Magnetic Resonance Imaging and Review of the Literature. AB - Intrasellar meningioma originating from the sellar floor is extremely rare and is often indistinguishable from pituitary macroadenoma, both clinically and radiologically. Here, we report a case involving a 68-year-old patient with intrasellar meningioma possibly originating from the sellar floor and present a brief review of all previous cases reported in the English literature. PMID- 27126910 TI - Syringomyelia Caused by Traumatic Intracranial Hypotension: Case Report and Literature Review. AB - BACKGROUND: Syringomyelia due to intracranial hypotension is rarely described. As a consequence, intracranial hypotension is less recognized as a potential cause of syringomyelia or mistaken with Chiari type 1 malformation. The pathogeny is poorly understood, and we lack diagnostic and therapeutic strategies for this particular setting. CASE DESCRIPTION: We describe a 45-year-old patient who developed syringomyelia after about 10 years of undiagnosed intracranial hypotension caused by traumatic C6 cerebrospinal fluid (CSF) leak. Surgical closing of the leak was required to treat intracranial hypotension after failure of conservative measures and blind epidural patches. It led to a marked improvement of cerebral and spinal signs. We discuss the pathogeny of syringomyelia caused by intracranial hypotension and highlight a mechanical theory of hyperpressure against the cervical spine due to blockage of CSF flow by descent of cerebellar tonsils at the foramen magnum level. We describe discriminating clinical and radiologic signs to differentiate intracranial hypotension from Chiari type 1 malformation and discuss mechanisms and causality relating trauma and intracranial hypotension. CONCLUSIONS: Syringomyelia can be a consequence of long-term progression of intracranial hypotension, which must be differentiated from Chiari type 1 malformation. In our case, resolution was achieved by detecting and closing the CSF leak causing the intracranial hypotension. Reports of similar cases are necessary to understand the origin of CSF leak in traumatic intracranial hypotension and assess the best therapeutic strategy. PMID- 27126912 TI - Genotypic Prediction of Co-receptor Tropism of HIV-1 Subtypes A and C. AB - Antiretroviral treatment of Human Immunodeficiency Virus type-1 (HIV-1) infections with CCR5-antagonists requires the co-receptor usage prediction of viral strains. Currently available tools are mostly designed based on subtype B strains and thus are in general not applicable to non-B subtypes. However, HIV-1 infections caused by subtype B only account for approximately 11% of infections worldwide. We evaluated the performance of several sequence-based algorithms for co-receptor usage prediction employed on subtype A V3 sequences including circulating recombinant forms (CRFs) and subtype C strains. We further analysed sequence profiles of gp120 regions of subtype A, B and C to explore functional relationships to entry phenotypes. Our analyses clearly demonstrate that state-of the-art algorithms are not useful for predicting co-receptor tropism of subtype A and its CRFs. Sequence profile analysis of gp120 revealed molecular variability in subtype A viruses. Especially, the V2 loop region could be associated with co receptor tropism, which might indicate a unique pattern that determines co receptor tropism in subtype A strains compared to subtype B and C strains. Thus, our study demonstrates that there is a need for the development of novel algorithms facilitating tropism prediction of HIV-1 subtype A to improve effective antiretroviral treatment in patients. PMID- 27126913 TI - Torso, a Drosophila receptor tyrosine kinase, plays a novel role in the larval fat body in regulating insulin signaling and body growth. AB - Torso is a receptor tyrosine kinase whose localized activation at the termini of the Drosophila embryo is mediated by its ligand, Trunk. Recent studies have unveiled a second function of Torso in the larval prothoracic gland (PG) as the receptor for the prothoracicotropic hormone, which triggers pupariation. As such, inhibition of Torso in the PG prolongs the larval growth period, thereby increasing the final pupa size. Here, we report that Torso also acts in the larval fat body, regulating body size in a manner opposite from that of Torso in PG. We confirmed the expression of torso mRNA in the larval fat body and its reduction by RNA interference (RNAi). Fat body-specific knockdown of torso, by either of the two independent RNAi transgenes, significantly decreased the final pupal size. We found that torso knockdown suppresses insulin/target of rapamycin (TOR) signaling in the fat body, as confirmed by repression of Akt and S6K. Notably, the decrease in insulin/TOR signaling and decrease of pupal size induced by the knockdown of torso were rescued by the expression of a constitutively active form of the insulin receptor or by the knockdown of FOXO. Our study revealed a novel role for Torso in the fat body with respect to regulation of insulin/TOR signaling and body size. This finding exemplifies the contrasting effects of the same gene expressed in two different organs on organismal physiology. PMID- 27126914 TI - Synthesis and preliminary characterization of radioiodinated benzofuran-3-yl (indol-3-yl)maleimide derivatives as potential SPECT imaging probes for the detection of glycogen synthase kinase-3beta (GSK-3beta) in the brain. AB - We report on the synthesis and preliminary characterization of two radioiodinated benzofuran-3-yl-(indol-3-yl)maleimides, 3-(benzofuran-3-yl)-4-(5-[(125) I]iodo-1 methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione ([(125) I]5), and 3-(5-[(125) I]iodo-1 methyl-1H-indol-3-yl)-4-(6-methoxybenzofuran-3-yl)-1H-pyrrole-2,5-dione ([(125) I]6), as the first potential SPECT imaging probes targeting glycogen synthase kinase-3beta (GSK-3beta). In this study, we used (125) I as a surrogate of (123) I because of its ease of use. The radioiodinated ligands were prepared from the corresponding tributyltin precursors through an iododestannylation reaction using hydrogen peroxide as an oxidant with a radiochemical yield of 10-30%. In vitro binding experiments suggested that both compounds show high affinity for GSK 3beta at a level similar to a known GSK-3beta inhibitor. Biodistribution studies with normal mice revealed that the radioiodinated compounds display sufficient uptake into (1.8%ID/g at 10 min postinjection) and clearance from the brain (1.0%ID/g at 60 min postinjection). These preliminary results suggest that the further optimization of radioiodinated benzofuran-3-yl-(indol-3-yl)maleimide derivatives may facilitate the development of clinically useful SPECT imaging probes for the in vivo detection of GSK-3beta. PMID- 27126915 TI - Pseudomonas aeruginosa produces phosphatidyltris(hydroxymethyl)aminomethane and derivatives when grown in Tris-buffered medium. AB - For optimal growth of a microorganism, the pH of the culture medium should be set at an optimum value. For that reason, growth media require buffering agents. We show in this study that, when grown in a medium supplemented with tris(hydroxymethyl)aminomethane (Tris), Pseudomonas aeruginosa is able to use this organic compound to produce new phospholipids. We thus pointed out that phosphatidyltris(hydroxymethyl)aminomethane as well as diphosphatidyltris(hydroxymethyl)aminomethane was detected in membrane lipid extracts of bacteria grown in Tris-buffered medium. Moreover, the amounts of lysoglycerophospholipids in the lipidome of P. aeruginosa grown in Tris-buffered medium increased leading to the presence of lysophosphatidylglycerol and lysophosphatidyltris(hydroxymethyl)aminomethane as well as other lysophospholipid derivatives. Finally, we investigated the effect of the presence of these exogenous phospholipids on the susceptibility of P. aeruginosa to some antibiotics. We observed a decrease of the minimal inhibitory concentrations of different antibiotic families, i.e., fluoroquinolones, aminoglycosides, beta lactams and polymyxins, proving the importance of the buffer choice for growth medium and its impact on the lipidome. PMID- 27126916 TI - Frederik Ruysch (1638-1731): Historical perspective and contemporary analysis of his teratological legacy. AB - The Peter the Great Museum of Anthropology and Ethnography (Kunstkamera) in Saint Petersburg is the oldest museum in Russia. It keeps the remains of the anatomical collection of the world-famous 17th century Dutch anatomist Frederik Ruysch. This unique collection was bought and shipped in 1717 by Czar Peter the Great, and presently still comprises more than 900 specimens, a modest number of which concerns specimens with congenital anomalies. We searched for teratological clues in the existing collection and in all his descriptions and correspondence regarding specimens and cases he encountered during his career as doctor anatomiae and chief instructor of the surgeons and midwives in Amsterdam. A total of 63 teratological specimens and case descriptions were identified in this legacy, including some exceedingly rare anomalies. As it turns out, Ruysch was the first to describe several of the conditions we encountered, including intracranial teratoma, enchondromatosis, and Majewski syndrome. Although his comments pose an interesting view on how congenital anomalies were scientifically perceived in early 18th century Europe, Ruysch mostly refrained from explaining the causes of the conditions he encountered. Instead, he dedicated himself to careful descriptions of his specimens. Almost 300 years after his demise, Ruysch's legacy still impresses and inspires both scientists and lay men. (c) 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. PMID- 27126917 TI - Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study. AB - The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep-related phenotypes, known genetic variants explain only a small proportion of the phenotypical variance. However, most previous studies were based solely upon self-report measures. The present study aimed to conduct the first genome-wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle- to older-aged subjects (40-79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night- and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P <= 5* 10-8 (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 * 10-8 ). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 * 10-8 ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow-up studies. PMID- 27126919 TI - Infectious diseases in the Tuscan detention setting: data from the Health Agency of Tuscany. PMID- 27126918 TI - Different effects of arginine vasopressin on high-mobility group box 1 expression in astrocytes isolated from stroke-prone spontaneously hypertensive rats and congenic SHRpch1_18 rats. AB - Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension and astrocytic oedema following ischaemic stimulation. During ischaemic stress high-mobility group box 1 (Hmgb1) expression in astrocytes is induced, and subsequently potentiates deterioration of the brain due to ischaemic injury, which manifests as both cerebral inflammation and astrocytic oedema. Arginine vasopressin (AVP) induces brain injury and increases astrocytic swelling. After stroke, Hmgb1 and peroxiredoxin (Prx) are released at different times and activate macrophages in the brain via Toll-like receptors (Tlr2s). The purpose of this study was to examine whether AVP and/or hypoxia and reoxygenation (H/R) contribute to Hmgb1 regulation following ischaemic stroke. Thus, Hmgb1, Prx2 and Tlr2 expression levels in astrocytes isolated from Wistar Kyoto rats (WKY/Izm), spontaneously hypertensive rats (SHR/Izm), SHRSP/Izm and congenic rat strain SHRpch1_18 treated with AVP and/or H/R were compared. Gene and protein expression levels were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative PCR, and Western blot. mRNA expression of Hmgb1, Prx2 and Tlr2 induced by AVP was dose-dependent, and Hmgb1 and Prx2 expression was higher in SHR/Izm, SHRSP/Izm and SHRch1_18 than in WKY/Izm. Tlr2 expression with AVP was reduced in SHR/Izm compared to WKY/Izm. In SHRpch1_18, Hmgb1 expression increased after AVP plus H/R. AVP-modulated expression of Hmgb1 protein was reduced by the addition of the antioxidant N acetylcysteine (NAC). These results suggest that oxidative stress by AVP enhanced expression of Hmgb1, Prx2 and Tlr2 in astrocytes. We hypothesize that regulation of Hmgb1 by AVP during H/R might be related to induction of inflammation and stroke in SHRSP/Izm and SHRpch1_18 rats. PMID- 27126920 TI - Aggregation process of paramagnetic particles in fluid in the magnetic field. AB - Magnetic targeting is a promising therapeutic strategy for localizing systemically delivered magnetic responsive drugs or cells to target tissue, but excessive aggregation of magnetic particles could result in vascular embolization. To analyze the reason for embolization, the attractive process of magnetic particles in magnetic field (MF) was studied in this paper by analyzing the form of the aggregated paramagnetic particles while the particle suspension flowed through a tube, which served as a model of blood vessels. The effects of magnetic flux density and fluid velocity on the formation of aggregated paramagnetic particles were investigated. The number of large aggregated clusters dramatically increased with increment in the magnetic flux density and decreased with increment in the fluid velocity. The analysis of accumulative process demonstrates the MF around initially attracted particles was focused, which induced the formation of clusters and increased the possibility of embolism. Bioelectromagnetics. 37:323-330, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27126921 TI - Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy. AB - Myotonic dystrophy type 1 (DM1) is caused by abnormal expansion of CTG repeats in the 3' untranslated region of the DMPK gene. Expanded CTG repeats are transcribed into RNA and make an aggregate with a splicing regulator, MBNL1, in the nucleus, which is called the nuclear foci. The nuclear foci sequestrates and downregulates availability of MBNL1. Symptomatic treatments are available for DM1, but no rational therapy is available. In this study, we found that a nonsteroidal anti inflammatory drug (NSAID), phenylbutazone (PBZ), upregulated the expression of MBNL1 in C2C12 myoblasts as well as in the HSA(LR) mouse model for DM1. In the DM1 mice model, PBZ ameliorated aberrant splicing of Clcn1, Nfix, and Rpn2. PBZ increased expression of skeletal muscle chloride channel, decreased abnormal central nuclei of muscle fibers, and improved wheel-running activity in HSA(LR) mice. We found that the effect of PBZ was conferred by two distinct mechanisms. First, PBZ suppressed methylation of an enhancer region in Mbnl1 intron 1, and enhanced transcription of Mbnl1 mRNA. Second, PBZ attenuated binding of MBNL1 to abnormally expanded CUG repeats in cellulo and in vitro. Our studies suggest that PBZ is a potent therapeutic agent for DM1 that upregulates availability of MBNL1. PMID- 27126923 TI - Comparison of heart rate variability and classic autonomic testing for detection of cardiac autonomic dysfunction in patients with fibromyalgia. AB - AIM: Cardiac autonomic dysfunction (CAD) is frequently found in patients with fibromyalgia (FM). Thus, we evaluated whether heart rate variability (HRV) is superior to the Ewing tests in detecting CAD in FM patients. METHODS: We studied 35 females with FM and 25 age-matched healthy females. In Ewing tests, results were added to yield an overall score. An abnormal result on deep breathing, the Valsalva maneuver, or orthostatic standing was counted as 1 point. A change in systolic blood pressure (SBP) of > 10 mmHg while standing counted as 1 point, and a change of > 20 mmHg as 2 points. A score of 0 was regarded as no CAD, a score of >= 2 as severe CAD and a score of 1 as mild CAD. HRV was measured in two ways: by R-R intervals (time-domain analysis) and by spectral analysis of a series of successive R-R intervals (frequency-domain analysis). RESULTS: FM patients had significantly lower expiratory/inspiratory (E/I) ratios, lower Valsalva ratios and higher SBP values than healthy controls (P < 0.05, P < 0.05, P < 0.01, respectively). In the frequency domain, very low-frequency and low-frequency bands were also lower in FM patients than controls (both P < 0.05). Based on the discriminant analysis of the Ewing tests, 54.4% of cases were correctly classified. The addition of HRV parameters did not improve the reclassification. CONCLUSION: HRV does not improve detection of CAD in FM patients over classic autonomic testing. PMID- 27126922 TI - Permeabilization activated reduction in fluorescence: A novel method to measure kinetics of protein interactions with intracellular structures. AB - Understanding kinetic information is fundamental in understanding biological function. Advanced imaging technologies have fostered the development of kinetic analyses in cells. We have developed Permeabilization Activated Reduction in Fluorescence (PARF) analysis for determination of apparent t1/2 and immobile fraction, describing the dissociation of a protein of interest from intracellular structures. To create conditions where dissociation events are observable, cells expressing a fluorescently-tagged protein are permeabilized with digitonin, diluting the unbound protein into the extracellular media. As the media volume is much larger than the cytosolic volume, the concentration of the unbound pool decreases drastically, shifting the system out of equilibrium, favoring dissociation events. Loss of bound protein is observed as loss of fluorescence from intracellular structures and can be fit to an exponential decay. We compared PARF dissociation kinetics with previously published equilibrium kinetics as determined by FRAP. PARF dissociation rates agreed with the equilibrium-based FRAP analysis predictions of the magnitude of those rates. When used to investigate binding kinetics of a panel of cytoskeletal proteins, PARF analysis revealed that filament stabilization resulted in slower fluorescence loss. Additionally, commonly used "general" F-actin labels display differences in kinetic properties, suggesting that not all fluorescently-tagged actin labels interact with the actin network in the same way. We also observed differential dissociation kinetics for GFP-VASP depending on which cellular structure was being labeled. These results demonstrate that PARF analysis of non-equilibrium systems reveals kinetic information without the infrastructure investment required for other quantitative approaches such as FRAP, photoactivation, or in vitro reconstitution assays. (c) 2016 Wiley Periodicals, Inc. PMID- 27126925 TI - On the Lived Experience of Sex Offenders' Therapists: Their Perceptions of Intrapersonal and Interpersonal Consequences and Patterns of Coping. AB - In the last two decades, there has been a growing understanding that the therapeutic encounter with sex offenders takes a cost and has consequences on therapists. Despite the increasing research on the consequences of treating sex offenders, these studies in fact, have merely described the consequences, without providing an outlook for how therapists cope with them. The study presented in this article was part of a larger qualitative research project conducted among social workers, using in-depth semi-structured interviews. Emphasis is placed on therapists' perceptions of the intrapersonal and interpersonal consequences they experience from treating sex offenders, as well as the strategies they use to cope with these consequences. The study's central findings concern the therapists' perception of the intrapersonal consequences, which included two levels: primary responses and cumulative responses, and their perception of the interpersonal consequences that included their parenting relationships, intimate relationships, their attitude toward others (strangers and acquaintances), loss of their quality of life, and further positive consequences. The findings indicated a sequence and integrated use of the strategies to cope with the consequences. The results are discussed in light of the theoretical framework of Lazarus and Folkman's stress and coping theory. The limitations of the study as well as its implications for future research are discussed. PMID- 27126924 TI - Psychometrically Informed Approach to Integration of Multiple Informant Ratings in Adult ADHD in a Community-Recruited Sample. AB - Although Diagnostic and Statistical Manual of Mental Disorders-Fifth edition requires that attention-deficit/hyperactivity disorder (ADHD) symptoms are apparent across settings, assessed by multiple informants, there remains no standardized approach to integration of multiple sources in adult ADHD diagnosis. The goal of the study was to evaluate informant effects on adult ADHD symptom ratings. Participants were 406 adults, ages 18 to 37, and identified second reporters, recruited from the community, and completing a comprehensive diagnostic and cognitive assessment, including a clinician-administered diagnostic interview and self- and other-report questionnaires of ADHD symptoms. Structural equation modeling indicated good fit for a trifactor model of ADHD, including general ADHD, specific inattention and hyperactivity-impulsivity, and self- and other-perspective factors. Yet there were a number of symptoms on the specific hyperactive-impulsive and self-factors that exhibited nonsignificant loadings. Significant differential item functioning across self-ratings and informant ratings was also noted. The external validation indices of laboratory executive function and diagnostic team-rated impairment was significantly correlated with the specific inattentive factor. While executive function was marginally significantly correlated with the other perspective factor, impairment was associated with the self-perspective factor. Overall, inattentive symptoms may be more sensitive measures of adult ADHD, and other and self-ratings may provide different information in relation to external criteria. PMID- 27126926 TI - The influence of ethnicity on diagnosis of cancer. PMID- 27126928 TI - Pars Plana Vitrectomy Alone for the Management of Pseudophakic Rhegmatogenous Retinal Detachment with Only Inferior Breaks. AB - PURPOSE: To report the surgical results of primary pseudophakic rhegmatogenous retinal detachment (RRD) with only inferior retinal breaks (IRBs) repaired by pars plana vitrectomy (PPV) alone and complete drainage of subretinal fluid. DESIGN: Prospective, interventional cohort study. PARTICIPANTS: A total of 147 consecutive pseudophakic eyes of 147 patients with primary RRD with causative inferior breaks. METHODS: All eyes underwent PPV alone and complete drainage of subretinal fluid, with air, 20% sulfur hexafluoride (SF6), or 12% perfluoropropane (C3F8) as tamponade and with no face-down position in the postoperative period. MAIN OUTCOME MEASURES: Postoperative primary and final anatomic outcome, visual acuity, and complications. RESULTS: The patient population consisted of 44 women (30%) and 103 men (70%) with a mean age of 60.8+/-12.9 years. The mean follow-up period was 24.9+/-19.4 months. The mean number of quadrants affected was 2.4 (range, 1-4). A single break was present in 90 cases (61.2%), and 2 to 4 breaks were present in 57 cases (38.8%). The macula was found to be detached in 118 cases (80.3%) and attached in 29 cases (19.7%) intraoperatively. Of 152 breaks located between 5 and 7 clock-hours, 124 breaks (81.6%) were located outside the limits of the gas bubble on the first or third day postoperatively. Initial reattachment was achieved in 139 cases (94.5%; 95% confidence interval, 89.5-97.6). Final reattachment was achieved in 147 cases (100%). Two cases (1.3%) redetached because of new or missed retinal breaks. Six cases (4.1%) redetached because of incomplete retinal adhesion of the treated break(s). Mean preoperative best-corrected visual acuity (BCVA) was 1.11+/-0.59 logarithm of the minimum angle of resolution (logMAR). The mean final postoperative BCVA was 0.42+/-0.33 logMAR. CONCLUSIONS: Pars plana vitrectomy alone with complete drainage of subretinal fluid achieves a high reattachment rate in the management of primary pseudophakic RRD due to IRBs. PMID- 27126929 TI - Incidence of Intraocular Pressure Elevation and Glaucoma after Lamellar versus Full-Thickness Penetrating Keratoplasty. AB - PURPOSE: To analyze the cumulated incidence of glaucoma after penetrating keratoplasty (PK), anterior lamellar keratoplasty (ALK), and endothelial keratoplasty (EK). DESIGN: Cohort study. Data were recorded prospectively and analyzed retrospectively. PARTICIPANTS: A total of 1657 consecutive eyes of 1657 patients undergoing corneal transplantation between 1992 and 2013. METHODS: Penetrating keratoplasty (date range, 1992-2013), ALK (date range, 2002-2013), and Descemet's stripping automated EK (date range, 2006-2013). MAIN OUTCOME MEASURES: Postoperative intraocular pressure (IOP), glaucoma treatments, and glaucoma-related loss of vision (loss of central visual function resulting in absence of light perception or light perception limited to the temporal visual field). Cox proportional hazard regression model was used to analyze risk factors for glaucoma after keratoplasty. RESULTS: The 10-year cumulated incidence of elevated IOP and elevated IOP requiring treatment was 46.5% and 38.7%, respectively. In multivariate analysis, 4 variables were significantly associated with a higher incidence of elevated IOP requiring treatment after keratoplasty: preoperative glaucoma or IOP >20 mmHg (adjusted hazard ratio [HR], 1.56; P < 0.001), penetrating keratoplasty (PK) (adjusted HR, 1.12 vs. ALK and 1.10 vs. EK; P < 0.001), postoperative lens status (adjusted HR vs. phakic eyes: 1.15 for posterior chamber intraocular lens, 1.43 for anterior chamber intraocular lens [IOL], 2.83 for aphakic eyes; P < 0.001), and IOL exchange or removal during surgery (adjusted HR, 1.48; P < 0.001). Recipient age, preoperative diagnosis, filtering surgery before keratoplasty, vitrectomy associated with keratoplasty, and filtering surgery associated with keratoplasty were significantly associated with a higher incidence of elevated IOP requiring treatment after keratoplasty in univariate analysis but not in multivariate analysis. The 10-year probability of loss of vision related to glaucoma was 1.0% after EK, 2.1% after ALK, and 3.6% after PK (P = 0.036). CONCLUSIONS: The incidence of elevation of IOP after keratoplasty and development of glaucoma are significantly decreased with ALK and EK compared with PK. We believe this is due to diminished surgery-induced damage to the anterior chamber angle and trabecular meshwork, and reduced postoperative use of steroids. PMID- 27126931 TI - [IFN-gamma stimulates the release of cathepsin S in mouse mast cells]. AB - OBJECTIVE: To investigate the impact of interferon gamma (IFN-gamma) on cathepsin S (CTSS) expressed by P815 mouse mast cells and mouse bone marrow-derived mast cells (BMMCs). METHODS: IFN-gamma of 10, 25 and 50 ng/mL were respectively used to stimulate P815 cells and mouse BMMCs. Real-time PCR and ELISA were applied to detect mRNA and protein levels of CTSS in P815 cells and BMMCs. 25 ng/mL IFN gamma was used to treat P815 cells for 6, 12, 18, 24, 48 and 72 hours and mouse BMMCs for 12, 24 and 48 hours; the above mentioned detection steps were then repeated. RESULTS: IFN-gamma induced P815 cells and BMMCs to express CTSS on the mRNA and protein levels in the time- and dose-dependent manners. CONCLUSION: IFN gamma could stimulate mast cells to release CTSS. PMID- 27126932 TI - [Dexamethason suppresses the activation of rat microglia induced by glutamic acid]. AB - OBJECTIVE: To investigate the effect of dexamethasone (DEX) on the microglia activation induced by glutamic acid (GLU) in rats. METHODS: We isolated and cultured the microglia from the spinal cord of SD infant rats in vitro. The cell purity was tested by immunofluorescence technique. The cells were then randomly divided into 5 groups: Dulbecco' s phosphate buffered saline treatment (DPBS group); GLU treatment (GLU group); DEX pretreatment and then GLU stimulation; simultaneous treatment of DEX and GLU; GLU stimulation followed by DEX treatment. Finally, immunofluorescence technique was used to investigate the expressions of glucocorticoid receptor (GR) and CD11b/c protein. RESULTS: Compared with the DPBS group, GLU group presented the increased expression of CD11b/c protein, the shorten length of cell processes as well as cell shape turning round. Furthermore, compared with the GLU group, the CD11b/c protein expression significantly decreased in the group treated simultaneously with DEX and GLU and the group treated with DEX after GLU stimulation. However, the expression was not different between the GLU group and the group treated with DEX and then stimulated by GLU. CONCLUSION: DEX could inhibit microglia activation induced by GLU, while DEX pretreatment have no such an effect on microglia. PMID- 27126930 TI - Prognostic implications of baseline anaemia and changes in haemoglobin concentrations with amphotericin B therapy for cryptococcal meningitis. AB - OBJECTIVES: Anaemia represents a common toxicity with amphotericin B-based induction therapy in HIV-infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin-related anaemia on survival. METHODS: We used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2- and 10-week mortality risk. We also estimated 10-week mortality risk among participants with nadir haemoglobin < 8.5 g/dL during amphotericin induction and who survived >= 2 weeks post-enrolment. RESULTS: The median haemoglobin concentration at meningitis diagnosis was 11.5 g/dL [interquartile range (IQR) 9.7-13 g/dL; n = 311] with a mean decline of 4.2 g/dL [95% confidence interval (CI) -4.6 to -3.8; P < 0.001; n = 148] from diagnosis to nadir value among participants with baseline haemoglobin >= 8.5 g/dL. The median haemoglobin concentration was 8.1 g/dL (IQR 6.5-9.5 g/dL) at 2 weeks, increasing to 9.4 g/dL (IQR 8.2-10.9 g/dL) by 4 weeks and continuing to increase to 12 weeks. Among participants with haemoglobin < 8.5 g/dL at diagnosis, mortality risk was elevated at 2 weeks [hazard ratio (HR) 2.7; 95% CI 1.5-4.9; P < 0.01] and 10 weeks (HR 1.8; 95% CI 1.1-2.2; P = 0.03), relative to those with haemoglobin >= 8.5 g/dL. New-onset anaemia occurring with amphotericin therapy did not have a statistically significant association with 10-week mortality (HR 2.0; 95% CI 0.5 9.1; P = 0.4). CONCLUSIONS: Amphotericin induced significant haemoglobin declines, which were mostly transient and did not impact 10-week mortality. Individuals with moderate to life-threatening anaemia at baseline had a higher mortality risk at 2 and 10 weeks post-enrolment. PMID- 27126933 TI - [Overexpression of IL-8 promotes migration of BT549 breast cancer cells]. AB - OBJECTIVE: To construct a recombinant adenovirus vector containing IL-8 gene and observe its effect on the proliferation, cell cycle and migration of BT549 breast cancer cells. METHODS: IL-8 gene was amplified by PCR using the cDNA from 143B bone sarcoma cells and inserted into shuttle plasmid pAdTrack-TO4. The recombinant shuttle plasmid pAdTrack-TO4-IL-8 was digested by PmeI and then transformed to AdEasier competent cells. The obtained recombinant adenovirus plasmid pAdIL-8 was digested by PacI, and then transfected to HEK293 cells for package and amplification by Lipofectamine(TM) 2000. The titer was tested by dilution assay. The expression of IL-8 mRNA and protein in BT549 cells was detected by reverse transcription PCR and ELISA, respectively. Effect of IL-8 overexpression on proliferation, cell cycle and migration in BT549 cells was respectively investigated by MTT assay, flow cytometry and wound-healing test. RESULTS: PCR and DNA sequence analysis verified the recombinant shuttle plasmid pAdTrack-TO4-IL-8. Restriction enzymes PacI confirmed the recombinant adenovirus plasmid pAdIL-8. IL-8 was overexpressed in BT549 cells after AdIL-8 infection. Overexpression of IL-8 promoted BT549 cell migration and arrested the cell cycle in the S phase, but it made no significant difference in the proliferation of BT549 cells. CONCLUSION: IL-8 overexpression can promote migration of BT549 breast cancer cells. PMID- 27126934 TI - [IL-33 promotes airway remodeling in a mouse model of asthma via ERK1/2 signaling pathway]. AB - OBJECTIVE: To explore the role of IL-33 in asthmatic airway remodeling. METHODS: Male BALB/c mice were randomly divided into 3 groups: a control group, an ovalbumin (OVA) group, and an anti-IL-33 antibody combined with OVA group. The airway remodeling features in mice were observed by HE staining. In addition, the expressions of IL-33, alpha smooth muscle actin (alpha-SMA), and type 1 collagen (Col1) in the airway of mice were detected by immunohistochemistry and Western blotting. Finally, Western blotting was used to determine the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen- and stress activated protein kinase 1 (MSK1) in the lungs of mice. In vitro, human lung fibroblasts (HLF-1) were pretreated with the ERK1/2 inhibitor U0126 or the MSK1 inhibitor H89 respectively, and then treated with the human recombinant IL-33 (rIL-33). Then real-time quantitative PCR and Western blotting were used to test the expressions of alpha-SMA and Col1. Immunofluorescence cytochemistry and Western blotting were also used to observe the phosphorylation of ERK1/2 and MSK1 in HLF-1 cells. RESULTS: The pre-treatment with the ERK1/2 inhibitor U0126 or anti-IL-33 antibody significantly abolished the OVA-induced airway remodeling, increased expressions of IL-33, alpha-SMA, Col1, and phosphorylation of ERK1/2 and MSK1 in the airway of mice. In vitro, the increased expressions of alpha-SMA and Col1 and the phosphorylation of ERK1/2 and MSK1 induced by rIL-33 in HLF-1 cells were markedly inhibited by the pre-treatment with U0126 or H89. CONCLUSION: IL-33 promotes airway remodeling in asthmatic mice via the ERK1/2-MSK1 signaling pathway. PMID- 27126935 TI - [The combination of dasatinib and gefitinib enhances the killing effect of gefitinib on HCC827 lung cancer cells]. AB - OBJECTIVE: To investigate the molecular mechanism underlying that dasatinib enhances the killing effect of gefitinib on HCC827 lung cancer cells. METHODS: HCC827 cells and gefitinib-resistant HCC827GR cells were treated with 0, 100, 500, 1000 nmol/L gefitinib alone or in combination with 1000 nmol/L dasatinib. The proliferation of HCC827 cells and HCC827GR cells was detected by MTT assay, the activity of caspase 3 was tested by spectrophotometry, and the protein phosphorylation levels of Src and epidermal growth factor receptor (EGFR) were examined by Western blotting. RESULTS: Src phosphorylation level was obviously enhanced in HCC827GR cells. Dasatinib significantly inhibited Src phosphorylation, promoted the cell proliferation and the expression of caspase 3. The combination of gefitinib and dasatinib had the stronger killing effect than gefitinib alone did. CONCLUSION: The combination of dasatinib and gefitinib can enhance the inhibition on the expression of Src protein and the killing effect of gefitinib on HCC827 lung cancer cells. PMID- 27126936 TI - [Stable expression of human anti-IL-33 scFv-IgG1Fc fusion protein in CHO k1 cells]. AB - OBJECTIVE: To construct two different eukaryotic expression vectors of human anti interleukin 33 (IL-33) single-chain antibody fragment (scFv-Fc) to transfect Chinese hamster ovary (CHO) k1 cells and select the stably and high-level expressed cell lines to improve the expression level of the fusion protein. METHODS: The previously constructed recombinant plasmid pcDNA3.1/SP-scFv-Fc was digested to obtain SP-scFv-Fc fragments, and the fragments were inserted into the plasmid PMH3(EN) to construct recombinant plasmid PMH3(EN)/SP-scFv-Fc. The plasmids PMH3(EN)/SP-scFv-Fc and pcDNA3.1/SP-scFv-Fc were separately transfected into CHO k1 cells. The transcription and translation level of the SP-scFv-Fc were detected by reverse transcription PCR (RT-PCR) and Western blotting, respectively. The stably and high-level expressed cell lines were screened by Dot blotting. The expression level and binding activity of the expressed scFv-Fc were measured by ELISA. RESULTS: The recombinant plasmid PMH3(EN)/SP-scFv-Fc was successfully constructed and the size of the inserted SP-scFv-Fc was about 1560 bp. The RT-PCR results showed that the SP-scFv-Fc was successfully transfected into CHO k1 cells. The scFv-Fc proteins could be secreted into the cultural supernatant and specifically bind to human IL-33 and anti human IgG1 Fc antibody. The expression level of scFv-Fc in plasmid PMH3(EN) was higher than that in plasmid pcDNA3.1. After four rounds of screening, the stably and high-level expressed cell strains were obtained. The expression level of the scFv-Fc was about 10 mg/L. The competitive ELISA results showed that the expressed scFv-Fc fusion proteins could inhibit the binding of IL-33 to ST2. CONCLUSION: The anti IL-33 scFv-Fc proteins were highly expressed in CHO k1 cells. PMID- 27126937 TI - [Dexamethasone increases the expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in lung tissues of bronchial asthmatic mice]. AB - OBJECTIVE: To investigate the expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in the lung tissues of bronchial asthmatic mice and the effect of dexamethasone treatment on its expression. METHODS: Thirty BALB/c mice were randomly divided into three equal groups: a control group, an asthmatic group and a dexamethasone-treated group. The asthmatic mouse models were established by intraperitoneal injection and inhalation with ovalbumin (OVA). The number of eosinophils (EOS) and lymphocytes (Lym) in bronchoalveolar lavage fluid (BALF) were counted. HE staining was used to observe airway inflammation and remodeling. The mRNA and protein expression of RECK were determined by real-time PCR and immunohistochemistry, respectively. RESULTS: Compared with the control group and the dexamethasone-treated group, the total cell number and EOS number in the BALF of the asthma group significantly increased. The expression of RECK mRNA in the asthmatic group was significantly lower than that in the control group and the dexamethasone-treated group. Immunohistochemistry showed that RECK was mainly expressed in the airway epithelial cells and inflammatory cells. RECK protein expression was highest in the control group and lowest in the asthmatic group. CONCLUSION: Dexamethasone can increase the expression of RECK in the lung tissues of asthmatic mice. PMID- 27126938 TI - [Downregulation of proteinase activated receptor 4 inhibits migration of SW620 human colorectal cancer cells]. AB - OBJECTIVE: To establish the human colorectal cancer cell model SW620/PAR4D with inducible suppression of proteinase activated receptor 4 (PAR4) expression, and investigate the role PAR4 plays in the proliferation and migration of cancer cells. METHODS: A human colorectal cancer cell line with tetracycline-inducible expression regulatory system, namely SW620/Tet-on, was established; inducible expression lentiviral vector with artificial microRNA targeting PAR4, pLVX-Tight Puro-PAR4-miR, was constructed and transfected into SW620/Tet-on to make an inducible PAR4-suppressed cell model SW620/PAR4D. Western blotting was used to confirm the suppression of PAR4 expression after the doxycycline (DOX) treatment. CCK-8 assay was used to evaluate the impact of suppressed PAR4 expression on cell proliferation, and wound-healing assay was used to analyze the migration of the cells. RESULTS: The SW620/PAR4D cell model was established successfully. Suppression of PAR4 expression by DOX treatment had no significant impact on the growth/proliferation of SW620/PAR4D cells, but markedly inhibited the cell migration. CONCLUSION: Suppression of PAR4 expression has no significant effect on the proliferation of SW620 cells, but can inhibit the migration of the cells. PMID- 27126939 TI - [Increased apoptosis and down-regulation of RhoA in HepG2 cells infected by Listeria monocytogenes]. AB - OBJECTIVE: To explore the apoptosis of HepG2 cells infected by Listeria monocytogenes EGD strain (Lm-EGD) as well as Rho family small GTPases RhoA expression. METHODS: HepG2 cells were infected with Lm-EGD (MOI=10 and MOI=100) and collected 1 hour and 20 hours after infection. After harvesting, the apoptosis of HepG2 cells was determined by flow cytometry combined with annexin V FITC/PI assay. RhoA and caspase 3 mRNAs were analyzed by reverse-transcription PCR. The caspase 3 activity was detected by colorimetric assay. And Western blotting was used to detect RhoA expression in HepG2 cells. RESULTS: Lm invasion promoted HepG2 cell apoptosis and down-regulated RhoA mRNA and protein expression. Additionally, caspase 3 expression was up-regulated following Lm infection. CONCLUSION: Lm infection could promote host cell apoptosis and down regulate RhoA expression. PMID- 27126940 TI - [Cannabinoid WIN55, 212-2 inhibits proliferation, invasion and migration of human SMMC-7721 hepatocellular carcinoma cells]. AB - OBJECTIVE: To investigate the effects of WIN55, 212-2 (WIN) on the proliferation, invasion and migration of SMMC-7721 hepatocellular carcinoma cells and its underlying mechanisms. METHODS: SMMC-7721 cells were treated with (0, 1, 5, 10, 20) MUmol/L WIN, and cell viability was determined by CCK-8 assay. The morphological changes of the cells were observed under a fluorescence microscope with Hoechst33258 staining. Cell apoptosis was measured by flow cytometry combined with annexin V-FITC/PI staining. The expression levels of apoptosis related proteins P53, P21, Bcl-2 and Bax, and the phosphorylated AKT (p-AKT) and phosphorylated extracellular signal-regulated kinase (p-ERK) were analyzed by Western blotting. Transwell(TM) invasion assay was used to detect cell invasion ability. Would healing assay was performed to test cell migration ability. The expression level of matrix metalloproteinase 14 (MMP-14) was evaluated by Western blotting. RESULTS: WIN inhibited the proliferation of SMMC-7721 cells and induced cell apoptosis in a dose-dependent manner. After treatment with WIN, the cell nucleus concentrated and broken, indicating obvious cell apoptosis. Western blotting exhibited an up-regulation in the protein expression of P53, P21 and Bax. And the anti-apoptotic protein Bcl-2 was repressed. The expression levels of AKT, p-AKT and p-ERK were down-regulated, whereas the expression of total ERK was not obviously changed. Compared with control group, there was a significant inhibition of cell invasion and migration abilities when SMMC-7721 cells were treated with WIN. The expression level of MMP-14 decreased as well. CONCLUSION: WIN can inhibit the proliferation of SMMC-7721 cells and induce cell apoptosis. The mechanism is associated with the activation of P53 and the inhibition of AKT, p-AKT and p-ERK. WIN can inhibit the invasion and migration of SMMC-7721 cells through down-regulating the protein expression of MMP-14. PMID- 27126941 TI - [Inhibitory effects of pseudolaric acid B on inflammatory response and M1 phenotype polarization in RAW264.7 macrophages induced by lipopolysaccharide]. AB - OBJECTIVE: To investigate the effects of pseudolaric acid B (PLAB) on the inflammatory response and M1 phenotype polarization in RAW264.7 cells induced by lipopolysaccharide (LPS) and the related mechanisms. METHODS: The inflammatory model in vitro was made using RAW264.7 cells stimulated by LPS, and then was treated with 0.5 MUmol/L PLAB and 1 MUmol/L GW9662, a peroxisome proliferators activated receptor gamma (PPARgamma) antagonist. The cell cycle was tested by flow cytometry. The mRNA expressions of PPARgamma and M1 phenotype markers interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) were measured by real-time PCR. The expression levels of signal molecules involved in nuclear factor-kappaB (NF-kappaB) signal pathway were detected by Western blotting. RESULTS: PLAB markedly decreased the expressions of IL-1beta and TNF alpha mRNAs induced by LPS and increased PPARgamma mRNA level. Moreover, the expressions of NF-kappaB p65, pNF-kappaB p65, IKKalpha, IKKbeta, pIKKalpha/beta, IkappaBalpha and pIkappaBalpha decreased in PLAB-treated cells. Meanwhile, RAW264.7 cells were arrested in G0 and G2 phase after the treatment with PLAB. However, the effects of PLAB on RAW264.7 cells could be reversed by GW9662 obviously. CONCLUSION: PLAB could inhibit the inflammatory response and M1 phenotype polarization in RAW264.7 cells induced by LPS via modulating cell cycle and NF-kappaB/PPARgamma signal pathway. PMID- 27126942 TI - [Sonic hedgehog (SHH) promotes the proliferation of synovial fibroblasts of rats with collagen-induced arthritis]. AB - OBJECTIVE: To investigate the effect of sonic hedgehog (SHH) on the proliferation of synovial fibroblasts (SFs). METHODS: The serum samples were collected from 30 rheumatoid arthritis (RA) patients, 30 systemic lupus erythematosus (SLE) patients, 30 ankylosing spondylitis (AS) patients and 30 healthy subjects. The concentrations of serum SHH were detected by ELISA. Collagen induced arthritis (CIA) were developed by type 2 collagen in Sprague-Dawley rats. The SFs were isolated from knee synovial tissues of CIA rats, and then identified by the detection of vimentin by immunofluorescence technique. Before and 72 hours after blocking SHH-glioma-associated oncogene 1 (Gli-1) signaling pathway with GANT61, the expression level of SHH in SFs was detected by Western blotting, and the proliferation of SFs was examined with CCK-8 assay. RESULTS: The level of serum SHH in the RA patients was remarkably higher than that in the SLE, AS patients and the healthy controls. In the CIA rats, the expression of SHH in SFs in vitro was higher than that in the healthy control rats. After 72-hour treatment of GANT61 to block SHH-Gli-1 signaling pathway, the expression level of SHH protein in SFs from CIA rats was reduced, and meanwhile the proliferation of the SFs was inhibited. CONCLUSION: SHH plays an important role in the proliferation of SFs and could be used as a potential therapeutic target for RA. PMID- 27126943 TI - [Identification of serological antigens in excretory-secretory antigens of Trichinella spiralis muscle larvae]. AB - OBJECTIVE: To isolate and identify serological antigens in the excretory secretory antigens of Trichinella spiralis muscle larvae by the combination of co immunoprecipitation and mass spectrometric technology. METHODS: The serum IgG of New Zealand rabbits infected with Trichinella spiralis was isolated by ammonium sulfate precipitation. Muscle larvaes were isolated from the infected muscle, and then purified and cultured to collect excretory-secretory antigens. Serological antigens in excretory-secretory antigens were isolated by co-immunoprecipitation and SDS-PAGE, and analyzed by Western blotting. Moreover, the protein bands in New Zealand rabbit sera infected with Trichinella spiralis were identified by mass spectrometric technology. RESULTS: Indirect ELISA showed that the titer of serum antibody of New Zealand rabbits infected with Trichinella spiralis was 1:6400. The rabbit serum IgG was effectively isolated by ammonium sulfate precipitation. A total of four clear protein bands of the excretory-secretory antigens of Trichinella spiralis were obtained by electrophoresis. Among them, three clear protein bands with relative molecular mass (Mr) being 40 kDa, 50 kDa and 83 kDa were recognized by the rabbit sera infected with Trichinella spiralis but not recognized by the normal rabbit sera. The obtained four protein molecules were confirmed as serine protease, specific serine protease of muscle larvae, 43 kDa secreted glycoprotein and 53 kDa excretory-secretory antigen. CONCLUSION: Four proteins were obtained from the excretory-secretory antigens of Trichinella spiralis muscle larvae by combination of co-immunoprecipitation and mass spectrometric technique analysis, which provided new sources and insights for the diagnosis and vaccine candidates of Trichinellosis. PMID- 27126944 TI - [Preparation of human soluble FcepsilonR1alpha and detection of serum FcepsilonR1alpha antibodies in patients with allergic rhinitis]. AB - OBJECTIVE: To induce the expression of human soluble Fc epsilon receptor I alpha (sFcepsilonR1alpha) in a prokaryotic expression vector, purify the recombinant human sFcepsilonR1alpha protein, detect its binding affinity for human serum IgE antibodies and detect the levels of sFcepsilonR1alpha, sFcepsilonR1alpha-IgE and FcepsilonR1alpha antibodies. METHODS: The FcepsilonR1alpha extracellular region gene was amplified using nested polymerase chain reaction (PCR) and was expressed in a prokaryotic expression vector pET-sFcepsilonR1alpha using recombinant DNA technology under optimal conditions. The human sFcepsilonR1alpha protein was purified using iminodiacetic acid (IDA) His binding resin and identified using Western blotting. The affinity between the recombinant human sFcepsilonR1alpha and serum IgE antibodies and the levels of total sFcepsilonR1alpha, sFcepsilonR1alpha-IgE and FcepsilonR1alpha antibodies were measured using ELISA. RESULTS: The amplified gene corresponding to the extracellular region FcepsilonR1alpha was approximately 600 bp. PCR, double enzyme digestion and sequencing confirmed the correct sequence of the expression vector pET sFcepsilonR1alpha. After human sFcepsilonR1alpha protein was induced in the expression vector pET-FcepsilonR1alpha and purified, Western blotting showed that its relative molecular mass (Mr) was approximately 42,000. ELISA revealed that the human sFcepsilonR1alpha bound with a high affinity to serum IgE, and the lower levels of total sFcepsilonR1alpha and sFcepsilonR1alpha-IgE and higher levels of serum anti-FcepsilonR1alpha antibodies in the patients with allergic rhinitis than in the normal subjects. CONCLUSION: We successfully synthesized human sFcepsilonR1alpha which had a strong binding affinity for human serum IgE. The higher levels of serum anti-FcepsilonR1alpha antibodies in the patients with allergic rhinitis than the normal subjects. PMID- 27126945 TI - [Down-regulation of receptor-tyrosine-kinase-like orphan receptor 1 suppresses cell growth and enhances apoptosis in human colorectal carcinoma]. AB - OBJECTIVE: To investigate the expression of receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) and its role in cell growth in human colorectal carcinoma (CRC). METHODS: Real-time quantitative PCR (qRT-PCR) and immunohistochemistry (IHC) were used to detect the expression of ROR1 in CRC (n=60) and matched tumor adjacent tissues. The relationship between the expression of ROR1 and clinical features was analyzed by Pearson chi-square test. siRNA was used to down-regulate the expression of ROR1 in SW480 cells in vitro. The qRT-PCR and Western blotting were performed to confirm the down-regulation of ROR1 expression. The effects of down-regulated ROR1 on cell proliferation and apoptosis were measured by MTT assay and flow cytometry combined with annexin V-FITC/PI staining, respectively. RESULTS: Both the mRNA and protein expression of ROR1 were significantly up regulated in CRC tissues than in tumor-adjacent tissues, and the expression of ROR1 was positively correlated with tumor size (>=5 cm), lymphatic metastasis and TNM stage (III and IV). siRNA could significantly down-regulate the expression of ROR1 in SW480 cells, then suppressed proliferation and enhanced apoptosis in SW480 cells. CONCLUSION: The expression of ROR1 was significantly higher in CRC tissues than in tumor-adjacent tissues. Down-regulation of ROR1 could play an anti-cancer role through inhibiting proliferation and inducing apoptosis in CRC. PMID- 27126946 TI - [TLR9 expression is positively correlated with the levels of CD38, HLA-DR and CD95 on peripheral blood mononuclear cells in chronic HBV infected patients]. AB - OBJECTIVE: To explore the relationship between the expression of TLR9 and the levels of CD38, HLA-DR and CD95 on peripheral blood mononuclear cells (PBMCs) of chronic hepatitis B virus (HBV) infected patients. METHODS: 70 chronic HBV infected patients and 12 healthy donors were enrolled in this study, and density gradient centrifugation was used to isolate PBMCs from peripheral blood with EDTA for anticoagulation. Flow cytometry was used to detect the levels of TLR9, CD38, HLA-DR and CD95 on PBMCs. RESULTS: Compared to the healthy donors, chronic HBV infected patients with low viral load or high viral load had significantly higher levels of TLR9, HLA-DR and CD95 on PMBCs. Furthermore, the co-expression rates of TLR9 and CD38, HLA-DR, CD95 on PBMCs were obviously higher than those of the healthy donors. Correlation analysis showed that the expression of TLR9 was positively correlated with CD38 (r=0.345), HLA-DR (r=0.334), CD95 (r=0.227) on PBMCs in the patients with chronic HBV infection. CONCLUSION: The expression of TLR9 increased and was positively associated with CD38, HLA-DR and CD95 on PBMCs during chronic HBV infection. PMID- 27126947 TI - [Changes of Tim-3 and PD-1 on peripheral blood monocyte subsets in patients with chronic hepatitis C]. AB - OBJECTIVE: To investigate the distribution of peripheral blood monocyte subsets of chronic hepatitis C (CHC) patients and observe the expression of negative regulators T cell immunoglobulin and mucin domain-3 (Tim-3) and programmed cell death-1 (PD-1) on the monocyte subsets. METHODS: Flow cytometry was employed to determine the distribution of three monocyte subsets as well as Tim-3 and PD-1 expression on the three monocyte subsets. Their correlations with the clinical parameters were analyzed by Spearman test. RESULTS: Compared with healthy controls, an increased distribution of CD14(+)CD16(+) monocytes, especially CD14(++)CD16(+) monocyte subset, was observed in CHC patients. Tim-3 expression was significantly elevated on CD14(++)CD16(-) and CD14(+)CD16(++) subsets in CHC patients. Obviously increased PD-1 expression was found mainly on CD14(++)CD16(-) and CD14(++)CD16(+) subsets. There were no significant correlations between monocyte subsets, PD-1, Tim-3 and the clinical parameters. CONCLUSION: The levels Tim-3 and PD-1 are different in three monocyte subsets. PMID- 27126948 TI - [Changes and clinical significance of innate-like lymphocyte subsets in peripheral blood of patients with advanced non-small cell lung cancer]. AB - OBJECTIVE: To investigate the percentages and correlations of innate-like lymphocyte subsets, alphabetaT cells and B2 cells in peripheral blood of patients with non-small cell lung cancer (NSCLC) and normal individuals. METHODS: A total of 16 healthy controls, 5 NSCLC first-visit patients and 15 NSCLC stable-state patients were included to take the peripheral blood samples. Flow cytometry was performed to detect the percentages of invariant natural killer T (iNKT), gammadeltaT, B1, alphabetaT and B2 cell subsets in peripheral blood lymphocytes. RESULTS: The percentage of iNKT cells in the stable-state patients was significantly lower than that of the healthy people and first-visit patients. In addition, the percentage of alphabetaT cells in the stable-state patients was significantly higher than that of the healthy people. The fist-visit patients had a markedly higher percentage of gammadeltaT cells than the stable-state patients, but a significantly lower percentage of B1 cells than the healthy people. There was an obviously positive correlation between iNKT cells and gammadeltaT cells in the stable-state patients. We also found a significantly positive correlation between B1 cells and B2 cells in both stable-state patients and healthy people. CONCLUSION: The percentages of innate-like lymphocyte subsets in patients with NSCLC are in disequilibrium. PMID- 27126949 TI - [Preparation of monoclonal antibodies against His-tag and epitope analysis of cross antigens]. AB - OBJECTIVE: To explore the influence of His-tag on recombinant proteins in vaccination, immunization and pathogenesis. METHODS: Multiple mouse monoclonal antibodies (mAb) against His-tag were prepared. The biological and immunoreactive characteristics of these mAbs and their cross-reactivity with the normal human tissues were investigated by ELISA, Western blotting and immunohistochemistry (IHC), respectively. RESULTS: The binding activity of these anti-His mAbs was associated with the steric configuration of the his-tagged antigen. In addition, most of these mAbs reacted with human hemoglobin and some normal human tissues. CONCLUSION: Anti-His antibodies could be elicited by His-tagged recombinant proteins in vivo experiments. Moreover, the functional studies of the His-tagged recombinant proteins might be affected by the reactions of anti-His6 antibodies with human hemoglobin and normal human tissues. PMID- 27126950 TI - [Preparation and identification of the polyclonal antibody against mouse IL 23p19]. AB - OBJECTIVE: To prepare the polyclonal antibody against mouse interleukine-23 p19 (IL-23p19). METHODS: The murine full-length IL-23p19 gene was subcloned into pET16 expression vector to construct the recombinant plasmid pET-16b-IL-23p19. The plasmid was transformed into E. coli BL 21 (DE3) and IL-23p19 protein expression was induced by IPTG and identified with SDS-PAGE analysis and Western blotting. After purified by Ni(+) affinity column chromatography, the IL-23p19 protein was used as the antigen to immunize New Zealand rabbit to prepare the antiserum. The polyclonal antibody against the mouse IL-23p19 was isolated from antiserum by affinity chromatography. Antibody titer was detected by ELISA. Antibody specificity was evaluated by Western blotting. RESULTS: The pET-16b-IL 23p19 recombinant plasmid was successfully constructed and the IL-23p19 protein was effectively expressed in E. coli BL 21 (DE3). The antibody was successfully prepared by immunizing New Zealand rabbit with the IL-23p19 protein four times. ELISA showed that the titer of the anti-mouse IL-23p19 polyclonal antibody was about 1:256,000. Western blotting confirmed that anti-mouse IL-23p19 polyclonal antibody could specifically recognize the IL-23p19 protein. CONCLUSION: We have successfully prepared the anti-IL-23p19 polyclonal antibody with the high titer and specificity. PMID- 27126951 TI - Diagnosis and treatment of uncomplicated type B aortic dissection. AB - A type B dissection involves the aorta distal to the subclavian artery, and accounts for 25-40% of aortic dissections. Approximately 75% of these are uncomplicated with no malperfusion or ischemia. Multiple consensus statements recommend thoracic endovascular aortic repair (TEVAR) as the treatment of choice for acute complicated type B aortic dissections, while uncomplicated type B dissections are traditionally treated with medical management alone, including strict blood pressure control, as open repairs have a prohibitively high morbidity of up to 31%. However, with medical treatment alone, the morbidity, including aneurysm degeneration of the affected segment, is 30%, and mortality is 10% over 5 years. For both chronic and acute uncomplicated type B aortic dissections, emerging evidence supports the use of both best medical therapy and TEVAR. This paper reviews the current diagnosis and treatment of uncomplicated type B aortic dissections. PMID- 27126952 TI - Nucleation pathway and kinetics of phase-separating active Brownian particles. AB - Suspensions of purely repulsive but self-propelled Brownian particles might undergo phase separation, a phenomenon that strongly resembles the phase separation of passive particles with attractions. Here we employ computer simulations to study the nucleation kinetics and the microscopic pathway active Brownian disks take in two dimensions when quenched from the homogeneous suspension to propulsion speeds beyond the binodal. We find the same qualitative behavior for the nucleation rate as a function of density as for a passive suspension undergoing liquid-vapor separation, suggesting that the scenario of an effective free energy also extends to the kinetics of phase separation. We study the transition in more detail through a committor analysis and find that transition states are best described by a combination of cluster size and the radial polarization of particles in the cluster. PMID- 27126953 TI - Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs. AB - Acute graft-versus-host disease (aGVHD), caused by donor T cell-mediated injury to host tissues, is a problem in allogeneic bone marrow transplantation. The transition from naive to effector T cells is accompanied by shift in metabolism main pathway; from glucose oxidative phosphorylation to aerobic glycolysis. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase that is a metabolic sensor that helps maintain cellular energy homeostasis. Although AMPK activation can exert anti-inflammatory properties by negatively regulating pro-inflammatory mediators, its role as a therapeutic potential of graft-versus-host disease development remains unclear. In this study, we found that the intraperitoneal administration of metformin, which activates AMPK signaling significantly, ameliorated the clinical severity of aGHVD and lethality. This was associated with reductions in type I T helper (Th1) and Th17 and rises in Th2 and regulatory T (Treg) cell. The enhanced signal transducer and activator of transcription 3 activation noted during the development of aGVHD was reduced by metformin treatment. Furthermore, metformin treated Th17 cells became converted into Treg cells via enhanced autophagy. The reduction in mortality associated with metformin treatment was associated with inhibition of the mammalian target of rapamycin/signal transducer and activator of transcription 3 pathway. These results suggest that metformin might be of significant use in the treatment of patients with aGVHD. PMID- 27126954 TI - Long-term Outcomes after Truncus Arteriosus Repair: A Single-center Experience for More than 40 Years. AB - OBJECTIVES: This study aimed to analyze long-term survival and functional outcomes after truncus arteriosus repair in a single institution with more than 40 years of follow-up. METHODS: Medical records were analyzed retrospectively in 52 patients who underwent the Rastelli procedure for truncus arteriosus repair between 1974 and 2002. Thirty-five patients survived the initial repair. The median age at the initial operation was 2.8 months (range, 0.1-123 months) and the body weight was 3.9 kg (range, 1.6 to 15.0 kg). RESULTS: The median age at follow-up was 23.6 years (range, 12.4 to 44.5 years). The median follow-up duration was 23.4 years (range, 12.3 to 40.7 years). The actuarial survival rate was 97% at 10 years and 93% at both 20 years and 40 years after the initial operation. At follow-up, most patients were in New York Heart Association (NYHA) functional classes I (73%) and II (24%). Thirty-six percent of patients had full time jobs, 40% were students, and 21% were unemployed. Most patients (97%) had undergone conduit reoperations. Freedom from reoperation for right ventricular (RV) outflow and pulmonary artery (PA) stenosis was 59% at 5 years, 28% at 10 years, and 3% at 20 years after the initial operation. Freedom from catheter interventions for RV outflow and PA stenosis was 59% at 5 years, 47% at 10 years, and 38% at 20 years after the initial operation. Freedom from truncal valve replacement was 88% at 5 years, 85% at 10 years, and 70% at 20 years after the initial operation. CONCLUSIONS: In this single-center retrospective study, with long-term follow-up after repair of truncus arteriosus, long-term survival and functional outcomes were acceptable, despite the requirement for reoperation and multiple catheter interventions for RV outflow and PA stenosis in almost all patients, and the frequent requirement for late truncal valve operations. PMID- 27126955 TI - MicroRNA-127-5p regulates osteopontin expression and osteopontin-mediated proliferation of human chondrocytes. AB - The aim of this study was to determine the specific microRNA (miRNA) that regulates expression of osteopontin (OPN) in osteoarthritis (OA). The potential regulatory miRNAs for OPN messenger RNA (mRNA) were predicted by miRNA prediction programs. Among eight potential regulatory miRNAs, miR-220b, miR-513a-3p and miR 548n increased, while miR-181a, miR-181b, miR-181c, miR-181d and miR-127-5p decreased in OA patients. miRNA-127-5p mimics suppressed OPN production as well as the activity of a reporter construct containing the 3'-UTR of human OPN mRNA. In addition, mutation of miR-127-5p binding site in the 3'-UTR of OPN mRNA abolished miR-127-5p-mediated repression of reporter activity. Conversely, treatment with miR-127-5p inhibitor increased reporter activity and OPN production. Interestingly, miR-127-5p inhibited proliferation of chondrocytes through OPN. In conclusion, miRNA-127-5p is an important regulator of OPN in human chondrocytes and may contribute to the development of OA. PMID- 27126956 TI - Why women with previous caesarean and eligible for a trial of labour have an elective repeat caesarean delivery? A national study in France. AB - OBJECTIVE: To identify the characteristics of women and maternity units associated with elective repeat caesarean delivery (ERCD) in women eligible for trial of labour after caesarean (TOLAC). DESIGN: Cross-sectional study. SETTING: France. POPULATION AND SAMPLE: Using data from the 2010 French National Perinatal Survey, a representative sample of births in France (n = 14 681 women), we studied two groups of women with prior caesarean section: (i) women eligible for TOLAC according to guidelines (n = 1179) and (ii) a subgroup of these women without any medical characteristics that might indicate ERCD (n = 575). METHODS: Associations were analysed by multilevel logistic regression. MAIN OUTCOME MEASURES: Adjusted odds ratios. RESULTS: Among the 1584 women with a previous caesarean, 1179 (74.4%) were eligible for TOLAC according to guidelines (group 1); 490 (41.6%) had ERCD. Risk of ERCD increased with increasing maternal age and body mass index, pre-existing condition and suspected macrosomia and decreased with previous vaginal deliveries. Among the unit characteristics, private status (aOR = 2.3, 95% CI 1.3-4.1) and low level of care (aOR = 2.5, 95% CI 1.4-4.5]) were independently associated with a higher risk of ERCD after adjustment on patient/pregnancy characteristics. The variability of ERCD rate between hospitals was mainly (78%) explained by the status and level of care, and not (0%) by patient/pregnancy characteristics. Associations with unit characteristics were similar for group 2. CONCLUSION: For women eligible for TOLAC, the rate of ERCD is high and not in agreement with guidelines. Some characteristics of women are associated with ERCD, but the main determinants are at the unit level, which suggests that non-medical reasons are involved in the decision process. TWEETABLE ABSTRACT: Elective repeat caesarean in women eligible for trial of labour mainly depends on maternity unit characteristics. PMID- 27126957 TI - Beneficial effects of Bifidobacterium lactis on lipid profile and cytokines in patients with metabolic syndrome: A randomized trial. Effects of probiotics on metabolic syndrome. AB - OBJECTIVE: Human studies have shown the beneficial effects of probiotic microorganisms on the parameters of metabolic syndrome (MetS) and other cardiovascular risks, but to our knowledge the effect of Bifidobacterium lactis has not yet been reported. The aim of this study was to evaluate the effect of consumption of milk containing the probiotic B. lactis HN019 on the classical parameters of MetS and other related cardiovascular risk factors. METHODS: Fifty one patients with MetS were selected and divided into a control group (n = 25) and a probiotic group (n = 26). The probiotic group consumed fermented milk with probiotics over the course of 45 d. The effects of B. lactis on lipid profile, glucose metabolism, and proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) were assessed in blood samples of the individuals at the baseline and after 45 d. RESULTS: Daily ingestion of 80 mL fermented milk with 2.72 * 10(10) colony-forming units of B. lactis HN019 showed significant reduction in body mass index (P = 0.017), total cholesterol (P = 0.009), and low density lipoprotein (P = 0.008) compared with baseline and control group values. Furthermore, a significant decrease in tumor necrosis factor-alpha (P = 0.033) and interleukin-6 (P = 0.044) proinflammatory cytokines was observed. CONCLUSION: These data showed potential effects of B. lactis HN019 in reducing obesity, blood lipids, and some inflammatory markers, which may reduce cardiovascular risk in patients with MetS. PMID- 27126958 TI - Guanidinoacetic acid increases skeletal muscle creatine stores in healthy men. PMID- 27126959 TI - Non suicidal self injury resulting in dental trauma in an adolescent. AB - BACKGROUND/AIM: Non-suicidal self injury may be a possible etiologic factor for dental trauma in adolescents. The aim of this case report is to present a case of non-suicidal self injury resulting in dental trauma in a 16 year old adolescent boy. CASE REPORT: This report illustrates a case of non-suicidal self injury in a 16 year old healthy boy with resultant trauma to the maxillary central incisors and the left lateral incisor (teeth 11, 21, and 22). Three tests were applied; Wechsler Abbreviated Scale of IntelligenceTM (WASI), Inventory of Statements about Self Injury (ISAS), and UPPS Impulsive Behavior Scale (UPPS); to assess the patient's intellectual and behavioral functioning. Dental treatment was rendered in the form of composite restorations on teeth 11, 21, and 22. RESULTS AND DISCUSSION: The patient had a general intelligence quotient (IQ) of 92 (SD = 10.9), verbal score of 86.6 (SD = 14.6), and performance IQ of 93.4 (SD = 23.66) which implied that the intelligence levels were well within the normal range. The patient demonstrated self hitting behavior and predominantly intrapersonal functions of his NSSI on testing with the ISAS scale and elevated urgency scores on the UPPS scale. The total UPPS score was 115.9 and urgency score was 35.9. NSSI was an outlet for negative emotions and to release self directed anger. This resulted in dental trauma to teeth 11, 21, and 22. CONCLUSION: NSSI may be an etiologic or risk factor for dental trauma in intellectually normal adolescents as seen in the present case. Self hitting, intrapersonal factors or self directed factors and impulsivity are more likely to predispose an adolescent toward performance of such behavior. PMID- 27126960 TI - Resveratrol attenuates oxidative stress in mitochondrial Complex I deficiency: Involvement of SIRT3. AB - The pathophysiological mechanisms underlying Complex I (CI) deficiencies are understood only partially which severely limits the treatment of this common, devastating, mitochondrial disorder. Recently, we have shown that resveratrol (RSV), a natural polyphenol, has beneficial effects on CI deficiency of nuclear origin. Here, we demonstrate that RSV is able to correct the biochemical defect in oxygen consumption in five of thirteen CI-deficient patient cell lines. Other beneficial effects of RSV include a decrease of total intracellular ROS and the up-regulation of the expression of mitochondrial superoxide dismutase (SOD2) protein, a key antioxidant defense enzyme. The molecular mechanisms leading to the up-regulation of SOD2 protein expression by RSV require the estrogen receptor (ER) and the estrogen-related receptor alpha (ERRalpha). Although RSV increases the level of SOD2 protein in patients' fibroblasts, the enzyme activity is not increased, in contrast to normal fibroblasts. This led us to hypothesize that SOD2 enzyme activity is regulated post-translationally. This regulation involves SIRT3, a mitochondrial NAD(+)-dependent deacetylase and is critically dependent on NAD(+) levels. Taken together, our data show that the metabolic effects of RSV combined with its antioxidant capacities makes RSV particularly interesting as a candidate molecule for the therapy of CI deficiencies. PMID- 27126961 TI - Morphological and Molecular Identification of Anagrus 'atomus' Group (Hymenoptera: Mymaridae) Individuals from Different Geographic Areas and Plant Hosts in Europe. AB - Morphological identification and molecular study on the COI gene were simultaneously conducted on Anagrus Haliday 'atomus' group individuals collected in the field in Italy or supplied from a UK biofactory. Females were morphologically identified as A. atomus L. and A. parvus Soyka sensu Viggiani (=A. ustulatus sensu Chiappini). Alignment of COI gene sequences from this study permitted recognition of a total of 34 haplotypes. Phylogenetic and network analyses of molecular data not only confirmed that A. atomus is a species distinct from A. parvus, but also suggested that two species may be included within morphologically identified A. parvus. Different geographical distribution and frequency of haplotypes were also evidenced. For males considered in this study, morphometric analyses revealed a character that could be useful to discriminate A. atomus from A. parvus Both species were found in vineyards and surrounding vegetation, confirming the potential role of spontaneous vegetation as a source of parasitoids for leafhopper control in vineyards. PMID- 27126962 TI - Selaginella and the Satyr: Euptychia westwoodi (Lepidoptera: Nymphalidae) Oviposition Preference and Larval Performance. AB - Members of the plant genus Selaginella (de Beauvois 1805) have few known insect herbivores even though they are considered by some to be 'living fossils', with extant taxa virtually indistinguishable from 300 Mya fossils. Butterflies are well-known herbivores, and the satyrs are among the most speciose of them despite having radiated ~ 35 Mya ago. Nearly all satyrs feed on grass or sedges, but members of the Neotropical genus Euptychia Hubner 1818 feed on Selaginella; little is known about the degree to which this butterfly favors this ancient plant over those that its close relatives utilize. To advance our knowledge of Euptychia natural history, we conducted a series of experiments to examine oviposition preference and growth rates across a series of potential host plants on a Euptychia westwoodi population in Costa Rica. We found that Euptychia westwoodi Butler 1867 exhibit a strong preference to oviposit on Selaginella eurynota over the sympatric Selaginella arthritica, though they perform equally well as larvae on both plants. We did not observe oviposition on a sympatric grass that is commonly consumed by close relatives of E. westwoodi, and when larvae were offered the grass they refused to eat. These results suggest that E. westwoodi in Costa Rica exhibit a strong preference for Selaginella and may have lost the ability to feed on a locally abundant grass commonly used by other Satyrinae. PMID- 27126964 TI - Lyophilized artificial diet for rearing the Neotropical Euschistus heros (Hemiptera: Pentatomidae). AB - An artificial diet to mass-rear Euschistus heros (F. 1798) (Hemiptera: Pentatomidae) was developed in the laboratory. Biological studies were conducted under controlled conditions of temperature (25 +/- 2 degrees C), RH: 60 +/- 10%, and photoperiod of 14:10 (L:D) h. Out of 13 diets tested, 2 diets (D9 and D11) were the most suitable. The artificial diets selected had the same composition (green beans, peanuts, sucrose, water, Nipagin, and sorbic acid) except for different antimicrobial agents (D11 has tetracycline, and D9 doesn't). The 68% viability for the egg-adult period of insects reared on these lyophilized artificial diets (LAD) was almost twice as high as the 38% viability obtained with the natural diet. Although adults reared on LAD weighed 17% less than those reared on the natural diet, mean fecundity was higher than on the natural diet (282 eggs/female), reaching 430 eggs/female. The net reproductive rate (Ro) increased over the generations for the diets with lyophilized material and antimicrobial agents. The opposite occurred with the diet of lyophilized material without antimicrobial agents, showing that the insects either adapted or degenerated through generations. Lyophilized diets supported the production of E. heros through at least 10 generations, with no degeneration. PMID- 27126963 TI - Complete Mitochondrial Genome of Helicoverpa zea (Lepidoptera: Noctuidae) and Expression Profiles of Mitochondrial-Encoded Genes in Early and Late Embryos. AB - The mitochondrial genome (mitogenome) of the bollworm, Helicoverpa zea (Boddie), was assembled using paired-end nucleotide sequence reads generated with a next generation sequencing platform. Assembly resulted in a mitogenome of 15,348 bp with greater than 17,000-fold average coverage. Organization of the H. zea mitogenome (gene order and orientation) was identical to other known lepidopteran mitogenome sequences. Compared with Helicoverpa armigera (Hubner) mitogenome, there were a few differences in the lengths of gaps between genes, but the lengths of nucleotide overlaps were essentially conserved between the two species. Nucleotide composition of the H. zea mitochondrial genome was very similar to those of the related species H. armigera and Helicoverpa punctigera Wallengren. Mapping of RNA-Seq reads obtained from 2-h eggs and 48-h embryos to protein coding genes (PCG) revealed that all H. zea PCGs were processed as single mature gene transcripts except for the bicistronic atp8 + atp6 transcript. A tRNA like sequence predicted to form a hammer-head-like secondary structure that may play a role in transcription start and mitogenome replication was identified within the control region of the H. zea mitogenome. Similar structures were also found within the control regions of several other lepidopteran species. Expression analysis revealed significant differences in levels of expression of PCGs within each developmental stage, but the pattern of variation was similar in both developmental stages analyzed in this study. Mapping of RNA-Seq reads to PCG transcripts also identified transcription termination and polyadenylation sites that differed from the sites described in other lepidopteran species. PMID- 27126965 TI - {NiLn} (Ln = Gd, Dy) rod-like nano-sized heteronuclear coordination clusters with a double carbonate bridge skeleton and remarkable MCE behaviour. AB - The newly obtained complexes [NiLn(Piv)16(teaH)6(OCH3)2(CO3)2(H2O)2] Ln = Gd, Dy, show a remarkable MU5-carbonate bridged octanuclear planar {Ni4Ln4} core further capped with embedded {Ni3Ln} cubane motifs to afford a rod shaped nano-sized molecule of about 1.2 * 2.8 nm. Unusual MCE behaviour has been found due to multiple low lying excited states arising from competing ferromagnetic and anti ferromagnetic Ni-Ni and Ni-Ln exchange interactions. PMID- 27126966 TI - The effect of textural complexity of solid foods on satiation. AB - Previous studies have shown that food texture affects satiation by influencing the eating rate, bite size and oral transit time. However, investigations into the direct effect of texture on satiation are limited. The objective of the current study was to investigate the effect of textural complexity on satiation, independent of oral processing time and energy density. A preload-test meal design was used in this study; model foods with three levels of textural complexity (low, medium and high) were consumed as preload foods followed by a two-course ad libitum meal. This study was a randomized cross-over trial with 38 subjects. The results clearly showed that food with greater textural complexity led to significantly lower food intake overall. The first course of the meal and total food intake was significantly reduced (p<0.05) although food intake at the second course did not differ between groups. Despite the differing total intake, all subjects rated to have the same sense of satiety after three hours post-trial and the time taken to the next eating occasion did not differ between different preload conditions. Increased textural complexity in food enhances satiation and may potentially impact on satiety however this needs to be further confirmed in future studies. The findings suggest that foods with more complex textures can be a helpful tool in reducing the short-term food intake and enhancing the satiation response. PMID- 27126967 TI - Association of eating three meals irregularly with changes in BMI and weight among young Japanese men and women: A 2-year follow-up. AB - OBJECTIVE: Epidemiological longitudinal investigations of the association between not eating three meals regularly and changes in BMI and weight are scarce. The aim of this study was to investigate whether or not regularly eating three meals was associated with changes in BMI and weight in young Japanese men and women. METHODS: Study participants were 1241 men and 897 women aged 19.0+/-1.2 and 18.8+/-0.8years, respectively, who underwent health checkups at a university in Japan in 2001 as the baseline and subsequently in 2003. Weight and height were measured at baseline and 2years later. Whether an individual ate three meals regularly was determined by a self-report questionnaire in 2001. RESULTS: During the 2-year follow-up, the BMI gain was 0.347 for men and 0.067 for women. In the logistic regression analysis, for men, eating three meals irregularly was significantly associated with a 4% BMI gain (OR 1.60, CI 1.11-2.30), 6% BMI gain (OR 1.72, CI 1.12-2.63), 4kg weight gain (OR 2.01, CI 1.29-3.13), 6kg weight gain (OR 1.86, CI 1.02-3.37), and incidence of obesity (BMI ? 25)(OR 2.96, CI 1.22 7.17). For women, eating three meals irregularly was significantly associated with a 4% BMI loss (OR 1.99, CI 1.01-3.94), 6% BMI loss (OR 2.79, CI 1.29-6.03), 4kg weight loss (OR 3.85, CI 1.62-9.12), 6kg weight loss (OR 7.65, CI 2.06 28.46), and the incidence of underweight (OR 3.95, CI 1.32-11.89). CONCLUSIONS: The current results suggested that eating three meals irregularly was associated with subsequent BMI and weight gains for men and subsequent BMI and weight losses for women; both groups were around 20years of age. Self-reported eating behavior in this study might be used to screen and evaluate young Japanese men and women at high risk for changes in BMI and weight in a practical clinical setting. PMID- 27126968 TI - Circuit organization of sugar reinforcement. AB - Sugar's potent reinforcing properties arise from the complex interplay between gustatory and nutritive signals. This commentary addresses a unique organizational aspect of the neuronal circuitry that mediates sugar reinforcement in both Drosophila and rodents. Specifically, current evidence supports a general circuit model where separate populations of dopaminergic neurons encode the gustatory and nutritive values of sugar. This arrangement allows animals to prioritize energy seeking over taste quality, and implies that specialized subpopulations of dopamine-containing neurons form a class of evolutionary conserved chemo- and nutrient-sensors. PMID- 27126970 TI - Anaerobic training in hypoxia: A new approach to stimulate the rating of effort perception. AB - This study compared subjective effort perception with objective physiological measures during high-intensive intermittent exercise performed in normoxia, moderate hypoxia (FiO2: 16.5%) and severe hypoxia (FiO2: 13.5%). Sixteen physically active subjects performed an equal training session on three different days. Training consisted of 6 "all-out" series of continuous jumps lasting for 15s each. Average power output during the jumps was similar in all three conditions (~3200W). Greater hypoxemia was observed in hypoxia as compared to normoxia. Likewise, a significantly higher value in perceived effort was observed after hypoxia training as compared to normoxia training (p<0.05). Whereas blood lactate concentrations immediately after training were not different between normoxia and hypoxia, creatine kinase increased in moderate (p=0.02) and severe (p<0.01) hypoxia compared to normoxia 24h after the training. Perceived fatigue was also significantly elevated 24h after hypoxic exercise only. Heart rate variability pre and 24h after exercise showed a tendency to sympathetic predominance in severe hypoxia as compared to moderate hypoxia and normoxia. In conclusion, a single session of anaerobic exercise can be executed at the same intensity in moderate/severe hypoxia as in normoxia. This type of hypoxic training may be considered as a method potentially to improve the ability tolerating discomfort and consequently also exercise performance. PMID- 27126969 TI - The food-insecurity obesity paradox: A resource scarcity hypothesis. AB - Food insecurity is paradoxically associated with obesity in the United States. Current hypotheses to explain this phenomenon are descriptive regarding the low food security population's dietary and physical activity habits, but are not mechanistic. Herein it is proposed that a resource scarcity hypothesis may explain this paradox, such that fattening is a physiologically regulated response to threatened food supply that occurs specifically in low social status individuals. Evidence that this may be occurring, the implications for addressing the food insecurity-obesity paradox, and future areas of research, are reviewed and discussed. PMID- 27126971 TI - Clomiphene citrate before and after withdrawal bleeding for induction of ovulation in women with polycystic ovary syndrome: Randomized cross-over trial. AB - AIM: To compare the ovarian response to early versus late clomiphene citrate (CC) in women with polycystic ovary syndrome (PCOS). METHODS: This cross-over randomized controlled clinical trial included 90 infertile amenorrheic women with PCOS. After inducing withdrawal bleeding, patients were randomly divided into two equal groups to receive ovulation induction with CC 100 mg/day for 5 days. Group I started treatment the next day after finishing medroxyprogesterone acetate course for a menstrual cycle, and after a washout period of another menstrual cycle, the treatment was shifted to start on day 2 of withdrawal bleeding. Group II received a reversed protocol: late then early treatment. Women were followed up on transvaginal ultrasonography to monitor follicular growth, endometrial thickness and evidence of ovulation. Human chorionic gonadotropin 10 000 IU was given i.m. to trigger ovulation when at least one mature follicle measured >=18 mm at day 14. RESULTS: In all cases, early induction protocol resulted in significantly higher proportion of ovulating patients, thicker endometrium and higher number of follicles 14-17 mm in diameter, >= 18 mm in diameter and total number of follicles (P < 0.001 for all comparisons). CONCLUSION: In women with PCOS, early initiation of CC before withdrawal bleeding or during the last days of the luteal phase can achieve a better ovulatory response. PMID- 27126972 TI - Dual roles of DNA repair enzymes in RNA biology/post-transcriptional control. AB - Despite consistent research into the molecular principles of the DNA damage repair pathway for almost two decades, it has only recently been found that RNA metabolism is very tightly related to this pathway, and the two ancient biochemical mechanisms act in alliance to maintain cellular genomic integrity. The close links between these pathways are well exemplified by examining the base excision repair pathway, which is now well known for dual roles of many of its members in DNA repair and RNA surveillance, including APE1, SMUG1, and PARP1. With additional links between these pathways steadily emerging, this review aims to provide a summary of the emerging roles for DNA repair proteins in the post transcriptional regulation of RNAs. WIREs RNA 2016, 7:604-619. doi: 10.1002/wrna.1353 For further resources related to this article, please visit the WIREs website. PMID- 27126973 TI - Temperature and collision energy effects on dissociation of hydrochloric acid on water surfaces. AB - Collisions of HCl at the air-water interface modelled by a 72 molecule water slab are studied for a range of various impact energies and temperatures using ab initio molecular dynamics with density functional theory. A range of short timescale events can follow the collision, from direct scattering to nondissociative trapping on the surface. In most cases, HCl dissociation occurs within a few picoseconds, followed by the formation of a solvent-separated ion pair, or rarely, the reformation of HCl. With increasing impact energy and/or system temperature, dissociation occurs more rapidly, with Cl(-) tending to diffuse deeper into the slab. At temperatures corresponding to the frozen water regime, dissociation is seen only once out of the five thermal collisions, but with the addition of a total of 4kT or more of kinetic energy to HCl, it occurs in all our trajectories within a few ps. PMID- 27126974 TI - Evaluation of the correlation between type 1 diabetes and cognitive function in children and adolescents, and comparison of this correlation with structural changes in the central nervous system: a study protocol. AB - INTRODUCTION: Diabetes mellitus type 1 (T1DM) affects nearly 15 million children worldwide and failure to achieve and maintain good glycaemic control in this group can lead to diabetes-related complications. Children with T1DM can experience impairment in cognitive function such as memory, attention and executive function. This study is designed to evaluate the correlation between diabetes and cognitive dysfunction as well as to clarify whether this correlation can be linked to neurological structural changes in 6-11-year-old children with diabetes. METHODS AND ANALYSIS: 310 eligible children with diabetes will be divided into two groups based on glycaemic control according to their HbA1c index. The control group will include 150 children aged 6-11 without diabetes. The following parameters will be measured and investigated: duration of the disease since diagnosis, required daily insulin dose, frequency of insulin administration, hospital admissions due to diabetes, hypoglycaemic episodes during the last year, and episodes of diabetic ketoacidosis. The following components of cognitive function will be evaluated: memory, attention, executive function, decision-making and academic performance. Cognitive function and subsequent subtests will be assessed using Cambridge Neuropsychological Test Automated Battery (CANTAB) tools. Brain structural indices such as intracranial vault (ICV), as well as cerebrospinal fluid (CSF), ventricle, hippocampus, total intracranial, total brain, grey matter and white matter volume will be measured using MRI. ANOVA, correlational tests (Spearman) and regression models will be used to evaluate the hypothesis. ETHICS AND DISSEMINATION: This study is approved by the ethics committee of the Endocrinology and Metabolism Research Institute (EMRI) of Tehran University of Medical Sciences (TUMS) under reference number 00300. Our findings are to be published in a peer-reviewed journal and disseminated both electronically and in print. PMID- 27126975 TI - Effect of FTY720 (fingolimod) on graft survival in renal transplant recipients: a systematic review protocol. AB - INTRODUCTION: Studies have shown that FTY720 has inconsistent effects in kidney transplant recipients. Several review articles on FTY720 have been published, but most have focused on the mechanism of action of FTY720. Therefore, this review aims to evaluate and determine the beneficial and harmful effects of FTY720 therapy in kidney transplant recipients. METHODS AND ANALYSIS: We electronically searched the following databases: PubMed, Scopus, the Web of Sciences, EMBASE, Cochrane databases and the Cochrane Central Registry of Controlled Trials. Any clinical, randomised controlled trials relating to FTY720 for treating kidney transplant recipients were included without publication status or language restriction. Study selection, data extraction and assessment of study quality were performed independently by two researchers. Data were synthesised by either the fixed effects or the random effects model according to a heterogeneity test. If the extracted data were suitable for meta-analysis, STATA software was used to combine the relative risks for dichotomous outcomes, and the mean differences for continuous outcomes with 95% CIs were measured. Death, loss of function and incidence of acute kidney rejection were assessed as the primary outcomes. Renal graft function, malignancy, delayed graft function and infection were evaluated as secondary outcomes. ETHICS/DISSEMINATION: This review does not require formal ethics approval because the data are not individualised. The resulting review article will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42015024648. PMID- 27126976 TI - Impact of previous open renal surgery on the outcomes of subsequent percutaneous nephrolithotomy: a meta-analysis. AB - OBJECTIVE: The aim of this study was to systematically compare the perioperative outcomes of percutaneous nephrolithotomy in patients with or without previous ipsilateral open renal surgery (POS). DESIGN: Systematic searches of the PubMed, Web of Science and Cochrane Library databases were used to identify relevant studies, and, following literature screening and data extraction, a meta-analysis was performed. RESULTS: 17 retrospective cohort studies involving 4833 procedures (4784 patients) were included. No statistically significant differences were observed between patients with or without POS in terms of supracostal access; single/multiple tracts; metal dilator need; time required to access the collecting system; fluoroscopic duration; demand for analgesics; hospital stay; final stone-free rate; and risk of developing certain complications (eg, fever, haemorrhage, haemo/hydro/pneumothorax, blood transfusion, urinary tract infection and sepsis) as well as regarding the risk of total complications. Patients with POS, however, had a greater drop in haemoglobin (weighted mean difference (WMD), 1.78 g/L; 95% CI 1.09 to 2.47; p<0.00001) and higher risk of bleeding that required angiographic embolisation (relative risk (RR), 3.73; 95% CI 1.36 to 10.21; p=0.01). In addition, patients with POS also had a lower initial stone free rate (RR, 0.96; 95% CI 0.92 to 0.99; p=0.007) and more secondary treatment (RR, 1.61; 95% CI 1.09 to 2.37; p=0.02). Sensitivity analysis produced comparable results except for differences in operative time and initial stone-free rate, which did, however, prove to be statistically insignificant (p=0.16 and 0.69, respectively). CONCLUSIONS: Current evidence suggests that percutaneous nephrolithotomy in patients with POS is associated with a significantly greater drop in haemoglobin, higher risk of requiring angiographic embolisation and auxiliary procedures, potentially longer operative time, and lower initial stone free rate than percutaneous nephrolithotomy in patients without POS. PMID- 27126977 TI - Primary care-led survivorship care for patients with colon cancer and the use of eHealth: a qualitative study on perspectives of general practitioners. AB - OBJECTIVES: The aim of this study was to explore the perspectives of general practitioners (GPs) regarding their current and future role in survivorship care of patients with colon cancer, and to assess their perspectives on patients' self management capacities and the value of the eHealth application Oncokompas(2.0) used by patients. SETTING: GPs from the central part of the Netherlands were interviewed at their location of preference. PARTICIPANTS: 20 GPs participated (10 men, 10 women, age range 34-65 years, median age 49.5 years). The median years of experience as a GP was 14.5 years (range 3-34 years). RESULTS: GPs indicated attempting to keep in contact with patients after colon cancer treatment and mentioned being aware of symptoms of recurrent disease. Most participants would have liked to be more involved and expected to be able to provide survivorship care of colon cancer. Requirements mentioned were agreements with secondary care and a protocol. GPs considered Oncokompas(2.0), which stimulates patients to structure their own survivorship care, as a useful additional tool for a specific group of patients (ie, young and highly-educated patients). CONCLUSIONS: Based on the perspectives of the GPs, survivorship care of colon cancer in primary care is deemed feasible and the use of an eHealth application such as Oncokompas(2.0) is expected to benefit specific groups of patients after colon cancer treatment. PMID- 27126978 TI - Marking sutures to orientate specimens of basal cell carcinoma: do they really make a difference? AB - Traditionally, marking sutures have been used to orientate specimens of non melanomatous skin cancers, and they provide an identifiable point as a reference for monitoring and further treatment. For histopathological purposes, the orientated specimen is marked with different inks, which enables measurement to the nearest lateral and deep margins, and if invaded, guides further excision. We retrospectively analysed 688 specimens of basal cell carcinoma (BCC) from the head and neck from two separate years: 2010 and 2012. Marking sutures were used in 663 (96%) cases. There were 21 invaded margins (3%), 17 (81%) at the lateral margin and 4 (19%) at the deep margin. Of the 17 with invaded lateral margins, 10 were from the nose, and the remaining 7 from other sites including the ear (n=2), and neck, forehead, temple, eyelid, and cheek (n=1 each). Of the 663 marked specimens, the marking stitch was useful in only one patient who needed another operation (0.2%). We suggest that routine orientation of BCC, even from high risk areas, is not necessary. If the operating surgeon questions the size of the margin when a lesion is ill-defined or of a high-risk histological subtype, then excision with monitored en-face margins should be considered with traditional Mohs surgery or a reliable modified version. PMID- 27126979 TI - Response to letter Re: Extensive oral mucosal hyperkeratosis caused by over-the counter long lasting snoring relief agent. PMID- 27126981 TI - How Extreme Temperatures Impact Organisms and the Evolution of their Thermal Tolerance. AB - SynopsisUnderstanding the biological impacts of extreme temperatures requires translating meteorological estimates into organismal responses, but that translation is complex. In general, the physiological stress induced by a given thermal extreme should increase with the extreme's magnitude and duration, though acclimation may buffer that stress. However, organisms can differ strikingly in their exposure to and tolerance of a given extreme temperatures. Moreover, their sensitivity to extremes can vary during ontogeny, across seasons, and among species; and that sensitivity and its variation should be subject to selection. We use a simple quantitative genetic model and demonstrate that thermal extremes even when at low frequency-can substantially influence the evolution of thermal sensitivity, particularly when the extremes cause mortality or persistent physiological injury, or when organisms are unable to use behavior to buffer exposure to extremes. Thermal extremes can drive organisms in temperate and tropical sites to have similar thermal tolerances despite major differences in mean temperatures. Indeed, the model correctly predicts that Australian Drosophila should have shallower latitudinal gradients in thermal tolerance than would be expected based only on gradients in mean conditions. Predicting responses to climate change requires understanding not only how past selection to tolerate thermal extremes has helped establish existing geographic gradients in thermal tolerances, but also how increasing the incidence of thermal extremes will alter geographic gradients in the future. PMID- 27126980 TI - Polypeptide-Based Gold Nanoshells for Photothermal Therapy. AB - Targeted killing of cancer cells by engineered nanoparticles holds great promise for noninvasive photothermal therapy applications. We present the design and generation of a novel class of gold nanoshells with cores composed of self assembled block copolypeptide vesicles with photothermal properties. Specifically, poly(L-lysine)60- block-poly(L-leucine)20 (K60L20) block copolypeptide vesicles coated with a thin layer of gold demonstrate enhanced absorption of light due to surface plasmon resonance (SPR) in the near-infrared range. We show that the polypeptide-based K60L20 gold nanoshells have low toxicity in the absence of laser exposure, significant heat generation upon exposure to near-infrared light, and, as a result, localized cytotoxicity within the region of laser irradiation in vitro. To gain a better understanding of our gold nanoshells in the context of photothermal therapy, we developed a comprehensive mathematical model for heat transfer and experimentally validated this model by predicting the temperature as a function of time and position in our experimental setup. This model can be used to predict which parameters of our gold nanoshells can be manipulated to improve heat generation for tumor destruction. To our knowledge, our results represent the first ever use of block copolypeptide vesicles as the core material of gold nanoshells. PMID- 27126982 TI - Predicting the Dispersal Potential of an Invasive Polychaete Pest along a Complex Coastal Biome. AB - Boccardia proboscidea is a recently introduced polychaete in South Africa where it is a notorious pest of commercially reared abalone. Populations were originally restricted to abalone farms but a recent exodus into the wild at some localities has raised conservation concerns due to the species' invasive status in other parts of the world. Here, we assessed the dispersal potential of B. proboscidea by using a population genetic and oceanographic modeling approach. Since the worm is in its incipient stages of a potential invasion, we used the closely related Polydora hoplura as a proxy due its similar reproductive strategy and its status as a pest of commercially reared oysters in the country. Populations of P. hoplura were sampled from seven different localities and a section of the mtDNA gene, Cyt b and the intron ATPSa was amplified. A high resolution model of the coastal waters around southern Africa was constructed using the Regional Ocean Modeling System. Larvae were represented by passive drifters that were deployed at specific points along the coast and dispersal was quantified after a 12-month integration period. Our results showed discordance between the genetic and modeling data. There was low genetic structure (Phi = 0.04 for both markers) and no geographic patterning of mtDNA and nDNA haplotypes. However, the dispersal model found limited connectivity around Cape Point-a major phylogeographic barrier on the southern African coast. This discordance was attributed to anthropogenic movement of larvae and adult worms due to vectors such as aquaculture and shipping. As such, we hypothesized that cryptic dispersal could be overestimating genetic connectivity. Though wild populations of B. proboscidea could become isolated due to the Cape Point barrier, anthropogenic movement may play the critical role in facilitating the dispersal and spread of this species on the southern African coast. PMID- 27126983 TI - Identification of locally available structural material as co-substrate for organic waste composting in Tamil Nadu, India. AB - Owing to the lack in structural strength while composting certain kinds of organic wastes, 11 co-substrates were tested that are generally locally available in rural areas of northern Tamil Nadu, India. In addition to the classical composting parameters such as carbon/nitrogen ratio, moisture content, dry matter and organic dry matter, a compression test was conducted to evaluate the structural strength and the suitability as bulking agent for composting processes. Additionally, with respect to the climatic conditions in India, the water holding capacity was also evaluated. PMID- 27126984 TI - Nyquist and Bode stability criteria to assess changes in dynamic knee stability in healthy and anterior cruciate ligament reconstructed individuals during walking. AB - Anterior cruciate ligament (ACL) injuries are one of the most frequently injured knee ligaments. Despite reconstruction, many individuals report difficulty returning to high level activities that require greater dynamic stability. Since few methods have been tested to assess dynamic stability post ACL reconstruction (ACLR), the purpose of this study was to evaluate between and within dynamic knee stability in control and ACLR individuals using Nyquist and Bode stability criteria. Sixteen control and sixteen post ACLR individuals performed a walking protocol. Nyquist and Bode stability criteria were implemented to classify and quantify individual step-to-step sagittal plane dynamic knee stability from the gait waveforms at initial contact, 15% and 30% of stance based on the resulting gain and phase margins. An ANOVA compared differences in phase margins between the control and ACLR limbs and found that the ACLR limbs were overall significantly more unstable than the non-reconstructed and control limbs (p=0.001). The results indicated that the ACLR individuals who exhibited stable steps adopted a more compensatory strategy aimed to stabilize the knee. These methods of evaluating dynamic knee stability may help clinicians to assess dynamic knee stability progression throughout rehabilitation and help assess return-to-sport with minimal risk to the individual. PMID- 27126985 TI - A parametric study of mucociliary transport by numerical simulations of 3D non homogeneous mucus. AB - Mucociliary clearance is the natural flow of the mucus which covers and protects the lung from the outer world. Pathologies, like cystic fibrosis, highly change the biological parameters of the mucus flow leading to stagnation situations and pathogens proliferation. As the lung exhibits a complex dyadic structure, in-vivo experimental study of mucociliary clearance is almost impossible and numerical simulations can bring important knowledge about this biological flow. This paper brings a detailed study of the biological parameters influence on the mucociliary clearance, in particular for pathological situations such as cystic fibrosis. Using recent suitable numerical methods, a non-homogeneous mucus flow (including non-linearities) can be simulated efficiently in 3D, allowing the identification of the meaningful parameters involved in this biological flow. Among these parameters, it is shown that the mucus viscosity, the stiffness transition between pericilliary fluid and mucus, the pericilliary fluid height as well as both cilia length and beating frequency have a great influence on the mucociliary transport. PMID- 27126986 TI - Longitudinal measurements of postnatal rat brain mechanical properties in-vivo. AB - Information on pediatric brain tissue mechanical properties and, more pertinently, how they change during postnatal development remains scarce despite its importance to investigate mechanisms of neural injury. The aim of this study is to determine whether brain mechanical properties change in-vivo during early postnatal development in a rat model. Rat brain viscoelastic properties were measured longitudinally in ten healthy Sprague Dawley rats at five different time points from postnatal week one to week six using magnetic resonance elastography at 800Hz. Myelination and cell density were assessed histologically at the same time points to understand how the underlying tissue microstructure may be associated with changes in mechanical properties at different brain regions. Longitudinal changes in each variable were assessed using a generalized linear model with pairwise comparisons of means between weeks. The brain shear modulus in the cortical gray matter at postnatal week one was 6.3+/-0.4kPa, and increased significantly from week one to week two (pairwise comparison, p<0.01), remained stable from week two to week four and decreased significantly by week six (pairwise comparison, p<0.001). In the deep gray matter, brain tissue stiffness at postnatal week one was 6.1+/-2.0kPa, and increased significantly from one to week four (pairwise comparison, p<0.05) before decreasing significantly by week six (pairwise comparison, p<0.001). Stiffness changes were not directly correlated to histological observations. These data suggest that brain tissue shear modulus initially increases during a period equivalent to early childhood, and then decreases during a period equivalent to adolescence. PMID- 27126987 TI - Mate vocal recognition in the Scopoli's shearwater Calonectris diomedea: do females and males share the same acoustic code? AB - Vocal recognition is an important process allowing partners' reunion in most seabirds. Although the acoustic basis of this recognition has been explored in several species, only a few studies have experimentally tested the acoustic coding-decoding strategy used for mate identification. Here, we investigated mate recognition in the Scopoli's shearwater (Calonectris diomedea) by conducting playbacks of calls with modified acoustic features. We showed that females and males in a seabird species with a moderate vocal dimorphism are likely to share the same coding-decoding rule for vocal mate identification. Specifically, a disruption of call temporal structure prevented mate recognition in both sexes, in line with the parameters previously identified as supporting an individual signature. Modifications of spectral cues and envelope structure also impaired recognition, but at a lesser extent: almost half of the tested males and females were still able to recognise their partner. It is likely that this equal ability of female and male Scopoli's shearwaters to vocally recognise their partner could be found in other seabirds. PMID- 27126988 TI - Reliability, Validity, and Usability of Data Extraction Programs for Single-Case Research Designs. AB - Single-case experimental designs (SCEDs) have been increasingly used in recent years to inform the development and validation of effective interventions in the behavioral sciences. An important aspect of this work has been the extension of meta-analytic and other statistical innovations to SCED data. Standard practice within SCED methods is to display data graphically, which requires subsequent users to extract the data, either manually or using data extraction programs. Previous research has examined issues of reliability and validity of data extraction programs in the past, but typically at an aggregate level. Little is known, however, about the coding of individual data points. We focused on four different software programs that can be used for this purpose (i.e., Ungraph, DataThief, WebPlotDigitizer, and XYit), and examined the reliability of numeric coding, the validity compared with real data, and overall program usability. This study indicates that the reliability and validity of the retrieved data are independent of the specific software program, but are dependent on the individual single-case study graphs. Differences were found in program usability in terms of user friendliness, data retrieval time, and license costs. Ungraph and WebPlotDigitizer received the highest usability scores. DataThief was perceived as unacceptable and the time needed to retrieve the data was double that of the other three programs. WebPlotDigitizer was the only program free to use. As a consequence, WebPlotDigitizer turned out to be the best option in terms of usability, time to retrieve the data, and costs, although the usability scores of Ungraph were also strong. PMID- 27126990 TI - Adverse events associated with acupuncture: A clinicopathologic review. Authors' reply. PMID- 27126991 TI - TAS-102 for Treatment of Advanced Colorectal Cancers That Are No Longer Responding to Other Therapies. AB - TAS-102 is a novel oral formulation of trifluridine (TFT) and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TFT was originally synthesized in the 1960s and is a nucleoside analogue that impedes DNA synthesis by inhibition of thymidylate synthase. TFT's main mechanism of action, however, seems to be its incorporation into DNA, which distinguishes TFT from current well known antimetabolites like 5-fluorouracil (5-FU). The rapid degradation of TFT brought initial clinical development to a halt, but TFT reentered clinical trials when addition of a TPI was found to improve the bioavailability of TFT. The combined TFT-TPI formulation was tested in patients with treatment-refractory metastatic colorectal cancer in the randomized phase III RECOURSE study. Compared with placebo, TAS-102 was associated with an overall survival (OS) and progression-free survival (PFS) benefit and a 32% reduction in risk of death [median OS, 7.1 (95% CI, 6.5-7.8) vs. 5.3 months (95% CI, 4.6-6.0); median PFS, 2.0 (95% CI, 1.9-2.1) vs. 1.7 months (95% CI, 1.7-1.8); HR for death, 0.68 (95% CI, 0.58-0.81, P < 0.001)]. Based on the results of this pivotal trial and supported by results from an earlier phase II study, TAS-102 recently gained FDA approval. This article reviews the development of TAS-102 and its therapeutic value for the proposed indication. Clin Cancer Res; 22(12); 2835-9. (c)2016 AACR. PMID- 27126989 TI - A Genetic Screen Identifies a Critical Role for the WDR81-WDR91 Complex in the Trafficking and Degradation of Tetherin. AB - Tetherin (BST2/CD317) is a viral restriction factor that anchors enveloped viruses to host cells and limits viral spread. The HIV-1 Vpu accessory protein counteracts tetherin by decreasing its cell surface expression and targeting it for ubiquitin-dependent endolysosomal degradation. Although the Vpu-mediated downregulation of tetherin has been extensively studied, the molecular details are not completely elucidated. We therefore used a forward genetic screen in human haploid KBM7 cells to identify novel genes required for tetherin trafficking. Our screen identified WDR81 as a novel gene required for tetherin trafficking and degradation in both the presence and absence of Vpu. WDR81 is a BEACH-domain containing protein that is also required for the degradation of EGF stimulated epidermal growth factor receptor (EGFR) and functions in a complex with the WDR91 protein. In the absence of WDR81 the endolysosomal compartment appears swollen, with enlarged early and late endosomes and reduced delivery of endocytosed dextran to cathepsin-active lysosomes. Our data suggest a role for the WDR81-WDR91 complex in the fusion of endolysosomal compartments and the absence of WDR81 leads to impaired receptor trafficking and degradation. PMID- 27126992 TI - Development and Clinical Validation of a Blood Test Based on 29-Gene Expression for Early Detection of Colorectal Cancer. AB - PURPOSE: A blood test for early detection of colorectal cancer is a valuable tool for testing asymptomatic individuals and reducing colorectal cancer-related mortality. The objective of this study was to develop and validate a novel blood test able to differentiate patients with colorectal cancer and adenomatous polyps (AP) from individuals with a negative colonoscopy. EXPERIMENTAL DESIGN: A case control, multicenter clinical study was designed to collect blood samples from patients referred for colonoscopy or surgery. Predictive algorithms were developed on 75 controls, 61 large AP (LAP) >=1 cm, and 45 colorectal cancer cases and independently validated on 74 controls, 42 LAP, and 52 colorectal cancer cases (23 stages I-II) as well as on 245 cases including other colorectal findings and diseases other than colorectal cancer. The test is based on a 29 gene panel expressed in peripheral blood mononuclear cells alone or in combination with established plasma tumor markers. RESULTS: The 29-gene algorithm detected colorectal cancer and LAP with a sensitivity of 79.5% and 55.4%, respectively, with 90.0% specificity. Combination with the protein tumor markers carcinoembryonic antigen (CEA) and CYFRA21-2 resulted in a specificity increase (92.2%) with a sensitivity for colorectal cancer and LAP detection of 78.1% and 52.3%, respectively. CONCLUSIONS: We report the validation of a novel blood test, Colox(r), for the detection of colorectal cancer and LAP based on a 29-gene panel and the CEA and CYFRA21-1 plasma biomarkers. The performance and convenience of this routine blood test provide physicians a useful tool to test average-risk individuals unwilling to undergo upfront colonoscopy. Clin Cancer Res; 22(18); 4604-11. (c)2016 AACR. PMID- 27126993 TI - Transforming Growth Factor-beta Limits Secretion of Lumican by Activated Stellate Cells within Primary Pancreatic Adenocarcinoma Tumors. AB - PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is lethal cancer whose primary tumor is characterized by dense composition of cancer cells, stromal cells, and extracellular matrix (ECM) composed largely of collagen. Within the PDAC tumor microenvironment, activated pancreatic stellate cells (PSC) are the dominant stromal cell type and responsible for collagen deposition. Lumican is a secreted proteoglycan that regulates collagen fibril assembly. We have previously identified that the presence of lumican in the ECM surrounding PDAC cells is associated with improved patient outcome after multimodal therapy and surgical removal of localized PDAC. EXPERIMENTAL DESIGN: Lumican expression in PDAC from 27 patients was determined by IHC and quantitatively analyzed for colocalization with PSCs. In vitro studies examined the molecular mechanisms of lumican transcription and secretion from PSCs (HPSCs and HPaSteC), and cell adhesion and migration assays examined the effect of lumican on PSCs in a collagen-rich environment. RESULTS: Here we identify PSCs as a significant source of extracellular lumican production through quantitative IHC analysis. We demonstrate that the cytokine, TGF-beta, negatively regulates lumican gene transcription within HPSCs through its canonical signaling pathway and binding of SMAD4 to novel SBEs identified within the promoter region. In addition, we found that the ability of HPSCs to produce and secrete extracellular lumican significantly enhances HPSCs adhesion and mobility on collagen. CONCLUSIONS: Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-beta; once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen-rich environment. Clin Cancer Res; 22(19); 4934-46. (c)2016 AACR. PMID- 27126994 TI - A Phase Ib Study of Alpelisib (BYL719), a PI3Kalpha-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. AB - PURPOSE: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110alpha, has shown synergistic antitumor activity with endocrine therapy against ER+/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy. EXPERIMENTAL DESIGN: Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing. RESULTS: Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression >=6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment >=12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. (c)2016 AACR. PMID- 27126995 TI - SIRPalpha-Antibody Fusion Proteins Selectively Bind and Eliminate Dual Antigen Expressing Tumor Cells. AB - PURPOSE: CD47 is highly expressed on a variety of tumor cells. The interaction of CD47 with signal regulatory protein alpha (SIRPalpha), a protein on phagocytic cells, transmits a "don't eat me" signal that negatively regulates phagocytosis. CD47-SIRPalpha antagonists enable phagocytosis by disrupting the inhibitory signal and can synergize with Fc-mediated pro-phagocytic signals for potent elimination of tumor cells. A potential limitation of therapeutic CD47-SIRPalpha antagonists is that expression of CD47 on normal cells may create sites of toxicity or an "antigen sink." To overcome these limitations and address selective tumor targeting, we developed SIRPabodies to improve the therapeutic benefits of CD47-SIRPalpha blockade specifically toward tumor. EXPERIMENTAL DESIGN: SIRPabodies were generated by grafting the wild-type SIRPalpha either to the N-terminus or to the C-terminus of the heavy chain of rituximab. Selective tumor binding was tested using CFSE-labeled human primary CLL cells in the presence of 20-fold excess of human RBCs. NSG mice were transplanted with Raji luciferase cells and were assigned to controls versus SIRPabody treatment. Cynomolgus nonhuman primates were administered a single intravenous infusion of SIRPabody at 3, 10, or 30 mg/kg. RESULTS: SIRPabodies selectively bound to dual antigen-expressing tumor cells in the presence of a large antigen sink. SIRPabody reduced tumor burden and extended survival in mouse xenograft lymphoma models. SIRPabody caused no significant toxicity in nonhuman primates. CONCLUSIONS: These findings establish SIRPabodies as a promising approach to deliver the therapeutic benefit of CD47-SIRPalpha blockade specifically toward tumor cells. SIRPabodies may be applied to additional cancer types by grafting SIRPalpha onto other tumor specific therapeutic antibodies. Clin Cancer Res; 22(20); 5109-19. (c)2016 AACR. PMID- 27126997 TI - Associations of Sedentary Behavior, Physical Activity, Cardiorespiratory Fitness, and Body Fat Content With Pain Conditions in Children: The Physical Activity and Nutrition in Children Study. AB - We investigated the cross-sectional associations of sedentary behavior, physical activity, cardiorespiratory fitness, and body fat content with pain conditions in prepubertal children. The participants were a population sample of 439 children aged 6 to 8 years. Sedentary behavior, physical activity, and pain conditions were assessed using questionnaires, cardiorespiratory fitness using maximal cycle ergometer test, and body fat percentage using dual-energy X-ray absorptiometry. The associations of sedentary behavior, physical activity, cardiorespiratory fitness, and body fat percentage with the risk of pain conditions were analyzed using multivariate logistic regression. Children in the highest sex-specific third of sedentary behavior had 1.95 (95% confidence interval [CI], 1.20-3.17; P = .007 for trend across thirds) times higher odds of any pain than children in the lowest third. Children in the highest sex-specific third of cardiorespiratory fitness had 46% (odds ratio [OR] = .54; 95% CI, .32-.91; P = .019) lower odds of any pain and 50% (OR = .50; 95% CI, .28-.87; P = .015) lower odds of headache than children in the lowest third. Children in the highest sex-specific third of body fat percentage had 44% (OR = .56; 95% CI, .34-.93; P = .023) lower odds of any pain, 49% (OR = .51; 95% CI, .30-.86; P = .011) lower risk of multiple pain, and 48% (OR = .52; 95% CI, .31-.86; P = .010) lower odds of lower limb pain than children in the lowest third. Physical activity was not associated with pain conditions. These findings suggest that prepubertal children with high levels of sedentary behavior, low levels of cardiorespiratory fitness, and low body fat content have increased likelihood of various pain conditions. This information could be used to develop strategies to prevent chronic pain in childhood. PERSPECTIVE: Our findings suggest that low cardiorespiratory fitness, high levels of sedentary behavior, and low body fat content are associated with increased likelihood of various pain conditions among prepubertal children. This information could be used to develop strategies to prevent chronic pain in childhood. PMID- 27126998 TI - Whole-body MR neurography: Prospective feasibility study in polyneuropathy and Charcot-Marie-Tooth disease. AB - PURPOSE: To evaluate the feasibility of whole-body magnetic resonance neurography (WBMRN) in polyneuropathy for technical feasibility, distribution of nerve abnormalities, and differentiation. MATERIALS AND METHODS: Twenty WBMRN examinations were performed on a 3T scanner over 2 years. Patient demographics including history of hereditary and acquired neuropathy were recorded. The images were evaluated by two independent readers with nerve imaging experience for quality. The nerve signal and size alterations were measured in the brachial plexus, lumbosacral plexus, and femoral and sciatic nerves; diffusion tensor imaging parameters (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]) were determined in plexuses, and tractography was performed. Nonparametric Wilcoxon rank sum test, receiver operating characteristic (ROC) analysis, and intraclass correlation coefficients (ICCs) were obtained. RESULTS: Excellent image quality was obtained for the majority of lumbosacral (LS) plexus (18/20) and 50% of brachial plexus (10/20) regions. Qualitatively among cases, the nerve hyperintensity and/or thickening involved the brachial plexus (11/11), LS plexus (7/11), and both plexuses (7/11), with most nerve thickenings observed in Charcot Marie-Tooth disease type 1. The nerve signal intensity alterations were significantly different for both brachial (P < 0.05) and LS (P < 0.05) plexuses in cases versus controls. The femoral and sciatic nerve size alterations were different (P < 0.05), while signal intensity differences were not significant (P = 0.1-0.97). Transverse dimensions of C8 (4 mm), L5 (6.2 mm) and S1 (5.1 mm) nerve roots, and sciatic nerves (10.2 mm) were the most accurate diagnostic performance measures in distinguishing cases from controls. CONCLUSION: WBMRN is feasible for use in the clinical practice for the identification and potential characterization of polyneuropathy. J. Magn. Reson. Imaging 2016;44:1513-1521. PMID- 27126996 TI - A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers. AB - PURPOSE: Despite significant progress in cancer research, many tumor entities still have an unfavorable prognosis. Activating transcription factor 5 (ATF5) is upregulated in various malignancies and promotes apoptotic resistance. We evaluated the efficacy and mechanisms of the first described synthetic cell penetrating inhibitor of ATF5 function, CP-d/n-ATF5-S1. EXPERIMENTAL DESIGN: Preclinical drug testing was performed in various treatment-resistant cancer cells and in vivo xenograft models. RESULTS: CP-d/n-ATF5-S1 reduced the transcript levels of several known direct ATF5 targets. It depleted endogenous ATF5 and induced apoptosis across a broad panel of treatment-refractory cancer cell lines, sparing non-neoplastic cells. CP-d/n-ATF5-S1 promoted tumor cell apoptotic susceptibility in part by reducing expression of the deubiquitinase Usp9X and led to diminished levels of antiapoptotic Bcl-2 family members Mcl-1 and Bcl-2. In line with this, CP-d/n-ATF5-S1 synergistically enhanced tumor cell apoptosis induced by the BH3-mimetic ABT263 and the death ligand TRAIL. In vivo, CP-d/n-ATF5-S1 attenuated tumor growth as a single compound in glioblastoma, melanoma, prostate cancer, and triple receptor-negative breast cancer xenograft models. Finally, the combination treatment of CP-d/n-ATF5-S1 and ABT263 significantly reduced tumor growth in vivo more efficiently than each reagent on its own. CONCLUSIONS: Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe, and efficient antineoplastic agent against treatment-resistant cancers. Clin Cancer Res; 22(18); 4698-711. (c)2016 AACR. PMID- 27126999 TI - Effects of long term treatment with high doses of odanacatib on bone mass, bone strength, and remodeling/modeling in newly ovariectomized monkeys. AB - The objectives here were to evaluate the effects of odanacatib (ODN) at doses exceeding the clinical exposure on biomechanical properties of lumbar vertebrae (LV), hip and central femur (CF), and compare ODN to alendronate (ALN) on bone remodeling/modeling in ovariectomized (OVX) monkeys. Ten days post-surgery, animals were treated with vehicle (VEH), ODN-L (2mg/kg/day, p.o.), ODN-H (8/4mg/kg/day), or ALN (30MUg/kg/week, s.c.) for 20months. An intact group was also included. ODN-L provided systemic exposures of 1.8-fold of clinical exposure. ODN-H started at 20-fold for 5.5months, and then reduced to 7.8-fold of clinical exposure, compared to ALN at approximated clinical exposure. From cross sectional analyses, LV density and peak load in ODN at both doses or ALN were not different from VEH or Intact. However, cortical thickness of femoral neck (FN) and CF in ODN were higher (21-34%, p<0.05) than VEH, due to smaller endocortical (Ec) perimeter of FN (10-11%; p<0.05) and CF (9-12%; ODN-L, p<0.05), and larger CF periosteal (Ps) perimeter (2-12%; ODN-H, p<0.001) versus VEH. ODN groups also showed slightly higher cortical porosity and Ps non-lamellar bone in CF. ODN-H treatment resulted in higher CF peak load (p<0.05) versus VEH. For all bone sites analyzed, a positive, linear relationship (r(2)=0.46-0.69, p<0.0001) of peak load to density or structural parameters was demonstrated. No treatment-related differences in the derived intrinsic strength properties were evidenced as compared between groups. ALN reduced all remodeling surfaces without affecting Ps modeling. Trabecular and intracortical remodeling were reduced in ODN groups, similar to ALN. Ec mineralizing surface in ODN-H trended to be lower than VEH by month 20, but Ec bone formation indices in ODN groups generally were not different from VEH. Ps modeling in ODN groups was significantly higher than other treatment groups. This study overall demonstrated the bone safety profile of ODN and its unique mechanism on cortical bone supporting the clinical application for osteoporosis treatment. PMID- 27127001 TI - Tractography at 3T MRI of Corpus Callosum Tracts Crossing White Matter Hyperintensities. AB - BACKGROUND AND PURPOSE: The impact of white matter hyperintensities on the diffusion characteristics of crossing tracts is unclear. This study used quantitative tractography at 3T MR imaging to compare, in the same individuals, the diffusion characteristics of corpus callosum tracts that crossed white matter hyperintensities with the diffusion characteristics of corpus callosum tracts that did not pass through white matter hyperintensities. MATERIALS AND METHODS: Brain T2 fluid-attenuated inversion recovery-weighted and diffusion tensor 3T MR imaging scans were acquired in 24 individuals with white matter hyperintensities. Tractography data were generated by the Fiber Assignment by Continuous Tracking method. White matter hyperintensities and corpus callosum tracts were manually segmented. In the corpus callosum, the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts crossing white matter hyperintensities were compared with the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts that did not cross white matter hyperintensities. The cingulum, long association fibers, corticospinal/bulbar tracts, and thalamic projection fibers were included for comparison. RESULTS: Within the corpus callosum, tracts that crossed white matter hyperintensities had decreased fractional anisotropy compared with tracts that did not pass through white matter hyperintensities (P = .002). Within the cingulum, tracts that crossed white matter hyperintensities had increased radial diffusivity compared with tracts that did not pass through white matter hyperintensities (P = .001). CONCLUSIONS: In the corpus callosum and cingulum, tracts had worse diffusion characteristics when they crossed white matter hyperintensities. These results support a role for white matter hyperintensities in the disruption of crossing tracts. PMID- 27127000 TI - Overexpression of trophoblast cell surface antigen 2 as an independent marker for a poor prognosis and as a potential therapeutic target in epithelial ovarian carcinoma. AB - Most patients with epithelial ovarian cancer (EOC) are diagnosed at an advanced stage, and therapeutic options for these patients are limited. The identification of suitable biomarkers could be helpful for patients with EOC, who might benefit from targeted therapies even in advanced stages of the disease. Trophoblast cell surface antigen 2 (TROP2) is highly expressed in various human malignant tumours; however, this has not been demonstrated clearly in EOC. In this study, we further evaluated whether TROP2 is a promising marker for EOC, and thus also a potential target for EOC immunotherapy. Quantitative real-time polymerase chain reaction (qPCR) and fluorescence-activated cell sorting (FACS) analysis were employed to determine TROP2 mRNA and protein expression in both human EOC and normal ovarian cell lines. Additionally, TROP2 protein expression was measured by immunohistochemistry in 128 EOC tissue samples, 21 normal ovarian tissues and 18 normal fallopian tubes. The correlations between TROP2 protein expression and patients' clinicopathological features were investigated, and survival outcomes were analysed. TROP2 mRNA and protein levels were upregulated significantly in EOC cell lines compared with normal cell lines. The protein of TROP2 was expressed in the majority of EOC tissue samples (90.6%) and overexpressed in 75 (58.6%) of the 128 tumour samples. TROP2 overexpression was correlated with relevant clinicopathological characteristics and was associated with significantly shortened overall survival and disease-free survival. Furthermore, TROP2 was an independent prognostic marker for EOCs as analysed by Cox regression. TROP2 was a potential biomarker for targeted therapy in patients with TROP2-overexpressing EOC. PMID- 27127003 TI - Uremic Encephalopathy: MR Imaging Findings and Clinical Correlation. AB - BACKGROUND AND PURPOSE: Uremic encephalopathy is a metabolic disorder in patients with renal failure. The purpose of this study was to describe the MR imaging findings of uremic encephalopathy. MATERIALS AND METHODS: This study retrospectively reviewed MR imaging findings in 10 patients with clinically proved uremic encephalopathy between May 2005 and December 2014. Parameters evaluated were lesion location and appearance; MR signal intensity of the lesions on T1WI, T2WI, and T2 fluid-attenuated inversion recovery images; the presence or absence of restricted diffusion on diffusion-weighted images and apparent diffusion coefficient maps; and the reversibility of documented signal-intensity abnormalities on follow-up MR imaging. RESULTS: MR imaging abnormalities accompanying marked elevation of serum creatinine (range, 4.3-11.7 mg/dL) were evident in the 10 patients. Nine patients had a history of chronic renal failure with expansile bilateral basal ganglia lesions, and 1 patient with acute renal failure had reversible largely cortical lesions. Two of 6 patients with available arterial blood gas results had metabolic acidosis. All basal ganglia lesions showed expansile high signal intensity (lentiform fork sign) on T2WI. Varied levels of restricted diffusion and a range of signal intensities on DWI were evident and were not correlated with serum Cr levels. All cortical lesions demonstrated high signal intensity on T2WI. Four patients with follow-up MR imaging after hemodialysis showed complete resolution of all lesions. CONCLUSIONS: The lentiform fork sign is reliable in the early diagnosis of uremic encephalopathy, regardless of the presence of metabolic acidosis. Cytotoxic edema and/or vasogenic edema on DWI/ADC maps may be associated with uremic encephalopathy. PMID- 27127002 TI - Application of Blood-Brain Barrier Permeability Imaging in Global Cerebral Edema. AB - BACKGROUND AND PURPOSE: Blood-brain barrier permeability is not routinely evaluated in the clinical setting. Global cerebral edema occurs after SAH and is associated with BBB disruption. Detection of global cerebral edema using current imaging techniques is challenging. Our purpose was to apply blood-brain barrier permeability imaging in patients with global cerebral edema by using extended CT perfusion. MATERIALS AND METHODS: Patients with SAH underwent CTP in the early phase after aneurysmal rupture (days 0-3) and were classified as having global cerebral edema or nonglobal cerebral edema using established noncontrast CT criteria. CTP data were postprocessed into blood-brain barrier permeability quantitative maps of PS (permeability surface-area product), K(trans) (volume transfer constant from blood plasma to extravascular extracellular space), Kep (washout rate constant of the contrast agent from extravascular extracellular space to intravascular space), VE (extravascular extracellular space volume per unit of tissue volume), VP (plasmatic volume per unit of tissue volume), and F (plasma flow) by using Olea Sphere software. Mean values were compared using t tests. RESULTS: Twenty-two patients were included in the analysis. Kep (1.32 versus 1.52, P < .0001), K(trans) (0.15 versus 0.19, P < .0001), VP (0.51 versus 0.57, P = .0007), and F (1176 versus 1329, P = .0001) were decreased in global cerebral edema compared with nonglobal cerebral edema while VE (0.81 versus 0.39, P < .0001) was increased. CONCLUSIONS: Extended CTP was used to evaluate blood brain barrier permeability in patients with SAH with and without global cerebral edema. Kep is an important indicator of altered blood-brain barrier permeability in patients with decreased blood flow, as Kep is flow-independent. Further study of blood-brain barrier permeability is needed to improve diagnosis and monitoring of global cerebral edema. PMID- 27127004 TI - Intervention versus Aggressive Medical Therapy for Cognition in Severe Asymptomatic Carotid Stenosis. AB - BACKGROUND AND PURPOSE: Asymptomatic carotid stenosis of >=70% increases the incidence of microembolism and/or chronic hypoperfusion, which may consequently impair neurocognition and brain connections. We sought controlled evidence for any cognitive benefit of aggressive medical therapy and combined carotid revascularization. MATERIALS AND METHODS: Patients with asymptomatic, unilateral, ?70% stenosis of the extracranial ICA chose either aggressive medical therapy alone or in combination with carotid artery stent placement in this nonrandomized controlled study. They were examined with a battery of neuropsychological tests, structural MR imaging, DTI, and resting-state fMRI before and 3 months after treatment. RESULTS: Forty patients were included with 15 in the medical group and 25 in the stent-placement group. Among them, 13 and 21 in the respective groups completed neuroimaging follow-up. The baseline characteristics and the changes in cognitive performance during 3 months showed no differences between treatment groups. Nevertheless, compared with the medical group, the stent-placement group showed subjective dizziness alleviation (P = .045) and a small increase in fractional anisotropy at the splenium of the corpus callosum and the posterior periventricular white matter ipsilateral to carotid artery stent placement. Moreover, only the stent-placement group showed interval improvement in immediate memory and visuospatial performance, which was accompanied by an increase of functional connectivity at the insular cortex of the dorsal attention network and the medial prefrontal cortex of the default mode network. CONCLUSIONS: Both aggressive medical therapy alone and combined carotid revascularization in ?70% asymptomatic carotid stenosis similarly preserved cognition during 3-month follow up, though the latter had the potential for dizziness alleviation and cognitive and connectivity enhancement. PMID- 27127005 TI - MR Imaging of the Pituitary Gland and Postsphenoid Ossification in Fetal Specimens. AB - BACKGROUND AND PURPOSE: A thorough knowledge of fetal growth and development is key to understanding both the normal and abnormal fetal MR imaging findings. We investigated the size and signal intensity of the normal pituitary gland and the intrasphenoidal ossification around the Rathke pouch in formalin-fixed fetuses on MR imaging. MATERIALS AND METHODS: Thirty-two fetuses with undamaged brains were included in this study (mean age, 19.93 weeks; age range, 12-31 weeks). Visual inspection of the pituitary and ossification around the Rathke pouch in the sphenoid bone or the postsphenoid ossification was conducted. The extent of pituitary and postsphenoid ossification, pituitary/pons signal ratio, and postsphenoidal ossification/sphenoid bone signal ratio was compared according to gestational age. RESULTS: The pituitary gland was identified as a hyperintense intrasellar structure in all cases, and postsphenoid ossification was identified as an intrasphenoidal hyperintense area in 27 of the 32 cases (84%). The mean pituitary/pons signal ratio was 1.13 +/- 0.18 and correlated weakly with gestational age (R(2) = 0.243), while the mean postsphenoid ossification/sphenoid bone signal ratio was 2.14 +/- 0.56 and did not show any increase with gestational age (R(2) = 0.05). No apparent change in the size of pituitary hyperintensity was seen with gestational age (R(2) = 0.001). Postsphenoid ossification showed an increase in size with gestational age (R(2) = 0.307). CONCLUSIONS: The fetal pituitary gland was hyperintense on T1-weighted images and the pituitary/pons ratio and extent of postsphenoid ossification correlated weakly with gestational age. PMID- 27127006 TI - Response Assessment in Pediatric Neuro-Oncology: Implementation and Expansion of the RANO Criteria in a Randomized Phase II Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas. AB - Determination of tumor response to treatment in neuro-oncology is challenging, particularly when antiangiogenic agents are considered. Nontumoral factors (eg, blood-brain barrier disruption, edema, and necrosis) can alter contrast enhancement independent of true tumor response/progression. Furthermore, gliomas are often infiltrative, with nonenhancing components. In adults, the Response Assessment in Neuro-Oncology (RANO) criteria attempted to address these issues. No such guidelines exist yet for children. The ongoing randomized phase II trial, A Study of Avastin (bevacizumab) in Combination With Temolozomide (TMZ) and Radiotherapy in Paediatric and Adolescent Patients With High-Grade Glioma (HERBY), will establish the efficacy and safety of the antiangiogenic agent bevacizumab for the first-line treatment of newly diagnosed high-grade glioma in children (n = 121 patients, enrollment complete). The primary end point is event free survival (tumor progression/recurrence by central review, second primary malignancy, or death). Determination of progression or response is based on predefined clinical and radiographic criteria, modeled on the RANO criteria and supported by expert pseudoprogression review and the use of standardized imaging protocols. The HERBY trial will also compare conventional MR imaging (T1-weighted and T2/fluid-attenuated inversion recovery sequences) with conventional MR imaging plus diffusion/perfusion imaging for response assessment. It is anticipated that HERBY will provide new insights into antiangiogenic-treated pediatric brain tumors. HERBY will also investigate the practicality of obtaining adequate quality diffusion/perfusion scans in a trial setting, and the feasibility of implementing standard imaging protocols across multiple sites. To date, 61/73 (83.6%) patients with available data have completed diffusion weighted imaging (uptake of other nonconventional techniques has been limited). Harmonization of imaging protocols and techniques may improve the robustness of pediatric neuro-oncology studies and aid future trial comparability. PMID- 27127007 TI - Shwachman-Diamond syndrome presenting with early ichthyosis, associated dermal and epidermal intracellular lipid droplets, hypoglycemia, and later distinctive clinical SDS phenotype. AB - Shwachman-Diamond syndrome (SDS) is a recessive ribosomopathy, characterized by bone marrow failure and exocrine pancreatic insufficiency (ePI) often associated with neurodevelopmental and skeletal abnormalities. The aim of this report is to describe a SDS patient with early ichthyosis associated with dermal and epidermal intracellular lipid droplets (iLDs), hypoglycemia and later a distinctive clinical SDS phenotype. At 3 months of age, she had ichthyosis, growth retardation, and failure to thrive. She had not cytopenia. Ultrasonography (US) showed pancreatic diffuse high echogenicity. Subsequently fasting hypoketotic hypoglycemia occurred without permanent hepatomegaly or hyperlipidemia. Continuous gavage feeding was followed by clinical improvement including ichthyosis and hypoglycemia. After 14 months of age, she developed persistent neutropenia and ePI consistent with SDS. The ichthyotic skin biopsy, performed at 5 months of age, disclosed iLDs in all epidermal layers, in melanocytes, eccrine sweat glands, Schwann cells and dermal fibroblasts. These iLDs were reminiscent of those described in Dorfman-Chanarin syndrome (DCS) or Wolman's disease. Both LIPA and CGI-58 analysis did not revealed pathogenic mutation. By sequencing SBDS, a compound heterozygous for a previously reported gene mutation (c.258 + 2T>C) and a novel mutation (c.284T>G) were found. Defective SBDS may hypothetically interfere as in DCS, with neutral lipid metabolism and play a role in the SDS phenotype such as ichthyosis with dermal and epidermal iLDs and hypoglycemia. This interference with neutral lipid metabolism must most likely occur in the cytoplasm compartment as in DCS and not in the lysosomal compartment as in Wolman's disease. (c) 2016 Wiley Periodicals, Inc. PMID- 27127008 TI - The population benefit of radiotherapy for gynaecological cancer: Local control and survival estimates. AB - BACKGROUND: The population benefit of radiotherapy for gynaecological cancer (GC) if evidence-based guidelines were routinely followed is not known. This study's aim was to address this. METHODS: Decision trees were utilised to estimate benefit. Radiotherapy alone (RT) benefit was the absolute proportional benefit of radiotherapy over no radiotherapy for radical indications, and over surgery alone for adjuvant indications. Chemoradiotherapy (CRT) benefit was the absolute incremental benefit of concurrent chemotherapy and RT over RT alone. Citation databases were systematically queried for the highest level of evidence defining 5-year Local Control (LC), and 2-year and 5-year Overall Survival (OS) benefit. Meta-analysis was performed if there were multiple sources of the same evidence level. Deterministic and probabilistic sensitivity analysis was performed. FINDINGS: Guidelines supported 22 radiotherapy indications, of which 8 were for CRT. 21% of all GC had an adjuvant or curative radiotherapy indication. The absolute estimated population-based 5-year LC and OS benefits of RT, if all patients were treated according to guidelines, were: endometrial cancer LC 5.7% (95% CI (3.5%,8.2%)), OS 2.3% (1.2%,3.4%), ovarian cancer (nil), vulval cancer LC 10.0% (1.6%,18.2%), OS 8.5% (0.5%,15.9%). Combined with prior estimates for cervical cancer, RT benefits for all GC were LC 9.0% (7.8%,10.3%), OS 4.6% (3.8%,5.4%). The incremental benefit of CRT for all GC was LC 0.7% (0.4%,0.9%), OS 0.5% (0.2%,0.8%). Benefits were distinct from the contribution of other modalities. The model was robust in sensitivity analysis. Most radiotherapy benefit was irreplaceable by other modalities. INTERPRETATION: Radiotherapy provides important and irreplaceable LC and OS benefits for GC when optimally utilised. The population model provided a robust means for estimating this benefit. PMID- 27127009 TI - Moving Word Learning to a Novel Space: A Dynamic Systems View of Referent Selection and Retention. AB - Theories of cognitive development must address both the issue of how children bring their knowledge to bear on behavior in-the-moment, and how knowledge changes over time. We argue that seeking answers to these questions requires an appreciation of the dynamic nature of the developing system in its full, reciprocal complexity. We illustrate this dynamic complexity with results from two lines of research on early word learning. The first demonstrates how the child's active engagement with objects and people supports referent selection via memories for what objects were previously seen in a cued location. The second set of results highlights changes in the role of novelty and attentional processes in referent selection and retention as children's knowledge of words and objects grows. Together this work suggests that understanding systems for perception, action, attention, and memory, and their complex interaction, is critical to understand word learning. We review recent literature that highlights the complex interactions between these processes in cognitive development and point to critical issues for future work. PMID- 27127010 TI - Nutritional strategies to improve the lipid composition of meat, with emphasis on Thailand and Asia. AB - This article reviews opportunities for enriching the lipids of meat with n-3 fatty acids and conjugated linoleic acids (CLAs), both considered beneficial to human health. Special focus is put on feeds available and research carried out in Thailand. A differentiated consideration concerning the value of different n-3 fatty acids and isomers of CLAs is necessary. In ruminants, it is difficult to enrich the meat with n-3 fatty acids due to the extensive ruminal biohydrogenation of unsaturated fatty acids, but several possibilities to enhance the proportion of the most desired CLA isomer, rumenic acid, exist. By contrast, pork and poultry meat can be easily enriched with n-3 fatty acids. With purified CLA sources, CLAs also can be enhanced, but it is difficult to achieve this exclusively for rumenic acid. An interesting approach might consist in supplementing the CLA precursor vaccenic acid instead. Possible constraints for meat quality and in the fatty acid levels achieved are outlined. PMID- 27127011 TI - Re: "using data sources beyond PubMed has a modest impact on the results of systematic reviews of therapeutic interventions". PMID- 27127012 TI - Iodine excretion in school children in Copenhagen. AB - INTRODUCTION: Studies of dietary habits show a high iodine intake in children in Denmark. Iodine excretion in children has not previously been assessed. Iodine excretion in adults is below the recommended threshold, and it is therefore being discussed to increase the fortification level. The main objective of this study was to assess iodine excretion in children living in Copenhagen to establish whether a moderate increase in iodine fortification would lead to excess iodine intake in this group. METHODS: Children in first and fifth grade were recruited through schools in Copenhagen. In total, 244 children de-ivered a urine sample. Urine samples were analysed for iodine and creatinine, and the results were expressed as urinary iodine concentration (UIC) and as estimated 24-h iodine excretion. Iodine excretion in children was also compared with that of adults living in the same area, investigated in a prior study. RESULTS: The median UIC was within the recommended level; 145 (range: 116-201) ug/l for boys and 128 (range: 87-184) ug/l for girls, and was lower in fifth grade students than in first grade students. Estimated 24-h iodine excretion was higher in boys than in girls, but did not differ according to grade. The UIC was higher in children than in adults from the same area. CONCLUSIONS: The iodine excretion among schoolchildren in Copenhagen, an area with a relatively high iodine content in tap water, was within the recommended range as assessed by the UIC. An increased iodine fortification will not have negative consequences for this group. FUNDING: The Ministry of Food, Agriculture and Fisheries. TRIAL REGISTRATION: not relevant. PMID- 27127013 TI - Familial hypercholesterolaemia reduces the quality of life of patients not reaching treatment targets. AB - INTRODUCTION: Familial hypercholesterolaemia (FH) is the most common monogenic disorder associated with premature cardiovascular disease. If untreated, life expectancy in heterozygous FH patients is shortened by 20-30 years compared with the general population. Nevertheless, treatment goals are only met in approximately 50% of patients. This comparative study examined the quality of life (QoL) impact of FH in patients who had and had not reached the target of treatment. METHODS: Two qualitative focus group interviews were carried out with a total of ten FH patients. A semi-structured interview guide included questions identified in a preceding literature study. The data were analysed using a medical anthropological approach. RESULTS: While having FH did not have much impact on well-treated patients' QoL, patients who had not reached the treatment target had markedly more concerns. They had experienced severe side-effects and worried about their own and their relatives' health. They were concerned about the long-term impact of not being effectively treated including the risk that coronary heart disease could cause their premature death or disability and inability to care for their children, in particular. The women had issues with stigma and self-efficacy. CONCLUSIONS: The QoL impact of FH is related to treatment efficacy. These findings need to be addressed in the management of FH patients. Particular attention should be paid to those who are not presently reaching the target of treatment. FUNDING: The study was funded by a research grant from Amgen. TRIAL REGISTRATION: not relevant. PMID- 27127014 TI - Tonsillotomy in children with sleep-disordered breathing is safe and results in high parent satisfaction. AB - INTRODUCTION: Sleep-disordered breathing in children is often associated with tonsillar hypertrophy. For many years, total tonsillectomy (TE) was the treatment of choice, but performing an intracapsular tonsillotomy (TT) is becoming increasingly widespread. In this Danish study, we have investigated the long-term results on efficacy and parent satisfaction after TT performed on children. METHODS: This was a retrospective study based on a questionnaire that was sent to the parents of 335 children who underwent TT due to sleep-related obstructive symptoms. RESULTS: A total of seven children had unilateral re-TT due to tonsillar regrowth, leaving a total of 342 operations performed. The response rate was 71% and the median follow-up was 90 months. None of the patients in this study ex-perienced post-operative bleeding requiring medical assistance. A total of 97% of parents reported total or partial relief of all symptoms, whereas 3% experienced no effect of treatment on preoperative symptoms. A total of 5% of the children later underwent tonsillectomy after their primary TT. The majority of parents (89%) would choose the operation again in a similar situation. CONCLUSIONS: TT has previously been shown to have a lower morbidity and risk of post-operative bleeding and a better recovery than TE. In this study, we found it to be a long-term efficient and safe treatment for children with obstructive symptoms during sleep and it was associated with a high degree of parent satisfaction. FUNDING: none. TRIAL REGISTRATION: This was a retrospective study. PMID- 27127015 TI - Large discrepancies in otomycosis treatment in private ear, nose, and throat clinics in Denmark. AB - INTRODUCTION: Otomycosis is a fungal infection of the external ear canal that can involve the middle ear in case of tympanic membrane perforation and also extend to the auricle. Fungi cause 7-15% of external otitis. Diagnosing otomycosis is often based entirely on non-specific clinical signs and symptoms. A multitude of antifungal drugs are available. Some are ototoxic in animals, a few are proven safe, but the ototoxicity of many drugs remains unknown. The aim of this study was to describe how otomycosis was diagnosed and treated by private ear, nose, and throat (ENT) consultants in Denmark and to investigate if the patient's immune status and the presence of a tympanic membrane perforation affected the chosen treatment modality. METHOD: A questionnaire on the treatment of otomycosis was sent to 147 private ENT consultants. RESULTS: In total, 103 (70%) responded. 95% performed intensive aural cleaning using an otomicroscope. The initial diagnosis was based on symptoms as only 20% required to see fungal hypha. 42% sent material for culture and sensitivity (C + S) before starting treatment and 92% sent for C + S if treatment failed. 89% used a variety of topical antifungal drugs as the first line of medical treatment. Antiseptics were used in 5%. The presence of a tympanic membrane perforation did not alter the treatment modality. Only 13% treated immunocompromised patients differently. CONCLUSION: The initial diagnosis was based on non-specific symptoms and there were large discrepancies in the chosen antifungal treatment. Topical antifungal drugs were preferred. Additional research is needed. FUNDING: Department of Otorhinolaryngolgy and Maxillofacial Surgery, Zealand University Hospital, Koge, Denmark. The Danish Association of Research-interested Otorhinolaryngology Consultants: Kim Werther, Peter Tingsgaard, Mads Stougaard, Steen Telmer, Henrik Moller, Liviu Guldfred. TRIAL REGISTRATION: No trial registration was necessary as the questionnaire was anonymous and contained no patient data. PMID- 27127016 TI - Non-physician delivered intravitreal injection service is feasible and safe - a systematic review. AB - INTRODUCTION: Non-physicians such as nurses are trained to give injections into the vitreous body of the eye to meet the increasing demand for intravitreal therapy with vascular endothelial growth factor inhibitors against common eye diseases, e.g. age-related macular degeneration and diabetic retinopathy. We systematically reviewed the existing literature to provide an overview of the experiences in this transformational process. METHODS: We searched for literature on 22 September 2015 using PubMed, Embase, the Cochrane Library, CINAHL and the Web of Science. Eligible studies had to address any outcome based on non physician delivered intravitreal therapy regardless of the study design. Being non-physician was defined as the injecting personnel not being a physician, but no further restrictions were made. RESULTS: Five studies were included with a total of 31,303 injections having been performed by 16 nurses. The studies found that having nurses perform the intravitreal injections produced to a short-term capacity improvement and liberated physicians for other clinical work. Training was provided through courses and direct supervision. The rates of endophthalmitis were 0-0.400/00, which is comparable to reported rates when the intravitreal therapy is given by physicians. CONCLUSION: Non-physician delivered intravitreal therapy seems feasible and safe. PMID- 27127017 TI - The CYTONOX trial. AB - INTRODUCTION: In Denmark, it is estimated that 3-5% of children are obese. Obesity is associated with pathophysiological alterations that may lead to alterations in the pharmacokinetics of drugs. In adults, obesity was found to influence important drug-metabolising enzyme pathways. The impact of obesity related alterations on drug metabolism and its consequences for drug dosing remains largely unknown in both children and adults. An altered drug metabolism may contribute significantly to therapeutic failure or toxicity. The aim of this trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 substrates in obese versus non-obese children. METHODS: The CYTONOX trial is an open-label explorative pharmacokinetic trial. We intend to include 50 obese and 50 non-obese children. The primary end points are: in vivo clearance of CYP3A4, CYP2E1 and CYP1A2 substrates, which will be defined by using well-tested probes; midazolam, chlorzoxazone and caffeine. Each of the probes will be administered as a single dose. Subsequently, blood and urine samples will be collected at pre specified times. CONCLUSION: The aim of the CYTONOX trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 in obese and non-obese children. The results are expected to be used in the future as a basis for drug dosing recommendations in obese children. FUNDING: The study was funded by the Danish Regions' "Medicinpuljen". The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. TRIAL REGISTRATION: EudraCT: 2014-004554-34. PMID- 27127018 TI - Adjuvant chemotherapy in early breast cancer. AB - With long-term follow-up, the DBCG 77B trial demonstrates that oral single-agent cyclophosphamide significantly reduces the risk of recurrence and mortality as compared with no systemic therapy in pre-menopausal patients with high-risk early breast cancer. DBCG 77B is the only randomised trial assessing single-agent cyclophosphamide; and a second comparison suggests that its benefits are comparable to what may be achieved by classic CMF. The lack of benefits from adding methotrexate and fluorouracil to cyclophosphamide paved the way for combining cyclophosphamide with anthracyclines and later taxanes. DBCG 89D showed an incremental benefit in DFS and OS from substituting methotrexate with epirubicin. The advantage of anthracycline-containing three-drug combinations over CMF was confirmed by others and in the individual-patient EBCTCG meta analysis, while standard AC or EC for four cycles not was superior to classic CMF. A further reduction in breast cancer mortality appeared in the EBCTCG meta analysis from the addition of a taxane to a standard AC, while the substitution of cycles or drugs with a taxane was not associated with a reduction in mortality. No apparent benefit was observed in an early analysis of the DBCG 82C evaluating the addition of CMF to tamoxifen in post-menopausal high-risk breast cancer patients. Apart from menopausal status, the two trials had identical selection criteria, and the differences in outcome warranted a long-term follow up of the 82C trial. After ten years of follow-up, CMF in the DBCG 82C was associated with a significant improvement in DFS; but even with 24 years of follow-up, mortality was not significantly improved. The diversity in outcome from the 77C and the 82B trials triggered further studies. The 77B trial used classic CMF with oral cyclophospamide, while a four-weekly intravenous CMF regimen was used in the 82B and C trials, and a three-weekly CMF regimen was used in the succeeding 89B and D trials. The outcome following these CMF regimens has not been compared within the context of a randomised trial. Shifting from the 77B's classic CMF regimen to the 82B four-weekly IV regimen or the 89B three weekly IV regimen was associated with a 30% increased risk of a DFS event in a multivariate analysis of a population-based cohort study. Furthermore, the four weekly regimen used in 82B was associated with a 40% increase in mortality. The strengths of the design include identical selection criteria, uniform and prospective registration of treatment, tumour and patient characteristics. Caution is still required due to the non-experimental design of the comparison. Another finding was a substantial difference in the risk of amenorrhoea; and while 15% of patients aged 40 or younger in 77B had regular menses throughout chemotherapy, the corresponding percentage was 37 in 82B and 47 in 89B. The DBCG in collaboration with a Swedish and a Dutch centre participating in the DBCG trial 89B compared CMF with ovarian ablation in premenopausal high-risk breast cancer patients with ER-positive tumours. No significant differences were found in DFS or OS in the preplanned analysis, suggesting that the benefits of CMF may, at least in part, be explained by ovarian suppression in premenopausal patients with ER-positive tumours. However, these results are not clinically useful by themselves as other chemotherapy regimens have been more efficacious, and knowledge is still lacking regarding the benefits from adding ovarian suppression to chemotherapy plus tamoxifen. The results from the DBCG 77B and 82C are in accordance with other large adjuvant trials and the EBCTCG meta-analyses. The benefits obtained with any individual anticancer drug are largely determined by the cancer (somatic) genome; and by being a molecular target of anthracyclines, TOP2A aberrations could obviously be associated with cancer drug benefits. In the DBCG 89D, a significant heterogeneity was observed between a beneficial effect on DFS and OS of epirubicin and the presence of TOP2A, but not the presence of HER2 aberrations. The results obtained in the 89D trial regarding TOP2A have been reproduced by others, but not consistently. However, a recent individual-patient pooled analysis of five adjuvant trials demonstrated that patients with either TOP2A or centromere 17 aberrations, but not with HER2 amplification, benefit from anthracycline-containing adjuvant chemotherapy. Anthracyclins have additional distinct biological mechanisms; and results from the DBCG 89D suggested that tumours with normal TOP2A were only non-responsive to anthracyclines if they were TIMP1 immunoreactive. The DBCG READ trial (N = 2,015) prospectively included patients without TOP2A-aberrated breast cancers, and its results are awaited for prospective confirmation of the results from the DBCG 89D and the individual patient pooled analysis. Adjuvant chemotherapy substantially reduces the risk of recurrence and mortality of breast cancer, but is also associated with significant toxicity. However, according to a large cohort study from DBCG, chemotherapy can safely be withheld in one fourth of postmenopausal patients who will be without excess mortality following sufficient adjuvant endocrine therapy for ER positive breast cancer. A prognostic standard mortality rate index (PSI) was constructed using regression coefficients obtained in a multivariate fractional polynomials model, and most accurately identified those who could be spared chemotherapy. In addition to age, tumour size, nodal status, histological type and malignancy grade, the PSI also includes ER level addressed as a continuous variable in the MFP model. In the MFP model, absence of LVI was sufficient to counteract the impact of other risk factors, while that could not be achieved with a categorical multivariate model in a prior study. An evaluation of whether the addition of results from a molecular assay may improve the clinical utility of the PSI is on-going, but when used alone evidence from such assays has been insufficient. PMID- 27127019 TI - Effect of metabolic gases and water vapor, perfluorocarbon emulsions, and nitric oxide on tissue bubbles during decompression sickness. AB - In aviation and diving, fast decrease in ambient pressure, such as during accidental loss of cabin pressure or when a diver decompresses too fast to sea level, may cause nitrogen (N2) bubble formation in blood and tissue resulting in decompression sickness (DCS). Conventional treatment of DCS is oxygen (O2) breathing combined with recompression. However, bubble kinetic models suggest, that metabolic gases, i.e. O2 and carbon dioxide (CO2), and water vapor contribute significantly to DCS bubble volume and growth at hypobaric altitude exposures. Further, perfluorocarbon emulsions (PFC) and nitric oxide (NO) donors have, on an experimental basis, demonstrated therapeutic properties both as treatment and prophylactic intervention against DCS. The effect was ascribed to solubility of respiratory gases in PFC, plausible NO elicited nuclei demise and/or N2 washout through enhanced blood flow rate. Accordingly, by means of monitoring injected bubbles in exposed adipose tissue or measurements of spinal evoked potentials (SEPs) in anaesthetized rats, the aim of this study was to: 1) evaluate the contribution of metabolic gases and water vapor to bubble volume at different barometrical altitude exposures, 2) clarify the O2 contribution and N2 solubility from bubbles during administration of PFC at normo- and hypobaric conditions and, 3) test the effect of different NO donors on SEPs during DCS upon a hyperbaric air dive and, to study the influence of NO on tissue bubbles at high altitude exposures. The results support the bubble kinetic models and indicate that metabolic gases and water vapor contribute significantly to bubble volume at 25 kPa (~10,376 m above sea level) and constitute a threshold for bubble stabilization or decay at the interval of 47-36 kPa (~6,036 and ~7,920 m above sea level). The effect of the metabolic gases and water vapor seemed to compromise the therapeutic properties of both PFC and NO at altitude, while PFC significantly increased bubble disappearance rate at sea level following a hyperbaric airdive. We found no protective effect of NO donors during DCS from diving. On the contrary, there was a tendency towards a poorer outcome when decompression was combined with NO donor administration. This observation is seemingly contradictive to recent publications and may be explained by the multifactorial effect of NO in combination with a fast decompression profile, speeding up the N2 release from tissues and thereby aggravating the DCS symptoms. PMID- 27127020 TI - Preoperative airway assessment - experience gained from a multicentre cluster randomised trial and the Danish Anaesthesia Database. AB - Difficulties with airway management in relation to general anaesthesia have been a challenge for the anaesthesiologist since the birth of anaesthesia. Massive landmark improvements have been made and general anaesthesia is now regarded as a safe procedure. However, rare, difficult airway management still occurs and it prompts increased risk of morbidity and mortality - especially when not anticipated. Several preoperative risk factors for airway difficulties have been identified, yet none have convincing diagnostic accuracy as stand alone tests. Combining several risk factors increase the predictive value of the test and multivariable risk models have been developed. The Simplified Airway Risk Index (SARI) is a predictive model developed for anticipation of a difficult direct laryngoscopy. However, neither the diagnostic accuracy of the SARI nor of any other model has been tested prospectively and compared with existing practice for airway assessment in a randomised trial setting. The first objective of this thesis was to quantify the proportion of unanticipated difficult intubation and difficult mask ventilation in Denmark. The second objective was to design a cluster randomised trial, using state of the art methodology, in order to test the clinical impact of using the SARI for preoperative airway assessment compared with a clinical judgement based on usual practice for airway assessment. Finally, to test if implementation of the SARI would reduce the proportion of unanticipated difficult intubation compared with usual care for airway assessment. This thesis is based on data from the Danish Anaesthesia Database (DAD). Paper 1 presents an observational cohort study on 188,064 patients who underwent tracheal intubation from 2008 to 2011. Data on the anaesthesiologists' preoperative anticipations of airway difficulties was compared with actual airway management conditions, thus enabling an estimation of the proportion of unanticipated difficulties with intubation and mask ventilation. Papers 2 and 3 outline the methodology and the pre-trial calculations and considerations leading to the DIFFICAIR trial described in Paper 4. The trial was designed to randomise anaesthesia department to either thorough education in, and subsequent use of the SARI for preoperative airway assessment or to continue usual care. Registration of the SARI in DAD was made mandatory in SARI departments and impossible in usual care departments. Conditions regarding anticipation of difficulties and actual airway managements were recorded as for Paper 1. DAD data made it possible to estimate an appropriate sample size, considering the between cluster variation, and to construct a stratification variable based on 2011 baseline values of the primary outcome used in the DIFFICAIR trial. Paper 1 revealed that 1.86% of all patients who were intubated, but not planned for advanced intubation techniques (e.g. video laryngoscopy), were unanticipated difficult to intubate. However, 75 to 93% of all difficult intubations were unanticipated. Furthermore, 94% of all difficult mask ventilations were unanticipated. In Paper 4, 59,514 patients were included in the primary analyses. The proportion of unanticipated difficult intubations was 2.38% (696/29,209) in SARI departments and 2.39% (723/30,305) in usual care departments. The adjusted odds ratio was 1.03 (95% CI: 0.77-1.38), p = 0.84. No significant differences were detected in other adjusted outcome measures and neither a 58% increase in patients anticipated to have intubation difficulties nor an 84% increase in patients scheduled for advanced intubation techniques in SARI departments reached statistical significance, p = 0.29 and p = 0.06 respectively. The papers constituting this thesis demonstrate that at high proportion of airway management difficulties are unanticipated. In a cluster randomised trial it was not possible to reduce the proportion of unanticipated difficult intubation in daily clinical practice by implementing a systematic approach for airway assessment compared with usual care. However, implementation of the SARI may increase the anticipation of intubation difficulties and it may change practice towards advanced intubation techniques. This thesis underlines the continued challenge anaesthesiologists face in predicting airway management related difficulties. PMID- 27127021 TI - Ventricular fibrillation and sudden cardiac death during myocardial infarction. AB - In this PhD thesis, we report that VF is still a common complication of STEMI, with an incidence of 11.6% in the population of Danish STEMI patients who survive to reach the hospital. In this STEMI population, we identified several risk factors associated with VF independent of MI. We identified and confirmed findings from several previous studies and found several risk factors, such as younger age, a family history of sudden death, a TIMI flow grade of 0, the absence of angina, anterior infarction (i.e., VF before PPCI), and inferior infarction (i.e., VF during PPCI) that were associated with VF in a Danish cohort. Furthermore, a history of atrial fibrillation and alcohol intake were identified as novel risk factors for VF. To the best of our knowledge, this study contains data on the largest VF cohort with the longest reported follow-up published; we found that VF mortality is significantly higher within the first 30 days for patients who experience VF before and during PPCI compared with STEMI patients without VF. However, the long-term mortality rates of the three groups are the same. Importantly, our results contradict the previous understanding that VF during PPCI is "benign"; the mortality rate within the first 30 days was as high for patients with VF during PPCI as the mortality rate of patients with VF before PPCI. Finally, although it is difficult to draw clinical implications from a descriptive study, due to the comprehensiveness of Danish death certificates, we reported a high incidence of cardiac symptoms and contact with healthcare professionals based on cardiac symptoms in young SCD patients who died due to CAD, although death was not avoided. PMID- 27127022 TI - Relevant aspects in the surface properties in titanium dental implants for the cellular viability. AB - Roughness and topographical features are the most relevant of the surface properties for a dental implant for its osseointegration. For that reason, we studied the four surfaces more used in titanium dental implants: machined, sandblasted, acid etching and sandblasted plus acid etching. The roughness and wettability (contact angle and surface free energy) was studied by means 3D interferometric microscope and sessile drop method. Normal human gingival fibroblasts (HGF) were obtained from small oral mucosa biopsies and were used for cell cultures. To analyze cell integrity, we first quantified the total amount of DNA and LDH released from dead cells to the culture medium. Then, LIVE/DEAD assay was used as a combined method assessing cell integrity and metabolism. All experiments were carried out on each cell type cultured on each Ti material for 24h, 48h and 72h. To evaluate the in vivo cell adhesion capability of each Ti surface, the four types of discs were grafted subcutaneously in 5 Wistar rats. Sandblasted surfaces were significantly rougher than acid etching and machined. Wettability and surface free energy decrease when the roughness increases in sand blasted samples. This fact favors the protein adsorption. The DNA released by cells cultured on the four Ti surfaces did not differ from that of positive control cells (p>0.05). The number of cells per area was significantly lower (p<0.05) in the sand-blasted surface than in the machined and surface for both cell types (7+/-2 cells for HGF and 10+/-5 cells for SAOS-2). The surface of the machined-type discs grafted in vivo had a very small area occupied by cells and/or connective tissue (3.5%), whereas 36.6% of the sandblasted plus acid etching surface, 75.9% of sandblasted discs and 59.6% of acid etching discs was covered with cells and connective tissue. Cells cultured on rougher surfaces tended to exhibit attributes of more differentiated osteoblasts than cells cultured on smoother surfaces. These surface properties justify that the sandblasted implants is able to significantly increase bone contact and bone growth with very good osseointegration results in vivo. PMID- 27127023 TI - Graphene oxide decorated electrospun gelatin nanofibers: Fabrication, properties and applications. AB - Gelatin nanofiber fabricated by electrospinning process is found to mimic the complex structural and functional properties of natural extracellular matrix for tissue regeneration. In order to improve the physico-chemical and biological properties of the nanofibers, graphene oxide is incorporated in the gelatin to form graphene oxide decorated gelatin nanofibers. The current research effort is focussed on the fabrication and evaluation of physico-chemical and biological properties of graphene oxide-gelatin composite nanofibers. The presence of graphene oxide in the nanofibers was established by transmission electron microscopy (TEM). We report the effect of incorporation of graphene oxide on the mechanical, thermal and biological performance of the gelatin nanofibers. The tensile strength of gelatin nanofibers was increased from 8.29+/-0.53MPa to 21+/ 2.03MPa after the incorporation of GO. In order to improve the water resistance of nanofibers, natural based cross-linking agent, namely, dextran aldehyde was employed. The cross-linked composite nanofibers showed further increase in the tensile strength up to 56.4+/-2.03MPa. Graphene oxide incorporated gelatin nanofibers are evaluated for bacterial activity against gram positive (Staphylococcus aureus) and gram negative (Escherichia coli) bacteria and cyto compatibility using mouse fibroblast cells (L-929 cells). The results indicate that the graphene oxide incorporated gelatin nanofibers do not prevent bacterial growth, nevertheless support the L-929 cell adhesion and proliferation. PMID- 27127024 TI - Magnetic silica hybrids modified with guanidine containing co-polymers for drug delivery applications. AB - Guanidine containing co-polymers grafted onto silica nanoparticles to form core shell structure were prepared by sol-gel method in the presence of gamma-Fe2O3 nanoparticles. The morphological features for uncoated and coated silica particles have been characterized with scanning electron microscopy. The results show that the polymer coated silicas exhibit spherical morphology with rough polymeric surface covered by gamma-Fe2O3 nanoparticles. The grafting amount of guanidine containing co-polymers evaluated by thermogravimetric analysis was in the range from 17 to 30%. Then, the drug loading properties and cumulative release of silica hybrids modified with guanidine containing co-polymers were evaluated using molsidomine as a model drug. It was shown that after polymer grafting the loading content of molsidomine could reach up to 3.42+/-0.21 and 2.34+/-0.14mg/g respectively. The maximum drug release of molsidomine is achieved at pH1.6 (approximately 71-75% release at 37 degrees C), whereas at pH7.4 drug release is lower (50.4-59.6% release at 37 degrees C). These results have an important implication that our magneto-controlled silica hybrids modified with guanidine containing co-polymers are promising as drug carriers with controlled behaviour under influence of magnetic field. PMID- 27127025 TI - "Off-the-shelf" microfluidic devices for the production of liposomes for drug delivery. AB - An "off-the-shelf" microfluidic chip approach, utilizing lowcost, commercially available components, for liposome production, is presented. Microfluidic devices with different geometries have been conveniently designed and assembled, allowing the production of narrowly dispersed unilamellar and very reproducible liposomes. The presented results indicate that off-the-shelf microfluidic devices can hold great promises for the efficient preparation of different lipid based colloidal systems for biomedical applications. PMID- 27127026 TI - Modification of the protein corona-nanoparticle complex by physiological factors. AB - Nanoparticle (NP) effects in a biological system are driven through the formation and structure of the protein corona-NP complex, which is dynamic by nature and dependent upon factors from both the local environment and NP physicochemical parameters. To date, considerable data has been gathered regarding the structure and behavior of the protein corona in blood, plasma, and traditional cell culture medium. However, there exists a knowledge gap pertaining to the protein corona in additional biological fluids and following incubation in a dynamic environment. Using 13nm gold NPs (AuNPs), functionalized with either polyethylene glycol or tannic acid, we demonstrated that both particle characteristics and the associated protein corona were altered when exposed to artificial physiological fluids and under dynamic flow. Furthermore, the magnitude of observed behavioral shifts were dependent upon AuNP surface chemistry. Lastly, we revealed that exposure to interstitial fluid produced protein corona modifications, reshaping of the nano-cellular interface, modified AuNP dosimetry, and induction of previously unseen cytotoxicity. This study highlights the need to elucidate both NP and protein corona behavior in biologically representative environments in an effort to increase accurate interpretation of data and transfer of this knowledge to efficacy, behavior, and safety of nano-based applications. PMID- 27127027 TI - Alginate/PEG based microcarriers with cleavable crosslinkage for expansion and non-invasive harvest of human umbilical cord blood mesenchymal stem cells. AB - Porous microcarriers are increasingly used to expand and harvest stem cells. Generally, the cells are harvested via proteolytic enzyme treatment, which always leads to damages to stem cells. To address this disadvantage, a series of alginate/PEG (AL/PEG) semi-interpenetrating network microcarriers are prepared in this study. In this AL/PEG system, the chemically cross-linked alginate networks are formed via the reaction between carboxylic acid group of alginate and di terminated amine groups of cystamine. PEG is introduced to modulate the degradation of microcarriers, which does not participate in this cross-linked reaction, while it interpenetrates in alginate network via physical interactions. In addition, chitosan are coated on the surface of AL/PEG to improve the mechanical strength via the electrostatic interactions. Biocompatible fibronectin are also coated on these microcarriers to modulate the biological behaviors of cells seeded in microcarriers. Results suggest that the size of AL/PEG microcarriers can be modulated via adjusting the contents and molecular weight of PEG. Moreover, the microcarriers are designed to be degraded with cleavage of disulfide crosslinkage. By changing the type and concentration of reductant, the ratio of AL to PEG, and the magnitude of chitosan coating, the degradation ability of AL/PEG microcarriers can be well controlled. In addition, AL/PEG microcarriers can support the attachment and proliferation of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs). More importantly, the expanded hUCB-MSCs can be detached from microcarriers after addition of reductant, which indeed reduce the cell damage caused by proteolytic enzyme treatment. Therefore, it is convinced that AL/PEG based microcarriers will be a promising candidate for large-scale expansion of hUCB-MSCs. PMID- 27127028 TI - Development of sensitive amperometric hydrogen peroxide sensor using a CuNPs/MB/MWCNT-C60-Cs-IL nanocomposite modified glassy carbon electrode. AB - A sensitive hydrogen peroxide (H2O2) sensor was constructed based on copper nanoparticles/methylene blue/multiwall carbon nanotubes-fullerene-chitosan-ionic liquid (CuNPs/MB/MWCNTs-C60-Cs-IL) nanocomposites. The MB/MWCNTs-C60-Cs-IL and CuNPs were modified glassy carbon electrode (GCE) by the physical adsorption and electrodeposition of copper nitrate solution, respectively. The physical morphology and chemical composition of the surface of modified electrode was investigated by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS), respectively. The electrochemical properties of CuNPs/MB/MWCNTs-C60-Cs-IL/GCE were investigated by cyclic voltammetry (CV) and amperometry techniques and the sensor exhibited remarkably strong electrocatalytic activities toward the reduction of hydrogen peroxide. The peak currents possess a linear relationship with the concentration of H2O2 in the range of 0.2MUM to 2.0mM, and the detection limit is 55.0nM (S/N=3). In addition, the modified electrode was used to determine H2O2 concentration in human blood serum sample with satisfactory results. PMID- 27127029 TI - Synthesis and characterization of polycaprolactone urethane hollow fiber membranes as small diameter vascular grafts. AB - The design of bioresorbable synthetic small diameter (<6mm) vascular grafts (SDVGs) capable of sustaining long-term patency and endothelialization is a daunting challenge in vascular tissue engineering. Here, we synthesized a family of biocompatible and biodegradable polycaprolactone (PCL) urethane macromers to fabricate hollow fiber membranes (HFMs) as SDVG candidates, and characterized their mechanical properties, degradability, hemocompatibility, and endothelial development. The HFMs had smooth surfaces and porous internal structures. Their tensile stiffness ranged from 0.09 to 0.11N/mm and their maximum tensile force from 0.86 to 1.03N, with minimum failure strains of approximately 130%. Permeability varied from 1 to 14*10(-6)cm/s, burst pressures from 1158 to 1468mmHg, and compliance from 0.52 to 1.48%/100mmHg. The suture retention forces ranged from 0.55 to 0.81N. HFMs had slow degradation profiles, with 15 to 30% degradation after 8weeks. Human endothelial cells proliferated well on the HFMs, creating stable cell layer coverage. Hemocompatibility studies demonstrated low hemolysis (<2%), platelet activation, and protein adsorption. There were no significant differences in the hemocompatibility of HFMs in the absence and presence of endothelial layers. These encouraging results suggest great promise of our newly developed materials and biodegradable elastomeric HFMs as SDVG candidates. PMID- 27127031 TI - Design and development of anisotropic inorganic/polystyrene nanocomposites by surface modification of zinc oxide nanoparticles. AB - Anisotropic yolk/shell or Janus inorganic/polystyrene nanocomposites were prepared by combining miniemulsion polymerization and sol-gel reaction. The morphologies of the anisotropic composites were found to be greatly influenced by surface modification of zinc oxide (ZnO) nanoparticle seeds. Two different types of the oleic acid modified ZnO nanoparticles (OA-ZnO) were prepared by post treatment of commercial ZnO powder and homemade OA-ZnO nanoparticles. The morphologies and properties of the nanocomposites were investigated by transmission electron microscope (TEM), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), and energy dispersive X-ray spectroscopy (EDX). It was found that both post-treated OA-ZnO and in-situ prepared OA-ZnO nanoparticles resulted in the yolk-shell and Janus structure nanocomposites, but with varied size and morphology. These nanocomposites showed stable and strong fluorescence by introducing quantum dots as the co-seeds. The fluorescent anisotropic nanocomposites were decorated separately with surface carboxyl and hydroxyl groups. These composites with unique anisotropic properties will have high potential in biomedical applications, particularly in bio-detection. PMID- 27127030 TI - PDMS-SiO2-TiO2-CaO hybrid materials - Cytocompatibility and nanoscale surface features. AB - Two PDMS-SiO2-TiO2-CaO porous hybrid materials were prepared using the same base composition, precursors, and solvents, but following two different sol-gel procedures, based on the authors' previous works where for the first time, in this hybrid system, calcium acetate was used as calcium source. The two different procedures resulted in monolithic materials with different structures, microstructures, and surface wettability. Even though both are highly hydrophobic (contact angles of 127.2 degrees and 150.6 degrees ), and present different filling regimes due to different surface topographies, they have demonstrated to be cytocompatible when tested with human osteoblastic cells, against the accepted idea that high-hydrophobic surfaces are not suitable to cell adhesion and proliferation. At the nanoscale, the existence of hydrophilic silica domains containing calcium, where water molecules are physisorbed, is assumed to support this capability, as discussed. PMID- 27127032 TI - Galvanic deposition and characterization of brushite/hydroxyapatite coatings on 316L stainless steel. AB - In this work, brushite and brushite/hydroxyapatite (BS, CaHPO4.H2O; HA, Ca10(PO4)6(OH)2) coatings were deposited on 316L stainless steel (316LSS) from a solution containing Ca(NO3)2.4H2O and NH4H2PO4 by a displacement reaction based on a galvanic contact, where zinc acts as sacrificial anode. Driving force for the cementation reaction arises from the difference in the electrochemical standard potentials of two different metallic materials (316LSS and Zn) immersed in an electrolyte, so forming a galvanic contact leading to the deposition of BS/HA on nobler metal. We found that temperature and deposition time affect coating features (morphology, structure, and composition). Deposits were characterized by means of several techniques. The morphology was investigated by scanning electron microscopy, the elemental composition was obtained by X-ray energy dispersive spectroscopy, whilst the structure was identified by Raman spectroscopy and X-ray diffraction. BS was deposited at all investigated temperatures covering the 316LSS surface. At low and moderate temperature, BS coatings were compact, uniform and with good crystalline degree. On BS layers, HA crystals were obtained at 50 degrees C for all deposition times, while at 25 degrees C, its presence was revealed only after long deposition time. Electrochemical studies show remarkable improvement in corrosion resistance. PMID- 27127033 TI - Functionally graded polymeric materials: A brif review of current fabrication methods and introduction of a novel fabrication method. AB - The present work reviews the current fabrication methods of the functionally graded polymeric material (FGPM) and introduces a novel fabrication method that is versatile in applications as compared to those of existing used methods. For the first time electrophoresis was used to control the distribution of the tetracycline hydrochloride (TC) in a film made of polylactic acid (PLA), aiming to induce antimicrobial effect on the film prepared. The elemental analysis on the film surface showed that by employing electrophoresis force, higher amount of TC was detected near the top surface of the film. Results also showed that the FGPM samples with higher percentage of the TC on the film surface were highly effective to minimize the growth of Escherichia coli. These findings are useful and important to improve dispersion quality of the particles in the composite material and further enhance its antibacterial property. PMID- 27127034 TI - Gentamicin-loaded poly(lactic-co-glycolic acid) microparticles for the prevention of maxillofacial and orthopedic implant infections. AB - Trauma and orthopedic surgery can cause infections as any open surgical procedures. Such complications occur in only1 to 5% of the cases, but the treatment is rather complicated due to bacterial biofilm formation and limited drug access to the site of infection upon systemic administration. An interesting strategy to overcome this type of complications is to prevent bacterial proliferation and biofilm formation via the local and controlled release of antibiotic drugs from the implant itself. Obviously, the incorporation of the drug into the implant should not affect the latter's biological and mechanical properties. In this context, we optimized the preparation process for gentamicin loaded poly(lactic-co-glycolic acid) (PLGA) microparticles, which can be incorporated in the macropores of calcium phosphate-based bone substitutes. Microparticles were prepared using a double emulsion solvent extraction/evaporation technique. The processing parameters were optimized in order to provide an average microparticle size of about 60MUm, allowing for incorporation inside the macropores (100MUm) of the hydroxyapatite scaffold. Gentamicin-loaded PLGA microparticles showed a sustained release for 25-30days and a rapid antibacterial activity due to a burst effect, the extent of which was controlled by the initial loading of the microparticles. SEM pictures revealed a highly porous microparticle structure, which can help to reduce the micro environmental pH drop and autocatalytic effects. The biological evaluation showed the cytocompatibility and non-hemolytic property of the microparticles, and the antibacterial activity against Staphylococcus aureus under the given conditions. PMID- 27127035 TI - Comparative study on in vivo response of porous calcium carbonate composite ceramic and biphasic calcium phosphate ceramic. AB - In a previous study, robust calcium carbonate composite ceramics (CC/PG) were prepared by using phosphate-based glass (PG) as an additive, which showed good cell response. In the present study the in vivo response of porous CC/PG was compared to that of porous biphasic calcium phosphate ceramics (BCP), using a rabbit femoral critical-size grafting model. The materials degradation and bone formation processes were evaluated by general observation, X-ray radiography, micro-computed tomography, and histological examination. The results demonstrated excellent biocompatibility and osteoconductivity, and progressive degradation of CC/PG and BCP. Although the in vitro degradation rate of CC/PG was distinctly faster than that of BCP, at 4week post-implantation, the bone generation and material degradation of CC/PG were less than those of BCP. Nevertheless, at postoperative week 8, the increment of bone formation and material degradation of CC/PG was pronouncedly larger than that of BCP. These results show that CC/PG is a potential resorbable bone graft aside from the traditional synthetic ones. PMID- 27127036 TI - Antitumor drug effect of betulinic acid mediated by polyethylene glycol modified liposomes. AB - Betulinic acid (BA), as a natural pentacyclic lupine-type triterpene, principally derives from bark of white birch, due to its potent pharmacological properties and low side-effect, which has been demonstrated a prominent efficiency on cancer therapy. However, the poor solubility and low bioavailability limit its pharmaceutical effect. Herein, we reported the rapid efficient synthesis of the polyethylene glycol modified (PEGylated) BA liposomes using ethanol injection technique for the first time. In the study, hydrophobic BA was encapsulated in the lipid bilayer of liposomes, meanwhile hydrophilic PEG layer covered the surface of liposomes. The mean diameter of PEGylated BA liposomes was 142nm, which can effectively accumulate in the tumor tissues. In vitro drug release study showed that the PEGylated BA liposomes had a better sustained drug release effect than BA liposomes. The PEGylated BA liposomes also exhibited a better tumor inhibitory effect compared with those of free BA or BA liposomes in vitro and in vivo experiments. Therefore, the PEGylated BA liposomes could serve as a better alternative for the cancer therapy in future. PMID- 27127037 TI - A hydrazone Schiff base single crystal (E)-Methyl N(')-(3,4,5 trimethoxybenzylidene) hydrazine carboxylate: Physicochemical, in vitro investigation of antimicrobial activities and molecular docking with DNA gyrase protein. AB - Hydrazone Schiff bases have been widely explored for their antimicrobial, anticancer, anticonvulsant properties. The aim of the present work is to investigate the spectroscopic, electrochemical, thermal properties, in vitro study of antimicrobial activity and molecular docking studies of the MBHC compound. Slow evaporation solution growth technique was used to grow the single crystal of the MBHC compound. Single crystal X-ray diffraction, FTIR and FT-Raman spectroscopic studies are performed and confirmed the grown MBHC compound. UV-Vis spectroscopy and electrochemical studies deduced the absorption region and HOMO LUMO band gap value of the compound. Resazurin reduction assay method was utilized to perform antibacterial and antifungal studies which resulted in lesser effectiveness of the MBHC compound compared to the erythromycin and fluconazole tablets. Molecular docking of the MBHC compound with the DNA gyrase protein exhibited the good binding affinity with energy of -43.196kcal/mol and docking score of -6.266 and having good interaction with aminoacids - ASP81 and ARG84. PMID- 27127038 TI - Sustained release of aspirin and vitamin C from titanium nanotubes: An experimental and stimulation study. AB - Anodization is a promising method to change the topography and wettability of titanium (Ti) implant. The formed TiO2 nanotubes (TiNTs) arrays could enhance the biological properties of Ti implants. In this study, to investigate the possibility of TiNTs arrays on a Ti implant surface as nano-reservoirs for small molecular drugs when using in orthopedic and dental prosthesis, TiNTs on a Ti implant surface were prepared. Then, aspirin and/or vitamin C were loaded into TiNTs as model drugs. Meanwhile, low molecular weight polylactic acid (PLA, Mw=3000) was synthesized and loaded alternately along with aspirin or vitamin C. The release rates of aspirin and vitamin C with/or without PLA loading were investigated by using a UV-Vis spectrometer. The results showed that when loading without PLA, drugs released quickly with presence of burst release. However, when loading with PLA, the cumulative release duration of aspirin and vitamin C was prolonged to over 240h. Molecular dynamics (MD) simulation and dissipative particle dynamics (DPD) simulation results proved that when loading with PLA, PLA molecules aggregated gradually and formed clusters or micelles in these nanotubes. Meanwhile, drug molecules were captured and distributed inside the PLA matrix, which retarding the release of drugs. Only when PLA micelles degrade gradually in body fluid, drugs could be released slowly from nanotubes. These knowledge laid ground basis for the following biological experiments. PMID- 27127039 TI - Novel meloxicam releasing electrospun polymer/ceramic reinforced biodegradable membranes for periodontal regeneration applications. AB - Periodontal disease is associated with the destruction of periodontal tissues, along with other disorders/problems including inflammation of tissues and severe pain. This paper reports the synthesis of meloxicam (MX) immobilized biodegradable chitosan (CS)/poly(vinyl alcohol) (PVA)/hydroxyapatite (HA) based electrospun (e-spun) fibers and films. Electrospinning was employed to produce drug loaded fibrous mats, whereas films were generated by solvent casting method. In-vitro drug release from materials containing varying concentrations of MX revealed that the scaffolds containing higher amount of drug showed comparatively faster release. During initial first few hours fast release was noted from membranes and films; however after around 5h sustained release was achieved. The hydrogels showed good swelling property, which is highly desired for soft tissue engineered implants. To investigate the biocompatibility of our synthesized materials, VERO cells (epithelial cells) were selected and cell culture results showed that these all materials were non-cytotoxic and also these cells were very well proliferated on these synthesized scaffolds. These properties along with the anti-inflammatory potential of our fabricated materials suggest their effective utilization in periodontital treatments. PMID- 27127040 TI - Development of novel wound care systems based on nanosilver nanohydrogels of polymethacrylic acid with Aloe vera and curcumin. AB - This study is aimed at the development of a composite material for wound dressing containing nanosilver nanohydrogels (nSnH) along with Aloe vera and curcumin that promote antimicrobial nature, wound healing and infection control. Nanosliver nanohydrogels were synthesized by nanoemulsion polymerization of methacrylic acid (MAA) followed by subsequent crosslinking and silver reduction under irradiation. Both the polymerization and irradiation time had significant influence on the nanoparticle shape, size and its formation. Polyvinyl alcohol/polyethylene oxide/carboxymethyl cellulose matrix was used as gel system to blend with nSnH, A. vera, curcumin and coat it on the hydrolysed PET fabric to develop antimicrobial dressings. The cumulative release of silver from the dressing was found to be ~42% of the total loading after 48h. The antimicrobial activity of the dressings was studied against both Staphylococcus aureus and Escherichia coli. In vivo wound healing studies were carried out over a period of 16d on full thickness skin wounds created on Swiss albino mice. Fast healing was observed in Gel/nSnH/Aloe treated wounds with minimum scarring, as compared to other groups. The histological studies showed A. vera based dressings to be the most optimum one. These results suggest that nSnH along with A. vera based dressing material could be promising candidates for wound dressings. PMID- 27127041 TI - Hydrothermal synthesis of highly luminescent blue-emitting ZnSe(S) quantum dots exhibiting low toxicity. AB - Highly luminescent quantum dots (QDs) that emit in the visible spectrum are of interest to a number of imaging technologies, not least that of biological samples. One issue that hinders the application of luminescent markers in biology is the potential toxicity of the fluorophore. Here we show that hydrothermally synthesized ZnSe(S) QDs have low cytotoxicity to both human colorectal carcinoma cells (HCT-116) and human skin fibroblast cells (WS1). The QDs exhibited a high degree of crystallinity, with a strong blue photoluminescence at up to 29% quantum yield relative to 4',6-diamidino-2-phenylindole (DAPI) without post synthetic UV-irradiation. Confocal microscopy images obtained of HCT-116 cells after incubation with the QDs highlighted the stability of the particles in cell media. Cytotoxicity studies showed that both HCT-116 and WS1 cells retain 100% viability after treatment with the QDs at concentrations up to 0.5g/L, which makes them of potential use in biological imaging applications. PMID- 27127042 TI - Mimicked cartilage scaffolds of silk fibroin/hyaluronic acid with stem cells for osteoarthritis surgery: Morphological, mechanical, and physical clues. AB - Osteoarthritis is a critical disease that comes from degeneration of cartilage tissue. In severe cases surgery is generally required. Tissue engineering using scaffolds with stem cell transplantation is an attractive approach and a challenge for orthopedic surgery. For sample preparation, silk fibroin (SF)/hyaluronic acid (HA) scaffolds in different ratios of SF/HA (w/w) (i.e., 100:0, 90:10, 80:20, and 70:30) were formed by freeze-drying. The morphological, mechanical, and physical clues were considered in this research. The morphological structure of the scaffolds was observed by scanning electron microscope. The mechanical and physical properties of the scaffolds were analyzed by compressive and swelling ratio testing, respectively. For the cell experiments, scaffolds were seeded and cultured with human umbilical cord-derived mesenchymal stem cells (HUMSCs). The cultured scaffolds were tested for cell viability, histochemistry, immunohistochemistry, and gene expression. The SF with HA scaffolds showed regular porous structures. Those scaffolds had a soft and elastic characteristic with a high swelling ratio and water uptake. The SF/HA scaffolds showed a spheroid structure of the cells in the porous structure particularly in the SF80 and SF70 scaffolds. Cells could express Col2a, Agg, and Sox9 which are markers for chondrogenesis. It could be deduced that SF/HA scaffolds showed significant clues for suitability in cartilage tissue engineering and in surgery for osteoarthritis. PMID- 27127043 TI - Flower like Bi structures on Pt surface facilitating effective cholesterol biosensing. AB - This work demonstrates effective biosensing of cholesterol with the help of an efficient inorganic H2O2 transducer based on Pt-Bi combined with the organic enzyme platform. It could be shown that the Bi (bismuth) adatoms modified Pt (platinum) surface displays enhanced catalytic oxidation of H2O2 at neutral pH and the catalytic oxidation of H2O2 occurs at a lower potential of 0.25V vs NCE (normal calomel electrode). The sensing platform is highly sensitive and shows linear response towards [H2O2] in the absence of any redox mediator or enzyme. The H2O2 sensing platform, further modified with cholesterol oxidase led to cholesterol biosensing with a sensitivity of 3.41MUAmM(-1)cm(-2). The apparent Michaelis-Menten constant (Km(app)) was calculated to be 0.43mM which indicates high binding affinity with the substrate. The cholesterol biosensor does not suffer from the interferences due to other common electroactive species and is highly stable. PMID- 27127044 TI - Jellyfish collagen and alginate: Combined marine materials for superior chondrogenesis of hMSC. AB - Marine, hybrid constructs of porous scaffolds from fibrillized jellyfish collagen and alginate hydrogel are mimicking both of the main tissue components of cartilage, thus being a promising approach for chondrogenic differentiation of human mesenchymal stem cells (hMSC). Investigating their potential for articular cartilage repair, the present study examined scaffolds being either infiltrated with an alginate-cell-suspension (ACS) or seeded with hMSC and embedded in alginate after cell adhesion (EAS). Hybrid constructs with 2*10(5) and 4.5*10(5)hMSC/scaffold were compared to hMSC encapsulated in pure alginate discs, both chondrogenically stimulated for 21days. Typical round, chondrocyte-like morphology was observed in pure alginate gels and ACS scaffolds, while cells in EAS were elongated and tightly attached to the collagen pores. Col 2 gene expression was comparable in all scaffold types examined. However, the Col 2/Col 1 ratio was higher for pure alginate discs and ACS scaffolds compared to EAS. In contrast, cells in EAS scaffolds displayed higher gene expression of Sox 9, Col 11 and ACAN compared to ACS and pure alginate. Secretion of sulfated glycosaminoglycans (sGAG) was comparable for ACS and EAS scaffolds. In conclusion hybrid constructs of jellyfish collagen and alginate support hMSC chondrogenic differentiation and provide more stable and constructs compared to pure hydrogels. PMID- 27127045 TI - Potential use of SERS-assisted theranostic strategy based on Fe3O4/Au cluster/shell nanocomposites for bio-detection, MRI, and magnetic hyperthermia. AB - A surface-enhanced Raman scattering (SERS)-assisted theranostic strategy was designed based on a synthesized multifunctional Fe3O4/Au cluster/shell nanocomposite. This theranostic strategy was used for free prostate specific antigen (free-PSA) detection, magnetic resonance imaging (MRI), and magnetic hyperthermia. The lowest protein concentration detected was 1ngmL(-1), and the limit of detection (LOD) of the calculated PSA was 0.75ngmL(-1). Then, MRI was carried out to visualize the tumor cell. Lastly, magnetic hyperthermia was employed and revealed a favorable killing effect for the tumor cells. Thus, this SERS-assisted strategy based on a Fe3O4/Au cluster/shell nanocomposite showed great advantages in theranostic treatment. PMID- 27127046 TI - A dual-targeting drug co-delivery system for tumor chemo- and gene combined therapy. AB - Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers, and chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor, without apparent toxicity in normal tissues. Combining DCA and p53 gene could be an effective way to treat tumors. The progress towards broad applications of DCA/p53 combination requires the development of safe and efficient vectors that target to specific cells. In this study, we developed a DSPE-PEG-AA (1,2-distearoryl-sn-glycero-3 phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide) modified reconstituted high-density lipoprotein-based DCA/p53-loaded nanoparticles (DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes), which was fabricated as a drug/gene dual-targeting co-delivery system for potential cancer therapy. Here, DCA-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL and to act as an antitumor drug to inhibit tumor cell growth. The DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge and low cytotoxicity for normal cells in vitro. The results of confocal laser scanning microscopy (CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug delivery and gene transfection in human lung adenocarcinoma cell line A549. And in vivo investigation on nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes possessed specific tumor targeting and strong antitumor activity. The work described here demonstrated that the DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes might offer a promising tool for effective cancer therapy. PMID- 27127047 TI - Study of hMSC proliferation and differentiation on Mg and Mg-Sr containing biphasic beta-tricalcium phosphate and amorphous calcium phosphate ceramics. AB - Biphasic mixtures of either Mg(2+) or combined Mg(2+) and Sr(2+) cation substituted beta-tricalcium phosphate (beta-TCP) and amorphous calcium phosphate (ACP) were prepared using a low temperature chemical phosphatizing and hydrolysis reaction approach. Scaffolds prepared using the cation substituted calcium phosphates were capable of supporting similar levels of human mesenchymal stem cell proliferation in comparison to commercially available beta-TCP. The concentrations of Mg(2+), Sr(2+), and PO4(3-) released from these scaffolds were also within the ranges desired from previous reports to support both hMSC proliferation and osteogenic differentiation. Interestingly, hMSCs cultured directly on scaffolds prepared with only Mg(2+) substituted beta-TCP were capable of supporting statistically significantly increased alkaline phosphatase activity, osteopontin, and osteoprotegerin expression in comparison to all compositions containing both Mg(2+) and Sr(2+), and commercially available beta TCP. hMSCs cultured in the presence of scaffold extracts also exhibited similar trends in the expression of osteogenic markers as was observed during direct culture. Therefore, it was concluded that the enhanced differentiation observed was due to the release of bioactive ions rather than the surface microstructure. The role of these ions on transforming growth factor-beta and bone morphogenic protein signaling was also evaluated using a PCR array. It was concluded that the release of these ions may support enhanced differentiation through SMAD dependent TGF-beta and BMP signaling. PMID- 27127048 TI - Light-activated polymethylmethacrylate nanofibers with antibacterial activity. AB - The creation of an antibacterial material with triggerable properties enables us to avoid the overuse or misuse of antibacterial substances and, thus, prevent the emergence of resistant bacterial strains. As a potential light-activated antibacterial material, polymethylmethacrylate (PMMA) nanofibers doped with silver nanoparticles (AgNPs) and meso-tetraphenylporphyrin (TPP) were prepared by electrospinning. TPP was chosen as an effectively reactive oxygen species (ROS) producer. Antibacterial tests on Staphylococcus epidermidis (S. epidermidis) and Enterococcus faecalis (E. faecalis) showed the excellent light-triggerable antibacterial activity of the doped materials. Upon light irradiation at the wavelength corresponding to the TPP absorption peak (405nm), antibacterial activity dramatically increased, mostly due to the release of AgNPs from the polymer matrix. Furthermore, under prolonged light irradiation, the AgNPs/TPP/PMMA nanofibers, displayed enhanced longevity and photothermal stability. Thus, our results suggest that the proposed material is a promising option for the photodynamic inactivation of bacteria. PMID- 27127049 TI - Construction of a fucoidan/laminin functional multilayer to direction vascular cell fate and promotion hemocompatibility. AB - Surface biofunctional modification of cardiovascular stents is a versatile approach to reduce the adverse effects after implantation. In this work, a novel multifunctional coating was fabricated by coimmobilization of the sulfated polysaccharide of brown algae fucoidan and laminin to biomimic the vascular intimal conditions in order to support rapid endothelialization, prevent restenosis and improve hemocompatibility. The surface properties of the coating such as hydrophilicity, bonding density of biomolecules and stability were evaluated and optimized. According to the biocompatibility tests, the fucoidan/laminin multilayer coated surface displayed less platelet adhesion with favorable anticoagulant property. In addition, the fucoidan/laminin complex showed function to selectively regulate vascular cells growth behavior. The proliferation of endothelial cells (ECs) on the fucoidan/laminin biofunctional coating was significantly promoted. For the smooth muscle cells (SMCs), inhibitory effects on cell adhesion and proliferation were observed. In conclusion, the fucoidan/laminin biofunctional coating was successfully fabricated with desirable anticoagulant and endothelialization properties which show a promising application in the vascular devices such as vascular stents or grafts surface modification. PMID- 27127050 TI - A novel biosensor based on the direct electrochemistry of horseradish peroxidase immobilized in the three-dimensional flower-like Bi2WO6 microspheres. AB - Three-dimensional flower-like Bi2WO6 microspheres (3D-Bi2WO6 MSs) have been synthesized through a simple hydrothermal method. The morphology and structure of 3D-Bi2WO6 MSs were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The 3D-Bi2WO6 MSs subsequently were used to immobilize horseradish peroxidase (HRP) and fabricate a mediator-free biosensor for the detection of H2O2. Spectroscopic and electrochemical results reveal that 3D Bi2WO6 MSs constitute an excellent immobilization matrix with biocompatibility for enzymes. Meanwhile, due to unique morphology of the flower-like microspheres, the direct electron transfer of HRP is facilitated and the prepared biosensors display good performances for the detection of H2O2 with a wide linear range, including two linear sections: 0.5-100MUM (R(2)=0.9983) and 100-250MUM (R(2)=0.9981), as well as an extremely low method detection limit of 0.18MUM. PMID- 27127051 TI - Phyto-mediated nanostructured carriers based on dual vegetable actives involved in the prevention of cellular damage. AB - The growing scientific interest in exploitation of vegetable bioactives has raised a number of questions regarding their imminent presence in pharmaceutical formulations. This study intends to demonstrate that a dual combination between vegetable oil (e.g. thistle oil, safflower oil, sea buckthorn oil) and a carrot extract represents an optimal approach to formulate safe carrier systems that manifest cell regeneration effect and promising antioxidant and anti-inflammatory activity. Inclusion of both natural actives into lipid carriers imparted a strong negative charge on the nanocarrier surface (up to -45mV) and displayed average sizes of 70nm to 140nm. The entrapment efficiency of carrot extract into nanostructured carriers ranged between 78.3 and 88.3%. The in vitro release study has demonstrated that the entrapment of the extract represents a viable way for an equilibrated release of carotenoids. Besides the excellent antioxidant properties (e.g. scavenging up to 98% of the free oxygen radicals), the results of cellular integrity (e.g. cell viability of 133%) recommend these nanocarriers based on dual carrot extract-bioactive oil as a promising trend for the treatment of certain disorders in which oxidative stress plays a prominent role. In addition, the lipid nanocarriers based on safflower oil and sea buckthorn oil demonstrated an anti-inflammatory effect on LPS induced THP-1 macrophages, by inhibiting the secretion of two pro-inflammatory cytokines, IL-6 and TNF-alpha. PMID- 27127052 TI - Effects of surface friction treatment on the in vitro release of constituent metals from the biomedical Co-29Cr-6Mo-0.16N alloy. AB - Due to the ignorance by many researchers on the influence of starting microstructure on the metal release of biomedical materials in human body after implant, in this study, the effect of surface friction treatment on the in vitro release of the constituent elements of the biomedical Co-29Cr-6Mo-0.16N (CCM) alloy is investigated for the first time by immersion test in lactic acid solution combined with electron backscatter diffraction, transmission electron microscope, X-ray diffraction, X-ray photoelectron spectroscopy, and inductively coupled plasma atomic emission spectroscopy (ICP-EOS). The results indicate that friction treatment on the as-annealed CCM alloy sample surface leads to a planar strain-induced martensitic transformation (SIMT) on sample surface; this greatly accelerates the release of all the constituent elements and, in particular, that of Co as indicated by the ICP-EOS analysis. This increase can be ascribed to a localized deformation that occurred over the entire sample surface, with the dislocation density being high within the SIMTed phase and low in the alloy matrix. PMID- 27127053 TI - Cytocompatible cellulose hydrogels containing trace lignin. AB - Sugarcane bagasse was used as a cellulose resource to prepare transparent and flexible cellulose hydrogel films. On the purification process from bagasse to cellulose, the effect of lignin residues in the cellulose was examined for the properties and cytocompatibility of the resultant hydrogel films. The cellulose was dissolved in lithium chloride/N,N-dimethylacetamide solution and converted to hydrogel films by phase inversion. In the purification process, sodium hydroxide (NaOH) treatment time was changed from 1 to 12h. This resulted in cellulose hydrogel films having small amounts of lignin from 1.62 to 0.68%. The remaining lignin greatly affected hydrogel properties. Water content of the hydrogel films was increased from 1153 to 1525% with a decrease of lignin content. Moreover, lower lignin content caused weakening of tensile strength from 0.80 to 0.43N/mm(2) and elongation from 45.2 to 26.5%. Also, similar tendency was observed in viscoelastic behavior of the cellulose hydrogel films. Evidence was shown that the lignin residue was effective for the high strength of the hydrogel films. In addition, scanning probe microscopy in the morphological observation was suggested that the trace lignin in the cellulose hydrogel affected the cellulose fiber aggregation in the hydrogel network. The trace of lignin in the hydrogels also influenced fibroblast cell culture on the hydrogel films. The hydrogel film containing 1.68% lignin showed better fibroblast compatibility as compared to cell culture polystyrene dish used as reference. PMID- 27127054 TI - Strong attachment of circadian pacemaker neurons on modified ultrananocrystalline diamond surfaces. AB - Diamond is a promising material for a number of bio-applications, including the fabrication of platforms for attachment and investigation of neurons and of neuroprostheses, such as retinal implants. In the current work ultrananocrystalline diamond (UNCD) films were deposited by microwave plasma chemical vapor deposition, modified by UV/O3 treatment or NH3 plasma, and comprehensively characterized with respect to their bulk and surface properties, such as crystallinity, topography, composition and chemical bonding nature. The interactions of insect circadian pacemaker neurons with UNCD surfaces with H-, O- and NH2-terminations were investigated with respect to cell density and viability. The fast and strong attachment achieved without application of adhesion proteins allowed for advantageous modification of dispersion protocols for the preparation of primary cell cultures. Centrifugation steps, which are employed for pelletizing dispersed cells to separate them from dispersing enzymes, easily damage neurons. Now centrifugation can be avoided since dispersed neurons quickly and strongly attach to the UNCD surfaces. Enzyme solutions can be easily washed off without losing many of the dispersed cells. No adverse effects on the cell viability and physiological responses were observed as revealed by calcium imaging. Furthermore, the enhanced attachment of the neurons, especially on the modified UNCD surfaces, was especially advantageous for the immunocytochemical procedures with the cell cultures. The cell losses during washing steps were significantly reduced by one order of magnitude in comparison to controls. In addition, the integration of a titanium grid structure under the UNCD films allowed for individual assignment of physiologically characterized neurons to immunocytochemically stained cells. Thus, employing UNCD surfaces free of foreign proteins improves cell culture protocols and immunocytochemistry with cultured cells. The fast and strong attachment of neurons was attributed to a favorable combination of topography, surface chemistry and wettability. PMID- 27127055 TI - Development of silane grafted ZnO core shell nanoparticles loaded diglycidyl epoxy nanocomposites film for antimicrobial applications. AB - In this article a series of epoxy nanocomposites film were developed using amine functionalized (ZnO-APTES) core shell nanoparticles as the dispersed phase and a commercially available epoxy resin as the matrix phase. The functional group of the samples was characterized using FT-IR spectra. The most prominent peaks of epoxy resin were found in bare epoxy and in all the functionalized ZnO dispersed epoxy nanocomposites (ZnO-APTES-DGEBA). The XRD analysis of all the samples exhibits considerable shift in 2theta, intensity and d-spacing values but the best and optimum concentration is found to be 3% ZnO-APTES core shell nanoparticles loaded epoxy nanocomposites supported by FT-IR results. From TGA measurements, 100wt% residue is obtained in bare ZnO nanoparticles whereas in ZnO core shell nanoparticles grafted DGEBA residue percentages are 37, 41, 45, 46 and 52% for 0, 1, 3, 5 and 7% ZnO-APTES-DGEBA respectively, which is confirmed with ICP-OES analysis. From antimicrobial activity test, it was notable that antimicrobial activity of 7% ZnO-APTES core shell nanoparticles loaded epoxy nanocomposite film has best inhibition zone effect against all pathogens under study. PMID- 27127056 TI - Synergistic radical scavenging potency of curcumin-in-beta-cyclodextrin-in nanomagnetoliposomes. AB - Curcumin is a highly potent nutraceutical associated with various health benefits. However, its hydrophobic nature affects its bioavailability and bioactivity, and limits nutraceutical applications. Drug-in-cyclodextrin-in liposome has the ability to mask the hydrophobic nature of drug and achieve better encapsulation. Also, encapsulating iron oxide nanoparticles (IONPs) within liposomes endow additional beneficial functionalities of IONPs. In the present study, curcumin-beta-cyclodextrin inclusion complex (IC) and IONPs were co encapsulated within liposomes (curcumin-in-beta-cyclodextrin-in nanomagnetoliposomes) to achieve the synergistic antioxidant potential of curcumin and IONPs. IC of curcumin-beta-cyclodextrin was prepared by a simple rapid method and successful inclusion was confirmed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). Mean diameter of IONPs was found to be 180nm and X-ray diffraction pattern confirmed the formation of hematite nanoparticles. Band gap energy calculated using absorption spectra was 2.25eV, which falls in close proximity with the theoretically calculated values of hematite. Mean diameter of curcumin-in-beta-cyclodextrin-in nanomagnetoliposomes was 67nm and encapsulation efficiency of curcumin was found to be 71%. Further, the co-encapsulated particles possessed significantly low IC50 value (64.7791MUg/ml, p<0.01) compared to conventional curcumin liposome and IONPs, indicating its synergistically enhanced radical scavenging property. PMID- 27127057 TI - Design, preparation and characterization of cyclic RGDfK peptide modified poly(ethylene glycol)-block-poly(lactic acid) micelle for targeted delivery. AB - Molecular targeted cancer therapy is a promising strategy to overcome the lack of specificity of anticancer drug. While the binding of c(RGDfK) (cyclic Arginine Glycine-Aspartic acid-Phenylalanine-Lysine) to alphavbeta3 over-expressed on tumor cell has been validated, the underlying interaction remains poorly understood. In this work, docking calculation was applied to investigate the interactions between c(RGDfK)/c(RGDfK)-PEG and alphavbeta3. The calculated results indicated that c(RGDfK) interacted with alphavbeta3 mainly by electrostatic interaction, stabilization interaction, and hydrophobic interaction. Conjugation of PEG chain to the c(RGDfK) weakened the binding affinity of c(RGDfK) to alphavbeta3. Accordingly, docetaxel(DTX)-loaded target micelles (c(RGDfK)-PEG-PLA/PEG-PLA/DTX) were designed, characterized and evaluated using HeLa cells. In vitro release studies demonstrated both target and non-target micelles displayed almost the same profiles, which best fit in Ritger Peppas model. Cellular uptake and MTT studies revealed that the target micelles with the presence of c(RGDfK) were more efficiently taken up by HeLa cells and significantly improved the cytotoxicity compared to that of non-target micelles. Cell inhibition rate of target micelles was improved by 20% after 24h. Our findings suggest that target micelles may be a potential anticancer drug delivery system in the treatment of integrin alphavbeta3 over-expressed on tumor cell. PMID- 27127058 TI - Development and pharmacological evaluation of in vitro nanocarriers composed of lamellar silicates containing copaiba oil-resin for treatment of endometriosis. AB - In this work, newly developed nanocomposites based upon lamellar silicates are evaluated to determine their potential in controlling endometriosis. The preparation of the new nanocarriers is detailed, properties characterized and in vitro pharmacological evaluation performed. The nanocomposites in this study were obtained from the reaction of copaiba oil-resin (COPA) with the polymer polyvinylpyrrolidone (PVP K-30). COPA was selected due to its antiinflammatory and anticancer activities along with the organophilic derivatives of sodium montmorillonite, Viscogel B8, S7 and S4. The results indicated that it was feasible to obtain a good yield of a COPA nanocomposite using a simple process. Intercalation was confirmed by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). In vitro release experiments demonstrated that COPA was released from the nanocomposite in a delayed fashion. Whereas, in vitro pharmacological studies showed a reduction in viability and proliferation of endometriotic cell cultures upon COPA nanocomposite treatment, suggesting that the system developed here can be a promising alternative therapy for the oral treatment of endometriosis. PMID- 27127059 TI - Spray-dried Eudragit(r) L100 microparticles containing ferulic acid: Formulation, in vitro cytoprotection and in vivo anti-platelet effect. AB - This paper aimed to obtain new spray-dried microparticles containing ferulic acid (FA) prepared by using a methacrylic polymer (Eudragit(r) L100). Microparticles were intended for oral use in order to provide a controlled release, and improved in vitro and in vivo biological effects. FA-loaded Eudragit(r) L100 microparticles were obtained by spray-drying. Physicochemical properties, in vitro cell-based effects, and in vivo platelet aggregation were investigated. FA loaded Eudragit(r) L100 microparticles were successfully prepared by spray drying. Formulations showed suitable encapsulation efficiency, i.e. close to 100%. Microparticles were of spherical and almost-spherical shape with a smooth surface and a mean diameter between 2 and 3MUm. Fourier-transformed infrared spectra demonstrated no chemical bond between FA and polymer. X-ray diffraction and differential scanning calorimetry analyses indicated that microencapsulation led to drug amorphization. FA-loaded microparticles showed a slower dissolution rate than pure drug. The chosen formulation demonstrated higher in vitro cytoprotection, anti-inflammatory and immunomodulatory potential and also improved in vivo anti-platelet effect. These results support an experimental basis for the use of FA spray-dried microparticles as a feasible oral drug delivery carrier for the controlled release of FA and improved cytoprotective and anti-platelet effects. PMID- 27127060 TI - Nasal inserts containing ondansetron hydrochloride based on Chitosan-gellan gum polyelectrolyte complex: In vitro-in vivo studies. AB - The aim of this study was the production of ondansetron hydrochloride loaded lyophilized insert for nasal delivery. The nasal insert was prepared by the lyophilisation technique using Chitosan-gellan gum polyelectrolyte complex as the polymer matrix. The ondansetron loaded inserts were evaluated with respect to water uptake, bioadhesion, drug release kinetic study, ex vivo permeation study, and in vivo study. Lyophilised nasal inserts were characterized by differential scanning calorimetry, scanning electron microscopy and X-ray diffraction study. Scanning electron microscopy confirmed the porous sponge like structure of inserts whereas release kinetic model revealed that drug release followed non fickian case II diffusion. The nasal delivery showed improved bioavailability as compared to oral delivery. In conclusion, the ondansetron containing nasal inserts based on Chitosan-gellan gum complex with potential muco-adhesive potential is suitable for nasal delivery. PMID- 27127062 TI - Fabrication and biocompatibility of poly(l-lactic acid) and chitosan composite scaffolds with hierarchical microstructures. AB - The scaffold microstructure is crucial to reconstruct tissue normal functions. In this article, poly(l-lactic acid) and chitosan fiber (PLLA/CTSF) composite scaffolds with hierarchical microstructures both in fiber and pore sizes were successfully fabricated by combining thermal induced phase separation and salt leaching techniques. The composite scaffolds consisted of a nanofibrous PLLA matrix with diameter of 50-500nm, and chitosan fibers with diameter of about 20MUm were homogenously distributed in the PLLA matrix as a microsized reinforcer. The composite scaffolds also had high porosity (>94%) and hierarchical pore size, which were consisted of both micropores (50nm-10MUm) and macropores (50-300MUm). By tailoring the microstructure and chemical composition, the mechanical property, pH buffer and protein adsorption capacity of the composite scaffold were improved significantly compared with those of PLLA scaffold. Cell culture results also revealed that the PLLA/CTSF composite scaffolds supported MG-63 osteoblast proliferation and penetration. PMID- 27127061 TI - Effects of silica sol on the microstructure and mechanical properties of CaSiO3 bioceramics. AB - CaSiO3 ceramics were fabricated with silica sol addition by pressureless sintering. The effects of silica sol on phase composition, microstructure and mechanical properties of CaSiO3 ceramics were investigated. The silica sol additive was found to be effective in speeding up pore elimination, improving the grain growth, decreasing the sintering temperature and shortening the sintering time. When the amount of SiO2 was 5wt%, a flexural strength of 186.2MPa was achieved with an open porosity of 3.9%. The main crystal phase was beta-CaSiO3 below sintering temperature of 1150 degrees C. PMID- 27127063 TI - Novel self-assembled pH-responsive biomimetic nanocarriers for drug delivery. AB - Novel pH-responsive biodegradable biomimetic nanocarriers were prepared by the self-assembly of N-acetyl-l-histidine-phosphorylcholine-chitosan conjugate (NAcHis-PCCs), which was synthesized via Atherton-Todd reaction to couple biomembrane-like phosphorylcholine (PC) groups, and N,N'-carbonyldiimidazole (CDI) coupling reaction to link pH-responsive N-acetyl-l-histidine (NAcHis) moieties to chitosan. In vitro biological assay revealed that NAcHis-PCCs nanoparticles had excellent biocompatibility to avoid adverse biological response mainly owing to their biomimetic PC shell, and DLS results confirmed their pH responsive behavior in acidic aqueous solution (pH<=6.0). Quercetin (QUE), an anti-inflammatory, antioxidant and potential anti-tumor hydrophobic drug, was effectively loaded in NAcHis-PCCs nanocarriers and showed a pH-triggered release behavior with the enhanced QUE release at acidic pH5.5 compared to neutral pH7.4. The results indicated that pH-responsive biomimetic NAcHis-PCCs nanocarriers might have great potential for site-specific delivery to pathological acidic microenvironment avoiding unfavorable biological response. PMID- 27127064 TI - Electrochemical sensor for bisphenol A based on ionic liquid functionalized Zn-Al layered double hydroxide modified electrode. AB - The plate-like Zn-Al layered double hydroxide modified with 1-aminopropyl-3 methylimidzaolium tetrafluoroborate (named as ILs-LDH) was synthesized by coprecipitation method. Several techniques confirmed the layered structure of ILs LDH with a disk-like morphology. A novel electrochemical sensor based on ILs-LDH modified glass carbon electrode (GCE) was developed for bisphenol A (BPA) determination. Experimental factors including modified content, pH, scan rate, accumulation time and potential had been carefully optimized. ILs-LDH/GCE performed the excellent electro-oxidation ability toward BPA with the more negative oxidation overpotential and larger peak current than bare GCE or LDH/GCE. Differential pulse voltammetry determination of BPA afforded a wider linear range from 0.02 to 3MUM with the detection limit of 4.6nM (S/N=3). The fabricated sensor demonstrated an acceptable reproducibility, good stability and high sensitivity. The proposed method was successfully used to detect BPA in real water samples with satisfactory recovery ranging from 94.9% to 102.0%. PMID- 27127065 TI - Glass-ceramic coated Mg-Ca alloys for biomedical implant applications. AB - Biodegradable metals and alloys are promising candidates for biomedical bone implant applications. However, due to the high rate of their biodegradation in human body environment, they should be coated with less reactive materials, such, for example, as bioactive glasses or glass-ceramics. Fort this scope, RKKP composition glass-ceramic coatings have been deposited on Mg-Ca(1.4wt%) alloy substrates by Pulsed Laser Deposition method, and their properties have been characterized by a number of techniques. The prepared coatings consist of hydroxyapatite and wollastonite phases, having composition close to that of the bulk target material used for depositions. The 100MUm thick films are characterized by dense, compact and rough morphology. They are composed of a glassy matrix with various size (from micro- to nano-) granular inclusions. The average surface roughness is about 295+/-30nm due to the contribution of micrometric aggregates, while the roughness of the fine-texture particulates is approximately 47+/-4nm. The results of the electrochemical corrosion evaluation tests evidence that the RKKP coating improves the corrosion resistance of the Mg Ca (1.4wt%) alloy in Simulated Body Fluid. PMID- 27127066 TI - Osteogenic activity of cyclodextrin-encapsulated doxycycline in a calcium phosphate PCL and PLGA composite. AB - Composites of biodegradable polymers and calcium phosphate are bioactive and flexible, and have been proposed for use in tissue engineering and bone regeneration. When associated with the broad-spectrum antibiotic doxycycline (DOX), they could favor antimicrobial action and enhance the action of osteogenic composites. Composites of polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), and a bioceramic of biphasic calcium phosphate Osteosynt(r) (BCP) were loaded with DOX encapsulated in beta-cyclodextrin (betaCD) and were evaluated for effects on osteoblastic cell cultures. The DOX/betaCD composite was prepared with a double mixing method. Osteoblast viability was assessed with methyl tetrazolium (MTT) assays after 1day, 7day, and 14days of composite exposure; alkaline phosphatase (AP) activity and collagen production were evaluated after 7days and 14days, and mineral nodule formation after 14days. Composite structures were evaluated by scanning electron microscopy (SEM). Osteoblasts exposed to the composite containing 25MUg/mL DOX/betaCD had increased cell proliferation (p<0.05) compared to control osteoblast cultures at all experimental time points, reaching a maximum in the second week. AP activity and collagen secretion levels were also elevated in osteoblasts exposed to the DOX/betaCD composite (p<0.05 vs. controls) and reached a maximum after 14days. These results were corroborated by Von Kossa test results, which showed strong formation of mineralization nodules during the same time period. SEM of the composite material revealed a surface topography with pore sizes suitable for growing osteoblasts. Together, these results suggest that osteoblasts are viable, proliferative, and osteogenic in the presence of a DOX/betaCD-containing BCP ceramic composite. PMID- 27127067 TI - Formation of different gold nanostructures by silk nanofibrils. AB - Metal nanostructures that have unique size- and shape-dependent electronic, optical and chemical properties gain more and more attention in modern science and technology. In this article, we show the possibility that we are able to obtain different gold nanostructures simply with the help of silk nanofibrils. We demonstrate that only by varying the pH of the reaction solution, we get gold nanoparticles, nano-icosahedrons, nanocubes, and even microplates. Particularly, we develop a practical method for the preparation of gold microplates in acid condition in the presence of silk nanofibrils, which is impossible by using other forms of silk protein. We attribute the role of silk nanofibrils in the formation of gold nanostructure to their reduction ability from several specific amino acid residues, and the suitable structural anisotropic features to sustain the crystal growth after the reduction process. Although the main purpose of this article is to demonstrate that silk nanofibrils are able to mediate the formation of different gold nanostructure, we show the potential applications of these resulting gold nanostructures, such as surface-enhanced Raman scattering (SERS) and photothermal transformation effect, as same as those produced by other methods. In conclusion, we present in this communication a facile and green synthesis route to prepare various gold nanostructures with silk nanofibrils by simply varying pH in the reaction system, which has remarkable advantages in future biomedical applications. PMID- 27127068 TI - Preparation and characterization of naproxen-loaded electrospun thermoplastic polyurethane nanofibers as a drug delivery system. AB - The design and production of drug-loaded nanofiber based materials produced by electrospinning is of interest for use in innovative drug delivery systems. In the present study, ultra-fine fiber mats of thermoplastic polyurethane (TPU) containing naproxen (NAP) were successfully prepared by electrospinning from 8 and 10% (w/w) TPU solutions. The amount of NAP in the solutions was 10 and 20% based on the weight of TPU. The collection period of the drug-loaded electrospun TPU fibers was 5, 10 and 20h, and they were characterized by FTIR, DSC and TGA analysis. The morphology of the NAP-loaded electrospun TPU fiber mats was smooth, and the average diameters of these fibers varied between 523.66 and 723.50nm. The release characteristics of these fiber mats were determined by the total immersion method in the phosphate buffer solution at 37 degrees C. It was observed that the collection period in terms of the mat thickness played a major role in the release rate of NAP from the electrospun TPU mats. PMID- 27127069 TI - Ultra-sensitive determination of epinephrine based on TiO2-Au nanoclusters supported on reduced graphene oxide and carbon nanotube hybrid nanocomposites. AB - A highly efficient and sensitive electrochemical sensor for EP based on reduced graphene and multi-walled carbon nanotube hybrid nanocomposites loaded TiO2-Au nano-clusters modified glassy carbon electrode was developed. The surface nature and morphology of the nanocomposite film and the electrochemical properties of the sensor were characterized by Raman spectra, X-ray powder diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectra (EDX), Fourier transform infrared spectroscopy (FT-IR), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV), respectively. Carbon nanomaterials were widely used in sensing due to its large electroactive surface area, fast electron transport and strong adsorption capacity. Meanwhile, TiO2-Au nano-clusters could accelerate the electron transfer, increase reactive site and extend electrochemical response window. The nanocomposite film could greatly enhance the response sensitivity and decrease the overpotential. The resulting sensor showed an excellent electrocatalytic activity toward EP. Under the optimum conditions (i.e. pH6.0, 0.1M PBS, preconcentration for 110s), Differential pulse voltammetry was employed to detect ultra-trace amounts of EP. The result of a wide linear range of 1.0-300nM and limited of detection 0.34nM (S/N=3) were obtained. The constructed sensor exhibited excellent accuracy and precision, the relative standard deviation (RSD) was less than 5%. The nanocomposite film sensor was successfully used to accurately detect the content of EP in practical samples, and the recoveries for the standards added are 97%-105%. PMID- 27127070 TI - A solvent induced crystallisation method to imbue bioactive ingredients of neem oil into the compact structure of poly (ethylene terephthalate) polyester. AB - Neem oil, a natural antibacterial agent from neem tree (Azadarichtaindica) has been used to impart antibacterial activity to polyester fabrics. Solvent induced polymer modification method was used and that facilitated the easy entry of neem molecules into the compact structure of polyethylene terephthalate (PET) polyester. The polyester fabric was treated with trichloroacetic acid-methylene chloride (TCAMC) solvent system at room temperature prior to treatment with neem oil. The concentration of TCAMC and the treatment time were optimised. XRD and SEM results showed that the TCAMC treatment causes polymer modification and morphological changes in the PET polyester. Antibacterial activity of TCAMC pre treated and neem-oil-treated polyester fabric was tested using AATCC qualitative and quantitative methods. Both Gram-positive and Gram-negative organisms were used to determine the antimicrobial activity. It was observed that the treated fabric registers substantial antimicrobial activity against both the Staphylococcus aureus (Gram-positive) and the Escherichia coli (Gram-negative) and the effect increases with the increase in concentration of TCAMC treatment. The antibacterial effect remains substantial even after 25 launderings. A kinetic growth study involving the effect of antibacterial activity at various incubation times was carried out. PMID- 27127071 TI - Adding functionality with additive manufacturing: Fabrication of titanium-based antibiotic eluting implants. AB - Additive manufacturing technologies have been utilised in healthcare to create patient-specific implants. This study demonstrates the potential to add new implant functionality by further exploiting the design flexibility of these technologies. Selective laser melting was used to manufacture titanium-based (Ti 6Al-4V) implants containing a reservoir. Pore channels, connecting the implant surface to the reservoir, were incorporated to facilitate antibiotic delivery. An injectable brushite, calcium phosphate cement, was formulated as a carrier vehicle for gentamicin. Incorporation of the antibiotic significantly (p=0.01) improved the compressive strength (5.8+/-0.7MPa) of the cement compared to non antibiotic samples. The controlled release of gentamicin sulphate from the calcium phosphate cement injected into the implant reservoir was demonstrated in short term elution studies using ultraviolet-visible spectroscopy. Orientation of the implant pore channels were shown, using micro-computed tomography, to impact design reproducibility and the back-pressure generated during cement injection which ultimately altered porosity. The amount of antibiotic released from all implant designs over a 6hour period (<28% of the total amount) were found to exceed the minimum inhibitory concentrations of Staphylococcus aureus (16MUg/mL) and Staphylococcus epidermidis (1MUg/mL); two bacterial species commonly associated with periprosthetic infections. Antibacterial efficacy was confirmed against both bacterial cultures using an agar diffusion assay. Interestingly, pore channel orientation was shown to influence the directionality of inhibition zones. Promisingly, this work demonstrates the potential to additively manufacture a titanium-based antibiotic eluting implant, which is an attractive alternative to current treatment strategies of periprosthetic infections. PMID- 27127072 TI - Fabrication and characterization of novel nano-biocomposite scaffold of chitosan gelatin-alginate-hydroxyapatite for bone tissue engineering. AB - A novel nano-biocomposite scaffold was fabricated in bead form by applying simple foaming method, using a combination of natural polymers-chitosan, gelatin, alginate and a bioceramic-nano-hydroxyapatite (nHAp). This approach of combining nHAp with natural polymers to fabricate the composite scaffold, can provide good mechanical strength and biological property mimicking natural bone. Environmental scanning electron microscopy (ESEM) images of the nano-biocomposite scaffold revealed the presence of interconnected pores, mostly spread over the whole surface of the scaffold. The nHAp particulates have covered the surface of the composite matrix and made the surface of the scaffold rougher. The scaffold has a porosity of 82% with a mean pore size of 112+/-19.0MUm. Swelling and degradation studies of the scaffold showed that the scaffold possesses excellent properties of hydrophilicity and biodegradability. Short term mechanical testing of the scaffold does not reveal any rupturing after agitation under physiological conditions, which is an indicative of good mechanical stability of the scaffold. In vitro cell culture studies by seeding osteoblast cells over the composite scaffold showed good cell viability, proliferation rate, adhesion and maintenance of osteoblastic phenotype as indicated by MTT assay, ESEM of cell-scaffold construct, histological staining and gene expression studies, respectively. Thus, it could be stated that the nano-biocomposite scaffold of chitosan-gelatin alginate-nHAp has the paramount importance for applications in bone tissue engineering in future regenerative therapies. PMID- 27127073 TI - Fabrication of chitosan-g-poly(acrylamide)/CuS nanocomposite for controlled drug delivery and antibacterial activity. AB - In present study, we reported the synthesis of chitosan-g-poly(acrylamide)/CuS (CPA/CS) nanocomposite for controlled delivery of ofloxacin. The CPA/CS nanocomposites were characterized by Fourier transmission infrared spectroscopy (FTIR), UV-visible spectroscopy (UV), scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis. From the FTIR spectra, the various groups present in CPA/CS nanocomposite were monitored. The homogeneity, morphology and crystallinity of the CPA/CS nanocomposite were ascertained from SEM/EDX and XRD data, respectively. The kinetics of ofloxacin drug delivery was investigated at different pH. The drug released studies were investigated at different pH (2.2, 7.4 and 9.4) and time intervals (2, 4, 6, 8, 10, 12, 14, 16h). The drug release behavior depends upon the pH of medium and the nature of matrix. The maximum drug loading efficiency of 85% was recorded for CPA/CS. The maximum drug release of 76% was observed at 2.2. pH after 18h onto CPA/CS. Nanocomposites were also tested for antibacterial activity against Escherichia coli bacteria. About 97% killing of E. coli was observed after 24h. PMID- 27127074 TI - Understanding compressive deformation behavior of porous Ti using finite element analysis. AB - In the present study, porous commercially pure (CP) Ti samples with different volume fraction of porosities were fabricated using a commercial additive manufacturing technique namely laser engineered net shaping (LENSTM). Mechanical behavior of solid and porous samples was evaluated at room temperature under quasi-static compressive loading. Fracture surfaces of the failed samples were analyzed to determine the failure modes. Finite Element (FE) analysis using representative volume element (RVE) model and micro-computed tomography (CT) based model have been performed to understand the deformation behavior of laser deposited solid and porous CP-Ti samples. In vitro cell culture on laser processed porous CP-Ti surfaces showed normal cell proliferation with time, and confirmed non-toxic nature of these samples. PMID- 27127075 TI - Functional assessment of the ex vivo vocal folds through biomechanical testing: A review. AB - The human vocal folds are complex structures made up of distinct layers that vary in cellular and extracellular composition. The mechanical properties of vocal fold tissue are fundamental to the study of both the acoustics and biomechanics of voice production. To date, quantitative methods have been applied to characterize the vocal fold tissue in both normal and pathologic conditions. This review describes, summarizes, and discusses the most commonly employed methods for vocal fold biomechanical testing. Force-elongation, torsional parallel plate rheometry, simple-shear parallel plate rheometry, linear skin rheometry, and indentation are the most frequently employed biomechanical tests for vocal fold tissues and each provide material properties data that can be used to compare native tissue to diseased or treated tissue. Force-elongation testing is clinically useful, as it allows for functional unit testing, while rheometry provides physiologically relevant shear data, and nanoindentation permits micrometer scale testing across different areas of the vocal fold as well as whole organ testing. Thoughtful selection of the testing technique during experimental design to evaluate a hypothesis is critical to optimize biomechanical testing of vocal fold tissues. PMID- 27127076 TI - Corrigendum to "Surface modification of Ni-Ti alloys for stent application after magnetoelectropolishing" [Mater. Sci. Eng. C 50 (2015) 37-44]. PMID- 27127077 TI - Lymphoid hyperplasia of the orbit and ocular adnexa: A clinical pathologic review. AB - Lymphoid hyperplasia (LH) is a benign lymphoproliferative disorder that, in a minority of cases, may be associated with concurrent or metachronous non-Hodgkin lymphoma. LH cases are further subdivided into "reactive" and "atypical" categories based on the presence or absence of unequivocal malignant features. With improving molecular diagnostic technologies, "reactive" LH is by far the most common category of LH, with atypical LH accounting for only a small minority of specimens. Similarly, lesions previously diagnosed as LH are now being revised as low-grade B-cell non-Hodgkin lymphoma or diagnosed as newly described benign conditions such as IgG4-related disease. Additional differential diagnoses include specific and nonspecific orbital inflammations, infiltrative processes, and depositions. Hence, there are emerging changes in the patterns and proportions of entities that fall within the spectrum of lymphoproliferative disorders of the orbit and ocular adnexa. Reactive LH and low-grade malignant lymphoproliferative disorders in the orbit and ocular adnexa are clinically and radiologically indistinguishable from each other, requiring tissue biopsy in all cases. The prognosis of ocular adnexal LH is generally favorable, but the small risk of non-Hodgkin lymphoma mandates follow-up for at least 5 years. We summarize the current state of knowledge on LH occurring in the orbit and ocular adnexa. PMID- 27127079 TI - FSA rethinks Campylobacter in chickens survey. PMID- 27127080 TI - New strategy to raise welfare standards in rescue and rehoming shelters. PMID- 27127078 TI - Use of lipidomics to investigate sebum dysfunction in juvenile acne. AB - Acne is a multifactorial skin disorder frequently observed during adolescence with different grades of severity. Multiple factors centering on sebum secretion are implicated in acne pathogenesis. Despite the recognized role of sebum, its compositional complexity and limited analytical approaches have hampered investigation of alterations specifically associated with acne. To examine the profiles of lipid distribution in acne sebum, 61 adolescents (29 males and 32 females) were enrolled in this study. Seventeen subjects presented no apparent clinical signs of acne. The 44 affected individuals were clinically classified as mild (13 individuals), moderate (19 individuals), and severe (12 individuals) acne. Sebum was sampled from the forehead with Sebutape(TM) adhesive patches. Profiles of neutral lipids were acquired with rapid-resolution reversed phase/HPLC-TOF/MS in positive ion mode. Univariate and multivariate statistical analyses led to the identification of lipid species with significantly different levels between healthy and acne sebum. The majority of differentiating lipid species were diacylglycerols (DGs), followed by fatty acyls, sterols, and prenols. Overall, the data indicated an association between the clinical grading of acne and sebaceous lipid fingerprints and highlighted DGs as more abundant in sebum from adolescents affected with acne. PMID- 27127081 TI - Website to help pig producers record data on antibiotic use. PMID- 27127082 TI - Grants awarded to support small animal research in Africa. PMID- 27127083 TI - Peer calls for continued funding for equine research and education. PMID- 27127084 TI - Volunteer vets complete 100th charitable equine castration. PMID- 27127085 TI - A voice for vets on World Veterinary Day. PMID- 27127086 TI - EU membership - benefits for animal health and welfare. AB - Elizabeth Truss, Secretary of State for Environment, Food and Rural Affairs, explains why she believes being a member of the European Union benefits animal health and welfare, agriculture and the veterinary profession. PMID- 27127087 TI - Who is responsible for developing experienced vets? AB - Reports from practice suggest an apparent shortage of experienced vets. A debate at this year's BSAVA congress explored what was meant by 'experienced vet' and who should be responsible for helping new graduates gain the necessary experience. Kathryn Clark reports. PMID- 27127088 TI - Career pathways for new graduates: exploring the options. AB - Most veterinary professionals will work in primary care practice at some point in their career, but what other options are available? Laura Honey reports on a series of sessions in the student stream at this year's BSAVA congress, which examined some of the other career paths a vet might take. PMID- 27127089 TI - Industry as a career option. PMID- 27127090 TI - Awards recognise dedication to animal welfare. PMID- 27127091 TI - Interventions in wild animal health. AB - Alexandra Thomas of the Institute of Zoology at the Zoological Society of London reports on the first field course to be held as part of an online masters degree in conservation medicine awarded by the University of Edinburgh. PMID- 27127092 TI - Disease surveillance in England and Wales, April 2016. AB - Current and emerging issuesHighlights from the scanning surveillance networkUpdate on international disease threatsHighlights from the Veterinary Risk GroupDisease risks at turnout in cattle These are among matters discussed in the Animal and Plant Health Agency's (APHA's) April disease surveillance report. PMID- 27127093 TI - Cattle: disease risks at turnout. AB - This article is prepared by the Cattle Expert Group and is intended to highlight seasonal issues related to turnout. The Cattle Expert Group is a virtual network of veterinary surveillance expertise in Great Britain, led by APHA. It is one of six Species Expert Groups that form part of the APHA Surveillance Intelligence Unit, which identifies and characterises potential New and Re-emerging Threats (NRTs) and other risks to livestock and wildlife in Great Britain. These are then considered by the Veterinary Risk Group for appropriate mitigation. PMID- 27127094 TI - Mastitis management: increasing the uptake of veterinary advice. PMID- 27127095 TI - Risk to animals from oak processionary moth caterpillars. PMID- 27127096 TI - Feminisation: thinking beyond gender stereotypes. PMID- 27127098 TI - Early detection of pain in cats. PMID- 27127097 TI - Addressing vectorborne diseases. PMID- 27127099 TI - Driven by a passion for people and their pets (and dancing). AB - Paula Bailey thought she might enter academia after gaining clinical experience. However, a period of travelling and locum work confirmed her enjoyment of practice life. PMID- 27127100 TI - In beta-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects. AB - Actin and nuclear myosin 1 (NM1) are regulators of transcription and chromatin organization. Using a genome-wide approach, we report here that beta-actin binds intergenic and genic regions across the mammalian genome, associated with both protein-coding and rRNA genes. Within the rDNA, the distribution of beta-actin correlated with NM1 and the other subunits of the B-WICH complex, WSTF and SNF2h. In beta-actin(-/-) mouse embryonic fibroblasts (MEFs), we found that rRNA synthesis levels decreased concomitantly with drops in RNA polymerase I (Pol I) and NM1 occupancies across the rRNA gene. Reintroduction of wild-type beta-actin, in contrast to mutated forms with polymerization defects, efficiently rescued rRNA synthesis underscoring the direct role for a polymerization-competent form of beta-actin in Pol I transcription. The rRNA synthesis defects in the beta actin(-/-) MEFs are a consequence of epigenetic reprogramming with up-regulation of the repressive mark H3K4me1 (monomethylation of lys4 on histone H3) and enhanced chromatin compaction at promoter-proximal enhancer (T0 sequence), which disturb binding of the transcription factor TTF1. We propose a novel genome-wide mechanism where the polymerase-associated beta-actin synergizes with NM1 to coordinate permissive chromatin with Pol I transcription, cell growth, and proliferation.-Almuzzaini, B., Sarshad, A. A. , Rahmanto, A. S., Hansson, M. L., Von Euler, A., Sangfelt, O., Visa, N., Farrants, A.-K. O., Percipalle, P. In beta actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects. PMID- 27127101 TI - Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade. AB - Null mutations in for pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, are the cause of osteogenesis imperfecta (OI) type VI. The PEDF-knockout (KO) mouse captures crucial elements of the human disease, including diminished bone mineralization and propensity to fracture. Our group and others have demonstrated that PEDF directs human mesenchymal stem cell (hMSC) commitment to the osteoblast lineage and modulates Wnt/beta-catenin signaling, a major regulator of bone development; however, the ability of PEDF to restore bone mass in a mouse model of OI type VI has not been determined. In this study, PEDF delivery increased trabecular bone volume/total volume by 52% in 6-mo-old PEDF-KO mice but not in wild-type mice. In young (19-d-old) PEDF-KO mice, PEDF restoration increased bone volume fraction by 35% and enhanced biomechanical parameters of bone plasticity. A Wnt-green fluorescent protein reporter demonstrated dynamic changes in Wnt/beta-catenin signaling characterized by early activation and marked suppression during terminal differentiation of hMSCs. Continuous Wnt3a exposure impeded mineralization of hMSCs, whereas the combination of Wnt3a and PEDF potentiated mineralization. Interrogation of the PEDF sequence identified a conserved motif found in other Wnt modulators, such as the dickkopf proteins. Mutation of a single amino acid on a 34-mer PEDF peptide increased mineralization of hMSC cultures compared with the native peptide sequence. These results indicate that PEDF counters Wnt signaling to allow for osteoblast differentiation and provides a mechanistic insight into how the PEDF null state results in OI type VI.-Belinsky, G. S., Sreekumar, B., Andrejecsk, J. W., Saltzman, W. M., Gong, J., Herzog, R. I., Lin, S., Horsley, V., Carpenter, T. O., Chung, C. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade. PMID- 27127103 TI - Single-port video-assisted thoracoscopic wedge resection: novel approaches in different genders. AB - OBJECTIVES: To discuss the feasibility, safety and superiority of novel approaches in single-port video-assisted thoracoscopic wedge resection in different genders. METHODS: The clinical data of patients who underwent thoracoscopic pulmonary wedge resection were analysed. A total of 197 consecutive male patients from January 2012 to December 2014, and 72 female patients from June 2013 to December 2014 were included retrospectively. Of the males, 65 received a transareolar single-port procedure (TASP Group) and 132 received a standard two-port procedure (Standard Group A). Among the females, 18 were treated with a subxiphoid single-port procedure (SXSP Group), and 54 were treated with the standard procedure (Standard Group B). The general clinical materials and surgical outcomes were evaluated. RESULTS: All patients underwent total thoracoscopic wedge resection successfully, and no severe complications were observed. In men, there were no significant differences in operation time, blood loss, postoperative drainage amount, chest drainage duration, postoperative hospital stay or pain score on the first postoperative day (P = 0.827; 0.423; 0.174; 0.440; 0.115; 0.159, respectively). The pain scores of the TASP Group on the day before and after removal of the chest tube were lower (P = 0.006; 0.023, respectively) than those of Standard Group A, and the incision-associated paraesthesia in the third and sixth month after operation was reduced (P = 0.041; 0.026, respectively). The incision satisfaction degree was significantly improved in the TASP Group (P = 0.001). In women, there were no significant differences in blood loss, drainage amount, chest drainage duration or postoperative hospital stay (P = 0.680; 0.757; 0.651; 0.608, respectively). The operation time of the SXSP Group was longer (P = 0.000), and the pain scores on the first postoperative day and the days before and after removal were all significantly lower (P = 0.000; 0.000; 0.000, respectively) than those of the Standard Group B. Furthermore, the incision paraesthesia 3 and 6 months after surgery was greatly reduced (P = 0.001; 0.001, respectively), although the patients were not very satisfied with the cosmetic results (P = 0.577). CONCLUSIONS: In single-port thoracoscopic pulmonary wedge resection, we performed 'individualized' procedures based on gender, namely, the transareolar approach in males and the subxiphoid approach in females. These procedures were considered feasible and safe, and showed superiority in reducing postoperative pain. However, the cosmetic results of the subxiphoid approach require further improvement. PMID- 27127102 TI - Gender difference in the response to valsartan/amlodipine single-pill combination in essential hypertension (China Status II): An observational study. AB - BACKGROUND: The China STATUS II is a prospective, multicentre, open-label, post marketing, observational study including Chinese adults (aged ? 18 years) with essential hypertension who were prescribed once-daily valsartan/amlodipine (Val/Aml 80/5 mg) single-pill combination. In order to examine gender differences in treatment response to Val/Aml, we further analysed data from the China STATUS II study. METHODS: A total of 11,312 patients (6456 (57%) men and 4856 (43%) women) received the Val/Aml treatment for 8 weeks. After the treatment, we compared the proportion of patients not achieving the target systolic blood pressure (SBP: < 140 mm Hg) or diastolic blood pressure (DBP: < 90 mm Hg) in different age groups (by Fisher exact probability test) and estimated the changes in blood pressure (BP) according to age and gender, using a mixed model. RESULTS: At enrolment, mean SBP was higher in the female versus the male patients (160.0 +/- 12.71 versus 159.3 +/- 12.31 mm Hg; p = 0.003), whereas the mean DBP was higher in the male versus the female patients (96.4 +/- 10.65 versus 94.5 +/- 10.72 mm Hg; p < 0.001). The overall proportion of women not achieving the target BP was less than that of men (57.41% versus 59.59%; p < 0.05) at 4 weeks and (22.22% versus 23.78%; p < 0.05) at 8 weeks after the Val/Aml treatment. Among both men and women, the proportion of patients not achieving the target SBP increased with age; however, the proportion not achieving the target DBP decreased with age. The mixed-model analysis showed that the changes in SBP were closely related to gender, indicating that the SBP-lowering effect after Val/Aml treatment might be better in women. In addition, the changes in DBP were closely related to age. CONCLUSIONS: Gender might be a factor for consideration in the decision-making process of individualised antihypertensive therapy, in the future. PMID- 27127104 TI - Putative role of 5-HT2B receptors in migraine pathophysiology. AB - Objective In this review we attempt to characterize the acute and chronic role of 5-HT2B receptors with regard to meningeal nociception in animal experiments and clinical data targeting migraine therapy. Background Migraine is a common disabling neurovascular primary headache disease, the pathomechanism of which is still unclear. Serotonin (5-HT) and its receptors might play an important role in some aspects of migraine pathogenesis. The ability of the unselective 5-HT2B receptor agonist m-chlorophenylpiperazine to induce migraine attacks in migraine sufferers, the high affinity of prophylactic antimigraine drugs to this receptor and its expression in migraine-relevant structures like the dura mater argue for a role of 5-HT2B receptors in the pathogenesis of migraine attacks. Methods For this review, the relevant databases such as PubMed, MEDLINE(r), Cochrane Library and EMBASE, respectively, were searched to December 2015 using the keywords "migraine, 5-HT2, trigeminal, neurogenic inflammation, nitric oxide, nitroxyl, vasodilatation, plasma protein extravasation" and combinations thereof. Conclusion Our literature review suggests an important role of 5-HT2B receptor activation in meningeal nociception and the generation of migraine pain. PMID- 27127105 TI - PARP Inhibitors in Epithelial Ovarian Cancer: State of Art and Perspectives of Clinical Research. AB - Homologous recombination (HR) and base excision repair (BER) are two of the major DNA-repair pathways. The proteins encoded by breast-related cancer antigen (BRCA) and poly(adenosine diphosphate-ribose) polymerases (PARP) are involved in HR and BER, respectively. Tumors with HR deficiency, including those in BRCA mutation carriers, are sensitive to BER blockade via PARP inhibitors. These represent novel therapeutic tools for HR-deficient ovarian cancer, able to improve progression-free survival of women with recurrent, platinum-sensitive disease in response to recent platinum-based chemotherapy. More research is needed to assesses whether inhibitors of PARP have any role as maintenance treatment after first-line chemotherapy and as palliative treatment of platinum-resistant disease. Germline BRCA testing should be offered to all patients with ovarian cancer, regardless of age and family history. HR deficiency has been observed not only in germline BRCA mutation carriers, but also in patients with somatic mutations or epigenetic silencing of BRCA, and with loss of function of other genes. Half of all high-grade ovarian carcinomas are HR-deficient, and additional biological and clinical investigations are strongly warranted to identify patients with this subset of tumors. PMID- 27127106 TI - Methods to Increase Future Liver Remnant Volume in Patients with Primarily Unresectable Colorectal Liver Metastases: Current State and Future Perspectives. AB - Radical liver resection of colorectal liver metastases (CLMs) is the only potentially curative treatment. But primary resectability of CLMs ranges from 15% to 20%. Insufficient future liver remnant volume (FLRV) is the main cause of primary unresectability of CLMs. Currently, there are several methods that can optimize FLRV and permit radical resection of CLMs. The basic methods include two stage liver resection, portal vein embolization (PVE) and portal vein ligation. These methods have very low morbidity and mortality rate. Their disadvantage is the relatively long interval for increase of FLRV, with danger of tumour growth, and also the significant number of patients in whom optimal FLRV increase does not occur. For this reason, two other methods were developed - associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) and PVE with application of hematopoietic stem cells (HSCs). The advantage of ALPPS is the very rapid increase of FLRV, but the method is burdened by higher morbidity and mortality. PVE with HSC application is not associated with complications, it has a faster increase of FLRV compared to PVE and two-staged liver resection, but the role of autologous HSCs in carcinogenesis is not yet clear. All the methods offer secondary resectability for patients with primarily inoperable CLMs, with long term survival comparable to primary CLM resections. The optimal choice of specific method must be made on a strictly individual basis for the given patient, and depends on the decision of the multidisciplinary team. PMID- 27127107 TI - The NFkappaB Signaling Pathway in Papillomavirus-induced Lesions: Friend or Foe? AB - Papillomaviruses induce a range of benign and malignant lesions in their hosts, including cervical cancer, that is associated with high-risk human papillomavirus (HPV) types. The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFkappaB) plays a pivotal role in HPV-infected cells, and its expression and activity are modulated by several viral oncoproteins. NFkappaB modulation seems to first facilitate viral persistence and immune evasion, and later to drive tumour progression, but the many conflicting results and the complexity of its signaling networks require great prudence while interpreting the role of NFkappaB in papillomaviral lesions. Accordingly, the pharmacological targeting of the NFkappaB pathway in HPV-induced lesions is a complex and currently unmet challenge. This review deals with recent findings concerning NFkappaB activation in HPV-infected cells, its role in viral persistence, cell transformation and tumour progression, and with current efforts to target this pathway for cancer prevention and therapy. PMID- 27127108 TI - Sphingosine Kinase Inhibitors as Maintenance Therapy of Glioblastoma After Ceramide-Induced Response. AB - Ceramide and sphingosine 1-phosphate (S1P) are sphingolipid metabolites with important signaling functions. Ceramides promote apoptosis, whereas S1P favors proliferation, angiogenesis and cell survival. The balance between these opposing signaling functions is referred to as the sphingolipid rheostat. A shift in this balance toward S1P is seen in glioblastoma (GBM) and other cancers, and results in tumor cell survival and resistance to chemotherapy. Sphingosine kinase (SK), the enzyme responsible for transforming sphingosine into S1P, plays the critical role in modulating the balance between S1P and ceramides. Chemotherapeutic agents or radiation therapy may induce short-term responses in GBM patients by increasing ceramide levels. However, we believe that the enzyme SK may cause the increased ceramide to be metabolized to S1P, restoring the abnormally high S1P to ceramide balance, and that this may be part of the reason for the near-100% recurrence rate of GBM. The use of maintenance therapy with an SK inhibitor, in patients with GBM who have tumor reduction or stable disease after therapy, should be investigated. PMID- 27127109 TI - Unique Boron Carbide Nanoparticle Nanobio Interface: Effects on Protein-RNA Interactions and 3-D Spheroid Metastatic Phenotype. AB - AIM: The effect of boron carbide (B4C) nanoparticles (NP) on protein-RNA complexes and metastatic phenotype of 3-D tumor spheroids was investigated. MATERIALS AND METHODS: Characterization was performed by transmission electron microscopy (TEM), zeta potential (ZP), 2-dimensional fluorescence difference spectroscopy (2-D FDS), gel electrophoresis, MTT, haemolysis and 3-D tumor spheroid assays. RESULTS: TEM showed NP were homogenous (<=50 nm) and spherical in shape. Zeta potential (zeta) of NP (-43.3) shifted upon protein:RNA interaction (+26.9). Protein:RNA complex interaction with NP was confirmed by 2-D FDS, demonstrating excitation/emission blue shift and lowered fluorescence intensity, and electrophoretic mobility shift assay (EMSA), where presence of B4C ablated visualization of the complex. B4C NP cytotoxicity was less than zinc oxide by MTT assay, protected haemolysis and effected 3-D tumor spheroid metastatic phenotype. CONCLUSION: Nanobio interface of B4C nanoparticles is unique and its anticancer potential may be mediated by altering protein and RNA interactions. PMID- 27127110 TI - A Novel 1,2-Dihydroquinoline Anticancer Agent and Its Delivery to Tumor Cells Using Cationic Liposomes. AB - AIM: We screened nine 1,2-dihydro-quinolines using the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay in HepG2 and SMMC cells and identified ethyl-2-cyano-2-(2- (methoxycarbonyl)allyl)quinoline-1(2H) carboxylate (compound 5) as a potential anticancer agent. In order to further develop its anticancer therapeutic potential, we incorporated this agent into cationic liposomes for delivery to tumor cells. The characteristics of liposomes, their cytotoxicity and cellular uptake by tumor cells were investigated. We demonstrated that cationic 1,2-dioleoyl-3- trimethyl-ammonium-propane containing liposomes (cLips) loaded with compound 5 has superior antitumor activity compared to neutral liposomes. These data suggest cLip-compound 5 to be a promising agent that warrants further evaluation. PMID- 27127111 TI - Imaging Nuclear-Cytoplasmic Dynamics in Primary and Metastatic Colon Cancer in Nude Mice. AB - BACKGROUND: Colon cancer frequently results in metastasis to the liver, where it becomes the main cause of death. However, the cell cycle in primary tumors and metastases is poorly understood. MATERIALS AND METHODS: We developed a mouse model of liver metastasis using the human colon cancer cell line HCT-116, which expresses green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm (HCT-116-GFP-RFP). HCT-116 GFP-RFP cells were injected into the spleen of nu/nu nude mice. RESULTS: HCT-116-GFP-RFP cells subsequently formed primary tumors in the spleen, as well as metastatic colonies in the liver and retroperitoneum by 28 days after cell transplantation. Using an Olympus FV1000 confocal microscope, it was possible to clearly image mitosis of the dual-colored colon cancer cells in the primary tumor as well as liver and other metastases. Multi-nucleate cancer cells, in addition to mono-nucleate cancer cells and their mitosis, were observed in the primary tumor and metastasis. Multi-nucleate HCT-116-GFP-RFP cells were also observed after culture of the primary and metastatic tumors. A similar ratio of mono-nucleate, multi nucleate, and mitotic cells grew from the primary and metastatic tumors in culture, suggesting similarity of the nuclear-cytoplasmic dynamics of primary and metastatic cancer cells, further emphasizing the stochastic nature of metastasis. CONCLUSION: Our results demonstrate a similar heterogeneity of nuclear cytoplasmic dynamics within primary tumors and metastases, which may be an important factor in the stochastic nature of metastasis. PMID- 27127112 TI - Survival After Surgical Treatment of Lung Cancer Arising in the Population Exposed to Illegal Dumping of Toxic Waste in the Land of Fires ('Terra dei Fuochi') of Southern Italy. AB - AIM: Terra dei Fuochi (TdF), the so-called 'Land of Fires' in Southern Italy, is an agricultural territory characterized by illegal dumping of toxic waste known to occur since the 1980s. It is unknown whether prognosis of patients developing cancer and living in that area may differ compared to those living in areas not exposed to this specific type of pollution. We retrospectively analyzed the 5 year survival rates of patients originating from the TdF diagnosed with lung cancer compared to patients from other areas. MATERIALS AND METHODS: Patients consecutively operated on for non-small cell lung cancer (NSCLC) between November 2004 and April 2013 at the Division of Thoracic Surgery of the National Cancer Institute of Naples were eligible. The study outcome was overall survival (OS). In addition, the TdF and non-TdF groups were compared through propensity score matching (PSM). RESULTS: Overall, 439 patients with resectable NSCLC were operated on, 123 (28%) from the TdF and 316 (72%) from other referral centers of our catchment area. There were 301 males and 138 females; the median age of the entire surgical population was 65 years (range=25-83) years. Apart from a different prevalence of hypertension and underweight patients, preoperative factors were evenly distributed between the two groups. At univariate analysis, OS was not different between the TdF and non TdF group (median 72 and 68 months, respectively; p=0.75 log-rank test). Multivariable analysis confirmed that living in the TdF area had no prognostic impact (hazard ratio=1.05; 95% confidence interval=0.70-1.57; p=0.78) on OS. PSM confirmed no statistically significant difference of OS (hazard ratio=1.01, 95% confidence interval=0.67-1.52; p=0.93). CONCLUSION: Following surgery for lung cancer, TdF and non-TdF surgical candidates had similar long-term survival. Originating from the TdF does not seem to be associated with worse outcomes after surgical treatment of patients with lung cancer. PMID- 27127113 TI - Orthotopic Implantation of Intact Tumor Tissue Leads to Metastasis of OCUM-2MD3 Human Gastric Cancer in Nude Mice Visualized in Real Time by Intravital Fluorescence Imaging. AB - BACKGROUND/AIM: Orthotopic (literally "correct place") implantation of cancer in nude mice has long been known to be superior to subcutaneous transplantation because the orthotopic tumor can metastasize. We reported previously on surgical orthotopic implantation (SOI) of gastric cancer tissue in nude mice resulting in the formation of metastases in 100% of the mice with extensive primary growth to the regional lymph nodes, liver, and lung. In contrast, when cell suspensions were used to inject gastric cancer cells orthotopically, metastases occurred in only 6.7% of the mice with local tumor formation, emphasizing the importance of orthotopically implanting intact tissue to allow full expression of metastatic potential. However, the different behavior of tumors implanted orthotopically by the two methods has not been visualized in real time. MATERIALS AND METHODS: OCUM 2MD3 human gastric cancer cells labeled with the fluorescent protein Azami-Green were implanted orthotopically as cells or tissue in nude mice. RESULTS: Orthotopic implantation of cells resulted in local spread on the stomach. In contrast, SOI of tumor tissue of OCUM-2MD3 resulted in vessel spread of the Azami Green-expressing cancer cells. Metastasis was also observed in the left lobe of the liver after SOI. CONCLUSION: These results demonstrate the physiological importance of intact cancer tissue for orthotopic implantation in order for tumors to properly grow and express their metastatic potential. PMID- 27127114 TI - Normal Oral Keratinocytes and Head and Neck Squamous Carcinoma Cells Induce an Innate Response of Fibroblasts. AB - BACKGROUND: Tumor stroma is similar to the connective tissue of chronic inflammation. The extracellular matrix of tumors is formed by cancer-associated fibroblasts that also modulate the inflammatory response. MATERIALS AND METHODS: We studied the ability of oral keratinocytes (NOK) and oral squamous cell carcinoma cells (SCC) to induce an innate immune response in fibroblasts. Co cultures with fibroblasts in collagen gels and keratinocytes in inserts were used. Pentraxin 3 (PTX3) was used as an indicator of an innate immune response. RESULTS: SCC and NOK up-regulated fibroblast mRNA expression and protein release of PTX3. mRNA levels were more pronounced in cultures with malignant cells. The induction of PTX3 was abrogated by an interleukin-1 receptor antagonist CONCLUSION: Keratinocytes have the capacity to induce an interleukin-1-dependent innate immune response by fibroblasts in vitro. This could be important for subsequent fibroblast modulation of the inflammatory reaction in non-malignant and malignant disease processes. PMID- 27127115 TI - Increased Copy Number of the Gene Encoding SF3B4 Indicates Poor Prognosis in Hepatocellular Carcinoma. AB - BACKGROUND/AIM: Defects in alternative splicing contribute to carcinogenesis, cancer progression and chemoresistance. The spliceosome pathway, including SF3B4, a component of spliceosomal complex is suggested to play a role in progression of hepatocellular carcinoma (HCC); however, the clinical relevance of SF3B4 in HCC remains unknown. PATIENTS AND METHODS: SF3B4 expression was evaluated by real time reverse transcription polymerase chain reaction in 72 HCC samples and non cancerous liver samples. The relationship between the DNA copy number and SF3B4 expression levels was investigated using TCGA datasets. RESULTS: SF3B4 expression was significantly higher in cancerous than in non-cancerous tissues and positively correlated with SF3B4 DNA copy number. High SF3B4 expression is significantly associated with intrahepatic metastasis and poor prognosis. These results were consistent with data from the public datasets. CONCLUSION: Overexpression of SF3B4, that is due to DNA copy number increase, is suggested to play a role in progression of HCC. PMID- 27127116 TI - Vitamin D Pathway Gene Polymorphisms and Keratinocyte Cancers: A Nested Case Control Study and Meta-Analysis. AB - BACKGROUND: The vitamin D endocrine system is implicated in skin carcinogenesis and polymorphisms in genes associated with the vitamin D receptor (VDR) gene may alter the risk of keratinocyte cancers (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). MATERIALS AND METHODS: In a nested case-control study of 1,124 adults, we investigated associations between polymorphisms in VDR-related pathways and incident keratinocyte cancers during 11 years of follow-up using adjusted multivariate regression analysis. We also performed a meta-analysis of rs2228570, rs7975232, rs1544410 and rs739837 polymorphisms. RESULTS: A total of 286 BCCs and 161 SCCs were newly-diagnosed during follow-up. Participants with rs2228570 and rs927650 recessive genotypes had a decreased risk of SCC (odds ratio (OR)=0.34, 95% confidence interval (CI)=0.17-0.68; OR=0.48, CI=0.27-0.84, respectively). Meta-analysis showed a lower SCC risk in rs1544410 recessive genotypes (summary OR (SOR)=0.74, CI=0.53-0.94), while rs7975232 and rs739837 recessive genotypes were associated with a decreased BCC risk (SOR=0.74, CI=0.56 0.98; SOR=0.65, CI=0.43-0.88). CONCLUSION: Our meta-analysis indicated that vitamin D receptor polymorphisms may be associated with the risk of keratinocyte cancers. PMID- 27127117 TI - Expression of Activin During and After Chemotherapy in Peripheral Blood of Patients with Primary Breast Cancer. AB - BACKGROUND/AIM: Activins are dimeric glycoproteins that play a significant role in reproduction and in endocrine-active tumors. The aim of this study was to evaluate the potential correlation between the concentration of activins (activin A, activin B, and activin AB) in patients receiving adjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: The serum concentration of activins in 30 patients receiving chemotherapy within the German SUCCESS A study was analyzed using different enzyme-linked immunosorbent assays at three time points: After primary surgery, but before chemotherapy; 4 weeks after the end of chemotherapy; and 2 years after chemotherapy during recurrence-free follow-up. RESULTS: The activin concentration decreased in all patients after chemotherapy. Premenopausal patients had significantly lower concentrations of activin AB during follow-up than postmenopausal women (p=0.037). Thirteen out of 16 premenopausal patients developed chemotherapy-related amenorrhea (CRA) but did not significantly differ in their activin concentrations compared to the other premenopausal women. A positive human epidermal growth factor receptor 2/neu status was associated with a significant reduction of activin AB concentration (p=0.02), and trastuzumab treatment correlated with significantly decreased activin A concentration (p=0.012). CONCLUSION: Serial measurements of activin A concentration might be used for monitoring trastuzumab treatment. A sudden increase of activin concentration could be an early indicator of disease recurrence. PMID- 27127118 TI - Synthetic Terrein Inhibits Progression of Head and Neck Cancer by Suppressing Angiogenin Production. AB - BACKGROUND/AIM: Head and neck cancers are the fifth most common cancer type worldwide, affecting more than half a million patients annually. Development of effective therapeutic drugs is, therefore, required for this type of disease. This study assessed the effects of synthetic terrein on head and neck cancer. MATERIALS AND METHODS: Synthetic terrein was prepared by using the modified Altenhach's procedure. The effect of synthetic terrein on cell proliferation of head and neck cancer cells and HUVECs was assessed. Angiogenin secretion and ribosome biogenesis were examined by ELISA and silver staining of the nucleolar organizer region. A mouse xenograft model was prepared by inoculating mice with suspensions of cells of the human head and neck cancer cell line OSC-19 subcutaneously into the dorsal region of each mouse. Ki-67, CD31 and angiogenin expression in xenografted tumors was examined by immunohistochemistry. RESULTS: Synthetic terrein inhibited the growth of various head and neck cancer cells. In addition, an in vivo experiment revealed that synthetic terrein inhibited a xenograft tumor growth in athymic mice. Immunohistochemical analysis revealed that expression of Ki-67, CD31 and ANG was down-regulated in synthetic terrein treated tumors, compared to controls. Synthetic terrein suppressed the ANG secretion and ribosome biogenesis in cancer cells, and cell proliferation in vascular endothelial cells. CONCLUSION: The mechanism underlying the anti-tumor effects of synthetic terrein against head and neck cancer consists of the inhibition of both tumor cell proliferation and angiogenesis via the suppression of ANG production. PMID- 27127119 TI - Absence of Canonical WNT Signaling in Adult Renal Cell Tumors of Embryonal Origin. AB - BACKGROUND/AIM: The canonical beta-catenin pathway is involved in the development of Wilms' tumor, but its role in adult renal cell tumors (RCT) of embryonal origin is not yet known. MATERIALS AND METHODS: We sequenced the catenin beta 1 (CTNNB1) gene in papillary RCTs, applied the TOPflash/FOPflash reporter plasmid system on cell lines, and examined the beta-catenin protein expression by immunohistochemistry. RESULTS: The absence of mutations in CTNNB1 and low TOPflash/FOPflash ratio in tumor cell lines indicated the absence of active Wingless-type MMTV integration site family (WNT) signaling in RCTs. The weakly cytoplasmic tending towards membranous expression of beta-catenin in RCT is analogous to cellular differentiation in the embryonal kidney rather than tumorigenic activation of WNT signaling. CONCLUSION: The localization of beta catenin in papillary RCT, metanephric adenoma and mucinous tubular and spindle cell carcinoma corresponds to that of emerging tubules of kidney at distinct stage of maturation, indicating their embryonal origin. PMID- 27127120 TI - Prediction of Early Recurrence After Curative Resection of Colorectal Liver Metastasis and Subsequent S-1 Chemotherapy. AB - BACKGROUND: S-1, an oral 5-fluorouracil (5-FU)-based medicine that combines tegafur, gimeracil and oteracil potassium is commonly used as an adjuvant chemotherapeutic drug for the treatment of colorectal cancer. PATIENTS AND METHODS: We enrolled 53 patients who underwent curative resection for colorectal cancer and liver metastasis (synchronous, n=24; metachronous, n=29). The subsequent adjuvant chemotherapy with oral S-1 administration was initiated within 56 days after liver resection. Recurrence was evaluated by imaging studies, that were performed during the first year after liver resection. Of the 53 patients, 25 who did not recur within 1 year were defined as being in the no recurrence (NREC) group and the remaining 18 patients were defined as being in the early-recurrence (EREC) group. There were no significant differences in gene expression profiling for drug resistance and metabolism between the NREC group and the EREC group. RESULTS: In synchronous liver metastasis, there was no significant difference in early recurrence between serum carcinoembryonic antigen (CEA) <=5 ng/ml and serum CEA >5 ng/ml (8/24 vs. 16/24, respectively). In metachronous liver metastasis, the early recurrence rate was significantly higher in patients with CEA >5 ng/ml compared to patients with CEA <=5 ng/ml (15/29 vs. 14/29, p=0.05). The expression of cytochrome P450 2C19 (CYP2C19) and ATP-binding cassette, sub-family B member 1 (ABCB1) were significantly lower in the EREC group (6/15) compared to the NREC group (9/15) in colorectal cancer with metachronous liver metastasis and with serum CEA >5 ng/ml. CONCLUSION: Although the exact reason for down-regulation of these genes in the group with poor prognosis is unknown, the information obtained in this study may be useful in clinical practice for colorectal cancer. PMID- 27127121 TI - Prognostic Factors in an Exercised Model of Chemically-induced Mammary Cancer. AB - BACKGROUND/AIM: Estrogen receptor alpha (ERalpha) and Ki-67 are strong prognostic and predictive markers in woman breast cancer. This study aimed to evaluate the immunoexpression of prognostic factor markers ERalpha, Ki-67 proliferation index (Ki-67 PI) and the mitotic activity index (MAI) in mammary tumors induced by 1 methyl-1-nitrosourea (MNU) in female Sprague-Dawley rats submitted to lifelong exercise training. MATERIALS AND METHODS: Thirty female rats were injected with MNU and randomly divided into two groups: sedentary and exercised. RESULTS: All neoplasms from both groups were ERalpha-positive with an H-score >=20. Statistically significant differences were not found in the ERalpha H-score, Ki 67 PI and MAI between groups. The absolute value of ERalpha H-score was higher in the exercised group, while the Ki-67 PI and MAI were higher in the sedentary group. CONCLUSION: Tumors from the exercised group were less proliferative and more differentiated, suggesting that long-term exercise training had positive effects on mammary carcinogenesis. PMID- 27127122 TI - Connexin 43 Expression in Primary Colorectal Carcinomas in Patients with Stage III and IV Disease. AB - BACKGROUND/AIM: Protein connexin 43 (Cx43), a part of intercellular gap junctions, is frequently down-regulated in tumors. The aim of the study was to compare Cx43 expression in primary colorectal tumors of patients with stage III and IV disease. PATIENTS AND METHODS: Immunohistochemical expression of Cx43 was analyzed in 50 colorectal adenocarcinomas from surgically-treated patients of stage pT3N1-2 without metastases (M0) and 50 specimens of the same pTN stage from patients with synchronous liver metastases (M1). Association of Cx43 expression with clinicopathological factors and tumor site was also analyzed. RESULTS: There was no significant difference in Cx43 expression between M0 and M1 tumor specimens (p=0.817), as well as in Cx43 expression between colonic and rectal tumors (p=0.116), respectively. Stromal expression of Cx43 was higher in M1 than in M0 tumors (p=0.004). CONCLUSION: Stromal Cx43 expression is possible indicator of metastatic potential of colorectal adenocarcinoma. PMID- 27127123 TI - Nuclear Accumulation of Heat-shock Protein 90 Is Associated with Poor Survival and Metastasis in Patients with Non-small Cell Lung Cancer. AB - BACKGROUND/AIM: Heat-shock protein 90 (HSP90) is a molecular chaperone that stabilizes many client proteins in normal and cancer cells, and approximately 3% of intracellular HSP90 is located in the nucleus. HSP90 is also targeted for the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to elucidate the clinical role of nuclear HSP90 levels in tissues from patients with NSCLC. MATERIALS AND METHODS: Nuclear and total HSP90 levels were assessed using immunohistochemistry. RESULTS: Multivariate logistic regression showed that the total HSP90 level was independently positively associated with age (p=0.041) and tumor histology of squamous type (p=0.007). By contrast, nuclear HSP90 level was independently positively associated with higher performance score (p=0.011), ever smoking history (p=0.006) and presence of lymph node (p=0.036) or distant (p<0.001) metastasis, but not age or tumor histology. The level of nuclear HSP90, but not total HSP90, was negatively correlated with patient survival time (p<0.001). CONCLUSION: Nuclear accumulation of HSP90 might be a predictor of metastasis and survival in patients with NSCLC. PMID- 27127124 TI - The Role of IL-10 Promoter Polymorphisms in Renal Cell Carcinoma. AB - BACKGROUND/AIM: Renal cell carcinoma (RCC) accounts for approximately 3% of all cancer-related mortalities worldwide and the risk factors for the development of RCC have not yet been fully elucidated. Mounting proteomic evidence suggests that inflammatory process plays a role in RCC etiology and interleukin-10 (IL-10) is an important immunosuppressive cytokine. However, little is known on the contribution of IL-10 genotypes to RCC. This study aimed at evaluating the contribution of IL-10 promoter A-1082G (rs1800896), T-819C (rs3021097), A-592C (rs1800872) genetic polymorphisms to the risk of RCC in Taiwan. MATERIALS AND METHODS: Associations of the three IL-10 polymorphic genotypes with the risk of RCC were examined among 92 RCC patients and 580 age- and gender-matched cancer free controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: The pilot results showed that the percentages of TT and TC for IL-10 T-819C genotypes were significantly higher in the RCC patient group than those in the healthy control group. The CC genotype carriers were of lower risk for RCC (odds ratio (OR)=0.33, 95% confidence interval (CI)=0.12-0.93, p=0.0369). There is no difference in the distribution of A-1082G or A-592C genotype between the RCC and control groups. CONCLUSION: The CC genotype of IL-10 T-819C genotype may have a protective effect on RCC risk in Taiwan. Further investigation with larger sample size in addition to genotype phenotype correlation and intracellular mechanisms are our future work. PMID- 27127125 TI - Reoxygenation Reverses Hypoxia-related Radioresistance in Head and Neck Cancer Cell Lines. AB - BACKGROUND/AIM: Head and neck cancer (HNC) is characterized by epidermal growth factor receptor (EGFR) overexpression and radiotherapy (RT) resistance. Cancer cells are able to survive and proliferate in hypoxic conditions. Hypoxia can be transiently interrupted by phases of reoxygenation. This work aimed to analyze the reoxygenation effect on proliferation in response to radiation in HNC cells. MATERIALS AND METHODS: HNC cell lines CAL33 and CAL166 were subjected to an 8-Gy radiation dose in hypoxia and/or after reoxygenation. Cell proliferation and molecular factors involved in response to treatments were studied. RESULTS: Cytotoxicity test confirmed radioresistance in hypoxia and highlighted that reoxygenation before RT restores sensitivity in both cell lines. Our results showed a similar proliferation inhibition effect and EGFR modulation but a different cell death mechanism in the two cell lines after treatment. CONCLUSION: Reoxygenation before RT rescued radiosensitivity in HNC cells. PMID- 27127126 TI - Impact of Apparent Antagonism of Estrogen Receptor beta by Fulvestrant on Anticancer Activity of 2-Methoxyestradiol. AB - Osteosarcoma is one of the most malignant bone tumors of childhood and adolescence. Interestingly, the presence of estrogen receptors alpha and beta has been reported in human bone cells, including osteosarcoma. Thus, inhibitors of estrogens such as fulvestrant, are considered candidates for novel endocrine therapy in treatment of osteosarcoma. Another anticancer agent that seems to be very effective in treatment of osteosarcoma is a derivative of 17beta-estradiol, 2-methoxyestradiol. The aim of this study was to determine the anticancer activities of pure anti-estrogen, fulvestrant and combined treatment of fulvestrant and 2-methoxyestradiol towards highly metastatic osteosarcoma 143B cells. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used in order to determine the antiproliferative potential of the compounds, and western blotting for estrogen receptors alpha and beta. Flow cytometry was used in order to determine induction of cell death, cell-cycle arrest, mitochondrial depolarization, and DNA damage. Herein, we showed that fulvestrant has anticancer activity only at high concentrations. We were able to find and expression of estrogen receptor beta, while we did not detect estrogen receptor alpha in osteosarcoma 143B cells. Moreover, fulvestrant down-regulated the expression of estrogen receptor beta, and this effect was reversed by 2-methoxyestradiol. Thus, the obtained data suggest that 2-methoxyestradiol may exert part of its anticancer activity through modulation of expression of estrogen receptor beta. PMID- 27127127 TI - Low Molecular Weight Protein Tyrosine Phosphatase Slow Isoform Knockdown in MDA MB-435 Cells Decreases RAW 264.7 Osteoclastic Differentiation. AB - BACKGROUND/AIM: During the bone metastatic process, tumor cells and bone cells drive a vicious cycle stimulating growth and activity of each other. We here address how low molecular weight protein tyrosine phosphatase (LMW-PTP) could be involved in this process. MATERIALS AND METHODS: We targeted LMW-PTP by siRNA and evaluated the effect of various soluble factors released to the culture medium by the MDA-MB-435 breast cancer cell line, in RAW 264.7 osteoclastogenesis. RESULTS: We showed that these soluble factors did not change RAW 264.7 osteoclastogenic potential. The knockdown of the LMW-PTP slow isoform decreased osteoclastogenesis of RAW 264.7, showing less active Src. The knockdown of LMW-PTP and its slow isoform decreased the release of IL-8 but not IL-6 in MDA-MB-435. CONCLUSION: The LMW-PTP slow isoform can be an important protein in bone metastatic disease, with a fundamental role in the interplay between tumor cells and osteoclasts, through the regulation of Src activity and IL-8 secretion. PMID- 27127128 TI - 3-Bromopyruvic Acid Inhibits Tricarboxylic Acid Cycle and Glutaminolysis in HepG2 Cells. AB - BACKGROUND/AIM: 3-bromopyruvate (3BrPA) is an antitumor agent able to inhibit aerobic glycolysis and oxidative phosphorylation, therefore inducing cell death. However, cancer cells are also highly dependent of glutaminolysis and tricarboxylic acid cycle (TCA) regarding survival and 3BrPA action in these metabolic routes is poorly understood. MATERIALS AND METHODS: The effect of 3BrPA was characterized in mice liver and kidney mitochondria, as well as in human HepG2 cells. RESULTS: Low concentration of 3-BrPA significantly affected both glutaminolysis and TCA cycle functions, through inhibition of isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase. Additionally, 3-BrPA treatment significantly decreased the reduced status of thiol groups in HepG2 cells without proportional increase of oxidizing groups, suggesting that these chemical groups are the target of alkylation reactions induced by 3-BrPA. CONCLUSION: This work demonstrates, for the first time, the effect of 3-BrPA in glutaminolysis and TCA cycle. Our results suggest that the combined action of 3-BrPA in glutaminolysis, TCA and glycolysis, inhibiting steps downstream of the glucose and glutamine metabolism, has an antitumor effect. PMID- 27127129 TI - PIK3CA Mutations Detected in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer. AB - BACKGROUND: In non-small cell lung cancer (NSCLC) the phosphatidylinositol-4,5 bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene mutations have been reported in fewer than 5% of primary tumors. MATERIALS AND METHODS: We assessed PIK3CA gene mutations in 145 tissue samples from central nervous system (CNS) metastases of NSCLC using three polymerase chain reaction (PCR) techniques: high resolution melting-PCR (HRM-PCR), allele-specific-quantitative PCR (ASP-qPCR) and TaqMan PCR. RESULTS: HRM analysis allowed us to select three PIK3CA-positive specimens (2.1% of the studied group) and ASP-qPCR techniques identified them as one E542K and two H1047R substitutions, which were confirmed by TaqMan probes. The PIK3CA mutations were indicated only in males (3% of all males). One of the patients was reported to be a non-smoker with adenocarcinoma (AC; 2.5% of the AC group), however, the other two patients were smokers with squamous cell carcinoma (SCC; 3.4% of SCC group). CONCLUSION: This is the first report of the presence of PIK3CA gene mutation in CNS-metastatic lesions of NSCLC worldwide that could broaden therapeutic choices in such patients. PMID- 27127130 TI - Altered Expression of Imprinted Genes in Squamous Cell Carcinoma of the Head and Neck. AB - BACKGROUND: Genomic imprinting is associated with many human diseases, including various types of cancers, however, no studies on gene imprinting are related to squamous cell carcinoma of the head and neck (SCCHN) directly. MATERIALS AND METHODS: In this study, the expression of a panel of 15 imprinted genes in cancerous and non-cancerous tissues from 73 patients with SCCHN were investigated. RESULTS: Altered expression of carboxypeptidase A4 (CPA4); protein phosphatase 1 regulatory subunit 9A (PPP1R9A); H19, imprinted maternally expressed transcript (non-protein coding) (H19); paternally expressed gene 3 antisense RNA 1 (PEG3-AS1); retrotransposon-like 1 (RTL1), insulin-like growth factor 2 (IGF2); solute carrier family 22 member 3 (SLC22A3); and gamma aminobutyric acid type A receptor beta3 subunit (GABRB3) was observed. Down regulation of PPP1R9A (p<0.05) and GABRB3 (p<0.05) was correlated with more advanced cancer stages. Down-regulation of PEG3-AS1 (p<0.05) and GABRB3 (p<0.01) was correlated with lymph node metastasis. Poor survival was related to higher expression of CPA4 (p<0.01) and lower expression of PEG3-AS1 (p<0.05) and IGF2 (p<0.05). Chemotherapy was also found to have an impact on the expression of imprinted genes. CONCLUSION: Loss of imprinting is involved in tumorigenesis of SCCHN. PMID- 27127131 TI - Euphorbia Species-derived Diterpenes and Coumarins as Multidrug Resistance Modulators in Human Colon Carcinoma Cells. AB - BACKGROUND: Recently, many new potent multidrug resistance (MDR) reversal agents have been discovered, among them lathyrane and jatrophane diterpenes isolated from various Euphorbia species. In the present study, the cytotoxicity, P glycoprotein inhibition activity, and MDR reversal potency of six diterpenes and two coumarins from two Euphorbia species were studied in human colon carcinoma LoVo cells, and doxorubicin-resistant, LoVo/Dx cells. MATERIALS AND METHODS: Cytotoxicity of the studied compounds (alone and in combination with doxorubicin) was investigated. Inhibition of P-glycoprotein transport activity was monitored by flow cytometry. Changes in intracellular doxorubicin accumulation were observed by means of fluorescence microscopy. RESULTS: Latilagascene B was demonstrated to be an effective P-glycoprotein inhibitor, able to increase doxorubicin accumulation in resistant cells, however not able to restore doxorubicin cytotoxicity in LoVo/Dx cells. CONCLUSION: The structure of latilagascene B seems to be an interesting candidate for further synthesis of new derivatives of reduced cytotoxicity and high anti-MDR potency. PMID- 27127132 TI - The Diagnostic Value of Alcohol Dehydrogenase Isoenzymes and Aldehyde Dehydrogenase Measurement Sera of Cervical Cancer Patients. AB - AIM: The aim of this study was to investigate a potential role of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as tumor markers for cervical cancer. MATERIALS AND METHODS: Blood samples were obtained from 43 women with cervical cancer. Isoenzymes class III, IV of ADH and total ADH activity were measured in the sera by the photometric method and class I, II ADH and ALDH activity by the fluorometric method. RESULTS: The total activity of ADH and ADH I was significantly higher in the serum of patients with cervical cancer than in control groups. The diagnostic sensitivity for ADH I was 61,76%, specificity 65,7%, PPV and NPV were 70 and 62,16% respectively. AUC for ADH I was 0,654 and for total ADH 0,618. CONCLUSION: The results suggest a potential role of ADH I as a marker for cervical cancer. PMID- 27127133 TI - Syndecan-1, Epithelial-Mesenchymal Transition Markers (E-cadherin/beta-catenin) and Neoangiogenesis-related Proteins (PCAM-1 and Endoglin) in Colorectal Cancer. AB - The Syndecan-1 protein plays a crucial role in cell proliferation, cell adhesion, cell migration and angiogenesis and, at the same time, its co-expression with E cadherin is regulated during epithelial-mesenchymal transition (EMT). In colorectal cancer (CRC), the expression of syndecan-1, E-cadherin/beta-catenin complex is frequently disturbed. Angiogenesis is critical for the growth and metastatic spread of tumors. In the present study, we focused on the expression of these biological molecules and their prognostic significance in human CRC. Formalin-fixed paraffin-embedded surgical specimens from 69 patients with CRC were immunostained for syndecan-1, E-cadherin, beta-catenin, endoglin (CD105) and CD31 (platelet cell adhesion molecule (PCAM-1)). A significant association was found between syndecan-1 with E-cadherin (p<0.0001), as well with beta-catenin (p<0.0001). High beta-catenin expression appeared to reduce the risk of poor outcome. Endoglin microvascular density (MVD) count was correlated significantly with Dukes' stage (p<0.0001), vessel invasion (p<0.0001), lymph node metastasis (p=0.039), liver metastasis (p<0.0001), recurrence of disease (p=0.010) and poor survival rate (p<0.0001). Endoglin tumor epithelial cell expression was associated with E-cadherin, beta-catenin and syndecan-1 (p=0.001, p=0.068 and p=0.005, respectively). In conclusion, changes in the pattern of expression of syndecan-1, EMT markers, E-cadherin/beta-catenin, in association with endoglin (CD105), may be involved in tumor progression and prognosis of CRC patients. Further studies are needed to clarify the interaction between these proteins and tumor initiation and progression. PMID- 27127134 TI - Induction of Endoplasmic Reticulum Stress via Reactive Oxygen Species Mediated by Luteolin in Melanoma Cells. AB - BACKGROUND: This study aimed to investigate whether luteolin, a flavonoid, induces apoptosis in human melanoma cells via endoplasmic reticulum (ER) stress. MATERIALS AND METHODS: To investigate the effects of luteolin in human melanoma cells, the anti-proliferation, apoptosis, ER stress induction and reactive oxygen species (ROS) generation were evaluated using MTT, Hoechst 33342, ER-tracker Blue White DPX and DCF-DA staining assays, respectively. RESULTS: Luteolin inhibited cell proliferation and increased apoptotic body formation. Luteolin induced ER stress, as shown by ER staining and mitochondrial Ca(2+) overloading. Luteolin increased expression of the ER stress-related proteins; protein kinase RNA-like ER kinase, phospho eukaryotic translation initiation factor 2alpha, activating transcription factor (ATF) 6, CCAAT/enhancer-binding protein-homologous protein (CHOP), and cleaved caspase 12. Furthermore, luteolin increased the level of intracellular ROS, leading to ROS-mediated apoptosis and ER stress. However, N acetyl cysteine, a ROS scavenger, decreased ROS levels, apoptosis, and ER stress induced by luteolin treatment. In addition, knockdown of CHOP and ATF6 by small interfering RNA inhibited luteolin-induced cell death. CONCLUSION: Luteolin induces apoptosis by ER stress via increasing ROS levels. PMID- 27127135 TI - The Involvement of PDGF-B/PDGFRbeta Axis in the Resistance to Antiangiogenic and Antivascular Therapy in Renal Cancer. AB - BACKGROUND/AIM: Studies developed in the field of platelet-derived growth factors/platelet-derived growth factor receptors (PDGFs/PDGFRs) inhibition have focused on the therapeutic effects on tumor cells, neglecting their potential effects on tumor blood vessels. We herein propose a differential and critic assessment of platelet-derived growth factor B (PDGF-B) and platelet-derived growth factor receptor beta (PDGFRbeta) in renal cell carcinoma, correlated with the four main vascular patterns previously reported by our team. MATERIALS AND METHODS: PDGF-B and PDGFRbeta were evaluated on 50 archival paraffin embedded specimens related to vascular endothelial growth factor (VEGF), its inhibitory isoform VEGF165b and vascular patterns. RESULTS AND CONCLUSION: Our results support the involvement of VEGF165b in the phosphorylation of PDGFRbeta with an inhibitory effect on endothelial proliferation and migration. The simultaneous action of PDGF-B/PDGFRbeta and VEGF165b on the same type of receptor may explain the resistance to antiangiogenic therapy, which depends on the degree of modulation of PDGFRbeta phosphorylation. PMID- 27127136 TI - Elimination of Cigarette Smoke-derived Acetaldehyde in Saliva by Slow-release L Cysteine Lozenge Is a Potential New Method to Assist Smoking Cessation. A Randomised, Double-blind, Placebo-controlled Intervention. AB - BACKGROUND/AIM: Harmans are condensation products of acetaldehyde and biogenic amines in saliva. Like other monoamine oxidase inhibitors, harmans help maintain behavioral sensitization to nicotine and mediate the addictive potential of cigarette smoke-derived acetaldehyde. The aim of this study was to test the hypothesis that effective elimination of acetaldehyde in saliva by slow-release L cysteine (AcetiumTM lozenge; Biohit Oyj, Helsinki, Finland) blocks the formation of harmans and eliminates acetaldehyde-enhanced nicotine addiction in smokers. STUDY DESIGN: A double-blind, randomized, placebo-controlled trial comparing Acetium lozenges and placebo in smoking intervention was undertaken. MATERIALS AND METHODS: A cohort of 423 cigarette smokers were randomly allocated to intervention (n=212) and placebo arms (n=211). Smoking-related data were recorded by questionnaires, together with nicotine dependence testing by Fagerstrom scale. The participants used a smoking diary to record the daily number of cigarettes, test lozenges and sensations of smoking. The data were analyzed separately for point prevalence of abstinence and prolonged abstinence endpoints. RESULTS: Altogether, 110 study participants completed the trial per protocol, 234 had minor violations, and the rest (n=79) were lost to follow-up. During the 6-month trial, 65 participants quit smoking; 38 (17.9%) in the intervention arm and 27 (12.8%) in the placebo arm [odds ratio (OR)=1.48; 95% confidence intervals (CI)=0.87-2.54; p=0.143]. Success in the per protocol group was better (42.9% vs. 31.1%, respectively; OR=1.65, 95% CI=0.75-3.62; p=0.205) than in the modified intention-to-treat group: 13.5% vs. 7.4% (p=0.128). CONCLUSION: If the efficacy of Acetium lozenge can be confirmed in an adequately powered study, this new approach would represent a major breakthrough in smoking quit intervention because slow-release L-cysteine is non-toxic with no side-effects or limitations of use. PMID- 27127137 TI - A Prospective Observational Study of Adoptive Immunotherapy for Cancer Using Zoledronate-Activated Killer (ZAK) Cells - An Analysis for Patients with Incurable Pancreatic Cancer. AB - BACKGROUND/AIM: Adoptive immunotherapy (AIT) using autologous zoledronate activated killer (ZAK) cells has been performed for developing a novel modality of cancer treatment. In this study, data series from incurable pancreatic cancer were analyzed. PATIENTS AND METHODS: Patients were treated with AIT using intravenous administration of ZAK cells every 3 to 4 weeks in combination with standard chemotherapy and possible clinical benefits were examined. RESULTS: Seventy-five patients were treated. A median overall survival (OS) time of 6.7 months was achieved for all patients and 13.1 months for those treated 5 times or more, that increased to 14.6 and 18.3 months, respectively, when the previous treatment period of chemotherapy alone was included in the analysis. The disease control rate was 58.5 %. Multivariate regression analysis showed a significant positive correlation between the survival and baseline value of lymphocyte percentage in white blood cell counts (p=0.031). CONCLUSION: The data suggest that AIT using ZAK cells in combination with chemotherapy is safe and feasible and may be effective in prolonging survival for patients with incurable pancreatic cancer. The lymphocyte percentage at baseline may be a good biomarker for predicting the survival benefit of ZAK cell AIT. PMID- 27127138 TI - Lymphocytic Oesophagitis Preliminary Ultrastructural Observations. AB - BACKGROUND/AIM: Lymphocytic oesophagitis (LyE) is a newly described entity characterized by a high number of intraepithelial lymphocytes/ high power field (>=40 CD3+IELs/HPF) in the oesophageal epithelium. The aim of the study was to investigate possible ultrastructural changes taking place in LyE at the transmission electron microscopic (TEM) level. MATERIALS AND METHODS: Oesopageal biopsies from seven patients were investigated: four were consecutive patients with LyE, one with reflux oesopagitis, one with eosinophilic oesopagitis (EoE) and one with histologically normal squamous epithelium. RESULTS: In LyE, marked intercellular oedema (spongiosis) and a gamut of regressive changes were found in squamous cells, ranging from cytoplasmic oedema and vacuolization, to total cell disintegration. IELs also showed regressive changes ranging from ballooned, oedematous cytoplasm to signs of intracytoplasmatic disintegration. CONCLUSION: Besides hampered cell nutrition conveyed by spongiosis, putative noxious molecules contained in the intercellular spongiotic oedema might account for the dramatic TEM alterations found in LyE. The present findings provide, for the first time, "inside information" on the ultrastructural alterations taking place in LyE, both in squamous cells and in IELs. PMID- 27127139 TI - Adenocarcinoma of the Oesophagus and Oesophagogastric Junction: Analysis of Incidence and Risk Factors. AB - BACKGROUND/AIM: Conflicting data exist on the changes in the incidence of oesophageal (EAC) and oesophagogastric junction adenocarcinoma (EGJAC). In addition, risk factors of the disease are only partly known. The aim of the study was to evaluate the incidence of EAC and EGJAC in Finland as well as risk factors of these cancers. PATIENTS AND METHODS: The complete number of new EAC and EGJAC cases between January 1980 and December 2007 in Finland was provided by the Finnish Cancer Registry. All treated EAC and EGJAC patients in the Pirkanmaa Hospital District between January 1980 and December 2007 were included in the study. RESULTS: The incidence of EAC increased significantly in Finland. Barrett's oesophagus (BE) was associated with the risk of EAC and cholecystectomy with the risk of EGJAC. CONCLUSION: A significant increase in EAC was found in Finland over the course of nearly 30 years, indicating that the increase in EAC in Finland is existent in the long term. BE was associated with the risk of EAC and cholecystectomy with the risk of EGJAC. PMID- 27127140 TI - Genome-based Mutational Analysis by Next Generation Sequencing in Patients with Malignant Pleural and Peritoneal Mesothelioma. AB - BACKGROUND/AIM: Malignant mesothelioma is a rare malignancy with limited therapeutic options. Exome-based next-generation sequencing (NGS) techniques may direct the future of molecular targeting and improve systemic therapies for patients with mesothelioma. MATERIALS AND METHODS: Eleven patients with NGS testing were selected, with a total of 236 somatic cancer-related mutations analyzed. Descriptive and Kaplan-Meier statistics were applied. RESULTS: The median age was 65 years (range=27-73 years); 4 (36%) patients were females. Seven (64%) and four patients (36%) had pleural and peritoneal mesothelioma, respectively. Detectable mutations were found in 86% of the pleural and 50% of the peritoneal mesothelioma patients (overall, 73% of patients). The families of BAP1 (36%), CDKNA2A/B (27%) and NF2 (27%) represented the most frequently mutated genes. The median overall survival for all patients was 20.8 months, with 1- and 2-year survival rates of 91% and 40%, respectively. CONCLUSION: Genomic alterations as potential therapeutic targets were found by NGS. These findings will help in the development of new screening tools and targeting therapies, and in turn impact the standard-of-care and potentially lengthen disease control and survival periods in the future. PMID- 27127141 TI - Tail of Superficial Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma After Preoperative Radiotherapy. AB - BACKGROUND/AIM: Superficial myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are highly associated with infiltrative growth (tail sign) and local recurrence, but the impact of preoperative radiotherapy is uncertain. PATIENTS AND METHODS: Eight consecutive superficial MFS and 10 superficial UPS cases treated with preoperative radiotherapy and surgery were reviewed. Pathological response, surgical margin and magnetic resonance imaging (MRI) were retrospectively evaluated. Oncological events were reported in a descriptive form. RESULTS: Pathologically, nearly-complete response was observed in six UPS cases. Tail sign was pathologically detected in 13 cases, eight of which remained viable. Among the eight cases with viable tail, three cases, including two with positive margin, locally recurred. No major discrepancy was observed between tail length on pre-treatment T1-weighted post-contrast, fat saturated MRI and pathological tail length. CONCLUSION: Tail of superficial MFS and UPS can retain viability even after radiotherapy and cause local recurrence unless they respond to radiotherapy well. Wider resection including the tail on MRI is recommended. PMID- 27127142 TI - Relationship Between Hematogenous Tumor Cell Dissemination and Cellular Immunity in DCIS Patients. AB - BACKGROUND/AIM: By definition, tumor cells do not pass the epithelial basement membrane in pre-invasive lesions. However, recently, it was shown that hematogenous tumor cell dissemination already takes place in patients with ductal carcinoma in situ (DCIS), giving disseminated tumor cells (DTCs) in the bone marrow the opportunity to interact with the peripheral immune system. We, therefore, investigated the relationship between DTCs and the peripheral innate and adaptive immune system of DCIS patients, as immunosurveillance might also be impaired in pre-invasive lesions. MATERIALS AND METHODS: We analyzed the peripheral immune status of 115 DCIS patients by flow cytometry. Results were correlated with presence of DTCs, that were detected in the bone marrow by immunocytochemistry (pan-cytokeratin antibody A45-B/B3) using the automated cellular imaging system (ACIS) according to the international society of hematotherapy and graft engineering (ISHAGE) evaluation criteria. Apoptotic DTCs were characterized by positive M30 staining and cytomorphological criteria. RESULTS: In contrast to breast cancer, we found no significant correlation between appearance of DTCs and quantitative distribution of T-cell sub populations, B and NK-cells neither in the bone marrow nor in the peripheral blood. Moreover, DTCs did not affect the expression of important immunomodulatory antigens for functional integrity of specific immune response such as, TCR-zeta, CD28 or CD95. Interestingly, 39% of DTCs were positive for M30 expression and showed cytomorphological signs of apoptosis. CONCLUSION: In contrast to breast cancer, DTCs of DCIS seem to be less immunogenic, which might result in a diverging way to evade immunosurveillance. PMID- 27127143 TI - Endometrial Adenocarcinoma Presenting as Hematometra with Underlying Thickened Endometrial Lining in a Postmenopausal Woman - A Case Report. AB - BACKGROUND: Although most postmenopausal women diagnosed with endometrial cancer usually present with vaginal bleeding, when complete cervical stenosis is present, this sign may be missing. In these cases, the patient usually complaints for pelvic or abdominal pain while the transvaginal ultrasonography might reveal the presence of an intrauterine fluid collection in association with a thickened endometrial lining. CASE REPORT: We present the case of a 65-year-old patient who presented with association of pelvic pain, enlarged uterine cavity with an underlying hematometra and an irregular, thickened endometrium who was submitted to surgery for total histerectomy, bilateral adnexectomy, pelvic and para-aortic lymph node dissection. CONCLUSION: Histopathological studies revealed the presence of a well-differentiated endometrial adenocarcinoma. At three years of follow-up, the patient is free of any recurrent disease. PMID- 27127144 TI - Weekly Multi-agent Chemotherapy (CMF-b) for Advanced Non-melanoma Skin Cancer. AB - BACKGROUND/AIM: Advanced unresectable and metastatic non-melanoma skin cancers (NMSC) are rare, but often arise in elderly patients. When surgery or irradiation are no longer feasible, chemotherapy is often precluded by the patient's age and comorbidities. Whether low-dose multi-agent chemotherapy could be an alternative for this vulnerable population in an outpatient setting was the issue examined in this retrospective analysis. PATIENTS AND METHODS: Twenty-six patients with advanced unresectable or metastatic NMSC received weekly multi-agent chemotherapy with carboplatin at an area under the curve of 2 or 40 mg total dose of cisplatin, with 15 IU total dose of bleomycin, 40 mg total dose of methotrexate, and 500 mg total dose of 5-fluorouracil (CMF-b) until best response, toxicity, or progression of their disease. RESULTS: Twenty-four patients were treated as outpatients; two were hospitalized. Twenty-three patients were previously treated with surgery or radiotherapy. The median age was 68 years (range=44-100 years). The median number of cycles was 6 (range=1 to 17). The overall response rate was 61.5% (seven complete remissions, nine partial remissions) for the entire cohort and 63.6% (two complete remissions and five partial remissions) for patients >80 years. The median duration of response was 6.1 months (range=1.6-63 months). Responses longer than 6 months were obtained in 11/26 (42.3%) of the entire cohort and in 4/11 (36.3%) patients >80 years. Symptom improvement was observed in 17 patients (65.3%). Toxicity was acceptable, with grade 3 renal failure (n=1) and grade 3 or 4 myelotoxicity (n=2). CONCLUSION: CMF-b is a safe, weekly low dose multi-agent regimen that offers palliation for vulnerable patients with NMSC. PMID- 27127145 TI - Interaction Between Beta-Catenin and EGFR Expression by Immunohistochemistry Identifies Prognostic Subgroups in Early High-risk Triple-negative Breast Cancer. AB - Wnt and epidermal growth factor receptor (EGFR) pathway abnormalities and de stabilization of cell adhesion are all important aspects of the pathogenesis of triple-negative breast cancer (TNBC). Herein we investigated how the expression of related protein markers may affect the outcome of patients bearing TNBC treated in the adjuvant setting. Immunohistochemistry for beta-catenin, Myc (Wnt pathway), E-cadherin, P-cadherin (cell-adhesion), EGFR and cytokeratin 5 (CK5) (identification of basal-like tumors) was carried out in 364 centrally confirmed TNBCs. Survival analysis was performed with Cox-regression models according to dichotomized continuous protein expression data and marker interactions. In 352 evaluable tumors, 81.5% were basal-like TNBC. E-cadherin and P-cadherin were positively associated, with co-expression being present in 68% of tumors. Individual markers did not affect patient outcome. However, a statistically significant interaction was shown such that low expression of beta-catenin in the cell membrane, defined as expression below the median of the H-score distribution, was associated with unfavourable disease-free survival among tumors that expressed EGFR, but not in the absence of EGFR expression (interaction p=0.0085). The interaction persisted after correcting for clinicopathological variables. A considerable number of TNBC co-expresses E-cadherin and P-cadherin, while membranous localization of beta-catenin may predict patient outcome in an EGFR-dependent manner. This novel interaction seems worthy for validating with regards to its biological and clinical relevance. PMID- 27127146 TI - SOX18 Expression in Non-melanoma Skin Cancer. AB - BACKGROUND/AIM: SRY-related HMG box protein 18 (SOX18) is a transcription factor involved in a range of physiological processes, including differentiation of endothelial cells during new vessel formation. Numerous studies are being conducted to determine its role in carcinogenesis. MATERIALS AND METHODS: Thirty five cases of squamous cell carcinoma (SCC), 61 cases of basal cell carcinoma (BCC), 15 cases of actinic keratosis (AK) and 15 normal skin (NS) cases were examined in the study. Expression of SOX18 was investigated with immunohistochemistry and light optic microscopy. The obtained results were subjected to statistical analysis including available clinicopathological data. RESULTS: Nuclear expression of SOX18 was shown in vascular endothelial cells, basal layer cells of NS epidermis, as well as in AK, BCC and SCC cancer cells. Expression of SOX18 in SCC, BCC and AK cells was significantly higher than in NS (p<0.01, p<0.001 and p<0.01, respectively). Additionally, higher expression of SOX18 in BCC than in SCC cells (p<0.001) was observed. CONCLUSION: SOX18 may play a role in the development of BCC and SCC. Further studies with the use of additional markers tested at the mRNA and protein level are necessary for better explanation of SOX18 function in cancer transformation. PMID- 27127147 TI - Is the Isolated Pericardial Fat Pad Sufficient to Cover the Bronchial Stump and Separate the Pulmonary Artery in Order to Prevent Bronchopleural Fistula in Patients with Lung Cancer? AB - BACKGROUND: The development of a bronchopleural fistula (BPF) is the most serious postoperative complication of thoracic surgery. All surgical techniques that have been reported as preventive measures against BPF have disadvantages. PATIENTS AND METHODS: We herein introduce a new technique (Yatsuhashi method) for covering the bronchial stump after right lower lobectomy using isolated pericardial fat tissue (PFT). Between 2012 and 2015, 878 consecutive patients with lung disease underwent surgery at our Institution. Among these patients, 26 underwent right lower lobectomy. Their clinical records were retrospectively reviewed to identify the presence of residual fat, in patients in whom the traditional pedicle method was applied and in those in whom an isolated PFT method was applied. The data on the characteristics, surgical details, and perioperative outcomes were analyzed. RESULTS: There were no cases of BPF and the 90-day mortality rate was 0%. The mean period of time from the day of surgery until the computed tomographic examination was 207 days. There were no significant differences in the age, gender, clinical stage, pathological stage, the presence of comorbidities or complications, the duration until computed tomography, nor the presence of residual fat between the patients in whom the isolated PFT (n=17) and the standard pedicle (n=9) methods were applied. Furthermore, no postoperative complications due to the use of isolated PFT itself were observed in the patients who were treated using this method. The existence of residual isolated PFT was also confirmed in five out of six cases who underwent surgical treatment with the novel Yatsuhashi method. CONCLUSION: The simple technique using PFT for covering the bronchial stump after right lower lobectomy was satisfactorily effective and was not associated with any complications. PMID- 27127148 TI - Accurate Diagnosis of Aortic Invasion in Patients with Lung Cancer. AB - BACKGROUND: The information regarding the optimal treatment of locally advanced lung tumor for achieving a cure remains limited. This is particularly true for an accurate diagnosis of tumor invasion of adjacent structures, especially the aorta. PATIENTS AND METHODS: Between June 2014 and January 2016, 505 consecutive patients with chest disease underwent surgery at our Institution. Among these patients, five (1.0%) with lung tumor were strongly suspected of having aortic invasion. Their clinical records were retrospectively reviewed to identify factors to accurately diagnose aortic invasion in patients with lung cancer. The data on patient characteristics including modern-era clinical imaging, surgical details, and perioperative outcomes were analyzed. RESULTS: The study population comprised of four males and one female. The histological types were non-small cell carcinoma lung cancer in four cases and metastatic carcinoma from renal cell carcinoma in one. No cases were determined to be negative by both computed tomography and magnetic resonance imaging. However, an intraoperative assessment showed the resectability of lesions without invasion in all cases. CONCLUSION: The diagnosis of aortic invasion may be overestimated, although aortic invasion is considered an absolute contraindication to surgical management with radical intent. Physicians should pay attention to the possibility of aortic invasion, even if the angle in contact with the tumor indicates a wide field of view, in order to provide a chance for a cure. PMID- 27127149 TI - ZKSCAN3 Facilitates Liver Metastasis of Colorectal Cancer Associated with CEA expressing Tumor. AB - AIM: Zinc finger with KRAB and SCAN domain 3 (ZKSCAN3) is overexpressed in invasive colorectal cancer (CRC) cells and regulates the expression of several genes favoring tumor progression, including vascular endothelial growth factor (VEGF) and integrin beta4. We evaluated the association of ZKSCAN3 and colorectal cancer liver metastasis (CLM) to determine whether it is related to invasive signaling pathways. MATERIALS AND METHODS: The ratios of expression by primary tumor to normal tissue and metastatic tumor to normal tissue were compared between ZKSCAN3-overexpressing and underexpressing primary tumor groups. RESULTS: In terms of CLM, the ZKSCAN3 overexpression was positively correlated with carcinoembryonic antigen (CEA), VEGF, and AKT expression. The protein-expression analysis showed that ZKSCAN-specific siRNA knockdown reduced CEA expression in LoVo and LS174T CRC cells. Matrigel invasion by ZKSCAN3-overexpressing HCT116 cells was increased when examined on CEA-coated filters compared with phosphate buffered saline-treated controls. Additionally, matrix metalloproteinase 9 (MMP9) expression was greater in cells with reference allele (GG) than substitution allele (CC) for ZKSCAN3 rs733743 (p=0.032). ZKSCAN3 protein expression of the high serum CEA group was increased in hepatic metastatic tissue compared with the primary tumor tissue, while in the group with normal serum CEA it decreased or was similar. Reference ZKSCAN3 alleles were correlated with male dominance, a family history of malignancy, high serum CEA concentration and stage IV CRC in 450 patients with sporadic CRC. In conclusion, ZKSCAN3 appears to promote colorectal tumor progression and invasion. ZKSCAN3 may facilitate hepatic metastasis of CRC associated with CEA particularly in cases with CEA-producing tumor. PMID- 27127150 TI - Surgical Results of Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma: a Multi-institutional Retrospective Study of 174 patients. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) remains a major complication after pancreaticoduodenectomy (PD), and the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) after PD is poor. PATIENTS AND METHODS: A multi institutional retrospective study was performed in 174 patients who underwent PD for PDAC from 2007 to 2012. The details of clinical data were examined, and risk factors for POPF and poor prognostic factors after PD were identified. RESULTS: POPF occured in 26 patients (15%), and 18 patients (10%) were diagnosed as Grade B/C POPF. The independent risk factors for Grade B/C POPF were body mass index (BMI) >=25 (Odds Ratio [OR]=21.1, p=0.006) and absence of post-operative enteral nutrition (EN) (OR=10.2, p=0.04). The 1-, 3-, and 5-year overall survivals of patients with PDAC after PD were 76%, 35%, and 18%, respectively. R1/2 operation was identified as the only independent poor prognostic factor (Hazard Ratio=3.66; p=0.0002). CONCLUSION: Patients with BMI >=25 should be closely monitored for POPF after PD. Post-operative EN might help prevent POPF. Performing R0 resection is an important goal for ensuring patient survival after PD for PDAC. PMID- 27127151 TI - Salvage High-dose-rate Interstitial Brachytherapy for Pelvic Recurrent Cervical Carcinoma After Hysterectomy. AB - BACKGROUND: The aim of this study was to report the clinical results of salvage high-dose-rate interstitial brachytherapy (HDR-ISBT) for patients with cervical cancer with pelvic recurrence after hysterectomy. PATIENTS AND METHODS: When there was no indication for total pelvic extenteration (TPE) and the tumor depth was more than 5 mm of invasion in the paracolpium, salvage HDR-ISBT was applied. RESULTS: A total of 26 patients were included in this study. The median number of fractions and dose per fraction of HDR-ISBT were 5 (range=3-20 fractions) and 6 Gy (range=2.5-6 Gy), respectively. Three-year local control, progression-free survival, and overall survival were 51.1%, 34.4% and 57.1%, respectively. Combination of external-beam radiation therapy, clinical target volume D90 greater than 65 Gy, and dose per fraction greater than 5 Gy were associated with favorable local control. CONCLUSION: For patients with recurrent cervical cancer post hysterectomy who are not candidates for TPE, salvage HDR-ISBT is a possible curative treatment modality. PMID- 27127152 TI - Wire-guided Localization in Non-palpable Breast Cancer: Results from Monocentric Experience. AB - BACKGROUND: Breast-conserving surgery (BCS) is considered the gold-standard treatment for early breast cancer. Ultrasound-guided percutaneous biopsy or stereotactic biopsy of a breast lesion allows preoperative histological diagnosis. Various techniques have been proposed for identifying non-palpable breast tumors, but the most popular method is the wire-guided localization (WGL) technique. The aim of this study was to propose an alternative technique for optimizing the WGL procedure, facilitating breast surgery and reducing complications. PATIENTS AND METHODS: We performed a prospective study on 40 patients with a single non-palpable breast lesion. For the preoperative localization of mammary lesions, patients were divided randomly into two groups: 20 patients underwent conventional WGL technique and 20 underwent 'optimized' personalized technique. RESULTS: In the group treated with the optimized technique, dislocation of the wire occurred in only 2/20 cases, whereas in those with the conventional technique, dislocation occurred in 9/20 cases (p=0.03). In 5/20 cases of the conventional WGL technique, the wire was accidentally cut by the surgeon, whereas no similar complications were observed in the group that underwent the optimized technique (p=0.047). Re-excision of the surgical margins was necessary in 6/20 cases with the conventional technique, while re-excision was not required for any case using the optimized technique (p=0.02). CONCLUSION: The proposed optimized technique ensures good esthetic results, enabling the surgeon to identify the lesion and perform oncoplastic breast surgery, and allows surgical time to be reduced. PMID- 27127153 TI - Ifosfamide and Etoposide Chemotherapy in the Treatment of Recurrent/Refractory Rhabdomyosarcoma in Adults. AB - BACKGROUND: No standard chemotherapy for adults with recurrent/refractory rhabdomyosarcoma (RMS) has yet been established. The present study aimed to assess the effect of ifosfamide and etoposide (IE) chemotherapy on previously treated RMS. PATIENTS AND METHODS: Adults with recurrent/refractory RMS were treated with ifosfamide (1,800 g/m(2)/day), etoposide (100 mg/m(2)/day) and mesna (1,080 mg/m(2)/day) for 5 days. The effect and toxicity were evaluated by chart review. RESULTS: Fifteen patients, with a median age of 33 years (range=25-67 years), were treated with IE chemotherapy. A median of six cycles of chemotherapy were administered and an objective response was obtained in eight patients. The median progression-free survival was 5.2 months (95% confidence interval=2.3-6.7 months) and overall survival was 14.4 months (95% confidence interval=4.6-28.3 months). Toxicity greater than grade 3 was as follows: neutropenia in all patients, anemia in seven, thrombocytopenia in seven and febrile neutropenia in eight. CONCLUSION: IE chemotherapy could be an alternative optional treatment method in adults with recurrent/refractory RMS. PMID- 27127154 TI - Increase in Gene Expression of TYMP, DPYD and HIF1A Are Associated with Response to Preoperative Chemoradiotherapy Including S-1 or UFT for Rectal Cancer. AB - AIM: The aim of the study was to identify biomarkers capable of predicting response to preoperative chemoradiotherapy (CRT) including S-1 or UFT for rectal cancer using biopsy specimens obtained before CRT (Pre-samples) and 7 days after the start of CRT (Day-7 samples). MATERIALS AND METHODS: Preoperative CRT including S-1 or UFT was performed in 82 patients with locally advanced rectal cancer. The expression levels of 18 genes related to 5-fluorouracil, folate, and radiation in the Pre-samples and the Day-7 samples were evaluated using reverse transcription polymerase chain reaction (RT-PCR) assay. RESULTS: The gene expression levels of hypoxia inducible factor 1 alpha subunit (HIF1A), dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) were found significantly increased in Day-7 samples compared to Pre-samples in responders, but not in non-responders. CONCLUSION: Increases in gene expression levels of TYMP, DPYD, and HIF1A in tumor tissues at 7 days after the start of CRT may be useful for predicting the efficacy of CRT including S-1 or UFT. PMID- 27127155 TI - Risk Factors and Time to Occurrence of Genitourinary Toxicity After External Beam Radiotherapy for Prostate Cancer. AB - AIM: To retrospectively investigate the risk factors and time to occurrence of genitourinary (GU) toxicity after radiotherapy for localized prostate cancer. PATIENTS AND METHODS: The study included 320 patients. The radiotherapy planning target volume encompassed the prostate with a 1-cm margin in the transverse plane and a 1-cm margin (Group A) or a 1.5-cm margin (Group B) in the longitudinal plane. Incidence rates, risk factors and time to occurrence of GU toxicity were evaluated. RESULTS: After a median follow-up of 38.2 months, the rate of late grade 2-3 GU toxicity was 5.9% and the median interval was 18.3 months. The wider longitudinal margin was the single significant independent factor. The 2-year cumulative incidence rates of late grade >=2 GU toxicity were 2.8% and 7.5% in Group A and B patients. CONCLUSION: A wider radiotherapy margin increased the risk of GU toxicity and led to earlier occurrence. PMID- 27127156 TI - Urinary 5-Aminolevulinic Acid Concentrations as a Potential Tumor Marker for Colorectal Cancer Screening and Recurrence. AB - BACKGROUND/AIM: Tumor biomarkers, such as carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9), are used to screen and monitor tumor recurrence in patients with colorectal cancer (CRC). 5-Aminolevulinic acid (5-ALA) is used in photodynamic diagnosis and therapy. Porphyrins produced by tumor cells are excreted in the urine after 5-ALA administration. In this study, we evaluated the use of porphyrins as novel tumor markers in urine samples from patients with CRC. PATIENTS AND METHODS: Porphyrin metabolite concentrations were measured in urine samples of 33 patients with CRC, 16 patients with benign disease and 8 healthy adults, after 5-ALA administration. RESULTS: The porphyrin metabolite concentrations were significantly increased in the CRC group compared to the control group, while in CRC patients, the porphyrin metabolite concentrations in urine were significantly decreased after surgery. CONCLUSION: These results suggest that the measurement of porphyrin metabolites in urine may potentially serve as a new screening and recurrence marker for CRC. PMID- 27127157 TI - Frequency of Acentric Fragments Are Associated with Cancer Risk in Subjects Exposed to Ionizing Radiation. AB - BACKGROUND/AIM: Biomonitoring is currently applied in the estimation of health risks after overexposure to ionizing radiation (IR). The aim of this study was to compare the association of dicentric chromosomes and acentric fragments (AF) with cancer risk in subjects exposed to IR, as well as in control subjects. MATERIALS AND METHODS: The study was performed on 3,574 subjects (2,030 subjects exposed to IR and 1,544 control subjects). The mean follow-up period was 8 years. RESULTS: In subjects reporting exposure to IR, the presence of AFs and dicentric chromosomes was associated with a significant increase in cancer risk, hazard ratio (HR)=1.78 (95% confidence interval (CI)=1.01-3.13) and HR=1.73 (95% CI=1.03 2.90), respectively. CONCLUSION: AFs are associated with cancer risk and have a similar sensitivity to dicentric chromosomes in subjects exposed to IR. Because automated AF scoring can be easily introduced using fast flow cytometry combined with the pan-centromere staining, this biomarker may hold promise as a potential sensitive biomarker of exposure to IR and cancer risk. PMID- 27127158 TI - Change in Serum Lactate Dehydrogenase Is Associated with Outcome of Patients with Advanced-stage NSCLC Treated with Erlotinib. AB - BACKGROUND: Serum lactate dehydrogenase (LDH) has been reported as a prognostic biomarker in malignant diseases. However, little is known on the dynamics of serum LDH levels during systemic treatment. We focused on the association of changes in serum LDH with outcome of patients with advanced-stage non-small cell lung cancer (NSCLC) treated with erlotinib. PATIENTS AND METHODS: Clinical data of 309 patients were analyzed. Serum samples were collected within one week before initiation and after one month of treatment. RESULTS: The change in serum LDH during the first month of erlotinib treatment was independently associated with disease control rate (p=0.006), progression-free survival (PFS) (p=0.010) and overall survival (OS) (p<0.001). CONCLUSION: LDH is a commonly used serum biomarker, that is cheap and easy to detect. The results of our study suggest that the change in LDH serum level during the first month is a surrogate marker on the efficacy of erlotinib in patients with advanced NSCLC. PMID- 27127159 TI - Combining the Glasgow Prognostic Score and Serum Carbohydrate Antigen 19-9 Level Improves the Ability to Predict Early Recurrence in Resected Pancreatic Cancer Patients Receiving Adjuvant Gemcitabine. AB - AIM: The aim of this study was to confirm the predictive/prognostic value of the preadjuvant Glasgow Prognostic Score (GPS) and carbohydrate antigen (CA) 19-9 level in pancreatic cancer patients receiving adjuvant gemcitabine (GEM) after surgery. PATIENTS AND METHODS: A total of 67 resected pancreatic cancer patients, treated with adjuvant GEM, were included. The GPS and CA19-9 level were calculated prior to administration of adjuvant therapy and were found to correlate with the outcomes and rate of early recurrence. RESULTS: An elevated preadjuvant GPS or CA19-9 level was significantly associated with a shorter overall survival (OS) (p=0.003 and p<0.001, respectively). Either an elevated GPS or CA19-9 level predicted early recurrence and the combined use of these two factors improved the ability to predict early recurrence, with a specificity and accuracy up to 0.958 and 0.821, respectively. CONCLUSION: Both an elevated preadjuvant GPS and CA19-9 level, when used alone, are significant predictors of poor outcomes in pancreatic cancer patients receiving adjuvant GEM. The combined use of these parameters improves the ability to predict early recurrence in such patients. PMID- 27127160 TI - Symptomatic Radiation Pneumonitis After Accelerated Partial Breast Irradiation Using Three-dimensional Conformal Radiotherapy. AB - AIM: To examine the relationship between symptomatic radiation pneumonitis and lung dose-volume parameters for patients receiving accelerated partial breast irradiation (APBI) using three dimensional-conformal radiotherapy (3D-CRT). PATIENTS AND METHODS: The prescribed radiation dose was 30 Gy in 5 fractions over 10 days. Toxicity was graded according to the Common Terminology Criteria for Adverse Events (version 4.0). RESULTS: Fifty-five patients were enrolled from August 2010 to October 2013 and the median follow-up time was 30 months (range=18 46 months). Three patients (5%) developed grade 2 symptomatic radiation pneumonitis after 3D-CRT APBI. Among 16 patients with ILV10Gy (% ipsilateral lung receiving >=10 Gy) of 10% or higher, three patients (19%) developed symptomatic radiation pneumonitis. This trend was not observed in any of the patients with ILV10Gy less than 10% (p=0.005). CONCLUSION: High ILV10Gy might be associated with symptomatic radiation pneumonitis after 3D-CRT APBI. PMID- 27127161 TI - Prognostic Factors for Gastric Cancer with Cancer Cells in the Peritoneal Cavity. AB - AIM: To identify the prognostic factors for gastric cancer with positive peritoneal cytology (CY1) or peritoneal metastasis (P1). PATIENTS AND METHODS: We retrospectively analyzed clinicopathological and survival data of 78 patients who had undergone gastrectomy and/or S-1 based chemotherapy for CY1 or P1 gastric cancer. RESULTS: The median overall survival (OS) did not differ significantly between patients with CY1P0, CY0P1 and CY1P1 disease (24, 17 vs. 14 months, respectively). Among 12 clinicopathological factors, clinical N3 (odds ratio [OR]=2.18; 95% confidence interval [CI]=1.22-4.00; p=0.01) and gastrectomy not performed (OR=1.80; 95% CI=1.29-2.51; p<0.01) were significant independent prognostic factors. The median OS significantly differed between patients who had undergone gastrectomy plus chemotherapy versus chemotherapy alone (22 vs. 10 months, respectively; p<0.01). CONCLUSION: Gastrectomy and perioperative chemotherapy may both be indicated in CY1 or P1 gastric cancer patients with clinical N0-2. PMID- 27127162 TI - Importance of Chemotherapy and Radiation Dose After Microscopically Incomplete Resection of Stage III/IV Head and Neck Cancer. AB - AIM: To investigate the importance of chemotherapy and radiation dose after R1 resection of squamous cell carcinoma of the head-and-neck (SCCHN). PATIENTS AND METHODS: One hundred and twenty-two patients receiving radiotherapy alone or with concurrent chemotherapy [cisplatin or cisplatin/5-fluorouracil (5-FU)] were retrospectively analyzed. RESULTS: On multivariate analysis, chemotherapy was significantly associated with improved locoregional control (p=0.048). Three-year locoregional control rates were 61% for those treated without chemotherapy, 83% for those treated with cisplatin and 77% for those treated with cisplatin/5-FU. Radiation doses of 66 and 70 Gy were non-significantly superior to 60-64 Gy (p=0.18). On multivariate analysis, chemotherapy showed a trend for improving survival (p=0.055). Three-year OS rates were 51% for those without chemotherapy, 65% for those treated with cisplatin and 57% for those treated with cisplatin/5 FU. Radiation doses of 66 Gy (3-year survival=61%) and 70 Gy (70%) were superior to 60-64 Gy (25%) (p=0.021). CONCLUSION: Concurrent chemotherapy and a radiation dose of 66 Gy resulted in better outcomes. Cisplatin and cisplatin/5-FU were similarly effective. Radiation doses >66 Gy appear not to be necessary. PMID- 27127163 TI - Impact of Recombinant Human Soluble Thrombomodulin for Disseminated Intravascular Coagulation. AB - BACKGROUND: Early treatment of disseminated intravascular coagulation (DIC) can be associated with improved early outcomes. We aimed to evaluate the effectiveness of recombinant human soluble thrombomodulin (rTM) administration in patients with peritonitis-induced DIC. PATIENTS AND METHODS: We treated 39 patients with DIC or pre-DIC caused by peritonitis at the Department of Surgery and Science, Kyushu University, and related facilities between January and December 2013. RESULTS: Patients surviving to 28 days after DIC treatment had significantly better platelet counts, DIC scores, and sequential organ failure assessment scores at 7 days than did those who died earlier than 28 days. Patients receiving rTM had significantly better overall survival rates at 28 days and the results of multivariate analysis showed that rTM administration for DIC treatment was a prognostic indicator of 28-day survival in patients with peritonitis. CONCLUSION: rTM administration for the treatment of DIC or pre-DIC complicated by peritonitis had acceptable early outcomes. PMID- 27127164 TI - The Surgical Apgar Score Is an Independent Prognostic Factor in Patients with Pancreatic Cancer Undergoing Pancreatoduodenectomy Followed by Adjuvant Chemotherapy. AB - BACKGROUND: We investigated the impact of the surgical Apgar score (SAS) on survival in patients with pancreatic cancer and recurrence after curative surgery followed by adjuvant chemotherapy. PATIENTS AND METHODS: This study included 103 patients who underwent curative surgery for pancreatic cancer between 2005 and 2014. Patients with a SAS of 0-4 were classified into the low SAS group, while those with a SAS of 5-10 were classified into the high SAS group. The risk factors for overall (OS) and recurrence-free (RFS) survival were identified. RESULTS: The OS rates at 3 and 5 years after surgery were 23.0% and 14.4%, respectively, in the low-SAS group and 32.3% and 21.4%, respectively, in the high SAS group, which was a statistically significant difference (p=0.039). The RFS rates at 3 and 5 years after surgery were 13.1% and 13.1%, respectively, in the low-SAS group and 21.4% and 19.2%, respectively, in the high-SAS group, which was a marginally significant difference (p=0.100). Multivariate analysis demonstrated that the SAS was a significant independent risk factor for OS and a marginally significant risk factor for RFS. CONCLUSION: The SAS was a risk factor for OS in patients who underwent curative surgery followed by adjuvant chemotherapy for pancreatic cancer. The surgical procedure, perioperative care and surgical strategy should be carefully planned to improve survival. PMID- 27127165 TI - Initial Report of Phase II Study on Bi-weekly SOX plus Cetuximab Treatment for Wild-type K-RAS Advanced and Recurrent Colorectal Cancer. AB - AIM: This prospective study was designed to evaluate the tolerability and the efficacy of bi-weekly SOX (S-1 and oxaliplatin)+cetuximab as first-line chemotherapy for wild-type K-RAS metastatic colorectal cancer. PATIENTS AND METHODS: We studied patients with previously untreated, unresectable, advanced or recurrent colorectal cancer who were treated in our hospital between October 2010 and March 2013. Their performance status (PS) was 0 to 1. Cetuximab was combined with S-1 and oxaliplatin (SOX+cetuximab). S-1 was given orally at a dose of 40 mg/m(2) (40-60 mg, calculated according to body surface area) twice daily after meals for 2 weeks, followed by a 2-week rest (course 1). Oxaliplatin (85 mg/m(2)) was given on days 1 and 15 of each course. Cetuximab was administered on days 1 (400 mg/m(2)), 8 (250 mg/m(2)) and 15 (500 mg/m(2)) of course 1, followed by every 2 weeks (500 mg/m(2)) thereafter. RESULTS: The study group comprised of 18 patients. The mean age was 61 (range=32-72) years, the male:female ratio was 10:8 and the PS was 0 in 12 patients and 1 in 6 patients. The median number of administered courses was 6 (range=2-12). The treatment response was complete response (CR) in 2 and partial response (PR) in 10 (response rate=67% (12/18 patients)). The minimum number of treatment courses until a PR was 2, indicating an early response. Liver resection was performed in 4 patients (22.2%). The incidence of any adverse events (Grade 3/4) was 28% (5/18), including skin disorder (16.7%) as dry skin, cutaneous pruritus, contusion and paronychia, as well as peripheral sensory neuropathy (11.1%). The any-grade events of skin disorders and peripheral sensory neuropathy were mostly observed in all patients. These events were controllable by preventive skin care and by withdrawal and dose reduction, respectively. Death due to adverse events was not observed. Adverse events did not require the withdrawal of this regimen. CONCLUSION: Based on the 18 patients studied, combined therapy with SOX+cetuximab was free of serious adverse events and could be safely administered by reducing the dose or temporarily suspending treatment, as required. These regimens seem to be promising for conversion therapy (4 out of 18 patients) because of good outcomes and an early response. PMID- 27127166 TI - Hypofractionated Radiotherapy for Breast Cancer Including Risk-adapted Boost: Update on Tolerance and Efficacy of an Accelerated START A Regime. AB - AIM: To present an update of a prospective study evaluating an accelerated hypofractionated whole breast irradiation (WBI) schedule of the START A trial plus hypofractionated boost in breast cancer patients. PATIENTS AND METHODS: One hundred and forty consecutive patients >=55 years were included in this study. Patients received postoperative WBI with 13*3.2 Gy to 41.6 Gy plus a boost of 3.0 Gy/fraction to 9-12 Gy applied in <3.5 weeks, depending on the resection margin. Prospectively planned follow-up (FU) visits, including objective and subjective assessment of treatment tolerance, were performed at 0 and 8 weeks, as well as one, two, four or more years following radiotherapy (RT). RESULTS: The 3-year rates of local control, nodal control, disease-free and overall survival were 99%, 100%, 96% and 91%, respectively. Cosmetic outcome was very good with 99% (n=110/111), 98% (n=99/101) and 100% (n=59/59) of the patients being satisfied or very satisfied one, two and four years after RT, respectively. CONCLUSION: Acceleration of the START A regime with 41.6 Gy WBI plus additional boost of 9-12 Gy remained effective and well-tolerated. PMID- 27127167 TI - Prognostic Factors After Definitive Radio(Chemo)Therapy of Locally Advanced Head and Neck Cancer. AB - AIM: To identify predictors of locoregional control (LRC) and overall survival (OS) after definitive radio(chemo)therapy for squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Two hundred and seventy-five patients were evaluated; 261 patients received radiochemotherapy with 30-40 mg/m(2) of cisplatin weekly, three courses of cisplatin 100 mg/m(2), two courses of cisplatin 5x20 mg/m(2) or two courses of cisplatin 5*20 mg/m(2)plus 5 fluorouracil. Ten characteristics were analyzed: Pre-radiotherapy hemoglobin, T /N-category, Karnofsky performance-score (KPS), gender, age, chemotherapy type, tumor site, grading and radiation dose. RESULTS: On multivariate analyses, hemoglobin 12-14 g/dl (p=0.040), lower T-category (p=0.010), lower N-category (p=0.042) and female gender (p=0.006) were predictive of LRC. Hemoglobin >12 g/dl (p=0.020), lower N-category (p<0.001), KPS >=80 (p<0.001), female gender (p=0.024) and cisplatin 100 mg/m(2) or 5*20 mg/m(2) (p<0.001) were predictors of improved OS. CONCLUSION: Predictors of LRC and OS were identified that can improve personalization of treatment. Since chemotherapy type was associated with OS, studies comparing different regimens are warranted. PMID- 27127168 TI - Immunohistochemical Characterization of Histone Deacetylase as a Potential Prognostic Marker and Therapeutic Target in Endometrial Stromal Sarcoma. AB - AIM: Endometrial stromal sarcoma (ESS) is a rare tumor with limited treatment options. Histone deacetylase (HDAC) is a potential therapeutic target in ESS showing a good rate of response in laboratory studies. In this study we investigated the expression of HDAC enzymes in 41 ESS patients. MATERIALS AND METHODS: Immunohistochemical expression of HDACs was analyzed by tissue microarrays. RESULTS: Strong positive immunoreactivity was observed in 32 (78.0%), 23 (56.1%), 8 (19.5%), 36 (87.8%), 7 (17.1%), 30 (73.2%), 31 (75.6%), and 33 (80.5%) for HDACs 1-8, respectively. Although not statistically significant, HDAC 1, 4, 6, 7, and 8 exhibited a high frequency of strong immunoreactivity linked to a lower 10-year DFS (100.0% vs. 81.3%, p=0.202; 100.0% vs. 83.3%, p=0.393; 90.9% vs. 83.3%, p=0.579; 90.0% vs. 83.9%; and 100.0% vs. 81.8%, p=0.207; respectively). CONCLUSION: HDACs 1, 4, 6, 7, and 8, that showed an especially high frequency of strong immunoreactivity, may represent potential therapeutic targets for ESS. PMID- 27127169 TI - Errata. PMID- 27127170 TI - Complications in multiple gestation pregnancy: A cross-sectional study of ten maternal-fetal medicine centers in China. AB - Complications in women with multiple gestation pregnancy have not been studied in China. We aimed to establish a database of women with multiple gestation pregnancy and investigate the complications related to multiple pregnancy. We conducted a cross-sectional study that included 3246 women with multiple gestation pregnancy and who had multiple live-birth deliveries; the women were registered at ten maternal-fetal medicine centers in China in 2013. All participants completed a detailed questionnaire that included basic demographic information, history of gestation and abnormal fetal development, risk factors during pregnancy, and pregnancy outcomes. Overall, 1553 (47.8%) women experienced pregnancy complications; these women were more likely to have lower height and less education than women who did not experience complications. However, women who experienced complications had a higher twin birth rate and were more likely to have received regular antenatal care and assisted reproductive technology than women without complications (P < 0.05). Notably, preterm birth was a primary complication in multiple pregnancy (n = 960). In conclusion, pregnancy complications, especially preterm birth, were relatively common in women with multiple gestation pregnancy. The findings from this cross-sectional study in China may be used as a foundation for investigating risk factors for complications in women with multiple gestation pregnancy in the future. PMID- 27127171 TI - A Toll-like receptor 2 agonist-fused antigen enhanced antitumor immunity by increasing antigen presentation and the CD8 memory T cells population. AB - The induction of long-lived effector CD8+ T cells is key to the development of efficient cancer vaccines. In this study, we demonstrated that a Toll-like receptor 2 (TLR2) agonist-fused antigen increased antigen presentation via TLR2 signaling and induced effector memory-like CD8+ T cells against cancer after immunization. The N-terminus of ovalbumin (OVA) was biologically fused with a bacterial lipid moiety TLR2 agonist to produce a recombinant lipidated ovalbumin (rlipo-OVA). We demonstrated that rlipo-OVA activated bone marrow-derived dendritic cells (BM-DCs) maturation and increased antigen presentation by major histocompatibility complex (MHC) class I via TLR2. After immunization, rlipo-OVA skewed the immune response towards T helper (Th) 1 and induced OVA-specific cytotoxic T lymphocyte (CTL) responses. Moreover, immunization with rlipo-OVA induced higher numbers of effector memory (CD44+CD62L-) CD8+ T cells compared with recombinant ovalbumin (rOVA) alone or rOVA mixed with the TLR2 agonist Pam3CSK4. Accordingly, the CD27+CD43+ effector memory CD8+ T cells expressed high levels of the long-lived CD127 marker. The administration of rlipo-OVA could inhibit tumor growth, but the anti-tumor effects were lost after the depletion of CD8 or CD127 cells in vivo. These findings suggested that the TLR2 agonist-fused antigen induced long-lived memory CD8+ T cells for efficient cancer therapy. PMID- 27127172 TI - Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody. AB - Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells. Cancer cells acquire the ability to proliferate anchorage-independently, a characteristic feature of malignantly transformed cells. However, the molecular mechanisms underlying this escape of the normal control mechanisms remain unclear. The current study aimed to identify adhesion-induced reactions regulating the cytokinesis of non-transformed human fibroblasts.The adhesion dependent control of cytokinesis was found to occur at a late stage close to the abscission, during which the endosomal sorting complex required for transport (ESCRT) severs the thin intercellular bridge connecting two nascent daughter cells. CEP55, a key protein involved in the abscission process, was localized at the midbody in both adherent and non-adherent fibroblasts, but it was unable to efficiently recruit ALIX, TSG101, and consequently the ESCRT-III subunit CHMP4B was missing in the non-adherent cells. PLK1, a kinase that prevents premature recruitment of CEP55 to the midbody, disappeared from this site more rapidly in the non-adherent cells. A FAK-Src signaling pathway downstream of integrin mediated cell adhesion was found to decelerate both PLK1 degradation and CEP55 accumulation at the midbody. These data identify the regulation of PLK1 and CEP55 as steps where integrins exert control over the cytokinetic abscission. PMID- 27127173 TI - Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation. AB - TBLR1/TBL1XR1, a core component of the nuclear receptor corepressor (NCoR) complex critical for the regulation of multiple nuclear receptors, is a transcriptional coactivator of androgen receptor (AR) and functions as a tumor suppressor when expressed in the nucleus in prostate. Subcellular localization of a protein is critical for its function, and although TBLR1, as a transcriptional cofactor, has been primarily viewed as a nuclear protein, many cells also express variable levels of cytoplasmic TBLR1 and its cytoplasmic specific functions have not been studied. Prostate cancer (PCa) cells express moderately higher level of cytoplasmic TBLR1 compared to benign prostate cells. When comparing androgen dependent (AD) to androgen-independent (AI) PCa, AI cells contain very high levels of TBLR1 cytoplasmic expression and low levels of nuclear expression. Overexpression of cytoplasmic TBLR1 in AD cells inhibits apoptosis induced by androgen deprivation therapy, either in an androgen free condition or in the presence of bicalutamide. Additionally, we identified a cytoplasmic specific isoform of TBLR1 (cvTBLR1) approximately 5 kDa lower in molecular weight, that is expressed at higher levels in AI PCa cells. By immunoprecipitation, we purified cvTBLR1 and using mass spectrometry analysis combined with N-terminal TMPP labeling and Edman degradation, we identified the cleavage site of cvTBLR1 at amino acid 89, truncating the first 88 amino acids of the N-terminus of the full length protein. Functionally, cvTBLR1 expressed in the cytoplasm reduced apoptosis in PCa cells and promoted growth, migration, and invasion. Finally, we identified a nuclear export signal sequence for TBLR1 cellular localization by deletion and site-directed mutagenesis. The roles of TBLR1 and cvTBLR1 provide novel insights into the mechanism of castration resistance and new strategies for PCa therapy. PMID- 27127174 TI - Focal adhesion kinase and paxillin promote migration and adhesion to fibronectin by swine skeletal muscle satellite cells. AB - The focal adhesion kinase (FAK) signaling pathway contributes to the cell migration and adhesion that is critical for wound healing and regeneration of damaged muscle, but its function in skeletal muscle satellite cells (SCs) is less clear. We compared the migration and adhesion of SCs derived from two species of pig (Lantang and Landrace) in vitro, and explored how FAK signaling modulates the two processes. The results showed that Lantang SCs had greater ability to migrate and adhere to fibronection (P < 0.05) than Landrace SCs. Compared to Landrace SCs, Lantang SCs expressed many more focal adhesion (FA) sites, which were indicated by the presence of p-paxillin (Tyr118), and exhibited less F-actin reorganization 24 h after seeding onto fibronectin. Levels of p-FAK (Tyr397) and p-paxillin (Tyr118) were greater (P < 0.05) in Lantang SCs than Landrace SCs after migration for 24 h. Similarly, Lantang SCs showed much higher levels of p FAK (Tyr397), p-paxillin (Tyr118) and p-Akt (Ser473) than Landrace SCs 2 h after adhesion. Treatment with the FAK inhibitor PF-573228 (5 or 10 MUmol/L) inhibited Lantang SC migration and adhesion to fibronectin (P < 0.05), decreased levels of p-paxillin (Tyr118) and p-Akt (Ser473) (P < 0.05), and suppressed the formation of FA sites on migrating SCs. Thus FAK appears to play a key role in the regulation of SC migration and adhesion necessary for muscle regeneration. PMID- 27127175 TI - Monocarboxylate transporter 1 contributes to growth factor-induced tumor cell migration independent of transporter activity. AB - Tumor progression to metastatic disease contributes to the vast majority of incurable cancer. Understanding the processes leading to advanced stage cancer is important for the development of future therapeutic strategies. Here, we establish a connection between tumor cell migration, a prerequisite to metastasis, and monocarboxylate transporter 1 (MCT1). MCT1 transporter activity is known to regulate aspects of tumor progression and, as such, is a clinically relevant target for treating cancer. Knockdown of MCT1 expression caused decreased hepatocyte growth factor (HGF)-induced as well as epidermal growth factor (EGF)-induced tumor cell scattering and wound healing. Western blot analysis suggested that MCT1 knockdown (KD) hinders signaling through the HGF receptor (c-Met) but not the EGF receptor. Exogenous, membrane-permeable MCT1 substrates were not able to rescue motility in MCT1 KD cells, nor was pharmacologic inhibition of MCT1 able to recapitulate decreased cell motility as seen with MCT1 KD cells, indicating transporter activity of MCT1 was dispensable for EGF- and HGF-induced motility. These results indicate MCT1 expression, independent of transporter activity, is required for growth factor-induced tumor cell motility. The findings presented herein suggest a novel function for MCT1 in tumor progression independent of its role as a monocarboxylate transporter. PMID- 27127176 TI - Tumour-associated circulating microparticles: A novel liquid biopsy tool for screening and therapy monitoring of colorectal carcinoma and other epithelial neoplasia. AB - Up to date, novel tools for low-cost, minimal invasive cancer surveillance, cancer screening and treatment monitoring are in urgent need. Physicians consider the so-called liquid biopsy as a possible future tool successfully achieving these ultimate goals. Here, we aimed to identify circulating tumour-associated MPs (taMPs) that could aid in diagnosing minimal-invasively the presence and follow up treatment in non-small cell lung carcinoma (NSCLC), colorectal carcinoma (CRC) and pancreas carcinoma (PaCa). Tumour-associated MPs (taMPs) were quantified after isolation by centrifugation followed by flow cytometry analysis from the serum of cancer patients with CRC (n = 52), NSCLC (n = 40) and PaCa (n = 11). Healthy subjects (n = 55) or patients with struma nodosa (thyroid nodules) (n = 43) served as negative controls. In all three types of tumour entities, the presence of tumour was associated with an increase of circulating EpCAM+ and EpCAM+CD147+ taMPs. The presence of CD147+EpCAM+ taMPs were specific to tumour bearing patients thus allowing the specific distinction of malignancies from patients with thyroid nodules. Increased level of EpCAM single positive MPs were, in turn, also detected in patients with thyroid nodules. Importantly, EpCAM+CD147+ taMPs correlated with the measured tumour-volume in CRC patients. EpCAM+ taMPs decreased at 7 days after curative R0 tumour resection suggesting a close dependence with tumour presence. AUROC values (up to 0.85 and 0.90), sensitivity/specificity scores, and positive/negative predictive values indicated a high diagnostic accuracy of EpCAM+CD147+ taMPs. Taken together, EpCAM+CD147+ double positive taMPs could potentially serve as novel promising clinical parameter for cancer screening, diagnosis, surveillance and therapy monitoring. PMID- 27127177 TI - Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling. AB - Macrophage infiltration promotes tumorigenesis. However, the macrophage infiltration regulatory molecules have not been fully determined. Nerve injury induced protein 1 (ninjurin1) is a homophilic cell surface adhesion molecule that plays an important role in cell migration and attachment. Although ninjurin1 is believed to play a role in several malignancies, it is unclear whether ninjurin1 expression contributes to cancer progression. We used transgenic mice (tg mice) that overexpressed ninjurin1 on macrophages. We subjected ninjurin1 tg mice to a well-known mouse model of colitis-associated colon cancer in which animals are treated with azoxymethane (AOM) and dextran sulfate sodium (DSS). After AOM and DSS treatment, ninjurin1 tg mice developed fewer and smaller tumors compared with wild-type (wt) mice. Ninjurin1 tg mice also showed reduced infiltration of macrophages and suppressed angiogenesis in the tumor mass. We therefore explored whether ninjurin1 decreases macrophage migration into the tumor sites. After adoptive transfer to tumor-bearing recipients, wild type and ninjurin1 tg mice's peritoneal macrophages were freshly isolated and labeled with carboxyfluorescein succinimidyl ester (CFSE). As expected, compared with that of wt type macrophages, tumor infiltration of ninjurin1-overexpressing macrophages was significantly decreased. We also found that ninjurin1 overexpression suppressed FAK activity. In addition, knockdown of ninjurin1 enhanced FAK activity and migration activity of RAW264.7 cells. Ninjurin1 overexpression on macrophage inhibits tumor growth by suppression of macrophage infiltration through repression of FAK signaling. Ninjurin1 is a key regulator molecule for macrophage migration and Tumor-associated macrophages (TAM) mediated tumorigenesis in vivo. PMID- 27127178 TI - Long-term vemurafenib treatment drives inhibitor resistance through a spontaneous KRAS G12D mutation in a BRAF V600E papillary thyroid carcinoma model. AB - The BRAF V600E mutation is commonly observed in papillary thyroid cancer (PTC) and predominantly activates the MAPK pathway. Presence of BRAF V600E predicts increasing risk of recurrence and higher mortality rate, and treatment options for such patients are limited. Vemurafenib, a BRAF V600E inhibitor, is initially effective, but cells inevitably develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in short-term cultures of PTC cells; however, mechanisms of acquired resistance have not. In the present study, we investigated possible adaptive mechanisms of BRAF V600E inhibitor resistance in KTC1 thyroid cancer cells following long-term vemurafenib exposure. We found that a subpopulation of KTC1 cells acquired resistance to vemurafenib following 5 months of treatment with the inhibitor. Resistance coincided with the spontaneous acquisition of a KRAS G12D activating mutation. Increases in activated AKT, ERK1/2, and EGFR were observed in these cells. In addition, the resistant cells were less sensitive to combinations of vemurafenib and MEK1 inhibitor or AKT inhibitor. These results support the KRAS G12D mutation as a genetic mechanism of spontaneously acquired secondary BRAF inhibitor resistance in BRAF V600E thyroid cancer cells. PMID- 27127179 TI - Genetic association of deleted in colorectal carcinoma variants with breast cancer risk: A case-control study. AB - Deleted in colorectal carcinoma (DCC), a netrin-1 dependence receptor, is correlated with cell progression, migration, and adhesion. Evidence indicated that DCC was frequently down-regulated in many cancers. However, the association of DCC with breast cancer remains uncertain. We conducted a case-control study to investigate the impact of three DCC gene variants (rs2229080, rs7504990, and rs4078288) on breast cancer susceptibility in Chinese women. This study included 560 breast cancer patients and 583 age-matched healthy controls from Northwest China. The three gene variants were genotyped via Sequenom MassARRAY. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to evaluate the associations. We found that individuals with the rs2229080 C/G, C/C, and C/G-CC genotypes had a higher breast cancer risk, and the minor allele C was associated with increased breast cancer risk in an allele model. We observed a significantly decreased breast cancer risk with the rs7504990 C/T, T/T, and C/T-T/T genotypes, and the minor allele T was protective against breast cancer in an allele model. In addition, rs2229080 was associated with the axillary lymph node (LN) metastasis status. An age-stratified analysis revealed an association between rs2229080 and reduced breast cancer risk among older patients (>= 49 years). Furthermore, the haplotype analysis showed that the Crs2229080Crs7504990Ars4078288 haplotype was associated with a decreased breast cancer risk. However, the results indicated a lack of association between rs4078288 and breast cancer risk. These findings affirmed that rs2229080 and rs7504990 polymorphisms in DCC might be related with breast cancer susceptibility in Chinese women. PMID- 27127180 TI - Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis. AB - The biological and molecular events that underlie bone marrow fibrosis in patients with myelodysplastic syndromes are poorly understood, and its prognostic role in the era of the Revised International Prognostic Scoring System (IPSS-R) is not yet fully determined. We have evaluated the clinical and biological events that underlie bone marrow fibrotic changes, as well as its prognostic role, in a well-characterized prospective patient cohort (n=77) of primary MDS patients. The degree of marrow fibrosis was linked to parameters of erythropoietic failure, marrow cellularity, p53 protein accumulation, WT1 gene expression, and serum levels of CXCL9 and CXCL10, but not to other covariates including the IPSS-R score. The presence of bone marrow fibrosis grade 2 or higher was associated with the presence of mutations in cohesin complex genes (31.5% vs. 5.4%, p=0.006). By contrast, mutations in CALR, JAK2, PDGFRA, PDGFRB,and TP53 were very rare. Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis. PMID- 27127181 TI - Glucocorticoid impairs cell-cell communication by autophagy-mediated degradation of connexin 43 in osteocytes. AB - Osteocytes comprising over 90% of the bone cell population are highly susceptible to the adverse effects of glucocorticoids (GC) administration. Here we observed that Dexamethasone (Dex) induces a robust cytoskeleton rearrangement and decreases Cx43 protein expression in osteocyte-like MLO-Y4 cells. Using a Dmp1Cre mT/mG osteocyte ex vivo culture system, we found significant shortening of dendritic processes in primary osteocytes following Dex administration. Loss of dendritic processes is a consequence of reduced Cx43 connectivity upon Dex induced autophagy in both RFP-GFP-LC3B transfected MLO-Y4 cells and primary calvarial osteocytes from LC3GFP transgenic mice. Upon the induction of autophagy by Dex, Cx43 was internalized into autophagosome/autolysosomes and degraded by autophagy. The degradation was attenuated following lysosomal inhibition using chloroquine (CLQ) and suppression of autophagy by Atg5 silencing. Inhibition Akt mTORC1 signaling by Dex induces autophagy subsequently resulting in Cx43 degradation.Activation of Akt phosphorylation by IGF-1 attenuated Dex induced autophagy and degradation of Cx43. Together, we demonstrated that GC impair osteocyte cell-cell connectivity via autophagy mediated degradation of Cx43 through inhibition of the Akt-mTORC1 signaling. This may account for the deleterious effect of GC-induced bone loss. PMID- 27127182 TI - The Promise-and Pitfalls-of Computerized Provider Alerts for Laboratory Test Ordering. PMID- 27127183 TI - High-Sensitivity Sandwich ELISA for Plasma NT-proUcn2: Plasma Concentrations and Relationship to Mortality in Heart Failure. AB - BACKGROUND: Urocortin 2 (Ucn2) has powerful hemodynamic, renal, and neurohormonal actions and likely participates in normal circulatory homeostasis and the compensatory response to heart failure (HF). A validated assay for endogenous circulating Ucn2 would facilitate investigations into Ucn2 physiology and elucidate its derangement and potential as a biomarker in heart disease. METHOD: We developed a chemiluminescence-based sandwich ELISA to measure plasma N terminal (NT)-proUcn2 in non-HF patients (control; n = 160) and HF patients with reduced (HFREF; n = 134) and preserved (HFPEF; n = 121) left ventricular ejection fraction (LVEF). RESULTS: The ELISA had a limit of detection of 8.47 ng/L (1.52 pmol/L) and working range of 23.8-572 ng/L. Intra- and interassay CV and total error were 4.8, 16.2, and 17.7%, respectively. The median (interquartile range) plasma NT-proUcn2 concentration in controls was 112 (86-132) ng/L. HFREF, HFPEF, and all HF plasma concentrations were significantly increased [117 (98-141) ng/L, P = 0.0007; 119 (93-136) ng/L, P = 0.0376, and 119 (97-140) ng/L, P = 0.001] compared with controls but did not differ significantly between HFREF and HFPEF. NT-proUcn2 was modestly related to age (r = 0.264, P = 0.001) and cardiac troponin T (r = 0.258, P = 0.001) but not N-terminal pro-B-type natriuretic peptide, body mass index, LVEF, or estimated glomerular filtration rate. On multivariate analysis, plasma NT-proUcn2 was independently and inversely related to 2-year mortality in HF. CONCLUSIONS: The validated ELISA measured human NT proUcn2 in plasma and showed modest but significant increases in HF patients compared with controls. In HF, the unusual inverse relationship between plasma NT proUcn2 and 2-year mortality portends potential prognostic value but requires further corroboration. PMID- 27127184 TI - Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells. AB - Reprogramming of somatic cells into a pluripotent state is known to be accompanied by extensive restructuring of mitochondria and switch in metabolic requirements. Here we utilized Leber's hereditary optic neuropathy (LHON) as a mitochondrial disease model to study the effects of homoplasmic mtDNA mutations and subsequent oxidative phosphorylation (OXPHOS) defects in reprogramming. We obtained fibroblasts from a total of 6 LHON patients and control subjects, and showed a significant defect in complex I respiration in LHON fibroblasts by high resolution respiratory analysis. Using episomal vector reprogramming, our results indicated that human induced pluripotent stem cell (hiPSC) generation is feasible in LHON fibroblasts. In particular, LHON-specific OXPHOS defects in fibroblasts only caused a mild reduction and did not significantly affect reprogramming efficiency, suggesting that hiPSC reprogramming can tolerate a certain degree of OXPHOS defects. Our results highlighted the induction of genes involved in mitochondrial biogenesis (TFAM, NRF1), mitochondrial fusion (MFN1, MFN2) and glycine production (GCAT) during reprogramming. However, LHON-associated OXPHOS defects did not alter the kinetics or expression levels of these genes during reprogramming. Together, our study provides new insights into the effects of mtDNA mutation and OXPHOS defects in reprogramming and genes associated with various aspects of mitochondrial biology. PMID- 27127185 TI - Acute kidney injury and outcome following aortic valve replacement for aortic stenosis. AB - OBJECTIVES: Most studies on acute kidney injury (AKI) following open-heart surgery have focused on short-term outcome following coronary artery bypass grafting. We reviewed the incidence, risk factors and outcome, including long term survival, of AKI after aortic valve replacement (AVR) in a population-based cohort. METHODS: A retrospective review of 365 patients who underwent AVR for aortic stenosis during 2002-2011 was made. AKI was defined according to the RIFLE criteria. All patients requiring dialysis were followed up in a centralized registry. Risk factors for AKI were analysed with univariable and multivariable analysis, and survival was graphically presented with the Kaplan-Meier method. RESULTS: The rate of AKI was 82/365 (22.5%); 40, 28 and 14 patients belonging to the Risk, Injury and Failure groups, respectively. Preoperatively, 37 (45.1%) AKI patients had reduced kidney function. Transfusion of red blood cells, obesity and prolonged cardiopulmonary bypass time were independent risk factors for AKI. Acute postoperative dialysis was required in 15 patients (4.1%), and 1 patient developed dialysis-dependent end-stage renal disease. Major postoperative complications were more common in the AKI group (65 vs 22%, P < 0.001). The 30 day mortality rate in the AKI group was 18%, as opposed to 2% in the non-AKI group (P < 0.001), with a 5-year survival rate of 66 vs 87%, respectively (P < 0.001). In multivariable analysis AKI was an independent predictor of operative mortality [odds ratio = 5.89, 95% confidence interval (CI) = 1.99-18.91] but not of long-term survival (hazard ratio = 1.44, 95% CI = 0.86-2.42). CONCLUSIONS: More than 1 in 5 patients (22.5%) who underwent AVR developed AKI postoperatively. AKI was associated with higher morbidity and was an independent predictor of operative mortality. However, AKI was not a determinant of long-term survival. PMID- 27127186 TI - The challenge of consent in clinical genome-wide testing. AB - Genome-wide testing methods include array comparative genomic hybridisation (aCGH), multiple gene panels, whole exome sequencing (WE) and whole genome sequencing (WGS). Here we introduce some of the key ethical and social considerations relating to informed consent for the testing of children, particularly the management of incidental findings and variants of unknown significance. PMID- 27127187 TI - Overcoming Barriers in Kidney Health-Forging a Platform for Innovation. AB - Innovation in kidney diseases is not commensurate with the effect of these diseases on human health and mortality or innovation in other key therapeutic areas. A primary cause of the dearth in innovation is that kidney diseases disproportionately affect a demographic that is largely disenfranchised, lacking sufficient advocacy, public attention, and funding. A secondary and likely consequent cause is that the existing infrastructure supporting nephrology research pales in comparison with those for other internal medicine specialties, especially cardiology and oncology. Citing such inequities, however, is not enough. Changing the status quo will require a coordinated effort to identify and redress the existing deficits. Specifically, these deficits relate to the need to further develop and improve the following: understanding of the disease mechanisms and pathophysiology, patient engagement and activism, clinical trial infrastructure, and investigational clinical trial designs as well as coordinated efforts among critical stakeholders. This paper identifies potential solutions to these barriers, some of which are already underway through the Kidney Health Initiative. The Kidney Health Initiative is unique and will serve as a current and future platform from which to overcome these barriers to innovation in nephrology. PMID- 27127189 TI - Housebound versus nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome. AB - OBJECTIVES: The objective of this study was to examine individuals with myalgic encephalomyelitis and chronic fatigue syndrome who are confined to their homes due to severe symptomatology. The existing literature fails to address differences between this group, and less severe, nonhousebound patient populations. METHODS: Participants completed the DePaul Symptom Questionnaire, a measure of myalgic encephalomyelitis and chronic fatigue syndrome symptomology, and the SF-36, a measure of health impact on physical/mental functioning. ANOVAs and, where appropriate, MANCOVAS were used to compare housebound and nonhousebound patients with myalgic encephalomyelitis and chronic fatigue syndrome across areas of functioning, symptomatology, and illness onset characteristics. RESULTS: Findings indicated that the housebound group represented one quarter of the sample, and were significantly more impaired with regards to physical functioning, bodily pain, vitality, social functioning, fatigue, postexertional malaise, sleep, pain, neurocognitive, autonomic, neuroendocrine, and immune functioning compared to individuals who were not housebound. DISCUSSION: Findings indicated that housebound patients have more impairment on functional and symptom outcomes compared to those who were not housebound. Understanding the differences between housebound and not housebound groups holds implications for physicians and researchers as they develop interventions intended for patients who are most severely affected by this chronic illness. PMID- 27127188 TI - Sex Differences in Renal Proximal Tubular Cell Homeostasis. AB - Studies in human patients and animals have revealed sex-specific differences in susceptibility to renal diseases. Because actions of female sex hormones on normal renal tissue might protect against damage, we searched for potential influences of the female hormone cycle on basic renal functions by studying excretion of urinary marker proteins in healthy human probands. We collected second morning spot urine samples of unmedicated naturally ovulating women, postmenopausal women, and men daily and determined urinary excretion of the renal tubular enzymes fructose-1,6-bisphosphatase and glutathione-S-transferase-alpha Additionally, we quantified urinary excretion of blood plasma proteins alpha1 microglobulin, albumin, and IgG. Naturally cycling women showed prominent peaks in the temporal pattern of urinary fructose-1,6-bisphosphatase and glutathione-S transferase-alpha release exclusively within 7 days after ovulation or onset of menses. In contrast, postmenopausal women and men showed consistently low levels of urinary fructose-1,6-bisphosphatase excretion over comparable periods. We did not detect changes in urinary alpha1-microglobulin, albumin, or IgG excretion. Results of this study indicate that proximal tubular tissue architecture, representing a nonreproductive organ-derived epithelium, undergoes periodical adaptations phased by the female reproductive hormone cycle. The temporally delimited higher rate of enzymuria in ovulating women might be a sign of recurring increases of tubular cell turnover that potentially provide enhanced repair capacity and thus, higher resistance to renal damage. PMID- 27127190 TI - Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta analysis of Published Randomized, Controlled Trials. AB - This article highlights the role of prucalopride in the management of chronic constipation based upon the principles of meta-analysis using data reported in the published randomized, controlled trials. Sixteen randomized, controlled trials on 3943 patients reported the effectiveness of prucalopride in patients with chronic constipation. Prucalopride successfully increased the frequency of spontaneous bowel movements per week in all variable doses of 1 mg (standardized mean difference [SMD], 0.42 [95% CI, 0.18-0.66; P = 0.006]), 2 mg (SMD, 0.34 [95% CI, 0.11-0.56; P = 0.003]), and 4 mg (SMD, 0.33 [95% CI, 0.22-0.44; P = 0.00001]). The risks of adverse events or side effects such as headache, abdominal cramps, excessive flatulence, dizziness, diarrhea, and rash were higher (odds ratio, 1.70 [95% CI, 1.27 to -2.27; P = 0.0004]) in prucalopride group. Prucalopride is clinically a beneficial pharmacotherapy for chronic constipation and its routine use may be considered in patients with chronic simple laxative resistant constipation. PMID- 27127191 TI - T-cell adoptive immunotherapy using tumor-infiltrating T cells and genetically engineered TCR-T cells. AB - Immunotherapy has received the expectation that it should contribute to the therapy of cancer patients for >100 years. At long last, recent clinical trials of immunotherapy with immune checkpoint inhibitors and adoptive cell therapy with genetically engineered T cells have reported their remarkable efficacies. Nowadays, it is expected that T-cell adoptive immunotherapy can not only control tumor progression but even cure cancer in some patients. Conversely, severe adverse events associated with efficacy have frequently been reported in clinical trials, suggesting that the assessment and control of safety will be indispensable in the future development of the therapy. New approaches in T-cell adoptive immunotherapy such as reduction of adverse events, targeting of new antigens or utilization of allogeneic cells will open a new gate for less harmful and more effective immunological treatment of cancer patients. PMID- 27127192 TI - The performance of bioinspired valveless piezoelectric micropump with respect to viscosity change. AB - This study investigated the effect of the serial connection of two pumping chambers on transport of liquid with increased viscosity. A serially connected valveless piezoelectric micropump was fabricated inspired by the liquid-feeding strategy of a female mosquito drinking liquid with a wide range of viscosities, from nectar to blood. The performance of the micropump was investigated by varying the viscosity of working liquid. Results showed that the optimal phase difference between the two chambers was 180 degrees out-of-phase for all viscosity conditions. The two chambers operating at 180 degrees out-of-phase exhibited higher pumping performance compared with the sum of each single chamber solely actuated, when viscosity increased. The flow patterns in the micropump showed that the rectification efficiency improved with the increase in viscosity. Results indicated that the serially connected valveless piezoelectric micropump is more robust to the increase of viscosity than a single-chamber piezoelectric micropump. This study would be helpful in the design of microfluidic devices for transporting liquids with a wide range of viscosities. PMID- 27127193 TI - Testosterone Replacement Therapy: New Data on Efficacy and Cardiovascular Safety. PMID- 27127194 TI - A dynamic ultrasonic emitter inspired by horseshoe bat noseleaves. AB - The emission of biosonar pulses in horseshoe bats (family Rhinolophidae) differs from technical sonar in that it has dynamic features at the interface to the free field. When the horseshoe bats emit their biosonar pulses through the nostrils, the walls of a horn-shaped baffle (anterior leaf) are in motion while diffracting the outgoing ultrasonic wave packets. Here, biomimetic reproductions of the dynamic emission shapes of horseshoe bats have been studied for their ability to impose time-variant signatures onto the outgoing pulses. It was found that an elliptical sound outlet with rotating baffles that were attached along the direction of the major axis can be well suited for this purpose. Most importantly, concave baffle shapes were found to produce strongly time-dependent devices characteristics that could reach a root-mean-square-difference between beampatterns of almost 6 dB within a rotation angle of 10 degrees . In contrast to this, a straight baffle shape needs to be rotated over 60 degrees for a similar result. When continuously rotated in synchrony with the emitted pulses, the concave biomimetic baffles produced time-variant device characteristics that depended jointly on direction, frequency, and time. Since such device properties are so easily produced, it appears well worthwhile to explore their use in engineering. PMID- 27127195 TI - Natural decay process affects the abundance and community structure of Bacteria and Archaea in Picea abies logs. AB - Prokaryotes colonize decaying wood and contribute to the degradation process, but the dynamics of prokaryotic communities during wood decay is still poorly understood. We studied the abundance and community composition of Bacteria and Archaea inhabiting naturally decaying Picea abies logs and tested the hypothesis that the variations in archaeal and bacterial abundances and community composition are coupled with environmental parameters related to the decay process. The data set comprises >500 logs at different decay stages from five geographical locations in south and central Finland. The results show that Bacteria and Archaea are an integral and dynamic component of decaying wood biota. The abundances of bacterial and archaeal 16S rRNA genes increase as wood decay progresses. Changes in bacterial community composition are clearly linked to the loss of density of wood, while specific fungal-bacterial interactions may also affect the distribution of bacterial taxa in decaying wood. Thaumarchaeota were prominent members of the archaeal populations colonizing decaying wood, providing further evidence of the versatility and cosmopolitan nature of this phylum in the environment. The composition and dynamics of the prokaryotic community suggest that they are an active component of biota that are involved in processing substrates in decaying wood material. PMID- 27127196 TI - Selective isolation of potentially phosphate-mobilizing, biosurfactant-producing and biodegradative bacteria associated with a sub-Arctic, terricolous lichen, Peltigera membranacea. AB - Lichens are the symbiotic association of fungi and a photosynthetic partner. However, non-phototrophic bacteria are also present and thought to comprise an essential part of the lichen symbiosis, although their roles in the symbiosis are still poorly understood. In this study, we isolated and characterized 110 non phototrophic bacterial lichen associates from thalli of the terricolous lichen Peltigera membranacea The biodegradative and other nutrient-scavenging properties studied among selected isolates were phosphate mobilization, biosurfactant production and degradation of napthalene and several biopolymers, suggesting organic and inorganic nutrient scavenging as roles for bacteria in the lichen symbiotic association. Identification by partial 16S rRNA gene sequencing revealed that the isolates comprised 18 genera within the Proteobacteria, Actinobacteria, Bacteroidetes and Firmicutes, many with high similarities with bacteria typically associated with the plant and rhizosphere environments, could suggest that plants may be important sources of terricolous lichen-associated bacteria, or vice versa. PMID- 27127197 TI - Molecular exploration of fecal microbiome in quinoa-supplemented obese mice. AB - Diet affects gut microorganisms and dietary interventions can help treat obesity and overweight. Our aim was to investigate the effect of quinoa supplementation on fecal microbial ecology of obese diabetic mice. Obese db/db mice were fed commercial diets with and without quinoa supplementation for eight weeks; non obese mice consuming non-supplemented diet served as lean-control. Fecal bacterial communities were analyzed using marker gene sequencing of 16S rRNA genes. Over 300 000 good-quality sequences were studied and assigned to 5774 different bacterial species (Operational Taxonomic Units at 97% similarity). Significant differences in bacterial abundances were found among the treatment groups, including some associated specifically with quinoa consumption. Analysis of weighted UniFrac distances revealed a distinctive clustering of lean microbial communities independently from obese-control and quinoa-supplemented mice (Analysis of Similarities, P < 0.01). Predicted functional profiles showed significant differences in 38 metabolic functions but most were due to a difference between lean samples compared to both obese-control and quinoa. Quinoa supplementation was associated with lower butyrate and succinic acid concentrations in cecum that were not necessarily more similar to those concentrations in lean mice. This study provides insight into the complex interactions between nutritional supplements and the gut microbiota thus informing future molecular analysis of the health benefits. PMID- 27127198 TI - Variation in coastal Antarctic microbial community composition at sub-mesoscale: spatial distance or environmental filtering? AB - Spatial environmental heterogeneity influences diversity of organisms at different scales. Environmental filtering suggests that local environmental conditions provide habitat-specific scenarios for niche requirements, ultimately determining the composition of local communities. In this work, we analyze the spatial variation of microbial communities across environmental gradients of sea surface temperature, salinity and photosynthetically active radiation and spatial distance in Fildes Bay, King George Island, Antarctica. We hypothesize that environmental filters are the main control of the spatial variation of these communities. Thus, strong relationships between community composition and environmental variation and weak relationships between community composition and spatial distance are expected. Combining physical characterization of the water column, cell counts by flow cytometry, small ribosomal subunit genes fingerprinting and next generation sequencing, we contrast the abundance and composition of photosynthetic eukaryotes and heterotrophic bacterial local communities at a submesoscale. Our results indicate that the strength of the environmental controls differed markedly between eukaryotes and bacterial communities. Whereas eukaryotic photosynthetic assemblages responded weakly to environmental variability, bacteria respond promptly to fine-scale environmental changes in this polar marine system. PMID- 27127199 TI - Toward cell-inspired materials that feel: measurements and modeling of mechanotransduction in droplet-based, multi-membrane arrays. AB - The droplet interface bilayer (DIB) was recently used to show that a 5 nm thick lipid membrane placed near a vibrating synthetic hair could transduce hair motion into electrical current. Herein, we study for the first time mechanoelectrical transduction of hair motion using multi-membrane DIB arrays formed with more than 2 droplets connected in series, and we introduce a transduction model to investigate how airflow across the hair generates current in a membrane-based hair cell. Measurements of sensing currents across every membrane in serial chains of up to 5 connected droplets demonstrate that perturbation of a single hair creates vibrations that propagate across several droplets, allowing for membranes that are not directly attached to the hair to still transduce its motion. Membranes positioned closest to the hair generate the largest currents, while those farther away produce less current due to energy loss from fluid damping. Inserting multiple hairs of different lengths into different droplets in the array yields sensing currents that exhibit multiple characteristic frequencies in addition to location specific current intensities, features that can be used to spatially localize mechanical perturbations. We also develop a transduction model that provides an order-of-magnitude approximation of the sensing current generated by a membrane in response to airflow across the hair. This model provides physical insights into how membrane-based materials can be used for sensing mechanical stimuli--just like nature does. PMID- 27127200 TI - Caregiving demands and caregivers' psychological outcomes: the mediating role of perceived injustice. AB - OBJECTIVES: This study hypothesized that higher caregiving demands are related to higher perceived injustice. Furthermore, this study investigated the mediating role of perceived injustice in the link between caregiving demands and caregivers' psychological well-being. DESIGN: A cross-sectional design. SETTING: The Pain Centre of the university medical centre. SUBJECTS: Participants were 184 family caregivers of patients with chronic musculoskeletal pain. MAIN MEASURES: Participants completed questionnaires that assessed caregiving demands (i.e. The Dutch Objective Burden Inventory), perceived injustice (i.e. The Injustice Experience Questionnaire), how much they considered different sources responsible for the injustice they experienced (i.e. A newly developed inventory), perceived burden (i.e. The Zarit Burden Interview), distress (i.e. The Depression, Anxiety, and Stress Scale), and anger (i.e. The Hostility subscale of the Symptom Checklist-90-Revised). RESULTS: The findings showed that caregiving demands are significantly related to perceived injustice in family caregivers (r = .44; P < .001). Only a small group of family caregivers considered the patient or themselves responsible, but more than half of the caregivers considered healthcare providers at least somewhat responsible for the unjust situation. Finally, perceived injustice mediated the association between caregiving demands and burden (b = .11, CI: .04-.23) and distress (b = .05, CI: .006-.12), but not anger (b = .008, CI: -.01-.06). CONCLUSION: The findings suggest that perceived injustice plays an important role in the well-being of family caregivers and caregivers' well-being may be improved by changing their perceptions about their caregiving tasks and their condition. PMID- 27127201 TI - Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation. AB - OBJECTIVE: Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activation. Here, we tested a novel hypothesis that mitochondrial reactive oxygen species (mtROS) serve as signaling mediators for EC activation in early atherosclerosis. APPROACH AND RESULTS: Metabolomics and transcriptomics analyses revealed that several lysophosphatidylcholine (LPC) species, such as 16:0, 18:0, and 18:1, and their processing enzymes, including Pla2g7 and Pla2g4c, were significantly induced in the aortas of apolipoprotein E knockout mice during early atherosclerosis. Using electron spin resonance and flow cytometry, we found that LPC 16:0, 18:0, and 18:1 induced mtROS in primary human aortic ECs, independently of the activities of nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, using confocal microscopy and Seahorse XF mitochondrial analyzer, we showed that LPC induced mtROS via unique calcium entry-mediated increase of proton leak and mitochondrial O2 reduction. In addition, we found that mtROS contributed to LPC-induced EC activation by regulating nuclear binding of activator protein-1 and inducing intercellular adhesion molecule-1 gene expression in vitro. Furthermore, we showed that mtROS inhibitor MitoTEMPO suppressed EC activation and aortic monocyte recruitment in apolipoprotein E knockout mice using intravital microscopy and flow cytometry methods. CONCLUSIONS: ATP synthesis-uncoupled, but proton leak-coupled, mtROS increase mediates LPC-induced EC activation during early atherosclerosis. These results indicate that mitochondrial antioxidants are promising therapies for vascular inflammation and cardiovascular diseases. PMID- 27127202 TI - Micro-RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor. AB - OBJECTIVE: Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)-driven TF expression and thrombogenicity in diabetes mellitus. APPROACH AND RESULTS: Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3' untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. CONCLUSIONS: Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus. PMID- 27127203 TI - Rare Genetic Variants and High-Density Lipoprotein: Marching to a Different Drum. PMID- 27127204 TI - Neonatal outcomes of waterbirth: a systematic review and meta-analysis. AB - INTRODUCTION: In 2015, 9% of babies born in the UK were delivered underwater. Waterbirth is increasing in popularity, despite uncertainty regarding its safety for neonates. This systematic review and meta-analysis appraises the existing evidence for neonatal outcomes following waterbirth. METHODS: A structured electronic database search was performed with no language restrictions. All comparative studies which reported neonatal outcomes following waterbirth, and that were published since 1995, were included. Quality appraisal was performed using a modified Critical Appraisal Skills Programme scoring system. The primary outcome was neonatal mortality. Data for each neonatal outcome were tabulated and analysed. Meta-analysis was performed for comparable studies which reported sufficient data. RESULTS: The majority of the 29 included studies were small, with limited follow-up and methodological flaws. They were mostly conducted in Europe and high-income countries. Reporting of data was heterogeneous. No significant difference in neonatal mortality, neonatal intensive care unit/special care baby unit admission rate, Apgar scores, umbilical cord gases or infection rates was found between babies delivered into water and on land. CONCLUSIONS: This systematic review and meta-analysis did not identify definitive evidence that waterbirth causes harm to neonates compared with land birth. However, there is currently insufficient evidence to conclude that there are no additional risks or benefits for neonates when comparing waterbirth and conventional delivery on land. PMID- 27127205 TI - What is new in the European and UK neonatal resuscitation guidance? PMID- 27127206 TI - Impacts of somatic mutations on gene expression: an association perspective. AB - Assessing the functional impacts of somatic mutations in cancer genomes is critical for both identifying driver mutations and developing molecular targeted therapies. Currently, it remains a fundamental challenge to distinguish the patterns through which mutations execute their biological effects and to infer biological mechanisms underlying these patterns. To this end, we systematically studied the association between somatic mutations in protein-coding regions and expression profiles, which represents an indirect measurement of impacts. We defined mutation features (mutation type, cluster and status) and built linear regression models to assess mutation associations with mRNA expression and protein expression. Our results presented a comprehensive landscape of the associations between mutation features and expression profile in multiple cancer types, including 62 genes showing mutation type associated expression changes, 21 genes showing mutation cluster associations and 51 genes showing mutation status associations. We revealed four characteristics of the patterns that mutations impact on expression. First, we showed that mutation type (truncation versus amino acid-altering mutations) was the most important determinant of expression levels. Second, we detected mutation clusters in well-studied oncogenes that were associated with gene expression. Third, we found both similarities and differences in association patterns existed within and across cancer types. Fourth, although many of the observed associations stay stable at both mRNA and protein expression levels, there are also novel associations uniquely observed at the protein level, which warrant future investigation. Taken together, our findings provided implications for cancer driver gene prioritization and insights into the functional consequences of somatic mutations. PMID- 27127207 TI - Using Large Diabetes Databases for Research. AB - There are an increasing number of clinical, administrative and trial databases that can be used for research. These are particularly valuable if there are opportunities for linkage to other databases. This paper describes examples of the use of large diabetes databases for research. It reviews the advantages and disadvantages of using large diabetes databases for research and suggests solutions for some challenges. Large, high-quality databases offer potential sources of information for research at relatively low cost. Fundamental issues for using databases for research are the completeness of capture of cases within the population and time period of interest and accuracy of the diagnosis of diabetes and outcomes of interest. The extent to which people included in the database are representative should be considered if the database is not population based and there is the intention to extrapolate findings to the wider diabetes population. Information on key variables such as date of diagnosis or duration of diabetes may not be available at all, may be inaccurate or may contain a large amount of missing data. Information on key confounding factors is rarely available for the nondiabetic or general population limiting comparisons with the population of people with diabetes. However comparisons that allow for differences in distribution of important demographic factors may be feasible using data for the whole population or a matched cohort study design. In summary, diabetes databases can be used to address important research questions. Understanding the strengths and limitations of this approach is crucial to interpret the findings appropriately. PMID- 27127208 TI - CALCULATION OF GAMMA SPECTRA IN A PLASTIC SCINTILLATOR FOR ENERGY CALIBRATIONAND DOSE COMPUTATION. AB - Plastic scintillation detectors have practical advantages in the field of dosimetry. Energy calibration of measured gamma spectra is important for dose computation, but it is not simple in the plastic scintillators because of their different characteristics and a finite resolution. In this study, the gamma spectra in a polystyrene scintillator were calculated for the energy calibration and dose computation. Based on the relationship between the energy resolution and estimated energy broadening effect in the calculated spectra, the gamma spectra were simply calculated without many iterations. The calculated spectra were in agreement with the calculation by an existing method and measurements. PMID- 27127209 TI - INDIVIDUALISED CALCULATION OF TISSUE IMPARTED ENERGY IN BREAST TOMOSYNTHESIS. AB - The imparted energy to the glandular tissue in the breast (glandular imparted energy, GIE) is proposed for an improved assessment of the individual radiation induced risk resulting from X-ray breast imaging. GIE is computed from an estimation of the quantity and localisation of glandular tissue in the breast. After a digital breast tomosynthesis (DBT) acquisition, the volumetric glandular content (volumetric breast density, VBD) is computed from the central X-ray projection. The glandular tissue distribution is determined by labelling the DBT voxels to ensure the conservation of the VBD. Finally, the GIE is calculated by Monte Carlo computation on the resulting tissue-labelled DBT volume. For verification, the method was applied to 10 breast-shaped digital phantoms made of different glandular spheres in an adipose background, and to a digital anthropomorphic phantom. Results were compared to direct GIE computations on the phantoms considered as 'ground-truth'. The major limitations in accuracy are those of DBT, in particular the limited z-resolution. However, for most phantoms, the results can be considered as acceptable. PMID- 27127210 TI - OPTIMISATION IN X-RAY AND MOLECULAR IMAGING 2015. PMID- 27127211 TI - THE MAYAK WORKER DOSIMETRY SYSTEM (MWDS 2013): A RE-ANALYSIS OF USTUR CASE 0269 TO DETERMINE WHETHER PLUTONIUM BINDS TO THE LUNGS. AB - Radionuclides in ionic form can become chemically bound in the airways of the lungs following dissolution of inhaled particulates in lung fluid. The presence of long-term binding can greatly increase lung doses from inhaled plutonium, particularly if it occurs in the bronchial and bronchiolar regions. However, the only published evidence that plutonium binding occurs in humans comes from an analysis of the autopsy and bioassay data of United States Transuranium and Uranium Registries Case 0269, a plutonium worker who experienced a very high (58 kBq) acute inhalation of plutonium nitrate. This analysis suggested a bound fraction of around 8 %, inferred from an unexpectedly low ratio of estimated total thoracic lymph node activity:total lung activity, at the time of death. However, there are some limitations with this study, the most significant being that measurements of the regional distribution of plutonium activity in the lungs, which provide more direct evidence of binding, were not available when the analysis was performed. The present work describes the analysis of new data, which includes measurements of plutonium activity in the alveolar-interstitial (AI) region, bronchial (BB) and bronchiolar (bb) regions, and extra-thoracic (ET) regions, at the time of death. A Bayesian approach is used that accounts for uncertainties in model parameter values, including particle transport clearance, which were not considered in the original analysis. The results indicate that a long-term bound fraction between 0.4 and 0.7 % is required to explain this data, largely because plutonium activity is present in the extra-thoracic (ET2), bronchial and bronchiolar airways at the time of death. PMID- 27127212 TI - Understanding lichenicolous heterobasidiomycetes: new taxa and reproductive innovations in Tremella s.l. AB - Four new lichenicolous Tremella species are described and characterized morphologically and molecularly. Tremella celata grows on Ramalina fraxinea, inducing the formation of inconspicuous galls, and having hyphae with incomplete clamps. Tremella endosporogena develops intrahymenially in the apothecia of Lecanora carpinea, having single-celled basidia and clampless hyphae. Tremella diederichiana is the name proposed for a species micromorphologically close to T. christiansenii but inducing the formation of small, pale galls on the thallus and apothecia of Lecidea aff. erythrophaea Tremella variae grows on Lecanora varia thallus, instead of on the apothecia, as do the other known Tremella species parasitizing Lecanora s.l. Phylogenetic relationships and host specificity of these species are investigated and compared with other taxa that show morphological resemblances, phylogenetic affinities or similar hosts. The formation of mitotic conidia inside old basidia (endospores), which is a poorly known reproductive strategy in the Basidiomycota, is also a distinctive character of Tremella endosporogena A discussion on the reproductive role and systematic implications of endospores is included. PMID- 27127213 TI - Cultural and cytological characterization of Dacryopinax primogenitus, a new species in the Dacrymycetes with a fully sequenced genome. AB - A Dacryopinax species that was cultured in Costa Rica and fruited in the laboratory provided DNA for the first sequenced genome for the Dacrymycetes. Here we characterize the isolate morphologically and cytologically and name it D. primogenitus Molecular sequences from the nuclear large subunit gene and internal transcribed spacer indicated that it is closely related to the South American D. indacocheae with which it agrees structurally. Both species form conidia on the basidiocarp, and D primogenitus also forms them on the mycelium. Unlike previous reports for the Dacrymycetales postmeiotic nuclear division results in uninucleate basidiospores and six residual nuclei in the basidium after basidiospore discharge. Ultrastructural analysis shows the characteristic septal pore apparatus for the class and endogenous origin of the epibasidia/sterigmata, which may be a common occurrence in Dacrymycetes and the early diverging orders of its sister class, the Agaricomycetes. PMID- 27127214 TI - Erratum. PMID- 27127217 TI - Vascular Targeted Radioimmunotherapy for the Treatment of Glioblastoma. AB - : Glioblastoma is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 mo despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium of glioblastoma with cytotoxic short-range, high-energy alpha-particles would be an effective therapeutic approach. METHODS: E4G10, an antibody directed at an epitope of monomeric vascular endothelium cadherin that is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow, was labeled with alpha-particle-emitting 225Ac. Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac E4G10 radioimmunoconstruct in a transgenic Nestin-tumor virus A (Ntva) mouse model of high-grade glioblastoma. Histologic analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in Ntva mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent. RESULTS: 225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Antivascular alpha-particle therapy of glioblastoma in the transgenic Ntva model resulted in significantly improved survival compared with controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 d (vs. 9 d for vehicle-treated animals). Histologic analyses showed a remodeled glioblastoma vascular microenvironment. CONCLUSION: Targeted alpha-particle antivascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic glioblastoma mouse model. PMID- 27127218 TI - Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide 1 Receptor Ligands Using Antagonistic Tracers. AB - The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic beta-cell mass and detection of benign insulinomas. Using GLP 1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, (125)I-Bolton-Hunter-Exendin(9-39)NH2 ((125)I-BH-Ex(9-39)NH2), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. METHODS: The affinity and biodistribution of Ex(9-39)NH2-based antagonists, modified with DOTA or NODAGA chelators at positions Lys(27) and Lys(40) and labeled with (68)Ga and (125)I-BH-Ex(9-39)NH2, were compared with the reference GLP-1 receptor agonist [Nle(14),Lys(40)(Ahx-DOTA (68)Ga)NH2]Ex-4. The inhibitory concentration of 50% (IC50) values were determined using autoradiography on human tissues with (125)I-GLP-1(7-36)NH2 as a radioligand. Pharmacokinetics and PET imaging were studied in nude mice bearing rat Ins-1E tumors. RESULTS: Conjugation of DOTA and NODAGA chelators at positions Lys(27) and Lys(40) of Ex(9-39)NH2 resulted in a distinct loss of affinity toward GLP-1 receptor in vitro. Among the studied antagonists, [Lys(40)(NODAGA (nat)Ga)NH2]Ex(9-39) showed the lowest IC50 value (46.7 +/- 16.3 nM). The reference agonist [Nle(14),Lys(40)(Ahx-DOTA)NH2]Ex-4 demonstrated the highest affinity (IC50 = 0.9 +/- 0.3 nM). Biodistribution of [Nle(14),Lys(40)(Ahx-DOTA (68)Ga)NH2]Ex-4 at 1 h after injection demonstrated 40.2 +/- 8.2 percentage injected activity per gram (%IA/g) uptake in Ins-1E tumor, 12.5 +/- 2.2 %IA/g in the pancreas, and 235.8 +/- 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys(40)(NODAGA-(68)Ga)NH2]Ex(9-39) showed only 2.2 +/- 0.2 %IA/g uptake in Ins 1E tumor, 1.0 +/- 0.1 %IA/g in the pancreas, and 78.4 +/- 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, (125)I-BH-Ex(9-39)NH2 showed tumor uptake (42.5 +/- 8.1 %IA/g) comparable to the agonist and 28.8 +/- 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of (125)I BH-Ex(9-39)NH2 was low, only 12.1 +/- 1.4 %IA/g at 1 h after injection. The tumor to-kidney ratio of (125)I-BH-Ex(9-39)NH2 was improved 20-fold. CONCLUSION: Our results suggest that iodinated Ex(9-39)NH2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumor-to kidney ratio (125)I-BH-Ex(9-39)NH2 may offer higher sensitivity in the detection of insulinomas and imaging of beta-cell mass in diabetic patients. Further studies with (124)I-BH-Ex(9-39)NH2 are warranted. PMID- 27127219 TI - Automatic Extraction of Myocardial Mass and Volume Using Parametric Images from Dynamic Nongated PET. AB - Dynamic cardiac PET is used to quantify molecular processes in vivo. However, measurements of left ventricular (LV) mass and volume require electrocardiogram gated PET data. The aim of this study was to explore the feasibility of measuring LV geometry using nongated dynamic cardiac PET. METHODS: Thirty-five patients with aortic-valve stenosis and 10 healthy controls underwent a 27-min (11)C acetate PET/CT scan and cardiac MRI (CMR). The controls were scanned twice to assess repeatability. Parametric images of uptake rate K1 and the blood pool were generated from nongated dynamic data. Using software-based structure recognition, the LV wall was automatically segmented from K1 images to derive functional assessments of LV mass (mLV) and wall thickness. End-systolic and end-diastolic volumes were calculated using blood pool images and applied to obtain stroke volume and LV ejection fraction (LVEF). PET measurements were compared with CMR. RESULTS: High, linear correlations were found for LV mass (r = 0.95), end systolic volume (r = 0.93), and end-diastolic volume (r = 0.90), and slightly lower correlations were found for stroke volume (r = 0.74), LVEF (r = 0.81), and thickness (r = 0.78). Bland-Altman analyses showed significant differences for mLV and thickness only and an overestimation for LVEF at lower values. Intra- and interobserver correlations were greater than 0.95 for all PET measurements. PET repeatability accuracy in the controls was comparable to CMR. CONCLUSION: LV mass and volume are accurately and automatically generated from dynamic (11)C-acetate PET without electrocardiogram gating. This method can be incorporated in a standard routine without any additional workload and can, in theory, be extended to other PET tracers. PMID- 27127220 TI - Left Ventricular Function Assessment Using 2 Different Cadmium-Zinc-Telluride Cameras Compared with a gamma-Camera with Cardiofocal Collimators: Dynamic Cardiac Phantom Study and Clinical Validation. AB - This study compared two SPECT cameras with cadmium-zinc-telluride (CZT) detectors to a conventional Anger camera with cardiofocal collimators for the assessment of left ventricular (LV) function in a phantom and patients. METHODS: A gated dynamic cardiac phantom was used. Eighteen acquisitions were processed on each CZT camera and the conventional camera. The total number of counts within a myocardial volume of interest varied from 0.25 kcts to 1.5 Mcts. Ejection fraction was set to 33%, 45%, or 60%. Volume, LV ejection fraction (LVEF), regional wall thickening, and motion (17-segment model) were assessed. One hundred twenty patients with a low pretest likelihood of coronary artery disease and normal findings on stress perfusion SPECT were retrospectively analyzed to provide the reference limits for end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction, and regional function for each camera model. RESULTS: In the phantom study, for each ejection fraction value, volume was higher for the CZT cameras than for the conventional camera, resulting in a decreased but more accurate LVEF (all P < 0.001). In clinical data, body-surface-indexed EDV and ESV (mL/m(2)) were higher for one of the CZT cameras (Discovery NM 530c) than for the other (D-SPECT) or the conventional camera (respectively, 40.5 +/- 9.2, 37 +/- 7.9, and 35.8 +/- 6.8 for EDV [P < 0.001] and 12.5 +/- 5.3, 9.4 +/- 4.2, and 8.3 +/- 4.4 for ESV [P < 0.001]), resulting in a significantly decreased LVEF: 70.3% +/- 9.1% vs. 75.2% +/- 8.1% vs. 77.8% +/- 9.3%, respectively (P < 0.001). CONCLUSION: The new CZT cameras yielded global LV function results different from those yielded by the conventional camera. LV volume was higher for the Discovery NM 530c than for the D-SPECT or the conventional camera, leading to decreased LVEF in healthy subjects. These differences should be considered in clinical practice and warrant the collection of a specific reference database. PMID- 27127222 TI - Evaluation of a Fluorescent and Radiolabeled Hybrid Somatostatin Analog In Vitro and in Mice Bearing H69 Neuroendocrine Xenografts. AB - In the treatment of neuroendocrine tumors (NETs), complete surgical removal of malignancy is generally desirable, because it offers curative results. Preoperative guidance with radiolabeled somatostatin analogs, commonly used for NET diagnosis and preoperative planning, is limited by its low resolution, with the risk that tumor margins and small metastases will be incompletely resected with subsequent recurrence. A single hybrid probe combining radiotracer and optical dye would enable high-resolution optical guidance, also during surgery. In the current study, the hybrid labeled somatostatin analog Cy5-DTPA-Tyr(3) octreotate (DTPA is diethylene triamine pentaacetic acid) was synthesized and evaluated for its ability to specifically trace NET cells in vitro and in an animal model. The performance of the hybrid tracer was compared with that of octreotate with only radiolabel or only optical label. METHODS: The binding affinity and internalization capacity of Cy5-DTPA-Tyr(3)-octreotate were assessed in vitro. Biodistribution profiles and both nuclear and optical in vivo imaging of Cy5-(111)In -DTPA-Tyr(3)-octreotate were performed in NET-bearing mice and compared with the performance of (111)In-DTPA-Tyr(3)-octreotate. RESULTS: In vitro studies showed a low receptor affinity and internalization rate for Cy5 DTPA-Tyr(3)-octreotate. The dissociation constant value was 387.7 +/- 97.9 nM for Cy5-DTPA-Tyr(3)-octreotate, whereas it was 120.5 +/- 18.1 nM for DTPA-Tyr(3) octreotate. Similarly, receptor-mediated internalization reduced from 33.76% +/- 1.22% applied dose for DTPA-Tyr(3)-octreotate to 1.32% +/- 0.02% applied dose for Cy5-DTPA-Tyr(3)-octreotate. In contrast, in vivo and ex vivo studies revealed similar tumor uptake values of Cy5-(111)In-DTPA-Tyr(3)-octreotate and (111)In DTPA-Tyr(3)-octreotate (6.93 +/- 2.08 and 5.16 +/- 1.27, respectively). All organs except the kidneys showed low background radioactivity, with especially low activities in the liver, and high tumor-to-tissue ratios were achieved-both favorable for the tracer's toxicity profile. Hybrid imaging in mice confirmed that the nuclear and fluorescence signals colocalized. CONCLUSION: The correlation between findings with the optical and the nuclear probes underlines the potential of combining SPECT imaging with fluorescence guidance and shows the promise of this novel hybrid peptide for preoperative and intraoperative imaging of NET. PMID- 27127223 TI - Molecular Imaging of Ovarian Cancer. AB - Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Over the past decade, medical imaging has played an increasingly valuable role in the diagnosis, staging, and treatment planning of the disease. In this "Focus on Molecular Imaging" review, we seek to provide a brief yet informative survey of the current state of the molecular imaging of ovarian cancer. The article is divided into sections according to modality, covering recent advances in the MR, PET, SPECT, ultrasound, and optical imaging of ovarian cancer. Although primary emphasis is given to clinical studies, preclinical investigations that are particularly innovative and promising are discussed as well. Ultimately, we are hopeful that the combination of technologic innovations, novel imaging probes, and further integration of imaging into clinical protocols will lead to significant improvements in the survival rate for ovarian cancer. PMID- 27127224 TI - Anatomic or Functional Evaluation as an Initial Test for Stable Coronary Artery Disease: A Propensity Score Analysis. AB - Little data are available to compare the clinical implications of coronary angiography (CAG) or myocardial perfusion imaging (MPI) as an initial evaluation for stable coronary artery disease (CAD). METHODS: From national health insurance claims data in South Korea, patients aged 18 y or older without a known history of CAD, who underwent CAG or MPI for the diagnosis of stable CAD between 2009 and 2013, were enrolled. Patients were divided into CAG (n = 117,134) and MPI (n = 19,932) groups. The primary endpoint, defined as a composite of all-cause death and myocardial infarction, was compared by a propensity score analysis between the 2 groups. RESULTS: There was a significant increase (39%) in the annual rate of CAG from 23,985 in 2009-2010 to 33,373 in 2012-2013. However, a substantial reduction (41%) in the annual MPI rate was also noted from 6,389 in 2009-2010 to 3,790 in 2012-2013. During the follow-up period (median, 2.4 y; interquartile range, 1.5-3.5), coronary revascularization was more frequently performed in the CAG group (adjusted hazard ratio [aHR] of CAG, 24.15; 95% confidence interval [CI], 19.66-29.68; P < 0.001). However, the incidence of the primary endpoint was significantly higher in the CAG group (aHR, 1.26; 95% CI, 1.17-1.36; P < 0.001). The individual endpoints of death (aHR, 1.16; 95% CI, 1.06-1.25; P = 0.001) and myocardial infarction (aHR, 1.95; 95% CI, 1.60-2.36; P < 0.001) were also higher in the CAG group. CONCLUSION: As an initial diagnostic test in patients with stable CAD, MPI is associated with a better clinical outcomes than CAG. PMID- 27127225 TI - Imaging Reveals the Connection Between Spontaneous Coronary Plaque Ruptures, Atherothrombosis, and Myocardial Infarctions in HypoE/SRBI-/- Mice. AB - The hyperlipidemic mouse model HypoE/SRBI(-/-) has been shown to develop occlusive coronary atherosclerosis followed by myocardial infarctions and premature deaths in response to high-fat, high-cholesterol diet (HFC). However, the causal connection between myocardial infarctions and atherosclerotic plaque rupture events in the coronary arteries has not been investigated so far. The objective of this study was to assess whether diet-induced coronary plaque ruptures trigger atherothrombotic occlusions, resulting in myocardial infarctions in HFC-fed HypoE/SRBI(-/-) mice. METHODS: HypoE/SRBI(-/-) mice were characterized with respect to the individual dynamics of myocardial infarctions and features of infarct-related coronary atherosclerosis by serial noninvasive molecular and functional imaging, histopathology, and a pharmaceutical intervention. Detailed histologic analysis of whole mouse hearts was performed when spontaneously occurring acute myocardial infarctions were diagnosed by imaging. RESULTS: Using the imaging-triggered approach, we discovered thrombi in 32 (10.8%) of all 296 atherosclerotic coronary plaques in 14 HFC-fed HypoE/SRBI(-/-) mice. These thrombi typically were found in arteries presenting with inflammatory plaque phenotypes. Acetylsalicylic acid treatment did not attenuate the development of atherosclerotic coronary plaques but profoundly reduced the incidence of premature deaths, the number of thrombi (7 in 249 plaques), and also the degree of inflammation in the culprit lesions. CONCLUSION: HFC-induced ruptures of coronary plaques trigger atherothrombosis, vessel occlusions, myocardial infarctions, and sudden death in these mice. Thus, the HypoE/SRBI(-/-) mouse model mimics major features of human coronary heart disease and might therefore be a valuable model for the investigation of molecular and cellular parameters driving plaque rupture-related events and the development of new interventional approaches. PMID- 27127226 TI - How to Achieve Approval of Radiolabeled-PSMA Diagnostic and Therapeutic Agents. PMID- 27127227 TI - Response Assessment Criteria and Their Applications in Lymphoma: Part 1. AB - The effectiveness of cancer therapy, both in individual patients and across populations, requires a systematic and reproducible method for evaluating response to treatment. Early efforts to meet this need resulted in the creation of numerous guidelines for quantifying posttherapy changes in disease extent, both anatomically and metabolically. Over the past few years, criteria for disease response classification have been developed for specific cancer histologies. To date, the spectrum of disease broadly referred to as lymphoma is perhaps the most common for which disease response classification is used. This review article provides an overview of the existing response assessment criteria for lymphoma and highlights their respective methodologies and validities. Concerns over the technical complexity and arbitrary thresholds of many of these criteria, which have impeded the long-standing endeavor of standardizing response assessment, are also discussed. PMID- 27127228 TI - Social conformity is due to biased stimulus processing: electrophysiological and diffusion analyses. AB - Hundreds of studies have found that humans' decisions are strongly influenced by the opinions of others, even when making simple perceptual decisions. In this study, we aimed to clarify whether this effect can be explained by social influence biasing (early) perceptual processes. We employed stimulus evoked potentials, lateralized readiness potentials (LRPs) and a diffusion model analysis of reaction time data to uncover the neurocognitive processes underlying social conformity in perceptual decision-making. The diffusion model analysis showed that social conformity was due to a biased uptake of stimulus information and accompanied by more careful stimulus processing. As indicated by larger N1 amplitudes, social influence increased early attentional resources for stimulus identification and discrimination. Furthermore, LRP analyses revealed that stimulus processing was biased even in cases of non-conformity. In conclusion, our results suggest that the opinion of others can cause individuals to selectively process stimulus information supporting this opinion, thereby inducing social conformity. This effect is present even when individuals do not blindly follow the majority but rather carefully process stimulus information. PMID- 27127229 TI - The EZH1-SUZ12 complex positively regulates the transcription of NF-kappaB target genes through interaction with UXT. AB - Unlike other members of the polycomb group protein family, EZH1 has been shown to positively associate with active transcription on a genome-wide scale. However, the underlying mechanism for this behavior still remains elusive. Here, we report that EZH1 physically interacts with UXT, a small chaperon-like transcription co activator. UXT specifically interacts with EZH1 and SUZ12, but not EED. Similar to upon knockdown of UXT, knockdown of EZH1 or SUZ12 through RNA interference in the cell impairs the transcriptional activation of nuclear factor (NF)-kappaB target genes induced by TNFalpha. EZH1 deficiency also increases TNFalpha-induced cell death. Interestingly, chromatin immunoprecipitation and the following next generation sequencing analysis show that H3K27 mono-, di- and tri-methylation on NF-kappaB target genes are not affected in EZH1- or UXT-deficient cells. EZH1 also does not affect the translocation of the p65 subunit of NF-kappaB (also known as RELA) from the cytosol to the nucleus. Instead, EZH1 and SUZ12 regulate the recruitment of p65 and RNA Pol II to target genes. Taken together, our study shows that EZH1 and SUZ12 act as positive regulators for NF-kappaB signaling and demonstrates that EZH1, SUZ12 and UXT work synergistically to regulate pathway activation in the nucleus. PMID- 27127230 TI - Citation classics in neurointerventional research: a bibliometric analysis of the 100 most cited articles. AB - BACKGROUND AND PURPOSE: The number of citations that an article has received can be used to evaluate its impact on the scientific community. This study aimed to identify the 100 most cited articles in the field of neurointervention and to analyze their characteristics. MATERIALS AND METHODS: We selected the 669 journals that were considered potentially to publish neurointervention articles based on the database of Journal Citation Reports. Using the Web of Science citation search tool, we identified the 100 most cited articles relevant to neurointervention within the selected journals. Each article was evaluated for several characteristics including publication year, journal, journal category, impact factor, number of citations, number of citations per year, authorship, department, institution, country, type of article, and topic. RESULTS: The number of citations for the top 100 articles ranged from 1912 to 170 (mean 363.4) and citations per year ranged from 271.0 to 4.1 (mean 40.0). The majority of articles were published in clinical neurology journals (63%), were published in 2000-2009 (39%), originated in the USA (45%), were original articles (95%), and dealt with endovascular treatment of cerebral aneurysm (42%). The Department of Radiology, University of California School of Medicine (n=12) was the leading institution and Vinuela F (n=11) was the most prolific author. CONCLUSIONS: Our study presents a detailed list and analysis of the 100 most cited articles in the field of neurointervention and provides a historical perspective on the scientific progress in this field. PMID- 27127231 TI - Novel methodology to replicate clot analogs with diverse composition in acute ischemic stroke. AB - BACKGROUND: Translational research on clot composition may be advanced by the use of clot analogs for the preclinical evaluation of mechanical thrombectomy devices. This work describes a novel set of clot analogs to represent a diverse range of fibrin and red blood cell (RBC) compositions for use in acute ischemic stroke (AIS) occlusion models. METHOD: Fresh whole blood obtained from ovine species was used to create seven different clot analog types. Five replicates were formed for each clot type. Varying amounts of whole blood constituents were mixed with thrombotic factors to create clots of varying compositions. Following histological processing, five sections from each clot were stained with H&E and Martius Scarlet Blue. Fibrin, RBC and white blood cell compositions were quantified. RESULTS: Histological examination demonstrated that the clot types had a distinct RBC and fibrin composition. No significant difference in composition was shown between replicates (p>0.05), indicating that the method of clot formation was reproducible. Percentage fibrin composition of the clot types was 1%, 8%, 31%, 38%, 64%, 79%, and 100%. A significant difference in fibrin and RBC composition between clot types was observed (p<0.05). CONCLUSIONS: Seven different clot types were developed to replicate common AIS thrombi. These clot analogs may be beneficial for the preclinical evaluation of endovascular therapies, and may be applied to interventional technique training. PMID- 27127232 TI - Reducing the Density and Number of Tobacco Retailers: Policy Solutions and Legal Issues. AB - INTRODUCTION: Because higher density of tobacco retailers is associated with greater tobacco use, U.S. communities seek ways to reduce the density and number of tobacco retailers. This approach can reduce the concentration of tobacco retailers in poorer communities, limit youth exposure to tobacco advertising, and prevent misleading associations between tobacco and health messaging. METHODS: Communities can reduce the density and number of tobacco retailers by imposing minimum distance requirements between existing retailers, capping the number of retailers in a given geographic area, establishing a maximum number of retailers proportional to population size, and prohibiting sales at certain types of establishments, such as pharmacies, or within a certain distance of locations serving youth. Local governments use direct regulation, licensing, or zoning laws to enact these changes. We analyze each approach under U.S. constitutional law to assist communities in selecting and implementing one or more of these methods. There are few published legal opinions that address these strategies in the context of tobacco control. But potential constitutional challenges include violations of the Takings Clause of the Fifth Amendment, which protects property owners from onerous government regulations, and under the Fourteenth Amendment's Equal Protection and Due Process Clauses, which protect business owners from arbitrary or unreasonable regulations that do not further a legitimate government interest. CONCLUSION: Because there is an evidentiary basis linking the density of tobacco retailers to smoking rates in a community, courts are likely to reject constitutional challenges to carefully crafted laws that reduce the number of tobacco retailers. IMPLICATIONS: Our review of the relevant constitutional issues confirms that local governments have the authority to utilize laws and policies to reduce the density and number of tobacco retailers in their communities, given existing public health data. The analysis guides policy makers in crafting laws that comply with constitutional requirements by outlining the most important procedures and evidentiary justifications to use in development, implementation, and enforcement. This perspective also highlights the importance of reviewing state constitutions, statutes, and municipal codes and getting local input from attorneys and community stakeholders to assess the likely success of some methods over others. PMID- 27127233 TI - Occupational activity across adult life and its association with grip strength. PMID- 27127235 TI - Extracellular electron transfer systems fuel cellulose oxidative degradation. AB - Ninety percent of lignocellulose-degrading fungi contain genes encoding lytic polysaccharide monooxygenases (LPMOs). These enzymes catalyze the initial oxidative cleavage of recalcitrant polysaccharides after activation by an electron donor. Understanding the source of electrons is fundamental to fungal physiology and will also help with the exploitation of LPMOs for biomass processing. Using genome data and biochemical methods, we characterized and compared different extracellular electron sources for LPMOs: cellobiose dehydrogenase, phenols procured from plant biomass or produced by fungi, and glucose-methanol-choline oxidoreductases that regenerate LPMO-reducing diphenols. Our data demonstrate that all three of these electron transfer systems are functional and that their relative importance during cellulose degradation depends on fungal lifestyle. The availability of extracellular electron donors is required to activate fungal oxidative attack on polysaccharides. PMID- 27127234 TI - Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. AB - The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life threatening infections characterized by an acutely exacerbated immune response. PMID- 27127236 TI - NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. AB - Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve life span in mammals. PMID- 27127237 TI - Native functionality in triple catalytic cross-coupling: sp3 C-H bonds as latent nucleophiles. AB - The use of sp(3) C-H bonds--which are ubiquitous in organic molecules--as latent nucleophile equivalents for transition metal-catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize alpha-amino and alpha-oxy sp(3) C-H bonds in both cyclic and acyclic systems. PMID- 27127238 TI - Large optical nonlinearity of indium tin oxide in its epsilon-near-zero region. AB - Nonlinear optical phenomena are crucial for a broad range of applications, such as microscopy, all-optical data processing, and quantum information. However, materials usually exhibit a weak optical nonlinearity even under intense coherent illumination. We report that indium tin oxide can acquire an ultrafast and large intensity-dependent refractive index in the region of the spectrum where the real part of its permittivity vanishes. We observe a change in the real part of the refractive index of 0.72 +/- 0.025, corresponding to 170% of the linear refractive index. This change in refractive index is reversible with a recovery time of about 360 femtoseconds. Our results offer the possibility of designing material structures with large ultrafast nonlinearity for applications in nanophotonics. PMID- 27127240 TI - Greg Miller. PMID- 27127242 TI - Commentary. PMID- 27127239 TI - Conversion of human fibroblasts into functional cardiomyocytes by small molecules. AB - Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells into specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds that we term 9C. The chemically induced cardiomyocyte-like cells uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters and enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to chemically induced cardiomyocyte-like cells. This pharmacological approach to lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells. PMID- 27127241 TI - A Girl with Bone Sclerosis and Fracture. PMID- 27127243 TI - Commentary. PMID- 27127246 TI - Chronically Hypocalcemic Patient with Hypercalcemia. PMID- 27127245 TI - Now You See It, Now You Don't: Unidentified Plasma Amino Acid Peak. PMID- 27127244 TI - Optimization and Standardization of Circulating MicroRNA Detection for Clinical Application: The miR-Test Case. AB - BACKGROUND: The identification of circulating microRNAs (miRNAs) in the blood has been recently exploited for the development of minimally invasive tests for the early detection of cancer. Nevertheless, the clinical transferability of such tests is uncertain due to still-insufficient standardization and optimization of methods to detect circulating miRNAs in the clinical setting. METHODS: We performed a series of tests to optimize the quantification of serum miRNAs that compose the miR-Test, a signature for lung cancer early detection, and systematically analyzed variables that could affect the performance of the test. We took advantage of a large-scale (>1000 samples) validation study of the miR Test that we recently published, to evaluate, in clinical samples, the effects of analytical and preanalytical variables on the quantification of circulating miRNAs and the clinical output of the signature (risk score). RESULTS: We developed a streamlined and standardized pipeline for the processing of clinical serum samples that allows the isolation and analysis of circulating miRNAs by quantitative reverse-transcription PCR, with a throughput compatible with screening trials. The major source of analytical variation came from RNA isolation from serum, which could be corrected by use of external (spike-in) or endogenous miRNAs as a reference for normalization. We also introduced standard operating procedures and QC steps to check for unspecific fluctuations that arise from the lack of standardized criteria in the collection or handling of the samples (preanalytical factors). CONCLUSIONS: We propose our methodology as a reference for the development of clinical-grade blood tests on the basis of miRNA detection. PMID- 27127247 TI - Push-button Phlebotomy. PMID- 27127248 TI - The Comfort of Pattern Recognition. PMID- 27127249 TI - Rationalism, Science, and Freedom of Speech: Voltaire. PMID- 27127250 TI - David Mechanic: Professional Zombie Hunter. AB - Within the fields of medicine and sociology, the descriptor "profession" (along with its brethren: profession, professionalization, and professionalism) has had a rich etymological history, with terms taking on different meanings at different times-sometimes trespassing into shibboleth and jargon. This etymological journey has co-evolved with the career of David Mechanic to whom this issue of the Journal of Health Politics, Policy and Law is devoted. We exploit a provocative metaphor applied to Mechanic's work on the challenges facing medicine as a profession as a playful exegesis on what we call "profession" to excavate an ensconced and encrusted domain of health jargon operating at the tensive interface of society and modern medical work. PMID- 27127251 TI - Bringing the Social Sciences to Health Policy: An Appreciation of David Mechanic. AB - David Mechanic has been a pioneering leader in the social and behavioral sciences of health, health services, and health and mental health policy for more than fifty years. One of David's most distinctive qualities has been his vision in identifying trends and defining new research areas and perspectives in health care policy. His early work on how methods of physician payment by capitation and fee-for-service in England and the United States affected physicians' responses to patients and patient care addressed present challenges and many ongoing studies of payment mechanisms. His papers on rationing of health care established a framework for examining alternative allocation mechanisms and just decision making. Influential papers dealt with risk selection, policy challenges in managed care, reducing racial disparities, trust relationships between patients, doctors, and the public and health institutions, and the predicaments of health reform. Focusing on the implementation of the Affordable Care Act, David explored its opportunities and challenges especially in providing comprehensive and effective behavioral health services. A hallmark of his work has been his redirecting our attention to the most severely ill and those in greatest need. Less visible is the leadership and institution building endeavors and the many honors David has received. PMID- 27127252 TI - Medicaid Long-Term Care: State Variation and the Intergovernmental Lobby. AB - Medicaid is vastly more important than Medicare or private insurance in funding long-term care (LTC). However, states vary tremendously in their commitment to Medicaid LTC. This article advances knowledge of the origins, nature, and implications of this variation. After examining the degree of variation in state spending on Medicaid LTC, we show how federal policy has over the past fifty years steadily increased state discretion to shape these services. This decentralization largely reflects the potency of the intergovernmental lobby governors and other state officials-in influencing federal policy. While fueling state variation, the intergovernmental lobby has also provided valuable political support that has helped Medicaid grow and resist retrenchment. After considering policy options that could mitigate Medicaid LTC inequities rooted in state differences, we assess how the catalytic forces that have fueled growth in Medicaid LTC may be insufficient to protect the program from future erosion. PMID- 27127253 TI - Reform of the Individual Insurance Market in New Jersey: Lessons for the Affordable Care Act. AB - The individual health insurance market has played a small but important role in providing coverage to those without access to group insurance or public programs. With implementation of the Affordable Care Act (ACA), the individual market has attained a more prominent role. However, achieving accessible and affordable coverage in this market is a long-standing challenge, in large part due to the threat of adverse risk selection. New Jersey pursued comprehensive reforms beginning in the 1990s to achieve a stable, accessible, and affordable individual market. We review how adverse risk selection can pose a challenge to achieving such objectives in the individual health insurance market. We follow this discussion by describing the experience of New Jersey through three rounds of legislative reform and through the first year of the implementation of the ACA coverage provisions. While the New Jersey reforms did not require individuals to purchase coverage, its experiences with direct and indirect market subsidies and regulations guiding plan design, issuance, and rating have important implications for how the ACA may achieve its coverage goals in the absence of the controversial individual purchase mandate. PMID- 27127254 TI - Incomplete Markets and Imperfect Institutions: Some Challenges Posed by Trust for Contemporary Health Care and Health Policy. AB - As contemporary health policy promotes evidence-based practices using targeted incentives, policy makers may lose track of vital aspects of care that are difficult to measure. For more than a half century, scholars have recognized that these latter aspects play a crucial role in high-quality care and equitable health system performance but depend on the potentially frail reed of providers' trustworthiness: that is, their commitment to facets and outcomes of care not easily assessed by external parties. More recently, early experience with pay for performance in health settings suggests that enhancing financial rewards for the measurable undermines providers' commitment to the unmeasurable, degrading the trustworthiness of their practices. Reformers have looked to revised professional norms or reorganized practice arrangements to bolster the intrinsic motivations required for trustworthiness. We suggest here that these responses are likely to prove inadequate. We propose that they be complemented by a renewed policy-making commitment to nonprofit ownership among health care providers, insurers, and integrated delivery systems. We identify some of the concerns raised in the past with ownership-based policies and propose a set of responses. If these are pursued in combination, they hold the promise of a sustainable ownership-based policy reform for the United States. PMID- 27127255 TI - The Troubled History of Psychiatry's Quest for Specificity. AB - Over the course of the nineteenth century, medical disciplines replaced holistic conceptions of body and mind with specific diagnoses that were unrelated to the qualities and circumstances of the individuals who harbored them. Despite periodic attempts from the late nineteenth through the mid-twentieth centuries to implement diagnostic systems based on the principle of specificity, psychiatric diagnoses remained undifferentiated, overlapping, and capacious. The need for medical legitimacy, compatibility with a biomedical model, and conditions that third parties would reimburse led psychiatry to replace the psychodynamically oriented DSM-I and DSM-II with the radically empiricist DSM-III in 1980. This manual emphasized explicit measurement, symptom-based entities, and homogeneous categories that were compatible with the specific disorders embraced in the rest of medicine. Yet the diagnostic system that the DSM-III launched was incongruent with the underlying nature of the continuous, fluid, and intersecting conditions with which psychiatry deals. The widespread institutionalization of the specific diagnostic system in psychiatric practice, however, prevented any thoroughgoing revisions when the DSM-5 was published in 2013. The result is an impasse between psychiatry's classificatory system and the need for scientific progress in understanding the causes of and treatments for mental disorders. PMID- 27127256 TI - Regulating and Paying for Hospice and Palliative Care: Reflections on the Medicare Hospice Benefit. AB - Hospice began as a social movement outside of mainstream medicine with the goal of helping those dying alone and in unbearable pain in health care institutions. The National Hospice Study, undertaken to test whether hospice improved dying cancer patients' quality of life while saving Medicare money, found hospice care achieved comparable outcomes to traditional cancer care and was less costly as long as hospice lengths of stay were not too long. In 1982, before study results were final, Congress created a Medicare hospice benefit under a capitated per diem payment system restricting further treatment. In 1986 the benefit was extended to beneficiaries living in nursing homes. This change resulted in longer average lengths of stay, explosive growth in the number of hospices, particularly of the for-profit variety, and increases in total Medicare expenditures on hospice care. An increasingly high proportion of beneficiaries receive hospice care. However, over 30 percent are served fewer than seven days before they die, while very long stays are also increasingly common. These and other factors raise quality concerns about hospice being disconnected from the rest of the health care system. We offer suggestions regarding how hospice could be better integrated into the broader health care delivery system. PMID- 27127257 TI - Using the Courts to Shape Medicaid Policy: Olmstead v. L.C. by Zimring and Its Community Integration Legacy. AB - In Olmstead v. L.C. by Zimring, the United States Supreme Court addressed the relationship between the Americans with Disabilities Act (ADA), a landmark in US civil rights law, and the Medicaid program. Olmstead holds that qualified individuals with disabilities who are protected by the ADA have the right to receive publicly funded services in community-integrated treatment settings and that medically unnecessary institutionalization violates the ADA. But the Court had to wrestle with the extent to which the ADA requires state Medicaid programs to make deep and structural reforms in how long-term care services are organized, financed, and delivered. From a strictly legal perspective, Olmstead's impact has been limited by the fact that the ADA does not require fundamental alterations in public programs. Despite this fact, Olmstead remains a watershed decision in US disability law that has helped spur transformational changes in how Medicaid addresses community-based long-term care. PMID- 27127258 TI - Stigma as an Unrecognized Determinant of Population Health: Research and Policy Implications. AB - Stigma processes play an underrecognized role in the distribution of life chances, influencing health through the production of disadvantage and the induction of stress. Policies enact stigma processes, mitigate them, or ignore them. If each of these two statements is correct, the intersection of stigma and policy demands our attention. We propose a change of perspective from an approach that considers one stigmatized status and one outcome at a time to a perspective that considers the full range of stigmatized statuses and outcomes so as to reveal stigma's full impact. Concerning the second statement, literature addressing "structural stigma" provides compelling evidence that policy enacts stigma and harms health in some circumstances and mitigates stigma and improves health in others. In addition to the effects of active policies, we also bring attention to policy inattention-doing nothing. A core feature of stigma is a discounting-a mattering less-that allows and even fosters policy inattention toward the concerns of stigmatized groups. We end by engaging David Mechanic and Linda H. Aiken's ideas concerning how social science influences policy by changing how people think about problems and hope that our consideration of stigma and policy might ultimately have such a consequence. PMID- 27127259 TI - Opportunities and Challenges for Payment Reform: Observations from Massachusetts. AB - Policy makers and private health plans are expanding their efforts to implement new payment models that will encourage providers to improve quality and deliver health care more efficiently. Over the past five years, payment reforms have progressed faster in Massachusetts than in any other state. The reasons include a major effort by Blue Cross Blue Shield of Massachusetts to implement global payment, the presence of large integrated systems willing to take on financial risk, and a supportive state policy environment. By 2014, thirty-seven percent of Massachusetts's residents enrolled in health plans were covered under risk-based payment models tied to global budgets. But the expansion of payment reform in Massachusetts slowed between 2012 and 2015 because some commercial enrollment shifted from risk-based health maintenance organization products to fee-for service preferred provider organization (PPO) plans, and the state Medicaid program fell short of its payment reform goals. Provider groups will not fully commit to population-based clinical models if they believe it will result in large reductions in fee-for-service revenue. The use of alternative payment models will accelerate in 2016 when Blue Cross begins implementing PPO payment reforms, but it is unknown how quickly other payers will follow. Massachusetts's experience illustrates the complexity of payment reform in pluralistic health care markets and the need for complementary efforts by public and private stakeholders. PMID- 27127261 TI - Implementing the Affordable Care Act: The Promise and Limits of Health Care Reform. AB - The Obama administration has confronted a formidable array of obstacles in implementing the Affordable Care Act (ACA). The ACA has overcome those obstacles to substantially expand access to health insurance, though significant problems with its approach have emerged. What does the ACA's performance to date tell us about the possibilities and limits of health care reform in the United States? I identify key challenges in ACA implementation-the inherently disruptive nature of reform, partisan polarization, the limits of "near universal" coverage, complexity, and divided public opinion-and analyze how these issues have shaped its evolution. The article concludes by exploring the political and policy challenges that lie ahead for the ACA. PMID- 27127262 TI - Partisanship, Dysfunction, and Racial Fears: The New Normal in Health Care Policy? AB - Partisan politics snarled both the passage and the implementation of the Affordable Care Act (ACA). This essay examines partisanship's effects on health policy and asks whether the ACA experience was an exception or the new political normal. Partisanship itself has been essential for American democracy, but American institutions were not designed to handle its current form-ideologically pure, racially sorted, closely matched parties playing by "Gingrich rules" before a partisan media. The new partisanship injects three far-reaching changes into national health policy: an unprecedented lack of closure, a decline in the traditional political arts of compromise and bargaining, and a failure to define and debate alternative health policies. We can get a better sense of how far partisanship reaches by turning to state health policies. The highly charged national debate has migrated into some of the states; others retain the traditional politics of compromise and problem solving. There are preliminary indications that the difference lies in the dynamics of race and ethnicity. PMID- 27127263 TI - Economics and the Transformation of the Mental Health System. AB - Mental illnesses provide a difficult set of challenges to American health and social institutions. Those challenges have been a continuous concern of David Mechanic's over the course of his career. In this article we trace the development of modern economic and organizational structures that drive the delivery of mental health care in the early part of the twenty-first century. We show how the nature of mental disorders themselves and the treatment for addressing those illnesses pose fundamental difficulties to health care organizational and financing structures. We analyze the factors that have caused the dramatic changes in how American society has addressed mental illnesses over the past fifty years. Specifically, we note the central influence that mainstream health, income support, and disability programs have had in shaping mental health care. We argue that the interaction of the unique features of mental illnesses and changes in mainstream health and social policy led mental health care to evolve so differently from general medical care. PMID- 27127264 TI - The Rise of Primary Care Physicians in the Provision of US Mental Health Care. AB - Primary care physicians have assumed an increasingly important role in US outpatient mental health care. They are providing an increasing volume of outpatient mental health services, prescribing a growing number and variety of psychotropic medications, and treating patients with a broader array of mental health conditions. These trends, which run counter to a general trend toward specialization and subspecialization within US health care, place new strains on the clinical competencies of primary care physicians. They also underscore the importance of implementing more effective models of collaboration between primary care physicians and mental health specialists. Several elements of the Affordable Care Act provide options for financing and organizing the delivery of integrated general medical and behavioral services. Such integrated services have the potential to improve access and quality of outpatient mental health care for a range of psychiatric disorders. Because people with severe and persisting mental disorders commonly require a higher-level medical expertise than is readily available within primary care as well as a complex array of social services, separate specialized mental health will likely continue to play a vitally important role in caring for this population. PMID- 27127265 TI - Evolving Concepts of Patient-Centered Care and the Assessment of Patient Care Experiences: Optimism and Opposition. AB - In his seminal work on health care quality, Avedis Donabedian noted that patient satisfaction was a key indicator of health care quality, and in the 1970s and 1980s a great deal of research explored the determinants of patient satisfaction. Subsequently, attention shifted toward assessing care experiences, and there is now a large body of evidence related to the reliability and validity of survey based assessments of care. As the use of such surveys has increased, so too have concerns about the validity and uses of such surveys. The available research, however, indicates that such surveys are reliable, valid, correlated across individuals and settings with other quality indicators, and predictive of better outcomes. Patient experiences are now routinely measured, and substantial effort is being devoted to providing high-quality patient-centered care. Providing patient-centered care need not divert resources away from other quality improvement efforts. Improving the infrastructure supporting certain aspects of care may have broad effects because system changes can influence multiple outcomes. Thus, rather than detract from general quality improvement efforts, making changes that facilitate patient-centered care may lead to broader improvements. There is good reason to be optimistic that our health care system will increasingly be "patient centered." PMID- 27127266 TI - Social Determinants and Disparities in Health: Their Crucifixion, Resurrection, and Ultimate Triumph(?) in Health Policy. AB - David Mechanic has been a principal founder of modern sociological and social science approaches to health, especially in relation to health policy. These approaches have since the 1950s and 1960s resurrected ideas that had currency in the mid-nineteenth century but seemed crucified, dead, and buried by the rise of modern biomedicine from the mid-nineteenth century through the mid-twentieth century. Problems and lacunae in purely biomedical approaches to health in the later twentieth century, along with developments of new biopsychosocial approaches to health, have spawned a return toward ideas of Rudolf Virchow and mid-nineteenth-century social medicine that social determinants and disparities are major drivers of population health. Since individual health and population health constitute the major determinants of health care utilization and expenditures, social determinants and disparities in health are arguably the foundation of a new "demand-side" health policy that can resolve America's paradoxical health policy crisis of spending increasingly more than any nation on health care and insurance yet achieving increasingly worsening health outcomes relative to virtually all developed countries and some developing ones as well, something that current "supply-side" health policy, including Obamacare, cannot do, important as it is for expanding access to health insurance and care. PMID- 27127267 TI - Needed Interventions to Reduce Racial/Ethnic Disparities in Health. AB - Large racial/ethnic and socioeconomic status (SES) differences in health persist in the United States. Eliminating these health disparities is a public health challenge of our time. This article addresses what is needed for social and behavioral interventions to be successful. We draw on important insights for reducing social inequalities in health that David Mechanic articulated more than a decade ago in his article "Disadvantage, Inequality, and Social Policy." We begin by outlining the challenge that interventions that have the potential to improve health at the population level can widen social inequalities in health. Next, given that there are racial differences in SES at every level of SES, we review research on race/ethnicity-related aspects of social experience that can contribute to racial inequalities in SES and health. We then explore what is needed for social and behavioral interventions to be successful in addressing disparities and consider the significance of race/ethnicity in designing and developing good policies to address this added dimension of inequality. We conclude that there is a pressing need to develop a scientific research agenda to identify how to build and sustain the political will needed to create policy to eliminate racial/ethnic health disparities. PMID- 27127268 TI - Dachsous1b cadherin regulates actin and microtubule cytoskeleton during early zebrafish embryogenesis. PMID- 27127269 TI - Fault Lines. PMID- 27127270 TI - Child health care: adequate training for all UK GPs is long overdue. PMID- 27127271 TI - Preoperative blood pressure measurement: what should GPs be doing? PMID- 27127272 TI - Day surgery: implications for general practice. PMID- 27127273 TI - Front door surgeons: the rise of consultant-delivered acute surgical care. PMID- 27127274 TI - Understanding and managing dental and orofacial pain in general practice. PMID- 27127275 TI - After Achilles. PMID- 27127276 TI - Fishing. PMID- 27127277 TI - Correction. PMID- 27127278 TI - Viewpoint: Healthcare professional education: its role in influencing career choices in primary care. PMID- 27127279 TI - Sitting is the new smoking: where do we stand? PMID- 27127280 TI - General practice in meltdown. PMID- 27127281 TI - The GP waiting room under examination. PMID- 27127282 TI - Yonder: Self-harm, repeat prescribing, deprescribing, and worry. PMID- 27127283 TI - Maurice Wood: an appreciation. PMID- 27127284 TI - Exhibition: Health and the Body: the Ingram Collection at the RCGP: A Medical Story in the Home of General Practice. PMID- 27127285 TI - Postcards from India. PMID- 27127286 TI - Poetry: Sonnet on pain. PMID- 27127287 TI - BJGP Library: The Code of The Woosters: A Perfect Escape. PMID- 27127288 TI - Home and away. PMID- 27127289 TI - Good practice in shared care for inflammatory arthritis. PMID- 27127290 TI - The Roundhouse: an alternative model for primary care. PMID- 27127291 TI - Data and performance: can education and health learn from each other? PMID- 27127292 TI - Atomic data: James Mackenzie Lecture 2015. PMID- 27127293 TI - Glaucoma: the patient's perspective. PMID- 27127295 TI - Swimming in H2O: two parts heart + one part obsession. PMID- 27127294 TI - Revisiting the continuum model of tendon pathology: what is its merit in clinical practice and research? AB - The pathogenesis of tendinopathy and the primary biological change in the tendon that precipitates pathology have generated several pathoaetiological models in the literature. The continuum model of tendon pathology, proposed in 2009, synthesised clinical and laboratory-based research to guide treatment choices for the clinical presentations of tendinopathy. While the continuum has been cited extensively in the literature, its clinical utility has yet to be fully elucidated. The continuum model proposed a model for staging tendinopathy based on the changes and distribution of disorganisation within the tendon. However, classifying tendinopathy based on structure in what is primarily a pain condition has been challenged. The interplay between structure, pain and function is not yet fully understood, which has partly contributed to the complex clinical picture of tendinopathy. Here we revisit and assess the merit of the continuum model in the context of new evidence. We (1) summarise new evidence in tendinopathy research in the context of the continuum, (2) discuss tendon pain and the relevance of a model based on structure and (3) describe relevant clinical elements (pain, function and structure) to begin to build a better understanding of the condition. Our goal is that the continuum model may help guide targeted treatments and improved patient outcomes. PMID- 27127297 TI - Mannick JA, Lochte HL Jr, Ashley CA, Thomas ED, Ferrebee JW. Autografts of bone marrow in dogs after lethal total-body radiation. Blood. 1960;15(2):255-266. PMID- 27127296 TI - Exercise and pregnancy in recreational and elite athletes: 2016 evidence summary from the IOC expert group meeting, Lausanne. Part 1-exercise in women planning pregnancy and those who are pregnant. PMID- 27127298 TI - Glucocorticoid selection for pediatric ALL. PMID- 27127299 TI - HLH susceptibility: genetic lesions add up. PMID- 27127300 TI - Not all subclones matter in CLL. PMID- 27127301 TI - Pathogenic role of B-cell receptor signaling and canonical NF-kappaB activation in mantle cell lymphoma. AB - To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-kappaB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-kappaB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib mediated inhibition of NF-kappaB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-kappaB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors. PMID- 27127304 TI - Supplements such as fish oils improve antidepressant effectiveness, review finds. PMID- 27127302 TI - Protease-activated receptors in hemostasis. AB - Protease signaling in cells elicits multiple physiologically important responses via protease-activated receptors (PARs). There are 4 members of this family of G protein-coupled receptors (PAR1-4). PARs are activated by proteolysis of the N terminus to reveal a tethered ligand. The rate-limiting step of PAR signaling is determined by the efficiency of proteolysis of the N terminus, which is regulated by allosteric binding sites, cofactors, membrane localization, and receptor dimerization. This ultimately controls the initiation of PAR signaling. In addition, these factors also control the cellular response by directing signaling toward G-protein or beta-arrestin pathways. PAR1 signaling on endothelial cells is controlled by the activating protease and heterodimerization with PAR2 or PAR3. As a consequence, the genetic and epigenetic control of PARs and their cofactors in physiologic and pathophysiologic conditions have the potential to influence cellular behavior. Recent studies have uncovered polymorphisms that result in PAR4 sequence variants with altered reactivity that interact to influence platelet response. This further demonstrates how interactions within the plasma membrane can control the physiological output. Understanding the structural rearrangement following PAR activation and how PARs are allosterically controlled within the plasma membrane will determine how best to target this family of receptors therapeutically. The purpose of this article is to review how signaling from PARs is influenced by alternative cleavage sites and the physical interactions within the membrane. Going forward, it will be important to relate the altered signaling to the molecular arrangement of PARs in the cell membrane and to determine how these may be influenced genetically. PMID- 27127305 TI - The Growing Gap in Life Expectancy: Using the Future Elderly Model to Estimate Implications for Social Security and Medicare. PMID- 27127303 TI - APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. AB - Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-kappaB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor beta, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-kappaB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM. PMID- 27127306 TI - Long-range electrothermal fluid motion in microfluidic systems. AB - AC electrothermal flow (ACEF) is the fluid motion created as a result of Joule heating induced temperature gradients. ACEF is capable of performing major microfluidic operations, such as pumping, mixing, concentration, separation and assay enhancement, and is effective in biological samples with a wide range of electrical conductivity. Here, we report long-range fluid motion induced by ACEF, which creates centimeter-scale vortices. The long-range fluid motion displays a strong voltage dependence and is suppressed in microchannels with a characteristic length below ~300 MUm. An extended computational model of ACEF, which considers the effects of the density gradient and temperature-dependent parameters, is developed and compared experimentally by particle image velocimetry. The model captures the essence of ACEF in a wide range of channel dimensions and operating conditions. The combined experimental and computational study reveals the essential roles of buoyancy, temperature rise, and associated changes in material properties in the formation of the long-range fluid motion. Our results provide critical information for the design and modeling of ACEF based microfluidic systems toward various bioanalytical applications. PMID- 27127307 TI - A Fast Experimental Scanner for Proton CT: Technical Performance and First Experience with Phantom Scans. AB - We report on the design, fabrication, and first tests of a tomographic scanner developed for proton computed tomography (pCT) of head-sized objects. After extensive preclinical testing, pCT is intended to be employed in support of proton therapy treatment planning and pre-treatment verification in patients undergoing particle-beam therapy. The scanner consists of two silicon-strip telescopes that track individual protons before and after the phantom, and a novel multistage scintillation detector that measures a combination of the residual energy and range of the proton, from which we derive the water equivalent path length (WEPL) of the protons in the scanned object. The set of WEPL values and the associated paths of protons passing through the object over a 360 degrees angular scan are processed by an iterative, parallelizable reconstruction algorithm that runs on modern GP-GPU hardware. In order to assess the performance of the scanner, we have performed tests with 200 MeV protons from the synchrotron of the Loma Linda University Medical Center and the IBA cyclotron of the Northwestern Medicine Chicago Proton Center. Our first objective was calibration of the instrument, including tracker channel maps and alignment as well as the WEPL calibration. Then we performed the first CT scans on a series of phantoms. The very high sustained rate of data acquisition, exceeding one million protons per second, allowed a full 360 degrees scan to be completed in less than 10 minutes, and reconstruction of a CATPHAN 404 phantom verified accurate reconstruction of the proton relative stopping power in a variety of materials. PMID- 27127308 TI - The Mechanisms of Alcohol Control. AB - A substantial economics literature documents that tighter alcohol controls reduce alcohol-related harms, but far less is known about mechanisms. We use the universe of Canadian mortality records to document that Canada's Minimum Legal Drinking Age (MLDA) significantly reduces mortality rates of young men but has much smaller effects on women. Using drinking data that are far more detailed than in prior work, we document that the MLDA substantially reduces 'extreme' drinking among men but not women. Our results suggest that alcohol control efforts targeting young adults should focus on reducing extreme drinking behavior. PMID- 27127309 TI - Attachment Security in Three-Year-Olds who Entered Substitute Care in Infancy. AB - This study assessed relations among number of out-of-home placement changes, time in caregivers' care, caregiver type (i.e., foster parent, adoptive parent, kinship relation, and biological parent), child gender, and caregiver-child Emotional Availability (EA) as predictive of child attachment security when children were 3 years old in a sample of 104 caregivers and children. Children entered court-ordered care by six months of age. On average, children at the age of three spent 30 months with their caregivers, and nearly half of them were adopted by that time. Child attachment was assessed using the Attachment Q-set (Waters & Deane, 1985), and caregiver-child EA was assessed using the EA Scales, 4th edition (Biringen, 2008). Sixty-six percent of children at age 3 showed secure attachments with caregivers, and EA subscale scores were also relatively high on average. The study predictor variables of EA Caregiver Sensitivity, Child Responsiveness, and Child Involvement predicted attachment security, with girls more likely to be securely attached to their substitute caregivers at age three than boys. Study limitations and directions for future research are discussed. PMID- 27127310 TI - Potential for measurement of the distribution of DNA folds in complex environments using Correlated X-ray Scattering. AB - In vivo chromosomal behavior is dictated by the organization of genomic DNA at length scales ranging from nanometers to microns. At these disparate scales, the DNA conformation is influenced by a range of proteins that package, twist and disentangle the DNA double helix, leading to a complex hierarchical structure that remains undetermined. Thus, there is a critical need for methods of structural characterization of DNA that can accommodate complex environmental conditions over biologically relevant length scales. Based on multiscale molecular simulations, we report on the possibility of measuring supercoiling in complex environments using angular correlations of scattered X-rays resulting from X-ray free electron laser (xFEL) experiments. We recently demonstrated the observation of structural detail for solutions of randomly oriented metallic nanoparticles [D. Mendez et al., Philos. Trans. R. Soc. B360 (2014) 20130315]. Here, we argue, based on simulations, that correlated X-ray scattering (CXS) has the potential for measuring the distribution of DNA folds in complex environments, on the scale of a few persistence lengths. PMID- 27127311 TI - The revised guidelines of the Medical Council of India for academic promotions: Need for a rethink. PMID- 27127312 TI - Contemplation on marking scheme for Type X multiple choice questions, and an illustration of a practically applicable scheme. AB - Ever since its inception 100 years back, multiple choice items have been widely used as a method of assessment. It has certain inherent limitations such as inability to test higher cognitive skills, element of guesswork while answering, and issues related with marking schemes. Various marking schemes have been proposed in the past but they are not balanced, skewed, and complex, which are based on mathematical calculations which are typically not within the grasp of medical personnel. Type X questions has many advantages being easy to construct, can test multiple concepts/application/facets of a topic, cognitive skill of various level of hierarchy can be tested, and unlike Type K items, they are free from complicated coding. In spite of these advantages, they are not in common use due to complicated marking schemes. This is the reason we explored the aspects of methods of evaluation of multiple correct options multiple choice questions and came up with the simple, practically applicable, nonstringent but logical scoring system for the same. The rationale of the illustrated marking scheme is that it takes into consideration the distracter recognition ability of the examinee rather than relying on the ability only to select the correct response. Thus, examinee's true knowledge is tested, and he is rewarded accordingly for selecting a correct answer and omitting a distracter. The scheme also penalizes for not recognizing a distracter thus controlling guessing behavior. It is emphasized that if the illustrated scoring scheme is adopted, then Type X questions would come in common practice. PMID- 27127313 TI - Carrot (Daucus carota L.): Nephroprotective against gentamicin-induced nephrotoxicity in rats. AB - OBJECTIVES: Daucus carota L.(DC) commonly known as carrot, folkorically used as ethnomedicine to treat nephrosis and other urinary disorders. Hence, the present study was aimed to investigate the nephroprotective effects of ethanolic root extract of DC against gentamicin-induced nephrotoxicity in Albino Wistar rats. METHODS: Nephrotoxicity in rats was induced by intraperitoneal administration of gentamicin (100 mg/kg/day) for 8 days. Rats of either sex were divided into four groups (n = 6). Group 1 served as control that received normal saline (i.p.) whereas Group 2 (GM) was treated with gentamicin which served as gentamicin intoxicated group. Group 3-4 (DC200, DC 400) were pretreated with DC at doses of 200 mg/kg and 400 mg/kg (p.o.), respectively, 1 h before the gentamicin intoxication. Following treatment, the nephroprotective effects of DC were evaluated by using serum levels of urea, blood urea nitrogen (BUN), uric acid, and creatinine levels; change in body weight and wet kidney weight along with the histological observations among the experimental groups. RESULTS: Gentamicin intoxication induced elevated serum urea, BUN, uric acid, and creatinine levels which was found to be significantly (P < 0.01) decreased in a dose-dependent manner in groups received DC which was also evidenced by the histological observations. CONCLUSION: DC showed a significant nephroprotective effect in a dose-dependent manner by ameliorating the gentamicin-induced nephrotoxicity and thus authenticates its ethnomedicinal use. PMID- 27127314 TI - Halometasone monohydrate (0.05%) in occupational contact dermatitis. AB - OBJECTIVE: The impact of occupational contact dermatitis (OCD) is often underestimated because of underreporting, and its management is also inadequate, especially in developing countries. Topical corticosteroids have remained the first line treatment but till date, there is no study on efficacy and safety of halometasone in OCD, and there is a paucity of data on its comparative efficacy in allergic and irritant variety. This study aims to evaluate the efficacy and safety of halometasone in OCD and to compare its effect in allergic and irritant types of OCD. METHODS: The present study is a prospective, interventional, single arm clinical study conducted on 150 patients of OCD. Detailed history and clinical examination was done at baseline, and all enrolled patients underwent patch test with the Indian Standard Battery of allergens. Eczema severity was assessed by the Investigator's Global Assessment (IGA) scale, SCORing Atopic Dermatitis (SCORAD) index, and patient-oriented eczema measure (POEM). Change in quality of life was assessed by using the Dermatology Life Quality Index (DLQI). After baseline assessments, they were prescribed halometasone 0.05% ointment and were followed up after 4 weeks, and efficacy variables were evaluated. RESULTS: At follow-up, 19 patients were lost, and data of 131 patients were analyzed. After 4 weeks of halometasone therapy, there was statistically significant (P < 0.001) improvement in SCORAD index, IGA, POEM, and DLQI. Considering improvement in IGA as treatment success criteria, treatment was found to be successful in 87.8%. Subgroup analysis revealed no significant difference in effect of halometasone in allergic and irritant OCD. CONCLUSIONS: Halometasone is efficacious with a good safety profile in patients with OCD, and there is no significant difference in efficacy of the drug in allergic and irritant OCD. PMID- 27127315 TI - A randomized, comparative, open-label study of efficacy and tolerability of alfuzosin, tamsulosin and silodosin in benign prostatic hyperplasia. AB - OBJECTIVES: Benign prostatic hyperplasia (BPH) is a common and progressive disease affecting elderly males, often associated with lower urinary tract symptoms (LUTS). alpha1-blockers are the mainstay in symptomatic therapy of BPH. Because of their greater uroselectivity and minimal hemodynamic effects, alfuzosin, tamsulosin, and silodosin are generally preferred. The aim of this study was to compare the efficacy and tolerability of alfuzosin, tamsulosin, and silodosin in patients with BPH and LUTS. METHODS: Ninety subjects with BPH and LUTS were randomized into three groups of thirty in each, to receive alfuzosin sustained release (SR) 10 mg, tamsulosin 0.4 mg, or silodosin 8 mg for 12 weeks. The primary outcome measure was a change in the International Prostate Symptom Score (IPSS), and the secondary outcome measures were changes in individual subjective symptom scores, quality of life score (QLS), and peak flow rate (Qmax) from baseline. The treatment response was monitored at 2, 4, 8, and 12 weeks. RESULTS: IPSS improved by 88.18%, 72.12%, and 82.23% in alfuzosin SR, tamsulosin and silodosin groups (P < 0.001) at 12 weeks. Improvement in QLS was >75% in all the three groups (P < 0.001). A significant improvement in Qmax was seen with alfuzosin and tamsulosin (P = 0.025 and P < 0.001) but not with silodosin (P = 0.153). However, the intergroup differences in IPSS, QLS, and Qmax were not significant. Ejaculatory dysfunction was more common with silodosin and corrected QT (QTc) prolongation occurred only with alfuzosin (two subjects) and tamsulosin (three subjects). CONCLUSION: Alfuzosin, tamsulosin, and silodosin showed similar efficacy in improvement of LUTS secondary to BPH, with good tolerability, acceptability, and minimum hemodynamic adverse effects. Alfuzosin, tamsulosin, and silodosin are comparable in efficacy in symptomatic management of BPH. The occurrence of QTc prolongation in three subjects with tamsulosin in the present study is an unexpected adverse event as there are no reports of QTc prolongation with tamsulosin in any of the previous studies. PMID- 27127316 TI - Anti-inflammatory effect of aqueous extracts of spent Pleurotus ostreatus substrates in mouse ears treated with 12-O-tetradecanoylphorbol-13-acetate. AB - AIMS: To evaluate the application of spent Pleurotus ostreatus substrates, enriched or not with medicinal herbs, as a source of anti-inflammatory compounds. SUBJECTS AND METHODS: P. ostreatus was cultivated on five different substrates: Barley straw (BS) and BS combined 80:20 with medicinal herbs (Chenopodium ambrosioides L. [BS/CA], Rosmarinus officinalis L. [BS/RO], Litsea glaucescens Kunth [BS/LG], and Tagetes lucida Cav. [BS/TL]). The anti-inflammatory activity of aqueous extracts of spent mushroom substrates (SMSs) (4 mg/ear) was studied using an acute inflammation model in the mouse ear induced with 2.5 MUg/ear 12-O tetradecanoylphorbol13-acetate (TPA). RESULTS: Groups treated with BS/CA, BS/RO, and BS/LG aqueous extracts exhibited the best anti-inflammatory activity (94.0% +/- 5.5%, 92.9% +/- 0.6%, and 90.4% +/- 5.0% inhibition of auricular edema [IAO], respectively), and these effects were significantly different (P < 0.05) from that of the positive control indomethacin (0.5 mg/ear). BS/TL and BS were also able to reduce TPA-induced inflammation but to a lesser extent (70.0% +/- 6.7% and 43.5% +/- 6.6% IAO, respectively). CONCLUSIONS: Spent P. ostreatus substrate of BS possesses a slight anti-inflammatory effect. The addition of CA L. to mushroom substrate showed a slightly synergistic effect while RO L. had an additive effect. In addition, LG Kunth and TL Cav. enhanced the anti-inflammatory effect of SMS. However, to determine whether there is a synergistic or additive effect, it is necessary to determine the anti-inflammatory effect of each medicinal herb. PMID- 27127317 TI - Effect of ethanol extract of an ayurvedic preparation (Pathyadya Churna) on arthritis in rats. AB - OBJECTIVES: To study the anti-arthritic activity of Pathyadya Churna ethanol extract (PCE) in rats. MATERIALS AND METHODS: Formaldehyde (2% v/v) or complete Freund's adjuvant (CFA 0.l mL) was injected in the left hind paw of male Wistar rats to develop arthritis. These rats were treated with three doses (135, 270, and 540 mg/kg) of PCE and one dose (10 mg/kg) of indomethacin. Anti-arthritic activity of the extract was assessed by noting paw volumes, rheumatoid factor (RF), blood parameters, and histological changes. RESULTS: PCE treatment reduced paw swelling in arthritis caused by both formaldehyde and CFA. In CFA-treated rats, a significant decrease (P < 0.001) was seen in hemoglobin (13.92 g/dL to 9.97 g/dL), red blood cell count (7.32 million/mm(3) to 6.58 million/mm(3)), and packed cell volume (44.04% to 30.56%). There were also significant (P < 0.001) elevations in white blood cell count (8220/-11,420/mm(3)), platelets (2.46-4.15 lakhs/mL), erythrocyte sedimentation rate (3.76-8.03/60 min), RF (7.17-26.77 IU/mL), triglycerides (71.69-96.60 mg/dL), total cholesterol (96.85-145.05 mg/dL), low-density lipoprotein (53.11-109.60 mg/dL), and very low-density lipoprotein (14.34-19.32 mg/dL). In CFA-induced arthritic rats, high-density lipoprotein decreased significantly (29.40 mg/dL to 16.13 mg/dL). Marked changes were noted in the histology of ankles. Treatment with PCE significantly reversed all these hematological and histological changes in a dose-dependent manner. CONCLUSIONS: PCE has a significant anti-arthritic activity in rats and is free from toxic effects. PMID- 27127318 TI - A novel method of extraction of bamboo seed oil (Bambusa bambos Druce) and its promising effect on metabolic symptoms of experimentally induced polycystic ovarian disease. AB - OBJECTIVE: To evaluate the potential effect of bamboo seed oil in decreasing the major metabolic symptoms associated with letrozole-induced polycystic ovarian disease using female rat model. MATERIALS AND METHODS: A new method of microwave assisted extraction was developed. Female rats were grouped into four with six animals each. All rats were daily administered with letrozole (1 mg/kg b.wt.) for 21 days except control, and during this period, changes in estrous cycle were observed. After letrozole treatment, Group 2 was considered negative control, Groups 3 and 4 were treated orally with bamboo oil, 0.5 ml/kg b.wt. and 1 ml/kg b.wt., respectively, for 3 weeks (five consecutive estrus cycles). Various parameters such as estrus cycle, blood sugar level, lipid profile, and weights of reproductive system were determined. The characteristics of cystic ovaries were evaluated by histopathological studies. RESULTS: The isolated bamboo oil restored estrus cyclicity showed hypoglycemic and hypolipidemic effects. 1 ml/kg b.wt. of bamboo oil showed a marked glucose reduction from 254.04 +/- 2.08 to 92.6 +/- 1.63, and levels of total cholesterol, very low-density lipoprotein, triglyceride were reduced from 186.45 +/- 2.28, 30.07 +/- 2.36, 100.36 +/- 2.35 to 152.14 +/- 2.63, 25.94 +/- 1.66, 93.32 +/- 1.09, respectively. Histopathological results showed the presence of ovulation and recovery from cystic ovaries. CONCLUSION: A novel and promising drug was isolated in the treatment and maintenance of various metabolic symptoms associated with polycystic ovary disease. PMID- 27127319 TI - Enhanced therapeutic efficacy and amelioration of cisplatin-induced nephrotoxicity by quercetin in 1,2-dimethyl hydrazine-induced colon cancer in rats. AB - OBJECTIVE: The aim of quercetin treatment in combination of cisplatin (CP) induced nephrotoxicity as well on 1,2-dimethyl hydrazine (DMH)-induced colon cancer. MATERIALS AND METHODS: In this study, animals are exposed to DMH hydrochloride to induce colon cancer. In these groups, nephrotoxicity was assessed with the help of blood urea nitrogen, urea, and creatinine. The antitumor activity of quercetin and CP assessed with the help of number of aberrant crypts and foci formation. Tumor size in different treatment group determined with the help of vernier caliper. RESULTS: CP is one of the most widely used antineoplastic drugs against colon cancer, but it has a major dose limiting drawbacks of causing nephrotoxicity. Therefore, there is a need for a novel therapeutic regimen which will reduce the nephrotoxicity and enhance the anticancer activity of CP. The protective effect of quercetin on CP-induced nephrotoxicity is well-known. Moreover, quercetin is proven to have antitumor activity in colon cancer. Keeping all the facts in view, this study was conceived to evaluate the role of quercetin on therapeutic efficacy and nephrotoxicity of CP in DMH-induced colon cancer in male Sprague-Dawley rats. Treatment of quercetin with CP (7.5 mg/kg) prevents the CP-induced nephrotoxicity along with enhance the anticancer activity confirmed by the reduction of aberrant crypt foci number. Treatment of CP and quercetin alone leads to significant increase in the anticancer activity as compared to control colon tumor rats. CONCLUSION: In DMH induced colon cancer model, combination of quercetin and CP ameliorates CP induced nephrotoxicity as well as enhanced antitumor activity. PMID- 27127320 TI - Immunomodulatory activity of mefenamic acid in mice models of cell-mediated and humoral immunity. AB - OBJECTIVES: Previously, different nonsteroidal anti-inflammatory drugs (NSAIDs) have been evaluated for their potential immunomodulatory activities. Mefenamic acid is a well-known NSAID and is used in the treatment of musculoskeletal disorders, inflammation, fever, and pain. To the best of our knowledge, promising data regarding the immunomodulatory activity of mefenamic acid is scarce. Current study investigates the immunomodulatory activity of mefenamic acid in different models of cell-mediated and humoral immunity. MATERIALS AND METHODS: Immunomodulatory effects on cell-mediated immunity were evaluated using dinitrochlorobenzene-induced delayed type hypersensitivity (DTH) and cyclophosphamide-induce myelosuppression assays. While effects on humoral immunity were evaluated using hemagglutination assay and mice lethality test. RESULTS: Hematological analysis showed that mefenamic acid significantly reduced white blood cell count, red blood cell (RBC) count, hemoglobin content, lymphocytes levels, and neutrophils levels in healthy mice as compared with control, suggesting the immunosuppressive activity of mefenamic acid. Treatment with mefenamic acid also significantly reduced all the hematological parameters in cyclophosphamide-induced neutropenic mice, as compared with positive control group. We found that treatment with mefenamic acid significantly suppressed DTH after 24 h, 48 h, and 72 h, as compared with positive control group. Mefenamic acid treated groups showed a significant reduction in antibody titer against sheep RBCs as compared to control group, similar to the effect of cyclophosphamide. We also found increased mice lethality rate in mefenamic acid treated groups, as compared with positive control group. CONCLUSIONS: The results provided basic information of immunosuppression of mefenamic acid on both cell mediated and humoral immunity. PMID- 27127321 TI - Apoptotic activity and anti-Toxoplasma effects of artemether on the tachyzoites and experimental infected Vero and J774 cell lines by Toxoplasma gondii. AB - OBJECTIVES: Drugs used for toxoplasmosis have limited efficacy and also severe side effects. A new drug with good efficacy and limited side effects is need of the hour. We studied the effects of artemether on Toxoplasma gondii in vitro conditions. MATERIALS AND METHODS: Artemether (methyl-ether-qinghaosu) was tested for tachyzoites, J774, and Vero cell lines infected by T. gondii. For evaluating the effect of drugs on Vero cells infected with T. gondii, we designed two separate experiments; in the first experiment, the Vero cells were infected with tachyzoites and then treated with artemether; while in the second one, the tachyzoites were exposed to artemether and then Vero cells were infected with treated tachyzoites. For evaluating the apoptotic effect of artemether on tachyzoites and infected J774 macrophages cell line with T. gondii, we used flow cytometry method. Inhibitory concentration (IC50) was evaluated by intracellular replication of tachyzoites in Vero cells. RESULTS: IC50 for infected Vero cells with tachyzoites was determined as 49.13 MUg/ml. In pretreated tachyzoites with artemether before entering into Vero cells, IC50 was calculated as 13.15 MUg/ml. In both experiments, artemether showed a higher inhibitory effect than sulfadiazine (positive control). Artemether even at the highest concentrations only showed low cytotoxicity on Vero and J774 cell lines. Apoptosis in tachyzoites rise with an increasing concentration of artemether. CONCLUSIONS: Our findings indicate that artemether is effective to control the tachyzoites of T. gondii in vitro and maybe a good alternative drug for toxoplasmosis. PMID- 27127322 TI - Bedaquiline versus placebo for management of multiple drug-resistant tuberculosis: A systematic review. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is associated with significant morbidity and mortality. Bedaquiline is the first drug approved for treating MDR-TB. OBJECTIVES: We performed a systematic review and meta-analysis to summarize the totality of all available evidence on the efficacy of bedaquiline for the management of MDR-TB. MATERIALS AND METHODS: We searched the following PubMed and Cochrane Registry of Clinical Trials. Randomized controlled trials (RCTs) with a parallel design comparing bedaquiline versus any treatment for the management of MDR-TB in adults were eligible for inclusion. Data were pooled under a random effects model. RESULTS: Two trials published as three manuscripts with a total of 207 patients were included. As per the Cochrane risk of bias tool, majority of parameter were labeled as high or unclear risk of bias. Bedaquiline compared with placebo was associated with a statistically significant decrease in time to conversion of positive sputum culture to negative at 8 and 24 weeks with a significant increase in mortality on long-term follow-up. There was no difference in completion rates between bedaquiline and placebo. CONCLUSION: Bedaquiline is an effective treatment modality for MDR-TB but needs to be balanced against significant mortality. Future Phase 3 RCTs are needed to make a conclusive recommendation. PMID- 27127323 TI - Use of methimazole and risk of acute pancreatitis: A case-control study in Taiwan. AB - OBJECTIVE: Some cases of acute pancreatitis have been reported to be associated with use of methimazole. The aim of this study was to investigate the relationship between use of methimazole and risk of acute pancreatitis on the basis of a systematic analysis. METHODS: This was a population-based case-control study analyzing the database of the Taiwan National Health Insurance Program. There were 5764 individuals aged 20-84 years with a first attack of acute pancreatitis from 1998 to 2011 as the cases and 23,056 randomly selected sex- and age-matched individuals without acute pancreatitis as the controls. Use of methimazole was categorized as "never use" and "ever use." We estimated the relative risk of acute pancreatitis associated with the use of methimazole by calculating the odds ratio (OR) with 95% confidence interval (CI) using a multivariable logistic regression model. RESULTS: After adjustment for confounding factors, the OR of acute pancreatitis was 0.91 in individuals with ever use of methimazole, when compared with individuals with never use of methimazole (95% CI, 0.60-1.38). Unlike methimazole use, alcohol-related disease, biliary stone, cardiovascular disease, chronic obstructive pulmonary disease, diabetes mellitus, hepatitis B, hepatitis C, and hypertriglyceridemia were factors significantly associated with acute pancreatitis. CONCLUSIONS: Our study does not detect a substantial association between the use of methimazole and risk of acute pancreatitis on the basis of systematic analysis. There appears to be a discrepancy between case reports and our systematic analysis about the association between the use of methimazole and risk of acute pancreatitis. PMID- 27127324 TI - The effect of 5-aminosalicylic acid on renal ischemia-reperfusion injury in rats. AB - OBJECTIVES: Ischemia-reperfusion (IR) contributes to the development acute renal failure. Oxygen free radicals are involved in the pathophysiology of IR injury (IRI). This study was designed to investigate the effects of 5-aminosalicylic acid (5-ASA), which is known antioxidant agent, in IR-induced renal injury in rats. MATERIALS AND METHODS: Male Wistar albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h of reperfusion. 5-ASA (300 mg/kg, i.p) was administered prior to ischemia. After 24 h reperfusion, urine and blood samples were collected for the determination of creatinine (Cr) and nitric oxide (NO) levels, and renal samples were taken for the histological evaluation. RESULTS: Treatment with 5-ASA significantly decreased serum Cr and NO levels, also significantly increased urinary Cr level and decreased histopathological changes induced by IR. CONCLUSION: Treatment with 5-ASA had a beneficial effect on renal IRI. These results may indicate that 5-ASA exerts nephroprotective effects in renal IRI. PMID- 27127325 TI - Azithromycin buccal patch in treatment of chronic periodontitis. AB - AIM: This study aims to explore the clinical, microbiological, and biochemical impact of azithromycin (AZM) buccal patch in chronic generalized patients as a monotherapy as well as an adjunct to nonsurgical therapy. MATERIALS AND METHODS: A parallel design was used forty periodontitis patients were randomly allocated into five groups, namely Group 1 scaling root planing (SRP) alone, Group 2 (SRP + AZM patch group), Group 3 (SRP + AZM tablet group), Group 4 (AZM patch monotherapy), and Group 5 (AZM tablet as monotherapy). Plaque index, gingival bleeding index, modified gingival index, probing pocket depth (PPD), and clinical attachment level (CAL) were assessed at baseline and 21 and 90 days. Subgingival pooled plaque sample was collected to assess periodontopathogens like Porphyromonas gingivalis and Prevotella intermedia (Pi) by anaerobic culture method. Tumor necrosis factor alpha (TNF-alpha) was also evaluated at baseline and 21 days. Periodontal maintenance was performed in Group 1 until 90(th) day, and clinical parameter was assessed at the end of 90(th) day. RESULTS: SRP + AZM tablets showed greater reduction in clinical parameters (P < 0.05) AZM as monotherapy did not offer clinical benefits over SRP. Baseline data were compared at the end, i.e., 90(th) day a significant reduction in plaque scores, gingival bleeding, and PPD was observed however no significant gain in the clinical attachment was observed. CONCLUSION: The monotherapy resulted in no improvement of periodontal parameters, microbial parameters, and TNF-alpha level. It is safe to use AZM + SRP as a mode of nonsurgical treatment in periodontitis patients. PMID- 27127326 TI - The effect of methanolic extract of Buchanania lanzan Spreng seeds on hematological indices. AB - OBJECTIVE: The objective of the current study was carried out to investigate the effects of methanolic extract of Buchanania lanzan Spreng seeds on hematological indices. MATERIALS AND METHODS: Eighteen male albino Wistar rats were divided into three groups, six in each. Group I animals received distilled water, Group II and III were treated with an oral dose of 1000 mg oil/kg and 2000 mg oil/kg of extract, respectively, for 7 days. At the end of the study, blood was collected and evaluated for packed cell volume (PCV), hemoglobin (Hb) concentration, and red blood cell (RBC) and white blood cell (WBC) counts. RESULTS: There was a significant dose-dependent increase in the hematological indices such as PCV, Hb, RBC, and WBC count in the treatment group. CONCLUSIONS: The improvement of PCV, Hb, and RBC values is an indication of the anti-anemic effect which may be due to the stimulation of RBC production in bone marrow. Further, stimulated production of WBC could be as a result of possible stimulus of the immune system. Hence, this study confirms that the extract of B. lanzan could be useful for the treatment of anemia. PMID- 27127327 TI - Ranitidine-induced perioperative anaphylaxis: A rare occurrence and successful management. AB - Perioperative anaphylaxis is a rare and catastrophic event. Anaphylaxis during perioperative period changes the entire management plan for the patient. Since a large number of drugs are administered to the patient during the short span of time, it becomes difficult to identify the culprit drug. This has an impact on the management of the patients who have to undergo surgery. Ranitidine is considered a safe drug used in perioperative period; however, rarely it can lead to perioperative anaphylaxis. We present one such case of ranitidine-induced perioperative anaphylaxis which was successfully managed by early diagnosis and avoidance of drug. PMID- 27127328 TI - On the Fallacy of Quantitative Segmentation for T1-Weighted MRI. AB - T1-weighted magnetic resonance imaging (MRI) generates contrasts with primary sensitivity to local T1 properties (with lesser T2 and PD contributions). The observed signal intensity is determined by these local properties and the sequence parameters of the acquisition. In common practice, a range of acceptable parameters is used to ensure "similar" contrast across scanners used for any particular study (e.g., the ADNI standard MPRAGE). However, different studies may use different ranges of parameters and report the derived data as simply "T1 weighted". Physics and imaging authors pay strong heed to the specifics of the imaging sequences, but image processing authors have historically been more lax. Herein, we consider three T1-weighted sequences acquired the same underlying protocol (MPRAGE) and vendor (Philips), but "normal study-to-study variation" in parameters. We show that the gray matter/white matter/cerebrospinal fluid contrast is subtly but systemically different between these images and yields systemically different measurements of brain volume. The problem derives from the visually apparent boundary shifts, which would also be seen by a human rater. We present and evaluate two solutions to produce consistent segmentation results across imaging protocols. First, we propose to acquire multiple sequences on a subset of the data and use the multi-modal imaging as atlases to segment target images any of the available sequences. Second (if additional imaging is not available), we propose to synthesize atlases of the target imaging sequence and use the synthesized atlases in place of atlas imaging data. Both approaches significantly improve consistency of target labeling. PMID- 27127329 TI - Evaluation of Body-Wise and Organ-Wise Registrations For Abdominal Organs. AB - Identifying cross-sectional and longitudinal correspondence in the abdomen on computed tomography (CT) scans is necessary for quantitatively tracking change and understanding population characteristics, yet abdominal image registration is a challenging problem. The key difficulty in solving this problem is huge variations in organ dimensions and shapes across subjects. The current standard registration method uses the global or body-wise registration technique, which is based on the global topology for alignment. This method (although producing decent results) has substantial influence of outliers, thus leaving room for significant improvement. Here, we study a new image registration approach using local (organ-wise registration) by first creating organ-specific bounding boxes and then using these regions of interest (ROIs) for aligning references to target. Based on Dice Similarity Coefficient (DSC), Mean Surface Distance (MSD) and Hausdorff Distance (HD), the organ-wise approach is demonstrated to have significantly better results by minimizing the distorting effects of organ variations. This paper compares exclusively the two registration methods by providing novel quantitative and qualitative comparison data and is a subset of the more comprehensive problem of improving the multi-atlas segmentation by using organ normalization. PMID- 27127330 TI - Structural Functional Associations of the Orbit in Thyroid Eye Disease: Kalman Filters to Track Extraocular Rectal Muscles. AB - Pathologies of the optic nerve and orbit impact millions of Americans and quantitative assessment of the orbital structures on 3-D imaging would provide objective markers to enhance diagnostic accuracy, improve timely intervention and eventually preserve visual function. Recent studies have shown that the multi atlas methodology is suitable for identifying orbital structures, but challenges arise in the identification of the individual extraocular rectus muscles that control eye movement. This is increasingly problematic in diseased eyes, where these muscles often appear to fuse at the back of the orbit (at the resolution of clinical computed tomography imaging) due to inflammation or crowding. We propose the use of Kalman filters to track the muscles in three-dimensions to refine multi-atlas segmentation and resolve ambiguity due to imaging resolution, noise, and artifacts. The purpose of our study is to investigate a method of automatically generating orbital metrics from CT imaging and demonstrate the utility of the approach by correlating structural metrics of the eye orbit with clinical data and visual function measures in subjects with thyroid eye disease. The pilot study demonstrates that automatically calculated orbital metrics are strongly correlated with several clinical characteristics. Moreover, the superior, inferior, medial and lateral rectus muscles obtained using Kalman filters are each correlated with different categories of functional deficit. These findings serve as foundation for further investigation in the use of CT imaging in the study, analysis and diagnosis of ocular diseases, specifically thyroid eye disease. PMID- 27127331 TI - A Bayesian Framework for Early Risk Prediction in Traumatic Brain Injury. AB - Early detection of risk is critical in determining the course of treatment in traumatic brain injury (TBI). Computed tomography (CT) acquired at admission has shown latent prognostic value in prior studies; however, no robust clinical risk predictions have been achieved based on the imaging data in large-scale TBI analysis. The major challenge lies in the lack of consistent and complete medical records for patients, and an inherent bias associated with the limited number of patients samples with high-risk outcomes in available TBI datasets. Herein, we propose a Bayesian framework with mutual information-based forward feature selection to handle this type of data. Using multi-atlas segmentation, 154 image based features (capturing intensity, volume and texture) were computed over 22 ROIs in 1791 CT scans. These features were combined with 14 clinical parameters and converted into risk likelihood scores using Bayes modeling. We explore the prediction power of the image features versus the clinical measures for various risk outcomes. The imaging data alone were more predictive of outcomes than the clinical data (including Marshall CT classification) for discharge disposition with an area under the curve of 0.81 vs. 0.67, but less predictive than clinical data for discharge Glasgow Coma Scale (GCS) score with an area under the curve of 0.65 vs. 0.85. However, in both cases, combining imaging and clinical data increased the combined area under the curve with 0.86 for discharge disposition and 0.88 for discharge GCS score. In conclusion, CT data have meaningful prognostic value for TBI patients beyond what is captured in clinical measures and the Marshall CT classification. PMID- 27127332 TI - Combining Multi-atlas Segmentation with Brain Surface Estimation. AB - Whole brain segmentation (with comprehensive cortical and subcortical labels) and cortical surface reconstruction are two essential techniques for investigating the human brain. The two tasks are typically conducted independently, however, which leads to spatial inconsistencies and hinders further integrated cortical analyses. To obtain self-consistent whole brain segmentations and surfaces, FreeSurfer segregates the subcortical and cortical segmentations before and after the cortical surface reconstruction. However, this "segmentation to surface to parcellation" strategy has shown limitations in various situations. In this work, we propose a novel "multi-atlas segmentation to surface" method called Multi atlas CRUISE (MaCRUISE), which achieves self-consistent whole brain segmentations and cortical surfaces by combining multi-atlas segmentation with the cortical reconstruction method CRUISE. To our knowledge, this is the first work that achieves the reliability of state-of-the-art multi-atlas segmentation and labeling methods together with accurate and consistent cortical surface reconstruction. Compared with previous methods, MaCRUISE has three features: (1) MaCRUISE obtains 132 cortical/subcortical labels simultaneously from a single multi-atlas segmentation before reconstructing volume consistent surfaces; (2) Fuzzy tissue memberships are combined with multi-atlas segmentations to address partial volume effects; (3) MaCRUISE reconstructs topologically consistent cortical surfaces by using the sulci locations from multi-atlas segmentation. Two data sets, one consisting of five subjects with expertly traced landmarks and the other consisting of 100 volumes from elderly subjects are used for validation. Compared with CRUISE, MaCRUISE achieves self-consistent whole brain segmentation and cortical reconstruction without compromising on surface accuracy. MaCRUISE is comparably accurate to FreeSurfer while achieving greater robustness across an elderly population. PMID- 27127333 TI - Whole Abdominal Wall Segmentation using Augmented Active Shape Models (AASM) with Multi-Atlas Label Fusion and Level Set. AB - The abdominal wall is an important structure differentiating subcutaneous and visceral compartments and intimately involved with maintaining abdominal structure. Segmentation of the whole abdominal wall on routinely acquired computed tomography (CT) scans remains challenging due to variations and complexities of the wall and surrounding tissues. In this study, we propose a slice-wise augmented active shape model (AASM) approach to robustly segment both the outer and inner surfaces of the abdominal wall. Multi-atlas label fusion (MALF) and level set (LS) techniques are integrated into the traditional ASM framework. The AASM approach globally optimizes the landmark updates in the presence of complicated underlying local anatomical contexts. The proposed approach was validated on 184 axial slices of 20 CT scans. The Hausdorff distance against the manual segmentation was significantly reduced using proposed approach compared to that using ASM, MALF, and LS individually. Our segmentation of the whole abdominal wall enables the subcutaneous and visceral fat measurement, with high correlation to the measurement derived from manual segmentation. This study presents the first generic algorithm that combines ASM, MALF, and LS, and demonstrates practical application for automatically capturing visceral and subcutaneous fat volumes. PMID- 27127335 TI - Performance Management of High Performance Computing for Medical Image Processing in Amazon Web Services. AB - Adopting high performance cloud computing for medical image processing is a popular trend given the pressing needs of large studies. Amazon Web Services (AWS) provide reliable, on-demand, and inexpensive cloud computing services. Our research objective is to implement an affordable, scalable and easy-to-use AWS framework for the Java Image Science Toolkit (JIST). JIST is a plugin for Medical Image Processing, Analysis, and Visualization (MIPAV) that provides a graphical pipeline implementation allowing users to quickly test and develop pipelines. JIST is DRMAA-compliant allowing it to run on portable batch system grids. However, as new processing methods are implemented and developed, memory may often be a bottleneck for not only lab computers, but also possibly some local grids. Integrating JIST with the AWS cloud alleviates these possible restrictions and does not require users to have deep knowledge of programming in Java. Workflow definition/management and cloud configurations are two key challenges in this research. Using a simple unified control panel, users have the ability to set the numbers of nodes and select from a variety of pre-configured AWS EC2 nodes with different numbers of processors and memory storage. Intuitively, we configured Amazon S3 storage to be mounted by pay-for-use Amazon EC2 instances. Hence, S3 storage is recognized as a shared cloud resource. The Amazon EC2 instances provide pre-installs of all necessary packages to run JIST. This work presents an implementation that facilitates the integration of JIST with AWS. We describe the theoretical cost/benefit formulae to decide between local serial execution versus cloud computing and apply this analysis to an empirical diffusion tensor imaging pipeline. PMID- 27127334 TI - Improving Cerebellar Segmentation with Statistical Fusion. AB - The cerebellum is a somatotopically organized central component of the central nervous system well known to be involved with motor coordination and increasingly recognized roles in cognition and planning. Recent work in multi-atlas labeling has created methods that offer the potential for fully automated 3-D parcellation of the cerebellar lobules and vermis (which are organizationally equivalent to cortical gray matter areas). This work explores the trade offs of using different statistical fusion techniques and post hoc optimizations in two datasets with distinct imaging protocols. We offer a novel fusion technique by extending the ideas of the Selective and Iterative Method for Performance Level Estimation (SIMPLE) to a patch-based performance model. We demonstrate the effectiveness of our algorithm, Non-Local SIMPLE, for segmentation of a mixed population of healthy subjects and patients with severe cerebellar anatomy. Under the first imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard segmentation techniques. In the second imaging protocol, we show that Non-Local SIMPLE outperforms previous gold standard techniques but is outperformed by a non-locally weighted vote with the deeper population of atlases available. This work advances the state of the art in open source cerebellar segmentation algorithms and offers the opportunity for routinely including cerebellar segmentation in magnetic resonance imaging studies that acquire whole brain T1-weighted volumes with approximately 1 mm isotropic resolution. PMID- 27127336 TI - Farm-level prevalence and risk factors for detection of hepatitis E virus, porcine enteric calicivirus, and rotavirus in Canadian finisher pigs. AB - Hepatitis E virus (HEV), norovirus (NoV), and rotavirus (RV) are all hypothesized to infect humans zoonotically via exposure through swine and pork. Our study objectives were to estimate Canadian farm-level prevalence of HEV, NoV [specifically porcine enteric calicivirus (PEC)], and RV in finisher pigs, and to study risk factors for farm level viral detection. Farms were recruited using the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) and FoodNet Canada on-farm sampling platforms. Six pooled groups of fecal samples were collected from participating farms, and a questionnaire capturing farm management and biosecurity practices was completed. Samples were assayed using validated real-time polymerase chain reaction (RT-PCR). We modeled predictors for farm level viral RNA detection using logistic and exact logistic regression. Seventy-two herds were sampled: 51 CIPARS herds (15 sampled twice) and 21 FoodNet Canada herds (one sampled twice). Hepatitis E virus was detected in 30/88 farms [34.1% (95% CI 25.0%, 44.5%)]; PEC in 18 [20.5% (95% CI: 13.4%, 30.0%)], and RV in 6 farms [6.8% (95% CI: 3.2%, 14.1%)]. Farm-level prevalence of viruses varied with province and sampling platform. Requiring shower-in and providing boots for visitors were significant predictors (P < 0.05) in single fixed effect mixed logistic regression analysis for detection of HEV and PEC, respectively. In contrast, all RV positive farms provided boots and coveralls, and 5 of 6 farms required shower-in. We hypothesized that these biosecurity measures delayed the mean age of RV infection, resulting in an association with RV detection in finishers. Obtaining feeder pigs from multiple sources was consistently associated with greater odds of detecting each virus. PMID- 27127337 TI - Genetic diversity of Streptococcus suis serotype 2 isolated from pigs in Brazil. AB - Streptococcus suis is an emerging zoonotic pathogen that causes septicemia, meningitis, arthritis, and pneumonia in swine and humans. The present study aimed to characterize the genetic diversity of S. suis serotype 2 isolated from pigs showing signs of illness in Brazil using pulsed-field gel electrophoresis (PFGE), single-enzyme amplified fragment length polymorphism (SE-AFLP), and profiling of virulence-associated markers. A total of 110 isolates were studied, 62.7% of which were isolated from the central nervous system and 19.1% from the respiratory tract. Eight genotypes were obtained from the combination of virulence genes, with 43.6% and 5.5% frequencies for the mrp (+) /epf (+) /sly (+) and mrp (-) /epf (-) /sly (-) genotypes, respectively. The presence of isolates with epf gene variation with higher molecular weight also appears to be a characteristic of Brazilian S. suis serotype 2. The PFGE and SE-AFLP were able to type all isolates and, although they presented a slight tendency to cluster according to state and year of isolation, it was also evident the grouping of different herds in the same PFGE subtype and the existence of isolates originated from the same herd classified into distinct subtypes. No further correlation between the isolation sites and mrp/epf/sly genotypes was observed. PMID- 27127338 TI - Comparison of 2 commercial single-dose Mycoplasma hyopneumoniae vaccines and porcine reproductive and respiratory syndrome virus (PRRSV) vaccines on pigs dually infected with M. hyopneumoniae and PRRSV. AB - The objective of this study was to compare the efficacy of 2 different commercial Mycoplasma hyopneumoniae vaccines and porcine reproductive and respiratory syndrome virus (PRRSV) vaccines in regard to growth performance, microbiological and immunological analyses, and pathological observation from wean to finish (175 d of age). Pigs were administered M. hyopneumoniae and PRRSV vaccines at 7 and 21 d of age, respectively, or both at 21 d old and then challenged with both M. hyopneumoniae and PRRSV at 49 d old. Significant (P < 0.05) differences were observed between the 2 vaccinated challenged groups in average daily weight gain, nasal shedding of M. hyopneumoniae, M. hyopneumoniae-specific interferon-gamma secreting cells, and macroscopic and microscopic lung lesions. Induction of interleukin-10 following PRRSV vaccination does not interfere with the immune responses induced by M. hyopneumoniae vaccine. The present study demonstrated that the single-dose vaccination regimen for M. hyopneumoniae and PRRSV vaccine is efficacious for controlling coinfection with M. hyopneumoniae and PRRSV based on clinical, microbiological, immunological, and pathological evaluation. PMID- 27127339 TI - Safety and early onset of immunity with a novel European porcine reproductive and respiratory syndrome virus vaccine in young piglets. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) can be difficult to manage in commercial settings. A novel type I PRRSV vaccinal strain (94881) was evaluated for safety and efficacy/onset of immunity (OOI) in piglets. In 2 experiments, groups of piglets were vaccinated intramuscularly (IM) at approximately 14 d of age with a maximum-range commercial dose, an overdose, or a placebo in experiment 1 and either a minimum-range commercial dose or a placebo in experiment 2. The piglets in experiment 1 were evaluated for local and systemic reactions from days -2 through 14 after vaccination. The piglets in experiment 2 were challenged with a virulent heterologous type I PRRSV isolate 14 d after vaccination and observed once daily for general health from days -1 through 12 after vaccination and once daily for clinical signs associated with challenge from days 13 through 24 after vaccination. The average daily weight gain (ADWG) and the results of serologic and viremia testing were evaluated in experiments 1 and 2. Lung lesion scores and results of testing for PRRSV in lung tissue were evaluated in experiment 2. In experiment 1 the vaccine was shown to be safe, as there were no relevant differences between the vaccinated piglets and the piglets given a placebo. In experiment 2 the vaccine's efficacy, with an OOI of 14 d after vaccination, was established, as the vaccinated and challenged piglets exhibited significantly lower lung lesion scores, viremia, viral load in lung tissue, and total clinical sign scores, along with a significantly greater ADWG, compared with the placebo-vaccinated and challenged piglets. PMID- 27127340 TI - Development of a double-monoclonal antibody sandwich ELISA: Tool for chicken interferon-gamma detection ex vivo. AB - The aim of the present work was to develop reagents to set up a chicken interferon-gamma (ChIFN-gamma) assay. Four monoclonal antibodies (mAbs) specific for ChIFN-gamma were generated to establish sandwich ELISA based on 2 different mAbs. To improve the detection sensitivity of ChIFN-gamma, a double-monoclonal antibody sandwich ELISA was developed using mAb 3E5 as capture antibody and biotinylated mAb 3E3 as a detection reagent. The results revealed that this ELISA has high sensitivity, allowing for the detection of 125 to 500 pg/mL of recombinant ChIFN-gamma, and also has an excellent capacity for detecting native ChIFN-gamma. This ELISA was then used to detect ChIFN-gamma level in chickens immunized with a Newcastle disease virus (NDV) vaccine, the immunized chicken splenocytes were stimulated by NDV F protein as recall antigen. From our results, it appears that the sensitivity range of this sandwich ELISA test is adequate to measure the ex vivo release of ChIFN-gamma. PMID- 27127341 TI - Effects of ketamine and lidocaine in combination on the sevoflurane minimum alveolar concentration in alpacas. AB - This study investigated the effects of ketamine and lidocaine in combination on the minimum alveolar concentration of sevoflurane (MACSEVO) in alpacas. Eight healthy, intact male, adult alpacas were studied on 2 separate occasions. Anesthesia was induced with SEVO, and baseline MAC (MACB) determination began 45 min after induction. After MACB determination, alpacas were randomly given either an intravenous (IV) loading dose (LD) and infusion of saline or a loading dose [ketamine = 0.5 mg/kg body weight (BW); lidocaine = 2 mg/kg BW] and an infusion of ketamine (25 MUg/kg BW per minute) in combination with lidocaine (50 MUg/kg BW per minute), and MACSEVO was re-determined (MACT). Quality of recovery, time-to extubation, and time-to-standing, were also evaluated. Mean MACB was 1.88% +/- 0.13% and 1.89% +/- 0.14% for the saline and ketamine + lidocaine groups, respectively. Ketamine and lidocaine administration decreased (P < 0.05) MACB by 57% and mean MACT was 0.83% +/- 0.10%. Saline administration did not change MACB. Time to determine MACB and MACT was not significantly different between the treatments. The quality of recovery, time-to-extubation, and time-to-standing, were not different between groups. The infusion of ketamine combined with lidocaine significantly decreased MACSEVO by 57% and did not adversely affect time-to-standing or quality of recovery. PMID- 27127342 TI - Breed- and age-related differences in canine mammary tumors. AB - Triple-negative breast cancer is a type of breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). It is an important and clinically relevant condition as it has a poor prognosis and is difficult to treat. Basal like triple-negative cancer is highly prevalent in both African-Americans and adolescents. We therefore examined whether such a cancer likewise occurs in specific breeds and age groups in dogs, focusing on basal-like triple-negative cancer in particular. In this study, 181 samples from dogs with malignant mammary carcinoma from the 5 most common breeds and 2 age groups in Korea were analyzed. Histological classification and molecular subtyping, including assessment of immunohistochemical findings, were carried out. Twenty-five of 28 (89.3%) triple negative carcinomas were identified as basal-like triple-negative carcinomas. Analysis of associations of classified factors revealed that the shih tzu breed (9/25, 36.0%) and advanced-age (19/25, 76.0%) groups were characterized by higher prevalence of basal-like triple-negative tumors with diverse histological types and of a higher grade. These results suggest that breed- and age-related differences can be identified in canine mammary carcinoma and, notably, in the shih tzu breed and at older ages. Further investigation of these distinguishing characteristics of the shih tzu breed is warranted. PMID- 27127343 TI - The effects of intravenous alfaxalone with and without premedication on intraocular pressure in healthy dogs. AB - The objective of this study was to investigate the effects of intravenous alfaxalone with and without premedication on intraocular pressure (IOP) in healthy dogs. Thirty-three dogs were randomized to receive 1 of 3 treatments: acepromazine [0.03 mg/kg body weight (BW)] with butorphanol (0.2 mg/kg BW) intramuscularly (IM), followed by intravenous (IV) alfaxalone (1.5 mg/kg BW); dexmedetomidine (0.002 mg/kg BW) with hydromorphone (0.1 mg/kg BW) IM, followed by alfaxalone (1 mg/kg BW) IV; and saline 0.9% (0.02 mL/kg BW) IM, followed by alfaxalone (3 mg/kg BW) IV. Intraocular pressure (IOP) was measured at baseline, 15 min, and 30 min after premedication, after pre-oxygenation, after administration of alfaxalone, and after intubation. After induction and after intubation, the IOP was significantly increased in all groups compared to baseline. While premedication with acepromazine/butorphanol or dexmedetomidine/hydromorphone did not cause a significant increase in IOP, the risk of vomiting and the associated peak in IOP after dexmedetomidine/hydromorphone should be considered when selecting an anesthetic protocol for dogs with poor tolerance for transient increases in IOP. PMID- 27127344 TI - Evaluation of the effect of 4 types of knots on the mechanical properties of 4 types of suture material used in small animal practice. AB - The influence of the type of material used, knot configuration, and use of an additional throw on the tensile force at failure, the elongation, and the mode of failure of different configurations of linear sutures and knotted suture loops was evaluated in this in-vitro mechanical study. We hypothesized that all types of knots would significantly influence the initial force and elongation of suture materials and would influence the force and elongation at which the knotted loops break, but not their mode of failure. A total of 432 samples of 4 types of size 3 0 suture material (polydioxanone, polyglecaprone 25, polyglactin 910, and nylon), representing 9 configurations, were tested in a tensiometer. The configurations were 1 linear suture without a knot and the following loops: square (SQ) knot; surgeon's (SU) knot; granny (GR) knot; and sliding half-hitch (SHH) knot using either 4 and 5 or 3 and 4 throws, depending on the material. For polydioxanone, SQ and SU knots did not decrease the initial force at failure of the suture. Granny (GR) and SHH knots decreased the tensile force at failure and elongation by premature failure of the loop. For polyglecaprone 25, all knots decreased the initial force at failure of the suture, with SHH being weaker than the other knots. For coated polyglactin 910, all knots decreased the initial force at failure of the suture and slippage increased significantly compared with the other 3 sutures. The use of SQ knots with 3 throws did not result in a safe knot. For nylon, knots did not alter the original mechanics of the suture. In conclusion, all knots and types of suture material do not necessarily have the same effect on the initial tensile force at failure of suture materials. PMID- 27127345 TI - Active surveillance of Anaplasma marginale in populations of arthropod vectors (Acari: Ixodidae; Diptera: Tabanidae) during and after an outbreak of bovine anaplasmosis in southern Manitoba, Canada. AB - Bovine anaplasmosis is the disease caused by the bacterium Anaplasma marginale. It can cause production loss and death in cattle and bison. This was a reportable disease in Canada until April 2014. Before then, infected herds were quarantined and culled, removing infected animals. In North America, A. marginale is biologically vectored by hard ticks (Acari: Ixodidae), Dermacentor variabilis and D. andersoni. Biting flies, particularly horse flies (Diptera: Tabanidae), can also act as mechanical vectors. An outbreak of bovine anaplasmosis, consisting of 14 herds, was detected in southern Manitoba in 2008. This outbreak lasted multiple rounds of testing and culling before eradication in 2011, suggesting local maintenance of the pathogen was occurring. We applied novel approaches to examine the vector ecology of this disease in this region. We did not detect A. marginale by screening of 2056 D. variabilis (2011 and 2012) and 520 horse flies (2011) using polymerase chain reaction (PCR). PMID- 27127346 TI - Effects of Low-Dose and Long-Term Treatment with Erythromycin on Interleukin-17 and Interleukin-23 in Peripheral Blood and Induced Sputum in Patients with Stable Chronic Obstructive Pulmonary Disease. AB - OBJECTIVE: To study the effects of low-dose and long-term treatment with erythromycin on IL-17 and IL-23, in peripheral blood and induced sputum, in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: Patients were randomly divided into placebo-treated group, group A (12 months of additive treatment with erythromycin, N = 18), and group B (6 months of additive treatment with erythromycin followed by 6 months of follow-up, N = 18). Inflammatory cells in induced sputum, pulmonary function, and the 6-minute walk distance (6MWD) were analyzed. Concentrations of IL-17 and IL-23 in peripheral blood and sputum were measured using enzyme-linked immunosorbent assays. RESULTS: After treatment, sputum and peripheral blood concentrations of IL-17 and IL-23 significantly decreased in groups A and B compared with placebo-treated group. There were no significant differences after erythromycin withdrawal at months 9 and 12 in group B compared with placebo-treated group. An increase in 6MWD was observed after treatment. CONCLUSIONS: Erythromycin was beneficial and reduced airway inflammation in COPD patients. Underlying mechanisms may involve inhibition of IL-17 and IL-23 mediated airway inflammation. COPD patients treated with erythromycin for 6 months experienced improved exercise capacity. Finally, treatment for 12 months may be more effective than treatment for 6 months. PMID- 27127348 TI - Patient-reported outcomes: The next step? PMID- 27127347 TI - Associations of Trauma Severity with Mean Platelet Volume and Levels of Systemic Inflammatory Markers (IL1beta, IL6, TNFalpha, and CRP). AB - We investigated the associations of injury severity scores (ISSs) with the mean platelet volume, the serum levels of two interleukins (IL1beta and IL6), and the serum levels of tumour necrosis factor-alpha (TNFalpha) and C-reactive protein (CRP). We sought to identify biochemical parameters that could be used as components of a new biochemical parameter-based ISS system. The levels of CRP, TNFalpha, IL1beta, and IL6 differed significantly (all p values < 0.05) between severely injured patients and controls. The mean platelet volume (MPV) did not correlate with the ISSs (p > 0.05). The TNFalpha and IL6 levels were useful for determining the severity of injury, and the CRP level was elevated in all trauma patients but did not correlate with the ISS. The IL1beta level was higher in the study group but did not increase as the ISS increased. IL6 and TNFalpha levels were higher in the study group and increased as the ISS increased. We found no significant difference between the trauma group and healthy individuals in terms of MPV values. IL6 and TNFalpha levels can be used to assess trauma severity. However, neither the MPV nor the CRP or IL1beta level is useful for this purpose. PMID- 27127349 TI - Do we need new patient reported measures to evaluate lower urinary tract dysfunction? PMID- 27127350 TI - Reconstructive surgery for hypospadias: A systematic review of long-term patient satisfaction with cosmetic outcomes. AB - INTRODUCTION: Research on long-term results of hypospadias has focused on surgical techniques and functional outcomes, and it is only recently that patient satisfaction with appearance and psychosocial outcomes have been considered. The aim of this study was to provide an evidence-based systematic review of adolescent and adult patient perceptions of cosmetic outcomes following childhood surgery for hypospadias. METHODS: A systematic review was performed in accordance with the PRISMA and PICO guidelines, and studies assessed using the Oxford Centre for Evidence-Based Medicine system. MEDLINE, PsycInfo, EMBASE, and CINAHL databases were searched from 1974 to 2014 for clinical studies containing patient perceptions of appearance, deformity, and social embarrassment following hypospadias surgery. RESULTS: A total of 495 publications were retrieved, of which 28 met the inclusion criteria. Due to study design/outcome measure, heterogeneity data were synthesized narratively. Results indicate (i) patient perceptions of penile size do not differ greatly from the norm; (ii) perceptions of appearance findings are inconsistent, partially due to improving surgical techniques; (iii) patients who are approaching, or have reached, sexual maturity hold more negative perceptions and are more critical about the cosmetic outcomes of surgery than their prepubertal counterparts; (iv) patients report high levels of perceptions of deformity and social embarrassment; and (v) there is a lack of data using validated measurement tools assessing long-term patient perceptions of cosmetic outcomes, particularly with patients who have reached genital maturity. CONCLUSIONS: Protocols for clinical postpuberty follow-up and methodologically sound studies, using validated assessment tools, are required for the accurate assessment of cosmetic and psychological outcomes of hypospadias surgery. PMID- 27127351 TI - Demography and disease characteristics of prostate cancer in India. AB - INTRODUCTION: The incidence of prostate cancer has shown significant variation across the globe. Though the prevalence and characteristics of this disease have been extensively studied in many countries, data regarding the true incidence of prostate cancer in India is limited. MATERIALS AND METHODS: MEDLINE publications from 1990 to 2014 were searched and reviewed and compiled to assess the demographic profile of prostate cancer in India and characteristics unique to this disease in India. RESULTS: The limited data available on prostate cancer showed significant differences in incidence, precipitating factors, and disease characteristics of prostate cancer in India. CONCLUSIONS: Since India would be having more number of cases of prostate cancer than most others in the years to come, adequate population-based data regarding the demography and disease characteristics of this disease are of paramount importance in this country. PMID- 27127353 TI - Analysis of outcome following robotic assisted radical prostatectomy for patients with high risk prostate cancer as per D'Amico classification. AB - INTRODUCTION: Prognosis of prostate cancer depends on the risk stratification. D'Amico classification, the most commonly used risk stratification method is based on three factors, i.e., prostate specific antigen (PSA), Gleason grade and clinical stage. The impact of presence of multiple risk factors on prognosis after radical prostatectomy has not been studied in Indian patients. We analyzed the outcome of patients with high-risk disease undergoing robotic-assisted radical prostatectomy (RARP), as per D'Amico classification. MATERIALS AND METHODS: Our study is a review of the data of all patients with high-risk prostate cancer who underwent RARP between July 2010 and January 2015. Preoperative, perioperative and outcome data were analyzed for patients with high risk disease as per D'Amico classification. RESULTS: Of 227 patients who underwent RARP, 90 (39.6%) were in the high-risk group. PSA > 20 ng/ml was the most common risk factor, present in 50 (55.6%) patients. All three risk factors were present in 3 patients, and single risk factor was present in 65 patients. Nine (10%) patients had lymphnode involvement, 18 (20%) had positive margin, and 38 (41.1%) had extraprostatic extension (EPE). Among these adverse outcomes, only EPE showed significant association with multiplicity of risk factors. At 12 months, 27.8% had biochemical recurrence (BCR). 92% of patients were continent at 12 months. CONCLUSION: About 92% of patients with high-risk disease were continent at 12 months, whereas less than one-third of the patients had BCR. EPE was the only outcome associated with multiplicity of risk factors. Adjuvant treatment is not required in two-thirds of patients. PMID- 27127352 TI - Extended lymph node dissection in robotic radical prostatectomy: Current status. AB - INTRODUCTION: The role and extent of extended pelvic lymph node dissection (ePLND) during radical prostatectomy (RP) for prostate cancer patients remains unclear. MATERIALS AND METHODS: A PubMed literature search was performed for studies reporting on treatment regimens and outcomes in patients with prostate cancer treated by RP and extended lymph node dissection between 1999 and 2013. RESULTS: Studies have shown that RP can improve progression-free and overall survival in patients with lymph node-positive prostate cancer. While this finding requires further validation, it does allow urologists to question the former treatment paradigm of aborting surgery when lymph node invasion from prostate cancer occurred, especially in patients with limited lymph node tumor infiltration. Studies show that intermediate- and high-risk patients should undergo ePLND up to the common iliac arteries in order to improve nodal staging. CONCLUSIONS: Evidence from the literature suggests that RP with ePLND improves survival in lymph node-positive prostate cancer. While studies have shown promising results, further improvements and understanding of the surgical technique and post-operative treatment are required to improve treatment for prostate cancer patients with lymph node involvement. PMID- 27127354 TI - Selective indication for check cystogram before catheter removal following robot assisted radical prostatectomy. AB - INTRODUCTION: With the improvement in anastomotic technique, it is rare to find anastomotic site leak after robot-assisted radical prostatectomy (RARP). It may not always be necessary to do regular check cystogram before catheter removal. We evaluated our 230 consecutive RARP patients and their cystograms to determine the indications for selective use of cystogram before catheter removal. MATERIALS AND METHODS: We reviewed our prospectively collected RARP database of 230 consecutive patients. Cystography was performed at low pressure by gravity instillation of diluted contrast through the catheter. Patients were observed under fluoroscopy in lateral oblique position for any contrast leak at the site of anastomosis. All patients were followed for a minimum of 6 months, and the longest follow-up was 5 years. RESULTS: A total of 207 patients (90%) underwent catheter removal on postoperative day 7. Nine patients (3.9%) had extravasation on initial cystogram. Two patients with leak had a history of transurethral resection of prostate (TURP) and seven other had bladder neck reconstruction for wide bladder neck. Three patients with minimal leak did not require catheter replacement. In rest of the 6 patient with leak, continued catheter drainage was done. No significant difference in the intraoperative variables, blood loss, duration of drain, length of hospital stay, and continence outcomes was noted between the patients with leak compared to rest of the patients. None of the patient needed any procedure/intervention related to the surgery and none developed bladder neck stenosis. CONCLUSION: In usual circumstances, catheter removal can be done safely on a postoperative day 7 without routine cystography. Selective use of check cystogram can be done in the case where bladder neck reconstruction is performed or those had a prior TURP and a wide bladder neck. PMID- 27127355 TI - Is surgeon intuition equivalent to models of operative complexity in determining the surgical approach for nephron sparing surgery? AB - INTRODUCTION: The choice of approach for partial nephrectomy often depends on surgical complexity. We aimed to determine if surgeon intuition was equivalent to markers of operative complexity, such as RENAL nephrometry and Mayo adhesive probability (MAP) score, in determining the surgical approach for partial nephrectomy (PN). MATERIALS AND METHODS: We retrospectively identified 119 masses removed for suspected renal cell carcinoma from January 2012 to September 2014 by a single surgeon who intuitively chose treatment with one of three surgical approaches: Open PN (OPN), robotic-assisted transperitoneal PN (RATPN), or robotic-assisted retroperitoneal PN (RARPN). Clinicodemographic characteristics, pathological features, and postoperative outcomes were compared for each approach. Logistic regression was performed to identify independent predictors of open surgical resection, our primary endpoint. RESULTS: Fifty-four tumors (45%) were resected via OPN, 40 (34%) via RATPN, and 25 (21%) via RARPN. OPN was performed in patients with more comorbidities (P = 0.02), lower baseline renal function (P < 0.01), more solitary kidneys (P < 0.01), and more multifocal disease (P < 0.01). Patients undergoing OPN had higher median nephrometry scores compared to RATPN and RARPN patients (8 vs. 7 vs. 7, respectively; P = 0.03), but MAP scores were no different among all three groups (P = 0.36). On multivariate analysis, higher nephrometry scores (odds ratio: 1.41, 95% confidence interval: 1.10-1.81; P = 0.007) were independently associated with open surgical resection. Nephrometry score was predictive of OPN (area under curve = 0.64, P = 0.01) with a score of 6.5 having the highest sensitivity and specificity (76% and 42%, respectively). CONCLUSIONS: RENAL nephrometry score was associated with surgical approach intuitively chosen by an experienced surgeon, but the presence of adherent perinephric fat did not correlate with decision-making. PMID- 27127356 TI - Ultra-mini-percutaneous nephrolithotomy: A minimally-invasive option for percutaneous stone removal. AB - INTRODUCTION: Percutaneous nephrolithotomy (PCNL) has witnessed rapid advancements, the latest being ultra-mini-percutaneous nephrolithotomy (UMP), which makes the use of 11-13F sheaths as compared to 24-30F sizes used in conventional PCNL. This miniaturization aims to reduce morbidity and improve patient outcomes. We evaluated the safety and efficacy of UMP and report our ourtcomes. PATIENTS AND METHODS: A total of 120 patients underwent UMP from July 2012 to March 2014. These patients had a single unilateral renal stone measuring between 8 and 20 mm. All patients underwent UMP using a 3F nephroscope, 7.5F inner sheath, and 11F or 13F outer metallic cannula, which served as the Amplatz sheath. Stone fragmentation and clearance were achieved with holmium laser. No nephrostomy or stent was used routinely. RESULTS: Complete stone fragmentation was achieved in 114 out of 120 patients (95%) using UMP; whereas the remaining 6 were converted into mini-PCNL using a 12.5F nephroscope and 15F Amplatz sheath. The mean operative time was 39.7 +/- 15.4 min, and the mean postoperative hospital stay was 22.3 +/- 2.2 h. Postoperatively, 6 (5%) patients had residual fragments measuring <=4 mm. At the 2 weeks follow-up, the stone-free status was >99% (119/120). There were no significant postoperative complications. CONCLUSION: This study shows UMP to be an effective and safe procedure for managing stones up to 20 mm. This procedure offers an attractive alternative to shock wave lithotripsy and retrograde intrarenal surgery for managing small stones. PMID- 27127357 TI - Plateau pattern of detrusor contraction: A surrogate indicator of presence of external sphincter dysfunction during micturitional phase of urodynamic study. AB - INTRODUCTION: Dysfunctional voiding results from a disturbance in the coordination between sphincter relaxation and detrusor contraction. Video urodynamic studies with electromyography (EMG) are used for diagnosis but have limitations of availability and interpretation. We identified a plateau type voiding detrusor pressure tracing pattern in these patients with a potential of helping diagnosis. MATERIALS AND METHODS: Urodynamic data and tracings of adult patients having been diagnosed with external urethral sphincter dysfunction (EUSD) were retrospectively analyzed. The urodynamic studies comprised of pressure flow studies, micturitional urethral pressure profilometry, and voiding cystourethrogram (VCUG). Diagnosis of EUSD was based on the presence of intermittent or continuous narrowing in the region of EUS on VCUG along with a urethral-vesical pressure gradient of >20 cm H2O in males and >5 cm H2O in females. RESULTS: A total of 25 patients (14 men and 11 women) with a mean age 36.6 +/- 16.5 years, presented with lower urinary tract symptoms (international prostate symptom score 18 +/- 5) and were diagnosed with EUSD on urodynamics/cystourethrography. The cause of EUSD was neurogenic DESD in four, dysfunctional voiding in 20 and voluntary pelvic floor squeeze in one. Resting maximum urethral closure pressure at EUS was 142.2 +/- 38.3 cmH2O in both sexes. Three patients had detrusor overactivity. EMG activity during voiding was high in 10 patients, low in three, inconclusive in seven, and not performed in three. A plateau type pattern of detrusor contraction was observed in all the patients. This was qualitatively different from the roughly bell-shaped curve of detrusor contraction in men with prostatic obstruction (n = 14) and women with stress urinary incontinence (n = 11). CONCLUSIONS: Patients with EUSD have a characteristic plateau pattern of detrusor contraction on urodynamics which can be used as a surrogate for urodynamic diagnosis of nonrelaxing EUSD. PMID- 27127359 TI - Molecular cystoscopy: Micro-RNAs could be a marker for identifying genotypic changes for transitional cell carcinoma of the urinary bladder. AB - INTRODUCTION: Normal-looking mucosa may harbor genetic changes preceding a visible tumor. This study was aimed at exploring the role of the quantitative expression of micro-RNAs (miRNAs) in bladder cancer tissue in comparison with normal mucosa and healthy controls (HCs) as a molecular marker. MATERIALS AND METHODS: Between October 2011 to December 2012, tissue from the bladder tumor of 21 patients (cases tumor, CT), normal mucosa (case control, CC) of the same patients (n-21) and normal bladder mucosa from 10 HCs were obtained. miRNAs of angiogenesis, endothelial mesenchymal transition and apoptosis were quantified using stem-loop RT Taq Man polymerase chain reaction. Statistical analysis was performed using the Chi square and independent sample T tests by using SPSS version 16. RESULTS: The mean age of the patients and controls were 55.41 +/- 11.03 and 52.14 +/- 13.04 years. miR-21, miR-205, miR-126, miR-10b and miR-200a were highly expressed in CT (P < 0.027, <0.048, <0.025, <0.029 and < 0.005) as compared with HC. Expression of miR-21 and miR-129 were both correlated with grade and stage (P = 0.001 and < 0.009, respectively) and the level of expression was different in the same grade of non-muscle invasive tumors. The fold change of miR129, miR205 and miR200a was significantly higher in the normal-looking mucosa of bladder tumor patients than the HC (P < 0.005). CONCLUSION: Expression of miR129, miR205 and miR200a in the normal-looking mucosa of bladder cancer patients was significantly higher than the normal mucosa of a HC. This may help in predicting recurrence and formulating the follow-up strategy. PMID- 27127358 TI - Management of venous hypertension following arteriovenous fistula creation for hemodialysis access. AB - INTRODUCTION: Venous hypertension (VH) is a distressing complication following the creation of arteriovenous fistula (AVF). The aim of management is to relieve edema with preservation of AVF. Extensive edema increases surgical morbidity with the loss of hemodialysis access. We present our experience in management of VH. METHODS: A retrospective study was conducted on 37 patients with VH managed between July 2005 to May 2014. Patient demographics, evaluation, and procedures performed were noted. A successful outcome of management with surgical ligation (SL), angioembolization (AE), balloon dilatation (BD) or endovascular stent (EVS) was defined by immediate disappearance of thrill and murmur with resolution of edema in the next 48-72 h, no demonstrable flow during check angiogram and resolution of edema with preservation of AVF respectively. RESULTS: All 8 distal AVF had peripheral venous stenosis and were managed with SL in 7 and BD in one patient. In 29 proximal AVF, central and peripheral venous stenosis was present in 16 and 13 patients respectively. SL, AE, BD, and BD with EVS were done in 18, 5, 4, and 3 patients, respectively. All patients had a successful outcome. SL was associated with wound related complications in 11 (29.73 %) patients. A total of 7 AVF were salvaged. One had restenosis after BD and was managed with AE. BD, EVS, and AE had no associated morbidity. CONCLUSIONS: Management of central and peripheral venous stenosis with VH should be individualized and in selected cases it seems preferable to secure a new access in another limb and close the native AVF in edematous limb for better overall outcome. PMID- 27127360 TI - Successful management of renal mucormycosis with antifungal therapy and drainage. AB - We report a case of isolated extensive renal mucormycosis in an immunocompetent adult, who was successfully managed conservatively without surgical debridement. To the best of our knowledge, this is the first case where antifungal therapy alone was sufficient even with such an extensive involvement. PMID- 27127362 TI - Instrument malfunction during robotic surgery: A case report. AB - Robotic assistance is the new dimension of minimally invasive surgery. Despite being the state-of-the-art technology, newer technical problems still occur during robotic surgeries which are not addressed in the trouble shooting manual. We report one such problem being encountered with the tip cover accessory of monopolar scissors. In the current report, we discuss the technical fault and its correction. We feel that this problem needs to be registered into the trouble shooting manual to prevent such incidents in future. PMID- 27127361 TI - Urethral duplication with unusual cause of bladder outlet obstruction. AB - A 12-year-old boy presented with poor flow and recurrent urinary tract infections following hypospadias repair at the age of 3 years. The evaluation revealed urethral duplication with a hypoplastic dorsal urethra and patent ventral urethra. He also had duplication of the bladder neck, and on voiding cystourethrogram the ventral bladder neck appeared hypoplastic and compressed by the dorsal bladder neck during voiding. The possibility of functional obstruction of the ventral urethra by the occluded dorsal urethra was suspected, and he underwent a successful urethro-urethrostomy. PMID- 27127363 TI - Adrenocortical carcinoma with inferior vena cava thrombus: Renal preserving surgery. AB - Adrenocortical carcinoma with tumor thrombus extending via an adrenal vein into the inferior vena cava is uncommon. We describe a left side kidney-preserving surgery in such a patient where, after transection of the main renal vein at the point of insertion of the adrenal vein, the left kidney was being drained by lumbar and gonadal veins. PMID- 27127364 TI - Pseudoaneurysm secondary to transvesical prostatectomy. AB - Pseudoaneurysms associated with the internal pudendal artery is rare and may occur as a complication of prostatic surgery or or pelvic trauma. We present images of the first case in literature of an isolated pseudoaneurysm secondary to transvesical prostatic adenomectomy, which was successfully treated by transarterial coil embolization. This complication can be difficult to diagnose, manage, and cause significant postoperative bleeding. Management requires as a multidisciplinary approach. PMID- 27127365 TI - Steroid-responsive IgG4-related disease with isolated prostatic involvement: An unusual presentation with elevated serum PSA. AB - Autoimmune prostatitis is known to occur as a part of multisystem fibro inflammatory disorder known as IgG4 related disease (IgG4 RD). The usual presentation is with symptoms of gastro-intestinal disease with prostatic involvement presenting as lower urinary tract symptoms. The disease responds to corticosteroids. We report an asymptomatic young man who was diagnosed to have IgG4 related prostatitis on TRUS-guided prostate biopsy done for elevated serum PSA, in the absence of any other systemic involvement. The treatment with steroid resulted in normalization of S PSA levels. PMID- 27127366 TI - Peri-incisional catheters through open surgical wound in converted nephrectomies: A novel modification of transverse abdominis plane block. PMID- 27127367 TI - Bird's Nest View from a Dermatologist's Eye. AB - Plica neuropathica also known as "birds nest" is irreversible matting of hair seen in otherwise healthy individuals and is usually associated with use of ionic/herbal soaps, shampoos, parasitic infestations, psychiatric alterations, or neglect. Anagen effluvium is a known side effect of many immunosuppressive drugs. Rarely matting of hair has been reported following azathioprine. We report plica neuropathica in two chronically ill patients on immunosuppressive drugs, that is, azathioprine and methotrexate along with a review of literature of its etiological factors and pathogenesis. PMID- 27127368 TI - Trichoscopy: The Best Auxiliary Tool in the Evaluation of Nevus Sebaceous. AB - INTRODUCTION: Nevus sebaceous (NS) presents as alopecia and yellowish discoloration during infantile stage. In adult stage, lesions become verrucous. Importantly, various appendageal tumors such as trichoblastoma, syringocystadenoma papilliferum and basal cell carcinoma develop during this stage. Hence it is very important to follow the course of NS for early detection of neoplasms. Trichoscopy, being in vivo diagnostic technique, can be utilized in this condition. as it demonstrates specific trichoscopic patterns. Patterns of NS on trichoscopy are evaluated. MATERIALS AND METHODS: Study was conducted in SN Medical College, Bagalkot. It is a case series study. Ten patients with NS were studied using polarised dermoscopy. All NS lesions were subjected to histopathology for confirmation of diagnosis. Correlation of histopathological changes and trichoscopic patterns was done. Data were tabulated in Microsoft excel sheet. The results are presented in proportions and percentages. RESULTS: Total of 10 patients including 6males and 4 females were present in the study. The mean age was 20years. Two patients were with childhood stage and 8 patients were with adulthood stage of NS. Trichoscopy showed 'cobble stone pattern' in 20% and 'cerebriform pattern' in 80% of patients. Histopathological features showed numerous and hyperplastic sebaceous glands with primordial hair follicles which were consistent with NS in all the patients. CONCLUSION: Trichoscopy helps in the diagnosis of NS with specific patterns. Yellowish globules in the cobblestone pattern and cerebriform patterns are specific to childhood and adult stages of NS respectively. Hence, trichoscopy is good, non-invasive diagnostic technique in NS. Authors strongly recommend regular trichoscopic examination of NS. PMID- 27127369 TI - Factors Associated with Premature Hair Graying in a Young Indian Population. AB - CONTEXT: Although the primary cause of premature hair graying (PHG) is considered to be genetic, certain environmental factors also play a role. Trace element deficiencies such as Vitamin B12, Vitamin D3, and calcium may also be associated with PHG. However, India-specific data are relatively sparse. AIMS: The present study aimed at identifying factors associated with PHG in Indian patients. SETTINGS AND DESIGN: A case-control study was conducted at a trichology clinic in Bengaluru between October 2013 and April 2014 with a total of 37 cases of PHG and 37 age- and gender-matched controls. MATERIALS AND METHODS: A total of 100 subjects were investigated for various parameters such as hemoglobin, serum ferritin, zinc, copper, calcium, Vitamin B12, and Vitamin D after obtaining informed consent. STATISTICAL ANALYSIS USED: Chi-square test was used to compare proportions between groups. Means were compared between groups using Student's t test. RESULTS: Serum ferritin levels were lower in patients with PHG as compared to the control group and the differences were statistically significant (P < 0.001). Furthermore, as compared to the controls, patients with PHG had lower serum Vitamin B12 levels (P < 0.001). Individuals with PHG had significantly lower levels of high-density lipoprotein cholesterol (HDL-C) as compared to the control group (P < 0.001). Significant proportions of patients with PHG had a sedentary lifestyle and admitted to having irregular eating habits. CONCLUSION: PHG is associated with low serum ferritin, Vitamin B12, and HDL-C levels in Indian patients aged <25 years. However, studies with large sample sizes may be required to conclusively define these putative associations. PMID- 27127370 TI - Liquid Nitrogen Cryotherapy in Recalcitrant Alopecia Areata: A Study of 11 Patients. AB - CONTEXT: Recalcitrant alopecia areata (AA) is not uncommon in clinical practice. In certain patients, treatment failures are known with almost every conventional therapy either singly or in combination. AIMS: To study the efficacy of liquid nitrogen (LN) cryotherapy in patients with recalcitrant AA. SUBJECTS AND METHODS: We present series of eleven patients of recalcitrant AA, who consulted us after getting no response to various modalities of treatment for 6 months. We treated them with LN cryotherapy every 2 weeks till significant hair regrowth or maximum five sittings (at 0, 2, 4, 6, and 8 weeks) whichever was earlier. Inclusion and exclusion criteria were applied. Each patient was counseled and a written consent was taken. Every session consisted of dual freeze and thaw cycles of 15 s each with a cryo unit spray. Two months of follow-up after last treatment was done to observe sustained re-growth of hair. STATISTICAL ANALYSIS USED: The clinical response was evaluated by using regrowth scale at 4(th), 8(th), and 16(th) week. RESULTS: 11 patients were recruited, one patient dropped due to inability to attend follow-ups. Remaining ten patients completed the treatment and follow-up. Out of 10 patients, five patients (50%) showed an excellent response, three (30%) had a satisfactory response, one (10%) had a fair response, and one patient (10%) had a poor response. No serious adverse effects were seen. Sustained hair regrowth was seen in 80% of patients at the 16(th) week. CONCLUSIONS: LN cryotherapy may be worth trying treatment in the management of recalcitrant AA. PMID- 27127371 TI - Trichostasis Spinulosa: An Unusual Diagnosis Presenting as a Double Lower Eyelid. AB - Trichostasis spinulosa (TS) is a relatively common but underdiagnosed disorder of the pilosebaceous follicles in which there is follicular hyperkeratosis of a dilated hair follicle with retention of telogen hairs. Clinical presentation of this disorder can be confused with comedogenic acne, keratosis pilaris, eruptive vellus hair cysts, and Favre-Racouchot syndrome. A case of a nonpruritic variant of TS in a 16-year-old boy is reported because of its unusual location as well as presentation in the lower eyelid, giving an appearance of a double eyelid. Although TS is common, it is mostly under diagnosed and henceforth underreported hair follicular disorder. The differential diagnosis of this disorder should be always kept in mind even if it presents in unusual location to avoid unnecessary application of various therapeutic modalities. PMID- 27127372 TI - Whisker Hair (Acquired Progressive Kinking of the Hair): An Indication for Finasteride 1 mg? AB - Acquired progressive kinking of the hair (APKH) and whisker hair are relatively rare conditions. To our knowledge, fewer than 25 cases have been reported in the English literature. We present the case of a 23-year-old man whose hair on the parietal and occipital areas changed and turned curlier and shorter. Patients suffering from APKH have higher risk of developing androgenetic alopecia and therefore finasteride 1 mg daily is proposed as an adequate treatment for these patients. PMID- 27127373 TI - Dermatitis Artefacta Presenting with Localized Alopecia of Right Eyebrow and Scalp. AB - Dermatitis artefacta (DA) and trichotemnomania are self-inflicted dermatoses often preceded by psychosocial stressful events. A 38-year-old female presented with sudden loss of hair in the right frontal area along with discoloration and edema of skin. On examination, there was complete loss of hair involving the right frontal area and the lateral half of right eyebrow with skin over that area appearing scalded, edematous, bruised, and discolored. After a detailed medical and psychological evaluation, a clinical diagnosis of DA with trichotemnomania was made. A tactful multidisciplinary approach is essential in managing such patients as outright referral to a psychiatrist could be counterproductive. PMID- 27127374 TI - A Rare Association of Pili Multigemini and Rolled Hairs in a Young Female. AB - Pili multigemini and circle hairs (CHs) both are hair shaft deformities. Being asymptomatic and benign they are often under-reported in medical science. Till now, literature showed the involvement of only males. CHs are seen in obese individuals with sedentary lifestyle and pili multigemini is seen in adults over beard and children over scalp. Cosmetic concern in a young female with asymptomatic hyperpigmented papular lesions brought her to dermatology clinic. Apart from histopathology, dermatoscopy is a noninvasive technique that can be utilized for the evaluation of various hair disorders, especially like this. PMID- 27127375 TI - Report of a Rare Case of Alopecia Areata Coexisting with Trichotillomania. AB - Alopecia areata (AA) is a common dermatological disease characterized by patchy areas of nonscarring alopecia. Trichotillomania (TT) is an expression of obsessive-compulsive disorder defined by the urge to pull out his/her hair. We describe a case of AA coexisting with TT. A 6-year-old male child presented with a localized patch of hair loss in the occipital area of 2 years duration. Dermoscopy revealed numerous exclamation mark hairs along with signs of scratching and bleeding. A detailed medical anamnesis and thorough examination of the child during the consultation put in evidence TT. PMID- 27127376 TI - Concentric Polycyclic Regrowth Pattern in Alopecia Areata. AB - Alopecia areata (AA) is a common form of autoimmune nonscarring hair loss of scalp and/or body. Atypical hair regrowth in AA is considered a rare phenomenon. It includes atypical pattern of hair growth (sudden graying, perinevoid alopecia, Renbok phenomenon, castling phenomenon, and concentric or targetoid regrowth) and atypical dark color hair regrowth. We report a case of AA that resulted in a concentric targetoid hair regrowth and discuss the possible related theories regarding the significance of this phenomenon. PMID- 27127377 TI - Interdigital Pilonidal Sinus, Report of Two Cases. AB - Hairdresser's disease is an occupational acquired interdigital pilonidal sinus (IPS) of especially male barbers. Here, two cases of IPSs are reported. Both cases underwent surgical excision and primary closure. Six months follow-up period did not present any complications or recurrence. Caused by repeated implantation of foreign hair to the interdigital web space, IPS is preventable, but once acquired treated with surgical excision and primary closure or with a skin flap for postoperative comfort. PMID- 27127378 TI - Clinical and Dermoscopic Study of Pseudofolliculitis of the Beard Area. AB - BACKGROUND: Pseudofolliculitis of the beard area is a very common dermatological problem in our geographical region. This could be partly because of the racial predilection as a large percentage of the population has curly hair and also may be due to local cultural customs, unlike the west do not encourage daily shaving of facial hair. OBJECTIVES: We aimed to mainly study the dermoscopic features of cases presenting with pseudofolliculitis. Secondary objectives included evaluating clinical patterns and possible etiological factors. METHODS: Twenty four consecutive male patients presenting to a University Health Center with a clinical diagnosis of pseudofolliculitis involving beard area were included in the study. Patient history with regards to shaving habits, patient hair type, morphological patterns of the skin lesions, and dermoscopic findings were recorded. RESULTS: Majority of the patients had "curly" hair. Most of the patients had a usual shaving frequency of 2 or less per week. All the patients who were using razors mentioned that they tended to stretch the skin while shaving. The most common dermoscopic findings included - "Handle bar" sign showing curved hair attached to the skin on both ends, white areas indicate fibrosis and scaling, underlying linear bluish pigmentation (indicating the buried hair shaft), and linear vessels with occasional areas of hemorrhage. CONCLUSION: Dermoscopy can be a useful adjunct for diagnosis and patient counseling in pseudofolliculitis. Stretching the skin while using razors and growing the facial hair to a point where it has the length to curve might be important risk factors in the development of pseudofolliculitis. LIMITATIONS: The lack of histopathological correlation is the main limitation in our study. PMID- 27127379 TI - Giant Pilomatricoma of the arm: A diagnostic challenge for cytopathologist. PMID- 27127380 TI - Polarized Versus Nonpolarized Dermoscopy for Hair and Scalp Evaluation. PMID- 27127381 TI - Plica Polonica After Use of Shampoo. PMID- 27127382 TI - Two Episodes of Simultaneous Identical Alopecia Areata in Identical Twins. PMID- 27127383 TI - Anterolateral Leg Alopecia. PMID- 27127384 TI - Congenital Triangular Alopecia: The 127(th) Case. PMID- 27127385 TI - Concurrence of Immune Thrombocytopenic Purpura and Alopecia Areata: A Rare Association. PMID- 27127386 TI - Carvajal Syndrome. PMID- 27127387 TI - Abuse of topical corticosteroids in India: Concerns and the way forward. PMID- 27127389 TI - Variability in plasma concentration of cefotaxime in critically ill patients in an Intensive Care Unit of India and its pharmacodynamic outcome: A nonrandomized, prospective, open-label, analytical study. AB - BACKGROUND: Cefotaxime is a widely utilized cephalosporin in most intensive care units of India. However, no data are available about its pharmacokinetic/pharmacodynamic variability in critically ill patients of the Indian population. AIM: To investigate the variability in the plasma concentration and pharmacodynamic profile of intermittent dosing of cefotaxime in critically ill patients, according to their locus of infection and causative organism. MATERIALS AND METHODS: Cefotaxime levels were determined using high performance liquid chromatography by grouping patients according to their locus of infection as hepatobiliary, renal, pulmonary, and others. Patients with cefotaxime concentration below the minimum inhibitory concentration (MIC) and 5 times below the MIC for the isolated organism were determined. RESULTS: The difference in the plasma cefotaxime concentration between the hepatobiliary and the nonhepatobiliary groups was significant at 1 h (P = 0.02) following drug dosing, while the difference was significant between the renal and nonrenal group at 1 h (P = 0.001), 4 h (P = 0.009), and 8 h (P = 0.02) after drug dosing. The pulmonary group showed significantly (P < 0.05) lower plasma cefotaxime levels than the nonpulmonary group at all-time points. The cefotaxime levels were below the MIC and below 5 times the MIC for the isolated organism in 16.67% and 43.33% of the patients, respectively. CONCLUSION: The concentration of cefotaxime differs according to the locus of an infection in critically ill patients. Use of another class of antibiotic or shifting to continuous dosing of cefotaxime, for organisms having MIC values above 1 mg/L, is advisable due to the fear of resistance. PMID- 27127390 TI - Inhibition of astrocyte activation is involved in the prevention of postoperative latent pain sensitization by ketamine and gabapentin in mice. PMID- 27127388 TI - Asenapine modulates nitric oxide release and calcium movements in cardiomyoblasts. AB - OBJECTIVE: To examine the effects of asenapine on nitric oxide (NO) release and Ca(2+) transients in H9C2 cell line, which were either subjected to peroxidation or not. MATERIALS AND METHODS: H9C2 were treated with asenapine alone or in presence of intracellular kinase blockers, serotoninergic and dopaminergic antagonists, and voltage Ca(2+) channels inhibitors. Experiments were also performed in H9C2 treated with hydrogen peroxide. NO release and intracellular Ca(2+) were measured through specific probes. RESULTS: In H9C2, asenapine differently modulated NO release and Ca(2+) movements depending on peroxidative condition. The Ca(2+) pool mobilized by asenapine mainly originated from the extracellular space and was slightly affected by thapsigargin. Moreover, the effects of asenapine were reduced or prevented by kinases blockers, dopaminergic and serotoninergic receptors inhibitors, and voltage Ca(2+) channels blockers. CONCLUSIONS: On the basis of our findings, we can conclude that asenapine by interacting with its specific receptors, exerts dual effects on NO release and Ca(2+) homeostasis in H9C2; this would be of particular clinical relevance when considering their role in cardiac function modulation. PMID- 27127391 TI - Effect of flumazenil on memory retrieval determined by trial-to-criteria inhibitory avoidance method in mice. PMID- 27127392 TI - Nonsteroidal anti-inflammatory drugs causing local inflammation of tissue at the site of injection. PMID- 27127393 TI - Incidence of metabolic syndrome in breast cancer survivors on adjuvant hormonal therapy. PMID- 27127394 TI - Evaluation of inter-rater agreement between three causality assessment methods used in pharmacovigilance. PMID- 27127395 TI - "Ping-pong gaze" secondary to monoamine oxidase inhibitor overdose. AB - An infrequent manifestation of monoamine oxidase inhibitor (MAOI) toxicity is "ping-pong gaze" (PPG). We describe the case of a 26-year-old female who was found unresponsive after taking 40 tablets of phenelzine. On presentation to the hospital, her eyes were moving in characteristic "ping pong" fashion. After 6 hours her gaze terminated. The following day her neurologic exam was benign and she had no long-term sequelae. While the etiology of PPG is unknown, it is most often seen with irreversible structural brain damage. However, a detailed literature review revealed that previous cases of MAOI toxicity where the patient survived have all had complete neurologic recovery. PMID- 27127396 TI - Tamoxifen-induced hypertriglyceridemia causing acute pancreatitis. AB - Tamoxifen has both antagonistic and agonistic tissue-specific actions. It can have a paradoxical estrogenic effect on lipid metabolism resulting in elevated triglyceride and chylomicron levels. This can cause life-threatening complications like acute pancreatitis. To our knowledge, very few cases of tamoxifen-induced pancreatitis have been reported in the literature. We report a case of severe hypertriglyceridemia and acute pancreatitis following tamoxifen use. A 50-year-old diabetic lady was on tamoxifen (20mg/day) hormonal therapy for breast cancer. Within 3 months of starting therapy, she developed hypertriglyceridemia and acute pancreatitis. Laboratory values include: Serum amylase 778 IU/L, total cholesterol 785 mg/dL, triglycerides 4568 mg/dL and high density lipoproteins (HDL) 12 mg/dL. Tamoxifen was substituted with letrozole and atorvastatin started. There was a prompt reversal of the adverse effects. Effects on lipid profile must be considered while initiating tamoxifen in predisposed individuals as the consequences are life threatening. PMID- 27127397 TI - Pioglitazone-induced congestive heart failure and pulmonary edema in a patient with preserved ejection fraction. AB - Pioglitazone-induced heart failure is known in patients with underlying heart disease, but is not well documented in patients with normal left ventricular function. Pioglitazone has been very popular as it is an insulin sensitizer and insulin resistance is prevalent among Indians. Fluid retention exacerbates pre existing heart failure or precipitates heart failure in a patient with underlying left ventricular dysfunction. However, pathogenesis of heart failure in a patient with normal left ventricular function is not known. Probably it is due to dose related effect on pulmonary endothelial permeability, rather than alterations in left ventricular mass or ejection fraction. We report a patient who developed congestive heart failure and pulmonary edema with normal left ventricular function within 1 year of starting pioglitazone therapy. We have to be careful in monitoring all possible side effects during followup when patients are on pioglitazone therapy. PMID- 27127398 TI - Acute compartment syndrome of hand resulting from radiographic contrast iohexol extravasation. AB - Intravenous (IV) administration of iodinated contrast agents (ICAs) is frequently employed for image enhancement while performing radiographic studies such as computed tomography and angiography. Complications related to IV administration of ICAs such as immediate hypersensitivity reactions and nephrotoxicity are well known. However, severe skin and soft tissue injuries and acute compartment syndrome resulting from contrast extravasation are rare. This is especially so with small volume extravasation of a low osmolar, nonionic ICA such as iohexol. Here, we report a 63-year-old woman who developed acute compartment syndrome of left hand following iohexol extravasation and had swelling, blistering, cutaneous and soft tissue necrosis. She underwent fasciotomy for acute compartment syndrome of hand and later surgical debridement of necrotic skin and soft tissues was carried out. Clinical pharmacology of ICAs, extravasation injuries following their IV administration, their management and measures to reduce them are discussed in brief. PMID- 27127399 TI - Exercise-induced urticaria, cholinergic urticaria, and Kounis syndrome. PMID- 27127400 TI - A closer look at the World Health Organization's prescribing indicators. AB - This communication focuses on the World Health Organization's prescribing indicators. It describes the methods for computing the indicators and highlights their applicability as well as limitations in evaluating the patterns of medicines usage. PMID- 27127401 TI - Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir. AB - Combination antiretroviral therapy (cART) is successfully used for prevention of perinatal HIV transmission. To investigate safety, we compared adverse events (AE) among infants exposed to different maternal cART regimens. We reviewed 158 HIV-uninfected infants born between 1997 and 2009, using logistic regression to model grade >=1 AE and grade >=3 AE as a function of maternal cART and confounding variables (preterm, C-section, illicit drug use, race, ethnicity, infant antiretrovirals, and maternal viremia). Frequently used cART regimens included zidovudine (63%), lamivudine (80%), ritonavir-boosted lopinavir (37%), nelfinavir (26%), and atazanavir (10%). At birth, anemia occurred in 13/140 infants (9%), neutropenia in 27/107 (25%), thrombocytopenia in 5/133 (4%), and liver enzyme elevation in 21/130 (16%). Corresponding rates of AE at 4 weeks were 59/141 (42%), 54/130 (42%), 3/137 (2%), and 3/104 (3%), respectively. Serious AE (grade >= 3) exceeded 2% only for neutropenia (13% at birth; 9% at 4 weeks). Compared with infants exposed to maternal lopinavir/ritonavir, infants exposed to nelfinavir and atazanavir had a 5-fold and 4-fold higher incidence of AE at birth, respectively. In conclusion, hematologic and hepatic AE were frequent, but rarely serious. In this predominantly protease inhibitor-treated population, lopinavir/ritonavir was associated with the lowest rate of infant AE. PMID- 27127402 TI - Evolutionary Genomics. PMID- 27127404 TI - Data Requirements for Model-Based Cancer Prognosis Prediction. AB - Cancer prognosis prediction is typically carried out without integrating scientific knowledge available on genomic pathways, the effect of drugs on cell dynamics, or modeling mutations in the population. Recent work addresses some of these problems by formulating an uncertainty class of Boolean regulatory models for abnormal gene regulation, assigning prognosis scores to each network based on intervention outcomes, and partitioning networks in the uncertainty class into prognosis classes based on these scores. For a new patient, the probability distribution of the prognosis class was evaluated using optimal Bayesian classification, given patient data. It was assumed that (1) disease is the result of several mutations of a known healthy network and that these mutations and their probability distribution in the population are known and (2) only a single snapshot of the patient's gene activity profile is observed. It was shown that, even in ideal settings where cancer in the population and the effect of a drug are fully modeled, a single static measurement is typically not sufficient. Here, we study what measurements are sufficient to predict prognosis. In particular, we relax assumption (1) by addressing how population data may be used to estimate network probabilities, and extend assumption (2) to include static and time series measurements of both population and patient data. Furthermore, we extend the prediction of prognosis classes to optimal Bayesian regression of prognosis metrics. Even when time-series data is preferable to infer a stochastic dynamical network, we show that static data can be superior for prognosis prediction when constrained to small samples. Furthermore, although population data is helpful, performance is not sensitive to inaccuracies in the estimated network probabilities. PMID- 27127403 TI - Human Dispersal Out of Africa: A Lasting Debate. AB - Unraveling the first migrations of anatomically modern humans out of Africa has invoked great interest among researchers from a wide range of disciplines. Available fossil, archeological, and climatic data offer many hypotheses, and as such genetics, with the advent of genome-wide genotyping and sequencing techniques and an increase in the availability of ancient samples, offers another important tool for testing theories relating to our own history. In this review, we report the ongoing debates regarding how and when our ancestors left Africa, how many waves of dispersal there were and what geographical routes were taken. We explore the validity of each, using current genetic literature coupled with some of the key archeological findings. PMID- 27127406 TI - Use of Metatranscriptomics in Microbiome Research. AB - The human intestinal microbiome is a microbial ecosystem that expresses as many as 100 times more genes than the human host, thereby constituting an important component of the human holobiome, which contributes to multiple health and disease processes. As most commensal species are difficult or impossible to culture, genomic characterization of microbiome composition and function, under various environmental conditions, comprises a central tool in understanding its roles in health and disease. The first decade of microbiome research was mainly characterized by usage of DNA sequencing-based 16S rDNA and shotgun metagenome sequencing, allowing for the elucidation of microbial composition and genome structure. Technological advances in RNA-seq have recently provided us with an ability to gain insight into the genes that are actively expressed in complex bacterial communities, enabling the elucidation of the functional changes that dictate the microbiome functions at given contexts, its interactions with the host, and functional alterations that accompany the conversion of a healthy microbiome toward a disease-driving configuration. Here, we highlight some of the key metatranscriptomics strategies that are implemented to determine microbiota gene expression and its regulation and discuss the advantages and potential challenges associated with these approaches. PMID- 27127405 TI - Risk of Infectious Complications in Hemato-Oncological Patients Treated with Kinase Inhibitors. AB - Infectious complications are a major cause of morbidity and mortality in patients with hemato-oncological diseases. Although disease-related immunosuppression represents one factor, aggressive treatment regimens, such as chemotherapy, stem cell transplantation, or antibody treatment, account for a large proportion of infectious side effects. With the advent of targeted therapies affecting specific kinases in malignant diseases, the outcome of patients has further improved. Nonetheless, dependent on the specific pathway targeted or off-target activity of the kinase inhibitor, therapy-associated infectious complications may occur. We review the most common and approved kinase inhibitors targeting a variety of hemato-oncological malignancies for their immunosuppressive potential and evaluate their risk of infectious side effects based on preclinical evidence and clinical data in order to raise awareness of the potential risks involved. PMID- 27127407 TI - A Randomized Pilot Study of Inositol in Association with Betaine and Boswellia in the Management of Mastalgia and Benign Breast Lump in Premenopausal Women. AB - Benign mammary lumps and mastalgia are the most common breast disorders; yet, there is no clear-cut consensus about the best strategy for their treatment. We hypothesized that a combination, including boswellic acid, betaine, and myoinositol, would be beneficial in breast disorders by exerting a pleiotropic effect on multiple pathways. Indeed, myoinositol has already been proven to modulate some factors involved in the genesis of breast diseases, such as fibrosis and metabolic and endocrine cues. In our study, 76 women were randomly assigned to either the experimental or the placebo arm. After six months of treatment, statistically significant differences between the two groups were recorded for pain relief (56% vs 17%) and breast density reduction (60% vs 9%). Furthermore, benign breast mass dimension showed a reduction in the experimental group (40% vs 16%). The combination of boswellic acid, betaine, and myoinositol has been demonstrated to be effective in the treatment of breast pain and radiologically and histologically confirmed benign breast mass and in the reduction of breast density, one of the pivotal risk factors for the development of breast cancer, without any side effects. PMID- 27127408 TI - Breast Cancer in the Bahamas in 2009-2011. AB - BACKGROUND: Breast cancer is the most common form of cancer affecting women in the Bahamas, which consists of many islands. This is the first attempt to identify which island has the highest occurrence of breast cancer. OBJECTIVE: The aim of this study was to describe the sociodemographical and spatial features of breast cancer in the Bahamas in 2009-2011. METHODS: A review of the medical records of all women with a confirmed diagnosis of breast cancer during the period January 1, 2009-December 31, 2011, was undertaken. Data were first obtained from the National Oncology Board of the Bahamas and validated by a review of the medical records. The patient address was geocoded and mapped using ArcGIS 10.0 Environmental Systems Research Institute (ESRI) to satellite images obtained from The Nature Conservancy in the Bahamas. RESULTS: We recruited 270 patients who satisfied the entry criteria. The cumulative incidences of breast cancer for the years 2009-2011 were 51.4, 45.4, and 51.4, respectively. Breast cancer occurred most often in women of African origin with a mean age at diagnosis of 56.6 +/- 13.8 years. Ductal carcinoma was the most common histological type observed with most cancers occurring in Grade II or higher and presenting as late stage (>= Stage II). Surgery was the preferred method of treatment with modified radical mastectomy being the procedure of choice. Spatial distribution of cases across the Bahamas revealed one cluster, which is present on the island of New Providence. Further analysis of New Providence showed a consistently skewed kernel density in the central and eastern regions, compared with a scattered distribution in the southern and western regions. CONCLUSION: The island of New Providence had the highest occurrence of breast cancer among all the islands of the Bahamas. The increasing incidence of breast cancer in young women is likely to impose a significant burden on the future of Bahamian health care. PMID- 27127409 TI - Distribution of Acanthamoeba Genotypes Isolated from Recreational and Therapeutic Geothermal Water Sources in Southwestern Iran. AB - A comprehensive survey was conducted along 10 km of geothermal rivers in southwestern Iran. A total of 40 water samples were tested for the presence of Acanthamoeba spp., and genotypes were determined by targeting the diagnostic fragment 3 region of the 18S rRNA gene. The pathogenic potential of all positive isolates was also identified using tolerance ability test. High occurrences of Acanthamoeba (50%) were detected in the sampling areas. Based on sequencing analysis, isolates belonging to T4 (93.7%) and T2 (6.25%) genotypes were reported. Thermo- and osmotolerance tests revealed that five strains are highly pathogenic. Since every collection site of this study was associated with high human activity, posting of warning signs, monitoring of recreational water sources, and awareness of high-risk people are of utmost importance. To the best of our knowledge, the present research is the first to report T2 genotype from geothermal water sources in Iran. PMID- 27127411 TI - Effects of Feeding Garlic and Juniper Berry Essential Oils on Milk Fatty Acid Composition of Dairy Cows. AB - Essential oils (EOs) from plant extracts have been reported to have an antibacterial activity against gram-negative and gram-positive bacteria. Several of the gram-positive bacteria are involved in ruminal biohydrogenation of fatty acids (FAs), thus suggesting that feeding EOs could lower biohydrogenation of FA because of a decrease in the number of bacteria involved in that process. As a result, milk FA profiles are expected to be modified. In addition, monensin was approved as an antibiotic to be fed in dairy cattle, and it was reported that dairy cows supplemented with monensin produced milk containing higher concentration of 18:1 t10 and 18:1 t11. The objective of this study was to evaluate the effects of two EOs (garlic and juniper berry oils) and monensin on FA profiles of milk fat. Four ruminally fistulated Holstein dairy cows were used in a 4 * 4 Latin square experiment. Cows were fed for ad libitum intake a total mixed ration without supplementation (control), or supplemented with monensin (330 mg/head per day), garlic oil (5 g/head per day), or juniper berry oil (2 g/head per day). The FA composition of saturated, monounsaturated, or polyunsaturated was not affected by supplementation of EO and monensin. However, proportion of conjugated linoleic acid trans 10, cis 12 (CLA t10, c12) was higher (P < 0.05) for cows fed EO or monensin than for control cows. Supplementation of monensin increased (P < 0.05) the proportion of total trans FA compared with the control. These results indicate that supplementation of the dairy cow diet with garlic or juniper berry EO or monensin had the potential to increase the proportion of CLA t10, c12 in milk fat with minimal overall effects on FA of milk fat. The results also confirm the increase of 18:1 t10 in milk fat by feeding monensin to dairy cows. PMID- 27127412 TI - Biomarkers For Colon Cancer. PMID- 27127410 TI - Relating Anaerobic Digestion Microbial Community and Process Function. AB - Anaerobic digestion (AD) involves a consortium of microorganisms that convert substrates into biogas containing methane for renewable energy. The technology has suffered from the perception of being periodically unstable due to limited understanding of the relationship between microbial community structure and function. The emphasis of this review is to describe microbial communities in digesters and quantitative and qualitative relationships between community structure and digester function. Progress has been made in the past few decades to identify key microorganisms influencing AD. Yet, more work is required to realize robust, quantitative relationships between microbial community structure and functions such as methane production rate and resilience after perturbations. Other promising areas of research for improved AD may include methods to increase/control (1) hydrolysis rate, (2) direct interspecies electron transfer to methanogens, (3) community structure-function relationships of methanogens, (4) methanogenesis via acetate oxidation, and (5) bioaugmentation to study community-activity relationships or improve engineered bioprocesses. PMID- 27127413 TI - Benign Sphenoid Wing Meningioma Presenting with an Acute Intracerebral Hemorrhage - A Case Report. AB - BACKGROUND AND STUDY OBJECT: We report an unusual case of a benign lateral sphenoid wing meningioma that presented with, and was masked by, an acute intracerebral hemorrhage. CASE REPORT: A 68-year-old woman was admitted after sudden onset of coma. Computed tomography (CT) revealed an intracerebral hemorrhage, without any underlying vascular pathology on CT angiography. During the surgery, we found a lateral sphenoid wing meningioma with intratumoral bleeding that extended into the surrounding brain parenchyma. RESULTS: We removed the hematoma and resected the tumor completely in the same session. The histopathological classification of the tumor was a WHO grade I meningothelial meningioma. The patient recovered very well after surgery, without significant neurological sequelae. CONCLUSIONS: Having reviewed the relevant references from the medical literature, we consider this event as an extremely rare presentation of a benign sphenoid wing meningioma in a patient without any predisposing medical factors. The possible mechanisms of bleeding from this tumor type are discussed. PMID- 27127414 TI - Lung-On-A-Chip Technologies for Disease Modeling and Drug Development. AB - Animal and two-dimensional cell culture models have had a profound impact on not only lung research but also medical research at large, despite inherent flaws and differences when compared with in vivo and clinical observations. Three dimensional (3D) tissue models are a natural progression and extension of existing techniques that seek to plug the gaps and mitigate the drawbacks of two dimensional and animal technologies. In this review, we describe the transition of historic models to contemporary 3D cell and organoid models, the varieties of current 3D cell and tissue culture modalities, the common methods for imaging these models, and finally, the applications of these models and imaging techniques to lung research. PMID- 27127415 TI - Prediction of Peaks of Seasonal Influenza in Military Health-Care Data. AB - Influenza is a highly contagious disease that causes seasonal epidemics with significant morbidity and mortality. The ability to predict influenza peak several weeks in advance would allow for timely preventive public health planning and interventions to be used to mitigate these outbreaks. Because influenza may also impact the operational readiness of active duty personnel, the US military places a high priority on surveillance and preparedness for seasonal outbreaks. A method for creating models for predicting peak influenza visits per total health care visits (ie, activity) weeks in advance has been developed using advanced data mining techniques on disparate epidemiological and environmental data. The model results are presented and compared with those of other popular data mining classifiers. By rigorously testing the model on data not used in its development, it is shown that this technique can predict the week of highest influenza activity for a specific region with overall better accuracy than other methods examined in this article. PMID- 27127416 TI - Predictors of English Health Literacy among U.S. Hispanic Immigrants: The importance of language, bilingualism and sociolinguistic environment. AB - In the United States, data confirm that Spanish-speaking immigrants are particularly affected by the negative health outcomes associated with low health literacy. Although the literature points to variables such as age, educational background and language, only a few studies have investigated the factors that may influence health literacy in this group. Similarly, the role that bilingualism and/or multilingualism play in health literacy assessment continues to be an issue in need of further research. The purpose of this study was to examine the predictors of English health literacy among adult Hispanic immigrants whose self-reported primary language is Spanish, but who live and function in a bilingual community. It also explored issues related to the language of the instrument. An analysis of data collected through a randomized controlled study was conducted. Results identified English proficiency as the strongest predictor of health literacy (p < 0.001). The results further point to the importance of primary and secondary language in the assessment of heath literacy level. This study raises many questions in need of further investigation to clarify how language proficiency and sociolinguistic environment affect health literacy in language minority adults; proposes language approaches that may be more appropriate for measuring health literacy in these populations; and recommends further place-based research to determine whether the connection between language proficiency and health is generalizable to border communities. PMID- 27127417 TI - Effectiveness of needle/syringe programmes and opiate substitution therapy in preventing HCV transmission among people who inject drugs. AB - : This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the impact of needle/syringe programmes with and without opiate substitution therapy (OST) on the incidence of HCV infection among people who inject drugs (PWID).To assess the effect of OST alone on the incidence of HCV infection among PWID. RESEARCH QUESTIONS: How effective are needle/syringe programmes (NSP) with and without the use of OST for reducing HCV incidence among PWID?How effective is OST alone for reducing HCV incidence among PWID?How does the effect of NSP and OST vary according to duration of treatment (i.e. for NSPs weekly attendance versus monthly)?How does the effect of NSP vary according to the type of service (fixed site versus mobile; high coverage versus low coverage)?How does the effect of OST vary according to the dosage of OST, type of substitution used and adherence to treatment? PMID- 27127418 TI - Manoeuvring along the edge of breathlessness: an ethnographic case study of two nurses. AB - BACKGROUND: There appears to be divergence between nurses' and patients' perceptions of dyspnoea onset and on how help should be given. This may affect how nurses understand and assess their patients' anxiety and the severity of dyspnoea, potentially diminishing their chances of relieving patients' dyspnoea. The aim of this study was to explore nurse-patient interaction in situations where patients with chronic obstructive pulmonary disease are experiencing acute or worsened dyspnoea in a hospital setting. METHODS: An ethnographic study using participant observation of two nurses' interactions with six patients, followed by qualitative in-depth interviews with the nurses. Data were analysed in three steps. First, they were coded for identification of preliminary themes. Second, data were regrouped into preliminary themes for focused analysis which led to formulation of themes and subthemes. Third, hermeneutical principles were used as all data were interpreted from the viewpoint of each theme. RESULTS: Three themes were identified: Manoeuvring along the edge; Dyspnoea within the pattern; and Dyspnoea outside the pattern. They were encompassed by the main finding: Manoeuvring along the edge of breathlessness. The nurses attempted to navigate between implicit and explicit care approaches and to create a sphere for relieving or avoiding further worsening of dyspnoea. Depending on the identified pattern for a particular dyspnoeic episode, nurses attributed different significance to the dyspnoea. CONCLUSIONS: Interacting in dyspnoeic situations places nurses in a dilemma: an implicit approach risk, deriving from exclusion of patients and performing hesitantly; or an explicit negotiation risk, where patients are exhausted and removed from focusing and breathing. The dilemma weakens nurses' opportunities to relieve or avoid a worsening of the dyspnoea. Likewise, the divergence between nurses' and patients' assessment of dyspnoea as within or outside the pattern appears to jeopardize the efficiency of care. Our findings contribute to a deeper understanding of the challenges of respiratory nursing care in general, and the challenges of relieving in-patients' dyspnoea in particular. PMID- 27127419 TI - Improving the usefulness of US mortality data: new methods for reclassification of underlying cause of death. AB - BACKGROUND: Mortality data are affected by miscertification of the medical cause of death deaths and changes to cause of death classification systems. We present both mappings of ICD9 and ICD10 to a unified list of causes, and a new statistical model for reducing the impact of misclassification of cause of death. METHODS: We propose a Bayesian mixed-effects multinomial logistic model that can be run on individual record level death certificates to reclassify "garbage coded" deaths onto causes that are more meaningful for public health purposes. The model uses information on the contributing causes of death and demographic characteristics of each decedent to make informed predictions of the underlying cause of death. We apply our method to death certificate data in the US from 1979 to 2011, creating more directly comparable series of cause-specific mortality for 25 major causes of death. RESULTS: We find that many death certificates coded to garbage codes contain other information that provides strong clues about the valid underlying cause of death. In particular, a plausible underlying cause often appears in the contributing causes of death, implying that it may be incorrect ordering of the causal chain and not missed cause assignment that leads to many garbage-coded deaths. We present an example that redistributes 48 % of heart failure deaths to other cardiovascular diseases, 25 % to ischemic heart disease, and 15 % to chronic respiratory diseases. CONCLUSIONS: Our methods take advantage of more detailed micro-level data than is typically considered in garbage code redistribution algorithms, making it a useful tool in circumstances in which detailed death certificate data needs to be aggregated for public health purposes. We find that this method gives different redistribution results than commonly used methods that only consider population-level proportions. PMID- 27127421 TI - Texas Heart Institute Medal and the Ray C. Fish Award for Scientific Achievement in Cardiovascular Diseases. PMID- 27127420 TI - Endothelial Mesenchymal Transition: Comparative Analysis of Different Induction Methods. AB - BACKGROUND: Endothelial-Mesenchymal-Transition (EndMT) plays an essential role in cardiovascular development, and recently became an attractive therapeutic target based on evidence supporting its involvement in fibrosis and cancer. Important questions that remain to be answered are related to the molecular mechanisms that control EndMT in different organs and distinct pathological conditions. The lack of a detailed protocol for induction of EndMT and the assumption that TGF-beta isoforms play similar roles on different types of endothelial cells, limit progress in the field. The aim of this study was to compare the induction of EndMT by TGF-beta isoforms in endothelial cells of different sources, and define a detailed protocol for EndMT assessment in vitro. RESULTS: We compared the dose dependent effect of TGF-beta isoforms, under normoxia and hypoxia, on the induction of EndMT in human coronary and pulmonary artery endothelial cells. Our results suggest that endothelial cells undergo spontaneous EndMT with time in culture under the conditions tested. The extent of EndMT induction by TGF-beta was dependent on the dose and endothelial cell type. Furthermore, the potential of TGF-beta to induce EndMT was reduced under hypoxia relative to normoxia. CONCLUSIONS: Our work suggests that the response of endothelial cells to TGF-beta is intrinsic to the dose, cell type and environment. Optimization of induction conditions may be essential, as pathways triggering EndMT may vary during development and pathological conditions. Therefore, caution is needed regarding indiscriminate use of TGF-beta to induce EndMT for mechanistic studies. PMID- 27127422 TI - A Life-Saving Cancer: More on the Double Whammy. PMID- 27127423 TI - Surviving a Double Whammy. PMID- 27127424 TI - Effect of Elective Bentall Procedure on Left Ventricular Systolic Function and Functional Status: Long-Term Follow-Up in 90 patients. AB - Because there are so few data on the long-term effects on left ventricular systolic function and functional status in patients who electively undergo Bentall procedures, we established a retrospective study group of 90 consecutive patients. This group consisted of 71 male and 19 female patients (mean age, 54 +/ 10 yr) who had undergone the Bentall procedure to correct aortic valve disease and aneurysm of the ascending aorta, from 1997 through 2003 in a single tertiary care center. We monitored these patients for a mean period of 117 +/- 41 months for death, left ventricular ejection fraction and volume indices, and functional capacity as determined by New York Heart Association (NYHA) class. There were no operative deaths. The survival rate was 73.3% during follow-up. There were 10 cardiac and 13 noncardiac deaths, and 1 death of unknown cause. Echocardiography was performed before the index procedure and again after 117 +/- 41 months. In surviving patients, statistically significant improvement in left ventricular ejection fraction, in comparison with preoperative values (0.49 +/- 0.11 vs 0.41 +/- 0.11; P <0.0001), was noted at follow-up. Similarly, we observed statistically significant reductions in left ventricular end-systolic (39.24 +/- 28.7 vs 48.77 +/- 28.62 mL/m(2)) and end-diastolic volumes (54.63 +/- 6.97 vs 59.17 +/- 8.92 mL/m(2); both P <0.0001). Most patients (53/66 [80.3%]) progressed from a higher to a lower NYHA class during the follow-up period. The Bentall procedure significantly improved long-term left ventricular systolic function and functional status in surviving patients who underwent operation on a nonemergency basis. PMID- 27127425 TI - Biventricular Myocardial Performance Is Impaired in Proportion to Severity of Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular morbidity and death. Little information is available regarding the relationship between the severity of OSA and myocardial performance in OSA patients who have normal ejection fractions. We prospectively investigated this relationship, using the tissue-Doppler myocardial performance index (TD-MPI). We conducted overnight, full-laboratory polysomnographic examinations of 116 patients, and calculated the left and right ventricular TD-MPIs. Patients were classified into 3 groups in accordance with their apnea-hypopnea index (AHI) levels: AHImild (>=5 to <15), AHImoderate (>=15 to <30), and AHIsevere (>=30). Left and right ventricular TD MPI values were higher in the AHIsevere group than in the AHImild and AHImoderate groups (all P <0.05). In addition, right ventricular TD-MPI values in the AHImoderate group were higher than those in the AHImild group (P <0.05). Right ventricular TD-MPI was significantly associated with AHI (beta=0.468, P <0.001), left ventricular TD-MPI, and right ventricular early-to-late filling velocities (E/A ratio) in multiple linear regression analysis. On the other hand, left ventricular TD-MPI was significantly associated with right ventricular TD-MPI and left ventricular E/A ratio (both P <0.05). Our results show that OSA severity, determined by means of AHI, is independently associated with impaired right and left ventricular function as indicated by TD-MPI in patients who have OSA and normal ejection fractions. PMID- 27127426 TI - Biodegradable-Polymer Biolimus-Eluting Stents versus Durable-Polymer Everolimus Eluting Stents at One-Year Follow-Up: A Registry-Based Cohort Study. AB - We compared outcomes of percutaneous coronary intervention patients who received biodegradable-polymer biolimus-eluting stents with those who received durable polymer everolimus-eluting stents. At Tehran Heart Center, we performed a retrospective analysis of the data from January 2007 through December 2011 on 3,270 consecutive patients with coronary artery disease who underwent percutaneous coronary intervention with the biodegradable-polymer biolimus eluting stent or the durable-polymer everolimus-eluting stent. We excluded patients with histories of coronary artery bypass grafting or percutaneous coronary intervention, acute ST-segment-elevation myocardial infarction, or the implantation of 2 different stent types. Patients were monitored for 12 months. The primary endpoint was a major adverse cardiac event, defined as a composite of death, nonfatal myocardial infarction, and target-vessel and target-lesion revascularization. Durable-polymer everolimus-eluting stents were implanted in 2,648 (81%) and biodegradable-polymer biolimus-eluting stents in 622 (19%) of the study population. There was no significant difference between the 2 groups (2.7% vs 2.7%; P=0.984) in the incidence of major adverse cardiac events. The cumulative adjusted probability of major adverse cardiac events in the biodegradable-polymer biolimus-eluting stent group did not differ from that of such events in the durable-polymer everolimus-eluting stent group (hazard ratio=0.768; 95% confidence interval, 0.421-1.44; P=0.388). We conclude that in our patients the biodegradable-polymer biolimus-eluting stent was as effective and safe, during the 12-month follow-up period, as was the durable-polymer everolimus-eluting stent. PMID- 27127427 TI - Longitudinal Changes in Vascular Risk Markers and Mortality Rates among a Latino Population with Hypertension. AB - Vascular markers such as pulse-wave velocity and carotid intima-media thickness (CIMT) might improve the prediction of incident cardiovascular disease beyond traditional risk factors. These vascular markers have not been well characterized in minority populations and might be more useful than inflammatory biomarkers. We conducted a prospective, longitudinal cohort study among hypertensive patients in an urban safety-net hospital. We evaluated inflammatory biomarkers, arterial pulse-wave velocity, and carotid intima-media thickness at baseline, 1 year, and 2 years. The primary outcome variable was CIMT. Generalized linear mixed-effects models were used to evaluate associations between CIMT and predictive variables accounting for the correlation of multiple measurements within subjects over time. For our secondary outcome, we used administrative and National Death Index data to determine all-cause death, and univariate relationships were evaluated. Among 175 subjects, 117 were Latino (67%) and 117 were female (67%). Pulse-wave velocity and CIMT regressed over time (both P <0.001) and were highly correlated (P <0.001). Only pulse-wave velocity (P=0.002) and total cholesterol (P=0.03) were associated with CIMT in time-varying covariate analysis. At a median follow up period of 80 months, 17 of 175 subjects had died (10%). Higher baseline CIMT and pulse-wave velocity were associated with increased mortality rates (both P <0.01). No serum inflammatory marker was significantly correlated with longitudinal changes in CIMT or death. In conclusion, both arterial stiffness and preclinical carotid atherosclerosis were associated with increased mortality rates and might be useful risk-stratification markers among this minority population. PMID- 27127428 TI - Retrograde Transcatheter Closure of Mitral Paravalvular Leak through a Mechanical Aortic Valve Prosthesis: 2 Successful Cases. AB - The presence of a mechanical aortic valve prosthesis has been considered a contraindication to retrograde percutaneous closure of mitral paravalvular leaks, because passing a catheter through the mechanical aortic valve can affect the function of a mechanical valve and thereby lead to severe hemodynamic deterioration. We report what we believe are the first 2 cases of retrograde transcatheter closure of mitral paravalvular leaks through a mechanical aortic valve prosthesis without transseptal or transapical puncture. Our experience shows that retrograde transcatheter closure of mitral paravalvular leaks in this manner can be an optional approach for transcatheter closure of such leaks, especially when a transapical or transseptal puncture approach is not feasible. This technique might also be applied to other transcatheter procedures in which there is a need to pass a catheter through a mechanical aortic valve prosthesis. PMID- 27127429 TI - Advancing a Guiding Catheter Across a Mechanical Aortic Valve. PMID- 27127430 TI - Left Brachiocephalic Vein Cannulation in Bicaval Venous Drainage Is Safe, Effective, and Technically Advantageous. AB - Direct cannulation of both venae cavae (bicaval venous cannulation) is the gold standard for right atrial isolation in intracavitary surgery, but there has been no consensus about an alternative site. Therefore, we studied an alternative method for bicaval venous drainage in which the left brachiocephalic vein (LBCV) is cannulated instead of the superior vena cava. From 2012 through 2014, we performed routine LBCV cannulation in 150 consecutive patients as part of bicaval venous drainage before right atrial isolation. We prospectively collected demographic information, operative data, total pump and LBCV cannula flows with their respective calculated and indexed rates, central venous pressures, and perioperative complications. All patients survived surgery. There were no adverse technical outcomes or functional deficits associated with the technique. The mean indexed LBCV cannula flow was 1,520 +/- 216 mL/min/m(2), representing an LBCV cannula-to-calculated pump-flow ratio of 64%. The mean central venous pressure during right atrial isolation was 3.7 +/- 1.9 mmHg. Cannulation of the LBCV is intrinsically a safe and reproducible procedure with proven hemodynamic adequacy. Its versatility can be an asset to surgical techniques and perfusion methods. Furthermore, the hemodynamic results in our series promise alternative intrathoracic and extracardiac cannulation sites for mini-extracorporeal circulation, on-pump beating-heart procedures, and short-term circulatory assist device implementation. PMID- 27127431 TI - Cardiac Papillary Fibroelastoma: Single-Institution Experience with 14 Surgical Patients. AB - In general, treatment for symptomatic and asymptomatic cardiac papillary fibroelastoma is surgical resection-particularly of left-sided lesions, because of the risk of systemic embolization. However, few institutions have enough experience with these tumors to validate this approach. We present our institutional experience with papillary fibroelastoma and discuss our current approach. We searched our institution's cardiac tumor database, identified all patients diagnosed with cardiac papillary fibroelastoma from 1992 through 2014, and recorded the clinical and pathologic characteristics of each case. We found 14 patients (mean age, 60.5 +/- 12.3 yr) who had 18 lesions. Eleven patients (79%) were symptomatic; however, we could not always definitively associate their symptoms with a cardiac tumor. Most lesions were solitary and <=1.5 cm in diameter; half involved the left side of the heart. All 18 lesions were surgically excised. There were no operative or 30-day deaths, and no patient needed valve replacement postoperatively. There was one late death; at one year, another 3 patients were lost to follow-up, and the others were alive without tumor recurrence. Because of the embolic risk inherent to intracardiac masses and our relatively good postoperative outcomes, we recommend the surgical resection of all left-sided papillary fibroelastomas in surgical candidates, and we discuss with patients the advisability of resecting right-sided lesions. PMID- 27127432 TI - Recurrent Takotsubo Cardiomyopathy Related to Recurrent Thyrotoxicosis. AB - Takotsubo cardiomyopathy, or transient left ventricular apical ballooning syndrome, is characterized by acute left ventricular dysfunction caused by transient wall-motion abnormalities of the left ventricular apex and mid ventricle in the absence of obstructive coronary artery disease. Recurrent episodes are rare but have been reported, and several cases of takotsubo cardiomyopathy have been described in the presence of hyperthyroidism. We report the case of a 55-year-old woman who had recurrent takotsubo cardiomyopathy, documented by repeat coronary angiography and evaluations of left ventricular function, in the presence of recurrent hyperthyroidism related to Graves disease. After both episodes, the patient's left ventricular function returned to normal when her thyroid function normalized. These findings suggest a possible role of thyroid-hormone excess in the pathophysiology of some patients who have takotsubo cardiomyopathy. PMID- 27127433 TI - Takotsubo Cardiomyopathy: Establishing Diagnosis and Causes through Prospective Testing. PMID- 27127435 TI - Bacterial Endocarditis Caused by Lactobacillus acidophilus Leading to Rupture of Sinus of Valsalva Aneurysm. AB - Lactobacillus acidophilus rarely causes bacterial endocarditis, because it usually resides in the mucosa of the vagina, gastrointestinal tract, and oropharynx. Moreover, sinus of Valsalva aneurysms are rare cardiac anomalies, either acquired or congenital. We present the case of a middle-aged man whose bacterial endocarditis, caused by Lactobacillus acidophilus, led to an aneurysmal rupture of the sinus of Valsalva into the right ventricular outflow tract. The patient underwent successful surgical repair, despite numerous complications and sequelae. PMID- 27127434 TI - Normal Pregnancy and Birth Despite Ruptured Sinus of Valsalva Aneurysm: Another Case for the Record. AB - Sinus of Valsalva aneurysm is a rare cardiac abnormality. Ruptured sinus of Valsalva aneurysms in pregnancy are of course rarer still. We present a case in which an aneurysm ruptured into the right ventricular outflow tract during pregnancy. In 2012, a 26-year-old Chinese woman, in the 18th week of pregnancy and with no apparent evidence of cardiac problems, was diagnosed with atrioventricular septal defects and a sinus of Valsalva aneurysm that had ruptured into her right ventricular outflow tract. After an uncomplicated full term pregnancy, she gave birth to a healthy baby boy by cesarean section. Fifty days postpartum, the patient underwent surgical repair of the ruptured aneurysm and other cardiac defects. Her surgical outcome was good. As of May 2013, the patient and her baby were healthy. Ruptured sinus of Valsalva aneurysm in pregnancy can be asymptomatic, and women with such a rupture can have a normal full-term pregnancy and give birth to healthy babies. Cesarean section is preferable for pregnant women with ruptured sinus of Valsalva aneurysm because the hemodynamic changes associated with labor can aggravate the aneurysm. Surgical repair should be performed as soon as the patient's condition allows. PMID- 27127436 TI - Bioprosthetic Aortic Valve Endocarditis in Association with Enterococcus durans. AB - Enterococci are common organisms associated with endocarditis, but infection by Enterococcus durans is very rare. To our knowledge, only 3 cases have been reported in the medical literature, and all 3 have involved native valves. Here we publish the first reported case (to our knowledge) of E. durans endocarditis in association with a bioprosthetic aortic valve. After the organism and its antibiotic susceptibility were identified, the 74-year-old male patient was treated successfully with teicoplanin and gentamicin, over a course of 6 weeks. PMID- 27127437 TI - Getting to a Man's Heart through His Colon. AB - A 69-year-old man presented with a progressively enlarging pulsatile mass in the left side of his chest. Because of a history of an ischemic cardiomyopathy, he had been randomized in 2003 to undergo coronary artery bypass grafting with a Dor procedure, as part of the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Our patient's imaging studies, including a thoracic computed tomogram and transthoracic echocardiogram, were now of concern for left ventricular pseudoaneurysm. He was taken immediately for surgical exploration. Purulent material, with empyema, extended from the anterior chest wall through the chest cavity into the mediastinum, with communication into the pericardial space. Notably, there was no compromise of the left ventricular cavity, and there was no pseudoaneurysm. The chest was copiously irrigated before closure. The epicardial patch placed 10 years earlier in the STICH trial was not thought to be the nidus of the abscess and was therefore not removed. Three months later, the patient presented again, this time with hemorrhagic shock and bleeding from his left anterior thoracotomy site, which we then re-entered. He was found to have a left ventricular pseudoaneurysm with disruption of the ventricular apex. The epicardial felt-and-Dacron patch, placed 10 years previously during his Dor procedure, was found to be infected with Clostridium difficile and was removed. The left ventricular apex was repaired. Whereas C. difficile bacteremia is rare, the seeding of prosthetic cardiac material with delayed presentation, as in this case, is extraordinarily uncommon. PMID- 27127438 TI - Stepwise Progression of Right-to-Left Atrial Shunting through a Combination of Patent Foramen Ovale and Tricuspid Regurgitation. AB - Patent foramen ovale is a common clinical finding that generally becomes a concern in the presence of transient ischemic attack or stroke. Rarely, patent foramen ovale is associated with hypoxemia in the presence of substantial right to-left atrial shunting. We present the case of an 86-year-old woman with a pacemaker, who was initially asymptomatic notwithstanding a patent foramen ovale. Over 1.5 years, her symptoms progressed in a stepwise fashion, in the setting of progressive pacemaker-associated tricuspid regurgitation. Ultimately, the patient's symptoms and her hypoxemia resolved after percutaneous closure of her patent foramen ovale with use of a 25-mm "Cribriform" occluder device. This case highlights the fact that clinically significant right-to-left shunting requires an anatomic lesion, such as patent foramen ovale, together with elevated right atrial pressure, which in this case was contributed by severe tricuspid regurgitation. PMID- 27127439 TI - Right Atrial Tumor Resection and Reconstruction with Use of an Acellular Porcine Bladder Membrane. AB - Malignant cardiac tumors typically have a grave prognosis; their resection with negative margins is optimal. We present the case of a 21-year-old woman in whom we surgically resected a primary cardiac sarcoma and reconstructed the right atrium with use of a porcine urinary bladder membrane-the MatriStem((r)) Surgical Matrix PSMX. The patient recovered uneventfully. Six months postoperatively, the right atrial wall had retained its integrity. In addition to our patient's case, we discuss the benefits of using the MatriStem membrane in cardiac reconstruction. PMID- 27127440 TI - Rapid Extracorporeal Membrane Oxygenation Overcomes Fulminant Myocarditis Induced by 5-Fluorouracil. AB - Fulminant myocarditis is a rare but potentially life-threatening illness caused by 5-fluorouracil cardiotoxicity. Data supporting the use of extracorporeal membrane oxygenation for the treatment of fulminant myocarditis are limited. A 49 year-old, previously healthy white man, recently diagnosed with anal squamous cell carcinoma, developed severe chest pain hours after completing his first 96 hour intravenous 5-fluorouracil treatment. Over a period of 3 days from onset of symptoms, the patient developed cardiogenic shock secondary to fulminant myocarditis induced by 5-fluorouracil cardiotoxicity. This required emergency initiation of extracorporeal membrane oxygenation. The patient's systolic function recovered by day 5, and on the 17th day he was discharged in hemodynamically stable condition, without symptoms of heart failure. This case shows the importance of prompt recognition of cardiogenic shock secondary to 5 fluorouracil-induced myocarditis and how the immediate initiation of extracorporeal membrane oxygenation can restore adequate tissue perfusion, leading to myocardial recovery and ultimately the survival of the patient. PMID- 27127441 TI - No Electromagnetic Interference Occurred in a Patient with a HeartMate II Left Ventricular Assist System and a Subcutaneous Implantable Cardioverter Defibrillator. AB - The use of subcutaneous implantable cardioverter-defibrillators is a novel option for preventing arrhythmia-mediated cardiac death in patients who are at risk of endovascular-device infection or in whom venous access is difficult. However, the potential for electromagnetic interference between subcutaneous defibrillators and left ventricular assist devices is largely unknown. We report the case of a 24-year-old man in whom we observed no electromagnetic interference between a subcutaneous implanted cardioverter-defibrillator and a HeartMate II Left Ventricular Assist System, at 3 different pump speeds. To our knowledge, this is the first report of such findings in this circumstance. PMID- 27127442 TI - Valve Replacement with a Sutureless Aortic Prosthesis in a Patient with Concomitant Mitral Valve Disease and Severe Aortic Root Calcification. AB - Aortic valve replacement with concomitant mitral valve surgery in the presence of severe aortic root calcification is technically difficult, with long cardiopulmonary bypass and aortic cross-clamp times. We performed sutureless aortic valve replacement and mitral valve annuloplasty in a 68-year-old man who had severe aortic stenosis and moderate-to-severe mitral regurgitation. Intraoperatively, we found severe calcification of the aortic root. We approached the aortic valve through a transverse aortotomy, performed in a higher position than usual, and we replaced the valve with a Sorin Perceval S sutureless prosthesis. In addition, we performed mitral annuloplasty with use of an open rigid ring. The aortic cross-clamp time was 63 minutes, and the cardiopulmonary bypass time was 83 minutes. No paravalvular leakage of the aortic prosthesis was detected 30 days postoperatively. Our case shows that the Perceval S sutureless bioprosthesis can be safely implanted in patients with aortic root calcification, even when mitral valve disease needs surgical correction. PMID- 27127444 TI - Evaluation of Suspected Device Malfunction on ECG. PMID- 27127443 TI - Heavy Lifting Causing Spontaneous Coronary Artery Dissection with Anterior Myocardial Infarction in a 54-Year-Old Woman. AB - Spontaneous coronary artery dissection in association with strenuous exercise and weightlifting is rather sparsely described in the medical literature. Diagnosis and treatment of this rare condition is a challenge, but prompt recognition and appropriate early choice of angioplasty or surgery can lead to a good outcome. We report the case of a postmenopausal 54-year-old woman who presented with anterior myocardial infarction caused by spontaneous dissection of the left anterior descending coronary artery after she had lifted a heavy weight while gardening. The patient was treated successfully by means of angioplasty and the implantation of 3 drug-eluting stents. In addition to presenting the patient's case, we review the topical medical literature. PMID- 27127445 TI - Percutaneous Left Main Coronary Artery Intervention in a Case of Dextrocardia. PMID- 27127446 TI - Straight Back Syndrome Masquerading as a Mass, with Near-Syncope. PMID- 27127447 TI - Giant Aortopulmonary Collateral Artery in an Adult with Bronchiectasis. PMID- 27127448 TI - Erratum: Pacing on the T Wave: PAVB, Not PVAB. AB - [This corrects the article on p. 94 in vol. 43, PMID: 27047297.]. PMID- 27127450 TI - Peruvian Maca (Lepidium peruvianum): (II) Phytochemical Profiles of Four Prime Maca Phenotypes Grown in Two Geographically-Distant Locations. AB - Peruvian Maca crops (Lepidium peruvianum), grown in two geographically-distant cultivation sites located at similar altitudes in the highlands of the Peruvian Andes (Junin at 4,200 m a.s.l. and Ancash 4,150 m a.s.l.), were used in the study. Four prime Maca phenotypes, distinguished by hypocotyl colours labelled as "Yellow", "Purple", "Red" and "Black" were selected to determine distribution in levels and corresponding ratios between individual Glucosinolates (Glucotropaeolin and m-methylglucotropaeolin) in an attempt to identify four Peruvian Maca phenotypes from analyses of powdered hypocotyls. There were highly significant differences (P<0.01) in hypocotyl weight/size of four Maca phenotypes harvested in two locations. The Junin crop represented a mostly "large" class (13.3 g) with "small" size hypocotyls (7.2 g), while a "small" class was predominant in Ancash (3.5 g). Powdered Yellow Maca showed significantly higher (P<0.001) microbial contamination than the other three, with Black Maca being the least infected. Only minor, statistically-confirmed differences were detected in nutritive characteristics between the four Maca phenotypes grown in Junin, however highly significant differences (P<0.01) in Glucosinolates existed between the Red and Black Maca grown in Junin and Ancash. Irrespective of the cultivation location, Red phenotypes showed the highest content of Total Glucosinolates, followed by Black and Purple, with the Yellow phenotype showing consistently lower levels. Highly significant P<0.01) differences determined in ratios of individual Glucosinolates between four Maca phenotypes grown in two locations, confirms an earlier assumption that sums of individual Glucosinolates, their ratios and profiles, may be feasible to explore in analytically identifying individual Maca phenotypes in pulverised marketed Maca products. PMID- 27127449 TI - Genetic Variation of Fatty Acid Oxidation and Obesity, A Literature Review. AB - Modulation of fat metabolism is an important component of the etiology of obesity as well as individual response to weight loss program. The influence of lipolysis process had receives many attentions in recent decades. Compared to that, fatty acid oxidation which occurred after lipolysis seems to be less exposed. There are limited publications on how fatty acid oxidation influences predisposition to obesity, especially the importance of genetic variations of fatty acid oxidation proteins on development of obesity. The aim of this review is to provide recent knowledge on how polymorphism of genes related fatty acid oxidation is obtained. Studies in human as well as animal model showed that disturbance of genes related fatty acid oxidation process gave impact on body weight and risks to obesity. Several polymorphisms on CD36, CPT, ACS and FABP had been shown to be related to obesity either by regulating enzymatic activity or directly influence fatty acid oxidation process. PMID- 27127451 TI - Involvement of Nitric Oxide on Calcium Mobilization and Arachidonic Acid Pathway Activation during Platelet Aggregation with different aggregating agonists. AB - Platelet aggregation by different aggregating agonists is essential in the normal blood coagulation process, the excess of which caused acute coronary syndrome (ACS). In all cases, the activation of arachidonic acid by cycloxygenase was needed for the synthesis of thromboxane A2 (TXA2) but the mechanism of arachidonic acid release in platelets remains obscure. Studies were conducted to determine the role of nitric oxide (NO), if any, on the release of arachidonic acid in platelets. The cytosolic Ca(2+) was visualized and quantitated by fluorescent spectroscopy by using QUIN-2. NO was measured by methemoglobin method. Arachidonic acid was determined by HPLC. TXA2 was measured as ThromboxaneB2 (TXB2) by ELISA. Treatment of platelets in platelet-rich plasma (PRP) with different aggregating agents resulted in the inhibition of nitric oxide synthase (NOS) which inhibited the production of NO synthesis and increased TXA2 synthesis. Furthermore, the treatment of washed PRP with different platelet aggregating agents resulted in the increase of [Ca(2+)] in nM ranges. In contrast, the pre-treatment of washed PRP with aspirin increased platelet NO level and inhibited the Ca(2+) mobilization and TXA2 synthesis. These results indicated that the aggregation of platelets by different aggregating agonists was caused by the cytosolic Ca(2+) mobilization due to the inhibition of NOS. PMID- 27127452 TI - Unhappiness with the Fetal Gender is associated with Depression in Adult Pregnant Women Attending Prenatal Care in a Public Hospital in Durango, Mexico. AB - Depression during pregnancy has been scantily studied in Mexican women. We aimed to determine the prevalence and correlates of depression in adult pregnant women attending a public hospital in the northern Mexican city of Durango, Mexico. Through a cross-sectional study design, we assessed depression in 270 adult pregnant women attended for prenatal care in a public hospital using a validated Mexican version of the Edinburg Postnatal Depression Scale in pregnancy and further confirmation by a psychiatric evaluation using the DSM-IV criteria for depression. Prevalence association with socio-demographic, clinical and psychosocial characteristics of the pregnant women was also investigated. Of the 270 pregnant women studied, 101 (37.4%) had EPDS scores equal to or higher than nine. Depression was confirmed in 56 (20.7%) women. Of them, 42 suffered from minor depression and 14 from major depression. Multivariate analysis of socio demographic, clinical and psychosocial characteristics of the women showed that depression was associated with depression before pregnancy (OR = 3.36; 95% CI: 1.20-9.40; P=0.02), anxiety during pregnancy (OR = 9.38; 95% CI: 1.87-46.96; P=0.006), smoking (OR = 25.05; 95% CI: 1.77-353.07; P=0.01), unhappy with the fetal sex (OR = 8.53; 95% CI: 2.46-29.48; P<0.001), and unintended pregnancy (OR = 2.90; 95% CI: 1.07-7.86; P=0.03). Results indicate that about one fifth of the pregnant women studied had confirmed depression. This is the first report of an association of prenatal depression with unhappiness with the fetal sex. Factors associated with prenatal depression found in this study may help for the optimal design of preventive measures against prenatal depression. PMID- 27127453 TI - Total Body Capacitance for Estimating Human Basal Metabolic Rate in an Egyptian Population. AB - Determining basal metabolic rate (BMR) is important for estimating total energy needs in the human being yet, concerns have been raised regarding the suitability of sex-specific equations based on age and weight for its calculation on an individual or population basis. It has been shown that body cell mass (BCM) is the body compartment responsible for BMR. The objectives of this study were to investigate the relationship between total body capacitance (TBC), which is considered as an expression for BCM, and BMR and to develop a formula for calculating BMR in comparison with widely used equations. Fifty healthy nonsmoking male volunteers [mean age (+/- SD): 24.93 +/- 4.15 year and body mass index (BMI): 25.63 +/- 3.59 kg/m(2)] and an equal number of healthy nonsmoking females matched for age and BMI were recruited for the study. TBC and BMR were measured for all participants using octopolar bioelectric impedance analysis and indirect calorimetry techniques, respectively. A significant regressing equation based on the covariates: sex, weight, and TBC for estimating BMR was derived (R=0.96, SEE=48.59 kcal, and P<0.0001), which will be useful for nutritional and health status assessment for both individuals and populations. PMID- 27127455 TI - Health and Health Care of Medicare Beneficiaries in 2030. AB - On Medicare's 50th anniversary, we use the Future Elderly Model (FEM) - a microsimulation model of health and economic outcomes for older Americans - to generate a snapshot of changing Medicare demographics and spending between 2010 and 2030. During this period, the baby boomers, who began turning 65 and aging into Medicare in 2011, will drive Medicare demographic changes, swelling the estimated US population aged 65 or older from 39.7 million to 67.0 million. Among the risks for Medicare sustainability, the size of the elderly population in the future likely will have the highest impact on spending but is easiest to forecast. Population health and the proportion of the future elderly with disabilities are more uncertain, though tools such as the FEM can provide reasonable forecasts to guide policymakers. Finally, medical technology breakthroughs and their effect on longevity are most uncertain and perhaps riskiest. Policymakers will need to keep these risks in mind if Medicare is to be sustained for another 50 years. Policymakers may also want to monitor the equity of Medicare financing amid signs that the program's progressivity is declining, resulting in higher-income people benefiting relatively more from Medicare than lower-income people. PMID- 27127454 TI - Effects of Increased Psychiatric Treatment Contact and Acculturation on the Causal Beliefs of Chinese Immigrant Relatives of Individuals with Psychosis. AB - Encounters with Western psychiatric treatment and acculturation may influence causal beliefs of psychiatric illness endorsed by Chinese immigrant relatives, thus affecting help-seeking. We examined causal beliefs held by forty-six Chinese immigrant relatives and found that greater acculturation was associated with an increased number of causal beliefs. Further, as Western psychiatric treatment and acculturation increased, causal models expanded to incorporate biological/physical causes. However, frequency of Chinese immigrant relatives' endorsing spiritual beliefs did not appear to change with acculturation. Clinicians might thus account for spiritual beliefs in treatment even after acculturation increases and biological causal models proliferate. PMID- 27127456 TI - Hair Mercury Levels Detection in Fishermen from Sicily (Italy) by ICP-MS Method after Microwave-Assisted Digestion. AB - A number of ninety-six hair samples from Sicilian fishermen were examined for total mercury detection by an Inductively Coupled Plasma Mass Spectrometry (ICP MS) method. The mercury levels obtained were compared with mercury levels of 96 hair samples from a control group, in order to assess potential exposure to heavy metals of Sicilian fishermen due to fish consumption and closeness to industrial activities. Furthermore, the mercury levels obtained from hair samples were sorted by sampling area in order to verify the possible risks linked to the different locations. The overall mean concentration in the hair of the population of fishermen was 6.45 +/- 7.03 MUg g(-1), with a highest value in a fisherman of Sciacca (16.48 MUg g(-1)). Hair mercury concentration in fishermen group was significantly higher than in control group (p < 0.01). There was no significant difference in hair total mercury concentrations between sampling areas (p > 0.05). The results of this study indicate a greater risk of exposure to mercury in Sicilian fishermen, in comparison to the control population, due to the high consumption of fish and the close relationship with sources of exposure (ports, dumps, etc.). PMID- 27127457 TI - Matrix metalloproteinases in neural development: a phylogenetically diverse perspective. AB - The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases originally characterized as secreted proteases responsible for degrading extracellular matrix proteins. Their canonical role in matrix remodelling is of significant importance in neural development and regeneration, but emerging roles for MMPs, especially in signal transduction pathways, are also of obvious importance in a neural context. Misregulation of MMP activity is a hallmark of many neuropathologies, and members of every branch of the MMP family have been implicated in aspects of neural development and disease. However, while extraordinary research efforts have been made to elucidate the molecular mechanisms involving MMPs, methodological constraints and complexities of the research models have impeded progress. Here we discuss the current state of our understanding of the roles of MMPs in neural development using recent examples and advocate a phylogenetically diverse approach to MMP research as a means to both circumvent the challenges associated with specific model organisms, and to provide a broader evolutionary context from which to synthesize an understanding of the underlying biology. PMID- 27127458 TI - Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology. AB - Brain-derived neurotrophic factor (BDNF) plays an important role in neurodevelopment, synaptic plasticity, learning and memory, and in preventing neurodegeneration. Despite decades of investigations into downstream signaling cascades and changes in cellular processes, the mechanisms of how BDNF reshapes circuits in vivo remain unclear. This informational gap partly arises from the fact that the bulk of studies into the molecular actions of BDNF have been performed in dissociated neuronal cultures, while the majority of studies on synaptic plasticity, learning and memory were performed in acute brain slices or in vivo. A recent study by Bowling-Bhattacharya et al., measured the proteomic changes in acute adult hippocampal slices following treatment and reported changes in proteins of neuronal and non-neuronal origin that may in concert modulate synaptic release and secretion in the slice. In this paper, we place these findings into the context of existing literature and discuss how they impact our understanding of how BDNF can reshape the brain. PMID- 27127459 TI - Acute development of collateral circulation and therapeutic prospects in ischemic stroke. AB - In acute ischemic stroke, collateral circulation plays an important role in maintaining blood flow to the tissue that is at risk of progressing into ischemia, and in increasing the successful recanalization rate without hemorrhagic transformation. We have reported that well-developed collateral circulation is associated with smaller infarct volume and better long-term neurological outcome, and it disappears promptly once the effective recanalization is achieved. Contrary to the belief that collateral vessels develop over time in chronic stenotic condition, there exists a phenomenon that collateral circulation develops immediately in acute stenosis or occlusion of the arteries and it seems to be triggered by fluid shear stress, which occurs between the territories of stenotic/occluded arteries and those fed by surrounding intact arteries. We believe that this acute development of collateral circulation is a target of novel therapeutics in ischemic stroke and refer our recent attempt in enhancing collateral circulation by modulating sphingosine-1-phosphate receptor 1, which is a known shear-stress mechanosensing protein. PMID- 27127461 TI - Microscale tissue-engineered models: overcoming barriers to adoption for neural regeneration research. PMID- 27127462 TI - Can we protect the brain via preconditioning? Role of microRNAs in neuroprotection. PMID- 27127463 TI - 76nt RNAs are transported axonally into regenerating axons and growth cones. What are they doing there? PMID- 27127464 TI - Recent advances and future directions in preclinical research of arginine vasopressin (AVP) receptor blocker conivaptan in the context of stroke. PMID- 27127465 TI - The role of the unfolded protein response in myelination. PMID- 27127466 TI - Dimethyltryptamine (DMT): a biochemical Swiss Army knife in neuroinflammation and neuroprotection? PMID- 27127460 TI - Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. AB - Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic beta-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM. PMID- 27127467 TI - Inhibition of the AMPK/nNOS pathway for neuroprotection in stroke. PMID- 27127468 TI - Intranasal insulin neuroprotection in ischemic stroke. PMID- 27127469 TI - Estrogen/Huntingtin: a novel pathway involved in neuroprotection. PMID- 27127470 TI - Glial plasticity after hexahydrobenzene exposure. PMID- 27127471 TI - An open-label pilot study with high-dose thiamine in Parkinson's disease. PMID- 27127472 TI - Enzymatic remodeling of heparan sulfate: a therapeutic strategy for systemic and localized amyloidoses? PMID- 27127474 TI - ApoE2 and Alzheimer's disease: time to take a closer look. PMID- 27127473 TI - Multiple sclerosis and neuromyelitis optica spectrum disorders: some similarities in two distinct diseases. PMID- 27127475 TI - Ischemia and reperfusion injury of the spinal cord: experimental strategies to examine postischemic paraplegia. PMID- 27127476 TI - Drosophila neuronal injury model allows for temporal dissection of neurodegenerative events. PMID- 27127477 TI - Contribution of purinergic receptors to spinal cord injury repair: stem cell based neuroregeneration. PMID- 27127478 TI - Vasopressor administration in spinal cord injury: should we apply a universal standard to all injury patterns? PMID- 27127479 TI - Peripheral nerve regeneration monitoring using multilayer microchannel scaffolds. PMID- 27127480 TI - Neuroinflammation in glaucoma: soluble tumor necrosis factor alpha and the connection with excitotoxic damage. PMID- 27127481 TI - GIT1 enhances neurite outgrowth by stimulating microtubule assembly. AB - GIT1, a G-protein-coupled receptor kinase interacting protein, has been reported to be involved in neurite outgrowth. However, the neurobiological functions of the protein remain unclear. In this study, we found that GIT1 was highly expressed in the nervous system, and its expression was maintained throughout all stages of neuritogenesis in the brain. In primary cultured mouse hippocampal neurons from GIT1 knockout mice, there was a significant reduction in total neurite length per neuron, as well as in the average length of axon-like structures, which could not be prevented by nerve growth factor treatment. Overexpression of GIT1 significantly promoted axon growth and fully rescued the axon outgrowth defect in the primary hippocampal neuron cultures from GIT1 knockout mice. The GIT1 N terminal region, including the ADP ribosylation factor GTPase activating protein domain, the ankyrin domains and the Spa2 homology domain, were sufficient to enhance axonal extension. Importantly, GIT1 bound to many tubulin proteins and microtubule-associated proteins, and it accelerated microtubule assembly in vitro. Collectively, our findings suggest that GIT1 promotes neurite outgrowth, at least partially by stimulating microtubule assembly. This study provides new insight into the cellular and molecular pathogenesis of GIT1-associated neurological diseases. PMID- 27127482 TI - Buyanghuanwu decoction promotes angiogenesis after cerebral ischemia/reperfusion injury: mechanisms of brain tissue repair. AB - Buyanghuanwu decoction has been shown to protect against cerebral ischemia/reperfusion injury, but the underlying mechanisms remain unclear. In this study, rats were intragastrically given Buyanghuanwu decoction, 15 mL/kg, for 3 days. A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion. In rats administered Buyanghuanwu decoction, infarct volume was reduced, serum vascular endothelial growth factor and integrin alphavbeta3 levels were increased, and brain tissue vascular endothelial growth factor and CD34 expression levels were increased compared with untreated animals. These effects of Buyanghuanwu decoction were partially suppressed by an angiogenesis inhibitor (administered through the lateral ventricle for 7 consecutive days). These data suggest that Buyanghuanwu decoction promotes angiogenesis, improves cerebral circulation, and enhances brain tissue repair after cerebral ischemia/reperfusion injury. PMID- 27127483 TI - Radix Ilicis Pubescentis total flavonoids ameliorates neuronal damage and reduces lesion extent in a mouse model of transient ischemic attack. AB - Flavonoids are a major component in the traditional Chinese medicine Radix Ilicis Pubescentis. Previous studies have shown that the administration of Radix Ilicis Pubescentis total flavonoids is protective in cerebral ischemia. However, to our knowledge, no studies have examined whether the total flavonoids extracted from Radix Ilicis Pubescentis prevent or ameliorate neuronal damage following transient ischemic attacks. Therefore, Radix Ilicis Pubescentis total flavonoids question and the potential underlying mechanisms. Thus, beginning 3 days before the induction of a mouse model of transient ischemic attack using tert-butyl hydroperoxide injections, mice were intragastrically administered 0.3, 0.15, or 0.075 g/kg of Radix Ilicis Pubescentis total flavonoids daily for 10 days. The results of spectrophotometric analyses demonstrated that Radix Ilicis Pubescentis total flavonoids enhanced oxygen free radical scavenging and reduced pathological alterations in the brain. Hematoxylin-eosin staining results showed that Radix Ilicis Pubescentis total flavonoids reduced hippocampal neuronal damage and cerebral vascular injury in this mouse model of transient ischemic attack. These results suggest that the antioxidant effects of Radix Ilicis Pubescentis total flavonoids alleviate the damage to brain tissue caused by transient ischemic attack. PMID- 27127484 TI - BACE1 in the retina: a sensitive biomarker for monitoring early pathological changes in Alzheimer's disease. AB - Because of a lack of sensitive biomarkers, the diagnosis of Alzheimer's disease (AD) cannot be made prior to symptom manifestation. Therefore, it is crucial to identify novel biomarkers for the presymptomatic diagnosis of AD. While brain lesions are a major feature of AD, retinal pathological changes also occur in patients. In this study, we investigated the temporal changes in beta-site APP cleaving enzyme 1 (BACE1) expression in the retina and brain to determine whether it could serve as a suitable biomarker for early monitoring of AD. APP/PS-1 transgenic mice, 3, 6 and 8 months of age, were used as an experimental group, and age-matched C57/BL6 wild-type mice served as the control group. In the Morris water maze test, there were no significant differences in escape latency or in the number of crossings in the target area among mice of different ages. Compared with wild-type mice, no changes in learning or memory abilities were detected in transgenic mice at 3 months of age. However, compared with wild-type mice, the escape latency was significantly increased in transgenic mice at 6 months, starting on day 3, and at 8 months, starting on day 2, during Morris water maze training. In addition, the number of crossings of the target area was significantly decreased in transgenic mice. The learning and memory abilities of transgenic mice were further worsened at 8 months of age. Immunohistochemical staining revealed no BACE1 plaques in wild-type mice at 3, 6 or 8 months or in transgenic mice at 3 months, but they were clearly found in the entorhinal cortex, hippocampus and prefrontal cortex of transgenic mice at 6 and 8 months. BACE1 expression was not detected in the retina of wild-type mice at 3 months, but weak BACE1 expression was detected in the ganglion cell layer, inner plexiform layer and outer plexiform layer at 6 and 8 months. In transgenic mice, BACE1 expression in the ganglion cell layer was increased at 3 months, and BACE1 expression in the ganglion cell layer, inner plexiform layer and outer plexiform layer was significantly increased at 6 and 8 months, compared with age-matched wild-type mice. Taken together, these results indicate that changes in BACE1 expression appear earlier in the retina than in the brain and precede behavioral deficits. Our findings suggest that abnormal expression of BACE1 in the retina is an early pathological change in APP/PS-1 transgenic mice, and that BACE1 might have potential as a biomarker for the early diagnosis of AD in humans. PMID- 27127486 TI - Neuroprotection against vascular dementia after acupuncture combined with donepezil hydrochloride: P300 event related potential. AB - Acupuncture can be used to treat various nervous system diseases. Here, 168 vascular dementia patients were orally administered donepezil hydrochloride alone (5 mg/day, once a day for 56 days), or combined with acupuncture at Shenting (DU24), Tianzhu (BL10), Sishencong (Extra), Yintang (Extra), Renzhong (DU26), Neiguan (PC6), Shenmen (HT7), Fengchi (GB20), Wangu (GB12) and Baihui (DU20) (once a day for 56 days). Compared with donepezil hydrochloride alone, P300 event related potential latency was shorter with an increased amplitude in patients treated with donepezil hydrochloride and acupuncture. Mini-Mental State Examination score was also higher. Moreover, these differences in P300 latency were identified within different infarcted regions in patients treated with donepezil hydrochloride and acupuncture. These findings indicate that acupuncture combined with donepezil hydrochloride noticeably improves cognitive function in patients with vascular dementia, and exerts neuroprotective effects against vascular dementia. PMID- 27127485 TI - Neuroprotective effects of tetrandrine against vascular dementia. AB - Tetrandrine is one of the major active ingredients in Menispermaceae Stephania tetrandra S. Moore, and has specific therapeutic effects in ischemic cerebrovascular disease. Its use in vascular dementia has not been studied fully. Here, we investigated whether tetrandrine would improve behavioral and cellular impairments in a two-vessel occlusion rat model of chronic vascular dementia. Eight weeks after model establishment, rats were injected intraperitoneally with 10 or 30 mg/kg tetrandrine every other day for 4 weeks. Behavioral assessment in the Morris water maze showed that model rats had longer escape latencies in training trials, and spent less time swimming in the target quadrant in probe trials, than sham-operated rats. However, rats that had received tetrandrine showed shorter escape latencies and longer target quadrant swimming time than untreated model rats. Hematoxylin-eosin and Nissl staining revealed less neuronal necrosis and pathological damage, and more living cells, in the hippocampus of rats treated with tetrandrine than in untreated model rats. Western blot assay showed that interleukin-1beta expression, and phosphorylation of the N-methyl-D aspartate 2B receptor at tyrosine 1472, were lower in model rats that received tetrandrine than in those that did not. The present findings suggest that tetrandrine may be neuroprotective in chronic vascular dementia by reducing interleukin-1beta expression, N-methyl-D-aspartate receptor 2B phosphorylation at tyrosine 1472, and neuronal necrosis. PMID- 27127487 TI - "Warming yang and invigorating qi" acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis. AB - Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. "Warming yang and invigorating qi" acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following "warming yang and invigorating qi" acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10), Zusanli (ST36), Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that "warming yang and invigorating qi" acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis. PMID- 27127488 TI - Macular thickness as a predictor of loss of visual sensitivity in ethambutol induced optic neuropathy. AB - Ethambutol is a common cause of drug-related optic neuropathy. Prediction of the onset of ethambutol-induced optic neuropathy and consequent drug withdrawal may be an effective method to stop visual loss. Previous studies have shown that structural injury to the optic nerve occurred earlier than the damage to visual function. Therefore, we decided to detect structural biomarkers marking visual field loss in early stage ethambutol-induced optic neuropathy. The thickness of peripapillary retinal nerve fiber layer, macular thickness and visual sensitivity loss would be observed in 11 ethambutol-induced optic neuropathy patients (22 eyes) using optical coherence tomography. Twenty-four healthy age- and sex matched participants (48 eyes) were used as controls. Results demonstrated that the temporal peripapillary retinal nerve fiber layer thickness and average macular thickness were thinner in patients with ethambutol-induced optic neuropathy compared with healthy controls. The average macular thickness was strongly positively correlated with central visual sensitivity loss (r (2) =0.878, P=0.000). These findings suggest that optical coherence tomography can be used to efficiently screen patients. Macular thickness loss could be a potential factor for predicting the onset of ethambutol-induced optic neuropathy. PMID- 27127489 TI - Imipramine protects retinal ganglion cells from oxidative stress through the tyrosine kinase receptor B signaling pathway. AB - Retinal ganglion cell (RGC) degeneration is irreversible in glaucoma and tyrosine kinase receptor B (TrkB)-associated signaling pathways have been implicated in the process. In this study, we attempted to examine whether imipramine, a tricyclic antidepressant, may protect hydrogen peroxide (H2O2)-induced RGC degeneration through the activation of the TrkB pathway in RGC-5 cell lines. RGC 5 cell lines were pre-treated with imipramine 30 minutes before exposure to H2O2. Western blot assay showed that in H2O2 -damaged RGC-5 cells, imipramine activated TrkB pathways through extracellular signal-regulated protein kinase/TrkB phosphorylation. TUNEL staining assay also demonstrated that imipramine ameliorated H2O2 -induced apoptosis in RGC-5 cells. Finally, TrkB-IgG intervention was able to reverse the protective effect of imipramine on H2O2 induced RGC-5 apoptosis. Imipramine therefore protects RGCs from oxidative stress induced apoptosis through the TrkB signaling pathway. PMID- 27127490 TI - Characteristics of mRNA dynamic expression related to spinal cord ischemia/reperfusion injury: a transcriptomics study. AB - Following spinal cord ischemia/reperfusion injury, an endogenous damage system is immediately activated and participates in a cascade reaction. It is difficult to interpret dynamic changes in these pathways, but the examination of the transcriptome may provide some information. The transcriptome reflects highly dynamic genomic and genetic information and can be seen as a precursor for the proteome. We used DNA microarrays to measure the expression levels of dynamic evolution-related mRNA after spinal cord ischemia/reperfusion injury in rats. The abdominal aorta was blocked with a vascular clamp for 90 minutes and underwent reperfusion for 24 and 48 hours. The simple ischemia group and sham group served as controls. After rats had regained consciousness, hindlimbs showed varying degrees of functional impairment, and gradually improved with prolonged reperfusion in spinal cord ischemia/reperfusion injury groups. Hematoxylin-eosin staining demonstrated that neuronal injury and tissue edema were most severe in the 24-hour reperfusion group, and mitigated in the 48-hour reperfusion group. There were 8,242 differentially expressed mRNAs obtained by Multi-Class Dif in the simple ischemia group, 24-hour and 48-hour reperfusion groups. Sixteen mRNA dynamic expression patterns were obtained by Serial Test Cluster. Of them, five patterns were significant. In the No. 28 pattern, all differential genes were detected in the 24-hour reperfusion group, and their expressions showed a trend in up-regulation. No. 11 pattern showed a decreasing trend in mRNA whereas No. 40 pattern showed an increasing trend in mRNA from ischemia to 48 hours of reperfusion, and peaked at 48 hours. In the No. 25 and No. 27 patterns, differential expression appeared only in the 24-hour and 48-hour reperfusion groups. Among the five mRNA dynamic expression patterns, No. 11 and No. 40 patterns could distinguish normal spinal cord from pathological tissue. No. 25 and No. 27 patterns could distinguish simple ischemia from ischemia/reperfusion. No. 28 pattern could analyze the need for inducing reperfusion injury. The study of specific pathways and functions for different dynamic patterns can provide a theoretical basis for clinical differential diagnosis and treatment of spinal cord ischemia/reperfusion injury. PMID- 27127491 TI - Salvianolic acid B protects the myelin sheath around injured spinal cord axons. AB - Salvianolic acid B, an active pharmaceutical compound present in Salvia miltiorrhiza, exerts a neuroprotective effect in animal models of brain and spinal cord injury. Salvianolic acid B can promote recovery of neurological function; however, its protective effect on the myelin sheath after spinal cord injury remains poorly understood. Thus, in this study, in vitro tests showed that salvianolic acid B contributed to oligodendrocyte precursor cell differentiation, and the most effective dose was 20 MUg/mL. For in vivo investigation, rats with spinal cord injury were intraperitoneally injected with 20 mg/kg salvianolic acid B for 8 weeks. The amount of myelin sheath and the number of regenerating axons increased, neurological function recovered, and caspase-3 expression was decreased in the spinal cord of salvianolic acid B-treated animals compared with untreated control rats. These results indicate that salvianolic acid B can protect axons and the myelin sheath, and can promote the recovery of neurological function. Its mechanism of action is likely to be associated with inhibiting apoptosis and promoting the differentiation and maturation of oligodendrocyte precursor cells. PMID- 27127492 TI - Substance P combined with epidermal stem cells promotes wound healing and nerve regeneration in diabetes mellitus. AB - Exogenous substance P accelerates wound healing in diabetes, but the mechanism remains poorly understood. Here, we established a rat model by intraperitoneally injecting streptozotocin. Four wounds (1.8 cm diameter) were drilled using a self made punch onto the back, bilateral to the vertebral column, and then treated using amniotic membrane with epidermal stem cells and/or substance P around and in the middle of the wounds. With the combined treatment the wound-healing rate was 100% at 14 days. With prolonged time, type I collagen content gradually increased, yet type III collagen content gradually diminished. Abundant protein gene product 9.5- and substance P-immunoreactive nerve fibers regenerated. Partial nerve fiber endings extended to the epidermis. The therapeutic effects of combined substance P and epidermal stem cells were better than with amniotic membrane and either factor alone. Our results suggest that the combination of substance P and epidermal stem cells effectively contributes to nerve regeneration and wound healing in diabetic rats. PMID- 27127493 TI - Altered microRNA expression profiles in a rat model of spina bifida. AB - MicroRNAs (miRNAs) are dynamically regulated during neurodevelopment, yet few reports have examined their role in spina bifida. In this study, we used an established fetal rat model of spina bifida induced by intragastrically administering olive oil-containing all-trans retinoic acid to dams on day 10 of pregnancy. Dams that received intragastric administration of all-trans retinoic acid-free olive oil served as controls. The miRNA expression profile in the amniotic fluid of rats at 20 days of pregnancy was analyzed using an miRNA microarray assay. Compared with that in control fetuses, the expression of miRNA 9, miRNA-124a, and miRNA-138 was significantly decreased (> 2-fold), whereas the expression of miRNA-134 was significantly increased (> 4-fold) in the amniotic fluid of rats with fetuses modeling spina bifida. These results were validated using real-time quantitative reverse-transcription polymerase chain reaction. Hierarchical clustering analysis of the microarray data showed that these differentially expressed miRNAs could distinguish fetuses modeling spina bifida from control fetuses. Our bioinformatics analysis suggested that these differentially expressed miRNAs were associated with many cytological pathways, including a nervous system development signaling pathway. These findings indicate that further studies are warranted examining the role of miRNAs through their regulation of a variety of cell functional pathways in the pathogenesis of spina bifida. Such studies may provide novel targets for the early diagnosis and treatment of spina bifida. PMID- 27127494 TI - Verapamil inhibits scar formation after peripheral nerve repair in vivo. AB - The calcium channel blocker, verapamil, has been shown to reduce scar formation by inhibiting fibroblast adhesion and proliferation in vitro. It was not clear whether topical application of verapamil after surgical repair of the nerve in vivo could inhibit the formation of excessive scar tissue. In this study, the right sciatic nerve of adult Sprague-Dawley rats was transected and sutured with No. 10-0 suture. The stoma was wrapped with gelfoam soaked with verapamil solution for 4 weeks. Compared with the control group (stoma wrapped with gelfoam soaked with physiological saline), the verapamil application inhibited the secretion of extracellular matrix from fibroblasts in vivo, suppressed type I and III collagen secretion and increased the total number of axons and the number of myelinated axons. These findings suggest that verapamil could reduce the formation of scar tissue and promote axon growth after peripheral nerve repair. PMID- 27127495 TI - Cartilage oligomeric matrix protein enhances the vascularization of acellular nerves. AB - Vascularization of acellular nerves has been shown to contribute to nerve bridging. In this study, we used a 10-mm sciatic nerve defect model in rats to determine whether cartilage oligomeric matrix protein enhances the vascularization of injured acellular nerves. The rat nerve defects were treated with acellular nerve grafting (control group) alone or acellular nerve grafting combined with intraperitoneal injection of cartilage oligomeric matrix protein (experimental group). As shown through two-dimensional imaging, the vessels began to invade into the acellular nerve graft from both anastomotic ends at day 7 post operation, and gradually covered the entire graft at day 21. The vascular density, vascular area, and the velocity of revascularization in the experimental group were all higher than those in the control group. These results indicate that cartilage oligomeric matrix protein enhances the vascularization of acellular nerves. PMID- 27127496 TI - Recovery of an injured corticospinal tract during the early stage of rehabilitation following pontine infarction. PMID- 27127497 TI - Appropriate Contrast Enhancement Measures for Brain and Breast Cancer Images. AB - Medical imaging systems often produce images that require enhancement, such as improving the image contrast as they are poor in contrast. Therefore, they must be enhanced before they are examined by medical professionals. This is necessary for proper diagnosis and subsequent treatment. We do have various enhancement algorithms which enhance the medical images to different extents. We also have various quantitative metrics or measures which evaluate the quality of an image. This paper suggests the most appropriate measures for two of the medical images, namely, brain cancer images and breast cancer images. PMID- 27127498 TI - Intelligent Flow Friction Estimation. AB - Nowadays, the Colebrook equation is used as a mostly accepted relation for the calculation of fluid flow friction factor. However, the Colebrook equation is implicit with respect to the friction factor (lambda). In the present study, a noniterative approach using Artificial Neural Network (ANN) was developed to calculate the friction factor. To configure the ANN model, the input parameters of the Reynolds Number (Re) and the relative roughness of pipe (epsilon/D) were transformed to logarithmic scales. The 90,000 sets of data were fed to the ANN model involving three layers: input, hidden, and output layers with, 2, 50, and 1 neurons, respectively. This configuration was capable of predicting the values of friction factor in the Colebrook equation for any given values of the Reynolds number (Re) and the relative roughness (epsilon/D) ranging between 5000 and 10(8) and between 10(-7) and 0.1, respectively. The proposed ANN demonstrates the relative error up to 0.07% which had the high accuracy compared with the vast majority of the precise explicit approximations of the Colebrook equation. PMID- 27127499 TI - Development of a Prediction Model Based on RBF Neural Network for Sheet Metal Fixture Locating Layout Design and Optimization. AB - Fixture plays an important part in constraining excessive sheet metal part deformation at machining, assembly, and measuring stages during the whole manufacturing process. However, it is still a difficult and nontrivial task to design and optimize sheet metal fixture locating layout at present because there is always no direct and explicit expression describing sheet metal fixture locating layout and responding deformation. To that end, an RBF neural network prediction model is proposed in this paper to assist design and optimization of sheet metal fixture locating layout. The RBF neural network model is constructed by training data set selected by uniform sampling and finite element simulation analysis. Finally, a case study is conducted to verify the proposed method. PMID- 27127500 TI - A Genetic Algorithm and Fuzzy Logic Approach for Video Shot Boundary Detection. AB - This paper proposed a shot boundary detection approach using Genetic Algorithm and Fuzzy Logic. In this, the membership functions of the fuzzy system are calculated using Genetic Algorithm by taking preobserved actual values for shot boundaries. The classification of the types of shot transitions is done by the fuzzy system. Experimental results show that the accuracy of the shot boundary detection increases with the increase in iterations or generations of the GA optimization process. The proposed system is compared to latest techniques and yields better result in terms of F1score parameter. PMID- 27127501 TI - Fecal Microbiota Transplantation Using Upper Gastrointestinal Tract for the Treatment of Refractory or Severe Complicated Clostridium difficile Infection in Elderly Patients in Poor Medical Condition: The First Study in an Asian Country. AB - Background and Aims. Fecal microbiota transplantation (FMT) is a highly effective treatment option for refractory Clostridium difficile infection (CDI). FMT may be challenging in patients with a low performance status, because of their poor medical condition. The aims of this study were to describe our experience treating patients in poor medical condition with refractory or severe complicated CDI using FMT via the upper GI tract route. Methods. This study was a retrospective review of seven elderly patients with refractory or severe complicated CDI and a poor medical condition who were treated with FMT through the upper GI tract route from May 2012 through August 2013. The outcomes studied included the cure rate of CDI and adverse events. Results. Of these seven patients who received FMT via the upper GI tract route, all patients were cured. During the 11-month follow-up period, CDI recurrence was observed in two patients; rescue FMT was performed in these patients, which led to a full cure. Vomiting was observed in two patients. Conclusions. FMT via the upper gastrointestinal tract route may be effective for the treatment of refractory or severe complicated CDI in patients with a low performance status. Physicians should be aware of adverse events, especially vomiting. PMID- 27127502 TI - Effectiveness of Magnifying Narrow-Band Imaging Endoscopy for Differential Diagnosis between the High-Risk Mixed-Type and Low-Risk Simple-Type of Low-Grade, Well-Differentiated Gastric Tubular Adenocarcinoma. AB - Backgrounds. Magnifying endoscopy with narrow-band imaging (NBI-ME) is useful for diagnosing differentiated early gastric cancer (D-EGC). D-EGC is classified as high- or low-grade based on its glandular architectural and cytological atypia. Low-grade, well-differentiated tubular adenocarcinoma (LG-tub1) mixed with high grade tub1 (HG-tub1) and/or other histological types (M-LG-tub1) may indicate a primitive high-risk malignant lesion compared to histologically simple-type LG tub1 (S-LG-tub1). Because LG-tub1 is occasionally difficult to diagnose due to its unclear demarcation under conventional white light endoscopy, early precise diagnoses are important. Methods. We compared NBI-ME and postendoscopic submucosal dissection histological findings for 30 S-LG-tub1 and 15 M-LG-tub1 lesions. We classified the NBI-ME findings of S-LG-tub1 (and not D-EGC) into four patterns. The differential diagnosis between M-LG-tub1 and S-LG-tub1 depended on the presence of more than one of these patterns without or with other patterns (referred to as "limited-to-four-pattern [LFP] sign-positive" and "sign negative", resp.). Result. The sensitivity, specificity, accuracy, positive and negative predictive values, and intraobserver and interobserver agreement, using the "LFP sign" for the differential diagnosis between M-LG-tub1 and S-LG-tub1, were 87.9%, 91.7%, 88.9%, 96.7%, 73.3%, and k = 0.842 and k = 0.737, respectively. Conclusion. NBI-ME may be useful in differentiating between high risk M-LG-tub1 and low-risk S-LG-tub1. PMID- 27127503 TI - Genetic Abnormalities in Biliary Brush Samples for Distinguishing Cholangiocarcinoma from Benign Strictures in Primary Sclerosing Cholangitis. AB - Background. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and is strongly associated with cholangiocarcinoma (CCA). The lack of efficient diagnostic methods for CCA is a major problem. Testing for genetic abnormalities may increase the diagnostic value of cytology. Methods. We assessed genetic abnormalities for CDKN2A, TP53, ERBB2, 20q, MYC, and chromosomes 7 and 17 and measures of genetic clonal diversity in brush samples from 29 PSC patients with benign biliary strictures and 12 patients with sporadic CCA or PSC associated CCA. Diagnostic performance of cytology alone and in combination with genetic markers was evaluated by sensitivity, specificity, and area under the curve analysis. Results. The presence of MYC gain and CDKN2A loss as well as a higher clonal diversity was significantly associated with malignancy. MYC gain increased the sensitivity of cytology from 50% to 83%. However, the specificity decreased from 97% to 76%. The diagnostic accuracy of the best performing measures of clonal diversity was similar to the combination of cytology and MYC. Adding CDKN2A loss to the panel had no additional benefit. Conclusion. Evaluation of MYC abnormalities and measures of clonal diversity in brush cytology specimens may be of clinical value in distinguishing CCA from benign biliary strictures in PSC. PMID- 27127504 TI - Bone Mineral Density in the Noninstitutionalized Elderly: Influence of Sociodemographic and Anthropometric Factors. AB - Objective. Analysis of bone mineral density (BMD) in the elderly and its associated factors according to sex. Methods. A cross-sectional study is presented herein, with a random sample of 132 noninstitutionalized elderly people. Individuals who did not use diuretics were excluded. BMD was obtained from examination of total body densitometry and its association with sociodemographic variables, lifestyle, anthropometric, and body composition was verified. Results. Mean BMD for men was 1.17 +/- 0.12 g/cm(2) and for women was 1.04 +/- 0.11 g/cm(2). Higher education was associated with higher BMD values in men (p < 0.05). There was a reduction in BMD in the age group 75-79 years of age in women and over 80 years of age in men (p < 0.05). Underweight was associated with significantly low BMD for both sexes (p < 0.01), while normal weight was associated with low BMD in women (p < 0.001). Discussion. The elderly with low schooling and in older age groups are more probable to also present low BMD. Lower levels of body mass index also indicated towards low BMD. PMID- 27127505 TI - Using MALDI-TOF Mass Spectrometry to Identify Drug Resistant Staphylococcal Isolates from Nonhospital Environments in Brunei Darussalam. AB - Drug resistant bacteria have been a growing threat to the community and hospitals due to the misuse of antibiotics by humans, industrialization, and lack of novel antimicrobials currently available. Little is known about the prevalence of drug resistant bacteria in nonhealthcare environments in Brunei Darussalam and about how antibiotic resistant genes are transferred within these environments. Human contact points from different types of environments in Brunei Darussalam, varying from urban to jungle settings, were swabbed and cultured onto selective media to isolate staphylococci bacteria before performing antimicrobial susceptibility testing on the isolates. The identity of the isolates was determined using MALDI TOF mass spectrometry (MS). Staphylococci isolates resistant to oxacillin were further tested for their minimum inhibitory concentration (MIC). PCR analysis of the mecA gene, a gene that confers resistance to oxacillin, is done to determine the level of resistance to oxacillin. Ten different staphylococcal species were identified by MALDI-TOF-MS analysis. Out of the 36 staphylococci isolates, 24 were resistant to multiple antibiotics including two isolates which were oxacillin resistant. Some staphylococci isolates had similar antibiotic resistance profiles to other staphylococci isolates of different species in the same location. This work provides the first-ever evidence of drug resistant staphylococci in the nonhospital environment in Brunei Darussalam. PMID- 27127506 TI - Robust Feature Selection from Microarray Data Based on Cooperative Game Theory and Qualitative Mutual Information. AB - High dimensionality of microarray data sets may lead to low efficiency and overfitting. In this paper, a multiphase cooperative game theoretic feature selection approach is proposed for microarray data classification. In the first phase, due to high dimension of microarray data sets, the features are reduced using one of the two filter-based feature selection methods, namely, mutual information and Fisher ratio. In the second phase, Shapley index is used to evaluate the power of each feature. The main innovation of the proposed approach is to employ Qualitative Mutual Information (QMI) for this purpose. The idea of Qualitative Mutual Information causes the selected features to have more stability and this stability helps to deal with the problem of data imbalance and scarcity. In the third phase, a forward selection scheme is applied which uses a scoring function to weight each feature. The performance of the proposed method is compared with other popular feature selection algorithms such as Fisher ratio, minimum redundancy maximum relevance, and previous works on cooperative game based feature selection. The average classification accuracy on eleven microarray data sets shows that the proposed method improves both average accuracy and average stability compared to other approaches. PMID- 27127507 TI - A Study on Central Lymph Node Metastasis in 543 cN0 Papillary Thyroid Carcinoma Patients. AB - Background. Papillary thyroid carcinoma (PTC) with central lymph node metastases (CLNMs) is common. The objective of this study was to investigate the incidence and risk factors of lymph node metastasis patients with PTC. Patients and Methods. Between January 2013 and February 2015, a retrospective study of 543 patients with PTC undergoing hemithyroidectomy or total thyroidectomy with routine central lymph node dissection (CLND) was analyzed. Clinicopathologic risk factors for CLNM were studied using univariate and multivariate analysis by SPSS 22.0 software. Results. The incidence of CLNMs in PTC patients was 38.1% (207/543). In the multivariate analysis, male gender (p < 0.001, OR: 1.984), age <45 years (p < 0.001, OR: 1.934), bilaterality (p = 0.006, OR: 1.585), tumor size >=0.25 cm (p = 0.001, OR: 7.655), and external extension (p = 0.001, OR: 7.579) were independent risk factors of CLNMs. Furthermore, in PTC patients with tumor size <0.25 cm, all 7 males and 21 patients with unilaterality were not found to have CLNMs. Conclusions. CLNMs are prevalent in the PTC patients with the following risk factors: male gender, age <45 years, bilaterality, tumor size >=0.25 cm, and external extension. PTC patients with tumor size <0.25 cm, male patients, and patients with unilateral lesion could be considered safe from CLNMs. PMID- 27127508 TI - Extending the Impact of RAC1b Overexpression to Follicular Thyroid Carcinomas. AB - RAC1b is a hyperactive variant of the small GTPase RAC1 known to be a relevant molecular player in different cancers. Previous studies from our group lead to the evidence that its overexpression in papillary thyroid carcinoma (PTC) is associated with an unfavorable prognosis. In the present study, we intended to extend the analysis of RAC1b expression to thyroid follicular neoplasms and to seek for clinical correlations. RAC1b expression levels were determined by RT qPCR in thyroid follicular tumor samples comprising 23 follicular thyroid carcinomas (FTCs) and 33 follicular thyroid adenomas (FTAs). RAC1b was found to be overexpressed in 33% of carcinomas while no RAC1b overexpression was documented among follicular adenomas. Patients with a diagnosis of FTC were divided into two groups based on longitudinal evolution and final outcome. RAC1b overexpression was significantly associated with both the presence of distant metastases (P = 0.01) and poorer clinical outcome (P = 0.01) suggesting that, similarly to that previously found in PTCs, RAC1b overexpression in FTCs is also associated with worse outcomes. Furthermore, the absence of RAC1b overexpression in follicular adenomas hints its potential as a molecular marker likely to contribute, in conjunction with other putative markers, to the preoperative differential diagnosis of thyroid follicular lesions. PMID- 27127509 TI - Maternal High-Fat Diet during Pregnancy and Lactation Influences Obestatin and Ghrelin Concentrations in Milk and Plasma of Wistar Rat Dams and Their Offspring. AB - The study aims to establish the effect of a maternal high-fat diet on obestatin concentration, total ghrelin, and ghrelin/obestatin ratio during pregnancy and lactation of Wistar rats and their offspring in the first 21 days of life. On the mating day, females were randomly allocated and fed either a high-fat diet (30% of fat; HF) or breeding diet (5% fat; BD) till the 21st day of lactation. Hormones were analyzed in the blood plasma and milk of rat dams as well as in the blood plasma of their offspring. HF resulted in a significant decrease in obestatin level on the 14th day of lactation and elevation on the 21st day. Plasma obestatin in HFD offspring was significantly higher than in BD ones. HF diet did not significantly affect dam plasma ghrelin until the 21st day of lactation. The ghrelin concentrations in milk after both diets were significantly lower than in blood plasma. Milk ghrelin in HF dams was significantly higher than in the BD ones. Plasma ghrelin from HF offspring was significantly higher than that from BD dams. Our results demonstrate that a maternal HF diet during pregnancy and lactation influences ghrelin and obestatin level in both dams and their offspring. PMID- 27127510 TI - Computer-Assisted Technique for Surgical Tooth Extraction. AB - Introduction. Surgical tooth extraction is a common procedure in dentistry. However, numerous extraction cases show a high level of difficulty in practice. This difficulty is usually related to inadequate visualization, improper instrumentation, or other factors related to the targeted tooth (e.g., ankyloses or presence of bony undercut). Methods. In this work, the author presents a new technique for surgical tooth extraction based on 3D imaging, computer planning, and a new concept of computer-assisted manufacturing. Results. The outcome of this work is a surgical guide made by 3D printing of plastics and CNC of metals (hybrid outcome). In addition, the conventional surgical cutting tools (surgical burs) are modified with a number of stoppers adjusted to avoid any excessive drilling that could harm bone or other vital structures. Conclusion. The present outcome could provide a minimally invasive technique to overcome the routine complications facing dental surgeons in surgical extraction procedures. PMID- 27127511 TI - Direct Analysis of Low-Volatile Molecular Marker Extract from Airborne Particulate Matter Using Sensitivity Correction Method. AB - Molecular marker analysis of environmental samples often requires time consuming preseparation steps. Here, analysis of low-volatile nonpolar molecular markers (5 6 ring polycyclic aromatic hydrocarbons or PAHs, hopanoids, and n-alkanes) without the preseparation procedure is presented. Analysis of artificial sample extracts was directly conducted by gas chromatography-mass spectrometry (GC-MS). After every sample injection, a standard mixture was also analyzed to make a correction on the variation of instrumental sensitivity caused by the unfavorable matrix contained in the extract. The method was further validated for the PAHs using the NIST standard reference materials (SRMs) and then applied to airborne particulate matter samples. Tests with the SRMs showed that overall our methodology was validated with the uncertainty of ~30%. The measurement results of airborne particulate matter (PM) filter samples showed a strong correlation between the PAHs, implying the contributions from the same emission source. Analysis of size-segregated PM filter samples showed that their size distributions were found to be in the PM smaller than 0.4 MUm aerodynamic diameter. The observations were consistent with our expectation of their possible sources. Thus, the method was found to be useful for molecular marker studies. PMID- 27127512 TI - Measurement of Circulating 1,25-Dihydroxyvitamin D: Comparison of an Automated Method with a Liquid Chromatography Tandem Mass Spectrometry Method. AB - Background. The clinical relevance of circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) is probably underappreciated, but variations in the measurement of this difficult analyte between different methods limit comparison of results. Methods. In 129 clinical samples, we compared a new automated assay with a commercially available liquid chromatography tandem mass spectrometry (LC-MS/MS) kit. Results. Median (interquartile range) 1,25(OH)2D concentrations with the automated assay and the LC-MS/MS method were 26.6 pg/mL (18.5-39.0 pg/mL) and 23.6 pg/mL (16.1-31.3 pg/mL), respectively (P = 0.001). Using the method-specific cut-offs for deficient 1,25(OH)2D levels (<20 pg/mL for the automated assay and <17 pg/mL for the LC-MS/MS method), the percentage of patients classified as 1,25(OH)2D deficient was 28.7% and 27.1%, respectively. However, concordance between the two methods for deficient levels was only 62% and the concordance correlation coefficient was poor (0.534). The regression equation resulted in an intercept of -1.99 (95% CI: -7.33-1.31) and a slope of 1.27 (95% CI: 1.04-1.52) for the automated assay. The mean bias with respect to the mean of the two methods was -3.8 (1.96 SD: -28.3-20.8) pg/mL for the LC-MS/MS method minus the automated assay. Conclusions. The two methods show only modest correlation and further standardization is required to improve reliability and comparability of 1,25(OH)2D test procedures. PMID- 27127513 TI - Preparation Methods for Improving PEEK's Bioactivity for Orthopedic and Dental Application: A Review. AB - There is an increased interest in the use of polyether ether ketone (PEEK) for orthopedic and dental implant applications due to its elastic modulus close to that of bone, biocompatibility, and its radiolucent properties. However, PEEK is still categorized as bioinert due to its low integration with surrounding tissues. Many studies have reported on methods to increase the bioactivity of PEEK, but there is still one-preparation method for preparing bioactive PEEK implant where the produced implant with desirable mechanical and bioactivity properties is required. The aim of this review is to present the progress of the preparation methods for improvement of the bioactivity of PEEK and to discuss the strengths and weaknesses of the existing methods. PMID- 27127514 TI - The Diagnostic Value of Alpha-1-Antitrypsin Phenotype in Patients with Granulomatosis with Polyangiitis. AB - The deficiency of alpha-1 protease inhibitor, or alpha-1-antitrypsin (A1AT), predisposes to chronic lung diseases and extrapulmonary pathology. Besides classical manifestations, such as pulmonary emphysema and liver disease, alpha-1 antitrypsin deficiency (A1ATD) is also known to be associated with granulomatosis with polyangiitis (GPA or Wegener's granulomatosis). The aim of our study was to evaluate the frequency of allelic isoforms of A1AT and their clinical significance among GPA patients. Detailed clinical information, including Birmingham Vasculitis Activity Score (BVAS), incidence of lung involvement, anti proteinase 3 (PR3) antibodies concentrations, and other laboratory data were collected in 38 GPA patients. We also studied serum samples obtained from 46 healthy donors. In all collected samples A1AT phenotyping by isoelectrofocusing (IEF) and turbidimetric A1AT measurement were performed. Abnormal A1AT variants were found in 18.4% (7/38) of cases: 1 ZZ, 4 MZ, 2 MF, and only 1 MZ in control group (2%). The mean A1AT concentration in samples with atypical A1AT phenotypes was significantly lower (P = 0.0038) than in normal A1AT phenotype. We found that patients with abnormal A1AT phenotypes had significantly higher vasculitis activity (BVAS) as well as anti-PR3 antibodies concentration. We conclude that A1AT deficiency should be considered in all patients with GPA. PMID- 27127515 TI - Encephalopathy Associated with Autoimmune Thyroid Disease: A Potentially Reversible Condition. AB - Autoimmune thyroid disease may occasionally associate with unspecific neurological symptoms, which are more commonly insidious, include cognitive or behavioural symptoms, and may associate with tremor, myoclonus, or ataxia. We report a 61-year-old female patient who presented with chronic headache, insidious mood, and cognitive disturbance which evolved in a few months to dementia associated with exuberant limb myoclonus. Diagnostic workup revealed high anti-thyroid peroxidase antibody titers and an inflammatory CSF profile, and it was negative for other possible etiologies. Treatment with steroids induced significant improvement. The diagnosis of encephalopathy associated with autoimmune thyroid disease is still controversial given the fact that the clinical presentation and diagnostic workup are unspecific, the pathophysiology is still undetermined, and the diagnosis is mostly of exclusion. No direct correlation is found between anti-thyroid antibody titers and clinical presentation, and it is currently speculated that other still unrecognized antibodies may be responsible for this clinical entity. It is extremely important to recognize this entity because it is potentially treatable with immunotherapies. It is also increasingly recognized that clinical improvement with first-line treatment with steroids may be absent or incomplete, and other immunotherapies as immunosuppressants, intravenous immunoglobulin, or plasma exchange must be attempted in the clinical suspicion of EEAT. PMID- 27127517 TI - XPC Promotes Pluripotency of Human Dental Pulp Cells through Regulation of Oct 4/Sox2/c-Myc. AB - Introduction. Xeroderma pigmentosum group C (XPC), essential component of multisubunit stem cell coactivator complex (SCC), functions as the critical factor modulating pluripotency and genome integrity through interaction with Oct 4/Sox2. However, its specific role in regulating pluripotency and multilineage differentiation of human dental pulp cells (DPCs) remains unknown. Methods. To elucidate the functional role XPC played in pluripotency and multilineage differentiation of DPCs, expressions of XPC in DPCs with long-term culture were examined by real-time PCR and western blot. DPCs were transfected with lentiviral mediated human XPC gene; then transfection rate was investigated by real-time PCR and western blot. Cell cycle, apoptosis, proliferation, senescence, multilineage differentiation, and expression of Oct-4/Sox2/c-Myc in transfected DPCs were examined. Results. XPC, Oct-4, Sox2, and c-Myc were downregulated at P7 compared with P3 in DPCs with long-term culture. XPC genes were upregulated in DPCs at P2 after transfection and maintained high expression level at P3 and P7. Cell proliferation, PI value, and telomerase activity were enhanced, whereas apoptosis was suppressed in transfected DPCs. Oct-4/Sox2/c-Myc were significantly upregulated, and multilineage differentiation in DPCs with XPC overexpression was enhanced after transfection. Conclusions. XPC plays an essential role in the modulation of pluripotency and multilineage differentiation of DPCs through regulation of Oct-4/Sox2/c-Myc. PMID- 27127516 TI - Harnessing the Angiogenic Potential of Stem Cell-Derived Exosomes for Vascular Regeneration. AB - Mesenchymal stem cells (MSCs) are known to display important regenerative properties through the secretion of proangiogenic factors. Recent evidence pointed at the key role played by exosomes released from MSCs in this paracrine mechanism. Exosomes are key mediators of intercellular communication and contain a cargo that includes a modifiable content of microRNA (miRNA), mRNA, and proteins. Since the biogenesis of the MSCs-derived exosomes is regulated by the cross talk between MSCs and their niche, the content of the exosomes and consequently their biological function are dependent on the cell of origin and the physiologic or pathologic status of their microenvironment. Recent preclinical studies revealed that MSCs-derived exosomes have a critical implication in the angiogenic process since the use of exosomes-depleted conditioned medium impaired the MSCs angiogenesis response. In this review, we discuss the current knowledge related to the angiogenic potential of MSCs exosomes and methods to enhance their biological activities for improved vascular regeneration. The current gain of insight in exosomes studies highlights the power of combining cell based therapies and their secreted products in therapeutic angiogenesis. PMID- 27127518 TI - Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders. AB - Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson's disease, and cerebral ischemia. PMID- 27127519 TI - Magnetic Nanoparticles for Targeting and Imaging of Stem Cells in Myocardial Infarction. AB - Stem cell therapy has broad applications in regenerative medicine and increasingly within cardiovascular disease. Stem cells have emerged as a leading therapeutic option for many diseases and have broad applications in regenerative medicine. Injuries to the heart are often permanent due to the limited proliferation and self-healing capability of cardiomyocytes; as such, stem cell therapy has become increasingly important in the treatment of cardiovascular diseases. Despite extensive efforts to optimize cardiac stem cell therapy, challenges remain in the delivery and monitoring of cells injected into the myocardium. Other fields have successively used nanoscience and nanotechnology for a multitude of biomedical applications, including drug delivery, targeted imaging, hyperthermia, and tissue repair. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been widely employed for molecular and cellular imaging. In this mini-review, we focus on the application of superparamagnetic iron oxide nanoparticles in targeting and monitoring of stem cells for the treatment of myocardial infarctions. PMID- 27127520 TI - Human Liver Stem Cells Suppress T-Cell Proliferation, NK Activity, and Dendritic Cell Differentiation. AB - Human liver stem cells (HLSCs) are a mesenchymal stromal cell-like population resident in the adult liver. Preclinical studies indicate that HLSCs could be a good candidate for cell therapy. The aim of the present study was to evaluate the immunogenicity and the immunomodulatory properties of HLSCs on T-lymphocytes, natural killer cells (NKs), and dendritic cells (DCs) in allogeneic experimental settings. We found that HLSCs inhibited T-cell proliferation by a mechanism independent of cell contact and dependent on the release of prostaglandin E2 (PGE2) and on indoleamine 2,3-dioxygenase activity. When compared with mesenchymal stromal cells (MSCs), HLSCs were more efficient in inhibiting T-cell proliferation. At variance with MSCs, HLSCs did not elicit NK degranulation. Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release. When tested on DC generation from monocytes, HLSCs were found to impair DC differentiation and DCs ability to induce T-cell proliferation through PGE2. This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response. PMID- 27127521 TI - Leukemia Stem Cell-Released Microvesicles Promote the Survival and Migration of Myeloid Leukemia Cells and These Effects Can Be Inhibited by MicroRNA34a Overexpression. AB - Leukemia stem cells (LSCs) play the major role in relapse of acute myeloid leukemia (AML). Recent evidence indicates that microvesicles (MVs) released from cancer stem cells can promote tumor growth and invasion. In this study, we investigated whether LSCs-released MVs (LMVs) can regulate the malignance of AML cells and whether overexpression of tumor suppressive microRNA (miR), miR34a, is able to interrupt this process. LSCs were transfected with miRNA control (miRCtrl) or miR34a mimic for producing LMVs, respectively, defined as LMVs(miRCtrl) and LMVs(miR34a). The effect of miR34a transfection on LSC proliferation and the effects of LMVs(miRCtrl) or LMVs(miR34a) on the proliferation, migration, and apoptosis of AML cells (after LSC depletion) were determined. The levels of miR34a targets, caspase-3 and T cell immunoglobulin mucin-3 (Tim-3), were analyzed. Results showed that (1) LMVs(miRCtrl) promoted proliferation and migration and inhibited apoptosis of AML cells, which were associated with miR34a deficit; (2) transfection of miR34a mimic inhibited LSC proliferation and increased miR34a level in LMVs(miR34a); (3) LMVs(miR34a) produced opposite effects as compared with LMVs(miRCtrl), which were associated with the changes of caspase-3 and Tim-3 levels. In summary, LMVs support AML cell malignance and modulating miR34a could offer a new approach for the management of AML. PMID- 27127522 TI - Molecular Characterization of Leptospira spp. in Environmental Samples from North Eastern Malaysia Revealed a Pathogenic Strain, Leptospira alstonii. AB - The presence of pathogenic Leptospira spp. in the environment poses threats to human health. The aim of this study was to detect and characterize Leptospira spp. from environmental samples. A total of 144 samples comprised of 72 soil and 72 water samples were collected from markets and recreational areas in a north eastern state in Malaysia. Samples were cultured on Ellinghausen and McCullough modified by Johnson and Harris media. Leptospires were positive in 22.9% (n = 33) of the isolates. Based on partial sequences of 16S rRNA, a pathogenic leptospire, Leptospira alstonii (n = 1/33), was identified in 3% of the isolates followed by intermediate leptospire (L. wolffii, n = 1/33, and L. licerasiae, n = 7/33) and nonpathogenic leptospire, L. meyeri (n = 22/33) in 24.2% and 66.7%, respectively. This study demonstrates the presence of a clinically significant pathogenic L. alstonii in the environments which could pose health risks to the occupants and visitors. PMID- 27127523 TI - Evaluation of circulating vascular endothelial growth factor and its soluble receptors in patients suffering from persistent allergic rhinitis. AB - BACKGROUND: Overexpression and enhanced release of vascular endothelial growth factor (VEGF) have been detected in various types of allergic inflammation, including asthma. AIM: To further evaluate the pattern of systemic release of VEGF in atopic allergy, free circulating VEGF was measured in patients with persistent allergic rhinitis (PAR). METHODS: The concentrations of VEGF and its soluble receptors (sVEGF-R1 and VEGF-R2) in plasma were measured in patients with PAR sensitized to house dust mites and the healthy subjects. RESULTS: No significant differences were found between PAR patients and healthy subjects with respect to plasma levels of VEGF and its receptors. CONCLUSIONS: It seems that free circulating VEGF may not be elevated in PAR patients. Moreover, on the basis of the present study as well as the earlier ones, it appears likely that systemic release of VEGF varies among patients with distinct clinical manifestation of atopy; may depend on severity/activity and the extent of inflammatory response. PMID- 27127524 TI - IgE serum concentration against airborne fungi in children with respiratory allergies. AB - BACKGROUND: To evaluate total and specific E immunoglobulin (IgE) antibody concentrations in underage subjects with respiratory allergic diseases. METHODS: This study was a transversal-type study in 100 underage subjects between 4 and 14 years old, with asthma and/or allergic rhinitis. Total and specific IgE were quantified for airborne fungi in the city of Sao Luis, Maranhao, Brazil. Five distinct regions-North, South, Center, East and West-were selected so fungi could be collected monthly for 1 year. Twenty genera were identified. Aspergillus, Penicillium, Fusarium and Neurospora were selected for the preparation of sensitizing antigens from ELISA dishes. IgE total concentrations were estimated using the same method. RESULTS: IgE total serum concentration was increased in 97 % of the atopic subjects: 75 % of the subjects presented increased IgE anti Aspergillus concentrations, 87 % presented IgE anti-Penicillium, 45 % presented IgE anti-Fusarium, and 46 % presented IgE anti-Neurospora. CONCLUSIONS: Atopic subjects presented simultaneous IgE total and specific elevations for the tested fungi, possibly due to polysensitization caused by the presence of fungi in all of the areas all year. However, determining the clinical significance of the results was not yet possible because most of the data were isolated variables. PMID- 27127525 TI - Cytokine patterns in nasal secretion of non-atopic patients distinguish between chronic rhinosinusitis with or without nasal polys. AB - BACKGROUND: Being one of the most common nasal diseases, chronic rhinosinusitis (CRS) is subdivided into CRS with nasal polyps (NP) and CRS without nasal polyps (CRSsNP). CRSsNP presents itself with a TH1 milieu and neutrophil infiltration, while NP is characterised by a mixed TH1/TH2 profile and an influx of predominantly eosinophils, plasma cells and mast cells. For the purpose of discovering disease-specific cytokine profiles, the present study compares levels of mediators and cytokines in nasal secretions between CRSsNP, NP, and healthy controls. METHODS: The study included 45 participants suffering from NP, 48 suffering from CRSsNP and 48 healthy controls. Allergic rhinitis constituted an exclusion criterion. Nasal secretions, sampled using the cotton wool method, were analysed for IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, IL-8, GM-CSF, G-CSF, IFN gamma, MCP-1, MIP-1alpha, MIP-1beta, eotaxin, and RANTES, and for ECP and tryptase, using Bio-Plex Cytokine assay or ELISA, respectively. RESULTS: Elevated levels of IL-5, IL-17, G-CSF, MCP-1, MIP-1alpha, MIP-1beta, ECP, and tryptase, as well as decreased levels of IL-10, IL-12, IL-13, and IFN-gamma were detected in NP. CRSsNP presented increased levels of RANTES and MIP-1beta while IL-13 was decreased. No differences between the three groups were found for IL-4, IL-8, GM CSF, and eotaxin. CONCLUSIONS: The present work suggests a disequilibrium of TH1 and TH2, together with a down-regulation of regulatory T lymphocytes and up regulated TH17 in NP. Moreover, elevated levels of diverse mediators represent the activation of various inflammatory cells in this disease entity. The inflammation in CRSsNP, however, is only weakly depicted in nasal secretions. Therefore, cytokines in nasal secretions may provide helpful information for differential diagnosis. PMID- 27127526 TI - Diagnostic accuracy of skin-prick testing for allergic rhinitis: a systematic review and meta-analysis. AB - BACKGROUND: Allergic rhinitis is the most common form of allergy worldwide. The accuracy of skin testing for allergic rhinitis is still debated. Our primary objective was to evaluate the diagnostic accuracy of skin-prick testing for allergic rhinitis using the nasal provocation as the reference standard. We also evaluated the diagnostic accuracy of intradermal testing as a secondary objective. METHODS: We searched EBM Reviews from 2005 to March 2015; Embase from 1980 to March 2015; and Ovid MEDLINE(R) from 1946 to until March 2015. We included any study with at least 10 subjects including children. We excluded non English studies. We performed data extraction and quality assessment using the QUADAS-2 tool. RESULTS: We meta-analysed seven studies assessing the accuracy of skin-prick testing using the bivariate random-effects model, including a total of 430 patients. The pooled estimate for sensitivity and specificity for skin-prick testing was 85 and 77 % respectively. We did not pool results for intradermal testing due to few number of studies (n = 4), each with very small sample size. Of these, two evaluated the accuracy of intradermal testing in confirming skin prick testing results, with sensitivity ranging from 27 to 50 % and specificity ranging from 60 to 100 %. The other two evaluated the accuracy of intradermal testing as a stand-alone test for diagnosing allergic rhinitis with sensitivity ranging from 60 to 79 % and specificity ranging from 68 to 69 %. CONCLUSIONS: Findings from this review suggest that skin-prick testing is accurate in discriminating subjects with or without allergic rhinitis. PMID- 27127527 TI - Multisystem reactions during egg oral food challenges may be associated with less severe reactions on initial presentation. AB - In this study, we assessed whether multisystem reactions to egg and extensively heated (EH) egg during OFCs were associated with a history of multisystem reactions. Records of children, who underwent OFC to egg or EH egg over a five year period were reviewed. Of the 120 challenges, 26 (21.67 %) failed, with 38.4 % (10/26) having multisystem reactions. Of the 13 who had multisystem reactions on initial presentation, only two (15.4 %) had a similar OFC outcome. Eighty percent (8/10) of those who had a multisystem OFC reaction had a less severe initial presentation. Initial and OFC multisystem reactions were not associated with each other. PMID- 27127528 TI - Efficacy of Chinese Herbal Medicine as an Adjunctive Therapy on in-Hospital Mortality in Patients with Acute Kidney Injury: A Systematic Review and Meta Analysis. AB - Objective. We aimed to systematically assess the efficacy of Chinese herbal medicine (CHM) as an adjunctive therapy on in-hospital mortality in patients with acute kidney injury (AKI). Methods. We did a systematic review of articles published in any language up until Jun 23, 2015, by searching PubMed, Embase, the Cochrane Library, CBM, and CNKI. We included all RCTs that compared outcomes of patients with AKI taking CHM plus Western treatment (WT) with those taking WT alone. We applied Cochrane risk-of-bias tool to assess the methodological quality of the included trials. Results. Of 832 citations, 15 studies involving 966 patients met inclusion criteria. The methodological quality was assessed with unclear risk of bias. In the primary outcome of meta-analysis, pooled outcome of in-hospital mortality showed that patients randomly assigned to CHM treatment group were associated with low risk of in-hospital mortality compared with those randomly assigned to WT alone (RR = 0.41; 95% CI = 0.24 to 0.71; P = 0.001). Conclusions. CHM as an adjunctive therapy is associated with a decreased risk of in-hospital mortality compared with WT in patients with AKI. Further studies with high quality and large sample size are needed to verify our conclusions. PMID- 27127529 TI - Predicting Outcome in Comatose Patients: The Role of EEG Reactivity to Quantifiable Electrical Stimuli. AB - Objective. To test the value of quantifiable electrical stimuli as a reliable method to assess electroencephalogram reactivity (EEG-R) for the early prognostication of outcome in comatose patients. Methods. EEG was recorded in consecutive adults in coma after cardiopulmonary resuscitation (CPR) or stroke. EEG-R to standard electrical stimuli was tested. Each patient received a 3-month follow-up by the Glasgow-Pittsburgh cerebral performance categories (CPC) or modified Rankin scale (mRS) score. Results. Twenty-two patients met the inclusion criteria. In the CPR group, 6 of 7 patients with EEG-R had good outcomes (positive predictive value (PPV), 85.7%) and 4 of 5 patients without EEG-R had poor outcomes (negative predictive value (NPV), 80%). The sensitivity and specificity were 85.7% and 80%, respectively. In the stroke group, 6 of 7 patients with EEG-R had good outcomes (PPV, 85.7%); all of the 3 patients without EEG-R had poor outcomes (NPV, 100%). The sensitivity and specificity were 100% and 75%, respectively. Of all patients, the presence of EEG-R showed 92.3% sensitivity, 77.7% specificity, 85.7% PPV, and 87.5% NPV. Conclusion. EEG-R to quantifiable electrical stimuli might be a good positive predictive factor for the prognosis of outcome in comatose patients after CPR or stroke. PMID- 27127530 TI - The Clinical Effect of Acupuncture in the Treatment of Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Purpose. This study aims to determine the clinical efficacy of acupuncture therapy in the treatment of obstructive sleep apnea. Methods. A systematic literature search was conducted in five databases including PubMed, EMBASE, CENTRAL, Wanfang, and CNKI to identify randomized controlled trials (RCTs) on the effect of acupuncture therapy for obstructive sleep apnea. Meta-analysis was conducted using the RevMan version 5.3 software. Results. Six RCTs involving 362 subjects were included in our study. Compared with control groups, manual acupuncture (MA) was more effective in the improvement of apnea/hypopnea index (AHI), apnea index, hypopnea index, and mean SaO2. Electroacupuncture (EA) was better in improving the AHI and apnea index when compared with control treatment, but no statistically significant differences in hypopnea index and mean SaO2 were found. In the comparison of MA and nasal continuous positive airway pressure, the results favored MA in the improvement of AHI; there was no statistical difference in the improvement in mean SaO2. No adverse events associated with acupuncture therapy were documented. Conclusion. Compared to control groups, both MA and EA were more effective in improving AHI and mean SaO2. In addition, MA could further improve apnea index and hypopnea index compared to control. PMID- 27127531 TI - Retracted: Sagunja-Tang Improves Lipid Related Disease in a Postmenopausal Rat Model and HepG2 Cells. AB - [This retracts the article DOI: 10.1155/2015/321407.]. PMID- 27127534 TI - The Virtual Screening of the Drug Protein with a Few Crystal Structures Based on the Adaboost-SVM. AB - Using the theory of machine learning to assist the virtual screening (VS) has been an effective plan. However, the quality of the training set may reduce because of mixing with the wrong docking poses and it will affect the screening efficiencies. To solve this problem, we present a method using the ensemble learning to improve the support vector machine to process the generated protein ligand interaction fingerprint (IFP). By combining multiple classifiers, ensemble learning is able to avoid the limitations of the single classifier's performance and obtain better generalization. According to the research of virtual screening experiment with SRC and Cathepsin K as the target, the results show that the ensemble learning method can effectively reduce the error because the sample quality is not high and improve the effect of the whole virtual screening process. PMID- 27127535 TI - Fluid Structural Analysis of Urine Flow in a Stented Ureter. AB - Many urologists are currently studying new designs of ureteral stents to improve the quality of their operations and the subsequent recovery of the patient. In order to help during this design process, many computational models have been developed to simulate the behaviour of different biological tissues and provide a realistic computational environment to evaluate the stents. However, due to the high complexity of the involved tissues, they usually introduce simplifications to make these models less computationally demanding. In this study, the interaction between urine flow and a double-J stented ureter with a simplified geometry has been analysed. The Fluid-Structure Interaction (FSI) of urine and the ureteral wall was studied using three models for the solid domain: Mooney Rivlin, Yeoh, and Ogden. The ureter was assumed to be quasi-incompressible and isotropic. Data obtained in previous studies from ex vivo and in vivo mechanical characterization of different ureters were used to fit the mentioned models. The results show that the interaction between the stented ureter and urine is negligible. Therefore, we can conclude that this type of models does not need to include the FSI and could be solved quite accurately assuming that the ureter is a rigid body and, thus, using the more simple Computational Fluid Dynamics (CFD) approach. PMID- 27127532 TI - What happens to cardiovascular system behind the undetectable level of HIV viremia? AB - Despite the combined antiretroviral therapy has improved the length and quality of life of HIV infected patients, the survival of these patients is always decreased compared with the general population. This is the consequence of non infectious illnesses including cardio vascular diseases. In fact large studies have indicated an increased risk of coronary atherosclerotic disease, myocardial infarction even in HIV patients on cART. In HIV infected patients several factors may contribute to the pathogenesis of cardiovascular problems: life-style, metabolic parameters, genetic predisposition, viral factors, immune activation, chronic inflammation and side effects of antiretroviral therapy. The same factors may also contribute to complicate the clinical management of these patients. Therefore, treatment of these non-infectious illnesses in HIV infected population is an emerging challenge for physicians. The purpose of this review is to focus on the new insights in non AIDS-related cardiovascular diseases in patients with suppressed HIV viremia. PMID- 27127533 TI - Role of BAF60a/BAF60c in chromatin remodeling and hepatic lipid metabolism. AB - The switching defective/sucrose non-fermenting (SWI/SNF) complexes play an important role in hepatic lipid metabolism regulating both transcriptional activation and repression. BAF60a is a core subunit of the SWI/SNF chromatin remodeling complexes that activates the transcription of fatty acid oxidation genes during fasting/glucagon. BAF60c, another subunit of SWI/SNF complexes, is recruited to form the lipoBAF complex that activates lipogenic genes, promoting lipogenesis and increasing the triglyceride level in response to feeding/insulin. Interestingly, hepatocytes located in the periportal and perivenous zones of the liver display a remarkable heterogeneity in the activity of various enzymes, metabolic functions and gene expression. Especially, fatty-acid oxidation was shown to be mostly periportal, whereas lipogenesis was mostly perivenous. Therefore, the present review highlights the role of of SWI/SNF regulating lipid metabolism under nutritional and hormonal control, which may be associated with hepatocyte heterogeneity. PMID- 27127536 TI - Automatic Liver Segmentation on Volumetric CT Images Using Supervoxel-Based Graph Cuts. AB - Accurate segmentation of liver from abdominal CT scans is critical for computer assisted diagnosis and therapy. Despite many years of research, automatic liver segmentation remains a challenging task. In this paper, a novel method was proposed for automatic delineation of liver on CT volume images using supervoxel based graph cuts. To extract the liver volume of interest (VOI), the region of abdomen was firstly determined based on maximum intensity projection (MIP) and thresholding methods. Then, the patient-specific liver VOI was extracted from the region of abdomen by using a histogram-based adaptive thresholding method and morphological operations. The supervoxels of the liver VOI were generated using the simple linear iterative clustering (SLIC) method. The foreground/background seeds for graph cuts were generated on the largest liver slice, and the graph cuts algorithm was applied to the VOI supervoxels. Thirty abdominal CT images were used to evaluate the accuracy and efficiency of the proposed algorithm. Experimental results show that the proposed method can detect the liver accurately with significant reduction of processing time, especially when dealing with diseased liver cases. PMID- 27127537 TI - The role of conviction in personal disease risk perceptions: What can we learn from research on attitude strength? AB - Perceived risk for disease is included as a predictor of intentions and behavior in many health behavior theories. However, perceived risk is not always a strong predictor of intentions and behaviors. One reason may be suboptimal conceptualization and measurement of risk perceptions; in particular, research may not capture the conviction and certainty with which a risk perception is held. The rich and independent literature on attitudes might be leveraged to explore whether conviction is an important moderator of the effects of risk perceptions on intentions and behavior. Attitudes are more predictive of intentions when they are high in multiple aspects of attitude strength, including attitude certainty and being more accessible and stable over time. Working from the assumption that risk perceptions have a similar structure and function to attitudes, we consider whether factors known to strengthen the attitude-behavior correspondence might also strengthen the risk perception-behavior correspondence. Although by strict definition risk perceptions are not evaluations (a critical component of attitudes), the predictive validity of risk perceptions may be increased by attention to one's "conviction" or certainty of perceived risk. We also review recent strategies designed to improve risk perception measurement, including affective and experiential assessments of perceived risk and the importance of allowing people to indicate that they "don't know" their disease risk. The aim of this paper is to connect two disparate literatures-attitudes and persuasion in social psychology with risk perceptions in health psychology and decision science-in an attempt to stimulate more work on characteristics and proper measurement of risk perceptions. PMID- 27127538 TI - Regioselectivity of the alkylation of S-substituted 1,2,4-triazoles with dihaloalkanes. AB - BACKGROUND: 1,2,4-Triazole3-thiones are good scaffolds for preparation of new lead compounds. Their derivatives attracted the attention of chemists due to their wide spectrum of biological activities. Alkylsulfanyl-1,2,4-triazoles have three nucleophilic sites (nitrogens) ready for reaction with electrophiles. Herein, new regioselective isomers were synthesized by the reaction of benzylsulfanyl-1,2,4-triazole with various dihaloalkanes. Regioselectivity was determined by X-ray crystallography and NMR. RESULTS: Coupling of 3-benzylsufanyl 5-(1H-indolyl)-1,2,4-triazole with dibromomethane, 1,2-dichloroethane, 1,3 dibromopropane and di(bromomethyl)quinoxaline was investigated in the presence of potassium carbonate in acetone. In the case of dibromomethane three different bis(triazolyl)methane isomers (-N (1)-CH2-N (1)-4, -N (1)-CH2-N (2)-5, -N (2)-CH2 N (2)-6) were formed in which the two bromide atoms were replaced by two triazole moieties. Among these isomers the reaction was regioselective towards the -N (1) CH2-N (2)-5 isomer due to the steric effect. In the case of 1,3-dibromopropane two compounds were obtained due to the alkylation at N(2) to give 2-(3 bromopropyl)-triazole 8 and alkylation at N(1) was followed by cyclization at the indole nitrogen to form a condensed indolo-triazolo-diazepine 10. Upon alkylation of 3-benzylsufanyl-5-(1H-indolyl)-1,2,4-triazole with di(bromomethyl)quinoxaline, two bis(triazolyl-methyl)quinoxaline isomers were separated and characterized as (-N (1)-CH2-N (1)-) 11 and (-N (2)-CH2-N (2)-) 12. Single-crystal X-ray diffraction assisted the elucidation and confirmation of the structures of the isomers. An AM1 theoretical study explained the regioselectivity of the alkylation. CONCLUSIONS: On reacting S-protected 1,2,4-triazoles with various alkylating agents, only N(1) and N(2) attack the electrophilic carbons. N(2) alkylated isomers are preferentially formed. Graphical abstract. PMID- 27127539 TI - Energy-efficient biomass processing with pulsed electric fields for bioeconomy and sustainable development. AB - Fossil resources-free sustainable development can be achieved through a transition to bioeconomy, an economy based on sustainable biomass-derived food, feed, chemicals, materials, and fuels. However, the transition to bioeconomy requires development of new energy-efficient technologies and processes to manipulate biomass feed stocks and their conversion into useful products, a collective term for which is biorefinery. One of the technological platforms that will enable various pathways of biomass conversion is based on pulsed electric fields applications (PEF). Energy efficiency of PEF treatment is achieved by specific increase of cell membrane permeability, a phenomenon known as membrane electroporation. Here, we review the opportunities that PEF and electroporation provide for the development of sustainable biorefineries. We describe the use of PEF treatment in biomass engineering, drying, deconstruction, extraction of phytochemicals, improvement of fermentations, and biogas production. These applications show the potential of PEF and consequent membrane electroporation to enable the bioeconomy and sustainable development. PMID- 27127540 TI - Visual programming for next-generation sequencing data analytics. AB - BACKGROUND: High-throughput or next-generation sequencing (NGS) technologies have become an established and affordable experimental framework in biological and medical sciences for all basic and translational research. Processing and analyzing NGS data is challenging. NGS data are big, heterogeneous, sparse, and error prone. Although a plethora of tools for NGS data analysis has emerged in the past decade, (i) software development is still lagging behind data generation capabilities, and (ii) there is a 'cultural' gap between the end user and the developer. TEXT: Generic software template libraries specifically developed for NGS can help in dealing with the former problem, whilst coupling template libraries with visual programming may help with the latter. Here we scrutinize the state-of-the-art low-level software libraries implemented specifically for NGS and graphical tools for NGS analytics. An ideal developing environment for NGS should be modular (with a native library interface), scalable in computational methods (i.e. serial, multithread, distributed), transparent (platform-independent), interoperable (with external software interface), and usable (via an intuitive graphical user interface). These characteristics should facilitate both the run of standardized NGS pipelines and the development of new workflows based on technological advancements or users' needs. We discuss in detail the potential of a computational framework blending generic template programming and visual programming that addresses all of the current limitations. CONCLUSION: In the long term, a proper, well-developed (although not necessarily unique) software framework will bridge the current gap between data generation and hypothesis testing. This will eventually facilitate the development of novel diagnostic tools embedded in routine healthcare. PMID- 27127541 TI - The relationship between foot posture, body mass, age and ankle, lower-limb and whole-body flexibility in healthy children aged 7 to 15 years. AB - BACKGROUND: The complex relationship between foot posture, flexibility, body mass and age in children is not well understood. The objectives of this post hoc analysis were to explore the relationships between foot posture, flexibility, body mass in children aged seven to 15 years. METHODS: Thirty healthy, asymptomatic children (20 girls, 10 boys) aged 7 to 15 years with a mean age (SD) of 10.7 (2.3) years, were recruited through the Auckland University of Technology (AUT) Podiatry Clinic, Auckland, New Zealand. Clinical data were collected by a podiatrist with 20 years' experience and included: height and weight (for Body Mass Index), Foot Posture Index-6 (FPI), Beighton score, Lower Limb Assessment Scale score (LLAS); and ankle lunge angle. For this post hoc analysis, Pearson's test and Spearman's rho were used to explore relationships between variables. Statistical significance level was p < 0.05. RESULTS: Data for each of the 30 participants for each variable were included in analyses, which returned the following statistically significant results: higher FPI was associated moderately with higher Beighton score (r = 0.44, p = 0.01); greater lunge angle was associated moderately with higher Beighton (r = 0.40, p = 0.02) and LLAS (r = 0.42, p = 0.02) scores; older age was associated strongly with higher BMI (r = 0.52, p = <0.01) and moderately with lower Beighton (r = -0.41, p = 0.024) and LLAS (r = -0.40, p = 0.03) scores; and higher Beighton score was associated strongly with higher LLAS (r = 0.85, p = <0.01). There was no difference in foot posture between girls and boys (p = 0.21). CONCLUSIONS: In this sample of healthy, asymptomatic children age 7 to 15 years, children with a more pronated foot type exhibited greater lower limb and whole-body flexibility, but not greater ankle joint flexibility. There was strong agreement between lower-limb and whole-body flexibility. This study highlights the importance of assessing the paediatric flat foot in the context of a developing body. PMID- 27127542 TI - Establishing an analytic pipeline for genome-wide DNA methylation. AB - The need for research investigating DNA methylation (DNAm) in clinical studies has increased, leading to the evolution of new analytic methods to improve accuracy and reproducibility of the interpretation of results from these studies. The purpose of this article is to provide clinical researchers with a summary of the major data processing steps routinely applied in clinical studies investigating genome-wide DNAm using the Illumina HumanMethylation 450K BeadChip. In most studies, the primary goal of employing DNAm analysis is to identify differential methylation at CpG sites among phenotypic groups. Experimental design considerations are crucial at the onset to minimize bias from factors related to sample processing and avoid confounding experimental variables with non-biological batch effects. Although there are currently no de facto standard methods for analyzing these data, we review the major steps in processing DNAm data recommended by several research studies. We describe several variations available for clinical researchers to process, analyze, and interpret DNAm data. These insights are applicable to most types of genome-wide DNAm array platforms and will be applicable for the next generation of DNAm array technologies (e.g., the 850K array). Selection of the DNAm analytic pipeline followed by investigators should be guided by the research question and supported by recently published methods. PMID- 27127543 TI - The European Paediatric Mycology Network (EPMyN): Towards a Better Understanding and Management of Fungal Infections in Children. AB - The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. The EPMyN aims to address the lack of paediatric specific evidence and knowledge needed to (1) improve the management and outcome of invasive fungal infections in children and neonates and to (2) enhance and develop paediatric antifungal stewardship programmes. PMID- 27127544 TI - Role of Myeloperoxidase in Patients with Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is a worldwide public health problem. Patients with CKD have a number of disorders in the organism, and the presence of oxidative stress and systemic inflammation in these patients is the subject of numerous studies. Chronic inflammation joined with oxidative stress contributes to the development of numerous complications: accelerated atherosclerosis process and cardiovascular disease, emergence of Type 2 diabetes mellitus, development of malnutrition, anaemia, hyperparathyroidism, and so forth, affecting the prognosis and quality of life of patients with CKD. In this review we presented the potential role of the myeloperoxidase enzyme in the production of reactive/chlorinating intermediates and their role in oxidative damage to biomolecules in the body of patients with chronic kidney disease and end-stage renal disease. In addition, we discussed the role of modified lipoprotein particles under the influence of prooxidant MPO intermediates in the development of endothelial changes and cardiovascular complications in renal failure. PMID- 27127545 TI - Cross Talk Mechanism among EMT, ROS, and Histone Acetylation in Phorbol Ester Treated Human Breast Cancer MCF-7 Cells. AB - Epithelial-mesenchymal transition (EMT) plays a pivotal role in the progression of cancer, and some transcription factors including Slug and Snail are known to be involved in EMT processes. It has been well established that the excess production of reactive oxygen species (ROS) and epigenetics such as DNA methylation and histone modifications participate in carcinogenesis; however, the cross talk mechanism among EMT, ROS, and epigenetics remains unclear. In the present study, we demonstrated that the treatment of human breast cancer MCF-7 cells with phorbol ester (TPA), a protein kinase C activator, significantly induced cell proliferation and migration, and these were accompanied by the significant induction of Slug expression. Moreover, the TPA-elicited induction of Slug expression was regulated by histone H3 acetylation and NADPH oxidase (NOX) 2 derived ROS signaling, indicating that ROS and histone acetylation are involved in TPA-elicited EMT processes. We herein determined the cross talk mechanism among EMT, ROS, and histone acetylation, and our results provide an insight into the progression of cancer metastasis. PMID- 27127547 TI - Oxidative Stress in Children with Chronic Spontaneous Urticaria. AB - The pathogenesis of chronic spontaneous urticaria (CSU) has not been fully understood; nevertheless, significant progress has been achieved in recent years. The aim of this study was to investigate the possible role of reactive oxygen species (ROS) in the pathogenesis of CSU. Sixty-two children with CSU and 41 healthy control subjects were enrolled in the study. An extensive evaluation of demographic and clinical features was done, and serum oxidative stress was evaluated by plasma total oxidant status (TOS) and total antioxidant status (TAS) measurements. The median value of plasma TOS was found to be 10.49 MUmol H2O2 equiv./L (interquartile range, 7.29-17.65) in CSU patients and 7.68 MUmol H2O2 equiv./L (5.95-10.39) in the control group. The difference between the groups was statistically significant (p = 0.003). Likewise, the median plasma TAS level in the CSU group was decreased significantly compared to that of the control group (2.64 [2.30-2.74] versus 2.76 [2.65-2.86] mmol Trolox equiv./L, resp., p = 0,001). Our results indicated that plasma oxidative stress is increased in children with CSU when compared to healthy subjects, and plasma oxidative stress markers are positively correlated with disease activity. PMID- 27127546 TI - ROS-Mediated NLRP3 Inflammasome Activation in Brain, Heart, Kidney, and Testis Ischemia/Reperfusion Injury. AB - Ischemia and reperfusion (I/R) causes a reduction in arterial blood supply to tissues, followed by the restoration of perfusion and consequent reoxygenation. The reestablishment of blood flow triggers further damage to the ischemic tissue through reactive oxygen species (ROS) accumulation, interference with cellular ion homeostasis, and inflammatory responses to cell death. In normal conditions, ROS mediate important beneficial responses. When their production is prolonged or elevated, harmful events are observed with peculiar cellular changes. In particular, during I/R, ROS stimulate tissue inflammation and induce NLRP3 inflammasome activation. The mechanisms underlying the activation of NLRP3 are several and not completely elucidated. It was recently shown that NLRP3 might sense directly the presence of ROS produced by normal or malfunctioning mitochondria or indirectly by other activators of NLRP3. Aim of the present review is to describe the current knowledge on the role of NLRP3 in some organs (brain, heart, kidney, and testis) after I/R injury, with particular regard to the role played by ROS in its activation. Furthermore, as no specific therapy for the prevention or treatment of the high mortality and morbidity associated with I/R is available, the state of the art of the development of novel therapeutic approaches is illustrated. PMID- 27127548 TI - The Combination of alpha-Tocopheryl Succinate and Sodium Selenite on Breast Cancer: A Merit or a Demerit? AB - alpha-Tocopheryl succinate (alpha-TOS), a mitochondria-targeting agent, induces apoptosis in malignant cells in vitro and in vivo. Selenite is a nutritional supplement that has been shown to stimulate apoptosis in cancer cells. This study was designed to investigate the cytotoxic effect of combined treatment of alpha TOS and sodium selenite (SSe) in vitro and in vivo and to explore their effect on apoptosis and autophagy in breast cancer. The type of interaction between alpha TOS and SSe was evaluated and levels of oxidative stress and apoptotic and autophagic markers were determined. SSe alone showed varying degrees of cytotoxicity on all the tested cell lines. Its combination with alpha-TOS was antagonistic in vitro in MCF7 and in vivo in mice bearing Ehrlich tumor compared to alpha-TOS-treated one. Combination of TOS with 2 MUM of SSe increased the level of glutathione without changes in antiapoptotic markers Bcl-2 and Mcl-1 at 16 and 48 hrs. SSe decreased caspase 3 activity and protein level of caspases 7 and 9, while it increased autophagic markers beclin-1 and LC3B protein levels of MCF7 cells treated with alpha-TOS. In conclusion, SSe antagonizes alpha-TOS induced apoptosis via inhibition of oxidative stress and promoting prosurvival machinery of autophagy. PMID- 27127549 TI - Antioxidant Effects of Sheep Whey Protein on Endothelial Cells. AB - Excessive production of reactive oxygen species (ROS) may cause endothelial dysfunction and consequently vascular disease. In the present study, the possible protective effects of sheep whey protein (SWP) from tert-butyl hydroperoxide- (tBHP-) induced oxidative stress in endothelial cells (EA.hy926) were assessed using oxidative stress biomarkers. These oxidative stress biomarkers were glutathione (GSH) and ROS levels determined by flow cytometry. Moreover, thiobarbituric acid-reactive substances (TBARS), protein carbonyls (CARB), and oxidized glutathione (GSSG) were determined spectrophotometrically. The results showed that SWP at 0.78, 1.56, 3.12, and 6.24 mg of protein mL(-1) increased GSH up to 141%, while it decreased GSSG to 46.7%, ROS to 58.5%, TBARS to 52.5%, and CARB to 49.0%. In conclusion, the present study demonstrated for the first time that SWP protected endothelial cells from oxidative stress. Thus, SWP may be used for developing food supplements or biofunctional foods to attenuate vascular disturbances associated with oxidative stress. PMID- 27127550 TI - Phytochemical Composition, Antifungal and Antioxidant Activity of Duguetia furfuracea A. St.-Hill. AB - Background. Duguetia furfuracea is popular plant used in popular medicine. Hypothesis/Purpose. This claim evaluated the phytochemical composition of the hydroethanolic extract (HEDF), fractions of Duguetia furfuracea, and antioxidant and antifungal activity. Methods. The chemical profile was carried out by HPLC DAD. The total phenolic contents and flavonoid components were determined by Folin-Ciocalteu and aluminium chloride reaction. The antioxidant activity was measured by scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and ferric reducing ability of plasma (FRAP) methods. The antifungal activity was determined by microdilution assay. RESULTS: HPLC analysis revealed caffeic acid and rutin as major compounds (HEDF), caffeic acid and quercitrin (Mt-OH fraction), and quercitrin and isoquercitrin (Ac-OEt fraction). The highest levels of phenols and total flavonoids were found for Ac-OEt fraction, and the crude extract showed higher in vitro antioxidant potential. The antifungal activity showed synergic effect with fluconazole and EHDF against C. krusei, fluconazole and Mt-OH against C. krusei and C. tropicalis, and Ac-OE and fluconazole against C. albicans. Conclusion. The highest levels of phenols and total flavonoids were marked with antioxidant effect. This is the first report of bioactivity of the synergic effect of HEDF and fractions. More studies would be required to better clarify its mechanism of synergic action. PMID- 27127551 TI - Bayesian Estimation and Testing in Random Effects Meta-analysis of Rare Binary Adverse Events. AB - Meta-analysis has been widely applied to rare adverse event data because it is very difficult to reliably detect the effect of a treatment on such events in an individual clinical study. However, it is known that standard meta-analysis methods are often biased, especially when the background incidence rate is very low. A recent work by Bhaumik et al. (2012) proposed new moment-based approaches under a natural random effects model, to improve estimation and testing of the treatment effect and the between-study heterogeneity parameter. It has been demonstrated that for rare binary events, their methods have superior performance to commonly-used meta-analysis methods. However, their comparison does not include any Bayesian methods, although Bayesian approaches are a natural and attractive choice under the random-effects model. In this paper, we study a Bayesian hierarchical approach to estimation and testing in meta-analysis of rare binary events using the random effects model in Bhaumik et al. (2012). We develop Bayesian estimators of the treatment effect and the heterogeneity parameter, as well as hypothesis testing methods based on Bayesian model selection procedures. We compare them with the existing methods through simulation. A data example is provided to illustrate the Bayesian approach as well. PMID- 27127552 TI - Dr. Basel Ramlawi Guides Special Issue on Minimally Invasive Cardiac Surgery for the Methodist Debakey Cardiovascular Journal. PMID- 27127553 TI - William L. Winters, Jr., MD and Miguel Quinones, MD, Announce the Transition of Editorship of the Methodist DeBakey Cardiovascular Journal. PMID- 27127554 TI - The Era of Catheter-Based and Minimally Invasive Cardiac Surgery. PMID- 27127555 TI - Minimally Invasive Cardiovascular Surgery: Incisions and Approaches. AB - Throughout the modern era of cardiac surgery, most operations have been performed via median sternotomy with cardiopulmonary bypass. This paradigm is changing, however, as cardiovascular surgery is increasingly adopting minimally invasive techniques. Advances in patient evaluation, instrumentation, and operative technique have allowed surgeons to perform a wide variety of complex operations through smaller incisions and, in some cases, without cardiopulmonary bypass. With patients desiring less invasive operations and the literature supporting decreased blood loss, shorter hospital length of stay, improved postoperative pain, and better cosmesis, minimally invasive cardiac surgery should be widely practiced. Here, we review the incisions and approaches currently used in minimally invasive cardiovascular surgery. PMID- 27127556 TI - Cannulation Strategies and Pitfalls in Minimally Invasive Cardiac Surgery. AB - For any given cardiac surgery, there are two invasive components: the surgical approach and the cardiopulmonary bypass circuit. The standard approach for cardiac surgery is the median sternotomy, which offers unrestricted access to the thoracic organs-the heart, lung, and major vessels. However, it carries a long list of potential complications such as wound infection, brachial plexus palsies, respiratory dysfunction, and an unpleasant-looking scar. The cardiopulmonary bypass component also carries potential complications such as end-organ dysfunction, coagulopathy, hemodilution, bleeding, and blood transfusion requirement. Furthermore, the aortic manipulation during cannulation and cross clamping increases the risk of dissection, arterial embolization, and stroke. Minimally invasive cardiac surgery is an iconic event in the history of cardiothoracic medicine and has become a widely adapted approach as it minimizes many of the inconvenient side effects associated with the median sternotomy and bypass circuit placement. This type of surgery requires the use of novel perfusion strategies, especially in patients who hold the highest potential for postoperative morbidity. Cannulation techniques are a fundamental element in minimally invasive cardiac surgery, and there are numerous cannulation procedures for each type of minimally invasive operation. In this review, we will highlight the strategies and pitfalls associated with a minimally invasive cannulation. PMID- 27127557 TI - Minimally Invasive Multivessel Coronary Surgery and Hybrid Coronary Revascularization: Can We Routinely Achieve Less Invasive Coronary Surgery? AB - Coronary artery bypass grafting (CABG) is the gold standard in managing severe coronary artery disease. However, it is associated with prolonged recovery and potential complications, in part due to the invasiveness of the procedure. Less invasive CABG techniques attempt to improve the quality and quantity of life in the same way as surgical revascularization but with fewer complications. Minimally invasive coronary surgery (MICS) through a small thoracotomy allows for complete revascularization with good results in graft patency. Perioperative mortality is low, and there is decreased need for blood transfusion, lower surgical site infection rates, and an earlier return to full physical function. Hybrid coronary revascularization (HCR) attempts to combine the advantages of coronary artery bypass grafting with those of percutaneous coronary intervention. Several studies have shown that HCR provides better short-term outcomes with regard to decreased ventilation and ICU time, reduced need for blood transfusion, and shortened hospital stay. However, the rates for major adverse cardiovascular events and mortality are comparable to conventional CABG, except for patients with a high SYNTAX score who displayed increased mortality rates. There is also strong evidence of a higher need for repeat revascularization with HCR compared to CABG. Overall, MICS and HCR appear to be viable alternatives to conventional CABG, offering a less invasive approach to coronary revascularization, which may be especially beneficial to high-risk patients. This article discusses approaches that deliver the advantages of minimally invasive surgical revascularization that can be adapted by surgeons with minimal investment with regards to training and infrastructure. PMID- 27127558 TI - Mitral Valve Surgery: Current Minimally Invasive and Transcatheter Options. AB - The mitral valve is a highly complex structure, the competency and function of which relies on the harmonious action of its component parts. Minimally invasive cardiac surgery (MICS) for mitral valve repair or replacement (MVR/r) has been performed successfully with incremental improvements in techniques over the past decade. These minimally invasive procedures, while attractive to patients and referring physicians, should meet the same high bar for optimal clinical outcomes and long-term durability of valve repair as traditional sternotomy procedures. The majority of MICS MVR/r procedures are performed via a right minithoracotomy approach with direct or camera-assisted visualization, with a minority of centers performing robotic MVR/r. Outcomes with MICS MVR/r have been shown to have similar morbidity and mortality rates as traditional sternotomy MV procedures but with the advantage of reduced transfusions, postoperative atrial fibrillation, and time to recovery. More recently, transcatheter mitral valve repair and replacement (TMVR/r) has become a reality. Percutaneous MV repair technology is currently FDA approved for patients with nonsurgical high-risk degenerative mitral regurgitation. Other TMVR/r technology is at various levels of preclinical and clinical investigation, although these devices are proving to be more challenging compared to transcatheter aortic valve replacement (TAVR) due to the significantly more complex mitral anatomy and the greater heterogeneity of mitral disease requiring treatment. In this article, we review current techniques for MICS MVR/r and upcoming catheter-based therapies for the mitral valve. PMID- 27127559 TI - Aortic Valve Surgery: Minimally Invasive Options. AB - Minimally invasive aortic valve surgery has not been adopted by a significant proportion of cardiac surgeons despite proven benefits. This may be related to a high learning curve and technical issues requiring retraining. In this review, we discuss the data for minimally invasive aortic valve surgery and describe our operative technique for both ministernotomy and anterior thoracotomy approaches. We also discuss the advent of novel sutureless valves and how these techniques compare to available transcatheter aortic valve procedures. PMID- 27127560 TI - Advances in Transcatheter Aortic Valve Replacement. AB - Transcatheter aortic valve replacement (TAVR) is becoming widely used for the treatment of symptomatic severe aortic stenosis in patients with high surgical risk. Data from The PARTNER Trial (Placement of AoRtic TraNscathetER Valves) and the Medtronic CoreValve(r) U.S. Pivotal Investigational Device Exemption trial indicate that survival for extreme-risk patients is superior to best medical therapy and equivalent or superior to surgical aortic valve replacement (SAVR), although long-term durability remains unknown. Paravalvular leak remains higher in TAVR than SAVR, as does permanent pacemaker implantation in self-expanding valves. New-generation valves are addressing these issues, especially for paravalvular leak. There is strong evidence that TAVR is appropriate for both extreme-risk and high-risk patients with symptomatic severe aortic stenosis, and the continued development of new valves are making implantation more reliable. This review discusses the studies supporting the use of TAVR and explores current advances in the field. PMID- 27127561 TI - Minimally Invasive Atrial Fibrillation Surgery: Hybrid Approach. AB - Atrial fibrillation is a challenging pathologic process. There continues to be a great need for the development of a reproducible, durable cure when medical management has failed. An effective, minimally invasive, sternal-sparing intervention without the need for cardiopulmonary bypass is a promising treatment approach. In this article, we describe a hybrid technique being refined at our center that combines a thoracoscopic epicardial surgical approach with an endocardial catheter-based procedure. We also discuss our results and review the literature describing this unique treatment approach. PMID- 27127562 TI - Minimally Invasive Techniques for Total Aortic Arch Reconstruction. AB - The cumulative experience with endovascular aortic repair in the descending thoracic and infrarenal aorta has led to increased interest in endovascular aortic arch reconstruction. Open total arch replacement is a robust operation that can be performed with excellent results. However, it requires cardiopulmonary bypass and circulatory arrest and, therefore, may not be tolerated by all patients. Minimally invasive techniques have been considered as an alternative and include hybrid arch debranching, parallel stent graft deployment in the chimney and snorkel configurations, and complete endovascular branched reconstruction with multi-branched devices. This review discusses the evolving use of endovascular techniques in the management of aortic arch pathology and considers their relevance in an era of safe and durable open aortic arch reconstruction. PMID- 27127564 TI - Case Report: Chronic Recurrent Unilateral Pulmonary Infection: Result of Congenital Unilateral Agenesis of Pulmonary Artery. AB - Unilateral agenesis of the pulmonary artery (UAPA) is a rare congenital anomaly. This report describes a 52-year-old female who gave a long history of chronic, recurrent, left-sided pulmonary infections related to UAPA. For many years, she was managed medically but the infection continued to recur. She eventually underwent left pneumonectomy and made a good recovery. PMID- 27127563 TI - Case Report: Delayed Type A Aortic Dissection Following Complete Debranching of the Aortic Arch and Stent Graft Placement. AB - Treatment options for aortic arch disease in high-risk patients includes supra aortic debranching and thoracic endovascular aortic repair (TEVAR). Acute ascending aortic dissection is a concerning complication of this approach and has been reported to occur in a retrograde fashion. We report a case of a 60-year-old gentleman who had undergone thoracic endovascular aortic repair with debranching and presented 31 months later with acute isolated ascending aortic dissection. The patient underwent successful total replacement of the ascending aorta with a 30-mm gelwave Valsalva(TM) graft using cardiopulmonary bypass. PMID- 27127566 TI - Museum Image: Three Birds on a Wire. PMID- 27127567 TI - Museum Image: Transcatheter Closure and Reintervention on an Expanding Post Myocardial Infarction Ventricular Septal Rupture. PMID- 27127565 TI - Case Report: A Rare Case of Left Atrial Hemangioma: Surgical Resection and Reconstruction. AB - Hemangioma of the heart presenting as a primary cardiac tumor is extremely rare, accounting for approximately 2% of all primary resected heart tumors. Only a few cases of cardiac hemangiomas have been reported to arise from the left atrial wall. In this case report we share our experience in the diagnosis and surgical resection of a large (9 * 7 cm) left atrial hemangioma and reconstruction of the heart using porcine urinary bladder membrane. PMID- 27127568 TI - Editorial: Hard to Catch: A Most Memorable Atlantic Salmon. PMID- 27127569 TI - Points To Remember: The Skin in the Cardiovascular Patient. PMID- 27127570 TI - Poet's Pen: To Be Or Not To Be? PMID- 27127571 TI - Dr. Phil's Art Corner: Crystal Flower and Found in the Desert. PMID- 27127572 TI - Primary Hyperparathyroidism Misdiagnosed as Giant Cell Bone Tumor of Maxillary Sinus: A Case Report. AB - Primary hyperparathyroidism is an endocrine disorder recognized by hyperfunction of parathyroid gland, which can result in persistent bone absorption and brown tumor. Facial involvement of brown tumor is rare and usually involves the mandible. Giant cell tumor ( GCT) is an expansile osteolytic bone tumor which is very similar in clinical, radiological and histological features to brown tumor. Herein, we present a 35-year-old woman with an 11-month history of gradually swelling of the right maxilla and buccal spaces began during pregnancy two years ago. No other clinical or laboratory problems were detected. Postpartum CT scan demonstrated a lytic expansile multi-septated mass lesion containing enhancing areas, which initially described as GCT of the right maxillary sinus following surgery. Four months later, gradual progressive swelling of the bed of tumor was recurred and revised pathological slices were compatible with GCT. Regarding patient recent paresthesia, repeated laboratory tests were performed. Finally, according to laboratory results (elevation of serum calcium and parathyroid hormone), ultrasonographic findings and radioisotope scan (Sestamibi), probable parathyroid mass and brown tumor of maxilla was diagnosed. Pathology confirmed hyperplasia of right inferior parathyroid gland. Our case was thought-provoking due to its interesting clinical presentation and unusual presentation of brown tumor in parathyroid hyperplasia. PMID- 27127573 TI - Nodular Fasciitis of the Breast. AB - Nodular fasciitis of the breast is a rare benign pathology of soft tissue that is a consequence of fibroblastic hyperplasia within breast. It can mimic breast cancer clinically, radiologically, and histopathologically. A-43 year-old female with a painless mass within upper-lateral quadrant of her left breast complained of rapid and progressive growth during previous few days. No evidence of nipple discharge or sensation of pain was expressed. The mass was tender to palpation, but the size was too tiny to detect. The definitive diagnosis was established with sonography, which detected a hypoechogenic lesion, 10 mm in diameter. The excisional biopsy delivered a tissue composed of fusiform fibroblastic cells with bright ellipsoid-like nuclei and elevated nucleolus. Mitotic formations were also obvious. Low cellular and high cellular zones with hyaline fibrosis and erythrocyte accumulation existed, as well as a light lymphocytic infiltration. All of these features, in addition to adipocytic accumulation within the margins of this lesion, suggested a definitive diagnosis of Nodular fasciitis. The diagnosis of nodular fasciitis is difficult and often is indiscriminable from breast cancer, so paying close attention to this matter is critical. PMID- 27127574 TI - Defining the Collateral Flow of Posterior Tibial Artery and Dorsalis Pedis Artery in Ischemic Foot Disease: Is It a Preventing Factor for Ischemia? AB - BACKGROUND: Critical limb ischemia, a worldwide prevalent morbidity cause, is mostly secondary to vascular insufficiency due to atherosclerosis. The disease presents with intermittent claudication, which can progress to critical limb ischemia requiring amputation. Research has emphasized that the quality or existence of the pedal arch have a direct effect on wound healing and, therefore, on limb salvage, through the mechanism of collateral vascularization to the ischemic regions. OBJECTIVES: This study aimed to determine the existence and, if present, grade of retrograde blood flow from plantar arch to dorsal foot artery (dorsalis pedis artery, DPA). The correlation between clinical symptoms and presence of collateral flow were also investigated. PATIENTS AND METHODS: Study group consisted of 34 cases, which included patient group (n = 17, all male, mean age: 68 years) and control group (n = 17, all male, mean age: 66 years). After physical examination and lower extremity Doppler examination, spectral morphology of DPA flow was recorded, before and during manual compression of posterior tibial artery (PTA), for a period of 5 seconds. At the end, findings of Doppler ultrasound, computed tomography angiography, magnetic resonance angiography and, physical examination finding and symptomatology were gathered and analyzed. RESULTS: In the patient group, 31 lower limb arteries, of total of 17 cases, were included. After compression maneuver, DPA in 11 cases (six right, five left) showed retrograde filling from plantar arch. This retrograde flow support was triphasic in three cases, biphasic in five cases, and monophasic in three cases. In other DPAs of these 20 limbs, PTA based retrograde collateral flow was not determined. In nine of these 20 limbs, with no or diminished retrograde filling, symptoms were worse than in other cases. Contrarily, only two of 11 limbs, with retrograde collaterals, have claudication during walking. CONCLUSION: In cases with critical atherosclerotic disease of anterior tibial artery, PTA-based biphasic or triphasic retrograde collateral flow prevents ischemia, whereas monophasic support or no retrograde flow remains incapable. PMID- 27127575 TI - Correlating Whole-Body Bone Mineral Densitometry Measurements to Those From Local Anatomical Sites. AB - BACKGROUND: Using the same cutoff points for whole-body measurements as for site specific measurements will result in underestimation of osteoporosis. OBJECTIVES: We assessed the correlation between densitometry measurements for the whole body with those for the femur, lumbar spine, and forearm to evaluate the possibility of replacing site-specific values with whole-body measurements. PATIENTS AND METHODS: In this cross-sectional study, we evaluated all patients referred to a single rheumatology clinic for bone mineral density measurements from 2009 to 2010. All patients who had bone mineral density measurements taken from the hip, lumbar spine, forearm, and whole body were enrolled in the study. Standard bone mineral density measurements were performed using a dual energy X-ray absorptiometry device (Hologic Delphi A; Hologic, Bedford, MA, USA). Bone mineral density, Z-score, and T-score were measured for all patients and all body regions. RESULTS: The mean age of the 152 participating patients was 56.7 +/- 12.6 years, and 97.4% were female. Pearson correlation coefficients of the whole body bone mineral density values compared with site-specific values in patients over age 50 were 0.66 - 0.75. Using T-score cutoff points of -1 and -2.5 for osteopenia and osteoporosis, whole-body measurements underestimated the percentage of abnormal patients compared with the site-specific measurements (all P < 0.001). Using receiver operating characteristic (ROC) analysis, the whole body bone mineral density showed respective areas under the curve of 0.96 and 0.84 for the diagnosis of abnormal hip bone mineral density and osteoporosis. CONCLUSION: Using the same cutoff points for whole-body measurements as for site specific measurements will result in overestimation or especially underestimation of osteopenia and osteoporosis diagnosis. Choosing new and appropriate cutoff points for whole-body densitometric measurements when we want to substitutes this assessment instead of site specific measurements seems mandatory and will decrease the rate of false diagnoses of densitometric deficiencies in these anatomical sites. PMID- 27127576 TI - Transjugular Intrahepatic Portosystemic Shunt Occlusion Complicated with Biliary Fistula Successfully Treated with a Stent Graft: A Case Report. AB - A 43-year-old man with liver cirrhosis received transjugular intrahepatic portosystemic shunt (TIPS) for the treatment of recurrent variceal bleeding and F3 esophageal varices. During routine follow up liver ultrasound examination, six months after the implantation, TIPS occlusion was suspected and TIPS revision was performed. During the revision, moderate to severe stenosis at the hepatic venous segment of the tract and a total occlusion at the parenchymal segment of TIPS tract near the portal vein with biliary-TIPS fistula were identified with a clear visualization of the common bile duct. After the successful TIPS revision with the placement of an additional stent-graft, the biliary fistula and common bile duct were no more delineated. We herein report a rare case with an obvious visualization of biliary-TIPS fistula associated with obstruction of TIPS shunt on the tractogram and recanalization with an additional stent-graft. PMID- 27127577 TI - Application of Analytical Hierarchy Process Approach for Service Quality Evaluation in Radiology Departments: A Cross-Sectional Study. AB - BACKGROUND: Radiology department as a service provider organization requires realization of quality concept concerning service provisioning knowledge, satisfaction and all issues relating to the customer as well as quality assurance and improvement issues. At present, radiology departments in hospitals are regarded as income generating units and they should continuously seek performance improvement so that they can survive in the changing and competitive environment of the health care sector. OBJECTIVES: The aim of this study was to propose a method for ranking of radiology departments in selected hospitals of Tehran city using analytical hierarchical process (AHP) and quality evaluation of their service in 2015. MATERIALS AND METHODS: This study was an applied and cross sectional study, carried out in radiology departments of 6 Tehran educational hospitals in 2015. The hospitals were selected using non-probability and purposeful method. Data gathering was performed using customized joint commission international (JCI) standards. Expert Choice 10.0 software was used for data analysis. AHP method was used for prioritization. RESULTS: "Management and empowerment of human resources'' (weight = 0.465) and "requirements and facilities" (weight = 0.139) were of highest and lowest significance respectively in the overall ranking of the hospitals. MS (weight = 0.316), MD (weight = 0.259), AT (weight = 0.14), TS (weight = 0.108), MO (weight = 0.095), and LH (0.082) achieved the first to sixth rankings respectively. CONCLUSION: The use of AHP method can be promising for fostering the evaluation method and subsequently promotion of the efficiency and effectiveness of the radiology departments. The present model can fill in the gap in the accreditation system of the country's hospitals in respect with ranking and comparing them considering the significance and value of each individual criteria and standard. Accordingly, it can predict an integration of qualitative and quantitative criteria involved and thereby take a decisive step towards further efficiency and effectiveness of the health care evaluation systems. PMID- 27127578 TI - Diffusion Weighted Imaging, Diffusion Tensor Imaging, and T2* Mapping of Lumbar Intervertebral Disc in Young Healthy Adults. AB - BACKGROUND: Although conventional magnetic resonance imaging (MRI) could provide excellent detection of morphological changes in the diagnosis of lumbar disc degeneration (LDD), it has some difficulties in discriminating minimal changes associated with early LDD before morphological or clinical alterations. Therefore, newer MRI techniques have emerged for investigation of early LDD. OBJECTIVES: The aim of this study was to use diffusion weighted imaging (DWI), diffusion Tensor Imaging (DTI) and T2* mapping to detect lumbar discs in healthy young adults, to evaluate if they could depict the microstructural changes of early LDD. PATIENTS AND METHODS: Apparent diffusion coefficient (ADC), fractional anisotropy (FA), and T2* images of the lumbar discs were obtained for 40 asymptomatic young subjects (19 males and 21 females; mean age of 24.3 years), using DWI, DTI and T2* mapping with a 1.5-T MRI scanner. ADC, FA, and T2* values were measured to compare five regions of interest (ROI) selected in each nucleus pulposus (NP) of the images. RESULTS: The ADC, FA, and T2* values were different (P < 0.05) among different ROIs within the same disc or among corresponding ROIs in different level discs. While the average values of ADC increased regularly with the lowering of the anatomical location (P < 0.05), the average FA and T2* values also associated with the anatomic locations, showed an increase in L4-L5 and L5-S1 discs (P < 0.05). CONCLUSION: ADC, FA, and T2* values may quantitatively reflect the microstructural characteristics of NP, therefore they could be used to detect the minimal changes of early LDD. PMID- 27127579 TI - Significance of Additional Non-Mass Enhancement in Patients with Breast Cancer on Preoperative 3T Dynamic Contrast Enhanced MRI of the Breast. AB - BACKGROUND: In preoperative assessment of breast cancer, MRI has been shown to identify more additional breast lesions than are detectable using conventional imaging techniques. The characterization of additional lesions is more important than detection for optimal surgical treatment. Additional breast lesions can be included in focus, mass, and non-mass enhancement (NME) on MRI. According to the fifth edition of the breast imaging reporting and data system (BI-RADS(r)), which includes several changes in the NME descriptors, few studies to date have evaluated NME in preoperative assessment of breast cancer. OBJECTIVES: We investigated the diagnostic accuracy of BI-RADS descriptors in predicting malignancy for additional NME lesions detected on preoperative 3T dynamic contrast enhanced MRI (DCE-MRI) in patients with newly diagnosed breast cancer. PATIENTS AND METHODS: Between January 2008 and December 2012, 88 patients were enrolled in our study, all with NME lesions other than the index cancer on preoperative 3T DCE-MRI and all with accompanying histopathologic examination. The MRI findings were analyzed according to the BI-RADS MRI lexicon. We evaluated the size, distribution, internal enhancement pattern, and location of NME lesions relative to the index cancer (i.e., same quadrant, different quadrant, or contralateral breast). RESULTS: On histopathologic analysis of the 88 NME lesions, 73 (83%) were malignant and 15 (17%) were benign. Lesion size did not differ significantly between malignant and benign lesions (P = 0.410). Malignancy was more frequent in linear (P = 0.005) and segmental (P = 0.011) distributions, and benignancy was more frequent in focal (P = 0.004) and regional (P < 0.001) NME lesions. The highest positive predictive value (PPV) for malignancy occurred in segmental (96.8%), linear (95.1%), clustered ring (100%), and clumped (92.0%) enhancement. Asymmetry demonstrated a high positive predictive value of 85.9%. The frequency of malignancy was higher for NME lesions located in the same quadrant with the index cancer (P = 0.006), and benignancy was higher in the contralateral breast (P = 0.015). On multivariate analysis, linear (P = 0.001) and segmental (P = 0.005) distributions were significant predictors of malignancy. CONCLUSION: The possibility of malignancy is strongly indicated when additional NME lesions show linear or segmental enhancement on preoperative 3T DCE-MRI in patients with recently diagnosed breast cancer. PMID- 27127580 TI - Primary Nasopharyngeal Tuberculosis Combined with Tuberculous Otomastoiditis and Facial Nerve Palsy. AB - Primary nasopharyngeal tuberculosis (TB) without pulmonary involvement is rare, even in endemic areas. Herein, we present a rare complication of primary nasopharyngeal TB accompanied with tuberculous otomastoiditis (TOM) and ipsilateral facial nerve palsy, in a 24-year-old female patient, with computed tomography and magnetic resonance imagery findings. PMID- 27127581 TI - Predicting Factors for Successful Maturation of Autogenous Haemodialysis Fistulas After Salvage Percutaneous Transluminal Angioplasty in Diabetic Nephropathy: A Study on Follow-Up Doppler Ultrasonography. AB - BACKGROUND: Maturation failure of autogenous arteriovenous fistula (aAVF) has been increasing after surgical procedures and the salvage percutaneous transluminal angioplasty (sPTA) for immature aAVF has been identified as an effective treatment modality. OBJECTIVES: The aim of this study was to identify factors predicting successful aAVF maturation and to determine positive technical aspects of sPTA. PATIENTS AND METHODS: We retrospectively reviewed medical records and radiological images of 59 patients who had undergone sPTA for non maturing aAVFs. We analysed images from pre-surgical mapping Doppler ultrasonography, angiography, and angioplasty and follow-up Doppler ultrasonography performed within two weeks after sPTA. We assessed the following factors, for their ability to predict successful aAVF maturation: 1) patient factors (age; sex; co-morbidities; and aAVF age, side and type); 2) vessel factors (cephalic vein diameter and depth, presence of accessory veins, and pre- and postoperative radial artery disease); 3) lesion factors (stenosis number, location and severity); and 4) technical factors (presence of residual stenosis and anatomic success ratio (ASR) on follow-up Doppler ultrasonography). RESULTS: The technical and clinical success rates were both 94.9% (56/59); the mean ASR was 0.84. An ASR of >= 0.7 and no significant residual stenosis (< 30%) (both P < 0.001) on two-week follow-up Doppler ultrasonography predicted successful aAVF maturation. CONCLUSION: For more precise prediction of successful aAVF maturation after sPTA, short-term follow-up Doppler ultrasonography (< 2 weeks) was useful. If the ASR was < 0.7 or if residual stenosis was >= 30%, immediate repeat sPTA is recommended. PMID- 27127582 TI - Additional Value of Diffusion-Weighted Imaging to Evaluate Prognostic Factors of Breast Cancer: Correlation with the Apparent Diffusion Coefficient. AB - BACKGROUND: Breast cancer is a heterogeneous disease with diverse prognoses. The main prognostic determinants are lymph node status, tumor size, histological grade, and biological factors, such as hormone receptors, human epidermal growth factor receptor 2 (HER2), Ki-67 protein levels, and p53 expression. Diffusion weighted imaging (DWI) can be used to measure the apparent diffusion coefficient (ADC) that provides information related to tumor cellularity and the integrity of the cell membranes. OBJECTIVES: The goal of this study was to evaluate whether ADC measurements could provide information on the prognostic factors of breast cancer. PATIENTS AND METHODS: A total of 71 women with invasive breast cancer, treated consecutively, who underwent preoperative breast MRIs with DWI at 3.0 Tesla and subsequent surgery, were prospectively included in this study. Each DWI was acquired with b values of 0 and 1000 s/mm(2). The mean ADC values of the lesions were measured, including the entire lesion on the three largest sections. We performed histopathological analyses for the tumor size, lymph node status, histological grade, hormone receptors, human epidermal growth factor receptor 2 (HER2), Ki-67, p53, and molecular subtypes. The associations with the ADC values and prognostic factors of breast cancer were evaluated using the independent samples t test and the one-way analysis of variance (ANOVA). RESULTS: A low ADC value was associated with lymph node metastasis (P < 0.01) and with high Ki-67 protein levels (P = 0.03). There were no significant differences in the ADC values among the histological grade (P = 0.48), molecular subtype (P = 0.51), tumor size (P = 0.46), and p53 protein level (P = 0.62). CONCLUSION: The pre operative use of the 3.0 Tesla DWI could provide information about the lymph node status and tumor proliferation for breast cancer patients, and could help determine the optimal treatment plan. PMID- 27127583 TI - Comparison of Conventional Versus Spiral Computed Tomography with Three Dimensional Reconstruction in Chronic Otitis Media with Ossicular Chain Destruction. AB - BACKGROUND: Chronic otitis media (COM) can be treated with tympanoplasty with or without mastoidectomy. In patients who have undergone middle ear surgery, three dimensional spiral computed tomography (CT) scan plays an important role in optimizing surgical planning. OBJECTIVES: This study was performed to compare the findings of three-dimensional reconstructed spiral and conventional CT scan of ossicular chain study in patients with COM. PATIENTS AND METHODS: Fifty patients enrolled in the study underwent plane and three dimensional CT scan (PHILIPS-MX 8000). Ossicles changes, mastoid cavity, tympanic cavity, and presence of cholesteatoma were evaluated. Results of the two methods were then compared and interpreted by a radiologist, recorded in questionnaires, and analyzed. Logistic regression test and Kappa coefficient of agreement were used for statistical analyses. RESULTS: Sixty two ears with COM were found in physical examination. A significant difference was observed between the findings of the two methods in ossicle erosion (11.3% in conventional CT vs. 37.1% in spiral CT, P = 0.0001), decrease of mastoid air cells (82.3% in conventional CT vs. 93.5% in spiral CT, P = 0.001), and tympanic cavity opacity (12.9% in conventional CT vs. 40.3% in spiral CT, P=0.0001). No significant difference was observed between the findings of the two methods in ossicle destruction (6.5% conventional CT vs. 56.4% in spiral CT, P = 0.125), and presence of cholesteatoma (3.2% in conventional CT vs. 42% in spiral CT, P = 0.172). In this study, spiral CT scan demonstrated ossicle dislocation in 9.6%, decrease of mastoid air cells in 4.8%, and decrease of volume in the tympanic cavity in 1.6%; whereas, none of these findings were reported in the patients' conventional CT scans. CONCLUSION: Spiral-CT scan is superior to conventional CT in the diagnosis of lesions in COM before operation. It can be used for detailed evaluation of ossicular chain in such patients. PMID- 27127584 TI - Bacterial Otitis Externa in Patients Attending an ENT Clinic in Babol, North of Iran. AB - BACKGROUND: Acute otitis externa, an inflammatory condition of the external auditory canal, is a common clinical problem in general medicine. OBJECTIVES: This study aimed to determine the etiology of otitis externa in patients from the Mazandaran province, north of Iran, which has a humid climate, as humidity can affect the prevalence of pathogenic microorganisms. PATIENTS AND METHODS: This cross-sectional study involved 116 patients with otitis externa. Two sets of samples were collected from their ears; one set was used for slide preparations, and the other for microbial culturing. After culturing, the microorganisms were identified by conventional methods. RESULTS: Patients between 35 and 44 years of age were most frequently affected (25.00%) by otitis externa (average age, 43.87 +/- 18.08 years). Moreover, women (54.31%) were more frequently affected than men (45.69%). Upon direct investigation, Gram-positive bacilli were the most commonly identified microorganisms (22.41%). Furthermore, Bacillus spp. and coagulase negative staphylococci (22.41% and 19.83%, respectively), were the organisms most frequently identified from cultures of otitis externa samples. CONCLUSIONS: Direct examination and culture showed that a mixed infection of fungi and bacteria is the most common cause of otitis externa. The present study revealed that Bacilli spp. were the most abundant bacteria isolated from patients with otitis externa. Thus, it is recommended that both organisms should be considered as etiologic agents in protocols for treatment of otitis externa. PMID- 27127585 TI - Comparative Effect of Recombinant Shiga Toxin in Induction of Pro- and Anti Apoptotic Markers and Inflammatory Cytokines in Epithelial and Monocytic Cells. AB - BACKGROUND: Shiga toxins (Stxs, also referred to as verotoxins) are a family of bacterial protein toxins generated by Stx producing-Escherichia coli (STEC), such as E. coli serotype O157:H7. OBJECTIVES: The aim of this study was to investigate the effect of recombinant and native Shiga toxin (Stx) in induction of pro- and anti-apoptosis factors and stimulation of immune response to HeLa and THP-1 cells. MATERIALS AND METHODS: The HeLa and THP-1 cells were used to study the effect of native and recombinant Shiga toxin. For this purpose, 10(6) cells were cultured overnight in six-well plates and different concentrations of Stx were added to each well. The cells were then collected after 24 hours of incubation. Total RNA and protein was extracted. Firstly, the total RNA was used in reverse transcription-polymerase chain reaction (RT-PCR) for detection of interleukin (IL)-1alpha, IL-1beta, IL-8, tumor necrosis factor (TNF)-alpha, B-cell lymphoma (Bcl)-2 and Bcl-xl transcript. Protein expression of pro- and anti-apoptotic factors was also confirmed by western blot analysis. RESULTS: The IL-1alpha and IL-8 were increased by recombinant and native Stx. Interleukin-1beta was detected in THP-1, while TNF-alpha was detected HeLa cells. Furthermore, Bcl-2 and Bcl-xl expression was observed in HeLa cells. However, expression of Bak was reduced by recombinant Stx and native toxin at the protein level, while Bcl-xl expression was increased. CONCLUSIONS: These results suggest that toxins induce inflammatory responses, particularly through expression of chemokine. Recombinant Stx and native toxin induced apoptosis by balancing between different pro- and anti apoptotic Bcl-2 family-factors in epithelial cells. In this study, for the first time, recombinant and native Stx induction of apoptotic factors and stimulation of immune response to HeLa and THP-1 cells were compared. PMID- 27127586 TI - Pathotypic and Phylogenetic Study of Diarrheagenic Escherichia coli and Uropathogenic E. coli Using Multiplex Polymerase Chain Reaction. AB - BACKGROUND: Acute diarrheal disease and urinary tract infection are leading causes of childhood morbidity and mortality in the developing world. Diarrheagenic Escherichia coli (DEC) has been identified as a major etiologic agent of diarrhea worldwide, and urinary tract infection (UTI) caused by uropathogenic Escherichia coli (UPEC) is one of the most common bacterial infections among human beings. Quick and precise detection of these bacteria help provide more effective intervention and management of infection. OBJECTIVES: In this study we present a precise and sensitive typing and phylogenetic study of UPEC and DEC using multiplex PCR in order to simplify and improve the intervention and management of diarrheal and UT infections. MATERIALS AND METHODS: In total, 100 urinary tract infection samples (UTI) and 200 specimens from children with diarrhea, which had been diagnosed with E. coli as the underlying agent by differential diagnosis using MacConkey's agar and biochemical study, were submitted for molecular detection. Pathotyping of E. coli pathotypes causing urinary tract infection and diarrhea were examined using a two set multiplex PCR, targeting six specific genes. Phylogenetic typing was done by targeting three genes, including ChuA, YjaA and TspE4C2. RESULTS: Overall, 88% of DEC and 54% of UTI isolates were positive for one or more of the six genes encoding virulence factors. Prevalence of the genes encoding virulence factors for DEC were 62%, 25%, 24%, 13%, 7% and 5% for ST (ETEC), LT (ETEC), aggR (EAggEC), daaD (DAEC), invE (EIEC) and eae (EPEC), respectively; whereas, the prevalence rates for the UTI samples were 23%, 14%, 6%, 6% and 4% for aggR (EAggEC), LT (ETEC), daaD (DAEC), invE (EIEC) and ST (ETEC), respectively. No coding virulence factors were detected for eae (EPEC). Group B2 was the most prevalent phylogroup and ST was the most frequently detected pathotype in all phylogroups. CONCLUSIONS: ETEC and EAggEC were the most detected E. coli among stool and UTI samples, emphasizing the need to dedicate more health care attention to this group. In addition, our phylogenetic study may be helpful in figuring out the infection origin and for epidemiological studies. Nonetheless, more research studies with larger sample sizes are suggested for confirming our results. PMID- 27127587 TI - In Vitro Susceptibility and Trailing Growth Effect of Clinical Isolates of Candida Species to Azole Drugs. AB - BACKGROUND: Emergence of resistance to respective antifungal drugs is a primary concern for the treatment of candidiasis. Hence, determining antifungal susceptibility of the isolated yeasts is of special importance for effective therapy. For this purpose, the clinical laboratory standard institute (CLSI) has introduced a broth microdilution method to determine minimum inhibitory concentration (MIC). However, the so-called "Trailing effect" phenomenon might sometimes pose ambiguity in the interpretation of the results. OBJECTIVES: The present study aimed to determine the in vitro susceptibility of clinical isolates of Candida against azoles and the frequency of the Trailing effect. MATERIALS AND METHODS: A total of 193 Candida isolates were prospectively collected and identified through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Using a broth microdilution test, according to the guidelines of CLSI M27-A3, antifungal susceptibilities of the isolated yeasts against Fluconazole (FLU), Itraconazole (ITR), Ketoconazole (KET) and Voriconazole (VOR) were assessed. Moreover, trailing growth was determined when a susceptible MIC was incubated for 24 hours, and turned into a resistant one after 48 hours of incubation. RESULTS: Among the tested antifungal drugs in this study, the highest rate of resistance was observed against ITR (28.5%) followed by VOR (26.4%), FLU (20.8%) and KET (1.5%). The trailing effect was induced in 27 isolates (14.0%) by VOR, in 26 isolates (13.5%) by ITR, in 24 isolates (12.4%) by FLU, and in 19 isolates (9.8%) by KET. CONCLUSIONS: The monitoring of antifungal susceptibilities of Candida species isolated from clinical sources is highly recommended for the efficient management of patients. Moreover, the trailing effect should be taken into consideration once the interpretation of the results is intended. PMID- 27127588 TI - Detection of Toxoplasma gondii in Diabetic Patients Using the Nested PCR Assay via RE and B1 Genes. AB - BACKGROUND: Toxoplasma gondii is an obligate intracellular protozoan parasite that exists worldwide. Various techniques have been developed for T. gondii detection. OBJECTIVES: The aim of this study was the detection of T. gondii in diabetic patients with RE and B1 genes and the comparison of these two genes for diagnosis using the nested-PCR assay method. PATIENTS AND METHODS: DNA samples from 205 diabetic patients who had been referred to the diabetes center of Ali Asghar hospital in Zahedan, Iran, were collected and analyzed using the nested PCR assay method. Toxoplasma antibody data gathered using the enzyme-linked immunosorbent assay (ELISA) method from a previous study was used to group patients. The data were analyzed using SPSS 18. The chi-square test was used for comparison. RESULTS: Of the diabetic patients selected, the following results were obtained: 53 (IgG+, IgM+); 20 (IgG-, IgM+); 72 (IgG+, IgM-); and 60 (IgG-, IgM-). The nested-PCR detected the following: in the acute group, 21/53 (39.63%), 30/53 (56.60%) (IgM+, IgG+); in the chronic group, 40/72 (55.56%), 51/72 (70.83%), (IgG+, IgM-); in the false positive group, 18/20 (90%), 17/20 (85%) (IgM+, IgG-); and sero-negative samples of 38/60 (63.33%) and 60/ 41 (77.35%) for RE and B1 genes, respectively. The prevalence of toxoplasmosis showed positive in patients with diabetes in the B1 gene 139 (67.8%) and RE gene 117 (57.1%). CONCLUSIONS: Our study demonstrated that the B1 gene, more so than the RE gene, showed positive samples and can be used to detect toxoplasmosis, although the B1 gene, in comparison to the RE gene, did not show any superiority of molecular diagnosing capability. Results also showed that toxoplasma molecular detection methods can be used instead of routine serological detection methods in a clinical laboratory testing. PMID- 27127589 TI - In Silico Analysis of the cadF Gene and Development of a Duplex Polymerase Chain Reaction for Species-Specific Identification of Campylobacter jejuni and Campylobacter coli. AB - BACKGROUND: Campylobacteriosis is a zoonotic infectious disease caused by Campylobacter jejuni and C. coli. The cadF gene is considered as a genus-specific gene while other genes are mainly used for discrimination at the species level. OBJECTIVES: This study aimed to analyze the cadF gene and to develop a duplex PCR assay for simultaneous detection of C. coli and C. jejuni, the two commonly encountered species. MATERIALS AND METHODS: In silico analysis of the cadF gene was carried out by several software and available online tools. A duplex PCR optimized with specific primers was used for detection and differentiation of both species. To evaluate specificity and sensitivity of the test, a panel of different Campylobacter spp. together with several intestinal bacterial pathogens was tested. The limit of detection (LOD) of method was determined using serial dilutions of standard genomes. RESULTS: The analysis of the full size cadF gene indicated variations in this gene, which can be used to differentiate C. jejuni and C. coli. The duplex PCR designed in this study showed that it could simultaneously detect and differentiate both C. jejuni and C. coli with product sizes of 737 bp and 461 bp, respectively. This assay, with 100% specificity and sensitivity, had a limit of detection (LOD) of about 14 and 0.7 ug/mL for C. jejuni and C. coli, respectively. CONCLUSIONS: In silico analysis of the cadF full-gene showed variations between the two species that can be used as a molecular target for differentiating C. jejuni and C. coli in a single-step duplex-PCR assay with high specificity and sensitivity. PMID- 27127590 TI - Detection of 23SrRNA Mutations Strongly Related to Clarithromycin Resistance in Helicobacter pylori Strains Isolated From Patients in the North of Iran. AB - BACKGROUND: Helicobacter pylori is curved Gram negative and microaerophilic bacilli that have infected half of the world's population. It is recognized as the causative agent of duodenal ulcer, gastritis peptic ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma and is associated with gastric adenocarcinoma. Resistance to clarithromycin is related to point mutations in 23SrRNA gene on nt 2143 and 2144, when A turns to G, and A2143G is the most important type. These mutations lead to reduced affinity of antibiotics to their ribosomal target and are considered as the main cause of treatment failure. OBJECTIVES: The aim of this study was to determine the frequency of A2143G point mutation in 23SrRNA of H. pylori strains isolated from gastric biopsies of patients in Rasht, north of Iran, by polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). PATIENTS AND METHODS: A descriptive study was performed on 89 H. pylori strains, which were isolated from gastric biopsies of patients with gastric disorders such as gastritis, peptic ulcer, duodenal ulcer, non-ulcer dyspepsia and gastric adenocarcinoma. Isolated strains were tested for clarithromycin resistance using as breakpoint a minimum inhibitory concentration (MIC) of >= 1 mg/L by the E-test. The presence of H. pylori DNA was confirmed by amplifying the ureC (glmM) gene by PCR. Also, point mutation on 23SrRNA gene (A2142G and A2143G) was detected by PCR-RFLP using MboII and BsaI restriction endonucleases in all extracted DNA. RESULTS: Of the 89 H. pylori isolates, eighty-four were susceptible to clarithromycin, while five (5.6%) were resistant. All DNA samples of resistant strains, which were treated with BsaI had A2143G mutation. There was no point mutation in the sensitive strains of H. pylori. Also, we detected no mutation on nt A2142G of resistant strains. CONCLUSIONS: In the present study, the frequency of clarithromycin resistance was lower than the other studies conducted in Iran. Resistance frequency in samples isolated from gastric ulcer was higher than other gastric disorders. Women and patients aged more than 60 years old showed the most resistance frequency in this study. All resistant strains had the A2143G genotype. PMID- 27127591 TI - Survey of the Antibiofilm and Antimicrobial Effects of Zingiber officinale (in Vitro Study). AB - BACKGROUND: Candidiasis is one of the most prevalent and important opportunistic fungal infections of the oral cavity caused by Candida yeast species like Candida albicans, C. glabrata, and C. krusei. In addition, several bacteria can cause oral infections. The inhibition of microbial biofilm is the best way to prevent oral infections. OBJECTIVES: The aim of the present study is to evaluate the antifungal, antimicrobial, and anti-biofilm properties of ginger (Zingiber officinale) extract against Candida species and some bacterial pathogens and the extract's effects on biofilm formation. MATERIALS AND METHODS: Ginger ethanolic extract as a potential mouthwash was used to evaluate its effect against fungi and bacteria using the microdilution method, and biofilm was evaluated using the crystal violet staining method and dead/alive staining. MTT assay was used to evaluate the possible cytotoxicity effects of the extract. RESULTS: The minimum inhibitory concentrations (MICs) of ginger extract for evaluated strains were 40, 40, 20, 20, 20, 20, 10, and 5 mg/mL for Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Bacillus cereus, Acinetobacter baumannii, C. albicans, and C. krusei, respectively. Ginger extract successfully inhibited biofilm formation by A. baumannii, B. cereus, C. krusei, and C. albicans. MTT assay revealed no significant reduction in cell viability after 24 hours. The minimum inhibitory biofilm concentrations (MIBCs) of ginger extract for fungi strains (C. krusei and C. albicans) were greater than those of fluconazole and nystatin (P = 0.000). CONCLUSIONS: The findings of the present study indicate that ginger extract has good antifungal and antibiofilm formation by fungi against C. albicans and C. Krusei. Concentrations between 0.625 mg/mL and 5 mg/mL had the highest antibiofilm and antifungal effects. Perhaps, the use of herbal extracts such as ginger represents a new era for antimicrobial therapy after developing antibiotic resistance in microbes. PMID- 27127592 TI - Molecular Characterization of Streptococcus agalactiae Isolates From Pregnant and Non-Pregnant Women at Yazd University Hospital, Iran. AB - BACKGROUND: Streptococcus agalactiae (Group B streptococcus, GBS) that colonize the vaginas of pregnant women may occasionally cause neonatal infections. It is one of the most common causes of sepsis and meningitis in neonates and of invasive diseases in pregnant women. It can also cause infectious disease among immunocompromised individuals. The distribution of capsular serotypes and genotypes varies over time and by geographic era. The serotyping and genotyping data of GBS in Iranian pregnant and non-pregnant women seems very limited. OBJECTIVES: The aim of this study was to investigate the GBS molecular capsular serotype and genotype distribution of pregnant and non-pregnant carrier women at Yazd university hospital, in Iran.. PATIENTS AND METHODS: In this cross-sectional study, a total of 100 GBS strains isolated from 237 pregnant and 413 non-pregnant women were investigated for molecular capsular serotypes and surface protein genes using the multiplex PCR assay. The Chi-square method was used for statistical analysis. RESULTS: Out of 650 samples, 100 (15.4%) were identified as GBS, with a predominance of capsular serotypes III (50%) [III-1 (49), III-3 (1)], followed by II (25%), Ia (12%), V (11%), and Ib (2%), which was similar with another study conducted in Tehran, Iran, but they had no serotype Ia in their report. The surface protein antigen genes distribution was rib (53%), epsilon (38%), alp2/3 (6%), and alpha-c (3%). CONCLUSIONS: The determination of serotype and surface proteins of GBS strains distribution would be relevant for the future possible formulation of a GBS vaccine. PMID- 27127593 TI - Serum Levels of Soluble CD26, A Novel Prognostic Marker for Hepatitis E Infection. AB - BACKGROUND: Even without treatment, most acute hepatitis E virus (HEV) infected patients resolve HEV but sometimes the disease leads to acute liver failure, chronic infection, or extrahepatic symptoms. The mechanisms of HEV pathogenesis appear to be substantially immune mediated. However, the immune responses to HEV are not precisely identified. OBJECTIVES: This study aimed to evaluate the Th1/Th2 ratio by investigating serum soluble markers from Th1 and Th2 cells in acute HEV infected patients. PATIENTS AND METHODS: This case-control study included 35 acute HEV infected patients and 35 age and gender matched anti-HEV negative healthy controls. The serum levels of Interferon (IFN)-gamma, IL-4, soluble CD26 (sCD26) and sCD30 were determined by the enzyme-linked immunosorbent assay. RESULTS: The results showed a significant difference in IFN-gamma and sCD26 (P < 0.0001 and P = 0.001) yet not IL-4 and sCD30 (P = 0.354 and P = 0.159) between acute HEV patients and controls, respectively. There was a positive direct correlation between serum levels of sCD26 and IFN-gamma in acute HEV patients (r = 0.64, P = 0.001). In addition, the ratio of sCD26/sCD30 in the acute HEV group was more than two folds higher than in the HEV negative controls. CONCLUSIONS: Acute HEV infection shows a pattern of Th1-type immune response, and the direct significant positive correlation between the serum level of sCD26 and IFN-gamma in acute HEV infected patients, suggests that the trend of sCD26 levels is a valuable marker for predicting hepatic inflammation in hepatitis E. PMID- 27127594 TI - The Prevalence of Hepatitis B and C Among Prisoners in Kahramanmaras, Turkey. AB - BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are among the most important health issues in Turkey. Human immunodeficiency virus (HIV) infections are less frequently observed in the country. The individuals who had blood transfusions, patients undergoing hemodialysis, and intravenous drug addicted individuals, people who had tattoos/piercings, communal living environments, contamination of a family member, and prisoners are the main risk groups. OBJECTIVES: The current study aimed to discuss the prevalence and the genotypes of hepatitis and HIV infections among a specific group, namely individuals incarcerated in prisons. PATIENTS AND METHODS: Two-hundred and sixty six prisoners sentenced for crimes such as robbery, sexual assault, assault substance abuse or selling drugs in the Kahramanmaras closed prison were recruited for the study. Demographic data and the presence of hepatitis B, hepatitis C and HIV were investigated in the study subjects. RESULTS: Out of the 266 cases included in the study, 89.5% were male, 10.5% were female and the mean age was 31.21 +/- 8.99 years. Risk factors were detected in 27.4% of the subjects. Out of the 73 subjects, among whom the risk factors were detected, 20.3% had intravenous substance use, 3.8% had a history of operation/transfusion, 1.9% had a history of indentation and 1.5% had unprotected sexual contact. The rate of hepatitis B surface antigen (HBsAg) positivity was 2.6%, the ratio of anti-HBs positive subjects was 35.0% and immunity was achieved with vaccination in 43% of the subjects. Anti-HCV was positive in 17.7% of the prisoners and the genotype 3 and genotype 1 were 68.1% (n = 32) and 2.1% (n = 1), respectively. CONCLUSIONS: Continued substance abuse among most of the drug addicted individuals in prisons, common use of injection materials, tattoos and other circumstances that cause blood contact increase the risk of blood-borne infections. PMID- 27127595 TI - Plasma Levels of IFN-gamma, IL-4, IL-6 and IL-17 in HIV-Positive Patients With Oral Candidiasis. AB - BACKGROUND: Cell-mediated immunity (CMI) by CD4 + Th (T helper)-type cells is the predominant host defense mechanism against Oral Candidiasis (OC) in HIV-infected individuals. Weakened CMI and depletion of CD4 + T cells are the main factor contributing to the output of OC in HIV-positive individuals. The cytokines produced by Th1, Th2 and Th17 cells play a role in mediating an increased susceptibility to OC during HIV infection. OBJECTIVES: The present study investigated plasma concentration of IFN-gamma, IL-4, IL-6 and IL-17 in HIV-1 patients suffering from OC. PATIENTS AND METHODS: In total, 98 samples in four groups (HIV-positive and HIV-negative persons with and without OC) were obtained from the oral cavities and cultured on Sabouraud's dextrose agar and CHROMagar. Also blood samples were obtained to assess plasma level of IFN-gamma, IL-4, IL-6 and IL-17 using ELISA technique. RESULTS: There was a statistically significant difference in the plasma concentration of IFN-gamma, IL-6 and IL-17 but not about IL-4. Our findings suggest a significant interaction between fungal infection and HIV on expression of assessed cytokines. CONCLUSIONS: Fungal infection and HIV alone and together could seriously alter immune system function as assessed by measuring the levels of the plasma cytokines. Therefore, these results provide important new information relative to the putative immune-based factors associated with resistance and/or susceptibility to OC in HIV-positive persons. PMID- 27127596 TI - Molecular Epidemiological Survey of Cutaneous Leishmaniasis in Two Highly Endemic Metropolises of Iran, Application of FTA Cards for DNA Extraction From Giemsa Stained Slides. AB - BACKGROUND: PCR has been used for confirmation of leishmaniasis in epidemiological studies, but complexity of DNA extraction and PCR approach has confined its routine use in developing countries. OBJECTIVES: In this study, recent epidemiological situation of cutaneous leishmaniasis (CL) in two hyper endemic metropolises of Shiraz and Isfahan in Iran was studied using DNA extraction by commercial FTA cards and kinetoplastid DNA (kDNA)-PCR amplification for detection/identification of Leishmania directly from stained skin scraping imprints. PATIENTS AND METHODS: Fifty four and 30 samples were collected from clinically diagnosed CL patients referred to clinical laboratories of leishmaniasis control centers in Isfahan and Shiraz cities, respectively. The samples were examined by direct microscopy and then scrapings of the stained smears were applied to FTA cards and used directly as DNA source in a nested-PCR to amplify kDNA to detect and identify Leishmania species. RESULTS: Fifty four of 84 (64.2%) slides obtained from patients had positive results microscopically, while 79/84 (94%) of slides had positive results by FTA card-nested-PCR. PCR and microscopy showed a sensitivity of 96.4% and 64.2% and specificity of 100% and 100%, respectively. Interestingly, Leishmania major as causative agent of zoonotic CL was identified in 100% and 90.7% of CL cases from Isfahan and Shiraz cities, respectively, but L. tropica was detected from only 9.3% of cases from Shiraz city. All cases from central regions of Shiraz were L. tropica and no CL case was found in Isfahan central areas. CONCLUSIONS: Filter paper-based DNA extraction can facilitate routine use of PCR for diagnosis of CL in research and diagnostic laboratories in Iran and countries with similar conditions. Epidemiologic changes including dominancy of L. major in suburbs of Shiraz and Isfahan metropolises where anthroponotic CL caused by L. tropica had been established, showed necessity of precise studies on CL epidemiology in old urban and newly added districts in the suburbs. PMID- 27127598 TI - The Stop-Bang Questionnaire as a Screening Tool for Obstructive Sleep Apnea Induced Hypertension in Asian Population. AB - Obstructive sleep apnea (OSA) is a common public health issue. If left untreated, OSA may cause a large health economic burden from cardiovascular complications particularly stroke. The diagnosis of OSA can be made by polysomnography, but its availability is limited in the developing countries in Asia. STOP-BANG questionnaire is a good screening tool but may need some adjustment for Asian population. STOP-BANG stands for: Snoring history, Tired during the day, Observed stop breathing while sleep, High blood pressure, body mass index (BMI) more than 35 kg/m(2), Age more than 50 years, Neck circumference more than 40 cm and male Gender. We compared clinical features in STOP-BANG questionnaire between 42 OSA induced hypertension patients and 82 healthy control subjects in the Faculty of Medicine, Khon Kaen University, Thailand. The best cutoff point for the BMI and the neck circumference were 24.5 kg/m(2) and 36 cm, respectively. The sensitivity and specificity of the BMI cutoff point were 97.2% and 91.40, while those of the neck circumference were 94.7% and 82.9%. In conclusion, the appropriate cutoff points of BMI and neck circumference for Thai STOP-BANG questionnaire were 25 kg/m(2) and 36 cm. PMID- 27127599 TI - Revisiting the Term Neuroprotection in Chronic and Degenerative Diseases. AB - Thanks to the development of several new researches, the lifetime presented a significant increase, even so, we still have many obstacles to overcome - among them, manage and get responses regarding neurodegenerative diseases. Where we are in the understanding of neuroprotection? Do we really have protective therapies for diseases considered degeneratives such as amyotrophic lateral sclerosis and its variants, Parkinson's disease, Alzheimer's disease and many others? Neuroprotection is defined by many researches as interactions and interventions that can slow down or even inhibit the progression of neuronal degeneration process. We make some considerations on this neuroprotective effect. PMID- 27127600 TI - Metronidazole-Induced Cerebellar Toxicity. AB - Metronidazole is a very common antibacterial and antiprotozoal with wide usage across the globe, including the least developed countries. It is generally well tolerated with a low incidence of serious side-effects. Neurological toxicity is fairly common with this drug, however majority of these are peripheral neuropathy with very few cases of central nervous toxicity reported. We report the imaging findings in two patients with cerebellar dysfunction after Metronidazole usage. Signal changes in the dentate and red nucleus were seen on magnetic resonance imaging in these patients. Most of the cases reported in literature reported similar findings, suggesting high predilection for the dentate nucleus in metronidazole induced encephalopathy. PMID- 27127597 TI - Time Perception Mechanisms at Central Nervous System. AB - The five senses have specific ways to receive environmental information and lead to central nervous system. The perception of time is the sum of stimuli associated with cognitive processes and environmental changes. Thus, the perception of time requires a complex neural mechanism and may be changed by emotional state, level of attention, memory and diseases. Despite this knowledge, the neural mechanisms of time perception are not yet fully understood. The objective is to relate the mechanisms involved the neurofunctional aspects, theories, executive functions and pathologies that contribute the understanding of temporal perception. Articles form 1980 to 2015 were searched by using the key themes: neuroanatomy, neurophysiology, theories, time cells, memory, schizophrenia, depression, attention-deficit hyperactivity disorder and Parkinson's disease combined with the term perception of time. We evaluated 158 articles within the inclusion criteria for the purpose of the study. We conclude that research about the holdings of the frontal cortex, parietal, basal ganglia, cerebellum and hippocampus have provided advances in the understanding of the regions related to the perception of time. In neurological and psychiatric disorders, the understanding of time depends on the severity of the diseases and the type of tasks. PMID- 27127601 TI - Central Neurogenic Hyperventilation Related to Post-Hypoxic Thalamic Lesion in a Child. AB - Central neurogenic hyperventilation (CNH) is a rare clinical condition, whose mechanism is still unclear. Here, we report a 3-year-old male patient, who had bilateral thalamic, putaminal and globus pallideal infarction resulted in CNH without brainstem involvement. This case may illustrate a possible role for the thalamus in regulating ventilation. PMID- 27127602 TI - Artery reopening is required for the neurorestorative effects of angiotensin modulation after experimental stroke. AB - BACKGROUND: Blood flow restoration with fibrinolysis and thrombectomy is recommended to limit injury in stroke patients with proximal artery occlusion. Angiotensin receptor blockers have been shown to be neuroprotective in models of permanent and temporary occlusion, but the benefits on expression of trophic factors have been seen only when the artery is reopened. It is possible that early artery opening with endovascular intervention may increase the likelihood of identifying an effective combination therapy for patients. METHODS: Normotensive male Wistar rats were subjected to mechanical middle cerebral artery occlusion (either temporary or permanent), followed by randomization to receive candesartan (0.3 mg/kg IV) or saline. Functional outcome, infarct size, and biochemical changes were assessed 24 h after ischemia induction. RESULTS: Lack of reperfusion blunted candesartan induced neuroprotection (p < 0.05) and reduced the improvement of functional outcome (p < 0.05). With reperfusion, candesartan increased mature BDNF expression in the contralateral hemisphere (p < 0.05) and activated prosurvival (Akt-GSK3-beta) signaling (p < 0.05). Without reperfusion, candesartan significantly reduced VEGF expression and MMP activation and increased NOGO A expression, creating an environment hostile to recovery. CONCLUSION: Candesartan induced pro-recovery effects are dependent on the presence of reperfusion. PMID- 27127603 TI - Active learning for ontological event extraction incorporating named entity recognition and unknown word handling. AB - BACKGROUND: Biomedical text mining may target various kinds of valuable information embedded in the literature, but a critical obstacle to the extension of the mining targets is the cost of manual construction of labeled data, which are required for state-of-the-art supervised learning systems. Active learning is to choose the most informative documents for the supervised learning in order to reduce the amount of required manual annotations. Previous works of active learning, however, focused on the tasks of entity recognition and protein-protein interactions, but not on event extraction tasks for multiple event types. They also did not consider the evidence of event participants, which might be a clue for the presence of events in unlabeled documents. Moreover, the confidence scores of events produced by event extraction systems are not reliable for ranking documents in terms of informativity for supervised learning. We here propose a novel committee-based active learning method that supports multi-event extraction tasks and employs a new statistical method for informativity estimation instead of using the confidence scores from event extraction systems. METHODS: Our method is based on a committee of two systems as follows: We first employ an event extraction system to filter potential false negatives among unlabeled documents, from which the system does not extract any event. We then develop a statistical method to rank the potential false negatives of unlabeled documents 1) by using a language model that measures the probabilities of the expression of multiple events in documents and 2) by using a named entity recognition system that locates the named entities that can be event arguments (e.g. proteins). The proposed method further deals with unknown words in test data by using word similarity measures. We also apply our active learning method for the task of named entity recognition. RESULTS AND CONCLUSION: We evaluate the proposed method against the BioNLP Shared Tasks datasets, and show that our method can achieve better performance than such previous methods as entropy and Gibbs error based methods and a conventional committee-based method. We also show that the incorporation of named entity recognition into the active learning for event extraction and the unknown word handling further improve the active learning method. In addition, the adaptation of the active learning method into named entity recognition tasks also improves the document selection for manual annotation of named entities. PMID- 27127604 TI - Use of the gamma probe to identify multigland disease in primary hyperparathyroidism. AB - AIM: The purpose of this study was to determine threshold gamma probe counts to distinguish single adenoma (SA) from multigland disease (MGD) during radioguided parathyroidectomy. METHODS: A retrospective analysis of 1656 patients was performed. Ex vivo counts of the first excised gland were taken and recorded as a percentage of background counts. RESULTS: 69.4% of MGD patients had counts below the 50% threshold. The 50% threshold correctly grouped 72.8% of our cohort. Counts of more than 100% were accurate for grouping SA, with only 6.8% of patients with counts more than 100% having MGD. CONCLUSIONS: The gamma probe can aid surgeons in deciding to continue neck exploration if MGD is suspected or wait for labs to confirm cure if SA is suspected. PMID- 27127605 TI - Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients. AB - BACKGROUND: Zoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity. METHODS: The purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression. RESULTS: In our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18-20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA. CONCLUSIONS: Single agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases. PMID- 27127606 TI - Dietary intake and risk of asthma in children and adults: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Diet has been proposed to modulate the risk of asthma in children and adults. An increasing body of epidemiological studies have been published in the last year investigating the association between dietary intake and asthma. As part of the Evidence-Based Clinical Practice Guideline Task Force on 'Lifestyle Interventions in Allergy and Asthma' funded by the European Academy of Allergy and Clinical Immunology, we will use a systematic approach to review the evidence from published scientific literature on dietary intake and asthma in children and adults. METHODS: This systematic review will be carried out following the PRISMA guidelines. The protocol has been published in PROSPERO (CRD42016036078). We will review the evidence from epidemiological studies in children (from the age of 2 years) and adults and dietary intake of foods and nutrients. DISCUSSION: The findings from this review will be used as a reference to inform guideline recommendations. PMID- 27127607 TI - Assessing the geographic scale of genetic population management with microsatellites and introns in the clam Ruditapes decussatus. AB - The clam Ruditapes decussatus is commercially important in southwestern Europe, suffering from population decline and hybridization with exotic Manila clam (R. philippinarum). Previous studies with intronic markers showed a genetic subdivision of the species in three races (Atlantic, West Mediterranean, and Adriatic-Aegean). However, detailed population genetic studies to help management of the main production areas in the southwest of Europe are missing. We have analyzed eight Atlantic and two Mediterranean populations from the Spanish coasts using 14 microsatellites and six intronic markers. Microsatellites confirmed the Atlantic and West Mediterranean races detected with introns and showed that genetic variability was higher in Mediterranean than in Atlantic populations. Both marker types showed that genetic differentiation of Atlantic populations was low and indicated that populations could be managed at the regional level in the case of Cantabrian and Gulf of Cadiz areas, but not in the case of Rias Baixas and the Mediterranean. This study shows the interest of including different types of markers in studies of genetic population structure of marine organisms. PMID- 27127608 TI - Winners and losers: tropical forest tree seedling survival across a West African forest-savanna transition. AB - Forest encroachment into savanna is occurring at an unprecedented rate across tropical Africa, leading to a loss of valuable savanna habitat. One of the first stages of forest encroachment is the establishment of tree seedlings at the forest-savanna transition. This study examines the demographic bottleneck in the seedlings of five species of tropical forest pioneer trees in a forest-savanna transition zone in West Africa. Five species of tropical pioneer forest tree seedlings were planted in savanna, mixed/transition, and forest vegetation types and grown for 12 months, during which time fire occurred in the area. We examined seedling survival rates, height, and stem diameter before and after fire; and seedling biomass and starch allocation patterns after fire. Seedling survival rates were significantly affected by fire, drought, and vegetation type. Seedlings that preferentially allocated more resources to increasing root and leaf starch (starch storage helps recovery from fire) survived better in savanna environments (frequently burnt), while seedlings that allocated more resources to growth and resource-capture traits (height, the number of leaves, stem diameter, specific leaf area, specific root length, root-to-shoot ratio) survived better in mixed/transition and forest environments. Larger (taller with a greater stem diameter) seedlings survived burning better than smaller seedlings. However, larger seedlings survived better than smaller ones even in the absence of fire. Bombax buonopozense was the forest species that survived best in the savanna environment, likely as a result of increased access to light allowing greater investment in belowground starch storage capacity and therefore a greater ability to cope with fire. SYNTHESIS: Forest pioneer tree species survived best through fire and drought in the savanna compared to the other two vegetation types. This was likely a result of the open-canopied savanna providing greater access to light, thereby releasing seedlings from light limitation and enabling them to make and store more starch. Fire can be used as a management tool for controlling forest encroachment into savanna as it significantly affects seedling survival. However, if rainfall increases as a result of global change factors, encroachment may be more difficult to control as seedling survival ostensibly increases when the pressure of drought is lifted. We propose B. buonopozense as an indicator species for forest encroachment into savanna in West African forest-savanna transitions. PMID- 27127609 TI - Intrasexual competition underlies sexual selection on male breeding coloration in the orangethroat darter, Etheostoma spectabile. AB - Elaborate, sexually dimorphic traits are widely thought to evolve under sexual selection through female preference, male-male competition, or both. The orangethroat darter (Etheostoma spectabile) is a sexually dichromatic fish in which females exhibit no preferences for male size or coloration. We tested whether these traits affect individual reproductive success in E. spectabile when multiple males are allowed to freely compete for a female. The quality and quantity of male coloration were associated with greater success in maintaining access to the female and in spawning as the primary male (first male to participate). On the other hand, sneaking behavior showed little correlation with coloration. Male breeding coloration in E. spectabile may therefore demonstrate how intrasexual competition can be a predominant factor underlying the evolution of male ornaments. PMID- 27127610 TI - Seasonal phenotype-specific transcriptional reprogramming during metamorphosis in the European map butterfly Araschnia levana. AB - The European map butterfly (Araschnia levana) is a classic example of seasonal polyphenism because the spring and summer imagoes display two distinct morphological phenotypes. The light regime and temperature during larval and prepupal development determine whether or not the pupae commit to diapause and overwintering and thus whether spring or summer imagoes emerge. We used suppression subtractive hybridization to experimentally screen for genes that are differentially expressed in prepupae committed either to accelerated metamorphosis and egg production or diapause and overwintering. The range and ontology of the differentially expressed genes in prepupae developing from larvae exposed either to long-day (LD) or short-day (SD) conditions revealed fundamental differences. The SD prepupae preferentially expressed genes related to cuticle formation and immunity, reflecting the formation of a robust pupal exoskeleton and the upregulation of antimicrobial peptides as preparations for overwintering. One protein preferentially expressed in SD prepupae has a counterpart in Bombyx mori that functions as a diapause duration clock. The differentially expressed genes in LD prepupae included several members of the dusky and osiris families. We also observed the strong induction of different yellow-like genes under SD and LD conditions which suggest a role in the developmental choice between seasonal phenotypes. Our transcriptomic data will facilitate the more detailed analysis of molecular mechanisms underlying seasonal polyphenism. PMID- 27127611 TI - Is my study system good enough? A case study for identifying maternal effects. AB - In this paper, we demonstrate how simulation studies can be used to answer questions about identifiability and consequences of omitting effects from a model. The methodology is presented through a case study where identifiability of genetic and/or individual (environmental) maternal effects is explored. Our study system is a wild house sparrow (Passer domesticus) population with known pedigree. We fit pedigree-based (generalized) linear mixed models (animal models), with and without additive genetic and individual maternal effects, and use deviance information criterion (DIC) for choosing between these models. Pedigree and R-code for simulations are available. For this study system, the simulation studies show that only large maternal effects can be identified. The genetic maternal effect (and similar for individual maternal effect) has to be at least half of the total genetic variance to be identified. The consequences of omitting a maternal effect when it is present are explored. Our results indicate that the total (genetic and individual) variance are accounted for. When an individual (environmental) maternal effect is omitted from the model, this only influences the estimated (direct) individual (environmental) variance. When a genetic maternal effect is omitted from the model, both (direct) genetic and (direct) individual variance estimates are overestimated. PMID- 27127612 TI - Transcriptome response to temperature stress in the wolf spider Pardosa pseudoannulata (Araneae: Lycosidae). AB - The wolf spider Pardosa pseudoannulata is a dominant predator in paddy ecosystem and an important biological control agent of rice pests. Temperature represents a primary factor influencing its biology and behavior, although the underlying molecular mechanisms remain unknown. To understand the response of P. pseudoannulata to temperature stress, we performed comparative transcriptome analyses of spider adults exposed to 10 degrees C and 40 degrees C for 12 h. We obtained 67,725 assembled unigenes, 21,765 of which were annotated in P. pseudoannulata transcriptome libraries, and identified 905 and 834 genes significantly up- or down-regulated by temperature stress. Functional categorization revealed the differential regulation of transcription, signal transduction, and metabolism processes. Calcium signaling pathway and metabolic pathway involving respiratory chain components played important roles in adapting to low temperature, whereas at high temperature, oxidative phosphorylation and amino acid metabolism were critical. Differentially expressed ribosomal protein genes contributed to temperature stress adaptation, and heat shock genes were significantly up-regulated. This study represents the first report of transcriptome identification related to the Araneae species in response to temperature stress. These results will greatly facilitate our understanding of the physiological and biochemical mechanisms of spiders in response to temperature stress. PMID- 27127614 TI - Signaling mechanism by the Staphylococcus aureus two-component system LytSR: role of acetyl phosphate in bypassing the cell membrane electrical potential sensor LytS. AB - The two-component system LytSR has been linked to the signal transduction of cell membrane electrical potential perturbation and is involved in the adaptation of Staphylococcus aureus to cationic antimicrobial peptides. It consists of a membrane-bound histidine kinase, LytS, which belongs to the family of multiple transmembrane-spanning domains receptors, and a response regulator, LytR, which belongs to the novel family of non-helix-turn-helix DNA-binding domain proteins. LytR regulates the expression of cidABC and lrgAB operons, the gene products of which are involved in programmed cell death and lysis. In vivo studies have demonstrated involvement of two overlapping regulatory networks in regulating the lrgAB operon, both depending on LytR. One regulatory network responds to glucose metabolism and the other responds to changes in the cell membrane potential. Herein, we show that LytS has autokinase activity and can catalyze a fast phosphotransfer reaction, with 50% of its phosphoryl group lost within 1 minute of incubation with LytR. LytS has also phosphatase activity. Notably, LytR undergoes phosphorylation by acetyl phosphate at a rate that is 2-fold faster than the phosphorylation by LytS. This observation is significant in lieu of the in vivo observations that regulation of the lrgAB operon is LytR-dependent in the presence of excess glucose in the medium. The latter condition does not lead to perturbation of the cell membrane potential but rather to the accumulation of acetate in the cell. Our, study provides for the first time the molecular basis for regulation of lrgAB in a LytR-dependent manner under conditions that do not involve sensing by LytS. PMID- 27127613 TI - Directional genetic differentiation and relative migration. AB - Understanding the population structure and patterns of gene flow within species is of fundamental importance to the study of evolution. In the fields of population and evolutionary genetics, measures of genetic differentiation are commonly used to gather this information. One potential caveat is that these measures assume gene flow to be symmetric. However, asymmetric gene flow is common in nature, especially in systems driven by physical processes such as wind or water currents. As information about levels of asymmetric gene flow among populations is essential for the correct interpretation of the distribution of contemporary genetic diversity within species, this should not be overlooked. To obtain information on asymmetric migration patterns from genetic data, complex models based on maximum-likelihood or Bayesian approaches generally need to be employed, often at great computational cost. Here, a new simpler and more efficient approach for understanding gene flow patterns is presented. This approach allows the estimation of directional components of genetic divergence between pairs of populations at low computational effort, using any of the classical or modern measures of genetic differentiation. These directional measures of genetic differentiation can further be used to calculate directional relative migration and to detect asymmetries in gene flow patterns. This can be done in a user-friendly web application called divMigrate-online introduced in this study. Using simulated data sets with known gene flow regimes, we demonstrate that the method is capable of resolving complex migration patterns under a range of study designs. PMID- 27127615 TI - CRE: a cost effective and rapid approach for PCR-mediated concatenation of KRAS and EGFR exons. AB - Molecular diagnostics has changed the way lung cancer patients are treated worldwide. Of several different testing methods available, PCR followed by directed sequencing and amplification refractory mutation system (ARMS) are the two most commonly used diagnostic methods worldwide to detect mutations at KRAS exon 2 and EGFR kinase domain exons 18-21 in lung cancer. Compared to ARMS, the PCR followed by directed sequencing approach is relatively inexpensive but more cumbersome to perform. Moreover, with a limiting amount of genomic DNA from clinical formalin-fixed, paraffin-embedded (FFPE) specimens or fine biopsies of lung tumors, multiple rounds of PCR and sequencing reactions often get challenging. Here, we report a novel and cost-effective single multiplex-PCR based method, CRE (for Co-amplification of five K RAS and E GFR exons), followed by concatenation of the PCR product as a single linear fragment for direct sequencing. CRE is a robust protocol that can be adapted for routine use in clinical diagnostics with reduced variability, cost and turnaround time requiring a minimal amount of template DNA extracted from FFPE or fresh frozen tumor samples. As a proof of principle, CRE is able to detect the activating EGFR L858R and T790M EGFR mutations in lung cancer cell line and primary tumors. PMID- 27127616 TI - Possible identification of CENP-C in fish and the presence of the CENP-C motif in M18BP1 of vertebrates. AB - The centromeric protein CENP-C is a base component of the kinetochore. This protein, along with CENP-A has been shown to adaptively evolve in a number of animal and plant species. In order to determine if CENP-C also evolves in fish species, I attempted to retrieve fish CENP-C sequences from GenBank. No Teleostei CENP-C sequences were found either by name or by BLASTP searches with the vertebrate CENP-C motif sequence. A number of putative Teleostei protein sequences were identified in GenBank that have homology to the C-terminal cupin domain of vertebrate CENP-C. These proteins only have partial homology to the CENP-C motif, but evidence is presented that makes it likely that these fish proteins are orthologs of CENP-C. Interestingly, it was also discovered that the CENP-C motif sequence is also mostly present in M18BP1 proteins of fish and some other vertebrates but not in mammals. This finding may have implications for CENP C and M18BP1 assembly in centromeric regions of different vertebrate taxa. PMID- 27127617 TI - Associations between chlorophyll a and various microcystin-LR health advisory concentrations. AB - Cyanobacteria harmful algal blooms (cHABs) are associated with a wide range of adverse health effects that stem mostly from the presence of cyanotoxins. To help protect against these impacts, several health advisory levels have been set for some toxins. In particular, one of the more common toxins, microcystin-LR, has several advisory levels set for drinking water and recreational use. However, compared to other water quality measures, field measurements of microcystin-LR are not commonly available due to cost and advanced understanding required to interpret results. Addressing these issues will take time and resources. Thus, there is utility in finding indicators of microcystin-LR that are already widely available, can be estimated quickly and in situ, and used as a first defense against high concentrations of microcystin-LR. Chlorophyll a is commonly measured, can be estimated in situ, and has been shown to be positively associated with microcystin-LR. In this paper, we use this association to provide estimates of chlorophyll a concentrations that are indicative of a higher probability of exceeding select health advisory concentrations for microcystin LR. Using the 2007 National Lakes Assessment and a conditional probability approach, we identify chlorophyll a concentrations that are more likely than not to be associated with an exceedance of a microcystin-LR health advisory level. We look at the recent US EPA health advisories for drinking water as well as the World Health Organization levels for drinking water and recreational use and identify a range of chlorophyll a thresholds. A 50% chance of exceeding one of the microcystin-LR advisory concentrations of 0.3, 1, 1.6, and 2 g/L is associated with chlorophyll a concentration thresholds of 23.4, 67.0, 83.5, and 105.8, respectively. When managing for these various microcystin-LR levels, exceeding these reported chlorophyll a concentrations should be a trigger for further testing and possible management action. PMID- 27127618 TI - A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma. AB - Intratumor heterogeneity (ITH) is an inherent process in cancer development which follows for most of the cases a branched pattern of evolution, with different cell clones evolving independently in space and time across different areas of the same tumor. The determination of ITH (in both spatial and temporal domains) is nowadays critical to enhance patient treatment and prognosis. Clear cell renal cell carcinoma (CCRCC) provides a good example of ITH. Sometimes the tumor is too big to be totally analyzed for ITH detection and pathologists decide which parts must be sampled for the analysis. For such a purpose, pathologists follow internationally accepted protocols. In light of the latest findings, however, current sampling protocols seem to be insufficient for detecting ITH with significant reliability. The arrival of new targeted therapies, some of them providing promising alternatives to improve patient survival, pushes the pathologist to obtain a truly representative sampling of tumor diversity in routine practice. How large this sampling must be and how this must be performed are unanswered questions so far. Here we present a very simple method for tumor sampling that enhances ITH detection without increasing costs. This method follows a divide-and-conquer (DAC) strategy, that is, rather than sampling a small number of large-size tumor-pieces as the routine protocol (RP) advises, we suggest sampling many small-size pieces along the tumor. We performed a computational modeling approach to show that the usefulness of the DAC strategy is twofold: first, we show that DAC outperforms RP with similar laboratory costs, and second, DAC is capable of performing similar to total tumor sampling (TTS) but, very remarkably, at a much lower cost. We thus provide new light to push forward a shift in the paradigm about how pathologists should sample tumors for achieving efficient ITH detection. PMID- 27127619 TI - Innovations and best practice in undergraduate education. AB - University-based scientists hold the collective responsibility for educating the next generation of citizens, scientists and voters, but the degree to which they are individually trained and rewarded for this pursuit is variable. This F1000Research channel has its origin in a Society for Experimental Biology Conference held in Prague, 2015 and brings together researchers who excel at undergraduate education or the scholarship of teaching and learning to discuss challenges and best practices in contemporary higher science education. PMID- 27127620 TI - Activity-relevant similarity values for fingerprints and implications for similarity searching. AB - A largely unsolved problem in chemoinformatics is the issue of how calculated compound similarity relates to activity similarity, which is central to many applications. In general, activity relationships are predicted from calculated similarity values. However, there is no solid scientific foundation to bridge between calculated molecular and observed activity similarity. Accordingly, the success rate of identifying new active compounds by similarity searching is limited. Although various attempts have been made to establish relationships between calculated fingerprint similarity values and biological activities, none of these has yielded generally applicable rules for similarity searching. In this study, we have addressed the question of molecular versus activity similarity in a more fundamental way. First, we have evaluated if activity-relevant similarity value ranges could in principle be identified for standard fingerprints and distinguished from similarity resulting from random compound comparisons. Then, we have analyzed if activity-relevant similarity values could be used to guide typical similarity search calculations aiming to identify active compounds in databases. It was found that activity-relevant similarity values can be identified as a characteristic feature of fingerprints. However, it was also shown that such values cannot be reliably used as thresholds for practical similarity search calculations. In addition, the analysis presented herein helped to rationalize differences in fingerprint search performance. PMID- 27127621 TI - Advances in understanding - genetic basis of intellectual disability. AB - Intellectual disability is the most common developmental disorder characterized by a congenital limitation in intellectual functioning and adaptive behavior. It often co-occurs with other mental conditions like attention deficit/hyperactivity disorder and autism spectrum disorder, and can be part of a malformation syndrome that affects other organs. Considering the heterogeneity of its causes (environmental and genetic), its frequency worldwide varies greatly. This review focuses on known genes underlying (syndromic and non-syndromic) intellectual disability, it provides a succinct analysis of their Gene Ontology, and it suggests the use of transcriptional profiling for the prioritization of candidate genes. PMID- 27127622 TI - Advances in multimodality molecular imaging of bone structure and function. AB - The skeleton is important to the body as a source of minerals and blood cells and provides a structural framework for strength, mobility and the protection of organs. Bone diseases and disorders can have deteriorating effects on the skeleton, but the biological processes underlying anatomical changes in bone diseases occurring in vivo are not well understood, mostly due to the lack of appropriate analysis techniques. Therefore, there is ongoing research in the development of novel in vivo imaging techniques and molecular markers that might help to gain more knowledge of these pathological pathways in animal models and patients. This perspective provides an overview of the latest developments in molecular imaging applied to bone. It emphasizes that multimodality imaging, the combination of multiple imaging techniques encompassing different image modalities, enhances the interpretability of data, and is imperative for the understanding of the biological processes and the associated changes in bone structure and function relationships in vivo. PMID- 27127624 TI - The pre-metastatic niche: is metastasis random? AB - The metastasis of solid tumours is a vastly complex, dynamic and systemic process involving both primary tumour cells as well as a wide array of stromal and vascular cells. The recruitment and activation of host cells by tumours at both the primary and metastatic sites is crucial for successful metastatic dissemination highlighting the systemic nature of disease progression. The appropriation of distant metastatic sites by primary tumours and the generation of so-called pre-metastatic niches have gained much interest in the last decade complementing the century old 'seed and soil' hypothesis. The idea that tumours are capable of pre-defining future sites of metastasis is both exciting and terrifying as we try to understand the dynamic networks associated with solid tumour metastasis. Exactly how a tumour cell can alter the distant metastatic microenvironment is of great importance and will unlock novel strategies for successfully targeting these processes. PMID- 27127623 TI - Genetic aspects of skeletal muscle strength and mass with relevance to sarcopenia. AB - Skeletal muscle is a highly heritable quantitative trait, with heritability estimates ranging 30-85% for muscle strength and 50-80% for lean mass. That strong genetic contribution indicates the possibility of using genetic information to individualize treatments for sarcopenia or even aid in prevention strategies through the use of genetic screening prior to the functional limitations. Though these possibilities provide the rationale for genetic studies of skeletal muscle traits, few genes have been identified that appear to contribute to variation in either skeletal muscle strength or mass phenotypes, and sarcopenia per se is remarkably understudied as a trait in this regard. This review examines the heritability of skeletal muscle traits, findings of linkage and genome-wide association analyses and impact of specific genes and gene sequence variants on these traits as relevant to sarcopenia. Despite considerable work in the area, the genetic underpinnings of skeletal muscle traits remain largely unknown and the genetic aspects of sarcopenia are even less clear. Large scale longitudinal clinical studies relying on advanced genome-wide association and other techniques are needed to provide further insights into the genes and gene variants that contribute to skeletal muscle strength and mass, and ultimately to susceptibility to sarcopenia. PMID- 27127625 TI - Sclerosing bone disorders: a lot of knowns but still some unknowns. AB - In the last decade, many advances have been made in understanding how osteoclasts and osteoblasts work and communicate by elucidation of the molecular genetic causes of many rare bone dysplasias. The relationship between the clinical findings and the molecular defects underlying these aberrant bone phenotypes has given new insights into the molecular machinery of the different bone cell types, and into how they act and interact to regulate bone mass. The study of sclerosing bone dysplasias caused by a disturbance of the balance between bone formation and bone resorption has had an especially high impact. Furthermore, it has also become clear that genetic variation within several of the identified genes contributes to the risk to develop osteoporosis and that in some cases the metabolic pathways involved provide interesting targets for the development of novel treatments for osteoporosis. In this review, some of the sclerosing bone diseases are discussed, focusing on the underlying mechanisms and the broader implications of the insights gained. PMID- 27127626 TI - Sustainable employability for older workers: an explorative survey of belgian companies. AB - BACKGROUND: The European Agency for Safety and Health at Work (EU-OSHA) is developing an online e-guide, which will provide tips and practical information for each EU country (in their national language(s)) on ageing and occupational health and safety. The e-guide will be launched in 2016 as part of the EU-OSHA campaign on Healthy Workplaces for all ages. The e-guide will present evidence, tools and practical examples of how companies can take action and effectively promote sustainable employability. METHODS: As part of the development of the e guide, a cross-sectional study was conducted to survey Belgian employers in April 2015 to determine their specific needs concerning older workers' occupational health and safety issues. Researchers from Milieu Ltd. (Brussels, Belgium), the consultancy company coordinating the e-guide project, and Mensura Occupational Health Services (Brussels, Belgium) developed a 13-item questionnaire. The survey addressed the needs and importance given to sustainable employability of older workers in Belgian companies and evaluated corporate knowledge regarding relevant national policies. The questionnaire was distributed electronically to the management of 22,084 private-sector companies affiliated with Mensura. RESULTS: Ten percent (n = 2133) of recipients opened the e-mail, and 37 % (n = 790) of these completed the questionnaire. In 89 % of the responding companies, sustainable employability of workers aged >=55 years plays an important role; 70 % have no active sustainable employability policy/initiative; 18 % experience difficulties promoting sustainable employability; and 86 % indicate no need for support to promote sustainable employability. Respondents noted the following health complaints among workers aged >=55 years: work-related health problems (31 %), stress (26 %), work agreements/type of work (17 %), work/life balance (15 %), and career development and/or training (9 %). Topics concerning health and well being of workers aged >=55 years requiring the most attention include motivation (30 %) and adaptation of the workplace to their health requirements (26 %). CONCLUSIONS: The e-guide should raise further awareness among employers about the importance of implementing an active sustainable employability policy to prolong working life in a healthy and productive way. The e-guide should also include tools to address work-related health problems and stress, motivation, and adaptation of the workplace to the health requirements of workers aged >=55 years. PMID- 27127627 TI - Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations. AB - OBJECTIVES: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia. METHODS: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared. RESULTS: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant. CONCLUSIONS: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia. PMID- 27127628 TI - Validity of Center for Epidemiologic Studies Depression (CES-D) scale in a sample of Iraq and Afghanistan Veterans. AB - OBJECTIVES: Optimal depression screening necessitates measurement tools that are valid across varied populations and in the presence of comorbidities. METHODS: This study assessed the test properties of two versions of the Center for Epidemiologic Studies Depression scale against psychiatric diagnoses established by the Mini International Neuropsychiatric Interview among a clinical sample of US Veterans deployed during Operations Enduring Freedom, Iraqi Freedom, and New Dawn. Participants (N = 359) recruited from two Department of Veterans Affairs hospitals completed a clinical interview, structured diagnostic interview, and self-reported measures. RESULTS: Based on diagnostic interview and the Diagnostic and Statistical Manual of Mental Disorders 4th Edition criteria, 29.5% of the sample met diagnostic criteria for major depressive disorder and 26.5% met diagnostic criteria for post-traumatic stress disorder. Both Center for Epidemiologic Studies Depression-20 and Center for Epidemiologic Studies Depression-10 scales performed well and almost identically against the Mini International Neuropsychiatric Interview-major depressive disorder in identifying Veterans with major depressive disorder (Center for Epidemiologic Studies Depression-20 area under the Receiver Operating Characteristic curve 91%; Center for Epidemiologic Studies Depression-10 area under the ROC curve 90%). Overall, higher cut points for the Center for Epidemiologic Studies Depression scales performed better in correctly identifying true positives and true negatives for major depressive disorder (Center for Epidemiologic Studies Depression-20 cut point 18+ sensitivity 92% specificity 72%; Center for Epidemiologic Studies Depression-10 cut point 10+ sensitivity 92% specificity 69%). CONCLUSIONS: The specificity of the Center for Epidemiologic Studies Depression scales was poor among Veterans with co-occurring post-traumatic stress disorder (13% and 16%). Veterans with post-traumatic stress disorder who have a positive depression screen should have a more thorough assessment of mental health symptoms and comorbidities, rather than immediate diagnosis of and treatment for depression. PMID- 27127629 TI - The effects of distress and the dimensions of coping strategies on physicians' satisfaction with competence. AB - OBJECTIVES: The purposes of this study were to (1) articulate the dimensions of Coping strategies used by physicians, and (2) determine whether Coping strategies alleviated Distress and enhanced Satisfaction with Competence. METHODS: Comprehensive questionnaires on factors associated with Satisfaction with Competence were sent to a stratified sample of 5300 physicians across Canada. The response rate was 57% with negligible bias. Factor analysis was used to articulate the dimensions of Coping strategies. The classic Baron and Kenny regression series was used to establish whether Coping mediates the effects of Distress on Satisfaction with Competence. Years in Practice, Self-Reported Health, and Duties of Physicians were control factors. RESULTS: A reliable 15 item measure of Coping was confirmed (alpha = .76) with four reasonably reliable dimensions: Collegiality (alpha = .80), Attitude (alpha = .63), Managing Work (alpha = .60), and Self-Care (alpha = .62). Physicians reported a mean Satisfaction with Competence of (M = 4.26 out of 6.0, standard deviation (SD) = 0.64) with General practitioners reporting slightly lower levels of Satisfaction with Competence than average. Conversely, chronic disease, clinical, and procedural specialists reported higher levels of Satisfaction with Competence. The mean Distress level for all physicians was (M = 3.66 out of 7.0, SD = 0.93). The highest levels of distress were reported by emergency physicians, general practitioners, and surgeons. Clinical specialists, anesthesiologists, and psychiatrists reported the lowest levels of distress. Physicians reported (M = 4.48 out of 7.0, SD = 0.78) as the mean level of Coping ability with clinical specialists and general practitioners reporting lower than average abilities to cope. Laboratory and chronic care specialists reported greater than average coping abilities. Regression analyses established Coping as a mediator of Distress which predicted physicians' Satisfaction with Competence. CONCLUSION: Four groups of coping strategies were significant in relieving the pressures of work: (1) Collegiality, (2) Self-Care, (3) Managing Work, and (4) Positive Attitude. PMID- 27127630 TI - Enhanced User-Control of Small Molecule Drug Release from a Poly(ethylene glycol) Hydrogel via Azobenzene/Cyclodextrin Complex Tethers. AB - We present a versatile and facile method to enhance user-control of small molecule drug release from a poly(ethylene glycol)-based hydrogel using the host/guest complex formed between an azobenzene derivative guest and a beta cyclodextrin host. A model drug is formed from a short peptide containing a fluorophore and an azobenzene functional group on one terminus. Upon irradiation with UV light, azobenzene isomerization leads to decreased complex formation and an on-demand acceleratation of the release rate of an entrapped model drug. PMID- 27127631 TI - Ratiometric mechanosensitive fluorescent dyes: Design and applications. AB - Fluorescent molecules, with their almost instantaneous response to external influences and relatively low-cost measurement instrumentation, have been attractive analytical tools and biosensors for centuries. More recently, advanced chemical synthesis and targeted design have accelerated the development of fluorescent probes. This article focuses on dyes with segmental mobility (known as fluorescent molecular rotors) that act as mechanosensors, which are known for their relationship of emission quantum yield with microviscosity. Fluorescence lifetime is directly related to quantum yield, but steady-state emission intensity is not. To remove confounding factors with steady-state instrumentation, dual-band emission dyes can be used, and molecular rotors have been developed that either have intrinsic dual emission or that have a non sensitive reference unit to provide a calibration emission band. We report on theory, chemical structure, applications and targeted design of several classes of dual-emission molecular rotors. PMID- 27127632 TI - Change of serum prealbumin levels and serum protein markers between egg white powder and casein protein additives in standard enteral feeding formulas in critically ill patients with acute respiratory failure. AB - BACKGROUND: Protein deficiency is a major problem in critically ill patients. Egg white powder recently became a standard additive for protein supplementation in our unit. However, clinical data are not available to support egg white powder supplementation compared to standard protein casein supplementation. This study aimed to determine the change of serum prealbumin (PAB) levels of egg white powder compared to casein additive in standard enteral feeding in critically ill patients with respiratory failure. METHODS: A prospective double-blind, randomized, non-inferiority study was conducted in patients with acute respiratory failure in the medical intensive care unit and respiratory care unit. These patients randomly received 1500 kcal/day of enteral nutrition support with 40 g/day of protein additives by either egg white protein powder or casein protein for 7 days. The serum PAB and C-reactive protein (CRP) levels were measured on days 1, 3, 5, and 7. Repeated-measures ANOVA determined the group effects displayed by serum PAB and CRP levels. p values <0.05 were considered statistically significant. RESULTS: Thirty-four patients were in two groups: 17 in the casein protein group and 17 in the egg white powder group. The clinical characteristics, baseline nutritional status, and biochemistries were not significantly different between the groups. No statistically significant differences were seen in the serum PAB and serum CRP levels between the two groups. The average mean +/- SEM difference of serum PAB level between the groups was 2.3 +/- 2.5 mg% (p = 0.58). CONCLUSIONS: The levels of PAB between the egg white protein additive and casein protein additive were not significantly different and less than the non-inferior margin. TRIAL REGISTRATION: Thai Clinical Trials Registry TCTR20160126002. PMID- 27127633 TI - Kinetics of Langerhans cell chimerism in the skin of dogs following 2 Gy TBI allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Langerhans cells (LC) are bone marrow-derived cells in the skin. The LC donor/recipient chimerism is assumed to influence the incidence and severity of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). In nonmyeloablative (NM) HSCT the appearance of acute GVHD is delayed when compared with myeloablative conditioning. Therefore, we examined the development of LC chimerism in a NM canine HSCT model. METHODS: 2 Gy conditioned dogs received bone marrow from dog leukocyte antigen identical littermates. Skin biopsies were obtained pre- and post-transplant. LC isolation was performed by immunomagnetic separation and chimerism analysis by PCR analyzing variable-number of-tandem-repeat markers with subsequent capillary electrophoresis. RESULTS: All dogs engrafted. Compared to peripheral blood chimerism the development of LC chimerism was delayed (earliest at day +56). None of the dogs achieved complete donor LC chimerism, although two dogs manifested a 100 % donor chimerism in peripheral blood at days +91 and +77. Of interest, one dog remained LC chimeric despite loss of donor chimerism in the peripheral blood cells. CONCLUSION: Our study indicates that LC donor chimerism correlates with chimerism development in the peripheral blood but occurs delayed following NM-HSCT. PMID- 27127634 TI - Systematic review and meta-analysis of optimal P2Y12 blockade in dual antiplatelet therapy for patients with diabetes with acute coronary syndrome. AB - BACKGROUND: Patients with diabetes are at increased risk of acute coronary syndromes (ACS) and their mortality and morbidity outcomes are significantly worse following ACS events, independent of other comorbidities. This systematic review sought to establish the optimum management strategy with focus on P2Y12 blockade in patients with diabetes with ACS. METHODS: MEDLINE (1946 to present) and EMBASE (1974 to present) databases, abstracts from major cardiology conferences and previously published systematic reviews were searched to June 2014. Relevant randomised control trials with clinical outcomes for P2Y12 inhibitors in adult patients with diabetes with ACS were scrutinised independently by 2 authors with applicable data was extracted for primary composite end point of cardiovascular death, myocardial infarction (MI) and stroke; enabling calculation of relative risks with 95% CI with subsequent direct and indirect comparison. RESULTS: Four studies studied clopidogrel in patients with diabetes, with two (3122 patients) having primary outcome data showing superiority of clopidogrel against placebo with RR0.84 (95% CI 0.72-0.99). Irrespective of management strategy, the newer agents prasugrel (2 studies) and ticagrelor (1 study) had a lower primary event rate compared with clopidogrel; RR 0.80 (95% CI 0.66 to 0.97) and RR 0.89 (95% CI 0.77 to 1.02), respectively. When ticagrelor was indirectly compared with prasugrel, there was a trend to an improved primary outcome with prasugrel (RR 1.11 (95% CI 0.94 to 1.31)) particularly in those managed with percutaneous coronary intervention (PCI) (RR 1.23 (95% CI 0.95 to 1.59)). Prasugrel demonstrated a statistical superiority with prevention of further MI with RR 1.48 (95% CI 1.11 to 1.97). This was not at the expense of increased major thrombolysis in MI (TIMI) bleeding rates RR 0.94 (95% CI 0.59 to 1.51). CONCLUSIONS: This meta-analysis shows the addition of a P2Y12 inhibitor is superior to placebo, with a trend favouring the use of prasugrel in patients with diabetes with ACS, particularly those undergoing PCI. PMID- 27127635 TI - Prehospital and in-hospital use of healthcare resources in patients surviving acute coronary syndromes: an analysis of the EPICOR registry. AB - OBJECTIVE: The aim of this report is to provide insight into real-world healthcare resource use (HCRU) during the critical management of patients surviving acute coronary syndromes (ACS), using data from EPICOR (long-tErm follow-up of antithrombotic management Patterns In acute CORonary syndrome patients) (NCT01171404). METHODS: EPICOR was a prospective, multinational, observational study that enrolled 10 568 ACS survivors from 555 hospitals in 20 countries in Europe and Latin America, between September 2010 and March 2011. HCRU was evaluated in patients with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation ACS (NSTE-ACS), with or without a history of cardiovascular disease (CVD). Multivariable analysis was performed to determine factors that affected resource use. RESULTS: Before hospitalisation, more patients with STEMI than with NSTE-ACS had their first ECG (44.1% vs 36.4%, p<0.0001) and received antithrombotic medication (26.6% vs 15.2%, p<0.0001). Patients with NSTE-ACS with prior CVD were less likely than those without to be catheterised (73.1% vs 82.8%, p<0.0001). More patients with STEMI than with NSTE ACS had percutaneous coronary intervention (77.1% vs 54.9%, p<0.0001), but fewer underwent coronary artery bypass grafting (1.2% vs 3.7%, p<0.0001). Multivariable analysis showed that resource use, including length of hospital stay and coronary revascularisation, was significantly influenced by multiple factors, including ACS type, site characteristics and region (all p<=0.05). CONCLUSIONS: In this large-scale, real-life study, findings were generally in line with clinical logic, although site characteristics and region still significantly affected resource use. Moreover, and unexpectedly, resource use tended to be slightly higher in patients without a history of CVD. TRIAL REGISTRATION NUMBER: NCT01171404 (ClinicalTrials.gov). PMID- 27127636 TI - Dynamic cycling in atrial size and flow during obstructive apnoea. AB - OBJECTIVE: Obstructive sleep apnoea (OSA) is strongly associated with cardiovascular disease. However, acute cardiovascular effects of repetitive airway obstruction are poorly understood. While past research used a sustained Mueller manoeuver to simulate OSA we employed a series of gasping efforts to better simulate true obstructive apnoeas. This report describes acute changes in cardiac anatomy and flow related to sudden changes in intrathoracic pressure. METHODS AND RESULTS: 26 healthy, normal weight participants performed 5-6 gasping efforts (target intrathoracic pressure -40 mm Hg) while undergoing Doppler echocardiography. 14 participants had sufficient echocardiographic images to allow comparison of atrial areas during the manoeuver with baseline measurements. Mitral and tricuspid E-wave and A-wave velocities postmanoeuver were compared with baseline in all participants. Average atrial areas changed little during the manoeuver, but variance in both atrial areas was significantly greater than baseline. Further, an inverse relationship was noted with left atrial collapse and right atrial enlargement at onset of inspiratory effort. Significant inverse changes were noted in Doppler flow when comparing the first beat postmanoeuver (pMM1) with baseline. Mitral E-wave velocity increased 9.1 cm/s while tricuspid E wave velocity decreased 7.0 cm/s; by the eighth beat postmanoeuver (pMM8) values were not different from baseline. Mitral and tricuspid A-wave velocities were not different from baseline at pMM1, but both were significantly higher by pMM8. CONCLUSIONS: Repetitive obstructive apnoeas produce dynamic, inverse changes in atrial size and Doppler flow across the atrioventricular valves. These observations have important implications for understanding the pathophysiology of OSA. PMID- 27127637 TI - Risk factors and therapeutic coverage at 6 years in patients with previous myocardial infarction: the CASTUO study. AB - OBJECTIVES: To determine the degree of risk factor control, the clinical symptoms and the therapeutic management of patients with a history of previous myocardial infarction. METHODS: Cross-sectional study at 6 years of a first episode of acute myocardial infarction between 2000 and 2009, admitted at a hospital in the region of Extremadura (Spain). Of 2177 patients with this diagnosis, 1365 remained alive and therefore were included in the study. RESULTS: We conducted a person-to person survey in 666 (48.8%) individuals and telephone survey in 437 (31.9%) individuals. The former are analysed. 130 were female (19.5%). The mean age was 67.4 years and the median time since the event was 5.8 (IQR 3.6-8.2) years. Active smokers made up 13.8%, low-density lipoprotein (LDL) cholesterol was >=70 mg/dL: 82%, blood pressure >=140/90 mm Hg (>=140/85 in diabetics): 49.8%, fasting glucose >=126 mg/dL: 26%, heart rate 50-59 bpm: 60.7%, and obesity: 45.9%. Patients reported presenting angina comprised 22.4% and those with dyspnoea, 29.3%. Drug coverage was: 88.0% antiplatelet drugs, 86.5% statins, 75.6% beta blockers and 65.8% blockers of the renin-angiotensin system. Patients receiving all four types of drugs made up 41.9%, with only 3.0% having jointly controlled cholesterol, blood pressure, heart rate and glycaemia. CONCLUSIONS: LDL cholesterol, heart rate and blood pressure were risk factors with less control. More than 1/5 of patients had angina and more than 1/4, dyspnoea. Risk factor control and the clinical condition were far from optimal, as was drug coverage, although to a lesser degree. PMID- 27127638 TI - Subclinical cardiopulmonary dysfunction in stage 3 chronic kidney disease. AB - OBJECTIVE: Reduced exercise capacity is well documented in end-stage chronic kidney disease (CKD), preceded by changes in cardiac morphology in CKD stage 3. However, it is unknown whether subclinical cardiopulmonary dysfunction occurs in CKD stage 3 independently of heart failure. METHODS: Prospective observational cross-sectional study of exercise capacity assessed by cardiopulmonary exercise testing in 993 preoperative patients. Primary outcome was peak oxygen consumption (VO2peak). Anaerobic threshold (AT), oxygen pulse and exercise-evoked measures of autonomic function were analysed, controlling for CKD stage 3, age, gender, diabetes mellitus and hypertension. RESULTS: CKD stage 3 was present in 93/993 (9.97%) patients. Diabetes mellitus (RR 2.49 (95% CI 1.59 to 3.89); p<0.001), and hypertension (RR 3.20 (95% CI 2.04 to 5.03); p<0.001)) were more common in CKD stage 3. Cardiac failure (RR 0.83 (95% CI 0.30 to 2.24); p=0.70) and ischaemic heart disease (RR 1.40 (95% CI 0.97 to 2.02); p=0.09) were not more common in CKD stage 3. Patients with CKD stage 3 had lower predicted VO2peak (mean difference: 6% (95% CI 1% to 11%); p=0.02), lower peak heart rate (mean difference:9 bpm (95% CI 3 to 14); p=0.03)), lower AT (mean difference: 1.1 mL/min/kg (95% CI 0.4 to 1.7); p<0.001) and impaired heart rate recovery (mean difference: 4 bpm (95% CI 1 to 7); p<0.001)). CONCLUSIONS: Subclinical cardiopulmonary dysfunction in CKD stage 3 is common. This study suggests that maladaptive cardiovascular/autonomic dysfunction may be established in CKD stage 3, preceding pathophysiology reported in end-stage CKD. PMID- 27127639 TI - Exercise training characteristics in cardiac rehabilitation programmes: a cross sectional survey of Australian practice. AB - INTRODUCTION: Exercise training is a core component of cardiac rehabilitation (CR), however, little information exists regarding the specific exercise interventions currently provided for coronary heart disease in Australian practice. We aimed to analyse the current status of exercise-based CR services across Australia. DESIGN: Cross-sectional survey. METHODS: Australian sites offering exercise-based CR were identified from publically available directories. All sites were invited by email to participate in an online Survey Monkey questionnaire between October 2014 and March 2015, with reminders via email and phone follow-up. Questions investigated the demographics and format of individual programmes, as well as specific exercise training characteristics. RESULTS: 297 eligible programmes were identified, with an 82% response rate. Most sites (82%) were based at hospital or outpatient centres, with home (15%), community (18%) or gym-based options (5%) less common. While CR was most often offered in a comprehensive format (72% of sites), the level of exercise intervention varied greatly among programmes. Most frequently, exercise was prescribed 1-2 times per week for 60 min over 7 weeks. Almost one-quarter (24%) had a sole practitioner supervising exercise, although the majority used a nurse/physiotherapist combination. Low to moderate exercise intensities were used in 60% of programmes, however, higher intensity prescriptions were not uncommon. Few sites (<6%) made use of technology, such as mobile phones or the internet, to deliver or support exercise training. CONCLUSIONS: While advances have been made towards providing flexible and accessible exercise-based CR, much of Australia's service remains within traditional models of care. A continuing focus on service improvement and evidence-based care should, therefore, be considered a core aim of those providing exercise for CR in order to improve health service delivery and optimise outcomes for patients. PMID- 27127640 TI - Wolf in sheep's clothing: a case of carcinoma erysipeloides. AB - Cutaneous metastases of the breast carcinomas can present clinically as nodules, plaques and tumors (most commonly as nodules) as well as 'erysipelas-like' lesions are known as 'carcinoma erysipeloides'. We want to share our experience in diagnosing a middle-aged lady with carcinoma erysipeloides secondary to breast carcinoma and her management as this is commonly misdiagnosed as cellulitis or scleroderma in general practice. Unfortunately, the patient had presented to us at a late stage with wide-spread metastasis, and as such, chemotherapy was the only available option. She expired after her third cycle of chemotherapy. PMID- 27127641 TI - Atypical presentation of atypical mycobacteria in atypical diabetes. AB - A 45-year-old, non-obese male presented with low-grade, remittent fever and a fluctuant swelling over the posterior aspect of his lower left flank. Laboratory tests revealed leukocytosis, raised ESR, hyperglycemia and raised HbA1C levels. Light microscopy of Ziehl-Neelsen-stained pus sample revealed numerous acid-fast bacilli. After 72 h of incubating aspirated pus in Lowenstein-Jensen media, non pigmented, cream-colored colonies were observed, suggestive of rapid-growing atypical forms of mycobacteria. Polymerase chain reaction of isolated bacteria identified Mycobacterium chelonae as causative organism. Abdominal skiagram revealed extensive pancreatic intraductal calcifications suggestive of fibrocalculous pancreatic diabetes and lumbar vertebral body destruction with evidence of paravertebral abscess. The patient was prescribed a split-mixed insulin regimen, clarithromycin and ciprofloxacin with complete resolution of the subcutaneous abscess at 6 months. Diabetic patients are prone to infections. Mycobacteria, especially atypical ones, involving the spine and subcutaneous tissues have rarely been reported. PMID- 27127643 TI - Prevalence of Intestinal Parasitic Infection among Food Handlers in Northwest Iran. AB - Parasitic diseases are among the most important infectious diseases and pose health problems in many countries, most especially in developing countries. Workers at food centers could transmit parasitic infections in the absence of sanitation. This is a descriptive study conducted to determine the prevalence of intestinal parasitic infections in food clerks in the city of Tabriz in 2014. Data was recorded in the offices of the health center for all food handlers who were referred to the laboratory for demographic and stool tests to receive the health card. Parasitic infection was observed in 172 cases (3.73%) of 4612 samples. A total of 156 positive samples (90.69%) were related to protozoa and 16 (9.3%) were related to helminthes. Most of the parasitic infections were related to Giardia and Entamoeba coli and the lowest infection was related to H. nana. Also, there was a significant relationship between level of education and parasitic infection rate (P = 0.0044). But there was no significant difference between the type of infection and amount of intestinal parasites. The results show that the prevalence of intestinal parasites, especially pathogenic protozoa, is common in some food handlers. Therefore, more sanitary controls are required and increasing of education will play a crucial role in improving the health of these people. PMID- 27127642 TI - Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host. AB - Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts1. Host adaptation can potentially progress to host restriction where the pathogen is strictly limited to a single host species and is frequently associated with more severe symptoms. Host-adapted and host restricted bacterial clades evolve from within a broader host-promiscuous species and sometimes target different niches within their specialist hosts, such as adapting from a mucosal to a systemic lifestyle. Genome degradation, marked by gene inactivation and deletion, is a key feature of host adaptation, although the triggers initiating genome degradation are not well understood. Here, we show that a chronic systemic non-typhoidal Salmonella infection in an immunocompromised human patient resulted in genome degradation targeting genes that are expendable for a systemic lifestyle. We present a genome-based investigation of a recurrent blood-borne Salmonella enterica serotype Enteritidis (S. Enteritidis) infection covering 15 years in an interleukin (IL)-12 beta-1 receptor-deficient individual that developed into an asymptomatic chronic infection. The infecting S. Enteritidis harbored a mutation in the mismatch repair gene mutS that accelerated the genomic mutation rate. Phylogenetic analysis and phenotyping of multiple patient isolates provides evidence for a remarkable level of within-host evolution that parallels genome changes present in successful host-restricted bacterial pathogens but never before observed on this timescale. Our analysis identifies common pathways of host adaptation and demonstrates the role that immunocompromised individuals can play in this process. PMID- 27127644 TI - Comparison of Transcanalicular Multidiode Laser Dacryocystorhinostomy with and without Silicon Tube Intubation. AB - Aim. To compare the surgical outcomes of surgery with and without bicanalicular silicon tube intubation for the treatment of patients who have primary uncomplicated nasolacrimal duct obstruction. Methods. This retrospective study is comprised of 113 patients with uncomplicated primary nasolacrimal duct obstruction. There were 2 groups in the study: Group 1 (n = 58) patients underwent transcanalicular diode laser dacryocystorhinostomy surgery with bicanalicular silicon tube intubation and Group 2 (n = 55) patients underwent transcanalicular diode laser dacryocystorhinostomy surgery without bicanalicular silicon tube intubation. The follow-up period was 18.42 +/- 2.8 months for Group 1 and 18.8 +/- 2.1 months for Group 2. Results. Success was defined by irrigation of the lacrimal system without regurgitation and by the absence of epiphora. Success rates were 84.4% for Group 1 and 63.6% for Group 2 (P = 0.011). Statistically a significant difference was found between the two groups. Conclusion. The results of the study showed that transcanalicular diode laser dacryocystorhinostomy surgery with bicanalicular silicon tube intubation was more successful than the other method of surgery. Consequently, the application of silicone tube intubation in transcanalicular diode laser dacryocystorhinostomy surgery is recommended. PMID- 27127645 TI - In Vivo Imaging of Intraocular Fluidics in Vitrectomized Swine Eyes Using a Digital Fluoroscopy System. AB - Purpose. To describe the characteristics of intraocular fluidics during cataract surgery in swine eyes with prior vitrectomy. Methods. We prepared three groups of enucleated swine eyes (nonvitrectomized, core, and totally vitrectomized). Irrigation and aspiration were performed (2.7 mm conventional sleeved phacosystem) using a balanced saline solution mixed with a water-soluble radiopaque contrast medium at 1 : 1 ratio. We imaged the eyes using a digital fluoroscopy system (DFS) during phacoemulsification and compared the characteristics of the intraocular fluid dynamics between the groups. Results. The anterior chamber depth (ACD) after the commencement of irrigation differed between groups (2.25 +/- 0.06 mm; 2.33 +/- 0.06 mm; 3.17 +/- 0.11 mm), as well as the height of the fluid flowing from the anterior chamber into the posterior cavity that was identified by lifting up the iris to correct the infusion deviation syndrome (0.00 +/- 0.00 mm; 0.41 +/- 0.04 mm; 2.19 +/- 0.35 mm). Conclusions. DFS demonstrated differences in fluid dynamics during phacoemulsification in swine eyes with or without prior vitrectomy. In completely vitrectomized eyes, the large ACD, which developed during phacoemulsification, could be reduced by lifting the iris and allowing the fluid to shift to the posterior cavity. Recognizing the differences in fluidics of vitrectomized eyes as compared to those of the nonvitrectomized eyes may reduce the frequency of intraoperative complications. PMID- 27127647 TI - Magnitude of Anemia and Hematological Predictors among Children under 12 Years in Odisha, India. AB - Background. Anemia is a wide spread public health problem in India which affects children. The present study evaluates the prevalence of anemia and status of various hematological parameters among children of Khurda district, Odisha. Method. A total of 313 children aged 0-12 years were enrolled for the study which included preschool (0-5 years) and school aged (6-12 years) groups. Hematological indicators were measured by standard procedures, which include red blood cell (RBC) indicators, white blood cell (WBC) indicators, and plasma ferritin. Results. Mean hemoglobin (Hb) of the study population was 10.43 +/- 3.33 g/dL and prevalence of anemia was 62%. In this population, boys had a lower mean Hb value than that of the girls. All grades of anemia were higher among school age children than preschool children. Mean plasma ferritin was found to be higher in school age boys than their counterpart girls. The mean level of WBC count was found to be higher among preschool age boys than among the school age boys (p = 0.025). Conclusion. The prevalence of anemia was higher with concomitant acute infection among study population, which is a matter of concern. Since the hematological parameters are interrelated with each other as well as with the age and gender, relevant intervention strategy and constant monitoring are needed while providing public health nutrition programs to eradicate anemia. PMID- 27127646 TI - Prevalence of Hypertension and Determination of Its Risk Factors in Rural Delhi. AB - Introduction. Hypertension is an important public health challenge in both economically developing and developed countries. It is one of the risk factors for cardiovascular mortality. Data is available on hypertension in urban population but few studies are reported in rural areas. Materials and Methods. It was a community based cross-sectional study conducted in two rural areas in Delhi among 1005 subjects selected using systematic random sampling method. WHO STEPS approach was used to collect data. Blood pressure, body mass index, and blood sugar were measured. Data analysis was done using SPSS version 16. Odds of hypertension among subjects with risk factors were calculated. p value less than 0.05 was considered significant. Results. The prevalence of hypertension was 14.1% among study subjects. Hypertension was significantly higher in individuals more than 35 years than those less than 35 years. Hypertension was significantly higher in those who take alcohol and in subjects with raised total cholesterol level but in multivariate analysis only age, education, and cholesterol levels were independently associated with hypertension. Conclusion. There is significant burden of hypertension in rural areas in Delhi. Age, education, and cholesterol levels were independent risk factors of hypertension. PMID- 27127648 TI - Applicability of Pulse Pressure Variation during Unstable Hemodynamic Events in the Intensive Care Unit: A Five-Day Prospective Multicenter Study. AB - Pulse pressure variation can predict fluid responsiveness in strict applicability conditions. The purpose of this study was to describe the clinical applicability of pulse pressure variation during episodes of patient hemodynamic instability in the intensive care unit. We conducted a five-day, seven-center prospective study that included patients presenting with an unstable hemodynamic event. The six predefined inclusion criteria for pulse pressure variation applicability were as follows: mechanical ventilation, tidal volume >7 mL/kg, sinus rhythm, no spontaneous breath, heart rate/respiratory rate ratio >3.6, absence of right ventricular dysfunction, or severe valvulopathy. Seventy-three patients presented at least one unstable hemodynamic event, with a total of 163 unstable hemodynamic events. The six predefined criteria for the applicability of pulse pressure variation were completely present in only 7% of these. This data indicates that PPV should only be used alongside a strong understanding of the relevant physiology and applicability criteria. Although these exclusion criteria appear to be profound, they likely represent an absolute contraindication of use for only a minority of critical care patients. PMID- 27127649 TI - Open versus Laparoscopic Surgery: Does the Surgical Technique Influence Pain Outcome? Results from an International Registry. AB - Postoperative pain management relevant for specific surgical procedures is debated. The importance of evaluating pain with consideration given to type of surgery and the patient's perspective has been emphasized. In this prospective cohort study, we analysed outcome data from 607 patients in the international PAIN OUT registry for assessment and comparison of postoperative pain outcome within the 24 first hours after laparoscopic and open colonic surgery. Patients from the laparoscopic group scored minimum pain at a higher level than the open group (P = 0.012). Apart from minimum pain, no other significant differences in patient reported outcomes were observed. Maximum pain scores >3 were reported from 77% (laparoscopic) and 68% (open) patients (mean >= 5 in both groups). Pain interference with mobilization was reported by 87-93% of patients. Both groups scored high levels of patient satisfaction. In the open group, a higher frequency of patients received a combination of general and regional anaesthesia, which had an impact of the minimum pain score. Our results from registry data indicate that surgical technique does not influence the quality of postoperative pain management during the first postoperative day if adequate analgesia is given. PMID- 27127651 TI - Benzyl-1,2,4-triazoles as CB 1 Cannabinoid Receptor Ligands: Preparation and In Vitro Pharmacological Evaluation. AB - In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range. PMID- 27127650 TI - Tolerability of Nasal Delivery of Humidified and Warmed Air at Different Temperatures: A Randomised Double-Blind Pilot Study. AB - OBJECTIVES: Delivery of warmed, humidified air via nasal high flow therapy could potentially reduce replication of temperature-sensitive viruses in the upper respiratory tract. This study investigates whether nasal high flow therapy is well tolerated by healthy adults at 37 degrees C and 41 degrees C. METHODS: In this randomised, double-blind, controlled crossover pilot trial, nasal high flow therapy was used to deliver humidified air at 35 L/min, at either 37 degrees C or 41 degrees C, for three one-hour sessions of use over one day. The alternative was delivered at least 14 days later. Ten healthy, nonsmoking adults were asked, via questionnaire after each day's use, whether they would use nasal high flow therapy while being unwell with a cold or flu if it was demonstrated to improve symptoms. RESULTS: All participants completed both interventions. Eighty percent responded "yes" to future use of nasal high flow therapy, for both 37 degrees C and 41 degrees C. There was no significant change from baseline in saccharin times following either intervention or in the following morning. CONCLUSIONS: Delivering humidified air via nasal high flow therapy at both 37 degrees C and 41 degrees C is well tolerated by healthy adults. This supports investigation into the potential use of nasal high flow therapy as treatment in viral upper respiratory tract infections. Trial Registration. This trial is registered with ACTRN12614000183684 (tolerability study of nasal delivery of humidified & warmed air). PMID- 27127652 TI - Potential Antioxidant Activity of New Tetracyclic and Pentacyclic Nonlinear Phenothiazine Derivatives. AB - The global increase in oxidative stress related diseases such as cancer, cardiovascular, and inflammatory diseases caused by overwhelming level of free radicals in the body has encouraged the search for new antioxidant agents. Based on the ability of newly synthesized phenothiazine derivatives (6-chloro-11 azabenzo[a]phenothiazine-5-one and 6-[4-bromophenyl]-10-methyl-11 azabenzo[a]phenothiazine-5-one) to oxidize H2O2, a known free radical to sulfoxide, this study assessed the in vitro and in vivo antioxidant activity. The synthesized phenothiazine derivatives exhibited reducing power potential to convert Fe(3+) to Fe(2+) and high ability to scavenge H2O2 free radical in vitro. These activities were comparable to ascorbic acid, a standard antioxidant. The catalase activity significantly increased (p < 0.05) in groups 1 and 2 animals that received the phenothiazine derivatives compared to the controls (groups 3 and 4) suggesting the ability of the phenothiazine derivatives to scavenge H2O2 in vivo. The malondialdehyde level in groups 1 and 2 animals was lower than that in group 3 that received the reference compound (ascorbic acid) and group 4 that received the solvent suggesting the ability of the phenothiazine derivatives to prevent lipid membrane damage. AST and bilirubin levels were higher in group 2 animals which received 6-[4-bromophenyl]-10-methyl-11-azabenzo[a]phenothiazine-5 one compared to group 3, the positive control. The results suggest that phenothiazine derivatives, especially 6-chloro-11-azabenzo[a]phenothiazine-5-one, possess antioxidant activity though 6-[4-bromophenyl]-10-methyl-11 azabenzo[a]phenothiazine-5-one was slightly toxic. This activity may be due to the presence of electron donors such as sulfur as well as the richness of hydrogen in the additional benzene rings for substitution. Further study is needed to identify tolerable doses for possible therapeutic purposes. PMID- 27127653 TI - Estimating HIV Incidence during Pregnancy and Knowledge of Prevention of Mother to-Child Transmission with an Ad Hoc Analysis of Potential Cofactors. AB - BACKGROUND: We determined the incidence of HIV seroconversion during the second and third trimesters of pregnancy and ad hoc potential cofactors associated with HIV seroconversion after having an HIV-negative result antenatally. We also studied knowledge of PMTCT among pregnant women in seven health facilities in Fako Division, South West Region, Cameroon. METHOD: During the period between September 12 and December 4, 2011, we recruited a cohort of 477 HIV-negative pregnant women by cluster sampling. Data collection was with a pretested interviewer-administered questionnaire. Sociodemographic information, knowledge of PMTCT, and methods of HIV prevention were obtained from the study population and we did Voluntary Counselling and Testing (VCT) for HIV. RESULTS: The incidence rate of HIV seroconversion during pregnancy was 6.8/100 woman-years. Ninety percent of the participants did not use condoms throughout pregnancy but had a good knowledge of PMTCT of HIV. Only 31.9% of participants knew their HIV status before the booking visit and 33% did not know the HIV status of their partners. CONCLUSION: The incidence rate of HIV seroconversion in the Fako Division, Cameroon, was 6.8/100 woman-years. No risk factors associated with HIV seroconversion were identified among the study participants because of lack of power to do so. PMID- 27127654 TI - Use of the Vocera Communications Badge Improves Public Safety Response Times. AB - Objectives. Violence in the Emergency Department (ED) has been a long-standing issue complicated by deficiencies in staff training, ease of weapons access, and response availability of public safety officers. The Vocera Badge is being used by our staff to request public safety assistance in lieu of a formal phone call to the University Police Communications Center. We sought to learn if use of this technology improved officer response times to the ED. Methods. Mean response times were reviewed and descriptive statistics analyzed to determine if the use of the Vocera Badge improved public safety officer response times to the ED. Results. Average response times improved from an average of 3.2 minutes (SD = 0.456) in the 6 months before the use of the communication badges to an average of 1.02 minutes (SD = 0.319) in the 6 months after use began. Conclusions. The use of the Vocera Badge seemed to decrease response times of public safety officers to our ED compared with the traditional method of calling a dispatch center to request assistance. PMID- 27127655 TI - The Efficacy of Umbelliferone, Arbutin, and N-Acetylcysteine to Prevent Microbial Colonization and Biofilm Development on Urinary Catheter Surface: Results from a Preliminary Study. AB - We evaluated, in a preliminary study, the efficacy of umbelliferone, arbutin, and N-acetylcysteine to inhibit biofilm formation on urinary catheter. We used 20 urinary catheters: 5 catheters were incubated with Enterococcus faecalis (control group); 5 catheters were incubated with E. faecalis in presence of umbelliferone (150 mg), arbutin (60 mg), and N-acetylcysteine (150 mg) (group 1); 5 catheters were incubated with E. faecalis in presence of umbelliferone (150 mg), arbutin (60 mg), and N-acetylcysteine (400 mg) (group 2); and 5 catheters were incubated with E. faecalis in presence of umbelliferone (300 mg), arbutin (60 mg), and N acetylcysteine (150 mg) (group 3). After 72 hours, planktonic microbial growth and microorganisms on catheter surface were assessed. In the control group, we found a planktonic load of >=10(5) CFU/mL in the inoculation medium and retrieved 3.69 * 10(6) CFU/cm from the sessile cells adherent to the catheter surface. A significantly lower amount in planktonic (p < 0.001) and sessile (p = 0.004) bacterial load was found in group 3, showing <100 CFU/mL and 0.12 * 10(6) CFU/cm in the incubation medium and on the catheter surface, respectively. In groups 1 and 2, 1.67 * 10(6) CFU/cm and 1.77 * 10(6) CFU/cm were found on catheter surface. Our results document that umbelliferone, arbutin, and N-acetylcysteine are able to reduce E. faecalis biofilm development on the surface of urinary catheters. PMID- 27127656 TI - Molecular Mechanisms of Dendritic Spine Development and Plasticity. PMID- 27127657 TI - Seizure-Induced Regulations of Amyloid-beta, STEP61, and STEP61 Substrates Involved in Hippocampal Synaptic Plasticity. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Pathologic accumulation of soluble amyloid-beta (Abeta) oligomers impairs synaptic plasticity and causes epileptic seizures, both of which contribute to cognitive dysfunction in AD. However, whether seizures could regulate Abeta-induced synaptic weakening remains unclear. Here we show that a single episode of electroconvulsive seizures (ECS) increased protein expression of membrane-associated STriatal-Enriched protein tyrosine Phosphatase (STEP61) and decreased tyrosine-phosphorylation of its substrates N-methyl D aspartate receptor (NMDAR) subunit GluN2B and extracellular signal regulated kinase 1/2 (ERK1/2) in the rat hippocampus at 2 days following a single ECS. Interestingly, a significant decrease in ERK1/2 expression and an increase in APP and Abeta levels were observed at 3-4 days following a single ECS when STEP61 level returned to the baseline. Given that pathologic levels of Abeta increase STEP61 activity and STEP61-mediated dephosphorylation of GluN2B and ERK1/2 leads to NMDAR internalization and ERK1/2 inactivation, we propose that upregulation of STEP61 and downregulation of GluN2B and ERK1/2 phosphorylation mediate compensatory weakening of synaptic strength in response to acute enhancement of hippocampal network activity, whereas delayed decrease in ERK1/2 expression and increase in APP and Abeta expression may contribute to the maintenance of this synaptic weakening. PMID- 27127659 TI - Promoting Motor Cortical Plasticity with Acute Aerobic Exercise: A Role for Cerebellar Circuits. AB - Acute aerobic exercise facilitated long-term potentiation-like plasticity in the human primary motor cortex (M1). Here, we investigated the effect of acute aerobic exercise on cerebellar circuits, and their potential contribution to altered M1 plasticity in healthy individuals (age: 24.8 +/- 4.1 years). In Experiment 1, acute aerobic exercise reduced cerebellar inhibition (CBI) (n = 10, p = 0.01), elicited by dual-coil paired-pulse transcranial magnetic stimulation. In Experiment 2, we evaluated the facilitatory effects of aerobic exercise on responses to paired associative stimulation, delivered with a 25 ms (PAS25) or 21 ms (PAS21) interstimulus interval (n = 16 per group). Increased M1 excitability evoked by PAS25, but not PAS21, relies on trans-cerebellar sensory pathways. The magnitude of the aerobic exercise effect on PAS response was not significantly different between PAS protocols (interaction effect: p = 0.30); however, planned comparisons indicated that, relative to a period of rest, acute aerobic exercise enhanced the excitatory response to PAS25 (p = 0.02), but not PAS21 (p = 0.30). Thus, the results of these planned comparisons indirectly provide modest evidence that modulation of cerebellar circuits may contribute to exercise-induced increases in M1 plasticity. The findings have implications for developing aerobic exercise strategies to "prime" M1 plasticity for enhanced motor skill learning in applied settings. PMID- 27127661 TI - Severe Sepsis Associated with Lemierre's Syndrome: A Rare but Life-Threatening Disease. AB - Background. The incidence of Lemierre's syndrome has increased in the past decade. This posttonsillitis complication may be life threatening. Case Presentation. A 19-year-old patient was admitted to Surgical Intensive Care Unit of a French University Hospital for high fever, low blood pressure, and haemoptysis following a sore throat episode. Blood analysis revealed a thrombopenia, an acute renal failure, and an elevated lactate serum. Fusobacterium necrophorum was found in blood cultures. Computed tomography of the neck and lungs confirmed the diagnosis of Lemierre's syndrome: pleural effusions, bilateral lung infiltrates, and an internal jugular vein thrombosis. Fluid administration and antibiotic treatment were quickly initiated. Patient left the unit four days after his admission without any organ dysfunction. Conclusion. Lemierre's syndrome may lead to multiorgan dysfunction and should be rapidly identified. PMID- 27127660 TI - Spontaneous, Postpartum Coronary Artery Dissection and Cardiogenic Shock with Extracorporeal Membrane Oxygenation Assisted Recovery in a 30-Year-Old Patient. AB - Coronary artery dissection is an infrequent cause of acute coronary syndrome in the general population. There is, however, a greater incidence of spontaneous coronary artery dissection (SCAD) in young women, especially in the peripartum period. However, the majority of cases have favorable outcomes with medical management or percutaneous coronary intervention; coronary artery bypass grafting (CABG) and transplantation are utilized in severe cases. This case is a one of a 30-year-old postpartum female with multivessel SCAD requiring CABG with subsequent biventricular failure and inability to wean from bypass. We believe this is the first reported case in which venoarterial extracorporeal membrane oxygenation (VA-ECMO) was used in the management of biventricular heart failure in a postpartum patient with SCAD. PMID- 27127662 TI - Confluent and Reticulated Papillomatosis of Gougerot-Carteaud on Black Skin: Two Observations. AB - Confluent and reticulated papillomatosis of Goujerot-Carteaud is a rare and benign skin disease characterized by flat papules taking a reticulated appearance. It is a skin disease of unknown etiology and nosology that is always discussed. This disease preferentially involves the chest and interscapular regions. It is a condition probably underdiagnosed in black skin because it generally simulates a pigmented tinea versicolor. This pathology withstands antifungal treatment but has a particular sensitivity to cyclines thus constituting a distinguishing criterion, useful for diagnosis which should be evoked in front of these reticulated confluent papules. PMID- 27127663 TI - Marked Improvement in Refractory TTP Directly after H. pylori Eradication Therapy. AB - Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder involving thrombotic microangiopathy and is characterized by increased platelet aggregation throughout the body. Acquired TTP can be triggered by a variety of conditions including infections. We hereby describe a case report of an 81-year old female presenting to the internal medicine department with TTP and active chronic gastritis, positive for Helicobacter pylori (H. pylori) on biopsy. The TTP was highly resistant to medical therapy; however the patient underwent complete resolution of her TTP following H. pylori eradication. We conclude that acquired TTP may be triggered by H. pylori infection and that treating the underlying infection may play a role in improving TTP's outcome in some patients, especially when disease is refractory to medical therapy. PMID- 27127664 TI - Complete Remission of Acute Myeloid Leukemia following Cisplatin Based Concurrent Therapy with Radiation for Squamous Cell Laryngeal Cancer. AB - Acute myeloid leukemia (AML) is a myeloid disorder with several established treatment regimens depending on patient and leukemic factors. Cisplatin is known to have strong leukemogenic potential and is rarely used even as salvage therapy in relapsed or refractory AML. We present a patient simultaneously diagnosed with AML and squamous cell carcinoma of the larynx, who was found to be in complete remission from AML following treatment with cisplatin based chemoradiotherapy for his laryngeal cancer. PMID- 27127658 TI - Regulation of the Postsynaptic Compartment of Excitatory Synapses by the Actin Cytoskeleton in Health and Its Disruption in Disease. AB - Disruption of synaptic function at excitatory synapses is one of the earliest pathological changes seen in wide range of neurological diseases. The proper control of the segregation of neurotransmitter receptors at these synapses is directly correlated with the intact regulation of the postsynaptic cytoskeleton. In this review, we are discussing key factors that regulate the structure and dynamics of the actin cytoskeleton, the major cytoskeletal building block that supports the postsynaptic compartment. Special attention is given to the complex interplay of actin-associated proteins that are found in the synaptic specialization. We then discuss our current understanding of how disruption of these cytoskeletal elements may contribute to the pathological events observed in the nervous system under disease conditions with a particular focus on Alzheimer's disease pathology. PMID- 27127665 TI - Acute Pyelonephritis with Bacteremia Caused by Enterococcus hirae: A Rare Infection in Humans. AB - Enterococci are one of the usual residents of the microflora in humans. In the last decade this genus has been reported as the third most common cause of bacteremia. We present the case of a 78-year-old female who was admitted to the emergency room because of nausea, lipothymia, and weakness. She was diagnosed with a pyelonephritis with bacteremia, with the isolation in blood and urine cultures of Escherichia coli and Enterococcus hirae. This last microorganism is a rarely isolated pathogen in humans. Currently it is estimated to represent 1-3% of all enterococcal species isolated in clinical practice. PMID- 27127666 TI - Reversible Fluindione-Induced Chronic Interstitial Nephritis. AB - Fluindione is well known to induce acute drug-induced interstitial nephritis (IN). Most cases occurred soon after the onset of treatment. We report a unique case of severe subacute fluindione-induced IN diagnosed 2 years after the treatment was begun. Renal function dramatically improved after fluindione withdrawal and steroid therapy. PMID- 27127667 TI - Primary Intradural Extramedullary Spinal Melanoma in the Lower Thoracic Spine. AB - Background Context. Up to date, only four cases of primary intradural extramedullary spinal cord melanoma (PIEM) have been reported. No previous reports have described a case of PIEM located in the lower thoracic spine with long-term follow-up. Purpose. Demonstrating an unusual, extremely rare case of melanoma manifestation. Study Design. CASE REPORT: Methods. We report a case of a 57-year-old female suffering from increasing lower extremity pain, left-sided paresis, and paraesthesia due to spinal cord compression caused by PIEM in the lower thoracic spine. Results. Extensive investigation excluded other possible primary melanoma sites and metastases. For spinal cord decompression, the tumor at level T12 was resected, yet incompletely. Adjuvant radiotherapy was administered two weeks after surgery. The patient was recurrence-free at 104 weeks after radiotherapy but presents with unchanged neurological symptoms. Conclusion. Primary intradural extramedullary melanoma (PIEM) is extremely rare and its clinical course is unpredictable. PMID- 27127668 TI - Total Hip Arthroplasty Using a Polished Tapered Cemented Stem in Hereditary Multiple Exostosis. AB - A 61-year-old Japanese man underwent right total hip arthroplasty for hereditary multiple exostosis. At first presentation, he had suffered from coxalgia for a long time. On radiographic images, there was a gigantic femoral head, increased shaft angle, and large diameter of the femoral neck. He had also developed coxarthrosis and severe pain of the hip joint. The transformation of the proximal femur bone causes difficulty in setting a cementless total hip prosthesis. Therefore, total hip arthroplasty using a cemented polished tapered stem was performed via a direct lateral approach. Using a cemented polished tapered stem allowed us to deal with the femoral bone transformation and bone substance defectiveness due to exostosis and also minimized the invasiveness of the operation. PMID- 27127669 TI - An Undescribed Monteggia Type 3 Equivalent Lesion: Lateral Dislocation of Radial Head with Both-Bone Forearm Fracture. AB - Monteggia fractures are accepted as hard-to-recognize and easy-to-handle fractures. Adequate radiographic investigations and clinical examinations are necessities. This case holds unique features involving diagnosis and treatment. In this case, the radial head was dislocated laterally while both bones were fractured in the proximal diaphysis, being the first to be mentioned in the literature. Closed reduction of the ulna is the preferred method of handling and almost always results in reduction of the radial head. Literature obligates ulnar reduction as a preliminary to reduce and stabilize the radial head. Closed reduction reduced the ulna but the radial head was not reduced. Hence an intramedullary K-wire was used to reduce the radial head and a long arm cast was used to stabilize the reduction. The operation was successful and follow-up showed no complications. PMID- 27127670 TI - Laryngeal Langerhans Cell Histiocytosis Presenting with Neck Mass in an Adult Woman. AB - Langerhans cell histiocytosis (LCH) is a very rare condition that commonly affects the head and neck region. There are very few cases of isolated laryngeal involvement by LCH, mostly reported in pediatric patients. Here, we report a case of laryngeal LCH in a 62-year-old woman presenting with a neck mass several weeks ago. The clinical and histopathological findings are reported with a brief discussion about the disease. PMID- 27127671 TI - Impact of Heart Transplantation on Cheyne-Stokes Respiration in a Child. AB - Sleep disordered breathing is well described in adults with heart failure but not in pediatric population. We describe a 13-year-old Caucasian male with severe heart failure related to dilated cardiomyopathy who demonstrated polysomnographic features of Cheyne-Stokes respiration, which completely resolved following cardiac transplantation. Cheyne-Stokes respiration in children with advanced heart failure and its resolution after heart transplant can be observed similar to adults. PMID- 27127672 TI - Splenorenal Manifestations of Bartonella henselae Infection in a Pediatric Patient. AB - Bartonella henselae is a bacterium which can cause a wide range of clinical manifestations, ranging from fever of unknown origin to a potentially fatal endocarditis. We report a case of Bartonella henselae infection in a pediatric aged patient following a scratch from a kitten. The patient initially presented with a prolonged fever of unknown origin which was unresponsive to antibiotic treatment. The patient was hospitalized with worsening fevers and night sweat. Subsequent ultrasound imaging demonstrated multiple hypoechoic foci within the spleen. A contrast-enhanced CT of the abdomen and pelvis was also obtained which showed hypoattenuating lesions in the spleen and bilateral kidneys. Bartonella henselae IgG and IgM titers were positive, consistent with an acute Bartonella henselae infection. The patient was discharged with a course of oral rifampin and trimethoprim-sulfamethoxazole, and all symptoms had resolved following two weeks of therapy. PMID- 27127673 TI - Hyperintense Acute Reperfusion Marker on FLAIR in a Patient with Transient Ischemic Attack. AB - The hyperintense acute reperfusion marker (HARM) has initially been described in acute ischemic stroke. The phenomenon is caused by blood-brain barrier disruption following acute reperfusion and consecutive delayed gadolinium enhancement in the subarachnoid space on fluid attenuated inversion recovery (FLAIR) images. Here we report the case of an 80-year-old man who presented with transient paresis and sensory loss in the right arm. Initial routine stroke MRI including diffusion- and perfusion-weighted imaging demonstrated no acute pathology. Follow-up MRI after three hours demonstrated subarachnoid gadolinium enhancement in the left middle cerebral artery territory consistent with HARM that completely resolved on follow-up MRI three days later. This case illustrates that even in transient ischemic attack patients disturbances of the blood-brain barrier may be present which significantly exceed the extent of acute ischemic lesions on diffusion weighted imaging. Inclusion of FLAIR images with delayed acquisition after intravenous contrast agent application in MRI stroke protocols might facilitate the diagnosis of a recent acute ischemic stroke. PMID- 27127674 TI - Novel Desorber for Online Drilling Mud Gas Logging. AB - This work presents the construction solution and experimental results of a novel desorber for online drilling mud gas logging. The traditional desorbers use mechanical mixing of the liquid to stimulate transfer of hydrocarbons to the gaseous phase that is further analyzed. The presented approach is based on transfer of hydrocarbons from the liquid to the gas bubbles flowing through it and further gas analysis. The desorber was checked for gas logging from four different drilling muds collected from Polish boreholes. The results of optimization studies are also presented in this study. The comparison of the novel desorber with a commercial one reveals strong advantages of the novel one. It is characterized by much better hydrocarbons recovery efficiency and allows reaching lower limits of detection of the whole analytical system. The presented desorber seems to be very attractive alternative over widely used mechanical desorbers. PMID- 27127676 TI - The Antibacterial Activity of Chitosan Products Blended with Monoterpenes and Their Biofilms against Plant Pathogenic Bacteria. AB - This study focuses on the biological activities of eleven chitosan products with a viscosity-average molecular weight ranging from 22 to 846 kDa in combination with the most active monoterpenes (geraniol and thymol), out of 10 tested, against four plant pathogenic bacteria, Agrobacterium tumefaciens, Erwinia carotovora, Corynebacterium fascians, and Pseudomonas solanacearum. The antibacterial activity was evaluated in vitro by the agar dilution technique as a minimum inhibitory concentration (MIC) that was found to be dependent on the type of the microorganism tested. The most active product of chitosan was used for biofilm production enriched with geraniol and thymol (0.1 and 0.5%) and the films were also evaluated against the tested bacteria. The biological bioactivities summarized here may provide novel insights into the functions of chitosan and some monoterpenes and potentially allow their use for food protection from microbial attack. PMID- 27127675 TI - The Three Paralogous MicroRNA Clusters in Development and Disease, miR-17-92, miR 106a-363, and miR-106b-25. AB - MicroRNAs (miRNAs) form a class of noncoding RNA genes whose products are small single-stranded RNAs that are involved in the regulation of translation and degradation of mRNAs. There is a fine balance between deregulation of normal developmental programs and tumor genesis. An increasing body of evidence suggests that altered expression of miRNAs is entailed in the pathogenesis of human cancers. Studies in mouse and human cells have identified the miR-17-92 cluster as a potential oncogene. The miR-17-92 cluster is often amplified or overexpressed in human cancers and has recently emerged as the prototypical oncogenic polycistron miRNA. The functional analysis of miR-17-92 is intricate by the existence of two paralogues: miR-106a-363 and miR-106b-25. During early evolution of vertebrates, it is likely that the three clusters commenced via a series of duplication and deletion occurrences. As miR-106a-363 and miR-106b-25 contain miRNAs that are very similar, and in some cases identical, to those encoded by miR-17-92, it is feasible that they regulate a similar set of genes and have overlapping functions. Further understanding of these three clusters and their functions will increase our knowledge about cancer progression. The present review discusses the characteristics and functions of these three miRNA clusters. PMID- 27127677 TI - Exploring the Barriers of Home Care Services in Iran: A Qualitative Study. AB - With increasing chronic diseases, the use of home care is rising in the world. Home care in Iran has many challenges and to improve that, we should identify the challenges and barriers of home care. The aim of this study was to identify and explore the barriers of home care in Iran. This is a qualitative study with content analysis approach that was conducted in Iran in 2015. Fourteen key informants comprising health policymakers, faculty members, nurses, and physicians as well as patients and families engaged in home care purposefully participated in this study. Data was obtained using face-to-face semistructured interviews. A focus group discussion was also used to complete the findings. Graneheim and Lundman's approach was used for analysis of data and Lincoln and Guba's criteria were used to confirm the trustworthiness of study's findings. The data were divided into three main categories and eight subcategories. Main categories included treatment-based approach in the healthcare system, cultural dimensions, and the lack of adequate infrastructure. A position for home care in the healthcare system, considering cultural dimensions in Iranian society and providing an appropriate infrastructure, can be beneficial to improve the situation of home care services in Iran. PMID- 27127678 TI - Bubaline Cholecyst Derived Extracellular Matrix for Reconstruction of Full Thickness Skin Wounds in Rats. AB - An acellular cholecyst derived extracellular matrix (b-CEM) of bubaline origin was prepared using anionic biological detergent. Healing potential of b-CEM was compared with commercially available collagen sheet (b-CS) and open wound (C) in full thickness skin wounds in rats. Thirty-six clinically healthy adult Sprague Dawley rats of either sex were randomly divided into three equal groups. Under general anesthesia, a full thickness skin wound (20 * 20 mm(2)) was created on the dorsum of each rat. The defect in group I was kept as open wound and was taken as control. In group II, the defect was repaired with commercially available collagen sheet (b-CS). In group III, the defect was repaired with cholecyst derived extracellular matrix of bovine origin (b-CEM). Planimetry, wound contracture, and immunological and histological observations were carried out to evaluate healing process. Significantly (P < 0.05) increased wound contraction was observed in b-CEM (III) as compared to control (I) and b-CS (II) on day 21. Histologically, improved epithelization, neovascularization, fibroplasia, and best arranged collagen fibers were observed in b-CEM (III) as early as on postimplantation day 21. These findings indicate that b-CEM have potential for biomedical applications for full thickness skin wound repair in rats. PMID- 27127681 TI - Review of the Trifolium amabile Complex in Peru, with the Description of a New Species. AB - Here, we describe Trifolium absconditum sp. nov., a new species of the T. amabile complex from South America. It differs from other Peruvian Trifolia of the complex by having smaller stipules, leaves, inflorescences, and floral pieces. A key for Peruvian species of the complex is presented, and typifications for them are made when necessary and material is available in Peruvian herbaria. Thus, the number of Peruvian species in the complex is elevated to three: T. amabile, T. absconditum, and a resurrected T. peruvianum. Finally, it is suggested that Chile must be excluded from the distribution of this complex. PMID- 27127680 TI - Calcium Alginate and Calcium Alginate-Chitosan Beads Containing Celecoxib Solubilized in a Self-Emulsifying Phase. AB - In this work alginate and alginate-chitosan beads containing celecoxib solubilized into a self-emulsifying phase were developed in order to obtain a drug delivery system for oral administration, able to delay the drug release in acidic environment and to promote it in the intestinal compartment. The rationale of this work was linked to the desire to improve celecoxib therapeutic effectiveness reducing its gastric adverse effects and to favor its use in the prophylaxis of colon cancer and as adjuvant in the therapy of familial polyposis. The systems were prepared by ionotropic gelation using needles with different diameters (400 and 600 MUm). Morphology, particle size, swelling behavior, and in vitro drug release performance of the beads in aqueous media with different pH were investigated. The experimental results demonstrated that the presence of chitosan in the formulation caused an increase of the mechanical resistance of the bead structure and, as a consequence, a limitation of the bead swelling ability and a decrease of the drug release rate at neutral pH. Alginate-chitosan beads could be a good tool to guarantee a celecoxib colon delivery. PMID- 27127679 TI - Acupuncture Anxiolytic Effects on Physiological and Psychological Assessments for a Clinical Trial. AB - In a randomized controlled trial we examined the effect of acupuncture on anxiety of the adolescent football players prior to the competition using psychological and physiological markers. A total of 45 athletes were equally allocated to either acupuncture group, sham group, or wait-list control group. Thereafter, all participants were asked to complete an anxiety questionnaire before and after the intervention. Their heart rate and skin conductance were also examined before and after the intervention. The results of ANOVA on posttest scores showed that acupuncture had a significant effect on cognitive anxiety (p = 0.001) and somatic anxiety (p < 0.001) but not on self-confidence (p > 0.05). Furthermore, the results showed that acupuncture significantly decreased the skin conductance in acupuncture group compared to sham group (p = 0.006) and wait-list control group (p < 0.001). In conclusion, the results suggested that acupuncture has the capacity to decrease cognitive anxiety and somatic anxiety prior to competition in adolescent athletes, while this was accompanied by significant physiological changes. This trial is registered with IRCT138904074264N1 (IRCT is a Primary Registry in the WHO Registry Network). PMID- 27127682 TI - An Overview of Seasonal Changes in Oxidative Stress and Antioxidant Defence Parameters in Some Invertebrate and Vertebrate Species. AB - Antioxidant defence system, a highly conserved biochemical mechanism, protects organisms from harmful effects of reactive oxygen species (ROS), a by-product of metabolism. Both invertebrates and vertebrates are unable to modify environmental physical factors such as photoperiod, temperature, salinity, humidity, oxygen content, and food availability as per their requirement. Therefore, they have evolved mechanisms to modulate their metabolic pathways to cope their physiology with changing environmental challenges for survival. Antioxidant defences are one of such biochemical mechanisms. At low concentration, ROS regulates several physiological processes, whereas at higher concentration they are toxic to organisms because they impair cellular functions by oxidizing biomolecules. Seasonal changes in antioxidant defences make species able to maintain their correct ROS titre to take various physiological functions such as hibernation, aestivation, migration, and reproduction against changing environmental physical parameters. In this paper, we have compiled information available in the literature on seasonal variation in antioxidant defence system in various species of invertebrates and vertebrates. The primary objective was to understand the relationship between varied biological phenomena seen in different animal species and conserved antioxidant defence system with respect to seasons. PMID- 27127683 TI - A Simple HPLC-UV Method for the Determination of Glutathione in PC-12 Cells. AB - A highly sensitive and simple HPLC-UV method was developed and validated for the assay of glutathione (GSH) in PC-12 cells. Glutathione is a major intracellular antioxidant having multiple biological effects, best known for its cytoprotective effects against cell damage from reactive oxygen species and toxic reactive metabolites and regulating the cellular redox homeostasis. Due to its own sulfhydryl (SH) group, GSH readily reacts with Ellman's reagent to form a stable dimer which allows for quantitative estimation of GSH in biological systems by UV detection. The separation was achieved using a C8 column with a mobile phase consisting of phosphate buffer adjusted to pH 2.5 (mobile phase A) and acetonitrile (mobile phase B), running in a segmented gradient manner at a flow rate of 0.8 mL/min, and UV detection was performed at 280 nm. The developed HPLC UV method was validated with respect to precision, accuracy, robustness, and linearity within a range of 1-20 MUg/mL. Limit of detection (LOD) and limit of quantification (LOQ) were 0.05 and 0.1 MUg/mL, respectively. Furthermore, the method shows the applicability for monitoring the oxidative stress in PC-12 cells. PMID- 27127684 TI - Concurrent Training Decreases Cortisol but Not Zinc Concentrations: Effects of Distinct Exercise Protocols. AB - Objectives. To investigate the effects of distinct concurrent training (CT) protocols on zinc and cortisol concentrations and test the correlation between these blood variables. Methods. Samples of serum zinc and cortisol were assessed from 10 male subjects (27.1 +/- 4.8 years old; BMI 25.38 +/- 0.09) before and immediately after each study session: control (CS = no exercises), concurrent training 1 (CT1 = indoor cycling + strength training), and concurrent training 2 (CT2 = strength training + indoor cycle) with five days of interval between each. Results. There were no significant changes in zinc concentrations after the CS (Delta% = 8.45; p = 0.07), CT1 (Delta% = 4.77; p = 0.49), and CT2 (Delta% = 2.90; p = 0.12) sessions. Cortisol levels showed significant decrease after CS (Delta% = -6.02; p = 0.00), CT1 (Delta% = -26.32; p = 0.02), and CT2 (Delta% = 33.57; p = 0.05) sessions. There was a significant correlation between the variables only at CS (zinc post versus cortisol pre: r = 0.82 and cortisol post: r = 0.82). Conclusions. CT decreases cortisol concentrations regardless of the sequence performed. No changes were found in zinc concentrations after the study sessions. The reduction in serum cortisol concentrations appear to occur by a mechanism independent of the zinc status. PMID- 27127685 TI - Posttraining Epinephrine Reverses Memory Deficits Produced by Traumatic Brain Injury in Rats. AB - The aim of this research is to evaluate whether posttraining systemic epinephrine is able to improve object recognition memory in rats with memory deficits produced by traumatic brain injury. Forty-nine two-month-old naive male Wistar rats were submitted to surgical procedures to induce traumatic brain injury (TBI) or were sham-operated. Rats were trained in an object recognition task and, immediately after training, received an intraperitoneal injection of distilled water (Sham-Veh and TBI-Veh group) or 0.01 mg/kg epinephrine (TBI-Epi group) or no injection (TBI-0 and Sham-0 groups). Retention was tested 3 h and 24 h after acquisition. The results showed that brain injury produced severe memory deficits and that posttraining administration of epinephrine was able to reverse them. Systemic administration of distilled water also had an enhancing effect, but of a lower magnitude. These data indicate that posttraining epinephrine and, to a lesser extent, vehicle injection reduce memory deficits associated with TBI, probably through induction of a low-to-moderate emotional arousal. PMID- 27127687 TI - Leaving Bethesda. PMID- 27127686 TI - Oral Feeding of Probiotic Bifidobacterium infantis: Colonic Morphological Changes in Rat Model of TNBS-Induced Colitis. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. It has been proposed that modifying the bacterial flora in intestine with probiotics may decrease the inflammatory process and prevent relapses in UC. We investigated the possible protective and therapeutic effects of a single strand of probiotic, Bifidobacterium infantis (BI), on colonic inflammation, in rats with regular feedings. Two groups of Lewis rats were prepared (n = 8). The first group was the control, sham-fed group (n = 4). The other group was the experimental BI-fed group (n = 4). Colitis was induced in both groups by intrarectal administration of TNBS under light anesthesia. The sham-fed colitis induced groups received a daily oral gavage feeding of 1.0 mL distilled water, whereas the B. infantis-fed group received 0.205 g of B. infantis dissolved in 1.0 mL distilled water daily. The change in body weight and food and water intake was recorded over the course of each study and analyzed. The rats were euthanized and tissues from the descending colon were harvested and analyzed microscopically and histologically. Results of our study indicated significant reduction in inflammation, mucosal damage, and preservation of goblet cells, as compared to the control animals. Modulation of gastrointestinal (GI) flora suggests a promising field in developing strategies for prevention and treatment of inflammatory bowel diseases by dietary modifications. PMID- 27127688 TI - Retrospective long-term analysis of bone level changes after horizontal alveolar crest reconstruction with autologous bone grafts harvested from the posterior region of the mandible. AB - PURPOSE: The goal of this study was to evaluate the long-term success of horizontal alveolar crest augmentation of the retromolar region of the mandible with particulated bone, as well as factors affecting subsequent peri-implant bone loss. METHODS: A total of 109 patients (68 female, 41 male) suffering from alveolar ridge deficiencies of the maxilla and mandible were included in this study. All patients were treated with particulated retromolar bone grafts from the mandible prior to the insertion of endosseous dental implants. Mesial and distal peri-implant crestal bone changes were assessed at six time points. Several parameters, including implant survival and the influence of age, gender, localisation of the implant, diameter, covering procedures, and time points of implant placement, were analysed to identify associations with bone level changes using the Mann-Whitney U-test, the Kruskal-Wallis test, and Spearman's rank-order correlation coefficient. RESULTS: A total of 164 dental implants were placed in the maxilla (n=97) and in the mandible (n=67). The mean observation period was 105.26+/-21.58 months after implantation. The overall survival rate was 97.6% after 10 years. Overall, peri-implant bone loss was highest during the first year, but decreased over time. The mean amount of bone loss after 10 years was 2.47 mm mesially and 2.50 mm distally. Bone loss was significantly influenced by implant type and primary stability. CONCLUSIONS: The use of particulated autologous retromolar bone grafts is a reliable technique for the horizontal reconstruction of local alveolar ridge deficiencies. Our results demonstrate that implants placed in augmented bone demonstrated similar bone level changes compared to implants inserted in non-augmented regions. PMID- 27127689 TI - Assessment of MMP-1, MMP-8 and TIMP-2 in experimental periodontitis treated with kaempferol. AB - PURPOSE: The objective of this study was to investigate the effect of a dietary flavonoid, kaempferol, which has been shown to possess antiallergic, anti inflammatory, anticarcinogenic, and antioxidant activities on the periodontium by histomorphometric analysis and on gingival tissue matrix metalloproteinase-1 (MMP 1), MMP-8, and tissue inhibitor of metalloproteinase-2 (TIMP-2) by biochemical analysis of rats after experimental periodontitis induction. METHODS: Sixty Wistar rats were randomly divided into six groups of ten rats each, and silk ligatures were placed around the cervical area of the mandibular first molars for 15 days, except in the healthy control rats. In the experimental periodontitis groups, systemic kaempferol (10 mg/kg/2d) and saline were administered by oral gavage at two different periods (with and without the presence of dental biofilm) to all rats except for the ten non-medicated rats. Alveolar bone area, alveolar bone level, and attachment level were determined by histomorphometric analysis, and gingival tissue levels of MMP-1, MMP-8, and TIMP-2 were detected by biochemical analysis. RESULTS: Significantly greater bone area and significantly less alveolar bone and attachment loss were observed in the kaempferol application groups compared to the control groups (P<0.05). In addition, gingival tissue MMP-1 and -8 levels were significantly lower in the kaempferol application groups compared to the control groups and the periodontitis group (P<0.001). There were no statistically significant differences in TIMP-2 levels between the kaempferol and saline application groups (P>0.05). CONCLUSIONS: Kaempferol application may be useful in decreasing alveolar bone resorption, attachment loss, and MMP-1 and -8 production in experimental periodontitis. PMID- 27127690 TI - Three-dimensional finite element analysis of unilateral mastication in malocclusion cases using cone-beam computed tomography and a motion capture system. AB - PURPOSE: Stress distribution and mandible distortion during lateral movements are known to be closely linked to bruxism, dental implant placement, and temporomandibular joint disorder. The present study was performed to determine stress distribution and distortion patterns of the mandible during lateral movements in Class I, II, and III relationships. METHODS: Five Korean volunteers (one normal, two Class II, and two Class III occlusion cases) were selected. Finite element (FE) modeling was performed using information from cone-beam computed tomographic (CBCT) scans of the subjects' skulls, scanned images of dental casts, and incisor movement captured by an optical motion-capture system. RESULTS: In the Class I and II cases, maximum stress load occurred at the condyle of the balancing side, but, in the Class III cases, the maximum stress was loaded on the condyle of the working side. Maximum distortion was observed on the menton at the midline in every case, regardless of loading force. The distortion was greatest in Class III cases and smallest in Class II cases. CONCLUSIONS: The stress distribution along and accompanying distortion of a mandible seems to be affected by the anteroposterior position of the mandible. Additionally, 3-D modeling of the craniofacial skeleton using CBCT and an optical laser scanner and reproduction of mandibular movement by way of the optical motion-capture technique used in this study are reliable techniques for investigating the masticatory system. PMID- 27127691 TI - Characteristics of the molar surface after removal of cervical enamel projections: comparison of three different rotating instruments. AB - PURPOSE: The aim of this study was to evaluate and compare tooth surface characteristics in extracted human molars after cervical enamel projections (CEPs) were removed with the use of three rotating instruments. METHODS: We classified 60 extracted molars due to periodontal lesion with CEPs into grade I, II, or III, according to the Masters and Hoskins' criteria. Each group contained 20 specimens. Three rotating instruments were used to remove the CEPs: a piezoelectric ultrasonic scaler, a periodontal bur, and a diamond bur. Tooth surface characteristics before and after removal of the projections were then evaluated with scanning electron microscopy (SEM). We analyzed the characteristics of the tooth surfaces with respect to roughness and whether the enamel projections had been completely removed. RESULTS: In SEM images, surfaces treated with the diamond bur were smoothest, but this instrument caused considerable harm to tooth structures near the CEPs. The piezoelectric ultrasonic scaler group produced the roughest surface but caused less harm to the tooth structure near the furcation. In general, the surfaces treated with the periodontal bur were smoother than those treated with the ultrasonic scaler, and the periodontal bur did not invade adjacent tooth structures. CONCLUSIONS: For removal of grade II CEPs, the most effective instrument was the diamond bur. However, in removing grade III projections, the diamond bur can destroy both adjacent tooth structures and the periodontal apparatus. In such cases, careful use of the periodontal bur may be an appropriate substitute. PMID- 27127693 TI - Rescue of a periodontally compromised tooth by non-surgical treatment: a case report. AB - PURPOSE: This article describes a case of the successful non-surgical management of a periodontally compromised maxillary premolar. METHODS: A combination therapy, including root planing, occlusal adjustment, and tooth splinting, was applied. Clinical and radiographic examinations were performed during the 16 month follow-up period. RESULTS: All periodontal parameters were improved. There were dramatic decreases (3-6 mm) in the probing pocket depth, tooth mobility, and marginal bone loss. Interestingly, gradual resolution of the periapical radiolucency and alveolar bone regeneration were observed in the radiographs, and the periodontal condition was maintained during the follow-up period. CONCLUSIONS: Within the limits of this study, these results demonstrate the importance of natural tooth preservation through proper periodontal treatment and occlusal adjustment of the periodontally compromised tooth, which is typically targeted for tooth extraction and dental implantation. PMID- 27127692 TI - The relationship between dental implant stability and trabecular bone structure using cone-beam computed tomography. AB - PURPOSE: The objective of this study was to investigate the relationships between primary implant stability as measured by impact response frequency and the structural parameters of trabecular bone using cone-beam computed tomography(CBCT), excluding the effect of cortical bone thickness. METHODS: We measured the impact response of a dental implant placed into swine bone specimens composed of only trabecular bone without the cortical bone layer using an inductive sensor. The peak frequency of the impact response spectrum was determined as an implant stability criterion (SPF). The 3D microstructural parameters were calculated from CT images of the bone specimens obtained using both micro-CT and CBCT. RESULTS: SPF had significant positive correlations with trabecular bone structural parameters (BV/TV, BV, BS, BSD, Tb.Th, Tb.N, FD, and BS/BV) (P<0.01) while SPF demonstrated significant negative correlations with other microstructural parameters (Tb.Sp, Tb.Pf, and SMI) using micro-CT and CBCT (P<0.01). CONCLUSIONS: There was an increase in implant stability prediction by combining BV/TV and SMI in the stepwise forward regression analysis. Bone with high volume density and low surface density shows high implant stability. Well connected thick bone with small marrow spaces also shows high implant stability. The combination of bone density and architectural parameters measured using CBCT can predict the implant stability more accurately than the density alone in clinical diagnoses. PMID- 27127694 TI - Programming for physicians: A free online course. AB - This article is an introduction for clinical readers into programming and computational thinking using the programming language Python. Exercises can be done completely online without any need for installation of software. Participants will be taught the fundamentals of programming, which are necessarily independent of the sort of application (stand-alone, web, mobile, engineering, and statistical/machine learning) that is to be developed afterward. PMID- 27127695 TI - The double massa intermedia. AB - BACKGROUND: To describe the rare finding of a double massa intermedia (MI). Typically, the MI (interthalamic adhesion) is a single bridge of gray matter connecting the medial surfaces of the thalami. METHODS: Twelve formalin- and alcohol-fixed human third ventricles were examined from superior to inferior by fiber dissection technique under *6 to *40 magnifications and with the endoscope. RESULTS: In all hemispheres, the anterior and posterior commissure were defined. The MI, which bridges the medial surfaces of the thalami, was defined in all hemispheres. In one hemisphere, there was a second bridge between the thalami, located posteroinferior to the common MI. Endoscopic view confirmed that there was a second MI in this specimen. The MI usually traverses the third ventricle posterior to the foramen of Monro and connects the paired thalami. The MI is an important landmark during endoscopic and microscopic surgeries of the third ventricle. Although a double MI is very rare, surgeons should be aware of the possibility in their surgical planning. CONCLUSION: The surgeon should be aware of the possibility of a double MI to avoid confusion during third ventricle surgery. PMID- 27127696 TI - A rare case of solitary brain Langerhans cell histiocytosis with intratumoral hemorrhage in a patient affected by Turner syndrome. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of cells with characteristics similar to bone marrow-derived Langerhans cells. The case of a young woman, affected by Turner syndrome and a solitary intraparenchymal LCH associated with an osteolytic lesion of the overlying skull, is presented. CASE DESCRIPTION: The patient, with an insidious history of headache and a growing soft mass in the left frontal region, presented with a sudden generalized tonic-clonic epileptic seizure. Neuroradiological investigations showed an osteolytic lesion of the left frontal bone and an underlying brain lesion associated with recent signs of bleeding. The patient was operated on with a complete removal of the lesion. The postoperative course was uneventful. CONCLUSIONS: The clinical, neuroradiological, and intraoperative findings are presented, along with a review of the literature. Although rare, LCH should be considered in the differential diagnosis when a scalp lesion occurs with a progressive growing. PMID- 27127697 TI - Pathological correlation of Magnetic Resonance Imaging features in a classical case of lipomatous meningioma. PMID- 27127699 TI - Bioethics - Part 2: Is it compassion, personal autonomy, or ulterior utilitarian motives at heart? PMID- 27127698 TI - Are there a guidelines for implantable spinal cord stimulator therapy in patients using chronic anticoagulation therapy? - A review of decision-making in the high risk patient. AB - BACKGROUND: Spinal cord stimulators (SCSs) are gaining increasing indications and utility in an expanding variety of clinical conditions. Complications and initial expenses have historically prevented the early use of SCS therapy despite ongoing efforts to educate and promote its utilization. At present, there exists no literature evidence of SCS implantation in a chronically anticoagulated patient, and neuromodulation manufacturers are conspicuously silent in providing warnings or recommendations in the face of anticoagulant use chronically. It would appear as through these issues demand scrutiny and industry as well as neuromodulation society advocacy and support in terms of the provision of coherent guidelines on how to proceed. CASE DESCRIPTION: A 79-year-old male returned to the neurosurgical clinic with persistent low back pain and leg heaviness due to adjacent level degenerative spondylosis and severe thoracic spinal stenosis. The patient had a notable history of multiple comorbidities along with atrial fibrillation requiring chronic anticoagulation. On initial presentation, he was educated with three choice of conservative medical therapy, intrathecal drug delivery system implantation, or additional lumbar decompression laminectomy with instrumented fusion of T10-L3 and a palliative surgical lead SCS implantation. DESCRIPTION: A 79-year-old male returned to the neurosurgical clinic with persistent low back pain and leg heaviness due to adjacent level degenerative spondylosis and severe thoracic spinal stenosis. The patient had a notable history of multiple comorbidities along with atrial fibrillation requiring chronic anticoagulation. On initial presentation, he was educated with three choice of conservative medical therapy, intrathecal drug delivery system implantation, or additional lumbar decompression laminectomy with instrumented fusion of T10-L3 and a palliative surgical lead SCS implantation. CONCLUSION: Our literature search did not reveal any evidence of SCS therapy among patients with chronic anticoagulation. This case illustrated a complicated clinical case scenario wherein a percutaneous SCS implantation would normally be contraindicated due to severe thoracic spinal stenosis and chronic anticoagulation which could lead to possible paralysis or even a lethal consequences associated with the possible formation of a thoracic epidural hematoma. PMID- 27127700 TI - Epidemiology of the neural tube defects in Kashmir Valley. AB - BACKGROUND: Neural tube defects (NTDs) are the most common congenital malformations affecting the brain and spinal cord and have a multifactorial etiology. Genetic and environmental factors have been found to cause these defects, both individually and in combination. METHODS: A 2-year hospital-based prospective study was carried out from November 2013 to October 2015 to determine the incidence, types, demographics, risk factors, and other associated anamolies relevant to NTDs in Kashmir Valley. A detailed history of the mother was taken along with detailed clinical examination of neonate including measurement of head circumference and checking the status of fontanella, whether lax/full/bulging/or tense, type of NTD. Investigations that were done included were X-ray skull: Anterior-posterior (AP) and lateral, X-ray spine: AP and lateral, ultrasonography abdomen, magnetic resonance imaging: Spine and brain. RESULTS: The total number of babies with NTD's was 125 with an overall incidence of 0.503. Kupwara district was having the highest incidence (1.047) and Srinagar district the lowest incidence of NTD's (0.197). Majority of NTD's (116 cases, 92.8%) were found in the rural areas. Among the different types of NTD's, spina bifida had an incidence of 0.342 (85 cases, 68%) and anencephaly had an incidence of 0.113 (28 cases, 22.4%). There was a slight preponderance of females over males with NTD's. There were 70 females (56%) and 55 males (44%), respectively, with a male: female ratio of 0.8:1. CONCLUSIONS: The incidence rates of NTDs is very high for Kashmir Valley. Geographical distribution of NTDs at this place confirms a relationship between the socioeconomic status, educational status, maternal too young or advanced age, and environmental factors for the development of a NTD. The results of this study point to the importance establishing a health policy to prevent NTD in Kashmir Valley. PMID- 27127701 TI - Effect of a hypercholesterolemia as a starting factor on spinal degeneration in rabbits and role of Vitamin E (alpha-tocopherol). AB - BACKGROUND: To identify the role of the hypercholesterolemia as a starting factor in discovertebral degeneration that ultimately causes lower back pain, and investigate the role of Vitamin E in this process. METHODS: The rabbits (n = 32) were divided into two broad experimental groups: A control group, and a hypercholesterolemia group, namely cholesterol, and cholesterol plus Vitamin E groups and they were fed sequentially for 4 or 8 weeks. Serum cholesterol and Vitamin E (alpha-tocopherol) levels were determined; vascular tissue was prepared for histopathological analyses and vertebra was decalcified for the study. RESULTS: Cholesterol diet group resulted approximately 44-fold of increase plasma cholesterol levels over the 4-week control values. Additional supplementation with Vitamin E group induced a plasma cholesterol level increase of only 37-fold as compared to the control group. In the cholesterol groups, light microscope examination revealed atherosclerotic plaque in major arteries. However, in the cholesterol plus Vitamin E treatment groups, no lipid accumulation or foam cell formation was visible in the abdominal aorta and vertebral segmental artery. In histopathological examination, we found degenerative changes in the discovertebral unit in cholesterol treated groups. CONCLUSION: Hypercholesterolemia causes fat accumulation in the disc endplate and vertebral body that causes blood supply disturbances which might be a starting factor of discovertebral degeneration. This event was not reversed by the elimination of cholesterol from the diet. Vitamin E supplementation was not effective in reducing fat accumulation in vertebral bone marrow. As a result, we conclude that degeneration of the discovertebral unit is not related to atherosclerotic changes in the major blood vessels. PMID- 27127702 TI - Apoplectic presentation of a cauda equina paraganglioma. AB - BACKGROUND: Cauda equina paragangliomas (CEPs) are rare spinal tumors that are mostly misdiagnosed preoperatively as ependymomas or schwannomas on magnetic resonance imaging (MRI). Clinically, they usually present with the gradual onset of back pain and radiculopathy rather than an acute cauda equina syndrome. CASE DESCRIPTION: A 36-year-old female presented with an acute flaccid paraparesis/cauda equina syndrome. Based upon MRI studies, the predominant differential diagnoses included ependymoma or schwannoma. The intraoperative findings revealed an acute intralesional hemorrhage or apoplexy, responsible for the acute clinical deterioration. Histopathology and immunohistochemistry (IHC) revealed that the tumor was a paraganglioma. CONCLUSION: CEPs commonly present with mild symptoms and signs rather than the acute-onset of a flaccid paraparesis/cauda equina syndrome as seen in this case. Here, the authors review the radiological and histopathological characteristics of CEP and emphasize the role of IHC in differentiating "CEP" from the more common ependymomas. PMID- 27127703 TI - The role of surgery for treatment of low back pain: insights from the randomized controlled Spine Patient Outcomes Research Trials. AB - Low back pain (LBP) is a common medical problem with high morbidity and healthcare costs. The optimal management strategy, including the role of surgical intervention, remains controversial. The Spine Patient Outcomes Research Trials were randomized controlled studies conducted to assess the effectiveness of surgery for three of the most common conditions implicated in LBP: Intervertebral disc herniation, degenerative spondylolisthesis, and spinal stenosis. Despite challenges in data interpretation related to patient cross over, these studies support the efficacy of surgery as treatment for these three common conditions. PMID- 27127705 TI - Empirical antitubercular therapy even in endemic area should be started with caution: Missed case of calvarial epidermoid presenting with discharging sinus. PMID- 27127704 TI - Bilateral internal auditory canal gangliogliomas mimicking neurofibromatosis Type II. AB - BACKGROUND: Gangliogliomas are rare low grade, typically well-differentiated, tumors that are composed of mature ganglion cells and neoplastic glial cells. These tumors can appear at virtually any location along the neuroaxis but classically occur in the temporal lobe of young patients. In a small number of cases, gangliogliomas have presented as masses in the brainstem or involving cranial nerves. With the exception of vestibular schwannomas, bilateral tumors in the region of the internal auditory canal (IAC) or cerebellopontine angle (CPA) are exceedingly rare. CASE DESCRIPTION: We report a case of a 58-year-old male who presented with hearing loss, tinnitus, and vertigo. Initial magnetic resonance imaging revealed bilateral nonenhancing IAC/CPA tumors. Based on this finding, a presumptive diagnosis of neurofibromatosis Type II was made, which was initially managed conservatively with close observation. He returned for follow up with worsening vertigo and tinnitus, thus prompting the decision to proceed with surgical resection of the symptomatic mass. Intriguingly, pathological study demonstrated a WHO Grade I ganglioglioma. DESCRIPTION: We report a case of a 58 year-old male who presented with hearing loss, tinnitus, and vertigo. Initial magnetic resonance imaging revealed bilateral nonenhancing IAC/CPA tumors. Based on this finding, a presumptive diagnosis of neurofibromatosis Type II was made, which was initially managed conservatively with close observation. He returned for follow-up with worsening vertigo and tinnitus, thus prompting the decision to proceed with surgical resection of the symptomatic mass. Intriguingly, pathological study demonstrated a WHO Grade I ganglioglioma. CONCLUSION: This is the first reported case of bilateral IAC/CPA gangliogliomas. When evaluating bilateral IAC/CPA lesions with unusual imaging characteristics, ganglioglioma should be included in the differential diagnosis. PMID- 27127706 TI - Spontaneous leaking craniopharyngioma causing preoperative chemical meningitis. PMID- 27127707 TI - Retraction: Solid hemangioblastoma in the cerebellopontine angle: Importance of external carotid blood supply with regard to the probable site of origin and preoperative embolization. AB - [This retracts the article on p. S1 in vol. 7, PMID: 26862451.]. PMID- 27127708 TI - [Microvascular decompression in hemifacial spasm: 13 cases report and review of the literature]. AB - OBJECTIVE: The aim of this study is to describe the results of 13 patients with facial hemispasm, treated with microvascular decompression. METHODS: Between June 2005 and May 2014, 13 patients with facial hemispasm were operated, underwent microvascular decompression. The age, sex, duration of symptoms before surgery, and surgical finds, were all evaluated. In addition, postoperative results were also analyzed. RESULTS: Seven patients were women and 6 were men. The average age of the patients was 53 years. The average time between onset of symptoms and surgery ranged from 3 to 9 years. In all cases the facial hemispasm was typical, one with concomitant trigeminal neuralgia, observed in all neurovascular compression intraoperative. In decreasing order of frequency, the cause of compression was anterior inferior cerebellar artery, posterior inferior cerebellar artery, dolicomega basilar artery and dolicomega vertebral artery. The average time of postoperative follow-up after the surgery was 24 months. Complete relief from spasm occurred in 62%; 30% disappearance after 3 weeks-2 months (8% partial) and in 8% had no improvement. Regarding postoperative complications: 3 patients had facial paresis II-III in House-Brackman scale and 1 patient presented CSF leak. None of the patients in the serie had hearing loss or deafness. CONCLUSION: The microvascular decompression for facial hemispasm is a safe an effective procedure, which allows complete resolution of the disease in most cases. PMID- 27127709 TI - Middle cerebral artery fusiform aneurysm presented with stroke and delayed subarachnoid hemorrhage trapping, thrombectomy, and bypass. AB - BACKGROUND: Ischemic stroke is a well-described but less frequent consequence of ruptured or unruptured intracranial aneurysms. To date, the optimal form of treatment for patients with a thrombosed cerebral aneurysm has not yet been well defined. CASE DESCRIPTION: Here, we report a case of a 68-year-old female patient presenting with cerebral stroke. Five days poststroke multislice computed tomography (MSCT) and MSCT angiography were performed for the evaluation of clinical deterioration, showing a left M2 middle cerebral artery (MCA) bifurcation aneurysm and subarachnoid hemorrhage. Having in mind the high mortality and morbidity rates after a re-rupture, as well as the digital subtraction angiography features of the aneurysm, urgent surgery was performed consisting of aneurysm trapping and superficial temporal artery (STA) to M3 MCA segment end-to-side anastomosis. The surgery and early postoperative period proceeded uneventfully and the patient gradually recovered from the previously diagnosed expressive dysphasia and cranial and extremity motor deficit. CONCLUSION: Our case describes a complex aneurysm treatment that consisted of aneurysm trapping, thrombus removal and an STA-M3 MCA branch bypass creation for the protection of the patent M3 insular MCA branch and prevention of further ischemia. This procedure rewarded us with an excellent clinical result. PMID- 27127710 TI - Giant pseudoaneurysm originated from distal middle cerebral artery dissection treated by trapping under sensitive evoked potential and motor evoked potential monitoring: Case report and discussion. AB - BACKGROUND: Dissecting giant pseudoaneurysm of the middle cerebral artery (MCA) is a rare lesion often presenting challenges to neurosurgical teams dealing with this specific pathology. Giant pseudoaneurysm originating from a dissecting distal segment of the MCA treated with aneurysm trapping under motor and sensitive evoked potential monitoring with a successful outcome is presented in the article followed by a brief discussion on the subject. CASE DESCRIPTION: A case of a previously healthy young female patient admitted at the emergency room of Santa Paula Hospital with a history of a sudden headache and syncope, dysphasia, and Grade 4 right hemiparesis due to a large brain hemorrhage secondary to a 25 mm ruptured pseudoaneurysm originated from a distal left MCA dissecting segment is described. Because the patient risked neurological worsening, aneurysm was treated with parent and efferent vessel trapping technique and no changes on the sensitive and motor evoked potential (MEP) from baseline informed on this decision. Hemorrhage was completely drained after aneurysm was secured. CONCLUSION: Neurophysiological sensitive and MEP monitoring, on this specific case was a valuable tool and informed on the decision of trapping of this large vascular lesion. PMID- 27127711 TI - Middle meningeal arteriovenous fistulas: A rare and potentially high-risk dural arteriovenous fistula. AB - BACKGROUND: Middle meningeal arteriovenous fistulas (MMAVFs) are rare lesions with a poorly established natural history. We report our experience with patients with MMAVFs who presented with intracranial hemorrhage. METHODS: We reviewed our prospectively maintained endovascular database for patients with MMAVFs, who were treated by embolization during a 15-year period. Hospital and outpatient medical records and imaging studies were reviewed. RESULTS: Nine patients with MMAVFs, who presented with intracranial hemorrhage, underwent embolization (mean age 60.3 years, range 21-76; four male and five female). Four patients presented after trauma and five after spontaneous hemorrhage. All nine patients were angiographically cured after embolization of the fistula with liquid embolic agents (n = 8) or coils (n = 1). There were no procedure-related complications. CONCLUSION: MMAVFs represent a rarely reported class of vascular lesions. They are typically associated with trauma, but also develop spontaneously, and may be associated with intracranial hemorrhage, which warrants classification of these lesions as high risk. Endovascular treatment is safe and effective and should be considered for these patients, particularly for those who have lesions with intracranial venous drainage. PMID- 27127712 TI - Intracranial dural arteriovenous fistula as a cause for symptomatic superficial siderosis: A report of two cases and review of the literature. AB - BACKGROUND: Superficial siderosis (SS) is the occult deposition of hemosiderin within the cerebral cortex due to repeat microhemorrhages within the central nervous system. The collection of hemosiderin within the pia and superficial cortical surface can lead to injury to the nervous tissue. The most common presentation is occult sensorineural hearing loss although many patients have been misdiagnosed with diseases such as multiple sclerosis and amyotrophic lateral sclerosis before being diagnosed with SS. Only one case report exists in the literature describing an intracranial dural arteriovenous fistula (dAVF) as the putative cause for SS. CASE DESCRIPTION: We describe two cases of SS caused by a dAVF. Both patients had a supratentorial, cortical lesion supplied by the middle meningeal artery with venous drainage into the superior sagittal sinus. In both patients, symptoms improved after endovascular embolization. The similar anatomic relationship of both dAVFs reported presents an interesting question about the pathogenesis of SS. Similar to the pathologic changes seen in the formation of intracranial arterial aneurysms; it would be possible that changes in the blood vessel lining and wall might predispose a patient to chronic, microhemorrhage resulting in SS. CONCLUSIONS: We describe the second and third cases of a dAVF as the cause of SS, and the first cases of successful treatment of SS-associated dAVF with endovascular embolization. As noninvasive imaging techniques become more sensitive and easily obtained, one must consider their limitations in detecting occult intracranial vascular malformations such as dAVF as a possible etiology for SS. PMID- 27127713 TI - Arteriovenous malformations of the corpus callosum: Pooled analysis and systematic review of literature. AB - BACKGROUND: Arteriovenous malformations (AVMs) of the corpus callosum (CC) are rare entities. We performed a systematic review of the available literature to better define the natural history, patient characteristics, and treatment options for these lesions. METHODS: A MEDLINE, Google Scholar, and The Cochrane Library search were performed for studies published through June 2015. Data from all eligible studies were used to examine epidemiology, natural history, clinical features, treatment strategies, and outcomes of patients with CC-AVMs. A systematic review and pooled analysis of the literature were performed. RESULTS: Our search yielded 37 reports and 230 patients. Mean age at presentation was 26.8 years (+/-13.12 years). AVMs were most commonly located in the splenium (43%), followed by the body (31%), and then the genu (23%) of the CC. A Spetzler-Martin grade of III was the most common (37%). One hundred eighty-seven (81.3%) patients presented with hemorrhage, 91 (40%) underwent microsurgical excision, and 87 (38%) underwent endovascular embolization. Radiosurgery was performed on 57 (25%) patients. Complete obliteration of the AVM was achieved in 102 (48.1%) patients and approximately twice as often when microsurgery was performed alone or in combination with other treatment modalities (94% vs. 49%; P < 0.001). Mean modified Rankin Scale (mRS) at presentation was 1.54 and mean mRS at last follow up was 1.31. This difference was not statistically significant (P = 0.35). CONCLUSION: We present an analysis of the pooled data in the form of a systematic review focusing on management of CC-AVMs. This review aims to provide a valuable tool to aid in decision making when dealing with this particular subtype of AVM. PMID- 27127714 TI - Radical surgical treatment for recurrent giant fusiform thrombosed vertebral artery aneurysm previously coiled. AB - BACKGROUND: Fusiform aneurysms are rare (<1%) and the underlying pathophysiology is not well known. Endovascular coiling is the standard of treatment; however, a surgical procedure with vascular reconstruction by excluding the pathological segment of the vessel and restoring the blood flow, seems to be the most effective and definitive treatment. CASE DESCRIPTION: We report a patient who presented a fusiform vertebral artery aneurysm previously coiled which developed a giant enlargement and a new contralateral fusiform aneurysm. Hemodynamic changes resulting in the formation of contralateral aneurysm might be the result of aneurysm occlusion without revascularization. In addition, continued blood flow to the aneurysmal wall through the vasa vasorum might result in aneurysm recanalization or regrowth. In order to account for these possible sources of complications, we performed a vascular reconstruction with high and low flow bypasses after trapping the aneurysm. CONCLUSIONS: We hypothesize that, in this and similar cases, surgical vascular reconstruction should be the first and definitive treatment under experienced cerebrovascular surgeons. PMID- 27127715 TI - Long-term drug-resistant temporal lobe epilepsy associated with a mixed ganglioglioma and dysembryoplastic neuroepithelial tumor in an elderly patient. AB - BACKGROUND: Mixed ganglioglioma and dysembryoplastic neuroepithelial tumor (DNET) is an extremely rare neuropathological diagnosis. The sparse number of patients described are children or young adults with long-term drug-resistant epilepsy. CASE DESCRIPTION: We report on a rare case of this tumor in a 61-year-old patient with an epilepsy duration of almost 60 years. This patient received an epilepsy surgery work-up with the intention to cure his drug-resistant epilepsy by performing a complete lesionectomy. The available literature on these mixed tumors is reviewed. CONCLUSION: A contrast-enhancing mixed ganglioglioma and DNET can mimic a malignant tumor and appears not only in children and young adults, but also in the elderly patients with chronic epilepsy. A long-lasting epilepsy, in this case almost 60 years, can be completely cured by a complete lesionectomy. PMID- 27127716 TI - A spontaneous superficial temporal artery pseudoaneurysm possibly related to atherosclerosis: Case report and review of literature. AB - BACKGROUND: Spontaneous superficial temporal artery (STA) pseudoaneurysms are very rare; only four cases, including ours, have been reported to date. Therefore, the cause of them has not been studied. CASE DESCRIPTION: A 57-year old woman was admitted to our hospital with a pulsatile mass in the left preauricular region. Her medical history included hypertension, dyslipidemia, and angina pectoris. She denied a history of head injury or minor head trauma. Three dimensional computed tomography angiography showed a well-enhanced saccular aneurysm on the main trunk of the STA. To prevent rupture it was removed surgically. The histological diagnosis was pseudoaneurysm with atherosclerosis. By the 2(nd) postoperative day, she had completely recovered and was discharged home. There has been no relapse. CONCLUSIONS: As all four documented patients were at high risk for atherosclerosis, we posit that a causal factor was weakening of the arterial wall due to atherosclerosis and chronic pressure on the STA from anatomical structures. Here, we present histological evidence to support this hypothesis. PMID- 27127717 TI - Histological Appearance of Placental Solomonization in the Treatment of Twin-Twin Transfusion Syndrome. AB - Background Placental laser equatorialization or "solomonization" during treatment for twin-twin transfusion syndrome (TTTS) is associated with improved pregnancy outcomes. Concern exists, however, about the extent of placental injury caused by the technique, and of its ability to create "dichorionization," or complete separation of the fetal vascular circuits. Case Study A "solomonized" placenta was histologically examined for depth of cell damage. Solomonization produces complete devascularization of the chorionic plate, but has minimal effect on the underlying villi. The median depth of the effect was 2,823 um, or < 3 mm. Conclusion Solomonization produces complete devascularization of the chorionic plate, but has little effect on the underlying villi. "Dichorionization" is therefore not achieved. Ongoing surveillance of treated pregnancies is warranted. PMID- 27127718 TI - Physical Activity Volumes during Pregnancy: A Systematic Review and Meta-Analysis of Observational Studies Assessing the Association with Infant's Birth Weight. AB - Objective This study aims to examine the association between different maternal physical activity exposures during pregnancy and infant's birth weight, body composition, and risk of inadequate weight. Methods Two reviewers (M.B. and J.L.G.) identified observational studies reporting total or leisure time activity during pregnancy and birth weight outcomes. Pooled analyses were performed to summarize the risk associated with high or moderate volumes of physical activity on birth weight. Results A total of 54 studies among 4,080 reported the association between physical activity and birth weight (37 studies) or risks of small or large birth weight. The association between physical activity and birth weight was evaluated by physical activity levels (low, moderate, or high). Despite heterogeneity, pooled results (23 studies) suggested that moderate levels of activity are associated with an increased birth weight (mean difference: 61.5 g, 95% confidence interval [CI]: 16.6, 106.5, 15 studies), while high levels were associated with lower birth weight (mean difference: -69.9 g, 95% CI: -114.8, 25.0, 15 studies). Data were insufficient to provide robust estimates for other outcomes. Conclusions The results of observational studies suggest an inverted u shaped association between physical activity and birth weight, despite methodological variability. These results could help refining physical activity guidelines for pregnancy and provide guidance for future research. PMID- 27127720 TI - Ipsilateral Hemichorea-hemiballism in a Case of Postoperative Stroke. AB - BACKGROUND: Ipsilateral hemiballismus refers to the rare occurrence of hemiballism developing on the same side of a brain lesion. CASE REPORT: We describe a rare case of postoperative ipsilateral hemiballism in a patient who underwent pituitary adenoma resection and experienced a right internal cerebral artery territory infarct. We review the literature on hemichorea hemiballismus (HCHB) and explore various mechanisms for its occurrence. DISCUSSION: Only three cases of ipsilateral hemiballism have been described, and the exact pathophysiology remains unknown. A dominant left hemisphere with corpus callosal connections to the right basal ganglia is the most probable explanation for this unusual event. PMID- 27127719 TI - Daily Self-Weighing to Control Body Weight in Adults: A Critical Review of the Literature. AB - The objective of this study is to review the history of daily self-weighing for weight control, discuss the possibility that self-weighing may cause adverse psychological symptoms, and propose mechanisms that explain how self-weighing facilitates weight control. A systematic forward (citation) tracking approach has been employed in this study. In the early literature, experimental tests did not demonstrate a benefit of adding daily self-weighing to traditional behavioral modification for weight loss. More recent studies have shown that daily self weighing combined with personalized electronic feedback can produce and sustain weight loss with and without a traditional weight loss program. Daily self weighing appears to be effective in preventing age-related weight gain. Apart from these experimental findings, there is considerable agreement that the frequency of self-weighing correlates with success in losing weight and sustaining the weight loss. The early literature suggested frequent self-weighing may be associated with negative psychological effects. However, more recent experimental trials do not substantiate such a causal relationship. In conclusion, daily self-weighing may be a useful strategy for certain adults to prevent weight gain, lose weight, or prevent weight regain after loss. More research is needed to better understand the role of different types of feedback, who benefits most from self-weighing, and at what frequency. PMID- 27127721 TI - PLA2G6 Mutations Related to Distinct Phenotypes: A New Case with Early-onset Parkinsonism. AB - BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) is a recessive neurodegenerative disorder characterized by three distinct phenotypes: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. METHODS: A consanguineous index case from Turkey was diagnosed with early-onset Parkinsonism at the Istanbul Faculty of Medicine. She and her unaffected brother were subjected to whole-genome sequencing. RESULTS: In this report, we describe a 33-year-old index case with parental consanguinity and early-onset Parkinsonism. Whole-genome sequencing of this individual revealed that a homozygous p.R747W mutation in PLA2G6 segregates with the disease in this family. DISCUSSION: This result supports the importance of prioritizing this gene in mutational analysis of autosomal recessive Parkinsonism, and confirms the clinical heterogeneity of PLAN. PMID- 27127722 TI - Post-mortem Findings in Huntington's Deep Brain Stimulation: A Moving Target Due to Atrophy. AB - BACKGROUND: Deep brain stimulation (DBS) has been shown to be effective for Parkinson's disease, essential tremor, and primary dystonia. However, mixed results have been reported in Huntington's disease (HD). CASE REPORT: A single case of HD DBS was identified from the University of Florida DBS Brain Tissue Network. The clinical presentation, evolution, surgical planning, DBS parameters, clinical outcomes, and brain pathological changes are summarized. DISCUSSION: This case of HD DBS revealed that chorea may improve and be sustained. Minimal histopathological changes were noted around the DBS leads. Severe atrophy due to HD likely changed the DBS lead position relative to the internal capsule. PMID- 27127723 TI - GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke. AB - BACKGROUND: Stroke could lead to serious morbidity, of which ischemic stroke counts for majority of the cases. Inflammation plays an important role in the pathogenesis of ischemic stroke, thus drugs targeting inflammation could be potentially neuroprotective. Estradiol was shown to be neuroprotective as well as anti-inflammatory in animal models of ischemic stroke with unclear mechanism. We hypothesize that the anti-inflammatory and neuroprotective effect of estradiol is mediated by the estradiol receptor G protein-coupled estrogen receptor 1 (GPER) expressed on microglia. METHODS: We have generated the rat global cerebral ischemic model and the primary microglia culture to study the neuroprotective and anti-inflammatory effect of estradiol. We have further used pharmacological methods and siRNA knockdown approach to study the underlying mechanism. RESULTS: We found that estradiol reduced the level of proinflammatory cytokines including IL-1beta and TNF-alpha, both in vivo and in vitro. We also found that the specific GPER agonist G1 could reduce the level of IL-1beta (P = 0 P = 0.0017, one-way ANOVA and post hoc test) and TNF-alpha (P < 0.0001) in the primary microglia culture. Moreover, the specific GPER antagonist G15 was able to abolish the anti-inflammatory effect of estradiol. Estradiol failed to reduce the level of IL-1beta (P = 0.4973, unpaired Student's t-test) and TNF-alpha (P = 0.1627) when GPER was knocked down. CONCLUSIONS: Our studies have suggested that GPER expressed on microglia mediated the anti-inflammatory effect of estradiol after ischemic stroke. Our studies could potentially help to develop more specific drugs to manage inflammation postischemic stroke. PMID- 27127724 TI - Correlation of thyroid dysfunction and cognitive impairments induced by subcortical ischemic vascular disease. AB - BACKGROUND: To date, the relationship between thyroid dysfunction and subcortical ischemic vascular disease (SIVD)-induced cognitive impairments still remains elusive. METHODS: Cognitive performances were examined in 215 participants, including 54 healthy participants, 52 SIVD patients with no dementia (SIVDND), 55 patients with mild cognitive impairment (SVMCI), and 54 patients with vascular dementia (VD). Serum thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4) and free thyroxine (FT4), thyroglobulin antibody (TGA), and antithyroid peroxidase antibody (TPO Abs) were quantified by radioimmunoassay or ELISA. RESULTS: A close correlation between thyroid status and cognitive dysfunction in SIVD was observed. Serum TT3 and FT3 levels decreased, whereas serum TSH level increased, with the decline in cognitive functions. Furthermore, TT3 levels showed a positive correlation, whereas TSH level showed a negative correlation, with the Mini-Mental State Examination (MMSE) scores. Our results suggested that thyroid function was associated with cognitive impairments induced by SIVD. Also, thyroid function and thyroid hormone level could be a risk factor in the development of SIVD. Serum TT3 and TSH levels might also be used as biomarkers for cognitive dysfunction. CONCLUSIONS: These findings might contribute to a more accurate clinical diagnosis and differentiation among normal controls, SIVDND, SVMCI, and VD patients, in order to develop appropriate intervention approaches for SIVD therapeutic treatment. PMID- 27127725 TI - A systematic classification of megakaryocytic dysplasia and its impact on prognosis for patients with myelodysplastic syndromes. AB - BACKGROUND: Dys-megakaryopoiesis is defined as >=10 % of dysplastic megakaryocytes in bone marrow smears by the World Health Organization. However, concordance rates for dysplastic megakaryocytes between different observers is low and, consequently, evaluation of dysmegakaryopoiesis is also often discordant. RESULTS: We performed CD41 immune staining and proposed a systematic classification of dys-megakaryopoiesis on bone marrow films: (1) micro megakaryocytes (<12 um); (2) micro-megakaryocytes (12-40 um) with 1 nucleus; (3) micro-megakaryocytes (12-40 um) with 2 nuclei; (4) micro-megakaryocytes (12-40 um) with multiple (more than 2) nuclei; (5) dysplastic megakaryocytes (>=40 um) with 1 nucleus; (6) dysplastic megakaryocytes (>=40 um) with 2 nuclei; and (7) dysplastic megakaryocytes (>=40 um) with multiple (more than 2) nuclei. Further, we evaluated the prognostic impact of micro-megakaryocytes and dysplastic mono nucleated megakaryocytes on MDS patients. The best discriminator cut-off point for each group was determined by the minimal P value approach. In multivariate analyses micro-megakaryocytes >=25 % and dysplastic mono-nucleated megakaryocytes >=30 % were independent adverse prognostic factors (hazard ratio [HR] = 1.58 [95 % confidence interval [CI], 1.11, 2.23]; P = 0.010 and 1.53 [1.09, 2.16]; P = 0.014). CONCLUSIONS: Our data suggest integration of micro-megakaryocytes and dysplastic mono-nucleated megakaryocytes improve predictive accuracy of the international prognostic scoring system-revised (IPSS-R) scoring system. PMID- 27127726 TI - Diagnostic and therapeutic challenges of EBV-positive mucocutaneous ulcer: a case report and systematic review of the literature. AB - BACKGROUND: Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a recently recognized B cell lymphoproliferative disorder that is driven by latent EBV infection and causes discrete ulcerations in the oropharynx, gastrointestinal tract, and skin. Local attenuation of immunosurveillance associated with iatrogenic immunosuppressant use, primary immunodeficiency, or age-associated immunosenescence has been implicated as a predisposing factor. This disorder is likely under reported, as it was only first defined in 2010 and shares histological features with other B-cell proliferative neoplasms. The first case series that described EBVMCU suggested that EBVMCU is generally self-limited and is likely to resolve without treatment. Since that publication, additional cases have been reported that describe a more heterogeneous clinical course, often requiring aggressive therapy. We now systematically review all published cases of EBVMCU and detail a case of aggressive and progressive EBVMCU, including diagnostic and management challenges, as well as successful treatment with radiation therapy. CASE PRESENTATION: A forty-nine year old woman presented with painful and debilitating multifocal oral EBVMCU that initially responded to four weekly doses of rituximab. Her disease relapsed within 3 months and continued to progress and cause significant morbidity. She was successfully treated with local external beam radiation therapy of 30 Gy in 15 fractions, with duration of response of at least 6 months. CONCLUSIONS: We suggest that although many patients with EBVMCU experience a self-limited course, for others EBVMCU can be a debilitating, persistent disorder that requires aggressive therapy to prevent disease progression. CD20- and CD30-directed antibody therapy, local radiation therapy, local surgical excision, systemic chemotherapy, and a combination of these therapies have all been successfully used to treat EBVMCU with high rates of durable clinical remission. As EBVMCU is not currently included in the 2008 WHO classification of lymphoproliferative disorders and no evidence-based guidelines or expert opinions have been proposed to guide therapy, this case report and systematic review provides a foundation on which to guide therapeutic decisions. PMID- 27127727 TI - Mitochondrial STAT3 and reactive oxygen species: A fulcrum of adipogenesis? AB - The balance between cellular lineages can be controlled by reactive oxygen species (ROS). Cellular differentiation into adipocytes is highly dependent on the production of ROS to initiate the process through activation of multiple interlinked factors that stimulate mitotic clonal expansion and cellular maturation. The signal transducer and activator of transcription family of signaling proteins have accepted roles in adipogenesis and associated lipogenesis. Non-canonical mitochondrial localization of STAT3 and other members of the STAT family however opens up new avenues for investigation of its role in the aforementioned processes. Following recent observations of differences in mitochondrially localized serine 727 phosphorylated STAT3 (mtSTAT3-pS727) in preadipocytes and adipocytes, here, we hypothesize and speculate further on the role of mitochondrial STAT3 in adipogenesis. PMID- 27127729 TI - Promoting Tobacco Cessation in a Community-Based Women's Health Centre. AB - OBJECTIVE: This report assesses the impact of a series of education sessions delivered to office staff on the delivery of smoking cessation services among patients seeking care at a community-based women's health center. METHODS: A quasi-experimental design was used to examine the delivery of smoking cessation services to patients in a medical office before and after office staff attended a series of 3 educational sessions intended to increase their knowledge and self efficacy to address cessation. Delivery of smoking cessation services was documented through a systematic review of medical records using a structured abstraction form. RESULTS: While nearly all smokers (93%) were asked about smoking status at their last office visit, few smokers at baseline or follow-up were assessed for interest in setting a quit date or offered pharmacotherapy. Referrals to the smokers quit line increased from <1% at baseline to 8% at follow up (p<0.001) and "any assistance" also showed a modest but significant increase (<1% baseline, 9% follow-up, p<0.001). CONCLUSION: This evaluation failed to identify clinical meaningful changes in the delivery of smoking cessation services in this women's health office before and after completion of a series of educational interventions for office staff. It is anticipated that the implementation of patient centered medical homes, and EMR systems, will help to enhance the delivery of smoking cessation services to women seeking medical care. PMID- 27127728 TI - LIF signal in mouse embryonic stem cells. AB - Since the establishment of mouse embryonic stem cells (mESCs) in the 1980s, a number of important notions on the self-renewal of pluripotent stem cells in vitro have been found. In serum containing conventional culture, an exogenous cytokine, leukemia inhibitory factor (LIF), is absolutely essential for the maintenance of pluripotency. In contrast, in serum-free culture with simultaneous inhibition of Map-kinase and Gsk3 (so called 2i-culture), LIF is no longer required. However, recent findings also suggest that LIF may have a role not covered by the 2i for the maintenance of naive pluripotency. These suggest that LIF functions for the maintenance of naive pluripotency in a context dependent manner. We summarize how LIF-signal pathway is converged to maintain the naive state of pluripotency. PMID- 27127730 TI - Investigating Progression in Substance Use Initiation Using a Discrete-Time Multiple Event Process Survival Mixture (MEPSUM) Approach. AB - The order and timing of substance initiation has significant implications for later problematic patterns of use. Despite the need to study initiation from a multivariate framework, survival analytic methods typically cannot accommodate more than two substances in one model. The Discrete-Time Multiple Event Process Survival Mixture (MEPSUM; Dean, Bauer, & Shanahan, 2014) model represents an advance by incorporating more than two outcomes and enabling establishment of latent classes within a multivariate hazard distribution. Employing a MEPSUM approach, we evaluated patterns of tobacco, alcohol, and cannabis initiation in the National Longitudinal Study of Adolescent to Adult Health (N=18,923). We found four classes that differed in their ages and ordering of peak initiation risk. Demographics, externalizing psychopathology, and personality significantly predicted class membership. Sex differences in the association between delinquency and initiation patterns also emerged. Findings support the utility of the MEPSUM approach in elucidating developmental pathways underlying clinically relevant phenomena. PMID- 27127731 TI - Social Validity Assessment of Training Methods to Improve Treatment Integrity of Special Education Service Providers. AB - We report the results of a social validity assessment that was administered to special education service providers (N = 44) to document the acceptability and effectiveness ratings of several treatment integrity training methods. The participants judged performance feedback as the most likely method to improve their treatment integrity, followed by avoidance (negative reinforcement) of supervision meetings, online training, and financial incentive. Performance feedback was also rank-ordered as most effective among the four training methods. We discuss the merits of social validity assessment in designing programs for enhancing treatment integrity among practitioners within educational and clinical settings. PMID- 27127733 TI - Pharmacogenetics: A hope for difficult to treat chronic pain patients. PMID- 27127732 TI - Exosomal Protein Deficiencies: How Abnormal RNA Metabolism Results in Childhood Onset Neurological Diseases. AB - Defects of RNA metabolism have been increasingly identified in various forms of inherited neurological diseases. Recently, abnormal RNA degradation due to mutations in human exosome subunit genes has been shown to cause complex childhood onset neurological presentations including spinal muscular atrophy, pontocerebellar hypoplasia and myelination deficiencies. This paper summarizes our current knowledge about the exosome in human neurological disease and provides some important insights into potential disease mechanisms. PMID- 27127735 TI - Human papillomavirus-associated cancers: A growing global problem. AB - Human papillomavirus (HPV) infection is linked with several cancers such as cancer cervix, vagina, vulva, head and neck, anal, and penile carcinomas. Although there is a proven association of HPV with these cancers, questions regarding HPV testing, vaccination, and treatment of HPV-related cancers continue to remain unanswered. The present article provides an overview of the HPV associated cancers. PMID- 27127734 TI - Endocrine dysfunction and recurrent spontaneous abortion: An overview. AB - Miscarriage is the spontaneous loss of a fetus before it is viable, occurring at a rate of 15-20%. Recurrent spontaneous abortion (RSA) or habitual miscarriage is defined as repeated occurrence of 3 or more miscarriages before 20(th) week of gestation accounting for the most common complication of early pregnancy in humans. Various etiological factors responsible for recurrent miscarriage are anatomical, genetical, endocrinological, immunological, and infectious. The endocrinological abnormalities may be polycystic ovarian syndrome, hyperprolactinemia, luteal phase defect, thyroid dysfunction, diabetes, or hyperandrogenism contributing to recurrent pregnancy loss. In the present article, the role of endocrinological disorders in patients with RSA has been reviewed. The article search was done using electronic databases, Google scholarly articles, and PubMed based on different key words. We have further combined the searches and made grouping as per various endocrine abnormalities, which might be responsible to cause spontaneous loss of fetus. PMID- 27127736 TI - Initial outcome following invasive cardiac electrophysiologic studies and radiofrequency ablation of atrial fibrillation. AB - BACKGROUND: Cardiac electrophysiologic study and radiofrequency ablation (RFA) have become an established mode of treatment for patients with refractory arrhythmias. These procedures are carried out regularly at the cardiac catheterization laboratory of Madras Medical Mission India. OBJECTIVE: The purpose of this study was to evaluate our experience with cardiac electrophysiologic studies (EPS) and RFA catheter of atrial fibrillation (AF). MATERIALS AND METHODS: This was a retrospective study carried out in the Cardiac Electrophysiology Department of the Institute of Cardiovascular Diseases, Madras Medical Mission, India. All cases diagnosed to have AF following cardiac EPS between January 2010 and April 2014 was selected for the study. The records, which were obtained from the Cardiac Electrophysiology Clinical Research Office of Madras Medical Mission, were reviewed. Forty-nine cases were chosen for analysis, using SPSS statistical software version 15. RESULTS: There were 49 patients, 23 males and 26 females. The mean age was 57.53 years. Commonly associated diseases were diabetes mellitus 8 (16.3%), hypertension 18 (36.7%), and coronary heart disease 14 (28.5%). The ventricular rate was rapid most cases (91.2%). AF was diagnosed as being paroxysmal in 40 (81.6%), persistent in 5 (10.2%), chronic in 3 (6.1%), and lone in 1 (2.0%). Ablation was carried out in 28 (57.1%), the success rate being 90% for pulmonary vein isolation, and 90.9% for atrioventricular node ablation. Complication rate was 2.04%. CONCLUSIONS: Treatment of AF by RFA is highly effective and safe. PMID- 27127737 TI - Aqueous leaf extract of Ocimum gratissimum improves hematological parameters in alloxan-induced diabetic rats via its antioxidant properties. AB - OBJECTIVE: This study was designed to investigate the effects of Ocimum gratissimum (OG) on hematological parameters and oxidative stress in diabetic rats. MATERIALS AND METHODS: Twenty-five male rats (150-200 g) were randomly grouped into five as control, normal + OG, diabetic untreated, diabetic + OG, and diabetic + glibenclamide groups. Diabetes was induced by 100 mg/kg of alloxan monohydrate in the diabetic untreated and diabetic + OG groups followed by treatment with distilled water and 400 mg/kg OG, respectively, whereas control, normal + OG, and diabetic + glibenclamide groups were treated with distilled water, 400 mg/kg OG, and 5 mg/kg glibenclamide, respectively. Body weight and fasting blood glucose level were monitored weekly. After 28 days of treatments, under anesthesia induced by 50 mg/kg sodium thiopental i.p., blood samples were obtained for hematological analysis, malondialdehyde (MDA) level determination, and superoxide dismutase (SOD) activity. Data were compared using analysis of variance and Student's t-test. RESULTS: There was a significant decrease in the fasting blood glucose of the diabetic + OG animals compared to the diabetic untreated and the initial reduction in weight observed in this group was reversed at the end of the experiments. Packed cell volume, red blood cell count, and hemoglobin concentration were significantly increased (P < 0.05) in the diabetic + OG when compared with the untreated group. The MDA concentration was significantly lowered (P < 0.01) in the diabetic + OG group when compared with diabetic untreated while SOD activity was significantly reduced in the diabetic untreated group. CONCLUSION: It was concluded that OG reverses anemia secondary to alloxan-induced diabetes mellitus in rats probably via its antioxidant activity. PMID- 27127738 TI - Role of radiological-assisted cytology in intra-abdominal lesions: A 3 years' experience in a tertiary care center. AB - BACKGROUND: Fine needle aspiration (FNA) with assistance of radiological tools such as ultrasonography (USG) and computed tomography (CT) is an effective and safe technique for diagnosing intra-abdominal neoplastic and nonneoplastic lesions. AIMS AND OBJECTIVES: (1) To assess the utility of image-guided cytology in the diagnosis of intra-abdominal lesions. (2) To categorize various intra abdominal lesions according to their site of occurrence and study their cytomorphological features. MATERIALS AND METHODS: A cross-sectional study was conducted in the Department of Pathology between January 2012 and January 2015. A total of 174 cases with intra-abdominal lesions were included in the study. RESULTS: In our study, diagnostic yield was 84.5%. The mean age was found to be 52 years with M: F ratio 1.1:1. We found that 92 (52.87%) cases were in hepatobiliary region, 33 (18.96%) in adnexa, 13 (7.47%) in pancreatic-ampullary region, 14 (8.04%) in unknown abdominal lumps, 8 (4.6%) in lymph nodes, 6 (3.4%) in renal, 5 (2.87%) in retroperitoneum, 2 (1.1%) in omental nodules, and 1 (0.5%) in splenic mass. Of total 174 cases, 106 (61%) cases were malignant, 10 (5.7%) benign, 16 (9.1%) inflammatory, 27 (15.5%) inadequate, and 15 (8.7%) suspicious for malignancy. CONCLUSION: Ultrasound and CT-guided FNA cytology had a significant role in diagnosis of palpable and nonpalpable intra-abdominal lesions. Being a relatively quick and safe method, it also avoids invasive diagnostic procedures. PMID- 27127739 TI - Contribution of various lipid profile parameters in determining creatine kinase MB levels in unstable angina patients. AB - CONTEXT: In India, the correlation of severity of minor myocardial damage with dyslipidemia has rarely been studied in patients of unstable angina (UA). Dyslipidemia is proven to be a major risk factor for developing acute coronary syndrome (ACS) but still there is doubt about the type of lipoproteins involved in causing minor myocardial damage occurring in UA patients of ACS. AIMS: The aim of our study was to find out the contribution of various types of lipoproteins to predict the severity of minor myocardial damage occurring in the patients of UA. SETTINGS AND DESIGN: Correlation design was used for the study. A single group of individuals was selected. Data were collected on dependent variable creatine kinase-MB (CK-MB) and independent variables (lipid profile parameters). SUBJECTS AND METHODS: The study comprised fifty patients admitted in cardiac care unit with typical history of UA with electrocardiogram showing no ST-segment elevation. The severity of myocardial damage was assessed from on admission CK-MB levels. The lipid profile was estimated from fasting blood samples of all the patients. STATISTICAL ANALYSIS USED: For the purpose of the study, Pearson correlation and multiple linear regression analysis methods were applied. RESULTS: The triacylglycerol (TAG), very-low-density lipoprotein (VLDL), total cholesterol/high-density lipoprotein (TC/HDL) showed significant positive correlation whereas HDL was negatively correlating with CK-MB levels. CONCLUSIONS: The TAG, VLDL, and TC/HDL were found to be significantly affecting the severity of myocardial damage in the patients of UA. PMID- 27127740 TI - Effect of dill tablet (Anethum graveolens L) on antioxidant status and biochemical factors on carbon tetrachloride-induced liver damage on rat. AB - BACKGROUND: Liver damage induced by carbon tetrachloride (CCl4) has been presented as an experimental model for research in hepatoprotective effects of natural product. A commercial medicine prepared from Anethum graveolens L (dill) is being used as dill tablet (DT) as a hypolipidemic agent. This experiment aimed to investigate the protective effect of DT against hepatic damage. MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups (n = 6) as following for a 10 days experiments. (1) Normal animals; (2) normal animals +CCl4 1 ml/kg (1:1 of CCl4 in olive oil, by gastric tube); (3) CCl4 treated animals +100 mg DT/kg; (4) CCl4 treated animals +300 mg DT/kg. After 10 days of treatment, biochemical factors were measured; also antioxidant tests such as thiol group, malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase (CAT) activity in the liver samples were carried out. RESULTS: In dill treated animals, a significant decrease in liver enzymes lactate dehydrogenase, alkaline phosphatase, aspartate transaminase, alanine transaminase, gamma glutamyl transferase, total bilirubin, direct bilirubin, as well as triglyceride, total cholesterol (P < 0.05) were observed. Total protein and albumin concentrations were significantly increased in dill treated groups (P < 0.05). Furthermore, treatment with dill declined liver cholesterol, triglyceride, MDA, and increased TAC and CAT activity compared with untreated group (P < 0.05). CONCLUSION: Dill displayed a potential hepatoprotective effect against CCl4 induced liver damage based on both biochemical markers and antioxidant status. PMID- 27127741 TI - Clinical significance of nonspecificity of antiphospholipid antibodies in recurrent abortions and unexplained infertility. AB - BACKGROUND: Antiphospholipid antibodies (APLA) are acquired autoantibodies directed to phospholipids which are associated with slow progressive thrombosis and infarction of placenta. Infertility and recurrent pregnancy loss may occur because of impaired trophoblast function, placental infarction, and abnormal blood clotting. AIM: To evaluate APLA (IgG and IgM) in cases of infertility and recurrent abortions. MATERIALS AND METHODS: A prospective study comprising 70 subjects was carried out. Fifty cases of unexplained infertility and recurrent abortions (25 each) constituted the study group. Twenty healthy multipara females of same reproductive age group constituted the control group. Venous blood samples were collected, and serum was analyzed for two types of APLA (IgG and IgM) by ELISA method. RESULTS: The mean IgM and IgG levels in recurrent abortions group were 8.10 MPL-U/ml and 6.17 GPL-U/ml, respectively whereas in control group, the levels were 4.67 MPL-U/ml and 4.53 GPL-U/ml, respectively. The difference was statistically nonsignificant. The mean IgM and IgG levels in unexplained infertility group were 7.30 MPL-U/ml and 6.12 GPL-U/ml, respectively whereas in control group, the levels were 4.67 MPL-U/ml and 4.53 GPL-U/ml, respectively. Again the difference was statistically nonsignificant. CONCLUSIONS: The present study concludes that there is no significance of raised APLA in cases of infertility and recurrent abortions. PMID- 27127742 TI - Segregation of blood inventory: A key driver for optimum blood stock management in a resource-poor setting. AB - BACKGROUND: Blood inventory management entails maintaining a delicate balance between guaranteeing blood availability and minimizing wastage. The study was conducted to identify and analyze various factors of wastage which can provide insight to ideal inventory management, thus help in formulating policies and improve efficiency of blood transfusion services. MATERIALS AND METHODS: The study was conducted in a tertiary care hospital. To determine various causes of wastage, a retrospective analysis was done over 6 months and preventive strategies adopted. Issuable stock index (ISI) and wastage as percentage of issue (WAPI) were used to compare the effect on blood inventory before and after adoption of strategies. The average number of times each ABO group and Rh type was crossmatched before final transfusion was calculated and compared for randomly selected units over the first 6 months of 2012 and 2013. RESULTS: Outdating was found to be the largest cause, and decrease in discarding rate was observed after adoption of strategies. Mean ISI for different study periods was comparable. However, significant decrease (P = 0.015) was observed for WAPI and WAPI with respect to outdating. Significant decrease in average number of times a unit was crossmatched before final transfusion for all positive blood groups and O-negative blood group was observed over corresponding first 6 months of 2012 and 2013. CONCLUSION: Division of inventory into two parts, enlistment of soon to outdate blood components, and reduction of holding of blood units to minimum period for elective surgery patients are simple measures which can minimize wastage. PMID- 27127743 TI - Comparison of injuries due to lethal weapons during and after civil strife in Sri Lanka: A medico-legal study. AB - BACKGROUND AND AIMS: "Injuries due to lethal weapons" has emerged as a subject of public discussion in Sri Lanka. This study was conducted to describe the nature and characteristics of injuries due to lethal weapons during civil strife and to compare those with injuries after civil strife. METHODS: A cross-sectional study was conducted on patients reported with injuries caused by lethal weapons from 2004 to 2014. Periods before and after May 19, 2009 were considered as during and after civil strife periods, respectively. A total of 21,210 medico-legal examination forms were studied. RESULTS: There were 358 (1.7%) injuries caused by lethal weapons. Of them, 41% (n = 148) were during and 59% (n = 210) were after the civil strife. During civil strife, 63% occurred during daytime (P < 0.05). Types of lethal weapons that caused injuries were sharp weapons (n = 282), explosives (n = 49), and firearms (n = 27). Of them, 32% of during and 01% of after civil strife were explosive injuries (P < 0.01). Regarding severity, 73% of during and 57% of after civil strife injuries were severe (P < 0.05). During civil strife, 34% injuries were in lower limbs (P < 0.01) and after civil strife, 37% were in upper limbs (P < 0.05). CONCLUSIONS: The presence of many similarities indicated that both groups learnt their basis in a society that breeds violence. During civil strife, more injuries occurred during daytime, to lower limbs by explosive weapons and after the civil strife during nighttime, to upper limbs by nonexplosive weapons. Nonexplosive lethal weapon use after civil strife needs further investigation to develop evidence-based interventions. PMID- 27127744 TI - Effectiveness of discharge-planning on physical quality of life of patients with ischemic heart disease. AB - BACKGROUND AND AIM: One of the goals of health care team is to improve the quality of life of patients during and after hospitalization period. Therefore, this study aimed to examine the effect of performing discharge planning on ischemic heart disease patient's physical quality of life. METHODS: This quasi experimental study was performed on 74 ischemic heart disease patients which randomly allocated to discharge-planning group (n = 37) and usual care group (n = 37). The discharge-planning included the patients' educational needs, self-care instructions for patients, and caregivers. This program was performed through supporting patients during hospitalization and after discharge. The physical aspect of quality of life was assessed by standard questionnaire Short Form 36 and the data were analyzed through Mann-Whitney, independent t-test, variance analysis, Friedman and Wilcoxon. RESULTS: There was no significant difference between intervention and control groups in physical aspects of the quality of life before intervention (P = 0.423) while two groups were significantly different after intervention (P = 0.000) and quality of life of patients in the case group improved significantly. CONCLUSION: Applying the discharge-planning program as an effective, efficient, cost-effective, and noninvasive intervention on physical aspects of the quality of ischemic heart disease patients' lives is useful and helpful. Hence, it is recommended to use this program to promote and improve the quality of ischemic heart disease patients' lives. PMID- 27127745 TI - Uterine lipoleiomyoma: A case report of a rare entity. AB - Lipomatous tumors of the uterus are rare neoplasms which can be divided into three broad groups - pure, mixed, and the exceedingly rare malignant liposarcoma. Lipoleiomyoma is a rare benign variant of leiomyoma with an incidence ranging between 0.03% and 0.2%. These tumors are usually seen in obese postmenopausal women and are usually asymptomatic but may also present with typical leiomyoma symptoms. The most common site of occurrence is the uterine corpus. Imaging plays an important role with magnetic resonance imaging being the modality of choice as it delineates the fat component better. The pathogenesis of this lesion is poorly understood. Histology shows a characteristic pattern with an encapsulated lesion with an admixture of smooth muscle cells, lobules of adipocytes and fibrous tissue. Prognosis is excellent. We report a case of lipoleiomyoma in an elderly, obese postmenopausal woman, who presented with abdominal discomfort and discuss the important differential diagnosis. PMID- 27127746 TI - A fatal case of menthol poisoning. AB - Menthol is a monocyclic terpene alcohol, which is present naturally in peppermint and can be synthesized artificially as well. Generally, it is considered as very safe and has wide usage in medicine and food. There are case reports of toxicity due to excessive consumption of menthol, but a fatal intoxication has never been reported in the medical literature. We present a case of fatal menthol intoxication in a worker, who accidently got exposed when he was working in a peppermint factory. Emergency physicians must keep in mind this extremely rare manifestation of menthol poisoning. All necessary precaution should be taken to reduce its intake or exposure, as it has no specific antidote. Early recognition and supportive treatment of this poisoning is the key for a successful outcome. PMID- 27127747 TI - A pure primary transitional cell carcinoma of the ovary: A rare case report with literature review. AB - Primary transitional cell carcinoma (TCC) of the ovary is a rare and recently recognized subtype of ovarian surface epithelial-stromal cancer. Pure forms of the TCC ovary account for only 1% of surface epithelial carcinomas. The clinical presentation is indistinguishable from other types of ovarian cancers. They have a favorable response to chemotherapy than other surface epithelial cancers. We report a case of 55-year-old woman who presented with a hard mass in the abdomen. Computed tomography-diagnosed it as a carcinoma of the ovary. Tumor was immunoreactive with Wilms' tumor protein-1 and nonreactive with cytokeratin 7 (CK7) and CK20. Histopathology diagnosis of primary TCC of the ovary was made. These tumors are needed to be differentiated from metastatic TCC from other sites and undifferentiated carcinomas of ovaries. Clinical features and immunohistochemistry are helpful. Surgical resection is the primary therapeutic approach followed by standardized chemotherapy. PMID- 27127748 TI - Periocular basal cell carcinoma in a young school teacher. AB - A 34-year-old female patient presented with a nodular mass near the right lateral canthus since 1 year. The mass was nodular, pigmented with irregular surface and had a very well-defined margins. A wide excisional biopsy was done for the same. Histopathology reported a basal cell carcinoma (BCC) of the skin. BCC is very rare in young females and also the site of occurrence in this case was unusual. The mass was excised with a safety margin of 3 mm to ensure complete removal. PMID- 27127749 TI - Malignant chondroblastoma of extraskeletal origin. AB - Chondroblastoma is a rare benign neoplasm of cartilaginous origin. It typically arises in the epiphysis of a long bone. They occur mostly in the second decade of life and is more common in males. Extraskeletal origin of chondroblastoma is a rarity and virulent behavior by its local aggressive nature or metastasis is reported in very few cases. We hereby, present a case of chondroblastoma in the left popliteal fossa first of its kind in a 62-year-old female, primary tumor extraskeletal in origin which turned locally aggressive and eventually metastasized to lungs. The patient is now on palliative therapy. PMID- 27127750 TI - Comparison of esthetics perception and satisfaction of facial profile among male adolescents and adults with different profiles. AB - OBJECTIVE: To evaluate esthetics perception and satisfaction of the facial profile among Iranian male adolescents and adults. MATERIALS AND METHODS: In this cross-sectional study, male subjects referred to Orthodontic Department of Mashhad Dental School were enrolled (n = 84) and were divided into two groups: Adolescents (n = 39), and adults (n = 45). They were also assigned to straight, convex, or concave profile groups based on the facial profile angle (G-Sn-Pog'). An ideal silhouette of the lower facial profile was designed in Adobe(r) Photoshop(r) CS2 software (Kansas, USA). Then, eight other silhouettes representing different relations of the maxilla and mandible were constructed. Patients were asked to use numbers 1-10 to rank the facial profiles in the order of the attractiveness, and choose a silhouette that best closely resembled their own profile. Moreover, using a questionnaire patients were asked to rank their satisfaction with their profile, and asked to assign a number (1-5) to each question as follows; one represented the least satisfaction, while five reflected the highest satisfaction. RESULTS: Adult and adolescent subjects with straight (adults: 12.0 +/- 1.9, adolescents: 12.8 +/- 1.05) and concave (adults: 10.0 +/- 2.14, adolescents: 10.0 +/- 2.08) profile showed the highest and the least satisfaction with their own profile, respectively. Both adult and adolescent group selected "retrognathic maxilla, prognathic mandible" as the least attractive profile. Overall, "straight" and "bimaxillary dentoalveolar retrusion" were chosen as the most attractive silhouettes in adolescent and adults, respectively. In comparison to a professional opinion (clinician ranking), 42.9% of adolescents and 22% of adults were able to correctly diagnose their own profiles type. CONCLUSION: Most of the male adolescents and especially adults diagnosis of their own profile differed with a professional assessment. PMID- 27127751 TI - Comparative evaluation of pentraxin 3 levels in GCF during canine retraction with active tieback and NiTi coil spring: An in vivo study. AB - OBJECTIVES: To compare the levels of pentraxin 3 (PTX-3) in gingival crevicular fluid (GCF) in patients undergoing orthodontic canine retraction with active tieback and nickel titanium (NiTi) coil spring. MATERIALS AND METHODS: Fifteen patients of the age group 15-25 years with first premolar extraction undergoing canine retraction were selected. One month after placement of 0.019" * 0.025" stainless steel wire, canine retraction was started with active tieback (150 g force) on upper right quadrant and NiTi coil spring (150 g force) on upper left quadrant. GCF samples were collected 1 h before commencement of canine retraction and thereafter at intervals of 1 h, 1 day, 1 week, and 2 weeks after application of force. The collected GCF was eluted from the microcapillary pipette in 100 MUl phosphate-buffered saline (pH 5-7.2). The samples were analyzed for PTX-3 levels by the ELISA technique. RESULTS: The mean levels of PTX-3 at 1 h before canine retraction (baseline) was 1.30 +/- 0.22 ng/ml and at 1 h 1.66 +/- 0.33 ng/ml, 1 day 2.65 +/- 0.09 ng/ml, 1 week 1.96 +/- 0.15 ng/ml, and 2 weeks 1.37 +/- 0.18 ng/ml in active tieback group. The mean levels of PTX-3 at 1 h before canine retraction was 1.32 +/- 0.30 ng/ml, and at 1 h 1.71 +/- 0.39 ng/ml, 1 day 2.78 +/ 0.12 ng/ml, 1 week 2.52 +/- 0.18 ng/ml, and 2 weeks 2.12 +/- 0.17 ng/ml in NiTi coil spring group. A significant difference of P < 0.001 was found in PTX-3 levels in GCF during canine retraction between active tieback and NiTi coil spring at 1 day, 1 week, and 2 weeks. CONCLUSION: The results showed that PTX-3 levels increased from 1 h after application of orthodontic force and reached peak at 1 day, followed by a gradual decrease at 1 week and 2 weeks in both active tie back and NiTi coil spring groups. PMID- 27127752 TI - The Facial Aesthetic index: An additional tool for assessing treatment need. AB - OBJECTIVES: Facial Aesthetics, a major consideration in orthodontic diagnosis and treatment planning, may not be judged correctly and completely by simply analyzing dental occlusion or osseous structures. Despite this importance, there is no index to guarantee availability of treatment or prioritize patients based on their soft tissue treatment needs. Individuals having well-aligned teeth but unaesthetic convex profiles do not get included for treatment as per current malocclusion indices. The aim of this investigation is to develop an aesthetic index based on facial profiles which could be used as an additional tool with malocclusion indices. MATERIALS AND METHODS: A chart showing typical facial profile changes due to underlying malocclusions was generated by soft tissue manipulations of standardized profile photographs of a well-balanced male and female face. A panel of 62 orthodontists judged the profile photographs of 100 patients with different soft tissue patterns for assessing profile variations and treatment need. The index was later tested in a cross-section of school population. Statistical analysis was done using "irr" package of R environment version 2.15.1. RESULTS: The index exhibited very good reliability in determining profile variations (Fleiss kappa 0.866, P < 0.001), excellent reproducibility (kappa 0.9078), high sensitivity, and specificity (95.7%). Testing in population yielded excellent agreement among orthodontists (kappa 0.9286). CONCLUSIONS: A new Facial Aesthetic index, based on patient's soft tissue profile requirements is proposed, which can complement existing indices to ensure treatment to those in need. PMID- 27127753 TI - Stress distributions of a bracket type orthodontic miniscrew and the surrounding bone under moment loadings: Three-dimensional finite element analysis. AB - OBJECTIVES: To evaluate the effect of moments and the combination of forces and moments on the mechanical properties of a bracket type miniscrew, resembling engagement of a rectangular wire by three-dimensional (3D) finite element study. MATERIALS AND METHODS: By solid work software (Dassaunlt systems solid works, concord, Mass), a 3D miniscrew model of 6, 8, 10 mm lengths was designed and inserted in the osseous block, consisted of the cortical, and cancellous bones. The stress distributions, maximum stresses, and deflections of the miniscrew were evaluated for all parts using ANSYS (Work Bench, 2014). RESULTS: As the magnitudes of the load increased from 100 to 200, 400 and 800 grf-mm, the peak of stresses in the 6 mm long miniscrew were increased from 7.7 to 61.5 Mpa. The maximum values of Von Mises in the cancellous bone were tremendously lower in comparison to the cortical bone by one hundredth. As the length of the miniscrew in contact with the bone was increased, the amounts and patterns of stress distribution in the cortical bone and the miniscrew did not change significantly. CONCLUSIONS: As the moment magnitude increased, the pick stresses increased linearly. The existence of cancellous bone was not significantly responsible for the stress distribution. The pattern of stress distribution did not change by the length of the miniscrew. PMID- 27127754 TI - The effect of dietary pigmentation on the esthetic appearance of clear orthodontic elastomeric modules. AB - OBJECTIVE: To compare the stain resistance of three types of clear elastomeric modules exposed to several common dietary substances through the assessment of the perception of a group of dentists to discoloration using visual analog scale (VAS). MATERIALS AND METHODS: Elastomeric modules from Unitek (AU), Ormco (OR), and dentaurum (DE) were immersed in the following food substances: Coffee, black tea, chocolate, energy drink, ketchup, and Coca-Cola for 72 h. VAS was used to reflect the module staining severity. RESULTS: Significant difference was found among the three types of modules examined in this study. OR modules showed the least mean staining ratings by the examiners. There was no statistical difference in the staining properties between AU and DE modules. Coffee and tea showed higher staining potential as compared to all staining media. Furthermore, there was no difference in the staining characteristics of coffee and black tea. CONCLUSIONS: Coffee and tea are strong staining media that should be avoided by patients who opted to have esthetic appliances for their orthodontic treatment. Elastomeric modules manufactured by AU showed higher staining optical properties as compared to the other two companies, which could be related to the manufacturing processing of these modules. PMID- 27127755 TI - Surgical orthodontic correction of mandibular laterognathism. AB - This case report describes the successful treatment of a patient with mandibular laterognathism and associated facial asymmetry with combined surgical orthodontic approach. After 7 months of presurgical orthodontic treatment, intraoral vertical ramus osteotomy, and straightening genioplasty were performed as two step surgeries to reposition the deviated mandible and chin, respectively. The total active treatment period was 14 months. After surgical orthodontic treatment, significant improvement in occlusion, masticatory function, and facial appearance was discernible. Posttreatment records at 3 years showed stable results with good occlusion. PMID- 27127756 TI - Increased cerebellar activation after repetitive transcranial magnetic stimulation over the primary motor cortex in patients with multiple system atrophy. AB - BACKGROUND: Previous review reported that the high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor area (M1) of Parkinson's disease (PD) patients could alleviate their symptoms. This study aimed to investigate the effect of rTMS over the left M1 of patients with multiple system atrophy (MSA). METHODS: Fifteen MSA patients were randomly assigned to receive a 10-session real (EP: group of experimental patients; n=7) or sham (CP: group of control patients; n=8) rTMS stimulation over two weeks. The overall experimental procedure consisted of two functional magnetic resonance imaging (fMRI) sessions, before and after a 10-session rTMS treatment. A complex self-paced sequential tapping task was performed during fMRI scanning. In addition, 18 age and gender matched healthy controls (HC) were enrolled. Subjects from the HC group did not receive any rTMS treatment and they underwent fMRI examination only once. The primary end point was the motor score change of the Unified Multiple System Atrophy Rating Scale (UMSARS-II) measured before and after the 5th and 10th session. Task-related activation was also compared among groups. RESULTS: After active rTMS treatment, only patients of EP group significant improvement in UMSARS-II score. Compared to HC, MSA patients showed significant activation over similar brain areas except for the cerebellum. Increased activation was obtained in the bilateral cerebellum after rTMS treatment in the EP group. On the contrary, no increased activation was identified in the CP group. CONCLUSIONS: Our results highlight rTMS over M1 induced motor improvement in MSA patients that may be associated with increased activation in the cerebellum. PMID- 27127757 TI - Toward precision medicine in neurological diseases. AB - Technological development has paved the way for accelerated genomic discovery and is bringing precision medicine into view. The goal of precision medicine is to deliver optimally targeted and timed interventions tailored to an individual's molecular drivers of disease. Neurological diseases are promisingly suited models for precision medicine because of the rapidly expanding genetic knowledge base, phenotypic classification, the development of biomarkers and the potential modifying treatments. Moving forward, it is crucial that through these integrated research platforms to provide analysis both for accurate personal genome analysis and gene and drug discovery. Here we describe our vision of how precision medicine can bring greater clarity to the clinical and biological complexity of neurological diseases. PMID- 27127758 TI - Migraine in the era of precision medicine. AB - Migraine is a common neurovascular disorder in the neurologic clinics whose mechanisms have been explored for several years. The aura has been considered to be attributed to cortical spreading depression (CSD) and dysfunction of the trigeminovascular system is the key factor that has been considered in the pathogenesis of migraine pain. Moreover, three genes (CACNA1A, ATP1A2, and SCN1A) have come from studies performed in individuals with familial hemiplegic migraine (FHM), a monogenic form of migraine with aura. Therapies targeting on the neuropeptids and genes may be helpful in the precision medicine of migraineurs. 5 hydroxytryptamine (5-HT) receptor agonists and calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated efficacy in the acute specific treatment of migraine attacks. Therefore, ongoing and future efforts to find new vulnerabilities of migraine, unravel the complexity of drug therapy, and perform biomarker-driven clinical trials are necessary to improve outcomes for patients with migraine. PMID- 27127761 TI - Association study of the PLXNA4 gene with the risk of Alzheimer's disease. AB - BACKGROUND: The Plexin-A 4 (PLXNA4) gene has recently been recognized as a functional candidate gene of late-onset Alzheimer's disease (LOAD). The single nucleotide polymorphism (SNP) rs13232207 of PLXNA4 gene has been reported to be associated with Alzheimer's disease (AD) in Japanese cohorts. We sought to clarify whether this novel locus gains the same effect in northern Han Chinese. METHODS: To investigate the relationship between SNP rs13232207 and AD sufferers, a case-control study of unrelated individuals was conducted with a total sample size of 2,318 subjects (978 cases and 1,340 age and gender matched healthy controls) in a Northern Han Chinese population. SPSS 22.0 was applied for the statistical process. RESULTS: No significant difference in polymorphic distribution of rs13232207 was observed on LOAD risk independently under dominant (P=0.057), additive (P=0.233) or recessive model (P=0.392). In terms of interaction with apolipoprotein E (APOE), there is also no positive interaction in dominant (P=0.438), additive (P=0.055) or recessive model (P=0.095). CONCLUSIONS: Replication of association between the PLXNA4 rs13232207 and AD in a Han ethnic group indicates that this link is not the result of chance. PMID- 27127760 TI - Toward precision medicine in Alzheimer's disease. AB - In Western societies, Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death. In recent years, the concept of precision medicine, an approach for disease prevention and treatment that is personalized to an individual's specific pattern of genetic variability, environment and lifestyle factors, has emerged. While for some diseases, in particular select cancers and a few monogenetic disorders such as cystic fibrosis, significant advances in precision medicine have been made over the past years, for most other diseases precision medicine is only in its beginning. To advance the application of precision medicine to a wider spectrum of disorders, governments around the world are starting to launch Precision Medicine Initiatives, major efforts to generate the extensive scientific knowledge needed to integrate the model of precision medicine into every day clinical practice. In this article we summarize the state of precision medicine in AD, review major obstacles in its development, and discuss its benefits in this highly prevalent, clinically and pathologically complex disease. PMID- 27127759 TI - Precision medicine in myasthenia graves: begin from the data precision. AB - Myasthenia gravis (MG) is a prototypic autoimmune disease with overt clinical and immunological heterogeneity. The data of MG is far from individually precise now, partially due to the rarity and heterogeneity of this disease. In this review, we provide the basic insights of MG data precision, including onset age, presenting symptoms, generalization, thymus status, pathogenic autoantibodies, muscle involvement, severity and response to treatment based on references and our previous studies. Subgroups and quantitative traits of MG are discussed in the sense of data precision. The role of disease registries and scientific bases of precise analysis are also discussed to ensure better collection and analysis of MG data. PMID- 27127762 TI - Diffusion tensor imaging study in Duchenne muscular dystrophy. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. The aim of this study was to investigate brain microstructural changes in DMD and to explore the relationship between such changes and cognitive impairment. METHODS: All participants (12 DMD patients, 14 age-matched healthy boys), intelligence quotients (IQs) [both full (FIQ) and verbal (VIQ)] were evaluated using the Wechsler intelligence scale for children China revised (WISC-CR) edition, and brain gray matter (GM) and white matter (WM) changes were mapped using diffusion tensor imaging (DTI) with fractional anisotropy (FA). The differences between groups were analyzed using the t-test and the association of cognition with neuroimaging parameters was evaluated using Pearson's correlation coefficient. RESULTS: Compared to the normal controls, the DMD group had lower FIQ (82.0+/ 15.39 vs. 120.21+/-16.06) and significantly lower splenium of corpus callosum (CC) FA values (P<0.05). Splenium of CC FA was positively correlated with VIQ (r=0.588, P=0.044). CONCLUSIONS: There were microstructural changes of splenium of CC in DMD patients, which was associated with cognitive impairment. PMID- 27127764 TI - Model building strategy for logistic regression: purposeful selection. AB - Logistic regression is one of the most commonly used models to account for confounders in medical literature. The article introduces how to perform purposeful selection model building strategy with R. I stress on the use of likelihood ratio test to see whether deleting a variable will have significant impact on model fit. A deleted variable should also be checked for whether it is an important adjustment of remaining covariates. Interaction should be checked to disentangle complex relationship between covariates and their synergistic effect on response variable. Model should be checked for the goodness-of-fit (GOF). In other words, how the fitted model reflects the real data. Hosmer-Lemeshow GOF test is the most widely used for logistic regression model. PMID- 27127763 TI - Predictive value of BRCA1 expression on the efficacy of chemotherapy based on anti-microtubule agents: a pooled analysis across different malignancies and agents. AB - BACKGROUND: Breast cancer susceptibility gene 1 (BRCA1) expression has been suggested as a predictor in anti-neoplastic treatment with anti-microtubule agents. However, the existing evidence is conflicting. Consulting the literature, we sought to examine the true impact of BRCA1 expression on the efficacy of anti microtubule agents. METHODS: Medline by PubMed and Embase databases were searched for eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Additional subgroup analyses stratified for detection methods, regimen, and patient origin were also performed. RESULTS: A total of 13 relevant studies involving a total of 1,490 cases were enrolled. Involved agents included paclitaxel, docetaxel and vinorelbine; Malignancies included non-small cell lung cancer, gastric cancer, esophageal carcinoma, ovarian carcinoma, malignant pleural mesothelioma, breast cancer, and small cell lung cancer. Through meta-analyses, we observed a potentially greater ORR in the population with high BRCA1 expression vs. low BRCA1 expression (OR 1.63, 95% CI: 0.92 to 2.88, P=0.09) but the heterogeneity is severe (P=0.01; I(2)=61%). Similar results were observed in PFS (high vs. low expression, HR 0.93, 95% CI: 0.75 to 1.15, P=0.49; heterogeneity, P<0.01, I(2)=75%). After stratification by testing methods, a significantly higher ORR in the population with high BRCA1 expression was shown in the subgroup using mRNA as a quantitative method (OR 2.90, 95% CI: 1.92 to 4.39, P<0.01; I(2)=0) whereas the difference in the subgroup using immunohistochemistry (IHC) was not significant (OR 0.60, 95% CI: 0.33 to 1.10, P=0.10; I(2)=0). Stratification by regimen (platinum-based vs. non platinum based) and patient origin (Asian vs. Caucasian) did not reduce the heterogeneity. CONCLUSIONS: Although the predictive value of BRCA1 expression on the anti microtubule chemotherapy remained uncertain based on overall results, our exploratory analyses suggested that detection using mRNA might be a preferred technique, however, further validation is required to substantiate our findings. PMID- 27127765 TI - Long-term survival with repeated resections of recurrent hepatocellular carcinoma in a non-cirrhotic liver: case report and brief review of the literature. AB - A healthy and asymptomatic 55-year-old woman underwent a complete (R0) non anatomical resection of an incidentally detected solitary hepatocellular carcinoma (HCC) in a non-cirrhotic liver. Six years following the initial R0 non anatomical resection, intrahepatic recurrence was diagnosed and the patient underwent a second R0 non-anatomical resection. At 12.5 years following the initial resection, a further intrahepatic recurrence was diagnosed, which was once again completely resected by left lateral hepatectomy. This represents one of the longest reported periods between initial resection and HCC recurrence, following repeated R0 resections in the absence of cirrhosis. The appropriate surveillance period and genetic testing protocol for such cases remains to be established. PMID- 27127767 TI - Pathology analysis of a rare case of diffuse pulmonary lymphangiomatosis. AB - Diffuse pulmonary lymphangiomatosis (DPL) is a rare lymphatic disorder characterized by uncontrolled proliferation of lymphatic vessels. Histologically benign, however, it can lead to death because of its progression. In this paper, we would like to present an unusual case of diffuse pulmonary lymphangiomatosis involving a 28-year-old young female who was suffered chest pain and polypnea for one year, and also a lot of chylous effusion in left chest. Lymphoma and lymphangitic metastasis was the primary diagnosis in other hospitals. However, histologic sections of pleural biopsy revealed diffuse pleural lymphatic proliferation characteristic of DPL, wherein the histologic findings can be subtle and could be overlooked as nonspecific reactive changes or misdiagnosed as an idiopathic interstitial lung disease. Recognition of the characteristic lymphangitic distribution of abnormally dilated or reduplicated lymphatic spaces is the key to the correct diagnosis. PMID- 27127766 TI - Primary small bowel melanomas: fact or myth? AB - Small bowel melanoma (SBM) is a rare entity, which often evades diagnosis and therefore presents late. Its origin, whether arising primarily or metastatically from an unidentified or regressed primary cutaneous melanoma, remains debatable. In this report, we present a rare case of primary SBM and review the current literature. A 60-year-old man presented with melena and microcytic anemia. A series of investigations including abdominal ultrasonography (US), esophago gastro-duodenoscopy (EGD) and colonoscopy were normal. Abdominal computed tomography revealed no specific pathology. Subsequent capsule endoscopy identified a jejunal mass, which was confirmed on laparotomy, was resected, and histologically diagnosed as melanoma. Extensive postoperative clinical examination revealed no cutaneous lesions. This report discusses gastrointestinal (GI) malignant melanoma, and examines the evidence both for and against the existence of true primary vs. metastatic disease. Furthermore, this case highlights the capabilities of capsule endoscopy in identifying an extremely rare GI tumor, which evaded other diagnostic modalities. Finally, the origins and pathophysiology of this rare cancer are evaluated, with the aim of promoting early diagnosis and treatment, and therefore improving current poor outcomes. PMID- 27127768 TI - The International Committee of Medical Journal Editors proposal for sharing clinical trial data and the possible implications for the peer review process. PMID- 27127769 TI - Urolift: a new chapter in benign prostate hyperplasia (BPH) therapy. PMID- 27127770 TI - The effect of time interval on esophagectomy after neoadjuvant treatment. AB - "Esophagectomy timing after neoadjuvant therapy for distal esophageal adenocarcinoma" published in the Annals of Thoracic Surgery (doi: 10.1016/j.athoracsur.2015.09.044) states that 30- and 90-day mortality after esophagectomy for adenocarcinoma in patients with neoadjuvant chemoradiation, is significantly higher in patients with a postradiation interval of 9 weeks or more. The authors suggest that a "wait and see" approach after neoadjuvant therapy for esophageal adenocarcinoma may not be safe. PMID- 27127771 TI - Radiation therapy and the abscopal effect: a concept comes of age. PMID- 27127772 TI - What is new for the prevention of catheter-related bloodstream infections? AB - After the publication in 2011 of latest guidelines of the Centers for Disease Control and Prevention (CDC) for the prevention of catheter-related bloodstream infections (CRBSI) some interesting findings have been published in that field. There has been published that skin disinfection with chlorhexidine alcohol reduced the risk of CRBSI compared to skin disinfection with povidone iodine alcohol, that the implementation of quality improvement interventions reduced the incidence of CRBSI, that the use of chlorhexidine impregnated dressing compared to standard dressings reduced the risk of CRBSI and catheter related cost in an health economic model, and that the use of antimicrobial/antiseptic impregnated catheters reduced the incidence of CRBSI and catheter related cost in clinical studies. PMID- 27127773 TI - Perspective on malignant pleural mesothelioma diagnosis and treatment. PMID- 27127774 TI - Choice of crystalloids in sepsis: a conundrum waiting to be solved. PMID- 27127775 TI - TGFbeta signaling: a friend or a foe to hepatic fibrosis and tumorigenesis. PMID- 27127776 TI - The epidemiology of urinary incontinence: a case still open. AB - Urinary incontinence (UI) is a widespread and well-known disorder affecting millions of women all over the world with impressive and probably still underestimated rebounds on personal and social wellbeing. Unfortunately, the available studies on the epidemiology of female UI have used different definitions of UI, obtaining data not homogeneous. In a very recently published article, Bedretdinova et al. have demonstrated that UI definitions and sampling strategies both influence estimates of UI prevalence among women. The ICIQ-UI-SF questionnaire appears to be appropriate for estimating national prevalence in representative samples. PMID- 27127777 TI - Looking forward lung metastasectomy-do we need a staging system for lung metastases? PMID- 27127778 TI - When doctors meet with AlphaGo: potential application of machine learning to clinical medicine. PMID- 27127779 TI - Roots and Tuber Crops as Functional Foods: A Review on Phytochemical Constituents and Their Potential Health Benefits. AB - Starchy roots and tuber crops play a pivotal role in the human diet. There are number of roots and tubers which make an extensive biodiversity even within the same geographical location. Thus, they add variety to the diet in addition to offering numerous desirable nutritional and health benefits such as antioxidative, hypoglycemic, hypocholesterolemic, antimicrobial, and immunomodulatory activities. A number of bioactive constituents such as phenolic compounds, saponins, bioactive proteins, glycoalkaloids, and phytic acids are responsible for the observed effects. Many starchy tuber crops, except the common potatoes, sweet potatoes, and cassava, are not yet fully explored for their nutritional and health benefits. In Asian countries, some edible tubers are also used as traditional medicinal. A variety of foods can be prepared using tubers and they may also be used in industrial applications. Processing may affect the bioactivities of constituent compounds. Tubers have an immense potential as functional foods and nutraceutical ingredients to be explored in disease risk reduction and wellness. PMID- 27127781 TI - Retracted: The Immune System in Hepatocellular Carcinoma and Potential New Immunotherapeutic Strategies. AB - [This retracts the article DOI: 10.1155/2015/731469.]. PMID- 27127780 TI - Curcumin Downregulates Phosphate Carrier and Protects against Doxorubicin Induced Cardiomyocyte Apoptosis. AB - Aim. To explore the effects of curcumin on phosphate carrier (PiC) and its role in protection against doxorubicin induced myocyte toxicity. Methods. Using H9c2 cell line, the cardiotoxic effect of doxorubicin and its mitigation by curcumin were studied. H9c2 cells were cultured with doxorubicin and/or curcumin at various concentrations. Analysis for apoptosis of H9c2 was done using flow cytometry. Confocal laser scanning microscopy was used to record the fluorescence intensity ratios and to determine the mitochondrial permeability transition pore (MPTP) opening state. Oxidative stress was measured using glutathione level, superoxide dismutase activities, and malondialdehyde content. The effect of doxorubicin and curcumin on PiC gene expression was measured by real-time PCR. Results. Curcumin decreased mRNA of PiC and was partly protective against oxidative stress, loss of mitochondrial transmembrane potential, and apoptosis induced by doxorubicin. Interestingly, the effect was not clearly dose dependent and the concentration of 12 mg/L was more efficient than 15 and 10 mg/L. Conclusion. Curcumin downregulates PiC and partly protects against doxorubicin induced oxidative stress and myocyte apoptosis. PMID- 27127782 TI - Comparison of Imaging Characteristics of (124)I PET for Determination of Optimal Energy Window on the Siemens Inveon PET. AB - Purpose. (124)I has a half-life of 4.2 days, which makes it suitable for imaging over several days over its uptake and washout phases. However, it has a low positron branching ratio (23%), because of prompt gamma coincidence due to high energy gamma-photons (602 to 1,691 keV), which are emitted in cascade with positrons. Methods. In this study, we investigated the optimal PET energy window for (124)I PET based on image characteristics of reconstructed PET. Image characteristics such as nonuniformities, recovery coefficients (RCs), and the spillover ratios (SORs) of (124)I were measured as described in NEMA NU 4-2008 standards. Results. The maximum and minimum prompt gamma coincidence fraction (PGF) were 33% and 2% in 350~800 and 400~590 keV, respectively. The difference between best and worst uniformity in the various energy windows was less than 1%. The lowest SORs of (124)I were obtained at 350~750 keV in nonradioactive water compartment. Conclusion. Optimal energy window should be determined based on image characteristics. Our developed correction method would be useful for the correction of high-energy prompt gamma photon in (124)I PET. In terms of the image quality of (124)I PET, our findings indicate that an energy window of 350~750 keV would be optimal. PMID- 27127783 TI - Navigated Transtubular Extraforaminal Decompression of the L5 Nerve Root at the Lumbosacral Junction: Clinical Data, Radiographic Features, and Outcome Analysis. AB - Purpose. Extraforaminal decompression of the L5 nerve root remains a challenge due to anatomic constraints, severe level-degeneration, and variable anatomy. The purpose of this study is to introduce the use of navigation for transmuscular transtubular decompression at the L5/S1 level and report on radiological features and clinical outcome. Methods. Ten patients who underwent a navigation-assisted extraforaminal decompression of the L5 nerve root were retrospectively analyzed. Results. Six patients had an extraforaminal herniated disc and four had a foraminal stenosis. The distance between the L5 transverse process and the para articular notch of the sacrum was 12.1 mm in patients with a herniated disc and 8.1 mm in those with a foraminal stenosis. One patient had an early recurrence and another developed dysesthesia that resolved after 3 months. There was a significant improvement from preoperative to postoperative NRS with the results being sustainable at follow-up. ODI was also significantly improved after surgery. According to the Macnab grading scale, excellent or good outcomes were obtained in 8 patients and fair ones in 2. Conclusions. The navigated transmuscular transtubular approach to the lumbosacral junction allows for optimal placement of the retractor and excellent orientation particularly for foraminal stenosis or in cases of complex anatomy. PMID- 27127784 TI - Identification of a Large SLC25A13 Deletion via Sophisticated Molecular Analyses Using Peripheral Blood Lymphocytes in an Infant with Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD): A Clinical and Molecular Study. AB - Background. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a Mendelian disorder arising from biallelic SLC25A13 mutations, and SLC25A13 genetic analysis was indispensable for its definite diagnosis. However, conventional SLC25A13 analysis could not detect all mutations, especially obscure large insertions/deletions. This paper aimed to explore the obscure SLC25A13 mutation in an NICCD infant. Methods. Genomic DNA was extracted to screen for 4 high-frequency SLC25A13 mutations, and then all 18 exons and their flanking sequences were analyzed by Sanger sequencing. Subsequently, cDNA cloning, SNP analyses, and semiquantitative PCR were performed to identify the obscure mutation. Results. A maternally inherited mutation IVS16ins3kb was screened out, and then cDNA cloning unveiled paternally inherited alternative splicing variants (ASVs) featuring exon 5 skipping. Ultimately, a large deletion c.329 1687_c.468+3865del5692bp, which has never been described in any other references, was identified via intensive study on the genomic DNA around exon 5 of SLC25A13 gene. Conclusions. An NICCD patient was definitely diagnosed as a compound heterozygote of IVS16ins3kb and c.329-1687_c.468+3865del5692bp. The large deletion enriched the SLC25A13 mutation spectrum, and its identification supported the concept that cDNA cloning analysis, along with other molecular tools such as semiquantitative PCR, could provide valuable clues, facilitating the identification of obscure SLC25A13 deletions. PMID- 27127785 TI - Hemispheric Coherence in ASD with and without Comorbid ADHD and Anxiety. AB - There is a growing body of evidence suggesting that altered brain connectivity may be a defining feature of disorders such as autism spectrum disorder (ASD), anxiety, and ADHD. This study investigated whether resting state functional connectivity, measured by 128-channel EEG oscillation coherence, differs between developmental disorders. Analyses were conducted separately on groups with and without comorbid conditions. Analyses revealed increased coherence across central electrodes over the primary motor cortex and decreased coherence in the frontal lobe networks in those with ASD compared to neurotypical controls. There was increased coherence in occipital lobe networks in the ADHD group compared to other groups. Symptoms of generalised anxiety were positively correlated with both frontal-occipital intrahemispheric (alpha only) coherence and occipital interhemispheric coherence (alpha, approaching theta band). The patterns of coherence in the ASD pure group were different when comorbid conditions were included in the analyses, suggesting that aberrant coherence in the frontal and central areas of the brain is specifically associated with ASD. Our findings support the idea that comorbid conditions are additive, rather than being symptoms of the same disorder. PMID- 27127786 TI - Estrogen Modulates Expression of Tight Junction Proteins in Rat Vagina. AB - Background. The objectives of this study were to investigate the localization of tight junctions and the modulation of zonula occludens- (ZO-) 1, occludin and claudin-1 expression by estrogen in castrated female rat vagina. Female Sprague Dawley rats (230-240 g, n = 45) were divided into three groups and subjected to a sham operation (control group, n = 15), bilateral ovariectomy (Ovx group, n = 15), or bilateral ovariectomy followed by daily subcutaneous injection of 17beta estradiol (50 MUg/kg/day, Ovx + Est group, n = 15). The cellular localization and expression of ZO-1, occludin, and claudin-1 were determined in each group by immunohistochemistry and western blot. Results. Expression of ZO-1 was diffuse in all groups, with the highest intensity in the superficial epithelium in the control group. Occludin was localized in the intermediate and basal epithelium. Claudin-1 was most intense in the superficial layer of the vaginal epithelium in the control group. Expression of ZO-1, occludin, and claudin-1 was significantly decreased after ovariectomy and was restored to the level of the control after estrogen replacement. Conclusions. Tight junctions are distinctly localized in rat vagina, and estrogen modulates the expression of tight junctions. Further researches are needed to clarify the functional role of tight junctions in vaginal lubrication. PMID- 27127787 TI - Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1alpha. AB - In this study, rat models of acute kidney injury (AKI) induced by renal ischemia reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1alpha). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1alpha. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1alpha during hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1alpha can regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1alpha. PMID- 27127789 TI - 27.12 MHz Radiofrequency Ablation for Benign Cutaneous Lesions. AB - As surgical and/or ablative modalities, radiofrequency (RF) has been known to produce good clinical outcomes in dermatology. Recently, 27.12 MHz RF has been introduced and has several advantages over conventional 4 or 6 MHz in terms of the precise ablation and lesser pain perception. We aimed to evaluate the clinical efficacy and safety of 27.12 MHz RF for the treatment of benign cutaneous lesions. Twenty female patient subjects were enrolled. Digital photography and a USB microscope camera were used to monitor the clinical results before one session of treatment with 27.12 MHz RF and after 1 and 3 weeks. Treated lesions included telangiectasias, cherry and spider angiomas, skin tags, seborrheic keratoses, lentigo, milium, dilated pore, acne, piercing hole, and one case of neurofibroma. For vascular lesions, clinical results were excellent for 33.3%, good for 44.4%, moderate for 11.1%, and poor for 11.1%. For nonvascular lesions (epidermal lesions and other benign cutaneous lesions), clinical results were excellent for 48.3%, good for 45.2%, moderate for 3.2%, and poor for 3.2%. No serious adverse events were observed. Mild adverse events reported were slight erythema, scale, and crust. The 27.12 MHz RF treatment of benign vascular and nonvascular lesions appears safe and effective after 3 weeks of follow-up. PMID- 27127788 TI - Sociodemographic Correlates of Tobacco Consumption in Rural Gujarat, India. AB - Background. The purpose of this study was to examine occupation-, education-, and gender-specific patterns of tobacco use and knowledge of its health effects among 23,953 rural Asian Indians >=18 years in Gujarat. Methodology. A statewide, community-based, cross-sectional survey was conducted in 26 districts of Gujarat (December 2010-May 2015), using face-to-face interviews by trained community health workers called SEVAKS. Results. Mean age was 39.8 +/- 15.2 years. Eighteen percent of respondents used tobacco in various forms. Tobacco consumption was significantly higher among males (32%), 18-34 years' age group (35%), those who were self-employed (72%), and those with elementary education (40%). The prevalence was 11 times higher among males than females (95% CI = 9.78, 13.13). Adjusted ORs for tobacco use showed strong gradient by age and educational level; consumption was lower among the illiterates and higher for older participants (>=55 years). Tobacco consumption also varied by occupation; that is, those who were self-employed and employed for wages were more likely to use tobacco than those who were unemployed. Knowledge of health effects of tobacco lowered the odds of consumption by 30-40%. Conclusions. Effective educational programs should be tailored by gender, to improve knowledge of health risks and dispel myths on perceived benefits of tobacco. PMID- 27127790 TI - Incidence and Predictors of Catheterization-Related Cerebral Infarction on Diffusion-Weighted Magnetic Resonance Imaging. AB - Introduction. The aim of this study was to examine the incidence and risk factors of catheterization-related CI in the contemporary era, using diffusion-weighted magnetic resonance imaging. Methods. We retrospectively analyzed consecutive 84 patients who underwent MRI (magnetic resonance imaging) after 2.81 +/- 2.4 days (mean +/- SD) of catheterization via aortic arch. We categorized the patients by the presence or absence of acute CI determined by diffusion-weighted MRI and analyzed the incidence and predictors. Results. Of 84 patients that underwent MRI after catheterization, acute CI was determined in 27 (32.1%) patients. In univariate analysis, dyslipidemia, age, coronary artery disease, antiplatelet agents, number of catheters used, urgent settings, and interventional procedures were significantly different. Multivariate analysis revealed dyslipidemia (odds ratio [OR], 4.46; 95% confidence interval [CI], 1.41-16.03; p = 0.01), higher age (OR, 1.09; 95% CI, 1.007-1.19; p = 0.03), and the number of catheters used (OR, 2.21; 95% CI, 1.21-4.36; p = 0.01) as independent predictors of the incidence of catheterization-related acute CI. Conclusions. Dyslipidemia, higher age, and number of catheters used were independent predictors for acute CI after catheterization. These findings imply that managing dyslipidemia and comprehensive planning to minimize the numbers of catheters are important. PMID- 27127791 TI - Automatic Tissue Differentiation Based on Confocal Endomicroscopic Images for Intraoperative Guidance in Neurosurgery. AB - Diagnosis of tumor and definition of tumor borders intraoperatively using fast histopathology is often not sufficiently informative primarily due to tissue architecture alteration during sample preparation step. Confocal laser microscopy (CLE) provides microscopic information of tissue in real-time on cellular and subcellular levels, where tissue characterization is possible. One major challenge is to categorize these images reliably during the surgery as quickly as possible. To address this, we propose an automated tissue differentiation algorithm based on the machine learning concept. During a training phase, a large number of image frames with known tissue types are analyzed and the most discriminant image-based signatures for various tissue types are identified. During the procedure, the algorithm uses the learnt image features to assign a proper tissue type to the acquired image frame. We have verified this method on the example of two types of brain tumors: glioblastoma and meningioma. The algorithm was trained using 117 image sequences containing over 27 thousand images captured from more than 20 patients. We achieved an average cross validation accuracy of better than 83%. We believe this algorithm could be a useful component to an intraoperative pathology system for guiding the resection procedure based on cellular level information. PMID- 27127792 TI - Cardiovascular Function in Intensive Care Medicine or Homo Mensura Est. PMID- 27127796 TI - Dendritic Cells in Tolerance and Immunity against Pathogens. PMID- 27127793 TI - Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer. AB - Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review. PMID- 27127794 TI - Venovenous Extracorporeal Membrane Oxygenation in Intractable Pulmonary Insufficiency: Practical Issues and Future Directions. AB - Venovenous extracorporeal membrane oxygenation (vv-ECMO) is a highly invasive method for organ support that is gaining in popularity due to recent technical advances and its successful application in the recent H1N1 epidemic. Although running a vv-ECMO program is potentially feasible for many hospitals, there are many theoretical concepts and practical issues that merit attention and require expertise. In this review, we focus on indications for vv-ECMO, components of the circuit, and management of patients on vv-ECMO. Concepts regarding oxygenation and decarboxylation and how they can be influenced are discussed. Day-to-day management, weaning, and most frequent complications are covered in light of the recent literature. PMID- 27127795 TI - Central Administration of Galanin Receptor 1 Agonist Boosted Insulin Sensitivity in Adipose Cells of Diabetic Rats. AB - Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats. The ratios of GLUT4 contents were higher in plasma membranes to total cell membranes in both nondiabetic and diabetic M617 groups than each control. In addition, the central administration of M617 enhanced the ratios of pAkt/Akt and pAS160/AS160, but not phosphorylative cAMP response element-binding protein (pCREB)/CREB in the adipose cells of nondiabetic and diabetic rats. These results suggest that excitation of central galanin receptor 1 facilitates insulin sensitivity via activation of the Akt/AS160 signaling pathway in the fat cells of type 2 diabetic rats. PMID- 27127797 TI - The Italian Catquest-9SF cataract questionnaire: translation, validation and application. AB - BACKGROUND: To validate the Catquest-9SF questionnaire in Italian, assess the change in visual disability with cataract surgery and determine the correlation between pre-operative Catquest-9SF scores and Lens Opacities Classification System (LOCS) III cataract grading. METHODS: Prospective, questionnaire validation study. The Catquest-9SF questionnaire was forward and back translated and completed by 209 Italian patients before and three months following cataract surgery. Rasch analysis was used to assess its psychometric properties. RESULTS: The Italian Catquest-9SF demonstrated ordered response categories, unidimensionality (item fit statistics range: 0.73-1.34), adequate person separation (2.04), and no differential item functioning. Mistargeting was evident with a mean difference in item difficulty and person ability of 2.04 logits but improved with inclusion of pre-operative data only. There was a statistically significant (Friedman tests, p < 0.001) median improvement in visual disability of 1.92, 3.57, 1.44 and 2.94 logits in patients undergoing first eye surgery with and without ocular comorbidity, and second eye surgery with and without ocular comorbidity respectively. There was no statistically significant difference in the improvements among the four groups (Kruskal-Wallis H test, X (2) (3) = 5.445, p = 0.142). There was no correlation between Catquest-9SF scores and nuclear opalescence (r s = 0.049, p = 0.478), nuclear colour (r s = 0.008, p = 0.909), cortical (r s = 0.066, p = 0.341), and posterior subcapsular components (r s = 0.048, p = 0.494). CONCLUSIONS: The Italian Catquest-9SF demonstrated good psychometric properties and is suitable for use in Italian speaking patients. There were similar improvements in visual disability in patients undergoing first or second eye surgery, with or without ocular comorbidity. There was no correlation between pre-operative Catquest-9SF scores and LOCS III cataract grading. PMID- 27127798 TI - CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. AB - BACKGROUND & AIMS: Constipation is a common clinical problem that negatively impacts quality of life and is associated with significant health care costs. Activation of the cystic fibrosis transmembrane regulator (CFTR) chloride channel is the primary pathway that drives fluid secretion in the intestine, which maintains lubrication of luminal contents. We hypothesized that direct activation of CFTR would cause fluid secretion and reverse the excessive dehydration of stool found in constipation. METHODS: A cell-based high-throughput screen was done for 120,000 drug-like, synthetic small molecules. Active compounds were characterized for mechanism of action and one lead compound was tested in a loperamide-induced constipation model in mice. RESULTS: Several classes of novel CFTR activators were identified, one of which, the phenylquinoxalinone CFTRact J027, fully activated CFTR chloride conductance with EC50 ~ 200 nM, without causing elevation of cytoplasmic cAMP. Orally administered CFTRact-J027 normalized stool output and water content in a loperamide-induced mouse model of constipation with ED50 ~0.5 mg/kg; CFTRact-J027 was without effect in cystic fibrosis mice lacking functional CFTR. Short-circuit current, fluid secretion and motility measurements in mouse intestine indicated a pro-secretory action of CFTRact-J027 without direct stimulation of intestinal motility. Oral administration of 10 mg/kg CFTRact-J027 showed minimal bioavailability, rapid hepatic metabolism and blood levels <200 nM, and without apparent toxicity after chronic administration. CONCLUSIONS: CFTRact-J027 or alternative small-molecule CFTR-targeted activators may be efficacious for the treatment of constipation. PMID- 27127799 TI - Effect of Opioid on Adult Hippocampal Neurogenesis. AB - During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal's opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse. PMID- 27127801 TI - Perturbational Blowup Solutions to the Two-Component Dullin-Gottwald-Holm System. AB - We construct a family of nonradially symmetric exact solutions for the two component DGH system by the perturbational method. Depending on the parameters, the class of solutions includes both blowup type and global existence type. PMID- 27127800 TI - Variability Assessment of Aromatic and Fine Rice Germplasm in Bangladesh Based on Quantitative Traits. AB - The study was conducted to investigate genetic variability among 113 aromatic and fine local rice genotypes of which five were exotic in origin. The test genotypes were evaluated for 19 growth traits, yield components, and yield. All the quantitative traits varied significantly among the test genotypes. High heritability along with high genetic advance was observed for flag leaf area, secondary branches per panicle, filled grains per panicle, grain length, grain breadth, grain length breadth ratio, and 1000 grain weight. Such findings suggested preponderance of additive gene action in gene expression for these characters. Grain yield was significantly and positively correlated with days to flowering, days to maturity, panicle length, filled grains per panicle, and 1000 grain weight. According to D (2) cluster analysis, 113 test genotypes formed 10 clusters. Selection of parents from the clusters V and X followed by hybridization would possibly result in desirable heterosis for the development of heterotic rice hybrids. Finally, molecular characterizations of the studied germplasm are required for high resolution QTL mapping and validating the presence of candidate genes responsible for valuable characters. PMID- 27127802 TI - Multiagent Systems Based Modeling and Implementation of Dynamic Energy Management of Smart Microgrid Using MACSimJX. AB - The objective of this paper is implementation of multiagent system (MAS) for the advanced distributed energy management and demand side management of a solar microgrid. Initially, Java agent development environment (JADE) frame work is used to implement MAS based dynamic energy management of solar microgrid. Due to unstable nature of MATLAB, when dealing with multithreading environment, MAS operating in JADE is linked with the MATLAB using a middle ware called Multiagent Control Using Simulink with Jade Extension (MACSimJX). MACSimJX allows the solar microgrid components designed with MATLAB to be controlled by the corresponding agents of MAS. The microgrid environment variables are captured through sensors and given to agents through MATLAB/Simulink and after the agent operations in JADE, the results are given to the actuators through MATLAB for the implementation of dynamic operation in solar microgrid. MAS operating in JADE maximizes operational efficiency of solar microgrid by decentralized approach and increase in runtime efficiency due to JADE. Autonomous demand side management is implemented for optimizing the power exchange between main grid and microgrid with intermittent nature of solar power, randomness of load, and variation of noncritical load and grid price. These dynamics are considered for every time step and complex environment simulation is designed to emulate the distributed microgrid operations and evaluate the impact of agent operations. PMID- 27127803 TI - Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing. AB - OBJECTIVES: The present study sought to investigate the mechanisms underlying the mitogenic function of telomerase and to test the hypothesis that everolimus, commonly used on drug-eluting stents, suppresses smooth muscle cells (SMC) proliferation by targeting telomerase. BACKGROUND: Proliferation of SMC during neointima formation is prevented by drug-eluting stents. Although the replicative capacity of mammalian cells is enhanced by telomerase expression, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target remain to be investigated. METHODS: We first employed constitutive expression of telomerase reverse transcriptase (TERT) in cell systems to study transcriptional mechanisms by which telomerase activates a mitogenic program. Second, overexpression of telomerase in mice provided a model to study the role of telomerase as a drug target for the antiproliferative efficacy of everolimus. RESULTS: Inhibition of neointima formation by everolimus is lost in mice overexpressing TERT, indicating that repression of telomerase confers the antiproliferative efficacy of everolimus. Everolimus reduces TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1->S phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Using chromatin immunoprecipitation assays, we finally demonstrate that TERT induces E2F binding to S-phase gene promoters and supports histone acetylation, effects that are inhibited by everolimus and mediate its antiproliferative activity. CONCLUSIONS: These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus. Our studies further identify a novel mitogenic pathway in SMC, which depends on the epigenetic activation of S-phase gene promoters by TERT. PMID- 27127804 TI - Force-Based Puncture Detection and Active Position Holding for Assisted Retinal Vein Cannulation. AB - Retinal vein cannulation is a demanding procedure proposed to treat retinal vein occlusion by direct therapeutic agent delivery methods. Challenges in identifying the moment of venous puncture, achieving cannulation and maintaining cannulation during drug delivery currently limit the feasibility of the procedure. In this study, we respond to these problems with an assistive system combining a handheld micromanipulator, Micron, with a force-sensing microneedle. The integrated system senses the instant of vein puncture based on measured forces and the position of the needle tip. The system actively holds the cannulation device securely in the vein following cannulation and during drug delivery. Preliminary testing of the system in a dry phantom, stretched vinyl membranes, demonstrates a significant improvement in the total time the needle could be maintained stably inside of the vein. This was especially evident in smaller veins and is attributed to decreased movement of the positioned cannula following venous cannulation. PMID- 27127805 TI - Visualization Techniques for the Developing Chicken Heart. AB - We present a geometric surface parameterization algorithm and several visualization techniques adapted to the problem of understanding the 4D peristaltic-like motion of the outflow tract (OFT) in an embryonic chick heart. We illustrated the techniques using data from hearts under normal conditions (four embryos), and hearts in which blood flow conditions are altered through OFT banding (four embryos). The overall goal is to create quantitative measures of the temporal heart-shape change both within a single subject and between multiple subjects. These measures will help elucidate how altering hemodynamic conditions changes the shape and motion of the OFT walls, which in turn influence the stresses and strains on the developing heart, causing it to develop differently. We take advantage of the tubular shape and periodic motion of the OFT to produce successively lower dimensional visualizations and quantifications of the cardiac motion. PMID- 27127807 TI - Simultaneous characterization of protein-material and cell-protein interactions using dynamic QCM-D analysis on SAM surfaces. AB - Understanding the interactions among materials, proteins and cells is critical for the development of novel biomaterials, and establishing a highly sensitive and quantitative method to standardize these interactions is desired. In this study, quartz crystal microbalance with dissipation (QCM-D) combined with microscopy was utilized to quantitatively monitor the entirety of the cell adhesion processes, starting from the protein adsorption, on various self assembled monolayer (SAM) surfaces. Although the resulting cell adhesion morphologies were similar on most of the surfaces, the dynamic QCM-D signal patterns were unique on each surface, suggesting different forms of material protein-cell interactions. The viscoelasticity and the density of the surface adsorbed fibronectin (FN), as well as the relative exposure of the cell adhesive arginine-glycine-aspartic acid (RGD) motifs, were correlated to the different cell adhesion dynamics and mechanics. Some surfaces exhibited complicated behaviors alluding to the detachment/rearrangement of surface proteins or highly sparse but bioactive proteins that promote a slow adhesion process. This study underscores the potential use of the QCM-D signal pattern as a rule of thumb for delineating different protein-material and cell-protein interactions, and offers a rapid in vitro platform for the dynamic evaluation of protein and cell behaviors on novel biomaterials. PMID- 27127806 TI - Fast and single-step immunoassay based on fluorescence quenching within a square glass capillary immobilizing graphene oxide-antibody conjugate and fluorescently labelled antibody. AB - A single-step, easy-to-use, and fast capillary-type immunoassay device composed of a polyethylene glycol (PEG) coating containing two kinds of antibody-reagents, including an antibody-graphene oxide conjugate and fluorescently labelled antibody, was developed in this study. The working principle involved the spontaneous dissolution of the PEG coating, diffusion of reagents, and subsequent immunoreaction, triggered by the capillary action-mediated introduction of a sample solution. In a sample solution containing the target antigen, two types of antibody reagents form a sandwich-type antigen-antibody complex and fluorescence quenching takes place via fluorescence resonance energy transfer between the labelled fluorescent molecules and graphene oxide. Antigen concentration can be measured based on the decrease in fluorescence intensity. An antigen concentration-dependent response was obtained for the model target protein sample (human IgG, 0.2-10 MUg mL(-1)). The present method can shorten the reaction time to within 1 min (approximately 40 s), while conventional methods using the same reagents require reaction times of approximately 20 min because of the large reaction scale. The proposed method is one of the fastest immunoassays ever reported. Finally, the present device was used to measure human IgG in diluted serum samples to demonstrate that this method can be used for fast medical diagnosis. PMID- 27127809 TI - Energy-conserving coarse-graining of complex molecules. AB - Coarse-graining (CG) of complex molecules is a method to reach time scales that would be impossible to access through brute force molecular simulations. In this paper, we formulate a coarse-grained model for complex molecules using first principles caculations that ensures energy conservation. Each molecule is described in a coarse way by a thermal blob characterized by the position and momentum of the center of mass of the molecule, together with its internal energy as an additional degree of freedom. This level of description gives rise to an entropy-based framework instead of the usual one based on the configurational free energy (i.e. potential of mean force). The resulting dynamic equations, which account for an appropriate description of heat transfer at the coarse grained level, have the structure of the dissipative particle dynamics with energy conservation (DPDE) model but with a clear microscopic underpinning. Under suitable approximations, we provide explicit microscopic expressions for each component (entropy, mean force, friction and conductivity coefficients) appearing in the coarse-grained model. These quantities can be computed directly using MD simulations. The proposed non-isothermal coarse-grained model is thermodynamically consistent and opens up a first principles CG strategy for the study of energy transport issues that are not accessible using current isothermal models. PMID- 27127808 TI - Stacking of purines in water: the role of dipolar interactions in caffeine. AB - During the last few decades it has been ascertained that base stacking is one of the major contributions stabilizing nucleic acid conformations. However, the understanding of the nature of the interactions involved in the stacking process remains under debate and it is a subject of theoretical and experimental studies. Structural similarity between purine bases (guanine and adenine) in DNA and the caffeine molecule makes caffeine an excellent model for the purine bases. The present study clearly shows that dipolar interactions play a fundamental role in determining stacking of purine molecules in solution. In order to reach this achievement, polarized ultraviolet Raman resonant scattering experiments have been carried out on caffeine aqueous solutions as a function of concentration and temperature. The investigation pointed out at the aggregation and solvation properties, particularly at elevated temperatures. Kubo-Anderson theory was used as a framework to investigate the non-coincidence effect (NCE) occurring in the totally symmetric breathing modes of the purine rings, and in the bending modes of the methyl groups of caffeine. The NCE concentration dependence shows that caffeine aggregation at 80 degrees C occurs by planar stacking of the hydrophobic faces. The data clearly indicate that dipolar interactions determine the reorientational motion of the molecules in solution and are the driving force for the stacking of caffeine. In parallel, the observed dephasing times imply a change in caffeine interactions as a function of temperature and concentration. A decrease, at low water content, of the dephasing time for the ring breathing vibration mode indicates that self-association alters the solvation structure that is detectable at low concentration. These results are in agreement with simulation predictions and serve as an important validation of the models used in those calculations. PMID- 27127810 TI - Strong electrochemiluminescent interactions between carbon nitride nanosheet reduced graphene oxide nanohybrids and folic acid, and ultrasensitive sensing for folic acid. AB - Graphite-like carbon nitride nanosheets (g-C3N4 NSs) have recently emerged as electrochemiluminescent (ECL) nanomaterials and have attracted more and more attention due to their excellent ECL properties and promising applications in ECL sensing. However, the ECL study of g-C3N4 NSs is still in the early stages. Many studies are required to reveal the exact ECL mechanisms of g-C3N4 NSs and thus boost their sensing applications. In this paper, we have investigated ECL interactions between folic acid (FA) and a g-C3N4 NS/S2O8(2-) ECL system at a g C3N4 NS-reduced graphene oxide (rGO) nanohybrid/glassy carbon electrode in aqueous solutions. Compared with bare g-C3N4 NSs, the nanohybrids of g-C3N4 NS rGO give a much stable ECL emission due to the prevention of over electrochemical reduction of g-C3N4 by rGO. The stable ECL emission from the g-C3N4 NS-rGO/S2O8(2 ) ECL system can be strongly quenched by FA, even in a very low concentration (pM levels). The ECL quenching mechanisms are investigated and discussed in detail. Based on the strong interactions between FA and g-C3N4 NSs, a novel, sensitive, stable and selective ECL sensor has been constructed for the detection of FA, with a wide linear response range from 0.1 to 90 nM, and an excellent detection limit (62 pM). This work not only further clarifies ECL mechanisms of g-C3N4 NSs, but also suggests a promising application of the newly emerging ECL nanomaterial. PMID- 27127811 TI - Fc-fusion mimetics. AB - The Fc-fusion mimetic RpR 2[combining low line] was prepared by disulfide bridging conjugation using PEG in the place of the Fc. RpR 2[combining low line] displayed higher affinity for VEGF than aflibercept. This is caused primarily by a slower dissociation rate, which can prolong a drug at its site of action. RpRs have considerable potential for development as stable, organ specific therapeutics. PMID- 27127812 TI - Dendrimer mediated clustering of bacteria: improved aggregation and evaluation of bacterial response and viability. AB - Here, we evaluate how cationic gallic acid-triethylene glycol (GATG) dendrimers interact with bacteria and their potential to develop new antimicrobials. We demonstrate that GATG dendrimers functionalised with primary amines in their periphery can induce the formation of clusters in Vibrio harveyi, an opportunistic marine pathogen, in a generation dependent manner. Moreover, these cationic GATG dendrimers demonstrate an improved ability to induce cluster formation when compared to poly(N-[3-(dimethylamino)propyl]methacrylamide) [p(DMAPMAm)], a cationic linear polymer previously shown to cluster bacteria. Viability of the bacteria within the formed clusters and evaluation of quorum sensing controlled phenotypes (i.e. light production in V. harveyi) suggest that GATG dendrimers may be activating microbial responses by maintaining a high concentration of quorum sensing signals inside the clusters while increasing permeability of the microbial outer membranes. Thus, the reported GATG dendrimers constitute a valuable platform for the development of novel antimicrobial materials that can target microbial viability and/or virulence. PMID- 27127813 TI - Cancer: Authenticate new xenograft models. PMID- 27127814 TI - Legal aids: Science primers in the courtroom. PMID- 27127815 TI - Biodiversity assessments: IPBES reaches out to social scientists. PMID- 27127817 TI - Archaeology: A different take on Indus evidence. PMID- 27127816 TI - Open hardware: Self-built labware stimulates creativity. PMID- 27127818 TI - Geoffrey Eglinton (1927-2016). PMID- 27127819 TI - Ecology: Change is in the air. PMID- 27127820 TI - Climate science: Misconceptions of global catastrophe. PMID- 27127821 TI - Recent improvement and projected worsening of weather in the United States. AB - As climate change unfolds, weather systems in the United States have been shifting in patterns that vary across regions and seasons. Climate science research typically assesses these changes by examining individual weather indicators, such as temperature or precipitation, in isolation, and averaging their values across the spatial surface. As a result, little is known about population exposure to changes in weather and how people experience and evaluate these changes considered together. Here we show that in the United States from 1974 to 2013, the weather conditions experienced by the vast majority of the population improved. Using previous research on how weather affects local population growth to develop an index of people's weather preferences, we find that 80% of Americans live in counties that are experiencing more pleasant weather than they did four decades ago. Virtually all Americans are now experiencing the much milder winters that they typically prefer, and these mild winters have not been offset by markedly more uncomfortable summers or other negative changes. Climate change models predict that this trend is temporary, however, because US summers will eventually warm more than winters. Under a scenario in which greenhouse gas emissions proceed at an unabated rate (Representative Concentration Pathway 8.5), we estimate that 88% of the US public will experience weather at the end of the century that is less preferable than weather in the recent past. Our results have implications for the public's understanding of the climate change problem, which is shaped in part by experiences with local weather. Whereas weather patterns in recent decades have served as a poor source of motivation for Americans to demand a policy response to climate change, public concern may rise once people's everyday experiences of climate change effects start to become less pleasant. PMID- 27127822 TI - Reply from the Author. PMID- 27127823 TI - Reply from the Author. PMID- 27127824 TI - Non-profit work: Take my advice. PMID- 27127825 TI - Human African trypanosomiasis diagnosis by peripheral blood smear review in a Spanish traveler. PMID- 27127826 TI - Systemic AL amyloidosis associated with Waldenstrom macroglobulinemia: an unusual presenting complication. PMID- 27127827 TI - South Carolina Children's Hospital Collaborative. PMID- 27127828 TI - The Department of Social Services. PMID- 27127829 TI - From the Physicians Foundation: Latest Physicians Foundation White Paper Examines ACA Roll-Out, Offers Perspective on Critical Issues. PMID- 27127830 TI - Formulation and Stability of Solutions. AB - Ready-to-use solutions are the most preferable and most common dosage forms for injectable and topical ophthalmic products. Drugs formulated as solution almost always have chemical and physical stability challenges as well as solubility limitations and the need to prevent inadvertent microbial contamination issues. This article, which takes us through a discussion of optimizing the physical stability of solutions, represents the first of a series of articles discussing how these challenges and issues are addressed. PMID- 27127831 TI - In Situ Observation of Hematite Nanoparticle Aggregates Using Liquid Cell Transmission Electron Microscopy. AB - Aggregation of nanoparticles impacts their reactivity, stability, transport, and fate in aqueous environments, but limited methods are available to characterize structural features and movement of aggregates in liquid. Here, liquid cell transmission electron microscopy (LCTEM) was utilized to directly observe the size, morphology, and motion of aggregates that were composed of 9 and 36 nm hematite nanoparticles, respectively, in water or NaCl solution. When mass concentrations were same, the aggregates of 9 nm nanoparticles were statistically more compact and slightly larger than those of 36 nm nanoparticles. Aggregates in both samples were typically nonspherical. Increasing ionic strength resulted in larger aggregates, and also enhanced the stability of aggregates under electron beam irradiation. In water, small aggregates moved randomly and approached repeatedly to large aggregates before final attachment. In NaCl solution, small aggregates moved directly toward large aggregates and attached to the latter quickly. This observation provided a direct confirmation of the DLVO theory that the energy barrier to aggregation is higher in water than in salt solutions. This study not only presented the influences of particle size and ionic strength on aggregation state, but also demonstrated that LCTEM is a promising method to link aggregation state to dynamic processes of nanoparticles. PMID- 27127832 TI - Reply: The Use of Autologous Fat Grafting for Treatment of Scar Tissue and Scar Related Conditions: A Systematic Review. PMID- 27127833 TI - National Institutes of Health Funding in Plastic Surgery: A Crisis? AB - BACKGROUND: Decreasing funding rates and increasing competition for National Institutes of Health research grants have prompted diverse interventions in various fields of biomedicine. Currently, the state of National Institutes of Health funding for plastic surgery research is poorly understood. The purpose of this study was to describe the portfolio of National Institutes of Health grants in academic plastic surgery. METHODS: Plastic surgery faculty at integrated and independent programs were queried individually in the National Institutes of Health RePORTER database for grants awarded in 2014. Funding totals, mechanisms, and institutes were calculated. Abstracts were categorized by research type and field of interest. Characteristics of National Institutes of Health-funded principal investigators were elucidated. RESULTS: Eight hundred sixty-one academic plastic surgeons at 94 programs were queried, and only 18 investigators (2.1 percent) were funded at 12 programs (12.8 percent). National Institutes of Health-funded investigators were predominately male (72 percent), fellowship trained (61 percent), and aged 49.3 +/- 7.8 years. A total of 20 awards amounted to $6,916,886, with an average award of $345,844 +/- $222,909. Costs were primarily awarded through the R01 mechanism (77.2 percent). The top three National Institutes of Health institutes awarded 72.9 percent of the entire portfolio. Funding supported clinical (41.1 percent), translational (36.9 percent), and basic science (22.0 percent) research. Craniofacial (20.5 percent), hand (18.7 percent), and breast (16.2 percent) had the greatest funding. CONCLUSIONS: Few programs and faculty drive the National Institutes of Health portfolio of plastic surgery research. These data suggest a tenuous funding situation that may be susceptible to future spending cuts. Future research is needed to identify barriers to National Institutes of Health funding procurement in academic plastic surgery. PMID- 27127834 TI - Allergan Style 410 Implants for Breast Reconstruction: A Prospective Study in Efficacy, Safety, and Symmetry. AB - BACKGROUND: Implant-based breast reconstruction is performed with both saline and silicone. In 2001, a study was conducted in which a novel implant made of highly cohesive silicone gel in anatomical shape was used. It differs from others because it holds its anatomical shape and forces tissue to conform to the implant. METHODS: Two hundred twelve consecutive patients who underwent reconstruction with Allergan 410 cohesive gel anatomical implants were enrolled prospectively over a 12-year period. Complications and satisfaction rates were recorded. RESULTS: Average age of the patients was 48.5 years and average body mass index was 24.1 kg/m. Bilateral reconstruction was performed in 83 percent of patients. Long-term follow-up was achieved in all patients and averaged 3.3 years (range, 0.5 to 10.2 years). The overall complication rate was 19.8 percent; most were minor complications, such as rippling (9.4 percent) and asymmetry (4.2 percent). Major complications included infection (2.4 percent), malposition (1.4 percent), capsular contracture (0.9 percent), seroma (0.5 percent), extrusion (0.5 percent), and implant rupture (0.5 percent). The rate of implant-related reoperation, excluding cancer recurrence, was 9.0 percent, consisting of implant replacement (5.7 percent), implant removal (1.9 percent), and implant repositioning (1.4 percent). Patient satisfaction averaged 4.83 (range, 2 to 5) on a five-point scale. Surgeon satisfaction averaged 4.9 (range, 2 to 5). CONCLUSIONS: Allergan 410 cohesive gel anatomical implants have a favorable risk profile in reconstruction, with excellent patient and surgeon satisfaction. This novel implant allows for a paradigm shift in implant-based breast reconstruction. Surgeons can now use an implant to help shape the final contour of the breast mound rather than rely on mastectomy flaps and suture techniques to create aesthetic contours needed to create an attractive breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27127835 TI - Comparison of Allergan, Mentor, and Sientra Contoured Cohesive Gel Breast Implants: A Single Surgeon's 10-Year Experience. PMID- 27127837 TI - Cell-in-Shell Hybrids: Chemical Nanoencapsulation of Individual Cells. AB - Nature has developed a fascinating strategy of cryptobiosis ("secret life") for counteracting the stressful, and often lethal, environmental conditions that fluctuate sporadically over time. For example, certain bacteria sporulate to transform from a metabolically active, vegetative state to an ametabolic endospore state. The bacterial endospores, encased within tough biomolecular shells, withstand the extremes of harmful stressors, such as radiation, desiccation, and malnutrition, for extended periods of time and return to a vegetative state by breaking their protective shells apart when their environment becomes hospitable for living. Certain ciliates and even higher organisms, for example, tardigrades, and others are also found to adopt a cryptobiotic strategy for survival. A common feature of cryptobiosis is the structural presence of tough sheaths on cellular structures. However, most cells and cellular assemblies are not "spore-forming" and are vulnerable to the outside threats. In particular, mammalian cells, enclosed with labile lipid bilayers, are highly susceptible to in vitro conditions in the laboratory and daily life settings, making manipulation and preservation difficult outside of specialized conditions. The instability of living cells has been a main bottleneck to the advanced development of cell-based applications, such as cell therapy and cell-based sensors. A judicious question arises: can cellular tolerance against harmful stresses be enhanced by simply forming cell-in-shell hybrid structures? Experimental results suggest that the answer is yes. A micrometer-sized "Iron Man" can be generated by chemically forming an ultrathin (<100 nm) but durable shell on a "non-spore-forming" cell. Since the report on silica nanoencapsulation of yeast cells, in which cytoprotective yeast-in-silica hybrids were formed, several synthetic strategies have been developed to encapsulate individual cells in a cytocompatible fashion, mimicking the cryptobiotic cell-in-shell structures found in nature, for example, bacterial endospores. Bioinspired silicification and phenolics-based coatings are, so far, the main approaches to the formation of cytoprotective cell-in-shell hybrids, because they ensure cell viability during encapsulations and also generate durable nanoshells on cell surfaces. The resulting cell-in-shell hybrids extrinsically possess enhanced resistance to external aggressors, and more intriguingly, the encapsulation alters their metabolic activity, exemplified by retarded or suppressed cell cycle progression. In addition, recent developments in the field have further advanced the synthetic tools available to the stage of chemical sporulation and germination of mammalian cells, where cytoprotective shells are formed on labile mammalian cells and broken apart on demand. For example, individual HeLa cells are coated with a metal-organic complex of ferric ion and tannic acid, and cellular adherence and proliferation are controlled by the programmed shell formation and degradation. Based on these demonstrations, the (degradable) cell-in-shell hybrids are anticipated to find their applications in various biomedical and bionanotechnological areas, such as cytotherapeutics, high-throughput screening, sensors, and biocatalysis, as well as providing a versatile research platform for single-cell biology. PMID- 27127836 TI - Distraction Osteogenesis for Surgical Treatment of Craniosynostosis: A Systematic Review. AB - BACKGROUND: Distraction osteogenesis has been proposed as an alternative to cranial remodeling surgery for craniosynostosis, but technique descriptions and outcome analyses are limited to small case series. This review summarizes operative characteristics and outcomes of distraction osteogenesis and presents data comparing distraction osteogenesis to cranial remodeling surgery. METHODS: A systematic review of the literature was undertaken. Descriptive analysis, operative technical data, outcomes, or postoperative complications of distraction osteogenesis for craniosynostosis were included. RESULTS: A total of 1325 citations were reviewed, yielding 53 articles and 880 children who underwent distraction osteogenesis for craniosynostosis. Distraction plates were used in 754 patients (86 percent), whereas springs were used for the remaining 126 patients (14 percent). Standard and spring distraction osteogenesis was reported to successfully treat the primary condition 98 percent of the time. Suboptimal results were reported in 11 patients (1.3 percent), and minor complications were reported in 19.5 percent of cases (n = 172).Major complications were rare, occurring in 3.5 percent of cases (n = 31), and included two reported deaths. Absolute operative times and blood loss were marginally greater for cranial remodeling surgery cases, but the differences were not statistically significant. CONCLUSIONS: Distraction osteogenesis is an effective cranial vault remodeling technique for treating craniosynostosis. No statistical differences were found with respect to operative time, blood loss, need for transfusion, or intensive care unit resources compared with cranial remodeling surgery. Outcome studies with longer follow-up periods specifically investigating cost, relapse, and reoperation rates are necessary to effectively compare this treatment modality as an alternative to cranial remodeling surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 27127838 TI - Detection of human adenoviruses in organic fresh produce using molecular and cell culture-based methods. AB - The consumption of organic fresh produce has increased in recent years due to consumer demand for healthy foods without chemical additives. However, the number of foodborne outbreaks associated with fresh produce has also increased. Contamination of food with enteric viruses is a major concern because the viruses have a low infectious dose and high persistence in the environment. Human adenovirus (HAdV) has been proposed as a good marker of faecal contamination. Therefore, the aim of this study was to evaluate the efficiency of the plaque assay (PA), real time PCR (qPCR) and integrated cell culture-RT-qPCR (ICC-RT qPCR) for the recovery of HAdV from artificially and naturally contaminated fresh produce. Organic lettuce, strawberries and green onions were selected because these fresh products are frequently associated with foodborne outbreaks. The virus extraction efficiencies from artificially contaminated samples varied from 2.8% to 32.8% depending on the food matrix and the quantification method used. Although the HAdV recoveries determined by qPCR were higher than those determined by PA and ICC-RT-qPCR, PA was defined as the most reproducible method. The qPCR assays were more sensitive than the PA and ICC-RT-qPCR assays; however, this technique alone did not provide information about the viability of the pathogen. ICC-RT-qPCR was more sensitive than PA for detecting infectious particles in fresh produce samples. HAdV genome copies were detected in 93.3% of the analysed naturally contaminated samples, attesting to the common faecal contamination of the fresh produce tested. However, only 33.3% of the total samples were positive for infectious HAdV particles based on ICC-RT-qPCR. In conclusion, this study reported that HAdV can be an efficient viral marker for fresh produce contamination. Good detection of infectious HAdV was obtained with the ICC-RT qPCR and PA assays. Thus, we suggest that the ICC-RT-qPCR and PA assays should be considered when quantitative microbial risk assessment (QMRA) studies are required and to establish reliable food safety guidelines. PMID- 27127839 TI - Predicting outgrowth and inactivation of Clostridium perfringens in meat products during low temperature long time heat treatment. AB - With low temperature long time (LTLT) cooking it can take hours for meat to reach a final core temperature above 53 degrees C and germination followed by growth of Clostridium perfringens is a concern. Available and new growth data in meats including 154 lag times (tlag), 224 maximum specific growth rates (MUmax) and 25 maximum population densities (Nmax) were used to developed a model to predict growth of C. perfringens during the coming-up time of LTLT cooking. New data were generate in 26 challenge tests with chicken (pH6.8) and pork (pH5.6) at two different slowly increasing temperature (SIT) profiles (10 degrees C to 53 degrees C) followed by 53 degrees C in up to 30h in total. Three inoculum types were studied including vegetative cells, non-heated spores and heat activated (75 degrees C, 20min) spores of C. perfringens strain 790-94. Concentrations of vegetative cells in chicken increased 2 to 3logCFU/g during the SIT profiles. Similar results were found for non-heated and heated spores in chicken, whereas in pork C. perfringens 790-94 increased less than 1logCFU/g. At 53 degrees C C. perfringens 790-94 was log-linearly inactivated. Observed and predicted concentrations of C. perfringens, at the time when 53 degrees C (log(N53)) was reached, were used to evaluate the new growth model and three available predictive models previously published for C. perfringens growth during cooling rather than during SIT profiles. Model performance was evaluated by using mean deviation (MD), mean absolute deviation (MAD) and the acceptable simulation zone (ASZ) approach with a zone of +/-0.5logCFU/g. The new model showed best performance with MD=0.27logCFU/g, MAD=0.66logCFU/g and ASZ=67%. The two growth models that performed best, were used together with a log-linear inactivation model and D53-values from the present study to simulate the behaviour of C. perfringens under the fast and slow SIT profiles investigated in the present study. Observed and predicted concentrations were compared using a new fail-safe acceptable zone (FSAZ) method. FSAZ was defined as the predicted concentration of C. perfringens plus 0.5logCFU/g. If at least 85% of the observed log-counts were below the FSAZ, the model was considered fail-safe. The two models showed similar performance but none of them performed satisfactorily for all conditions. It is recommended to use the models without a lag phase until more precise lag time models become available. PMID- 27127840 TI - Effect of environmental factors on Fusarium population and associated trichothecenes in wheat grain grown in Jiangsu province, China. AB - The present study was performed to identify prevailing Fusarium species and the environmental factors affecting their frequencies and the contamination of grain with major mycotoxins in Jiangsu province. The precipitation levels were 184.2mm, 156.4mm, and 245.8mm in the years 2013-2015, respectively, and the temperature fluctuated by an average of 10.6+/-7.2 degrees C in 2013, 10.9+/-7.2 degrees C in 2014, and 10.6+/-6.3 degrees C in 2015. Co-occurrence of deoxynivalenol (DON), 3 acetyldeoxynivalenol (3ADON), and 15-acetyldeoxynivalenol (15ADON) were observed in wheat. The average concentrations of DON were 879.3+/-1127.8, 627.8+/-640.5, and 1628.6+/-2,168.0MUg/kg in 2013-2015, respectively. The average concentrations of 3ADON were 43.5+/-59.0, 71.2+/-102.5, and 33.5+/-111.9MUg/kg in 2013-2015, respectively. We found that the average concentration of DON in wheat was positively correlated with precipitation (r=0.998, p<0.01), and 3ADON was negatively correlated with precipitation (r=-0.887, p<0.05). However, there was no correlation between precipitation and 15ADON or nivalenol (NIV). The differences in temperature were not as significant as the differences in rainfall amount over a short time period. Therefore, there were no correlations between temperature and the concentrations of trichothecenes, excluding 3ADON (r=0.996, p<0.01). Our data indicated that Fusarium asiaticum is the primary pathogenic fungus prevalent in the Fusarium head blight disease nursery. The trichothecene chemotype composition differed between Fusarium graminearum sensu stricto (s. str.) and F. asiaticum isolates. The 3ADON chemotype was found only among strains of F. asiaticum. The NIV chemotype was not observed among strains of F. graminearum, while the 15ADON chemotype represented 100% of the F. graminearum strains collected. The results of this study indicated no correlations between environmental conditions and the species or genetic chemotype composition of pathogens in Jiangsu province in 2013-2015. PMID- 27127841 TI - A Phase II Study of the Combination of Bevacizumab, Pertuzumab, and Octreotide LAR for Patients with Advanced Neuroendocrine Cancers. AB - PURPOSE: To evaluate efficacy and safety of bevacizumab, pertuzumab, and octreotide depot for advanced neuroendocrine tumors. METHODS: Patients received bevacizumab 15 mg/kg and pertuzumab 420 mg IV q21 days with octreotide depot 30 mg IM q28 days. RESULTS: Toxicities in 43 patients included diarrhea (63%), fatigue (63%), hypertension (44%), and nausea (44%). Reversible G3 hypertension (26%) and LVEF decline (9%) occurred. 7/43 patients achieved objective response (typical carcinoid, 5; pancreatic NET, 2). Median PFS and OS were 6.5 and 26.4 months, respectively. DISCUSSION: Bevacizumab, pertuzumab, and octreotide depot was well-tolerated with a 16% ORR. Results in the well-differentiated carcinoid tumors are thought provoking. PMID- 27127842 TI - Instrument-Free Synthesizable Fabrication of Label-Free Optical Biosensing Paper Strips for the Early Detection of Infectious Keratoconjunctivitides. AB - We introduce a surface-enhanced Raman scattering (SERS)-functionalized, gold nanoparticle (GNP)-deposited paper strip capable of label-free biofluid sensing for the early detection of infectious eye diseases. The GNP biosensing paper strip was fabricated by the direct synthesis and deposition of GNPs on wax divided hydrophilic areas of a permeable porous substrate through a facile, power free synthesizable, and highly reproducible successive ionic layer absorption and reaction (SILAR) technique. To maximize localized surface plasmon resonance generated SERS activity, the concentration of the reactive solution and number of SILAR cycles were optimized by controlling the size and gap distance of GNPs and verified by computational modeling with geometrical hypotheses of Gaussian estimated metallic nanoparticles. The responses of our SERS-functionalized GNP paper strip to Raman intensities exhibited an enhancement factor of 7.8 * 10(8), high reproducibility (relative standard deviation of 7.5%), and 1 pM 2 naphthalenethiol highly sensitive detection limit with a correlation coefficient of 0.99, achieved by optimized SILAR conditions including a 10/10 mM/mM HAuCl4/NaBH4 concentration and six SILAR cycles. The SERS-functionalized GNP paper is supported by a multivariate statistics-preprocessed machine learning judged bioclassification system to provide excellent label-free chemical structure sensitivity for identifying infectious keratoconjunctivitis. The power free synthesizable fabrication, label-free, rapid analysis, and high sensitivity feature of the SILAR-fabricated SERS-functionalized GNP biosensing paper strip makes it an excellent alternative in point-of-care applications for the early detection of various infectious diseases. PMID- 27127843 TI - DNA methylation profiling in different phases of temporomandibular joint osteoarthritis in rats. AB - OBJECTIVE: Temporomandibular joint osteoarthritis (TMJOA) is a complex disease with strong genetic and epigenetic components in its pathogenesis. The aim of this study was to evaluate DNA methylation in mandibular head cartilage in different phases of experimentally-induced TMJOA in rats. DESIGN: DNA methylation was evaluated using microarrays in the mandibular head cartilage of early, intermediate and late stage experimentally-induced TMJOA, and of the normal age matched control groups. Genes with differentially methylated CpG sites were analyzed to reveal the over-represented gene ontologies and pathways at different stages, and were compared with published expression profiles to assess their overlappings. The DNA methylation patterns of the target genes were validated by methylated DNA immunoprecipitation qPCR in additional independent cartilage samples and mRNA levels were analyzed by real-time PCR. RESULTS: We observed 9489 differentially methylated regions between the TMJOA and controls. A total of 440 consistently altered genes were revealed in all three stages; most (80%) were hypomethylated and many were associated with cell cycle regulation. We also detected different DNA methylation changes in early and late stage TMJOA (Rearly=0.68, Rlate=0.47), while the differences between age-matched healthy cartilage were subtle. Strong inverse changes between methylation status and mRNA levels were confirmed in Adamts5, Chad, Cldn11 and Tnf. CONCLUSIONS: Our data reveals dynamic DNA methylation patterns during the progression of TMJOA, with a different host of genes and pathways. The changes of cartilage DNA methylation patterns might contribute to understand the etiologic mechanisms of TMJOA epigenetically. PMID- 27127845 TI - Appearance of trustworthiness: an implicit source of bias in judgments of patients' pain. PMID- 27127844 TI - N-Linked Glycosylation Is Required for Vacuolar H+ -ATPase (V-ATPase) a4 Subunit Stability, Assembly, and Cell Surface Expression. AB - The a subunit is the largest of 14 different subunits that make up the V-ATPase complex. In mammalian species this membrane protein has four paralogous isoforms, a1-a4. Clinically, a subunit isoforms are implicated in diverse diseases; however, little is known about their structure and function. The subunit has conserved, predicted N-glycosylation sites, and the a3 isoform has been directly shown to be N-glycosylated. Here we ask if human a4 (ATP6V0A4) is N-glycosylated at the predicted site, Asn489. We transfected HEK 293 cells, using the pCDNA3.1 expression-vector system, to express cDNA constructs of epitope-tagged human a4 subunit, with or without mutations to eliminate the putative glycosylation site. Glycosylation was characterized also by treatment with endoglycosidases; expression and localization were assessed by immunoblotting and immunofluorescence. Endoglycosidase-treated wild type (WT) a4 showed increased relative mobility on immunoblots, compared with untreated WT a4. This relative mobility was identical to that of unglycosylated mutant a4N489D , demonstrating that the a4 subunit is glycosylated. Cycloheximide pulse-chase experiments showed that the unglycosylated subunit degraded at a higher rate than the N-glycosylated form. Unglycosylated a4 was degraded mostly in the proteasomal pathway, but also, in part, through the lysosomal pathway. Immunofluorescence colocalization data showed that unglycosylated a4 was mostly retained in the ER, and that plasma membrane trafficking was defective. Co-immunoprecipitation studies suggested that a4N489D does not assemble with the V-ATPase V1 domain. Taken together, these data show that N-glycosylation plays a crucial role in a4 stability, and in V-ATPase assembly and trafficking to the plasma membrane. J. Cell. Biochem. 117: 2757 2768, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27127846 TI - Nociceptin/orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons. AB - The nociceptin/orphanin FQ peptide receptor (NOP), activated by its endogenous peptide ligand nociceptin/orphanin FQ (N/OFQ), exerts several effects including modulation of pain signalling. We have examined, for the first time, the tissue distribution of the NOP receptor in clinical visceral and somatic pain disorders by immunohistochemistry and assessed functional effects of NOP and MU-opioid receptor activation in cultured human and rat dorsal root ganglion (DRG) neurons. Quantification of NOP-positive nerve fibres within the bladder suburothelium revealed a remarkable several-fold increase in detrusor overactivity (P < 0.0001) and painful bladder syndrome patient specimens (P = 0.0014) compared with controls. In postmortem control human DRG, 75% to 80% of small/medium neurons (<=50 MUm diameter) in the lumbar (somatic) and sacral (visceral) DRG were positive for NOP, and fewer large neurons; avulsion-injured cervical human DRG neurons showed similar numbers. NOP immunoreactivity was significantly decreased in injured peripheral nerves (P = 0.0004), and also in painful neuromas (P = 0.025). Calcium-imaging studies in cultured rat DRG neurons demonstrated dose dependent inhibition of capsaicin responses in the presence of N/OFQ, with an IC50 of 8.6 pM. In cultured human DRG neurons, 32% inhibition of capsaicin responses was observed in the presence of 1 pM N/OFQ (P < 0.001). The maximum inhibition of capsaicin responses was greater with N/OFQ than MU-opioid receptor agonist DAMGO. Our findings highlight the potential of NOP agonists, particularly in urinary bladder overactivity and pain syndromes. The regulation of NOP expression in visceral and somatic sensory neurons by target-derived neurotrophic factors deserves further study, and the efficacy of NOP selective agonists in clinical trials. PMID- 27127847 TI - Dipeptidyl peptidase-4 inhibitor use is not associated with elevated risk of severe joint pain in patients with type 2 diabetes: a population-based cohort study. AB - This is the first large longitudinal cohort study to investigate the putative association of severe joint pain (SJP) with dipeptidyl peptidase-4 inhibitor (DPP4i) use in patients with type 2 diabetes. The propensity score-matched population-based cohort study was performed between 2009 and 2013 in a group of type 2 diabetes patients with stable metformin use. In total, 4743 patients with type 2 diabetes used a DPP4i as the second-line antidiabetic drug (ie, DPP4i users), and the same number of matched non-DPP4i users was selected. The 2 study groups were followed up until SJP diagnosis (International Classification of Diseases, Ninth Reversion, Clinical Modification code 719.4), health insurance policy termination, or the end of 2013. The incidence rate of SJP was estimated under the Poisson assumption. Multiple Cox proportional hazard model was used to estimate the covariate-adjusted hazard ratio and 95% CI of SJP in association with DPP4i use. Over a maximum follow-up of 5 years, 679 DPP4i users and 767 non DPP4i users were newly diagnosed with SJP, representing incidence rates of 47.20 and 50.66 per 1000 person-years, respectively. Cox proportional hazard model indicated that DPP4i use slightly but nonsignificantly reduced the risk of SJP (adjusted hazard ratio: 0.92 [95% CI: 0.83-1.02]). Such null results were also observed among all age and sex stratifications and in a sensitivity analysis using all nonspecific arthropathies as the study endpoint. This study provides no support for the putative risk of SJP related to DPP4i use in type 2 diabetes patients during a maximum follow-up of 5 years. PMID- 27127848 TI - Presence of Fusarium Species and Other Toxigenic Fungi in Malting Barley and Multi-Mycotoxin Analysis by Liquid Chromatography-High-Resolution Mass Spectrometry. AB - A study was carried out on 43 malting barley samples collected in 2013 across the Umbria region (central Italy) to determine the incidence of the principal mycotoxigenic fungal genera, to identify the Fusarium species isolated from the grains, and to detect the presence of 34 fungal secondary metabolites by liquid chromatography-high-resolution mass spectrometry. The multimycotoxin-method development involved the evaluation of both a two-step solvent and QuEChERS protocol for metabolite extraction. The former protocol was selected because of better accuracy, which was evaluated on the basis of spike-recovery experiments. The most frequently isolated fungal species belonged to the genera Alternaria and Fusarium. The predominant Fusarium species was F. avenaceum, followed by F. graminearum. HT-2 toxin was the most frequently detected mycotoxin, followed by enniatin B, enniatin B1, T-2 toxin, and nivalenol. As a consequence of the observed mixed fungal infections, mycotoxin co-occurrence was also detected. A combination of mycological and mycotoxin analyses allowed the ability to obtain comprehensive information about the presence of mycotoxigenic fungi and their contaminants in malting barley cultivated in a specific geographic area. PMID- 27127849 TI - Quantum Mode Selectivity of Plasmon-Induced Water Splitting on Gold Nanoparticles. AB - Plasmon induced water splitting is a promising research area with the potential for efficient conversion of solar to chemical energy, yet its atomic mechanism is not well understood. Here, ultrafast electron-nuclear dynamics of water splitting on gold nanoparticles upon exposure to femtosecond laser pulses was directly simulated using real time time-dependent density functional theory (TDDFT). Strong correlation between laser intensity, hot electron transfer, and reaction rates has been identified. The rate of water splitting is dependent not only on respective optical absorption strength, but also on the quantum oscillation mode of plasmonic excitation. Odd modes are more efficient than even modes, owing to faster decaying into hot electrons whose energy matches well the antibonding orbital of water. This finding suggests photocatalytic activity can be manipulated by adjusting the energy level of plasmon-induced hot carriers, through altering the cluster size and laser parameter, to better overlap adsorbate unoccupied level in plasmon-assisted photochemistry. PMID- 27127850 TI - Strategies for improving C4 photosynthesis. AB - Recent activities to improve photosynthetic performance in crop plants has focused mainly on C3 photosynthesis where there are clear identified targets such as improving Rubisco kinetics, installation of a CO2 concentrating mechanism and alleviating limitations in chloroplast electron transport. Here we address strategies to improve photosynthetic performance in C4 plants, which utilize a CO2 concentrating mechanism, having evolved a complex blend of anatomy and biochemistry to achieve this. While the limitations to photosynthetic flux are not as well studied in C4 plants, work in transgenic Flaveria bidentis, a transformable model C4 dicot, and recent transcriptional analysis of leaves from diverse C4 plants, provides several gene candidates for improvement of carbon metabolism (such as pyruvate orthophosphate dikinase, phosphoenolpyruvate carboxylase and Rubisco) and for access of CO2 to phosphoenolpyruvate carboxylase in the mesophyll cells (such as carbonic anhydrase and CO2 porins). Chloroplast electron transport in C4 plants is shared between the two cell types, providing opportunities not only to alleviate limitations to flux through intersystem electron transport by targeting nuclear encoded proteins in the cytochrome (Cyt) b6/f complex, but in better sharing the harvesting of light energy between mesophyll and bundle sheath chloroplasts. Gene candidates for improvement of C4 photosynthesis could be utilized either through transgenic approaches or via mining natural allelic variation in sequenced populations of crop species. PMID- 27127851 TI - Healthcare Managers' Perceptions of Patient Perpetrated Aggression and Prevention Strategies: A Cross Sectional Survey. AB - Patient or client aggression towards staff is a risk in healthcare. Healthcare takes place in a variety of settings, including hospitals, community, and Aged Care facilities. A minimal amount is known regarding the existence of safety and training measures available throughout the broad range of hospital and community healthcare services. A web-based survey of the type and frequency of violence experienced by healthcare staff was sent to unit managers working in mental health and older peoples' services of District Health Boards, Non-Governmental Organisations, and Aged Care facilities across New Zealand. One hundred and forty one managers responded to the survey with a response rate of 79.21%. Managers reported high rates of verbal aggression and assaults against staff within their services. A total of 60% of respondents stated that an increase in assaults against staff was due to an increase in violent events and 43.1% related this to increased staff awareness and reporting of violent events to management. Communication skills and de-escalation training were provided across approximately 95% of organisations. The availability of safety measures including panic buttons, personal alarms, use of security personnel, and police assistance were more widely available and accessible within hospital settings and the community sector was found to mostly rely on police for assistance when violence occurs. The perception of violence is high in healthcare. Prevention and management training is provided in public hospital and aged care setting but not so much in NGOs. All areas of healthcare provision could benefit from increased evidence based aggression prevention programmes. PMID- 27127875 TI - Spinal intramedullary hamartoma with acute presentation in a 13-month old infant: case report. AB - True hamartomas of the spinal cord are very rare, and although several have been reported in the literature, there are few detailed radiological and pathological descriptions of the condition. There is also considerable overlap with other entities, the most common being spinal cord teratomas. The authors report the case of a 13-month-old child with a supragluteal sacral dimple who presented with acute neurological deterioration. MRI of the spine revealed a big intramedullary lesion with heterogeneous signal intensity. A near-total resection was performed, and histopathological examination demonstrated findings consistent with a spinal cord hamartoma. The authors believe that careful preoperative evaluation and rigorous pathological examination are mandatory to establish diagnosis and direct further management of cases in which such a lesion is suspected. PMID- 27127876 TI - Kelvin probe force microscopy of DNA-capped nanoparticles for single-nucleotide polymorphism detection. AB - Kelvin probe force microscopy (KPFM) is a robust toolkit for profiling the surface potential (SP) of biomolecular interactions between DNAs and/or proteins at the single molecule level. However, it has often suffered from background noise and low throughput due to instrumental or environmental constraints, which is regarded as limiting KPFM applications for detection of minute changes in the molecular structures such as single-nucleotide polymorphism (SNP). Here, we show KPFM imaging of DNA-capped nanoparticles (DCNP) that enables SNP detection of the BRCA1 gene owing to sterically well-adjusted DNA-DNA interactions that take place within the confined spaces of DCNP. The average SP values of DCNP interacting with BRCA1 SNP were found to be lower than the DCNP reacting with normal (non mutant) BRCA1 gene. We also demonstrate that SP characteristics of DCNP with different substrates (e.g., Au, Si, SiO2, and Fe) provide us with a chance to attenuate or augment the SP signal of DCNP without additional enhancement of instrumentation capabilities. PMID- 27127877 TI - Chromatin dysregulation by mutant p53. PMID- 27127878 TI - FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression. AB - Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC. PMID- 27127880 TI - FOXO3a promotes gastric cancer cell migration and invasion through the induction of cathepsin L. AB - Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E cadherin expression, causing gastric cancer cells to undergo epithelial mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis. PMID- 27127879 TI - S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide. AB - S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-kappaB activity and decreases TNFalpha-induced MMP9 expression. Furthermore, inhibition of the NF-kappaB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-kappaB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-kappaB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer. PMID- 27127881 TI - Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background. AB - Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/ protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high risk classification for a specific population. PMID- 27127882 TI - Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer. AB - Genetic profiling of urine cell free DNA (cfDNA) has not been evaluated in advanced prostate cancer. We performed whole genome sequencing of urine cfDNAs to identify tumor-associated copy number variations in urine before and after initiating androgen deprivation therapy in HSPC stage and docetaxel chemotherapy in CRPC stage. A log2 ratio-based copy number analysis detected common genomic abnormalities in prostate cancer including AR amplification in 5/10 CRPC patients. Other abnormalities identified included TMPRSS2-ERG fusion, PTEN gene deletion, NOTCH1 locus amplification along with genomic amplifications at 8q24.3, 9q34.3, 11p15.5 and 14q11.2, and deletions at 4q35.2, 5q31.3, 7q36.3, 12q24.33, and 16p11.2. By comparing copy number between pre- and post-treatment, we found significant copy number changes in 34 genomic loci. To estimate the somatic tumor DNA fraction in urine cfDNAs, we developed a Urine Genomic Abnormality (UGA) score algorithm that summed the top ten most significant segments with copy number changes. The UGA scores correlated with tumor burden and the change in UGA score after stage-specific therapies reflected disease progression status and overall survival. The study demonstrates the potential clinical utility of urine cfDNAs in predicting treatment response and monitoring disease progression. PMID- 27127883 TI - Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines. AB - Patients with HPV-positive head and neck squamous cell carcinoma (HNSCC) show better survival rates than those with HPV-negative HNSCC. While an enhanced radiosensitivity of HPV-positive tumors is clearly evident from single modality treatment, cisplatin is never administered as monotherapy and therefore its contribution to the enhanced cure rates of HPV-positive HNSCC is not known. Both cisplatin and radiotherapy can cause severe irreversible side effects and therefore various clinical studies are currently testing deintensified regimes for patients with HPV-positive HNSCC. One strategy is to omit cisplatin-based chemotherapy or replace it by less toxic treatments but the risk assessment of these approaches remains difficult. In this study we have compared the cytotoxic effects of cisplatin in a panel of HPV-positive and -negative HNSCC cell lines alone and when combined with radiation.While cisplatin-treated HPV-positive strains showed a slightly stronger inhibition of proliferation, there was no difference regarding colony formation. Cellular responses to the drug, namely cell cycle distribution, apoptosis and gammaH2AX-induction did not differ between the two entities but assessment of cisplatin-DNA-adducts suggests differences regarding the mechanisms that determine cisplatin sensitivity. Combining cisplatin with radiation, we generally observed an additive but only in a minority of strains from both entities a clear synergistic effect on colony formation. In summary, HPV-positive and -negative HNSCC cells were equally sensitive to cisplatin. Therefore replacing cisplatin may be feasible but the substituting agent should be of similar efficacy in order not to jeopardize the high cure rates for HPV-positive HNSCC. PMID- 27127884 TI - Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models. AB - Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and -87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS 754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy. PMID- 27127885 TI - GCGene: a gene resource for gastric cancer with literature evidence. AB - Gastric cancer (GC) is the fifth most common cancer and third leading cause of cancer-related deaths worldwide. Its lethality primarily stems from a lack of detection strategies for early stages of GC and a lack of noninvasive detection strategies for advanced stages. The development of early diagnostic biomarkers largely depends on understanding the biological pathways and regulatory mechanisms associated with putative GC genes. Unfortunately, the GC-implicated genes that have been identified thus far are scattered among thousands of published studies, and no systematic summary is available, which hinders the development of a large-scale genetic screen. To provide a publically accessible resource tool to meet this need, we constructed a literature-based database GCGene (Gastric Cancer Gene database) with comprehensive annotations supported by a user-friendly website. In the current release, we have collected 1,815 unique human genes including 1,678 protein-coding and 137 non-coding genes curated from extensive examination of 3,142 PubMed abstracts. The resulting database has a convenient web-based interface to facilitate both textual and sequence-based searches. All curated genes in GCGene are downloadable for advanced bioinformatics data mining. Gene prioritization was performed to rank the relative relevance of these genes in GC development. The 100 top-ranked genes are highly mutated according to the cohort of published studies we reviewed. By conducting a network analysis of these top-ranked GC-associated genes in the human interactome, we were able to identify strong links between 8 highly connected genes with low expression and patient survival time. GCGene is freely available to academic users at http://gcgene.bioinfo-minzhao.org/. PMID- 27127887 TI - Prognostic significance of cancer family history for patients with gastric cancer: a single center experience from China. AB - Family history of cancer is a risk factor for gastric cancer. In this study, we investigated the prognoses of gastric cancer patients with family history of cancer. A total of 1805 gastric cancer patients who underwent curative gastrectomy from 2000 to 2008 were evaluated. The clinicopathologic parameters and prognoses of gastric cancer patients with a positive family history (PFH) of cancer were compared with those with a negative family history (NFH). Of 1805 patients, 382 (21.2%) patients had a positive family history of cancer. Positive family history of cancer correlated with younger age, more frequent alcohol and tobacco use, worse differentiation, smaller tumor size, and more frequent tumor location in the lower 1/3 of the stomach. The prognoses of patients with a positive family history of cancer were better than that of patients with a negative family history. Family history of cancer independently correlated with better prognosis after curative gastrectomy in gastric cancer patients. PMID- 27127886 TI - Protein kinase D-dependent CXCR4 down-regulation upon BCR triggering is linked to lymphadenopathy in chronic lymphocytic leukaemia. AB - In Chronic Lymphocytic Leukemia (CLL), infiltration of lymph nodes by leukemic cells is observed in patients with progressive disease and adverse outcome. We have previously demonstrated that B-cell receptor (BCR) engagement resulted in CXCR4 down-regulation in CLL cells, correlating with a shorter progression-free survival in patients. In this study, we show a simultaneous down-regulation of CXCR4, CXCR5 and CD62L upon BCR triggering. While concomitant CXCR4 and CXCR5 down-regulation involves PKDs, CD62L release relies on PKC activation. BCR engagement induces PI3K-delta-dependent phosphorylation of PKD2 and 3, which in turn phosphorylate CXCR4 Ser324/325. Moreover, upon BCR triggering, PKD phosphorylation levels correlate with the extent of membrane CXCR4 decrease. Inhibition of PKD activity restores membrane expression of CXCR4 and migration towards CXCL12 in BCR-responsive cells in vitro. In terms of pathophysiology, BCR dependent CXCR4 down-regulation is observed in leukemic cells from patients with enlarged lymph nodes, irrespective of their IGHV mutational status. Taken together, our results demonstrate that PKD-mediated CXCR4 internalization induced by BCR engagement in B-CLL is associated with lymph node enlargement and suggest PKD as a potential druggable target for CLL therapeutics. PMID- 27127889 TI - Current-induced changes of migration energy barriers in graphene and carbon nanotubes. AB - An electron current can move atoms in a nanoscale device with important consequences for the device operation and breakdown. We perform first principles calculations aimed at evaluating the possibility of changing the energy barriers for atom migration in carbon-based systems. In particular, we consider the migration of adatoms and defects in graphene and carbon nanotubes. Although the current-induced forces are large for both the systems, in graphene the force component along the migration path is small and therefore the barrier height is little affected by the current flow. In contrast, the same barrier is significantly reduced in carbon nanotubes as the current increases. Our work also provides a real-system numerical demonstration that current-induced forces within density functional theory are non-conservative. PMID- 27127890 TI - Short-Term Water Deficit Changes Cuticular Sterol Profile in the Eggplant (Solanum melongena). AB - Crop irrigation uses a majority of a total world water supply, at the same time displaying low efficiency. As the expected, future water requirements are higher than the current ones; there is a risk of a growing deficit of water for the agricultural use. Hence, there is an arising need for better understanding the effects of water deprivation on the crop plants. Eggplant (Solanum melongena L.) is a vegetable crop cultivated in arid and semi-arid parts of the world. Because of its high water demands, the eggplant is a convenient model organism for studies concerning the effects of water deficit on the plant growth. The objective of the study was to determine the impact of short-term water deficit on eggplant leaf cuticular waxes and total sterols. Water deprivation did not affect the amount and composition of aliphatic components of cuticular waxes. Significant decrease in the total cuticular sterols and the increase in cuticular cholesterol were observed as an effect of water deficit. In contrast, some of the free internal sterols were more abundant in water-deprived plants. The possible importance of these observations, including increased biosynthesis of defensive compounds and the need to maintain the cell membrane stability, was discussed. PMID- 27127888 TI - Functional networks of aging markers in the glomeruli of IgA nephropathy: a new therapeutic opportunity. AB - IgA nephropathy(IgAN) is the most common primary glomerular disease in China. Primary infections always occur before IgAN. However, the pathology of IgAN is still unclear. Previously we found that LL37, a protein secreted by senescent cells, was specific for the progression of IgAN, and also played a role in the neutrophil function. So we hypothesized that the infiltration of neutrophils, inflammation factors, and aging markers , which were modulated by functional networks, induced the immune response and renal injury. RNA-Sequencing (RNA-seq) can be used to study the whole transcriptome and detect splicing variants that are expressed in a specific cell type or tissue. We separate glomerulus from the renal biopsy tissues. After RNA extraction, the sequences were analyzed with Illumina HiSeq 2000/2500. 381 genes with differential expression between the IgAN patients and the healthy controls were identified. Only PLAU, JUN, and FOS were related to DNA damage, telomere dysfunction-induced aging markers, neutrophil function and IgA nephropathy. The networks showed the possibility of these genes being connected. We conclude that DNA damage and telomere dysfunction could play important roles in IgA nephropathy. In addition, neutrophils are also important factors in this disease. The networks of these markers showed the mechanism pathways that are involved in the duration of the occurrence and progression of IgA nephropathy and might be a new therapeutic opportunity for disease treatment. PMID- 27127892 TI - Social choice functions: A tool for ranking variables involved in action plans against road noise. AB - Traffic noise is gaining importance in planning and operation of roads in developing countries, and particularly in Europe and Latin America. Many variables with different degrees of importance influence the perception of noise from roads. Thus, the problem of prioritizing road stretches for action against such noise is an important issue in environmental noise management. For example, it can be addressed using multicriteria methods. However, these methodologies require criteria or suitable variables to be ranked according to their relative importance. In the present study, for this ranking, a list of nine variables involved in the decision-making process (called "road stretch priority variables") was presented in the form of questionnaires to high-level experts from Andalusia, southern Spain. These experts ranked the variables by relevance. Using the same data, seven social choice functions (Plurality, Raynaud, Kemeny Young, Copeland, Simpson, Schulze, and Borda) were used in order to rank the variables. The results indicate that the most important variables were those that take into account the parameters of greatest exposure for the citizens, followed by variables related to the intensity of the problem analyzed. The results show that a combination of the use of social choice functions on aggregated information from expert panels can provide a consensus for ranking priority variables related to road stretches. PMID- 27127891 TI - Association Between CHRNA3 and CHRNA5 Nicotine Receptor Subunit Gene Variants and Nicotine Dependence in an Isolated Populationof Kashubians in Poland. AB - BACKGROUND Genome-wide and allelic association studies have shown the contribution of CHRNA5-A3-B4 nicotinic receptor subunit gene cluster within chromosome 15 to nicotine dependence (ND). While an association between several single-nucleotide polymorphisms (SNPs) at that locus and smoking quantity (cigarettes per day; CPD) has been well recognized, there are some inconsistencies in demonstrating the influence of these SNPs on other ND phenotypes. This uncertainty motivated us to examine the association of 3 selected SNPs (CHRNA3 rs1051730, rs6495308, and CHRNA5 rs55853898) with ND in an isolated population of Kashubians from Poland. MATERIAL AND METHODS The study sample consisted of 788 current daily smokers. ND was assessed by CPD, the Fagerstrom Test for Nicotine Dependence (FTND), its brief version - Heavy Smoking Index (HSI), and time to first cigarette after waking (TTF). The correlation between studied SNPs and dichotomized values of ND measures was assessed in the regression analysis. Bonferroni corrected p-value of 0.017 was set for a type 1 error. RESULTS We found a robust association between risk allele A of rs1051730 and CPD >10 (odds ratio (OR)=1.77, 95% confidence interval (CI): 1.20-2.59, p=0.004), and a weak association, which did not survive correction for multiple testing, with FTND 34. No associations between studied SNPs and HSI or TTF were demonstrated. CONCLUSIONS Our findings confirm that rs1051730 influences ND phenotype, as defined by CPD. PMID- 27127893 TI - Occurrence and removal of antibiotics in ecological and conventional wastewater treatment processes: A field study. AB - The occurrence and removal of 19 antibiotics (including four macrolides, eight sulfonamides, three fluoroquinolones, three tetracyclines, and trimethoprim) were investigated in two ecological (constructed wetland (CW) and stabilization pond (SP)) and two conventional wastewater treatment processes (activated sludge (AS) and micro-power biofilm (MP)) in a county of eastern China. All target antibiotics were detected in the influent and effluent samples with detection frequencies of >90%. Clarithromycin, ofloxacin, roxithromycin and erythromycin H2O were the dominant antibiotics with maximum concentrations reaching up to 6524, 5411, 964 and 957 ng/L, respectively; while the concentrations of tiamulin, sulfamerazine, sulfathiazole, sulfamethazine, sulfamethizole and sulfisoxazole were below 10 ng/L. Although the mean effluent concentrations of target antibiotics were obviously lower than the influent ones (except ciprofloxacin), their removals were usually incomplete. Principal component analysis showed that the AS and CW outperformed the MP and SP processes and the AS performed better than the CW process in terms of antibiotics removal. Both the AS and CW processes exhibited higher removal efficiencies in summer than in winter, indicating biological degradation could play an important role in antibiotics removal. Because of the incomplete removal, the total concentration of detected antibiotics increased in the mixing and downstream sections of a local river receiving the effluent from a typical wastewater treatment facility practicing AS process. Nowadays, ecological wastewater treatment processes are being rapidly planned and constructed in rural areas of China; however, the discharge of residual antibiotics to the aquatic environment may highlight a necessity for optimizing or upgrading their design and operation. PMID- 27127894 TI - Texture based classification of the severity of mitral regurgitation. AB - Clinically, the severity of valvular regurgitation is assessed by manual tracing of the regurgitant jet in the respective chambers. This work presents a computer aided diagnostic (CAD) system for the assessment of the severity of mitral regurgitation (MR) based on image processing that does not require the intervention of the radiologist or clinician. Eight different texture feature sets from the regurgitant area (selected through an arbitrary criterion) have been used in the present approach. First order statistics have been used initially, however, observing their limitations, the other texture features such as spatial gray level difference matrix, gray level difference statistics, neighborhood gray tone difference matrix, statistical feature matrix, Laws' textures energy measure, fractal dimension texture analysis and Fourier power spectrum have additionally been used. For the classification task a supervised classifier i.e., support vector machine has been used in the present approach. The classification accuracy has been improved significantly by using these texture features in combination, in comparison to when fed individually as input to the classifier. The classification accuracy of 95.65+/-1.09, 95.65+/-1.09 and 95.36+/-1.13 has been obtained in apical two chamber, apical four chamber and parasternal long axis views, respectively. Therefore, the results of this paper indicate that the proposed CAD system may effectively assist the radiologists in establishing (confirming) the MR stages, namely, mild, moderate and severe. PMID- 27127895 TI - A flexible data-driven comorbidity feature extraction framework. AB - Disease and symptom diagnostic codes are a valuable resource for classifying and predicting patient outcomes. In this paper, we propose a novel methodology for utilizing disease diagnostic information in a predictive machine learning framework. Our methodology relies on a novel, clustering-based feature extraction framework using disease diagnostic information. To reduce the data dimensionality, we identify disease clusters using co-occurrence statistics. We optimize the number of generated clusters in the training set and then utilize these clusters as features to predict patient severity of condition and patient readmission risk. We build our clustering and feature extraction algorithm using the 2012 National Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP) which contains 7 million hospital discharge records and ICD-9-CM codes. The proposed framework is tested on Ronald Reagan UCLA Medical Center Electronic Health Records (EHR) from 3041 Congestive Heart Failure (CHF) patients and the UCI 130-US diabetes dataset that includes admissions from 69,980 diabetic patients. We compare our cluster-based feature set with the commonly used comorbidity frameworks including Charlson's index, Elixhauser's comorbidities and their variations. The proposed approach was shown to have significant gains between 10.7-22.1% in predictive accuracy for CHF severity of condition prediction and 4.65-5.75% in diabetes readmission prediction. PMID- 27127896 TI - Fullerene-Assisted Photoinduced Charge Transfer of Single-Walled Carbon Nanotubes through a Flavin Helix. AB - One of the greatest challenges with single-walled carbon nanotube (SWNT) photovoltaics and nanostructured devices is maintaining the nanotubes in their pristine state (i.e., devoid of aggregation and inhomogeneous doping) so that their unique spectroscopic and transport characteristics are preserved. To this effect, we report on the synthesis and self-assembly of a C60-functionalized flavin (FC60), composed of PCBM and isoalloxazine moieties attached on either ends of a linear, C-12 aliphatic spacer. Small amounts of FC60 (up to 3 molar %) were shown to coassembly with an organic soluble derivative of flavin (FC12) around SWNTs and impart effective dispersion and individualization. A key annealing step was necessary to perfect the isoalloxazine helix and expel the C60 moiety away from the nanotubes. Steady-state and transient absorption spectroscopy illustrate that 1% or higher incorporation of FC60 allows for an effective photoinduced charge transfer quenching of the encased SWNTs through the seamless helical encase. This is enabled via the direct pi-pi overlap between the graphene sidewalls, isoalloxazine helix, and the C60 cage that facilitates SWNT exciton dissociation and electron transfer to the PCBM moiety. Atomistic molecular simulations indicate that the stability of the complex originates from enhanced van der Waals interactions of the flexible spacer wrapped around the fullerene that brings the C60 in pi-pi overlap with the isoalloxazine helix. The remarkable spectral purity (in terms of narrow E(S)ii line widths) for the resulting ground-state complex signals a new class of highly organized supramolecular nanotube architecture with profound importance for advanced nanostructured devices. PMID- 27127897 TI - Reply: High Seroprevalence of Hepatitis B in Children With Cancer in India is not Related to Transfusions or Hospital Admissions. PMID- 27127898 TI - From one to two: the effect of women and the economy on China's One Child Policy. PMID- 27127899 TI - BFS Annual Meeting 2016. PMID- 27127900 TI - Society Pages for March 2016 issue. PMID- 27127901 TI - Corrigendum. PMID- 27127902 TI - Retinal Neovascularisation in Susac Syndrome: A Rare Complication. AB - PURPOSE: To report a case of Susac syndrome with ocular complications in the chronic stage of the disease. METHODS: Case report. RESULTS: A 37-year-old male patient of Indian origin presented with painless blurring of vision in the right eye. Ophthalmoscopic examination revealed vitreous hemorrhage in the right eye and NVE in both eyes well-documented angiographically. Old medical records revealed a previous attack of bilateral BRAO as a complete triad of Susac syndrome 10 years before, with an uncomplicated clinical course. Panretinal photocoagulation helped in stabilization of the condition. CONCLUSION: Ocular neovascularisation like NVE with vitreous hemorrhage can be a late manifestation of occlusive arteriolitis in Susac syndrome. PMID- 27127903 TI - Burnout Syndrome Among Medical Students at One University in Serbia: Validity and Reliability of the Maslach Burnout Inventory-Student Survey. AB - The Maslach Burnout Inventory-Student Survey (MBI-SS) contains 15 items that evaluate the following burnout dimensions: Emotional Exhaustion, Cynicism, and Academic Efficacy. The purpose of this study was to evaluate the dimensionality of the MBI-SS on a sample of Serbian medical students (N = 760). The overall Cronbach's alpha coefficient of the MBI-SS questionnaire was 0.757, while the Cronbach's alpha coefficients for Emotional Exhaustion, Cynicism, and Academic Efficacy were 0.869, 0.856, and 0.852, respectively. Principal Component Analysis with Oblimin rotation indicated 3 main components that explained 64.9% variance. The confirmatory factor analysis revealed good fit indices (chi2/df = 575.74/87, RMSEA = 0.086 (90% Confidence Interval for RMSEA = 0.079 to 0.092), CFI = 0.949, NNFI = 0.939, IFI = 0.949, GFI = 0.904) of the MBI-SS scale. The Serbian version of MBI-SS represents a valid and reliable instrument in the Serbian sample of medical students. PMID- 27127904 TI - In vivo induction of neutrophil chemotaxis by secretory aspartyl proteinases of Candida albicans. AB - Secretory aspartyl proteinases (Saps) of Candida albicans are key virulence traits which cause inflammasome-dependent, aseptic inflammation in a mouse model of vaginitis. In this paper, neutrophil migration in response to Sap2, Sap6 and chemo-attractive products released from Sap-treated vaginal epithelium was measured in vitro, ex vivo and in vivo. Our results show that Sap2 and Sap6 induce neutrophil migration and production of potent chemoattractive chemokines such as IL-8 and MIP-2 by vaginal epithelial cells. Our data suggest that at least part of MIP-2 production depends upon IL-1beta activity. The vaginal fluid of Candida-infected mice contained a heat-labile inhibitor of neutrophil candidacidal activity that was absent from the vaginal fluid of Sap-treated mice. Overall, our data provide additional information on the capacity of C. albicans Saps to cause aseptic vaginal inflammation and highlight the potential role of some chemokines released from vaginal epithelial cells in this phenomenon. PMID- 27127906 TI - Mixed Electronic and Ionic Conductor-Coated Cathode Material for High-Voltage Lithium Ion Battery. AB - A lithium ionic conductor, Li1.3Al0.3Ti1.7(PO4)3 (LATP), is introduced as a coating material on the surface of Mg-doped LiCoO2 to improve electrochemical performances for high-voltage (4.5 V) lithium ion batteries. Structure, morphology, elemental distribution, and electrical properties of the materials are thoroughly characterized by SEM, TEM, EELS, EDS, and C-AFM. The coating layer is electrically conductive with the aid of Mg ions which are used as a dopant for the active materials; therefore, this mixed electronic ionic conductor strongly enhances the electrochemical performances of initial capacity, cycling property, and rate capability. The LATP coating layer also demonstrates very promising applicability for 4.4 V prismatic full cells with graphite anode, which correspond to the 4.5 V half-cells with lithium anode. The 2900 mA h full cells show 85% of capacity retention after 500 cycles and more than 60% after 700 cycles. PMID- 27127907 TI - Intramolecular Hydrogen-Bonding Effects on the Fluorescence of PRODAN Derivatives. AB - The effects of intramolecular hydrogen-bonding on the fluorescence behavior of three derivatives of 6-propionyl-2-dimethylaminonaphthalene are reported. The H bonding effects are revealed through comparisons with corresponding reference compounds in which the H-bond-donating hydroxyl groups are replaced with methoxy groups. In toluene, intramolecular H bonding gives rise to a dramatic increase in the fluorescence intensity but only a slight red shift in the position. This behavior is attributed to decreased efficiency in intersystem crossing due to an increase in the energy of the n -> pi* triplet state. The intramolecular H bond does not induce quenching in acetonitrile; however, in the presence of a very small concentration of methanol, a dual intramolecular, intermolecular H-bonding arrangement does lead to partial quenching as revealed by preferential solvation studies. PMID- 27127905 TI - Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials. AB - Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first line treatment during the 2008-2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43-86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score >=7), and 140 (50.2%) had creatinine clearance <=70 ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS >=7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity <80% were independently associated with shorter PFS. Grade III or IV neutropenia, thrombocytopenia, and anaemia were observed in 25.9%, 15.4%, and 15.1% of patients, respectively. Twenty-four patients (8.6%) had severe infections. BR is also an effective and safe regimen for untreated CLL patients, outside of controlled clinical trials. PMID- 27127908 TI - Adsorption behavior and mechanism of perfluorooctane sulfonate on nanosized inorganic oxides. AB - Adsorption of perfluorooctane sulfonate (PFOS) on manufactured nanoparticles (NPs) is critical for understanding their transport and fate in aquatic environments. In this study, the adsorption behavior of PFOS on nanosized Al2O3, Fe2O3, SiO2 and TiO2 was examined in terms of adsorption isotherms and influences of pH, ionic strength and heavy metallic cations. The nano-oxides had much higher adsorption capacities than bulk particles due to higher surface hydroxyl density. PFOS adsorption showed strong pH dependence due to different species of surface hydroxyl groups on nano-oxides. Besides electrostatic interaction, sulfonic group of PFOS possibly formed hydrogen bonds on the surface of nano-oxides. Because of the bridging effect in the co-adsorption process, the coexisting PFOS and heavy metallic cations greatly enhanced their adsorption onto the nano-oxides. Comparative adsorption of different perfluorinated sulfonates indicated the possible formation of bilayer PFOS adsorption on the nano-oxides, leading to the enhanced Cu(II) adsorption on the sulfonic groups of PFOS on the surfaces through electrostatic interaction. PMID- 27127910 TI - Circulatory effect of TCS-80, a new imidazoline compound, in rats. AB - BACKGROUND: Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1 [(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I1-imidazoline receptors and the lowest alpha2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through alpha2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether alpha2-adrenergic and/or I1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. METHODS: Anesthetized rats were infused iv with the tested compounds and selective alpha2-adrenoceptor antagonist, RX821002, or nonselective alpha2-adrenergic/I1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. RESULTS: Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. CONCLUSION: Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the alpha2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the alpha2-adrenergic ones. PMID- 27127911 TI - l-NAME differential effects on diazepam and flunitrazepam responses of rats in the object recognition test. AB - BACKGROUND: The present study was undertaken to better understand possible interaction(s) between a non-selective nitric oxide inhibitor: N(G)-nitro-l arginine methyl ester (l-NAME) and benzodiazepines (BZs) in recognition memory. METHODS: The study was carried out on adult male albino Wistar rats. A novel object recognition (NOR) task was used to evaluate memory process. RESULTS: Combined administration of l-NAME (50mg/kg, ip) with a threshold dose of DZ (0.25mg/kg) induced amnesic effects in rats, participating in the NOR test. On the other hand, following a combined administration of l-NAME (100mg/kg, ip) with flunitrazepam (FNZ; 0.1mg/kg), it was found out that l-NAME inhibited the amnesic effects of FNZ on rats in the NOR test. CONCLUSIONS: The obtained results suggest that suppressed NO synthesis may lead to a facilitation of DZ-induced memory impairment but surprisingly may prevent amnesic effect after FNZ in rats, submitted to NOR task. PMID- 27127909 TI - Cortical Bone Morphological and Trabecular Bone Microarchitectural Changes in the Mandible and Femoral Neck of Ovariectomized Rats. AB - OBJECTIVE: This study used microcomputed tomography (micro-CT) to evaluate the effects of ovariectomy on the trabecular bone microarchitecture and cortical bone morphology in the femoral neck and mandible of female rats. MATERIALS AND METHODS: Twelve female Wister rats were divided into two groups: the control and ovariectomized groups. The rats in the ovariectomized group received ovariectomy at 8 weeks of age; all the rats were sacrificed at 20 weeks of age, and their mandibles and femurs were removed and scanned using micro-CT. Four microstructural trabecular bone parameters were measured for the region below the first mandibular molar and the femoral neck region: bone volume fraction (BV/TV), trabecular thickness (TbTh), trabecular separation (TbSp), and trabecular number (TbN). In addition, four cortical bone parameters were measured for the femoral neck region: total cross-sectional area (TtAr), cortical area (CtAr), cortical bone area fraction (CtAr/TtAr), and cortical thickness (CtTh). The CtTh at the masseteric ridge was used to assess the cortical bone morphology in the mandible. The trabecular bone microarchitecture and cortical bone morphology in the femoral necks and mandibles of the control group were compared with those of the ovariectomized group. Furthermore, Spearman's correlation (rs) was conducted to analyze the correlation between the osteoporosis conditions of the mandible and femoral neck. RESULTS: Regarding the trabecular bone microarchitectural parameters, the BV/TV of the trabecular bone microarchitecture in the femoral necks of the control group (61.199+/-11.288%, median +/- interquartile range) was significantly greater than that of the ovariectomized group (40.329+/-5.153%). Similarly, the BV/TV of the trabecular bone microarchitecture in the mandibles of the control group (51.704+/-6.253%) was significantly greater than that of the ovariectomized group (38.486+/-9.111%). Furthermore, the TbSp of the femoral necks in the ovariectomized group (0.185+/-0.066 mm) was significantly greater than that in the control group (0.130+/-0.026mm). Similarly, the TbSp of the mandibles in the ovariectomized group (0.322+/-0.047mm) was significantly greater than that in the control group (0.285+/-0.041mm). However, the TbTh and TbN trends for the mandibles and femoral necks were inconsistent between the control and ovariectomized groups. Regarding the cortical bone morphology parameters, the TtAr of the femoral necks in the ovariectomized group was significantly smaller than that in the control group. There was no significant difference in the TtAr, CtAr, or CtTh of the femoral necks between the control and ovariectomized groups, and no significant difference in the CtTh of the mandibles between the control and ovariectomized groups. Moreover, the BV/TV and TbSp of the mandibles were highly correlated with those of the femurs (rs = 0.874 and rs = 0.755 for BV/TV and TbSp, respectively). Nevertheless, the TbTh, TbN, and CtTh of the mandibles were not correlated with those of the femoral necks. CONCLUSION: After the rats were ovariectomized, osteoporosis of the trabecular bone microarchitecture occurred in their femurs and mandibles; however, ovariectomy did not influence the cortical bone morphology. In addition, the parametric values of the trabecular bone microarchitecture in the femoral necks were highly correlated with those of the trabecular bone microarchitecture in the mandibles. PMID- 27127912 TI - Pharmacokinetics of paracetamol in patients with chronic pancreatitis. AB - BACKGROUND: Chronic pancreatitis (CP) is a progressive, irreversible disease causing damage of the gland. Abdominal pains are a typical symptom of pancreatitis both in the chronic and acute form. Paracetamol is one of analgesics used for treating mild or moderate pain. Functional and anatomical changes in the gastrointestinal tract caused by pancreatitis may influence on the pharmacokinetics of administered drugs. METHODS: In the present study we analysed the pharmacokinetics of paracetamol after oral and intravenous administration to patients with CP. The patients were allocated to one of the two groups of the drug under study: I iv, intravenous administration of paracetamol 1000mg (n=17; mean [SD] age, 46.18 [13.78] years; and BMI, 22.03 [2.62]kg/m(2)) and II po, oral administration of paracetamol 1000mg (n=17; mean [SD] age, 48.29 [10.08] years; and BMI, 22.50 [2.92]kg/m(2). The plasma concentrations of paracetamol and its metabolite (glucuronide) were measured with the validated high-pressure liquid chromatography (HPLC) method with ultraviolet (UV) detection. RESULTS: The main pharmacokinetic parameters for paracetamol after iv and po administration to patients with CP were as follows: Cmax, 19.00 [4.50] and Cmax, 9.26 [3.35]MUg/ml; AUC0-t, 42.37 [13.92] and 36.68 [11.7]MUg*h/mL, respectively. After iv and po administration the AUC ratio between the metabolite (glucuronide) and paracetamol was enhanced. CONCLUSIONS: The research findings revealed that patients with chronic pancreatitis had lower concentrations of paracetamol. Therefore, it may be necessary to apply additional analgesic therapy. Moreover, we observed enhanced glucuronidation in our patients. PMID- 27127913 TI - A Single-Center 10-Year Experience with Pasireotide in Cushing's Disease: Patients' Characteristics and Outcome. AB - Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing's disease (CD). Our 10-year experience with pasireotide in CD is reported here. Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor((r)); Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months). Urinary free cortisol (UFC) levels mean percentage change (+/- SD) at last follow-up was-40.4% (+/- 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients. Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients. PMID- 27127915 TI - Global and regional lung function in cystic fibrosis measured by electrical impedance tomography. AB - BACKGROUND: Electrical impedance tomography (EIT) delivers information about global and regional ventilation. Linearity of EIT during tidal breathing is known. We investigated the feasibility of EIT during lung function tests in pediatric patients with cystic fibrosis (CF) and healthy controls. METHODS: Eleven CF patients and 11 age-matched controls underwent spirometry and simultaneous EIT. Global EIT results were scaled to spirometric forced vital capacity (FVC). Subsequently, global and regional "EIT-spirometry" was calculated and correlated with clinical findings, radiology, and lung function results before and after bronchospasmolysis (BSL). RESULTS: Spirometry and global EIT results correlated essentially (r2 = 0.71-1.0, P < 0.001). While lung function results were comparable for both groups, EIT demonstrated inhomogeneous ventilation and individual changes after BSL. CONCLUSIONS: EIT changes during forced expiration correlate with lung function parameters, clinical findings, and radiology. Regional analysis of EIT illustrates regional lung function and visualizes individual therapeutic effects. Pediatr Pulmonol. 2016;51:1191-1199. (c) 2016 Wiley Periodicals, Inc. PMID- 27127916 TI - Probing Exciton Diffusion and Dissociation in Single-Walled Carbon Nanotube-C(60) Heterojunctions. AB - The efficiency of thin-film organic photovoltaic (OPV) devices relies heavily upon the transport of excitons to type-II heterojunction interfaces, where there is sufficient driving force for exciton dissociation and ultimately the formation of charge carriers. Semiconducting single-walled carbon nanotubes (SWCNTs) are strong near-infrared absorbers that form type-II heterojunctions with fullerenes such as C60. Although the efficiencies of SWCNT-fullerene OPV devices have climbed over the past few years, questions remain regarding the fundamental factors that currently limit their performance. In this study, we determine the exciton diffusion length in the C60 layer of SWCNT-C60 bilayer active layers using femtosecond transient absorption measurements. We demonstrate that hole transfer from photoexcited C60 molecules to SWCNTs can be tracked by the growth of narrow spectroscopic signatures of holes in the SWCNT "reporter layer". In bilayers with thick C60 layers, the SWCNT charge-related signatures display a slow rise over hundreds of picoseconds, reflecting exciton diffusion through the C60 layer to the interface. A model based on exciton diffusion with a Beer Lambert excitation profile, as well as Monte Carlo simulations, gives the best fit to the data as a function of C60 layer thickness using an exciton diffusion length of approximately 5 nm. PMID- 27127918 TI - Dementia after Cardiac Surgery: Is It the Procedure or the Patient? PMID- 27127917 TI - Pharmacometabolomics in Early-Phase Clinical Development. PMID- 27127919 TI - Prevalence of Dementia 7.5 Years after Coronary Artery Bypass Graft Surgery. AB - BACKGROUND: Although postoperative cognitive dysfunction (POCD) is well described after coronary artery bypass graft (CABG) surgery, a major concern has been that a progressive decline in cognition will ultimately lead to dementia. Since dementia interferes with the ability to carry out daily functions, the impact has far greater ramifications than cognitive decline defined purely by a decreased ability to perform on a battery of neurocognitive tests. The authors hypothesized that early cognitive impairment measured as baseline cognitive impairment is associated with an increased risk of long-term dementia. METHODS: The authors conducted a prospective longitudinal study on 326 patients aged 55 yr and older at the time of undergoing CABG surgery. Dementia was classified by expert opinion on review of performance on the Clinical Dementia Rating Scale and several other assessment tasks. Patients were also assessed for POCD at 3 and 12 months and at 7.5 yr using a battery of neuropsychologic tests and classified using the reliable change index. Associations were assessed using univariable analysis. RESULTS: At 7.5 yr after CABG surgery, the prevalence of dementia was 36 of 117 patients (30.8%; 95% CI, 23 to 40). POCD was detected in 62 of 189 patients (32.8%; 95% CI, 26 to 40). Due to incomplete assessments, the majority (113 patients), but not all, were assessed for both dementia and POCD. Fourteen of 32 (44%) patients with dementia were also classified as having POCD. Preexisting cognitive impairment and peripheral vascular disease were both associated with dementia 7.5 yr after CABG surgery. POCD at both 3 (odds ratio, 3.06; 95% CI, 1.39 to 9.30) and 12 months (odds ratio, 4.74; 95% CI, 1.63 to 13.77) was associated with an increased risk of mortality by 7.5 yr. CONCLUSIONS: The prevalence of dementia at 7.5 yr after CABG surgery is greatly increased compared to population prevalence. Impaired cognition before surgery or the presence of cardiovascular disease may contribute to the high prevalence. PMID- 27127920 TI - Faecal bacterial composition in dairy cows shedding Mycobacterium avium subsp. paratuberculosis in faeces in comparison with nonshedding cows. AB - The aim of this study was to determine possible differences in the faecal microbiota of dairy cows infected with Mycobacterium avium subsp. paratuberculosis (Johne's disease) in comparison with noninfected cows from the same herds. Faecal samples from cows in 4 herds were tested for M. avium subsp. paratuberculosis by real-time PCR, and faecal bacterial populations were analysed by 454 pyrosequencing of the 16S rRNA gene. The most notable differences between shedding and nonshedding cows were an increase in the genus Psychrobacter and a decrease in the genera Oscillospira, Ruminococcus, and Bifidobacterium in cows infected with M. avium subsp. paratuberculosis. The present study is the first to report the faecal microbial composition in dairy cows infected with M. avium subsp. paratuberculosis. PMID- 27127921 TI - Transcriptome analysis of bovine oocytes from distinct follicle sizes: Insights from correlation network analysis. AB - Follicle size is recognized as a predictor of the potential for the enclosed oocyte to yield an embryo following in vitro maturation and in vitro fertilization. Oocytes from larger follicles are more likely to reach the blastocyst stage than those from smaller follicles. A growing oocyte accumulates all the transcripts needed to ensure development until the maternal embryonic transition, and this accumulation must be completed before the period of transcriptional arrest. Accordingly, the transcriptomes of bovine germinal vesicle-stage oocytes collected from follicles of increasing sizes (<3, 3-5, >5 8, and >8 mm) were evaluated, using the EmbryoGENE bovine transcriptomic platform (custom Agilent 4 * 44 K), to better understand transcriptional modulation in the oocyte as the follicle becomes larger. Microarray analyses revealed very few differences between oocytes from small follicles (<3 vs. 3-5 mm), whereas an important number of differences were detected at the mRNA level between oocytes from larger follicles. Weighted gene correlation network analysis allowed for the identification of several hub genes involved in crucial functions such as transcriptional regulation (TAF2), chromatin remodeling (PPP1CB), energy production (SLC25A31), as well as transport of key molecules within the cell (NAGPA, CYHR1, and SLC3A12). The results presented here thus reinforce the hypothesis that developmental competence acquisition cannot be seen as a simple one-step process, especially in regards to the modulation of mRNA. Mol. Reprod. Dev. 83: 558-569, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27127922 TI - Mechanistic Aspects of the Palladium-Catalyzed Isomerization of Allenic Sulfones to 1-Arylsulfonyl 1,3-Dienes. AB - When an allenic sulfone is treated under palladium catalysis in the presence of a weak acid, isomerization to a 1-arylsulfonyl 1,3-diene occurs. Investigations of the mechanistic aspects of this isomerization were performed, leading to the mechanism proposed herein. Some further studies of reaction parameters are reported. PMID- 27127923 TI - Electrokinetic treatment of an agricultural soil contaminated with heavy metals. AB - The high organic matter content in agricultural soils tends to complex and retain contaminants such as heavy metals. Electrokinetic remediation was tested in an agricultural soil contaminated with Co(+2), Zn(+2), Cd(+2), Cu(+2), Cr(VI), Pb(+2) and Hg(+2). The unenhanced electrokinetic treatment was not able to remove heavy metals from the soil due to the formation of precipitates in the alkaline environment in the soil section close to the cathode. Moreover, the interaction between metals and organic matter probably limited metal transportation under the effect of the electric field. Citric acid and ethylenediaminetetraacetic acid (EDTA) were used in the catholyte as complexing agents in order to enhance the extractability and removal of heavy metals from soil. These complexing agents formed negatively charged complexes that migrated towards the anode. The acid front electrogenerated at the anode favored the dissolution of heavy metals that were transported towards the cathode. The combined effect of the soil pH and the complexing agents resulted in the accumulation of heavy metals in the center of the soil specimen. PMID- 27127924 TI - Evaluation of Glaucoma Progression in Large-Scale Clinical Data: The Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG). AB - PURPOSE: To develop a large-scale real clinical database of glaucoma (Japanese Archive of Multicentral Databases in Glaucoma: JAMDIG) and to investigate the effect of treatment. METHODS: The study included a total of 1348 eyes of 805 primary open-angle glaucoma patients with 10 visual fields (VFs) measured with 24 2 or 30-2 Humphrey Field Analyzer (HFA) and intraocular pressure (IOP) records in 10 institutes in Japan. Those with 10 reliable VFs were further identified (638 eyes of 417 patients). Mean total deviation (mTD) of the 52 test points in the 24 2 HFA VF was calculated, and the relationship between mTD progression rate and seven variables (age, mTD of baseline VF, average IOP, standard deviation (SD) of IOP, previous argon/selective laser trabeculoplasties (ALT/SLT), previous trabeculectomy, and previous trabeculotomy) was analyzed. RESULTS: The mTD in the initial VF was -6.9 +/- 6.2 dB and the mTD progression rate was -0.26 +/- 0.46 dB/year. Mean IOP during the follow-up period was 13.5 +/- 2.2 mm Hg. Age and SD of IOP were related to mTD progression rate. However, in eyes with average IOP below 15 and also 13 mm Hg, only age and baseline VF mTD were related to mTD progression rate. CONCLUSIONS: Age and the degree of VF damage were related to future progression. Average IOP was not related to the progression rate; however, fluctuation of IOP was associated with faster progression, although this was not the case when average IOP was below 15 mm Hg. PMID- 27127925 TI - Analysis of Peripapillary Atrophy in Relation to Macular Geographic Atrophy in Age-Related Macular Degeneration. AB - PURPOSE: The purpose of this study was to investigate the presence, configuration, and progression of peripapillary atrophy (PPA) relative to macular geographic atrophy (GA) in AMD. METHODS: Confocal scanning laser ophthalmoscopy images of 413 eyes of 413 patients with GA secondary to AMD (median age, 77.0 years) were evaluated for the presence and configuration of PPA at baseline. In addition, the progression of PPA and the regression of the shortest linear dimension between PPA and GA ("buffer zone") were assessed in 164 eyes that had completed 12 months of follow-up. RESULTS: At baseline, PPA was present in 357 (86.4%) of 413 eyes, of which 330 eyes (79.9%) were classified as nonconfluent and 27 eyes (6.5%) as confluent PPA. At month 12, eight eyes had transformed from nonconfluent to confluent PPA. The median buffer zone at baseline was significantly smaller in these latter eyes than in eyes where the PPA remained nonconfluent (168.46 vs. 1451.64 MUm; P < 0.001). The mean regression rate of the buffer zone was 163.0 MUm/y (interquartile range, 77.2-281.3). CONCLUSIONS: Peripapillary atrophy is highly prevalent in eyes with GA due to AMD. Assessment of the buffer zone in eyes with nonconfluent PPA at baseline may be helpful to identify subjects at risk for the progression to confluent PPA. In future interventional clinical trials, it may be useful to exclude any eyes both with confluent PPA at baseline and at risk for development of confluent PPA over time to improve the accuracy of GA lesion size quantification and its enlargement over time. PMID- 27127926 TI - Semiautomatic Segmentation of Rim Area Focal Hyperautofluorescence Predicts Progression of Geographic Atrophy Due to Dry Age-Related Macular Degeneration. AB - PURPOSE: To develop image analysis software usable by nonexpert graders to segment geographic atrophy (GA) from dry AMD and to quantify rim area focal hyperautofluorescence (RAFH) surrounding GA on fundus autofluorescence (FAF) images. To compare the GA progression predictions based on RAFH with those of a validated qualitative classification system. METHODS: Retrospective analysis of serial FAF images from 49 eyes of 30 subjects with GA was performed using MATLAB based software (MathWorks, Natick, MA, USA). Correlation between RAFH and progression of GA was analyzed using Spearman correlation. Comparisons of lesion growth rate between RAFH tertiles used generalized estimating equations and Kruskal-Wallis testing. Interobserver variability in lesion size, growth rate and RAFH were compared between two expert and one nonexpert grader using Bland-Altman statistics. RESULTS: Rim area focal hyperautofluorescence was positively correlated with GA progression rate (rho = 0.49, P < 0.001). Subjects in the middle or highest RAFH tertile were at greater risk of progression (P = 0.005 and P = 0.001, respectively). Mean difference in RAFH was 0.012 between expert and 0.005 to 0.017 between expert and nonexperts. Mean difference in lesion size (mm2) was 0.11 between expert and -0.29 to 0.41 between expert and nonexperts. Mean difference in lesion growth rate (mm2/mo) was 0.0098 between expert and 0.027 to 0.037 between expert and nonexperts. Risk stratification based on RAFH tertile was 96% identical across all graders. CONCLUSIONS: Our semiautomated image analysis software facilitates stratification of progression risk based on RAFH and enabled a nonexpert grader with minimal training to obtain results comparable to expert graders. Predictions based on RAFH were similar to those of a validated qualitative classification system. PMID- 27127927 TI - Cataract-Related Visual Impairment Corrected by Cataract Surgery and 10-Year Mortality: The Liwan Eye Study. AB - PURPOSE: To assess 10-year mortality in people who had undergone cataract surgery with no residual visual impairment (VI) and those who had persistent VI due to cataract using a population-based cohort. METHODS: The Liwan Eye Study is a 10 year longitudinal study commenced in 2003. According to the World Health Organization, presenting VI was defined as visual acuity less than 20/63 in the better-seeing eye. History of cataract surgery was defined as cataract surgery performed on either eye. Information on the date of surgery was recorded. Dates of death occurring between baseline and April 30, 2014 were obtained from the National Death Index data. Information on socioeconomic factors was obtained from questionnaire interviews. Cox proportional hazards regression models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Fifty nine participants had undergone cataract surgery without residual VI and 67 participants had persistent cataract-related VI. The 10-year mortality rate for participants who had undergone cataract surgery without residual VI was statistically significant lower than that in participants who had VI due to cataract based on log-rank test (32.2% vs. 64.2%; P = 0.002). This finding remained significant in the unadjusted Cox proportional hazards model (HR, 0.43; 95% CI, 0.25-0.74; P = 0.002). After adjusting for age, sex, history of diabetes, and hypertension, body mass index (BMI), education level, and personal income, participants with cataract surgery and no residual VI did not have a higher chance of survival than participants with persistent VI due to cataract (HR, 0.56; 95% CI, 0.26-1.20; P = 0.136). CONCLUSIONS: Cataract-related VI corrected by cataract surgery was not associated with better survival after adjusting for a number of possible confounders. Given our sample size is relatively small and limited power, further studies with larger sample are needed. PMID- 27127928 TI - Increased Levels of Dickkopf 3 in the Aqueous Humor of Patients With Diabetic Macular Edema. AB - PURPOSE: To investigate associations between diabetic macular edema (DME) and levels of the Wnt modulator Dickkopf 3 (DKK-3) in the aqueous humor (AH) of patients with DME and to analyze the clinical implications of this association. METHODS: Forty-four eyes of 39 patients with DME and 27 eyes of 27 controls were studied. Aqueous humor DKK-3 levels were measured by ELISA before the first intravitreal injection of bevacizumab (IVB). Visual acuity assessments and spectral-domain optical coherence tomography (SD-OCT) were performed before and 3 months after the first IVB. DKK-3 expression in high glucose-treated human Muller cells was examined by Western blot and immunofluorescence. Concentration of secreted DKK-3 in conditioned medium from human Muller cell cultures were analyzed by ELISA. RESULTS: ELISA showed increased DKK-3 levels in the eyes of DME patients compared with control subjects (median 207.86 ng/mL, range, 66.75 499.64 vs. 94.94 ng/mL, 33.34-164.45 ng/mL; P < 0.001). Based on multivariate analyses, elevated DKK-3 levels were associated with increased inner nuclear layer (INL) volume on SD-OCT before IVB. Western blot and immunofluorescence analyses showed higher DKK-3 expression in high glucose-treated Muller cells than in control cells, with DKK-3 secretion also being increased. CONCLUSIONS: DKK-3 expression was elevated in the AH of DME patients and in high glucose-treated human Muller cells. The observation of increased DKK-3 expression levels in the AH of DME patients with prominent edema in the INL suggests that the area of INL thickening might correlate with the area of reactive responses by Muller cells in these patients. PMID- 27127929 TI - Objective Evaluation of Functionality of Filtering Bleb Based on Polarization Sensitive Optical Coherence Tomography. AB - PURPOSE: The fibrosis score is a new diagnostic score that we have developed to evaluate the function of bleb structures after glaucoma filtration surgery using polarization-sensitive optical coherence tomography (PS-OCT). This study aims to assess the efficacy of the fibrosis score in discriminating nonfunctional from the functional blebs. METHODS: A total of 20 patients who had undergone glaucoma filtration surgery were imaged at different time periods after surgery using PS OCT. Birefringence tomography of blebs was obtained from PS-OCT, and the fibrosis score was computed for each patient. The fibrosis score is defined as the area of occupation of high birefringence area in the conjunctiva. The blebs were classified as functional or nonfunctional according to the IOP and the application of medication. The power of the fibrosis score to discriminate nonfunctional blebs from functional blebs was evaluated. RESULTS: The difference in the mean fibrosis score between the functional and nonfunctional bleb group was statistically significant. The fibrosis score showed good ability to discriminate nonfunctional from functional blebs. The area under the receiver operating characteristic curve was 0.82. The best combination of the sensitivity and specificity was 67% and 100%, respectively, for classifying nonfunctional cases. CONCLUSIONS: The fibrosis score showed a high ability to discriminate nonfunctional from functional blebs. Polarization-sensitive OCT is a noninvasive technique that provides not only the fibrosis score but also standard structural tomography. It can be a comprehensive tool for longitudinal evaluation after filtration surgery for glaucoma. PMID- 27127930 TI - Progressive Loss of Retinal Ganglion Cells and Axons in Nonoptic Neuritis Eyes in Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study. AB - PURPOSE: To examine the rate of retinal ganglion cell (RGC) layer and retinal nerve fiber layer (RNFL) changes in nonoptic neuritis (NON) eyes of relapsing remitting multiple sclerosis (RRMS) patients, and to find a specific imaging parameter useful for identifying disease progression. METHODS: Forty-five consecutive RRMS patients and 20 age- and sex-matched healthy subjects were enrolled. All patients were followed up for 3 years with annual optical coherence tomography (OCT) scans, which included a peripapillary ring scan protocol for RNFL analysis and a macular radial star-like scan to obtain RGC/inner plexiform layer (IPL) thickness measures. Healthy controls were scanned twice, 3 years apart. RESULTS: Retinal ganglion cell/inner plexiform layer and temporal RNFL (tRNFL) demonstrated highly significant thinning (P < 0.01), but all nasal segments and global RNFL (gRNFL) were not significantly different from normal controls. While receiver operating characteristics (ROC) analysis showed no advantage of RGC/IPL over tRNFL in cross-sectional detection of thinning, cut-off point based of fifth percentile in healthy controls demonstrated higher rate of abnormality for RGC/IPL. There was a significant progressive loss of RGC/IPL and tRNFL during the follow-up period. The largest thickness reduction was observed in tRNFL. ROC analysis demonstrated that tRNFL provided better sensitivity/specificity for detecting change over time than RGC/IPL (area under the curve [AUC] 0.78 vs. 0.52), which was confirmed by higher detection rate when 95th percentile of progression in healthy controls was used as a cut-off. CONCLUSIONS: This study confirmed significant thinning of RGC/IPL and tRNFL in NON eyes of RRMS patients. Progressive losses were more apparent on tRNFL, while RGC/IPL showed less change over the follow-up period. PMID- 27127931 TI - Optical Coherence Tomography: A Potential Noninvasive Follow-up Tool in Multiple Sclerosis. PMID- 27127932 TI - UV-A Irradiation Activates Nrf2-Regulated Antioxidant Defense and Induces p53/Caspase3-Dependent Apoptosis in Corneal Endothelial Cells. AB - PURPOSE: To examine whether Nrf2-regulated antioxidant defense and p53 are activated in human corneal endothelial cells (CEnCs) by environmental levels of ultraviolet A (UV-A), a known stimulator of oxidative stress. METHODS: Immortalized human CEnCs (HCEnCi) were exposed to UV-A fluences of 2.5, 5, 10, or 25 J/cm2, then allowed to recover for 3 to 24 hours. Control HCEnCi did not receive UV-A. Reactive oxygen species (ROS) were measured using H2DCFDA. Cell cytotoxicity was evaluated by lactate dehydrogenase (LDH) release. Levels of Nrf2, HO-1, NQO-1, p53, and caspase3 were detected by immunnoblotting or real time PCR. Activated caspase3 was measured by immunoblotting and a fluorescence assay. RESULTS: Exposure of HCEnCi to 5, 10, and 25 J/cm2 UV-A increased ROS levels compared with controls. Nrf2, HO-1, and NQO-1 mRNA increased 1.7- to 3.2 fold at 3 and 6 hours after irradiation with 2.5 and 5 J/cm2 UV-A. At 6 hours post irradiation, UV-A (5 J/cm2) enhanced nuclear Nrf2 translocation. At 24 hours post treatment, UV-A (5, 10, and 25 J/cm2) produced a 1.8- to 2.8-fold increase in phospho-p53 and a 2.6- to 6.0-fold increase in activated caspase3 compared with controls, resulting in 20% to 42% cell death. CONCLUSIONS: Lower fluences of UV-A induce Nrf2-regulated antioxidant defense and higher fluences activate p53 and caspase3, indicating that even near-environmental levels of UV-A may affect normal CEnCs. This data suggest that UV-A may especially damage cells deficient in antioxidant defense, and thus may be involved in the etiology of Fuchs' endothelial corneal dystrophy (FECD). PMID- 27127933 TI - Characterization of Rat Meibomian Gland Ion and Fluid Transport. AB - PURPOSE: We establish novel primary rat meibomian gland (MG) cell culture systems and explore the ion transport activities of the rat MG. METHODS: Freshly excised rat MG tissues were characterized as follows: (1) mRNA expression of selected epithelial ion channels/transporters were measured by RT-PCR, (2) localization of epithelial sodium channel (ENaC) mRNAs was performed by in situ hybridization, and (3) protein expression and localization of betaENaC, the Na+/K+/Cl- cotransporter (NKCC), and the Na+/K+ ATPase were evaluated by immunofluorescence. Primary isolated rat MG cells were cocultured with 3T3 feeder cells and a Rho associated kinase (ROCK) inhibitor (Y-27632) for expansion. Passaged rat MG cells were cultured as planar sheets under air-liquid interface (ALI) conditions for gene expression and electrophysiologic studies. Passaged rat MG cells also were cultured in matrigel matrices to form spheroids, which were examined ultrastructurally by transmission electron microscopy (TEM) and functionally using swelling assays. RESULTS: Expression of multiple ion channel/transporter genes was detected in rat MG tissues. beta-ENaC mRNA and protein were localized more to MG peripheral acinar cells than central acinar cells or ductular epithelial cells. Electrophysiologic studies of rat MG cell planar cultures demonstrated functional sodium, chloride, and potassium channels, and cotransporters activities. Transmission electron microscopic analyses of rat MG spheroids revealed highly differentiated MG cells with abundant lysosomal lamellar bodies. Rat MG spheroids culture-based measurements demonstrated active volume regulation by ion channels. CONCLUSIONS: This study demonstrates the presence and function of ion channels and volume transport by rat MG. Two novel primary MG cell culture models that may be useful for MG research were established. PMID- 27127935 TI - Interactive high-quality visualization of color volume datasets using GPU-based refinements of segmentation data. AB - Data sets containing colored anatomical images of the human body, such as Visible Human or Visible Korean, show realistic internal organ structures. However, imperfect segmentations of these color images, which are typically generated manually or semi-automatically, produces poor-quality rendering results. We propose an interactive high-quality visualization method using GPU-based refinements to aid in the study of anatomical structures. In order to represent the boundaries of a region-of-interest (ROI) smoothly, we apply Gaussian filtering to the opacity values of the color volume. Morphological grayscale erosion operations are performed to reduce the region size, which is expanded by Gaussian filtering. Pseudo-coloring and color blending are also applied to the color volume in order to give more informative rendering results. We implement these operations on GPUs to speed up the refinements. As a result, our method delivered high-quality result images with smooth boundaries and provided considerably faster refinements. The speed of these refinements is sufficient to be used with interactive renderings as the ROI changes, especially compared to CPU-based methods. Moreover, the pseudo-coloring methods used presented anatomical structures clearly. PMID- 27127936 TI - Analysis of esophageal cancer cell lines exposed to X-ray based on radiosensitivity influence by tumor necrosis factor-alpha. AB - Assess the effects of tumor necrosis factor-alpha (TNF-alpha) in enhancing the radiosensitivity of esophageal cancer cell line in vitro. Three esophageal cancer cell line cells were exposed to X-ray with or without TNF-alpha treatment. MTT assay was used to evaluate the cell growth curve, and flow cytometry was performed to assess the cell apoptosis. The radiosensitizing effects of TNF-alpha were detected by cell colony formation assay. Western blotting was applied to observe the expression of NF-kappaB and caspase-3 protein in the exposed cells. Our results indicated that cellular inhibition rate increased over time, the strongest is combined group (P < 0.05). Western blotting showed that the decline expression of NF-kappaB protein was stated between only rhTNF-alpha and only X ray radiation group and the maximum degree was manifested in combined group. Caspase-3 protein content expression just works opposite. Three kinds of cells in the NF-kappaB protein were similar without rhTNF-alpha. Then SEG1 NF-kappaB protein content was reduced more than other two kinds. We concluded that the cells treated with TNF-alpha showed significantly suppressed cell proliferation, increasing the cell apoptosis, and caspase-3 protein expression after X-ray exposure. TNF-alpha can enhance the radiosensitivity of esophageal cancer to enhancing the effect of the former. PMID- 27127937 TI - Disparities in Retinoblastoma Presentation, Treatment, and Outcomes in Developed and Less-Developed Countries. AB - Retinoblastoma (RB) is the most common intraocular malignancy in children. In the past century, RB survival rates in developed countries (DCs) have improved from <5% to as high as 99%. In contrast, in less developed countries (LDCs) where the tumor burden is greatest, survival rates remain poor, with some countries reporting survival rates as low as 0-5%. In addition, there are disparities between DCs and LDCs in RB presentation, treatment modalities, and prognosis. These disparities are due to many underlying causes, including delays in diagnosis, access to medical care, patient and physician familiarity with the disease, availability and cost of treatment, and patient acceptance of enucleation. It is our belief that attempts to extend the improvements in prognosis achieved in DCs to various LDCs must be culturally sensitive and tailored to each country's specific challenges, and thus, a "one-size-fits-all" approach to improving patient outcomes in LDCs is unlikely to work well. We discuss several culturally sensitive approaches that have been successfully implemented in various LDCs, including those that make use of telemedicine and "twinning" with centers of excellence around the world. PMID- 27127939 TI - Insights from the Adsorption of Halide Ions on Graphene Materials. AB - Graphene has recently found applications in a wide range of fields. Density functional calculations show that halide ions can be adsorbed on pristine graphene, but only F(-) has an appreciable binding energy (-97.0 kJ mol(-1) ). Graphene materials, which are mainly electron donors, can be made strong electron acceptors by edge functionalization with F atoms. The binding strengths of halide ions are greatly enhanced by edge functionalization and show direct proportionality with the degree of functionalization Theta and increased charge transfer. In contrast, the adsorption strengths of metal ions on pristine graphene are clearly superior to those of halide ions but decline substantially with increasing degree of edge functionalization, and for Theta=100 %, the binding energies of -95.7, -44.8, and -25.9 kJ mol(-1) that are calculated for Li(+) , Na(+) , and K(+) , respectively, are obviously inferior to that of F(-) ( 186.3 kJ mol(-1) ). Thus, the electronic properties of graphene are fundamentally regulated by edge functionalization, and the preferential adsorption of certain metal ions or anions can be facilely realized by choice of an appropriate degree of functionalization. Adsorbed metal ions and anions behave differently on gradual addition of water molecules, and their binding strengths remain substantial when graphene materials are in the pristine and highly edge functionalized states, respectively. PMID- 27127938 TI - Dietary patterns and the risk of obesity, type 2 diabetes mellitus, cardiovascular diseases, asthma, and neurodegenerative diseases. AB - Diet and lifestyle play a significant role in the development chronic diseases; however the full complexity of this relationship is not yet understood. Dietary pattern investigation, which reflects the complexity of dietary intake, has emerged as an alternative and complementary approach for examining the association between diet and chronic diseases. Literature on this association has largely focused on individual nutrients, with conflicting outcomes, but individuals consume a combination of foods from many groups that form dietary patterns. Our objective was to systematically review the current findings on the effects of dietary patterns on chronic diseases. In this review, we describe and discuss the relationships between dietary patterns, such as the Mediterranean, the Dietary Approach to Stop Hypertension, Prudent, Seventh-day Adventists, and Western, with risk of obesity, type-2 diabetes mellitus, cardiovascular diseases, asthma, and neurodegenearive diseases. Evidence is increasing from both observational and clinical studies that plant-based dietary patterns, which are rich in fruits, vegetables, and whole grains, are valuable in preventing various chronic diseases, whereas a diet high in red and processed meat, refined grains and added sugar seems to increase said risk. Dietary pattern analysis might be especially valuable to the development and evaluation of food-based dietary guidelines. PMID- 27127934 TI - Antioxidant Treatment Limits Neuroinflammation in Experimental Glaucoma. AB - PURPOSE: Besides primary neurotoxicity, oxidative stress may compromise the glial immune regulation and shift the immune homeostasis toward neurodegenerative inflammation in glaucoma. We tested this hypothesis through the analysis of neuroinflammatory and neurodegenerative outcomes in mouse glaucoma using two experimental paradigms of decreased or increased oxidative stress. METHODS: The first experimental paradigm tested the effects of Tempol, a multifunctional antioxidant, given through osmotic mini-pumps for drug delivery by constant infusion. Following a 6-week treatment period after microbead/viscoelastic injection-induced ocular hypertension, retina and optic nerve samples were analyzed for markers of oxidative stress and cytokine profiles using specific bioassays. We also analyzed a redox-sensitive transcriptional regulator of neuroinflammation, namely NF-kappaB. The second paradigm included a similar analysis of the effects of overloaded oxidative stress on retina and optic nerve inflammation in mice knockout for a major antioxidant enzyme (SOD1(-/-)). RESULTS: Increased antioxidant capacity and decreased protein carbonyls and HNE adducts with Tempol treatment verified the drug delivery and biological function. Among a range of cytokines measured, proinflammatory cytokines, including IL-1, IL-2, IFN-gamma, and TNF-alpha, exhibited more than 2-fold decreased titers in Tempol-treated ocular hypertensive eyes. Antioxidant treatment also resulted in a prominent decrease in NF-kappaB activation in the ocular hypertensive retina and optic nerve. Although pharmacological treatment limiting the oxidative stress resulted in decreased neuroinflammation, ocular hypertension-induced neuroinflammatory responses were increased in SOD1(-/-) mice with defective antioxidant response. CONCLUSIONS: These findings support the oxidative stress related mechanisms of neuroinflammation and the potential of antioxidant treatment as an immunomodulation strategy for neuroprotection in glaucoma. PMID- 27127940 TI - Mild and Copper-Free Stereoselective Cyanation of gem-Difluoroalkenes by Using Benzyl Nitrile as a Cyanating Reagent. AB - A novel copper-free highly stereoselective cyanation of gem-difluoroalkenes by using benzyl nitrile as a cyanating reagent with the assistance of tBuOLi under air atmosphere at room temperature was developed. A variety of versatile fluorinated alkenyl nitriles were obtained. The proposed mechanism involved the C H bond oxidation, C-CN bond cleavage, and then nucleophilic vinylic substitution (SN V). PMID- 27127941 TI - Fish and chips: Curious to know what those little white spots might be on your next fish? PMID- 27127943 TI - Editorial: Climate Science: An Invitation for Physicists. PMID- 27127944 TI - No Fine Theorem for Macrorealism: Limitations of the Leggett-Garg Inequality. AB - Tests of local realism and macrorealism have historically been discussed in very similar terms: Leggett-Garg inequalities follow Bell inequalities as necessary conditions for classical behavior. Here, we compare the probability polytopes spanned by all measurable probability distributions for both scenarios and show that their structure differs strongly between spatially and temporally separated measurements. We arrive at the conclusion that, in contrast to tests of local realism where Bell inequalities form a necessary and sufficient set of conditions, no set of inequalities can ever be necessary and sufficient for a macrorealistic description. Fine's famous proof that Bell inequalities are necessary and sufficient for the existence of a local realistic model, therefore, cannot be transferred to macrorealism. A recently proposed condition, no signaling in time, fulfills this criterion, and we show why it is better suited for future experimental tests and theoretical studies of macrorealism. Our work thereby identifies a major difference between the mathematical structures of local realism and macrorealism. PMID- 27127945 TI - Hardware-Efficient and Fully Autonomous Quantum Error Correction in Superconducting Circuits. AB - Superconducting qubits are among the most promising platforms for building a quantum computer. However, individual qubit coherence times are not far past the scalability threshold for quantum error correction, meaning that millions of physical devices would be required to construct a useful quantum computer. Consequently, further increases in coherence time are very desirable. In this Letter, we blueprint a simple circuit consisting of two transmon qubits and two additional lossy qubits or resonators, which is passively protected against all single-qubit quantum error channels through a combination of continuous driving and engineered dissipation. Photon losses are rapidly corrected through two photon drive fields implemented with driven superconducting quantum interference device couplings, and dephasing from random potential fluctuations is heavily suppressed by the drive fields used to implement the multiqubit Hamiltonian. Comparing our theoretical model to published noise estimates from recent experiments on flux and transmon qubits, we find that logical state coherence could be improved by a factor of 40 or more compared to the individual qubit T_{1} and T_{2} using this technique. We thus demonstrate that there is substantial headroom for improving the coherence of modern superconducting qubits with a fairly modest increase in device complexity. PMID- 27127946 TI - Robustness of Coherence: An Operational and Observable Measure of Quantum Coherence. AB - Quantifying coherence is an essential endeavor for both quantum foundations and quantum technologies. Here, the robustness of coherence is defined and proven to be a full monotone in the context of the recently introduced resource theories of quantum coherence. The measure is shown to be observable, as it can be recast as the expectation value of a coherence witness operator for any quantum state. The robustness of coherence is evaluated analytically on relevant classes of states, and an efficient semidefinite program that computes it on general states is given. An operational interpretation is finally provided: the robustness of coherence quantifies the advantage enabled by a quantum state in a phase discrimination task. PMID- 27127947 TI - Qubit Noise Spectroscopy for Non-Gaussian Dephasing Environments. AB - We introduce open-loop quantum control protocols for characterizing the spectral properties of non-Gaussian noise, applicable to both classical and quantum dephasing environments. By engineering a multidimensional frequency comb via repetition of suitably designed pulse sequences, the desired high-order spectra may be related to observable properties of the qubit probe. We prove that access to a high time resolution is key to achieving spectral reconstruction over an extended bandwidth, overcoming the limitations of existing schemes. Non-Gaussian spectroscopy is demonstrated for a classical noise model describing quadratic dephasing at an optimal point, as well as a quantum spin-boson model out of equilibrium. In both cases, we obtain spectral reconstructions that accurately predict the qubit dynamics in the non-Gaussian regime. PMID- 27127948 TI - Distribution of Quantum Coherence in Multipartite Systems. AB - The distribution of coherence in multipartite systems is examined. We use a new coherence measure with entropic nature and metric properties, based on the quantum Jensen-Shannon divergence. The metric property allows for the coherence to be decomposed into various contributions, which arise from local and intrinsic coherences. We find that there are trade-off relations between the various contributions of coherence, as a function of parameters of the quantum state. In bipartite systems the coherence resides on individual sites or is distributed among the sites, which contribute in a complementary way. In more complex systems, the characteristics of the coherence can display more subtle changes with respect to the parameters of the quantum state. In the case of the XXZ Heisenberg model, the coherence changes from a monogamous to a polygamous nature. This allows us to define the shareability of coherence, leading to monogamy relations for coherence. PMID- 27127949 TI - Gatemon Benchmarking and Two-Qubit Operations. AB - Recent experiments have demonstrated superconducting transmon qubits with semiconductor nanowire Josephson junctions. These hybrid gatemon qubits utilize field effect tunability characteristic of semiconductors to allow complete qubit control using gate voltages, potentially a technological advantage over conventional flux-controlled transmons. Here, we present experiments with a two qubit gatemon circuit. We characterize qubit coherence and stability and use randomized benchmarking to demonstrate single-qubit gate errors below 0.7% for all gates, including voltage-controlled Z rotations. We show coherent capacitive coupling between two gatemons and coherent swap operations. Finally, we perform a two-qubit controlled-phase gate with an estimated fidelity of 91%, demonstrating the potential of gatemon qubits for building scalable quantum processors. PMID- 27127950 TI - Testing the Equivalence Principle and Lorentz Invariance with PeV Neutrinos from Blazar Flares. AB - It was recently proposed that a giant flare of the blazar PKS B1424-418 at redshift z=1.522 is in association with a PeV-energy neutrino event detected by IceCube. Based on this association we here suggest that the flight time difference between the PeV neutrino and gamma-ray photons from blazar flares can be used to constrain the violations of equivalence principle and the Lorentz invariance for neutrinos. From the calculated Shapiro delay due to clusters or superclusters in the nearby universe, we find that violation of the equivalence principle for neutrinos and photons is constrained to an accuracy of at least 10^{-5}, which is 2 orders of magnitude tighter than the constraint placed by MeV neutrinos from supernova 1987A. Lorentz invariance violation (LIV) arises in various quantum-gravity theories, which predicts an energy-dependent velocity of propagation in vacuum for particles. We find that the association of the PeV neutrino with the gamma-ray outburst set limits on the energy scale of possible LIV to >0.01E_{pl} for linear LIV models and >6*10^{-8}E_{pl} for quadratic order LIV models, where E_{pl} is the Planck energy scale. These are the most stringent constraints on neutrino LIV for subluminal neutrinos. PMID- 27127951 TI - Circular Polarizations of Gravitational Waves from Core-Collapse Supernovae: A Clear Indication of Rapid Rotation. AB - We propose to employ the circular polarization of gravitational waves emitted by core-collapse supernovae as an unequivocal indication of rapid rotation deep in their cores just prior to collapse. It has been demonstrated by three dimensional simulations that nonaxisymmetric accretion flows may develop spontaneously via hydrodynamical instabilities in the postbounce cores. It is not surprising, then, that the gravitational waves emitted by such fluid motions are circularly polarized. We show, in this Letter, that a network of the second generation detectors of gravitational waves worldwide may be able to detect such polarizations up to the opposite side of the Galaxy as long as the rotation period of the core is shorter than a few seconds prior to collapse. PMID- 27127952 TI - White Dwarf Critical Tests for Modified Gravity. AB - Scalar-tensor theories of gravity can lead to modifications of the gravitational force inside astrophysical objects. We exhibit that compact stars such as white dwarfs provide a unique setup to test beyond Horndeski theories of G^{3} type. We obtain stringent and independent constraints on the parameter Upsilon characterizing the deviations from Newtonian gravity using the mass-radius relation, the Chandrasekhar mass limit, and the maximal rotational frequency of white dwarfs. We find that white dwarfs impose stronger constraints on Upsilon than red and brown dwarfs. PMID- 27127953 TI - Interstellar ^{60}Fe on the Surface of the Moon. AB - A dying massive star ends in a supernova explosion ejecting a large fraction of its mass into the interstellar medium. If this happens nearby, part of the ejecta might end on Solar System bodies and, in fact, radioactive ^{60}Fe has been detected on the Pacific ocean floor in about 2 Ma old layers. Here, we report on the detection of this isotope also in lunar samples, originating presumably from the same event. The concentration of the cosmic ray produced isotope ^{53}Mn, measured in the same samples, proves the supernova origin of the ^{60}Fe. From the ^{60}Fe concentrations found we deduce a reliable value for the local interstellar fluence in the range of 1*10^{8} at/cm^{2}. Thus, we obtain constraints on the recent and nearby supernova(e). PMID- 27127955 TI - Quantum Gravitational Force Between Polarizable Objects. AB - Since general relativity is a consistent low energy effective field theory, it is possible to compute quantum corrections to classical forces. Here we compute a quantum correction to the gravitational potential between a pair of polarizable objects. We study two distant bodies and compute a quantum force from their induced quadrupole moments due to two-graviton exchange. The effect is in close analogy to the Casimir-Polder and London-van der Waals forces between a pair of atoms from their induced dipole moments due to two photon exchange. The new effect is computed from the shift in vacuum energy of metric fluctuations due to the polarizability of the objects. We compute the potential energy at arbitrary distances compared to the wavelengths in the system, including the far and near regimes. In the far distance, or retarded, regime, the potential energy takes on a particularly simple form: V(r)=-3987hcG^{2}alpha_{1S}alpha_{2S}/(4pir^{11}), where alpha_{1S}, alpha_{2S} are the static gravitational quadrupole polarizabilities of each object. We provide estimates of this effect. PMID- 27127957 TI - Footprints of New Strong Dynamics via Anomaly and the 750 GeV Diphoton. AB - The chiral anomaly provides smoking-gun evidence of a new confining gauge theory. Motivated by a reported event excess in a diphoton invariant mass distribution at the LHC, we discuss a scenario that a pseudo-Nambu-Goldstone (PNG) boson of a new QCD-like theory is produced by gluon fusion and decays into a pair of the standard model gauge bosons. Despite the strong dynamics, the production cross section and the decay widths are determined by an anomaly matching condition. The excess can be explained by the PNG boson with mass of around 750 GeV. The model also predicts exotic hadrons such as a color-octet scalar and baryons. Some of them are within the reach of the LHC experiment. PMID- 27127956 TI - Probing the Dark Sector with Dark Matter Bound States. AB - A model of the dark sector where O(few GeV) mass dark matter particles chi couple to a lighter dark force mediator V, m_{V}?m_{chi}, is motivated by the recently discovered mismatch between simulated and observed shapes of galactic halos. Such models, in general, provide a challenge for direct detection efforts and collider searches. We show that for a large range of coupling constants and masses, the production and decay of the bound states of chi, such as 0^{-+} and 1^{--} states, eta_{D} and Upsilon_{D}, is an important search channel. We show that e^{+}e^{-}->eta_{D}+V or Upsilon_{D}+gamma production at B factories for alpha_{D}>0.1 is sufficiently strong to result in multiple pairs of charged leptons and pions via eta_{D}->2V->2(l^{+}l^{-}) and Upsilon_{D}->3V->3(l^{+}l^{ }) (l=e,MU,pi). The absence of such final states in the existing searches performed at BABAR and Belle sets new constraints on the parameter space of the model. We also show that a search for multiple bremsstrahlung of dark force mediators, e^{+}e^{-}->chichi[over -]+nV, resulting in missing energy and multiple leptons, will further improve the sensitivity to self-interacting dark matter. PMID- 27127958 TI - Pseudoscalar Decaying Only via Loops as an Explanation for the 750 GeV Diphoton Excess. AB - We construct a weakly coupled renormalizable model to explain the 750 GeV diphoton excess. The 750 GeV resonance [denoted as X(750)] is interpreted as a pseudoscalar coming from a complex singlet. The model also naturally provides a dark matter candidate. One of the most attractive feature of the model is that decays of X(750) are all loop induced, so the diphoton rate is not diluted by unwanted tree level branching fractions. Relevant Yukawa interactions need not be tuned to the near-nonperturbative region to explain the rate. The model is highly predictive, including the pseudoscalar nature of X(750) and two nearly mass degenerate exotic quarks carrying electric charge 5/3 and 2/3, respectively. Rich phenomenology is expectedf with respect to collider searches, flavor physics, and dark matter detection, if X(750) can be pinned down by future LHC experiments. PMID- 27127959 TI - 750 GeV Diphoton Excess from the Goldstino Superpartner. AB - We interpret the diphoton excess recently reported by the ATLAS and CMS Collaborations as a new resonance arising from the sgoldstino scalar, which is the superpartner of the Goldstone mode of spontaneous supersymmetry breaking, the goldstino. The sgoldstino is produced at the LHC via gluon fusion and decays to photons, with interaction strengths proportional to the corresponding gaugino masses over the supersymmetry breaking scale. Fitting the excess, while evading bounds from searches in the dijet, Zgamma, ZZ, and WW final states, selects the supersymmetry breaking scale to be a few TeV and particular ranges for the gaugino masses. The two real scalars, corresponding to the CP-even and CP-odd parts of the complex sgoldstino, both have narrow widths, but their masses can be split of the order of 10-30 GeV by electroweak mixing corrections, which could account for the preference of a wider resonance width in the current low statistics data. In the parameter space under consideration, tree level F-term contributions to the Higgs mass arise, in addition to the standard D-term contribution proportional to the Z-boson mass, which can significantly enhance the tree level Higgs mass. PMID- 27127960 TI - 750 GeV Diphoton Excess May Not Imply a 750 GeV Resonance. AB - We discuss nonstandard interpretations of the 750 GeV diphoton excess recently reported by the ATLAS and CMS Collaborations which do not involve a new, relatively broad resonance with a mass near 750 GeV. Instead, we consider the sequential cascade decay of a much heavier, possibly quite narrow, resonance into two photons along with one or more additional particles. The resulting diphoton invariant mass signal is generically rather broad, as suggested by the data. We examine three specific event topologies-the "antler," the "sandwich," and the two step cascade decay-and show that they all can provide a good fit to the observed published data. In each case, we delineate the preferred mass parameter space selected by the best fit. In spite of the presence of extra particles in the final state, the measured diphoton p_{T} spectrum is moderate due to its anticorrelation with the diphoton invariant mass. We comment on the future prospects of discriminating with higher statistics between our scenarios, as well as from more conventional interpretations. PMID- 27127954 TI - Resolving the Extragalactic gamma-Ray Background above 50 GeV with the Fermi Large Area Telescope. AB - The Fermi Large Area Telescope (LAT) Collaboration has recently released a catalog of 360 sources detected above 50 GeV (2FHL). This catalog was obtained using 80 months of data re-processed with Pass 8, the newest event-level analysis, which significantly improves the acceptance and angular resolution of the instrument. Most of the 2FHL sources at high Galactic latitude are blazars. Using detailed Monte Carlo simulations, we measure, for the first time, the source count distribution, dN/dS, of extragalactic gamma-ray sources at E>50 GeV and find that it is compatible with a Euclidean distribution down to the lowest measured source flux in the 2FHL (~8*10^{-12} ph cm^{-2} s^{-1}). We employ a one-point photon fluctuation analysis to constrain the behavior of dN/dS below the source detection threshold. Overall, the source count distribution is constrained over three decades in flux and found compatible with a broken power law with a break flux, S_{b}, in the range [8*10^{-12},1.5*10^{-11}] ph cm^{-2} s^{-1} and power-law indices below and above the break of alpha_{2}?[1.60,1.75] and alpha_{1}=2.49+/-0.12, respectively. Integration of dN/dS shows that point sources account for at least 86_{-14}^{+16}% of the total extragalactic gamma-ray background. The simple form of the derived source count distribution is consistent with a single population (i.e., blazars) dominating the source counts to the minimum flux explored by this analysis. We estimate the density of sources detectable in blind surveys that will be performed in the coming years by the Cherenkov Telescope Array. PMID- 27127962 TI - Z-Boson Production in Association with a Jet at Next-To-Next-To-Leading Order in Perturbative QCD. AB - We present the first complete calculation of Z-boson production in association with a jet in hadronic collisions through next-to-next-to-leading order in perturbative QCD. Our computation uses the recently proposed N-jettiness subtraction scheme to regulate the infrared divergences that appear in the real emission contributions. We present phenomenological results for 13 TeV proton proton collisions with fully realistic fiducial cuts on the final-state particles. The remaining theoretical uncertainties after the inclusion of our calculations are at the percent level, making the Z+jet channel ready for precision studies at the LHC run II. PMID- 27127963 TI - Static Response of Neutron Matter. AB - We generalize the problem of strongly interacting neutron matter by adding a periodic external modulation. This allows us to study from first principles a neutron system that is extended and inhomogeneous, with connections to the physics of both neutron-star crusts and neutron-rich nuclei. We carry out fully nonperturbative microscopic quantum Monte Carlo calculations of the energy of neutron matter at different densities, as well as different strengths and periodicities of the external potential. In order to remove systematic errors, we examine finite-size effects and the impact of the wave function ansatz. We also make contact with energy-density functional theories of nuclei and disentangle isovector gradient contributions from bulk properties. Finally, we calculate the static density-density linear response function of neutron matter and compare it with the response of other physical systems. PMID- 27127964 TI - Pairing Nambu-Goldstone Modes within Nuclear Density Functional Theory. AB - We show that the Nambu-Goldstone formalism of the broken gauge symmetry in the presence of the T=1 pairing condensate offers a quantitative description of the binding-energy differences of open-shell superfluid nuclei. We conclude that the pairing-rotational moments of inertia are excellent pairing indicators, which are free from ambiguities attributed to odd-mass systems. We offer a new, unified interpretation of the binding-energy differences traditionally viewed in the shell model picture as signatures of the valence nucleon properties. We present the first systematic analysis of the off-diagonal pairing-rotational moments of inertia and demonstrate the mixing of the neutron and proton pairing-rotational modes in the ground states of even-even nuclei. Finally, we discuss the importance of mass measurements of neutron-rich nuclei for constraining the pairing energy density functional. PMID- 27127965 TI - Stark Interference of Electric and Magnetic Dipole Transitions in the A-X Band of OH. AB - An experimental method is demonstrated that allows determination of the ratio between the electric (E1) and magnetic (M1) transition dipole moments in the A-X band of OH, including their relative sign. Although the transition strengths differ by more than 3 orders of magnitude, the measured M1-to-E1 ratio agrees with the ratio of the ab initio calculated values to within 3%. The relative sign is found to be negative, also in agreement with theory. PMID- 27127966 TI - Supercooling of Atoms in an Optical Resonator. AB - We investigate laser cooling of an ensemble of atoms in an optical cavity. We demonstrate that when atomic dipoles are synchronized in the regime of steady state superradiance, the motion of the atoms may be subject to a giant frictional force leading to potentially very low temperatures. The ultimate temperature limits are determined by a modified atomic linewidth, which can be orders of magnitude smaller than the cavity linewidth. The cooling rate is enhanced by the superradiant emission into the cavity mode allowing reasonable cooling rates even for dipolar transitions with ultranarrow linewidth. PMID- 27127967 TI - Recurrent Delocalization and Quasiequilibration of Photons in Coupled Systems in Circuit Quantum Electrodynamics. AB - We explore the photon population dynamics in two coupled circuit QED systems. For a sufficiently weak intercavity photon hopping, as the photon-cavity coupling increases, the dynamics undergoes double transitions first from a delocalized to a localized phase and then from the localized to another delocalized phase. The latter delocalized phase is distinguished from the former one; instead of oscillating between the two cavities, the photons rapidly quasiequilibrate over the two cavities. These intriguing features are attributed to an interplay between two qualitatively distinctive nonlinear behaviors of the circuit QED systems in the utrastrong coupling regime, whose distinction has been widely overlooked. PMID- 27127968 TI - Quasimomentum-Space Image for Ultrafast Melting of Silicon. AB - By exciting electron-hole pairs that survive for picoseconds strong femtosecond lasers may transiently influence the bonding properties of semiconductors, causing structure changes, in particular, ultrafast melting. In order to determine the energy flow during this process in silicon we performed ab initio molecular dynamics simulations and an analysis in quasimomentum space. We found that energy flows very differently as a function of increasing excitation density, namely, mainly through long wavelength, L-point, or X-point lattice vibrations, respectively. PMID- 27127969 TI - Intrinsic Negative Mass from Nonlinearity. AB - We propose and provide experimental evidence of a mechanism able to support negative intrinsic effective mass. The idea is to use a shape-sensitive nonlinearity to change the sign of the mass in the leading linear propagation equation. Intrinsic negative-mass dynamics is reported for light beams in a ferroelectric crystal substrate, where the diffusive photorefractive nonlinearity leads to a negative-mass Schrodinger equation. The signature of inverted dynamics is the observation of beams repelled from strongly guiding integrated waveguides irrespective of wavelength and intensity and suggests shape-sensitive nonlinearity as a basic mechanism leading to intrinsic negative mass. PMID- 27127970 TI - Scaling Behavior for Ionic Transport and its Fluctuations in Individual Carbon Nanotubes. AB - In this Letter, we perform an experimental study of ionic transport and current fluctuations inside individual carbon nanotubes (CNTs). The conductance exhibits a power law behavior at low salinity, with an exponent close to 1/3 versus the salt concentration in this regime. This behavior is rationalized in terms of a salinity dependent surface charge, which is accounted for on the basis of a model for hydroxide adsorption at the (hydrophobic) carbon surface. This is in contrast to boron nitride nanotubes which exhibit a constant surface conductance. Further, we measure the low frequency noise of the ionic current in CNTs and show that the amplitude of the noise scales with the surface charge, with data collapsing on a master curve for the various studied CNTs at a given pH. PMID- 27127971 TI - Rayleigh-Taylor Instability in Elastoplastic Solids: A Local Catastrophic Process. AB - We show that the Rayleigh-Taylor instability in elastoplastic solids takes the form of local perturbations penetrating the material independently of the interface size, in contrast with the theory for simple elastic materials. Then, even just beyond the stable domain, the instability abruptly develops as bursts rapidly moving through the other medium. We show that this is due to the resistance to penetration of a finger which is minimal for a specific finger size and drops to a much lower value beyond a small depth (a few millimeters). PMID- 27127972 TI - Generation of Superponderomotive Electrons in Multipicosecond Interactions of Kilojoule Laser Beams with Solid-Density Plasmas. AB - The interaction of a multipicosecond, kilojoule laser pulse with a surface of a solid target has been shown to produce electrons with energies far beyond the free-electron ponderomotive limit m_{e}c^{2}a_{0}^{2}/2. Particle-in-cell simulations indicate that an increase in the pulse duration from 1 to 10 ps leads to the formation of a low-density shelf (about 10% of the critical density). The shelf extends over 100 MUm toward the vacuum side, with a nonstationary potential barrier forming in that area. Electrons reflected from the barrier gain superponderomotive energy from the potential. Some electrons experience an even greater energy gain due to ponderomotive acceleration when their "dephasing rate" R=gamma-p_{x}/m_{e}c drops well below unity, thus increasing acceleration by a factor of 1/R. Both 1D and 2D simulations indicate that these mechanisms are responsible for the generation of extensive thermal distributions with T_{e}>10 MeV and a high-energy cutoff of hundreds of MeV. PMID- 27127973 TI - Two-Plasmon Decay Mitigation in Direct-Drive Inertial-Confinement-Fusion Experiments Using Multilayer Targets. AB - Multilayer direct-drive inertial-confinement-fusion targets are shown to significantly reduce two-plasmon decay (TPD) driven hot-electron production while maintaining high hydrodynamic efficiency. Implosion experiments on the OMEGA laser used targets with silicon layered between an inner beryllium and outer silicon-doped plastic ablator. A factor-of-5 reduction in hot-electron generation (>50 keV) was observed in the multilayer targets relative to pure CH targets. Three-dimensional simulations of the TPD-driven hot-electron production using a laser-plasma interaction code (lpse) that includes nonlinear and kinetic effects show good agreement with the measurements. The simulations suggest that the reduction in hot-electron production observed in the multilayer targets is primarily caused by increased electron-ion collisional damping. PMID- 27127961 TI - First Measurement of Electron Neutrino Appearance in NOvA. AB - We report results from the first search for nu_{MU}->nu_{e} transitions by the NOvA experiment. In an exposure equivalent to 2.74*10^{20} protons on target in the upgraded NuMI beam at Fermilab, we observe 6 events in the Far Detector, compared to a background expectation of 0.99+/-0.11(syst) events based on the Near Detector measurement. A secondary analysis observes 11 events with a background of 1.07+/-0.14(syst). The 3.3sigma excess of events observed in the primary analysis disfavors 0.1pi